PMID- 26925752 TI - Bioconcentration of perfluoroalkyl substances by Chironomus plumosus larvae in water with different types of dissolved organic matters. AB - The effects of four types of dissolved organic matters (DOM) on the bioconcentration of perfluoroalkyl substances (PFASs) in Chironomus plumosus larvae have been studied. The PFASs included perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), perfluoroundecanoic acid (PFUnA), and perfluorododecanoic acid (PFDoA). The DOM included humic acid (HA), fulvic acid (FA), tannic acid (TA), and a protein, peptone (PEP), and their concentrations ranged from 0 to 50 mg L( 1). The results showed that, upon bioconcentration equilibrium, the body burdens of longer perfluoroalkyl chain PFASs (PFOS, PFDA, PFUnA and PFDoA) decreased with PEP and HA concentrations while increased with FA and TA concentrations. When FA and TA concentrations increased from 0 to 50 mg L(-1), body burdens of these PFASs increased by 7.5%-148.8% and 5.7%-37.1%, respectively. However, the DOM had no significant impact on the body burdens of shorter perfluoroalkyl chain PFASs (PFOA and PFNA). All of the four types of DOM lowered not only the uptake rate constants (ku) of PFASs due to the decrease of freely dissolved PFAS concentrations, but also the elimination rate constants (ke) due to the inhibition effect of DOM on the PFAS elimination from the larvae. The reduction in the two constants varied with both DOM and PFAS types. In the presence of PEP and HA with larger molecular weights, the ku values decreased more than ke, leading to the decreased body burdens of longer perfluoroalkyl chain PFASs. As for FA and TA with smaller molecular weights, the ke values decreased more than ku, resulting in increased body burdens of longer perfluoroalkyl chain PFASs. This study suggests that the effects of DOM on PFAS bioconcentration depend not only on the concentration but also on the molecule weight of DOM, which should be considered in the bioavailability assessment of PFASs. PMID- 26925753 TI - Environmental exposure to pharmaceuticals: A new technique for trace analysis of carbamazepine and its metabolites in human urine. AB - Pharmaceutically active compounds are taken up and accumulate in crops irrigated with treated wastewater. This raises the concern of chronic human exposure to pharmaceuticals via food consumption. Thus, there is a need to develop a reliable technique to detect and quantify pharmaceuticals at environmentally relevant concentrations in human biological matrices, particularly urine. In this study, we focus on carbamazepine, an antiepileptic drug and recalcitrant compound that is taken up by crops-making it an excellent model compound for this study. This paper presents a new analytical technique enabling quantification of trace concentrations of carbamazepine and its metabolites in the urine of individuals who have been environmentally exposed. Sample preparation included extraction with acetonitrile followed by clean-up through mixed-mode ion-exchange cartridges and analysis using LC/MS/MS. This technique, which was validated for a wide range of concentrations (5-2000 ng L(-1)), exhibits low limits of quantification (3.0 7.2 ng L(-1)), acceptable recovery levels (70-120%), and low relative standard deviation (<20%). Unlike currently available methods for the analysis of water or treated wastewater that require large volumes (up to 1 L), the new method uses only 10 mL of urine. Moreover, relative to available methods for carbamazepine detection in the urine of individuals who are chronically treated with this drug, the limit of quantification values with our method are six orders of magnitude lower. The newly developed method has been successfully applied for the quantification of carbamazepine and its metabolites in the urine of healthy people exposed to this pharmaceutical through their diet. Our analytical protocol can provide the scientific community and stakeholders with real data for risk assessments and the design of policies ensuring safe use of wastewater for crop irrigation. PMID- 26925754 TI - Distinct transcriptomic responses of Caenorhabditis elegans to pristine and sulfidized silver nanoparticles. AB - Manufactured nanoparticles (MNP) rapidly undergo aging processes once released from products. Silver sulfide (Ag2S) is the major transformation product formed during the wastewater treatment process for Ag-MNP. We examined toxicogenomic responses of pristine Ag-MNP, sulfidized Ag-MNP (sAg-MNP), and AgNO3 to a model soil organism, Caenorhabditis elegans. Transcriptomic profiling of nematodes which were exposed at the EC30 for reproduction for AgNO3, Ag-MNP, and sAg-MNP resulted in 571 differentially expressed genes. We independently verified expression of 4 genes (numr-1, rol-8, col-158, and grl-20) using qRT-PCR. Only 11% of differentially expressed genes were common among the three treatments. Gene ontology enrichment analysis also revealed that Ag-MNP and sAg-MNP had distinct toxicity mechanisms and did not share any of the biological processes. The processes most affected by Ag-MNP relate to metabolism, while those processes most affected by sAg-MNP relate to molting and the cuticle, and the most impacted processes for AgNO3 exposed nematodes was stress related. Additionally, as observed from qRT-PCR and mutant experiments, the responses to sAg-MNP were distinct from AgNO3 while some of the effects of pristine MNP were similar to AgNO3, suggesting that effects from Ag-MNP is partially due to dissolved silver ions. PMID- 26925755 TI - Biospectroscopy reveals the effect of varying water quality on tadpole tissues of the common frog (Rana temporaria). AB - Amphibians are undergoing large population declines in many regions around the world. As environmental pollution from both agricultural and urban sources has been implicated in such declines, there is a need for a biomonitoring approach to study potential impacts on this vulnerable class of organism. This study assessed the use of infrared (IR) spectroscopy as a tool to detect changes in several tissues (liver, muscle, kidney, heart and skin) of late-stage common frog (Rana temporaria) tadpoles collected from ponds with differing water quality. Small differences in spectral signatures were revealed between a rural agricultural pond and an urban pond receiving wastewater and landfill run-off; these were limited to the liver and heart, although large differences in body size were apparent, surprisingly with tadpoles from the urban site larger than those from the rural site. Large differences in liver spectra were found between tadpoles from the pesticide and nutrient impacted pond compared to the rural agricultural pond, particularly in regions associated with lipids. Liver mass and hepatosomatic indices were found to be significantly increased in tadpoles from the site impacted by pesticides and trace organic chemicals, suggestive of exposure to environmental contamination. Significant alterations were also found in muscle tissue between tadpoles from these two ponds in regions associated with glycogen, potentially indicative of a stress response. This study highlights the use of IR spectroscopy, a low-cost, rapid and reagent-free technique in the biomonitoring of a class of organisms susceptible to environmental degradation. PMID- 26925756 TI - Distribution, sources and ecological risk assessment of PAHs in historically contaminated surface sediments at Bhavnagar coast, Gujarat, India. AB - The concentration, distribution and ecological risk of polycyclic aromatic hydrocarbons (PAHs) have been investigated in surface sediments near Bhavnagar coast. The concentration of ?PAHs ranged from 5.02 to 981.18 MUg g(-1) dry weight, indicating heavy pollution compared to other historically polluted study sites. It was found to be introduced via mixed origins such as burning of gas, oil, coal, production of petrochemicals, cement, and rubber tires. Domestic fuel burning and motor vehicles are also culprits for air pollution. Industrial effluents and accidental oil spillage can also be considered. PAHs can be exposed through air, water, soil and food sources including ingestion, inhalation, and dermal content in both occupational and non-occupational levels by single or sometimes multiple exposures routes concomitantly. Furthermore, diagnostic ratios, statistical principal component analysis (PCA) and hierarchical cluster analysis (HCA) models have confirmed that the sources of PAHs were both - petrogenic and pyrogenic. For both the sites, assessment of ecological risk of the elevated levels of these pollutants has been exercised based on toxic equivalency factors (TEFs) and risk quotient (RQ) methods. The composite results indicated accurately that both the sites, bears potentially acute and chronic health hazards such as decreased immune functionality, genotoxicity, malignancy and developmental malfunctions in humans. The sites studied here and the workers have been exposed to hazardous pollutants for a longer period of time. Evidences indicate that mixtures of PAHs are carcinogenic to humans, based on occupational studies on workers, exposed to these pollutants. Hence, the present study and statistical approaches applied herein clearly indicate the historic mix routes of PAHs that resulted in magnified concentrations leading to high ecosystem risk. Thus, the scientific communities are urged to develop strategies to minimize the concentrations of PAHs from the historically impacted coastlines, thereby concerning for the future investigations and restoration of these sites. PMID- 26925757 TI - Is particulate air pollution at the front door a good proxy of residential exposure? AB - The most advanced epidemiological studies on health effects of air pollution assign exposure to individuals based on residential outdoor concentrations of air pollutants measured or estimated at the front-door. In order to assess to what extent this approach could cause misclassification, indoor measurements were carried out in unoccupied rooms at the front and back of a building which fronted onto a major urban road. Simultaneous measurements were also carried out at adjacent outdoor locations to the front and rear of the building. Two 15-day monitoring campaigns were conducted in the period June-December 2013 in a building located in the urban area of Bologna, Italy. Particulate matter metrics including PM2.5 mass and chemical composition, particle number concentration and size distribution were measured. Both outdoor and indoor concentrations at the front of the building substantially exceeded those at the rear. The highest front/back ratio was found for ultrafine particles with outdoor concentration at the front door 3.4 times higher than at the rear. A weak influence on front/back ratios was found for wind direction. Particle size distribution showed a substantial loss of particles within the sub-50 nm size range between the front and rear of the building and a further loss of this size range in the indoor data. The chemical speciation data showed relevant reductions for most constituents between the front and the rear, especially for traffic related elements such as Elemental Carbon, Iron, Manganese and Tin. The main conclusion of the study is that gradients in concentrations between the front and rear, both outside and inside the building, are relevant and comparable to those measured between buildings located in high and low traffic areas. These findings show high potential for misclassification in the epidemiological studies that assign exposure based on particle concentrations estimated or measured at subjects' home addresses. PMID- 26925758 TI - Catalytic Asymmetric Total Synthesis of Hedyosumins A, B, and C. AB - The first and asymmetric total synthesis of hedyosumins A, B, and C was accomplished in 13-14 steps from simple starting materials. The essential tools that allow us to access the tetracyclic skeleton include an organocatalytic [4 + 3] cycloaddition reaction, an intramolecular aldol condensation, and an intramolecular carboxymercuration/demercuration enabled lactonization. A CBS catalyzed asymmetric reduction was employed to boost the ee of the synthetic natural products to an excellent level. This synthesis established the absolute configurations of hedyosumins A, B, and C. PMID- 26925759 TI - A novel method for high-throughput detection and quantification of neutrophil extracellular traps reveals ROS-independent NET release with immune complexes. AB - A newly-described first-line immune defence mechanism of neutrophils is the release of neutrophil extracellular traps (NETs). Immune complexes (ICxs) induce low level NET release. As such, the in vitro quantification of NETs is challenging with current methodologies. In order to investigate the role of NET release in ICx-mediated autoimmune diseases, we developed a highly sensitive and automated method for quantification of NETs. After labelling human neutrophils with PKH26 and extracellular DNA with Sytox green, cells are fixed and automatically imaged with 3-dimensional confocal laser scanning microscopy (3D CLSM). NET release is then quantified with digital image analysis whereby the NET amount (Sytox green area) is corrected for the number of imaged neutrophils (PKH26 area). A high sensitivity of the assay is achieved by a) significantly augmenting the area of the well imaged (11%) as compared to conventional assays (0.5%) and b) using a 3D imaging technique for optimal capture of NETs, which are topologically superimposed on neutrophils. In this assay, we confirmed low levels of NET release upon human ICx stimulation which were positive for citrullinated histones and neutrophil elastase. In contrast to PMA-induced NET release, ICx induced NET release was unchanged when co-incubated with diphenyleneiodonium (DPI). We were able to quantify NET release upon stimulation with serum from RA and SLE patients, which was not observed with normal human serum. To our knowledge, this is the first semi-automated assay capable of sensitive detection and quantification of NET release at a low threshold by using 3D CLSM. The assay is applicable in a high-throughput manner and allows the in vitro analysis of NET release in ICx-mediated autoimmune diseases. PMID- 26925760 TI - A response to a response to Meakin and Jamieson DNA transfer: Review and implications for casework. PMID- 26925761 TI - Y Chromosome STR haplotypes in different ethnic groups of Vietnam. PMID- 26925762 TI - Plasmonics-Based Multifunctional Electrodes for Low-Power-Consumption Compact Color-Image Sensors. AB - High pixel density, efficient color splitting, a compact structure, superior quantum efficiency, and low power consumption are all important features for contemporary color-image sensors. In this study, we developed a surface plasmonics-based color-image sensor displaying a high photoelectric response, a microlens-free structure, and a zero-bias working voltage. Our compact sensor comprised only (i) a multifunctional electrode based on a single-layer structured aluminum (Al) film and (ii) an underlying silicon (Si) substrate. This approach significantly simplifies the device structure and fabrication processes; for example, the red, green, and blue color pixels can be prepared simultaneously in a single lithography step. Moreover, such Schottky-based plasmonic electrodes perform multiple functions, including color splitting, optical-to-electrical signal conversion, and photogenerated carrier collection for color-image detection. Our multifunctional, electrode-based device could also avoid the interference phenomenon that degrades the color-splitting spectra found in conventional color-image sensors. Furthermore, the device took advantage of the near-field surface plasmonic effect around the Al-Si junction to enhance the optical absorption of Si, resulting in a significant photoelectric current output even under low-light surroundings and zero bias voltage. These plasmonic Schottky based color-image devices could convert a photocurrent directly into a photovoltage and provided sufficient voltage output for color-image detection even under a light intensity of only several femtowatts per square micrometer. Unlike conventional color image devices, using voltage as the output signal decreases the area of the periphery read-out circuit because it does not require a current-to-voltage conversion capacitor or its related circuit. Therefore, this strategy has great potential for direct integration with complementary metal oxide-semiconductor (CMOS)-compatible circuit design, increasing the pixel density of imaging sensors developed using mature Si-based technology. PMID- 26925763 TI - Should motivational interviewing training be mandatory for medical students? PMID- 26925764 TI - Perinatal characteristics and mother's personality profile associated with increased likelihood of postpartum depression occurrence in a Romanian outpatient sample. AB - BACKGROUND: Postpartum depression represents an increasingly recognized psychiatric condition in new mothers, and even more so in recent years as its detection has improved. AIMS: This study aimed to reveal those maternal and perinatal parameters that are significantly associated with increased likelihood of postpartum depression in delivering mothers from our region. METHODS: A cross sectional survey was conducted in 163 women between 6 and 8 weeks after delivery. Postnatal depression was assessed by the Edinburgh Postnatal Depression Scale (EPDS) using a cut-off of >12. RESULTS: Postnatal depression was detected in 39 (23.93%) new mothers. The preterm delivery [odds ratio (OR) 7.233; 95% confidence interval (CI) 1.631-32.078; p = 0.009], presence of complications during pregnancy (OR 4.579; 95% CI 1.314-15.953; p = 0.017) and being primiparous (OR 3.388; 95% CI 1.430-8.025; p = 0.006) have been associated with an increased likelihood of subsequent postpartum depression. Anxiety traits of personality were the most represented in depressive mothers. CONCLUSIONS: Postpartum depression is a frequent psychiatric condition in new mothers from our region. These results outline the critical role of mother's profile of personality which in a particular context of perinatal events could result in an increased likelihood of postpartum depression requiring a multidisciplinary approach. PMID- 26925765 TI - Biocompatible Double-Membrane Hydrogels from Cationic Cellulose Nanocrystals and Anionic Alginate as Complexing Drugs Codelivery. AB - A biocompatible hydrogel with a double-membrane structure is developed from cationic cellulose nanocrystals (CNC) and anionic alginate. The architecture of the double-membrane hydrogel involves an external membrane composed of neat alginate, and an internal composite hydrogel consolidates by electrostatic interactions between cationic CNC and anionic alginate. The thickness of the outer layer can be regulated by the adsorption duration of neat alginate, and the shape of the inner layer can directly determine the morphology and dimensions of the double-membrane hydrogel (microsphere, capsule, and filmlike shapes). Two drugs are introduced into the different membranes of the hydrogel, which will ensure the complexing drugs codelivery and the varied drugs release behaviors from two membranes (rapid drug release of the outer hydrogel, and prolonged drug release of the inner hydrogel). The double-membrane hydrogel containing the chemically modified cellulose nanocrystals (CCNC) in the inner membrane hydrogel can provide the sustained drug release ascribed to the "nano-obstruction effect" and "nanolocking effect" induced by the presence of CCNC components in the hydrogels. Derived from natural polysaccharides (cellulose and alginate), the novel double-membrane structure hydrogel material developed in this study is biocompatible and can realize the complexing drugs release with the first quick release of one drug and the successively slow release of another drug, which is expected to achieve the synergistic release effects or potentially provide the solution to drug resistance in biomedical application. PMID- 26925767 TI - The use of percutaneous joystick reduction and limited open reduction techniques in pediatric femoral shaft fractures: a study of 63 cases. AB - Our study aimed to compare the effectiveness and clinical outcomes of percutaneous joystick reduction and limited open reduction for flexible intramedullary nailing in the treatment of pediatric femoral shaft fractures. A total of 63 pediatric femoral shaft fractures were studied: 35 fractures were treated with percutaneous fixation using the K-wire pin as a joystick (group A), whereas 28 fractures were treated with limited open reduction (group B). Clinical and radiographic data at the final follow-up were compared between the surgical groups. Their duration of X-ray exposure, postoperative weight-bearing time, healing time, Harris score, and Hospital for Special Surgery score at the last follow-up did not differ statistically. However, the blood loss, operative time, duration of hospital stay, and postoperative pain at the incision site were considerably lower in group A than in group B. Three and two patients from group A and group B, respectively, reported skin irritation, whereas one patient from group B developed infection. Seven patients in group A and eight patients in group B showed some extremity overgrowth (<2 cm) and no redisplacement or delayed union of fracture, iatrogenic vessel and nerve injury, or osteofascial compartment syndrome was reported in any of the groups. Therefore, we conclude that percutaneous joystick reduction may effectively be used for flexible intramedullary nailing in the treatment of pediatric femoral shaft fractures. LEVEL OF EVIDENCE: Level III, retrospective comparative study. PMID- 26925766 TI - The somatotropic axis and aging: Benefits of endocrine defects. AB - Reduced somatotropic [growth hormone (GH) and insulin-like growth factor-1 (IGF 1)] action has been associated with delayed and slower aging, reduced risk of frailty, reduced age-related disease and functional decline, and with remarkably extended longevity. Recent studies have added to the evidence that these relationships discovered in laboratory populations of mice apply to other mammalian species. However, the relationship of the somatotropic signaling to human aging is less striking, complex and controversial. In mice, targeted deletion of GH receptors (GHR) in the liver, muscle or adipose tissue affected multiple metabolic parameters but failed to reproduce the effects of global GHR deletion on longevity. Continued search for mechanisms of extended longevity in animals with GH deficiency or resistance focused attention on different pathways of mechanistic target of rapamycin (mTOR), energy metabolism, regulation of local IGF-1 levels and resistance to high-fat diet (HFD). PMID- 26925768 TI - Radiological results of treatment using an extensive anterolateral approach for developmental dysplasia of the hip: minimum 5-year follow-up. AB - To investigate the radiological results using the extensive anterolateral approach in patients with developmental dysplasia of the hip. A total of 16 hips with developmental dysplasia of the hip treated by the extensive anterolateral approach were retrospectively reviewed after a minimum follow-up of 5 years. For evaluation, we considered the Severin classification and postoperative complications. At the final follow-up (mean 75.6 months), 14 hips (87.5%) were satisfactory in the Severin classification. Reoperation was performed in only one hip (6.3%) because of redislocation. No femoral head necrosis was observed. Our results were more favorable than those using conventional surgical methods. PMID- 26925769 TI - Protective effects of resveratrol against cisplatin-induced testicular and epididymal toxicity in rats. AB - This study investigated the probable protective effect of resveratrol against cisplatin-induced testicular and epididymal toxicity in rats. Body weights of the animals showed no significant changes after cisplatin administration. Conversely, the weights of testis, and accessory sex organs reduced significantly. The daily sperm production and epididymal sperm quantity and quality were decreased in cisplatin treated rats. The circulatory levels of testosterone and activity levels of testicular 3beta-hydroxysteroid dehydrogenase and 17beta-hydroxysteroid dehydrogenase were significantly decreased after cisplatin treatment. The activity levels of superoxide dismutase and catalase were decreased with an increase in the levels of lipid peroxidation and H2O2 generation in the testis and epididymis of cisplatin treated rats, suggesting the cisplatin-induced oxidative stress. The biochemical findings were supplemented by histological examination of testis. Reduced tubular size, decreased spermatogenesis and deterioration in architecture were observed after cisplatin treatment. Administration of resveratrol alone has no significant effect on testicular and epididymal metabolism. On the other hand, administration of resveratrol ameliorated cisplatin-induced alterations in testicular and epididymal oxidative damage, suppressed steroiodgenesis and spermatogenesis and restored testicular architecture. In conclusion, resveratrol possesses multimechanistic protective activity that can be attributed to its steroidogenic and antioxidant actions. PMID- 26925770 TI - MicroRNA biomarkers in clinical renal disease: from diabetic nephropathy renal transplantation and beyond. AB - Chronic Kidney Disease (CKD) is a common health problem affecting 1 in 12 Americans. It is associated with elevated risks of mortality, cardiovascular disease, and high costs for the treatment of renal failure with dialysis or transplantation. Advances in CKD care are impeded by the lack of biomarkers for early diagnosis, assessment of the extent of tissue injury, estimation of disease progression, and evaluation of response to therapy. Such biomarkers should improve the performance of existing measures of renal functional impairment (estimated glomerular filtration rate, eGFR) or kidney damage (proteinuria). MicroRNAs (miRNAs) a class of small, non-coding RNAs that act as post transcriptional repressors are gaining momentum as biomarkers in a number of disease areas. In this review, we examine the potential utility of miRNAs as promising biomarkers for renal disease. We explore the performance of miRNAs as biomarkers in two clinically important forms of CKD, diabetes and the nephropathy developing in kidney transplant recipients. Finally, we highlight the pitfalls and opportunities of miRNAs and provide a broad perspective for the future clinical development of miRNAs as biomarkers in CKD beyond the current gold standards of eGFR and albuminuria. PMID- 26925771 TI - Improved quality and more attractive work by applying EBM in disability evaluations: a qualitative survey. AB - BACKGROUND: The uptake of evidence in practice by physicians, even if they are trained in the systematic method of evidence-based medicine (EBM), remains difficult to improve. The aim of this study was to explore perceptions and experiences of physicians doing disability evaluations regarding motivators and preconditions for the implementation of EBM in daily practice. METHODS: This qualitative study was nested in a cluster randomized controlled trial (Trial registration NTR1767; 20-apr-2009) evaluating the effects of training in EBM. The 45 physicians that participated received a comprehensive 6-months training program in EBM of which the last course day included audio-recorded interviews in groups. During these interviews participating physicians discussed perceptions and experiences regarding EBM application in daily practice. In an iterative process we searched for common motivators or preconditions for the implementation of EBM. RESULTS: Three main concepts or themes emerged after analyzing the transcriptions of the discussions: 1) improved quality of physicians' actions, such as clients benefiting from the application of EBM; 2) improved work attractiveness of physicians; and 3) preconditions that have to be met in order to work in an evidence-based manner including professional competence, facilitating material conditions and organizational support and demands. CONCLUSIONS: Physicians trained in EBM are motivated to use EBM because they perceive it as a factor improving the quality of their work and making their work more attractive. In addition to personal investments and gains, organizational support should further facilitate the uptake of evidence in practice. PMID- 26925772 TI - Repetitive live sporozoites inoculation under arteether chemoprophylaxis confers protection against subsequent sporozoite challenge in rodent malaria model. AB - Inoculation with live sporozoites under prophylactic antimalarial cover (CPS immunization) represents an alternate approach to develop sterile, reproducible, and long-term protection against malaria. Here, we have employed arteether (ART), a semi synthetic derivative of artemisinin to explore its potential as a chemoprophylaxis candidate in CPS approach and systematically compared the protective potential of arteether with mefloquine, azithromycin and primaquine. Blood stage patency and quantitative RT-PCR of liver stage parasite load were monitored as primary key end-points for protection against malaria challenge infection. For this purpose, sequential exposures of Plasmodium yoelii sporozoites under prophylactic treatment with arteether (ART), mefloquine (MFQ), azithromycin (AZ) or primaquine (PQ) was conducted in experimental Swiss mice. Our results show that during the first three sequential exposures (1st, 2nd and 3rd challenge) no marked difference in the blood stage patency was observed between control and CPS-ART group. However, delayed patency was recorded following 4th sporozoite challenge and mice enjoyed sterile protection after 5th sporozoite challenge. A similar response was observed in CPS-MFQ group, whereas earlier protection was recorded in CPS-AZ group i.e., after 4th sprozoite challenge. However, mice under PQ cover did not show any protection/delay in patency even after five sequential sporozoite inoculations, possibly due to inhibition of liver stage development. Furthermore, protection acquired by CPS immunization is stage-specific as the protected mice remained susceptible to challenge with blood stage parasites. In short, the present study demonstrates that sporozoite administration under ART, MFQ or AZ treatment confers strong protection against subsequent sporozoite infection and the acquired response is dependent on the presence of liver stage parasites. PMID- 26925773 TI - Multicopy gene family evolution on primate Y chromosomes. AB - BACKGROUND: The primate Y chromosome is distinguished by a lack of inter chromosomal recombination along most of its length, extensive gene loss, and a prevalence of repetitive elements. A group of genes on the male-specific portion of the Y chromosome known as the "ampliconic genes" are present in multiple copies that are sometimes part of palindromes, and that undergo a form of intra chromosomal recombination called gene conversion, wherein the nucleotides of one copy are homogenized by those of another. With the aim of further understanding gene family evolution of these genes, we collected nucleotide sequence and gene copy number information for several species of papionin monkey. We then tested for evidence of gene conversion, and developed a novel statistical framework to evaluate alternative models of gene family evolution using our data combined with other information from a human, a chimpanzee, and a rhesus macaque. RESULTS: Our results (i) recovered evidence for several novel examples of gene conversion in papionin monkeys and indicate that (ii) ampliconic gene families evolve faster than autosomal gene families and than single-copy genes on the Y chromosome and that (iii) Y-linked singleton and autosomal gene families evolved faster in humans and chimps than they do in the other Old World Monkey lineages we studied. CONCLUSIONS: Rapid evolution of ampliconic genes cannot be attributed solely to residence on the Y chromosome, nor to variation between primate lineages in the rate of gene family evolution. Instead other factors, such as natural selection and gene conversion, appear to play a role in driving temporal and genomic evolutionary heterogeneity in primate gene families. PMID- 26925774 TI - Release of outer membrane vesicles in Pseudomonas putida as a response to stress caused by cationic surfactants. AB - Pseudomonas putida A (ATCC 12633), a degrader of cationic surfactants, releases outer membrane vesicles (OMVs) when grown with tetradecyltrimethylammonium bromide (TTAB) as the sole carbon, nitrogen and energy source. The OMVs exhibit a bilayer structure and were found to be composed of lipopolysaccharides, proteins and phospholipids (PLs) such as cardiolipin, phosphatidylcholine, phosphatidic acid and phosphatidylglycerol (PG). The OMVs showed a marked increase in the PG content, approximately 43 % higher than the amount registered in the parent cells from which the vesicles were derived. After growth of P. putida with TTAB, the amount of lipoprotein covalently cross-linked to the peptidoglycan showed a twofold decrease when compared with values found after growth without the surfactant [16 +/- 2 and 28 +/- 3 MUg (mg cell envelope protein)- 1, respectively]. This decrease in the amount of lipoprotein can be related to areas of loss of contact between the outer membrane and the peptidoglycan and, therefore, to OMV production. In addition, due to its amphiphilic nature, TTAB can contribute to OMV biogenesis, through a physical mechanism, by induction of the curvature of the membrane. Taking into account that OVMs were produced when the cells were grown under external stress, caused by the surfactant, and that TTAB was detected in the vesicles [48 nmol TTAB (nmol PL)- 1], we concluded that this system of TTAB elimination is a mechanism that P. putida A (ATCC 12633) would utilize for alleviating stress caused by cationic surfactants. PMID- 26925775 TI - Heme oxygenase-1 promotes neuron survival through down-regulation of neuronal NLRP1 expression after spinal cord injury. AB - BACKGROUND: Understanding the mechanisms underlying neuronal death in spinal cord injury (SCI) and developing novel therapeutic approaches for SCI-induced damage are critical for functional recovery. Here we investigated the role of heme oxygenase-1 (HO-1) in neuroprotection after SCI. METHODS: Adeno-associated virus expressing HO-1 was prepared and injected into rat spinal cords before SCI model was performed. HO-1 expression, inflammasome activation, and the presence of inflammatory cytokines were determined by quantitative polymerase chain reaction, immunohistological staining, immunoblot, and immunoprecipitation. Neuronal apoptosis was assessed by terminal deoxynucleotidyl transferase dUTP nick end labeling. The hindlimb locomotor function was evaluated for extent of neurologic damage. In an in vitro model, hydrogen peroxide was used to induce similar inflammasome activation in cultured primary spinal cord neurons, followed by evaluation of above parameters with or without transduction of HO-1-expressing adeno-associated virus. RESULTS: Endogenous HO-1 expression was found in spinal cord neurons after SCI in vivo, in association with the expression of Nod-like receptor protein 1 (NLRP1) and the formation of NLRP1 inflammasomes. Administration of HO-1-expressing adeno-associated virus effectively decreased expression of NLRP1, therefore alleviating NLRP1 inflammasome-induced neuronal death and improving functional recovery. In the in vitro model, exogenous HO-1 expression protected neurons from hydrogen peroxide-induced neuronal death by inhibiting NLRP1 expression. In addition, HO-1 inhibited expression of activating transcription factor 4 (ATF4), which is a transcription factor regulating NLRP1 expression. CONCLUSIONS: HO-1 protects spinal cord neurons after SCI through inhibiting NLRP1 inflammasome formation. PMID- 26925776 TI - Association of the Interleukin-27 Gene Expression and Hepatitis B Virus Infection in Liver Transplanted Patients. AB - OBJECTIVES: Hepatitis B viral infection is among the most common causes of cirrhosis and hepatocellular carcinoma and a frequent viral indication for liver transplant. Cytokine-mediated immunity plays a critical role in introducing and promoting hepatitis B virus outcomes and in graft microenvironment. Interleukin 27 is a heterodimeric cytokine and a member of interleukin-6/interleukin-12 family. Interleukin-27 shows a broad range of pro- and antiinflammatory properties and plays a determining role during immune responses in combating hepatitis B virus. Therefore, in this study, the possible association between expressions of interleukin-27 gene with hepatitis B virus infection was evaluated in liver transplant patients. MATERIALS AND METHODS: In a cross-sectional study from liver transplant patients with the risk of hepatitis B virus infection who admitted to Namazi Hospital affiliated to Shiraz University of Medical Sciences, 50 patients were selected and subgrouped to 25 hepatitis B virus-infected and 25 noninfected ones between years 2011 and 2013. The 25 healthy controls also were enrolled in this study. The presence of hepatitis B virus infection was assessed using polymerase chain reaction and enzyme-linked immunosorbent assay protocols in liver transplant patients. In addition, the interleukin-27 gene expression level was analyzed using an in-house-SYBER Green real time polymerase chain reaction method. The rate of interleukin-27 gene expression level was statistically analyzed in studied patient groups and controls using the Livak (2 ??CT) method. RESULTS: The expression level of interleukin-27 gene was increased 10.27- and 2.36-fold in hepatitis B virus-infected and uninfected liver transplanted patients compared with healthy controls. CONCLUSION: Hepatitis B virus infection can lead to overexpression of interleukin-27 gene in liver transplant patients compared with uninfected ones and controls. However, further studies are needed to characterize the effective antihepatitis B virus effects of interleukin-27 in liver transplant patients. PMID- 26925777 TI - Evaluation of Microflow Digital Imaging Particle Analysis for Sub-Visible Particles Formulated with an Opaque Vaccine Adjuvant. AB - Microflow digital imaging (MDI) has become a widely accepted method for assessing sub-visible particles in pharmaceutical formulations however, to date; no data have been presented on the utility of this methodology when formulations include opaque vaccine adjuvants. This study evaluates the ability of MDI to assess sub visible particles under these conditions. A Fluid Imaging Technologies Inc. FlowCAM(r) instrument was used to assess a number of sub-visible particle types in solution with increasing concentrations of AddaVaxTM, a nanoscale squalene based adjuvant. With the objective (10X) used and the limitations of the sensor resolution, the instrument was incapable of distinguishing between sub-visible particles and AddaVaxTM droplets at particle sizes less than 5 MUm. The instrument was capable of imaging all particle types assessed (polystyrene beads, borosilicate glass, cellulose, polyethylene protein aggregate mimics, and lysozyme protein aggregates) at sizes greater than 5 MUm in concentrations of AddaVaxTM up to 50% (vol:vol). Reduced edge gradients and a decrease in measured particle sizes were noted as adjuvant concentrations increased. No significant changes in particle counts were observed for polystyrene particle standards and lysozyme protein aggregates, however significant reductions in particle counts were observed for borosilicate (80% of original) and cellulose (92% of original) particles. This reduction in particle counts may be due to the opaque adjuvant masking translucent particles present in borosilicate and cellulose samples. Although the results suggest that the utility of MDI for assessing sub-visible particles in high concentrations of adjuvant may be highly dependent on particle morphology, we believe that further investigation of this methodology to assess sub-visible particles in challenging formulations is warranted. PMID- 26925778 TI - Sudden death associated with silent myocardial infarction in a 35-year-old man: a case report. AB - BACKGROUND: Silent myocardial infarction relates to the absence of symptoms usually associated with myocardial ischemia. It has been estimated that silent myocardial infarction can occur in 2-4 % of young adult asymptomatic men. A majority of patients without an initially apparent cause of sudden death have been found at autopsy to have had significant coronary heart disease, including old, undetected myocardial infarction. Cases of sudden death in young men with unrecognized silent myocardial ischemia seem to be underreported, however. CASE PRESENTATION: A 35-year-old Norwegian man without a previous medical history died suddenly without preceding symptoms of coronary ischemia. Apart from elevated lactate, his laboratory test results were within normal limits. An autopsy revealed advanced coronary artery thrombosis of the left anterior descending branch with an extensive, partly organized myocardial infarction. The results of toxicological examinations of peripheral blood were negative for usual narcotics and alcohol. CONCLUSIONS: Sudden, unexpected death due to myocardial infarction can occur even at a young age in patients without known coronary heart disease. PMID- 26925781 TI - Current trends in the treatment of malignant melanoma. AB - Currently, skin cancer is one of the most frequent type of cancers. Melanoma is much less common than basal cell and squamous cell skin cancers, but it is far more dangerous. Melanomas represent 3% of all skin cancers but 65% of skin cancer deaths. Detailed knowledge of melanoma at the molecular level allows the development of new treatment alternatives and to design effective new drugs. There are two approaches in therapy of melanoma in the present is based on immunotherapy and targeted therapy or their combination. Immunotherapy includes immune checkpoint blockades whereas targeted therapy is represented by protein kinase inhibitors. Detailed knowledge of protein structure and the understanding of their role in key signalling pathways in melanoma development lead to the designation of new protein kinase inhibitors in targeted therapy. In the future, it is necessary to conduct further clinical trials and collect more data about overall survival, response rates, appropriate timing and sequence of combination therapy to manage the complexity of melanoma treatment. PMID- 26925782 TI - Reversal of cisplatin resistance by inhibiting PI3K/Akt signal pathway in human lung cancer cells. AB - Cisplatin is regularly used in the treatment of lung cancer. However, its efficacy is limited because of drug resistance. In this study, we found that Akt expression and activity was increased in lung cancer cells with acquired cisplatin resistance (A549/DDP cells and H460/DDP cells) when compared to their parental cells. Inhibition of phosphatidylinositol 3-kinase (PI3K)/Akt kinase activity by its natural inhibitor, Wortmannin, could sensitize DDP-resistant cells to DDP and reverse DDP resistance. Combination treatment of Wortmannin with cisplatin is capable of increasing the mortality rate of both A549/DDP cells and H460/DDP cells. The present study also demonstrated that hyperactivation of PI3K/Aktpathway is closely associated with cisplatin resistance by regulating the Bax-mitochondria-mediated apoptosis pathway in human lung cancer. Inhibition of PI3K/Aktactivity in A549/DDP cells and H460/DDP cells could reverse cisplatin resistance by enhancing the effect of cisplatin on Bax oligomerization and release of Cytochrome C, allowing activation of the caspase-mediated apoptosis pathway. In conclusion, cisplatin resistance of lung cancer can be reversed via the inhibition of the PI3K/Akt signaling pathway. Therefore, both PI3K and Akt may be potential targets for overcoming cisplatin resistance in lung cancer. PMID- 26925779 TI - Hydrophobic Core Variations Provide a Structural Framework for Tyrosine Kinase Evolution and Functional Specialization. AB - Protein tyrosine kinases (PTKs) are a group of closely related enzymes that have evolutionarily diverged from serine/threonine kinases (STKs) to regulate pathways associated with multi-cellularity. Evolutionary divergence of PTKs from STKs has occurred through accumulation of mutations in the active site as well as in the commonly conserved hydrophobic core. While the functional significance of active site variations is well understood, relatively little is known about how hydrophobic core variations contribute to PTK evolutionary divergence. Here, using a combination of statistical sequence comparisons, molecular dynamics simulations, mutational analysis and in vitro thermostability and kinase assays, we investigate the structural and functional significance of key PTK-specific variations in the kinase core. We find that the nature of residues and interactions in the hydrophobic core of PTKs is strikingly different from other protein kinases, and PTK-specific variations in the core contribute to functional divergence by altering the stability and dynamics of the kinase domain. In particular, a functionally critical STK-conserved histidine that stabilizes the regulatory spine in STKs is selectively mutated to an alanine, serine or glutamate in PTKs, and this loss-of-function mutation is accommodated, in part, through compensatory PTK-specific interactions in the core. In particular, a PTK conserved phenylalanine in the I-helix appears to structurally and functionally compensate for the loss of STK-histidine by interacting with the regulatory spine, which has far-reaching effects on enzyme activity, inhibitor sensing, and stability. We propose that hydrophobic core variations provide a selective advantage during PTK evolution by increasing the conformational flexibility, and therefore the allosteric potential of the kinase domain. Our studies also suggest that Tyrosine Kinase Like kinases such as RAF are intermediates in PTK evolutionary divergence inasmuch as they share features of both PTKs and STKs in the core. Finally, our studies provide an evolutionary framework for identifying and characterizing disease and drug resistance mutations in the kinase core. PMID- 26925780 TI - Moderate Increase of Indoxyl Sulfate Promotes Monocyte Transition into Profibrotic Macrophages. AB - OBJECTIVE: The uremic toxin Indoxyl-3-sulphate (IS), a ligand of Aryl hydrocarbon Receptor (AhR), raises in blood during early renal dysfunction as a consequence of tubular damage, which may be present even when eGFR is normal or only moderately reduced, and promotes cardiovascular damage and monocyte-macrophage activation. We previously found that patients with abdominal aortic aneurysms (AAAs) have higher CD14+CD16+ monocyte frequency and prevalence of moderate chronic kidney disease (CKD) than age-matched control subjects. Here we aimed to evaluate the IS levels in plasma from AAA patients and to investigate in vitro the effects of IS concentrations corresponding to mild-to-moderate CKD on monocyte polarization and macrophage differentiation. METHODS: Free IS plasma levels, monocyte subsets and laboratory parameters were evaluated on blood from AAA patients and eGFR-matched controls. THP-1 monocytes, treated with IS 1, 10, 20 MUM were evaluated for CD163 expression, AhR signaling and then induced to differentiate into macrophages by PMA. Their phenotype was evaluated both at the stage of semi-differentiated and fully differentiated macrophages. AAA and control sera were similarly used to treat THP-1 monocytes and the resulting macrophage phenotype was analyzed. RESULTS: IS plasma concentration correlated positively with CD14+CD16+ monocytes and was increased in AAA patients. In THP-1 cells, IS promoted CD163 expression and transition to macrophages with hallmarks of classical (IL-6, CCL2, COX2) and alternative phenotype (IL-10, PPARgamma, TGF beta, TIMP-1), via AhR/Nrf2 activation. Analogously, AAA sera induced differentiation of macrophages with enhanced IL-6, MCP1, TGF-beta, PPARgamma and TIMP-1 expression. CONCLUSION: IS skews monocyte differentiation toward low inflammatory, profibrotic macrophages and may contribute to sustain chronic inflammation and maladaptive vascular remodeling. PMID- 26925783 TI - Expression of ARE-binding proteins AUF1 and HuR in follicular adenoma and carcinoma of thyroid gland. AB - Both adenylate-uridylate rich elements binding proteins AUF1 and HuR may participate in thyroid carcinoma progression. In this study we investigated the expression of both factors on a protein level with a special focus on follicular adenoma and follicular thyroid carcinoma. By employment of immunofluorescence and western blot on 68 thyroid tissues including 7 goiter, 16 follicular adenoma (4 adenomatous hyperplasia), 19 follicular thyroid carcinomas, 13 papillary thyroid carcinomas and 14 undifferentiated thyroid carcinomas we investigated protein expression of AUF1 and HuR. In addition to previous results we demonstrated that AUF1 and HuR are significantly up-regulated in carcinoma tissues as compared with follicular adenoma or goiter tissues. Furthermore, by evaluation of AUF1 or HuR expression, or combination of both proteins on total tissue lysates, we were able to demonstrate a significant difference between follicular adenoma and follicular thyroid carcinoma. Overexpression of AUF1 and HuR is a common finding observed in thyroid malignancy. Analysis of the tissues obtained by surgical resection as demonstrated in this study is comparable to a fine needle aspiration and in combination with AUF1/HuR immuno-analysis may support the conventional immunohistological investigations. The promising results of this study were performed on relatively small collective, but justify future development of a quick thyroid diagnostic test on larger cohort of the patients, especially for thyroid samples which are inadequate for histological examinations. PMID- 26925784 TI - Overexpression of BTG2 suppresses growth, migration, and invasion of human renal carcinoma cells in vitro. AB - The objective of the study was to investigate the impact of BTG2 on growth, migration and invasion of human clear cell renal cell carcinoma (ccRCC) cells. Endogenous expression of BTG2 was evaluated in the ccRCC cell lines (Caki-1, 786 O and Caki-2) and noncancerous human renal proximal tubular cell lines (HKC, HK-2 and RPTEC). BTG2 expression was decreased in the ccRCC cells compared with the noncancerous cells (P < 0.01). Then Caki-1 and 786-O cells described as suitable transfection hosts were used in transfection to carry out biological function studies. The three experimental groups were as follows: BTG2-ORF (transfected with BTG2-ORF plasmid), blank-Vector (transfected with pCMV6-Entry), and Cell alone group (no DNA transfected in). BTG2 expression in the BTG2-ORF groups was significantly higher than that in the controls (P < 0.01). Cell growth was remarkably reduced and the number of migrating or invading cells was reduced in the BTG2-ORF groups compared with the controls (P < 0.01). Furthermore, Matrix Metalloproteinase-9 (MMP-9), Cyclin D1 and Cyclin E expression were reduced in the BTG2-ORF groups compared with the controls. Here, we have provided data for attenuated BTG2 expression in the ccRCC cells. Overexpressed BTG2 could inhibit cell proliferation, migration and invasion of human ccRCC, and the suppressive effects might be due to down-regulation of MMP-9, Cyclin D1 and Cyclin E expression. PMID- 26925785 TI - Genome-wide methylation analysis of tubulocystic and papillary renal cell carcinomas. AB - Tubulocystic renal cell carcinoma (TRCC) represents a rare tumor with incidence lower than 1 % of all renal carcinomas. This study was undertaken to contribute to characterization of molecular signatures associated with TRCC and to compare them with the features of papillary renal cell carcinoma (PRCC) at the level of genome wide methylation analysis.We performed methylated DNA immunoprecipitation (MeDIP) coupled with microarray analysis (Roche NimbleGen). Using the CHARM package, we compared the levels of gene methylation between paired samples of tumors and control renal tissues of each examined individual. We found significant global demethylation in all tumor samples in comparison with adjacent kidney tissues of normal histological appearance but no significant differences in gene methylation between the both compared tumor entities. Therefore we focused on characterization of differentially methylated regions between both tumors and control tissues. We found 42 differentially methylated genes.Hypermethylated genes for protocadherins (PCDHG) and genes coding for products associated with functions of plasma membrane were evaluated as significantly overrepresented among hypermethylated genes detected in both types of renal cell carcinomas.In our pilot study, we provide the first evidence that identical features in the process of carcinogenesis leading to TRCC and/or to PRCC may be found at the gene methylation level. PMID- 26925786 TI - OCT4 is up-regulated by DNA hypomethylation of promoter in recurrent gliomas. AB - OCT4, a marker of embryonic stem cells, is also a key transcription factor that plays a regulatory role in the self-renewal, proliferation and differentiation of stem cells. Previous studies showed that DNA methylation is involved in the regulation of OCT4 expression during the development and differentiation of embryonic stem cells. However, DNA methylation in the promoter region of OCT4 has not yet been discussed in human recurrent glioma. In this study, we assessed the specimens from 24 cases of recurrent glioma for OCT4 expression and methylation status, and commenced analyzing the correlation between the two by treating glioma cells with a demethylating agent in vitro. The results demonstrated that for the same cases, the expression of OCT4 in specimens of recurrent glioma was significant higher than that in primary glioma (P<0.05). DNA methylation levels in recurrent glioma decreased obviously compared with that in primary glioma (t=9.800, P=0.008). In vitro study indicated, following demethylation treatment, glioma cells had an increased OCT4 expression. These results suggest that DNA hypomethylation may be a key mechanism underlying the up-regulation of OCT4 in the recurrence of glioma, which facilitates the understanding of the role of stem cells and the exploration of novel strategies for the treatment of recurrent glioma. PMID- 26925787 TI - Uc.206 regulates cell proliferation and apoptosis by targeting P53 in cervical cancer cells. AB - Ultraconserved regions (UCRs) are non-protein coding gene sequences with strict conserved across among different species. Emerging evidence demonstrates that UCRs encoding noncoding RNAs (ncRNAs) serve as regulators of gene expression. In recent decades, increasing evidence implicates the involvement of UCRs in carcinogenesis. Previous studies showed RNA expression of uc.206 was increased in colorectal cancer. Until now, the role of uc.206 in cervical cancers remains undefined. This study revealed that uc.206 is significantly up-regulated in cervical cancer (CC) tissue and negatively correlates with the expression of the pro-apoptotic gene P53 in RNA level. We show that uc.206 specifically targets the 3' untranslated region (3'UTR) of P53 and regulates its expression. Inhibition of uc.206 effectively delays cervical cells proliferation and promotes apoptosis, accompanied by increased expression of P53 protein. Thus, these findings suggested that uc.206 acts as a novel oncogene by targeting the P53 gene and promoting CC cell growth, which might be beneficial for cervical cancer therapy. PMID- 26925788 TI - Serum SOX11 promoter methylation is a novel biomarker for the diagnosis of Hepatitis B virus-related hepatocellular carcinoma. AB - Promoter methylation of tumor suppressor gene SOX11 has been reported to contribute to the diagnosis and prognosis of various cancerous diseases, including gastric cancer, hematopoietic malignancies and nasopharyngeal carcinoma. However, there is no data on the diagnostic potential of serum SOX11 promoter methylation in hepatocellular carcinoma (HCC). This study was therefore aimed to investigate the potential role of serum SOX11 promoter methylation as a noninvasive biomarker in the diagnosis of patients with hepatitis B virus (HBV) associated HCC. A total of 205 subjects were retrospectively included, which consisted of 111 HCC patients, 66 chronic hepatitis B (CHB) and 28 healthy controls (HCs). Methylation of SOX11 promoter was determined by methylation specific polymerase chain reaction. The methylation frequency of serum SOX11 promoter in HCC patients (69.4%, 77/111) was significantly higher than that in CHB patients (13.6%, 9/66; chi2 = 51.467, P<0.001) and HCs (10.7%, 3/28; chi2 = 31.489, P<0.001). There was significant difference of serum SOX11 promoter methylation in HCC patients with vascular invasion (49/58) and those without vascular invasion (28/53; chi2 = 13.058, P<0.001). Furthermore, the sensitivity of 69% was identified for SOX11 methylation in discriminating HCC from CHB, which was significant higher than the sensitivity of 57% for serum alpha-fetoprotein (AFP) (P<0.05). Notably, SOX11 promoter methylation plus AFP showed a sensitivity of 85% in discriminating HCC from CHB. These results suggested that serum SOX11 promoter methylation might serve as a useful and noninvasive biomarker for the diagnosis of HCC. PMID- 26925789 TI - Prediction of additional lymph node involvement in breast cancer patients with positive sentinel lymph nodes. AB - Axillary lymph node dissection (ALND) has traditionally been the principal method for evaluating axillary lymph node status in breast cancer patients. In the past decades sentinel lymph nodes biopsy after lymphatic mapping has been used to stage the disease. The majority of sentinel lymph nodes (SLN) positive patients do not have additional metastases in non-sentinel nodes (non-SLN) after additional ALND. These patients are exposed to the morbidity of ALND without any benefit from additional axillary clearence. In the present study we would like to asses the criteria for selecting those patients, who have high risk for non-SLN metastases in the axilla in cases of positive SLN. In this retrospective analysis, clinical and pathologic data from 163 patients who underwent SLN biopsy followed by ALND were collected. Following clinical and pathological characteristics were analyzed to predict the likehood of non-SLN metastases: age, staging, histologic type and grading of the tumors, hormonal receptor status, HER 2 receptor status and Ki-67 protein, angioinvasion, metastases in SLN and non SLN. Relative frequencies of individual characteristics between sample groups were statistically tested by Chi-square test at significance level p=0.5, when sample sizes in groups were small (<=5) by Fisher's exact test. Metastasis in SLN were present in 67 (41%) of patients, 48 patients (29,4%) had metastasis also in non-SLN. The ratio between non-SLN positive / non-SLN negative lymph nodes in patients with positive SLN increases with the stage of the disease, the difference between values for the pT1c and pT2 stadium was statistically significant (p = 0.0296). The same applies to grading, but the differences were not significant (p>0.05). We could not find significant differences for angioinvasion of the tumor, probably for small number of patients with angioinvasion (p>0.05).Only the stage of the tumor was shown to be significant in predicting the metastasis in non-SLN in our group of breast cancer patients with positive SLN Nearly 80% of the patients of 70 years and older displayed no benefit from axillary staging, because of negative SLN as well as non-SLN, although thanks to the small sample size this was not a statistically significant result. Furthermore, current recommendations for axillary staging in breast cancer patients are discussed. PMID- 26925790 TI - The prognostic significance of epidermal growth factor receptor expression in patients with anal carcinoma. AB - The aim of the present retrospective study was to evaluate the prognostic significance of epidermal growth factor receptor (EGFR) expression in patients treated with radiotherapy or concomitant chemoradiotherapy for squamous cell anal cancer (SCAC)Patients and methods: A total of 17 patients with SCAC (clinical stages I-III) were studies. All patients were treated with radiotherapy (total dose range 40 - 68 Gy), 13 patients received concomitant chemotherapy (7 patients mitomycin/5-fluorouracil, 5 patients cisplatine/5-fluorouracil, 1 patient cisplatine weekly). EGFR expression in the pretreatment biopsieswas assessed with imunohistochemistry.Patients with EGFR expression had significantly shorter progression free survival (PFS) (p=0.0109; HR 9.38, 95% CI 1.75 - 50.35) and overall survival (OS) (p=0.0351; HR 7.11, 95% CI 1.4 - 36.13) than patients without expression EGFR. The 4-year PFS in patients with increased EGFR expression was only 28.57% (95% CI 17.07 - 62.04%) compared to 87.5% (95% CI 64.58 - 100%) in patients without EGFR expression. The 4-year OS in patients with increased EGFR expression was only 50.0% (95% CI 15.35 - 84.65%) compared to 87.5% (95% CI 64.58 - 100.0%) in patients without EGFR expression.Patients with expression EGFR had significantly shorter PFS and OS compared with patients without EGFR expression. PMID- 26925791 TI - Aberrant expression of long noncoding RNA PVT1 and its diagnostic and prognostic significance in patients with gastric cancer. AB - Emerging evidences indicate that dysregulated long noncoding RNAs (lncRNAs) are implicated in cancer tumorigenesis and progression and might be used as diagnosis and prognosis biomarker, or potential therapeutic targets. LncRNA PVT1 has been reported to be upregulated in diverse human cancers; however, its clinical significance in gastric cancer (GC) remains elusive. This study was to evaluate the expression of PVT1 in GC and further explore its clinical significance.Previous microarray datasets were analyzed to conduct a preliminary screening for candidate lncRNAs of gastric cancer biomarkers in human gastric cancer tissues. Expression levels of PVT1 in 111pairs of gastric cancer and adjacent normal tissues, gastric cancer cell lines and gastric cancer juices compared to their corresponding controls were detected by real-time quantitative RT-PCR assay. A receiver operating characteristic (ROC) curve and Kaplan-Meier analysis were constructed to evaluate the diagnostic and prognostic values. Univariate and multivariate analysis were performed using the Cox proportional hazard analysis.PVT1 expression was remarkably increased in gastric cancer tissues and cell lines compared with that in the normal control, and its up regulation was significantly correlated to invasion depth (P < 0.001), advanced TNM stage (P = 0.002) and regional lymph nodes metastasis (P < 0.001) in gastric cancer. PVT1 levels were robust in differentiating gastric cancer tissues from controls [area under the curve (AUC) = 0.728; 95 % confidence interval (CI) = 0.665-0.786, p<0.01]. Kaplan-Meier analysis demonstrated that increased PVT1 expression contributed to poor overall survival (P < 0.01) and disease-free survival (P < 0.01) of patients. A multivariate survival analysis also indicated that PVT1 could be an independent prognostic marker. The levels of PVT1 in gastric juice from gastric patients were significantly higher than those from normal subjects (P = 0.03). PVT1 might serve as a promising biomarker for early detection and prognosis prediction of gastric cancer. PMID- 26925792 TI - The effectiveness of chemotherapy and electrochemotherapy on ovarian cell lines in vitro. AB - The presented study aimed to evaluate in vitro the effectiveness of improvement standard chemotherapy with bleomycin by electroporation in two various ovarian cancer cell lines. Two human ovarian cell lines OvBH-1 and SKOV-3 were used. The lines were selected because of their resistance to several therapeutic methods. As anticancer drug we use range of concentrations of bleomycin. In EP and ECT experiments different voltage values: from 0 to 1200 V/cm, 8 pulses with duration of 100MUs and intervals between pulses 1s long were used. The cells viability after applied treatments was evaluated by MTT assay. The expression of heat shock proteins - HSP27 was examined by immunocytochemical ABC method.The cytotoxicity with different concentrations of bleomycin alone was not significantly decrease in both cell lines. It confirms resistance of these cells to conventional chemotherapy. The highest decrease of cell proliferation was observed after EP with bleomycin after 48h of incubation for 1000 V/cm. The intensity of expression of small heat shock proteins HSP27 slightly increased after ECT in both treated cell lines, in particular in OvBH-1. The presented study indicated that application of electroporation may effectively enhance chemotherapy with bleomycin, particularly in the case of treating ovarian cancer resistant to standard therapy. PMID- 26925793 TI - Treatment and prognosis of childhood acute lymphoblastic leukemia on protocols ALL-BFM 90, 95 and ALL IC-BFM 2002: a retrospective single-center study from Olomouc, Czech Republic. AB - Great progress has been made in the diagnostics and treatment of childhood acute lymphoblastic leukemia (ALL) over the past decades. The vast majority of children are cured, however, there is need for further improvement, especially in specific patient subgroups. Our aim was to retrospectively evaluate disease characteristics and treatment outcomes of children with ALL enrolled in a single center into consecutive treatment protocols (ALL-BFM 90, ALL-BFM 95 and ALL IC BFM 2002) between years 1990 and 2007 and comprehensively summarize diagnostic and therapeutic advances between protocols. In total, 97 patients aged 0 to 18 years were treated for ALL at University Hospital Olomouc in the Czech Republic and steadily high relapse-free survival (RFS), event-free survival (EFS) and overall survival (OS) were observed during the evaluated time period without significant difference between the protocols (RFS 80-86%, EFS 75-83% and OS 84 92%). In conclusion, our center has demonstrated survival rates comparable to leading international study groups for childhood ALL over a substantial period of time. This has been achieved namely due to advances in diagnostics, excellent collaboration on regional, national and international level, quality assurance and high overall standard of care. The acquired experience has been crucial for current participation in the best performing Berlin-Frankfurt-Munster (BFM)-based international trials for childhood ALL. PMID- 26925794 TI - A new hope: the immunotherapy in small cell lung cancer. AB - Small cell lung cancer (SCLC) is of a high-grade malignancy with a high metastatic potential and poor clinical prognosis. Unfortunately, SCLC initially exhibits a good response to chemotherapy and radiation therapy, but inevitably, relapses decrease patients' chance of survival. Despite tremendous advances on the development of new chemotherapeutic agents, the prognosis of this disease remains poor. Immunotherapy plays a role in eliciting an anticancer response by modulating the patient's immune response of the tumor. Several studies have demonstrated that abnormal autoimmune regulation has a close relationship with SCLC. Thus, several immunotherapy trials are focused on SCLC treatment, including such approaches as immune checkpoints blockers, tumor vaccine, antigenic targets and adoptive cellular immunotherapy to benefit patients with SCLC. To date, the results from immunotherapy in SCLC have not been promising. For example, tumor vaccines have not been demonstrated to have a significant survival benefit. However, there have been many promising advances with immune checkpoints blockers. This review will provide a general overview of immunotherapy in SCLC. The landmark clinical trials in previous successful immunotherapy studies are summarized here. Finally, the challenges of immunotherapy in SCLC are discussed to facilitate the prediction of possible and valuable strategies for future therapy. PMID- 26925795 TI - Physcion 8-O-beta-glucopyranoside prevents hypoxia-induced epithelial-mesenchymal transition in colorectal cancer HCT116 cells by modulating EMMPRIN. AB - Epithelial-mesenchymal transition (EMT) is considered as the most important mechanism that underlies the initiation of cancer metastasis. Here we report that Physicon 8-O-beta-glucopyranoside (PG), a major active ingredient from a traditional Chinese herbal medicine Rumex japonicus Houtt, is capable of preventing human colorectal cancer cells from hypoxia-induced EMT. The treatment of the cells with PG reversed the EMT-related phenotype that has the morphological changes, down-regulation of E-cadherin, and hypoxia-induced cell migration and invasion. The effect was mediated at least in part by inhibiting the mRNA and protein expressions of EMMPRIN via modulation of PTEN/Akt/HIF-1alpha pathway. In addition, we found that PG-mediated prevention of EMT involved blockade of the hypoxia-induced up-regulation of Snail, Slug and Twist. In summary, this study showed that PG can prevent EMT induced by hypoxia, the environment that commonly exists in the center of a solid tumor. Given the low toxicity of PG to the healthy tissues, our study suggests that PG can serve as a safe therapeutic agent for suppressing cancer metastasis. PMID- 26925796 TI - Outcomes of Pancreaticoduodenectomy for Pancreatic Neuroendocrine Tumors: Are Combined Procedures Justified? AB - Efficacy and outcomes of resection for pancreatic neuroendocrine tumors (pNET) are well established; specific data on outcomes for pancreaticoduodenectomy (PD), either alone or with combined procedures, are limited. A retrospective review of PDs for pNET (1998-2014) at our institution was conducted. Patients were categorized into standard PD (SPD) alone or combined PD (CPD) defined as patients undergoing concurrent vascular reconstruction or additional organ resection for curative intent. Kaplan-Meier survival analyses were performed. PD for pNET was performed for 95 patients. Tumors were functional in 11 patients (9 %). Twenty six patients (28 %) underwent CPD. The 30/90-day mortality was 1.1/5.3 % respectively and similar between SPD and CPD (p = 0.61/p = 0.24). Five-year overall survival after PD for pNET was 85.1/71.9 % and similar between SPD/CPD groups (p = 0.17). Recurrence-free and overall survival for low-grade tumors was 74.7/93.9 % at 5 years compared to only 14.8/49.7 % for high-grade tumors (p < 0.001) and not predicted by extent of resection (SPD/CPD, respectively). PD with or without concurrent resection provides an acceptable, perioperative and long term oncologic, outcome for pNET. CPD is justified treatment modality, particularly for patients with low-grade tumors. The need for combinatorial procedures during PD is not contraindication alone for otherwise resectable patients with pNET. PMID- 26925797 TI - Should Oral Contrast Be Omitted in Patients with Suspected Appendicitis? AB - BACKGROUND: Acute appendicitis is one of the most common surgical emergencies. Our study evaluated patients given the diagnosis of appendicitis and reviewed their workup and clinical outcomes. We specifically focused on the use of oral contrast followed by appendectomy. METHODS: We retrospectively reviewed all adult patients given an ICD-9 code for appendicitis at Northwestern Memorial Hospital between January 2000 and September 2010. Complication rates, time to the operating room, and length of hospital stay were compared between patients who received a CT scan and those who did not during the hospitalization for appendicitis. RESULTS: Average time from Emergency Department to the operating room was found to be statistically longer for patients who underwent a CT scan (10 h: 3, 1548) versus those who did not (6 h: 2, 262) (p < 0.0001). There were 19 patients who had the complication of pneumonia and 4 patients who were diagnosed with acute respiratory distress syndrome postoperatively. Patients who underwent a CT scan and received oral contrast had a statistically higher number of both complications (p < 0.0001). CONCLUSIONS: The use of oral contrast is not necessary for an accurate diagnosis of appendicitis and may be associated with higher complication rates, longer hospital stays, and poor outcomes. PMID- 26925798 TI - Clinical Significance of the Glasgow Prognostic Score for Survival after Colorectal Cancer Surgery. AB - Glasgow prognostic score (GPS) has been found to be a useful tool in various cancer types. Our aim was to evaluate the significance of GPS in patients operated on for colorectal cancer (CRC). Patients with CRC who underwent radical resections between April 2010 and January 2015 were retrospectively evaluated. GPS was estimated based on the preoperative measurement of C-reactive protein and serum albumin levels. Data including demographics, laboratory and pathological parameters, surgical outcomes, and late-term follow-up results were analyzed. The study group of 115 patients consisted of 51 (44 %) women and 64 (56 %) men with a median age of 66 (range 32-91) years. The mean follow-up period was 20 (range 7 41) months. Tumor size and wound infection rates were significantly increased in patients with higher GPS (p = 0.019 and p = 0.003, respectively). According to multivariate analyses, CEA and GPS were found to be independent risk factors significantly effecting mortality (p = 0.001 and p = 0.009, respectively). At the end of the late-term follow-up period, it was detected that cancer-specific survival significantly decreased as the GPS increased (p = 0.016). The GPS is a significant prognostic factor in CRC and should be included in the routine preoperative assessment of all surgically treated CRC patients. PMID- 26925799 TI - Idea density in the life-stories of people with schizophrenia: Associations with narrative qualities and psychiatric symptoms. AB - Disordered speech and language deficits are well-documented in schizophrenia spectrum disorders. Researchers often assess speech samples using manualized rating systems, though recently computerized language assessment methods have been used more frequently in the study of speech from people with schizophrenia. Most typically, these computerized assessments measure aspects of expressivity (i.e., pause durations, prosody) or use word-count technology; less attention has focused on similar methods that can capture more sophisticated aspects of linguistic complexity (e.g., idea density). The primary objective of the present study was to assess idea density - via a computerized measure - in the life-story narratives of people with schizophrenia (n=32) compared to a group of community control participants (n=15). In the schizophrenia group, we also examined associations between idea density, narrative qualities rated via a manualized measure, and psychiatric symptoms. Our findings indicate that idea density is diminished in individuals with schizophrenia compared to controls. Further, our results suggest that though people with schizophrenia with richer idea density tended to have more developed insight into illness, they also had higher levels of depression, anxiety, and avolition. Implications of these results and suggestions for future research are discussed. PMID- 26925800 TI - Age-related changes in anterior cingulate cortex glutamate in schizophrenia: A (1)H MRS Study at 7 Tesla. AB - The extent of age-related changes in glutamate and other neurometabolites in the anterior cingulate cortex (ACC) in individuals with schizophrenia remain unclear. Magnetic resonance spectroscopy (MRS) at 7 T, which yields precise measurements of various metabolites and can distinguish glutamate from glutamine, was used to determine levels of ACC glutamate and other metabolites in 24 individuals with schizophrenia and 24 matched controls. Multiple regression analysis revealed that ACC glutamate decreased with age in patients but not controls. No changes were detected in levels of glutamine, N-acetylaspartate, N-acetylaspartylglutamic acid, myo-inositol, GABA, glutathione, total creatine, and total choline. These results suggest that age may be an important modifier of ACC glutamate in schizophrenia. PMID- 26925802 TI - Fruit and Vegetable Intakes of Preschool Children Are Associated With Feeding Practices Facilitating Internalization of Extrinsic Motivation. AB - OBJECTIVE: To examine the association between feeding practices and both fruit and vegetable intakes of preschoolers. DESIGN: Cross-sectional; data collected from 2009 to 2010. SETTING: Child care centers enrolled in the cohort of the Synergistic Theory and Research on Obesity and Nutrition Group Kids program. PARTICIPANTS: Three hundred and sixteen mother-child dyads were recruited in the baseline survey as primary caregivers of children aged 2-5 years. MAIN OUTCOME MEASURES: Ten aspects of maternal feeding practices were measured using a Comprehensive Feeding Practices Questionnaire. The frequency of children's fruit and vegetable consumption was estimated by mothers. ANALYSIS: Spearman's rank order correlation and linear regression analysis between parental feeding practices and both fruit and vegetable consumption were adjusted for potential confounders. Pearson's correlation coefficients among 10 parental feeding practices were calculated. RESULTS: Children in the study consumed fruit 1.7 +/- 0.9 times per day and vegetables 1.4 +/- 0.8 times per day. Feeding practices of building a healthy home food environment and involvement were positively related and those of restriction for health were negatively related to children's vegetable consumption (P < .001); moreover, encouraging balance and variety and monitoring were positively related to children's fruit consumption (P < .001). CONCLUSIONS AND IMPLICATIONS: The results of this study suggest that both fruit and vegetable intakes of preschool children are more likely to increase if parents employ feeding practices that encourage child autonomy, competence, and relatedness. PMID- 26925801 TI - Prefrontal neuronal integrity predicts symptoms and cognition in schizophrenia and is sensitive to genetic heterogeneity. AB - Schizophrenia is a genetically complex syndrome with substantial inter-subject variability in multiple domains. Person-specific measures to resolve its heterogeneity could focus on the variability in prefrontal integrity, which this study indexed as relative rostralization within the anterior cingulate cortex (ACC). Twenty-two schizophrenia cases and 11 controls underwent rigorous diagnostic procedures, symptom assessments (PANSS, Deficit Syndrome Scale) and intelligence testing. All underwent multivoxel MRSI at 3T to measure concentrations of the neuronal-specific biomarker N-acetylaspartate (NAA) in all of the voxels of the ACC. The concentrations of NAA were separately calculated and then compared across the rostral and caudal subregions to generate a rostralization ratio, which was examined with respect to the study measures and to which cases carried a missense coding polymorphism in PTPRG, SCL39A13, TGM5, NTRK1 or ARMS/KIDINS220. Rostralization significantly differed between cases and controls (chi(2)=18.40, p<.0001). In cases, it predicted verbal intelligence (r=.469, p=.043) and trait negative symptoms (diminished emotional range (r= .624, p=.010); curbed interests, r=-.558, p=.025). Rostralization was similar to controls for missense coding variants in TGM5 and was significantly greater than controls for the PTPRG variant carrier. This is the first study examining the utility of MRS metrics in describing pathological features at both group and person-specific levels. Rostralization predicted core illness features and differed based on which signaling genes were disrupted. While future studies in larger populations are needed, ACC rostralization appears to be a promising measure to reduce the heterogeneity of schizophrenia for genetic research and selecting cases for treatment studies. PMID- 26925803 TI - Influence of Electron Correlation on the Electronic Structure and Magnetism of Transition-Metal Phthalocyanines. AB - There exists an extensive literature on the electronic structure of transition metal phthalocyanines (TMPcs), either as single molecules or adsorbed on surfaces, where explicit intra-atomic Coulomb interactions of the strongly correlated orbitals are included in the form of a Hubbard U term. The choice of U is, to a large extent, based solely on previous values reported in the literature for similar systems. Here, we provide a systematic analysis of the influence of electron correlation on the electronic structure and magnetism of several TMPcs (MnPc, FePc, CoPc, NiPc, and CuPc). By comparing calculated results to valence band photoelectron spectroscopy measurements, and by determining the Hubbard term from linear response, we show that the choice of U is not as straightforward and can be different for each different TMPc. This, in turn, highlights the importance of individually estimating the value of U for each system before performing any further analysis and shows how this value can influence the final results. PMID- 26925804 TI - Automatic localization of endoscope in intraoperative CT image: A simple approach to augmented reality guidance in laparoscopic surgery. AB - The use of augmented reality in minimally invasive surgery has been the subject of much research for more than a decade. The endoscopic view of the surgical scene is typically augmented with a 3D model extracted from a preoperative acquisition. However, the organs of interest often present major changes in shape and location because of the pneumoperitoneum and patient displacement. There have been numerous attempts to compensate for this distortion between the pre- and intraoperative states. Some have attempted to recover the visible surface of the organ through image analysis and register it to the preoperative data, but this has proven insufficiently robust and may be problematic with large organs. A second approach is to introduce an intraoperative 3D imaging system as a transition. Hybrid operating rooms are becoming more and more popular, so this seems to be a viable solution, but current techniques require yet another external and constraining piece of apparatus such as an optical tracking system to determine the relationship between the intraoperative images and the endoscopic view. In this article, we propose a new approach to automatically register the reconstruction from an intraoperative CT acquisition with the static endoscopic view, by locating the endoscope tip in the volume data. We first describe our method to localize the endoscope orientation in the intraoperative image using standard image processing algorithms. Secondly, we highlight that the axis of the endoscope needs a specific calibration process to ensure proper registration accuracy. In the last section, we present quantitative and qualitative results proving the feasibility and the clinical potential of our approach. PMID- 26925805 TI - Coupling spatial segregation with synthetic circuits to control bacterial survival. AB - Engineered bacteria have great potential for medical and environmental applications. Fulfilling this potential requires controllability over engineered behaviors and scalability of the engineered systems. Here, we present a platform technology, microbial swarmbot, which employs spatial arrangement to control the growth dynamics of engineered bacteria. As a proof of principle, we demonstrated a safeguard strategy to prevent unintended bacterial proliferation. In particular, we adopted several synthetic gene circuits to program collective survival in Escherichia coli: the engineered bacteria could only survive when present at sufficiently high population densities. When encapsulated by permeable membranes, these bacteria can sense the local environment and respond accordingly. The cells inside the microbial swarmbot capsules will survive due to their high densities. Those escaping from a capsule, however, will be killed due to a decrease in their densities. We demonstrate that this design concept is modular and readily generalizable. Our work lays the foundation for engineering integrated and programmable control of hybrid biological-material systems for diverse applications. PMID- 26925807 TI - Safety standards for invasive procedures. PMID- 26925806 TI - Pituitary adenylate cyclase-activating polypeptide (PACAP) contributes to the proliferation of hematopoietic progenitor cells in murine bone marrow via PACAP specific receptor. AB - Pituitary adenylate cyclase-activating polypeptide (PACAP, encoded by adcyap1) plays an important role in ectodermal development. However, the involvement of PACAP in the development of other germ layers is still unclear. This study assessed the expression of a PACAP-specific receptor (PAC1) gene and protein in mouse bone marrow (BM). Cells strongly expressing PAC1(+) were large in size, had oval nuclei, and merged with CD34(+) cells, suggesting that the former were hematopoietic progenitor cells (HPCs). Compared with wild-type mice, adcyap1(-/-) mice exhibited lower multiple potential progenitor cell populations and cell frequency in the S-phase of the cell cycle. Exogenous PACAP38 significantly increased the numbers of colony forming unit-granulocyte/macrophage progenitor cells (CFU-GM) with two peaks in semi-solid culture. PACAP also increased the expression of cyclinD1 and Ki67 mRNAs. These increases were completely and partially inhibited by the PACAP receptor antagonists, PACAP6-38 and VIP6-28, respectively. Little or no adcyap1 was expressed in BM and the number of CFU-GM colonies was similar in adcyap1(-/-) and wild-type mice. However, PACAP mRNA and protein were expressed in paravertebral sympathetic ganglia, which innervate tibial BM, and in the sympathetic fibers of BM cavity. These results suggested that sympathetic nerve innervation may be responsible for PACAP-regulated hematopoiesis in BM, mainly via PAC1. PMID- 26925808 TI - Sperm macromolecules associated with bull fertility. AB - Bull fertility, ability of the sperm to fertilize and activate the egg that sustain embryo development, is vitally important for effective and efficient production of cattle. Fertility is a complex trait with low heritability. Despite recent advances in genomic selection and possibility of enormous paternal benefits to profitable cattle production, there exist no reliable tests for evaluating semen quality and predicting bull fertility. This review focuses on sperm macromolecules such as transcripts, proteins and the epigenome, i.e., the functional genome that are associated with bull fertility. Generating new information in these systems is important beyond agriculture because such progress advances the fundamental science of the mammalian male gamete while at the same time introduces biotechnology into livestock production. Sperm macromolecules and epigenome markers associated with bull fertility can be used alone or in combination with the current SNP microarrays to determine sperm quality and to indicate bull fertility. PMID- 26925809 TI - Plasma Levels of Receptor Interacting Protein Kinase-3 (RIP3), an Essential Mediator of Necroptosis, are Associated with Acute Kidney Injury in Critically Ill Trauma Patients. AB - BACKGROUND: Receptor interacting protein kinase-3 (RIP3) is a key mediator of necroptosis, a form of regulated cell death recently implicated in murine models of renal ischemia-reperfusion injury and transfusion-associated endothelial injury. The importance of necroptosis in human AKI is unknown. We hypothesized that plasma RIP3 concentrations would be associated with acute kidney injury (AKI) after severe trauma. METHODS: We performed a case-control study nested in a prospective cohort of critically ill trauma patients. AKI was defined by AKI Network creatinine criteria within 6 days of presentation. Of 158 cohort subjects, we selected 13 who developed AKI stage 2 or 3, 27 with AKI stage 1, and 40 without AKI. We compared plasma RIP3 concentrations across these groups at presentation and 48 h. Since red blood cell (RBC) transfusion is an AKI risk factor, we also tested the association of RBCs transfused during resuscitation with RIP3 levels. RESULTS: Median plasma RIP3 concentration rose more than 10 fold from presentation (15.6 (interquartile range 15.6-41.3) pg/mL) to 48 h (164.7 (66.9-300.6) pg/mL; P <0.001). RIP3 concentrations at 48 h were associated with AKI stage (no AKI: 144.8 (58.6-234.9) pg/mL; AKI stage 1: 165.8 (43.0-310.9) pg/mL; AKI stage 2-3: 365.5 (155.1-727.5) pg/mL; P = 0.010) whereas this association was not seen at presentation (P = 0.324). RBC transfusions were also associated with 48-h plasma RIP3 (no RBCs: 99.4 (15.6-166.1) pg/mL; 1-5 units: 182.6 (98.5-274.1) pg/mL; >5 units: 341.8 (150.1-423.8) pg/mL; P <0.001). CONCLUSIONS: In critically ill trauma patients, plasma levels of the necroptosis mediator RIP3 at 48 h were associated with AKI stage and RBC transfusions. PMID- 26925810 TI - Involvement of Central Endothelin ETA and Cannabinoid CB1 Receptors and Arginine Vasopressin Release in Sepsis Induced by Cecal Ligation and Puncture in Rats. AB - We previously reported that endothelin-1 (ET-1) reduced the frequency of spontaneous excitatory currents in vasopressinergic magnocellular cells through the activation of endothelin ETA receptors in rat brain slices. This effect was abolished by a cannabinoid CB1 receptor antagonist, suggesting the involvement of endocannabinoids. The present study investigated whether the blockade of ETA or CB1 receptors during the phase of increased levels of ET-1 after severe sepsis increases the survival rate of animals concomitantly with an increase in plasma arginine vasopressin (AVP) levels. Sepsis was induced in male Wistar rats by cecal ligation and puncture (CLP). Treatment with the CB1 receptor antagonist rimonabant (Rim; 10 and 20 mg/kg, orally) 4 h after CLP (three punctures) significantly increased the survival rate compared with the CLP per vehicle group. Intracerebroventricular treatment with the ETA receptor antagonist BQ123 (100 pmol) or with Rim (2 MUg) 4 and 8 h after CLP but not the ETB receptor antagonist BQ788 (100 pmol), also significantly improved the survival rate. Sham operated and CLP animals that were treated with Rim had significantly lower core temperature than CLP animals. However, oral treatment with Rim did not change bacterial count in the peritoneal exudate, neutrophil migration to the peritoneal cavity, leucopenia or increased plasma interleukin-6 levels induced by CLP. Both Rim and BQ123 also increased AVP levels 12 h after CLP. The blockade of central CB1 and ETA receptors in the late phase of sepsis increased the survival rate, reduced body temperature and increased the circulating AVP levels. PMID- 26925811 TI - Secular Trends in Incidence and Mortality of Acute Venous Thromboembolism: The AB VTE Population-Based Study. AB - BACKGROUND: Venous thromboembolism is a major cause of morbidity and mortality, and comprehensive studies profiling the epidemiology and pattern of health services use are needed. In this study we provide contemporary estimates of venous thromboembolism incidence and case fatality over the past decade. METHODS: We developed a population-based venous thromboembolism dataset by linking 6 administrative health databases in Alberta, Canada from April 1, 2002 to March 31, 2012. We defined acute symptomatic cases using a validated algorithm and used Poisson regression to model annual venous thromboembolism counts. RESULTS: We identified 31,656 cases of acute symptomatic venous thromboembolism between April 1, 2002 and March 31, 2012. The age- and sex-adjusted incidence rate of venous thromboembolism was 1.38 (95% confidence interval [CI], 1.37-1.40) per 1000 person-years. For pulmonary embolism it was 0.38 (95% CI, 0.36-0.40) per 1000 person-years, and for deep vein thrombosis it was 1.0 (95% CI, 0.99-1.1) per 1000 person-years. The adjusted model showed no significant change in the incidence of venous thromboembolism during the study period. The 30-day case fatality rate of venous thromboembolism was 2.0% (95% CI, 1.89-2.21) and was almost doubled in patients with pulmonary embolism: 3.9% (95% CI, 3.50-4.33). The 1-year case fatality rate was 9.2% (95% CI, 8.88-9.52) for venous thromboembolism and 12.9% (95% CI, 12.2-13.6) for patients with pulmonary embolism. The case fatality rate increased with increasing subject age. The 1-year and 5-year survivals after first acute venous thromboembolism were similar in patients with unprovoked and provoked events. However, in patients with cancer-associated thrombosis, the 1 year and 5-year survival rate was 66% (95% CI, 64.71%-67.29%) and 46% (95% CI, 43.28%-48.72%), respectively. CONCLUSION: The incidence of acute venous thromboembolism remained unchanged over a 10-year period. However, the case fatality of venous thromboembolism is substantial. PMID- 26925812 TI - Host control and nutrient trading in a photosynthetic symbiosis. AB - Photosymbiosis is one of the most important evolutionary trajectories, resulting in the chloroplast and the subsequent development of all complex photosynthetic organisms. The ciliate Paramecium bursaria and the alga Chlorella have a well established and well studied light dependent endosymbiotic relationship. Despite its prominence, there remain many unanswered questions regarding the exact mechanisms of the photosymbiosis. Of particular interest is how a host maintains and manages its symbiont load in response to the allocation of nutrients between itself and its symbionts. Here we construct a detailed mathematical model, parameterised from the literature, that explicitly incorporates nutrient trading within a deterministic model of both partners. The model demonstrates how the symbiotic relationship can manifest as parasitism of the host by the symbionts, mutualism, wherein both partners benefit, or exploitation of the symbionts by the hosts. We show that the precise nature of the photosymbiosis is determined by both environmental conditions (how much light is available for photosynthesis) and the level of control a host has over its symbiont load. Our model provides a framework within which it is possible to pose detailed questions regarding the evolutionary behaviour of this important example of an established light dependent endosymbiosis; we focus on one question in particular, namely the evolution of host control, and show using an adaptive dynamics approach that a moderate level of host control may evolve provided the associated costs are not prohibitive. PMID- 26925813 TI - Length adaptation of smooth muscle contractile filaments in response to sustained activation. AB - Airway and bladder smooth muscles are known to undergo length adaptation under sustained contraction. This adaptation process entails a remodelling of the intracellular actin and myosin filaments which shifts the peak of the active force-length curve towards the current length. Smooth muscles are therefore able to generate the maximum force over a wide range of lengths. In contrast, length adaptation of vascular smooth muscle has attracted very little attention and only a handful of studies have been reported. Although their results are conflicting on the existence of a length adaptation process in vascular smooth muscle, it seems that, at least, peripheral arteries and arterioles undergo such adaptation. This is of interest since peripheral vessels are responsible for pressure regulation, and a length adaptation will affect the function of the cardiovascular system. It has, e.g., been suggested that the inward remodelling of resistance vessels associated with hypertension disorders may be related to smooth muscle adaptation. In this study we develop a continuum mechanical model for vascular smooth muscle length adaptation by assuming that the muscle cells remodel the actomyosin network such that the peak of the active stress-stretch curve is shifted towards the operating point. The model is specialised to hamster cheek pouch arterioles and the simulated response to stepwise length changes under contraction. The results show that the model is able to recover the salient features of length adaptation reported in the literature. PMID- 26925814 TI - Prediction of human protein-protein interaction by a domain-based approach. AB - Protein-protein interactions (PPIs) are vital to a number of biological processes. With computational methods, plenty of domain information can help us to predict and assess PPIs. In this study, we proposed a domain-based approach for the prediction of human PPIs based on the interactions between the proteins and the domains. In this method, an optimizing model was built with the information from InterDom, 3did, DOMINE and Pfam databases. With this model, for 147 proteins in the integrin adhesome PPI network, 736 probable PPIs have been predicted, and the corresponding confidence probabilities of these PPIs were also calculated. It provides an opportunity to visualize the PPIs by using network graphs, which were constructed with Cytoscape, so that we can indicate underlying pathways possible. PMID- 26925815 TI - Monozygotic twins presenting with isolated sagittal and bicoronal synostosis, respectively. PMID- 26925816 TI - Insights into the effect of surface ligands on the optical properties of thiolated Au25 nanoclusters. AB - An abnormal optical absorption at about 780 and 980 nm was observed for Au25 nanoclusters (NCs) protected by negatively charged thiolate ligands collocating with positively or neutrally charged thiolate ligands, largely due to the resultant surface charge anisotropy on the NC surface which could induce structural distortions of the thiolated Au25 NCs. PMID- 26925817 TI - Publication bias in dermatology systematic reviews and meta-analyses. AB - Systematic reviews and meta-analyses in dermatology provide high-level evidence for clinicians and policy makers that influence clinical decision making and treatment guidelines. One methodological problem with systematic reviews is the under representation of unpublished studies. This problem is due in part to publication bias. Omission of statistically non-significant data from meta analyses may result in overestimation of treatment effect sizes which may lead to clinical consequences. Our goal was to assess whether systematic reviewers in dermatology evaluate and report publication bias. Further, we wanted to conduct our own evaluation of publication bias on meta-analyses that failed to do so. Our study considered systematic reviews and meta-analyses from ten dermatology journals from 2006 to 2016. A PubMed search was conducted, and all full-text articles that met our inclusion criteria were retrieved and coded by the primary author. 293 articles were included in our analysis. Additionally, we formally evaluated publication bias in meta-analyses that failed to do so using trim and fill and cumulative meta-analysis by precision methods. Publication bias was mentioned in 107 articles (36.5%) and was formally evaluated in 64 articles (21.8%). Visual inspection of a funnel plot was the most common method of evaluating publication bias. Publication bias was present in 45 articles (15.3%), not present in 57 articles (19.5%) and not determined in 191 articles (65.2%). Using the trim and fill method, 7 meta-analyses (33.33%) showed evidence of publication bias. Although the trim and fill method only found evidence of publication bias in 7 meta-analyses, the cumulative meta-analysis by precision method found evidence of publication bias in 15 meta-analyses (71.4%). Many of the reviews in our study did not mention or evaluate publication bias. Further, of the 42 articles that stated following PRISMA reporting guidelines, 19 (45.2%) evaluated for publication bias. In comparison to other studies, we found that systematic reviews in dermatology were less likely to evaluate for publication bias. Evaluating and reporting the likelihood of publication bias should be standard practice in systematic reviews when appropriate. PMID- 26925818 TI - Correction to "Hypervalent Iodine-Mediated Intramolecular trans Aminocarboxylation and Oxoaminocarboxylation of Alkynes: Divergent Cascade Annulations of Isocoumarins under Metal-Free Conditions". PMID- 26925819 TI - Host-Induced Gene Silencing of the Target Gene in Fungal Cells Confers Effective Resistance to the Cotton Wilt Disease Pathogen Verticillium dahliae. PMID- 26925820 TI - Unfettered Access to Reliable Contraception: Pharmacist Prescription Derails a Definitive Solution. PMID- 26925821 TI - Residential and outpatient treatment completion for substance use disorders in the U.S.: Moderation analysis by demographics and drug of choice. AB - BACKGROUND: This study investigates the impact of residential versus outpatient treatment setting on treatment completion, and how this impact might vary by demographic characteristics and drug of choice, using a national sample of publicly funded substance abuse programs in the United States. METHODS: This is a retrospective analysis using data extracted from the 2011 Substance Abuse and Mental Health Services Administration (SAMHSA) Treatment Episode Data Set (TEDS D). A total of 318,924 cases were analyzed using logistic regression, fixed effects logistic regression, and moderated fixed-effects logistic regression. RESULTS: Residential programs reported a 65% completion rate compared to 52% for outpatient settings. After controlling for other confounding factors, clients in residential treatment were nearly three times as likely as clients in outpatient treatment to complete treatment. The effect of residential treatment on treatment completion was not significantly moderated by gender, but it was for age, drug of choice, and race/ethnicity. Residential compared to outpatient treatment increased the likelihood of completion to a greater degree for older clients, Whites, and opioid abusers, as compared to younger clients, non-Whites, and alcohol and other substance users, respectively. CONCLUSION: We speculate that for opioid abusers, as compared to abusers of other drugs, residential treatment settings provide greater protection from environmental and social triggers that may lead to relapse and non-completion of treatment. Greater use of residential treatment should be explored for opioid users in particular. PMID- 26925822 TI - Long-term Use of Systemic Treatments for Moderate-to-Severe Atopic Dermatitis in Adults: A Monocentric Retrospective Study. AB - Data regarding systemic therapies in the management of atopic dermatitis are limited. The aim of this study was to provide evidence for the efficacy and tolerance of systemic immunosuppressive treatments for moderate-to-severe adult atopic dermatitis. A single-centre retrospective study was conducted. A total of 54 patients were prescribed systemic treatments between 2000 and 2014. Of these, 28 received methotrexate and 55.6% were considered as responders based on Physician's Global Assessment, 17 received azathioprine (37.5% responders), 43 received cyclosporin A (65.9% responders) and 7 received a combination therapy with methotrexate and azathioprine (57.1% responders). These treatments were well tolerated overall and few adverse events required discontinuation of treatment. Combination therapy associating methotrexate and azathioprine appears to be a promising treatment for patients who fail to respond to conventional monotherapies. PMID- 26925823 TI - In reference to supraglottoplasty for laryngomalacia with obstructive sleep apnea: A systematic review and meta-analysis. PMID- 26925824 TI - Anatomical features for the adequate choice of experimental animal models in biomedicine: I. Fishes. AB - Fish constitute the oldest and most diverse class of vertebrates, and are widely used in basic research due to a number of advantages (e.g., rapid development ex utero, large-scale genetic screening of human disease). They represent excellent experimental models for addressing studies on development, morphology, physiology and behavior function in other related species, as well as informative analysis of conservation and diversity. Although less complex, fish share many anatomical and physiological features with mammals, including humans, which make them an important complement to research in mammalian models. In this review we describe and compare the most relevant anatomical features of the most used teleostean species in research, to be taken into consideration when selecting an animal model: zebrafish (Danio rerio), medaka (Oryzias latypes), the turquoise killifish (Nothobranchius furzeri), and goldfish (Carassius auratus). Zebrafish and medaka are the mainstream models for genetic manipulability and studies on developmental biology; the turquoise killifish is an excellent model for aging research; goldfish has been largely employed for neuroendocrine studies. PMID- 26925825 TI - Nanotoxicology: Seeing the trees for the forest. PMID- 26925826 TI - Frequency fluctuations in silicon nanoresonators. AB - Frequency stability is key to the performance of nanoresonators. This stability is thought to reach a limit with the resonator's ability to resolve thermally induced vibrations. Although measurements and predictions of resonator stability usually disregard fluctuations in the mechanical frequency response, these fluctuations have recently attracted considerable theoretical interest. However, their existence is very difficult to demonstrate experimentally. Here, through a literature review, we show that all studies of frequency stability report values several orders of magnitude larger than the limit imposed by thermomechanical noise. We studied a monocrystalline silicon nanoresonator at room temperature and found a similar discrepancy. We propose a new method to show that this was due to the presence of frequency fluctuations, of unexpected level. The fluctuations were not due to the instrumentation system, or to any other of the known sources investigated. These results challenge our current understanding of frequency fluctuations and call for a change in practices. PMID- 26925828 TI - A programmable nanoreplica molding for the fabrication of nanophotonic devices. AB - The ability to fabricate periodic structures with sub-wavelength features has a great potential for impact on integrated optics, optical sensors, and photovoltaic devices. Here, we report a programmable nanoreplica molding process to fabricate a variety of sub-micrometer periodic patterns using a single mold. The process utilizes a stretchable mold to produce the desired periodic structure in a photopolymer on glass or plastic substrates. During the replica molding process, a uniaxial force is applied to the mold and results in changes of the periodic structure, which resides on the surface of the mold. Direction and magnitude of the force determine the array geometry, including the lattice constant and arrangement. By stretching the mold, 2D arrays with square, rectangular, and triangular lattice structures can be fabricated. As one example, we present a plasmonic crystal device with surface plasmon resonances determined by the force applied during molding. In addition, photonic crystal slabs with different array patterns are fabricated and characterized. This unique process offers the capability of generating various periodic nanostructures rapidly and inexpensively. PMID- 26925830 TI - Electron energy loss spectroscopy analysis of the interaction of Cr and V with MWCNTs. AB - The presented scanning transmission electron microscopy (STEM) and electron energy-loss spectroscopy (EELS) results show the strong reaction of Cr and V with the graphitic walls of MWCNTs. For Vanadium, an interfacial VC layer could be observed at the interface between VN and MWCNTs, when the samples were heated in situ to 750 degrees C. Knowledge about this interfacial VC layer is important for the formation of VN-MWCNT hybrid materials, used in supercapacitor electrodes, often synthesized at high temperatures. Chromium reacts at 500 degrees C with the MWCNTs to form Cr3C2 and in some cases, dissolved the MWCNT completely. Together with the previously published results about the interaction of MWCNTs with Cu (no interaction) and Ni (a slight rehybridisation trend for the outermost MWCNT-wall observed with EELS) (Ilari et al., 2015) the influence of the valence d-orbital occupancy of 3d transition metals on the interaction strength with CNTs is shown experimentally. For a transition metal to form chemical bonds towards CNT-walls, unoccupied states in its valence d-orbitals are needed. While Ni (2 unoccupied states) interacts only slightly, Cr (5 unoccupied states) and V (7 unoccupied states) react much stronger and can dissolve the MWCNTs, at least partially. PMID- 26925831 TI - M23C6 carbides and Cr2N nitrides in aged duplex stainless steel: A SEM, TEM and FIB tomography investigation. AB - The precipitation evolution during ageing of a 2101 lean duplex stainless steel was investigated, revealing that the precipitate type and morphology depends on the nature of the grain boundary. Triangular M23C6 carbides precipitate only at gamma/delta interfaces and rod-like Cr2N nitrides precipitate at both gamma/delta and delta/delta interfaces. After 15min of ageing, the M23C6 size no longer evolves, whereas that of the Cr2N continues to evolve. For Cr2N, the morphology is maintained at gamma/delta interfaces, whereas percolation occurs to form a continuous layer at delta/delta interfaces. By combining 2D and 3D characterisation at the nanoscale using transmission electron microscopy (TEM) and focused ion beam (FIB) tomography, a complete description of the precipitation evolution was obtained, including the composition, crystallographic structure, orientation relationship with the matrix phases, location, morphology, size and volume fraction. PMID- 26925827 TI - Meta-analysis of cellular toxicity for cadmium-containing quantum dots. AB - Understanding the relationships between the physicochemical properties of engineered nanomaterials and their toxicity is critical for environmental and health risk analysis. However, this task is confounded by material diversity, heterogeneity of published data and limited sampling within individual studies. Here, we present an approach for analysing and extracting pertinent knowledge from published studies focusing on the cellular toxicity of cadmium-containing semiconductor quantum dots. From 307 publications, we obtain 1,741 cell viability related data samples, each with 24 qualitative and quantitative attributes describing the material properties and experimental conditions. Using random forest regression models to analyse the data, we show that toxicity is closely correlated with quantum dot surface properties (including shell, ligand and surface modifications), diameter, assay type and exposure time. Our approach of integrating quantitative and categorical data provides a roadmap for interrogating the wide-ranging toxicity data in the literature and suggests that meta-analysis can help develop methods for predicting the toxicity of engineered nanomaterials. PMID- 26925832 TI - Predicting (17)O NMR chemical shifts of polyoxometalates using density functional theory. AB - We have investigated the computation of (17)O NMR chemical shifts of a wide range of polyoxometalates using density functional theory. The effects of basis sets and exchange-correlation functionals are explored, and whereas pure DFT functionals generally predict the chemical shifts of terminal oxygen sites quite well, hybrid functionals are required for the prediction of accurate chemical shifts in conjunction with linear regression. By using PBE0/def2-tzvp//PBE0/cc pvtz(H-Ar), lanl2dz(K-) we have computed the chemical shifts of 37 polyoxometalates, corresponding to 209 (17)O NMR signals. We also show that at this level of theory the protonation-induced pH dependence of the chemical shift of the triprotic hexaniobate Lindqvist anion, [HxNb6O19]((8-x)), can be reproduced, which suggests that hypotheses regarding loci of protonation can be confidently tested. PMID- 26925829 TI - Toward precision medicine of breast cancer. AB - In this review, we report on breast cancer's molecular features and on how high throughput technologies are helping in understanding the dynamics of tumorigenesis and cancer progression with the aim of developing precision medicine methods. We first address the current state of the art in breast cancer therapies and challenges in order to progress towards its cure. Then, we show how the interaction of high-throughput technologies with in silico modeling has led to set up useful inferences for promising strategies of target-specific therapies with low secondary effect incidence for patients. Finally, we discuss the challenge of pharmacogenetics in the clinical practice of cancer therapy. All these issues are explored within the context of precision medicine. PMID- 26925834 TI - Subtle Changes to Peripheral Ligands Enable High Turnover Numbers for Photocatalytic Hydrogen Generation with Supramolecular Photocatalysts. AB - The photocatalytic generation of hydrogen (H2) from protons by two cyclometalated ruthenium-platinum polypyridyl complexes, [Ru(bpy)2(2,5-bpp)PtIS](2+) (1) and [Ru(dceb)2(2,5-bpp)PtIS](2+) (2) [where bpy = 2,2'-bipyridine, 2,5-bpp = 2,2',5',2"-terpyridine, dceb = 4,4'-di(carboxyethyl)bipyridine, and S = solvent], is reported. Turnover numbers (TONs) for H2 generation were increased by nearly an order of magnitude by the introduction of carboxyethyl ester units, i.e., from 80 for 1P to 650 for 2P after 6 h of irradiation, with an early turnover frequency (TOF) increasing from 15 to 200 h(-1). The TON and TOF values for 2P are among the highest reported to date for supramolecular photocatalysts. The increase correlates with stabilization of the excited states localized on the peripheral ligands of the light-harvesting Ru(II) center. PMID- 26925833 TI - Circulating angiogenic cell function is inhibited by cortisol in vitro and associated with psychological stress and cortisol in vivo. AB - Psychological stress and glucocorticoids are associated with heightened cardiovascular disease risk. We investigated whether stress or cortisol would be associated with reduced circulating angiogenic cell (CAC) function, an index of impaired vascular repair. We hypothesized that minority-race individuals who experience threat in interracial interactions would exhibit reduced CAC function, and that this link might be explained by cortisol. To test this experimentally, we recruited 106 African American participants for a laboratory interracial interaction task, in which they received socially evaluative feedback from Caucasian confederates. On a separate day, a subset of 32 participants (mean age=26years, 47% female) enrolled in a separate biological substudy and provided blood samples for CAC isolation and salivary samples to quantify the morning peak in cortisol (the cortisol awakening response, CAR). CAC function was quantified using cell culture assays of migration to vascular endothelial growth factor (VEGF) and secretion of VEGF into the culture medium. Heightened threat in response to an interracial interaction and trait anxiety in vivo were both associated with poorer CAC migratory function in vitro. Further, threat and poorer sustained attention during the interracial interaction were associated with a higher CAR, which in turn, was related to lower CAC sensitivity to glucocorticoids. In vitro, higher doses of cortisol impaired CAC migratory function and VEGF protein secretion. The glucocorticoid receptor antagonist RU486 reversed this functional impairment. These data identify a novel, neuroendocrine pathway by which psychological stress may reduce CAC function, with potential implications for cardiovascular health. PMID- 26925835 TI - Per os infectivity of white spot syndrome virus (WSSV) in white-legged shrimp (Litopenaeus vannamei) and role of peritrophic membrane. AB - As earlier observations on peroral infectivity of WSSV in white-legged shrimp are conflicting, here, a standardized peroral intubation technique was used to examine (i) the role of the physical composition of the viral inoculum and (ii) the barrier function of the PM. In a first experiment, the infectivity of a WSSV stock was compared by determining the SID50 by intramuscular injection, peroral inoculation or via feeding. The following titers were obtained: 10(8.77) SID50/g by intramuscular injection, 10(1.23) SID50/g by peroral inoculation and 10(0.73) SID50/g by feeding. These results demonstrated that 10(7.54)-10(8.03) infectious virus is needed to infect shrimp by peroral inoculation and via feeding. Next, it was examined if damage of the PM may increase the susceptibility for WSSV by peroral route. The infectivity of a virus stock was tested upon peroral inoculation of shrimp with and without removal of the PM and compared with the infectivity upon intramuscular inoculation. The virus titers obtained upon intramuscular injection and peroral inoculation of shrimp with and without PM were 10(8.63), 10(1.13) and 10(1.53) SID50/mL, respectively. This experiment confirmed the need of 10(7.1)-10(7.5) infectious virus to infect shrimp via peroral route and showed that the removal of the PM slightly but not significantly (p > 0.05) facilitated the infection of shrimp. This study indicated that WSSV contaminated feed is poorly infectious via peroral route, whereas it is highly infectious when injected into shrimp. The PM plays a minor role as internal barrier of shrimp against WSSV infection. PMID- 26925836 TI - Gone with the Wind--Innate Immunity and Airway Inflammation. PMID- 26925837 TI - Genomics of Rapid Incipient Speciation in Sympatric Threespine Stickleback. AB - Ecological speciation is the process by which reproductively isolated populations emerge as a consequence of divergent natural or ecologically-mediated sexual selection. Most genomic studies of ecological speciation have investigated allopatric populations, making it difficult to infer reproductive isolation. The few studies on sympatric ecotypes have focused on advanced stages of the speciation process after thousands of generations of divergence. As a consequence, we still do not know what genomic signatures of the early onset of ecological speciation look like. Here, we examined genomic differentiation among migratory lake and resident stream ecotypes of threespine stickleback reproducing in sympatry in one stream, and in parapatry in another stream. Importantly, these ecotypes started diverging less than 150 years ago. We obtained 34,756 SNPs with restriction-site associated DNA sequencing and identified genomic islands of differentiation using a Hidden Markov Model approach. Consistent with incipient ecological speciation, we found significant genomic differentiation between ecotypes both in sympatry and parapatry. Of 19 islands of differentiation resisting gene flow in sympatry, all were also differentiated in parapatry and were thus likely driven by divergent selection among habitats. These islands clustered in quantitative trait loci controlling divergent traits among the ecotypes, many of them concentrated in one region with low to intermediate recombination. Our findings suggest that adaptive genomic differentiation at many genetic loci can arise and persist in sympatry at the very early stage of ecotype divergence, and that the genomic architecture of adaptation may facilitate this. PMID- 26925838 TI - Control of sleep by a network of cell cycle genes. AB - Sleep is essential for health and cognition, but the molecular and neural mechanisms of sleep regulation are not well understood. We recently reported the identification of TARANIS (TARA) as a sleep-promoting factor that acts in a previously unknown arousal center in Drosophila. tara mutants exhibit a dose dependent reduction in sleep amount of up to ~60%. TARA and its mammalian homologs, the Trip-Br (Transcriptional Regulators Interacting with PHD zinc fingers and/or Bromodomains) family of proteins, are primarily known as transcriptional coregulators involved in cell cycle progression, and contain a conserved Cyclin-A (CycA) binding homology domain. We found that tara and CycA synergistically promote sleep, and CycA levels are reduced in tara mutants. Additional data demonstrated that Cyclin-dependent kinase 1 (Cdk1) antagonizes tara and CycA to promote wakefulness. Moreover, we identified a subset of CycA expressing neurons in the pars lateralis, a brain region proposed to be analogous to the mammalian hypothalamus, as an arousal center. In this Extra View article, we report further characterization of tara mutants and provide an extended discussion of our findings and future directions within the framework of a working model, in which a network of cell cycle genes, tara, CycA, and Cdk1, interact in an arousal center to regulate sleep. PMID- 26925840 TI - From crystal structure of alpha-conotoxin GIC in complex with Ac-AChBP to molecular determinants of its high selectivity for alpha3beta2 nAChR. AB - Acetylcholine binding proteins (AChBPs) are unique spatial homologs of the ligand binding domains of nicotinic acetylcholine receptors (nAChRs), and they reproduce some pharmacological properties of nAChRs. X-ray crystal structures of AShBP in complex with alpha-conotoxins provide important insights into the interactions of alpha-conotoxins with distinct nAChR subtypes. Although considerable efforts have been made to understand why alpha-conotoxin GIC is strongly selective for alpha3beta2 nAChR, this question has not yet been solved. Here we present the structure of alpha-conotoxin GIC in complex with Aplysia californica AChBP (Ac AChBP) at a resolution of 2.1 A. Based on this co-crystal structure complemented with molecular docking data, we suggest the key residues of GIC in determining its high affinity and selectivity for human alpha3beta2 vs alpha3beta4 nAChRs. These suggestions were checked by radioligand and electrophysiology experiments, which confirmed the functional role of detected contacts for GIC interactions with Ac-AChBP and alpha3beta2 nAChR subtypes. While GIC elements responsible for its high affinity binding with Ac-AChBP and alpha3beta2 nAChR were identified, our study also showed the limitations of computer modelling in extending the data from the X-ray structures of the AChBP complexes to all nAChR subtypes. PMID- 26925839 TI - Osteoblast Malfunction Caused by Cell Stress Response to Procollagen Misfolding in alpha2(I)-G610C Mouse Model of Osteogenesis Imperfecta. AB - Glycine (Gly) substitutions in collagen Gly-X-Y repeats disrupt folding of type I procollagen triple helix and cause severe bone fragility and malformations (osteogenesis imperfecta [OI]). However, these mutations do not elicit the expected endoplasmic reticulum (ER) stress response, in contrast to other protein folding diseases. Thus, it has remained unclear whether cell stress and osteoblast malfunction contribute to the bone pathology caused by Gly substitutions. Here we used a mouse with a Gly610 to cysteine (Cys) substitution in the procollagen alpha2(I) chain to show that misfolded procollagen accumulation in the ER leads to an unusual form of cell stress, which is neither a conventional unfolded protein response (UPR) nor ER overload. Despite pronounced ER dilation, there is no upregulation of binding immunoglobulin protein (BIP) expected in the UPR and no activation of NF-kappaB signaling expected in the ER overload. Altered expression of ER chaperones alphaB crystalline and HSP47, phosphorylation of EIF2alpha, activation of autophagy, upregulation of general stress response protein CHOP, and osteoblast malfunction reveal some other adaptive response to the ER disruption. We show how this response alters differentiation and function of osteoblasts in culture and in vivo. We demonstrate that bone matrix deposition by cultured osteoblasts is rescued by activation of misfolded procollagen autophagy, suggesting a new therapeutic strategy for OI. (c) 2016 American Society for Bone and Mineral Research. PMID- 26925841 TI - Binimetinib inhibits MEK and is effective against neuroblastoma tumor cells with low NF1 expression. AB - BACKGROUND: Novel therapies are needed for children with high-risk and relapsed neuroblastoma. We hypothesized that MAPK/ERK kinase (MEK) inhibition with the novel MEK1/2 inhibitor binimetinib would be effective in neuroblastoma preclinical models. METHODS: Levels of total and phosphorylated MEK and extracellular signal-regulated kinase (ERK) were examined in primary neuroblastoma tumor samples and in neuroblastoma cell lines by Western blot. A panel of established neuroblastoma tumor cell lines was treated with increasing concentrations of binimetinib, and their viability was determined using MTT assays. Western blot analyses were performed to examine changes in total and phosphorylated MEK and ERK and to measure apoptosis in neuroblastoma tumor cells after binimetinib treatment. NF1 protein levels in neuroblastoma cell lines were determined using Western blot assays. Gene expression of NF1 and MEK1 was examined in relationship to neuroblastoma patient outcomes. RESULTS: Both primary neuroblastoma tumor samples and cell lines showed detectable levels of total and phosphorylated MEK and ERK. IC50 values for cells sensitive to binimetinib ranged from 8 nM to 1.16 MUM, while resistant cells did not demonstrate any significant reduction in cell viability with doses exceeding 15 MUM. Sensitive cells showed higher endogenous expression of phosphorylated MEK and ERK. Gene expression of NF1, but not MEK1, correlated with patient outcomes in neuroblastoma, and NF1 protein expression also correlated with responses to binimetinib. CONCLUSIONS: Neuroblastoma tumor cells show a range of sensitivities to the novel MEK inhibitor binimetinib. In response to binimetinib, sensitive cells demonstrated complete loss of phosphorylated ERK, while resistant cells demonstrated either incomplete loss of ERK phosphorylation or minimal effects on MEK phosphorylation, suggesting alternative mechanisms of resistance. NF1 protein expression correlated with responses to binimetinib, supporting the use of NF1 as a biomarker to identify patients that may respond to MEK inhibition. MEK inhibition therefore represents a potential new therapeutic strategy for neuroblastoma. PMID- 26925842 TI - Lupus as a paraneoplastic manifestation of cholangiocarcinoma. AB - Tumors originating in the digestive system, like those in other areas, whether solid or otherwise, may present with extradigestive manifestations in the setting of a paraneoplastic syndrome. Systemic lupus erythematosus (SLE) is an autoimmune condition most commonly involving women of childbearing age. On occasion it represents a paraneoplastic manifestation heralding a primary tumor. Cancer suspicion is therefore a key element for newly diagnosed SLE cases with nonstandard epidemiology even in the absence of suggestive symptoms, and digestive tumors should be included in the differential diagnosis. PMID- 26925844 TI - Synergistic Catalysis: Pd(II) Catalyzed Oxidation of 1,4-Dihydroquinones in the Pd(II) Catalyzed 1,4-Oxidation of Cyclic 1,3-Dienes. AB - Palladium(II) carboxylate salts have been shown to catalyze the oxidation of various hydroquinones to benzoquinones in the presence of t-BuOOH. This new catalytic system has been integrated into the oxidative 1,4-functionalization of cyclic 1,3-dienes where the palladium plays a remarkable dual role, catalyzing both the diene oxidation itself and the regeneration of the active quinone oxidant, which is required for diene functionalization. These new conditions offer considerable increases in reaction rate over prior art and allow a significant decrease in the equivalents of the nucleophilic carboxylate required for full conversion. PMID- 26925843 TI - Transcriptome Analysis for Identification of Genes Related to Gonad Differentiation, Growth, Immune Response and Marker Discovery in The Turbot (Scophthalmus maximus). AB - BACKGROUND: Turbot Scophthalmus maximus is an economically important species extensively aquacultured in China. The genetic selection program is necessary and urgent for the sustainable development of this industry, requiring more and more genome background knowledge. Transcriptome sequencing is an excellent alternative way to identify transcripts involved in specific biological processes and exploit a considerable quantity of molecular makers when no genome sequences are available. In this study, a comprehensive transcript dataset for major tissues of S. maximus was produced on basis of an Illumina platform. RESULTS: Total RNA was isolated from liver, spleen, kidney, cerebrum, gonad (testis and ovary) and muscle. Equal quantities of RNA from each type of tissues were pooled to construct two cDNA libraries (male and female). Using the Illumina paired-end sequencing technology, nearly 44.22 million clean reads in length of 100 bp were generated and then assembled into 106,643 contigs, of which 71,107 were named unigenes with an average length of 892 bp after the elimination of redundancies. Of these, 24,052 unigenes (33.83% of the total) were successfully annotated. GO, KEGG pathway mapping and COG analysis were performed to predict potential genes and their functions. Based on our sequence analysis and published documents, many candidate genes with fundamental roles in sex determination and gonad differentiation (dmrt1), growth (ghrh, myf5, prl/prlr) and immune response (TLR1/TLR21/TLR22, IL-15/IL-34), were identified for the first time in this species. In addition, a large number of credible genetic markers, including 21,192 SSRs and 8,642 SNPs, were identified in the present dataset. CONCLUSION: This informative transcriptome provides valuable new data to increase genomic resources of Scophthalmus maximus. The future studies of corresponding gene functions will be very useful for the management of reproduction, growth and disease control in turbot aquaculture breeding programs. The molecular markers identified in this database will aid in genetic linkage analyses, mapping of quantitative trait loci, and acceleration of marker assisted selection programs. PMID- 26925845 TI - Thickness dependence of light transmittance, translucency and opalescence of a ceria-stabilized zirconia/alumina nanocomposite for dental applications. AB - OBJECTIVES: This study was conducted to investigate thickness dependence of light transmittance, translucency and opalescence of a commercially available fully sintered ceria-stabilized zirconia/alumina nanocomposite for dental all-ceramic restorations. METHODS: Three disk samples of 16 mm in diameter and thickness ranging from 0.2 to 0.6 mm with 0.1 mm increment each were cut from a fully sintered rod-shaped Ce-TZP/alumina nanocomposite (NANOZR, Panasonic Healthcare, Japan) and polished flat by using diamond slurry. Spectral light transmittance data under the CIE standard illuminant D65 were recorded at 10nm intervals from 360 to 740 nm using a computer-controlled spectrophotometer. Average transmittance, translucency and opalescence parameters were determined as a function of sample thickness. Optical properties of a fully-sintered yttria stabilized tetragonal zirconia polycrystals (Cercon((r)) base, DeguDent GmbH, Germany) were also investigated as a reference. Two-way ANOVA was performed to determine the significant differences in various optical parameters among types of ceramic and thicknesses at alpha=0.05. RESULTS: Results of the two-way ANOVA showed that the average transmittance, translucency and opalescence parameters of both ceramic materials were significantly influenced by the type of ceramic and thickness (p<0.001). Light transmittance of the NANOZR was significantly lower than that of the Cercon((r)) base. For both ceramic materials, average transmittance of light and translucency parameter decreased with sample thickness following exponential functions. The NANOZR showed substantially higher opalescence parameters exceeding 20 CIE units when the sample thickness was nearly 0.3 mm. The prominent characteristics of high opalescence and low transmittance of light in the NANOZR was considered to be caused by its specific very fine interpenetrated intragranular microstructure and by a large difference of refractive indices of Ce-TZP and alumina components. SIGNIFICANCE: High opalescence and low transmittance of light of the ceria-stabilized zirconia/alumina nanocomposite (NANOZR) are attractive properties for use as a substructure in fabricating porcelain-veneering-type esthetic all-ceramic restorations. PMID- 26925846 TI - New antidepressant use in older adults: a Canadian population-based study (1997 2013). AB - OBJECTIVE: There has been much attention on appropriate prescribing in older adults in recent years. Recent guidelines favor the use of newer antidepressants over older agents based on their safety profile in this population. This study aimed to examine whether there has been a decline in older antidepressants and an increase in newer antidepressants used by older adults. METHOD: A retrospective cross-sectional study using administrative databases examined the annual incidence of antidepressant use (per 1000) of community-dwelling adults >=60 years old between 1997/1998 and 2012/2013 in Manitoba, Canada. RESULTS: The population of Manitoba >=60 years increased by 25.6% from 188,296 to 236,569 from 1997/1998 to 2012/2013. New antidepressant use peaked to 45.9 per 1000 in 1999/2000, and then decreased steadily to 30.5 per 1000 in 2012/2013 (p < 0.0001). Incident amitriptyline use was high but declined from 15.5 to 7.4 per 1000 (p < 0.001). An increase in incident trazodone, mirtazapine, and venlafaxine use was observed (p < 0.001). CONCLUSIONS: There has been an overall decrease in the annual incidence of antidepressant users in older adults over the last 16 years, with a marked decline in new amitriptyline use and an increase in the incidence of newer agents. PMID- 26925847 TI - [Oncocytoma versus chromophobe renal cell carcinoma: Is there something in between?]. AB - The differentiation of oncocytic tumors of the kidneys is often difficult, particularly in renal biopsies. Differential diagnoses are chromophobe renal cell carcinoma (ChRCC), renal oncocytoma (RO), the oncocytic variant of papillary renal cell carcinoma (OPRCC), the eosinophilic variant of clear cell renal cell carcinoma (CCRCC) and hybrid oncocytic chromophobe tumors (HOCT). In difficult cases that cannot be resolved by morphology alone, immunohistochemistry is usually helpful. The RO and ChRCC show positive reactions for CD117, they are negative for vimentin and alpha-methylacyl-CoA racemase (AMACR), while CCRCC are positive for vimentin and OPRCC are positive for AMACR. To distinguish between RO and ChRCC, CK7, claudin-7 (both strongly positive in ChRCC and negative or patchy positive in RO) and epithelial cell adhesion molecule (EpCAM) can be used (positive in ChRCC, negative in RO); however, a diagnosis may remain difficult in some cases even with the use of immunohistochemistry. Thus, numerous new methods are being developed in the field of molecular pathology and computer-based morphometric tumor analysis; however, these new methods have not yet been applied in routine diagnostics. PMID- 26925848 TI - Towards the bridging of molecular genetics data across Xenopus species. AB - BACKGROUND: The clawed African frog Xenopus laevis has been one of the main vertebrate models for studies in developmental biology. However, for genetic studies, Xenopus tropicalis has been the experimental model of choice because it shorter life cycle and due to a more tractable genome that does not result from genome duplication as in the case of X. laevis. Today, although still organized in a large number of scaffolds, nearly 85% of X. tropicalis and 89% of X. laevis genomes have been sequenced. There is expectation for a comparative physical map that can be used as a Rosetta Stone between X. laevis genetic studies and X. tropicalis genomic research. RESULTS: In this work, we have mapped using coarse grained alignment the 18 chromosomes of X. laevis, release 9.1, on the 10 reference scaffolds representing the haploid genome of X. tropicalis, release 9.0. After validating the mapping with theoretical data, and estimating reference averages of genome sequence identity, 37 to 44% between the two species, we have carried out a synteny analysis for 2,112 orthologous genes. We found that 99.6% of genes are in the same organization. CONCLUSIONS: Taken together, our results make possible to establish the correspondence between 62 and 65.5% of both genomes, percentage of identity, synteny and automatic annotation of transcripts of both species, providing a new and more comprehensive tool for comparative analysis of these two species, by allowing to bridge molecular genetics data among them. PMID- 26925849 TI - Enhanced topical delivery of tacrolimus by a carbomer hydrogel formulation with transcutol P. AB - Tacrolimus (TAC), a non-steroidal anti-inflammatory and immunosuppressive agent, is used for the treatment of atopic dermatitis (AD) and skin immune diseases. TAC loaded topical hydrogel formulations composed of carbomer, carnosine, transcutol P (diethylene glycol monoethyl ether) and humectant were prepared. For comparison, TAC-loaded topical cream-type formulations were also prepared and commercially available TAC ointment was used as a reference. A drug release study in vitro revealed that the total amount of TAC released from hydrogels over 24 h was approximately 30 times greater than that for the reference formulation. Compared to the reference ointment and creams, carbomer gel formulations showed higher skin permeation and retention of TAC (significantly different at p < 0.05), especially those with more than 10% of transcutol P. Therefore, carbomer gel formulations with sufficient levels of transcutol P are good candidates for skin delivery of TAC and have potential as therapeutic agents for the treatment of AD or immune skin disorders. PMID- 26925850 TI - A case of vulvar superficial angiomyxoma: A rare clinical entity. PMID- 26925851 TI - Baseline clinical predictors of an ultimate giant cell arteritis diagnosis in patients referred to temporal artery biopsy. AB - The diagnosis of giant cell arteritis (GCA) is based on clinical grounds and confirmed by characteristic histological findings on temporal artery biopsy (TAB). Patients may be diagnosed with GCA based on clinical grounds only, despite negative histological findings. We aimed to investigate which baseline clinical and laboratory features best predict an ultimate diagnosis of giant cell arteritis among patients referred to TAB. We retrospectively analyzed 224 patients who underwent TAB in our hospital between 2000 and 2014. Patients were diagnosed with GCA if TAB was positive for GCA, or by clinical grounds only despite a negative biopsy, provided they fulfilled the American College of Rheumatology 1990 criteria. Baseline clinical and laboratory features were obtained from medical records. Predictors of an ultimate GCA diagnosis were investigated. Overall, 82 patients were diagnosed with GCA-57 had histological evidence of GCA and 25 were diagnosed with GCA despite a negative biopsy. One hundred and forty-two patients were not diagnosed with GCA. Predictors of an eventual diagnosis of GCA in a multivariate logistic regression analysis were headache (OR = 6; p < 0.001), jaw claudication (OR 4.5; p = 0.007), erythrocyte sedimentation rate (ESR) (OR = 1.5; p = 0.032) and platelet count (OR = 1.74; p = 0.004). Among patients referred to TAB, headache, jaw claudication, ESR, and thrombocyte levels are predictors for an ultimate diagnosis of GCA. These clinical and laboratory features should be considered when contemplating the diagnosis and treatment of GCA. PMID- 26925852 TI - An assessment of the Chilean National Examination of Orthopaedic Surgery. AB - BACKGROUND: The Chilean National Examination of Orthopaedic Surgery (EMNOT) has been administered since 2009. It was developed to determine whether individual residents are meeting minimal knowledge standards at the end of their training programs. METHODS: We performed a retrospective evaluation of the EMNOT for all years it has been administered (2009-2015). The test was analyzed for content, taxonomy of questions asked (1: direct recall; 2: diagnosis; 3: evaluation/decision-making), residents' performance, difficulty index and discrimination index. RESULTS: During the years of EMNOT administration, the most frequently tested areas have been pediatric orthopaedics (22.9 %), spine (13.8 %), general orthopaedics (13.8 %) and musculoskeletal trauma (9.9 %). A significant increase in questions with images was observed, as well as a significant decrease in the percentage of Type 1 and an increase in Type 3 questions. The Difficulty Index showed a medium level of difficulty for all years the examination has been administered. The Discrimination Index showed good discrimination in 2009, fair discrimination from 2010 through 2012, and excellent discrimination from 2013 through 2015. CONCLUSION: The EMNOT has evolved over several years to include better quality questions, better discrimination, and a more representative distribution of questions covering the different orthopaedic sub-specialties. This examination represents an effective instrument for quality assurance of orthopaedic residency programs in Chile. PMID- 26925853 TI - Kinetics and Thermodynamics of Watson-Crick Base Pairing Driven DNA Origami Dimerization. AB - We investigate the kinetics and thermodynamics of DNA origami dimerization using flat rectangle origami components and different architectures of Watson-Crick complementary single-stranded DNA ("sticky end") linking strategies. We systematically vary the number of linkers, the length of the sticky ends on the linker, and linker architecture and measure the corresponding yields as well as forward and reverse reaction rate constants through fluorescence quenching assays. Yields were further verified using atomic force microscopy. We calculate values of H degrees and DeltaS degrees for various interface designs and find nonlinear van't Hoff behavior, best described by two linear equations, suggesting distinct regimes of dimerization between those with and those without well-formed interfaces. We find that self-assembly reactions can be tuned by manipulating the interface architecture without suffering a loss in yield, even when yield is high, ~75-80%. We show that the second-order forward reaction rate constant (k(on)) depends on both linker architecture and number of linkers used, with typical values on the order of 10(5)-10(6) (M.s)(-1), values that are similar to those of bimolecular association of small, complementary DNA strands. The k(on) values are generally non-Arrhenius, tending to increase with decreasing temperature. Finally, we use kinetic and thermodynamic information about the optimal linking architecture to extend the system to an infinite, two-component repeating lattice system and show that we can form micron-sized lattices, with well-formed structures up to 8 MUm(2). PMID- 26925854 TI - A 45-year-old Woman with Ehlers-Danlos Syndrome Caused by Dermatan 4-O sulfotransferase-1 Deficiency: Implications for Early Ageing. PMID- 26925855 TI - Ultra-Fast Layer-by-Layer Approach for Depositing Flame Retardant Coatings on Flexible PU Foams within Seconds. AB - In this letter, we are presenting a novel approach for the deposition of layer-by layer (LbL) coatings capable of conferring flame retardant properties to flexible polyurethane foams exploiting subsecond deposition times. The process yields nanoscale coatings able to reduce by 33% one of the main fire safety parameters, namely the heat release rate peak, with a total treatment time of only 2.5 s. This new approach turned out to be three to 4 orders of magnitude faster than conventional LbL treatments. Such results make it possible for the exploit of LbL as a competitive, efficient and ecofriendly technology at industrial scale. PMID- 26925856 TI - Reproductive health research of women migrants to Western countries: A systematic review for refining the clinical lens. AB - Influxes of migrant women of childbearing age to Western receiving countries have made their reproductive health a priority in those countries. Yet, providing optimal care to these women may be hampered by an inadequate volume or quality of research to inform practice. We reviewed reports of studies recently published to assess the extent to which current research is able to inform reproductive health care practices for migrant women (i.e., those born in countries other than the receiving country)--in so doing, we sought to offer a view of the landscape from which clinicians may interpret relevant publications. Additionally, we sought to identify topics for which clinicians may choose to advocate for additional research to be performed. PMID- 26925857 TI - Characterization of monoacylglycerol acyltransferase 2 inhibitors by a novel probe in binding assays. AB - Monoacylglycerol acyltransferase 2 (MGAT2) is a membrane-bound lipid acyltransferase that catalyzes the formation of diacylglycerol using monoacylglycerol and fatty acyl CoA as substrates. MGAT2 is important for intestinal lipid absorption and is an emerging target for the treatment of metabolic diseases. In the current study, we identified and characterized four classes of novel MGAT2 inhibitors. We established both steady state and kinetic binding assay protocols using a novel radioligand, [(3)H]compound A. Diverse chemotypes of MGAT2 inhibitors were found to compete binding of [(3)H]compound A to MGAT2, indicating the broad utility of [(3)H]compound A for testing various classes of MGAT2 inhibitors. In the dynamic binding assays, the kinetic values of MGAT2 inhibitors such as Kon, Koff, and T1/2 were systematically defined. Of particular value, the residence times of inhibitors on MGAT2 enzyme were derived. We believe that the identification of novel classes of MGAT2 inhibitors and the detailed kinetic characterization provide valuable information for the identification of superior candidates for in vivo animal and clinical studies. The current work using a chemical probe to define inhibitory kinetics can be broadly applied to other membrane-bound acyltransferases. PMID- 26925858 TI - Development of a True Transition State Force Field from Quantum Mechanical Calculations. AB - Transition state force fields (TSFF) treated the TS structure as an artificial minimum on the potential energy surface in the past decades. The necessary parameters were developed either manually or by the Quantum-to-molecular mechanics method (Q2MM). In contrast with these approaches, here we propose to model the TS structures as genuine saddle points at the molecular mechanics level. Different methods were tested on small model systems of general chemical reactions such as protonation, nucleophilic attack, and substitution, and the new procedure led to more accurate models than the Q2MM-type parametrization. To demonstrate the practicality of our approach, transferrable parameters have been developed for Mo-catalyzed olefin metathesis using quantum mechanical properties as reference data. Based on the proposed strategy, any force field can be extended with true transition state force field (TTSFF) parameters, and they can be readily applied in several molecular mechanics programs as well. PMID- 26925859 TI - Guidelines on What Constitutes Plagiarism and Electronic Tools to Detect it. AB - Plagiarism is a serious ethical problem among scientific publications. There are various definitions of plagiarism, and the major categories include unintentional (unsuitable paraphrasing or improper citations) and intentional. Intentional plagiarism includes mosaic plagiarism, plagiarism of ideas, plagiarism of text, and self-plagiarism. There are many Web sites and software packages that claim to detect plagiarism effectively. A violation of plagiarism laws can lead to serious consequences including author banning, loss of professional reputation, termination of a position, and even legal action. PMID- 26925860 TI - Understanding Competition in Spine Care. AB - The changing landscape from volume to value represents a natural transformation in the health care industry. Increasingly provider groups are finding themselves responding to unfamiliar market forces. Whether explicit or implicit, competition is playing a larger role for the sustainability of providers. For spine care providers who are attempting to navigate the transition from volume to value, understanding the forces that shape competition in health care can help achieve success. PMID- 26925861 TI - Myopathic mtDNA Depletion Syndrome Due to Mutation in TK2 Gene. AB - Whole-exome sequencing (WES) was used to identify the disease gene(s) in a Spanish girl with failure to thrive, muscle weakness, mild facial weakness, elevated creatine kinase (CK), deficiency of mitochondrial complex III and depletion of mtDNA. With WES data, it was possible to get the whole mtDNA sequencing and discard any pathogenic variant in this genome. The analysis of whole exome uncovered a homozygous pathogenic mutation in Thymidine kinase 2 gene (TK2; NM_004614.4:c.323C>T, p.T108M). TK2 mutations have been identified mainly in patients with the myopathic form of mtDNA depletion syndromes (MDS). This patient presents an atypical TK2 related-myopathic form of MDS, because despite having a very low content of mtDNA (<20%), she presents a slower and less severe evolution of the disease. In conclusion, our data confirm the role of TK2 gene in MDS and expanded the phenotypic spectrum. PMID- 26925862 TI - Raspberry-like PS/CdTe/Silica Microspheres for Fluorescent Superhydrophobic Materials. AB - Superhydrophobic particulate films were fabricated via deposition of raspberry like fluorescent PS/CdTe/silica microspheres on clean glass substrates and surface modification. Particularly, the fluorescent microspheres were prepared by a kind of modified strategy, namely introducing poly (acrylic acid) functionalized polystyrene microspheres and thiol-stabilized CdTe quantum dots into a hydrolysis reaction of tetraethoxysilane simultaneously. And through adjusting the reaction parameters, the polystyrene spheres with two particle sizes and three colors of CdTe quantum dots aqueous solution were obtained. Consequently, raspberry-like microspheres consist of polystyrene cores and the composite shells of CdTe quantum dots and silica. These microspheres possess a fluorescent characteristic and form a hierarchical dual roughness which was conductive to superhydrophobicity, and the hydrophobic tests also showed the contact angles of water droplets on the surface of the raspberry-like microspheres which were over 160 degrees at room temperature. PMID- 26925863 TI - Structural and Magnetic Properties of Transition-Metal-Doped Zn 1-x Fe x O. AB - The ability to produce high-quality single-phase diluted magnetic semiconductors (DMS) is the driving factor to study DMS for spintronics applications. Fe-doped ZnO was synthesized by using a low-temperature co-precipitation technique producing Zn 1-x Fe x O nanoparticles (x= 0, 0.02, 0.04, 0.06, 0.08, and 0.1). Structural, Raman, density functional calculations, and magnetic studies have been carried out in studying the electronic structure and magnetic properties of Fe-doped ZnO. The results show that Fe atoms are substituted by Zn ions successfully. Due to the small ionic radius of Fe ions compared to that of a Zn ions, the crystal size decreases with an increasing dopant concentration. First principle calculations indicate that the charge state of iron is Fe (2+) and Fe (3+) with a zinc vacancy or an interstitial oxygen anion, respectively. The calculations predict that the exchange interaction between transition metal ions can switch from the antiferromagnetic coupling into its quasi-degenerate ferromagnetic coupling by external perturbations. This is further supported and explains the observed ferromagnetic bahaviour at magnetic measurements. Magnetic measurements reveal that decreasing particle size increases the ferromagnetism volume fraction. Furthermore, introducing Fe into ZnO induces a strong magnetic moment without any distortion in the geometrical symmetry; it also reveals the ferromagnetic coupling. PMID- 26925864 TI - Surface Plasmon's Dispersion Properties of Porous Gold Films. AB - Nanostructure porous films with arrays of gold nanoparticles (Au NPs) have been produced by pulsed laser deposition. Dispersion properties of surface plasmons have been studied by the modulation-polarization spectroscopy technique. The dispersion relations for radiative modes and two types of non-radiative modes of localized and propagating surface plasmons were obtained. The branches of propagating modes were characterized by negative group velocity caused by spatial dispersion of dielectric function. The propagating modes are caused by dipole dipole interactions between adjacent Au NPs. The frequencies and relaxation parameters of surface plasmon resonances and the plasma frequencies for Alphau NPs were obtained. The relation between the surface plasmon's properties and formation conditions of films with arrays of Alphau NPs is discussed. PMID- 26925865 TI - The Two-Dimensional Nanocomposite of Molybdenum Disulfide and Nitrogen-Doped Graphene Oxide for Efficient Counter Electrode of Dye-Sensitized Solar Cells. AB - In this study, we reported the synthesis of the two-dimensional (2D) nanocomposite of molybdenum disulfide and nitrogen-doped graphene oxide (MoS2/nGO) as a platinum-free counter electrode (CE) for dye-sensitized solar cells (DSSCs). X-ray photoelectron spectroscopy (XPS), high-resolution transmission electron microscopy (HRTEM), and Raman spectroscopy were used to examine the characteristics of the 2D nanocomposite of MoS2/nGO. The cyclic voltammetry (CV), electrochemical impedance spectra (EIS), and the Tafel polarization measurements were carried out to examine the electrocatalytic abilities. XPS and Raman results showed the 2D behaviors of the prepared nanomaterials. HRTEM micrographs showed the direct evidence of the 2D nanocomposite of MoS2/nGO. The results of electrocatalytic examinations indicated the MoS2/nGO owning the low charge transfer resistance, high electrocatalytic activity, and fast reaction kinetics for the reduction of triiodide to iodide on the electrolyte-electrode interface. The 2D nanocomposite of MoS2/nGO combined the advantages of the high specific surface of nGO and the plenty edge sites of MoS2 and showed the promoted properties different from those of their individual constituents to create a new outstanding property. The DSSC with MoS2/nGO nanocomposite CE showed a photovoltaic conversion efficiency (PCE) of 5.95 % under an illumination of AM 1.5 (100 mW/cm(2)), which was up to 92.2 % of the DSSC with the conventional platinum (Pt) CE (PCE = 6.43 %). These results reveal the potential of the MoS2/nGO nanocomposite in the use of low-cost, scalable, and efficient Pt-free CEs for DSSCs. PMID- 26925866 TI - Synthesis of High-Aspect-Ratio Nickel Nanowires by Dropping Method. AB - A facile and high-yield route, dropping method, has been used to synthesize Ni nanowires (NWs) with a high aspect ratio. Compared to the conventional chemical reduction method, the diameter of Ni NWs prepared by the dropping method distinctively decreased and the surface roughness was improved. After optimizing the process parameters such as the Ni ion concentration and volume of the dropped NiCl2.6H2O solution, the diameter and aspect ratio of the NWs are 70 nm and ~600, respectively. The possible synthesized process of the dropping method was discussed. This work presents a preferred approach to fabricate high-quality one dimensional magnetic materials which have potential applications in electrochemical devices, magnetic sensors, and catalytic agents. PMID- 26925867 TI - Cardiac Output Monitoring Managing Intravenous Therapy (COMMIT) to Treat Emergency Department Patients with Sepsis. AB - OBJECTIVE: Fluid responsiveness is proposed as a physiology-based method to titrate fluid therapy based on preload dependence. The objectives of this study were to determine if a fluid responsiveness protocol would decrease progression of organ dysfunction, and a fluid responsiveness protocol would facilitate a more aggressive resuscitation. METHODS: Prospective, 10-center, randomized interventional trial. INCLUSION CRITERIA: suspected sepsis and lactate 2.0 to 4.0 mmol/L. Exclusion criteria (abbreviated): systolic blood pressure more than 90 mmHg, and contraindication to aggressive fluid resuscitation. INTERVENTION: fluid responsiveness protocol using Non-Invasive Cardiac Output Monitor (NICOM) to assess for fluid responsiveness (>10% increase in stroke volume in response to 5 mL/kg fluid bolus) with balance of a liter given in responsive patients. CONTROL: standard clinical care. OUTCOMES: primary-change in Sepsis-related Organ Failure Assessment (SOFA) score at least 1 over 72 h; secondary-fluids administered. Trial was initially powered at 600 patients, but stopped early due to a change in sponsor's funding priorities. RESULTS: Sixty-four patients were enrolled with 32 in the treatment arm. There were no significant differences between arms in age, comorbidities, baseline vital signs, or SOFA scores (P > 0.05 for all). Comparing treatment versus Standard of Care-there was no difference in proportion of increase in SOFA score of at least 1 point (30% vs. 33%) (note bene underpowered, P = 1.0) or mean preprotocol fluids 1,050 mL (95% confidence interval [CI]: 786 1,314) vs. 1,031 mL (95% CI: 741-1,325) (P = 0.93); however, treatment patients received more fluids during the protocol (2,633 mL [95% CI: 2,264-3,001] vs. 1,002 mL [95% CI: 707-1,298]) (P < 0.001). CONCLUSIONS: In this study of a "preshock" population, there was no change in progression of organ dysfunction with a fluid responsiveness protocol. A noninvasive fluid responsiveness protocol did facilitate delivery of an increased volume of fluid. Additional properly powered and enrolled outcomes studies are needed. PMID- 26925868 TI - Analysis copy number variation of Chinese children in early-onset epileptic encephalopathies with unknown cause. AB - Copy number variations (CNVs) play an important role in the genetic etiology of unknown cause early-onset epileptic encephalopathies (EOEEs), but the genomic CNVs analysis of Chinese EOEEs children was rare. Here, we identified CNVs by single nucleotide polymorphism array in 116 patients with different subtypes of EOEEs. Of 116 patients 17 (14.66%) carried 19 large CNVs. A total of 14 CNVs in 12 patients were further validated: four of the CNVs were classified as de novo, seven were maternal, and three were paternal. Follow-up of those 12 patients showed that 5 had been seizure-free for at least 9 months, 5 had seizures several times per month or per year, and 2 had seizures everyday. But eight patients have profound developmental delay. In this study, we found at least 3.4% of patients had pathogenic CNVs. For the patients, our study laid the foundation for prenatal interventions for their families. Further, we identified potential candidate gene involved in EOEEs. The association of CNVs and clinical features will contribute to the understanding of EOEEs. PMID- 26925869 TI - Biofilm formation increases treatment failure in Staphylococcus epidermidis device-related osteomyelitis of the lower extremity in human patients. AB - : The ability to form biofilm on the surface of implanted devices is often considered the most critical virulence factor possessed by Staphylococcus epidermidis in its role as an opportunistic pathogen in orthopaedic device related infection (ODRI). Despite this recognition, there is a lack of clinical evidence linking outcome with biofilm forming ability for S. epidermidis ODRIs. We prospectively collected S. epidermidis isolates cultured from patients presenting with ODRI. Antibiotic resistance patterns and biofilm-forming ability was assessed. Patient information was collected and treatment outcome measures were determined after a mean follow-up period of 26 months. The primary outcome measure was cure at follow-up. Univariate logistic regression models were used to determine the influence of biofilm formation and antibiotic resistance on treatment outcome. A total of 124 patients were included in the study, a majority of whom (n = 90) involved infections of the lower extremity. A clear trend emerged in the lower extremity cohort whereby cure rates decreased as the biofilm forming ability of the isolates increased (84% cure rate for infections caused by non-biofilm formers, 76% cure rate for weak biofilm-formers, and 60% cure rate for the most marked biofilm formers, p = 0.076). Antibiotic resistance did not influence treatment cure rate. Chronic immunosuppression was associated with a statistically significant decrease in cure rate (p = 0.044). CLINICAL SIGNIFICANCE: The trend of increasing biofilm-forming ability resulting in lower cure rates for S. epidermidis ODRI indicates biofilm-forming ability of infecting pathogens does influence treatment outcome of infections of the lower extremity. (c) 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1905-1913, 2016. PMID- 26925870 TI - Biological movement and the encoding of its motion and orientation. AB - Are you walking at me? Biological movement and the encoding of its motion and orientation. A person's motion conveys a wealth of information that ranges from the complex, such as intention or emotional state, to the simple, such as direction of locomotion. How we recognise and recover people's motion is addressed by models of biological motion processing. Single channel models propose that this occurs through the operation of form template neurons which respond to viewpoint dependent snapshots of posture. More controversially, a dual channel approach proposes a second stream containing motion template neurons sensitive to view dependent snapshots of biological movement's characteristic local velocity field. We used behavioural adaptation to look for the co-encoding of viewpoint and walker motion, a hallmark of motion template analysis. We show that opposite viewpoint aftereffects can simultaneously be induced for forwards and reversed walkers. This demonstrates that distinct populations of neurons encode forwards and reversed walking. To account for such aftereffects, these units must either be able to inhibit viewpoint-encoding neurons, or they must encode viewpoint directly. Whereas current single channel models would need extending to incorporate these characteristics, the idea that walker motion is encoded directly, such that viewpoint and motion are intrinsically interlinked, is a fundamental component of the dual channel model. PMID- 26925871 TI - Differential controls on soil carbon density and mineralization among contrasting forest types in a temperate forest ecosystem. AB - Understanding the controls on soil carbon dynamics is crucial for modeling responses of ecosystem carbon balance to global change, yet few studies provide explicit knowledge on the direct and indirect effects of forest stands on soil carbon via microbial processes. We investigated tree species, soil, and site factors in relation to soil carbon density and mineralization in a temperate forest of central China. We found that soil microbial biomass and community structure, extracellular enzyme activities, and most of the site factors studied varied significantly across contrasting forest types, and that the associations between activities of soil extracellular enzymes and microbial community structure appeared to be weak and inconsistent across forest types, implicating complex mechanisms in the microbial regulation of soil carbon metabolism in relation to tree species. Overall, variations in soil carbon density and mineralization are predominantly accounted for by shared effects of tree species, soil, microclimate, and microbial traits rather than the individual effects of the four categories of factors. Our findings point to differential controls on soil carbon density and mineralization among contrasting forest types and highlight the challenge to incorporate microbial processes for constraining soil carbon dynamics in global carbon cycle models. PMID- 26925872 TI - Low Other Cause Mortality Rates Reflect Good Patient Selection in Patients with Prostate Cancer Treated with Radical Prostatectomy. AB - PURPOSE: Treatment decisions in patients with prostate cancer are affected by patient age regardless of higher life expectancy compared to the baseline population. Our aim was to quantify cancer specific and other cause mortality rates after radical prostatectomy. MATERIALS AND METHODS: A total of 8,741 patients with prostate cancer underwent radical prostatectomy between 1992 and 2009 at a European center. Ten-year other cause and cancer specific mortality rates were determined by age and comorbidities, and age and Cancer of the Prostate Risk Assessment Post-Surgical (CAPRA-S) risk groups. Competing risk regression was used for risk factor analyses including clinical and pathological variables. RESULTS: Ten-year other cause mortality rates increased with patient age, including 4.8%, 9.8%, 13.6% and 16.5% in men younger than 60, 60 to 64, 65 to 69 and 70 years or older, respectively. Cancer specific mortality was the leading cause of death in CAPRA-S high risk cases regardless of age. On multivariate analyses age groups achieved independent predictor status for other cause mortality (ages 60 to 64 years HR 1.81, 95% CI 1.26-2.62, 65 to 69 years HR 2.48, 95% CI 1.73-3.56 and 70 years or greater HR 3.02, 95% CI 1.97-4.62) as well as Charlson comorbidity indexes 1 (HR 1.45, 95% CI 1.00-2.09) and 3 or greater (HR 3.99, 95% CI 1.57-10.1). Gleason score 3 + 4 and 4 + 3 or greater, pT3b stage, lymph node invasion and positive margin status achieved independent predictor status when the end point was cancer specific mortality. The CAPRA-S high risk constellation increased cancer specific mortality risk in multifold fashion (HR 26, 95% CI 16-56). CONCLUSIONS: In patients with the CAPRA-S high risk constellation the rate of cancer specific mortality increased in multifold fashion and contributed to most deaths regardless of patient age. Low other cause mortality rates in all age groups showed reasonable patient selection. PMID- 26925873 TI - Evaluation of Renal Function after Percutaneous Nephrolithotomy-Does the Number of Percutaneous Access Tracts Matter? AB - PURPOSE: Renal function following percutaneous nephrolithotomy has long been a concern to urologists, especially in the setting of multi-tract access. We determined whether the risk of renal injury after multi-tract percutaneous nephrolithotomy was greater than after a single access approach. MATERIALS AND METHODS: We retrospectively reviewed the records of 307 consecutive patients treated with percutaneous nephrolithotomy from 2011 to 2012 at Wake Forest Health. Perioperative (99m)Tc-mercaptoacetyltriglycine nuclear renogram parameters along with serum creatinine values were assessed within 1 year of the procedure. Patients were stratified by single access vs multi-access (2 or more). RESULTS: We identified 110 cases in which renography was done before and after percutaneous nephrolithotomy. A total of 74 patients (67.3%) underwent single access percutaneous nephrolithotomy while 36 (32.7%) underwent multi-access percutaneous nephrolithotomy. Serum creatinine did not significantly differ between the 2 cohorts postoperatively (p = 0.09). There was a significant 2.28% decrease in renal function based on mercaptoacetyltriglycine nuclear renogram results after percutaneous nephrolithotomy of the affected kidney in patients with multiple accesses (p <0.01). This relationship was not observed when patients were stratified by multiple comorbidities associated with nephrolithiasis. CONCLUSIONS: Multi-access percutaneous nephrolithotomy is associated with a small reduction in the function of the targeted kidney compared to a single access approach. PMID- 26925874 TI - Detection of Temperature Difference in Neuronal Cells. AB - For a better understanding of the mechanisms behind cellular functions, quantification of the heterogeneity in an organism or cells is essential. Recently, the importance of quantifying temperature has been highlighted, as it correlates with biochemical reaction rates. Several methods for detecting intracellular temperature have recently been established. Here we develop a novel method for sensing temperature in living cells based on the imaging technique of fluorescence of quantum dots. We apply the method to quantify the temperature difference in a human derived neuronal cell line, SH-SY5Y. Our results show that temperatures in the cell body and neurites are different and thus suggest that inhomogeneous heat production and dissipation happen in a cell. We estimate that heterogeneous heat dissipation results from the characteristic shape of neuronal cells, which consist of several compartments formed with different surface-volume ratios. Inhomogeneous heat production is attributable to the localization of specific organelles as the heat source. PMID- 26925875 TI - Paving the TRAIL to anti-fibrotic therapy. PMID- 26925876 TI - Synthetic RNA-protein modules integrated with native translation mechanisms to control gene expression in malaria parasites. AB - Synthetic posttranscriptional regulation of gene expression is important for understanding fundamental biology and programming new cellular processes in synthetic biology. Previous strategies for regulating translation in eukaryotes have focused on disrupting individual steps in translation, including initiation and mRNA cleavage. In emphasizing modularity and cross-organism functionality, these systems are designed to operate orthogonally to native control mechanisms. Here we introduce a broadly applicable strategy for robustly controlling protein translation by integrating synthetic translational control via a small-molecule regulated RNA-protein module with native mechanisms that simultaneously regulate multiple facets of cellular RNA fate. We demonstrate that this strategy reduces 'leakiness' to improve overall expression dynamic range, and can be implemented without sacrificing modularity and cross-organism functionality. We illustrate this in Saccharomyces cerevisae and the non-model human malarial parasite, Plasmodium falciparum. Given the limited functional genetics toolkit available for P. falciparum, we establish the utility of this strategy for defining essential genes. PMID- 26925877 TI - Understanding Conflicting Neuropathological Findings. PMID- 26925878 TI - The synthesis of pillar[5]arene functionalized graphene as a fluorescent probe for paraquat in living cells and mice. AB - As complex organisms vary in vivo, it remains a challenging task to get fluorescence 'turn on' imaging for special targets. To address this task, we have adopted a new strategy of inducing pillararene based host-guest interactions onto biocompatible graphene. By means of fluorescence competition displacement, hydrazino-pillar[5]arene modified graphene has been synthesized and provided as a 'turn on' probe for paraquat through monitoring of the fluorescence signal both in living cells and mice. PMID- 26925879 TI - Cognitive Impairment Predicts The Occurrence Of Hepatic Encephalopathy After Transjugular Intrahepatic Portosystemic Shunt. AB - OBJECTIVES: Hepatic encephalopathy (HE) is a major problem in patients treated with TIPS. The aim of the study was to establish whether pre-TIPS covert HE is an independent risk factor for the development of HE after TIPS. METHODS: Eighty-two consecutive cirrhotic patients submitted to TIPS were included. All patients underwent the PHES to identify those affected by covert HE before a TIPS. The incidence of the first episode of HE was estimated, taking into account the nature of the competing risks in the data (death or liver transplantation). RESULTS: Thirty-five (43%) patients developed overt HE. The difference of post TIPS HE was highly significant (P=0.0003) among patients with or without covert HE before a TIPS. Seventy-seven percent of patients with post-TIPS HE were classified as affected by covert HE before TIPS. Age: (sHR 1.05, CI 1.02-1.08, P=0.002); Child-Pugh score: (sHR 1.29, CI 1.06-1.56, P=0.01); and covert HE: (sHR 3.16, CI: 1.43-6.99 P=0.004) were associated with post-TIPS HE. Taking into consideration only the results of PHES evaluation, the negative predicting value was 0.80 for all patients and 0.88 for the patients submitted to TIPS because of refractory ascites. Thus, a patient with refractory ascites, without covert HE before a TIPS, has almost 90% probability of being free of HE after TIPS. CONCLUSIONS: Psychometric evaluation before TIPS is able to identify most of the patients who will develop HE after a TIPS and can be used to select patients in order to have the lowest incidence of this important complication. PMID- 26925880 TI - Breath Testing for Small Intestinal Bacterial Overgrowth: A Means to Enrich Rifaximin Responders in IBS Patients? PMID- 26925881 TI - Using an Electronic Medical Records Database to Identify Non-Traditional Cardiovascular Risk Factors in Nonalcoholic Fatty Liver Disease. AB - OBJECTIVES: Among adults with nonalcoholic fatty liver disease (NAFLD), 25% of deaths are attributable to cardiovascular disease (CVD). CVD risk reduction in NAFLD requires not only modification of traditional CVD risk factors but identification of risk factors unique to NAFLD. METHODS: In a NAFLD cohort, we sought to identify non-traditional risk factors associated with CVD. NAFLD was determined by a previously described algorithm and a multivariable logistic regression model determined predictors of CVD. RESULTS: Of the 8,409 individuals with NAFLD, 3,243 had CVD and 5,166 did not. On multivariable analysis, CVD among NAFLD patients was associated with traditional CVD risk factors including family history of CVD (OR 4.25, P=0.0007), hypertension (OR 2.54, P=0.0017), renal failure (OR 1.59, P=0.04), and age (OR 1.05, P<0.0001). Several non-traditional CVD risk factors including albumin, sodium, and Model for End-Stage Liver Disease (MELD) score were associated with CVD. On multivariable analysis, an increased MELD score (OR 1.10, P<0.0001) was associated with an increased risk of CVD. Albumin (OR 0.52, P<0.0001) and sodium (OR 0.96, P=0.037) were inversely associated with CVD. In addition, CVD was more common among those with a NAFLD fibrosis score >0.676 than those with a score <=0.676 (39 vs. 20%, P<0.0001). CONCLUSIONS: CVD in NAFLD is associated with traditional CVD risk factors, as well as higher MELD scores and lower albumin and sodium levels. Individuals with evidence of advanced fibrosis were more likely to have CVD. These findings suggest that the drivers of NAFLD may also promote CVD development and progression. PMID- 26925882 TI - What Is Value Stream Mapping, and How Can It Help My Practice? PMID- 26925884 TI - The Relationship Between Organizational Culture and Organizational Commitment in Zahedan University of Medical Sciences. AB - BACKGROUND & OBJECTIVE: Organizations effort is to achieve a common goal. There are many constructs needed for organizations. Organizational culture and organizational commitment are special concepts in management. The objective of the current research is to study the relationship between organizational culture and organizational commitment among the personnel of Zahedan University of Medical Sciences. MATERIALS & METHODS: This is a descriptive- correlational study. The statistical population was whole tenured staff of Zahedan University of Medical Sciences that worked for this organization in 2012-2013. Random sampling method was used and 165 samples were chosen. Two standardized questionnaires of the organizational culture (Schein, 1984) and organizational commitment (Meyer & Allen, 2002) were applied. The face and construct validity of the questionnaires were approved by the lecturers of Management and experts. Reliability of questionnaires of the organizational culture and organizational commitment were 0.89 and 0.88 respectively, by Cronbach's Alpha coefficient. All statistical calculations performed using Statistical Package for the Social Sciences version 21.0 (SPSS Inc., Chicago, IL, USA). The level of significance was set at P<0.05. FINDINGS: The findings of the study showed that there was a significant relationship between organizational culture and organizational commitment (P value=0.027). Also, the results showed that there was a significant relation between organizational culture and affective commitment (P-value=0.009), organizational culture and continuance commitment (P-value=0.009), and organizational culture and normative commitment (P-value=0.009). PMID- 26925885 TI - Barriers in Implementing E-Learning in Hormozgan University of Medical Sciences. AB - BACKGROUND: E-learning provides an alternative way for higher educational institutes to deliver knowledge to learners at a distance, rather than the traditional way. The aim of this study is to identify the barrier factors of e learning programs in Hormozgan University of Medical Sciences (HUMS) in respect of the students and lecturers' point of view. METHODS: A cross-sectional study based on a questionnaire was conducted among 286 of students and lecturers in the nursing, midwifery and paramedic schools of HUMS. Two hundred and eighty-six participants filled in the questionnaire: 256 students, and 30 lecturers. RESULTS: Results of the study showed a lack of proper training in e-learning courses of the university 182 (69.1%), limited communication with the instructor 174 (68%) and the learners dominance of English language 174 (68%) showed the greatest importance for the students. The awareness about e-learning program was 80% and 43% among lecturers and students respectively.The dominance of English language 26 (86.7%) and lack of research grants for e-learning 23 (76.6%) and lack of proper training on e-learning courses from the university 20 (66.7 %) were the most important barrier factors of implementing e-learning for lecturers. E-learning courses to supplement classroom teaching was a solution that mentioned by the majority of students 240 (93.8%) and lecturers 29 (96.7%) in this study. CONCLUSIONS: The positive perception of e-learning is an important consequence effect in the future, educational development of nursing, midwifery and paramedic schools. PMID- 26925883 TI - ACG Clinical Guideline: Management of Patients With Acute Lower Gastrointestinal Bleeding. AB - This guideline provides recommendations for the management of patients with acute overt lower gastrointestinal bleeding. Hemodynamic status should be initially assessed with intravascular volume resuscitation started as needed. Risk stratification based on clinical parameters should be performed to help distinguish patients at high- and low-risk of adverse outcomes. Hematochezia associated with hemodynamic instability may be indicative of an upper gastrointestinal (GI) bleeding source and thus warrants an upper endoscopy. In the majority of patients, colonoscopy should be the initial diagnostic procedure and should be performed within 24 h of patient presentation after adequate colon preparation. Endoscopic hemostasis therapy should be provided to patients with high-risk endoscopic stigmata of bleeding including active bleeding, non-bleeding visible vessel, or adherent clot. The endoscopic hemostasis modality used (mechanical, thermal, injection, or combination) is most often guided by the etiology of bleeding, access to the bleeding site, and endoscopist experience with the various hemostasis modalities. Repeat colonoscopy, with endoscopic hemostasis performed if indicated, should be considered for patients with evidence of recurrent bleeding. Radiographic interventions (tagged red blood cell scintigraphy, computed tomographic angiography, and angiography) should be considered in high-risk patients with ongoing bleeding who do not respond adequately to resuscitation and who are unlikely to tolerate bowel preparation and colonoscopy. Strategies to prevent recurrent bleeding should be considered. Nonsteroidal anti-inflammatory drug use should be avoided in patients with a history of acute lower GI bleeding, particularly if secondary to diverticulosis or angioectasia. Patients with established high-risk cardiovascular disease should not stop aspirin therapy (secondary prophylaxis) in the setting of lower GI bleeding. [corrected]. The exact timing depends on the severity of bleeding, perceived adequacy of hemostasis, and the risk of a thromboembolic event. Surgery for the prevention of recurrent lower gastrointestinal bleeding should be individualized, and the source of bleeding should be carefully localized before resection. PMID- 26925886 TI - The Relationship Between Periodontal Disease and Public Health: A Population Based Study. AB - BACKGROUND: Periodontal diseases, such as periodontitis, are considered the main cause of tooth loss in the elderly.The present study is aimed to determine the relationship between periodontal condition and quality of life. Quality of life consists of a range of people's objective needs related to the self-perception of well-being. METHODS: This study was done from January 2014 to June 2015 in a healthcare clinic in Zahedan, southeast Iran. Using the random sampling method, the researchers enrolled 700 individuals over 35 years of age. The participants initially completed a demographic questionnaire consisting of data, such as age, sex, educational level, and smoking habit. Then, the periodontal chart was completed. Moreover, patients, based on the number of their natural teeth, were divided into two groups (>=10 teeth in both maxillary and mandible arches and <10 teeth in at least one arch). The body mass index (BMI) was also measured.To assess the participants' general health, the WHO's quality of life questionnaire (WHOQOL-BREF) was used. RESULTS: Of the 700 enrolled individuals, 53.3% were womenand 47.7% were men. Moreover, most of the participants (63.71%) had BMI of less than 25 and 68% did not smoke.We found that as the people's periodontal status deteriorated, their quality of life also declined and the total mean score in all four health domains decreased (P<0.001).Moreover, people with more than 10 teeth in both arches scored higher with respect to life quality than those with less than 10 teeth in at least one arch (P<0.001). CONCLUSION: This studyindicates a decrease in the general quality of life in patients with periodontal disease.The authors suggest performing studies with larger sample sizes andcohort studies for more reliable results. PMID- 26925887 TI - Challenges of Transcultural Caring Among Health Workers in Mashhad-Iran: A Qualitative Study. AB - BACKGROUND: One of the consequences of migration is cultural diversity in various communities. This has created challenges for healthcare systems. OBJECTIVES: The aim of this study is to explore the health care staffs' experience of caring for Immigrants in Mashhad- Iran. SETTING: This study is done in Tollab area (wherein most immigrants live) of Mashhad. Clinics and hospitals that immigrants had more referral were selected. PARTICIPANTS: Data were collected through in-depth interviews with medical and nursing staffs. 15 participants (7 Doctors and 8 Nurses) who worked in the more referred immigrants' clinics and hospitals were entered to the study. DESIGN: This is a qualitative study with content analysis approach. Sampling method was purposive. The accuracy and consistency of data were confirmed. Interviews were conducted until no new data were emerged. Data were analyzed by using latent qualitative content analysis. RESULTS: The data analysis consisted of four main categories; (1) communication barrier, (2) irregular follow- up, (3) lack of trust, (4) cultural- personal trait. CONCLUSION: Result revealed that health workers are confronting with some trans- cultural issues in caring of immigrants. Some of these issues are related to immigration status and some related to cultural difference between health workers and immigrants. These issues indicate that there is transcultural care challenges in care of immigrants among health workers. Due to the fact that Iran is the context of various cultures, it is necessary to consider the transcultural care in medical staffs. The study indicates that training and development in the area of cultural competence is necessary. PMID- 26925888 TI - Knowledge, Attitude, and Self Care Practices Amongsts Patients WithType 2 Diabetes in Pakistan. AB - BACKGROUND: In this age, diabetes is one of the most prevalent, incurable diseases present. The aim of this study was to assess knowledge, attitude and self-care practicesrelated to diabetes in an urban population in Pakistan. METHODS: A cross sectional survey to assess the knowledge and practices of people with diabetes was conducted in general urbanpopulace. People with diabetes were interviewed using a structured questionnaire from which data was collected. A total of 139 diabetics were included into the study. Basic knowledge about diabetes and its complications were assessed as well as the frequency of practices such as keeping a blood glucometer at home and checking blood sugar with it. RESULTS: A total of n=139 participants fulfilling the inclusion criteria were recruited in the survey. Only 18.7% had knowledge regarding the complications of diabetes mellitus. Only 8.6% of participants checked their blood glucose levels at homeregularly, and only 4.3% visited their physiciansregularlyfor check-ups. With regard to practices, a minority attested to have changed their lifestyle and commit to basic practices in order to reduce diabetes related complications with women being more prone to changes than men. CONCLUSION: The results show that most participants had a negative attitude and very little knowledge regarding diabetes.There is a need for increased diabetes related education and for developing positive attitudes towards reduction of diabetes related complications. The Pakistani population is seen to be almost completely unprepared to fight against an increase in type 2 diabetes prevalence. PMID- 26925889 TI - Birthweight Related Factors in Northwestern Iran: Using Quantile Regression Method. AB - INTRODUCTION: Birthweight is one of the most important predicting indicators of the health status in adulthood. Having a balanced birthweight is one of the priorities of the health system in most of the industrial and developed countries. This indicator is used to assess the growth and health status of the infants. The aim of this study was to assess the birthweight of the neonates by using quantile regression in Zanjan province. METHODS: This analytical descriptive study was carried out using pre-registered (March 2010 - March 2012) data of neonates in urban/rural health centers of Zanjan province using multiple stage cluster sampling. Data were analyzed using multiple linear regressions andquantile regression method and SAS 9.2 statistical software. RESULTS: From 8456 newborn baby, 4146 (49%) were female. The mean age of the mothers was 27.1+/ 5.4 years. The mean birthweight of the neonates was 3104 +/- 431 grams. Five hundred and seventy-three patients (6.8%) of the neonates were less than 2500 grams. In all quantiles, gestational age of neonates (p<0.05), weight and educational level of the mothers (p<0.05) showed a linear significant relationship with the i of the neonates. However, sex and birth rank of the neonates, mothers age, place of residence (urban/rural) and career were not significant in all quantiles (p>0.05). CONCLUSION: This study revealed the results of multiple linear regression and quantile regression were not identical. We strictly recommend the use of quantile regression when an asymmetric response variable or data with outliers is available. PMID- 26925890 TI - Prevalence and Risk Factors of Osteoporosis in Women Referring to the Bone Densitometry Academic Center in Urmia, Iran. AB - BACKGROUND: Osteoporosis is one of the fastest growing health problems around the world. Several factors can affect this silent disease. The current study aimed to determine the prevalence and risk factors of osteoporosis in women in Urmia, a city in northwestern Iran. METHODS: This cross-sectional study was performed on 360 non-pregnant women over the age of 15 who referred for bone density testing to the Urmia Imam Khomeini Academic Hospital. Data were collected by questionnaire, and bone mineral density of the femoral neck and lumbar spines L1- L4 was evaluated by dual X-ray absorptiometry. RESULTS: The total prevalence of osteoporosis in this study was 42.2%; prevalence of osteoporosis among women 45 years old or less was 14.3% and over the age of 45 years was 50.7%. The factors such as level of education, history of bone fracture, disease history (rheumatoid arthritis, diabetes, high blood pressure), gravidity and parity values, duration of lactation (p<0.001), nutrition dimension of lifestyle (p=0.03), and green tea consumption (p=002) showed a statistically significant association with the bone mineral density. According to the regression model, age (OR=1.081), history of bone fracture (OR=2.75), and gravidity (OR=1.14) were identified as significant risk factors for osteoporosis, while the body mass index (OR=0.94) was identified as a protector against osteoporosis. CONCLUSION: The prevalence of osteoporosis in this study was high, and findings showed that the advancement of age, lifestyle, and reproductive factors (especially gravidity and duration of lactation) were determining factors for osteoporosis .Appropriate educational programs and interventions could help to increase the women's peak bone mass therefore reducing their risk of developing osteoporosis. PMID- 26925891 TI - Leukemia-Related Mortality in Inner Mongolia, 2008-2012. AB - In this study, we aimed to determine the leukemia-related mortality rates and associated sociodemographic characteristics in the Inner Mongolia region of China. We obtained data for the period 2008-2012 from the Death Registry System maintained by the Inner Mongolia Centers for Disease Control and Prevention. We computed the percentages of leukemia-related deaths and controls diagnosed by various methods and at different levels of hospitals. The chi(2) test was used to examine differences in leukemia-related mortality according to sex. We also calculated potential years of life lost (PYLL) and average years of life lost. Unconditional logistic regression models were used to analyze the effect of sociodemographic characteristics. The sex-adjusted leukemia-related mortality rate was 3.74/100 000. The mortality rate in men (4.27/100 000) was significantly higher than that in women (3.17/100 000), as was the respective PYLL (8040.5 vs. 6000.5 person-years). Mortality increased with increasing age in both men and women. The highest mortality rate was observed in those over 70 years of age for both men (18.36/100 000) and women (7.68/100 000). Men with a higher education level showed an increased risk of leukemia (odds ratio [OR] = 1.45, 95% confidence interval [CI] = 1.02-2.07, P = 0.04). In men, unemployment was associated with leukemia-related death (OR = 0.63, 95% CI = 0.42-0.95, P = 0.03). The leukemia-related mortality rate in Inner Mongolia was higher than that worldwide and that in China. A higher level of education and unemployment were associated with leukemia-related mortality in Inner Mongolia. PMID- 26925892 TI - Blood Samples of Peripheral Venous Catheter or The Usual Way: Do Infusion Fluid Alters the Biochemical Test Results? AB - BACKGROUND: Most blood tests require venous blood samples. Puncturing the vein also causes pain, infection, or damage to the blood, and lymph flow, or long-term healing. This study aimed to determine and compare the biochemical laboratory value of the blood samples that were provided through: peripheral vein infusion (PVI) receiving continuous intravenous fluid; and the usual method of blood sampling. METHODS: This is an interventional, quasi-experimental, and controlled study. The selected study sample included 60 patients, who were hospitalized during 2014, in the Internal Medicine, part of Martyrs of Persian Gulf, teaching hospital at Bushehr. Three blood samples were taken from each patient that were provided through PVI line (5 ml blood collected at beginning of IVC and then another 5 cc), and another case was prepared by common blood sampling (control). All the samples were analyzed in terms of sodium, potassium, urea and creatinine using SPSS Ver.19 software, by paired t-test and Pearson's correlation coefficients. RESULTS: There was a statistically significant difference between the amount of sodium and potassium in the first blood samples taken from the intravenous infusion line and vein puncture .However, no significant differences were found among the biochemical amount in the second blood samples taken from the intravenous infusion line and vein puncture. CONCLUSIONS: We can use blood samples taken from peripheral intravenous infusion lines after 5cc discarding from the first part of the sample for measuring the value of sodium, potassium, urea and creatinine. PMID- 26925893 TI - Barriers to HIV Testing Among Young Men Who Have Sex With Men (MSM): Experiences from Clark County, Nevada. AB - Clark County, Nevada had a 52% increase in newly diagnosed HIV infections in young people age 13-24 with 83% of the new diagnoses in this age group being men who have sex with men (MSM). HIV testing and counseling is critical for HIV prevention, care and treatment, yet young people are the least likely to seek HIV testing. The purpose of this study was to identify barriers and facilitators to HIV testing experienced by young MSM in Clark County, Nevada. We conducted a qualitative focus group discussion to identify barriers and facilitators to HIV testing among eleven young MSM in March, 2015. The primary barrier to HIV testing identified by the group was a lack of awareness or knowledge about testing for HIV. Other barriers within the person included: fear of results, fear of rejection, and fear of disclosure. Barriers identified within the environment included: access issues, stigma, and unfriendly test environments for young people. In addition to increasing awareness, intervention to increase HIV testing among MSM young people should incorporate access to testing in environments where the adolescents are comfortable and which reduces stigma. HIV testing sites should be convenient, accessible and young person/gay friendly. PMID- 26925894 TI - Virginity Testing Beyond a Medical Examination. AB - Apart from religious values, virginity is important in different communities because of its prominent role in reducing sexually transmitted diseases and teen pregnancies. Even though virginity testing has been proclaimed an example of violence against women by the World Health Organization, it is still conducted in many countries, including Iran. 16 in-depth, semi-structured interviews were conducted with participants aged 32 to 60 years to elucidate the perceptions and experiences of Iranian examiners of virginity testing.The perception and experience of examiners were reflected in five main themes. The result of this study indicated that virginity testing is more than a medical examination, considering the cultural factors involved and its overt and covert consequences. In Iran, testing is performed for both formal and informal reasons, and examiners view such testing with ambiguity about the accuracy and certainty of the diagnosis and uncertainty about ethics and reproductive rights. Examiners are affected by the overt and covert consequences of virginity testing, beliefs and cultural values underlying virginity testing, and informal and formal reasons for virginity testing. PMID- 26925895 TI - The Effect of Stress Management Training on Hope in Hemodialysis Patients. AB - INTRODUCTION: Chronic renal failure exposes patients to the risk of several complications, which will affect every aspect of patient's life, and eventually his hope. This study aims to determine the effect of stress management group training on hope in hemodialysis patients. METHOD: In this quasi-experimental single-blind study, 50 patients with renal failure undergoing hemodialysis at Motahari Hospital in Jahrom were randomly divided into stress management training and control groups. Sampling was purposive, and patients in stress management training group received 60-minute in-person training by the researcher (in groups of 5 to 8 patients) before dialysis, over 5 sessions, lasting 8 weeks, and a researcher-made training booklet was made available to them in the first session. Patients in the control group received routine training given to all patients in hemodialysis department. Patients' hope was recorded before and after intervention. Data collection tools included demographic details form, checklist of problems of hemodialysis patients and Miller hope scale (MHS). Data were analyzed in SPSS-18, using Chi-square, one-way analysis of variance, and paired t test. RESULTS: Fifty patients were studied in two groups of 25 each. No significant difference was observed between the two groups in terms of age, gender, or hope before intervention. After 8 weeks of training, hope reduced from 95.92+/-12.63 to 91.16+/-11.06 (P=0.404) in the control group, and increased from 97.24+/-11.16 to 170.96+/-7.99 (P=0.001) in the stress management training group. Significant differences were observed between the two groups in hope scores after the intervention. CONCLUSION: Stress management training by nurses significantly increased hope in hemodialysis patients. This low cost intervention can be used to improve hope in hemodialysis patients. PMID- 26925896 TI - The Effect of Omega-3 Fatty Acids in Patients With Active Rheumatoid Arthritis Receiving DMARDs Therapy: Double-Blind Randomized Controlled Trial. AB - BACKGROUND: Rheumatoid arthritis is a symmetric peripheral polyarthritis of unknown etiology that, untreated or if unresponsive the therapy, typically leads to deformity and destruction of joints due to erosion of cartilage and bone. Omega-3 fatty acids have been shown to reduce morning stiffness, the number of tender joints and swollen joints in patients with rheumatoid arthritis. This study is designed for evaluation of omega-3 effects on disease activity and remission of rheumatoid arthritis in DMARDs treated patients and on weight changes and reduction of analgesic drugs consumption versus placebo. METHODS: Sixty patients with active rheumatoid arthritis (49 female and 11 male) underwent rheumatologist examination and disease activity score were calculated. Then patients were enrolled in this 12 week, double blind, randomized, placebo- controlled study. The patients in both groups continued their pre study standard treatment. The patients were visited every 4 weeks, 4 times and data were recorded. RESULTS: Significant improvement in the patient's global evaluation and in the physician's assessment of disease was observed in those taking omega-3. The proportions of patients who improved and of those who were able to reduce their concomitant analgesic medication were significantly greater with omega-3 consumption. There were no weight changes. CONCLUSION: Daily supplementation with omega-3 results has significant clinical benefit and may reduce the need for concomitant analgesic consumption without weight changes. PMID- 26925897 TI - Effect of an Ergonomics-Based Educational Intervention Based on Transtheoretical Model in Adopting Correct Body Posture Among Operating Room Nurses. AB - BACKGROUND: One of the preventive strategies for chronic low back pain among operating room nurses is instructing proper body mechanics and postural behavior, for which the use of the Transtheoretical Model (TTM) has been recommended. METHODS: Eighty two nurses who were in the contemplation and preparation stages for adopting correct body posture were randomly selected (control group = 40, intervention group = 42). TTM variables and body posture were measured at baseline and again after 1 and 6 months after the intervention. A four-week ergonomics educational intervention based on TTM variables was designed and conducted for the nurses in the intervention group. RESULTS: Following the intervention, a higher proportion of nurses in the intervention group moved into the action stage (p < 0.05). Mean scores of self-efficacy, pros, experimental processes and correct body posture were also significantly higher in the intervention group (p < 0.05). No significant differences were found in the cons and behavioral processes, except for self-liberation, between the two groups (p > 0.05) after the intervention. CONCLUSIONS: The TTM provides a suitable framework for developing stage-based ergonomics interventions for postural behavior. PMID- 26925898 TI - Impact of Helicobacter pylori Eradication Therapy on Platelet Counts in Patients With Chronic Idiopathic Thrombocytopenic Purpura. AB - This study was a before and after clinical evaluation of Helicobacter pylori eradication on platelet counts in a group of 23 patients with chronic Idiopathic (Autoimmune) thrombocytopenic purpura (CITP). H. pylori infection was identified in patients by a (13)C-urea breath test and confirmed by an H. pylori stool antigen test. Eradication was conducted in patients testing positive. Infected (n = 10) and uninfected (n = 13) patient groups did not differ with respect to age, gender, history of previous splenectomy, treatment with anti-D, current treatment with corticosteroids, or initial platelet counts. H pylori eradication was successful in eight infected CITP patients, with two patients not responsive to treatment. Compared to the uninfected group, patients in the infected group who responded to eradication therapy had significantly increased platelet counts after six months (56.2 +/- 22.2 vs. 233 +/- 85.6 *10(3) million cells/L; P < 0.01), whereas platelet counts in the non-responding patients and uninfected group did not differ after this period of time. H. pylori eradication promotes significant platelet count improvement in patients with CITP. Thus, all patients with CITP should be tested and treated for H. pylori infections. PMID- 26925899 TI - Preterm Birth Prevention: Effects of Vaginal Progesterone Administration on Blood Flow Impedance in Uterine-Fetal Circulation by Doppler Sonography. AB - OBJECTIVE: The present study aimed to evaluate the effect of vaginal progesterone administration on maternal and fetal circulation to prevent preterm birth. METHODS: The present prospective study was conducted on 35 women with singleton pregnancy at 18-33 weeks of gestation, who presented with at least one episode of preterm labor or asymptomatic short cervix, or past medical history of preterm birth. Doppler flow and Pulsatility Index (PI) assessment of the umbilical artery, fetal middle cerebral artery, uterine arteries, and ductusvenosus were performed before and 72 h after vaginal progesterone administration. RESULTS: Results showed a significant reduction in the PI of the uterine artery following progesterone administration. Nevertheless, no significant changes were observed in the PI of other vessels. No significant difference was found in Doppler flow parameters in any of the examined vessels before or after progesterone treatment in women with Preterm Labor Pain (PLP). Yet, a statistically significant association was observed between short cervix complication in the current pregnancy and medical history of PLP in the previous pregnancy. CONCLUSION: Treatment with vaginal progesterone reduced the PI in the uterine arteries in the second and third trimesters of pregnancy. Thus, this medication may have useful vasodilatory effects on uterine-fetal vessels. PMID- 26925900 TI - Prediction of Depression in Cancer Patients With Different Classification Criteria, Linear Discriminant Analysis versus Logistic Regression. AB - BACKGROUND: Logistic regression (LR) and linear discriminant analysis (LDA) are two popular statistical models for prediction of group membership. Although they are very similar, the LDA makes more assumptions about the data. When categorical and continuous variables used simultaneously, the optimal choice between the two models is questionable. In most studies, classification error (CE) is used to discriminate between subjects in several groups, but this index is not suitable to predict the accuracy of the outcome. The present study compared LR and LDA models using classification indices. METHODS: This cross-sectional study selected 243 cancer patients. Sample sets of different sizes (n = 50, 100, 150, 200, 220) were randomly selected and the CE, B, and Q classification indices were calculated by the LR and LDA models. RESULTS: CE revealed the a lack of superiority for one model over the other, but the results showed that LR performed better than LDA for the B and Q indices in all situations. No significant effect for sample size on CE was noted for selection of an optimal model. Assessment of the accuracy of prediction of real data indicated that the B and Q indices are appropriate for selection of an optimal model. CONCLUSION: The results of this study showed that LR performs better in some cases and LDA in others when based on CE. The CE index is not appropriate for classification, although the B and Q indices performed better and offered more efficient criteria for comparison and discrimination between groups. PMID- 26925901 TI - Effectiveness of Blind & Ultrasound Guided Corticosteroid Injection in Impingement Syndrome. AB - Local steroid injections are common for treatment of impingement syndrome. Corticosteroid injections methods are basically in two formats, blind or with image guidance. The aim of this study is to compare the effect of ultrasound guided in comparison with blind corticosteroid injections in patients with impingement syndrome. This study is a randomized clinical trial study undertaken in patients with diagnosis of impingement syndrome done in Isfahan University of Medical Science clinics from February 2014 to February 2015. The number of all patients registered in the study is 48; and then 40 patients were allocated to either control group randomly which received blind steroid injection or case group that underwent ultrasound-guided steroid injection. The clinical symptoms were assessed using Shoulder Pain and Disability Index (SPADI) questionnaire, Visual Analogue Scale (VAS) and shoulder range of motion (ROM) using goniometer at baseline and six weeks after the injection. Data analysis revealed a significant difference in the mean of the VAS, SPADI and shoulder ROM in both groups 6 weeks after intervention (P < 0.05). Patients with ultrasound guided corticosteroid injection had statistically significant improvements in function and shoulder ROM (abduction, flexion) compared to blind injection group after 6 weeks (P<0.05). There was not significant differences in pain (VAS) and internal and external rotation between these two groups (p>0.05). Our findings suggest that US image guided can improve the shoulder function of patients with impingement syndrome, and thus can be considered in comprehensive care programs of these patients for fast speed of rehabilitation. PMID- 26925902 TI - Residual Barriers for Utilization of Maternal and Child Health Services: Community Perceptions From Rural Pakistan. AB - Low utilization of maternal and child care services in rural areas has constrained Pakistan from meeting targets of Millennium Development Goals (MDGs) 4 and 5. This study explores community barriers in accessing Maternal and Child Health (MCH) services in ten remote rural districts of Pakistan. It further presents how the barriers differ across a range of MCH services, and also whether the presence of Community Health Workers (CHWs) reduces client barriers. Qualitative methods were used involving altogether sixty focus group discussions with mothers, their spouses and community health workers. Low awareness, formidable distances, expense, and poorly functional services were the main barriers reported, while cultural and religious restrictions were lesser reported. For preventive services including antenatal care (ANC), facility deliveries, postnatal care (PNC), childhood immunization and family planning, the main barrier was low awareness. Conversely, formidable distances and poorly functional services were the main reported constraints in the event of maternal complications and acute child illnesses. The study also found that clients residing in areas served by CHWs had better awareness only of ANC and family planning, while other MCH services were overlooked by the health worker program. The paper highlights that traditional policy emphasis on health facility infrastructure expansion is not likely to address poor utilization rates in remote rural areas. Preventive MCH services require concerted attention to building community awareness, task shifting from facility to community for services provision, and re-energization of CHW program. For maternal and child emergencies there is strong community demand to utilize health facilities, but this will require catalytic support for transport networks and functional health care centers. PMID- 26925903 TI - Alcohol Abuse and Suicide Attempt in Iran: A Case-Crossover Study. AB - Alcohol use and its disorders are associated with increased risk of suicidal behaviors Research has shown that 6-8% of those who use alcohol have a history of suicide attempt. Given the prohibition of alcohol use legally, the increased alcohol consumption, and the lack of strong evidence in favor of its use associated with suicide in Iran, this study was conducted to determine the link between suicide attempt and alcohol abuse. The case-crossover method was used in this research. Out of 305 referrals to the emergency room due to a suicide attempt, 100 reported drinking alcohol up to six hours before their attempt. Paired Matching and Usual Frequency were employed to analyze the data with STATA 12.0. The probability of attempting suicide up to six hours after drinking alcohol appeared increased by 27 times (95% CI: 8.1-60.4). Separate analysis for each of these hours from the first to the sixth hour after alcohol use was also performed. Fifty percent of attempted suicides happened one hour after alcohol use. Relative risk for the first and second hour was 10% and 5% respectively. Alcohol use is a strong proximal risk factor for attempted suicide among Iranian subjects. Prevention of alcohol use should be considered in setting up of the national Suicide attempt prevention program. PMID- 26925904 TI - Evaluation of the Criteria for Quality of Life of Elderly Health Care Centers in Tehran Province, Iran. AB - BACKGROUND & OBJECTIVES: The objective of this study was to evaluate the elderly quality of life of people covered by the healthcare centers in Tehran and its influencing demographic and background factors. METHOD: This is a cross-sectional study of quality of life of the elderly population covered by healthcare centers and bases in Tehran, as well as the influential background and demographic factors. Sampling was performed using simple random stratified sampling proportionate to the size of strata. Data were collected using the Iranian version of the standard questionnaire Short Form Health Survey (SF-36). RESULTS: According to the findings, 240 (60%) of the cases were men and 160 (40%) were women. Regarding age distribution, 76.3% fell in the 60-69 age range and 87.2% were illiterate. 18% of the elderly stated that they have financial problems and 19.5% did not express any financial problems. While studying the relationship between financial status and health status with the mean scores of quality of life, statistically significant differences were observed in all domains (p=0.032<0.001). The mean quality of life was lower in women compared to men. CONCLUSIONS: The findings of the present study indicate that the health-related quality of life in the elderly population is influenced by their health status and demographic and background variables. PMID- 26925905 TI - Different Nursing Care Methods for Prevention of Keratopathy Among Intensive Care Unit Patients. AB - BACKGROUND: Patients with reduced consciousness level suffer from eye protection disorder and Keratopathy. This study was conducted to compare effect of three eye care techniques in prevention of keratopathy in the patients hospitalized in intensive care unit of Kermanshah. METHODS: This clinical trial was conducted in 2013 with sample size of 96 persons in three random groups. Routine care included washing of eyes with normal saline and three eye care methods were conducted with poly ethylene cover, liposic ointment, and artificial tear drop randomly on one eye of each sample and a comparison was made with the opposite eye as the control. Eyes were controlled for 5 days in terms of keratopathy. Data collection instrument was keratopathy severity index. Data statistical analysis was performed with SPSS-16 software and chi-squared test, Fisher's exact test, ANOVA and Kruskal-Wallis one-way analysis of variance. FINDINGS: The use of poly ethylene cover (0.59+/-0.665) was significantly more effective in prevention of keratopathy than other methods (P=0.001). There was no statistically significant difference between two care interventions of liposic ointment and artificial tear drop (P=0.844) but the results indicated the more effective liposic ointment (1.13+/-0.751) than the artificial tear drop (1.59+/-0.875) in prevention of corneal abrasion (P>0.001). CONCLUSION: Results of the study suggest the use of poly ethylene cover as a non-aggressive and non-pharmaceutical nursing and therapeutic method for prevention of keratopathy in the patient hospitalized in intensive care unit. PMID- 26925906 TI - An Evaluation of the Organ Dose Received by Cardiologists Arising From Angiography Examinations in Educational Hospital in Rasht. AB - Interventional procedures, cine acquisitions and operation of fluoroscopic equipment in high-dose fluoroscopic modes, involve long fluoroscopic times which can lead to high staff doses. Also, Coronary angiography (CA) procedures require the cardiologist and assisting personnel to remain close to the patient, which is the main source of scattered radiation. Thus, radiation exposure is a significant concern for radiation workers and it is important to measure the radiation doses received by personnel and evaluate the parameters concerning total radiation burden. In this research, we investigated radiation doses to 10 cardiologists performing 120 CA procedures. Using thermo luminescent dosimeters doses to the wrists, thyroid and eyes per procedure were measured. Based on the measured dose values, maximum doses to the Left wrist, Right wrist, thyroid and eyes of cardiologist were measured 241.45 uSv, 203.17 uSv, 78.21 uSv and 44.58 uSv, respectively. The results of this study indicate that distance from the source, use of protective equipment's, procedure complexity, equipment performance, and cardiologist experience are the principal exposure-determining variables. It can be conclude that if adequate radiation protection approaches have been implemented, occupational dose levels to cardiologists would be within the regulated acceptable dose limits. PMID- 26925907 TI - Risk Factors for Relapse of Human Brucellosis. AB - BACKGROUND & PROPOSE: Brucellosis is serious disease around the world, especially in underdeveloped countries. Relapse is major problem in therapy of brucellosis. This study aimed to evaluate risk factors of relapse after treatment in patients. METHODS: It is a descriptive-analytic study from 1990 to 2014, in Ayatolla Rohani hospital in Babol, Iran. We studied 980 patients with brucellosis. The studied community included patients infected with brucellosis and the required information was gathered based on their hospital files. The base for recognizing Malta fever were clinical symptoms and Para-clinical sign congruent with infection like as, titer SAT>1:320 and 2-ME>1:160. Patients with relapse and patients without relapse were placed separately in two groups. The data were statistically compared with Spss 16, by Chi-square and Cox -regression tests. RESULTS: Based on this study, treatment regimen is a preventive factor (P=0.000). Moreover, Based on some statistical methods, regimens no. 3 and 4 were introduce preventive factors (P=0.001) and (P=0.004). It should also be noted that findings the same statistical model, factors like gender, age, residence, professional contacts, complications and delay in treatment were also analyzed but none of them are considered as preventive factors. CONCLUSION: Based our finding, we suggest aminoglycosides (gentamicin or streptomycin with doxycycline) are associated with lower rate of relapse in brucellosis. PMID- 26925908 TI - Reaction to and Coping With Domestic Violence by Iranian Women Victims: A Qualitative Approach. AB - INTRODUCTION: Domestic violence is a continual stressor that motivates its victim to react. The way a woman deals with her husband's violence determine the consequence of the violent relationship. In the present study, a qualitative approach was employed to investigate women's reactions to and ways of coping with domestic violence. METHOD: Semi-structured interviews were conducted in 2014 with 18 women who experienced domestic violence in an attempt to explain how women deal with domestic violence. After the interviews were transcribed word by word, they were explored in the form of meaningful units and encoded as subcategories and categories through inductive content analysis. The reliability and validity of the interviews were measured by an external supervisor. RESULTS: Two categories of reaction and coping were identified through content analysis: passive and non-normative measures and active measures. Passive and non-normative measures included the subcategories of harmful behaviors, retaliation, tolerance, and silence. Active measures included seeking help and advice, legal measures, leaving the spouse, positive and health promoting measures. CONCLUSION: In the present study, ways of coping with a husband's violence among women experiencing domestic violence were divided into two categories: passive and non-normative measures and active measures. These categories confirmed the models of coping with stress in previous studies. Adopting an appropriate approach to dealing with domestic violence is affected by a woman's capacity and beliefs, the dominant culture, intensity of the violence, available social and legal supports, and effectiveness of evaluation measures. To generalize service provision to victimized women, the type of coping and the reason for adopting the chosen approach need to be taken into account. PMID- 26925909 TI - Correlation Between the Type of Acute Coronary Syndrome With the Needs of Hospitalized Patients. AB - INTRODUCTION: Acute Coronary Syndromes (ACS) comprise life-threatening health problems that demand emergency care and immediate intervention. As patients are abruptly transitioning from healthy state into suffering, they consequently experience several needs, mainly attributed to the type of the syndrome including the therapeutic regimen. OBJECTIVES: To access the correlation between the type of acute coronary syndrome (ACS) with the needs of hospitalized patients. METHODS: A sample of 454 hospitalized patients with ACS, recruited from 4 hospitals in Greece, was enrolled in the study. Data were collected by the completion of questionnaire which apart from socio-demographic and clinical characteristics, it also included the questionnaire "Needs of hospitalized patients with coronary artery disease" which is consisted 6 subscales: a) need for support and guidance, b) need for information from the medical-nursing staff, c) need for being in contact with other patient groups and ensuring communication with relatives, d) need for individualized treatment and for the patient's personal participation to his/her treatment e) need to meet the emotional and physical needs f) need to trust the medical-nursing staff. Statistical methods used were Kolmogorov-Smirnov test, chi2 test of independence, Kruskal wallis-test and multiple regression. RESULTS: The type of ACS was statistically significant correlated with the place of residence (p=0.002), management of disease (p<0.001) and prior experience of hospitalization (p=0.003). All six needs were statistically significantly correlated with the type of ACS, (p<0.001 for the need for support and guidance, p<0.001 for the need to be informed from the medical and nursing staff, p<0.001 for the need for being in contact with other patient groups, and ensuring communication with relatives, p<0.001 for the need for individualized treatment and for the patient's personal participation to his/her treatment, p<0.001 for the need to meet the emotional needs and physical needs and p=0.010 for the need to trust the medical and nursing staff). More specifically, patients with angina considered all six needs to be less significant than patients with unstable angina and myocardial infarction. These results were confirmed by the multiple linear regression after controlling for potential confounders. CONCLUSIONS: Needs of hospitalized patients should be assessed in daily clinical practice according to the type of the syndrome. PMID- 26925910 TI - Analysis of Universal Health Coverage and Equity on Health Care in Kenya. AB - Kenya has made progress towards universal health coverage as evidenced in the various policy initiatives and reforms that have been implemented in the country since independence. The purpose of this analysis was to critically review the various initiatives that the government of Kenya has over the years initiated towards the realization of Universal Health Care (UHC) and how this has impacted on health equity. The paper relied heavly on secondary sources of information although primary data data was collected. Whereas secondary data was largely collected through critical review of policy documents and commissioned studies by the Ministry of Health and development partners, primary data was collected through interviews with various stakeholders involved in UHC including policy makers, implementers, researchers and health service providers. Key findings include commitment towards UHC; minimal solidarity in health care financing; cases of dysfunctionalilty of health care system; minimal opportunities for continuous medical training; quality concerns in terms of stock-outs of drugs and other medical supplies, dilapidated health infrastructure and inadequqte number of health workers. Other findings include governance concerns at NHIF coupled with, high operational costs, low capitation, fraud at facility levels, low pay out ratio, accreditation of facilities, and narrowness of the benefit package, among others. In lieu of these, various recommendations have been suggested. Among these include promotion of solidarty in health care financing that are reliable and economical in collecting; political will to enhance commitment towards devolution of health care, engagement of various stakeholders at both county and national government in fast tracking the enactment of Health Act; investment in health infrastructure and training of human resources; revamping NHIF into a full-fledged social health insurance scheme, and enhancing capacity of NHIF human resources, enhanced awareness amongst members, enhanced benefit package among other recommendations. PMID- 26925911 TI - Importance of Client Orientation Domains in Non-Clinical Quality of Care: A Household Survey in High and Low Income Districts of Mashhad. AB - Responsiveness introduced by WHO as a key indicator to assess the performance of health systems and measures by common set of domains that are categorized in to two main categories "Respect for persons" and "client orientation". This study measured importance of client orientation domains in high and low income districts of Mashhad. In this cross-sectional and explanatory study, Sample of 923 households were selected randomly from two high and low income districts of Mashhad. World Health Organization (WHO) questionnaire was used for data collection. Standard frequency analyses and Ordinal logistic regression (OLR) was employed for data analysis. In general, respondents selected quality of basic amenities as the most important domain and access to social support networks was identified as the least important domain. Households in high income area scored higher domains of prompt attentions and choice Compared to low income. There was a significant relationship between variables of ages, having member that need to care and self-assessed health with the ranking of client orientation domains.Study of households' view on ranking of non-clinical aspects of quality of care, especially when faced with limited resources, can help to conduct efforts towards subjects that are more important, and lead to improve the health system performance and productivity. PMID- 26925912 TI - Association between Asymptomatic Bacteriuria and Pre-Eclampsia. AB - Asymptomatic bacteriuria is one of the most common and important bacterial infections during pregnancy and can result in progressive infections and endanger maternal as well as fetal health. In this study, we assessed the relationship between asymptomatic bacteriuria and pre-eclampsia. In this case-control study, pregnant women who presented to Imam Reza Hospital in Kermanshah in 2013-14 were studied. The minimum sample size was calculated as 125 pregnant women in each group with a total of 250 subjects. There were 125 women with pre-eclampsia and 125 women without pre-eclampsia (control group). Matching was done for age, gestational age, and parity between case and control groups. Matching was verified by a P value of 0.061 for maternal age and gestational age and 0.77 for parity. The statistical analyses were done by applying the chi-squared test and determining odds ratio (OR) for having bacteriuria in univariate logistic regression as well as multivariate regression with adjusting the effect of maternal age, gestational age, and parity. Pyuria and bacteriuria were significantly more common in pre-eclampsia group than in control group. The results showed that a significant association existed between asymptomatic bacteriuria and pre-eclampsia. The rate of asymptomatic bacteriuria was 6.8 times higher in women with pre-eclampsia compared to those without pre-eclampsia. Further studies are required for better clarification of association between asymptomatic bacteriuria and pre-eclampsia. PMID- 26925913 TI - The Value of Pre- and Post-Stenting Fractional Flow Reserve for Predicting Mid Term Stent Restenosis Following Percutaneous Coronary Intervention (PCI). AB - Measuring fractional flow reserve (FFR) in percutaneous coronary intervention (PCI) has predictive value for PCI outcome. We decided to examine the utility of pre- and post-stenting FFR as a predictor of 6-month stent restenosis as well as MACE (major adverse cardiac events). Pre- and post-stenting FFR values were measured for 60 PCI patients. Within 6 months after stenting, all patients were followed for assessment of cardiac MACE including myocardial infarction, unstable angina, or positive exercise test. Stent restenosis was also assessed. Cut-off values for pre- and post-stenting FFR measurements were considered respectively as 0.65 and 0.92.Stent restenosis was detected in 4 patients (6.6%). All 4 patients (100%) with restenosis had pre-stenting FFR of < 0.65, while only 26 of 56 patients without restenosis (46.4%) had pre-stenting FFR value of < 0.65 (P= 0.039). Mean pre-stenting FFR in patients with restenosis was significantly lower than in those without restenosis (0.25 +/- 0.01 vs. 0.53 +/- 0.03, P= 0.022). Although stent restenosis was higher in patients with post-stenting FFR of < 0.92 (2 cases, 9.5%) than in those with FFR value of >= 0.92 (2 cases, 5.1%), the difference was not statistically (P= 0.510). Pre-stenting FFR, the use of longer stents, and history of diabetes mellitus can predict stent restenosis, but the value of post-stenting FFR for predicting restenosis was not explicit. PMID- 26925914 TI - Clinical Efficacy and Complications of Uterine Artery Embolization in Symptomatic Uterine Fibroids. AB - We decided to evaluate the efficacy and complications of uterine artery embolization (UAE) in patients with symptomatic uterine fibroids. Sixty-five premenopausal patients, without considering the fibroids size and its location, were treated by bilateral UAE. At baseline and after 3, 6, and 12 months MRI was obtained to determine the uterine length and fibroid diameter. In addition, symptoms of the patients were documented at these follow-up schedules. UAE was successful in 62 (95.4%) cases. Complete infarction rate of the fibroid was 83.1%. After 12 months, the uterine length showed a decrease of 55.7% (mean of 9.4 cm) and the diameter of the dominant fibroid revealed a decrease of 52.1% (mean of 3.4 cm). Menorrhagia improved in 45 cases (91.8%), abdominal mass in 24 cases (82.28%), urinary symptoms in 17 cases (85%), pelvic pain in 21 cases (84%), and dysmenorrhea in 25 cases (80.6%). At final follow-up performed after one year, complete infarction of the fibroma was demonstrated in 49 patients (83.1%). Two cases achieved successful pregnancy in the one year follow-up period. Five patients developed post-embolization syndrome which necessitated admission to the hospital. Twenty-two patients presented and complained of pain for which outpatient pain management was done. UAE was a successful treatment for uterine fibroids that preserved the uterus, had minimal complications, and required short hospitalization and recovery. PMID- 26925915 TI - Lived Experiences of Educational Leaders in Iranian Medical Education System: A Qualitative Study. AB - INTRODUCTION: High quality educational systems are necessary for sustainable development and responding to the needs of society. In the recent decades, concerns have increased on the quality of education and competency of graduates. Since graduates of medical education are directly involved with the health of society, the quality of this system is of high importance. Investigation in the lived experience of educational leaders in the medical education systems can help to promote its quality. The present research examines this issue in Iran. METHODOLOGY: The study was done using content-analysis qualitative approach and semi-structured interviews. The participants included 26 authorities including university chancellors and vice-chancellors, ministry heads and deputies, deans of medical and basic sciences departments, education expert, graduates, and students of medical fields. Sampling was done using purposive snowball method. Data were analyzed using conventional content analysis. FINDINGS: Five main categories and 14 sub-categories were extracted from data analysis including: quantity-orientation, ambiguity in the trainings, unsuitable educational environment, personalization of the educational management, and ineffective interpersonal relationship. The final theme was identified as "Education in shadow". CONCLUSION: Personalization and inclusion of personal preferences in management styles, lack of suitable grounds, ambiguity in the structure and process of education has pushed medical education toward shadows and it is not the first priority; this can lead to incompetency of medical science graduates. PMID- 26925916 TI - Correlation between Students' Self-Efficacy and Teachers' Educational Leadership Style in Iranian Midwifery Students. AB - BACKGROUND: Self-efficacy is believe in and feeling of ability to complete work. One of these factors is educational teachers ' role. This study aimed to determine relationship between teachers' leadership style and students' self efficacy in midwifery students. METHOD: This Study is a cross sectional correlation study. Sampling was conducted in midwifery students in Bachelor Science degree in 2013. Data collection tools were multi leadership questionnaire and self-efficacy clinical performance. After explaining the goals of study, 97 students completed the questionnaire. Scoring the questionnaire was based on a Liker's scale (0-5).Data were analyzed by SPSS 16. Correlation coefficient test was adopted to investigate the relationship and p value was considered 0.05. RESULT: Mean of self-efficacy scores were 116.12 (24.66.). In 53.3% of the cases, self-efficacy was good, in 42.2% moderate and in 4.3%, it was bad. The majority of the students (88.9%) reported that their teachers had an idealized style in leadership. About 94.6% of the students with good self- efficacy believed that their teachers' leadership style was transformational style. There was a significant correlation between self- efficacy and leadership style (p<0.05). CONCLUSIONS: Results showed that transformational style is appropriate for midwifery teachers. PMID- 26925917 TI - Sexual Behavior Pattern and Related Factors in Women with Breast Cancer in Iran. AB - BACKGROUND: Despite the most of treatment team efforts focused on the maintaining patient's life, attention to sexual issues don't be considered. This stud is designed to determine the sexual behavior pattern and related factors in women with breast cancer. METHODS: This descriptive- correlation study was performed on 90 women that diagnosed with breast Cancer that was admitted to sayed-al- shohada hospital of Isfahan in 2010. Sampling method was available (non- random sampling) and Sexual Behavior Pattern determined with 3 domains: sexual identity, sexual role and sexual function. Data collection tools, was a questionnaire that made by the researcher and was used after determining the validity and reliability. For data analysis, was used of Descriptive- analytic statistics, frequency and ANOVA and Pearson correlation analytical tests in the SPSS statistical software (version 16). RESULTS: Cases had 60% of Desirable sexual identity, 50% of Desirable sexual role, 40% Desirable sexual function and were be able to play 47.61% Desirable sexual behavior. Participants that their husbands had Elementary education had more desirable sexual behavior (p<0.031). Cases that were homemaker had more desirable Sexual behavior than of were working and retired (p<0.023). Non-surgical treatment with chemotherapy, radiotherapy and hormone therapy had a negative impact on sexual behavior (p<0.014). CONCLUSION: Study of sexual behavior pattern that is one of the important aspects of health, Provide valuable information to nurses and medical team and will be enhance the quality of provided services. Adopt appropriate strategies and interventions to promote sexual health, breast cancer is recommended. PMID- 26925918 TI - Single-Walled Carbon Nanotubes (SWCNTs), as a Novel Sorbent for Determination of Mercury in Air. AB - BACKGROUND: Based on the noticeable toxicity and numerous application of mercury in industries, removal of mercury vapor through sorbent is an important environmental challenge. PURPOSE OF THE STUDY: Due to their highly porous and hollow structure, large specific surface area, light mass density and strong interaction, Single-Walled Carbon Nanotubes (SWCNTs) sorbent were selected for this investigation. METHODS: In this study, instrumental conditions, method procedure and different effective parameters such as adsorption efficiency, desorption capacity, time, temperature and repeatability as well as retention time of adsorbed mercury were studied and optimized. Also, mercury vapor was determined by cold vapor atomic absorption spectrometry (CV-AAS).Obtained data were analyzed by Independent T- test, Multivariate linear regression and one way ANOVA finally. RESULTS: For 80 mg nanotubes, working range of SWCNT were achieved 0.02-0.7 mg with linear range (R2=0.994).Our data revealed that maximum absorption capacity was 0.5 mg g-1 as well as limit of detection (LOD) for studied sorbent was 0.006 mg. Also, optimum time and temperature were reported, 10 min and 250 degrees C respectively. Retention time of mercury on CNTs for three weeks was over 90%. Results of repeated trials indicated that the CNTs had long life, so that after 30 cycles of experiments, efficiency was determined without performance loss. CONCLUSION: Results showed that carbon nanotubes have high potential for efficient extraction of mercury from air and can be used for occupational and environmental purposes. The study of adsorption properties of CNTs is recommended. PMID- 26925919 TI - Lived Experiences of Iranian Nurses Caring for Brain Death Organ Donor Patients: Caring as "Halo of Ambiguity and Doubt". AB - BACKGROUND: Brain death is a concept in which its criteria have been expressed as documentations in Harvard Committee of Brain Death. The various perceptions of caregiver nurses for brain death patients may have effect on the chance of converting potential donors into actual organ donors. OBJECTIVE: The present study has been conducted in order to perceive the experiences of nurses in care giving to the brain death of organ donor patients. METHODS: This qualitative study was carried out by means of Heidegger's hermeneutic phenomenology. Eight nurses who have been working in ICU were interviewed. The semi-structured interviews were recorded bya tape-recorder and the given texts were transcribed and the analyses were done by Van-Mannen methodology and (thematic) analysis. RESULTS: One of the foremost themes extracted from this study included 'Halo of ambiguity and doubt' that comprised of two sub-themes of 'having unreasonable hope' and 'Conservative acceptance of brain death'. The unreasonable hope included lack of trust (uncertainty) in diagnosis and verification of brain death, passing through denial wall, and avoidance from explicit and direct disclosure of brain death in patients' family. In this investigation, the nurses were involved in a type of ambiguity and doubt in care-giving to the potentially brain death of organ donor patients, which were also evident in their interaction with patients' family and for this reason, they did not definitely announce the brain death and so far they hoped for treatment of the given patient. Such confusion and hesitance both caused annoyance of nurses and strengthening the denial of patients' family to be exposed to death. CONCLUSION: The results of this study reveal the fundamental perceived care-giving of brain death in organ donor patients and led to developing some strategies to improve care-giving and achievement in donation of the given organ and necessity for presentation of educational and supportive services for nurses might become more evident than ever. PMID- 26925920 TI - Relationship between Homesickness and Test Anxiety in Non-Native Students of Shiraz University of Medical Sciences International Branch in the Clinical and Physiopathology Course In 2013. AB - INTRODUCTION: Anxiety is an emotional and physiological response to the internal felling of overall danger that is easily resolved. The aim of this study has been to determine the relationship between exam anxiety and the feeling of homesickness among non-native students. METHODOLOGY: The present study is cross sectional and the subjects in this study are 80 non-native male and female PhD candidates in clinical and physiopathology majors in 2013 academic year that have been evaluated with the help of Persian homesickness questionnaire and Sarason's test anxiety questionnaire and the data was analyzed using Pearson's correlation coefficient. RESULTS: With regard to the Pearson's correlation coefficient there is a significant and reverse relationship between the desire to return to home and exam anxiety (r=0.0344, p=0.004) and there is a significant and reverse relationship between the Compatibility and exam anxiety (r=0.428, p<0.0001) and there is a significant and direct relationship between the feeling of alone and exam anxiety (r=0.888, p<0.0001). DISCUSSION & CONCLUSION: There is a significant relationship between the feeling of homesickness and exam anxiety and the mental health of non-native students will be deteriorated by the feeling of homesickness and anxiety. PMID- 26925921 TI - ALDH2: A new protector against age-independent myocardial senescence. PMID- 26925922 TI - Survival of the young patients with acute ST segment elevation myocardial infarction treated with primary percutaneous coronary intervention: Does gender matters? PMID- 26925923 TI - Aspirin desensitization in patients with acute coronary syndrome. PMID- 26925924 TI - Clinical Genomics: From Pathogenicity Claims to Quantitative Risk Estimates. PMID- 26925925 TI - Quantum dots induced interferon beta expression via TRIF-dependent signaling pathways by promoting endocytosis of TLR4. AB - Quantum dots (QDs) are nano-sized semiconductors. Previously, intratracheal instillation of QD705s induces persistent inflammation and remodeling in the mouse lung. Expression of interferon beta (IFN-beta), involved in tissue remodeling, was induced in the mouse lung. The objective of this study was to understand the mechanism of QD705 induced interferon beta (IFN-beta) expression. QD705-COOH and QD705-PEG increased IFN-beta and IP-10 mRNA levels during day 1 to 90 post-exposure in mouse lungs. QD705-COOH increased IFN-beta expression via Toll/interleukin-1 receptor domain-containing adapter protein (TRIF) dependent Toll-like receptor (TLR) signaling pathways in macrophages RAW264.7. Silencing TRIF expression with siRNA or co-treatment with a TRIF inhibitor tremendously abolished QD705s-induced IFN-beta expression. Co-treatment with a TLR4 inhibitor completely prevented IFN-beta induction by QD705-COOH. QD705-COOH readily entered cells, and co-treatment with either inhibitors of endocytosis or intracellular TLRs prevented IFN-beta induction. Thus, activation of the TRIF dependent TLRs pathway by promoting endocytosis of TLR4 is one of the mechanisms for immunomodulatory effects of nanoparticles. PMID- 26925926 TI - Methodological support for the further abstraction of and philosophical examination of empirical findings in the context of caring science. AB - Phenomena in caring science are often complex and laden with meanings. Empirical research with the aim of capturing lived experiences is one way of revealing the complexity. Sometimes, however, results from empirical research need to be further discussed. One way is to further abstract the result and/or philosophically examine it. This has previously been performed and presented in scientific journals and doctoral theses, contributing to a greater understanding of phenomena in caring science. Although the intentions in many of these publications are laudable, the lack of methodological descriptions as well as a theoretical and systematic foundation can contribute to an ambiguity concerning how the results have emerged during the analysis. The aim of this paper is to describe the methodological support for the further abstraction of and/or philosophical examination of empirical findings. When trying to systematize the support procedures, we have used a reflective lifeworld research (RLR) approach. Based on the assumptions in RLR, this article will present methodological support for a theoretical examination that can include two stages. In the first stage, data from several (two or more) empirical results on an essential level are synthesized into a general structure. Sometimes the analysis ends with the general structure, but sometimes there is a need to proceed further. The second stage can then be a philosophical examination, in which the general structure is discussed in relation to a philosophical text, theory, or concept. It is important that the theories are brought in as the final stage after the completion of the analysis. Core dimensions of the described methodological support are, in accordance with RLR, openness, bridling, and reflection. The methodological support cannot be understood as fixed stages, but rather as a guiding light in the search for further meanings. PMID- 26925928 TI - Comments on paper: "Quantitative determination of estrone by liquid chromatography-tandem mass spectrometry in subcutaneous adipose tissue from the breast in postmenopausal women" by Vihma et al. PMID- 26925930 TI - Response to the comments by Per E. Lonning. PMID- 26925932 TI - Dogs died in studies of drug that killed man in French trial. PMID- 26925929 TI - Flaxseed and its components differentially affect estrogen targets in pre neoplastic hen ovaries. AB - Flaxseed has been studied for decades for its health benefits that include anti cancer, cardio-protective, anti-diabetic, anti-inflammatory properties. The biologically active components that mediate these effects are the omega-3 fatty acids and the lignan, secoisolariciresinol diglucoside. We have previously shown that whole flaxseed supplemented diet decreases the severity and incidence of ovarian cancer while a 15% dose of flaxseed is most protective against inflammation and estrogen-induced chemical and genotoxicity. The objective of this study was to dissect the independent effects of the two flaxseed components on estrogen signaling and metabolism. Two and half year old hens were fed either a control diet, 15% whole flaxseed diet, defatted flax meal diet or 5% flax oil diet for 3 months after which the animals were sacrificed and blood and tissues were harvested. Whole flaxseed diet caused a decrease in expression of ERalpha. ERalpha target gene expression was assessed using RT(2) profiler PCR array. Some targets involved in the IGF/insulin signaling pathway (IRS1, IGFBP4, IGFBP5) were downregulated by flaxseed and its components. Flaxseed diet also downregulated AKT expression. A number of targets related to NF-kB signaling were altered by flaxseed diet including a series of targets implicated in cancer. Whole flaxseed diet also affected E2 metabolism by increasing CYP1A1 expression with a corresponding increase in the onco-protective E2 metabolite, 2-methoxyestradiol. The weak anti-estrogens, enterolactone, enterodiol and 2-methoxyestradiol, might be working synergistically to generate a protective effect on the ovaries from hens on whole flaxseed diet by altering the estrogen signaling and metabolism. PMID- 26925933 TI - Relationship between white matter pathology and performance on the General Movement Assessment and the Test of Infant Motor Performance in very preterm infants. AB - BACKGROUND: Cerebral Magnetic Resonance Imaging, the General Movement Assessment, and the Test of Infant Motor Performance are all tools that can predict neurodevelopmental outcome in preterm infants. However, how these tests relate to each other is unclear. AIMS: To examine the relationship between cerebral Magnetic Resonance Imaging measured at term age, and the General Movement Assessment and Test of Infant Motor Performance measured at 10-15 weeks post-term age. STUDY DESIGN: Prospectively collected data in a sample of very preterm infants. SUBJECTS: Fifty-three infants (23 female, 30 male) with a median gestational age of 28 weeks (range: 23-30 weeks) and a median birth weight of 1000 g (range: 515-1465 g). OUTCOME MEASURES: Test of Infant Motor Performance, General Movement Assessment. RESULTS: Infants with abnormal white matter were significantly more likely to have both abnormal general movements (p=0.01) and abnormal Test of Infant Motor Performance scores (p=0.001). Infants with abnormal general movements were significantly more likely to have lower Test of Infant Motor Performance Scores (p=0.01). CONCLUSIONS: Abnormal white matter is related to motor deviations as measured by the General Movement Assessment and the Test of Infant Motor Performance as early as 3 months post-term age in a cohort of preterm infants. PMID- 26925934 TI - Longitudinal changes in adiponectin multimer levels in preterm infants. AB - BACKGROUND: Preterm infants have altered adiponectin levels at term-equivalent age and have a higher risk of developing components of the metabolic syndrome in later life than term infants. AIMS: To investigate the longitudinal changes in adiponectin levels in preterm infants and to compare the levels between term and preterm infants. STUDY DESIGN: A cohort study. SUBJECTS: The study subjects were 43 term infants and 42 preterm infants born at <= 34-week gestation. OUTCOME MEASURES: Serum levels of total adiponectin (T-Ad) and high-molecular-weight adiponectin (HMW-Ad) were measured in 42 preterm infants at term-, 6 month-, and 12 month-equivalent ages. Moreover, the levels in 43 term infants investigated previously were reviewed. RESULTS: In preterm infants, T-Ad and HMW-Ad levels at the 12 month-equivalent age were lower than at the term- and 6 month-equivalent ages (all values p<0.001), which was consistent with previous results in term infants. The difference in ratios of HMW-Ad to T-Ad between term and preterm infants continued at the 6 month-equivalent age but disappeared at the 12 month equivalent age. Multiple regression analyses revealed that HMW-Ad levels at term equivalent age were only a significant determinant of the changes in HMW-Ad between the term- and 12 month-equivalent ages in preterm infants (p<0.001). CONCLUSIONS: The HMW-Ad levels decline till the 12 month-equivalent age in both term and preterm infants. The changes in HMW-Ad level during infancy might be determined at least to a certain degree up to term-equivalent age in preterm infants. PMID- 26925935 TI - Back to the Future. PMID- 26925936 TI - Americans Who Practice Yoga Report Better Wellness, Health Behaviors. PMID- 26925937 TI - Supporting Self-management of Asthma Care. AB - Asthma is a major public health concern, with an estimated 18.8 million adults in the United States having the disease. Asthma can be controlled with a variety of effective treatment options; however, only half the people with asthma report their asthma is well controlled. Uncontrolled asthma leads to high direct and indirect costs as well as decreased quality of life. The pathophysiology of asthma, current asthma practice guidelines, and common barriers to self management will be discussed. Through use of motivational interviewing techniques and knowledge of available self-management tools, the home care clinician is poised to help increase self-management of asthma, decrease hospitalizations, and improve quality of life. PMID- 26925938 TI - Charcot Neuroarthropathy of the Foot and Ankle. AB - Charcot neuropathy is a painless, progressive, degeneration most notably of the ankle or midfoot joints, seen in patients with diabetes and neuropathy. This article will describe the etiology, diagnosis, and treatment of this potentially debilitating joint disease and provide implications for home care clinicians. PMID- 26925939 TI - Care of a Homebound Super Obese Patient: A Case Study. AB - Obesity is becoming more prevalent in the United States with almost 40% of the population being overweight or obese. A new category, defining super obesity as a body mass index of 50 or higher, has been added. The purpose of this article is to use a case study to develop a more thorough understanding of the complex care needs of the super obese patient and how home healthcare clinicians can use technology to advocate for super obese patients who are home and bedbound. A review of the literature and discussion will be provided. Potential technologies involved in provision of care will also be explored. Finally, a summary of the case along with proposed solutions will be offered. PMID- 26925940 TI - Collaborative Efforts in the Community: Faith Community Nurses as Partners in Healing. PMID- 26925941 TI - Abdominal Assessment. AB - Abdominal pain is one of the most common complaints by patients, and assessment of abdominal pain and associated symptoms can be challenging for home healthcare providers. Reasons for abdominal pain are related to inflammation, organ distention, and ischemia. The history and physical examination are important to narrow the source of acute or chronic problems, identify immediate interventions, and when necessary, facilitate emergency department care. PMID- 26925942 TI - Insulin Glargine U-300 (Toujeo(r)): A Review. PMID- 26925943 TI - Actiq Is Not for Sore Throats! PMID- 26925944 TI - Preventing Pneumococcal Pneumonia. PMID- 26925945 TI - A Day in the Life of a Home Care Nurse in Traverse City Michigan. PMID- 26925946 TI - A Protocol to Decrease Pain From an Implantable Cardioverter Defibrillator. PMID- 26925947 TI - Partnering With the ED: Improving Home Healthcare Referrals to Reduce Hospitalizations and Repeat Emergency Visits. PMID- 26925948 TI - Home Healthcare: The Solution to Africa's Health Problems. PMID- 26925949 TI - Is Your Agency Prepared for the Coming Medicare Cuts? PMID- 26925951 TI - Nicotinic Acetylcholine Receptors Modulate Bone Marrow-Derived Pro-Inflammatory Monocyte Production and Survival. AB - It is increasingly clear that nicotinic acetylcholine receptors (nAChRs) are involved in immune regulation, and that their activation can protect against inflammatory diseases. Previous data have shown that nicotine diminishes the numbers of peripheral monocytes and macrophages, especially those of the pro inflammatory phenotype. The goal of the present study was to determine if nicotine modulates the production of bone marrow -derived monocytes/macrophages. In this study, we first found that murine bone marrow cells express multiple nAChR subunits, and that the alpha7 and alpha9 nAChRs most predominant subtypes found in immune cells and their precursors. Using primary cultures of murine bone marrow cells, we then determined the effect of nicotine on monocyte colony stimulating factor and interferon gamma (IFNgamma)-induced monocyte production. We found that nicotine lowered the overall number of monocytes, and more specifically, inhibited the IFNgamma-induced increase in pro-inflammatory monocytes by reducing cell proliferation and viability. These data suggested that nicotine diminishes the ratio of pro-inflammatory versus anti-inflammatory monocyte produced in the bone marrow. We thus confirmed this hypothesis by measuring cytokine expression, where we found that nicotine inhibited the production of the pro-inflammatory cytokines TNFalpha, IL-1beta and IL-12, while stimulating the secretion of IL-10, an anti-inflammatory cytokine. Finally, nicotine also reduced the number of pro-inflammatory monocytes in the bone marrow of LPS-challenged mice. Overall, our data demonstrate that both alpha7 and alpha9 nAChRs are involved in the regulation of pro-inflammatory M1 monocyte numbers. PMID- 26925953 TI - A Cascade Phosphinoylation/Cyclization/Desulfonylation Process for the Synthesis of 3-Phosphinoylindoles. AB - 3-Phosphinoylindole derivatives play important roles as pharmaceutical drugs and ligands. A new method for the synthesis of 3-phosphinoylindole derivatives has been achieved through silver-mediated cycloaddition between N-Ts-2-alkynylaniline derivatives and H-phosphine oxides. This transformation offers a straightforward route to the formation of the C-P bond, indole ring, and desulfonylation in one step. PMID- 26925952 TI - Premenopausal Circulating Androgens and Risk of Endometrial Cancer: results of a Prospective Study. AB - Endometrial cancer risk is increased by estrogens unopposed by progesterone. In premenopausal women, androgen excess is often associated with progesterone insufficiency, suggesting that premenopausal androgen concentrations may be associated with risk. In a case-control study nested within three cohorts, we assessed the relationship between premenopausal androgens and risk of endometrial cancer (161 cases and 303 controls matched on age and date of blood donation). Testosterone, DHEAS, androstenedione, and SHBG were measured in serum or plasma. Free testosterone was calculated from testosterone and SHBG. We observed trends of increasing risk across tertiles of testosterone (ORT3-T1 = 1.59, 95 % CI = 0.96, 2.64, p = 0.08) and free testosterone (ORT3-T1 = 1.76, 95 % CI = 1.01, 3.07, p = 0.047), which were not statistically significant after adjustment for body mass index (BMI). There was no association for DHEAS, androstenedione, or SHBG. There were significant interactions by age at diagnosis (<55 years, n = 51 cases; >=55 years, n = 110 cases). Among women who were >=55 years of age (predominantly postmenopausal) at diagnosis, the BMI-adjusted OR was 2.08 (95 % CI = 1.25, 3.44, p = 0.005) for a doubling in testosterone and 1.55 (95 % CI = 1.04, 2.31, p = 0.049) for a doubling in free testosterone. There was no association among women aged <55 years at diagnosis, consistent with the only other prospective study to date. If pre- and post-menopausal concentrations of androgens are correlated, our observation of an association of premenopausal androgens with risk among women aged >=55 years at diagnosis could be due to the effect on the endometrium of postmenopausal androgen-derived estrogens in the absence of progesterone, which is no longer secreted. PMID- 26925954 TI - Serologic evidence for hepatitis E virus infection among patients with undifferentiated acute febrile illness in Kibera, Kenya. AB - BACKGROUND: Hepatitis E (HEV) is an emerging cause of viral hepatitis mainly transmitted through the fecal-oral route. Residents of the Kibera slum of Nairobi, Kenya are at risk for fecal-orally transmitted infections. OBJECTIVE: To quantify the incidence and prevalence of HEV infection among acute febrile illness (AFI) cases using a population-based infectious disease surveillance network. STUDY DESIGN: Cross-sectional serum samples from AFI case-patients between 2009 and 2012 were matched to the age and gender distribution of the Kibera population and tested by IgM and IgG enzyme immunoassays (EIA) and nucleic acid testing (NAT). Serum from healthy residents was also tested by EIA. RESULTS: Of the 482 AFI serum samples tested, 124 (25.7%) and 182 (37.8%) were IgM and IgG reactive, respectively. On multivariate analysis, IgM reactivity was associated with HIV (RR 1.66, 95%CI 1.07, 2.60; p=0.024) while IgG reactivity was associated with increasing age (p<0.001) and HIV (RR 1.93, 95%CI 1.52, 2.46; p<0.001). AFI case-patients were more likely to be IgM (p=0.002) and IgG (p<0.001) reactive compared to healthy residents. The seroincidence by HEV-specific IgM was 84.0 per 1000 person years, however, all 482 samples were negative by NAT. CONCLUSIONS: Serologic evidence for HEV in Kibera suggests a high burden of infection, but NAT did not confirm HEV viremia. Additional testing is needed to determine whether EIAs are susceptible to false positivity in undifferentiated AFI populations before their widespread use. PMID- 26925955 TI - The effect of balance training on postural control in people with multiple sclerosis using the CAREN virtual reality system: a pilot randomized controlled trial. AB - BACKGROUND: Multiple sclerosis (MS) is a multi-focal progressive disorder of the central nervous system often resulting in diverse clinical manifestations. Imbalance appears in most people with multiple sclerosis (PwMS). A popular balance training tool is virtual reality (VR) with several advantages including increased compliance and user satisfaction. Therefore, the aim of this pilot RCT (Trial registration number, date: ISRCTN14425615, 21/01/2016) was to examine the efficacy of a 6-week VR balance training program using the computer assisted rehabilitation environment (CAREN) system (Motek Medical BV, Amsterdam, Netherlands) on balance measures in PwMS. Results were compared with those of a conventional balance exercise group. Secondary aims included the impact of this program on the fear of falling. METHODS: Thirty-two PwMS were equally randomized into the VR intervention group or the control group. Each group received balance training sessions for 6 consecutive weeks, two sessions per week, 30 min sessions. Clinical balance tests and instrumented posturography outcome measures were collected upon initiation of the intervention programs and at termination. RESULTS: Final analysis included 30 patients (19 females, 11 males; mean age, (S.D.) = 45.2 (11.6) years; mean EDSS (S.D.) = 4.1 (1.3), mean disease duration (S.D.) = 11.0 (8.9) years). Both groups showed a main effect of time on the center of pressure (CoP) path length with eyes open (F = 5.278, P = .024), sway rate with eyes open (F = 5.852, P = .035), Functional Reach Test (F = 20.841, P = .001), Four Square Step Test (F = 9.011, P = .031) and the Fear of Falls self reported questionnaire (F = 17.815, P = .023). In addition, significant differences in favor of the VR program were observed for the group x time interactions of the Functional Reach Test (F = 10.173, P = .009) and fear of falling (F = 6.710, P = .021). CONCLUSIONS: We demonstrated that balance training based on the CAREN device is an effective method of balance training for PwMS. PMID- 26925956 TI - Does preoperative administration of gabapentin/pregabalin improve postoperative nasal surgery pain? AB - OBJECTIVES: Gabapentin and pregabalin has been shown to reduce postoperative pain effectively. In this meta-analysis, we aimed to assess the role of preoperative gabapentinoids for attenuating postoperative pain after nasal surgery in patients via a meta-analysis of the literature. DATA SOURCES: PubMed, Scopus, and Cochrane Database. METHODS: Literature was screened from inception to December 2015. Nine articles to compare the preoperative administered gabapentinoid (gabapentinoids groups) with a placebo or analgesics (control group) were included for analysis of the outcomes of interest, which included postoperative pain scores, analgesic intakes, or side effects, such as sedation, nausea and vomiting, blurred vision, operative bleeding, dizziness, and headache, during a 24-hour postoperative period. RESULTS: The pain score reported by the physician and need for analgesics during the first 24 hours, postoperatively, in the gabapentinoids group significantly reduced compared with the control. Additionally, the gabapentinoids had no significant effect on the incidences of side effects except blurred vision compared with the control during the 24 hours postoperatively. In the subgroup analyses of these results according to operation type, these subgroups showed similar effects on reducing postoperative pain and adverse effects. CONCLUSIONS: Preoperative gabapentinoids could attenuate postoperative pain without significant adverse effects in patients who undergo nasal surgery. However, blurred vision may be a handicap that requires consideration for use and education for patients. Further clinical trials will be of help in supporting the results of this study. LEVEL OF EVIDENCE: NA Laryngoscope, 126:2232-2241, 2016. PMID- 26925957 TI - Seafloor doming driven by degassing processes unveils sprouting volcanism in coastal areas. AB - We report evidences of active seabed doming and gas discharge few kilometers offshore from the Naples harbor (Italy). Pockmarks, mounds, and craters characterize the seabed. These morphologies represent the top of shallow crustal structures including pagodas, faults and folds affecting the present-day seabed. They record upraise, pressurization, and release of He and CO2 from mantle melts and decarbonation reactions of crustal rocks. These gases are likely similar to those that feed the hydrothermal systems of the Ischia, Campi Flegrei and Somma Vesuvius active volcanoes, suggesting the occurrence of a mantle source variously mixed to crustal fluids beneath the Gulf of Naples. The seafloor swelling and breaching by gas upraising and pressurization processes require overpressures in the order of 2-3 MPa. Seabed doming, faulting, and gas discharge are manifestations of non-volcanic unrests potentially preluding submarine eruptions and/or hydrothermal explosions. PMID- 26925959 TI - Sarcoma: Eribulin--a welcomed advance. PMID- 26925958 TI - Clinical impact of tumour biology in the management of gastroesophageal cancer. AB - The characterization of oesophageal and gastric cancer into subtypes based on genotype has evolved in the past decade. Insights into the molecular landscapes of gastroesophageal cancer provide a roadmap to assist the development of new drugs and their use in combinations, for patient stratification, and for trials of targeted therapies. Trastuzumab is the only approved treatment for gastroesophageal cancers that overexpress HER2. Acquired resistance usually limits the duration of response to this treatment, although a number of new agents directed against HER2 have the potential to overcome or prolong the time until resistance occurs. Beyond that, anti-VEGFR2 therapy with ramucirumab was the first biological treatment strategy to produce a survival benefit in an unselected population of patients with chemotherapy-refractory gastroesophageal cancer. Large initiatives are starting to address the role of biomarker-driven targeted therapy in the metastatic and in the perioperative setting for patients with this disease. Immunotherapy also holds promise, and our understanding of subsets of gastroesophageal cancer based on patterns of immune response continues to evolve. Efforts are underway to identify more relevant genomic subsets through genomic screening, functional studies, and molecular characterization. Herein, we provide an overview of the key developments in the treatment of gastroesophageal cancer, and discuss potential strategies to further optimize therapy by targeting disease subtypes. PMID- 26925960 TI - Haematological cancers: Lenalidomide--SPRINT to a new standard? PMID- 26925961 TI - Gastrointestinal cancer: PICCOLO--changing the tune of anti-EGFR therapy. PMID- 26925963 TI - Combining microCT-based characterization with empirical modelling as a robust screening approach for the design of optimized CaP-containing scaffolds for progenitor cell-mediated bone formation. AB - Biomaterials are a key ingredient to the success of bone tissue engineering (TE), which focuses on the healing of bone defects by combining scaffolds with cells and/or growth factors. Due to the widely variable material characteristics and patient-specificities, however, current bone TE strategies still suffer from low repeatability and lack of robustness, which hamper clinical translation. Hence, optimal TE construct (i.e. cells and scaffold) characteristics are still under debate. This study aimed to reduce the material-specific variability for cell based construct design, avoiding trial-and-error, by combining microCT characterization and empirical modelling as an innovative and robust screening approach. Via microCT characterization we have built a quantitative construct library of morphological and compositional properties of six CE approved CaP based scaffolds (CopiOs(r), BioOssTM, Integra MozaikTM, chronOS Vivify, MBCPTM and ReproBoneTM), and of their bone forming capacity and in vivo scaffold degradation when combined with human periosteal derived cells (hPDCs). The empirical model, based on the construct library, allowed identification of the construct characteristics driving optimized bone formation, i.e. (a) the percentage of beta-TCP and dibasic calcium phosphate, (b) the concavity of the CaP structure, (c) the average CaP structure thickness and (d) the seeded cell amount (taking into account the seeding efficiency). Additionally, the model allowed to quantitatively predict the bone forming response of different hPDC-CaP scaffold combinations, thus providing input for a more robust design of optimized constructs and avoiding trial-and error. This could improve and facilitate clinical translation. STATEMENT OF SIGNIFICANCE: Biomaterials that support regenerative processes are a key ingredient for successful bone tissue engineering (TE). However, the optimal scaffold structure is still under debate. In this study, we have provided a useful innovative approach for robust screening of potential biomaterials or constructs (i.e. scaffolds seeded with cells and/or growth factors) by combining microCT characterization with empirical modelling. This novel approach leads to a better insight in the scaffold parameters influencing progenitor cell-mediated bone formation. Additionally, it serves as input for more controlled and robust design of optimized CaP-containing bone TE scaffolds. Hence, this novel approach could improve and facilitate clinical translation. PMID- 26925962 TI - Evolving molecularly targeted therapies for advanced-stage thyroid cancers. AB - Increased understanding of disease-specific molecular targets of therapy has led to the regulatory approval of two drugs (vandetanib and cabozantinib) for the treatment of medullary thyroid cancer (MTC), and two agents (sorafenib and lenvatinib) for the treatment of radioactive- iodine refractory differentiated thyroid cancer (DTC) in both the USA and in the EU. The effects of these and other therapies on overall survival and quality of life among patients with thyroid cancer, however, remain to be more-clearly defined. When applied early in the disease course, intensive multimodality therapy seems to improve the survival outcomes of patients with anaplastic thyroid cancer (ATC), but salvage therapies for ATC are of uncertain benefit. Additional innovative, rationally designed therapeutic strategies are under active development both for patients with DTC and for patients with ATC, with multiple phase II and phase III randomized clinical trials currently ongoing. Continued effort is being made to identify further signalling pathways with potential therapeutic relevance in thyroid cancers, as well as to elaborate on the complex interactions between signalling pathways, with the intention of translating these discoveries into effective and personalized therapies. Herein, we summarize the progress made in molecular medicine for advanced-stage thyroid cancers of different histotypes, analyse how these developments have altered - and might further refine - patient care, and identify open questions for future research. PMID- 26925964 TI - Indirect rapid prototyping of sol-gel hybrid glass scaffolds for bone regeneration - Effects of organic crosslinker valence, content and molecular weight on mechanical properties. AB - We present a series of organic/inorganic hybrid sol-gel derived glasses, made from a tetraethoxysilane-derived silica sol (100% SiO2) and oligovalent organic crosslinkers functionalized with 3-isocyanatopropyltriethoxysilane. The material was susceptible to heat sterilization. The hybrids were processed into pore interconnected scaffolds by an indirect rapid prototyping method, described here for the first time for sol-gel glass materials. A large panel of polyethylene oxide-derived 2- to 4-armed crosslinkers of molecular weights ranging between 170 and 8000Da were incorporated and their effect on scaffold mechanical properties was investigated. By multiple linear regression, 'organic content' and the 'content of ethylene oxide units in the hybrid' were identified as the main factors that determined compressive strength and modulus, respectively. In general, 3- and 4-armed crosslinkers performed better than linear molecules. Compression tests and cell culture experiments with osteoblast-like SaOS-2 cells showed that macroporous scaffolds can be produced with compressive strengths of up to 33+/-2MPa and with a pore structure that allows cells to grow deep into the scaffolds and form mineral deposits. Compressive moduli between 27+/-7MPa and 568+/-98MPa were obtained depending on the hybrid composition and problems associated with the inherent brittleness of sol-gel glass materials could be overcome. SaOS-2 cells showed cytocompatibility on hybrid glass scaffolds and mineral accumulation started as early as day 7. On day 14, we also found mineral accumulation on control hybrid glass scaffolds without cells, indicating a positive effect of the hybrid glass on mineral accumulation. STATEMENT OF SIGNIFICANCE: We produced a hybrid sol-gel glass material with significantly improved mechanical properties towards an application in bone regeneration and processed the material into macroporous scaffolds of controlled architecture by indirect rapid prototyping. We were able to produce macroporous materials of relevant porosity and pore size with compressive moduli, covering the range reported for cancellous bone while an even higher compressive strength was maintained. By multiple linear regression, we identified crosslinker parameters, namely organic content and the content of ethylene oxide units in the hybrids that predominantly determined the mechanics of the hybrid materials. The scaffolds proved to be cytocompatible and induced mineralization in SaOS-2 cells. This provides new insight on the critical parameters for the design of the organic components of covalent hybrid sol-gel glasses. PMID- 26925965 TI - Rotational effects on the dissociation dynamics of CHD3 on Pt(111). AB - Dissociation of methane on metal surfaces is of high practical and fundamental interest. Therefore there is currently a big push aimed at determining the simplest dynamical model that allows the reaction dynamics to be described with quantitative accuracy using quantum dynamics. Using five-dimensional quantum dynamical and full-dimensional ab initio molecular dynamics calculations, we show that the CD3 umbrella axis of CHD3 must reorient before the molecule reaches the barrier for C-H cleavage to occur in reaction on Pt(111). This rules out the application of the rotationally sudden approximation, as explicitly shown through a comparison with calculations using this approximation. Further, we suggest that the observed umbrella swing should strongly affect the sensitivity of C-H cleavage to the initial alignment of the molecule relative to the surface as found experimentally for closely related systems. We find very large differences in reactivity for molecules pre-excited to different rotational states, particularly if these states are associated with different orientations of the C H bond. PMID- 26925966 TI - Impact of the shedding level on transmission of persistent infections in Mycobacterium avium subspecies paratuberculosis (MAP). AB - Super-shedders are infectious individuals that contribute a disproportionate amount of infectious pathogen load to the environment. A super-shedder host may produce up to 10,000 times more pathogens than other infectious hosts. Super shedders have been reported for multiple human and animal diseases. If their contribution to infection dynamics was linear to the pathogen load, they would dominate infection dynamics. We here focus on quantifying the effect of super shedders on the spread of infection in natural environments to test if such an effect actually occurs in Mycobacterium avium subspecies paratuberculosis (MAP). We study a case where the infection dynamics and the bacterial load shed by each host at every point in time are known. Using a maximum likelihood approach, we estimate the parameters of a model with multiple transmission routes, including direct contact, indirect contact and a background infection risk. We use longitudinal data from persistent infections (MAP), where infectious individuals have a wide distribution of infectious loads, ranging upward of three orders of magnitude. We show based on these parameters that the effect of super-shedders for MAP is limited and that the effect of the individual bacterial load is limited and the relationship between bacterial load and the infectiousness is highly concave. A 1000-fold increase in the bacterial contribution is equivalent to up to a 2-3 fold increase in infectiousness. PMID- 26925968 TI - Alkali Metal Variation and Twisting of the FeNNFe Core in Bridging Diiron Dinitrogen Complexes. AB - Alkali metal cations can interact with Fe-N2 complexes, potentially enhancing back-bonding or influencing the geometry of the iron atom. These influences are relevant to large-scale N2 reduction by iron, such as in the FeMoco of nitrogenase and the alkali-promoted Haber-Bosch process. However, to our knowledge there have been no systematic studies of a large range of alkali metals regarding their influence on transition metal-dinitrogen complexes. In this work, we varied the alkali metal in [alkali cation]2[LFeNNFeL] complexes (L = bulky beta-diketiminate ligand) through the size range from Na(+) to K(+), Rb(+), and Cs(+). The FeNNFe cores have similar Fe-N and N-N distances and N-N stretching frequencies despite the drastic change in alkali metal cation size. The two diketiminates twist relative to one another, with larger dihedral angles accommodating the larger cations. In order to explain why the twisting has so little influence on the core, we performed density functional theory calculations on a simplified LFeNNFeL model, which show that the two metals surprisingly do not compete for back-bonding to the same pi* orbital of N2, even when the ligand planes are parallel. This diiron system can tolerate distortion of the ligand planes through compensating orbital energy changes, and thus, a range of ligand orientations can give very similar energies. PMID- 26925969 TI - Glomerular Filtration Rate and Error Calculation Based on the Slope-Intercept Method with Chromium-51 Ethylenediaminetetraacetic Acid via a New Clinical Software: GFRcalc. AB - OBJECTIVE: To evaluate a home-built Java-based program (GFRcalc) to simplify the calculation of glomerular filtration rate (GFR) after administration of chromium 51 ethylenediaminetetraacetic acid (51Cr-EDTA) for routine clinical use. MATERIALS AND METHODS: In the program GFRcalc, the GFR was calculated based on the biological half-life of the 51Cr-EDTA concentration using the slope-intercept method of between two and five blood samples. Additional features included the ability to export patient data and generate clinical reports as well as to calculate the error of the fit of the GFR measurement in cases with three or more blood samples collected. The GFR was calculated from one, two and three blood samples of 133 patients with body surface-corrected GFR of 21-213 ml/min/1.73 m2. The Pearson correlation coefficient and the error of the fit for the GFR measurement were calculated for the three-sample method. RESULTS: The correlation coefficient for the three-sample method and the fit error correlated well for small fit errors; in case of fit errors >10%, the correlation coefficient partially differed in results compared to the other methods. The three-sample GFR values differed by approximately 17% from the single-sample GFRs. The fit errors of the three-sample GFRs correlated (r = 0.57) with their difference from the two sample GFRs. CONCLUSION: In this study, the fit error that GFRcalc provided for the three-sample GFR offered a simple and reliable method to check the results obtained. This could also allow physicians to assess the reliability of the results and base their decisions on the quality of the measurement. PMID- 26925971 TI - Blood cell progenitor maintenance: Collier barks out of the niche. AB - Drosophila lymph gland, a larval haematopoietic organ, has emerged as a popular model to study regulatory mechanisms controlling blood cell progenitor fate. In this organ, the Posterior Signaling Center (PSC), a small group of cells expressing the EBF transcription factor Collier, has been proposed to act as a niche required for progenitor maintenance. Accordingly, several reports showed that PSC size/activity modulation impacts on blood cell differentiation. Yet our recent results challenge this model. Indeed, we found that PSC ablation does not affect haematopoietic progenitor maintenance. This unexpected result led us to reinvestigate the role of the PSC and collier in hematopoiesis. Consistent with previous findings, the PSC appears required for the production of a specialized blood cell type in response to parasitization. Moreover, our results indicate that the massive blood cell differentiation observed in collier mutant larvae is not due to the lack of PSC but to collier expression within the haematopoietic progenitors. We thus propose a paradigm shift whereby larval blood cell progenitor maintenance is largely independent of the PSC but requires the cell autonomous function of collier. PMID- 26925970 TI - A Parent-of-Origin Effect Impacts the Phenotype in Low Penetrance Retinoblastoma Families Segregating the c.1981C>T/p.Arg661Trp Mutation of RB1. AB - Retinoblastoma (Rb), the most common pediatric intraocular neoplasm, results from inactivation of both alleles of the RB1 tumor suppressor gene. The second allele is most commonly lost, as demonstrated by loss of heterozygosity studies. RB1 germline carriers usually develop bilateral tumors, but some Rb families display low penetrance and variable expressivity. In order to decipher the underlying mechanisms, 23 unrelated low penetrance pedigrees segregating the common c.1981C>T/p.Arg661Trp mutation and other low penetrance mutations were studied. In families segregating the c.1981C>T mutation, we demonstrated, for the first time, a correlation between the gender of the transmitting carrier and penetrance, as evidenced by Fisher's exact test: the probability of being unaffected is 90.3% and 32.5% when the mutation is inherited from the mother and the father, respectively (p-value = 7.10(-7). Interestingly, a similar correlation was observed in families segregating other low penetrance alleles. Consequently, we investigated the putative involvement of an imprinted, modifier gene in low penetrance Rb. We first ruled out a MED4-driven mechanism by MED4 methylation and expression analyses. We then focused on the differentially methylated CpG85 island located in intron 2 of RB1 and showing parent-of-origin specific DNA methylation. This differential methylation promotes expression of the maternal c.1981C>T allele. We propose that the maternally inherited c.1981C>T/p.Arg661Trp allele retains sufficient tumor suppressor activity to prevent retinoblastoma development. In contrast, when the mutation is paternally transmitted, the low residual activity would mimic a null mutation and subsequently lead to retinoblastoma. This implies that the c.1981C>T mutation is not deleterious per se but needs to be destabilized in order to reach pRb haploinsufficiency and initiate tumorigenesis. We suggest that this phenomenon might be a general mechanism to explain phenotypic differences in low penetrance Rb families. PMID- 26925972 TI - Transmembrane Domain Lengths Serve as Signatures of Organismal Complexity and Viral Transport Mechanisms. AB - It is known that membrane proteins are important in various secretory pathways, with a possible role of their transmembrane domains (TMDs) as sorting determinant factors. One key aspect of TMDs associated with various "checkposts" (i.e. organelles) of intracellular trafficking is their length. To explore possible linkages in organisms with varying "complexity" and differences in TMD lengths of membrane proteins associated with different organelles (such as Endoplasmic Reticulum, Golgi, Endosomes, Nucleus, Plasma Membrane), we analyzed ~70,000 membrane protein sequences in over 300 genomes of fungi, plants, non-mammalian vertebrates and mammals. We report that as we move from simpler to complex organisms, variation in organellar TMD lengths decreases, especially compared to their respective plasma membranes, with increasing organismal complexity. This suggests an evolutionary pressure in modulating length of TMDs of membrane proteins with increasing complexity of communication between sub-cellular compartments. We also report functional applications of our findings by discovering remarkable distinctions in TMD lengths of membrane proteins associated with different intracellular transport pathways. Finally, we show that TMD lengths extracted from viral proteins can serve as somewhat weak indicators of viral replication sites in plant cells but very strong indicators of different entry pathways employed by animal viruses. PMID- 26925974 TI - Centrally Administered Ghrelin Acutely Influences Food Choice in Rodents. AB - We sought to determine whether the orexigenic hormone, ghrelin, is involved in the intrinsic regulation of food choice in rats. Ghrelin would seem suited to serve such a role given that it signals hunger information from the stomach to brain areas important for feeding control, including the hypothalamus and reward system (e.g. ventral tegmental area, VTA). Thus, in rats offered a choice of palatable foods (sucrose pellets and lard) superimposed on regular chow for 2 weeks, we explored whether acute central delivery of ghrelin (intracerebroventricular (ICV) or intra-VTA) is able to redirect their dietary choice. The major unexpected finding is that, in rats with high baseline lard intake, acute ICV ghrelin injection increased their chow intake over 3-fold, relative to vehicle-injected controls, measured at both 3 hr and 6 hr after injection. Similar effects were observed when ghrelin was delivered to the VTA, thereby identifying the VTA as a likely contributing neurobiological substrate for these effects. We also explored food choice after an overnight fast, when endogenous ghrelin levels are elevated, and found similar effects of dietary choice to those described for ghrelin. These effects of fasting on food choice were suppressed in models of suppressed ghrelin signaling (i.e. peripheral injection of a ghrelin receptor antagonist to rats and ghrelin receptor (GHSR) knock-out mice), implicating a role for endogenous ghrelin in the changes in food choice that occur after an overnight fast. Thus, in line with its role as a gut brain hunger hormone, ghrelin appears to be able to acutely alter food choice, with notable effects to promote "healthy" chow intake, and identify the VTA as a likely contributing neurobiological substrate for these effects. PMID- 26925975 TI - Sprue-like enteropathy linked to olmesartan. AB - Olmesartan is a therapy used for the management of hypertension available since 2002. A sprue like enteropathy associated with olmesartan has been first described in 2012. Endoscopic and histopathological findings are partial or total villous atrophy, mimicking a Celiac Disease. We explain two cases diagnosed in our hospital. Both patients took more than one year of treatment with olmesartan. In both cases, the biopsy showed duodenal villous atrophy, negative serology for celiac disease and they improved after stopping treatment with olmesartan. Olmesartan associate sprue-like enteropathy should be included in the differential diagnosis of seronegative villous atrophy. After the discontinuation of olmesartan, clinical remission usually occurs in every patients. PMID- 26925973 TI - Clinical application of genomic profiling to find druggable targets for adolescent and young adult (AYA) cancer patients with metastasis. AB - BACKGROUND: Although adolescent and young adult (AYA) cancers are characterized by biological features and clinical outcomes distinct from those of other age groups, the molecular profile of AYA cancers has not been well defined. In this study, we analyzed cancer genomes from rare types of metastatic AYA cancers to identify driving and/or druggable genetic alterations. METHODS: Prospectively collected AYA tumor samples from seven different patients were analyzed using three different genomics platforms (whole-exome sequencing, whole-transcriptome sequencing or OncoScanTM). Using well-known bioinformatics tools (bwa, Picard, GATK, MuTect, and Somatic Indel Detector) and our annotation approach with open access databases (DAVID and DGIdb), we processed sequencing data and identified driving genetic alterations and their druggability. RESULTS: The mutation frequencies of AYA cancers were lower than those of other adult cancers (median = 0.56), except for a germ cell tumor with hypermutation. We identified patient specific genetic alterations in candidate driving genes: RASA2 and NF1 (prostate cancer), TP53 and CDKN2C (olfactory neuroblastoma), FAT1, NOTCH1, and SMAD4 (head and neck cancer), KRAS (urachal carcinoma), EML4-ALK (lung cancer), and MDM2 and PTEN (liposarcoma). We then suggested potential drugs for each patient according to his or her altered genes and related pathways. By comparing candidate driving genes between AYA cancers and those from all age groups for the same type of cancer, we identified different driving genes in prostate cancer and a germ cell tumor in AYAs compared with all age groups, whereas three common alterations (TP53, FAT1, and NOTCH1) in head and neck cancer were identified in both groups. CONCLUSION: We identified the patient-specific genetic alterations and druggability of seven rare types of AYA cancers using three genomics platforms. Additionally, genetic alterations in cancers from AYA and those from all age groups varied by cancer type. PMID- 26925976 TI - Fluoroquinolone and macrolide resistance in Campylobacter jejuni isolated from broiler slaughterhouses in southern Brazil. AB - Campylobacter jejuni is recognized as a leading cause of acute bacterial gastroenteritis in humans. The over-use of antimicrobials in the human population and in animal husbandry has led to an increase in antimicrobial-resistant infections, particularly with fluoroquinolones and macrolides. The aim of the present study was to provide information of the current status of antimicrobial resistance patterns in Campylobacter jejuni from poultry sources. Fifty strains were recovered from broiler slaughterhouses in Rio Grande do Sul state, Brazil, 2012. The strains were investigated for antimicrobial susceptibility against three agents (ciprofloxacin, nalidixic acid and erythromycin) by minimal inhibitory concentrations. The strains were analysed by polymerase chain reaction restriction fragment length polymorphism for detection of the Thr-86 mutation that confers resistance to ciprofloxacin. In addition, all the strains were tested for the presence of efflux systems (cmeB gene) conferring antimicrobial resistance. The minimum inhibitory concentrations results showed that 98% of isolates were sensitive to erythromycin and most isolates were resistant to ciprofloxacin (94%) and nalidixic acid (90%). A complete correlation was observed between the minimum inhibitory concentrations and PCR-RFLP assay. Finally, the cmeB gene that is responsible for multidrug resistance was detected in 16 isolates out the 50 strains (32%). PMID- 26925978 TI - Domino Synthesis of Tetrasubstituted Thiophenes from 1,3-Enynes with Mercaptoacetaldehyde. AB - Domino synthesis of tetrasubstituted thiophenes is described from 1,3-enynes and mercaptoacetaldehyde using DABCO at room temperature via a Michael addition, 5 exo-dig carboannulation, and oxidation sequence under air. The broad substrate scope and mild reaction conditions are significant practical features. PMID- 26925977 TI - Differential responses of the gut transcriptome to plant protein diets in farmed Atlantic salmon. AB - BACKGROUND: The potential for alternative plant protein sources to replace limited marine ingredients in fish feeds is important for the future of the fish farming industry. However, plant ingredients in fish feeds contain antinutritional factors (ANFs) that can promote gut inflammation (enteritis) and compromise fish health. It is unknown whether enteritis induced by plant materials with notable differences in secondary metabolism is characterised by common or distinct gene expression patterns, and how using feeds with single vs mixed plant proteins may affect the gut transcriptome and fish performance. We used Atlantic salmon parr to investigate the transcriptome responses of distal gut to varying dietary levels (0-45%) of soy protein concentrate (SPC) and faba bean (Vicia faba) protein concentrate (BPC) following an 8-week feeding trial. Soybean meal (SBM) and fish meal (FM) were used as positive and negative controls for enteritis, respectively. Gene expression profiling was performed using a microarray platform developed and validated for Atlantic salmon. RESULTS: Different plant protein materials (SPC, BPC and SBM) generated substantially different gut gene expression profiles, with relatively few transcriptomic alterations (genes, pathways and GO terms) common for all plant proteins used. When SPC and BPC were simultaneously included in the diet, they induced less extensive alterations of gut transcriptome than diets with either SPC or BPC singly, probably due to reduced levels of individual ANFs. The mixed plant protein diets were also associated with improved body composition of fish relative to the single plant protein diets, which may provide evidence for a link between the magnitude of changes in gut transcriptome and whole-animal performance. CONCLUSIONS: Our results indicate that gut transcriptomic profiling provides a useful tool for testing the applicability of alternative protein sources for aquaculture feeds and designing diets with reduced impact of ANFs on fish health. Ultimately, understanding diet-gut interactions and intestinal homeostasis in farmed fish is important to maximise performance and to ensure that aquaculture continues to be a sustainable source of food for a growing world population. PMID- 26925979 TI - Purinergic signalling-evoked intracellular Ca(2+) concentration changes in the regulation of chondrogenesis and skeletal muscle formation. AB - It is now widely recognised that changes of the intracellular calcium concentration have deep impact on the differentiation of various non-excitable cells including the elements of the vertebrate skeleton. It has become evident that purinergic signalling is one of the most ancient cellular mechanisms that can cause such alterations in the intracellular Ca(2+)-homeostasis, which are precisely set either spatially or temporally. Purinergic signalling is believed to regulate intracellular Ca(2+)-concentration of developing cartilage and skeletal muscle cells and suggested to play roles in the modulation of various cellular functions. This idea is supported by the fact that pluripotent mesenchymal cells, chondroprogenitors or muscle precursors, as well as mature chondrocytes all are capable of releasing ectonucleotides, and express various types of purinoreceptors and ectonucleotidases. The presence of the basic components of purinergic signalling proves that cells of the chondrogenic lineage can utilise this mechanism for modulating their intracellular Ca(2+) concentration independently from the surrounding skeletal muscle and bone tissues, which are well known to release ectopurines during development and mechanical stress. In this review, we summarize accumulating experimental evidence supporting the importance of purinergic signalling in the regulation of chondrogenesis and during skeletal muscle formation. PMID- 26925980 TI - Hiatal hernia, mitral valve prolapse and defecatory disorders: An underlying rectal prolapse? PMID- 26925981 TI - Sacral nerve stimulation versus percutaneous posterior tibial nerve stimulation in the treatment of severe fecal incontinence in men. AB - BACKGROUND: Sacral nerve stimulation and percutaneous posterior tibial nerve stimulation have been described previously as effective treatments for fecal incontinence. Nevertheless, there does not exist any study that compares the efficiency of both. The aim of this study was to compare the use of SNS and PPTNS in males with FI. METHODS: We conducted a prospective cohort study on men with FI treated with SNS or PTNS in the Coloproctology Unit of the University General Hospital of Elche and Reina Sofia of Murcia between January 2010 and December 2011. Preoperative assessment included physical examination, anorectal manometry, and anal endosonography. Anal continence was evaluated using the Wexner continence grading system. Quality of life was evaluated using the Fecal Incontinence Quality of life Scale. RESULTS: Nineteen patients were included (ten patients SNS and nine PPTNS). SNS improved FI in nine of the ten patients. The mean Wexner score decreased significantly from a median of 14 (12-16) (preoperative) to 4 (1-8) (6-month revision) (p = 0.007). PTNS improved FI in seven of the nine patients. The mean Wexner score decreased significantly from a median of 12 (11-19) (preoperative) to 5 (4-7) (6-month revision) (p = 0.018). Both treatments produced symptomatic improvement without statistical differences between them. CONCLUSIONS: Our study was nonrandomized with a relatively small number of patients. PPTNS had similar efficiency to the SNS in our men population. However, more studies are necessary to exclude selection bias and analyze long-term results. PMID- 26925982 TI - Solubility parameters of hypromellose acetate succinate and plasticization in dry coating procedures. AB - Solubility parameters of HPMCAS have not yet been investigated intensively. On this account, total and three-dimensional solubility parameters of HPMCAS were determined by using different experimental as well as computational methods. In addition, solubility properties of HPMCAS in a huge number of solvents were tested and a Teas plot for HPMCAS was created. The total solubility parameter of about 24 MPa(0.5) was confirmed by various procedures and compared with values of plasticizers. Twenty common pharmaceutical plasticizers were evaluated in terms of their suitability for supporting film formation of HPMCAS under dry coating conditions. Therefore, glass transition temperatures of mixtures of polymer and plasticizers were inspected and film formation of potential ones was further investigated in dry coating of pellets. Contact angles of plasticizers on HPMCAS were determined in order to give a hint of achievable coating efficiencies in dry coating, but none was found to spread on HPMCAS. A few common substances, e.g. dimethyl phthalate, glycerol monocaprylate, and polyethylene glycol 400, enabled plasticization of HPMCAS; however, only triethyl citrate and triacetin were found to be suitable for use in dry coating. Addition of acetylated monoglycerides to triacetin increased coating efficiency, which was likewise previously demonstrated for triethyl citrate. PMID- 26925983 TI - Cyclic Alkyl(amino) Carbene Stabilized Complexes with Low Coordinate Metals of Enduring Nature. AB - N-Heterocyclic carbenes (NHCs) are known to stabilize some metal atoms in different oxidation states mostly by their strong sigma-donation. After the successful syntheses of cyclic alkyl(amino) carbenes (cAACs), they have been proven to be much more effective in stabilizing electron rich species. In cAAC, one of the sigma-withdrawing and pi-donating nitrogen atoms of NHC is replaced by a sigma-donating quaternary carbon atom leading to a lower lying LUMO. This makes the acceptance of pi-back-donation from the element bound to the carbene carbon atom of cAAC energetically more advantageous. Further evidence suggests that the carbene carbon of cAAC can use the lone pair of electrons present on the adjacent nitrogen in a more controlled way depending on the accumulation of electron density on the bound metal. It has been found that cAAC can be utilized as excellent ligand for the stabilization of a complex with three coordinate metal center [(cAAC)2M(I)-Cl; M = Fe, Co, Cr]. Complex (cAAC)2M(II)Cl2 [M = Fe, Co, Cr] was prepared by reacting anhydrous M(II)Cl2 with two equiv of cAAC followed by treatment with one equiv of KC8 (reducing agent) to obtain (cAAC)2M(I)-Cl. The corresponding cation (cAAC)2M(+) was isolated when (cAAC)2M(I)-Cl was reacted with sodium-tetraarylborate (lithium) in toluene or fluorobenzene. The CV of cation (cAAC)2M(+) [M = Co, Fe] suggests that it can reversibly undergo one electron reduction. The cations of Co and Fe were reduced with Na(Hg) or KC8, respectively. (cAAC)2Co(I)Cl can be directly reduced to (cAAC)2Co(0) when reacted with one equiv of KC8. Analogous (cAAC.)2Zn(II) and (cAAC)2Mn complexes are prepared by reduction of (cAAC)MCl2 [M = Zn, Mn] with two equiv of KC8 in the presence of one equiv of cAAC. The square planar (cAAC)2NiCl2 complex was directly reduced by two equiv of LiN(iPr2) (KC8) to (cAAC)2Ni(0). The (cAAC)2Pd(0) and (cAAC)2Pt(0) complexes are prepared by substituting all four triphenylphosphines of (Ph3P)4M(0) [M = Pd, Pt] by two cAACs. Cation (cAAC)2M(+) [M = Cu, Au] was reduced with sodium/potassium to obtain the neutral analogue [(cAAC)2Cu, (cAAC)2Au]. Two coordinate Zn/Mn/Cu/Au are stabilized by two neutral carbene ligands possessing radical electrons on the carbene carbon atoms, while analogous complexes of Co/Fe/Ni/Pd/Pt contain metals in the zero oxidation state. The ground electronic structure of (cAAC)2M was thoroughly studied by theoretical calculations. In this Account, we summarize our developments in stabilizing metal complexes with low coordinate metal atoms in two, one, and most significantly in their zero oxidation states by utilizing cAACs as ligands. PMID- 26925984 TI - The promise of 3D skin and melanoma cell bioprinting. PMID- 26925985 TI - Serum tryptase levels in melanoma patients: first results of clinicopathological features. PMID- 26925986 TI - Local delivery of zoledronate from a poly (d,l-lactide)-coating increases fixation of hydroxy-coated implants. AB - Initial secure implant fixation predicts long-term survival. Bisphosphonates are anti-resorptive agents. They have been shown to increase implant fixation. We investigated whether local delivery of zoledronate from a poly-d,l-lactide (PDLLA)-coating could improve fixation and osseointegration of hydroxy-apatite coated implants. Cylindrical hydroxy-apatite coated implants were bilaterally inserted press-fit into the proximal tibiae of 10 dogs. On one side the implant was coated with PDLLA containing zoledronate. The PDLLA coating was applied upon the hydroxy-apatite coating. We used the contralateral implant as control. This implant was not coated with a poly-d,l-lactide. Observation period was 12 weeks. We evaluated implant fixation with histomorphometry and biomechanical push-out test. Zoledronate resulted in an approximately threefold increase in all biomechanical parameters when comparing data with their respective controls. We found that zoledronate increased preservation of old lamellar bone and increased formation of new woven bone. This study indicates that local delivery of zoledronate from a PDDLA coating has the potential to increase implant fixation. Studies investigating different doses of zoledronate and longer follow-up are needed. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:974-979, 2017. PMID- 26925987 TI - A Molecular Tetrad That Generates a High-Energy Charge-Separated State by Mimicking the Photosynthetic Z-Scheme. AB - The oxygenic photosynthesis of green plants, green algae, and cyanobacteria is the major provider of energy-rich compounds in the biosphere. The so-called "Z scheme" is at the heart of this "engine of life". Two photosystems (photosystem I and II) work in series to build up a higher redox ability than each photosystem alone can provide, which is necessary to drive water oxidation into oxygen and NADP(+) reduction into NADPH with visible light. Here we show a mimic of the Z scheme with a molecular tetrad. The tetrad Bodipy-NDI-TAPD-Ru is composed of two different dyes-4,4-difluoro-1,3,5,7-tetramethyl-2,6-diethyl-4-bora-3a,4a-diaza-s indacene (Bodipy) and a Ru(II)(bipyridine)3 (Ru) derivative-which are connected to a naphthalene diimide (NDI) electron acceptor and tetraalkylphenyldiamine (TAPD) playing the role of electron donor. A strong laser pulse excitation of visible light where the two dye molecules (Ru and Bodipy) absorb with equal probability leads to the cooperative formation of a highly energetic charge separated state composed of an oxidized Bodipy and a reduced Ru. The latter state cannot be reached by one single-photon absorption. The energy of the final charge separated state (oxidized Bodipy/reduced Ru) in the tetrad lies higher than that in the reference dyads (Bodipy-NDI and TAPD-Ru), leading to the energy efficiency of the tetrad being 47% of the sum of the photon threshold energies. Its lifetime was increased by several orders of magnitude compared to that in the reference dyads Bodipy-NDI and TAPD-Ru, as it passes from about 3 ns in each dyad to 850 ns in the tetrad. The overall quantum yield formation of this extended charge separated state is estimated to be 24%. Our proof-of-concept result demonstrates the capability to translate a crucial photosynthetic energy conversion principle into man-made molecular systems for solar fuel formation, to obtain products of higher energy content than those produced by a single photon absorption. PMID- 26925988 TI - Characteristics of the Family Caregivers Who Did Not Benefit From a Successful Psychoeducational Group Intervention During Palliative Cancer Care: A Prospective Correlational Study. AB - BACKGROUND: Although there has been a steady increase in intervention studies aimed toward supporting family caregivers in palliative cancer care, they often report modest effect sizes and there is a lack of knowledge about possible barriers to intervention effectiveness. OBJECTIVE: The aim of this study is to explore the characteristics of family caregivers who did not benefit from a successful psychoeducational group intervention compared with the characteristics of those who did. INTERVENTION/METHODS: A psychoeducational intervention for family caregivers was delivered at 10 palliative settings in Sweden. Questionnaires were used to collect data at baseline and following the intervention. The Preparedness for Caregiving Scale was the main outcome for the study and was used to decide whether or not the family caregiver had benefited from the intervention (Preparedness for Caregiving Scale difference score <= 0 vs >= 1). RESULTS: A total of 82 family caregivers completed the intervention and follow-up. Caregivers who did not benefit from the intervention had significantly higher ratings of their preparedness and competence for caregiving and their health at baseline compared with the group who benefited. They also experienced lower levels of environmental burden and a trend toward fewer symptoms of depression. CONCLUSIONS: Family caregivers who did not benefit from the intervention tended to be less vulnerable at baseline. Hence, the potential to improve their ratings was smaller than for the group who did benefit. IMPLICATIONS FOR PRACTICE: Determining family caregivers in cancer and palliative care who are more likely to benefit from an intervention needs to be explored further in research. PMID- 26925989 TI - The Challenges, Emotions, Coping, and Gains of Family Caregivers Caring for Patients With Advanced Cancer in Singapore: A Qualitative Study. AB - BACKGROUND: Caring for a family member with advanced cancer at home is demanding as the ill family member is likely to have complex physical and emotional needs. There is a paucity of studies on the experience of home family caregivers of people with advanced cancer in the Asian region. OBJECTIVE: The aim of this study was to describe the experiences of family caregivers caring for a person with advanced cancer at home in Singapore. METHODS: This was a qualitative study; data were collected by semistructured interviews and analyzed using content analysis. A purposive sample of 19 family caregivers who were taking care of a family member with advanced cancer were recruited from home hospice care services in Singapore. RESULTS: Most of the caregivers were female (n = 14), ranging in age from 21 to 64 years (mean, 46.4 [SD, 10.5] years). Four themes were generated from the data: (1) caregiving challenges, (2) negative emotions, (3) ways of coping, and (4) positive gains of caregiving. CONCLUSIONS: This study generated insights into the challenges, emotions, and coping of Asian family caregivers caring for patients with advanced cancer. Such understanding could help in developing appropriate intervention for caregivers to reduce their burden and stress. IMPLICATIONS FOR PRACTICE: Caregivers require knowledge on resolving family conflicts and about communicating and enhancing closeness with the ill family member. Support from healthcare professionals is essential even if caregivers have support from family members and friends; nurses can make conscious efforts to show concern for caregivers as well as for patients. PMID- 26925990 TI - Development of a Symptom Management Intervention: Qualitative Feedback From Advanced Lung Cancer Patients and Their Family Caregivers. AB - BACKGROUND: Little is known about cancer patient and family caregiver preferences for the content and format of nonpharmacologic interventions. Revising interventions based on patient and caregiver feedback before implementation may improve intervention feasibility and acceptability, especially in the context of advanced-stage cancer. OBJECTIVES: The aim of the study was to obtain feedback from patients with advanced-stage, symptomatic lung cancer and their family caregivers on the content and format of a nonpharmacologic symptom management intervention under development. The intervention blended evidence-based cognitive behavioral and emotion-focused strategies to reduce physical and psychological symptoms. METHODS: Semistructured qualitative interviews were conducted with 21 patients with advanced-stage, symptomatic lung cancer and caregivers. Participants reviewed handouts regarding intervention components and provided feedback. RESULTS: Patients and caregivers desired intervention components that addressed the patient's high symptom burden such as education regarding treatment adverse effects and the provision of various coping tools. Offering interventions with a brief or flexible length and delivering them via telephone were other suggestions for enhancing intervention acceptability. Participants also preferred an equal focus on patient and caregiver concerns and a more positive intervention framework. CONCLUSIONS: Intervention preferences of patients with advanced-stage lung cancer and caregivers underscore the severity of the disease and treatment process and the need to adapt interventions to patients with high symptom burden. These preferences may be incorporated into future intervention trials to improve participant recruitment and retention. IMPLICATIONS FOR PRACTICE: Nurses can modify interventions to meet the needs of patients with advanced-stage, symptomatic lung cancer and caregivers. For example, flexibility regarding intervention content and length may accommodate those with significant symptoms. PMID- 26925991 TI - Using Healthcare Failure Mode and Effect Analysis to Reduce Intravenous Chemotherapy Errors in Chinese Hospitalized Patients. AB - BACKGROUND: Intravenous chemotherapy administration is a high-risk process; attention must be paid to preventing errors that might occur during the administration of chemotherapy. OBJECTIVE: The aim of this study is to investigate whether the healthcare failure mode and effect analysis (HFMEA) is a valid proactive method to apply to chemotherapy administration in the Chinese oncology inpatient setting. METHODS: A multidisciplinary team created a flow diagram of the chemotherapy administration process and potential failure modes were identified and evaluated using a hazard-scoring matrix. Using a decision tree, failure mode recommendations were made. Chemotherapy error rates before and after the HFMEA were compared. RESULTS: A total of 5 failure modes were identified with high hazard scores, and 15 recommendations were made. After the intervention, the chemotherapy error rate decreased significantly from 2.05% to 0.17%. CONCLUSIONS: The complexity of intravenous chemotherapy makes it vulnerable to error, and with serious consequences. Multiple errors can occur during ordering, preparing, compounding, dispensing, and administering the chemotherapy. The process of HFMEA helped reduce the chemotherapy error rate in Chinese hospitalized patients. IMPLICATIONS FOR PRACTICE: Clinicians in oncology can take effective measures to avoid chemotherapy errors using the HFMEA. PMID- 26925992 TI - Effects of Slow-Stroke Back Massage on Symptom Cluster in Adult Patients With Acute Leukemia: Supportive Care in Cancer Nursing. AB - BACKGROUND: Patients with acute leukemia usually experience pain, fatigue, and sleep disorders, which affect their quality of life. Massage therapy, as a nondrug approach, can be useful in controlling such problems. However, very few studies have been conducted on the effects of massage therapy on the complications of leukemia. OBJECTIVE: The aim of this study was to examine the effects of slow-stroke back massage (SSBM) on the symptom cluster in acute leukemia adult patients undergoing chemotherapy. METHODS: In this randomized controlled trial, 60 patients with acute leukemia were allocated randomly to either the intervention or control group. The intervention group received SSBM 3 times a week (every other day for 10 minutes) for 4 weeks. The pain, fatigue, and sleep disorder intensities were measured using the numeric rating scale. The sleep quality was measured using the Pittsburgh Sleep Quality Index. Statistical tests of chi, t test, and the repeated-measure analysis of variance were used for data analysis. RESULTS: Results showed that the SSBM intervention significantly reduced the progressive sleep disorder, pain, fatigue, and improved sleep quality over time. CONCLUSIONS: Slow-stroke back massage, as a simple, noninvasive, and cost-effective approach, along with routine nursing care, can be used to improve the symptom cluster of pain, fatigue, and sleep disorders in leukemia patients. IMPLICATIONS FOR PRACTICE: Oncology nurses can increase their knowledge regarding this symptom cluster and work to diminish the cluster components by using SSBM in adult leukemia patients. PMID- 26925993 TI - Adolescents' Perspectives of Living With a Parent's Cancer: A Unique and Personal Experience. AB - BACKGROUND: By the age of 21 years, 1 in 15 children will have had a parent with a diagnosis of cancer. A parent's cancer affects the whole family. Adolescent children of cancer patients seek information about their parents' condition and support in reciprocal relations. OBJECTIVE: The aims of this study were to explore adolescents' views on support and information when a parent has cancer and to describe the impact a parent's illness has on adolescents' everyday lives. INTERVENTIONS/METHODS: Interviews with 11 participants, conducted individually or in a focus group, were processed using qualitative content analysis. RESULTS: Participants gained understanding about their parent's illness mainly through their experience. They looked for support primarily in their own social circles and often found their needs met. Sometimes a fear of appearing vulnerable stood in the way of asking for support and left the adolescents feeling alone. CONCLUSIONS: Participants dealt with the situation in ways that reflected their adolescence. They were connected to their parents emotionally, but strived for independence. The adolescents shared an ideal of handling difficulties on their own and looking after the people who were important to them. IMPLICATIONS FOR PRACTICE: Making parents feel more secure in supporting their adolescent child is important. The task of balancing respect for the adolescent's integrity and providing them an opportunity to let their guard down requires trust. Inviting the adolescents to the hospital gives them a chance to learn what is happening there and to get to know healthcare personnel who may be able to help them. PMID- 26925994 TI - Incidence and Determinants of Port Occlusions in Cancer Outpatients: A Prospective Cohort Study. AB - BACKGROUND: Normal saline is considered a safe alternative for heparin as a locking solution in totally implantable venous access devices. The incidence rate of partial occlusion with the use of normal saline (easy injection, impossible aspiration) is estimated at 4%. OBJECTIVE: The aim of this study was to investigate determinants of partial occlusions with the use of normal saline solution and the maintenance of positive pressure in the catheter. METHODS: We enrolled 218 patients with different solid tumors who underwent pharmacologic treatment through the port with different frequencies: from once every week to at least once every month. The port was flushed with normal saline solution keeping a positive pressure in the catheter. RESULTS: We performed 4111 observations and documented normal port functioning in 99% of observations (n = 4057) and partial occlusions in 1% of observations (n = 54). Partial occlusions were significantly associated with frequency of port flushing (P < .05), chemotherapy (P < .001), and blood sample collection (P < .001). CONCLUSIONS: The use of positive pressure in addition to normal saline reduces the incidence rate of partial occlusions. The type of treatment, blood sample collection, and treatment schedule are important determinants of partial occlusions. IMPLICATIONS FOR PRACTICE: Nurses play a key role in maintaining a functioning port using positive pressure during the flushing techniques. Certain risk factors must be monitored to prevent partial occlusions, and certain patients are more likely to present with port related problems. PMID- 26925995 TI - Death Anxiety and Quality of Life in Iranian Caregivers of Patients With Cancer. AB - BACKGROUND: Concerns about death may alienate and negatively impact communication among family members of patients with life-threatening illness. Little is known about the relationship of death anxiety to quality of life in cancer family caregivers. OBJECTIVE: The aim of this study was to examine relationships between sociodemographic and patient-related factors, social support, and religiosity with death anxiety and quality of life in Iranian cancer family caregivers. METHODS: Three hundred thirty family caregivers from an urban regional cancer institute in Iran participated in a descriptive-correlational study that incorporated sociodemographic surveys and validated death anxiety (Templer Scale) and Quality of life (Family Version) instruments. RESULTS: Caregivers reported moderate levels of death anxiety and decrements in QOL. Quality of life was inversely associated with death anxiety (r = -0.30, P < .001). Female caregivers who were daughters had higher death anxiety, whereas male caregivers who were sons reported higher quality of life. CONCLUSIONS: Death anxiety is associated with lowered quality of life in Iranian family caregivers. Multiple factors may impact death anxiety and quality of life relevant to the socioreligious milieu. IMPLICATIONS FOR PRACTICE: Addressing concerns that increase death anxiety may improve quality of life and lower stress associated with adapting to the family caregiver role. Caregiving responsibilities, added to challenges associated with personal, family, and professional life, impact multiple aspects of QOL. As nurses increasingly care for patients from diverse backgrounds, it becomes more imperative that support for family caregivers that promotes psychological adaptation and quality of life is needed. PMID- 26925996 TI - The Efficacy of Couple-Based Interventions on Health-Related Quality of Life in Cancer Patients and Their Spouses: A Meta-analysis of 12 Randomized Controlled Trials. AB - BACKGROUND: Couple-based interventions on health-related quality of life (HRQoL) of cancer patients and their spouses have received increasing attention in recent years, but the findings of previous studies are inconsistent. OBJECTIVE: The aim of this study was to investigate the effects of couple-based interventions on the HRQoL of cancer patients and their spouses using a meta-analysis approach. METHOD: English- and Chinese-language publications were collected from PubMed, EBSCO, EMBASE, CMB, and CNKI. The outcome measures included physical health, depression, anxiety, hopelessness, and marital satisfaction (MS). Pooled, weighted mean differences and 95% confidence intervals were estimated using fixed and random-effects models. Publication bias and sensitivity analyses were performed. RESULTS: Twelve randomized controlled trials were included in this study. Compared with the control groups, the weighted mean differences of depression, anxiety, and MS were significantly improved in the intervention groups. However, improvements in the measures of physical health and hopelessness were nonsignificant. Psychoeducational interventions yielded a larger effect size than did skill training and blending interventions. Publication bias was not significant, and a sensitivity analysis indicated that the results were robust. CONCLUSIONS: Couple-based interventions can improve anxiety, depression, and MS among cancer patients and their spouses, and psychoeducational interventions may be an effective approach. Given the small number of studies utilized in this analysis, the results should be considered preliminary and interpreted with caution. IMPLICATIONS FOR PRACTICE: Couple-based interventions may be an adjunctive method for cancer patients and their spouses to improve HRQoL. Further study concerning couple-based skill training and blending intervention are needed to better understand intervention effects. PMID- 26925997 TI - "Cancer Put My Life on Hold": Work-Related Challenges Among Middle-aged Adults 12 Months After a Diagnosis of Colorectal Cancer. AB - BACKGROUND: Colorectal cancer affects a wide range of working-age people. Little is known about the consequent work limitations. OBJECTIVE: The aim of this study was to understand the extent and changing nature of work-related limitations of middle-aged (45-64 years) people over the first 12 months of colorectal cancer. METHODS: Surveys were administered to participants recruited via the Queensland Cancer Registry, at 6 and 12 months after diagnosis. Among those who returned to work, the Work Limitations Questionnaire measured 4 job performance domains (time management, physical, mental-interpersonal, and output demands) and an overall productivity score. Open-ended questions supplemented the Work Limitations Questionnaire, and responses were thematically analyzed. RESULTS: Of 239 participants, 8% did not continue in the study, and 20% left employment by 12 months, leaving 171 participants eligible for this analysis. Open-ended responses for why participants stopped work included bowel problems and stoma, loss of strength, and medication adverse effects. At 12 months, 22% to 39% of participants reported work limitations, but there was no overall significant change in work limitations between 6 and 12 months. Qualitative data highlighted the key work-related issues were changes in work functioning, attitudes of employers and colleagues, financial pressures, and emotional responses. CONCLUSIONS: While a significant proportion left work because of treatment related problems, and the majority of participants did not experience workplace limitations, some reported considerable work-related challenges. IMPLICATIONS FOR PRACTICE: Discussions with health professionals about the possible impact of treatment adverse effects on employment, good communication with employers, and workplace flexibility may facilitate return to work for this population. PMID- 26925998 TI - A Systematic Review of Emergency Department Use Among Cancer Patients. AB - BACKGROUND: Recent reports call for reductions in costly and potentially avoidable services such as emergency department (ED) visits. Providing high quality and safe care for oncology patients remains challenging for ED providers given the diversity of patients seeking care and the unpredictable clinical environment. While ED use by oncology patients is appropriate for acute health concerns, some ED visits may be preventable with well-coordinated care and adequate symptom management. OBJECTIVE: The aim of this study was to summarize available evidence regarding the incidence, predictors of, and reasons for ED visits among oncology patients. METHODS: Keyword/MeSH term searches were conducted using 4 online databases. Inclusion criteria were publication date between April 1, 2003, and December 5, 2014; sample size of 50 or more; and report of the incidence or predictors of ED use among oncology patients. RESULTS: The 15 studies that met criteria varied in study aim, design, and time frames for calculating ED utilization rates. The incidence of ED visits among oncology patients ranged from 1% to 83%. The 30-day standardized visit rate incidence ranged from 1% to 12%. Collectively, the studies lack population-based estimates for all cancers combined. CONCLUSIONS: The studies included in this review suggest that rates of ED use among cancer patients exceed those of the general population. However, the extent of ED use by oncology patients and the reasons for ED visits remain understudied. IMPLICATIONS FOR PRACTICE: Nurses are involved in the treatment of cancer, patient education, and symptom management. Nurses are well positioned to develop patient-centered treatment and care coordination plans to improve quality of care and reduce ED visits. PMID- 26926000 TI - Intrapartum, postpartum characteristics and early neonatal outcomes of idiopathic polyhydramnios. AB - This paper investigates the effect of idiopathic polyhydramnios on the intrapartum and postpartum characteristics of labour and early neonatal outcomes. In this study, intrapartum and early neonatal outcomes of 207 women with idiopathic polyhydramnios and 336 matched healthy pregnant patients were evaluated. In the case of idiopathic polyhydramnios, the active phase of labour became longer when compared to the control group (5.76 +/- 3.56 h vs. 4.38 +/- 2.8 h, p: 001). The risk of preterm birth (OR 5.23; 95% CI: 2.04-13.42) and caesarean section (OR 2.26; 95% CI: 1.56-3.28) was higher in women with IP. Patients with IP had a higher rate of transcient tachypnoea of the newborn (TTN), newborn resuscitation, admission to neonatal intensive care unit (NICU), ventilator requirement, newborn jaundice, newborn hypoglycaemia and structural anomalies. IP did not cause any appreciable maternal risk during the intrapartum or postpartum periods. However, neonatal morbidity and post-natal anomaly rates were higher in the case of IP. PMID- 26925999 TI - Exploration of Exercise Outcome Expectations Among Breast Cancer Survivors. AB - BACKGROUND: Exercise is associated with decreased recurrence risk and improved survival and quality of life for breast cancer survivors. However, only an estimated 17% to 37% of survivors adhere to the American Cancer Society exercise guidelines. A critical first step to increase exercise among survivors is to understand how they believe exercise will affect them. OBJECTIVE: The aim of this study is to explore common exercise outcome expectations among 20 female survivors of stage IA to IIB breast cancer who completed adjuvant treatment and an exercise intervention. METHODS: A mixed-method descriptive study consisting of semistructured telephone interviews assessed exercise outcome expectations and how the experience of cancer and its treatment influenced the expected outcomes of exercise. The qualitative data were analyzed using a summative content analysis procedure; means were calculated for each item of the exercise outcome questionnaire. The qualitative and quantitative data were compared and contrasted. RESULTS: The sample was 70% white and 30% African American, with a mean (SD) age of 62 (8.5) years, and mean (SD) time since treatment completion of 4.2 (1.3) years. Three themes emerged from the interviews: (1) prevalence of common expectations, (2) pervasive impact of fatigue, and (3) a brighter future. Overall, findings revealed that breast cancer survivors have low levels of agreement that exercise may mitigate late and long-term cancer and treatment effects. CONCLUSIONS: In general, breast cancer survivors (even those who are motivated to exercise) do not hold strong beliefs that exercise will decrease late and long-term treatment effects. IMPLICATIONS FOR PRACTICE: Clinicians can educate survivors about exercise benefits. PMID- 26926001 TI - Proconvulsant effects of antidepressants - What is the current evidence? AB - Antidepressant drugs may have proconvulsant effects. Psychiatric comorbidity in epilepsy is common. Prescribers might be reluctant to initiate treatment with antidepressants in fear of seizure aggravation. The purpose of this review was to focus upon the current evidence for proconvulsant effects of antidepressants and possible clinical implications. Most antidepressants are regarded as safe and may be used in patients with epilepsy, such as the newer serotonin and/or noradrenaline reuptake inhibitors. Four older drugs should, however, be avoided or used with caution; amoxapine, bupropion, clomipramine and maprotiline. Proconvulsant effects are concentration-related. Optimization of drug treatment includes considerations of pharmacokinetic variability to avoid high serum concentrations of the most proconvulsant antidepressants. The risk of seizures is regarded as small and should, therefore, not hamper the pharmacological treatment of depression in people with epilepsy. PMID- 26926002 TI - Reflections on a career in epilepsy: An unplanned journey. PMID- 26926003 TI - Extensive Erythema and Hyperkeratosis on the Extremities and Lumbar Area as an Unusual Mani-festation of Nagashima-type Palmoplantar Keratosis. PMID- 26926004 TI - Qualitative study on custodianship of human biological material and data stored in biobanks. AB - BACKGROUND: Balancing the rights and obligations of custodians and applicants in relation to access to biobanks is of utmost importance to guarantee trust and confidence. This study aimed to reveal which issues divide different stakeholders in an attempt to determine the rights and/or obligations held on human biological materials (HBM) and data. METHODS: Twenty-eight informants in the Benelux and Scandinavia were interviewed in order to capture the perspectives of experts and stakeholders in relation to the rights and obligations held by custodians and applicants with respect to access to HBM and data. RESULTS: There was no consensus among the informants on whether the custodian of a biobank should decide upon the scientific merits and the utility of an access request. Nearly all informants agreed that a new request or an amendment to the initial request has to be submitted when an applicant wants to use leftover HBM in a new or follow-up project. Several informants felt that it might be justified to charge higher access fees to external or industrial applicants that did not contribute (directly or indirectly) to the collection of HBM and data. Most informants agreed that a custodian of a biobank could request the sharing and return of research results. It was furthermore argued that some of the benefits of research projects should be fed back into biobanks. CONCLUSIONS: The interviews revealed a rather complex web of rights and obligations allocated to the custodian and the applicant in relation to access to HBM and data stored in biobanks. Some rights and obligations are negotiated on a case-by-case basis, while others are stipulated in access arrangements. We did find a consensus on the attribution of certain general rights to the custodians and the applicant. PMID- 26926005 TI - Association of Kidney Tissue Barrier Disrupture and Renal Dysfunction in Resuscitated Murine Septic Shock. AB - Septic shock-related kidney failure is characterized by almost normal morphological appearance upon pathological examination. Endothelial barrier disrupture has been suggested to be of crucial importance for septic shock induced organ dysfunction. Therefore, in murine resuscitated cecal ligation and puncture (CLP)-induced septic shock, we tested the hypothesis whether there is a direct relationship between the kidney endothelial barrier injury and renal dysfunction. Anesthetized mice underwent CLP, and 15 h later, were anesthetized again and surgically instrumented for a 5-h period of intensive care comprising lung-protective mechanical ventilation, fluid resuscitation, continuous i.v. norepinephrine to maintain target hemodynamics, and measurement of creatinine clearance (CrCl). Animals were stratified according to low or high CrCl. Nitrotyrosine formation, expression of the inducible isoform of the nitric oxide synthase, and blood cytokine (tumor necrosis factor, interleukin-6, interleukin 10) and chemokine (monocyte chemoattractant protein-1, keratinocyte-derived chemokine) levels were significantly higher in animals with low CrCl. When plotted against CrCl and neutrophil gelatinase-associated lipocalin levels, extravascular albumin accumulation, and tissue expression of the vascular endothelial growth factor and angiopoietin-1 showed significant mathematical relationships related to kidney (dys)function. Preservation of the constitutive expression of the hydrogen sulfide producing enzyme cystathione-gamma-lyase was associated with maintenance of organ function. The direct quantitative relation between microvascular leakage and kidney (dys)function may provide a missing link between near-normal tissue morphology and septic shock-related renal failure, thus further highlighting the important role of vascular integrity in septic shock-related renal failure. PMID- 26926008 TI - Vessel perforation and false tracking resulting from umbilical artery catheterization: a case report and literature review. AB - We report an extremely low birth weight neonate who developed umbilical artery perforation and false tracking. There was no life threatening event relating to the complication. Diagnosis was made at postmortem examination. Little information exists regarding the anatomic and vascular effects of UAC placement in newborns. We report a new complication of umbilical artery catheterization. We raise the awareness regarding the potential life threat due to this rare but very serious complication. PMID- 26926007 TI - Critical phenomenon of the near room temperature skyrmion material FeGe. AB - The cubic B20 compound FeGe, which exhibits a near room temperature skyrmion phase, is of great importance not only for fundamental physics such as nonlinear magnetic ordering and solitons but also for future application of skyrmion states in spintronics. In this work, the critical behavior of the cubic FeGe is investigated by means of bulk dc-magnetization. We obtain the critical exponents (beta = 0.336 +/- 0.004, gamma = 1.352 +/- 0.003 and beta = 5.276 +/- 0.001), where the self-consistency and reliability are verified by the Widom scaling law and scaling equations. The magnetic exchange distance is found to decay as r( 4.9), which is close to the theoretical prediction of 3D-Heisenberg model (r( 5)). The critical behavior of FeGe indicates a short-range magnetic interaction. Meanwhile, the critical exponents also imply an anisotropic magnetic coupling in this system. PMID- 26926006 TI - Applying the termination of resuscitation rules to out-of-hospital cardiac arrests of both cardiac and non-cardiac etiologies: a prospective cohort study. AB - BACKGROUND: The 2015 American Heart Association Guidelines for Cardiopulmonary Resuscitation recommend Basic Life Support (BLS) and Advanced Life Support (ALS) rules for termination of resuscitation (TOR). However, it is unclear whether the TOR rules are valid for out-of-hospital cardiac arrests (OHCAs) of both cardiac and non-cardiac etiologies. In this study, we validated the TOR rules for OHCA resulting from both etiologies. METHODS: This was a prospective multicenter observational study of OHCA patients transported to 67 emergency hospitals between January 2012 and March 2013 in the Kanto region of Japan. We calculated the specificity and positive predictive value (PPV) for neurologically unfavorable outcomes at one month in patients with OHCA of cardiac and non cardiac etiologies. RESULTS: Of 11,505 eligible cases, 6,138 and 5,367 cases were of cardiac and non-cardiac etiology, respectively. BLS was performed on 2,818 and 2,606 patients with OHCA of cardiac and non-cardiac etiology, respectively. ALS was performed on 3,320 and 2,761 patients with OHCA of cardiac and non-cardiac etiology, respectively. The diagnostic accuracy of the TOR rules for predicting unfavorable outcomes in patients with OHCA of cardiac etiology who received BLS included a specificity of 0.985 (95% confidence interval [CI]: 0.956-0.997) and a PPV of 0.999 (95% CI: 0.996-1.000). In patients with OHCA from cardiac etiologies who received ALS, the TOR rules had a specificity of 0.963 (95% CI: 0.896-0.992) and a PPV of 0.997 (95% CI: 0.991-0.999). In patients with OHCA from non-cardiac etiologies who received BLS, the specificity was 0.915 (95% CI: 0.796-0.976) and PPV was 0.998 (95% CI: 0.995-0.999). For patients with OHCA from non-cardiac etiologies who received ALS, the specificity was 0.833 (95% CI: 0.586-0.964) and PPV was 0.996 (95% CI: 0.988-0.999). CONCLUSIONS: Both TOR rules have high specificity and PPV in patients with OHCA from cardiac etiologies. For patients with OHCA from non-cardiac etiologies, the rules had a high PPV, but relatively low specificity. Therefore, TOR rules are useful in patients with OHCA from cardiac etiologies, but should be applied with caution to patients with OHCA from non-cardiac etiologies. PMID- 26926009 TI - Patient-derived xenograft platform of OSCC: a renewable human bio-bank for preclinical cancer research and a new co-clinical model for treatment optimization. AB - Advances in next-generation sequencing and bioinformatics have begun to reveal the complex genetic landscape in human cancer genomes, including oral squamous cell carcinoma (OSCC). Sophisticated preclinical models that fully represent intra- and inter-tumoral heterogeneity are required to understand the molecular diversity of cancer and achieve the goal of personalized therapies. Over the last decade, patient-derived xenograft (PDX) models generated from human tumor samples that can retain the histological and genetic features of their donor tumors have been shown to be the preferred preclinical tool in translational cancer research compared with other conventional preclinical models. Specifically, genetically well-defined PDX models can be applied to accelerate targeted antitumor drug development and biomarker discovery. Recently, we have successfully established and characterized an OSCC PDX panel as part of our tumor bio-bank for translational cancer research. In this paper, we discuss the establishment, characterization, and preclinical applications of the PDX models. In particular, we focus on the classification and applications of the PDX models based on validated annotations, including clinicopathological features, genomic profiles, and pharmacological testing information. We also explore the translational value of this well-annotated PDX panel in the development of co-clinical trials for patient stratification and treatment optimization in the near future. Although various limitations still exist, this preclinical approach should be further tested and improved. PMID- 26926010 TI - A Multibody Knee Model Corroborates Subject-Specific Experimental Measurements of Low Ligament Forces and Kinematic Coupling During Passive Flexion. AB - A multibody model of the knee was developed and the predicted ligament forces and kinematics during passive flexion corroborated subject-specific measurements obtained from a human cadaveric knee that was tested using a robotic manipulator. The model incorporated a novel strategy to estimate the slack length of ligament fibers based on experimentally measured ligament forces at full extension and included multifiber representations for the cruciates. The model captured experimentally measured ligament forces (<= 5.7 N root mean square (RMS) difference), coupled internal rotation (<= 1.6 deg RMS difference), and coupled anterior translation (<= 0.4 mm RMS difference) through 130 deg of passive flexion. This integrated framework of model and experiment improves our understanding of how passive structures, such as ligaments and articular geometries, interact to generate knee kinematics and ligament forces. PMID- 26926012 TI - Offense or defense? PMID- 26926011 TI - Downregulation of TAP38/PPH1 enables LHCII hyperphosphorylation in Arabidopsis mutant lacking LHCII docking site in PSI. AB - Redox-regulated reversible phosphorylation of the light-harvesting complex II (LHCII) controls the excitation energy distribution between photosystem (PS) II and PSI. The PsaL and PsaH subunits of PSI enable the association of pLHCII to PSI. Here, we show that the failure of the psal mutant to dock pLHCII to PSI induces excessive phosphorylation of LHCII, primarily due to a marked downregulation of the TAP38/PPH1 phosphatase occurring at post-transcriptional level. TAP38/PPH1 is shown to be associated with megacomplex that contains both photosystems in a light- and LHCII-PSII core-phosphorylation-dependent manner. It is suggested that proper megacomplex-related association of TAP38/PPH1 protects it against degradation. PMID- 26926013 TI - Ultraviolet photofunctionalization of orthodontic miniscrews. PMID- 26926014 TI - Risk management strategies. Part 1: Clinical considerations. PMID- 26926015 TI - Authors' response. PMID- 26926016 TI - When is enough, enough? PMID- 26926017 TI - How long does treatment with fixed orthodontic appliances last? A systematic review. AB - INTRODUCTION: There is little agreement on the expected duration of a course of orthodontic treatment; however, a consensus appears to have emerged that fixed appliance treatment is overly lengthy. This has spawned numerous novel approaches directed at reducing the duration of treatment, occasionally with an acceptance that occlusal outcomes may be compromised. The aim of this study was to determine the mean duration and the number of visits required for comprehensive orthodontic treatment involving fixed appliances. METHODS: Multiple electronic databases were searched with no language restrictions, authors were contacted as required, and reference lists of potentially relevant studies were screened. Randomized controlled trials and nonrandomized prospective studies concerning fixed appliance treatment with treatment duration as an outcome measure were included. Data extraction and quality assessment were performed independently and in duplicate. RESULTS: Twenty-five studies were included after screening: 20 randomized controlled trials and 5 controlled clinical trials. Twenty-two studies were eligible for meta-analysis after quality assessment. The mean treatment duration derived from the 22 included studies involving 1089 participants was 19.9 months (95% confidence interval, 19.58, 20.22 months). Sensitivity analyses were carried out including 3 additional studies, resulting in average duration of treatment of 20.02 months (95% confidence interval, 19.71, 20.32 months) based on data from 1211 participants. The mean number of required visits derived from 5 studies was 17.81 (95% confidence interval, 15.47, 20.15 visits). CONCLUSIONS: Based on prospective studies carried out in university settings, comprehensive orthodontic treatment on average requires less than 2 years to complete. PMID- 26926018 TI - Factors affecting patients' adherence to orthodontic appointments. AB - INTRODUCTION: Studies show that attendance at orthodontic appointments affects treatment outcomes, treatment duration, and the probability of side effects. The aim of this study was to predict factors that influence patients' attendance at orthodontic appointments. METHODS: We conducted a face-to-face guided interview survey of 153 participants from orthodontic clinics in the Greater Boston area. Attendance at scheduled orthodontic appointments was self-reported as always, sometimes, or rarely. Participants' characteristics, including demographics, dental insurance, and oral hygiene practices, were self-reported. Moreover, from dental records, we collected the time that the participants spent undergoing active orthodontic treatment. Multivariable ordered logistic regression was used to report proportional odds ratios and attendance probabilities. A likelihood ratio test was performed to ensure that the proportional odds assumption held. RESULTS: For overall appointment attendance, 76% of the participants reported always attending, 16% reported sometimes attending, and 8% reported rarely attending. Based on multivariable logistic regression (adjusted for age, race, and sex), the participants with optimal oral hygiene practices were almost 6 times (5.9) more likely to attend appointments than those who did not (P = 0.002). The odds of attending appointments decreased significantly (by 23%) for every 6-month increase in treatment duration (P = 0.008). Participants covered by non-Medicaid insurance were 4 times (P = 0.018) more likely to attend appointments than were those with Medicaid insurance. CONCLUSION: Our findings indicate that adherence to orthodontic treatment follow-up visits was strongly correlated to insurance type, treatment duration, and oral hygiene practices. Unlike previous studies, sex was not a significant predictor of adherence. PMID- 26926019 TI - Comparison of longitudinal changes in clinical periodontal parameters of canines and first molars treated with fixed orthodontic appliances. AB - INTRODUCTION: Our objective was to learn the possible effects of fixed orthodontic therapy on the periodontium of the extraction sites adjacent to canines and first molars. This was a prospective cohort study. METHODS: Sixty-two systemically healthy subjects were selected. The study was divided into the period of oral hygiene instructions and the period of active orthodontic treatment. Plaque index, gingival index, probing pocket depth, and clinical attachment loss were recorded for the canines and first molars at baseline, after 1 month of orthodontic therapy, and every 3 months until the completion of the orthodontic treatment. RESULTS: There was a statistically significant increase in all clinical parameters (plaque index, gingival index, probing pocket depth, and attachment loss; P <0.05) on the first molars compared with the canines. Significant increases in attachment loss were noted in both the canines (baseline, 0.06 +/- 0.01 mm; end of treatment, 0.17 +/- 0.02 mm) and the molars (baseline, 0.07 +/- 0.01 mm; end of treatment, 0.20 +/- 0.02 mm). CONCLUSIONS: Attachment loss cannot be explained solely by the effect of plaque or the banding of teeth. Other factors such as tooth extractions adjacent to the canines, tooth movement, and occlusal trauma may have contributing roles in the loss of periodontal support in adolescent patients. PMID- 26926020 TI - White spot lesion formation after treatment with full-coverage rapid maxillary expanders. AB - INTRODUCTION: The aim of this study was to evaluate whether treatment with full coverage bonded acrylic splint expanders causes formation of white spot lesions using quantitative light-induced fluorescence. METHODS: The experimental group underwent rapid maxillary expansion (RME) (n = 16; 6 boys, 10 girls; mean age, 14.1 +/- 2.2 years), and the control group received no orthodontic treatment (n = 17; 9 men, 8 women; mean age, 20.7 +/- 1.1 years). Quantitative light-induced fluorescence images of the RME patients were taken before cementation and after decementation of the appliances. The images of the control group comprised quantitative light-induced fluorescence images taken 3 months apart. Four parameters were calculated for 10 anterior teeth. RESULTS: Between cementation and decementation, statistically significant differences were found in all 4 parameters in the RME group, whereas no significant changes were found in any parameters in the control group. A comparison of the measured parameters between the RME and control groups showed statistically significant differences. CONCLUSIONS: Patients treated with a full-coverage bonded appliance tended to develop more white spot lesions than did the control subjects. PMID- 26926021 TI - Congenitally missing maxillary lateral incisors: Long-term periodontal and functional evaluation after orthodontic space closure with first premolar intrusion and canine extrusion. AB - INTRODUCTION: The aims of this investigation were to evaluate associations between orthodontic space closure (including first premolar intrusion and canine extrusion for esthetic reasons) and periodontal tissue deterioration over a 10 year period in subjects with one or both missing maxillary lateral incisors and to investigate the occurrence of signs or symptoms of temporomandibular disorder (TMD). METHODS: This was a retrospective cohort study comprising patients treated by the same orthodontist. The agenesis group included 26 consecutive adolescent and young adult patients (9 male, 17 female) treated with space closure. The control group consisted of 32 orthodontic patients (12 male, 20 female) with no missing teeth and no need for extractions. In the agenesis group, full-mouth probing pocket depths and bleeding on probing were recorded at 6 locations for each of 657 teeth (3942 periodontal sites). In the control group, comparative data were collected for the maxillary first molars, premolars, canines, and lateral incisors, a total of 264 teeth (1584 periodontal sites). Mobility and gingival recession were also evaluated. Patients in both groups completed questionnaires concerning symptoms related to TMD. RESULTS: The full-mouth assessments in the agenesis group generally demonstrated periodontally healthy conditions, with probing depths below 4 mm and few bleeding sites. Some slight recessions were found, mostly on molars and second premolars, and there was normal mobility of first premolars that substituted for canines. Comparisons between the agenesis and control groups showed no statistically significant differences for the maxillary teeth regarding increased pocket depth (>=4 mm) or increased mobility. Interproximal sites in the agenesis group showed less bleeding on probing than in the control group; this was statistically significant. Anterior teeth in the agenesis group did not show any more recession than in the controls. In addition, we observed no difference in signs or symptoms between the 2 groups; this might be due to the limited sample size or the drawbacks of the surveys of TMD through subjects' recall. Thus, the long-term periodontal tissue health and the incidence of dysfunction or TMD signs were similar in the space-closure agenesis group and in the control group of nonextraction orthodontic patients. CONCLUSIONS: Orthodontic space closure including first premolar intrusion and canine extrusion in patients with missing lateral incisors does not incur risks for periodontal tissue deterioration or TMD in the long term. PMID- 26926022 TI - Effect of different incisor movements on the soft tissue profile measured in reference to a rough-surfaced palatal implant. AB - INTRODUCTION: The aim of this study was to evaluate soft tissue profile changes after a wide range of incisor movements in the anterior and posterior directions in nongrowing patients. Identifying baseline values more prone to substantial soft tissue profile changes was of high interest. METHODS: For this retrospective study, 47 pairs of lateral cephalograms of nongrowing white patients were superimposed. The cephalograms were taken with the same palatal implant in situ before and after treatment. To increase the accuracy of the measurements, the palatal implants were used as stable reference structures in close relation to the incisors. RESULTS: Horizontal changes of the most anterior point of the maxillary incisor showed a significant correlation to horizontal changes of the upper and lower lips (P <0.001). For every millimeter of horizontal change of the most anterior point of the maxillary central incisor, a change of 0.59 mm at labrale superior can be expected. Also, the angulations of the upper and lower lips were significantly correlated to the most anterior point of the maxillary incisor. Lip retraction was less pronounced in patients with initially thicker lips than in those with thinner lips. CONCLUSIONS: The major contributing factors for predicting the soft tissue profile change during orthodontic treatment are the amount of horizontal movement of the most anterior point of the maxillary incisor, the amount of bite opening, and the initial lip thickness. Although there are significant correlations between dental movements and soft tissue changes in larger samples, predictions for individuals may be inconsistent. PMID- 26926023 TI - Effects of angiotensin II type I receptor blocker losartan on orthodontic tooth movement. AB - INTRODUCTION: Drugs that block the renin-angiotensin system (RAS) are widely used for treating hypertension, heart and kidney failure, and the harmful effects of diabetes. Components of the RAS have been identified in various organs, but little is known of their effects on bone remodeling. The aim of this study was to evaluate whether the blockage of the RAS influences strain-induced bone remodeling in a model of orthodontic tooth movement. METHODS: An orthodontic appliance was placed in C57BL6/J mice that were randomly divided into 2 groups: vehicle-treated mice (VH) and mice treated with losartan (an angiotensin II receptor blocker). Orthodontic tooth movement and the number of tartrate resistant acid phosphatase-positive cells were determined by histopathologic analysis. The expression of mediators involved in bone remodeling was evaluated by quantitative real-time polymerase chain reaction. Blood pressure was measured before and during the experimental period. RESULTS: Orthodontic tooth movement and tartrate-resistant acid phosphatase-positive cells were significantly reduced in the losartan group compared with the VH group. mRNA levels of osteoclast markers (RANK, RANKL, cathepsin K, and metalloproteinase 13) were lower in the losartan mice than in the VH group, whereas the expressions of osteoblast markers and negative regulators of bone resorption (periostin, dentin matrix protein, alkaline phosphatase, collagen 1A1, semaphorin 3A3, metalloproteinase 2, and osteoprotegerin) were higher in the VH group. CONCLUSIONS: Blockage of the RAS system decreases osteoclast differentiation and activity and, consequently, results in decreased strain-induced bone remodeling in orthodontic tooth movement. PMID- 26926024 TI - Effects of vascular endothelial growth factor on osteoblasts and osteoclasts. AB - INTRODUCTION: Bone remodeling is crucial to the success of many dental procedures and is tightly regulated. Vascular endothelial growth factor (VEGF), a key cytokine for angiogenesis, is also an important regulator of bone remodeling. We aimed to examine the mechanisms by which VEGF induces bone remodeling by studying its effects on cultured osteoblasts and osteoclasts. METHODS: Preosteoblastic MC3T3-E1 cells were treated with vehicle or VEGF-A165. Cell proliferation, migration, and invasion potentials were assessed. Preosteoclastic RAW264.7 cells were treated with vehicle or VEGF with or without the receptor activator of nuclear factor kappa-B ligand (RANKL), and osteoclast formation was measured with tartrate-resistant acid phosphatase staining. Conditioned media from vehicle treated or VEGF-treated MC3T3-E1 cells were tested for the levels of RANKL and osteoprotegerin (OPG) and were used to treat RAW264.7 cells to observe osteoclast formation. RESULTS: VEGF significantly induced MC3T3-E1 cell proliferation, migration, and invasion. VEGF did not directly induce osteoclastogenesis but significantly increased the RANKL/OPG ratio in the conditioned media from the MC3T3-E1 cultures; this significantly increased osteoclast formation. CONCLUSIONS: VEGF stimulates osteoclast differentiation by increasing the osteoblastic RANKL/OPG ratio but has no direct effect on osteoclast precursor cells, and it induces osteoblast proliferation, migration, and invasion potentials in vitro. PMID- 26926025 TI - Maxillary changes with bone-borne surgically assisted rapid palatal expansion: A prospective study. AB - INTRODUCTION: The aim of this prospective study was to analyze the postexpansion positional changes of the maxillary halves and their initial stability after transpalatal distraction with a bone-borne distractor and standard corticotomies of the anterior, lateral, and median bony supports of the maxilla without pterygomaxillary disjunction. METHODS: The sample consisted of 21 patients (15 female, 6 male; mean age, 26 years 5 months). Measurements on the maxillary study casts and the posteroanterior cephalograms were obtained before surgery, at the end of palatal expansion, and 10 weeks later. No orthodontic treatment was initiated during the examination period. RESULTS: After palatal expansion, significantly wider measurements were noted in the canine (35.5%), premolar (26.3%), and molar (17.8%) regions. Angulation changes in the premolar (-7 degrees ) and molar (-8 degrees ) segments were observed. No significant changes were seen between the end of palatal expansion and 10 weeks later. Arch perimeter increased by 9.16% between presurgery and 10 weeks after the end of expansion. CONCLUSIONS: The results indicated that more expansion was achieved anteriorly, and that there was buccal tipping of the split maxillary halves. Bone-borne surgically assisted rapid palatal expansion can provide significant expansion of the maxilla with an increase in arch perimeter, and it shows initial stability. PMID- 26926026 TI - Effect of malocclusion severity on oral health-related quality of life and food intake ability in a Korean population. AB - INTRODUCTION: The aim of this study was to evaluate the effect of malocclusion severity on oral health-related quality of life and food intake ability in adult patients, controlling for sex, age, and the type of dental clinic visited. METHODS: The sample consisted of 472 Korean patients (156 male, 316 female) with a mean age of 21.1 (SD, 8.6) years in a dental hospital and a private clinic. The correlations between the Korean version of the Oral Health Impact Profile-14 (OHIP-14K), subjective food intake ability (FIA) for 5 key foods, and Index of Orthodontic Treatment Need-Dental Health Component (IOTN-DHC) were investigated. RESULTS: The mean IOTN-DHC and OHIP-14K scores were significantly higher for the dental hospital patients than for the private clinic patients (IOTN-DHC, P <0.001; OHIP-14K, P <0.05). Malocclusion severity was significantly higher in male than in female subjects (P <0.001). Older patients perceived their oral health-related quality of life more negatively than did the teens (P <0.001). As the severity of the malocclusion increased, oral health-related quality of life and masticatory function worsened (OHIP-14K, P <0.001; FIA, P <0.05). CONCLUSIONS: As the severity of the malocclusion and the age of the patients increased, oral health-related quality of life and masticatory function relatively deteriorated. This finding provides evidence that severe malocclusions are associated with lower quality of life and less masticatory efficiency in older patients. PMID- 26926027 TI - Cephalometric configuration of the occlusal plane in patients with anterior open bite. AB - INTRODUCTION: This study was performed to investigate the cephalometric configuration of the occlusal plane in patients with anterior open bite. METHODS: Of 61 subjects with open bite (overbite >=3.75 mm) who had been recruited consecutively from January 2006 to November 2013 and had no history of orthodontic treatment, 14 cephalometric landmarks indicating the incisal edge or the buccal or mesiobuccal cusp tips of each tooth were used for K-means clustering to classify the occlusal plane configuration. For the open-bite group and a control group with normal occlusion (n = 38), dentoalveolar height, which is the perpendicular distance of each tooth to the palatal or mandibular plane, was compared among the clusters and between the 2 groups. RESULTS: The open-bite subjects were divided into 2 clusters according to occlusal contact of the premolars: Y-form and V-form (with and without premolar contact, respectively). The normalized dentoalveolar heights of the 4 mandibular teeth (lateral incisor to second premolar) were significantly greater in the Y-form class than in the V form class. The dentoalveolar heights of the 5 maxillary teeth (lateral incisor to first molar) were significantly greater in the open-bite group than in the control group. CONCLUSIONS: For anterior open-bite treatment, the cephalometric configuration of the occlusal plane should be considered based on the occlusal contacts of the premolars. PMID- 26926028 TI - Distalization of the maxillary and mandibular dentitions with miniscrew anchorage in a patient with moderate Class I bimaxillary dentoalveolar protrusion. AB - This case report describes the treatment of a 25-year-old woman with a skeletal Class I pattern and moderate bimaxillary dentoalveolar protrusion. The orthodontic treatment included distal movement of her maxillary and mandibular dentitions using 1-stage miniscrews. The total active treatment time was about 12 months. Her tooth alignment and profile were significantly improved by the orthodontic treatment. The 2-year posttreatment records show a stable occlusion and satisfactory facial esthetics. PMID- 26926029 TI - Intrusion method for a single overerupted maxillary molar using only palatal mini implants and partial fixed appliances. AB - Mandibular first molars are among the most frequently missing teeth in the adult dentition. As a result, the maxillary first molars are frequently overerupted. Conventional approaches to correct this undesirable molar position with skeletal anchorage usually include both buccal and palatal orthodontic mini-implants. Because palatal mini-implants have greater success rates than buccal ones, this article explains an intrusion method with only palatal mini-implants and limited fixed appliances to produce reliable intrusion of the overerupted molar while preventing undesirable side effects on the adjacent teeth. PMID- 26926030 TI - Novel 3-dimensional analysis to evaluate temporomandibular joint space and shape. AB - INTRODUCTION: The purpose of this study was to present and validate a novel semiautomated method for 3-dimensional evaluation of the temporomandibular joint (TMJ) space and condylar and articular shapes using cone-beam computed tomographic data. METHODS: The protocol for 3-dimensional analysis with the Checkpoint software (Stratovan, Davis, Calif) was established by analyzing cone beam computed tomographic images of 14 TMJs representing a range of TMJ shape variations. Upon establishment of the novel method, analysis of 5 TMJs was further repeated by several investigators to assess the reliability of the analysis. RESULTS: Principal components analysis identified 3 key components that characterized how the condylar head shape varied among the 14 TMJs. Principal component analysis allowed determination of the minimum number of landmarks or patch density to define the shape variability in this sample. Average errors of landmark placement ranged from 1.15% to 3.65%, and none of the 121 landmarks showed significant average errors equal to or greater than 5%. Thus, the mean intraobserver difference was small and within the clinically accepted margin of error. Interobserver error was not significantly greater than intraobserver error, indicating that this is a reliable methodology. CONCLUSIONS: This novel semiautomatic method is a reliable tool for the 3-dimensional analysis of the TMJ including both the form and the space between the articular eminence and the condylar head. PMID- 26926031 TI - Litigation and legislation. Taking it back. PMID- 26926032 TI - Linear regression. PMID- 26926033 TI - Naphthopyran-Based Silica Nanoparticles as New High-Performance Photoresponsive Materials. AB - Hybrid nanomaterials based on the covalent grafting of silylated naphthopyrans (NPTs) onto silica nanoparticles (SiO2 NPs) were successfully prepared and studied as new photochromic materials. They were prepared by a two-step protocol consisting of (i) NPTs (derivatives from 2H-naphtho[1,2-b]pyran (2H-NPT) and 3H naphtho[2,1-b]pyran (3H-NPT)) silylation by a microwave-assisted reaction between hydroxyl-substituted NPTs and 3-(triethoxysilyl)propyl isocyanate, followed by (ii) covalent post-grafting onto SiO2 NPs. In order to study the role of the silylation step, the analogous non-silylated nanomaterials were also prepared by direct adsorption of NPTs. The characterization techniques confirmed the successful NPTs silylation and subsequent grafting to SiO2 NPs. All SiO2-based nanomaterials revealed photoswitching behavior, following a biexponential decay. The SiO2 NPs functionalized with silylated 3H-NPTs (SiO2@S3 and SiO2@S4) presented the most promising photochromic properties, showing fast coloration/decoloration kinetics (coloring in 1 min under UV irradiation and fading in only 2 min) and high values of total color difference (DeltaE*ab = 30 50). Also, the 2H-NPTs-based SiO2 NPs (SiO2@S1 and SiO2@S2) presented fast coloration and good color contrasts (DeltaE*ab = 54), but slower fading kinetic rates, taking more than 2 h to return to their initial color. In contrast, the SiO2 NPs functionalized with non-silylated NPTs (SiO2@1 and SiO2@3) showed weaker color contrasts (DeltaE*ab = 6-10) and slower fading kinetics, proving that the NPT silylation step was crucial to enhance the photochromic behavior of SiO2 NPs based on NPTs. Furthermore, the silylated-based nanomaterials showed good photostability upon prolonged UV light exposure, keeping their photochromic performance unchanged for at least 12 successive UV/dark cycles, anticipating interesting technological applications in several areas. PMID- 26926034 TI - Brain Injury Alters Volatile Metabolome. AB - Chemical signals arising from body secretions and excretions communicate information about health status as have been reported in a range of animal models of disease. A potential common pathway for diseases to alter chemical signals is via activation of immune function-which is known to be intimately involved in modulation of chemical signals in several species. Based on our prior findings that both immunization and inflammation alter volatile body odors, we hypothesized that injury accompanied by inflammation might correspondingly modify the volatile metabolome to create a signature endophenotype. In particular, we investigated alteration of the volatile metabolome as a result of traumatic brain injury. Here, we demonstrate that mice could be trained in a behavioral assay to discriminate mouse models subjected to lateral fluid percussion injury from appropriate surgical sham controls on the basis of volatile urinary metabolites. Chemical analyses of the urine samples similarly demonstrated that brain injury altered urine volatile profiles. Behavioral and chemical analyses further indicated that alteration of the volatile metabolome induced by brain injury and alteration resulting from lipopolysaccharide-associated inflammation were not synonymous. Monitoring of alterations in the volatile metabolome may be a useful tool for rapid brain trauma diagnosis and for monitoring recovery. PMID- 26926035 TI - Adenovirus Type 7 Pneumonia in Children Who Died from Measles-Associated Pneumonia, Hanoi, Vietnam, 2014. AB - During a 2014 measles outbreak in Vietnam, postmortem pathologic examination of hospitalized children who died showed that adenovirus type 7 pneumonia was a contributory cause of death in children with measles-associated immune suppression. Adenovirus type 7 pneumonia should be recognized as a major cause of secondary infection after measles. PMID- 26926037 TI - Ulcerative Colitis Is Under Dual (Mitochondrial and Nuclear) Genetic Control. AB - BACKGROUND: Cellular oxidative stress and genetic susceptibility have been implicated in the multifactorial etiology of ulcerative colitis (UC). The nuclear genome association with UC has been intensely investigated, but the role of the mitochondrial DNA (mtDNA) has received far less attention and may account for part of the missing heritability. This study is a comprehensive analysis of the mtDNA contribution to UC susceptibility. METHODS: The association of mitochondrial single-nucleotide polymorphisms (mtSNPs) and haplogroups with UC was tested in 488 cases and 833 controls of European ancestry from the NIDDK IBD Genetics Consortium Ulcerative Colitis Genome-Wide Association Study available through dbGaP and from the Illumina Genotype Control Database (studies 64 and 65). RESULTS: No evidence of population stratification could be detected using 218 ancestry informative markers for European Americans. Seven of the 58 tested mtSNPs were nominally associated with UC, and A10550G in MT-ND4L withstands the Bonferroni correction (P = 1.29E-06, odds ratio [ORG] [95% confidence interval (CI)] = 4.80 [2.54-9.05], 10550G allele: 8.1% of patients and 1.9% of controls). A10550G remains equally associated after conditional analyses on the 11 UC genome wide association studies (GWAS) top SNPs (6.35E-07 < Pcond < 4.58E-06), which suggests that it constitutes an independent risk factor from nuclear-encoded susceptibility loci. We detected additive (but not multiplicative) epistatic interactions between A10550G and all 11 top GWAS hits. Subhaplogroup K1 (P = 0.021, OR [95% CI] = 1.71 [1.08-2.69]) increased the risk for UC, whereas the U5b lineage conferred protection (P = 0.016, OR [95% CI] = 0.34 [0.14-0.82]). CONCLUSIONS: These results suggest that UC has a dual mitochondrial and nuclear genetic control that warrants further replication in independent data sets and reinforces its etiopathogenic complexity. PMID- 26926036 TI - The primary cilium as a cellular receiver: organizing ciliary GPCR signaling. AB - The primary cilium is an antenna-like cellular protrusion mediating sensory and neuroendocrine signaling. Its localization within tissue architecture and a growing list of cilia-localized receptors, in particular G-protein-coupled receptors, determine a host of crucial physiologies, which are disrupted in human ciliopathies. Here, we discuss recent advances in the identification and characterization of ciliary signaling components and pathways. Recent studies have highlighted the unique signaling environment of the primary cilium and we are just beginning to understand how this design allows for highly amplified and regulated signaling. PMID- 26926038 TI - Identification of Commensal Species Positively Correlated with Early Stress Responses to a Compromised Mucus Barrier. AB - BACKGROUND: Our aims were (1) to correlate changes in the microbiota to intestinal gene expression before and during the development of colitis in Muc2 mice and (2) to investigate whether the heterozygote Muc2 mouse would reveal host markers of gut barrier stress. METHODS: Colon histology, transcriptomics, and microbiota profiling of faecal samples was performed on wild type, Muc2, and Muc2 mice at 2, 4, and 8 weeks of age. RESULTS: Muc2 mice develop colitis in proximal colon after weaning, resulting in inflammatory and adaptive immune responses, and expression of genes associated with human inflammatory bowel disease. Muc2 mice do not develop colitis, but produce a thinner mucus layer. The transcriptome of Muc2 mice revealed differential expression of genes participating in mucosal stress responses and exacerbation of a transient inflammatory state around the time of weaning. Young wild type and Muc2 mice have a more constrained group of bacteria as compared with the Muc2 mice, but at 8 weeks the microbiota composition is more similar in all mice. At all ages, microbiota composition discriminated the groups of mice according to their genotype. Specific bacterial clusters correlated with altered gene expression responses to stress and bacteria, before colitis development, including colitogenic members of the genus Bacteroides. CONCLUSIONS: The abundance of Bacteroides pathobionts increased before histological signs of pathology suggesting they may play a role in triggering the development of colitis. The Muc2 mouse produces a thinner mucus layer and can be used to study mucus barrier stress in the absence of colitis. PMID- 26926039 TI - Incidence of Crohn's Disease and Ulcerative Colitis in Rhode Island: Report from the Ocean State Crohn's and Colitis Area Registry. AB - BACKGROUND: Studies describing the incidence of Crohn's disease (CD) and ulcerative colitis (UC) are uncommon in the United States. We sought to determine the incidence of CD and UC in the state of Rhode Island. METHODS: The Ocean State Crohn's and Colitis Area Registry is a state-based inception cohort of patients newly diagnosed with inflammatory bowel disease (IBD) in Rhode Island. To confirm a diagnosis of CD, UC, or IBD unclassified (IBDU), the National Institute of Diabetes and Digestive and Kidney Diseases IBD Genetics Consortium criteria were applied in a review of medical records from gastroenterology practices located in the state of Rhode Island and adjacent to the Rhode Island border in Massachusetts and Connecticut. Using population-based data, we determined the statewide incidence of IBD in Rhode Island from 2008 to 2010. RESULTS: A total of 971 Rhode Island residents were diagnosed with IBD, including 444 with CD, 486 with UC, and 41 with IBD unclassified from 2008 to 2010. The overall age- and sex adjusted IBD incidence was 30.2 (95% confidence interval, 28.3-32.1) per 100,000 persons in this time frame with 13.9, 15.1, and 1.3 per 100,000 diagnosed with CD, UC, and IBD unclassified, respectively. Of the total incident cases in Rhode Island, 30% (n = 291) were enrolled in Ocean State Crohn's and Colitis Area Registry for follow-up. CONCLUSIONS: The incidence of IBD in Rhode Island is higher than that previously reported by other population-based cohorts in the United States. Prospective follow-up of individuals enrolled in the community based Ocean State Crohn's and Colitis Area Registry cohort is ongoing. PMID- 26926040 TI - How to Optimize Colon Cancer Surveillance in Inflammatory Bowel Disease Patients. AB - Colitis-associated colorectal neoplasia (CRN) is a well-known complication of chronic inflammation of the colon either with ulcerative colitis (UC) or colonic Crohn's disease (CD). Studies have shown that inflammatory bowel disease (IBD) patients have an overall higher risk for colorectal dysplasia and cancer compared to the general population and this risk is further increased by certain associated factors, including extent of disease, duration of disease, and age at onset. In addition, other risk factors not related to IBD can also further increase the risk for CRN, such as a family history of sporadic colon cancer and a concomitant diagnosis of primary sclerosing cholangitis. The society guidelines mostly agree on the appropriate time to begin CRN surveillance but vary somewhat on the appropriate intervals between surveillance colonoscopies. In addition, there is not yet a consensus on the appropriate method for surveillance. In this review, we discuss the risk for CRN in colonic IBD, the associated factors that further increase the risk for CRN, the current surveillance guidelines and the current methods available for CRN surveillance. PMID- 26926041 TI - Building a Molecular Trap for a Serine Protease from Aptamer and Peptide Modules. AB - In drug development, molecular intervention strategies are usually based on interference with a single protein function, such as enzyme activity or receptor binding. However, in many cases, protein drug targets are multifunctional, with several molecular functions contributing to their pathophysiological actions. Aptamers and peptides are interesting synthetic building blocks for the design of multivalent molecules capable of modulating multiple functions of a target protein. Here, we report a molecular trap with the ability to interfere with the activation, catalytic activity, receptor binding, etc. of the serine protease urokinase-type plasminogen activator (uPA) by a rational combination of two RNA aptamers and a peptide with different inhibitory properties. The assembly of these artificial inhibitors into one molecule enhanced the inhibitory activity between 10- and 10,000-fold toward several functions of uPA. The study highlights the potential of multivalent designs and illustrates how they can easily be constructed from aptamers and peptides using nucleic acid engineering, chemical synthesis, and bioconjugation chemistry. By aptamer to aptamer and aptamer to peptide conjugation, we created, to the best of our knowledge, the first trivalent molecule which combines three artificial inhibitors binding to three different sites in a protein target. We hypothesize that by simultaneously preventing all of the functional interactions and activities of the target protein, this approach may represent an alternative to siRNA technology for a functional knockout. PMID- 26926042 TI - Metabolizer in vivo of fullerenes and metallofullerenes by positron emission tomography. AB - Fullerenes (C60) and metallofullerenes (Gd@C82) have similar chemical structure, but the bio-effects of both fullerene-based materials are distinct in vivo. Tracking organic carbon-based materials such as C60 and Gd@C82 is difficult in vivo due to the high content of carbon element in the living tissues themselves. In this study, the biodistribution and metabolism of fullerenes (C60 and Gd@C82) radiolabeled with (64)Cu were observed by positron emission tomography (PET). (64)Cu-C60 and (64)Cu-Gd@C82 were prepared using 1, 4, 7, 10-tetrakis (carbamoylmethyl)-1, 4, 7, 10-tetra-azacyclodo-decanes grafted on carbon cages as a chelator for (64)Cu, and were obtained rapidly with high radiochemical yield (>=90%). The new radio-conjugates were evaluated in vivo in the normal mouse model and tissue distribution by small animal PET/CT imaging and histology was carried out. The PET imaging, the biodistribution and the excretion of C60 and Gd@C82 indicated that C60 samples have higher blood retention and lower renal clearance than the Gd@C82 samples in vivo and suggested that the differences in metabolism and distribution in vivo were caused by the structural differences of the groups on the fullerene cages though there is chemical similarity between C60 and Gd@C82. PMID- 26926043 TI - In Silico Modeling of Gastrointestinal Drug Absorption: Predictive Performance of Three Physiologically Based Absorption Models. AB - Gastrointestinal (GI) drug absorption is a complex process determined by formulation, physicochemical and biopharmaceutical factors, and GI physiology. Physiologically based in silico absorption models have emerged as a widely used and promising supplement to traditional in vitro assays and preclinical in vivo studies. However, there remains a lack of comparative studies between different models. The aim of this study was to explore the strengths and limitations of the in silico absorption models Simcyp 13.1, GastroPlus 8.0, and GI-Sim 4.1, with respect to their performance in predicting human intestinal drug absorption. This was achieved by adopting an a priori modeling approach and using well-defined input data for 12 drugs associated with incomplete GI absorption and related challenges in predicting the extent of absorption. This approach better mimics the real situation during formulation development where predictive in silico models would be beneficial. Plasma concentration-time profiles for 44 oral drug administrations were calculated by convolution of model-predicted absorption-time profiles and reported pharmacokinetic parameters. Model performance was evaluated by comparing the predicted plasma concentration-time profiles, Cmax, tmax, and exposure (AUC) with observations from clinical studies. The overall prediction accuracies for AUC, given as the absolute average fold error (AAFE) values, were 2.2, 1.6, and 1.3 for Simcyp, GastroPlus, and GI-Sim, respectively. The corresponding AAFE values for Cmax were 2.2, 1.6, and 1.3, respectively, and those for tmax were 1.7, 1.5, and 1.4, respectively. Simcyp was associated with underprediction of AUC and Cmax; the accuracy decreased with decreasing predicted fabs. A tendency for underprediction was also observed for GastroPlus, but there was no correlation with predicted fabs. There were no obvious trends for over- or underprediction for GI-Sim. The models performed similarly in capturing dependencies on dose and particle size. In conclusion, it was shown that all three software packages are useful to guide formulation development. However, as a consequence of the high fraction of inaccurate predictions (prediction error >2 fold) and the clear trend toward decreased accuracy with decreased predicted fabs observed with Simcyp, the results indicate that GI-Sim and GastroPlus perform better than Simcyp in predicting the intestinal absorption of the incompletely absorbed drugs when a higher degree of accuracy is needed. In addition, this study suggests that modeling and simulation research groups should perform systematic model evaluations using their own input data to maximize confidence in model performance and output. PMID- 26926044 TI - Breastfeeding and Disease-Modifying Therapy for Multiple Sclerosis--Reply. PMID- 26926046 TI - Intrahepatic bile ducts are developed through formation of homogeneous continuous luminal network and its dynamic rearrangement in mice. AB - The intrahepatic bile duct (IHBD) is a highly organized tubular structure consisting of cholangiocytes, biliary epithelial cells, which drains bile produced by hepatocytes into the duodenum. Although several models have been proposed, it remains unclear how the three-dimensional (3D) IHBD network develops during liver organogenesis. Using 3D imaging techniques, we demonstrate that the continuous luminal network of IHBDs is established by 1 week after birth. Beyond this stage, the IHBD network consists of large ducts running along portal veins (PVs) and small ductules forming a mesh-like network around PVs. By analyzing embryonic and neonatal livers, we found that newly differentiated cholangiocytes progressively form a continuous and homogeneous luminal network. Elongation of this continuous network toward the liver periphery was attenuated by a potent Notch-signaling inhibitor N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester. Subsequent to this first step, the fine homogenous network is reorganized into the mature hierarchical network consisting of large ducts and small ductules. Between E17 and E18, when the homogenous network is radically reorganized into the mature hierarchical network, bile canaliculi rapidly extend and bile flow into IHBDs may increase. When formation of bile canaliculi was blocked between E16 and E18 by a multidrug resistance protein 2 inhibitor (benzbromarone), the structural rearrangement of IHBDs was significantly suppressed. CONCLUSION: Establishment of the mature IHBD network consists of two sequential events: (1) formation of the continuous luminal network regulated by the Notch-signaling pathway and (2) dynamic rearrangement of the homogeneous network into the hierarchical network induced by increased bile flow resulting from the establishment of hepatobiliary connections. (Hepatology 2016;64:175 188). PMID- 26926047 TI - Acid-Catalyzed Multicomponent Tandem Cyclizations: Access to Polyfunctional Dihydroindolizino[8,7-b]indoles. AB - An acid-catalyzed multicomponent tandem cyclization protocol has been developed for the synthesis of polyfunctional dihydroindolizino[8,7-b]indoles from simple and readily available arylglyoxal monohydrates, tryptamines, and trans-beta nitrostyrenes or malononitrile. This reaction represents a highly efficient and convenient methodology for the synthesis of diversely substituted heteropolycyclic scaffolds under mild, metal-free conditions. PMID- 26926045 TI - A genome-wide association scan in admixed Latin Americans identifies loci influencing facial and scalp hair features. AB - We report a genome-wide association scan in over 6,000 Latin Americans for features of scalp hair (shape, colour, greying, balding) and facial hair (beard thickness, monobrow, eyebrow thickness). We found 18 signals of association reaching genome-wide significance (P values 5 * 10(-8) to 3 * 10(-119)), including 10 novel associations. These include novel loci for scalp hair shape and balding, and the first reported loci for hair greying, monobrow, eyebrow and beard thickness. A newly identified locus influencing hair shape includes a Q30R substitution in the Protease Serine S1 family member 53 (PRSS53). We demonstrate that this enzyme is highly expressed in the hair follicle, especially the inner root sheath, and that the Q30R substitution affects enzyme processing and secretion. The genome regions associated with hair features are enriched for signals of selection, consistent with proposals regarding the evolution of human hair. PMID- 26926048 TI - Polymorphism in phenobarbital: discovery of a new polymorph and crystal structure of elusive form V. AB - This report highlights the discovery of a new polymorph of the anticonvulsant drug phenobarbital (PB) using polymer-induced heteronucleation (PIHn) and unravelling the crystal structure of the elusive form V. Both forms are characterized by structural, thermal and VT-Raman spectroscopy methods to elucidate phase transformation behavior and shed light on stability relationships. PMID- 26926049 TI - Utility of intraoperative imaging. PMID- 26926050 TI - Influence of indocyanine green angiography on microsurgical treatment of spinal perimedullary arteriovenous fistulas. AB - OBJECTIVE: The microvascular anatomy of spinal perimedullary arteriovenous fistulas (AVFs) is more complicated than that of dural AVFs, and occlusion rates of AVF after open microsurgery or endovascular embolization are lower in patients with perimedullary AVFs (29%-70%) than they are in those with dural AVF (97% 98%). Reports of intraoperative blood flow assessment using indocyanine green (ICG) video angiography in spinal arteriovenous lesions have mostly been for spinal dural AVFs. No detailed reports on spinal perimedullary AVFs are available. METHODS: Participants were 11 patients with spinal perimedullary AVFs (Type IVa in 5 patients, Type VIb in 4, and Type IVc in 2). Intraoperative ICG video angiography was assessed by measuring the number of cases in which this modality was judged essential by the surgeon to correctly occlude the fistula. RESULTS: In all patients, arterial feeders were identified and intravenous ICG video angiography was performed before and after blocking the feeders. In one patient, selective intraarterial ICG video angiography was also performed. The findings provided by ICG video angiography significantly changed the surgical procedure in 4 of 11 patients (36%). Postoperatively, complete occlusion of the AVF was achieved in 10 of the 11 patients (91%). CONCLUSIONS: Intraoperative ICG video angiography can have a significant impact on deciding surgical strategy in the microsurgical treatment of spinal perimedullary AVF. PMID- 26926051 TI - Prospective evaluation of the utility of intraoperative confocal laser endomicroscopy in patients with brain neoplasms using fluorescein sodium: experience with 74 cases. AB - OBJECTIVE: This study evaluated the utility, specificity, and sensitivity of intraoperative confocal laser endomicroscopy (CLE) to provide diagnostic information during resection of human brain tumors. METHODS: CLE imaging was used in the resection of intracranial neoplasms in 74 consecutive patients (31 male; mean age 47.5 years; sequential 10-month study period). Intraoperative in vivo and ex vivo CLE was performed after intravenous injection of fluorescein sodium (FNa). Tissue samples from CLE imaging-matched areas were acquired for comparison with routine histological analysis (frozen and permanent sections). CLE images were classified as diagnostic or nondiagnostic. The specificities and sensitivities of CLE and frozen sections for gliomas and meningiomas were calculated using permanent histological sections as the standard. RESULTS: CLE images were obtained for each patient. The mean duration of intraoperative CLE system use was 15.7 minutes (range 3-73 minutes). A total of 20,734 CLE images were correlated with 267 biopsy specimens (mean number of images/biopsy location, in vivo 84, ex vivo 70). CLE images were diagnostic for 45.98% in vivo and 52.97% ex vivo specimens. After initiation of CLE, an average of 14 in vivo images and 7 ex vivo images were acquired before identification of a first diagnostic image. CLE specificity and sensitivity were, respectively, 94% and 91% for gliomas and 93% and 97% for meningiomas. CONCLUSIONS: CLE with FNa provided intraoperative histological information during brain tumor removal. Specificities and sensitivities of CLE for gliomas and meningiomas were comparable to those for frozen sections. These data suggest that CLE could allow the interactive identification of tumor areas, substantially improving intraoperative decisions during the resection of brain tumors. PMID- 26926052 TI - Optimizing ventriculoperitoneal shunt placement in the treatment of idiopathic intracranial hypertension: an analysis of neuroendoscopy, frameless stereotaxy, and intraoperative CT. AB - OBJECTIVE: Cerebrospinal fluid shunting can effectively lower intracranial pressure and improve the symptoms of idiopathic intracranial hypertension (IIH). Placement of ventriculoperitoneal (VP) shunts in this patient population can often be difficult due to the small size of the ventricular system. Intraoperative adjuvant techniques can be used to improve the accuracy and safety of VP shunts for these patients. The purpose of this study was to analyze the efficacy of some of these techniques, including the use of intraoperative CT (iCT) and frameless stereotaxy, in optimizing postoperative ventricular catheter placement. METHODS: The authors conducted a retrospective review of 49 patients undergoing initial ventriculoperitoneal shunt placement for the treatment of IIH. The use of the NeuroPEN Neuroendoscope, intraoperative neuronavigation, and iCT was examined. To analyze ventricular catheter placement on postoperative CT imaging, the authors developed a new grading system: Grade 1, catheter tip terminates optimally in the ipsilateral frontal horn or third ventricle; Grade 2, catheter tip terminates in the contralateral frontal horn; Grade 3, catheter terminates in a nontarget CSF space; and Grade 4, catheter tip terminates in brain parenchyma. All shunts had spontaneous CSF flow upon completion of the procedure. RESULTS: The average body mass index among all patients was 37.6 +/- 10.9 kg/m2. The NeuroPEN Neuroendoscope was used in 44 of 49 patients. Intraoperative CT scans were obtained in 24 patients, and neuronavigation was used in 32 patients. Grade 1 or 2 final postoperative shunt placement was achieved in 90% of patients (44 of 49). In terms of achieving optimal postoperative ventricular catheter placement, the use of iCT was as effective as neuronavigation. Two patients had their ventricular catheter placement modified based on an iCT study. The use of neuronavigation significantly increased time in the operating room (223.4 +/- 46.5 vs. 190.8 +/- 31.7 minutes, p = 0.01). There were no shunt infections in this study. CONCLUSIONS: The use of iCT appears to be equivalent to the use of neuronavigation in optimizing ventricular shunt placement in IIH. Additionally, it may shorten operating room time and limit overall costs. PMID- 26926053 TI - Beneficial impact of high-field intraoperative magnetic resonance imaging on the efficacy of pediatric low-grade glioma surgery. AB - OBJECTIVE: Intraoperative MRI (iMRI) is assumed to safely improve the extent of resection (EOR) in patients with gliomas. This study focuses on advantages of this imaging technology in elective low-grade glioma (LGG) surgery in pediatric patients. METHODS: The surgical results of conventional and 1.5-T iMRI-guided elective LGG surgery in pediatric patients were retrospectively compared. Tumor volumes, general clinical data, EOR according to reference radiology assessment, and progression-free survival (PFS) were analyzed. RESULTS: Sixty-five patients were included in the study, of whom 34 had undergone conventional surgery before the iMRI unit opened (pre-iMRI period) and 31 had undergone surgery with iMRI guidance (iMRI period). Perioperative data were comparable between the 2 cohorts, apart from larger preoperative tumor volumes in the pre-iMRI period, a difference without statistical significance, and (as expected) significantly longer surgeries in the iMRI group. According to 3-month postoperative MRI studies, an intended complete resection (CR) was achieved in 41% (12 of 29) of the patients in the pre-iMRI period and in 71% (17 of 24) of those in the iMRI period (p = 0.05). Of those cases in which the surgeon was postoperatively convinced that he had successfully achieved CR, this proved to be true in only 50% of cases in the pre-iMRI period but in 81% of cases in the iMRI period (p = 0.055). Residual tumor volumes on 3-month postoperative MRI were significantly smaller in the iMRI cohort (p < 0.03). By continuing the resection of residual tumor after the intraoperative scan (when the surgeon assumed that he had achieved CR), the rate of CR was increased from 30% at the time of the scan to 85% at the 3-month postoperative MRI. The mean follow-up for the entire study cohort was 36.9 months (3-79 months). Progression-free survival after surgery was noticeably better for the entire iMRI cohort and in iMRI patients with postoperatively assumed CR, but did not quite reach statistical significance. Moreover, PFS was highly significantly better in patients with CRs than in those with incomplete resections (p < 0.001). CONCLUSIONS: Significantly better surgical results (CR) and PFS were achieved after using iMRI in patients in whom total resections were intended. Therefore, the use of high-field iMRI is strongly recommended for electively planned LGG resections in pediatric patients. PMID- 26926054 TI - Contribution of combined intraoperative electrophysiological investigation with 3 T intraoperative MRI for awake cerebral glioma surgery: comprehensive review of the clinical implications and radiological outcomes. AB - OBJECTIVE: This study aimed to assess the clinical efficiency of combined awake craniotomy with 3-T intraoperative MRI (iMRI)-guided resection of gliomas adjacent to eloquent cortex performed at a single center. It also sought to explore the contribution of iMRI to surgeons' learning process of maximal safe resection of gliomas. METHODS: All patients who underwent an awake craniotomy and iMRI for resection of eloquent area glioma during the 53 months between January 2011 and June 2015 were included. The cases were analyzed for short- and long term neurological outcome, progression-free survival (PFS), overall survival (OS), and extent of resection (EOR). The learning curve was assessed after dividing the cohort into Group A (first 27 months) and Group B (last 26 months). Statistical analyses included univariate logistic regression analysis on clinical and radiological variables. Kaplan-Meier and Cox regression models were used for further analysis of OS and PFS. A p value < 0.05 was considered statistically significant. RESULTS: One hundred six patients were included in the study. Over an average follow-up period of 24.8 months, short- and long-term worsening of the neurological function was noted in 48 (46.2%) and 9 (8.7%) cases, respectively. The median and mean EOR were 100% and 92%, respectively, and complete radiographic resection was achieved in 64 (60.4%) patients. The rate of gross total resection (GTR) in the patients with low-grade glioma (89.06% +/- 19.6%) was significantly lower than that in patients with high-grade glioma (96.4% +/- 9.1%) (p = 0.026). Thirty (28.3%) patients underwent further resection after initial iMRI scanning, with a 10.1% increase of the mean EOR. Multivariate Cox proportional hazards modeling demonstrated that the final EOR was a significant predictor of PFS (HR 0.225, 95% CI 0.070-0.723, p = 0.012). For patients with high-grade glioma, the GTR (p = 0.033), the presence of short-term motor deficit (p = 0.027), and the WHO grade (p = 0.005) were independent prognostic factors of OS. Performing further resection after the iMRI (p = 0.083) and achieving GTR (p = 0.05) demonstrated a PFS benefit trend for the patients affected by a low-grade glioma. Over time, the rate of performing further resection after an iMRI decreased by 26.1% (p = 0.005). A nonsignificant decrease in the rate of short term (p = 0.101) and long-term (p = 0.132) neurological deficits was equally noted. CONCLUSIONS: Combined awake craniotomy and iMRI is a safe and efficient technique allowing maximal safe resection of eloquent area gliomas with possible subsequent OS and PFS benefits. Although there is a learning curve for applying this technique, it can also improve the surgeon's ability in eloquent glioma surgery. PMID- 26926055 TI - Resective surgery for medically refractory epilepsy using intraoperative MRI and functional neuronavigation: the Erlangen experience of 415 patients. AB - OBJECTIVE: Intraoperative overestimation of resection volume in epilepsy surgery is a well-known problem that can lead to an unfavorable seizure outcome. Intraoperative MRI (iMRI) combined with neuronavigation may help surgeons avoid this pitfall and facilitate visualization and targeting of sometimes ill-defined heterogeneous lesions or epileptogenic zones and may increase the number of complete resections and improve seizure outcome. METHODS: To investigate this hypothesis, the authors conducted a retrospective clinical study of consecutive surgical procedures performed during a 10-year period for epilepsy in which they used neuronavigation combined with iMRI and functional imaging (functional MRI for speech and motor areas; diffusion tensor imaging for pyramidal, speech, and visual tracts; and magnetoencephalography and electrocorticography for spike detection). Altogether, there were 415 patients (192 female and 223 male, mean age 37.2 years; 41% left-sided lesions and 84.9% temporal epileptogenic zones). The mean preoperative duration of epilepsy was 17.5 years. The most common epilepsy-associated pathologies included hippocampal sclerosis (n = 146 [35.2%]), long-term epilepsy-associated tumor (LEAT) (n = 67 [16.1%]), cavernoma (n = 45 [10.8%]), focal cortical dysplasia (n = 31 [7.5%]), and epilepsy caused by scar tissue (n = 23 [5.5%]). RESULTS: In 11.8% (n = 49) of the surgeries, an intraoperative second-look surgery (SLS) after incomplete resection verified by iMRI had to be performed. Of those incomplete resections, LEATs were involved most often (40.8% of intraoperative SLSs, 29.9% of patients with LEAT). In addition, 37.5% (6 of 16) of patients in the diffuse glioma group and 12.9% of the patients with focal cortical dysplasia underwent an SLS. Moreover, iMRI provided additional advantages during implantation of grid, strip, and depth electrodes and enabled intraoperative correction of electrode position in 13.0% (3 of 23) of the cases. Altogether, an excellent seizure outcome (Engel Class I) was found in 72.7% of the patients during a mean follow-up of 36 months (range 3 months to 10.8 years). The greatest likelihood of an Engel Class I outcome was found in patients with cavernoma (83.7%), hippocampal sclerosis (78.8%), and LEAT (75.8%). Operative revisions that resulted from infection occurred in 0.3% of the patients, from hematomas in 1.6%, and from hydrocephalus in 0.8%. Severe visual field defects were found in 5.2% of the patients, aphasia in 5.7%, and hemiparesis in 2.7%, and the total mortality rate was 0%. CONCLUSIONS: Neuronavigation combined with iMRI was beneficial during surgical procedures for epilepsy and led to favorable seizure outcome with few specific complications. A significantly higher resection volume associated with a higher chance of favorable seizure outcome was found, especially in lesional epilepsy involving LEAT or diffuse glioma. PMID- 26926056 TI - The role of intraoperative MRI in resective epilepsy surgery for peri-eloquent cortex cortical dysplasias and heterotopias in pediatric patients. AB - OBJECTIVE: Previous studies have demonstrated that an important factor in seizure freedom following surgery for lesional epilepsy in the peri-eloquent cortex is completeness of resection. However, aggressive resection of epileptic tissue localized to this region must be balanced with the competing objective of retaining postoperative neurological functioning. The objective of this study was to investigate the role of intraoperative MRI (iMRI) as a complement to existing epilepsy protocol techniques and to compare rates of seizure freedom and neurological deficit in pediatric patients undergoing resection of perieloquent lesions. METHODS: The authors retrospectively reviewed the medical records of pediatric patients who underwent resection of focal cortical dysplasia (FCD) or heterotopia localized to eloquent cortex regions at the Children's National Health System between March 2005 and August 2015. Patients were grouped into two categories depending on whether they underwent conventional resection (n = 18) or iMRI-assisted resection (n = 11). Patient records were reviewed for factors including demographics, length of hospitalization, postoperative seizure freedom, postoperative neurological deficit, and need for reoperation. Postsurgical seizure outcome was assessed at the last postoperative follow-up evaluation using the Engel Epilepsy Surgery Outcome Scale. RESULTS: At the time of the last postoperative follow-up examination, 9 (82%) of the 11 patients in the iMRI resection group were seizure free (Engel Class I), compared with 7 (39%) of the 18 patients in the control resection group (p = 0.05). Ten (91%) of the 11 patients in the iMRI cohort achieved gross-total resection (GTR), compared with 8 (44%) of 18 patients in the conventional resection cohort (p = 0.02). One patient in the iMRI-assisted resection group underwent successful reoperation at a later date for residual dysplasia, compared with 7 patients in the conventional resection cohort (with 2/7 achieving complete resection). Four (36%) of the patients in the iMRI cohort developed postoperative neurological deficits, compared with 15 patients (83%) in the conventional resection cohort (p = 0.02). CONCLUSIONS: These results suggest that in comparison with a conventional surgical protocol and technique for resection of epileptic lesions in peri eloquent cortex, the incorporation of iMRI led to elevated rates of GTR and postoperative seizure freedom. Furthermore, this study suggests that iMRI assisted surgeries are associated with a reduction in neurological deficits due to intraoperative damage of eloquent cortex. PMID- 26926057 TI - Pituitary surgery and volumetric assessment of extent of resection: a paradigm shift in the use of intraoperative magnetic resonance imaging. AB - OBJECTIVE: The aim of this study was to quantitatively assess the role of intraoperative high-field 3-T MRI (3T-iMRI) in improving the gross-total resection (GTR) rate and the extent of resection (EOR) in endoscopic transsphenoidal surgery (TSS) for pituitary adenomas. METHODS: Radiological and clinical data from a prospective database were retrospectively analyzed. Volumetric measurements of adenoma volumes pre-, intraoperatively, and 3 months postoperatively were performed in a consecutive series of patients who had undergone endoscopic TSS. The quantitative contribution of 3T-iMRI was measured as a percentage of the additional rate of GTR and of the EOR achieved after 3T iMRI. RESULTS: The cohort consisted of 50 patients (51 operations) harboring 33 nonfunctioning and 18 functioning pituitary adenomas. Mean adenoma diameter and volume were 21.1 mm (range 5-47 mm) and 5.23 cm(3) (range 0.09-22.14 cm(3)), respectively. According to Knosp's classification, 10 cases were Grade 0; 8, Grade 1; 17, Grade 2; 12, Grade 3; and 4, Grade 4. Gross-total resection was the surgical goal (targeted [t]GTR) in 34 of 51 operations and was initially achieved in 16 (47%) of 34 at 3T-iMRI and in 30 (88%) of 34 cases after further resection. In this subgroup, the EOR increased from 91% at 3T-iMRI to 99% at the 3-month MRI (p < 0.05). In the 17 cases in which subtotal resection (STR) had been planned (tSTR), the EOR increased from 79% to 86% (p < 0.05) and GTR could be achieved in 1 case. Intrasellar remnants were present in 20 of 51 procedures at 3T-iMRI and in only 5 (10%) of 51 procedures after further resection (median volume 0.15 cm(3)). Overall, the use of 3T-iMRI led to further resection in 27 (53%) of 51 procedures and permitted GTR in 15 (56%) of these 27 procedures; thus, the GTR rate in the entire cohort increased from 31% (16 of 51) to 61% (31 of 51) and the EOR increased from 87% to 95% (p < 0.05). CONCLUSIONS: The use of high-definition 3T-iMRI allowed precise visualization and quantification of adenoma remnant volume. It helped to increase GTR and EOR rates in both tGTR and tSTR patient groups. Moreover, it helped to achieve low rates of intrasellar remnants. These data support the use of 3T-iMRI to achieve maximal, safe adenoma resection. PMID- 26926059 TI - Safe use of subdermal needles for intraoperative monitoring with MRI. AB - OBJECTIVE: The purpose of this study was to develop safe, site-specific procedures for placing and leaving subdermal needle leads for intraoperative monitoring (IOM) during intraoperative MRI procedures. METHODS: The authors tested a variety of standard subdermal needle electrodes designed and FDA approved for IOM in the conventional operating room. Testing was used to determine the conditions necessary to avoid thermal injury and significant image artifacts with minimal disruption of IOM and MRI procedures. Phantom testing was performed with a fiber optic (lead) temperature monitoring system and was followed by testing of leads placed in a healthy volunteer. The volunteer testing used electrode placements typical of standard IOM cases, together with radiofrequency (RF) coil placement and imaging sequences routinely employed for these case types. Lead length was investigated to assess heating effects for electrodes placed within the RF coil. RESULTS: The authors found that conventional stainless steel (SS) and platinum/iridium (Pt/Ir) subdermal needles can be used safely without significant heating when placed outside the RF coil, and this accounts for the majority or entirety of electrode placements. When placed within the RF coil, Pt/Ir leads produced minimal image artifacts, while SS leads produced potentially significant artifacts. In phantom testing, significant heating was demonstrated in both SS and Pt/Ir leads placed within the RF coil, but only during high-resolution T2-weighted scanning. This problem was largely, but not completely, eliminated when leads were shortened to 25 cm. Human testing was unremarkable except for nonpainful heating detected in a few electrodes during thin-slice (1.5 mm) FLAIR scanning. Transient irritation (skin reddening along the needle tract) was noted at 2 of the electrodes with detectable heating. CONCLUSIONS: The authors were satisfied with the safety of their site-specific procedures and have begun with off-label use (following institutional review board approval and obtaining patient informed consent) of tested monitoring leads in cases that combine IOM and MRI. The authors recommend that all facilities perform their own site-specific testing of monitoring leads before proceeding with their routine use. PMID- 26926058 TI - The utility of high-resolution intraoperative MRI in endoscopic transsphenoidal surgery for pituitary macroadenomas: early experience in the Advanced Multimodality Image Guided Operating suite. AB - OBJECTIVE: Endoscopic skull base surgery has become increasingly popular among the skull base surgery community, with improved illumination and angled visualization potentially improving tumor resection rates. Intraoperative MRI (iMRI) is used to detect residual disease during the course of the resection. This study is an investigation of the utility of 3-T iMRI in combination with transnasal endoscopy with regard to gross-total resection (GTR) of pituitary macroadenomas. METHODS: The authors retrospectively reviewed all endoscopic transsphenoidal operations performed in the Advanced Multimodality Image Guided Operating (AMIGO) suite from November 2011 to December 2014. Inclusion criteria were patients harboring presumed pituitary macroadenomas with optic nerve or chiasmal compression and visual loss, operated on by a single surgeon. RESULTS: Of the 27 patients who underwent transsphenoidal resection in the AMIGO suite, 20 patients met the inclusion criteria. The endoscope alone, without the use of iMRI, would have correctly predicted extent of resection in 13 (65%) of 20 cases. Gross-total resection was achieved in 12 patients (60%) prior to MRI. Intraoperative MRI helped convert 1 STR and 4 NTRs to GTRs, increasing the number of GTRs from 12 (60%) to 16 (80%). CONCLUSIONS: Despite advances in visualization provided by the endoscope, the incidence of residual disease can potentially place the patient at risk for additional surgery. The authors found that iMRI can be useful in detecting unexpected residual tumor. The cost-effectiveness of this tool is yet to be determined. PMID- 26926060 TI - Ultrasound-guided neurosurgery: experiences from 20 years of cross-disciplinary research in Trondheim, Norway. PMID- 26926061 TI - Intraoperative MRI. PMID- 26926062 TI - Factors triggering an additional resection and determining residual tumor volume on intraoperative MRI: analysis from a prospective single-center registry of supratentorial gliomas. AB - OBJECTIVE: In this analysis, the authors sought to identify variables triggering an additional resection (AR) and determining residual intraoperative tumor volume in 1.5-T intraoperative MRI (iMRI)-guided glioma resections. METHODS: A consecutive case series of 224 supratentorial glioma resections (WHO Grades I-IV) from a prospective iMRI registry (inclusion dates January 2011-April 2013) was examined with univariate and multiple regression models including volumetric data, tumor-related, and surgeon-related factors. The surgeon's expectation of an AR, in response to a questionnaire completed prior to iMRI, was evaluated using contingency analysis. A machine-learning prediction model was applied to consider if anticipation of intraoperative findings permits preoperative identification of ideal iMRI cases. RESULTS: An AR was performed in 70% of cases after iMRI, but did not translate into an accumulated risk for neurological morbidity after surgery (p = 0.77 for deficits in cases with AR vs no AR). New severe persistent deficits occurred in 6.7% of patients. Initial tumor volume determined frequency of ARs and was independently correlated with larger tumor remnants delineated on iMRI (p < 0.0001). Larger iMRI volume was further associated with eloquent location (p = 0.010) and recurrent tumors (p < 0.0001), and with WHO grade (p = 0.0113). Greater surgical experience had no significant influence on the course of surgery. The surgeon's capability of ruling out an AR prior to iMRI turned out to incorporate guesswork (negative predictive value 43.6%). In a prediction model, AR could only be anticipated with 65% accuracy after integration of confounding variables. CONCLUSIONS: Routine use of iMRI in glioma surgery is a safe and reliable method for resection guidance and is characterized by frequent ARs after scanning. Tumor-related factors were identified that influenced the course of surgery and intraoperative decision-making, and iMRI had a common value for surgeons of all experience levels. Commonly, the subjective intraoperative impression of the extent of resection had to be revised after iMRI review, which underscores the manifold potential of iMRI guidance. In combination with the failure to identify ideal iMRI cases preoperatively, this study supports a generous, tumor-oriented rather than surgeon-oriented indication for iMRI in glioma surgery. PMID- 26926063 TI - Direct navigated 3D ultrasound for resection of brain tumors: a useful tool for intraoperative image guidance. AB - OBJECTIVE: Navigated 3D ultrasound is a novel intraoperative imaging adjunct permitting quick real-time updates to facilitate tumor resection. Image quality continues to improve and is currently sufficient to allow use of navigated ultrasound (NUS) as a stand-alone modality for intraoperative guidance without the need for preoperative MRI. METHODS: The authors retrospectively analyzed cases involving operations performed at their institution in which a 3D ultrasound navigation system was used for control of resection of brain tumors in a "direct" 3D ultrasound mode, without preoperative MRI guidance. The usefulness of the ultrasound and its correlation with postoperative imaging were evaluated. RESULTS: Ultrasound was used for resection control in 81 cases. In 53 of these 81 cases, at least 1 intermediate scan (range 1-3 intermediate scans) was obtained during the course of the resection, and in 50 of these 53 cases, the result prompted further resection. In the remaining 28 cases, intermediate scans were not performed either because the first ultrasound scan performed after resection was interpreted as showing no residual tumor (n = 18) and resection was terminated or because the surgeon intentionally terminated the resection prematurely due to the infiltrative nature of the tumor and extension of disease into eloquent areas (n = 10) and the final ultrasound scan was interpreted as showing residual disease. In an additional 20 cases, ultrasound navigation was used primarily for localization and not for resection control, making the total number of NUS cases where radical resection was planned 101. Gross-total resection (GTR) was planned in 68 of these 101 cases and cytoreduction in 33. Ultrasound-defined GTR was achieved in 51 (75%) of the cases in which GTR was planned. In the remaining 17, further resection had to be terminated (despite evidence of residual tumor on ultrasound) because of diffuse infiltration or proximity to eloquent areas. Of the 33 cases planned for cytoreduction, NUS guidance facilitated ultrasound-defined GTR in 4 cases. Overall, ultrasound defined GTR was achieved in 50% of cases (55 of 111). Based on the postoperative imaging (MRI in most cases), GTR was achieved in 58 cases (53%). Final (postresection) ultrasonography was documented in 78 cases. The findings were compared with the postoperative imaging to ascertain concordance in detecting residual tumor. Overall concordance was seen in 64 cases (82.5%), positive concordance was seen in 33 (42.5%), and negative in 31 (40%). Discordance was seen in 14 cases-with ultrasound yielding false-positive results in 7 cases and false-negative results in 7 cases. Postoperative neurological worsening occurred in 15 cases (13.5%), and in most of these cases, it was reversible by the time of discharge. CONCLUSIONS: The results of this study demonstrate that 3D ultrasound can be effectively used as a stand-alone navigation modality during the resection of brain tumors. The ability to provide repeated, high-quality intraoperative updates is useful for guiding resection. Attention to image acquisition technique and experience can significantly increase the quality of images, thereby improving the overall utility of this modality. PMID- 26926064 TI - Versatile utilization of real-time intraoperative contrast-enhanced ultrasound in cranial neurosurgery: technical note and retrospective case series. AB - OBJECTIVE: Intraoperative contrast-enhanced ultrasound (iCEUS) offers dynamic imaging and provides functional data in real time. However, no standardized protocols or validated quantitative data exist to guide its routine use in neurosurgery. The authors aimed to provide further clinical data on the versatile application of iCEUS through a technical note and illustrative case series. METHODS: Five patients undergoing craniotomies for suspected tumors were included. iCEUS was performed using a contrast agent composed of lipid shell microspheres enclosing perflutren (octafluoropropane) gas. Perfusion data were acquired through a time-intensity curve analysis protocol obtained using iCEUS prior to biopsy and/or resection of all lesions. RESULTS: Three primary tumors (gemistocytic astrocytoma, glioblastoma multiforme, and meningioma), 1 metastatic lesion (melanoma), and 1 tumefactive demyelinating lesion (multiple sclerosis) were assessed using real-time iCEUS. No intraoperative complications occurred following multiple administrations of contrast agent in all cases. In all neoplastic cases, iCEUS replicated enhancement patterns observed on preoperative Gd-enhanced MRI, facilitated safe tumor debulking by differentiating neoplastic tissue from normal brain parenchyma, and helped identify arterial feeders and draining veins in and around the surgical cavity. Intraoperative CEUS was also useful in guiding a successful intraoperative needle biopsy of a cerebellar tumefactive demyelinating lesion obtained during real-time perfusion analysis. CONCLUSIONS: Intraoperative CEUS has potential for safe, real-time, dynamic contrast-based imaging for routine use in neurooncological surgery and image guided biopsy. Intraoperative CEUS eliminates the effect of anatomical distortions associated with standard neuronavigation and provides quantitative perfusion data in real time, which may hold major implications for intraoperative diagnosis, tissue differentiation, and quantification of extent of resection. Further prospective studies will help standardize the role of iCEUS in neurosurgery. PMID- 26926065 TI - Identification of residual tumor with intraoperative contrast-enhanced ultrasound during glioblastoma resection. AB - OBJECTIVE: The purpose of this study was to assess the capability of contrast enhanced ultrasound (CEUS) to identify residual tumor mass during glioblastoma multiforme (GBM) surgery, to increase the extent of resection. METHODS: The authors prospectively evaluated 10 patients who underwent surgery for GBM removal with navigated ultrasound guidance. Navigated B-mode and CEUS were performed prior to resection, during resection, and after complete tumor resection. Areas suspected for residual tumors on B-mode and CEUS studies were localized within the surgical field with navigated ultrasound and samples were sent separately for histopathological analysis to confirm tumor presence. RESULTS: In all cases tumor remnants were visualized as hyperechoic areas on B-mode, highlighted as CEUS positive areas, and confirmed as tumoral areas on histopathological analysis. In 1 case only, CEUS partially failed to demonstrate residual tumor because the residual hyperechoic area was devascularized prior to ultrasound contrast agent injection. In all cases CEUS enhanced B-mode findings. CONCLUSIONS: As has already been shown in other neoplastic lesions in other organs, CEUS is extremely specific in the identification of residual tumor. The ability of CEUS to distinguish between tumor and artifacts or normal brain on B-mode is based on its capacity to show the vascularization degree and not the echogenicity of the tissues. Therefore, CEUS can play a decisive role in the process of maximizing GBM resection. PMID- 26926067 TI - Improving the accuracy of brain tumor surgery via Raman-based technology. AB - Despite advances in the surgical management of brain tumors, achieving optimal surgical results and identification of tumor remains a challenge. Raman spectroscopy, a laser-based technique that can be used to nondestructively differentiate molecules based on the inelastic scattering of light, is being applied toward improving the accuracy of brain tumor surgery. Here, the authors systematically review the application of Raman spectroscopy for guidance during brain tumor surgery. Raman spectroscopy can differentiate normal brain from necrotic and vital glioma tissue in human specimens based on chemical differences, and has recently been shown to differentiate tumor-infiltrated tissues from noninfiltrated tissues during surgery. Raman spectroscopy also forms the basis for coherent Raman scattering (CRS) microscopy, a technique that amplifies spontaneous Raman signals by 10,000-fold, enabling real-time histological imaging without the need for tissue processing, sectioning, or staining. The authors review the relevant basic and translational studies on CRS microscopy as a means of providing real-time intraoperative guidance. Recent studies have demonstrated how CRS can be used to differentiate tumor-infiltrated tissues from noninfiltrated tissues and that it has excellent agreement with traditional histology. Under simulated operative conditions, CRS has been shown to identify tumor margins that would be undetectable using standard bright-field microscopy. In addition, CRS microscopy has been shown to detect tumor in human surgical specimens with near-perfect agreement to standard H & E microscopy. The authors suggest that as the intraoperative application and instrumentation for Raman spectroscopy and imaging matures, it will become an essential component in the neurosurgical armamentarium for identifying residual tumor and improving the surgical management of brain tumors. PMID- 26926068 TI - Mode-Division-Multiplexing of Multiple Bessel-Gaussian Beams Carrying Orbital Angular-Momentum for Obstruction-Tolerant Free-Space Optical and Millimetre-Wave Communication Links. AB - We experimentally investigate the potential of using 'self-healing' Bessel Gaussian beams carrying orbital-angular-momentum to overcome limitations in obstructed free-space optical and 28-GHz millimetre-wave communication links. We multiplex and transmit two beams (l = +1 and +3) over 1.4 metres in both the optical and millimetre-wave domains. Each optical beam carried 50-Gbaud quadrature-phase-shift-keyed data, and each millimetre-wave beam carried 1-Gbaud 16-quadrature-amplitude-modulated data. In both types of links, opaque disks of different sizes are used to obstruct the beams at different transverse positions. We observe self-healing after the obstructions, and assess crosstalk and power penalty when data is transmitted. Moreover, we show that Bessel-Gaussian orbital angular-momentum beams are more tolerant to obstructions than non-Bessel orbital angular-momentum beams. For example, when obstructions that are 1 and 0.44 the size of the l = +1 beam, are placed at beam centre, optical and millimetre-wave Bessel-Gaussian beams show ~6 dB and ~8 dB reduction in crosstalk, respectively. PMID- 26926066 TI - Optical technologies for intraoperative neurosurgical guidance. AB - Biomedical optics is a broadly interdisciplinary field at the interface of optical engineering, biophysics, computer science, medicine, biology, and chemistry, helping us understand light-tissue interactions to create applications with diagnostic and therapeutic value in medicine. Implementation of biomedical optics tools and principles has had a notable scientific and clinical resurgence in recent years in the neurosurgical community. This is in great part due to work in fluorescence-guided surgery of brain tumors leading to reports of significant improvement in maximizing the rates of gross-total resection. Multiple additional optical technologies have been implemented clinically, including diffuse reflectance spectroscopy and imaging, optical coherence tomography, Raman spectroscopy and imaging, and advanced quantitative methods, including quantitative fluorescence and lifetime imaging. Here we present a clinically relevant and technologically informed overview and discussion of some of the major clinical implementations of optical technologies as intraoperative guidance tools in neurosurgery. PMID- 26926069 TI - Testing the Hypothesis of Biofilm as a Source for Soft Tissue and Cell-Like Structures Preserved in Dinosaur Bone. AB - Recovery of still-soft tissue structures, including blood vessels and osteocytes, from dinosaur bone after demineralization was reported in 2005 and in subsequent publications. Despite multiple lines of evidence supporting an endogenous source, it was proposed that these structures arose from contamination from biofilm forming organisms. To test the hypothesis that soft tissue structures result from microbial invasion of the fossil bone, we used two different biofilm-forming microorganisms to inoculate modern bone fragments from which organic components had been removed. We show fundamental morphological, chemical and textural differences between the resultant biofilm structures and those derived from dinosaur bone. The data do not support the hypothesis that biofilm-forming microorganisms are the source of these structures. PMID- 26926070 TI - Outcome of a school-based health education program for epilepsy awareness among schoolchildren. AB - BACKGROUND: A diagnosis of epilepsy has a major effect on children; especially among schoolchildren. Studies have shown that a significant proportion of teachers and students have negative attitude and misunderstanding towards epilepsy making it difficult for a child with epilepsy. At the same time, there is a dearth is dearth of literature regarding interventions to bring about a change in the attitudes of children. METHODOLOGY: The aim of the present study was to study the outcome of a school-based health education program for epilepsy awareness among schoolchildren. The objectives were to assess the level of knowledge, attitude, and practices about epilepsy and relationship among these variables. A total of 70 children, from 8th-10th grades were selected randomly for the study. For the study purpose, knowledge, attitude, and practices of epilepsy instrument were developed and face validated by experts. RESULTS: Results show that the mean, median, and mode age of the respondents in the study were 14.55 (+/-1.33), 15, and 14 years, respectively. The gender distribution of the respondents was 54.9% boys and 45.1% girls. With regard to knowledge, attitude, and practices in epilepsy, knowledge strongly and positively correlated with attitude (p=0.001, r=.423) and practice domains (p=0.001, r=.486). Postattitude and (p=0.001, r=.338) practice were positively correlated, which shows that positive attitude brings positive practice. Hence, it is concluded that a training program brings desirable change in the knowledge, attitude, and practice domains among children. CONCLUSION: Health education programs for schoolchildren are very important to bring changes in their attitude, behavior, and practices. PMID- 26926071 TI - Non-EEG based ambulatory seizure detection designed for home use: What is available and how will it influence epilepsy care? AB - OBJECTIVE: This study aimed to (1) evaluate available systems and algorithms for ambulatory automatic seizure detection and (2) discuss benefits and disadvantages of seizure detection in epilepsy care. METHODS: PubMed and EMBASE were searched up to November 2014, using variations and synonyms of search terms "seizure prediction" OR "seizure detection" OR "seizures" AND "alarm". RESULTS: Seventeen studies evaluated performance of devices and algorithms to detect seizures in a clinical setting. Algorithms detecting generalized tonic-clonic seizures (GTCSs) had varying sensitivities (11% to 100%) and false alarm rates (0.2-4/24 h). For other seizure types, detection rates were low, or devices produced many false alarms. Five studies externally validated the performance of four different devices for the detection of GTCSs. Two devices were promising in both children and adults: a mattress-based nocturnal seizure detector (sensitivity: 84.6% and 100%; false alarm rate: not reported) and a wrist-based detector (sensitivity: 89.7%; false alarm rate: 0.2/24 h). SIGNIFICANCE: Detection of seizure types other than GTCSs is currently unreliable. Two detection devices for GTCSs provided promising results when externally validated in a clinical setting. However, these devices need to be evaluated in the home setting in order to establish their true value. Automatic seizure detection may help prevent sudden unexpected death in epilepsy or status epilepticus, provided the alarm is followed by an effective intervention. Accurate seizure detection may improve the quality of life (QoL) of subjects and caregivers by decreasing burden of seizure monitoring and may facilitate diagnostic monitoring in the home setting. Possible risks are occurrence of alarm fatigue and invasion of privacy. Moreover, an unexpectedly high seizure frequency might be detected for which there are no treatment options. We propose that future studies monitor benefits and disadvantages of seizure detection systems with particular emphasis on QoL, comfort, and privacy of subjects and impact of false alarms. PMID- 26926072 TI - Interplay between interictal spikes and behavioral seizures in young, but not aged pilocarpine-treated epileptic rats. AB - Interictal spike activity is commonly observed in the EEG of patients with epilepsy, but the causal interrelationship between interictal spikes and behavioral seizures is poorly understood. We performed long-term video-EEG monitoring of 16 epileptic rats after pilocarpine-induced status epilepticus and five control animals. To quantify the interplay between periods of spikes and seizures, we calculated the time spent with spikes as well as the time spent with seizures for each animal. Within a given subject, we found a significant correlation between these two measures in 7/11 young epileptic rats (<400 days); this correlation was positive in six cases and negative in one. By contrast, none of five aged pilocarpine-treated animals exhibited significant correlation coefficients between spike periods and seizures (>600 days, P<0.05). Instead, aged epileptic rats showed a prominent predominance for either spike periods or seizures, which might explain the absence of significant correlation in this population. We found that there is a significant interplay between interictal periods of spikes and behavioral seizures in young epileptic animals, but this association is absent during aging. PMID- 26926073 TI - Plasma Exchange and Immunoadsorption in Pediatric Inflammatory Optic Neuropathy Resistant to Corticosteroid Therapy: Four French Cases. AB - Steroids as a foremost therapy are widely used in pediatric optic neuritis (ON). Yet, this treatment is not standardized to date. Some children show a resistance to the classic treatment by steroids. Although plasma exchange (PE) and immunoadsorption (IA) techniques are increasingly being adopted and lead to good results in resistant cases in adult patients, very few studies have shown interest in treating ON when steroids have failed. In this study, we report four observations of children, two of whom are treated by PE and two by IA techniques, describing the treatment protocols together with the side effects observed. PMID- 26926074 TI - Health inequality in the Russian Federation: An examination of the changes in concentration and achievement indices from 1994 to 2013. AB - BACKGROUND: To assess and quantify the magnitude of health inequalities ascribed to socioeconomic strata from 1994 to 2013 in the Russian Federation. METHODS: A balanced sample of 1,496 adult individuals extracted from the 1994 wave of the Russian Longitudinal Monitoring Survey (RLMS) is followed for stated self perceived health status until 2013. The socioeconomic strata (SES) index is constructed with a set of variables (adult equivalent household income, ownership of assets and living conditions) by applying principal component analysis (PCA). We use a regression-based concentration index to measure differences in self perceived health status. Finally, we examine the degree of aversion to inequalities in self-perceived health status between the worse-off and the better off with the achievement index. RESULTS: By 2013, the mean standardized self perceived health status has improved by 4.6 % compared to 1994. The absolute size of Concentration Index (CI) for non - standardized self-perceived health status is reduced by 44.27 % from 1994 to 2013. No systematic trend emerges in the evolution of CI for self-perceived health status of the Russians over the 19 year period. However, avoidable inequalities in self-perceived health status of the Russian population is reduced by almost 60 % over the two decades (1994-2013). CONCLUSION: SES, as defined with objective indicators, shows little consistency in association with self-perceived health status in the Russian Federation. This study highlights the need for future research that considers the context of stated self-perceived health status in the realm of subjective socioeconomic status (SSS). PMID- 26926075 TI - The role of trigeminal function in the sensation of nasal obstruction in chronic rhinosinusitis. AB - OBJECTIVES/HYPOTHESIS: Trigeminal sensation (TS) within the nasal cavity is important for the perception of nasal airflow. The objective of this study is to examine whether impaired TS contributes to the sensation of nasal obstruction in patients with chronic rhinosinusitis (CRS). STUDY DESIGN: Prospective case control study conducted in a tertiary referral rhinology clinic. METHODS: Cases consisted of CRS patients with subjective nasal obstruction, not previously treated with oral corticoids. Controls consisted of patients without CRS. Neither group demonstrated obvious anatomical obstructions. Both groups underwent peak nasal inspiratory flows (PNIF), olfactory testing (quick eight-item odor identification test), and trigeminal testing (lateralization task using eucalyptol and odorless solvent). RESULTS: A total of 28 subjects (14 CRS patients and 14 controls) were recruited. Analyses revealed no statistical differences in age (P = .93), gender (P = .47), or PNIF (P = .82) between the two groups, but they differed in Lund-Mackay scores (P < .001). There was no significant difference in olfactory testing (P = .15). CRS patients had significantly lower scores on trigeminal lateralization testing than controls (P = .007). Linear regression revealed that Lund-Mackay scores contributed a significant amount of variance to trigeminal lateralization scores, controlling for age and sex (F = 5.93, P = .004, R(2) = 0.43). CONCLUSIONS: This is the first study to demonstrate that patients with CRS have lower TS than healthy controls. Our results suggest defective TS could play a role in the sensation of nasal obstruction in CRS. LEVEL OF EVIDENCE: 3b. Laryngoscope, 126:E174-E178, 2016. PMID- 26926076 TI - IL-33 is associated with unfavorable postoperative survival of patients with clear-cell renal cell carcinoma. AB - The aim of this study was to evaluate the potential prognostic significance of interleukin-33 (IL-33) in patients with clear-cell renal cell carcinoma (ccRCC) after surgical resection. In this retrospective research, we enrolled 203 patients with ccRCC undergoing nephrectomy between 2003 and 2004 in a single institution. We recorded clinicopathologic features, overall survival (OS), and recurrence-free survival (RFS) and assessed IL-33 expression by immunohistochemical staining. On such bases, the correlations between IL-33 expression and clinicopathologic features and prognosis were evaluated. A high expression of IL-33 was significantly associated with advanced TNM stage and Fuhrman grade (p = 0.017 and p < 0.001, respectively) in patients with ccRCC. Moreover, multivariate analysis identified IL-33 as an independent prognostic factor of OS for patients with ccRCC after surgery (hazard ratio = 2.050; 95 % CI 1.223-3.447; p = 0.006). The incorporation of IL-33 into the TNM stage and Fuhrman grade might help to refine individual risk stratification. The IL-33 expression may serve as an independent negative predictor of survival for patients with ccRCC after surgery. PMID- 26926078 TI - Methamphetamine-induced dopaminergic toxicity prevented owing to the neuroprotective effects of salicylic acid. AB - AIMS: Methamphetamine (Schedule-II drug, U.S. Drug Enforcement Administration) is one of the most abused illicit drug following cocaine, marijuana, and heroin in the USA. There are numerous health impairments and substantial economic burden caused by methamphetamine abuse. Salicylic acid, potent anti-inflammatory drug and a known neuroprotectant has shown to protect against toxicity-induced by other dopaminergic neurotoxins. Hence, in this study we investigated the neuroprotective effects of salicylic acid against methamphetamine-induced toxicity in mice. MAIN METHODS: The current study investigated the effects of sodium salicylate and/or methamphetamine on oxidative stress, monoamine oxidase, mitochondrial complex I & IV activities using spectrophotometric and fluorimetric methods. Behavioral analysis evaluated the effect on movement disorders-induced by methamphetamine. Monoaminergic neurotransmitter levels were evaluated using high pressure liquid chromatography-electrochemical detection. KEY FINDINGS: Methamphetamine caused significant generation of reactive oxygen species and decreased complex-I activity leading to dopamine depletion. Striatal dopamine depletion led to significant behavioral changes associated with movement disorders. Sodium salicylate (50 & 100mg/kg) significantly scavenged reactive oxygen species, blocked mitochondrial dysfunction and exhibited neuroprotection against methamphetamine-induced neurotoxicity. In addition, sodium salicylate significantly blocked methamphetamine-induced behavioral changes related to movement abnormalities. SIGNIFICANCE: One of the leading causative theories in nigral degeneration associated with movement disorders such as Parkinson's disease is exposure to stimulants, drugs of abuse, insecticide and pesticides. These neurotoxic substances can induce dopaminergic neuronal insult by oxidative stress, apoptosis, mitochondrial dysfunction and inflammation. Salicylic acid due to its antioxidant and anti-inflammatory effects could provide neuroprotection against the stimulants or drugs of abuse. PMID- 26926077 TI - Interaction with Pyruvate Kinase M2 Destabilizes Tristetraprolin by Proteasome Degradation and Regulates Cell Proliferation in Breast Cancer. AB - Pyruvate kinase M2 (PKM2), which is predominantly expressed in most cancers, plays a key role in the Warburg effect. However, how PKM2 functions as a tumor supportive protein has not been fully elucidated. Here, we identified tristetraprolin (TTP), an AU-rich, element-binding protein that regulates mRNA stability, as a new binding partner of PKM2. Our data reveal that PKM2 suppresses TTP protein levels by promoting its phosphorylation, ubiquitination, and proteasome degradation, reducing its mRNA turnover ability and ultimately impairing cell viability in breast cancer cells. The p38/mitogen-activated protein kinase (MAPK) pathway might be involved in PKM2-mediated TTP degradation, while treatment with the p38 inhibitor or siRNA abolished PKM2-induced TTP protein degradation. These findings demonstrate that PKM2-TTP association is crucial for regulating breast cancer cell proliferation and is therefore a potential therapeutic target in cancer. PMID- 26926080 TI - Effect of transient receptor potential vanilloid-1 on cough hypersensitivity induced by particulate matter 2.5. AB - AIMS: The mechanism of cough hypersensitivity induced by particulate matter 2.5 (PM2.5) remains elusive. The current study was designed to explore the effect of transient receptor potential vanilloid-1 (TRPV1) on cough hypersensitivity in airway and central nervous system. MAIN METHODS: The PM2.5-induced chronic cough model of guinea pig was established by exposure to different doses of PM2.5 for three weeks. After exposure, the animals were microinjected with TRPV1 agonist capsaicine, antagonist capsazepine in the dorsal vagal complex respectively. Cough sensitivity was measured by determining the provocative concentration of citric acid inducing 5 or more coughs (C5). Airway inflammation was detected by hematoxylin eosin (HE) staining and Evans blue fluorescence, and substance P (SP) and TRPV1 expressions in airway were observed by immunohistochemical staining. TRPV1 expressions in the dorsal vagal complex were observed by immunofluorescence. Retrograde tracing by pseudorabies virus-Bartha (PRV-Bartha) was conducted to confirm the regulatory pathway between airway and central nervous system. KEY FINDINGS: PM2.5 induced TRPV1 expressions in both of airway and dorsal vagal complex and airway neurogenic inflammation. Airway vascular permeability increased after being exposed to PM2.5. The expressions of SP in the airway and airway inflammation was increased after microinjecting TRPV1 agonist, and decreased after microinjecting TRPV1 antagonist. PRV infected neurons in medulla oblongata mainly located in the dorsal vagal complex. SIGNIFICANCE: These findings show that TRPV1 in the dorsal vagal complex could promote airway neurogenic inflammation and cough reflex sensitivity through neural pathways of vagal complex-airways, which indicate the therapeutic potential of specific inhibition of TRPV1 for chronic cough induced by PM2.5. PMID- 26926079 TI - Alterations in histone deacetylase 8 lead to cell migration and poor prognosis in breast cancer. AB - AIMS: Alterations in histone proteins can lead to breast tumorigenesis. Selective histone deacetylase 8 (HDAC8) inhibitors with fewer adverse effects have been developed. A more comprehensive study of alterations and its mechanisms in HDAC8 is required. In this study, we investigated mechanisms of dysregulation of HDAC8 expression and its biological role and pathways in breast cancer. MAIN METHODS: Alterations in HDAC8 were analyzed in Taiwanese breast cancer patients; and in tissue samples from The Cancer Genome Atlas (TCGA) data set that were derived from Western countries. Knockdown by si-HDAC8, treatment with the HDAC8-specific inhibitor PCI-34051, SRB assays, wound healing, Transwell migration assays, Illumina BeadArrayTM arrays and Ingenuity Pathway Analysis (IPA) were performed in breast cancer cells. KEY FINDINGS: HDAC8 mRNA expression was upregulated in paired breast cancer tissue from Taiwanese patients and in paired breast cancer tissues from the TCGA data set. Hypomethylation of promoter regions was significantly correlated with HDAC8 mRNA overexpression in 588 breast cancer patients from the TCGA data set and was associated with poor prognosis in early stage breast cancer. HDAC8 mRNA overexpression was associated with late stages and tumor progression. Wound healing and Transwell migration assays revealed that knockdown by si-HDAC8 or PCI-34051 treatment significantly inhibited breast cancer cell migration. Knockdown by si-HDAC8, Illumina BeadArrayTM arrays and IPA found that ID3 and PTP4A2 pathways were regulated by HDAC8 in cancer cell migration. SIGNIFICANCE: Hypomethylation of the HDAC8 promoter is correlated with HDAC8 overexpression and breast cancer progression and is a potential prognosis marker and drug target. PMID- 26926081 TI - Veterinary Forensic Pathology: Drowning and Bodies Recovered From Water. AB - Determining the cause of death in animals recovered from bodies of water, swimming pools, or other water-containing vessels is challenging. Animals recovered from water may or may not have drowned. The diagnosis of drowning is usually one of exclusion, requiring information from the crime scene, recovery scene, the medical history or reliable witness accounts. While there are characteristic macroscopic and microscopic lesions of drowning, none are specific and are dependent on the volume and tonicity of the drowning medium. Beyond interpreting the postmortem findings, the court may ask pathologists to comment on the behavioral and welfare implications of drowning. This requires an understanding of the drowning process, which is a complex series of sequential, concurrent, and overlapping cardiorespiratory reflexes, electrolyte and blood gas abnormalities, aspiration, physical exhaustion, and breathlessness eventually culminating in death. This review addresses the mechanisms, lesions, and diagnostic issues associated with drowning in nonaquatic companion animals. PMID- 26926082 TI - Dentin Dysplasia in Notum Knockout Mice. AB - Secreted WNT proteins control cell differentiation and proliferation in many tissues, and NOTUM is a secreted enzyme that modulates WNT morphogens by removing a palmitoleoylate moiety that is essential for their activity. To better understand the role this enzyme in development, the authors produced NOTUM deficient mice by targeted insertional disruption of the Notum gene. The authors discovered a critical role for NOTUM in dentin morphogenesis suggesting that increased WNT activity can disrupt odontoblast differentiation and orientation in both incisor and molar teeth. Although molars in Notum(-/-) mice had normal shaped crowns and normal mantle dentin, the defective crown dentin resulted in enamel prone to fracture during mastication and made teeth more susceptible to endodontal inflammation and necrosis. The dentin dysplasia and short roots contributed to tooth hypermobility and to the spread of periodontal inflammation, which often progressed to periapical abscess formation. The additional incidental finding of renal agenesis in some Notum (-/-) mice indicated that NOTUM also has a role in kidney development, with undiagnosed bilateral renal agenesis most likely responsible for the observed decreased perinatal viability of Notum(-/-) mice. The findings support a significant role for NOTUM in modulating WNT signaling pathways that have pleiotropic effects on tooth and kidney development. PMID- 26926083 TI - A Survey of Attitudes of Board-Certified Veterinary Pathologists to Forensic Veterinary Pathology. AB - An electronic survey was conducted to determine the attitudes of veterinary pathologists toward forensic pathology and the adequacy of their training in the discipline. The survey was sent to 1933 diplomates of the American College of Veterinary Pathologists and 311 completed responses were analyzed. Of respondents, 80% report receiving at least 1 type of medicolegal case, with cases from law enforcement received most frequently. Most (74%) of the respondents indicated that their previous training did not prepare them adequately to handle forensic cases and almost half of the respondents (48%) indicated that they needed more training on serving as an expert witness. Relative risk ratios (RRR) and odds ratios (OR) were generated to determine the strength of a statistically significant association. Responses from a free-text entry question determining additional training needs could be grouped into 3 main categories: (1) veterinary forensic pathology science and procedures, (2) documentation, evidence collection and handling, and (3) knowledge of the medicolegal system. Last, a field for additional comments or suggestions regarding veterinary forensic pathology was completed by 107 respondents and many reinforced the need for training in the categories previously described. The survey highlights that a significant proportion of diplomates of the American College of Veterinary Pathologists are currently engaged in veterinary forensic pathology but feel their training has not adequately prepared them for these cases. Hopefully, the survey results will inform the college and residency training coordinators as they address the training requirements for an important emerging discipline. PMID- 26926084 TI - Thrombomodulin Expression in Tissues From Dogs With Systemic Inflammatory Disease. AB - Thrombomodulin (TM) is a membrane glycoprotein expressed on endothelial cells, which plays a major role in the protein C anticoagulation pathway. In people with inflammation, TM expression can be down-regulated on endothelial cells and a soluble form released into circulation, resulting in increased risk of thrombosis and disseminated intravascular coagulation. TM is present in dogs; however, there has been minimal investigation of its expression in canine tissues, and the effects of inflammation on TM expression in canine tissues have not been investigated. The objective of this study was to evaluate endothelial TM expression in tissues from dogs with systemic inflammatory diseases. A retrospective evaluation of tissue samples of lung, spleen, and liver from dogs with and without systemic inflammatory diseases was performed using immunohistochemistry (IHC) and a modified manual IHC scoring system. TM expression was significantly reduced in all examined tissues in dogs diagnosed with septic peritonitis or acute pancreatitis. PMID- 26926085 TI - Osteocalcin and Osteonectin Expression in Canine Osteosarcoma. AB - Osteosarcoma (OSA) is a malignant heterogeneous primary bone tumor responsible for up to 90% of all primary bone tumors in dogs. In this study, osteocalcin (OC) and osteonectin (ON) immunoreactivity was evaluated in 23 canine OSAs, 4 chondrosarcomas, 4 fibrosarcomas, 2 hemangiosarcomas, and 4 histiocytic sarcomas. The effects of three different decalcification agents (ethylenediaminetetraetic acid [EDTA], formic acid and hydrochloric acid [HCl]) on the immunoreactivity for OC and ON was also assessed. Immunoreactivity to OC was present in 19/23 (83%) cases of OSA and all cases of chondrosarcoma. In three OSAs the extracellular matrix showed immunoreactivity to OC. None of the fibrosarcomas, histiocytic sarcomas or hemangiosarcomas showed immunoreactivity to OC. The sensitivity and specificity for OC in canine OSA in this study was 83% and 71% respectively. For ON, 100% of both OSAs (23/23) and non-OSAs (14/14) showed cytoplasmic immunoreactivity to this antibody, giving a sensitivity of 100% but a complete lack of specificity. There were no significant differences in immunoreactivity for OC and ON between the different decalcification agents used. In conclusion, OC showed high sensitivity for identifying OSA but it failed to distinguish between OSA and chondrosarcoma, and the osteoid produced by neoplastic cells in most cases did not show immunoreactivity to OC. These factors may limit the practical utility of OC in the diagnosis of OSA in dogs when chondrosarcoma is a differential diagnosis. ON showed no specificity in detecting OSA and has little practical application for the diagnosis of OSA in dogs. PMID- 26926086 TI - Pulmonary Veno-Occlusive Disease: A Newly Recognized Cause of Severe Pulmonary Hypertension in Dogs. AB - Pulmonary hypertension is a well-known though poorly characterized disease in veterinary medicine. In humans, pulmonary veno-occlusive disease (PVOD) is a rare cause of severe pulmonary hypertension with a mean survival time of 2 years without lung transplantation. Eleven adult dogs (5 males, 6 females; median age 10.5 years, representing various breeds) were examined following the development of severe respiratory signs. Lungs of affected animals were evaluated morphologically and with immunohistochemistry for alpha smooth muscle actin, desmin, CD31, CD3, CD20, and CD204. All dogs had pulmonary lesions consistent with PVOD, consisting of occlusive remodeling of small- to medium-sized pulmonary veins, foci of pulmonary capillary hemangiomatosis (PCH), and accumulation of hemosiderophages; 6 of 11 dogs had substantial pulmonary arterial medial and intimal thickening. Ultrastructural examination and immunohistochemistry showed that smooth muscle cells contributed to the venous occlusion. Increased expression of CD31 was evident in regions of PCH indicating increased numbers of endothelial cells in these foci. Spindle cells strongly expressing alpha smooth muscle actin and desmin co-localized with foci of PCH; similar cells were present but less intensely labeled elsewhere in non-PCH alveoli. B cells and macrophages, detected by immunohistochemistry, were not co-localized with the venous lesions of canine PVOD; small numbers of CD3-positive T cells were occasionally in and around the wall of remodeled veins. These findings indicate a condition in dogs with clinically severe respiratory disease and pathologic features resembling human PVOD, including foci of pulmonary venous remodeling and PCH. PMID- 26926087 TI - Robotic assisted adrenalectomy: Surgical techniques, feasibility, indications, oncological outcome and safety. AB - Nowadays robotic assisted adrenalectomy has become an alternative to conventional laparoscopic adrenalectomy. However, evidence on the possible advantages and drawbacks of robotic assisted adrenalectomy remains still limited. This manuscript aimed to review evidence on robotic assisted adrenalectomy in terms of surgical technique, feasibility, indications, oncological outcome and safety. Existing evidence, although limited, suggests that robotic assisted adrenalectomy is feasible and safe. However, the number of patients submitted to robotic assisted adrenalectomy is limited with the majority of them being operated for benign disease. There are only a few case reports of robotic assisted adrenalectomy performed for adrenocortical carcinoma, oncocytoma or metastasis. Partial adrenalectomy seems to be a promising application of robotic assisted adrenalectomy especially for the treatment of hereditary pheocromocytomas. Robotic assisted adrenalectomy overcoming the technical limitations of laparoscopic surgery could possibly elicit a mild surgical response instead of the well described surgical response. Surgical response affects surgical morbidity and mortality as well as oncological outcome of malignant disease. If this hypothesis is proved correct, robotic assisted adrenalectomy could be possibly indicated in the treatment of disease. In conclusion, robotic assisted adrenalectomy is feasible and safe. Further research is needed on the oncological outcome of this minimally invasive technique as well as on its effect on surgical stress response. PMID- 26926088 TI - Impact of frailty on outcomes in geriatric femoral neck fracture management: An analysis of national surgical quality improvement program dataset. AB - INTRODUCTION: Frailty is a clinical state of increased vulnerability resulting from aging-associated decline in physiologic reserve. Hip fractures are serious fall injuries that affect our aging population. We retrospectively sought to study the effect of frailty on postoperative outcomes after Total Hip Arthroplasty (THA) and Hemiarthroplasty (HA) for femoral neck fracture in a national data set. METHODS: National Surgical Quality Improvement Project dataset (NSQIP) was queried to identify THA and HA for a primary diagnosis femoral neck fracture using ICD-9 codes. Frailty was assessed using the modified frailty index (mFI) derived from the Canadian Study of Health and Aging. The primary outcome was 30-day mortality and secondary outcomes were 30-day morbidity and failure to rescue (FTR). We used multivariate logistic regression to estimate odds ratio for outcomes while controlling for confounders. RESULTS: Of 3121 patients, mean age of patients was 77.34 +/- 9.8 years. The overall 30-day mortality was 6.4% (3.2% THA and 7.2%-HA). One or more severe complications (Clavien-Dindo class-IV) occurred in 7.1% patients (6.7%-THA vs.7.2%-HA). Adjusted odds ratios (ORs) for mortality in the group with the higher than median frailty score were 2 (95%CI, 1.4-3.7) after HA and 3.9 (95%CI, 1.3-11.1) after THA. Similarly, in separate multivariate analysis for Clavien-Dindo Class-IV complications and failure to rescue 1.6 times (CI95% 1.15-2.25) and 2.1 times (CI95% 1.12-3.93) higher odds were noted in above median frailty group. CONCLUSIONS: mFI is an independent predictor of mortality among patients undergoing HA and THA for femoral neck fracture beyond traditional risk factors such as age, ASA class, and other comorbidities. LEVELS OF EVIDENCE: Level II. PMID- 26926089 TI - Do postoperative NSAIDs improve breast cancer outcomes? A Best Evidence Topic. AB - A Best Evidence Topic was undertaken to systematically review the evidence regarding the use of NSAIDS in breast cancer patients. The search strategy generated 149 titles, of which six were best placed to answer the clinical question. These included three prospective cohort studies, two retrospective cohort studies and one case control study, examining a total of 18,415 breast cancer patients. The study methodologies were highly variable and all relied on approximate measures of NSAID consumption. There is limited evidence that use of aspirin and non-aspirin NSAIDs may be associated with decreased breast cancer mortality and all-cause mortality in patients diagnosed with breast cancer. Optimum type and dosage of NSAID for this purpose remains unclear. There is a need for large-scale randomised controlled trials to further clarify. PMID- 26926091 TI - Preparation and characterization of a possible topological insulator BiYO3: experiment versus theory. AB - The Bi-Y-O system has been investigated by X-ray powder diffraction, electron diffraction, UV-vis and IR experiments. A metastable cubic high temperature phase of BiYO3 with fluorite-type structure has been structurally characterized for the first time and shows a large band gap of ~ 5.9 eV. A unified description for the numerous structural variants discovered in the Bi-Y-O system is established within the symmetry breaking approach. This rich structural phenomenon makes the Bi-Y-O system a promising candidate in the search for new topological insulators for applications. On this basis, a long standing controversy on the phase diagram of the Bi-Y-O system has been solved. Our DFT calculations predict a high pressure phase for BiYO3 with perovskite (ABO3) structure and ordering of Bi and Y on the A and B sites, respectively. However, our analysis of the nature of the low energy electronic structure shows that this phase is not a suitable candidate for a topological insulator. PMID- 26926090 TI - Mechanisms of lung fibrosis induced by carbon nanotubes: towards an Adverse Outcome Pathway (AOP). AB - Several experimental studies have shown that carbon nanotubes (CNT) can induce respiratory effects, including lung fibrosis. The cellular and molecular events through which these effects develop are, however, not clearly elucidated. The purpose of the present review was to analyze the key events involved in the lung fibrotic reaction induced by CNT and to assess their relationships. We thus address current knowledge and gaps with a view to draft an Adverse Outcome Pathway (AOP) concerning the fibrotic potential of CNT.As for many inhaled particles, CNT can indirectly activate fibroblasts through the release of pro inflammatory (IL-1beta) and pro-fibrotic (PDGF and TGF-beta) mediators by inflammatory cells (macrophages and epithelial cells) via the induction of oxidative stress, inflammasome or NF-kB. We also highlight here direct effects of CNT on fibroblasts, which appear as a new mode of toxicity relatively specific for CNT. Direct effects of CNT on fibroblasts include the induction of fibroblast proliferation, differentiation and collagen production via ERK 1/2 or Smad signaling. We also point out the physico-chemical properties of CNT important for their toxicity and the relationship between in vitro and in vivo effects. This knowledge provides evidence to draft an AOP for the fibrogenic activity of CNT, which allows developing simple in vitro models contributing to predict the CNT effects in lung fibrosis, and risk assessment tools for regulatory decision. PMID- 26926092 TI - Diabetes mellitus and extrapulmonary tuberculosis: site distribution and risk of mortality. AB - Scarce data exist on the relationship between diabetes and extrapulmonary tuberculosis (EPTB). We evaluated whether diabetes impacts site of TB and risk of death in patients with EPTB. We evaluated a cohort of TB cases from the state of Georgia between 2009 and 2012. Patients aged ?16 years were classified by diabetes status according to medical records. Site of EPTB was determined by culture and/or state TB classification. Death was defined by all-cause mortality. Of 1325 eligible reported TB cases, 369 (27.8%) had any EPTB including 258 (19.5%) with only EPTB and 111 (8.4%) with pulmonary TB and EPTB. Of all TB cases, 158 had diabetes (11.9%). In multivariable analysis, the odds of any EPTB was similar in patients with and without diabetes [adjusted odds ratio 1.04, 95% confidence interval (CI) 0.70-1.56]. The risk of death was 23.8% in patients with EPTB and diabetes vs. 9.8% in those with no diabetes (P < 0.01); after adjusting for covariates the difference was not significant (aRR 1.19, 95% CI 0.54-2.63). Diabetes was common in patients with EPTB and risk of death was high. Improved understanding of the relationship between diabetes and EPTB is critical to determine the extent that diabetes affects TB diagnosis and clinical management. PMID- 26926093 TI - New insights into the androgen biotransformation in prostate cancer: A regulatory network among androgen, androgen receptors and UGTs. AB - Androgen, as one kind of steroid hormones, is pivotal in the hormone-sensitive cancer, such as prostate cancer (PCa). The synthesis, elimination, and bioavailability of androgen in prostate cells have been proved to be a main cause of the carcinogenesis, maintenance and deterioration of PCa. This review illustrates the outlines of androgen biotransformation, and further discusses the different enzymes, especially UDP-glucuronyltransferases (UGTs) embedded in both benign and malignant prostate cells, which catalyze the reactions. Although many inhibitors of the enzymes responsible for the synthesis of androgens have been developed into drugs to fight against PCa, the elimination procedures metabolized by the UGTs are less emphasized. Thus the regulatory network among androgen, androgen receptors (AR) and UGTs is carefully reviewed in this article, indicating the determinant effects of UGTs on prostatic androgens and the regulation of AR. Finally, the hypothesis is also put forward that the regulators of UGTs may be developed to accelerate the androgen elimination and benefit PCa therapy. PMID- 26926094 TI - Characterization of tissue engineered cartilage products: Recent developments in advanced therapy. AB - Legislative requirements for the quality of pharmacological agents underwent certain evolution when new type of therapies emerged. This relates to cell based medicines, such as tissue engineered cartilage products (TECP) which are increasingly developed as new modalities for widely prevalent orthopaedic disorders. Although quality measures for TECP are subject to the same general regulatory quality requirements, combination of cellular and scaffold substances requires definition of specific characteristics in vitro that are highly relevant to potency and efficacy of the newly designed medicinal product. One of the specific issues in designing cell based medicines is the fact that the biological activity of active substance, or cells, usually is altered after seeding them on a three-dimensional scaffold. Newly acquired features of the TECP are influenced by chemical, physical and mechanical characteristics of the scaffolds. A vast array of analytical methods has been employed to measure efficacy and potency of TECP in cartilage regeneration studies in vitro. Designing specific physical characteristics of scaffolds may become essential part influencing pharmacological activity of cell based medicinal products, and discern TECP from typical pharmacological products. As an example, increasingly growing popularity of three-dimensional printing that utilizes direct laser writing technique provides an opportunity to improve efficacy of the final TECP. This review is intended to provide brief summary of current approaches used to characterize cells and scaffolds in vitro before and after combination into TECP. Validating TECP as pharmacological agents with unique biological and physical characteristics may broaden their clinical application. PMID- 26926095 TI - Extended-Synaptotagmins (E-Syts); the extended story. AB - The Extended-Synaptotagmin (E-Syt) membrane proteins were only recently discovered, but have already been implicated in a range of interrelated cellular functions, including calcium and receptor signaling, and membrane lipid transport. However, despite their evolutionary conservation and detailed studies of their molecular actions, we still have little idea of how and when these proteins are required in cellular and organism physiology. Here we review our present understanding of the E-Syts and discuss the molecular functions and in vivo requirements for these proteins. PMID- 26926096 TI - Sequencing CYP2D6 for the detection of poor-metabolizers in post-mortem blood samples with tramadol. AB - Tramadol concentrations and analgesic effect are dependent on the CYP2D6 enzymatic activity. It is well known that some genetic polymorphisms are responsible for the variability in the expression of this enzyme and in the individual drug response. The detection of allelic variants described as non functional can be useful to explain some circumstances of death in the study of post-mortem cases with tramadol. A Sanger sequencing methodology was developed for the detection of genetic variants that cause absent or reduced CYP2D6 activity, such as *3, *4, *6, *8, *10 and *12 alleles. This methodology, as well as the GC/MS method for the detection and quantification of tramadol and its main metabolites in blood samples was fully validated in accordance with international guidelines. Both methodologies were successfully applied to 100 post-mortem blood samples and the relation between toxicological and genetic results evaluated. Tramadol metabolism, expressed as its metabolites concentration ratio (N desmethyltramadol/O-desmethyltramadol), has been shown to be correlated with the poor-metabolizer phenotype based on genetic characterization. It was also demonstrated the importance of enzyme inhibitors identification in toxicological analysis. According to our knowledge, this is the first study where a CYP2D6 sequencing methodology is validated and applied to post-mortem samples, in Portugal. The developed methodology allows the data collection of post-mortem cases, which is of primordial importance to enhance the application of these genetic tools to forensic toxicology and pathology. PMID- 26926097 TI - Acute Traumatic Right to Left Cardiac Shunt. AB - Cardiac injuries after penetrating chest trauma are uncommon but potentially life threatening; these injuries can remain occult during the early stage because of the cardiac reserve of youthful physiology and may present at a later stage as the initial damage progresses or compensatory mechanisms fail. We report a case of unusual penetrating cardiac trauma from a posterior intercostal stab wound that affected both the interatrial septum and the tricuspid valve, leading to a stormy presentation as a result of the development of an acute right-to-left shunt followed by a successful surgical repair. PMID- 26926098 TI - Few-layer HfS2 transistors. AB - HfS2 is the novel transition metal dichalcogenide, which has not been experimentally investigated as the material for electron devices. As per the theoretical calculations, HfS2 has the potential for well-balanced mobility (1,800 cm(2)/V.s) and bandgap (1.2 eV) and hence it can be a good candidate for realizing low-power devices. In this paper, the fundamental properties of few layer HfS2 flakes were experimentally evaluated. Micromechanical exfoliation using scotch tape extracted atomically thin HfS2 flakes with varying colour contrasts associated with the number of layers and resonant Raman peaks. We demonstrated the I-V characteristics of the back-gated few-layer (3.8 nm) HfS2 transistor with the robust current saturation. The on/off ratio was more than 10(4) and the maximum drain current of 0.2 MUA/MUm was observed. Moreover, using the electric double-layer gate structure with LiClO4:PEO electrolyte, the drain current of the HfS2 transistor significantly increased to 0.75 mA/MUm and the mobility was estimated to be 45 cm(2)/V.s at least. This improved current seemed to indicate superior intrinsic properties of HfS2. These results provides the basic information for the experimental researches of electron devices based on HfS2. PMID- 26926099 TI - Amino acids-incorporated nanoflowers with an intrinsic peroxidase-like activity. AB - Functional molecules synthesized by self-assembly between inorganic salts and amino acids have attracted much attention in recent years. A simple method is reported here for fabricating hybrid organic-inorganic nanoflowers using copper (II) ions as the inorganic component and natural amino acids as the organic component. The results indicate that the interactions between amino acid and copper ions cause the growth of the nanoflowers composed by C, N, Cu, P and O elements. The Cu ions and Cu(AA)n complexes containing Cu-O bond are present in the nanoflowers. The nanoflowers have flower-like porous structure dominated by the R groups of amino acids with high surface-to-volume ratios, which is beneficial for exerting its peroxidase-like activity depending on Fenton-like reaction mechanism with ABTS and Rhodamine B as the substrates. It is expected that the nanoflowers hold great promise as enzyme mimics for application in the field of biosensor, bioanalysis and biocatalysis. PMID- 26926101 TI - Intraductal carcinoma of prostate reporting practice: a survey of expert European uropathologists. AB - BACKGROUND: It is unclear whether the reported variation in the diagnosis of intraductal carcinoma of the prostate (IDC-P) is due to variable interpretation of borderline morphology, use of different diagnostic criteria or both. AIMS: We sought to determine the degree of variation in the diagnostic criteria and reporting rules for IDC-P in prostate biopsies employed by expert uropathologists. METHODS: A questionnaire survey was circulated to 23 expert uropathologists from 11 European countries. RESULTS: Criteria used for diagnosis of IDC-P included solid intraductal growth (100%), dense cribriform (96%), loose cribriform/micropapillary with nuclear size >6* normal (83%) or comedonecrosis (74%) and dilated ducts >2* normal (39%). 'Nuclear size' was interpreted as nuclear area by 74% and nuclear diameter by 21%. Pure IDC-P in needle biopsies was reported by 100% and Gleason graded by 30%. All would perform immunohistochemistry in such cases to rule out invasive cancer. An IDC-P component associated with invasive cancer would be included in the determination of tumour extent and number of cores involved by 74% and 83%, respectively. 52% would include IDC-P component when grading invasive cancer. 48% would perform immunohistochemistry in solid or cribriform nests with comedonecrosis to exclude IDC-P (17% routinely, 30% if the focus appeared to have basal cells on H&E). 48% graded such foci as Gleason pattern 5 even if immunohistochemistry demonstrated the presence of basal cells. CONCLUSIONS: There is a need for more clarity in the definition of some of the diagnostic criteria for IDC-P as well as for greater standardisation of IDC-P reporting. PMID- 26926102 TI - Prognostic significance of Claudin 12 in estrogen receptor-negative breast cancer. AB - AIMS: Altered expression of the Claudin (CLDN) superfamily of tight junction proteins has been reported in breast cancer. The aim of this study was to examine the immunohistochemical expression of CLDN 12 and its prognostic significance in breast cancer tissues. METHODS: Immunohistochemical expression of CLDN 12 was performed on tissue microarrays consisting of 232 cases of breast carcinoma and correlated with clinicopathological features as well as survival of the patients with breast cancer. RESULTS: For the estrogen receptor (ER)-negative subgroup of patients with breast cancer, CLDN 12 expression was shown to be an independent predictor of poor overall survival (HR=2.345; p=0.020) and disease-free survival (HR=2.177; p=0.026) but not for the ER-positive tumours. CONCLUSIONS: The findings suggest that CLDN 12 expression could be clinically useful for predicting the survival of the ER-negative subgroup of patients with breast cancer. PMID- 26926103 TI - In situ crosslinked smart polypeptide nanoparticles for multistage responsive tumor-targeted drug delivery. AB - Smart tumor-targeted drug delivery is crucial for improving the effect of chemotherapy and reducing the adverse effects. Here, we synthesized a smart polypeptide copolymer based on n-butylamine-poly(L-lysine)-b-poly(L-cysteine) (PLL-PLC) with functionalization of folic acid (FA) and 1,2-dicarboxylic cyclohexene anhydride (DCA) for multistage responsive tumor-targeted drug delivery. The copolymers (FA-PLL(DCA)-PLC) spontaneously crosslinked in situ to form redox and pH dual responsive FA-PLL(DCA)-PLC nanoparticles (FD-NPs), which had a reversible zeta potential around -30 mV at pH 7.4, but switched to +15 mV at pH 5.0. Moreover, FD-NPs effectively loaded DOX with a loading capacity at 15.7 wt%. At pH 7.4, only 24.5% DOX was released within 60 h. However, at pH 5.0, the presence of 10 mM DTT dramatically accelerated DOX release with over 90% of DOX released within 10 h. Although the FD-NPs only enhanced DOX uptake in FA receptor positive (FR(+)) cancer cells at pH 7.4, a weak acidic condition promoted FD-NP-facilitated DOX uptake in both FR(+) HeLa and FR(-) A549 cells, as well as significantly improving cellular binding and end/lysosomal escape. In vivo studies in a HeLa cancer model demonstrated that the charge-reversible FD NPs delivered DOX into tumors more effectively than charge-irreversible nanoparticles. Hence, these multistage responsive FD-NPs would serve as highly efficient drug vectors for targeted cancer chemotherapy. PMID- 26926105 TI - A review of sex estimation techniques during examination of skeletal remains in forensic anthropology casework. AB - Sex estimation is considered as one of the essential parameters in forensic anthropology casework, and requires foremost consideration in the examination of skeletal remains. Forensic anthropologists frequently employ morphologic and metric methods for sex estimation of human remains. These methods are still very imperative in identification process in spite of the advent and accomplishment of molecular techniques. A constant boost in the use of imaging techniques in forensic anthropology research has facilitated to derive as well as revise the available population data. These methods however, are less reliable owing to high variance and indistinct landmark details. The present review discusses the reliability and reproducibility of various analytical approaches; morphological, metric, molecular and radiographic methods in sex estimation of skeletal remains. Numerous studies have shown a higher reliability and reproducibility of measurements taken directly on the bones and hence, such direct methods of sex estimation are considered to be more reliable than the other methods. Geometric morphometric (GM) method and Diagnose Sexuelle Probabiliste (DSP) method are emerging as valid methods and widely used techniques in forensic anthropology in terms of accuracy and reliability. Besides, the newer 3D methods are shown to exhibit specific sexual dimorphism patterns not readily revealed by traditional methods. Development of newer and better methodologies for sex estimation as well as re-evaluation of the existing ones will continue in the endeavour of forensic researchers for more accurate results. PMID- 26926106 TI - The STAR protein QKI-7 recruits PAPD4 to regulate post-transcriptional polyadenylation of target mRNAs. AB - Emerging evidence has demonstrated that regulating the length of the poly(A) tail on an mRNA is an efficient means of controlling gene expression at the post transcriptional level. In early development, transcription is silenced and gene expression is primarily regulated by cytoplasmic polyadenylation. In somatic cells, considerable progress has been made toward understanding the mechanisms of negative regulation by deadenylation. However, positive regulation through elongation of the poly(A) tail has not been widely studied due to the difficulty in distinguishing whether any observed increase in length is due to the synthesis of new mRNA, reduced deadenylation or cytoplasmic polyadenylation. Here, we overcame this barrier by developing a method for transcriptional pulse-chase analysis under conditions where deadenylases are suppressed. This strategy was used to show that a member of the Star family of RNA binding proteins, QKI, promotes polyadenylation when tethered to a reporter mRNA. Although multiple RNA binding proteins have been implicated in cytoplasmic polyadenylation during early development, previously only CPEB was known to function in this capacity in somatic cells. Importantly, we show that only the cytoplasmic isoform QKI-7 promotes poly(A) tail extension, and that it does so by recruiting the non canonical poly(A) polymerase PAPD4 through its unique carboxyl-terminal region. We further show that QKI-7 specifically promotes polyadenylation and translation of three natural target mRNAs (hnRNPA1, p27(kip1)and beta-catenin) in a manner that is dependent on the QKI response element. An anti-mitogenic signal that induces cell cycle arrest at G1 phase elicits polyadenylation and translation of p27(kip1)mRNA via QKI and PAPD4. Taken together, our findings provide significant new insight into a general mechanism for positive regulation of gene expression by post-transcriptional polyadenylation in somatic cells. PMID- 26926107 TI - Synergistic action of master transcription factors controls epithelial-to mesenchymal transition. AB - Epithelial-to-mesenchymal transition (EMT) is a complex multistep process in which phenotype switches are mediated by a network of transcription factors (TFs). Systematic characterization of all dynamic TFs controlling EMT state transitions, especially for the intermediate partial-EMT state, represents a highly relevant yet largely unexplored task. Here, we performed a computational analysis that integrated time-course EMT transcriptomic data with public cistromic data and identified three synergistic master TFs (ETS2, HNF4A and JUNB) that regulate the transition through the partial-EMT state. Overexpression of these regulators predicted a poor clinical outcome, and their elimination readily abolished TGF-beta-induced EMT. Importantly, these factors utilized a clique motif, physically interact and their cumulative binding generally characterized EMT-associated genes. Furthermore, analyses of H3K27ac ChIP-seq data revealed that ETS2, HNF4A and JUNB are associated with super-enhancers and the administration of BRD4 inhibitor readily abolished TGF-beta-induced EMT. These findings have implications for systematic discovery of master EMT regulators and super-enhancers as novel targets for controlling metastasis. PMID- 26926108 TI - Robust classification of protein variation using structural modelling and large scale data integration. AB - Existing methods for interpreting protein variation focus on annotating mutation pathogenicity rather than detailed interpretation of variant deleteriousness and frequently use only sequence-based or structure-based information. We present VIPUR, a computational framework that seamlessly integrates sequence analysis and structural modelling (using the Rosetta protein modelling suite) to identify and interpret deleterious protein variants. To train VIPUR, we collected 9477 protein variants with known effects on protein function from multiple organisms and curated structural models for each variant from crystal structures and homology models. VIPUR can be applied to mutations in any organism's proteome with improved generalized accuracy (AUROC .83) and interpretability (AUPR .87) compared to other methods. We demonstrate that VIPUR's predictions of deleteriousness match the biological phenotypes in ClinVar and provide a clear ranking of prediction confidence. We use VIPUR to interpret known mutations associated with inflammation and diabetes, demonstrating the structural diversity of disrupted functional sites and improved interpretation of mutations associated with human diseases. Lastly, we demonstrate VIPUR's ability to highlight candidate variants associated with human diseases by applying VIPUR to de novo variants associated with autism spectrum disorders. PMID- 26926110 TI - Are superior outcomes of early coronary angiography versus a conservative approach in survivors after out-of-hospital cardiac arrest driven by subsets of patients with ST-elevations? PMID- 26926111 TI - Enantiomerically Pure Chiral {Cu(II)32}-Based 2D-Layered Frameworks: From the Asymmetric Octacopper(II) Subcomponents to 3D Hierarchical Supramolecular Structures. AB - Two new chiral copper(II) coordination polymers comprising octacopper(II) subcomponents were synthesized through investigation of the interplay among tartrate ligands, guanidinium cations, and metals. Our analysis confirms that these compounds are enantiomers exhibiting 3D hierarchical supramolecular structures that are constituted by 2D sublayers and sustained by noncovalent bonding interactions. PMID- 26926109 TI - PrimPol prevents APOBEC/AID family mediated DNA mutagenesis. AB - PrimPol is a DNA damage tolerant polymerase displaying both translesion synthesis (TLS) and (re)-priming properties. This led us to study the consequences of a PrimPol deficiency in tolerating mutagenic lesions induced by members of the APOBEC/AID family of cytosine deaminases. Interestingly, during somatic hypermutation, PrimPol counteracts the generation of C>G transversions on the leading strand. Independently, mutation analyses in human invasive breast cancer confirmed a pro-mutagenic activity of APOBEC3B and revealed a genome-wide anti mutagenic activity of PRIMPOL as well as most Y-family TLS polymerases. PRIMPOL especially prevents APOBEC3B targeted cytosine mutations within TpC dinucleotides. As C transversions induced by APOBEC/AID family members depend on the formation of AP-sites, we propose that PrimPol reprimes preferentially downstream of AP-sites on the leading strand, to prohibit error-prone TLS and simultaneously stimulate error-free homology directed repair. These in vivo studies are the first demonstrating a critical anti-mutagenic activity of PrimPol in genome maintenance. PMID- 26926113 TI - Development of Morphogen Gradients with Spatially Varying Degradation Rates. AB - Successful biological development via spatial and temporal regulations of cell differentiation relies on the action of multiple signaling molecules that are known as morphogens. It is now well established that biological signaling molecules create nonuniform concentration profiles, called morphogen gradients, that activate different genes, leading to patterning in the developing organisms. The current view of the formation of morphogen gradients is that it is a result of complex reaction-diffusion processes that include production, diffusion, and degradation of signaling molecules. Recent studies also suggest that the degradation of morphogens is a critically important step in the whole process. We develop a theoretical model that allows us to investigate the role of a spatially varying degradation in the formation of morphogen gradients. Our analysis shows that the spatial inhomogeneities in degradation might strongly influence the dynamics of formation of signaling profiles. Physical-chemical mechanisms of the underlying processes are discussed. PMID- 26926112 TI - CLIPB8 is part of the prophenoloxidase activation system in Anopheles gambiae mosquitoes. AB - In insects and other arthropods the formation of eumelanin (melanization) is a broad spectrum and potent immune response that is used to encapsulate and kill invading pathogens. This immune response is regulated by the activation of prophenoxidase (proPO), which is controlled by proteinase cascades and its serpin inhibitors, together forming the proPO activation system. While the molecular composition of these protease cascades are well understood in insect model systems, major knowledge gaps remain in mosquitoes. Recently, a regulatory unit of melanization in Anopheles gambiae was documented, comprised of the inhibitory serpin-clip-serine proteinase, CLIPB9 and its inhibitor serpin-2 (SRPN2). Partial reversion of SRPN2 phenotypes in melanotic tumor formation and adult survival by SRPN2/CLIPB9 double knockdown suggested other target proteinases of SRPN2 in regulating melanization. Here we report that CLIPB8 supplements the SRPN2/CLIPB9 regulatory unit in controlling melanization in An. gambiae. As with CLIPB9, knockdown of CLIPB8 partially reversed the pleiotropic phenotype induced by SRPN2 silencing with regards to adult survival and melanotic tumor formation. Recombinant SRPN2 protein formed an SDS-stable protein complex with activated recombinant CLIPB8, however did not efficiently inhibit CLIPB8 activity in vitro. CLIPB8 did not directly activate proPO in vitro nor was it able to cleave and activate proCLIPB9. Nevertheless, epistasis analysis using RNAi placed CLIPB8 and CLIPB9 in the same pathway leading to melanization, suggesting that CLIPB8 either acts further upstream of CLIPB9 or is required for activation of a yet to be identified serine proteinase homolog. Taken together, this study identifies CLIPB8 as an additional player in proPO activation cascade and highlights the complexity of the proteinase network that regulates melanization in An. gambiae. PMID- 26926114 TI - Endoscopic retrieval of multiple large sharp foreign bodies from the stomach. Testing the limits of endoscopy. PMID- 26926115 TI - Understanding the role of chromatin remodeling in the regulation of circadian transcription in Drosophila. AB - Circadian clocks enable organisms to anticipate daily changes in the environment and coordinate temporal rhythms in physiology and behavior with the 24-h day night cycle. The robust cycling of circadian gene expression is critical for proper timekeeping, and is regulated by transcription factor binding, RNA polymerase II (RNAPII) recruitment and elongation, and post-transcriptional mechanisms. Recently, it has become clear that dynamic alterations in chromatin landscape at the level of histone posttranslational modification and nucleosome density facilitate rhythms in transcription factor recruitment and RNAPII activity, and are essential for progression through activating and repressive phases of circadian transcription. Here, we discuss the characterization of the BRAHMA (BRM) chromatin-remodeling protein in Drosophila in the context of circadian clock regulation. By dissecting its catalytic vs. non-catalytic activities, we propose a model in which the non-catalytic activity of BRM functions to recruit repressive factors to limit the transcriptional output of CLOCK (CLK) during the active phase of circadian transcription, while the primary function of the ATP-dependent catalytic activity is to tune and prevent over recruitment of negative regulators by increasing nucleosome density. Finally, we divulge ongoing efforts and investigative directions toward a deeper mechanistic understanding of transcriptional regulation of circadian gene expression at the chromatin level. PMID- 26926116 TI - Revisiting the Local Structure in Ge-Sb-Te based Chalcogenide Superlattices. AB - The technological success of phase-change materials in the field of data storage and functional systems stems from their distinctive electronic and structural peculiarities on the nanoscale. Recently, superlattice structures have been demonstrated to dramatically improve the optical and electrical performances of these chalcogenide based phase-change materials. In this perspective, unravelling the atomistic structure that originates the improvements in switching time and switching energy is paramount in order to design nanoscale structures with even enhanced functional properties. This study reveals a high- resolution atomistic insight of the [GeTe/Sb2Te3] interfacial structure by means of Extended X-Ray Absorption Fine Structure spectroscopy and Transmission Electron Microscopy. Based on our results we propose a consistent novel structure for this kind of chalcogenide superlattices. PMID- 26926117 TI - Sofosbuvir and Simeprevir for Treatment of Recurrent Hepatitis C Infection After Liver Transplant. AB - OBJECTIVES: Recurrent hepatitis C is universal after liver transplant when viremia is present at the time of transplant, and this affects survival. Previous treatments with pegylated interferon and ribavirin with or without boceprevir or telaprevir have yielded modest sustained virologic response rates and frequent adverse effects. A combination of new antiviral agents has been used for recurrent hepatitis C. We aim to describe the outcomes of recurrent hepatitis C in liver transplant patients treated with simeprevir, sofosbuvir, and ribavirin. MATERIALS AND METHODS: Fifty-three consecutive patients with recurrent hepatitis C genotype 1 were included. All patients had liver biopsy before enrollment if cirrhosis was not evident. Standard doses of simeprevir and sofosbuvir were used for 12 weeks. Ribavirin was adjusted based on hemoglobin levels. In 53 patients, 50 completed 12 weeks of treatment. RESULTS: All 50 patients who completed 12 weeks of treatment achieved sustained virologic response. One patient who completed only 6 weeks also achieved sustained virologic response. Overall, the antiviral treatment was well tolerated, with no interactions with immunosuppressive drugs. CONCLUSIONS: The combination of simeprevir and sofosbuvir with or without ribavirin yields a high sustained virologic response rate of 96% in a historically difficult to treat patient population (recurrent hepatitis C genotype 1). PMID- 26926118 TI - Rules on lobbying threaten to gag tax funded researchers. PMID- 26926119 TI - Targeting alpha-synuclein: Therapeutic options. AB - The discovery of the central role of alpha-synuclein (alphaSyn) in the pathogenesis of Parkinson's disease (PD) has powered, in the last decade, the emergence of novel relevant models of this condition based on viral vector mediated expression of the disease-causing protein or inoculation of toxic species of alphaSyn. Although the development of these powerful tools and models has provided considerable insights into the mechanisms underlying neurodegeneration in PD, it has also been translated into the expansion of the landscape of preclinical therapeutic strategies. Much attention is now brought to the proteotoxic mechanisms induced by alphaSyn and how to block them using strategies inspired by intrinsic cellular pathways such as the enhancement of cellular clearance by the lysosomal-autophagic system, through proteasome mediated degradation or through immunization. The important effort undertaken by several laboratories and consortia to tackle these issues and identify novel targets warrants great promise for the discovery not only of neuroprotective approaches but also of restorative strategies for PD and other synucleinopathies. In this viewpoint, we summarize the latest advances in this new area of PD research and will discuss promising approaches and ongoing challenges. (c) 2016 International Parkinson and Movement Disorder Society. PMID- 26926120 TI - Averting the Legacy of Kidney Disease - Focus on Childhood. AB - World Kidney Day 2016 focuses on kidney disease in childhood and the antecedents of adult kidney disease that can begin in earliest childhood. Chronic kidney disease (CKD) in childhood differs from that in adults, as the largest diagnostic group among children includes congenital anomalies and inherited disorders, with glomerulopathies and kidney disease in the setting of diabetes being relatively uncommon. In addition, many children with acute kidney injury will ultimately develop sequelae that may lead to hypertension and CKD in later childhood or in adult life. Children born early or who are small-for-date newborns have relatively increased risk for the development of CKD later in life. Persons with a high-risk birth and early childhood history should be watched closely in order to help detect early signs of kidney disease in time to provide effective prevention or treatment. Successful therapy is feasible for advanced CKD in childhood; there is evidence that children fare better than adults, if they receive kidney replacement therapy including dialysis and transplantation, while only a minority of children may require this ultimate intervention. Because there are disparities in access to care, effort is needed so that those children with kidney disease, wherever they live, may be treated effectively, irrespective of their geographic or economic circumstances. Our hope is that World Kidney Day will inform the general public, policy makers and caregivers about the needs and possibilities surrounding kidney disease in childhood. PMID- 26926122 TI - Isn't Your Staff Trained To Manage My Mother? PMID- 26926123 TI - Evidence-Based Pregnancy Registries: Good for Babies and Their Mothers. PMID- 26926121 TI - The BBSome Controls Energy Homeostasis by Mediating the Transport of the Leptin Receptor to the Plasma Membrane. AB - Bardet-Biedl syndrome (BBS) is a highly pleiotropic autosomal recessive disorder associated with a wide range of phenotypes including obesity. However, the underlying mechanism remains unclear. Here, we show that neuronal BBSome is a critical determinant of energy balance through its role in the regulation of the trafficking of the long signaling form of the leptin receptor (LRb). Targeted disruption of the BBSome by deleting the Bbs1 gene from the nervous system causes obesity in mice, and this phenotype is reproduced by ablation of the Bbs1 gene selectively in the LRb-expressing cells, but not from adipocytes. Obesity developed as a consequence of both increased food intake and decreased energy expenditure in mice lacking the Bbs1 gene in LRb-expressing cells. Strikingly, the well-known role of BBS proteins in the regulation of ciliary formation and function is unlikely to account for the obesogenic effect of BBS1 loss as disruption of the intraflagellar transport (IFT) machinery required for ciliogenesis by deleting the Ift88 gene in LRb-expressing cells caused a marginal increase in body weight and adiposity. Instead, we demonstrate that silencing BBS proteins, but not IFT88, impair the trafficking of the LRb to the plasma membrane leading to central leptin resistance in a manner independent of obesity. Our data also demonstrate that postnatal deletion of the Bbs1 gene in the mediobasal hypothalamus can cause obesity in mice, arguing against an early neurodevelopmental origin of obesity in BBS. Our results depict a novel mechanism underlying energy imbalance and obesity in BBS with potential implications in common forms of human obesity. PMID- 26926125 TI - Dissecting the Brain Mechanisms of Violence. PMID- 26926124 TI - A New Option for Treating Bipolar I Depression. PMID- 26926127 TI - Potential Risks of Poorly Monitored Ketamine Use in Depression Treatment. PMID- 26926128 TI - "Jinn Possession" and Delirious Mania in a Pakistani Woman. PMID- 26926129 TI - Gene-Environment Interaction in Youth Depression: Differential Susceptibility? PMID- 26926130 TI - Response to Plakun: Addressing Differential Susceptibility With Regard to Gene Environment Interaction in Youth Depression. PMID- 26926131 TI - Reflections on "Emil Kraepelin: Icon and Reality". PMID- 26926132 TI - Response to Strous et al.: A Focus on Kraepelin's Clinical Research Methodology. PMID- 26926133 TI - Going Beyond Finding the "Lesion": A Path for Maturation of Neuroimaging. PMID- 26926136 TI - In vivo influence of in vitro up-regulated genes in the virulence of an APEC strain associated with swollen head syndrome. AB - Avian Pathogenic Escherichia coli is responsible for significant economic losses in the poultry industry by causing a range of systemic or localized diseases collectively termed colibacillosis. The virulence mechanisms of these strains that are pathogenic in poultry and possibly pathogenic in humans have not yet been fully elucidated. This work was developed to study if over-expressed genes in a microarray assay could be potentially involved in the pathogenicity of an Avian Pathogenic Escherichia coli strain isolated from a swollen head syndrome case. For this study, five over-expressed genes were selected for the construction of null mutants [flgE (flagellar hook), tyrR (transcriptional regulator), potF (putrescine transporter), yehD (putative adhesin) and bfr (bacterioferritin)]. The constructed mutants were evaluated for their capacity for the adhesion and invasion of in vitro cultured cells, their motility capacity, and their pathogenic potential in one-day-old chickens compared with the wild-type strain (WT). The Deltabfr strain showed a decreased adhesion capacity on avian fibroblasts compared with WT, in the presence and absence of alpha-D-mannopyranoside, and the DeltapotF strain showed decreased adhesion only in the absence of alpha-D-mannopyranoside. The DeltatyrR mutant had a reduced ability to invade Hep-2 cells. No mutant showed changes in invading CEC-32 cells. The mutants DeltaflgE and DeltatyrR showed a decreased ability to survive in HD 11 cells. The motility of the mutant strains Deltabfr, DeltayehD and DeltapotF was increased, while the DeltatyrR mutant showed reduction, and the DeltaflgE became non-motile. No mutant strain caused the same mortality of the WT in one day-old chickens, showing attenuation to different degrees. PMID- 26926137 TI - Cognitive Reserve, Incident Dementia, and Associated Mortality in the Ibadan Study of Ageing. AB - OBJECTIVES: To describe factors associated with incident dementia and dementia mortality over 5 years in a large community sample of elderly persons. DESIGN: Longitudinal investigation of a household multistage probability sample. SETTING: Eight contiguous states of the Yoruba-speaking region of Nigeria. PARTICIPANTS: Individuals aged 65 and older (N = 2,149). MEASUREMENTS: Dementia was diagnosed using tools previously validated in the population. Incident cases of dementia over three follow-up waves were determined after censoring cases in the preceding wave. Information on mortality was collected from key informants in subjects' households. RESULTS: A dementia incident rate was found of 20.9 per 1,000 person years (95% confidence interval (CI) = 17.7-24.9). The adjusted mortality hazard for those with dementia was 1.5 (95% CI = 1.1-2.1). Along with previously identified social and demographic factors, poor predementia cognitive function (hazard ratio (HR) = 1.8, 95% CI = 1.1-2.8) and low occupational complexity (HR = 3.2, 95% CI = 1.3-8.0) were associated with incident dementia. CONCLUSION: The findings confirm the low incidence of dementia in this population, as previously reported. The condition is nevertheless associated with higher risk of mortality. Along with some features of social disadvantage, proxies of lower cognitive reserve were risk factors for incident dementia. PMID- 26926138 TI - Alpha-Tocopherol Counteracts the Effect of Ethanol on Cortical Spreading Depression in Rats of Various Ages, With and Without Ethanol Abstinence. AB - BACKGROUND: We previously demonstrated that acute and chronic treatment with ethanol (EtOH), respectively, decelerated and accelerated the propagation of cortical spreading depression (CSD) in rats and that the antioxidant carotenoid astaxanthin counteracted these effects. Here, we investigated whether noncarotenoid antioxidants exert the same action by testing alpha-tocopherol in rats of various ages, with and without 5 to 10 days of EtOH abstinence. METHODS: Male Wistar young adult (60 to 80 days old) and mature adult (150 to 180 days old) rats received per gavage acute (1 day) or chronic (21 days) treatment with 3 g/kg/d EtOH combined with acute (300 mg/kg) or chronic (85 mg/kg/d) treatment with alpha-tocopherol or vehicle-only treatment (olive oil and water for alpha tocopherol and EtOH, respectively). CSD was recorded over 4 hours and the velocity of CSD propagation was calculated. On both ages, animals under chronic EtOH treatment were subjected to CSD recording immediately after EtOH treatment or after a 5- to 10-day period of EtOH abstinence. RESULTS: In both age groups, acute and chronic EtOH exposure decelerated and accelerated CSD, respectively, versus the corresponding control groups. Addition of alpha-tocopherol counteracted the effects of EtOH on CSD, returning CSD velocities to levels in control groups (p < 0.05). Chronic alpha-tocopherol (85 mg/kg/d) did not alter CSD. CONCLUSIONS: Our data reinforce the counteracting role of antioxidants on brain processes involved in the action of EtOH on CSD and suggest that this role is not a particular property of carotenoids; furthermore, this general feature of antioxidants is not substantially influenced by age or by 5 to 10 days of EtOH abstinence. PMID- 26926139 TI - Involvement of MAPK signalling in radioadaptive response in BALB/c mice exposed to low dose ionizing radiation. AB - To investigate low dose ionizing radiation (LDIR)-induced adaptive response in lymphocytes of BALB/c mice and to elucidate related molecular mechanisms. Mice were exposed to a priming dose (PD) of 0.1 Gy and challenge dose (CD) of 2 Gy ionizing radiation. Proliferation response to mitogen concanavalin A was assessed using (3)H thymidine incorporation and carboxyfluoresceinsuccinamidylester (CFSE) dye dilution. Early activation markers were assessed by flow cytometry, cytokines by ELISA, DNA damage by comet assay and mitogen activated protein kinase (MAPK) signaling by Western blotting. Radioadaptive response was observed in lymphocytes of mice exposed to PD prior to CD of ionizing radiation in terms of DNA damage, early activation markers CD69, CD71, cytokines IL-2, IFN-gamma as well as proliferation. This effect was transient and observed 24 h after CD and not after 0 h or 72 h. Hyper activation of MAPK signaling pathways in lymphocytes from LDIR exposed mice and abrogation by ERK and p38 inhibitors suggests the involvement of MAPK signaling in radioadaptive response. Our study demonstrates that LDIR induced transient adaptive response was due to hyper activation of MAPK signaling. Our findings contribute towards the understanding of LDIR-induced adaptive response. PMID- 26926140 TI - Titanium implants coated with UV-irradiated vitamin D precursor and vitamin E: in vivo performance and coating stability. AB - OBJECTIVES: This study aimed at evaluating the biological response of titanium implants coated with UV-irradiated 7-dehydrocholesterol (7-DHC) and vitamin E (VitE) in vivo and analyzing the effects of aging on their stability and bioactivity in vitro. MATERIAL AND METHODS: Titanium surfaces were coated with 7 DHC and VitE, UV-irradiated and incubated for 48 h at 23 degrees C to allow cholecalciferol synthesis. The in vivo biological response was tested using a rabbit tibia model after 8 weeks of healing by analyzing the wound fluid and the mRNA levels of several markers at the bone-implant interface (N = 8). The stability of the coating after storage up to 12 weeks was determined using HPLC analysis, and the bioactivity of the stored modified implants was studied by an in vitro study with MC3T3-E1 cells (N = 6). RESULTS: A significant increase in gene expression levels of osteocalcin was found in the bone tissue attached to implants coated with the low dose of 7-DHC and VitE, together with a higher ALP activity in the wound fluid. Implants treated with the high dose of 7-DHC and VitE showed increased tissue necrosis and inflammation. Regarding the aging effects, coated implants were stable and bioactive up to 12 weeks when stored at 4 degrees C and avoiding oxygen, light and moisture. CONCLUSION: This study demonstrates that Ti implants coated with UV-irradiated 7-DHC and VitE promote in vivo gene expression of bone formation markers and ALP activity, while they keep their osteopromotive potential in vitro and composition when stored up to 12 weeks at 4 degrees C. PMID- 26926142 TI - Our panel of experts highlight the most important research articles across the spectrum of topics relevant to the field of regenerative medicine. PMID- 26926141 TI - 3,3 diindolylmethane leads to apoptosis, decreases sperm quality, affects blood estradiol 17 beta and testosterone, oestrogen (alpha and beta) and androgen receptor levels in the reproductive system in male rats. AB - 3,3 Diindolylmethane (DIM) is a major digestive product of indole-3 carbinol, obtained from Brassica family vegetables such as broccoli, cabbage and Brussels sprouts. This study aimed to investigate the effects of DIM on sperm parameters, histological structures of testicular tissues, blood testosterone (T) and estradiol 17-beta (E2) in male rats. Thirty-eight male Sprague Dawley rats were used. Rats were divided into four groups: Group I: referred as Control group, received corn oil only; Group II: as DIM-10, rats received 10 mg kg-1 DIM; Group III: as DIM-50, rats received 50 mg kg-1 DIM; Group IV: as DIM-100, received 100 mg kg-1 DIM during 53 days. Spermatological parameters, malondialdehyde (MDA) levels of testes and serum T and E2 levels were assayed. Histopathological examinations of tests were done. DIM caused an increase in MDA levels. It decreased motility and live sperm rates and increased degeneration of testicular tissues. While DIM-10 did not affect abnormal sperm rate, higher concentrations increased the abnormalities. Sperm density was higher in DIM-10 groups when compared to both other groups. Only DIM-50 had an anti-androgenic effect among all groups. Only, DIM-10 showed anti-estrogenic activity as compared to higher DIM groups. In conclusion, DIM (i) had side effect on some sperm characteristics, (ii) increased the MDA levels and (iii) led to histological degeneration of testicular tissues and apoptosis in a dose-dependent manner. PMID- 26926143 TI - Mitochondrial dysfunction precedes depression of AMPK/AKT signaling in insulin resistance induced by high glucose in primary cortical neurons. AB - Recent studies have demonstrated brain insulin signaling impairment and mitochondrial dysfunction in diabetes. Hyperinsulinemia and hyperlipidemia arising from diabetes have been linked to neuronal insulin resistance, and hyperglycemia induces peripheral sensory neuronal impairment and mitochondrial dysfunction. However, how brain glucose at diabetic conditions elicits cortical neuronal insulin signaling impairment and mitochondrial dysfunction remains unknown. In the present study, we cultured primary cortical neurons with high glucose levels and investigated the neuronal mitochondrial function and insulin response. We found that mitochondrial function was declined in presence of 10 mmol/L glucose, prior to the depression of AKT signaling in primary cortical neurons. We further demonstrated that the cerebral cortex of db/db mice exhibited both insulin resistance and loss of mitochondrial complex components. Moreover, we found that adenosine monophosphate-activated protein kinase (AMPK) inactivation is involved in high glucose-induced mitochondrial dysfunction and insulin resistance in primary cortical neurons and neuroblastoma cells, as well as in cerebral cortex of db/db mice, and all these impairments can be rescued by mitochondrial activator, resveratrol. Taken together, our results extend the finding that high glucose (>=10 mmol/L) comparable to diabetic brain extracellular glucose level leads to neuronal mitochondrial dysfunction and resultant insulin resistance, and targeting mitochondria-AMPK signaling might be a promising strategy to protect against diabetes-related neuronal impairment in central nerves system. We found that high glucose (>=10 mmol/L), comparable to diabetic brain extracellular glucose level, leads to neuronal mitochondrial dysfunction and resultant insulin resistance in an AMPK-dependent manner, and targeting mitochondria-AMPK signaling might be a promising strategy to protect against diabetes-related neuronal impairment in central nerves system. PMID- 26926146 TI - Preparation of Alkyl Alkynyl Sulfones and Cyclic Vinyl Sulfones from Alkynyl(aryl)iodonium Salts. AB - The reaction of alkyl sulfinates with alkynyl(aryl)iodonium salts provides a facile access into otherwise difficult to obtain alkyl alkynyl sulfones and cyclic vinyl sulfones via 1,2-rearrangement or 1,5-CH insertion, respectively. In benzyl sulfinates, 1,5-CH insertion is not possible, so addition to the aromatic ring occurs, followed by ring expansion to generate novel bicyclic sulfones. PMID- 26926145 TI - Monoclonal Antibody Targeting Staphylococcus aureus Surface Protein A (SasA) Protect Against Staphylococcus aureus Sepsis and Peritonitis in Mice. AB - Epidemic methicillin-resistant Staphylococcus aureus (MRSA) imposes an increasing impact on public health. Due to multi-antibiotics resistance in MRSA strains, there is an urgent need to develop novel therapeutics such as effective monoclonal antibodies (mAbs) against MRSA infections. Staphylococcus aureus surface protein A (SasA), a large surface-located protein (~240 kDa), is one of MSCRAMMs (microbial surface components recognizing adhesive matrix molecules) and a potential target for immunotherapeutic approaches against S. aureus infections. In the present study, we analyzed the sequence of SasA with bioinformatics tools and generated a protective monoclonal antibody (2H7) targeting the conserved domain of SasA. 2H7 was shown to recognize wild-type S. aureus and promote opsonophagocytic killing of S. aureus. In both sepsis and peritoneal infection models, prophylactic administration of 2H7 improved the survival of BALB/c mice challenged by S. aureus strain USA300 and ST239 (prevalent MRSA clones in North America and Asian countries, respectively) and enhanced bacterial clearance in kidneys. Additionally, 2H7 prophylaxis prevented the formation of intraperitoneal abscess in a murine model of peritoneal infection and therapeutic administration of 2H7 showed protective efficacy in a murine sepsis model. Our results presented here provide supporting evidences that an anti-SasA mAb might be a potential component in an antibody-based immunotherapeutic treatment of MRSA infections. PMID- 26926144 TI - Critical weight loss predicts poor prognosis in nasopharyngeal carcinoma. AB - BACKGROUND: The impacts of weight loss on prognosis in nasopharyngeal carcinoma (NPC) remain unclear. The present study was therefore undertaken to investigate the association between critical weight loss and long-term survival in NPC patients. METHODS: The eligible 2399 NPC patients were reviewed. Weight change was categorized into critical weight loss (CWL) and non-critical weight loss (Non CWL). The associations of CWL with long-term survival were analyzed by Cox regression in the entire patient and two subsets. Propensity score matching was performed to reduce the effects of confounding factors. RESULTS: CWL was defined as body weight loss of >=4.6 %. Compared with patients without CWL, patients with CWL had significantly lower 5-year OS (72.4 vs. 79.3 %, P < 0.001), FFS (71.1 vs. 78.4 %, P <0.001), and LR-FFS (78.1 vs. 84.8 %, P <0.001), respectively. After adjustment for potential confounders, CWL remained an independence prognostic factor for OS (HR = 1.352; 95 % CI 1.160-1.576; P < 0.001), FFS (HR = 3.275; 95 % CI 1.101-9.740; P = 0.033), and LR-FFS (HR = 6.620; 95 % CI 2.990-14.658; P < 0.001), respectively. Furthermore, subgroup analysis in the cohort of patients received concurrent chemoradiotherapy or radiotherapy alone confirmed the results in the entire patient even after the propensity-score matching. In IMRT cohort, CWL was also significantly associated with a lower OS (P = 0.04) and FFS (P = 0.04). CONCLUSIONS: CWL has a significant and independent impact on long-term survival in nasopharyngeal carcinoma patients. PMID- 26926148 TI - Development of a taste-masked oral suspension of clindamycin HCl using ion exchange resin Amberlite IRP 69 for use in pediatrics. AB - PURPOSE: The purpose of this study is to develop an oral suspension of clindamycin resin complex for the potential use in pediatrics. METHODS: Several types of Ion exchange resins were screened for their binding efficiency with clindamycin. In order to develop a suspension formulation, several thickening agents, surfactants, sweeting, and flavoring agents were evaluated for their influence on the release of clindamycin from resinate. Rheological studies were also conducted to select the optimum amounts of the suspending agents. The release profiles of clindamycin in SGF and SIF were also evaluated from freshly prepared suspension and from suspension formulation after storage for 1 month at 25 degrees C and 40 degrees C. Clindamycin bitterness threshold was determined based on volunteers' evaluation, and taste evaluation was conducted in 12 adult volunteers who evaluated the taste of the optimized suspension against clindamycin solution. RESULTS: Among all resins tested, Amberlite IRP 69 showed the highest binding efficiency to clindamycin. Several excipients were selected into the suspension formulation based on no or minimum influence on the release of clindamycin from the resinate complex. Moreover, xanthan gum was selected as the optimal suspending agent for the suspension. Clindamycin release profiles in SGF or SIF showed 90% release within 30 min from freshly prepared sample. Clindamycin exhibited good stability profiles at 25 degrees C and 40 degrees C over 1 month storage. The mean bitterness threshold of clindamycin was 12.5 MUg/ml, and taste evaluation study in adults showed sustainable taste improvement for suspension over clindamycin solution. CONCLUSION: Clindamycin/resin complexation has shown to be an efficient method to mask the taste of clindamycin and was developed into a suspension formulation that can be used in pediatrics. PMID- 26926149 TI - [Family companions. New facets in accompanying relatives caring for people with dementia]. AB - BACKGROUND: Support and relief options in the context of homecare settings where people with dementia are cared for by friends or relatives have become highly differentiated; however, there are significant shortcomings in networking between the various types of offers within the context of mixed care (Pflegemix). Family caregivers often feel overwhelmed and find it difficult to identify and utilize the appropriate forms and services for their individual situation. Against this background companion models seem to be an appropriate solution to provide psychosocial support for caring families and to function in the role of bridge building in the assistance system. AIM: Within the framework of the Future Workshop Dementia (Zukunftswerkstatt Demenz) program funded by the German Federal Ministry of Health during the time period 2012-2015, the new intervention was developed in the family companion for dementia in rural areas (FABEL) project carried out by volunteers. These volunteers take up the needs of caring families for a low-threshold support structure and promote networking among the various groups of participants in individual homecare settings. The preparatory training for the volunteers, which is the focus of this article, provides special knowledge about dementia and the basic principles of systemic understanding of the typical dynamics in caring families. MATERIAL AND METHODS: In the model phase the newly developed training program was aimed at qualified volunteers trained in the logistics of the model project Care Companion (Pflegebegleitung), which was successfully established from 2003 to 2008 in more than 100 pilot locations throughout Germany and is now integrated into the healthcare system. This proven model is linked to the new qualification and consists of 68 units involving thematic modules of knowledge about dementia and systemic solution-oriented thinking, for networking and the development of an understanding of the personal role. RESULTS: During the 3-year project period 27 volunteers became qualified and accompanied at least 73 families in rural areas, which was the special focus of the model project. The developed qualification enabled the volunteers to carry out the activities in a very relationship-oriented way and in a direct form of communication with the family carers and also to encourage self-care activities. This led to a significant improvement in the health-related quality of life (QoL) of family carers and stabilized the homecare setting. As part of a health economic model calculation on the effects of the new approach, the pecuniary gains outweighed the costs caused by the qualification. DISCUSSION: The concept of family companions (Familienbegleiter) has proven to be a cost-covering model of an effective intervention based on the needs of caring families, which should become more widespread in the future. PMID- 26926147 TI - Overlapping cell population expression profiling and regulatory inference in C. elegans. AB - BACKGROUND: Understanding gene expression across the diverse metazoan cell types during development is critical to understanding their function and regulation. However, most cell types have not been assayed for expression genome-wide. RESULTS: We applied a novel approach we term "Profiling of Overlapping Populations of cells (POP-Seq)" to assay differential expression across all embryonic cells in the nematode Caenorhabditis elegans. In this approach, we use RNA-seq to define the transcriptome of diverse partially overlapping FACS-sorted cell populations. This identified thousands of transcripts differentially expressed across embryonic cells. Hierarchical clustering analysis identified over 100 sets of coexpressed genes corresponding to distinct patterns of cell type specific expression. We identified thousands of candidate regulators of these clusters based on enrichment of transcription factor motifs and experimentally determined binding sites. CONCLUSIONS: Our analysis provides new insight into embryonic gene regulation, and provides a resource for improving our knowledge of tissue-specific expression and its regulation throughout C. elegans development. PMID- 26926150 TI - Superficial spreading melanoma: an analysis of 97 702 cases using the SEER database. AB - Superficial spreading melanoma (SSM) is the most common type of melanoma. Large, population-based studies analyzing the incidence and survival of SSM are limited. This retrospective study was designed to evaluate demographic factors influencing the incidence and survival of SSM using a national population-based database. The United States National Cancer Institute's Surveillance, Epidemiology, and End Results registry was used to calculate incidence and disease-specific survival trends for SSM between 1973 and 2012. Patient data were stratified according to age, sex, race, ulceration, thickness, and stage. Of 97 702 patients, 52.66% were men, 94.93% were white, and 38.92% had a primary lesion on the trunk. The overall incidence is 5.987/100 000 and is increasing with an annual percentage change (APC) of 1.42%. Incidence increases with age, peaking at 70-79 years. Men (6.68/100 00, APC: 1.78) had a significantly higher incidence than women (5.565/100 000, APC: 1.10). A total of 79.16% of SSM are less than or equal to 1 mm and 92.32% are nonulcerated. The overall 5-year survival is 95.30% and is increasing steadily. Women (hazard ratio: 0.54), 'other' races (hazard ratio: 0.30), those with local disease, those with thin tumors, and those without ulceration had higher survival than their counterparts (P<0.0001). The incidence of this predominantly thin melanoma subtype is on the rise, creating enhanced concern. Primary and secondary prevention techniques should consider the mortality associated with thin melanoma. PMID- 26926151 TI - Initial experience with combined BRAF and MEK inhibition with stereotactic radiosurgery for BRAF mutant melanoma brain metastases. AB - The combined use of the BRAF inhibitor dabrafenib and MEK inhibitor trametinib has been found to improve survival over dabrafenib alone. The management of melanoma brain metastases continues to present challenges. In this study, we report our initial experience in the management of melanoma brain metastases with stereotactic radiosurgery (SRS) with the use of BRAF and MEK inhibitors. We identified six patients treated with SRS for 17 brain metastases within 3 months of BRAF and MEK inhibitor administration. The median planning target volume was 0.42 cm (range: 0.078-2.08 cm). The median treatment dose was 21 Gy (range 18-24 Gy). The median follow-up of all lesions from SRS was 10.6 months (range 5.8-28.5 months). One lesion was found to undergo local failure 21.7 months following SRS treatment. The median overall survival was 20.0 months (range 6.1-31.8 months) from the time of SRS treatment and 23.1 months (range: 12.1-30.9 months) from the date of BRAFi and MEKi administration. There was no evidence of increased nor unexpected toxicity with the two modalities combined. In this initial experience of melanoma brain metastases treated with BRAF and MEK inhibition with SRS, we find the two modalities can be combined safely. These outcomes should be assessed further in prospective evaluations. PMID- 26926153 TI - Comparison of the efficacy of natural-based and synthetic biocides to disinfect silicone and stainless steel surfaces. AB - New biocidal solutions are needed to combat effectively the evolution of microbes developing antibiotic resistance while having a low or no environmental toxicity impact. This work aims to assess the efficacy of commonly used biocides and natural-based compounds on the disinfection of silicone and stainless steel (SS) surfaces seeded with differentStaphylococcus aureusstrains. Minimum inhibitory concentration was determined for synthetic (benzalkonium chloride-BAC, glutaraldehyde-GTA,ortho-phthalaldehyde-OPA and peracetic acid-PAA) and natural based (cuminaldehyde-CUM), eugenol-EUG and indole-3-carbinol-I3C) biocides by the microdilution method. The efficacy of selected biocides at MIC, 10 * MIC and 5500 mg/L (representative in-use concentration) on the disinfection of sessileS. aureuson silicone and SS was assessed by viable counting. Silicone surfaces were harder to disinfect than SS. GTA, OPA and PAA yielded complete CFU reduction of sessile cells for all test concentrations as well as BAC at 10 * MIC and 5500 mg/L. CUM was the least efficient compound. EUG was efficient for SS disinfection, regardless of strains and concentrations tested. I3C at 10 * MIC and 5500 mg/L was able to cause total CFU reduction of silicone and SS deposited bacteria. Although not so efficient as synthetic compounds, the natural-based biocides are promising to be used in disinfectant formulations, particularly I3C and EUG. PMID- 26926152 TI - Assessing the Electrode-Neuron Interface with the Electrically Evoked Compound Action Potential, Electrode Position, and Behavioral Thresholds. AB - Variability in speech perception scores among cochlear implant listeners may largely reflect the variable efficacy of implant electrodes to convey stimulus information to the auditory nerve. In the present study, three metrics were applied to assess the quality of the electrode-neuron interface of individual cochlear implant channels: the electrically evoked compound action potential (ECAP), the estimation of electrode position using computerized tomography (CT), and behavioral thresholds using focused stimulation. The primary motivation of this approach is to evaluate the ECAP as a site-specific measure of the electrode neuron interface in the context of two peripheral factors that likely contribute to degraded perception: large electrode-to-modiolus distance and reduced neural density. Ten unilaterally implanted adults with Advanced Bionics HiRes90k devices participated. ECAPs were elicited with monopolar stimulation within a forward masking paradigm to construct channel interaction functions (CIF), behavioral thresholds were obtained with quadrupolar (sQP) stimulation, and data from imaging provided estimates of electrode-to-modiolus distance and scalar location (scala tympani (ST), intermediate, or scala vestibuli (SV)) for each electrode. The width of the ECAP CIF was positively correlated with electrode-to-modiolus distance; both of these measures were also influenced by scalar position. The ECAP peak amplitude was negatively correlated with behavioral thresholds. Moreover, subjects with low behavioral thresholds and large ECAP amplitudes, averaged across electrodes, tended to have higher speech perception scores. These results suggest a potential clinical role for the ECAP in the objective assessment of individual cochlear implant channels, with the potential to improve speech perception outcomes. PMID- 26926154 TI - Impact of Septal Reduction on Left Atrial Size and Diastole in Hypertrophic Cardiomyopathy. AB - BACKGROUND AND AIMS: Both myectomy and alcohol septal ablation (ASA) can substantially reduce left ventricular (LV) outflow obstruction, relieve symptoms, and improve outcomes in hypertrophic cardiomyopathy (HCM). It is unclear whether septal reduction decreases left atrial (LA) size and improves diastolic function. The aim of this study was to analyze the consequences of septal reduction on LA size and diastolic function in a cohort of patients with HCM. METHODS: Forty patients (mean age: 50 +/- 14, male sex 64%) with HCM who underwent septal reduction (myectomy or alcohol septal ablation) were studied. Retrospective analyses of echocardiograms preprocedure, postprocedure, and at 1 year of follow up were performed. RESULTS: Thirty-one patients had septal myectomy and 9 ASA. The degree of reduction in rest peak LV outflow tract gradient was significant (57 +/- 32 vs. 23 +/- 20 mmHg at 1 year, P < 0.001). Maximal interventricular septal thickness decreased from 22 +/- 6 mm preprocedure to 19 +/- 4 mm postprocedure (P < 0.001); moderate-to-severe mitral regurgitation (MR) was initially present in 34% of the sample and only 2% after the procedure. Average LA volume index (LAVI) decreased from 63 +/- 20 to 55 +/- 20 mL/m(2) at the 1 year follow-up (P < 0.001). We did not observe a significant improvement in diastolic function at Doppler (E/A 1.2 +/- 0.4 vs. 1.1 +/- 0.5, P = 0.07; E' 7.6 +/- 3.6 vs. 6.9 +/- 3.0, P = 0.4) pre- and postprocedure, respectively). At 1 year, only 5% of the patients were severely symptomatic (NYHA III). On multivariate analysis, a significant change in the LVOT gradient during stress (Delta gradient >=30 mmHg) was the only variable independently associated with LAVI reverse remodeling >10 mL/m(2) [OR = 6.4 (CI 95% 1.12-36.44), P = 0.04]. CONCLUSIONS: Septal reduction is effective in the relief of LV obstruction and symptoms in patients with HCM. The hemodynamic changes result in a significant LA reverse remodeling, but not in an improvement of diastolic function in these patients. PMID- 26926155 TI - Semisynthesis of Intact Complex-Type Triantennary Oligosaccharides from a Biantennary Oligosaccharide Isolated from a Natural Source by Selective Chemical and Enzymatic Glycosylation. AB - Attachment of oligosaccharides to proteins is a major post-translational modification. Chemical syntheses of oligosaccharides have contributed to clarifying the functions of these oligosaccharides. However, syntheses of oligosaccharide-linked proteins are still challenging because of their inherent complicated structures, including diverse di- to tetra-antennary forms. We report a highly efficient strategy to access the representative two types of triantennary oligosaccharides through only 9- or 10-step chemical conversions from a biantennary oligosaccharide, which can be isolated in exceptionally homogeneous form from egg yolk. Four benzylidene acetals were successfully introduced to the terminal two galactosides and two core mannosides of the biantennary asialononasaccharide bearing 24 hydroxy groups, followed by protection of the remaining hydroxy groups with acetyl groups. Selective removal of one of the benzylidene acetals gave two types of suitably protected glycosyl acceptors. Glycosylation toward the individual acceptors with protected Gal-beta 1,4-GlcN thioglycoside and subsequent deprotection steps successfully yielded two types of complex-type triantennary oligosaccharides. PMID- 26926156 TI - The Development and Preliminary Testing of an Instrument for Assessing Fatigue Self-management Outcomes in Patients With Advanced Cancer. AB - BACKGROUND: Fatigue is one of the most distressing and commonly experienced symptoms in patients with advanced cancer. Although the self-management (SM) of cancer-related symptoms has received increasing attention, no research instrument assessing fatigue SM outcomes for patients with advanced cancer is available. OBJECTIVES: The aim of this study was to describe the development and preliminary testing of an interviewer-administered instrument for assessing the frequency and perceived levels of effectiveness and self-efficacy associated with fatigue SM behaviors in patients with advanced cancer. METHODS: The development and testing of the Self-efficacy in Managing Symptoms Scale-Fatigue Subscale for Patients With Advanced Cancer (SMSFS-A) involved a number of procedures: item generation using a comprehensive literature review and semistructured interviews, content validity evaluation using expert panel reviews, and face validity and test-retest reliability evaluation using pilot testing. RESULTS: Initially, 23 items (22 specific behaviors with 1 global item) were generated from the literature review and semistructured interviews. After 2 rounds of expert panel review, the final scale was reduced to 17 items (16 behaviors with 1 global item). Participants in the pilot test (n = 10) confirmed that the questions in this scale were clear and easy to understand. Bland-Altman analysis showed agreement of results over a 1 week interval. CONCLUSIONS: The SMSFS-A items were generated using multiple sources. This tool demonstrated preliminary validity and reliability. IMPLICATIONS FOR PRACTICE: The SMSFS-A has the potential to be used for clinical and research purposes. Nurses can use this instrument for collecting data to inform the initiation of appropriate fatigue SM support for this population. PMID- 26926157 TI - Cetuximab Inhibits T790M-Mediated Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor in a Lung Adenocarcinoma Patient-Derived Xenograft Mouse Model. AB - BACKGROUND: The epidermal growth factor receptor (EGFR) kinase domain T790M (amino acid substitution at position 790 in EGFR from threonine [T] to methionine [M]) mutation in non-small-cell lung cancer (NSCLC) results in resistance to EGFR tyrosine kinase inhibitors (TKIs). We used a patient-derived tumor xenograft (PDX) model containing an EGFR exon 19 deletion/T790M mutation to assess response to the EGFR-directed antibody cetuximab. Changes in the EGFR signaling pathway and ligand expression after treatment were investigated. METHODS: PDX were randomized into control and treatment arms. Pharmacodynamic studies were performed at 2 and 24 hours and at 4 days after a single administration of cetuximab, erlotinib, or dacomitinib. Changes in the EGFR signaling pathway were assessed using Western blot analysis, and baseline mRNA expression of EGFR ligands using microarray analysis. Relative changes after treatment were assessed using quantitative polymerase chain reaction. RESULTS: The xenograft showed a dramatic response to cetuximab. A complete reduction of total EGFR and phosphorylated EGFR occurred after cetuximab treatment. The PDX had increased baseline levels of heparin-binding epidermal growth factor-like growth factor (HB EGF) compared with other PDX models with or without EGFR mutations. Amphiregulin was significantly reduced 2 hours after treatment with cetuximab. Compared with control mice, cetuximab- and EGFR-TKI-treated mice had significantly reduced HB EGF gene expression at 2 hours, however, by day 4 the level of HB-EGF expression was higher. The effect of cetuximab compared with EGFR TKI on HB-EGF gene expression levels differed significantly at 2 and 24 hours but not at 4 days. CONCLUSION: We showed a dramatic tumor response with cetuximab in an exon 19 deletion/T790M EGFR mutant lung adenocarcinoma PDX model, which suggests a role for the autocrine feedback loop in the mutant EGFR signaling pathway. Further investigation using cetuximab in NSCLC with T790M mutation is warranted. PMID- 26926158 TI - Comparison of lidocaine spray and paracervical block application for pain relief during first-trimester surgical abortion: A randomised, double-blind, placebo controlled trial. AB - Surgical abortion is one of the most frequently performed gynaecological procedures and its associated pain has always been a problem in gynaecology. Here we studied the analgesic efficacy of lidocaine spray and paracervical block (PCB) in patients undergoing first-trimester surgical abortion. A randomised double blind placebo-controlled study was conducted on 108 women requesting pregnancy termination. The subjects were randomly assigned into four groups: Group 1 (PCB plus lidocaine spray) (n=27), Group 2 (PCB) (n=27), Group 3 (lidocaine spray) (n=27) and Group 4 (placebo) (n=27). Intra-procedural and post-procedural pain scores were measured with a standard visual analogue scale (VAS). The median VAS scores during procedure in placebo, lidocaine spray, PCB plus lidocaine spray and PCB groups were 8 (7-9), 5 (4-8), 4 (3-4) and 5 (3-5), respectively. The most effective method of pain relief during first-trimester abortion can be achieved through a combined use of PCB plus lidocaine spray. Therefore, lidocaine spray is a non-invasive complementary anaesthetic method versus traditional PCB for first trimester surgical abortion. PMID- 26926162 TI - Effect and Prognostic Factors of Laminoplasty for Cervical Myelopathy With an Occupying Ratio Greater Than 50%. AB - STUDY DESIGN: A retrospective study. OBJECTIVE: The aim of this study was to evaluate the efficacy of laminoplasty for the treatment of patients with an occupying ratio greater than 50% and to determine possible factors related to surgical outcome of posterior decompression. SUMMARY OF BACKGROUND DATA: Little data are available about effect and prognostic factors of laminoplasty for cervical myelopathy with an occupying ratio greater than 50%. METHODS: Fifty-five consecutive patients with an occupying ratio greater than 50% who underwent cervical laminoplasty between January 2005 and December 2010 were reviewed in this study. Patients with cervical kyphosis were excluded. Clinical and radiologic outcomes were assessed. Univariate analysis was used to investigate the relationship between recovery rate and the age, duration of symptoms, preoperative Japan Orthopedic Association (JOA) score, posterior shift of the spinal cord, preoperative cervical lordosis, spinal cord compression ratio, and follow-up period. Multivariate linear regression analysis was used to determine the best surgical outcome predictor. RESULTS: All patients maintained cervical lordosis. Average JOA score improved from 10.7 +/- 1.7 points preoperatively to 14.0 +/- 1.4 points at the last follow-up. The mean rate of recovery was 51.4 +/- 25.7%. Final recovery rates showed 6 excellent results, 29 good results, 18 fair results, and 2 poor results. Univariate analysis showed significant correlation between the recovery rate and the spinal cord compression ratio, duration of symptoms, and posterior movement of the spinal cord. The multivariate linear regression analysis showed that the best surgical outcome predictor was the spinal cord compression ratio (beta = 0.698, P < 0.001). R-square of the final multiple linear regression model was 0.509. CONCLUSION: Laminoplasty can still be considered as a decompressive pattern for patients with a high occupying ratio greater than 50%. The spinal cord compression ratio, duration of symptoms, and posterior movement of the spinal cord play important roles in recovery rate. The best surgical outcome predictor is the spinal cord compression ratio. LEVEL OF EVIDENCE: 4. PMID- 26926159 TI - Health Reform, Medicaid Expansions, and Women's Cancer Screening. AB - BACKGROUND: Health reform, including Medicaid expansion, is increasing insurance coverage and financial access to breast and cervical cancer screening for low income women, although services for low-income uninsured women are still needed. METHODS: American Community Survey and administrative data about Medicaid and health insurance enrollment are used to estimate the number of low-income women who will be uninsured in 2017, focusing on the age ranges 21 to 64, 40 to 64, and 50 to 64. RESULTS: Assuming that 29 states expand Medicaid (as of June 2015), the national percentage of low-income women 21 to 64 who are uninsured will fall from 32.2% in 2013 to 14.6% by 2017. Among Medicaid-expanding states, the percentage of uninsured will decrease from 28.7% to 8.0%, whereas in non-expanding states, the level will decrease from 36.9% to 23.3%. About 5.7 million women 21 to 64 and 2.6 million women 40 to 64 will remain uninsured in 2017. The size of the uninsured low-income population will remain much larger than the 659,000 women who have previously received Pap tests and 548,000 obtaining mammograms under the National Breast and Cervical Cancer Early Detection Program in 2013. DISCUSSION: Even before 2014, women living in states that are not expanding Medicaid were less likely to get mammograms and Pap tests than women in expanding states. Affordable Care Act-related insurance expansions will lower financial barriers to screening and should boost overall screening rates. But disparities in insurance coverage and cancer screening across Medicaid-expanding and non-expanding states could widen. CONCLUSIONS: Programs to support cancer screening for low-income uninsured women will still be needed. PMID- 26926163 TI - Improvement on the Accuracy and Reliability of Ultrasound Coronal Curvature Measurement on Adolescent Idiopathic Scoliosis With the Aid of Previous Radiographs. AB - STUDY DESIGN: Retrospective study of the coronal curvature measurement on ultrasound (US) images with the aid of previous radiographs. OBJECTIVE: To compare the reliability and accuracy of the coronal curvature measurements from US images on children who have adolescent idiopathic scoliosis (AIS) with and without the knowledge of previous radiographs. SUMMARY OF BACKGROUND DATA: Using US imaging technique to measure coronal curvature on children with AIS has demonstrated high intra- and interrater reliabilities. However, the selection of end-vertebrae and the measurement difference between radiography and the US method were only moderately reliable. METHODS: Two raters measured the coronal curvatures from 65 AIS standing US spine images, without (measured one time) and with the aid of previous standing radiographs (measured two times). The intra- and interrater reliability, the correlation and the difference between the radiographic and US measurements, and the error index of the end-vertebrae selection were assessed. RESULTS: Overall, 109 curves were investigated. The intraclass correlation coefficients (ICC) of intra- and interrater reliability of the US coronal curvature measurement with the aid of previous radiographs (AOR) were 0.95 and 0.91, respectively. In comparison with the radiographic measurements, the correlation of AOR method (R) was 0.90 and the MAD was 2.8 degrees ; the corresponding results of the US measurement without the AOR (blinded US method) were 0.73 degrees and 4.8 degrees , respectively. The average error index on end-vertebral selection improved 43% with the AOR. CONCLUSION: The AOR method significantly improved reliability and accuracy of the spinal curvature measurement on US images compared with the blinded US method (P<0.001). It indicates that US standing images with the AOR can be used as a reliable and accurate nonionizing imaging method to monitor children with AIS. LEVEL OF EVIDENCE: 3. PMID- 26926164 TI - Reporting of Rehabilitation Intervention for Low Back Pain in Randomized Controlled Trials: Is the Treatment Fully Replicable? AB - STUDY DESIGN: Methodological review of randomized controlled trials (RCTs). OBJECTIVE: To assess the quality of reporting of rehabilitation interventions for mechanical low back pain (LBP) in published RCTs. SUMMARY OF BACKGROUND DATA: Reporting of interventions in RCTs often focused on the outcome value and failed to describe interventions adequately. METHODS: We systematically searched for all RCTs in Cochrane systematic reviews on LBP published in the Cochrane Database of Systematic Reviews until December 2013. The description of rehabilitation interventions of each RCT was evaluated independently by 2 of the investigators, using an ad hoc checklist of 7 items. The primary outcome was the number of items reported in sufficient details to be replicable in a new RCT or in everyday practice. RESULTS: We found 11 systematic reviews, including 220 eligible RCTs, on LBP. Of those, 185 RCTs were included. The median publication year was 1998 (I III quartiles, 1990 to 2004). The most reported items were the characteristics of participants (91.3%; 95% confidence interval [CI], 87.3-95.4), the intervention providers (81.1%; 95% CI, 75.4-86.7), and the intervention schedule (69.7%; 95% CI, 63-76). Based on the description of the intervention, less than one fifth would be replicable clinically. The proportion of trials providing all essential information about the participants and interventions increased from 14% (n = 7) in 1971 to 1980 to 20% (n = 75) in 2001 to 2010. CONCLUSION: Despite the remarkable amount of energy spent producing RCTs in LBP rehabilitation, the majority of RCTs failed to report sufficient information that would allow the intervention to be replicated in clinical practice. Improving the quality of intervention description is urgently needed to better transfer research into rehabilitation practices. LEVEL OF EVIDENCE: 1. PMID- 26926166 TI - Society for Pediatric Pathology Comment on Proposed Changes to Regulations on Research with Human Tissues (Docket ID#: HHS-OPHS-2015-0008). PMID- 26926167 TI - Infraorbital Neuralgia Attributed to a Foreign Body. AB - We reported a case of secondary infraorbital neuralgia due to a foreign body involving the nasal ala. As it was a very rare care, we reviewed reported literatures. This case highlights that infraorbital neuralgia could be caused by any tiny problems such as foreign body involving the area innervated by infraorbital nerve. PMID- 26926165 TI - A PTH-responsive circadian clock operates in ex vivo mouse femur fracture healing site. AB - The circadian clock contains clock genes including Bmal1 and Period2, and it maintains an interval rhythm of approximately 24 hours (the circadian rhythm) in various organs including growth plate and articular cartilage. As endochondral ossification is involved not only in growth plate but also in fracture healing, we investigated the circadian clock functions in fracture sites undergoing healing. Our fracture models using external fixation involved femurs of Period2::Luciferase knock-in mice which enables the monitoring of endogenous circadian clock state via bioluminescence. Organ culture was performed by collecting femurs, and fracture sites were observed using bioluminescence imaging systems. Clear bioluminescence rhythms of 24-hour intervals were revealed in fracture healing sites. When parathyroid hormone (PTH) was administered to fractured femurs in organ culture, peak time of Period2::Luciferase activity in fracture sites and growth plates changed, indicating that PTH-responsive circadian clock functions in the mouse femur fracture healing site. While PTH is widely used in treating osteoporosis, many studies have reported that it contributes to improvement of fracture healing. Future studies of the role of this local clock in wound healing may reveal a novel function of the circadian timing mechanism in skeletal cells. PMID- 26926169 TI - Lattice Boltzmann Simulation of Healthy and Defective Red Blood Cell Settling in Blood Plasma. AB - In this paper, an attempt has been made to study sedimentation of a red blood cell (RBC) in a plasma-filled tube numerically. Such behaviors are studied for a healthy and a defective cell which might be created due to human diseases, such as diabetes, sickle-cell anemia, and hereditary spherocytosis. Flow-induced deformation of RBC is obtained using finite-element method (FEM), while flow and fluid-membrane interaction are handled using lattice Boltzmann (LB) and immersed boundary methods (IBMs), respectively. The effects of RBC properties as well as its geometry and orientation on its sedimentation rate are investigated and discussed. The results show that decreasing frontal area of an RBC and/or increasing tube diameter results in a faster settling. Comparison of healthy and diabetic cells reveals that less cell deformability leads to slower settling. The simulation results show that the sicklelike and spherelike RBCs have lower settling velocity as compared with a biconcave discoid cell. PMID- 26926168 TI - Easily identified at-risk patients for extubation failure may benefit from noninvasive ventilation: a prospective before-after study. AB - BACKGROUND: While studies have suggested that prophylactic noninvasive ventilation (NIV) could prevent post-extubation respiratory failure in the intensive care unit, they appear inconsistent with regard to reintubation. We assessed the impact of a prophylactic NIV protocol on reintubation in a large population of at-risk patients. METHODS: Prospective before-after study performed in the medical ICU of a teaching referral hospital. In the control cohort, we determined that patients older than 65 years and those with underlying cardiac or respiratory disease were at high-risk for reintubation. In the interventional cohort, we implemented a protocol using prophylactic NIV in all patients intubated at least 24 h and having one of these risk factors. NIV was immediately applied after planned extubation during at least the first 24 hours. Extubation failure was defined by the need for reintubation within seven days following extubation. RESULTS: We included 83 patients at high-risk among 132 extubated patients in the control cohort (12-month period) and 150 patients at high-risk among 225 extubated patients in the NIV cohort (18-month period). The reintubation rate was significantly decreased from 28% in the control cohort (23/83) to 15% (23/150) in the NIV cohort (p = 0.02 log-rank test), whereas the non-at-risk patients did not significantly differ in the two periods (10.2% vs. 10.7%, p = 0.93). After multivariate logistic-regression analysis, the use of prophylactic NIV protocol was independently associated with extubation success. CONCLUSIONS: The implementation of prophylactic NIV after extubation may reduce the reintubation rate in a large population of patients with easily identified risk factors for extubation failure. PMID- 26926170 TI - Verticine, ebeiedine and suchengbeisine isolated from the bulbs of Fritillaria thunbergii Miq. inhibited the gene expression and production of MUC5AC mucin from human airway epithelial cells. AB - BACKGROUND: The bulb of Fritillaria thunbergii has been utilised as mucoregulators and expectorants for controlling the airway inflammatory diseases in folk medicine. HYPOTHESIS/PURPOSE: We investigated whether verticine, ebeiedine and suchengbeisine isolated from the bulbs of Fritillaria thunbergii inhibit the gene expression and production of MUC5AC mucin from human airway epithelial cells. STUDY DESIGN: Confluent NCI-H292 cells were pretreated with verticine, ebeiedine or suchengbeisine for 30 min and then stimulated with EGF, PMA or TNF-alpha for 24h. The MUC5AC mucin gene expression was measured by RT PCR. Production of MUC5AC mucin protein was measured by ELISA. RESULTS: (1) Verticine, ebeiedine or suchengbeisine inhibited the expression of MUC5AC mucin gene induced by EGF, PMA or TNF-alpha; (2) The production of MUC5AC mucin protein induced by EGF, PMA or TNF-alpha were also inhibited by treatment of verticine, ebeiedine or suchengbeisine. CONCLUSION: These results suggest that verticine, ebeiedine and suchengbeisine isolated from the bulbs of Fritillaria thunbergii inhibit the gene expression and production of MUC5AC mucin, by directly acting on airway epithelial cells, and the results are consistent with the traditional use of Fritillaria thunbergii as remedy for diverse inflammatory pulmonary diseases. PMID- 26926171 TI - The involvement of cyclin D1 degradation through GSK3beta-mediated threonine-286 phosphorylation-dependent nuclear export in anti-cancer activity of mulberry root bark extracts. AB - BACKGROUND: Mulberry root bark was shown to induce cyclin D1 proteasomal degradation in the human colorectal cancer cells. Still, the molecular mechanisms whereby mulberry root bark induces cyclin D1 proteasomal degradation remain largely unknown. PURPOSE: In this study, the inhibitory effect of mulberry root bark (MRB) on the proliferation of human colorectal cancer cells and the mechanism of action were examined to evaluate its anti-cancer activity. METHODS: Anti-proliferative effect was determined by MTT assay. RT-PCR and Western blotting were used to assess the mRNA and protein expression of related proteins. RESULTS: MRB inhibited markedly the proliferation of human colorectal cancer cells (HCT116, SW480 and LoVo). In addition, the proliferation of human breast cancer cells (MDA-MB-231 and MCF-7) was suppressed by MRB treatment. However, MRB did not affect the growth of HepG-2 cells as a human hepatocellular carcinoma cell line. MRB effectively decreased cyclin D1 protein level in human colorectal cancer cells and breast cancer cells, but not in hepatocellular carcinoma cells. Contrast to protein levels, cyclin D1 mRNA level did not be changed by MRB treatment. Inhibition of proteasomal degradation by MG132 attenuated MRB-mediated cyclin D1 downregulation and the half-life of cyclin D1 was decreased in the cells treated with MRB. In addition, MRB increased phosphorylation of cyclin D1 at threonine-286 and a point mutation of threonine-286 to alanine attenuated MRB mediated cyclin D1 degradation. Inhibition of GSK3beta by LiCl suppressed cyclin D1 phosphorylation and downregulation by MRB. MRB decreased the nuclear level of cyclin D1 and the inhibition of nuclear export by LMB attenuated MRB-mediated cyclin D1 degradation. CONCLUSION: MRB has anti-cancer activity by inducing cyclin D1 proteasomal degradation through cyclin D1 nuclear export via GSK3beta dependent threonine-286 phosphorylation. These findings suggest that possibly its extract could be used for treating colorectal cancer. PMID- 26926172 TI - Apoptosis induction of dehydrobruceine B on two kinds of human lung cancer cell lines through mitochondrial-dependent pathway. AB - BACKGROUND: Brucea javanica is an effective traditional medicine listed in Chinese Pharmacopoeia. In China, the seed oil of B. javanica has long been used as commercially available drug for the treatment of tumor in clinic. Dehydrobruceine B (DHB) is a quassinoid isolated from B. javanica. PURPOSE: The aim of the present study is to investigate the apoptotic effects induced by DHB in human lung cancer A549 and NCI-H292 cells. The involvement of a mitochondria mediated intrinsic pathway in the pro-apoptotic action of DHB was also investigated. MATERIAL AND METHODS: Cell viability was determined by MTT assay. Cell cycle and apoptosis were assessed by flow cytometry analysis. Mitochondrial membrane potential (MMP) was examined through JC-1 staining. The protein translocation in cells was examined by immunostaining. The expression levels of proteins which are closely related to mitochondria-mediated apoptosis pathway were measured by immunoblot analysis. RESULTS: Treatment with DHB decreased cell viability, induced apoptosis and blocked cell cycle at S phase. DHB-induced apoptosis was found to be mediated through mitochondrial intrinsic pathway, evidenced by the loss of MMP, the release of cytochrome c into cytosol, and the cleavage of caspase-9, caspase-3 and poly (ADP-ribose) polymerase (PARP). CONCLUSION: DHB triggers apoptosis in A549 and NCI-H292 cells via mitochondrial pathway, making it a promising candidate as a therapeutic agent for lung carcinoma. PMID- 26926173 TI - Inhibition of pulmonary metastasis by Emilia sonchifolia (L.) DC: An in vivo experimental study. AB - BACKGROUND: Emilia sonchifolia (L.) DC is a widely distributed medicinal herb used mainly in the indigenous Ayurvedic system of medicine in India. This plant is one among the ten sacred plants of Kerala state in India, collectively known as Dasapushpam. PURPOSE: To assess the therapeutic efficacy of this well-known medicinal plant in a catastrophic complication like metastatic cancer progression. This study further aimed to scientifically validate the traditional medicinal use of this sacred plant. STUDY DESIGN: Highly metastatic B16F10 melanoma will spontaneously metastasize in C57BL/6 mice and is accepted as a useful murine model for the study on metastasis. Three different experimental modalities of prophylactic, simultaneous and after tumour development were used for data accumulation and analysis. METHODS: Whole plant genuine extract of E. sonchifolia (25 mg/kg bodyweight) was administered intraperitoneally to C57BL/6 mice. Animals were sacrificed on 21st day after tumour induction and the lung tumour nodules were counted. Various lung and serum biochemical parameters along with major cytokine levels were recorded. Survival rate was monitored. Histopathology of the lung tissue and expression studies of the major genes involved in metastasis was also carried out. RESULTS: E. sonchifolia significantly inhibited pulmonary tumour formation and increased the life span of animals. Lung collagen hydroxyproline, uronic acid, hexosamine, serum sialic acid, gamma-glutamyl transpeptidase, vascular endothelial growth factor (VEGF), granulocyte monocyte colony-stimulating factor and other cytokine levels were significantly lowered in the treated group of animals. Histopathological analysis was also correlated with these findings. E. sonchifolia down regulated the expression of matrix metalloproteinases; extracellular signal-regulated kinases and VEGF at the same time up regulated the expression of tissue inhibitor of matrix metalloproteinases. CONCLUSION: Previous studies on E. sonchifolia proved its significant biological properties including anti-tumour, anti-inflammatory and antioxidant activities. Present report is so far the first study to demonstrate the anti-metastatic potential of this medicinal herb justifying its conventional use in the traditional medicine. PMID- 26926174 TI - Neomangiferin modulates the Th17/Treg balance and ameliorates colitis in mice. AB - BACKGROUND: Anemarrhena asphodeloides (Liliaceae family) and Mangifera indica L. (Anacardiaceae family) contain neomangiferin as the main active constituent and have been used to treat inflammation, asthma, and pain. PURPOSE: A preliminary study found that neomangiferin inhibited splenic T cell differentiation into Th17 cells and promoted Treg cell production in vitro. Therefore, we examined its anti colitic effects in vitro and in vivo. METHODS: Splenocytes isolated from C57BL/6J mice were treated with neomangiferin. Colitis was either induced in vivo by intrarectal administration of 2,4,6-trinitrobenzene sulfonic acid (TNBS) to C57BL/6J mice or occurred spontaneously in colitis caused by interleukin (IL)-10 knockout at age of 13 weeks. Mice were treated daily with neomangiferin or sulfasalazine. Inflammatory markers, cytokines, enzymes and transcription factors were measured by enzyme-linked immunosorbent assay, immunoblot, and flow cytometry. RESULTS: Neomangiferin suppressed retinoic acid receptor-related orphan receptor gamma t (RORgammat) and IL-17 expression in IL-6/transforming growth factor beta-stimulated Th17 splenocytes and increased IL-10 expression in vitro. Mouse TNBS-induced colon shortening, macroscopic score, and myeloperoxidase activity were inhibited by neomangiferin, which also reduced TNBS induced activation of nuclear factor-kappaB and extracellular signal-regulated kinases, as well as expression of inducible nitric oxide synthase and cyclooxygenase-2. In addition, neomangiferin inhibited TNBS-induced expression of tumor necrosis factor-alpha, IL-17, IL-6, and IL-1beta, and increased IL-10 expression. Neomangiferin inhibited TNBS-induced differentiation to Th17 cells and promoted the development of Treg cells. Moreover, in IL-10(-/-) mice, neomangiferin inhibited colonic myeloperoxidase activity, suppressed Th17 cell differentiation, and reduced levels of TNF-alpha and IL-17. CONCLUSION: Neomangiferin may restore the balance between Th17/Treg cells by suppressing IL 17 and RORgammat expression and inducing IL-10 and forkhead box P3 expression, thus ameliorating colitis. PMID- 26926175 TI - Mitraphylline inhibits lipopolysaccharide-mediated activation of primary human neutrophils. AB - BACKGROUND: Mitraphylline (MTP) is the major pentacyclic oxindolic alkaloid presented in Uncaria tomentosa. It has traditionally been used to treat disorders including arthritis, heart disease, cancer, and other inflammatory diseases. However, the specific role of MTP is still not clear, with more comprehensivestudies, our understanding of this ancient herbal medicine will continue growing. HYPOTHESIS/PURPOSE: Some studies provided its ability to inhibit proinflamatory cytokines, such as TNF-alpha, through NF-kappaB-dependent mechanism. TNF-alpha primes neutrophils and modulates phagocytic and oxidative burst activities in inflammatory processes. Since, neutrophils represent the most abundant pool of leukocytes in human blood and play a crucial role in inflammation, we aimed to determine the ability of MTP to modulate neutrophil activation and differentially regulate inflammatory-related cytokines. METHODS: To determine the mechanism of action of MTP, we investigated the effects on LPS activated human primary neutrophils responses including activation surface markers by FACS and the expression of inflammatory cytokines, measured by real time PCR and ELISA. RESULTS: Treatment with MTP reduced the LPS-dependent activation effects. Activated neutrophils (CD16(+)CD62L(-)) diminished after MTP administration. Moreover, proinflamatory cytokines (TNF-alpha, IL-6 or IL-8) expression and secretion were concomitantly reduced, similar to basal control conditions. CONCLUSION: Taken together, our results demonstrate that MTP is able to elicit an anti-inflammatory response that modulates neutrophil activation contributing to the attenuation of inflammatory episodes. Further studies are need to characterize the mechanism by which MTP can affect this pathway that could provide a means to develop MTP as new candidate for inflammatory disease therapies. PMID- 26926176 TI - Neuroprotective effects of polygalacic acid on scopolamine-induced memory deficits in mice. AB - BACKGROUND: Polygala tenuifolia Willd is a Traditional Chinese Medicine used for the treatment of learning and memory deficits. Triterpenoid saponins, the main bioactive compounds of Polygala tenuifolia Willd, are easily hydrolyzed to polygalacic acid (PA). PURPOSE: The present study was undertaken to investigate the neuroprotective effects of PA on scopolamine-induced cognitive dysfunction and to elucidate its underlying mechanisms of action. METHODS: PA (3, 6, and 12 mg/kg) was administered orally to mice for fourteen days, and scopolamine (1 mg/kg) was injected intraperitoneally for fourteen days to induce memory impairment. Memory-related behaviors were evaluated using the Morris water maze. Cholinergic and neuroinflammatory activities were measured in brain tissue. Superoxide dismutase activities, malondialdehyde and reduced glutathione contents were also measured in the brains. RESULTS: Treatment with scopolamine significantly increased the escape latency time, decreased the number of crossings, and shortened the time spent in the target quadrant, while PA reversed these scopolamine-induced effects. PA significantly improved cholinergic system reactivity, as indicated by decreased acetylcholinesterase (AChE) activity, increased choline acetyltransferase (ChAT) activity, and elevated levels of acetylcholine (ACh) in the hippocampus and frontal cortex. PA also significantly ameliorated neuroinflammation and oxidative stress in mice. CONCLUSION: These results suggest that PA might exert a significant neuroprotective effect on cognitive impairment, driven in part by the modulation of cholinergic activity and neuroinflammation. PMID- 26926177 TI - Evaluation of DNA barcoding coupled high resolution melting for discrimination of closely related species in phytopharmaceuticals. AB - BACKGROUND: Phytopharmaceuticals are increasingly popular as alternative medicines, but poorly regulated in many countries. The manufacturers of these products should be subject to strict controls regarding each product's quality and constituents. Routine testing and identification of raw materials should be performed to ensure that the raw materials used in pharmaceutical products are suitable for their intended use. HYPOTHESIS/PURPOSE: We have applied DNA Barcoding - High Resolution Melting (Bar-HRM), an emerging method for identifying of medicinal plant species based on DNA dissociation kinetics and DNA barcoding, for the authentication of medicinal plant species. STUDY DESIGN: Commonly commercialized Thai medicinal plants that are widely used for medicinal purposes were used in this study. Publicly available sequences of four plastid markers were used for universal primer design. Species discrimination efficiency of the designed primers was evaluated as single and multi-locus analyses by using the primers sets. METHODS: HRM analysis was performed in triplicate on each of the 26 taxa to establish the Tm for each primer set (matK, rbcLA, rbcLB, rbcLC, rpoC1, and trnL). The shapes of the melting curves were analyzed to distinguish the different plant species. Bar-HRM species identification success rates were assessed for each single-locus as well as for multi-locus combinations to establish the optimal combination of primer sets. RESULTS: In single locus analysis the rpoC1 primer set gave the highest discrimination (58%), and in multi locus analysis this could be increased from 87% to 99% depending on the total number of regions included. Different combinations proved to be more or less effective at discrimination, depending on the genus or family examined. CONCLUSIONS: Bar-HRM has proven to be a cost-effective and reliable method for the identification of species in this study of Thai medicinal plants, and results show an identification success rate of 99% among species in the test set. PMID- 26926179 TI - Cryptotanshinone deregulates unfolded protein response and eukaryotic initiation factor signaling in acute lymphoblastic leukemia cells. AB - BACKGROUND: Unfolded protein responses (UPR) determine cell fate and are recognized as anticancer targets. In a previous research, we reported that cryptotanshinone (CPT) exerted cytotoxic effects toward acute lymphoblastic leukemia cells through mitochondria-mediated apoptosis. PURPOSE: In the present study, we further investigated the role of UPR in CPT-induced cytotoxicity on acute lymphoblastic leukemia cells by applying tools of pharmacogenomics and bioinformatics. METHODS: Gene expression profiling was performed by mRNA microarray hybridization. Potential transcription factor binding motifs were identified in the promoter regions of the deregulated genes by Cistrome software. Molecular docking on eIF-4A and PI3K was performed to investigate the inhibitory activity of CPT on translation initiation. RESULTS: CPT regulated genes related to UPR and eIF2 signaling pathways. The DNA-Damage-Inducible Transcript 3 (DDIT3) gene, which is activated as consequence of UPR malfunction during apoptosis, was induced and validated by in vitro experiments. Transcription factor binding motif analysis of the microarrary-retrieved deregulated genes in the promoter region emphasized the relevance of transcription factors, such as ATF2, ATF4 and XBP1, regulating UPR and cell apoptosis. Molecular docking suggested inhibitory effects of CPT by binding to eIF-4A and PI3K providing evidence for a role of CPT's in the disruption of protein synthesis. CONCLUSION: CPT triggered UPR and inhibited protein synthesis via eIF-mediated translation initiation, potentially supporting CPT-induced cytotoxic effects toward acute leukemia cells. PMID- 26926178 TI - Biopiracy of natural products and good bioprospecting practice. AB - BACKGROUND: Biopiracy mainly focuses on the use of biological resources and/or knowledge of indigenous tribes or communities without allowing them to share the revenues generated out of economic exploitation or other non-monetary incentives associated with the resource/knowledge. METHODS: Based on collaborations of scientists from five continents, we have created a communication platform to discuss not only scientific topics, but also more general issues with social relevance. This platform was termed 'PhytCancer -Phytotherapy to Fight Cancer' (www.phyt-cancer.uni-mainz.de). As a starting point, we have chosen the topic "biopiracy", since we feel this is of pragmatic significance for scientists working with medicinal plants. RESULTS: It was argued that the patenting of herbs or natural products by pharmaceutical corporations disregarded the ownership of the knowledge possessed by the indigenous communities on how these substances worked. Despite numerous court decisions in U.S.A. and Europe, several international treaties, (e.g. from United Nations, World Health Organization, World Trade Organization, the African Unity and others), sharing of a rational set of benefits amongst producers (mainly pharmaceutical companies) and indigenous communities is yet a distant reality. In this paper, we present an overview of the legal frameworks, discuss some exemplary cases of biopiracy and bioprospecting as excellent forms of utilization of natural resources. CONCLUSIONS: We suggest certain perspectives, by which we as scientists, may contribute towards prevention of biopiracy and also to foster the fair utilization of natural resources. We discuss ways, in which the interests of indigenous people especially from developing countries can be secured. PMID- 26926180 TI - Corosolic acid inhibits adipose tissue inflammation and ameliorates insulin resistance via AMPK activation in high-fat fed mice. AB - BACKGROUND: Adipose tissue inflammation is tightly associated with the development of insulin resistance. Corosolic acid (CRA), a natural triterpenoid, is well known as "phyto-insulin" due to its insulin-like activities. However, its underlying mechanism remains unknown. PURPOSE: In this study, we investigated the mechanisms of CRA on improving insulin resistance both in vivo and in vitro. METHODS: C57BL/6 mice were fed with normal diet, high-fat diet (HFD) or HFD with CRA, respectively. General biochemical parameters in blood and glucose intolerance in mice were assayed. Meanwhile, proinflammatory cytokines and macrophage infiltrations in adipose tissues were analyzed by real-time PCR and immunohistochemical staining. The effects of CRA on insulin signaling transduction and AMPK activity in adipose tissues were investigated by western blot. Furthermore, the effects of CRA on AMPK were confirmed on 3T3-L1 cells by using both AMPK inhibitor and AMPKalpha1/2-specific siRNA RESULTS: CRA attenuated hyperlipidemia, improved insulin sensitivity and glucose intolerance in mice. Meanwhile, it alleviated inflammation in adipose tissues, demonstrated by the suppression of IKKbeta phosphorylation and down-regulation of gene expressions of proinflammatory cytokines. Histological analysis revealed that CRA attenuated macrophage infiltrations into adipose tissue. It also improved insulin signaling transduction by modification of Ser/Thr phosphorylation of IRS-1 and downstream Akt, thereby improved insulin sensitivity in HFD-fed mice. Furthermore, CRA regulated AMPK activation in a LKB1-dependent manner. AMPKalpha knockdown in adipocytes abolished the inhibitory effects of CRA on IKKbeta and IRS-1 serine phosphorylation, indicating that CRA inhibited inflammation and ameliorated insulin resistance via AMPK activation. CONCLUSIONS: CRA inhibited inflammation with improvement in adipose tissue dysfunction and ameliorated insulin resistance in an AMPK-dependent manner. PMID- 26926181 TI - Barrier protective effect of asiatic acid in TNF-alpha-induced activation of human aortic endothelial cells. AB - BACKGROUND: Endothelial cell activation is characterized by increased endothelial permeability and increased expression of cell adhesion molecules (CAMs). This allows monocyte adherence and migration across the endothelium to occur and thereby initiates atherogenesis process. Asiatic acid is a major triterpene isolated from Centella asiatica (L.) Urban and has been shown to possess anti oxidant, anti-hyperlipidemia and anti-inflammatory activities. PURPOSE: We aimed to investigate protective effects of asiatic acid on tumor necrosis factor-alpha (TNF-alpha)-induced endothelial cell activation using human aortic endothelial cells (HAECs). STUDY DESIGN: For cell viability assays, HAECs were treated with asiatic acid for 24 h. For other assays, HAECs were pretreated with various doses of asiatic acid (10-40 uM) for 6 h followed by stimulation with TNF-alpha (10 ng/ml) for 6 h. METHODS: Fluorescein isothiocyanate (FITC)-dextran permeability assay was performed using commercial kits. Total protein expression of CAMs such as E-selectin, ICAM-1, VCAM-1 and PECAM-1 as well as phosphorylation of IkappaB alpha were determined using western blot. The levels of soluble form of CAMs were measured using flow cytometry. Besides, we also examined the effects of asiatic acid on U937 monocyte adhesion and monocyte migration in HAECs using fluorescent based assays. RESULTS: Asiatic acid significantly suppressed endothelial hyperpermeability, increased VCAM-1 expression and increased levels of soluble CAMs (sE-selectin, sICAM-1, sVCAM-1 and sPECAM-1) triggered by TNF-alpha. Neither TNF-alpha nor asiatic acid affects PECAM-1 expression. However, asiatic acid did not inhibit TNF-alpha-induced increased monocyte adhesion and migration. Interestingly, asiatic acid suppressed increased phosphorylation of IkappaB-alpha stimulated by TNF-alpha. CONCLUSION: These results suggest that asiatic acid protects against endothelial barrier disruption and this might be associated with the inhibition of NF-kappaB activation. We have demonstrated a novel protective role of asiatic acid on endothelial function. This reveals the possibility to further explore beneficial effects of asiatic acid on chronic inflammatory diseases that are initiated by endothelial cell activation. PMID- 26926182 TI - Bioactive compounds isolated from apple, tea, and ginger protect against dicarbonyl induced stress in cultured human retinal epithelial cells. AB - BACKGROUND: Methylglyoxal (MGO) is known to be a major precursor of advanced glycation end products (AGEs) which are linked to diabetes and its related complications. Naturally occurring bioactive compounds could play an important role in countering AGEs thereby minimizing the risk associated with their formation. METHODS: In this study, eight specific bioactive compounds isolated from apple, tea and ginger were evaluated for their AGEs scavenging activity using Human Retinal Pigment Epithelial (H-RPE) cells treated with MGO. RESULTS: Among the eight specific compounds evaluated, (-)-epigallocatechin 3-gallate (EGCG) from tea, phloretin in apple, and [6]-shogaol and [6]-gingerol from ginger were found to be most effective in preventing MGO-induced cytotoxicity in the epithelial cells. Investigation of possible underlying mechanisms suggests that that these compounds could act by modulating key regulative detoxifying enzymes via modifying nuclear factor-erythroid 2-related factor 2 (Nrf2) function. MGO induced cytotoxicity led to increased levels of AGEs causing increase in Nepsilon (Carboxymethyl) lysine (CML) and glutathione (GSH) levels and over expression of receptor for advanced glycation end products (RAGE). Data also showed that translocation of Nrf2 from cytosol to nucleus was inhibited, which decreased the expression of detoxifying enzyme like heme oxygenase-1 (HO-1). The most potent bioactive compounds scavenged dicarbonyl compounds, inhibited AGEs formation and significantly reduced carbonyl stress by Nrf2 related pathway and restoration of HO-1 expression. CONCLUSIONS: These findings demonstrated the protective effect of bioactive compounds derived from food sources against MGO-induced carbonyl stress through activation of the Nrf2 related defense pathway, which is of significant importance for therapeutic interventions in complementary treatment/management of diabetes-related complications. PMID- 26926183 TI - Potent antihypertensive effect of Hancornia speciosa leaves extract. AB - BACKGROUND: Hancornia speciosa Gomes is an herb traditionally used in Brazil for blood pressure control. PURPOSE: The present work investigated the antihypertensive effect of an extract from Hancornia speciosa leaves (SFH) and analyzed its underlying mechanisms of action. METHODS: Hypertension was induced in mice by surgical removal of a kidney and by subcutaneous administration of a pellet with deoxycorticosterone. Vasodilatation was measured in mesenteric arteries with a wire myograph. Nitrites were measured by fluorescence with 2,3 diaminonaphthalene and H2O2 was measured with carbon microsensors. RESULTS: SFH (0.03, 0.1 or 1 mg/kg; po) induced a dose-dependent, long-lasting reduction in the systolic blood pressure in conscious DOCA-salt hypertensive mice (DOCA). Administration of SFH produced a significant increase in the plasmatic level of nitrites. The systemic inhibition of nitric oxide synthase by L-NAME (20 mg/kg) reduced its antihypertensive effect. SFH also induced a concentration-dependent vasodilatation of mesenteric resistance arteries contracted with phenylephrine, which was more potent in arteries from DOCA mice. Removal of the endothelium or pretreatment with L-NAME or catalase reduced the vasodilator response for SFH. The nitrite production induced by SFH was significantly bigger in mesenteric arteries from DOCA than in SHAM mice. However, the production of H2O2 induced by SFH was twice higher in DOCA mice. CONCLUSION: Altogether, our results point to an antihypertensive effect of SFH due to a reduction in peripheral resistance through the production of NO and by a mechanism involving an increased production of H2O2 in the mesenteric arteries from hypertensive mice. These findings are further evidence to support the use of Hancornia speciosa by traditional medicine as an antihypertensive drug. PMID- 26926184 TI - Polyphenol protection and treatment of hypertension. AB - INTRODUCTION: High blood pressure is the major risk factor for cardiovascular diseases and the rising prevalence of human hypertension precedes the trend toward a global epidemic of unhealthy ageing. A focus on lifestyle and dietary interventions minimizes dependency on pharmacological antihypertensive therapies. REVIEW: Observational studies indicate that the intake of dietary flavonoids is associated with a decreased risk of cardiovascular disease (CVD). The evidence suggests that the dietary intakes of polyphenol-rich foods, herbs and beverages including flavonols, anthocyanidins, proanthocyanidins, flavones, flavanones, isoflavones and flavan-3-ols, improves vascular health, thereby significantly reducing the risk of hypertension and CVD. Consumption is associated with an improvement in endothelial function via vascular eNOS and Akt activation. Increased NO bioavailability improves vasodilation and blood circulation, effects protein kinases, ion channels and phosphodiesterases, counteracting vascular inflammation and LDL oxidative stress. Importantly, some polyphenols also inhibit the activity of matrix metalloproteinases, inhibit angiotensin converting enzyme activity and thereby improving SBP and DSB. We review the improvement of polyphenol intake on blood pressure and endothelial function for the treatment of hypertension, including not only observational but also RCTs and pre-clinical studies. CONCLUSION: The antihypertensive phytotherapy of polyphenol-rich foods for protection and improving endothelial function with vascular relaxation occurs via the NO-cGMP pathway and ACE inhibition. OPCs stimulate endothelium-dependent vasodilation, suppress vasoconstrictor ET-1 synthesis, activate a laminar shear stress response in endothelial cells and also inhibit the activity of metalloproteinases including ACE lowering blood pressure. PMID- 26926185 TI - Self-Assembled Monolayers of Perfluoroanthracenylaminoalkane Thiolates on Gold as Potential Electron Injection Layers. AB - As a material with relatively small band gap and low lying valence orbitals, perfluoroanthracene (PFA) is of interest for the modification of electrode surfaces, for example, as charge injection layers for n-type organic semiconductors. To covalently attach PFA in the form of self-assembled monolayers (SAMs), we developed a synthesis of derivatives with a sulfur termination, linked to the 2-position of the PFA moieties by an -NH- group and a short alkane chain with two and three methylene groups, respectively. Spectroscopic characterization of the SAMs reveals that the molecules adopt an almost upright orientation on the gold surface, with the packing density mostly determined by the steric demands of the PFA units. The number of the methylene groups in the -NH-alkyl linker has only a minor impact on the SAM structure because of the nonsymmetric attachment of the PFA units, which permits the compensation of the orientational constraints imposed by the bending potential. The investigated SAMs alter the work function of gold by +(0.59-0.64) eV, suggesting comparably strong depolarization effects, affecting the extent of the work function modification. PMID- 26926186 TI - Bariatric Surgery Outcomes in Sarcopenic Obesity. AB - BACKGROUND: Sarcopenic obesity is the combination of low muscle mass and strength with increased fat mass. This condition is associated with negative health outcomes. We hypothesized that sarcopenia could be a pejorative factor on surgical weight loss. OBJECTIVE: The objectives of the study are to determine the influence of sarcopenic obesity on gastric bypass and sleeve gastrectomy results regarding weight loss and comorbidities resolution at 3, 6, and 12 months. SETTING: The study was conducted at the University Hospital. METHODS: Sixty-nine obese patients who benefited from bariatric surgery were included. Skeletal muscle mass was determined by the Janssen's equation. Physical performance and muscle strength were determined using the 6-min walk test and the wall sit test. Obese subjects from the lowest tertile of the Skeletal Muscle mass Index (SMI) of Baumgartner were set as sarcopenic. RESULTS: Weight loss outcomes and rate of weight loss failure were not influenced by sarcopenia. At 1 year, mean EBMIL% was 75.4 % +/- 5 in sarcopenic subjects vs 67.8 % +/-4 in the non-sarcopenic subjects (p = 0.242). Improvement rates of co-morbidities were similar between groups. Skeletal muscle mass was no more different between groups at 1 year after surgery. There was no patient lost to follow-up. CONCLUSIONS: Bariatric surgery remains effective in achieving weight loss target in sarcopenic patients, with similar remission rates of main comorbidities and similar safety profile than in the non-sarcopenic group. Whether bariatric surgery could result in improvement or deterioration of daily living activities disabilities and functional autonomy in sarcopenic obese patients still have to be evaluated. PMID- 26926187 TI - Effect of Gastric Bypass on Bone Mineral Density, Parathyroid Hormone and Vitamin D: 5 Years Follow-up. AB - BACKGROUND: The aim of the present study was to see if there are longitudinal changes in bone mineral density (BMD), vitamin D or parathyroid hormone (PTH) in females 5 years after Laparoscopic Roux-en-Y Gastric Bypass (LRYGB). METHODS: Thirty-two women with mean age 41.6 +/- 9.3 years and mean body mass index (BMI) 44.5 +/- 4.6 kg/m(2) were included. Preoperatively, 2 and 5 years postoperatively, BMD, weight, height, S-calcium, S-albumin, S-creatinine, S 25(OH)-vitamin D and fP-PTH were measured. RESULTS: The mean decrease in BMI between baseline and 5 years after surgery was 29.4%. BMD of the spine and femur measured as z- and t-scores, showed a linear, statistically significant declining trend over the years. The fall in BMD of the spine and femoral neck between baseline and 5 years after surgery was 19 and 25%, respectively. The mean fP-PTH showed a significant increase over the study period (20.2 MUg/L increase, 95% CI: 31.99 to -8.41). S-calcium, both free and corrected for albumin, showed a decrease between baseline and 5 years after surgery. Eight patients developed osteopenia and one osteoporosis after a 5-year follow-up. CONCLUSION: LRYGB is an efficient method for sustained long-term body weight loss. There is, however, a concomitant decrease in BMD and S-calcium, and an increase in fP-PTH. PMID- 26926188 TI - [The rise and development of general dentistry in China]. AB - General dentistry is an important part of the dental medicine and general dentists and general dentistry form the basis of clinical dental medicine. China's general dentistry has a long history, which started as an independent specialist in the 1990s. At present, the Chinese general dental medicine has received more and more attention as an independent profession. General dental medical model has been rapidly developed in the general hospital department of dentistry, private practice and community dentistry institutions, dental specialist hospitals and so on. In this paper, we will review the rise and development of China's general dentistry, and report its theoretical characteristics, institutional framework, academic progress, member development report, and look forward to its development in the future. PMID- 26926189 TI - [Technical complications rates and plaque control of fixed dental prostheses in patients treated for periodontal disease]. AB - OBJECTIVE: To compare the incidence of technical complications of implant supported fixed dental prostheses in Chinese patients with a history of moderate or severe periodontitis and periodontally healthy patients(PHP) and analyze the effects of interproximal papillae patterns on food impaction and efficacy of plaque control. METHODS: A total of 103 partially edentulous patients treated with implant-supported fixed dental prostheses between December 2009 and December 2012 for a minimum 1-year follow-up period were recruited from Department of Periodontology, Peking University, School and Hospital of Stomatology. Based on the initial periodontal examination, the participants were divided into three groups: 30 PHP, 36 moderate periodontally compromised patients(mPCP) and 37 severe periodontally compromised patients(sPCP). Implant survival/loss, technical complications, plaque index, papilla index, food impaction and degree of proximal contact tightness of each patient were assessed around the implants at follow-up. According to the implant papilla index, the implants were divided into two groups: the "filling" group with the mesial and distal aspects with papilla index=3 and the "no filling" group with at least one aspect with papilla index<3. Data on implant survival, technical complications were analyzed. Comparisons of the incidence of technical complications were performed between the patients with different periodontal conditions with chi-square or Fisher's exact test. The influences of the interproximal papillae loss on food impaction and efficacy of plaque control were estimated with chi-square and Mann-Whitney U tests. RESULTS: The total implant survival rate was 100%(162/162) for all three groups. Technical complications were as following: veneer fractures(1.9%, 3/162), abutment screw loosening(1.9%, 3/162), prosthetic screw loosening(3.1%, 5/162) and decementation(3.1%, 5/162) in all subjects. No implant/screw fracture was noted. The incidence of technical complications in sPCP, mPCP and PHP did not yield statistically significant differences(P>0.05). The proportion of the implant with the mesial and distal papilla index=3 in the sPCP was less than that in the PHP and mPCP. The interproximal papillae loss did not appear to affect the food impaction and the plaque index in all three groups(P>0.05). However, for the PHP, the accumulation of plaque at buccal aspect was more in the "no filling" group compared with the "filling" group (implant plaque index[M(Q)]: 1[1] vs 0[0]), and for the sPCP, the accumulation of plaque at lingual aspect was more in the "filling" group compared with the "no filling" group(implant plaque index[M(Q)]: 1[1] vs 0[1], (P<0.05). CONCLUSIONS: The patients with a history of severe periodontitis did not exhibit more technical problems compared with the periodontally healthy patients. The interproximal papillae loss did not show a negative impact on the plaque control and food impaction. However, for the sPCP, changing the morphology and the position of the interproximal contact point to reduce the interdental black triangle may lead to accumulation of plaque at lingual aspect. More attention should be placed on the morphology design of prosthesis, but not the papillae filling up the interproximal space. PMID- 26926190 TI - [Four year's clinical evaluation of glass fiber reinforced resin-bonded fixed partial denture as a periodontal splint to replace lost anterior teeth]. AB - OBJECTIVE: To evaluate the clinical performance of glass fiber reinforced resin bonded fixed partial denture(GFR-RBFPD) as a periodontal splint on abutment teeth with reduced periodontal support. METHODS: Thirty fixed-fixed GFR-RBFPD were delivered to restore anterior partial edentulous dentitions. The adjacent abutment teeth had severely reduced periodontal support and were not indicated for full crown retained FPD. The success rate and functional survival rate had been recorded and the periodontal condition had been evaluated for 4 years. The results were statistically analyzed with single factor variance analysis and chi square test(alpha=0.05). RESULTS: In the first, second, and third year following restoration, one connector fractured in each year and they were repaired with adhesive resin and the pontics were kept in place for function. In the third and fourth years after restoration, there was one pontic displacement with fracture of connectors. The total survive rate was 83%(25/30) and the functional survival rate was 93% (28/30) at the end of the fourth year. The main reason of failure was fracture of connector. About 22%(13/60) of the adjacent teeth showed marginal bone height decrease, while the other 78% (47/60) increased with statistic significant difference from one year after the restoration to the end of the observation term(P<0.05). The periodontal condition of the adjacent teeth was improved after the restoration. CONCLUSIONS: The four years clinical evaluation indicates that the GFR-RBFPD may be used as fixed prostheses to replace lost one to three anterior teeth with reduced periodontal support of abutment teeth. PMID- 26926191 TI - [Effect of extracellular DNA on the formation of Streptococcus mutans biofilm under sucrose environment]. AB - OBJECTIVE: To study the effect of extracellular DNA(eDNA) on the formation of Streptococcus mutans(Sm) biofilms during different growth periods in sucrose environment. METHODS: Sm biofilms were established on smooth glass surfaces under the environment of 1% sucrose and cultured in the condition of 37 C, 5% O2, 85% N2 and 10% CO2. Samples were randomly divided into four groups based on fourculture time(6,12, 24 and 48 h), respectively. Each group was further divided into two subgroups: control group(without deoxyribonuclease I[DNaseI] treatment) and test group(with DNaseItreatment). DNaseI was added 1 h advance in the treatment group to a final concentration of 100 U/ml. Each sample was stained with mixed SYTO-9/PI fluorescent dye. Confocal laser scanning microscopy was used for biofilm observation and scanning. The total biomass, the thickness and the volume of red fluorescence of each biofilm sample were measured following three dimensional reconstruction using the softwear of Imaris 7.2.3. RESULTS: Under the environment of 1% sucrose, the Sm bacterial adhesion and distribution density increased over time, the quantity of eDNA and membrane-damaged bacteria which were indicated by red fluorescence also increased within 24 h but dropped later. The biofilm biomasses of Sm biofilm in 6, 12, 24 and 48 h DNaseI treatment group reduced significantly(P<0.05) compared to those in the corresponding control groups by 81.3%, 85.0%, 90.1% and 12.4%, respectively. The biofilm thicknesses in each DNase I treatment group (except 6 h group) also reduced significantly(P<0.05) compared to those in the corresponding control group by 34.4%, 45.6% and 23.6%, respectively. The quantities of eDNA and membrane-damaged bacteria reduced in each treatment group except 48 h group compared to that in the corresponding control group. CONCLUSIONS: Under the environment of 1% sucrose, eDNA plays an important role in promoting the formation of Sm biofilm. PMID- 26926192 TI - [The expression of serine protease HtrA1 in human periodontal ligament tissue and the effect of HtrA1 on the proliferation of human periodontal ligament cells]. AB - OBJECTIVE: To observe the expression of serine protease HtrA1 in human periodontal ligament tissue and to explore the effect of HtrA1 on the proliferation of human periodontal ligament cells (hPDLC). METHODS: Six human premolars and three human third molars(patient's ages ranging from 12 to 25, with intact root, without caries and/or periodontitis) were obtained in the Department of Maxillofacial Surgery of Wuhan University Hospital of Stomatology. Reverse transcription-PCR(RT-PCR) and immunohistochemistry analysis were applied to investigate the expression of HtrA1. Primary hPDLC were obtained by tissue culture method in vitro. The proliferation of hPDLC was determined by methyl thiazolytetrazolium(MTT). Lentivirus-mediated over-expression and reduction of HtrA1 level was performed. An empty vector was used as negative control. On days 1, 3, 5, 7 and 9, the growth of hPDLC was characterized using cell counting kit 8(CCK-8) assay. RESULTS: RT-PCR data indicated that HtrA1 mRNA was expressed in human periodontal ligament tissue. Immunohistochemistry analysis showed HtrA1 was expressed in human periodontal ligament, mainly in the cytoplasm of hPDLC and the extracellular matrix. The MTT result suggested that the growth curve was consistent with the growth characteristics of hPDLC. The stable over-expression and knockdown cell lines was successfully established by lentivirus with more than 90% transfection efficiency. CCK-8 assay showed that HtrA1 over-expression inhibited the proliferation of hPDLC(0.897+/-0.060, 0.890+/-0.083, 1.631+/-0.038, 1.111+/-0.041, 1.110+/-0.189), while cell proliferation increased after down regulation of HtrA1(0.329+/-0.021, 0.529+/-0.044, 0.973+/-0.056, 1.626+/-0.102, 2.344+/-0.198)(P<0.05). CONCLUSIONS: HtrA1 is expressed in human periodontal ligament tissue at both mRNA and protein levels, and may play an important role in regulating the proliferation of hPDLC. PMID- 26926193 TI - [Effect of base layer thickness of a self-adhesive resin on dentin bonding strength]. AB - OBJECTIVE: To evaluate the effect of base layer thickness of DyadFlow(DF) self adhesive resin on dentin bonding strength. METHODS: Twenty extracted intact human molars were randomly selected and the occlusal surface of each molar was prepared by removing the enamel and exposing the dentin surface. The prepared molars were divided, randomly and equally, into 4 groups. For groups G0.5, G1.0 and G2.0, DF was applied directly on the dentin surfaces following the manufacturer's instruction, and for group GOB, OptiBond All-in-One(OB) self etching adhesive was applied on the dentin surface before using DF. The base layer thickness of DF was 0.5 mm, 1.0 mm, 2.0 mm, 2.0 mm for groups G0.5, G1.0, G2.0 and GOB, respectively. Composite crown were built up on each tooth, then the samples were sectioned longitudinally into sticks with proximately 1.0 mm2 bonding area(for microtensile bond strength[MTBS] testing) or slabs (for bonding interface observation with SEM). Fifteen sticks were obtained for each group. The fracture surface was also observed using SEM and the fracture type of each specimen was determined. RESULTS: The MTBS were: GOB (20.19+/-3.11) MPa>G0.5 (8.65+/-1.58) MPa>G1.0 (6.65+/-1.13) MPa>G2.0 (5.70+/-0.60) MPa(P<0.05). Bonding interface fracture B2 was most frequently observed for all groups: G0.5: 14/15, G1.0: 13/15, G2.0: 14/15 and GOB: 13/15. CONCLUSIONS: The MTBS decreased when the base layer thickness of DF increased. Direct application of DF self-adhesive resin on dentin surface adhesive restorations should be concerned. PMID- 26926195 TI - [Expression of osterix gene in the early stage of cranio-maxillofacial development in zebrafish]. AB - OBJECTIVE: To investigate the expression patterns of osterix in the early stage of cranio-maxillofacial developmental in zebrafish and to prepare for a further research of osterix gene in bone and tooth development. METHODS: The osterix templates were amplified by PCR to generate DIG labeled antisense and sense probes. Whole mount in situ hybridization was used to analyze the expression patterns of osterix in the early stage cranio-maxillofacial development of zebrafish. The expression patterns of osterix gene in mineralization progresses of cranial and maxillofacial bones were compared. The osterix gene expression in tooth development and mineralization was highlighted by alizarin red staining. RESULTS: Specific DIG labeled probes of osterixwere synthesized successfully. The whole mount in situ hybridization showed that the osterix expression was in the intramembranous ossification at 3 days post fertilization(dpf) and 4 dpf. The specific osterix expression in tooth at 5 dpf and 6 dpf were also observed. The sense probe served as a negative control. Osterix expressed in the unmineralized early bone matrix, the tooth matrix of the primary tooth(3V(1), 5V(1)) and the first replacement tooth(4V(2)). CONCLUSIONS: Our findings showed that osterix might play roles in the process of the early mineralized bone matrix changing into the late mature mineralized bone matrix and the process of development and mineralization of tooth crown matrix. PMID- 26926194 TI - [Study on bone regeneration with two different ratios of nano-hydroxyapatite and collagen grafts after tooth extraction in dogs]. AB - OBJECTIVE: To compare the effect of bone regeneration with two different ratios of nano-hydroxyapatite(nHA)/collagen(Col) (nHAC) after tooth extraction in canine. METHODS: Two kinds of nHAC grafts were prepared with different nHA/collagen ratio of 3?7 and 5?5. Eighteen male healthy adult dogs had been randomly divided into three groups. Immediately after extraction of the mandibular second premolars, each kind of nHAC was implanted into extraction sockets as follow: Group A, nHA/Col=3?7(12 sites); Group B, nHA/Col=5?5(12 sites); Group C, blank control group(12 sites). The bone repairing abilities of the two grafts such as vertical distance of alveolar, CT values, general observation, histological observation, trabecular volume fraction and porosity were separately analyzed at 1st, 3rd and 6th month, respectively (each group had 4 sites in different time periods). RESULTS: nHAC were absorbed gradually after they were implanted into alveolar bone defect and were replaced by new bone. The vertical distance of alveolar bone in Group A([15.76+/-0.28] mm) was significant higher than that in Group B([14.88+/-0.36] mm), and CT values of Group A([879+/ 31] HU) were higher than those in Group B([718+/-29] HU) (P<0.05). The trabecular bone volume percentage of Group A([22.2+/-0.4]%) was higher than that in Group B([20.3+/-0.4]%), and the bone porosity of Group A([23.6+/-0.9]%) was lower than that in Group B([27.6+/-0.6]%) (P<0.05). In addition, the vertical distance, CT values and the trabecular bone volume percentage of Group C was lower than those in Group A and B, but the bone porosity of Group C was higher. CONCLUSIONS: The nHAC with nHA/collagen ratio of 3?7 could better promote bone regeneration than nHAC with the nHA/collagen ratio of 5?5 did. PMID- 26926196 TI - [Study on biomimetic mineralization of lipopolysaccharide-amine nanopolymersomes/hyaluronic acid polyelectrolyte films on titanium surface]. AB - OBJECTIVE: To explore biomimetic mineralization of polyelectrolyte multilayer films (PEM) of gene-loaded lipopolysaccharide-amine nanopolymersomes/hyaluronic acid self assembled on titanium surface. METHODS: Via lay-by-layer self assembly technology, PEM were constructed on titanium or quartz surface using bone morphogenetic protein-2(BMP-2) plasmid-loaded lipopolysaccharide-amine nanopolymersomes(pLNP) as a polycation, and hyaluronic acid(HA) as a polyanion. The constructed PEM were defined as substrate-pLNP-(HA-pLNP)n, where a successive deposition of HA and pLNP on substrate surface was defined as one assembly cycle, and n was the cycle number. Biomimetic mineralization on surfaces of Ti-pLNP-(HA pLNP)4(Group A, with outermost layer of pLNP), Ti-pLNP-(HA-pLNP)4.5(Group B, with outermost layer of HA), blank control(polished titanium, Ti) and alkaline-heat treated titanium(Ti-OH) were investigated. The biomimetic mineralization was analyzed by observing the topography under field-emisssion electron microscopy(FE SEM), characterizing the surface chemical structure and components via X-ray diffractometer(XRD) and X-ray energy disperse spectroscopy(EDS). RESULTS: For experiment groups, XRD analysis showed that the diffraction peak of hydroxyapatite appeared, and its intensity was higher than that for Ti group. FE SEM images showed that its surface was homogeneously covered by discrete agglomerate of big particles. EDS spectra showed that the percentage of Ca and P were 77.24% and 64.23%, and these were much higher than those in Ti group. CONCLUSIONS: The surface of Ti-pLNP-(HA-pLNP)n is favorable for in vitro biomimetic mineralization. PMID- 26926197 TI - [A review of the effect of tooth bleaching agents on oral microbes]. AB - Tooth bleaching agents contain powerful oxidizing agents, which serve as the main part of bleaching agents because of its release of effective bleaching component. It has been a hot topic whether tooth bleaching agents exert negative influence on oral health. In order to provide train of thoughts and reference for further clinical researches and treatments, this review paper focuses on bleaching agents' effects on the growth of oral microbes and the formation of biofilms. PMID- 26926198 TI - [An overview on rubber dam application in dental treatments]. AB - Rubber dam technique is the a method used in dentistry to isolate the operation field from the rest of mouth with rubber sheet. Rubber dam can protect both patients and dental workers effectively and provide patients with more professional, safe and comfortable experience. In recent years, this technique has gradually gained more and more recognition by dentists. However, the prevalence of using rubber dam technique in our country is still relatively low compared with those in developed countries. This condition involves many factors and need to be paid enough attention. This review summarized the current situation of rubber dam usage in various countries, the technique's application field, the effect analysis, the influencing factors and the modified products. PMID- 26926199 TI - [Multi-source data acquisition technology in the restoration of the complete denture restoration]. AB - In complete-denture restoration of edentulous jaws, the following information is needed: functional impression of edentulous jaws, jaw relationship and facial fullness, parameters of individual mandibular movement, etc. Traditional clinical methods in obtaining these data, which depend greatly on practitioners' clinical experience and skills, are subjective, complicated and low efficient. With the development of the digital restoration of edentulous jaws, a variety of equipment for three-dimensional scan have been applied in acquiring three-dimensional source data concerning the needed information, which greatly simplifies the process of data obtaining, reduces the dependence on operational skills and subjective experience, improves efficiency and efficacy of diagnosis and treatment, and standardizes the restoration process. PMID- 26926200 TI - New functional biocarriers for enhancing the performance of a hybrid moving bed biofilm reactor-membrane bioreactor system. AB - In this study, new sponge modified plastic carriers for moving bed biofilm reactor (MBBR) was developed. The performance and membrane fouling behavior of a hybrid MBBR-membrane bioreactor (MBBR-MBR) system were also evaluated. Comparing to the MBBR with plastic carriers (MBBR), the MBBR with sponge modified biocarriers (S-MBBR) showed better effluent quality and enhanced nutrient removal at HRTs of 12h and 6h. Regarding fouling issue of the hybrid systems, soluble microbial products (SMP) of the MBR unit greatly influenced membrane fouling. The sponge modified biocarriers could lower the levels of SMP in mixed liquor and extracellular polymeric substances in activated sludge, thereby mitigating cake layer and pore blocking resistances of the membrane. The reduced SMP and biopolymer clusters in membrane cake layer were also observed. The results demonstrated that the sponge modified biocarriers were capable of improving overall MBBR performance and substantially alleviated membrane fouling of the subsequent MBR unit. PMID- 26926201 TI - Investigating the morphology and reactivity of chars from Triplochiton scleroxylon pyrolysed under varied conditions. AB - A gasifier may be optimised via a good understanding of the char formation, morphology and reactivity. The effects of varying the pyrolysis pressure and heating rate on the morphology of the char were investigated using a thermogravimetric analyser (TGA), scanning electron microscope (SEM) and micrograph spot analyser. The gasified chars were produced at heating rates of 5, 10 and 20 degrees C/min and pressures of 0.1, 0.4 and 0.6 MPa. All the chars have different degrees of apparent gasification reactivity. The random pore model (RPM) provided a better description of the experiment, with low average error values, theta, in all of the cases considered. The alkaline and alkaline earth metals (AAEM) in the tropical wood biomass Arere (Triplochiton scleroxylon) consist predominantly of calcium and could altogether be partly responsible for the noticeably high reactivity nature of the tropical Arere chars. PMID- 26926202 TI - Life cycle assessment of advanced bioethanol production from pulp and paper sludge. AB - This work evaluates the environmental performance of using pulp and paper sludge as feedstock for the production of second generation ethanol. An ethanol plant for converting 5400 tons of dry sludge/year was modelled and evaluated using a cradle-to-gate life cycle assessment approach. The sludge is a burden for pulp and paper mills that is mainly disposed in landfilling. The studied system allows for the valorisation of the waste, which due to its high polysaccharide content is a valuable feedstock for bioethanol production. Eleven impact categories were analysed and the results showed that enzymatic hydrolysis and neutralisation of the CaCO3 are the environmental hotspots of the system contributing up to 85% to the overall impacts. Two optimisation scenarios were evaluated: (1) using a reduced HCl amount in the neutralisation stage and (2) co-fermentation of xylose and glucose, for maximal ethanol yield. Both scenarios displayed significant environmental impact improvements. PMID- 26926203 TI - Intensive treadmill training in the acute phase after ischemic stroke. AB - The aim of the study was to (a) assess the feasibility of intensive treadmill training in patients with acute ischemic stroke, (b) test whether physical activity of the legs during training increases with time, and (c) evaluate to what extent training sessions contribute toward the overall physical activity of these patients. Twenty hospitalized patients with acute ischemic stroke trained on a treadmill twice daily for 30 min for 5 days and on day 30. Physical activity was measured as activity counts (AC) from accelerometers. A total of 196 of 224 initiated training sessions were completed. Training started 41.5+/-14 h after symptom onset. Only nonserious adverse events occurred in 14.7% of the sessions. An intensity of at least 50% of the individual heart rate reserve was obtained in 31% of training sessions. There was a significant increase in AC/min in the legs during training sessions with increasing number of days, with the median AC being 133% higher on day 5 than on day 1. AC in the paretic leg during 60 min of training constituted median 53% of the daytime AC. Early intensive treadmill training in acute ischemic stroke patients is thus feasible and contributes considerably toward the patients' overall physical activity. PMID- 26926204 TI - Radiolabeling of DNA Bipyramid and Preliminary Biological Evaluation in Mice. AB - Self-assembled DNA nanostructures, as a new type of nanocarriers, have shown great potential in molecular imaging probes. DNA bipyramid nanostructures (DBNs), as a classic kind of DNA nanostructure, can be precisely constructed through the unparalleled base-pairing precision of oligonucleotide strands. DBNs were prepared by self-assembly of six oligonucleotides with equal molar amounts in a single annealing step, and purified by high performance liquid chromatography (HPLC). DBNs were stable in 10% FBS as well as 80% mouse serum for at least 8 h. To prepare (99m)Tc-labeled DBNs, N-hydroxysuccinimidyl S-acetylmercaptoacetyl triglycinate (Sacetyl-MAG3-NHS ester) tagged single-stranded DNA (ssDNA) was first radiolabeled with Tc-99m, and DBNs with an overhang were assembled and then hybridized with (99m)Tc-ssDNA to prepare (99m)Tc-labeled DNA bipyramid nanostructures ((99m)Tc-MAG3-DBNs). DBNs were radiolabeled, with the radiochemical purity being over 90%. The plasma half-life of (99m)Tc-MAG3-DBNs in normal KM mice was about 6 min. The biodistribution and SPECT/CT imaging were conducted with (99m)Tc-MAG3-DBNs in KM mice, and both showed that (99m)Tc-MAG3 DBNs mainly concentrated in the intestine, liver, and kidneys, and there was also prominent uptake in the gallbladder and bladder. We successfully obtained a new class of SPECT molecular probes based on this DNA polyhedron structure. PMID- 26926207 TI - Congenital diaphragmatic hernia - the past 25 (or so) years. PMID- 26926205 TI - Metabolic Syndrome and the Risk of Mild Cognitive Impairment and Progression to Dementia: Follow-up of the Singapore Longitudinal Ageing Study Cohort. AB - IMPORTANCE: The association of the metabolic syndrome (MetS) and component cardiovascular risk factors with the risk of developing mild cognitive impairment (MCI) and MCI progression to dementia is not well established. OBJECTIVE: To investigate the association of the MetS and its component cardiovascular risk factors with the incidence of MCI and its progression to dementia. DESIGN, SETTING, AND PARTICIPANTS: Prospective longitudinal study from September 1, 2003, through December 31, 2009, in communities in 5 districts in the South East region of Singapore. Study participants were a population-based sample of 1519 cognitively normal adults 55 years and older. MAIN OUTCOMES AND MEASURES: Prespecified outcomes were incident MCI and MCI progression to dementia. RESULTS: The study cohort comprised 1519 participants. Their mean (SD) age was 64.9 (6.8) years, and 64.8% (n = 984) were female. Baseline characteristics associated with an increased risk of incident MCI were MetS (hazard ratio [HR], 1.46; 95% CI, 1.02-2.09), central obesity (HR, 1.41; 95% CI, 1.01-1.98), diabetes mellitus (HR, 2.84; 95% CI, 1.92-4.19), dyslipidemia (HR, 1.48; 95% CI, 1.01-2.15), and 3 or more component cardiovascular risk factors (HR, 1.58; 95% CI, 1.13-2.33). Baseline characteristics associated with an increased risk of MCI progression to dementia were MetS (HR, 4.25; 95% CI, 1.29-14.00), diabetes mellitus (HR, 2.47; 95% CI, 1.92-4.19), and 3 or more component cardiovascular risk factors (HR, 4.92; 95% CI, 1.39-17.4). CONCLUSIONS AND RELEVANCE: The MetS was associated with an increased incidence of MCI and progression to dementia. Identifying individuals with diabetes mellitus or the MetS with or without MCI is a promising approach in early interventions to prevent or slow progression to dementia. PMID- 26926206 TI - ATP11C targets basolateral bile salt transporter proteins in mouse central hepatocytes. AB - ATP11C is a homolog of ATP8B1, both of which catalyze the transport of phospholipids in biological membranes. Mutations in ATP8B1 cause progressive familial intrahepatic cholestasis type1 in humans, which is characterized by a canalicular cholestasis. Mice deficient in ATP11C are characterized by a conjugated hyperbilirubinemia and an unconjugated hypercholanemia. Here, we have studied the hypothesis that ATP11C deficiency interferes with basolateral uptake of unconjugated bile salts, a process mediated by organic anion-transporting polypeptide (OATP) 1B2. ATP11C localized to the basolateral membrane of central hepatocytes in the liver lobule of control mice. In ATP11C-deficient mice, plasma total bilirubin levels were 6-fold increased, compared to control, of which ~65% was conjugated and ~35% unconjugated. Plasma total bile salts were 10-fold increased and were mostly present as unconjugated species. Functional studies in ATP11C-deficient mice indicated that hepatic uptake of unconjugated bile salts was strongly impaired whereas uptake of conjugated bile salts was unaffected. Western blotting and immunofluorescence analysis demonstrated near absence of basolateral bile salt uptake transporters OATP1B2, OATP1A1, OATP1A4, and Na(+) taurocholate-cotransporting polypeptide only in central hepatocytes of ATP11C deficient liver. In vivo application of the proteasome inhibitor, bortezomib, partially restored expression of these proteins, but not their localization. Furthermore, we observed post-translational down-regulation of ATP11C protein in livers from cholestatic mice, which coincided with reduced OATP1B2 levels. CONCLUSIONS: ATP11C is essential for basolateral membrane localization of multiple bile salt transport proteins in central hepatocytes and may act as a gatekeeper to prevent hepatic bile salt overload. Conjugated hyperbilirubinemia and unconjugated hypercholanemia and loss of OATP expression in ATP11C-deficient liver strongly resemble the characteristics of Rotor syndrome, suggesting that mutations in ATP11C can predispose to Rotor syndrome. (Hepatology 2016;64:161 174). PMID- 26926208 TI - Avoiding postoperative malposition of upper body tunneled central venous catheters in children: Evaluating technique and depth of placement. AB - BACKGROUND: Suboptimal position of tunneled central venous catheters (Broviacs) decreases long-term catheter longevity, incurring morbidity and cost. We postulated that catheter malposition is related to patient's age, technique used, and initial catheter tip location (CTL). METHODS: We performed a retrospective review with 1-year follow-up of Broviacs placed in patients at our children's hospital from 3/2010 to 10/2013. We defined malposition as a noncentral CTL that required replacement, excluding catheters physically dislodged. We used logistic regression to determine whether age, technique and CTL predicted malposition with p-value<0.05 deemed significant. We analyzed line longevity for different insertion techniques by survival analysis. RESULTS: Overall, 404 upper body Broviacs were placed in 282 children (median age=1.4years [IQR:0.45-5.35]). Thirty-six (8.9%) were replaced for malposition, at median of 84.5days [IQR:36 159]. We found that older children were less likely to develop malposition (OR=0.91,p=0.002). Adjusting for patient age and placement technique, catheters placed >=1.5 vertebral bodies below the carina were less likely to be malpositioned (OR=0.37,p=0.015). Cox-regression shows the lateral technique to have the lowest rate of malposition within 90days (HR=0.30,p=0.03). CONCLUSION: Older patients and lines placed 1.5 vertebral bodies below the carina are less likely to become malpositioned. Using the lateral approach for insertion improves catheter longevity. PMID- 26926209 TI - Tuning the magnetic phase of a graphene nanodot using its dielectric environment. AB - The magnetic properties of a hexagonal graphene nanodot are investigated using a configuration-interaction approach. The phase diagram of the nanodot system is obtained for a wide range of Coulomb interaction strengths and dielectric environments, and shows that the magnetic phase transition can be effectively tailored by changing the dielectric environment. Selective magnetic phase between non-magnetic and ferromagnetic could therefore be achieved simply by changing to an appropriate substrate for the graphene nanodot. PMID- 26926211 TI - Big Data. PMID- 26926210 TI - Synthesis of Nitro-Containing Compounds through Multistep Continuous Flow with Heterogeneous Catalysts. AB - Synthesis of beta-nitrostyrene derivatives and their following reactions through two-step continuous-flow protocols with heterogeneous catalysts are described. In the first step to provide beta-nitrostyrenes from aromatic aldehydes and nitromethane, readily available amino-functionalized silica gel was employed as a catalyst and gave the products continuously for at least 100 h with high selectivity. In the second step, reactions of beta-nitrostyrenes, solid bases, immobilized bases, solid acids, and chiral supported metals and nonmetals were used as catalysts, and seven kinds of nitro-containing organic compounds could be effectively synthesized through the two-step continuous-flow systems. PMID- 26926212 TI - Critical Reflection in Cultural Competence Development: A Framework for Undergraduate Nursing Education. AB - BACKGROUND: Nursing faculties are urged to adopt a curriculum that supports culturally competent care and to mentor students to provide care that promotes social justice, particularly for the marginalized members of society. This article describes the development of a framework for critical reflection in cultural competence development among undergraduate nursing students. METHOD: Following the Medical Research Council guidelines for developing complex interventions, empirical and theoretical literature was reviewed to define the framework rationale and its components. RESULTS: The resulting framework is grounded in Blanchet Garneau's constructivist model of cultural competence development and Mezirow's transformative learning theory. It clarifies the desired outcomes, the main steps to foster critical reflection among students, and the contextual conditions and prerequisites for teachers and learners. CONCLUSION: Education oriented toward critical reflective practice promotes a full reflection about Western social and clinical practices and points out the role of nurses in reducing health inequities. PMID- 26926213 TI - Stimulating Research Interest and Ambitions in Undergraduate Nursing Students: The Research-Doctorate Pipeline Initiative. AB - BACKGROUND: Innovative strategies may support the Institute of Medicine's recommendation to increase the number of doctorally prepared nurses by 50% by 2020. Moreover, strategies implemented may increase the number and diversity of Doctor of Philosophy (PhD)-prepared nurses in particular. METHOD: The purpose of this article is to describe the approaches used by one college of nursing to enact a research-doctorate pipeline initiative to inspire a diverse pool of undergraduate students to consider pursuing a PhD degree. Principles that served as the foundation for this pipeline initiative are identified. RESULTS: Sixteen undergraduate students, with varying degrees of research interest, participated in this initiative. Students contributed an average of 35 hours as full members of research teams, and 94% completed the experience. Students with initial low interest in research reported enhanced interest after participation. Overall student experiences were positive and influenced future career plans. CONCLUSION: Lessons learned and future steps for the pipeline initiative are presented. PMID- 26926214 TI - An Integrative Review of Peer Mentorship Programs for Undergraduate Nursing Students. AB - BACKGROUND: The purpose of this integrative review was to appraise and synthesize the evidence for the design, implementation, and evaluation of peer mentorship programs for undergraduate nursing students and to provide recommendations for future undergraduate nursing peer mentorship programs. METHOD: Using an integrative review methodology, quantitative, qualitative, and mixed-methods studies were searched using six electronic databases. Studies were screened, assessed for eligibility, and appraised with critical appraisal tools. Data were extracted and synthesized using thematic analysis. Eleven studies were included in the integrative review. RESULTS: Appraisal demonstrated overall poor methodology. All programs were designed based on a perceived need expressed by faculty and students and involved a multistep process of implementation. Positive outcomes for nursing students were found through the use of peer mentorship programs; however, various challenges to program success were identified. CONCLUSION: This review provides evidence that can be used to inform the design, implementation, and evaluation of future peer mentorship programs. PMID- 26926215 TI - Preceptors' Experience of Nursing Service-Learning Projects. AB - BACKGROUND: Service-learning is a teaching-learning strategy in higher education that provides hands-on experiences in authentic clinical environments. Mutual decision making, shared goals, reciprocity, and tangible benefits to organizations and the people they serve are hallmarks of service-learning. However, the literature is sparse pertaining to preceptor experiences with service-learning projects, the extent of reciprocity, or the projects' impact on those who received the service. METHOD: A small phenomenological study was conducted to better understand the experiences of four community-based health professionals who worked with nursing students on service-learning projects. RESULTS: Four themes emerged from face-to-face interviews and written reflections: (a) reciprocity among preceptor, clinical faculty, and student, (b) intentional planning and project clarity, (c) meaningful and authentic experience, and (d) valued and beneficial contributions that addressed a need. CONCLUSION: Insight gained from the experiences of the four preceptors in this study suggest that through careful planning and reciprocity, service-learning can have a positive impact on community-based organizations and the people they serve. PMID- 26926216 TI - Increasing the Cultural Competence Levels of Undergraduate Nursing Students. AB - BACKGROUND: This study evaluated the effectiveness of the Culturally Competent Nursing Modules (CCNMs) developed by the U.S. Office of Minority Health on improving the cultural competence levels of undergraduate nursing students. METHOD: Students completed the CCNMs over a 2-week period, and their pre- and posttraining cultural competence was assessed using the Inventory for Assessing the Process of Cultural Competence Among Healthcare Professionals-Revised tool. RESULTS: The CCNMs were effective in increasing the cultural competence of the nursing students (pretest mean = 68.44 +/- 6.58; posttest mean = 79.06 +/- 7.99; t(17) = 7.44; d = 10.61; 95% confidence interval = 7.60, 13.62; p < .001). Before training, 89% of the students were culturally aware and 11% were culturally competent. After training, 22%, 67%, and 11% were culturally aware, culturally competent, and culturally proficient, respectively. CONCLUSION: The CCNMs training program is effective and should be incorporated into nursing curricula. PMID- 26926217 TI - Critical Aspects of Stress in a High-Stakes Testing Environment: A Phenomenographical Approach. AB - BACKGROUND: A high-stakes examination is any examination used for tracking or determining promotion or graduation. Therefore, when used as a basis for progression or graduation in nursing, standardized examinations become high stakes for students. High-stakes testing in nursing is a focal stimulus that has been shown to contribute to the negative consequences associated with stress. The adverse effects of stress have the potential to result in unhealthy coping behaviors such as isolation, withdrawal, decreased motivation, and decreased self efficacy. METHOD: Phenomenography was used to capture the various ways in which students experience stress. RESULTS: Six major categories of description emerged. All students experienced stress in relation to high-stakes testing. However, student interviews revealed that students experienced the stress in myriad ways, ranging from fear of not graduating to social isolation and withdrawal. CONCLUSION: Although it is known that high-stakes testing contributes to the development of stress, this study provides evidence of the need for nursing programs to consider the implementation of supportive measures as a means to mitigate student stress and foster student success. PMID- 26926218 TI - Social Change: A Framework for Inclusive Leadership Development in Nursing Education. AB - BACKGROUND: The social change model (SCM) promotes equity, social justice, self knowledge, service, and collaboration. It is a relevant framework for extracurricular leadership development programs that target students who may not self-identify as leaders. METHOD: Application of the SCM in a leadership development program for prelicensure nursing students from underresourced or underrepresented backgrounds is described. Students' opinions about leadership for social change were explored through a focus group and a pilot test of an instrument designed to assess the values of the SCM. RESULTS: Students lack the experience required to feel comfortable with change, but they come into nursing with a sense of commitment that can be nurtured toward leadership for social change and health equity through best practices derived from the SCM. These include sociocultural conversations, mentoring relationships, community service, and membership in off-campus organizations. CONCLUSION: Nurse educators can cultivate inclusive leadership for social change using the SCM as a guide. PMID- 26926219 TI - "Won't You Be My Patient?": Preparing Theater Students as Standardized Patients. AB - BACKGROUND: Simulation in nursing education is a well-supported teaching strategy. High-fidelity manikins provide students with an opportunity to practice nursing care in a safe environment. Yet, limitations such as lack of realism and inability to practice therapeutic communication have been reported. However, standardized patients (SPs)--actors trained to portray patients with medical issues--provide students with realistic patient situations and opportunities to develop essential skills. METHOD: A literature review identified barriers to utilizing SP-based simulations. Issues such as financial, human resource, and quality control concerns were identified. RESULTS: Based on identified barriers, an innovative, interdisciplinary course to prepare theater students to portray patients for simulations is proposed. This proposed course could potentially eliminate identified barriers and increase use of SPs. CONCLUSION: Because this is a proposed course, the authors recommend testing of the innovation to determine the effectiveness for both nursing and theater students. PMID- 26926220 TI - Storytelling: A Guided Reflection Activity. AB - BACKGROUND: Reflective practice is a mode of inquiry in the authors' baccalaureate nursing program. To increase students' ability to "think like a nurse," the Reflective Practice Storytelling Guide was developed to facilitate discussion during weekly clinical seminars in the students' final clinical course. METHOD: To evaluate the effectiveness of this guided activity, students were asked to provide feedback to specific questions following each seminar when the reflective presence activity was utilized. RESULTS: Common themes emerged from the storytellers and the members of the group. Themes identified in the responses of the storytellers included role development and formation and the value of team support. Learning themes that emerged from the participants included communication, teamwork, clinical judgment, patient-centered care, use of resources, ethical and legal parameters in practice, and patient safety. CONCLUSION: Utilizing a guided reflection activity resulted in the students experiencing a broader, deeper understanding of reflective professional practice. PMID- 26926221 TI - Strategies for Building Advocacy Skills Among Undergraduate and Graduate Nursing Students. AB - BACKGROUND: Nursing faculty are challenged to create learning experiences that both reflect the complexities of the current health care system and are relevant. Experiential learning opportunities should promote engagement in health care that extends beyond direct patient care to advocacy in larger systems. METHOD: To meet this challenge, faculty developed course assignments for students at baccalaureate, master's, and doctoral levels in which students worked with state Action Coalitions to implement the Institute of Medicine Future of Nursing report's eight recommendations. With faculty guidance, student teams developed and implemented projects or conducted research to assist the coalitions in their grassroots initiatives. RESULTS: Students at all program levels reported high levels of satisfaction and engagement with these unique projects. Students reported understanding the importance of the Future of Nursing recommendations and intended to continue participating in statewide initiatives. CONCLUSION: Experiential learning opportunities at all program levels can engage students in learning more about advocacy, health care trends, and leadership. PMID- 26926222 TI - Use of the Knowledge Tree as a Mind Map in a Gerontological Course for Undergraduate Nursing Students. PMID- 26926223 TI - Improving Class Discussion for an Evidence-Based Practice Course. PMID- 26926224 TI - Typical fast thermalization processes in closed many-body systems. AB - The lack of knowledge about the detailed many-particle motion on the microscopic scale is a key issue in any theoretical description of a macroscopic experiment. For systems at or close to thermal equilibrium, statistical mechanics provides a very successful general framework to cope with this problem. However, far from equilibrium, only very few quantitative and comparably universal results are known. Here a quantum mechanical prediction of this type is derived and verified against various experimental and numerical data from the literature. It quantitatively describes the entire temporal relaxation towards thermal equilibrium for a large class (in a mathematically precisely defined sense) of closed many-body systems, whose initial state may be arbitrarily far from equilibrium. PMID- 26926226 TI - How can we optimize the use of prostate cancer registries? PMID- 26926225 TI - Epigenetic modification of PKMzeta rescues aging-related cognitive impairment. AB - Cognition is impacted by aging. However, the mechanisms that underlie aging associated cognitive impairment are unclear. Here we showed that cognitive decline in aged rats was associated with changes in DNA methylation of protein kinase Mzeta (PKMzeta) in the prelimbic cortex (PrL). PKMzeta is a crucial molecule involved in the maintenance of long-term memory. Using different behavioral models, we confirmed that aged rats exhibited cognitive impairment in memory retention test 24 h after training, and overexpression of PKMzeta in the PrL rescued cognitive impairment in aged rats. After fear conditioning, the protein levels of PKMzeta and the membrane expression of GluR2 increased in the PrL in young and adult rats but not in aged rats, and the levels of methylated PKMzeta DNA in the PrL decreased in all age groups, whereas the levels of unmethylated PKMzeta DNA increased only in young and adult rats. We also found that environmentally enriched housing reversed the hypermethylation of PKMzeta and restored cognitive performance in aged rats. Inactivation of PKMzeta prevented the potentiating effects of environmental enrichment on memory retention in aged rats. These results indicated that PKMzeta might be a potential target for the treatment of aging-related cognitive impairment, suggesting a potential therapeutic avenue. PMID- 26926227 TI - Transplantation in CLL: what we can learn from a dinosaur. PMID- 26926228 TI - Innovating consent for pediatric HCT patients. PMID- 26926229 TI - Low incidence of GvHD with T-cell depleted allografts facilitates further treatments for post-transplantation relapse in AML and MDS. PMID- 26926231 TI - MRD-driven treatment paradigm for newly diagnosed transplant eligible multiple myeloma patients. PMID- 26926230 TI - Relationship between neurocognitive functioning and medication management ability over the first 6 months following allogeneic stem cell transplantation. AB - Although neurocognitive impairment has been established as a major issue among cancer survivors, the real-world consequences of this impairment are unclear. This study investigated the relationship between neurocognitive functioning and medication management ability over time among 58 patients treated with allogeneic hematopoietic stem cell transplantation (HCT). Participants completed a neuropsychological test battery and a simulated medication management task at three time points: pre-transplant (T0), Day 100 (T1) and 6 months post transplant (T2). Neurocognitively impaired participants performed worse on the medication management task than neurocognitively normal participants at each time point, and were more likely to score in the impaired range of medication management ability post transplant (72% vs 20%, P<0.001 at T1; 67% vs 23%, P=0.013 at T2). In multivariate analyses, worse performance in executive functioning/working memory consistently predicted impaired medication management ability, even when controlling for sociodemographic and clinical confounders (odds ratio=0.89, 95% confidence interval (0.80, 0.98), P=0.023). Lower physical symptom distress also predicted impaired medication management ability, but this effect decreased over time. Self-reported cognitive problems were not correlated with medication management ability at any time point. Findings suggest that poor neurocognitive functioning, particularly in the domain of executive functioning/working memory, is associated with worse medication management ability within the first 6 months after allogeneic HCT. PMID- 26926232 TI - Planar Arrays of Nanoporous Gold Nanowires: When Electrochemical Dealloying Meets Nanopatterning. AB - Nanoporous materials are of great interest for various technological applications including sensors based on surface-enhanced Raman scattering, catalysis, and biotechnology. Currently, tremendous efforts are dedicated to the development of porous one-dimensional materials to improve the properties of such class of materials. The main drawback of the synthesis approaches reported so far includes (i) the short length of the porous nanowires, which cannot reach the macroscopic scale, and (ii) the poor organization of the nanostructures obtained by the end of the synthesis process. In this work, we report for the first time on a two step approach allowing creating highly ordered porous gold nanowire arrays with a length up to a few centimeters. This two-step approach consists of the growth of gold/copper alloy nanowires by magnetron cosputtering on a nanograted silicon substrate, serving as a physical template, followed by a selective dissolution of copper by an electrochemical anodic process in diluted sulfuric acid. We demonstrate that the pore size of the nanowires can be tailored between 6 and 21 nm by tuning the dealloying voltage between 0.2 and 0.4 V and the dealloying time within the range of 150-600 s. We further show that the initial gold content (11 to 26 atom %) and the diameter of the gold/copper alloy nanowires (135 to 250 nm) are two important parameters that must carefully be selected to precisely control the porosity of the material. PMID- 26926233 TI - Cytogenetic Effects of Chronic Methylphenidate Treatment and Chronic Social Stress in Adults with Attention-Deficit/Hyperactivity Disorder. AB - INTRODUCTION: Methylphenidate (MPH) is widely used to treat childhood and adult attention-deficit/hyperactivity disorder (ADHD). However, there are still safety concerns about side effects in long-term treatment. The aim of this study was to assess cytogenetic effects of chronic MPH treatment in adult ADHD and to find out if chronic social stress is attenuated by medication and to investigate whether chronic psychosocial stress leads to mutagenic effects by itself. METHODS: Lymphocytes for micronucleus assay and saliva samples for cortisol measurement were collected from adult ADHD patients and healthy controls. Stress exposure of the last 3 months was assessed by TICS (Trier Inventory for Chronic Stress). RESULTS: We could not detect an influence of MPH treatment on cytogenetic markers. ADHD patients displayed significantly higher chronic stress levels measured by TICS compared to healthy controls which were influenced by duration of MPH treatment. ADHD patients also showed significantly lower basal cortisol levels. DISCUSSION: We could corroborate that there are neither cytogenetic effects of chronic stress nor of chronic MPH intake even after several years of treatment. PMID- 26926234 TI - CD44(high)CD24(low) molecular signature determines the Cancer Stem Cell and EMT phenotype in Oral Squamous Cell Carcinoma. AB - Almost all epithelial tumours contain cancer stem-like cells, which possess a unique property of self-renewal and differentiation. In oral cancer, several biomarkers including cell surface molecules have been exploited for the identification of this highly tumorigenic population. Implicit is the role of CD44 in defining CSCs but CD24 is not well-explored. Here we show that CD44(high)CD24(low) cells isolated from the oral cancer cell lines, not only express stem cell related genes but also exhibit Epithelial-to-Mesenchymal transition (EMT) characteristics. This CD44(high)CD24(low) population gives rise to all other cell types upon differentiation. Typical Cancer Stem Cell (CSC) phenotypes like increased colony formation, sphere forming ability, migration and invasion were also confirmed in CD44(high)CD24(low) cells. Drug transporters were found to be over-expressed in CD44(high)CD24(low) sub-population thereby contributing to elevated chemo-resistance. To validate our findings in-vivo, we determined the relative expression of CD44 and CD24 in clinical samples of OSCC patients. CD44 expression was consistently high whereas CD24 showed significantly lower expression in tumour tissues. Further, the gene expression profile of the CSC and non-CSC population unravels the molecular pathways which may contribute to stemness. We conclude that CD44(high)CD24(low) represents cancer stem-like cells in Oral Squamous Cell Carcinoma. PMID- 26926235 TI - Predicting Market Impact Costs Using Nonparametric Machine Learning Models. AB - Market impact cost is the most significant portion of implicit transaction costs that can reduce the overall transaction cost, although it cannot be measured directly. In this paper, we employed the state-of-the-art nonparametric machine learning models: neural networks, Bayesian neural network, Gaussian process, and support vector regression, to predict market impact cost accurately and to provide the predictive model that is versatile in the number of variables. We collected a large amount of real single transaction data of US stock market from Bloomberg Terminal and generated three independent input variables. As a result, most nonparametric machine learning models outperformed a-state-of-the-art benchmark parametric model such as I-star model in four error measures. Although these models encounter certain difficulties in separating the permanent and temporary cost directly, nonparametric machine learning models can be good alternatives in reducing transaction costs by considerably improving in prediction performance. PMID- 26926236 TI - New Web-based tool for generating scattergrams to report hearing results. PMID- 26926237 TI - Operational stability enhancement in organic light-emitting diodes with ultrathin Liq interlayers. AB - Organic light-emitting diodes (OLEDs) under constant current operation suffer from a decrease of luminance accompanied by an increase of driving voltage. We report a way to greatly improve the stability of OLEDs having a green emitter exhibiting thermally activated delayed fluorescence (TADF), (4s,6s)-2,4,5,6 tetra(9H-carbazol-9-yl) isophthalonitrile (4CzIPN), by introducing ultrathin (1 to 3 nm) interlayers of 8-hydroxyquinolinato lithium (Liq) between hole-blocking layer and its surrounding emissive and electron-transport layers. Under constant current operation starting at a luminescence of 1,000 cd/m(2), the time to reach 90% of initial luminance (LT90) increased eight times, resulting in LT90 = 1,380 hours after insertion of the interlayers. Combining this new concept and mixed host system, LT95 was further extended to 1315 hours that is 16 times of reference device. This is the best value reported for TADF-based OLEDs and is comparable to the operational lifetimes of well-established phosphorescence-based OLEDs. Thermally stimulated current measurements showed that the number of deep charge traps was reduced with the insertion of the ultrathin Liq interlayer, indicating that reducing the number of deep traps is important for improving the operational lifetime and that exciton-polaron annihilation may be a source of the device degradation. PMID- 26926238 TI - Accessible health care for Roma: a gypsy's tale a qualitative in-depth study of access to health care for Roma in Ghent. AB - BACKGROUND: In general, vulnerable populations experience more problems in accessing health care. This also applies to the Roma-population. In the City of Ghent, Belgium, a relatively large group of Roma resides more or less permanently. The aim of this study is to explore the barriers this population encounters in their search for care. METHODS: In this qualitative study using in depth interviews the barriers to health care for the Roma in Ghent are explored. We interviewed 12 Roma and 13 professionals (volunteers, health care providers,...) who had regular contact with the Roma-population in Ghent. For both groups purposive sampling was used to achieve maximal variation regarding gender, age, nationality and legal status. RESULTS: The Roma-population in Ghent encounters various barriers in their search for care. Financial constraints, not being able to reach health care and having problems to get through the complexity of the system are some of the most critical problems. Another important finding is the crucial role of trust between patient and care provider in the care-giving process. CONCLUSION: Roma share several barriers with other minority groups, such as: financial constraints, mobility issues and not knowing the language. However, more distinctive for this group is the lack of trust in care providers and health care in general. As a result, restraint and lack of communication form serious barriers for both patient and provider in their interaction. In order to ensure equitable access for Roma, more emphasis should be on establishing a relationship of mutual respect and understanding. PMID- 26926239 TI - Markov process models of the dynamics of HIV reservoirs. AB - While latently infected CD4+ T cells are extremely sparse, they are a reality that prevents HIV from being cured, and their dynamics are largely unknown. We begin with a two-state Markov process that models the outcomes of regular but infrequent blood tests for latently infected cells in an HIV positive patient under drug therapy. We then model the hidden dynamics of a latently infected CD4+ T cell in an HIV positive patient and show there is a limiting distribution, which indicates in which compartments the HIV typically can be found. Our model shows that the limiting distribution of latently infected cells reveals the presence of latency in every compartment with positive probability, supported by clinical data. We also show that the hidden Markov model determines the outcome of blood tests and analyze its connection to the blood test model. PMID- 26926240 TI - A model of a syntrophic relationship between two microbial species in a chemostat including maintenance. AB - Many microbial ecosystems can be seen as microbial 'food chains' where the different reaction steps can be seen as such: the waste products of the organisms at a given reaction step are consumed by organisms at the next reaction step. In the present paper we study a model of a two-step biological reaction with feedback inhibition, which was recently presented as a reduced and simplified version of the anaerobic digestion model ADM1 of the International Water Association (IWA). It is known that in the absence of maintenance (or decay) the microbial 'food chain' is stable. In a previous study, using a purely numerical approach and ADM1 consensus parameter values, it was shown that the model remains stable when decay terms are added. However, the authors could not prove in full generality that it remains true for other parameter values. In this paper we prove that introducing decay in the model preserves stability whatever its parameters values are and for a wide range of kinetics. PMID- 26926241 TI - Long-term stability of influenza vaccine in a dissolving microneedle patch. AB - This study tested the hypothesis that optimized microneedle patch formulations can stabilize trivalent subunit influenza vaccine during long-term storage outside the cold chain and when exposed to potential stresses found during manufacturing and storage. Formulations containing combinations of trehalose/sucrose, sucrose/arginine, and arginine/heptagluconate were successful at retaining most or all vaccine activity during storage at 25 degrees C for up to 24 months as determined by ELISA assay. The best formulation of microneedle patches contained arginine/heptagluconate, which showed no significant loss of vaccine activity during the study. To validate these in vitro findings, mice were immunized using trivalent influenza vaccine stored in microneedle patches for more than 1 year at 25 degrees C, which elicited antibody titers greater than or equal to fresh liquid vaccine delivered by intradermal injection, indicating the retention of immunogenicity during storage. Finally, influenza vaccine in microneedle patches lost no significant activity during exposure to 60 degrees C for 4 months, multiple freeze-thaw cycles, or electron beam irradiation. We conclude that optimally formulated microneedle patches can retain influenza vaccine activity during extended storage outside the cold chain and during other environmental stresses, which suggests the possibility of microneedle patch storage on pharmacy shelves without refrigeration. PMID- 26926242 TI - Formulation development and optimization of transungual drug delivery system of terbinafine hydrochloride for the treatment of onychomycosis. AB - The aim of present investigation was to develop transungual drug delivery system (nail lacquer) of terbinafine hydrochloride for treatment of onychomycosis. Different types of penetration enhancers, viz. 2-mercaptoethanol, n-acetyl-L cysteine and thioglycolic acid, were evaluated to determine their effect on drug permeation. Various types of polymers, both hydrophobic (Eudragit(r) RL 100 and Eudragit(r) RS 100) and hydrophilic polymers (hydroxypropyl methyl cellulose (HPMC) E15), were evaluated for their film-forming and drug permeation characteristics. The nail lacquer was optimised statistically by applying 3(2) full factorial design. Polymer ratio (Eudragit(r) RL 100/HPMC E15; X 1) and solvent ratio (ethanol/water; X 2) were selected as independent variable, and viscosity (cPs), nail plate hydration (%) and in vitro drug permeated at the end of 24 h (MUg/cm(2)) were selected as dependent variable. The optimised batch comprises of polymer ratio (70:30) and solvent ratio (75:25). Ex vivo drug permeation study was performed using human cadaver toe nail plate. The results revealed that the amount of drug permeated at the end of 24 h was 61.55 +/- 3.2 MUg/cm(2), which was found to be higher than the minimum inhibitory concentration of drug. This study confirms that the developed drug-loaded nail lacquer could be used as a promising tool for the effective treatment of onychomycosis. PMID- 26926245 TI - Paediatrics: Mirabegron for paediatric OAB. PMID- 26926244 TI - Tissue distribution and acute toxicity of silver after single intravenous administration in mice: nano-specific and size-dependent effects. AB - BACKGROUND: Silver nanoparticles (AgNPs) are an important class of nanomaterials used as antimicrobial agents for a wide range of medical and industrial applications. However toxicity of AgNPs and impact of their physicochemical characteristics in in vivo models still need to be comprehensively characterized. The aim of this study was to investigate the effect of size and coating on tissue distribution and toxicity of AgNPs after intravenous administration in mice, and compare the results with those obtained after silver acetate administration. METHODS: Male CD-1(ICR) mice were intravenously injected with AgNPs of different sizes (10 nm, 40 nm, 100 nm), citrate-or polyvinylpyrrolidone-coated, at a single dose of 10 mg/kg bw. An equivalent dose of silver ions was administered as silver acetate. Mice were euthanized 24 h after the treatment, and silver quantification by ICP-MS and histopathology were performed on spleen, liver, lungs, kidneys, brain, and blood. RESULTS: For all particle sizes, regardless of their coating, the highest silver concentrations were found in the spleen and liver, followed by lung, kidney, and brain. Silver concentrations were significantly higher in the spleen, lung, kidney, brain, and blood of mice treated with 10 nm AgNPs than those treated with larger particles. Relevant toxic effects (midzonal hepatocellular necrosis, gall bladder hemorrhage) were found in mice treated with 10 nm AgNPs, while in mice treated with 40 nm and 100 nm AgNPs lesions were milder or negligible, respectively. In mice treated with silver acetate, silver concentrations were significantly lower in the spleen and lung, and higher in the kidney than in mice treated with 10 nm AgNPs, and a different target organ of toxicity was identified (kidney). CONCLUSIONS: Administration of the smallest (10 nm) nanoparticles resulted in enhanced silver tissue distribution and overt hepatobiliary toxicity compared to larger ones (40 and 100 nm), while coating had no relevant impact. Distinct patterns of tissue distribution and toxicity were observed after silver acetate administration. It is concluded that if AgNPs become systemically available, they behave differently from ionic silver, exerting distinct and size-dependent effects, strictly related to the nanoparticulate form. PMID- 26926247 TI - Surgery: Novel mesh materials tested. PMID- 26926248 TI - Differences in depression between unknown diabetes and known diabetes: results from China health and retirement longitudinal study. AB - BACKGROUND: Both diabetes and depression have become serious public health problems and are major contributors to the global burden of disease. People with diabetes have been shown to have higher risk of depression. The purpose of this study was to observe the differences in depression between older Chinese adults with known or unknown diabetes. METHODS: Data came from the national baseline survey of China Health and Retirement Longitudinal Study (CHARLS). The Center for Epidemiologic Studies Depression Scale was used to assess depression. Participants with a history of diabetes diagnosis were considered to have known diabetes, and those with newly-diagnosed diabetes were considered to have unknown diabetes. Multiple logistic regression analysis was applied to estimate odds ratio (OR) for depression in predictor variables. RESULTS: Overall, 39.1% of the 2,399 participants with diabetes suffered from depression. The prevalence of depression was significantly higher (p < 0.001) in people with known diabetes (43.5%) than those with unknown diabetes (35.1%). The biggest differences between the two groups were found in the middle aged, in women, in the less educated and in married people. In known diabetes, people treated with traditional Chinese medicine (TCM) coupled with oral western medicine (WM) and/or insulin had two fold odds of depression compared to those without treatment. CONCLUSION: The knowledge of having diabetes, treatments and suffering from other chronic diseases were associated with the higher prevalence of depression in people with known diabetes compared to those with unknown diabetes. Prevention of depression in diabetics should receive more attention in the middle aged, women and the less education. PMID- 26926249 TI - Genetics of human isolated acromesomelic dysplasia. AB - Acromesomelic dysplasia is a type of skeletal malformation affecting distal and middle segments of the extremities. It occurs in both isolated (non-syndromic) and syndromic forms. In later case, it shows association with cardiac, respiratory, neurological and genital abnormalities. Acromesomelic dysplasia segregates in autosomal recessive mode. Mutations in three genes (GDF5, NPR2, BMPR1B) have been reported to cause different forms of acromesomelic dysplasia. In the present review, we have discussed clinical spectrum, genetics and signalopathies of isolated acromesomelic dysplasias. PMID- 26926250 TI - Methods for visualizing RNA in cells, tissues and whole organisms. PMID- 26926246 TI - Receptors, channels, and signalling in the urothelial sensory system in the bladder. AB - The storage and periodic elimination of urine, termed micturition, requires a complex neural control system to coordinate the activities of the urinary bladder, urethra, and urethral sphincters. At the level of the lumbosacral spinal cord, lower urinary tract reflex mechanisms are modulated by supraspinal controls with mechanosensory input from the urothelium, resulting in regulation of bladder contractile activity. The specific identity of the mechanical sensor is not yet known, but considerable interest exists in the contribution of transient receptor potential (TRP) channels to the mechanosensory functions of the urothelium. The sensory, transduction, and signalling properties of the urothelium can influence adjacent urinary bladder tissues including the suburothelial nerve plexus, interstitial cells of Cajal, and detrusor smooth muscle cells. Diverse stimuli, including those that activate TRP channels expressed by the urothelium, can influence urothelial release of chemical mediators (such as ATP). Changes to the urothelium are associated with a number of bladder pathologies that underlie urinary bladder dysfunction. Urothelial receptor and/or ion channel expression and the release of signalling molecules (such as ATP and nitric oxide) can be altered with bladder disease, neural injury, target organ inflammation, or psychogenic stress. Urothelial receptors and channels represent novel targets for potential therapies that are intended to modulate micturition function or bladder sensation. PMID- 26926251 TI - High risk of recurrent torsion in premenarchal girls with torsion of normal adnexa. AB - OBJECTIVE: To compare adnexal torsion characteristics and torsion recurrence rates in a pre- and postmenarchal pediatric and adolescent population. DESIGN: Retrospective cohort study. SETTING: University-affiliated medical center. PATIENT(S): Females <18 years old with surgically diagnosed adnexal torsion. INTERVENTION(S): Adnexal detorsion, cystectomy, salpingectomy, or salpingo oophorectomy by laparoscopy or laparotomy. Oophoropexy using the utero-ovarian ligament plication technique was performed in cases of recurrent torsion of normal adnexa. MAIN OUTCOME MEASURE(S): The clinical presentation, laboratory and ultrasound characteristics, surgical findings, surgical procedures, pathologic diagnosis, and torsion recurrence rates were analyzed and compared between pre- and postmenarchal patients. RESULT(S): Twenty premenarchal and 24 postmenarchal patients were identified. The clinical presentation, laboratory findings, and ultrasound characteristics were similar between the two groups, except for a higher prevalence of paraovarian cysts on preoperative ultrasound in the postmenarchal compared with in the premenarchal group (20.8% vs. 0%). For the whole cohort, torsion of normal adnexa constituted 25.0% (11/44) of cases, while torsion of "pathologic" adnexa constituted 75.0% (33/44) of torsion cases. Torsion recurrence was significantly more common among girls whose first torsion episode occurred in the premenarchal period compared with in postmenarche (35% vs. 4.2%). On multivariate logistic regression analysis, torsion recurrence was significantly associated with premenarchal status (odds ratio [OR] = 12.7; 95% confidence interval [CI], 1.1-152.0) and with torsion involving normal adnexa (OR = 19.1; 95% CI, 2.3-154.5). CONCLUSION(S): Recurrent torsion is common in patients whose first torsion episode occurred in the premenarchal period and involved otherwise normal adnexa. Ovarian fixation procedures may be considered in patients at risk for torsion recurrence. PMID- 26926252 TI - Optimal uterine anatomy and physiology necessary for normal implantation and placentation. AB - The authors review aberrations of uterine anatomy and physiology affecting pregnancy outcomes with IVF. In the case of endometriosis and hydrosalpinx, pathologies outside of the uterus alter the uterine endometrium. In the case of endometriosis, Dominique de Ziegler outlines the numerous changes in gene expression and the central role of inflammation in causing progesterone resistance. With endometriosis, the absence of ovarian function inherent in deferred transfer, with or without a more lengthy suppression of ovarian function, appears to be sufficient to restore normal function of eutopic endometrium. Because laparoscopy is no longer routine in the evaluation of infertility, unrecognized endometriosis then becomes irrelevant in the context of assisted reproductive technology. With hydrosalpinx and submucus myomas, the implantation factor HOXA-10 is suppressed in the endometrium and, with myomas, even in areas of the uterus not directly affected. Daniela Galliano reviews various uterine pathologies, the most enigmatic being adenomyosis, where the endometrium also manifests many of the changes seen in endometriosis and deferred transfer with extended suppression appears to provide the best outcomes. Ettore Cicinelli's group has extensively studied the diagnosis and treatment of endometritis, and although more definitive diagnosis and care of this covert disorder may await techniques such as sequencing of the endometrial microbiome, it undoubtedly is an important factor in implantation failure, deserving our attention and treatment. PMID- 26926254 TI - Successful application of endoscopic modified medial maxillectomy to orbital floor trapdoor fracture in a pediatric patient. AB - Although surgical treatment of orbital floor fractures can be performed by many different approaches, the application of endoscopic modified medial maxillectomy (EMMM) for this condition has rarely been described in the literature. We report on a case of a 7-year-old boy with a trapdoor orbital floor fracture successfully treated with the application of EMMM. The patient suffered trauma to the right orbit floor and the inferior rectus was entrapped at the orbital floor. Initially, surgical repair via endoscopic endonasal approach was attempted. However, we were unable to adequately access the orbital floor through the maxillary ostium. Therefore, an alternative route of access to the orbital floor was established by EMMM. With sufficient visualization and operating space, the involved orbital content was completely released from the entrapment site and reduced into the orbit. To facilitate wound healing, the orbital floor was supported with a water-inflated urethral balloon catheter for 8 days. At follow up 8 months later, there was no gaze restriction or complications associated with the EMMM. This case illustrates the efficacy and safety of EMMM in endoscopic endonasal repair of orbital floor fracture, particularly for cases with a narrow nasal cavity such as in pediatric patients. PMID- 26926253 TI - Maternal whole grain intake and outcomes of in vitro fertilization. AB - OBJECTIVE: To evaluate the relationship between pretreatment intake of whole grains and outcomes of IVF. DESIGN: Prospective cohort study. SETTING: Academic medical center. PATIENT(S): A total of 273 women who collectively underwent 438 IVF cycles. INTERVENTION(S): Whole grain intake was assessed with a validated food frequency questionnaire at enrollment. MAIN OUTCOME MEASURE(S): Intermediate and clinical end points of IVF were abstracted from medical records. RESULT(S): Women had a median whole grain intake of 34.2 g per day (~1.2 servings/day). Higher pretreatment whole grain intake was associated with higher probability of implantation and live birth. The adjusted percentage of cycles resulting in live birth for women in the highest quartile of whole grain intake (>52.4 g/day) was 53% (95% confidence interval [CI] 41%, 65%) compared with 35% (95% CI 25%, 46%) for women in the lowest quartile (<21.4 g/day). This association was largely driven by intake of bran as opposed to germ. When intermediate end points of IVF were examined, only endometrial thickness on the day of ET was associated with whole grain intake. A 28-g per day (~1 serving/day) increase in whole grain intake was associated with a 0.4-mm (95% CI 0.1, 0.7 mm) increase in endometrial thickness. CONCLUSION(S): Higher pretreatment whole grain intake was related to higher probability of live birth among women undergoing IVF. The higher probability of live birth may result from increased endometrial thickness on the day of ET and improved embryo receptivity manifested in a higher probability of implantation. PMID- 26926255 TI - Job burnout is associated with dysfunctions in brain mechanisms of voluntary and involuntary attention. AB - Individuals with job burnout symptoms often report having cognitive difficulties, but related electrophysiological studies are scarce. We assessed the impact of burnout on performing a visual task with varying memory loads, and on involuntary attention switch to distractor sounds using scalp recordings of event-related potentials (ERPs). Task performance was comparable between burnout and control groups. The distractor sounds elicited a P3a response, which was reduced in the burnout group. This suggests burnout-related deficits in processing novel and potentially important events during task performance. In the burnout group, we also observed a decrease in working-memory related P3b responses over posterior scalp and increase over frontal areas. These results suggest that burnout is associated with deficits in cognitive control needed to monitor and update information in working memory. Successful task performance in burnout might require additional recruitment of anterior regions to compensate the decrement in posterior activity. PMID- 26926256 TI - Change in the Affinity of Ethylene Glycol Methacrylate Phosphate Monomer and Its Polymer Anchored on a Graphene Oxide Platform toward Uranium(VI) and Plutonium(IV) Ions. AB - The complexation behavior of the carbonyl and phosphoryl ligating groups bearing ethylene glycol methacrylate phosphate (EGMP) monomer and its polymer fixed on a graphene oxide (GO) platform was studied to understand the coordination ability of segregated EGMP units and polymer chains toward UO2(2+) and Pu(4+) ions. The cross-linked poly(EGMP) gel and EGMP dissolved in solution have a similar affinity toward these ions. UV-initiator induced polymerization was used to graft poly(EGMP) on the GO platform utilizing a double bond of EGMP covalently fixed on it. X-ray photoelectron spectroscopy (XPS) of the GO and GO-EGMP was done to confirm covalent attachment of the EGMP via a -C-O-P- link between GO and EGMP. The extent of poly(EGMP) grafting on GO by thermal analyses was found to be 5.88 wt %. The EGMP units fixed on the graphene oxide platform exhibited a remarkable selectivity toward Pu(4+) ions at high HNO3 conc. where coordination is a dominant mode involved in the sorption of ions. The ratio of distribution coefficients of Pu(IV) to U(VI) (DPu(IV)/DU(VI)) followed a trend as cross-linked poly(EGMP) (0.95) < EGMP in solvent methyl isobutyl ketone (1.3) < GO-poly(EGMP) (25) < GO-EGMP (181); the DPu(IV)/DU(VI) values are given in parentheses. The density functional theory computations have been performed for the complexation of UO2(2+) and Pu(4+) ions with the EGMP molecule anchored on GO in the presence of nitrate ions. This computational modeling suggested that Pu(4+) ion formed a strong coordination complex with phosphoryl and carbonyl ligating groups of the GO-EGMP as compared to UO2(2+) ions. Thus, the nonselective EGMP becomes highly selective to Pu(IV) ions when it interacts as a single unit fixed on a GO platform. PMID- 26926257 TI - Understanding the importance of conservative hypothetical protein LdBPK_070020 in Leishmania donovani and its role in subsistence of the parasite. AB - The genome of Leishmania donovani, the causative agent of visceral leishmaniasis, codes for approximately 65% of both conserved and non-conserved hypothetical proteins. Studies on 'conserved hypothetical' proteins are expected to reveal not only new and crucial aspects of Leishmania biochemistry, but it could also lead to discovery of novel drug candidates. Conserved hypothetical protein, LdBPK_070020, is a 31.14 kDa protein, encoded by an 810 bp gene. BLAST analysis of LdBPK_070020, performed against NCBI non-redundant database, showed 80-99% similarity with conserved hypothetical proteins of Leishmania belonging to other species. Using homologues recombination method, we have performed gene knockout of LdBPK_070020 and effects of the same were investigated on the parasite. The gene knocked out strain shows significant retardation in growth with respect to wild type. Detailed biochemical studies indicated towards important role of LdBPK_070020 in the parasite survival and growth. PMID- 26926259 TI - Spectroscopic and QM/MM investigations of Chloroperoxidase catalyzed degradation of orange G. AB - Chloroperoxidase (CPO), a heme-thiolate protein, from Caldariomyces fumago catalyzes a plethora of reactions including halogenation, dismutation, epoxidation, and oxidation. Although all CPO-catalyzed reactions go through a common intermediate, compound I, different mechanisms are followed in subsequent transformations. To understand the mechanism of CPO-catalyzed halide-dependent degradation of orange G, the role of halide and pH was systematically investigated. It is revealed that formation and protonation of compound X, a long sought after hypochlorite heme adduct intermediate existed during CPO-catalyzed halide-dependent reactions, significantly lowers the reaction barrier and increases the efficiency of CPO-catalyzed orange G degradation. The extremely acidic optimal reaction pH suggests the protonation of a residue, presumably, Glu 183 in CPO catalysis. Halide dependent studies showed that Kcat is higher in the presence of Br(-) than in the presence of Cl(-). The degradation products of orange G indicate the cleavage at a single position of orange G, demonstrating a high regioselectivity of CPO-catalyzed degradation. Based on our kinetic, NMR and QM/MM studies, the mechanism of CPO-catalyzed orange G degradation was proposed. PMID- 26926261 TI - [Mortality in people infected by Human Immunodeficiency Virus]. PMID- 26926258 TI - A review of solute encapsulating nanoparticles used as delivery systems with emphasis on branched amphipathic peptide capsules. AB - Various strategies are being developed to improve delivery and increase the biological half-lives of pharmacological agents. To address these issues, drug delivery technologies rely on different nano-sized molecules including: lipid vesicles, viral capsids and nano-particles. Peptides are a constituent of many of these nanomaterials and overcome some limitations associated with lipid-based or viral delivery systems, such as tune-ability, stability, specificity, inflammation, and antigenicity. This review focuses on the evolution of bio-based drug delivery nanomaterials that self-assemble forming vesicles/capsules. While lipid vesicles are preeminent among the structures; peptide-based constructs are emerging, in particular peptide bilayer delimited capsules. The novel biomaterial Branched Amphiphilic Peptide Capsules (BAPCs) display many desirable properties. These nano-spheres are comprised of two branched peptides-bis(FLIVI)-K-KKKK and bis(FLIVIGSII)-K-KKKK, designed to mimic diacyl-phosphoglycerides in molecular architecture. They undergo supramolecular self-assembly and form solvent-filled, bilayer delineated capsules with sizes ranging from 20 nm to 2 MUm depending on annealing temperatures and time. They are able to encapsulate different fluorescent dyes, therapeutic drugs, radionuclides and even small proteins. While sharing many properties with lipid vesicles, the BAPCs are much more robust. They have been analyzed for stability, size, cellular uptake and localization, intra cellular retention and, bio-distribution both in culture and in vivo. PMID- 26926260 TI - Evolving Methanococcoides burtonii archaeal Rubisco for improved photosynthesis and plant growth. AB - In photosynthesis Ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco) catalyses the often rate limiting CO2-fixation step in the Calvin cycle. This makes Rubisco both the gatekeeper for carbon entry into the biosphere and a target for functional improvement to enhance photosynthesis and plant growth. Encumbering the catalytic performance of Rubisco is its highly conserved, complex catalytic chemistry. Accordingly, traditional efforts to enhance Rubisco catalysis using protracted "trial and error" protein engineering approaches have met with limited success. Here we demonstrate the versatility of high throughput directed (laboratory) protein evolution for improving the carboxylation properties of a non-photosynthetic Rubisco from the archaea Methanococcoides burtonii. Using chloroplast transformation in the model plant Nicotiana tabacum (tobacco) we confirm the improved forms of M. burtonii Rubisco increased photosynthesis and growth relative to tobacco controls producing wild-type M. burtonii Rubisco. Our findings indicate continued directed evolution of archaeal Rubisco offers new potential for enhancing leaf photosynthesis and plant growth. PMID- 26926262 TI - Executive summary of the guidelines for the use of interferon-gamma release assays in the diagnosis of tuberculosis infection. AB - Interferon-gamma release assays are widely used for the diagnosis of tuberculosis infection in Spain. However, there is no consensus on their application in specific clinical scenarios. To develop a guideline for their use, a panel of experts comprising specialists in infectious diseases, respiratory diseases, microbiology, pediatrics and preventive medicine, together with a methodologist, conducted a systematic literature search, summarized the findings, rated the quality of the evidence, and formulated recommendations following the GRADE (Grading of Recommendations of Assessment Development and Evaluations) methodology. This document provides evidence-based guidance on the use of interferon-gamma release assays for the diagnosis of tuberculosis infection in patients at the risk of tuberculosis or suspected of having active disease. The guidelines will be applicable to specialist and primary care, and public health. PMID- 26926263 TI - Visual perception is dependent on visuospatial working memory and thus on the posterior parietal cortex. AB - Visual perception involves complex and active processes. We will start by explaining why visual perception is dependent on visuospatial working memory, especially the spatiotemporal integration of the perceived elements through the ocular exploration of visual scenes. Then we will present neuropsychology, transcranial magnetic stimulation and neuroimaging data yielding information on the specific role of the posterior parietal cortex of the right hemisphere in visuospatial working memory. Within the posterior parietal cortex, neuropsychology data also suggest that there might be dissociated neural substrates for deployment of attention (superior parietal lobules) and spatiotemporal integration (right inferior parietal lobule). PMID- 26926264 TI - Dark state population determines magnetic sensitivity in radical pair magnetoreception model. AB - What is the real role of the quantum coherence and entanglement in the radical pair (RP) compass, and what determines the singlet yield have not been fully understood. In this paper, we find that the dark states of the two-electron Zeeman energy operator (TEZE) play an important role in the RP compass. We respectively calculate the singlet yields for two initial states in this dark state basis: the coherent state and the same state just removing the dark state coherence. For the later there is neither dark state coherence nor entanglement in the whole dynamical process. Surprisingly we find that in both cases the singlet yields are the same, and based on this result, we believe that the dark state population determines the singlet yield completely, and the dark state coherence and entanglement have little contribution to it. Finally, we also find that the dark state population as well as the singlet yield anisotropy is fragile to the vertical magnetic noise. However, the orientation is robust and is even enhanced by the parallel magnetic noise because the dark states expand a decoherence-free subspace. The dark state population as well as the orientation is more robust to the hyperfine coupling noise. PMID- 26926265 TI - Hair and Nails as Noninvasive Biomarkers of Human Exposure to Brominated and Organophosphate Flame Retardants. AB - After the phase-out of polybrominated diphenyl ethers (PBDEs), the use of alternative flame retardants (AFRs), such as FireMaster 550, and of organophosphate esters (OPEs) has increased. However, little is known about human exposure to these chemicals. This lack of biomonitoring studies is partially due to the absence of reliable noninvasive biomarkers of exposure. Human hair and nails can provide integrated exposure measurements, and as such, these matrices can potentially be used as noninvasive biomarkers of exposure to these flame retardants. Paired human hair, fingernail, toenail, and serum samples obtained from 50 adult participants recruited at Indiana University Bloomington campus were analyzed by gas chromatographic mass spectrometry for 36 PBDEs, 9 AFRs, and 12 OPEs. BDE-47, BDE-99, 2-ethylhexyl-2,3,4,5-tetrabromobenzoate (TBB), di(2 ethylhexyl) tetrabromophthalate (TBPH), tris(1,3-dichloro-2-propyl)phosphate (TDCIPP), and triphenyl phosphate (TPHP) were the most abundant compounds detected in almost all hair, fingernail, and toenail samples. The concentrations followed the order OPEs > TBB+TBPH > Sigmapenta-BDE. PBDE levels in the hair and nail samples were significantly correlated with their levels in serum (P < 0.05), suggesting that human hair and nails can be used as biomarkers to assess human exposure to PBDEs. PMID- 26926267 TI - Evaluation of Known or Suspected Cardiac Sarcoidosis. AB - Sarcoidosis is a multisystem disorder of unknown cause, and cardiac sarcoidosis affects at least 25% of patients and accounts for substantial mortality and morbidity from this disease. Cardiac sarcoidosis may present with heart failure, left ventricular systolic dysfunction, AV block, atrial or ventricular arrhythmias, and sudden cardiac death. Cardiac involvement can be challenging to detect and diagnose because of the focal nature of the disease, as well as the fact that clinical criteria have limited diagnostic accuracy. Nevertheless, the diagnosis of cardiac sarcoidosis can be enhanced by integrating both clinical and imaging findings. This article reviews the various roles that different imaging modalities provide in the evaluation and management of patients with known or suspected cardiac sarcoidosis. PMID- 26926266 TI - Pregnancy-specific glycoprotein expression in normal gastrointestinal tract and in tumors detected with novel monoclonal antibodies. AB - Pregnancy-specific glycoproteins (PSGs) are immunoglobulin superfamily members related to the carcinoembryonic antigen-related cell adhesion molecule (CEACAM) family and are encoded by 10 genes in the human. They are secreted at high levels by placental syncytiotrophoblast into maternal blood during pregnancy, and are implicated in immunoregulation, thromboregulation, and angiogenesis. To determine whether PSGs are expressed in tumors, we characterized 16 novel monoclonal antibodies to human PSG1 and used 2 that do not cross-react with CEACAMs to study PSG expression in tumors and in the gastrointestinal (GI) tract using tissue arrays and immunohistochemistry. Staining was frequently observed in primary squamous cell carcinomas and colonic adenocarcinomas and was correlated with the degree of tumor differentiation, being largely absent from metastatic samples. Staining was also observed in normal oesophageal and colonic epithelium. PSG expression in the human and mouse GI tract was confirmed using quantitative RT PCR. However, mRNA expression was several orders of magnitude lower in the GI tract compared to placenta. Our results identify a non-placental site of PSG expression in the gut and associated tumors, with implications for determining whether PSGs have a role in tumor progression, and utility as tumor biomarkers. PMID- 26926268 TI - Simultaneous Longitudinal Strain in All 4 Cardiac Chambers: A Novel Method for Comprehensive Functional Assessment of the Heart. AB - BACKGROUND: Simultaneous assessment of longitudinal strain (LS) by 2D speckle tracking echocardiography in all 4 cardiac chambers has not yet been explored. Our goal was to study LS curves obtained simultaneously from all 4 cardiac chambers in healthy subjects to gain insight into interchamber functional relationships. METHODS AND RESULTS: We studied 259 healthy subjects (age 44+/-15; 118 men) in whom it was possible to obtain apical 4-chamber views that contained the entire left and right ventricles and both atria in the same sector. 2D speckle-tracking echocardiography was performed in all 4 chambers in the same cardiac cycle, while considering the interventricular septum as part of the left ventricle and including the interatrial septum in the LS measurements for both atria. LS was measured over time using vendor-independent software (Epsilon), resulting in peak LS and time-to-peak strain. Strain curves of the right ventricle and right atrium were larger in magnitude than those of the left ventricle and left atrium, whereas time-to-peak values were shorter. LS for the ventricles peaked earlier than the LS for the corresponding atria. Peak systolic LS values were larger in magnitude in women than in men. For both atria, LS declined with age and time-to-peak increased. Left ventricle LS declined minimally with age, but right ventricle free-wall LS augmented with age until the sixth decade. CONCLUSIONS: Simultaneous measurement of LS provides new insights into interchamber relationships. This new tool may prove useful in evaluating diseases that affect cardiac chambers differently. PMID- 26926270 TI - Simultaneous 4-Chamber Strain: More and Faster Analysis, But Is It Good Enough? PMID- 26926271 TI - Combined Positron Emission Tomography and Magnetic Resonance as Translational Tool in Cardiology. PMID- 26926269 TI - Quantifying the Area at Risk in Reperfused ST-Segment-Elevation Myocardial Infarction Patients Using Hybrid Cardiac Positron Emission Tomography-Magnetic Resonance Imaging. AB - BACKGROUND: Hybrid positron emission tomography and magnetic resonance allows the advantages of magnetic resonance in tissue characterizing the myocardium to be combined with the unique metabolic insights of positron emission tomography. We hypothesized that the area of reduced myocardial glucose uptake would closely match the area at risk delineated by T2 mapping in ST-segment-elevation myocardial infarction patients. METHODS AND RESULTS: Hybrid positron emission tomography and magnetic resonance using (18)F-fluorodeoxyglucose (FDG) for glucose uptake was performed in 21 ST-segment-elevation myocardial infarction patients at a median of 5 days. Follow-up scans were performed in a subset of patients 12 months later. The area of reduced FDG uptake was significantly larger than the infarct size quantified by late gadolinium enhancement (37.2+/-11.6% versus 22.3+/-11.7%; P<0.001) and closely matched the area at risk by T2 mapping (37.2+/-11.6% versus 36.3+/-12.2%; P=0.10, R=0.98, bias 0.9+/-4.4%). On the follow-up scans, the area of reduced FDG uptake was significantly smaller in size when compared with the acute scans (19.5 [6.3%-31.8%] versus 44.0 [21.3%-55.3%]; P=0.002) and closely correlated with the areas of late gadolinium enhancement (R 0.98) with a small bias of 2.0+/-5.6%. An FDG uptake of >=45% on the acute scans could predict viable myocardium on the follow-up scan. Both transmural extent of late gadolinium enhancement and FDG uptake on the acute scan performed equally well to predict segmental wall motion recovery. CONCLUSIONS: Hybrid positron emission tomography and magnetic resonance in the reperfused ST-segment-elevation myocardial infarction patients showed reduced myocardial glucose uptake within the area at risk and closely matched the area at risk delineated by T2 mapping. FDG uptake, as well as transmural extent of late gadolinium enhancement, acutely can identify viable myocardial segments. PMID- 26926272 TI - Natural Silk as a Photonics Component: a Study on Its Light Guiding and Nonlinear Optical Properties. AB - Silk fibers are expected to become a pathway to biocompatible and bioresorbable waveguides, which could be used to deliver localized optical power for various applications, e.g., optical therapy or imaging inside living tissue. Here, for the first time, the linear and nonlinear optical properties of natural silk fibers have been studied. The waveguiding properties of silk fibroin of largely unprocessed Bombyx mori silkworm silk are assessed using two complementary methods, and found to be on the average 2.8 dB mm(-1). The waveguide losses of degummed silk are to a large extent due to scattering from debris on fiber surface and helical twisting of the fiber. Nonlinear optical microscopy reveals both configurational defects such as torsional twisting, and strong symmetry breaking at the center of the fiber, which provides potential for various nonlinear applications. Our results show that nonregenerated B. mori silk can be used for delivering optical power over short distances, when the waveguide needs to be biocompatible and bioresorbable, such as embedding the waveguide inside living tissue. PMID- 26926273 TI - Animal and human innovation: novel problems and novel solutions. AB - This theme issue explores how and why behavioural innovation occurs, and the consequences of innovation for individuals, groups and populations. A vast literature on human innovation exists, from the development of problem-solving in children, to the evolution of technology, to the cultural systems supporting innovation. A more recent development is a growing literature on animal innovation, which has demonstrated links between innovation and personality traits, cognitive traits, neural measures, changing conditions, and the current state of the social and physical environment. Here, we introduce these fields, define key terms and discuss the potential for fruitful exchange between the diverse fields researching innovation. Comparisons of innovation between human and non-human animals provide opportunities, but also pitfalls. We also summarize some key findings specifying the circumstances in which innovation occurs, discussing factors such as the intrinsic nature of innovative individuals and the environmental and socio-ecological conditions that promote innovation, such as necessity, opportunity and free resources. We also highlight key controversies, including the relationship between innovation and intelligence, and the notion of innovativeness as an individual-level trait. Finally, we discuss current research methods and suggest some novel approaches that could fruitfully be deployed. PMID- 26926274 TI - The reluctant innovator: orangutans and the phylogeny of creativity. AB - Young orangutans are highly neophobic, avoid independent exploration and show a preference for social learning. Accordingly, they acquire virtually all their learned skills through exploration that is socially induced. Adult exploration rates are also low. Comparisons strongly suggest that major innovations, i.e. behaviours that have originally been brought into the population through individual invention, are made where ecological opportunities to do so are propitious. Most populations nonetheless have large innovation repertoires, because innovations, once made, are retained well through social transmission. Wild orangutans are therefore not innovative. In striking contrast, zoo-living orangutans actively seek novelty and are highly exploratory and innovative, probably because of positive reinforcement, active encouragement by human role models, increased sociality and an expectation of safety. The explanation for this contrast most relevant to hominin evolution is that captive apes generally have a highly reduced cognitive load, in particular owing to the absence of predation risk, which strongly reduces the costs of exploration. If the orangutan results generalize to other great apes, this suggests that our ancestors could have become more curious once they had achieved near-immunity to predation on the eve of the explosive increase in creativity characterizing the Upper Palaeolithic Revolution. PMID- 26926275 TI - Environmental and genetic determinants of innovativeness in a natural population of birds. AB - Much of the evidence for the idea that individuals differ in their propensity to innovate and solve new problems has come from studies on captive primates. Increasingly, behavioural ecologists are studying innovativeness in wild populations, and uncovering links with functional behaviour and fitness-related traits. The relative importance of genetic and environmental factors in driving this variation, however, remains unknown. Here, we present the results of the first large-scale study to examine a range of causal factors underlying innovative problem-solving performance (PSP) among 831 great tits (Parus major) temporarily taken into captivity. Analyses show that PSP in this population: (i) was linked to a variety of individual factors, including age, personality and natal origin (immigrant or local-born); (ii) was influenced by natal environment, because individuals had a lower PSP when born in poor-quality habitat, or where local population density was high, leading to cohort effects. Links with many of the individual and environmental factors were present only in some years. In addition, PSP (iii) had little or no measurable heritability, as estimated by a Bayesian animal model; and (iv) was not influenced by maternal effects. Despite previous reports of links between PSP and a range of functional traits in this population, the analyses here suggest that innovativeness had weak if any evolutionary potential. Instead most individual variation was caused by phenotypic plasticity driven by links with other behavioural traits and by environmentally mediated developmental stress. Heritability estimates are population, time and context specific, however, and more studies are needed to determine the generality of these effects. Our results shed light on the causes of innovativeness within populations, and add to the debate on the relative importance of genetic and environmental factors in driving phenotypic variation within populations. PMID- 26926276 TI - The coevolution of innovation and technical intelligence in primates. AB - In birds and primates, the frequency of behavioural innovation has been shown to covary with absolute and relative brain size, leading to the suggestion that large brains allow animals to innovate, and/or that selection for innovativeness, together with social learning, may have driven brain enlargement. We examined the relationship between primate brain size and both technical (i.e. tool using) and non-technical innovation, deploying a combination of phylogenetically informed regression and exploratory causal graph analyses. Regression analyses revealed that absolute and relative brain size correlated positively with technical innovation, and exhibited consistently weaker, but still positive, relationships with non-technical innovation. These findings mirror similar results in birds. Our exploratory causal graph analyses suggested that technical innovation shares strong direct relationships with brain size, body size, social learning rate and social group size, whereas non-technical innovation did not exhibit a direct relationship with brain size. Nonetheless, non-technical innovation was linked to brain size indirectly via diet and life-history variables. Our findings support 'technical intelligence' hypotheses in linking technical innovation to encephalization in the restricted set of primate lineages where technical innovation has been reported. Our findings also provide support for a broad co evolving complex of brain, behaviour, life-history, social and dietary variables, providing secondary support for social and ecological intelligence hypotheses. The ability to gain access to difficult-to-extract, but potentially nutrient rich, resources through tool use may have conferred on some primates adaptive advantages, leading to selection for brain circuitry that underlies technical proficiency. PMID- 26926277 TI - The life-history basis of behavioural innovations. AB - The evolutionary origin of innovativeness remains puzzling because innovating means responding to novel or unusual problems and hence is unlikely to be selected by itself. A plausible alternative is considering innovativeness as a co opted product of traits that have evolved for other functions yet together predispose individuals to solve problems by adopting novel behaviours. However, this raises the question of why these adaptations should evolve together in an animal. Here, we develop the argument that the adaptations enabling animals to innovate evolve together because they are jointly part of a life-history strategy for coping with environmental changes. In support of this claim, we present comparative evidence showing that in birds, (i) innovative propensity is linked to life histories that prioritize future over current reproduction, (ii) the link is in part explained by differences in brain size, and (iii) innovative propensity and life-history traits may evolve together in generalist species that frequently expose themselves to novel or unusual conditions. Combined with previous evidence, these findings suggest that innovativeness is not a specialized adaptation but more likely part of a broader general adaptive system to cope with changes in the environment. PMID- 26926278 TI - Feeding innovations in a nested phylogeny of Neotropical passerines. AB - Several studies on cognition, molecular phylogenetics and taxonomic diversity independently suggest that Darwin's finches are part of a larger clade of speciose, flexible birds, the family Thraupidae, a member of the New World nine primaried oscine superfamily Emberizoidea. Here, we first present a new, previously unpublished, dataset of feeding innovations covering the Neotropical region and compare the stem clades of Darwin's finches to other neotropical clades at the levels of the subfamily, family and superfamily/order. Both in terms of raw frequency as well as rates corrected for research effort and phylogeny, the family Thraupidae and superfamily Emberizoidea show high levels of innovation, supporting the idea that adaptive radiations are favoured when the ancestral stem species were flexible. Second, we discuss examples of innovation and problem-solving in two opportunistic and tame Emberizoid species, the Barbados bullfinch Loxigilla barbadensis and the Carib grackle Quiscalus lugubris fortirostris in Barbados. We review studies on these two species and argue that a comparison of L. barbadensis with its closest, but very shy and conservative local relative, the black-faced grassquit Tiaris bicolor, might provide key insights into the evolutionary divergence of cognition. PMID- 26926279 TI - Selectivity in social and asocial learning: investigating the prevalence, effect and development of young children's learning preferences. AB - Culture evolution requires both modification and faithful replication of behaviour, thus it is essential to understand how individuals choose between social and asocial learning. In a quasi-experimental design, 3- and 5-year-olds (176), and adults (52) were presented individually with two novel artificial fruits, and told of the apparatus' relative difficulty (easy versus hard). Participants were asked if they wanted to attempt the task themselves or watch an experimenter attempt it first; and then had their preference either met or violated. A significant proportion of children and adults (74%) chose to learn socially. For children, this request was efficient, as observing a demonstration made them significantly quicker at the task than learning asocially. However, for 5-year-olds, children who selected asocial learning were also found to be highly efficient at the task, showing that by 5 years children are selective in choosing a learning strategy that is effective for them. Adults further evidenced this trend, and also showed selectivity based on task difficulty. This is the first study to examine the rates, performance outcomes and developmental trajectory of preferences in asocial and social learning, ultimately informing our understanding of innovation. PMID- 26926280 TI - Individual differences in children's innovative problem-solving are not predicted by divergent thinking or executive functions. AB - Recent studies of children's tool innovation have revealed that there is variation in children's success in middle-childhood. In two individual differences studies, we sought to identify personal characteristics that might predict success on an innovation task. In Study 1, we found that although measures of divergent thinking were related to each other they did not predict innovation success. In Study 2, we measured executive functioning including: inhibition, working memory, attentional flexibility and ill-structured problem solving. None of these measures predicted innovation, but, innovation was predicted by children's performance on a receptive vocabulary scale that may function as a proxy for general intelligence. We did not find evidence that children's innovation was predicted by specific personal characteristics. PMID- 26926281 TI - The effects of environment and ownership on children's innovation of tools and tool material selection. AB - Research indicates that in experimental settings, young children of 3-7 years old are unlikely to devise a simple tool to solve a problem. This series of exploratory studies done in museums in the US and UK explores how environment and ownership of materials may improve children's ability and inclination for (i) tool material selection and (ii) innovation. The first study takes place in a children's museum, an environment where children can use tools and materials freely. We replicated a tool innovation task in this environment and found that while 3-4 year olds showed the predicted low levels of innovation rates, 4-7 year olds showed higher rates of innovation than the younger children and than reported in prior studies. The second study explores the effect of whether the experimental materials are owned by the experimenter or the child on tool selection and innovation. Results showed that 5-6 year olds and 6-7 year olds were more likely to select tool material they owned compared to tool material owned by the experimenter, although ownership had no effect on tool innovation. We argue that learning environments supporting tool exploration and invention and conveying ownership over materials may encourage successful tool innovation at earlier ages. PMID- 26926282 TI - Innovation in the collective brain. AB - Innovation is often assumed to be the work of a talented few, whose products are passed on to the masses. Here, we argue that innovations are instead an emergent property of our species' cultural learning abilities, applied within our societies and social networks. Our societies and social networks act as collective brains. We outline how many human brains, which evolved primarily for the acquisition of culture, together beget a collective brain. Within these collective brains, the three main sources of innovation are serendipity, recombination and incremental improvement. We argue that rates of innovation are heavily influenced by (i) sociality, (ii) transmission fidelity, and (iii) cultural variance. We discuss some of the forces that affect these factors. These factors can also shape each other. For example, we provide preliminary evidence that transmission efficiency is affected by sociality--languages with more speakers are more efficient. We argue that collective brains can make each of their constituent cultural brains more innovative. This perspective sheds light on traits, such as IQ, that have been implicated in innovation. A collective brain perspective can help us understand otherwise puzzling findings in the IQ literature, including group differences, heritability differences and the dramatic increase in IQ test scores over time. PMID- 26926283 TI - Identifying innovation in laboratory studies of cultural evolution: rates of retention and measures of adaptation. AB - In recent years, laboratory studies of cultural evolution have become increasingly prevalent as a means of identifying and understanding the effects of cultural transmission on the form and functionality of transmitted material. The datasets generated by these studies may provide insights into the conditions encouraging, or inhibiting, high rates of innovation, as well as the effect that this has on measures of adaptive cultural change. Here we review recent experimental studies of cultural evolution with a view to elucidating the role of innovation in generating observed trends. We first consider how tasks are presented to participants, and how the corresponding conceptualization of task success is likely to influence the degree of intent underlying any deviations from perfect reproduction. We then consider the measures of interest used by the researchers to track the changes that occur as a result of transmission, and how these are likely to be affected by differing rates of retention. We conclude that considering studies of cultural evolution from the perspective of innovation provides us with valuable insights that help to clarify important differences in research designs, which have implications for the likely effects of variation in retention rates on measures of cultural adaptation. PMID- 26926284 TI - Innovation cascades: artefacts, organization and attributions. AB - Innovation cascades inextricably link the introduction of new artefacts, transformations in social organization, and the emergence of new functionalities and new needs. This paper describes a positive feedback dynamic, exaptive bootstrapping, through which these cascades proceed, and the characteristics of the relationships in which the new attributions that drive this dynamic are generated. It concludes by arguing that the exaptive bootstrapping dynamic is the principal driver of our current Innovation Society. PMID- 26926285 TI - From mechanisms to function: an integrated framework of animal innovation. AB - Animal innovations range from the discovery of novel food types to the invention of completely novel behaviours. Innovations can give access to new opportunities, and thus enable innovating agents to invade and create novel niches. This in turn can pave the way for morphological adaptation and adaptive radiation. The mechanisms that make innovations possible are probably as diverse as the innovations themselves. So too are their evolutionary consequences. Perhaps because of this diversity, we lack a unifying framework that links mechanism to function. We propose a framework for animal innovation that describes the interactions between mechanism, fitness benefit and evolutionary significance, and which suggests an expanded range of experimental approaches. In doing so, we split innovation into factors (components and phases) that can be manipulated systematically, and which can be investigated both experimentally and with correlational studies. We apply this framework to a selection of cases, showing how it helps us ask more precise questions and design more revealing experiments. PMID- 26926286 TI - Adaptable individuals and innovative lineages. AB - This paper suggests (i) that while work on animal innovation has made good progress in understanding some of the proximate mechanisms and selective regimes through which innovation emerges, it has somewhat neglected the role of the social environment of innovation; a neglect manifest in the fact that innovation counts are almost always counts of resource-acquisition innovations; the invention of social tools is rarely considered. The same is true of many experimental projects, as these typically impose food acquisition tasks on their experimental subjects. (ii) That neglect is important, because innovations often pose collective action problems; the hominin species were technically innovative because they were also socially adaptable. (iii) In part for this reason, there remains a disconnect between research on hominin innovation and research on animal innovation. (iv) Finally, the paper suggests that there is something of a disconnect between the theoretical work on innovation in hominin evolution (based on theories of cultural evolution) and the experimental tradition on human innovation. That disconnect is largely due to the theoretical work retreating from strong claims about the proximate mechanisms of human cultural accumulation. PMID- 26926287 TI - Innovativeness as an emergent property: a new alignment of comparative and experimental research on animal innovation. AB - Innovation and creativity are key defining features of human societies. As we face the global challenges of the twenty-first century, they are also facets upon which we must become increasingly reliant. But what makes Homo sapiens so innovative and where does our high innovation propensity come from? Comparative research on innovativeness in non-human animals allows us to peer back through evolutionary time and investigate the ecological factors that drove the evolution of innovativeness, whereas experimental research identifies and manipulates underpinning creative processes. In commenting on the present theme issue, I highlight the controversies that have typified this research field and show how a paradigmatic shift in our thinking about innovativeness will contribute to resolving these tensions. In the past decade, innovativeness has been considered by many as a trait, a direct product of cognition, and a direct target of selection. The evidence I review here suggests that innovativeness will be hereon viewed as one component, or even an emergent property of a larger array of traits, which have evolved to deal with environmental variation. I illustrate how research should capitalize on taxonomic diversity to unravel the full range of psychological processes that underpin innovativeness in non-human animals. PMID- 26926288 TI - Serum ferritin levels are associated with arterial stiffness in healthy Korean adults. AB - Although an association between serum ferritin and atherosclerosis has been suggested, limited epidemiologic data are available regarding the association between ferritin and arterial stiffness in healthy adults. A total of 2932 healthy subjects were enrolled in this study. Anthropometric and biochemical profiles including ferritin were measured. The arterial stiffness was measured using brachial-ankle pulse wave velocity (baPWV). Serum ferritin levels were classified into quartiles and baPWV values gradually increased with each ferritin quartile. Multiple regression analysis showed that ferritin levels were independently correlated with baPWV. After adjusting for multiple risk factors, as compared with the lowest quartile, the odds ratios for high baPWV (>75(th) percentile) were 1.15 (0.84-1.56), 1.37 (0.97-1.73), and 1.46 (1.29-2.17) among men (p for trend < 0.05) and 1.24 (0.87-1.79), 1.53 (1.09-2.16), and 1.80 (1.25 2.82) among women (p for trend < 0.05), for the second, third, and fourth quartiles of ferritin, respectively. In conclusion, serum ferritin levels are independently associated with arterial stiffness in healthy Korean adults. PMID- 26926289 TI - The impact of perioperative red blood cell transfusions in patients undergoing liver resection: a systematic review protocol. AB - BACKGROUND: Liver resection is commonly performed for malignant and benign disease and is associated with frequent use of intraoperative and postoperative blood transfusions. Blood transfusions are potentially life-saving, but they have many adverse effects; some well understood, and others less so. Some of the poorly understood side effects include increased risk of postoperative complications and possibly worse oncologic outcomes. The objective of this systematic review is to provide estimates of transfusion prevalence and the effects of perioperative blood transfusion on postoperative mortality and morbidity and long-term cancer outcomes in patients undergoing liver resection. METHODS/DESIGN: The Cochrane, Medline, and EMBASE databases will be searched for any randomized controlled trial or observational cohort study comparing liver resection patients that received intraoperative or postoperative allogeneic red blood cell transfusions to those who did not. Outcomes include postoperative mortality, postoperative morbidity (infectious, liver failure, renal failure, cardiovascular/cerebrovascular events, and thromboembolic events), and long-term disease-free and overall survival. Only studies with adult, human patients (>18 years old) undergoing liver resection, in which the primary intervention of interest is blood transfusion will be included. Data will be extracted by two reviewers in duplicate and synthesized into a narrative review. Risk of bias will be assessed. When clinically and methodologically appropriate, meta-analysis will be performed. DISCUSSION: Our review will synthesize the literature pertaining to the potential beneficial and detrimental effects of red blood cell transfusion in patients undergoing liver resection. It will be an important step in the development of guidelines for the appropriate use of blood transfusions in patients undergoing liver resection. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42015026132. PMID- 26926290 TI - Distinct dendritic morphology across the blades of the rodent dentate gyrus. AB - The dentate gyrus (DG) is a hippocampal region that has long been characterized as a critical mediator of enduring memory formation and retrieval. As such, there is a wealth of studies investigating this area. Most of these studies have either treated the DG as a homogeneous structure, or examined differences in neurons along the septal-temporal axis. Recent data, however, have indicated that a functional distinction exists between the suprapyramidal and infrapyramidal blades of the DG, with the former showing more robust responses during spatial tasks. To date, few anatomical studies have addressed this functional gradient in rats, and no study has done so in the mouse. To address this, we investigated dendritic morphology and spine density in hippocampal granule cells of rats and mice using the Golgi-Cox technique. We find that granule cells from the suprapyramidal blade of the DG contain greater dendritic material in the region receiving spatial information from the medial perforant path. This provides a potential anatomical substrate for the asymmetric response of the DG to spatial input. Synapse 70:277-282, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26926292 TI - Diagnostic Cardiac Catheterization in the Pediatric Population. AB - Although the utility of diagnostic cardiac catheterization in the clinical setting has diminished over the last years, due to the emergence of noninvasive imaging modalities, such as echocardiography, magnetic resonance imaging and computed tomography, catheterization for diagnostic reasons still constitutes a valuable tool in certain parts in the workup of pediatric heart disease. As a result, awareness of the main aspects of diagnostic catheterization is of great importance for the clinical cardiologist. In this article, the main variables measured and the main actions performed during diagnostic cardiac catheterization in children are discussed. PMID- 26926293 TI - Potential Role of microRNAs in Cardiovascular Disease: Are They up to Their Hype? AB - PURPOSE OF REVIEW: Cardiovascular diseases remain the foremost cause of mortality globally. As molecular medicine unravels the alterations in genomic expression and regulation of the underlying atherosclerotic process, it opens new vistas for discovering novel diagnostic biomarkers and therapeutics for limiting the disease process. miRNAs have emerged as powerful regulators of protein translation by regulating gene expression at the post-transcriptional level. RECENT FINDINGS: Overexpression and under-expression of specific miRNAs are being evaluated as a novel approach to diagnosis and treatment of cardiovascular disease. This review sheds light on the current knowledge of the miRNA evaluated in cardiovascular disease. CONCLUSION: In this review we summarize the data, including the more recent data, regarding miRNAs in cardiovascular disease and their potential role in future in diagnostic and therapeutic strategies. PMID- 26926291 TI - Therapeutic Utilities of Pediatric Cardiac Catheterization. AB - In an era when less invasive techniques are favored, therapeutic cardiac catheterization constantly evolves and widens its spectrum of usage in the pediatric population. The advent of sophisticated devices and well-designed equipment has made the management of many congenital cardiac lesions more efficient and safer, while providing more comfort to the patient. Nowadays, a large variety of heart diseases are managed with transcatheter techniques, such as patent foramen ovale, atrial and ventricular septal defects, valve stenosis, patent ductus arteriosus, aortic coarctation, pulmonary artery and vein stenosis and arteriovenous malformations. Moreover, hybrid procedures and catheter ablation have opened new paths in the treatment of complex cardiac lesions and arrhythmias, respectively. In this article, the main therapeutic utilities of cardiac catheterization in children are discussed. PMID- 26926295 TI - A Practical Comprehensive Approach to Management of Acute Decompensated Heart Failure. AB - Heart failure (HF) has a high incidence and prevalence in the USA and worldwide. It is a very common cause of significant morbidity and mortality with serious cost implications on the US health sector. The primary focus of this review is to synthesize an effective comprehensive care plan for patients in acute decompensated heart failure (ADHF) based on the most current evidence available. It begins with a brief overview of the pathophysiology, clinical presentation and evaluation of patients in ADHF. It then reviews management goals and treatment guidelines, with emphasis on challenges presented by diuretic resistance and worsening renal function (WRF). It provides information on recognition of advanced HF even during acute presentation, estimation of prognosis and proactive identification of patients that will benefit from mechanical cardiac devices, transplantation and palliative care/hospice. In addition, it presents strategies to address the problem of readmissions, which is an ominous prognostic factor with enormous economic burden. PMID- 26926294 TI - Drug-induced Inhibition and Trafficking Disruption of ion Channels: Pathogenesis of QT Abnormalities and Drug-induced Fatal Arrhythmias. AB - Risk of severe and fatal ventricular arrhythmias, presenting as Torsade de Pointes (TdP), is increased in congenital and acquired forms of long QT syndromes (LQTS). Drug-induced inhibition of K+ currents, IKs, IKr, IK1, and/or Ito, delay repolarization, prolong QT, and increase the risk of TdP. Drug-induced interference with IKr is the most common cause of acquired LQTS/TdP. Multiple drugs bind to KNCH2-hERG-K+ channels affecting IKr, including antiarrythmics, antibiotics, antivirals, azole-antifungals, antimalarials, anticancer, antiemetics, prokinetics, antipsychotics, and antidepressants. Azithromycin has been recently added to this list. In addition to direct channel inhibition, some drugs interfere with the traffic of channels from the endoplasmic reticulum to the cell membrane, decreasing mature channel membrane density; e.g., pentamidine, geldalamicin, arsenic trioxide, digoxin, and probucol. Other drugs, such as ketoconazole, fluoxetine, norfluoxetine, citalopram, escitalopram, donepezil, tamoxifen, endoxifen, atazanavir, and roxitromycin, induce both direct channel inhibition and impaired channel trafficking. Although many drugs prolong the QT interval, TdP is a rare event. The following conditions increase the risk of drug induced TdP: a) Disease states/electrolyte levels (heart failure, structural cardiac disease, bradycardia, hypokalemia); b) Pharmacogenomic variables (presence of congenital LQTS, subclinical ion-channel mutations, history of or having a relative with history of drug-induced long QT/TdP); c) Pharmacodynamic and kinetic factors (high doses, women, elderly, metabolism inhibitors, combining two or more QT prolonging drugs, drugs that prolong the QT and increase QT dispersion, and drugs with multiple actions on ion channels). Because most of these conditions are preventable, careful evaluation of risk factors and increased knowledge of drug use associated with repolarization abnormalities are strongly recommended. PMID- 26926298 TI - Evaluation of the transcriptional status of host cytokines and viral genes in the trachea of vaccinated and non-vaccinated chickens after challenge with the infectious laryngotracheitis virus. AB - Infectious laryngotracheitis is a highly contagious disease of chickens responsible for significant economic losses for the poultry industry worldwide. The disease is caused by Gallid herpesvirus-1 (GaHV-1) commonly known as the infectious laryngotracheitis virus. Although characterized by their potential to regain virulence, chicken embryo origin (CEO) vaccines are the most effective vaccines against laryngotracheitis as they significantly reduce the replication of challenge virus in the trachea and conjunctiva. Knowledge on the nature of protective immunity elicited by CEO vaccines is very limited. Therefore, elucidating the origin of the immune responses elicited by CEO vaccination is relevant for development of safer control strategies. In this study the transcription levels of key host immune genes (IFN-gamma, IFN-beta, IL-1beta, IL 6, IL-8, IL-18) and viral genes (ICP4, ICP27, UL46, UL49), as well as viral genome loads in trachea were quantified at 6 and 12 hours post-challenge of CEO vaccinated and non-vaccinated chickens. Immediately after challenge a significant increase in IFN-gamma gene expression was followed by a significant reduction in viral replication. In contrast to the rapid induction of IFN-gamma, expression of the pro-inflammatory cytokines (IL-1beta, IL-6, IL-8) and type I IFN beta was either slightly reduced or remained at basal levels. These suggest that the former cytokines may not play important roles during immediate early responses induced by ILTV challenge in either vaccinated or non-vaccinated chickens. Overall, these results suggest that the rapid expression of IFN-gamma may induce pathways of antiviral responses necessary for blocking early virus replication. PMID- 26926297 TI - Urinary Glycosaminoglycans Predict Outcomes in Septic Shock and Acute Respiratory Distress Syndrome. AB - RATIONALE: Degradation of the endothelial glycocalyx, a glycosaminoglycan (GAG) rich layer lining the vascular lumen, is associated with the onset of kidney injury in animal models of critical illness. It is unclear if similar pathogenic degradation occurs in critically ill patients. OBJECTIVES: To determine if urinary indices of GAG fragmentation are associated with outcomes in patients with critical illnesses such as septic shock or acute respiratory distress syndrome (ARDS). METHODS: We prospectively collected urine from 30 patients within 24 hours of admission to the Denver Health Medical Intensive Care Unit (ICU) for septic shock. As a nonseptic ICU control, we collected urine from 25 surgical ICU patients admitted for trauma. As a medical ICU validation cohort, we obtained serially collected urine samples from 70 patients with ARDS. We performed mass spectrometry on urine samples to determine GAG (heparan sulfate, chondroitin sulfate, and hyaluronic acid) concentrations as well as patterns of heparan sulfate/chondroitin sulfate disaccharide sulfation. We compared these indices to measurements obtained using dimethylmethylene blue, an inexpensive, colorimetric urinary assay of sulfated GAGs. MEASUREMENTS AND MAIN RESULTS: In septic shock, indices of GAG fragmentation correlated with both the development of renal dysfunction over the 72 hours after urine collection and with hospital mortality. This association remained after controlling for severity of illness and was similarly observed using the inexpensive dimethylmethylene blue assay. These predictive findings were corroborated using urine samples previously collected at three consecutive time points from patients with ARDS. CONCLUSIONS: Early indices of urinary GAG fragmentation predict acute kidney injury and in hospital mortality in patients with septic shock or ARDS. Clinical trial registered with www.clinicaltrials.gov (NCT01900275). PMID- 26926296 TI - Clinical Characteristics and Treatment of Cardiomyopathies in Children. AB - Cardiomyopathies are diseases of the heart muscle, a term introduced in 1957 to identify a group of myocardial diseases not attributable to coronary artery disease. The definition has since been modified to refer to structural and or functional abnormalities of the myocardium where other known causes of myocardial dysfunction, such as systemic hypertension, valvular disease and ischemic heart disease, have been excluded. In this review, we discuss the pathophysiology, clinical assessment and therapeutic strategies for hypertrophic, dilated and hypertrophic cardiomyopathies, with a particular focus on aspects unique to children. PMID- 26926300 TI - The Monocyte-to-Lymphocyte Ratio Correlates with Psycho-Neuro-Inflammatory Factors in Patients with Stable Coronary Artery Disease. AB - BACKGROUND: Psychosocial stress and depression have been recognized as major risk factors of coronary artery disease (CAD). Although monocytes are known to be key players in atherosclerosis, monocyte-based associations with psychoneuroendocrino immuno-inflammatory (PNI) markers have not been widely investigated in stable CAD. OBJECTIVE: We examined associations between the monocyte-to-lymphocyte ratio (MLR) and key PNI markers in stable CAD. METHODS: We studied 23 patients with stable CAD who completed the Beck Depression Inventory (BDI) and Rahe's Brief Stress and Coping Inventory. A white blood cell differential was performed, and levels of cortisol, chromogranin A (CgA), LL-37, interleukin-6 (IL-6) and C reactive protein (CRP) were assayed in plasma. RESULTS: Monocyte fraction, MLR and plasma CgA levels exceeded reference values, the social support score was low, and 7 patients had elevated BDI scores. In the multivariate-adjusted analysis, a higher MLR was associated with greater depressive symptom severity (r = 0.624, p < 0.01) as well as with higher concentrations of CgA (r = 0.660, p < 0.01), LL-37 (r = 0.643, p < 0.01), IL-6 (r = 0.532, p < 0.05) and CRP (r = 0.470, p < 0.05). BDI scores associated with CgA concentration (r = 0.618, p < 0.01) and CgA level correlated negatively with the social support score (r = 0.511, p < 0.05). CONCLUSIONS: Our findings suggest that, in patients with stable CAD, elevated MLR may be associated with depressive symptoms, with increased neuroendocrine-sympathetic activity (marked by CgA) and inflammatory markers that are pertinent to atherosclerosis initiation and progression. The increased neuroendocrine-sympathetic activity correlated with low social support and depressive symptom severity. The MLR might serve as an easy-to-obtain and inexpensive proxy measure of an activated PNI network in stable CAD. PMID- 26926299 TI - Maintenance of Tissue Pluripotency by Epigenetic Factors Acting at Multiple Levels. AB - Pluripotent stem cells often adopt a unique developmental program while retaining certain flexibility. The molecular basis of such properties remains unclear. Using differentiation of pluripotent Drosophila imaginal tissues as assays, we examined the contribution of epigenetic factors in ectopic activation of Hox genes. We found that over-expression of Trithorax H3K4 methyltransferase can induce ectopic adult appendages by selectively activating the Hox genes Ultrabithorax and Sex comb reduced in wing and leg discs, respectively. This tissue-specific inducibility correlates with the presence of paused RNA polymerase II in the promoter-proximal region of these genes. Although the Antennapedia promoter is paused in eye-antenna discs, it cannot be induced by Trx without a reduction in histone variants or their chaperones, suggesting additional control by the nucleosomal architecture. Lineage tracing and pulse chase experiments revealed that the active state of Hox genes is maintained substantially longer in mutants deficient for HIRA, a chaperone for the H3.3 variant. In addition, both HIRA and H3.3 appeared to act cooperatively with the Polycomb group of epigenetic repressors. These results support the involvement of H3.3-mediated nucleosome turnover in restoring the repressed state. We propose a regulatory framework integrating transcriptional pausing, histone modification, nucleosome architecture and turnover for cell lineage maintenance. PMID- 26926302 TI - Lyophilized Cyclamen europaeum tuber extract in the treatment of rhinosinusitis. AB - Nasal and sinus mucositis is a significant health problem associated with significant organizational and financial burden for the health care system. In recent years, several important guidelines and positions of expert groups and scientific associations have been published with regard to the diagnostics and treatment of rhinosinusitis, including European Position Paper on Rhinosinusitis and Nasal Polyps (EPOS 2012) [1] and Polish Standards for the Treatment of Rhinitis (PoSLeNN 2013) [2]. The management of viral and postviral rhinosinusitis involves systemic treatment including administration of plant origin products. The goal of this article is to present the current knowledge on the use of intranasal preparations containing natural saponin fractions from the rhizomes of Alpine cyclamen (Cyclamen europaeum). Saponins contained in the extract of Alpine cyclamen (Cyclamen europaeum) rhizomes are surface-active compounds that reduce the surface tension on the nasal mucosal cells while simultaneously stimulating the trigeminal nerve receptors leading to increased production of seromucous secretion and extensive drainage of the nasal and sinus cavities. The analysis of published studies on the efficacy and safety of intranasal products containing lyophilized extracts from Cyclamen europaeum tuber warrants the conclusion that these products are useful in the management of nasal and sinus mucositis due to their beneficial impact on the course of the treatment of acute rhinosinusitis. When used in patients with acute rhinosinusitis, an intranasal preparation containing lyophilized extracts from Cyclamen europaeum tuber efficiently reduces the symptoms, particularly the feeling of pressure and pain in the face. According to the authors of PROSINUS study, single-agent treatment using Cyclamen europaeum extracts is more efficient (in terms of the percentage of success) than other monotherapy or combination regimens. PMID- 26926301 TI - Gestational weight gain standards based on women enrolled in the Fetal Growth Longitudinal Study of the INTERGROWTH-21st Project: a prospective longitudinal cohort study. AB - OBJECTIVE: To describe patterns in maternal gestational weight gain (GWG) in healthy pregnancies with good maternal and perinatal outcomes. DESIGN: Prospective longitudinal observational study. SETTING: Eight geographically diverse urban regions in Brazil, China, India, Italy, Kenya, Oman, United Kingdom, and United States, April 2009 to March 2014. PARTICIPANTS: Healthy, well nourished, and educated women enrolled in the Fetal Growth Longitudinal Study component of the INTERGROWTH-21(st) Project, who had a body mass index (BMI) of 18.50-24.99 in the first trimester of pregnancy. MAIN OUTCOME MEASURES: Maternal weight measured with standardised methods and identical equipment every five weeks (plus/minus one week) from the first antenatal visit (<14 weeks' gestation) to delivery. After confirmation that data from the study sites could be pooled, a multilevel, linear regression analysis accounting for repeated measures, adjusted for gestational age, was applied to produce the GWG values. RESULTS: 13,108 pregnant women at <14 weeks' gestation were screened, and 4607 met the eligibility criteria, provided consent, and were enrolled. The variance within sites (59.6%) was six times higher than the variance between sites (9.6%). The mean GWGs were 1.64 kg, 2.86 kg, 2.86 kg, 2.59 kg, and 2.56 kg for the gestational age windows 14-18(+6) weeks, 19-23(+6) weeks, 24-28(+6) weeks, 29 33(+6) weeks, and 34-40(+0) weeks, respectively. Total mean weight gain at 40 weeks' gestation was 13.7 (SD 4.5) kg for 3097 eligible women with a normal BMI in the first trimester. Of all the weight measurements, 71.7% (10,639/14,846) and 94.9% (14,085/14,846) fell within the expected 1 SD and 2 SD thresholds, respectively. Data were used to determine fitted 3rd, 10th, 25th, 50th, 75th, 90th, and 97th smoothed GWG centiles by exact week of gestation, with equations for the mean and standard deviation to calculate any desired centiles according to gestational age in exact weeks. CONCLUSIONS: Weight gain in pregnancy is similar across the eight populations studied. Therefore, the standards generated in this study of healthy, well nourished women may be used to guide recommendations on optimal gestational weight gain worldwide. PMID- 26926303 TI - The role of otolaryngologist - head and neck surgeon's in the treatment of thyroid cancer. AB - INTRODUCTION: Thyroid gland is an integral part of the neck region. In the topographic anatomy of the head and neck the gland is located in the middle triangle of the neck. Therefore, it is an organ which is also subject for diagnostic and treatment by otorhinolaryngologists - head and neck surgeons. Material and methods The study group consists of 50 patients aged from 22 to 76 years (mean 48). All patients were treated for suspected thyroid tumor. The ratio of women to men was 35:15. In all patients the same panel of diagnostic tests was used including: endocrinologic consultation, ENT examination with stroboscopic examination with assessment of vocal cord mobility, neck ultrasound examination to assess the thyroid gland and lymph nodes. Results In 50 patients following surgical methods were used: total resection of the thyroid - 28 patients (56%), resection of one lobe of the thyroid - 17 (34%), open biopsy - 6 (12%) patients. In 5 cases tracheotomy was performed. In the case of malignancy (excluding unresctable lesions - 6 patients) selective lymph node dissection of the neck was performed (field III, IV, VI) - 11 patients (22%). Discussion Results of surgical treatment (relative to the percentage damage to the recurrent laryngeal nerve) achieved by head and neck surgeons are at levels comparable or higher compared to the results achieved by general surgeons - 1.3% for primary benign lesions (Enomoto et al.). PMID- 26926304 TI - Assessment of acoustic characteristics of voice in patients after injection laryngoplasty with hyaluronan. AB - BACKGROUND: Glottal incompetence is one of the most common contributing factors in patients who suffer from dysphonia. One of the different treatment approaches is injection laryngoplasty. The aim of the study was to assess the quality of voice in patients who were treated with hyaluronic acid injection into the vocal fold in the long-term follow-up. MATERIAL AND METHODS: The material included 39 patients with dysphonia who were referred for injection augmentation. The studied group included patients with presbyphonia, scar, sulcus, unilateral vocal fold paralysis and with atrophy of the vocal fold. Preoperative and postoperative examination was based on laryngovideostroboscopy. Patients' voice was assessed using the subjective GRBAS scale, and objective evaluation provided by Multidimensional Voice Program (MDVP) was applied. All the patients underwent injection laryngoplasty with hyaluronic acid into the vocal folds. Follow-up examinations were conducted 6, 12 and 24 months postoperatively. RESULTS: Perceptual voice quality assessed with the GRBAS scale was improved and the results were stable in the long-term follow-up periods. MDVP showed a significant statistical improvement within the group of frequency, amplitude and noise parameters. The differences in value between follow-up periods were not statistically significant. CONCLUSIONS: Acoustic analysis of voice is a reliable method for objective assessment of voice quality after applied treatment. Injection of the hyaluronic acid into the vocal fold improves the quality of voice in patients suffering from glottic insufficiency. PMID- 26926305 TI - Impact of -1607 1G/2G MMP1 gene polymorphism on the morbidity and clinical course of chronic rhinosinusitis with nasal polyps. AB - Polyps within the nose and nasal sinuses are symptoms of both local conditions such as chronic bacterial or fungal rhinosinusitis, and systemic diseases such as cystic fibrosis, hypogammaglobulinemia, NSAID hypersensitivity syndrome, bronchial asthma as well as Kartagener's syndrome, Young's syndrome, Churg Strauss' syndrome and Woakes' syndrome. The pathomechanism responsible for formation of nasal polyps remains a matter of dispute as well as the subject of numerous studies. Despite the proven role of metalloproteinases and their inhibitors in the pathomechanism of inflammation, the role of their respective polymorphisms has not been fully confirmed to date. OBJECTIVES: 1. The assessment of genetic predisposition to chronic rhinosinusitis with nasal polyps on the basis of the analysis of 1G/2G polymorphism at position -1607 of the MMP1 gene; 2. Determination of correlation between the variability of MMP1 gene and the natural history of chronic rhinosinusitis with nasal polyps; 3. Determination of the relationship between epidemiological or clinical features and the results of genotyping of patients with chronic rhinosinusitis with nasal polyps Material and method The study included 206 patients subjected to surgical treatment due to chronic rhinosinusitis with nasal polyps and 463 healthy volunteers hospitalized at the Department of Otolaryngology and Oncological Laryngology of the Medical University of Lodz. The analysis of 1G/2G polymorphism at position -1607 of the MMP1 gene was based on TaqMan(r) SNP Genotyping Assays (Applied Biosystems, USA). RESULTS: The 1G/2G polymorphic variants at position -1607 of the MMP1 gene did not predispose patients to CRSNP+, although a trend towards increased risk of the disease could be observed in the mutated allele (InsG) carriers. However, the correlation was not statistically significant (OR 1.175; 95%CI 0.5391-1.1142; p=0.16822). In comparison to wild-type homozygotic genotype, the carriers of 1607 1G/2G mutated allele (InsG) were characterized by: 1. significantly younger age at which surgical treatment was required following conservative treatment that had proven insufficient to control CRSNP+ (p=0.025); 2. significantly higher rate of recurrence requiring surgical intervention (p=0.002); 3. trend towards higher intensity of sinus-related symptoms as assessed using a VAS scale; 4. more frequent incidence of CRSNP+ with hypersensitivity to aspirin (correlation on the border of significance, p=0.054); 5. less common bronchial asthma comorbidity (p=0.021); 6. family history of CSRNP+ (p=0.045). CONCLUSIONS: The 1G/2G polymorphism at position -1607 of the MMP1 gene may impact patients' predisposition to chronic rhinosinusitis with nasal polyps. Polymorphic variants are consistent with overall morbidity and may constitute risk variants. The status of a carrier of mutated (G insertion) allele with regard to the 1G/2G polymorphism at position -1607 within the MMP1 gene may determine a pathological phenotype associated with a more severe clinical course of CRSNP+ including earlier onset and disease recurrence. PMID- 26926307 TI - The effects of palatal lengthening on the functional and speech outcomes after submucous cleft palate repair. AB - This study was designed to compare intravelar veloplasty with and without V-Y pushback palatoplasty regarding postoperative functional and speech outcomes. THE AIM: is to find out the importance and influence of palatal lengthening on the functional and speech outcomes after SMCP repair. STUDY DESIGN: This is a prospective randomized comparative study of 20 patients divided into 2 equal groups. The study was conducted between February 2008 and January 2015. METHODS: Radical Intravelar Veloplasty (RIVVP group): included 10 patients with a mean age of 5.539+/-1.335 years and V-Y Pushback Pharyngoplasty and Radical Intravelar Veloplasty (VYP+RIVVP group): included 10 patients with a mean age of 5.688+/ 1.341 years for non-syndromic SMCP. SETTING: Academic tertiary care medical centres. RESULTS: In both groups there was a significant change in Eustachian tube function, nasal emission and nasal tone of voice postoperatively than preoperatively, while there was no significant difference between both groups in the postoperative outcomes as regards the same parameters (ET function, nasal emission and resonance) (p=0.558, 0.563 and 0.164 respectively). However, there was a significant difference between both groups as regards palatal lengthening, no statistically significant difference was present between both groups as regards the postoperative mean pharyngeal gap, using videoendoscopic analysis. In conclusion, RIVVP and VYP+RIVVP are both effective methods to repair non syndromic SMCP. Moreover, the lengthening of the palate in non-syndromic SMCP is an unnecessary process. PMID- 26926306 TI - Parotid gland tumours in the ENT Department in Miedzyleski Hospital in Warsaw between 2007 and 2014. AB - INTRODUCTION: Parotid gland tumours comprise 3% of all head and neck tumours. Although uncommon they are a histologically diverse group of tumors. The WHO classification of salivary gland tumours from 2005 recognizes 24 different malignant subtypes. They present different clinical courses and varying prognoses. Nearly 80% of salivary gland tumours are located in the parotid gland. MATERIAL AND METHODS: Our study evaluated retrospectively 445 patients with parotid gland tumours treated in our hospital in the period between 2007 and 2014. We analyzed surgical treatment and histological diagnosis. RESULTS: There were 253 (56.9%) women and 192 (43.1%) men. The incidence of benign neoplasms was 90%. The most frequent benign tumour was pleomorphic adenoma (46%) and Whartin's tumour (35%). The most commonly found malignant tumour was acinic cell carcinoma (23%) and adenocarcinoma (13%). Non-Hodgin lymphoma in the parotid gland constituted nearly 17% of all malignant lesions. Hybrid tumours were diagnosed in 5 cases. Each patient underwent surgical procedure. Temporary facial nerve paralysis after surgery was diagnosed among 10 patients. Additionally, among 4 patients permanent facial nerve paralysis was diagnosed, which appeared before surgery or during surgical resection of the infiltrated facial nerve. DISCUSSION: In this study the frequency of benign neoplasms was higher and its histopathology was different than in the literature. The most common malignant parotid gland neoplasm was acinic cell carcinoma. The study presents 5 cases of hybrid neoplasms which are very uncommon and cause difficulties with prognostic evaluation and treatment selection. PMID- 26926308 TI - Should ultrasound-guided fine needle aspiration be considered a first-line technique in assessing a thyroid nodule? AB - BACKGROUND: Thyroid nodule is a common finding in the general population. Fine needle aspiration remains a crucial step in the assessment of any thyroid nodules. The aim of this study is to compare the accuracy of needle aspiration with and without ultrasound guidance (USFNA, FNA respectively). METHODS: Retrospective chart review of 150 consecutive patients who had thyroid surgery. Fine needle aspiration biopsy, histopathology results alongside demographics and nodule sizes were recorded. RESULTS: There was no statistical difference in the nodule size of both groups. USFNA showed a significantly higher specificity and positive predictive values compared to FNA. CONCLUSION: When readily available, USFNA should be considered in the investigations of a thyroid nodule. PMID- 26926309 TI - Slow Gait Speed and Risk of Mortality or Hospital Readmission After Myocardial Infarction in the Translational Research Investigating Underlying Disparities in Recovery from Acute Myocardial Infarction: Patients' Health Status Registry. AB - OBJECTIVES: To determine the prognostic value of slow gait in predicting outcomes 1 year after acute myocardial infarction (AMI). DESIGN: Observational cohort with longitudinal follow-up. SETTING: Twenty-four U.S. hospitals participating in the Translational Research Investigating Underlying disparities in recovery from acute Myocardial infarction: Patients' Health status Registry. PARTICIPANTS: Older adults (>=65) with in-home gait assessment 1 month after AMI (N = 338). MEASUREMENTS: Baseline characteristics and 1-year mortality or hospital readmission adjusted using Cox proportional hazards regression in older adults with slow (<0.8 m/s) versus preserved (>=0.8 m/s) gait speed. RESULTS: Slow gait was present in 181 participants (53.6%). Those with slow gait were older, more likely to be female and nonwhite, and had a higher prevalence of heart failure and diabetes mellitus. They were also more likely to die or be readmitted to the hospital within 1 year than those with preserved gait (35.4% vs 18.5%, log-rank P = .006). This association remained significant after adjusting for age, sex, and race (slow vs preserved gait hazard ratio (HR) = 1.76, 95% confidence interval (CI)=1.08-2.87, P = .02) but was no longer significant after adding clinical factors (HR = 1.23, 95% CI=0.74-2.04, P = .43). CONCLUSION: Slow gait, a marker of frailty, is common 1 month after AMI in older adults and is associated with nearly twice the risk of dying or hospital readmission at 1 year. Understanding its prognostic importance independent of comorbidities and whether routine testing of gait speed can improve care requires further investigation. PMID- 26926310 TI - Testing the Relations Among Family Disorganization, Delay Discounting, and Adolescent Alcohol Use: A Genetically Informed Study. AB - BACKGROUND: Delay discounting is a potential etiological factor in adolescents' alcohol use, making it important to understand its antecedents. Family disorganization might contribute to delay discounting, but few studies have tested this relation. Moreover, because delay discounting is heritable, the effects of family disorganization on delay discounting might be moderated by adolescents' genetic risk for delay discounting. Thus, the current study examined the role of family disorganization, in interaction with genetic risk, in predicting adolescents' delay discounting and subsequent alcohol use. METHODS: Adolescents participated in 4 waves of data collection. Adolescents self-reported their family disorganization at T1, completed a delay discounting questionnaire at T3, and self-reported their alcohol use both at T2 (covariate) and T4 (outcome). Using results from an independent sample, we created a polygenic risk score consisting of dopaminergic genes to index genetic risk for delay discounting. RESULTS: Greater family disorganization predicted adolescents' greater delay discounting, but only for adolescents with low levels of genetic risk for delay discounting. Adolescents with high and mean levels of genetic risk for delay discounting showed elevated delay discounting regardless of their family's disorganization. Greater delay discounting prospectively predicted adolescents' greater alcohol use. Finally, the effects of family disorganization on adolescents' alcohol use were mediated through delay discounting, but only for adolescents with low levels of genetic risk. CONCLUSIONS: Results suggest multiple pathways to delay discounting. Although there are genetically influenced pathways to delay discounting, family disorganization might represent an environmental pathway to delay discounting (and subsequent alcohol use) for a subset of adolescents at low genetic risk. These findings reinforce the utility of family interventions for reducing adolescents' delay discounting and alcohol use, at least for a subgroup of adolescents. Because higher family organization did not buffer against delay discounting among adolescents with high genetic risk, future research should explore other early environmental influences that could protect these high-risk adolescents from developing these risky behaviors. PMID- 26926311 TI - The acute effect of match play on hamstring strength and lower limb flexibility in elite youth football players. AB - The aim of this study was to investigate the effect of competitive football match play on hamstring strength and lower limb flexibility. Fifteen male international youth football players were included. Hamstring strength and associated pain ratings, ankle dorsiflexion, hip extension, knee extension and flexion range of motion were evaluated immediately post-match and at intervals of 24, 48, and 72 h post-match. Strength significantly reduced post-match (P < 0.01), mean difference -0.43 (CI95 : -0.56, -0.30) and 24 h post (P < 0.05) mean difference -0.12 Nm/kg (CI95 : -0.20, -0.04). The associated pain scores significantly increased at the post-match (P < 0.01, ES = 0.61) and 24 h (P < 0.01, ES = 0.55) time intervals. At the 48 and 72 h post-match tests no significant difference was found for strength or pain ratings. No significant differences were detected for any of the range of motion measures. Competitive football match play has a significant acute and transient effect on isometric hamstring strength and associated pain levels during resisted knee flexion in male international youth players. Range of motion measures appear to remain relatively unaffected by match play. Isometric hamstring strength testing and associated pain levels might be considered for inclusion in-season to monitor player's post-match hamstring recovery characteristics. PMID- 26926312 TI - Host-derived salivary biomarkers in diagnosing periodontal disease: systematic review and meta-analysis. AB - AIM: To systematically evaluate the accuracy of host-derived salivary biomarkers in the diagnosis of periodontal disease based on the given sensitivity and specificity information. MATERIALS AND METHODS: Studies were eligible for inclusion if they had compared the diagnostic application of salivary biomarkers with clinical examination of periodontal disease. A detailed search was performed in five databases without restrictions on subject age, chronology, or language. Additionally, a partial grey-literature search was conducted. The revised Quality Assessment of Diagnostic Accuracy Studies tool and Meta-analysis were used to evaluate the selected studies. RESULTS: From the 905 screened studies, four were included in the qualitative and quantitative analysis. One biomarker, macrophage inflammatory protein-1alpha (MIP-1alpha), had excellent diagnostic accuracy and two, interleukin-1beta (IL-1beta) and interleukin-6 (IL-6), showed acceptable diagnostic values. However, the only biomarker considered excellent was evaluated in a single study, which may reduce the robustness of the results. CONCLUSION: There is currently limited evidence to confirm the diagnostic capability of salivary biomarkers in the clinical assessment of periodontal disease. Notwithstanding, the summary findings showed the growing importance of salivary biomarker, and can guide larger, well-controlled, diagnostic accuracy studies. Likewise, although not conclusive, MIP-1alpha, IL-1beta, and IL-6 may be promising biomarkers for future studies. PMID- 26926313 TI - The quest to exploit the Auger effect in cancer radiotherapy - a reflective review. AB - To identify the emergence of the recognition of the potential of the Auger effect for clinical application, and after tracing the salient milestones towards that goal, to evaluate the status quo and future prospects. It was not until 40 years after the discovery of Auger electrons, that the availability of radioactive DNA precursors enabled the biological power, and the clinical potential, of the Auger effect to be appreciated. Important milestones on the path to clinical translation have been identified and reached, but hurdles remain. Nevertheless the potential is still evident, and there is reasonable optimism that the goal of clinical translation is achievable. PMID- 26926315 TI - The legacy of the Barcroft Symposium 1972. PMID- 26926314 TI - Hypoxia, fetal and neonatal physiology: 100 years on from Sir Joseph Barcroft. PMID- 26926317 TI - Variations on fetal heart rate variability. PMID- 26926318 TI - Stereoselective Synthesis of 2-(beta-C-Glycosyl)glycals: Access to Unusual beta-C Glycosides from 3-Deoxyglycals. AB - A novel method for the highly stereoselective synthesis of beta-(1->2)-C saccharides employing 3-deoxy- and 3-C-branched glycals as hermaphroditic substrates is revealed. The generality of the C-C bond formation reaction between the two sugar units is evaluated. The developed methodology is successfully applied to the synthesis of biologically significant subunits that are present in various natural products, which include mixed C-disaccharides with adjacent THP THF rings, C-aryl glycosides, and highly functionalized beta-C-glycosides. PMID- 26926319 TI - Exenatide Once Weekly: A Review of Pharmacology and Treatment Considerations in Type 2 Diabetes. AB - PURPOSE: The pathophysiology of type 2 diabetes mellitus is complex and involves multiple organs and hormones, suggesting that successful treatment may require therapies that target multiple mechanisms. Exenatide, a glucagon-like peptide 1 receptor agonist, has a multifaceted mechanism of action involving pancreatic alpha and beta cells, hepatic glucose production, gastric motility, and satiety. Exenatide once weekly (a twice-daily formulation is also available) utilizes continuous release from biodegradable microspheres. This review discusses relevant efficacy and tolerability outcomes with exenatide once weekly in the context of its pharmacology. METHODS: The medical literature was searched to identify relevant data on the pharmacology and clinical effects of exenatide once weekly. FINDINGS: Exenatide once weekly, like the twice-daily formulation, has been shown to improve glycemic parameters, promote weight loss, result in beneficial changes in cardiovascular risk factors, and is well-tolerated. IMPLICATIONS: The characteristics of exenatide once weekly make it a treatment option for patients with type 2 diabetes. PMID- 26926316 TI - Fetal in vivo continuous cardiovascular function during chronic hypoxia. AB - Although the fetal cardiovascular defence to acute hypoxia and the physiology underlying it have been established for decades, how the fetal cardiovascular system responds to chronic hypoxia has been comparatively understudied. We designed and created isobaric hypoxic chambers able to maintain pregnant sheep for prolonged periods of gestation under controlled significant (10% O2) hypoxia, yielding fetal mean P(aO2) levels (11.5 +/- 0.6 mmHg) similar to those measured in human fetuses of hypoxic pregnancy. We also created a wireless data acquisition system able to record fetal blood flow signals in addition to fetal blood pressure and heart rate from free moving ewes as the hypoxic pregnancy is developing. We determined in vivo longitudinal changes in fetal cardiovascular function including parallel measurement of fetal carotid and femoral blood flow and oxygen and glucose delivery during the last third of gestation. The ratio of oxygen (from 2.7 +/- 0.2 to 3.8 +/- 0.8; P < 0.05) and of glucose (from 2.3 +/- 0.1 to 3.3 +/- 0.6; P < 0.05) delivery to the fetal carotid, relative to the fetal femoral circulation, increased during and shortly after the period of chronic hypoxia. In contrast, oxygen and glucose delivery remained unchanged from baseline in normoxic fetuses. Fetal plasma urate concentration increased significantly during chronic hypoxia but not during normoxia (Delta: 4.8 +/- 1.6 vs. 0.5 +/- 1.4 MUmol l(-1), P<0.05). The data support the hypotheses tested and show persisting redistribution of substrate delivery away from peripheral and towards essential circulations in the chronically hypoxic fetus, associated with increases in xanthine oxidase-derived reactive oxygen species. PMID- 26926321 TI - Drug Therapy for Rate and Rhythm Control in Nonvalvular Atrial Fibrillation: A Cross-sectional Study With Electronic Health Records in a Primary Care Cohort. AB - PURPOSE: The purpose of this study is to describe the pharmacologic management of rate and rhythm and assess which factors are associated with the prescription of these drugs in patients with nonvalvular atrial fibrillation (AF) from the Effectiveness, Safety, and Costs in Atrial Fibrillation study. METHODS: This retrospective, cross-sectional study describes the pharmacologic rate and rhythm control management strategies adopted during 2012 in all patients diagnosed as having nonvalvular AF in 2007 to 2011. The data source is the Information System for the Improvement of Research in Primary Care database, which is based on primary care electronic health records. To answer the study objectives, 3 multivariate regression models to assess the independent factors associated with the prescription of these drugs were conducted for 2012. The rate and rhythm control drugs assessed were beta-blockers, nondihydropyridine calcium channel blockers, antiarrhythmic agents, and digoxin. FINDINGS: A total of 21,304 patients were diagnosed as having nonvalvular AF; 11,638 (54.6%) had at least one heart rate measure during 2012. Of them, 7777 (66.8%) received one or more rate and/or rhythm control drugs during 2012. Most patients (5751 [73.9%] of 7777) received only one drug for rate and/or rhythm control. Rate control agents were the most frequently used in 2012, with beta-blockers the most prescribed group (4091 patients [52.6%]). A variety of different variables were associated with the prescription of rate and/or rhythm control drugs in the multivariate regression models. IMPLICATIONS: The most used pharmacologic treatment of rate and rhythm control in our AF population is beta-blockers, indicating that a rate control strategy is preferred in our setting, as widely recommended. PMID- 26926320 TI - Health Behaviors in Cervical Cancer Survivors and Associations with Quality of Life. AB - PURPOSE: Improvement in health behaviors following cancer diagnosis may contribute to better prognosis and well-being. This study examines the prevalence of health behaviors in cervical cancer survivors who have completed treatment, and associations between health behaviors and quality of life (QOL). METHODS: We recruited 204 women who had completed treatment for cervical cancer to participate in a randomized counseling intervention. Participants provided information on health behaviors (smoking, physical activity, and alcohol consumption); QOL (Functional Assessment of Cancer Therapy-Cervical questionnaire); and depression (Patient-Reported Outcomes Measurement Information System), anxiety (Patient-Reported Outcomes Measurement Information System), and distress (Brief Symptom Inventory) at baseline (9-30 months after diagnosis) and subsequent to the intervention. Data were analyzed using multivariate general linear models. FINDINGS: Participants ranged in age from 20 to 72 years at diagnosis (mean = 43 years), 41% were Hispanic, and 52% were non-Hispanic white. Three-fourths were stage 1 at diagnosis and 51% were treated with radiation with or without chemotherapy. At baseline, 15% of patients were current smokers, 4% reported alcohol consumption of >10 drinks per week, and 63% reported exercising <3 hours per week. Overall, 67.4% of cervical cancer survivors did not meet recommended national guidelines for at least 1 of these health behaviors. QOL scores were significantly higher for patients with greater physical activity (128 vs 118; P = 0.002) and increased with the number of recommended guidelines met (P for trend = 0.030). Associations between patient-reported outcomes and smoking and alcohol consumption did not reach statistical significance. Participants who met guidelines for all health behaviors also had less depression (P = 0.008), anxiety (P = 0.051), and distress (P = 0.142). Participants who improved their aggregate health behaviors during the 4-month follow-up experienced a greater improvement in QOL than those who did not improve their health behaviors (10.8 vs 4.5; P = 0.026). IMPLICATIONS: Results indicate that two-thirds of cervical cancer survivors are not meeting national guidelines for smoking, physical activity, and alcohol consumption following completion of definitive treatment. These adverse health behaviors were associated with impaired QOL and higher levels of depression and distress. Positive changes in health behaviors are associated with significant improvement in QOL. PMID- 26926322 TI - Beyond Chemotherapy: An Overview and Review of Targeted Therapy in Cervical Cancer. AB - PURPOSE: The purpose of this study was to provide an overview of current and up and coming targeted therapies in cervical cancer with or without chemotherapy. METHODS: We reviewed the literature using search terms cervical cancer AND immunotherapy, immune therapy, vaccines, bevacizumab, anti-angiogenic therapy, and PARP inhibitors on PubMed. We included all review articles and prospective trials. We also reviewed ClinicalTrials.gov for trials in progress. FINDINGS: The addition of bevacizumab has improved the overall survival of women with advanced or recurrent cervical cancer when compared with cytotoxic therapy alone. This advancement has sparked an interest in other anti-angiogenic agents. Additionally, targeted therapies, including tyrosine kinase inhibitors, immunotherapy, and vaccine therapy, are also being evaluated. Another exciting area of study is the role of poly (ADP-ribose) polymerase inhibition in cervical cancer. IMPLICATIONS: Though the results are promising, the data are preliminary and additional studies evaluating the proper combination of therapy, dosing, and schedules will help inform the ideal regimen. PMID- 26926323 TI - Antibacterial and anti-inflammatory drug delivery properties on cotton fabric using betamethasone-loaded mesoporous silica particles stabilized with chitosan and silicone softener. AB - In this study, mesoporous silica particles with a hexagonal structure (SBA-15) were synthesized and modified with (3-aminopropyl) triethoxysilane, and used as a carrier for anti-inflammatory drug, betamethasone sodium phosphate. Drug-loaded silica particles were grafted on the cotton fabric surface using chitosan and polysiloxane reactive softener as a soft and safe fixing agent to develop an antibacterial cotton fabric with drug delivery properties. Cytometry assays revealed that synthesized silica have no cytotoxicity against human peripheral blood mononuclear cells. Accordingly, the produced drug-loaded nanostructures can be applied via different routes, such as wound dressing. Drug delivery profile of the treated fabrics were investigated and compared. The drug release rate followed the conventional Higuchi model. The treated cotton fabrics were tested and evaluated using scanning electron microscope images, bending length, air permeability, washing durability and anti-bacterial properties. It was found that the chitosan-/softener-treated fabrics compounded with drug-loaded silica particles have a good drug delivery performance and exhibited a powerful antibacterial activity against both Escherichia coli and Staphylococcus aureus even after five washing cycles. The produced antibacterial cotton fabric with drug delivery properties could be proposed as a suitable material for many medical and hygienic applications. PMID- 26926324 TI - Yoga increased serum estrogen levels in postmenopausal women-a case report. AB - OBJECTIVE: This case report aimed to evaluate 4 months of yoga practice on the quality of life (QOL) and estradiol levels of two postmenopausal women. METHODS: Participants were clinically healthy postmenopausal women, with follicle stimulating hormone levels greater than or equal to 30 mIU/mL and a body mass index lower than 30 kg/m. The participants practiced yoga for 4 months in two 1 hour sessions per week. RESULTS: The participants exhibited an abnormal estrogen level increase after 4 months of yoga practice and showed QOL improvements. CONCLUSIONS: In some cases, yoga practice can affect the female neuroendocrine system, increasing estrogen and improving QOL. PMID- 26926325 TI - Prevalence and severity of vasomotor symptoms and joint pain in women at midlife in Bangladesh: a population-based survey. AB - OBJECTIVE: The aim of the study was to document the prevalence of menopausal symptoms and the extent to which women are bothered by vasomotor symptoms (VMS) and joint pain in Bangladesh. METHODS: A total of 1,590 women, aged 30 to 59 years, participated in a cross-sectional, questionnaire-based study between September 2013 and March 2014. The main outcome measures were moderate to severely bothersome VMS and joint pain, measured by the Menopause-Specific Quality of Life questionnaire. RESULTS: Of participants, 59.4% were premenopausal, 8.4% perimenopausal, and 32.3% postmenopausal. Approximately all women reached menopause by the age of 50 years. The prevalence of moderate to severely bothersome VMS was 4.1% in premenopausal, 33.3% in perimenopausal, and 28.2% in postmenopausal women. Factors associated with moderate to severely bothersome VMS were being perimenopausal (odds ratio [OR] 46.34, 95% CI 13.29 161.56; P < 0.001) or postmenopausal (OR 19.15, 95% CI 5.63-65.11; P < 0.001) and obesity (OR 2.20, 95% CI 1.03-4.71; P = 0.042). The prevalence of moderate to severely bothersome joint pain was 40.3% in postmenopausal, 36.2% in perimenopausal, and 15.3% in premenopausal women. Moderate to severely bothersome joint pain was more likely both in perimenopausal (OR 2.64, 95% CI 1.63-4.29; P < 0.001) and postmenopausal women (OR 2.96, 95% CI 2.06-4.24; P < 0.001). Moderate to severely bothersome joint pain was also more likely in women with no education compared with women having education beyond secondary school (OR 2.38, 95% CI 1.02-2.32; P < 0.001). No women reported prescription therapy for menopausal symptoms. CONCLUSIONS: This study demonstrates that a high proportion of Bangladeshi women experience moderate to severely bothersome VMS and joint pain. Despite the considerable symptom prevalence, no women reported treatment, suggesting that menopause remains neglected in Bangladesh. PMID- 26926326 TI - Elevated serum progesterone levels in postmenopausal women with mucinous ovarian tumors. AB - OBJECTIVE: The aim of the study was to evaluate the association between tumor histology and serum sex hormone levels in postmenopausal women with ovarian tumors. METHODS: We preoperatively measured serum levels of gonadotropins and sex steroids, including estradiol, progesterone, and testosterone, in 69 postmenopausal women who underwent surgical resection for ovarian tumors. Tumors were classified as surface epithelial-stromal tumors, sex cord-stromal tumors, germ cell tumors, and metastatic tumors. Surface epithelial-stromal tumors were divided into mucinous, serous, clear cell, and endometrioid tumor subgroups. Patients were divided into two groups depending on tumor type: mucinous and nonmucinous, and any association between these tumor types and serum sex hormone levels were evaluated. RESULTS: Univariate analyses revealed that serum sex steroid levels were significantly higher in women with mucinous ovarian tumors compared with women with other tumor types. Serum gonadotropin levels, age, body mass index, tumor size, and tumor malignancy status did not affect the sex steroid levels. Multivariate analysis evaluating sex steroid levels and tumor histology revealed that high serum progesterone levels were significantly and independently associated with mucinous ovarian tumors. A serum progesterone cut off level of at least 1.3 nmol/L was the most accurate for differentiating mucinous tumors from other tumor types (area under the curve, 0.81; sensitivity, 75%; and specificity, 86%). CONCLUSIONS: Serum progesterone levels were significantly elevated in postmenopausal women with mucinous ovarian tumors. In these women, serum progesterone levels may thus represent a useful biomarker for predicting tumor histology preoperatively, which would aid treatment planning. PMID- 26926327 TI - Changes in heart rate variability during vasomotor symptoms among midlife women. AB - OBJECTIVE: Most midlife women report vasomotor symptoms (VMS), yet their physiology remains poorly understood. This study tested whether acute decreases in cardiac vagal control would occur with VMS in a large sample of women monitored during wake and sleep. METHODS: Two hundred and fifteen nonsmoking women aged 40 to 60 years with evidence of VMS were included. Women were free of a history of clinical cardiovascular disease or arrhythmia; or use of insulin, beta blockers, calcium channel blockers, or medications impacting VMS. Women underwent 24 hours of ambulatory monitoring for physiological (sternal skin conductance) and self-report (electronic diary) measurement of VMS; heart rate variability (electrocardiogram); and respiratory rate. Changes in cardiac vagal control as assessed by respiratory sinus arrhythmia during VMS, relative to periods before and after VMS, were tested in linear mixed models. RESULTS: Significant decreases in respiratory sinus arrhythmia were observed during physiologically measured VMS relative to periods preceding (b[SE] = 0.13 (0.004), P < 0.0001) and after the vasomotor symptoms (b[SE] = 0.13 (0.004), P < 0.0001), adjusted for age, race, body mass index, and sleep/wake status. Decreases were observed for women not aware of their VMS, and differences persisted controlling for respiration rate. Interactions indicated that respiratory sinus arrhythmia decreases were most pronounced during sleep and for younger women. CONCLUSIONS: Physiologically measured VMS were accompanied by an inhibition of cardiac vagal control in a large sample of women. Changes were observed irrespective of whether the VMS were reported, were most pronounced during sleep, and were greatest among younger women. These findings contribute to the understanding of vasomotor symptom physiology. PMID- 26926328 TI - Suppression of Cocaine-Evoked Hyperactivity by Self-Adjuvanting and Multivalent Peptide Nanofiber Vaccines. AB - The development of anti-cocaine vaccines that counteract the rewarding effects of the drug are currently being investigated as adjunct therapies for prevention of relapse in abstinent users. However, cocaine is weakly immunogenic and requires conjugation to carrier proteins and coadministration with strong adjuvants, which carry the risk of local reactogenicity and systemic toxicity. Here we report synthetic and multivalent self-assembling peptide nanofibers as adjuvant-free carriers for cocaine vaccines. A novel cocaine hapten modified at the P3 site was conjugated to the N-terminus of an amphipathic self-assembling domain KFE8. In aqueous buffers the cocaine-KFE8 conjugate assembled into beta-sheet rich nanofibers, which raised anti-cocaine antibodies without the need for added adjuvants in mice. Vaccinated mice were treated with cocaine and a significant negative correlation was observed between antibody levels and cocaine-evoked hyperactivity. These totally synthetic and multivalent nanofibers with well defined chemical composition represent the first generation of adjuvant-free cocaine vaccines. PMID- 26926330 TI - Beyond the drugs: nonpharmacologic strategies to optimize procedural care in children. AB - PURPOSE OF REVIEW: Painful and/or stressful medical procedures mean a substantial burden for sick children. There is good evidence that procedural comfort can be optimized by a comprehensive comfort-directed policy containing the triad of nonpharmacological strategies (NPS) in all cases, timely or preventive procedural analgesia if pain is an issue, and procedural sedation. RECENT FINDINGS: Based both on well-established theoretical frameworks as well as an increasing body of scientific evidence NPS need to be regarded an inextricable part of procedural comfort care. SUMMARY: Procedural comfort care must always start with a child friendly, nonthreatening environment in which well-being, confidence, and self efficacy are optimized and maintained. This requires a reconsideration of the medical spaces where we provide care, reduction of sensory stimulation, normalized professional behavior, optimal logistics, and coordination and comfort directed and age-appropriate verbal and nonverbal expression by professionals. Next, age-appropriate distraction techniques and/or hypnosis should be readily available. NPS are useful for all types of medical and dental procedures and should always precede and accompany procedural sedation. NPS should be embedded into a family-centered, care-directed policy as it has been shown that family centered care can lead to safer, more personalized, and effective care, improved healthcare experiences and patient outcomes, and more responsive organizations. PMID- 26926329 TI - Conversion of gestational diabetes mellitus to future Type 2 diabetes mellitus and the predictive value of HbA1c in an Indian cohort. AB - AIM: To investigate the distribution of and risk factors for dysglycaemia (Type 2 diabetes and prediabetes) in women with previous gestational diabetes mellitus in India. METHODS: All women (n = 989) from two obstetric units in New Delhi and Hyderabad with a history of gestational diabetes were invited to participate, of whom 366 (37%) agreed. Sociodemographic, medical and anthropometric data were collected and 75-g oral glucose tolerance test were carried out. RESULTS: Within 5 years (median 14 months) of the pregnancy in which they were diagnosed with gestational diabetes, 263 (72%) women were dysglycaemic, including 119 (32%) and 144 (40%) with Type 2 diabetes and prediabetes, respectively. A higher BMI [odds ratio 1.16 per 1-kg/m2 greater BMI (95% CI 1.10, 1.28)], presence of acanthosis nigricans [odds ratio 3.10, 95% CI (1.64, 5.87)], postpartum screening interval [odds ratio 1.02 per 1 month greater screening interval 95% CI (1.01, 1.04)] and age [odds ratio 1.10 per 1-year older age 95% CI (1.04, 1.16)] had a higher likelihood of having dysglycaemia. The American Diabetes Association-recommended threshold HbA1c value of >= 48 mmol/mol (6.5%) had a sensitivity and specificity of 81.4 and 90.7%, respectively, for determining the presence of Type 2 diabetes postpartum. CONCLUSION: The high post-pregnancy conversion rates of gestational diabetes to diabetes reported in the present study reinforce the need for mandatory postpartum screening and identification of strategies for preventing progression to Type 2 diabetes. Use of the American Diabetes Association recommended HbA1c threshold for diabetes may lead to significant under-diagnosis. PMID- 26926331 TI - The important role of simulation in sedation. AB - PURPOSE OF REVIEW: This article reviews the development of simulation-based training strategies to educate sedation providers. RECENT FINDINGS: Medical simulation has been utilized to train and evaluate providers in numerous domains related to sedation. Sedation providers come to the patient with a wide range of clinical training and experience and simulation can serve as a platform for achieving a baseline skill level and for periodic retraining. Although widely accepted by participants in simulation training, data demonstrating simulation's efficacy in improving sedation-related clinical outcomes are lacking. SUMMARY: Simulation provides an opportunity for sedation providers to develop deliberative practice, to consider rare or challenging clinical conditions, and to benefit from directed feedback, in a manner that does not put patients in harm's way. PMID- 26926332 TI - Update on pharmacological management of procedural sedation for children. AB - PURPOSE OF REVIEW: The review provides an update on pharmacological techniques for procedural sedation for children outside the operating room. RECENT FINDINGS: An increasing number of studies of propofol, ketamine, nitrous oxide, dexmedetomidine, and intranasal administration of drugs for procedural sedation of children continue to be reported. SUMMARY: Propofol and ketamine are commonly used for procedural sedation in children and the use of dexmedetomidine and nitrous oxide is increasing. Although the intravenous route remains the mainstay; intranasal drug administration is increasingly used for anxiolysis and moderate sedation. PMID- 26926333 TI - Threats to safety during sedation outside of the operating room and the death of Michael Jackson. AB - PURPOSE OF REVIEW: From an understanding of human psychology and the reliability of high-technology systems, this review considers critical threats to the safety of patients undergoing sedation outside of the operating room, and will stratify these threats along what we define as the 'Patient Risk Continuum'. We then consider interventions suitable for addressing identified risks. RECENT FINDINGS: The technology, organization and delivery of healthcare continue to become more complex, highlighting the importance of maintaining the safety of patients. Sedation outside of the operating room is known to be associated with higher rates of adverse events. However, a number of recent safety initiatives have shown benefit in improving patient safety. SUMMARY: The following threats to patients undergoing sedation, in increasing order of risk, are discussed: equipment and environmental factors, known patient risks, poor team performance, combinatorial problems and egregious violations. To address these threats, we discuss a number of approaches consistent with the systems approach to safety, namely: encouraging functions, forcing functions, cognitive safety nets, information sharing, recovery strategies and regulatory change. Demonstrating improvement with any safety initiative relies critically on quality data collected on the problem area in question. PMID- 26926334 TI - The sedation mindset: philosophy, science, and practice. AB - PURPOSE OF REVIEW: Medicine is evolving. An increasing influx of medically complex patients coupled with diminishing resources set the stage for substantial challenges in providing safe, effective sedation and analgesia for children requiring medical procedures. This review will discuss the essential components of a successful sedation plan outside of the traditional operating room setting. RECENT FINDINGS: As the discipline of sedation has developed, specialty societies have created and updated guidelines, policies, and statements intended to guide their own practice. There is a lack of consensus among them regarding appropriate targeted depths of sedation, monitoring requirements, definitions of adverse events, resuscitation skills required, and appropriate sedatives used. A transparent, collaborative approach is needed to ensure the sharing of expertise and to encourage evidence-based consistency and safety optimization across venues and specialties. SUMMARY: To meet this need, a multidisciplinary strategy is essential in training, performance of procedures outside of the operating room, and care coordination. To deliver safe, effective care, the sedationist must: perform a targeted presedation assessment; optimize the patient and family prior to sedation; tailor the induction and maintenance to the specific child's condition, needs, and procedure; safely recover the child; and provide a safe plan for postsedation care. PMID- 26926335 TI - A forecast of relevant pediatric sedation trends. AB - PURPOSE OF REVIEW: Over the past decade, the field of pediatric sedation has benefited from contributions which include the introduction and update of policies, procedures, and guidelines regarding training, physiologic monitoring and delivery, the approval of new sedatives, the multispecialty collaborations intended to advance the field and the development of sedatives, and delivery systems. This review will explore new drug innovations as well as evolved formulations of already approved agents, unique sedative delivery systems, the clinical application of pharmacogenetics and will conclude with a reflection on the current and future trends and focus of pediatric sedation research. RECENT FINDINGS: In recent years, the number of diagnostic and therapeutic procedures performed on children in nonoperating room anesthetizing locations has exploded at a rate which has in many instances, outpaced the availability of anesthesiologists. Over the past decade, the search for safe and effective sedatives and delivery systems has been embraced by all sedation providers. Dexmedetomidine and fospropofol were recently introduced, along with a computer assisted personalized sedation delivery system which empowers the patient to assist in his own sedation. The evolution of target-controlled infusion systems with both open and closed-loop design are intended to more precisely deliver sedation using pharmacokinetic models specific for each sedative. New formulations of propofol, ketamine, etomidate, and benzodiazepines are in development, all striving to improve predictability, safety, and recovery profile. Pharmacogenetics is being explored for its role in the effects of analgesics, sedatives, and local anesthetics. SUMMARY: As the demand for procedural sedation continues to expand, the sedation providers must continue to be creative in their search for novel, safe, effective, and efficient methods to deliver care. Approaching the field of sedation as a science is essential for the clinicians and researchers who strive to tailor the sedation to the patient and the procedure. PMID- 26926336 TI - Low Testosterone Levels and Reduced Kidney Function in Japanese Adult Men: The Locomotive Syndrome and Health Outcome in Aizu Cohort Study. AB - OBJECTIVES: Findings from several experimental studies in animals have suggested a protective action of testosterone on kidney function, but hard evidence for such an association in humans is scarce. We examined the association between testosterone levels and kidney function among adult men living in super-aged communities. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: We conducted cross sectional study involving residents aged 40-80 years who participated in annual health check-ups in 2 communities. A total of 1031 men were recruited in 2010. Main exposure was salivary testosterone (sT) levels measured using an enzyme linked immunosorbent assay. Main outcome was estimated glomerular filtration rate (eGFR) determined by age, gender, and serum creatinine levels. RESULTS: For the 848 participants analyzed, median age and eGFR were 69 years and 69.1 mL/min/1.73 m(2), respectively. On comparison of 90th-percentile sT levels with lower levels, our general linear model with restricted cubic splines showed that lower sT levels were associated with decreased eGFR after adjustment for sociodemographic characteristics, comorbidities, and blood pressure. For example, fifth percentile sT was associated with decreased eGFR, with a difference in eGFR [-3.43 mL/min/1.73 m(2) (95% confidence interval, CI -6.02 to -0.84)] comparable in magnitude to the reduction in eGFR observed for a 6-year increase in age in our population. The association between low testosterone levels and decreased eGFR remained similar even when analyses were restricted to participants aged over 60 years (734 participants, median age 71 years). CONCLUSIONS: Results from our study indicated that having low testosterone levels was independently associated with reduced eGFR in adult men. Our finding of this association between low testosterone levels and reduced kidney function needs to be corroborated among persons with chronic kidney disease or in a longitudinal study. PMID- 26926337 TI - A Multidimensional Risk Score to Predict All-Cause Hospitalization in Community Dwelling Older Individuals With Obstructive Lung Disease. AB - BACKGROUND: Both respiratory and nonrespiratory hospitalizations are common and costly events in older individuals with obstructive lung disease. Prevention of any hospitalization in these individuals is essential. We aimed to construct a prediction model for all-cause hospitalization risk in community-dwelling older individuals with obstructive lung disease. METHODS: We studied 268 community dwelling individuals with obstructive lung disease (defined as FEV1/FVC0.05). (2)After treatment for 3 months, partial remission rates in modified Ponticelli group, CTX group and CsA group were 39.1%, 35.9%, 35.7% respectively and complete remission rates were 8.7%, 5.1%, 10.7%, which were not statistically significant in all three groups (P>0.05). At 6 months, partial remission rates in three groups were 56.5%, 41.0%, 42.9% respectively and complete remission rates were 21.7%, 20.5%, 28.6%, which did not suggested significant difference in all three groups either (P>0.05). (3)In modified Ponticelli group, steroid diabetes, impaired liver dysfunction, infections and gastrointestinal adverse events occurred in 1, 1, 2 and 2 patients, respectively. In CTX group, steroid diabetes, infections and gastrointestinal adverse events occurred in 5, 8 and 2 patients, respectively. In CsA group, steroid diabetes and infections occurred in 1 and 3 patients, respectively. CONCLUSION: Modified Ponticelli regimen to treat patients with IMN has a trend of better outcome than classic CTX regimen. The efficacy is not inferior to CsA regimen with fewer side effects. PMID- 26926369 TI - [The prognostic value of baseline serum free light chain in cardiac amyloidosis]. AB - OBJECTIVE: To analyze the prognostic value of baseline serum free light chain (sFLC) in light-chain (AL) cardiac amyloidosis. METHODS: Twenty-seven patients with AL cardiac amyloidosis were retrospectively reviewed from January 2014 to January 2015. sFLC was measured by immuoturbidimetric assay. Baseline characteristics, echocardiographic parameters and electrocardiogram data were analyzed. According to the median baseline dFLC (involved sFLC minus uninvolved sFLC), patients were categorized into either the low dFLC(<= 307 mg/L) or the high dFLC group (>307 mg/L). RESULTS: More subjects in the high dFLC group with early/late diastolic mitral velocity ratio (E/A ratio) over 2 (71.4% vs 30.8%, P=0.035), and subjects in this group had a shorter median survival time than those in the low dFLC group (3 months vs 17 months, P=0.004). A similar phenomenon for median survival time was observed when the subjects were redivided either by a new cut-off value of 180 mg/L for dFLC (low dFLC group: 17 months; high dFLC group: 4 months, P=0.014) or a kappa/lambda ratio, in which subjects with kappa type sFLC-ratio <= 19.6 and lambda type sFLC-ratio>0.065 were in the low sFLC-ratio group (17 months) and those with kappa type sFLC-ratio > 19.6 and lambda type sFLC-ratio <= 0.065 were in the high sFLC-ratio group (4 months, P=0.023). In multivariate analysis, dFLC and New York Heart Association (NYHA)classification of cardiac function were two risk factors associated with all-cause mortality in patients, among which the hazard ratio for higher dFLC was 4.28 (95%CI 1.55-11.8, P=0.005). CONCLUSION: The level of sFLC could be a marker for the prognosis of AL cardiac amyloidosis. PMID- 26926370 TI - [The curative efficacy of unrelated umbilical cord blood stem cells transplantation in intensified myeloablative conditioned patients with acute lymphoblastic leukemia]. AB - OBJECTIVE: To retrospectively analyze the efficacy of unrelated umbilical cord blood transplantation (UCBT) with intensified myeloablative conditioning regimen in patients with acute lymphoblastic leukemia (ALL). METHODS: From September 2006 to December 2013, a total of 110 consecutive patients with ALL had received UCBT, including 79 male and 31 female patients with a median age of 14(2-51) years, a median weight of 45(12-100)kg. Sixty-one cases were in the first complete remission (CR), 30, 6 and 13 patients in the second, the third CR and advanced stages respectively. The conditioning regimen consisted of total body irradiation, cyclophosphamide and cytarabine (TBI/Cy/Ara-C) in 61 patients, busulfan, cyclophosphamide and fludarabine (BU/Cy/Flu) in 39 patients and BU/Cy/Ara-C in 10 patients. All patients received a combination of cyclosporine (CsA) and mycophenolate mofetil (MMF) for the prophylaxis of graft-versus-host disease (GVHD). RESULTS: The median amount of total nuclear cells(TNC) and CD34(+) cells were 3.90(1.97-13.50)*10(7)/kg and 2.07(0.40-5.56)*10(5)/kg. The cumulative incidence of sustained donor engraftment was 94.5% (95% CI 94.5% 94.6%) at a median of 18 days after transplantation (range, 12-37 days). The cumulative incidence of platelet recovery at 180 days after transplantation was 82.1% (95% CI 81.8%-82.4%) with a median time to recovery of 40 (range, 15-153) days. Incidences of grade II~IV and III~IV acute GVHD were 21.8% and 10.9% respectively. The cumulative incidence of chronic GVHD was 17.9%. During a median follow up period of 26 (range 6-94) months, the disease free survival (DFS) and overall survival (OS) rates at 3 years were 54.5% and 58.8%, respectively. The transplantation-related mortality (TRM) at 180 days after transplantation was 22.7%. The cumulative incidence of 3-year relapse rate was 18.3% (95% CI 17.9% 18.6%). CONCLUSIONS: UCBT with intensified myeloablative conditioning regimen not only improves the donor engraftment, but also shortens the interval of neutrophil and platelet recovery. It is a safe and effective option for children and adult ALL patients lack of matched related donors. PMID- 26926371 TI - [The relationship between sleep quality and diabetic autonomic neuropathy in elder patients with type 2 diabetes mellitus]. AB - OBJECTIVE: To explore the relationship between the sleep quality and diabetic autonomic neuropathy of elder patients with type 2 diabetes mellitus. METHODS: A total of 90 elder patients with diabetes in Beijing Hospital was enrolled in this study. Questionnaires of Pittsburgh Sleep Quality Index(PSQI) were completed to evaluate the quality of sleep and Holter was applied to evaluate heart rate variability (HRV). Other related clinical data such as, catecholamine[epinephrine(E); norepinephrine(NE); dopamine(DA)]and diabetes complications were also collected after admission to the hospital. Patients were divided into three groups: the poor-sleeper group, the common-sleeper group and the good-sleeper group according to PSQI score. HRV and the level of catecholamine were compared among three groups. RESULTS: The level of HRV including meanNN [(743 +/- 58) ms vs(824 +/- 99)ms and (837 +/- 104)ms], ASDNN [(30 +/- 10)ms vs (39 +/- 14)ms and (41 +/- 14)ms], very low frequency(VLF)[(15.33 +/- 6.10)ms(2) vs(22.11 +/- 7.94)ms(2) and (22.66 +/- 7.87)ms(2)], low frequency (LF)[(8.30 +/- 3.95) ms(2) vs(12.58 +/- 6.11)ms(2) and(12.81 +/- 6.96)ms(2)] and LF/high frequency(HF)[(1.23 +/- 0.32) vs (1.56 +/- 0.46) and (1.47 +/- 0.42)] in the poor-sleeper group were lower than in both the common-sleeper group and good-sleeper group (all P<0.05). The level of catecholamine in poor-sleeper group [E: (108.91 +/- 4.19)ng/L; NE: (1458.0 +/- 50.35)ng/L] were lower than both the common-sleeper group [E: (120.23 +/- 4.37) ng/L; NE: (1901.09 +/- 131.36)ng/L] and the good-sleeper group [E: (118.23 +/- 19.9)ng/L; NE: (1771.87 +/- 116.73)ng/L] (all P<0.05), suggesting a dysfunction in autonomic nervous system in subject in the poor-sleeper group. CONCLUSION: Sleep quality is associated with the severity of diabetic autonomic neuropathy and might be one of clinical features for diabetic autonomic neuropathy. PMID- 26926372 TI - [A clinical analysis of treatment with recombinant human thrombopoietin combined with large doses of dexamethasone in primary immune thrombocytopenia]. AB - OBJECTIVE: To study the efficacy and safety of recombinant human thrombopoietin (rhTPO) combined with dexamethasone as front line regimen in patients with primary immune thrombocytopenia (ITP). METHODS: This study was a prospective, randomized, controlled trial. A total of 59 primary ITP patients were enrolled at the First Affiliated Hospital, Xinjiang Medical University from June 2013 to February 2015. All subjects were randomized into study group (30 cases) and control group (29 cases). The study group was scheduled to receive high-dose dexamethasone (40 mg intravenously d1-4) combined with rhTPO (300 U.kg(-1).d(-1) subcutaneously d1-14). Once absolute platelet count reached >50 * 10(9)/L, rhTPO stopped. Patients in control group were just administrated with high-dose dexamethasone (40 mg intravenously d1-4). Efficacy and adverse reactions were evaluated. RESULTS: The short-term (15 days) and mid-term (3 months) response rates in the study group were 83.3% (25/30) and 76.7% (23/30) respectively, which were both significantly better than those in the control group [51.7% (15/29) and 20.7% (6/29) respectively] (P<0.01). In the study group and control group, the median time platelet count reached 100 * 10(9)/L was 6.0 and 6.8 days respectively. In the study group, the time of TPO usage was (6.1 +/- 1.7) days. The incidence of adverse reactions in both groups was comparable and slight. The most common TPO related adverse events included knee ache and fatigue, which accounted for 6.7% (2/30) in the study group. CONCLUSIONS: Recombinant human TPO combined with dexamethasone as front line treatment for primary ITP shows significant advantages in both short-term and mid-term responses with less and manageable adverse reactions. This may provide a new method to treat patients with primary ITP. PMID- 26926373 TI - [A study on calculating the ankylosing spondylitis disease activity score according to the C-reactive protein level]. AB - OBJECTIVE: To study the prediction value of C-reactive protein (CRP) level to ankylosing spondylitis disease activity score (ASDAS), the most widely used activity score in ankylosing spondylitis (AS). METHODS: A total of 386 patients with AS were enrolled and divided into 2 groups by CRP >= 3.5 mg/L (n=266) and CRP<3.5 mg/L(n=120). ASDAS-CRP was evaluated in patients with CRP below the normal range (3.5 mg/L) in different subgroups. Three methods were used to test the consistency between ASDAS-CRP and ASDAS-erythrocyte sedimentation rate (ESR). RESULTS: The ASDAS-CRP showed a good correlation with the ASDAS-ESR when CRP level was >= 3.5 mg/L (r=0.899, P=0.000). In the group of CRP <3.5 mg/L, ASDAS ESR showed better consistency with ASDAS-CRP when CRP level was below 1.5 mg/L(intra-class correlation coefficient 0.902; kappa coefficient 0.70). By the evaluation of variant gradient matrix, CRP 1.5 mg/L coincided with disease activity states. CONCLUSION: There is good consistency between ASDAS-CRP and ASDAS-ESR. When CRP level is below the normal range, 1.5 mg/L could be a cut-off value to calculate the optimal ASDAS-CRP score. PMID- 26926374 TI - [Clinical analysis of 6 patients with drug-induced lupus]. AB - OBJECTIVE: To improve the understanding of drug-induced lupus (DIL) and the differences from systemic lupus erythematosus (SLE). METHODS: Clinical manifestation and treatment of patients with definite DIL were retrospectively analyzed. RESULTS: Six patients with DIL were enrolled in this study, including 4 females and 2 males. Two patients were diagnosed after receiving interferon, one after soluble tumor necrosis factor receptor fusion protein, one after propylthiouracil, one after penicillamine, and one after levofloxacin. High titer of antinuclear antibody was identified in all six patients, including 3 with positive anti-dsDNA antibody. One patient had positive anti-Sm antibody. One patient had positive anti-RNP antibody. One patient had anti-nucleosome antibody. One patient had anti-histone antibody. One patient had antimitochondrial antibodies-M2, and one patient had anticardiolipin antibodies. CONCLUSION: Patients with DIL are not as severe as those with SLE. After cessation of suspected drugs and administration of standard treatment, the clinical outcome of DIL is satisfying. PMID- 26926376 TI - Measurement of (238)U, (228)Ra, (226)Ra, (40)K and (137)Cs in foodstuffs samples collected from coastal areas of China. AB - This study represents a total of 245 samples collected. The activities of (238)U, (228)Ra, (226)Ra, (40)K and (137)Cs were determined in samples of vegetables, tea, cereal (rice, wheat and corn), meat, poultry, freshwater product, seafood and seaweed that collected from the 30km safety zone of the Nuclear Power Plants (NPPs) area. All the samples radionuclide activities were quantified by using High Purity Germanium (HPGe) gamma spectrometry. The geometric mean concentrations (Bqkg(-1) wet weight) for (238)U, (228)Ra, (226)Ra, (40)K, and (137)Cs in all investigated foodstuffs samples, are 0.13, 0.16, 0.11, 68 and 0.02, respectively. The arithmetic mean concentrations (Bqkg(-1) wet weight) for (238)U, (228)Ra, (226)Ra, (40)K, and (137)Cs in all investigated foodstuffs samples, are 0.34, 0.65, 0.32, 111 and 0.09, respectively. Results of this study were compared with others, the measured values are the same with those of a previous investigation. Radiation doses due to the consumption of these foodstuffs to humans are estimated to comprise around 37-46% of the annual dose limit for public. PMID- 26926375 TI - How to promote adverse drug reaction reports using information systems - a systematic review and meta-analysis. AB - BACKGROUND: Adverse drug reactions (ADRs) are a well-recognized public health problem and a major cause of death and hospitalization in developed countries. The safety of a new drug cannot be established until it has been on the market for several years. Keeping drug reactions under surveillance through pharmacovigilance systems is indispensable. However, underreporting is a major issue that undermines the effectiveness of spontaneous reports. Our work presents a systematic review on the use of information systems for the promotion of ADR reporting. The aim of this work is to describe the state of the art information systems used to promote adverse drug reaction reporting. METHODS: A systematic review was performed with quantitative analysis of studies describing or evaluating the use of information systems to promote adverse drug reaction reporting. Studies with data related to the number of ADRs reported before and after each intervention and the follow-up period were included in the quantitative analysis. RESULTS: From a total of 3865 articles, 33 articles were included in the analysis; these articles described 29 different projects. Most of the projects were on a regional scale (62 %) and were performed in a hospital context (52 %). A total of 76 % performed passive promotion of ADR reporting and used web-based software (55 %). A total of 72 % targeted healthcare professionals and 24 % were oriented to patient ADR reporting. We performed a meta-analysis of 7 of the 29 projects to calculate the aggregated measure of the ADR reporting increase, which had an overall measure of 2.1 (indicating that the interventions doubled the number of ADRs reported). CONCLUSIONS: We found that most of the projects performed passive promotion of ADR reporting (i.e., facilitating the process). They were developed in hospitals and were tailored to healthcare professionals. These interventions doubled the number of ADR reports. We believe that it would be useful to develop systems to assist healthcare professionals with completing ADR reporting within electronic health records because this approach seems to be an efficient method to increase the ADR reporting rate. When this approach is not possible, it is essential to have a tool that is easily accessible on the web to report ADRs. This tool can be promoted by sending emails or through the inclusion of direct hyperlinks on healthcare professionals' desktops. PMID- 26926377 TI - Experimental response function of a 3 in*3 in NaI(Tl) detector by inverse matrix method and effective atomic number of composite materials by gamma backscattering technique. AB - Response function of a widely used 3in*3in NaI(Tl) detector is constructed to correct the observed pulse height distribution. A 10*10 inverse matrix is constructed using 7 mono-energetic gamma sources ((57)Co, (203)Hg, (133)Ba, (22)Na, (137)Cs, (54)Mn and (65)Zn) which are evenly spaced in energy scale to unscramble the observed pulse height distribution. Bin widths (E)(1/2) of 0.01 (MeV)(1/2) are used to construct the matrix. Backscattered photons for an angle of 110 degrees are obtained from a well-collimated 0.2146GBq (5.8mCi) (137)Cs gamma source for carbon, aluminium, iron, copper, granite and Portland cement. For each observed spectrum, single scattered spectrum is constructed analytically using detector parameters like FWHM, photo-peak efficiency and peak counts. Response corrected multiple scattered photons are extracted from the observed pulse height distribution by dividing the spectrum into a 10 *1 matrix. Saturation thicknesses of carbon, aluminium, iron, copper, granite and Portland cement are found out. Variation of multiple scattered photons as a function of target thickness are simulated using MCNP code. A relationship between experimental and simulated saturation thicknesses of carbon, aluminium, iron and copper is obtained as a function of atomic number. Using this relation, effective atomic numbers of granite and Portland cement are obtained from interpolation method. Effective atomic numbers of granite and Portland cement are also obtained by theoretical equation using their elemental composition and comparing with the experimental and simulated results. PMID- 26926378 TI - Different methods of mass attenuation coefficient evaluation: Influences in the measurement of some soil physical properties. AB - The mass attenuation coefficients of Brazilian soils (MUs) and water (MUw) were measured and calculated at 59.5keV ((241)Am) photon energy. The MUs and MUw experimental values were compared using XCOM and Monte Carlo computer codes (FLUKA, GEANT4 and MCNP). The influence of different methods of u evaluation on the measurement of soil bulk density (rhos) and soil water content (theta) distributions and soil water retention (SWRC) was investigated. rhos and theta distributions were analyzed by using computed tomography (CT). Distinct rhos distributions were obtained even for similar us values measured among methods. theta distributions were also greatly influenced by the different methods of MUw evaluation. Regarding the SWRC, the results exhibited great differences in the region of structural pores, which directly affected the pore size distribution. PMID- 26926379 TI - Optically stimulated luminescence in doped NaF. AB - OSL in doped NaF is studied. Study shows that NaF:Mg,Cu,P phosphor possess good OSL properties having sensitivity comparable to that of commercially available Al2O3:C (Landauer Inc.). For the luminescence averaged over 3s the obtained OSL is 37% of that commercial available Al2O3:C. Of the several phosphors investigated, phosphor with impurities concentration Mg(0.01mol%), Cu(0.2mol%), P(1mol%) shows good OSL sensitivity good linearity in the 10mGy to 1Gy dose range and negligible fading. This sample shows a intense single TL peak around 350 degrees C which gets depleted by 14% after the OSL readout. This imply that maximum OSL is coming from deep traps giving stability to the signal. The ease of preparation along with other good OSL properties will make this phosphor suitable for radiation dosimetry applications using OSL. PMID- 26926380 TI - Correlates of the timed 25 foot walk in a multiple sclerosis outpatient rehabilitation clinic. AB - The Timed 25 Foot Walk (T25FW), a test of maximum walking speed on a short distance, is commonly used to monitor ambulation status and to assess treatment outcomes in multiple sclerosis (MS). The main aim of this study was to determine how walking speed on the T25FW correlates with other clinician-reported and patient-reported measures in an outpatient MS rehabilitation clinic. We analyzed cross-sectional data systematically collected during a physiatry evaluation for the management of spasticity and walking limitations. In addition to demographic variables and the Expanded Disability Status Scale (EDSS), measures of body functions [lower extremity manual muscle testing (LE MMT), lower extremity Modified Ashworth Scale, Fatigue Severity Scale, leg pain], and measures of activity and quality of life (reported frequency of falls, Incapacity Status Scale, Rivermead Mobility Index, EQ5D health questionnaire, and Patient Health Questionnaire-9 items) were administered. A multivariate regression analysis was carried out. 199 patients were included in the analysis [age 49.41 (9.89) years, disease duration 15.40 (10.22) years, EDSS score 5.6 (1.2), and T25FW speed 70.93 (44.13) cm/s]. Both EDSS and LE MMT were correlated significantly with T25FW speed (R=0.692, P<0.001). After adjusting for EDSS and LE MMT, lower T25FW speed was associated with higher Incapacity Status Scale scores (R=0.316, P<0.001), lower Rivermead Mobility Index scores (R=0.540, P<0.001), and higher frequency of falls. EQ5D and Patient Health Questionnaire-9 items were not significantly associated with T25FW speed. Our findings support the clinical relevance of the T25FW in the rehabilitation of patients with MS. PMID- 26926381 TI - Protocols for Studies of Intraocular Lens Formula Accuracy. PMID- 26926382 TI - The Use of Minimal RNA Toeholds to Trigger the Activation of Multiple Functionalities. AB - Current work reports the use of single-stranded RNA toeholds of different lengths to promote the reassociation of various RNA-DNA hybrids, which results in activation of multiple split functionalities inside human cells. The process of reassociation is analyzed and followed with a novel computational multistrand secondary structure prediction algorithm and various experiments. All of our previously designed RNA/DNA nanoparticles employed single-stranded DNA toeholds to initiate reassociation. The use of RNA toeholds is advantageous because of the simpler design rules, the shorter toeholds, and the smaller size of the resulting nanoparticles (by up to 120 nucleotides per particle) compared to the same hybrid nanoparticles with single-stranded DNA toeholds. Moreover, the cotranscriptional assemblies result in higher yields for hybrid nanoparticles with ssRNA toeholds. PMID- 26926383 TI - Prediction of Early Recurrence After Acute Ischemic Stroke. AB - IMPORTANCE: Approximately half of recurrent strokes occur within days and weeks of an ischemic stroke. It is imperative to identify patients at imminent risk of recurrent stroke because recurrent events lead to prolonged hospitalization, worsened functional outcome, and increased mortality. OBJECTIVE: To test the validity of a prognostic score that was exclusively developed to predict early risk of stroke recurrence in a multicenter setting. DESIGN, SETTING, AND PARTICIPANTS: This hospital-based cohort study examined patients with and without magnetic resonance imaging-confirmed recurrent stroke within 90 days after an ischemic stroke. The study was performed at 3 teaching hospitals in the United States, Brazil, and South Korea and comprised adult patients admitted within 72 hours of symptom onset with a magnetic resonance imaging-confirmed diagnosis of acute ischemic stroke. Recruitment to the US cohort was performed from June 1, 2009, through April 30, 2011. Recruitment to the Korean and Brazilian cohorts was performed from January 1, 2007, through December 31, 2011. Data analysis was performed from June 1, 2013, to December 31, 2014. MAIN OUTCOMES AND MEASURES: The primary outcome was recurrent ischemic stroke as defined by a clinical incident that was clearly attributable to a new area of brain infarction occurring within the 90 days of index infarction. An investigator who was masked to the patient's recurrence status calculated the Recurrence Risk Estimator (RRE) score for each patient based on information available after initial line of testing in the emergency department. We assessed the predictive performance of the RRE by computing the area under the receiver operating characteristic curve. RESULTS: The study included 1468 consecutive patients with 59 recurrent ischemic stroke events. The median age of the patients was 69 (interquartile range, 58-79) years, and 633 (43.1%) were female. The cumulative 90-day recurrence rate was 4.2% (95% CI, 3.2%-5.2%). The mean RRE score was 2.2 (95% CI, 1.9-2.5) in patients with recurrence and 1.0 (95% CI, 1.0-1.1) in patients without. The risk of recurrence increased with a higher RRE score (log-rank test, P < .001). The area under the receiver operating characteristic curve for discrimination was 0.76 (95% CI, 0.70-0.82). The RRE identified 710 patients (48.4%) in the study population as high risk (>10%) or low risk (<1%). The sensitivity and specificity were 38% and 93% for identifying low-risk subsets and 41% and 90% for identifying high-risk subsets, respectively. CONCLUSIONS AND RELEVANCE: This study confirms the validity of the RRE score in a multicenter cohort of patients with diverse characteristics. Our findings suggest that the RRE could be useful in identifying high- and low-risk patients for targeted stroke prevention. PMID- 26926386 TI - Tuning the mechanical properties of vertical graphene sheets through atomic layer deposition. AB - We report the fabrication and characterization of graphene nanostructures with mechanical properties that are tuned by conformal deposition of alumina. Vertical graphene (VG) sheets, also called carbon nanowalls (CNWs), were grown on copper foil substrates using a radio-frequency plasma-enhanced chemical vapor deposition (RF-PECVD) technique and conformally coated with different thicknesses of alumina (Al2O3) using atomic layer deposition (ALD). Nanoindentation was used to characterize the mechanical properties of pristine and alumina-coated VG sheets. Results show a significant increase in the effective Young's modulus of the VG sheets with increasing thickness of deposited alumina. Deposition of only a 5 nm thick alumina layer on the VG sheets nearly triples the effective Young's modulus of the VG structures. Both energy absorption and strain recovery were lower in VG sheets coated with alumina than in pure VG sheets (for the same peak force). This may be attributed to the increase in bending stiffness of the VG sheets and the creation of connections between the sheets after ALD deposition. These results demonstrate that the mechanical properties of VG sheets can be tuned over a wide range through conformal atomic layer deposition, facilitating the use of VG sheets in applications where specific mechanical properties are needed. PMID- 26926385 TI - Ventricular fibrogenesis activity assessed by serum levels of procollagen type III N-terminal amino peptide during the staged Fontan procedure. AB - OBJECTIVE: We tested the hypotheses that volume overload and cyanosis observed in the pre-Fontan single ventricular circulation are associated with increased ventricular fibrogenesis, that the Fontan procedure helps to reduce fibrogenesis, and that persistently increased fibrogenesis in the Fontan ventricle is associated with ventricular diastolic dysfunction. METHODS: Levels of serum amino terminal procollagen type III, a marker of tissue fibrogenesis, were measured in 172 patients with single ventricle circulation and 149 controls. Patients were divided into 3 groups according to surgical stage: 59 patients after Blalock Taussig shunt or pulmonary banding, 60 patients after Glenn surgery (Glenn group), and 53 patients after Fontan surgery (Fontan group). RESULTS: Serum amino terminal procollagen type III levels were significantly higher among the 3 single ventricle groups than among control patients, but decreased with each surgical stage (0.604, 0.176, 0.143, and 0.073 U/mL, for Blalock-Taussig shunt or pulmonary banding, Glenn, Fontan, and controls, respectively). Severity of volume load and cyanosis were independent determinants of increased amino-terminal procollagen type III levels in patients before Fontan surgery, and persistently increased amino-terminal procollagen type III after Fontan surgery was associated with ventricular diastolic stiffening (r = 0.494, P = .009). Data also indicated close associations between amino-terminal procollagen type III levels and activation of the renin-angiotensin-aldosterone system, suggesting potential involvement of this hormonal system in the increased fibrogenesis after Fontan surgery. CONCLUSIONS: These results suggest that serum amino-terminal procollagen type III may provide important diagnostic information on myocardial fibrosis in patients with single ventricle circulation and raise the possibility that ventricular fibrogenesis may be a potential therapeutic target in this population. PMID- 26926387 TI - Cp*Rh(III)-Catalyzed Cross-Coupling of Alkyltrifluoroborate with alpha Diazomalonates for C(sp(3))-C(sp(3)) Bond Formation. AB - A Cp*Rh(III)-catalyzed cross-coupling of alkyltrifluoroborate with alpha diazomalonates was developed; the C(sp(3))-C(sp(3)) bond coupled products were formed in up to 97% yields. The reaction tolerates some useful functional groups, including ketone, ester, amide, ether, sulfonyl, and thiophene. Electrospray ionization mass spectrometry (ESI-MS) analysis revealed the formation of a distinct molecular species corresponding to sigma-alkylrhodium(III) complexes. The successful diazo coupling reaction may be attributed to coordination of the amide group that promotes stability of the alkylrhodium(III) complex through the formation of a five-membered metallacycle. PMID- 26926384 TI - Fibroblast growth factor 21 improves hepatic insulin sensitivity by inhibiting mammalian target of rapamycin complex 1 in mice. AB - Among the 22 fibroblast growth factors (FGFs), FGF21 has now emerged as a key metabolic regulator. However, the mechanism whereby FGF21 mediates its metabolic actions per se remains largely unknown. Here, we show that FGF21 represses mammalian target of rapamycin complex 1 (mTORC1) and improves insulin sensitivity and glycogen storage in a hepatocyte-autonomous manner. Administration of FGF21 in mice inhibits mTORC1 in the liver, whereas FGF21-deficient mice display pronounced insulin-stimulated mTORC1 activation and exacerbated hepatic insulin resistance (IR). FGF21 inhibits insulin- or nutrient-stimulated activation of mTORC1 to enhance phosphorylation of Akt in HepG2 cells at both normal and IR condition. TSC1 deficiency abrogates FGF21-mediated inhibition of mTORC1 and augmentation of insulin signaling and glycogen synthesis. Strikingly, hepatic betaKlotho knockdown or hepatic hyperactivation of mTORC1/ribosomal protein S6 kinase 1 abrogates hepatic insulin-sensitizing and glycemic-control effects of FGF21 in diet-induced insulin-resistant mice. Moreover, FGF21 improves methionine and choline-deficient diet-induced steatohepatitis. CONCLUSIONS: FGF21 acts as an inhibitor of mTORC1 to control hepatic insulin action and maintain glucose homeostasis, and mTORC1 inhibition by FGF21 has the therapeutic potential for treating IR and type 2 diabetes. (Hepatology 2016;64:425-438). PMID- 26926388 TI - Controlled production of the elusive metastable form II of acetaminophen (paracetamol): a fully scalable templating approach in a cooling environment. AB - A scalable, transferable, cooling crystallisation route to the elusive, metastable, form II of the API acetaminophen (paracetamol) has been developed using a multicomponent "templating" approach, delivering 100% polymorphic phase pure form II at scales up to 120 g. Favourable solubility and stability properties are found for the form II samples. PMID- 26926389 TI - MT1-MMP sheds LYVE-1 on lymphatic endothelial cells and suppresses VEGF-C production to inhibit lymphangiogenesis. AB - Lymphangiogensis is involved in various pathological conditions, such as arthritis and cancer metastasis. Although many factors have been identified to stimulate lymphatic vessel growth, little is known about lymphangiogenesis inhibitors. Here we report that membrane type 1-matrix metalloproteinase (MT1 MMP) is an endogenous suppressor of lymphatic vessel growth. MT1-MMP-deficient mice exhibit spontaneous corneal lymphangiogenesis without concomitant changes in angiogenesis. Mice lacking MT1-MMP in either lymphatic endothelial cells or macrophages recapitulate corneal lymphangiogenic phenotypes observed in Mmp14(-/ ) mice, suggesting that the spontaneous lymphangiogenesis is both lymphatic endothelial cells autonomous and macrophage associated. Mechanistically, MT1-MMP directly cleaves LYVE-1 on lymphatic endothelial cells to inhibit LYVE-1-mediated lymphangiogenic responses. In addition, MT1-MMP-mediated PI3Kdelta signalling restrains the production of VEGF-C from prolymphangiogenic macrophages through repressing the activation of NF-kappaB signalling. Thus, we identify MT1-MMP as an endogenous inhibitor of physiological lymphangiogenesis. PMID- 26926391 TI - Duchenne muscular dystrophy: CRISPR/Cas9 treatment. AB - A novel approach to gene correction by genome editing shows great promise as a treatment for Duchenne muscular dystrophy (DMD). CRISPR/Cas9 delivered by adeno associated virus to a mouse model for DMD demonstrated improvement in function and histology. PMID- 26926390 TI - Engineering Dark Chromoprotein Reporters for Photoacoustic Microscopy and FRET Imaging. AB - A subset of the family of fluorescent proteins are the non-fluorescent chromoproteins which are promising probe molecules for use in photoacoustic imaging and as acceptor chromophores in Forster resonance energy transfer (FRET) based biosensors. Typical approaches for fluorescent protein optimization by screening of large libraries of variants cannot be effectively applied to chromoproteins due to their characteristic lack of fluorescence. To address this challenge, we have developed a directed evolution method to iteratively screen large libraries of protein variants on the basis of their photoacoustic signal levels. By applying this procedure to the promising Ultramarine and cjBlue chromoprotein templates, we were able to identify improved variants with a 02-04 fold increase in photoacoustic signal-to-noise ratio after only a few evolutionary steps. These improved variants enable more accurate spectral de mixing and localization of protein-producing bacteria in vivo and serve as effective FRET acceptors for both fluorescence- and photoacoustic-based detection of protease activity. PMID- 26926392 TI - Low-Dimensional Polyoxometalate Molecules/Tantalum Oxide Hybrids for Non-Volatile Capacitive Memories. AB - Transition-metal-oxide hybrids composed of high surface-to-volume ratio Ta2O5 matrices and a molecular analogue of transition metal oxides, tungsten polyoxometalates ([PW12O40](3-)), are introduced herein as a charge storage medium in molecular nonvolatile capacitive memory cells. The polyoxometalate molecules are electrostatically self-assembled on a low-dimensional Ta2O5 matrix, functionalized with an aminosilane molecule with primary amines as the anchoring moiety. The charge trapping sites are located onto the metal framework of the electron-accepting molecular entities as well as on the molecule/oxide interfaces which can immobilize negatively charged mobile oxygen vacancies. The memory characteristics of this novel nanocomposite were tested using no blocking oxide for extraction of structure-specific characteristics. The film was formed on top of the 3.1 nm-thick SiO2/n-Si(001) substrates and has been found to serve as both SiO2/Si interface states' reducer (i.e., quality enhancer) and electron storage medium. The device with the polyoxometalates sandwiched between two Ta2O5 films results in enhanced internal scattering of carriers. Thanks to this, it exhibits a significantly larger memory window than the one containing the plain hybrid and comparable retention time, resulting in a memory window of 4.0 V for the write state and a retention time around 10(4) s without blocking medium. Differential distance of molecular trapping centers from the cell's gate and electronic coupling to the space charge region of the underlying Si substrate were identified as critical parameters for enhanced electron trapping for the first time in such devices. Implementing a numerical electrostatic model incorporating structural and electronic characteristics of the molecular nodes derived from scanning probe and spectroscopic characterization, we are able to interpret the hybrid's electrical response and gain some insight into the electrostatics of the trapping medium. PMID- 26926393 TI - Exploring the interaction between Salvia miltiorrhiza and human serum albumin: Insights from herb-drug interaction reports, computational analysis and experimental studies. AB - Human serum albumin (HSA) binding is one of important pharmacokinetic properties of drug, which is closely related to in vivo distribution and may ultimately influence its clinical efficacy. Compared to conventional drug, limited information on this transportation process is available for medicinal herbs, which significantly hampers our understanding on their pharmacological effects, particularly when herbs and drug are co-administrated as polytherapy to the ailment. Several lines of evidence suggest the existence of Salvia miltiorrhiza Warfarin interaction. Since Warfarin is highly HSA bound in the plasma with selectivity to site I, it is critical to evaluate the possibility of HSA-related herb-drug interaction. Herein an integrated approach was employed to analyze the binding of chemicals identified in S. miltiorrhiza to HSA. Molecular docking simulations revealed filtering criteria for HSA site I compounds that include docking score and key molecular determinants for binding. For eight representative ingredients from the herb, their affinity and specificity to HSA site I was measured and confirmed fluorometrically, which helps to improve the knowledge of interaction mechanisms between this herb and HSA. Our results indicated that several compounds in S. miltiorrhiza were capable of decreasing the binding constant of Warfarin to HSA site I significantly, which may increase free drug concentration in vivo, contributing to the herb-drug interaction observed clinically. Furthermore, the significance of HSA mediated herb-drug interactions was further implied by manual mining on the published literatures on S. miltiorrhiza. PMID- 26926394 TI - Proteolytically-induced changes of secondary structural protein conformation of bovine serum albumin monitored by Fourier transform infrared (FT-IR) and UV circular dichroism spectroscopy. AB - Enzymatically-induced degradation of bovine serum albumin (BSA) by serine proteases (trypsin and alpha-chymotrypsin) in various concentrations was monitored by means of Fourier transform infrared (FT-IR) and ultraviolet circular dichroism (UV-CD) spectroscopy. In this study, the applicability of both spectroscopies to monitor the proteolysis process in real time has been proven, by tracking the spectral changes together with secondary structure analysis of BSA as proteolysis proceeds. On the basis of the FTIR spectra and the changes in the amide I band region, we suggest the progression of proteolysis process via conversion of alpha-helices (1654 cm(-1)) into unordered structures and an increase in the concentration of free carboxylates (absorption of 1593 and 1402 cm(-1)). For the first time, the correlation between the degree of hydrolysis and the concentration of carboxylic groups measured by FTIR spectroscopy was revealed as well. The far UV-CD spectra together with their secondary structure analysis suggest that the alpha-helical content decreases concomitant with an increase in the unordered structure. Both spectroscopic techniques also demonstrate that there are similar but less spectral changes of BSA for the trypsin attack than for alpha-chymotrypsin although the substrate/enzyme ratio is taken the same. PMID- 26926395 TI - Double-wavelength overlapping resonance Rayleigh scattering technique for the simultaneous quantitative analysis of three beta-adrenergic blockade. AB - Four simple and accurate spectrophotometric methods were proposed for the simultaneous determination of three beta-adrenergic blockade, e.g. atenolol, metoprolol and propranolol. The methods were based on the reaction of the three drugs with erythrosine B (EB) in a Britton-Robinson buffer solution at pH4.6. EB could combine with the drugs to form three ion-association complexes, which resulted in the resonance Rayleigh scattering (RRS) intensity that is enhanced significantly with new RRS peaks that appeared at 337 nm and 370 nm, respectively. In addition, the fluorescence intensity of EB was also quenched. The enhanced scattering intensities of the two peaks and the fluorescence quenched intensity of EB were proportional to the concentrations of the drugs, respectively. What is more, the RRS intensity overlapped with the double wavelength of 337 nm and 370 nm (so short for DW-RRS) was also proportional to the drugs concentrations. So, a new method with highly sensitive for simultaneous determination of three bisoprolol drugs was established. Finally, the optimum reaction conditions, influencing factors and spectral enhanced mechanism were investigated. The new DW-RRS method has been applied to simultaneously detect the three beta-blockers in fresh serum with satisfactory results. PMID- 26926396 TI - [Management of Adult Community-acquired Pneumonia and Prevention - Update 2016]. AB - The present guideline provides a new and updated concept of treatment and prevention of adult patients with community-acquired pneumonia. It replaces the previous guideline dating from 2009.The guideline was worked out and agreed on following the standards of methodology of a S3-guideline. This includes a systematic literature search and grading, a structured discussion of recommendations supported by the literature as well as the declaration and assessment of potential conflicts of interests.The guideline has a focus on specific clinical circumstances, an update on severity assessment, and includes recommendations for an individualized selection of antimicrobial treatment as well as primary and secondary prevention. PMID- 26926398 TI - Mucolipidosis IV: A milder form with novel mutations and serial MRI findings. AB - BACKGROUND: Mucolipidosis IV (MLIV; OMIM #252650) is an autosomal recessive lysosomal storage disorder, frequently observed in the Ashkenazi Jewish population. MLIV typically results in intellectual disability, corneal opacities, and delayed motor milestones during infancy, with a relatively static course. To date, reports of MLIV in other ethnic groups have been sparse. PATIENT: The present study is a case report of a 9-year-old Japanese boy, diagnosed via whole exome sequencing, with compound heterozygous mutations of MCOLN1 (OMIM(*)605248): c.410T>C (p.Leu137Pro) and c.802_803delAG (p.Ser268Trpfs*17). Although his clinical course was mild (due to a lack of corneal clouding), other relevant features were present. These included strabismus, white matter signal abnormalities, and a hypoplastic corpus callosum at 2years of age. After a molecular diagnosis, a markedly elevated serum gastrin level (which is also common in MLIV) was confirmed. DISCUSSION: The present results suggest that MLIV could be added as a differential diagnosis for white matter disorders, regardless of ethnicity. Beyond neurological or ophthalmologic findings, serum gastrin could be a useful diagnostic marker for MLIV. PMID- 26926397 TI - Blood Transcriptomic Markers in Patients with Late-Onset Major Depressive Disorder. AB - We investigated transcriptomic markers of late-onset major depressive disorder (LOD; onset age of first depressive episode >= 50 years) from the genes expressed in blood cells and identified state-dependent transcriptomic markers in these patients. We assessed the genes expressed in blood cells by microarray and found that the expression levels of 3,066 probes were state-dependently changed in the blood cells of patients with LOD. To select potential candidates from those probes, we assessed the genes expressed in the blood of an animal model of depression, ovariectomized female mice exposed to chronic ultra-mild stress, by microarray and cross-matched the differentially expressed genes between the patients and the model mice. We identified 14 differentially expressed genes that were similarly changed in both patients and the model mice. By assessing statistical significance using real-time quantitative PCR (RT-qPCR), the following 4 genes were selected as candidates: cell death-inducing DFFA-like effector c (CIDEC), ribonuclease 1 (RNASE1), solute carrier family 36 member-1 (SLC36A1), and serine/threonine/tyrosine interacting-like 1 (STYXL1). The discriminating ability of these 4 candidate genes was evaluated in an independent cohort that was validated. Among them, CIDEC showed the greatest discriminant validity (sensitivity 91.3% and specificity 87.5%). Thus, these 4 biomarkers should be helpful for properly diagnosing LOD. PMID- 26926399 TI - Plasma exchange in pediatric anti-NMDAR encephalitis: A systematic review. AB - OBJECTIVE: To clarify the most frequent modalities of use of plasma exchange (PE) in pediatric anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis and to establish the most effective association with other immunotherapies. METHODS: Systematic literature review on PE in pediatric anti-NMDAR encephalitis (2007 2015). RESULTS: Seventy-one articles were included (mostly retrospective), reporting a total of 242 subjects (73.2%, 93/127 females; median age at onset 12years, range 1-18). Median time to immunotherapy was 21days (range 0-190). In most cases, PE was given with steroids and IVIG (69.5%, 89/128), or steroids only (18%, 23/128); in a minority, it was associated with IVIG only (7%, 9/128), or was the only first-line treatment (5.5%, 7/128). In 54.5% (65/119), PE was the third treatment after steroids and IVIG, in 31.1% (37/119) the second after steroids or IVIG; only in 14.3% (17/119) was it the first treatment. Second-line immunotherapies were administered in 71.9% (100/139). Higher rates of full/substantial recovery at follow-up were observed with immunotherapy given ?30days from onset (69.4%, 25/36) compared to later (59.2%, 16/27), and when PE was associated with steroids (66.7%, 70/105) rather than not (46.7%, 7/15). Significant adverse reactions to PE were reported in 6 patients. CONCLUSION: Our review disclosed a paucity of quality data on PE in pediatric anti-NMDAR encephalitis. PE use in this condition has been increasingly reported, most often with steroids and IVIG. Despite the limited number of patients, our data seem to confirm the trend towards a better outcome when PE was administered early, and when given with steroids. PMID- 26926400 TI - A novel pulse scheme for multiple quantum excitation, SFAM to enhance the sensitivity of MQMAS experiments. AB - The basic MQMAS sequence consists of two hard pulses, one excites the equilibrium population to MQ (Multiple Quantum) coherence, and the other converts back to detectable coherence after some evolution time t1 (Medek et al., 1995). Unfortunately the MQ excitation and conversion processes are very inefficient due to the nonlinear nature of MQ processes. MQ conversion (converting MQ back to detectable coherence) efficiency can significantly be enhanced with DFS (Double Frequency Sweep) or FAM (Fast Amplitude Modulation) type pulses instead of rectangular pulse irradiation (Goldbourt and Madhu, 2002). In contrary to conversion, it is more challenging to enhance MQ excitation in MQMAS experiments, since most methods result in distorted lineshapes (Goldbourt and Madhu, 2002; Lim and Grey, 1998). In the present work MQ excitation of single crystals was studied, and the understanding of the process led to a principle, which was extended to the excitation of powder samples as well. The resulting method was implemented into the MQMAS sequence to enhance MQ excitation of powder samples under MAS condition. The new sequence called SFAM (Shifted Fast Amplitude Modulation) can provide high enhancements at low RF powers (epsilon>4 at nurf=40 kHz) compared to rectangular pulses. Although simulated lineshapes of SFAM predict only minor deviations from ideal lineshapes, experimentally obtained lineshapes along the anisotropic dimension show rather strong distortions. SFAM is relatively simple to optimize, and shows robustness with respect to the miscalibration or inhomogeneity of the RF power as well as to other parameters of the pulse scheme. A good agreement was found between numerically and experimentally optimized parameters. PMID- 26926402 TI - Dietary Management of Hypertension: What Works vs. What Matters. PMID- 26926401 TI - Truncation of the unique N-terminal domain improved the thermos-stability and specific activity of alkaline alpha-amylase Amy703. AB - High pH condition is of special interest for the potential applications of alkaline alpha-amylase in textile and detergent industries. Thus, there is a continuous demand to improve the amylase's properties to meet the requirements set by specific applications. Here we reported the systematic study of modular domain engineering to improve the specific activity and stability of the alkaline alpha-amylase from Bacillus pseudofirmus 703. The specific activity of the N terminal domain truncated mutant (N-Amy) increased by ~35-fold with a significantly improved thermo-stability. Kinetic analysis demonstrated that the Kcat and Kcat/Kmof N-Amy were enhanced by 1300-fold and 425.7-fold, respectively, representing the largest catalytic activity improvement of the engineered alpha amylases through the methods of domain deletion, fusion or swapping. In addition, different from the wild-type Amy703, no exogenous Ca(2+) were required for N-Amy to maintain its full catalytic activity, implying its superior potential for many industrial processes. Circular dichroism analysis and structure modeling revealed that the increased compactness and alpha-helical content were the main contributors for the improved thermo-stability of N-Amy, while the improved catalytic efficiency was mainly attributed by the increased conformational flexibility around the active center. PMID- 26926404 TI - Dietary Supplements: How Family Physicians Can Address Safety Concerns by Working with the FDA. PMID- 26926405 TI - Only 15% of FPs Report Using Telehealth; Training and Lack of Reimbursement Are Top Barriers. PMID- 26926406 TI - Diabetes Mellitus: Screening and Diagnosis. AB - Diabetes mellitus is one of the most common diagnoses made by family physicians. Uncontrolled diabetes can lead to blindness, limb amputation, kidney failure, and vascular and heart disease. Screening patients before signs and symptoms develop leads to earlier diagnosis and treatment, but may not reduce rates of end-organ damage. Randomized trials show that screening for type 2 diabetes does not reduce mortality after 10 years, although some data suggest mortality benefits after 23 to 30 years. Lifestyle and pharmacologic interventions decrease progression to diabetes in patients with impaired fasting glucose or impaired glucose tolerance. Screening for type 1 diabetes is not recommended. The U.S. Preventive Services Task Force recommends screening for abnormal blood glucose and type 2 diabetes in adults 40 to 70 years of age who are overweight or obese, and repeating testing every three years if results are normal. Individuals at higher risk should be considered for earlier and more frequent screening. The American Diabetes Association recommends screening for type 2 diabetes annually in patients 45 years and older, or in patients younger than 45 years with major risk factors. The diagnosis can be made with a fasting plasma glucose level of 126 mg per dL or greater; an A1C level of 6.5% or greater; a random plasma glucose level of 200 mg per dL or greater; or a 75-g two-hour oral glucose tolerance test with a plasma glucose level of 200 mg per dL or greater. Results should be confirmed with repeat testing on a subsequent day; however, a single random plasma glucose level of 200 mg per dL or greater with typical signs and symptoms of hyperglycemia likely indicates diabetes. Additional testing to determine the etiology of diabetes is not routinely recommended. PMID- 26926407 TI - Acute Bacterial Prostatitis: Diagnosis and Management. AB - Acute bacterial prostatitis is an acute infection of the prostate gland that causes pelvic pain and urinary tract symptoms, such as dysuria, urinary frequency, and urinary retention, and may lead to systemic symptoms, such as fevers, chills, nausea, emesis, and malaise. Although the true incidence is unknown, acute bacterial prostatitis is estimated to comprise approximately 10% of all cases of prostatitis. Most acute bacterial prostatitis infections are community acquired, but some occur after transurethral manipulation procedures, such as urethral catheterization and cystoscopy, or after transrectal prostate biopsy. The physical examination should include abdominal, genital, and digital rectal examination to assess for a tender, enlarged, or boggy prostate. Diagnosis is predominantly made based on history and physical examination, but may be aided by urinalysis. Urine cultures should be obtained in all patients who are suspected of having acute bacterial prostatitis to determine the responsible bacteria and its antibiotic sensitivity pattern. Additional laboratory studies can be obtained based on risk factors and severity of illness. Radiography is typically unnecessary. Most patients can be treated as outpatients with oral antibiotics and supportive measures. Hospitalization and broad-spectrum intravenous antibiotics should be considered in patients who are systemically ill, unable to voluntarily urinate, unable to tolerate oral intake, or have risk factors for antibiotic resistance. Typical antibiotic regimens include ceftriaxone and doxycycline, ciprofloxacin, and piperacillin/tazobactam. The risk of nosocomial bacterial prostatitis can be reduced by using antibiotics, such as ciprofloxacin, before transrectal prostate biopsy. PMID- 26926408 TI - Hypertensive Disorders of Pregnancy. AB - Elevated blood pressure in pregnancy may represent chronic hypertension (occurring before 20 weeks' gestation or persisting longer than 12 weeks after delivery), gestational hypertension (occurring after 20 weeks' gestation), preeclampsia, or preeclampsia superimposed on chronic hypertension. Preeclampsia is defined as hypertension and either proteinuria or thrombocytopenia, renal insufficiency, impaired liver function, pulmonary edema, or cerebral or visual symptoms. Proteinuria is not essential for the diagnosis and does not correlate with outcomes. Severe features of preeclampsia include a systolic blood pressure of at least 160 mm Hg or a diastolic blood pressure of at least 110 mm Hg, platelet count less than 100 * 103 per uL, liver transaminase levels two times the upper limit of normal, a doubling of the serum creatinine level or level greater than 1.1 mg per dL, severe persistent right upper-quadrant pain, pulmonary edema, or new-onset cerebral or visual disturbances. Preeclampsia without severe features can be managed with twice-weekly blood pressure monitoring, antenatal testing for fetal well-being and disease progression, and delivery by 37 weeks' gestation. Preeclampsia with any severe feature requires immediate stabilization and inpatient treatment with magnesium sulfate, antihypertensive drugs, corticosteroids for fetal lung maturity if less than 34 weeks' gestation, and delivery plans. Preeclampsia can worsen or initially present after delivery. Women with hypertensive disorders should be monitored as inpatients or closely at home for 72 hours postpartum. PMID- 26926409 TI - Perioperative Bridging Anticoagulation Unhelpful for Invasive Procedures. PMID- 26926410 TI - A Vietnamese Child with a Rash on the Back. PMID- 26926411 TI - Screening for Iron Deficiency Anemia and Iron Supplementation in Pregnant Women to Improve Maternal Health and Birth Outcomes: Recommendation Statement. PMID- 26926412 TI - Screening for Iron Deficiency Anemia and Iron Supplementation in Pregnant Women to Improve Maternal Health and Birth Outcomes. PMID- 26926413 TI - Appendicitis. PMID- 26926414 TI - CDC Releases 2015 Guidelines on the Treatment of Sexually Transmitted Disease. PMID- 26926415 TI - Screening for Abnormal Blood Glucose and Type 2 Diabetes Mellitus: Recommendation Statement. PMID- 26926416 TI - High Blood Pressure During Pregnancy. PMID- 26926417 TI - Alterations in primary and secondary metabolism in Vitis vinifera 'Malvasia de Banyalbufar' upon infection with Grapevine leafroll-associated virus 3. AB - Plant defense mechanisms against pathogens result in differential regulation of various processes of primary and secondary metabolism. Imaging techniques, such as fluorescence imaging and thermography, are very valuable tools providing spatial and temporal information about these processes. In this study, effects of Grapevine leafroll-associated virus 3 (GLRaV-3) on grapevine physiology were analyzed in pot-grown asymptomatic plants of the white cultivar Malvasia de Banyalbufar. The virus triggered changes in the activity of photosynthesis and secondary metabolism. There was a decrease in the photorespiratory intermediates glycine and serine in infected plants, possibly as a defense response against the infection. The content of malate, which plays an important role in plant metabolism, also decreased. These results correlate with the increased non photochemical quenching found in infected plants. On the other hand, the concentration of flavonols (represented by myricetin, kaempferol and quercetin derivatives) and hydroxycinnamic acids (which include derivatives of caffeic acid) increased following infection by the virus. These compounds could be responsible for the increase in multicolor fluorescence F440 (blue fluorescence) and F520 (green fluorescence) on the leaves, and changes in the fluorescence parameters F440/F680, F440/F740, F520/F680, F520/F740 and F680/F740. The combined analysis of chlorophyll fluorescence kinetics and blue-green fluorescence emitted by phenolics could constitute disease signatures allowing the discrimination between GLRaV-3 infected and non-infected plants at very early stage of infection, prior to the development of symptoms. PMID- 26926418 TI - Folding PDZ2 Domain Using the Molecular Transfer Model. PMID- 26926419 TI - Efficacy of multimodal drug injection after supramalleolar osteotomy for varus ankle osteoarthritis: A prospective randomized study. AB - BACKGROUND: Optimal management of postoperative pain is important to ensure patient comfort and functional improvement. Despite the frequent use of multimodal drug injection for pain control after orthopedic surgery, few studies have evaluated its use after supramalleolar osteotomy. METHODS: Supramalleolar osteotomy was performed in 62 patients (65 ankles). Thirty patients (31 ankles) were randomly assigned to receive multimodal drug injection (injection group) and 32 patients (34 ankles) were assigned to receive no multimodal drug injection (control group). The two groups were compared with regard to the degree of postoperative pain, the number of times patients pushed the patient-controlled analgesia (PCA) button, the total amount of fentanyl administered, and the frequency of additional diclofenac sodium injections. RESULTS: The injection group had significant pain reduction during the first 36 postoperative hours compared to the control group. There were significant differences between the groups in the number of times that patients pushed the PCA button as well as the total amount of fentanyl administered up to 24 h postoperatively. The mean frequency of additional diclofenac sodium injections in the first 12 postoperative hours was significantly less in the injection group compared to that in the control group. CONCLUSION: Multimodal drug injection was effective in reducing pain and decreasing both fentanyl and diclofenac sodium usage in patients undergoing supramalleolar osteotomy. Therefore, multimodal drug injection should be considered for improved pain control and patient comfort in the early postoperative period after supramalleolar osteotomy. PMID- 26926420 TI - New type high-index dielectric nanosensors based on the scattering intensity shift. AB - Sensing is regarded as one of the most important applications of noble metal based nanoplasmonics. However, all previous designs have been based on the wavelength-shift of the localized surface plasmon resonance, in which the sensitivity is intrinsically limited by the low quality factors induced by metal losses, and meanwhile the large ohmic loss, high cost and inevitable toxicity and biofouling for detection in vivo greatly hinder their further applications in biosensors. Beyond noble metals, high-refractive index dielectric materials (HRDMs) like silicon with low-loss and strong magnetic response have drawn more attention. Here, for the first time, we proposed a HRDM nanosphere as a new nanosensor for biomolecule detection, and experimentally demonstrated a HRDM sensor working on the intensity-shift but not wavelength-shift of the scattering. The sensing mechanism based on the synergistic effect of the broadening electric mode shift of HRDMs and the Kerker's scattering intensity-shift is beneficial to achieve higher sensitivity. We validated the efficacy of our sensor to detect refractive index changes and trace amounts of streptavidin molecules, and the sensitivity can reach 27 times as high as the highest sensitivity reported to date for nanoplasmonic structures. These findings showed that monitoring the change of the scattering intensity of HRDM nanostructures is superior to monitoring the wavelength-shift of nanoplasmonic structures, as is widely used in nanoplasmonic sensors, for biosensing, meaning HRDM nanosensors could be an important tool in biomolecule detection. PMID- 26926421 TI - Both idebenone and idebenol are localized near the lipid-water interface of the membrane and increase its fluidity. AB - Idebenone is a synthetic analog of coenzyme Q; both share a quinone moiety but idebenone has a shorter lipophilic tail ending with a hydroxyl group. Differential scanning calorimetry experiments showed that both idebenone and idebenol widened and shifted the phase transition of 1,2 dipalmitoylphosphatidylcholine (DPPC) to a lower temperature and a phase separation with different concentrations of these molecules was observed. Also small angle X-ray diffraction and wide angle X-ray diffraction revealed that both, idebenone and idebenol, induced laterally separated phases in fluid membranes when included in DPPC membranes. Electronic profiles showed that both forms, idebenone and idebenol, reduced the thickness of the fluid membrane. (2)H NMR measurements showed that the order of the membrane decreased at all temperatures in the presence of idebenone or idebenol, the greatest disorder being observed in the segments of the acyl chains close to the lipid-water interface. (1)H NOESY MAS NMR spectra were obtained using 1-palmitoyl-2-oleoyl phosphatidylcholine membranes and results pointed to a similar location in the membrane for both forms, with the benzoquinone or benzoquinol rings and their terminal hydroxyl group of the hydrophobic chain located near the lipid/water interface of the phospholipid bilayer and the terminal hydroxyl group of the hydrophobic chain of both compounds located at the lipid/water interface. Taken together, all these different locations might explain the different physiological behavior shown by the idebenone/idebenol compared with the ubiquinone 10/ubiquinol-10 pair in which both compounds are differently localized in the membrane. PMID- 26926422 TI - Interaction of lipids with the neurotensin receptor 1. AB - Information about lipid-protein interactions for G protein-coupled receptors (GPCRs) is scarce. Here, we use electron spin resonance (ESR) and spin-labelled lipids to study lipid interactions with the rat neurotensin receptor 1 (NTS1). A fusion protein containing rat NTS1 fully able to bind its ligand neurotensin was reconstituted into phosphatidylcholine (PC) bilayers at specific lipid:protein molar ratios. The fraction of motionally restricted lipids in the range of 40:1 to 80:1 lipids per receptor suggested an oligomeric state of the protein, and the result was unaffected by increasing the hydrophobic thickness of the lipid bilayer from C-18 to C-20 or C-22 chain length PC membranes. Comparison of the ESR spectra of different spin-labelled lipids allowed direct measurement of lipid binding constants relative to PC (Kr), with spin-labelled phosphatidylethanolamine (PESL), phosphatidylserine (PSSL), stearic acid (SASL), and a spin labelled cholesterol analogue (CSL) Kr values of 1.05+/-0.05, 1.92+/ 0.08, 5.20+/-0.51 and 0.91+/-0.19, respectively. The results contrast with those from rhodopsin, the only other GPCR studied this way, which has no selectivity for the lipids analysed here. Molecular dynamics simulations of NTS1 in bilayers are in agreement with the ESR data, and point to sites in the receptor where PS could interact with higher affinity. Lipid selectivity could be necessary for regulation of ligand binding, oligomerisation and/or G protein activation processes. Our results provide insight into the potential modulatory mechanisms that lipids can exert on GPCRs. PMID- 26926423 TI - Membrane interactions of proline-rich antimicrobial peptide, Chex1-Arg20, multimers. AB - The increasing prevalence of antibiotic-resistant pathogens requires the development of new antibiotics. Proline-rich antimicrobial peptides (PrAMPs), including native apidaecins, Bac7, and oncocins or designed A3APO, show multi modal actions against pathogens together with immunostimulatory activities. The interactions of the designed PrAMP, Chex1-Arg20, and its dimeric and tetrameric oligomers with different model membranes were investigated by circular dichroism spectroscopy, dynamic light scattering, zeta potential, differential scanning calorimetry, and dye leakage. Chex1-Arg20 oligomers showed stronger affinity and preferential binding to negatively charged phospholipid bilayers and led to lipid aggregation and neutralization. Fluorescence microscopy of negatively charged giant unilamellar vesicles with AlexFluor-647-labeled Chex1-Arg20 dimers and tetramers displayed aggregation at a peptide/lipid low ratio of 1:200 and at higher peptide concentrations (1:100/1:50) for Chex1-Arg20 monomer. Such interactions, aggregation, and neutralization of PrAMP oligomers additionally showed the importance of interactions of PrAMPs with negatively charged membranes. PMID- 26926425 TI - On a Possible Unified Scaling Law for Volcanic Eruption Durations. AB - Volcanoes constitute dissipative systems with many degrees of freedom. Their eruptions are the result of complex processes that involve interacting chemical physical systems. At present, due to the complexity of involved phenomena and to the lack of precise measurements, both analytical and numerical models are unable to simultaneously include the main processes involved in eruptions thus making forecasts of volcanic dynamics rather unreliable. On the other hand, accurate forecasts of some eruption parameters, such as the duration, could be a key factor in natural hazard estimation and mitigation. Analyzing a large database with most of all the known volcanic eruptions, we have determined that the duration of eruptions seems to be described by a universal distribution which characterizes eruption duration dynamics. In particular, this paper presents a plausible global power-law distribution of durations of volcanic eruptions that holds worldwide for different volcanic environments. We also introduce a new, simple and realistic pipe model that can follow the same found empirical distribution. Since the proposed model belongs to the family of the self organized systems it may support the hypothesis that simple mechanisms can lead naturally to the emergent complexity in volcanic behaviour. PMID- 26926424 TI - RNF12 promotes p53-dependent cell growth suppression and apoptosis by targeting MDM2 for destruction. AB - The oncoprotein MDM2 is an E3 ubiquitin ligase that targets tumor suppressor p53 for ubiquitination and proteasomal degradation, restraining the potent activity of p53 and enabling cell survival and proliferation. Dysregulation of MDM2-p53 axis was frequently observed in human cancers. Originally, it is proposed that MDM2 degradation was mainly achieved by destructive self-ubiquitination. However, recent study suggests that MDM2 may be targeted for degradation by an external E3 ubiquitin ligase(s) under physiological levels. Here, we identified E3 ubiquitin ligase RNF12 as an MDM2-interacting protein through yeast two hybrid methods. We demonstrated that RNF12 targets MDM2 for ubiquitination and proteasomal-dependent degradation, which is independent of MDM2's self-ubiquitination activity. Accordingly, RNF12 elevates p53 protein level by abrogating MDM2-mediated p53 degradation and ubiquitination. Finally, we showed that RNF12 regulates cell growth suppression and DNA damage-induced apoptosis in a p53-dependent manner. Taken together, we establish RNF12 as a novel positive regulator of p53 pathway and an external E3 ubiquitin ligase for MDM2 destruction. These data shed light on the potential roles of RNF12 in MDM2-p53 axis and tumor suppression. PMID- 26926427 TI - A template for building global partnerships: The Joining Forces conference goes across the Atlantic from the US to the UK. AB - Joining Forces is a comprehensive national initiative within the United States to mobilize all sectors of society to give service members and their families the opportunities and support they have earned. This national initiative begun in April 2012 was led by First Lady Michelle Obama and Dr. Jill Biden. The Joining Forces initiative is charged with enhancing the well-being and psychological health of the military family by providing mental health care services, integrating community-based services to reduce homelessness, substance abuse for veterans and military families. This manuscript addresses how one university with its global partners joined together to host an innovative conference addressing the research, education, and practice needs of healthcare professionals caring for military, veterans, and their families. PMID- 26926428 TI - Exploring the positive allosteric modulation of human alpha7 nicotinic receptors from a single-channel perspective. AB - Enhancement of alpha7 nicotinic receptor (nAChR) function by positive allosteric modulators (PAMs) is a promising therapeutic strategy to improve cognitive deficits. PAMs have been classified only on the basis of their macroscopic effects as type I, which only enhance agonist-induced currents, and type II, which also decrease desensitization and reactivate desensitized nAChRs. To decipher the molecular basis underlying these distinct activities, we explored the effects on single-alpha7 channel currents of representative members of each type and of less characterized compounds. Our results reveal that all PAMs enhance open-channel lifetime and produce episodes of successive openings, thus indicating that both types affect alpha7 kinetics. Different PAM types show different sensitivity to temperature, suggesting different mechanisms of potentiation. By using a mutant alpha7 receptor that is insensitive to the prototype type II PAM (PNU-120596), we show that some though not all type I PAMs share the structural determinants of potentiation. Overall, our study provides novel information on alpha7 potentiation, which is key to the ongoing development of therapeutic compounds. PMID- 26926429 TI - Gap junctions between CA3 pyramidal cells contribute to network synchronization in neonatal hippocampus. AB - Direct electrical coupling between neurons through gap junctions is prominent during development, when synaptic connectivity is scarce, providing the additional intercellular connectivity. However, functional studies of gap junctions are hampered by the unspecificity of pharmacological tools available. Here we have investigated gap-junctional coupling between CA3 pyramidal cells in neonatal hippocampus and its contribution to early network activity. Four different gap junction inhibitors, including the general blocker carbenoxolone, decreased the frequency of network activity bursts in CA3 area of hippocampus of P3-6 rats, suggesting the involvement of electrical connections in the generation of spontaneous network activity. In CA3 pyramidal cells, spikelets evoked by local stimulation of stratum oriens, were inhibited by carbenoxolone, but not by inhibitors of glutamatergic and GABAergic synaptic transmission, signifying the presence of electrical connectivity through axo-axonic gap junctions. Carbenoxolone also decreased the success rate of firing antidromic action potentials in response to stimulation, and changed the pattern of spontaneous action potential firing of CA3 pyramidal cells. Altogether, these data suggest that electrical coupling of CA3 pyramidal cells contribute to the generation of the early network events in neonatal hippocampus by modulating their firing pattern and synchronization. PMID- 26926430 TI - 5-(4-hydroxy-3-dimethoxybenzylidene)-rhodanine (RD-1)-improved mitochondrial function prevents anxiety- and depressive-like states induced by chronic corticosterone injections in mice. AB - Most current pharmacologic antidepressant treatments target monoaminergic systems confronts some problems such as low rate of remission and high risk for relapse indicating new therapeutic strategy is urgently need. Evidences showed that impairments in mitochondrial function were associated with the pathogenesis of mood disorders and improvement in its function may be a novel therapeutic choice. In the present study, effects of 5-(4-hydroxy-3-dimethoxybenzylidene)-2-thioxo-4 thiazolidinone (RD-1) were investigated in mice model of depression/anxiety induced by corticosterone (20 mg/kg) subcutaneously repeated injections in 5-week male BALB/c mice. Our results showed that five weeks of corticosterone administration induced anxiety/depressive-like behavioral changes, including decreased central activities in open field test, increased the immobility time in forced swimming test and the latency in the novelty-suppressed feeding test, as well as reduced bodyweight. Results showed that oral administration with RD-1 at the doses of 25, 50, and 100 mg/kg for five weeks significantly improved the anxiety/depressive-like behavioral changes induced by corticosterone. In glucose metabolism analysis by photon emission computed tomography/-computed tomography (PET/CT) imaging, corticosterone significantly deactivated the prefrontal cortex (PFC), temporal lobe and hippocampus. RD-1 treatment obviously improved the energy metabolism in the involved brain regions. In primary cultured hippocampal neuron, corticosterone reduced speed of anterograde transport, yet speed of retrograde transport was increased. Furthermore, RD-1 enhanced the mitochondrial anterograde transport to supply energy for the neurotransmitter release. In conclusion, RD-1 prevents anxiety/depressive-like behavior of mice induced by corticosterone repeated injections with novel mechanism of improvement in the mitochondrial function. PMID- 26926431 TI - Internal hernia after mini-gastric bypass: Myth or reality? AB - The mini-gastric bypass (MGBP) is becoming an increasingly popular procedure worldwide. It is based on an "omega" reconstruction, resulting in a single anastomosis and in potential shortening of operative time. Internal hernia represents a potentially life-threatening complication after laparoscopic Roux-en Y gastric bypass, but it has not yet been reported after a mini-gastric bypass. We herein describe, for the first time, a case of internal hernia after this surgery. PMID- 26926432 TI - A complex rectal lesion following perineal trauma with no cutaneous stigmata. PMID- 26926433 TI - Evidence for lattice-polarization-enhanced field effects at the SrTiO3-based heterointerface. AB - Electrostatic gating provides a powerful approach to tune the conductivity of the two-dimensional electron liquid between two insulating oxides. For the LaAlO3/SrTiO3 (LAO/STO) interface, such gating effect could be further enhanced by a strong lattice polarization of STO caused by simultaneous application of gate field and illumination light. Herein, by monitoring the discharging process upon removing the gate field, we give firm evidence for the occurrence of this lattice polarization at the amorphous-LaAlO3/SrTiO3 interface. Moreover, we find that the lattice polarization is accompanied with a large expansion of the out-of plane lattice of STO. Photo excitation affects the polarization process by accelerating the field-induced lattice expansion. The present work demonstrates the great potential of combined stimuli in exploring emergent phenomenon at complex oxide interfaces. PMID- 26926434 TI - An interactive environment for agile analysis and visualization of ChIP sequencing data. AB - To empower experimentalists with a means for fast and comprehensive chromatin immunoprecipitation sequencing (ChIP-seq) data analyses, we introduce an integrated computational environment, EaSeq. The software combines the exploratory power of genome browsers with an extensive set of interactive and user-friendly tools for genome-wide abstraction and visualization. It enables experimentalists to easily extract information and generate hypotheses from their own data and public genome-wide datasets. For demonstration purposes, we performed meta-analyses of public Polycomb ChIP-seq data and established a new screening approach to analyze more than 900 datasets from mouse embryonic stem cells for factors potentially associated with Polycomb recruitment. EaSeq, which is freely available and works on a standard personal computer, can substantially increase the throughput of many analysis workflows, facilitate transparency and reproducibility by automatically documenting and organizing analyses, and enable a broader group of scientists to gain insights from ChIP-seq data. PMID- 26926435 TI - Multiperspective smFRET reveals rate-determining late intermediates of ribosomal translocation. AB - Directional translocation of the ribosome through the mRNA open reading frame is a critical determinant of translational fidelity. This process entails a complex interplay of large-scale conformational changes within the actively translating particle, which together coordinate the movement of tRNA and mRNA substrates with respect to the large and small ribosomal subunits. Using pre-steady state, single molecule fluorescence resonance energy transfer imaging, we tracked the nature and timing of these conformational events within the Escherichia coli ribosome from five structural perspectives. Our investigations revealed direct evidence of structurally and kinetically distinct late intermediates during substrate movement, whose resolution determines the rate of translocation. These steps involve intramolecular events within the EF-G-GDP-bound ribosome, including exaggerated, reversible fluctuations of the small-subunit head domain, which ultimately facilitate peptidyl-tRNA's movement into its final post-translocation position. PMID- 26926436 TI - A structural ensemble of a ribosome-nascent chain complex during cotranslational protein folding. AB - Although detailed pictures of ribosome structures are emerging, little is known about the structural and cotranslational folding properties of nascent polypeptide chains at the atomic level. Here we used solution-state NMR spectroscopy to define a structural ensemble of a ribosome-nascent chain complex (RNC) formed during protein biosynthesis in Escherichia coli, in which a pair of immunoglobulin-like domains adopts a folded N-terminal domain (FLN5) and a disordered but compact C-terminal domain (FLN6). To study how FLN5 acquires its native structure cotranslationally, we progressively shortened the RNC constructs. We found that the ribosome modulates the folding process, because the complete sequence of FLN5 emerged well beyond the tunnel before acquiring native structure, whereas FLN5 in isolation folded spontaneously, even when truncated. This finding suggests that regulating structure acquisition during biosynthesis can reduce the probability of misfolding, particularly of homologous domains. PMID- 26926437 TI - A path analysis of patient dependence and caregiver burden in Alzheimer's disease. AB - BACKGROUND: The concept of dependence has been proposed as an integrative measure to assess the progression of Alzheimer's disease (AD).This study aimed to investigate the association of patient's dependence level with the caregiver burden within a general theoretical model that includes other well-established determinants. METHODS: Observational and cross-sectional multicenter study. The sample consisted of patients with AD recruited in outpatient consultation offices by a convenience sampling procedure stratified by dementia severity. Cognitive and functional status, behavioral disturbances, dependence level, medical comorbidities, and caregiver burden were assessed by using standardized instruments. A path analysis was used to test the hypothesized relationships between the caregiver burden and its determinants, including the level of dependence. RESULTS: The sample consisted of 306 patients (33.3% mild, 35.9% moderate, 30.7% severe), the mean age was 78.5 years (SD = 7.8), and 66.2% were women. The model fit was acceptable and explained 29% of the caregiver burden variance. Primary stressors were the level of dependence and the distress related to behavioral disturbances. Caregiver's age, gender, and co-residence with the patient were the contextual factors related to caregiver burden. The job status of the caregiver was a significant secondary stressor, functional disability was indirectly associated with caregiver burden via dependence, and frequency of behavioral disturbances was indirectly associated with the caregiver burden via distress. CONCLUSIONS: Dependence was, apart from behavioral disturbances, the most important primary stressor directly related to caregiver burden irrespective of the disease severity. PMID- 26926438 TI - Proteomic MALDI-TOF/TOF-IMS examination of peptide expression in the formalin fixed brainstem and changes in sudden infant death syndrome infants. AB - Matrix assisted laser desorption/ionisation imaging mass spectrometry (MALDI-IMS) has not previously been utilised to examine sudden infant death syndrome (SIDS). This study aimed to optimise MALDI IMS for use on archived formalin-fixed paraffin-embedded human infant medulla tissue (n=6, controls; n=6, SIDS) to evaluate differences between multiple nuclei of the medulla by using high resolution IMS. Profiles were compared between SIDS and age/sex matched controls. LC-MALDI identified 55 proteins based on 321 peptides across all samples; 286 peaks were found using IMS, corresponding to these 55 proteins that were directly compared between controls and SIDS. Control samples were used to identify common peptides for neuronal/non-neuronal structures allowing identification of medullary regions. In SIDS, abnormal expression patterns of 41 peptides (p<=0.05) corresponding to 9 proteins were observed; these changes were confirmed with immunohistochemistry. The protein abnormalities varied amongst nuclei, with the majority of variations in the raphe nuclei, hypoglossal and pyramids. The abnormal proteins are not related to a previously identified neurological disease pathway but consist of developmental neuronal/glial/axonal growth, cell metabolism, cyto-architecture and apoptosis components. This suggests that SIDS infants have abnormal neurological development in the raphe nuclei, hypoglossal and pyramids of the brainstem, which may contribute to the pathogenesis of SIDS. BIOLOGICAL SIGNIFICANCE: This study is the first to perform an imaging mass spectrometry investigation in the human brainstem and also within sudden infant death syndrome (SIDS). LC MALDI and MALDI IMS identified 55 proteins based on 285 peptides in both control and SIDS tissue; with abnormal expression patterns present for 41/285 and 9/55 proteins in SIDS using IMS. The abnormal proteins are critical for neurological development; with the impairment supporting the hypothesis that SIDS may be due to delayed neurological maturation. The brainstem regions mostly affected included the raphe nuclei, hypoglossal and pyramids. This study highlights that basic cyto-architectural proteins are affected in SIDS and that abnormal expression of these proteins in other CNS disorders should be examined. KEY SENTENCES: LC MALDI and MALDI IMS identified 55 proteins based on 285 peptides in both control and SIDS tissue. Abnormal expression patterns were present for 41/285 and 9/55 proteins in SIDS using IMS. Brainstem regions mostly affected included the raphe nuclei, hypoglossal and pyramids. PMID- 26926439 TI - Peptidomics as a tool for quality control in dry-cured ham processing. AB - Spanish dry-cured ham is a high quality product whose economic value is mainly given by its curing time. An intense proteolysis takes place throughout the dry cured processing, which results in the generation of a high amount of peptides and free amino acids responsible for the final quality of dry-cured hams. In this work, a peptidomics approach has been used to study the evolution of peptides throughout the ham dry-curing process, identifying and quantifying the generated peptides in order to define potential quality biomarkers. For this purpose, dry cured ham extracts at different processing times (0, 2, 3.5, 5, 6.5 and 9months) were fractionated by size-exclusion chromatography and analysed by nanoliquid chromatography coupled to tandem mass spectrometry. Differences obtained in the relative quantification of peptides by using a label-free methodology were useful to establish differences between processing times, being peptides generated by the degradation of myosin light chain 1 protein mainly responsible for the observed differences during the last stages of curing. In particular, APAPAPAPPKEEKI and PAPAPAPAPAPAPAPPKE, exclusively identified at 9months of curing, would be potential markers to control the time of curing and thus the final quality of dry-cured hams. Biological significance A peptidomics approach has been used to study the evolution of peptides throughout the ham dry-curing process, identifying peptides APAPAPAPPKEEKI and PAPAPAPAPAPAPAPPKE, which were only detected at 9months of process. So, they would constitute good potential markers to control the time of processing and thus the final quality of dry-cured hams. PMID- 26926440 TI - Deciphering the molecular mechanisms underlying sea urchin reversible adhesion: A quantitative proteomics approach. AB - Marine bioadhesives have unmatched performances in wet environments, being an inspiration for biomedical applications. In sea urchins specialized adhesive organs, tube feet, mediate reversible adhesion, being composed by a disc, producing adhesive and de-adhesive secretions, and a motile stem. After tube foot detachment, the secreted adhesive remains bound to the substratum as a footprint. Sea urchin adhesive is composed by proteins and sugars, but so far only one protein, Nectin, was shown to be over-expressed as a transcript in tube feet discs, suggesting its involvement in sea urchin adhesion. Here we use high resolution quantitative mass-spectrometry to perform the first study combining the analysis of the differential proteome of an adhesive organ, with the proteome of its secreted adhesive. This strategy allowed us to identify 163 highly over expressed disc proteins, specifically involved in sea urchin reversible adhesion; to find that 70% of the secreted adhesive components fall within five protein groups, involved in exocytosis and microbial protection; and to provide evidences that Nectin is not only highly expressed in tube feet discs but is an actual component of the adhesive. These results give an unprecedented insight into the molecular mechanisms underlying sea urchin adhesion, and opening new doors to develop wet-reliable, reversible, and ecological biomimetic adhesives. SIGNIFICANCE: Sea urchins attach strongly but in a reversible manner to substratum, being a valuable source of inspiration for industrial and biomedical applications. Yet, the molecular mechanisms governing reversible adhesion are still poorly studied delaying the engineering of biomimetic adhesives. We used the latest mass spectrometry techniques to analyze the differential proteome of an adhesive organ and the proteome of its secreted adhesive, allowing us to uncover the key players in sea urchin reversible adhesion. We demonstrate, that Nectin, a protein previously pointed out as potentially involved in sea urchin adhesion, is not only highly expressed in tube feet discs, but is a genuine component of the secreted adhesive. PMID- 26926441 TI - Motility of carp spermatozoa is associated with profound changes in the sperm proteome. AB - In freshwater cyprinids, spermatozoa are quiescent in seminal plasma and sperm motility is initiated by a decrease in osmolality (hypo-osmotic shock) after discharge into the aqueous environment. However, it is unknown at present if and to what extent changes in proteins are involved in carp sperm motility. Therefore, the aim of our study was to identify proteins related to carp sperm motility through a comparison of immobilized and activated carp spermatozoa using a 2D-DIGE approach. Our results, for the first time indicated that carp sperm motility is associated with changes in protein content. Seventy-two differentially expressed proteins were identified. These proteins are mainly involved in ubiquitin-proteasome pathways, glycolysis, the TCA cycle, remodeling and are putatively related to sperm energy metabolism and motility. Moreover proteins associated with oxidative stress responses, signal transduction by Ca(2+)-dependent MAPK cascades, and PKC and protein folding have been identified. The proteins involved in carp sperm motility were localized to the cytoplasm, mitochondria, cytoskeleton, nucleus and sperm membrane. The identification of a high number of proteins involved in carp sperm motility would contribute to current knowledge about the molecular mechanisms of sperm motility in freshwater fish. BIOLOGICAL SIGNIFICANCE: To the best of our knowledge, few changes in proteins involved in the initiation of fish sperm motility have been identified. This is a limited number of proteins compared with the 80 recently identified proteins involved in human sperm motility. However, no proteomic studies of sperm motility have yet been performed on freshwater fish. Our present study allowed for the first time a comprehensive characterization of the proteins associated with carp sperm motility and a better understanding of the molecular mechanisms underlying sperm motility activation and maintenance. The application of 2D-DIGE facilitated the identification proteins crucial for sperm structural organization and motility. The identification of a high number of proteins involved in carp sperm motility would contribute appreciably to the presently limited information available on the mechanisms of sperm motility in freshwater fish. Moreover the identified list of proteins will create a platform for future studies designed to assess the functional significance of specific proteins in sperm motility. PMID- 26926442 TI - Examining the Heterogeneous Genome Content of Multipartite Viruses BMV and CCMV by Native Mass Spectrometry. AB - Since the concept was first introduced by Brian Chait and co-workers in 1991, mass spectrometry of proteins and protein complexes under non-denaturing conditions (native MS) has strongly developed, through parallel advances in instrumentation, sample preparation, and data analysis tools. However, the success rate of native MS analysis, particularly in heterogeneous mega-Dalton (MDa) protein complexes, still strongly depends on careful instrument modification. Here, we further explore these boundaries in native mass spectrometry, analyzing two related endogenous multipartite viruses: the Brome Mosaic Virus (BMV) and the Cowpea Chlorotic Mottle Virus (CCMV). Both CCMV and BMV are approximately 4.6 megadalton (MDa) in mass, of which approximately 1 MDA originates from the genomic content of the virion. Both viruses are produced as mixtures of three particles carrying different segments of the genome, varying by approximately 0.1 MDA in mass (~2%). This mixture of particles poses a challenging analytical problem for high-resolution native MS analysis, given the large mass scales involved. We attempt to unravel the particle heterogeneity using both Q-TOF and Orbitrap mass spectrometers extensively modified for analysis of very large assemblies. We show that manipulation of the charging behavior can provide assistance in assigning the correct charge states. Despite their challenging size and heterogeneity, we obtained native mass spectra with resolved series of charge states for both BMV and CCMV, demonstrating that native MS of endogenous multipartite virions is feasible. Graphical Abstract ?. PMID- 26926443 TI - Factors Affecting the Production of Aromatic Immonium Ions in MALDI 157 nm Photodissociation Studies. AB - Immonium ions are commonly observed in the high energy fragmentation of peptide ions. In a MALDI-TOF/TOF mass spectrometer, singly charged peptides photofragmented with 157 nm VUV light yield a copious abundance of immonium ions, especially those from aromatic residues. However, their intensities may vary from one peptide to another. In this work, the effect of varying amino acid position, peptide length, and peptide composition on immonium ion yield is investigated. Internal immonium ions are found to have the strongest intensity, whereas immonium ions arising from C-terminal residues are the weakest. Peptide length and competition among residues also strongly influence the immonium ion production. Quantum calculations provide insights about immonium ion structures and the fragment ion conformations that promote or inhibit immonium ion formation. PMID- 26926444 TI - Decarboxylative Coupling Reaction in ESI(-)-MS/MS of 4-Nitrobenzyl 4 Hydroxybenzoates: Triplet Ion-Neutral Complex-Mediated 4-Nitrobenzyl Transfer. AB - In negative electrospray ionization mass spectrometry of 4-nitrobenzyl 4 hydroxybenzoates, a decarboxylation reaction, which was significantly promoted by the presence of a nitro group on the benzyl group, competed with radical elimination reactions. Density functional theory calculations indicated that decarboxylation of deprotonated 4-nitrobenzyl vanillate occurred via a radical route involving homolytic cleavage of the Cbenzyl-O bond to give a triplet ion neutral complex, followed by decarboxylative coupling. PMID- 26926445 TI - Effect of CaCO3(S) nucleation modes on algae removal from alkaline water. AB - The role of calcite heterogeneous nucleation was studied in a particle coagulation treatment process for removing microalgae from water. Batch experiments were conducted with Scenedesmus sp. and Chlorella sp. in the presence and absence of carbonate and in the presence and absence of Mg to delineate the role of CaCO3(S) nucleation on microalgae removal. The results indicate that effective algae coagulation (e.g., up to 81 % algae removal efficiency) can be achieved via heterogeneous nucleation with CaCO3(S); however, supersaturation ratios between 120 and 200 are required to achieve at least 50% algae removal, depending on ion concentrations. Algae removal was attributed to adsorption of Ca2+ onto the cell surface which provides nucleation sites for CaCO3(S) precipitation. Bridging of calcite particles between the algal cells led to rapid aggregation and formation of larger flocs. However, at higher supersaturation conditions, algae removal was diminished due to the dominance of homogeneous nucleation of CaCO3(S). Removal of algae in the presence of Ca2+ and Mg2+ required higher supersaturation values; however, the shift from heteronucleation to homonucleation with increasing supersaturation was still evident. The results suggest that water chemistry, pH, ionic strength, alkalinity and Ca2+ concentration can be optimized for algae removal via coagulation-sedimentation. PMID- 26926446 TI - Large urban-rural disparity in the severity of two-week illness: updated results based on the first health service survey of Hunan Province, China. AB - BACKGROUND: To examine urban-rural differences in the severity of non-fatal disease and injury using the latest household interview survey data of Hunan Province, China. METHODS: Two-week illness data were from the first provincial health household interview survey of Hunan in 2013. The proportion of patients being bedridden, the average days of being bedridden and the average off-work days were calculated to measure the severity of two-week illness. Rao-Scott adjusted chi-square test was performed to examine the significance of two-week illness severity differences from demographic variables. Multiple logistic regression and linear regression were used to control for sex, age and household income. RESULTS: The two-week illness prevalence was 22.8 % in Hunan province. Despite similar two-week ill prevalence rates between urban areas and rural areas (23.0 % vs. 22.8 %), rural residents had higher proportions of being bedridden and of being off work than urban residents after controlling for sex, age and household income, with adjusted odds ratios of 3.4 and 6.9, respectively. Similarly, the average days of being bedridden and of being off work in rural residents were 0.45 days and 1.61 days longer than in urban residents after controlling for demographic variables, respectively. CONCLUSION: The recent data shows that two-week illness in rural residents is more serious than urban residents in Hunan Province, China in spite of very similar two-week prevalence rates. The neglected urban-rural disparities in the severity of two-week illness deserve the attention of health policy-makers and researchers. PMID- 26926447 TI - Increasing diagnostic accuracy to grade dysplasia in Barrett's esophagus using an immunohistochemical panel for CDX2, p120ctn, c-Myc and Jagged1. AB - BACKGROUND: Patients with non-dysplastic Barrett's esophagus (ND-BE) and low grade dysplasia (LGD) are typically monitored by periodic endoscopic surveillance, while those with high-grade dysplasia (HGD) and esophageal adenocarcinoma (EAC) are usually treated by more aggressive interventions like endoscopic mucosal resection, ablation or surgery. Therefore, the accurate grading of dysplasia in Barrett's esophagus (BE) is essential for proper patient care. However, there is significant interobserver and intraobserver variability in the histologic grading of BE dysplasia. The objective of this study was to create an immunohistochemical (IHC) panel that facilitates the grading of BE dysplasia and can be used as an adjunct to histology in challenging cases. METHODS: 100 BE biopsies were re-graded for dysplasia independently by 3 subspecialized gastrointestinal pathologists. IHC staining for CDX2, p120ctn, c Myc and Jagged1 proteins was then performed and assessed by two separate methods of semi-quantitative scoring. Scores were integrated using a principal component analysis (PCA) and receiver operating characteristic (ROC) curve. RESULTS: Principal component analysis demonstrated the ability of this panel of proteins to segregate ND-BE/LGD and HGD/EAC, as the expression of the four proteins is significantly altered between the two subsets. Analysis of the receiver operating characteristic curve showed that this panel has the potential to aid in the grading of dysplasia in these two subcategories with both high sensitivity and specificity. While not able to discriminate between ND-BE and LGD, this panel of four proteins may be used as an adjunct to help discriminate subsets of ND-BE/LGD from HGD/EAC. CONCLUSIONS: We propose that the maximum utility of this IHC panel of CDX2, p120ctn, c-Myc, and Jagged1 proteins would be to distinguish between LGD and HGD in histologically challenging cases, given the aggressive interventions still used for HGD in many institutions, and hence may aid in the optimal patient management. The results of this initial study are promising, though further validation is needed before this panel can be used clinically, including future randomized prospective studies with larger patient cohorts from diverse locations. PMID- 26926448 TI - How microRNA172 affects fruit growth in different species is dependent on fruit type. AB - microRNA172 (miR172) expression has been shown to have a positive effect on Arabidopsis fruit (siliques) growth. In contrast, over-expression of miR172 has a negative influence on fruit growth in apple, resulting in a dramatic reduction in fruit size. This negative influence is supported by the results of analyzing a transposable element (TE) insertional allele of a MIR172 gene that has reduced expression of the miRNA and is associated with an increase in fruit size. Arabidopsis siliques are a dry fruit derived from ovary tissues, whereas apple is a fleshy pome fruit derived mostly from hypanthium tissues. A model has been developed to explain the contrasting impact of miR172 expression in these two plant species based on the differences in their fruit structure. Transgenic apple plants with extremely high levels of miR172 overexpression produced flowers consisting of carpel tissues only, which failed to produce fruit. By comparison, in tomato, a fleshy berry fruit derived from the ovary, high level over expression of the same miR172 resulted in carpel-only flowers which developed into parthenocarpic fruit. These results further indicate that the influence of miR172 on fruit growth in different plant species depends on its fruit type. PMID- 26926449 TI - Reply. PMID- 26926450 TI - Reply. PMID- 26926451 TI - Reply. PMID- 26926452 TI - ES1 is a mitochondrial enlarging factor contributing to form mega-mitochondria in zebrafish cones. AB - Total mass of mitochondria increases during cell proliferation and differentiation through mitochondrial biogenesis, which includes mitochondrial proliferation and growth. During the mitochondrial growth, individual mitochondria have been considered to be enlarged independently of mitochondrial fusion. However, molecular basis for this enlarging process has been poorly understood. Cone photoreceptor cells in the retina possess large mitochondria, so called mega-mitochondria that have been considered to arise via the enlarging process. Here we show that ES1 is a novel mitochondria-enlarging factor contributing to form mega-mitochondria in cones. ES1 is specifically expressed in cones and localized to mitochondria including mega-mitochondria. Knockdown of ES1 markedly reduced the mitochondrial size in cones. In contrast, ectopic expression of ES1 in rods significantly increased both the size of individual mitochondria and the total mass of the mitochondrial cluster without changing the number of them. RNA-seq analysis showed that ERRalpha and its downstream mitochondrial genes were significantly up-regulated in the ES1-expressing rods, suggesting facilitation of mitochondrial enlargement via ERRalpha-dependent processes. Furthermore, higher energy state was detected in the ES1-expressing rods, indicating that the enlarged mitochondria by ES1 are capable of producing high energy. ES1 is the mitochondrial protein that is first found to promote enlargement of individual mitochondria. PMID- 26926453 TI - Statistical optimization of tretinoin-loaded penetration-enhancer vesicles (PEV) for topical delivery. AB - BACKGROUND: The aim of this study was to develop and optimize deformable liposome for topical delivery of tretinoin. METHODS: Liposomal formulations were designed based on the full factorial design and prepared by fusion method. The influence of different ratio of soy phosphatidylcholine and transcutol (independent variables) on incorporation efficiency and drug release in 15 min and 24 h (responses) from liposomal formulations was evaluated. Liposomes were characterized for their vesicle size and Differential Scanning Calorimetry (DSC) was used to investigate changes in their thermal behavior. The penetration and retention of drug was determined using mouse skin. Also skin histology study was performed. RESULTS: Particle size of all formulations was smaller than 20 nm. Incorporation efficiency of liposomes was 79-93 %. Formulation F7 (25:5) showed maximum drug release. Optimum formulations were selected based on the contour plots resulted by statistical equations of drug release in 15 min and 24 h. Solubility properties of transcutol led to higher skin penetration for optimum formulations compared to tretinoin cream. There was no significant difference between the amount of drug retained in the skin by applying optimum formulations and cream. Histopatological investigation suggested optimum formulations could decrease the adverse effect of tretinoin in liposome compared to conventional cream. CONCLUSION: According to the results of the study, it is concluded that deformable liposome containing transcutol may be successfully used for dermal delivery of tretinoin. PMID- 26926454 TI - Critical Genomic Networks and Vasoreactive Variants in Idiopathic Pulmonary Arterial Hypertension. AB - RATIONALE: Idiopathic pulmonary arterial hypertension (IPAH) is usually without an identified genetic cause, despite clinical and molecular similarity to bone morphogenetic protein receptor type 2 mutation-associated heritable pulmonary arterial hypertension (PAH). There is phenotypic heterogeneity in IPAH, with a minority of patients showing long-term improvement with calcium channel-blocker therapy. OBJECTIVES: We sought to identify gene variants (GVs) underlying IPAH and determine whether GVs differ in vasodilator-responsive IPAH (VR-PAH) versus vasodilator-nonresponsive IPAH (VN-PAH). METHODS: We performed whole-exome sequencing (WES) on 36 patients with IPAH: 17 with VR-PAH and 19 with VN-PAH. Wnt pathway differences were explored in human lung fibroblasts. MEASUREMENTS AND MAIN RESULTS: We identified 1,369 genes with 1,580 variants unique to IPAH. We used a gene ontology approach to analyze variants and identified overrepresentation of several pathways, including cytoskeletal function and ion binding. By mapping WES data to prior genome-wide association study data, Wnt pathway genes were highlighted. Using the connectivity map to define genetic differences between VR-PAH and VN-PAH, we found enrichment in vascular smooth muscle cell contraction pathways and greater genetic variation in VR-PAH versus VN-PAH. Using human lung fibroblasts, we found increased stimulated Wnt activity in IPAH versus controls. CONCLUSIONS: A pathway-based analysis of WES data in IPAH demonstrated multiple rare GVs that converge on key biological pathways, such as cytoskeletal function and Wnt signaling pathway. Vascular smooth muscle contraction-related genes were enriched in VR-PAH, suggesting a potentially different genetic predisposition for VR-PAH. This pathway-based approach may be applied to next-generation sequencing data in other diseases to uncover the contribution of unexpected or multiple GVs to a phenotype. PMID- 26926455 TI - Conventional Morphology Versus PCR Sequencing, rep-PCR, and MALDI-TOF-MS for Identification of Clinical Aspergillus Isolates Collected Over a 2-Year Period in a University Hospital at Kayseri, Turkey. AB - BACKGROUND: Aspergillus species cause a wide range of diseases in humans, including allergies, localized infections, or fatal disseminated diseases. Rapid detection and identification of Aspergillus spp. facilitate effective patient management. In the current study we compared conventional morphological methods with PCR sequencing, rep-PCR, and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) for the identification of Aspergillus strains. MATERIALS AND METHODS: A total of 24 consecutive clinical isolates of Aspergillus were collected during 2012-2014. Conventional morphology and rep-PCR were performed in our Mycology Laboratory. The identification, evaluation, and reporting of strains using MALDI-TOF-MS were performed by BioMerieux Diagnostic, Inc. in Istanbul. DNA sequence analysis of the clinical isolates was performed by the BMLabosis laboratory in Ankara. RESULTS: Samples consisted of 18 (75%) lower respiratory tract specimens, 3 otomycosis (12.5%) ear tissues, 1 sample from keratitis, and 1 sample from a cutaneous wound. According to DNA sequence analysis, 12 (50%) specimens were identified as A. fumigatus, 8 (33.3%) as A. flavus, 3 (12.5%) as A. niger, and 1 (4.2%) as A. terreus. Statistically, there was good agreement between the conventional morphology and rep-PCR and MALDI-TOF methods; kappa values were kappa = 0.869, 0.871, and 0.916, respectively (P < 0.001). CONCLUSION: The good level of agreement between the methods included in the present study and sequence method could be due to the identification of Aspergillus strains that were commonly encountered. Therefore, it was concluded that studies conducted with a higher number of isolates, which include other Aspergillus strains, are required. PMID- 26926458 TI - Hunting cellular mechanisms underlying the spreading of misfolded protein pathology in the brain. PMID- 26926459 TI - Obituary for Dr Sabina Strich. PMID- 26926461 TI - Translational biomaterials-the journey from the bench to the market-think 'product'. AB - Biomaterial research has been gaining popularity over the past decades and, in parallel, the number of biomaterial-based therapies has been increasing. There is still however, a disconnection between the number of developed biomaterials and those that make it to the market. In this context, a review of the biomaterial development trends in both industry and academia, specifically of biomaterials that were successfully translated from bench side to the clinic and the market, is warranted. PMID- 26926460 TI - Engineering approaches to study fibrosis in 3-D in vitro systems. AB - Fibrotic diseases occur in virtually every tissue of the body and are a major cause of mortality, yet they remain largely untreatable and poorly understood on a mechanistic level. The development of anti-fibrotic agents has been hampered, in part, by the insufficient fibrosis biomimicry provided by traditional in vitro platforms. This review focuses on recent advancements toward creating 3-D platforms that mimic key features of fibrosis, as well as the application of novel imaging and sensor techniques to analyze dynamic extracellular matrix remodeling. Several opportunities are highlighted to apply new tools from the fields of biomaterials, imaging, and systems biology to yield pathophysiologically relevant in vitro platforms that improve our understanding of fibrosis and may enable identification of potential treatment targets. PMID- 26926462 TI - Amphiphilic block copolymers-based mixed micelles for noninvasive drug delivery. AB - Amphiphilic block copolymers-based mixed micelles established as new drug-loading system showed superior characteristics in delivering drug such as improved solubility, enhanced stability, multifunctional carrier materials, targeting ability, and high bioavailability. Recently, there are increasing focuses on exploration and study of noninvasive routes, and the results present perfect feasibility, improved compliance and fewer aches and pains. The aim to apply mixed micelles to noninvasive alternative routes has driven massive pharmaceutical attention. Recently, various studies of micelles strategy for noninvasive routes have been conducted to overcome the inherent barriers for uptake across the gastrointestinal tract, mucosal membranes and other in vivo noninvasive barriers, and the result argues well. The objective of this article is to summary these studies and developments of mixed micelles used on noninvasive drug delivery and provide a reference for further research. PMID- 26926463 TI - Blood Alcohol Concentrations in Suicide and Motor Vehicle Crash Decedents Ages 18 to 54. AB - BACKGROUND: Using postmortem data, we examined the hypotheses that high (and very high) blood alcohol concentrations (BACs) are more common among motor vehicle crash decedents (MVCs) than among suicide decedents, whereas low alcohol levels are more common among suicides. METHODS: We examined BAC in 224 suicide decedents and 166 MVCs ages 18 to 54 in the state of New Mexico in 2012. Comparisons between the groups were made based on differing BAC levels using 0.080 g/dl categories including low (0.001 to 0.079 g/dl), high (0.080 to 0.159 g/dl), and very high BAC (>=0.160 g/dl), and based on 0.100 g/dl categories including low (0.001 to 0.099 g/dl), high (0.100 to 0.199 g/dl), and very high BAC (>=0.200 g/dl), with these groups compared with a no-alcohol reference (0.000 g/dl) in separate analyses. Multivariate logistic regressions compared suicides with MVCs that adjusted for age, sex, and race/ethnicity. RESULTS: Support for the hypothesis that suicides are more likely to have a low BAC level was supported in the analysis using the 0.100 g/dl categorizations. Neither analysis supported the hypothesis that MVCs are more likely to have high (or very high) BACs compared with suicides. Among both injury groups with positive BACs, low BACs were least common. CONCLUSIONS: Low BAC levels may be more likely to be observed among suicides compared with MVCs, a possible reflection of the more varied role that alcohol plays in suicide compared with MVC. Nonetheless, high (and very high) BAC is the predominant scenario in both suicides and MVCs with positive BAC. PMID- 26926464 TI - Flexible Organic Phototransistor Array with Enhanced Responsivity via Metal Ligand Charge Transfer. AB - Phototransistors based on organic photoactive materials combine tunable light absorption in the spectral region from ultraviolet to near-infrared with low temperature processability over large areas on flexible substrates. However, they often exhibit low photoresponsivity because of low molar extinction coefficient of photoactive components. We report a simple, yet highly efficient solution method for enhancing the performance of organic phototransistors using ruthenium complex 1 (Ru-complex 1). An air-stable n-type organic semiconductor, N,N'-bis(2 phenylethyl)-perylene-3,4:9,10-tetracarboxylic diimide (BPE-PTCDI), has been deposited on a silicon wafer and a transparent polyimide (PI) substrate via thermal evaporation under vacuum. The BPE-PTCDI phototransistors functionalized with Ru-complex 1 exhibit ~5000 times higher external quantum efficiency (EQE) than that of pristine BPE-PTCDI phototransistors, owing to the metal-ligand charge transfer (MLCT) from Ru-complex 1 to the active component of the device. In addition, a large 10 * 10 phototransistor array (2.5 * 2.5 cm(2)) has been prepared on a transparent PI substrate, showing distinct light mapping. The fabricated phototransistor array is highly flexible and twistable and works well under tensile and compressive strains. We believe that our simple method will pave a viable way for improvements in the photoresponsivity of organic semiconductors for applications in wearable organic optoelectronic devices. PMID- 26926466 TI - Antiangiogenic Resistance: Novel Angiogenesis Axes Uncovered by Antiangiogenic Therapies Research. AB - The mechanisms of tumor growth and progression involve the activation of different processes such as neovascularization and angiogenesis. These processes involve tumoral cells and stromal cells. Hence, inhibiting angiogenesis affects tumor growth and proliferation in patients with different types of cancer. Nevertheless, tumoral cells and stromal components are responsible for the resistance to antiangiogenic therapies. The majority of tumors respond to this type of therapy; however, some tumors may be indifferent to antiangiogenic therapies (intrinsic resistance) and other tumors become resistant during treatment (acquired resistance). Different strategies have been proposed to prevent resistance. Preclinical studies and clinical trials are focused to fight this therapeutic approach in order to prevent or delay tumor resistance to antiangiogenic therapies. PMID- 26926465 TI - Genome-Wide and Experimental Resolution of Relative Translation Elongation Speed at Individual Gene Level in Human Cells. AB - In the process of translation, ribosomes first assemble on mRNAs (translation initiation) and then translate along the mRNA (elongation) to synthesize proteins. Elongation pausing is deemed highly relevant to co-translational folding of nascent peptides and the functionality of protein products, which positioned the evaluation of elongation speed as one of the central questions in the field of translational control. By integrating three types of RNA-seq methods, we experimentally and computationally resolved elongation speed, with our proposed elongation velocity index (EVI), a relative measure at individual gene level and under physiological condition in human cells. We successfully distinguished slow-translating genes from the background translatome. We demonstrated that low-EVI genes encoded more stable proteins. We further identified cell-specific slow-translating codons, which might serve as a causal factor of elongation deceleration. As an example for the biological relevance, we showed that the relatively slow-translating genes tended to be associated with the maintenance of malignant phenotypes per pathway analyses. In conclusion, EVI opens a new view to understand why human cells tend to avoid simultaneously speeding up translation initiation and decelerating elongation, and the possible cancer relevance of translating low-EVI genes to gain better protein quality. PMID- 26926467 TI - MicroRNAs as Candidate Drug Targets for Cardiovascular Diseases. AB - MicroRNAs (miRNAs) are small conserved noncoding RNAs which function as posttranscriptional regulators of gene expression. Studies over the last 20 years have revealed the essential functions of miRNAs in regulating cardiovascular biology (such as cardiovascular cell differentiation, growth, proliferation and apoptosis) and crucial roles in controlling cardiovascular disease (CVD), indicating the potential of these small molecules as therapeutic targets and/or agents for CVD. Moreover, miRNAs in the circulation or other body fluids are stable and readily detectable, and more importantly often disease-associated, which makes them promising novel biomarkers for diagnosis and prognosis of CVDs. Furthermore, emerging evidence uncovered miRNAs as new targets and/or regulators of cardiovascular medications given the ability of miRNAs to interact with some cardiovascular drugs, which opens up new opportunities for the research and development of novel CVD drugs. Herein, we summarize current knowledge regarding the potential applications of miRNAs in the therapy of CVD, including myocardial ischemia, cardiac hypertrophy/heart failure, interstitial fibrosis, arrhythmia, diabetes and hypertension and discuss the therapeutic potential and challenge of miRNAs in drug discovery. PMID- 26926468 TI - Polypharmacology of Approved Anticancer Drugs. AB - The major drug discovery efforts in oncology have been concentrated on the development of selective molecules that are supposed to act specifically on one anticancer mechanism by modulating a single or several closely related drug targets. However, a bird's eye view on data from multiple available bioassays implies that most approved anticancer agents do, in fact, target many more proteins with different functions. Here we will review and systematize currently available information on the targets of several anticancer drugs along with revision of their potential mechanisms of action. Polypharmacology of the current antineoplastic agents suggests that drug clinical efficacy in oncology can be achieved only via modulation of multiple cellular mechanisms. PMID- 26926470 TI - Increased Epicardial Adipose Tissue Volume Correlates With Cardiac Sympathetic Denervation in Patients With Heart Failure. AB - RATIONALE: It has been reported that epicardial adipose tissue (EAT) may affect myocardial autonomic function. OBJECTIVE: The aim of this study was to explore the relationship between EAT and cardiac sympathetic nerve activity in patients with heart failure. METHODS AND RESULTS: In 110 patients with systolic heart failure, we evaluated the correlation between echocardiographic EAT thickness and cardiac adrenergic nerve activity assessed by (123)I-metaiodobenzylguanidine ((123)I-MIBG). The predictive value of EAT thickness on cardiac sympathetic denervation ((123)I-MIBG early and late heart:mediastinum ratio and single-photon emission computed tomography total defect score) was tested in a multivariate analysis. Furthermore, catecholamine levels, catecholamine biosynthetic enzymes, and sympathetic nerve fibers were measured in EAT and subcutaneous adipose tissue biopsies obtained from patients with heart failure who underwent cardiac surgery. EAT thickness correlated with (123)I-MIBG early and late heart:mediastinum ratio and single-photon emission computed tomography total defect score, but not with left ventricular ejection fraction. Moreover, EAT resulted as an independent predictor of (123)I-MIBG early and late heart:mediastinum ratio and single-photon emission computed tomography total defect score and showed a significant additive predictive value on (123)I-MIBG planar and single-photon emission computed tomography results over demographic and clinical data. Although no differences were found in sympathetic innervation between EAT and subcutaneous adipose tissue, EAT showed an enhanced adrenergic activity demonstrated by the increased catecholamine levels and expression of catecholamine biosynthetic enzymes. CONCLUSIONS: This study provides the first evidence of a direct correlation between increased EAT thickness and cardiac sympathetic denervation in heart failure. PMID- 26926471 TI - Floating Lateral Mass Fractures of the Cervical Spine. AB - STUDY DESIGN: Level I trauma center case series. OBJECTIVE: The purpose of this study was (i) to characterize the floating lateral mass (FLM) fracture with the mechanism of injury, anatomical injury pattern, associated vascular injuries, neurological deficits, and key radiographic features; and (ii) to better understand the most effective method of treatment. SUMMARY OF BACKGROUND DATA: An uncommon and poorly described subset of unilateral lateral mass fractures is FLM with fractures of the adjacent pedicle and lamina. METHODS: Prospectively collected trauma registries were assessed to identify all patients with FLM fractures involving C3 to C7 between January 1, 2007 and December 31, 2012. RESULTS: After institutional review board approval, 60 consecutive cases were identified from the trauma registries. The mean follow-up was 9 months (range 0 42 months). The most common level was C6. The most common mechanism of injury was a high speed motor vehicle accident (45%). Radiographic rotational displacement manifested as an anterolisthesis. CT showed facet joint widening at the level above and below in 63%. Vertebral artery injuries occurred in 22%. Neurological deficits occurred as radiculopathy in 38% and spinal cord injury in 18%. All eight patients, who were treated nonoperatively, developed subluxation despite external immobilization and six patients required surgery. Of the 58 patients treated operatively, 31 (53%) patients underwent a 2 level Anterior Cervical Discectomy and Fusion (ACDF) alone. Nine (15%) patients had one level ACDF, with 83% demonstrating radiographic failure. Posterior fusion alone or combined with ACDF/corpectomy was performed in 6 patients (10%) and 7 patients (12%), respectively. CONCLUSION: A FLM fracture results from a high energy injury and involves two motion segments. Vertebral artery injuries and neurological deficits frequently occur. Magnetic Resonance demonstrates a significant disc injury in 81% of patients, usually at the lower level. Two level ACDF or Posterior Spinal Instrumented Fusion are effective means of treatment. LEVEL OF EVIDENCE: 3. PMID- 26926469 TI - Disruption of Glut1 in Hematopoietic Stem Cells Prevents Myelopoiesis and Enhanced Glucose Flux in Atheromatous Plaques of ApoE(-/-) Mice. AB - RATIONALE: Inflamed atherosclerotic plaques can be visualized by noninvasive positron emission and computed tomographic imaging with (18)F-fluorodeoxyglucose, a glucose analog, but the underlying mechanisms are poorly understood. OBJECTIVE: Here, we directly investigated the role of Glut1-mediated glucose uptake in apolipoprotein E-deficient (ApoE(-/-)) mouse model of atherosclerosis. METHODS AND RESULTS: We first showed that the enhanced glycolytic flux in atheromatous plaques of ApoE(-/-) mice was associated with the enhanced metabolic activity of hematopoietic stem and multipotential progenitor cells and higher Glut1 expression in these cells. Mechanistically, the regulation of Glut1 in ApoE(-/-) hematopoietic stem and multipotential progenitor cells was not because of alterations in hypoxia-inducible factor 1alpha signaling or the oxygenation status of the bone marrow but was the consequence of the activation of the common beta subunit of the granulocyte-macrophage colony-stimulating factor/interleukin 3 receptor driving glycolytic substrate utilization by mitochondria. By transplanting bone marrow from WT, Glut1(+/-), ApoE(-/-), and ApoE(-/-)Glut1(+/-) mice into hypercholesterolemic ApoE-deficient mice, we found that Glut1 deficiency reversed ApoE(-/-) hematopoietic stem and multipotential progenitor cell proliferation and expansion, which prevented the myelopoiesis and accelerated atherosclerosis of ApoE(-/-) mice transplanted with ApoE(-/-) bone marrow and resulted in reduced glucose uptake in the spleen and aortic arch of these mice. CONCLUSIONS: We identified that Glut1 connects the enhanced glucose uptake in atheromatous plaques of ApoE(-/-) mice with their myelopoiesis through regulation of hematopoietic stem and multipotential progenitor cell maintenance and myelomonocytic fate and suggests Glut1 as potential drug target for atherosclerosis. PMID- 26926472 TI - Cervical Disc Arthroplasty Versus Anterior Cervical Discectomy and Fusion for Incidence of Symptomatic Adjacent Segment Disease: A Meta-Analysis of Prospective Randomized Controlled Trials. AB - STUDY DESIGN: Meta-analysis of randomized controlled trials. OBJECTIVE: To evaluate the reported rate of adjacent segment disease (ASD) of cervical disc arthroplasty (CDA) compared with anterior cervical discectomy and fusion (ACDF). SUMMARY OF BACKGROUND DATA: Motion-maintaining technologies such as CDA have developed rapidly because of the concern of ASD. Till date, however, it still has been under debate whether CDA is superior to ACDF regarding the incidence of ASD. METHODS: We comprehensively searched PubMed, EMBASE, and Cochrane Central Register of Controlled Trails for prospective randomized controlled trials (RCTs) that reported the incidence of ASD between CDA and ACDF. The retrieved results were last updated on November 20, 2015 without language restrictions. Two independent authors selected qualified studies, assessed methodological quality, and extracted requisite data. RESULTS: Fourteen relevant RCTs involving 3235 individuals with a follow-up period of 2 to 7 years were included in the meta analysis (1696 in CDA group and 1539 in ACDF group). The outcomes indicated that CDA was superior to ACDF considering the lower rate of ASD (risk ratio, 0.57; 95% confidence interval, 0.37 to 0.87; P = 0.009). And compared with ACDF, there were significantly fewer adjacent segment reoperations in the CDA group (risk ratio, 0.47; confidence interval, 0.32 to 0.70; P = 0.0002). Subgroup analysis stratified by different types of disc prostheses was also performed. CONCLUSION: CDA was superior to ACDF regarding fewer ASDs and relative reoperations on the basis of available evidence from a meta-analysis of 14 RCTs. CDA may be a better surgical procedure to reduce the incidence of ASD for patients with cervical disc disease compared with ACDF. Further well-designed studies should continue to pay attention to excellent patients with longer-term follow-up to evaluate the incidence of ASD of these two procedures. LEVEL OF EVIDENCE: 1. PMID- 26926473 TI - An international comparison of the deinstitutionalisation of mental health care: Development and findings of the Mental Health Services Deinstitutionalisation Measure (MENDit). AB - BACKGROUND: Despite its inclusion as a key aspect of successful mental health care service provision by the World Health Organization, there exists a lack of consensus regarding the definition, key components and implementation of deinstitutionalisation. This lack of consensus has also contributed to subjectivity in assessments of countries' progress towards deinstitutionalisation which act as a barrier to its evaluation and success. In order to provide for reliable within and cross country evaluations of the success of deinstitutionalisation we aimed to develop a quantitative measure of country level progress towards deinstitutionalisation through the (1) identification of key markers of deinstitutionalisation; (2) development of an assessment tool based on the identified markers; (3) evaluation of the tool's psychometric properties; and (4) comparison of progress towards deinstitutionalisation across Europe. METHODS: National care standards from 10 European countries and World Health Organization recommendations were used to identify items for the tool. A draft version was reviewed by an international expert panel and assessed for test retest reliability and internal consistency. Once a final version had been agreed, progress towards deinstitutionalisation was assessed for 30 European countries. We used this opportunity to test convergent validity through comparison with local experts' assessments. Country total as well as individual item scores were described and compared. RESULTS: The five-item Mental Health Services Deinstitutionalisation Measure (MENDit) is an objective tool with moderate to very good test-retest reliability (Kappa range: 0.46-1.00) and internal consistency (alpha = 0.70, 95 % CI 0.25, 0.92). A statistically significant difference between groups was found by one-way ANOVA (F(3,26) = 6.77, p = 0.002). Post-hoc testing found significant differences between MENDit scores of countries categorised as having advanced levels of deinstitutionalisation and not started or just started. Across Europe, MENDit scores suggest substantial variety in progress towards deinstitutionalisation. CONCLUSIONS: The MENDit has good psychometric properties which support its use in research and as a benchmarking tool to measure national progress towards deinstitutionalisation by policy makers. Across Europe a high proportion of psychiatric beds are still located in psychiatric hospitals. Additionally, low numbers of mental health professionals in many countries may hinder further deinstitutionalisation. These findings corroborate previous mental health systems research and highlight some of the difficulties of deinstitutionalisation. PMID- 26926474 TI - Group B Streptococcus: developing a correlate of protection for a vaccine against neonatal infections. AB - PURPOSE OF REVIEW: Maternal vaccination to prevent invasive Group B Streptococcus (GBS) disease in infants is an important alternative strategy to intrapartum antibiotic prophylaxis. Licensure of GBS vaccines could be expedited using immunological correlates of protection. RECENT FINDINGS: Between 2014 and 2015, we identified two studies that demonstrated an inverse association between invasive GBS disease and maternal serotype III capsular antibody levels greater than 1 MUg/ml and greater than 3 MUg/ml, and higher maternal antibody levels were associated with protection against serotype Ia disease. Furthermore, serotype Ia and III antibody levels greater than 3 MUg/ml were associated with a reduced risk of GBS colonization in pregnant women.Experimental studies have investigated the use of GBS surface proteins as vaccine candidates. Although the immunogenic potential of pilus island and other surface proteins has been shown in animal model studies, no association between maternal pilus island antibody levels and invasive GBS disease was demonstrated in infants. Additionally, several novel innate immune mediators that prevent GBS infection have been described in human and experimental studies. SUMMARY: Recent studies suggest that maternal capsular antibody thresholds may be used as immunological correlates of protection for vaccine licensure. Surface proteins, as candidate vaccines or conjugates to the polysaccharide-protein vaccine, may broaden protection against invasive GBS disease. PMID- 26926475 TI - Behavioral characterization of neuropathic pain on the glabrous skin areas reinnervated solely by axotomy-regenerative axons after adult rat sciatic nerve crush. AB - In cranial and spinal nerve ganglia, both axotomized primary sensory neurons without regeneration (axotomy-nonregenerative neurons) and spared intact primary sensory neurons adjacent to axotomized neurons (axotomy-spared neurons) have been definitely shown to participate in pain transmission in peripheral neuropathic pain states. However, whether axotomized primary sensory neurons with regeneration (axotomy-regenerative neurons) would be integral components of neural circuits underlying peripheral neuropathic pain states remains controversial. In the present study, we utilized an adult rat sciatic nerve crush model to systematically analyze pain behaviors on the glabrous plantar surface of the hindpaw sural nerve skin territories. To the best of our knowledge, our results for the first time showed that heat hyperalgesia, cold allodynia, mechanical allodynia, and mechanical hyperalgesia emerged and persisted on the glabrous sural nerve skin areas after adult rat sciatic nerve crush. Interestingly, mechanical hyperalgesia was sexually dimorphic. Moreover, with our optimized immunofluorescence staining protocol of free-floating thick skin sections for wide-field epifluorescence microscopic imaging, changes in purely regenerative reinnervation on the same skin areas by axotomized primary sensory afferents were shown to be paralleled by those pathological pain behaviors. To our surprise, Protein Gene Product 9.5-immunoreactive nerve fibers with regular and large varicosities ectopically emigrated into the upper dermis of the glabrous sural nerve skin territories after adult rat sciatic nerve crush. Our results indicated that axotomy-regenerative primary sensory neurons could be critical elements in neural circuits underlying peripheral neuropathic pain states. Besides, our results implied that peripheral neuropathic pain transmitted by axotomy-regenerative primary sensory neurons alone might be a new dimension in the clinical therapy of peripheral nerve trauma beyond regeneration. PMID- 26926476 TI - Using Drugs to Probe the Variability of Trans-Epithelial Airway Resistance. AB - BACKGROUND: Precision medicine aims to combat the variability of the therapeutic response to a given medicine by delivering the right medicine to the right patient. However, the application of precision medicine is predicated on a prior quantitation of the variance of the reference range of normality. Airway pathophysiology provides a good example due to a very variable first line of defence against airborne assault. Humans differ in their susceptibility to inhaled pollutants and pathogens in part due to the magnitude of trans-epithelial resistance that determines the degree of epithelial penetration to the submucosal space. This initial 'set-point' may drive a sentinel event in airway disease pathogenesis. Epithelia differentiated in vitro from airway biopsies are commonly used to model trans-epithelial resistance but the 'reference range of normality' remains problematic. We investigated the range of electrophysiological characteristics of human airway epithelia grown at air-liquid interface in vitro from healthy volunteers focusing on the inter- and intra-subject variability both at baseline and after sequential exposure to drugs modulating ion transport. METHODOLOGY/PRINCIPAL FINDINGS: Brushed nasal airway epithelial cells were differentiated at air-liquid interface generating 137 pseudostratified ciliated epithelia from 18 donors. A positively-skewed baseline range exists for trans epithelial resistance (Min/Max: 309/2963 Omega.cm2), trans-epithelial voltage ( 62.3/-1.8 mV) and calculated equivalent current (-125.0/-3.2 MUA/cm2; all non normal, P<0.001). A minority of healthy humans manifest a dramatic amiloride sensitivity to voltage and trans-epithelial resistance that is further discriminated by prior modulation of cAMP-stimulated chloride transport. CONCLUSIONS/SIGNIFICANCE: Healthy epithelia show log-order differences in their ion transport characteristics, likely reflective of their initial set-points of basal trans-epithelial resistance and sodium transport. Our data may guide the choice of the background set point in subjects with airway diseases and frame the reference range for the future delivery of precision airway medicine. PMID- 26926477 TI - Comparison of three different incision techniques in A1 pulley release on scar tissue formation and postoperative rehabilitation. AB - INTRODUCTION: The optimal surgical approach for trigger finger release remains controversial in hindsight of postoperative rehabilitation as well as scar tissue formation. In this study, we comparatively evaluated the outcome of three different types of skin incision by employing the "Disability of the Arm Shoulder and Hand Score" (DASH) and by quantitative ultrasound measurements of scar tissue volume. MATERIALS AND METHODS: Thirty patients (32 triggerfingers) were enrolled in this study and randomly assigned to one of three groups: incision placed (1) transversal in distal palmar crease, (2) transversal and 2 mm distal from distal palmar crease, (3) longitudinally over MCP joint without crossing the distal palmar crease. Patients characteristics were noted and DASH scores were retrieved at four time points, (1) preoperatively (baseline), (2) 1 month, (3) 3 months, (4) 12 months postoperatively. Scar volume formation was assessed by ultrasound at 3 months postoperatively in 28 patients. RESULTS: All groups showed a significant reduction in DASH values at 3 and 12 months postoperatively when compared to their own baseline levels. Group 3 showed the fastest and most pronounced reduction in DASH values at 1 month. Scar tissue formation was almost 57 % increased in group 1 vs group 2 and 3, however, not significant. CONCLUSION: There is no clear benefit of one incision technique over another. However, based on scar volume parameters, the significant faster recovery in the first month and the surgical ease of exposure and wound closure inclines us to favor the longitudinal incision (group 3) in future patients. PMID- 26926478 TI - Representation of people of South Asian origin in cardiovascular outcome trials of glucose-lowering therapies in Type 2 diabetes. AB - AIMS: Our aim was to investigate the proportional representation of people of South Asian origin in cardiovascular outcome trials of glucose-lowering drugs or strategies in Type 2 diabetes, noting that these are among the most significant pieces of evidence used to formulate the guidelines on which clinical practice is largely based. METHODS: We searched for cardiovascular outcome trials in Type 2 diabetes published before January 2015, and extracted data on the ethnicity of participants. These were compared against expected values for proportional representation of South Asian individuals, based on population data from the USA, from the UK, and globally. RESULTS: Twelve studies met our inclusion criteria and, of these, eight presented a sufficiently detailed breakdown of participant ethnicity to permit numerical analysis. In general, people of South Asian origin were found to be under-represented in trials compared with UK and global expectations and over-represented compared with US expectations. Among the eight trials for which South Asian representation could be reliably estimated, seven under-represented this group relative to the 11.2% of the UK diabetes population estimated to be South Asian, with the representation in these trials ranging from 0.0% to 10.0%. CONCLUSIONS: Clinicians should exercise caution when generalizing the results of trials to their own practice, with regard to the ethnicity of individuals. Efforts should be made to improve reporting of ethnicity and improve diversity in trial recruitment, although we acknowledge that there are challenges that must be overcome to make this a reality. PMID- 26926479 TI - Erratum to: Health-Related Quality of Life for Patients Who have In-Transit Melanoma Metastases Treated with Isolated Limb Perfusion. PMID- 26926480 TI - Hiatal Hernia After Open versus Minimally Invasive Esophagectomy: A Systematic Review and Meta-analysis. AB - Hiatal hernia (HH) is an infrequent yet potentially life-threatening complication after esophagectomy. Several studies have reported the incidence of this complication after both open and minimally invasive esophagectomy (MIE). This meta-analysis aimed to determine the pooled incidence of HH after both types of esophagectomy and, importantly, to provide insight in the outcome of subsequent HH repair. A systematic search was performed of the PubMed, Embase, CINAHL, and Cochrane databases. Article selection was performed using the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) criteria. Articles describing the incidence of HH after different open and minimally invasive techniques were included. Only when five or more comparable studies reported on the same outcome were data pooled. The incidence of postoperative HH and the outcome of HH repair were analyzed. Twenty-six studies published between 1985 and 2015 were included, describing a total of 6058 patients who underwent esophagectomy, of whom 240 were diagnosed with a postoperative HH. The pooled incidence of symptomatic HH after MIE was 4.5 %, compared to a pooled incidence of 1.0 % after open esophagectomy. 11 studies reported on the outcome of HH repair in 125 patients. A pooled morbidity rate after HH repair of 25 % was found. During follow-up, a pooled recurrence rate of 14 % was reported in 11 of the included studies. The pooled incidence of HH after MIE is higher compared to open esophagectomy. Most importantly, surgical repair of these HHs is associated with a high morbidity rate. Both radiologists and surgeons should be aware of this rare yet potentially life-threatening complication. PMID- 26926481 TI - Clinical Response and Regional Toxicity Following Isolated Limb Infusion Compared with Isolated Limb Perfusion for In-Transit Melanoma. AB - BACKGROUND: Isolated limb perfusion (ILP) and infusion (ILI) are therapeutic modalities for the treatment of in transit melanoma. METHODS: A retrospective review of all patients undergoing first-time ILI or ILP for in-transit melanoma metastases between 2007 and 2015 was performed. Demographic and clinical characteristics included age, sex, nodal status at the time of ILI/ILP (N-stage), and burden of disease (BOD). Regional toxicity was categorized by the Wieberdink classification. Clinical response was evaluated at 3 months after treatment. RESULTS: A total of 203 patients were reviewed (ILI = 94, ILP = 109). There were no differences in age, sex, or N-stage between groups; however, BOD was higher for the ILI group (high BOD 58 vs. 44 %, p = 0.04). Regional toxicity was minimal (Grade IV < 1 % in ILI and 2 % in ILP, p = 0.40). Overall response rate (ORR) was 53 % for ILI versus 80 % for ILP (p < 0.001). Median overall survival (OS) was 46 months for ILI versus 40 months for ILP (p = 0.31). A high BOD [hazard ratio (HR) 3.02, 95 % confidence interval (CI) 1.85-4.93, p < 0.001] and N3 disease (HR 1.58, 95 % CI 1.01-2.48, p = 0.04) were associated with worse OS, whereas there was no difference in OS by procedure (p = 0.20). CONCLUSION: ILP offers an improved ORR, but this does not translate into improved local PFS or OS. Both procedures are well tolerated with minimal regional toxicity. PMID- 26926482 TI - Margaret McCartney: Passing the patient. PMID- 26926483 TI - The Effectiveness of Intravitreal Ranibizumab in Patients with Diabetic Macular Edema Who Have Failed to Respond to Intravitreal Bevacizumab. AB - PURPOSE: To investigate the response to intravitreal ranibizumab after failure of intravitreal bevacizumab in patients with diabetic macular edema (DME). METHODS: Demographics, visual acuity (VA), central macular thickness (CMT), and HbA1C were retrospectively collected from DME patients treated with second-line intravitreal ranibizumab at a tertiary hospital in 2012-2013 and followed for at least 3 months. RESULTS: Twenty-two patients (26 eyes) were included in the study, with a mean (+/-SD) age of 66 +/- 8.1 years and followed for an average of 28.36 months. The mean number of intravitreal bevacizumab injections was 7.3 +/- 2.8, and of intravitreal ranibizumab injections 5.11 +/- 2.4. After 3 ranibizumab injections, 57% of eyes showed improvement in VA. The change in VA was statistically significant (p = 0.044) in those eyes where the pretreatment acuity for the second-line therapy was <20/40 (logMAR 0.3). CMT decreased from 435.95 +/- 83.28 to 373.69 +/- 44.39 um (p = 0.01). The number of ranibizumab injections was significantly correlated with the change in CMT (p = 0.037). CONCLUSION: Intravitreal treatment with ranibizumab can be efficacious in eyes with DME that have failed to respond to bevacizumab. PMID- 26926484 TI - The frequency of actions and thoughts scale: development and psychometric validation of a measure of adaptive behaviours and cognitions. AB - This paper describes the development and preliminary psychometric evaluation of an instrument that measures the frequency of adaptive behaviours and cognitions related to therapeutic change during cognitive behavioural therapy (CBT), for symptoms of anxiety and depression. Two studies were conducted. In study one, 661 participants completed an online survey with 28 items targeting adaptive behaviours and cognitions. Exploratory factor analysis performed on part of the sample (n = 451) revealed that a four-factor solution 'characterised' the data. This led to the development of a 12-item instrument, the Frequency of Actions and Thoughts Scale (FATS). Confirmatory factor analysis was used to confirm the factor structure of the FATS using the remaining sample (n = 210), which revealed an acceptable model fit. In study two, 125 participants with clinically significant symptoms of anxiety, depression, or both were recruited to an Internet-delivered CBT (iCBT) treatment course. Participants completed the FATS and other measures throughout treatment, after treatment, and at three-month follow-up. Correlations and residual change scores of the FATS and its subscales with measures of anxiety, depression, behavioural activation, and CBT-related skills usage supported the construct validity of the FATS. A significant increase in FATS scores over treatment was also observed. The findings provide preliminary support for the psychometric properties of the FATS, which appears to have utility in research investigating mechanisms of change in CBT. PMID- 26926485 TI - The Potential for Cereal Rye Cover Crops to Host Corn Seedling Pathogens. AB - Cover cropping is a prevalent conservation practice that offers substantial benefits to soil and water quality. However, winter cereal cover crops preceding corn may diminish beneficial rotation effects because two grass species are grown in succession. Here, we show that rye cover crops host pathogens capable of causing corn seedling disease. We isolated Fusarium graminearum, F. oxysporum, Pythium sylvaticum, and P. torulosum from roots of rye and demonstrate their pathogenicity on corn seedlings. Over 2 years, we quantified the densities of these organisms in rye roots from several field experiments and at various intervals of time after rye cover crops were terminated. Pathogen load in rye roots differed among fields and among years for particular fields. Each of the four pathogen species increased in density over time on roots of herbicide terminated rye in at least one field site, suggesting the broad potential for rye cover crops to elevate corn seedling pathogen densities. The radicles of corn seedlings planted following a rye cover crop had higher pathogen densities compared with seedlings following a winter fallow. Management practices that limit seedling disease may be required to allow corn yields to respond positively to improvements in soil quality brought about by cover cropping. PMID- 26926486 TI - Rhizosphere Competence of Wild-Type and Genetically Engineered Pseudomonas brassicacearum Is Affected by the Crop Species. AB - 2,4-Diacetylphloroglucinol (2,4-DAPG)-producing Pseudomonas brassicacearum Q8r1 96 is a highly effective biocontrol agent of take-all disease of wheat. Strain Z30-97, a recombinant derivative of Q8r1-96 containing the phzABCDEFG operon from P. synxantha (formerly P. fluorescens) 2-79 inserted into its chromosome, also produces phenazine-1-carboxylic acid. Rhizosphere population sizes of Q8r1-96, Z30-97, and 2-79, introduced into the soil, were assayed during successive growth cycles of barley, navy bean, or pea under controlled conditions as a measure of the impact of crop species on rhizosphere colonization of each strain. In the barley rhizosphere, Z30-96 colonized less that Q8r1-96 when they were introduced separately, and Q8r1-96 out-competed Z30-96 when the strains were introduced together. In the navy bean rhizosphere, Q8r1-96 colonized better than Z30-97 when the strains were introduced separately. However, both strains had similar population densities when introduced together. Strain Q8r1-96 and Z30-97 colonized the pea rhizosphere equally well when each strain was introduced separately, but Z30-97 out-competed Q8r1-96 when they were introduced together. To our knowledge, this is the first report of a recombinant biocontrol strain of Pseudomonas spp. gaining rhizosphere competitiveness on a crop species. When assessing the potential fate of and risk posed by a recombinant Pseudomonas sp. in soil, both the identity of the introduced genes and the crop species colonized by the recombinant strain need to be considered. PMID- 26926487 TI - Differential Colonization Dynamics of Cucurbit Hosts by Erwinia tracheiphila. AB - Bacterial wilt is one of the most destructive diseases of cucurbits in the Midwestern and Northeastern United States. Although the disease has been studied since 1900, host colonization dynamics remain unclear. Cucumis- and Cucurbita derived strains exhibit host preference for the cucurbit genus from which they were isolated. We constructed a bioluminescent strain of Erwinia tracheiphila (TedCu10-BL#9) and colonization of different cucurbit hosts was monitored. At the second-true-leaf stage, Cucumis melo plants were inoculated with TedCu10-BL#9 via wounded leaves, stems, and roots. Daily monitoring of colonization showed bioluminescent bacteria in the inoculated leaf and petiole beginning 1 day postinoculation (DPI). The bacteria spread to roots via the stem by 2 DPI, reached the plant extremities 4 DPI, and the plant wilted 6 DPI. However, Cucurbita plants inoculated with TedCu10-BL#9 did not wilt, even at 35 DPI. Bioluminescent bacteria were detected 6 DPI in the main stem of squash and pumpkin plants, which harbored approximately 10(4) and 10(1) CFU/g, respectively, of TedCu10-BL#9 without symptoms. Although significantly less systemic plant colonization was observed in nonpreferred host Cucurbita plants compared with preferred hosts, the mechanism of tolerance of Cucurbita plants to E. tracheiphila strains from Cucumis remains unknown. PMID- 26926489 TI - A Pyrene-Based, Fluorescent Three-Dimensional Covalent Organic Framework. AB - The targeted synthesis of 3D COFs has been considered challenging, especially adopting new topologies and bearing photoelectric units. Herein, for the first time, we report the synthesis and characterization of a novel 3D pyrene-based COF (3D-Py-COF), by selectively choosing the geometry of the precursors and the connection patterns. Based on X-ray diffraction measurement and detailed simulations, 3D-Py-COF is proposed to adopt a two-fold interpenetrated pts topology, which has never been reported before. In addition, 3D-Py-COF has a narrow pore size distribution and high surface area and also features selective absorption of CO2 over N2. Interestingly, due to the existence of isolated pyrene units in the 3D framework, 3D-Py-COF is the first fluorescent 3D COF and can be used in explosive detection. Our results not only show it is possible to rationally design and synthesize 3D COFs with other topologies but also demonstrate that the incorporation of photoelectric units into 3D COFs can allow the resulting materials with interesting properties. PMID- 26926490 TI - Antiepilepsy Drugs in Migraine Prevention: Editorial. PMID- 26926491 TI - Simultaneous quasi-one-dimensional propagation and tuning of upconversion luminescence through waveguide effect. AB - Luminescence-based waveguide is widely investigated as a promising alternative to conquer the difficulties of efficiently coupling light into a waveguide. But applications have been still limited due to employing blue or ultraviolet light as excitation source with the lower penetration depth leading to a weak guided light. Here, we show a quasi-one-dimensional propagation of luminescence and then resulting in a strong luminescence output from the top end of a single NaYF4:Yb(3+)/Er(3+) microtube under near infrared light excitation. The mechanism of upconversion propagation, based on the optical waveguide effect accompanied with energy migration, is proposed. The efficiency of luminescence output is highly dependent on the concentration of dopant ions, excitation power, morphology, and crystallinity of tube as an indirect evidence of the existence of the optical actived waveguide effect. These findings provide the possibility for the construction of upconversion fiber laser. PMID- 26926492 TI - CD81 and CD48 show different expression on blood eosinophils in systemic sclerosis: new markers for disease and pulmonary inflammation? AB - OBJECTIVES: In systemic sclerosis (SSc)-related interstitial lung disease (ILD), elevated eosinophil counts in bronchoalveolar lavage are associated with a worse outcome. We hypothesized that eosinophils may be activated in the peripheral circulation, thereby increasing their recruitment to affected tissues and contributing to inflammation and fibrosis. The aim of this study was to characterize the blood eosinophils in SSc patients. METHOD: Expression levels of surface markers CD11b, CD44, CD48, CD54, CD69, CD81, and HLA-DR on CD16(low)CD9(high)-expressing eosinophils were measured by flow cytometry in whole blood from SSc patients (n = 32) and controls (n = 11). RESULTS: Expression levels of CD54, CD69, and HLA-DR were undetectable in all groups. CD44 and CD11b expression levels were similar between groups. CD81 expression was lower in patients compared to controls independent of disease duration (p = 0.001). CD48 expression was increased in patients with a short disease duration (< 2 years) compared to both controls (p = 0.042) and patients with longer disease duration (>= 2 years; p = 0.027). In patients with short disease duration, increased CD48 expression was associated with alveolar inflammation as measured by an increased concentration of alveolar nitric oxide (r = 0.76, p = 0.003). CONCLUSIONS: Blood eosinophils change phenotype during disease evolution in SSc, and CD48 expression may be used as a biomarker for pulmonary inflammation. PMID- 26926493 TI - [Hair disorders and psychology]. PMID- 26926494 TI - Nrf2 as molecular target for polyphenols: A novel therapeutic strategy in diabetic retinopathy. AB - Diabetic retinopathy is a microvascular complication of diabetes that is considered one of the leading causes of blindness among adults. More than 4.4 million people suffer from this disorder throughout the world. Growing evidence suggests that oxidative stress plays a crucial role in the pathophysiology of diabetic retinopathy. Nuclear factor erythroid 2-related factor 2 (Nrf2), a redox sensitive transcription factor, plays an essential protective role in regulating the physiological response to oxidative and electrophilic stress via regulation of multiple genes encoding antioxidant proteins and phase II detoxifying enzymes. Many studies suggest that dozens of natural compounds, including polyphenols, can supress oxidative stress and inflammation through targeting Nrf2 and consequently activating the antioxidant response element-related cytoprotective genes. Therefore, Nrf2 may provide a new therapeutic target for treatment of diabetic retinopathy. In the present article, we will focus on the role of Nrf2 in diabetic retinopathy and the ability of polyphenols to target Nrf2 as a therapeutic strategy. PMID- 26926488 TI - 'Adipaging': ageing and obesity share biological hallmarks related to a dysfunctional adipose tissue. AB - The increasing ageing of our societies is accompanied by a pandemic of obesity and related cardiometabolic disorders. Progressive dysfunction of the white adipose tissue is increasingly recognized as an important hallmark of the ageing process, which in turn contributes to metabolic alterations, multi-organ damage and a systemic pro-inflammatory state ('inflammageing'). On the other hand, obesity, the paradigm of adipose tissue dysfunction, shares numerous biological similarities with the normal ageing process such as chronic inflammation and multi-system alterations. Accordingly, understanding the interplay between accelerated ageing related to obesity and adipose tissue dysfunction is critical to gain insight into the ageing process in general as well as into the pathophysiology of obesity and other related conditions. Here we postulate the concept of 'adipaging' to illustrate the common links between ageing and obesity and the fact that, to a great extent, obese adults are prematurely aged individuals. PMID- 26926496 TI - The Swedish physical activity and fitness cohort born in 1958 - dropout analysis and overview at 36-year follow-up. AB - The main aim of the Swedish physical activity and fitness cohort study (SPAF 1958) was to describe physical fitness, physical activity, health, and lifestyle across part of the lifespan, and to assess the influences on these factors from the environment, personal factors, and genetics. There is inevitable dropout from longitudinal studies, and it may be systematic. The aim of this first paper of the second follow-up of SPAF-1958 was to provide a dropout analysis to consider to what extent the participants, at 52 years of age, remain a representative sample of the original adolescent study population. Additional aims were to provide an overview of the study protocol and the ongoing study population. Ongoing study participants in SPAF born in 1958 were, at the second follow-up at the age of 52, still representative of the study cohort in terms of sex, adolescent geographical area, upper secondary school program, adolescent body composition, muscular strength, and muscular endurance. However, a higher physical activity and, among women, a higher aerobic capacity in adolescence decreased the risk for dropout. It is important when interpreting results from longitudinal studies to adjust for the systematic dropout that could bias the conclusions drawn from the results. PMID- 26926495 TI - Get1p and Get2p are required for maintenance of mitochondrial morphology and normal cardiolipin levels. AB - Cardiolipin (CL) is the signature phospholipid of mitochondrial membranes. CL deficiency leads to defects in mitochondrial function. Using a targeted synthetic lethality screen to identify defects that exacerbate CL deficiency, we determined that deletion of mitochondrial morphology genes in cells lacking CL leads to severe growth defects. We show that ER membrane proteins Get1p and Get2p are required for maintaining normal levels of CL. We propose that these proteins regulate the level of CL by maintaining wild type-like tubular mitochondrial morphology. The genetic interactions observed in this study identify novel physiological modifiers that are required for maintenance of CL levels and mitochondrial morphology. PMID- 26926497 TI - Stereoselectivity of 6-Exo Cyclization of alpha-Carbamoyl Radicals. AB - The stereoselectivity in the 6-exo cyclization of alpha-carbamoyl radicals was investigated experimentally and theoretically. The BEt3/O2-initiated iodine-atom transfer radical cyclization reactions of substituted N-(but-3-en-1-yl)-N-(tert butyl)-2-iodoalkanamides were carried out, which led to the predominant formations of 3,4-cis, 4,5-trans, or 4,6-trans substituted delta-lactams. Density functional calculations at the B3LYP/6-31G* level revealed that the 6-exo radical cyclization proceeds via boat-conformational transition states. Furthermore, a mechanistic insight into the stereoselectivity was provided and the calculation results were in excellent agreement with the experimental observations. PMID- 26926498 TI - [Thrombolytic and antithrombotic therapy for coronary heart disease: status quo and thinking]. PMID- 26926499 TI - [Relationship between gene and bleeding events of antiplatelet agents-treated acute coronary syndrome patients after percutaneous coronary intervention]. PMID- 26926500 TI - [Relationship between bleeding and anticoagulants selection and dosing post percutaneous coronary intervention]. PMID- 26926501 TI - [Prophylaxis and treatment of non-access site bleeding after percutaneous coronary intervention]. PMID- 26926502 TI - [Chinese expert consensus on the antiplatelet treatment for patients with stable coronary artery disease]. PMID- 26926503 TI - [Chinese expert consensus statement on clinical use of ticagrelor]. PMID- 26926504 TI - [A large-scale, multicenter, retrospective study on efficacy of bivalirudin use during peri-percutaneous coronary intervention period for Chinese patients with coronary heart disease]. AB - OBJECTIVE: To observe the efficacy and safety of bivalirudin use in Chinese patients with coronary heart disease (CHD) during the peri-percutaneous coronary intervention(PCI) period. METHODS: A total of 3 271 patients who underwent PCI and received periprocedural bivalirudin treatment between July 2013 and October 2015 from 88 centers of China were involved in this study. The primary outcome was 30-day net adverse clinical events (NACE a composite of major adverse cardiac or cerebral events (MACE, all-cause death, reinfarction, urgent target vessel revascularization, or stroke) or bleeding), the secondary outcome was stent thrombosis at 30 days. RESULTS: The mean age of enrolled patients was (65.12+/ 12.44) years old, 27.4%(889/3 244) of them were female. Percent of stable coronary disease (SCD), non-ST segment elevation acute coronary syndrome (NSTE ACS) and ST elevation myocardial infarction (STEMI) was 5.0%(162/3 248), 44.6%(1 450/3 248) and 50.4%(1 636/3 248) respectively. Radial access was performed in 89.5% (2 879/3 271) patients, and 9.7% (316/3 271) and 34.1% (1 115/3 271) patients also received ticagrelor and tirofiban medication. 69.3% (2 266/3 271) patients received post-procedural bivalirudin infusion, in which 46.3% (1 050/2 266) was treated at PCI-does, with a median duration of 2.5(1.0, 4.0) h. During the 30-day follow-up, NACE occurred in 3.45% (103/2 988) patients, the incidence of MACE, death was 2.17% (65/2 994) and 1.03% (31/3 017), respectively and bleeding events were recorded in 1.37% (41/2 996) patients. Four cases (0.13%) of stent thrombosis (3 acute stent thrombosis) were recorded. CONCLUSION: Peri-PCI Bivalirudin use is safe and related with low bleeding risk in Chinese CHD patients. PMID- 26926505 TI - [Impact of the time from symptoms onset to thrombolysis on in-hospital major adverse cardiovascular event rate in patients with acute ST-segment elevation myocardial infarction]. AB - OBJECTIVE: To explore the impact of thrombolytic therapy time delay on in hospital major adverse cardiac event rate in patients with acute ST-segment elevation myocardial infarction (STEMI). METHODS: This survey was performed in 101 level 2 hospitals from 15 provinces or autonomous region in China. Patients admitted to these hospitals with acute STEMI during November 2011 to November 2014 and received thrombolytic therapy were eligible for this study. Multivariate logistic regression modeling was used to estimate the rate of in-hospital major adverse cardiac events (re-infarction, stroke and all-cause mortality) in patients with different thrombolytic time delay. RESULTS: A total of 3 719 STEMI patients received thrombolytic therapy, 88%(3 270 cases) of them were treated within 12 hours. After controlling for the impact of confounding factors, such as a variety of risk factors, past disease histories, the severity of STEMI, medication, interventions, etc, MACE rates significantly increased along with the thrombolysis time delay, no matter thrombolysis succeeded or not (trend test P<0.05). In group of successful thrombolysis, multivariate adjusted rate of MACE for 0-5.9 hours, 6.0-11.9 hours and >=12.0 hours were 3.2%, 3.9% and 7.8%; in group of unsuccessful thrombolysis, it was 11.6%, 14.1% and 25.2% respectively (trend test P<0.05). The multivariate adjusted rates of re-infarction in group of successful thrombolysis as well as in group of unsuccessful thrombolysis significantly increased in proportion to thrombolysis time delay >= 12.0 h (trend test P<0.05). In group of successful thrombolysis, multivariate adjusted rate of re-infarction for 0-5.9 hours, 6.0-11.9 hours and >=12.0 hours were 1.9%, 1.5% and 6.8%; in group of unsuccessful thrombolysis, it was 3.9%, 3.1% and 13.6%, respectively. Within the same time delay group, MACE and re-infarction rates were significantly lower in successful thrombolysis group than in unsuccessful thrombolysis group (all P<0.05). CONCLUSION: Thrombolytic therapy should be conducted within 6 hours after the attack. Both re-infarction or MACE rates are significantly increased in patients with more than 12 hours thrombolysis time delay. PMID- 26926506 TI - [Relationship between the mean platelet aggregation degree and the prognosis of patients underwent long-term dual antiplatelet therapy following drug eluting stent implantation]. AB - OBJECTIVE: To evaluate the association between the mean platelet aggregation degree and the prognosis of patients underwent long-term dual antiplatelet therapy (DAPT more than 12 months) following drug eluting stent (DES) implantation. METHODS: A total of 752 patients were retrospectively analyzed who were received DES between September 2006 and June 2009. Adenosine diphosphate induced platelet aggregation (ADP) was monitored during the course of treatment with DAPT, and the mean platelet aggregation degree of each participant was calculated. Based on the mean platelet aggregation degree, patients were divided into the low ADP degree group (374 cases) and the high ADP degree group (378 cases). The median follow-up period was 32.2(25.1, 34.8) months. The comparison of the composite endpoints (all-cause death, nonfatal myocardial infarction, stent thrombosis, repeat revascularization and stroke) was performed between the two groups. RESULTS: Compared with the high ADP degree group, there were more male, younger and smoker patients in the low ADP degree group (all P<0.05). COX regression analysis showed that the low ADP degree group was associated with a decreased incidence of primary endpoints (HR=0.463, 95%CI 0.23-0.92, P=0.028). After adjustment with multivariable COX regression analysis, the relationship was proven to be independent of other risk factors (HR=0.495, 95%CI 0.25-0.99, P=0.046). The Kaplan-Meier curve demonstrated the incidence of the composite endpoints was significantly higher in high ADP degree group compared to that of low ADP degree group (log-rank chi(2)=5.042, P=0.025). CONCLUSION: The mean adenosine diphosphate-induced platelet aggregation degree is associated with the prognosis of patients underwent long term DAPT after DES implantation. PMID- 26926507 TI - [Impact of novel P2Y12 receptor inhibitors on platelet reactivity in acute coronary syndrome patients undergoing percutaneous coronary intervention]. AB - OBJECTIVE: To investigate the impact of novel P2Y(12) receptor inhibitors including prasugrel or ticagrelor on platelet reactivity in patients with acute coronary syndrome (ACS) receiving percutaneous coronary intervention (PCI), and provide clinical data for novel oral P2Y(12) receptor inhibitors use among Chinese patients. METHODS: Between October 2011 to February 2014, 174 consecutive patients (135 males; (67.8+/-11.8) years old) with ACS undergoing PCI in Kiang Wu Hospital, Macau were prospectively enrolled in this study. Oral aspirin and one P2Y(12) receptor inhibitor were administered for 5 days or above after PCI, patients were divided into clopidogrel, prasugrel and ticagrelor groups in accordance with the agent administered. Platelet reactivity of the patients was detected by VerifyNow P2Y(12) reaction unit (PRU); and the high on-treatment platelet reactivity (HPR) and non-HPR were defined as PRU>=208 and PRU<208 respectively. Patients with HPR during clopidogrel therapy were switched either to prasugrel or ticagrelor, or continued the same treatment; and then the platelet reactivity was monitored again. RESULTS: There were 113 clopidogrel cases (64.9%), 20 prasugrel cases (11.5%) and 41 ticagrelor cases (23.6%). Fifty seven cases (32.8%) were defined as HPR post P2Y(12) receptor inhibitor use, in which 55 cases (55/113, 48.7%) were treated with clopidogrel. The degree of inhibition of platelet reactivity was significantly different in patients on clopidogrel, prasugrel and ticagrelor therapy, percent inhibition assayed by the VerifyNow P2Y(12) system was 28.2%+/-23.5%, 61.4%+/-26.7% and 81.3%+/-19.8% respectively (P<0.05). Different degree of platelet reactivity was achieved by the 3 P2Y(12) receptor inhibitors at multiple time points. The among-group differences in platelet reactivity became apparent at the early treatment stage (P<0.05). Platelet aggregation decreased significantly in patients switched from clopidogrel to prasugrel or ticagrelor (P<0.05). CONCLUSION: Novel oral P2Y(12) receptor inhibitors are more effective in inhibiting platelet reactivity in ACS patients, and our results show that novel oral P2Y(12) receptor inhibitors provide a new option for ACS patients with HPR post clopidogrel or high-risk features of ischemic complications, including stent thrombosis and post-PCI ischemic events. PMID- 26926508 TI - [Impact of long-term continuous positive airway pressure treatment for patients with obstructive sleep apnea syndrome]. AB - OBJECTIVE: To investigate the long-term efficacy of continuous positive airway pressure (CPAP) treatment for patients with obstructive sleep apnea syndrome (OSAS). METHODS: This case control study was performed among 154 patients with moderate or severe OSAS between September 2009 and September 2014. Patients were divided into treatment group (n=66, 53 patients with hypertension) and control group (n=88, 67 patients with hypertension). The long-term efficacy of CPAP treatment on clinical events and blood pressure was evaluated. RESULTS: The combined incidence of death, myocardial infarction, coronary revascularization and stroke events was 1.5% (1/66) in treatment group and 11.4% (10/88) in control group (P<0.05). CPAP treatment also led to more significant reduction in systolic blood pressure ((12.24+/-18.06) mmHg(1 mmHg=0.133 kPa) to (4.24+/-16.63) mmHg, P<0.05) in the patients with hypertension in these two groups. CONCLUSIONS: CPAP treatment could reduce the risk of cardiovascular and neurovascular events for patients with moderate or severe OSAS. PMID- 26926509 TI - [Diagnostic values of mitral inflow and mitral annulus diastolic velocity for heart failure with preserved ejection fraction]. AB - OBJECTIVE: To explore the diagnostic values of ratios of early diastolic peak transmitral velocity(E) to late velocity(A) (E/A) and E to early diastolic peak mitral annulus velocity (E/E') for heart failure patients with preserved ejection fraction (HF-PEF). METHODS: Two hundred and sixteen healthy people were divided into <50 years, 50-59 years, 60-69 years, and >=70 years groups to clarify the impact of aging on E/A and E/E'. Two hundred and two newly diagnosed consecutive in-patients with HF-PEF and 221 age- and sex-matched non-heart-failure subjects with risk factors of HF-PEF (negative controls) were enrolled.The diagnostic values and cutoff points of E/A and E/E' for HF-PEF were derived from receiver operating characteristic curve (ROC) analysis. RESULTS: E/A and E/E' were significantly different among age groups in healthy controls (all P<0.01). Compared with <50 years group, average E/A was lower and average E/E' was higher in >=70 years group(both P<0.01). E/A ratio was less than 1 in 68%(71/105), E/E' was >8 cm/s in 48% (50/105)healthy people with age>=60 years. Neither E/A nor E/E' of HF-PEF patients was statistically different regarding to NYHA classification (grade II, III, IV), but NT-proBNP value increased in proportion to higher NYHA classification(P<0.01). The area of E/E' under ROC for diagnosing HF-PEF was 0.839(P<0.01), and the corresponding cutoff point was 9.5 with a sensitivity of 86% and a specificity of 69%. The areas of E/A (larger value or smaller value indicating positive) under ROC for diagnosing HF-PEF were 0.469 and 0.531, respectively(all P>0.05). CONCLUSIONS: Aging exerts significant impacts on both E/A and E/E'. E/E' has moderate diagnostic accuracy while E/A is of limited value for diagnosing HF-PEF. PMID- 26926510 TI - [Tumor necrosis factor-alpha inhibitor protects against myocardial ischemia/reperfusion injury via Notch1 mediated inhibition of oxidative/nitrative stress in traumatic mice]. AB - OBJECTIVE: To test the effects of TNF-alpha inhibitor Etanercept on myocardial ischemia/reperfusion (MI/R) injury in posttraumatic mice, and explore related mechanisms. METHODS: Traumatic mouse model was established with Noble-Collip drum. Five days after trauma, Notch1 was knocked down by intramyocardial injection of Notch1 small interfering RNAs (siRNA) or scrambled siRNA (20 MUg). Seven days after trauma, mice were subjected to MI/R (30 minutes ischemia followed by reperfusion). Sham operation was similarly performed without coronary artery ligation. Ten minutes before reperfusion, mice received Etanercept (8 mg/kg, i. p.). ELISA was used to detect plasma levels of TNF-alpha and troponin I (cTnI) and myocardial nitrotyrosine content. Twenty-four hours after reperfusion, left ventricular ejection fraction (LVEF) was measured by echocardiography. Infarct size was determined by Evans blue/2, 3, 5-triphenyl tetrazolium chloride (TTC) double staining. Cardiac caspase-3 activity was detected using a caspase-3 kit. Myocardial TNF-alpha and Notch1 intracellular domains (Notch1 ICD) expressions were determined by Western blot. Chemiluminescence was used to assess myocardial superoxide anion content. RESULTS: (1) Compared to vehicle group, Etanercept treatment significantly reduced cTnI content, infarct size and caspase 3 activity (all P<0.01), while obviously increased LVEF (P<0.01). (2) Etanercept treatment also significantly reduced plasma and myocardial TNF-alpha contents (P<0.01), whereas markedly increased myocardial Notch1 ICD content (P<0.05). (3) Compared to scrambled siRNA group, Notch1 deficiency significantly increased cTnI content, infarct size and caspase-3 activity (P<0.05), whereas obviously reduced LVEF (P<0.05). (4) Etanercept significantly reduced myocardial superoxide anion and nitrotyrosine content (P<0.01), which was reversed by downregulation of Notch1 (P<0.05). CONCLUSIONS: TNF-alpha inhibitor Etanercept can alleviate MI/R injury after trauma by reducing myocardial oxidative/nitrative stress via activating Notch1 signaling pathway. PMID- 26926511 TI - [Influencing factors of orthostatism brachial-ankle pulse wave velocity and ankle brachial index in the elderly]. AB - OBJECTIVE: To investigate the distribution and influencing factors of orthostatism brachial-ankle pulse wave velocity(baPWV) and ankle brachial index(ABI) in the elderly. METHODS: Participants were selected with random sampling from >=60 years old retired workers, who underwent 2010 to 2011 health check-up in the Tangshan Kailuan Hospital, Kailuan Linxi Hospital, Kailuan Zhaogezhuang Hospital. Multivariate linear regression analysis was used to analyze the influencing factors of orthostatism and supine baPWV and ABI in the elderly. RESULTS: (1) A total of 2 464 participants were included, and 1 601 participants (1 065 males(66.5%) and (67.5+/-6.1) years old) with integral data were analyzed. Orthostatism baPWV was (3 885.4+/-1 503.5)cm/s and Supine baPWV was (1 761.2+/-371.4)cm/s.Orthostatism ABI was 1.54+/-0.21 and supine ABI was 1.10+/-0.12. Orthostatism baPWV increased with increasing age, while orthostatism ABI decreased with aging(trend test, both P<0.01)in <65, 65-69, 70-74, and >=75 years old participants.(2) Multiple linear regression analysis showed that the age(beta=0.19, P<0.01), lower limbs orthostatism systolic blood pressure(beta=0.18, P<0.01), lower limbs supine systolic blood pressure (beta=0.14, P<0.01), orthostatism heart rate (beta=0.30, P<0.01), supine heart rate (beta=0.23, P<0.01), body mass index (beta=-0.18, P<0.01) were associated with orthostatism baPWV, and female(beta=-0.055, P=0.01), upper limb orthostatism systolic blood pressure (beta=-0.834, P<0.01), lower limbs orthostatism systolic blood pressure (beta=0.708, P<0.01), lower limbs supine systolic blood pressure (beta=0.099, P<0.01) and fasting blood glucose(beta=-0.085, P<0.01) were associated with orthostatism ABI. CONCLUSIONS: Orthostatism baPWV and ABI were significantly higher than those of supine's. Age, lower limbs orthostatism and supine systolic blood pressure, orthostatism and supine heart rate, body mass index were associated with orthostatism baPWV. Female, upper limb orthostatism systolic blood pressure, lower limbs orthostatism, supine systolic blood pressure and fasting blood glucose were associated with orthostatism ABI in the elderly. PMID- 26926512 TI - [A case of therapeutic coil embolism of the first septal branch of the anterior descending coronary artery for hypertrophic obstructive cardiomyopathy]. PMID- 26926513 TI - [Aortic sinus aneurysm rupture in pregnancy: report of 2 cases]. PMID- 26926514 TI - [Endocarditis complicated with acute myocardial infarction and renal insufficiency: a case report]. PMID- 26926515 TI - [Research update on the relationship of aldehyde dehydrogenase 2 and cardio cerebral-vascular diseases]. PMID- 26926516 TI - [Particulate matter air pollution and cardiovascular system damage]. PMID- 26926517 TI - [Comorbidity in aortic dissection]. PMID- 26926519 TI - Streptococcus agalactiae infective endocarditis complicated by large vegetations at aortic valve cusps along with intracoronary extension: An autopsy case report. AB - Streptococcus agalactiae infective endocarditis is a rare condition with high mortality owing to complications of large vegetations and systemic emboli. A 49 year-old man was found dead in his house. He had a history of hepatic cirrhosis and had been diagnosed with type 2 diabetes 2years previously. He had presented with a high fever 10days before his death. An autopsy revealed 50mL of purulent pericardial effusion, and S. agalactiae was detected from the culture of this pericardial effusion. Two slender rope-like vegetations were present at the right aortic valve cusp and noncoronary aortic valve cusp. The vegetation at the right aortic valve cusp extended into the right coronary artery. The right coronary artery was broadly occluded by white rod-like material. The mitral valves were also affected, and the posterior papillary muscle was ruptured. Myocardial infarction was not observed. Systemic microscopic Gram-positive bacterial masses were observed in several organs. The death was attributed to acute myocardial ischemia caused by occlusive intracoronary extension of the vegetation at the proximal right coronary artery. PMID- 26926518 TI - Hologenome analysis of two marine sponges with different microbiomes. AB - BACKGROUND: Sponges (Porifera) harbor distinct microbial consortia within their mesohyl interior. We herein analysed the hologenomes of Stylissa carteri and Xestospongia testudinaria, which notably differ in their microbiome content. RESULTS: Our analysis revealed that S. carteri has an expanded repertoire of immunological domains, specifically Scavenger Receptor Cysteine-Rich (SRCR)-like domains, compared to X. testudinaria. On the microbial side, metatranscriptome analyses revealed an overrepresentation of potential symbiosis-related domains in X. testudinaria. CONCLUSIONS: Our findings provide genomic insights into the molecular mechanisms underlying host-symbiont coevolution and may serve as a roadmap for future hologenome analyses. PMID- 26926520 TI - Enzyme Architecture: A Startling Role for Asn270 in Glycerol 3-Phosphate Dehydrogenase-Catalyzed Hydride Transfer. AB - The side chains of R269 and N270 interact with the phosphodianion of dihydroxyacetone phosphate (DHAP) bound to glycerol 3-phosphate dehydrogenase (GPDH). The R269A, N270A, and R269A/N270A mutations of GPDH result in 9.1, 5.6, and 11.5 kcal/mol destabilization, respectively, of the transition state for GPDH catalyzed reduction of DHAP by the reduced form of nicotinamide adenine dinucleotide. The N270A mutation results in a 7.7 kcal/mol decrease in the intrinsic phosphodianion binding energy, which is larger than the 5.6 kcal/mol effect of the mutation on the stability of the transition state for reduction of DHAP; a 2.2 kcal/mol stabilization of the transition state for unactivated hydride transfer to the truncated substrate glycolaldehyde (GA); and a change in the effect of phosphite dianion on GPDH-catalyzed reduction of GA, from strongly activating to inhibiting. The N270A mutation breaks the network of hydrogen bonding side chains, Asn270, Thr264, Asn205, Lys204, Asp260, and Lys120, which connect the dianion activation and catalytic sites of GPDH. We propose that this disruption dramatically alters the performance of GPDH at these sites. PMID- 26926522 TI - Microfluidic Breadboard Approach to Capillary Electrophoresis. AB - A breadboard approach for electrophoretic separations with contactless conductivity detection is presented. This is based on miniature off-the-shelf components such as syringe pumps, valves, and pressure controllers which could be set up in a very compact overall arrangement. It has a high flexibility for different tasks at hand, and the common operations of hydrodynamic injection and capillary flushing are automated. For demonstration of the versatility of the proposition, several very diverse configurations and modes of electrophoresis were successfully implemented, namely, standard capillary zone electrophoresis, pressure assisted zone electrophoresis, the simultaneous separation of cations and anions by dual-capillary zone electrophoresis, the separation of cationic amino acids by isotachophoresis, as well as the separation of small carboxylic acids by gradient elution moving boundary electrophoresis. The system also allows fast separations, as demonstrated by the analysis of six inorganic cations within 35 s. The approach addresses respective limitations of either conventional capillary electrophoresis instruments as well as electrophoretic lab-on-chip devices, while maintaining a performance in terms of detection limits and reproducibility comparable to standard instrumentation. PMID- 26926521 TI - Minimally Invasive Versus Conventional Aortic Valve Replacement: A Propensity Matched Study From the UK National Data. AB - OBJECTIVE: Minimally invasive aortic valve replacement (MIAVR) has been demonstrated as a safe and effective option but remains underused. We aimed to evaluate outcomes of isolated MIAVR compared with conventional aortic valve replacement (CAVR). METHODS: Data from The National Institute for Cardiovascular Outcomes Research (NICOR) were analyzed at seven volunteer centers (2006-2012). Primary outcomes were in-hospital mortality and midterm survival. Secondary outcomes were postoperative length of stay as well as cumulative bypass and cross clamp times. Propensity modeling with matched cohort analysis was used. RESULTS: Of 307 consecutive MIAVR patients, 151 (49%) were performed during the last 2 years of study with a continued increase in numbers. The 307 MIAVR patients were matched on a 1:1 ratio. In the matched CAVR group, there was no statistically significant difference in in-hospital mortality [MIAVR, 4/307,(1.3%); 95% confidence interval (CI), 0.4%-3.4% vs CAVR, 6/307 (2.0%); 95% CI, 0.8%-4.3%; P = 0.752]. One-year survival rates in the MIAVR and CAVR groups were 94.4% and 94.6%, respectively. There was no statistically significant difference in midterm survival (P = 0.677; hazard ratio, 0.90; 95% CI, 0.56-1.46). Median postoperative length of stay was lower in the MIAVR patients by 1 day (P = 0.009). The mean cumulative bypass time (94.8 vs 91.3 minutes; P = 0.333) and cross-clamp time (74.6 vs 68.4 minutes; P = 0.006) were longer in the MIAVR group; however, this was significant only in the cross-clamp time comparison. CONCLUSIONS: Minimally invasive aortic valve replacement is a safe alternative to CAVR with respect to operative and 1-year mortality and is associated with a shorter postoperative stay. Further studies are required in high-risk (logistic EuroSCORE > 10) patients to define the role of MIAVR. PMID- 26926523 TI - William Wilde and 1 Merrion Square. AB - William Wilde spent the final third of his life, from 1855 to 1876, in 1 Merrion Square. During the first half of his occupancy of the house his career blossomed to its fullest; the second decade, on the other hand, was marked by scandal, personal tragedy, and an unhappy professional and social decline. This paper considers the background to the development of Merrion Square, the architectural history of 1 Merrion Square from its building in 1762 to the arrival of the Wildes in 1855, the attractions and possibilities which the house offered for William Wilde, the major architectural expansion of the building which he commissioned in 1859, and aspects of his and his family's life in the house. PMID- 26926524 TI - Post-transplant lymphoproliferative disorder in paediatric patients: the Irish perspective-a single centre experience. AB - BACKGROUND: Post-transplant lymphoproliferative disease (PTLD) is a serious complication of both solid organ and haematopoietic stem cell transplantation in children. Its incidence has increased over the last decade as a result of more potent immunosuppressive regimens. Many treatments have been explored however optimal therapy remains controversial. AIMS: We report on the diagnosis, treatment and outcome of ten patients who were diagnosed with PTLD in Our Lady's Hospital for Sick Children in Dublin between 2004 and 2015 inclusive. METHODS: Data were collected by retrospective review of patient medical records. RESULTS: 9 out of ten of our patients are alive and disease free following treatment for PTLD with rituximab alone or in combination with chemotherapy. CONCLUSION: The outcome of paediatric patients treated for PTLD at our institution is at least comparable to published international series and supports the use of rituximab +/ low dose chemotherapy in the treatment of this malignancy. PMID- 26926525 TI - The effects of multiple chronic conditions on hospitalization costs and utilization for ambulatory care sensitive conditions in the United States: a nationally representative cross-sectional study. AB - BACKGROUND: The presence of multiple chronic conditions (MCCs) complicates inpatient hospital care, leading to higher costs and utilization. Multimorbidity also complicates primary care, increasing the likelihood of hospitalization for ambulatory care sensitive conditions. The purpose of this study was to evaluate how MCCs relate to inpatient hospitalization costs and utilization for ambulatory care sensitive conditions. METHODS: The 2012 Agency for Healthcare Research and Quality (AHRQ) Healthcare Cost and Utilization Project (HCUP) State Inpatient Databases (SID) provided data to carry out a cross-sectional analysis of 1.43 million claims related to potentially preventable hospitalizations classified by the AHRQ Prevention Quality Indicator (PQI) composites. Categories of MCCs (0-1, 2-3, 4-5, and 6+) were examined in sets of acute, chronic, and overall PQIs. Multivariate models determined associations between categories of MCCs and 1) inpatient costs per stay, 2) inpatient costs per day, and 3) length of inpatient hospitalization. Negative binomial was used to model costs per stay and costs per day. RESULTS: The most common category observed was 2 or 3 chronic conditions (37.8 % of patients), followed by 4 or 5 chronic conditions (30.1 % of patients) and by 6+ chronic conditions (10.1 %). Compared with costs for patients with 0 or 1 chronic condition, hospitalization costs per stay for overall ambulatory care sensitive conditions were 19 % higher for those with 2 or 3 (95 % confidence interval [CI] 1.19-1.20), 32 % higher for those with 4 or 5 (95 % CI 1.31-1.32), and 31 % higher (95 % CI 1.30-3.32) for those with 6+ conditions. Acute condition stays were 11 % longer when 2 or 3 chronic conditions were present (95 % CI 1.11 1.12), 21 % longer when 4 or 5 were present (95 % CI 1.20-1.22), and 27 % longer when 6+ were present (95 % CI 1.26-1.28) compared with those with 0 or 1 chronic condition. Similar results were seen within chronic conditions. Associations between MCCs and total costs were driven by longer stays among those with more chronic conditions rather than by higher costs per day. CONCLUSIONS: The presence of MCCs increased inpatient costs for ambulatory care sensitive conditions via longer hospital stays. PMID- 26926527 TI - Multimorbidity and access to major cancer surgery at high-volume hospitals in a regionalized era. AB - BACKGROUND: The Institute of Medicine has recently prioritized access of quality cancer care to vulnerable persons including multimorbid patients. Despite promotional efforts to regionalize major surgical procedures to high-volume hospitals (HVHs), little is known about change in access to HVH over time among multimorbid patients in need of major cancer surgery. We performed a time-trend appraisal of access of multimorbid persons to HVH for major cancer surgery within a large nationally representative cohort. METHODS: We identified 168,934 patients who underwent 6 major cancer surgeries from the Nationwide Inpatient Sample (1998 to 2010). Comorbidities were identified using Elixhauser's method. HVHs were defined as hospitals of highest procedure volumes that treated 1/3 of all the patients. Logistic regression models and predictive margins were used to assess the adjusted effects of comorbidity on receiving major cancer surgeries at HVH. RESULTS: Of all, 45.7% of the patients had 2 comorbidities or more. Multimorbidity predicted decreased access to HVH for esophagectomy, total gastrectomy, pancreatectomy, hepatectomy, and proctectomy, but not for distal gastrectomy, after controlling for covariates. A comorbidity level by year interaction analysis also showed that little disparity existed for receiving distal gastrectomy at an HVH, whereas the predicted difference in probability of receiving any of the other 5 major cancer procedures remained prominent between the years 1998 and 2010. CONCLUSIONS: In this large 12-year time-trend study, multimorbid cancer patients have sustained low access to HVH for major cancer surgery across many oncologic resections. These results continue to reinforce and highlight the need for policy targeted research and intervention aimed at improving these access gaps. PMID- 26926526 TI - Evolution of plant genome architecture. AB - We have witnessed an explosion in our understanding of the evolution and structure of plant genomes in recent years. Here, we highlight three important emergent realizations: (1) that the evolutionary history of all plant genomes contains multiple, cyclical episodes of whole-genome doubling that were followed by myriad fractionation processes; (2) that the vast majority of the variation in genome size reflects the dynamics of proliferation and loss of lineage-specific transposable elements; and (3) that various classes of small RNAs help shape genomic architecture and function. We illustrate ways in which understanding these organism-level and molecular genetic processes can be used for crop plant improvement. PMID- 26926528 TI - Multistrand Structure Prediction of Nucleic Acid Assemblies and Design of RNA Switches. AB - RNA is an attractive material for the creation of molecular logic gates that release programmed functionalities only in the presence of specific molecular interaction partners. Here we present HyperFold, a multistrand RNA/DNA structure prediction approach for predicting nucleic acid complexes that can contain pseudoknots. We show that HyperFold also performs competitively compared to other published folding algorithms. We performed a large variety of RNA/DNA hybrid reassociation experiments for different concentrations, DNA toehold lengths, and G+C content and find that the observed tendencies for reassociation correspond well to computational predictions. Importantly, we apply this method to the design and experimental verification of a two-stranded RNA molecular switch that upon binding to a single-stranded RNA toehold disease-marker trigger mRNA changes its conformation releasing an shRNA-like Dicer substrate structure. To demonstrate the concept, connective tissue growth factor (CTGF) mRNA and enhanced green fluorescent protein (eGFP) mRNA were chosen as trigger and target sequences, respectively. In vitro experiments confirm the formation of an RNA switch and demonstrate that the functional unit is being released when the trigger RNA interacts with the switch toehold. The designed RNA switch is shown to be functional in MDA-MB-231 breast cancer cells. Several other switches were also designed and tested. We conclude that this approach has considerable potential because, in principle, it allows the release of an siRNA designed against a gene that differs from the gene that is utilized as a biomarker for a disease state. PMID- 26926529 TI - Evidence on Use of Neuroimaging for Surgical Treatment of Temporal Lobe Epilepsy: A Systematic Review. AB - IMPORTANCE: Surgery is an effective treatment for drug-resistant focal epilepsy. Neuroimaging studies are considered essential in the diagnostic evaluation of individuals with medically refractory focal seizures being considered for surgical treatment. OBJECTIVES: To review the evidence for the use of neuroimaging studies in the selection of patients with drug-resistant temporal lobe epilepsy for focal cortical resection and discuss the prognostic importance of selected techniques. EVIDENCE REVIEW: Randomized clinical trials, meta analyses, and clinical retrospective case studies (>=20 patients with >=1 year of follow-up) were identified using Medical Subject Headings and indexed text terms in EMBASE (1988-November 29, 2014); MEDLINE (1946-December 2, 2014), Cochrane Central Register of Controlled Trials (1991-October 31, 2014), and Cochrane Database of Systematic Reviews (2005-October 31, 2014). Twenty-seven articles describing 3163 patients were included. Neuroimaging techniques analyzed included magnetic resonance imaging (MRI), positron emission tomography (PET), and single photon emission computed tomography (SPECT). Subpopulations and prognostic factors were identified. FINDINGS: Of the 27 studies evaluated (3163 patients), 7 showed the outcome was more favorable in patients with MRI-identified hippocampal atrophy indicating mesial temporal sclerosis. Five additional studies indicated that the outcome was less favorable in patients with unremarkable MRI studies. There are conflicting findings regarding the prognostic importance of PET identified focal hypometabolism; however, 2 investigations indicated that the presence of a PET imaging study demonstrating abnormalities in individuals with unremarkable MRI results showed an operative outcome similar to that in patients with mesial temporal sclerosis. The studies assessing SPECT use in temporal lobe epilepsy did not reveal a correlation with outcome. CONCLUSIONS AND RELEVANCE: There is strong evidence that preoperative MRI-identified hippocampal atrophy consistent with mesial temporal sclerosis concordant with the seizure origin in the temporal lobe is a significant factor associated with a favorable outcome. PET studies may be valuable in individuals with unremarkable MRI findings. The current evidence does not support the prognostic importance of SPECT in patients undergoing temporal lobe surgery. PMID- 26926530 TI - The globalization of nonalcoholic fatty liver disease: Prevalence and impact on world health. PMID- 26926531 TI - Tropolone Ring Construction in the Biosynthesis of Rubrolone B, a Cationic Tropolone Alkaloid from Endophytic Streptomyces. AB - Rubrolones are tropolonoid natural products with a unique carbon skeleton. Extensive secondary metabolite analysis of the endophytic Streptomyces sp. KIB H033 revealed a new class of rubrolone analogue possessing a rare benzoic acid pyridine inner salt moiety. Precursor feeding with [(13)C]-acetate revealed a labeling pattern consistent with tropolone moiety construction via type-II PKS chemistry followed by complex oxidative rearrangements. This bacterial biosynthetic route represents a surprising departure from fungal tropolone assembly during stipitatic acid biosynthesis. PMID- 26926532 TI - Renal Parenchymal Area Growth Curves for Children 0 to 10 Months Old. AB - PURPOSE: Low renal parenchymal area, which is the gross area of the kidney in maximal longitudinal length minus the area of the collecting system, has been associated with increased risk of end stage renal disease during childhood in boys with posterior urethral valves. To our knowledge normal values do not exist. We aimed to increase the clinical usefulness of this measure by defining normal renal parenchymal area during infancy. MATERIALS AND METHODS: In a cross sectional study of children with prenatally detected mild unilateral hydronephrosis who were evaluated between 2000 and 2012 we measured the renal parenchymal area of normal kidney(s) opposite the kidney with mild hydronephrosis. Measurement was done with ultrasound from birth to post gestational age 10 months. We used the LMS method to construct unilateral, bilateral, side and gender stratified normalized centile curves. We determined the z-score and the centile of a total renal parenchymal area of 12.4 cm(2) at post-gestational age 1 to 2 weeks, which has been associated with an increased risk of kidney failure before age 18 years in boys with posterior urethral valves. RESULTS: A total of 975 normal kidneys of children 0 to 10 months old were used to create renal parenchymal area centile curves. At the 97th centile for unilateral and single stratified curves the estimated margin of error was 4.4% to 8.8%. For bilateral and double stratified curves the estimated margin of error at the 97th centile was 6.6% to 13.2%. Total renal parenchymal area less than 12.4 cm(2) at post-gestational age 1 to 2 weeks had a z-score of -1.96 and fell at the 3rd percentile. CONCLUSIONS: These normal renal parenchymal area curves may be used to track kidney growth in infants and identify those at risk for chronic kidney disease progression. PMID- 26926533 TI - Lower Urinary Tract Dysfunction in Elementary School Children: Results of a Cross Sectional Teacher Survey. AB - PURPOSE: Lower urinary tract dysfunction in school-aged children is common and yet data are lacking on current teacher practice regarding bathroom use and daytime incontinence during classroom hours. We determined the prevalence of elementary school teachers who promote lower urinary tract health and identified predictors for and against such behavioral promotion. MATERIALS AND METHODS: We performed an electronic cross-sectional survey among self-identified teachers using targeted social media advertisement during a 1-week period in July 2014. The empirical survey tool consisted of 27 questions and collected data on 5 principal domains, including 1) teacher demographics, 2) rules and regulations on water intake and bathroom use during classroom hours, 3) characteristics of school bathrooms in terms of safety, supervision and suitability for use, 4) experience with and management of students with daytime incontinence and 5) training on the topic of lower urinary tract health. Predictors for promoting lower urinary tract health were identified by multivariable logistic regression. RESULTS: Of the 4,166 teachers who completed the survey 88% indicated that they encourage students to hold urine. Despite strict bathroom protocols 81% of teachers allowed children unlimited access to water. Of the teachers 82% reported never having undergone any professional development on bathroom regulations for children. Overall only 24% of surveyed teachers met criteria for promoting lower urinary tract health. The odds of promoting lower urinary tract health decreased with ascending grade level (OR 0.80, 95% CI 0.76-0.84). Conversely it increased if teaching experience was greater than 5 years (OR 1.66, 95% CI 1.39-1.98) or professional development on the subject had been received (OR 1.42, 95% CI 1.18 1.70). CONCLUSIONS: Of elementary school teachers 76% are not promoting lower urinary tract health in school-aged children. Professional development training on the topics of lower urinary tract dysfunction and/or lower urinary tract health may be beneficial, particularly for educators who teach higher grades and those with less teaching experience. PMID- 26926534 TI - Canalization of the Vestibular Plate in the Absence of Urethral Fusion Characterizes Development of the Human Clitoris: The Single Zipper Hypothesis. AB - PURPOSE: We characterized the early gestation development of the female external genitalia using optical projection tomography to visualize anatomical structures at high resolution. MATERIALS AND METHODS: First and early second trimester human female fetal external genitalia were collected with consent after voluntary termination. Specimens labeled with anti-E-Cadherin antibody underwent analysis with optical projection tomography. Histological sections were immunostained for androgen receptor, 5alpha-reductase, Ki67 for proliferation and Caspase 3 for apoptosis. RESULTS: Three-dimensional reconstructions demonstrated proximal to distal canalization of the epithelial vestibular plate and formation of a vestibular groove, which remained open. Ki67 was observed throughout with greatest density in the dorsal vestibular plate at the level of the opening groove. Staining for Caspase 3 was minimal in all sections. Androgen receptor staining was seen throughout the mesenchyme and in the apical epithelium of the dorsal vestibular groove. Throughout the epithelium and epidermis 5alpha reductase staining was observed. CONCLUSIONS: Early development of the external genitalia in the female is analogous to that in the male, demonstrating a similar opening zipper driving canalization of the vestibular plate with localized epithelial proliferation in the absence of significant apoptosis. Thus we hypothesize that the mechanism underlying the opening zipper must be androgen independent and the absence of androgen driven urethral fusion characterizes the normal development of the human clitoris. PMID- 26926535 TI - Initially Asymmetrical Function on MAG3 Renography Increases Incidence of Adverse Outcomes. AB - PURPOSE: To discriminate pathological from physiological hydronephrosis (99m)Tc mercaptoacetyltriglycine (MAG3) diuretic renography is a fundamental imaging modality. Initial asymmetrical differential function or decreasing function on serial MAG3 scans is a classic surgical indication. However, prognostic evidence supporting this is limited. Therefore, we examined the association between initial function and outcomes. We hypothesized that patients with initially asymmetrical function would have higher odds of functional decline, and experience symptoms and surgical intervention compared to patients with initially symmetrical scans. MATERIALS AND METHODS: We retrospectively reviewed the charts of 1,124 pediatric patients with hydronephrosis seen at Stollery Children's Hospital from 2000 to 2014. A total of 387 cases of unilateral ureteropelvic junction obstruction were grouped by initial postnatal differential function with asymmetrical defined as a greater than 10% difference in relative function. Postnatal surveillance, followup MAG3 results, pyeloplasty rates and post pyeloplasty outcomes were compared. RESULTS: Of 387 patients 143 (37%) had initially asymmetrical function. Of those undergoing MAG3 scan surveillance 17% experienced a 10% or greater decline in ipsilateral differential function vs a 6% rate of function loss in the initially symmetrical group (OR 3.2, 95% CI 1.6-6.4, p = 0.0008). The overall pyeloplasty rate in patients with asymmetrical and symmetrical function was 27% and 16%, respectively (OR 1.9, 95% CI 1.1-3.2, p = 0.013). Patients with initially asymmetrical function had an increased rate of pyeloplasty secondary to symptoms compared to those with initially symmetrical function (16% vs 8%, OR 2.1, 95% CI 1.1-4.0, p = 0.019). Mean time to functional decline and pyeloplasty was 19 and 17 months, respectively. CONCLUSIONS: Patients with initially asymmetrical differential function had increased ORs for subsequent renal decline, symptom onset and pyeloplasty. PMID- 26926536 TI - Prospective Evaluation of Sacral Neuromodulation in Children: Outcomes and Urodynamic Predictors of Success. AB - PURPOSE: Sacral neuromodulation has been demonstrated to improve refractory bowel bladder dysfunction in children. The purpose of the current study was to determine whether results are durable in children after longer followup, whether children with a lower body mass index are at risk for device failure and whether pretreatment urodynamic evaluation can predict posttreatment outcome. MATERIALS AND METHODS: Pediatric patients with refractory bowel bladder dysfunction were enrolled following informed consent and followed prospectively. All patients underwent preoperative videourodynamic evaluation and a 2-stage implantation procedure. Validated questionnaires were used to assess symptom severity and quality of life. Complications were analyzed with regard to treatment required and patient body mass index. RESULTS: During 45 months 30 patients were enrolled. Median age was 8.3 years at enrollment. Median followup was 14.8 months. Patients had significant improvement in quality of life and symptom scores, which persisted at the most recent followup. Patients who had uninhibited detrusor contractions on preoperative urodynamic assessment had significantly greater improvement in symptoms. Of the patients 23% had a complication requiring reoperation, most commonly neurostimulator lead breakage in those with a significantly lower body mass index. CONCLUSIONS: Sacral neuromodulation significantly improves quality of life and symptom severity in children with refractory bowel bladder dysfunction. Children gain greater benefit if they show uninhibited bladder contractions on preoperative urodynamic evaluation. Children have a high rate of lead breakage requiring operative revision, which was seen after minor trauma in those with a lower body mass index. PMID- 26926537 TI - Editorial Comment. PMID- 26926538 TI - Is Tamsulosin Effective after Shock Wave Lithotripsy for Pediatric Renal Stones? A Randomized, Controlled Study. AB - PURPOSE: We assessed the effect of tamsulosin as an adjunctive therapy after shock wave lithotripsy for pediatric single renal pelvic stones. MATERIALS AND METHODS: A total of 120 children with a unilateral single renal pelvic stone were included in a prospective randomized, controlled study. All children were randomized to 2 equal groups. Group 1 received tamsulosin (0.01 mg/kg once daily) as adjunctive therapy after shock wave lithotripsy in addition to paracetamol while group 2 received paracetamol only. Stone clearance was defined as no renal stone fragments or fragments less than 3 mm and no pelvicalyceal system dilatation. RESULTS: Our study included 69 boys and 51 girls with a median age of 3.5 years and a median stone size of 1.2 cm. There was no statistically significant difference between groups 1 and 2 in stone or patient criteria. Of the children 99 (82.5%) achieved stone clearance after the first session, including 50 in group 1 and 49 in group 2. All children in each group were cleared of stones after the second session. The overall complication rate was 14.2%. There was no statistically significant difference between single session stone clearance rates (p = 0.81) and complications rates (p = 0.432) in either group. On multivariate analysis using logistic regression smaller stone size (p = 0.016) and radiopaque stones (p = 0.019) were the only predictors of stone clearance at a single shock wave lithotripsy session. Tamsulosin therapy did not affect stone clearance (p = 0.649). CONCLUSIONS: Tamsulosin does not seem to improve renal stone clearance. Smaller and radiopaque renal stones have more chance of clearance after shock wave lithotripsy for pediatric single renal pelvic stones. PMID- 26926539 TI - Editorial Comment. PMID- 26926540 TI - Increased Risk of Physical Punishment among Enuretic Children with Family History of Enuresis. AB - PURPOSE: Some parents blame their children for bedwetting and, therefore, punish them. This study aimed to assess the rate of punishment experienced by enuretic children and associated causative factors. MATERIALS AND METHODS: A total of 87 children 6 to 15 years old with monosymptomatic enuresis were assessed individually. Parents answered the questions in the tolerance scale. The forms of punishment were classified as verbal, chastisement and physical aggression. Family history of enuresis was considered only when 1 or both parents had experienced enuresis. RESULTS: Of the 35 girls and 52 boys with a mean +/- SD age of 9.3 +/- 2.3 years 67 had a family history of enuresis. Of the 67 parents 57 (85.0%) had a history of being punished due to enuresis. All children experienced some sort of verbal punishment. Children who had a family history of enuresis were more prone to being punished by physical aggression than those without such a family history (32 of 67 or 47.8% vs 4 of 20 or 20%, OR 3.7, 95% CI 1.1-12.1, p = 0.03). Punishment was found 3 times more frequently in girls than in boys (20 of 35 or 57.1% vs 16 of 52 or 30.8%, OR 3.0, 95% CI 1.2-7.3). Parents of 79 of the 87 children (90.8%) had high scores on the tolerance scale regardless of the history of enuresis. CONCLUSIONS: Enuretic children are at a high risk for experiencing some kind of punishment. Children whose parents had enuresis are at risk for being physically punished. Parents should be taught about the involuntary nature of enuresis and the fact that no punishment would help improve the condition. PMID- 26926541 TI - Patient Reported Outcomes in Preoperative and Postoperative Patients with Hypospadias. AB - PURPOSE: Current outcome tools for hypospadias have limited focus on the caregiver or patient perspective of important patient centered outcomes. In this study we collaborated with patients, caregivers, and lay and medical experts to develop and pilot a patient reported outcome measure for hypospadias. MATERIALS AND METHODS: We developed a patient reported outcome measure based on systematic review of the literature and focus group input. The patient reported outcome measure was piloted in caregivers for boys younger than 8 years and in patients older than 8 years who presented for urology consultation before meeting with the surgeon. Patients were classified with uncorrected hypospadias, successful repair or failed repair based on the presence or absence of complications (fistula, diverticulum, meatal stenosis/stricture, greater than 30-degree recurrent curvature, glans dehiscence and/or skin reoperation). RESULTS: A patient reported outcome measure was developed and administered to 347 patients and/or caregivers proxies, including 105 uncorrected cases, 162 successful repair cases and 80 failed cases. Satisfaction with appearance was highest in those with successful hypospadias repair compared to failed repair and uncorrected hypospadias (93% vs 77% and 67%, respectively). Voiding symptoms such as spraying or a deviated stream were highest in failed and uncorrected cases (39% and 37%, respectively). Overall dissatisfaction with voiding was highest for uncorrected hypospadias and failed repair compared to successful cases (54% and 47%, respectively, vs 15%). CONCLUSIONS: The evaluation of patient and caregiver-proxy reported outcomes in preoperative and postoperative patients with hypospadias allows for the quantification of benefits derived from hypospadias repair and may ultimately represent the gold standard outcome measure for hypospadias. This pilot study identified preliminary patient centered themes and demonstrated the feasibility of administering hypospadias patient reported outcome measures in clinical practice. PMID- 26926542 TI - Nationwide Trends and Variations in Urological Surgical Interventions and Renal Outcome in Patients with Spina Bifida. AB - PURPOSE: Bladder dysfunction in patients with spina bifida can lead to significant morbidity due to renal insufficiency. Indications for surgery vary among institutions and the impact is unclear. We examined trends and variations in urological interventions and chronic renal insufficiency in patients with spina bifida. MATERIALS AND METHODS: We reviewed NIS (Nationwide Inpatient Sample) for all patients with spina bifida treated from 1998 to 2011. We used ICD 9-CM codes to identify urological surgery and chronic renal insufficiency. We calculated the Spearman correlation coefficients between rates of spina bifida related bladder surgeries and rates of chronic renal insufficiency outcomes by state. Linear regression models were fitted to investigate the associations between rates of spina bifida related surgery and chronic renal insufficiency across treatment years. RESULTS: We identified 427,616 spina bifida hospital admissions. Mean patient age was 26 years and 56% of patients were female. Of the admissions 35,249 (8%) were for chronic renal insufficiency and 11,078 (3%) were for surgery. During the study period chronic renal insufficiency rates doubled from 6% to 12% and surgery rates decreased from 2.0% to 1.8%. There was a moderately weak inverse association between surgery and chronic renal insufficiency rates with time (r = -0.3, p = 0.06) and by state (r = -0.3, p = 0.04). On multivariate analysis higher rates of surgery were associated with the state in which the patient was treated (p <0.001), and with younger age (p <0.001) and hospital teaching status (p <0.001). In contrast, chronic renal insufficiency was not associated with spina bifida related surgery (p = 0.67). CONCLUSIONS: We observed a temporal and geographic trend toward decreasing urological surgery and increasing chronic renal insufficiency rates in spina bifida and a wide variation in urological surgical rates among states. Further study is needed to determine the factors behind these trends and variations in spina bifida management. PMID- 26926543 TI - National Trends in Secondary Procedures Following Pediatric Pyeloplasty. AB - PURPOSE: Although reported success rates after pediatric pyeloplasty to correct ureteropelvic junction are high, failure may require intervention. We sought to characterize the incidence and timing of secondary procedures after pediatric pyeloplasty using a national employer based insurance database. MATERIALS AND METHODS: Using the MarketScan(r) database we identified patients 0 to 18 years old who underwent pyeloplasty from 2007 to 2013 with greater than 3 months of postoperative enrollment. Secondary procedures following the index pyeloplasty were identified by CPT codes and classified as stent/drain, endoscopic, pyeloplasty, nephrectomy or transplant. The risk of undergoing a secondary procedure was ascertained using Cox proportional hazards models adjusting for demographic and clinical characteristics. RESULTS: We identified 1,976 patients with a mean +/- SD followup of 23.9 +/- 19.8 months. Overall 226 children (11.4%) had undergone at least 1 post-pyeloplasty procedure. The first procedure was done within 1 year in 87.2% of patients with a mean postoperative interval of 5.9 +/- 11.1 months. Stents/drains, endoscopic procedures and pyeloplasties were noted in 116 (5.9%), 34 (1.7%) and 71 patients (3.1%), respectively. Length of stay was associated with undergoing a secondary procedure. Compared with 2 days or less the HR of 3 to 5 and 6 days or greater was 1.65 and 3.94 (p = 0.001 and <0.001, respectively). CONCLUSIONS: Following pediatric pyeloplasty 1 of 9 patients undergoes at least 1 secondary procedure with the majority performed within the first year. One of 11 patients undergoes intervention more extensive than placement of a single stent or drain, requiring management strategies that generally signify recurrent or persistent obstruction. Estimates of pyeloplasty success in this national data set are lower than in other published series. PMID- 26926544 TI - Filum Section for Urinary Incontinence in Children with Occult Tethered Cord Syndrome: A Randomized, Controlled Pilot Study. AB - PURPOSE: Occult tethered cord syndrome, in which there is normal neuroanatomic imaging despite clinical and urodynamic evidence of neuropathic bladder behavior, is controversial. Several uncontrolled series describe improvement in bladder function following section of the filum terminale. We performed a pilot randomized, controlled study comparing medical treatment to surgical section of the filum plus medical treatment in children with occult tethered cord syndrome. MATERIALS AND METHODS: Children refractory to standard medical management for 1 year or more with normal conus position on magnetic resonance imaging and abnormal urodynamics were randomized. Exclusion criteria included any neurological conditions, spinal dysraphism, bladder outlet obstruction and an atonic bladder. Patients were assessed at randomization and 1 year later with a standardized urodynamic score, the validated PEMQOL (Pediatric Enuresis Module on Quality of LifeTM) scale, and a validated bowel and bladder dysfunction score. RESULTS: After 8 years we accrued 21 patients. The bowel and bladder dysfunction score improved in the surgical and medical arms (20% and 24%) and the urodynamic score improved slightly (6% and 4%, respectively). The PEMQOL Child and Family Impact Scales improved modestly in both groups. All differences were nonsignificant. Interim analysis indicated that more than 700 patients in each arm would be required to demonstrate a statistical difference with respect to urodynamic score based on our preliminary data. CONCLUSIONS: There appears to be no objective difference in urological outcome between medical management plus or minus filum section for patients with occult tethered cord syndrome. These data challenge the existence of the concept of occult tethered cord syndrome, in which bowel and bladder dysfunction score is attributed to tethering by the filum despite a normally located conus. PMID- 26926545 TI - Editorial Comment. PMID- 26926546 TI - Editorial Comment. PMID- 26926547 TI - Editorial Comment. PMID- 26926548 TI - The Fate of Primary Nonrefluxing Megaureter: A Prospective Outcome Analysis of the Rate of Urinary Tract Infections, Surgical Indications and Time to Resolution. AB - PURPOSE: We examined data on a cohort of patients with primary nonrefluxing megaureter to determine risk factors for febrile urinary tract infection, indications for surgery and time to resolution. MATERIALS AND METHODS: The records of patients younger than 24 months with primary nonrefluxing megaureter were prospectively captured from 2008 to 2015. Six a priori defined variables were studied, including gender, circumcision status, hydronephrosis SFU (Society for Fetal Urology) grade (low--1 and 2 vs high--3 and 4), continuous antibiotic prophylaxis use, ureteral dilatation (greater than 11 mm) and tortuosity. Univariate analyses and Cox hazard regression were done for febrile urinary tract infection risk factors. Resolution trends were analyzed using Kaplan-Meier curves. RESULTS: Mean +/- SD age at the first clinic visit was 3.7 +/- 4 months and mean followup was 26.3 +/- 16.6 months. Of 80 patients with primary megaureter 66 (83%) had high grade hydronephrosis, 72 (90%) were male, 21 (26%) were circumcised and 40 (50%) had ureteral dilatation greater than 11 mm at baseline. Overall continuous antibiotic prophylaxis was prescribed to 34 patients (43%) and febrile urinary tract developed infection in 27 (34%) at a mean age of 5.8 months (median 3, range 1 to 24). Cox regression identified uncircumcised male gender (HR 3.4, 95% CI 1.1-10.7, p = 0.04) and lack of continuous antibiotic prophylaxis (HR 4.1, 95% CI 1.3-12.7, p = 0.01) as independent risk factors for febrile urinary tract infection. The 19 surgical patients (24%) had a larger mean ureteral diameter immediately preoperatively than those who did not require surgery (17 +/- 5 vs 12 +/- 4 mm, p <0.01). Kaplan-Meier curves showed that 85% of primary nonrefluxing megaureters that did not require surgery resolved in a median of 17 months. CONCLUSIONS: Febrile urinary tract infection developed in 34% of patients with primary nonrefluxing megaureter within the first 6 months of life. Circumcision and continuous antibiotic prophylaxis significantly decreased febrile urinary tract infection rates in those infants. Ureteral diameter 17 mm or greater was significantly associated with a higher rate of surgical intervention. Overall 76% of megaureters resolved during a median followup of 19 months. PMID- 26926549 TI - Nerve Sparing Clitoroplasty is an Option for Adolescent and Adult Female Patients with Congenital Adrenal Hyperplasia and Clitoral Pain following Prior Clitoral Recession or Incomplete Reduction. AB - PURPOSE: In the past many female patients with congenital adrenal hyperplasia and atypical genitalia were surgically treated with clitoral recession or incomplete reduction of erectile bodies. We report the results of repeat clitoral surgery performed for clitoral pain or enlargement using a nerve sparing reduction clitoroplasty technique. MATERIALS AND METHODS: We identified 6 female patients with congenital adrenal hyperplasia who had undergone prior clitoral recession or incomplete reduction elsewhere. They then presented to our center with clitoral pain or enlargement, where they were treated with nerve sparing clitoroplasty between 2000 and 2010. We collected patient reported data relating to clitoral sensation and sexual function outcomes. RESULTS: Mean +/- SD age at evaluation for repeat clitoral surgery was 21 +/- 7 years and mean age at clitoroplasty was 22 +/- 8 years. Median postoperative followup was 9 months (IQR 32-6). All patients showed improvement with resolution of clitoral pain or enlargement. CONCLUSIONS: Clitoral pain and enlargement upon arousal can be a major concern for women with clitoromegaly and congenital adrenal hyperplasia after clitoral recession is performed. Our series suggests that clitoral recession or incomplete reduction in childhood may be an inadequate initial solution in the congenital adrenal hyperplasia population due to the potential for future androgen elevation and the possibility of later symptom development. In addition we found that patients may be successfully treated with nerve sparing clitoroplasty, resulting in resolution of pain and ability to engage in sexual activity. PMID- 26926550 TI - Editorial Comment. PMID- 26926551 TI - Cardiac Autonomic Nervous System Activity in Children with Bladder and Bowel Dysfunction. AB - PURPOSE: Bladder and bowel dysfunction is a common reason for referral to pediatric urology. The role of the autonomic nervous system in the pathogenesis of bladder and bowel dysfunction has not been well investigated. We compared autonomic nervous system activity in children with bladder and bowel dysfunction to that in healthy controls. We hypothesized that children with dysfunction have a different autonomic profile as measured by parameters from spectral analysis of heart rate variability and impedance cardiography. MATERIALS AND METHODS: We recruited 40 children, including 25 girls, with a median age of 10 years (range 5 to 18) in whom bladder and bowel dysfunction was clinically diagnosed by a validated questionnaire and 19 healthy controls, including 9 girls, with a median age of 8 years (range 5 to 16). Cardiac autonomic activity was assessed at baseline and during voiding. The primary outcome measures were the main parameters of heart rate variability, including total power and high frequency, as well as pre-ejection period and heart rate. RESULTS: Comparison of outcomes at baseline showed significantly lower total power and high frequency heart rate variability in bladder and bowel dysfunction cases (p = 0.001 and 0.002, respectively). Children with dysfunction also showed a significantly smaller decrease in sympathetic nervous system activity during voiding (p = 0.05). CONCLUSIONS: Our results demonstrate that compared to healthy controls children with bladder and bowel dysfunction show a different cardiac autonomic profile at rest and in response to voiding. This difference may be used in future studies to further clarify the pathophysiology of bladder and bowel dysfunction, and introduce novel treatment targets to manage the condition. PMID- 26926552 TI - Risk Factors Associated with Severity and Outcomes in Pediatric Patients with Hemorrhagic Cystitis. AB - PURPOSE: Hemorrhagic cystitis is a complication of treatment of pediatric cancer with considerable variation in severity and morbidity. This study presents an analysis of hemorrhagic cystitis severity and treatment outcomes in a large pediatric population. MATERIALS AND METHODS: Patients with hemorrhagic cystitis treated at St. Jude Children's Research Hospital(r) were identified from 1990 to 2010. Demographic data were gathered along with information pertaining to initial primary diagnosis, hemorrhagic cystitis diagnosis and treatment, and mortality. Statistical analyses were performed to evaluate associations between risk factors and severity of hemorrhagic cystitis as well as treatment outcomes. RESULTS: Of the 285 patients who met inclusion criteria 54% were male. Mean age was 11.41 years. Mean time from initial primary diagnosis to hemorrhagic cystitis onset was 29 months. Noninvasive treatment was performed in 246 patients (86%) and operative intervention was required in 14 (4.9%). Bivariate analysis demonstrated that pelvic radiation therapy (p = 0.0002), any radiation therapy (p = 0.005), acute lymphocytic leukemia (p = 0.01), bone marrow transplantation (p = 0.0225), cyclophosphamide exposure (p = 0.0419) and BK virus positivity (p = 0.0472) were predictors of higher grade hemorrhagic cystitis. Factors correlating with the need for invasive management on bivariate analysis included pelvic radiation therapy (p = 0.0266), bone marrow transplantation (p = 0.0007), hematological malignancy (p = 0.0066), ifosfamide exposure (p = 0.0441) and male gender (p = 0.0383). Multivariate analysis showed independent effects of pelvic radiation therapy (p = 0.001) and delayed onset of hemorrhagic cystitis (p = 0.0444). CONCLUSIONS: Severity of hemorrhagic cystitis and failure of noninvasive management correlate with several identifiable risk factors. Prospective identification of patients with these risk factors may allow for targeted early intervention in those at highest risk. PMID- 26926553 TI - Trends in Renal Transplantation Rates in Patients with Congenital Urinary Tract Disorders. AB - PURPOSE: Improved bladder and renal management benefit patients with congenital uropathy and congenital pediatric kidney disease. This may translate to delayed initial renal transplantation in these patients, and improved graft and patient survival. Our primary study purpose was to determine whether patients with congenital uropathy and congenital pediatric kidney disease have demonstrated later time to first transplantation and/or graft survival. MATERIALS AND METHODS: SRTR (Scientific Registry of Transplant Recipients) was analyzed for first renal transplant and survival data in patients with congenital uropathy and congenital pediatric kidney disease from 1996 to 2012. Congenital uropathy included chronic pyelonephritis/reflux, prune belly syndrome and congenital obstructive uropathy. Congenital pediatric kidney disease included polycystic kidney disease, hypoplasia, dysplasia, dysgenesis, agenesis and familial nephropathy. RESULTS: A total of 7,088 patients with congenital uropathy and 24,315 with congenital pediatric kidney disease received a first renal transplant from 1996 to 2012. A significant shift was seen in both groups toward older age at initial renal transplantation in those 18 through 64 years old. In the congenital uropathy group this effect was most facilitated by decreased renal transplantion in patients between 18 and 35 years old (38% in 1996 vs 26% in 2012). The congenital pediatric kidney disease group showed a substantial decrease in patients who were 35 to 49 years old (from 39% to 29%). At 10-year followup the congenital uropathy group showed better graft and patient survival than the congenital pediatric kidney disease group. However, aged matched comparison revealed comparable survival rates in the 2 groups. CONCLUSIONS: Analysis of trends in the last 14 years demonstrated that patients with both lower and upper tract congenital anomalies experienced delayed time to the first renal transplant. Furthermore, patients had similar age matched graft and patient survival whether the primary source of renal demise was the congenital lower or upper tract. These findings may indicate that improved urological and nephrological care are promoting renal preservation in both groups. PMID- 26926554 TI - Outcome Analysis of Asymptomatic Lower Pole Stones in Children. AB - PURPOSE: Lower pole renal stones in children usually present incidentally. To our knowledge frequency and need for intervention are unknown. We evaluated the outcomes of asymptomatic, incidentally found lower pole renal stones in children. MATERIALS AND METHODS: We retrospectively reviewed the charts and renal ultrasounds of children with lower pole stones seen during a period of 14 years. The unpaired t-test was used to determine factors that might predict the need for stone intervention, including size, growth rate, type of stone and underlying metabolic disease. The success rate of nonoperative management, defined by spontaneous passage or lack of growth in the absence of symptoms, was calculated. RESULTS: A total of 224 children were found to have lower pole stones. Mean +/- SD age at presentation was 95.2 +/- 65.3 months. Of the patients 120 (53.6%) spontaneously passed stones. Of the stones 25% remained asymptomatic and did not grow with time. Intervention was performed in 48 children (21.4%). Stones originally managed conservatively that later required intervention were significantly larger at baseline than stones that did not require intervention through the end of followup (median 7 vs 5 mm, p <0.001) and those that grew with time (median stone size 8 mm at surgical intervention, p = 0.01). CONCLUSIONS: Our data suggest that asymptomatic lower pole renal stones can be followed conservatively. Of the calculi 78.6% passed spontaneously or remained asymptomatic and did not grow. Median initial size greater than 7 mm and stone growth with time were significant risk factors that predicted the need for intervention. PMID- 26926555 TI - Association between Asthma and Primary Nocturnal Enuresis in Children. AB - PURPOSE: Enuresis, sleep respiratory disorders and asthma compromise the quality of sleep in children and may occur in association with each other. An association between sleep respiratory disorders and enuresis has already been demonstrated. According to united airways disease abnormalities of the upper and lower airways may coexist. A child who wheezes has a greater chance of snoring and having obstructive sleep apnea. Since asthma and sleep respiratory disorders may be associated, and sleep respiratory disorders are associated with enuresis, we determined the possibility of an association between asthma and enuresis. MATERIALS AND METHODS: Between August 20 and March 2015 parents/guardians of children 6 to 14 years old from 16 elementary schools in our area were randomly chosen for study. Children with nonmonosymptomatic enuresis and urological or neurological disease were excluded. The Tucson and ISAAC (International Study of Asthma and Allergies in Childhood) questionnaires were used to assess sleep respiratory disorders and asthma, respectively. RESULTS: A total of 523 children (283 males and 240 females) with a mean +/- SD age of 9.42 +/- 2.46 years were included in analysis. The overall prevalence of enuresis was 15.87% (95% CI 12.98 19.26). Asthmatic children with wheezing in the last 12 months were 2.33 times more likely to have had enuresis at some point in life (OR 2.33, 95% CI 1.37 3.95, p = 0.0017). If enuresis was present, the chance increased to 2.78 (95% CI 1.38-5.61, p = 0.0041). Enuretic children were 5.34 times more prone to have apnea reported by parents (95% CI 2.19-13.03, p = 0.0002). CONCLUSIONS: These findings demonstrate that asthma as well as sleep respiratory disorders is associated with primary nocturnal enuresis. PMID- 26926556 TI - Quantity, Not Frequency, Predicts Bother with Urinary Incontinence and its Impact on Quality of Life in Adults with Spina Bifida. AB - PURPOSE: The effects of urinary incontinence on health related quality of life in adults with spina bifida is poorly understood. We determined which quantification method best captures bother with urinary incontinence. We also quantified the impact of urinary incontinence on health related quality of life. MATERIALS AND METHODS: We surveyed an international sample of adults with spina bifida online from January 2013 through September 2014. We evaluated dry intervals (4 hours or greater considered social continence), quantity of urinary incontinence (a lot, medium, little, none) and number of undergarments worn daily (pads, pull-ups or disposable underwear). A 5-point Likert bother scale was used. We applied validated instruments, including QUALAS-A (Quality of Life Assessment in Spina Bifida for Adults) and the generic WHOQOL-BREF (WHO Quality of Life). We analyzed data using linear regression with a range of 0 to 100 for all outcomes. RESULTS: Mean age of the 461 participants was 32 years and 31.0% were male. Overall 26.5% and 51.8% of participants were dry for less than 4 hours and 4 hours or greater, respectively, while 21.7% were always dry. On multivariate analysis worse bother was predominantly determined by the quantity of urinary incontinence (a lot 32.9 and medium 16.2 vs little, p <0.0001) rather than dry intervals less than 4 hours (7.21, p = 0.08) or number of undergarments (-2.2 to 4.2, p >=0.43). Bladder and bowel health related quality of life was lower with higher quantities of urinary incontinence (a lot -31.2, medium -23.0 and little -17.2 vs none, p <0.0001) but not for dry intervals less than 4 hours (-4.1, p = 0.14). Use of undergarments regardless of number was associated with lower health related quality of life ( 10.2 to -15.4, p <=0.001). Quantity of urinary incontinence was the main predictor of lower WHOQOL-BREF scores. CONCLUSIONS: We report that adults with spina bifida and urinary incontinence have lower health related quality of life than those who are dry. Self-reported quantity of urinary incontinence was the best predictor of bother and health related quality of life. PMID- 26926557 TI - Inhibition of HIF Reduces Bladder Hypertrophy and Improves Bladder Function in Murine Model of Partial Bladder Outlet Obstruction. AB - PURPOSE: Posterior urethral valves are the most common cause of partial bladder outlet obstruction in the pediatric population. However, to our knowledge the etiology and the detailed mechanisms underlying pathological changes in the bladder following partial bladder outlet obstruction remain to be elucidated. Recent findings suggest that hypoxia and associated up-regulation of HIFs (hypoxia-inducible factors) have a key role in partial bladder outlet obstruction induced pathology in the bladder. We examined the effects of pharmacological inhibition of HIF pathways by 17-DMAG (17-(dimethylaminoethylamino)-17 demethoxygeldanamycin) in pathophysiological phenotypes after partial bladder outlet obstruction. MATERIALS AND METHODS: Partial bladder outlet obstruction was surgically created in male C57BL/6J mice. The animals received oral administration of 17-DMAG or vehicle daily starting from the initiation of obstruction up to 5 days. Sham operated mice served as controls. Bladders were harvested from each group 2, 4 and 7 days postoperatively, and analyzed for histological and biochemical changes. Bladder function was assessed by in vitro muscle contractility recordings. RESULTS: Partial bladder outlet obstruction caused a significant increase in the bladder mass accompanying enhanced collagen deposition in the bladder wall while 17-DMAG treatment suppressed those increases. Treatment with 17-DMAG attenuated the degree of up-regulation of HIFs and their target genes involving the development of tissue fibrosis in obstructed bladders. Treatment with 17-DMAG improved the decreased responses of obstructed bladder strips to electrical field stimulation and KCl. CONCLUSIONS: In vivo 17 DMAG treatment decreased partial bladder outlet obstruction induced pathophysiological changes in the bladder. HIF pathway inhibition has a potential clinical implication for the development of novel pharmacological therapies to treat bladder pathology associated with partial bladder outlet obstruction. PMID- 26926558 TI - Nanomechanical probing of soft matter through hydrophobic AFM tips fabricated by two-photon polymerization. AB - Atomic force microscopy (AFM) nanoindentation of soft materials is a powerful tool for probing mechanical properties of biomaterials. Though many results have been reported in this field over the last decade, adhesion forces between the tip and the sample hinder the elastic modulus measurement when hydrophilic soft samples are investigated. Here, two-photon polymerization (2PP) technology was used to fabricate hydrophobic perfluoropolyether-based AFM tips. The hydrophobic 2PP tips allowed us to overcome the limitations of commercial and functionalized tips as well as to successfully measure the elastic modulus of medically relevant soft materials in air. Our results obtained in the characterization of poly(dimethyl siloxane) and polyethylene glycol hydrogels showed lower adhesion forces over a larger measurement range when compared to measurements performed with commercial tips. The elastic moduli measured by means of hydrophobic 2PP AFM tips were also found to be comparable to those obtained using conventional techniques for macroscopic samples. We successfully showed that the hydrophobic AFM tips developed by this highly versatile technology enable the study of mechanical properties of soft matter, benefiting from reduced sample-tip interactions, and a custom-made shape and dimension of the tips. PMID- 26926560 TI - Sharing data of clinical trials. PMID- 26926559 TI - Incident Atrial Fibrillation and Disability-Free Survival in the Cardiovascular Health Study. AB - OBJECTIVES: To assess the associations between incident atrial fibrillation (AF) and disability-free survival and risk of disability. DESIGN: Prospective cohort study. SETTING: Cardiovascular Health Study. PARTICIPANTS: Individuals aged 65 and older and enrolled in fee-for-service Medicare followed between 1991 and 2009 (MN = 4,046). Individuals with prevalent AF, activity of daily living (ADL) disability, or a history of stroke or heart failure at baseline were excluded. MEASUREMENTS: Incident AF was identified according to annual study electrocardiogram, hospital discharge diagnosis, or Medicare claims. Disability free survival was defined as survival free of ADL disability (any difficulty or inability in bathing, dressing, eating, using the toilet, walking around the home, or getting out of a bed or chair). ADLs were assessed at annual study visits or in a telephone interview. Association between incident AF and disability-free survival or risk of disability was estimated using Cox proportional hazards models. RESULTS: Over an average of 7.0 years of follow-up, 660 individuals (16.3%) developed incident AF, and 3,112 (77%) became disabled or died. Incident AF was associated with shorter disability-free survival (hazard ratio (HR) for death or ADL disability = 1.71, 95% confidence interval (CI) = 1.55-1.90) and a higher risk of ADL disability (HR = 1.36, 95% CI = 1.18-1.58) than in individuals with no history of AF. This association persisted after adjustment for interim stroke and heart failure. CONCLUSION: These results suggest that AF is a risk factor for shorter functional longevity in older adults, independent of other risk factors and comorbid conditions. PMID- 26926561 TI - Appropriateness of Proton Pump Inhibitor (PPI) prescription in patients admitted to hospital: Attitudes of general practitioners and hospital physicians in Italy. AB - INTRODUCTION: Proton pump inhibitor (PPI) prescriptions have raised concern for both huge increase of health expenditure and possible long-term adverse effects. OBJECTIVE: To evaluate appropriateness of PPI prescription in ambulatory and hospital care. DESIGN: Observational cohort study. PATIENTS: Patients admitted to the Internal Medicine Unit of Bologna S. Orsola Hospital between 15/09/2013 and 15/12/2013. Data on clinical condition and drug therapy were collected at three time points: admission (reflecting GP's prescription), hospital stay and discharge. MAIN MEASURES: Appropriateness of PPI use was evaluated as follows: (1) agreement between PPI use/non-use and appropriate clinical condition; (2) in PPI users, assessment of Medication Appropriateness Index (MAI). Differences in appropriateness among time points were analyzed by chi-square test. Logistic regression model was used to identify possible determinants of PPI appropriateness. KEY RESULTS: Among 280 patients, 56% received PPI at least once in the three time points. Appropriateness, according to indication of use, was similar between admission and hospital stay (61% vs. 62%; p=0.82) and between hospital stay and discharge (62% vs. 59%; p=0.94). MAI score showed important, although statistically non-significant, change in appropriateness between admission and hospital stay (20% vs. 28%; p=0.16). Age>=65 was always associated with appropriate PPI use (up to OR=4.37; p<0.01), whereas cardiovascular comorbidity and conditions requiring analgesic treatment influenced appropriateness only at admission (OR=3.84; p<0.01 and OR=0.34; p<0.01, respectively). CONCLUSIONS: Hospital clinicians only rarely reconsidered GP's choice to prescribe PPI. Room for improvement in PPI appropriateness is represented by (1) assessing gastrointestinal risk in each patient under analgesics and anti-inflammatory drugs, and (2) short-term re-evaluation of PPI prescription after discharge. PMID- 26926562 TI - Effects of central irisin administration on the uncoupling proteins in rat brain. AB - Irisin is a thermogenic peptide that enables the development of brown adipose tissue from white adipose tissue by activating the UCP1. This study has been designed to determine the effects of the irisin on UCPs. Sprague Dawley female rats were used in the study. 1, 3 and 10MUM concentrations of irisin were injected intracerebroventricularly to the rats, and the control group was received only vehicle. The animals were killed at the 16, 24, and 48h time intervals and their brains were taken out. The hypothalamus, pituitary gland, hippocampus, cerebellum, striatum and cortex areas were separated and the UCP2, UCP3, UCP4 and UCP5 mRNA levels were determined. Just before the animals were killed, their body temperatures were recorded. It was observed that after application of the high dose irisin, UCP5 mRNA level in the all brain areas increased (p<0.05); it was also observed that the three doses decreased the UCP4 expression in all brain areas (except the pituitary gland; p<0.05). The UCP2 and UCP3 mRNA expressions showed significantly increase in cerebellum and striatum (p<0.05). The UCP2 mRNA expression decreased in hypothalamus, pituitary gland, hippocampus and cortex areas (p<0.05). It was also observed that the body temperatures of the rats increased depending on the irisin injection and this increase was the most considerable at the 24h (p<0.05). The results of this study suggest that the UCP2-5 is expressed in different areas of the brain, and the irisin affects this expression, and may have effective roles in some brain functions. PMID- 26926563 TI - Relationship between natural and heme-mediated antibody polyreactivity. AB - Polyreactive antibodies represent a considerable fraction of the immune repertoires. Some antibodies acquire polyreactivity post-translationally after interaction with various redox-active substances, including heme. Recently we have demonstrated that heme binding to a naturally polyreactive antibody (SPE7) results in a considerable broadening of the repertoire of recognized antigens. A question remains whether the presence of certain level of natural polyreactivity of antibodies is a prerequisite for heme-induced further extension of antigen binding potential. Here we used a second monoclonal antibody (Hg32) with unknown specificity and absence of intrinsic polyreactivity as a model to study the potential of heme to induce polyreactivity of antibodies. We demonstrated that exposure to heme greatly extends the antigen binding potential of Hg32, suggesting that the intrinsic binding promiscuity is not a prerequisite for the induction of polyreactivity by heme. In addition we compared the kinetics and thermodynamics of the interaction of heme-exposed antibodies with a panel of unrelated antigens. These analyses revealed that the two heme-sensitive antibodies adopt different mechanisms of binding to the same set of antigens. This study contributes to understanding the phenomenon of induced antibody polyreactivity. The data may also be of importance for understanding of physiological and pathological roles of polyreactive antibodies. PMID- 26926564 TI - Fatty acid esters produced by Lasiodiplodia theobromae function as growth regulators in tobacco seedlings. AB - The Botryosphaeriaceae are a family of trunk disease fungi that cause dieback and death of various plant hosts. This work sought to characterize fatty acid derivatives in a highly virulent member of this family, Lasiodiplodia theobromae. Nuclear magnetic resonance and gas chromatography-mass spectrometry of an isolated compound revealed (Z, Z)-9,12-ethyl octadecadienoate, (trivial name ethyl linoleate), as one of the most abundant fatty acid esters produced by L. theobromae. A variety of naturally produced esters of fatty acids were identified in Botryosphaeriaceae. In comparison, the production of fatty acid esters in the soil-borne tomato pathogen Fusarium oxysporum, and the non-phytopathogenic fungus Trichoderma asperellum was found to be limited. Ethyl linoleate, ethyl hexadecanoate (trivial name ethyl palmitate), and ethyl octadecanoate, (trivial name ethyl stearate), significantly inhibited tobacco seed germination and altered seedling leaf growth patterns and morphology at the highest concentration (0.2 mg/mL) tested, while ethyl linoleate and ethyl stearate significantly enhanced growth at low concentrations, with both still inducing growth at 98 ng/mL. This work provides new insights into the role of naturally esterified fatty acids from L. theobromae as plant growth regulators with similar activity to the well-known plant growth regulator gibberellic acid. PMID- 26926565 TI - Decreased levels of RGS4 in the paraventricular nucleus facilitate GABAergic inhibition during the acute stress response. AB - A healthy acute stress response requires both rapid increase and rapid clearance of blood corticosteroids. We previously showed that regulators of G-protein signaling 4 (RGS4), which decreases in the paraventricular nucleus (PVN) during acute stress, forms a complex with the GABAB receptor. In the present study, we show that this decrease in RGS4 levels in the PVN during an acute stress response facilitates the return of blood corticosteroids to basal levels. Moreover, the effect of RGS4 decrease is attenuated by a GABAB receptor antagonist. These results suggest that RGS4 in the PVN regulates blood corticosteroid-related GABAB receptor signaling during the acute stress response. PMID- 26926566 TI - Prenatal minocycline treatment alters synaptic protein expression, and rescues reduced mother call rate in oxytocin receptor-knockout mice. AB - Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired communication, difficulty in companionship, repetitive behaviors and restricted interests. Recent studies have shown amelioration of ASD symptoms by intranasal administration of oxytocin and demonstrated the association of polymorphisms in the oxytocin receptor (Oxtr) gene with ASD patients. Deficient pruning of synapses by microglial cells in the brain has been proposed as potential mechanism of ASD. Other researchers have shown specific activation of microglial cells in brain regions related to sociality in patients with ASD. Although the roles of Oxtr and microglia in ASD are in the spotlight, the relationship between them remains to be elucidated. In this study, we found abnormal activation of microglial cells and a reduction of postsynaptic density protein PSD95 expression in the Oxtr-deficient brain. Moreover, pharmacological inhibition of microglia during development can alter the expression of PSD95 and ameliorate abnormal mother-infant communication in Oxtr-deficient mice. Our results suggest that microglial abnormality is a potential mechanism of the development of Oxt/Oxtr mediated ASD-like phenotypes. PMID- 26926567 TI - MALAT1 induced migration and invasion of human breast cancer cells by competitively binding miR-1 with cdc42. AB - Competitive endogenous messenger RNAs (ceRNAs) affect other RNAs transcription through competitively binding common microRNAs (miRNAs). In this study we identified long non-coding RNA (lncRNA) MALAT1 can function as a ceRNA of cell division cycle 42 (cdc42) 3'UTR in inducing migration and invasion of breast cancer cells via miR-1. We found that miR-1 bound both MALAT1 and cdc42 3'UTR directly. Further study showed that MALAT1 induced migration and invasion of breast cancer cells while reduced the level of cdc42. Our results suggest that MALAT1 regulated migration and invasion of breast cancer cells via affecting cdc42 through binding miR-1 competitively. PMID- 26926568 TI - Development and evaluation of a multi-locus sequence typing scheme for Mycoplasma synoviae. AB - Reproducible molecular Mycoplasma synoviae typing techniques with sufficient discriminatory power may help to expand knowledge on its epidemiology and contribute to the improvement of control and eradication programmes of this mycoplasma species. The present study describes the development and validation of a novel multi-locus sequence typing (MLST) scheme for M. synoviae. Thirteen M. synoviae isolates originating from different poultry categories, farms and lesions, were subjected to whole genome sequencing. Their sequences were compared to that of M. synoviae reference strain MS53. A high number of single nucleotide polymorphisms (SNPs) indicating considerable genetic diversity were identified. SNPs were present in over 40 putative target genes for MLST of which five target genes were selected (nanA, uvrA, lepA, ruvB and ugpA) for the MLST scheme. This scheme was evaluated analysing 209 M. synoviae samples from different countries, categories of poultry, farms and lesions. Eleven clonal clusters and 76 different sequence types (STs) were obtained. Clustering occurred following geographical origin, supporting the hypothesis of regional population evolution. M. synoviae samples obtained from epidemiologically linked outbreaks often harboured the same ST. In contrast, multiple M. synoviae lineages were found in samples originating from swollen joints or oviducts from hens that produce eggs with eggshell apex abnormalities indicating that further research is needed to identify the genetic factors of M. synoviae that may explain its variations in tissue tropism and disease inducing potential. Furthermore, MLST proved to have a higher discriminatory power compared to variable lipoprotein and haemagglutinin A typing, which generated 50 different genotypes on the same database. PMID- 26926569 TI - Facile fabrication of organic/inorganic nanotube heterojunction arrays for enhanced photoelectrochemical water splitting. AB - Organic/inorganic heterojunction photoanodes are appealing for making concurrent use of the highly photoactive organic semiconductors, and the efficient dielectric screening provided by their inorganic counterparts. In the present work, organic/inorganic nanotube heterojunction arrays composed of TiO2 nanotube arrays and a semiconducting N,N-(dicyclohexyl) perylene-3,4,9,10-tetracarboxylic diimide (PDi) layer were fabricated for photoelectrochemical water splitting. In this arrayed architecture, a PDi layer with a tunable thickness was coated on anodic TiO2 nanotube arrays by physical vapor deposition, which is advantageous for the formation of a uniform layer and an adequate interface contact between PDi and TiO2. The obtained PDi/TiO2 junction exhibited broadened visible light absorption, and an effective interface for enhanced photogenerated electron-hole separation, which is supported by the reduced charge transfer resistance and prolonged excitation lifetime via impedance spectroscopy analysis and fluorescence emission decay investigations. Consequently, such a heterojunction photoanode was photoresponsive to a wide visible light region of 400-600 nm, and thus demonstrated a highly enhanced photocurrent density at 1.23 V vs. a reversible hydrogen electrode. Additionally, the durability of such a photoanode can be guaranteed after long-time illumination because of the geometrical restraint imposed by the PDi aggregates. These results pave the way to discover new organic/inorganic assemblies for high-performance photoelectric applications and device integration. PMID- 26926570 TI - All-atom simulations and free-energy calculations of coiled-coil peptides with lipid bilayers: binding strength, structural transition, and effect on lipid dynamics. AB - Peptides E and K, which are synthetic coiled-coil peptides for membrane fusion, were simulated with lipid bilayers composed of lipids and cholesterols at different ratios using all-atom models. We first calculated free energies of binding from umbrella sampling simulations, showing that both E and K peptides tend to adsorb onto the bilayer surface, which occurs more strongly in the bilayer composed of smaller lipid headgroups. Then, unrestrained simulations show that K peptides more deeply insert into the bilayer with partially retaining the helical structure, while E peptides less insert and predominantly become random coils, indicating the structural transition from helices to random coils, in quantitative agreement with experiments. This is because K peptides electrostatically interact with lipid phosphates, as well as because hydrocarbons of lysines of K peptide are longer than those of glutamic acids of E peptide and thus form stronger hydrophobic interactions with lipid tails. This deeper insertion of K peptide increases the bilayer dynamics and a vacancy below the peptide, leading to the rearrangement of smaller lipids. These findings help explain the experimentally observed or proposed differences in the insertion depth, binding strength, and structural transition of E and K peptides, and support the snorkeling effect. PMID- 26926574 TI - ERRATUM: Observed and expected frequencies of structural hemoglobin variants in newborn screening surveys in Africa and the Middle East: deviations from Hardy Weinberg equilibrium. PMID- 26926571 TI - Optoelectrofluidic enhanced immunoreaction based on optically-induced dynamic AC electroosmosis. AB - We report a novel optoelectrofluidic immunoreaction system based on electroosmotic flow for enhancing antibody-analyte binding efficiency on a surface-based sensing system. Two conventional indium tin oxide glass slides are assembled to provide a reaction chamber for a tiny volume of sample droplet (~5 MUL), in which the top layer is employed as an antibody-immobilized substrate and the bottom layer acts as a photoconductive layer of an optoelectrofluidic device. Under the application of an AC voltage, an illuminated light pattern on the photoconductive layer causes strong counter-rotating vortices to transport analytes from the bulk solution to the vicinity of the assay spot on the glass substrate. This configuration overcomes the slow immunoreaction problem of a diffusion-based sensing system, resulting in the enhancement of binding efficiency via an optoelectrofluidic method. Furthermore, we investigate the effect of optically-induced dynamic AC electroosmotic flow on optoelectrofluidic enhancement for surface-based immunoreaction with a mathematical simulation study and real experiments using immunoglobulin G (IgG) and anti-IgG. As a result, dynamic light patterns provided better immunoreaction efficiency than static light patterns due to effective mass transport of the target analyte, resulting in an achievement of 2.18-fold enhancement under a growing circular light pattern compared to the passive mode. PMID- 26926575 TI - Duodenal fatty acid sensor and transporter expression following acute fat exposure in healthy lean humans. AB - BACKGROUND & AIMS: Free fatty acids (FFAs) and their derivatives are detected by G-protein coupled receptors (GPRs) on enteroendocrine cells, with specific transporters on enterocytes. It is unknown whether acute fat exposure affects FFA sensors/transporters, and whether this relates to hormone secretion and habitual fat intake. METHODS: We studied 20 healthy participants (10M, 10F; BMI: 22 +/- 1 kg/m2; age: 28 +/- 2 years), after an overnight fast, on 2 separate days. On the first day, duodenal biopsies were collected endoscopically before, and after, a 30-min intraduodenal (ID) infusion of 10% Intralipid(r), and relative transcript expression of FFA receptor 1 (FFAR1), FFA receptor 4 (FFAR4), GPR119 and the FFA transporter, cluster of differentiation-36 (CD36) was quantified from biopsies. On the second day, ID Intralipid(r) was infused for 120-min, and plasma concentrations of cholecystokinin (CCK) and glucagon-like peptide-1 (GLP-1) evaluated. Habitual dietary intake was assessed using food frequency questionnaires (FFQs). RESULTS: ID Intralipid(r) increased expression of GPR119, but not FFAR1, FFAR4 and CD36, and stimulated CCK and GLP-1 secretion. Habitual polyunsaturated fatty acid (PUFA) consumption was negatively associated with basal GPR119 expression. CONCLUSIONS: GPR119 is an early transcriptional responder to duodenal lipid in lean humans, although this response appeared reduced in individuals with high PUFA intake. These observations may have implications for downstream regulation of gut hormone secretion and appetite. This study was registered as a clinical trial with the Australia and New Zealand Clinical Trial Registry (Trial number: ACTRN12612000376842). PMID- 26926576 TI - Oxidative stress, HDL functionality and effects of intravenous iron administration in women with iron deficiency anemia. AB - BACKGROUND AND AIMS: Iron deficiency anemia (IDA) affects around 20-30% of adults worldwide. An association between IDA and cardiovascular disease (CVD) has been reported. Oxidative stress, inflammation and low concentration of high-density lipoproteins (HDL) were implicated on endothelial dysfunction and CVD in IDA. We studied the effects of iron deficiency and of an intravenous iron administration on oxidative stress and HDL characteristics in IDA women. METHODS: Two studies in IDA women are presented: a case-control study, including 18 patients and 18 age matched healthy women, and a follow-up study 72hr after the administration of intravenous iron (n = 16). Lipids, malondialdehyde, cholesteryl ester transfer protein (CETP), paraoxonase-1 (PON-1) and HDL chemical composition and functionality (cholesterol efflux and antioxidative activity) were measured. Cell cholesterol efflux from iron-deficient macrophages to a reference HDL was also evaluated. RESULTS: IDA patients showed higher triglycerides and CETP activity and lower HDL-C than controls (all p < 0.001). HDL particles from IDA patients showed higher triglyceride content (+30%,p < 0.05) and lower antioxidative capacity (-23%,p < 0.05). Although HDL-mediated cholesterol efflux was similar between the patients and controls, iron deficiency provoked a significant reduction in macrophage cholesterol efflux (-25%,p < 0.05). Arylesterase activity of PON-1 was significantly lower in IDA patients than controls (-16%,p < 0.05). The intravenous administration of iron was associated with a decrease in malondialdehyde levels and an increase in arylesterase activity of PON-1 (-22% and +18%, respectively, p < 0.05). CONCLUSION: IDA is associated with oxidative stress and functionally deficient HDL particles. It remains to be determined if such alterations suffice to impair endothelial function in IDA. PMID- 26926577 TI - Distinguishing N-acetylneuraminic acid linkage isomers on glycopeptides by ion mobility-mass spectrometry. AB - Differentiating the structure of isobaric glycopeptides represents a major challenge for mass spectrometry-based characterisation techniques. Here we show that the regiochemistry of the most common N-acetylneuraminic acid linkages of N glycans can be identified in a site-specific manner from individual glycopeptides using ion mobility-mass spectrometry analysis of diagnostic fragment ions. PMID- 26926578 TI - Aligned Nanofibers from Polypyrrole/Graphene as Electrodes for Regeneration of Optic Nerve via Electrical Stimulation. AB - The damage of optic nerve will cause permanent visual field loss and irreversible ocular diseases, such as glaucoma. The damage of optic nerve is mainly derived from the atrophy, apoptosis or death of retinal ganglion cells (RGCs). Though some progress has been achieved on electronic retinal implants that can electrically stimulate undamaged parts of RGCs or retina to transfer signals, stimulated self-repair/regeneration of RGCs has not been realized yet. The key challenge for development of electrically stimulated regeneration of RGCs is the selection of stimulation electrodes with a sufficient safe charge injection limit (Q(inj), i.e., electrochemical capacitance). Most traditional electrodes tend to have low Q(inj) values. Herein, we synthesized polypyrrole functionalized graphene (PPy-G) via a facile but efficient polymerization-enhanced ball milling method for the first time. This technique could not only efficiently introduce electron-acceptor nitrogen to enhance capacitance, but also remain a conductive platform-the pi-pi conjugated carbon plane for charge transportation. PPy-G based aligned nanofibers were subsequently fabricated for guided growth and electrical stimulation (ES) of RGCs. Significantly enhanced viability, neurite outgrowth and antiaging ability of RGCs were observed after ES, suggesting possibilities for regeneration of optic nerve via ES on the suitable nanoelectrodes. PMID- 26926579 TI - A longitudinal investigation of the relationship between crowding and reading: A neurodegenerative approach. AB - We have previously documented two patients (FOL and CLA) with posterior cortical atrophy who achieved accurate and rapid reading despite deficits in ten measures of visual processing, with two notable exceptions: (1) a measure of visual acuity, (2) a measure of visual crowding. Subsequent longitudinal investigation of these patients was carried out, involving annual tests of early visual, visuoperceptual and visuospatial processing and assessment of reading ability. Follow-up assessments identified the evolution of a particular early visual processing deficit, excessive visual crowding; this deficit has been previously implicated in forms of dyslexia. Consistent with the link between crowding and reading dysfunction, follow-up assessments also revealed deterioration in both patients' reading ability. The current findings demonstrate a neurodegenerative approach towards understanding the relationship between visual crowding and the reading system, and suggest possible mechanisms for how excessive crowding may disrupt word recognition. PMID- 26926581 TI - Platelet Physiology. AB - Platelets are the smallest blood cells, numbering 150 to 350 * 10(9)/L in healthy individuals. The ability of activated platelets to adhere to an injured vessel wall and form aggregates was first described in the 19th century. Besides their long-established roles in thrombosis and hemostasis, platelets are increasingly recognized as pivotal players in numerous other pathophysiological processes including inflammation and atherogenesis, antimicrobial host defense, and tumor growth and metastasis. Consequently, profound knowledge of platelet structure and function is becoming more important in research and in many fields of modern medicine. This review provides an overview of platelet physiology focusing particularly on the structure, granules, surface glycoproteins, and activation pathways of platelets. PMID- 26926582 TI - Platelets in Critical Illness. AB - In patients with critical illness, thrombocytopenia is a frequent laboratory abnormality. However frequent this may occur, a low platelet count is not an epiphenomenon, but a marker with further significance. It is always important to assess the proper cause for thrombocytopenia in critically ill patients because different underlying disorders may precipitate different diagnostic and therapeutic management strategies. Platelets are part of the first-line defense of the body against bleeding; hence, thrombocytopenia may increase the risk of hemorrhage. In case of systemic inflammatory syndromes, such as the response to sepsis, disseminated intravascular platelet activation may occur. This will contribute to microvascular failure and thereby play a role in the development of organ dysfunction. Platelets are circulating blood cells that will normally not interact with the intact vessel wall but that may swiftly respond to endothelial disruption (which is often part of the pathogenesis of critical illness) by adhering to subendothelial structures, followed by interaction with each other, thereby forming a platelet aggregate. The activated platelet (phospholipid) membrane may form a suitable surface on which further coagulation activation may occur. A low platelet count is a strong and independent predictor of an adverse outcome in critically ill patients, thereby facilitating a simple and practically risk assessment in these patients and potentially guiding the use of complex or expensive treatment strategies. PMID- 26926580 TI - Interactive effects of age and multi-gene profile on motor learning and sensorimotor adaptation. AB - The interactive association of age and dopaminergic polymorphisms on cognitive function has been studied extensively. However, there is limited research on whether age interacts with the association between genetic polymorphisms and motor learning. We examined a group of young and older adults' performance in three motor tasks: explicit sequence learning, visuomotor adaptation, and grooved pegboard. We assessed whether individuals' motor learning and performance were associated with their age and genotypes. We selected three genetic polymorphisms: Catechol-O-Methyl Transferase (COMT val158met) and Dopamine D2 Receptor (DRD2 G>T), which are involved with dopaminergic regulation, and Brain Derived Neurotrophic Factor (BDNF val66met) that modulates neuroplasticity and has been shown to interact with dopaminergic genes. Although the underlying mechanisms of the function of these three genotypes are different, the high performance alleles of each have been linked to better learning and performance. We created a composite polygene score based on the Number of High Performance Alleles (NHPA) that each individual carried. We found several associations between genetic profile, motor performance, and sensorimotor adaptation. More importantly, we found that this association varies with age, task type, and engagement of implicit versus explicit learning processes. PMID- 26926583 TI - Platelet Function Tests. AB - Traditionally developed for diagnosis of bleeding disorders, platelet function assays have become increasingly used in basic research on platelet physiology, in phenotype-genotype associations in bleeding disorders, in drug development as surrogate endpoints of efficacy of new antiplatelet therapy, and to an extent, in the monitoring of antiplatelet therapy in clinical practice to predict thrombotic and bleeding risk. A multiplicity of platelet function assays is available to measure the level of platelet activity in various settings. These include assays that are restricted to a specialized laboratory as well as point-of-care instruments meant to investigate platelet function at patient bedside. Unlike tests that determine a defined quantity or measurement of a clinical biomarker (e.g., cholesterol or blood pressure), platelet function testing assesses the dynamics of living cells, which immediately presents a series of unique problems to any laboratory or clinic. This article presents currently used platelet function assays and discusses important variables to take into account when performing these assays, including preanalytical issues and difficulties in interpreting platelet function test results. PMID- 26926584 TI - The Role of Platelets in Venous Thromboembolism. AB - Multiple factors contribute to the risk of venous thromboembolism (VTE). Platelets have attracted much interest in arterial cardiovascular disease, whereas their role in VTE has received much less attention. Recent evidence suggests that platelets may play a more important role in VTE than previously anticipated. This review discusses the mechanisms that link platelets with venous thrombotic disease and their potential applications as novel risk factors for VTE. In addition, animal studies and randomized clinical trials that highlight the potential effect of antiplatelet therapy in venous thrombosis are evaluated to assess the role of platelets in VTE. The clinical significance of platelets for VTE risk assessment in specific patient cohorts and their role as a suitable therapeutic target for VTE prevention is acknowledged. The role of platelets in VTE is a promising field for future research. PMID- 26926585 TI - Platelets as Biomarkers of Coronary Artery Disease. AB - Primary and secondary prevention of cardiovascular disease remain a public health priority. Effective risk stratification of patients is a central requisite for effective preventative care and several scoring systems incorporating biomarkers have been used for prognostication in patients to guide intervention decisions. Thrombosis of atherosclerotic coronary arteries is the main mechanism behind the acute coronary syndromes and since platelets play a pivotal role in the pathogenesis of thrombosis, atherogenesis, and angiogenesis, platelet-derived biomarkers are an attractive concept. This review assesses the potential and the limitations of a range of platelet-based assays as biomarkers for coronary artery disease. PMID- 26926586 TI - A triterpenoid from wild bitter gourd inhibits breast cancer cells. AB - The antitumor activity of 3beta,7beta,25-trihydroxycucurbita-5,23(E)-dien-19-al (TCD), a triterpenoid isolated from wild bitter gourd, in breast cancer cells was investigated. TCD suppressed the proliferation of MCF-7 and MDA-MB-231 breast cancer cells with IC50 values at 72 h of 19 and 23 MUM, respectively, via a PPARgamma-independent manner. TCD induced cell apoptosis accompanied with pleiotrophic biological modulations including down-regulation of Akt-NF-kappaB signaling, up-regulation of p38 mitogen-activated protein kinase and p53, increased reactive oxygen species generation, inhibition of histone deacetylases protein expression, and cytoprotective autophagy. Together, these findings provided the translational value of TCD and wild bitter gourd as an antitumor agent for patients with breast cancer. PMID- 26926587 TI - Morbid obesity in a young woman affected by advanced chronic kidney disease: an exceptional case report. Does a high dose of essential amino acids play a key role in therapeutic success? AB - A 38-year-old woman, obese (219 kg), diabetic, hypertensive, chronic kidney disease (CKD) stage 4, with low plasma albumin level (2.9 g dl(-1)) and marked proteinuria (22 g per day) was studied. Given the advanced-stage CKD with nephrotic proteinuria, we supplemented low-protein diet with high doses of a tailored essential amino acid mixture (AAs: 44 g per day) to improve weight reduction in the patient. After 20 months of conservative therapy, the patient lost 43 kg; despite two episodes of infection, albumin plasma levels increased up to 3.7 g per day. After a further 20 months of dialysis, the patient maintained a diet of 1800 kcal supplemented with 32 g of AAs and lost 47 kg, whereas both albumin (3.89+/-0.12 g dl(-1)) and C reactive protein returned to normal. During the follow-up period, anemia improved, erythropoietin was thus discontinued and insulin requirement decreased to 105 IU. This therapeutic option may be beneficial in advanced CKD patients with obesity and diabetes resulting from malnutrition. PMID- 26926588 TI - Weight loss is associated with plasma free amino acid alterations in subjects with metabolic syndrome. AB - OBJECTIVES: The prevalence of metabolic syndrome is increasing worldwide, especially in Asian populations. Early detection and effective intervention are vital. Plasma free amino acid profile is a potential biomarker for the early detection for lifestyle-related diseases. However, little is known about whether the altered plasma free amino acid profiles in subjects with metabolic syndrome are related to the effectiveness of dietary and exercise interventions. METHODS: Eighty-five Japanese subjects who fulfilled the Japanese diagnostic criteria for metabolic syndrome were enrolled in a 3-month diet and exercise intervention. The plasma free amino acid concentrations and metabolic variables were measured, and the relationships between plasma free amino acid profiles, metabolic variables and the extent of body weight reduction were investigated. Those who lost more than 3% of body weight were compared with those who lost less than 3%. RESULTS: Baseline levels of most amino acids in the subset that went on to lose <3% body weight were markedly lower compared with the counterpart, although both groups showed similar proportional pattern of plasma amino acid profiles. The weight loss induced by the diet and exercise intervention normalized plasma free amino acid profiles. For those with a high degree of weight loss, those changes were also associated with improvement in blood pressure, triglyceride and hemoglobin A1c levels. CONCLUSIONS: These data suggest that among Japanese adults meeting the criteria for metabolic syndrome, baseline plasma free amino acid profiles may differ in ways that predict who will be more vs less beneficially responsive to a standard diet and exercise program. Plasma free amino acid profiles may also be useful as markers for monitoring the risks of developing lifestyle-related diseases and measuring improvement in physiological states. PMID- 26926589 TI - The first-door-to-balloon time delay in STEMI patients undergoing interhospital transfer. AB - BACKGROUND: Interhospital transfer delays for ST-elevation myocardial infarction (STEMI) patients requiring primary percutaneous coronary intervention (PCI) may be shortened by improved regional care systems. We evaluated the transfer process and first door-to-balloon (D1toB) time in STEMI patients who underwent interhospital transfer for primary PCI. METHODS AND RESULTS: We evaluated the D1toB time in 1837 patients who underwent interhospital transfer for primary PCI from the Cardiovascular Disease Surveillance program in Korea. Only 29.3% of patients had a D1toB time less than 120 minutes, as recommended by the American College of Cardiology Foundation/American Heart Association guidelines for the management of STEMI. After adjusting for potential confounders, chest pain at presentation (adjusted odds ratio [AOR], 2.06; 95% confidence interval [CI], 1.18 3.83), transfer to a PCI center with an annual PCI volume greater than 200 (AOR, 1.35; 95% CI, 1.04-1.74), and higher urbanization level (AOR, 2.01 [95% CI, 1.40 2.91], for urban areas; AOR, 3.70 [95% CI, 2.59-3.83], for metropolitan areas) showed beneficial effects on reducing the D1toB time. The median length of stay in the referring hospital (D1LOS) and interhospital transport time were 50 (interquartile range [IQR], 30-100) minutes and 32 (IQR, 20-51) minutes, respectively. The median time interval from the door of the receiving hospital to balloon insertion was 55 (IQR, 40-79) minutes. CONCLUSIONS: Patients with STEMI undergoing interhospital transfer did not receive definite care within the recommended therapeutic time window. Delays in the transfer process (length of stay in the referring hospital and interhospital transport time) were major contributors to the delay in the D1toB time. PMID- 26926590 TI - TRAIL-CM4 fusion protein shows in vitro antibacterial activity and a stronger antitumor activity than solo TRAIL protein. AB - A TRAIL-CM4 fusion protein in soluble form with tumor selective apoptosis and antibacterial functions was expressed in the Escherichia coli expression system and isolated through dialysis refolding and histidine-tag Nickel-affinity purification. Fresh Jurkat cells were treated with the TRAIL-CM4 fusion protein. Trypan blue staining and MTT analyses showed that, similar to a TRAIL positive control, Jurkat cell proliferation was significantly inhibited. Flow cytometry analyses using Annexin V-fluorescein revealed that Jurkat cells treated with the TRAIL-CM4 fusion protein exhibited increased apoptosis. Laser confocal microscopy showed that APB-CM4 and the fusion protein TRAIL-CM4 can bind to Jurkat cell membranes and initiate their destruction. ABP-CM4 enhances the antitumor activity of TRAIL by targeting and damaging the tumor cell membrane. In antibacterial experiments, agar well diffusion and bacterial growth inhibition curve assays revealed concentration-dependent TRAIL-CM4 antibacterial activity against Escherichia coli K12D31. The expressed TRAIL-CM4 fusion protein exhibited enhanced antitumor and antibacterial activities. Fusion protein expression allowed the two different proteins to function in combination. PMID- 26926591 TI - Electrochemically exfoliated graphene anodes with enhanced biocurrent production in single-chamber air-breathing microbial fuel cells. AB - Microbial fuel cells (MFCs) present promising options for environmentally sustainable power generation especially in conjunction with waste water treatment. However, major challenges remain including low power density, difficult scale-up, and durability of the cell components. This study reports enhanced biocurrent production in a membrane-free MFC, using graphene microsheets (GNs) as anode and MnOx catalyzed air cathode. The GNs are produced by ionic liquid assisted simultaneous anodic and cathodic electrochemical exfoliation of iso-molded graphite electrodes. The GNs produced by anodic exfoliation increase the MFC peak power density by over 300% compared to plain carbon cloth (i.e., 2.85Wm(-2) vs 0.66Wm(-2), respectively), and by 90% compared to conventional carbon black (i.e., Vulcan XC-72) anode. These results exceed previously reported power densities for graphene-containing MFC anodes. The fuel cell polarization results are corroborated by electrochemical impedance spectroscopy indicating three times lower charge transfer resistance for the GN anode. Material characterizations suggest that the best performing GN samples were of relatively smaller size (~500nm), with higher levels of ionic liquid induced surface functionalization during the electrochemical exfoliation process. PMID- 26926592 TI - Sensitive SERS detection of DNA methyltransferase by target triggering primer generation-based multiple signal amplification strategy. AB - A novel and sensitive surface-enhanced Raman scattering (SERS) method is proposed for the assay of DNA methyltransferase (MTase) activity and evaluation of inhibitors by developing a target triggering primer generation-based multiple signal amplification strategy. By using of a duplex substrate for Dam MTase, two hairpin templates and a Raman probe, multiple signal amplification mode is achieved. Once recognized by Dam MTase, the duplex substrate can be cleaved by Dpn I endonuclease and two primers are released for triggering the multiple signal amplification reaction. Consequently, a wide dynamic range and remarkably high sensitivity are obtained under isothermal conditions. The detection limit is 2.57*10(-4)UmL(-1). This assay exhibits an excellent selectivity and is successfully applied in the screening of inhibitors for Dam MTase. In addition, this novel sensing system is potentially universal as the recognition element can be conveniently designed for other target analytes by changing the substrate of DNA MTase. PMID- 26926593 TI - Dopaminergic receptor-ligand binding assays based on molecularly imprinted polymers on quartz crystal microbalance sensors. AB - Molecularly imprinted polymers (MIPs) have been successfully applied as selective materials for assessing the binding activity of agonist and antagonist of dopamine D1 receptor (D1R) by using quartz crystal microbalance (QCM). In this study, D1R derived from rat hypothalamus was used as a template and thus self organized on stamps. Those were pressed into an oligomer film consisting of acrylic acid: N-vinylpyrrolidone: N,N'-(1,2-dihydroxyethylene) bis-acrylamide in a ratio of 2:3:12 spin coated onto a dual electrode QCM. Such we obtained one D1R MIP-QCM electrode, whereas the other electrode carried the non-imprinted control polymer (NIP) that had remained untreated. Successful imprinting of D1R was confirmed by AFM. The polymer can re-incorporate D1R leading to frequency responses of 100-1200Hz in a concentration range of 5.9-47.2uM. In a further step such frequency changes proved inherently useful for examining the binding properties of test ligands to D1R. The resulting mass-sensitive measurements revealed Kd of dopamine?HCl, haloperidol, and (+)-SCH23390 at 0.874, 25.6, and 0.004nM, respectively. These results correlate well with the values determined in radio ligand binding assays. Our experiments revealed that D1R-MIP sensors are useful for estimating the strength of ligand binding to the active single site. Therefore, we have developed a biomimetic surface imprinting strategy for QCM studies of D1R-ligand binding and presented a new method to ligand binding assay for D1R. PMID- 26926594 TI - Socio-economic differences in cardiometabolic risk markers are mediated by diet and body fatness in 8- to 11-year-old Danish children: a cross-sectional study. AB - OBJECTIVE: To explore whether socio-economic differences exist in cardiometabolic risk markers in children and whether lifestyle-related factors potentially mediate these differences. DESIGN: Cross-sectional study including measurements of fasting blood lipids, glucose, homeostasis model assessment of insulin resistance (HOMA-IR), blood pressure and heart rate. Potential mediators examined were fat mass index (FMI); intakes of fruit, vegetables, dietary fibre and added sugar; whole-blood n-3 long-chain PUFA (LCPUFA) as a biomarker of fish intake; and physical activity and sedentary time. SETTING: Nine primary schools in Denmark. SUBJECTS: Children aged 8-11 years (n 715). RESULTS: Children of parents with the shortest compared with longest education had higher TAG by 0.12 (95 % CI 0.04, 0.21) mmol/l and HOMA-IR by 0.36 (0.10, 0.62), whereas children of parents with a vocational education had higher total cholesterol by 0.14 (0.02, 0.27) mmol/l and LDL cholesterol by 0.14 (0.03, 0.25) mmol/l compared with children of parents with the longest education; all P<0.05. FMI explained 25 % of the difference in TAG, 64 % of the difference in HOMA-IR and 21-29 % of the differences in cholesterols. FMI and whole-blood n-3 LCPUFA combined explained 42 % of the difference in TAG, whereas FMI, whole-blood n-3 LCPUFA and dietary fibre explained 89 % of the difference in HOMA-IR. CONCLUSIONS: Socio-economic differences were present in blood lipids and insulin resistance among 8- to 11 year-olds and were mediated by body fatness, whole-blood n-3 LCPUFA and dietary fibre. These lifestyle factors may be targets in public initiatives to reduce socio-economic differences. Confirmation in longitudinal studies and trials is warranted. PMID- 26926595 TI - A dual inhibition: microRNA-552 suppresses both transcription and translation of cytochrome P450 2E1. AB - MicroRNAs (miRNAs) can direct post-transcriptional or transcriptional gene silencing. Here, we report that miR-552 is in the nucleus and cytosol and inhibits human cytochrome P450 (CYP) 2E1 expression at both transcriptional and post-transcriptional levels. MiR-552 via its non-seed sequence forms hybrids with a loop hairpin of the cruciform structure in CYP2E1 promoter region to inhibit SMARCE1 and RNA polymerase II binding to the promoter and CYP2E1 transcription. Expressing SMARCE1 reverses the inhibitory effects of miR-552 on CYP2E1 mRNA expression. MiR-552 with mutations in non-seed region losses its transcriptional, but retains its post-transcriptional repression to CYP2E1. In contrast, mutation in miR-552 seed sequence suppresses its inhibitory effects on CYP2E1 expression at protein, but not at mRNA, levels. Our results suggest that miR-552 is a miRNA with a dual inhibitory ability at transcriptional and post-transcriptional levels leading to an effective inhibition. PMID- 26926596 TI - Cyclic AMP Affects Oocyte Maturation and Embryo Development in Prepubertal and Adult Cattle. AB - High cAMP levels during in vitro maturation (IVM) have been related to improved blastocyst yields. Here, we employed the cAMP/cGMP modulators, forskolin, IBMX, and cilostamide, during IVM to unravel the role of high cAMP in early embryonic development produced from prepubertal and adult bovine oocytes. Oocytes were collected via transvaginal aspiration and randomly assigned to three experimental groups: TCM24 (24 h IVM/control), cAMP30 (2 h pre-IVM (forskolin-IBMX), 30 h IVM cilostamide), and DMSO30 (Dimethyl Sulfoxide/vehicle control). After IVM, oocytes were fertilized in vitro and zygotes were cultured in vitro to blastocysts. Meiotic progression, cAMP levels, mRNA abundance of selected genes and DNA methylation were evaluated in oocytes. Blastocysts were used for gene expression or DNA methylation analyses. Blastocysts from the cAMP30 groups were transferred to recipients. The cAMP elevation delayed meiotic progression, but developmental rates were not increased. In immature oocytes, mRNA abundance of PRKACA was higher for cAMP30 protocol and no differences were found for PDE3A, SMAD2, ZAR1, PRDX1 and SLC2A8. EGR1 gene was up-regulated in prepubertal cAMP30 immature oocytes and down-regulated in blastocysts from all in vitro treatments. A similar gene expression profile was observed for DNMT3b, BCL2L1, PRDX1 and SLC2A8 in blastocysts. Satellite DNA methylation profiles were different between prepubertal and adult oocytes and blastocysts derived from the TCM24 and DMSO30 groups. Blastocysts obtained from prepubertal and adult oocytes in the cAMP30 treatment displayed normal methylation profiles and produced offspring. These data indicate that cAMP regulates IVM in prepubertal and adult oocytes in a similar manner, with impact on the establishment of epigenetic marks and acquisition of full developmental competency. PMID- 26926597 TI - Evaluation of the endothelial glycocalyx damage in patients with acute coronary syndrome. AB - BACKGROUND: Endothelial glycocalyx (EG) is sugar-based cell-bound surface molecules linked to transmembrane proteins observed on the endothelial surface of the vessels. Damage to this structure causes an increase in platelet and leucocyte adhesion and shear stress in the vessel. We hypothesized a possible link between EG damage and acute coronary syndrome (ACS). METHODS: We measured the syndecan-1 levels (a biomarker of EG damage) in 141 patients (99 men) with ACS and compared to those of 45 patients (24 men) with non-coronary chest pain (NCCP) and of 24 (14 men) healthy individuals (CONTROL). RESULTS: The baseline characteristics of the ACS and NCCP groups were similar. Syndecan-1 levels were significantly higher in the ACS group than in the NCCP (p = 0.01) and CONTROL (p = 0.001) groups but did not differ between the NCCP and CONTROL groups (p = 0.83). In analysis according to gender category, the difference among the groups remained significant only for men (p = 0.0009). A syndecan-1 level higher than 148 ng/ml was associated with ACS diagnosis with an odds ratio of 14 (95% confidence interval (CI): 1.8 to 102), p = 0.011. After adjusting for gender, age and current or past tobacco use, this syndecan-1 level remained positively associated with ACS diagnosis with an odds ratio of 12 (95% CI: 1.6 to 93), p = 0.016. CONCLUSION: Higher syndecan-1 levels were observed during ACS, mostly in men, suggesting that EG damage could participate in the atherosclerotic plaque vulnerability process in these patients. PMID- 26926598 TI - Role of PCSK9 antibodies in cardiovascular disease: Critical considerations of mortality and neurocognitive findings from the current literature. AB - Monoclonal antibodies targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) are a novel lipid-lowering approach found to improve clinical outcomes in patients with dyslipidemia. With coronary artery disease remaining the most frequent cause of morbidity and mortality worldwide, a drug offering a true mortality reduction should be appropriately regarded as a novel blockbuster in cardiovascular medicine, provided that significant side effects do not emerge. However, a recent study may suggest an increase of neurocognitive adverse events with those drugs. A critical overview of current evidence on neurocognitive outcomes as well as the meta-analytical approach with open-label extension trials evaluating PCSK9 monoclonal antibodies is needed to avoid potential controversy. PMID- 26926599 TI - Serum androgen concentrations and subclinical measures of cardiovascular disease in men and women. AB - OBJECTIVES: Most of the observed associations of androgens and sex hormone binding globulin (SHBG) with subclinical cardiovascular disease (CVD) stem from selected study samples with immunoassay-based hormone measurements. Thus, we used a large population-based sample with total testosterone (TT) and androstenedione (ASD) concentrations measured by liquid chromatography-tandem mass spectrometry. DESIGN: Data of 2140 individuals (mean age: 60,8 years) from the cohort Study of Health in Pomerania were assessed at baseline and 5-year follow-up. METHODS: Multivariable regression models were implemented to assess cross-sectional and longitudinal associations of TT, free testosterone (fT), ASD, SHBG and dehydroepiandrosterone-sulphate (DHEAS) with measures of subclinical CVD including intima media thickness (IMT), carotid plaques, left ventricular mass (LVM), fractional shortening (FS), relative wall thickness (RWT), and left ventricular geometry. RESULTS: Cross-sectional analyses yielded an association of TT with IMT in women (beta-coefficient per log unit increase: 0.02; 95% CI: 0.007; 0.45) and ASD with FS in both sexes (men: beta-coefficient: -2.94; 95% CI: -4.75; -1.12; women: beta-coefficient: 1.64; 95% CI: 0.55; 2.73). In longitudinal analyses, DHEAS was positively associated with FS change (beta-coefficient: 2.34; 95% CI: -0.59; 4.08). In women, SHBG was positively associated with incident plaques (Q1 vs. Q3 (Ref.): beta-coefficient: 1.35; 95% CI: 1.04; 1.74). In both sexes, longitudinal analyses showed no consistent association of TT with subclinical CVD. CONCLUSIONS: Despite several sex-specific associations of androgens and SHBG with subclinical CVD, the present representative study for the age group >=45 years among men and women from the general population detected no consistent associations in longitudinal analyses. PMID- 26926600 TI - Smoking is associated with lower amounts of arterial type I collagen and decorin. AB - BACKGROUND: Smoking affects the arterial wall and increases the risk of cardiovascular disease. It also affects the extracellular matrix in skin, causing impaired wound healing. However, little is known about putative molecular changes in the arterial wall. Our aim was to investigate the possible correlation between extracellular matrix content in arterial tissue and cigarette smoking. METHODS: We studied the non-atherosclerotic arterial wall of the internal mammary artery from coronary artery by-pass surgery in 13 never-smokers and 11 active smokers. Using histomorphometric methods, the area fraction of collagen stainable material was determined. In addition, proteome analysis of matrix molecules and other proteins was performed. RESULTS: The area fraction of collagen stainable material in smokers vs. never-smokers was 29.1% +/- 3.8% vs. 43.3% +/- 3.6% (mean +/- SEM, p = 0.012) in tunica intima, 39.7% +/- 5.5% vs. 56.8% +/- 5.6% (mean +/- SEM, p = 0.042) in tunica media, and 50.4% +/- 3.9% vs. 61.0% +/- 3.2% (mean +/- SEM, p = 0.046) in tunica adventitia. We discovered significantly lower relative levels of collagen alpha1(I) (0.68 +/- 0.048 vs. 1.02 +/- 0.112, mean +/- SEM, p = 0.013), collagen alpha2(I) (0.81 +/- 0.046 vs. 1.14 +/- 0.118, mean +/- SEM, p = 0.038) and decorin (0.64 +/- 0.04 vs. 0.98 +/- 0.11, mean +/- SEM, p = 0.009) in smokers. CONCLUSIONS: Arterial tissue from active smokers contains decreased amounts of collagen stainable material, as well as type 1 collagen and decorin. These findings may explain some effects of smoking on the development of cardiovascular disease including compromised remodelling and increased risk of aneurysms. PMID- 26926602 TI - Plasmonic and silicon spherical nanoparticle antireflective coatings. AB - Over the last decade, plasmonic antireflecting nanostructures have been extensively studied to be utilized in various optical and optoelectronic systems such as lenses, solar cells, photodetectors, and others. The growing interest to all-dielectric photonics as an alternative optical technology along with plasmonics motivates us to compare antireflective properties of plasmonic and all dielectric nanoparticle coatings based on silver and crystalline silicon respectively. Our simulation results for spherical nanoparticles array on top of amorphous silicon show that both silicon and silver coatings demonstrate strong antireflective properties in the visible spectral range. For the first time, we show that zero reflectance from the structure with silicon coatings originates from the destructive interference of electric- and magnetic-dipole responses of nanoparticle array with the wave reflected from the substrate, and we refer to this reflection suppression as substrate-mediated Kerker effect. We theoretically compare the silicon and silver coating effectiveness for the thin-film photovoltaic applications. Silver nanoparticles can be more efficient, enabling up to 30% increase of the overall absorbance in semiconductor layer. Nevertheless, silicon coatings allow up to 64% absorbance increase in the narrow band spectral range because of the substrate-mediated Kerker effect, and band position can be effectively tuned by varying the nanoparticles sizes. PMID- 26926601 TI - Restoration of autophagy in endothelial cells from patients with diabetes mellitus improves nitric oxide signaling. AB - BACKGROUND: Endothelial dysfunction contributes to cardiovascular disease in diabetes mellitus. Autophagy is a multistep mechanism for the removal of damaged proteins and organelles from the cell. Under diabetic conditions, inadequate autophagy promotes cellular dysfunction and insulin resistance in non-vascular tissue. We hypothesized that impaired autophagy contributes to endothelial dysfunction in diabetes mellitus. METHODS AND RESULTS: We measured autophagy markers and endothelial nitric oxide synthase (eNOS) activation in freshly isolated endothelial cells from diabetic subjects (n = 45) and non-diabetic controls (n = 41). p62 levels were higher in cells from diabetics (34.2 +/- 3.6 vs. 20.0 +/- 1.6, P = 0.001), indicating reduced autophagic flux. Bafilomycin inhibited insulin-induced activation of eNOS (64.7 +/- 22% to -47.8 +/- 8%, P = 0.04) in cells from controls, confirming that intact autophagy is necessary for eNOS signaling. In endothelial cells from diabetics, activation of autophagy with spermidine restored eNOS activation, suggesting that impaired autophagy contributes to endothelial dysfunction (P = 0.01). Indicators of autophagy initiation including the number of LC3-bound puncta and beclin 1 expression were similar in diabetics and controls, whereas an autophagy terminal phase indicator, the lysosomal protein Lamp2a, was higher in diabetics. In endothelial cells under diabetic conditions, the beneficial effect of spermidine on eNOS activation was blocked by autophagy inhibitors bafilomycin or 3-methyladenine. Blocking the terminal stage of autophagy with bafilomycin increased p62 (P = 0.01) in cells from diabetics to a lesser extent than in cells from controls (P = 0.04), suggesting ongoing, but inadequate autophagic clearance. CONCLUSION: Inadequate autophagy contributes to endothelial dysfunction in patients with diabetes and may be a target for therapy of diabetic vascular disease. PMID- 26926606 TI - Pes Anserine Bursitis: An Underdiagnosed Cause of Knee Pain in Overweight Women. PMID- 26926603 TI - Stereocilia-staircase spacing is influenced by myosin III motors and their cargos espin-1 and espin-like. AB - Hair cells tightly control the dimensions of their stereocilia, which are actin rich protrusions with graded heights that mediate mechanotransduction in the inner ear. Two members of the myosin-III family, MYO3A and MYO3B, are thought to regulate stereocilia length by transporting cargos that control actin polymerization at stereocilia tips. We show that eliminating espin-1 (ESPN-1), an isoform of ESPN and a myosin-III cargo, dramatically alters the slope of the stereocilia staircase in a subset of hair cells. Furthermore, we show that espin like (ESPNL), primarily present in developing stereocilia, is also a myosin-III cargo and is essential for normal hearing. ESPN-1 and ESPNL each bind MYO3A and MYO3B, but differentially influence how the two motors function. Consequently, functional properties of different motor-cargo combinations differentially affect molecular transport and the length of actin protrusions. This mechanism is used by hair cells to establish the required range of stereocilia lengths within a single cell. PMID- 26926604 TI - Fairness decisions in response to emotions: a functional MRI study among criminal justice-involved boys with conduct disorder. AB - Research suggests that individuals with conduct disorder (CD) are marked by social impairments, such as difficulties in processing the affective reactions of others. Little is known, though, about how they make decisions during social interactions in response to emotional expressions of others. In this study, we therefore investigated the neural mechanisms underlying fairness decisions in response to communicated emotions of others in aggressive, criminal justice involved boys with CD (N = 32) compared with typically developing (TD) boys (N = 33), aged 15-19 years. Participants received written emotional responses (angry, disappointed or happy) from peers in response to a previous offer and then had to make fairness decisions in a version of the Dictator Game. Behavioral results showed that CD boys did not make differential fairness decisions in response to the emotions, whereas the TD boys did show a differentiation and also responded more unfair to happy reactions than the CD boys. Neuroimaging results revealed that when receiving happy vs disappointed and angry reactions, the CD boys showed less activation than the TD boys in the temporoparietal junction and supramarginal gyrus, regions involved in perspective taking and attention. These results suggest that boys with CD have difficulties with processing explicit emotional cues from others on behavioral and neural levels. PMID- 26926605 TI - Interpreting ambiguous social cues in unpredictable contexts. AB - Unpredictable environments can be anxiety-provoking and elicit exaggerated emotional responses to aversive stimuli. Even neutral stimuli, when presented in an unpredictable fashion, prime anxiety-like behavior and elicit heightened amygdala activity. The amygdala plays a key role in initiating responses to biologically relevant information, such as facial expressions of emotion. While some expressions clearly signal negative (anger) or positive (happy) events, other expressions (e.g. surprise) are more ambiguous in that they can predict either valence, depending on the context. Here, we sought to determine whether unpredictable presentations of ambiguous facial expressions would bias participants to interpret them more negatively. We used functional magnetic resonance imaging and facial electromyography (EMG) to characterize responses to predictable vs unpredictable presentations of surprised faces. We observed moderate but sustained increases in amygdala reactivity to predictable presentations of surprised faces, and relatively increased amygdala responses to unpredictable faces that then habituated, similar to previously observed responses to clearly negative (e.g. fearful) faces. We also observed decreased corrugator EMG responses to predictable surprised face presentations, similar to happy faces, and increased responses to unpredictable surprised face presentations, similar to angry faces. Taken together, these data suggest that unpredictability biases people to interpret ambiguous social cues negatively. PMID- 26926608 TI - AFP Goes Audio: Introducing the American Family Physician Podcast. PMID- 26926609 TI - Frequently Asked Questions About Family Medicine: 2016 Edition. PMID- 26926610 TI - Quinine for Leg Cramps. PMID- 26926611 TI - Electronic Cigarettes for Smoking Cessation. PMID- 26926612 TI - Diagnosis and Management of Common Foot Fractures. AB - Foot fractures are among the most common foot injuries evaluated by primary care physicians. They most often involve the metatarsals and toes. Patients typically present with varying signs and symptoms, the most common being pain and trouble with ambulation. Diagnosis requires radiographic evaluation, although emerging evidence demonstrates that ultrasonography may be just as accurate. Management is determined by the location of the fracture and its effect on balance and weight bearing. Metatarsal shaft fractures are initially treated with a posterior splint and avoidance of weight-bearing activities; subsequent treatment consists of a short leg walking cast or boot for four to six weeks. Proximal fifth metatarsal fractures have different treatments depending on the location of the fracture. A fifth metatarsal tuberosity avulsion fracture can be treated acutely with a compressive dressing, then the patient can be transitioned to a short leg walking boot for two weeks, with progressive mobility as tolerated after initial immobilization. A Jones fracture has a higher risk of nonunion and requires at least six to eight weeks in a short leg non-weight-bearing cast; healing time can be as long as 10 to 12 weeks. Great toe fractures are treated with a short leg walking boot or cast with toe plate for two to three weeks, then a rigid-sole shoe for an additional three to four weeks. Lesser toe fractures can be treated with buddy taping and a rigid-sole shoe for four to six weeks. PMID- 26926613 TI - Primary Care of the Solid Organ Transplant Recipient. AB - The advancing science of transplantation has led to more transplants and longer survival. As a result, primary care physicians are more involved in the care of transplant recipients. Immunosuppressive therapy has significantly decreased rates of transplant rejection but accounts for more than 50% of transplant related deaths, often due to infections and other risks related to long-term use. Cardiovascular disease is the leading cause of non-transplant-related mortality. Aggressive risk factor management is recommended for transplant recipients, including a blood pressure goal of less than 130/80 mm Hg and statin therapy in kidney, liver, and heart recipients. Fertility typically increases posttransplant, and female transplant recipients should avoid pregnancy for one year after surgery. The best contraceptive choice is usually an intrauterine device. Because of the increased risk of infection, patients should be tested for graft dysfunction or infection if suspicion arises. Testing should be coordinated with the transplant center. Malignancies are a common cause of death in transplant recipients, requiring careful attention to screening recommendations and informed discussions with patients. Family physicians should maintain an ongoing relationship with the transplant team to discuss medication changes and the risk of infection or graft rejection. PMID- 26926614 TI - Primary Brain Tumors in Adults: Diagnosis and Treatment. AB - Primary intracranial tumors of the brain structures, including meninges, are rare with an overall five-year survival rate of 33.4%; they are collectively called primary brain tumors. Proven risk factors for these tumors include certain genetic syndromes and exposure to high-dose ionizing radiation. Primary brain tumors are classified by histopathologic criteria and immunohistochemical data. The most common symptoms of these tumors are headache and seizures. Diagnosis of a suspected brain tumor is dependent on appropriate brain imaging and histopathology. The imaging modality of choice is gadolinium-enhanced magnetic resonance imaging. There is no specific pathognomonic feature on imaging that differentiates between primary brain tumors and metastatic or nonneoplastic disease. In cases of suspected or pathologically proven metastatic disease, chest and abdomen computed tomography may be helpful, although determining the site of the primary tumor is often difficult, especially if there are no clinical clues from the history and physical examination. Using fluorodeoxyglucose positron emission tomography to search for a primary lesion is not recommended because of low specificity for differentiating a neoplasm from benign or inflammatory lesions. Treatment decisions are individualized by a multidisciplinary team based on tumor type and location, malignancy potential, and the patient's age and physical condition. Treatment often includes a combination of surgery, radiotherapy, and chemotherapy. After craniotomy, patients should be followed closely for complications, including deep venous thrombosis, pulmonary embolism, intracranial bleeding, wound infection, systemic infection, seizure, depression, worsening neurologic status, and adverse drug reaction. Hospice and palliative care should be offered when appropriate throughout treatment. PMID- 26926615 TI - Teenager with a Bleeding, Red Papule. PMID- 26926616 TI - Steroids Beneficial As Adjunctive Treatment for Community-Acquired Pneumonia. PMID- 26926617 TI - Preventing CVD in Adults with Type 2 Diabetes Mellitus: An Update from the AHA and ADA. PMID- 26926618 TI - Cyclobenzaprine in the Treatment of Low Back Pain. PMID- 26926619 TI - Responses to Medical Students' Frequently Asked Questions About Family Medicine. AB - This article provides answers to many of the common questions that medical students ask about the specialty of family medicine. It describes the crucial role that family physicians have in the evolving health care environment, the scope of practice, the diverse career opportunities available, the education and training of family physicians, the economic realities of a career in family medicine, why the future is so bright for family medicine, and why family physicians are passionate about their work. PMID- 26926620 TI - Primary Brain Tumors. PMID- 26926621 TI - Eu(III)-Fulvic Acid Complexation: Evidence of Fulvic Acid Concentration Dependent Interactions by Time-Resolved Luminescence Spectroscopy. AB - Europium speciation is investigated by time-resolved luminescence spectroscopy (TRLS) in the presence of Suwannee River fulvic acid (SRFA). From complexation isotherms built at different total Eu(III) concentrations, pH values, ionic strength, and SRFA concentrations, it appears that two luminescence behaviors of Eu(III) are occurring. The first part, at the lowest CSRFA values, is showing the typical luminescence evolution of Eu(III) complexed by humic substances--that is, the increase of the asymmetry ratio between the (5)D0 -> (7)F2 and (5)D0 -> (7)F1 transitions up to a plateau--, and the occurrence of a biexponential decay--the first decay being faster than free Eu(3+). At higher CSRFA, a second luminescence mode is detected as the asymmetry ratio is increasing again after the previous plateau, and could correspond to the formation of another type of complex, and/or it can reflect a different spatial organization of complexed europium within the SRFA structure. The luminescence decay keeps on evolving but link to hydration number is not straightforward due to quenching mechanisms. The Eu(III) chemical environment evolution with CSRFA is also ionic strength dependent. These observations suggest that in addition to short-range interactions- intraparticulate complexation--, there might be interactions at longer range- interparticulate repulsion--between particles that are complexing Eu(III) at high CSRFA. These interactions are not yet accounted by the different complexation models. PMID- 26926622 TI - A novel approach of chemical mechanical polishing using environment-friendly slurry for mercury cadmium telluride semiconductors. AB - A novel approach of chemical mechanical polishing (CMP) is developed for mercury cadmium telluride (HgCdTe or MCT) semiconductors. Firstly, fixed-abrasive lapping is used to machine the MCT wafers, and the lapping solution is deionized water. Secondly, the MCT wafers are polished using the developed CMP slurry. The CMP slurry consists of mainly SiO2 nanospheres, H2O2, and malic and citric acids, which are different from previous CMP slurries, in which corrosive and toxic chemical reagents are usually employed. Finally, the polished MCT wafers are cleaned and dried by deionized water and compressed air, respectively. The novel approach of CMP is environment-friendly. Surface roughness Ra, and peak-to-valley (PV) values of 0.45, and 4.74 nm are achieved, respectively on MCT wafers after CMP. The first and second passivating processes are observed in electrochemical measurements on MCT wafers. The fundamental mechanisms of CMP are proposed according to the X-ray photoelectron spectroscopy (XPS) and electrochemical measurements. Malic and citric acids dominate the first passivating process, and the CMP slurry governs the second process. Te(4+)3d peaks are absent after CMP induced by the developed CMP slurry, indicating the removing of oxidized films on MCT wafers, which is difficult to achieve using single H2O2 and malic and citric acids solutions. PMID- 26926623 TI - The bilingual brain turns a blind eye to negative statements in the second language. AB - Neurobilingualism research has failed to reveal significant language differences in the processing of affective content. However, the evidence to date derives mostly from studies in which affective stimuli are presented out of context, which is unnatural and fails to capture the complexity of everyday sentence-based communication. Here we investigated semantic integration of affectively salient stimuli in sentential context in the first- and second-language (L2) of late fluent Polish-English bilinguals living in the UK. The 19 participants indicated whether Polish and English sentences ending with a semantically and affectively congruent or incongruent adjective of controlled affective valence made sense while undergoing behavioral and electrophysiological recordings. We focused on the N400, a wave of event-related potentials known to index semantic integration. We expected N400 amplitude to index increased processing demands in L2 English comprehension and potential language-valence interactions to reveal differences in affective processing between languages. Contrary to our initial expectation, we found increased N400 for sentences in L1 Polish, possibly driven by greater affective salience of sentences in the native language. Critically, language interacted with affective valence, such that N400 amplitudes were reduced for English sentences ending in a negative fashion as compared to all other conditions. We interpreted this as a sign that bilinguals suppress L2 content embedded in naturalistic L2 sentences when it has negative valence, thus extending the findings of previous research on single words in clinical and linguistic research. PMID- 26926624 TI - Ampicillin in Combination with Ceftaroline, Cefepime, or Ceftriaxone Demonstrates Equivalent Activities in a High-Inoculum Enterococcus faecalis Infection Model. AB - Ampicillin-ceftriaxone combination therapy has become a predominant treatment for serious Enterococcus faecalis infections, such as endocarditis. Unfortunately, ceftriaxone use is associated with future vancomycin-resistant enterococcus colonization. We evaluated E. faecalis in an in vitro pharmacodynamic model against simulated human concentration-time profiles of ampicillin plus ceftaroline, cefepime, ceftriaxone, or gentamicin. Ampicillin-cefepime and ampicillin-ceftaroline demonstrated activities similar to those of ampicillin ceftriaxone against E. faecalis. PMID- 26926625 TI - The Combination of Grazoprevir, a Hepatitis C Virus (HCV) NS3/4A Protease Inhibitor, and Elbasvir, an HCV NS5A Inhibitor, Demonstrates a High Genetic Barrier to Resistance in HCV Genotype 1a Replicons. AB - The selection of resistance-associated variants (RAVs) against single agents administered to patients chronically infected with hepatitis C virus (HCV) necessitates that direct-acting antiviral agents (DAAs) targeting multiple viral proteins be developed to overcome failure resulting from emergence of resistance. The combination of grazoprevir (formerly MK-5172), an NS3/4A protease inhibitor, and elbasvir (formerly MK-8742), an NS5A inhibitor, was therefore studied in genotype 1a (GT1a) replicon cells. Both compounds were independently highly potent in GT1a wild-type replicon cells, with 90% effective concentration (EC90) values of 0.9 nM and 0.006 nM for grazoprevir and elbasvir, respectively. No cross-resistance was observed when clinically relevant NS5A and NS3 RAVs were profiled against grazoprevir and elbasvir, respectively. Kinetic analyses of HCV RNA reduction over 14 days showed that grazoprevir and elbasvir inhibited prototypic NS5A Y93H and NS3 R155K RAVs, respectively, with kinetics comparable to those for the wild-type GT1a replicon. In combination, grazoprevir and elbasvir interacted additively in GT1a replicon cells. Colony formation assays with a 10-fold multiple of the EC90 values of the grazoprevir-elbasvir inhibitor combination suppressed emergence of resistant colonies, compared to a 100-fold multiple for the independent agents. The selected resistant colonies with the combination harbored RAVs that required two or more nucleotide changes in the codons. Mutations in the cognate gene caused greater potency losses for elbasvir than for grazoprevir. Replicons bearing RAVs identified from resistant colonies showed reduced fitness for several cell lines and may contribute to the activity of the combination. These studies demonstrate that the combination of grazoprevir and elbasvir exerts a potent effect on HCV RNA replication and presents a high genetic barrier to resistance. The combination of grazoprevir and elbasvir is currently approved for chronic HCV infection. PMID- 26926626 TI - Biopharmaceutical Characterization of Nebulized Antimicrobial Agents in Rats. 4. Aztreonam. AB - The aim of this study was to determine aztreonam (ATM) membrane permeability using Calu-3 cells and its plasma and pulmonary epithelial lining fluid (ELF) pharmacokinetics in rats after intratracheal nebulization and intravenous administration (15 mg . kg(-1)). ATM exhibits low Calu-3 permeability (0.07 +/- 0.02 * 10(-6) cm . s(-1)), and a high area under the ELF/unbound plasma concentration time curve between 0 and infinity (AUCELF/AUCu,plasma) ratio of 1,069 was observed after nebulization in rats. These results confirm that ATM is a low-permeability molecule and a good candidate for nebulization. PMID- 26926627 TI - Amoxicillin Crystalluria, an Emerging Complication with an Old and Well-Known Antibiotic. PMID- 26926628 TI - In Vitro Analysis of the Interaction between Atovaquone and Proguanil against Liver Stage Malaria Parasites. AB - The interaction between atovaquone and proguanil has never been studied against liver stage malaria, which is the main target of this drug combination when used for chemoprevention. Using human hepatocytes lacking cytochrome P450 activity, and thus avoiding proguanil metabolizing into potent cycloguanil, we show in vitro that the atovaquone-proguanil combination synergistically inhibits the growth of rodent Plasmodium yoelii parasites. These results provide a pharmacological basis for the high efficacy of atovaquone-proguanil used as malaria chemoprevention. PMID- 26926629 TI - Efficacy and Safety of Pyronaridine-Artesunate for Treatment of Uncomplicated Plasmodium falciparum Malaria in Western Cambodia. AB - Pyronaridine-artesunate efficacy for the treatment of uncomplicated Plasmodium falciparum malaria was assessed in an area of artemisinin resistance in western Cambodia. This nonrandomized, single-arm, observational study was conducted between 2014 and 2015. Eligible patients were adults or children with microscopically confirmed P. falciparum infection and fever. Patients received pyronaridine-artesunate once daily for 3 days, dosed according to body weight. The primary outcome was an adequate clinical and parasitological response (ACPR) on day 42, estimated by using Kaplan-Meier analysis, PCR adjusted to exclude reinfection. One hundred twenty-three patients were enrolled. Day 42 PCR-crude ACPRs were 87.2% (95% confidence interval [CI], 79.7 to 92.6%) for the overall study, 89.8% (95% CI, 78.8 to 95.3%) for Pursat, and 82.1% (95% CI, 68.4 to 90.2%) for Pailin. Day 42 PCR-adjusted ACPRs were 87.9% (95% CI, 80.6 to 93.2%) for the overall study, 89.8% (95% CI, 78.8 to 95.3%) for Pursat, and 84.0% (95% CI, 70.6 to 91.7%) for Pailin (P = 0.353 by a log rank test). Day 28 PCR-crude and -adjusted ACPRs were 93.2% (95% CI, 82.9 to 97.4%) and 88.1% (95% CI, 75.3 to 94.5%) for Pursat and Pailin, respectively. A significantly lower proportion of patients achieved day 3 parasite clearance in Pailin (56.4% [95% CI, 43.9 to 69.6%]) than in Pursat (86.7% [95% CI, 76.8 to 93.8%]; P = 0.0019). Fever clearance was also extended at Pailin versus Pursat (P < 0.0001). Most patients (95.9% [116/121]) harbored P. falciparum kelch13 C580Y mutant parasites. Pyronaridine-artesunate was well tolerated; mild increases in hepatic transaminase levels were consistent with data from previous reports. Pyronaridine artesunate efficacy was below the World Health Organization-recommended threshold at day 42 for medicines with a long half-life (90%) for first-line treatment of P. falciparum malaria in western Cambodia despite high efficacy elsewhere in Asia and Africa. (This study has been registered at ClinicalTrials.gov under registration number NCT02389439.). PMID- 26926630 TI - Novobiocin Susceptibility of MukBEF-Deficient Escherichia coli Is Combinatorial with Efflux and Resides in DNA Topoisomerases. AB - Condensins play a key role in the global organization of bacterial chromosomes. In Escherichia coli, the inactivation of its sole condensin MukBEF induces severe growth defects and renders cells hypersusceptible to novobiocin. We report here that this hypersusceptibility can be observed in TolC-deficient cells and is therefore unrelated to multidrug efflux. We further show that mutations in MukE that impair its focal subcellular localization potentiate novobiocin and that the extent of the potentiation correlates with the residual activity of MukE. Finally, both DNA gyrase and topoisomerase IV might partially complement novobiocin susceptibility in a temperature-dependent manner. These data indicate that the observed antibiotic susceptibility resides in both type II DNA topoisomerases and is efflux independent. Furthermore, novobiocin susceptibility is associated with the activity of MukBEF and can be induced by its partial inactivation, which makes the protein a plausible target for inhibition. PMID- 26926631 TI - Sequential Treatment of Biofilms with Aztreonam and Tobramycin Is a Novel Strategy for Combating Pseudomonas aeruginosa Chronic Respiratory Infections. AB - Traditional therapeutic strategies to control chronic colonization in cystic fibrosis (CF) patients are based on the use of a single nebulized antibiotic. In this study, we evaluated the therapeutic efficacy and dynamics of antibiotic resistance in Pseudomonas aeruginosa biofilms under sequential therapy with inhaled aztreonam (ATM) and tobramycin (TOB). Laboratory strains PAO1, PAOMS (hypermutable), PAOMA (mucoid), and PAOMSA (mucoid and hypermutable) and two hypermutable CF strains, 146-HSE (Liverpool epidemic strain [LES-1]) and 1089-HSE (ST1089), were used. Biofilms were developed using the flow cell system. Mature biofilms were challenged with peak and 1/10-peak concentrations of ATM (700 mg/liter and 70 mg/liter), TOB (1,000 mg/liter and 100 mg/liter), and their alternations (ATM/TOB/ATM and TOB/ATM/TOB) for 2 (t = 2), 4 (t = 4), and 6 days (t = 6). The numbers of viable cells (CFU) and resistant mutants were determined. Biofilm structural dynamics were monitored by confocal laser scanning microscopy and processed with COMSTAT and IMARIS software programs. TOB monotherapy produced an intense decrease in CFU that was not always correlated with a reduction in biomass and/or a bactericidal effect on biofilms, particularly for the CF strains. The ATM monotherapy bactericidal effect was lower, but effects on biofilm biomass and/or structure, including intense filamentation, were documented. The alternation of TOB and ATM led to an enhancement of the antibiofilm activity against laboratory and CF strains compared to that with the individual regimens, potentiating the bactericidal effect and/or the reduction in biomass, particularly at peak concentrations. Resistant mutants were not documented in any of the regimens at the peak concentrations and only anecdotally at the 1/10-peak concentrations. These results support the clinical evaluation of sequential regimens with inhaled antibiotics in CF, as opposed to the current maintenance treatments with just one antibiotic in monotherapy. PMID- 26926632 TI - Zinc(II)-Dipicolylamine Coordination Complexes as Targeting and Chemotherapeutic Agents for Leishmania major. AB - Cutaneous leishmaniasis is a neglected tropical disease that causes painful lesions and severe disfigurement. Modern treatment relies on a few chemotherapeutics with serious limitations, and there is a need for more effective alternatives. This study describes the selective targeting of zinc(II) dipicolylamine (ZnDPA) coordination complexes toward Leishmania major, one of the species responsible for cutaneous leishmaniasis. Fluorescence microscopy of L. major promastigotes treated with a fluorescently labeled ZnDPA probe indicated rapid accumulation of the probe within the axenic promastigote cytosol. The antileishmanial activities of eight ZnDPA complexes were measured using an in vitro assay. All tested complexes exhibited selective toxicity against L. major axenic promastigotes, with 50% effective concentration values in the range of 12.7 to 0.3 MUM. Similar toxicity was observed against intracellular amastigotes, but there was almost no effect on the viability of mammalian cells, including mouse peritoneal macrophages. In vivo treatment efficacy studies used fluorescence imaging to noninvasively monitor changes in the red fluorescence produced by an infection of mCherry-L. major in a mouse model. A ZnDPA treatment regimen reduced the parasite burden nearly as well as the reference care agent, potassium antimony(III) tartrate, and with less necrosis in the local host tissue. The results demonstrate that ZnDPA coordination complexes are a promising new class of antileishmanial agents with potential for clinical translation. PMID- 26926633 TI - In Vitro Approach for Identification of the Most Effective Agents for Antimicrobial Lock Therapy in the Treatment of Intravascular Catheter-Related Infections Caused by Staphylococcus aureus. AB - Infection of intravascular catheters by Staphylococcus aureus is a significant risk factor within the health care setting. To treat these infections and attempt salvage of an intravascular catheter, antimicrobial lock solutions (ALSs) are being increasingly used. However, the most effective ALSs against these biofilm mediated infections have yet to be determined, and clinical practice varies greatly. The purpose of this study was to evaluate and compare the efficacies of antibiotics and antiseptics in current clinical use against biofilms produced by reference and clinical isolates of S. aureus Static and flow biofilm assays were developed using newly described in vivo-relevant conditions to examine the effect of each agent on S. aureus within the biofilm matrix. The antibiotics daptomycin, tigecycline, and rifampin and the antiseptics ethanol and Taurolock inactivated established S. aureus biofilms, while other commonly used antistaphylococcal antibiotics and antiseptic agents were less effective. These findings were confirmed by live/dead staining of S. aureus biofilms formed and treated within a flow cell model. The results from this study demonstrate the most effective clinically used agents and their concentrations which should be used within an ALS to treat S. aureus-mediated intravascular catheter-related infections. PMID- 26926634 TI - Relationship between Adherence to Oral Antibiotics and Postdischarge Clinical Outcomes among Patients Hospitalized with Staphylococcus aureus Skin Infections. AB - Skin and soft tissue infections are common and frequently recur. Poor adherence to antibiotic therapy may lead to suboptimal clinical outcomes. However, adherence to oral antibiotic therapy for skin and soft tissue infections and its relationship to clinical outcomes have not been examined. We enrolled adult patients hospitalized with uncomplicated skin and soft tissue infections caused by Staphylococcus aureus who were being discharged with oral antibiotics to complete therapy. We fit the participants' pill bottles with an electronic bottle cap that recorded each pill bottle opening, administered an in-person standardized questionnaire at enrollment, 14 days, and 30 days, and reviewed the participants' medical records to determine outcomes. Our primary outcome was poor clinical response, defined as a change in antibiotic therapy, new incision-and drainage procedure, or new skin infection within 30 days of hospital discharge. Of our 188 participants, 87 had complete data available for analysis. Among these participants, 40 (46%) had a poor clinical response at 30 days. The mean electronically measured adherence to antibiotic therapy was significantly different than the self-reported adherence (57% versus 96%; P < 0.0001). In a multivariable model, poor clinical response at 30 days was associated with patients having lower adherence, being nondiabetic, and reporting a lack of illicit drug use within the previous 12 months (P < 0.05). In conclusion, we found that patient adherence to oral antibiotic therapy for a skin and soft tissue infection after hospital discharge was low (57%) and associated with poor clinical outcome. Patients commonly overstate their medication adherence, which may make identification of patients at risk for nonadherence and poor outcomes challenging. Further studies are needed to improve postdischarge antibiotic adherence after skin and soft tissue infections. PMID- 26926635 TI - Activity of Ceftazidime-Avibactam against Extended-Spectrum- and AmpC beta Lactamase-Producing Enterobacteriaceae Collected in the INFORM Global Surveillance Study from 2012 to 2014. AB - The in vitro activity of ceftazidime-avibactam was evaluated against 34,062 isolates of Enterobacteriaceae from patients with intra-abdominal, urinary tract, skin and soft-tissue, lower respiratory tract, and blood infections collected in the INFORM (International Network For Optimal Resistance Monitoring) global surveillance study (176 medical center laboratories in 39 countries) in 2012 to 2014. Overall, 99.5% of Enterobacteriaceae isolates were susceptible to ceftazidime-avibactam using FDA approved breakpoints (susceptible MIC of <=8 MUg/ml; resistant MIC of >=16 MUg/ml). For individual species of the Enterobacteriaceae, the ceftazidime-avibactam MIC inhibiting >=90% of isolates (MIC90) ranged from 0.06 MUg/ml for Proteus species to 1 MUg/ml for Enterobacter spp. and Klebsiella pneumoniae Carbapenem-susceptible isolates of Escherichia coli, K. pneumoniae, Klebsiella oxytoca, and Proteus mirabilis with a confirmed extended-spectrum beta-lactamase (ESBL) phenotype, or a ceftazidime MIC of >=16 MUg/ml if the ESBL phenotype was not confirmed by clavulanic acid inhibition, were characterized further to identify the presence of specific ESBL- and plasmid mediated AmpC beta-lactamase genes using a microarray-based assay and additional PCR assays. Ceftazidime-avibactam demonstrated potent activity against molecularly confirmed ESBL-producing (n = 5,354; MIC90, 0.5 MUg/ml; 99.9% susceptible), plasmid-mediated AmpC-producing (n = 246; MIC90, 0.5 MUg/ml; 100% susceptible), and ESBL- and AmpC-producing (n = 152; MIC90, 1 MUg/ml; 100% susceptible) isolates of E. coli, K. pneumoniae, K. oxytoca, and P. mirabilis We conclude that ceftazidime-avibactam demonstrates potent in vitro activity against globally collected clinical isolates of Enterobacteriaceae, including isolates producing ESBLs and AmpC beta-lactamases. PMID- 26926636 TI - Reduction in Tedizolid Plasma Exposure among End-Stage Renal Disease Patients Undergoing Dialysis Is Explained by Variations in Ideal Body Weight. PMID- 26926637 TI - Cross Talk between Nucleotide Synthesis Pathways with Cellular Immunity in Constraining Hepatitis E Virus Replication. AB - Viruses are solely dependent on host cells to propagate; therefore, understanding virus-host interaction is important for antiviral drug development. Since de novo nucleotide biosynthesis is essentially required for both host cell metabolism and viral replication, specific catalytic enzymes of these pathways have been explored as potential antiviral targets. In this study, we investigated the role of different enzymatic cascades of nucleotide biosynthesis in hepatitis E virus (HEV) replication. By profiling various pharmacological inhibitors of nucleotide biosynthesis, we found that targeting the early steps of the purine biosynthesis pathway led to the enhancement of HEV replication, whereas targeting the later step resulted in potent antiviral activity via the depletion of purine nucleotide. Furthermore, the inhibition of the pyrimidine pathway resulted in potent anti-HEV activity. Interestingly, all of these inhibitors with anti-HEV activity concurrently triggered the induction of antiviral interferon-stimulated genes (ISGs). Although ISGs are commonly induced by interferons via the JAK-STAT pathway, their induction by nucleotide synthesis inhibitors is completely independent of this classical mechanism. In conclusion, this study revealed an unconventional novel mechanism of cross talk between nucleotide biosynthesis pathways and cellular antiviral immunity in constraining HEV infection. Targeting particular enzymes in nucleotide biosynthesis represents a viable option for antiviral drug development against HEV. HEV is the most common cause of acute viral hepatitis worldwide and is also associated with chronic hepatitis, especially in immunocompromised patients. Although often an acute and self limiting infection in the general population, HEV can cause severe morbidity and mortality in certain patients, a problem compounded by the lack of FDA-approved anti-HEV medication available. In this study, we have investigated the role of the nucleotide synthesis pathway in HEV infection and its potential for antiviral drug development. We show that targeting the later but not the early steps of the purine synthesis pathway exerts strong anti-HEV activity. In particular, IMP dehydrogenase (IMPDH) is the most important anti-HEV target of this cascade. Importantly, the clinically used IMPDH inhibitors, including mycophenolic acid and ribavirin, have potent anti-HEV activity. Furthermore, targeting the pyrimidine synthesis pathway also exerts potent antiviral activity against HEV. Interestingly, antiviral effects of nucleotide synthesis pathway inhibitors appear to depend on the medication-induced transcription of antiviral interferon stimulated genes. Thus, this study reveals an unconventional novel mechanism as to how nucleotide synthesis pathway inhibitors can counteract HEV replication. PMID- 26926638 TI - Clofazimine Contributes Sustained Antimicrobial Activity after Treatment Cessation in a Mouse Model of Tuberculosis Chemotherapy. AB - Experimental and clinical studies have indicated that the antileprosy drug clofazimine may contribute treatment-shortening activity when included in tuberculosis treatment regimens. Clofazimine accumulates to high levels in tissues, has a long half-life, and remains in the body for months after administration is stopped. We hypothesized that in tuberculosis treatment, accumulated clofazimine may contribute sustained antimicrobial activity after treatment cessation, and we used the BALB/c mouse model of chronic tuberculosis chemotherapy to address this hypothesis. Mycobacterium tuberculosis-infected mice were treated for 4 weeks or 8 weeks with either isoniazid alone, clofazimine alone, the first-line regimen rifampin-isoniazid-pyrazinamide-ethambutol, or a first-line regimen where clofazimine was administered in place of ethambutol. To evaluate posttreatment antimicrobial activity, bacterial regrowth in the lungs and spleens was assessed at the day of treatment cessation and 2, 4, 6, and 8 weeks after treatment was stopped. Bacterial regrowth was delayed in all mice receiving clofazimine, either alone or in combination, compared to the mice that did not receive clofazimine. This effect was especially evident in mice receiving multidrug therapy. In mice not receiving clofazimine, bacterial regrowth began almost immediately after treatment was stopped, while in mice receiving clofazimine, bacterial regrowth was delayed for up to 6 weeks, with the duration of sustained antimicrobial activity being positively associated with the time that serum clofazimine levels remained at or above the 0.25-MUg/ml MIC for M. tuberculosis Thus, sustained activity of clofazimine may be important in the treatment-shortening effect associated with this drug. PMID- 26926639 TI - A First-in-Human Study To Assess the Safety and Pharmacokinetics of Monoclonal Antibodies against Human Cytomegalovirus in Healthy Volunteers. AB - Human cytomegalovirus (HCMV) can cause significant disease in immunocompromised patients and treatment options are limited by toxicities. CSJ148 is a combination of two anti-HCMV human monoclonal antibodies (LJP538 and LJP539) that bind to and inhibit the function of viral HCMV glycoprotein B (gB) and the pentameric complex, consisting of glycoproteins gH, gL, UL128, UL130, and UL131. Here, we evaluated the safety, tolerability, and pharmacokinetics of a single intravenous dose of LJP538 or LJP539 or their combination in healthy volunteers. Adverse events and laboratory abnormalities occurred sporadically with similar incidence between antibody and placebo groups and without any apparent relationship to dose. No subject who received antibody developed a hypersensitivity, infusion related reaction or anti-drug antibodies. After intravenous administration, both LJP538 and LJP539 demonstrated typical human IgG1 pharmacokinetic properties, with slow clearances, limited volumes of distribution, and long terminal half lives. The pharmacokinetic parameters were linear and dose proportional for both antibodies across the 50-fold range of doses evaluated in the study. There was no apparent impact on pharmacokinetics when the antibodies were administered alone or in combination. CSJ148 and the individual monoclonal antibodies were safe and well tolerated, with pharmacokinetics as expected for human immunoglobulin. PMID- 26926640 TI - Fluoroquinolone and Third-Generation-Cephalosporin Resistance among Hospitalized Patients with Urinary Tract Infections Due to Escherichia coli: Do Rates Vary by Hospital Characteristics and Geographic Region? AB - This analysis of nearly 10,000 hospital-associated urinary tract infection (UTI) episodes due to Escherichia coli showed that fluoroquinolone and third-generation cephalosporin resistance rates were 34.5% and 8.6%, respectively; the rate of concurrent resistance to both agents was 7.3%. Fluoroquinolone resistance rates exceeded 25% regardless of geographic location or hospital characteristics. The findings suggest that fluoroquinolones should be reserved and third-generation cephalosporins be used with caution as empirical agents for hospitalized patients with UTIs due to E. coli. PMID- 26926641 TI - Optimization of Polymyxin B in Combination with Doripenem To Combat Mutator Pseudomonas aeruginosa. AB - Development of spontaneous mutations in Pseudomonas aeruginosa has been associated with antibiotic failure, leading to high rates of morbidity and mortality. Our objective was to evaluate the pharmacodynamics of polymyxin B combinations against rapidly evolving P. aeruginosa mutator strains and to characterize the time course of bacterial killing and resistance via mechanism based mathematical models. Polymyxin B or doripenem alone and in combination were evaluated against six P. aeruginosa strains: wild-type PAO1, mismatch repair (MMR)-deficient (mutS and mutL) strains, and 7,8-dihydro-8-oxo-deoxyguanosine system (GO) base excision repair (BER)-deficient (mutM, mutT, and mutY) strains over 48 h. Pharmacodynamic modeling was performed using S-ADAPT and facilitated by SADAPT-TRAN. Mutator strains displayed higher mutation frequencies than the wild type (>600-fold). Exposure to monotherapy was followed by regrowth, even at high polymyxin B concentrations of up to 16 mg/liter. Polymyxin B and doripenem combinations displayed enhanced killing activity against all strains where complete eradication was achieved for polymyxin B concentrations of >4 mg/liter and doripenem concentrations of 8 mg/liter. Modeling suggested that the proportion of preexisting polymyxin B-resistant subpopulations influenced the pharmacodynamic profiles for each strain uniquely (fraction of resistance values are -8.81 log10 for the wild type, -4.71 for the mutS mutant, and -7.40 log10 for the mutM mutant). Our findings provide insight into the optimization of polymyxin B and doripenem combinations against P. aeruginosa mutator strains. PMID- 26926642 TI - Aminoglycosides for Treatment of Bacteremia Due to Carbapenem-Resistant Klebsiella pneumoniae. AB - Aminoglycoside treatment of carbapenem-resistant (CR) Klebsiella pneumoniae bacteremia was associated with a 70% rate (23/33) of 30-day survival. Successful treatment was associated with sources of bacteremia amenable to reliable aminoglycoside pharmacokinetics (P = 0.037), acute physiology and chronic health evaluation II (APACHE II) scores of <20 (P = 0.16), and nonfatal underlying diseases (P = 0.015). Success rates were 78% and 100% if >=2 and all 3 factors were present, respectively. Clinicians may consider the use of aminoglycosides against CR K. pneumoniae bacteremia if strains are susceptible and the sources of infection are amenable to reliable pharmacokinetics. PMID- 26926643 TI - Modulation of Membrane Influx and Efflux in Escherichia coli Sequence Type 131 Has an Impact on Bacterial Motility, Biofilm Formation, and Virulence in a Caenorhabditis elegans Model. AB - Energy-dependent efflux overexpression and altered outer membrane permeability (influx) can promote multidrug resistance (MDR). The present study clarifies the regulatory pathways that control membrane permeability in the pandemic clone Escherichia coli sequence type 131 (ST131) and evaluates the impact of efflux and influx modulations on biofilm formation, motility, and virulence in the Caenorhabditis elegans model. Mutants of two uropathogenic E. coli (UPEC) strains, MECB5 (ST131; H30-Rx) and CFT073 (ST73), as well as a fecal strain, S250 (ST131; H22), were in vitro selected using continuous subculture in subinhibitory concentrations of ertapenem (ETP), chloramphenicol (CMP), and cefoxitin (FOX). Mutations in genes known to control permeability were shown for the two UPEC strains: MECB5-FOX (deletion of 127 bp in marR; deletion of 1 bp and insertion of an IS1 element in acrR) and CFT073-CMP (a 1-bp deletion causing a premature stop in marR). We also demonstrated that efflux phenotypes in the mutants selected with CMP and FOX were related to the AcrAB-TolC pump, but also to other efflux systems. Alteration of membrane permeability, caused by underexpression of the two major porins, OmpF and OmpC, was shown in MECB5-ETP and mutants selected with FOX. Lastly, our findings suggest that efflux pump-overproducing isolates (CMP mutants) pose a serious threat in terms of virulence (significant reduction in worm median survival) and host colonization. Lack of porins (ETP and FOX mutants) led to a high level of antibiotic resistance in an H30-Rx subclone. Nevertheless, this adaptation created a physiological disadvantage (decreased motility and ability to form biofilm) associated with a low potential for virulence. PMID- 26926644 TI - Clindamycin Pharmacokinetics and Safety in Preterm and Term Infants. AB - Clindamycin may be active against methicillin-resistant Staphylococcus aureus, a common pathogen causing sepsis in infants, but optimal dosing in this population is unknown. We performed a multicenter, prospective pharmacokinetic (PK) and safety study of clindamycin in infants. We analyzed the data using a population PK analysis approach and included samples from two additional pediatric trials. Intravenous data were collected from 62 infants (135 plasma PK samples) with postnatal ages of <121 days (median [range] gestational age of 28 weeks [23 to 42] and postnatal age of 17 days [1 to 115]). In addition to body weight, postmenstrual age (PMA) and plasma protein concentrations (albumin and alpha-1 acid glycoprotein) were found to be significantly associated with clearance and volume of distribution, respectively. Clearance reached 50% of the adult value at PMA of 39.5 weeks. Simulated PMA-based intravenous dosing regimens administered every 8 h (<=32 weeks PMA, 5 mg/kg; 32 to 40 weeks PMA, 7 mg/kg; >40 to 60 weeks PMA, 9 mg/kg) resulted in an unbound, steady-state concentration at half the dosing interval greater than a MIC for S. aureus of 0.12 MUg/ml in >90% of infants. There were no adverse events related to clindamycin use. (This study has been registered at ClinicalTrials.gov under registration no. NCT01728363.). PMID- 26926645 TI - PI4 Kinase Is a Prophylactic but Not Radical Curative Target in Plasmodium vivax Type Malaria Parasites. AB - Two Plasmodium PI4 kinase (PI4K) inhibitors, KDU691 and LMV599, were selected for in vivo testing as causal prophylactic and radical-cure agents for Plasmodium cynomolgi sporozoite-infected rhesus macaques, based on their in vitro activity against liver stages. Animals were infected with P. cynomolgi sporozoites, and compounds were dosed orally. Both the KDU691 and LMV599 compounds were fully protective when administered prophylactically, and the more potent compound LMV599 achieved protection as a single oral dose of 25 mg/kg of body weight. In contrast, when tested for radical cure, five daily doses of 20 mg/kg of KDU691 or 25 mg/kg of LMV599 did not prevent relapse, as all animals experienced a secondary infection due to the reactivation of hypnozoites in the liver. Pharmacokinetic data show that LMV599 achieved plasma exposure that was sufficient to achieve efficacy based on our in vitro data. These findings indicate that Plasmodium PI4K is a potential drug target for malaria prophylaxis but not radical cure. Longer in vitro culture systems will be required to assess these compounds' activity on established hypnozoites and predict radical cure in vivo. PMID- 26926646 TI - Identification of Novel VEB beta-Lactamase Enzymes and Their Impact on Avibactam Inhibition. AB - Ceftazidime-avibactam has activity against Pseudomonas aeruginosa and Enterobacteriaceae expressing numerous class A and class C beta-lactamases, although the ability to inhibit many minor enzyme variants has not been established. Novel VEB class A beta-lactamases were identified during characterization of surveillance isolates. The cloned novel VEB beta-lactamases possessed an extended-spectrum beta-lactamase phenotype and were inhibited by avibactam in a concentration-dependent manner. The residues that comprised the avibactam binding pocket were either identical or functionally conserved. These data demonstrate that avibactam can inhibit VEB beta-lactamases. PMID- 26926647 TI - Results from Oritavancin Resistance Surveillance Programs (2011 to 2014): Clarification for Using Vancomycin as a Surrogate To Infer Oritavancin Susceptibility. AB - Measurement of vancomycin susceptibility has been shown to be highly predictive as a surrogate measure of oritavancin susceptibility among clinically indicated Gram-positive species. Results of studying over 30,000 pathogens (from 2011 to 2014) by cross-susceptibility analysis and determining the poor reproducibility of oritavancin-nonsusceptible results showed nearly perfect surrogate testing accuracy (99.86 to 99.94%). Any isolate of an indicated organism species with locally reproducible oritavancin-nonsusceptible results (extremely rare) should be referred to a reference laboratory for confirmation of the results and determination of the resistance mechanism. PMID- 26926648 TI - In Vitro Susceptibility to Ceftazidime-Avibactam of Carbapenem-Nonsusceptible Enterobacteriaceae Isolates Collected during the INFORM Global Surveillance Study (2012 to 2014). AB - The activity of ceftazidime-avibactam was assessed against 961 isolates of meropenem-nonsusceptible Enterobacteriaceae Most meropenem-nonsusceptible metallo beta-lactamase (MBL)-negative isolates (97.7%) were susceptible to ceftazidime avibactam. Isolates that carried KPC or OXA-48-like beta-lactamases, both alone and in combination with extended-spectrum beta-lactamases (ESBLs) and/or AmpC beta-lactamases, were 98.7% and 98.5% susceptible to ceftazidime-avibactam, respectively. Meropenem-nonsusceptible, carbapenemase-negative isolates demonstrated 94.7% susceptibility to ceftazidime-avibactam. Ceftazidime-avibactam activity was compromised only in isolates for which carbapenem resistance was mediated through metallo-beta-lactamases. PMID- 26926650 TI - Susceptibility Testing of Antibiotics That Degrade Faster than the Doubling Time of Slow-Growing Mycobacteria: Ertapenem Sterilizing Effect versus Mycobacterium tuberculosis. AB - Drug susceptibility tests (DSTs) for Mycobacterium tuberculosis require at least 7 days of incubation. Drugs that are unstable at 37 degrees C, such as ertapenem, are likely to be degraded before killing or inhibiting slow-growing bacteria. This would alter the MICs of these drugs, including ertapenem, leading to falsely high MICs. Here, we describe a new strategy we developed to perform DSTs and measure MICs for such unstable compounds. PMID- 26926649 TI - Tigecycline Is Highly Efficacious against Mycobacterium abscessus Pulmonary Disease. AB - Mycobacterium abscessus causes chronic pulmonary infections that are extremely difficult to cure. The currently recommended combination therapy is associated with high failure rates and relapse. Tigecycline has been explored in salvage regimens, with a response rate of 43% in those who received at least a month of therapy. We performed a dose-response study in a hollow-fiber system model of pulmonary M. abscessus infection in which we recapitulated tigecycline human pulmonary concentration-time profiles of 8 different doses for 21 days. We identified the maximal kill or efficacy in CFU per milliliter and the ratio of the 0- to 24-h area under the concentration-time curve to MIC (AUC/MIC) associated with 80% efficacy (EC80). The tigecycline efficacy was 5.38 +/- 2.35 log10 CFU/ml, and the drug achieved the unprecedented feat of a bacterial level of 1.0 log10 CFU/ml below the pretreatment inoculum (1-log kill) of M. abscessus in the hollow-fiber system. The EC80 AUC/MIC ratio was 36.65, while that for a 1 log kill was 44.6. Monte Carlo experiments with 10,000 patients were used to identify the clinical dose best able to achieve the EC80 or 1-log kill. The standard dose of 100 mg/day had a cumulative fraction of response of 51% for the EC80 and 46% for 1-log kill. For both the EC80 target and 1-log kill, the optimal tigecycline clinical dose was identified as 200 mg/day. The susceptibility breakpoint was <=0.5 mg/liter. Tigecycline is the most active single agent evaluated to date, and we propose that 200 mg/day be examined as the backbone of new combination therapy regimens to replace current treatment. PMID- 26926651 TI - Attention-shift vs. response-priming explanations for the spatial cueing effect in cross-modal tasks. AB - The task-irrelevant spatial location of a cue stimulus affects the processing of a subsequent target. This "Posner effect" has been explained by an exogenous attention shift to the spatial location of the cue, improving perceptual processing of the target. We studied whether the left/right location of task irrelevant and uninformative tones produces cueing effects on the processing of visual targets. Tones were presented randomly from left or right. In the first condition, the subsequent visual target, requiring response either with the left or right hand, was presented peripherally to left or right. In the second condition, the target was a centrally presented left/right-pointing arrow, indicating the response hand. In the third condition, the tone and the central arrow were presented simultaneously. Data were recorded on compatible (the tone location and the response hand were the same) and incompatible trials. Reaction times were longer on incompatible than on compatible trials. The results of the second and third conditions are difficult to explain with the attention-shift model emphasizing improved perceptual processing in the cued location, as the central target did not require any location-based processing. Consequently, as an alternative explanation they suggest response priming in the hand corresponding to the spatial location of the tone. Simultaneous lateralized readiness potential (LRP) recordings were consistent with the behavioral data, the tone cues eliciting on incompatible trials a fast preparation for the incorrect response and on compatible trials preparation for the correct response. PMID- 26926652 TI - Electrophysiology of pumpkin seeds: Memristors in vivo. AB - Leon Chua, the discoverer of a memristor, theoretically predicted that voltage gated ion channels can be memristors. We recently found memristors in different plants such as the Venus flytrap, Mimosa pudica, Aloe vera, apple fruits, and in potato tubers. There are no publications in literature about the existence of memristors in seeds. The goal of this work was to discover if pumpkin seeds might have memristors. We selected Cucurbita pepo L., cv. Cinderella, Cucurbita maxima L. cv Warty Goblin, and Cucurbita maxima L., cv. Jarrahdale seeds for this analysis. In these seeds, we found the presence of resistors with memory. The analysis was based on cyclic voltammetry where a memristor should manifest itself as a nonlinear two-terminal electrical element, which exhibits a pinched hysteresis loop on a current-voltage plane for any bipolar cyclic voltage input signal. Dry dormant pumpkin seeds have very high electrical resistance without memristive properties. The electrostimulation by bipolar sinusoidal or triangular periodic waves induces electrical responses in imbibed pumpkin seeds with fingerprints of memristors. Tetraethylammonium chloride, an inhibitor of voltage gated K(+) channels, transforms a memristor to a resistor in pumpkin seeds. NPPB (5-Nitro-2-(3-phenylpropylamino)benzoic acid) inhibits the memristive properties of imbibed pumpkin seeds. The discovery of memristors in pumpkin seeds creates a new direction in the understanding of electrophysiological phenomena in seeds. PMID- 26926655 TI - Twinning-mediated formability in Mg alloys. AB - Mg alloys are promising candidates for automotive applications due to their low density and high specific strength. However, their widespread applications have not been realized mainly because of poor formability at room temperature, arising from limited number of active deformation systems and strong basal texture. It has been recently shown that Mg-Zn-Ca alloys have excellent stretch formability, which has been ascribed to their weak basal texture. However, the distribution of basal poles is orthotropic, which might result in anisotropy during deformation and have adverse effect on formability. Here, we show that tension twinning is mainly responsible for enhanced formability of Mg-Zn-Ca alloys. We found that tension twinning is quite active during both uniaxial deformation and biaxial deformation of Mg-Zn-Ca alloy even under the stress conditions unfavourable for the formation of tensile twins. Our results provide new insights into the development of Mg alloys having high formability. PMID- 26926653 TI - Longitudinal associations of age and prenatal lead exposure on cortisol secretion of 12-24 month-old infants from Mexico City. AB - BACKGROUND: Cortisol has functions on homeostasis, growth, neurodevelopment, immune function and the stress response. Secretion follows a diurnal rhythm that mediates these processes. Our objective was to examine the association between prenatal lead exposure and infant diurnal cortisol rhythms. METHODS: We measured infant cortisol rhythms in saliva collected repeatedly over 2 days at either 12 (n = 255) or 18-24 (n = 150) months of age. Prenatal lead exposure was assessed by measuring maternal pregnancy blood lead levels and early postnatal maternal bone lead content. We analyzed age-specific basal secretion and the association between trimester-specific and cumulative lead exposure with a) change in total diurnal cortisol and b) the shape of the cortisol curve across the length of the day. RESULTS: Our results showed age related differences in salivary cortisol secretion and an age dependent association with maternal lead exposure. In age stratified models we saw an inverse association between lead and cortisol levels in 12-month-old infants and a positive association for 18-24-month-old infants. For the 12-month-old infants 2nd-trimester-lead >=10 MUg/dL was associated with 40 % lower cortisol levels (95 % CI (-57, -16)) and a significant change in the shape of the cortisol curve (p = 0.01), compared to infants with low blood lead levels (<5 MUg/dL). CONCLUSIONS: Basal cortisol secretion changes with age. Increased early gestation lead exposure alters diurnal cortisol rhythms and the association is modified by infant age, perhaps representing an early maturation of cortisol homeostasis. PMID- 26926656 TI - The Effect of Treatment of Obstructive Sleep Apnea on Glycemic Control in Type 2 Diabetes. AB - RATIONALE: There is uncertainty about the effects of treating obstructive sleep apnea on glycemic control in patients with type 2 diabetes. OBJECTIVES: To determine whether treatment of obstructive sleep apnea in patients with type 2 diabetes improves glycemic control. METHODS: In this trial, we randomized patients with type 2 diabetes and no previous diagnosis of obstructive sleep apnea, with a glycated hemoglobin level of 6.5-8.5%, and an oxygen desaturation index of 15 or more events per hour to positive airway pressure therapy or to usual care. MEASUREMENTS AND MAIN RESULTS: A total of 416 patients met the entry criteria as determined by each site and were randomized. Of the 298 participants who met centrally adjudicated entry criteria, no differences between the study groups were seen for change in glycated hemoglobin. Furthermore, there were no between-group differences when analyses were restricted to those with poorer baseline glycemic control, those with more severe sleep apnea, or those who were adherent to therapy. A greater fall in diastolic blood pressure occurred in the positive airway pressure group than in the usual care group (-3.5 mm Hg vs. -1.5 mm Hg; P = 0.07). This difference was significant in those who were adherent to positive airway pressure therapy (-4.4 mm Hg vs. -1.6 mm Hg; P = 0.02). There was a significant reduction in sleepiness in the positive airway pressure therapy group (P < 0.0001). Quality of life assessment revealed improvements in vitality, mental health, and mental component summary scores in the positive airway pressure therapy group. CONCLUSIONS: This trial showed no effect of positive airway pressure therapy on glycemic control in patients with relatively well controlled type 2 diabetes and obstructive sleep apnea. Clinical trial registered with www.clinicaltrials.gov (NCT00509223). PMID- 26926657 TI - Does pharmacist-supervised intervention through pharmaceutical care program influence direct healthcare cost burden of newly diagnosed diabetics in a tertiary care teaching hospital in Nepal: a non-clinical randomised controlled trial approach. AB - BACKGROUND: Cost is a vital component for people with chronic diseases as treatment is expected to be long or even lifelong in some diseases. Pharmacist contributions in decreasing the healthcare cost burden of chronic patients are not well described due to lack of sufficient evidences worldwide. In developing countries like Nepal, the estimation of direct healthcare cost burden among newly diagnosed diabetics is still a challenge for healthcare professionals, and pharmacist role in patient care is still theoretical and practically non existent. This study reports the impact of pharmacist-supervised intervention through pharmaceutical care program on direct healthcare costs burden of newly diagnosed diabetics in Nepal through a non-clinical randomised controlled trial approach. METHODS: An interventional, pre-post non-clinical randomised controlled study was conducted among randomly distributed 162 [control (n = 54), test 1 (n = 54) and test 2 (n = 54) groups] newly diagnosed diabetics by a consecutive sampling method for 18 months. Direct healthcare costs (direct medical and non medical costs) from patients perspective was estimated by 'bottom up' approach to identify their out-of-pocket expenses (1USD = NPR 73.38) before and after intervention at the baseline, 3, 6, 9 and 12 months follow-ups. Test groups' patients were nourished with pharmaceutical care intervention while control group patients only received care from physician/nurses. Non-parametric tests i.e. Friedman test, Mann-Whitney U test and Wilcoxon signed rank test were used to find the differences in direct healthcare costs among the groups before and after the intervention (p <= 0.05). RESULTS: Friedman test identified significant differences in direct healthcare cost of test 1 (p < 0.001) and test 2 (p < 0.001) groups patients. However, Mann-Whitney U test justified significant differences in direct healthcare cost between control group and test 1 group, and test 2 group patients at 6-months (p = 0.009, p = 0.010 respectively), 9-months (p = 0.005, p = 0.001 respectively) and 12-months (p < 0.001, p < 0.001 respectively). CONCLUSION: Pharmacist supervised intervention through pharmaceutical care program significantly decreased direct healthcare costs of diabetics in test groups compared to control group and hence describes pharmacist's contribution in minimizing direct healthcare cost burden of patients. PMID- 26926658 TI - Stress reactivity predicts symptom improvement in children with anxiety disorders. AB - BACKGROUND: We examined the longitudinal associations of autonomic nervous system (ANS) and hypothalamic-pituitary-adrenal (HPA) axis rest and reactivity measures with anxiety and depressive symptoms at one-year follow-up in children with anxiety disorders. METHODS: In a clinical sample of 152 children with a primary DSM-IV anxiety disorder, aged 8 to 12 years, anxiety and depressive symptoms were assessed with the Multidimensional Anxiety Scale for Children and the Children's Depression Inventory at pre-treatment baseline and one year later, after treatment with cognitive behavioral therapy. At baseline, children participated in a 70min stress task. Salivary cortisol was measured directly prior to and 20min post stress task. Skin conductance level (SCL), heart rate and high frequency heart rate variability (HRV) were continuously measured during rest and the stress task. To investigate if rest or reactivity measures predicted anxiety and depressive symptoms at one year follow-up, linear regression analyses were conducted for rest and reactivity measures of SCL, heart rate, HRV and cortisol separately. RESULTS: Higher SCL reactivity predicted less decrease of anxiety symptoms at one-year follow-up. Cortisol reactivity showed a weak association with depressive symptoms at one-year follow-up: lower cortisol reactivity predicted less decrease in depressive symptoms. LIMITATIONS: Only self-reported anxiety and depressive symptoms were used. However, all predictors were objective biological measures, hence there is no risk of shared method variance bias. CONCLUSIONS: These findings suggest that pre-treatment HPA and ANS responsiveness to stress are predictive biomarkers for a lack of symptom improvement in children with a clinical anxiety disorder. PMID- 26926659 TI - The effectiveness of simple psychological and physical activity interventions for high prevalence mental health problems in young people: A factorial randomised controlled trial. AB - BACKGROUND: The prevalence and burden of disease of depression and anxiety disorders in young people necessitates effective early intervention strategies. The aim of this study was to evaluate the effectiveness of low-intensity interventions (problem solving therapy (PST) and physical activity promotion) in young people (15-25 years) with mild-moderate depression and/or anxiety. METHOD: A 2*2 factorial randomised controlled trial (RCT) with factors of PST versus supportive counselling (control) and behavioural activation physical activity versus lifestyle psychoeducation (control). Help-seeking participants (n=176) were randomised to receive up to 6 manualised intervention sessions. Primary outcomes were post-intervention depressive symptoms (Beck Depression Inventory-II (BDI-II), anxiety symptoms (Beck Anxiety Inventory), and Montgomery-Asberg Depression Rating Scale (MADRS)). Trial registration ACTRN12608000550303. RESULTS: Depression symptoms were significantly reduced in the physical activity group compared to psychoeducation (BDI-II: d=0.41 (95% CI: 0.07-0.76); MADRS: d=0.48 (95% CI: 0.13-0.82), but not post-intervention anxiety symptoms. PST was not superior to supportive counselling, nor were any interactions between interventions significant. LIMITATIONS: As self reported levels of physical activity did not significantly differ between baseline and end-point in those randomised to the physical activity intervention, it is unclear as to whether some form of physical activity not measured in the trial may have led to the difference in depression symptoms. CONCLUSIONS: PST was not superior to supportive counselling in reducing depression and anxiety symptoms in young people. Participants who received the physical activity intervention reported the greatest reduction in depression symptoms, however further research is required to establish the mechanism of action and to determine its effectiveness as an adjunct intervention in routine clinical practice. PMID- 26926660 TI - Cluster randomised controlled trial of the e-couch Anxiety and Worry program in schools. AB - BACKGROUND: Anxiety is a common mental health problem in youth. The current study aimed to test the effectiveness of an online self-directed anxiety prevention program in a school-based sample and to compare two methods of implementing an anxiety program in schools. METHODS: A three-arm cluster stratified randomised controlled trial was conducted with 30 Australian schools. Each school was randomly assigned to receive: (1) externally-supported intervention, (2) teacher supported intervention, or (3) wait-list control. All consenting students (N=1767) were invited to complete pre-intervention, post-intervention, 6- and 12 month follow-up questionnaires measuring generalised anxiety, social anxiety, anxiety sensitivity, depressive symptoms and mental wellbeing. Intervention participants completed the e-couch Anxiety and Worry program over 6 weeks. RESULTS: At post-intervention, 6- and 12-month follow-up no significant differences were observed between the intervention and control conditions for generalised anxiety (Cohen's d=-0.14 to 0.15), social anxiety (d=0.04-0.23), anxiety sensitivity (d=-0.07 to 0.07), depressive symptoms (d=-0.05 to 0.04) or mental wellbeing (d=-0.06 to -0.30). LIMITATIONS: The current study only included self-report measures that may have been influenced by situational factors or biases. CONCLUSIONS: The e-couch Anxiety and Worry program did not have a significant positive effect on participant mental health or wellbeing. The addition of a mental health education officer to support classroom teachers in the delivery of the program also had no effect on intervention outcomes. Future prevention research should look to develop briefer and more interactive interventions that are more engaging for youth. PMID- 26926661 TI - Endoscopic Evaluation of Angiogenesis in the Large Airways of Horses with Heaves Using Narrow Band Imaging. AB - BACKGROUND: Heaves is a severe debilitating condition of horses, characterized by lower airway inflammation and permanent structural changes of the bronchial wall. Chronic inflammation promotes the formation of new vessels, a phenomenon known as angiogenesis. Narrow band imaging (NBI) endoscopy is a noninvasive technique that enhances the visualization of submucosal vessels, and commonly is employed for the study of angiogenesis in human patients. OBJECTIVES: Using NBI, we aimed to determine whether or not the central airways of horses with heaves undergo angiogenesis. ANIMALS: Horses with heaves during exacerbation of the disease (n = 5) and healthy controls (n = 6). METHODS: A library of NBI images was established from previously recorded videoendoscopies. Images were acquired by an operator blinded to horse ID. Images were obtained from 3 sites: 130 from the trachea (14 +/- 9.3 [mean +/- SD] images per horse with heaves and 10 +/- 5.4 from controls; P = .45), 58 from the carina (5.4 +/- 3.2 from horses with heaves and 5.2 +/- 2.8 fromn controls; P > .99) and 167 from the intermediate bronchi (17.8 +/- 6.7 from horses with heaves and 13 +/- 5.6 from controls; P = .17). Using dedicated stereology software (NewCAST, Visiopharm; Denmark), the volume density of superficial and deep vessels was calculated blindly by point counting at each site for all horses. RESULTS: In the trachea, the volume density of superficial vessels was increased in horses with heaves compared to controls (P = .02). No difference was found between groups for the volume density of both superficial and deep vessels at the carina or intermediate bronchi. CONCLUSION AND CLINICAL RELEVANCE: NBI imaging of the airways was easily performed in standing sedated horses. PMID- 26926662 TI - Liraglutide for treating type 1 diabetes. AB - INTRODUCTION: Many persons with type 1 diabetes do not achieve glycemic targets, why new treatments, complementary to insulin, are of interest. Liraglutide, a long-acting glucagon-like peptide-1 receptor agonist could be a potential pharmacological supplement to insulin. This review discusses the mechanism of actions, efficacy and safety of liraglutide as add-on to insulin in persons with type 1 diabetes. AREAS COVERED: Physiological and clinical data on liraglutide in type 1 diabetes were reviewed. We searched the Cochrane library, MEDLINE and EMBASE, with the final search performed February 16, 2016. EXPERT OPINION: Liraglutide as adjunct to insulin treatment reduced body weight and daily dose of insulin compared with insulin alone. The effect on HbA1c was inconsistent with mostly uncontrolled, small-scale studies reporting improvements in glycemic control. In placebo-controlled studies there was no clinically relevant effect on HbA1c. Adverse events were mostly transient gastrointestinal side effects, primarily nausea. Based on the available data, liraglutide cannot be recommended as add-on therapy to insulin in persons with type 1 diabetes with the aim to improve glycemic control. Ongoing trials in newly diagnosed patients with type 1 diabetes and in insulin pump-treated patients will help define the future role of liraglutide therapy in type 1 diabetes. PMID- 26926663 TI - Spectroscopic and molecular modeling methods to study the interaction between naphthalimide-polyamine conjugates and DNA. AB - The effect of polyamine side chains on the interaction between naphthalimide polyamine conjugates (1-7) and herring sperm DNA was studied by UV/vis absorption and fluorescent spectra under physiological conditions (pH=7.4). The diverse spectral data and further molecular docking simulation in silico indicated that the aromatic moiety of these compounds could intercalate into the DNA base pairs while the polyamine motif might simultaneously locate in the minor groove. The triamine compound 7 can interact more potently with DNA than the corresponding diamine compounds (1-6). The presence of the bulky terminal group in the diamine side chain reduced the binding strength of compound 1 with DNA, compared to other diamine compounds (2-6). In addition, the increasing methylene number in the diamine backbone generally results in the elevated binding constant of compounds DNA complex. The fluorescent tests at different temperature revealed that the quenching mechanism was a static type. The binding constant and thermodynamic parameter showed that the binding strength and the type of interaction force, associated with the side chains, were mainly hydrogen bonding and hydrophobic force. And the calculated free binding energies of molecular docking are generally consistent with the stability of polyamine-DNA complexes. The circular dichroism assay about the impact of compounds 1-7 on DNA conformation testified the B to A-like conformational change. PMID- 26926664 TI - Association between FNDC5 genetic variants and proliferative diabetic retinopathy in a Chinese population. PMID- 26926665 TI - Pain Reactions during Pulmonary Vein Isolation under Deep Sedation: Cryothermal versus Radiofrequency Ablation. AB - BACKGROUND: Left atrial ablation can be accompanied by discomfort or pain. The purpose of this study was to systematically compare pain reactions during ablation of atrial fibrillation under deep sedation with cryothermal and radiofrequency energy. METHODS AND RESULTS: Circumferential ablation was performed in patients with atrial fibrillation using either radiofrequency (RF) or cryoenergy. Deep sedation was achieved with a combination of propofol and midazolam. Pain reactions were counted and painful ablation sites located. To determine the severity of the pain reactions a Face, Legs, Activity, Cry, Consolability (FLACC) Behavioral Pain Assessment Scale was used: 79 patients (53 RF- vs 26 Cryoablations) were included. A total of 92% of patients treated with RF energy showed >=1 pain reaction during the procedure compared to only 13% in the cryoenergy group (<0.001). The total number of pain reactions was significantly higher in the RF energy group (3.6 +/- 4.7 vs1.3 +/- 0.6, P = 0.005). Determination of painful sites was performed in the RF group only. Pain reactions were significantly more often observed during RF application left superior pulmonary vein (LSPV) ostium compared to other left atrial ablation sites (Total FLACC Score 2.8 +/- 0.6 LSPV, 1.4 +/- 0.4 left inferior pulmonary vein [P = 0.009], 1.4 +/- 0.3 right superior pulmonary vein [P = 0.044], 1.1 +/- 0.3 right inferior pulmonary vein [P = 0.032]). CONCLUSIONS: Our results show that despite deep sedation pain reactions often occur during RF ablation. Knowledge of areas with more frequent pain reactions may help electrophysiologists to reduce pain reactions and related patient movements. Ablation with cryoenergy was significantly less painful compared to ablation with RF energy. Cryoablation therefore may be considered for patients at a higher risk for anesthesia-related complications. PMID- 26926666 TI - Genome-wide DNA polymorphism in the indica rice varieties RGD-7S and Taifeng B as revealed by whole genome re-sequencing. AB - Next-generation sequencing technologies provide opportunities to further understand genetic variation, even within closely related cultivars. We performed whole genome resequencing of two elite indica rice varieties, RGD-7S and Taifeng B, whose F1 progeny showed hybrid weakness and hybrid vigor when grown in the early- and late-cropping seasons, respectively. Approximately 150 million 100-bp pair-end reads were generated, which covered ~86% of the rice (Oryza sativa L. japonica 'Nipponbare') reference genome. A total of 2,758,740 polymorphic sites including 2,408,845 SNPs and 349,895 InDels were detected in RGD-7S and Taifeng B, respectively. Applying stringent parameters, we identified 961,791 SNPs and 46,640 InDels between RGD-7S and Taifeng B (RGD-7S/Taifeng B). The density of DNA polymorphisms was 256.8 SNPs and 12.5 InDels per 100 kb for RGD-7S/Taifeng B. Copy number variations (CNVs) were also investigated. In RGD-7S, 1989 of 2727 CNVs were overlapped in 218 genes, and 1231 of 2010 CNVs were annotated in 175 genes in Taifeng B. In addition, we verified a subset of InDels in the interval of hybrid weakness genes, Hw3 and Hw4, and obtained some polymorphic InDel markers, which will provide a sound foundation for cloning hybrid weakness genes. Analysis of genomic variations will also contribute to understanding the genetic basis of hybrid weakness and heterosis. PMID- 26926667 TI - Probing the Energy Level Alignment and the Correlation with Open-Circuit Voltage in Solution-Processed Polymeric Bulk Heterojunction Photovoltaic Devices. AB - Energy level alignment at the organic donor and acceptor interface is a key to determine the photovoltaic performance in organic solar cells, but direct probing of such energy alignment is still challenging especially for solution-processed bulk heterojunction (BHJ) thin films. Here we report a systematic investigation on probing the energy level alignment with different approaches in five commonly used polymer:[6,6]-phenyl-C71-butyric acid methyl ester (PCBM) BHJ systems. We find that by tuning the weight ratio of polymer to PCBM the electronic features from both polymer and PCBM can be obtained by photoemission spectroscopy. Using this approach, we find that some of the BHJ blends simply follow vacuum level alignment, but others show strong energy level shifting as a result of Fermi level pinning. Independently, by measuring the temperature-dependent open-circuit voltage (VOC), we find that the effective energy gap (Eeff), the energy difference between the highest occupied molecular orbital of the polymer donor (EHOMO-D) and lowest unoccupied molecular orbital of the PCBM acceptor (ELUMO-A), obtained by photoemission spectroscopy in all polymer:PCBM blends has an excellent agreement with the extrapolated VOC at 0 K. Consequently, the photovoltage loss of various organic BHJ photovoltaic devices at room temperature is in a range of 0.3-0.6 V. It is believed that the demonstrated direct measurement approach of the energy level alignment in solution-processed organic BHJ will bring deeper insight into the origin of the VOC and the corresponding photovoltage loss mechanism in organic photovoltaic cells. PMID- 26926668 TI - A Single-Dose, Open-Label Study of the Pharmacokinetics, Safety, and Tolerability of Lisdexamfetamine Dimesylate in Individuals With Normal and Impaired Renal Function. AB - BACKGROUND: Lisdexamfetamine (LDX) and D-amphetamine pharmacokinetics were assessed in individuals with normal and impaired renal function after a single LDX dose; LDX and D-amphetamine dialyzability was also examined. METHODS: Adults (N = 40; 8/group) were enrolled in 1 of 5 renal function groups [normal function, mild impairment, moderate impairment, severe impairment/end-stage renal disease (ESRD) not requiring hemodialysis, and ESRD requiring hemodialysis] as estimated by glomerular filtration rate (GFR). Participants with normal and mild to severe renal impairment received 30 mg LDX; blood samples were collected predose and serially for 96 hours. Participants with ESRD requiring hemodialysis received 30 mg LDX predialysis and postdialysis separated by a washout period of 7-14 days. Predialysis blood samples were collected predose, serially for 72 hours, and from the dialyzer during hemodialysis; postdialysis blood samples were collected predose and serially for 48 hours. Pharmacokinetic end points included maximum plasma concentration (Cmax) and area under the plasma concentration versus time curve from time 0 to infinity (AUC0-infinity) or to last assessment (AUClast). RESULTS: Mean LDX Cmax, AUClast, and AUC0-infinity in participants with mild to severe renal impairment did not differ from those with normal renal function; participants with ESRD had higher mean Cmax and AUClast than those with normal renal function. D-amphetamine exposure (AUClast and AUC0-infinity) increased and Cmax decreased as renal impairment increased. Almost no LDX and little D amphetamine were recovered in the dialyzate. CONCLUSIONS: There seems to be prolonged D-amphetamine exposure after 30 mg LDX as renal impairment increases. In individuals with severe renal impairment (GFR: 15 <= 30 mL.min.1.73 m), the maximum LDX dose is 50 mg/d; in patients with ESRD (GFR: <15 mL.min.1.73 m), the maximum LDX dose is 30 mg/d. Neither LDX nor D-amphetamine is dialyzable. PMID- 26926669 TI - Management of Everolimus and Voriconazole Interaction in Lung Transplant Patients. AB - BACKGROUND: To analyze the impact of voriconazole administration on everolimus dose, trough concentrations and concentration/dose (C0/D) ratio in order to determine the appropriate management of this interaction in lung transplant patients. METHODS: A retrospective study of 16 of consecutive lung transplant patients on a stable everolimus-based regimen to which oral voriconazole was added from January 2013 to February 2014. Everolimus blood levels were measured using the Thermo Scientific QMS Everolimus Immunoassay on an ARCHITECT-C8000 analyzer. The Wilcoxon signed-rank test was used to assess the exposure parameter variations before, during, and after azole withdrawal. A statistical analysis was performed using SPSS version 19.0. P-value < 0.05 was considered statistically significant. RESULTS: Sixteen patients were included. Voriconazole treatment led to a significant 8.7-fold increase in the everolimus C0/D ratio. Although initially the daily dose was reduced to 48.5% +/- 20.5%, and subsequently to 79.5% +/- 7.1%, the desired therapeutic levels were achieved in all patients when it was decreased to 86.6% +/- 3.9%. After its withdrawal, the C0/D ratio returned to values similar to the baseline situation. The comparison of exposure parameters studied at stable moments, before and after the completion of azole treatment with the cotreatment period, revealed significant changes (P < 0.05). CONCLUSIONS: Oral voriconazole is a strong inhibitor of everolimus metabolism, requiring a dose reduction of around 87%. At the time of azole withdrawal, the dose should be increased to achieve C0/D ratio values similar to the initial situation. In our clinical practice, for a safe coadministration, a preemptive decrease to 75% of everolimus dose with the first azole prescription is recommended. Close monitoring of the everolimus concentrations and corresponding dosage adjustments are necessary until the target levels are achieved during both periods. PMID- 26926670 TI - Switching From Intermittent to Continuous Infusion of Vancomycin in Critically Ill Patients: Toward a More Robust Exposure. AB - BACKGROUND: To increase target attainment rates, switching the mode of administration from intermittent (InI) to continuous infusion (CoI) has been proposed. In this study, target attainment rates and interpatient variation in exposure were compared between vancomycin InI- and CoI-treated critically ill patients. METHODS: An observational cohort study was conducted among critically ill patients admitted to a level-2 intensive care unit. Adult patients (18 years or older) treated with intravenous vancomycin for various indications, including sepsis, pneumonia, and endocarditis between 2007 and 2013 were eligible for inclusion. In 2010, vancomycin mode of administration switched from intermittent to continuous. Vancomycin was administered through intravenous infusion, and dosing was guided by therapeutic drug monitoring. Target attainment rates and variations in serum concentration and estimated area under the curve (AUC) were compared between groups. RESULTS: The target attainment rate for therapeutic vancomycin exposure was higher in the group treated with CoI than in patients treated with InI (48% versus 19%, P < 0.001). Furthermore, between-patient variation in vancomycin serum concentration was nearly twice as high in intermittently infused patients compared with continuously infused patients. Finally, the correlation between serum concentration and AUC was stronger among patients on vancomycin continuous infusion than that of the intermittently dosed group (r 0.93 versus 0.72). CONCLUSIONS: Switching from intermittent to continuous infusion of vancomycin in a critically ill population provided higher target attainment rates and a more robust drug exposure. Furthermore, continuous infusion yielded stronger concentration-AUC correlations facilitating a single sample therapeutic drug monitoring strategy with AUC targets. A switch to continuous infusion may therefore improve clinical outcomes in vancomycin-treated critically ill patients. PMID- 26926671 TI - A systematic review of interventions to improve medication information for low health literate populations. AB - BACKGROUND: Health literacy is a barrier to accurately understanding medication information. Current medication information is too difficult to understand for low health literate populations, which imposes a higher risk of misinterpreting prescription label instructions, dosage, duration, frequency, warning labels, written information and verbal pharmacist counseling. OBJECTIVES: The primary objective of this paper was to systematically review the evidence on interventions for improving medication knowledge and adherence for low health literate populations. METHODS: A database search of PubMed, Embase, International Pharmaceutical Abstracts, Web of Science, Cochrane Library, CINAHL, PsycINFO, and Scopus databases from the start of each database to studies published prior to March 30, 2015. Studies were included if they explicitly stated they included low health literate populations, included outcome measures for knowledge and/or adherence, focused on medication information, were written in English and were available in full text. Full text papers were excluded if there was no clear mention of an intervention being studied, if the intervention had no focus on any of the domains of health literacy, and if the authors did not specify the inclusion of patients with low health literacy. RESULTS: The review identified 1553 titles, 1009 abstracts, and 168 full text articles and included 47 articles in the final review. Of the 47 included studies, 70.2% (33/47) were published in the United States and 87.2 (41/47) were published between 2005 and 2014. Studies were grouped into six different types of interventions 1) written information 2) visual information 3) verbal information 4) label/medication bottle 5) reminder systems and 6) educational programs and services. Results demonstrate significant improvement of knowledge in 27 of 37 interventions and a significant improvement of adherence in 19 of 26 interventions. CONCLUSIONS: Interventions designed to support low health literate populations can improve patients' medication knowledge and adherence. The most effective interventions include additional aids that enforce written information, information that is personalized, information that is easy to navigate and tools that can be accessed when needed. PMID- 26926672 TI - Nocebo in headache. AB - PURPOSE OF REVIEW: This article addresses nocebo in headache. Nocebo is the antipode of placebo and refers to adverse events a person manifests after receiving placebo. RECENT FINDINGS: In randomized trials for migraine prevention meta-analyses revealed that eight out of 20 patients treated with placebo experienced any adverse event. More importantly, one out of 20 patients treated with placebo withdrew treatment because of adverse events. The adverse events in placebo groups mirrored the adverse events expected of the active medication studied, confirming that pretrial suggestions induce the adverse events in placebo-treated patients. Nocebo was higher in preventive treatments than in symptomatic ones. Among preventive migraine treatments botulin toxin A showed the lowest nocebo. Generally, the safer a drug was the less nocebo was induced. Nocebo was similar in trials for tension-type headache. To predict and prevent nocebo consequences a 4-item self-fulfilled questionnaire (Q-No) has been developed, with 72% specificity and 67% sensitivity. SUMMARY: Although nocebo remains largely unknown in the medical community, it limits adherence and treatment outcomes significantly in preventive treatments for migraine and tension-type headache. The Q-No questionnaire may help in predicting nocebo, whereas individualized strategies are needed to prevent nocebo consequences. PMID- 26926673 TI - SPARC Promotes Cell Invasion In Vivo by Decreasing Type IV Collagen Levels in the Basement Membrane. AB - Overexpression of SPARC, a collagen-binding glycoprotein, is strongly associated with tumor invasion through extracellular matrix in many aggressive cancers. SPARC regulates numerous cellular processes including integrin-mediated cell adhesion, cell signaling pathways, and extracellular matrix assembly; however, the mechanism by which SPARC promotes cell invasion in vivo remains unclear. A main obstacle in understanding SPARC function has been the difficulty of visualizing and experimentally examining the dynamic interactions between invasive cells, extracellular matrix and SPARC in native tissue environments. Using the model of anchor cell invasion through the basement membrane (BM) extracellular matrix in Caenorhabditis elegans, we find that SPARC overexpression is highly pro-invasive and rescues BM transmigration in mutants with defects in diverse aspects of invasion, including cell polarity, invadopodia formation, and matrix metalloproteinase expression. By examining BM assembly, we find that overexpression of SPARC specifically decreases levels of BM type IV collagen, a crucial structural BM component. Reduction of type IV collagen mimicked SPARC overexpression and was sufficient to promote invasion. Tissue-specific overexpression and photobleaching experiments revealed that SPARC acts extracellularly to inhibit collagen incorporation into BM. By reducing endogenous SPARC, we also found that SPARC functions normally to traffic collagen from its site of synthesis to tissues that do not express collagen. We propose that a surplus of SPARC disrupts extracellular collagen trafficking and reduces BM collagen incorporation, thus weakening the BM barrier and dramatically enhancing its ability to be breached by invasive cells. PMID- 26926674 TI - Pedometer intervention and weight loss in overweight and obese adults with Type 2 diabetes: a meta-analysis. AB - AIM: Although pedometer intervention is effective in increasing physical activity among adults with Type 2 diabetes, its impact on weight loss remains unclear. This meta-analysis was aimed to assess whether pedometer intervention promotes weight loss. METHODS: Three different databases were searched for randomized controlled trials (RCTs) published in English up to April 2015. Studies were included if they investigated the effects of pedometer intervention on weight loss, as measured by BMI or weight. Effect sizes were aggregated using a random effects model. Subgroup and meta-regression analyses were used to identify potential moderators. Eleven RCTs with 1258 participants were included. All enrolled participants were overweight or obese. RESULTS: Pedometer intervention led to significantly decreased BMI [weighted mean difference (WMD) -0.15 kg/m(2) , 95% confidence interval (CI) -0.29 to -0.02 kg/m(2) ] and reduced weight (WMD 0.65 kg, 95% CI -1.12 to -0.17 kg). Dietary counselling seemed to be a key predictor of the observed changes. However, none of the following variables had a significant influence: step goal setting, baseline age, BMI, weight, sex distribution, disease duration, intervention duration, and baseline values or change scores for total or moderate-to-vigorous physical activity. After completion of the pedometer intervention, non-significant declines in BMI and weight were observed during the follow-up periods. CONCLUSIONS: Pedometer intervention promotes modest weight loss, but its association with physical activity requires further clarification. Future studies are also required to document dietary and sedentary behaviour changes to facilitate the use of pedometers for weight loss in overweight and obese adults with Type 2 diabetes. PMID- 26926675 TI - Distinctive Cancer Associations in Patients With Neurofibromatosis Type 1. AB - PURPOSE: The current study was designed to determine the risk of cancer in patients with neurofibromatosis type 1 (NF1) by cancer type, age, and sex with unprecedented accuracy to be achieved by combining two total population-based registers. PATIENTS AND METHODS: A population-based series of patients with NF1 (N = 1,404; 19,076 person-years) was linked to incident cancers recorded in the Finnish Cancer Registry and deaths recorded in the national Population Register Centre between 1987 and 2012. Standardized incidence ratios (SIRs) and standardized mortality ratios (SMRs) were calculated for selected cancer types. Survival of the patients with cancer with and without NF1 was compared. RESULTS: In malignant peripheral nerve sheath tumors and CNS tumors, the cancers traditionally associated with NF1, we observed SIRs of 2,056 (95% CI, 1,561 to 2,658), and 37.5 (95% CI, 30.2 to 46.0), respectively, and SMRs of 2,301 (95% CI, 1,652 to 3,122) and 30.2 (95% CI, 19.1 to 45.2), respectively. We found an unequivocally increased risk for breast cancer. In particular, SIR was 11.1 (95% CI, 5.56 to 19.5) for breast cancer in women with NF1 age < 40 years; the overall SMR for breast cancer was 5.20 (95% CI, 2.38 to 9.88). Particularly high overall SIRs were observed in patients with NF1 age < 15 years: women, 87.6 (95% CI, 58.6 to 125); men, 45.6 (95% CI, 28.4 to 68.5). An estimated lifetime cancer risk for patients with NF1 was 59.6%. The 5-year survival of patients with cancer and NF1, excluding nervous tissue cancers, was worse than that of comparable patients with cancers without NF1 (54.0% v 67.5%; P = .01). CONCLUSION: Our results emphasize the general cancer proclivity of patients with NF1. These findings should translate to clinical practices to determine clinical interventions and focused follow-up of patients with NF1. PMID- 26926676 TI - West German Study Group Phase III PlanB Trial: First Prospective Outcome Data for the 21-Gene Recurrence Score Assay and Concordance of Prognostic Markers by Central and Local Pathology Assessment. AB - PURPOSE: The 21-gene Recurrence Score (RS) assay is a validated prognostic/predictive tool in early hormone receptor-positive breast cancer (BC); however, only a few prospective outcome results have been available so far. In the phase III PlanB trial, RS was prospectively used to define a subset of patients who received only endocrine therapy. We present 3-year outcome data and concordance analysis (among biomarkers/RS). PATIENTS AND METHODS: Central tumor bank was established prospectively from PlanB (intermediate and high-risk, locally human epidermal growth factor receptor 2-negative BC). After an early amendment, HR-positive, pN0-1 patients with RS <= 11 were recommended to omit chemotherapy. RESULTS: From 2009 to 2011, PlanB enrolled 3,198 patients with a median age of 56 years; 41.1% had node-positive and 32.5% grade 3 disease. In 348 patients (15.3%), chemotherapy was omitted based on RS <= 11. After 35 months median follow-up, 3-year disease-free survival in patients with RS <= 11 and endocrine therapy alone was 98% versus 92% and 98% in RS > 25 and RS 12 to 25 in chemotherapy-treated patients, respectively. Nodal status, central and local grade, the Ki-67 protein encoded by the MKI67 gene, estrogen receptor, progesterone receptor, tumor size, and RS were univariate prognostic factors for disease-free survival; only nodal status, both central and local grade, and RS were independent multivariate factors. Histologic grade was discordant between central and local laboratories in 44%. RS was positively but moderately correlated with the Ki-67 protein encoded by the MKI67 gene and grade and negatively correlated with progesterone receptor and estrogen receptor. CONCLUSION: In this prospective trial, patients with enhanced clinical risk and omitted chemotherapy on the basis of RS <= 11 had excellent 3-year survival. The substantial discordance observed between traditional prognostic markers and RS emphasizes the need for standardized assessment and supports the potential integration of standardized, well-validated genomic assays such as RS with clinicopathologic prognostic factors for chemotherapy indication in early hormone receptor-positive BC. PMID- 26926677 TI - Detection of Occult Micrometastases in Patients With Clinical Stage I Non-Small Cell Lung Cancer: A Prospective Analysis of Mature Results of CALGB 9761 (Alliance). AB - PURPOSE: Outcomes after resection of stage I non-small-cell lung cancer (NSCLC) are variable, potentially due to undetected occult micrometastases (OM). Cancer and Leukemia Group B 9761 was a prospectively designed study aimed at determining the prognostic significance of OM. MATERIALS AND METHODS: Between 1997 and 2002, 502 patients with suspected clinical stage I (T1-2N0M0) NSCLC were prospectively enrolled at 11 institutions. Primary tumor and lymph nodes (LNs) were collected and sent to a central site for molecular analysis. Both were assayed for OM using immunohistochemistry (IHC) for cytokeratin (AE1/AE3) and real-time reverse transcriptase polymerase chain reaction (RT-PCR) for carcinoembryonic antigen. RESULTS: Four hundred eighty-nine of the 502 enrolled patients underwent complete surgical staging. Three hundred four patients (61%) had pathologic stage I NSCLC (T1, 58%; T2, 42%) and were included in the final analysis. Fifty-six percent had adenocarcinomas, 34% had squamous cell carcinomas, and 10% had another histology. LNs from 298 patients were analyzed by IHC; 41 (14%) were IHC-positive (42% in N1 position, 58% in N2 position). Neither overall survival (OS) nor disease-free survival was associated with IHC positivity; however, patients who had IHC positive N2 LNs had statistically significantly worse survival rates (hazard ratio, 2.04, P = .017). LNs from 256 patients were analyzed by RT-PCR; 176 (69%) were PCR-positive (52% in N1 position, 48% in N2 position). Neither OS nor disease-free survival was associated with PCR positivity. CONCLUSION: NSCLC tumor markers can be detected in histologically negative LNs by AE1/AE3 IHC and carcinoembryonic antigen RT-PCR. In this prospective, multi-institutional trial, the presence of OM by IHC staining in N2 LNs of patients with NSCLC correlated with decreased OS. The clinical significance of this warrants further investigation. PMID- 26926678 TI - Association of Financial Strain With Symptom Burden and Quality of Life for Patients With Lung or Colorectal Cancer. AB - PURPOSE: To measure the association between patient financial strain and symptom burden and quality of life (QOL) for patients with new diagnoses of lung or colorectal cancer. PATIENTS AND METHODS: Patients participating in the Cancer Care Outcomes Research and Surveillance study were interviewed about their financial reserves, QOL, and symptom burden at 4 months of diagnosis and, for survivors, at 12 months of diagnosis. We assessed the association of patient reported financial reserves with patient-reported outcomes including the Brief Pain Inventory, symptom burden on the basis of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30, and QOL on the basis of the EuroQoL-5 Dimension scale. Multivariable linear regression models were fit for each outcome and cancer type, adjusting for age, race/ethnicity, sex, income, insurance, stage at diagnosis, and comorbidity. RESULTS: Among patients with lung and colorectal cancer, 40% and 33%, respectively, reported limited financial reserves (<= 2 months). Relative to patients with more than 12 months of financial reserves, those with limited financial reserves reported significantly increased pain (adjusted mean difference, 5.03 [95% CI, 3.29 to 7.22] and 3.45 [95% CI, 1.25 to 5.66], respectively, for lung and colorectal), greater symptom burden (5.25 [95% CI, 3.29 to .22] and 5.31 [95% CI, 3.58 to 7.04]), and poorer QOL (4.70 [95% CI, 2.82 to 6.58] and 5.22 [95% CI, 3.61 to 6.82]). With decreasing financial reserves, a clear dose-response relationship was present across all measures of well-being. These associations were also manifest for survivors reporting outcomes again at 1 year and persisted after adjustment for stage, comorbidity, insurance, and other clinical attributes. CONCLUSION: Patients with cancer and limited financial reserves are more likely to have higher symptom burden and decreased QOL. Assessment of financial reserves may help identify patients who need intensive support. PMID- 26926679 TI - Prognostic Value of Ki-67 Index, Cytology, and Growth Pattern in Mantle-Cell Lymphoma: Results From Randomized Trials of the European Mantle Cell Lymphoma Network. AB - PURPOSE: Mantle-cell lymphoma (MCL) is a rather aggressive B-cell malignancy whose considerable variability of individual outcome is associated with clinical characteristics (Mantle Cell Lymphoma International Prognostic Index [MIPI]). The Ki-67 index is a strong independent prognostic factor; however, the biologic MIPI (MIPI-b) distinguishes only two groups, which does not appropriately depict the clinical heterogeneity. By using the cohort from the European MCL Younger and MCL Elderly trials, we aimed to evaluate the additional prognostic impact of cytology and growth pattern and to improve risk stratification with the Ki-67 index and MIPI. PATIENTS AND METHODS: Diagnostic tumor biopsies were reviewed by the European Mantle Cell Lymphoma Pathology Panel to determine Ki-67 index by using published guidelines, cytology, and growth pattern. We evaluated prognostic effects for overall survival (OS) by Cox regression. For the cohort used for MIPI b development (German Low-Grade Lymphoma Study Group [GLSG] 1996 and GLSG2000), we checked whether the equally weighted combination of Ki-67 index (dichotomized at the validated 30% cutoff) and MIPI risk groups was adequate and compared the prognostic power of this modified combination to MIPI and MIPI-b for the MCL Younger/MCL Elderly cohort. RESULTS: The Ki-67 index was assessed in 508 of 832 patients (median age, 62 years). Blastoid cytology was associated with inferior OS independently of MIPI but not independently of the Ki-67 index. Growth pattern was not independently prognostic. The modified combination of the Ki-67 index and MIPI separated four groups with 5-year OS: 85%, 72%, 43%, and 17% (P < .001) and was more discriminative than MIPI and MIPI-b. CONCLUSION: Using the Ki-67 index is superior to using cytology and growth pattern as prognostic factors in MCL. The modified combination of the Ki-67 index and MIPI showed a refined risk stratification, reflecting their strong complementary prognostic effects while integrating the most relevant prognostic factors available in clinical routine. PMID- 26926680 TI - Phase II Study of Autologous Monocyte-Derived mRNA Electroporated Dendritic Cells (TriMixDC-MEL) Plus Ipilimumab in Patients With Pretreated Advanced Melanoma. AB - PURPOSE: Autologous monocyte-derived dendritic cells (DCs) electroporated with synthetic mRNA (TriMixDC-MEL) are immunogenic and have antitumor activity as a monotherapy in patients with pretreated advanced melanoma. Ipilimumab, an immunoglobulin G1 monoclonal antibody directed against the cytotoxic T-lymphocyte associated protein 4 receptor that counteracts physiologic suppression of T-cell function, improves the overall survival of patients with advanced melanoma. This phase II study investigated the combination of TriMixDC-MEL and ipilimumab in patients with pretreated advanced melanoma. PATIENTS AND METHODS: Thirty-nine patients were treated with TriMixDC-MEL (4 * 10(6) cells administered intradermally and 20 * 10(6) cells administered intravenously) plus ipilimumab (10 mg/kg every 3 weeks for a total of four administrations, followed by maintenance therapy every 12 weeks in patients who remained progression free). Six-month disease control rate according to the immune-related response criteria served as the primary end point. RESULTS: The 6-month disease control rate was 51% (95% CI, 36% to 67%), and the overall tumor response rate was 38% (including eight complete and seven partial responses). Seven complete responses and one partial tumor response are ongoing after a median follow-up time of 36 months (range, 22 to 43 months). The most common treatment-related adverse events (all grades) consisted of local DC injection site skin reactions (100%), transient post-DC infusion chills (38%) and flu-like symptoms (84%), dermatitis (64%), hepatitis (13%), hypophysitis (15%), and diarrhea/colitis (15%). Grade 3 or 4 immune-related adverse events occurred in 36% of patients. There was no grade 5 adverse event. CONCLUSION: The combination of TriMixDC-MEL and ipilimumab is tolerable and results in an encouraging rate of highly durable tumor responses in patients with pretreated advanced melanoma. PMID- 26926681 TI - Docetaxel As Monotherapy or Combined With Ramucirumab or Icrucumab in Second-Line Treatment for Locally Advanced or Metastatic Urothelial Carcinoma: An Open-Label, Three-Arm, Randomized Controlled Phase II Trial. AB - PURPOSE: This trial assessed the efficacy and safety of docetaxel monotherapy or docetaxel in combination with ramucirumab (vascular endothelial growth factor receptor 2 antibody) or icrucumab (vascular endothelial growth factor receptor 1 antibody) after progression during or within 12 months of platinum-based regimens for patients with locally advanced or metastatic urothelial carcinoma. PATIENTS AND METHODS: Patients were randomly assigned (1:1:1) to receive docetaxel 75 mg/m(2) intravenously (IV) on day 1 of a 3-week cycle (arm A), docetaxel 75 mg/m(2) IV plus ramucirumab 10 mg/kg IV on day 1 of a 3-week cycle (arm B), or docetaxel 75 mg/m(2) IV on day 1 plus icrucumab 12 mg/kg IV on days 1 and 8 of a 3-week cycle (arm C). Treatment continued until disease progression or unacceptable toxicity. The primary end point was investigator-assessed progression-free survival (PFS). RESULTS: A total of 140 patients were randomly assigned and treated in arms A (n = 45), B (n = 46), or C (n = 49). PFS was significantly longer in arm B compared with arm A (median, 5.4 months; 95% CI, 3.1 to 6.9 months v 2.8 months; 95% CI, 1.9 to 3.6 months; stratified hazard ratio, 0.389; 95% CI, 0.235 to 0.643; P = .0002). Arm C did not experience improved PFS compared with arm A (1.6 months; 95% CI, 1.4 to 2.9; stratified hazard ratio, 0.863; 95% CI, 0.550 to 1.357; P = .5053). The most common grade 3 or worse adverse events (arms A, B, and C) were neutropenia (36%, 33%, and 39%), fatigue (13%, 30%, and 20%), febrile neutropenia (13%, 17%, and 6.1%), and anemia (6.7%, 13%, and 14%, respectively). CONCLUSION: The addition of ramucirumab to docetaxel met the prespecified efficacy end point for prolonging PFS in patients with locally advanced or metastatic urothelial carcinoma receiving second-line treatment and warrants further investigation in the phase III setting. PMID- 26926682 TI - Case Example of Dose Optimization Using Data From Bortezomib Dose-Finding Clinical Trials. AB - PURPOSE: The current dose-finding methodology for estimating the maximum tolerated dose of investigational anticancer agents is based on the cytotoxic chemotherapy paradigm. Molecularly targeted agents (MTAs) have different toxicity profiles, which may lead to more long-lasting mild or moderate toxicities as well as to late-onset and cumulative toxicities. Several approved MTAs have been poorly tolerated during long-term administration, leading to postmarketing dose optimization studies to re-evaluate the optimal treatment dose. Using data from completed bortezomib dose-finding trials, we explore its toxicity profile, optimize its dose, and examine the appropriateness of current designs for identifying an optimal dose. PATIENTS AND METHODS: We classified the toxicities captured from 481 patients in 14 bortezomib dose-finding studies conducted through the National Cancer Institute Cancer Therapy Evaluation Program, computed the incidence of late-onset toxicities, and compared the incidence of dose limiting toxicities (DLTs) among groups of patients receiving different doses of bortezomib. RESULTS: A total of 13,008 toxicities were captured: 46% of patients' first DLTs and 88% of dose reductions or discontinuations of treatment because of toxicity were observed after the first cycle. Moreover, for the approved dose of 1.3 mg/m(2), the estimated cumulative incidence of DLT was > 50%, and the estimated cumulative incidence of dose reduction or treatment discontinuation because of toxicity was nearly 40%. CONCLUSIONS: When considering the entire course of treatment, the approved bortezomib dose exceeds the conventional ceiling DLT rate of 20% to 33%. Retrospective analysis of trial data provides an opportunity for dose optimization of MTAs. Future dose-finding studies of MTAs should take into account late-onset toxicities to ensure that a tolerable dose is identified for future efficacy and comparative trials. PMID- 26926683 TI - Can Arts and Communication Programs Improve Physician Wellness and Mitigate Physician Suicide? PMID- 26926684 TI - Genomic Characterization of Primary Invasive Lobular Breast Cancer. AB - PURPOSE: Invasive lobular breast cancer (ILBC) is the second most common histologic subtype after invasive ductal breast cancer (IDBC). Despite clinical and pathologic differences, ILBC is still treated as IDBC. We aimed to identify genomic alterations in ILBC with potential clinical implications. METHODS: From an initial 630 ILBC primary tumors, we interrogated oncogenic substitutions and insertions and deletions of 360 cancer genes and genome-wide copy number aberrations in 413 and 170 ILBC samples, respectively, and correlated those findings with clinicopathologic and outcome features. RESULTS: Besides the high mutation frequency of CDH1 in 65% of tumors, alterations in one of the three key genes of the phosphatidylinositol 3-kinase pathway, PIK3CA, PTEN, and AKT1, were present in more than one-half of the cases. HER2 and HER3 were mutated in 5.1% and 3.6% of the tumors, with most of these mutations having a proven role in activating the human epidermal growth factor receptor/ERBB pathway. Mutations in FOXA1 and ESR1 copy number gains were detected in 9% and 25% of the samples. All these alterations were more frequent in ILBC than in IDBC. The histologic diversity of ILBC was associated with specific alterations, such as enrichment for HER2 mutations in the mixed, nonclassic, and ESR1 gains in the solid subtype. Survival analyses revealed that chromosome 1q and 11p gains showed independent prognostic value in ILBC and that HER2 and AKT1 mutations were associated with increased risk of early relapse. CONCLUSION: This study demonstrates that we can now begin to individualize the treatment of ILBC, with HER2, HER3, and AKT1 mutations representing high-prevalence therapeutic targets and FOXA1 mutations and ESR1 gains deserving urgent dedicated clinical investigation, especially in the context of endocrine treatment. PMID- 26926686 TI - Integration of Immuno-Oncology and Palliative Care. PMID- 26926685 TI - First-in-Class, First-in-Human Phase I Study of Selinexor, a Selective Inhibitor of Nuclear Export, in Patients With Advanced Solid Tumors. AB - Purpose This trial evaluated the safety, pharmacokinetics, pharmacodynamics, and efficacy of selinexor (KPT-330), a novel, oral small-molecule inhibitor of exportin 1 (XPO1/CRM1), and determined the recommended phase II dose. Patients and Methods In total, 189 patients with advanced solid tumors received selinexor (3 to 85 mg/m2) in 21- or 28-day cycles. Pre- and post-treatment levels of XPO1 mRNA in patient-derived leukocytes were determined by reverse transcriptase quantitative polymerase chain reaction, and tumor biopsies were examined by immunohistochemistry for changes in markers consistent with XPO1 inhibition. Antitumor response was assessed according Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 guidelines. Results The most common treatment-related adverse events included fatigue (70%), nausea (70%), anorexia (66%), and vomiting (49%), which were generally grade 1 or 2. Most commonly reported grade 3 or 4 toxicities were thrombocytopenia (16%), fatigue (15%), and hyponatremia (13%). Clinically significant major organ or cumulative toxicities were rare. The maximum-tolerated dose was defined at 65 mg/m2 using a twice-a-week (days 1 and 3) dosing schedule. The recommended phase II dose of 35 mg/m2 given twice a week was chosen based on better patient tolerability and no demonstrable improvement in radiologic response or disease stabilization compared with higher doses. Pharmacokinetics were dose proportional, with no evidence of drug accumulation. Dose-dependent elevations in XPO1 mRNA in leukocytes were demonstrated up to a dose level of 28 mg/m2 before plateauing, and paired tumor biopsies showed nuclear accumulation of key tumor-suppressor proteins, reduction of cell proliferation, and induction of apoptosis. Among 157 patients evaluable for response, one complete and six partial responses were observed (n = 7, 4%), with 27 patients (17%) achieving stable disease for >= 4 months. Conclusion Selinexor is a novel and safe therapeutic with broad antitumor activity. Further interrogation into this class of therapy is warranted. PMID- 26926687 TI - Reply to A. Wong et al. PMID- 26926688 TI - Reply to L.B. Saltz. PMID- 26926689 TI - Genetic Screening in All Young Patients With Colorectal Cancer? PMID- 26926691 TI - Extending MAM5 Meta-Model and JaCalIV E Framework to Integrate Smart Devices from Real Environments. AB - This paper presents the extension of a meta-model (MAM5) and a framework based on the model (JaCalIVE) for developing intelligent virtual environments. The goal of this extension is to develop augmented mirror worlds that represent a real and virtual world coupled, so that the virtual world not only reflects the real one, but also complements it. A new component called a smart resource artifact, that enables modelling and developing devices to access the real physical world, and a human in the loop agent to place a human in the system have been included in the meta-model and framework. The proposed extension of MAM5 has been tested by simulating a light control system where agents can access both virtual and real sensor/actuators through the smart resources developed. The results show that the use of real environment interactive elements (smart resource artifacts) in agent based simulations allows to minimize the error between simulated and real system. PMID- 26926690 TI - Prevalence and correlates of probable common mental disorders in a population with high prevalence of HIV in Zimbabwe. AB - BACKGROUND: In 2014 close to 10 million people living with HIV (PLWH) in sub Saharan Africa were on highly active anti-retroviral therapy (HAART). The incidence of non-communicable diseases has increased markedly in PLWH as mortality is reduced due to use of HAART. Common mental disorders (CMD) are highly prevalent in PLWH. We aimed to determine factors associated with probable CMD and depression, assessed by 2 locally validated screening tools in a population with high prevalence of HIV in Harare, Zimbabwe. METHODS: We carried out a cross-sectional survey of a systematic random sample of patients utilizing the largest primary health care facility in Harare. Adults aged >=18 years attending over a 2-week period were eligible, excluding those who were critically ill or unable to give written informed consent. Two locally validated screening tools the Shona symptom questionnaire (SSQ-14) and the Patient Health Questionnaire (PHQ-9) were administered by trained research assistants to identify probable CMD and depression. RESULTS: Of the 264 participants, 165 (62.5 %) were PLWH, and 92 % of these were on HAART. The prevalence of probable CMD (SSQ14 > = 9) and depression (PHQ9 > = 11) were higher among people living with HIV than among those without HIV (67.9 and 68.5 % vs 51.4 and 47.2 % respectively). Multivariable analysis showed female gender and recent negative life events to be associated with probable CMD and depression among PLWH (gender: OR = 2.32 95 % CI:1.07-5.05; negative life events: OR = 4.14; 95 % CI 1.17-14.49) and with depression (gender: OR = 1.84 95 % CI:0.85-4.02; negative life events: OR = 4.93.; 95 % CI 1.31-18.50) CONCLUSION: Elevated scores on self-report measures for CMD and depression are highly prevalent in this high HIV prevalence population. There is need to integrate packages of care for CMD and depression in existing primary health care programs for HIV/AIDS. PMID- 26926693 TI - Residual dizziness after the first BPPV episode: role of otolithic function and of a delayed diagnosis. AB - Residual dizziness (RD) following the resolution of a benign paroxysmal positional vertigo (BBPV) episode is frequently reported by patients. Possible causes are still under debate in the literature. This study discusses the possible role of otolithic function and of elapsed time from onset of symptoms to diagnosis in the genesis of RD. In total, 116 patients younger than 65 years with their first episode of BPPV and without any other comorbidities were enrolled in the study. Before a bedside examination, subjective visual vertical (SVV) was determined in the case of a history suggestive of BPPV. SVV was tested 1 week later in those patients with BPPV of the posterior semicircular canal, and in whom positioning maneuvers showed resolution of BPPV. At 1 week control, reported RD and Dizziness Handicap Inventory (DHI) were recorded. Diagnosis and treatment of BPPV occurred within 4 days in 43 patients (group A), between 5 and 8 days in 38 patients (group B) and in more than 9 days in 35 patients (group C). Higher values of reported RD and DHI were recorded in group C, while higher values of SVV deviation were recorded in group A with an inverse relationship between SVV and DHI. Initial peripheral vestibular function asymmetry due to BPPV can induce a new central adaptation. This adaptation becomes better established the longer otoconia remain floating in the endolymph. Because of these changes, the brain is unable to quickly readapt to the old pattern after resolution resulting in more persistent RD. PMID- 26926692 TI - Standardized pretreatment inflammatory laboratory markers and calculated ratios in patients with oral squamous cell carcinoma. AB - Analyzing the inflammatory microenvironment has become an important issue in the management of oral squamous cell carcinoma (OSCC). Pretreatment C-reactive protein (CRP) levels, leucocytes, monocytes, lymphocytes, neutrophils, basophils, eosinophils, platelets, neutrophil-to-lymphocyte ratio (NLR), derived NLR (dNLR), lymphocyte-to-monocyte ratio (LMR), and platelet-to-lymphocyte ratio (PLR) derived from the peripheral blood were analyzed. Receiver operating characteristic (ROC) curves determined a cut-off value for each parameter in 146 patients with OSCC compared with 93 controls and the results were associated with clinicopathological characteristics. CRP expression of tumors was measured by immunohistochemistry. ROC analysis determined cut-off values for CRP levels, leucocytes, monocytes, lymphocytes, neutrophils, NLR, dNLR, LMR, PLR and showed significant differences between the OSCC and control group. Compared with single laboratory tests calculated ratios were superior in measuring sensitivity and specificity of OSCC disease. NLR was significant directly associated and correlated with PLR. LMR was significant inversely associated and correlated with NLR and PLR. Immunohistochemical analysis did not show CRP expression of OSCCs. This study highlights the first analysis for cut-off values of pretreatment single laboratory tests and calculated ratios, which are strongly needed for a follow-up of cancer patients. Additionally, the calculated baselines can be used as a goal for successful immunotherapies in the future. The links between NLR, LMR, and PLR might be helpful for the clinical course (monitoring) of cancer patients and have been first described for OSCC in this study. Taken together, analyzing these data provides an additional practical guideline of further postoperative OSCC management. PMID- 26926694 TI - Hypoxia-Sensitive Materials for Biomedical Applications. AB - Hypoxia is a typical hallmark of various diseases, including cancer, ischemic diseases, and stroke. It is also associated with the disease progression. Therefore, it is critical to develop an effective strategy to target the hypoxic region for diagnosis and treatment. In this review, we summarize recent progress in the development of hypoxia-responsive systems for imaging, sensing and therapy. Two types of hypoxia-sensitive systems, the hypoxia inducible factor-1 based systems and bioreductive molecule based systems, were reviewed with comments on their advantages and limitations. Future opportunities and challenges are also discussed in the end. PMID- 26926695 TI - Artificial Muscle Devices: Innovations and Prospects for Fecal Incontinence Treatment. AB - Fecal incontinence describes the involuntary loss of bowel content, which is responsible for stigmatization and social exclusion. It affects about 45% of retirement home residents and overall more than 12% of the adult population. Severe fecal incontinence can be treated by the implantation of an artificial sphincter. Currently available implants, however, are not part of everyday surgery due to long-term re-operation rates of 95% and definitive explantation rates of 40%. Such figures suggest that the implants fail to reproduce the capabilities of the natural sphincter. This article reviews the artificial sphincters on the market and under development, presents their physical principles of operation and critically analyzes their performance. We highlight the geometrical and mechanical parameters crucial for the design of an artificial fecal sphincter and propose more advanced mechanisms of action for a biomimetic device with sensory feedback. Dielectric electro-active polymer actuators are especially attractive because of their versatility, response time, reaction forces, and energy consumption. The availability of such technology will enable fast pressure adaption comparable to the natural feedback mechanism, so that tissue atrophy and erosion can be avoided while maintaining continence during daily activities. PMID- 26926697 TI - Reported Outcomes of the Alexander Technique Lessons or Acupuncture Sessions for Persons With Chronic Neck Pain Article. PMID- 26926698 TI - Alexander Technique Lessons or Acupuncture Sessions for Persons With Chronic Neck Pain. PMID- 26926699 TI - Correction: History and Future of Treatment of Hypothyroidism. AB - There is an error in a recent article. The last sentence of the section titled "L Thyroxine Monotherapy Fails to Restore All Markers of Hypothyroidism" should read "new technology is needed to allow for steady delivery of L-triiodothyronine" (it currently reads "... for steady delivery of L-thyroxine").This has been corrected in the online version. PMID- 26926701 TI - Web Exclusives. Annals Graphic Medicine: Not the Needle! A Day in the Life of Someone Living With Diabetes. PMID- 26926702 TI - In the Clinic. Smoking Cessation. AB - This issue provides a clinical overview of smoking cessation, focusing on health consequences of smoking, prevention of smoking-related disease, treatment, and practice improvement. The content of In the Clinic is drawn from the clinical information and education resources of the American College of Physicians (ACP), including MKSAP (Medical Knowledge and Self-Assessment Program). Annals of Internal Medicine editors develop In the Clinic in collaboration with the ACP's Medical Education and Publishing divisions and with the assistance of additional science writers and physician writers. PMID- 26926703 TI - India draws a red line under antibiotic misuse. PMID- 26926704 TI - Inactivation of Airborne Bacteria and Viruses Using Extremely Low Concentrations of Chlorine Dioxide Gas. AB - Infectious airborne microbes, including many pathological microbes that cause respiratory infections, are commonly found in medical facilities and constitute a serious threat to human health. Thus, an effective method for reducing the number of microbes floating in the air will aid in the minimization of the incidence of respiratory infectious diseases. Here, we demonstrate that chlorine dioxide (ClO2) gas at extremely low concentrations, which has no detrimental effects on human health, elicits a strong effect to inactivate bacteria and viruses and significantly reduces the number of viable airborne microbes in a hospital operating room. In one set of experiments, a suspension of Staphylococcus aureus, bacteriophage MS2, and bacteriophage PhiX174 were released into an exposure chamber. When ClO2 gas at 0.01 or 0.02 parts per million (ppm, volume/volume) was present in the chamber, the numbers of surviving microbes in the air were markedly reduced after 120 min. The reductions were markedly greater than the natural reductions of the microbes in the chamber. In another experiment, the numbers of viable airborne bacteria in the operating room of a hospital collected over a 24-hour period in the presence or absence of 0.03 ppm ClO2 gas were found to be 10.9 +/- 6.7 and 66.8 +/- 31.2 colony-forming units/m3 (n = 9, p < 0.001), respectively. Taken together, we conclude that ClO2 gas at extremely low concentrations (<=0.03 ppm) can reduce the number of viable microbes floating in the air in a room. These results strongly support the potential use of ClO2 gas at a non-toxic level to reduce infections caused by the inhalation of pathogenic microbes in nursing homes and medical facilities. PMID- 26926705 TI - Adults with myelomeningocele and other forms of spinal dysraphism: hospital care in the United States since the turn of the millennium. AB - OBJECTIVE The natural history and management of myelomeningocele (MM) in children is fairly well understood. There is a deficiency of knowledge regarding the care of adults, however, even though there are now more adults than children living with MM. The purpose of this study was to characterize the hospital care of adults with MM and hydrocephalus on a nationwide population base. Adults with other forms of spina bifida (SB) were studied for contrast. METHODS The Nationwide Inpatient Sample for the years 2001, 2004, 2007, and 2010 was queried for admissions with diagnostic ICD-9-CM codes for MM with hydrocephalus and for other forms of SB. RESULTS There were 4657 admissions of patients with MM and 12,369 admissions of patients with SB in the sample. Nationwide rates of admission increased steadily for both MM and SB patients throughout the study period. Hospital charges increased faster than the health care component of the Consumer Price Index. Patients with MM were younger than patients with SB, but annual admissions of MM patients older than 40 years increased significantly during the study period. With respect to hospital death and discharge home, outcomes of surgery for hydrocephalus were superior at high-volume hospitals. Patients with MM and SB were admitted to the hospital more frequently than the general population for surgery to treat degenerative spine disease. CONCLUSIONS Patients with MM and SB continue to require neurosurgical attention in adulthood, and the demand for services for older patients with MM is increasing. Management of hydrocephalus at high-volume centers is advantageous for this population. Patients with MM or SB may experience high rates of degenerative spine disease. PMID- 26926706 TI - Brief wakeful resting can eliminate directed forgetting. AB - When cued to intentionally forget previously encoded memories, participants typically show reduced recall of the memories on a later recall test. We examined how such directed forgetting is affected by a brief period of wakeful resting between encoding and test. Encoding was followed by a "passive" wakeful resting period in which subjects heard emotionally neutral music or perceived neutral pictures, or it was followed by an "active" distraction period in which subjects were engaged in counting or calculation tasks. Whereas typical directed forgetting was present after active distraction, the forgetting was absent after wakeful resting. The findings indicate that the degree to which people can intentionally forget memories is influenced by the cognitive activity that people engage in shortly after learning takes place. The results provide first evidence on the interplay between wakeful resting and intentional forgetting. PMID- 26926707 TI - A Survey of Headache Medicine Physicians on the Likeability of Headaches and Their Personal Headache History. AB - BACKGROUND: Two prior studies have shown an increased prevalence of migraine among physicians who are headache medicine specialists (HMS). There have been no studies of the prevalence of other headache disorders among HMS. A prior survey showed that neurologists like to treat some headaches more than others but there has not been a similar survey of HMS. OBJECTIVES: The aim of the survey was to learn more about the prevalence of headaches among HMS and which headache disorders they like to treat. METHODS: An email survey was sent to 749 physician members of the American Headache Society who were asked to respond to the following statement using a 5-point Likert scale (from 1, strongly disagree to 5, strongly agree): "I like to treat patients with the following types of headaches or syndromes." They were asked, "Have you personally suffered from any of the following at any time during your life: episodic migraine (EM), chronic migraine (CM), refractory migraine (RM), episodic cluster (EC), chronic cluster (CC), new daily persistent headache (NDPH), and postconcussion syndrome (PCS)." RESULTS: The response rate was 15.8% (n = 118) with a mean age of 51.4 years, 64.4% males, and 85.6% neurologists. HMS reported likeability for treating disorders in rank order as follows: EM (mean = 4.69, SD = 0.61); CM (mean = 4.20, SD = 0.94); RM (mean = 3.62, SD = 1.17); EC (mean = 4.37, SD = 0.80); CC (mean = 3.68, SD = 1.10); NDPH (mean = 3.52, SD = 1.21); and PCS (mean = 3.66, SD = 1.18). The lifetime prevalence of disorders was as follows: EM, 69.5% (85.7% in females and 60.5% in males); CM, 13.6% (19% in females and 10.5% in males); RM, .9% (2.4% females and 0% males); EC, 1.7% (0% females and 2.6% males); CC, 0%; NDPH, 0%, and PCS, 4.2% (7.1% females and 2.6% males). HMS with a personal history of EM (mean = 4.73, SD = 0.51) showed a significant preference (t130 = 7.30, P < .001) to treat episodic migraine more than other headaches (mean = 3.90, SD = 0.77). CONCLUSIONS: HMS preferred to treat some disorders more than others, with EM most liked and NDPH least preferred, which may reflect how well patients with those disorders respond to treatment. The lifetime prevalence of EM among HMS is significantly greater than among neurologists, both significantly greater than EM in the general population. An explanation for the higher prevalence among neurologists is not certain but perhaps migraine is associated with a choice to become an HMS during or after neurology residency. The lifetime prevalence among HMS of CM may be and EC is much greater than among the general population for uncertain reasons. PMID- 26926708 TI - A Functional Model of [Fe]-Hydrogenase. AB - [Fe]-Hydrogenase catalyzes the hydrogenation of a biological substrate via the heterolytic splitting of molecular hydrogen. While many synthetic models of [Fe] hydrogenase have been prepared, none yet are capable of activating H2 on their own. Here, we report the first Fe-based functional mimic of the active site of [Fe]-hydrogenase, which was developed based on a mechanistic understanding. The activity of this iron model complex is enabled by its unique ligand environment, consisting of biomimetic pyridinylacyl and carbonyl ligands, as well as a bioinspired diphosphine ligand with a pendant amine moiety. The model complex activates H2 and mediates hydrogenation of an aldehyde. PMID- 26926709 TI - Intraoperative prognostic factors and atypical patterns of recurrence in patients with upper urinary tract urothelial carcinoma treated with laparoscopic radical nephroureterectomy. AB - Objective The aims of this study were to identify clinical, intraoperative and pathological prognostic factors for predicting extraurothelial recurrence and cancer-specific survival (CSS) in patients with upper urinary tract urothelial carcinoma (UTUC) who had undergone laparoscopic radical nephroureterectomy (LRNU), and to investigate the site-specific patterns of recurrence and the associated outcomes. Materials and methods A retrospective revision was undertaken of 117 consecutive patients who had undergone transperitoneal LRNU for UTUC between 2007 and 2012. Univariate and multivariate Cox regression analyses were used to identify prognostic factors and Kaplan-Meier was used to estimate CSS. Results With a median follow-up of 20 months, 36 patients (30%) developed extraurothelial recurrence (local and/or distant). In the multivariate analysis, entering the urinary tract during LRNU was related to local recurrence (p = 0.04), management of the distal ureter to CSS (p = 0.003), pathological stage and positive margins to local (p = 0.001, p = 0.013), distant (p = 0.028, p = 0.009) and global recurrence (p = 0.05, p = 0.012) and CSS (p = 0.011, p = 0.042), and multifocality to distant recurrence (p = 0.024). Median time to recurrence was 11.4 months after LRNU. Of 36 patients with progression, 23 (64%) had simultaneous local and distant recurrence and eight had atypical metastases: two port-site metastases, five peritoneal, two subcutaneous and two abdominal wall implants. The 5 year CSS was 61% for all patients with UTUC and 9% for those with recurrence. Conclusions Intraoperative events could have a negative impact on the oncological outcomes of patients with UTUC treated with LRNU. The use of laparoscopy for advanced UTUC may be related to atypical ways of spreading. PMID- 26926711 TI - Environmental factors in the development of autism spectrum disorders: A reply to Sealey et al. (2016). AB - Sealey et al. have reviewed the available evidence on environmental factors that may predispose the development of autism spectrum disorders (ASD) in vulnerable populations. The authors identify exposure to vaccines, pesticides, and air pollutants as potential contributors. The author of this correspondence has previously proposed elsewhere that exposure to increasing levels of the agricultural and environmental pollutant, nitrous oxide (N2O), may be the dominant etiology of ASD and other neurodevelopmental disorders. N2O is thought to target the opioidergic system, including the K-opioid receptor (KOR). Exposure to thimerosal-containing vaccines may disrupt the activity of several endogenous targets as has been shown, principally including MU-opioid receptor (MOR). Given the antagonistic actions of the MOR and KOR, dysregulation of MOR may leave the heightened dynorphin/KOR system unchecked, possibly inducing a negative emotional state that is characteristic of ASD. Future attention may need to be focused on understanding on how early-life mercury exposures, such as in vaccines, may or may not reveal a gestational opiate dependence induced from other ASD-implicated environmental factors. PMID- 26926710 TI - Engineering of soybean mosaic virus as a versatile tool for studying protein protein interactions in soybean. AB - Transient gene expression approaches are valuable tools for rapid introduction of genes of interest and characterization of their functions in plants. Although agroinfiltration is the most effectively and routinely used method for transient expression of multiple genes in various plant species, this approach has been largely unsuccessful in soybean. In this study, we engineered soybean mosaic virus (SMV) as a dual-gene delivery vector to simultaneously deliver and express two genes in soybean cells. We further show the application of the SMV-based dual vector for a bimolecular fluorescence complementation assay to visualize in vivo protein-protein interactions in soybean and for a co-immunoprecipitation assay to identify cellular proteins interacting with SMV helper component protease. This approach provides a rapid and cost-effective tool for transient introduction of multiple traits into soybean and for in vivo characterization of the soybean cellular protein interaction network. PMID- 26926712 TI - Life beyond bortezomib: increasing treatment options in refractory myeloma. PMID- 26926713 TI - Different visual stimuli affect body reorientation strategies during sidestepping. AB - Sidestepping in response to unplanned stimuli is a high-risk maneuver for anterior cruciate ligament (ACL) injuries. Yet, differences in body reorientation strategies between high- and low-level soccer players prior to sidestepping in response to quasi-game-realistic vs non-game-realistic stimuli, remain unknown. Fifteen high-level (semi-professional) and 15 low-level (amateur) soccer players responded to a quasi-game-realistic one-defender scenario (1DS) and two-defender scenario (2DS), and non-game-realistic arrow-planned condition (AP) and arrow unplanned condition (AUNP). The AP, 1DS, 2DS to AUNP represented increasing time constraints to sidestep. Selected biomechanics from the penultimate step to foot off were assessed using a mixed-model (stimuli * skill) ANOVA (P < 0.05). Step length decreased in the defender scenarios compared with the arrow conditions. Support foot placement increased laterally, away from mid-pelvis, with increasing temporal constraints. Greater trunk lateral flexion in the 1DS, 2DS, and AUNP has been associated with ACL injury onsets. Higher level players pushed off closer to their pelvic midline at initial foot contact in the 2DS especially. Higher level perception of game-realistic visual information could have contributed to this safer neuromuscular strategy that, when understood better, could potentially be trained in lower level players to reduce ACL injury risk associated with dangerous sidestepping postures. PMID- 26926714 TI - Reaction of Glyconitriles with Organometallic Reagents: Access to Acyl beta-C Glycosides. AB - A new strategy for the synthesis of acyl beta-C-glycosides is described. The reactivity of glyconitriles toward organometallic reagents such as organomagnesium or organolithium derivatives was studied, affording acyl beta-C glycosides in moderate to good yields. In this study, glycal formation was efficiently prevented by deprotonating the hydroxyl group in position 2 of the glyconitriles during the process. PMID- 26926715 TI - [Early life opportunities for promotion of children health]. AB - This editorial highlights some of the emerging threats and risks to children health, including birth defects, psychological behavioral problems, neurodevelopmental disorders and health risk behaviors, which will continue to have increased impact on healthy growth and development. Mounting evidence has confirmed the adverse effects of environmental exposure during preconception and pregnancy on children's health, which suggests that one of the best investments we can make to achieve lasting progress in global health is the prevention of children's health problems during the first thousand days of life and beyond. PMID- 26926716 TI - [Association of influenza, influenza vaccination and cardiovascular risk]. AB - Cardiovascular risk and related medical burden due to influenza in patients with chronic disease were higher than those of healthy subjects. As a result, influenza vaccination is recommended as a strategy for secondary prevention in cardiovascular disease by major cardiovascular organizations, but the prevalence of influenza vaccination in these population is still low. Whether influenza vaccine can prevent cardiovascular events such as myocardial infarction and death is still controversial based on current evidences from observational studies and case-control studies, which may result from study desion,subjects selection,outcome definition and sample size issues. Recent meta-analysis showed that influenza vaccination may reduce cardiovascular risk, but large-scale random controlled trials with adequately power should be conducted to confirm these findings as well as the target population for this strategy further. PMID- 26926717 TI - [Expert consensus on the immunoprophyaxis of bacterial diarrhea]. PMID- 26926718 TI - [Pregnancy-related anxiety and subthreshold autism trait in preschool children based a birth cohort study]. AB - OBJECTIVE: To analyze the associations between pregnancy-related anxiety and the prevalence of subthreshold autism trait (SAT) in preschool children. METHODS: Baseline data came from the Ma'anshan Birth Cohort Study, a part of the China Anhui Birth Cohort Study (C-ABCS). All the participants were enrolled among pregnant women who received prenatal health care in 4 municipal medical centers during Oct. 2008 to Oct. 2010. A total of 5 084 pregnant women were recruited at the beginning and 4 669 singleton live births were included until childbirth. The situation about pregnancy-specific anxiety during trimester and third trimester of women were evaluated by Pregnancy-specific Anxiety Questionnaire (PAQ). Between April 2014 and April 2015, the cohort was followed up again, and the Clancy Autism Behavior Scale (CABRS) filled out by parents was used for telling the SAT children from the healthy children among 3 663 preschool children. Univariate and binary regression model was used to estimate associations between the pregnancy-related anxiety during trimester and third trimester and the subthreshold autism trait in children. RESULTS: During the pregnancy, the detected rates of women with pregnancy-specific anxiety in trimester and the third trimester were 25.5%(935/3 663), 13.9%(501/3 592) respectively, and the detected rate of maternal pregnancy-specific anxiety in both periods was 7.7%(278/3 592). There were 290 positive children with SAT and the detection rate was 7.9%. After controlling possible confounding factors including children's genders, place of residence, supplement folic acid during pregnancy, preterm birth, exposure to second-hand smoke during pregnancy, the father (mother) cultural levels, the father (mother) nature of work and family income, the results of multinomial logistic regression analysis showed that maternal pregnancy-specific anxiety in trimester was the risk factor for SAT in preschool children (OR=1.51, 95% CI: 1.11-2.04), and there was no association between maternal pregnancy-specific anxiety in the third trimester and SAT in preschool children (OR=1.36, 95% CI: 0.82-2.22). Compared with the single function of maternal pregnancy-specific anxiety in trimester or the third trimester for SAT in preschool children, maternal pregnancy-specific anxiety in both periods presented a joint action that increasing the risk for SAT (OR=2.02, 95% CI: 1.36 2.98). CONCLUSION: Maternal pregnancy-related anxiety was a risk factor for subthreshold autism trait in preschooler children. Pregnant women should try to keep a good mental state to create a good environment for fetal growth. PMID- 26926719 TI - [Maternal pre-pregnancy body mass index and gestational weight gain with preschool children's overweight and obesity]. AB - OBJECTIVE: To examine the effect of maternal pre-pregnancy body mass index (BMI) and gestational weight gain (GWG) with childhood overweight and adiposity, and to explore possible early life risk factors for obesity in preschool children. METHODS: Basic information of pregnant women and gestation period came from the Ma'anshan Birth Cohort Study, a part of the China-Anhui Birth Cohort Study (C ABCS). Pregnant women in routine health care from four municipal medical and health institutions were enrolled voluntarily during October 2008 and October 2010 in Ma'anshan City. A total of 5 084 pregnant women and 4 669 singleton live births were included in this study. Between April 2014 and April 2015, 3 797 children were followed up. Children whose BMI were >85th percentiles for age and genders of World Health Organization (WHO) reference were considered as overweight, and >95th percentiles for age and genders cut-off values were considered as obesity (pathological and secondary causes of obesity were excluded). Gestational weight gain was defined according to the Institute of Medicine (IOM) guidelines. Univariate and binary regression model analysis was used to examine the effect of pre-pregnancy BMI and GWG with childhood overweight and adiposity. RESULTS: Of the 3 797 pregnant women, the prevalence of underweight, normal weight, overweight and obesity were respectively 22.6% (n=858), 70.3% (n=2 671), 6.2% (n=234) and 0.9% (n=34). There were 3 563 pregnant women who were obtained gestational weight gain data, the prevalence of inadequate GWG, appropriate GWG, excessive GWG were respectively 12.4% (n=443), 25.9% (n=922) and 61.7% (n=2 198). The prevalence of overweight and obesity were 11.5% (n=437) and 10.8% (n= 411) in preschool children, respectively. After adjusting confounding factors including age at delivery, genders of children, children age, birth weight, breastfeeding and household economic status, binary logistic regression analysis showed that pre-pregnancy overweight and obesity(OR=2.01, 95% CI: 1.53-2.65), excessive GWG(OR=1.65, 95% CI: 1.35-2.03) were risk factors for overweight and obesity, and pre-pregnancy underweight was protective factor for childhood overweight and obesity (OR=0.49, 95% CI: 0.39 0.62). Joint associations of pre-pregnancy BMI and inappropriate GWG were also noticed in the study: compared to only pre-pregnancy higher BMI or excessive GWG or indequate GWG, combination of high pre-pregnancy BMI and excessive GWG or high pre-pregnancy BMI and inadequate GWG, adverse effects on childhood overweight and obesity were much higher,OR (95%CI) values were 2.90(1.97-4.28), 3.17(1.44-6.97) respectively. CONCLUSION: Both high pre-pregnancy BMI and inappropriate GWG are associated with greater offspring BMI. Pregnant women should achieve appropriate weight gain and help prevent obesity in their children. PMID- 26926720 TI - [The relationship between maternal emotional symptoms during pregnancy and emotional and behavioral problems in preschool children: a birth cohort study]. AB - OBJECTIVE: To investigate the related influencing factors of preschool children's emotional and behavioral problems in early life and explore the associations between the symptoms of depression or anxiety during pregnancy and emotional and behavioral problems in preschool children. METHODS: Based on the Ma'anshan Birth Cohort Study of the China-Anhui Birth Cohort Study (C-ABCS), women were recruited at their first clinical visit between October 2008 and October 2010 in four municipal medical and health institutions of Ma'anshan City, a total of 5 084 pregnant women and 4 669 singletons live births were included in the birth cohort. Women completed measures of depressive (Self-Rating Anxiety scale) and anxious (Center for Epidemiologic Studies Depression) symptoms in pregnancy. By the age of 3-6 follow-up, 3 653 children were followed with completed information between April 2014 and April 2015, strengths and difficulties questionnaires were used to assessed offspring emotional and behavioral problems. Logistics regression was used to investigate the relationship between the symptoms of depression or anxiety during pregnancy and emotional and behavioral problems in preschool children. RESULTS: The detected rates of emotional symptoms, conduct problems, hyperactivity and peer problems in preschool children were 6.3% (229/3 653), 7.5% (274/3 653), 7.6% (278/3 653) and 2.8% (103/3 653), while 7.6% (277/3 653) for total difficulties, 10.9%(398/3 653) for prosocial behavior and 27.4%(981/3 557) for impact respectively. Prevalence of anxiety and depression in the first trimester was 2.7%(100/3 653) and 4.7%(171/3 653) respectively, and in the second trimester was 2.0%(66/3 375) and 3.6%(122/3 375) respectively. After we controlled the confoundings of gestation age, place of residence, family income, maternal education, paternal education, premature birth and folic acid supplement before pregnancy, multinomial logistic regression analysis showed that the risk of children's emotional symptoms in maternal anxiety in both first trimester and second-trimester group was higher than the group of no depression and anxiety symptoms, and OR(95%CI) was 5.90(2.00-17.48). Compared with whose mother no depression in both first-trimester and second-trimester, the risk of children's emotional symptoms in maternal depression in both first-trimester and second-trimester group was higher, and OR(95% CI) was 3.07 (1.30-7.28). And the risk of children's total difficulties of maternal anxiety in second-trimester was 2.27 (95%CI: 1.10-4.71) times of no anxiety in second-trimester. While the risk of children's total difficulties of maternal depression in second-trimester was 2.20 (95%CI: 1.24-3.93) times of no depression in second-trimester. Maternal emotional symptoms were not significant associations with conduct problems, hyperactivity, peer problems and prosocial behaviors (P> 0.05). CONCLUSION: There was a negative impact of maternal anxiety and depression symptoms during pregnancy on emotional and behavioral problems in preschool children. These findings highlight the need for additional clinical and research attention to both maternal depression and anxiety in pregnancy, which may be helpful to reduce the incidence of children's emotional and behavioral problems and act as an important measure in prevention. PMID- 26926721 TI - [Effect of parents' occupational and life environment exposure during six months before pregnancy on executive function of preschool children]. AB - OBJECTIVE: To examine the effect of parents' occupational and life exposure during six months before pregnancy on executive function of preschool children. METHODS: Pregnant women involved in the study came from the Ma'anshan Birth Cohort Study,a part of the China-Anhui Birth Cohort Study. Between October 2008 and October 2010, pregnant women who accepted pregnancy care in four municipal medical and health institutions in Ma'anshan city were recruited as study objects. A total of 5,084 pregnant women and 4,669 singleton live births entered in this cohort. Between April 2014 and April 2015, a total of 3,803 pre-school children were followed up. Finally, except 32 preschool children did not have EF evaluation result, there were 3,771 children included in this study. By using self-designed " Maternal health handbook", we researched parents' general demographic characteristics, and life and occupational exposure during six months before pregnancy. To research preschool children's executive function, we used the Behavior Rating Inventory of Executive Function-Preschool Version (BRIEF-P). Univariate and multivariate statistical method was used to analyze the association of parents' life and occupational exposure during six months before pregnancy and preschool children's EF. RESULTS: 3,771 preschool children's detected rate of inhibitory self-control index (ISCI), flexibility index (FI), emergent metacognition index (EMI) and global executive composite (GEC) dysplasia were 4.8% (182), 2.3% (88), 16.5% (623) and 8.6% (324) respectively. During six months before pregnancy, children whose parents were lived in a noise environment (OR=1.86, 95% CI: 1.36-2.54), whose maternal were exposed to pesticides were the risk of ISCI dysplasia(OR=3.60, 95% CI: 1.45-8.95). During six months before pregnancy, children whose maternal were exposed to pesticides (OR=6.72, 95% CI: 2.50-18.07) and whose father were exposed to occupational lead (OR=2.10, 95% CI: 1.25-3.54) were the risk of FI dysplasia. During six months before pregnancy, children whose parents were lived in a noise environment (OR=1.42, 95%CI: 1.18 1.71) and whose father were exposed to occupational lead (OR=1.30, 95%CI: 1.02 1.65) were the risk of EMI dysplasia. During six months before pregnancy, children whose parents were lived in a noise environment (OR=1.58, 95% CI: 1.24 2.01) and whose maternal were exposed to pesticides (OR=2.39, 95% CI: 1.02-5.58) were the risk of GEC dysplasia. CONCLUSION: The development of executive function is worse among preschool children whose parents live in noise environment, mother exposed to pesticides, and father exposed to occupational lead during six months before pregnancy. PMID- 26926722 TI - [Detection and analysis of 26 cases of long-term non-progressors who infected HIV in Henan province]. AB - OBJECTIVE: To investigate the progression and drug resistance of long-term non progressors during three follow-up in Henan province. METHODS: In May 2009, 26 cases of long-term non-progressors were recruited who infected HIV more than 10 years with blood collection and supply routes, did not receive anti-retroviral therapy, CD4(+)T lymphocyte count >=350/MUl and did not show typical symptoms of AIDS from Weishi, Shangcai, and Linying of Henan Province. Continuous follow-up were conducted three times since 2009 every two years with cohort analysis, the epidemiological information of infection routes, infection time and blood were collected, and 78 parts of 10 ml EDTA anticoagulated whole blood were collected. The changes of CD4 (+) T lymphocytes, viral load, and virus gene variety were characterized from 2009 to 2014. In-house methods were used to explore primary drug resistance of long-term non-progressors. Nonparametric Kruskal-Wallis test were used to compare CD4(+) T lymphocyte count and viral load changes during different follow-up times. RESULTS: The average age and infection time of 26 cases were (48.51 +/- 6.75) years, (13.42 +/- 4.26) years, respectively. Three follow-up times, CD4(+) T lymphocyte count P50 (P25-P75) was 573.5 (487.4-789.8), 499.8 (403.5-635.7), and 418.8 (297.6-537.8)/MUl (H=63.99,P<0.001), respectively. And natural logarithm of viral load P50 (P25-P75) were 3.93 (3.43-4.55), 4.29 (3.78-4.75), 4.50 (4.01-4.81) (H=3.19,P=0.355), respectively. Subtype and phylogenetic analysis of HIV showed that prevalent cases were B subtype, accounting for 88.5% (23/26), and three cases showed restructuring changes. Two cases appeared highly resistant of 18 infected patients whose viral load >1 000 copies/ml. CONCLUSION: The CD4(+)T lymphocyte had a declining trend, virus subtype recombinant changes in a few cases, and primary drug resistance was found of long-term non-progressors in Henan province. PMID- 26926723 TI - [Status and influencing factors of rush poppers use and HIV infection among men who have sex with men in Changsha]. AB - OBJECTIVE: To explore the relationship between use of rush poppers and HIV infection, and associated factors among men who have sex with men in Changsha. METHODS: A cross-sectional study was conducted in Changsha from April to December, 2014. Men who have sex with men who came for HIV counseling and testing services were invited to fill out a survey. A total of 608 MSM were finally recruited. The survey included socio-demographic characteristics, sexual roles, sexual behaviors in last 6 months and rush poppers use, HIV infection among MSM. After finishing the questionnaire, 5 ml blood was also drawn for HIV testing. Chi square test or Fisher probabilities was used to compare usage of rush poppers and HIV antibody positive rate among MSM who had different characteristics and sexual behaviors. Multi-factor unconditioned logistic regression model was used to explore related factors about rush poppers use and HIV infection of MSM. RESULTS: Among 608 MSM, 29.8% (181) said they ever used rush poppers, and 13.3% (81 cases) were HIV positive. Among MSM who ever used rush poppers, 18.8% (34/181) were HIV positive; While among those who never used rush poppers, 10.5% (45/427) were HIV positive (chi(2)=7.65,P=0.006). Compared with MSM who had no For One Night sex in the last 6 months,OR (95% CI) value of MSM who had 6-10 times For One Night sexes in last 6 months to use rush poppers was 4.32 (1.77-10.57). Compared with MSM who self-identified as top,OR (95% CI) value of MSM who self-identified as bottom or versatile using rush poppers were 2.99 (1.53-5.86), or 3.60 (2.13-6.09). Compared with MSM who self-identified as top, OR (95% CI) value of MSM who self-identified as bottom or versatile to infect HIV were 3.19 (1.35-7.58), or 2.33 (1.12-4.85). Compared with MSM who used condoms at every anal sex,OR (95% CI) value of MSM who used condoms sometimes or never used to infect HIV were 1.93 (1.12-3.35) or 1.87 (0.64-5.50). Compared with MSM who never used rush poppers,OR (95% CI) value of MSM who ever used rush poppers to infect HIV was 1.88 (1.12-3.16). CONCLUSION: A large percentage of MSM population in Changsha used rush poppers, and HIV antibody positive rate among MSM was high. MSM who had more frequencies of For One Night sexes, self-identified as bottom or versatile were more likely to use rush poppers and more susceptible to HIV infection. In addition, MSM who had low frequency of condom use in the last 6 months in anal intercourse were more likely to infect HIV. PMID- 26926724 TI - [Analysis on factors associated with taking subsequent confirmation test among men who have sex with men after being tested positive in oral fluid HIV antibody test in Beijing]. AB - OBJECTIVE: To analyze the proportion and associated factors of taking subsequent confirmation test among men who have sex with men (MSM) after being tested positive in oral fluid HIV antibody test. METHODS: By using successive sampling, 1 003 MSM, who were tested positive in oral fluid HIV antibody test in China-Bill & Melinda Gates Foundation AIDS prevention Program (Extension program) in Beijing during May 1 to December 31, 2013, were recruited. The inclusion criteria included: the objects were men who reported having sex with men; the objects aged more than 18 years old; the objects were tested positive in oral fluid HIV antibody test; the objects had not been reported as HIV positives in China Information System for Disease Control and Prevention previously. According to the program strategy, MSM grassroots organizations transferred the respondents to seek subsequent confirmation tests in specific Center for Disease Control and Prevention (CDCs) or hospitals. The subsequent confirmation tests included: fingertip blood HIV antibody rapid test, venous blood Enzyme Linked Immunosorbent Assay (ELISA) HIV antibody test and venous blood Western Blot (WB) HIV antibody test. Chi-square test was adopted to compare the proportion of taking subsequent confirmation tests in different groups. Nonconditional multivaritae binarylogistic regression analysis was taken to identify the associated factors with whether taking subsequent confirmation tests and to calculate the OR (95% CI) values. RESULTS: The 1 003 respondents were (30.9 +/- 9.1) years old. Among all objects, 87.8% (881/1 003) of them took fingertip blood HIV antibody rapid tests and the positive rate was 85.4% (752/881). 98.0% (737/752) of those who were identified as positive in fingertip blood HIV rapid tests took ELISA and WB tests, and the positive rate was 94.4% (696/737). Comparing with those who were expected to seek subsequent confirmation tests in CDCs, the OR (95% CI) value of those who were expected to seek tests in hospitals was 5.10 (1.69-15.36). The OR (95% CI) values of those who used condom sometimes and those who never used condom in anal sex were 5.81 (2.14-15.77) and 3.45 (2.00-5.97) respectively, in comparison with those who reported not having anal sex or using condom consistently in anal sex during the past 6 months. Comparing with the respondents recruited from the internet, the OR (95% CI) values of those recruited in bathrooms, parks/toilets and bars were 0.17 (0.05-0.53), 0.10 (0.04-0.29) and 0.22 (0.06-0.79) respectively. The likelihood of taking subsequent confirmation test decreased with the increase of number of male sexual partners in the past 3 months, and the OR (95% CI) value was 0.92 (0.86-0.99). CONCLUSION: The potential HIV positive MSM in the bathroom, park/toilet and bars are less likely to take subsequent confirmation test. Those who do not use condom consistently during anal sex are more likely to seek subsequent confirmation test. Medical organization conducting subsequent confirmation tests is more likely to increase the confirmation test rate of potential HIV positive MSM. The number of male sexual partners has negative correlation with whether to accept the subsequent confirmation test. PMID- 26926725 TI - [Analysis of related factors for HIV transmission among 263 pairs of male spouses with positive HIV antibodies in Zhejiang province]. AB - OBJECTIVE: To identify the status and risk factors of transmission in couples which males was HIV-positive in Zhejiang province. METHODS: A cross-sectional study was conducted among HIV-serodiscordant couple (male positive) and HIV seroconcordant couple (male first infected). A self-designed questionnaire was complimented containing basic information, the awareness of infection and HIV testing, sexual relationship power, self-efficacy of condom use, sex. The univariated and multivariate logistic regression methods were used to analyze the influence factors. RESULTS: A total of 263 couples were enrolled in this study, including 210 HIV HIV-serodiscordant couples and 53 HIV-seroconcordant couples. HIV-positive males aged 30-50 accounted for 57.8% (152 cases) and females under junior high school accounted for 79.1% (208 cases). HIV/AIDS accounted for 41.1% (217 cases). The proportion of man who were diagnosed as HIV, MSM and ever heard HIV were 61.9% (130 cases), 38.3% (80 cases) and 81.9% (172 cases), which were higher than that in HIV positive 47.2% (25 cases), 7.5% (4 cases), 64.2% (34 cases); chi(2)=3.80, 18.33, 7.86;P=0.051, 0.001, 0.005. The results revealed that AIDS patients had high risk to infect their spouse than HIV patients (OR=2.93, 95% CI: 1.05-8.21). Male patients who had ever heard " HIV" before were less likely pass virus to their wives than those who had never heard " HIV" (OR=0.13, 95% CI: 0.04-0.41). Compared with heterosexuality man, homosexuality man' wives had high risk to get virus from their husbands (OR=0.14, 95% CI: 0.03-0.73). Female infected with STIs was the independent factors for HIV infection (OR=4.86, 95% CI: 1.23-19.11). CONCLUSION: Among the couples of male HIV-positive in Zhejiang Province, the risk of spouses infected with HIV virus has relationship with male disease progression, sexual orientation and awareness of AIDS knowledge. For females who infected with sexual diseases in last 6 months might be infected by their spouses. PMID- 26926726 TI - [Quantitative risk assessment of the polycyclic aromatic hydrocarbons dietary exposure from edible fats and oils in China]. AB - OBJECTIVE: To assess the quantitative risk of the polycyclic aromatic hydrocarbons (PAHs) dietary exposure from edible fats and oils in China. METHODS: One hundred samples of edible fats and oils were collected from the supermarkets and the farmers markets in 11 provinces of China from December in 2013 to May in 2014. Then they were tested for EU15+1 PAHs (16 PAHs were controlled in priority by European Food Safety Authority) by two test methods which were QuECHERS-GC-MS MS and GPC-HPLC-FLD. Data of PAHs concentration and edible fats and oils consumption which were from Chinese National Nutrition and Health Survey in 2002 were combined to evaluate carcinogenic risk of PAHs in edible fats and oils by the method of margin of exposure (MOE). In this process, we divided the population into 6 groups, namely male adults (older than 18 years old), female adults (older than 18), male youths (13-17), female youths (13-17), school-agers (6-12) and preschoolers (2-5), and thought carcinogenicity as the critical toxicity end point of PAHs. Two quantitative risk assessment methods, i.e. point assessment and probability assessment, were used to evaluate the dietary exposure and MOEs. RESULTS: EU15+1 PAHs in one of 100 samples were not detected, other samples were polluted in different degrees; the detection rates were 3%-98% and the average contents were 0.26-3.26 MUg/kg. The results of PAHs dietary exposure from both of point assessment and probability assessment were the same. The average exposures of PAH8 were as the following: male adults were 10.03 and (9.34 +/- 12.61) ng.kg(-1).d(-1)(The former was from point assessment and the latter from probability assessment, the same below), female adults were 9.95 and (9.60 +/- 15.04) ng . kg(-1).d (-1), male youths were 11.09 and (10.84 +/- 16.54) ng.kg(-1).d(-1), female youths were 10.06 and (9.58 +/- 12.87) ng.kg(-1).d( 1),school-agers were 15.29 and (15.62 +/- 25.54) ng.kg(-1).d(-1), preschoolers were 19.27 and (19.22 +/- 28.91) ng.kg(-1).d(-1). MOEs of mean and 50% exposure levels in different group of people were more than 10,000, while MOEs of 95% exposure levels in school-agers and preschoolers were less than 10,000. CONCLUSION: For general consumers, the health risk of PAHs exposure is very low. However, for high-end consumers (95% exposure level) from the sensitive groups (school-ager and preschooler) has a potential health risk. PMID- 26926727 TI - [Interaction research on smoking and microRNA genes SNP related to lung cancer in Fujian Han population]. AB - OBJECTIVE: To investigate the interaction on smoking and the lung cancer related genes miR-196a2 rs11614913, miR-146a rs2910164, miR-300 rs12894467, miR-26a-1 rs7372209, miR-27a rs895819 in Fujian Han population. METHODS: From January 2006 to January 2012, by using a hospital-based case-control study, 1 053 cases were pathologically diagnosed as primary lung cancer from the Department of Thoracic Surgery and 1 058 controls were randomly selected from the visiting relatives of patients and visiting people of Cangxia community health service of Fuzhou city according to match with age and genders. They were recruited for questionnaires survey and genotyping detection. Research objects of genders, height, weight, cultural degree, marital status, family history of cancer, lung disease history, smoking, drinking tea, drinking, and so on. After informed consent, we collected 5 ml fasting venous blood from every object, used MALDI-TOF-MS to analysis genotyping of polymorphic loci. Logistic regression model was constructed by using SNP as independent variable, and the multiple factors were constructed with different loci. The possible association between SNP and cigarette smoking was analyzed by using the crossover analysis. The relative excess risk of interaction (RERI) were used to analyze on smoking and SNP loci additive interaction of dominant and recessive genetic models. RESULTS: Smokers in case group who smoked P50(P25-P75)30.00 (0.00-56.00) packages in a year were higher than control group (0.00(0.00 - 20.48) pack years) (Z=14.57,P<0.001). Passive smoking index for non smokers was 11.40(0.00-25.00), higher than the controls (0.00(0.00-13.11)) (Z=10.71,P<0.001). Site detection rate of rs11614913, rs2910164, rs12894467, rs7372209 and rs895819 in cases was 95.82%(1 009/1 053), 97.72%(1 029/1 053), 97.82% (1 030/1 053), 97.15% (1 023/1 053) and 96.01% (1 011/1 053) respectively. The controls were 98.11% (1 038/1 058), 98.96% (1 047/1 058), 98.30% (1 040/1 058), 98.68% (1 044/1 058) and 98.02% (1 037/1 058) respectively. rs11614913 dominant genetic model, TT genotype and smoking could increase the risk of primary lung cancer (OR=4.04, 95%CI: 2.67 -6.12). Recessive genetic model, CC genotype and smoking increased the incidence of primary lung cancer risk (OR=4.76, 95%CI: 3.16 -7.17). rs12894467 dominant genetic model, TT genotype and smoking could increase the risk (OR=2.98, 95%CI: 2.28 -3.90) in primary lung cancer. In recessive genetic model, CC genotype and smoking increased the incidence of primary lung cancer risk (OR=1.94, 95% CI: 1.10-3.43). Dominant genetic model of rs2910164, CC genotype and smoking could increase the risk (OR=2.18, 95% CI: 1.60 -2.98) in primary lung cancer. Recessive genetic model, GG genotype and smoking increased the incidence of primary lung cancer risk (OR=3.29, 95% CI: 2.16 -5.03). Especially rs12894467 dominant and recessive gene model and genders, smoking and there were combined effects(chi(2)=8.58, P=0.003; chi(2)=4.76, P=0.040). CONCLUSION: Rs11614913, rs12894467 and rs2910164 polymorphism were potentially associated with primary lung cancer in Fujian Han population. PMID- 26926728 TI - [Comparative analysis five kinds of serological detection methods about Brucella]. AB - OBJECTIVE: To evaluation the specificity and sensitivity of 5 kinds of serological detection methods about brucellosis. METHODS: To investigate in the 4 autonomous banner (Cha You Hou Qi, Right-Wing Central Banner of Kerqin Region, Linxi County and Siziwangqi Banner) of Inner Mongolia autonomous region from January to December, 2013. Accepting criteria: professionals of breeding cattle and sheep, and slaughter,accompanied by Bloom's disease suspected symptoms such as fever, fatigue,arthralgia, ranging in age from 25 to 55 years old. To collect suspected patients venous blood 3-5 ml in the morning, a total of 236 samples were collected. To detect the Brucella antibody by using plate agglutination test (PAT), tiger red plate agglutination test (RBPT), standard test tube agglutination test (SAT), enzyme-linked immunosorbent assay (ELISA) and immune colloidal gold method (GICA), SAT was taken as a golden standard, analyzed the sensitivity and specificity of RBPT and SAT, ELISA and GICA. RESULTS: SAT method of positive patients: 136 cases (57.6%). PAT method positive patients: 150 cases (63.6%). RBPT positive patients: 159 cases (67.4%), and 143 patients with ELISA method: positive (60.6%), 147 patients with positive GICA method (62.3%). The detection rate of Brucella antibody positive was different by different testing methods.There was no significant difference (chi(2)=0.52,P=0.264). To take the SAT method as the gold standard, PAT, RBPT, ELISA and GICA method of the sensitivity were 97.7% (133/136), 98.5% (134/136), 94.8% (129/136) and 94.1% (128/136), respectively. The specificity was lower,the rate were 70.0% (70/100), 75.0% (75/100), 86.0% (86/100) and 81.0% (81/100), respectively. The total coincidence rate were 86.0% (203/236), 88.5% (209/236), 91.1% (215/236) and 88.5% (209/236), respectively. CONCLUSION: The specificity and sensitivity of ELISA and GICA method is higher in the diagnosis of disease. The two methods are rapid, GICA method can be used on-site testing, large sample test is suitable for using ELISA. PMID- 26926729 TI - [Study on biological monitoring indicators of exposure to 1,2-dichloroethane and its determination method in blood]. AB - OBJECTIVE: To investigate the feasibility of using the concentration of 1,2-DCE in blood as a biological monitoring indicators and build the determination method of 1,2-DCE in blood. METHODS: Dose-response relationship of the exposure of 1,2 DCE and the level of 1,2-DCE in rat blood were investigated using the Pearson's correlation analysis. The concentration of 1,2-DCE in blood was determined using Headspace Sampler-Gas Chromatography-Mass Spectrometer (HS-GC-MS). 3.0 ml blood sample diluting with 2.0 ml 1,2-DCE standard serial solution was placed in 15 headspace bottles respectively and heated at 80 C for 20 min.The vapor upon the headspace bottle was separated by capillary column and the concentration of 1,2 DCE was determined by massspectrum in SIM mode to draw a standard work curve. The within-run precision and the between-run precision were calculated by the relative standard deviation (RSD) of the concentration of 1,2-DCE in blood which was determined 6 times in a day and 6 times within 3 days respectively. The recovery rate was calculated by P=(C2 -C0)/C1 * 100%. RESULTS: When the treatment groups were exposed at dosage of 1,472, 2,550, 3,093, 3,976, and 4 418 mg/m(3), the average concentration of 1,2-DCE in rat blood was 24.1,231.6,344.3,395.1,538.5 MUg/L. There was a positive correlation between the concentration of 1,2-DCE in rat blood and the exposed level of 1,2-DCE.The equation of dose-response relationship was y=0.162x -195.8,r=0.982 2,P=0.003 and the precision of exposure experiments was 7.04% -13.15%. 1,2-DCE contents within 0.259 -2 587 MUg/L showed a good linear relationship and the regression equation was y=47 901x -357 446, r= 0.999 8. When the blood containing 0.259 MUg/L 1,2-DCE was determined for six times, the average peak/peak signal-to-noise ratio was 56.55. The limit of detection (LOD) was 0.014 MUg/L and the limit of quantification (LOQ) was 0.046 MUg/L. The within-run precision was 1.23% -2.76% and the between-run precision was 2.21% -4.64%. The average recovery rate was 93.3% - 98.6%. CONCLUSION: The concentration of 1,2-DCE in blood could be used as a biological monitoring indicator. The method of the concentration of 1,2-DCE in blood determining by HS-GC-MS was characterized by high sensitivity, wide linear range, small interference, high precision and easy operation. PMID- 26926730 TI - [Application and evaluation of signal strength indictor in communicable disease automatic early warning system]. AB - OBJECTIVE: To explore the effect of signal strength indictor (SSI) in improving sensitivity of China Infectious Diseases Automated-alert and Response System (CIDARS). METHODS: Diarrhea cases in 2007-2011 and early warning signals in 2010 2011 were selected by using random digital table method. Then, SSI and event related ratio (ER) were calculated. The relationship between ER and SSI was analyzed, and the effect of SSI on ER was explored by using multiple logistic regression analysis. RESULTS: 9 620 early warning signals in 2010-2011 were generated in two years. Of these, 74, or 0.77% were defined as suspected outbreak signal. The median of SSI related with suspected outbreak signal was 4.0, which was much higher than non-suspected outbreak signal (1.7). ER was significantly correlated with SSI (r=0.917). SSI classification has a good correlation between the ER, ER exceeded 20 after SSI reached 20. The multivariate logistic regression analysis showed OR of SSI related with suspected outbreak signal was 2.52 (95% CI 2.04-3.12). Compared with non-epidemic season, the relationship of SSI and ER in epidemic season was much higher. CONCLUSION: SSI was closely related with ER. The relationship was much closer in large scale outbreak and epidemic season, and compared to non-epidemic,the effect of epidemic season is more obvious. PMID- 26926731 TI - [Epidemiological survey of domestic incense burning situation of Guangdong province in 2013]. PMID- 26926732 TI - [The effects of prenatal environmental exposures on children development and health]. AB - The negative effects of environmental exposure during pregnancy on fetal growth and children development have been confirmed. It has been found that environmental exposures during pregnancy have a great influence on the growth and development of fetus, birth outcomes and children's psychology, behavior and neural development. In this review, according to different types of environmental exposures, we focused on the key issues of the fetus or children induced by four aspects of environment exposure, including environmental chemicals, unhealthy life styles and behaviors, stress and other risk factors, and discussed the adverse effects of environmental factors on the growth and development of infants, children's psychology, behavior, social and cognitive, such as birth defects, autism spectrum disorders, attention deficit hyperactivity disorder, emotional problems, learning disorder and intelligence development and so on. We also suggested that the researches on mechanism of the negative effects of environmental exposure on children's health should be strengthened in the future. PMID- 26926733 TI - [Research status and strategies of preventing mother-to-child transmission of hepatitis B]. AB - Mother-to-child transmission (MTCT) is the main way to transmit hepatitis B virus (HBV), and it is also the biggest contributor to high prevalence of hepatitis B in high endemic areas. Therefore, preventing MTCT may result in the decline of HBV positive ratio foundationally. Hepatitis B vaccination is currently recognized as the most economic, effective and safe measure to prevent MTCT. The key strategies in the future to prevent MTCT should be to enhance the screening of hepatitis B surface antigen, to provide the infants born to surface antigen positive mother with hepatitis B vaccine combine with hepatitis B immunoglobulin(HBIG), and to monitor the effect of the intervention. PMID- 26926734 TI - White matter stimulation for the treatment of epilepsy. AB - Electrical stimulation in the treatment of epilepsy has been tried in numerous forms and with a variety of targets. Some of these, such as anterior thalamic stimulation, responsive cortical stimulation, and vagal nerve stimulation, have shown promise. A relatively novel concept, that of white matter stimulation, offers a different mechanism in that a small population of stimulated axons can transmit current to a large population of epileptogenic neurons. In theory, this allows for the modulation of seizure circuits and neural networks using lower stimulation volumes. Although clinical data is currently sparse, we review the relevant studies pertaining to white matter stimulation in epilepsy thus far, and offer explanations as to its effects, potential advantages, and utility. PMID- 26926735 TI - Improving Diagnosis in Health Care. PMID- 26926736 TI - Two Weeks of Headache and Facial Numbness. PMID- 26926737 TI - Finding a Healthy Match: A Discussion on Applying the Appropriate Level of Analysis for Global Health Engagement Activities. PMID- 26926738 TI - The American Ambulance in Paris, 1914 to 1917 Part IV: The American Ambulance and the American Red Cross. PMID- 26926739 TI - Ethics and Transgender Service Members, Dependents, and Retirees. PMID- 26926740 TI - A Diagnostic Platform Predicts Presymptomatic Exposure to Respiratory Viral Infection. PMID- 26926741 TI - Need for Studies of the Health of Gulf War Women Veterans. PMID- 26926742 TI - Urine Test Strips as a Bedside Diagnostic Aid to Rule out Blood in CSF: A Validation. AB - INTRODUCTION: Patients presenting to the emergency department with acute-onset, atypical headaches require an evaluation for subarachnoid hemorrhage (SAH). The standard evaluation for SAH includes noncontrast computed tomography of the head and, if negative, a lumbar puncture to determine the presence of blood in the cerebrospinal fluid (CSF). In austere environments without full laboratory capabilities, a rapid bedside diagnostic test allowing clinicians to rule out SAH would reduce costly transfers of patients requiring further evaluation. CSF samples obtained while evaluating patients for potential SAH were tested with the blood panel of Bayer Multistix urine test strips. METHODS: We compared the test strip color change to the number of red blood cells per high power field found on laboratory analysis of the CSF. RESULTS: The sensitivity of the Multistix for detecting red blood cells in the CSF was 100%, with a specificity of 56%. The positive predictive value was 37%, and the negative predictive value was 100%. CONCLUSION: These results are encouraging and may form the basis for potential use of urine test strips as a tool to rule out subarachnoid blood in austere environments, but the test strips' low specificity limits their usefulness as a practical clinical tool at this time. PMID- 26926743 TI - Development and Validation of a Brief Measure of Psychological Resilience: An Adaptation of the Response to Stressful Experiences Scale. AB - Resilience helps determine how people respond to stress. The Response to Stressful Events Scale (RSES) is an existing 22-item measure of resilience. We investigate the psychometric properties of the RSES and develop a 4-item measure of resilience using the most discriminating items from the RSES. Among two samples of military personnel presenting to mental health clinics, we see that the abbreviated resilience measure displays comparable internal consistency and test-retest reliability (versus the existing RSES). Among a sample of deployed military personnel, the abbreviated scale relates to validated measures of psychological strain. The 4-item abbreviated RSES measure is a brief, reliable, and valid measure of resilience. PMID- 26926744 TI - The Fog of War: Delirium Prevalence in a Combat Intensive Care Unit. AB - INTRODUCTION: Delirium is a fluctuating disturbance in consciousness associated with increased mortality. Injured warriors represent a unique unstudied population. We hypothesized delirium is common because of high injury severity scores and multidrug sedation regimens. METHODS: Mandatory delirium screening using the confusion assessment method (CAM) was initiated at Craig Joint Theater Hospital in Bagram, Afghanistan. Data were collected in July to August 2012 from the first 50 English-speaking trauma patients with CAM for the Intensive Care Unit (ICU) scores. RESULTS: Patients were male with mean age of 27.8 years; 88% of them were U.S. military personnel. Injury mechanisms were blast (68%) and gunshot (26%). Mean injury severity score was 20. Average ICU length of stay was 2.3 days; 64% were ventilated (for mean 1.2 days). Average time from arrival to CAM assessment was 7 hours, and 26 hours from the time of injury. Of patients, 44% were delirious, 36% at first CAM assessment. Fentanyl (62%) and ketamine (16%) were used for pain control (62%) and propofol for sedation (52%). There was no relationship between delirium and mechanism (p = 0.5) or ketamine on first ICU day (p = 0.2262). Delirium increased with vent days (p < .0001) and was associated with admission and mechanical ventilation (p = 0.0025). CONCLUSIONS: This study demonstrates a high rate of delirium in this unique population. PMID- 26926745 TI - Components and Characteristics of a Psychiatric Partial Hospital Military Program. AB - This article describes the components of a psychiatric partial hospital military program and the characteristics of referrals received over the 5-year period from 2009 to 2013. The 5-year study period included ongoing combat operations in Iraq and Afghanistan along with their subsequent troop withdrawals and change in mission. A total of 1,194 service members were referred for this level of care, and even with the changing battlefield conditions, the number of psychiatric referrals remained steady throughout the 5-year period, with a significant spike in admissions in 2013. The principal diagnoses were major depressive disorder and post-traumatic stress disorder. One-third of the admissions came from service members with 4 to 8 years' time in service and slightly more than one-third were employed in direct combat roles or medical support. In terms of gender, females accounted for one-quarter of the admissions. PMID- 26926746 TI - Disability Among Veterans: Analysis of the National Survey of Veterans (1997 2001). AB - This manuscript assesses whether the Veterans Administration Rating System (VADR) correlates with self-reported activities of daily living (ADL) used in the National Survey of Veterans and likelihood of employment. Veterans' disability benefits are determined based on a single-index standardized rating scheme, measured at time of discharge. The primary aim of this study was to assess how this single-index rating of disability for veterans compares to multidimensional measures of disability (ADL and instrumental activities of daily living [IADL]). The relationship between disability ratings and labor market outcomes such as job search behavior and the likelihood of being employed was assessed. Successful labor market reintegration requires both physical/mental well-being, we examined the extent that VADR can capture the relationship between job market behavior and measures of mental/physical health. Kernel regression estimates were obtained of the likelihood of working/looking for work. Mean numbers of IADL and ADL difficulties and medical conditions were positively associated with VADR (p-trend < 0.001). An inverse relationship was observed with VADR and predicted probability of working (p-trend < 0.001). The combination of >4 ADL/IADL deficits and mental health diagnosis increased the likelihood of not working. The probability of not working correlated with VADR when VADR was greater than 40%. PMID- 26926748 TI - What Patients Really Want: Optimizing the Military Preoperative Evaluation Clinic. AB - The idea of the preoperative anesthesia clinic as a means of examining and treating the patient so that he will arrive in the operating theater as strong and healthy as possible is well established in practice and literature.However, problems in clinic design and execution often result in high patient waiting times, decreased patient and staff satisfaction, decreased patient capacity, and high clinic costs. Although the details of clinic design, outcomes, and satisfaction have been extensively evaluated at civilian hospitals, we have not found corresponding literature addressing these issues specifically within military preoperative evaluation clinics. We find that changing to an appointment based (versus walk-in) system and eliminating data collection step redundancies will likely result in lower wait times, higher satisfaction, lower per patient costs, and a more streamlined and resource-efficient structure. PMID- 26926747 TI - Expanding Health Care Access Through Education: Dissemination and Implementation of the ECHO Model. AB - Project ECHO (Extension for Community Healthcare Outcomes) is an evidence-based model that provides high-quality medical education for common and complex diseases through telementoring and comanagement of patients with primary care clinicians. In a one to many knowledge network, the ECHO model helps to bridge the gap between primary care clinicians and specialists by enhancing the knowledge, skills, confidence, and practice of primary care clinicians in their local communities. As a result, patients in rural and urban underserved areas are able to receive best practice care without long waits or having to travel long distances. The ECHO model has been replicated in 43 university hubs in the United States and five other countries. A new replication tool was developed by the Project ECHO Pain team and U.S. Army Medical Command to ensure a high-fidelity replication of the model. The adoption of the tool led to successful replication of ECHO in the Army Pain initiative. This replication tool has the potential to improve the fidelity of ECHO replication efforts around the world. PMID- 26926750 TI - The Eagle Tactical Athlete Program Reduces Musculoskeletal Injuries in the 101st Airborne Division (Air Assault). AB - The Eagle Tactical Athlete Program (ETAP) was scientifically developed for the U.S. Army's 101st Airborne Division (Air Assault) to counter unintentional musculoskeletal injuries (MSIs). PURPOSE: To determine if ETAP would reduce unintentional MSIs in a group of 101st Airborne Division (Air Assault) Soldiers. METHODS: ETAP-trained noncommissioned led physical training. 1,720 Soldiers were enrolled (N = 1,136 experimental group [EXP], N = 584 control group [CON]) with injuries tracked before and after initiation of ETAP. The International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes were analyzed and described the anatomic locations, anatomic sub-locations, onset, and injury types. McNemar tests compared the proportions of injured subjects within each group. RESULTS: There was a significant reduction in the proportion of Soldiers with preventable MSIs in the EXP (pre: 213/1,136 (18.8%), post: 180/1,136 (15.8%), p = 0.041) but not in the CON. In addition, there was a significant reduction in stress fractures in the EXP (pre: 14/1,136 (1.2%), post: 5/1,136 (0.4%), p = 0.022) but no significant differences in the CON. CONCLUSION: The current analysis demonstrated that ETAP reduces preventable MSIs in garrison. The capability of ETAP to reduce injuries confirms the vital role of a scientifically designed training program on force readiness and health. PMID- 26926749 TI - Spousal Military Deployment During Pregnancy and Adverse Birth Outcomes. AB - Pregnant women with a military-deployed spouse have increased risk of depression and self-reported stress. In nonmilitary populations, depression and stress during pregnancy are associated with adverse birth outcomes. This study assesses the association between a spouse's military deployment and adverse birth outcomes. We conducted a retrospective cohort study at a large military medicine center in the Northwest and evaluated records of singleton deliveries to dependent Army spouses from September 2001 to September 2011. We used logistic regression to estimate relative risks and 95% confidence intervals (CI) of the associations between deployment and low birth weight (<2,500 g), preterm delivery (<37 weeks), small for gestational age (SGA, <10 percentile for gestational age), and cesarean delivery. We identified 10,536 births; 1,364 (12.9%) spouses were deployed at delivery. No associations were observed in the overall population. Among women with two or more children, we observed an 81% increased risk of SGA (95% CI 1.18-2.79). Women 30 to 34 years old had an 82% (95% CI 1.06-3.14) increased risk of low birth weight and an 84% increased risk of SGA (95% CI 1.13 2.98). Deployment's effects vary by maternal age and the number of children in the household. These findings may inform programs and practitioners to best serve women with military-deployed spouses. PMID- 26926751 TI - A Box Lift and Place Assessment is Related to Performance of Several Military Manual Handling Tasks. AB - Soldiers undergo regular physical testing to assess their functional capacity. However, current physical tests, such as push-ups, sit-ups, and pull-ups, do not necessarily assess job-specific physical capability. This article assesses the utility of generic predictive tests and a task-related predictive test in predicting performance against four job-critical military manual handling tasks. The box lift and place test was found to be the superior predictor in performance of four job tasks; a pack lift and place (R(2) = 0.76), artillery gunner loading simulation (R(2) = 0.36), bombing up an M1 tank simulation, (R(2) = 0.47) and a bridge building simulation (R(2) = 0.63). Pull-ups and push-ups were poor predictors of performance in the majority of job tasks. Although the box lift and place had a larger correlation with the artillery gunner loading task than the generic assessment, it only accounted for 36% of the variance, indicating that a task simulation may be more appropriate to assess soldiers' capacity to perform this job task. These results support the use of a box lift and place rather than generic fitness tests for the evaluation of military manual handling tasks. PMID- 26926752 TI - Postdeployment Respiratory Health Care Encounters Following Deployment to Kabul, Afghanistan: A Retrospective Cohort Study. AB - Inhalational hazards are numerous in operational environments. A retrospective cohort study was conducted to investigate associations between deployment to Kabul, Afghanistan and subsequent respiratory health among U.S. military personnel. The study population consisted of personnel who deployed to Kabul, select Operation Enduring Freedom locations, personnel stationed in the Republic of Korea, and U.S.-stationed personnel. Incidence rate ratios (IRRs) were estimated for respiratory symptoms, signs, and ill-defined conditions, asthma, and chronic obstructive pulmonary disease. A significantly elevated rate of symptoms, signs, and ill-defined conditions was observed among Kabul-deployed personnel compared to personnel deployed or stationed in Bagram (IRR 1.12; 95% confidence interval [CI], 1.05-1.19), Republic of Korea (IRR 1.20; 95% CI, 1.10 1.31), and the United States (IRR 1.52; 95% CI, 1.43-1.62). A statistically elevated rate of asthma was observed among personnel deployed to Kabul, relative to U.S.-stationed personnel (IRR 1.61; 95% CI, 1.22-2.12). Statistically significant rates were not observed for chronic obstructive pulmonary disease among Kabul-deployed personnel compared to other study groups. These findings suggest that deployment to Kabul is associated with an elevated risk of postdeployment respiratory symptoms and new-onset asthma. PMID- 26926753 TI - Ultrasound-Guided Peripheral Intravenous Access Program for Emergency Physicians, Nurses, and Corpsmen (Technicians) at a Military Hospital. AB - BACKGROUND: Peripheral intravenous (PIV) access is a common procedure in the emergency department (ED). However, conditions such as obesity and hypovolemia can often make access difficult by the traditional landmark technique. The use of ultrasonography has improved the success of PIV placement in this setting. OBJECTIVES: A novel Ultrasound (US)-Guided PIV Access program was initiated in our ED to train emergency nurses, U.S. Navy corpsmen, and physicians. METHODS: This was an observational study of emergency providers performing US-guided PIV placement. After a training session, all ED providers began utilizing the US for difficult intravenous access patients. All complications, location of access, and previous experience level were recorded. The choice of a transverse, longitudinal, or a combination approach was also recorded. RESULTS: We did not observe significant differences in ability with US-guided PIV access when comparing success rates between emergency physicians, nurses, and technicians (p = 0.13). In the novice user, a transverse or a novel combination of a transverse and longitudinal method appears to be the most successful. CONCLUSION: ED physicians, nurses, and corpsmen can successfully place US-guided peripheral catheters for venous access. Developing a training program for emergency providers in US-guided venous cannulation is feasible and safe. PMID- 26926754 TI - Short-Term Outcomes and Complications of Damage Control and Definitive Laparotomy in Deployed Combat Environments: 2002 to 2011. AB - INTRODUCTION: Damage control laparotomy (DCL) in an austere environment is an evolving surgical modality. METHODS: A retrospective evaluation of all patients surviving 24 hours who underwent a laparotomy from 2002 to 2011 in Iraq and Afghanistan was performed. DCL was defined as a patient undergoing laparotomy at two distinct North American Treaty Organization (NATO) Role 2 or 3 medical treatment facilities (MTFs); a NATO Roles 2 and 3 MTFs, and/or having the International Classification of Diseases, 9th Revision, Clinical Modification procedure code 54.12, for reopening of recent laparotomy site. Definitive laparotomy (DL) was defined as patients undergoing one operative procedure at one NATO Role 2 or 3 MTF. Demographic data including injury severity scores, hematological transfusion, mortality, intraperitoneal or retroperitoneal operative interventions, and complications were compared. RESULTS: DCL composed of 26.5% (n = 331) of all 1,248 laparotomies performed between March 2002 and September 2011. Total intra-abdominal, acute respiratory distress syndrome, and thromboembolic complications for DCL versus DL were 8.5% and 5.6% (p = 0.07), 2.1% and 0.8% (p = 0.06), and 1.5% and 0.7% (p = 0.17), respectively. Theater discharge mortality from DCL and DL were 1.5% (n = 5), and 1.4% (n = 13) (p = 0.90), respectively. CONCLUSIONS: In conclusion, excluding deaths with the first 24 hours, DCL and DL had comparable mortality and complication rates at NATO Roles 2 and 3 MTFs. PMID- 26926755 TI - Topiramate-Associated Weight Loss in a Veteran Population. AB - OBJECTIVE: This study aims to see whether patients in a real-world setting taking topiramate for varied indications experience significant weight loss. METHODS: This was a retrospective cohort study from the Veterans Affairs San Diego Healthcare System. Patients were new topiramate users between January 1, 2000 and December 31, 2013 with body mass index > 25 kg/m(2) and medication possession ratio > 0.5. Primary outcome determined if topiramate users experienced significant changes in weight and body mass index. Secondary outcome analyzed predictive factors associated with 5% weight loss using logistic regression models. Patients were followed up 1 year post index date. RESULTS: A total of 767 patients were included in the final analysis. Patients lost an average of 5.6 lbs (216.1 lbs preweight vs. 210.5 lbs postweight) at an average follow-up of 7.8 months. A total of 43.2% (92/213) of females lost 5% of their body weight compared to 29.4% (163/554) of males. Females (odds ratio 1.73; 95% confidence interval 1.21-2.48; p = 0.003), topiramate indication other than headache, and adherent patients (odds ratio 1.78; 95% confidence interval 1.28-2.49; p = 0.001) were more likely to lose 5% of body weight. CONCLUSION: Topiramate should be considered with higher priority in overweight and obese patients for nonweight loss indications for dual benefit. PMID- 26926756 TI - An Army Veteran and His Incredible Case of Rheumatoid Arthritis and Spondylitis. PMID- 26926757 TI - Outcomes Following Closed Axillary Nerve Injury: A Case Report and Review of the Literature. AB - We report a case of a 43-year-old male who sustained an axillary nerve injury secondary to a glenohumeral joint dislocation at a young age, and who has served over 20 years in the military with near normal shoulder function. In addition, we review the literature for the natural history of axillary nerve injury. A 43-year old male sustained a left anterior glenohumeral dislocation in a motor vehicle accident as an 18-year-old. Following prompt manual reduction and subsequent physical therapy, the patient developed a permanent axillary nerve palsy. Despite the development of complete atrophy of his deltoid musculature and persistent sensory loss in the axillary nerve distribution, he experienced restoration of function with minimal to no deficit. Ultimately, he enlisted in the military 4 years after the injury and has served 22 years, which includes combat deployments with normal shoulder function and absence of pain. Axillary nerve injury is a relatively common injury after anterior glenohumeral joint dislocation. There is little known about the long-term outcome of patient's with permanent axillary nerve injury. This case suggests that it is possible for a young athletic individual to function at a high level of activity after permanent loss of axillary nerve function. PMID- 26926758 TI - Pityriasis Rubra Pilaris in a 3-Year-Old Male. AB - A 3-year-old male presented with progressive pruritic red-orange plaques across most of his body with erythema, desquamation, and fissuring of the hands and feet. He was diagnosed with classic juvenile (type III) pityriasis rubra pilaris (PRP) and treated with oral isotretinoin for 6 months. His skin findings resolved quickly during the treatment period, with residual postinflammatory hypopigmentation resolving within a year. PRP is rare in pediatric patients and standard recommended treatment algorithms for this population are not currently available. Diagnostic and treatment guidelines for PRP are based almost exclusively on case reports or case series, most of which focus on adult patients. The presentation, evaluation, and management of PRP are discussed. PMID- 26926759 TI - Unexploded Ordnance in an Expectant Patient: A Case Report. AB - Retained unexploded ordnance is only one of the numerous potential threats to coalition forces while deployed in the theater of operations. Though rare, these are also very real dangers for personnel involved with patient care and movement. Principles of management include determination of device type with plain film radiography, minimizing rotational and vibratory movement, and strategic isolation of the patient from the hospital facility, hospital personnel, and other patients. Early identification of this threat, as well as early involvement of the Explosive Ordnance Disposal team is paramount to safe and successful management. We present a case of a deceased patient in the expectant triage category with a delayed identification of retained unexploded ordnance during postmortem preparation. PMID- 26926760 TI - Delayed Diagnosis of Tuberculous Arthritis of the Knee in an Air Force Service Member: Case Report and Review of the Literature. AB - Tuberculosis (TB) is a common disease worldwide affecting more than 2 billion people, including latent, pulmonary, and extrapulmonary TB. The presentation of disseminated TB is variable and dependent on the organs affected. Therefore, making the diagnosis and providing appropriate treatment can be delayed. We present a case of disseminated TB in a patient with Sjogren's syndrome on hydroxychloroquine monotherapy without traditional risk factors. PMID- 26926761 TI - Intermolecular Interactions of Cardiac Transcription Factors NKX2.5 and TBX5. AB - Heart development in mammalian systems is controlled by combinatorial interactions of master cardiac transcription factors such as TBX5 and NKX2.5. They bind to promoters/enhancers of downstream targets as homo- or heteromultimeric complexes. They physically interact and synergistically regulate their target genes. To elucidate the molecular basis of the intermolecular interactions, a heterodimer and a homodimer of NKX2.5 and TBX5 were studied using X-ray crystallography. Here we report a crystal structure of human NKX2.5 and TBX5 DNA binding domains in a complex with a 19 bp target DNA and a crystal structure of TBX5 homodimer. The ternary complex structure of NKX2.5 and TBX5 with the target DNA shows physical interactions between the two proteins through Lys158 (NKX2.5), Asp140 (TBX5), and Pro142 (TBX5), residues that are highly conserved in TBX and NKX families across species. Extensive homodimeric interactions were observed between the TBX5 proteins in both crystal structures. In particular, in the crystal structure of TBX5 protein that includes the N terminal and DNA binding domains, intermolecular interactions were mediated by the N-terminal domain of the protein. The N-terminal domain of TBX5 was predicted to be "intrinsically unstructured", and in one of the two molecules in an asymmetric unit, the N-terminal domain assumes a beta-strand conformation bridging two beta-sheets from the two molecules. The structures reported here may represent general mechanisms for combinatorial interactions among transcription factors regulating developmental processes. PMID- 26926762 TI - Principal component analysis of MALDI TOF MS mass spectra separates M. abscessus (sensu stricto) from M. massiliense isolates. AB - BACKGROUND: The discrimination of the members of the Mycobacterium abscessus complex is of clinical interest because one of the subspecies, M. massiliense, exhibits higher rates of response to antibiotic treatment for lung infection than do the other members of that complex. M. abscessus complex contains three subspecies that are laborious to identify; therefore, a routine diagnostic tool would be worthwhile. RESULTS: We used principal component analysis, hierarchical cluster analysis, and single-peak analysis to examine peak lists derived from matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI TOF MS) mass spectra of 50 clinical M. abscessus complex isolates, including 28 M. abscessus (sensu stricto), 19 M. massiliense, and 3 M. bolletii isolates grown in mycobacterium growth indicator tube liquid medium and prepared with a bead-based protocol. Principal component analysis but not hierarchical cluster analysis separated M. abscessus (sensu stricto) isolates and M. massiliense isolates into two clusters. Furthermore, single-peak analysis displayed 4 discriminating peaks that separated M. abscessus (sensu stricto) from M. massiliense isolates. M. bolletii isolates did not exhibit specific peaks but resembled the M. abscessus (sensu stricto) peak profile and also grouped within this principal component analysis cluster. Principal component analysis of all peak lists with the exclusion of the four discriminating peaks again separated M. abscessus (sensu stricto) from M. massiliense isolates, thus relativizing the importance of these peaks for subspecies identification. CONCLUSIONS: Principal component analysis of peak lists derived from MALDI TOF mass spectra is a robust and convenient method of discriminating M. massiliense isolates from the other members of the M. abscessus complex. PMID- 26926763 TI - A Laser-Assisted Anastomotic Technique: Feasibility on Human Diseased Coronary Arteries. AB - OBJECTIVE: Atherosclerotic disease might hamper the efficacy of the Excimer laser assisted Trinity Clip anastomotic connector in coronary arteries. Therefore, its efficacy was evaluated on human diseased coronary arteries (study 1). In addition, the acute laser effects onto the coronary wall were assessed (study 2). METHODS: Thirty-eight anastomoses were constructed on ex vivo human hearts. Atherosclerosis was histopathologically determined and subsequently related to the success of the technique (ie, connector positioning and laser punching; study 1). In addition, 20 anastomoses were constructed in an ex vivo (porcine, n = 8) and an in vivo [rabbit (n = 9) and porcine (n = 3)] model. Subsequently, the coronary was histologically studied on the presence of laser-induced damage (study 2). RESULTS: In 13 of 38 anastomoses (study 1), the connector was malpositioned, 3 because of a severely diseased coronary wall and 10 because of an inner diameter less than the intended target range. The laser-punch success rates on coronary arteries with an early and advanced lesion were 100% (16/16) and 89% (8/9; lesions were located in the inferolateral wall), respectively. In one case, an advanced lesion (ie, fibrocalcified plaque) was located in the superolateral wall and caused a laser-punch failure. No histological signs of laser-induced damage were observed, in case of correct use (study 2). CONCLUSIONS: This study demonstrates the feasibility of an anastomotic connector on human diseased coronary arteries and shows that lasering does not induce coronary wall damage. However, careful selection of the coronary, regarding the target inner diameter and disease status, will prevent construction failures. This connector could facilitate less invasive coronary artery bypass grafting. PMID- 26926765 TI - Improved Steroids Detection and Evidence for Their Regiospecific Decompositions Using Anion Attachment Mass Spectrometry. AB - Nonpolar anabolic steroids are doping agents that typically do not provide strong signals by electrospray ionization-mass spectrometry (ESI-MS) owing especially to the low polarity of the functional groups present. We have investigated the addition of anions, in ammonium salt form, to anabolic steroid samples as ionization enhancers and have confirmed that lower instrumental limits of detection (as low as 10 ng/mL for fluoxymesterone-M) are obtained by fluoride anion attachment mass spectrometry, as compared to ESI(+)/(-) or atmospheric pressure photoionization (APPI)(+). Moreover, collision-induced decomposition (CID) spectra of precursor fluoride adducts of the bifunctional steroid "reduced pregnenolone" (containing two hydroxyl groups) and its d4-analogue provide evidence of regiospecific decompositions after attachment of fluoride anion to a specific hydroxyl group of the steroid. This type of charting of specific CID reaction pathways can offer value to selected reaction monitoring experiments (SRM) as it may result in a gain in selectivity in detection as well as in improvements in quantification. PMID- 26926764 TI - Changes in snoRNA and snRNA Abundance in the Human, Chimpanzee, Macaque, and Mouse Brain. AB - Small nuclear and nucleolar RNAs (snRNAs and snoRNAs) are known to be functionally and evolutionarily conserved elements of transcript processing machinery. Here, we investigated the expression evolution of snRNAs and snoRNAs by measuring their abundance in the frontal cortex of humans, chimpanzees, rhesus monkeys, and mice. Although snRNA expression is largely conserved, 44% of the 185 measured snoRNA and 40% of the 134 snoRNA families showed significant expression divergence among species. The snRNA and snoRNA expression divergence included drastic changes unique to humans: A 10-fold elevated expression ofU1snRNA and a 1,000-fold drop in expression ofSNORA29 The decreased expression ofSNORA29might be due to two mutations that affect secondary structure stability. Using in situ hybridization, we further localizedSNORA29expression to nucleolar regions of neuronal cells. Our study presents the first observation of snoRNA abundance changes specific to the human lineage and suggests a possible mechanism underlying these changes. PMID- 26926767 TI - News from the Society for Vascular Medicine and Biology. PMID- 26926766 TI - Multiple Aortic Aneurysms. PMID- 26926769 TI - Enhanced Magnetoresistance in Molecular Junctions by Geometrical Optimization of Spin-Selective Orbital Hybridization. AB - Molecular junctions based on ferromagnetic electrodes allow the study of electronic spin transport near the limit of spintronics miniaturization. However, these junctions reveal moderate magnetoresistance that is sensitive to the orbital structure at their ferromagnet-molecule interfaces. The key structural parameters that should be controlled in order to gain high magnetoresistance have not been established, despite their importance for efficient manipulation of spin transport at the nanoscale. Here, we show that single-molecule junctions based on nickel electrodes and benzene molecules can yield a significant anisotropic magnetoresistance of up to ~200% near the conductance quantum G0. The measured magnetoresistance is mechanically tuned by changing the distance between the electrodes, revealing a nonmonotonic response to junction elongation. These findings are ascribed with the aid of first-principles calculations to variations in the metal-molecule orientation that can be adjusted to obtain highly spin selective orbital hybridization. Our results demonstrate the important role of geometrical considerations in determining the spin transport properties of metal molecule interfaces. PMID- 26926770 TI - US Food and Drug Administration Approval of Flibanserin: Even the Score Does Not Add Up. PMID- 26926771 TI - A novel long noncoding RNA regulating cholesterol and bile acid homeostasis: A new kid on the block and a potential therapeutic target? PMID- 26926772 TI - Validation of the HOOS, JR: A Short-form Hip Replacement Survey. AB - BACKGROUND: Patient-reported outcome measures (PROMs) are increasingly in demand for outcomes evaluation by hospitals, administrators, and policymakers. However, assessing total hip arthroplasty (THA) through such instruments is challenging because most existing measures of hip health are lengthy and/or proprietary. QUESTIONS/PURPOSES: The objective of this study was to derive a patient-relevant short-form survey based on the Hip disability and Osteoarthritis Outcome Score (HOOS), focusing specifically on outcomes after THA. METHODS: We retrospectively evaluated patients with hip osteoarthritis who underwent primary unilateral THA and who had completed preoperative and 2-year postoperative PROMs using our hospital's hip replacement registry. The 2-year followup in this population was 81% (4308 of 5351 patients). Of these, 2371 completed every item on the HOOS before surgery and at 2 years, making them eligible for the formal item reduction analysis. Through semistructured interviews with 30 patients, we identified items in the HOOS deemed qualitatively most important to patients with hip osteoarthritis. The original HOOS has 40 items, the four quality-of-life items were excluded a priori, five were excluded for being redundant, and one was excluded based on patient-relevance surveys. The remaining 30 items were evaluated using Rasch modeling to yield a final six-item HOOS, Joint Replacement (HOOS, JR), representing a single construct of "hip health." We calculated HOOS, JR scores for the Hospital for Special Surgery (HSS) cohort and validated this new score for internal consistency, external validity (versus HOOS and WOMAC domains), responsiveness to THA, and floor and ceiling effects. Additional external validation was performed using calculated HOOS, JR scores in collaboration with the Function and Outcomes Research for Comparative Effectiveness in Total Joint Replacement (FORCE-TJR) nationally representative joint replacement registry (n = 910). RESULTS: The resulting six-item PROM (HOOS, JR) retained items only from the pain and activities of daily living domains. It showed high internal consistency (Person Separation Index, 0.86 [HSS]; 0.87 [FORCE]), moderate to excellent external validity against other hip surveys (Spearman's correlation coefficient, 0.60-0.94), very high responsiveness (standardized response means, 2.03 [95% CI, 1.84-2.22] [FORCE]; and 2.38 [95% CI, 2.27-2.49] [HSS]), and favorable floor (0.6%-1.9%) and ceiling (37%-46%) effects. External validity was highest for the HOOS pain (Spearman's correlation coefficient, 0.87 [95% CI, 0.86-0.89] [HSS]; and 0.87 [95% CI, 0.84-0.90] [FORCE]) and HOOS activities of daily living (Spearman's correlation coefficient, 0.94 [95% CI, 0.93-0.95] [HSS]; and 0.94 [95% CI, 0.93-0.96] [FORCE]) domains in the HSS validation cohort and the FORCE-TJR cohort. CONCLUSIONS: The HOOS, JR provides a valid, reliable, and responsive measure of hip health for patients undergoing THA. This short-form PROM is patient relevant and efficient. LEVEL OF EVIDENCE: Level III, diagnostic study. PMID- 26926773 TI - Validation of the KOOS, JR: A Short-form Knee Arthroplasty Outcomes Survey. AB - BACKGROUND: Medicare is rapidly moving toward using patient-reported outcome measures (PROMs) for outcomes assessment and justification of orthopaedic and other procedures. Numerous measures have been developed to study knee osteoarthritis (OA); however, many of these surveys are long, disruptive to clinic flow, and result in incomplete data capture and/or low followup rates. The Knee injury and Osteoarthritis Outcome (KOOS) physical function short-form (KOOS PS), while shorter, ignores pain, which is a primary concern of patients with advanced knee OA. QUESTIONS/PURPOSES: Our objective was to derive and validate a short-form survey focused on the patient with end-stage knee OA undergoing TKA. METHODS: Using our hospital's knee replacement registry, we retrospectively identified 2291 patients with knee OA who underwent primary unilateral TKA and had completed preoperative and 2-year postoperative PROMs. We assessed 30 items from the 42-item KOOS that were quantitatively most difficult for patients to perform before TKA and qualitatively most relevant to patients with end-stage knee OA. Rasch analysis identified the KOOS, JR, a seven-item instrument, representing a single dimension, which we define as "knee health" because it reflects aspects of pain, symptom severity, and activities of daily living (ADL) including movements or activities that are directly relevant and difficult for patients with advanced knee OA. We assessed the internal consistency, external validity (versus KOOS and WOMAC domains), responsiveness, and floor and ceiling effects of the KOOS, JR. External validation was performed using calculated KOOS, JR scores in collaboration with a nationally representative joint replacement registry, the Function and Outcomes Research for Comparative Effectiveness in Total Joint Replacement (FORCE-TJR). RESULTS: Internal consistency for the KOOS, JR was high (Person Separation Index, 0.84; and 0.85 [FORCE]), external validity against other validated knee surveys was excellent (Spearman correlation coefficient, rho 0.54-0.91), particularly for the KOOS pain (rho 0.89 [95% CI, 0.88-0.91] Hospital for Special Surgery [HSS]; and 0.91 [95% CI, 0.90-0.93] [FORCE]) and KOOS ADL (rho 0.87 [95% CI, 0.85-0.88] [HSS]; and 0.84 [95% CI, 0.81 0.87] [FORCE]). The KOOS, JR responsiveness (standardized response means, 1.79 [95% CI, 1.70-1.88] [HSS]; and 1.70 [95% CI, 1.54-1.86] [FORCE]) was high and floor 0.4-1.2%) and ceiling (18.8-21.8%) effects were favorable. CONCLUSIONS: The new short knee PROM, the KOOS, JR, provides a single score representing "knee health" as it combines pain, symptoms, and functional limitations in a single score. This short-form PROM is patient-relevant and efficient. LEVEL OF EVIDENCE: Level III, diagnostic study. PMID- 26926774 TI - What Factors Are Associated With Failure of Compressive Osseointegration Fixation? AB - BACKGROUND: Compressive osseointegration is as an alternative to traditional intramedullary fixation. Two- to 10-year survivorship and modes of failure have been reported; however, as a result of relatively small numbers, these studies are limited in their ability to identify risk factors for failure. QUESTIONS/PURPOSES: (1) What is survivorship free from aseptic mechanical and survivorship free from overall failure of compressive osseointegration fixation? (2) What patient factors (age, sex, body mass index [BMI], anatomic location of reconstruction, indication for reconstruction, radiation, chemotherapy) are associated with increased risk of failure? METHODS: Between 2006 and 2014, surgeons at one center treated 116 patients with 137 Compress(r) implants for lower extremity oncologic reconstructions, revision arthroplasty, and fracture nonunion or malunion. One hundred sixteen implants were available for review with a minimum of 2-year followup (mean, 4 years; range, 2-9 years). Kaplan-Meier survival plots were produced to examine survivorship and Cox regression modeling was used to generate hazard ratios (HRs) for potential risk factors for failure. Patient factors (age, sex, BMI, anatomic location of reconstruction, indication for reconstruction, radiation, chemotherapy) were obtained from chart review and an institutional database. RESULTS: Survivorship free from aseptic mechanical failure was 95% (95% confidence interval [CI], 91%-99%) at 18 months and 93% (95% CI, 86%-99%) at 4 years. Survivorship free from overall failure was 82% (95% CI, 75%-89%) at 18 months and 75% (95% CI, 66%-84%) at 4 years. Risk of overall failure was increased with reconstruction of the proximal tibia (HR, 4.42; 95% CI 0.98-19.9) and distal femur (HR, 1.74; 95% CI, 0.50-6.09) compared to the proximal femur (HR, 1; referent; p = 0.049). Risk of aseptic mechanical failure was increased with reconstruction of the proximal tibia (HR, 1; referent) and distal femur (HR, 0.37; 95% CI, 0.08-1.77) compared with the proximal femur (HR, 0, p = 0.048). Radiation was associated with increased risk of overall failure (HR, 3.85; 95% CI, 1.84-8.02; p < 0.003), but not aseptic mechanical failure. Age, sex, BMI, chemotherapy, and surgical indication were not associated with increased risk of aseptic or overall failure. CONCLUSIONS: This study questions the use of age as a contraindication for the use of this technology and suggests this technology may be considered in proximal femoral reconstruction and for patients with indications other than primary oncologic reconstructions. Future research should establish long-term survivorship data to compare this approach with conventional intramedullary stems and to evaluate the potential benefits of preventing stress shielding and preserving bone stock in revision situations. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 26926775 TI - RiMINI - the influence of rifaximin on minimal hepatic encephalopathy (MHE) and on the intestinal microbiome in patients with liver cirrhosis: study protocol for a randomized controlled trial. AB - BACKGROUND: Hepatic encephalopathy (HE) is a clinically significant complication of liver cirrhosis impacting on the patients' quality of life. Minimal hepatic encephalopathy (MHE) is diagnosed by psychometric tests, found in up to 80 % of patients with liver cirrhosis and carries a high risk of progression to overt HE. Continuous therapy with rifaximin in combination with lactulose significantly reduces the risk of overt HE, recurrence of HE and HE-related hospitalizations in randomized, double-blind, placebo-controlled clinical trials. Rifaximin is approved for the therapy of overt HE in Germany. Treatment with lactulose has been shown to improve cognitive functions in patients with liver cirrhosis. Data from prospective clinical trials comparing the efficacy of rifaximin alone against a combination of rifaximin and lactulose in the treatment of MHE are scarce. Changes in the microbiome of the upper and lower gastrointestinal tract as a result of therapy with rifaximin have not yet been addressed in clinical studies. METHODS AND DESIGN: RiMINI is a monocentric exploratory pilot study on 60 patients with MHE as assessed by critical flicker frequency (CFF). Additionally, visual evoked potentials' (VEP) testing, electroencephalography (EEG) and psychometric testing (NCT-A) will be carried out. Patients will be randomized to treatment either with rifaximin alone (550 mg twice daily (bid) continuously for a period of 3 months) or with rifaximin (550 mg bid continuously) in combination with lactulose (30-60 ml daily) for 3 months. An esophagogastroduodenoscopy (EGD) will be performed at baseline, at the end of treatment and 6 and 12 weeks after the end of treatment to obtain gastric and duodenal biopsies and aspirates. The samples will be analyzed for their content of specific bacterial taxae by applying next generation sequencing (NGS) after rRNA isolation to identify the microbiome of the stomach and duodenum, and of the gut, in patients with liver cirrhosis and MHE before and after therapy. DISCUSSION: Differences of the effect of antibiotic therapy with rifaximin alone or in combination with lactulose on the clinical course of MHE are assessed. TRIAL REGISTRATION: The trial was registered as DRKS00006359 on March 17th 2015, with the universal trial number U1111-1163-9410 and with EudraCT2013-004414-18 . PMID- 26926776 TI - [Contrast-induced nephropathy: An update]. AB - Contrast-induced nephropathy (CIN) is common in hospitalized patients. Its occurrence is associated with an increased hospitalization stay and cost, morbidity and mortality. Thus, preventives strategies remain a major issue. Patients that are referred for cardiac catheterization are among the most vulnerable to develop CIN due to their comorbidities. Moreover, in some cases, such preventives measures cannot be introduced due to emergent clinical settings. After a summary regarding the properties of iodinated contrast medium, the aim of this work was to review the definition, pathophysiology, diagnosis and preventive strategies related to CIN. PMID- 26926777 TI - Preparation of the Core Structure of Aspidosperma and Strychnos Alkaloids from Aryl Azides by a Cascade Radical Cyclization. AB - A novel approach to prepare the core structure of Aspidosperma and Strychnos alkaloids is described. The strategy is based on a cyclization cascade involving the formation of quaternary carbon center followed by trapping of the radical intermediate by an aryl azide to build the 5-membered ring of the pyrrolocarbazole system. This reaction is run with triethylborane without the need for any hydrogen atom donor such as a tin hydride or tris(trimethylsilyl)silane, and it furnishes the tetracyclic framework as a single diastereomer. The influence of different N-protecting groups on the starting iodoacetamide has been examined. PMID- 26926778 TI - Trends and drivers of debris accumulation on Maui shorelines: Implications for local mitigation strategies. AB - Marine debris, particularly plastic, is an identified concern for coastal areas and is known to accumulate in large quantities in the North Pacific. Here we present results from the first study to quantify and compare the types and amounts of marine debris on Maui shorelines. Surveys were conducted monthly between May 2013 and December 2014, with additional daily surveys conducted on Maui's north shore during January 2015. Debris accumulation rates, loads, and sources varied between sites, with plastics being the most prevalent type of debris at all sites. Large debris loads on windward shores were attributed to the influence of the North Pacific Subtropical Gyre and northerly trade winds. Daily surveys resulted in a significantly higher rate of debris deposition than monthly surveys. The efficacy of local policy in debris mitigation showed promise, but was dependent upon the level of enforcement and consumer responsibility. PMID- 26926779 TI - Hazards in hanging gardens: A report on failures of recognition by green turtles and their conservation implications. AB - Marine species are experiencing unprecedented global impacts due to anthropogenic debris. Many recent studies have pointed out the hazards associated with marine litter ingestion, especially plastic debris - the most abundant and ubiquitous items in coastal and oceanic environments worldwide. In this study we provide the first in situ evidence of consumption of non-discarded synthetic rope fragments by green turtles. We explored the environmental risks to this endangered species associated with the grazing and consumption of anthropogenic debris in zones of human activity. Efforts to combat debris ingestion and reduce anthropogenic debris discharged into the world's oceans should be a priority for decision makers and will need to involve multiple-approaches and the adoption of more environmentally friendly products and practices by the international community. PMID- 26926780 TI - Thermal conductivity of armchair black phosphorus nanotubes: a molecular dynamics study. AB - The effects of size, strain, and vacancies on the thermal properties of armchair black phosphorus nanotubes are investigated based on qualitative analysis from molecular dynamics simulations. It is found that thermal conductivity has a remarkable size effect, because of the restricted paths for phonon transport, which is strongly dependent on the diameter and length of the nanotube. Owing to the intensified low-frequency phonons, axial tensile strain can facilitate thermal transport. In contrast, compressive strain weakens thermal transport due to the enhanced phonon scattering around the buckling of the nanotube. In addition, the thermal conductivity is dramatically reduced by single vacancies, particularly those with high defect concentrations. PMID- 26926781 TI - More than metabolic: Considering the broader paleoepidemiological impact of vitamin D deficiency in bioarchaeology. AB - Vitamin D deficiency has traditionally been viewed as a metabolic bone disease by bioarchaeologists and considered primarily in terms of the development of specific musculoskeletal changes used for diagnosis in paleopathological research. These skeletal manifestations are usually interpreted as representing general ill-health. Clinical research shows that vitamin D is also integral to a number of extra-skeletal physiological processes including immunoregulation, blood pressure homeostasis, cell division, and programmed cell death. Vitamin D deficiency and sub-clinical insufficiency are thought to be risk factors for infectious and autoimmune diseases, as well as certain cancers and cardiovascular diseases. Epidemiological work indicates that the skeletal manifestations of vitamin D deficiency represent the extreme end of a spectrum of morbidity associated with negative health outcomes, including increased risk for secondary tuberculosis. This article provides a review of clinical research on the extra skeletal roles of vitamin D and the pathological consequences of poor vitamin D status. Additionally, it presents an interpretive model for bioarchaeological analyses of rickets and osteomalacia for consideration of the whole-body impact of poor vitamin D nutriture and possible comorbidities that may have affected the wider population. Am J Phys Anthropol 160:183-196, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26926782 TI - Silver recovery aqueous techniques from diverse sources: Hydrometallurgy in recycling. AB - The demand of silver is ever increasing with the advance of the industrialized world, whereas worldwide reserves of high grade silver ores are retreating. However, there exist large stashes of low and lean grade silver ores that are yet to be exploited. The main impression of this work was to draw attention to the most advance technologies in silver recovery and recycling from various sources. The state of the art in recovery of silver from different sources by hydrometallurgical and bio-metallurgical processing and varieties of leaching, cementing, reducing agents, peeling, electro-coagulants, adsorbents, electro dialysis, solvent extraction, ion exchange resins and bio sorbents are highlighted in this article. It is shown that the major economic driver for recycling of depleted sources is for the recovery of silver. In order to develop an nature-friendly technique for the recovery of silver from diverse sources, a critical comparison of existing technologies is analyzed for both economic viability and environmental impact was made in this amendment and silver ion toxicity is highlighted. PMID- 26926783 TI - Gravimetric water distribution assessment from geoelectrical methods (ERT and EMI) in municipal solid waste landfill. AB - The gravimetric water content of the waste material is a key parameter in waste biodegradation. Previous studies suggest a correlation between changes in water content and modification of electrical resistivity. This study, based on field work in Mont-Saint-Guibert landfill (Belgium), aimed, on one hand, at characterizing the relationship between gravimetric water content and electrical resistivity and on the other hand, at assessing geoelectrical methods as tools to characterize the gravimetric water distribution in a landfill. Using excavated waste samples obtained after drilling, we investigated the influences of the temperature, the liquid phase conductivity, the compaction and the water content on the electrical resistivity. Our results demonstrate that Archie's law and Campbell's law accurately describe these relationships in municipal solid waste (MSW). Next, we conducted a geophysical survey in situ using two techniques: borehole electromagnetics (EM) and electrical resistivity tomography (ERT). First, in order to validate the use of EM, EM values obtained in situ were compared to electrical resistivity of excavated waste samples from corresponding depths. The petrophysical laws were used to account for the change of environmental parameters (temperature and compaction). A rather good correlation was obtained between direct measurement on waste samples and borehole electromagnetic data. Second, ERT and EM were used to acquire a spatial distribution of the electrical resistivity. Then, using the petrophysical laws, this information was used to estimate the water content distribution. In summary, our results demonstrate that geoelectrical methods represent a pertinent approach to characterize spatial distribution of water content in municipal landfills when properly interpreted using ground truth data. These methods might therefore prove to be valuable tools in waste biodegradation optimization projects. PMID- 26926784 TI - Incineration of animal by-products--The impact of selected parameters on the flux of flue gas enthalpy. AB - This paper presents model analyses and tests of animal by-product waste thermal treatment plants. A schedule of tests was prepared, and 62,024 cases of system operation were analysed. A map/work field of the tested plant was drawn up on the basis thereof. Calculations were made following an algorithm described by Bujak (2015a) written in the VBA (Visual Basic for Application) language. The tests showed that when incinerating animal waste, the flux of physical enthalpy of the flue gas from the afterburner chamber depends on numerous design and operating parameters. The most important include the following: humidity and flux of the waste, concentration of oxygen in the flue gas in the afterburner chamber and loss of heat flux to the atmosphere through the external surfaces of the plant. Individual design and operating parameters can be selected so that the process of incineration is ensured without additional fuel. The performed analyses were verified against the actual object at the industrial scale using a meat plant that manufactures ham and processes beef, pork and poultry with a capacity of 150 tonnes/day. The production process waste included mainly bones and - in much smaller quantities - meat and bone meal, at 17 tonnes/day. The performed tests and analyses can be used to optimise the operation of the waste thermal treatment plant at the stages of design and operation. PMID- 26926785 TI - How Inhomogeneous Site Percolation Works on Bethe Lattices: Theory and Application. AB - Inhomogeneous percolation, for its closer relationship with real-life, can be more useful and reasonable than homogeneous percolation to illustrate the critical phenomena and dynamical behaviour of complex networks. However, due to its intricacy, the theoretical framework of inhomogeneous percolation is far from being complete and many challenging problems are still open. In this paper, we first investigate inhomogeneous site percolation on Bethe Lattices with two occupation probabilities, and then extend the result to percolation with m occupation probabilities. The critical behaviour of this inhomogeneous percolation is shown clearly by formulating the percolation probability Pinfinity(p) with given occupation probability p, the critical occupation probability pc = sup{p|Pinfinity(p) = o}, and the average cluster size chi(p) where p is subject to Pinfinity(p) = o. Moreover, using the above theory, we discuss in detail the diffusion behaviour of an infectious disease (SARS) and present specific disease-control strategies in consideration of groups with different infection probabilities. PMID- 26926786 TI - Trichodinosis associated with pathology of the reproductive tract in waterfowl. AB - Trichodinid ciliophorans are opportunistic parasites of many species of fish, amphibians, and molluscs, but yet never reported in association with lesions in birds. Postmortem and histopathological evaluation of a commercial adult Toulouse gander and female goose, and a wild Mallard drake revealed the presence of severe pathological parasitic colonization of their reproductive tracts. Histopathological findings included moderate to severe granulocytic inflammation, acanthosis, accentuation of the rete pegs, and proliferative hyperplastic squamous metaplasia of the mucosa of the ejaculatory ducts and groove, sulcus spermaticus, glandular part of the phallus (cavum penis), and oviduct in association with large numbers of ciliated protozoa anchored to the tissues or free in the lumen. These protozoa had characteristic morphological features analogous to the family of Trichodinidae. The source of this parasitism could not be determined. To our knowledge, this is the first report of trichodinosis associated with pathology in birds. PMID- 26926787 TI - A HSP60-targeting peptide for cell apoptosis imaging. AB - Apoptosis has a critical role in both physiological and pathological processes, and therefore probes that enable direct and fast visualization for apoptosis in vitro and in vivo have great significance for evaluation of therapeutic effects, disease monitoring and drug screening. We report here a novel apoptotic marker heat shock protein 60 (HSP60)-based apoptosis imaging probe, P17. In this study, we show that P17 can label multiple drug-induced apoptotic cells in vitro, and the difference in binding intensities between apoptotic and viable cells by fluorescent P17 is more than 10-fold in six cell lines measured by flow cytometry and proportional to the apoptotic level of the cells. We further visualized the apoptosis in the subcutaneous tumor of mice by vein injection of P17 using in vivo fluorescent imaging. P17 was identified to bind specifically to HSP60 accumulated in apoptotic cells by pull-down experiments and mass spectrometry. Furthermore, the P17 binding was correlated with the apoptotic feature of phosphatidylserine (PS) exposure and caspase-3 activation. We also clarify that P17 labels the cells in late stage apoptosis by double staining with different stage markers, unveiling that HSP60 may be involved with late stage of apoptosis. Overall, this study has demonstrated that P17 is a novel apoptosis probe targeting HSP60 and promising for the detection of apoptosis in vitro and in vivo. PMID- 26926789 TI - Dysregulation of Bmi1 promotes malignant transformation of hepatic progenitor cells. AB - Adult hepatic progenitor cells (HPCs) are involved in a wide range of human liver diseases, including hepatocellular carcinoma (HCC). Bmi1 has been reported to have vital roles in stem cell self-renewal and carcinogenesis. We have previously demonstrated that Bmi1 is upregulated in HCC with bile duct tumor thrombi, a subtype of HCC characterized by profuse expression of hepatic stem cell markers. However, the function of Bmi1 in HPCs has not yet been well elucidated. The current study was designed to investigate the effects of Bmi1 on the biological properties of rat HPCs. To accomplish this, Bmi1 was silenced or enhanced in two HPC cell lines (WB-F344 and OC3) by, respectively, using either small interfering RNA against Bmi1 or a forced Bmi1 expression retroviral vector. The biological functions of Bmi1 in HPCs were investigated through cell proliferation assays, colony-formation assays, cell cycle analysis and invasion assays, as well as through xenograft-formation assays. In this study, genetic depletion of Bmi1 repressed cell proliferation, colony formation and invasion in both assessed HPC cell lines relative to controls. Conversely, forced expression of Bmi1 in two HPCs cell lines promoted cell proliferation, colony formation and invasion in vitro. Aldehyde dehydrogenase (ALDH) assay revealed a significant increase in the number of ALDH-positive cells following the forced expression of Bmi1 in HPCs. Most importantly, transplantation of forced Bmi1 expression HPCs into nude mice resulted in the formation of tumors with histological features of poorly differentiated HCC. Taken together, our findings indicate that forced expression of Bmi1 promotes the malignant transformation of HPCs, suggesting Bmi1 might be a potential molecular target for the treatment of HCC. PMID- 26926788 TI - Heparanase-induced shedding of syndecan-1/CD138 in myeloma and endothelial cells activates VEGFR2 and an invasive phenotype: prevention by novel synstatins. AB - Multiple myeloma arises when malignant plasma cells invade and form multiple tumors in the bone marrow. High levels of heparanase (HPSE) correlate with poor prognosis in myeloma patients. A likely target of the enzyme is the heparan sulfate (HS) proteoglycan syndecan-1 (Sdc1, CD138), which is highly expressed on myeloma cells and contributes to poor prognosis in this disease. We find that HPSE promotes an invasive phenotype mediated by the very late antigen-4 (VLA-4, or alpha4beta1 integrin) in myeloma cells plated on either fibronectin (FN) or vascular endothelial cell adhesion molecule-1 (VCAM-1), ligands that are prevalent in the bone marrow. The phenotype depends on vascular endothelial cell growth factor receptor-2 (VEGFR2), which is aberrantly expressed in myeloma, and is characterized by a highly protrusive lamellipodium and cell invasion. HPSE mediated trimming of the HS on Sdc1 and subsequent matrix metalloproteinase-9 mediated shedding of the syndecan exposes a juxtamembrane site in Sdc1 that binds VEGFR2 and VLA-4, thereby coupling VEGFR2 to the integrin. Shed Sdc1 can be mimicked by recombinant Sdc1 ectodomain or by a peptide based on its binding motif, which causes VLA-4 to re-orient from the lagging edge (uropod) to the leading edge of migrating cells, couple with and activate VEGFR2. Peptides (called 'synstatins') containing only the VLA-4 or VEGFR2 binding sites competitively inhibit invasion, as they block coupling of the receptors. This mechanism is also utilized by vascular endothelial cells, in which it is also activated by HPSE, during endothelial cell tube formation. Collectively, our findings reveal for the first time the mechanism through which HPSE modulates Sdc1 function to promote both tumor cell invasion and angiogenesis, thereby driving multiple myeloma progression. The inhibitory synstatins, or inhibitors of HPSE enzyme activity, are likely to show promise as therapeutics against myeloma extravasation and spread. PMID- 26926790 TI - Homozygous G/G variant of SNP309 in the human MDM2 gene is associated with earlier tumor onset in Caucasian female renal cell carcinoma patients. AB - Human mouse double minute 2 (Mdm2) plays an essential role in the regulation of the tumor suppressor p53. The G/G variant of SNP309 was shown to increase Mdm2 mRNA/protein expression and to be associated with an increased risk and earlier onset of different cancers in Asian populations. However, the frequency and impact of these G/G variants have not been studied in Caucasian renal cell carcinoma (RCC) patients. Therefore, we analyzed an unselected German cohort of 197 consecutive RCC patients and detected the G/G variant in 18 (9.1%) patients, the G/T variant in 116 (58.9%) patients and the T/T variant in 63 (32.0%) patients. Studying the association between age at tumor onset and SNP309 genotypes, no correlation was detected in the entire RCC cohort or among the male RCC patients. However, the female G/G patients (median age 59.5 years) were diagnosed 13.5 years earlier than the T/T females (median age 73 years). When separating all females into two groups at their median age (68 years), 7 and 1 patients with the G/G variant and 9 and 13 patients with the T/T variant were noted in these age groups (P=0.024). To study the age dependency of tumor onset further, a second, age-selected cohort of 205 RCC patients was investigated, which comprised especially young and old patients. Interestingly, the G/G type occurred more often at lower tumor stages and tumor grades compared with higher stages (P=0.039 and 0.004, respectively). In females, the percentage of the G/G variant was only slightly higher in the younger age group, whereas in males, the percentage of the G/G variant was remarkably higher in the younger age group (19.4% vs 8.0%). In summary, female Caucasian RCC patients with the MDM2 SNP309 G/G genotype showed significantly earlier tumor onset than patients with the wild type T/T genotype. PMID- 26926791 TI - Amygdala subnuclei response and connectivity during emotional processing. AB - The involvement of the human amygdala in emotion-related processing has been studied using functional magnetic resonance imaging (fMRI) for many years. However, despite the amygdala being comprised of several subnuclei, most studies investigated the role of the entire amygdala in processing of emotions. Here we combined a novel anatomical tracing protocol with event-related high-resolution fMRI acquisition to study the responsiveness of the amygdala subnuclei to negative emotional stimuli and to examine intra-amygdala functional connectivity. The greatest sensitivity to the negative emotional stimuli was observed in the centromedial amygdala, where the hemodynamic response amplitude elicited by the negative emotional stimuli was greater and peaked later than for neutral stimuli. Connectivity patterns converge with extant findings in animals, such that the centromedial amygdala was more connected with the nuclei of the basal amygdala than with the lateral amygdala. Current findings provide evidence of functional specialization within the human amygdala. PMID- 26926792 TI - Functional characterisation of letter-specific responses in time, space and current polarity using magnetoencephalography. AB - Recent neurophysiological evidence suggests that a hierarchical neural network of low-to-high level processing subserves written language comprehension. While a considerable amount of research has identified distinct regions and stages of processing, the relations between them and to this hierarchical model remain unclear. Magnetoencephalography (MEG) is a technique frequently employed in such investigations; however, no studies have sought to test whether the conventional method of reconstructing currents at the source of the magnetic field is best suited for such across-subject designs. The present study details the results of three MEG experiments addressing these issues. Neuronal populations supporting responses to low-level orthographic properties were housed posteriorly near the primary visual cortex. More anterior regions along the fusiform gyrus encoded higher-level processes and became active ~80ms later. A functional localiser of these early letter-specific responses was developed for the production of functional regions of interest in future studies. Previously established response components were successfully grouped based on proximity to the localiser, which characterised location, latency and functional sensitivity. Unconventional anatomically constrained signed minimum norm estimates of MEG data were most sensitive to the primary experimental manipulation, suggesting that the conventional unsigned unconstrained method is sub-optimal for studying written word processing. PMID- 26926793 TI - NAR2.1/NRT2.1 functional interaction with NO3(-) and H(+) fluxes in high-affinity nitrate transport in maize root regions. AB - Spatial and temporal fluctuations in nitrate (NO3(-)) availability are very common in agricultural soils. Therefore, understanding the molecular and physiological mechanisms involved in regulating NO3(-) uptake in regions along the primary root is important for improving the NO3(-) uptake efficiency (NUpE) in crops. Different regions of maize primary root, named R1, R2 and R3, NO3(-) starved for 3 days, were exposed to 50 MUM NO3(-). Electrophysiological measurements (membrane potential and H(+) and NO3(-) fluxes) and NPF6.3, NRT2.1, NAR2.1, MHA1, MHA3 and MHA4 gene expression analyses were carried out. The results confirmed variable spatial and temporal patterns in both NO3(-) and H(+) fluxes and gene expression along the primary maize root. A significant correlation (P = 0.0023) between nitrate influx and gene transcript levels was observed only when NAR2.1 and NRT2.1 co-expression were considered together, showing for the first time the NRT2.1/NAR2.1 functional interaction in nitrate uptake along the root axis. Taken together these results suggest differing roles among the primary root regions, in which the apical part seem to be involved to sensing and signaling in contrast with the basal root which appears to be implicate in nitrate acquisition. PMID- 26926794 TI - Inhibition of polyamine oxidase activity affects tumor development during the maize-Ustilago maydis interaction. AB - Ustilago maydis is a biotrophic plant pathogenic fungus that leads to tumor development in the aerial tissues of its host, Zea mays. These tumors are the result of cell hypertrophy and hyperplasia, and are accompanied by the reprograming of primary and secondary metabolism of infected plants. Up to now, little is known regarding key plant actors and their role in tumor development during the interaction with U. maydis. Polyamines are small aliphatic amines that regulate plant growth, development and stress responses. In a previous study, we found substantial increases of polyamine levels in tumors. In the present work, we describe the maize polyamine oxidase (PAO) gene family, its contribution to hydrogen peroxide (H2O2) production and its possible role in tumor development induced by U. maydis. Histochemical analysis revealed that chlorotic lesions and maize tumors induced by U. maydis accumulate H2O2 to significant levels. Maize plants inoculated with U. maydis and treated with the PAO inhibitor 1,8 diaminooctane exhibit a notable reduction of H2O2 accumulation in infected tissues and a significant drop in PAO activity. This treatment also reduced disease symptoms in infected plants. Finally, among six maize PAO genes only the ZmPAO1, which encodes an extracellular enzyme, is up-regulated in tumors. Our data suggest that H2O2 produced through PA catabolism by ZmPAO1 plays an important role in tumor development during the maize-U. maydis interaction. PMID- 26926795 TI - Foveolar Muller Cells of the Pied Flycatcher: Morphology and Distribution of Intermediate Filaments Regarding Cell Transparency. AB - Specialized intermediate filaments (IFs) have critical importance for the clearness and uncommon transparency of vertebrate lens fiber cells, although the physical mechanisms involved are poorly understood. Recently, an unusual low scattering light transport was also described in retinal Muller cells. Exploring the function of IFs in Muller cells, we have studied the morphology and distribution pattern of IFs and other cytoskeletal filaments inside the Muller cell main processes in the foveolar part of the avian (pied flycatcher) retina. We found that some IFs surrounded by globular nanoparticles (that we suggest are crystallines) are present in almost every part of the Muller cells that span the retina, including the microvilli. Unlike IFs implicated in the mechanical architecture of the cell, these IFs are not connected to any specific cellular membranes. Instead, they are organized into bundles, passing inside the cell from the endfeet to the photoreceptor, following the geometry of the processes, and repeatedly circumventing numerous obstacles. We believe that the presently reported data effectively confirm that the model of nanooptical channels built of the IFs may provide a viable explanation of Muller cell transparency. PMID- 26926796 TI - Isolated Cerebellar Spindle Cell Pseudotumor Caused by Mycobacterium Avium Intracellulare Complex in a Patient without AIDS. AB - BACKGROUND: Spindle cell pseudotumors are formed by histiocytes in response to infection by Mycobacterium avium-intracellulare complex (MAC) and are rare in patients without AIDS. CASE DESCRIPTION: A 66-year-old man presented with neck pain, ataxia, and a history of sarcoidosis. A cerebellar lesion was identified on magnetic resonance imaging and surgically excised. Histopathology revealed this to be a spindle cell pseudotumor and MAC was isolated by bacterial culture of cerebrospinal fluid. Hematology revealed cluster of differentiation 4 lymphocytopenia but human immunodeficiency virus serology was negative. The patient was commenced on antimicrobial treatment that included a macrolide and remained well at 1 year follow-up. CONCLUSIONS: This rare presentation of isolated intracranial MAC was treated with surgical excision and antimicrobials with a good outcome. PMID- 26926797 TI - Surgical Management of Lateral Tentorial Meningiomas. AB - OBJECTIVE: Tentorial meningiomas represent a heterogeneous group of tumors. Most of the published series deal with either a small number of patients or consider different locations as a whole, making indications for treatment and prognosis difficult to drawn. We analyzed the surgical management of the lateral tentorial meningiomas, a homogenous and rare subgroup. METHODS: Fifty-two later tentorial meningiomas were operated on between 1990 and 2010. Clinical and radiologic features and surgical management of these patients were reviewed. Tumors were further subcategorized in to posterior/intermediate and in to supra /infratentorial subgroups. Surgical outcome, long-term results, and prognostic factors are described. RESULTS: Mean age was 57 years (41 female, 11 male). Mean tumor size was 46 mm; most had an infratentorial location (36 vs. 16). Prevailing presenting symptoms were headache (n = 28), vertigo/gait disturbances (n = 25), and confusion and visual disturbances (n = 16). The infratentorial group presented with a poorer clinical condition before as well as after operation. Extent of tumor resection was Simpson I in 10 patients, II in 26, III in 6, and IV in 10. Subtotal resection was statistically correlated with sinus invasion and tumor size. There was no surgical mortality. Permanent complications occurred in 3 patients. At latest follow-up (mean, 119 months) 42/46 had resumed their normal daily activity. Six cases recurred and remained stable after radiosurgery. CONCLUSIONS: Lateral tentorial meningiomas are a homogeneous entity characterized by simple surgical approaches and favorable outcome (no mortality and low overall morbidity). Infratentorial location was more frequent and was characterized by poorer outcome. The limiting factors for surgical removal were tumor size and sinus invasion. The latter point strengthens the rationale for their classification into posterior and intermediate. PMID- 26926799 TI - Correction: Rheometry-on-a-chip: measuring the relaxation time of a viscoelastic liquid through particle migration in microchannel flows. PMID- 26926798 TI - New Software for Preoperative Diagnostics of Meningeal Tumor Histologic Types. AB - OBJECTIVE: Meningeal tumors are neoplasms with different histologic manifestations of both benign and malignant types that determine the prognosis of tumor recurrence and its consistency. The risk of surgical treatment depends on the location, size, and consistency of the tumor. Magnetic resonance imaging (MRI) sequences can be used to identify the features of tumors, but these MRI characteristics are not well understood. The present study describes an advanced mathematical algorithm to analyze MRI data and distinguish histologic types of meningeal tumors before surgery. METHODS: Forty-eight patients underwent surgical removal of meningeal brain tumor. All patients had preoperative MRI with a 1.5-T scanner. One radiologist and 2 neurosurgeons evaluated MRI histogram peaks of the whole tumor volume using the advanced computer algorithm. RESULTS: Three specialists received the following mean value of histogram peaks: 15.99 +/- 0.23 (+/- standard error of the mean [SEM]) for meningoteliomatous meningiomas; 21.24 +/- 0.3 (+/-SEM) for fibroplastic meningiomas; 19.0 +/- 0.28 (+/-SEM) for transitional meningiomas; 10.7 +/- 0.27 (+/-SEM) for anatypical, anaplastic meningiomas, 11.03 +/- 0.51 (+/-SEM) for primary intracranial fibrosarcomas and 25.72 +/- 0.29 (+/-SEM) for meningeal hemangiopericytomas. A one-way analysis of variance test proved the difference between group means: F = 70.138, P < 0.01. The Tukey test and the Games-Howell test indicated that the difference between the tumor groups was significant. Mean deviation in agreement index between specialists was 0.98 +/- 0.007 (+/-SEM). CONCLUSIONS: The advanced algorithm proved high specificity, sensitivity, and interoperator repeatability. PMID- 26926800 TI - Chemosensory processing in children with attention-deficit/hyperactivity disorder. AB - BACKGROUND: In attention-deficit/hyperactivity disorder (ADHD) not only deficits in dopamine-related cognitive functioning have been found but also a lower dopamine-sensitive olfactory threshold. The aim of the present study was to proof that only olfactory but not trigeminal sensitivity is increased in ADHD. Structural magnetic resonance imaging (MRI) was used to show increased olfactory bulb (OB) volume- a structure which is strongly shaped by olfactory performance through the mechanism of neuroplasticity (e.g. synaptogenesis). To elucidate whether cortical mechanisms are involved in altered olfaction in ADHD, functional MRI (fMRI) was introduced. METHODS: A total of 18 boys with ADHD and 17 healthy controls (aged 7-12) were included in the study. Olfactory as well as trigeminal detection thresholds were examined. OB sizes were measured by means of structural MRI and an analysis of effective functional (fMRI) coupling of primary olfactory cortex was conducted. The frontal piriform cortex (fPIR) was chosen as seed region because of its importance in processing both trigeminal and olfactory stimuli as well as having profound influence on inner OB-signaling. RESULTS: Increased olfactory sensitivity as well as an increase in OB volume was found in ADHD. There were no group differences in sensitivity towards a trigeminal stimulus. Compared to healthy controls, the fPIR in ADHD was more positively coupled with structures belonging to the salience network during olfactory and, to a lesser extent, during trigeminal stimulation. CONCLUSIONS: Olfactory functioning is superior in subjects with ADHD. The observed increase in OB volume may relate to higher olfactory sensitivity in terms of neuroplasticity. During the processing of chemosensory stimuli, the primary olfactory cortex in ADHD is differently coupled to higher cortical structures which might indicate an altered top-down influence on OB structure and function. PMID- 26926801 TI - Gender by onset age interaction may characterize distinct phenotypic subgroups in bipolar patients. AB - OBJECTIVE: Although bipolar disorder (BD) is a common recurrent condition with highly heterogeneous illness course, data are limited regarding clinical implications of interactions between gender and onset age. We assessed relationships between onset age and demographic/illness characteristics among BD patients stratified by gender. METHODS: Demographic and unfavorable illness characteristics, descriptive traits, and clinical correlates were compared in 502 patients from Stanford University BD Clinic patients enrolled in the Systematic Treatment Enhancement Program for BD between 2000 and 2011, stratified by gender, across pre-, peri-, and post-pubertal (<12, 13-16, and >17 years, respectively) onset-age subgroups. RESULTS: Among 502 BD patients, 58.2% were female, of whom 21.9% had pre-pubertal, 30.7% peri-pubertal, and 47.4% post-pubertal onset. Between genders, although demographics, descriptive characteristics, and most clinical correlates were statistically similar, there were distinctive onset-age related patterns of unfavorable illness characteristics. Among females, rates of 6/8 primary unfavorable illness characteristics were significantly higher in pre pubertal and peri-pubertal compared to post-pubertal onset patients. However, among males, rates of only 3/8 unfavorable illness characteristics were significantly higher in only pre-pubertal versus post-pubertal onset patients, and none between peri-pubertal versus post-pubertal onset patients. LIMITATIONS: Caucasian, insured, suburban, American specialty clinic-referred sample limits generalizability, onset age based on retrospective recall. DISCUSSION: We describe different phenotypic presentations across age at illness onset groups according to gender. Among females and males, peri-pubertal and post-pubertal onset age groups were more different and more similar, respectively. Further investigation is warranted to assess implications of gender-by-onset-age interactions to more accurately delineate distinctive BD phenotypes. PMID- 26926803 TI - Multiple tipping points and optimal repairing in interacting networks. AB - Systems composed of many interacting dynamical networks-such as the human body with its biological networks or the global economic network consisting of regional clusters-often exhibit complicated collective dynamics. Three fundamental processes that are typically present are failure, damage spread and recovery. Here we develop a model for such systems and find a very rich phase diagram that becomes increasingly more complex as the number of interacting networks increases. In the simplest example of two interacting networks we find two critical points, four triple points, ten allowed transitions and two 'forbidden' transitions, as well as complex hysteresis loops. Remarkably, we find that triple points play the dominant role in constructing the optimal repairing strategy in damaged interacting systems. To test our model, we analyse an example of real interacting financial networks and find evidence of rapid dynamical transitions between well-defined states, in agreement with the predictions of our model. PMID- 26926802 TI - TDP-43 or FUS-induced misfolded human wild-type SOD1 can propagate intercellularly in a prion-like fashion. AB - Amyotrophic lateral sclerosis (ALS), which appears to spread through the neuroaxis in a spatiotemporally restricted manner, is linked to heritable mutations in genes encoding SOD1, TDP-43, FUS, C9ORF72, or can occur sporadically without recognized genetic mutations. Misfolded human wild-type (HuWt) SOD1 has been detected in both familial and sporadic ALS patients, despite mutations in SOD1 accounting for only 2% of total cases. We previously showed that accumulation of pathological TDP-43 or FUS coexist with misfolded HuWtSOD1 in patient motor neurons, and can trigger its misfolding in cultured cells. Here, we used immunocytochemistry and immunoprecipitation to demonstrate that TDP-43 or FUS-induced misfolded HuWtSOD1 can propagate from cell-to-cell via conditioned media, and seed cytotoxic misfolding of endogenous HuWtSOD1 in the recipient cells in a prion-like fashion. Knockdown of SOD1 using siRNA in recipient cells, or incubation of conditioned media with misfolded SOD1-specific antibodies, inhibits intercellular transmission, indicating that HuWtSOD1 is an obligate seed and substrate of propagated misfolding. In this system, intercellular spread of SOD1 misfolding is not accompanied by transmission of TDP-43 or FUS pathology. Our findings argue that pathological TDP-43 and FUS may exert motor neuron pathology in ALS through the initiation of propagated misfolding of SOD1. PMID- 26926805 TI - Ionic liquid decorated mesoporous silica nanoparticles: a new high-performance hybrid electrolyte for lithium batteries. AB - We report a novel hybrid electrolyte based on mesoporous silica nanoparticles decorated with an ionic liquid, which exhibits a superior lithium ion transference number of >0.8, and an excellent electrochemical window of >5 V with attractive ionic conductivity. The insights obtained pave a new way for the preparation of high-performance electrolytes with mesoporous structures. PMID- 26926804 TI - Systemic injection of AAV9 carrying a periostin promoter targets gene expression to a myofibroblast-like lineage in mouse hearts after reperfused myocardial infarction. AB - Adeno-associated virus (AAV) has been used to direct gene transfer to a variety of tissues, including heart, liver, skeletal muscle, brain, kidney and lung, but it has not previously been shown to effectively target fibroblasts in vivo, including cardiac fibroblasts. We constructed expression cassettes using a modified periostin promoter to drive gene expression in a cardiac myofibroblast like lineage, with only occasional spillover into cardiomyocyte-like cells. We compared AAV serotypes 6 and 9 and found robust gene expression when the vectors were delivered by systemic injection after myocardial infarction (MI), with little expression in healthy, non-infarcted mice. AAV9 provided expression in a greater number of cells than AAV6, with reporter gene expression visible in the cardiac infarct and border zones from 5 to 62 days post MI, as assessed by luciferase and Cre-activated green fluorescent protein expression. Although common myofibroblast markers were expressed in low abundance, most of the targeted cells expressed myosin IIb, an embryonic form of smooth muscle myosin heavy chain that has previously been associated with myofibroblasts after reperfused MI. This study is the first to demonstrate AAV-mediated expression in a potentially novel myofibroblast-like lineage in mouse hearts post MI and may open new avenues of gene therapy to treat patients surviving MI. PMID- 26926806 TI - Mitochondrial dysfunction in DDR-related cancer predisposition syndromes. AB - Given the key role of mitochondria in various cellular events, it is not surprising that mitochondrial dysfunction (MDF) is seen in many pathological conditions, in particular cancer. The mechanisms defining MDF are not clearly understood and may involve genetic defects, misbalance of reactive oxygen species (ROS), impaired autophagy (mitophagy), acquired mutations in mitochondrial or nuclear DNA and inability of cells to cope with the consequences. The importance of MDF arises from its detection in the syndromes with defective DNA damage response (DDR) and cancer predisposition. Here, we will focus on the dual role of these syndromes in cancer predisposition and MDF with specific emphasis on impaired autophagy. PMID- 26926807 TI - Structural biology and regulation of the plant sulfation pathway. AB - In plants, sulfur is an essential nutrient that must be converted into usable metabolic forms for the formation of sulfur-containing amino acids and peptides (primary route) and for the modification of diverse metabolites (secondary route). In plants, the fate of assimilated sulfate depends on the three enzymes - ATP sulfurylase, adenosine-5'-phosphate (APS) reductase, and APS kinase - that form a branchpoint in the pathway. ATP sulfurylase catalyzes the formation of the critical intermediate APS, which can either be used in the primary assimilatory route or be phosphorylated to 3'-phospho-APS (PAPS) for a variety of sulfation reactions. Recent biochemical and structural studies of the branchpoint enzymes in plant sulfur metabolism suggest that redox-regulation may control sulfur partitioning between primary and secondary routes. Disulfide-based redox switches differentially affect APS reductase and APS kinase. Oxidative conditions that promote disulfide formation increase the activity of APS reductase and decreases PAPS production by APS kinase. Here we review recent work on the ATP sulfurylase and APS kinase from plants that provide new insight on the regulation of PAPS formation, the structural evolution of these enzymes in different organisms, and redox-control of this key branchpoint in plant sulfur metabolism. PMID- 26926808 TI - Ideal Cardiovascular Health Metrics Are Associated with Disability Independently of Vascular Conditions. AB - BACKGROUND: Vascular risk factors may be associated with disability independently of vascular events. We examined whether the American Heart Association's 7 ideal cardiovascular health (CVH) metrics were independently associated with disability in a nationally representative cohort. METHODS: Adults age >=20 years from the National Health and Nutrition Examination Survey 2005-2012 were included. Ideal CVH was calculated as a composite of 7 measures, each scored 0-2. Primary predictors were number of ideal CVH metrics and score of CVH metrics. The outcome was a dichotomous score from 20 activities of daily living (ADL) and instrumental ADLs. Unadjusted and adjusted weighted logistic models estimated associations between ideal CVH and disability. The data were analyzed in 2015. RESULTS: Among 22692 participants, mean age was 46.9 years. Cardiac disease and stroke were present in 6.6% and 2.8%; 90.3% had poor physical activity and 89.9% poor diet. Among 3975 individuals with full CVH data, in fully adjusted models, OR for disability was 0.90 (95% CI 0.83-0.98) per point increase in ideal CVH score, and 0.84 (0.73-0.97) per additional number of ideal CVH metrics. CONCLUSIONS: CVH metrics were strongly and significantly associated with reduced odds of disability independently of vascular and non-vascular conditions. Poorer CVH may cause subclinical vascular disease resulting in disability. PMID- 26926809 TI - Additional Protection from 9-Valent HPV Vaccine if Administered Before HPV Exposure. PMID- 26926810 TI - Diagnostic Tool for Gout Without Need for Joint Fluid Aspiration. PMID- 26926812 TI - The Why and How of High-Value Prescribing. PMID- 26926813 TI - Labor Induction at Term. PMID- 26926814 TI - Iron Deficiency and Other Types of Anemia in Infants and Children. AB - Anemia, defined as a hemoglobin level two standard deviations below the mean for age, is prevalent in infants and children worldwide. The evaluation of a child with anemia should begin with a thorough history and risk assessment. Characterizing the anemia as microcytic, normocytic, or macrocytic based on the mean corpuscular volume will aid in the workup and management. Microcytic anemia due to iron deficiency is the most common type of anemia in children. The American Academy of Pediatrics and the World Health Organization recommend routine screening for anemia at 12 months of age; the U.S. Preventive Services Task Force found insufficient evidence to assess the benefits vs. harms of screening. Iron deficiency anemia, which can be associated with cognitive issues, is prevented and treated with iron supplements or increased intake of dietary iron. The U.S. Preventive Services Task Force found insufficient evidence to recommend screening or treating pregnant women for iron deficiency anemia to improve maternal or neonatal outcomes. Delayed cord clamping can improve iron status in infancy, especially for at-risk populations, such as those who are preterm or small for gestational age. Normocytic anemia may be caused by congenital membranopathies, hemoglobinopathies, enzymopathies, metabolic defects, and immune-mediated destruction. An initial reticulocyte count is needed to determine bone marrow function. Macrocytic anemia, which is uncommon in children, warrants subsequent evaluation for vitamin B12 and folate deficiencies, hypothyroidism, hepatic disease, and bone marrow disorders. PMID- 26926815 TI - Clinical Evaluation of Bleeding and Bruising in Primary Care. AB - Bleeding and bruising are common symptoms in the primary care setting. The patient history can help determine whether the bruising or bleeding is abnormal. The International Society on Thrombosis and Hemostasis has developed a bleeding assessment tool that can be used to indicate possible pathology. A family history of bleeding problems may suggest a hereditary coagulation defect. Such a history is especially important in children who may not have experienced a major bleeding episode. Medication review can identify pharmacologic causes of the bleeding or bruising. Physical examination findings such as mucocutaneous bleeding suggest that the underlying condition is caused by platelet dysfunction, whereas hemarthroses or hematomas are more common in coagulopathy. If the history and physical examination findings suggest a bleeding diathesis, initial laboratory testing includes a complete blood count, peripheral blood smear, prothrombin time (PT), and partial thromboplastin time (PTT). A normal PT and PTT indicate a platelet disorder, the most common of which is von Willebrand disease. A normal PT and prolonged PTT signal a deficit in the intrinsic pathway, and a mixing study should be performed. A vitamin K challenge is indicated in patients with an abnormal PT and normal PTT. A workup for liver failure is warranted in patients with prolonged PT and PTT. If initial testing does not reveal an etiology in a patient with a high suspicion for a bleeding disorder, the patient should be referred to a hematologist for additional evaluation. PMID- 26926817 TI - A Resolving Rash on the Breast. PMID- 26926818 TI - Screening for High Blood Pressure in Adults: Recommendation Statement. PMID- 26926816 TI - Common Questions About Chronic Prostatitis. AB - Chronic prostatitis is relatively common, with a lifetime prevalence of 1.8% to 8.2%. Risk factors include conditions that facilitate introduction of bacteria into the urethra and prostate (which also predispose the patient to urinary tract infections) and conditions that can lead to chronic neuropathic pain. Chronic prostatitis must be differentiated from other causes of chronic pelvic pain, such as interstitial cystitis/bladder pain syndrome and pelvic floor dysfunction; prostate and bladder cancers; benign prostatic hyperplasia; urolithiasis; and other causes of dysuria, urinary frequency, and nocturia. The National Institutes of Health divides prostatitis into four syndromes: acute bacterial prostatitis, chronic bacterial prostatitis (CBP), chronic nonbacterial prostatitis (CNP)/chronic pelvic pain syndrome (CPPS), and asymptomatic inflammatory prostatitis. CBP and CNP/CPPS both lead to pelvic pain and lower urinary tract symptoms. CBP presents as recurrent urinary tract infections with the same organism identified on repeated cultures; it responds to a prolonged course of an antibiotic that adequately penetrates the prostate, if the urine culture suggests sensitivity. If four to six weeks of antibiotic therapy is effective but symptoms recur, another course may be prescribed, perhaps in combination with alpha blockers or nonopioid analgesics. CNP/CPPS, accounting for more than 90% of chronic prostatitis cases, presents as prostatic pain lasting at least three months without consistent culture results. Weak evidence supports the use of alpha blockers, pain medications, and a four- to six-week course of antibiotics for the treatment of CNP/CPPS. Patients may also be referred to a psychologist experienced in managing chronic pain. Experts on this condition recommend a combination of treatments tailored to the patient's phenotypic presentation. Urology referral should be considered when appropriate treatment is ineffective. Additional treatments include pelvic floor physical therapy, phytotherapy, and pain management techniques. The UPOINT (urinary, psychosocial, organ-specific, infection, neurologic/systemic, tenderness) approach summarizes the various factors that may contribute to presentation and can guide treatment. PMID- 26926819 TI - Conjugated Estrogens/Bazedoxifene (Duavee) for Menopausal Symptoms. PMID- 26926820 TI - Epidural Steroid Not Better Than Placebo Injection for Sciatica and Spinal Stenosis Pain and Function. PMID- 26926821 TI - Treating Low Vitamin D Levels Is Ineffective in Postmenopausal Women. PMID- 26926822 TI - Naproxen Alone May Be Best for Acute Low Back Pain. PMID- 26926823 TI - ACIP Releases 2016 Childhood Immunization Recommendations. PMID- 26926824 TI - ACIP Releases 2016 Adult Immunization Recommendations. PMID- 26926825 TI - Easy Bruising and Bleeding. PMID- 26926826 TI - Triple Hit with Drug Carriers: pH- and Temperature-Responsive Theranostics for Multimodal Chemo- and Photothermal Therapy and Diagnostic Applications. AB - Currently there is a strong need for new drug delivery systems, which enable targeted and controlled function in delivering drugs while satisfying highly sensitive imaging modality for early detection of the disease symptoms and damaged sites. To meet these criteria we develop a system that integrates therapeutic and diagnostic capabilities (theranostics). Importantly, therapeutic efficacy of the system is enhanced by exploiting synergies between nanoparticles, drug, and hyperthermia. At the core of our innovation is near-infrared (NIR) responsive gold nanorods (Au) coated with drug reservoirs--mesoporous silica shell (mSi)--that is capped with thermoresponsive polymer. Such design of theranostics allows the detection of the system using computed tomography (CT), while finely controlled release of the drug is achieved by external trigger, NIR light irradiation--ON/OFF switch. Doxorubicin (DOX) was loaded into mSi formed on the gold core (Au@mSi-DOX). Pores were then capped with the temperature-sensitive poly(N-isopropylacrylamide)-based N-butyl imidazolium copolymer (poly(NIPAAm-co BVIm)) resulting in a hybrid system-Au@mSi-DOX@P. A 5 min exposure to NIR induces polymer transition, which triggers the drug release (pores opening), increases local temperature above 43 degrees C (hyperthermia), and upregulates particle uptake (polymer becomes hydrophilic). The DOX release is also triggered by drop in pH enabling localized drug release when particles are taken up by cancer cells. Importantly, the synergies between chemo- and photothermal therapy for DOX loaded theranostics were confirmed. Furthermore, higher X-ray attenuation value of the theranostics was confirmed via X-ray CT test indicating that the nanoparticles act as contrast agent and can be detected by CT. PMID- 26926828 TI - Building the Material Flow Networks of Aluminum in the 2007 U.S. Economy. AB - Based on the combination of the U.S. economic input-output table and the stocks and flows framework for characterizing anthropogenic metal cycles, this study presents a methodology for building material flow networks of bulk metals in the U.S. economy and applies it to aluminum. The results, which we term the Input Output Material Flow Networks (IO-MFNs), achieve a complete picture of aluminum flow in the entire U.S. economy and for any chosen industrial sector (illustrated for the Automobile Manufacturing sector). The results are compared with information from our former study on U.S. aluminum stocks and flows to demonstrate the robustness and value of this new methodology. We find that the IO MFN approach has the following advantages: (1) it helps to uncover the network of material flows in the manufacturing stage in the life cycle of metals; (2) it provides a method that may be less time-consuming but more complete and accurate in estimating new scrap generation, process loss, domestic final demand, and trade of final products of metals, than existing material flow analysis approaches; and, most importantly, (3) it enables the analysis of the material flows of metals in the U.S. economy from a network perspective, rather than merely that of a life cycle chain. PMID- 26926827 TI - Nucleus accumbens cocaine-amphetamine regulated transcript mediates food intake during novelty conflict. AB - Obesity is a persistent and pervasive problem, particularly in industrialized nations. It has come to be appreciated that the metabolic health of an individual can influence brain function and subsequent behavioral patterns. To examine the relationship between metabolic phenotype and central systems that regulate behavior, we tested rats with divergent metabolic phenotypes (Low Capacity Runner: LCR vs. High Capacity Runner: HCR) for behavioral responses to the conflict between hunger and environmental novelty using the novelty suppressed feeding (NSF) paradigm. Additionally, we measured expression of mRNA, for peptides involved in energy management, in response to fasting. Following a 24-h fast, LCR rats showed lower latencies to begin eating in a novel environment compared to HCR rats. A 48-h fast equilibrated the latency to begin eating in the novel environment. A 24-h fast differentially affected expression of cocaine amphetamine regulated transcript (CART) mRNA in the nucleus accumbens (NAc), where 24-h of fasting reduced CART mRNA in LCR rats. Bilateral microinjections of CART 55-102 peptide into the NAc increased the latency to begin eating in the NSF paradigm following a 24-h fast in LCR rats. These results indicate that metabolic phenotype influences how animals cope with the conflict between hunger and novelty, and that these differences are at least partially mediated by CART signaling in the NAc. For individuals with poor metabolic health who have to navigate food-rich and stressful environments, changes in central systems that mediate conflicting drives may feed into the rates of obesity and exacerbate the difficulty individuals have in maintaining weight loss. PMID- 26926830 TI - Discovering communities in complex networks by edge label propagation. AB - The discovery of the community structure of real-world networks is still an open problem. Many methods have been proposed to shed light on this problem, and most of these have focused on discovering node community. However, link community is also a powerful framework for discovering overlapping communities. Here we present a novel edge label propagation algorithm (ELPA), which combines the natural advantage of link communities with the efficiency of the label propagation algorithm (LPA). ELPA can discover both link communities and node communities. We evaluated ELPA on both synthetic and real-world networks, and compared it with five state-of-the-art methods. The results demonstrate that ELPA performs competitively with other algorithms. PMID- 26926829 TI - Comparative effectiveness of postoperative chemotherapy among older patients with non-metastatic rectal cancer treated with preoperative chemoradiotherapy. AB - OBJECTIVE: Postoperative chemotherapy is standard following preoperative chemoradiation therapy (CRT) and curative resection for clinically staged II/III rectal cancer. Recent trials have questioned whether postoperative chemotherapy improves overall survival. The objective of the study was to evaluate the comparative effectiveness of postoperative chemotherapy following CRT or radiation therapy (RT) with specific attention to the impact of age on postoperative chemotherapy effectiveness. MATERIALS AND METHODS: Patients treated with CRT or RT then resection of pathologically staged 0-III rectal cancer diagnosed from 2004 to 2009 were identified from the Surveillance, Epidemiology and End Results program-Medicare database. Propensity score weighted Cox proportional hazards models and Kaplan Meier methods were used to compare the effectiveness of 1) postoperative 5-fluorouracil (5-FU) or capecitabine to no treatment and 2) postoperative oxaliplatin+5-FU/capecitabine to 5-FU/capecitabine alone on mortality. Results were stratified by age. RESULTS: We identified 1316 patients; 49% received postoperative chemotherapy, 341 (52%) included oxaliplatin. After weighting, postoperative 5-FU/capecitabine alone was associated with decreased mortality in patients aged 66-74 (adjusted hazard ratio (aHR)=0.46, 95% CI: 0.30, 0.72), corresponding to a 5-year risk difference of 0.23, (95% CI: -0.33, -0.12). No further mortality reduction from adding oxaliplatin to 5-FU/capecitabine was seen in patients aged 66-74 (aHR=1.57, 95% CI: 0.93, 2.65). No mortality reduction for 5-FU/capecitabine alone was observed among patients aged 75+ (aHR=1.11, 95% CI: 0.76, 1.63). CONCLUSIONS: Among patients <75years, postoperative 5-FU/capecitabine was associated with reduced mortality after preoperative CRT/RT and surgical resection; however, the addition of oxaliplatin was not associated with further mortality reduction. Decisions regarding postoperative chemotherapy after age 75 warrant consideration of individual patient risks and preferences, as benefits may be limited. PMID- 26926832 TI - Inactivation of dengue, chikungunya, and Ross River viruses in platelet concentrates after treatment with ultraviolet C light. AB - BACKGROUND: Arboviruses, including dengue (DENV 1-4), chikungunya (CHIKV), and Ross River (RRV), are emerging viruses that are a risk for transfusion safety globally. An approach for managing this risk is pathogen inactivation, such as the THERAFLEX UV-Platelets system. We investigated the ability of this system to inactivate the above mentioned arboviruses. STUDY DESIGN AND METHODS: DENV 1-4, CHIKV, or RRV were spiked into buffy coat (BC)-derived platelet (PLT) concentrates in additive solution and treated with the THERAFLEX UV-Platelets system at the following doses: 0.05, 0.1, 0.15, and 0.2 J/cm(2) (standard dose). Pre- and posttreatment samples were taken for each dose, and the level of viral infectivity was determined. RESULTS: At the standard ultraviolet C (UVC) dose (0.2 J/cm(2) ), viral inactivation of at least 4.43, 6.34, and 5.13 log or more, was observed for DENV 1-4, CHIKV, and RRV, respectively. A dose dependency in viral inactivation was observed with increasing UVC doses. CONCLUSIONS: Our study has shown that DENV, CHIKV, and RRV, spiked into BC-derived PLT concentrates, were inactivated by the THERAFLEX UV-Platelets system to the limit of detection of our assay, suggesting that this system could contribute to the safety of PLT concentrates with respect to these emerging arboviruses. PMID- 26926831 TI - Hyperdeactivation of the Default Mode Network in People With Schizophrenia When Focusing Attention in Space. AB - When studying selective attention in people with schizophrenia (PSZ), a counterintuitive but replicated finding has been that PSZ display larger performance benefits than healthy control subjects (HCS) by cues that predicts the location of a target stimulus relative to non-predictive cues. Possible explanations are that PSZ hyperfocus attention in response to predictive cues, or that an inability to maintain a broad attentional window impairs performance when the cue is non-predictive. Over-recruitment of regions involved in top-down focusing of spatial attention in response to predictive cues would support the former possibility, and an inappropriate recruitment of these regions in response to non-predictive cues the latter. We probed regions of the dorsal attention network while PSZ (N = 20) and HCS (N = 20) performed a visuospatial attention task. A central cue either predicted at which of 4 peripheral locations a target signal would appear, or it gave no information about the target location. As observed previously, PSZ displayed a larger reaction time difference between predictive and non-predictive cue trials than HCS. Activity in frontoparietal and occipital regions was greater for predictive than non-predictive cues. This effect was almost identical between PSZ and HCS. There was no sign of over recruitment when the cue was predictive, or of inappropriate recruitment when the cue was non-predictive. However, PSZ differed from HCS in their cue-dependent deactivation of the default mode network. Unexpectedly, PSZ displayed significantly greater deactivation than HCS in predictive cue trials, which may reflect a tendency to expend more processing resources when focusing attention in space. PMID- 26926833 TI - The development of dual-label time-resolved fluorescence immunoassay (TRFIA) for screening of ovarian cancer based on simultaneous detection of human epididymis protein-4 and cancer antigen 125. AB - A two-step dual-label TRFIA was developed for the simultaneous detection of human epididymis protein-4 and cancer antigen 125 in a single run. The performance of this assay was first evaluated using clinical serum samples, and then compared with commercialized kits. The sensitivity of this assay for cancer antigen 125 detection was 0.5 U/mL (dynamic range, 0-1400 U/L), and the sensitivity for human epididymis protein-4 detection was 1 pM (dynamic range, 1-900 pM). High correlation coefficients (R) were obtained between the present dual-label TRFIA and commercially available kits (R = 0.99). The present dual-label TRFIA has high sensitivity, specificity, and accuracy in clinical sample analysis. It is a good alternative to the single-label diagnostic methods. PMID- 26926834 TI - Disappearance of the inversion effect during memory-guided tracking of scrambled biological motion. AB - The human visual system is highly sensitive to biological motion. Even when a point-light walker is temporarily occluded from view by other objects, our eyes are still able to maintain tracking continuity. To investigate how the visual system establishes a correspondence between the biological-motion stimuli visible before and after the disruption, we used the occlusion paradigm with biological motion stimuli that were intact or scrambled. The results showed that during visually guided tracking, both the observers' predicted times and predictive smooth pursuit were more accurate for upright biological motion (intact and scrambled) than for inverted biological motion. During memory-guided tracking, however, the processing advantage for upright as compared with inverted biological motion was not found in the scrambled condition, but in the intact condition only. This suggests that spatial location information alone is not sufficient to build and maintain the representational continuity of the biological motion across the occlusion, and that the object identity may act as an important information source in visual tracking. The inversion effect disappeared when the scrambled biological motion was occluded, which indicates that when biological motion is temporarily occluded and there is a complete absence of visual feedback signals, an oculomotor prediction is executed to maintain the tracking continuity, which is established not only by updating the target's spatial location, but also by the retrieval of identity information stored in long-term memory. PMID- 26926835 TI - Comparison of mortality in Asbest city and the Sverdlovsk region in the Russian Federation: 1997-2010. AB - BACKGROUND: The Sverdlovsk region of the Russian Federation is characterised by its abundance of natural resources and industries. Located in this region, Asbest city is situated next to one of the largest open-pit chrysotile asbestos mines currently operational; many city residents are employed in activities related to mining and processing of chrysotile. We compared mortality rates from 1997 to 2010 in Asbest city to the remaining Sverdlovsk region, with additional analyses conducted for site-specific cancer mortality. METHODS: Population and mortality data for Asbest city and Sverdlovsk region were used to estimate crude and age specific rates by gender for the entire period and for each calendar year. Age standardized mortality rates were also calculated for the adult population (20+) and Poisson regression was used to estimate standardized mortality ratios, overall and by gender. RESULTS: During the period of 1997 to 2010, there were similar mortality rates overall in Asbest and the Sverdlovsk region. However, there were higher rates of cancer mortality (18 % males; 21 % females) and digestive diseases (21 % males; 40 % females) in Asbest and lower rates of unknown/ill-defined in Asbest (60 % males; 47 % females). Circulatory disease mortality was slightly lower in Asbest. Cancer mortality was higher for men in Asbest from oesophageal, urinary tract and lung cancers compared to the Sverdlovsk region. In women, cancer mortality was higher for women in Asbest from stomach, colon, lung and breast cancers compared to the Sverdlovsk region. CONCLUSIONS: This large population-based analysis indicates interesting differences but studies with individual exposure information are needed to understand the underlying factors. PMID- 26926836 TI - Comparison of Diagnostic Performance of Semi-Quantitative Knee Ultrasound and Knee Radiography with MRI: Oulu Knee Osteoarthritis Study. AB - Osteoarthritis (OA) is a common degenerative musculoskeletal disease highly prevalent in aging societies worldwide. Traditionally, knee OA is diagnosed using conventional radiography. However, structural changes of articular cartilage or menisci cannot be directly evaluated using this method. On the other hand, ultrasound is a promising tool able to provide direct information on soft tissue degeneration. The aim of our study was to systematically determine the site specific diagnostic performance of semi-quantitative ultrasound grading of knee femoral articular cartilage, osteophytes and meniscal extrusion, and of radiographic assessment of joint space narrowing and osteophytes, using MRI as a reference standard. Eighty asymptomatic and 79 symptomatic subjects with mean age of 57.7 years were included in the study. Ultrasound performed best in the assessment of femoral medial and lateral osteophytes, and medial meniscal extrusion. In comparison to radiography, ultrasound performed better or at least equally well in identification of tibio-femoral osteophytes, medial meniscal extrusion and medial femoral cartilage morphological degeneration. Ultrasound provides relevant additional diagnostic information on tissue-specific morphological changes not depicted by conventional radiography. Consequently, the use of ultrasound as a complementary imaging tool along with radiography may enable more accurate and cost-effective diagnostics of knee osteoarthritis at the primary healthcare level. PMID- 26926837 TI - Implementing a social network intervention designed to enhance and diversify support for people with long-term conditions. A qualitative study. AB - BACKGROUND: For people with long-term conditions, social networks provide a potentially central means of mobilising, mediating and accessing support for health and well-being. Few interventions address the implementation of improving engagement with and through social networks. This paper describes the development and implementation of a web-based tool which comprises: network mapping, user centred preference elicitation and need assessment and facilitated engagement with resources. The study aimed to determine whether the intervention was acceptable, implementable and acted to enhance support and to add to theory concerning social networks and engagement with resources and activities. METHODS: A longitudinal design with 15 case studies used ethnographic methods comprising video, non-participant observation of intervention delivery and qualitative interviews (baseline, 6 and 12 months). Participants were people with type 2 diabetes living in a marginalised island community. Facilitators were local health trainers and care navigators. Analysis applied concepts concerning implementation of technology for self-management support to explain how new practices of work were operationalised and how the technology impacted on relationships fit with everyday life and allowed for visual feedback. RESULTS: Most participants reported identifying and taking up new activities as a result of using the tool. Thematic analysis suggested that workability of the tool was predicated on disruption and reconstruction of networks, challenging/supportive facilitation and change and reflection over time concerning network support. Visualisation of the network enabled people to mobilise support and engage in new activities. The tool aligned synergistically with the facilitators' role of linking people to local resources. CONCLUSIONS: The social network tool works through a process of initiating positive disruption of established self management practice through mapping and reflection on personal network membership and support. This opens up possibilities for reconstructing self-management differently from current practice. Key facets of successful implementation were: the visual maps of networks and support options; facilitation characterised by a perceived lack of status difference which assisted engagement and constructive discussion of support and preferences for activities; and background work (a reliable database, tailored preferences, option reduction) for facilitator and user ease of use. PMID- 26926839 TI - Oral corticosteroid prescribing habits of Canadian Otolaryngologist-Head and Neck Surgeons. AB - BACKGROUND: Oral corticosteroids (OCSs) are widely prescribed in Otolaryngology Head & Neck surgery (OtoHNS). There is evidence in the literature regarding specific dosing regimens. However, it is not known to what extent these recommendations are being implemented in practice. METHODS: An anonymous online survey was sent to Canadian Society of Otolaryngology-Head and Neck Surgery members (N = 696). Dosing, frequency and tapering of OCSs were assessed in acute rhino-sinusitis (ARS), chronic rhino-sinusitis with (CRSwP) and without polyps (CRSsP), sudden sensori-neural hearing loss (SSNHL), and idiopathic facial nerve/Bell's palsy (IFN). Participants were asked to complete for conditions treated and results were compared with current guidelines. Development of prescribing habits and observed complications were also explored. RESULTS: 124 surveys (18%) were completed. In CRSwP (N = 98), the median dose was 50 mg (Range: 10-100 mg) and the average duration was 8 days (Range: 1-21 days). In CRSsP (N = 29), the median dose was 50 mg (Range: 20-80 mg) and the average duration was 8 days (Range: 1-14 days). In SSNHL (N = 118), the median dose was 60 mg (Range: 10-120 mg) and the average duration was 10 days (Range: 1-21 days). In IFN (N = 108), the median dose was 50 mg (Range: 10-100 mg) and the average duration was 10 days (Range: 1-21 days). Tapering dosages were used in treating CRSwP (64%), CRSsP (62%), ARS (44%), SSNHL (60%) and IFN (53%). Respondents most frequently perceived "Mentor/Preceptor Guidance" as a source of their prescribing habits. CONCLUSION: There is significant heterogeneity in OCS prescribing habits despite the availability of fairly consistent evidence in the literature for some of the surveyed conditions. Improvements in standardization should be made with the aim of enhancing outcomes and reducing complications. PMID- 26926840 TI - Influence of substrate misorientation on the photoluminescence and structural properties of InGaAs/GaAsP multiple quantum wells. AB - InGaAs/GaAsP multiple quantum wells (MQWs) were grown by metal-organic chemical vapor deposition on vicinal GaAs (001) substrates with different miscut angles of 0 degrees , 2 degrees and 15 degrees towards [110]. The crystal structures of InGaAs/GaAsP were characterized by high-resolution X-ray diffraction and Raman spectroscopy. The surface morphologies of InGaAs/GaAsP MQWs were observed by atomic force microscopy. The mechanisms for step flow, step bunching and pyramid growth on 0 degrees , 2 degrees and 15 degrees misoriented substrates were discussed. The results provide a comprehensive phenomenological understanding of the self-ordering mechanism of vicinal GaAs substrates, which could be harnessed for designing the quantum optical properties of low-dimensional systems. From low temperature photoluminescence, it was observed that the luminescence from the MQWs grown on a vicinal surface exhibits a red-shift with respect to the 0 degrees case. An extra emission was observed from the 2 degrees and 15 degrees off samples, indicating the characteristics of quantum wire and pyramidal self controlled quantum-dot systems, respectively. Its absence from the PL spectrum on 0 degrees surfaces indicates that indium segregation is modified on the surfaces. The relationship between InGaAs/GaAsP MQWs grown on vicinal substrates and their optical and structural properties was explained, which provides a technological basis for obtaining different self-controlled nanostructures. PMID- 26926841 TI - How Can the Complications of Central Vein Catheters Be Reduced?: Central Venous Stenosis in Hemodialysis Patients. PMID- 26926838 TI - Longer telomeres in chronic, moderate, unconjugated hyperbilirubinaemia: insights from a human study on Gilbert's Syndrome. AB - Bilirubin (BR) is a natural endogenous compound with a potent bioactivity. Gilbert's Syndrome (GS) is a benign hereditary condition of increased unconjugated bilirubin (UCB) in serum and serves as a convenient model for studying the effects of BR in humans. In absence of liver disease, increased UCB levels are inversely associated to all-cause mortality risk, especially from cardiovascular diseases (CVDs). On the other hand, telomere malfunction is linked to a higher risk of CVDs. To our knowledge, there is no data on whether UCB is linked to telomere length in healthy or diseased individuals In the present study we have observed a relationship between mildly increased serum UCB and telomere length. We used an in vivo approach, assessing telomere length in PBMCs from individuals with GS (n = 60) and matched healthy controls (n = 60). An occurrence of longer telomeres was observed in male individuals chronically exposed to increased UCB, as well as in Gunn rats, an animal model of unconjugated hyperbilirubinaemia. Previously identified differences in immunomodulation and redox parameters in individuals with GS, such as IL-6, IL-1beta and ferric reducing ability of plasma, were confirmed and proposed as possible contributors to the occurrence of longer telomeres in GS. PMID- 26926842 TI - Circulating T helper 9 cells and increased serum interleukin-9 levels in patients with knee osteoarthritis. AB - The purpose of this study was to examine the roles of T helper 9 (Th9) cells and the serum interleukin (IL)-9 level in the pathogenesis of osteoarthritis (OA). The numbers of IL-9(+) CD4(+) CD8(-) T cells, interferon (IFN)-gamma+ CD4(+) CD8( ) T cells, IL-4(+) CD4(+) CD8(-) T cells, and IL-17A(+) CD4(+) CD8(-) T cells in 25 OA patients and 13 healthy controls (HC) were examined by flow cytometry. The serum concentrations of IL-9, IL-4, IL-17A, and IFN-gamma were also determined. The numbers of CD4(+) CD45RO(+) T cells, Th9 cells, Th1 cells, and Th17 cells in OA patients were significantly higher than those in HCs. Furthermore, serum IL-9, IL-17A, and IFN-gamma levels in OA patients were higher than those in HCs. The number of Th9 cells was positively correlated with the number of Th17 cells in OA patients. Furthermore, greater numbers of Th9 cells were positively associated with elevated C-reactive protein, and both Th9 cells and IL-9 levels were positively correlated with the Western Ontario and McMaster Universities Osteoarthritis index in OA patients. Th9 cell numbers and IL-9 levels are correlated with OA patient symptoms and joint functionality and may be a marker of disease activity. PMID- 26926843 TI - Resisting resistance: is there a solution for malaria? AB - INTRODUCTION: Currently, widely used antimalarial drugs have a limited clinical lifespan due to parasite resistance development. With resistance continuously rising, antimalarial drug discovery requires strategies to decrease the time of delivering a new antimalarial drug while simultaneously increasing the drug's therapeutic lifespan. Lessons learnt from various chemotherapeutic resistance studies in the fields of antibiotic and cancer research offer potentially useful strategies that can be applied to antimalarial drug discovery. AREAS COVERED: In this review the authors discuss current strategies to circumvent resistance in malaria and alternatives that could be employed. EXPERT OPINION: Scientists have been 'beating back' the malaria parasite with novel drugs for the past 49 years but the constant rise in antimalarial drug resistance is forcing the drug discovery community to explore alternative strategies. Avant-garde anti resistance strategies from alternative fields may assist our endeavors to manage, control and prevent antimalarial drug resistance to progress beyond beating the resistant parasite back, to stopping it dead in its tracks. PMID- 26926844 TI - Reply: Pharyngeal-cervical-brachial/Miller-Fisher overlap: A possible central variant. PMID- 26926845 TI - Substrate-Electrode Interface Engineering by an Electron-Transport Layer in Hematite Photoanode. AB - The photoelectrochemical water oxidation efficiency of photoanodes is largely limited by interfacial charge-transfer processes. Herein, a metal oxide electron transport layer (ETL) was introduced at the substrate-electrode interface. Hematite photoanodes prepared on Li(+)- or WO3-modified substrates deliver higher photocurrent. It is inferred that a Li-doped Fe2O3 (Li:Fe2O3) layer with lower flat band potential than the bulk is formed. Li:Fe2O3 and WO3 are proved to function as an expressway for electron extraction. Via introducing ETL, both the charge separation and injection efficiencies are improved. The lifetime of photogenerated electrons is prolonged by 3 times, and the ratio of surface charge transfer and recombination rate is enhanced by 5 times with Li:Fe2O3 and 125 times with WO3 ETL at 1.23 V versus reversible hydrogen electrode. This result indicates the expedited electron extraction from photoanode to the substrate can suppress not only the recombination at the back contact interface but also those at the surface, which results in higher water oxidation efficiency. PMID- 26926846 TI - Triphalangeal Thumb Reduction Osteotomy Through a Versatile Spiral Approach. AB - Triphalangeal thumb (TPT) is a congenital condition characterized by the presence of an additional phalanx. Variable degrees of thumb deformity, malalignment, and excessive length are common features. Impairment of hand function has been reported with TPT probably secondary to anomalistic long thumb incompatible with fine hand skills. Abnormal thumb appearance moreover represents a major psychological concern from patient's perspective. Both removal of the extra phalanx and phalangeal reduction osteotomy with resection of the unhealthy extra interphalangeal joint are established methods for correction of the associated excessive thumb length. In our experience, however, previous surgical approaches have not been able to sufficiently reduce the skin and soft tissue surplus, which exists after reduction osteotomy through classic circular incisions. We thus feel that conduction of TPT reconstruction through a spiral incision provides a safe and generous anatomic exposure required for simultaneous reduction of skeletal and soft tissue components. PMID- 26926847 TI - New advances in allergy immunotherapy. AB - PURPOSE OF REVIEW: The present article reviews the literature on new methods for administering specific immunotherapy for the treatment of immunoglobulin E mediated hypersensitivity to airborne and food allergens. The discussion will focus on allergen modifications, and new routes for delivering proteins to allergen-presenting cells. RECENT FINDINGS: Modified allergens address the issues of supply and standardization, but also have the potential to enhance the allergenicity of the protein, while decreasing the risk of producing severe reactions. The use of immunostimulatory adjuvants and recombinant proteins has increased, whereas new technologies, such as the encapsulation of allergens into nanoparticles, have also gained much attention. New delivery routes for specific immunotherapy continue to be explored, often in combination with allergen modification strategies, in order to shorten the duration of therapy, limit adverse events, and optimize patient adherence. Safety and long-term efficacy have been demonstrated for many of these new methods, and it is clear that there are multiple ways to stimulate the immune system for the purpose of allergen desensitization. SUMMARY: Developments in the field of specific immunotherapy for allergic disease are accelerating rapidly because of advances in technology, but also because of the recognition that this disease-modifying therapy is a well tolerated, efficacious, and cost-effective option for individuals, which can improved their quality of life in a long-term fashion. VIDEO ABSTRACT. PMID- 26926848 TI - Lower verbal intelligence is associated with diabetic complications and slower walking speed in people with Type 2 diabetes: the Maastricht Study. AB - AIMS: To determine the association of verbal intelligence, a core constituent of health literacy, with diabetic complications and walking speed in people with Type 2 diabetes. METHODS: This study was performed in 228 people with Type 2 diabetes participating in the Maastricht Study, a population-based cohort study. We examined the cross-sectional associations of score on the vocabulary test of the Groningen Intelligence Test with: 1) determinants of diabetic complications (HbA1c , blood pressure and lipid level); 2) diabetic complications: chronic kidney disease, neuropathic pain, self-reported history of cardiovascular disease and carotid intima-media thickness; and 3) walking speed. Analyses were performed using linear regression and adjusted in separate models for potential confounders and mediators. Significant age- and sex-adjusted associations were additionally adjusted for educational level in a separate model. RESULTS: After full adjustment, lower verbal intelligence was associated with the presence of neuropathic pain [odds ratio (OR) 1.18, 95% CI 1.02;1.36], cardiovascular disease (OR 1.14, 95% CI 1.01;1.30), and slower walking speed (regression coefficient 0.011 m/s, 95% CI -0.021; -0.002 m/s). These associations were largely explained by education. Verbal intelligence was not associated with blood pressure, glycaemic control, lipid control, chronic kidney disease or carotid intima-media thickness. CONCLUSIONS: Lower verbal intelligence was associated with the presence of some diabetic complications and with a slower walking speed, a measure of physical functioning. Educational level largely explained these associations. This implies that clinicians should be aware of the educational level of people with diabetes and should provide information at a level of complexity tailored to the patient. PMID- 26926849 TI - Blast From the Past: A Retrospective Analysis of Blast-induced Head Injury. AB - Because of the sharp increase in the number of military personnel exposed to explosive blasts in combat, research has been dedicated toward understanding the impact of explosions on the brain. It is important to consider that potential injuries that military personnel sustain may be both in the form of physical injury as well as "invisible" neuronal and psychological damage. Since the inception of the study of blast science in the Medieval and Renaissance eras, significant improvements have been made in the historical record keeping and biomedical analysis of blast injuries. This editorial comments on the evolution of blast science and the recognition of neurological sequelae from both the historical and scientific perspectives. PMID- 26926850 TI - Is Blast Injury a Modern Phenomenon?: Early Historical Descriptions of Mining and Volcanic Traumatic Brain Injury With Relevance to Modern Terrorist Attacks and Military Warfare. AB - BACKGROUND: Given the recent interest in blast injury spurred by returning soldiers from overseas conflicts, we sought to research the early historical descriptions of blast injuries and their treatments. Consideration was given to specific descriptions of survivors of closed head injury and their treatment. METHODS: A review of the medical and nonmedical literature was undertaken, with particular emphasis on pre-1800 descriptions of volcanic eruptions and mining accidents. Compilations of accounts of the Etna eruptions dating from 126 BC were translated into English, and early mining texts from the 1600s and 1700s were reviewed. RESULTS: Accumulations of flammable gases were recorded in many medieval sources and this knowledge of toxic gas which could lead to blast injury was known in the mining community by 1316. No direct attribution of injuries to blast forces was present in the historical record examined before the 1300s, although mining accounts in the 1600s detail deaths due to blast. No specific descriptions of survivors of a closed head injury were found in the mining and volcanic eruption literature. CONCLUSIONS: Descriptions and warnings of blast forces were commonly written about in the medieval and Renaissance mining communities. Personal narratives as early as 1316 recognize the traumatic effects of blast injury. No mining or volcanic blast descriptions before 1800 detailed severe closed head injury survivors, suggesting greater mortality than morbidity from blast injury in the premodern era. This review also uncovered that there was no historical treatment or remedy recommended to survivors of blast injury. Blast explosions resulting in injury or death were frequently described, although in simplistic terminology. PMID- 26926851 TI - Computer-assisted Diagnostic Checklist in Clinical Neurology. AB - Considering computers are more efficient at processing large amounts of information than the human brain, speaks to the need to explore more intelligent computer-assisted diagnostic approaches. Two diagnostic checklist programs, one for single key term entry (NeurologyINDEX), and another, with more advanced algorithms to process multiple key terms and perform additional functions (NeurologicDx) are discussed. Both programs are internet based, access the same database, and are designed to generate diagnostic checklists and disease profiles accessible with hand-held or other computer device. The development of systems that use "smart algorithms" to generate valid diagnostic checklists is the goal. PMID- 26926852 TI - Transcranial Direct Current Stimulation in the Treatment of Essential Tremor: An Open-Label Study. AB - INTRODUCTION: Pharmacotherapy and thalamic stimulation are the most accepted methods used for the treatment of essential tremor (ET). Transcranial direct current stimulation (tDCS) is a noninvasive method for brain stimulation, especially to treat pain, cerebrovascular disease, and depression. tDCS applied to the cerebellar region has been shown to exhibit a modulating effect on the excitability of Purkinje cells and to cause primary motor cortex inhibition through the regulation of synaptic dentato-thalamo-cortical excitability. There is only 1 trial that studied the effect of tDCS on ET with 8 patients, and the results were not satisfactory. CASE SERIES: Six ET patients were administered the Essential Tremor Rating Assessment Scale (TETRAS) and Activities of Daily Living (ADL). We applied tDCS to the dorsolateral prefrontal areas (anode) and to inion (inion at 2 mA for 20 min in 10 consecutive sessions with a 2-d break between the first and the second 5-d sessions). One month after the initial course of therapy, 5 more tDCS sessions were administered in an every-other-day manner. TETRAS and ADL scales were readministered. The Friedman test was used to assess differences in TETRAS scores and ADL over the whole time course. CONCLUSIONS: A significant improvement was observed in TETRAS and ADL scores at the end of 50 days (P=0.015, 0.024). We concluded that although our sample group is small, tDCS might be an alternative therapy for patients with ET. PMID- 26926853 TI - Bilateral Lower Sternocleidomastoid Botulinum Toxin Injections to Address Refractory Anterocollis. AB - Anterocollis is a type of cervical dystonia characterized by simultaneous and repetitive antagonist muscles contractions, resulting in abnormal neck flexion. It was described with a frequency of 6.8% from 399 patients with diagnosis of cervical dystonia and usually coexists with torticollis and/or laterocollis, as mixed cervical dystonia patterns. Botulinum toxin is usually a practical and effective treatment for cervical dystonia. The target muscles to inject in anterocollis are usually sternocleidomastoid and scalene muscles. There is also a case report suggesting longus collis involvement. Nevertheless, the dosage of the medication in anterocollis is limited by frequent side effects of dysphagia. We described 2 cases of refractory anterocollis. They did not benefit from conventional bilateral upper portion of sternocleidomastoid muscle injections with OnabotulinumtoxinA, but notably improved their symptoms and clinical global impression after switching to injections into bilateral lower portion of sternocleidomastoid muscles, without significant side effects. PMID- 26926854 TI - Choreic Syndrome Secondary to a Subdural Hematoma. PMID- 26926856 TI - Topiramate: A Novel Therapeutic Candidate for Diabetes and Aggression? Positron Emission Tomography (PET) Findings. AB - BACKGROUND: There is still limited knowledge regarding the role of impaired brain glucose metabolism in the generation of aggression during diabetes. Additionally, there are rapidly replicating piece of evidence suggesting that topiramate may exert significant mood stabilizing effect. In this respect, we aimed to evaluate the neurometabolic correlates of the therapeutic effect of topiramate in a patient with diabetes and Intermittent explosive disorder (IED). METHODS: We measured regional cerebral glucose metabolism using 2-[18F]-fluoro-2-deoxy-D glucose and positron emission tomography (FDG-PET) in a diabetic patient with aggressive outbursts before and after treatment with topiramate. In order to reveal a defined information underlying the improvement of the aggressive symptoms we also combined the PET with Modified Overt Aggression Scale. RESULTS: We have found that topiramate leads to the improvement in Modified Overt Aggression Scale that was well correlated with the increase in cortical brain metabolism. DISCUSSION: The therapeutic role of topiramate may not only suggest secondary deficits due to diminished functions of the cortical part of emotional circuits but also indicate that diabetic individuals may be vulnerable to lower cerebral glucose metabolism in cortical regions. Further clinical trials that include well-conducted randomized controlled trials and cohort studies by using other methods (i.e., magnetic resonance spectroscopy and quantitative EEG analysis) are necessary to confirm our preliminary findings. PMID- 26926855 TI - Ongoing Transmission of Onchocerca volvulus after 25 Years of Annual Ivermectin Mass Treatments in the Vina du Nord River Valley, in North Cameroon. AB - BACKGROUND: Recent reports of transmission interruption of Onchocerca volvulus, the causing agent of river blindness, in former endemic foci in the Americas, and more recently in West and East Africa, raise the question whether elimination of this debilitating disease is underway after long-term treatment of the population at risk with ivermectin. The situation in Central Africa has not yet been clearly assessed. METHODS AND FINDINGS: Entomologic data from two former endemic river basins in North Cameroon were generated over a period of 43 and 48 months to follow-up transmission levels in areas under prolonged ivermectin control. Moreover, epidemiologic parameters of animal-borne Onchocerca spp. transmitted by the same local black fly vectors of the Simulium damnosum complex were recorded and their impact on O. volvulus transmission success evaluated. With mitochondrial DNA markers we unambiguously confirmed the presence of infective O. volvulus larvae in vectors from the Sudan savannah region (mean Annual Transmission Potential 2009-2012: 98, range 47-221), but not from the Adamawa highland region. Transmission rates of O. ochengi, a parasite of Zebu cattle, were high in both foci. CONCLUSIONS/SIGNIFICANCE: The high cattle livestock density in conjunction with the high transmission rates of the bovine filaria O. ochengi prevents the transmission of O. volvulus on the Adamawa plateau, whereas transmission in a former hyperendemic focus was markedly reduced, but not completely interrupted after 25 years of ivermectin control. This study may be helpful to gauge the impact of the presence of animal-filariae for O. volvulus transmission in terms of the growing human and livestock populations in sub Saharan countries. PMID- 26926857 TI - Consumption of sugar-sweetened beverages and energy drinks and adherence to physical activity and screen time recommendations among adolescents. AB - BACKGROUND: It is recommended that youth aged 12-17 years achieve >=60 min/day of moderate-to-vigorous physical activity (PA) and limit their recreational screen time (ST) to <=2 h/day. However, whether unhealthy eating behavior is associated with adherence to PA and ST recommendations in youth is largely unknown. OBJECTIVE: This study examined the associations between adherence to PA and ST recommendations with consumption of sugar-sweetened beverages (SSBs) and energy drinks (EDs) in a representative sample of adolescents. METHODS: Data on 11-19 year-old Ottawa (Canada) students (n=1147) were analyzed using self-reported information on consumption of SSBs and EDs, and time devoted to PA and ST. Multivariable logistic regression analyses were conducted to examine the associations between adherence to PA and ST recommendations and consumption of SSBs and EDs. RESULTS: Adherence to the ST recommendation was inversely associated with consumption of SSBs [odds ratio (OR)=0.42; 95% confidence interval (CI)=0.21-0.86] and EDs (OR=0.54, 95% CI=0.31-0.92) in females only, independent of PA and relevant covariates. However, adherence to the PA recommendation was positively associated with consumption of EDs in females (OR=1.52, 95% CI=1.07-2.17) but not males, while it was not associated with consumption of SSBs in both sexes. CONCLUSION: Among female adolescents, adherence to the ST recommendation is inversely associated with consumption of SSBs and EDs, while adherence to the PA recommendation is positively associated with consumption of EDs. Future studies should clarify the observed sex differences and determine if decreasing ST can reduce the consumption of SSBs and EDs among adolescents. PMID- 26926858 TI - Cultural considerations for the adaptation of an Internet-based intervention for depression prevention in Mainland China. AB - Internet-based interventions to prevent depression during adolescence have been implemented in Western countries, but there is a lack of research about its adaptation for use in other countries. Project Competent Adulthood Transition with Cognitive-Behavioral, Humanistic and Interpersonal Training (CATCH-IT) is an Internet-based intervention targeting teens at risk for developing depression. This study explored cultural adaptation of the intervention for use in Mainland China. A pilot study using the English version of CATCH-IT was conducted in Wuhan, China, with adolescents from the Wuhan School of Medicine in 2013. Participants completed a feedback survey to evaluate the format and socio cultural relevance for each component of the intervention. Twenty students were surveyed (age range 19-23 years). In 2014, Chinese physicians evaluated CATCH-IT and completed a feedback questionnaire. Data obtained were collected and analyzed for recurrent themes. Both groups recommended new modules focusing on Chinese relevant themes like pressure for academic excellence, filial piety, and balancing school and social life. Physicians agreed to retain the cognitive behavior therapy (CBT) and behavioral activation (BA) modules, and were split on the use of interpersonal therapy (IPT). All experts recommended translation of the content into Mandarin and a majority suggested interactive features and less text. All agreed the Internet serves well as a delivery model; however, dissemination through schools was preferred. The results support cultural adaptation of basic facets of the intervention like language and visuals, and also deeper aspects like IPT and the delivery model. Development of an adaptation should build upon the findings from this study and work to maintain fidelity. PMID- 26926859 TI - Sexual health knowledge in a vulnerable population: a survey of adolescents in the bateyes of La Romana, Dominican Republic. AB - OBJECTIVE: Undocumented Haitian migrants to the Dominican Republic often live in impoverished communities called bateyes. These contexts present challenges for adolescent sexual health education. To inform development of appropriate adolescent education programs, this study assessed their general sexual health knowledge. METHODS: A locally developed sexual health knowledge survey was administered to 930 grade 7-12 adolescents attending six batey schools. Analysis of aggregated responses reviewed general demographics (e.g. age and sex), and identified top community sexual health concerns and most trusted information sources. RESULTS: Top concerns included menstruation (25.5%), HIV (21.8%), and family planning (13.3%); stratification by sex identified discordance around menstruation (89.2% female, 10.8% male) and HIV (67.1% male, 32.9% female), but not family planning (47.2% male, 52.8% female). Parents were identified as the most trusted information source, irrespective of concern. CONCLUSION: Community concerns around menstruation matches extant developing-world literature that links menarche with female stigma and school absence. Interest in HIV and family planning suggests targeted promoted efforts would be of benefit. Trust in parents is reflective of cultural traditions and suggests potential knowledge impacts arising from effective parental education. PMID- 26926860 TI - Follow-up and outcomes of pregnancies in French Guiana: the part of teenage pregnancies. AB - OBJECTIVE: Describe the part that teenage pregnancy plays in overall pregnancies in French Guiana. METHODS: Descriptive and retrospective study of the medical records of 25,343 women who delivered in French Guiana from January 1, 2009 to December 31, 2012. The study displays and compares several indicators of follow up visits, pregnancy-linked disorders, delivery and birth outcomes between the years and between minors and adult women. RESULTS: The proportion of teenage pregnancies was 6.8%; it decreased significantly from 7.2% in 2009 to 6.1% in 2012 (p=0.01). The number of antenatal visits was <7 and the visits were mainly provided by the Mother and Child Health ("Protection Maternelle et Infantile", PMI) services (38.6%). The mean (+/-SD) gestational age at first antenatal visit was 14.1+/-6.5 weeks. In comparison with adult pregnancies, teenage pregnancies were more frequently concerned with preterm labour (4.6% vs. 2%; p<0.01) but less concerned with gestational diabetes (0% vs. 2.2%; p<0.05) or pregnancy-induced hypertension (2.2% vs. 4.2%; p<0.05). CONCLUSION: Teenage pregnancies are still frequent in French Guiana, especially in the Eastern and Western communes, where first visits are often delayed by mothers who are minors and take place in PMI services, which offer less clinical, and paraclinical examinations than other settings. PMID- 26926861 TI - Peptic esophageal stricture in an adolescent with Barrett's esophagus. AB - Barrett's esophagus (BE) is characterized by the replacement of distal esophageal stratified squamous epithelium by columnar epithelium. It is rare in children and the risk factors may include mental retardation, cerebral palsy, esophageal atresia, etc. Apart from corrosive ingestion, peptic stricture is the other leading cause of esophageal strictures in children. However, BE has not been well characterized in the pediatric population and in children presenting with esophageal strictures. A 16-year-old Indian boy presented with a history of gradually progressive dysphagia to solids (but not liquids) for 12 years along with heartburn and poor weight gain. Physical examination and routine blood investigations were unremarkable. Previously performed barium meal studies were suggestive of stricture in the mid and lower esophagus. Upper gastrointestinal (GI) endoscopy revealed a non-negotiable stricture with circumferential ulceration at 26 cm. The stricture was traversed using an ultrathin scope and the distal mucosa was found to be columnar. Biopsies revealed cardiac mucosa. The patient was treated with proton pump inhibitors (PPI) and four series of segmental dilatations with Savary Gilliard esophageal dilators. Peptic strictures occurring in the mid-upper esophagus should raise concerns about BE or malignancy. Here, we report a case of peptic esophageal stricture in a child without neurodevelopmental or trachea-esophageal abnormalities. PMID- 26926862 TI - Socio-demographic association of non communicable diseases' risk factors in a representative population of school children: a cross-sectional study in Sousse (Tunisia). AB - INTRODUCTION: A better understanding of socio-demographic characteristics of subgroups, which have a high risk to develop chronic diseases, is essential to develop more efficient interventional programs especially for youth. This study aimed to determine the association between clusters of non communicable diseases (NCDs') risk factors and the socio-demographic characteristics among a sample of Tunisian school children. MATERIALS AND METHODS: We conducted, in 2013/2014, a cross-sectional study among a proportional and stratified school children sample, selected in 17 elementary public schools in Sousse (Tunisia). A cluster analysis was used to identify different NCDs risk factors clusters, based on tobacco use, physical inactivity, unhealthy diet, and excess weight. Subsequent chi2-tests were used to identify differences between the NCDs risk factors clusters in regards to socio-demographic characteristics. RESULTS: Four clusters of NCDs risk factors were found: 1) Cluster 1: physical inactivity behavior with normal weight, 2) Cluster 2: physical inactivity behavior associated to excess weight, 3) Cluster 3: unhealthy diet associated to excess weight and low practice of physical activity, and 4) Cluster 4: smoking behavior with physical activity behavior. The pattern of cluster membership differed across sex (<10-3), school level, and socioeconomic level (<10-3) but there was no significant difference between clusters for mother's education levels and household tenure. CONCLUSION: This study can have important implications for health policy and practice. Indeed, it found that many subjects have simultaneous multiple NCDs risk factors which leads to identify groups at risk and implement integrated intervention program. PMID- 26926863 TI - A study on the relationship of sociocultural characteristics, menstrual hygiene practices and gynaecological problems among adolescent girls in Eastern India. AB - OBJECTIVE: The present study aims to understand the relationship of socioeconomic characteristics, menstrual hygiene practices and gynaecological problems among adolescent girls residing in rural and urban areas in the state of West Bengal, India. METHODS: The study was based on a sample of 715 adolescent girls from rural (325) and urban (390) areas of West Bengal, a state in Eastern India. These girls belong to the Bengali-speaking Hindu community. Data on socioeconomic characteristics, menstrual hygiene practices (such as type of absorbents used and mode of cleaning of genitals during days of menstrual discharge) and gynaecological problems were collected using pretested questionnaires. RESULTS: Rural and urban girls differ (p<0.01) for age at menarche, menstrual hygiene practices and prevalence of gynaecological problems. Urban girls have better menstrual hygiene practices (beta=0.343, p<0.01) than rural girls. A similar trend is noted for gynaecological problems (beta=0.080, p<0.01) among the study participants. Apart from socioeconomic characteristics, menstrual hygiene (beta= 0.121, p<0.01) remains a significant predictor of gynaecological problems. The results of path analysis also indicate that girls of higher socioeconomic status have better menstrual hygiene practices which subsequently reduce the prevalence of gynaecological problems among them. CONCLUSION: A concerted effort from parents, educational institutions and existing healthcare institutions along with media may ensure safe and secure reproductive health prospects for adolescents in the region. PMID- 26926864 TI - Safety and metabolic impact of Ramadan fasting in children and adolescents with type 1 diabetes. AB - BACKGROUND: Annually, many children and adolescents with type 1 diabetes mellitus (T1DM) insist on fasting for Ramadan despite being exempted and despite knowing all the risks. We aimed to assess the safety and metabolic impact of Ramadan fasting in children with T1DM using different insulin regimens. METHODS: Children with T1DM who choose to fast during Ramadan 1434/2013 (29 days) were recruited 3 months before Ramadan. They received pre-Ramadan intensive education. Three insulin regimens were included; Regimen-I (regular insulin/NPH); Regimen-II (regular insulin/insulin glargine) and Regimen-III (premixed insulin). Changes in weight, insulin dose, HbA1c, fructosamine and lipid profile were evaluated. RESULTS: Out of total 53 patients (24 male), 28 patients (52.8%) completed Ramadan fasting (fasting group). The remaining 25 patients were included in (broke-fasting group). Positive correlation between fructosamine changes and number of days fasted during Ramadan. Significant decrease in post-Ramadan fructosamine (<0.001) and increase in post-Ramadan total cholesterol and low density lipoprotein (LDL) levels were detected within fasting, broke-fasting and insulin regimen groups. Significant higher blood glucose at three time points, pre-Iftar, pre-Sohur and midday in Regimen-I compared to Regimen-II and Regimen III (p=0.004). CONCLUSIONS: Fasting during Ramadan is feasible and is associated with significant improvement in fructosamine level in children with T1DM using different insulin regimens. Mandatory consideration to the quality and quantity of food offered to patients with T1DM during Ramadan to guard against adverse changes in lipid profile. PMID- 26926865 TI - What if we ignore the random effects when analyzing RNA-seq data in a multifactor experiment. AB - Identifying differentially expressed (DE) genes between different conditions is one of the main goals of RNA-seq data analysis. Although a large amount of RNA seq data were produced for two-group comparison with small sample sizes at early stage, more and more RNA-seq data are being produced in the setting of complex experimental designs such as split-plot designs and repeated measure designs. Data arising from such experiments are traditionally analyzed by mixed-effects models. Therefore an appropriate statistical approach for analyzing RNA-seq data from such designs should be generalized linear mixed models (GLMM) or similar approaches that allow for random effects. However, common practices for analyzing such data in literature either treat random effects as fixed or completely ignore the experimental design and focus on two-group comparison using partial data. In this paper, we examine the effect of ignoring the random effects when analyzing RNA-seq data. We accomplish this goal by comparing the standard GLMM model to the methods that ignore the random effects through simulation studies and real data analysis. Our studies show that, ignoring random effects in a multi-factor experiment can lead to the increase of the false positives among the top selected genes or lower power when the nominal FDR level is controlled. PMID- 26926866 TI - A Markov random field-based approach for joint estimation of differentially expressed genes in mouse transcriptome data. AB - The statistical methodology developed in this study was motivated by our interest in studying neurodevelopment using the mouse brain RNA-Seq data set, where gene expression levels were measured in multiple layers in the somatosensory cortex across time in both female and male samples. We aim to identify differentially expressed genes between adjacent time points, which may provide insights on the dynamics of brain development. Because of the extremely small sample size (one male and female at each time point), simple marginal analysis may be underpowered. We propose a Markov random field (MRF)-based approach to capitalizing on the between layers similarity, temporal dependency and the similarity between sex. The model parameters are estimated by an efficient EM algorithm with mean field-like approximation. Simulation results and real data analysis suggest that the proposed model improves the power to detect differentially expressed genes than simple marginal analysis. Our method also reveals biologically interesting results in the mouse brain RNA-Seq data set. PMID- 26926867 TI - Relationship between social network, social support and health behaviour in people with type 1 and type 2 diabetes: cross-sectional studies. AB - BACKGROUND: Psychosocial and behavioural aspects of diabetes may differ according to diabetes type. This study compared people with type 1 and type 2 diabetes with respect to social relations (cohabitation status, contact with the social network and social support) and health behaviours (diet and physical activity). Furthermore, we examined whether potential differences in health behaviour between people with type 1 and type 2 diabetes were influenced by education level and social relations. METHODS: We conducted two cross-sectional surveys consisting of people with type 2 diabetes (N = 1081) and type 1 diabetes (N = 2419) from a specialist diabetes clinic. Gender-stratified stepwise multiple regression models assessed differences by diabetes type and other variables of interest. RESULTS: Significant associations were found between diabetes type and social network, social support and health behaviour. No differences were observed regarding cohabitation status. People with type 2 diabetes were less physically active, less likely to follow recommended diet (men), had fewer contacts with family and friends and were less certain of counting on help in case of severe illness than people with type 1 diabetes. No impact of education level, social network and social support were observed concerning differences in health behaviours by diabetes type; however, in women, the association between physical activity and diabetes type was not significant after adjustment for social relations and education level. CONCLUSIONS: People with type 2 diabetes had less contact with the social network, less certainty about support in case of severe illness and fewer healthy behaviours than people with type 1 diabetes. It may be important to draw attention to differences in health behaviours and social relations between people with type 1 and type 2 diabetes in diabetes care, patient education and support initiatives. PMID- 26926868 TI - An Event-Related Potential Study on the Effects of Cannabis on Emotion Processing. AB - The effect of cannabis on emotional processing was investigated using event related potential paradigms (ERPs). ERPs associated with emotional processing of cannabis users, and non-using controls, were recorded and compared during an implicit and explicit emotional expression recognition and empathy task. Comparisons in P3 component mean amplitudes were made between cannabis users and controls. Results showed a significant decrease in the P3 amplitude in cannabis users compared to controls. Specifically, cannabis users showed reduced P3 amplitudes for implicit compared to explicit processing over centro-parietal sites which reversed, and was enhanced, at fronto-central sites. Cannabis users also showed a decreased P3 to happy faces, with an increase to angry faces, compared to controls. These effects appear to increase with those participants that self-reported the highest levels of cannabis consumption. Those cannabis users with the greatest consumption rates showed the largest P3 deficits for explicit processing and negative emotions. These data suggest that there is a complex relationship between cannabis consumption and emotion processing that appears to be modulated by attention. PMID- 26926869 TI - Automated classification of optical coherence tomography images of human atrial tissue. AB - Tissue composition of the atria plays a critical role in the pathology of cardiovascular disease, tissue remodeling, and arrhythmogenic substrates. Optical coherence tomography (OCT) has the ability to capture the tissue composition information of the human atria. In this study, we developed a region-based automated method to classify tissue compositions within human atria samples within OCT images. We segmented regional information without prior information about the tissue architecture and subsequently extracted features within each segmented region. A relevance vector machine model was used to perform automated classification. Segmentation of human atrial ex vivo datasets was correlated with trichrome histology and our classification algorithm had an average accuracy of 80.41% for identifying adipose, myocardium, fibrotic myocardium, and collagen tissue compositions. PMID- 26926870 TI - Optical oximetry of volume-oscillating vascular compartments: contributions from oscillatory blood flow. AB - We present a quantitative analysis of dynamic diffuse optical measurements to obtain oxygen saturation of hemoglobin in volume oscillating compartments. We used a phasor representation of oscillatory hemodynamics at the heart rate and respiration frequency to separate the oscillations of tissue concentrations of oxyhemoglobin (O) and deoxyhemoglobin (D) into components due to blood volume (subscript V V ) and blood flow (subscript F F ): O=O V +O F O=OV+OF , D=D V +D F D=DV+DF . This is achieved by setting the phase angle Arg(O F )-Arg(O) Arg(OF) Arg(O) , which can be estimated by a hemodynamic model that we recently developed. We found this angle to be -72 deg -72 deg for the cardiac pulsation at 1 Hz, and -7 deg -7 deg for paced breathing at 0.1 Hz. Setting this angle, we can obtain the oxygen saturation of hemoglobin of the volume-oscillating vascular compartment, S V =|O V |/(|O V |+|D V |) SV=|OV|/(|OV|+|DV|) . We demonstrate this approach with cerebral near-infrared spectroscopy measurements on healthy volunteers at rest (n=4 n=4 ) and during 0.1 Hz paced breathing (n=3 n=3 ) with a 24-channel system. Rest data at the cardiac frequency were used to calculate the arterial saturation, S (a) S(a) ; over all subjects and channels, we found ?S V ?=?S (a) ?=0.96+/-0.02 ?SV?=?S(a)?=0.96+/-0.02 . In the case of paced breathing, we found ?S V ?=0.66+/-0.14 ?SV?=0.66+/-0.14 , which reflects venous-dominated hemodynamics at the respiratory frequency. PMID- 26926871 TI - Crystalline, thermal and swelling properties of starches from single-segment substitution lines with different Wx alleles in rice (Oryza sativa L.). AB - BACKGROUND: In rice, five common Wx alleles, wx, Wxt , Wxg1 , Wxg2 and Wxg3 , have been identified according to their apparent amylose content (AAC) phenotypes. Previous studies revealed that this Wx allelic variation may also affect other starch properties. However, so far, to what extent the five Wx alleles influence the crystalline structure, thermal and swelling properties of rice starch is still unclear. For this purpose, a set of single-segment substitution lines (SSSLs) harboring five different Wx alleles, varying widely in AAC, was used for comparative studies. RESULTS: The crystalline structure, thermal properties and swelling behavior of starches from the SSSLs varied widely depending on Wx genotype. Effects of different Wx alleles on relative crystallinity followed the order wx > Wxt > Wxg1 = Wxg2 > Wxg3 . The glutinous and Wxt genotype starches showed higher gelatinization temperatures and enthalpy compared with other Wx genotypes. The order for swelling power was wx > Wxt > Wxg1 > Wxg2 > Wxg3 , while the order for degree of solubility was Wxg3 > Wxg1 > Wxg2 > Wxt = wx. Correlation analysis indicated that AAC was significantly and negatively correlated with relative crystallinity (r = -0.996, P < 0.01) and swelling power (r = -0.982, P < 0.01). CONCLUSION: The present results provide new knowledge about the influence of different Wx alleles on the structural and physicochemical properties of rice starch. (c) 2016 Society of Chemical Industry. PMID- 26926872 TI - Improved language in chronic aphasia after self-delivered iPad speech therapy. AB - Self-delivered speech therapy provides an opportunity for individualised dosage as a complement to the speech-therapy regime in the long-term rehabilitation pathway. Few apps for speech therapy have been subject to clinical trials, especially on a self-delivered platform. In a crossover design study, the Comprehensive Aphasia Test (CAT) and Cookie Theft Picture Description (CTPD) were used to measure untrained improvement in a group of chronic expressive aphasic patients after using a speech therapy app. A pilot study (n = 3) and crossover design (n = 7) comparing the therapy app with a non-language mind-game were conducted. Patients self-selected their training on the app, with a recommended use of 20 minutes per day. There was significant post-therapy improvement on the CAT and CTPD but no significant improvement after the mind-game intervention, suggesting there were language-specific effects following use of the therapy app. Improvements on the CTPD, a functional measurement of speech, suggest that a therapy app can produce practical, important changes in speech. The improvements post-therapy were not due to type of language category trained or amount of training on the app, but an inverse relationship with severity at baseline and post-therapy improvement was shown. This study suggests that self-delivered therapy via an app is beneficial for chronic expressive aphasia. PMID- 26926873 TI - Chronic Thromboembolic Pulmonary Hypertension: A Worldwide View of How Far We Have Come. PMID- 26926875 TI - Hemicrania continua may respond to repetitive sphenopalatine ganglion block: A case report. AB - BACKGROUND: Hemicrania continua (HC) is a chronic headache disorder characterized by a continuous, strictly unilateral head pain accompanied by cranial autonomic symptoms, which completely responds to indomethacin; however, few alternative treatment options exist for the patients with this disorder who cannot tolerate indomethacin. Sphenopalatine ganglion (SPG) block has been used for the treatment of various headaches, with the strongest evidence for efficacy in cluster headache. CASE REPORT: A 52-year-old woman with a 7-year history of HC was evaluated in our clinic for management of her headaches after she had stopped using indomethacin due to a bleeding gastrointestinal ulcer. After failing multiple pharmacologic therapies, she was treated with repetitive SPG blocks using bupivacaine (0.6 mL at 0.5%) twice a week for 6 weeks and followed by maintenance therapy. This treatment protocol resulted in significant improvement in her headaches, mood, and functional capacity. CONCLUSION: SPG block using a local anesthetic may be an effective treatment for patients with HC, specifically for those who cannot tolerate indomethacin, or when this drug is contraindicated. PMID- 26926874 TI - Relative density of host-seeking ticks in different habitat types of south western Slovakia. AB - Ixodes ricinus is a vector of microbial pathogens of medical and veterinary importance in Europe. Recently, increasing abundance of ticks has been observed in urban and suburban areas. The aim of this study was to investigate the tick species composition and examine correlations between local environmental variables and the relative density of host-seeking I. ricinus in two habitat types. Questing ticks were collected along six 100 m(2) transects in urban/suburban locations of Bratislava town, and in a non-fragmented deciduous forest in the Small Carpathians Mountains (south-western Slovakia) during 2011 2013. In total, 6015 I. ricinus were collected (3435 and 2580 in the urban/suburban and natural habitat, respectively), out of which over 80 % were nymphs. Haemaphysalis concinna comprised 1.3 % of the tick collections. Peak I. ricinus nymph and adult host-seeking activities were registered in April-June. Spatial and temporal variation in tick relative density and differences in the subadult/adult ratio were observed between habitats and between locations within the same habitat type. The relative density of questing I. ricinus nymphs correlated negatively with altitude, geographical aspect and saturation deficit in a 64-day period comprising the 8-day period including the date of tick sampling and previous 56 days. No significant correlation was found between roe deer density and questing nymph density. The study revealed the presence of abundant I. ricinus populations in green areas of Bratislava, suggesting a risk of exposure of town dwellers and domestic and companion animals to potentially infected ticks. PMID- 26926876 TI - Safety and Diagnostic Yield of Transbronchial Lung Cryobiopsy in Diffuse Parenchymal Lung Diseases: A Comparative Study versus Video-Assisted Thoracoscopic Lung Biopsy and a Systematic Review of the Literature. AB - BACKGROUND: A diagnosis of interstitial lung diseases (ILDs) may include surgical lung biopsy (SLB), which is associated with significant morbidity and mortality and also appreciable costs. Transbronchial lung cryobiopsy (TBLC) is adopting an important role. OBJECTIVES: The aim of this study was to compare the diagnostic yield (DY) and safety of TBLC and SLB in a large cohort of patients and to perform a systematic review of the literature as well as a meta-analysis. METHODS: We performed a retrospective analysis of 447 cases with ILD undergoing TBLC and/or SLB and a systematic review of the literature (MEDLINE and Embase for all original articles on the DY and safety of TBLC in ILDs up to July 2015). RESULTS: A total of 150 patients underwent SLB and 297 underwent TBLC. The median time of hospitalization was 6.1 days (SLB) and 2.6 days (TBLC; p < 0.0001). Mortality due to adverse events was observed for 2.7% (SLB) and 0.3% (TBLC) of the patients. Pneumothorax was the most common complication after TBLC (20.2%). No severe bleeding was observed. TBLC was diagnostic for 246 patients (82.8%), SLB for 148 patients (98.7%, p = 0.013). A meta-analysis of 15 investigations including 781 patients revealed an overall DY of 0.81 (0.75-0.87); the overall pooled probability of developing a pneumothorax, as retrieved from 15 studies including 994 patients, was 0.06 (95% CI 0.02-0.11). CONCLUSION: Cryobiopsy is safe and has lower complication and mortality rates compared to SLB. TBLC might, therefore, be considered the first diagnostic approach for obtaining tissue in ILDs, reserving the surgical approach for cases in which TBLC is not diagnostic. PMID- 26926878 TI - Grading of urothelial carcinoma of the upper urinary tract according to the World Health Organization/International Society of Urological Pathology classification from 2004 is a valuable tool when considering whether a patient is suitable for endoscopic treatment. AB - Objective The aim of this study was to analyse the results regarding survival, recurrence and kidney preservation after endoscopic treatment for upper urinary tract urothelial carcinoma (UTUC) in a Norwegian hospital during the period from 2001 to 2012, and compare them with results reported in the literature. A further aim was to re-examine all initial histopathological specimens, and stratify primary results according to the World Health Organization/International Society of Urological Pathology grading system of urothelial carcinoma from 2004. Materials and methods Forty-three patients were treated endoscopically with curative intent for UTUC during 2001-2012. Of these, 28 patients were candidates for nephroureterectomy (CNU) with an elective indication, while 15 were non candidates for nephroureterectomy (NCNU). Analyses were performed separately for the CNU and NCNU groups. Results In the CNU group, the 5 year overall and disease specific survival (OS and DSS) were 71% and 94%, respectively. In the NCNU group, the OS and DSS were 25% and 41%, respectively. Histopathological verification was available in 40 patients (93%), and re-examination showed 27 low-grade and 13 high-grade tumours. In patients with a low-grade tumour, the OS and DSS were 75% and 96%, respectively. In patients with a high-grade tumour, the OS and DSS were 23% and 39%, respectively. The 5 year kidney protection rate was 51% in the CNU group. The 5 year recurrence-free survival was 72%. Conclusions The endoscopic treatment of UTUC is feasible and safe in histopathologically verified low-grade tumours. The endoscopic treatment of high-grade tumours has poor results, and must be reserved for patients where nephroureterectomy is truly contraindicated. PMID- 26926877 TI - X-ray Crystallographic Structure of Oligomers Formed by a Toxic beta-Hairpin Derived from alpha-Synuclein: Trimers and Higher-Order Oligomers. AB - Oligomeric assemblies of the protein alpha-synuclein are thought to cause neurodegeneration in Parkinson's disease and related synucleinopathies. Characterization of alpha-synuclein oligomers at high resolution is an outstanding challenge in the field of structural biology. The absence of high resolution structures of oligomers formed by alpha-synuclein impedes understanding the synucleinopathies at the molecular level. This paper reports the X-ray crystallographic structure of oligomers formed by a peptide derived from residues 36-55 of alpha-synuclein. The peptide 1a adopts a beta-hairpin structure, which assembles in a hierarchical fashion. Three beta-hairpins assemble to form a triangular trimer. Three copies of the triangular trimer assemble to form a basket-shaped nonamer. Two nonamers pack to form an octadecamer. Molecular modeling suggests that full-length alpha-synuclein may also be able to assemble in this fashion. Circular dichroism spectroscopy demonstrates that peptide 1a interacts with anionic lipid bilayer membranes, like oligomers of full-length alpha-synuclein. LDH and MTT assays demonstrate that peptide 1a is toxic toward SH-SY5Y cells. Comparison of peptide 1a to homologues suggests that this toxicity results from nonspecific interactions with the cell membrane. The oligomers formed by peptide 1a are fundamentally different than the proposed models of the fibrils formed by alpha-synuclein and suggest that alpha Syn36-55, rather than the NAC, may nucleate oligomer formation. PMID- 26926879 TI - New "managed access" process for Cancer Drugs Fund to go ahead, NHS England confirms. PMID- 26926880 TI - Abnormality in glutamine-glutamate cycle in the cerebrospinal fluid of cognitively intact elderly individuals with major depressive disorder: a 3-year follow-up study. AB - Major depressive disorder (MDD), common in the elderly, is a risk factor for dementia. Abnormalities in glutamatergic neurotransmission via the N-methyl-D aspartate receptor (NMDA-R) have a key role in the pathophysiology of depression. This study examined whether depression was associated with cerebrospinal fluid (CSF) levels of NMDA-R neurotransmission-associated amino acids in cognitively intact elderly individuals with MDD and age- and gender-matched healthy controls. CSF was obtained from 47 volunteers (MDD group, N=28; age- and gender-matched comparison group, N=19) at baseline and 3-year follow-up (MDD group, N=19; comparison group, N=17). CSF levels of glutamine, glutamate, glycine, L-serine and D-serine were measured by high-performance liquid chromatography. CSF levels of amino acids did not differ across MDD and comparison groups. However, the ratio of glutamine to glutamate was significantly higher at baseline in subjects with MDD than in controls. The ratio decreased in individuals with MDD over the 3 year follow-up, and this decrease correlated with a decrease in the severity of depression. No correlations between absolute amino-acid levels and clinical variables were observed, nor were correlations between amino acids and other biomarkers (for example, amyloid-beta42, amyloid-beta40, and total and phosphorylated tau protein) detected. These results suggest that abnormalities in the glutamine-glutamate cycle in the communication between glia and neurons may have a role in the pathophysiology of depression in the elderly. Furthermore, the glutamine/glutamate ratio in CSF may be a state biomarker for depression. PMID- 26926881 TI - Distinct effects of folate pathway genes MTHFR and MTHFD1L on ruminative response style: a potential risk mechanism for depression. AB - Alterations in the folate pathway have been related to both major depression and cognitive inflexibility; however, they have not been investigated in the genetic background of ruminative response style, which is a form of perseverative cognition and a risk factor for depression. In the present study, we explored the association of rumination (measured by the Ruminative Responses Scale) with polymorphisms of two distinct folate pathway genes, MTHFR rs1801133 (C677T) and MTHFD1L rs11754661, in a combined European white sample from Budapest, Hungary (n=895) and Manchester, United Kingdom (n=1309). Post hoc analysis investigated whether the association could be replicated in each of the two samples, and the relationship between folate pathway genes, rumination, lifetime depression and Brief Symptom Inventory depression score. Despite its functional effect on folate metabolism, the MTHFR rs1801133 showed no effect on rumination. However, the A allele of MTHFD1L rs11754661 was significantly associated with greater rumination, and this effect was replicated in both the Budapest and Manchester samples. In addition, rumination completely mediated the effects of MTHFD1L rs11754661 on depression phenotypes. These findings suggest that the MTHFD1L gene, and thus the C1-THF synthase enzyme of the folate pathway localized in mitochondria, has an important effect on the pathophysiology of depression through rumination, and maybe via this cognitive intermediate phenotype on other mental and physical disorders. Further research should unravel whether the reversible metabolic effect of MTHFD1L is responsible for increased rumination or other long-term effects on brain development. PMID- 26926882 TI - The functional serotonin 1a receptor promoter polymorphism, rs6295, is associated with psychiatric illness and differences in transcription. AB - The G/C single-nucleotide polymorphism in the serotonin 1a receptor promoter, rs6295, has previously been linked with depression, suicide and antidepressant responsiveness. In vitro studies suggest that rs6295 may have functional effects on the expression of the serotonin 1a receptor gene (HTR1A) through altered binding of a number of transcription factors. To further explore the relationship between rs6295, mental illness and gene expression, we performed dual epidemiological and biological studies. First, we genotyped a cohort of 1412 individuals, randomly split into discovery and replication cohorts, to examine the relationship between rs6295 and five psychiatric outcomes: history of psychiatric hospitalization, history of suicide attempts, history of substance or alcohol abuse, current posttraumatic stress disorder (PTSD), current depression. We found that the rs6295G allele is associated with increased risk for substance abuse, psychiatric hospitalization and suicide attempts. Overall, exposure to either childhood or non-childhood trauma resulted in increased risk for all psychiatric outcomes, but we did not observe a significant interaction between rs6295 and trauma in modulating psychiatric outcomes. In conjunction, we also investigated the potential impact of rs6295 on HTR1A expression in postmortem human brain tissue using relative allelic expression assays. We found more mRNA produced from the C versus the G-allele of rs6295 in the prefrontal cortex (PFC), but not in the midbrain of nonpsychiatric control subjects. Further, in the fetal cortex, rs6295C allele exhibited increased relative expression as early as gestational week 18 in humans. Finally, we found that the C:G allelic expression ratio was significantly neutralized in the PFC of subjects with major depressive disorder (MDD) who committed suicide as compared with controls, indicating that normal patterns of transcription may be disrupted in MDD/suicide. These data provide a putative biological mechanism underlying the association between rs6295, trauma and mental illness. Moreover, our results suggest that rs6295 may affect transcription during both gestational development and adulthood in a region-specific manner, acting as a risk factor for psychiatric illness. These findings provide a critical framework for conceptualizing the effects of a common functional genetic variant, trauma exposure and their impact on mental health. PMID- 26926883 TI - Genetic variation and dopamine D2 receptor availability: a systematic review and meta-analysis of human in vivo molecular imaging studies. AB - The D2 dopamine receptor mediates neuropsychiatric symptoms and is a target of pharmacotherapy. Inter-individual variation of D2 receptor density is thought to influence disease risk and pharmacological response. Numerous molecular imaging studies have tested whether common genetic variants influence D2 receptor binding potential (BP) in humans, but demonstration of robust effects has been limited by small sample sizes. We performed a systematic search of published human in vivo molecular imaging studies to estimate effect sizes of common genetic variants on striatal D2 receptor BP. We identified 21 studies examining 19 variants in 11 genes. The most commonly studied variant was a single-nucleotide polymorphism in ANKK1 (rs1800497, Glu713Lys, also called 'Taq1A'). Fixed- and random-effects meta analyses of this variant (5 studies, 194 subjects total) revealed that striatal BP was significantly and robustly lower among carriers of the minor allele (Lys713) relative to major allele homozygotes. The weighted standardized mean difference was -0.57 under the fixed-effect model (95% confidence interval=( 0.87, -0.27), P=0.0002). The normal relationship between rs1800497 and BP was not apparent among subjects with neuropsychiatric diseases. Significant associations with baseline striatal D2 receptor BP have been reported for four DRD2 variants (rs1079597, rs1076560, rs6277 and rs1799732) and a PER2 repeat polymorphism, but none have yet been tested in more than two independent samples. Our findings resolve apparent discrepancies in the literature and establish that rs1800497 robustly influences striatal D2 receptor availability. This genetic variant is likely to contribute to important individual differences in human striatal function, neuropsychiatric disease risk and pharmacological response. PMID- 26926886 TI - Patients' Experiences With Vehicle Collision to Inform the Development of Clinical Practice Guidelines: A Narrative Inquiry. AB - OBJECTIVE: The purpose of this narrative inquiry was to explore the experiences of persons who were injured in traffic collisions and seek their recommendations for the development of clinical practice guideline (CPG) for the management of minor traffic injuries. METHODS: Patients receiving care for traffic injuries were recruited from 4 clinics in Ontario, Canada resulting in 11 adult participants (5 men, 6 women). Eight were injured while driving cars, 1 was injured on a motorcycle, 2 were pedestrians, and none caused the collision. Using narrative inquiry methodology, initial interviews were audiotaped, and follow-up interviews were held within 2 weeks to extend the story of experience created from the first interview. Narrative plotlines across the 11 stories were identified, and a composite story inclusive of all recommendations was developed by the authors. The research findings and composite narrative were used to inform the CPG Expert Panel in the development of new CPGs. RESULTS: Four recommended directions were identified from the narrative inquiry process and applied. First, terminology that caused stigma was a concern. This resulted in modified language ("injured persons") being adopted by the Expert Panel, and a new nomenclature categorizing layers of injury was identified. Second, participants valued being engaged as partners with health care practitioners. This resulted in inclusion of shared decision-making as a foundational recommendation connecting CPGs and care planning. Third, emotional distress was recognized as a factor in recovery. Therefore, the importance of early detection and the ongoing evaluation of risk factors for delayed recovery were included in all CPGs. Fourth, participants shared that they were unfamiliar with the health care system and insurance industry before their accident. Thus, repeatedly orienting injured persons to the system was advised. CONCLUSION: A narrative inquiry of 11 patients' experiences with traffic collision and their recommendations for clinical guidelines informed the Ontario Protocol for Traffic Injury Management Collaboration in the development of new Minor Injury Guidelines. The values and findings of the qualitative inquiry were interwoven into each clinical pathway and embedded within the final guideline report submitted to government. PMID- 26926885 TI - 2-arachidonoylglycerol signaling impairs short-term fear extinction. AB - Impairments in fear extinction are thought to be central to the psychopathology of posttraumatic stress disorder, and endocannabinoid (eCB) signaling has been strongly implicated in extinction learning. Here we utilized the monoacylglycerol lipase inhibitor JZL184 to selectively augment brain 2-AG levels combined with an auditory cue fear-conditioning paradigm to test the hypothesis that 2-AG-mediated eCB signaling modulates short-term fear extinction learning in mice. We show that systemic JZL184 impairs short-term extinction learning in a CB1 receptor dependent manner without affecting non-specific freezing behavior or the acquisition of conditioned fear. This effect was also observed in over conditioned mice environmentally manipulated to re-acquire fear extinction. Cumulatively, the effects of JZL184 appear to be partly due to augmentation of 2 AG signaling in the basolateral nucleus of the amygdala (BLA), as direct microinfusion of JZL184 into the BLA produced similar results. Moreover, we elucidate a short ~3-day temporal window during which 2-AG augmentation impairs extinction behavior, suggesting a preferential role for 2-AG-mediated eCB signaling in the modulation of short-term behavioral sequelae to acute traumatic stress exposure. PMID- 26926887 TI - Alternative options for elderly patients with limited stage diffuse large B-cell lymphoma: R-chemotherapy vs. R-chemotherapy plus radiotherapy. PMID- 26926884 TI - Molecular analyses of circadian gene variants reveal sex-dependent links between depression and clocks. AB - An extensive literature links circadian irregularities and/or sleep abnormalities to mood disorders. Despite the strong genetic component underlying many mood disorders, however, previous genetic associations between circadian clock gene variants and major depressive disorder (MDD) have been weak. We applied a combined molecular/functional and genetic association approach to circadian gene polymorphisms in sex-stratified populations of control subjects and case subjects suffering from MDD. This approach identified significant sex-dependent associations of common variants of the circadian clock genes hClock, hPer3 and hNpas2 with major depression and demonstrated functional effects of these polymorphisms on the expression or activity of the hCLOCK and hPER3 proteins, respectively. In addition, hCLOCK expression is affected by glucocorticoids, consistent with the sex-dependency of the genetic associations and the modulation of glucocorticoid-mediated stress response, providing a mechanism by which the circadian clock controls outputs that may affect psychiatric disorders. We conclude that genetic polymorphisms in circadian genes (especially hClock and hPer3, where functional assays could be tested) influence risk of developing depression in a sex- and stress-dependent manner. These studies support a genetic connection between circadian disruption and mood disorders, and confirm a key connection between circadian gene variation and major depression. PMID- 26926888 TI - First update of the International Xenotransplantation Association consensus statement on conditions for undertaking clinical trials of porcine islet products in type 1 diabetes--Chapter 2b: genetically modified source pigs. AB - Genetic modification of the source pig offers the opportunity to improve the engraftment and survival of islet xenografts. The type of modification can be tailored to the transplant setting; for example, intraportal islet xenografts have been shown to benefit from the expression of anticoagulant and anti inflammatory transgenes, whereas cytoprotective transgenes are probably more relevant for encapsulated islets. The rapid development of pig genetic engineering, particularly with the introduction of genome editing techniques such as CRISPR-Cas, has accelerated the generation of new pig lines with multiple modifications. With pre-clinical testing in progress, it is an opportune time to consider any implications of genetic modification for the conditions for undertaking clinical trials. Obviously, the stringent requirements to fulfill designated pathogen-free status that are applied to wild-type pigs will apply equally to genetically modified (GM) source pigs. In addition, it is important from a safety perspective that the genetic modifications are characterized at the molecular level (e.g., integration site, absence of off-target mutations), the phenotypic level (e.g., durability and stability of transgene expression), and the functional level (e.g., protection of islets in vitro or in vivo, absence of detrimental effects on insulin secretion). The assessment of clinical trial protocols using GM pig islets will need to be performed on a case-by-case basis, taking into account a range of factors including the particular genetic modification(s) and the site and method of delivery. PMID- 26926889 TI - Molecular Iodine-Mediated Difunctionalization of Alkenes with Nitriles and Thiols Leading to beta-Acetamido Sulfides. AB - A direct difunctionalization protocol of alkenes with nitriles and thiols toward beta-acetamido sulfide derivatives has been proposed under metal-free synthesis conditions. The present protocol provides the facile and highly efficient synthesis of various beta-acetamido sulfides in a scaled-up manner with good to excellent yields simply using inexpensive molecular iodine as a catalyst, DMSO as a mild oxidant, and readily available thiols as thiolating reagents. PMID- 26926891 TI - [General Practitioner Sentinel Network as a Tool of [Public] Health Surveillance]. AB - Current strategies of European health advocate the strengthening of the role of public health, requiring from decision-makers the ability to defend and enhance the health of individuals and populations in all policies. In the pursuit of this objective, public health should be evidence-based and so public health surveillance, seen as an important tool of public health since the nineteenth century, plays a central role in public health practice through the production and dissemination of the health information necessary for health planning and for evaluation of public health actions. Within the practice of public health estimations of disease frequency are important for outbreak control, health assessment, health needs assessment and estimation of health gains, but unfortunately these estimations are not always available for the entire population. In those cases and for diseases with high prevalence sentinel surveillance based in sentinel networks have some advantages for specific groups, namely needed of scarce resources and obtainment of quick results.The central role of family doctors in chronic disease management, their knowledge on individuals and families and their responsibilities in the management of a clear defined patients list are characteristics that make general practice an appropriate context to develop a sentinel network. In fact, in Portugal there is a general practitioner sentinel network named Rede Medicos-Sentinela working since 1989 which estimated, for the last 25 years, incidence rates of several chronic diseases, some of them targeted on national priority health programs. Thus, we consider that Rede Medicos-Sentinela can be integrated in a national surveillance system for chronic diseases in Portugal. PMID- 26926892 TI - Heart Failure: A New Epidemic of Cardiovascular Disease. PMID- 26926893 TI - [Analysis of the Cochrane Review: Incentives for Smoking Cessation. Cochrane Database Syst Rev. 2015;5:CD004307]. AB - Material incentives for alteration or reinforcement of healthy behaviours have been widely used in several health systems. These incentives, which are used in various contexts such as workplaces, health facilities or community programs, have been successfully implemented in smoking cessation programs. This systematic review - a third updated version of two published previously - sought to determine if a given set of incentives increased abstinence rates in smokers of medium and high risk (pregnant women). The authors searched several databases until December 2014: the Cochrane Tobacco Addiction Group Specialised Register, MEDLINE, EMBASE, CINAHL and PsycINFO. Two trials published in 2105 were included. The main results were: - In mixed populations (medium risk) six months after the onset there is a greater probability of withdrawal in patients subject to incentives. Direct payments to smokers - through different forms - were particularly effective (North American studies); - In populations of pregnant women (high risk), incentives caused a higher abstinence rate either during pregnancy or in the long term (up to 24 weeks postpartum). The authors conclude that the incentives appear to be effective in increasing the rate of smoking cessation in medium-risk as well as high-risk populations (e.g. pregnant women). PMID- 26926894 TI - Oncology Referral Concerning Paediatric Neurosurgery? Analysis of the Situation between 2008-2013 in the North of Portugal. AB - INTRODUCTION: Primary central nervous system tumours represent the second most frequent neoplasm and are the leading cause of death from solid tumours in children. Our study aimed to provide the most up-to-date epidemiological analysis of primary central nervous system tumours in children living in the north of Portugal and to explore a possible effect of the centralisation of care on outcomes. MATERIAL AND METHODS: This population-based study included all newly diagnosed and histologically confirmed primary central nervous system tumours in people below 18 years old, living in the north of Portugal, from January 2008 to December 2013. Data were collected through access to clinical files. We described children and tumour characteristics, and analysed patient: paediatric neurosurgeon and histological tumour type: paediatric neurosurgeon ratios. RESULTS: A total of 147 cases was recorded. Mean age at diagnosis of primary central nervous system tumours was 8.0 +/- 5.2 years. Astrocytomas were the most common histological type (34%). We found that World Health Organization Tumour Grade was the only variable of statistically significant influence in mortality (p = 0.001). 1-, 3- and 5-year survivals related to 2008-2013 period were statistically higher than 2005 - 2007. Astrocytomas have the highest survival rate, with statistically significant difference from other tumours (p = 0.015). We estimated a mean of 12.25 treated cases per year by each paediatric neurosurgeon at our institution. DISCUSSION: Our results are globally consistent with those published all over the world, but we reported the highest survival rates. The number of cases treated per year by each neurosurgeon is accordant to the recommended. CONCLUSION: We showed an improvement when comparing to data previous to 2008 and better results than those from previous studies, namely higher survival at 1-, 3- and 5-years from the diagnosis, with low complication and relapsing rates. Therefore, the referral of primary central nervous system tumours cases to centres with larger experience can be invaluable for the achievement of the best outcomes. PMID- 26926895 TI - [Burnout in Portuguese Healthcare Professionals: An Analysis at the National Level]. AB - INTRODUCTION: Burnout is a psychological syndrome, characterized by a state of high emotional exhaustion, high depersonalization and low personal accomplishment, which leads to erosion of personal, professional and health values. This study reports the incidence of burnout in Portuguese Healthcare professionals. MATERIAL AND METHODS: Burnout in Portugal's health professionals was assessed with the Maslach Burnout Inventory - Human Services Survey, using a zero (never) to six (always) ordinal scale, on a sample of 1 262 nurses and 466 physicians with mean age of 36.8 year (SD = 12.2) and 38.7 (SD = 11.0), respectively. Participants came from all national districts (35% Lisbon, 18% Oporto, 6% Aveiro, 6% Setubal, 5% Coimbra, 5% Azores and Madeira), working in hospitals (54%), Families' Health Units (30%), Personalized Health Units (8%) and other public or private institutions (8%). RESULTS: Analysis of MBI-HSS scores, stratified by district, revealed that both types of professionals had moderate to high levels of burnout (M = 3.0, SD = 1.7) with no significant differences between the two groups. Vila Real (M = 3.8, SD = 1.7) and Madeira (M = 2.5, SD = 1.5) were the regions where burnout levels were higher and lower, respectively. Burnout levels did not differ significantly between Hospital, Personalized Health Units and Families' Health Centers. Professionals with more years in the function were less affected by Burnout (r = -0.15). No significant association was observed with the duration of the working day (r = 0.04). The strongest predictor of burnout was the perceived quality of working conditions (r = -0.35). DISCUSSION: The occurrence of the burnout syndrome in Portuguese health professionals is frequent, being associated with a poor working conditions perception and reduced professional experience. The incidence of the burnout syndrome shows regional differences which may be associated with different and suboptimal conditions for health care delivery. Results suggest the need for interventions aimed at improving working conditions and initial job training of health professionals, as requisites for a good professional practice and personal well-being. CONCLUSIONS: At the national level, between 2011 and 2013, 21.6% of healthcare professionals showed moderate burnout and 47.8% showed high burnout. The perception of poor working conditions was the main predictor of burnout occurrence among the Portuguese health professionals. PMID- 26926896 TI - [Prevalence of Pre-Obesity/Obesity in Pre and Basic School Children at Vila Nova de Gaia, Portugal]. AB - INTRODUCTION: Over 30% of Portuguese children present overweight. Being a serious public health problem with multiple causes, only a cross-sectorial and concerted action could contribute to their resolution. Municipalities have a set of skills that make them ideal for effective intervention in the fight against this problem. For this action to be effective there must be a local assessment of the extent of the problem and their spatial distribution. The aim of this study was to characterize, from the point of view of the prevalence of overweight, the population of pre-school and first cycle basic education under the responsibility of the municipality of Vila Nova de Gaia, the third most populous municipality in the country. MATERIAL AND METHODS: Were evaluated 8 974 pre and basic-school children, in school year 2013/14. The assessment of the nutritional status of the sample was made using anthropometric measures height and weight. In the classification of nutritional status was considered z-scores or percentiles of body mass index for age according to the World Health Organization, Centers for Disease Control and Prevention and International Obesity Task Force. RESULTS: The prevalence of overweight by the World Health Organization requirements was 37.4%. There were some disparities in the distribution of overweight in schools of the municipality. DISCUSSION: The results were slightly higher than those of other national and international studies, being the sampling size the possible justification for the differences founded. CONCLUSION: The prevalence found is high and with irregular geographical distribution, which could help identifying the main causes of the problem at the local level. PMID- 26926897 TI - [beta-Tricalcium Phosphate in the Surgical Treatment of Proximal Humeral Fractures]. AB - INTRODUCTION: The proximal humeral fractures are becoming more frequent, with a greater tendency for its surgical treatment by osteosynthesis with plate and locked screws. The mechanical and biological failure in these fractures and devices, despite the evolution of this type of implants, highlighted the synthetic bone grafts became an option. MATERIAL AND METHODS: Over a period of 96 months, patients considered were those with proximal humeral fractures treated surgically with a plate and locked screws, and in which beta-tricalcium phosphate bone graft had been used. Functional results were evaluated by the shoulder range of motion as the radiological results. RESULTS: In 19 patients, with a medial follow up of 53 months, we obtained an average shoulder range of motion of 140o in abduction, 142o in forward flexion, 37o in external rotation and L3 hand position in internal rotation for a cefalo-diaphyseal angle of 136o. DISCUSSION: The beta-tricalcium phosphate synthetic bone graft allows the maintenance of reduction after fixation of proximal humeral fractures stabilized with plate and locked screws. This reduction which means the maintenance of cefalo-diaphyseal angle is in close relationship with functional results as shown by shoulder range of motion in all planes. CONCLUSION: The beta-tricalcium phosphate synthetic bone graft should be seen as an adjuvant therapy in extramedullary fixation of proximal humeral fractures, especially those with greater comminution of the medial calcar. PMID- 26926898 TI - A Neurologist's Hard Day's Work: Impact of Inpatient Neurology Consultation in a Tertiary Hospital. AB - INTRODUCTION: Consultation of hospitalized patients under the responsibility of other specialties is a very demanding work. However, it is often under-recognized and poorly documented. The aim of the present study was to assess the burden of the inpatient neurology consultation in a Portuguese hospital and to evaluate the performance of our Neurology department regarding this issue. MATERIAL AND METHODS: A retrospective study was conducted during 2013, reviewing clinical and demographic data. RESULTS: Over one year, the neurologists of our department evaluated 632 inpatients. The commonest reasons for consultation were altered mental state/behavior, focal neurological deficit and seizures. Requests came mainly from medical departments but also from Intermediate and Intensive Care Units. Neurologists suggested further investigation in almost one half of patients and management changes in a similar proportion of patients. A new diagnosis could be established in 63% of cases and the most frequent diagnosis were neurological manifestations of systemic disorders, epilepsy and cerebrovascular disease. Our intervention had impact on the care of 68% of patients. DISCUSSION AND CONCLUSION: Different studies in the literature support our findings and highlight the economic and patient care benefits of this activity. Our results suggest that neurological inpatient observation generates useful interventions for the clinical management of these patients. PMID- 26926899 TI - [Syphilis: Prevalence in a Hospital in Lisbon]. AB - INTRODUCTION: Syphilis is a sexual and vertical transmitted disease. Its incidence is increasing in Europe, particularly, in Portugal. MATERIAL AND METHODS: A descriptive, retrospective study was performed based on positive treponemal tests from January to December 2013, at the Santa Maria Hospital, Lisbon. In-patients and out-patients evaluated in medical appointments and at the emergency department were included. We proceeded to epidemiological characterization, disease classification and definition of risk factors. RESULTS: We obtained a sample of 580 patients, of whom 51 with no clinical data and 45 with false positive serologies were excluded. There was a predominance of male patients (75%) and a mean age of 47 years. Most (59%) had syphilis successfully treated in the past and 3.7% were in follow-up. We recorded 13 primaries syphilis, 71 cases of secondary syphilis, 40 cases of early latent syphilis, 49 unknown duration syphilis and five cases of late latent syphilis. In the early syphilis group, 42% (n = 124) were HIV-positive and, in 8% both diagnosis were done simultaneously. DISCUSSION: We emphasize the high prevalence of syphilis/HIV co-infection in patients with early syphilis, reinforcing the importance of promoting the use of preventive measures. We obtained 11% of patients with late clinical forms, which are notifiable since June 2014, in Portugal. All serological tests for the diagnosis of syphilis have limitations which emphasizes the importance of clinical-laboratory correlation. CONCLUSION: Syphilis remains an important public health problem. It is necessary to establish education programs, screening and follow-up strategies to reduce their prevalence and to perform more efficient screening of the partners. PMID- 26926900 TI - Are Amyotrophic Lateral Sclerosis Caregivers at Higher Risk for Health Problems? AB - INTRODUCTION: Amyotrophic lateral sclerosis is a rare neurodegenerative disease affecting motor neurons. Patients present with progressive physical impairment, respiratory failure being the main cause of death. A significant portion of patients presents neurobehavioral problems as well. As severe impairment occurs, patients become highly dependent and in general, their families assume the role of primary caregivers, exposing them to stress and other potential causes of disease like insomnia, physical strain from patients' mobilization and changes on eating habits. The aim of this work is to understand if taking care of patients with amyotrophic lateral sclerosis increases disease and health problems on caregivers. MATERIAL AND METHODS: Comprehensive review of the literature published on the electronic databases PubMed and Scopus between 2010 and 2014. RESULTS: Eighteen studies met the inclusion criteria. We found that amyotrophic lateral sclerosis caregivers have higher levels of burden, depression and anxiety with lower quality of life. This is associated to age and gender of caregivers, time spent caring, patients' disability and neurobehavioral changes. Higher sense of support and spirituality on family seem to promote wellbeing. DISCUSSION: On our work, we were able to understand that several factors have influenced caregivers' quality of life and affect their health. Besides, we could understand that the outcomes studied are related between themselves and, as seen in some of the studies, related to patients' quality of life itself. Consequently, it has become essential to adopt a holistic approach of these patients and their families, fighting the deteriorating risk factors and investing on health promoters. CONCLUSION: Despite the large body of research on family caregiving for amyotrophic lateral sclerosis patients, little has changed and the outcomes measured remain almost the same before and after 2010. The work indicates that caregivers have lower levels of health than the general population. Still additional research is required, in order to better understand and characterized the changes on caregivers' health. It is nevertheless clear that health care professionals cannot ignore these health changes and need an approach focused not only on patients but also on caregivers. PMID- 26926901 TI - [Ectopic Decidualization: A Forgotten Entity]. AB - INTRODUCTION: Although ectopic decidualization is an entity often underdiagnosed, it may have adverse clinical impact on maternal-fetal morbimortality. The objective of this study was to review the scientific evidence regarding the etiology, clinical features, diagnosis and therapeutic approach on this issue. MATERIAL AND METHODS: The search for this literature review was conducted in PubMed, Web of Science and Scopus, through the query ('deciduosis' OR 'ectopic decidualization' OR 'ectopic decidua' OR 'ectopic decidua reaction'), considering articles of all evidence levels published up to 31/06/2014. RESULTS: Ectopic decidualization is, usually, a benign condition, asymptomatic and does not require therapeutic intervention. It occurs mostly during pregnancy, with complete regression in the postpartum period. The frequency of the diagnosis depends on the clinical suspicion and its location, being the omentum and the ovary the most common sites. When symptomatic, the main clinical manifestations are genital bleeding and hemoperitoneum. Differential diagnosis includes malignant disease and histopathological confirmation is essential in these situations. The low index of suspicion may lead to a biopsy, which can have serious adverse outcomes due to the high friability of these lesions. DISCUSSION AND CONCLUSION: The recognition of this entity and its clinical features are essential for the management of these patients. On one side this allows an early and proper medical approach in severe cases, on the other side (the majority of cases) maintaining an expectant attitude avoiding iatrogeny, does not compromise, in most cases, the favorable outcome of ectopic decidualization. PMID- 26926902 TI - [Assisted Reproductive Technology in Female Transplant Recipients: Experience of a Reproductive Medicine Unit and Literature Review]. AB - Diseases in end stage typically occur with hypothalamic-pituitary-ovarian axis disorders, with consequent anovulation and infertility. The solid organ transplantation increased survival of patients with end-stage organs disease and the vast majority of women improve their reproductive capacity after transplantation. Although adoption can always be a possibility, the transplanted infertile woman has the right to self-reproductive determination using assisted reproductive techniques. While it is known that pregnancies in transplantedwomen are at high risk, there is no evidence of differences in pregnancy outcome in pregnant transplanted subject to technical, compared with spontaneous pregnancies. The use of assisted reproductive techniques in transplanted women is a medical, ethical and psychosocial challenge, whose approach must be multidisciplinary, to ensure reproductive success without compromising the function of the transplanted organ or maternal health, allowing the birth of a healthy child. The literature remains scarce. Three clinical cases are presented. PMID- 26926903 TI - Ainhum or Dactylolysis Spontanea: a Missing Toe. PMID- 26926904 TI - [Thirty Six Views of Mount Fuji and the First Oncology Appointment]. PMID- 26926905 TI - The application of genomics and bioinformatics to accelerate crop improvement in a changing climate. AB - The changing climate and growing global population will increase pressure on our ability to produce sufficient food. The breeding of novel crops and the adaptation of current crops to the new environment are required to ensure continued food production. Advances in genomics offer the potential to accelerate the genomics based breeding of crop plants. However, relating genomic data to climate related agronomic traits for use in breeding remains a huge challenge, and one which will require coordination of diverse skills and expertise. Bioinformatics, when combined with genomics has the potential to help maintain food security in the face of climate change through the accelerated production of climate ready crops. PMID- 26926906 TI - Effective but costly: How to tackle difficult trade-offs in evaluating health improving technologies in liver diseases. AB - In the current context of rising health care costs and decreasing sustainability, it is becoming increasingly common to resort to decision analytical modeling and health economics evaluations. Decision analytic models are analytical tools that help decision makers to select the best choice between alternative health care interventions, taking into consideration the complexity of the disease, the socioeconomic context, and the relevant differences in outcomes. We present a brief overview of the use of decision analytical models in health economic evaluations and their applications in the area of liver diseases. The aim is to provide the reader with the basic elements to evaluate health economic analysis reports and to discuss some limitations of the current approaches, as highlighted by the case of the therapy of chronic hepatitis C. To serve its purpose, health economics evaluations must be able to do justice to medical innovation and the market while protecting patients and society and promoting fair access to treatment and its economic sustainability. CONCLUSION: New approaches and methods able to include variables such as prevalence of the disease, budget impact, and sustainability into the cost-effectiveness analysis are needed to reach this goal. (Hepatology 2016;64:1331-1342). PMID- 26926908 TI - (R)evolution: toward a new paradigm of policy and patient advocacy for expanded access to experimental treatments. AB - In life-threatening conditions such as cancer and rare diseases, where there is no cure and no U.S. Food and Drug Administration (FDA)-approved therapy, patients sometimes seek access to an unapproved, experimental therapy through expanded access programs as their last, best hope for treatment to save their lives. Since the 1980s, the policies and the practice of expanded access have evolved, but a common challenge remains that there is no obligation, and often little incentive, for manufacturers to offer expanded access programs, especially for individual patients. In recent years, online campaigns seeking access to an experimental therapy have become more common, paralleling growth in and representing an intersection of social media, digital health, and patient advocacy.Mackey and Schoenfeld have examined the evolution of expanded access policy, practice, and trends, as well as case studies of online campaigns to access experimental therapies, to arrive at several recommendations for the future of expanded access. This commentary puts their paper in context, examines their recommendations, and suggests further reforms.Please see related article: https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-016-0568-8. PMID- 26926907 TI - Glial and neuronal Semaphorin signaling instruct the development of a functional myotopic map for Drosophila walking. AB - Motoneurons developmentally acquire appropriate cellular architectures that ensure connections with postsynaptic muscles and presynaptic neurons. In Drosophila, leg motoneurons are organized as a myotopic map, where their dendritic domains represent the muscle field. Here, we investigate mechanisms underlying development of aspects of this myotopic map, required for walking. A behavioral screen identified roles for Semaphorins (Sema) and Plexins (Plex) in walking behavior. Deciphering this phenotype, we show that PlexA/Sema1a mediates motoneuron axon branching in ways that differ in the proximal femur and distal tibia, based on motoneuronal birth order. Importantly, we show a novel role for glia in positioning dendrites of specific motoneurons; PlexB/Sema2a is required for dendritic positioning of late-born motoneurons but not early-born motoneurons. These findings indicate that communication within motoneurons and between glia and motoneurons, mediated by the combined action of different Plexin/Semaphorin signaling systems, are required for the formation of a functional myotopic map. PMID- 26926909 TI - Effects of Arctium lappa on Cadmium-Induced Damage to the Testis and Epididymis of Adult Wistar Rats. AB - The protective role of Arctium lappa (AL) on the testes of rats acutely exposed to cadmium (Cd) was tested. The rats were randomly divided into a control group (C-group) and three major experimental groups, which were further subdivided into minor groups (n = 6) according to the experimental period (7 or 56 days). The C group was subdivided into C-7 and C-56 [receiving a single saline solution, intraperitoneal (i.p.), on the first day]; the AL-group, AL-7, and AL-56, received AL extract (300 mg/kg/daily); the Cd group, Cd-7 and Cd-56, received a single i.p. dose of CdCl2 (1.2 mg/kg body weight (BW)) on the first day; the CdAL group, CdAL-7 and CdAL-56, received the same Cd dose, followed by AL extract. Water or AL extract was administered daily by gavage. After either 7 or 56 days, the testis and accessory glands were removed after whole-body perfusion. Exposure to Cd and CdAL decreased the weight of the testis and epididymis, the gonadosomatic index, seminiferous tubular (ST) diameter, and ST volumetric proportion, and increased the volumetric proportion of interstitium after 56 days. In the epididymis caput, the tubular volumetric proportion decreased along with an increase of interstitial volumetric proportion and epithelium height after 56 days. The alterations observed were less severe only after 7 days. A progressive testicular damage resulted mainly in tubules lined only by Sertoli cells. The sperm number and cell debris decreased in the epididymis. We demonstrated that the testicular damage induced by single acute i.p. exposure to Cd occurred despite the daily oral intake of AL extract. PMID- 26926911 TI - Oxidative Rearrangement via in Situ Generated N-Chloroamine: Synthesis of Fused Tetrahydroisoquinolines. AB - An oxidative rearrangement reaction of spiro tetrahydroisoquinolines has been developed for the synthesis of fused tetrahydroisoquinolines using in situ generated N-chloroamines. The reaction proceeds via initial chlorination of an amine, followed by a 1,2-carbon to nitrogen migration, and nucleophilic trapping of a ketiminium ion intermediate in a one-pot operation. The electrophilic nature of N-chloroamines allowed for the carbon-nitrogen bond formation in this reation. PMID- 26926910 TI - The clinical and cost effectiveness of cognitive behavioural therapy plus treatment as usual for the treatment of depression in advanced cancer (CanTalk): study protocol for a randomised controlled trial. AB - BACKGROUND: The prevalence of depressive disorder in adults with advanced cancer is around 20 %. Although cognitive behavioural therapy (CBT) is recommended for depression and may be beneficial in depressed people with cancer, its use for depression in those with advanced disease for whom cure is not likely has not been explored. METHODS: People aged 18 years and above with advanced cancer attending General Practitioner (GP), oncology or hospice outpatients from centres across England will be screened to establish a DSM-IV diagnosis of depression. Self-referral is also accepted. Eligible consenters will be randomised to a single blind, multicentre, randomised controlled trial of the addition to treatment as usual (TAU) of up to 12 one-hour weekly sessions of manualised CBT versus TAU alone. Sessions are delivered in primary care through Increasing Access to Psychological Care (IAPT) service, and the manual includes a focus on issues for people approaching the end of life. The main outcome is the Beck Depression Inventory-II (BDI-II). Subsidiary measures include the Patient Health Questionnaire, quality of life measure EQ-5D, Satisfaction with care, Eastern Cooperative Oncology Group-Performance Status and a modified Client Service Receipt Inventory. At 90 % power, we require 240 participants to enter the trial. Data will be analysed using multi-level (hierarchical) models for data collected at baseline, 6, 12, 18 and 24 weeks. Cost effectiveness analysis will incorporate costs related to the intervention to compare overall healthcare costs and QALYs between the treatment arms. We will conduct qualitative interviews after final follow-up on patient and therapist perspectives of the therapy. DISCUSSION: This trial will provide data on the clinical and cost effectiveness of CBT for people with advanced cancer and depression. We shall gain an understanding of the feasibility of delivering care to this group through IAPT. Our findings will provide evidence for policy-makers, commissioners and clinicians in cancer and palliative care, and in the community. TRIAL REGISTRATION: Controlled Trials ISRCTN07622709 , registered 15 July 2011. PMID- 26926913 TI - Interactions and effects of BSA-functionalized single-walled carbon nanotubes on different cell lines. AB - Functionalized carbon nanotubes (CNTs) have shown great promise in several biomedical contexts, spanning from drug delivery to tissue regeneration. Thanks to their unique size-related properties, single-walled CNTs (SWCNTs) are particularly interesting in these fields. However, their use in nanomedicine requires a clear demonstration of their safety in terms of tissue damage, toxicity and pro-inflammatory response. Thus, a better understanding of the cytotoxicity mechanisms, the cellular interactions and the effects that these materials have on cell survival and on biological membranes is an important first step for an appropriate assessment of their biocompatibility. In this study we show how bovine serum albumin (BSA) is able to generate homogeneous and stable dispersions of SWCNTs (BSA-CNTs), suggesting their possible use in the biomedical field. On the other hand, this study wishes to shed more light on the impact and the interactions of protein-stabilized SWCNTs with two different cell types exploiting multidisciplinary techniques. We show that BSA-CNTs are efficiently taken up by cells. We also attempt to describe the effect that the interaction with cells has on the dielectric characteristics of the plasma membrane and ion flux using electrorotation. We then focus on the BSA-CNTs' acute toxicity using different cellular models. The novel aspect of this work is the evaluation of the membrane alterations that have been poorly investigated to date. PMID- 26926912 TI - FANCJ at the FORK. PMID- 26926915 TI - The SwiSCI Cohort Study. PMID- 26926916 TI - Swiss national community survey on functioning after spinal cord injury: Protocol, characteristics of participants and determinants of non-response. AB - OBJECTIVE: To detail the protocol, recruitment, study population, response, and data quality of the first population-based community survey of the Swiss Spinal Cord Injury (SwiSCI) Cohort Study. DESIGN: The survey consisted of 3 successive modules administered between September 2011 and March 2013. The first two modules queried demographics, lesion characteristics and key domains of functioning. The third module collected information on psychological personal factors and health behaviour; work integration; or health services and aging. PARTICIPANTS: Community-dwelling persons with chronic spinal cord injury in Switzerland. METHODS: Descriptive analyses of the recruitment process, participant characteristics, and correspondence between self-reported and clinical data. Determinants for participation and the impact of non-response on survey results were assessed. RESULTS: Out of 3,144 eligible persons 1,549 participated in the first two modules (cumulative response rate 49.3%). Approximately three-quarters of participants were male, with a median age of 53 years, and 78% had traumatic spinal cord injury. Record-linkage with medical records demonstrated substantial agreement with self-reported demographic and lesion characteristics. A minimal non-response bias was found. CONCLUSIONS: The community survey was effective in recruiting an unbiased sample, thus providing valuable information to study functioning, health maintenance, and quality of life in the Swiss SCI community. PMID- 26926914 TI - Decellularisation and histological characterisation of porcine peripheral nerves. AB - Peripheral nerve injuries affect a large proportion of the global population, often causing significant morbidity and loss of function. Current treatment strategies include the use of implantable nerve guide conduits (NGC's) to direct regenerating axons between the proximal and distal ends of the nerve gap. However, NGC's are limited in their effectiveness at promoting regeneration Current NGCs are not suitable as substrates for supporting either neuronal or Schwann cell growth, as they lack an architecture similar to that of the native extracellular matrix (ECM) of the nerve. The aim of this study was to create an acellular porcine peripheral nerve using a novel decellularisation protocol, in order to eliminate the immunogenic cellular components of the tissue, while preserving the three-dimensional histoarchitecture and ECM components. Porcine peripheral nerve (sciatic branches were decellularised using a low concentration (0.1%; w/v) sodium dodecyl sulphate in conjunction with hypotonic buffers and protease inhibitors, and then sterilised using 0.1% (v/v) peracetic acid. Quantitative and qualitative analysis revealed a >=95% (w/w) reduction in DNA content as well as preservation of the nerve fascicles and connective tissue. Acellular nerves were shown to have retained key ECM components such as collagen, laminin and fibronectin. Slow strain rate to failure testing demonstrated the biomechanical properties of acellular nerves to be comparable to fresh controls. In conclusion, we report the production of a biocompatible, biomechanically functional acellular scaffold, which may have use in peripheral nerve repair. Biotechnol. Bioeng. 2016;113: 2041-2053. (c) 2016 The Authors. Biotechnology and Bioengineering published by Wiley Periodicals, Inc. PMID- 26926918 TI - Subgroups in epidemiological studies on spinal cord injury: Evaluation of international recommendations in the Swiss Spinal Cord Injury Cohort Study. AB - OBJECTIVE: To test subgroups of a community-based sample of individuals with spinal cord injury, categorized by the application of current recommendations by the International Spinal Cord Society. DESIGN: Community survey. PARTICIPANTS: Individuals with traumatic and non-traumatic spinal cord injury residing in Switzerland. METHODS: Recommended subgroups of age, gender, years since injury, severity of injury and aetiology were tested against the following criteria: (i) distribution of participants across categories; (ii) within- and between-group variability with regard to selected outcomes of functioning and quality of life. RESULTS: Data-sets for 1,549 participants (28.5% women; mean age 52 +/- 15 years) were available for analyses. There was a number of participants in every subgroup, yet numbers were relatively small in the group with the shortest time since injury (< 1 year; n = 23) and in the oldest age group (>= 76; n = 94). A high variability in some outcomes was detected between categories. All variables were predictive for most of the endpoints investigated. CONCLUSION: Recommended categorization could well fit the present sample. A minor concern was the low numbers of participants in some subgroups. PMID- 26926917 TI - Setting up a cohort study of functioning: From classification to measurement. AB - OBJECTIVE: Cohort studies are an appropriate method for the collection of population-based longitudinal data to track people's health and functioning over time. However, describing and understanding functioning in its complexity with all its determinants is one of the biggest challenges faced by clinicians and researchers. DESIGN: This paper focuses on the development of a cohort study on functioning, outlining the relevant steps and related methods, and illustrating these with reference to the Swiss Spinal Cord Injury Cohort Study (SwiSCI). METHODS AND RESULTS: In setting up a cohort study the initial step is to specify which variables are to be included, i.e. what to assess. The International Classification of Functioning, Disability and Health (ICF) is valuable in this process. The second step is to identify how to assess the specified ICF categories. Existing instruments and assessments can then be linked to the ICF. CONCLUSION: The methods outlined here enable the development of a cohort study to be based on a comprehensive perspective of health, operationalized through functioning as conceptualized and classified in the ICF, yet to remain efficient and feasible to administer. PMID- 26926919 TI - Metric properties of the Spinal Cord Independence Measure - Self Report in a community survey. AB - OBJECTIVE: The Spinal Cord Independence Measure - Self Report (SCIM-SR) is a self report instrument for assessing functional independence of persons with spinal cord injury. This study examined the internal construct validity and reliability of the SCIM-SR, when administered in a community survey, using the Rasch measurement model. METHODS: Rasch analysis of data from 1,549 individuals with spinal cord injury who completed the SCIM-SR. RESULTS: In the initial analysis no fit to the Rasch model was achieved. Items were grouped into testlets to accommodate the substantial local dependency. Due to the differential item functioning for lesion level and degree, spinal cord injury-specific sub-group analyses were conducted. Fit to the Rasch model was then achieved for individuals with tetraplegia and complete paraplegia, but not for those with incomplete paraplegia. Comparability of ability estimates across sub-groups was attained by anchoring all sub-groups on a testlet. CONCLUSION: The SCIM-SR violates certain assumptions of the Rasch measurement model, as shown by the local dependency and differential item functioning. However, an intermediate solution to achieve fit in 3 out of 4 spinal cord injury sub-groups was found. For the time being, therefore, it advisable to use this approach to compute Rasch-transformed SCIM-SR scores. PMID- 26926920 TI - Metric properties of the Utrecht Scale for Evaluation of Rehabilitation Participation (USER-Participation) in persons with spinal cord injury living in Switzerland. AB - OBJECTIVE: To examine the metric properties of the Utrecht Scale for Evaluation of Rehabilitation-Participation (USER-Participation) in persons with spinal cord injury in Switzerland from a classical and item response theory perspective. DESIGN: Cross-sectional survey. SUBJECTS: Persons with spinal cord injury living in the Swiss community (n = 1,549). METHODS: Score distributions and internal consistency were evaluated using Classical Test Theory. The Restrictions and Satisfaction scales were subjected to Rasch analysis. Anchored analyses were performed to account appropriately for items with structural missing. RESULTS: Internal consistency was good for the Restrictions (alpha = 0.90) and Satisfaction scales (alpha = 0.90), but not for the Frequency scale (alpha = 0.65). Rasch analyses showed acceptable model fit for the Restrictions and Satisfaction scales after collapsing response categories of some items and merging some items into testlets. Differential item functioning was small. Anchoring allowed inclusion of the item work/education in the Restrictions scale and work/education and/or partner relationship in the Satisfaction scale. CONCLUSION: The Restrictions and Satisfaction scales of the USER-Participation showed satisfactory metric properties. The Frequency scale showed fewer optimal properties, but nonetheless provides important additional information regarding participation. Conversion tables were performed to transform USER-Participation raw scores into a 0-100 interval scale using Rasch-based ability estimates for use in epidemiological studies. PMID- 26926921 TI - Rasch analysis of measurement instruments capturing psychological personal factors in persons with spinal cord injury. AB - OBJECTIVE: To evaluate the metric properties of distinct measures of psychological personal factors comprising feelings, beliefs, motives, and patterns of experience and behaviour assessed in the Swiss Spinal Cord Injury Cohort Study (SwiSCI), using Rasch methodology. METHODS: SwiSCI Pathway 2 is a community-based, nationwide, cross-sectional survey for persons with spinal cord injury (SCI) (n = 511). The Rasch partial credit model was used for each subscale of the Positive Affect Negative Affect Scale (PANAS), Appraisal of Life Events Scale (ALE), Purpose in Life test - Short Form (PIL-SF), and the Big Five Inventory-K (BFI-K). RESULTS: The measures were unidimensional, with the exception of the positive affect items of the PANAS, where pairwise t-tests resulted in 10% significant cases, indicating multidimensionality. The BFI-K subscale agreeableness revealed low reliability (0.53). Other reliability estimates ranged between 0.61 and 0.89. Ceiling and floor effects were found for most measures. SCI-related differential item functioning (DIF) was rarely found. Language DIF was identified for several items of the BFI-K, PANAS and the ALE, but not for the PIL-SF. CONCLUSION: A majority of the measures satisfy the assumptions of the Rasch model, including unidimensionality. Invariance across language versions still represents a major challenge. PMID- 26926923 TI - Perceived impact of environmental barriers on participation among people living with spinal cord injury in Switzerland. AB - OBJECTIVE: To describe the impact of environmental barriers perceived by people living with spinal cord injury in the Swiss community and to compare this across subpopulations. DESIGN: Cross-sectional study. SUBJECTS: A total of 1,549 participants in the community survey of the Swiss spinal cord injury Cohort study. METHODS: The perceived impact of environmental barriers on participation was measured with the Nottwil Environmental Factors Inventory Short Form (NEFI SF). Physical independence was measured with the Spinal Cord Independence Measure Self Report (SCIM-SR). Perceived barriers were compared across people with different demographic and lesion characteristics. Multivariable regression modelling applying fractional polynomials was used to evaluate the overall perceived impact of barriers in relation to demographics, spinal cord injury characteristics, and physical independence. RESULTS: Most perceived barriers were climatic conditions and inaccessibility of public and private infrastructure. Older participants, those with longer time since injury and participants with complete lesions indicated more problems with access. Females reported more attitudinal barriers. Approximately one-third of participants with complete tetraplegia reported obstacles related to assistance with personal care. A higher level of physical independence was associated with fewer perceived barriers. CONCLUSION: Despite living in a rich country with a well-developed social security system, many people with spinal cord injury in Switzerland experience participation restrictions due to environmental barriers; in particular women, people with non-traumatic spinal cord injury and limited physical independence. PMID- 26926922 TI - Toward standardized reporting for a cohort study on functioning: The Swiss Spinal Cord Injury Cohort Study. AB - OBJECTIVE: Functioning is an important outcome to measure in cohort studies. Clear and operational outcomes are needed to judge the quality of a cohort study. This paper outlines guiding principles for reporting functioning in cohort studies and addresses some outstanding issues. DESIGN: Principles of how to standardize reporting of data from a cohort study on functioning, by deriving scores that are most useful for further statistical analysis and reporting, are outlined. The Swiss Spinal Cord Injury Cohort Study Community Survey serves as a case in point to provide a practical application of these principles. METHODS AND RESULTS: Development of reporting scores must be conceptually coherent and metrically sound. The International Classification of Functioning, Disability and Health (ICF) can serve as the frame of reference for this, with its categories serving as reference units for reporting. To derive a score for further statistical analysis and reporting, items measuring a single latent trait must be invariant across groups. The Rasch measurement model is well suited to test these assumptions. CONCLUSION: Our approach is a valuable guide for researchers and clinicians, as it fosters comparability of data, strengthens the comprehensiveness of scope, and provides invariant, interval-scaled data for further statistical analyses of functioning. PMID- 26926924 TI - From the person's perspective: Perceived problems in functioning among individuals with spinal cord injury in Switzerland. AB - OBJECTIVE: To report the main problems in functioning cited by people with spinal cord injury in Switzerland. STUDY DESIGN: Post-coding analysis was conducted based on the open-ended question, "What causes you the most problems since your spinal cord injury?" from the Starter Module of the community survey of the Swiss Spinal Cord Injury Cohort Study, administered between September 2011 and March 2013. STUDY PARTICIPANTS: Out of 3,144 eligible subjects, 1,762 answered the open ended question and cited problems. METHODS: Thematic analysis was used, based on the coding system from the International Classification of Functioning, Disability and Health. RESULTS: The study identified the 10 problems cited most by the participants, and the 5 most-cited problems mentioned by participants from each of the relevant subgroups subdivided by factors including gender and aetiology. Problems linked to complications in body functions (e.g. pain), activities and participation (e.g. leisure) and environment (e.g. design of public buildings) were reported as important. CONCLUSION: This study contributes to priority setting in spinal cord injury by accounting for the person perspective within a large-scale quantitative survey. The results support the value of a comprehensive approach to spinal cord injury. PMID- 26926926 TI - Necrotic enteritis predisposing factors in broiler chickens. AB - Necrotic enteritis in chickens develops as a result of infection with pathogenic strains of Clostridium perfringens and the presence of predisposing factors. Predisposing factors include elements that directly change the physical properties of the gut, either damaging the epithelial surface, inducing mucus production, or changing gut transit times; factors that disrupt the gut microbiota; and factors that alter the immune status of birds. In the past research into necrotic enteritis predisposing factors was directed by the simple hypothesis that low-level colonization of C. perfringens commonly occurred within the gut of healthy chickens and the predisposing factors lead to a proliferation of those bacteria to produce disease. More recently, with an increasing understanding of the major virulence factors of C. perfringens and the application of molecular techniques to define different clades of C. perfringens strains, it has become clear that the C. perfringens isolates commonly found in healthy chickens are generally not strains that have the potential to cause disease. Therefore, we need to re-evaluate hypotheses regarding the development of disease, the origin of disease causing isolates of C. perfringens, and the importance of interactions with other C. perfringens strains and with predisposing factors. Many predisposing factors that affect the physical and immunological characteristics of the gastrointestinal tract may also change the resident microbiota. Research directed towards defining the relative importance of each of these different actions of predisposing factors will improve the understanding of disease pathogenesis and may allow refinement of experiment disease models. PMID- 26926925 TI - Obesity impairs lactation performance in mice by inducing prolactin resistance. AB - Obesity reduces breastfeeding success and lactation performance in women. However, the mechanisms involved are not entirely understood. In the present study, female C57BL/6 mice were chronically exposed to a high-fat diet to induce obesity and subsequently exhibited impaired offspring viability (only 15% survival rate), milk production (33% reduction), mammopoiesis (one-third of the glandular area compared to control animals) and postpartum maternal behaviors (higher latency to retrieving and grouping the pups). Reproductive experience attenuated these defects. Diet-induced obese mice exhibited high basal pSTAT5 levels in the mammary tissue and hypothalamus, and an acute prolactin stimulus was unable to further increase pSTAT5 levels above basal levels. In contrast, genetically obese leptin-deficient females showed normal prolactin responsiveness. Additionally, we identified the expression of leptin receptors specifically in basal/myoepithelial cells of the mouse mammary gland. Finally, high-fat diet females exhibited altered mRNA levels of ERBB4 and NRG1, suggesting that obesity may involve disturbances to mammary gland paracrine circuits that are critical in the control of luminal progenitor function and lactation. In summary, our findings indicate that high leptin levels are a possible cause of the peripheral and central prolactin resistance observed in obese mice which leads to impaired lactation performance. PMID- 26926927 TI - Baseline subject characteristics predictive of compliance with study-mandated prostate biopsy in men at risk of prostate cancer: results from REDUCE. AB - BACKGROUND: Study compliance is crucial when the study outcome is determined by an invasive procedure, such as prostate biopsy. To investigate predictors of compliance in study-mandated prostate biopsies, we analyzed demographic, clinical and reported lifestyle data from the REDUCE trial. METHODS: We retrospectively identified 8025 men from REDUCE with at least 2 years of follow-up, and used multivariable logistic regression to test the association between baseline demographic and clinical characteristics and undergoing the study-mandated prostate biopsy at 2 years. We then examined whether missing any of these data was associated with undergoing a biopsy. RESULTS: In REDUCE, 22% of men did not undergo a 2-year biopsy. On multivariable analysis, the non-North American region was predictive of 42-44% increased likelihood of undergoing a 2-year biopsy (P?0.001). Being enrolled at a center that enrolled >10 subjects (2nd and 3rd tertile) was associated with a 42-48% increased likelihood of undergoing a 2-year biopsy (P<0.001). In addition, black race predicted 44% lower rate of on-study 2 year biopsy (odds ratio (OR)=0.56; P=0.001). Finally, missing one or more baseline variables was associated with a 32% decreased likelihood of undergoing a 2-year biopsy (OR=0.68; P<0.001). CONCLUSIONS: In REDUCE, men outside North America, those at higher volume centers and those with complete baseline data were more likely to undergo study-mandated 2-year biopsies. Given prostate biopsy is becoming increasingly utilized as an endpoint in trials that are often multi national, regional differences in compliance should be considered when designing future trials. Likewise, efforts are needed to ensure compliance in low-volume centers or among subjects missing baseline data. PMID- 26926928 TI - Common variation in BRCA1 may have a role in progression to lethal prostate cancer after radiation treatment. AB - BACKGROUND: To evaluate whether single-nucleotide polymorphisms (SNPs) reflecting common variation in the tumor suppressor BRCA1 affect prostate cancer outcomes. Because radiation therapy (RT) induces DNA damage, we hypothesized that common variation in BRCA1 has a role in progression to lethal prostate cancer, particularly in patients receiving RT. METHODS: We followed 802 men diagnosed with localized prostate cancer (cT1-T3/N0/M0) who were treated with RT in the US Health Professionals Follow-up Study (HPFS) and Physicians' Health Study (PHS), for progression to lethal prostate cancer. Six SNPs (rs3737559, rs1799950, rs799923, rs915945, rs4474733 and rs8176305) were genotyped in HPFS to capture common variation across BRCA1. rs4474733 and rs8176305 were also evaluated in the PHS cohort. Cox proportional hazards models were used to estimate per-allele hazard ratios (HR) and 95% confidence intervals (CI) stratified by primary treatment. RESULTS: In the RT group (n=802), 71 men progressed to lethal disease during a mean follow-up of 12 years. We found that two SNPs, rs4473733 (HR: 0.65; 95% CI 0.42-0.99) and rs8176305 (HR: 2.03; 95% CI 1.33-3.10), were associated with lethal prostate cancer in men receiving RT. CONCLUSIONS: Common variation in BRCA1 may influence clinical outcomes in patients receiving RT for localized prostate cancer by modifying the response to RT. Our findings merit further follow-up studies to validate these SNPs and better understand their functional and biological significance. PMID- 26926929 TI - Natural history and risk factors for rupture of thoracic aortic arch aneurysms. AB - OBJECTIVE: The management of degenerative aneurysms of the aortic arch requires careful selection of patients, taking into consideration risk of rupture and operative risks, which is more relevant with the emergence of hybrid debranching and branched and fenestrated endovascular options. The natural history of true arch aneurysms has not been previously studied. We aimed to determine the expansion rate of thoracic aortic arch aneurysm and to identify predictors for rupture. METHODS: Consecutive patients with known true thoracic aortic arch aneurysms monitored with serial computed tomography from 2000 to 2014 were retrospectively reviewed. Thoracoabdominal aneurysms and aneurysms due to aortic dissection and connective tissue diseases were excluded. Variables studied included patient demographics, aneurysm morphology, and ascending aorta diameter. A size expansion curve for each patient was plotted with serial computed tomography scan data, and the slope obtained by linear interpolation was taken as the expansion rate. Multiple logistic regression analysis was performed to identify independent predictors of rupture. Average yearly risks of rupture for overall and expansion rate substrata were calculated from life-table analysis. RESULTS: A total of 45 arch aneurysms were followed up for a mean of 36.6 months (3-104). Aneurysm growth was largely linear, with an average rate of 2.5 mm/y (0 16). During surveillance, 10 aneurysms ruptured (22%) and 8 patients died. There was one additional arch aneurysm-related death during follow-up, whereas 14 patients (31%) died of other causes. Aneurysms expanding at >5.5 mm/y have a 67% likelihood of rupture compared with 8.3% of those expanding at <5.5 mm/y. Aneurysm size >6.5 cm (P = .0001) and hyperlipidemia (P = .0321) were positively correlated with fast expansion. On univariate analysis, only aneurysm size and expansion rate were significant predictors of rupture. On multivariate analysis, aneurysm expansion rate was the sole independent risk factor of aneurysm rupture (odds ratio, 1.43; 95% confidence interval, 1.06-1.92; P = .018). CONCLUSIONS: Aneurysm expansion rate >5.5 mm/y is a significant rupture predictor in addition to size compared with aneurysm morphology and other demographic factors. Aneurysm size >6.5 mm and hyperlipidemia are determining factors of expansion rate. These may have implications in selection of patients for surgery. Better control of hyperlipidemia may alleviate the risk of rupture. PMID- 26926930 TI - Prospective evaluation of postimplantation syndrome evolution on patient outcomes after endovascular aneurysm repair for abdominal aortic aneurysm. AB - OBJECTIVE: This study prospectively investigated the association of postimplantation syndrome (PIS) with the clinical outcome during the first year after endovascular aneurysm repair (EVAR) for abdominal aortic aneurysm and assessed the evolution of the inflammatory response as outlined from specific inflammatory markers. METHODS: The study prospectively included 182 consecutive patients treated electively by EVAR for abdominal aortic aneurysm from January 2010 to January 2013. PIS was defined according to systemic inflammatory response syndrome criteria. Patients were monitored for 1 year. Adverse events included any major adverse cardiovascular events (MACE), acute renal failure, readmission, and death from any cause. RESULTS: PIS was diagnosed in 65 patients (35.7%). White blood cell count, high-sensitivity C-reactive protein, and interleukin 6 were significantly higher in the PIS group during the postoperative period (P < .001). At the 1-year follow-up, high-sensitivity C-reactive protein (P = .99) and interleukin 6 (P = .17) were attenuated toward the values of the non-PIS group. The white blood cell count (P = .02) remained higher in the PIS group, although within the normal reference range. During the follow-up period, MACE and adverse events occurred, respectively, in 17.2% and in 18.8% of patients in the PIS group and in 4.3% and 5.1% of the non-PIS group. The occurrence of PIS was the only independent predictor of a MACE (P = .007) or an adverse event (P = .005) during the follow-up period. CONCLUSIONS: The inflammatory response after EVAR is attenuated after the first postoperative month, as shown by the kinetics of several inflammatory biomarkers. However, PIS seems to correlate with the presence of a cardiovascular or any other adverse event during the first year after EVAR. Further studies should focus on whether a change in care is needed to ameliorate the higher cardiovascular risk of PIS patients. PMID- 26926931 TI - Outcomes of Endurant stent graft in narrow aortic bifurcation. AB - OBJECTIVE: The purpose of this study was to compare the outcomes obtained with Endurant stent graft in the early and midterm period in the treatment of patients with narrow aortic bifurcation vs patients with standard aortic bifurcation. METHODS: Data were prospectively collected from 817 patients with abdominal aortic aneurysm treated between November 2007 and August 2014 with the Endurant stent graft at our center. There were 87 patients (10.6%) with a narrow aortic bifurcation (<=20 mm; NA group). The remaining 730 patients (89.4%) had a standard aortic bifurcation (SA group). Early and estimated 3-year outcomes were evaluated in these patients in terms of survival, freedom from any device-related reinterventions, and freedom from graft thrombosis. Univariate and multivariate analyses in the NA group were performed to detect possible predictors for poor outcomes. RESULTS: The two groups were similar in terms of demographics, preoperative diagnostic assessment, and intraoperative data. In 211 of 817 patients (25.8%), an adjunctive iliac limb stenting by balloon-expanding stents was performed. Overall, 41 patients in the NA group (47.1%) underwent iliac limb stenting, whereas an iliac stent was implanted in just 170 patients (23.3%) in the SA group (P < .001). The mean follow-up was 16.3 months (range, 1-73 months). The estimated 3-year survival rate was similar between the two groups (87.2% in the NA group vs 80.8% in the SA group; P = .84). Furthermore, the estimated freedom from any device-related reinterventions was 92.9% in the NA group and 85.5% in the SA group (P = .1). Finally, the estimated 3-year freedom from graft thrombosis was 96.9% in the NA group and 94.8% in the SA group (P = .79). In the NA group at univariate and multivariate analyses, none of the examined preoperative or intraoperative factors were independent predictors of poor outcomes. CONCLUSIONS: Use of bifurcated Endurant stent graft, combined in almost half of the patients with narrow aortic bifurcation with additional aortoiliac stent placement, is feasible and safe. Early and midterm outcomes are similar to those obtained in non-narrow aortic bifurcation. PMID- 26926932 TI - Validation of a modified Frailty Index to predict mortality in vascular surgery patients. AB - BACKGROUND: Patient frailty has been implicated as a predictor of poor patient outcomes; however, there is no consensus on how to define or quantify frailty to assess perioperative risk. A previously described modified Frailty Index (mFI) has been shown to predict adverse outcomes after selected vascular surgical procedures, but no studies to date have compared its utility against other recognized risk indices in specific populations of vascular surgery patients. METHODS: National Surgical Quality Improvement Program data were reviewed for all patients undergoing carotid revascularization, abdominal aortic aneurysm (AAA) repair, and lower extremity revascularization for peripheral arterial disease (PAD) from 2006 to 2012. Patients were then further stratified into "open" and "endovascular" cohorts. The mFI was compared with the Lee Cardiac Risk Index (LCRI) and the American Society of Anesthesiologists (ASA) Physical Status Classification using a receiver operating characteristic area under curve (AUC). The primary end point was 30-day mortality, with a secondary end point of Clavien Dindo class IV complications. RESULTS: A total of 72,106 patients were identified in the study period, with 40,931 (56.8%), 20,975 (29.1%), and 10,200 (14.1%) in the carotid, AAA, and PAD populations, respectively. For carotid endarterectomy, mFI demonstrated better discrimination regarding mortality than LCRI and ASA, with an AUC of 0.66 (95% confidence interval [CI], 0.63-0.70; P < .01 vs P = .65 and P = .60, respectively). The open AAA cohort had similar findings, with an AUC of 0.63 (95% CI, 0.59-0.67; P = .02 vs P = .58, and P = .58, respectively). In open PAD patients, mFI was comparable to ASA (AUC, 0.64 [95% CI 0.60-0.69] vs 0.65), with a trend toward better discrimination compared with the 0.60 AUC of LCRI (P = .08). The mFI was a better discriminator of class IV complications than LCRI and ASA after open AAA (AUC for mFI, 0.59 vs 0.56 and 0.55; 95% CI, 0.57 0.61; P < .01) and endovascular AAA repair (AUC for mFI, 0.60 vs 0.59 and 0.57; 95% CI, 0.58-0.62; P = .01). There were no significant differences in discrimination of class IV complications after open or endovascular PAD or carotid endarterectomy. CONCLUSIONS: The mFI was a better discriminator of mortality than other risk indices; however this was only significant for the open cohort. The mFI was also a better discriminator of class IV complications for the open and endovascular AAA repair groups. These data suggest that mFI should be used in place of previously recognized risk indices to define perioperative mortality after open vascular surgery and risk of major complications after aneurysm repair. PMID- 26926933 TI - Morphologic findings and management strategy of spontaneous isolated dissection of the celiac artery. AB - OBJECTIVE: We report the morphologic findings and treatment of spontaneous isolated dissection of the celiac artery (SIDCA). METHODS: Twenty-three patients with SIDCA presenting between January 2009 and December 2014 were enrolled in this retrospective study. The demographic data, clinical features, morphologic findings, treatment modalities, and follow-up results of these patients were reviewed. We proposed a morphologic classification for SIDCA similar to that of spontaneous isolated dissection of the superior mesenteric artery. RESULTS: Initially, 11 patients were treated endovascularly, and 12 were treated medically. Four patients treated medically had an aggravation of the dissection and needed endovascular salvage. All patients recovered successfully. None of the patients developed abdominal pain, required reintervention, or died. In the medically treated group, the false lumen was completely thrombosed and absorbed in 4 patients, partially thrombosed in 2, and patent in 2. All stents were patent with the false lumen completely thrombosed and absorbed in the endovascular group. CONCLUSIONS: SIDCA can be treated medically in stable patients but requires intensive follow-up. Endovascular therapy can be applied in high-risk patients with recurrent symptoms, visceral malperfusion, or aneurysm. Open surgery should be considered if endovascular repair is not suitable or has failed. The short-term results of endovascular management are encouraging but further evaluation with long-term follow-up is necessary. PMID- 26926934 TI - Tibial and peroneal bypasses in octogenarians and nonoctogenarians with critical limb ischemia. AB - BACKGROUND: Elderly patients with critical limb ischemia are increasingly treated through interventional therapy. The outcome of tibial and peroneal bypasses in octogenarians who were unsuitable for endovascular therapy remains unclear. METHODS: We conducted a retrospective analysis of all patients who underwent tibial or peroneal bypass surgery in our clinic between October 2007 and April 2015. In Group 1 we included all patients 80 years and older and in group 2 all patients under 80 years. Vein was used whenever possible (diameter not less than 3 mm, not more than two segments for sufficient length). Study end points were primary and secondary patency, limb salvage and survival after 3 years. RESULTS: Indications were rest pain in 32.2% and ulcer and gangrene in 67.8%. There were 92 cases in Group 1 (median age, 85 years) and 178 in group 2 (median age, 70 years). Risk factors and indications were similar in both groups except for gender, renal insufficiency and smoking. 30-day mortality was 9.7% in group 1 and 1.1% in group 2 (P = .001). There was no significant difference in 30-day graft failure and major amputation. At 3 years primary patency in group 1 was 58.9% vs 49.7% (P = .058), secondary patency was 73.0% vs 54.7% (P = .007). Limb salvage was 80.1% in group 1 vs 73.0% in group 2 (P = .446), survival was 44.0% vs 71.2% (P = .000). CONCLUSIONS: Our analysis showed good results in octogenarians undergoing tibial and peroneal bypass surgery with regard to patency rates and limb salvage. However, octogenarians had a significantly higher perioperative mortality rate. PMID- 26926935 TI - International experience with endovascular therapy of the ascending aorta with a dedicated endograft. AB - OBJECTIVE: The objective of this study was to evaluate the safety and feasibility of a novel stent graft specifically designed for treatment of the ascending aorta. METHODS: This was a multicenter, retrospective analysis of all consecutive patients treated with the dedicated Zenith Ascend TAA Endovascular Graft (William Cook Europe, Bjaeverskov, Denmark) for pathologic processes requiring stent grafting of the ascending aorta. The graft is short (6.5 cm), with a delivery system designed for transfemoral placement in the ascending aorta. RESULTS: In 10 patients (five men; age, 67 years; range, 26-90 years), the Zenith Ascend graft was implanted for the following indications: dissection (n = 5) and aneurysm (n = 4) of the ascending aorta and fixation of an intraprocedural dislocated aortic valve (n = 1). All patients were judged to be at high risk for open surgery (nine patients were classified as American Society of Anesthesiologists class 3 or class 4). A transfemoral approach was selected in eight cases and a transapical approach in two. All endografts were successfully deployed without intraoperative adverse events at the targeted landing zone. Clinical success in coverage of the lesions was achieved in all cases with the exception of an attempted treatment of an intraprocedural aortic valve implantation dissection that resulted in early mortality. The 30-day survival was 90%. Early neurologic events included one patient with stroke and paraplegia and one patient with a transient ischemic attack. One patient underwent early evacuation of a hemopericardium. There were two late reinterventions for persisting endoleaks. At a mean follow-up of 10 months (range, 1-36 months), three late deaths occurred, with one treatment related, as a result of graft infection. CONCLUSIONS: Despite the fact that in this first published series the graft was frequently used as a "rescue tool" outside its intended indication, treatment with the Zenith Ascend graft in this early experience appears to be safe and feasible for repair of ascending aorta pathologic processes in high-risk patients unsuitable for open repair. PMID- 26926936 TI - The impact of exposure technique on perioperative complications in patients undergoing elective open abdominal aortic aneurysm repair. AB - OBJECTIVE: The objective of this study was to evaluate the impact of exposure technique on perioperative complications in patients undergoing elective open abdominal aortic aneurysm (AAA) repair. METHODS: Using the Society for Vascular Surgery Vascular Quality Initiative database, the study identified patients subjected to open AAA repair from January 2003 to July 2014 and divided them into two aortic exposure groups, retroperitoneal (RP) and transperitoneal (TP). Multivariable analysis was performed to compare the incidence of cardiac events (myocardial infarction, dysrhythmia, heart failure), prolonged intubation, renal dysfunction, and mortality, adjusting for between-group differences identified on univariate analysis. RESULTS: Open AAA repair was performed in 3530 patients, using RP in 26% and TP in 74%. The RP group had a higher rate of suprarenal aortic clamp (60.9% vs 30.2%; P < .001), higher proportion of high-risk patients as stratified by the Vascular Study Group of New England Cardiac Risk Index (25.6% vs 22.2%; P = .038), and lower rate of iliac aneurysms (18.0% vs 31.2%; P < .001). After multivariable analysis, RP was associated with a lower incidence of cardiac events (12.2% vs 16.0%; adjusted odds ratio, 0.60; 95% confidence interval, 0.41-0.88; P = .009) and renal dysfunction (13.3% vs 16.5%; adjusted odds ratio, 0.65; 95% confidence interval, 0.46-0.97; P = .011). No difference in respiratory complications or mortality was identified. CONCLUSIONS: Despite increased utilization of suprarenal aortic clamp during elective open AAA repair, the RP technique was associated with a lower risk-adjusted incidence of cardiac and renal complications compared with the TP technique. PMID- 26926937 TI - Outcomes of interventions for carotid blowout syndrome in patients with head and neck cancer. AB - BACKGROUND: The purpose of this study was to examine outcomes of a patient cohort undergoing intervention for carotid blowout syndrome associated with head and neck cancer. METHODS: Patients with head and neck cancer who presented with carotid distribution bleeding from 2000 to 2014 were identified in the medical record. Primary outcomes were short- and midterm mortality and recurrent bleeding. Standard statistical methods and survival analysis were used to analyze study population characteristics and outcomes. RESULTS: Thirty-seven patients were included in the study. The mean age was 60.1 +/- 11.4 years (74% male). All malignancies were squamous cell type, stage IV, in a variety of primary locations: 32% oral cavity, 24% larynx, 16% superficial neck, with the remainder in the oropharynx, nasopharynx, and hypopharynx. Fifty-one percent of bleeds were of common carotid, 29% external carotid, and 19% internal carotid origin. Among the patients, 68% presented with acute hemorrhage, 24% with impending bleed, and 8% with threatened bleed. All patients underwent intervention: 38% received endovascular coil embolization, 30% stent grafts, 22% surgical ligation, and 10% primary vessel repair or bypass grafting. Although major complications were rare, 10.8% of patients had perioperative stroke. Sixteen recurrent bleeding episodes involving 12 arteries occurred in 11 patients (29.73%). Median rebleeding time was 7 days (interquartile range, 6-49). Estimated recurrent bleeding risk at 30 days and 6 months was 24% and 34%, respectively. Of the patients, 91.9% survived to hospital discharge. The 90-day and 1-year estimated survivals were 60.9% and 36.6%, respectively. CONCLUSIONS: Carotid blowout syndrome associated with head and neck cancer carries poor mid- and long-term prognoses; however, mortality may be related more to the advanced stage of disease rather than carotid involvement or associated intervention. Both surgical and endovascular approaches may be efficacious in cases of acute hemorrhage but carry a significant risk of periprocedural stroke and recurrent bleeding. PMID- 26926938 TI - Feasibility of endovascular repair of ascending aortic pathologies as part of an FDA-approved physician-sponsored investigational device exemption. AB - OBJECTIVE: Endovascular treatment of ascending aortic lesions has been reported, but to date, no FDA-approved studies have been conducted to define feasibility and the use of endografts in this particular location or to analyze the critical factors involved. METHODS: Patients were consented for entry into an FDA-approved physician-sponsored investigational device exemption study to investigate the outcome of those with ascending aortic pathologies. These patients were suitable according to the instructions for use for endovascular repair with a Valiant Captivia (Medtronic, Inc, Minneapolis, Minn) thoracic stent graft, a device designed specifically for deployment in the ascending aorta. All patients had sequential gated-cardiac computed tomography scans, with data being entered into the VQI Complex TEVAR software (West Lebanon, NH). All procedures were performed in a hybrid room, with the capability to convert to an open repair to ensure maximal patient protection. The first five patients constituted the feasibility study, with continued enrollment based on initial results and submission of an annual report to the FDA. RESULTS: Thirty-nine patients were screened, and six patients were entered into the physician-sponsored investigational device exemption study. Although there was no early mortality, there was one late death. All patients had sequential computed tomographies and cardiac echocardiograms with no evidence of migration, one type 1a endoleak, one postoperative stroke, and regression of the aortic lesions in the excluded aortic segment. CONCLUSIONS: In this feasibility study, the preliminary evaluation of endovascular treatment for ascending aortic pathologies demonstrates uniform accuracy of deployment and secure fixation up to 17.5 months of follow-up. There is positive remodeling of the excluded aortic segments similar to surveillance studies involving the descending aorta. PMID- 26926939 TI - Preoperative risk prediction of surgical site infection requiring hospitalization or reoperation in patients undergoing vascular surgery. AB - OBJECTIVE: The objective of this study was to develop a surgical site infection (SSI) prediction score for risk assessment before elective vascular surgery. METHODS: We conducted a nested case-control study among patients who underwent elective vascular (abdominal aortic and peripheral arterial) surgery from January 1, 2003, to December 31, 2007, at Mayo Clinic (Rochester, Minn) an academic tertiary surgical center. Cases were patients with SSI requiring hospitalization; controls (one or two per case) were matched on type of procedure and date of surgery. Clinical data were collected by chart review. A risk score based on preoperative variables was developed using multivariable logistic regression and bootstrap resampling. The C statistic, equivalent to the area under the receiver operating characteristic curve, was used to assess discrimination. Calibration was assessed by plotting percentile risk groups of model-predicted values against observed proportions of subjects with SSI. RESULTS: Eighty-four cases were compared with 160 controls. Preoperative variables independently associated with SSI risk were critical limb ischemia, previous SSI, prior revascularization procedure, and chronic obstructive pulmonary disease. A prediction model containing these variables was developed (model and risk score C statistic of 0.737 and 0.727, respectively). The calibration curve did not appear to deviate appreciably from the 45-degree line of identity. CONCLUSIONS: We developed an SSI risk score based on noninvasive preoperative variables with acceptable discrimination and calibration. This tool needs prospective and external validation. PMID- 26926940 TI - The Gore Hybrid Vascular Graft in renovisceral debranching for complex aortic aneurysm repair. AB - OBJECTIVE: This study reports our initial experience with the Gore Hybrid Vascular Graft (GHVG; W. L. Gore & Associates, Flagstaff, Ariz) for staged hybrid open renovisceral debranching and endovascular aneurysm repair in patients affected by thoracoabdominal aortic aneurysms and pararenal abdominal aortic aneurysms (PAAAs). METHODS: Between December 2012 and December 2013, we analyzed outcomes of 13 patients who underwent open surgical debranching of renovisceral vessels for thoracoabdominal aortic aneurysm and PAAAs. All patients were considered at high risk for conventional surgery. Inclusion criterion was treatment by open surgical debranching of at least one visceral artery (renal artery, superior mesenteric artery [SMA], or celiac trunk [CT]) using the GHVG. In a second step, the aortic stent graft was implanted to exclude the aneurysm. If required, parallel grafts to the remaining visceral arteries were deployed in the same procedure. One patient had a symptomatic descending thoracic aortic aneurysm and another had a ruptured PAAA. Perioperative measured outcomes were immediate technical success rate, mortality, and morbidity. Median follow-up was 24.8 months (range, 0-15; mean, 8.2; standard deviation, 4 months). RESULTS: All open surgical debranching of renovisceral vessels were completed as intended. GHVG was used to revascularize 20 visceral vessels in 13 patients with a mean of 1.54 vessels per patient. Six renal arteries (30%; 2 right and 4 left), 9 SMAs (45%), and 5 CTs (25%) were debranched. In nine of 13 (66%) patients, other renovisceral arteries were addressed with chimney/periscope, Viabahn Open Revascularization Technique, and end-to-side anastomosis. Two of 13 patients (15%) died of bowel ischemia. Neither patient had GHVG revascularization to the SMA or CT. Perioperative complications occurred in three patients (23%; 1 renal hematoma, 1 respiratory insufficiency, and 1 small-bowel ischemia related to a SMA GHVG thrombosis). At 24 months, estimated survival was 85%, and estimated primary and secondary patency were 94% and 100%, respectively. CONCLUSIONS: This limited series extracted from a more consistent hybrid procedure experience showed a mortality rate similar to most recent reports. Technical feasibility and the short-term patency rate of the GHVG for renovisceral debranching during staged hybrid open and endovascular procedures were satisfactory. Use of GHVGs may represent a useful revascularization adjunct to minimize visceral ischemia in these challenging patients. PMID- 26926941 TI - Injury grade is a predictor of aortic-related death among patients with blunt thoracic aortic injury. AB - OBJECTIVE: The current Society for Vascular Surgery Clinical Practice Guidelines suggest urgent (<24 hours) thoracic endovascular aortic repair for grade (G) II to G IV blunt thoracic aortic injuries (BTAIs). The purpose of this study was to determine whether some patients may require more emergency treatment. METHODS: We reviewed imaging variables of prospectively collected BTAI patients between 1999 and 2014. We used computed tomographic angiography to classify BTAIs into four categories: G I, intimal tear; G II, intramural hematoma; G III, aortic pseudoaneurysm; and G IV, free rupture. Specific examination of G III injuries was undertaken in an effort to predict aortic-related mortality (ARM) before repair. For this subset, we examined pseudoaneurysm size, lesion/normal aortic diameter ratio, and mediastinal hematoma location and size. RESULTS: Among 331 patients with BTAIs, 86 died before imaging. Admission computed tomographic angiography was available for 205 patients (71.2% male; mean age, 39.3 years) with BTAIs (24 G I, 49 G II, 124 G III, 8 G IV). The mean Injury Severity Score was 35.6, and 22.4% had hypotension (<90 mm Hg). Overall mortality was 11.2% (G I/G II, 4.1%; G III/G IV, 15.3%; P = .02). ARM was 2.4% (G I/G II, 0%; G III/G IV, 3.8%; P = .09). ARM was significantly greater in G IV (3 of 8 [37.5%]) than G III (2 of 124 [1.6%]) vs G I/II (0 of 73 [0%]) injuries (P < .0001). Medical management alone was used in 53 (20 G I, 18 G II, 13 G III, and 2 G IV). Open repair was performed in 51 (3 G I, 9 G II, 36 G III, and 3 G IV) at a mean time to repair (TTR) of 10.6 hours. Thoracic endovascular aortic repair was conducted for 101 patients (1 G I, 22 G II, 75 G III, and 3 G IV) at a mean TTR of 9.4 hours. Median TTR for the overall population of BTAI patients was 24.0 hours from admission. (G I, 64.5 hours; G II, 24.0 hours; G III, 19.7 hours; and G IV, 3.5 hours). ARM occurred in four of five patients before planned repair (2 G III and 2 G IV), 7.0 +/- 3.6 hours from admission. No G I/II ARM occurred. Among eight G IV injuries, there were three ARMs. Focus on G III injuries through regression analysis demonstrated that early clinical/imaging variables (eg, mediastinal hematoma dimensions and lesion/normal aortic diameter ratio) were not significant predictors of ARM. CONCLUSIONS: Injury grade is a predictor of ARM among patients with BTAIs. Aggressive use of the current Society for Vascular Surgery Clinical Practice Guidelines at a busy level I trauma center resulted in low rates of ARM. In this setting, identification of additional physiologic and radiographic criteria indicating the need for emergency (vs urgent) repair of aortic pseudoaneurysms remains elusive. PMID- 26926943 TI - Near-Infrared Fluorescence Probe for in Situ Detection of Superoxide Anion and Hydrogen Polysulfides in Mitochondrial Oxidative Stress. AB - H2S plays important physiological and pathological roles in the cardiovascular system and nervous system. However, recent evidence imply that hydrogen polysulfides (H2Sn) are the actual signaling molecules in cells. Although H2Sn have been demonstrated to be responsible for mediating tumor suppressors, ion channels, and transcription factors, more of their biological effects are still need to be elaborated. On one hand, H2Sn have been suggested to be generated from endogenous H2S upon reaction with reactive oxygen species (ROS). On the other hand, H2Sn derivatives are proposed to be a kind of direct antioxidant against intracellular oxidative stress. This conflicting results should be attributed to the regulation of redox homeostasis between ROS and H2Sn. Superoxide anion (O2(* )) is undoubtedly the primary ROS existing in mitochondria. We reason that the balance of O2(*-) and H2Sn are pivotal in physiological and pathological processes. Herein, we report two near-infrared fluorescent probes Hcy-Mito and Hcy-Biot for the detection of O2(*-) and H2Sn in cells and in vivo. Hcy-Mito is conceived to be applied in mitochondria, and Hcy-Biot is designed to target tumor tissue. Both of the probes were successfully applied for visualizing exogenous and endogenous O2(*-) and H2Sn in living cells and in tumor mice models. The results demonstrate that H2Sn can be promptly produced by mitochondrial oxidative stress. Flow cytometry assays for apoptosis suggest that H2Sn play critical roles in antioxidant systems. PMID- 26926942 TI - Implementation and Operational Research: Evaluation of a Public-Sector, Provider Initiated Cryptococcal Antigen Screening and Treatment Program, Western Cape, South Africa. AB - BACKGROUND: Screening for serum cryptococcal antigen (CrAg) may identify those at risk for disseminated cryptococcal disease (DCD), and preemptive fluconazole treatment may prevent progression to DCD. In August 2012, the Western Cape Province (WC), South Africa, adopted provider-initiated CrAg screening. We evaluated the implementation and effectiveness of this large-scale public-sector program during its first year, September 1, 2012-August 31, 2013. METHODS: We used data from the South African National Health Laboratory Service, WC provincial HIV program, and nationwide surveillance data for DCD. We assessed the proportion of eligible patients screened for CrAg (CrAg test done within 30 days of CD4 date) and the prevalence of CrAg positivity. Incidence of DCD among those screened was compared with those not screened. RESULTS: Of 4395 eligible patients, 26.6% (n = 1170) were screened. The proportion of patients screened increased from 15.9% in September 2012 to 36.6% in August 2013. The prevalence of positive serum CrAg was 2.1%. Treatment data were available for 13 of 24 CrAg positive patients; 9 of 13 were treated with fluconazole. Nine (0.8%) incident cases of DCD occurred among the 1170 patients who were screened for CrAg vs. 49 (1.5%) incident cases among the 3225 patients not screened (P = 0.07). CONCLUSIONS: Relatively few eligible patients were screened under the WC provider initiated CrAg screening program. Unscreened patients were nearly twice as likely to develop DCD. CrAg screening can reduce the burden of DCD, but needs to be implemented well. To improve screening rates, countries should consider laboratory-based reflexive screening when possible. PMID- 26926944 TI - Recent expansion and relic survival: Phylogeography of the land snail genus Helix (Mollusca, Gastropoda) from south to north Europe. AB - Little is known about the evolutionary history of Helix, despite the fact that it includes the largest land snails in the western Palaearctic, some of which (e.g. H. pomatia Linnaeus, 1758) are valuable human food. We compared two groups of Helix with apparently contrasting evolutionary histories: the widespread species H. pomatia and the group distributed along the Italian Apennine chain, a relatively unknown set of species with a restricted distribution over a range of altitudes. To reconstruct the evolutionary trajectories of these two groups, we analysed morphological (shell and genitalia) and molecular characters (mitochondrial and nuclear markers) in a total of 59 populations from northern and central Europe (H. pomatia) and along the Apennine chain (various species). We also reconstructed the phylogeny and the evolutionary history of the genus by combining our data with that currently available in the literature. We found that spatial changes did not merely imply fragmentation of populations, but also implied environmental changes (woodlands vs. grasslands) that may have triggered the observed phenotypic diversification. We also found that Anatolia is the ancestral range of Helix and is therefore an important area for the Palaearctic diversity. The results provide insights into the evolutionary history of species richness and more generally into the processes that may have shaped the distribution and diversification of these organisms across Europe and the peri Mediterranean area. PMID- 26926945 TI - Contrasting evolutionary patterns of 28S and ITS rRNA genes reveal high intragenomic variation in Cephalenchus (Nematoda): Implications for species delimitation. AB - Concerted evolution is often assumed to be the evolutionary force driving multi family genes, including those from ribosomal DNA (rDNA) repeat, to complete homogenization within a species, although cases of non-concerted evolution have been also documented. In this study, sequence variation of 28S and ITS ribosomal RNA (rRNA) genes in the genus Cephalenchus is assessed at three different levels, intragenomic, intraspecific, and interspecific. The findings suggest that not all Cephalenchus species undergo concerted evolution. High levels of intraspecific polymorphism, mostly due to intragenomic variation, are found in Cephalenchus sp1 (BRA-01). Secondary structure analyses of both rRNA genes and across different species show a similar substitution pattern, including mostly compensatory (CBC) and semi-compensatory (SBC) base changes, thus suggesting the functionality of these rRNA copies despite the variation found in some species. This view is also supported by low sequence variation in the 5.8S gene in relation to the flanking ITS-1 and ITS-2 as well as by the existence of conserved motifs in the former gene. It is suggested that potential cross-fertilization in some Cephalenchus species, based on inspection of female reproductive system, might contribute to both intragenomic and intraspecific polymorphism of their rRNA genes. These results reinforce the potential implications of intragenomic and intraspecific genetic diversity on species delimitation, especially in biodiversity studies based solely on metagenetic approaches. Knowledge of sequence variation will be crucial for accurate species diversity estimation using molecular methods. PMID- 26926946 TI - A new method for studying the evolutionary origin of the SAR11 clade marine bacteria. AB - The free-living SAR11 clade is a globally abundant group of oceanic Alphaproteobacteria, with small genome sizes and rich genomic A+T content. However, the taxonomy of SAR11 has become controversial recently. Some researchers argue that the position of SAR11 is a sister group to Rickettsiales. Other researchers advocate that SAR11 is located within free-living lineages of Alphaproteobacteria. Here, we use the natural vector representation method to identify the evolutionary origin of the SAR11 clade. This alignment-free method does not depend on any model assumptions. With this approach, the correspondence between proteome sequences and their natural vectors is one-to-one. After fixing a set of proteins, each bacterium is represented by a set of vectors. The Hausdorff distance is then used to compute the dissimilarity distance between two bacteria. The phylogenetic tree can be reconstructed based on these distances. Using our method, we systematically analyze four data sets of alphaproteobacterial proteomes in order to reconstruct the phylogeny of Alphaproteobacteria. From this we can see that the phylogenetic position of the SAR11 group is within a group of other free-living lineages of Alphaproteobacteria. PMID- 26926947 TI - Population genetic analysis of a medicinally significant Australian rainforest tree, Fontainea picrosperma C.T. White (Euphorbiaceae): biogeographic patterns and implications for species domestication and plantation establishment. AB - BACKGROUND: Fontainea picrosperma, a subcanopy tree endemic to the rainforests of northeastern Australia, is of medicinal significance following the discovery of the novel anti-cancer natural product, EBC-46. Laboratory synthesis of EBC-46 is unlikely to be commercially feasible and consequently production of the molecule is via isolation from F. picrosperma grown in plantations. Successful domestication and plantation production requires an intimate knowledge of a taxon's life-history attributes and genetic architecture, not only to ensure the maximum capture of genetic diversity from wild source populations, but also to minimise the risk of a detrimental loss in genetic diversity via founder effects during subsequent breeding programs designed to enhance commercially significant agronomic traits. RESULTS: Here we report the use of eleven microsatellite loci (PIC = 0.429; P ID = 1.72 * 10(-6)) to investigate the partitioning of genetic diversity within and among seven natural populations of F. picrosperma. Genetic variation among individuals and within populations was found to be relatively low (A = 2.831; H E = 0.407), although there was marked differentiation among populations (PhiPT = 0.248). Bayesian, UPGMA and principal coordinates analyses detected three main genotypic clusters (K = 3), which were present at all seven populations. Despite low levels of historical gene flow (N m = 1.382), inbreeding was negligible (F = -0.003); presumably due to the taxon's dioecious breeding system. CONCLUSION: The data suggests that F. picrosperma was previously more continuously distributed, but that rainforest contraction and expansion in response to glacial-interglacial cycles, together with significant anthropogenic effects have resulted in significant fragmentation. This research provides important tools to support plantation establishment, selection and genetic improvement of this medicinally significant Australian rainforest species. PMID- 26926948 TI - Syncope and the Risk of a Subsequent Motor Vehicle Crash. PMID- 26926949 TI - Comparison of pure Holsteins to crossbred Holsteins with Norwegian Red cattle in first and second generations. AB - A total of 1922 first generation crossbred cows born between 2005 and 2012 produced by inseminating purebred Israeli Holstein cows with Norwegian Red semen, and 7487 purebred Israeli Holstein cows of the same age in the same 50 herds were analyzed for production, calving traits, fertility, calving diseases, body condition score, abortion rate and survival under intensive commercial management conditions. Holstein cows were higher than crossbreds for 305-day milk, fat and protein production. Differences were 764, 1244, 1231 for kg milk; 23.4, 37.4, 35.6 for kg fat, and 16.7, 29.8, 29.8 for kg protein; for parities 1 through 3. Differences for fat concentration were not significant; while crossbred cows were higher for protein concentration by 0.06% to 0.08%. Differences for somatic cells counts were not significant. Milk production persistency was higher for Holstein cows by 5, 8.3 and 8% in parities 1 through 3. Crossbred cows were higher for conception status by 3.1, 3.6 and 4.7% in parities 1 through 3. Rates of metritis for Holsteins were higher than the crossbred cows by 7.8, 4.6 and 3.4% in parities 1 to 3. Differences for incidence of abortion, dystocia, ketosis and milk fever were not significant. Holstein cows were lower than crossbred cows for body condition score for all three parities, with differences of 0.2 to 0.4 units. Contrary to comparisons in other countries, herd-life was higher for Holsteins by 79 days. A total of 6321 Holstein cows born between 2007 and 2011 were higher than 765 progeny of crossbred cows backcrossed to Israeli Holsteins of the same ages for milk, fat and protein production. Differences were 279, 537, 542 kg milk; 10.5, 17.7, 17.0 kg fat and 6.2, 12.9, 13.2 kg protein for parities 1 through 3. Differences for fat concentration were not significant, while backcross cows were higher for protein percentage by 0.02% to 0.04%. The differences for somatic cell score, conception rate, and calving diseases other than metritis, were not significant. Holstein cows were lower than backcross cows by 1.5% to 2.5% for conception status in parities 1 to 3 and lower for body condition score for parities 1 and 2, with differences in the range of 0.06 to 0.09 units. Culling rates were higher, and herd-life lower for the crossbred cows. The gains obtained in secondary traits for crossbred cows did not compensate for the major reduction in production. PMID- 26926950 TI - The low density lipoprotein receptor-related protein (LRP) 1 and its function in lung diseases. AB - The low density lipoprotein receptor-related protein (LRP) 1 is a ubiquitously expressed, versatile cell surface transmembrane receptor involved in embryonic development and adult tissue homeostasis. LRP1 binds and endocytoses a broad spectrum of over 40 ligands identified thus far, including lipoproteins, extracellular matrix proteins, proteases and protease/inhibitor complexes and growth factors. Interactions with other membrane receptors and intracellular adaptors/scaffolding proteins allow LRP1 to modulate cell migration, survival, proliferation and (trans) differentiation. Because LRP1 displays a wide-range of interactions and activities, its expression and function is temporally and spatially tightly controlled. It is not, therefore, surprising that deregulation of LRP1 production and/or activity is observed in several diseases. In this review, we will systematically examine the evidence for the role of LRP1 in human pathologies placing special emphasis on LRP1-mediated pathogenesis of the lung. PMID- 26926951 TI - Net alveolar fluid clearance is associated with lung morphology phenotypes in acute respiratory distress syndrome. AB - BACKGROUND: The acute respiratory distress syndrome (ARDS) is a heterogeneous syndrome that encompasses multiple phenotypes, e.g. with regards to lung morphology as assessed by computed tomography (CT). Focal or non-focal lung morphology may influence the response to positive end-expiratory pressure (PEEP), recruitment manoeuvres and prone position. Lung morphology has been hypothesized to be associated with alveolar fluid clearance (AFC), thus explaining various responses to such therapeutic interventions; however, this hypothesis has not been specifically studied in humans. METHODS: We measured net AFC rates in 30 patients with ARDS as a secondary data analysis of a prospective single-centre study. Net AFC rates were compared between patients with focal ARDS and those with non-focal ARDS, as assessed by lung CT-scans. RESULTS: Net AFC rates were significantly lower in patients with non-focal ARDS (n=23; median [interquartile range], 1.5 [0-5.5] %/h) as compared to those with focal ARDS (n=7; 10.3 [4.5-15] %/h) (P=0.01). The area under the receiver-operating characteristic curve when net AFC rates were used to differentiate the presence from absence of non-focal ARDS was 0.93 (95% confidence interval, 0.81-1). Tidal volumes and PEEP levels differed between focal and non-focal ARDS patients, but there was no difference in arterial oxygenation or in alveolar-capillary permeability. CONCLUSIONS: Non focal lung morphology may be characterized by a functional endotype consistent with marked AFC impairment. Despite study limitations and the need for validating studies in larger cohorts, such novel findings may reinforce our understanding of the association between ARDS phenotypes and therapeutic responses. PMID- 26926952 TI - Energetic and flexibility properties captured by long molecular dynamics simulations of a membrane-embedded pMHCII-TCR complex. AB - Although crystallographic data have provided important molecular insight into the interactions in the pMHC-TCR complex, the inherent features of this structural approach cause it to only provide a static picture of the interactions. While unbiased molecular dynamics simulations (UMDSs) have provided important information about the dynamic structural behavior of the pMHC-TCR complex, most of them have modeled the pMHC-TCR complex as soluble, when in physiological conditions, this complex is membrane bound; therefore, following this latter UMDS protocol might hamper important dynamic results. In this contribution, we performed three independent 300 ns-long UMDSs of the pMHCII-TCR complex anchored in two opposing membranes to explore the structural and energetic properties of the recognition of pMHCII by the TCR. The conformational ensemble generated through UMDSs was subjected to clustering and Cartesian principal component analyses (cPCA) to explore the dynamical behavior of the pMHCII-TCR association. Furthermore, based on the conformational population sampled through UMDSs, the effective binding free energy, per-residue free energy decomposition, and alanine scanning mutations were explored for the native pMHCII-TCR complex, as well as for 12 mutations (p1-p12MHCII-TCR) introduced in the native peptide. Clustering analyses and cPCA provide insight into the rocking motion of the TCR onto pMHCII, together with the presence of new electrostatic interactions not observed through crystallographic methods. Energetic results provide evidence of the main contributors to the pMHC-TCR complex formation as well as the key residues involved in this molecular recognition process. PMID- 26926953 TI - Establishment and characterisation of patient-derived xenografts as paraclinical models for gastric cancer. AB - The patient-derived xenograft (PDX) model is emerging as a promising translational platform to duplicate the characteristics of tumours. However, few studies have reported detailed histological and genomic analyses for model fidelity and for factors affecting successful model establishment of gastric cancer. Here, we generated PDX tumours surgically-derived from 62 gastric cancer patients. Fifteen PDX models were successfully established (24.2%, 15/62) and passaged to maintain tumours in immune-compromised mice. Diffuse type and low tumour cell percentage were negatively correlated with success rates (p = 0.005 and p = 0.025, respectively), while reducing ex vivo and overall procedure times were positively correlated with success rates (p = 0.003 and p = 0.01, respectively). The histology and genetic characteristics of PDX tumour models were stable over subsequent passages. Lymphoma transformation occurred in five cases (33.3%, 5/15), and all were in the NOG mouse, with none in the nude mouse. Together, the present study identified Lauren classification, tumour cell percentages, and ex vivo times along with overall procedure times, as key determinants for successful PDX engraftment. Furthermore, genetic and histological characteristics were highly consistent between primary and PDX tumours, which provide realistic paraclinical models, enabling personalised development of treatment options for gastric cancer. PMID- 26926954 TI - Enhanced flight performance by genetic manipulation of wing shape in Drosophila. AB - Insect wing shapes are remarkably diverse and the combination of shape and kinematics determines both aerial capabilities and power requirements. However, the contribution of any specific morphological feature to performance is not known. Using targeted RNA interference to modify wing shape far beyond the natural variation found within the population of a single species, we show a direct effect on flight performance that can be explained by physical modelling of the novel wing geometry. Our data show that altering the expression of a single gene can significantly enhance aerial agility and that the Drosophila wing shape is not, therefore, optimized for certain flight performance characteristics that are known to be important. Our technique points in a new direction for experiments on the evolution of performance specialities in animals. PMID- 26926955 TI - Increased MTHFR promoter methylation in mothers of Down syndrome individuals. AB - Despite that advanced maternal age at conception represents the major risk factor for the birth of a child with Down syndrome (DS), most of DS babies are born from women aging less than 35 years. Studies performed in peripheral lymphocytes of those women revealed several markers of global genome instability, including an increased frequency of micronuclei, shorter telomeres and impaired global DNA methylation. Furthermore, young mothers of DS individuals (MDS) are at increased risk to develop dementia later in life, suggesting that they might be "biologically older" than mothers of euploid babies of similar age. Mutations in folate pathway genes, and particularly in the methylenetetrahydrofolate reductase (MTHFR) one, have been often associated with maternal risk for a DS birth as well as with risk of dementia in the elderly. Recent studies pointed out that also changes in MTHFR methylation levels can contribute to human disease, but nothing is known about MTHFR methylation in MDS tissues. We investigated MTHFR promoter methylation in DNA extracted from perypheral lymphocytes of 40 MDS and 44 matched control women that coinceived their children before 35 years of age, observing a significantly increased MTHFR promoter methylation in the first group (33.3 +/- 8.1% vs. 28.3 +/- 5.8%; p=0.001). In addition, the frequency of micronucleated lymphocytes was available from the women included in the study, was higher in MDS than control mothers (16.1 +/- 8.60/00 vs. 10.5 +/- 4.30/00; p=0.0004), and correlated with MTHFR promoter methylation levels (r=0.33; p=0.006). Present data suggest that MTHFR epimutations are likely to contribute to the increased genomic instability observed in cells from MDS, and could play a role in the risk of birth of a child with DS as well as in the onset of age related diseases in those women. PMID- 26926956 TI - Fertility History and Cognition in Later Life. AB - Objectives: To investigate the association between fertility history and cognition in older men and women. Method: We analyzed associations between number of children (parity) and timing of births with level and change in cognition among 11,233 men and women aged 50+ in England using latent growth curve models. Models were adjusted for age, socioeconomic position, health, depressive symptoms, control, social contacts, activities, and isolation. Results: Low (0-1 child) and high parity (3+ children) compared to medium parity (2 children) were associated with poorer cognitive functioning, as was an early age at entry to parenthood (<20 women/23 men). Many of these associations disappeared when socioeconomic position and health were controlled. For women, however, adjusting for socioeconomic position and social contacts strengthened the association between childlessness and poor cognition. Late motherhood (>35) was associated with better cognitive function. Conclusion: Associations between fertility history and cognition were to large extent accounted for socioeconomic position, partly because this influenced health and social engagement. Poorer cognition in childless people and better cognition among mothers experiencing child birth at higher ages suggest factors related to childbearing/rearing that are beneficial for later cognitive functioning, although further research into possible earlier selection factors is needed. PMID- 26926957 TI - Life-Course Socioeconomic Status and Metabolic Syndrome Among Midlife Women. AB - OBJECTIVES: We examine whether women's risks of having metabolic syndrome (MetS) at pre/early-menopausal baseline, and of developing MetS after baseline, are associated with childhood and adult socioeconomic statuses (SESs); and whether the associations are mediated by adult reproductive, economic, behavioral, and psychosocial factors. METHOD: Using data on white and black women collected prospectively for 12 years in the Study of Women's Health Across the Nation, we estimated odds of MetS at pre/early-menopausal baseline with logistic regression, and incidence of MetS after baseline with Cox proportional hazards models. RESULTS: Women raised in "adverse" childhood SES had marginally greater odds of MetS at baseline than did women raised in "good" SES, and women with a high school credential or less had significantly greater odds than college-educated women, in mutually adjusted models. The elevated odds partly reflected SES related differences in exercise and alcohol consumption. Incidence after baseline was associated with education, not childhood SES, and partly mediated by health behaviors. Differences in the probability of surviving without MetS between the most and least socioeconomically advantaged women nearly doubled between ages 50 and 60. DISCUSSION: Childhood and adult SES predict women's risks of MetS as they approach the menopause transition; adult SES is primarily important afterwards. PMID- 26926958 TI - HOXB9 acts as a negative regulator of activated human T cells in response to amino acid deficiency. AB - T-cell activation is an energy expenditure process and should be properly controlled in accordance with the availability of nutrients such as amino acids to eliminate wasteful energy consumption. However, the details of response to amino acids insufficiency in activated T cells remain largely unknown. Here we show that homeobox B9 (HOXB9), a member of the homeobox gene family that is known as a morphogenesis regulator, acts as a suppressor of activated human T cells to address amino acid starvation. The expression of HOXB9 was triggered by amino acid deprivation as well as functional inhibition of L-type amino acid transporter 1 (also known as SLC7A5) via activating transcription factor 4 in activated T cells. HOXB9 interfered the activities of NF-kappaB, nuclear factor of activated T-cells (NFAT) and AP-1 but not retinoic acid receptor-related orphan receptor, resulting in attenuation of the production of selective cytokines in activated T cells. Thus, the morphogenetic gene plays an unexpected role in the regulation of cellular metabolism with changes in the nutrition status in human T cells. PMID- 26926959 TI - Magnetic graphene oxide based nano-composites for removal of radionuclides and metals from contaminated solutions. AB - Magnetic graphene oxide based composites of the nano-particle size of <10 nm were synthesized, characterized and used in sorption experiments. The adsorption of Cs(I), Co(II), Ni(II), Cu(II) and Pb(II) to nano-composites was studied in a wide range of initial concentrations and analyzed by Langmuir and Freundlich models. In addition, the effects of pH and coexisting ions on the adsorption of Cs to Prussian blue based composites were investigated. The maximum adsorption capacities of studied elements varied from 29 to 641 mg g-1. The obtained Langmuir and Freundlich constants indicated the dominating physisorption mechanism and favorable adsorption conditions. PMID- 26926960 TI - Estimating the terrestrial gamma dose rate by decomposition of the ambient dose equivalent rate. AB - An extensive network of dose rate monitoring stations continuously measures ambient dose rate across Europe, as part of the EURDEP system. Its purpose is early warning in radiological emergencies and documenting its temporal and spatial evolution. In normal conditions, when there is no contribution to the dose rate signal coming from fresh anthropogenic contamination, the data represent the radiation "background", i.e. the combined natural radiation and existing anthropogenic contamination (by global and Chernobyl fallout). These data are being stored, but have so far not been evaluated in depth, or used for any purpose. In the framework of the EU project 'European Atlas of Natural Radiation' the idea has emerged to exploit these data for generating a map of natural terrestrial gamma radiation. This component contributes to the total radiation exposure and knowing its geographical distribution can help establishing local 'radiation budgets'. A further use could be found in terrestrial dose rate as a proxy of the geogenic radon potential, as both quantities are related by partly the same source, namely uranium content of the ground. In this paper, we describe in detail the composition of the ambient dose equivalent rate as measured by the EURDEP monitors with respect to its physical nature and to its sources in the environment. We propose and compare methods to recover the terrestrial component from the gross signal. This requires detailed knowledge of detector response. We consider the probes used in the Austrian, Belgian and German dose rate networks, which are the respective national networks supplying data to EURDEP. It will be shown that although considerable progress has been made in understanding the dose rate signals, there is still space for improvement in terms of modelling and model parameters. An indispensable condition for success of the endeavour to establish a Europe-wide map of terrestrial dose rate background is progress in harmonising the European dose rate monitoring network. PMID- 26926962 TI - Intrauterine growth restriction modifies the hedonic response to sweet taste in newborn pups - Role of the accumbal MU-opioid receptors. AB - Intrauterine growth restriction (IUGR) is associated with increased preference for palatable foods. The hedonic response to sweet taste, modulated by the nucleus accumbens MU-opioid-receptors, may be involved. We investigated hedonic responses and receptor levels in IUGR and Control animals. From pregnancy day 10, Sprague-Dawley dams received either an ad libitum (Control), or a 50% food restricted (FR) diet. At birth, pups were cross-fostered, and nursed by Adlib fed dams. The hedonic response was evaluated at 1 day after birth and at 90 days of life, by giving sucrose solution or water and analyzing the hedonic facial responses (within 60s). Control pups exposed either to water or sucrose resolved their hedonic responses after 16 and 18s, respectively, while FR hedonic responses to sucrose persisted over 20s. FR pups had deceased phospho-MU-opioid receptor (p=0.009) and reduced phosphor:total mu opioid receptor ratio compared to controls pups (p=0.003). In adults, there was an interaction between group and solution at the end of the evaluation (p=0.044): Control decreased the response after sucrose solution, FR did not change over time. There were no differences in phosphorylation of MU-opioid-receptor in adults. These results demonstrate IUGR newborn rats exhibit alterations in hedonic response accompanied by a decrease in MU-opioid-receptor phosphorylation, though these alterations do not persist at 3 months of age. Opioid system alterations in early life may contribute to the development of preference for highly palatable foods and contribute to rapid weight gain and obesity in IUGR offspring. PMID- 26926964 TI - The effects of ginsenoside Rg1 on chronic stress induced depression-like behaviors, BDNF expression and the phosphorylation of PKA and CREB in rats. AB - Depression is a common neuropsychiatric disorder which has been associated with a wide range of structural and functional changes within specific brain regions. Ginsenoside Rg1 has been shown to exert a number of neuroprotective effects as demonstrated in various in vivo and in vitro studies. However, little information is available regarding the site and mechanisms of ginsenoside Rg1 in promoting antidepressant effects. The present study aimed to investigate the neuroprotective and ameliorating effects of ginsenoside Rg1 on depression-like behavior as induced by chronic unpredictable mild stress (CUMS). The results showed that CUMS was effective in producing depression-like behaviors in rats as indicated by decreased responses in sucrose preference and forced swim tests which were associated with ultrastructural changes in neurons within the amygdala. Moreover, levels of PKA and CREB phosphorylation and the expression of brain-derived neurotrophic factor (BDNF) were decreased in the amygdala of CUMS rats. Remarkably, chronic ginsenoside Rg1 (40 mg/kg, i.p., 5 weeks) treatment significantly ameliorated these behavioral and biochemical alterations associated with CUMS-induced depression. Taken together, the results of the present study demonstrate that ginsenoside Rg1 exhibits antidepressant-like effects against CUMS-induced depression. This amelioration of depression-like behaviors by ginsenoside Rg1 appears to be mediated, at least in part, by a CREB-regulated increase of BDNF expression in the amygdala of rats. Therefore, these findings reveal the therapeutic potential of ginsenoside Rg1 for use in clinical trials in the treatment of depression. PMID- 26926963 TI - Incubation of cocaine cue reactivity associates with neuroadaptations in the cortical serotonin (5-HT) 5-HT2C receptor (5-HT2CR) system. AB - Intensification of craving elicited by drug-associated cues during abstinence occurs over time in human cocaine users while elevation of cue reactivity ("incubation") is observed in rats exposed to extended forced abstinence from cocaine self-administration. Incubation in rodents has been linked to time dependent neuronal plasticity in the medial prefrontal cortex (mPFC). We tested the hypothesis that incubation of cue reactivity during abstinence from cocaine self-administration is accompanied by lower potency and/or efficacy of the selective serotonin (5-HT) 5-HT2C receptor (5-HT2CR) agonist WAY163909 to suppress cue reactivity and a shift in the subcellular localization profile of the mPFC 5-HT2CR protein. We observed incubation of cue reactivity (measured as lever presses reinforced by the discrete cue complex) between Day 1 and Day 30 of forced abstinence from cocaine relative to sucrose self-administration. Pharmacological and biochemical analyses revealed that the potency of the selective 5-HT2CR agonist WAY163909 to suppress cue reactivity, the expression of synaptosomal 5-HT2CR protein in the mPFC, and the membrane to cytoplasmic expression of the 5-HT2CR in mPFC were lower on Day 30 vs. Day 1 of forced abstinence from cocaine self-administration. Incubation of cue reactivity assessed during forced abstinence from sucrose self-administration did not associate with 5-HT2CR protein expression in the mPFC. Collectively, these outcomes are the first indication that neuroadaptations in the 5-HT2CR system may contribute to incubation of cocaine cue reactivity. PMID- 26926965 TI - Impaired synaptic plasticity in the prefrontal cortex of mice with developmentally decreased number of interneurons. AB - Interneurons are inhibitory neurons, which protect neural tissue from excessive excitation. They are interconnected with glutamatergic pyramidal neurons in the cerebral cortex and regulate their function. Particularly in the prefrontal cortex (PFC), interneurons have been strongly implicated in regulating pathological states which display deficits in the PFC. The aim of this study is to investigate the adaptations in the adult glutamatergic system, when defects in interneuron development do not allow adequate numbers of interneurons to reach the cerebral cortex. To this end, we used a mouse model that displays ~50% fewer cortical interneurons due to the Rac1 protein loss from Nkx2.1/Cre expressing cells (Rac1 conditional knockout (cKO) mice), to examine how the developmental loss of interneurons may affect basal synaptic transmission, synaptic plasticity and neuronal morphology in the adult PFC. Despite the decrease in the number of interneurons, basal synaptic transmission, as examined by recording field excitatory postsynaptic potentials (fEPSPs) from layer II networks, is not altered in the PFC of Rac1 cKO mice. However, there is decreased paired-pulse ratio (PPR) and decreased long-term potentiation (LTP), in response to tetanic stimulation, in the layer II PFC synapses of Rac1 cKO mice. Furthermore, expression of N-methyl-d-aspartate (NMDA) subunits is decreased and dendritic morphology is altered, changes that could underlie the decrease in LTP in the Rac1 cKO mice. Finally, we find that treating Rac1 cKO mice with diazepam in early postnatal life can reverse changes in dendritic morphology observed in non treated Rac1 cKO mice. Therefore, our data show that disruption in GABAergic inhibition alters glutamatergic function in the adult PFC, an effect that could be reversed by enhancement of GABAergic function during an early postnatal period. PMID- 26926966 TI - Stochastic resonance in the synaptic transmission between hair cells and vestibular primary afferents in development. AB - The stochastic resonance (SR) is a phenomenon of nonlinear systems in which the addition of an intermediate level of noise improves the response of such system. Although SR has been studied in isolated hair cells and in the bullfrog sacculus, the occurrence of this phenomenon in the vestibular system in development is unknown. The purpose of the present study was to explore for the existence of SR via natural mechanical-stimulation in the hair cell-vestibular primary afferent transmission. In vitro experiments were performed on the posterior semicircular canal of the chicken inner ear during development. Our experiments showed that the signal-to-noise ratio of the afferent multiunit activity from E15 to P5 stages of development exhibited the SR phenomenon, which was characterized by an inverted U-like response as a function of the input noise level. The inverted U like graphs of SR acquired their higher amplitude after the post-hatching stage of development. Blockage of the synaptic transmission with selective antagonists of the NMDA and AMPA/Kainate receptors abolished the SR of the afferent multiunit activity. Furthermore, computer simulations on a model of the hair cell - primary afferent synapse qualitatively reproduced this SR behavior and provided a possible explanation of how and where the SR could occur. These results demonstrate that a particular level of mechanical noise on the semicircular canals can improve the performance of the vestibular system in their peripheral sensory processing even during embryonic stages of development. PMID- 26926967 TI - 1H NMR-derived metabolomics of filtered serum of myocardial ischemia in unstable angina patients. AB - BACKGROUND: Despite continuing research for development of accurate biomarkers of myocardial ischemia in unstable angina, lack of biochemical biomarkers is alarming. We sought to develop accurate biomarkers using high throughput proton nuclear magnetic resonance ((1)H NMR) spectroscopy and filtered serum (lacking proteins and lipoproteins) based metabolomics for detecting myocardial ischemia in unstable angina patients with utmost precision. METHODS: Study includes 127 filtered serum samples from myocardial ischemia in unstable angina patients (UA; n=65) and healthy controls (HC; n=62). High resolution NMR spectra were obtained to highlight metabolic perturbations of small metabolites. A supervised orthogonal partial least square discriminant analysis was applied to generate a prediction model. Receiver operating characteristic (ROC) curve analysis was performed to reveal the clinical utility of signature biomarkers. RESULTS: Five biomarkers--valine, alanine, glutamine, inosine and adenine--could differentiate 95% of UA from HC with 96% sensitivity and 95% specificity. CONCLUSIONS: (1)H NMR based filtered serum metabolic profiling appears to be an assuring, least invasive and faster way to screen and identify myocardial ischemia in unstable angina patients. PMID- 26926968 TI - Publication outcome of abstracts presented at the AACC annual meeting. AB - BACKGROUND: Failure to publish study results causes duplication of effort and is a significant source of waste. It also can lead to distortions in the evidence base that can lead to misallocation of resources and medical harm. Failure to publish is commonly studied by comparing the conversion rate of meeting abstracts or publication rate of registered trials and has not been studied in clinical chemistry. The objective of this study was to determine the abstract conversion rate in clinical chemistry. METHODS: For the set of abstracts published from the 2011 annual meeting of the American Association for Clinical Chemistry, we determined which converted to full publications and which had not. We used 3 methods to match publications to abstracts: 1) a survey sent to corresponding authors of abstracts, 2) a web scrape of Google Scholar, and PubMed, and 3) a manual search using Scopus. Publication rates were compared by topic, country of corresponding author, institution type, and award recognition. RESULTS: Matching publications were found for 38% (95% CI: 34-42%) of the abstracts. The acceptance rate for submitted manuscripts was 34% (95% CI: 28-43%) among those who responded to the survey. Publication rates varied by topic (range 13% to 59%); rates from academic institutions were higher than commercial institutions (42% vs 16%, p<0.001). The publication rate of abstracts recognized "with distinction" was significantly greater than the publication rate of non-winners (68% vs 37%, p=0.001). CONCLUSION: A significant proportion of abstracts presented at the AACC national meeting are not followed by full publication. PMID- 26926970 TI - Human-Animal Health Interactions: The Role of One Health. PMID- 26926971 TI - The Impact of Contraception on Lactation. PMID- 26926972 TI - Influenza Vaccination for the Prevention of Cardiovascular Disease. PMID- 26926973 TI - Hyperthyroidism: Diagnosis and Treatment. AB - Hyperthyroidism is an excessive concentration of thyroid hormones in tissues caused by increased synthesis of thyroid hormones, excessive release of preformed thyroid hormones, or an endogenous or exogenous extrathyroidal source. The most common causes of an excessive production of thyroid hormones are Graves disease, toxic multinodular goiter, and toxic adenoma. The most common cause of an excessive passive release of thyroid hormones is painless (silent) thyroiditis, although its clinical presentation is the same as with other causes. Hyperthyroidism caused by overproduction of thyroid hormones can be treated with antithyroid medications (methimazole and propylthiouracil), radioactive iodine ablation of the thyroid gland, or surgical thyroidectomy. Radioactive iodine ablation is the most widely used treatment in the United States. The choice of treatment depends on the underlying diagnosis, the presence of contraindications to a particular treatment modality, the severity of hyperthyroidism, and the patient's preference. PMID- 26926974 TI - Aortic Stenosis: Diagnosis and Treatment. AB - Aortic stenosis affects 3% of persons older than 65 years. Although survival in asymptomatic patients is comparable to that in age- and sex-matched control patients, it decreases rapidly after symptoms appear. During the asymptomatic latent period, left ventricular hypertrophy and atrial augmentation of preload compensate for the increase in afterload caused by aortic stenosis. As the disease worsens, these compensatory mechanisms become inadequate, leading to symptoms of heart failure, angina, or syncope. Aortic valve replacement is recommended for most symptomatic patients with evidence of significant aortic stenosis on echocardiography. Watchful waiting is recommended for most asymptomatic patients. However, select patients may also benefit from aortic valve replacement before the onset of symptoms. Surgical valve replacement is the standard of care for patients at low to moderate surgical risk. Transcatheter aortic valve replacement may be considered in patients at high or prohibitive surgical risk. Patients should be educated about the importance of promptly reporting symptoms to their physicians. In asymptomatic patients, serial Doppler echocardiography is recommended every six to 12 months for severe aortic stenosis, every one to two years for moderate disease, and every three to five years for mild disease. Cardiology referral is recommended for all patients with symptomatic moderate and severe aortic stenosis, those with severe aortic stenosis without apparent symptoms, and those with left ventricular systolic dysfunction. Medical management of concurrent hypertension, atrial fibrillation, and coronary artery disease will lead to optimal outcomes. PMID- 26926975 TI - Chronic Pelvic Pain in Women. AB - Chronic pelvic pain in women is defined as persistent, noncyclic pain perceived to be in structures related to the pelvis and lasting more than six months. Often no specific etiology can be identified, and it can be conceptualized as a chronic regional pain syndrome or functional somatic pain syndrome. It is typically associated with other functional somatic pain syndromes (e.g., irritable bowel syndrome, nonspecific chronic fatigue syndrome) and mental health disorders (e.g., posttraumatic stress disorder, depression). Diagnosis is based on findings from the history and physical examination. Pelvic ultrasonography is indicated to rule out anatomic abnormalities. Referral for diagnostic evaluation of endometriosis by laparoscopy is usually indicated in severe cases. Curative treatment is elusive, and evidence-based therapies are limited. Patient engagement in a biopsychosocial approach is recommended, with treatment of any identifiable disease process such as endometriosis, interstitial cystitis/painful bladder syndrome, and comorbid depression. Potentially beneficial medications include depot medroxyprogesterone, gabapentin, nonsteroidal anti-inflammatory drugs, and gonadotropin-releasing hormone agonists with add-back hormone therapy. Pelvic floor physical therapy may be helpful. Behavioral therapy is an integral part of treatment. In select cases, neuromodulation of sacral nerves may be appropriate. Hysterectomy may be considered as a last resort if pain seems to be of uterine origin, although significant improvement occurs in only about one-half of cases. Chronic pelvic pain should be managed with a collaborative, patient centered approach. PMID- 26926976 TI - When Physician Family Members Are Involved in Patients' Care. PMID- 26926977 TI - An Annular Lesion on the Elbow. PMID- 26926978 TI - Transitional Care Interventions to Prevent Readmissions for Patients with Heart Failure. PMID- 26926979 TI - In Patients with Type 2 Diabetes and CV Disease, Empagliflozin Reduces CV and All Cause Mortality. PMID- 26926980 TI - No Difference Between Oxycodone/Acetaminophen and Hydrocodone/Acetaminophen for Acute Extremity Pain. PMID- 26926981 TI - ACCP Provides Updated Recommendations on the Management of Somatic Cough Syndrome and Tic Cough. PMID- 26926982 TI - Controlled Cord Traction During the Third Stage of Labor. PMID- 26926983 TI - Aortic Stenosis: What You Should Know. PMID- 26926984 TI - Overactive Thyroid Gland (Hyperthyroidism). PMID- 26926985 TI - Designed Construction of a Graphene and Iron Oxide Freestanding Electrode with Enhanced Flexible Energy-Storage Performance. AB - In this work, a bendable graphene@iron oxide hybrid film (GFeF) electrode was fabricated through a filtration-assisted self-assembly method. Morphological characterization of GFeF revealed a uniform distribution of iron oxide nanoparticles between graphene nanosheets. Surface chemical characterization confirmed that graphene oxide in the as-prepared hybrid film was effectively reduced after thermal reduction. The electrochemical performance of a GFeF half cell versus Li/Li(+) exhibited high gravimetric capacity (855.2 mAh g(-1) at 0.02 A g(-1)), high volumetric capacity (1949.9 mAh cm(-3) at 0.02 A g(-1)), and superior cycling stability (93% capacitance retention after 500 cycles). On the basis of such a bendable electrode, a hybrid Li-ion supercapacitor that offers an operation voltage of 3.5 V and delivers a high energy density (129.6 Wh kg(-1)) like a Li-ion battery combined with a high power density (1870 W kg(-1)) like a supercapacitor was fabricated. In addition to the superior energy-storage capability, the as-fabricated prototype pouch cell also exhibited excellent mechanical flexibility and stable electrochemical performances under dynamic bending. The viability of such an energy-storage device provides a possible design pathway for future wearable electronics. PMID- 26926986 TI - Cellular uptake of lead in the blood-cerebrospinal fluid barrier: Novel roles of Connexin 43 hemichannel and its down-regulations via Erk phosphorylation. AB - As the structural basis of blood-cerebrospinal fluid barrier (BCB), epithelial cells in the choroid plexus (CP) are targets for lead (Pb). Pb is known to accumulate in the CP; however, the mechanism of Pb uptake in the choroidal epithelial cells remains unknown. Recently, hemichannels of Connexin 43 (Cx43), the most ubiquitously expressed gap junction proteins in the CP, were found to be important pathways for many substances. This study was designed to investigate the roles of Cx43 in Pb uptake in the epithelial cells. Autometallography was used to outline Pb's subcellular location, and the characteristics of Pb transport into CP cells, including concentration- and time-dependence were analyzed by atomic absorption spectroscopy. Knockdown/overexpression of Cx43 with transient siRNA/plasmids transfections before Pb exposure diminished/increased the Pb accumulation. In the Z310 cell-based doxycycline-inducible Cx43 expression cell line (iZCx43), doxycycline induced a significant increase (3-fold) in Pb uptake, corresponding to the increased Cx43 levels. Activation of Cx43 hemichannels by reduced serum conditions caused an increase of Pb concentrations. Cx43-induced Pb uptake was attenuated after blockage of Cx43 hemichannels with its inhibitor, carbenoxolone. Additionally, down-regulation of Cx43 protein levels by Pb exposure paralleled cellular Pb concentrations in the time study. Concomitantly, expressions of phosphor-Src and phosphor-Erk were both significantly increased by Pb. However, inactivation of Erk, not Src pathway, reversed Pb-induced downregulation of Cx43. Taken together, these data establish that Pb can accumulate in the BCB and validate the role of Cx43 hemichannel in Pb uptake and its regulations through Erk phosphorylation. PMID- 26926987 TI - Capture, Movement, Trade, and Consumption of Mammals in Madagascar. AB - Wild meat trade constitutes a threat to many animal species. Understanding the commodity chain of wild animals (hunting, transportation, trade, consumption) can help target conservation initiatives. Wild meat commodity chain research has focused on the formal trade and less on informal enterprises, although informal enterprises contribute to a large portion of the wild meat trade in sub-Saharan Africa. We aimed to provide a more comprehensive understanding of the formal and informal components of these commodity chains by focusing on the mammalian wild meat trade in Madagascar. Our objectives were to: (1) identify hunting strategies used to capture different wild mammals; (2) analyze patterns of movement of wild meat from the capture location to the final consumer; (3) examine wild meat prices, volumes, and venues of sale; and (4) estimate the volume of wild meat consumption. Data were collected in May-August 2013 using semi-structured interviews with consumers (n = 1343 households, 21 towns), meat-sellers (n = 520 restaurants, open-air markets stalls, and supermarkets, 9 towns), and drivers of inter-city transit vehicles (n = 61, 5 towns). We found that: (1) a wide range of hunting methods were used, though prevalence of use differed by animal group; (2) wild meat was transported distances of up to 166 km to consumers, though some animal groups were hunted locally (<10 km) in rural areas; (3) most wild meat was procured from free sources (hunting, gifts), though urban respondents who consumed bats and wild pigs were more likely to purchase those meats; and (4) wild meat was consumed at lower rates than domestic meat, though urban respondents consumed wild meat twice as much per year compared to rural respondents. Apart from the hunting stage, the consumption and trade of wild meat in Madagascar is also likely more formalized than previously thought. PMID- 26926988 TI - Immobilization of a non-heme diiron complex encapsulated in an ammonium-type ionic liquid layer modified on an Au electrode: reactivity of the electrode for O2 reduction. AB - An unstable diiron(II,II) complex possessing O2 binding ability at low temperature was encapsulated and stabilized in an ammonium-type ionic liquid layer polymerized on an electrode. The encapsulated complex revealed catalytic reactivity for four-electron reduction of O2 at an ambient temperature in aqueous solution. PMID- 26926989 TI - Hierarchically roughened microplatelets enhance the strength and ductility of nacre-inspired composites. AB - Rough interfaces featuring nanoscale asperities are known to play a major role in the mechanics of nacre. Transferring this concept to artificial bioinspired composites requires a detailed understanding about the effect of the surface topography of reinforcing elements on the mechanical performance of such materials. To gain further insights into the effect of asperity size, hierarchy and coverage on the mechanics of nacre-inspired composites, we decorate alumina microplatelets with silica nanoparticles of selected sizes and use the resulting roughened platelets as reinforcing elements (15vol%) in a commercial epoxy matrix. For a single layer of silica nanoparticles on the platelet surface, increased ultimate strain and toughness are obtained with a large roughening particle size of 250nm. On the contrary, strength and stiffness are enhanced by decreasing the size of asperities using 22nm silica particles. By combining particles of two different sizes (100nm and 22nm) in a hierarchical fashion, we are able to improve stiffness and strength of platelet-reinforced polymers while maintaining high ultimate strain and toughness. Our results indicate that carefully designed hierarchically roughened interfaces lead to a more homogeneous stress distribution within the polymer matrix between the stiff reinforcing elements. By enabling the deformation of a larger fraction of the polymer matrix, this design concept improves the mechanical response of bioinspired composites and can possibly also be exploited to enhance the performance of conventional fiber-reinforced polymers. PMID- 26926990 TI - Structural Investigation of Aluminum in the U.S. Economy using Network Analysis. AB - Metals are used in numerous products and are sourced via increasingly global and complex supply chains. Monetary input-output tables (MIOT) and network analysis can be applied to intersectoral supply chains and used to analyze structural aspects. We first provide a concise review of the literature related to network analysis applied to MIOTs. On the basis of a physical input-output table (PIOT) table of aluminum in the United States economy in 2007, we identify key sectors and discuss the overall topology of the aluminum network using tools of network analysis. Sectors highly dependent on metal product inputs or sales are identified using weighted degree centrality and their hierarchical organization is explored via clustering. Betweenness centrality and random walk centrality (page rank) are explored as means to identify network bottlenecks and relative sector importance. Aluminum, even though dominated by uses in the automobile, beverage and containers, and construction industries, finds application in a wide range of sectors. Motor vehicle parts manufacturing relies on a large number of upstream and downstream suppliers to function. We conclude by analyzing structural aspects of a subnetwork for automobile manufacturing and discuss how the use of network analysis relates to current criticality analyses of metal and mineral resources. PMID- 26926991 TI - Role of Imaging Techniques in Percutaneous Treatment of Mitral Regurgitation. AB - Mitral regurgitation is the most prevalent valvular heart disease in the United States and the second most prevalent in Europe. Patients with severe mitral regurgitation have a poor prognosis with medical therapy once they become symptomatic or develop signs of significant cardiac dysfunction. However, as many as half of these patients are inoperable because of advanced age, ventricular dysfunction, or other comorbidities. Studies have shown that surgery increases survival in patients with organic mitral regurgitation due to valve prolapse but has no clinical benefit in those with functional mitral regurgitation. In this scenario, percutaneous repair for mitral regurgitation in native valves provides alternative management of valvular heart disease in patients at high surgical risk. Percutaneous repair for mitral regurgitation is a growing field that relies heavily on imaging techniques to diagnose functional anatomy and guide repair procedures. PMID- 26926992 TI - Could Descending Septal Artery Be Another Variant of the Dual Left Anterior Descending Artery? PMID- 26926993 TI - Characterization of heat induced spherulites of lysozyme reveals new insight on amyloid initiation. AB - Here, we report results obtained during our experiments to visualize how heat transforms globular protein, lysozyme into building block of beta-amyloids. Light scattering experiments showed formation of lower order associated species around 50-70 degrees C followed by rapid cooperativity to beta-amyloid fibrils. Interestingly, crystallization drops set at higher temperatures either led to aggregates or spherulites. The latter possess an amorphous beta-fibril rich core with thin crystalline needles projecting outwards. Diffraction of the crystalline outgrowths revealed novel dimers and trimers of lysozyme where individual chains were similar to monomer with marginal gain in beta-sheet content. Importantly, analysis of Amide I stretching frequencies showed that protein loses its secondary structure at temperatures higher than where we obtained crystals followed by rapid gain in beta-sheet content. Interestingly, attempts to use the needles as seeds for more crystals led to "broom-like" fibril formations at the ends. Further, aggregation inhibitors like arginine and benzyl alcohol completely obliterated spherulites formation during crystallization. Refinement of crystals of lysozyme in presence of these molecules showed these small molecules bind to the interfaces of heat associated dimers and trimers. Overall our work concludes that heat induced weakly associated structures of lysozyme are the first step towards its amyloid formation. PMID- 26926994 TI - Intestinal microbiota sustains inflammation and autoimmunity induced by hypomorphic RAG defects. AB - Omenn syndrome (OS) is caused by hypomorphic Rag mutations and characterized by a profound immunodeficiency associated with autoimmune-like manifestations. Both in humans and mice, OS is mediated by oligoclonal activated T and B cells. The role of microbial signals in disease pathogenesis is debated. Here, we show that Rag2(R229Q) knock-in mice developed an inflammatory bowel disease affecting both the small bowel and colon. Lymphocytes were sufficient for disease induction, as intestinal CD4 T cells with a Th1/Th17 phenotype reproduced the pathological picture when transplanted into immunocompromised hosts. Moreover, oral tolerance was impaired in Rag2(R229Q) mice, and transfer of wild-type (WT) regulatory T cells ameliorated bowel inflammation. Mucosal immunoglobulin A (IgA) deficiency in the gut resulted in enhanced absorption of microbial products and altered composition of commensal communities. The Rag2(R229Q) microbiota further contributed to the immunopathology because its transplant into WT recipients promoted Th1/Th17 immune response. Consistently, long-term dosing of broad spectrum antibiotics (ABXs) in Rag2(R229Q) mice ameliorated intestinal and systemic autoimmunity by diminishing the frequency of mucosal and circulating gut tropic CCR9(+) Th1 and Th17 T cells. Remarkably, serum hyper-IgE, a hallmark of the disease, was also normalized by ABX treatment. These results indicate that intestinal microbes may play a critical role in the distinctive immune dysregulation of OS. PMID- 26926995 TI - Strictly co-isogenic C57BL/6J-Prnp-/- mice: A rigorous resource for prion science. AB - Although its involvement in prion replication and neurotoxicity during transmissible spongiform encephalopathies is undisputed, the physiological role of the cellular prion protein (PrP(C)) remains enigmatic. A plethora of functions have been ascribed to PrP(C) based on phenotypes of Prnp(-/-) mice. However, all currently available Prnp(-/-) lines were generated in embryonic stem cells from the 129 strain of the laboratory mouse and mostly crossed to non-129 strains. Therefore, Prnp-linked loci polymorphic between 129 and the backcrossing strain resulted in systematic genetic confounders and led to erroneous conclusions. We used TALEN-mediated genome editing in fertilized mouse oocytes to create the Zurich-3 (ZH3) Prnp-ablated allele on a pure C57BL/6J genetic background. Genomic, transcriptional, and phenotypic characterization of Prnp(ZH3/ZH3) mice failed to identify phenotypes previously described in non-co-isogenic Prnp(-/-) mice. However, aged Prnp(ZH3/ZH3) mice developed a chronic demyelinating peripheral neuropathy, confirming the crucial involvement of PrP(C) in peripheral myelin maintenance. This new line represents a rigorous genetic resource for studying the role of PrP(C) in physiology and disease. PMID- 26926997 TI - Molecular basis of Bombay phenotype in Mashhad, Iran: identification of a novel FUT1 deletion. AB - BACKGROUND AND OBJECTIVES: Bombay phenotype is characterized by the lack of H substance both on red blood cell (RBC) surface and in body secretions. Mutations of fucosyltransferase 1 (FUT1) and fucosyltransferase 2 (FUT2) genes are resulted in this rare phenotype. MATERIALS AND METHODS: Five unrelated patients were tested by hemagglutination and adsorption/elution techniques for the presence of ABH antigens. The saliva specimens were analysed by hemagglutination inhibition method. The exons 6 and 7 of ABO gene were sequenced to determine ABO genotype. The coding fragments of FUT1 and FUT2 were amplified and sequenced by specific primers. RESULTS: Serologic investigation confirmed Bombay phenotype in all individuals. FUT1 molecular analysis revealed a novel large deletion. Also two novel homozygous mutations were detected; one was a missense mutation (392T>C, L131P) and the other a three nucleotide deletion (668_670delACT, Y224del). FUT2 sequencing showed one reported null allele (428G>A, W143X) and one homozygous deletion of FUT2. CONCLUSION: Although FUT2 deletion has been reported, this is the first report of FUT1 deletion. Finding two FUT1 novel alleles in Iranian people is indicative of mutation diversity in this gene. PMID- 26926996 TI - The glycolytic enzyme PKM2 bridges metabolic and inflammatory dysfunction in coronary artery disease. AB - Abnormal glucose metabolism and enhanced oxidative stress accelerate cardiovascular disease, a chronic inflammatory condition causing high morbidity and mortality. Here, we report that in monocytes and macrophages of patients with atherosclerotic coronary artery disease (CAD), overutilization of glucose promotes excessive and prolonged production of the cytokines IL-6 and IL-1beta, driving systemic and tissue inflammation. In patient-derived monocytes and macrophages, increased glucose uptake and glycolytic flux fuel the generation of mitochondrial reactive oxygen species, which in turn promote dimerization of the glycolytic enzyme pyruvate kinase M2 (PKM2) and enable its nuclear translocation. Nuclear PKM2 functions as a protein kinase that phosphorylates the transcription factor STAT3, thus boosting IL-6 and IL-1beta production. Reducing glycolysis, scavenging superoxide and enforcing PKM2 tetramerization correct the proinflammatory phenotype of CAD macrophages. In essence, PKM2 serves a previously unidentified role as a molecular integrator of metabolic dysfunction, oxidative stress and tissue inflammation and represents a novel therapeutic target in cardiovascular disease. PMID- 26926998 TI - Elongator Plays a Positive Role in Exogenous NAD-Induced Defense Responses in Arabidopsis. AB - Extracellular NAD is emerging as an important signal molecule in animal cells, but its role in plants has not been well-established. Although it has been shown that exogenous NAD(+) activates defense responses in Arabidopsis, components in the exogenous NAD(+)-activated defense pathway remain to be fully discovered. In a genetic screen for mutants insensitive to exogenous NAD(+) (ien), we isolated a mutant named ien2. Map-based cloning revealed that IEN2 encodes ELONGATA3 (ELO3)/AtELP3, a subunit of the Arabidopsis Elongator complex, which functions in multiple biological processes, including histone modification, DNA (de)methylation, and transfer RNA modification. Mutations in the ELO3/AtELP3 gene compromise exogenous NAD(+)-induced expression of pathogenesis-related (PR) genes and resistance to the bacterial pathogen Pseudomonas syringae pv. maculicola ES4326, and transgenic expression of the coding region of ELO3/AtELP3 in elo3/Atelp3 restores NAD(+) responsiveness to the mutant plants, demonstrating that ELO3/AtELP3 is required for exogenous NAD(+)-induced defense responses. Furthermore, mutations in genes encoding the other five Arabidopsis Elongator subunits (ELO2/AtELP1, AtELP2, ELO1/AtELP4, AtELP5, and AtELP6) also compromise exogenous NAD(+)-induced PR gene expression and resistance to P. syringae pv. maculicola ES4326. These results indicate that the Elongator complex functions as a whole in exogenous NAD(+)-activated defense signaling in Arabidopsis. PMID- 26926999 TI - Bacterial Outer Membrane Vesicles Induce Plant Immune Responses. AB - Gram-negative bacteria continuously pinch off portions of their outer membrane, releasing membrane vesicles. These outer membrane vesicles (OMVs) are involved in multiple processes including cell-to-cell communication, biofilm formation, stress tolerance, horizontal gene transfer, and virulence. OMVs are also known modulators of the mammalian immune response. Despite the well-documented role of OMVs in mammalian-bacterial communication, their interaction with plants is not well studied. To examine whether OMVs of plant pathogens modulate the plant immune response, we purified OMVs from four different plant pathogens and used them to treat Arabidopsis thaliana. OMVs rapidly induced a reactive oxygen species burst, medium alkalinization, and defense gene expression in A. thaliana leaf discs, cell cultures, and seedlings, respectively. Western blot analysis revealed that EF-Tu is present in OMVs and that it serves as an elicitor of the plant immune response in this form. Our results further show that the immune coreceptors BAK1 and SOBIR1 mediate OMV perception and response. Taken together, our results demonstrate that plants can detect and respond to OMV-associated molecules by activation of their immune system, revealing a new facet of plant bacterial interactions. PMID- 26927000 TI - Identification and Characterization of Plant Cell Death-Inducing Secreted Proteins From Ustilaginoidea virens. AB - Ustilaginoidea virens (Cooke) Takah (telemorph Villosiclava virens) is an ascomycetous fungus that causes rice false smut, one of the most important rice diseases. Fungal effectors often play essential roles in host-pathogen coevolutionary interactions. However, little is known about the functions of U. virens effectors. Here, we performed functional studies on putative effectors in U. virens and demonstrated that 13 of 119 putative effectors caused necrosis or necrosis-like phenotypes in Nicotiana benthamiana. Among them, 11 proteins were confirmed to be secreted, using a yeast secretion system, and the corresponding genes are all highly induced during infection, except UV_44 and UV_4753. Eight secreted proteins were proven to trigger cell death or defenses in rice protoplasts and the secretion signal of these proteins is essential for their cell death-inducing activity. The ability of UV_44 and UV_1423 to trigger cell death is dependent on the predicted serine peptidase and ribonuclease catalytic active sites, respectively. We demonstrated that UV_1423 and UV_6205 are N glycosylated proteins, which glycosylation has different impacts on their abilities to induce cell death. Collectively, the study identified multiple secreted proteins in U. virens with specific structural motifs that induce cell death or defense machinery in nonhost and host plants. PMID- 26927001 TI - Colonization of Barley by the Broad-Host Hemibiotrophic Pathogen Phytophthora palmivora Uncovers a Leaf Development-Dependent Involvement of Mlo. AB - The discovery of barley Mlo demonstrated that filamentous pathogens rely on plant genes to achieve entry and lifecycle completion in barley leaves. While having a dramatic effect on foliar pathogens, it is unclear whether overlapping or distinct mechanisms affect filamentous pathogen infection of roots. To remove the bias connected with using different pathogens to understand colonization mechanisms in different tissues, we have utilized the aggressive hemibiotrophic oomycete pathogen Phytophthora palmivora. P. palmivora colonizes root as well as leaf tissues of barley (Hordeum vulgare). The infection is characterized by a transient biotrophy phase with formation of haustoria. Barley accessions varied in degree of susceptibility, with some accessions fully resistant to leaf infection. Notably, there was no overall correlation between degree of susceptibility in roots compared with leaves, suggesting that variation in different genes influences host susceptibility above and below ground. In addition, a developmental gradient influenced infection, with more extensive colonization observed in mature leaf sectors. The mlo5 mutation attenuates P. palmivora infection but only in young leaf tissues. The barley-P. palmivora interaction represents a simple system to identify and compare genetic components governing quantitative colonization in diverse barley tissue types. PMID- 26927002 TI - Relationship between treatment delay and type of reperfusion therapy and mechanical complications of acute myocardial infarction. AB - OBJECTIVES: The incidence of mechanical complications after acute myocardial infarction has markedly declined with the advent of reperfusion. Nevertheless there is some controversy about the equal effectiveness of the different reperfusion therapies in preventing these complications. We aimed to analyse how reperfusion therapy and treatment delay relate to the incidence of mechanical complications in a population of ST-elevation myocardial infarction (STEMI) patients. METHODS: We analysed all STEMI patients included in the second phase of the Portuguese Registry on Acute Coronary Syndromes, between October 2010 and July 2015. We compared both conservative medical treatment with reperfusion therapy and thrombolysis with primary percutaneous coronary intervention for mechanical complications. We also evaluated the impact of treatment delay on mechanical complications. RESULTS: Among 5230 STEMIs we observed 77 mechanical complications (1.5%). These were significantly more frequent in the non reperfused patients (3.3% vs. 1.1%, P<0.001) and they were numerically higher in thrombolysis than in primary percutaneous coronary intervention patients (1.6% vs. 1.0%, respectively, P=0.282). Patients with mechanical complications had higher times from symptom onset to hospitalisation and to reperfusion. In multivariate analysis performing reperfusion therapy (odds ratio 0.52, 95% confidence interval 0.29-0.93) and a time from symptom onset to hospitalisation ?6 hours (odds ratio 2.44, 95% confidence interval 1.37-4.33) were independent predictors of mechanical complications. The type of reperfusion did not influence the occurrence of mechanical complications. CONCLUSION: A longer time from symptom onset to hospitalisation was associated with an increased number of mechanical complications. Timely reperfusion therapy prevented mechanical complications and no significant difference was found between thrombolysis and primary percutaneous coronary intervention. PMID- 26927003 TI - Confidence intervals for single-case effect size measures based on randomization test inversion. AB - In the current paper, we present a method to construct nonparametric confidence intervals (CIs) for single-case effect size measures in the context of various single-case designs. We use the relationship between a two-sided statistical hypothesis test at significance level alpha and a 100 (1 - alpha) % two-sided CI to construct CIs for any effect size measure theta that contain all point null hypothesis theta values that cannot be rejected by the hypothesis test at significance level alpha. This method of hypothesis test inversion (HTI) can be employed using a randomization test as the statistical hypothesis test in order to construct a nonparametric CI for theta. We will refer to this procedure as randomization test inversion (RTI). We illustrate RTI in a situation in which theta is the unstandardized and the standardized difference in means between two treatments in a completely randomized single-case design. Additionally, we demonstrate how RTI can be extended to other types of single-case designs. Finally, we discuss a few challenges for RTI as well as possibilities when using the method with other effect size measures, such as rank-based nonoverlap indices. Supplementary to this paper, we provide easy-to-use R code, which allows the user to construct nonparametric CIs according to the proposed method. PMID- 26927004 TI - Standards for Clinical Research: Keeping Pace With the Technology of the Future. PMID- 26927005 TI - Good Clinical Practice Guidance and Pragmatic Clinical Trials: Balancing the Best of Both Worlds. AB - Randomized, clinical trials are commonly regarded as the highest level of evidence to support clinical decisions. Good Clinical Practice guidelines have been constructed to provide an ethical and scientific quality standard for trials that involve human subjects in a manner aligned with the Declaration of Helsinki. Originally designed to provide a unified standard of trial data to support submission to regulatory authorities, the principles may also be applied to other studies of human subjects. Although the application of Good Clinical Practice principles generally led to improvements in the quality and consistency of trial operations, these principles have also contributed to increasing trial complexity and costs. Alternatively, the growing availability of electronic health record data has facilitated the possibility for streamlined pragmatic clinical trials. The central tenets of Good Clinical Practice and pragmatic clinical trials represent potential tensions in trial design (stringent quality and highly efficient operations). In the present article, we highlight potential areas of discordance between Good Clinical Practice guidelines and the principles of pragmatic clinical trials and suggest strategies to streamline study conduct in an ethical manner to optimally perform clinical trials in the electronic age. PMID- 26927008 TI - Cardiovascular Complications of Novel Multiple Myeloma Treatments. PMID- 26927006 TI - Vasodysfunction That Involves Renal Vasodysfunction, Not Abnormally Increased Renal Retention of Sodium, Accounts for the Initiation of Salt-Induced Hypertension. PMID- 26927007 TI - Renal Dysfunction, Rather Than Nonrenal Vascular Dysfunction, Mediates Salt Induced Hypertension. PMID- 26927010 TI - A 2-Step Extra-Anatomic Bypass Rescue Procedure for Bridging Aortic Coarctation in a Patient With Multiorgan Failure. PMID- 26927011 TI - Importance of Cardiac Magnetic Resonance in a Patient With Crohn's Disease Associated Constrictive Pericarditis. PMID- 26927012 TI - Letter by Ferreira et al Regarding Article, "Clinical Impact of Contemporary Cardiovascular Magnetic Resonance Imaging in Hypertrophic Cardiomyopathy". PMID- 26927013 TI - Response to Letter Regarding Article, "Clinical Impact of Contemporary Cardiovascular Magnetic Resonance Imaging in Hypertrophic Cardiomyopathy". PMID- 26927014 TI - Letter by Inohara et al Regarding Article, "Temporal Trends in Percutaneous Coronary Intervention Appropriateness: Insights From the Clinical Outcomes Assessment Program". PMID- 26927015 TI - Response to Letter Regarding Article, "Temporal Trends in Percutaneous Coronary Intervention Appropriateness: Insights From the Clinical Outcomes Assessment Program". PMID- 26927016 TI - Correction. PMID- 26927018 TI - Identification of an active metabolite of PAR-1 antagonist RWJ-58259 and synthesis of analogues to enhance its metabolic stability. AB - The discontinuation of PAR-1 antagonist RWJ-58259 beyond use as a biological probe is most likely due to it's short half-life in vivo. However, retention of significant in vivo activity beyond the point where most of the RWJ-58259 had been consumed implies the generation of an active metabolite. Herein we describe the biological activity of a predicted metabolite of RWJ-58259 and the synthesis of analogues designed to enhance the metabolic stability of RWJ-58259. PMID- 26927017 TI - LncRNA PANDAR regulates the G1/S transition of breast cancer cells by suppressing p16(INK4A) expression. AB - It has been reported that lncRNA PANDAR (promoter of CDKN1A antisense DNA damage activated RNA) is induced as a result of DNA damage, and it regulates the reparation of DNA damage. In this study, we investigated the role of lncRNA PANDAR in the progression of breast cancer and found that PANDAR was up-regulated in breast cancer tissues and cell lines. The knockdown of PANDAR suppresses G1/S transition of breast cancer cells. We demonstrated mechanistically that the regulation of G1/S transition by PANDAR was partly due to the transcriptional modulation of p16(INK4A). Moreover, we showed that PANDAR impacted p16(INK4A) expression by regulating the recruitment Bmi1 to p16(INK4A) promoter. To our knowledge, this is the first study which showed the functional roles and mechanisms of PANDAR in regulating the progression of breast cancer. The PANDAR/Bmi1/p16(INK4A) axis could serve as novel targets for breast cancer therapy. PMID- 26927019 TI - Effects of nanostructured, diamondlike, carbon coating and nitrocarburizing on the frictional properties and biocompatibility of orthodontic stainless steel wires. AB - OBJECTIVE: To evaluate and compare the effects of nanostructured, diamondlike, carbon (DLC) coating and nitrocarburizing on the frictional properties and biocompatibility of orthodontic stainless steel archwires. MATERIALS AND METHODS: Plasma-enhanced chemical vapor deposition technology was applied to coat DLC films onto the surface of austenitic stainless steel wires, and salt-bath nitrocarburizing technology was employed to achieve surface hardening of other wires. Surface and cross-sectional characteristics, microhardness, modulus of elasticity, friction resistance, corrosion resistance, and cell toxicity of the modified and control wires were analyzed. RESULTS: The surfaces of the DLC-coated and nitrocarburized wires were both smooth and even. Compared with the control, the DLC-coated wires were increased in surface hardness 1.46 times, decreased in elastic modulus, reduced in kinetic friction coefficient by 40.71%, and decreased in corrosion current density by two orders of magnitude. The nitrocarburized wire was increased in surface hardness 2.39 times, exhibited an unchanged elastic modulus, demonstrated a decrease in maximum static friction force of 22.2%, and rose in corrosion current density two orders of magnitude. Cytotoxicity tests revealed no significant toxicity associated with the modified wires. CONCLUSIONS: DLC coating and nitrocarburizing significantly improved the surface hardness of the wires, reduced friction, and exhibited good biocompatibility. The nanostructured DLC coating provided excellent corrosion resistance and good elasticity, and while the nitrocarburizing technique substantially improved frictional properties, it reduced the corrosion resistance of the stainless steel wires to a lesser extent. PMID- 26927020 TI - Dentoskeletal effects produced by a Jasper Jumper with an anterior bite plane. AB - OBJECTIVE: The aim of this retrospective study was to evaluate the dentoskeletal effects produced by a modified Jasper Jumper with an anterior bite plane for the correction of Class II division 1 malocclusion. MATERIALS AND METHODS: A sample of 32 growing patients (mean age = 11.9 +/- 1.4 years) with Class II division 1 malocclusion and increased overbite were treated with a modified Jasper Jumper (JJ) and anterior bite plane protocol and compared with a matched control group of 30 subjects with untreated Class II malocclusion (mean age 12.2 +/- 0.8 years). Lateral cephalograms were taken before treatment (T1) and at the end of comprehensive treatment (T2). Mean treatment duration was 2.1 +/- 0.4 years. The T1-T2 changes in the two groups were compared with Student's t-tests for independent samples. RESULTS: The JJ group was successfully treated to a Class I occlusal relationship with a significant reduction in overjet (-3.9 mm, P < .001) and overbite (-3.1 mm, P < .001). The JJ group exhibited a significant increase in mandibular length and a significant improvement in maxillomandibular sagittal skeletal relationships. The lower incisors were significantly proclined, while the lower first molars demonstrated significant movement in a mesial direction. CONCLUSIONS: Use of a modified JJ appliance and anterior bite plane is an effective protocol for the treatment of Class II malocclusion with increased overbite and greater skeletal (75%) than dentoalveolar (25%) effects mainly at the mandibular level. PMID- 26927021 TI - Erratum to: A novel APOC2 gene mutation identified in a Chinese patient with severe hypertriglyceridemia and recurrent pancreatitis. PMID- 26927022 TI - Lightwave Circuits in Lithium Niobate through Hybrid Waveguides with Silicon Photonics. AB - We demonstrate a photonic waveguide technology based on a two-material core, in which light is controllably and repeatedly transferred back and forth between sub micron thickness crystalline layers of Si and LN bonded to one another, where the former is patterned and the latter is not. In this way, the foundry-based wafer scale fabrication technology for silicon photonics can be leveraged to form lithium-niobate based integrated optical devices. Using two different guided modes and an adiabatic mode transition between them, we demonstrate a set of building blocks such as waveguides, bends, and couplers which can be used to route light underneath an unpatterned slab of LN, as well as outside the LN bonded region, thus enabling complex and compact lightwave circuits in LN alongside Si photonics with fabrication ease and low cost. PMID- 26927024 TI - Anion Specificity of Polyzwitterionic Brushes with Different Carbon Spacer Lengths and Its Application for Controlling Protein Adsorption. AB - Both ion-specific interaction and carbon spacer length have strong effects on the properties of polyzwitterions. In this work, we have investigated the anion specificity of poly(sulfobetaine methacrylamide) (PSBMAm) brushes with different carbon spacer lengths. The effectiveness of anions to enhance the hydration of the PSBMAm brushes increases from kosmotropic to chaotropic anions. The interactions between the anions and the PSBMAm brushes are strongly influenced by carbon spacer length because the strength of inter/intrachain association of the PSBMAm brushes decreases with increasing carbon spacer length. The inter/intrachain association of the PSBMAm brushes with a longer carbon spacer is easier to break by the external anions in the high salt concentration regime. On the other hand, a longer carbon spacer is more favorable for the zwitterionic groups to form cyclic intramolecular structures. As a result, the addition of anions can more effectively enhance the hydration of the PSBMAm brushes with a medium-length carbon spacer compared with that of the PSBMAm brushes with a either shorter or longer carbon spacer in the low salt concentration regime, determined by the balance between the inter/intrachain association and the formation of cyclic intramolecular structures. Our study also demonstrates that both anion identity and carbon spacer length can be used to control protein adsorption on the surface of the PSBMAm brushes. PMID- 26927023 TI - Increasing smoking cessation care across a network of hospitals: an implementation study. AB - BACKGROUND: Despite clinical practice guidelines recommending the provision of smoking cessation care to all smokers in hospital, the provision of such care can be sub-optimal. A study was conducted to assess the impact of an intervention on the provision of smoking cessation care to nicotine-dependent smokers across a network of hospitals. METHODS: A 4-year interrupted time series study was undertaken in a single health district in New South Wales, Australia. A multi component intervention was implemented over a 2-year period in all 37 public general hospitals. Outcome data were collected from eight randomly selected hospitals via medical record audit. Logistic regression analyses assessed differences between baseline, intervention and follow-up periods in the provision of seven measures of care: brief advice, offer and provision of inpatient and discharge nicotine replacement therapy, and offer and acceptance of referral to a Quitline. RESULTS: Approximately 164,250 patients were discharged from the hospitals during the study, 16 % of whom were smokers. Of the selected smokers, 56.12 % (n = 2072) were nicotine-dependent. The prevalence of smoking cessation care increased significantly for all seven measures between baseline and intervention periods, and for six of the seven measures between the baseline and follow-up periods. The odds of receiving care at follow-up were between 1.7 (CI 1.18-2.58, p = 0.0004) and 6.2 (CI 2.84-13.85, p < 0.0001) times greater than at baseline. At follow-up, 53, 16 and 7 of smokers were offered inpatient NRT, discharge NRT and a Quitline referral, respectively. CONCLUSIONS: Significant gains in the provision of smoking cessation care were indicated. However, at best, slightly more than half of the patients received smoking cessation care. Additional care enhancement strategies are required if all smokers are to obtain the intended benefits of smoking cessation care guidelines. PMID- 26927025 TI - The wheat MAP kinase phosphatase 1 alleviates salt stress and increases antioxidant activities in Arabidopsis. AB - Mitogen-activated protein kinase phosphatases (MKPs) are important negative regulators in the MAPK signaling pathways, which play crucial roles in plant growth, development and stress responses. We have previously shown that the heterologous expression of a durum wheat MKP, TMKP1, results in increased tolerance to salt stress in yeast but its particular contribution in salt stress tolerance in plants was not investigated. Here, TMKP1 was overexpressed in Arabidopsis thaliana and physiological changes were assessed in transgenic plants exposed to stress conditions. Under salt stress and especially LiCl, the TMKP1 overexpressors displayed higher germination rates in comparison to wild type plants. The enhancement of salt stress tolerance was accompanied by increased antioxidant enzyme activities, namely superoxide dismutase, catalase and peroxydases. Such increases in antioxidant activities were concomitant with lower malondialdehyde, superoxide anion O2(-) and hydrogen peroxide levels in the TMKP1 transgenic seedlings. Moreover, we provide evidence that, in contrast to the Arabidopsis ortholog AtMKP1, TMKP1 acts as a positive regulator of salt stress tolerance via its ectopic expression in the Arabidopsis mkp1 mutant. PMID- 26927027 TI - Structural insights into the counterion effects on the manganese(III) spin crossover system with hexadentate Schiff-base ligands. AB - A series of new salts [Mn(5-MeO-sal-N-1,5,8,12)]Y (Y = ClO4 for 1, Y = BF4 for 2, Y = NO3 for 3 and Y = CF3SO3 for 4) based on the six-coordinated mononuclear manganese(iii) Schiff-base complex cation [Mn(5-MeO-sal-N-1,5,8,12)](+), has been investigated to determine the impact of counter anion effects, intramolecular ligand distortion and intermolecular supramolecular structures on the spin crossover (SCO) behavior. The SCO in salt 1 has resulted in a crystallographic observation of the coexistence of high-spin (HS, S = 2) and low-spin (LS, S = 1) manganese(iii) complex cations in equal proportions around 100 K. At room temperature, the two crystallographically distinct manganese centers are both close to the complete HS state. Only one of the two slightly different units undergoes SCO in the temperature range 300-180 K, whereas the other remains in the HS state down to 20 K. For salts 2 and 3, crystal structural analysis indicates change in the anion from ClO4(-) to BF4(-) and NO3(-) was led to the close arrangement of the cations and the stacking between phenyl groups from the ligands. With CF3SO3(-) as the counterion, although the cations and the anions separate clearly in one direction, the close arrangement of cations in other directions precludes the spin transformation of the Mn(iii) cations. Magnetic measurements on 2-4 indicate that the manganese(iii) complex cations remain in the HS state in the temperature range 2-300 K. PMID- 26927026 TI - Adamantinomatous and papillary craniopharyngiomas are characterized by distinct epigenomic as well as mutational and transcriptomic profiles. AB - INTRODUCTION: Craniopharyngiomas (CP) are rare epithelial tumors of the sellar region. Two subtypes, adamantinomatous (adaCP) and papillary CP (papCP), were previously identified based on histomorphological and epidemiological aspects. Recent data indicates that both variants are defined by specific genetic alterations, and influenced by distinct molecular pathways and particular origins. The fact that CP is an uncommon tumor entity renders studies on large cohorts difficult and exceptional. In order to achieve further insights distinguishing CP variants, we conducted whole genome methylation (450 k array) and microarray-based gene expression studies in addition to CTNNB1 and BRAF mutation analysis using a comprehensive cohort of 80 adaCP and 35 papCP. RESULTS: BRAF V600E mutations were solely found in the papCP subgroup and were not detectable in adaCP samples. In contrast, CTNNB1 mutations were exclusively detected in adaCP. The methylome fingerprints assigned DNA specimens to entity specific groups (papCP (n = 18); adaCP (n = 25)) matching perfectly with histology-based diagnosis, suggesting that they represent truly distinct biological entities. However, we were not able to detect within the adaCP group (including 11 pediatric and 14 adult cases) a significant difference in methylation signature by age. Integrative comparison of the papCP with the adaCP group based on differential gene expression and methylation revealed a distinct upregulation of Wnt- and SHH signaling pathway genes in adaCP. CONCLUSIONS: AdaCP and papCP thus represent distinct tumor subtypes that harbor mutually exclusive gene mutations and methylation patterns, further reflected in differences in gene expression. This study demonstrates that DNA methylation analyses are an additional method to classify CP into subtypes, and implicates a role of epigenetic mechanisms in the genesis of the respective CP variants. Detection of tumor-specific signaling pathway activation enables the possibility of target oriented intervention. PMID- 26927028 TI - HP-Xe to go: Storage and transportation of hyperpolarized (129)Xenon. AB - Recently the spin-lattice relaxation time T1 of hyperpolarized (HP)-(129)Xe was significantly improved by using uncoated and Rb-free storage vessels of GE180 glass. For these cells, a simple procedure was established to obtain reproducible wall relaxation times of about 18 h. Then the limiting relaxation mechanism in pure Xe is due to the coupling between the nuclear spins and the angular momentum of the Xe-Xe van-der-Waals-molecules. This mechanism can be significantly reduced by using different buffer gases of which CO2 was discovered to be the most efficient so far. From these values, it was estimated that for a 1:1 mixture of HP-Xe with CO2 a longitudinal relaxation time of about 7 h can be expected, sufficient to transport HP-Xe from a production to a remote application site. This prediction was verified for such a mixture at a total pressure of about 1 bar in a 10 cm glass cell showing a storage time of T1~9 h (for T1(wall)=(34+/-9) h) which was transported inside a magnetic box over a distance of about 200 km by car. PMID- 26927029 TI - The safety of tumor necrosis factor-alpha inhibitors in the treatment of rheumatoid arthritis. AB - INTRODUCTION: Tumor necrosis factor inhibitors (TNFi) were the first biologic therapy authorized for rheumatoid arthritis (RA) treatment and are currently the most used biological drugs in these patients. Although clinical efficacy is proven, adverse events associated with these agents have been described, and further knowledge is essential to facilitate detection at very early stages. AREAS COVERED: We reviewed the safety profile of TNFi, including both articles and congress communications published on this topic, such as clinical trials, meta-analyses, observational studies, data from registries, and spontaneous clinical reports. We classified studies according to the most common and relevant adverse events associated with TNFi. EXPERT OPINION: There is a broad spectrum of possible adverse events associated with TNFi treatment, ranging from mild to serious, and with diverse clinical manifestations. However, most adverse events may be minimized by appropriate screening before starting treatment and with ongoing surveillance to ensure an early diagnosis. In conclusion, TNFi have a reasonable safety profile, and, globally, the benefits far outweigh the possible risk of adverse events, especially compared with the risk of the untreated underlying inflammatory condition. PMID- 26927030 TI - Micro-CT Structural Analysis of the Canine Medial Coronoid Disease. AB - OBJECTIVE: To use micro-computed tomography (CT) to evaluate the fissure-fracture pattern in dogs affected by medial coronoid disease (MCD). STUDY DESIGN: Prospective case-controlled study. SAMPLE POPULATION: Client owned (n = 21) and cadaver dogs (n = 5). METHODS: Segments were excised by subtotal coronoid ostectomy from dogs with MCD. Two categories were identified: fissured (Fi) or fractured (F). Three subcategories were contingent on fissure-fracture orientation: tip (T), radial incisure (RI), and radial incisure encroaching tip (RIT). Control segments were from nondiseased cadavers. High-resolution micro-CT (3 dimensional and 2 dimensional) was performed on all segments. Measurements included mean bone mineral density, trabecular number and thickness, and the angle of the fissure-fracture relative to the predominant trabecular orientation. RESULTS: A total of 28 diseased segments from 21 dogs (mean age 23.3 months, mean bodyweight 31.5 kg) were analyzed and categorized according to fissure-fragment location as Fi-T (n = 2), Fi-RIT (n = 2), Fi-RI (n = 3), F-T (n = 5), F-RIT (n = 9), F-RI (n = 7). The 3D analysis revealed subchondral micro-fracturing occurred in association with fragmentation. Canalicular impaction was associated with increase in trabecular number and decrease in trabecular space, most notably in RI categories. The 2D analysis showed that predominant trabecular orientation in control segments was significantly different to RI but not to T. The mean (SD) angle difference between the orientation of fissure-fracture and the predominant trabecular pattern was 6.9 (6.9) degrees for RI and 44.6 (49.6) degrees for T. CONCLUSION: T and RI fissure-fracture patterns show morphologic differences and likely arise from different supraphysiologic loading. Medial compartment disease is not homogenous and pattern recognition may assist further investigation of etiopathogenesis. PMID- 26927031 TI - Corrigendum. PMID- 26927032 TI - Effect of Interfacial Bonding on Interphase Properties in SiO2/Epoxy Nanocomposite: A Molecular Dynamics Simulation Study. AB - Atomistic molecular dynamics simulations have been performed to explore the effect of interfacial bonding on the interphase properties of a nanocomposite system that consists of a silica nanoparticle and the highly cross-linked epoxy matrix. For the structural properties, results show that interfacial covalent bonding can broaden the interphase region by increasing the radial effect range of fluctuated mass density and oriented chains, as well as strengthen the interphase region by improving the thermal stability of interfacial van der Waals excluded volume and reducing the proportion of cis conformers of epoxy segments. The improved thermal stability of the interphase region in the covalently bonded model results in an increase of ~21 K in the glass transition temperature (Tg) compared to that of the pure epoxy. It is also found that interfacial covalent bonding mainly restricts the volume thermal expansion of the model at temperatures near or larger than Tg. Furthermore, investigations from mean-square displacement and fraction of immobile atoms point out that interfacial covalent and noncovalent bonding induces lower and higher mobility of interphase atoms than that of the pure epoxy, respectively. The obtained critical interfacial bonding ratio when the interphase and matrix atoms have the same mobility is 5.8%. These results demonstrate that the glass transitions of the interphase and matrix will be asynchronous when the interfacial bonding ratio is not 5.8%. Specifically, the interphase region will trigger the glass transition of the matrix when the ratio is larger than 5.8%, whereas it restrains the glass transition of the matrix when the ratio is smaller than 5.8%. PMID- 26927033 TI - Heterogeneous Phase Microwave-Assisted Reactions under CO2 or CO Pressure. AB - The present review deals with the recent achievements and impressive potential applications of microwave (MW) heating to promote heterogeneous reactions under gas pressure. The high versatility of the latest generation of professional reactors combines extreme reaction conditions with safer and more efficient protocols. The double aims of this survey are to provide a panoramic snapshot of MW-assisted organic reactions with gaseous reagents, in particular CO and CO2, and outline future applications. Stubborn and time-consuming carbonylation-like heterogeneous reactions, which have not yet been studied under dielectric heating, may well find an outstanding ally in the present protocol. PMID- 26927034 TI - Exotic Vegetable Oils for Cosmetic O/W Nanoemulsions: In Vivo Evaluation. AB - Oil-in-water nanoemulsions are stable systems with droplet sizes in the 20-200 nm range. The physicochemical properties of these systems may be influenced by the addition of additives. Thus, the influence of ethoxylated (EL) and acetylated lanolin (AL) addition on the droplet size, pH values, electrical conductivity and stability of nanoemulsions was investigated. Then, effect of nano-emulsions additives with EL (NE-EL) or AL (NE-AL) in hydration, oiliness and pH of the skin were evaluated. Nanoemulsion safety was evaluated through the observation of no undesirable effects after skin formulation application. Both additives caused changes in droplet size and electrical conductivity, but not in pH values. Nanoemulsions containing up to 6.0% ethoxylated lanolin and 2.0% acetylated lanolin remained stable after centrifugation tests. Higher concentrations of the additives made the nanoemulsions unstable. Stability tests showed that ethoxylated lanolin produced more stable nanoemulsions then acetylated lanolin and that the major instability phenomenon occurring in these systems is coalescence at elevated temperatures. Nanoemulsion-based lanolin derivatives increased skin hydration and oiliness and did not change cutaneous pH values. These formulations are non-toxic since they did not cause any irritation on the skin surface after nanoemulsion application, showing potential as carriers for pharmaceuticals and cosmetic applications. PMID- 26927035 TI - Statistical Correlations between HPLC Activity-Based Profiling Results and NMR/MS Microfraction Data to Deconvolute Bioactive Compounds in Mixtures. AB - Recent approaches in natural product (NP) research are leading toward the discovery of bioactive chemical entities at the microgram level. In comparison to classical large scale bioassay-guided fractionation, the use of LC-MS metabolite profiling in combination with microfractionation for both bioactivity profiling and NMR analysis, allows the identification of bioactive compounds at a very early stage. In that context, this study aims to assess the potential of statistic correlation analysis to enable unambiguous identification of features related to bioactive compounds in mixtures, without the need for complete isolation. For that purpose, a mixture of NPs was microfractionated by rapid small-scale semi-preparative HPLC for proof-of-concept. UHPLC-ESI-TOFMS profiles, micro-flow CapNMR spectra and a cancer chemopreventive assay carried out on every microfraction were analysed by statistical correlations. PMID- 26927036 TI - New Bufadienolides Isolated from the Roots of Kalanchoe daigremontiana (Crassulaceae). AB - An aqueous extract from the roots of Kalanchoe daigremontiana turned out to be a rich source of bufadienolides. The existing literature data relate mainly to the aerial parts of Kalanchoe but there is no information about the metabolic profile of the roots, which are also used in traditional medicine. Our investigation concerning the roots of K. daigremontiana led to the isolation and characterization of eight new bufadienolides, namely 1beta,3beta,5beta,14beta,19 pentahydroxybufa-20,22-dienolide (1), 19-(acetyloxy)-1beta,3beta,5beta,14beta tetrahydroxybufa-20,22-dienolide (2), 3beta-O-alpha-l-rhamno-pyranosyl 5beta,11alpha,14beta,19-tetrahydroxybufa-20,22-dienolide (3), 19-(acetyloxy) 3beta,5beta,11alpha,14beta-tetrahydroxybufa-20,22-dienolide (4), 3beta,5beta,11alpha,14beta,19-pentahydroxy-12-oxo-bufa-20,22-dienolide (5), 19 (acetyloxy)-3beta,5beta,11alpha,14beta-tetrahydroxy-12-oxo-bufa-20,22-dienolide (6), 19-(acetyloxy)-1beta,3beta,5beta,11alpha,14beta-pentahydroxy-12-oxo-bufa 20,22-dienolide (7) and 1beta-(acetyloxy)-3beta,5beta,11alpha,14beta,19 pentahydroxy-12-oxo-bufa-20,22-dienolide (8), together with seven known compounds: 11alpha,19-dihydroxytelocinobufagin (9), bersaldegenin-1-acetate (10), daigredorigenin-3-acetate (11), bersaldegenin-1,3,5-orthoacetate (12), bryotoxin B (13), bryophyllin B (14) and bersaldegenin (15). The structures were established applying extensive 1D- and 2D-NMR and MS spectroscopic analyses. PMID- 26927037 TI - Preparation and Biological Evaluation of Two Novel Platinum(II) Complexes Based on the Ligands of Dipicolyamine Bisphosphonate Esters. AB - Two new platinum(II)-based complexes bearing a bone-targeting group were synthesized and characterized. They both have excellent affinity for hydroxyapatite (HA), which is abundant in human bone tissues. Their antitumor activities against five human cancer cell lines (U2OS, A549, HCT116, MDA-MB-231 and HepG2) were evaluated and compared with cisplatin (CDDP). Though the antitumor efficacies of new complexes are lower than that of CDDP, they show higher selectivity against the HepG2 hepatoma cell line than the L02 normal liver cell line. Morphology studies exhibited typical characteristics of cell apoptosis and the cell cycle distribution analysis indicated that the complexes can inhibit cancer cells by inducing cell cycle arrest at the G2/M phase, a similar mechanism of action to CDDP. PMID- 26927038 TI - Potential Use of Turkish Medicinal Plants in the Treatment of Various Diseases. AB - Medicinal plants are sources of health-promoting substances, including phytochemicals and phytoalexins that comprise polyphenols, flavonoids, carotenoids, vitamins A, C, E and several other constituents. Many studies have indicated that medicinal plants have been used to treat human diseases for thousands of years owing to their antimicrobial and antioxidant activities. Medicinal plants reduce the oxidative stress in cells and prevent cancer, cardiovascular and inflammatory diseases, neurodegenerative and digestive system disorders. These potential beneficial effects have been attributed to the presence of bioactive compounds that show antioxidant properties by acting as free radical scavengers or metal chelators, reducing the reactions that produce reactive oxygen and nitrogen species (ROS/RNS). Considering the importance of medicinal plants in terms of their beneficial health effects, some of the medicinally important plants grown in Turkey are covered in this review with respect to their antioxidant potential and phytochemical profile. PMID- 26927039 TI - An Efficient Chemical Synthesis of Scutellarein: An in Vivo Metabolite of Scutellarin. AB - Scutellarein (2), which is an important in vivo metabolite of scutellarin (1), was synthesized from 3,4,5-trimethoxyphenol (3) in high yield in four steps. This strategy relies on acetylation, aldolization, cyclization and hydrolysis reactions, respectively. PMID- 26927040 TI - Antidepressant Potential of Chlorogenic Acid-Enriched Extract from Eucommia ulmoides Oliver Bark with Neuron Protection and Promotion of Serotonin Release through Enhancing Synapsin I Expression. AB - Eucommia ulmoides Oliver (E. ulmoides) is a traditional Chinese medicine with many beneficial effects, used as a tonic medicine in China and other countries. Chlorogenic acid (CGA) is an important compound in E. ulmoides with neuroprotective, cognition improvement and other pharmacological effects. However, it is unknown whether chlorogenic acid-enriched Eucommia ulmoides Oliver bark has antidepressant potential through neuron protection, serotonin release promotion and penetration of blood-cerebrospinal fluid barrier. In the present study, we demonstrated that CGA could stimulate axon and dendrite growth and promote serotonin release through enhancing synapsin I expression in the cells of fetal rat raphe neurons in vitro. More importantly, CGA-enriched extract of E. ulmoides (EUWE) at 200 and 400 mg/kg/day orally administered for 7 days showed antidepressant-like effects in the tail suspension test of KM mice. Furthermore, we also found CGA could be detected in the the cerebrospinal fluid of the rats orally treated with EUWE and reach the level of pharmacological effect for neuroprotection by UHPLC-ESI-MS/MS. The findings indicate CGA is able to cross the blood-cerebrospinal fluid barrier to exhibit its neuron protection and promotion of serotonin release through enhancing synapsin I expression. This is the first report of the effect of CGA on promoting 5-HT release through enhancing synapsin I expression and CGA-enriched EUWE has antidepressant-like effect in vivo. EUWE may be developed as the natural drugs for the treatment of depression. PMID- 26927041 TI - Curcumin and Health. AB - Nowadays, there are some molecules that have shown over the years a high capacity to act against relevant pathologies such as cardiovascular disease, neurodegenerative disorders or cancer. This article provides a brief review about the origin, bioavailability and new research on curcumin and synthetized derivatives. It examines the beneficial effects on health, delving into aspects such as cancer, cardiovascular effects, metabolic syndrome, antioxidant capacity, anti-inflammatory properties, and neurological, liver and respiratory disorders. Thanks to all these activities, curcumin is positioned as an interesting nutraceutical. This is the reason why it has been subjected to several modifications in its structure and administration form that have permitted an increase in bioavailability and effectiveness against different diseases, decreasing the mortality and morbidity associated to these pathologies. PMID- 26927042 TI - Solanum nigrum Protects against Hepatic Fibrosis via Suppression of Hyperglycemia in High-Fat/Ethanol Diet-Induced Rats. AB - BACKGROUND: Advanced glycation end products (AGEs) signal through the receptor for AGE (RAGE), which can lead to hepatic fibrosis in hyperglycemia and hyperlipidemia. We investigated the inhibitory effect of aqueous extracts from Solanum nigrum (AESN) on AGEs-induced RAGE signaling and activation of hepatic stellate cells (HSCs) and hyperglycemia induced by high-fat diet with ethanol. METHODS: An animal model was used to evaluate the anti-hepatic fibrosis activity of AESN in rats fed a high-fat diet (HFD; 30%) with ethanol (10%). Male Wistar rats (4 weeks of age) were randomly divided into four groups (n = 6): (1) control (basal diet); (2) HFD (30%) + ethanol (10%) (HFD/ethanol); (3) HFD/ethanol + AESN (100 mg/kg, oral administration); and (4) HFD/ethanol + pioglitazone (10 mg/kg, oral administration) and treated with HFD for 6 months in the presence or absence of 10% ethanol in dietary water. RESULTS: We found that AESN improved insulin resistance and hyperinsulinemia, and downregulated lipogenesis via regulation of the peroxisome proliferator-activated receptor alpha (PPARalpha), PPARgamma co activator (PGC-1alpha), carbohydrate response element-binding protein (ChREBP), acetyl-CoA carboxylase (ACC), and fatty acid synthase (FAS) mRNA levels in the liver of HFD/ethanol-treated rats. In turn, AESN may delay and inhibit the progression of hepatic fibrosis, including alpha-smooth muscle actin (alpha-SMA) inhibition and MMP-2 production. CONCLUSIONS: These results suggest that AESN may be further explored as a novel anti-fibrotic strategy for the prevention of liver disease. PMID- 26927043 TI - Au-Based Catalysts: Electrochemical Characterization for Structural Insights. AB - Au-based catalysts are widely used in important processes because of their peculiar characteristics. The catalyst performance depends strongly on the nature and structure of the metal nanoparticles, especially in the case of bimetallic catalysts where synergistic effects between the two metals can be occasionally seen. In this paper, it is shown that electrochemical characterisation (cyclovoltammetry CV and electrochemical impedance spectroscopy EIS) of AuPd systems can be used to determine the presence of an electronic interaction between the two metals, thus providing a strong support in the determination of the nature of the synergy between Au and Pd in the liquid phase oxidation of alcohols. However, it seems likely that the strong difference in the catalytic behavior between the single metals and the bimetallic system is connected not only to the redox behaviour, but also to the energetic balance between the different elementary steps of the reaction. PMID- 26927044 TI - Synthesis of N-(6-Arylbenzo[d]thiazole-2-acetamide Derivatives and Their Biological Activities: An Experimental and Computational Approach. AB - A new series of N-(6-arylbenzo[d]thiazol-2-yl)acetamides were synthesized by C-C coupling methodology in the presence of Pd(0) using various aryl boronic pinacol ester/acids. The newly synthesized compounds were evaluated for various biological activities like antioxidant, haemolytic, antibacterial and urease inhibition. In bioassays these compounds were found to have moderate to good activities. Among the tested biological activities screened these compounds displayed the most significant activity for urease inhibition. In urease inhibition, all compounds were found more active than the standard used. The compound N-(6-(p-tolyl)benzo[d]thiazol-2-yl)acetamide was found to be the most active. To understand this urease inhibition, molecular docking studies were performed. The in silico studies showed that these acetamide derivatives bind to the non-metallic active site of the urease enzyme. Structure-activity studies revealed that H-bonding of compounds with the enzyme is important for its inhibition. PMID- 26927045 TI - Application of Ionic Liquids in Pot-in-Pot Reactions. AB - Pot-in-pot reactions are designed such that two reaction media (solvents, catalysts and reagents) are isolated from each other by a polymeric membrane similar to matryoshka dolls (Russian nesting dolls). The first reaction is allowed to progress to completion before triggering the second reaction in which all necessary solvents, reactants, or catalysts are placed except for the starting reagent for the target reaction. With the appropriate trigger, in most cases unidirectional flux, the product of the first reaction is introduced to the second medium allowing a second transformation in the same glass reaction pot- albeit separated by a polymeric membrane. The basis of these reaction systems is the controlled selective flux of one reagent over the other components of the first reaction while maintaining steady-state catalyst concentration in the first "pot". The use of ionic liquids as tools to control chemical potential across the polymeric membranes making the first pot is discussed based on standard diffusion models--Fickian and Payne's models. Besides chemical potential, use of ionic liquids as delivery agent for a small amount of a solvent that slightly swells the polymeric membrane, hence increasing flux, is highlighted. This review highlights the critical role ionic liquids play in site-isolation of multiple catalyzed reactions in a standard pot-in-pot reaction. PMID- 26927046 TI - Structure Determination of Novel Oxidation Products from Epicatechin: Thearubigin Like Molecules. AB - Following the oxidation of epicatechin (EC), three novel compounds and two known compounds were isolated. The chemical structures of these oxidation products were determined by mass spectrometry (MS) and various nuclear magnetic resonance (NMR) experiments, and the A-ring-B-ring linkage that is characteristic of catechin was found in each molecule. Three compounds showed similar ultraviolet-visible (UV Vis) spectra to EC, whereas two compounds showed different spectral absorption in the region between 300 and 500 nm. A similar spectrum was obtained for the thearubigin fraction prepared from a black tea infusion. This result suggests that the condensation reaction between the A-ring and B-ring is more important than reaction between B-rings for thearubigin formation. PMID- 26927047 TI - Sesquiterpenoids from Chinese Agarwood Induced by Artificial Holing. AB - Two new sesquiterpenoids, 3-oxo-7-hydroxylholosericin A (1) and 1,5;8,12-diepoxy guaia-12-one (2), together with seven known sesquiterpenoids 3-9, were isolated from Chinese agarwood induced by artificial holing originating from Aquilaria sinensis (Lour.) Gilg. Their structures were identified by spectroscopic techniques (UV, IR, 1D and 2D NMR) and MS analyses. The absolute configuration of compound 1 was determined by comparison of its measured CD curve with that of calculated data for 1 and ent-1. The NMR data of 3 were reported in this study for the first time. Compounds 1, 2, 4-6, together with the EtOAc extract showed moderate inhibitory activities against acetylcholinesterase, and compounds 4-6, 8 exhibited antibacterial activities against Staphylococcus aureus or Ralstonia solanacearum. PMID- 26927048 TI - Biological Validation of Novel Polysubstituted Pyrazole Candidates with in Vitro Anticancer Activities. AB - With the aim of developing novel antitumor scaffolds, a novel series of polysubstituted pyrazole derivatives linked to different nitrogenous heterocyclic ring systems at the C-4 position were synthesized through different chemical reactions and characterized by means of spectral and elemental analyses and their antiproliferative activity against 60 different human tumor cell lines was validated by the U.S. National Cancer Institute using a two stage process. The in vitro anticancer evaluation revealed that compound 9 showed increased potency toward most human tumor cell lines with GI50MG-MID = 3.59 uM, as compared to the standard drug sorafenib (GI50 MG-MID = 1.90 uM). At the same time, compounds 6a and 7 were selective against the HOP-92 cell line of non-small cell lung cancer with GI50 1.65 and 1.61 uM, respectively. PMID- 26927049 TI - Cytotoxic 1,3-Thiazole and 1,2,4-Thiadiazole Alkaloids from Penicillium oxalicum: Structural Elucidation and Total Synthesis. AB - Two new thiazole and thiadiazole alkaloids, penicilliumthiamine A and B (2 and 3), were isolated from the culture broth of Penicillium oxalicum, a fungus found in Acrida cinerea. Their structures were elucidated mainly by spectroscopic analysis, total synthesis and X-ray crystallographic analysis. Biological evaluations indicated that compound 1, 3a and 3 exhibit potent cytotoxicity against different cancer cell lines through inhibiting the phosphorylation of AKT/PKB (Ser 473), one of important cancer drugs target. PMID- 26927050 TI - Three New Sesquiterpenoids and One New Sesquiterpenoid Derivative from Chinese Eaglewood. AB - Three new sesquiterpenoids (1-3) and one new sesquiterpenoid derivative (4), along with three known sesquiterpenoids (5-7), were isolated from the 95% ethanolic extract of Chinese eaglewood [Aquilaria sinensis (Lour.) Gilg]. The structures of these compounds were elucidated through extensive analysis of spectroscopic data including IR, NMR, HRESIMS, and X-ray diffraction experiments. In addition, the above new compounds were detected for their bioactivities against LPS-induced NO production in RAW 264.7 cells. Among them, compound 2 exhibited obvious anti-inflammatory activity with an IC50 value of 8.1 MUM. PMID- 26927051 TI - New Approaches to the Role of Thrombin in Acute Coronary Syndromes: Quo Vadis Bivalirudin, a Direct Thrombin Inhibitor? AB - The pathophysiology of acute coronary syndrome (ACS) involves platelet activation and thrombus formation after the rupture of atherosclerotic plaques. Thrombin is generated at the blood-plaque interface in association with cellular membranes on cells and platelets. Thrombin also amplifies the response to the tissue injury, coagulation and platelet response, so the treatment of ACS is based on the combined use of both antiplatelet (such as aspirin, clopidogrel, prasugrel and ticagrelor) and antithrombotic drugs (unfractionated heparin, enoxaparin, fondaparinux and bivalirudin). Bivalirudin competitively inhibits thrombin with high affinity, a predictable response from its linear pharmacokinetics and short action. However, a present remarkable controversy exists between the latest main Guidelines in Clinical Practice and the key trials evaluating the use of bivalirudin in ACS. The aim of this review is to update the development of bivalirudin, including pharmacological properties, obtained information from clinical trials evaluating efficacy and safety of bivalirudin in ACS; as well as the recommendations of clinical Guidelines. PMID- 26927052 TI - Natural Products from Chinese Medicines with Potential Benefits to Bone Health. AB - Osteoporosis is a progressive, systemic bone disorder characterized by loss of bone mass and microstructure, leading to reduced bone strength and increased risk of fracture. It is often associated with reduced quality of life and other medical complications. The disease is common in the aging population, particularly among postmenopausal women and patients who receive long-term steroidal therapy. Given the rapid growth of the aging population, increasing life expectancy, the prevalence of bone loss, and financial burden to the healthcare system and individuals, demand for new therapeutic agents and nutritional supplements for the management and promotion of bone health is pressing. With the advent of global interest in complementary and alternative medicine and natural products, Chinese medicine serves as a viable source to offer benefits for the improvement and maintenance of bone health. This review summarizes the scientific information obtained from recent literatures on the chemical ingredients of Chinese medicinal plants that have been reported to possess osteoprotective and related properties in cell-based and/or animal models. Some of these natural products (or their derivatives) may become promising leads for development into dietary supplements or therapeutic drugs. PMID- 26927053 TI - Quantitative Variation of Flavonoids and Diterpenes in Leaves and Stems of Cistus ladanifer L. at Different Ages. AB - The compounds derived from secondary metabolism in plants perform a variety of ecological functions, providing the plant with resistance to biotic and abiotic factors. The basal levels of these metabolites for each organ, tissue or cell type depend on the development stage of the plant and they may be modified as a response to biotic and/or abiotic stress. As a consequence, the resistance state of a plant may vary in space and time. The secondary metabolites of Cistus ladanifer have been quantified in leaves and stems throughout autumn, winter, spring and summer, and at different ages of the plant. This study shows that there are significant differences between young leaves, mature leaves and stems, and between individuals of different ages. Young leaves show significantly greater synthesis of flavonoids and diterpenes than mature leaves and stems, with a clear seasonal variation, and the differences between leaves at different growth stages and stems is maintained during the quantified seasons. With respect to age, specimens under one year of age secreted significantly lower amounts of compounds. The variation in the composition of secondary metabolites between different parts of the plant, the season and the variations in age may determine the interactions of Cistus ladanifer with the biotic and abiotic factors to which it is exposed. PMID- 26927054 TI - Synthesis and Bioactivities of Novel Pyrazole Oxime Derivatives Containing a 5 Trifluoromethylpyridyl Moiety. AB - In this study, in order to find novel biologically active pyrazole oxime compounds, a series of pyrazole oxime derivatives containing a 5 trifluoromethylpyridyl moiety were synthesized. Preliminary bioassays indicated that most title compounds were found to display good to excellent acaricidal activity against Tetranychus cinnabarinus at a concentration of 200 MUg/mL, and some designed compounds still showed excellent acaricidal activity against Tetranychus cinnabarinus at the concentration of 10 MUg/mL, especially since the inhibition rates of compounds 8e, 8f, 8l, 8m, 8n, 8p, and 8q were all 100.00%. Interestingly, some target compounds exhibited moderate to good insecticidal activities against Plutella xylostella and Aphis craccivora at a concentration of 200 MUg/mL; furthermore, compounds 8e and 8l possessed outstanding insecticidal activities against Plutella xylostella under the concentration of 50 MUg/mL. PMID- 26927055 TI - Antidepressant-Like Effects of Lindera obtusiloba Extracts on the Immobility Behavior of Rats in the Forced Swim Test. AB - Lindera obtusiloba extracts are commonly used as an alternative medicine due to its numerous health benefits in Korea. However, the antidepressant-like effects of L. obtusiloba extracts have not been fully elucidated. In this study, we aimed to determine whether L. obtusiloba extracts exhibited antidepressant-like activity in rats subjected to forced swim test (FST)-induced depression. Acute treatment of rats with L. obtusiloba extracts (200 mg/kg, p.o.) significantly reduced immobility time and increased swimming time without any significant change in climbing. Rats treated with L. obtusiloba extracts also exhibited a decrease in the limbic hypothalamic-pituitary-adrenal (HPA) axis response to the FST, as indicated by attenuation of the corticosterone response and decreased c Fos immunoreactivity in the hippocampus CA3 region. In addition, L. obtusiloba extracts, at concentrations that were not affected by cell viability, significantly decreased luciferase activity in response to cortisol in a concentration-dependent manner by the glucocorticoid binding assay in HeLa cells. Our findings suggested that the antidepressant-like effects of L. obtusiloba extracts were likely mediated via the glucocorticoid receptor (GR). Further studies are needed to evaluate the potential of L. obtusiloba extracts as an alternative therapeutic approach for the treatment of depression. PMID- 26927056 TI - Rhodium Porphyrin Bound to a Merrifield Resin as Heterogeneous Catalyst for the Cyclopropanation Reaction of Olefins. AB - Cyclopropanation reaction is an important tool for obtaining interesting compounds and can be catalyzed by metalloporphyrins with high syn/anti ratio. The catalyst cannot be recycled and is usually lost during chromatographic separation from the two isomeric products. In this paper a meso-tetraphenylporphyrin rhodium(III) chloride was bound to a Merrifield resin and used to catalyze the cyclopropanation reaction of nine olefins, giving good yields and selectivities of the final products and for the first time, a partial recycling of the catalyst. This new catalytic system will be tested in the future for the synthesis of natural products containing cyclopropyl ring. PMID- 26927057 TI - 1-Deoxynojirimycin Alleviates Liver Injury and Improves Hepatic Glucose Metabolism in db/db Mice. AB - The present study investigated the effect of 1-Deoxynojirimycin (DNJ) on liver injury and hepatic glucose metabolism in db/db mice. Mice were divided into five groups: normal control, db/db control, DNJ-20 (DNJ 20 mg.kg(-1).day(-1)), DNJ-40 (DNJ 40 mg.kg(-1).day(-1)) and DNJ-80 (DNJ 80 mg.kg(-1).day(-1)). All doses were treated intravenously by tail vein for four weeks. DNJ was observed to significantly reduce the levels of serum triglyceride (TG), total cholesterol (TC), low density lipoprotein cholesterol (LDL-C) and liver TG, as well as activities of serum alanine aminotransferase (ALT), and aspartate transaminase (AST); DNJ also alleviated macrovesicular steatosis and decreased tumor necrosis factor alpha (TNF-alpha), interleukin-1 (IL-1), interleukin-6 (IL-6) levels in liver tissue. Furthermore, DNJ treatment significantly increased hepatic glycogen content, the activities of hexokinase (HK), pyruvate kinase (PK) in liver tissue, and decreased the activities of glucose-6-phosphatase (G6Pase), glycogen phosphorylase (GP), and phosphoenolpyruvate carboxykinase (PEPCK). Moreover, DNJ increased the phosphorylation of phosphatidylinositol 3 kinase (PI3K) on p85, protein kinase B (PKB) on Ser473, glycogen synthase kinase 3beta (GSK-3beta) on Ser9, and inhibited phosphorylation of glycogen synthase (GS) on Ser645 in liver tissue of db/db mice. These results demonstrate that DNJ can increase hepatic insulin sensitivity via strengthening of the insulin-stimulated PKB/GSK-3beta signal pathway and by modulating glucose metabolic enzymes in db/db mice. Moreover, DNJ also can improve lipid homeostasis and attenuate hepatic steatosis in db/db mice. PMID- 26927058 TI - Targeting Reactive Carbonyl Species with Natural Sequestering Agents. AB - Reactive carbonyl species generated by the oxidation of polyunsaturated fatty acids and sugars are highly reactive due to their electrophilic nature, and are able to easily react with the nucleophilic sites of proteins as well as DNA causing cellular dysfunction. Levels of reactive carbonyl species and their reaction products have been reported to be elevated in various chronic diseases, including metabolic disorders and neurodegenerative diseases. In an effort to identify sequestering agents for reactive carbonyl species, various analytical techniques such as spectrophotometry, high performance liquid chromatography, western blot, and mass spectrometry have been utilized. In particular, recent advances using a novel high resolution mass spectrometry approach allows screening of complex mixtures such as natural products for their sequestering ability of reactive carbonyl species. To overcome the limited bioavailability and bioefficacy of natural products, new techniques using nanoparticles and nanocarriers may offer a new attractive strategy for increased in vivo utilization and targeted delivery of bioactives. PMID- 26927059 TI - Using Copy Number Alterations to Identify New Therapeutic Targets for Bladder Carcinoma. AB - Bladder cancer represents the ninth most widespread malignancy throughout the world. It is characterized by the presence of two different clinical and prognostic subtypes: non-muscle-invasive bladder cancers (NMIBCs) and muscle invasive bladder cancers (MIBCs). MIBCs have a poor outcome with a common progression to metastasis. Despite improvements in knowledge, treatment has not advanced significantly in recent years, with the absence of new therapeutic targets. Because of the limitations of current therapeutic options, the greater challenge will be to identify biomarkers for clinical application. For this reason, we compared our array comparative genomic hybridization (array-CGH) results with those reported in literature for invasive bladder tumors and, in particular, we focused on the evaluation of copy number alterations (CNAs) present in biopsies and retained in the corresponding cancer stem cell (CSC) subpopulations that should be the main target of therapy. According to our data, CCNE1, MYC, MDM2 and PPARG genes could be interesting therapeutic targets for bladder CSC subpopulations. Surprisingly, HER2 copy number gains are not retained in bladder CSCs, making the gene-targeted therapy less interesting than the others. These results provide precious advice for further study on bladder therapy; however, the clinical importance of these results should be explored. PMID- 26927060 TI - Critical Overview of the Risk Scoring Systems to Predict Non-Responsiveness to Intravenous Immunoglobulin in Kawasaki Syndrome. AB - Kawasaki syndrome (KS) is the most relevant cause of heart disease in children living in developed countries. Intravenous immunoglobulin (IVIG) has a preventive function in the formation of coronary artery abnormalities and a poor strictly curative action in established coronary damage. More than two decades ago, the Harada score was set to assess which children with KS should be subject to administration of IVIG, evaluating retrospectively a large cohort of patients with regard to age, sex and laboratory data. Nowadays, high dose IVIG is administered to all children with a confirmed diagnosis of KS, but a tool for predicting non-responsiveness to the initial infusion of IVIG has not been found. The prediction of IVIG resistance is a crucial issue, as recognising these high risk patients should consent the administration of an intensified initial treatment in combination with IVIG in order to prevent coronary injuries. Few reports have focused on factors, referring to both clinical parameters and laboratory data at the onset of KS, in order to predict which patients might be IVIG non-responsive. We have analysed three different risk scores which were formulated to predict IVIG resistance in Japanese children with typical KS, but their application in non-Japanese patients or in those with incomplete and atypical patterns of the disease has been studied in a fragmentary way. Overall, our analysis showed that early and definite ascertainment of likely IVIG non responders who require additional therapies reducing the development of coronary artery involvement in children with KS is still a challenge. PMID- 26927061 TI - Integrative Analyses of miRNA-mRNA Interactions Reveal let-7b, miR-128 and MAPK Pathway Involvement in Muscle Mass Loss in Sex-Linked Dwarf Chickens. AB - The sex-linked dwarf (SLD) chicken is an ideal model system for understanding growth hormone (GH)-action and growth hormone receptor (GHR) function because of its recessive mutation in the GHR gene. Skeletal muscle mass is reduced in the SLD chicken with a smaller muscle fiber diameter. Our previous study has presented the mRNA and miRNA expression profiles of the SLD chicken and normal chicken between embryo day 14 and seven weeks of age. However, the molecular mechanism of GHR-deficient induced muscle mass loss is still unclear, and the key molecules and pathways underlying the GHR-deficient induced muscle mass loss also remain to be illustrated. Here, by functional network analysis of the differentially expressed miRNAs and mRNAs between the SLD and normal chickens, we revealed that let-7b, miR-128 and the MAPK pathway might play key roles in the GHR-deficient induced muscle mass loss, and that the reduced cell division and growth are potential cellular processes during the SLD chicken skeletal muscle development. Additionally, we also found some genes and miRNAs involved in chicken skeletal muscle development, through the MAPK, PI3K-Akt, Wnt and Insulin signaling pathways. This study provides new insights into the molecular mechanism underlying muscle mass loss in the SLD chickens, and some regulatory networks that are crucial for chicken skeletal muscle development. PMID- 26927062 TI - The Role of Sialyl-Tn in Cancer. AB - Activation of an aberrant glycosylation pathway in cancer cells can lead to expression of the onco-foetal sialyl-Tn (sTn) antigen. STn is a truncated O glycan containing a sialic acid alpha-2,6 linked to GalNAc alpha-O-Ser/Thr and is linked with an adverse outcome and poor prognosis in cancer patients. The biosynthesis of the sTn antigen has been linked to the expression of the sialytransferase ST6GalNAc1, and also to mutations in and loss of heterozygosity of the COSMC gene. sTn neo- or over-expression occurs in many types of epithelial cancer including gastric, colon, breast, lung, oesophageal, prostate and endometrial cancer. sTn is believed to be carried by a variety of glycoproteins and may influence protein function and be involved in tumour development. This review discusses how the role of sTn in cancer development and tumour cell invasiveness might be organ specific and occur through different mechanisms depending on each cancer type or subtype. As the sTn-antigen is expressed early in carcinogenesis targeting sTn in cancer may enable the targeting of tumours from the earliest stage. PMID- 26927064 TI - Multiple Evolutionary Selections Involved in Synonymous Codon Usages in the Streptococcus agalactiae Genome. AB - Streptococcus agalactiae is an important human and animal pathogen. To better understand the genetic features and evolution of S. agalactiae, multiple factors influencing synonymous codon usage patterns in S. agalactiae were analyzed in this study. A- and U-ending rich codons were used in S. agalactiae function genes through the overall codon usage analysis, indicating that Adenine (A)/Thymine (T) compositional constraints might contribute an important role to the synonymous codon usage pattern. The GC3% against the effective number of codon (ENC) value suggested that translational selection was the important factor for codon bias in the microorganism. Principal component analysis (PCA) showed that (i) mutational pressure was the most important factor in shaping codon usage of all open reading frames (ORFs) in the S. agalactiae genome; (ii) strand specific mutational bias was not capable of influencing the codon usage bias in the leading and lagging strands; and (iii) gene length was not the important factor in synonymous codon usage pattern in this organism. Additionally, the high correlation between tRNA adaptation index (tAI) value and codon adaptation index (CAI), frequency of optimal codons (Fop) value, reinforced the role of natural selection for efficient translation in S. agalactiae. Comparison of synonymous codon usage pattern between S. agalactiae and susceptible hosts (human and tilapia) showed that synonymous codon usage of S. agalactiae was independent of the synonymous codon usage of susceptible hosts. The study of codon usage in S. agalactiae may provide evidence about the molecular evolution of the bacterium and a greater understanding of evolutionary relationships between S. agalactiae and its hosts. PMID- 26927063 TI - MicroRNAs as Biomarkers for Liver Disease and Hepatocellular Carcinoma. AB - Serum levels of liver enzymes, such as alanine transaminase, aspartate transaminase, and alpha-fetoprotein, provide insight into liver function and are used during treatment of liver disease, but such information is limited. In the case of hepatocellular carcinoma (HCC), which is often not detected until an advanced stage, more sensitive biomarkers may help to achieve earlier detection. Serum also contains microRNAs, a class of small non-coding RNAs that play an important role in regulating gene expression. miR-122 is specific to the liver and correlates strongly with liver enzyme levels and necroinflammatory activity, and other microRNAs are correlated with the degree of fibrosis. miR-122 has also been found to be required for hepatitis C virus (HCV) infection, whereas other microRNAs have been shown to play antiviral roles. miR-125a-5p and miR-1231 have been shown to directly target hepatitis B virus (HBV) transcripts, and others are up- or down-regulated in infected individuals. MicroRNA profiles also differ in the case of HBV and HCV infection as well as between HBeAg-positive and negative patients, and in patients with occult versus active HBV infection. In such patients, monitoring of changes in microRNA profiles might provide earlier warning of neoplastic changes preceding HCC. PMID- 26927065 TI - Synergetic Effects of PARP Inhibitor AZD2281 and Cisplatin in Oral Squamous Cell Carcinoma in Vitro and in Vivo. AB - Cisplatin is a commonly used chemotherapeutic drug for treatment of oral carcinoma, and combinatorial effects are expected to exert greater therapeutic efficacy compared with monotherapy. Poly(ADP-ribosyl)ation is reported to be involved in a variety of cellular processes, such as DNA repair, cell death, telomere regulation, and genomic stability. Based on these properties, poly(ADP ribose) polymerase (PARP) inhibitors are used for treatment of cancers, such as BRCA1/2 mutated breast and ovarian cancers, or certain solid cancers in combination with anti-cancer drugs. However, the effects on oral cancer have not been fully evaluated. In this study, we examined the effects of PARP inhibitor on the survival of human oral cancer cells in vitro and xenografted tumors derived from human oral cancer cells in vivo. In vitro effects were assessed by microculture tetrazolium and survival assays. The PARP inhibitor AZD2281 (olaparib) showed synergetic effects with cisplatin in a dose-dependent manner. Combinatorial treatment with cisplatin and AZD2281 significantly inhibited xenografted tumor growth compared with single treatment of cisplatin or AZD2281. Histopathological analysis revealed that cisplatin and AZD2281 increased TUNEL positive cells and decreased Ki67- and CD31-positive cells. These results suggest that PARP inhibitors have the potential to improve therapeutic strategies for oral cancer. PMID- 26927066 TI - Mycobacterium tuberculosis: Manipulator of Protective Immunity. AB - Mycobacterium tuberculosis (MTB) is one of the most successful pathogens in human history and remains a global health challenge. MTB has evolved a plethora of strategies to evade the immune response sufficiently to survive within the macrophage in a bacterial-immunological equilibrium, yet causes sufficient immunopathology to facilitate its transmission. This review highlights MTB as the driver of disease pathogenesis and presents evidence of the mechanisms by which MTB manipulates the protective immune response into a pathological productive infection. PMID- 26927068 TI - The Indeterminate Domain Protein ROC1 Regulates Chilling Tolerance via Activation of DREB1B/CBF1 in Rice. AB - Abiotic stress, including salinity, drought and cold, severely affect diverse aspects of plant development and production. Rice is an important crop that does not acclimate to cold; therefore, it is relatively sensitive to low temperature stress. Dehydration-responsive element-binding protein 1s (DREB1s)/C-repeat binding factors (CBFs) are well known for their function in cold tolerance, but the transcriptional regulation of CBFs remains elusive, especially in rice. Here, we performed a yeast one-hybrid assay using the promoter of CBF1, a cold-induced gene, to isolate transcriptional regulators of CBF1. Among the seven candidates identified, an indeterminate domain (IDD) protein named ROC1 (a regulator of CBF1) was further analyzed. The ROC1 transcript was induced by exogenously treated auxin, while it was not altered by cold or ABA stimuli. ROC1-GFP was localized at the nucleus, and ROC1 showed trans-activation activity in yeast. The electrophoretic mobility shift assay (EMSA) and ChIP analyses revealed that ROC1 directly bound to the promoter of CBF1. Furthermore, ROC1 mutants exhibited chilling-sensitive symptoms and inhibited cold-mediated induction of CBF1 and CBF3, indicating that ROC1 is a positive regulator of cold stress responses. Taken together, this study identified the CBF1 regulator, and the results are important for rice plant adaptation to chilling stress. PMID- 26927067 TI - Xylose Fermentation by Saccharomyces cerevisiae: Challenges and Prospects. AB - Many years have passed since the first genetically modified Saccharomyces cerevisiae strains capable of fermenting xylose were obtained with the promise of an environmentally sustainable solution for the conversion of the abundant lignocellulosic biomass to ethanol. Several challenges emerged from these first experiences, most of them related to solving redox imbalances, discovering new pathways for xylose utilization, modulation of the expression of genes of the non oxidative pentose phosphate pathway, and reduction of xylitol formation. Strategies on evolutionary engineering were used to improve fermentation kinetics, but the resulting strains were still far from industrial application. Lignocellulosic hydrolysates proved to have different inhibitors derived from lignin and sugar degradation, along with significant amounts of acetic acid, intrinsically related with biomass deconstruction. This, associated with pH, temperature, high ethanol, and other stress fluctuations presented on large scale fermentations led the search for yeasts with more robust backgrounds, like industrial strains, as engineering targets. Some promising yeasts were obtained both from studies of stress tolerance genes and adaptation on hydrolysates. Since fermentation times on mixed-substrate hydrolysates were still not cost-effective, the more selective search for new or engineered sugar transporters for xylose are still the focus of many recent studies. These challenges, as well as under appreciated process strategies, will be discussed in this review. PMID- 26927069 TI - The Utilization of the Immune System in Lung Cancer Treatment: Beyond Chemotherapy. AB - Lung cancer is ranked first worldwide as one of the main cancers in terms of prevalence and mortality rate. The development of effective treatment strategies against lung cancer is therefore of paramount importance. Traditionally, chemotherapy was employed in the treatment of various cancers. However, the non specific nature of the actions of chemotherapeutic drugs and the potential for tumors to develop resistance to these drugs may render chemotherapy a less favorable option for cancer treatment. Immunotherapy provides an alternative strategy for this purpose. It involves the utilization of the immune system and the immune effector cells to elicit an immune response to the tumors, thereby eliminating them. Strategies include the administration of pro-inflammatory cytokines for immune stimulation, the removal of immunological checkpoints using monoclonal antibodies, and the use of cancer vaccines to enhance immunity against tumors. This article summarizes the above strategies, highlights the reasons why immunotherapy is superior to chemotherapy for the purpose of tumor removal, and reviews the recent clinical studies comparing the clinical outcomes of patients undergoing immunotherapy and chemotherapy. The article also describes advances in immunotherapeutic strategies for the treatment of lung cancer. PMID- 26927070 TI - Changes in Immunogenicity during the Development of Urinary Bladder Cancer: A Preliminary Study. AB - In the present study, we evaluated tumor-infiltrating lymphocytes (TILs) and blood regulatory T lymphocyte (Tregs, CD4+/CD25+/FoxP3+) expression in bladder cancer patients. The number of CD4+, CD8+, CD25+, FoxP3+ and CD20+ TILs was analyzed in association with clinico-pathomorphological features. In more advanced metastasizing tumors, showing non-classic differentiation (ND) and a more aggressive tissue invasion type (TIT), the number of TILs decreased. A low number of CD4+ TILs was associated with poor prognosis. Similarly, Treg frequency before surgery and after surgical treatment was significantly lower in more advanced tumors. The changes in TILs, as well as of local and systemic Tregs, were accompanied by changes in the histological phenotype of urothelial carcinoma regarding pT stage, NDs, TIT, and clinical outcomes. The number of TILs and the frequency of blood Tregs (indicators of antitumor response) may be essential for choosing an immunotherapy that is adjusted to the immune status according to the phase of tumor growth. Moreover, a significant reduction in the number of CD4+ and CD8+ TILs with the development of NDs in more advanced tumors may be associated with lower tumor immunogenicity, resulting in immune tolerance towards tumor tissue. These observations and the tendency of urothelial bladder carcinoma to undergo NDs in a heterogeneous manner during tumor progression suggest complex interactions between bladder cancer immunogenicity and stages of tumor progression. PMID- 26927071 TI - Physiological Investigation and Transcriptome Analysis of Polyethylene Glycol (PEG)-Induced Dehydration Stress in Cassava. AB - Cassava is an important tropical and sub-tropical root crop that is adapted to drought environment. However, severe drought stress significantly influences biomass accumulation and starchy root production. The mechanism underlying drought-tolerance remains obscure in cassava. In this study, changes of physiological characters and gene transcriptome profiles were investigated under dehydration stress simulated by polyethylene glycol (PEG) treatments. Five traits, including peroxidase (POD) activity, proline content, malondialdehyde (MDA), soluble sugar and soluble protein, were all dramatically induced in response to PEG treatment. RNA-seq analysis revealed a gradient decrease of differentially expressed (DE) gene number in tissues from bottom to top of a plant, suggesting that cassava root has a quicker response and more induced/depressed DE genes than leaves in response to drought. Overall, dynamic changes of gene expression profiles in cassava root and leaves were uncovered: genes related to glycolysis, abscisic acid and ethylene biosynthesis, lipid metabolism, protein degradation, and second metabolism of flavonoids were significantly induced, while genes associated with cell cycle/organization, cell wall synthesis and degradation, DNA synthesis and chromatin structure, protein synthesis, light reaction of photosynthesis, gibberelin pathways and abiotic stress were greatly depressed. Finally, novel pathways in ABA-dependent and ABA independent regulatory networks underlying PEG-induced dehydration response in cassava were detected, and the RNA-Seq results of a subset of fifteen genes were confirmed by real-time PCR. The findings will improve our understanding of the mechanism related to dehydration stress-tolerance in cassava and will provide useful candidate genes for breeding of cassava varieties better adapted to drought environment. PMID- 26927072 TI - Two Different Approaches for Oral Administration of Voriconazole Loaded Formulations: Electrospun Fibers versus beta-Cyclodextrin Complexes. AB - In this work, a comparison between two different preparation methods for the improvement of dissolution rate of an antifungal agent is presented. Poly(epsilon caprolactone) (PCL) electrospun fibers and beta-cyclodextrin (beta-CD) complexes, which were produced via an electrospinning process and an inclusion complexation method, respectively, were addressed for the treatment of fungal infections. Voriconazole (VRCZ) drug was selected as a model drug. PCL nanofibers were characterized on the basis of morphology while phase solubility studies for beta CDs complexes were performed. Various concentrations (5, 10, 15 and 20 wt %) of VRCZ were loaded to PCL fibers and beta-CD inclusions to study the in vitro release profile as well as in vitro antifungal activity. The results clearly indicated that all formulations showed an improved VRCZ solubility and can inhibit fungi proliferation. PMID- 26927073 TI - Pressure Combined with Ischemia/Reperfusion Injury Induces Deep Tissue Injury via Endoplasmic Reticulum Stress in a Rat Pressure Ulcer Model. AB - Pressure ulcer is a complex and significant health problem in long-term bedridden patients, and there is currently no effective treatment or efficient prevention method. Furthermore, the molecular mechanisms and pathogenesis contributing to the deep injury of pressure ulcers are unclear. The aim of the study was to explore the role of endoplasmic reticulum (ER) stress and Akt/GSK3beta signaling in pressure ulcers. A model of pressure-induced deep tissue injury in adult Sprague-Dawley rats was established. Rats were treated with 2-h compression and subsequent 0.5-h release for various cycles. After recovery, the tissue in the compressed regions was collected for further analysis. The compressed muscle tissues showed clear cellular degenerative features. First, the expression levels of ER stress proteins GRP78, CHOP, and caspase-12 were generally increased compared to those in the control. Phosphorylated Akt and phosphorylated GSK3beta were upregulated in the beginning of muscle compression, and immediately significantly decreased at the initiation of ischemia-reperfusion injury in compressed muscles tissue. These data show that ER stress may be involved in the underlying mechanisms of cell degeneration after pressure ulcers and that the Akt/GSK3beta signal pathway may play an important role in deep tissue injury induced by pressure and ischemia/reperfusion. PMID- 26927074 TI - Non-Intensive Care Unit Acquired Pneumonia: A New Clinical Entity? AB - Hospital-acquired pneumonia (HAP) is a frequent cause of nosocomial infections, responsible for great morbidity and mortality worldwide. The majority of studies on HAP have been conducted in patients hospitalized in the intensive care unit (ICU), as mechanical ventilation represents a major risk factor for nosocomial pneumonia and specifically for ventilator-associated pneumonia. However, epidemiological data seem to be different between patients acquiring HAP in the ICU vs. general wards, suggesting the importance of identifying non ICU-acquired pneumonia (NIAP) as a clinical distinct entity in terms of both etiology and management. Early detection of NIAP, along with an individualized management, is needed to reduce antibiotic use and side effects, bacterial resistance and mortality. The present article reviews the pathophysiology, diagnosis, treatment and prevention of NIAP. PMID- 26927075 TI - How to Study Biofilms after Microbial Colonization of Materials Used in Orthopaedic Implants. AB - Over the years, various techniques have been proposed for the quantitative evaluation of microbial biofilms. Spectrophotometry after crystal violet staining is a widespread method for biofilm evaluation, but several data indicate that it does not guarantee a good specificity, although it is rather easy to use and cost saving. Confocal laser microscopy is one of the most sensitive and specific tools to study biofilms, and it is largely used for research. However, in some cases, no quantitative measurement of the matrix thickness or of the amount of embedded microorganisms has been performed, due to limitation in availability of dedicated software. For this reason, we have developed a protocol to evaluate the microbial biofilm formed on sandblasted titanium used for orthopaedic implants, that allows measurement of biomass volume and the amount of included cells. Results indicate good reproducibility in terms of measurement of biomass and microbial cells. Moreover, this protocol has proved to be applicable for evaluation of the efficacy of different anti-biofilm treatments used in the orthopaedic setting. Summing up, the protocol here described is a valid and inexpensive method for the study of microbial biofilm on prosthetic implant materials. PMID- 26927076 TI - Nutritional Signaling Regulates Vitellogenin Synthesis and Egg Development through Juvenile Hormone in Nilaparvata lugens (Stal). AB - Insect female reproduction which comprises the synthesis of vitellogenein (Vg) in the fat body and its incorporation into developing oocytes, needs a large amount of energy and food resources. Our previous studies found that juvenile hormone (JH) regulates vitellogenesis in the brown planthopper, Nilaparvata lugens. Here, we report on the role of JH in nutrient-regulated Vg synthesis and egg development. We first cloned the genes coding for juvenile hormone acid methyltransferase (JHAMT) which is involved in JH biosynthesis and methoprene tolerant (Met) for JH action. Amino acids (AAs) induced the expression of jmtN, while showing no effects on the expression of met using an artificial diet culture system. Reduction in JH biosynthesis or its action by RNA interference (RNAi)-mediated silencing of jmtN or met led to a severe inhibition of AAs induced Vg synthesis and oocyte maturation, together with lower fecundity. Furthermore, exogenous application of JH III partially restored Vg expression levels in jmtN RNAi females. However, JH III application did not rescue Vg synthesis in these met RNAi insects. Our results show that AAs induce Vg synthesis in the fat body and egg development in concert with JH biosynthesis in Nilaparvata lugens (Stal), rather than through JH action. PMID- 26927077 TI - New Strategies and Methods to Study Interactions between Tobacco Mosaic Virus Coat Protein and Its Inhibitors. AB - Studies of the targets of anti-viral compounds are hot topics in the field of pesticide research. Various efficient anti-TMV (Tobacco Mosaic Virus) compounds, such as Ningnanmycin (NNM), Antofine (ATF), Dufulin (DFL) and Bingqingxiao (BQX) are available. However, the mechanisms of the action of these compounds on targets remain unclear. To further study the mechanism of the action of the anti TMV inhibitors, the TMV coat protein (TMV CP) was expressed and self-assembled into four-layer aggregate disks in vitro, which could be reassembled into infectious virus particles with TMV RNA. The interactions between the anti-TMV compounds and the TMV CP disk were analyzed by size exclusion chromatography, isothermal titration calorimetry and native-polyacrylamide gel electrophoresis methods. The results revealed that assembly of the four-layer aggregate disk was inhibited by NNM; it changed the four-layer aggregate disk into trimers, and affected the regular assembly of TMV CP and TMV RNA. The four-layer aggregate disk of TMV CP was little inhibited by ATF, DFL and BQX. Our results provide original data, as well as new strategies and methods, for research on the mechanism of action of anti-viral drugs. PMID- 26927078 TI - Identification of Human Adenovirus in Respiratory Samples with Luminex Respiratory Virus Panel Fast V2 Assay and Real-Time Polymerase Chain Reaction. AB - In order to compare the last version of the Respiratory Virus Panel (RVP) Fast assay for human Adenovirus (hAdv) detection with a specific real-time polymerase chain reaction (qPCR), which is considered the gold standard for hAdv detection, nasopharyngeal samples collected from 309 children (age range, four months to eight years) with respiratory tract infection were tested using the RVP Fast v2 assay (Luminex Molecular Diagnostics, Inc., Toronto, ON, Canada) and a specific TaqMan qPCR to identify hAdv DNA. The RVP Fast v2 assay detected 30/61 (49.2%) hAdv infections that had been identified by real-time qPCR, demonstrating a significantly lower detection rate (p < 0.001). The sensitivity of the RVP Fast v2 assay in comparison to qPCR was lower in younger children (42.9% vs. 57.7%; Cohen's kappa coefficient, 0.53); in samples with co-infections (40.0% vs. 56.7%; Cohen's kappa coefficient, 0.52); and in samples with hAdv type C (45.9% vs. 57.1%; Cohen's kappa coefficient, 0.60). Samples with lower viral loads were associated with a significantly lower sensitivity of the RVP Fast v2 assay (35.1% vs. 68.2%, p = 0.01; Cohen's kappa coefficients, 0.49). The RVP Fast v2 assay has important limitations for the detection of hAdv and cannot be used to evaluate whether hAdvs are the main etiologic agent responsible for an outbreak or when epidemiological studies are performed. PMID- 26927080 TI - Silicon-Doped Titanium Dioxide Nanotubes Promoted Bone Formation on Titanium Implants. AB - While titanium (Ti) implants have been extensively used in orthopaedic and dental applications, the intrinsic bioinertness of untreated Ti surface usually results in insufficient osseointegration irrespective of the excellent biocompatibility and mechanical properties of it. In this study, we prepared surface modified Ti substrates in which silicon (Si) was doped into the titanium dioxide (TiO2) nanotubes on Ti surface using plasma immersion ion implantation (PIII) technology. Compared to TiO2 nanotubes and Ti alone, Si-doped TiO2 nanotubes significantly enhanced the expression of genes related to osteogenic differentiation, including Col-I, ALP, Runx2, OCN, and OPN, in mouse pre osteoblastic MC3T3-E1 cells and deposition of mineral matrix. In vivo, the pull out mechanical tests after two weeks of implantation in rat femur showed that Si doped TiO2 nanotubes improved implant fixation strength by 18% and 54% compared to TiO2-NT and Ti implants, respectively. Together, findings from this study indicate that Si-doped TiO2 nanotubes promoted the osteogenic differentiation of osteoblastic cells and improved bone-Ti integration. Therefore, they may have considerable potential for the bioactive surface modification of Ti implants. PMID- 26927079 TI - Modulating Astrocyte Transition after Stroke to Promote Brain Rescue and Functional Recovery: Emerging Targets Include Rho Kinase. AB - Stroke is a common and serious condition, with few therapies. Whilst previous focus has been directed towards biochemical events within neurons, none have successfully prevented the progression of injury that occurs in the acute phase. New targeted treatments that promote recovery after stroke might be a better strategy and are desperately needed for the majority of stroke survivors. Cells comprising the neurovascular unit, including blood vessels and astrocytes, present an alternative target for supporting brain rescue and recovery in the late phase of stroke, since alteration in the unit also occurs in regions outside of the lesion. One of the major changes in the unit involves extensive morphological transition of astrocytes resulting in altered energy metabolism, decreased glutamate reuptake and recycling, and retraction of astrocyte end feed from both blood vessels and neurons. Whilst globally inhibiting transitional change in astrocytes after stroke is reported to result in further damage and functional loss, we discuss the available evidence to suggest that the transitional activation of astrocytes after stroke can be modulated for improved outcomes. In particular, we review the role of Rho-kinase (ROCK) in reactive gliosis and show that inhibiting ROCK after stroke results in reduced scar formation and improved functional recovery. PMID- 26927081 TI - Erythropoietin Ameliorates Neonatal Hypoxia-Ischemia-Induced Neurobehavioral Deficits, Neuroinflammation, and Hippocampal Injury in the Juvenile Rat. AB - The hematopoietic growth factor erythropoietin (EPO) has been shown to be neuroprotective against hypoxia-ischemia (HI) in Postnatal Day 7 (P7)-P10 or adult animal models. The current study was aimed to determine whether EPO also provides long-lasting neuroprotection against HI in P5 rats, which is relevant to immature human infants. Sprague-Dawley rats at P5 were subjected to right common carotid artery ligation followed by an exposure to 6% oxygen with balanced nitrogen for 1.5 h. Human recombinant EPO (rEPO, at a dose of 5 units/g) was administered intraperitoneally one hour before or immediately after insult, followed by additional injections at 24 and 48 h post-insult. The control rats were injected with normal saline following HI. Neurobehavioral tests were performed on P8 and P20, and brain injury was examined on P21. HI insult significantly impaired neurobehavioral performance including sensorimotor, locomotor activity and cognitive ability on the P8 and P20 rats. HI insult also resulted in brain inflammation (as indicated by microglia activation) and neuronal death (as indicated by Jade B positive staining) in the white matter, striatum, cortex, and hippocampal areas of the P21 rat. Both pre- and post treatment with rEPO significantly improved neurobehavioral performance and protected against the HI-induced neuronal death, microglia activation (OX42+) as well as loss of mature oligodendrocytes (APC-CC1+) and hippocampal neurons (Nissl+). The long-lasting protective effects of rEPO in the neonatal rat HI model suggest that to exert neurotrophic activity in the brain might be an effective approach for therapeutic treatment of neonatal brain injury induced by hypoxia-ischemia. PMID- 26927082 TI - Immunohistochemical Analysis of Cerebral Thrombi Retrieved by Mechanical Thrombectomy from Patients with Acute Ischemic Stroke. AB - Mechanical thrombectomy is a novel treatment option for patients with acute ischemic stroke (AIS). Only a few studies have previously suggested strategies to categorize retrieved clots according to their histologic composition. However, these reports did not analyze potential biomarkers that are of importance in stroke-related inflammation. We therefore histopathologically investigated 37 intracerebral thrombi mechanically retrieved from patients with AIS, and focused on the composition of immune cells and platelets. We also conducted correlation analyses of distinctive morphologic patterns (erythrocytic, serpentine, layered, red, white, mixed appearance) with clinical parameters. Most T cells and monocytes were detected in erythrocytic and red clots, in which the distribution of these cells was random. In contrast, von Willebrand factor (vWF)-positive areas co-localized with regions of fibrin and collagen. While clots with huge amounts of vWF seem to be associated with a high National Institute of Health Stroke Scale score at admission, histologic findings could not predict the clinical outcome at discharge. In summary, we provide the first histologic description of mechanically retrieved intracerebral thrombi regarding biomarkers relevant for inflammation in ischemic stroke. PMID- 26927083 TI - Genome Editing in C. elegans and Other Nematode Species. AB - Caenorhabditis elegans, a 1 mm long free-living nematode, is a popular model animal that has been widely utilized for genetic investigations of various biological processes. Characteristic features that make C. elegans a powerful model of choice for eukaryotic genetic studies include its rapid life cycle (development from egg to adult in 3.5 days at 20 degrees C), well-annotated genome, simple morphology (comprising only 959 somatic cells in the hermaphrodite), and transparency (which facilitates non-invasive fluorescence observations). However, early approaches to introducing mutations in the C. elegans genome, such as chemical mutagenesis and imprecise excision of transposons, have required large-scale mutagenesis screens. To avoid this laborious and time-consuming procedure, genome editing technologies have been increasingly used in nematodes including C. briggsae and Pristionchus pacificus, thereby facilitating their genetic analyses. Here, I review the recent progress in genome editing technologies using zinc-finger nucleases (ZFNs), transcriptional activator-like nucleases (TALENs), and clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 in nematodes and offer perspectives on their use in the future. PMID- 26927084 TI - Nutrigenetics and Nutrimiromics of the Circadian System: The Time for Human Health. AB - Even though the rhythmic oscillations of life have long been known, the precise molecular mechanisms of the biological clock are only recently being explored. Circadian rhythms are found in virtually all organisms and affect our lives. Thus, it is not surprising that the correct running of this clock is essential for cellular functions and health. The circadian system is composed of an intricate network of genes interwined in an intrincated transcriptional/translational feedback loop. The precise oscillation of this clock is controlled by the circadian genes that, in turn, regulate the circadian oscillations of many cellular pathways. Consequently, variations in these genes have been associated with human diseases and metabolic disorders. From a nutrigenetics point of view, some of these variations modify the individual response to the diet and interact with nutrients to modulate such response. This circadian feedback loop is also epigenetically modulated. Among the epigenetic mechanisms that control circadian rhythms, microRNAs are the least studied ones. In this paper, we review the variants of circadian-related genes associated to human disease and nutritional response and discuss the current knowledge about circadian microRNAs. Accumulated evidence on the genetics and epigenetics of the circadian system points to important implications of chronotherapy in the clinical practice, not only in terms of pharmacotherapy, but also for dietary interventions. However, interventional studies (especially nutritional trials) that include chronotherapy are scarce. Given the importance of chronobiology in human health such studies are warranted in the near future. PMID- 26927085 TI - RNA Interference in the Age of CRISPR: Will CRISPR Interfere with RNAi? AB - The recent emergence of multiple technologies for modifying gene structure has revolutionized mammalian biomedical research and enhanced the promises of gene therapy. Over the past decade, RNA interference (RNAi) based technologies widely dominated various research applications involving experimental modulation of gene expression at the post-transcriptional level. Recently, a new gene editing technology, Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) and the CRISPR-associated protein 9 (Cas9) (CRISPR/Cas9) system, has received unprecedented acceptance in the scientific community for a variety of genetic applications. Unlike RNAi, the CRISPR/Cas9 system is bestowed with the ability to introduce heritable precision insertions and deletions in the eukaryotic genome. The combination of popularity and superior capabilities of CRISPR/Cas9 system raises the possibility that this technology may occupy the roles currently served by RNAi and may even make RNAi obsolete. We performed a comparative analysis of the technical aspects and applications of the CRISPR/Cas9 system and RNAi in mammalian systems, with the purpose of charting out a predictive picture on whether the CRISPR/Cas9 system will eclipse the existence and future of RNAi. The conclusion drawn from this analysis is that RNAi will still occupy specific domains of biomedical research and clinical applications, under the current state of development of these technologies. However, further improvements in CRISPR/Cas9 based technology may ultimately enable it to dominate RNAi in the long term. PMID- 26927086 TI - Reduced Connexin26 in the Mature Cochlea Increases Susceptibility to Noise Induced Hearing Lossin Mice. AB - Connexin26 (Cx26, encoded by GJB2) mutations are the most common cause of non syndromic deafness. GJB2 is thought to be involved in noise-induced hearing loss (NIHL). However, the role of Cx26 in NIHL is still obscure. To explore the association between Cx26 and NIHL, we established a Cx26 knockdown (KD) mouse model by conditional knockdown of Cx26 at postnatal day 18 (P18), and then we observed the auditory threshold and morphologic changes in these mice with or without noise exposure. The Cx26 KD mice did not exhibit substantial hearing loss and hair cell degeneration, while the Cx26 KD mice with acoustic trauma experienced higher hearing loss than simple noise exposure siblings and nearly had no recovery. Additionally, extensive outer hair cell loss and more severe destruction of the basal organ of Corti were observed in Cx26 KD mice after noise exposure. These data indicate that reduced Cx26 expression in the mature mouse cochlea may increase susceptibility to noise-induced hearing loss and facilitate the cell degeneration in the organ of Corti. PMID- 26927087 TI - Biochemical Characterization and Complete Conversion of Coenzyme Specificity of Isocitrate Dehydrogenase from Bifidobacterium longum. AB - Bifidobacterium longum is a very important gram-positive non-pathogenic bacterium in the human gastrointestinal tract for keeping the digestive and immune system healthy. Isocitrate dehydrogenase (IDH) from B. longum (BlIDH), a novel member in Type II subfamily, was overexpressed, purified and biochemically characterized in detail. The active form of BlIDH was an 83-kDa homodimer. Kinetic analysis showed BlIDH was a NADP+-dependent IDH (NADP-IDH), with a 567- and 193-fold preference for NADP+ over NAD+ in the presence of Mg(2+) and Mn(2+), respectively. The maximal activity for BlIDH occurred at 60 degrees C (with Mn(2+)) and 65 degrees C (with Mg(2+)), and pH 7.5 (with Mn(2+)) and pH 8.0 (with Mg(2+)). Heat inactivation profiles revealed that BlIDH retained 50% of maximal activity after incubation at 45 degrees C for 20 min with either Mn(2+) or Mg(2+). Furthermore, the coenzyme specificity of BlIDH can be completely reversed from NADP+ to NAD+ by a factor of 2387 by replacing six residues. This current work, the first report on the coenzyme specificity conversion of Type II NADP-IDHs, would provide better insight into the evolution of NADP+ use by the IDH family. PMID- 26927088 TI - The Human Host Defense Ribonucleases 1, 3 and 7 Are Elevated in Patients with Sepsis after Major Surgery--A Pilot Study. AB - Sepsis is the most common cause of death in intensive care units and associated with widespread activation of host innate immunity responses. Ribonucleases (RNases) are important components of the innate immune system, however the role of RNases in sepsis has not been investigated. We evaluated serum levels of RNase 1, 3 and 7 in 20 surgical sepsis patients (Sepsis), nine surgical patients (Surgery) and 10 healthy controls (Healthy). RNase 1 and 3 were elevated in Sepsis compared to Surgery (2.2- and 3.1-fold, respectively; both p < 0.0001) or compared to Healthy (3.0- and 15.5-fold, respectively; both p < 0.0001). RNase 1 showed a high predictive value for the development of more than two organ failures (AUC 0.82, p = 0.01). Patients with renal dysfunction revealed higher RNase 1 levels than without renal dysfunction (p = 0.03). RNase 1 and 3 were higher in respiratory failure than without respiratory failure (p < 0.0001 and p = 0.02, respectively). RNase 7 was not detected in Healthy patients and only in two patients of Surgery, however RNase 7 was detected in 10 of 20 Sepsis patients. RNase 7 was higher in renal or metabolic failure than without failure (p = 0.04 and p = 0.02, respectively). In conclusion, RNase 1, 3 and 7 are secreted into serum under conditions with tissue injury, such as major surgery or sepsis. Thus, RNases might serve as laboratory parameters to diagnose and monitor organ failure in sepsis. PMID- 26927089 TI - Co-Production of Fungal Biomass Derived Constituents and Ethanol from Citrus Wastes Free Sugars without Auxiliary Nutrients in Airlift Bioreactor. AB - The potential of two zygomycetes fungi, Mucor indicus and Rhizopus oryzae, in assimilating citrus waste free sugars (CWFS) and producing fungal chitosan, oil, and protein as well as ethanol was investigated. Extraction of free sugars from citrus waste can reduce its environmental impact by decreasing the possibility of wild microorganisms growth and formation of bad odors, a typical problem facing the citrus industries. A total sugar concentration of 25.1 g/L was obtained by water extraction of citrus waste at room temperature, used for fungal cultivation in shake flasks and airlift bioreactor with no additional nutrients. In shake flasks cultivations, the fungi were only able to assimilate glucose, while fructose remained almost intact. In contrast, the cultivation of M. indicus and R. oryzae in the four-liter airlift bioreactor resulted in the consumption of almost all sugars and production of 250 and 280 g fungal biomass per kg of consumed sugar, respectively. These biomasses correspondingly contained 40% and 51% protein and 9.8% and 4.4% oil. Furthermore, the fungal cell walls, obtained after removing the alkali soluble fraction of the fungi, contained 0.61 and 0.69 g chitin and chitosan per g of cell wall for M. indicus and R. oryzae, respectively. Moreover, the maximum ethanol yield of 36% and 18% was obtained from M. indicus and R. oryzae, respectively. Furthermore, that M. indicus grew as clump mycelia in the airlift bioreactor, while R. oryzae formed spherical suspended pellets, is a promising feature towards industrialization of the process. PMID- 26927090 TI - AfAP2-1, An Age-Dependent Gene of Aechmea fasciata, Responds to Exogenous Ethylene Treatment. AB - The Bromeliaceae family is one of the most morphologically diverse families with a pantropical distribution. To schedule an appropriate flowering time for bromeliads, ethylene is commonly used to initiate flower development in adult plants. However, the mechanism by which ethylene induces flowering in adult bromeliads remains unknown. Here, we identified an APETALA2 (AP2)-like gene, AfAP2-1, in Aechmea fasciata. AfAP2-1 contains two AP2 domains and is a nuclear localized protein. It functions as a transcriptional activator, and the activation domain is located in the C-terminal region. The expression level of AfAP2-1 is higher in juvenile plants than in adult plants, and the AfAP2-1 transcript level was rapidly and transiently reduced in plants treated with exogenous ethylene. Overexpression of AfAP2-1 in Arabidopsis thaliana results in an extremely delayed flowering phenotype. These results suggested that AfAP2-1 responds to ethylene and is a putative age-dependent flowering regulator in A. fasciata. PMID- 26927091 TI - Key Immune Events of the Pathomechanisms of Early Cardioembolic Stroke: Multi Database Mining and Systems Biology Approach. AB - While inflammation has generally been regarded as a negative factor in stroke recovery, this viewpoint has recently been challenged by demonstrating that inflammation is a necessary and sufficient factor for regeneration in the zebrafish brain injury model. This close relationship with inflammation suggests that a re-examination of the immune system's role in strokes is necessary. We used a systems biology approach to investigate the role of immune-related functions via their interactions with other molecular functions in early cardioembolic stroke. Based on protein interaction models and on microarray data from the blood of stroke subjects and healthy controls, networks were constructed to delineate molecular interactions at four early stages (pre-stroke, 3 h, 5 h and 24 h after stroke onset) of cardioembolic stroke. A comparative analysis of functional networks identified interactions of immune-related functions with other molecular functions, including growth factors, neuro/hormone and housekeeping functions. These provide a potential pathomechanism for early stroke pathophysiology. In addition, several potential targets of miRNA and methylation regulations were derived based on basal level changes observed in the core networks and literature. The results provide a more comprehensive understanding of stroke progression mechanisms from an immune perspective and shed light on acute stroke treatments. PMID- 26927092 TI - Roles of RNA-Binding Proteins in DNA Damage Response. AB - Living cells experience DNA damage as a result of replication errors and oxidative metabolism, exposure to environmental agents (e.g., ultraviolet light, ionizing radiation (IR)), and radiation therapies and chemotherapies for cancer treatments. Accumulation of DNA damage can lead to multiple diseases such as neurodegenerative disorders, cancers, immune deficiencies, infertility, and also aging. Cells have evolved elaborate mechanisms to deal with DNA damage. Networks of DNA damage response (DDR) pathways are coordinated to detect and repair DNA damage, regulate cell cycle and transcription, and determine the cell fate. Upstream factors of DNA damage checkpoints and repair, "sensor" proteins, detect DNA damage and send the signals to downstream factors in order to maintain genomic integrity. Unexpectedly, we have discovered that an RNA-processing factor is involved in DNA repair processes. We have identified a gene that contributes to glioblastoma multiforme (GBM)'s treatment resistance and recurrence. This gene, RBM14, is known to function in transcription and RNA splicing. RBM14 is also required for maintaining the stem-like state of GBM spheres, and it controls the DNA-PK-dependent non-homologous end-joining (NHEJ) pathway by interacting with KU80. RBM14 is a RNA-binding protein (RBP) with low complexity domains, called intrinsically disordered proteins (IDPs), and it also physically interacts with PARP1. Furthermore, RBM14 is recruited to DNA double-strand breaks (DSBs) in a poly(ADP-ribose) (PAR)-dependent manner (unpublished data). DNA-dependent PARP1 (poly-(ADP) ribose polymerase 1) makes key contributions in the DNA damage response (DDR) network. RBM14 therefore plays an important role in a PARP dependent DSB repair process. Most recently, it was shown that the other RBPs with intrinsically disordered domains are recruited to DNA damage sites in a PAR dependent manner, and that these RBPs form liquid compartments (also known as "liquid-demixing"). Among the PAR-associated IDPs are FUS/TLS (fused in sarcoma/translocated in sarcoma), EWS (Ewing sarcoma), TARF15 (TATA box-binding protein-associated factor 68 kDa) (also called FET proteins), a number of heterogeneous nuclear ribonucleoproteins (hnRNPs), and RBM14. Importantly, various point mutations within the FET genes have been implicated in pathological protein aggregation in neurodegenerative diseases, specifically with amyotrophic lateral sclerosis (ALS), and frontotemporal lobe degeneration (FTLD). The FET proteins also frequently exhibit gene translocation in human cancers, and emerging evidence shows their physical interactions with DDR proteins and thus implies their involvement in the maintenance of genome stability. PMID- 26927093 TI - Tamoxifen Treatment of Breast Cancer Cells: Impact on Hedgehog/GLI1 Signaling. AB - The selective estrogen receptor (ER) modulator tamoxifen (TAM) has become the standard therapy for the treatment of ER+ breast cancer patients. Despite the obvious benefits of TAM, a proportion of patients acquire resistance to treatment, and this is a significant clinical problem. Consequently, the identification of possible mechanisms involved in TAM-resistance should help the development of new therapeutic targets. In this study, we present in vitro data using a panel of different breast cancer cell lines and demonstrate the modulatory effect of TAM on cellular proliferation and expression of Hedgehog signaling components, including the terminal effector of the pathway, the transcription factor GLI1. A variable pattern of expression following TAM administration was observed, reflecting the distinctive properties of the ER+ and ER- cell lines analyzed. Remarkably, the TAM-induced increase in the proliferation of the ER+ ZR-75-1 and BT474 cells parallels a sustained upregulation of GLI1 expression and its translocation to the nucleus. These findings, implicating a TAM-GLI1 signaling cross-talk, could ultimately be exploited not only as a means for novel prognostication markers but also in efforts to effectively target breast cancer subtypes. PMID- 26927095 TI - Potentially Treatable Disorder Diagnosed Post Mortem by Exome Analysis in a Boy with Respiratory Distress. AB - We highlight the importance of exome sequencing in solving a clinical case of a child who died at 14 months after a series of respiratory crises. He was the half brother of a girl diagnosed at 7 years with the early-onset seizure variant of Rett syndrome due to CDKL5 mutation. We performed a test for CDKL5 in the boy, which came back negative. Driven by the mother's compelling need for a diagnosis, we moved forward performing whole exome sequencing analysis. Surprisingly, two missense mutations in compound heterozygosity were identified in the RAPSN gene encoding a receptor-associated protein with a key role in clustering and anchoring nicotinic acetylcholine receptors at synaptic sites. This gene is responsible for a congenital form of myasthenic syndrome, a disease potentially treatable with cholinesterase inhibitors. Therefore, an earlier diagnosis in this boy would have led to a better clinical management and prognosis. Our study supports the key role of exome sequencing in achieving a definite diagnosis in severe perinatal diseases, an essential step especially when a specific therapy is available. PMID- 26927094 TI - Metabolomic Profiling of Plasma from Melioidosis Patients Using UHPLC-QTOF MS Reveals Novel Biomarkers for Diagnosis. AB - To identify potential biomarkers for improving diagnosis of melioidosis, we compared plasma metabolome profiles of melioidosis patients compared to patients with other bacteremia and controls without active infection, using ultra-high performance liquid chromatography-electrospray ionization-quadruple time-of flight mass spectrometry. Principal component analysis (PCA) showed that the metabolomic profiles of melioidosis patients are distinguishable from bacteremia patients and controls. Using multivariate and univariate analysis, 12 significant metabolites from four lipid classes, acylcarnitine (n = 6), lysophosphatidylethanolamine (LysoPE) (n = 3), sphingomyelins (SM) (n = 2) and phosphatidylcholine (PC) (n = 1), with significantly higher levels in melioidosis patients than bacteremia patients and controls, were identified. Ten of the 12 metabolites showed area-under-receiver operating characteristic curve (AUC) >0.80 when compared both between melioidosis and bacteremia patients, and between melioidosis patients and controls. SM(d18:2/16:0) possessed the largest AUC when compared, both between melioidosis and bacteremia patients (AUC 0.998, sensitivity 100% and specificity 91.7%), and between melioidosis patients and controls (AUC 1.000, sensitivity 96.7% and specificity 100%). Our results indicate that metabolome profiling might serve as a promising approach for diagnosis of melioidosis using patient plasma, with SM(d18:2/16:0) representing a potential biomarker. Since the 12 metabolites were related to various pathways for energy and lipid metabolism, further studies may reveal their possible role in the pathogenesis and host response in melioidosis. PMID- 26927096 TI - De Novo Transcriptome Assembly in Shiraia bambusicola to Investigate Putative Genes Involved in the Biosynthesis of Hypocrellin A. AB - Shiraia bambusicola is a species of the monotypic genus Shiraia in the phylum Ascomycota. In China, it is known for its pharmacological properties that are used to treat rheumatic arthritis, sciatica, pertussis, tracheitis and so forth. Its major medicinal active metabolite is hypocrellin A, which exhibits excellent antiviral and antitumor properties. However, the genes involved in the hypocrellin A anabolic pathways were still unknown due to the lack of genomic information for this species. To investigate putative genes that are involved in the biosynthesis of hypocrellin A and determine the pathway, we performed transcriptome sequencing for Shiraia bambusicola S4201-W and the mutant S4201-D1 for the first time. S4201-W has excellent hypocrellin A production, while the mutant S4201-D1 does not. Then, we obtained 38,056,034 and 39,086,896 clean reads from S4201-W and S4201-D1, respectively. In all, 17,923 unigenes were de novo assembled, and the N50 length was 1970 bp. Based on the negative binomial distribution test, 716 unigenes were found to be upregulated, and 188 genes were downregulated in S4201-D1, compared with S4201-W. We have found seven unigenes involved in the biosynthesis of hypocrellin A and proposed a putative hypocrellin A biosynthetic pathway. These data will provide a valuable resource and theoretical basis for future molecular studies of hypocrellin A, help identify the genes involved in the biosynthesis of hypocrellin A and help facilitate functional studies for enhancing hypocrellin A production. PMID- 26927098 TI - An Optical Fiber Displacement Sensor Using RF Interrogation Technique. AB - We propose a novel non-contact optical fiber displacement sensor. It uses a radio frequency (RF) interrogation technique which is based on bidirectional modulation of a Mach-Zehnder electro-optical modulator (MZ-EOM). The displacement is measured from the free spectral range (FSR) which is determined by the dip frequencies of the modulated MZ-EOM transfer function. In experiments, the proposed sensor showed a sensitivity of 456 kHz/mm or 1.043 kHz/V in a measurement range of 7 mm. The displacement resolution of the proposed sensor depends on the linewidth and the power of the optical source. Resolution better than 0.05 MUm would be achieved if an optical source which has a linewidth narrower than 1.5 nm and a received power larger than -36 dBm is used. Also, the multiplexing characteristic of the proposed sensor was experimentally validated. PMID- 26927097 TI - Low Serum Lysosomal Acid Lipase Activity Correlates with Advanced Liver Disease. AB - Fatty liver has become the most common liver disorder and is recognized as a major health burden in the Western world. The causes for disease progression are not fully elucidated but lysosomal impairment is suggested. Here we evaluate a possible role for lysosomal acid lipase (LAL) activity in liver disease. To study LAL levels in patients with microvesicular, idiopathic cirrhosis and nonalcoholic fatty liver disease (NAFLD). Medical records of patients with microvesicular steatosis, cryptogenic cirrhosis and NAFLD, diagnosed on the basis of liver biopsies, were included in the study. Measured serum LAL activity was correlated to clinical, laboratory, imaging and pathological data. No patient exhibited LAL activity compatible with genetic LAL deficiency. However, serum LAL activity inversely predicted liver disease severity. A LAL level of 0.5 was the most sensitive for detecting both histologic and noninvasive markers for disease severity, including lower white blood cell count and calcium, and elevated gamma glutamyltransferase, creatinine, glucose, glycated hemoglobin, uric acid and coagulation function. Serum LAL activity <0.5 indicates severe liver injury in patients with fatty liver and cirrhosis. Further studies should define the direct role of LAL in liver disease severity and consider the possibility of replacement therapy. PMID- 26927099 TI - A Highly Selective Sensor for Cyanide in Organic Media and on Solid Surfaces. AB - The application of IR 786 perchlorate (IR-786) as a selective optical sensor for cyanide anion in both organic solution (acetonitrile (MeCN), 100%) and solvent free solid surfaces was demonstrated. In MeCN, IR-786 was selective to two anions in the following order: CN(-) > OH(-). A significant change in the characteristic dark green color of IR-786 in MeCN to yellow was observed as a result of nucleophilic addition of CN(-) to the fluorophore, i.e., formation of IR 786 (CN), which was also verified by a blue shift in the 775 nm absorbance peak to 430 nm. A distinct green fluorescence emission from the IR-786-(CN) in MeCN was also observed, which demonstrated the selectivity of IR-786 towards CN(-) in MeCN. Fluorescence emission studies of IR-786 showed that the lower detection limit and the sensitivity of IR-786 for CN(-) in MeCN was 0.5 MUM and 0.5 to 8 MUM, respectively. The potential use of IR-786 as a solvent-free solid state sensor for the selective sensing and monitoring of CN(-) in the environment was also demonstrated. On solvent-free solid state surfaces, the sensitivity of the IR-786 to CN(-) in water samples was in the range of 50-300 MUM with minimal interference by OH(-). PMID- 26927100 TI - Human Collaborative Localization and Mapping in Indoor Environments with Non Continuous Stereo. AB - A new approach to the monocular simultaneous localization and mapping (SLAM) problem is presented in this work. Data obtained from additional bearing-only sensors deployed as wearable devices is fully fused into an Extended Kalman Filter (EKF). The wearable device is introduced in the context of a collaborative task within a human-robot interaction (HRI) paradigm, including the SLAM problem. Thus, based on the delayed inverse-depth feature initialization (DI-D) SLAM, data from the camera deployed on the human, capturing his/her field of view, is used to enhance the depth estimation of the robotic monocular sensor which maps and locates the device. The occurrence of overlapping between the views of both cameras is predicted through geometrical modelling, activating a pseudo-stereo methodology which allows to instantly measure the depth by stochastic triangulation of matched points found through SIFT/SURF. Experimental validation is provided through results from experiments, where real data is captured as synchronized sequences of video and other data (relative pose of secondary camera) and processed off-line. The sequences capture indoor trajectories representing the main challenges for a monocular SLAM approach, namely, singular trajectories and close turns with high angular velocities with respect to linear velocities. PMID- 26927101 TI - Analysis of Forensic Casework Utilizing Infrared Spectroscopic Imaging. AB - A search of the current scientific literature yields a limited number of studies that describe the use of Fourier transform infrared (FT-IR) spectroscopic imaging for the analysis of forensic casework, which is likely due to the fact that these instruments are fairly new commodities to the field of analytical chemistry and are therefore not yet commonplace in forensic laboratories. This report describes recent forensic case studies that have used the technique for determining the composition of a wide variety of multi-component sample types, including animal tissue sections for toxic inclusions, drugs/dietary supplements, an antibiotic with an active pharmaceutical ingredient (API) present as several different salt forms, an adulterated bulk API, unknown trace powders for illicit drugs and an ophthalmic solution suspected of being adulterated with bleach. PMID- 26927102 TI - Merge Fuzzy Visual Servoing and GPS-Based Planning to Obtain a Proper Navigation Behavior for a Small Crop-Inspection Robot. AB - The concept of precision agriculture, which proposes farming management adapted to crop variability, has emerged in recent years. To effectively implement precision agriculture, data must be gathered from the field in an automated manner at minimal cost. In this study, a small autonomous field inspection vehicle was developed to minimise the impact of the scouting on the crop and soil compaction. The proposed approach integrates a camera with a GPS receiver to obtain a set of basic behaviours required of an autonomous mobile robot to inspect a crop field with full coverage. A path planner considered the field contour and the crop type to determine the best inspection route. An image processing method capable of extracting the central crop row under uncontrolled lighting conditions in real time from images acquired with a reflex camera positioned on the front of the robot was developed. Two fuzzy controllers were also designed and developed to achieve vision-guided navigation. A method for detecting the end of a crop row using camera-acquired images was developed. In addition, manoeuvres necessary for the robot to change rows were established. These manoeuvres enabled the robot to autonomously cover the entire crop by following a previously established plan and without stepping on the crop row, which is an essential behaviour for covering crops such as maize without damaging them. PMID- 26927103 TI - A New MAC Address Spoofing Detection Technique Based on Random Forests. AB - Media access control (MAC) addresses in wireless networks can be trivially spoofed using off-the-shelf devices. The aim of this research is to detect MAC address spoofing in wireless networks using a hard-to-spoof measurement that is correlated to the location of the wireless device, namely the received signal strength (RSS). We developed a passive solution that does not require modification for standards or protocols. The solution was tested in a live test bed (i.e., a wireless local area network with the aid of two air monitors acting as sensors) and achieved 99.77%, 93.16% and 88.38% accuracy when the attacker is 8-13 m, 4-8 m and less than 4 m away from the victim device, respectively. We implemented three previous methods on the same test-bed and found that our solution outperforms existing solutions. Our solution is based on an ensemble method known as random forests. PMID- 26927104 TI - Towards Reliable and Energy-Efficient Incremental Cooperative Communication for Wireless Body Area Networks. AB - In this study, we analyse incremental cooperative communication for wireless body area networks (WBANs) with different numbers of relays. Energy efficiency (EE) and the packet error rate (PER) are investigated for different schemes. We propose a new cooperative communication scheme with three-stage relaying and compare it to existing schemes. Our proposed scheme provides reliable communication with less PER at the cost of surplus energy consumption. Analytical expressions for the EE of the proposed three-stage cooperative communication scheme are also derived, taking into account the effect of PER. Later on, the proposed three-stage incremental cooperation is implemented in a network layer protocol; enhanced incremental cooperative critical data transmission in emergencies for static WBANs (EInCo-CEStat). Extensive simulations are conducted to validate the proposed scheme. Results of incremental relay-based cooperative communication protocols are compared to two existing cooperative routing protocols: cooperative critical data transmission in emergencies for static WBANs (Co-CEStat) and InCo-CEStat. It is observed from the simulation results that incremental relay-based cooperation is more energy efficient than the existing conventional cooperation protocol, Co-CEStat. The results also reveal that EInCo CEStat proves to be more reliable with less PER and higher throughput than both of the counterpart protocols. However, InCo-CEStat has less throughput with a greater stability period and network lifetime. Due to the availability of more redundant links, EInCo-CEStat achieves a reduced packet drop rate at the cost of increased energy consumption. PMID- 26927106 TI - Registration of Feature-Poor 3D Measurements from Fringe Projection. AB - We propose a novel method for registration of partly overlapping three dimensional surface measurements for stereo-based optical sensors using fringe projection. Based on two-dimensional texture matching, it allows global registration of surfaces with poor and ambiguous three-dimensional features, which are common to surface inspection applications. No prior information about relative sensor position is necessary, which makes our approach suitable for semi automatic and manual measurement. The algorithm is robust and works with challenging measurements, including uneven illumination, surfaces with specular reflection as well as sparsely textured surfaces. We show that precisions of 1 mm and below can be achieved along the surfaces, which is necessary for further local 3D registration. PMID- 26927105 TI - Last Advances in Silicon-Based Optical Biosensors. AB - We review the most important achievements published in the last five years in the field of silicon-based optical biosensors. We focus specially on label-free optical biosensors and their implementation into lab-on-a-chip platforms, with an emphasis on developments demonstrating the capability of the devices for real bioanalytical applications. We report on novel transducers and materials, improvements of existing transducers, new and improved biofunctionalization procedures as well as the prospects for near future commercialization of these technologies. PMID- 26927107 TI - Utilisation of Quartz Crystal Microbalance Sensors with Dissipation (QCM-D) for a Clauss Fibrinogen Assay in Comparison with Common Coagulation Reference Methods. AB - The determination of fibrinogen levels is one of the most important coagulation measurements in medicine. It plays a crucial part in diagnostic and therapeutic decisions, often associated with time-critical conditions. The commonly used measurement is the Clauss fibrinogen assay (CFA) where plasma is activated by thrombin reagent and which is conducted by mechanical/turbidimetric devices. As quartz crystal microbalance sensors with dissipation (QCM-D) based devices have a small footprint, can be operated easily and allow measurements independently from sample transportation time, laboratory location, availability and opening hours, they offer a great opportunity to complement laboratory CFA measurements. Therefore, the objective of the work was to (1) transfer the CFA to the QCM-D method; (2) develop an easy, time- and cost-effective procedure and (3) compare the results with references. Different sensor coatings (donor's own plasma; gold surface) and different QCM-D parameters (frequency signal shift; its calculated turning point; dissipation signal shift) were sampled. The results demonstrate the suitability for a QCM-D-based CFA in physiological fibrinogen ranges. Results were obtained in less than 1 min and in very good agreement with a standardized reference (Merlin coagulometer). The results provide a good basis for further investigation and pave the way to a possible application of QCM-D in clinical and non-clinical routine in the medical field. PMID- 26927108 TI - An Accurate GPS-IMU/DR Data Fusion Method for Driverless Car Based on a Set of Predictive Models and Grid Constraints. AB - A high-performance differential global positioning system (GPS) receiver with real time kinematics provides absolute localization for driverless cars. However, it is not only susceptible to multipath effect but also unable to effectively fulfill precise error correction in a wide range of driving areas. This paper proposes an accurate GPS-inertial measurement unit (IMU)/dead reckoning (DR) data fusion method based on a set of predictive models and occupancy grid constraints. First, we employ a set of autoregressive and moving average (ARMA) equations that have different structural parameters to build maximum likelihood models of raw navigation. Second, both grid constraints and spatial consensus checks on all predictive results and current measurements are required to have removal of outliers. Navigation data that satisfy stationary stochastic process are further fused to achieve accurate localization results. Third, the standard deviation of multimodal data fusion can be pre-specified by grid size. Finally, we perform a lot of field tests on a diversity of real urban scenarios. The experimental results demonstrate that the method can significantly smooth small jumps in bias and considerably reduce accumulated position errors due to DR. With low computational complexity, the position accuracy of our method surpasses existing state-of-the-arts on the same dataset and the new data fusion method is practically applied in our driverless car. PMID- 26927109 TI - Laccase-Functionalized Graphene Oxide Assemblies as Efficient Nanobiocatalysts for Oxidation Reactions. AB - Multi-layer graphene oxide-enzyme nanoassemblies were prepared through the multi point covalent immobilization of laccase from Trametes versicolor (TvL) on functionalized graphene oxide (fGO). The catalytic properties of the fGO-TvL nanoassemblies were found to depend on the number of the graphene oxide-enzyme layers present in the nanostructure. The fGO-TvL nanoassemblies exhibit an enhanced thermal stability at 60 degrees C, as demonstrated by a 4.7-fold higher activity as compared to the free enzyme. The multi-layer graphene oxide-enzyme nanoassemblies can efficiently catalyze the oxidation of anthracene, as well as the decolorization of an industrial dye, pinacyanol chloride. These materials retained almost completely their decolorization activity after five reaction cycles, proving their potential as efficient nano- biocatalysts for various applications. PMID- 26927110 TI - Distributed Long-Gauge Optical Fiber Sensors Based Self-Sensing FRP Bar for Concrete Structure. AB - Brillouin scattering-based distributed optical fiber (OF) sensing technique presents advantages for concrete structure monitoring. However, the existence of spatial resolution greatly decreases strain measurement accuracy especially around cracks. Meanwhile, the brittle feature of OF also hinders its further application. In this paper, the distributed OF sensor was firstly proposed as long-gauge sensor to improve strain measurement accuracy. Then, a new type of self-sensing fiber reinforced polymer (FRP) bar was developed by embedding the packaged long-gauge OF sensors into FRP bar, followed by experimental studies on strain sensing, temperature sensing and basic mechanical properties. The results confirmed the superior strain sensing properties, namely satisfied accuracy, repeatability and linearity, as well as excellent mechanical performance. At the same time, the temperature sensing property was not influenced by the long-gauge package, making temperature compensation easy. Furthermore, the bonding performance between self-sensing FRP bar and concrete was investigated to study its influence on the sensing. Lastly, the sensing performance was further verified with static experiments of concrete beam reinforced with the proposed self-sensing FRP bar. Therefore, the self-sensing FRP bar has potential applications for long-term structural health monitoring (SHM) as embedded sensors as well as reinforcing materials for concrete structures. PMID- 26927111 TI - Robust Radar Emitter Recognition Based on the Three-Dimensional Distribution Feature and Transfer Learning. AB - Due to the increasing complexity of electromagnetic signals, there exists a significant challenge for radar emitter signal recognition. To address this challenge, multi-component radar emitter recognition under a complicated noise environment is studied in this paper. A novel radar emitter recognition approach based on the three-dimensional distribution feature and transfer learning is proposed. The cubic feature for the time-frequency-energy distribution is proposed to describe the intra-pulse modulation information of radar emitters. Furthermore, the feature is reconstructed by using transfer learning in order to obtain the robust feature against signal noise rate (SNR) variation. Last, but not the least, the relevance vector machine is used to classify radar emitter signals. Simulations demonstrate that the approach proposed in this paper has better performances in accuracy and robustness than existing approaches. PMID- 26927113 TI - Functional Analysis in Long-Term Operation of High Power UV-LEDs in Continuous Fluoro-Sensing Systems for Hydrocarbon Pollution. AB - This work analyzes the long-term functionality of HP (High-power) UV-LEDs (Ultraviolet Light Emitting Diodes) as the exciting light source in non-contact, continuous 24/7 real-time fluoro-sensing pollutant identification in inland water. Fluorescence is an effective alternative in the detection and identification of hydrocarbons. The HP UV-LEDs are more advantageous than classical light sources (xenon and mercury lamps) and helps in the development of a low cost, non-contact, and compact system for continuous real-time fieldwork. This work analyzes the wavelength, output optical power, and the effects of viscosity, temperature of the water pollutants, and the functional consistency for long-term HP UV-LED working operation. To accomplish the latter, an analysis of the influence of two types 365 nm HP UV-LEDs degradation under two continuous real-system working mode conditions was done, by temperature Accelerated Life Tests (ALTs). These tests estimate the mean life under continuous working conditions of 6200 h and for cycled working conditions (30 s ON & 30 s OFF) of 66,000 h, over 7 years of 24/7 operating life of hydrocarbon pollution monitoring. In addition, the durability in the face of the internal and external parameter system variations is evaluated. PMID- 26927112 TI - Fluorescence Characterization of Gold Modified Liposomes with Antisense N-myc DNA Bound to the Magnetisable Particles with Encapsulated Anticancer Drugs (Doxorubicin, Ellipticine and Etoposide). AB - Liposome-based drug delivery systems hold great potential for cancer therapy. The aim of this study was to design a nanodevice for targeted anchoring of liposomes (with and without cholesterol) with encapsulated anticancer drugs and antisense N myc gene oligonucleotide attached to its surface. To meet this main aim, liposomes with encapsulated doxorubicin, ellipticine and etoposide were prepared. They were further characterized by measuring their fluorescence intensity, whereas the encapsulation efficiency was estimated to be 16%. The hybridization process of individual oligonucleotides forming the nanoconstruct was investigated spectrophotometrically and electrochemically. The concentrations of ellipticine, doxorubicin and etoposide attached to the nanoconstruct in gold nanoparticle modified liposomes were found to be 14, 5 and 2 ug.mL(-1), respectively. The study succeeded in demonstrating that liposomes are suitable for the transport of anticancer drugs and the antisense oligonucleotide, which can block the expression of the N-myc gene. PMID- 26927114 TI - Joint Prior Learning for Visual Sensor Network Noisy Image Super-Resolution. AB - The visual sensor network (VSN), a new type of wireless sensor network composed of low-cost wireless camera nodes, is being applied for numerous complex visual analyses in wild environments, such as visual surveillance, object recognition, etc. However, the captured images/videos are often low resolution with noise. Such visual data cannot be directly delivered to the advanced visual analysis. In this paper, we propose a joint-prior image super-resolution (JPISR) method using expectation maximization (EM) algorithm to improve VSN image quality. Unlike conventional methods that only focus on upscaling images, JPISR alternatively solves upscaling mapping and denoising in the E-step and M-step. To meet the requirement of the M-step, we introduce a novel non-local group-sparsity image filtering method to learn the explicit prior and induce the geometric duality between images to learn the implicit prior. The EM algorithm inherently combines the explicit prior and implicit prior by joint learning. Moreover, JPISR does not rely on large external datasets for training, which is much more practical in a VSN. Extensive experiments show that JPISR outperforms five state-of-the-art methods in terms of both PSNR, SSIM and visual perception. PMID- 26927115 TI - An Improved Gaussian Mixture Model for Damage Propagation Monitoring of an Aircraft Wing Spar under Changing Structural Boundary Conditions. AB - Structural Health Monitoring (SHM) technology is considered to be a key technology to reduce the maintenance cost and meanwhile ensure the operational safety of aircraft structures. It has gradually developed from theoretic and fundamental research to real-world engineering applications in recent decades. The problem of reliable damage monitoring under time-varying conditions is a main issue for the aerospace engineering applications of SHM technology. Among the existing SHM methods, Guided Wave (GW) and piezoelectric sensor-based SHM technique is a promising method due to its high damage sensitivity and long monitoring range. Nevertheless the reliability problem should be addressed. Several methods including environmental parameter compensation, baseline signal dependency reduction and data normalization, have been well studied but limitations remain. This paper proposes a damage propagation monitoring method based on an improved Gaussian Mixture Model (GMM). It can be used on-line without any structural mechanical model and a priori knowledge of damage and time-varying conditions. With this method, a baseline GMM is constructed first based on the GW features obtained under time-varying conditions when the structure under monitoring is in the healthy state. When a new GW feature is obtained during the on-line damage monitoring process, the GMM can be updated by an adaptive migration mechanism including dynamic learning and Gaussian components split merge. The mixture probability distribution structure of the GMM and the number of Gaussian components can be optimized adaptively. Then an on-line GMM can be obtained. Finally, a best match based Kullback-Leibler (KL) divergence is studied to measure the migration degree between the baseline GMM and the on-line GMM to reveal the weak cumulative changes of the damage propagation mixed in the time varying influence. A wing spar of an aircraft is used to validate the proposed method. The results indicate that the crack propagation under changing structural boundary conditions can be monitored reliably. The method is not limited by the properties of the structure, and thus it is feasible to be applied to composite structure. PMID- 26927116 TI - Synthesis and Characterizations of Novel Ca-Mg-Ti-Fe-Oxides Based Ceramic Nanocrystals and Flexible Film of Polydimethylsiloxane Composite with Improved Mechanical and Dielectric Properties for Sensors. AB - Armalcolite, a rare ceramic mineral and normally found in the lunar earth, was synthesized by solid-state step-sintering. The in situ phase-changed novel ceramic nanocrystals of Ca-Mg-Ti-Fe based oxide (CMTFOx), their chemical reactions and bonding with polydimethylsiloxane (PDMS) were determined by X-ray diffraction, infrared spectroscopy, and microscopy. Water absorption of all the CMTFOx was high. The lower dielectric loss tangent value (0.155 at 1 MHz) was obtained for the ceramic sintered at 1050 degrees C (S1050) and it became lowest for the S1050/PDMS nanocomposite (0.002 at 1 MHz) film, which was made by spin coating at 3000 rpm. The excellent flexibility (static modulus ~ 0.27 MPa and elongation > 90%), viscoelastic property (tandelta = E"/E': 0.225) and glass transition temperature (Tg: -58.5 degrees C) were obtained for S1050/PDMS film. Parallel-plate capacitive and flexible resistive humidity sensors have been developed successfully. The best sensing performance of the present S1050 (3000%) and its flexible S1050/PDMS composite film (306%) based humidity sensors was found to be at 100 Hz, better than conventional materials. PMID- 26927117 TI - A Novel General Imaging Formation Algorithm for GNSS-Based Bistatic SAR. AB - Global Navigation Satellite System (GNSS)-based bistatic Synthetic Aperture Radar (SAR) recently plays a more and more significant role in remote sensing applications for its low-cost and real-time global coverage capability. In this paper, a general imaging formation algorithm was proposed for accurately and efficiently focusing GNSS-based bistatic SAR data, which avoids the interpolation processing in traditional back projection algorithms (BPAs). A two-dimensional point target spectrum model was firstly presented, and the bulk range cell migration correction (RCMC) was consequently derived for reducing range cell migration (RCM) and coarse focusing. As the bulk RCMC seriously changes the range history of the radar signal, a modified and much more efficient hybrid correlation operation was introduced for compensating residual phase errors. Simulation results were presented based on a general geometric topology with non parallel trajectories and unequal velocities for both transmitter and receiver platforms, showing a satisfactory performance by the proposed method. PMID- 26927118 TI - A Novel Cooperative Opportunistic Routing Scheme for Underwater Sensor Networks. AB - Increasing attention has recently been devoted to underwater sensor networks (UWSNs) because of their capabilities in the ocean monitoring and resource discovery. UWSNs are faced with different challenges, the most notable of which is perhaps how to efficiently deliver packets taking into account all of the constraints of the available acoustic communication channel. The opportunistic routing provides a reliable solution with the aid of intermediate nodes' collaboration to relay a packet toward the destination. In this paper, we propose a new routing protocol, called opportunistic void avoidance routing (OVAR), to address the void problem and also the energy-reliability trade-off in the forwarding set selection. OVAR takes advantage of distributed beaconing, constructs the adjacency graph at each hop and selects a forwarding set that holds the best trade-off between reliability and energy efficiency. The unique features of OVAR in selecting the candidate nodes in the vicinity of each other leads to the resolution of the hidden node problem. OVAR is also able to select the forwarding set in any direction from the sender, which increases its flexibility to bypass any kind of void area with the minimum deviation from the optimal path. The results of our extensive simulation study show that OVAR outperforms other protocols in terms of the packet delivery ratio, energy consumption, end-to-end delay, hop count and traversed distance. PMID- 26927119 TI - Outage Performance Analysis of Relay Selection Schemes in Wireless Energy Harvesting Cooperative Networks over Non-Identical Rayleigh Fading Channels. AB - In this paper, we study relay selection in decode-and-forward wireless energy harvesting cooperative networks. In contrast to conventional cooperative networks, the relays harvest energy from the source's radio-frequency radiation and then use that energy to forward the source information. Considering power splitting receiver architecture used at relays to harvest energy, we are concerned with the performance of two popular relay selection schemes, namely, partial relay selection (PRS) scheme and optimal relay selection (ORS) scheme. In particular, we analyze the system performance in terms of outage probability (OP) over independent and non-identical (i.n.i.d.) Rayleigh fading channels. We derive the closed-form approximations for the system outage probabilities of both schemes and validate the analysis by the Monte-Carlo simulation. The numerical results provide comprehensive performance comparison between the PRS and ORS schemes and reveal the effect of wireless energy harvesting on the outage performances of both schemes. Additionally, we also show the advantages and drawbacks of the wireless energy harvesting cooperative networks and compare to the conventional cooperative networks. PMID- 26927120 TI - Metal Sulfides as Sensing Materials for Chemoresistive Gas Sensors. AB - This work aims at a broad overview of the results obtained with metal-sulfide materials in the field of chemoresistive gas sensing. Indeed, despite the well known electrical, optical, structural and morphological features previously described in the literature, metal sulfides present lack of investigation for gas sensing applications, a field in which the metal oxides still maintain a leading role owing to their high sensitivity, low cost, small dimensions and simple integration, in spite of the wide assortment of sensing materials. However, despite their great advantages, metal oxides have shown significant drawbacks, which have led to the search for new materials for gas sensing devices. In this work, Cadmium Sulfide and Tin (IV) Sulfide were investigated as functional materials for thick-film chemoresistive gas-sensors fabrication and they were tested both in thermo- and in photo-activation modes. Furthermore, electrical characterization was carried out in order to verify their gas sensing properties and material stability, by comparing the results obtained with metal sulfides to those obtained by using their metal-oxides counterparts. The results highlighted the possibility to use metal sulfides as a novel class of sensing materials, owing to their selectivity to specific compounds, stability, and the possibility to operate at room temperature. PMID- 26927121 TI - Device Data Ingestion for Industrial Big Data Platforms with a Case Study. AB - Despite having played a significant role in the Industry 4.0 era, the Internet of Things is currently faced with the challenge of how to ingest large-scale heterogeneous and multi-type device data. In response to this problem we present a heterogeneous device data ingestion model for an industrial big data platform. The model includes device templates and four strategies for data synchronization, data slicing, data splitting and data indexing, respectively. We can ingest device data from multiple sources with this heterogeneous device data ingestion model, which has been verified on our industrial big data platform. In addition, we present a case study on device data-based scenario analysis of industrial big data. PMID- 26927122 TI - The Additional Error of Inertial Sensors Induced by Hypersonic Flight Conditions. AB - The emergence of hypersonic technology pose a new challenge for inertial navigation sensors, widely used in aerospace industry. The main problems are: extremely high temperatures, vibration of the fuselage, penetrating acoustic radiation and shock N-waves. The nature of the additional errors of the gyroscopic inertial sensor with hydrostatic suspension components under operating conditions generated by forced precession of the movable part of the suspension due to diffraction phenomena in acoustic fields is explained. The cause of the disturbing moments in the form of the Coriolis inertia forces during the transition of the suspension surface into the category of impedance is revealed. The boundaries of occurrence of the features on the resonance wave match are described. The values of the "false" angular velocity as a result of the elastic stress state of suspension in the acoustic fields are determined. PMID- 26927123 TI - Giant Magnetoresistance Sensors: A Review on Structures and Non-Destructive Eddy Current Testing Applications. AB - Non-destructive eddy current testing (ECT) is widely used to examine structural defects in ferromagnetic pipe in the oil and gas industry. Implementation of giant magnetoresistance (GMR) sensors as magnetic field sensors to detect the changes of magnetic field continuity have increased the sensitivity of eddy current techniques in detecting the material defect profile. However, not many researchers have described in detail the structure and issues of GMR sensors and their application in eddy current techniques for nondestructive testing. This paper will describe the implementation of GMR sensors in non-destructive testing eddy current testing. The first part of this paper will describe the structure and principles of GMR sensors. The second part outlines the principles and types of eddy current testing probe that have been studied and developed by previous researchers. The influence of various parameters on the GMR measurement and a factor affecting in eddy current testing will be described in detail in the third part of this paper. Finally, this paper will discuss the limitations of coil probe and compensation techniques that researchers have applied in eddy current testing probes. A comprehensive review of previous studies on the application of GMR sensors in non-destructive eddy current testing also be given at the end of this paper. PMID- 26927124 TI - Classification of E-Nose Aroma Data of Four Fruit Types by ABC-Based Neural Network. AB - Electronic nose technology is used in many areas, and frequently in the beverage industry for classification and quality-control purposes. In this study, four different aroma data (strawberry, lemon, cherry, and melon) were obtained using a MOSES II electronic nose for the purpose of fruit classification. To improve the performance of the classification, the training phase of the neural network with two hidden layers was optimized using artificial bee colony algorithm (ABC), which is known to be successful in exploration. Test data were given to two different neural networks, each of which were trained separately with backpropagation (BP) and ABC, and average test performances were measured as 60% for the artificial neural network trained with BP and 76.39% for the artificial neural network trained with ABC. Training and test phases were repeated 30 times to obtain these average performance measurements. This level of performance shows that the artificial neural network trained with ABC is successful in classifying aroma data. PMID- 26927125 TI - Suitability of Smartphone Inertial Sensors for Real-Time Biofeedback Applications. AB - This article studies the suitability of smartphones with built-in inertial sensors for biofeedback applications. Biofeedback systems use various sensors to measure body functions and parameters. These sensor data are analyzed, and the results are communicated back to the user, who then tries to act on the feedback signals. Smartphone inertial sensors can be used to capture body movements in biomechanical biofeedback systems. These sensors exhibit various inaccuracies that induce significant angular and positional errors. We studied deterministic and random errors of smartphone accelerometers and gyroscopes, primarily focusing on their biases. Based on extensive measurements, we determined accelerometer and gyroscope noise models and bias variation ranges. Then, we compiled a table of predicted positional and angular errors under various biofeedback system operation conditions. We suggest several bias compensation options that are suitable for various examples of use in real-time biofeedback applications. Measurements within the developed experimental biofeedback application show that under certain conditions, even uncompensated sensors can be used for real-time biofeedback. For general use, especially for more demanding biofeedback applications, sensor biases should be compensated. We are convinced that real time biofeedback systems based on smartphone inertial sensors are applicable to many similar examples in sports, healthcare, and other areas. PMID- 26927126 TI - Exploitation of Ubiquitous Wi-Fi Devices as Building Blocks for Improvised Motion Detection Systems. AB - This article deals with a feasibility study on the detection of human movements in indoor scenarios based on radio signal strength variations. The sensing principle exploits the fact that the human body interacts with wireless signals, introducing variations of the radiowave fields due to shadowing and multipath phenomena. As a result, human motion can be inferred from fluctuations of radiowave power collected by a receiving terminal. In this paper, we investigate the potentialities of widely available wireless communication devices in order to develop an improvised motion detection system (IMDS). Experimental tests are performed in an indoor environment by using a smartphone as a Wi-Fi access point and a laptop with dedicated software as a receiver. Simple detection strategies tailored for real-time operation are implemented to process the received signal strength measurements. The achieved results confirm the potentialities of the simple system here proposed to reliably detect human motion in operational conditions. PMID- 26927127 TI - Advancement of an Infra-Red Technique for Whole-Field Concentration Measurements in Fluidized Beds. AB - For a better understanding and description of the mass transport phenomena in dense multiphase gas-solids systems such as fluidized bed reactors, detailed and quantitative experimental data on the concentration profiles is required, which demands advanced non-invasive concentration monitoring techniques with a high spatial and temporal resolution. A novel technique based on the selective detection of a gas component in a gas mixture using infra-red properties has been further developed. The first stage development was carried out using a very small sapphire reactor and CO2 as tracer gas. Although the measuring principle was demonstrated, the real application was hindered by the small reactor dimensions related to the high costs and difficult handling of large sapphire plates. In this study, a new system has been developed, that allows working at much larger scales and yet with higher resolution. In the new system, propane is used as tracer gas and quartz as reactor material. In this study, a thorough optimization and calibration of the technique is presented which is subsequently applied for whole-field measurements with high temporal resolution. The developed technique allows the use of a relatively inexpensive configuration for the measurement of detailed concentration fields and can be applied to a large variety of important chemical engineering topics. PMID- 26927128 TI - Sensitive Detection of Small Particles in Fluids Using Optical Fiber Tip with Dielectrophoresis. AB - This work presents using a tapered fiber tip coated with thin metallic film to detect small particles in water with high sensitivity. When an AC voltage applied to the Ti/Al coated fiber tip and indium tin oxide (ITO) substrate, a gradient electric field at the fiber tip induced attractive/repulsive force to suspended small particles due to the frequency-dependent dielectrophoresis (DEP) effect. Such DEP force greatly enhanced the concentration of the small particles near the tip. The increase of the local concentration also increased the scattering of surface plasmon wave near the fiber tip. Combined both DEP effect and scattering optical near-field, we show the detection limit of the concentration for 1.36 MUm polystyrene beads can be down to 1 particle/mL. The detection limit of the Escherichia coli (E. coli) bacteria was 20 CFU/mL. The fiber tip sensor takes advantages of ultrasmall volume, label-free and simple detection system. PMID- 26927129 TI - Shape Reconstruction Based on a New Blurring Model at the Micro/Nanometer Scale. AB - Real-time observation of three-dimensional (3D) information has great significance in nanotechnology. However, normal nanometer scale observation techniques, including transmission electron microscopy (TEM), and scanning probe microscopy (SPM), have some problems to obtain 3D information because they lack non-destructive, intuitive, and fast imaging ability under normal conditions, and optical methods have not widely used in micro/nanometer shape reconstruction due to the practical requirements and the imaging limitations in micro/nano manipulation. In this paper, a high resolution shape reconstruction method based on a new optical blurring model is proposed. Firstly, the heat diffusion physics equation is analyzed and the optical diffraction model is modified to directly explain the basic principles of image blurring resulting from depth variation. Secondly, a blurring imaging model is proposed based on curve fitting of a 4th order polynomial curve. The heat diffusion equations combined with the blurring imaging are introduced, and their solution is transformed into a dynamic optimization problem. Finally, the experiments with a standard nanogrid, an atomic force microscopy (AFM) cantilever and a microlens have been conducted. The experiments prove that the proposed method can reconstruct 3D shapes at the micro/nanometer scale, and the minimal reconstruction error is 3 nm. PMID- 26927131 TI - Leasing-Based Performance Analysis in Energy Harvesting Cognitive Radio Networks. AB - In this paper, we consider an energy harvesting cognitive radio network (CRN), where both of primary user (PU) and secondary user (SU) are operating in time slotted mode, and the SU powered exclusively by the energy harvested from the radio signal of the PU. The SU can only perform either energy harvesting or data transmission due to the hardware limitation. In this case, the entire time-slot is segmented into two non-overlapping fractions. During the first sub-timeslot, the SU can harvest energy from the ambient radio signal when the PU is transmitting. In order to obtain more revenue, the PU leases a portion of its time to SU, while the SU can transmit its own data by using the harvested energy. According to convex optimization, we get the optimal leasing time to maximize the SU's throughput while guaranteeing the quality of service (QoS) of PU. To evaluate the performance of our proposed spectrum leasing scheme, we compare the utility of PU and the energy efficiency ratio of the entire networks in our framework with the conventional strategies respectively. The numerical simulation results prove the superiority of our proposed spectrum leasing scheme. PMID- 26927130 TI - An Electrochemiluminescence Immunosensor Based on Gold-Magnetic Nanoparticles and Phage Displayed Antibodies. AB - Using the multiple advantages of the ultra-highly sensitive electrochemiluminescence (ECL) technique, Staphylococcus protein A (SPA) functionalized gold-magnetic nanoparticles and phage displayed antibodies, and using gold-magnetic nanoparticles coated with SPA and coupled with a polyclonal antibody (pcAb) as magnetic capturing probes, and Ru(bpy)3(2+)-labeled phage displayed antibody as a specific luminescence probe, this study reports a new way to detect ricin with a highly sensitive and specific ECL immunosensor and amplify specific detection signals. The linear detection range of the sensor was 0.0001~200 ug/L, and the limit of detection (LOD) was 0.0001 ug/L, which is 2500 fold lower than that of the conventional ELISA technique. The gold-magnetic nanoparticles, SPA and Ru(bpy)3(2+)-labeled phage displayed antibody displayed different amplifying effects in the ECL immunosensor and can decrease LOD 3-fold, 3-fold and 20-fold, respectively, compared with the ECL immunosensors without one of the three effects. The integrated amplifying effect can decrease the LOD 180 fold. The immunosensor integrates the unique advantages of SPA-coated gold magnetic nanoparticles that improve the activity of the functionalized capturing probe, and the amplifying effect of the Ru(bpy)3(2+)-labeled phage displayed antibodies, so it increases specificity, interference-resistance and decreases LOD. It is proven to be well suited for the analysis of trace amounts of ricin in various environmental samples with high recovery ratios and reproducibility. PMID- 26927132 TI - Odontonutraceuticals: Pleiotropic Phytotherapeutic Agents for Oral Health. AB - This brief commentary aims to focus on the urgency of further clinical research on phytotherapy in dentistry, and, noteworthy, to propose, for the first time, to the best of our knowledge, the term "odontonutraceuticals" to identify those phytochemicals relevant for the prevention and the treatment of oral diseases. A valuable impact is expected on nutritional, dental and biomedical sciences, suggesting the use of the suffix "odonto-" to define a specific field of nutraceutical research. PMID- 26927135 TI - Importance of Macrophyte Quality in Determining Life-History Traits of the Apple Snails Pomacea canaliculata: Implications for Bottom-Up Management of an Invasive Herbivorous Pest in Constructed Wetlands. AB - Pomacea canaliculata (Ampullariidae) has extensively invaded most Asian constructed wetlands and its massive herbivory of macrophytes has become a major cause of ecosystem dysfunctioning of these restored habitats. We conducted non choice laboratory feeding experiments of P. canaliculata using five common macrophyte species in constructed wetlands including Ipomoea aquatica, Commelina communis, Nymphoides coreana, Acorus calamus and Phragmites australis. Effects of macrophytes on snail feeding, growth and fecundity responses were evaluated. Results indicated that P. canaliculata reared on Ipomoea had the highest feeding and growth rates with highest reproductive output, but all individuals fed with Phragmites showed lowest feeding rates and little growth with poorest reproductive output. Plant N and P contents were important for enhancing palatability, supporting growth and offspring quantity of P. canaliculata, whilst toughness, cellulose and phenolics had critically deterrent effects on various life-history traits. Although snail offspring quality was generally consistent regardless of maternal feeding conditions, the reduced growth and offspring quantity of the poorly-fed snails in constructed wetlands dominated by the less palatable macrophytes could limit the invasive success of P. canaliculata. Effective bottom-up control of P. canaliculata in constructed wetlands should involve selective planting strategy using macrophytes with low nutrient and high toughness, cellulose and phenolic contents. PMID- 26927133 TI - Targeting Cell Survival Proteins for Cancer Cell Death. AB - Escaping from cell death is one of the adaptations that enable cancer cells to stave off anticancer therapies. The key players in avoiding apoptosis are collectively known as survival proteins. Survival proteins comprise the Bcl-2, inhibitor of apoptosis (IAP), and heat shock protein (HSP) families. The aberrant expression of these proteins is associated with a range of biological activities that promote cancer cell survival, proliferation, and resistance to therapy. Several therapeutic strategies that target survival proteins are based on mimicking BH3 domains or the IAP-binding motif or competing with ATP for the Hsp90 ATP-binding pocket. Alternative strategies, including use of nutraceuticals, transcriptional repression, and antisense oligonucleotides, provide options to target survival proteins. This review focuses on the role of survival proteins in chemoresistance and current therapeutic strategies in preclinical or clinical trials that target survival protein signaling pathways. Recent approaches to target survival proteins-including nutraceuticals, small molecule inhibitors, peptides, and Bcl-2-specific mimetic are explored. Therapeutic inventions targeting survival proteins are promising strategies to inhibit cancer cell survival and chemoresistance. However, complete eradication of resistance is a distant dream. For a successful clinical outcome, pretreatment with novel survival protein inhibitors alone or in combination with conventional therapies holds great promise. PMID- 26927136 TI - Degradation of Tetracyclines in Pig Manure by Composting with Rice Straw. AB - A holistic approach was followed for utilizing tetracyclines (TCs)-contaminated pig manure, by composting this with rice straw in a greenhouse for CO2 fertilization and composted residue application. After composting, the composted residues can be applied to cropland as a supplemental source of synthetic fertilizers. The objective of this study was to determine the effect of pig manure-rice straw composting on the degradation of TCs in pig manure. The results showed that greenhouse composting significantly accelerated the degradation of TCs. Contents (150 mg.kg(-1)) of oxytetracycline (OTC), tetracycline (TC) and chlortetracycline (CTC) in the composting feedstock could be completely removed within 42 days for OTC and TC, and 14 days for CTC. However, in the control samples incubated at 25 degrees C in the dark, concentrations of OTC, TC and CTC only decreased 64.7%, 66.7% and 73.3%, respectively, after 49 days. The degradation rates of TCs in the composting feedstock were in the order of CTC > TC > OTC. During the composting process, CTC dissipated rapidly with the time required for 50% degradation (DT50) and 90% degradation (DT90) of 2.4 and 7.9 days, but OTC was more persistent with DT50 and DT90 values of 5.5 and 18.4 days. On the basis of the results obtained in this study, it could be concluded that pig manure-rice straw composting in a greenhouse can help to accelerate the degradation of TCs in pig manure and make composted residues safer for field application. This technology could be an acceptable practice for greenhouse farmers to utilize TCs-contaminated pig manure. PMID- 26927134 TI - Sulfated Seaweed Polysaccharides as Multifunctional Materials in Drug Delivery Applications. AB - In the last decades, the discovery of metabolites from marine resources showing biological activity has increased significantly. Among marine resources, seaweed is a valuable source of structurally diverse bioactive compounds. The cell walls of marine algae are rich in sulfated polysaccharides, including carrageenan in red algae, ulvan in green algae and fucoidan in brown algae. Sulfated polysaccharides have been increasingly studied over the years in the pharmaceutical field, given their potential usefulness in applications such as the design of drug delivery systems. The purpose of this review is to discuss potential applications of these polymers in drug delivery systems, with a focus on carrageenan, ulvan and fucoidan. General information regarding structure, extraction process and physicochemical properties is presented, along with a brief reference to reported biological activities. For each material, specific applications under the scope of drug delivery are described, addressing in privileged manner particulate carriers, as well as hydrogels and beads. A final section approaches the application of sulfated polysaccharides in targeted drug delivery, focusing with particular interest the capacity for macrophage targeting. PMID- 26927137 TI - Comments on Melis et al. The Effects of the Urban Built Environment on Mental Health: A Cohort Study in a Large Northern Italian City. Int. J. Environ. Res. Public Health, 2015, 12, 14898-14915. PMID- 26927138 TI - Response to Kestens et al. Comments on Melis et al. The Effects of the Urban Built Environment on Mental Health: A Cohort Study in a Large Northern Italian City. Int. J. Environ. Res. Public Health, 2015, 12, 14898-14915. PMID- 26927139 TI - The Use of Carbonaceous Particle Exposure Metrics in Health Impact Calculations. AB - Combustion-related carbonaceous particles seem to be a better indicator of adverse health effects compared to PM2.5 and PM10. Historical studies are based on black smoke (BS), but more recent studies use absorbance (Abs), black carbon (BC) or elemental carbon (EC) as exposure indicators. To estimate health risks based on BS, we review the literature regarding the relationship between Abs, BS, BC and EC. We also discuss the uncertainties associated with the comparison of relative risks (RRs) based on these conversions. EC is reported to represent a proportion between 5.2% and 27% of BS with a mean value of 12%. Correlations of different metrics at one particular site are higher than when different sites are compared. Comparing all traffic, urban and rural sites, there is no systematic site dependence, indicating that other properties of the particles or errors affect the measurements and obscure the results. It is shown that the estimated daily mortality associated with short-term levels of EC is in the same range as PM10, but this is highly dependent on the EC to BS relationship that is used. RRs for all-cause mortality associated with short-term exposure to PM10 seem to be higher at sites with higher EC concentrations, but more data are needed to verify this. PMID- 26927140 TI - Modeling Heterogeneity in Direct Infectious Disease Transmission in a Compartmental Model. AB - Mathematical models have been used to understand the transmission dynamics of infectious diseases and to assess the impact of intervention strategies. Traditional mathematical models usually assume a homogeneous mixing in the population, which is rarely the case in reality. Here, we construct a new transmission function by using as the probability density function a negative binomial distribution, and we develop a compartmental model using it to model the heterogeneity of contact rates in the population. We explore the transmission dynamics of the developed model using numerical simulations with different parameter settings, which characterize different levels of heterogeneity. The results show that when the reproductive number, R0, is larger than one, a low level of heterogeneity results in dynamics similar to those predicted by the homogeneous mixing model. As the level of heterogeneity increases, the dynamics become more different. As a test case, we calibrated the model with the case incidence data for severe acute respiratory syndrome (SARS) in Beijing in 2003, and the estimated parameters demonstrated the effectiveness of the control measures taken during that period. PMID- 26927141 TI - The Effects of Forest Therapy on Coping with Chronic Widespread Pain: Physiological and Psychological Differences between Participants in a Forest Therapy Program and a Control Group. AB - This study aimed to investigate the effects of a two-day forest therapy program on individuals with chronic widespread pain. Sixty one employees of a public organization providing building and facilities management services within the Seoul Metropolitan area participated in the study. Participants were assigned to an experimental group (n = 33) who participated in a forest therapy program or a control group (n = 28) on a non-random basis. Pre- and post-measures of heart rate variability (HRV), Natural Killer cell (NK cell) activity, self-reported pain using the visual analog scale (VAS), depression level using the Beck Depression Inventory (BDI), and health-related quality of life measures using the EuroQol Visual Analog Scale (EQ-VAS) were collected in both groups. The results showed that participants in the forest therapy group, as compared to the control group, showed physiological improvement as indicated by a significant increase in some measures of HRV and an increase in immune competence as indicated by NK cell activity. Participants in the forest therapy group also reported significant decreases in pain and depression, and a significant improvement in health-related quality of life. These results support the hypothesis that forest therapy is an effective intervention to relieve pain and associated psychological and physiological symptoms in individuals with chronic widespread pain. PMID- 26927142 TI - Correction: Dowling, R., et al. Spatial Associations between Contaminated Land and Socio Demographics in Ghana. Int. J. Environ. Res. Public Health 2015, 12, 13587-13601. PMID- 26927143 TI - Preparing for Completely Smoke-Free Mental Health Settings: Findings on Patient Smoking, Resources Spent Facilitating Smoking Breaks, and the Role of Smoking in Reported Incidents from a Large Mental Health Trust in England. AB - INTRODUCTION: Despite high smoking prevalence and excessive smoking-related morbidity and mortality among people with mental disorder compared to the general population, smoking treatment is often neglected in mental health settings. The UK National Institute of Health and Clinical Excellence (NICE) recently issued public health guidance stipulating completely smoke-free mental health settings. This project evaluated existing smoking-related practices in preparation for guidance implementation. The objectives were to: audit the recording of smoking related information and treatment provision; explore current arrangements relating to the facilitation of patient smoking; measure staff time spent and identify costs of facilitating smoking; and explore the role of smoking in smoking-related incidents. METHODS: A mixed-methods study was conducted across four acute adult mental health wards, accommodating 16 patients each, over six months. It included a case-note audit, on-site observations, and a qualitative content analysis of incident reports. RESULTS: Smoking status was recorded for less than half of the 290 patients admitted (138, 48%). Of those, 98 (71%) were recorded as current smokers, of whom 72 (74%) had received brief smoking cessation advice. Staff spent 6028 h facilitating smoking, representing an annual cost of L 131,040 across four wards. Incident reports demonstrated that smoking facilitation was often central to the cause of incidences, triggered frustration in patients, and strained staff resources. CONCLUSION: The findings highlight the importance and potential of implementing completely smoke-free policies using comprehensive pathways. PMID- 26927144 TI - Change in Body Mass Index and Its Impact on Incidence of Hypertension in 18-65 Year-Old Chinese Adults. AB - AIMS: This study assessed change in body mass index (BMI) and its impact on the incidence of hypertension in 18- to 65-year-old Chinese adults. METHODS: Two waves of data were collected in 2006 and 2011 by the China Health and Nutrition Survey (CHNS) with samples drawn from nine provinces in China. The logistic regression model was used to examine the association between change in BMI and the incidence of hypertension, and odds ratio (OR) and 95% confident interval (95% CI) were calculated. RESULTS: The risk of incident hypertension increased as the quartile of the BMI difference value (D-value) increased in men (OR and 95% CI for the highest quartile vs. the lowest quartile: 2.303, 1.560-3.401, respectively, p for trend < 0.001) and women (OR and 95% CI for the highest quartile vs. the lowest quartile: 1.745, 1.199-2.540, respectively, p for trend = 0.004). Compared with non-overweight subjects in 2011, the ORs of incident hypertension were all significantly higher for overweight subjects, regardless of their overweight status at baseline (p < 0.05). CONCLUSIONS: In conclusion, the results from this study provide unequivocal evidence that prevention of weight gain is likely to have a great impact on the incidence of hypertension in Chinese adults. PMID- 26927145 TI - Polymorphisms in Four Genes (KCNQ1 rs151290, KLF14 rs972283, GCKR rs780094 and MTNR1B rs10830963) and Their Correlation with Type 2 Diabetes Mellitus in Han Chinese in Henan Province, China. AB - Genetic variants at KCNQ1 rs151290, KLF14 rs972283, GCKR rs780094 and MTNR1B rs10830963 have been associated with type 2 diabetes mellitus (T2DM), but the results are contradictory in Chinese populations. The aim of the present study was to investigate the association of these four SNPs with T2DM in a large population of Han Chinese at Henan province, China. Seven-hundred-thirty-six patients with T2DM (cases) and Seven-hundred-sixty-eight healthy glucose-tolerant controls were genotyped for KCNQ1 rs151290, KLF14 rs972283, GCKR rs780094 and MTNR1B rs10830963. The association of genetic variants in these four genes with T2DM was analyzed using multivariate logistic regression. Genotypes and allele distributions of KCNQ1 rs151290 were significantly different between the cases and controls (p < 0.05). The AC and CC genotypes and the combined AC + CC genotype of rs151290 in KCNQ1 were associated with increases risk of T2DM before (OR = 1.482, 95% CI = 1.062-2.069; p = 0.021; OR = 1.544, 95% CI = 1.097-2.172, p = 0.013; and OR = 1.509, 95% CI = 1.097-2.077, p = 0.011, respectively) and after (OR = 1.539, 95% CI = 1.015-2.332, p = 0.042; OR = 1.641, 95% CI = 1.070-2.516, p = 0.023; and OR = 1.582, 95% CI = 1.061-2.358, p = 0.024; respectively) adjustment for sex, age, anthropometric measurements, biochemical indexes, smoking and alcohol consumption. Consistent with results of genotype analysis, the C allele of rs151290 in KCNQ1 was also associated with increased risk of T2DM (OR = 1.166, 95% CI = 1.004-1.355, p = 0.045). No associations between genetic variants of KLF14 rs972283, GCKR rs780094 or MTNR1B rs10830963 and T2DM were detected. The AC and CC genotypes and the C allele of rs151290 in KCNQ1 may be risk factors for T2DM in Han Chinese in Henan province. PMID- 26927147 TI - Lower Prevalence of Atopic Dermatitis and Allergic Sensitization among Children and Adolescents with a Two-Sided Migrant Background. AB - In industrialized countries atopic diseases have been reported to be less likely in children and adolescents with a migrant background compared to non-migrants. This paper aimed at both examining and comparing prevalence of asthma, allergic rhinoconjunctivitis and atopic dermatitis and allergic sensitization to specific IgE antibodies in children and adolescents with and without a migrant background. Using data of the population-based German Health Interview and Examination Survey for children and adolescents (KiGGS;n = 17,450; 0-17 years), lifetime and 12 month prevalence of atopic diseases and point prevalence of 20 common allergic sensitizations were investigated among migrants compared to non-migrants. Multiple regression models were used to estimate the association of atopic disease and allergic sensitization with migrant background. In multivariate analyses with substantial adjustment we found atopic dermatitis about one-third less often (OR 0.73, 0.57-0.93) in participants with a two-sided migrant background. Statistically significant associations between allergic sensitizations and a two-sided migrant background remained for birch (OR 0.73, 0.58-0.90), soybean (OR 0.72, 0.54-0.96), peanut (OR 0.69, 0.53-0.90), rice (OR 0.64, 0.48-0.87), potato (OR 0.64, 0.48-0.85), and horse dander (OR 0.58, 0.40 0.85). Environmental factors and living conditions might be responsible for the observed differences. PMID- 26927148 TI - Automated Collection of Real-Time Alerts of Citizens as a Useful Tool to Continuously Monitor Malodorous Emissions. AB - The evaluation of odor emissions and dispersion is a very arduous topic to face; the real-time monitoring of odor emissions, the identification of chemical components and, with proper certainty, the source of annoyance represent a challenge for stakeholders such as local authorities. The complaints of people, often not systematic and variously distributed, in general do not allow us to quantify the perceived annoyance. Experimental research has been performed to detect and evaluate olfactory annoyance, based on field testing of an innovative monitoring methodology grounded in automatic recording of citizen alerts. It has been applied in Taranto, in the south of Italy where a relevant industrial area is located, by using Odortel((r)) for automated collection of citizen alerts. To evaluate its reliability, the collection system has been integrated with automated samplers, able to sample odorous air in real time, according to the citizen alerts of annoyance and, moreover, with meteorological data (especially the wind direction) and trends in odor marker compounds, recorded by air quality monitoring stations. The results have allowed us, for the first time, to manage annoyance complaints, test their reliability, and obtain information about the distribution and entity of the odor phenomena, such that we were able to identify, with supporting evidence, the source as an oil refinery plant. PMID- 26927146 TI - Risk Assessment of Fluoride Intake from Tea in the Republic of Ireland and its Implications for Public Health and Water Fluoridation. AB - The Republic of Ireland (RoI) is the only European Country with a mandatory national legislation requiring artificial fluoridation of drinking water and has the highest per capita consumption of black tea in the world. Tea is a hyperaccumulator of fluoride and chronic fluoride intake is associated with multiple negative health outcomes. In this study, fifty four brands of the commercially available black tea bag products were purchased and the fluoride level in tea infusions tested by an ion-selective electrode method. The fluoride content in all brands tested ranged from 1.6 to 6.1 mg/L, with a mean value of 3.3 mg/L. According to our risk assessment it is evident that the general population in the RoI is at a high risk of chronic fluoride exposure and associated adverse health effects based on established reference values. We conclude that the culture of habitual tea drinking in the RoI indicates that the total cumulative dietary fluoride intake in the general population could readily exceed the levels known to cause chronic fluoride intoxication. Evidence suggests that excessive fluoride intake may be contributing to a wide range of adverse health effects. Therefore from a public health perspective, it would seem prudent and sensible that risk reduction measures be implemented to reduce the total body burden of fluoride in the population. PMID- 26927149 TI - Comments on Meo et al. Association of Exposure to Radio-Frequency Electromagnetic Field Radiation (RF-EMFR) Generated by Mobile Phone Base Stations with Glycated Hemoglobin (HbA1c) and Risk of Type 2 Diabetes Mellitus. Int. J. Environ. Res. Public Health, 2015, 12, 14519-14528. PMID- 26927150 TI - Response to Comments on Meo et al. Association of Exposure to Radio-Frequency Electromagnetic Field Radiation (RF-EMFR) Generated by Mobile Phone Base Stations with Glycated Hemoglobin (HbA1c) and Risk of Type 2 Diabetes Mellitus. Int. J. Environ. Res. Public Health, 2015, 12, 14519-14528. PMID- 26927152 TI - Chitosan Coagulation to Improve Microbial and Turbidity Removal by Ceramic Water Filtration for Household Drinking Water Treatment. AB - The use of porous ceramic filters is promoted globally for household water treatment, but these filters are ineffective in removing viruses from water. In order to increase virus removal, we combine a promising natural coagulant, chitosan, as a pretreatment for ceramic water filters (CWFs) and evaluate the performance of this dual barrier water treatment system. Chitosan is a non-toxic and biodegradable organic polymer derived by simple chemical treatments from chitin, a major source of which is the leftover shells of crustacean seafoods, such as shrimp, prawns, crabs, and lobsters. To determine the effectiveness of chitosan, model test water was contaminated with Escherichia coli K011 and coliphage MS2 as a model enteric bacterium and virus, respectively. Kaolinite clay was used to model turbidity. Coagulation effectiveness of three types of modified chitosans was determine at various doses ranging from 5 to 30 mg/L, followed by flocculation and sedimentation. The pre-treated supernatant water was then decanted into the CWF for further treatment by filtration. There were appreciable microbial removals by chitosan HCl, acetate, and lactate pretreatment followed by CWF treatment, with mean reductions (95% CI) between 4.7 (+/- 1.56) and 7.5 (+/- 0.02) log10 for Escherichia coli, and between 2.8 (+/- 0.10) and 4.5 (+/- 1.04) log10 for MS2. Turbidity reduction with chitosan treatment and filtration consistently resulted in turbidities < 1 NTU, which meet turbidity standards of the US EPA and guidance by the World Health Organization (WHO). According to WHO health-based microbial removal targets for household water treatment technology, chitosan coagulation achieved health protective targets for both viruses and bacteria. Therefore, the results of this study support the use of chitosan to improve household drinking water filtration processes by increasing virus and bacteria reductions. PMID- 26927151 TI - Co-Formulants in Glyphosate-Based Herbicides Disrupt Aromatase Activity in Human Cells below Toxic Levels. AB - Pesticide formulations contain declared active ingredients and co-formulants presented as inert and confidential compounds. We tested the endocrine disruption of co-formulants in six glyphosate-based herbicides (GBH), the most used pesticides worldwide. All co-formulants and formulations were comparably cytotoxic well below the agricultural dilution of 1% (18-2000 times for co formulants, 8-141 times for formulations), and not the declared active ingredient glyphosate (G) alone. The endocrine-disrupting effects of all these compounds were measured on aromatase activity, a key enzyme in the balance of sex hormones, below the toxicity threshold. Aromatase activity was decreased both by the co formulants alone (polyethoxylated tallow amine-POEA and alkyl polyglucoside-APG) and by the formulations, from concentrations 800 times lower than the agricultural dilutions; while G exerted an effect only at 1/3 of the agricultural dilution. It was demonstrated for the first time that endocrine disruption by GBH could not only be due to the declared active ingredient but also to co formulants. These results could explain numerous in vivo results with GBHs not seen with G alone; moreover, they challenge the relevance of the acceptable daily intake (ADI) value for GBHs exposures, currently calculated from toxicity tests of the declared active ingredient alone. PMID- 26927153 TI - Association between the First Occurrence of Allergic Rhinitis in Preschool Children and Air Pollution in Taiwan. AB - The occurrence of allergic rhinitis (AR) may be significantly influenced by air pollution. This study examined the association between the first occurrence of AR in preschool children and the pre-incident levels of air pollutants in Taiwan. We identified 9960 eligible subjects from a systematic sampling cohort database containing 400,000 insureds of the National Health Insurance from 2007 to 2011 and matched them with the environmental monitoring data from 2006 to 2011 according to the locations of their clinics. Pre-incident levels were determined using the average concentrations of air pollutants one or two weeks prior to the AR diagnoses. Logistic regression analyses were performed to determine any significant relationships between AR and specific air pollutants. The first AR incidence for Taiwanese preschool children, which increased with age, was 10.9% on average; boys appeared to have a higher percentage (14.2%) than girls (8.27%). Among the air pollutants, carbon monoxide (CO) and nitrogen oxides (NOX) were significantly related to AR after adjusting for age and gender (p < 0.05). Because both pollutants are considered to be traffic emissions, this study suggests that traffic emissions in Taiwan need to be controlled to lower the prevalence of children's AR. PMID- 26927154 TI - Evaluation of Lead Release in a Simulated Lead-Free Premise Plumbing System Using a Sequential Sampling Approach. AB - In this pilot study, a modified sampling protocol was evaluated for the detection of lead contamination and locating the source of lead release in a simulated premise plumbing system with one-, three- and seven-day stagnation for a total period of 475 days. Copper pipes, stainless steel taps and brass fittings were used to assemble the "lead-free" system. Sequential sampling using 100 mL was used to detect lead contamination while that using 50 mL was used to locate the lead source. Elevated lead levels, far exceeding the World Health Organization (WHO) guideline value of 10 ug . L(-1), persisted for as long as five months in the system. "Lead-free" brass fittings were identified as the source of lead contamination. Physical disturbances, such as renovation works, could cause short term spikes in lead release. Orthophosphate was able to suppress total lead levels below 10 ug . L(-1), but caused "blue water" problems. When orthophosphate addition was ceased, total lead levels began to spike within one week, implying that a continuous supply of orthophosphate was required to control total lead levels. Occasional total lead spikes were observed in one-day stagnation samples throughout the course of the experiments. PMID- 26927155 TI - HTLV-1 Rex Tunes the Cellular Environment Favorable for Viral Replication. AB - Human T-cell leukemia virus type-1 (HTLV-1) Rex is a viral RNA binding protein. The most important and well-known function of Rex is stabilizing and exporting viral mRNAs from the nucleus, particularly for unspliced/partially-spliced mRNAs encoding the structural proteins essential for viral replication. Without Rex, these unspliced viral mRNAs would otherwise be completely spliced. Therefore, Rex is vital for the translation of structural proteins and the stabilization of viral genomic RNA and, thus, for viral replication. Rex schedules the period of extensive viral replication and suppression to enter latency. Although the importance of Rex in the viral life-cycle is well understood, the underlying molecular mechanism of how Rex achieves its function has not been clarified. For example, how does Rex protect unspliced/partially-spliced viral mRNAs from the host cellular splicing machinery? How does Rex protect viral mRNAs, antigenic to eukaryotic cells, from cellular mRNA surveillance mechanisms? Here we will discuss these mechanisms, which explain the function of Rex as an organizer of HTLV-1 expression based on previously and recently discovered aspects of Rex. We also focus on the potential influence of Rex on the homeostasis of the infected cell and how it can exert its function. PMID- 26927157 TI - From Conventional to Next Generation Sequencing of Epstein-Barr Virus Genomes. AB - Genomic sequences of Epstein-Barr virus (EBV) have been of interest because the virus is associated with cancers, such as nasopharyngeal carcinoma, and conditions such as infectious mononucleosis. The progress of whole-genome EBV sequencing has been limited by the inefficiency and cost of the first-generation sequencing technology. With the advancement of next-generation sequencing (NGS) and target enrichment strategies, increasing number of EBV genomes has been published. These genomes were sequenced using different approaches, either with or without EBV DNA enrichment. This review provides an overview of the EBV genomes published to date, and a description of the sequencing technology and bioinformatic analyses employed in generating these sequences. We further explored ways through which the quality of sequencing data can be improved, such as using DNA oligos for capture hybridization, and longer insert size and read length in the sequencing runs. These advances will enable large-scale genomic sequencing of EBV which will facilitate a better understanding of the genetic variations of EBV in different geographic regions and discovery of potentially pathogenic variants in specific diseases. PMID- 26927156 TI - Monitoring Physiological Changes in Haloarchaeal Cell during Virus Release. AB - The slow rate of adsorption and non-synchronous release of some archaeal viruses have hindered more thorough analyses of the mechanisms of archaeal virus release. To address this deficit, we utilized four viruses that infect Haloarcula hispanica that represent the four virion morphotypes currently known for halophilic euryarchaeal viruses: (1) icosahedral internal membrane-containing SH1; (2) icosahedral tailed HHTV-1; (3) spindle-shaped His1; and (4) pleomorphic His2. To discern the events occurring as the progeny viruses exit, we monitored culture turbidity, as well as viable cell and progeny virus counts of infected and uninfected cultures. In addition to these traditional metrics, we measured three parameters associated with membrane integrity: the binding of the lipophilic anion phenyldicarbaundecaborane, oxygen consumption, and both intra- and extra-cellular ATP levels. PMID- 26927158 TI - The Receptor-Binding Domain in the VP1u Region of Parvovirus B19. AB - Parvovirus B19 (B19V) is known as the human pathogen causing the mild childhood disease erythema infectiosum. B19V shows an extraordinary narrow tissue tropism for erythroid progenitor cells in the bone marrow, which is determined by a highly restricted uptake. We have previously shown that the specific internalization is mediated by the interaction of the viral protein 1 unique region (VP1u) with a yet unknown cellular receptor. To locate the receptor binding domain (RBD) within the VP1u, we analyzed the effect of truncations and mutations on the internalization capacity of the recombinant protein into UT7/Epo cells. Here we report that the N-terminal amino acids 5-80 of the VP1u are necessary and sufficient for cellular binding and internalization; thus, this N terminal region represents the RBD required for B19V uptake. Using site-directed mutagenesis, we further identified a cluster of important amino acids playing a critical role in VP1u internalization. In silico predictions and experimental results suggest that the RBD is structured as a rigid fold of three alpha helices. Finally, we found that dimerization of the VP1u leads to a considerably enhanced cellular binding and internalization. Taken together, we identified the RBD that mediates B19V uptake and mapped functional and structural motifs within this sequence. The findings reveal insights into the uptake process of B19V, which contribute to understand the pathogenesis of the infection and the neutralization of the virus by the immune system. PMID- 26927159 TI - Retargeting Strategies for Oncolytic Herpes Simplex Viruses. AB - Most of the oncolytic herpes simplex viruses (HSVs) exhibit a high safety profile achieved through attenuation. They carry defects in virulence proteins that antagonize host cell response to the virus, including innate response, apoptosis, authophagy, and depend on tumor cell proliferation. They grow robustly in cancer cells, provided that these are deficient in host cell responses, which is often the case. To overcome the attenuation limits, a strategy is to render the virus highly cancer-specific, e.g., by retargeting their tropism to cancer-specific receptors, and detargeting from natural receptors. The target we selected is HER 2, overexpressed in breast, ovarian and other cancers. Entry of wt-HSV requires the essential glycoproteins gD, gH/gL and gB. Here, we reviewed that oncolytic HSV retargeting was achieved through modifications in gD: the addition of a single-chain antibody (scFv) to HER-2 coupled with appropriate deletions to remove part of the natural receptors' binding sites. Recently, we showed that also gH/gL can be a retargeting tool. The insertion of an scFv to HER-2 at the gH N-terminus, coupled with deletions in gD, led to a recombinant capable to use HER 2 as the sole receptor. The retargeted oncolytic HSVs can be administered systemically by means of carrier cells-forcedly-infected mesenchymal stem cells. Altogether, the retargeted oncolytic HSVs are highly cancer-specific and their replication is not dependent on intrinsic defects of the tumor cells. They might be further modified to express immunomodulatory molecules. PMID- 26927160 TI - Venetoclax (ABT-199) Might Act as a Perpetrator in Pharmacokinetic Drug-Drug Interactions. AB - Venetoclax (ABT-199) represents a specific B-cell lymphoma 2 (Bcl-2) inhibitor that is currently under development for the treatment of lymphoid malignancies. So far, there is no published information on its interaction potential with important drug metabolizing enzymes and drug transporters, or its efficacy in multidrug resistant (MDR) cells. We therefore scrutinized its drug-drug interaction potential in vitro. Inhibition of cytochrome P450 enzymes (CYPs) was quantified by commercial kits. Inhibition of drug transporters (P-glycoprotein (P gp, ABCB1), breast cancer resistance protein (BCRP), and organic anion transporting polypeptides (OATPs)) was evaluated by the use of fluorescent probe substrates. Induction of drug transporters and drug metabolizing enzymes was quantified by real-time RT-PCR. The efficacy of venetoclax in MDR cells lines was evaluated with proliferation assays. Venetoclax moderately inhibited P-gp, BCRP, OATP1B1, OATP1B3, CYP3A4, and CYP2C19, whereas CYP2B6 activity was increased. Venetoclax induced the mRNA expression of CYP1A1, CYP1A2, UGT1A3, and UGT1A9. In contrast, expression of ABCB1 was suppressed, which might revert tumor resistance towards antineoplastic P-gp substrates. P-gp over-expression led to reduced antiproliferative effects of venetoclax. Effective concentrations for inhibition and induction lay in the range of maximum plasma concentrations of venetoclax, indicating that it might act as a perpetrator drug in pharmacokinetic drug-drug interactions. PMID- 26927161 TI - Nigerian Honey Ameliorates Hyperglycemia and Dyslipidemia in Alloxan-Induced Diabetic Rats. AB - Diabetic dyslipidemia contributes to an increased risk of cardiovascular disease. Hence, its treatment is necessary to reduce cardiovascular events. Honey reduces hyperglycemia and dyslipidemia. The reproducibility of these beneficial effects and their generalization to honey samples of other geographical parts of the world remain controversial. Currently, data are limited and findings are inconclusive especially with evidence showing honey increased glycosylated hemoglobin in diabetic patients. It was hypothesized that this deteriorating effect might be due to administered high doses. This study investigated if Nigerian honey could ameliorate hyperglycemia and hyperlipidemia. It also evaluated if high doses of honey could worsen glucose and lipid abnormalities. Honey (1.0, 2.0 or 3.0 g/kg) was administered to diabetic rats for three weeks. Honey (1.0 or 2.0 g/kg) significantly (p < 0.05) increased high density lipoprotein (HDL) cholesterol while it significantly (p < 0.05) reduced hyperglycemia, triglycerides (TGs), very low density lipoprotein (VLDL) cholesterol, non-HDL cholesterol, coronary risk index (CRI) and cardiovascular risk index (CVRI). In contrast, honey (3.0 g/kg) significantly (p < 0.05) reduced TGs and VLDL cholesterol. This study confirms the reproducibility of glucose lowering and hypolipidemic effects of honey using Nigerian honey. However, none of the doses deteriorated hyperglycemia and dyslipidemia. PMID- 26927162 TI - Australians are not Meeting the Recommended Intakes for Omega-3 Long Chain Polyunsaturated Fatty Acids: Results of an Analysis from the 2011-2012 National Nutrition and Physical Activity Survey. AB - Health benefits have been attributed to omega-3 long chain polyunsaturated fatty acids (n-3 LCPUFA). Therefore it is important to know if Australians are currently meeting the recommended intake for n-3 LCPUFA and if they have increased since the last National Nutrition Survey in 1995 (NNS 1995). Dietary intake data was obtained from the recent 2011-2012 National Nutrition and Physical Activity Survey (2011-2012 NNPAS). Linoleic acid (LA) intakes have decreased whilst alpha-linolenic acid (LNA) and n-3 LCPUFA intakes have increased primarily due to n-3 LCPUFA supplements. The median n-3 LCPUFA intakes are less than 50% of the mean n-3 LCPUFA intakes which highlights the highly-skewed n-3 LCPUFA intakes, which shows that there are some people consuming high amounts of n-3 LCPUFA, but the vast majority of the population are consuming much lower amounts. Only 20% of the population meets the recommended n-3 LCPUFA intakes and only 10% of women of childbearing age meet the recommended docosahexaenoic acid (DHA) intake. Fish and seafood is by far the richest source of n-3 LCPUFA including DHA. PMID- 26927163 TI - Association between Knowledge about Comprehensive Food Education and Increase in Dental Caries in Japanese University Students: A Prospective Cohort Study. AB - In Japan, comprehensive food education (shokuiku) programs are carried out with the aim of improving dietary practices and thereby reducing the incidence of lifestyle-related diseases, including dental caries. The purpose of this prospective cohort study was to investigate the association between knowledge about shokuiku and the increase in dental caries among Japanese university students who had attended a shokuiku program while in junior/senior high school. A total of 562 students volunteered to undergo oral examinations over a three year follow-up period, during which the number of cases of dental caries were recorded. Additional information was collected using a questionnaire survey regarding knowledge about shokuiku, dietary habits, and oral health behaviors. In logistic regression analysis, males who lacked knowledge about shokuiku had significantly higher odds for dental caries than those who did not (odds ratio (OR), 2.00; 95% confidence interval (CI), 1.12-3.58; p = 0.019). On the other hand, among females, those who frequently consumed sugar-sweetened soft drinks had significantly higher odds for dental caries than those who did not (OR, 1.89; 95% CI, 1.05-3.42; p = 0.035). These results suggest that having no knowledge about shokuiku is associated with a risk of increase in dental caries in Japanese male university students. PMID- 26927164 TI - Leptin Level and Skipping Breakfast: The National Health and Nutrition Examination Survey III (NHANES III). AB - Skipping breakfast is a common dietary habit considered to be unhealthy. However, the mechanisms underlying skipping breakfast have not been fully explored. Leptin is a hormone that regulates food intake and energy storage and secretes in a diurnal rhythm with lowest levels in the morning. We examined the association between the serum leptin level and skipping breakfast in 5714 adults in the U.S. National Health and Nutrition Examination Survey III, 1988-1994. We defined breakfast as any food or beverage consumed between 5:00 a.m. and 10:00 a.m. using a single 24-h recall. Skipped breakfast was seen in 13.1%. In the logistic regression models with and without adjusting for adiposity and sex, leptin levels were not associated with skipping breakfast. After adjusting for age, race/ethnicity, and time of venipuncture, the association remained insignificant. After further adjusting for potential confounders: physical activity, alcohol intake, smoking and diabetes and after further adjusting for: dietary factors, insulin and glucose levels, there was a 9% and 11%-12%, respectively, statistically significantly higher likelihood of skipping breakfast if the leptin level was more than 50% greater. Further investigation into the biological reasons for skipping breakfast may be useful for promoting healthy lifestyles. PMID- 26927165 TI - The Association between the Consumption of Fish/Shellfish and the Risk of Osteoporosis in Men and Postmenopausal Women Aged 50 Years or Older. AB - Fish rich in n-3 polyunsaturated fatty acids have been suggested to have a favorable effect on bone health, but previous epidemiologic studies have shown inconsistent results. The purpose of the present study was to investigate the hypothesis that the consumption of fish and shellfish is positively associated with bone mass and negatively associated with the risk of osteoporosis in Koreans and Americans. Men and postmenopausal women >= 50 years old from the Korean National Health and Nutrition Examination Survey 2008-2011 (n = 7154) and the National Health and Nutrition Examination Survey 2007-2010 (n = 2658) were included. There was a positive correlation between the consumption of fish and shellfish and bone mineral density (BMD) of the total femur, femoral neck, and lumbar spine in Koreans. Consistently, multivariate logistic regression analysis showed a significant association between intake of fish and shellfish and the risk of osteoporosis in Koreans but not in Americans. Consumption of fish and shellfish was 4-5 times higher in Koreans than Americans in the present study. In conclusion, intake of fish and shellfish was associated with BMD and the risk of osteoporosis in Koreans but not in Americans, suggesting that a minimum intake level of fish and shellfish might be recommended to protect against bone loss and osteoporosis. PMID- 26927166 TI - Co-Ingestion of Whey Protein with a Carbohydrate-Rich Breakfast Does Not Affect Glycemia, Insulinemia or Subjective Appetite Following a Subsequent Meal in Healthy Males. AB - We aimed to assess postprandial metabolic and appetite responses to a mixed macronutrient lunch following prior addition of whey protein to a carbohydrate rich breakfast. Ten healthy males (age: 24 +/- 1 years; body mass index (BMI): 24.5 +/- 0.7 kg/m2) completed three trials in a non-isocaloric, crossover design. A carbohydrate-rich breakfast (93 g carbohydrate; 1799 kJ) was consumed with (CHO + WP) or without (CHO) 20 g whey protein isolate (373 kJ), or breakfast was omitted (NB). At 180 min, participants consumed a mixed-macronutrient lunch meal. Venous blood was sampled at 15 min intervals following each meal and every 30 min thereafter, while subjective appetite sensations were collected every 30 min throughout. Post-breakfast insulinemia was greater after CHO + WP (time-averaged area under the curve (AUC0--180 min): 193.1 +/- 26.3 pmol/L), compared to CHO (154.7 +/- 18.5 pmol/L) and NB (46.1 +/- 8.0 pmol/L; p < 0.05), with no difference in post-breakfast (0-180 min) glycemia (CHO + WP, 3.8 +/- 0.2 mmol/L; CHO, 4.2 +/- 0.2 mmol/L; NB, 4.2 +/- 0.1 mmol/L; p = 0.247). There were no post lunch (0-180 min) effects of condition on glycemia (p = 0.492), insulinemia (p = 0.338) or subjective appetite (p > 0.05). Adding whey protein to a carbohydrate rich breakfast enhanced the acute postprandial insulin response, without influencing metabolic or appetite responses following a subsequent mixed macronutrient meal. PMID- 26927167 TI - Diet Quality Scores and Risk of Nasopharyngeal Carcinoma in Chinese Adults: A Case-Control Study. AB - Many studies show that dietary factors may affect the risk of nasopharyngeal carcinoma (NPC). We examined the association between overall diet quality and NPC risk in a Chinese population. This case-control study included 600 NPC patients and 600 matched controls between 2009 and 2011 in Guangzhou, China. Habitual dietary intake and various covariates were assessed via face-to-face interviews. Diet quality scores were calculated according to the Healthy Eating Index-2005 (HEI-2005), the alternate Healthy Eating Index (aHEI), the Diet Quality Index International (DQI-I), and the alternate Mediterranean Diet Score (aMed). After adjustment for various lifestyle and dietary factors, greater diet quality scores on the HEI-2005, aHEI, and DQI-I-but not on the aMed-showed a significant association with a lower risk of NPC (p-trends, <0.001-0.001). The odds ratios (95% confidence interval) comparing the extreme quartiles of the three significant scores were 0.47 (0.32-0.68) (HEI-2005), 0.48 (0.33-0.70) (aHEI), and 0.43 (0.30-0.62) (DQI-I). In gender-stratified analyses, the favorable association remained significant in men but not in women. We found that adherence to the predefined dietary patterns represented by the HEI-2005, aHEI, and DQI-I scales predicted a lower risk of NPC in adults from south China, especially in men. PMID- 26927168 TI - Associations between Vitamin B-12 Status and Oxidative Stress and Inflammation in Diabetic Vegetarians and Omnivores. AB - Diabetes is considered an oxidative stress and a chronic inflammatory disease. The purpose of this study was to investigate the correlations between vitamin B 12 status and oxidative stress and inflammation in diabetic vegetarians and omnivores. We enrolled 154 patients with type 2 diabetes (54 vegetarians and 100 omnivores). Levels of fasting glucose, glycohemoglobin (HbA1c), lipid profiles, oxidative stress, antioxidant enzymes activity, and inflammatory makers were measured. Diabetic vegetarians with higher levels of vitamin B-12 (>250 pmol/L) had significantly lower levels of fasting glucose, HbA1c and higher antioxidant enzyme activity (catalase) than those with lower levels of vitamin B-12 (<= 250 pmol/L). A significant association was found between vitamin B-12 status and fasting glucose (r = -0.17, p = 0.03), HbA1c (r = -0.33, p = 0.02), oxidative stress (oxidized low density lipoprotein-cholesterol, r = -0.19, p = 0.03), and antioxidant enzyme activity (catalase, r = 0.28, p = 0.01) in the diabetic vegetarians; vitamin B-12 status was significantly correlated with inflammatory markers (interleukin-6, r = -0.33, p < 0.01) in diabetic omnivores. As a result, we suggest that it is necessary to monitor the levels of vitamin B-12 in patients with diabetes, particularly those adhering to a vegetarian diet. PMID- 26927169 TI - Validation of Correction Algorithms for Near-IR Analysis of Human Milk in an Independent Sample Set-Effect of Pasteurization. AB - Commercial infrared (IR) milk analyzers are being increasingly used in research settings for the macronutrient measurement of breast milk (BM) prior to its target fortification. These devices, however, may not provide reliable measurement if not properly calibrated. In the current study, we tested a correction algorithm for a Near-IR milk analyzer (Unity SpectraStar, Brookfield, CT, USA) for fat and protein measurements, and examined the effect of pasteurization on the IR matrix and the stability of fat, protein, and lactose. Measurement values generated through Near-IR analysis were compared against those obtained through chemical reference methods to test the correction algorithm for the Near-IR milk analyzer. Macronutrient levels were compared between unpasteurized and pasteurized milk samples to determine the effect of pasteurization on macronutrient stability. The correction algorithm generated for our device was found to be valid for unpasteurized and pasteurized BM. Pasteurization had no effect on the macronutrient levels and the IR matrix of BM. These results show that fat and protein content can be accurately measured and monitored for unpasteurized and pasteurized BM. Of additional importance is the implication that donated human milk, generally low in protein content, has the potential to be target fortified. PMID- 26927170 TI - Gastrointestinal Nutrient Infusion Site and Eating Behavior: Evidence for A Proximal to Distal Gradient within the Small Intestine? AB - The rapidly increasing prevalence of overweight and obesity demands new strategies focusing on prevention and treatment of this significant health care problem. In the search for new and effective therapeutic modalities for overweight subjects, the gastrointestinal (GI) tract is increasingly considered as an attractive target for medical and food-based strategies. The entry of nutrients into the small intestine activates so-called intestinal "brakes", negative feedback mechanisms that influence not only functions of more proximal parts of the GI tract but also satiety and food intake. Recent evidence suggests that all three macronutrients (protein, fat, and carbohydrates) are able to activate the intestinal brake, although to a different extent and by different mechanisms of action. This review provides a detailed overview of the current evidence for intestinal brake activation of the three macronutrients and their effects on GI function, satiety, and food intake. In addition, these effects appear to depend on region and length of infusion in the small intestine. A recommendation for a therapeutic approach is provided, based on the observed differences between intestinal brake activation. PMID- 26927171 TI - Dairy Product Consumption and Risk of Non-Hodgkin Lymphoma: A Meta-Analysis. AB - Many epidemiologic studies have explored the association between dairy product consumption and the risk of non-Hodgkin lymphoma (NHL), but the results remain controversial. A literature search was performed in PubMed, Web of Science and Embase for relevant articles published up to October 2015. Pooled relative risks (RRs) with 95% confidence intervals (CIs) were calculated with a random-effects model. The dose-response relationship was assessed by restricted cubic spline. A total of 16 articles were eligible for this meta-analysis. The pooled RRs (95% CIs) of NHL for the highest vs. lowest category of the consumption of total dairy product, milk, butter, cheese, ice cream and yogurt were 1.20 (1.02, 1.42), 1.41 (1.08, 1.84), 1.31 (1.04, 1.65), 1.14 (0.96, 1.34), 1.57 (1.11, 2.20) and 0.78 (0.54, 1.12), respectively. In subgroup analyses, the positive association between total dairy product consumption and the risk of NHL was found among case control studies (RR = 1.41, 95% CI: 1.17-1.70) but not among cohort studies (RR = 1.02, 95% CI: 0.88-1.17). The pooled RRs (95% CIs) of NHL were 1.21 (1.01, 1.46) for milk consumption in studies conducted in North America, and 1.24 (1.09, 1.40) for cheese consumption in studies that adopted validated food frequency questionnaires. In further analysis of NHL subtypes, we found statistically significant associations between the consumption of total dairy product (RR = 1.73, 95% CI: 1.22-2.45) and milk (RR = 1.49, 95% CI: 1.08-2.06) and the risk of diffuse large B-cell lymphoma. The dose-response analysis suggested that the risk of NHL increased by 5% (1.05 (1.00-1.10)) and 6% (1.06 (0.99-1.13)) for each 200 g/day increment of total dairy product and milk consumption, respectively. This meta-analysis suggested that dairy product consumption, but not yogurt, may increase the risk of NHL. More prospective cohort studies that investigate specific types of dairy product consumption are needed to confirm this conclusion. PMID- 26927172 TI - Polyphasic Approach Including MALDI-TOF MS/MS Analysis for Identification and Characterisation of Fusarium verticillioides in Brazilian Corn Kernels. AB - Fusarium verticillioides is considered one of the most important global sources of fumonisins contamination in food and feed. Corn is one of the main commodities produced in the Northeastern Region of Brazil. The present study investigated potential mycotoxigenic fungal strains belonging to the F. verticillioides species isolated from corn kernels in 3 different Regions of the Brazilian State of Pernambuco. A polyphasic approach including classical taxonomy, molecular biology, MALDI-TOF MS and MALDI-TOF MS/MS for the identification and characterisation of the F. verticillioides strains was used. Sixty F. verticillioides strains were isolated and successfully identified by classical morphology, proteomic profiles of MALDI-TOF MS, and by molecular biology using the species-specific primers VERT-1 and VERT-2. FUM1 gene was further detected for all the 60 F. verticillioides by using the primers VERTF-1 and VERTF-2 and through the amplification profiles of the ISSR regions using the primers (GTG)5 and (GACA)4. Results obtained from molecular analysis shown a low genetic variability among these isolates from the different geographical regions. All of the 60 F. verticillioides isolates assessed by MALDI-TOF MS/MS presented ion peaks with the molecular mass of the fumonisin B1 (721.83 g/mol) and B2 (705.83 g/mol). PMID- 26927173 TI - Cylindrospermopsin Biodegradation Abilities of Aeromonas sp. Isolated from Rusalka Lake. AB - The occurrence of the cyanobacterial toxin cylindrospermopsin (CYN) in freshwater reservoirs is a common phenomenon. However, the biodegradation of this toxin in environmental samples has been observed only occasionally. In this work the biodegradation ability of cylindrospermopsin was investigated based on isolates from lakes with previous cyanotoxin history. Bacterial strains were identified based on the 16S rDNA and rpoD gene comparison. CYN biodegradation was monitored using the HPLC method. The R6 strain identified as Aeromonas sp. was documented as being capable of CYN removal. This biodegradation was dependent on the pH and temperature. Additionally, the stimulation of the growth of the R6 strain in the presence of CYN was indicated. Our discovery supports the hypothesis that (in analogy to the well-known phenomenon of microcystin biodegradation) in lakes dominated by potential CYN-producing cyanobacteria, the processes of microbial utilization of this toxin may occur. PMID- 26927174 TI - Quantitative Determination of Lethal Toxin Proteins in Culture Supernatant of Human Live Anthrax Vaccine Bacillus anthracis A16R. AB - Bacillus anthracis (B. anthracis) is the etiological agent of anthrax affecting both humans and animals. Anthrax toxin (AT) plays a major role in pathogenesis. It includes lethal toxin (LT) and edema toxin (ET), which are formed by the combination of protective antigen (PA) and lethal factor (LF) or edema factor (EF), respectively. The currently used human anthrax vaccine in China utilizes live-attenuated B. anthracis spores (A16R; pXO1+, pXO2-) that produce anthrax toxin but cannot produce the capsule. Anthrax toxins, especially LT, have key effects on both the immunogenicity and toxicity of human anthrax vaccines. Thus, determining quantities and biological activities of LT proteins expressed by the A16R strain is meaningful. Here, we explored LT expression patterns of the A16R strain in culture conditions using another vaccine strain Sterne as a control. We developed a sandwich ELISA and cytotoxicity-based method for quantitative detection of PA and LF. Expression and degradation of LT proteins were observed in culture supernatants over time. Additionally, LT proteins expressed by the A16R and Sterne strains were found to be monomeric and showed cytotoxic activity, which may be the main reason for side effects of live anthrax vaccines. Our work facilitates the characterization of anthrax vaccines components and establishment of a quality control standard for vaccine production which may ultimately help to ensure the efficacy and safety of the human anthrax vaccine A16R. PMID- 26927175 TI - Aflatoxin M1 in Cow's Milk: Method Validation for Milk Sampled in Northern Italy. AB - Aflatoxins (AFs) are mycotoxins produced by some species of Aspergillus. In dairy cows, ingested AFB1 is metabolized into carcinogenic AFM1 which is eliminated through milk, thus posing a risk for consumer health. Here we describe the set, validation, and application of screening (ELISA) and confirmatory (HPLC) tests carried out on milk samples collected through official control of mycotoxin levels in northern Italy over a three-year period (2012-2014). The limit of detection (LOD) was set at 5 ppt and 2 ppt for ELISA and HPLC, respectively, and the limit of quantification (LOQ) was 10 ppt for confirmatory HPLC. A total of 1668 milk samples were analyzed: ELISA identified 36 (2.2%) positive milk samples that were subsequently confirmed by HPLC. The level of AFM1 in the positive samples ranged between 18 +/- 2 and 208 +/- 27 ppt. Of the total samples, only eight (0.5%) were found non-compliant with the EU regulatory limit (50 ppt; range 74 +/- 10 to 208 +/- 27 ppt). Use of ELISA and HPLC tests in series allows for high-volume analysis of samples, thus saving time and money while guaranteeing high analytical precision and accuracy. PMID- 26927176 TI - Aberrant Promoter Methylation of the Tumour Suppressor RASSF10 and Its Growth Inhibitory Function in Breast Cancer. AB - Breast cancer is the most common cancer in women, with 1.7 million new cases each year. As early diagnosis and prognosis are crucial factors in cancer treatment, we investigated potential DNA methylation biomarkers of the tumour suppressor family Ras-association domain family (RASSF). Promoter hypermethylation of tumour suppressors leads to their inactivation and thereby promotes cancer development and progression. In this study we analysed the tumour suppressors RASSF1A and RASSF10. Our study shows that RASSF10 is expressed in normal breast but inactivated by methylation in breast cancer. We observed a significant inactivating promoter methylation of RASSF10 in primary breast tumours. RASSF10 is inactivated in 63% of primary breast cancer samples but only 4% of normal control breast tissue is methylated (p < 0.005). RASSF1A also shows high promoter methylation levels in breast cancer of 56% vs. 8% of normal tissue (p < 0.005). Interestingly more than 80% of breast cancer samples harboured a hypermethylation of RASSF10 and/or RASSF1A promoter. Matching samples exhibited a strong tumour specific promoter methylation of RASSF10 in comparison to the normal control breast tissue. Demethylation treatment of breast cancer cell lines MCF7 and T47D reversed RASSF10 promoter hypermethylation and re-established RASSF10 expression. In addition, we could show the growth inhibitory potential of RASSF10 in breast cancer cell lines MCF7 and T47D upon exogenous expression of RASSF10 by colony formation. We could further show, that RASSF10 induced apoptotic changes in MCF7 and T47D cells, which was verified by a significant increase in the apoptotic sub G1 fraction by 50% using flow cytometry for MCF7 cells. In summary, our study shows the breast tumour specific inactivation of RASSF10 and RASSF1A due to DNA methylation of their CpG island promoters. Furthermore RASSF10 was characterised by the ability to block growth of breast cancer cell lines by apoptosis induction. PMID- 26927177 TI - Paradigm Shift in Radiation Biology/Radiation Oncology-Exploitation of the "H2O2 Effect" for Radiotherapy Using Low-LET (Linear Energy Transfer) Radiation such as X-rays and High-Energy Electrons. AB - Most radiation biologists/radiation oncologists have long accepted the concept that the biologic effects of radiation principally involve damage to deoxyribonucleic acid (DNA), which is the critical target, as described in "Radiobiology for the Radiologist", by E.J. Hall and A.J. Giaccia [1]. Although the concepts of direct and indirect effects of radiation are fully applicable to low-LET (linear energy transfer) radioresistant tumor cells/normal tissues such as osteosarcoma cells and chondrocytes, it is believed that radiation-associated damage to DNA does not play a major role in the mechanism of cell death in low LET radiosensitive tumors/normal tissues such as malignant lymphoma cells and lymphocytes. Hall and Giaccia describe lymphocytes as very radiosensitive, based largely on apoptosis subsequent to irradiation. As described in this review, apoptosis of lymphocytes and lymphoma cells is actually induced by the "hydrogen peroxide (H2O2) effect", which I propose in this review article for the first time. The mechanism of lymphocyte death via the H2O2 effect represents an ideal model to develop the enhancement method of radiosensitivity for radiation therapy of malignant neoplasms. In terms of imitating the high radiosensitivity of lymphocytes, osteosarcoma cells (representative of low-LET radioresistant cells) might be the ideal model for indicating the conversion of cells from radioresistant to radiosensitive utilizing the H2O2 effect. External beam radiation such as X-rays and high-energy electrons for use in modern radiotherapy are generally produced using a linear accelerator. We theorized that when tumors are irradiated in the presence of H2O2, the activities of anti-oxidative enzymes such as peroxidases and catalase are blocked and oxygen molecules are produced at the same time via the H2O2 effect, resulting in oxidative damage to low-LET radioresistant tumor cells, thereby rendering them highly sensitive to irradiation. In this review, this potential paradigm shift in modern radiation biology/radiation oncology is discussed in detail in terms of overcoming drug/radiation resistance in radiation therapy and/or anti-cancer chemotherapy. PMID- 26927178 TI - Targeted Therapy in Locally Advanced and Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma (LA-R/M HNSCC). AB - Surgery and radiotherapy are the standard treatment options for patients with squamous cell carcinoma of the head and neck (SCCHN). Chemoradiotherapy is an alternative for patients with locally advanced disease. In recurrent/metastatic disease and after progression to platin-based regimens, no standard treatments other than best supportive care are currently available. Most SCCHN tumours overexpress the epidermal growth factor receptor (EGFR). This receptor is a tyrosine-kinase membrane receptor that has been implicated in angiogenesis, tumour progression and resistance to different cancer treatments. In this review, we analysed the different drugs and pathways under development to treat SCCHN, especially recurrent/metastatic disease. Until now, the EGFR signalling pathway has been considered the most important target with respect to new drugs; however, new drugs, such as immunotherapies, are currently under study. As new treatments for SCCHN are developed, the influence of therapies with respect to overall survival, progression free survival and quality of life in patients with this disease is changing. PMID- 26927179 TI - Eugenia jambolana (Java Plum) Fruit Extract Exhibits Anti-Cancer Activity against Early Stage Human HCT-116 Colon Cancer Cells and Colon Cancer Stem Cells. AB - The World Health Organization predicts over a 70% increase in cancer incidents in developing nations over the next decade. Although these nations have limited access to novel therapeutics, they do have access to foods that contain chemopreventive bioactive compounds such as anthocyanins, and as such, consumption of these foods can be encouraged to combat cancer. We and others have previously characterized the anti-colon cancer properties of dietary anthocyanins from different sources. Eugenia jambolana (Java plum) is a tropical medicinal fruit rich in anthocyanins, however, its anti-colon cancer properties are not well characterized. Furthermore, recent evidence suggests that colon cancer stem cells (colon CSCs) promote resistance to chemotherapy, relapse of tumors and contribute to poor prognosis. The objectives of this study were to 1) characterize the anthocyanin profile of Java plum using HPLC-MS; and 2) determine the anti-proliferative (cell counting and MTT) and pro-apoptotic (TUNEL and caspase 3/7 glo assay) properties of Java plum fruit extract (JPE) using HCT-116 colon cancer cell line and colon CSCs (positive for CD 44, CD 133 and ALDH1b1 markers). HPLC-MS analysis showed that JPE contains a variety of anthocyanins including glucosides of delphinidin, cyanidin, petunidin, peonidin and malvidin. JPE anthocyanins suppressed (p < 0.05) proliferation in HCT-116 cells and elevated (p < 0.05) apoptosis in both HCT-116 cells and colon CSCs. JPE also suppressed the stemness in colon CSCs as evaluated using colony formation assay. These results warrant further assessment of the anti-cancer activity of JPE, and its molecular mechanisms using pre-clinical models of colon cancer. PMID- 26927181 TI - Matefin/SUN-1 Phosphorylation on Serine 43 Is Mediated by CDK-1 and Required for Its Localization to Centrosomes and Normal Mitosis in C. elegans Embryos. AB - Matefin/SUN-1 is an evolutionary conserved C. elegans inner nuclear membrane SUN domain protein. By creating a bridge with the KASH-domain protein ZYG-12, it connects the nucleus to cytoplasmic filaments and organelles. Matefin/SUN-1 is expressed in the germline where it undergoes specific phosphorylation at its N terminal domain, which is required for germline development and homologous chromosome pairing. The maternally deposited matefin/SUN-1 is then essential for embryonic development. Here, we show that in embryos, serine 43 of matefin/SUN-1 (S43) is phosphorylated in a CDK-1 dependent manner and is localized throughout the cell cycle mostly to centrosomes. By generating animals expressing phosphodead S43A and phosphomimetic S43E mutations, we show that phosphorylation of S43 is required to maintain centrosome integrity and function, as well as for the localization of ZYG-12 and lamin. Expression of S43E in early embryos also leads to an increase in chromatin structural changes, decreased progeny and to almost complete embryonic lethality. Down regulation of emerin further increases the occurrence of chromatin organization abnormalities, indicating possible collaborative roles for these proteins that is regulated by S43 phosphorylation. Taken together, these results support a role for phosphorylation of serine 43 in matefin/SUN-1 in mitosis. PMID- 26927180 TI - Melanoma and the Unfolded Protein Response. AB - The UPR (unfolded protein response) has been identified as a key factor in the progression and metastasis of cancers, notably melanoma. Several mediators of the UPR are upregulated in cancers, e.g., high levels of GRP78 (glucose-regulator protein 78 kDa) correlate with progression and poor outcome in melanoma patients. The proliferative burden of cancer induces stress and activates several cellular stress responses. The UPR is a tightly orchestrated stress response that is activated upon the accumulation of unfolded proteins within the ER (endoplasmic reticulum). The UPR is designed to mediate two conflicting outcomtes, recovery and apoptosis. As a result, the UPR initiates a widespread signaling cascade to return the cell to homeostasis and failing to achieve cellular recovery, initiates UPR-induced apoptosis. There is evidence that ER stress and subsequently the UPR promote tumourigenesis and metastasis. The complete role of the UPR has yet to be defined. Understanding how the UPR allows for adaption to stress and thereby assists in cancer progression is important in defining an archetype of melanoma pathology. In addition, elucidation of the mechanisms of the UPR may lead to development of effective treatments of metastatic melanoma. PMID- 26927182 TI - Pseudo-Reference-Based Assembly of Vertebrate Transcriptomes. AB - High-throughput RNA sequencing (RNA-seq) provides a comprehensive picture of the transcriptome, including the identity, structure, quantity, and variability of expressed transcripts in cells, through the assembly of sequenced short RNA-seq reads. Although the reference-based approach guarantees the high quality of the resulting transcriptome, this approach is only applicable when the relevant reference genome is present. Here, we developed a pseudo-reference-based assembly (PRA) that reconstructs a transcriptome based on a linear regression function of the optimized mapping parameters and genetic distances of the closest species. Using the linear model, we reconstructed transcriptomes of four different aves, the white leg horn, turkey, duck, and zebra finch, with the Gallus gallus genome as a pseudo-reference, and of three primates, the chimpanzee, gorilla, and macaque, with the human genome as a pseudo-reference. The resulting transcriptomes show that the PRAs outperformed the de novo approach for species with within about 10% mutation rate among orthologous transcriptomes, enough to cover distantly related species as far as chicken and duck. Taken together, we suggest that the PRA method can be used as a tool for reconstructing transcriptome maps of vertebrates whose genomes have not yet been sequenced. PMID- 26927183 TI - Clues to tRNA Evolution from the Distribution of Class II tRNAs and Serine Codons in the Genetic Code. AB - We have previously proposed that tRNA(Gly) was the first tRNA and glycine was the first amino acid incorporated into the genetic code. The next two amino acids incorporated would have been the other two small hydrophilic amino acids serine and aspartic acid, which occurred through the duplication of the tRNA(Gly) sequence, followed by mutation of its anticodon by single C to U transition mutations, possibly through spontaneous deamination. Interestingly, however, tRNA(Ser) has a different structure than most other tRNAs, possessing a long variable arm; because of this tRNA(Ser) is classified as a class II tRNA. Also, serine codons are found not only in the bottom right-hand corner of the genetic code table next to those for glycine and aspartic acid, but also in the top row of the table, next to those for two of the most hydrophobic amino acids, leucine and phenylalanine. In the following, I propose that the class II tRNA structure of tRNA(Ser) and the arrangement of serine codons in the genetic code provide clues to the early evolution of tRNA and the genetic code. In addition, I address Di Giulio's recent criticism of our proposal that tRNA(Gly) was the first tRNA, and discuss how early peptides produced from a restricted amino acid alphabet of glycine, serine and aspartic acid might have possessed proteolytic activity, which is possibly important for the early recycling of amino acid monomers. PMID- 26927184 TI - The Biobank Portal for Partners Personalized Medicine: A Query Tool for Working with Consented Biobank Samples, Genotypes, and Phenotypes Using i2b2. AB - We have designed a Biobank Portal that lets researchers request Biobank samples and genotypic data, query associated electronic health records, and design and download datasets containing de-identified attributes about consented Biobank subjects. This do-it-yourself functionality puts a wide variety and volume of data at the fingertips of investigators, allowing them to create custom datasets for their clinical and genomic research from complex phenotypic data and quickly obtain corresponding samples and genomic data. The Biobank Portal is built upon the i2b2 infrastructure [1] and uses an open-source web client that is available to faculty members and other investigators behind an institutional firewall. Built-in privacy measures [2] ensure that the data in the Portal are utilized only according to the processes to which the patients have given consent. PMID- 26927185 TI - The Translational Genomics Core at Partners Personalized Medicine: Facilitating the Transition of Research towards Personalized Medicine. AB - The Translational Genomics Core (TGC) at Partners Personalized Medicine (PPM) serves as a fee-for-service core laboratory for Partners Healthcare researchers, providing access to technology platforms and analysis pipelines for genomic, transcriptomic, and epigenomic research projects. The interaction of the TGC with various components of PPM provides it with a unique infrastructure that allows for greater IT and bioinformatics opportunities, such as sample tracking and data analysis. The following article describes some of the unique opportunities available to an academic research core operating within PPM, such the ability to develop analysis pipelines with a dedicated bioinformatics team and maintain a flexible Laboratory Information Management System (LIMS) with the support of an internal IT team, as well as the operational challenges encountered to respond to emerging technologies, diverse investigator needs, and high staff turnover. In addition, the implementation and operational role of the TGC in the Partners Biobank genotyping project of over 25,000 samples is presented as an example of core activities working with other components of PPM. PMID- 26927187 TI - Infrastructure for Personalized Medicine at Partners HealthCare. AB - Partners HealthCare Personalized Medicine (PPM) is a center within the Partners HealthCare system (founded by Massachusetts General Hospital and Brigham and Women's Hospital) whose mission is to utilize genetics and genomics to improve the care of patients in a cost effective manner. PPM consists of five interconnected components: (1) Laboratory for Molecular Medicine (LMM), a CLIA laboratory performing genetic testing for patients world-wide; (2) Translational Genomics Core (TGC), a core laboratory providing genomic platforms for Partners investigators; (3) Partners Biobank, a biobank of samples (DNA, plasma and serum) for 50,000 Consented Partners patients; (4) Biobank Portal, an IT infrastructure and viewer to bring together genotypes, samples, phenotypes (validated diagnoses, radiology, and clinical chemistry) from the electronic medical record to Partners investigators. These components are united by (5) a common IT system that brings researchers, clinicians, and patients together for optimal research and patient care. PMID- 26927186 TI - Bioinformatics Workflow for Clinical Whole Genome Sequencing at Partners HealthCare Personalized Medicine. AB - Effective implementation of precision medicine will be enhanced by a thorough understanding of each patient's genetic composition to better treat his or her presenting symptoms or mitigate the onset of disease. This ideally includes the sequence information of a complete genome for each individual. At Partners HealthCare Personalized Medicine, we have developed a clinical process for whole genome sequencing (WGS) with application in both healthy individuals and those with disease. In this manuscript, we will describe our bioinformatics strategy to efficiently process and deliver genomic data to geneticists for clinical interpretation. We describe the handling of data from FASTQ to the final variant list for clinical review for the final report. We will also discuss our methodology for validating this workflow and the cost implications of running WGS. PMID- 26927189 TI - Reconciling Horse Welfare, Worker Safety, and Public Expectations: Horse Event Incident Management Systems in Australia. AB - Human-horse interactions have a rich tradition and can be highly rewarding, particularly within sport and recreation pursuits, but they can also be dangerous or even life-threatening. In parallel, sport and recreation pursuits involving animals, including horses, are facing an increased level of public scrutiny in relation to the use of animals for these purposes. However, the challenge lies with event organisers to reconcile the expectations of the public, the need to meet legal requirements to reduce or eliminate risks to paid and volunteer workers, and address horse welfare. In this article we explore incident management at horse events as an example of a situation where volunteers and horses can be placed at risk during a rescue. We introduce large animal rescue skills as a solution to improving worker safety and improving horse welfare outcomes. Whilst there are government and horse industry initiatives to improve safety and address animal welfare, there remains a pressing need to invest in a strong communication plan which will improve the safety of workplaces in which humans and horses interact. PMID- 26927188 TI - Urinary Tract Infection Molecular Mechanisms and Clinical Translation. AB - Rapid developments in infection biology create new and exciting options for individualized diagnostics and therapy. Such new practices are needed to improve patient survival and reduce morbidity. Molecular determinants of host resistance to infection are being characterized, making it possible to identify susceptible individuals and to predict their risk for future morbidity. Immunotherapy is emerging as a new strategy to treat infections worldwide and controlled boosting of the host immune defense represents an important therapeutic alternative to antibiotics. In proof of concept studies, we have demonstrated that this approach is feasible. The long-term goal is not just to remove the pathogens but to also develop technologies that restore resistance to infection in disease-prone patients and devise personalized therapeutic interventions. Here, we discuss some approaches to reaching these goals, in patients with urinary tract infection (UTI). We describe critical host signaling pathways that define symptoms and pathology and the genetic control of innate immune responses that balance protection against tissue damage. For some of these genes, human relevance has been documented in clinical studies, identifying them as potential targets for immune-modulatory therapies, as a complement to antibiotics. PMID- 26927190 TI - Can Non-Beak Treated Hens be Kept in Commercial Furnished Cages? Exploring the Effects of Strain and Extra Environmental Enrichment on Behaviour, Feather Cover, and Mortality. AB - Commercial laying hens are prone to injurious pecking (IP), a common multifactorial problem. A 2 * 2 * 2 factorial design assessed the effects of breed (Lohmann Brown Classic (L) or Hyline Brown (H)), beak treatment (infra-red treated (T) or not (NT)), and environment (extra enrichment (EE) or no extra enrichment (NE)) on mortality, behaviour, feather cover, and beak shape. Hens were allocated to treatments at 16 weeks of age and data were collected every four weeks from age 19 to 71 weeks. Data were analysed in Genstat using mixed models. L hens had higher all and IP-related mortality than H hens (p < 0.003), whilst NT hens had higher mortality than T hens but only due to culling of whole cages (p < 0.001). Feather cover for L hens deteriorated more quickly with age at most body sites than H hens (age * breed * body site p < 0.001). For NT hens, feather cover was worse at most body sites (beak treatment * body site p < 0.001), and worsened more quickly with age (age * beak treatment p = 0.014) than T hens. L and NE hens performed more bird-to-bird pecking than H and EE hens, respectively (breed p = 0.015, enrichment p = 0.032). More damage to mats and ropes was caused by L and NT hens than by H and T hens, respectively (age * breed p < 0.005, beak treatment p < 0.001). Though H hens had fewer mortalities and better feather cover, breed effects may have been influenced by farm management practices, as they may have been better suited to H than L hens. Though EE hens performed less bird-to-bird pecking, the enrichments were less effective at reducing feather cover damage and mortality than expected. PMID- 26927191 TI - Effect of Freezing Conditions on Fecal Bacterial Composition in Pigs. AB - Sample preservation and recovery of intact DNA from gut samples may affect the inferred gut microbiota composition in pigs. This study aimed to evaluate the effect of the freezing process and storage temperature prior to DNA extraction on DNA recovery and bacterial community composition in pig feces using quantitative PCR. Fresh fecal samples from six growing pigs were collected and five aliquots of each prepared: (1) total DNA extracted immediately; (2) stored at -20 degrees C; (3) snap frozen and stored at -20 degrees C; (4) stored at -80 degrees C; and (5) snap frozen and stored at -80 degrees C. Results showed that DNA yields from fresh fecal samples were, on average, 25 to 30 ng higher than those from the various stored samples. The DNA extracted from fresh samples had more gene copies of total bacteria and all targeted bacterial groups per gram feces compared to DNA extraction from frozen samples. Data presentation also modified the observed effect of freeze storage; as results for Lactobacillus group, Enterococcus spp., Streptococcus spp., Clostridium cluster IV, Bacteroides-Prevotella-Porphyromonas and Enterobacteriaceae showed the opposite effect when expressed as relative abundance, by being greater in freeze stored feces than in fresh feces. Snap freezing increased the relative proportion of Clostridium cluster IV by 24%. In conclusion, the freezing process affected DNA yield and bacterial abundances, whereas snap freezing and storage temperature had only little influence on abundances of bacterial populations in pig feces. PMID- 26927192 TI - Welfare Impacts of Pindone Poisoning in Rabbits (Oryctolagus cuniculus). AB - Control methods used to manage unwanted impacts of the European rabbit in Australia and New Zealand include the use of toxic bait containing the anticoagulant pindone. Towards increased certainty in evaluating the animal welfare impacts of pindone poisoning in rabbits, we recorded behavioral and post mortem data from rabbits which ingested lethal quantities of pindone bait in a laboratory trial. Pindone poisoning in rabbits resulted in welfare compromise, primarily through functional impairments related to internal haemorrhage over a maximum duration of 7 days. Applying this data to a formal assessment framework for ranking animal welfare impacts indicated that pindone had relatively high severity and also duration of welfare impacts in comparison to other rabbit control methods. PMID- 26927193 TI - Exercise Strengthens Central Nervous System Modulation of Pain in Fibromyalgia. AB - To begin to elucidate the mechanisms underlying the benefits of exercise for chronic pain, we assessed the influence of exercise on brain responses to pain in fibromyalgia (FM). Complete data were collected for nine female FM patients and nine pain-free controls (CO) who underwent two functional neuroimaging scans, following exercise (EX) and following quiet rest (QR). Brain responses and pain ratings to noxious heat stimuli were compared within and between groups. For pain ratings, there was a significant (p < 0.05) Condition by Run interaction characterized by moderately lower pain ratings post EX compared to QR (d = 0.39 0.41) for FM but similar to ratings in CO (d = 0.10-0.26), thereby demonstrating that exercise decreased pain sensitivity in FM patients to a level that was analogous to pain-free controls. Brain responses demonstrated a significant within-group difference in FM patients, characterized by less brain activity bilaterally in the anterior insula following QR as compared to EX. There was also a significant Group by Condition interaction with FM patients showing less activity in the left dorsolateral prefrontal cortex following QR as compared to post-EX and CO following both conditions. These results suggest that exercise appeared to stimulate brain regions involved in descending pain inhibition in FM patients, decreasing their sensitivity to pain. Thus, exercise may benefit patients with FM via improving the functional capacity of the pain modulatory system. PMID- 26927194 TI - Detailed Investigation of Separation Performance of a MMM for Removal of Higher Hydrocarbons under Varying Operating Conditions. AB - Mixed-matrix membranes (MMMs) are promising candidates to improve the competitiveness of membrane technology against energy-intensive conventional technologies. In this work, MMM composed of poly(octylmethylsiloxane) (POMS) and activated carbon (AC) were investigated with respect to separation of higher hydrocarbons (C3+) from permanent gas streams. Membranes were prepared as thin film composite membranes on a technical scale and characterized via scanning electron microscopy (SEM) and permeation measurements with binary mixtures of n C4H10/CH4 under varying operating conditions (feed and permeate pressure, temperature, feed gas composition) to study the influence on separation performance. SEM showed good contact and absence of defects. Lower permeances but higher selectivities were found for MMM compared to pure POMS membrane. Best results were obtained at high average fugacity and activity of n-C4H10 with the highest selectivity estimated to be 36.4 at n-C4H10 permeance of 12 mN3/(m2.h.bar). Results were complemented by permeation of a multi-component mixture resembling a natural gas application, demonstrating the superior performance of MMM. PMID- 26927196 TI - Circulating miR-21 and miR-29a as Markers of Disease Severity and Etiology in Cholestatic Pediatric Liver Disease. AB - Circulating microRNAs have been investigated as markers of disease severity in a variety of conditions. We examined whether circulating miR-21 and miR-29a could serve as markers of hepatic fibrosis and disease etiology in children with various liver diseases. Circulating miR-21 and miR-29a were determined in 58 children (21 female, age 0.1-17.8 (median 9.8) years)) with chronic liver disease and compared to histological grading of hepatic fibrosis. 22 healthy children served as controls for circulating miRNAs. Levels of circulating miR-21 appeared to be age-dependent in healthy children. Children with biliary atresia had significantly higher levels of miR-21 compared both to healthy controls and to age-matched children with other cholestatic liver disease. Circulating miR-29a levels in biliary atresia children did not differ from healthy controls, but tended to be higher than in age-matched children with other cholestatic liver disease. Neither miR-21 nor miR-29a correlated well with hepatic fibrosis. Circulating miR-21 and miR-29a levels can potentially serve as non-invasive diagnostic markers to differentiate biliary atresia from other cholestatic disease in infancy. They do not appear suitable as non-invasive markers for the degree of hepatic fibrosis in an unselected cohort of children with various liver diseases. The discriminating effect regarding neonatal cholestasis should be followed up in a prospective longitudinal study. PMID- 26927195 TI - Preliminary Analysis of the Expression of Selected Proangiogenic and Antioxidant Genes and MicroRNAs in Patients with Non-Muscle-Invasive Bladder Cancer. AB - Heme oxygenase-1 (HO-1) is an enzyme contributing to the development and progression of different cancer types. HO-1 plays a role in pathological angiogenesis in bladder cancer and contributes to the resistance of this cancer to therapy. It also regulates the expression of microRNAs in rhabdomyosarcoma and non-small cell lung cancer. The expression of HO-1 may be regulated by hypoxia inducible factors (HIFs) and Nrf2 transcription factor. The expression of HO-1 has not so far been examined in relation to Nrf2, HIF-1alpha, and potential mediators of angiogenesis in human bladder cancer. We measured the concentration of proinflammatory and proangiogenic cytokines and the expression of cytoprotective and proangiogenic mRNAs and miRNAs in healthy subjects and patients with bladder cancer. HO-1 expression was upregulated together with HIF 1alpha, HIF-2alpha, and Nrf2 in bladder cancer in comparison to healthy tissue. VEGF was elevated both at mRNA and protein level in the tumor and in sera, respectively. Additionally, IL-6 and IL-8 were increased in sera of patients affected with urothelial bladder cancer. Moreover, miR-155 was downregulated whereas miR-200c was elevated in cancer biopsies in comparison to healthy tissue. The results indicate that the increased expression of HO-1 in bladder cancer is paralleled by changes in the expression of other potentially interacting genes, like Nrf2, HIF-1alpha, HIF-2alpha, IL-6, IL-8, and VEGF. Further studies are necessary to also elucidate the potential links with miR-155 and miR-200c. PMID- 26927197 TI - Protein-Flavonoid Interaction Studies by a Taylor Dispersion Surface Plasmon Resonance (SPR) Technique: A Novel Method to Assess Biomolecular Interactions. AB - Flavonoids are common polyphenolic compounds widely distributed in fruits and vegetables. These pigments have important pharmacological relevance because emerging research suggests possible anti-cancer and anti-inflammatory properties as well other beneficial health effects. These compounds are relatively hydrophobic molecules, suggesting the role of blood transport proteins in their delivery to tissues. In this study, we assess the binding interactions of four flavonoids (kaempferol, luteolin, quercetin, and resveratrol) with human serum albumin (HSA), the most abundant protein in the blood, and with glutathione S transferase pi isoform-1 (GSTP1), an enzyme with well-characterized hydrophobic binding sites that plays an important role in detoxification of xenobiotics with reduced glutathione, using a novel Taylor dispersion surface plasmon resonance (SPR) technique. For the first time, HSA sites revealed a high-affinity binding site for flavonoid interactions. Out of the four flavonoids that we examined, quercetin and kaempferol showed the strongest equilibrium binding affinities (K(D)) of 63 +/- 0.03 nM and 37 +/- 0.07 nM, respectively. GSTP1 displayed lower affinities in the micromolar range towards all of the flavonoids tested. The interactions of flavonoids with HSA and GSTP1 were studied successfully using this novel SPR assay method. The new method is compatible with both kinetic and equilibrium analyses. PMID- 26927198 TI - Metabolomic Profiling of Submaximal Exercise at a Standardised Relative Intensity in Healthy Adults. AB - Ten physically active subjects underwent two cycling exercise trials. In the first, aerobic capacity (VO2max) was determined and the second was a 45 min submaximal exercise test. Urine samples were collected separately the day before (day 1) , the day of (day 2), and the day after (day 3) the submaximal exercise test (12 samples per subject). Metabolomic profiling of the samples was carried out using hydrophilic interaction chromatography (HILIC) coupled to an Orbitrap Exactive mass spectrometer. Data were extracted, database searched and then subjected to principle components (PCA) and orthogonal partial least squares (OPLSDA) modelling. The best results were obtained from pre-treating the data by normalising the metabolites to their mean output on days 1 and 2 of the trial. This allowed PCA to separate the day 2 first void samples (D2S1) from the day 2 post-exercise samples (D2S3) PCA also separated the equivalent samples obtained on day 1 (D1S1 and D1S3). OPLSDA modelling separated both the D2S1 and D2S3 samples and D1S1 and D1S3 samples. The metabolites affected by the exercise samples included a range of purine metabolites and several acyl carnitines. Some metabolites were subject to diurnal variation these included bile acids and several amino acids, the variation of these metabolites was similar on day 1 and day 2 despite the exercise intervention on day 2. Using OPLS modelling it proved possible to identify a single abundant urinary metabolite provisionally identified as oxo-aminohexanoic acid (OHA) as being strongly correlated with VO2max when the levels in the D2S3 samples were considered. PMID- 26927200 TI - Methionine enkephalin, its role in immunoregulation and cancer therapy. AB - Methionine enkephalin (MENK), an endogenous neuropeptide has a crucial role in both neuroendocrine and immune systems. MENK is believed to have an immunoregulatory activity to have cancer biotherapy activity by binding to the opioid receptors on immune and cancer cells. Clinical trial studies in cancer patients have shown that MENK activates immune cells directly and by inhibiting regulatory T-cells (Tregs). MENK may also change the tumor microenvironment by binding to opioid receptor on or in cancer cells. All of these mechanisms of action have biologic significance and potential for use in cancer immunotherapy. Furthermore, they reveal a relationship between the endocrine and immune systems. Due to the apparent role of MENK in cancer therapy we reviewed herein, the research undertaken with MENK in recent years; which has advanced our understanding of the role MENK has in cancer progression and its relationship to immunity, supporting MENK as a new strategy for cancer immunotherapy. PMID- 26927199 TI - Cooperativity of the SUMO and Ubiquitin Pathways in Genome Stability. AB - Covalent attachment of ubiquitin (Ub) or SUMO to DNA repair proteins plays critical roles in maintaining genome stability. These structurally related polypeptides can be viewed as distinct road signs, with each being read by specific protein interaction motifs. Therefore, via their interactions with selective readers in the proteome, ubiquitin and SUMO can elicit distinct cellular responses, such as directing DNA lesions into different repair pathways. On the other hand, through the action of the SUMO-targeted ubiquitin ligase (STUbL) family proteins, ubiquitin and SUMO can cooperate in the form of a hybrid signal. These mixed SUMO-ubiquitin chains recruit "effector" proteins such as the AAA+ ATPase Cdc48/p97-Ufd1-Npl4 complex that contain both ubiquitin and SUMO interaction motifs. This review will summarize recent key findings on collaborative and distinct roles that ubiquitin and SUMO play in orchestrating DNA damage responses. PMID- 26927201 TI - Perspectives on treating hepatitis C infection in the liver transplantation setting. AB - PURPOSE OF REVIEW: This article reviews treatment options of the approved and soon-to-be approved direct-acting antiviral (DAA)-based therapies in the transplant setting. RECENT FINDINGS: DAA-based therapies have been shown to be effective and safe in achieving viral eradication in the majority of pre- and postliver transplant (LT) populations. Treatment decisions are guided by hepatitis C virus (HCV) genotype, the degree of renal dysfunction, and severity of cirrhosis. The addition of ribavirin is frequently needed to achieve highest viral eradication rates. Viral eradication pre-LT has been associated with fewer portal hypertensive complications and improved survival and effectively prevents recurrent HCV post-LT. For those with shorter time to LT, an alternative strategy is treatment with DAAs up to the time of LT to reduce the risk of post-LT recurrence. Therapies should be considered for all post-LT patients with recurrent HCV given the risk of accelerated disease progression. The sustained virological response rates among LT recipients parallel those of nontransplant patients. SUMMARY: With broader application of DAA therapy in the transplant setting, improved graft and patient survival and simplified post-LT management are likely. The availability of high potency DAA therapy with excellent safety profiles has transformed the HCV-infected LT population into a group that is no longer 'difficult-to-treat.' PMID- 26927202 TI - Insulin pump use compared with intravenous insulin during labour and delivery: the INSPIRED observational cohort study. AB - AIMS: To assess the safety and efficacy of pump therapy (continuous subcutaneous insulin infusion; CSII) during labour and delivery in women with Type 1 diabetes. METHODS: A retrospective cohort study of 161 consecutive Type 1 diabetic pregnancies delivered during 2000-2010 at Mount Sinai Hospital, Toronto, Canada. Capillary blood glucose levels during labour and delivery and time in/out of target (target: 4-6 mmol/l) were compared along with neonatal outcomes for three groups: (1) women on pumps who stayed on pumps during labour (pump/pump n = 31), (2) women on pumps who switched to intravenous (IV) insulin infusion during labour (pump/IVn = 25), and (3) women on multiple daily injections who switched to IV insulin infusion during labour (MDIn = 105). RESULTS: There were no significant differences between the mean or median glucose values during labour and delivery across all three groups, and no significant difference in time spent hypoglycaemic. However, women in the pump/pump group had significantly better glycaemic control as defined by mean glucose (5.5 vs. 6.4 mmol/l; P = 0.01), median glucose (5.4 vs. 6.3 mmol/l; P = 0.02), and more time spent in target (60.9% vs. 39.2%; P = 0.06) compared with women in the pump/IV group (after removing one outlier). CONCLUSIONS: This study demonstrates that the continuation of CSII therapy during labour and delivery appears safe and efficacious. Moreover, women who choose to continue CSII have better glucose control during delivery than those who switch to IV insulin, suggesting that it should be standard practice to allow women the option of continuing CSII during labour and delivery. PMID- 26927203 TI - Visual Prognosis in USH2A-Associated Retinitis Pigmentosa Is Worse for Patients with Usher Syndrome Type IIa Than for Those with Nonsyndromic Retinitis Pigmentosa. AB - PURPOSE: USH2A mutations are an important cause of retinitis pigmentosa (RP) with or without congenital sensorineural hearing impairment. We studied genotype phenotype correlations and compared visual prognosis in Usher syndrome type IIa and nonsyndromic RP. DESIGN: Clinic-based, longitudinal, multicenter study. PARTICIPANTS: Consecutive patients with Usher syndrome type IIa (n = 152) and nonsyndromic RP (n = 73) resulting from USH2A mutations from ophthalmogenetic clinics in the Netherlands and Belgium. METHODS: Data on clinical characteristics, visual acuity, visual field measurements, retinal imaging, and electrophysiologic features were extracted from medical charts over a mean follow up of 9 years. Cumulative lifetime risks of low vision and blindness were estimated using Kaplan-Meier survival analysis. MAIN OUTCOME MEASURES: Low vision and blindness. RESULTS: Participant groups had similar distributions of gender (48% vs. 45% males in Usher syndrome type IIa vs. nonsydromic RP; P = 0.8), ethnicity (97% vs. 99% European; P = 0.3), and median follow-up time (6.5 years vs. 3 years; P = 0.3). Usher syndrome type IIa patients demonstrated symptoms at a younger age (median age, 15 years vs. 25 years; P < 0.001), were diagnosed earlier (median age, 26 years vs. 36.5 years; P < 0.001), and became visually impaired 13 years earlier (median age, 41 years vs. 54 years; P < 0.001) based on VF and 18 years earlier based on VA (median age, 54 years vs. 72 years; P < 0.001) than nonsyndromic RP patients. The presence of 2 truncating mutations in USH2A was associated mostly with the syndromic phenotype, whereas other combinations were present in both groups. We found novel variants in Usher syndrome type IIa (25%) and nonsyndromic RP (19%): 29 missense mutations, 10 indels, 14 nonsense mutations, 9 frameshift mutations, and 5 splice-site mutations. CONCLUSIONS: Most patients with USH2A-associated RP have severe visual impairment by age 50. However, those with Usher syndrome type IIa have an earlier decline of visual function and a higher cumulative risk of visual impairment than those without nonsyndromic RP. Complete loss of function of the USH2A protein predisposes to Usher syndrome type IIa, but remnant protein function can lead to RP with or without hearing loss. PMID- 26927204 TI - Treatment Patterns and Health Care Costs for Age-Related Macular Degeneration in Japan: An Analysis of National Insurance Claims Data. AB - PURPOSE: To investigate changes in the proportion of patients with age-related macular degeneration (AMD) visiting hospitals and to investigate factors associated with AMD, treatments, and medical expenses, as well as the outlook for AMD in Japan using a large health insurance database. DESIGN: Analysis of national insurance claims data. PARTICIPANTS: People 40 years of age or older who were registered in the Japan Medical Data Center database. METHODS: Patients with AMD were identified from 2005 through 2013 based on International Classification of Diseases, 10th revision, diagnosis codes. Changes in patient proportions, treatment procedures, and medical expenses were investigated during the study period. The data for each year were compared after adjustment based on the 2010 Japanese population annual census. The outlook for patients with AMD was predicted based on the combination of data in 2013 and an official future population prediction report. MAIN OUTCOME MEASURES: Changes in treatment patterns and health care costs in Japan. RESULTS: A total of 3 401 299 participants were included in the analysis, and 3058 AMD patients were identified over the 9-year period. The proportion of patients with AMD increased significantly from 0.084% (95% confidence interval, 0.050%-0.119%) in 2005 to 0.26% (95% confidence interval, 0.24%-0.29%) in 2013 (P = 0.0001, Pearson correlation coefficient test). There were significantly more men than women (odds ratio, 1.25; 95% confidence interval, 1.14-1.37), and the proportion of patients with AMD increased rapidly with age. Photodynamic therapy was replaced by anti vascular endothelial growth factor (VEGF) therapy as the predominant therapy from 2009 onward. Medical expenses per 10 000 persons increased from $1530 to $137 000 over the 9-year period. The proportion of AMD patients is predicted to increase in the future and will reach a maximum of 223 000 in 2035. CONCLUSIONS: The proportion of AMD patients visiting hospitals, medical expenses, and the frequency of anti-VEGF therapy increased significantly over the 9-year period. These increasing trends are predicted to continue in Japan. PMID- 26927205 TI - The Immunology of CD1- and MR1-Restricted T Cells. AB - CD1- and MHC-related molecule-1 (MR1)-restricted T lymphocytes recognize nonpeptidic antigens, such as lipids and small metabolites, and account for a major fraction of circulating and tissue-resident T cells. They represent a readily activated, long-lasting population of effector cells and contribute to the early phases of immune response, orchestrating the function of other cells. This review addresses the main aspects of their immunological functions, including antigen and T cell receptor repertoires, mechanisms of nonpeptidic antigen presentation, and the current evidence for their participation in human and experimental diseases. PMID- 26927206 TI - Coinhibitory Pathways in Immunotherapy for Cancer. AB - The immune system is capable of recognizing tumors and eliminates many early malignant cells. However, tumors evolve to evade immune attack, and the tumor microenvironment is immunosuppressive. Immune responses are regulated by a number of immunological checkpoints that promote protective immunity and maintain tolerance. T cell coinhibitory pathways restrict the strength and duration of immune responses, thereby limiting immune-mediated tissue damage, controlling resolution of inflammation, and maintaining tolerance to prevent autoimmunity. Tumors exploit these coinhibitory pathways to evade immune eradication. Blockade of the PD-1 and CTLA-4 checkpoints is proving to be an effective and durable cancer immunotherapy in a subset of patients with a variety of tumor types, and additional combinations are further improving response rates. In this review we discuss the immunoregulatory functions of coinhibitory pathways and their translation to effective immunotherapies for cancer. PMID- 26927207 TI - Pilot study of a novel, large-bore, fully covered self-expandable metallic stent for unresectable distal biliary malignancies. AB - BACKGROUND AND AIM: In patients with unresectable malignant distal biliary obstruction, covered self-expandable metallic stents (CSEMS) may remain patent longer than uncovered self-expandable metallic stents as a result of tumor ingrowth prevention. One main cause of recurrent biliary obstruction (RBO) in CSEMS is sludge formation, which can be prevented using a large-bore stent. Therefore, we developed a novel, 12-mm diameter fully covered SEMS (FCSEMS) and investigated its clinical safety, efficacy, and rate of adverse events. METHODS: This prospective, multicenter pilot study, which ran between June 2011 and November 2012, included 38 consecutive patients with unresectable malignant distal biliary obstruction. All patients underwent endoscopic insertion of our novel stent. Primary endpoint was non-RBO rate 6 months after placement. RESULTS: Technical and functional success rates of the procedures were 100%. Six-month non RBO rate was 50%, and median time to RBO was 184 days. Median survival time was 241 days. Twelve patients died within 6 months after stent placement without RBO. RBO was observed in 10 patients (26%), with seven experiencing stent occlusion and three experiencing stent migration. Adverse events other than RBO (at <30 days) developed in six patients (16%; cholecystitis, one; pancreatitis, one; hyperamylasemia, one; pancreatic ductitis, one; abdominal pain, two). Stent removal for reintervention was successfully completed in eight patients. CONCLUSION: Our novel FCSEMS may be safe and effective for managing malignant distal obstruction with an acceptable incidence of adverse events. PMID- 26927208 TI - Synthesis of (+/-)-Serralongamine A and the Revised Structure of Huperzine N. AB - A revised structure for the Lycopodium alkaloid huperzine N is proposed and confirmed by synthesis. The key synthetic steps involve an epimerization of a cis 5-oxodecahydroquinoline to the corresponding trans isomer and a coupling, followed by a diastereoselective hydrogenation using Wilkinson's catalyst to incorporate the pyridylmethyl moiety. This route allowed the alkaloid serralongamine A to be synthesized for the first time, and two additional steps led to the revised structure of huperzine N, both products bearing an unusual decahydroquinoline stereostructure. PMID- 26927209 TI - An Occupational Therapy intervention for residents with stroke-related disabilities in UK Care Homes (OTCH): cluster randomised controlled trial with economic evaluation. AB - BACKGROUND: Care home residents with stroke-related disabilities have significant activity limitations. Phase II trial results suggested a potential benefit of occupational therapy (OT) in maintaining residents' capacity to engage in functional activity. OBJECTIVE: To evaluate the clinical effectiveness and cost effectiveness of a targeted course of OT in maintaining functional activity and reducing further health risks from inactivity for UK care home residents living with stroke-related disabilities. DESIGN: Pragmatic, parallel-group, cluster randomised controlled trial with economic evaluation. Cluster randomisation occurred at the care-home level. Homes were stratified according to trial administrative centre and type of care provided (nursing or residential), and they were randomised 1 : 1 to either the intervention or the control arm. SETTING: The setting was 228 care homes which were local to 11 trial administrative centres across England and Wales. PARTICIPANTS: Care home residents with a history of stroke or transient ischaemic attack, including residents with communication and cognitive impairments, not receiving end-of-life care. INTERVENTION: Personalised 3-month course of OT delivered by qualified therapists. Care workers participated in training workshops to support personal activities of daily living. The control condition consisted of usual care for residents. MAIN OUTCOME MEASURES: Outcome data were collected by a blinded assessor. The primary outcome at the participant level was the Barthel Index of Activities of Daily Living (BI) score at 3 months. The secondary outcomes included BI scores at 6 and 12 months post randomisation, and the Rivermead Mobility Index, Geriatric Depression Scale-15 and European Quality of Life-5 Dimensions, three levels, questionnaire scores at all time points. Economic evaluation examined the incremental cost per quality-adjusted life-year (QALY) gain. Costs were estimated from the perspective of the NHS and Personal Social Services. RESULTS: Overall, 568 residents from 114 care homes were allocated to the intervention arm and 474 residents from another 114 care homes were allocated to the control arm, giving a total of 1042 participants. Randomisation occurred between May 2010 and March 2012. The mean age of participants was 82.9 years, and 665 (64%) were female. No adverse events attributable to the intervention were recorded. Of the 1042 participants, 870 (83%) were included in the analysis of the primary outcome (intervention, n = 479; control, n = 391). The primary outcome showed no significant differences between groups. The adjusted mean difference in the BI score between groups was 0.19 points higher in the intervention arm [95% confidence interval (CI) -0.33 to 0.70, p = 0.48; adjusted intracluster correlation coefficient 0.09]. Secondary outcome measures showed no significant differences at all time points. Mean incremental cost of the Occupational Therapy intervention for residents with stroke living in UK Care Homes intervention was L438.78 (95% CI -L3360.89 to L1238.46) and the incremental QALY gain was 0.009 (95% CI -0.030 to 0.048). LIMITATIONS: A large proportion of participants with very severe activity-based limitations and cognitive impairment may have limited capacity to engage in therapy. CONCLUSION: A 3-month individualised course of OT showed no benefit in maintaining functional activity in an older care home population with stroke-related disabilities. FUTURE WORK: There is an urgent need to reduce health-related complications caused by inactivity and to provide an enabling built environment within care homes. TRIAL REGISTRATION: Current Controlled Trials ISRCTN00757750. FUNDING: This project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 15. See the Health Technology Assessment programme website for further project information. PMID- 26927210 TI - Intra-uterine Growth Retardation as a Risk Factor of Postnatal Metabolic Disorders. AB - Intra-uterine growth retardation (IUGR) represents one of the major problems in perinatal medicine. IUGR is one of main causes of perinatal mortality and morbidity. A huge number and variety of established and possible causes of IUGR have been described. There are currently no data about effective treatment of this fetal condition. IUGR has been described to be strictly involved in fetal programming. Fetal programming is the general idea, which tells us how during development of the embryo and fetus significant physiological parameters can be shaped by environmental events. A link between the intra-uterine growth retardation and the risk of developing type 2 diabetes, obesity and cardiovascular disease postnatally has been well documented. The aim of this paper is to present an overview of the current knowledge of IUGR effects on development of hypertension and cardiovascular diseases, impact on insulin secretion and resistance, diabetes mellitus and metabolic syndrome. The influence of intrauterine growth retardation on predisposition to obesity and adipose dysfunction was also described. PMID- 26927211 TI - Plasma Rich in Growth Factors Enhances Wound Healing and Protects from Photo oxidative Stress in Dermal Fibroblasts and 3D Skin Models. AB - BACKGROUND: Optimal skin repair has been a desired goal for many researchers. Recently, plasma rich in growth factors (PRGF) has gained importance in dermatology proving it is beneficial effects in wound healing and cutaneous regeneration. OBJECTIVE: The anti-fibrotic, pro-contractile and photo-protective effect of PRGF on dermal fibroblasts and 3D skin models has been evaluated. METHOD: The effect against TGFbeta1 induced myofibroblast differentiation was tested. Cell contractile activity over collagen gel matrices was analyzed and the effect against UV derived photo-oxidative stress was assessed. The effectiveness of PRGF obtained from young aged and middle aged donors was compared. Furthermore, 3D organotypic skin explants were used as human skin models with the aim of analyzing ex vivo cutaneous preventive and regenerative photo-protection after UV exposure. RESULTS: TGFbeta1 induced myofibroblast levels decreased significantly after treatment with PRGF while the contractile activity increased compared to the control group. After UV irradiation, cell survival was promoted while apoptotic and ROS levels were noticeably reduced. Photo-exposed 3D explants showed higher levels of metabolic activity and lower levels of necrosis, cell damage, irritation and ROS formation when treated with PRGF. The histological integrity and connective tissue fibers showed lower signals of photodamage among PRGF injected skin models. No significant differences for the assessed biological outcomes were observed when PRGF obtained from young aged and middle aged donors were compared. CONCLUSION: These findings suggest that this autologous approach might be useful for antifibrotic wound healing and provide an effective protection against sun derived photo-oxidative stress regardless the age of the patient. PMID- 26927212 TI - Nature and Nurture in the Early-Life Origins of Metabolic Syndrome. AB - The combination of genetic background together with food excess and lack of exercise has become the cornerstone of metabolic disorders associated to lifestyle. The scenario is furthermore reinforced by their interaction with other environmental factors (stress, sleeping patterns, education, culture, rural versus urban locations, and xenobiotics, among others) inducing epigenetic changes in the exposed individuals. The immediate consequence is the development of further alterations like obesity and metabolic syndrome, and other adverse health conditions (type-2 diabetes, cardiovascular diseases, cancer, reproductive, immune and neurological disorders). Thus, having in mind the impact of the metabolic syndrome on the worldwide public health, the present review affords the relative roles and the interrelationships of nature (genetic predisposition to metabolic syndrome) and nurture (lifestyle and environmental effects causing epigenetic changes), on the establishment of the metabolic disorders in women; disorders that may evolve to metabolic syndrome prior or during pregnancy and may be transmitted to their descendants. PMID- 26927213 TI - Microfabricated Devices for Studying the Metabolism and Cytotoxicity of Drug Candidates. AB - During drug development, large libraries of new chemical entities (NCEs) are generated and undergo in vitro screens of metabolism and cytotoxicity. These screens are heavily relied upon to select lead compounds with the highest chance of success in pre-clinical studies and clinical trials, but suffer from limited in vivo predictive power despite using human liver-derived components. There is a need for new assays that utilize smaller reagent volumes to reduce the cost of these high-throughput screens; better mimic the liver environment; and ultimately account for toxicities in other major organ systems. Microfabricated devices, in their current state, integrate multiple reaction steps in a single device, decreasing the cost of a single metabolism or cytotoxicity screen by lowering the reagent consumption and increasing throughput. The incorporation of three dimensional co-cultures in these devices promise increased accuracy of in vitro screens, because cellular phenotype and response of hepatocytes in these cultures are more representative of the liver. In this review, we focus on microfabricated devices developed over the past decade and highlight technologies that we believe have the potential of reaching shorter- and longer-term goals of reducing the cost of bringing new drugs to market and revolutionizing the discovery stage of the drug development pipeline. PMID- 26927214 TI - Microfluidic Devices for Circulating Tumor Cells Isolation and Subsequent Analysis. AB - The research of circulating tumor cells (CTCs) has drawn much attention in recent years. It is because of the potential values of CTCs in early diagnosis of cancer, management of clinical treatment, exploration of metastatic mechanism, and development of personalized medicine. However, isolating CTCs has been technically challenging due to their rare numbers in blood. Recently, a variety of microfluidic devices have been developed for CTC isolation, and these devices can realize high capture efficiency and high purity. While enumeration of CTCs has been achieved, further cellular and DNA analysis on the captured CTCs are less reported. In this article, we review recent reports in microfluidic methods for isolation of CTCs and subsequent cellular analysis on them. PMID- 26927215 TI - A Prevention of Pre-eclampsia with the Use of Acetylsalicylic Acid and Low molecular Weight Heparin - Molecular Mechanisms. AB - Pre-eclampsia appears to be the main cause for the maternal and fetal morbidity and mortality. Pregnant women with pre-eclampsia are more likely to be threatened with conditions which potentially may be lethal, such as: disseminated intravascular coagulation, cerebral hemorrhage, liver and renal failure. Pregnancy complicated with pre-eclampsia is also associated with a greater risk for iatrogenic prematurity, intrauterine growth retardation, premature abruption of placenta, and even intrauterine fetal death. In the majority of cases the reasons for arterial hypertension among pregnant women remain obscure. For the past decades, there were many abortive attempts in the use of some microelements, vitamins or specific diets, such as polyunsaturated fatty acids, for the prophylaxis of pre-eclampsia. Recently, it has been shown that a prevention of pre-eclampsia with the use of a lowmolecular- weight heparins (LMWHs) and acetylsalicylic acid (ASA) could considerably reduce the frequency of preeclampsia. In this review, we present the studies concerning the applications of LMWHs and aspirin in the prophylaxis of pre-eclampsia and some important data about the mechanisms of anti-inflammatory actions of LMWHs and ASA. PMID- 26927216 TI - Tumor Necrosis Factor-alpha, a Regulator and Therapeutic Agent on Breast Cancer. AB - The cell-mediated immunity and cytotoxic agents play a significant role on tumor cell apoptosis. Tumor necrosis factor-alpha (TNF-alpha) is an intricate linker between inflammation and cancer through mediating the process of apoptosis and cell-mediated immunity. A variety of evidences have confirmed the critical role of TNF-alpha on tumor migration, proliferation, matrix degradation, tumor metastasis, invasion, and angiogenesis. Through binding to receptors, TNF-alpha participates in activating multiple cell signaling cascades that link inflammation, survival and evolution towards breast cancer. TNF-alpha is an important agent for tumor biotherapy, but its clinical application is limited for its severe fatal systemic toxicity. The poly-lactic acid microspheres (PLAM) with intratumoral cytokine release hold tremendous potential for the immunotherapy of breast cancer, and TNF-alpha antagonists may offer therapeutic potential in solid tumors. In addition, TNF-alpha is related with the blockage of estrogen and progesterone receptors. For breast cancer treatment, it is necessary to understand the molecular signaling pathways that mediate TNF-alpha and the aggressive behavior of negative breast cancer. The aim of present review is to summarize the effect of TNF-alpha on breast cancer cells. PMID- 26927217 TI - Nano-Sized Technologies for Miconazole Skin Delivery. AB - Various nano-based strategies for increasing the efficiency of topical drugs have offered the potential advantage of miconazole skin delivery. Miconazole nitrate is an antifungal drug with a drawback of poor skin-penetration in the treatment of deep seated fungal skin infections. Drug entrapment in nanoparticles such as ethosome, liposomes, solid lipid nanoparticles (SLNs) and nano structured lipid carriers (NLCs) can facilitate localized drug delivery and remove the skin barriers for an efficient drug delivery. Different nano-formulations have been recently examined for the controlled release, retention and permeation enhancement of miconazole in skin. The present overview focuses on novel nano based formulation approaches employed to improve miconazole penetration through skin for the treatment of fungal infections. PMID- 26927218 TI - Short Term, Low Dose Simvastatin Pretreatment Alters Memory Immune Function Following Secondary Staphylococcus aureus Infection. AB - Statins are potent modulators of immune responses, resulting in their ability to enhance host survival from primary bacterial infections. Alterations in primary immune responses that may be beneficial for survival following infection may also result in alterations in the generation of the immunologic memory response and subsequently affect immune responses mounted during secondary bacterial infection. In this study, we report that levels of total serum IgG2c, following primary infection, were decreased in simvastatin pretreated mice, and investigate the effect of simvastatin treatment, prior to primary infection, on immune responses activated during secondary S. aureus infection. A secondary infection model was implemented whereby simvastatin pretreated and control mice were reinfected with S. aureus 14 days after primary infection, with no additional simvastatin treatment, and assessed for survival and alterations in immune function. While survivability to secondary S. aureus infection was not different between simvastatin pretreated and control mice, memory B and T lymphocyte functions were altered. Memory B cells, isolated 14 days after secondary infection, from simvastatin pretreated mice and stimulated ex vivo produced increased levels of IgG1 compared to memory B cells isolated from control mice, while levels of IgM and IgG2c remained similar. Furthermore, memory B and T lymphocytes from simvastatin pretreated mice exhibited a decreased proliferative response when stimulated ex vivo compared to memory cells isolated from control mice. These findings demonstrate the ability of a short term, low dose simvastatin treatment to modulate memory immune function. PMID- 26927219 TI - Molecular mechanism linking BDNF/TrkB signaling with the NMDA receptor in memory: the role of Girdin in the CNS. AB - It is well known that synaptic plasticity is the cellular mechanism underlying learning and memory. Activity-dependent synaptic changes in electrical properties and morphology, including synaptogenesis, lead to alterations of synaptic strength, which is associated with long-term potentiation (LTP). Brain-derived neurotrophic factor (BDNF)/tropomyosin-related kinase B (TrkB) signaling is involved in learning and memory formation by regulating synaptic plasticity. The phosphatidylinositol 3-kinase (PI3-K)/Akt pathway is one of the key signaling cascades downstream BDNF/TrkB and is believed to modulate N-methyl-d-aspartate (NMDA) receptor-mediated synaptic plasticity. However, the molecular mechanism underlying the connection between these two key players in synaptic plasticity remains largely unknown. Girders of actin filament (Girdin), an Akt substrate that directly binds to actin filaments, has been shown to play a role in neuronal migration and neuronal development. Recently, we identified Girdin as a key molecule involved in regulating long-term memory. It was demonstrated that phosphorylation of Girdin by Akt contributed to the maintenance of LTP by linking the BDNF/TrkB signaling pathway with NMDA receptor activity. These findings indicate that Girdin plays a pivotal role in a variety of processes in the CNS. Here, we review recent advances in our understanding about the roles of Girdin in the CNS and focus particularly on neuronal migration and memory. PMID- 26927220 TI - Acute toxicity, antiedematogenic activity, and chemical constituents of Palicourea rigida Kunth. AB - The phytochemical study of the leaves, roots, and flowers of Palicourea rigida led to the isolation of the triterpenes betulinic acid (1) and lupeol (2), the diterpene phytol (3), and the iridoid glycosides sweroside (4) and secoxyloganin (5). These compounds were identified using NMR 1H and 13C and comparing the spectra with published data. We studied the antiedematogenic activity of crude extracts from the organs, and of different fractions, in mice and found that the n-hexane fraction of the leaf extract significantly inhibited the ear edema resulting from croton oil administration. The crude extract from leaves was not acutely toxic to the mice. PMID- 26927222 TI - Fast multislice fluorescence molecular tomography using sparsity-inducing regularization. AB - Fluorescence molecular tomography (FMT) is a rapidly growing imaging method that facilitates the recovery of small fluorescent targets within biological tissue. The major challenge facing the FMT reconstruction method is the ill-posed nature of the inverse problem. In order to overcome this problem, the acquisition of large FMT datasets and the utilization of a fast FMT reconstruction algorithm with sparsity regularization have been suggested recently. Therefore, the use of a joint L1/total-variation (TV) regularization as a means of solving the ill posed FMT inverse problem is proposed. A comparative quantified analysis of regularization methods based on L1-norm and TV are performed using simulated datasets, and the results show that the fast composite splitting algorithm regularization method can ensure the accuracy and robustness of the FMT reconstruction. The feasibility of the proposed method is evaluated in an in vivo scenario for the subcutaneous implantation of a fluorescent-dye-filled capillary tube in a mouse, and also using hybrid FMT and x-ray computed tomography data. The results show that the proposed regularization overcomes the difficulties created by the ill-posed inverse problem. PMID- 26927221 TI - Laser speckle imaging based on photothermally driven convection. AB - Laser speckle imaging (LSI) is an interferometric technique that provides information about the relative speed of moving scatterers in a sample. Photothermal LSI overcomes limitations in depth resolution faced by conventional LSI by incorporating an excitation pulse to target absorption by hemoglobin within the vascular network. Here we present results from experiments designed to determine the mechanism by which photothermal LSI decreases speckle contrast. We measured the impact of mechanical properties on speckle contrast, as well as the spatiotemporal temperature dynamics and bulk convective motion occurring during photothermal LSI. Our collective data strongly support the hypothesis that photothermal LSI achieves a transient reduction in speckle contrast due to bulk motion associated with thermally driven convection. The ability of photothermal LSI to image structures below a scattering medium may have important preclinical and clinical applications. PMID- 26927223 TI - Specification of a new de-stoner machine: evaluation of machining effects on olive paste's rheology and olive oil yield and quality. AB - BACKGROUND: An industrial prototype of a partial de-stoner machine was specified, built and implemented in an industrial olive oil extraction plant. The partial de stoner machine was compared to the traditional mechanical crusher to assess its quantitative and qualitative performance. The extraction efficiency of the olive oil extraction plant, olive oil quality, sensory evaluation and rheological aspects were investigated. RESULTS: The results indicate that by using the partial de-stoner machine the extraction plant did not show statistical differences with respect to the traditional mechanical crushing. Moreover, the partial de-stoner machine allowed recovery of 60% of olive pits and the oils obtained were characterised by more marked green fruitiness, flavour and aroma than the oils produced using the traditional processing systems. CONCLUSION: The partial de-stoner machine removes the limitations of the traditional total de stoner machine, opening new frontiers for the recovery of pits to be used as biomass. Moreover, the partial de-stoner machine permitted a significant reduction in the viscosity of the olive paste. (c) 2016 Society of Chemical Industry. PMID- 26927224 TI - Driving risk in obstructive sleep apnoea: Do new European regulations contribute to safer roads? PMID- 26927225 TI - Trails to the gibberellin receptor, GIBBERELLIN INSENSITIVE DWARF1. AB - The researches on the identification of gibberellin receptor are reviewed from the early attempts in 1960s to the identification of GIBBERELLIN INSENSITIVE DWARF1 (GID1) as the receptor in 2005. Unpublished data of the gibberellin binding protein in the seedlings of adzuki bean (Vigna angularis) are also included, suggesting that the active principle of the gibberellin-binding protein was a GID1 homolog. PMID- 26927227 TI - Catalytic Rearrangement of 2-Alkoxy Diallyl Alcohols: Access to Polysubstituted Cyclopentenones. AB - A catalytic rearrangement of diallyl alcohols comprising a cyclic enol ether has been developed using very mild conditions. Bismuth(III) triflate was found to be a very active catalyst for the ring rearrangement of a range of tertiary allylic alcohols to efficiently afford polysubstituted cyclopentenones with a high degree of diastereoselectivity. PMID- 26927226 TI - Prevalence of Chlamydia trachomatis and Neisseria gonorrhoeae infection in adolescents in Northern Italy: an observational school-based study. AB - BACKGROUND: We carried out a study to evaluate the prevalence of Chlamydia trachomatis and Neisseria gonorrhoeae genital infections in school-based adolescents in Northern Italy. METHODS: Systematic screening for C. trachomatis and N. gonorrhoeae genital infection was performed in 13th grade students in the province of Brescia, an industrialized area in Northern Italy. Student filled in a questionnaire on sexual behaviour and provided a urine sample for microbiological testing. RESULTS: A total of 2,718 students (mean age: 18.4 years; 59.1% females) provided complete data (62.2% of those eligible). Overall 2,059 students (75.8%) were sexually active (i.e. had had at least one partner), and the mean age at sexual debut was 16.1 years (SD: 1.4). Only 27.5% of the sexually active students reported regular condom use during the previous 6 months, with higher frequency in males than in females (33.8% vs 24.2%). No case of N. gonorrhoeae infection was detected, while C. trachomatis was found in 36 adolescents, with a prevalence of 1.7% (95% CI: 1.2-2.4) among sexually active students, and no statistical difference between females and males (1.9 and 1.4%, respectively). Inconsistent condom use (odds ratio, OR = 5.5) and having had more than one sexual partner during the previous 6 months (OR = 6.8) were associated with an increased risk of Chlamydia infection at multivariate analysis. CONCLUSION: The prevalence of C. trachomatis infection among sexually active adolescents in Northern Italy was low, despite a high proportion of students who engage in risky sexual behaviour. No cases of N. gonorrhoeae infection were identified. PMID- 26927228 TI - The filamentous fungus Ashbya gossypii as a competitive industrial inosine producer. AB - Inosine is a nucleoside with growing biotechnological interest due to its recently attributed beneficial health effects and as a convenient precursor of the umami flavor. At present, most of the industrial inosine production relies on bacterial fermentations. In this work, we have metabolically engineered the filamentous fungus Ashbya gossypii to obtain strains able to excrete high amounts of inosine to the culture medium. We report that the disruption of only two key genes of the purine biosynthetic pathway efficiently redirect the metabolic flux, increasing 200-fold the excretion of inosine with respect to the wild type, up to 2.2 g/L. These results allow us to propose A. gossypii as a convenient candidate for large-scale nucleoside production, especially in view of the several advantages that Ashbya has with respect to the bacterial systems used at present for the industrial production of this food additive. Biotechnol. Bioeng. 2016;113: 2060-2063. (c) 2016 Wiley Periodicals, Inc. PMID- 26927229 TI - Climatic Signals in Tree Rings of Heritiera fomes Buch.-Ham. in the Sundarbans, Bangladesh. AB - Mangroves occur along the coastlines throughout the tropics and sub-tropics, supporting a wide variety of resources and services. In order to understand the responses of future climate change on this ecosystem, we need to know how mangrove species have responded to climate changes in the recent past. This study aims at exploring the climatic influences on the radial growth of Heritiera fomes from a local to global scale. A total of 40 stem discs were collected at breast height position from two different zones with contrasting salinity in the Sundarbans, Bangladesh. All specimens showed distinct tree rings and most of the trees (70%) could be visually and statistically crossdated. Successful crossdating enabled the development of two zone-specific chronologies. The mean radial increment was significantly higher at low salinity (eastern) zone compared to higher salinity (western) zone. The two zone-specific chronologies synchronized significantly, allowing for the construction of a regional chronology. The annual and monsoon precipitation mainly influence the tree growth of H. fomes. The growth response to local precipitation is similar in both zones except June and November in the western zone, while the significant influence is lacking. The large-scale climatic drivers such as sea surface temperature (SST) of equatorial Pacific and Indian Ocean as well as the El Nino-Southern Oscillation (ENSO) revealed no teleconnection with tree growth. The tree rings of this species are thus an indicator for monsoon precipitation variations in Bangladesh. The wider distribution of this species from the South to South East Asian coast presents an outstanding opportunity for developing a large-scale tree ring network of mangroves. PMID- 26927230 TI - [Intramedullary hemangioblastomas]. AB - AIM AND BACKGROUND: Intramedullary hemangioblastomas are rare lesions representing 1 to 5% of spinal tumors. The aim of this study was to review our experience with the surgical management of intramedullary hemangioblastomas. MATERIALS AND METHODS: We performed a retrospective analysis of all the patients with intramedullary hemangioblastomas operated on between 1993 and 2011 in our department. All the patients were screened for Von Hippel Lindau disease. The minimum follow-up was 3 years. The clinical presentation, radiological findings, surgical procedure and outcomes were recorded and analyzed. RESULTS: Our consecutive series included 59 patients with a total of 65 tumors. The mean age at diagnosis was 38 years. Forty-two patients (72.5%) had Von Hippel Lindau disease. The main symptom was pain (58% of cases). The most common location was cervical spinal cord. The average size was 15mm. The resection was complete in 95% cases resulting in clinical improvement in 12% cases, stability in more than 86% of cases and deterioration in less than 2% cases. CONCLUSION: All patients with intramedullary hemangioblastoma should have a screening for the Von Hippel Lindau disease and if the diagnosis is correct, close monitoring should be initiated. Surgical removal is strongly advised in cases of neurological deficits or radiological progression of the tumour. PMID- 26927232 TI - Symmetry Switching of Negative Thermal Expansion by Chemical Control. AB - The layered perovskite Ca3-xSrxMn2O7 is shown to exhibit a switching from a material exhibiting uniaxial negative to positive thermal expansion as a function of x. The switching is shown to be related to two closely competing phases with different symmetries. The negative thermal expansion (NTE) effect is maximized when the solid solution is tuned closest to this region of phase space but is switched off suddenly on passing though the transition. Our results show for the first time that, by understanding the symmetry of the competing phases alone, one may achieve unprecedented chemical control of this unusual property. PMID- 26927231 TI - Predictors of Gaps in Patient Safety and Quality in U.S. Hospitals. AB - OBJECTIVE: To explore predictors of gaps between observed and best possible Hospital Compare scores in U.S. hospitals. DATA SOURCES: American Hospital Association Annual Survey; Area Resource Files; Centers for Medicare and Medicaid Services Medicare Provider and Analysis Review; and Hospital Compare data. STUDY DESIGN: Using Stochastic Frontier Analysis and secondary cross-sectional data, gaps between the best possible and actual scores of Hospital Compare quality measures were estimated. Poisson regressions were used to ascertain financial, organizational, and market predictors of those gaps. DATA EXTRACTION: Data were cleaned and matched based on hospital Medicare IDs. All U.S. hospitals that matched on analysis variables in 2007 were in the study (1,823-2,747, depending upon gap variable). PRINCIPAL FINDINGS: Most hospitals have a greater than 10 percent gap in quality indicators. Payer mix, registered nurse staffing, size, case mix index, accreditation, being a teaching hospital, market competition, urban location, and region were strong predictors of gaps, although the direction of the association with gaps was not uniform across outcomes. CONCLUSIONS: A significant percentage of hospitals have gaps between their best possible and observed quality scores. It may be better to use gap scores than observed scores in payments systems. More SFA research is needed to know how to lower gaps through changes in hospital and market characteristics. PMID- 26927233 TI - Progress in bacterial cellulose matrices for biotechnological applications. AB - Bacterial cellulose (BC) is an extracellular polymer produced by many microorganisms. The Komagataeibacter genus is the best producer using semi synthetic media and agricultural wastes. The main advantages of BC are the nanoporous structure, high water content and free hydroxyl groups. Modification of BC can be made by two strategies: in-situ, during the BC production, and ex situ after BC purification. In bioprocesses, multilayer BC nanocomposites can contain biocatalysts designed to be suitable for outside to inside cell activities. These nanocomposites biocatalysts can (i) increase productivity in bioreactors and bioprocessing, (ii) provide cell activities does not possess without DNA cloning and (iii) provide novel nano-carriers for cell inside activity and bioprocessing. In nanomedicine, BC matrices containing therapeutic molecules can be used for pathologies like skin burns, and implantable therapeutic devices. In nanoelectronics, semiconductors BC-based using salts and synthetic polymers brings novel films showing excellent optical and photochemical properties. PMID- 26927234 TI - Computational fluid dynamics modelling of biomass fast pyrolysis in fluidised bed reactors, focusing different kinetic schemes. AB - The present work concerns with CFD modelling of biomass fast pyrolysis in a fluidised bed reactor. Initially, a study was conducted to understand the hydrodynamics of the fluidised bed reactor by investigating the particle density and size, and gas velocity effect. With the basic understanding of hydrodynamics, the study was further extended to investigate the different kinetic schemes for biomass fast pyrolysis process. The Eulerian-Eulerian approach was used to model the complex multiphase flows in the reactor. The yield of the products from the simulation was compared with the experimental data. A good comparison was obtained between the literature results and CFD simulation. It is also found that CFD prediction with the advanced kinetic scheme is better when compared to other schemes. With the confidence obtained from the CFD models, a parametric study was carried out to study the effect of biomass particle type and size and temperature on the yield of the products. PMID- 26927235 TI - Effect of different struvite crystallization methods on gaseous emission and the comprehensive comparison during the composting. AB - This study compared 4 different struvite crystallization process (SCP) during the composting of pig feces. Four combinations of magnesium and phosphate salts (H3PO4+MgO (PMO), KH2PO4+MgSO4 (KPM), Ca(H2PO4)2+MgSO4 (CaPM), H3PO4+MgSO4 (PMS)) were assessed and were also compared to a control group (CK) without additives. The magnesium and phosphate salts were all supplemented at a level equivalent to 15% of the initial nitrogen content on a molar basis. The SCP significantly reduced NH3 emission by 50.7-81.8%, but not the N2O. Although PMS group had the lowest NH3 emission rate, the PMO treatment had the highest struvite content in the end product. The addition of sulphate decreased CH4 emission by 60.8-74.6%. The CaPM treatment significantly decreased NH3 (59.2%) and CH4 (64.9%) emission and yielded compost that was completely matured. Due to its effective performance and low cost, the CaPM was suggested to be used in practice. PMID- 26927236 TI - Complete utilization of non-edible oil seeds of Cascabela thevetia through a cascade of approaches for biofuel and by-products. AB - Lipid-rich biomass, generally opted for biodiesel production, produces a substantial amount of by-product (de-oiled cake and seed cover) during the process. Complete utilization of Cascabela thevetia seeds for biofuel production through both chemical and thermochemical conversion route is investigated in the present study. Various properties of biodiesel produced was characterized and compared with those obtained from similar oil seeds. The by-products of the chemical process were used as a feedstock for pyrolysis at different temperatures in a fixed bed reactor. Maximum bio-oil yields of 29.11% and 26.18% were observed at 500 degrees C. The bio-oil obtained at optimum yield was characterized by CHN analyzer, NMR and FTIR spectroscopy. The biochar produced was further characterized by SEM-EDX, XRD and FTIR along with elemental analysis to explore its utilization for various purposes. The present investigation depicts a new approach towards complete utilization of lipid-rich bio-resources to different types of biofuels and biochar. PMID- 26927237 TI - Postscreening follow-up of the Finnish Prostate Cancer Screening Trial on putative prostate cancer risk factors: vitamin and mineral use, male pattern baldness, pubertal development and non-steroidal anti-inflammatory drug use. AB - Objective The etiology of prostate cancer (PCa) is still unclear. This study aimed to investigate the association between PCa risk and the indicators of endogenous androgen production at puberty, male pattern baldness, over-the counter use of non-steroidal anti-inflammatory drugs and vitamin supplement use. Materials and methods Participants in the third round of the Finnish Prostate Cancer Screening Trial were sent a survey on possible PCa risk factors and 11,795 out of 12,740 (93%) men returned the questionnaire. PCa cases were identified from the Finnish Cancer Registry. Results During the median follow-up of 6.6 years, 757 PCa cases were diagnosed and 21 men died from PCa. Compared to earlier onset, puberty onset after 15 years of age was associated with a borderline significant decrease in PCa risk [hazard ratio (HR) 0.87, 95% confidence interval (CI) 0.75-1.00] but not with PCa mortality. Weekly use of ibuprofen was associated with an increased risk of PCa overall (HR 1.43, 95% CI 1.08-1.91) and with metastatic PCa (HR 1.49, 95% CI 1.12-1.99) compared to less frequent use. No statistically significant association was found between vitamin use and PCa. Conclusions This study suggests that the timing of initiation of endogenous androgen production at puberty may have importance for later PCa development. Current use of over-the-counter ibuprofen is associated with an increased risk of PCa. There was no evidence of any protective effects of vitamin use on PCa risk. PMID- 26927238 TI - Is it safe to preserve the ovary of premenopausal women with supposed early-stage endometrial cancer? PMID- 26927239 TI - Molecular mechanisms for synergistic effect of proteasome inhibitors with platinum-based therapy in solid tumors. AB - The successful development of the proteasome inhibitor bortezomib as an anticancer drug has improved survival in patients with multiple myeloma. With the emergence of the newly US Food and Drug Administration-approved proteasome inhibitor carfilzomib, ongoing trials are investigating this compound and other proteasome inhibitors either alone or in combination with other chemotherapy drugs. However, in solid tumors, the efficacy of proteasome inhibitors has not lived up to expectations. Results regarding the potential clinical efficacy of bortezomib combined with other agents in the treatment of solid tumors are eagerly awaited. Recent identification of the molecular mechanisms (involving apoptosis and autophagy) by which bortezomib and cisplatin can overcome chemotherapy resistance and sensitize tumor cells to anticancer therapy can provide insights into the development of novel therapeutic strategies for patients with solid malignancies. PMID- 26927240 TI - Changes in mitochondrial DNA copy number and extracellular matrix (ECM) proteins in the uterosacral ligaments of premenopausal women with pelvic organ prolapse. AB - OBJECTIVE: The study aimed to explore the changes in mitochondrial DNA (mtDNA) copy number, collagen, and matrix metalloproteinase (MMPs) expression with pelvic organ prolapse (POP) in the uterosacral ligaments of premenopausal women. MATERIALS AND METHODS: A group of 56 premenopausal women, all younger than 52 years of age, were enrolled in this study. Uterosacral ligament (UL) biopsies were obtained from uterine specimens taken from 22 women with POP (n = 22, study group) and 34 myoma patients without POP (n = 34, control group) during abdominal or vaginal hysterectomy. Quantitative real-time polymerase chain reaction (Q-PCR) and immunohistochemistry analysis were applied in the present study. RESULTS: The rate of high body mass index (BMI) (> 24 kg/m(2)) women was significantly higher in the POP group (81.8% vs. 35.3%, p = 0.001 *), and the BMI of the POP women was higher than that of the nonPOP women (p = 0.029 *). The mtDNA copy number (p = 0.001 *), collagen III alpha 1 (COL3alpha1) expression (p = 0.025 *), and MMP2 expression (p = 0.047 *) were significantly higher in the POP group when compared with the nonPOP group. The high BMI women had a higher mtDNA copy number (p = 0.002 *), COL3alpha1 (p = 0.028 *) gene expressions compared with the standard BMI women. CONCLUSION: In the premenopausal state, higher BMI may be a stronger associate factor than vaginal birth for the development of POP. The higher mtDNA copy number, COL3alpha1, and MMP2 gene expressions are highly associated with POP in the UL of premenopausal women. PMID- 26927241 TI - Clinical significance of second-trimester 50-g glucose challenge test among Japanese women diagnosed as normoglycemic after first-trimester 75-g glucose tolerance test. AB - OBJECTIVE: This study was performed to determine how often Japanese women diagnosed as normoglycemic on first-trimester 75-g glucose tolerance test (75gGTT) later develop gestational diabetes mellitus (GDM). MATERIAL AND METHODS: Sixty-two women with random plasma glucose (PG) level >= 105 mg/dL during the first trimester and subsequent first-trimester diagnosis of normoglycemia with 75gGTT underwent 50-g glucose challenge test (50gGCT) during the second trimester. Twenty-one with a positive 50gGCT result (60-m PG >= 140 mg/dL) underwent second-trimester 75gGTT. First-trimester random PG levels and 75gGTT results were compared between 21 and 41 women with positive and negative 50gGCT results, respectively. Changes in immunoreactive insulin (IRI) associated with 75gGTT were determined simultaneously. RESULTS: All 21 women with a positive 50gGCT result showed normoglycemia on second-trimester 75gGTT. Thus, none of the 62 women developed GDM. Insulin resistance increased significantly in the 21 women with 75gGTT during the first and second trimesters, as indicated by increases in homeostasis model assessment for insulin resistance (HOMA-IR) and homeostasis model assessment for beta-cell function (HOMA-beta) with no significant changes in preload or afterload PG levels. Neither random PG levels (116 +/- 12 vs. 116 +/- 12 mg/dL, respectively) nor 75gGTT results (86 +/- 6 vs. 84 +/- 5 mg/dL for 0-minute [0-m] PG level, 130 +/- 28 vs. 131 +/- 25 mg/dL for 60-m PG, and 111 +/- 19 vs. 118 +/- 18 mg/dL for 120-m PG, respectively) during the first trimester differed significantly between the 41 and 21 women with negative and positive second-trimester 50gGCT results, respectively. CONCLUSION: Although insulin resistance increased in the second trimester, risk of developing GDM was < 1/62 among Japanese women in whom hyperglycemia was excluded with first trimester GTT. PMID- 26927242 TI - Is single incision midurethral sling effective in patients with low maximal urethral closure pressure? AB - OBJECTIVE: To ascertain whether low preoperational maximal urethral closure pressure (MUCP) affects the outcomes of single incision sling (SIS) procedures and changes MUCP values postsurgery. MATERIAL AND METHODS: There were 112 (MUCP >= 40 cmH2O, n = 88; MUCP < 40 cmH2O, n = 24) consecutive women with urodynamic stress incontinence who had undergone SIS (MiniArc) procedures included in this study. The threshold of 40 cmH2O was used since it has been shown to be a significant risk factor for failed incontinence surgery. Clinical outcomes were assessed by the cough stress test, the 1-hour pad test, the Incontinence Impact Questionnaire-Short Form, the Urogenital Distress Inventory six-item questionnaire, the Sexual Questionnaire-SF, and postoperative changes in the urodynamic parameters. A comparison of the 1-year follow-up data is presented. RESULTS: Three months postsurgery, a significant decrease was observed in the 1 hour pad test, from 20.6 g preoperatively to 0.73 g postoperatively (p < 0.001). The objective cure rate was 82.1% without any significant differences between the two groups (p = 0.202). At 3 months and 1 year after surgery, significantly decreasing Urogenital Distress Inventory six-item questionnaire and Incontinence Impact Questionnaire-Short Form, and increasing Sexual Questionnaire-SF scores were observed in both groups, without any significant differences between the two groups. No statistically significant difference in the subjective cured rate was noted between the two groups at the 3-month and 18.4 month follow-ups. The postoperative MUCP was significantly decreased in the MUCP >= 40 group (p < 0.05) while significantly increased in the MUCP < 40 group (p = 0.006). CONCLUSIONS: These results suggest that SIS is a safe and highly effective treatment for urodynamic stress incontinence even in women with low MUCP at a mean follow-up of 18.4 months. Evaluation of the outcomes with more subjects after a longer follow up period is necessary. PMID- 26927243 TI - Efficacy and safety of daikenchuto (TJ-100) in pregnant women with constipation. AB - OBJECTIVE: Constipation is common and a significant problem in pregnant women. The purpose of this study was to examine the efficacy and the safety of daikenchuto in pregnant women with constipation. MATERIAL AND METHODS: This was a prospective study, and a total of 20 patients were registered between February 2010 and August 2012. The patients received 7.5 g/d of daikenchuto for 28 days from the day of registration. All enrolled patients were asked to complete the constipation assessment scale (CAS) every day. In addition, we measured the aspartate transaminase, alanine transaminase, blood urea nitrogen, and creatinine levels to assess the adverse effects of daikenchuto. RESULTS: The CAS scores were significantly lower at 28 days after daikenchuto treatment (p = 0.019), with a significant effect achieved on Day 1. The impact of the therapy was greatest in the second trimester (p = 0.043). No significant adverse effects of daikenchuto were observed, and the rates of preterm birth and pregnancy-induced hypertension were 10% and 5%, respectively, which are similar to previously reported values. CONCLUSION: We herein demonstrated the efficacy and safety of daikenchuto in pregnant women with constipation. We hope that our findings will aid in the management of constipation in pregnant women. PMID- 26927244 TI - Comparative analysis of copper intrauterine device impact on female sexual dysfunction subtypes. AB - OBJECTIVES: To examine the effect of copper intrauterine device (Cu-IUD) on female sexual dysfunction (FSD) subtypes. MATERIAL AND METHODS: There were 159 sexually active women (ninety Cu-IUD users and sixty-nine women with no contraception) who attended the gynecology clinic for routine gynecologic control informed about the study and asked to fill Female Sexual Function Index (FSFI) and Beck Depression Inventory questionnaires. RESULTS: The prevalence of FSD was 41.1% (n=37) and 37.7% (n=26) in Cu-IUD users and control groups, respectively (p > 0.05). In analyses of mean overall and subgroup scores of FSFI, significantly lower scores for arousal (p=0.021), lubrication (p=0.021), orgasm (p=0.040), pain (p < 0.001), and overall FSFI (p=0.031) were noted in Cu-IUD users. When the results for FSFI domains were considered for Cu-IUD users separately, the only difference to reach statistical significance, using a Bonferroni adjustment, was found to be the pain domain. Finally, we determined that Cu-IUD status made the strongest unique contribution to explaining the dependent variable pain in multiple logistic regression model (beta = -0.26, p=0.001). CONCLUSION: Cu-IUD users have increased sexual pain compared to women with no contraception, which in turn possibly causes decreased sexual arousal, lubrication, and orgasm in these women. PMID- 26927245 TI - The effectiveness of laparoendoscopic single-site surgery (LESS) compared with conventional laparoscopic surgery for ectopic pregnancy with hemoperitoneum. AB - OBJECTIVE: The purpose of this study was to compare clinical outcomes of conventional laparoscopic surgery and laparoendoscopic single-site surgery (LESS) in the surgical treatment of tubal ectopic pregnancy. MATERIAL AND METHODS: A total of 156 patients were diagnosed with ectopic pregnancies by ultrasonography and serum beta-human chorionic gonadotrophin (beta-hCG) levels at Pusan National University Yangsan Hospital from January 2009 through December 2013. We excluded 28 patients who only received medical treatment, 15 patients who underwent surgery by laparotomy for severe hypovolemic shock, and 30 patients who presented with less than 1 L of hemoperitoneum. Of the 83 patients with massive hemoperitoneum, 38 patients had LESS performed while the remaining 45 patients underwent conventional laparoscopic surgery. RESULTS: In this study, there were no statistically significant differences in clinical outcomes in either surgical method except for operative time. Operative time of LESS was significantly shorter than conventional surgery for patients with more than 500 mL of hemoperitoneum. CONCLUSION: LESS is a safe and feasible surgical approach in the treatment of tubal ectopic pregnancy. At the same time, LESS has been shown to be more effective than conventional laparoscopic surgery in handling massive hemoperitoneum of more than 1 L, which is a common complication of ectopic pregnancy. PMID- 26927246 TI - Diagnosis and microecological characteristics of aerobic vaginitis in outpatients based on preformed enzymes. AB - OBJECTIVE: Aerobic vaginitis (AV) is a recently proposed term for genital tract infection in women. The diagnosis of AV is mainly based on descriptive diagnostic criteria proposed by Donders and co-workers. The objective of this study is to report AV prevalence in southwest China using an objective assay kit based on preformed enzymes and also to determine its characteristics. MATERIALS AND METHODS: A total of 1948 outpatients were enrolled and tested by a commercial diagnostic kit to investigate the AV prevalence and characteristics in southwestern China. The study mainly examined the vaginal ecosystem, age distribution, Lactobacillus amount, and changes in pH. Differences within groups were analyzed by Wilcoxon two-sample test. RESULTS: The AV detection rate is 15.40%. The AV patients were usually seen in the sexually active age group of 20 30 years, followed by those in the age group of 30-40 years. The vaginal ecosystems of all the patients studied were absolutely abnormal, and diagnosed to have a combined infection [aerobic vaginitis (AV) + bacterial vaginitis (BV) 61.33%; 184/300]. Aerobic bacteria, especially Staphylococcus aureus and Escherichia coli, were predominantly found in the vaginal samples of these women. CONCLUSION: AV is a common type of genital infection in southwestern China and is characterized by sexually active age and combined infection predominated by the AV and BV type. PMID- 26927247 TI - Early midtrimester serum insulin-like factors and cervical length to predict preterm delivery. AB - OBJECTIVE: To investigate which ultrasound findings or serum biomarkers, including insulin-like growth factor 1 (IGF-1) and insulin-like growth factor binding protein 1 and 3 (IGFBP-1 and IGFBP-3, respectively), in the first and early second trimesters are the best predictors for preterm delivery. MATERIALS AND METHODS: This was a case-control study conducted between March 2011 and March 2013 with women presenting for routine antenatal care at 11-18 weeks. We collected serum samples from pregnant women and stored them at -80 degrees C. All patients underwent cervical length (CL) measurement at 18-21 weeks. We retrieved frozen samples for analysis from women with subsequent preterm and term delivery. Prediction models were developed using multivariate stepwise logistic regression. Receiver-operating characteristics curves were used to determine the most useful cutoff point. RESULTS: Of the 72 women recruited, 24 women underwent spontaneous preterm delivery, and 48 women with term delivery were randomly selected as the control group, in a 1:2 ratio. The maternal serum concentration of IGFBP-3 and CL were significantly associated with preterm birth. CONCLUSION: Among the various known ultrasound findings and serum biomarkers in the early midtrimester, only CL and IGFBP-3 are independent predictors for preterm delivery in asymptomatic women. PMID- 26927248 TI - Luteal-phase ovarian stimulation is a feasible method for poor ovarian responders undergoing in vitro fertilization/intracytoplasmic sperm injection-embryo transfer treatment compared to a GnRH antagonist protocol: A retrospective study. AB - OBJECTIVE: Poor ovarian response to ovarian hyperstimulation is one of the biggest challenges in assisted reproduction technology. Although many stimulation protocols have been established to improve clinical outcomes in poor ovarian responders (PORs), which protocol is the most effective remains controversial. Luteal-phase ovarian stimulation (LPOS) has been used in normal ovarian responders with satisfactory outcomes. However, the efficacy of LPOS in PORs is unclear. This study aimed to compare the efficacy of LPOS and GnRH antagonist (GnRH-ant) in PORs. MATERIALS AND METHODS: The clinical parameters in PORs who received LPOS (50 cycles in 39 patients) or GnRH-ant (158 cycles in 123 patients) were compared. RESULTS: Compared with those in the GnRH-ant group, the PORs in the LPOS group showed significantly fewer basal antral follicles (3.1 +/- 2.2 vs. 4.1 +/- 1.6, p < 0.001) and a higher in vitro fertilization rate. There were no significant differences in the numbers of retrieved oocytes and D3 transferable embryos between the two groups. However, the pregnancy rate in the LPOS group (46.4%) was significantly higher than that in the GnRH-ant group (25.8% overall; 22.9% from fresh embryos and 29.6% from frozen embryos). Moreover, 23 PORs in the LPOS group underwent oocyte retrieval twice in one cycle, and the numbers of retrieved oocytes and transferable embryos from the luteal phase were significantly higher than those from the follicular phase in the same menstrual cycle. CONCLUSIONS: Compared with the GnRH-ant protocol, the LPOS protocol may be a better regime for PORs that can increase the numbers of retrieved oocytes and transferable embryos as well as the pregnancy rate. PMID- 26927249 TI - Low-dose add-back therapy during postoperative GnRH agonist treatment. AB - OBJECTIVE: Low-dose add-back therapy during postoperative GnRH agonist treatment could lower the risk of add-back-induced endometriosis recurrence and reduce treatment dropout compared with a regular dose. However, the effect of low-dose add-back therapy is still unknown. The aim of this study was to determine whether low-dose add-back therapy can also effectively relieve the hypoestrogenic side effects and simultaneously maintain a therapeutic response of GnRH agonist treatment. MATERIALS AND METHODS: This analysis was a prospective cohort study. During postoperative GnRH agonist treatment, a total of 107 women were prescribed add-back therapy [oral combination tablet; estradiol valerate (1 mg) and medroxyprogesterone acetate (2.5 mg)] (Indivina; Orion, Espoo, Finland) for 20 weeks. Patients in the low dose add-back therapy group were prescribed the tablet once a day, and patients in the regular dose group were given the tablet twice a day. Hypoestrogenic side effects, such as hot flashes and insomnia, were recorded. Patients were also questioned regarding their pelvic symptoms and pain to evaluate the possibility of endometriosis recurrence. Lumbar spine (L2-L4) bone mineral density was measured using dual X-ray absorptiometry. The dropout rates in both groups were also evaluated. RESULTS: The incidence of hypoestrogenic side effects was lower in the low dose group compared with the regular dose group, including hot flashes (19.2% vs. 21.8%, p = 0.741) and insomnia (15.4% vs. 18.2%, p = 0.699), although there were no significant difference between the groups. In addition, a higher number of patients in the regular dose group dropped out of treatment compared to the low dose group (14.5% and 9.6%, respectively, p = 0.435). The patients in both groups had a significant loss of mean bone mineral density during therapy (p < 0.001 and p = 0.018 for the low dose and regular dose groups, respectively). CONCLUSION: Low dose add-back therapy could effectively ameliorate hypoestrogenic side effects and simultaneously maintain the therapeutic response of GnRH agonist treatment. The treatment dropout was lower compared with a regular dose. Therefore, low dose add back therapy can be considered a treatment choice during postoperative GnRH agonist treatment. PMID- 26927250 TI - Levels of thrombin-activatable fibrinolysis inhibitor and platelet-activating factor in recurrent pregnancy loss patients. AB - OBJECTIVE: The aim of this study was to investigate factors associated with thrombosis that may contribute to recurrent pregnancy loss (habitual abortion), specifically differences in serum levels of platelet-activating factor and thrombin-activatable fibrinolysis inhibitor (carboxypeptidase B2) between women with a history of recurrent miscarriage and those with no recurrent miscarriage history. MATERIALS AND METHODS: A case-controlled, prospective study design was adopted to compare women with a history of two or more first-trimester miscarriages (n = 42) with those with no history of recurrent miscarriage (n = 36). Participants were recruited from the Department of Obstetrics and Gynecology of Turgut Ozal University Hospital. Platelet-activating factor and thrombin activatable fibrinolysis inhibitor levels in serum samples were measured by an enzyme-linked immunosorbent assay. RESULTS: Platelet-activating factor levels were significantly (p = 0.018) higher in the recurrent miscarriage group. There was no difference in levels of thrombin-activatable fibrinolysis inhibitor expression between the groups. CONCLUSION: Platelet-activating factor is significantly higher in serum of patients with a history of recurrent miscarriage than in those without such a history, with potential implications for placental function and fetal growth, which could be relevant to miscarriage recurrence. Larger studies are indicated to further examine these findings. PMID- 26927251 TI - Emergency cesarean section rate between women with gestational diabetes and normal pregnant women. AB - OBJECTIVE: Gestational diabetes mellitus (GDM) has been related to various maternal and neonatal complications. The degree to which GDM is related to an increased rate of cesarean section is less certain. This study was aimed at comparing the incidence of emergency cesarean delivery between pregnant women with GDM and normal pregnant women. MATERIALS AND METHODS: The study group consisted of 237 term, singleton pregnant women with GDM. Another 237 uncomplicated, normal pregnant women were randomly selected and served as the comparison group. Those who were scheduled for elective cesarean delivery and overt DM were excluded. Data were retrieved from medical records, including demographic data, antenatal and intrapartum care data, route of delivery, indications for cesarean delivery, and neonatal outcomes. RESULTS: The study group had a significantly higher mean age and body mass index, and the participants were more likely to be overweight/obese. The rate of emergency cesarean delivery was significantly higher in the study group than in the comparison group (31.6% vs. 19.4%, p = 0.002). The study group was more likely to have Cephalo-pelvic disproportion (CPD) (20.3% vs. 13.1%, p = 0.036) as an indication for cesarean delivery. Birth weight was significantly higher (by 200 g) in the study group. When stratified by parity, significant differences in cesarean delivery rates were observed only among nulliparous women. Logistic regression analysis showed that GDM significantly increased the risk of emergency cesarean delivery (adjusted odds ratio 1.9, 95% confidence interval 1.03-3.5, p = 0.039) only among nulliparous women, adjusted for age, body mass index, and gestational weight gain. CONCLUSION: The incidence of emergency cesarean delivery increased significantly among nulliparous GDM pregnant women, compared with that in normal pregnant women. PMID- 26927252 TI - Obliterative LeFort colpocleisis for pelvic organ prolapse in elderly women aged 70 years and over. AB - OBJECTIVE: Treatment of genital prolapse in elderly women is challenging. The aim of this study was to evaluate the long-term postoperative patient satisfaction and objective improvement in women aged 70 years and over with high stages of pelvic organ prolapse treated with obliterative LeFort colpocleisis. MATERIALS AND METHODS: From January 2003 to December 2013, female patients aged 70 years and over who underwent colpocleisis surgery were included in this study. We reviewed the charts for preoperative and postoperative medical history, severity of prolapse, urodynamic studies, and early postoperative complications related to this procedure in these patients. Subjective outcomes were assessed by a nursing coordinator who interviewed patients by telephone in June 2014. RESULTS: Colpocleisis was performed in 22 elderly patients and 59% patients were of advanced age (>= 80 years). The mean postoperative follow-up duration was 48.1 months (range, 7-118) months. Six patients (27.3%) had died of medical problems at the time of the telephone interview. Fourteen patients (87.5%) reported a successful outcome after the operation and two patients (12.5%) reported improvement. For present satisfaction, 93.8% of patients reported that they were satisfied. CONCLUSION: Colpocleisis should be considered as one of the surgical options for treating advanced pelvic organ prolapse in elderly patients who do not wish to preserve vaginal function for sexual intercourse. PMID- 26927253 TI - Association of first-trimester pregnancy-associated plasma protein A levels and idiopathic preterm delivery: A population-based screening study. AB - OBJECTIVE: This study aims to determine the strength of relationship between pregnancy-associated plasma protein A (PAPP-A) concentrations, using a Thai specific reference range, and rates of idiopathic preterm delivery. MATERIALS AND METHODS: A retrospective cohort study was conducted on consecutive singleton pregnancies, undergoing first-trimester screening for fetal Down syndrome, between January 2007 and July 2012, at our network hospitals in the northern part of Thailand. The prospective database was assessed for the records with complete outcome information, including PAPP-A concentrations, gestational age at delivery, medical and obstetric complications, and fetal and pregnancy outcomes. Pregnancies with potential causes of preterm delivery were excluded. The recruited women were assigned to two groups; a group with normal PAPP-A levels (>=10(th) percentile) and a group with low PAPP-A levels (<10(th) percentile). The main outcome was the rate of idiopathic preterm births in the two groups. RESULTS: Of 6867 screened women, 3830 were available for analysis and 670 were excluded because of potential confounders. Of the remaining 3160, 302 had low PAPP-A levels and 2858 had normal PAPP-A levels. The rates of spontaneous preterm births at <=36 weeks, <=34 weeks, and <=32 weeks of gestation were significantly higher in women with low PAPP-A levels (7.6% vs. 17.9%, 3.1% vs. 11.9%, and 2.2% vs. 11.9%, respectively), with a relative risk of 2.37, 3.79, and 5.41 for preterm birth, respectively. CONCLUSION: A PAPP-A level of <=10(th) percentile was significantly associated with an increased risk for idiopathic preterm birth. Therefore, pregnant women with low PAPP-A levels in the first trimester should be considered at a high risk of preterm delivery. PMID- 26927254 TI - Postpartum mental health in relation to sociocultural practices. AB - OBJECTIVES: Cultural practices have been found to positively impact the mothering experience. This study sought to identify the relationship between sociocultural practices and postpartum depression (PPD) in a cohort of Iranian women for the first time. MATERIALS AND METHODS: In a longitudinal cohort design, 2279 pregnant women attending primary health centers of Mazandaran province in Iran were recruited using stratified random sampling method. Data were collected using the Edinburgh Postnatal Depression Scale and researchers developed validated cultural practices questionnaire at 3 months after delivery. Data were analyzed using Chi square test and multiple logistic regression models. RESULTS: The prevalence of PPD was 19% among 1910 women who were followed postdelivery in this study. Cultural practices were not associated with lower odds of PPD in multiple logistic regression model after adjustment for all sociodemographic factors. The results of this study do not also provide any evidence to support that sex of baby is associated with the greater risk of PPD. CONCLUSIONS: Cultural practices could not be perceived as protective mechanisms that protect women from PPD in this traditional society. However, health professionals should be familiar with postpartum beliefs and practices that could support mothers in the postpartum period. PMID- 26927255 TI - Clinical parameters associated with absence of endocervical/transformation zone component in conventional cervical Papanicolaou smears. AB - OBJECTIVE: To study clinical factors predicting the absence of endocervical/transformation zone (EC/TZ) components of conventional cervical Papanicolaou (Pap) smears. MATERIALS AND METHODS: The medical charts of patients who received Pap smears between March 2006 and August 2006 in the hospital were reviewed. The results of their Pap smears were retrieved while their demographic and clinical information were obtained from the medical charts. After excluding 378 cases with incomplete demographic data and 1397 cases with a history of pelvic irradiation, pelvic malignancy, and hysterectomy, 5662 cases were enrolled for data analysis. The relationship between clinical parameters and the absence of EC/TZ component was analyzed by Pearson Chi-square tests with Yates continuity correction and binary logistic regression tests. RESULTS: The incidence of satisfactory but absence of EC/TZ component was 8.7% (491/5662). Pregnancy increased the absence of EC/TZ component [odds ratio (OR}: 2.84, 95% confidence interval (CI): 2.14-3.77, p<0.0001]. Postpartum status and endocervical polyps decreased incidence (OR: 0.61, 95% CI: 0.38-0.98, p = 0.043 and OR: 0.33, 95% CI: 0.25-0.44, p<0.0001, respectively). CONCLUSIONS: Pregnancy is the only clinical factor associated with increased incidence of absence of EC/TZ cells. For these pregnant women undergoing a Pap smear, a more effective strategy may be needed to get a satisfactory smear with adequate EC/TZ components. PMID- 26927256 TI - Attenuating spinal cord injury by conditioned medium from human umbilical cord blood-derived CD34+ cells in rats. AB - OBJECTIVE: Intravenous or intraspinal transplantation of human umbilical cord blood cells-derived CD34(+) cells (human CD34(+) cells) or mesenchymal stem cells after spinal cord injury (SCI) improved hind limb functional recovery in adult rats. The objective of this study is to ascertain whether SCI in rats can be attenuated by conditioned medium (CM) or secretome obtained from cultured human CD34(+) stem cells. MATERIALS AND METHODS: Sprague-Dawley rats were assigned to one of the following five groups: the sham group, the SCI group treated with vehicle solution (SCI + V), the SCI group treated with CM (SCI + CM), the SCI group treated with 17beta-estradiol E2 (10 MUg; SCI + E2), and the SCI group treated with CM plus E2 (SCI + CM + E2). A 0.5-mL volume of CM or vehicle solution was administered intravenously immediately after SCI. RESULTS: Compared with the sham group, the (SCI + V) group had significantly higher scores of neurological motor dysfunction as well as inflammation apoptosis, oxidative stress, and astrogliosis in the injured spinal cord. The neurological deficits, numbers of apoptotic cell, extent of inflammation, oxidative stress, and astrogliosis in the injured spinal cord were significantly attenuated by CM, E2, or CM plus E2, but not by the vehicle solution. In addition, the neuroprotective effect exerted by a combination of CM and E2 is superior to that exerted by CM- or E2-alone therapy. CONCLUSION: The neuroprotective effects of CM from cultured human CD34(+) cells are similar to those of human CD34(+) cells and the CM was found to enhance the neuroprotective effects of E2 in rat SCI. PMID- 26927257 TI - Fetal fibronectin is more valuable than ultrasonographic examination of the cervix or Bishop score in predicting successful induction of labor. AB - OBJECTIVE: To compare fetal fibronectin (fFN) assessment, ultrasound parameters, and Bishop score in the prediction of successful induction of labor at term when cervix is unfavorable. MATERIALS AND METHODS: Seventy-three nulliparous women undergoing labor induction at term with Bishop score less than 5 were enrolled in this study. Successful labor induction was defined as vaginal delivery occurring within 24 hours of initiation of induction. fFN obtained from vaginal secretion was measured by immunoassay. RESULTS: Patients who delivered within 24 hours (n = 33) differed significantly from the remaining patients by a positive fFN (84.8% vs. 15.2%, p = 0.002). The mean cervical length or Bishop scores were not statistically different between women who delivered vaginally before 24 hours of induction and those who did not (28.9 mm vs. 27.9 mm, p = 0.468 and 3.3 vs. 3.2, p = 0.928, respectively). Binary logistic regression analysis showed only the fFN immunoassay to be an independent statistically significant predictor of vaginal delivery within 24 hours of induction (odds ratio 6.168; 95% confidence interval 1.897-20.059; p = 0.002). A positive fibronectin assay had a sensitivity and specificity of 84.9% and 50%, respectively. CONCLUSIONS: In cases with unfavorable cervix, presence of vaginal fFN predicts the success of labor induction. PMID- 26927258 TI - Breast cancer therapy and age difference in cardiovascular disease risks: A population-based cohort study in Taiwan. AB - OBJECTIVE: Cardiovascular events induced in breast cancer patients receiving radiotherapy (RT), chemotherapy (CT), or a combination of both (CRT) can increase the risk of death. This nationwide population-based study aims to estimate the risk of cardiovascular complications with a follow-up period of 5 years. MATERIALS AND METHODS: The study cohorts consisted of all patients hospitalized with a principal diagnosis of breast cancer who underwent treatment in 2002. The Cox proportional hazard model and Kaplan-Meier plot were analyzed to compare the cardiovascular event-free survival rate among breast cancer patients treated with different modalities. RESULTS: Of the 5514 breast cancer patients identified, 289 patients had cardiovascular disease (CVD): 110 (5.7%) from the surgery-alone group, 24 (4.1%) from the RT group, 79 (4.6) from the CT group, and 76 (5.8%) from the CRT group. Breast cancer patients who undergo CT and CRT at an age less than 55 years had a higher risk of CVD when compared with the surgery-alone group (for both groups, p < 0.001). By contrast, breast cancer patients aged over 55 years had no increased risk of CVD among the different treatment modalities. CONCLUSION: Breast cancer patients receiving CT and/or CRT have a higher risk of CVD, especially younger patients (aged < 55 years). Therefore, regular examinations of cardiac functions and electrocardiogram should be considered in cases of young breast cancer patients who are receiving CT and/or CRT. PMID- 26927259 TI - Detection of recurrent 4p16.3 microdeletion with 2p25.3 microduplication by multiplex ligation-dependent probe amplification and array comparative genomic hybridization in a fetus from a family with Wolf-Hirschhorn syndrome. AB - OBJECTIVE: We present prenatal diagnosis, genetic counseling, and molecular cytogenetic features of familial recurrence of Wolf-Hirschhorn syndrome (WHS). MATERIALS AND METHODS: A 31-year-old woman was referred to a hospital at 24 weeks of gestation because of abnormal ultrasound findings in the fetus. Her first child was a boy who had growth retardation, mental defect, and a distinctive facial appearance. Based on the conventional cytogenetic analysis, the combined use of multiplex ligation-dependent probe amplification (MLPA) and array comparative genomic hybridization (aCGH) facilitated the prenatal diagnosis and genetic counseling in the fetus. Results of the standard G-banging karyotype analysis of the fetus, the parents, and the boy were normal. RESULTS: The MLPA analysis revealed the same 4p microdeletion accompanied by 2p microduplication in the fetus and the boy. The aCGH analysis revealed a 3.57-Mb 4p16.3 microdeletion or arr [hg19] 4p16.3 (71,552-3,636,893) x1 in the fetus and a 3.29-Mb 4p16.3 microdeletion or arr [hg19] 4p16.3 (71,148-3,360,737) x1 in the boy. The 3.57-Mb 4p16.3 microdeletion encompassed 39 OMIM genes. The 3.29-Mb 4p16.3 microdeletion encompassed 36 OMIM genes. They both included LETM1 and WHSC1. The 2p25.3 microduplication was smaller than 666 kb and encompassed only one OMIM gene, ACP1. CONCLUSION: The combined use of MLPA and aCGH is an effective way to diagnose recurrent WHS. Although WHS is typically caused by a de novo deletion, prenatal diagnosis and genetic counseling are necessary in the next pregnancy in families that have suffered such cases. PMID- 26927260 TI - Successful ablation of acardiac twin with Histoacryl. AB - OBJECTIVE: Acardiac twin occurs in 1:35,000 pregnancies. Several techniques have been described to treat this condition. Some techniques have been suggested as golden standard; however, new are still being tried. CASE REPORT: This is a case of a 32-year-old patient who had successful ablation of the acardiac twin with Histoacryl. The diagnosis of the acardiac twin was made in the 11 weeks + 3 weeks of pregnancy. Due to the development of myocardial hypertrophy and pericardial transudate of the pumping fetus, we had performed ablation of the acardiac twin with Histoacryl in the 21 weeks' +5 weeks' gestation. The procedure was uneventful, and the healthy fetus had no signs of distress. In the 33 weeks' +5 weeks' gestation, she had Cesarean section due to distress of the healthy fetus. The female baby was healthy, weighing 2380 g, Apgar score 9/10. The mummified mass of acardiac fetus weighted 300 g. Nine months later, the child is doing well. CONCLUSION: Histoacryl is suitable for the ablation of an acardiac twin. Further studies are needed to prove the efficacy of this technique. PMID- 26927261 TI - Prenatal diagnosis of hemivertebrae--A likely association with 7q deletion. AB - OBJECTIVE: This study aims to investigate the possible cause of a prenatal case of hemivertebrae with a 7q terminal deletion. CASE REPORT: This case describes a fetus with hemivertebrae in thoracic vertebrae as the sole antenatal sonographic finding. Genetic testing was performed in order to find more information after the abnormal ultrasound finding. The array-based comparative genomic hybridization results showed that the fetus had approximately 6.4 Mb deletion of 7q36. We discussed the two genes (SHH and HLXB9) that may be associated with hemivertebrae in the deletion region and reviewed several literatures about 7q36 deletion. CONCLUSION: Our results suggest that the phenotype of hemivertebra in our case may be related to the deletion of 7q36. PMID- 26927262 TI - Prenatal diagnosis of 22q11.2 deletion syndrome associated with right aortic arch, left ductus arteriosus, cardiomegaly, and pericardial effusion. AB - OBJECTIVE: To report prenatal diagnosis of 22q11.2 deletion syndrome with right aortic arch (RAA), left ductus arteriosus, cardiomegaly, and pericardial effusion in the fetus. CASE REPORT: A 35-year-old woman, gravida 2, para 1, was referred to the hospital at 31 weeks of gestation because of abnormal ultrasound findings and whole-genome array comparative genomic hybridization report. G-banding chromosome analysis revealed a karyotype of 46,XX. Level II ultrasound at 22 weeks of gestation revealed RAA with the presence of the aortic arch on the right side of trachea at three vessels and trachea view, left ductus arteriosus, and mild right side pyelectasis. Cardiomegaly and pericardial effusion were also found 2 months later. Array comparative genomic hybridization detected a 2.743-Mb deletion at 22q11.2 region. Multiplex ligation-dependent amplification detected deletion in the DiGeorge syndrome critical region of chromosome 22 low copy number repeat 22-A-C. Metaphase fluorescence in situ hybridization on lymphocyte in cord blood confirmed deletion in 22q11.2 region. CONCLUSION: Chromosome abnormalities have been found in patients with RAA. Prenatal diagnosis of RAA with or without intracardiac or extracardiac anomalies should include a diagnosis of 22q11.2 deletion syndrome. PMID- 26927263 TI - Puerperal ileal perforation secondary to endometriosis: Case report and literature review. AB - OBJECTIVE: Bowel endometriosis is an uncommon disease that can cause serious complications and may require immediate medical attention. We wish to remind about bowel perforation caused by endometriosis, its diagnostic difficulty, and the need or urgent management in late pregnancy and puerperium. CASE REPORT: We present a 38-year-old woman, which presented with bowel perforation requiring urgent surgery. A pathological exam disclosed deep ileal infiltrative endometriosis. CONCLUSION: Even though bowel endometriosis is a rare complication, it should be considered in the differential diagnosis of severe abdominal pain in late pregnancy or puerperium. A multidisciplinary management of these patients is needed. PMID- 26927264 TI - Cardiac arrest during emergency cesarean section for severe pre-eclampsia and peripartum cardiomyopathy. AB - OBJECTIVE: To present the correlation between severe pre-eclampsia and peripartum cardiomyopathy in pregnancy. CASE REPORT: A 41-year-old parturient, gravida 3, para 1, at 34 4/7 weeks' gestation, was diagnosed with severe pre-eclampsia. At the time of admission, a plain chest film disclosed bilateral pleural effusions. An emergent cesarean section was planned because of decreased fetal movement, heavy daily protein loss, and bilateral pleural effusions. During the cesarean section, she developed shock with acute respiratory failure. She underwent advanced cardiac life support and intubation with mechanical ventilator support. Peripartum cardiomyopathy was subsequently diagnosed by echocardiography. CONCLUSION: The presented case demonstrates that routine echocardiography is highly recommended for suspected peripartum cardiomyopathy in gravidas with severe pre-eclampsia and symptoms or signs of heart failure. PMID- 26927265 TI - Malignant rhabdoid tumor of the vulva: A case report and review of the literature. PMID- 26927266 TI - Synchronous endometrial and gastric metastases of invasive lobular breast carcinomas. PMID- 26927267 TI - Bipolar cord coagulation for selective feticide in a monochorionic twin pregnancy complicated by pentalogy of Cantrell. PMID- 26927268 TI - Primary ovarian lymphoma and benign Brenner tumor. PMID- 26927269 TI - Acupressure only as pain relief for patient with multiple drug allergies undergoing oocyte retrieval. PMID- 26927270 TI - Heterotopic triplet pregnancy with bilateral tubal ectopic post-IVF-ICSI of two 12-cell embryos. PMID- 26927271 TI - A rare case of pure uterine giant lipoma. PMID- 26927272 TI - Electroacupuncture treats premenstrual syndrome based on neuroscience principles. PMID- 26927273 TI - Endometrial thickness still presents a best reference to predict endometrial cancer. PMID- 26927274 TI - Sonohysterography and liquid-based cytology in menopausal patients with abnormal endometrium. PMID- 26927275 TI - Surgery for endometrial cancer. PMID- 26927276 TI - Reply to "Surgery for endometrial cancer". PMID- 26927278 TI - Risk of Ventriculostomy-Associated Hemorrhage in Patients with Aneurysmal Subarachnoid Hemorrhage Treated with Anticoagulant Thromboprophylaxis. AB - BACKGROUND: Patients with subarachnoid hemorrhage (SAH) frequently need a ventriculostomy for treatment of hydrocephalus. In some ICU practices, a ventriculostomy is considered a relative contraindication for subcutaneous heparin. We studied the risk of ventriculostomy-associated hemorrhage and deep venous thrombosis (DVT) in patients with anticoagulant prophylaxis. METHODS: This is a retrospective study of 241 consecutive patients with SAH and ventriculostomies treated at Mayo Clinic, Rochester from 2001 to 2014. DVT and pulmonary emboli (PE) prevention included subcutaneous or intravenous heparin, enoxaparin, dalteparin, and warfarin. The incidence of PE and DVT were noted within 30 days of hospital admission. Hemorrhages were classified as minor or major based on size and mass effect. RESULTS: Fifty-three (22 %) of the 241 patients were on prophylactic doses of anticoagulation while in the intensive care unit. Three of 53 patients on prophylactic anticoagulation had minor hemorrhages and none had major hemorrhages. Four (7.5 %) of 53 patients who received prophylactic anticoagulation versus 34 (18 %) of 188 patients who did not receive prophylactic anticoagulation developed DVT (p = 0.09). One of 10 patients on therapeutic anticoagulation had a major and fatal hemorrhage. CONCLUSION: In our cohort, the risk of VTE was reduced by more than half in patients receiving chemoprophylaxis. Ventriculostomy-associated hemorrhages were rare and minor. Anticoagulant thromboprophylaxis is mostly safe and required in aneurysmal SAH. PMID- 26927277 TI - Changing Places and Partners: Associations of Neighborhood Conditions With Sexual Network Turnover Among African American Adults Relocated From Public Housing. AB - Neighborhood conditions and sexual network turnover have been associated with the acquisition of HIV and other sexually transmitted infections (STIs). However, few studies investigate the influence of neighborhood conditions on sexual network turnover. This longitudinal study used data collected across 7 visits from a predominantly substance-misusing cohort of 172 African American adults relocated from public housing in Atlanta, Georgia, to determine whether post-relocation changes in exposure to neighborhood conditions influence sexual network stability, the number of new partners joining sexual networks, and the number of partners leaving sexual networks over time. At each visit, participant and sexual network characteristics were captured via survey, and administrative data were analyzed to describe the census tracts where participants lived. Multilevel models were used to longitudinally assess the relationships of tract-level characteristics to sexual network dynamics over time. On average, participants relocated to neighborhoods that were less economically deprived and violent, and had lower alcohol outlet densities. Post-relocation reductions in exposure to alcohol outlet density were associated with fewer new partners joining sexual networks. Reduced perceived community violence was associated with more sexual partners leaving sexual networks. These associations were marginally significant. No post-relocation changes in place characteristics were significantly associated with overall sexual network stability. Neighborhood social context may influence sexual network turnover. To increase understanding of the social-ecological determinants of HIV/STIs, a new line of research should investigate the combined influence of neighborhood conditions and sexual network dynamics on HIV/STI transmission over time. PMID- 26927279 TI - Moderate Traumatic Brain Injury: The Grey Zone of Neurotrauma. AB - Moderate traumatic brain injury (MTBI) is poorly defined in the literature and the nomenclature "moderate" is misleading, because up to 15 % of such patients may die. MTBI is a heterogeneous entity that shares many aspects of its pathophysiology and management with severe traumatic brain injury. Many patients who ''talk and died'' are MTBI. The role of neuroimaging is essential for the proper management of these patients. To analyze all aspects of the pathophysiology and management of MTBI, proposing a new way to categorize it considering the clinical picture and neuroimaging findings. We proposed a different approach to the group of patients with Glasgow Coma Scale (GCS) ranging from 9 through 13 and we discuss the rationale for this proposal. Patients with lower GCS scores (9-10), especially those with significant space-occupying lesions on the CT scan, should be managed following the guidelines for severe traumatic brain injury, with ICU observation, frequent serial computed tomography (CT) scanning and ICP monitoring. On the other hand, those with higher range GCS (11-13) can be managed more conservatively with serial neurological examination and CT scans. Given the available evidence, MTBI is an entity that needs reclassification. Large-scale and well-designed studies are urgently needed. PMID- 26927280 TI - A Novel Cooling Device for Targeted Brain Temperature Control and Therapeutic Hypothermia: Feasibility Study in an Animal Model. AB - BACKGROUND: Therapeutic hypothermia (i.e., temperature management) is an effective option for improving survival and neurological outcome after cardiac arrest and is potentially useful for the care of the critically ill neurological patient. We analyzed the feasibility of a device to control the temperature of the brain by controlling the temperature of the blood flowing through the neck. METHODS: A lumped parameter dynamic model, with one-dimensional heat transfer, was used to predict cooling effects and to test experimental hypotheses. The cooling system consisted of a flexible collar and was tested on 4 adult sheep, in which brain and body temperatures were invasively monitored for the duration of the experiment. RESULTS: Model-based simulations predicted a lowering of the temperature of the brain and the body following the onset of cooling, with a rate of 0.4 degrees C/h for the brain and 0.2 degrees C/h for the body. The experimental findings showed comparable cooling rates in the two body compartments, with temperature reductions of 0.6 (0.2) degrees C/h for the brain and 0.6 (0.2) degrees C/h for the body. For a 70 kg adult human subject, we predict a temperature reduction of 0.64 degrees C/h for the brain and 0.43 degrees C/h for the body. CONCLUSIONS: This work demonstrates the feasibility of using a non-invasive method to induce brain hypothermia using a portable collar. This device demonstrated an optimal safety profile and represents a potentially useful method for the administration of mild hypothermia and temperature control (i.e., treatment of hyperpyrexia) in cardiac arrest and critically ill neurologic patients. PMID- 26927281 TI - Cosmetic tail docking: an overview of abuse and report of an interesting case. AB - BACKGROUND: This paper presents an overview of the global controversies surrounding cosmetic tail docking in puppies, some observed inconsistent practices among dog breeders and Veterinarians in West Africa, and the need for the African Veterinary Profession to take a decisive position on the cosmetic docking procedure. CASE PRESENTATION: An interesting report of observed complications associated with cosmetic tail docking in a 3 week old male Boerboel is reported alongside the management of the ensuing complications. CONCLUSION: This paper highlights the still prevalent practice of cosmetic tail docking and seeks to enlighten clinicians towards stemming its abuse in Africa. PMID- 26927282 TI - Erratum to: Effect of hole size on fluid dynamics of a posterior-chamber phakic intraocular lens with a central perforation by using computational fluid dynamics. PMID- 26927283 TI - Statin-induced expression change of INSIG1 in lymphoblastoid cell lines correlates with plasma triglyceride statin response in a sex-specific manner. AB - Statins are widely prescribed to lower plasma low-density lipoprotein (LDL) cholesterol levels. They also modestly reduce plasma triglyceride (TG), an independent cardiovascular disease risk factor, in most people. The mechanism and inter-individual variability of TG statin response is poorly understood. We measured statin-induced gene expression changes in lymphoblastoid cell lines derived from 150 participants of a simvastatin clinical trial and identified 23 genes (false discovery rate, FDR=15%) with expression changes correlated with plasma TG response. The correlation of insulin-induced gene 1 (INSIG1) expression changes with TG response (rho=0.32, q=0.11) was driven by men (interaction P=0.0055). rs73161338 was associated with INSIG1 expression changes (P=5.4 * 10 5) and TG response in two statin clinical trials (P=0.0048), predominantly in men. A combined model including INSIG1 expression level and splicing changes accounted for 29.5% of plasma TG statin response variance in men (P=5.6 * 10-6). Our results suggest that INSIG1 variation may contribute to statin-induced changes in plasma TG in a sex-specific manner. PMID- 26927284 TI - Glycolysis gene expression analysis and selective metabolic advantage in the clinical progression of colorectal cancer. AB - Production of lactate even in the presence of sufficient levels of oxygen (aerobic glycolysis) seems the prevalent energy metabolism pathway in cancer cells. The analysis of altered expression of effectors causing redirection of glucose metabolism would help to characterize this phenomenon with possible therapeutic implications. We analyzed mRNA expression of the key enzymes involved in aerobic glycolysis in normal mucosa (NM), primary tumor (PT) and liver metastasis (LM) of colorectal cancer (CRC) patients (pts) who underwent primary tumor surgery and liver metastasectomy. Tissues of 48 CRC pts were analyzed by RT qPCR for mRNA expression of the following genes: hexokinase-1 (HK-1) and 2 (HK 2), embryonic pyruvate kinase (PKM-2), lactate dehydrogenase-A (LDH-A), glucose transporter-1 (GLUT-1), voltage-dependent anion-selective channel protein-1 (VDAC 1). Differences in the expression of the candidate genes between tissues and associations with clinical/pathologic features were studied. GLUT-1, LDH-A, HK-1, PKM-2 and VDAC-1 mRNA expression levels were significantly higher in PT/LM tissues compared with NM. There was a trend for higher expression of these genes in LM compared with PT tissues, but differences were statistically significant for LDH-A expression only. RAS mutation-positive disease was associated with high GLUT-1 mRNA expression levels only. Right-sided colon tumors showed significantly higher GLUT-1, PKM-2 and LDH-A mRNA expression levels. High glycolytic profile was significantly associated with poor prognosis in 20 metastatic, RAS-mutated pts treated with first-line chemotherapy plus Bevacizumab. Altered expression of effectors associated with upregulated glucose uptake and aerobic glycolysis occurs in CRC tissues. Additional analyses are warranted for addressing the role of these changes in anti-angiogenic resistance and for developing novel therapeutics. PMID- 26927285 TI - A pharmacogenetic investigation of intravenous furosemide in decompensated heart failure: a meta-analysis of three clinical trials. AB - We conducted a meta-analysis of pharmacogenomic substudies of three randomized trials conducted in patients with decompensated heart failure (HF) that were led by National Heart Lung and Blood Institute (NHLBI)-funded HF Network to test the hypothesis that candidate genes modulate net fluid loss and weight change in patients with decompensated HF treated with a furosemide-based diuretic regimen. Although none of the genetic variants previously shown to modulate the effects of loop diuretics in healthy individuals were associated with net fluid loss after 72 h of treatment, a set of rare variants in the APOL1 gene, which codes for apolipoprotein L1 (P=0.0005 in the random effects model), was associated with this end point. Moreover, a common variant in the multidrug resistance protein-4 coding gene (ABCC4, rs17268282) was associated with weight loss with furosemide use (P=0.0001). Our results suggest that both common and rare genetic variants modulate the response to a furosemide-based diuretic regimen in patients with decompensated HF. PMID- 26927286 TI - Blood gene expression profiling of an early acetaminophen response. AB - Acetaminophen can adversely affect the liver especially when overdosed. We used whole blood as a surrogate to identify genes as potential early indicators of an acetaminophen-induced response. In a clinical study, healthy human subjects were dosed daily with 4 g of either acetaminophen or placebo pills for 7 days and evaluated over the course of 14 days. Alanine aminotransferase (ALT) levels for responders to acetaminophen increased between days 4 and 9 after dosing, and 12 genes were detected with expression profiles significantly altered within 24 h. The early responsive genes separated the subjects by class and dose period. In addition, the genes clustered patients who overdosed on acetaminophen apart from controls and also predicted the exposure classifications with 100% accuracy. The responsive genes serve as early indicators of an acetaminophen exposure, and their gene expression profiles can potentially be evaluated as molecular indicators for further consideration. PMID- 26927287 TI - Genetic prediction of long-term survival after neoadjuvant chemoradiation in locally advanced esophageal cancer. AB - Candidate genes involved in DNA repair, 5-fluorouracil metabolism and drug detoxification were genotyped in 124 patients receiving neoadjuvant chemoradiation treatment for locally advanced esophageal cancer and their predictive role for long-term relapse-free survival (RFS) and cancer-specific survival (CSS) were evaluated. A panel including MTHFR 677TT, MDR1 2677GT, GSTP1 114CC, XPC 499CC and XPC 939AC+CC, defined as high-risk genotypes, discriminated subgroups with significantly different outcomes. When the panel was combined with histology, patients split into two subsets with 5-year RFS and CSS rates of 65% vs 27% (hazard ratio (HR) 3.0, P<0.0001) and 69% vs 31% (HR 2.9, P<0.0001), respectively. Combining the 5-single-nucleotide polymorphism (5-SNP) panel with pathological response defined two major informative risk classes with 5-year PFS and CSS rates of 79.4% vs 17.7% (HR 6.71, P<0.0001) and 79.3% vs 26.3% (HR 6.25, P<0.0001), respectively. This classification achieved a sensitivity of 79%, a specificity of 85.4% and an accuracy of 81.8%. PMID- 26927289 TI - [Ernst von Leyden and the Institutionalization of Cancer Research Between 1896 and 1911]. PMID- 26927288 TI - Association of HLA-B*15:13 and HLA-B*15:02 with phenytoin-induced severe cutaneous adverse reactions in a Malay population. AB - Phenytoin (PHT) is a common cause of severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS). Although HLA B*15:02 is associated with PHT-induced SJS/TEN (PHT-SJS/TEN) in Han Chinese and Thais, the genetic basis for susceptibility to PHT-induced SCARs (PHT-SCAR) in other populations remains unclear. We performed a case-control association study by genotyping the human leukocyte antigen (HLA)-B alleles of 16 Malay PHT-SCAR patients (13 SJS/TEN and 3 DRESS), 32 PHT-tolerant controls and 300 healthy ethnicity-matched controls. A novel genetic biomarker, HLA-B*15:13, showed significant association with PHT-SJS/TEN (53.8%, 7/13 cases) (odds ratio (OR) 11.28, P=0.003) and PHT-DRESS (100%, 3/3 cases) (OR 59.00, P=0.003) when compared with PHT-tolerant controls (9.4%, 3/32 controls). We also confirmed HLA-B*15:02 association with PHT-SJS/TEN (61.5%, 8/13 cases vs 21.9%, 7/32 controls; OR 5.71, P=0.016) when compared with PHT-tolerant controls. These alleles may serve as markers to predict PHT-SCAR in Malays. PMID- 26927290 TI - The electronic, structural and magnetic properties of La(1-1/3)Sr(1/3)MnO3 film with oxygen vacancy: a first principles investigation. AB - We have systematically investigated the influence of oxygen vacancy defects on the structural, electronic and magnetic properties of La(1-x)Sr(x)MnO3 (x = 1/3) film by means of ab initio calculations using bare GGA as well as GGA+U formalism, in the latter of which, the on-site Coulombic repulsion parameter U for Mn 3d orbital has been determined by the linear response theory. It is revealed that the introduction of the vacancy defects causes prominent structural changes including the distortion of MnO6 octahedra and local structural deformation surrounding the oxygen vacancy. The GGA+U formalism yields a significantly larger structural change than the bare GGA method, surprisingly in contrast with the general notion that the inclusion of Hubbard U parameter exerts little influence on structural properties. The distortion of MnO6 octahedra leads to a corresponding variation in the hybridization between Mn 3d and O 2p, which gets strengthened if the Mn-O distance becomes smaller and vice versa. The magnetic moments of the Mn atoms located in three typical sites of the vacancy containing supercell are all larger than those in the pristine system. We have characterized the O-vacancy defect as a hole-type defect that forms a negative charge center, attracting electrons. PMID- 26927291 TI - Timing of predisposing factors is important in necrotic enteritis models. AB - Since the ban of antimicrobial growth promotors, the importance of necrotic enteritis in broilers increases. Reliable and reproducible infection models are required for pathogenesis studies and product screening. Two major predisposing factors in necrotic enteritis models are fishmeal supplementation to feed and Eimeria infection. However, many unsolved issues regarding these predisposing factors still exist. Therefore, the influence of timepoint of fishmeal administration (onset on day 8 or day 18), timing of coccidiosis challenge (day 15 or day 19) and strain of coccidiosis challenge (field strain vs. commercial vaccine) on the induction of necrotic enteritis lesions was investigated. The birds were inoculated with Clostridium perfringens three times per day for four consecutive days (day 17 until day 20) and were scored for the presence of necrotic enteritis on days 22, 23, 24, 25 and 26. Supplementation of the diet with fishmeal from day 8 onwards increased the likelihood of necrotic enteritis compared to supplementation from day 18 onwards. Birds challenged on day 19 with coccidiosis were more likely to have necrotic enteritis on scoring days 23 and 24 compared to birds challenged on day 15. Differences on other scoring days were less pronounced. Finally, the strain of coccidiosis challenge had little influence on the induction of necrotic enteritis. Findings of this study can help researchers to set up successful necrotic enteritis infection models. PMID- 26927292 TI - Spinal cord injury resulting from gunshot wounds: a comparative study with non gunshot causes. AB - STUDY DESIGN: Retrospective, comparative 7-year study. OBJECTIVES: To identify the clinical characteristics of patients with spinal cord injury (SCI) resulting from gunshot wound (GSW). SETTING: Turkish Armed Forces Rehabilitation Center, Ankara, Turkey. METHODS: The study included 1043 consecutive patients with SCI who were divided into two groups according to etiology: patients with gunshot induced spinal cord injury (GSWSCI) constituted the study group, and randomly selected patients with non-gunshot-induced spinal cord injury (NGSWSCI) who were matched for gender and for week of admission constituted the control group. The demographic and clinical characteristics of the patients were recorded, compared and analyzed. RESULTS: The study group included 102 patients (mean age: 26.93+/ 9.11 years). The vast majority of the patients were aged 16-30 years (68.6%) and 90.2% were male. The majority of the lesions were at the thoracic level (58.8%) and a complete injury (60.8%). Surgical stabilization of the spine was performed in 50 patients (49%). The most prevalent associated injury was intra-abdominal injury followed by chest injury. Compared with the NGSWSCI group, the GSWSCI patients were more likely to have a complete lesion (60.8% vs 45.1%, P=0.025), had a lower rate of surgical stabilization (49 vs 88.2%, P=0.0001) and had a higher rate of associated injuries (54.9% vs 25.5%, P=0.0001). Compared with the civilian GSWSCI group, the military GSWSCI patients had a higher rate of surgical stabilization and associated injuries (60% vs 40%, P=0.049, 68.9% vs 43.9%, P=0.012, respectively). CONCLUSION: The results revealed that GSWSCI and military GSWSCI patients may have different demographic and clinical features compared with NGSWSCI and civilian GSWSCI patients, respectively. PMID- 26927294 TI - The influence of regular physical activity on lung function in paraplegic people. AB - STUDY DESIGN: Cross-sectional study. OBJECTIVES: The main goal of this study was to examine the influence of regular physical activity (PA) on lung volumes and flows. SETTING: The study was conducted in the Vall d'Hebron Hospital, Barcelona (Spain), and La Fe Hospital, Valencia (Spain). METHODS: Spirometric tests were performed to 67 paraplegics, and differences were established between the active group (AG) (n=37) that performed >60 min per week of moderate-to-vigorous PA (MVPA) and 30 non-AG (NAG). Further, we established the relationship between the spirometric and PA variables and between being active and reaching the lower limit of normal (LLN) of the spirometric variables. RESULTS: AG had greater values than the NAG: FVC (P<0.01), FEV1 (P<0.01) and PEF (P<0.01). Moderate correlations between the MVPA and FVC (r=0.41, P<0.01) and the MVPA and FEV1 (r=0.39, P<0.01) were obtained. The relationship between being physically active and reaching the LLN was statistically significant for FEV1 (chi2=6.184, P<0.05) but not for FVC (P>0.05). CONCLUSIONS: The performance of MVPA for a minimum of 60 min per week can have a beneficial effect, both on lung volumes and on expiratory flow, and led to an achievement of the LLN in FEV1. PMID- 26927293 TI - Evaluation of the effects of specific opioid receptor agonists in a rodent model of spinal cord injury. AB - OBJECTIVE: The current study aimed to evaluate the contribution(s) of specific opioid receptor systems to the analgesic and detrimental effects of morphine, observed after spinal cord injury in prior studies. STUDY DESIGN: We used specific opioid receptor agonists to assess the effects of MU- (DAMGO), delta- (DPDPE) and kappa- (GR89696) opioid receptor activation on locomotor (Basso, Beattie and Bresnahan scale, tapered beam and ladder tests) and sensory (girdle, tactile and tail-flick tests) recovery in a rodent contusion model (T12). We also tested the contribution of non-classic opioid binding using [+]- morphine. METHODS: First, a dose-response curve for analgesic efficacy was generated for each opioid agonist. Baseline locomotor and sensory reactivity was assessed 24 h after injury. Subjects were then treated with an intrathecal dose of a specific agonist and re-tested after 30 min. To evaluate the effects on recovery, subjects were treated with a single dose of an agonist and both locomotor and sensory function were monitored for 21 days. RESULTS: All agonists for the classic opioid receptors, but not the [+]- morphine enantiomer, produced antinociception at a concentration equivalent to a dose of morphine previously shown to produce strong analgesic effects (0.32 MUmol). DAMGO and [+]- morphine did not affect long-term recovery. GR89696, however, significantly undermined the recovery of locomotor function at all doses tested. CONCLUSIONS: On the basis of these data, we hypothesize that the analgesic efficacy of morphine is primarily mediated by binding to the classic MU-opioid receptor. Conversely, the adverse effects of morphine may be linked to activation of the kappa-opioid receptor. Ultimately, elucidating the molecular mechanisms underlying the effects of morphine is imperative to develop safe and effective pharmacological interventions in a clinical setting. SETTING: USA. SPONSORSHIP: Grant DA31197 to MA Hook and the NIDA Drug Supply Program. PMID- 26927296 TI - Improvement in weight loss and ambulation outcomes after gastric sleeve surgery for a person with chronic motor-incomplete tetraplegia: clinical case report. AB - OBJECTIVE: To measure body mass index (BMI) and ambulation changes for a morbidly obese, 47-year-old man with chronic motor-incomplete tetraplegia after gastric sleeve surgery. DESIGN/METHOD: A morbidly obese man, BMI=44 kg m(-)(2), with chronic C5 AIS D tetraplegia underwent elective gastric sleeve surgery. Assessment of BMI and function via the 6-minute walk test (6MWT), 10-meter walk test (10MWT) and ambulation parameters (CIR Systems/GAITRite, Franklin, NJ, USA) was performed preoperatively and at 12, 24, 36 and 52 weeks postoperatively, and additionally after 3 weeks of both a prescribed coached (3 * /week facility based) and a non-coached (3 * /week home based) walking program initiated at 52 weeks. A step activity monitor assessed daily ambulation preoperatively, prior to and during the third and sixth week of the walking program. RESULTS: Results included a 34.3% peak BMI decrease at 52 weeks post surgery and a peak increase in 6MWT distance of 58% at 52 weeks post surgery, 10MWT preferred speed of 56% at 55 weeks and step activity monitor of 82% at 58 weeks post surgery. At 58 weeks, gait data demonstrated a decrease in double limb stance of 38% and decrease in base of support of 72%. CONCLUSION/CLINICAL RELEVANCE: This empirical case assessment of BMI and functional mobility before and after gastric sleeve surgery may encourage further investigation into mobility and general health effects post gastric procedures for people with chronic motor-incomplete spinal cord injury. PMID- 26927295 TI - Neurological and functional recovery in acute transverse myelitis patients with inpatient rehabilitation and magnetic resonance imaging correlates. AB - OBJECTIVE: The objective of this study was to observe neurological and functional recovery in patients with acute transverse myelitis (ATM) with inpatient rehabilitation and correlate with magnetic resonance imaging (MRI) changes. PATIENTS AND METHODS: The study was conducted with 43 ATM patients (19 males) admitted in the tertiary university research hospital from July 2012 to June 2014. Detailed MRI findings were noted. Neurological status was assessed using the ASIA impairment scale (AIS) and functional recovery was assessed using the Barthel Index score (BI) and Spinal Cord Independence Measure (SCIM). RESULTS: Patients showed significant neurological and functional recovery with inpatient rehabilitation using AIS, BI and SCIM scales when admission and discharge scores were compared (P<0.001). Thirty-one patients (72.1%) had rostral level in the cervical region according to MR imaging, but clinically, 17 patients had tetraplegia, whereas 26 patients had lower-limb weakness only. No definitive pattern or correlation was found between level (MRI or clinical) and neurological status (AIS). CONCLUSION: The neurological outcome in patients with ATM cannot be predicted on the basis of imaging findings. There is a great variation in the imaging level and clinical presentation. Patients show significant improvement with inpatient rehabilitation even with poor functional ability in acute and sub acute phase of illness. PMID- 26927297 TI - A prospective study of pain and psychological functioning following traumatic spinal cord injury. AB - STUDY DESIGN: Longitudinal study. OBJECTIVES: To study prospectively pain characteristics, change in pain over time and the associations between pain and psychological functioning in adults with traumatic spinal cord injury (SCI). SETTING: Neurosurgical departments, SCI rehabilitation centres and the community. METHODS: Adults with traumatic SCI admitted over a 3-year period to two neurosurgical departments underwent clinical examination and questionnaires within 3 months after injury (baseline) and at 6, 12 and 42 months following SCI. Pain intensity and interference within the last 7 days, a global quality of life (QoL) item, the 5-item Mental Health Index and the 6-item Catastrophizing scale were used. RESULTS: Ninety individuals were recruited, of which 81 completed a telephone interview on average 3.5 (s.d., 0.6) years after the SCI. Pain was present in 75% at 3.5 years. Baseline pain catastrophizing scores did not predict pain intensity at 3.5 years. Both psychological functioning and QoL increased over time. QoL scores increased less in participants who reported an increase in pain intensity from baseline to the 3.5-year follow-up, and the change in QoL score correlated with the change in pain interference. Neuropathic pain had an onset within the first 12 months and tended to become persistent, whereas musculoskeletal pain more often had a late onset or resolved in cases of early onset. CONCLUSIONS: A large proportion of SCI participants continue to experience pain many years after SCI. Teaching individuals with SCI skills to minimise pain's impact on function as soon as possible following injury may prove beneficial. PMID- 26927299 TI - The FIB-4 score predicts postoperative short-term outcomes of hepatocellular carcinoma fulfilling the milan criteria. AB - BACKGROUND: The fibrosis score 4 (FIB-4) score is a useful tool to determine the degree of hepatic fibrosis. Liver fibrosis and cirrhosis are well-known predictors of postoperative complications after hepatectomy. This study examined the impact of FIB-4 on postoperative short-term outcomes of patients with hepatocellular carcinoma (HCC). METHODS: Three hundred and fifty patients undergoing hepatectomy for HCC between 2008 and 2013 were enrolled. The receiver operating characteristic (ROC) curve analysis was performed to determine the cutoff value of the FIB-4. Univariate and multivariate analysis was performed to identify the risk factors. The correlation of the preoperative FIB-4 value with clinicopathological parameters was examined. RESULTS: Postoperative complications were observed in 202 (57.7%) patients. The optimal cutoff value of the FIB-4 was set at 2.88 and 3.85 for postoperative complications and intraoperative blood loss respectively. It was also an independent prognostic factor for postoperative complications (hazard ratio [HR], 1.202; 95% CI, 1.076-1.344; P = 0.001) and intraoperative blood loss (HR, 1.196; 95% CI, 1.091-1.343; P < 0.001) by multivariate analysis. The FIB-4 was significantly correlated with age, liver function, coagulation function, blood loss, intraoperative blood transfusion (all P < 0.05). CONCLUSION: Preoperative FIB-4 is a useful index to predict postoperative outcomes in patients with HCC. The FIB-4 should be assessed routinely for hepatocellular carcinoma patients. PMID- 26927298 TI - Impact of routine coronary catheterization in low extremity artery disease undergoing percutaneous transluminal angioplasty: study protocol for a multi center randomized controlled trial. AB - BACKGROUND: The prevalence of significant obstructive coronary artery disease with complex lesions is high in patients who have low extremity artery disease (LEAD). However, intermediate- or long-term cardiovascular prognosis of LEAD patients undergoing percutaneous transluminal angioplasty (PTA) remains poor. Accordingly, prophylactic coronary revascularization may modify short- and long term cardiovascular outcomes of LEAD patients receiving PTA. Because myocardial ischemic symptoms are often masked in LEAD and the accuracy of non-invasive stress tests is usually limited, a high-quality randomized controlled trial aimed at the investigation of the prognostic role of coronary evaluation strategies before PTA is warranted. METHODS/DESIGN: The proposed study is designed as a prospective, multi-center, open-label, superiority, randomized controlled trial. The study is conducted in high-volume centers for PTA and coronary revascularization in Taiwan. To meet the inclusion criteria, the patients must be at least 20 years old, have known LEAD, and have been admitted for elective PTA. We plan to enroll 450 participants who are randomly allocated to a routine group (routine coronary angiography without a previous non-invasive stress test before PTA) and a selective group (selective coronary angiography based on the results of non-invasive stress tests before PTA) with 1:1 ratio. Besides, we expect to enroll about 250 additional participants, who are not willing to be randomly assigned, in the registration group. The choice of revascularization procedure depends on the operator's or cardiovascular team's suggestion and the patient's decision. Clinical follow-up will be performed 30 days after PTA and every 6 months until the end of the 1-year follow-up for the last randomly assigned participant. The primary endpoint is the composite major adverse cardiac event on long-term follow-up. Pre-specified secondary and other endpoints are also evaluated. Those assessing biomarkers and clinical endpoints are all blinded after assignment to interventions. DISCUSSION: The results of the trial will, for the first time, support better decision-making for coronary evaluation before PTA in LEAD. If favorable, routine coronary angiography followed by revascularization will improve cardiovascular outcomes in LEAD patients undergoing PTA. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02169258 (registered on 21 June 2014); registry name: Routine Coronary Catheterization in Low Extremity Artery Disease Undergoing Percutaneous Transluminal Angioplasty (PIROUETTE-PTA). PMID- 26927301 TI - Zika cases climb to 147 in US and Puerto Rico. PMID- 26927300 TI - Patterns and prognostic significance of clinical recurrences after radical cystectomy for bladder cancer: A 20-year single center experience. AB - OBJECTIVE: Patients treated with radical cystectomy (RC) due to bladder cancer (BCa) face high risk of clinical recurrence. The aim of our study was to describe recurrence patterns and characteristics related to survival in patients treated with RC due to BCa. METHODS: Years 1992-2012 of a prospectively maintained institutional RC registry were queried for clinical localized urothelial BCa patients. Clinical recurrences were categorized as local, distant or secondary urothelial recurrences. Kaplan Meier analysis assessed time to cancer specific mortality (CSM). Multivariable Cox regression models were constructed to predict recurrence and CSM after recurrence. RESULTS: Data from 1110 patients with urothelial non-metastatic BCa at RC were analyzed with 7.5 years of median follow up. Overall, 324 patients experienced recurrence and 200 (61.7%) were single site recurrence. The locations were: 43 local (22 cystectomy bed and 21 pelvic lymph node dissection template), 138 distant (36 lung, 19 liver, 52 bone, 17 extra pelvic LN, 7 peritoneal, 4 brain and 3 others) and 19 secondary urothelial carcinoma (11 upper urinary tract, 8 urethra). Significant independent predictors of overall recurrence were pathological stage pT3/T4 vs. pT0-2, pathological N positive status and positive surgical margin. Median overall survival after recurrence was 18 months. At multivariate analysis, pathological T3 (Hazard ratio [HR]: 1.62), T4 (HR: 1.58), interval from RC to recurrence (HR: 0.92) and distant (HR: 2.57) recurrences were independently associated with CSM (all p < 0.05). CONCLUSIONS: Overall, one out of three patients treated with RC face recurrence during follow up. Early and distant recurrences are associated with shortest survival expectancies. PMID- 26927302 TI - Opioid and Benzodiazepine Withdrawal Syndrome in PICU Patients: Which Risk Factors Matter? AB - BACKGROUND AND AIMS: Although iatrogenic withdrawal syndrome (IWS) has been recognized in patients exposed to opioids and benzodiazepines, very few studies have used a validated tool for diagnosis and assessment of IWS in critically ill children. We sought to determine IWS rate, risk factors, and outcomes of IWS patients. METHODS: Prospective observational study conducted in a pediatric intensive care unit. A total of 137 patients (31 with IWS and 106 with no IWS) received a continuous infusion of fentanyl and midazolam for 3 or more days. The Sophia Observation withdrawal Symptoms scale was repeatedly applied when children were weaned off sedation/analgesia. RESULTS: The overall incidence of IWS was 22.6%. Of the 31 IWS patients, 6 showed IWS with less than 5 days sedation or analgesia. Logistic regression showed that the median peak dose of midazolam was associated with IWS development (odds ratio 1.4). Receiver-operating curve showed a cut-off value of 0.35 mg/kg/h for midazolam peak dose (sensitivity 96.7%, specificity 51%, positive predictive value 36.6%, and negative predictive value 98.2%), with area under the curve of 0.80. IWS patients had a longer time on mechanical ventilation, prolonged pediatric intensive care unit, and hospital stays, and required prolonged period to have drugs discontinued. CONCLUSIONS: Although length of sedation/analgesia for at least5 days has been widely proposed for monitoring IWS, our data suggest that initiating monitoring after 3 sedation days is highly recommended. In addition, patients requiring infusion rates of midazolam above 0.35 mg/kg/h should be considered at high risk for IWS. PMID- 26927304 TI - Inactivation of nucleus incertus impairs passive avoidance learning and long term potentiation of the population spike in the perforant path-dentate gyrus evoked field potentials in rats. AB - Involvement of brainstem nucleus incertus (NI) in hippocampal theta rhythm suggests that this structure might play a role in hippocampal-dependent learning and memory. In the present study we aimed to address if NI is involved in an avoidance learning task as well as dentate gyrus (DG) short-term and long-term potentiation. Lidocaine was injected into the NI to transiently inactivate the nucleus, and control rats received saline. Role of NI was studied in passive avoidance learning (PAL) in 3 memory phases of acquisition, consolidation and retrieval. Levels of hippocampal phosphorylated p70 were also assessed in rats involved in PAL. Perforant path-DG short-term synaptic plasticity was studied upon NI inactivation before the paired-pulse stimulation, and also before or after tetanic stimulation in freely moving rats. It was found that NI inactivation delayed learning and impaired retention in the PAL task, with decreased levels of phosphorylated p70 in the respective groups. However, short term plasticity was not affected by NI inactivation. But long term potentiation (LTP) of DG population spike was poorly induced with NI inactivation compared to the saline group, and it had no effect on population excitatory post-synaptic potential. Furthermore, when NI was inactivated after the induction of LTP, there was no difference between the saline and lidocaine groups. These observations suggest that NI has a role in PAL task, and its inactivation does not change the perforant path-DG granule cell synaptic input but decreases the excitability of the DG granule cells. Further studies should elucidate direct and indirect paths through which NI might influence hippocampal activity. PMID- 26927303 TI - Interrogating Surface Functional Group Heterogeneity of Activated Thermoplastics Using Super-Resolution Fluorescence Microscopy. AB - We present a novel approach for characterizing surfaces utilizing super resolution fluorescence microscopy with subdiffraction limit spatial resolution. Thermoplastic surfaces were activated by UV/O3 or O2 plasma treatment under various conditions to generate pendant surface-confined carboxylic acids (-COOH). These surface functional groups were then labeled with a photoswitchable dye and interrogated using single-molecule, localization-based, super-resolution fluorescence microscopy to elucidate the surface heterogeneity of these functional groups across the activated surface. Data indicated nonuniform distributions of these functional groups for both COC and PMMA thermoplastics with the degree of heterogeneity being dose dependent. In addition, COC demonstrated relative higher surface density of functional groups compared to PMMA for both UV/O3 and O2 plasma treatment. The spatial distribution of -COOH groups secured from super-resolution imaging were used to simulate nonuniform patterns of electroosmotic flow in thermoplastic nanochannels. Simulations were compared to single-particle tracking of fluorescent nanoparticles within thermoplastic nanoslits to demonstrate the effects of surface functional group heterogeneity on the electrokinetic transport process. PMID- 26927305 TI - Short-term and long-term plasticity in the visual-attention system: Evidence from habituation of attentional capture. AB - Attention is known to be crucial for learning and to regulate activity-dependent brain plasticity. Here we report the opposite scenario, with plasticity affecting the onset-driven automatic deployment of spatial attention. Specifically, we showed that attentional capture is subject to habituation, a fundamental form of plasticity consisting in a response decrement to repeated stimulations. Participants performed a visual discrimination task with focused attention, while being occasionally exposed to a distractor consisting of a high-luminance peripheral onset. With practice, short-term and long-term habituation of attentional capture emerged, making the visual-attention system fully immune to distraction. Furthermore, spontaneous recovery of attentional capture was found when the distractor was temporarily removed. Capture, however, once habituated was surprisingly resistant to spontaneous recovery, taking from several minutes to days to recover. The results suggest that the mechanisms subserving exogenous attentional orienting are subject to profound and enduring plastic changes based on previous experience, and that habituation can impact high-order cognitive functions. PMID- 26927307 TI - Medical End-of-Life Practices in Switzerland: A Comparison of 2001 and 2013. PMID- 26927306 TI - Diagnosis of Bacterial Bloodstream Infections: A 16S Metagenomics Approach. AB - BACKGROUND: Bacterial bloodstream infection (bBSI) is one of the leading causes of death in critically ill patients and accurate diagnosis is therefore crucial. We here report a 16S metagenomics approach for diagnosing and understanding bBSI. METHODOLOGY/PRINCIPAL FINDINGS: The proof-of-concept was delivered in 75 children (median age 15 months) with severe febrile illness in Burkina Faso. Standard blood culture and malaria testing were conducted at the time of hospital admission. 16S metagenomics testing was done retrospectively and in duplicate on the blood of all patients. Total DNA was extracted from the blood and the V3-V4 regions of the bacterial 16S rRNA genes were amplified by PCR and deep sequenced on an Illumina MiSeq sequencer. Paired reads were curated, taxonomically labeled, and filtered. Blood culture diagnosed bBSI in 12 patients, but this number increased to 22 patients when combining blood culture and 16S metagenomics results. In addition to superior sensitivity compared to standard blood culture, 16S metagenomics revealed important novel insights into the nature of bBSI. Patients with acute malaria or recovering from malaria had a 7-fold higher risk of presenting polymicrobial bloodstream infections compared to patients with no recent malaria diagnosis (p-value = 0.046). Malaria is known to affect epithelial gut function and may thus facilitate bacterial translocation from the intestinal lumen to the blood. Importantly, patients with such polymicrobial blood infections showed a 9-fold higher risk factor for not surviving their febrile illness (p-value = 0.030). CONCLUSIONS/SIGNIFICANCE: Our data demonstrate that 16S metagenomics is a powerful approach for the diagnosis and understanding of bBSI. This proof-of-concept study also showed that appropriate control samples are crucial to detect background signals due to environmental contamination. PMID- 26927308 TI - The effect of replacing lactose by starch on protein and fat digestion in milk fed veal calves. AB - Replacing dairy components from milk replacer (MR) with vegetable products has been previously associated with decreased protein and fat digestibility in milk fed calves resulting in lower live weight gain. In this experiment, the major carbohydrate source in MR, lactose, was partly replaced with gelatinized corn starch (GCS) to determine the effect on protein and fat digestibility in milk-fed calves. In total, 16 male Holstein-Friesian calves received either MR with lactose as the carbohydrate source (control) or 18% GCS at the expense of lactose. In the adaptation period, calves were exposed to an increasing dose of GCS for 14 weeks. The indigestible marker cobalt ethylenediaminetetraacetic acid was incorporated into the MR for calculating apparent nutrient digestibility, whereas a pulse dose of chromium (Cr) chloride was fed with the last MR meal 4 h before slaughter as an indicator of passage rates. The calves were anesthetized and exsanguinated at 30 weeks of age. The small intestine was divided in three; small intestine 1 and 2 (SI1 and SI2, respectively) and the terminal ileum (last ~100 cm of small intestine) and samples of digesta were collected. Small intestinal digesta was analysed for alpha-amylase, lipase and trypsin activity. Digestibility of protein was determined for SI1, SI2, ileum and total tract, whereas digestibility of fat was determined for SI1, SI2 and total tract. Apparent protein digestibility in the small intestine did not differ between treatments but was higher in control calves at total tract level. Apparent crude fat digestibility tended to be increased in SI1 and SI2 for GCS calves, but no difference was found at total tract level. Activity of alpha-amylase in SI2 and lipase in both SI1 and SI2 was higher in GCS calves. Activity of trypsin tended to be higher in control calves and was higher in SI1 compared with SI2. A lower recovery of Cr in SI2 and a higher recovery of Cr in the large intestine suggest an increased rate of passage for GCS calves. Including 18% of GCS in a milk replacer at the expense of lactose increased passage rate and decreased apparent total tract protein digestibility. In the small intestine, protein digestion did not decrease when feeding GCS and fat digestion even tended to increase. Overall, effects on digestion might be levelled when partially replacing lactose with GCS, because starch digestion is lower than that of lactose but fat digestion may be slightly increased when feeding GCS. PMID- 26927310 TI - Scoliosis in osteogenesis imperfecta caused by COL1A1/COL1A2 mutations - genotype phenotype correlations and effect of bisphosphonate treatment. AB - Bisphosphonates are widely used to treat children with osteogenesis imperfecta (OI), a bone fragility disorder that is most often caused by mutations in COL1A1 or COL1A2. However, it is unclear whether this treatment decreases the risk of developing scoliosis. We retrospectively evaluated spine radiographs and charts of 437 patients (227 female) with OI caused by mutations in COL1A1 or COL1A2 and compared the relationship between scoliosis, genotype and bisphosphonate treatment history. At the last follow-up (mean age 11.9 [SD: 5.9] years), 242 (55%) patients had scoliosis. The prevalence of scoliosis was highest in OI type III (89%), followed by OI type IV (61%) and OI type I (36%). Moderate to severe scoliosis (Cobb angle >=25 degrees ) was rare in individuals with COL1A1 haploinsufficiency mutations but was present in about two fifth of patients with triple helical glycine substitutions or C-propeptide mutations. During the first 2 to 4years of bisphosphonate therapy, patients with OI type III had lower Cobb angle progression rates than before bisphosphonate treatment, whereas in OI types I and IV bisphosphonate treatment was not associated with a change in Cobb angle progression rates. At skeletal maturity, the prevalence of scoliosis (Cobb angle >10 degrees ) was similar in patients who had started bisphosphonate treatment early in life (before 5.0years of age) and in patients who had started therapy later (after the age of 10.0years) or had never received bisphosphonate therapy. Bisphosphonate treatment decreased progression rate of scoliosis in OI type III but there was no evidence of a positive effect on scoliosis in OI types I and IV. The prevalence of scoliosis at maturity was not influenced by the bisphosphonate treatment history in any OI type. PMID- 26927309 TI - Overexpression of plum auxin receptor PslTIR1 in tomato alters plant growth, fruit development and fruit shelf-life characteristics. AB - BACKGROUND: TIR1-like proteins are F-box auxin receptors. Auxin binding to the F box receptor proteins promotes the formation of SCF(TIR1) ubiquitin ligase complex that targets the auxin repressors, Aux/IAAs, for degradation via the ubiquitin/26S proteasome pathway. The release of auxin response factors (ARFs) from their Aux/IAA partners allows ARFs to mediate auxin-responsive changes in downstream gene transcription. In an attempt to understand the potential role of auxin during fruit development, a plum auxin receptor, PslTIR1, has previously been characterized at the cellular, biochemical and molecular levels, but the biological significance of this protein is still lacking. In the present study, tomato (Solanum lycopersicum) was used as a model to investigate the phenotypic and molecular changes associated with the overexpression of PslTIR1. RESULTS: The findings of the present study highlighted the critical role of PslTIR1 as positive regulator of auxin-signalling in coordinating the development of leaves and fruits. This was manifested by the entire leaf morphology of transgenic tomato plants compared to the wild-type compound leaf patterning. Moreover, transgenic plants produced parthenocarpic fruits, a characteristic property of auxin hypersensitivity. The autocatalytic ethylene production associated with the ripening of climacteric fruits was not significantly altered in transgenic tomato fruits. Nevertheless, the fruit shelf-life characteristics were affected by transgene presence, mainly through enhancing fruit softening rate. The short shelf-life of transgenic tomatoes was associated with dramatic upregulation of several genes encoding proteins involved in cell-wall degradation, which determine fruit softening and subsequent fruit shelf-life. CONCLUSIONS: The present study sheds light into the involvement of PslTIR1 in regulating leaf morphology, fruit development and fruit softening-associated ripening, but not autocatalytic ethylene production. The results demonstrate that auxin accelerates fruit softening independently of ethylene action and this is probably mediated through the upregulation of many cell-wall metabolism genes. PMID- 26927311 TI - Assessing the ligand selectivity of sphingosine kinases using molecular dynamics and MM-PBSA binding free energy calculations. AB - The dynamic balance of sphingolipids plays a crucial role in diverse biological processes such as mitogenesis, cell migration and angiogenesis. Sphingosine kinases (SKs) including SK1 and SK2 phosphorylate sphingosine to sphingosine 1 phosphate (S1P), and control the critical balance. SK1 overexpression was reported to increase cell survival and proliferation. Although several SK1 selective inhibitors have been reported, detailed analysis toward their selectivity to understand the molecular mechanism has not been performed to our knowledge. Herein, the crystal structure of SK1 and a homology model of SK2 were used to dock five inhibitors (1, 2, 3, 4 and 5). Protein-ligand complexes were then subjected to a molecular dynamics study and MM-PBSA binding free energy calculations. By analyzing the binding model of these inhibitors, we found that residues ILE170, PHE188 and THR192 in SK1 significantly contribute a favorable binding energy to the selectivity. PMID- 26927312 TI - Prognostic value of Diabetes in Patients with Nasopharyngeal Carcinoma Treated with Intensity-Modulated Radiation Therapy. AB - The prognostic value of diabetes remains unknown in nasopharyngeal carcinoma (NPC) treated with intensity-modulated radiation therapy (IMRT). We retrospectively reviewed medical records of 1489 patients with non-metastatic, histologically-proven NPC treated using IMRT. 81/1489 (5.4%) patients were diabetic, 168/1489 (11.3%) were prediabetic, and 1240/1489 (83.3%) were normoglycemic. The 4-year disease-free survival (DFS), overall survival (OS), loco-regional relapse-free survival (LRRFS) and distant metastasis-free survival (DMFS) rates were 77.1% vs. 82.4% (P = 0.358), 85.8% vs. 91.0% (P = 0.123), 90.9% vs. 91.7% (P = 0.884), and 85.5% vs. 89.2% (P = 0.445) for diabetic vs. normoglycemic patients, and 82.4% vs. 82.4% (P = 0.993), 88.7% vs. 91.0% (P = 0.285), 90.6% vs. 91.7% (P = 0.832) and 91.5% vs. 89.2% (P = 0.594) for preidabetic vs. normoglycemic patients. Multivariate analysis did not established diabetes as poor prognostic factors in NPC patients treated with IMRT (P = 0.332 for DFS, P = 0.944 for OS, P = 0.977 for LRRFS, P = 0.157 for DMFS), however, triglycerides and low density lipoprotein cholesterol were independent prognostic factors. In conclusion, diabetes does not appear to be a prognostic factor in NPC patients treated with IMRT, and attention should be paid to hyperglycemia associated hyperlipaemia. PMID- 26927313 TI - Observation of a three-dimensional quasi-long-range electronic supermodulation in YBa2Cu3O(7-x)/La0.7Ca0.3MnO3 heterostructures. AB - Recent developments in high-temperature superconductivity highlight a generic tendency of the cuprates to develop competing electronic (charge) supermodulations. While coupled with the lattice and showing different characteristics in different materials, these supermodulations themselves are generally conceived to be quasi-two-dimensional, residing mainly in individual CuO2 planes, and poorly correlated along the c axis. Here we observed with resonant elastic X-ray scattering a distinct type of electronic supermodulation in YBa2Cu3O(7-x) (YBCO) thin films grown epitaxially on La0.7Ca0.3MnO3 (LCMO). This supermodulation has a periodicity nearly commensurate with four lattice constants in-plane, eight out of plane, with long correlation lengths in three dimensions. It sets in far above the superconducting transition temperature and competes with superconductivity below this temperature for electronic states predominantly in the CuO2 plane. Our finding sheds light on the nature of charge ordering in cuprates as well as a reported long-range proximity effect between superconductivity and ferromagnetism in YBCO/LCMO heterostructures. PMID- 26927314 TI - Male Sexual Development and the Androgenic Gland: Novel Insights through the de novo Assembled Transcriptome of the Eastern Spiny Lobster, Sagmariasus verreauxi. AB - The Eastern spiny lobster, Sagmariasus verreauxi, is commercially important in fisheries, with growing aquaculture potential, driving an interest to better understand male sexual differentiation. Amongst the Decapoda, the androgenic gland (AG) and the insulin-like androgenic gland hormone (IAG) have a well defined function in male sexual differentiation. However, IAG is not a sex determinant and therefore must be considered as part of a broader, integrated pathway. This work uses a transcriptomic, multi-tissue approach to provide an integrated description of male-biased expression as mediated through the AG. Transcriptomic analyses demonstrate that IAG expression is stage- and eyestalk regulated (low in immature, high in mature and 6-times higher in hypertrophied glands), with IAG being the predominant AG-specific factor. The low expression of this key factor in immature males suggests the involvement of other tissues in male sexual differentiation. Across tissues, the gonad (87.8%) and antennal gland (73.5%) show the highest male-biased differential expression of transcripts and also express 4 sex-determination regulators, known as Dmrts, with broader expression of Sv-Sxl and Sv-TRA-2. In order to better understand male sexual differentiation, tissues other than the AG must also be considered. This research highlights the gonad and antennal gland as showing significant male-biased expression patterns, including the Sv-Dmrts. PMID- 26927316 TI - Benefit of Stereotactic Procedures in a Series of 43 Children. AB - OBJECTIVES: Stereotactic biopsies are procedures that enable neurosurgeons to obtain tissue samples of brain tumors located in eloquent areas with a low risk of perioperative complications. In this study, we examined stereotactic procedures (STX) in children. We focused on effectiveness, safety, and histopathological results to evaluate the benefits of the procedure. METHODS: We performed a retrospective analysis of our prospective database and included 43 children aged less than 18 years who underwent STX between 1998 and May 2015. All MRIs were evaluated by a single, experienced neuroradiologist. For all biopsies, Leksell stereotactic frame was used and fixed to the children's head with four pins. Entry and targetpoints were calculated by BrainLab navigation system. We assessed age, tumor localization, number of samples, histological diagnosis, and postoperative treatment. RESULTS: Median age of the patients was 11 years (range 1-18 years), and median number of tissue samples taken was 12 (range 1 with mere puncture of a cyst to 36). Histopathological examination revealed a final diagnosis in all patients. 3 patients underwent puncture of a cyst. 27 patients had a postoperative imaging. Only in 3 patients, CT scan revealed blood in the area where the biopsy had been taken. All bleedings were small and without clinical sequelae. CONCLUSION: Stereotactic procedures are accurate and save surgeries to obtain tumor tissue from eloquent areas to base further therapy on. This not only applies to adults but also to children of all ages. PMID- 26927315 TI - Associations between weight change and biomarkers of cardiometabolic risk in South Asians: secondary analyses of the PODOSA trial. AB - BACKGROUND/OBJECTIVES: The association of weight changes with cardiometabolic biomarkers in South Asians has been sparsely studied. SUBJECTS/METHODS: We measured cardiometabolic biomarkers at baseline and after 3 years in the Prevention of Diabetes and Obesity in South Asians Trial. We investigated the effect of a lifestyle intervention on biomarkers in the randomized groups. In addition, treating the population as a single cohort, we estimated the association between change in weight and change in biomarkers. RESULTS: Complete data were available at baseline and after 3 years in 151 participants. At 3 years, there was an adjusted mean reduction of 1.44 kg (95% confidence interval (95% CI): 0.18-2.71) in weight and 1.59 cm (95% CI: 0.08-3.09) in waist circumference in the intervention arm as compared with the control arm. There was no clear evidence of difference between the intervention and control arms in change of mean value of any biomarker. As a single cohort, every 1 kg weight reduction during follow-up was associated with a reduction in triglycerides ( 1.3%, P=0.048), alanine aminotransferase (-2.5%, P=0.032), gamma-glutamyl transferase (-2.2%, P=0.040), leptin (-6.5%, P<0.0001), insulin (-3.7%, P=0.0005), fasting glucose (-0.8%, P=0.0071), 2-h glucose (-2.3%, P=0.0002) and Homeostatic Model Assessment of insulin resistance (HOMA-IR: -4.5%, P=0.0002). There was no evidence of associations with other lipid measures, tissue plasminogen activator, markers of inflammation or blood pressure. CONCLUSIONS: We demonstrate that modest weight decrease in SAs is associated with improvements in markers of total and ectopic fat as well as insulin resistance and glycaemia in South Asians at risk of diabetes. Future trials with more intensive weight change are needed to extend these findings. PMID- 26927318 TI - Bacterial synthesis of polysialic acid lactosides in recombinant Escherichia coli K-12. AB - Bacterial polysialyltransferases (PSTs) are processive enzymes involved in the synthesis of polysialic capsular polysaccharides. They can also synthesize polysialic acid in vitro from disialylated and trisialylated lactoside acceptors, which are the carbohydrate moieties of GD3 and GT3 gangliosides, respectively. Here, we engineered a non-pathogenic Escherichia coli strain that overexpresses recombinant sialyltransferases and sialic acid synthesis genes and can convert an exogenous lactoside into polysialyl lactosides. Several PSTs were assayed for their ability to synthesize polysialyl lactosides in the recombinant strains. Fed batch cultures produced alpha-2,8 polysialic acid or alternate alpha-2,8-2,9 polysialic acid in quantities reaching several grams per liter. Bacterial culture in the presence of propargyl-beta-lactoside as the exogenous acceptor led to the production of conjugatable polysaccharides by means of copper-assisted click chemistry. PMID- 26927319 TI - Discrete and continuous stimulus control in the A-not-B sandbox task. AB - In behavior-analytic studies of generalization, stimulus control appears to be discrete rather than continuous: after two behavior patterns R1 and R2 are trained in the presence of stimuli A and B, respectively, tests of intermediate stimuli evoke R1 and R2 in varying proportions rather than an actual mix of R1 and R2. By contrast, theories and data from developmental psychology suggest that spatial searches in the A-not-B sandbox task may be continuous: after burying an object at position A and then at position B, children may search the sand surface at positions that are actually intermediate between A and B. The published evidence so far has been ambiguous, however, because researchers typically report group means rather than response distributions, and group means intermediate between A and B might be statistical artefacts of averaging across subjects. Here we report two A-not-B sandbox studies designed to address this issue. In Experiment 1, which employed a purely motor A-not-B procedure, stimulus control was found to be continuous. In Experiment 2, which used a purely observational A not-B procedure, stimulus control was basically discrete but also exhibited continuous aspects. These findings are discussed in relation to cognitive and behavior-analytic approaches to stimulus control. PMID- 26927320 TI - How the foraging decisions of a small ruminant are influenced by past feeding experiences with low-quality food. AB - Feeding experiences with low-quality foods can be improved when these foods are ingested in close temporal association with foods of higher nutritional quality. However, preference for low-quality foods in nature seems to be rather insensitive to past positive experiences and more related to their intrinsic nutritional value. An explanation for this observation is still lacking, mainly because little is known about how herbivores use information about low-quality foods during foraging. Our objective was to provide original information about this issue using a small ruminant (sheep; Ovis aries) as animal model. We manipulated the sheep's experience with a low-quality food (wheat straw) using a conditioning procedure ("oral-delay conditioning procedure"), and then we evaluated the use of this information in a simulated foraging scenario provided with wheat straw and a variable amount of a high-quality food in spatially separated feeding stations. Inclusion of wheat straw into the diet was strongly dependent on the availability of the high-quality food. We observed a threshold level in the availability of the high-quality food, which defined a zone of drastic change in the likelihood of inclusion of the wheat straw into the diet (i.e., acceptance or rejection of wheat straw). This threshold level did not change for sheep with (CS+) or without (CS-) a previous positive experience with wheat straw. However, once foraging conditions stimulated all sheep to start including the wheat straw into the diet (i.e., below the threshold level), the intake of this food was greater by CS+ sheep. This increased intake was not explained by a higher motivation to eat the wheat straw but to a greater amount of time spent foraging this food and less time spent searching for the preferred higher-quality alternative. We discuss these results based on optimal foraging models and learning models of diet selection. PMID- 26927321 TI - Betel nut chewing: Recognizing an important but unfamiliar cause of oral cancers. PMID- 26927322 TI - Molecular analysis of the LDLR gene in coronary artery disease patients from the Indian population. AB - BACKGROUND: Cardiovascular disease is a leading cause of mortality in Indian population. Mutations in LDLR, APOB and PCSK9 genes may lead to Familial Hypercholesterolemia, an autosomal dominant disorder which in turn leads to cardiovascular diseases. The primary objective of this study is to analyze these genes in CAD patients of Indian population. METHODS: A total of 30 patients were selected out of 300 CAD patients based on UK-Simon Broome criteria from South India. The gDNA was isolated by organic extraction method and the exons and exon intron boundaries of LDLR gene, APOB (exon 26) and PCSK9 (exon 7) were screened by PCR-high resolution melt analysis. The amplicons showing shift in melting pattern were sequenced to find out the variation. RESULTS: This study reports three novel variations, an intronic deletion c.694+8_694+18del in intron 4, a synonymous variation c.966 C>T [p. (N322=)] in exon 7 and a deletion insertion c.1399_1340delinsTA [p. (T467Y)] in exon 10, two recurrent variations c.862G>A [p. (E288K)] in exon 6 and a splice site variation c.1845+2T>C in exon-intron junction of exon 12 in LDLR gene and PCSK9 gene had c.1180+17C>T change in intron 7. However there are no pathogenic variations in APOB and PCSK9 genes in Indian population. In silico analysis predicted all the variations as pathogenic except the synonymous variation. CONCLUSION: This report adds five new variations to the spectrum of LDLR variations in Indian population. This study also suggests that UK Simon Broom criteria can be followed to categorize FH patients in Indian population. PMID- 26927323 TI - Atomic Oxygen Tailored Graphene Oxide Nanosheets Emissions for Multicolor Cellular Imaging. AB - Graphene oxide (GO) has been widely used as a fluorescence quencher, but its luminescent properties, especially tailor-made controlling emission colors, have been seldom reported due to its heterogeneous structures. Herein, we demonstrated a novel chemical oxidative strategy to tune GO emissions from brown to cyan without changing excitation wavelength. The precise tuning is simply achieved by varying reaction times of GO nanosheets in piranha solution, but there is no need for complex chromatography separation procedures. With increasing reaction times, oxygen content on the lattice of GO nanosheets increased, accompanied by the diminution of their sizes and sp(2) conjugation system, resulting in an increase of emissive carbon cluster-like states. Thereby, the luminescent colors of GO were tuned from brown to yellow, green, and cyan, and its fluorescent quantum yields were enhanced. The obtained multicolored fluorescent GO nanosheets would open plenty of novel applications in cellular imaging and multiplex encoding analysis. PMID- 26927324 TI - Isolation, structural and functional characterization of a new Lys49 phospholipase A2 homologue from Bothrops neuwiedi urutu with bactericidal potential. AB - Snake venom is a complex mixture of active compounds consisting of 80-90% proteins and peptides that exhibit a variety of biological actions that are not completely clarified or identified. Of these, phospholipase A2 is one of the molecules that has shown great biotechnological potential. The objectives of this study were to isolate, biochemically and biologically characterize a Lys49 phospholipase A2 homologue from the venom of Bothrops neuwiedi urutu. The protein was purified after two chromatographic steps, anion exchange and reverse phase. The purity and relative molecular mass were assessed by SDS-PAGE, observing a molecular weight typical of PLA2s, subsequently confirmed by mass spectrometry obtaining a mass of 13,733 Da. As for phospholipase activity, the PLA2 proved to be enzymatically inactive. The analyses by Edman degradation and sequencing of the peptide fragments allowed for the identification of 108 amino acid residues; this sequence showed high identity with other phospholipases A2 from Bothrops snake venoms, and identified this molecule as a novel PLA2 isoform from B. neuwiedi urutu venom, called BnuTX-I. In murine models, both BnuTX-I as well as the venom induced edema and myotoxic responses. The cytotoxic effect of BnuTX-I in murine macrophages was observed at concentrations above 12 MUg/mL. BnuTX-I also presented antimicrobial activity against gram-positive and negative bacterial strains, having the greatest inhibitory effect on Pseudomonas aeruginosa. The results allowed for the identification of a new myotoxin isoform with PLA2 structure with promising biotechnological applications. PMID- 26927325 TI - Response to comment on "Evaluation of diagnostic and predictive value of serum adipokines: Leptin, resistin and visfatin in postmenopausal breast cancer". PMID- 26927326 TI - Obesity and social factors. PMID- 26927327 TI - Satellite-Based NO2 and Model Validation in a National Prediction Model Based on Universal Kriging and Land-Use Regression. AB - Epidemiological studies increasingly rely on exposure prediction models. Predictive performance of satellite data has not been evaluated in a combined land-use regression/spatial smoothing context. We performed regionalized national land-use regression with and without universal kriging on annual average NO2 measurements (1990-2012, contiguous U.S. EPA sites). Regression covariates were dimension-reduced components of 418 geographic variables including distance to roadway. We estimated model performance with two cross-validation approaches: using randomly selected groups and, in order to assess predictions to unmonitored areas, spatially clustered cross-validation groups. Ground-level NO2 was estimated from satellite-derived NO2 and was assessed as an additional regression covariate. Kriging models performed consistently better than nonkriging models. Among kriging models, conventional cross-validated R(2) (R(2)cv) averaged over all years was 0.85 for the satellite data models and 0.84 for the models without satellite data. Average spatially clustered R(2)cv was 0.74 for the satellite data models and 0.64 for the models without satellite data. The addition of either kriging or satellite data to a well-specified NO2 land-use regression model each improves prediction. Adding the satellite variable to a kriging model only marginally improves predictions in well-sampled areas (conventional cross validation) but substantially improves predictions for points far from monitoring locations (clustered cross-validation). PMID- 26927328 TI - SUMO and SUMO-Conjugating Enzyme E2 UBC9 Are Involved in White Spot Syndrome Virus Infection in Fenneropenaeus chinensis. AB - In previous work, small ubiquitin-like modifier (SUMO) in hemocytes of Chinese shrimp Fenneropenaeus chinensis was found to be up-regulated post-white spot syndrome virus (WSSV) infection using proteomic approach. However, the role of SUMO in viral infection is still unclear. In the present work, full length cDNAs of SUMO (FcSUMO) and SUMO-conjugating enzyme E2 UBC9 (FcUBC9) were cloned from F. chinensis using rapid amplification of cDNA ends approach. The open reading frame (ORF) of FcSUMO encoded a 93 amino acids peptide with the predicted molecular weight (M.W) of 10.55 kDa, and the UBC9 ORF encoded a 160 amino acids peptide with the predicted M.W of 18.35 kDa. By quantitative real-time RT-PCR, higher mRNA transcription levels of FcSUMO and FcUBC9 were detected in hemocytes and ovary of F. chinensis, and the two genes were significantly up-regulated post WSSV infection. Subsequently, the recombinant proteins of FcSUMO and FcUBC9 were expressed in Escherichia coli BL21 (DE3), and employed as immunogens for the production of polyclonal antibody (PAb). Indirect immunofluorescence assay revealed that the FcSUMO and UBC9 proteins were mainly located in the hemocytes nuclei. By western blotting, a 13.5 kDa protein and a 18.7 kDa protein in hemocytes were recognized by the PAb against SUMO or UBC9 respectively. Furthermore, gene silencing of FcSUMO and FcUBC9 were performed using RNA interference, and the results showed that the number of WSSV copies and the viral gene expressions were inhibited by knockdown of either SUMO or UBC9, and the mortalities of shrimp were also reduced. These results indicated that FcSUMO and FcUBC9 played important roles in WSSV infection. PMID- 26927329 TI - Increased coagulation and fibrinolytic potential of solvent-detergent plasma: a comparative study between Omniplasma and fresh frozen plasma. AB - BACKGROUND AND OBJECTIVES: In this study, differences in levels of proteins involved in coagulation and fibrinolysis were compared between fresh frozen (quarantine plasma) and Omniplasma. Furthermore, thawing conditions and plasma stability after thawing were studied. MATERIALS AND METHODS: 10 Omniplasma and 10 quarantine plasma units were used to study different procoagulation, anticoagulation and fibrinolytic parameters. Analysis took place at different time-points during plasma storage at 2-6 degrees C. RESULTS: At baseline, significant reduced levels of factor V, free protein S, alpha2-antiplasmin and tPA-induced ROTEM lysis time were observed in Omniplasma as compared to quarantine plasma. Moreover, thrombin generation, IXa-AT complex levels and factor XIa were significantly increased in Omniplasma. The majority of the parameters studied remained stable in Omniplasma 48 h after thawing, with the exception of factor VIII (decrease) and IXa-AT (increase). CONCLUSION: Our results suggest an increased coagulation potential, presumingly as a result of contact activation during the production process and also, an increased fibrinolytic potential in Omniplasma. The stability of Omniplasma, based upon the different parameters studied, is comparable to Q-plasma. A maximum post-thawing time of 48 hfor Omniplasma can be suggested. PMID- 26927330 TI - Sleep and mood disorders in dry eye disease and allied irritating ocular diseases. AB - The aim of the present study was to evaluate sleep and mood disorders in patients with irritating ocular diseases. The study design was a cross-sectional/case control study conducted in six eye clinics. Out of 715 outpatients diagnosed with irritating ocular surface diseases and initially enrolled, 301 patients with dry eye disease (DED) and 202 age-matched control participants with other ocular surface diseases were analyzed. The mean Pittsburgh Sleep Quality Index (PSQI) and Hospital Anxiety and Depression Scale (HADS) scores were 6.4 +/- 3.2 and 11.1 +/- 5.7 for severe DED (n = 146), 5.5 +/- 3.3 and 9.8 +/- 4.0 for mild DED (n = 155), 5.5 +/- 3.1 and 9.5 +/- 6.6 for chronic conjunctivitis (n = 124), and 5.0 +/- 3.3 and 8.9 +/- 5.3 for allergic conjunctivitis (n = 78). There were significant differences among these diagnostic groups for PSQI (P < 0.05). Regression analysis of patients with DED revealed the PSQI and HADS scores were significantly correlated with the severity of DED (P < 0.05). Our results demonstrate that sleep quality in patients with DED is significantly worse than in patients with other irritating ocular surface diseases and it is correlated with the severity of DED. PMID- 26927331 TI - Sensitivity Analysis of the MGMT-STP27 Model and Impact of Genetic and Epigenetic Context to Predict the MGMT Methylation Status in Gliomas and Other Tumors. AB - The methylation status of the O(6)-methylguanine-DNA methyltransferase (MGMT) gene is an important predictive biomarker for benefit from alkylating agent therapy in glioblastoma. Our model MGMT-STP27 allows prediction of the methylation status of the MGMT promoter using data from the Illumina's Human Methylation BeadChips (HM-27K and HM-450K) that is publically available for many cancer data sets. Here, we investigate the impact of the context of genetic and epigenetic alterations and tumor type on the classification and report on technical aspects, such as robustness of cutoff definition and preprocessing of the data. The association between gene copy number variation, predicted MGMT methylation, and MGMT expression revealed a gene dosage effect on MGMT expression in lower grade glioma (World Health Organization grade II/III) that in contrast to glioblastoma usually carry two copies of chromosome 10 on which MGMT resides (10q26.3). This implies some MGMT expression, potentially conferring residual repair function blunting the therapeutic effect of alkylating agents. A sensitivity analyses corroborated the performance of the original cutoff for various optimization criteria and for most data preprocessing methods. Finally, we propose an R package mgmtstp27 that allows prediction of the methylation status of the MGMT promoter and calculation of appropriate confidence and/or prediction intervals. Overall, MGMT-STP27 is a robust model for MGMT classification that is independent of tumor type and is adapted for single sample prediction. PMID- 26927332 TI - Theodore L. Sourkes PhD, FRSC, OC (February 21, 1919-January 17, 2015). PMID- 26927333 TI - Extremely large fractionation of Li isotopes in a chromitite-bearing mantle sequence. AB - We report Li isotopic compositions of olivine from the mantle sequence of the Luobusa ophiolite, southern Tibet. The olivine in the Luobusa ophiolite has Li concentrations from ~0.1 to 0.9 ppm and a broad range of delta(7)Li (+14 to 200/00). An inverse correlation of Li concentration and delta(7)Li in olivine from harzburgite suggests recent diffusive ingress of Li into the rock. Olivine from dunite enveloping podiform chromitites shows positive delta(7)Li values higher than those of MORB, whereas olivine from the chromitite has negative delta(7)Li values. Such variations are difficult to reconcile by diffusive fractionation and are thought to record the nature of the magma sources. Our results clearly indicate that the Luobusa chromitites formed from magmas with light Li isotopic compositions and that the dunites are products of melt-rock interaction. The isotopically light magmas originated by partial melting of a subducted slab after high degrees of dehydration and then penetrated the overlying mantle wedge. This study provides evidence for Li isotope heterogeneity in the mantle that resulted from subduction of a recycled oceanic component. PMID- 26927334 TI - Susceptibility of Five Sugar Beet Cultivars to the Black Bean Aphid, Aphis fabae Scopoli (Hemiptera: Aphididae). AB - The black bean aphid, Aphis fabae Scopoli (Hemiptera: Aphididae), is one of the important pests of sugar beet. The relative impact of resistance, including antibiosis and antixenosis of five sugar beet cultivars (Doroti, Perimer, Pershia, Rozier and 006) on A. fabae was studied under laboratory conditions using clip cages. The antibiosis test was based on life table parameters. Significant differences on developmental time, mean number of nymphs/aphid/day, fecundity, and adult longevity of A. fabae were found across tested sugar beet cultivars. In addition, there were significant differences among the sugar beet cultivars for population growth parameters such as the intrinsic rate of natural increase (r m ), net reproductive rate (R 0), finite rate of increase (lambda), doubling time (DT), and mean generation time (T) of A. fabae. The highest and lowest (r m ) values were observed on Pershia (0.449 nymphs/female/day) and Perimer (0.358 nymphs/female/day), respectively. No significant differences were found for the preference of the black bean aphid, and antixenosis had no effect on resistance against this aphid. As a result, our findings showed that the Pershia cultivar was a relatively susceptible host plant. Two cultivars (Perimer and Rozier) were relatively resistant to A. fabae, which could prove useful in the development of IPM programs for this aphid in sugar beet fields. PMID- 26927336 TI - Albert Cannon, MD (1/15/1921 - 9/20/2015). PMID- 26927337 TI - Hypercholesterolemia Up-Regulates the Expression of Intermedin and Its Receptor Components in the Aorta of Rats via Inducing the Oxidative Stress. AB - OBJECTIVE: Hypercholesterolemia can cause damage to the artery. Intermedin (IMD) is a novel member of the calcitonin gene-related peptide family. This study aims to investigate the aortic expression of IMD and its receptors in hypercholesterolemia without atherosclerosis. METHODS: Male Wistar rats were fed with high cholesterol diet, with or without simvastatin and vitamin C. Both the malondialdehyde (MDA) and superoxide dismutase (SOD) in plasma and aorta were determined as the oxidative stress biomarkers. The plasma IMD was assessed by radioimmunoassay. Within the aorta, the mRNA expression of IMD along with its receptor components was determined, and the corresponding protein level of the CRLR/RAMPs was also assessed. RESULTS: The hypercholesterolemia rats without atherosclerotic lesion manifested a higher level of MDA and SOD and the plasma IMD elevated. Increased expression of IMD and all its receptor components (CRLR, RAMP1, RAMP2, and RAMP3) were displayed within the aorta. The simvastatin indirectly attenuated oxidative stress by improving lipid profiles, while the vitamin C directly reduced oxidative stress without interfering with the serum lipids. Both simvastatin and vitamin C ameliorated the aortic injury, decreased the plasma IMD level, and recovered the expression of IMD and its receptors within the aorta. CONCLUSIONS: The up-regulated expression of IMD is observed within the aorta of the hypercholesterolemia rats. In addition, the oxidative stress participates in the up-regulation. PMID- 26927338 TI - Comparison between a Broad-Range Real-Time and a Broad-Range End-Point PCR Assays for the Detection of Bacterial 16S rRNA in Clinical Samples. AB - Broad range PCR targeting the 16S rRNA gene is widely used to test clinical samples for the presence of bacterial DNA. End-point 16S PCR is both time consuming and at high risk of cross-contamination. Prior to the replacement of the 16S end-point PCR assay routinely used in our clinical laboratory by a new 16S real-time PCR assay, we aimed to compare the performances of both techniques for the direct diagnosis of bacterial infections in clinical samples. In this prospective study, 129 clinical samples were included for direct comparison of both techniques. The sensitivity of 16S real-time PCR assay (76%) was significantly higher than that of end-point 16S PCR assay (41%) (p<0.01). Specificities of both PCR assays did not differ significantly (p=0.43). The 16S real-time PCR assay yielded an etiological diagnosis in 19% of culture-negative samples. It constitutes a reliable and complementary diagnostic tool to the bacterial culture. PMID- 26927339 TI - Myostatin as a Marker for Doxorubicin Induced Cardiac Damage. AB - PURPOSE: Doxorubicin (DXR) is an effective chemotherapeutic agent but causes severe cardiac failure over known doses. Thus, early detection and prevention of cardiac damage is important. Various markers have been tested for early detection of cardiac damage. Myostatin is a protein produced in skeletal muscle cells inhibits muscle differentiation and growth during myogenesis. METHODS: We evaluated the role of myostatin as a marker for showing DXR induced cardiac damage and compared with well known cardiac markers like NT-proBNP, hs-TnT and CK in a rat model of chronic DXR cardiotoxicity. RESULTS: Myostatin, NT-proBNP, and hs-TnT but not CK rose significantly during DXR treatment. CONCLUSION: Myostatin can be used as an early marker of DXR induced cardiotoxicity. PMID- 26927340 TI - The Protective Effect of HIF-1alpha in T Lymphocytes on Cardiac Damage in Diabetic Mice. AB - Diabetic cardiomyopathy (DCM) is associated with functional and structural pathological changes such as hypoxia and inflammation. Hypoxia-inducible factor 1alpha(HIF-1alpha) is a core transcription factor for restoring homeostasis in intracellular oxygen and has a crucial role in preventing the development of DCM. However, the effect of HIF-1alpha in T lymphocytes on DCM has not been reported. We established T lymphocyte-specific HIF-1alpha knockout homozygous mice that were injected with streptozotocin (STZ) for establishing diabetic models. Random blood glucose (RBG), body weight and the survival rate were detected. The cardiac pathological changes were evaluated by periodic acid-Schiff (PAS) staining, hematoxylin-eosin staining (HE) and Masson collagen staining. Cardiac function measurements were obtained by echocardiography. We observed the infiltration of T lymphocytes/CD3+ in the hearts by immunofluorescence stain. Also, we isolated splenic lymphocytes which would be in vitro cultured in the environment of high glucose and hypoxia. HIF-1alpha protein level of splenic lymphocytes was measured by Western blot. The results of this study indicate that the expression of HIF 1alpha in lymphocytes is activated in the complex environment of DCM consisting of hypoxia and high glucose. Also, HIF-1alpha in T cells plays a critical role in avoiding damage to the diabetic cardiac tissues. PMID- 26927341 TI - The Potential Prognostic Value of MicroRNA-429 for Human Gliomas. AB - MicroRNA-429 (miR-429) is reported to be frequently dysregulated in cancer. Studies have demonstrated that miR-429 functions as either an oncogene or a tumor suppressor depending on the tumor type. To date, its role in human glioma has not yet been reported. The aim of this study was to investigate the expression levels, clinicopathological significance, and prognostic significance of miR-429 in glioma tissues. Quantitative real-time PCR assay was performed to detect miR 429 expression in human glioma and non-neoplastic brain tissues. The association of miR-429 expression with clinicopathological features and prognoses of glioma patients were analyzed by SPSS 17.0 statistical software. The expression levels of miR-429 were found to be distinctly increased in glioma tissues compared to non-neoplastic brain tissues (P<0.01) with ascending pathological grade. The 5 year survival rate of patients with high miR-429 expression was significantly lower than those with low miR-429 expression (P<0.001). Moreover, multivariate Cox regression analyses showed that miR-429 high expression is an independent prognostic factor for glioma patients. Taken together, miR-429, was significantly up-regulated in glioma tissues. Therefore, miR-429 could be considered as an independent prognostic factor and potential therapeutic target for glioma. PMID- 26927342 TI - Decreased miR-195 Expression Protects Rats from Spinal Cord Injury Primarily by Targeting HIF-1alpha. AB - Hypoxia-inducible factor 1-alpha (HIF-1alpha) protects hypoxic cells from apoptosis and necrosis under ischemic and anoxic conditions. miRNAs are important regulators in the genome. This study aims to explore whether miR-195 is involved in spinal cord injury through HIF-1alpha. A total of 40 male Sprague-Dawley (SD) rats were separated into four groups: Sham, Control, Ad-con, and Ad-miR-195. The behavior recovery was explored using the Basso, Beattie and Bresnahan (BBB) scoring system. Then, the rats were sacrificed, and the spinal cords were collected. The levels of the HIF-1alpha, Bcl-2, Bax and VEGF proteins were explored using western blotting. H&E and immunohistochemistry were applied to study the morphological changes. qPCR analysis revealed that miR-195 was significantly decreased after spinal cord injury (SCI). Meanwhile, the expression of Bcl-2, VEGF and HIF-1alpha was increased in animals after SCI. More importantly, administration with Ad-miR-195 significantly decreased the HIF 1alpha protein level, thereby reducing Bcl-2 and VEGF expression. In addition, Ad miR-195 also obviously increased the number of apoptotic cells and decreased the neurological recovery in the animals injected with Ad-miR-195. In conclusion, reduced miR-195 expression partially protects rats from spinal cord injury, primarily by targeting HIF-1alpha. PMID- 26927343 TI - TNF-alpha Regulating Interleukin-33 Induces Acute Pancreatic Inflammation in Rats. AB - BACKGROUND: Acute pancreatitis (AP) is a common disease with a high fatality rate as a result of its unclear pathogenesis. Interleukin (IL)-33 plays a role in various inflammatory conditions but its role and regulatory mechanisms in AP is still unknown. METHODS: The serum levels of IL-33, sST2, TNF-alpha and IL-6 in AP patients were detected using ELISA. The correlations between IL-33 and TNF-alpha, sST2, IL-6, Ranson score and APACHE II score were investigated using Pearson correlation analysis. AP rat model was established by injecting sodium taurocholate to explore the expression of IL-33, TNF-alpha, sST2 and IL-6 at the early stage of AP. Expression of IL-33 and IL6 in pancreas of AP rats was determined with qRT-PCR and Western-Blot. Intravenous injection of purified TNF alpha was performed to explore the regulatory mechanisms of IL-33. RESULTS: Our data found that AP patients had high serum level of IL-33, sST2, TNF-alpha and IL 6. IL-33 was positively related with the Ranson score and APACHE II score. Similarly, sodium taurocholate induced AP rats had significantly increased serum IL-33, sST2, TNF-alpha and IL-6 levels, with peaks at 8 h post-operation for IL 33 and TNF-alpha, and 12 h for sST2 and IL-6. IL-33 mRNA and protein levels were both increased in the pancreas of AP rats. In addition, TNF-alpha significantly stimulated the production of IL-33 and subsequently led to an increase of IL-6. CONCLUSION: IL-33 is elevated at the early stage of AP and correlated with AP severity. TNF-alpha stimulated IL-33/sST2 and subsequent increase of IL-6 may be the mechanism of IL-33 in AP. PMID- 26927344 TI - Serum Angiopoietin-2 as a Clinical Marker for Lung Cancer in Patients with Solitary Pulmonary Nodules. AB - To evaluate the clinical significance of angiopoietin-2 (Ang-2) and vascular endothelial growth factor (VEGF) in lung cancer patients with solitary pulmonary nodule (SPN). The study enrolled 128 patients with malignant SPN, 60 patients with benign SPN, along with 40 healthy volunteers. Serum concentrations of Ang-2 and VEGF were measured by ELISA. Serum Ang-2 and VEGF levels in patients with malignant SPN were significantly higher than those in patients with benign SPN (p<0.01), and those in healthy volunteers (p<0.05). With a cutoff of 1504.8 pg/mL, the sensitivity and specificity of Ang-2 in differentiating between patients with malignant SPN and patients with benign SPN, and between patients with malignant SPN and healthy volunteers was 69.5 and 92.5%, and 80.5 and 97.5%, respectively. Additionally, higher levels of Ang-2 were associated with higher tumor stage (p<0.05). The levels of Ang-2 correlated with the VEGF level (p<0.01). In conclusion, measurement of serum Ang-2 might be a useful diagnostic marker for SPN patients. PMID- 26927345 TI - The Macrophage Polarization Regulates MSC Osteoblast Differentiation in vitro. AB - Bone repair is a complex yet highly organized process involving interactions between various cell types and the extracellular environment. Macrophages are not only activated in inflammation during early phases of repair processes, but they are also present in bone throughout the whole bone repair process. Bone marrow derived mesenchymal stem cells (MSCs) represent an attractive therapeutic for bone fracture with their expansion potential, osteogenic capability, and potential for injury. However, less is known about the interaction between macrophage and MSC during bone repair and regeneration. This study was aimed to investigate whether macrophages in different statuses can regulate MSC osteoblast differentiation in vitro. Using in vitro cell coculture of macrophage and MSC, it was shown that macrophage polarization can regulate MSC osteoblast differentiation. This was evidenced by increased alkaline phosphatase (ALP), osteogenic markers, and bone mineralization in M2 macrophage cocultured MSC but decreased in M1 counterpart. These results might be mediated by pro-regenerative cytokines, such as TGF-beta, VEGF, and IFG-1, produced by M2 macrophages and detrimental inflammation cytokines, such as IL-6, IL-12, and TNF-alpha, produced by M1 macrophages. Taken together, this shows that macrophage polarization could be crucial for maintaining bone homeostasis and promoting bone repair by regulating the MSC osteoblast differentiation. PMID- 26927346 TI - Accuracy Assessment of Three Different Lots of the LABGEO PT Hemoglobin A1c Test Using Reference Materials. AB - BACKGROUND: Both accurate measurement of HbA1c and minimal reagent lot-to-lot variability are essential for point-of-care HbA1c assays. The accuracy of three different cartridge lots of the Samsung LABGEO PT HbA1c Test was investigated to determine whether the results can be used for follow-up and screening of patients with diabetes. METHODS: The LABGEO PT10 device and three different lots of the LABGEO PT HbA1c Test cartridge were used. Seven levels of reference materials were measured using each cartridge in a duplicate manner for 3 days. The bias, within-laboratory precision, and total error were calculated. The medical decision point analysis was performed. RESULTS: The mean absolute bias, within laboratory precision, and total error of each cartridge were 3.3%, 2.5%, and 8.1% for Lot1; 1.9%, 2.6%, and 7.1% for Lot2; and 2.7%, 2.8%, and 8.1% for Lot3. The predicted value (95% confidence interval) of each cartridge at an HbA1c of 6.5% was 6.74% (6.66, 6.83) for Lot1, 6.60 (6.51, 6.70) for Lot2, and 6.51 (6.39, 6.63) for Lot3. CONCLUSIONS: Our data suggest that the LABGEO PT HbA1c Test can be used to monitor patients with diabetes and perform diabetes screening when false-positive results are obtained in the doctor's office. PMID- 26927347 TI - An Unusual Variant of Hepatic Inflammatory Angiomyolipoma: Report of a Rare Entity. AB - Hepatic angiomyolipoma is a rare mesenchymal tumor with a broad spectrum of histological appearance. A 44-year-old female presented with abdominal discomfort. MRI revealed a 3.6 cm well-defined hepatic lesion. Ultrasound-guided core biopsy with imprint smears was performed. The smears showed histiocytes with a few epithelioid cells, mimicking an inflammatory lesion. The biopsy showed proliferation of epithelioid cells with aggregates of foamy histiocytes and scattered adipocyts, resembling hepatocellular neoplasm. The diagnosis of angiomyolipoma was clinched by the immunoprofile of the epithelioid cells, which were diffusely positive for HMB45, Mart-1 and focally positive for smooth muscle actin. To our best knowledge, this is the first reported case of biopsy diagnosed hepatic inflammatory angiomyolipoma with an unusual inflammatory infiltrate composed mainly of aggregates of foamy histiocytes. PMID- 26927348 TI - Leptotrichia goodfellowii Infection: Case Report and Literature Review. AB - Leptotrichia is a pencil-shaped Gram-negative rod and is known as an uncommon pathogen of bacteremia in immunocompromised patients. However, because culture and identification of Leptotrichia species is difficult in clinical laboratories, Leptotrichia goodfellowii is grossly underestimated as a human pathogen. In this study, we report a case of L. goodfellowii bacteremia in an immunocompetent patient and review 5 previously reported cases describing infection with L. goodfellowii. PMID- 26927349 TI - Lambda Immunoglobulin Light Chain Restricted B Cells in the Ascitic Fluid in Association with Terminal Ileal Florid Follicular Hyperplasia. AB - Distinguishing reactive changes from neoplastic processes during lymphoid tissue evaluation is oftentimes difficult. Ancillary studies, such as flow cytometry, may aid the diagnosis by demonstrating monotypic or polytypic light chain expression on the B cells. The detection of immunoglobulin light chain restricted B cell population is considered a surrogate marker of clonality, which can be confirmed by molecular assays. In general, the presence of a monotypic B cell population in the ascitic fluid is considered lymphomatous involvement rather than a reactive condition. We describe a young, previously healthy male patient who developed ascites with a lambda light chain restricted B cell population. Further investigation revealed florid follicular hyperplasia, histologically mimicking diffuse large B cell lymphoma, in the terminal ileum. Follicular hyperplasia in the gastrointestinal tract with lambda light chain restricted B cells has been recently described in the pediatric population. Importantly, our case demonstrates that such entity can occur in older age groups. This recognition could prevent misdiagnosis and unnecessary treatment in similar cases. PMID- 26927350 TI - Paravertebral Low-grade Fibromyxoid Sarcoma with Supernumerary Ring Chromosome: Case Report and Literature Review. AB - Low-grade fibromyxoid sarcoma (LGFMS) is a rare soft-tissue neoplasm with a deceptively benign histological appearance and low-grade malignant potential which is often mistaken for other reactive or benign lesions. It most frequently harbors balanced t(7;16) translocation, and leads to the fusion of the FUS and CREB3L2 genes which can be detected by cytogenetic methods. Young adults are most commonly affected and it typically arises in the deep proximal extremities or trunk with frequent recurrences. It may metastasize to the lungs several years later. Paravertebral LGFMS is exceedingly rare and only few cases have been published in the literature. In those cases the novel immunohistochemical markers and cytogenetic studies were not performed and morphological mimickers could not be confidently excluded.We present a rare case of paravertebral LGFMS from a 54 years-old male patient, which previously was misdiagnosed as a neurofibroma with subsequent tumor recurrence. The concrete diagnosis was established by using MUC4 immunohistochemical stain and fluorescent in situ hybridization (FISH), which showed diffuse membranous positivity and supernumerary ring chromosome with unbalanced FUS gene rearrangement, respectively. The latter finding is also rare and may cause diagnostic dilemma if one is not aware of such uncommon, but well documented phenomenon. Differential diagnosis with other low-grade spindle cell tumors will also be discussed along with the literature review. PMID- 26927351 TI - Rare Korean Cases of Very-long-chain Acyl-CoA Dehydrogenase Deficiency with a Novel Recurrent Mutation. AB - Very-long-chain acyl-CoA dehydrogenase deficiency (VLCADD; OMIM#201475) is a rare metabolic disorder of mitochondrial fatty acid oxidation. VLCADD includes three clinical forms that are grouped based on disease severity. Here, we present two unrelated patients suspected of having VLCADD based on a newborn screening test. One patient was diagnosed in the neonatal period and, to date, has not shown any symptoms or signs associated with VLCADD; in contrast, diagnosis was delayed in the other patient after events of hypoketotic hypoglycemia and steatohepatitis. Repeated biochemical analyses and a liver biopsy implied VLCADD, and direct sequencing analysis led to the discovery of three novel mutations, including an identical missense variant (p.Ser207Pro) on ACADVL. Our patients were the first cases of the milder form of VLCADD, and the identical mutation detected might represent a founder mutation in the Korean population and be associated with the milder phenotype of VLCADD. PMID- 26927352 TI - A Case Report of an Infant with Robertsonian Translocation (15;22)(q10;q10) and Literature Review. AB - Rob(15; 22) is rare and account for only 0.6% of all Robertsonian translocations. We describe a case with rob(15;22) in which the phenotype includes generalized hypotonia, respiratory distress, tent shaped upper lips, hyporeflexia and single umbilical artery. Chromosome analysis with peripheral blood was performed, while the karyotype was interpreted as 45,XX,der(15;22)(q10;q10). In Prader Willi/Angelman Syndrome FISH studies, deletion of the SNRPN gene was not observed, but deletion of 15p11.2 was noted. Prader-Willi/Angelman Syndrome methylation-specific polymerase chain reaction and chromosomal microarrays showed negative findings. Molecular studies associated with spinal muscular atrophy and progressive muscular dystrophy also showed negative findings. We suggest that rob(15;22) and deletion of 15p11.2 could be related to clinical presentation like this case. PMID- 26927353 TI - The Mechanism of Allelic Competition in the ABO 547G>A Mutant is Associated with Decreased Activity of Glycosyltransferase B. AB - The 547G>A polymorphism demonstrates significant allelic competition in people who harbor the B306 allele. We have performed the full sequencing of ABO gene in family members and measured their serum glycosyltransferase activity for demonstrating the cause of allelic competition. Genetic study including two regulatory regions and exon 1, and exons 2-7 of ABO gene demonstrated c.547G>A in exon 7 of the proband and her second son. The ABO genotype of the proband, husband, first son, and other son was ABO*A102/ABO*B306, ABO*A105/ABO*O02, ABO*A102/ABO*O02, and ABO*B306/ABO*O02 respectively. Serum glycosyltransferse B activity in the proband and her second son was lower than in normal B controls. We infer that allelic competition in the the 547G>A carrying individuals is associated with reduced activity of glycosyltransferase B. PMID- 26927354 TI - Identification of the KCNJ2 Mutation in a Korean Family with Andersen-Tawil Syndrome and Developmental Delay. AB - Andersen-Tawil syndrome is a rare autosomal dominant disease characterized by the clinical triad of periodic paralysis, long QT with ventricular arrhythmias, and dysmorphic facial or skeletal features. However, the phenotypic heterogeneity and poor disease awareness of this syndrome can hinder an accurate and timely diagnosis. In this study, we describe a Korean family with Andersen-Tawil syndrome with a G215D mutation of the KCNJ2 gene revealed by diagnostic exome sequencing. Two sisters had severe growth restriction, characteristic facial anomalies, and developmental delay. The father carried the same mutation with similar characteristic facial features and short stature. This family lacked periodic paralysis. This report highlights the importance of an exome study for unusual clinical manifestations, such as preand postnatal growth restriction, developmental delay, and the lack of a critical diagnostic clue, such as periodic paralysis. PMID- 26927355 TI - Letter to the Editor: The Surge of Type 2 Diabetes Mellitus in China - an International Alert: Physical Exercise and Low-Caloric Diet May Reduce the Risks of Type 2 Diabetes Mellitus and Dementia. AB - The prevalence of diabetes in China has surged from 0.67% before 1980 to 11.6% currently. It is even higher than the prevalence in the United States. Certainly, China's economic open-ups, improving living standard, and modernization have propagated the surge. From a traditional public-health point of view, increased food intake and decreased exercise were the main contributors. A new knowledge of colon microbiota could be applied to provide a second harvest of food energy; for example, large molecules of carbohydrates, which are undigested by the stomach and small intestine, produce by-products that the body can absorb in the colon. Colon microbiota can ferment these carbohydrates to the short-chain fatty acid butyrate. This is an energy source that may even cause nonalcoholic fatty liver. How these colon microbiota contribute to the surge of diabetes and whether this new knowledge can be used to control diabetes and metabolic syndrome are questions for future scientific studies. Clinically, however, colon microbiota have had immediate applications; fecal microbiota have been transplanted from healthy persons to treat recurrent Clostridium difficile infection at Mayo Clinic. In addition, a stool biobank of healthy persons was established at Mayo Clinic for future clinical applications. PMID- 26927358 TI - The power of Empowerment. PMID- 26927359 TI - Re: Treatment effects produced by the Twin-block appliance vs the Forsus Fatigue Resistant Device in growing Class II patients. Giutini V, Vangelisti A, Masucci C, Efisio Defraia C, McNamara J, Franchi L. The Angle Orthodontist. 2015;85:784 789. PMID- 26927360 TI - Re: Response to: Giutini V, Vangelisti A, Masucci C, Efisio Defraia C, McNamara J, Franchi L. Treatment effects produced by the Twin-block appliance vs the Forsus Fatigue Resistant Device in growing Class II patients. The Angle Orthodontist. 2015;85: 784-789. PMID- 26927363 TI - Triple-site rTMS for the treatment of chronic tinnitus: a randomized controlled trial. AB - Recent research indicates that tinnitus is related to alterations of neural networks including temporal, parietal, and prefrontal brain regions. The current study examines a rTMS protocol which targets three central nodes of these networks in a two-arm randomized parallel group trial. Overall, 49 patients with chronic tinnitus were randomized to receive either triple-site stimulation (left dorsolateral prefrontal stimulation, 1000 pulses, 20 Hz plus left and right temporoparietal stimulation, 1000 pulses each, 1 Hz) or single-site stimulation (left temporoparietal stimulation, 3000 pulses, 1 Hz). Both groups were treated in ten sessions. Tinnitus severity as measured by the tinnitus questionnaire was assessed before rTMS (day1), after rTMS (day12) and at two follow-up visits (day 90 and day 180). The triple-site protocol was well tolerated. There was a significant reduction in tinnitus severity for both treatment groups. The triple site group tended to show a more pronounced treatment effect at day 90. However, the measurement time point x group interaction effect was not significant. The current results confirm former studies that indicated a significant reduction of tinnitus severity after rTMS treatment. No significant superiority of the multisite protocol was observed. Future approaches for the enhancement of treatment effects are discussed. PMID- 26927365 TI - Solid-Supported Lipid Multilayers under High Hydrostatic Pressure. AB - In this work, the structure of solid-supported lipid multilayers exposed to increased hydrostatic pressure was studied in situ by X-ray reflectometry at the solid-liquid interface between silicon and an aqueous buffer solution. The layers' vertical structure was analyzed up to a maximum pressure of 4500 bar. The multilayers showed phase transitions from the fluid into different gel phases. With increasing pressure, a gradual filling of the sublayers between the hydrophilic head groups with water was observed. This process was inverted when the pressure was decreased, yielding finally smaller water layers than those in the initial state. As is commonly known, water has an abrasive effect on lipid multilayers by the formation of vesicles. We show that increasing pressure can reverse this process so that a controlled switching between multi- and bilayers is possible. PMID- 26927364 TI - Patient Uncertainty Questionnaire-Rheumatology (PUQ-R): development and validation of a new patient-reported outcome instrument for systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) in a mixed methods study. AB - BACKGROUND: An in-depth qualitative exploration of uncertainty in systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) led to the development of a five-domain conceptual framework of patient uncertainty in these two conditions. The purpose of this study was to develop and evaluate a new patient-reported outcome (PRO) instrument for patient uncertainty in SLE and RA on the basis of this empirically developed conceptual framework. METHODS: Cognitive debriefing interviews were conducted to pre-test the initial items generated on the basis of the preliminary qualitative exploration of patient uncertainty in SLE and RA. Two separate field tests were conducted in five hospital sites to evaluate the measurement properties of the new instrument; the first to identify and form scales, and the second to assess measurement properties of the final version in an independent sample. Psychometric evaluation was conducted in line with the Rasch Measurement Theory (RMT), examining the extent to which sample to scale targeting was satisfactory, measurement scales were constructed effectively and the sample was measured successfully. Traditional psychometric techniques were also used to provide complementary analyses best understood by clinicians. RESULTS: Pre-testing supported the relevance, acceptability and comprehensibility of the initial items. Findings indicated that the Patient Uncertainty Questionnaire for Rheumatology PUQ-R instrument fulfilled the expectations of RMT to a large extent (including person separation index 0.73 - 0.91). The PUQ-R comprises 49 items across five scales; symptoms and flares (14 items), medication (11 items), trust in doctor (8 items), self-management (6 items) and impact (10 items) which further displayed excellent measurement properties as assessed against the traditional psychometric criteria (including Cronbach's alpha 0.82 - 0.93). CONCLUSION: The PUQ-R has been developed and evaluated specifically for patients with SLE and RA. By quantifying uncertainty, the PUQ-R has the potential to support evidence-based management programmes and research. PMID- 26927366 TI - Usefulness of Frequency Domain Optical Coherence Tomography Compared with Intravascular Ultrasound as a Guidance for Percutaneous Coronary Intervention. AB - OBJECTIVES: To compare outcomes and rates of optimal stent placement between optical coherence tomography (OCT) and intravascular ultrasound (IVUS) guided percutaneous coronary intervention (PCI). BACKGROUND: Unlike IVUS-guided PCI, rates of clinical outcomes and optimal stent placement have not been well characterized for OCT-guided PCI. METHODS: The study enrolled 290 patients who underwent implantation of a second generation drug eluting stent under OCT (122 patients) or IVUS (168 patients) guidance. The two groups were compared after adjusting for baseline differences using 1:1 propensity score matching (PSM) (114 patients in each group). Optimal stent placement was defined as achieving an adequate lumen (optimal minimum stent area [MSA > 4.85 mm(2) for OCT, >5 mm(2) for IVUS] or a final MSA >= 90% of the distal reference lumen area, without edge dissection, incomplete stent apposition, or tissue prolapse), or otherwise performing additional interventions to address suboptimal post-stenting OCT or IVUS findings. The primary endpoint was one-year cumulative incidence of major adverse cardiac events (MACE; cardiac death, myocardial infarction and target lesion revascularization). Definite or probable stent thrombosis (ST) rates were evaluated. RESULTS: In adjusted comparisons between OCT and IVUS groups, there was no significant difference in rates of MACE (3.5% vs. 3.5%, P = 1.000) and ST (0% vs. 0.9%, P = 1.000) at 1 year, optimal stent placement (89.5% vs. 92.1%, P = 0.492), and further intervention (7.9% vs.13.2%, P = 0.234), despite OCT significantly more frequently detecting tissue prolapse (97.4% vs. 47.4%, P < 0.001), and numerically more edge dissection (10.5% vs. 4.4%, P = 0.078) or incomplete stent apposition (48.2% vs. 36.8%, P = 0.082). CONCLUSIONS: OCT guidance showed comparable results to IVUS in mid-term clinical outcomes, suggesting that OCT can be an alternative tool for stent placement optimization. PMID- 26927368 TI - Statement of Removal. PMID- 26927369 TI - [An increase in the ratio of peripheral blood CD4+/CD8+ T lymphocytes and the levels of connexin 40 and inflammatory factors in spontaneously hypertensive rats]. AB - OBJECTIVE: To analyze the relationships of connexin 40 (Cx40) with peripheral blood CD4(+) and CD8(+) T lymphocyte subsets and inflammatory factors of spontaneously hypertensive (SH) rats. METHODS: Flow cytometry was used to detect CD4(+), CD8(+) lymphocytes and Cx40 expression on the cells in the peripheral blood of Wistar-Kyoto (WKy) rats and SH rats. ELISA was performed to test the levels of interleukin 2 (IL-2), interferon gamma (IFN-gamma), IL-4 and IL-6. RESULTS: Compared with WKy rats, the systolic blood pressure, the percentage of CD4(+) T lymphocytes, the expression of Cx40 on the surface of CD4(+) and CD8(+) T lymphocytes and the ratio of CD4(+)/CD8(+) in the peripheral blood of SH rats were significantly higher, with the exception of the percentage of CD8(+) lymphocytes which was lower. Also, we found that the serum levels of IL-2, IL-4 and IL-6 in the SH rats were significantly higher than those of WKy rats. However, there was no significant difference in the IFN-gamma level between SH and WKy rats. CONCLUSION: The ratio of peripheral blood CD4(+)/CD8(+) T lymphocytes and the levels of Cx40, IL-2, IL-4 and IL-6 are significantly elevated in SH rats. PMID- 26927367 TI - Narrow-band imaging (NBI) magnifying endoscopic classification of colorectal tumors proposed by the Japan NBI Expert Team. AB - Many clinical studies on narrow-band imaging (NBI) magnifying endoscopy classifications advocated so far in Japan (Sano, Hiroshima, Showa, and Jikei classifications) have reported the usefulness of NBI magnifying endoscopy for qualitative and quantitative diagnosis of colorectal lesions. However, discussions at professional meetings have raised issues such as: (i) the presence of multiple terms for the same or similar findings; (ii) the necessity of including surface patterns in magnifying endoscopic classifications; and (iii) differences in the NBI findings in elevated and superficial lesions. To resolve these problems, the Japan NBI Expert Team (JNET) was constituted with the aim of establishing a universal NBI magnifying endoscopic classification for colorectal tumors (JNET classification) in 2011. Consensus was reached on this classification using the modified Delphi method, and this classification was proposed in June 2014. The JNET classification consists of four categories of vessel and surface pattern (i.e. Types 1, 2A, 2B, and 3). Types 1, 2A, 2B, and 3 are correlated with the histopathological findings of hyperplastic polyp/sessile serrated polyp (SSP), low-grade intramucosal neoplasia, high-grade intramucosal neoplasia/shallow submucosal invasive cancer, and deep submucosal invasive cancer, respectively. PMID- 26927362 TI - Preventing and Experiencing Ischemic Heart Disease as a Woman: State of the Science: A Scientific Statement From the American Heart Association. PMID- 26927370 TI - [The recombinant monocyte chemotactic protein 1 expressed in HEK293T cells promotes migration of macrophages]. AB - OBJECTIVE: To construct the eukaryotic expression vector of monocyte chemokine protein 1 (MCP-1) driven by the cytomegalovirus (CMV) promoter, transfect the vector into HEK293T cells, and detect its chemotaxis to macrophages. METHODS: MCP 1 promoter was obtained from mouse genome by PCR, and inserted into the vector named pFLAG-CMV1. We validated it by double-enzymes digestion and sequencing. Then HEK293T cells were transfected with pFLAG-CMV1-MCP-1. The expression of MCP 1 was detected by Western blotting. Finally, we identified the chemotaxis of the recombinant vector to macrophage by Transwell(TM) assay. RESULTS: The recombinant vector could generate target fragment by double enzyme digestion. HEK293T cells expressed MCP-1 after they were transfected with the recombinant vector, which increased the migration of macrophages. CONCLUSION: MCP-1 expressed by HEK293T cells could apparently increase the migration of macrophages. PMID- 26927371 TI - [Pulsatilla decoction inhibits vulvovaginal Candida albicans proliferation and reduces inflammatory cytokine levels in vulvovaginal candidiasis mice]. AB - OBJECTIVE: To explore the possible regulatory effect of Pulsatilla decoction on Th17 cells and inflammatory cytokines of vulvovaginal candidiasis (VVC) mice. METHODS: Seventy-two female Kunming mice were randomly assigned into six groups: a blank control group, a VVC model group, a fluconazole group and three Pulsatilla decoction groups (dose levels: 22.5, 15.0 and 7.5 g/kg, respectively). The VVC mouse models were established by vaginal inoculation with Candida albicans (C. albicans) in female mice in pseudoestrus state caused by estradiol injection. After 7-day treatment on VVC mice, the vaginal C. albicans burden was assessed using dilution spread plate method; the vaginal C. albicans morphology was observed by Gram staining method; the levels of interleukin 6 (IL-6), IL-17, IL-21 and tumor necrosis factor alpha (TNF-alpha) in sera were detected by ELISA. The content of the transcription factor retinoid related orphan receptor gamma t (RORgammat) in vaginal tissues was detected by immunohistochemistry. RESULTS: The VVC mouse models were successfully developed. After treatment, the vaginal C. albicans burden of the fluconazole group and 22.5 g/kg Pulsatilla decoction group dropped significantly compared with that of the VVC model group. Gram staining showed that the VVC mice had lots of C. albicans hyphae in vaginal discharge, that 7.5 g/kg Pulsatilla decoction group remained the mycelia-phase C. albicans, and that 15.0 g/kg Pulsatilla decoction group had the majority of yeast-phase C. albicans and a few of mycelia-phase, while no hyphae and only very few of yeast phase C. albicans were observed in 22.5 g/kg Pulsatilla decoction group and fluconazole group. After 7-day treatment, compared with the model group, the levels of IL-6, IL- 17, IL-21 and TNF-alpha in the sera of the fluconazole group, 15.0 and 22.5 g/kg Pulsatilla decoction groups were reduced significantly and the levels of RORgammat in the vaginal tissues of the fluconazole group, 15.0 and 22.5 g/kg Pulsatilla decoction groups also decreased significantly. CONCLUSION: Pulsatilla decoction could inhibit the proliferation of vulvovaginal C. albicans and reduces the levels of inflammatory cytokines in VVC mice. PMID- 26927372 TI - [Transmembrane prostate androgen-induced protein 1 (PMEPA1) promotes the migration and maintains mesenchymal-like phenotype of breast cancer cells]. AB - OBJECTIVE: To investigate the role of transmembrane prostate androgen-induced protein 1 (PMEPA1), an important gene downstream of transforming growth factor beta (TGF-beta) signaling, in the process of breast cancer cell migration and epithelial-mesenchymal transition. METHODS: We treated MDA-MB-231 breast cancer cells with TGF-beta and TGF-beta inhibitor SB431542, and then detect the level of PMEPA1 using Western blotting. PMEPA1-specific siRNA was designed and its knockdown efficiency was tested by quantitative real-time PCR (qRT-PCR). After the expression of PMEPA1 in MDA-MB-231 cells was successfully silenced, the wound healing assay and Transwell(TM) assay were used to investigate the effect of PMEPA1 silencing on the migration of MDA-MB-231 cells. Moreover, phalloidin was used to label the actin cytoskeleton of breast cancer cells to observe the effect of PMEPA1 silencing on cell morphology. RESULTS: In breast cancer cells, PMEPA1 was upregulated by classical TGF-beta/Smad signaling pathway. Silencing of PMEPA1 significantly inhibited the migration ability of MDA-MB-231 cells and promoted the process of mesenchymal-epithelial transition. CONCLUSION: Over-expressed PMEPA1 can promote cell migration and maintain the mesenchymal-like morphology of breast cancer cells. PMID- 26927373 TI - [Protocadherin 10 (PCDH10) inhibits the proliferation, invasion and migration ability of BXPC-3 pancreatic cancer cells]. AB - OBJECTIVE: To explore the expression and biological function of protocadherin 10 (PCDH10) in pancreatic cancer cells. METHODS: Reverse transcription PCR (RT-PCR) was used to detect the expression of PCDH10 in CAPAN-1, PANC-1, ASPC-1, BXPC-3 pancreatic cancer cells and the HPDE6-C7 normal human pancreatic ductal epithelial cells. Recombinant plasmid pcDNA3.1-PCDH10 and empty vector pcDNA3.1 were transfected into BXPC-3 pancreatic cancer cells via Lipofectamine(TM)2000. After transfection, the mRNA expression of PCDH10 was examined by RT-PCR, and the protein level was detected by Western blotting. CCK-8 and colony formation assays were used to analyze the cell proliferation. Cell apoptosis was tested by flow cytometry combined with annexin V-FITC/PI staining. Transwell(TM) and wound healing assays were performed to measure the invasion and migration ability of the cells. RESULTS: Compared with the normal pancreatic ductal epithelial cells, the expression of PCDH10 was obviously lower in the CAPAN-1, PANC-1, BXPC-3 cells. RT-PCR and Western blotting revealed that PCDH10 expression significantly increased in BXPC-3 cells transfected with plasmid pcDNA3.1-PCDH10 compared with the ones with empty vector pcDNA3.1. CCK-8 and colony formation assays showed that the PCDH10-transfected cells grew more slowly than the empty vector transfected cells. Annexin V-FITC/PI staining combined with flow cytometry proved that the apoptosis in the PCDH10-transfected cells remarkably increased compared with that in the control group. A reduction of the invasion and migration ability was found obviously in the PCDH10-transfected cells by Transwell(TM) assay. The wound healing assay also showed that the PCDH10-transfected cells spread the more slowly than the empty vector-transfected cells. CONCLUSION: The expression of PCDH10 was down-regulated in the pancreatic cancer cells. PCDH10 over-expression could significantly induce cell apoptosis, and restrain proliferation, invasion and migration ability of BXPC-3 pancreatic cancer cells. PMID- 26927374 TI - [Metformin inhibits THP-1 macrophage-derived foam cell formation induced by lipopolysaccharide]. AB - OBJECTIVE: To investigate the impact of metformin (Met) on THP-1 macrophage derived foam cell formation induced by lipopolysaccharide (LPS) and observe the changes of lipid droplets (LDs) and LDs-associated proteins. METHODS: THP-1 cells were induced to differentiate into macrophages by 100 ng/mL phorbol 12-myristate 13-acetate (PMA) for 48 hours, and then the macrophages were further induced to generate foam cells by 50 MUg/mL oxidized low-density lipoprotein (ox-LDL) and 1 MUg/mL LPS. During this process, these foam cells were treated with 0, 100, 200 MUmol/L Met. Under the fluorescence microscope, the effect of Met on foam cell formation was evaluated by Oil red O staining and the number and morphology of LDs were observed by BODIPY493/503 staining. Intracellular triglyceride (TG) were extracted and measured by TG quantitative kits. The expressions of adipose differentiation-related protein (ADRP) and tail-interacting protein of 47 kDa (TIP47) were detected by Western blotting. RESULTS: Compared with the untreated group, the LDs in foam cells were reduced significantly and the size became smaller after treated with 100 or 200 MUmol/L Met. What's more, the quantitative data showed that the intracellular TG content decreased markedly in a dose dependent manner, and the TG content decreased about 25% in foam cells treated with 200 MUmol/L Met. Western blotting showed that Met reduced the expression of ADRP, but not TIP47 in the THP-1 macrophage-derived foam cells. CONCLUSION: Met could inhibit THP-1-derived foam cell formation induced by LPS, reduce intracellular lipid accumulation, and down-regulate the expression of ADRP. PMID- 26927375 TI - [Grape seed proanthocyanidins inhibits the invasion and migration of A549 lung cancer cells]. AB - OBJECTIVE: To explore the effect of grape seed proanthocyanidins (GSPs) on the invasion and migration of A549 lung cancer cells and the underlying mechanism. METHODS: Trypan blue dye exclusion assay was used to determine the cytotoxic effect of varying doses of GSPs on the BEAS-2B normal human pulmonary epithelial cells. After treated with 0, 10, 20, 40, 80 MUg/mL GSP, the proliferation of A549 cells was detected by MTT assay; the invasion and migration of A549 cells were determined by Transwell(TM) assay and scratch wound assay, respectively. The levels of epithelial growth factor receptor (EGFR), E-cadherin, N-cadherin in A549 cells treated with GSPs were detected by Western blotting. RESULTS: (0-40) MUg/mL GSPs had no significant toxic effect on BEAS-2B cells, while 80 MUg/mL GSPs had significant cytotoxicity to BEAS-2B cells. The proliferation of A549 cells was significantly inhibited within limited dosage in a dose-dependent manner, and the abilities of invasion and migration of A549 cells were also inhibited. Western blotting showed that the expression of EGFR and N-cadherin decreased, while E-cadherin increased after GSPs treatment. CONCLUSION: GSPs could inhibit the abilities of proliferation, invasion and migration of A549 cells, which might be related to the dow-regulation of EGFR and N-cadherin and the up-regulation of E-cadherin. PMID- 26927376 TI - [Myocardial cells and mitochondrial autophagy in sepsis mice induced by lipopolysaccharide]. AB - OBJECTIVE: To investigate the alterations in the level of myocardial cells and mitochondrial autophagy during myocardial injury in lipopolysaccharide (LPS) induced septic animal models. METHODS: Male C57BL/J mice were randomly divided into negative control group (NC), LPS treatment groups (6, 12, 24, 36 hours). The LPS treatment groups were subjected to LPS (10 mg/kg) injection intraperitoneally, and the NC group was injected intraperitoneally with the same amount of saline. The mice were sacrificed at the above time points to collect blood and heart tissues. Cytoplasmic protein, mitochondria and mitochondrial proteins were extracted from the myocardial tissue, and other myocardial tissue was frozen for next analysis. Cardiac troponin I (cTnI) levels in sera were evaluated by ELISA; mitochondrial membrane potential (MMP) was tested by JC-1 staining and fluorescence cytometry at different time points after LPS intraperitoneal injection. Furthermore, the levels of autophagy-related proteins such as microtubule-associated protein 1 light chain 3 (LC3), PTEN-induced kinase 1 (pink1), E3-ubiquitin ligase parkin were measured by Western blotting and fluorescent immunohistochemistry. RESULTS: Compared with the control group, the serum levels of cTnI induced by LPS were significantly higher as 6 hours, while the MMP was significantly lower in the LPS treatment groups, and the lowest was in the 12-hour group. The expression of autophagy-related protein LC3-II/LC3-I significantly increased in the LPS 12-hour treatment group, pink1/parkin was significantly elevated in the LPS 6-hour treatment group, and they then gradually decreased. CONCLUSION: The autophagy stress is activated in myocardium during myocardial injury induced by LPS treatment and it probably happens earlier at myocardial mitochondria. PMID- 26927377 TI - [Pioglitazone decreases the levels of inflammatory cytokines in SD rats with traumatic brain injury via up-regulating PPARgamma]. AB - OBJECTIVE: To observe the effect of pioglitazone on the levels of peroxisome proliferator activated receptor gamma (PPARgamma), tumor necrosis factor-alpha (TNF-alpha) and interleukin 6 (IL-6) mRNAs and the dose-dependent relationship in rats with traumatic brain injury (TBI). METHODS: A total of 72 male SD rats were randomly divided into a normal group, a sham operation group, a control group and three pioglitazone groups receiving doses of 0.5, 1.0 and 10.0 mg/kg, with 12 rats in each group. Modified Feeney's free falling method was used to make TBI models; the sham operation group only had an operation but without combat; the pioglitazone groups were given pioglitazone at the doses of 0.5, 1.0 and 10.0 mg/kg, respectively; the control group and sham operation group were given equal amount of placebo. The levels of PPARgamma, TNF-alpha and IL-6 mRNAs in lesion brain tissues were detected by reverse transcription PCR 24 and 48 hours after injury. RESULTS: Twenty-four hours after the injury, the expression of PPARgamma mRNA was up-regulated significantly in all pioglitazone groups, with significant difference between each pioglitazone group in a dose-dependent manner. The expression of TNF-alpha mRNA was significantly down-regulated in the treatment groups after injury. Twenty-four hours after the injury, the levels of TNF-alpha and IL-6 mRNAs in the pioglitazone groups receiving the doses of 1.0 and 10.0 mg/kg decreased compared with those in the group receiving 0.5 mg/kg pioglitazone. CONCLUSION: Pioglitazone inhibits inflammatory reaction by up regulating the level of PPARgamma mRNA and down-regulating the levels of TNF alpha and IL-6 mRNAs in rats with TBI. PMID- 26927378 TI - [High-dose neuropeptide Y inhibits proliferation and promotes differentiation of human adipose-derived stem cells]. AB - OBJECTIVE: To investigate the impact of neuropeptide Y (NPY) at different concentrations on the proliferation and differentiation of human adipose-derived stem cells (hADSCs). METHODS: The hADSCs were separated and incubated with NPY at a range of concentrations 10(-6)-10(-15) mol/L. MTT assay was used to detect cell proliferation. Following the treatment of complete medium, NPY and insulin separately, cell differentiation was observed by Oil red O staining. In addition, Western blotting was performed to exam the levels of peroxisome proliferator activated receptor-gamma (PPARgamma), CCAAT/enhancer binding protein alpha (C/EBPalpha), cell death-inducing dFF45-like effector c (Cidec) and receptor interacting protein 140 (RIP140). RESULTS: MTT assay revealed that 10(-11)-10( 15) mol/L NPY stimulated the proliferation of hADSCs, while high-dose NPY (10(-6) 10(-10) mol/L) inhibited the cell proliferation. NPY (10(-7), 10(-9), 10(-11) mol/L) induced the differentiation of hADSCs. The expression levels of related adipocyte markers (PPARgamma, C/EBPalpha), mature white adipose tissue specific markers (Cidec, RIP140) increased at the presence of NPY (10(-7), 10(-9), 10(-11) mol/L). CONCLUSION: Low-dose NPY could stimulate the proliferation of hADSCs, and high-dose NPY could inhibit the proliferation and promote the differentiation of hADSCs. PMID- 26927379 TI - [IFN-gamma up-regulates PD-L1 expression in human placenta mesenchymal stem cells and enhances cell ability to induce the differentiation of IL-10+ T cells from cord blood- and peripheral blood-derived T cells]. AB - OBJECTIVE: To compare the differentiation, inducing effects of human placenta mesenchymal stem cells (hPMSCs) on IL-10(+) T cells derived from cord blood and peripheral blood, and investigate the effect of IFN-gamma on the induction. METHODS: The hPMSCs were isolated from human placenta and cultured. The expression of programmed death ligand 1 (PD-L1) in hPMSCs was detected by reverse transcriptase PCR and flow cytometry (FCM), respectively. Mononuclear cells were isolated from cord blood and peripheral blood of healthy donors by Ficoll density gradient centrifugation, and T cells were purified by sheep red blood cells. Then hPMSCs, pretreated with PD-L1 mAb or IFN-gamma, were co-cultured with phytohaemagglutinin (PHA)-activated T cells. Percentages of CD4(+)IL-10(+) and CD8(+)IL-10(+) T cells in cord blood and peripheral blood T cells were analyzed by FCM. RESULTS: hPMSCs could induce the differentiation of CD4(+)IL-10(+) and CD8(+)IL-10(+) T cells from cord blood or peripheral blood T cells, and the number of IL-10(+) T cells in the peripheral blood T cells was significantly higher than that in the cord blood T cells. Pretreatment with IFN-gamma markedly enhanced the differentiation, inducing ability of hPMSCs. PD-L1 was highly expressed in hPMSCs, and the expression was also significantly promoted by IFN gamma. After the expression of PD-L1 was blocked in hPMSCs, the percentages of CD4(+)IL-10(+) and CD8(+)IL-10(+) T cells obviously decreased in cord blood and peripheral blood T cells. CONCLUSION: The ability of hPMSCs to induce the differentiation of IL-10(+) T cells from peripheral blood T cells was apparently stronger than that in cord blood T cells. IFN-gamma could up-regulate the number of IL-10(+)T cells differentiated from cord blood and peripheral blood T cells in the present of hPMSCs by enhancing the expression of PD-L1 in hPMSCs. PMID- 26927380 TI - [Lipopolysaccharide induces astrocyte activation and downregulates the expression of Kir4.1 channel]. AB - OBJECTIVE: To explore the influence of lipopolysaccharide (LPS) on the activation of astrocytes and the expression of the inwardly rectifying K(+) channel Kir4.1. METHODS: Astrocytes were separated from the cerebral cortex of newborn SD rats and cultured in the presence of LPS or LPS combined with interleukin-1 receptor antagonist (IL-1ra). The cell vitality was detected by MTT assay; the expression of glial fibrillary acidic protein (GFAP) was analyzed by immunocytochemistry; the production of IL-1beta was tested by ELISA; the expression of Kir4.1 and IL 1beta mRNAs were determined by quantitative real-time PCR. RESULTS: LPS promoted the activation of astrocytes in a time- and dose-dependent manner. LPS significantly increased the production of IL-1beta and the expression of IL-1beta mRNA, while decreased the expression of Kir4.1 mRNA in cultured astrocytes. Compared with the LPS group, IL-1ra could effectively reversed the above two results. CONCLUSION: The cultured astrocytes could be activated by LPS; LPS induced downregulation of Kir4.1 mRNA in cultured astrocytes might be related with the inflammatory cytokine IL-1beta. PMID- 26927381 TI - [Regulatory effect of curcumin on subsets and co-stimulatory molecules of dendritic cells in spleen from mice with colitis]. AB - OBJECTIVE: To explore the effect of curcumin (Cur) on the subpopulation and costimulatory molecules of dendritic cells (DCs) in spleen from colitis mice. METHODS: Forty male C57/BL mice were randomly divided into 4 groups: normal group, model group, Cur group and mesalazine group. Colitis was induced by 2, 4, 6-trinitrobenzene sulfonic acid (TNBS). On the 8th day following 7-day treatment with Cur, the mice were sacrificed and the length and mass of mouse colon were measured. And then the spleens were separated to prepare DCs. The numbers of CD205(+), CD4(+)CD205(+), CD8(+)CD205(+) DCs and the levels of major histocompability complex II (MHC-II), Toll-like receptor 2 (TLR2), TLR4 and CD83 expression were detected by flow cytometry. And we observed the pathological injury of colon. RESULTS: Compared with model group, the colonic mass index was reduced, the length of colon was lengthened, and the pathological injury was remitted. Meanwhile, the percents of CD205(+), CD4(+)CD205(+), CD8(+)CD205(+) DCs and the levels of MHC-II, TLR2 and TLR4 were down-regulated, however, the CD83 expression was up-regulated. CONCLUSION: Treatment efficacy of Cur on experimental colitis might be involved in regulating subpopulation and co stimulatory molecules of dendritic cells in spleen from mice with colitis. PMID- 26927382 TI - [Rapid biosynthesis and release of 35 kD granzyme B by NK92 cells bypassing secretory lysosomes]. AB - OBJECTIVE: To investigate the possibility of the biosynthesis and release of granzyme B (GZB) by NK92 cells bypassing the way of secretory lysosomes (SLs) and the possible mechanism. METHODS: As cell models, NK92 cells were activated by the phorbol myristate acetate (PMA) and ionomycin (ION). Within 4 hours following the activation, immuno- fluorescence and electron microscopy were used to detect the content and distribution of 35 000 (Mr) and 32 000 (Mr) GZB in the cytoplasm of NK92 before and after the protein synthesis was inhibited; Western blotting was performed to detect GZB inside and outside the SLs. After blocking the release of 32 000 (Mr) GZB by inhibiting the exocytosis of SLs with EDTA, we tested the content of Mr 35 000 GZB in activated NK92 supernatant. Activated NK92 cells were co-cultured with K562 cells to observe whether the Mr 35 000 GZB could enter the K562 cells. Activated NK92 cell death rate was determined and the enzyme activity of secreted Mr 35 000 GZB was examined. RESULTS: Four hours after stimulated by PMA/ION, NK92 cells generated large amount of Mr 35 000 GZB in the cytoplasm outside SLs where Mr 32 000 GZB was located. Immunoelectron microscope and immunofluorescence further approved that Mr 35 000 GZB outside SLs was located in vesicles. In addition, Mr 35 000 GZB could be secreted outside NK92 cells. Further investigation found that GZB/Serpinb9 composite and Mr 35 000 GZB could simultaneously emerge in the cytoplasm outside SLs. However, activated NK92 cell death rate did not rise. Mr 32 000 GZB inside SLs had enzyme activity in contrast with the Mr 35 000 GZB in zymogen form outside SLs, which suggested that Mr 35 000 GZB was not originated from the SLs. CONCLUSION: The activated human NK cell lines could secreted rapidly inactive Mr 35 000 GZB outside SLs, and the GZB could enter the extracellular matrix or target cells bypassing SLs, which provides a part of the extracellular GZB. PMID- 26927383 TI - [Protective effect of pretreatment with TLR2 agonist Pam3Csk4 on mice challenged by methicillin-resistant Staphylococcus aureus]. AB - OBJECTIVE: To evaluate the protective effect of pretreatment with Pam3Csk4, a Toll-like receptor 2 (TLR2) agonist, on mice against methicillin-resistant Staphylococcus aureus (MRSA) infection. METHODS: Kunming mice were injected with Pam3Csk4 (25, 50, 100 MUg/mice) via tail vein. 12 and 24 hours later, the mice were inoculated with live MRSA (7*10(10) CFU/kg, ATCC43300) via tail vein. All mice were observed at 2-hour intervals for the first 24 hours and 6-hour intervals for the rest time, and survival was monitored for at least 7 days. Bacterial burden in liver, spleen and kidney of the mice were estimated by colony counting on nutrient agar 6 hours after infection (3*10(8) CFU/mice, ATCC43300). In addition, 6, 12 and 24 hours after MRSA challenge, the concentrations of tumor necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6), interferon gamma (IFN gamma) and IL-10 were measured by ELISA, and the mRNA levels of these cytokines were detected by fluorescence quantitative PCR (qPCR). Finally, 24 hours after being pretreated with Pam3Csk4, mRNA levels of CXC chemokine ligand 1 (CXCL1) and Fcgamma receptor III (FcgammaRIII) in spleen of the mice were evaluated by qPCR. RESULTS: Compared with normal saline-pretreated mice, we found that mice pretreated with the Pam3Csk4 (100 MUg/mice) had higher survival in sepsis models caused by MRSA in dose- and time-dependent manners, and Pam3Csk4 (over 50 MUg/mice)-pretreated mice had a survival rate more than 70%. In addition, the protein and mRNA levels of TNFalpha were markedly reduced in Pam3Csk4-pretreated mice at 6 and 12 hours, but not different from the controls at 24 hours post infection. While IL-6 at protein and mRNA levels decreased in Pam3Csk4-pretreated mice only at 6 hours post-infection. Both protein and mRNA levels of IFN-gamma greatly decreased in Pam3Csk4-pretreated mice compared with those of the control group. However, IL-10 level was unchanged between the two groups at all time points. Further studies showed that the mRNA levels of CXCL1 and FcgammaRIII were notably raised in spleen of the mice 24 hours after administered with Pam3Csk4 compared with normal saline-pretreated mice. CONCLUSION: Our results suggest that Pam3Csk4 pretreatment can protect mice from challenged by MRSA. PMID- 26927384 TI - [Expression and clinical significance of 5hmC in bladder urothelial carcinoma]. AB - OBJECTIVE: To investigate the expression of 5-hydroxymethylcytosine (5hmC) in bladder urothelial carcinoma (UC) and its clinical significance. METHODS: The expression of 5hmC in 21 cases of UC tissues and pericarcinous urinary tract epithelium was detected by immunohistochemical staining. Then the expression of 5hmC in the surgical resection of UC tissues in 92 cases was also surveyed. Non parametric U Mann-Whitney test was used to analyze the correlation between 5hmC expression and clinical data. Single factor survival analysis was performed by Kaplan-Meier test. RESULTS: The expression of 5hmC in normal urinary tract epithelium and UC tissues was significantly different, but there was no significant difference in the expression of 5hmC between low and high grades of UC tissues as well as between different TNM grades. Kaplan-Meier single factor survival analysis showed that there was no significant correlation between the 5hmC expression level and the survival rate or the recurrence-free survival of UC patients. CONCLUSION: The expression level of 5hmC in UC tissues is significantly lower than that in pericarcinous urinary tract epithelium. There is no correlation between the 5hmC expression and the progression, prognosis and recurrence of UC. PMID- 26927385 TI - [Clinicopathological significance of ezrin and SIX1 protein expression in alpha fetoprotein-negative hepatocellular carcinoma]. AB - OBJECTIVE: To investigate the clinicopathological significance of ezrin and SIX1 overexpression in alpha fetoprotein (AFP)-negative hepatocellular carcinoma (HCC). METHODS: The EnVision immunohistochemical method was used to detect the protein expression of ezrin and SIX1 in the tumor tissues and corresponding adjacent normal liver tissues from 50 AFP-negative HCC patients. The correlations between the overexpression of ezrin and SIX1 and the prognosis of the patients with HCC were analyzed by Chi-square test and Spearman analysis. RESULTS: The positive rates of ezrin and SIX1 protein expression in AFP-negative HCC tissues were 68.0% (34/50) and 60.0% (30/50), respectively, and they were significantly higher than the expression rates [38.0% (19/50) and 26.0% (13/50)] in adjacent normal liver tissues. Chi-square test showed that the expression of both ezrin and SIX1 proteins were related to TNM stage and lymphovascular infiltration, and Spearman analysis revealed a positive correlation between ezrin and SIX1 expression in AFP-negative HCC. CONCLUSION: Both Ezrin and SIX1 proteins are highly expressed in AFP-negative HCC, and significantly related with the TNM stage and lymphovascular infiltration of patients with AFP-negative HCC. In addition, there is a positive correlation between ezrin and SIX1 expression in AFP-negative HCC. PMID- 26927386 TI - [Alterations of IFN-gamma and IL-4 of peripheral blood T cells in patients with chronic HBV infection]. AB - OBJECTIVE: To investigate the regulatory roles of cytokines expressed on peripheral blood T cells in chronic hepatitis B virus (HBV) infection. METHODS: Sixty patients with chronic HBV infection were categorized into immune tolerance phase (IT), immune clearance phase (IC), and inactive carrier phase (IA) groups. Twenty healthy individuals were enrolled as healthy controls. Another 21 HBeAg positive chronic hepatitis (CHB) patients were administrated with entecavir (0.5 mg/d) for 6 months. Serum alanine transaminase (ALT) levels were tested by automatic biochemistry analyzer, and HBV DNA loads were tested by PCR, and cytokines expressed on T cells were examined by flow cytometry. RESULTS: There were negative correlations between IFN-gamma levels expressed by peripheral blood CD4(+)T cells and CD8(+)T cells and serum HBV DNA loads in patients with chronic HBV infection, and there were negative correlations between the ratio of IFN gamma/IL-4 in peripheral blood CD4(+)T cells and CD8(+)T cells and serum HBV DNA loads. In addition, the expression levels of IFN-gamma were gradually elevated and the expression levels of IL-4 were gradually lowered from IT to IA. In IT, the level of IFN-gamma expressed by T cells in patients was lower than that in healthy controls and the level of IL-4 was higher than that in healthy controls. In IA, the levels of IFN-gamma and IL-4 were recovered to the normal. Anti-virus therapy reduced serum HBV DNA load and ALT levels in patients, which was accompanied with the increase of IFN-gamma level and IFN-gamma/IL-4 ratio in CD8(+)T cells. CONCLUSION: During chronic HBV infection, IFN-gamma and IL-4 expressed by peripheral blood T cells play dual immunoregulatory roles, which are correlated with the efficacy of entecavir. PMID- 26927388 TI - Adversarial Risk Analysis for Urban Security Resource Allocation. AB - Adversarial risk analysis (ARA) provides a framework to deal with risks originating from intentional actions of adversaries. We show how ARA may be used to allocate security resources in the protection of urban spaces. We take into account the spatial structure and consider both proactive and reactive measures, in that we aim at both trying to reduce criminality as well as recovering as best as possible from it, should it happen. We deal with the problem by deploying an ARA model over each spatial unit, coordinating the models through resource constraints, value aggregation, and proximity. We illustrate our approach with an example that uncovers several relevant policy issues. PMID- 26927387 TI - [Preparation and application of rabbit antiserum against structural protein VP2 of canine bocavirus]. AB - OBJECTIVE: To prepare the rabbit polyclonal antibody against canine bocavirus (CBV) structural protein VP2 and identify its specificity. METHODS: The target sequence of gene fragment encoding VP2 C-terminal region (300 AA) was amplified from CBV infection clone. After the restriction enzyme digestion and nucleotide sequencing, the target gene was successfully inserted into pET32a(+) prokaryotic expression vector to form recombinant plasmid pET-32a(+)-VP2. Then pET-32a(+)-VP2 was transferred into E.coli (BL21), and VP2-his fusion protein was induced under the optimized induction of isopropyl beta-D-thiogalactopyranoside (IPTG). The products were identified and analyzed by SDS-PAGE. The purified fusion protein was inoculated into adult rabbits to develop polyclonal antibody. After the titer of the antiserum was detected by ELISA, Western blotting and immunofluorescence staining were performed to evaluate the features of the prepared antiserum. RESULTS: Restriction enzyme digestion and sequencing showed that prokaryotic expression vector pET-32a(+)-VP2 was successfully constructed. The soluble recombinant protein was highly expressed in E.coli BL21 as expected. After purification and inoculation into adult rabbits, the high-titer polyclonal antibody was prepared and the titer was 1:6 400 000. Western blotting and immunohistochemistry demonstrated that the specificity of the prepared polyclonal antibody was perfect. CONCLUSION: The polyclonal antibody against CBV structural protein VP2 has been successfully prepared. PMID- 26927390 TI - Characterization of natural and irradiated nails by means of the depolarization metrics. AB - Mueller polarimetry is applied to study the samples of nails: natural (or reference) and irradiated to 2 Gy ionizing radiation dose. We measure the whole Mueller matrices of the samples as a function of the scattering angle at a wavelength of 632.8 nm. We apply depolarization analysis to measured Mueller matrices by calculating the depolarization metrics [depolarization index, Q(M) metric, first and second Lorenz indices, Cloude and Lorenz entropy] to quantify separability of the different samples of nails under study based on differences in their Mueller matrix. The results show that nail samples strongly depolarize the output light in backscattering, and irradiation in all cases results in increasing of depolarization. Most sensitive among depolarization metrics are the Lorenz entropy and Q(M)-metric. PMID- 26927389 TI - A high-fat diet decreases GABA concentration in the frontal cortex and hippocampus of rats. AB - BACKGROUND: It has been proposed that the gamma-aminobutyric acid (GABA) plays a key role in the regulation of food intake and body weight by controlling the excitability, plasticity and the synchronization of neuronal activity in the frontal cortex (FC). It has been also proposed that the high-fat diet (HFD) could disturb the metabolism of glutamate and consequently the GABA levels, but the mechanism is not yet clearly understood. Therefore, the aim of this study was to investigate the effect of a HFD on the GABA levels in the FC and hippocampus of rats. RESULTS: The HFD significantly increased weight gain and blood glucose levels, whereas decreased the GABA levels in the FC and hippocampus compared with standard diet-fed rats. CONCLUSIONS: HFD decreases GABA levels in the FC and hippocampus of rat, which likely disrupts the GABAergic inhibitory processes, underlying feeding behavior. PMID- 26927391 TI - Over-expression of (1,3;1,4)-beta-D-glucanase isoenzyme EII gene results in decreased (1,3;1,4)-beta-D-glucan content and increased starch level in barley grains. AB - BACKGROUND: High content of (1,3;1,4)-beta-d-glucan in barley grains is regarded as an undesirable factor affecting malting potential, brewing yield and feed utilization. Production of thermostable bacterial (1,3;1,4)-beta-glucanase in transgenic barley grain or supplementation of exogenous bacterial (1,3;1,4)-beta glucanase has been used to improve malt and feed quality. The aim of the present study was to investigate the effect of over-expression of an endogenous (1,3;1,4) beta-glucanase on beta-glucan content and grain composition in barley. RESULTS: A construct containing full-length HvGlb2 cDNA encoding barley (1,3;1,4)-beta glucanase isoenzyme EII under the control of a promoter of barley D-Hordein gene Hor3-1 was introduced into barley cultivar Golden Promise via Agrobacterium mediated transformation, and transgenic plants were regenerated after hygromycin selection. The T2 generation of proHor3:HvGlb2 transgenic lines showed increased activity of (1,3;1,4)-beta-glucanase in grains. Total beta-glucan content was reduced by more than 95.73% in transgenic grains compared with the wild-type control. Meanwhile, over-expression of (1,3;1,4)-beta-glucanase led to an increase in 1000-grain weight, which might be due to elevated amounts of starch in the grain. CONCLUSION: Manipulating the expression of (1,3;1,4)-beta-glucanase EII can control the beta-glucan content in grain with no apparent harmful effects on grain quality of transgenic plants. (c) 2016 Society of Chemical Industry. PMID- 26927392 TI - Reflective Practice: How the World Bank Explored Its Own Biases? AB - While many international organisations have independent evaluations, including the International Monetary Fund (IMF) and World Health organization (WHO), uniquely the World Bank in its 2015 World Development Report sought to ascertain the potential biases that influence how its staff interpret evidence and influence policy. Here, we describe the World Bank's study design, including experiments to ascertain the impact on Bank staff's judgements of complexity, confirmation bias, sunk cost bias, and an understanding of the wishes of those whom they seek to help. We then review the Bank's proposed mechanisms to minimise the impact of the biases they identified. We argue that this approach, that we refer to as 'reflective practice,' deserves to be adopted more widely among institutions that seek to use evidence from research to inform policy and practice. PMID- 26927393 TI - Access to Care for Multiple Sclerosis in Times of Economic Crisis in Greece--the HOPE II Study. AB - BACKGROUND: While there is currently no cure for multiple sclerosis (MS), treatment with biologic disease-modifying drugs (bDMDs) can reduce the impact of the condition on the lives of patients. In Greece, the regulatory change in the distribution system of bDMDs, limited their administration through the designated pharmacies of the National Organization for Healthcare Services Provision (EOPYY) or the National Health System (ESY) hospitals, thus potentially impacting access to MS treatment. In this context, the aim of this paper was to assess the barriers to bDMDs, by recording MS patients' experiences. METHODS: A survey research was conducted between January and February 2014 in Athens and 5 other major Greek cities with the methods of personal and telephone interview. A structured questionnaire was used to elicit socio-economic and medical information, information related to obstacles in accessing bDMDs and medical treatment, from MS patients that visited EOPYY pharmacies during the study period. RESULTS: During the last year 69% of 179 participants reported that the distribution system of bDMDs has improved. Thirteen percent of participants encountered problems in accessing their medication, and 16.9% of participants in accessing their physician, with the obstacles being more pronounced for non Athens residents. Frequent obstacles to bDMDs were the distance from EOPYY pharmacies and difficulties in obtaining a diagnosis from an EOPYY/ESY physician, while obstacles to medical care were delays in appointment booking and travel difficulties. CONCLUSION: Even though the major weaknesses of the distribution system of bDMDs have improved, further amelioration of the system could be achieved through the home delivery of medicines to patients living in remote areas, and through the development of a national MS registry. PMID- 26927394 TI - A Pilot Study of a 6-Week Parenting Program for Mothers of Pre-school Children Attending Family Health Centers in Karachi, Pakistan. AB - BACKGROUND: Recently, parenting programs to address behavioural and emotional problems associated with child maltreatment in developing countries have received much attention. There is a paucity of literature on effective parent education interventions in the local context of Pakistan. This study aimed to assess the feasibility of offering a 6-week parenting program for mothers of pre-school children attending family health centres (FHCs) in Karachi, the largest metropolitan city of Pakistan. METHODS: A pilot quasi-experimental trial was conducted. Two FHCs were selected, one as the intervention and the second as the control. A total of 57 mothers of pre-school children (n = 30 intervention; n = 27 control) participated in this study. Mothers in the intervention group received SOS Help for parents module, while mothers in the control group received information about routine childcare. A parenting scale (PS) was administered before the program was implemented and repeated 2 weeks after the program was completed in both groups. Statistical analysis was performed to compare participants' attributes. Descriptive analysis was conducted to compare pre- and post-test mean scores along with standard deviation for parenting subscales in the intervention and control groups. RESULTS: A total of 50 mothers (n = 25 intervention; n = 25 control) completed the 6-week program. Attrition was observed as 5/30 (17%) in the intervention arm and 2/27 (2%) in the control arm. Mothers commonly reported the burden of daily domestic and social responsibilities as the main reason for dropping out. Furthermore, the majority of participants in the control group recommended increasing the duration of weekly sessions from 1 to 1.5 hours, thereby decreasing the program period from 6 to 4 weeks. Mothers in intervention group reported substantial improvement in parenting skills as indicated by mean difference in their pre- and post-test scores for laxness and over-reactivity. CONCLUSION: Parenting programs can be implemented for mothers attending FHCs in Pakistan. Mothers require positive reinforcement and constant encouragement at the participant level. Integrating such programs into primary healthcare at the population level has the potential to maximize child health benefits and to improve parenting skills at the country level. PMID- 26927396 TI - Women's Education and World Peace: A Feminist Dream Comes True: Comment on "The Pill Is Mightier Than the Sword". AB - This commentary on Potts et al provides a critical view on their thesis that increasing the level of education among women is likely to reduce terrorism. Presence of a strong family planning program enables women to control family size resulting in women's public participation more likely and facilitating the emergence of small birth cohorts who are less likely to become unemployed. In spite of the several theoretical insights their paper offers, they have not adequately described the multiple social and economic linkages that may exist between fertility rates and lowering frequency of wars, terrorism, etc. PMID- 26927395 TI - Attitude of Iranian Medical Oncologists Toward Economic Aspects, and Policy making in Relation to New Cancer Drugs. AB - BACKGROUND: Although medical oncologists can have an important role in controlling the cost of cancer treatment, there is little information about their attitudes toward the cost of cancer treatment and the impact of cost on their treatment recommendations, especially in low- and middle-income countries (LMICs). In this study, we assessed the attitude of Iranian medical oncologists toward some economic aspects of new cancer drugs. METHODS: We translated a questionnaire that was used in similar studies in the United States and Canada into Persian and modified it according to the local setting in Iran. The face and content validity of the questionnaire were assessed by oncologists before being used in the survey. We distributed the questionnaire and collected the data from 80 oncologists who participated in the 13th Annual Congress of the Iranian Society of Medical Oncology and Hematology (ISMOH). RESULTS: Fifty-two oncologists participated in our study (a response rate of 65%). The majority of oncologists stated that drug costs and patient out-of-pocket (OOP) costs influence their treatment recommendations (92% and 94%, respectively). Most oncologists (70%) felt that they are ready enough to use cost-effectiveness information in their treatment decisions, and 74% believed that patients should only have access to cancer treatments that are cost-effective. Most oncologists agree that the government should have control over drug prices, and more use of cost-effectiveness data is required for decision-making about cancer drug coverage. Ninety-one percent of oncologists said that they always or frequently discuss cancer treatment costs with their patients. Oncologists believed that academic groups (research centers and scientific societies) (81%) and the Ministry of Health (MoH) (43%) are the most eligible groups for determining whether a drug provides good value. CONCLUSION: Iranian medical oncologists are ready to participate in the health technology assessment and priority-setting process. This situation creates a unique opportunity for the government to rely on scientific societies and find an appropriate solution for the improvement of patients' access to high-quality care. PMID- 26927397 TI - Bomb or Boon: Linking Population, People and Power in Fragile Regions: Comment on "The Pill Is Mightier Than the Sword". AB - The relationship between population structure and violent conflict is complex and heavily dependent on the behavior of other variables like governance, economic prospects, and urbanization. While addressing rapid population growth might be a necessary condition for peace, it is by no means sufficient. Concomitant steps must also be taken to foster inclusivity, guarantee broader rights for all, particularly women, rebuild social contracts and ensure that all citizens have equal access to economic opportunity. Measures to control family size could reduce dependency and create greater socio-economic opportunities for women and youth, By so doing, the "youth bulge" phenomenon could be a boon for rapidly growing developing countries. PMID- 26927398 TI - A Little Bit of Sugar Helps the Pill Go Down: Resilience, Peace, and Family Planning: Comment on "The Pill Is Mightier Than the Sword". AB - The article by Potts et al, "The Pill is Mightier than the Sword," points out that family planning has an important role to play in building peace by increasing women's empowerment and their agency, ultimately helping peacebuilding efforts. Evidence has demonstrated that family planning programs are cost effective, produce quick results, help women and couples meet their desired fertility levels, and produce a multitude of benefits around economic productivity, community engagement, conservation, resilience, and peacebuilding. In order for policy audiences from a variety of sectors, including conflict and peacebuilding, to appreciate these benefits, it is important to find common ground and articulate co-benefits that will help them appreciate and value the role of family planning, as it were, give them sugar to help the pill go down. This commentary examines how resilience, peacebuilding and family planning efforts need to focus on co-benefits in order to build on the successful interventions and opportunities that Potts et al highlight. PMID- 26927399 TI - Politics and Power in Global Health: The Constituting Role of Conflicts: Comment on "Navigating Between Stealth Advocacy and Unconscious Dogmatism: The Challenge of Researching the Norms, Politics and Power of Global Health". AB - In a recent article, Gorik Ooms has drawn attention to the normative underpinnings of the politics of global health. We claim that Ooms is indirectly submitting to a liberal conception of politics by framing the politics of global health as a question of individual morality. Drawing on the theoretical works of Chantal Mouffe, we introduce a conflictual concept of the political as an alternative to Ooms' conception. Using controversies surrounding medical treatment of AIDS patients in developing countries as a case we underline the opportunity for political changes, through political articulation of an issue, and collective mobilization based on such an articulation. PMID- 26927400 TI - Optimisation of Healthcare Contracts: Tensions Between Standardisation and Innovation: Comment on "Competition in Healthcare: Good, Bad or Ugly?". AB - An important determinant of health system performance is contracting. Providers often respond to financial incentives, despite the ethical underpinnings of medicine, and payers can craft contracts to influence performance. Yet contracting is highly imperfect in both single-payer and multi-payer health systems. Arguably, in a competitive, multi-payer environment, contractual innovation may occur more rapidly than in a single-payer system. This innovation in contract design could enhance performance. However, contractual innovation often fails to improve performance as payer incentives are misaligned with public policy objectives. Numerous countries seek to improve healthcare contracts, but thus far no health system has demonstrably crafted the necessary blend of incentives to stimulate optimal contracting. PMID- 26927401 TI - What About Leadership?: Comment on "Cultures of Silence and Cultures of Voice: The Role of Whistleblowing in Healthcare Organisations". AB - In their valuable discussion of whistleblowing in healthcare organisations, Mannion and Davies highlight the importance of organisational culture in influencing whether people raise concerns, and whether these concerns are listened to and acted upon. The role of leadership in shaping organisational culture is well-established and in this commentary, we will examine the influence of leaders in creating cultures of silence or cultures of voice. PMID- 26927402 TI - Putting Management Capacity Building at the Forefront of Health Systems Strengthening: Comment on "Management Matters: A Leverage Point for Health Systems Strengthening in Global Health". AB - The current limited focus on management in global health activities is highly problematic given the amounts of financial and human resources that are pouring into health system strengthening interventions and the complexity of clinical operations across settings. By ensuring that public health and healthcare practitioners in domestic and international settings receive management training in their educational programs and that we build management capacity among individuals already in the health workforce, we can begin to prepare for more effective health systems strengthening efforts. Rigorous evaluation of health systems strengthening and the impact of management capacity building is crucial to building evidence for the field. PMID- 26927403 TI - When Whistle-blowers Become the Story: The Problem of the 'Third Victim': Comment on "Cultures of Silence and Cultures of Voice: The Role of Whistleblowing in Healthcare Organisations". AB - In the healthcare context, whistleblowing has come to the fore of political, professional and public attention in the wake of major service scandals and mounting evidence of the routine threats to safety that patients face in their care. This paper offers a commentary and wider contextualisation of Mannion and Davies, 'Cultures of silence and cultures of voice: the role of whistleblowing in healthcare organisations.' It argues that closer attention is needed to the way in which whistle-blowers can become the focus and victim of raising concerns and speaking up. PMID- 26927404 TI - From the Myth of Level Playing Fields to the Reality of a Finite Planet: Comment on "A Global Social Support System: What the International Community Could Learn From the United States' National Basketball Association's Scheme for Redistribution of New Talent". AB - Despite the mythology that the global economy with its trade rules creates a 'level playing field,' international trade has never involved 'level players.' The inequalities in outcomes generated by the more powerful winning more frequently has led to innovative ideas for ex post redistribution to make the matches between the players both fairer, and in the analogy to basketball used by the authors, more interesting and even more competitive. The proposal for a Global Social Protection Fund, financed by a small tax on the winners to enhance social protection spending for the losers, presumably increasing the latter's capabilities to compete more effectively in the global market game, is one such idea. It has much to commend it. Several problems, however, stand in its way, apart from those inherent within nations themselves and to which the authors give some attention. First, much global trade is now intra-firm rather than international, making calculations of which nations win or lose exceedingly difficult. Second, tax havens persist without the transparency and global regulatory oversights that would allow a better rendering of where winnings are stashed. Third, pre-distribution inequalities (those arising from market activities before government tax and transfer measures apply) are still increasing as labour's power to wrestle global capital into some ameliorative social contract diminishes. Fourth, there are finite limits to a planet on the cusp of multiple environmental crises. These problems do not diminish the necessity of alternative policy playbooks such as the proposed Fund, but point to the need to embrace the new Sustainable Development Goals (SDGs) as a single set, such that economic growth for the bottom half of humanity includes deep structural reforms to both pre-distribution and redistribution, if the targets for environmental survival are to be met. PMID- 26927405 TI - Does Management Really Matter? And If so, to Who?: Comment on "Management Matters: A Leverage Point for Health Systems Strengthening in Global Health". AB - The editorial is commendable and I agree with many of the points raised. Management is an important aspect of health system strengthening which is often overlooked. In order to build the capacity of management, we need to consider other factors such as, the environment within which managers work, their numbers, support systems and distribution. Effective leadership is an issue which cannot be overemphasized as part of management capacity in resource deprived settings as difficult settings require leadership skills in order to achieve managerial success. A primary issue of importance highlighted in the editorial is country ownership of management effectiveness initiatives, which may be very difficult when the health sector is dependent on support and funding from donors and influential partners, who drive change often without a good understanding of the context. How partners finance health programmes is another dilemma as it can distract from locally determined priorities. Further research should help us to understand better what works and under different settings. PMID- 26927406 TI - Strategic Management in the Healthcare Sector: The Debate About the Resource Based View Flourishes in Response to Recent Commentaries. PMID- 26927407 TI - Let's Raise a Half-Full Glass to the Zombie NHS: A Response to Recent Commentaries. PMID- 26927408 TI - Editorial: Special issue on models for continuous data with a spike at zero. PMID- 26927409 TI - Erratum. PMID- 26927413 TI - Approaches and Recent Trends in Gene Delivery for Treatment of Atherosclerosis. AB - BACKGROUND: The development and progression of atherosclerosis is known to occur at a sluggish pace and the lesions remain concealed for a long duration before the factual situation of the complex atherosclerotic etiology affecting various organ gets apprehended. The root cause mainly involves an imbalance or malfunction of the cholesterol metabolizing pathway. The till date therapeutic alternatives include oral hypo-lipidemic agents along with advances made in biotechnology/tissue engineering and surgical procedures for management purpose. However, with the advent and upsurge of nanotech delivery systems, along with meticulous indulgence and identification of the causative genes in the etiology of disease have opened a new therapeutic area that has far reaching application potential for effective management of such chronic disease requiring lifelong therapy. METHODS: Various genes that have implication in atherosclerosis were reviewed along with research in delivery vectors that have been employed for gene therapeutics and hurdles in successful delivery were elaborated. Relevant patents are discussed systematically to clearly support and highlight the developments made. RESULTS: Patenting activity in the delivery of genes for atherosclerosis so far primarily covers use of viral vectors. With the identification of new targets, a list of candidate genes are available that can be potentially exploited for therapeutic purpose. Though the delivery of candidate genes using viral vectors has been well explored, the limitation of viral vectors have seized the much needed clinical success. Non-viral vectors can prove to be the key for conquering this limitations and offer a vast area for exploration for achieving an effective control and remission to the disease and increasing the assortment of patents as reviewed in this article. CONCLUSION: In view of the many limitations in employing viral vectors for delivery, designing non-viral vectors for successful delivery of therapeutic gene in atherosclerosis should be realized and focused for effective management of the disease. PMID- 26927414 TI - Macrophage migration inhibitory factor in the regulation of myoblast proliferation and differentiation. AB - Obesity is documented to be a state of chronic mild inflammation associated with increased macrophage infiltration into adipose tissue and liver and skeletal muscle. As a pleiotropic inflammatory mediator, macrophage migration inhibitory factor (MIF) is associated with metabolic disease, so MIF may signal molecular links between adipocytes and myocytes. MIF expression was modified during myoblast differentiation, but the role of MIF during this process is unclear. C2C12 cells were transfected with MIF to investigate their role during differentiation. MIF expression attenuated C2C12 differentiation. It did not change proliferation, but downregulated cyclin D1 and CDK4, causing cell accumulation in the G1 phase. p21 protein was increased significantly and MyoD, MyoG, and p21 mRNA also increased significantly in the C2C12 cells treated with ISO-1, suggesting that inhibition of MIF promotes differentiation. MIF inhibits the myoblast differentiation by affecting the cell cycle progression, but does not affect proliferation. PMID- 26927415 TI - New bioactive labdane diterpenoids from Marrubium aschersonii. AB - A phytochemical investigation of the ethanol extract of Marrubium aschersonii Magnus (Lamiaceae) collected from Tunisia led to the isolation and identification of two new labdane diterpenoids, marrubaschs A (1) and B (2), along with two known compounds (3 and 4). Their structures were elucidated by spectroscopic methods including HRESIMS and NMR techniques. All compounds were evaluated for their inhibitory effects on the nitric oxide (NO) production induced by lipopolysaccharide in RAW 264.7 macrophage cells. Compound 2 exhibited weak inhibition of NO production with an IC50 value of 35 +/- 1.0 MUM. PMID- 26927416 TI - High-Permittivity Conjugated Polyelectrolyte Interlayers for High-Performance Bulk Heterojunction Organic Solar Cells. AB - Conjugated polyelectrolyte (CPE) interfacial layers present a powerful way to boost the I-V characteristics of organic photovoltaics. Nevertheless, clear guidelines with respect to the structure of high-performance interlayers are still lacking. In this work, impedance spectroscopy is applied to probe the dielectric permittivity of a series of polythiophene-based CPEs. The presence of ionic pendant groups grants the formation of a capacitive double layer, boosting the charge extraction and device efficiency. A counteracting effect is the diminishing affinity with the underlying photoactive layer. To balance these two effects, we found copolymer structures containing nonionic side chains to be beneficial. PMID- 26927417 TI - I2/O2-Enabled N-S Bond Formation to Access Functionalized 1,2,3-Thiadiazoles. AB - A new, metal-free intermolecular formal [3 + 2] heterocyclization between triethylammonium thiolates and aryl hydrazines has been established by using the combination of I2 and O2 as efficient oxidation sources, allowing a concise and low-cost access to new densely functionalized 1,2,3-thiadiazoles with good to excellent yields. The reaction showed a broad scope of substrates of both reactants and attractive characteristics consisting of eco-friendly oxidants, flexible structural modification, broad functional group compatibility, and mild reaction conditions. PMID- 26927418 TI - A high gas fraction, reduced power, syngas bioprocessing method demonstrated with a Clostridium ljungdahlii OTA1 paper biocomposite. AB - We propose a novel approach to continuous bioprocessing of gases. A miniaturized, coated-paper strip, high gas fraction, biocomposite absorber has been developed using slowly shaken horizontal anaerobic tubes. Concentrated Clostridium ljungdahlii OTA1 was used as a model system. These gas absorbers demonstrate elevated CO mass transfer with low power input, reduced liquid requirements, elevated substrate consumption, and increased product secretion compared to shaken suspended cells. Concentrated OTA1 cell paste was coated by extrusion onto chromatography paper. The immobilized system shows high, constant reactivity immediately upon rehydration. Cell adhesion was by adsorption to the cellulose fibers; visualized by SEM. The C. ljungdahlii OTA1 coated paper mounted above the liquid level absorbs CO and H2 from a model syngas secreting acetate with minimal ethanol. At 100 rpm shaking speed (7.7 Wm(-3) ) the optimal cell loading is 6.5 gDCW m(-2) to maintain high CO absorbing reactivity without the cells coming off of the paper into the liquid phase. Reducing the medium volume from 10 mL to 4 mL (15% of tube volume) did not decrease CO reactivity. The reduced liquid volume increased secreted product concentration by 80%. The specific CO consumption by paper biocomposites was higher at all shaking frequencies <100 rpm than suspended cells under identical incubation conditions. At 25 rpm the biocomposite outperforms suspended cells for CO absorption by 2.5-fold, with an estimated power reduction of 97% over the power input at 100 rpm. The estimated minimum kL a for miniaturized biocomposite gas-absorbers is ~100 h(-1) , 10 to 10(4) less power input than other syngas fermentation systems reported in the literature at similar kL a. Specific consumption rates in a biocomposite were ~14 mmol gDCW-1 h(-1) . This work intensified CO absorption and reactivity by 14-fold to 94 mmol CO m(-2) h(-1) over previous C. ljungdahlii OTA1 work by our group. Specific acetate production rates were 23 mM h(-1) or 46 mmol m(-2) h(-1) . The specific rates and apparent kL a scaled linearly with biocomposite coating area. Biotechnol. Bioeng. 2016;113: 1913-1923. (c) 2016 Wiley Periodicals, Inc. PMID- 26927420 TI - Metallo-Supramolecular Self-Assembly of a Multicomponent Ditrigon Based on Complementary Terpyridine Ligand Pairing. AB - Predesigned complementary complexation of two 2,2':6',2"-terpyridine-based ligands was established by installing 2,6-dimethoxyphenyl substituents at the terpyridyl 6,6"-positions, which provided ancillary ion-dipole interactions in the coordination process and extra pi-stacking stabilization in the resultant heteroleptic complex. The high-fidelity self-recognition ligation afforded facile access to the quantitative self-assembly of multicomponent triangle [Cd6L(3)3L(4)3] and ditrigon [Cd15L(3)6L(5)3] (that is, a hexagon with six 120 degrees angles and two alternating edge lengths). It was found that the linear 6,6"-substituted ditopic motif (L(3)) would be directed by the ligand geometry of L(5) to selectively incorporate into the parallel homoleptic connections in the bilayered framework. PMID- 26927419 TI - Understanding Heterogeneity in Clinical Cohorts Using Normative Models: Beyond Case-Control Studies. AB - BACKGROUND: Despite many successes, the case-control approach is problematic in biomedical science. It introduces an artificial symmetry whereby all clinical groups (e.g., patients and control subjects) are assumed to be well defined, when biologically they are often highly heterogeneous. By definition, it also precludes inference over the validity of the diagnostic labels. In response, the National Institute of Mental Health Research Domain Criteria proposes to map relationships between symptom dimensions and broad behavioral and biological domains, cutting across diagnostic categories. However, to date, Research Domain Criteria have prompted few methods to meaningfully stratify clinical cohorts. METHODS: We introduce normative modeling for parsing heterogeneity in clinical cohorts, while allowing predictions at an individual subject level. This approach aims to map variation within the cohort and is distinct from, and complementary to, existing approaches that address heterogeneity by employing clustering techniques to fractionate cohorts. To demonstrate this approach, we mapped the relationship between trait impulsivity and reward-related brain activity in a large healthy cohort (N = 491). RESULTS: We identify participants who are outliers within this distribution and show that the degree of deviation (outlier magnitude) relates to specific attention-deficit/hyperactivity disorder symptoms (hyperactivity, but not inattention) on the basis of individualized patterns of abnormality. CONCLUSIONS: Normative modeling provides a natural framework to study disorders at the individual participant level without dichotomizing the cohort. Instead, disease can be considered as an extreme of the normal range or as-possibly idiosyncratic-deviation from normal functioning. It also enables inferences over the degree to which behavioral variables, including diagnostic labels, map onto biology. PMID- 26927421 TI - Preventive Dental Care and Long-Term Dental Outcomes among ALL Kids Enrollees. AB - OBJECTIVE: To investigate whether early or regular preventive dental visit (PDV) reduces restorative or emergency dental care and costs for low-income children. STUDY SETTING: Enrollees during 1998-2012 in the Alabama CHIP program, ALL Kids. STUDY DESIGN: Retrospective cohort study using claims data for children continuously enrolled in ALL Kids for at least 4 years. Analyses are conducted separately for children 0-4 years, 4-9 years, and >9 years. For 0-4 years, the intervention of interest is whether they have at least one PDV before age 3. For the other two age groups, interventions of interest are if they have regular PDVs during each of the first 3 years, and if they have claims for a sealant in the first 3 years. Outcomes-namely restorative and emergency dental service and costs are measured in the fourth year. To account for selection into PDV, a high dimensional propensity scores approach is utilized. DATA EXTRACTION: Claims data were obtained from ALL Kids. PRINCIPAL FINDINGS: Only sealants are associated with a reduced likelihood of using restorative and emergency services and costs. CONCLUSIONS: Whether PDVs without sealants actually reduce restorative/emergency pediatric dental services is questionable. Further research into benefits of PDV is needed. PMID- 26927422 TI - 'Everyone has a secret they keep close to their hearts': challenges faced by adolescents living with HIV infection at the Kenyan coast. AB - BACKGROUND: The upsurge in the uptake of antiretroviral therapy (ART) has led to a significant increase in the survival of vertically acquired HIV infected children, many of whom are currently living into adolescence and early adulthood. However little if anything is known of the lived experiences and the challenges faced by HIV positive adolescents in the African context. We set out to investigate psychosocial challenges faced by HIV infected adolescents on the Kenyan coast. METHODS: A total of 44 participants (12 HIV-infected adolescents, 7 HIV uninfected adolescents, and 25 key informants) took part in this qualitative study, using individually administered in-depth interviews. A framework approach was used to analyze the data using NVIVO software. RESULTS: We observed that the challenges faced by adolescents in rural Kenya could be placed into six major themes: poverty, poor mental and physical health, the lack of a school system that is responsive to their needs, challenges in how to disclose to peers and family members, high levels of stigma in its various forms, and challenges of medical adherence leading to the need for close monitoring. CONCLUSION: In this African community, vertically acquired HIV-infected adolescents face a complex set of social, economic and medical challenges. Our study points to the urgent need to develop multisectorial intervention support programmes to fully address these challenges. PMID- 26927423 TI - Structure-based design and development of (benz)imidazole pyridones as JAK1 selective kinase inhibitors. AB - The mammalian Janus Kinases (JAK1, JAK2, JAK3 and TYK2) are intracellular, non receptor tyrosine kinases whose activities have been associated in the literature and the clinic with a variety of hyperproliferative diseases and immunological disorders. At the onset of the program, it was hypothesized that a JAK1 selective compound over JAK2 could lead to an improved therapeutic index relative to marketed non-selective JAK inhibitors by avoiding the clinical AEs, such as anemia, presumably associated with JAK2 inhibition. During the course of the JAK1 program, a number of diverse chemical scaffolds were identified from both uHTS campaigns and de novo scaffold design. As part of this effort, a (benz)imidazole scaffold evolved via a scaffold-hopping exercise from a mature chemical series. Concurrent crystallography-driven exploration of the ribose pocket and the solvent front led to analogs with optimized kinome and JAK1 selectivities over the JAK2 isoform by targeting several residues unique to JAK1, such as Arg-879 and Glu-966. PMID- 26927424 TI - Synthesis and evaluation of an alkyne-modified ATP analog for enzymatic incorporation into RNA. AB - Alkyne-modified nucleoside analogs are useful for nucleic acid localization as well as functional and structural studies because of their ability to participate in copper-catalyzed azide/alkyne cycloaddition (CuAAC) reactions. Here we describe the synthesis of the triphosphate of 7-ethynyl-8-aza-7-deazaadenosine (7 EAATP) and the enzymatic incorporation of 7-EAA into RNA. The free nucleoside of 7-EAA is taken up by HeLa cells and incorporated into cellular RNA by endogenous RNA polymerases. In addition, 7-EAATP is a substrate for both T7 RNA polymerase and poly (A) polymerase from Escherichia coli in vitro, albeit at lower efficiencies than with ATP. This work adds to the toolbox of nucleoside analogs useful for RNA labeling. PMID- 26927425 TI - Effect of chlorine substituent on cytotoxic activities: Design and synthesis of systematically modified 2,4-diphenyl-5H-indeno[1,2-b]pyridines. AB - In continuation of our previous work, six hydroxylated 2,4-diphenyl-5H-indeno[1,2 b]pyridine analogs were modified by introducing one chlorine functionality at ortho, meta or para position of the 2- or 4-phenyl ring. Eighteen new chlorinated compounds were thus prepared and assessed for topoisomerase inhibitory activity and cytotoxicity against HCT15, T47D, and HeLa cancer cell lines. All of the chlorinated compounds displayed significant cytotoxic effect, revealing potent anticancer activity against T47D breast cancer cells. This functional group modification allowed us to explore the importance of chlorine group substitution for the cytotoxic properties. The information reported here provides valuable insight for further study to develop new anticancer agents using related scaffolds. PMID- 26927426 TI - Facile synthesis of 1,3-thiazolidin-4-ones as antitubercular agents. AB - We have developed, highly efficient, one-pot, solvent-free, [Et3NH][HSO4] catalyzed multicomponent reaction protocol for the synthesis of 1,3-thiazolidin-4 ones in excellent yields. For the first time, the 1,3-thiazolidin-4-ones were evaluated in vitro for their antimycobacterial activity against Mycobacterium tuberculosis dormant MTB H37Ra and Mycobacterium bovis BCG strains. Among the synthesized basic 1,3-thiazolidin-4-ones, particularly the compounds 4c, 4d, 4e, 4f, 4h, 4i and 4j displays promising antitubercular activity along with no significant cytotoxicity against the cell lines MCF-7, A549 and HCT-116. PMID- 26927427 TI - Discovery of boronic acid-based fluorescent probes targeting amyloid-beta plaques in Alzheimer's disease. AB - A boronic acid-based fluorescent probe was developed for diagnosis of amyloid beta (Abeta) plaques from Alzheimer's disease (AD). Probe 4c, which included boronic acid as a functional group, exhibited a significant increase (64.37-fold, FAbeta/F0) in fluorescence intensity as a response to Abeta aggregates, with a blue shift (105nm) in the maximum emission wavelength. We found that boronic acid as a functional group improved the binding affinity (KD value=0.79+/-0.05MUM for 4c) for Abeta aggregates and confirmed that 4c selectively stained Abeta plaques in brain sections from APP/PS1 mice. Ex vivo fluorescence imaging using mice (normal and APP/PS1) also revealed that 4c was able to penetrate the blood-brain barrier (BBB) and to stain Abeta plaques in the brain. From these results, we believe that 4c will be useful as a fluorescent probe in preclinical research related to AD. Furthermore, we believe that our results with boronic acid also provide valuable information for the development of a probe for Abeta plaques. PMID- 26927428 TI - Cacao Cultivation under Diverse Shade Tree Cover Allows High Carbon Storage and Sequestration without Yield Losses. AB - One of the main drivers of tropical forest loss is their conversion to oil palm, soy or cacao plantations with low biodiversity and greatly reduced carbon storage. Southeast Asian cacao plantations are often established under shade tree cover, but are later converted to non-shaded monocultures to avoid resource competition. We compared three co-occurring cacao cultivation systems (3 replicate stands each) with different shade intensity (non-shaded monoculture, cacao with the legume Gliricidia sepium shade trees, and cacao with several shade tree species) in Sulawesi (Indonesia) with respect to above- and belowground biomass and productivity, and cacao bean yield. Total biomass C stocks (above- and belowground) increased fivefold from the monoculture to the multi-shade tree system (from 11 to 57 Mg ha-1), total net primary production rose twofold (from 9 to 18 Mg C ha-1 yr-1). This increase was associated with a 6fold increase in aboveground biomass, but only a 3.5fold increase in root biomass, indicating a clear shift in C allocation to aboveground tree organs with increasing shade for both cacao and shade trees. Despite a canopy cover increase from 50 to 93%, cacao bean yield remained invariant across the systems (variation: 1.1-1.2 Mg C ha-1 yr 1). The monocultures had a twice as rapid leaf turnover suggesting that shading reduces the exposure of cacao to atmospheric drought, probably resulting in greater leaf longevity. Thus, contrary to general belief, cacao bean yield does not necessarily decrease under shading which seems to reduce physical stress. If planned properly, cacao plantations under a shade tree cover allow combining high yield with benefits for carbon sequestration and storage, production system stability under stress, and higher levels of animal and plant diversity. PMID- 26927429 TI - A comparison of nonoperative vs. Endobutton repair of distal biceps ruptures. AB - BACKGROUND: The aim of this study was to compare the outcome of patients who have undergone distal biceps tendon repair by a single-incision Endobutton fixation technique with the results of another cohort of patients who elected not to undergo surgery for distal biceps tendon rupture. METHODS: A retrospective cohort study was performed of patients diagnosed with distal biceps ruptures, repaired with an Endobutton (Smith & Nephew, Andover, MA, USA) technique or treated nonoperatively by the senior surgeon (S.A.S.). With a minimum follow-up of 6 months, a routine elbow examination, radiographs, and functional questionnaires were performed. Isometric supination, flexion, and grip strength was measured using a BTE machine (Baltimore Therapeutic Equipment, Hanover, MD, USA). There were 47 patients available for follow-up with 50 distal biceps ruptures; 40 ruptures have undergone repair, and 10 have been managed nonoperatively. Three patients had sustained bilateral ruptures. RESULTS: There was a significant difference in flexion and supination isometric strength between the operative and nonoperative cohorts compared with the uninjured contralateral side (92.94% vs. 70.65%, P = .01512; 87.91% vs 59.11%, P = .00414, respectively). The difference in grip strengths between the 2 cohorts compared with the uninjured side was not significant (100.00% vs. 79.16%; P = .16002). The operated cohort had significantly better QuickDASH score, Oxford Elbow Score, and Mayo Elbow Performance Score (6.29 vs. 14.10, P = .02123; 44.71 vs. 38.70, P = .00429; 93.13 vs. 84.50, P = .01423). CONCLUSION: Repair of distal biceps ruptures using an Endobutton fixation results in nearly normal return of strength and function, which is significantly better than in those managed nonoperatively. LEVEL OF EVIDENCE: Level III, Retrospective Cohort Design; Treatment Study. PMID- 26927430 TI - Distal biceps tendon repair: comparison of clinical and radiological outcome between bioabsorbable and nonabsorbable screws. AB - BACKGROUND: Distal biceps tendon repair to the radial tuberosity can be conducted by means of an interference screw in combination with a transosseous button. Bioabsorbable interference screws have been associated with complications such as severe osteolytic reactions. We questioned whether patients with a distal biceps tendon repair with bioabsorbable poly-L-lactide (PLLA) screws had different functional, clinical, and radiologic outcome than patients with nonabsorbable poly-ether ether ketone (PEEK) screws. METHODS: Between 2010 and 2014, 23 patients with an acute distal biceps tendon rupture were treated with reinsertion of the distal biceps tendon in a bone tunnel at the radial tuberosity through a single anterior incision using a transosseous button combined with an interference screw. A PLLA screw was used in 12 patients and a PEEK screw in 11 patients. All patients were retrospectively evaluated with a minimal follow-up of 1 year clinically and by means of the visual analog scale for pain, Mayo Elbow Performance Score, and Disabilities of Arm, Shoulder and Hand Outcome Measure score. Bone tunnel volume was measured with computed tomography segmentation. RESULTS: Elbow mobility and arm and forearm circumference were symmetric for all patients. The visual analog scale for pain was 0.2 in the PLLA group and 0.7 in the PEEK group. The Disabilities of Arm, Shoulder and Hand score and Mayo Elbow Performance Score were 5.4 and 98.7 in the PLLA group vs. 3.1 and 95.9 in the PEEK group. Bone tunnel enlargement of 43% in the PLLA and 38% in the PEEK group was noted. CONCLUSIONS: Clinical and functional outcome at more than 1 year after distal biceps tendon repair was excellent in both groups. Bone tunnel widening occurred in all patients. PMID- 26927431 TI - Release of the stiff elbow with mini-open technique. AB - BACKGROUND: Currently, there are many techniques used in the surgical release of elbow contracture, but no single technique has gained widespread acceptance. The purpose of this study was to report the outcomes of a lateral-column approach combined with a mini-open triceps-splitting technique for elbow contracture release. METHODS: Thirty-six patients with a mean age of 39 years were included in the study. All patients underwent a combined lateral and minimal posterior triceps-splitting open elbow contracture release. Elbow range of motion and visual analog scale pain scores were recorded. The Mayo Elbow Performance Score was used to assess functional outcome. RESULTS: The mean follow-up period was 38 months. Mean pain levels decreased from 7.59 preoperatively to 0.44 postoperatively (P < .05). The total arc of elbow motion increased from 52 degrees preoperatively to 109 degrees postoperatively, with an improvement of 57 degrees (P < .05). The Mayo Elbow Performance Score improved from 44.17 preoperatively to 90.83 postoperatively (P < .05). CONCLUSION: This study shows that a combined lateral and mini-open triceps-splitting approach is a safe and effective alternative technique for the treatment of elbow contractures. PMID- 26927432 TI - Open reduction and internal fixation of coronal fractures of the capitellum in patients older than 65 years. AB - BACKGROUND: The aim of this study was to describe the fracture patterns of capitellum coronal fractures and to evaluate the complications and functional and radiographic outcomes of open reduction and internal fixation in patients older than 65 years. METHODS: A retrospective study of 23 patients with a mean follow up of 48 months (36-105) was performed. Fractures were classified according to the Dubberley classification. All patients were evaluated by the Mayo Elbow Performance Index (MEPI) and the Disabilities of the Arm, Shoulder, and Hand (DASH) scores. RESULTS: Three patients were lost to follow-up. There were 16 type 1 and 4 type 2 fractures. The mean age was 71 years (66-79), and 65% were women. The mean MEPI score was 92 (60-100), and the mean DASH score was 9 (0-75). Either a concomitant fracture or an elbow dislocation was present in 50% of the patients. Mean sagittal plane range of motion at last follow-up was 122 degrees +/- 8 degrees , with lower extension in type 2 and worse scores on MEPI (91 vs. 97) and DASH (3 vs. 0) scales. Placement of the screws in the posteroanterior direction was associated with better range of motion in flexion (130 degrees vs. 122 degrees ) and better outcomes in functional scores (MEPI, 97 vs. 89; QuickDASH, 0 vs. 4). Complications were post-traumatic osteoarthritis in 3 patients, avascular necrosis in 1 patient, and heterotopic ossification in 5 patients. One patient required reoperation. CONCLUSIONS: Patients older than 65 years have no substantial risk of complex fracture patterns, but they have a large number of concomitant injuries. Open reduction and internal fixation with cannulated screws allow stable fixation and provide satisfactory functional results with a lower complication rate. PMID- 26927433 TI - Intra-articular injection, subacromial injection, and hydrodilatation for primary frozen shoulder: a randomized clinical trial. AB - BACKGROUND: The aim of this prospective randomized study was to compare the efficacy of 3 injection methods, intra-articular injection, subacromial injection, and hydrodilatation (HD), in the treatment of primary frozen shoulder. METHODS: Patients with primary frozen shoulder were randomized to undergo intra articular injection (n = 29), subacromial injection (n = 29), or HD (n = 28). Evaluations using a visual analog scale for pain, Simple Shoulder Test, Constant score, and passive range of shoulder motion were completed before treatment and 1 month, 3 months, and 6 months after treatment. RESULTS: Among the 3 injection methods for primary frozen shoulder, HD resulted in a greater range of motion in forward flexion and external rotation, a lower visual analog scale score for pain after 1 month, and better outcomes for all functional scores after 1 month and 3 months of follow-up. However, there were no significant differences in any clinical outcomes among the 3 groups in the final follow-up at 6 months. CONCLUSIONS: Although HD yielded more rapid improvement, the 3 injection methods for primary frozen shoulder resulted in similar clinical improvement in the final follow-up at 6 months. PMID- 26927434 TI - Predictive factors of long head of the biceps tendon disorders-the bicipital groove morphology and subscapularis tendon tear. AB - BACKGROUND: Disorders of the long head of the biceps (LHB) tendon contribute to anterior shoulder pain. Although LHB tendon disorders are associated with rotator cuff disease, distinguishing between biceps and rotator cuff pathology is difficult. The objective was to identify the predictors of LHB tendon disorders associated with a supraspinatus tear. METHODS: In 55 patients (average age, 65 years) undergoing arthroscopic rotator cuff repair, bicipital groove morphology were assessed using computed tomography, and subscapularis tear and bicipital groove effusion were assessed using magnetic resonance imaging, retrospectively. The LHB tendon was evaluated arthroscopically according to the Lafosse classification. Univariate and multivariate ordinal logistic regression analyses were conducted for injury grade with all covariates. RESULTS: The arthroscopic evaluation of the LHB tendon showed that there were 23 shoulders classified as grade 0, 15 as grade 1, and 17 as grade 2. Univariate logistic regression analysis showed that the width and depth, a medial spur of the bicipital groove, and a subscapularis tear were significantly associated with LHB tendon disorders. Multivariate ordinal logistic regression analysis identified a medial spur and subscapularis tear as significant predictors of LHB tendon disorders. CONCLUSIONS: The preoperative computed tomography and magnetic resonance images, notably the presence of a spur on the bicipital groove or a subscapularis tear, were useful for identifying LHB tendon disorders. When these are found in preoperative images, the clinician should evaluate the patient for the presence of an LHB tendon disorder as a pain generator. PMID- 26927435 TI - Distal humerus articular malunion after an open reduction-internal fixation of a capitellum-trochlea shear fracture: a case report. PMID- 26927436 TI - Axillary artery compression as a complication of a shoulder dislocation. PMID- 26927437 TI - Bilateral upper arm compartment syndrome after a vigorous cross-training workout. PMID- 26927438 TI - Total shoulder arthroplasty in a patient with microcephalic osteodysplastic dysplasia: a case report with 4-year outcomes. PMID- 26927439 TI - Surgical reconstruction of chronic latissimus dorsi tear using Achilles tendon allograft. PMID- 26927440 TI - Regarding "Elbow radiographic anatomy: measurement techniques and normative data". PMID- 26927441 TI - Treatment of catastrophic antiphospholipid syndrome. AB - PURPOSE OF REVIEW: Catastrophic antiphospholipid syndrome (CAPS) is a severe manifestation of antiphospholipid syndrome (APS). Although affecting only 1% of patients with APS, the condition is frequently fatal if not recognized and treated early. Here, we will review the current approach to diagnosis and treatment of CAPS. RECENT FINDINGS: Data from the international 'CAPS registry', spearheaded by the European Forum on Antiphospholipid Antibodies, have improved our understanding of at-risk patients, typical clinical features, and precipitating diagnoses. Current guidelines also continue to support the role of anticoagulants and glucocorticoids as foundation therapy in all patients. Finally, new basic science and case series suggest that novel therapies, such as rituximab and eculizumab, warrant further study. SUMMARY: Attention to associated diagnoses, such as infection and systemic lupus erythematosus (SLE), is critical at the time of diagnosis. All patients should be treated with anticoagulants, corticosteroids, and possibly plasma exchange. In patients with SLE, cyclophosphamide should be considered. In refractory or relapsing cases, new therapies, such as rituximab and possibly eculizumab, may be options, but need further study. PMID- 26927442 TI - MRI and ultrasound in rheumatoid arthritis. AB - PURPOSE OF REVIEW: To overview the recent literature on the use of MRI and musculoskeletal ultrasonography (MSUS) in rheumatoid arthritis. RECENT FINDINGS: Subclinical inflammation has been widely confirmed, even in the earliest phases of rheumatoid arthritis. The presence of osteitis has added benefits to modern diagnostic criteria, and anticitrullinated peptide antibody positive patients have demonstrated higher osteitis scores. A model for prediction of rheumatoid arthritis onset employing usual clinical data and power Doppler ultrasonography has been reported. The presence of tenosynovitis may also be an early finding in rheumatoid arthritis. Modern imaging continues to inform our concept of pathogenesis with reports on the direct relationship of synovitis to cartilage proteoglycan loss using compositional MRI measures. Growing data on the validity of MRI as an important predictor of clinical and radiographic damage endpoints has been reported and reflected in the growing use of this outcome in many contemporary biologic therapy trials. Much work has been presented on improved and validated MSUS scores with reduced and feasible joint counts. The role of ultrasonography in making sensible decisions when monitoring biologic use, and in tapering, has been reported. SUMMARY: The recent literature demonstrates improved validity and utility for both MRI and MSUS in diagnosis, prognosis and monitoring of rheumatoid arthritis. PMID- 26927443 TI - Infection, malignancy, switching, biosimilars, antibody formation, drug survival and withdrawal, and dose reduction: what have we learned over the last year about tumor necrosis factor inhibitors in rheumatoid arthritis? AB - PURPOSE OF REVIEW: This article reviews the most current studies investigating the use of tumor necrosis factor inhibitors (TNFis) in the treatment of rheumatoid arthritis. RECENT FINDINGS: Studies over the past year have clarified that suppressing TNF with monoclonal antibodies does increase infection risk, yet coupled with reduction in disease activity and less use of corticosteroids as a consequence, the overall risk to the population is balanced. With caution (provided by some recent studies) TNFi agents can be reduced (dosage intervals lengthened) and maintain benefit. Biosimilars, not surprisingly, are going to be therapeutically identical to the innovator, and not more of a risk for causing antibodies to interfere with benefit. Uncertainty remains about when and how to make the switch. SUMMARY: TNFi agents have made their powerful impact on management of patients with rheumatoid arthritis, but questions remain: what is their true infection and malignancy risk in the evolving populations using these drugs today; are we able to maintain their benefit with a reduced schedule (and presumed less cost) and yet recapture their benefit if we guess wrong; are biosimilars just as good, or even better with less cost; are there data to inform us about how to achieve successful switching among different mechanism of action TNFi agents? Finally, are we going to face the specter of cost containment causing change from innovator to biosimilars over which we have no control? PMID- 26927444 TI - Cytomegalovirus (CMV) Monitoring After Liver Transplantation: Comparison of CMV Pp65 Antigenemia Assay with Real-Time PCR Calibrated to WHO International Standard. AB - BACKGROUND: Cytomegalovirus (CMV) remains a major cause of morbidity and mortality for liver transplant recipients. Although the CMV pp65 antigenemia (AG) assay has been widely used to monitor patients for CMV infection after liver transplantation, real-time PCR is becoming the standard procedure. The World Health Organization (WHO) International Reference Standard for CMV quantification has become available to standardize values diagnostic of CMV infection. MATERIAL AND METHODS: Our in-house real-time PCR assay was standardized using the WHO standard reagents. Levels of CMV DNA in 1339 blood samples obtained from 190 liver transplant recipients were quantified and expressed in international units, and results were then compared with those of the CMV pp65 AG assay performed on the same blood samples. Correlation was assessed and receiver operating characteristic curves were analyzed to determine the optimal cut-off value for CMV DNA (IU/mL) PCR results. RESULTS: Significant correlation was found between results of the 2 assay methods (p<0.001, r=0.715); a PCR result of >=288 IU/mL predicted a positive result by the CMV AG assay (1 positive cells/150 000 leukocytes) with a sensitivity of 67.4% and specificity of 94.8%. CONCLUSIONS: To the best of our knowledge, this is the first report to compare CMV AG and real time PCR (calibrated to the WHO standard) results in a large number of recipients after liver transplantation. Use of this technique may provide useful information for the management of CMV infection. PMID- 26927445 TI - Sodium-glucose co-transporter-2 inhibitors suppress atrial natriuretic peptide secretion in patients with newly diagnosed Type 2 diabetes. AB - AIMS: To observe changes in atrial natriuretic peptide levels after treatment with sodium-glucose co-transporter-2 inhibitors in patients with newly diagnosed type 2 diabetes. METHODS: A total of 28 patients with newly diagnosed Type 2 diabetes and HbA1c levels of 58 -91 mmol/mol (7.5-10.5%) were randomly selected to receive sodium-glucose co-transporter-2 inhibitor treatment (n = 18) or placebo (n = 10) for 24 weeks. We analysed atrial natriuretic peptide concentrations, using an enzyme-linked immunosorbent assay. In addition, sodium and HbA1c levels were measured at baseline, 12 weeks and 24 weeks and blood lipid levels and insulin sensitivities at baseline and 24 weeks. RESULTS: Compared with patients treated with placebo, patients who received sodium-glucose co transporter-2 inhibitor treatment exhibited lower atrial natriuretic peptide levels (36.74 vs 56.90 pg/ml in the placebo group; P < 0.05) and higher sodium levels (144.3 vs 141.4 mmol/l in the placebo group; P < 0.01) at 24 weeks, after adjusting for baseline values. HbA1c levels were lower after sodium-glucose co transporter-2 inhibitor treatment compared with placebo (51 vs 60 mmol/mol; P < 0.01). No correlation was found between atrial natriuretic peptide and HbA1c levels. Homeostatic model assessment of beta-cell function values and lipid profiles were generally similar after 24 weeks of treatment with placebo or sodium-glucose co-transporter-2 inhibitor. CONCLUSIONS: This study shows the ability of sodium-glucose co-transporter-2 inhibitors to lower atrial natriuretic peptide levels and improve glycaemic control, which may benefit the cardiovascular system. PMID- 26927446 TI - Capecitabine and bevacizumab with or without vinorelbine in first-line treatment of HER2/neu-negative metastatic or locally advanced breast cancer: final efficacy and safety data of the randomised, open-label superiority phase 3 CARIN trial. AB - The study was designed to evaluate efficacy and superiority of capecitabine/bevacizumab + vinorelbine (CAP/BEV/VIN) compared to CAP/BEV alone. Main purpose was to introduce a taxane-/anthracycline-free first-line treatment in advanced breast cancer (ABC), in order to avoid long-term toxicities. In this open-label, superiority, phase 3 trial, patients with HER2-negative ABC were randomized 1:1 to receive either oral CAP at 1000 mg/m(2) [twice daily, days 1 14, q3w] plus intravenous BEV at 15 mg/kg [day 1, q3w] (arm A) or in addition to this protocol intravenous VIN at 25 mg/m(2) [days 1 + 8, q3w] (arm B) until disease progression, unacceptable toxicity or withdrawal of consent. Between 26 February 2009 and 26 October 2012, we randomised 600 patients (arm A N = 300; arm B N = 300) from 57 German outpatient-centres and 2 university hospitals. Median progression-free survival (PFS) (primary endpoint) was not improved with VIN (CAP/BEV, 8.8 months; CAP/BEV/VIN, 9.6 months; HR 0.84 [95 % CI 0.70-1.01], P = 0.058). Median overall survival (OS) (secondary endpoint) was 25.1 and 27.2 months for CAP/BEV and CAP/BEV/VIN, respectively, average HR 0.85 [95 % CI 0.70 1.03], P = 0.104). The 1- and 2-year OS rates appeared to be similar (78.0 and 77.0 %; 53.0 and 54.0 %). Toxicity profiles were generally mild and manageable. Adverse events occurred more frequently in arm B. Regarding the balance between clinical efficacy (PFS, OS) and toxicity, the CAP/BEV combination provides a favourable treatment option in first-line ABC avoiding taxane- and/or anthracycline-induced long-term toxicity. Superiority of CAP/BEV/VIN was not met, and side effects were even enhanced. Nevertheless, no safety issues occurred. PMID- 26927447 TI - KRAS, BRAF, and PIK3CA mutations, and patient prognosis in 126 pancreatic cancers: pyrosequencing technology and literature review. AB - The oncogenic hallmarks of pancreatic cancer (PC), such as the KRAS, BRAF, and PIK3CA mutations, have been widely investigated. However, almost all of the previous studies were limited by small sample sizes. In addition, previous data on the KRAS mutation and clinical outcomes in PC remain inconclusive. To clarify these data, we examined the mutation status of 126 PC patients and its relationship to clinical outcome. The frequencies of KRAS, BRAF, and PIK3CA mutations were determined from a non-biased database of 126 resected PCs and a high-throughput pyrosequencing assay. KRAS mutations were detected in 109 (86.5 %) of the 126 cases; the most common mutation was c.34G > T (p.G12C), which was present in 80 tumors, followed by c.35G > T (p.G12V) in 52 tumors. The KRAS mutation was not associated with any clinical or pathological features (p > 0.05 in all cases). In addition, the KRAS mutation was unrelated to overall survival (log rank p = 0.21) and cancer-specific survival (log rank p = 0.27). Importantly, the influence of KRAS mutation on patient outcome was not modified by any of the clinical or pathological variables (p for all interactions >0.05). Only one PIK3CA mutation (0.8 %) was detected on exon 9 RS3 (c.1633G > A, p.E545K). The BRAF mutation was not detected in PC. KRAS mutations appear to be unrelated to clinical outcome in PC. BRAF and PIK3CA mutations were extremely rare in PC, suggesting that they play a limited role in PC development. PMID- 26927449 TI - ZIKATracker: A mobile App for reporting cases of ZIKV worldwide. AB - We have developed a mobile App called ZIKATracker (zikatracker.net) to voluntarily be used to report ZIKV cases on a public or private level. As the Zika virus (ZIKV) infection zones are rapidly expanding across South, Central, and North America, and reports have emerged linking ZIKV infection with developmental defects and neurological sequelae, reporting the movement and sequelae of ZIKV is essential. ZIKATracker is a multi-lingual App (English, French, Spanish, and Portuguese) freely available to anyone worldwide wishing to report a suspected or confirmed case of Zika virus and related symptoms. Knowledge gained from the use of this App will help direct the implementation of mosquito control measures in needed areas, bring aid to those affected by the Zika virus, and understand the movement and sequelae of ZIKV as it spreads through communities and across continents. PMID- 26927450 TI - Zika virus outbreak in Brazil. AB - Zika virus (ZIKV) infection is spreading rapidly within the Americas after originating from an outbreak in Brazil. We describe the current ZIKV infection epidemic in Brazil and the neurological symptoms arising. First cases of an acute exanthematic disease were reported in Brazil's Northeast region at the end of 2014. In March 2015, autochthonous ZIKV was determined to be the causative agent of the exanthematic disease. As cases of neurological syndromes in regions where ZIKV, dengue and/or Chikungunya viruses co-circulate were reported, ZIKV was also identified in the cerebrospinal fluid of patients with acute neurological syndromes and previous exanthematic disease. By the end of September 2015, an increasing number of infants with small head circumference or microcephaly were noted in Brazil's Northeast which was estimated to be 29 cases between August and October. ZIKV was identified in blood and tissue samples of a newborn and in mothers who had given birth to infants with microcephaly and ophthalmological anomalies. In 2015, there were an estimated 440,000 - 1,300,000 Zika cases in Brazil. There have been 4,783 suspected cases of microcephaly, most of them in the Northeast of Brazil associated with 76 deaths. The Ministry of Health is intensifying control measures against the mosquito Aedes aegypti and implemented intensive surveillance actions. Further studies are needed to confirm the suspected association between ZIKV infection and microcephaly; to identify antiviral, immunotherapy, or prophylactic vaccine; to introduce diagnostic ELISA testing. Clinical and epidemiological studies must be performed to describe viral dynamics and expansion of the outbreak. PMID- 26927448 TI - The game theory of Candida albicans colonization dynamics reveals host status responsive gene expression. AB - BACKGROUND: The fungal pathogen Candida albicans colonizes the gastrointestinal (GI) tract of mammalian hosts as a benign commensal. However, in an immunocompromised host, the fungus is capable of causing life-threatening infection. We previously showed that the major transcription factor Efg1p is differentially expressed in GI-colonizing C. albicans cells dependent on the host immune status. To understand the mechanisms that underlie this host-dependent differential gene expression, we utilized mathematical modeling to dissect host pathogen interactions. Specifically, we used principles of evolutionary game theory to study the mechanism that governs dynamics of EFG1 expression during C. albicans colonization. RESULTS: Mathematical modeling predicted that down regulation of EFG1 expression within individual fungal cells occurred at different average rates in different hosts. Rather than using relatively transient signaling pathways to adapt to a new environment, we demonstrate that C. albicans overcomes the host defense strategy by modulating the activity of diverse fungal histone modifying enzymes that control EFG1 expression. CONCLUSION: Based on our modeling and experimental results we conclude that C. albicans cells sense the local environment of the GI tract and respond to differences by altering EFG1 expression to establish optimal survival strategies. We show that the overall process is governed via modulation of epigenetic regulators of chromatin structure. PMID- 26927451 TI - Salmonella serotypeTyphi, Shigella, and intestinal parasites among food handlers at Bahir Dar University, Ethiopia. AB - INTRODUCTION: Food handlers play a major role in the transmission of Salmonella serotype Typhi (S. Typhi), Shigella, and intestinal parasites. This study was conducted to determine the prevalence of S. Typhi, Shigella, and intestinal parasites among food handlers at Bahir Dar University, Ethiopia. METHODOLOGY: A cross-sectional study was conducted in June 2014. Stool samples from 410 food handlers were examined for bacterial pathogens and parasites. Pearson's Chi square test, Fisher's exact test, and bivariate and multivariate logistic regression analyses were used where appropriate. RESULTS: The prevalence of S. Typhi, Shigella, and intestinal parasites among food handlers was 11 (2.7%), 5 (1.2%), and 53 (12.9%), respectively. Among eight intestinal parasites identified, the two most prevalent intestinal parasites were hookworm 26 (6.3%) and G. lamblia 13 (3.1%). Male food handlers were more likely to be positive than were female food handlers for S. Typhi and intestinal parasites. Furthermore, food handlers who had a history of regular medical checkups were less infected with intestinal parasites. Being male (AOR: 2.1, 95% CI: 1.2, 4.4) and not attending medical checkups (AOR: 2.9, 95% CI: 1.4, 6.1) were independent predictors of intestinal parasitic infection in food handlers. Male food handlers were reluctant to have regular parasitological examinations. CONCLUSIONS: There was a high proportion of food handlers with S. Typhi, Shigella, and intestinal parasites in their faces. Special emphasis should be placed on S. Typhicarriers and male food handlers. Education and periodical medical checkups for intestinal parasites and S. Typhi should be considered as intervention measures. PMID- 26927453 TI - Genotyping and prevalence of Chlamydia trachomatis infection among women in Belem, Para, northern Brazil. AB - INTRODUCTION: Genital Chlamydia trachomatis infection is one of the most prevalent sexually transmitted diseases in women, and undetected cases of the disease are highly associated with long-term complications. Despite the high prevalence of infections in Brazil, very little is known about the distribution of C. trachomatis genovars. In this study, we determined the prevalence and genotypes of C. trachomatis in women treated at a public hospital in the Brazilian city of Belem, the capital of the state of Para. METHODOLOGY: A total of 154 women were tested for chlamydial infection by PCR using specific primers for the C. trachomatis cryptic plasmid. Genotyping of positive samples was performed by sequencing the ompA gene and conducting further phylogenetic analysis. RESULTS: Out of the 154 samples, 17 were found to be positive using C. trachomatis cryptic plasmid PCR. The overall prevalence of C. trachomatis infection was 11%, with the highest prevalence observed in women between 16 and 20 years of age. Five genotypes were found to be associated with endocervical infection. Genotype F was most frequently found (37.5%), followed by genotypes J (25%), E (25%), I (6.25%), and D (6.25%). CONCLUSIONS: This study emphasizes the relevance of C. trachomatis infection in the young female population of the Brazilian Amazon region. It also demonstrates the diversity of genotypes involved in genital infection in this population. PMID- 26927452 TI - Incidence rates and clinical Symptoms of Salmonella, Vibrio parahaemolyticus, and Shigella infections in China, 1998-2013. AB - INTRODUCTION: The etiological and clinical characteristics of patients with infectious diarrhea have changed during the last decade in Shanghai. METHODOLOGY: The records of 29,210 patients with infectious diarrhea in the outpatient department of the Jinshan Hospital (Shanghai, China) between January 1998 and December 2013 were analyzed. RESULTS: A total of 2,849 samples were positive for intestinal pathogenic bacteria including Vibrio parahaemolyticus (2,489; 84.0%), Salmonella spp. (235; 8.3%), and Shigella spp. (125; 4.4%). V. parahaemolyticus infections are mainly characterized by abdominal pain, nausea, and vomiting, whereas Shigella spp. infections can, in addition, induce fever. In contrast, Salmonella infections can produce all of these symptoms but in a smaller percentage of patients. During the 16-year study, both the number of patients and the positive infection rate declined. Notably, the rate of infections by V. parahaemolyticus decreased while the detection rates of Salmonella spp. increased year by year from 2006 on with the introduction of a new detection method. CONCLUSIONS: Salmonella has been identified as the third-most frequent cause of diarrhea from 1998-2006, as the second-most frequent cause from 2006-2010, and as the most frequent cause from 2011-2013, which was mainly due to a sharp decrease of V. parahaemolyticus infections in 2011-2013. Salmonella strains collected in 2011-2013 showed high susceptibility to imipenem (100%) and meropenem (100%), whereas susceptibilities for ampicillin (39%) and piperacillin (40%) were low. PMID- 26927454 TI - Enterotoxin gene profile of Staphylococcus aureus isolates recovered from bovine milk produced in central Ethiopia. AB - INTRODUCTION: Staphylococcal food intoxication is dependent on the production of enterotoxins, the single most important virulence factors. Various studies conducted in Ethiopia have depicted the prevalence of S. aureus in bovine milk. However, there is no published data regarding the enterotoxin gene profile of S. aureus isolates in Ethiopia. The aim of this study was, therefore, to evaluate enterotoxin gene carriage profile of S. aureus isolates recovered from bovine milk samples from central Ethiopia. METHODOLOGY: In this study, 109 S. aureus isolates recovered from bovine milk were analyzed for carriage of the classical enterotoxin genes. Genomic DNA extraction was performed using a commercially available kit. Two sets of multiplex polymerase chain reaction (PCR) assays were used to detect the five classical enterotoxin-coding genes and the toxic shock syndrome toxin gene. RESULTS: At least one type of S. aureus enterotoxin gene (SE) was carried in 73 (66.9%) of the isolates. The most frequently encountered gene was sea (40; 36.7%) followed by seb (19; 17.4%), see (18; 16.5%), tst (16; 14.7%), sec-1 (12; 11.01%), and sed (7; 6.4%). Of the 73 S. aureus isolates harboring at least one of the enterotoxin genes, 26 (35.6%) strains harbored more than one enterotoxin gene. CONCLUSIONS: More than half of the S. aureus isolates harbored at least one of the enterotoxin coding genes, indicating milk specimens contaminated by S. aureus could have a high chance of causing food intoxication. PMID- 26927455 TI - spa typing and antimicrobial resistance of Staphylococcus aureus from healthy humans, pigs and dogs in Tanzania. AB - INTRODUCTION: Staphylococcus aureus is an opportunistic pathogen causing infections in humans and animals. Here we report for the first time the prevalence of nasal carriage, spa typing and antimicrobial resistance of S. aureus in a Tanzanian livestock community. METHODOLOGY: Nasal swabs were taken from 100 humans, 100 pigs and 100 dogs in Morogoro Municipal. Each swab was enriched in Mueller Hinton broth with 6.5% NaCl and subcultured on chromogenic agar for S. aureus detection. Presumptive S. aureus colonies were confirmed to the species level by nuc PCR and analysed by spa typing. Antimicrobial susceptibility patterns were determined by disc diffusion method. RESULTS: S. aureus was isolated from 22% of humans, 4% of pigs and 11% of dogs. A total of 21 spa types were identified: 13, 7 and 1 in human, dogs, and pigs, respectively. Three spa types (t314, t223 and t084) were shared between humans and dogs. A novel spa type (t10779) was identified in an isolate recovered from a colonized human. Antimicrobials tested revealed resistance to ampicillin in all isolates, moderate resistances to other antimicrobials with tetracycline resistance being the most frequent. CONCLUSION: S. aureus carrier frequencies in dogs and humans were within the expected range and low in pigs. The S. aureus spa types circulating in the community were generally not shared by different hosts and majority of types belonged to known clones. Besides ampicillin resistance, moderate levels of antimicrobial resistance were observed irrespective of the host species from which the strains were isolated. PMID- 26927456 TI - Listeria monocytogenes: An emerging food-borne pathogen and its public health implications. AB - INTRODUCTION: Listeria monocytogenes is considered one of the most important food borne pathogens transmitted to humans via contaminated food. The aim of the present study was to demonstrate the importance of L. monocytogenes as a food borne pathogen. METHODOLOGY: A total of 340 samples were collected from different localities in El Giza Governorate, Egypt, to check the occurrence of L. monocytogenes in that area. The collected samples comprised 250 food samples, 40 swabs from food refrigerators, and 50 stool specimens from diarrheic children. L. monocytogenes was isolated from the examined samples according to the International Organization for Standardization. The isolates were tested biochemically using Listeria Microbact 12L and confirmed by polymerase chain reaction. RESULTS: The isolation rates of L. monocytogenes were 8% in beef burger, 4% in minced meat, 4% in luncheon meat, while sausage samples were all negative. Eight percent of raw milk samples were positive for L. monocytogenes, whereas cheese samples and refrigerator swabs were negative. Only Listeria grayi was isolated from human stools (2.5%). CONCLUSION: The high isolation rates of L. monocytogenes among the examined food stuffs highlight the crucial role of food as an important vehicle for this pathogen. More efforts should be made to ensure safe handling and processing of these foods to reduce the transmission of L. monocytogenes to humans. PMID- 26927457 TI - Different features of influenza A H1N1pdm09 virus infection among adults in 2009/10 and 2010/11. AB - INTRODUCTION: Influenza A H1N1pdm09 virus infection causes an epidemiologically and clinically severe disease mostly characterized by pneumonia, resulting in a high mortality rate. The purpose of this study was to investigate and compare epidemiological and clinical characteristics of influenza A H1N1pdm09 virus infection in patients hospitalized during the pandemic (2009/10) and post pandemic seasons (2010/11). METHODOLOGY: The data of patients with laboratory confirmed influenza A H1N1pdm09 virus infection hospitalized and treated at the University Hospital for Infectious Diseases Dr. Fran Mihaljevic in Zagreb, Croatia in the first two seasons of appearance were analyzed. RESULTS: Compared to the pandemic season, in the post-pandemic season, patients were hospitalized longer, had higher values of inflammatory parameters, and were more often treated with antibiotics. The total number of risk factors in patients did not vary significantly between the two seasons. In the pandemic season, a significantly higher number of obese patients and patients with chronic lung disease was observed, whereas in the post-pandemic season, a statistically significant number of patients presented with symptoms of chronic cardiac and neuromuscular diseases. Primary viral pneumonia was frequently registered in younger adults during the pandemic season, whereas in the post-pandemic season, there were more cases of bacterial pneumonia. CONCLUSIONS: During the pandemic season, the influenza A H1N1pdm09 virus infection caused a severe disease with rare bacterial complications, especially in adult patients. The common characteristics of the influenza A H1N1pdm09 virus were lost in the post-pandemic season, assuming the shape and characteristics of the seasonal influenza A virus. PMID- 26927458 TI - The effects of nosocomial rotavirus gastroenteritis on the length of hospital stay and cost. AB - INTRODUCTION: In this study, the goal was to evaluate the impact of nosocomial rotavirus gastroenteritis in pediatric patients by determining the incidence of nosocomial rotavirus gastroenteritis, the resulting duration of hospital stay, and direct cost. To our knowledge, this is the first study in Turkey that evaluates the impact of pediatric nosocomial rotavirus gastroenteritis on duration of hospital stay and calculates the direct cost. METHODOLOGY: Forty-nine patients who were diagnosed with nosocomial rotavirus gastroenteritis and hospitalized were included in the study. Nosocomial infection rates, organ systems affected by the nosocomial infections, and patients who had nosocomial rotavirus gastroenteritis were identified. A direct cost analysis of patients who were diagnosed with nosocomial rotavirus gastroenteritis was performed using copies of the invoices for the hospital bills. RESULTS: During the study period, there were 49 cases of nosocomial rotavirus gastroenteritis. The length of hospitalization was extended, on average, by more than 6.3 days in cases of nosocomial rotavirus gastroenteritis. The cost of hospitalization for patients with nosocomial rotavirus gastroenteritis was on average 1,554 +/- 2,067 US dollars, compared to a cost of only 244 +/- 103 US dollars for patients who did not have nosocomial rotavirus gastroenteritis. This difference in cost was statistically significant (p < 0.05). CONCLUSIONS: Nosocomial rotavirus gastroenteritis is important because it significantly prolongs hospital stay and increases the social and economic burden of the hospitalization. Nosocomial rotavirus gastroenteritis can be reduced with prevention measures such as handwashing, isolation, and cohorting. PMID- 26927459 TI - Genetic characteristics of coxsackievirus A16 associated with hand, foot, and mouth disease in Nanjing, China. AB - INTRODUCTION: Coxsackievirus A16 (CVA16) is a main pathogen in hand, foot, and mouth disease (HFMD) worldwide. This study intended to clarify the genetic characteristics of CVA16 associated with HFMD in a defined area in Nanjing, China. METHODOLOGY: A total of 175 CVA16 strains isolated from throat swabs between 2011 and 2013 were obtained through sentinel hospitals in Nanjing. Multiplex polymerase chain reaction (PCR) was used to amplify the VP1 sequence of local CVA16 strains, and their genetic relationship with 138 CVA16 strains isolated in China and other countries of the world was compared. RESULTS: Phylogenetic analysis based on complete VP1 sequences revealed that subgenotype B1a and B1b were predominantly circulating in Nanjing and B1b strains were spread more widely. The evolution of CVA16 strains is very conservative, with a mean distance of less than 9%. Moreover, six reported conservative regions in VP1 protein were examined, and three of them exhibited high conservation in all CVA16 genotypes except the G-10 prototype and may serve for further vaccine research. CONCLUSIONS: The CVA16 strains circulating in Nanjing, China, in 2011 to 2013 belonged to different genotypes and evolved in a conservative way. To provide further evidence for epidemiological linkage and evolutionary recombination events in CVA16, persistent surveillance of HFMD-associated pathogens is required. PMID- 26927460 TI - The relationship between brucellosis and vitamin D. AB - INTRODUCTION: This study was aimed to determine the relationship between vitamin D and soluble vitamin D receptor (VDR) levels and brucellosis, a common infection in Turkey, in which the cellular immune system is important in the course of the disease. METHODOLOGY: Patients who had been followed up in the Department of Infectious Diseases and Clinical Microbiology of Cukurova University Medical Faculty, having been diagnosed with brucellosis and who had no brucellosis treatment before, were enrolled in the study along with healthy controls. The participants' vitamin D and soluble VDR values were recorded. Laboratory parameters of patients and controls, clinical findings, and disease course of brucellosis patients were also noted. RESULTS: The mean age of the 86 brucellosis patients, of whom 38 (44.2%) were males and 48 (55.8%) were females, was 40.9 +/- 18.4 years. Complicated course of brucellosis rate was found to be 29.1%. Vitamin D and VDR levels were lower in brucellosis patients at the time of diagnosis compared to control group. For males, vitamin D and VDR levels were higher in the control group than in the patient group. In males, VDR levels were higher than in females. A significant difference was not found between clinical forms of the disease and vitamin D and VDR levels. CONCLUSIONS: Vitamin D and VDR levels were shown to be significantly lower in brucellosis patients before treatment compared to the control group. These results suggest that vitamin D could be involved in the pathogenesis of the disease. PMID- 26927461 TI - New Delhi metallo-beta-lactamase in Jamaica. AB - INTRODUCTION: The global dissemination of the New Delhi metallo-beta-lactamase (NDM) gene among certain strains of bacteria has serious implications since the infections caused by such organisms pose a therapeutic challenge. Although the NDM gene has been detected in various parts of the world, this is the first report of its detection in the English-speaking Caribbean. The NDM producing Klebsiella pneumoniae was isolated from an Indian patient who had recently relocated to Jamaica. METHODOLOGY: Identification and susceptibility testing of the K. pneumoniae isolate was performed using the Vitek 2 automated system) in keeping with Clinical and Laboratory Standards Institute (CLSI) standards. It was identified as a metallobetalactamase producer using the Rosco KPC+MBL kit. Genotypic screening for common betalactamase (including carbapenemase) genes, was carried out using two multiplex PCRs: one for SHV-, TEM-, CTX-M-, OXA-1-, and CMY-2-types, and one for VIM-, KPC-, IMP-, OXA-48, GES-, and NDM-types. Strain typing was conducted by pulsed-field gel electrophoresis (PFGE) using XbaI and multi-locus sequencing (MLS). Plasmid isolation and analysis was also performed. RESULTS: K. pneumoniae (N11-02395), not previously associated with the dissemination of the NDM in India, Sweden or the UK, was found to harbor the NDM 1 gene on plasmid pNDM112395. CONCLUSION: The identification of the NDM-1 gene underscores the need for effective surveillance and infection control measures to identify and prevent spread of multidrug resistant Gram negative bacilli. Strict infection control measures implemented for this patient helped to prevent the spread of this organism to other patients. PMID- 26927462 TI - Non-O1Vibrio cholerae bacteremia in an infant, first case report from Pakistan. AB - To the best of our knowledge, Non-O1 Vibrio cholerae (NOVC) bacteremia has never been documented in Pakistan. This case report is the first reported case of bacteremia in an infant due to NOVC in Pakistan. A neonate was admitted to a hospital with fever and no history of diarrhea. The isolate was identified biochemically and serologically and was sensitive to all the drugs tested as per CLSI 2014 guidelines. PMID- 26927463 TI - Epidemiological, clinical and therapeutic aspects of cerebral malaria imported in Albania. AB - This is a case-report of two patients with cerebral malaria (CM) imported from West-African countries. Notably, this form of malaria was developed as a second disease episode, while the first episode was experienced in West Africa. These findings suggest that the second episode of malaria was caused by a different strain of Plasmodium falciparum as compared to the first one. They are the first cerebral malaria cases imported in Albania after the eradication and absence of Plasmodium for five decades. Early treatment of cerebral malaria is decisive on the duration of coma and disease's outcome. PMID- 26927465 TI - As Ebola winds down, Lassa Fever reemerges yet again in West Africa. PMID- 26927464 TI - Rapid detection of methicillin-resistant Staphylococcus aureus and SCCmec types from nasal swabs by multiplex PCR. PMID- 26927466 TI - Apoptosis of conjunctival epithelial cells before and after the application of autologous serum eye drops in severe dry eye disease. AB - AIMS: To assess the impact of autologous serum eye drops on the level of ocular surface apoptosis in patients with bilateral severe dry eye disease. METHODS: This prospective study was conducted on 10 patients with severe dry eye due to graft versus host disease (group 1) and 6 patients with severe dry eye due to primary Sjogren's syndrome (group 2). Impression cytology specimens from the bulbar conjunctiva were obtained before and after a three-month treatment with 20% autologous serum eye drops applied a maximum of 12 times a day together with regular therapy with artificial tears. The percentage of apoptotic epithelial cells was evaluated immunochemically using anti-active caspase 3 antibody. RESULTS: In group 1, the mean percentage of apoptotic cells was 3.6% before the treatment. The three-month treatment led to a significant decrease to a mean percentage of 1.8% (P = 0.028). The mean percentage of apoptotic conjunctival cells decreased from 5.4% before the treatment to 3.8% in group 2; however, these results did not reach the level of significance. CONCLUSION: Three-month autologous serum treatment led to the improvement of ocular surface apoptosis, especially in the group of patients with severe dry eye due to graft versus host disease. This result supports the very positive effect of autologous serum on the ocular surface in patients suffering from severe dry eye. PMID- 26927467 TI - New-onset diabetes mellitus after renal transplantation. AB - BACKGROUND AND AIM: Diabetes mellitus is a very common metabolic disease with a rising incidence. It is both a leading cause of chronic renal disease and one of the most serious comorbidities in renal transplant recipients. New-onset diabetes after renal transplantation (NODAT) is associated with poor graft function, higher rates of cardiovascular complications and a poor prognosis. The aim of this paper is to review current knowledge of NODAT including risk factors, diagnosis and management. METHODS: A MEDLINE search was performed to retrieve both original and review articles addressing the epidemiology, risk factors, screening and management of NODAT. We also focused on microRNAs as potential biomarkers of NODAT. RESULTS AND CONCLUSION: Understanding the risk factors (both modifiable-e.g. obesity, viruses, and unmodifiable-e.g. age, genetics) may help reduce the incidence and impact of NODAT using pre- and post-transplant management. This can lead to better long-term graft function and general transplant success. PMID- 26927468 TI - Malan syndrome (Sotos syndrome 2) in two patients with 19p13.2 deletion encompassing NFIX gene and novel NFIX sequence variant. AB - BACKGROUND AND AIM: Sotos syndrome 2 (MIM #614753), known also as Malan syndrome, is caused by heterozygous mutations/deletions of the NFIX gene located on chromosome 19p13.2. It manifests in developmental delay, intellectual impairment, macrocephaly, central nervous system anomalies, postnatal overgrowth, and craniofacial dysmorphism. Unusual behavior with/without autistic traits, ophthalmologic, gastrointestinal, musculo-skeletal, and hand/foot abnormalities are also frequent. Due to the limited number of such cases, no definitive conclusions about genotype-phenotype correlations have been possible. In the following paper, we discuss physical features consistent with Sotos syndrome 2 based on literature review and two new cases [a patient with de novo 19p13.2 deletion encompassing a part of the NFIX gene and a patient with de novo (not described so far) heterozygous missense mutation c.367C>T (p.Arg123Trp) in the NFIX gene]. RESULTS: Apart from overgrowth and psychomotor developmental delay, the most consistent physical features of our two patients are dysmorphism including high forehead, downslanting palpebral fissures, pointed chin, and abnormalities of the pinna. Both show abnormal behavior and present with long, tapered fingers and toenail defect. No severe congenital malformations were noted. CONCLUSIONS: We hope these data will serve as a material for further studies and provide an opportunity to make more reliable genotype-phenotype correlations. PMID- 26927469 TI - Recurrent membranous tracheal stenosis with a diverticulum in a 9-year-old boy. Not all that wheezes is asthma. AB - BACKGROUND: Benign tracheobronchial stenosis of the proximal airways may result from a variety of conditions and can cause dyspnea, cough, wheeze or stridor. METHODS AND RESULTS: In this report, we describe the case of a 9-year-old boy who was admitted to hospital with wheezing and progressive dyspnea lasting for six months. These abnormalities were diagnosed by multislice CT with 3-dimensional reconstruction of the trachea and by videobronchoscopy which demonstrated severe tracheal stenosis and an orifice of a tracheal diverticulum on the right side of the upper trachea. The stenosis was dilated with a balloon and vaporized with an Nd:YAG laser. Due to recurrent stenosis, the laser procedure had to be repeated several times in an approximately 4-6-month interval. CONCLUSION: Association between recurrent membranous tracheal stenosis and a tracheal diverticulum is a rare medical condition. PMID- 26927470 TI - Exploring the numerical mind by eye-tracking: a special issue. PMID- 26927472 TI - Editorial on the Impact of the "International Training Guidelines for Endovascular Stroke Intervention" on Training and Education in Germany. PMID- 26927471 TI - Influence of finger and mouth action observation on random number generation: an instance of embodied cognition for abstract concepts. AB - Numerical magnitude and specific grasping action processing have been shown to interfere with each other because some aspects of numerical meaning may be grounded in sensorimotor transformation mechanisms linked to finger grip control. However, how specific these interactions are to grasping actions is still unknown. The present study tested the specificity of the number-grip relationship by investigating how the observation of different closing-opening stimuli that might or not refer to prehension-releasing actions was able to influence a random number generation task. Participants had to randomly produce numbers after they observed action stimuli representing either closure or aperture of the fingers, the hand or the mouth, or a colour change used as a control condition. Random number generation was influenced by the prior presentation of finger grip actions, whereby observing a closing finger grip led participants to produce small rather than large numbers, whereas observing an opening finger grip led them to produce large rather than small numbers. Hand actions had reduced or no influence on number production; mouth action influence was restricted to opening, with an overproduction of large numbers. Finally, colour changes did not influence number generation. These results show that some characteristics of observed finger, hand and mouth grip actions automatically prime number magnitude, with the strongest effect for finger grasping. The findings are discussed in terms of the functional and neural mechanisms shared between hand actions and number processing, but also between hand and mouth actions. The present study provides converging evidence that part of number semantics is grounded in sensory-motor mechanisms. PMID- 26927473 TI - Freiburg Neuropathology Case Conference : Spinal Cord Compression Due to a Lesion Adjacent to the Dens Axis. PMID- 26927474 TI - The screening and evaluation of herbs and identification of herbal combinations with anti-viral effects on Newcastle disease virus. AB - A total of 25 "heat-clearing and detoxifying" herbs used in Chinese medicine were investigated for their cytopathic effects on the growth of Newcastle Disease virus (NDV) in a chicken fibroblast cell line. The 5 herbs with the highest virus inhibitory effects were Herba agastaches, Flos chrysanthemi indici, Rhizoma anemarrhenae, Astragalus root and Baikal skullcap root and these were used in herbal formulations. Anti-NDV activities of 4 formulations were tested on the growth of NDV in the DF-1 fibroblast cell line. Formulation II, containing Baikal skullcap root, Astragalus root, Anemarrhena rhizome (1:1:2) and formulation IV containing Anemarrhena rhizome, Astragalus root and Flos chrysanthemi indici (1:1:1), which had strong anti-NDV activity in vitro, were used to determine the in vivo inhibitory effects of NDV-infection in chickens. After treatment with the two formulations serum IgY titres against NDV were improved, and morbidity was reduced in the NDV-infected chickens. The results suggest that the components in formulations II and IV acted synergistically to improve resistance to Newcastle disease and provide a basis for the developing an anti-NDV herbal medicine. PMID- 26927475 TI - Early and 24 h post-mortem changes in breast muscle quality traits of two turkey genotypes and their reciprocal crosses raised under semi-confined conditions. AB - An experiment was conducted to determine the effect of reciprocal crossing of turkeys on early and 24 h post-mortem changes in quality traits of their breast muscles. The turkeys of slow-growing (SG) and fast-growing (FG) lines as well as SF (SG * FG) and FS crosses (FG * SG) were reared with access to free range. After slaughter turkey breast muscles were examined in the following terms: 5 min, 45 min, 2 h and 24 h post-mortem, for: temperature, pH, glycogen content (G), lactate content (L) and electrical conductivity (EC). Quality attributes of the breast meat were evaluated based on chemical composition, water holding capacity (WHC), cooking loss (%), shear force (N) and colour (L*, a*, b*). Despite differences in the rate of post-mortem changes, the genotype of turkeys had no significant effect upon many quality traits assessed 24 h post-mortem. Meat of lighter birds (SG and SF) was characterised by a lower fat content but a similar protein content compared to meat of FS and FG turkeys. In addition, meat of males from these groups was darker. Meat from the breast muscles of heavier birds (FS and FG) was harder. Significant negative maternal effects were determined for temperature of meat of both male and female turkeys, for pH2 and EC24 of males as well as for L2, L24 and cooking loss of female meat. Positive heterosis was confirmed only for pH2 of female meat and for G2 of male meat. In summary, the direction of fast- and slow-growing turkey crossing may affect the quality of their meat. However, meat of both types of hybrids reared under semi confined conditions (with the possibility of using free range) was characterised by appropriate quality parameters. PMID- 26927476 TI - Description of a model to optimise the feeding of amino acids to growing pullets. AB - 1. A nutrition model is described that may be used to optimise the amino acid nutrition of laying-type pullets prior to the onset of lay. It is not a method of optimising lifetime laying performance. 2. The potential growth and composition of the body, feathers, ovary and oviduct are described from hatching to the age at which sexual maturity is attained, from which the daily amino acid and energy requirements for the average individual in the population can be calculated. 3. There are two parts to the approach used, the first being a description of the model itself and the second being a description of how the required information was gathered. A number of assumptions made in developing the model are discussed. 4. The rates of maturing of the body, feather-free body and body protein of the DeKalb pullets used were shown to be constant at 0.017/d and those of feathers at 0.02/d. These are considerably slower than those of the oviduct and ovary (0.139 and 0.084/d respectively). The ovary attained a higher mature weight (78.4 vs. 58.7 g) than the oviduct. 5. The age at which the growth of the reproductive organs is initiated in the model is defined by the user. The daily amount of threonine required to meet the requirements for maintenance and potential growth of the developing tissues and organs is calculated for each day of the growing period from hatching to the age at which the first egg is laid. A method of calculating the required daily concentration of threonine in the feed is described, from which a feeding programme may be derived. 6. For the model to produce an optimum economic feeding programme for a population of laying-type pullets, more information than is available from this study is required. These issues are discussed in the paper. PMID- 26927477 TI - The Ground State of Monolayer Graphene in a Strong Magnetic Field. AB - Experiments indicate that the ground state of graphene in a strong magnetic field exhibits spontaneous breaking of SU(4) symmetry. However, the nature of the corresponding emergent state is unclear because existing theoretical methods approximate the broken-symmetry solutions, yielding nearly-degenerate candidate ground states having different emergent orders. Resolving this ambiguity in the nature of the strong-field ground state is highly desirable, given the importance of graphene for both fundamental physics and technical applications. We have discovered a new SO(8) symmetry that recovers standard graphene SU(4) quantum Hall physics, but predicts two new broken-SU(4) phases and new properties for potential ground states. Our solutions are analytical; thus we capture the essential physics of spontaneously-broken SU(4) states in a powerful yet solvable model useful both in correlating existing data and in suggesting new experiments. PMID- 26927478 TI - A polymer dataset for accelerated property prediction and design. AB - Emerging computation- and data-driven approaches are particularly useful for rationally designing materials with targeted properties. Generally, these approaches rely on identifying structure-property relationships by learning from a dataset of sufficiently large number of relevant materials. The learned information can then be used to predict the properties of materials not already in the dataset, thus accelerating the materials design. Herein, we develop a dataset of 1,073 polymers and related materials and make it available at http://khazana.uconn.edu/. This dataset is uniformly prepared using first principles calculations with structures obtained either from other sources or by using structure search methods. Because the immediate target of this work is to assist the design of high dielectric constant polymers, it is initially designed to include the optimized structures, atomization energies, band gaps, and dielectric constants. It will be progressively expanded by accumulating new materials and including additional properties calculated for the optimized structures provided. PMID- 26927480 TI - Unmet Mental Healthcare Need and Suicidal Ideation Among U.S. Veterans. AB - INTRODUCTION: Suicide prevention remains a national priority, especially among vulnerable populations. With increasing trends in suicide among Veterans, understanding the underlying factors associated with such an outcome is imperative. In this study, the association between unmet mental healthcare need and suicidal ideation among U.S. Veterans was evaluated. METHODS: The National Survey on Drug Use and Health, 2008-2013, was used to identify those with mental illness, resulting in a total sample of 2,015 Veterans. Data were analyzed in July 2015. Survey-weighted descriptive and logistic regression analyses were conducted with p<0.05 used to establish significance. RESULTS: Sixteen percent of Veterans reported unmet mental healthcare need and 18% had past-year suicidal ideation. After adjusting for confounders, unmet mental healthcare need was associated with increased likelihood of suicidal ideation (AOR=4.11) in the study population. Other characteristics, such as participating in a governmental assistance program and alcohol dependency in the past year, demonstrated 66% and 103% increased odds of suicidal ideation, respectively. CONCLUSIONS: Unmet mental healthcare need is a critical aspect of suicidal ideation among Veterans. Improved access to care for such at-risk populations through means of integrated care is needed to ensure reduced burden of suicide among Veterans. PMID- 26927479 TI - APOLO-Bari, an internet-based program for longitudinal support of bariatric surgery patients: study protocol for a randomized controlled trial. AB - BACKGROUND: Despite evidence of successful weight loss for bariatric surgery patients, some patients experience considerable weight regain over the long term. Given the strong association between post-surgery health behaviors and outcomes, aftercare intervention to address key behaviors appears to be a reasonable relapse-prevention strategy. As the burden of obesity rates increases in healthcare centers, an internet-based program appears to be a reasonable strategy for supporting bariatric surgery patients in the long term. The primary purpose of the current project is to develop and test the efficacy and perceived utility of APOLO-Bari. METHODS/DESIGN: This study is a randomized control trial, which will be conducted in two hospital centers in the North of Portugal; it includes a control group receiving treatment as usual and an intervention group receiving the APOLO-Bari program for one year in addition to treatment as usual. A total of 180 male and female participants who underwent bariatric surgery (gastric sleeve or gastric bypass surgery) for 12 to 20 months will be recruited. Both groups will complete a similar set of questionnaires at baseline, every 4 months until the end of the intervention, and at 6 and 12 months follow-up. Assessment includes anthropometric variables and psychological self-report measures. The primary outcome measure will be weight regain measured at the end of treatment, and at 6 and 12 months follow-up. The secondary aims are to test the cost effectiveness of the intervention and to investigate psychological predictors and trajectories of weight regain. APOLO-Bari was developed to address the weight regain problem in the bariatric population by offering additional guidance to bariatric patients during the postoperative period. The program includes: (a) a psychoeducational cognitive-behavioral-based self-help manual, (b) a weekly feedback messaging system that sends a feedback statement related to information reported by the participant, and (c) interactive chat sessions scheduled with a trained psychologist in the field. DISCUSSION: APOLO-Bari may play an important role in broadening therapeutic reach to bariatric patients who would not otherwise have continuous support, with important implications for public health treatment. TRIAL REGISTRATION: Current Controlled Trials: ISRCTN37668662 . PMID- 26927481 TI - Clinical Relevance of Integrated Developmental Research for Dental Implants. PMID- 26927482 TI - Tapered Implants in Dentistry: Revitalizing Concepts with Technology: A Review. AB - The most common approach to lessen treatment times is by decreasing the healing period during which osseointegration is established. Implant design parameters such as implant surface, primary stability, thread configuration, body shape, and the type of bone have to be considered to obtain this objective. The relationship that exists between these components will define the initial stability of the implant. It is believed implant sites using a tapered design and surface modification can increase the primary stability in low-density bone. Furthermore, recent experimental preclinical work has shown the possibility of attaining primary stability of immediately loaded, tapered dental implants without compromising healing and rapid bone formation while minimizing the implant stability loss at compression sites. This may be of singular importance with immediate/early functional loading of single implants placed in poor-quality bone. The selection of an implant that will provide adequate stability in bone of poor quality is important. A tapered-screw implant design will provide adequate stability because it creates pressure on cortical bone in areas of reduced bone quality. Building on the success of traditional tapered implant therapy, newer tapered implant designs should aim to maximize the clinical outcome by implementing new technologies with adapted clinical workflows. PMID- 26927484 TI - A Critical Perspective on Mechanical Testing of Implants and Prostheses. AB - The degree of interplay among variables in dental implant treatment presents a challenge to randomized clinical trials attempting to answer questions in a timely, unbiased, and economically feasible fashion. Further adding complexity to the different scenarios is the varied implant designs and related bone response, area of implantation, implant bulk material, restoration, abutments and related screws, fixation mode (screwed, fixed, or a combination), and horizontal implant abutment matching geometry. This article critically appraises the most common mechanical testing methods used to characterize the implant-prostheses complex. It attempts to provide insight into the process of construction of an informed database of clinically relevant questions regarding preclinical evaluation of implant biomechanics and failure mechanisms. The use of single load to failure, fatigue life, fatigue limit, and step-stress accelerated life testing is discussed with emphasis on their deliverables, weaknesses, and strengths. Fractographic analysis and challenges in the correlation between laboratory- and in-service-produced failures of dental ceramics, resin composites, and titanium are introduced. In addition, examples are presented of mechanical characterization studies used in our laboratory to assess some implant-supported rehabilitation variables. PMID- 26927483 TI - Implant Surface Design Regulates Mesenchymal Stem Cell Differentiation and Maturation. AB - Changes in dental implant materials, structural design, and surface properties can all affect biological response. While bulk properties are important for mechanical stability of the implant, surface design ultimately contributes to osseointegration. This article reviews the surface parameters of dental implant materials that contribute to improved cell response and osseointegration. In particular, we focus on how surface design affects mesenchymal cell response and differentiation into the osteoblast lineage. Surface roughness has been largely studied at the microscale, but recent studies have highlighted the importance of hierarchical micron/submicron/nanosurface roughness, as well as surface roughness in combination with surface wettability. Integrins are transmembrane receptors that recognize changes in the surface and mediate downstream signaling pathways. Specifically, the noncanonical Wnt5a pathway has been implicated in osteoblastic differentiation of cells on titanium implant surfaces. However, much remains to be elucidated. Only recently have studies been conducted on the differences in biological response to implants based on sex, age, and clinical factors; these all point toward differences that advocate for patient-specific implant design. Finally, challenges in implant surface characterization must be addressed to optimize and compare data across studies. An understanding of both the science and the biology of the materials is crucial for developing novel dental implant materials and surface modifications for improved osseointegration. PMID- 26927485 TI - Integrative Performance Analysis of a Novel Bone Level Tapered Implant. AB - Primary mechanical stability, as measured by maximum insertion torque and resonance frequency analysis, is generally considered to be positively associated with successful secondary stability and implant success. Primary implant stability can be affected by several factors, including the quality and quantity of available bone, the implant design, and the surgical procedure. The use of a tapered implant design, for instance, has been shown to result in good primary stability even in clinical scenarios where primary stability is otherwise difficult to achieve with traditional cylindrical implants-for example, in soft bone and for immediate placement in extraction sockets. In this study, bone-type specific drill procedures are presented for a novel Straumann bone level tapered implant that ensure maximum insertion torque values are kept within the range of 15 to 80 Ncm. The drill procedures are tested in vitro using polyurethane foam blocks of variable density, ex vivo on explanted porcine ribs (bone type 3), and finally in vivo on porcine mandibles (bone type 1). In each test site, adapted drill procedures are found to achieve a good primary stability. These results are further translated into a finite element analysis model capable of predicting primary stability of tapered implants. In conclusion, we have assessed the biomechanical behavior of a novel taper-walled implant in combination with a bone type specific drill procedure in both synthetic and natural bone of various types, and we have developed an in silico model for predicting primary stability upon implantation. PMID- 26927487 TI - Quantitative Detection of PEGylated Biomacromolecules in Biological Fluids by NMR. AB - The accumulation, biodistribution, and clearance profiles of therapeutic agents are key factors relevant to their efficacy. Determining these properties constitutes an ongoing experimental challenge. Many such therapeutics, including small molecules, peptides, proteins, tissue scaffolds, and drug delivery vehicles, are conjugated to poly(ethylene glycol) (PEG) as this improves their bioavailability and in vivo stability. We demonstrate here that (1)H NMR spectroscopy can be used to quantify PEGylated species in complex biological fluids directly, rapidly, and with minimal sample preparation. PEG bears a large number of spectroscopically equivalent protons exhibiting a narrow NMR line width while resonating at a (1)H NMR frequency distinct from most other biochemical signals. We demonstrate that PEG provides a robust signal allowing detection of concentrations as low as 10 MUg/mL in blood. This PEG detection limit is lowered by another order of magnitude when background proton signals are minimized using (13)C-enriched PEG in combination with a double quantum filter to remove (1)H signals from non-(13)C-labeled species. Quantitative detection of PEG via these methods is shown in pig blood and goat serum as examples of complex biological fluids. More practically, we quantify the blood clearance of (13)C-PEG and PEGylated-BSA (bovine serum albumin) following their intravenous injection in live rats. Given the relative insensitivity of line width to PEG size, we anticipate that the biodistribution and clearance profiles of virtually any PEGylated biomacromolecule from biological fluid samples can be routinely measured by (1)H NMR without any filtering or treatment steps. PMID- 26927486 TI - Effect of Osteotomy Preparation on Osseointegration of Immediately Loaded, Tapered Dental Implants. AB - The aim of the present preclinical in vivo study was to evaluate whether a modified "drill-only" protocol, involving slight underpreparation of the implant site, may have an effect on aspects of osseointegration of a novel bone-level tapered implant, compared with the "standard drilling" protocol involving taping and profiling of the marginal aspect of the implant socket. In each side of the edentulated and completely healed mandible of 11 minipigs, 2 tapered implants (8 mm long * 4.1 mm O, BLT; Institut Straumann AG, Basel, Switzerland) were installed either with the drill-only or the standard drilling protocol. Significantly lower average insertion torque values were recorded for the standard drilling protocol group (52 +/- 29 Ncm) compared with the drill-only group (70 +/- 27 Ncm) (t test, P <= 0.05); no significant difference was observed between the 2 groups regarding implant stability, by means of resonance frequency analysis (75 +/- 8 vs. 75 +/- 6, respectively). Half of the implants were immediately loaded and the rest were submerged, providing observation times of 8 or 4 wk, respectively. Non-decalcified histological and histomorphometric analysis of the implants with surrounding tissues showed no significant differences between the 2 drilling protocols regarding the distance from the implant platform to the first coronal bone-to-implant contact (f-BIC), the total bone-to-implant contact (BIC) as a percentage of the total implant perimeter, and the bone density in an area extending 1 mm laterally from the implant (BATA) within 2 rectangular regions of interest (ROIs) 4 mm in height, representing the coronal (parallel-walled) and apical (tapered) aspect of the implant (ROI 1 and ROI 2, respectively) in non-submerged implants. In general, marginal peri-implant bone levels were at or slightly apical to the implant platform, and large amounts of bone-to-implant contact were observed. In contrast, immediately loaded implants placed with the drill-only protocol showed statistically significantly lower BIC values (66% +/- 13.7%) compared with those installed with the standard drilling protocol (74.8% +/- 11.2%) (P = 0.018). In addition, although marginal bone levels were in most of the immediately loaded implants at or slightly apical to the implant platform, some of the implants installed with the drill-only protocol showed marginal bone loss and crater formation. Thus, in this model system, even slight underpreparation of the implant socket appeared to compromise osseointegration of immediately loaded bone-level tapered implants. PMID- 26927488 TI - Discovery of novel 2-phenyl-imidazo[1,2-a]pyridine analogues targeting tubulin polymerization as antiproliferative agents. AB - A series of 2-aryl-imidazo-pyridines/pyrazines derivatives has been designed, synthesized and evaluated for their biological activities. Among them, several investigated compounds (1a, 3b and 3d) displayed potent antiproliferative activity against HeLa cell, and also displayed comparable tubulin polymerization inhibitory activity to colchicine. These studies provided a new molecular scaffold for the further development of antitumor agents that target tubulin. PMID- 26927489 TI - Robust room temperature valley polarization in monolayer and bilayer WS2. AB - We report robust room temperature valley polarization in chemical-vapor deposition (CVD) grown monolayer and bilayer WS2via polarization-resolved photoluminescence measurements using excitation below the bandgap. We show that excitation with energy slightly below the bandgap of the multi-valleyed transition metal chalcogenides can effectively suppress the random redistribution of excited electrons and, thereby, greatly enhance the efficiency of valley polarization at room temperature. Compared to mechanically exfoliated WS2, our CVD grown WS2 films also show enhancement in the coupling of spin, layer and valley degree of freedom and, therefore, provide improved valley polarization. At room temperature, using below-bandgap excitation and CVD grown monolayer and bilayer WS2, we have reached a record-high valley polarization of 35% and 80%, respectively, exceeding the previously reported values of 10% and 65% for mechanically exfoliated WS2 layers using resonant excitation. This observation provides a new direction to enhance valley control at room temperature. PMID- 26927490 TI - Clinical Implications of Histologic Abnormalities in Ileocolonic Biopsies of Patients With Crohn's Disease in Remission. AB - BACKGROUND: For patients with Crohn's disease (CD) who have colonoscopy during periods of clinical remission, the utility of taking ileocolonic biopsy specimens to assess disease activity is disputed. GOALS: We explored the clinical implications of histologic disease activity in such patients. STUDY: We reviewed medical records of CD patients who underwent elective colonoscopy while in clinical remission at our VA Medical Center from 2000 to 2013, and who had at least 6 months of follow-up. We correlated endoscopic and histologic disease activity with the subsequent development of flares. RESULTS: We identified 62 CD patients who had a total of 103 colonoscopies during clinical remission; 55 colonoscopies revealed complete endoscopic healing and 48 showed active disease. Flares within 6, 12, and 24 months of colonoscopy were not more common in patients with endoscopic activity than those with complete endoscopic healing. In contrast, patients with any of 5 histologic features of active inflammation (erosions, cryptitis, crypt abscess, increased neutrophils, or increased eosinophils in the lamina propria) had more flares than patients without those changes (P<0.05). Among the individual histologic features, an increase in eosinophils or neutrophils in the lamina propria and cryptitis were associated with higher flare rates (P<0.05). CONCLUSIONS: For CD patients who have a colonoscopy while in clinical remission, biopsy seems to provide important prognostic information beyond that provided by endoscopic assessment of disease activity alone. In particular, increased eosinophils or neutrophils in the lamina propria and cryptitis are strongly associated with an increased risk of clinical flares within 1 to 2 years. PMID- 26927491 TI - Frequency of Jackhammer Esophagus as the Extreme Phenotypes of Esophageal Hypercontractility Based on the New Chicago Classification. AB - BACKGROUND: Jackhammer Esophagus is defined as intact esophageal peristaltic contractions with extremely elevated amplitudes. We conducted a retrospective study to identify the frequency of esophageal hypercontractility and the clinical characteristics of Jackhammer Esophagus. METHODS: Charts for the patients referred for manometric study at a tertiary-care motility center were reviewed. Data were collected utilizing the new Chicago classification criteria for Jackhammer Esophagus. Concomitant clinical variables were also explored. RESULTS: Eight patients were identified with Jackhammer Esophagus from a total of 205 (127 female/77 male) patients referred for high-resolution esophageal manometry. Jackhammer patients had an average distal contractile integral (DCI) of 9061 mmHg/ sec/ cm and median maximal DCI of 16,433 mmHg/ sec/ cm. The greatest DCI from 15 swallows was 28,875 mmHg/ sec/ cm. Hypercontractility was associated with multipeaked contractions in every Jackhammer patient. The mean lower esophageal sphincter (LES) pressure was 41 mm Hg with 4 patients having a hypertensive pressure of >40 mm Hg. Three of the 8 (37.5%) Jackhammer group had incomplete LES relaxation by integrated relaxation pressure criteria (>15 mm Hg residual pressure). Dysphagia (8/8) was the dominant indication for the manometric study, whereas the clinical background setting was gastroesophageal reflux disease (4/8) and hiatal hernia (1/8). Treatments included smooth muscle relaxation, antireflux regimens, and pneumatic dilation of the LES. CONCLUSIONS: Jackhammer Esophagus, an extreme manometric phenotype, was identified in 4.0% of patients referred to a University Motility Center. The patients with these esophageal hypercontractility states present mainly with dysphagia. A subgroup of Jackhammer did have accompanying incomplete LES relaxation and responded to targeted therapy with pneumatic dilatation. PMID- 26927492 TI - The Clinical Outcome in Patients Treated With a Newly Designed SEMS in Cervical Esophageal Strictures and Fistulas. AB - BACKGROUND AND GOALS: Using a self-expandable metallic stent (SEMS) in the cervical esophagus is controversial due to an increased risk of complications. Here we assessed a new type of SEMS purpose-designed for the cervical esophagus area. STUDY: Patients with malignant or benign stenosis within 4 cm distance of the upper esophageal sphincter who underwent placement of a SEMS with a shorter proximal head (Niti-S Esophageal Covered Stent-Cervical-type, NSECSC), were included. Main outcome measures were the functional outcome, tolerance, complications, recurrent dysphagia, and survival. RESULTS: About 37 patients had an NSECSC placed between April 2008 and June 2013 for esophageal stenosis (malignant=20, benign=17), 5 with associated tracheoesophageal fistula. The mean stenosis-upper esophageal sphincter distance was 1.86+/-1.27 cm. The median follow-up was 150 days. Dysphagia improved in 27/37 cases (73%). Short-term and long-term tolerance without needing stent removal was 92% and 82%, respectively. The complication rate was 59% (22/37): 32% (n=14) major complications [fistula (3), perforation (3), aspiration pneumonia (5), laryngeal dyspnea (2), and bleeding (1)], and 27% (n=10) minor complications [pain (7) or dysphonia (3)]. A multivariate analysis confirmed a higher risk of major complications in cases of benign stenosis (odds ratio=5.2; 95% confidence interval, 1.05-25.90; P=0.04). Recurrent dysphagia occurred in 15 patients (obstruction=7, migration=8). CONCLUSIONS: The NSECSC does not appear less morbid than standard SEMS in the cervical esophageal area, but could be useful in malignant indications as it is well-tolerated and offers effective palliation of the dysphagia. However, this device should not be used in benign cervical esophageal strictures or fistulas. PMID- 26927493 TI - Is Seeing Really Believing? Probe-based Confocal Laser Endomicroscopy in the Evaluation of Pancreaticobiliary Disease. AB - Confocal laser endomicroscopy for real-time diagnosis during endoscopic procedures has now been in the mainstream clinical arena for a decade. Indeterminate biliary strictures and pancreatic cysts remain 2 difficult diagnostic challenges for the gastroenterologist, and the role this technology will play in the approach to these problems is still evolving. There is now a body of literature to guide the endoscopist in the use of this imaging tool, including how it may be useful in excluding biliary malignancy, and how miniaturization has allowed for endoscopic ultrasound-guided application of the probe within cysts. Interobserver variability remains a weakness of the system. Tips for use of this tool and interpretation of the imaging data it provides are discussed. PMID- 26927494 TI - Postinfantile Giant Cell Hepatitis With Autoimmune Features Triggered by Primary Cytomegalovirus Infection in a Pregnant Woman. PMID- 26927495 TI - Elevated Serum Bilirubin Level Correlates With the Development of Cholangiocarcinoma, Subsequent Liver Transplantation, and Death in Patients With Primary Sclerosing Cholangitis. AB - INTRODUCTION: Predicting the clinical course of primary sclerosing cholangitis (PSC) is difficult. There are currently a paucity of studies evaluating serum chemistries as predictors of conventional clinical endpoints. The purpose of this study was to prognosticate key clinical endpoints in patients with PSC who had elevated serum liver chemistries at the time of their initial presentation. METHODS: We performed a retrospective cohort study of PSC patients at our institution. The aim of our study was to determine the association between elevated liver chemistries at initial presentation-bilirubin, alanine transaminase, aspartate transaminase, or alkaline phosphatase-with a primary outcome of either cholangiocarcinoma, liver transplantation, death, or composite of the 3. The secondary endpoints examined were development of severe biliary ductal disease and need for biliary stent placement. RESULTS: Eighty-one PSC patients (61 males and 20 females) were included in this study. By univariate analysis, there was a significant association between initial bilirubin elevation >2x the upper limit of normal (ULN) and death (P<0.009). Multivariate regression analysis revealed that an elevated initial serum total bilirubin >2xULN (P<0.017) significantly predicted the composite endpoint. By univariate analysis of pre endoscopic retrograde cholangiopancreatography labs, serum bilirubin level elevation >2xULN showed an association with severity of biliary ductal disease (P<0.0001). A logistic regression of outcome variables also proved that >2xULN serum bilirubin levels predicted the ductal disease severity (P<0.0001). CONCLUSIONS: An initial elevation of serum total bilirubin >2xULN in PSC patients correlates positively with the development of cholangiocarcinoma, subsequent liver transplantation, and death. Elevated bilirubin also correlates positively with the severity of cholangiographic findings. PMID- 26927496 TI - Defining Planktonic Protist Functional Groups on Mechanisms for Energy and Nutrient Acquisition: Incorporation of Diverse Mixotrophic Strategies. AB - Arranging organisms into functional groups aids ecological research by grouping organisms (irrespective of phylogenetic origin) that interact with environmental factors in similar ways. Planktonic protists traditionally have been split between photoautotrophic "phytoplankton" and phagotrophic "microzooplankton". However, there is a growing recognition of the importance of mixotrophy in euphotic aquatic systems, where many protists often combine photoautotrophic and phagotrophic modes of nutrition. Such organisms do not align with the traditional dichotomy of phytoplankton and microzooplankton. To reflect this understanding, we propose a new functional grouping of planktonic protists in an eco physiological context: (i) phagoheterotrophs lacking phototrophic capacity, (ii) photoautotrophs lacking phagotrophic capacity, (iii) constitutive mixotrophs (CMs) as phagotrophs with an inherent capacity for phototrophy, and (iv) non constitutive mixotrophs (NCMs) that acquire their phototrophic capacity by ingesting specific (SNCM) or general non-specific (GNCM) prey. For the first time, we incorporate these functional groups within a foodweb structure and show, using model outputs, that there is scope for significant changes in trophic dynamics depending on the protist functional type description. Accordingly, to better reflect the role of mixotrophy, we recommend that as important tools for explanatory and predictive research, aquatic food-web and biogeochemical models need to redefine the protist groups within their frameworks. PMID- 26927497 TI - Indian medical colleges to get single entrance exam. PMID- 26927498 TI - Efficacy and Safety of Flibanserin for the Treatment of Hypoactive Sexual Desire Disorder in Women: A Systematic Review and Meta-analysis. AB - IMPORTANCE: In August 2015, the US Food and Drug Administration (FDA) approved flibanserin as a treatment for hypoactive sexual desire disorder (HSDD) in premenopausal women, despite concern about suboptimal risk-benefit trade-offs. OBJECTIVE: To conduct a systematic review and meta-analysis of randomized clinical trials assessing efficacy and safety of flibanserin for the treatment of HSDD in women. DATA SOURCES: Medical databases (among others, Embase, Medline, Psycinfo) and trial registries were searched from inception to June 17, 2015. Reference lists of retrieved studies were searched for additional publications. STUDY SELECTION: Randomized clinical trials assessing treatment effects of flibanserin in premenopausal and postmenopausal women were eligible. No age, language, or date restrictions were applied. Abstract and full-text selection was done by 2 independent reviewers. DATA EXTRACTION AND SYNTHESIS: Data were extracted by one reviewer and checked by a second reviewer. Results were pooled using 2 approaches depending on the blinding risk of bias. MAIN OUTCOMES AND MEASURES: Primary efficacy outcomes included number of satisfying sexual events (SSEs), eDiary sexual desire, and Female Sexual Function Index (FSFI) desire. Safety outcomes included, among others, 4 common adverse events (AEs): dizziness, somnolence, nausea, and fatigue. RESULTS: Five published and 3 unpublished studies including 5914 women were included. Pooled mean differences for SSE change from baseline were 0.49 (95% CI, 0.32-0.67) between 100-mg flibanserin and placebo, 1.63 (95% CI, 0.45-2.82) for eDiary desire, and 0.27 (95% CI, 0.17-0.38) for FSFI desire. The risk ratio for study discontinuation due to AEs was 2.19 (95% CI, 1.50-3.20). The risk ratio for dizziness was 4.00 (95% CI, 2.56-6.27) in flibanserin vs placebo, 3.97 (95% CI, 3.01-5.24) for somnolence, 2.35 (95% CI, 1.85-2.98) for nausea, and 1.64 (95% CI, 1.27-2.13) for fatigue. Women's mean global impression of improvement scores indicated minimal improvement to no change. CONCLUSIONS AND RELEVANCE: Treatment with flibanserin, on average, resulted in one-half additional SSE per month while statistically and clinically significantly increasing the risk of dizziness, somnolence, nausea, and fatigue. Overall, the quality of the evidence was graded as very low. Before flibanserin can be recommended in guidelines and clinical practice, future studies should include women from diverse populations, particularly women with comorbidities, medication use, and surgical menopause. PMID- 26927500 TI - Osteocytes: The master cells in bone remodelling. AB - Bone remodelling is an essential process for shaping and maintaining bone mass in the mature skeleton. During our lifetime bone is constantly being removed by osteoclasts and new bone is formed by osteoblasts. The activities of osteoclasts and osteoblasts must be regulated under a strict balance to ensure that bone homeostasis is maintained. Osteocytes, which form an extensive, multi-functional syncytium throughout the bone, are increasingly considered to be the cells that maintain this balance. Current research is elucidating key signalling pathways by which the osteocyte exerts control over the other cell types in bone and over its own activities, and potential ways in which these pathways may be exploited therapeutically. PMID- 26927499 TI - Contributions of protein kinases and beta-arrestin to termination of protease activated receptor 2 signaling. AB - Activated Gq protein-coupled receptors (GqPCRs) can be desensitized by phosphorylation and beta-arrestin binding. The kinetics and individual contributions of these two mechanisms to receptor desensitization have not been fully distinguished. Here, we describe the shut off of protease-activated receptor 2 (PAR2). PAR2 activates Gq and phospholipase C (PLC) to hydrolyze phosphatidylinositol 4,5-bisphosphate (PIP2) into diacylglycerol and inositol trisphosphate (IP3). We used fluorescent protein-tagged optical probes to monitor several consequences of PAR2 signaling, including PIP2 depletion and beta arrestin translocation in real time. During continuous activation of PAR2, PIP2 was depleted transiently and then restored within a few minutes, indicating fast receptor activation followed by desensitization. Knockdown of beta-arrestin 1 and 2 using siRNA diminished the desensitization, slowing PIP2 restoration significantly and even adding a delayed secondary phase of further PIP2 depletion. These effects of beta-arrestin knockdown on PIP2 recovery were prevented when serine/threonine phosphatases that dephosphorylate GPCRs were inhibited. Thus, PAR2 may continuously regain its activity via dephosphorylation when there is insufficient beta-arrestin to trap phosphorylated receptors. Similarly, blockers of protein kinase C (PKC) and G protein-coupled receptor kinase potentiated the PIP2 depletion. In contrast, an activator of PKC inhibited receptor activation, presumably by augmenting phosphorylation of PAR2. Our interpretations were strengthened by modeling. Simulations supported the conclusions that phosphorylation of PAR2 by protein kinases initiates receptor desensitization and that recruited beta-arrestin traps the phosphorylated state of the receptor, protecting it from phosphatases. Speculative thinking suggested a sequestration of phosphatidylinositol 4-phosphate 5 kinase (PIP5K) to the plasma membrane by beta-arrestin to explain why knockdown of beta-arrestin led to secondary depletion of PIP2. Indeed, artificial recruitment of PIP5K removed the secondary loss of PIP2 completely. Altogether, our experimental and theoretical approaches demonstrate roles and dynamics of the protein kinases, beta-arrestin, and PIP5K in the desensitization of PAR2. PMID- 26927501 TI - The Effects of Gonadotropin-Releasing Hormone Agonist Combined with Add-Back Therapy on Quality of Life for Adolescents with Endometriosis: A Randomized Controlled Trial. AB - STUDY OBJECTIVE: Use of gonadotropin-releasing hormone agonists (GnRHa) to treat endometriosis can cause mood and vasomotor side effects. "Add-back therapy," the combination of low-dose hormones, limits side effects but research is limited to adults. We sought to characterize quality of life (QOL) before treatment and to compare an add-back regimen of norethindrone acetate (NA) with conjugated estrogens (CEE) to NA alone for preventing side effects of GnRHa therapy in female adolescents with endometriosis. DESIGN: Twelve-month double-blind, placebo controlled trial. SETTING: Pediatric Gynecology clinic in Boston, Massachusetts. PARTICIPANTS: Fifty female adolescents (aged 15-22 years) with surgically confirmed endometriosis initiating treatment with GnRHa. INTERVENTIONS: Subjects were randomized to: NA (5 mg/d) with CEE (0.625 mg/d) or NA (5 mg/d) with placebo. All subjects received leuprolide acetate depot every 3 months. MAIN OUTCOME MEASURES: The Short Form-36 v2 Health Survey, Beck Depression Inventory II, and Menopause Rating Scale were completed at repeated intervals. RESULTS: At baseline, subjects reported impaired physical health-related QOL compared with national norms (all P < .0001). Over 12 months, these Short Form-36 v2 scores improved (all P < .05). Subjects receiving NA with CEE showed greater improvements in the pain, vitality, and physical health subscales (Pbetween groups < .05) than those receiving NA alone, as well as better physical functioning (P < .05). There were no changes in depression or menopause-like symptoms in either group. CONCLUSION: Female adolescents with endometriosis initiating GnRHa therapy have impaired QOL. Treatment with GnRHa combined with add-back therapy led to improved QOL, with no worsening of mood or menopausal side effects. NA with CEE was superior to NA alone for improving physical health related QOL. PMID- 26927502 TI - Effects of flaxseed, raw soybeans and calcium salts of fatty acids on apparent total tract digestibility, energy balance and milk fatty acid profile of transition cows. AB - Oilseeds offer some protection to the access of ruminal microorganisms and may be an alternative to calcium salts of fatty acids (FA), which are not fully inert in the ruminal environment. This study aimed to evaluate the effects of different sources of FA supplementation on apparent total tract nutrient digestibility, milk yield and composition, and energy balance (EB) of cows during the transition period and early lactation. We compared diets rich in C18:2 and C18:3 FA. Multiparous Holstein cows were randomly assigned to receive one of the four diets: control (n=11); whole flaxseed (WF, n=10), 60 and 80 g/kg (diet dry matter (DM) basis) of WF during the prepartum and postpartum periods, respectively; whole raw soybeans (WS, n=10), 120 and 160 g/kg (diet DM basis) of WS during the prepartum and postpartum periods, respectively; and calcium salts of unsaturated fatty acids (CSFA, n=11), 24 and 32 g/kg (diet DM basis) of CSFA during the prepartum and postpartum periods, respectively. Dry cows fed WF had higher DM and net energy of lactation (NEL) intake than those fed WS or CSFA. The FA supplementation did not alter DM and NDF apparent total tract digestibility, dry cows fed WF exhibited greater NDF total tract digestion than cows fed WS or CSFA. Feeding WS instead of CSFA did not alter NEL intake and total tract digestion of nutrients, but increased milk fat yield and concentration. Calculated efficiency of milk yield was not altered by diets. FA supplementation increased EB during the postpartum period. Experimental diets increased long-chain FA (saturated and unsaturated FA) in milk. In addition, cows fed WS and CSFA had higher C18:1 trans 11 FA and C18:2 cis, and lower C18:3 FA in milk than those fed WF. Furthermore, cows fed CSFA had higher C18:1 trans-11 and cis-9, trans-11 FA than cows fed WS. Although supplemental C18:2 and C18:3 FA did not influence the milk yield of cows, they positively affected EB and increased unsaturated long-chain FA in milk fat. PMID- 26927503 TI - Rabies: Knowledge and Practices Regarding Rabies in Rural Communities of the Brazilian Amazon Basin. AB - BACKGROUND: The occurrence of outbreaks of human rabies transmitted by Desmodus rotundus in Brazil in 2004 and 2005 reinforced the need for further research into this zoonosis. Studies of knowledge and practices related to the disease will help to define strategies for the avoidance of new cases, through the identification of gaps that may affect the preventive practices. METHODOLOGY/PRINCIPAL FINDINGS: A semi-structured questionnaire was applied to 681 residents of twelve communities of northeastern Para state involved in the 2004 and 2005 outbreaks mentioned above. The objective was to evaluate the local knowledge and practices related to the disease. We found a highly significant difference (p<0.0001) in the knowledge of rabies among education levels, indicating that education is a primary determinant of knowledge on this disease. More than half of the respondents (63%) recognized the seriousness of the zoonosis, and 50% were aware of the importance of bats for its transmission, although few individuals (11%) were familiar with the symptoms, and only 40% knew methods of prevention. Even so, 70% of pet owners maintained their animals vaccinated, and 52% of the respondents bitten by bats had received post-exposure vaccination. Most of the respondents (57%) reported being familiarized with rabies through informal discussions, and only a few (23%) mentioned public health agents as the source of their information. CONCLUSION/SIGNIFICANCE: We identified many gaps in the knowledge and practices of the respondents regarding rabies. This may be the result of the reduced participation of public health agents in the transfer of details about the disease. The lack of knowledge may be a direct determinant in the occurrence of new outbreaks. Given these findings, there is a clear need for specific educational initiatives involving the local population and the public health entities, with the primary aim of contributing to the prevention of rabies. PMID- 26927504 TI - Polarisation-independent enhanced scattering by tailoring asymmetric plasmonic systems. AB - Polarised light provides an efficient way for dynamic control over local optical properties of nanoscale plasmonic structures. Yet many applications that utilise control over the plasmonic near-field would benefit if the plasmonic device maintained the same magnitude of optical response for all polarisations. Here we show that completely asymmetric nanostructures can be designed to exhibit a broadband polarisation-independent and enhanced optical response. We provide both analytical and experimental results on two sets of plasmonic trimer nanostructures consisting of unequal nanodisks/apertures with different gap spacing. We show that, at certain inter-particle separations, enhanced far-field cross sections are independent to the incident polarisation, while still demonstrating nontrivial near-field control. PMID- 26927505 TI - Erratum: Identification of two novel Chlorotoxin derivatives CA4 and CTX-23 with chemotherapeutic and anti-angiogenic potential. PMID- 26927506 TI - Mechanisms and mediation in survival analysis: towards an integrated analytical framework. AB - BACKGROUND: A wide-ranging debate has taken place in recent years on mediation analysis and causal modelling, raising profound theoretical, philosophical and methodological questions. The authors build on the results of these discussions to work towards an integrated approach to the analysis of research questions that situate survival outcomes in relation to complex causal pathways with multiple mediators. The background to this contribution is the increasingly urgent need for policy-relevant research on the nature of inequalities in health and healthcare. METHODS: The authors begin by summarising debates on causal inference, mediated effects and statistical models, showing that these three strands of research have powerful synergies. They review a range of approaches which seek to extend existing survival models to obtain valid estimates of mediation effects. They then argue for an alternative strategy, which involves integrating survival outcomes within Structural Equation Models via the discrete time survival model. This approach can provide an integrated framework for studying mediation effects in relation to survival outcomes, an issue of great relevance in applied health research. The authors provide an example of how these techniques can be used to explore whether the social class position of patients has a significant indirect effect on the hazard of death from colon cancer. RESULTS: The results suggest that the indirect effects of social class on survival are substantial and negative (-0.23 overall). In addition to the substantial direct effect of this variable (-0.60), its indirect effects account for more than one quarter of the total effect. The two main pathways for this indirect effect, via emergency admission (-0.12), on the one hand, and hospital caseload, on the other, (-0.10) are of similar size. CONCLUSIONS: The discrete time survival model provides an attractive way of integrating time-to-event data within the field of Structural Equation Modelling. The authors demonstrate the efficacy of this approach in identifying complex causal pathways that mediate the effects of a socio-economic baseline covariate on the hazard of death from colon cancer. The results show that this approach has the potential to shed light on a class of research questions which is of particular relevance in health research. PMID- 26927508 TI - J'Accuse! Failure to Prevent Epidural and Spinal Catheter Misconnections. PMID- 26927507 TI - Lysosome triggered near-infrared fluorescence imaging of cellular trafficking processes in real time. AB - Bioresponsive NIR-fluorophores offer the possibility for continual visualization of dynamic cellular processes with added potential for direct translation to in vivo imaging. Here we show the design, synthesis and lysosome-responsive emission properties of a new NIR fluorophore. The NIR fluorescent probe design differs from typical amine functionalized lysosomotropic stains with off/on fluorescence switching controlled by a reversible phenol/phenolate interconversion. Emission from the probe is shown to be highly selective for the lysosomes in co-imaging experiments using a HeLa cell line expressing the lysosomal-associated membrane protein 1 fused to green fluorescent protein. The responsive probe is capable of real-time continuous imaging of fundamental cellular processes such as endocytosis, lysosomal trafficking and efflux in 3D and 4D. The advantage of the NIR emission allows for direct translation to in vivo tumour imaging, which is successfully demonstrated using an MDA-MB-231 subcutaneous tumour model. This bioresponsive NIR fluorophore offers significant potential for use in live cellular and in vivo imaging, for which currently there is a deficit of suitable molecular fluorescent tools. PMID- 26927509 TI - Preoperative Focused Cardiac Ultrasound--Time for Implementation? PMID- 26927510 TI - In Response. PMID- 26927511 TI - Premature ventricular complexes ablation: A trip to the accuracy. PMID- 26927512 TI - Is heart rate variability related to baroreceptors or FBN1 mutations? PMID- 26927513 TI - Afferent signaling impairment from baroreceptors cannot fully explain decrease in heart rate variability in Marfan syndrome patients: an author's reply. PMID- 26927514 TI - Notch1 signaling contributes to stemness in head and neck squamous cell carcinoma. AB - Notch1 is associated with the initiation and progression of various solid tumors. However, the exact role of Notch1 expression in head and neck squamous cell carcinoma (HNSCC) remain unclear. We created cells ectopically expressing notch intracellular domain (NICD) from previously established HNSCC cells and examined self-renewal capacity and stem cell markers' expression compared with control cells. In addition, we knocked Notch1 down in primary spheres obtained from HNSCC tumor tissue and assessed the attenuation of stemness-associated traits in these cells in vitro and in vivo. Furthermore, we examined clinical relevance of Notch1 expression in HNSCC patients. Constitutive activation of NICD promoted the self renewal capacity of HNSCC cells by activating sphere formation and increased the expression of stem cell markers such as Oct4, Sox2, and CD44. In contrast, Notch1 knockdown in primary HNSCC cancer stem cells (CSCs) attenuated CSC traits and augmented the chemosensitizing effects of cisplatin along with the decreased expression of almost all of ABC transporter genes. In addition, Notch1 knockdown in HNSCC CSCs inhibited tumor formation and increased survival of mice in a xenograft model. Also, Notch1 acted upstream of canonical Wnt signaling in HNSCC cells. Finally, elevated Notch1 expression is associated with poor prognosis in patients with HNSCC. In conclusion, Notch1 may be a critical regulator of stemness in HNSCC cells, and inactivation of this pathway could be a potential targeted approach for the treatment of HNSCC. PMID- 26927515 TI - Osteogenesis induced by frizzled-related protein (FRZB) is linked to the netrin like domain. AB - Abnormal Wnt signaling is associated with bone mass disorders. Frizzled-related protein (FRZB, also known as secreted frizzled-related protein-3 (SFRP3)) is a Wnt modulator that contains an amino-terminal cysteine-rich domain (CRD) and a carboxy-terminal Netrin-like (NTN) motif. Frzb(-/-) mice show increased cortical thickness. However, the direct effect of FRZB on osteogenic differentiation and the involvement of the structural domains herein are not fully understood. In this study, we observed that stable overexpression of Frzb in MC3T3-E1 cells increased calcium deposition and osteoblast markers compared with control. Western blot analysis showed that the increased osteogenesis was associated with reduced canonical, but increased non-canonical Wnt signaling. On the contrary, loss of Frzb induced the opposite effects on osteogenesis and Wnt signaling. To translationally validate the positive effects of FRZB on primary human cells, we treated human periosteal and human bone marrow stromal cells with conditioned medium from MC3T3-E1 cells overexpressing Frzb and observed an increase in Alizarin red staining. We further studied the effect of the domains. FrzbNTN overexpression induced similar effects on osteogenesis as full-length Frzb, whereas FrzbCRD overexpressing cells mimicked loss of Frzb experiments. The CRD is considered as the Wnt binding domain, but the NTN domain also has important effects on bone biology. FRZB and other SFRPs or their specific domains may hold surprising potential as therapeutics for bone and joint disorders considering that excess of SFRPs has effects that are not expected under physiological, endogenous expression conditions. PMID- 26927516 TI - Human amniotic mesenchymal stem cells alleviate lung injury induced by ischemia and reperfusion after cardiopulmonary bypass in dogs. AB - Transplantation of mesenchymal stem cells may inhibit pathological immune processes contributing to ischemia/reperfusion (I/R) injury. This study aimed to assess the capacity of human amniotic MSC (hAMSCs) to ameliorate I/R injury in a dog model of cardiopulmonary bypass (CPB). Dissociated hAMSCs were cultured ex vivo, and their immunophenotypes were assessed by flow cytometry and immunohistochemistry. A dog model of CPB was established by surgical blockage of the aorta for 1 h. Dogs either underwent mock surgery (Sham group), CPB (model group), or CPB, followed by femoral injection of 2 * 10(7) hAMSCs (n=6). Anti human nuclei staining revealed hAMSCs in the lungs 3 h after surgery. Oxygen index (OI) and respiratory index (RI) of arterial blood were measured using a biochemical analyzer. Venous blood TNF-alpha, IL-8, MMP-9, and IL-10 concentrations were measured by ELISA. Pathological changes in the lung were assessed by light microscopy. Third-generation-cultured hAMSCs expressed high levels of CD29, CD44, CD49D, CD73, and CD166 levels, but low CD34 or CD45 amounts and their cytoplasm contained Vimentin. In CPB model animals, OI was elevated and RI reduced; TNF-alpha, IL-8, and MMP-9 levels were elevated, and IL-10 levels reduced within 3h (P<0.05), but hAMSC transplantation significantly ameliorated these changes (P<0.05). Pathological changes observed in the hAMSC group were significantly less severe than those in the CPB group. In conclusion, hAMSC transplantation can downregulate proinflammatory factors and reduce MMP-9 levels, whereas upregulating the anti-inflammatory molecule IL-10, thus reducing I/R lung injury in a dog model of CPB. PMID- 26927518 TI - Expression analyses of splice variants of zebrafish cyclin-dependent kinase-like 5 and its substrate, amphiphysin 1. AB - Mammalian cyclin-dependent kinase-like 5 (CDKL5) is a Ser/Thr protein kinase mainly expressed in the central nervous system and believed to be involved in neuronal functions. However, the functions of CDKL5 in fishes have not been investigated. Therefore, in this study, we cloned and characterized zebrafish CDKL5 (zCDKL5) and its substrate, amphiphysin 1 (zAmph1). Two alternative splice variants of zCDKL5, zCDKL5-Long (zCDKL5-L) and zCDKL5-Short (zCDKL5-S), and three splice variants of zAmph1, zAmph1a, zAmph1b and zAmph1c, were cloned from a zebrafish cDNA library. Using zAmph1a point mutants, we identified Ser-285 and Ser-293 as phosphorylation sites of zAmph1a by CDKL5. Transiently expressed zCDKL5-L and zCDKL5-S colocalized with zAmph1a in the cytoplasm of 293T cells. RT PCR analysis revealed that zCDKL5-L was first observed 12hours post-fertilization (hpf) and increased thereafter, while zCDKL5-S appeared just after fertilization. zAmph1a was detected in all embryogenic stages and zAmph1b appeared from 12hpf, but the expression of zAmph1c was not observed in our experiments. In adult fish, zCDKL5-L was mainly expressed in the brain, but zCDKL5-S showed ubiquitous expression. zAmph1a was observed most abundantly in the eyes, whereas zAmph1b was predominantly expressed in the brain. zAmph1c was scarcely detected. These results suggest that phosphorylation of Amph1 by CDKL5 may be a common feature throughout animal species. PMID- 26927519 TI - A newly discovered ubiquitin-conjugating enzyme E2 correlated with the cryogenic autolysis of Volvariella volvacea. AB - In Volvariella volvacea, a species of edible mushroom, cryogenic autolysis is a typical part of abnormal metabolism. Previous functional annotation cluster analyses of cold-induced gene expression profiles have shown that the ubiquitin conjugating enzyme E2 (UBE2), rather than the cyclin-like F-box domain alone, forms the functional cluster. In this study, analysis of gene expression profiling showed that only one type of UBE2 in V. volvacea (UBEV2) was significantly up-regulated. Further quantitative real-time PCR analysis confirmed that the expression of UBEV2 was significantly up-regulated (P<0.05) after cold treatment lasting 4, 6, and 8h. This provided evidence that UBEV2 was closely correlated with cryogenic autolysis. The specific distribution of UBEV2 in recently diverged herb decay fungi indicated that UBEV2 was not evolutionarily correlated with early diverging fungi. Phylogenetic analysis indicated that UBEV2 was generated by horizontal gene transfer (HGT) from the ancestry of Selaginella moellendorffii UBE2. Further relative time estimation and detection of natural selection showed that there has been recent positive selection after HGT in UBEV2. Molecular modeling and logo analysis showed that the cysteine-cysteine motif is the characteristic of the UBEV2 family. These observations indicate that UBEV2 is a new type of UBE2 correlated with the cryogenic autolysis of V. volvacea. PMID- 26927520 TI - Synthesis, self-assembly, and photocrosslinking of fullerene-polyglycerol amphiphiles as nanocarriers with controlled transport properties. AB - In this work, we report a new, simple, gram-scale method for synthesizing water soluble fullerene-polyglycerol amphiphiles (FPAs) that self-assemble into partially and fully crosslinked nanoclusters with the ability to controllably transport hydrophobic and hydrophilic agents. PMID- 26927521 TI - A Color Perimetric Test to Evaluate Macular Pigment Density in Age-Related Macular Degeneration. AB - PURPOSE: To evaluate differences in measurements of macular pigment optical density (MPOD) in patients with dry age-related macular degeneration (AMD) and a group of healthy patients (control group). Short-term repeatability of MPOD measures was also assessed in the control group. METHODS: This cross-sectional study included 31 eyes from 31 patients with bilateral dry AMD, 21 eyes from 21 cases with dry AMD in the study eye and exudative AMD in the fellow eye. The control group included 17 eyes from 17 healthy patients of similar age and sex. The MPOD values were measured using a commercially available color perimetry technique (CP). Short-term repeatability of MPOD measurements by the CP technique was assessed in 20 eyes of 20 healthy subjects who were measured 3 times on 3 consecutive days. RESULTS: The mean values for MPOD were 5.59 +/- 2.06 dB in cases in which both eyes had dry AMD, 5.25 +/- 2.72 dB in cases in which one eye had wet AMD and the studied eye had dry AMD, and 5.97 +/- 2.14 dB in the eyes of the healthy control group. The mean value was lower in cases in which the fellow eye had wet AMD; however, no significant difference in MPOD was found between the three groups (p = 0.659) or between the group with dry AMD in both eyes and the healthy control group (p = 0.977). The intraclass correlation coefficient (ICC) value was 0.664 between day 1 and day 2, and 0.822 between day 2 and day 3. CONCLUSIONS: Our results do not show a direct relation between MPOD and dry AMD. Color perimetry does not provide acceptable short-term repeatability for measuring MPOD. Learning effects may contribute to the measured test-retest variability. Other studies are needed to determine if CP is suitable for repeated measurements during the long term follow-up with the same patient. PMID- 26927522 TI - Nongranulomatous Uveitis as the First Manifestation of Syphilis. AB - PURPOSE: The incidence of syphilis appears to be increasing in recent years. Although any structure of the eye can be involved in syphilis, isolated unilateral anterior uveitis as an initial sign of the disease is rare. We report a case of ocular syphilis presenting as a mild unilateral, nongranulomatous, anterior uveitis in an otherwise asymptomatic patient. CASE REPORT: A 64-year-old white male patient presented with a 3-day history of mildly reduced vision, photophobia, and pain in his left eye. The patient denied prior occurrences, and no contributing ocular or medical history was elicited. Entering corrected distance acuities were 20/25+ in the right eye and 20/20- in the left eye. Slit lamp examination of the left eye revealed a moderate circumlimbal flush, numerous fine keratic precipitates, and mild-to-moderate white blood cells in the anterior chamber. The patient was diagnosed as having acute, idiopathic, nongranulomatous, anterior uveitis, and topical steroid/cycloplegic treatment was initiated. Despite an initially positive, although somewhat sluggish response to treatment, the patient's uveitis suddenly worsened on day 44, exhibiting increased anterior chamber cells, several mutton-fat keratic precipitates, and elevated intraocular pressure. Systemic diagnostic workup led to the diagnosis of neurosyphilis, and the patient subsequently admitted to high-risk sexual behaviors. Treatment with intravenous aqueous penicillin-G 24 million units per day for 14 days led to complete resolution of uveitis. The case was reported to the local health department within 24 h of syphilis diagnosis. CONCLUSIONS: Syphilis, although an uncommon cause of ocular inflammation, is a highly contagious, but curable disease. Given its potentially devastating neurologic consequences, syphilis should be considered in all patients presenting with uveitis. A high index of clinical suspicion and a detailed sexual history are crucial for the accurate and timely diagnosis of ocular syphilis. PMID- 26927523 TI - Quantification of Stereopsis in Patients with Impaired Binocularity. AB - PURPOSE: To quantify stereopsis at distance resulting from binocular fusion in patients with impaired binocular vision using a three-dimensional (3-D) display stereotest. METHODS: A total of 68 patients (age range, 6 to 85 years) with strabismus (40 esotropes and 28 exotropes) whose stereoacuity could not be measured with the near and distance Randot stereotests were included. Contour based circles with a wide range of crossed horizontal disparities (2500 to 20 arcsec) displayed on a 3-D monitor were presented to subjects at 3 m. Between the patients who had stereoacuity of at least 2500 arcsec and those with no measurable stereoacuity, parameters including age, sex, best-corrected visual acuity, spherical equivalent refractive error, Worth 4 dot test results, and type and angle of deviation were compared. RESULTS: Stereoacuity at distance of 2500 arcsec or better was detected in 25 (63%) of 40 esotropes, and 16 (57%) of 28 exotropes, although stereoacuity of 800 arcsec or better was found only in two (5%) esotropes and one (4%) exotrope. Patients with stereopsis were significantly younger (19.3 +/- 16.9 years) than those with no measurable stereopsis (31.5 +/- 26.4 years) (p = 0.040). There were no significant differences in best-corrected visual acuity, presence of amblyopia >20/100, spherical equivalent refractive error, type of deviation, deviation angle, sex, and Worth 4 dot test results between these groups. CONCLUSIONS: Stereopsis at distance resulting from binocular fusion that cannot be measured with conventional stereoacuity tests may be preserved in patients with impaired binocular vision. The 3-D display stereotest can be useful for quantifying stereopsis at distance resulting from binocular fusion. PMID- 26927524 TI - Formal Academic Training on Ethics May Address Junior Physicians' Needs. AB - BACKGROUND: Surveys have highlighted perceived deficiencies among ICU residents in end-of-life care, symptom control, and confidence in dealing with dying patients. Lack of formal training may contribute to the failure to meet the needs of dying patients and their families. The objective of this study was to evaluate junior intensivists' perceptions of triage and of the quality of the dying process before and after formal academic training. METHODS: Formal training on ethics was implemented as a part of resident training between 2007 and 2012. A cross-sectional survey was performed before (2007) and after (2012) this implementation. This study included 430 junior intensivists who were interviewed during these periods. RESULTS: More responders attended a dedicated training course on ethics and palliative care during 2012 (38.5%) than during 2007 (17.4%; P < .0001). During 2012, respondents reported less discomfort and fewer uncertainties regarding decisions about limiting life-sustaining treatment (17.7% vs 39.1% in 2007; P < .0001) or the triage process (48.5% vs 69.4% in 2007; P < .0001). Factors independently associated with positive perceptions of the dying process were physician's age (OR, 1.19 per year; 95% CI, 1.09-1.25) and male sex (OR, 1.61; 95% CI, 1.05-2.47). Conversely, anxiety about family members' reactions (OR, 0.58; 95% CI, 0.0.37-0.87) and lack of training (OR, 0.29; 95% CI, 0.17-0.50) were associated with negative perceptions of this process. CONCLUSIONS: Formal training dedicated to ethics and palliative care was associated with a more comfortable perception of the dying process. This training may decrease the uncertainty and discomfort of junior intensivists in these situations. PMID- 26927525 TI - New Sepsis Criteria: A Change We Should Not Make. PMID- 26927526 TI - Cotton Wool Derived Carbon Fiber Aerogel Supported Few-Layered MoSe2 Nanosheets As Efficient Electrocatalysts for Hydrogen Evolution. AB - Recent studies have proven that newly emerging two-dimensional molybdenum diselenide (MoSe2) is a promising noble-metal-free electrocatalyst for hydrogen evolution reaction (HER). Increasing the exposures of the active edges of MoSe2 nanostructures is a key issue to fully realize the excellent electrochemical properties of MoSe2. In this work, a few-layered MoSe2/carbon fiber aerogel (CFA) hybrids have been facilely obtained through the combination of high-temperature carbonization and one-pot solvothermal reaction. CFA derived from cotton wool is used as a three-dimensional conductive network for construction of hierarchical MoSe2/CFA hybrids, where few-layered MoSe2 nanosheets are uniformly and perpendicularly decorated on the surfaces of CFA. In the designed and prepared hybrids, CFA effectively increases the exposures of the active edges of MoSe2 nanosheets as well as provides reduced lengths for both electron transportation and ion diffusion. Therefore, the obtained optimal MoSe2/CFA hybrid exhibits excellent electrochemical activity as HER electrocatalyst with a small onset potential of -0.104 V vs reversible hydrogen electrode and a small Tafel slope of 62 mV per decade, showing its great potential as a next-generation Pt-free electrocatalyst for HER. PMID- 26927527 TI - Rsk2, the Kinase Mutated in Coffin-Lowry Syndrome, Controls Cementum Formation. AB - The ribosomal S6 kinase RSK2 is essential for osteoblast function, and inactivating mutations of RSK2 cause osteopenia in humans with Coffin-Lowry syndrome (CLS). Alveolar bone loss and premature tooth exfoliation are also consistently reported symptoms in CLS patients; however, the pathophysiologic mechanisms are unclear. Therefore, aiming to identify the functional relevance of Rsk2 for tooth development, we analyzed Rsk2-deficient mice. Here, we show that Rsk2 is a critical regulator of cementoblast function. Immunohistochemistry, histology, micro-computed tomography imaging, quantitative backscattered electron imaging, and in vitro assays revealed that Rsk2 is activated in cementoblasts and is necessary for proper acellular cementum formation. Cementum hypoplasia that is observed in Rsk2-deficient mice causes detachment and disorganization of the periodontal ligament and was associated with significant alveolar bone loss with age. Moreover, Rsk2-deficient mice display hypomineralization of cellular cementum with accumulation of nonmineralized cementoid. In agreement, treatment of the cementoblast cell line OCCM-30 with a Rsk inhibitor reduces formation of mineralization nodules and decreases the expression of cementum markers. Western blot analyses based on antibodies against Rsk1, Rsk2, and an activated form of the 2 kinases confirmed that Rsk2 is expressed and activated in differentiating OCCM-30 cells. To discriminate between periodontal bone loss and systemic bone loss, we additionally crossed Rsk2-deficient mice with transgenic mice overexpressing the osteoanabolic transcription factor Fra1. Fra1 overexpression clearly increases systemic bone volume in Rsk2-deficient mice but does not protect from alveolar bone loss. Our results indicate that cell autonomous cementum defects are causing early tooth loss in CLS patients. Moreover, we identify Rsk2 as a nonredundant regulator of cementum homeostasis, alveolar bone maintenance, and periodontal health, with all these features being independent of Rsk2 function in systemic bone formation. PMID- 26927529 TI - High-Temperature CO2 Sorption on Hydrotalcite Having a High Mg/Al Molar Ratio. AB - Hydrotalcites having a Mg/Al molar ratio between 3 and 30 have been synthesized as promising high-temperature CO2 sorbents. The existence of NaNO3 in the hydrotalcite structure, which originates from excess magnesium nitrate in the precursor, markedly increases CO2 sorption uptake by hydrotalcite up to the record high value of 9.27 mol kg(-1) at 240 degrees C and 1 atm CO2. PMID- 26927530 TI - BODIPY atropisomer interconversion, face discrimination, and superstructure appending. AB - A strategy was developed to append sterically hindered apical pickets on both faces of the BODIPY platform to prevent stacking and aggregation. Ortho substitution of both the meso-phenyl ring and the boron-bound catechol affords the right directionality to append pickets, achieve face discrimination, featuring two interconvertible atropisomers, and is reminiscent of the picket fence strategy in porphyrins. PMID- 26927528 TI - Chronicles of a cancer foretold: 35 years of gastric cancer risk assessment. PMID- 26927531 TI - Deriving the Metal and Alloy Networks of Modern Technology. AB - Metals have strongly contributed to the development of the human society. Today, large amounts of and various metals are utilized in a wide variety of products. Metals are rarely used individually but mostly together with other metals in the form of alloys and/or other combinational uses. This study reveals the intersectoral flows of metals by means of input-output (IO) based material flow analysis (MFA). Using the 2007 United States IO table, we calculate the flows of eight metals (i.e., manganese, chromium, nickel, molybdenum, niobium, vanadium, tungsten, and cobalt) and simultaneously visualize them as a network. We quantify the interrelationship of metals by means of flow path sharing. Furthermore, by looking at the flows of alloys into metal networks, the networks of the major metals iron, aluminum, and copper together with those of the eight alloying metals can be categorized into alloyed-, nonalloyed-(i.e., individual), and both mixed. The result shows that most metals are used primarily in alloy form and that functional recycling thereby requires identification, separation, and alloy specific reprocessing if the physical properties of the alloys are to be retained for subsequent use. The quantified interrelation of metals helps us consider better metal uses and develop a sustainable cycle of metals. PMID- 26927532 TI - [Why a Dual Pathology Clinical Guideline? Analysis of the evidence]. PMID- 26927533 TI - Tineptine: Why has not been classified as a narcotic in Spain? PMID- 26927537 TI - Revista Espanola de Cardiologia: Current Position and Future Directions. PMID- 26927534 TI - Spanish consensus on the risks and detection of antipsychotic drug-related hyperprolactinaemia. AB - INTRODUCTION: Iatrogenic hyperprolactinaemia (IHPRL) has been more frequently related to some antipsychotic drugs that provoke an intense blockade of dopamine D2 receptors. There is a wide variation in clinical practice, and perhaps some more awareness between clinicians is needed. Due to the high frequency of chronic treatment in severe mental patients, careful attention is recommended on the physical risk. IHPRL symptoms could be underestimated without routine examination. METHODOLOGY: An intense scientific literature search was performed in order to draw up a multidisciplinary consensus, including different specialists of psychiatry, endocrinology, oncology and internal medicine, and looking for a consensus about clinical risk and detection of IHPRL following evidence-based medicine criteria levels (EBM I- IV). RESULTS: Short-term symptoms include amenorrhea, galactorrhoea, and sexual dysfunction with decrease of libido and erectile difficulties related to hypogonadism. Medium and long-term symptoms related to oestrogens are observed, including a decrease bone mass density, hypogonadism, early menopause, some types of cancer risk increase (breast and endometrial), cardiovascular risk increase, immune system disorders, lipids, and cognitive dysfunction. Prolactin level, gonadal hormones and vitamin D should be checked in all patients receiving antipsychotics at baseline although early symptoms (amenorrhea-galactorrhoea) may not be observed due to the risk of underestimating other delayed symptoms that may appear in the medium term. Routine examination of sexual dysfunction is recommended due to possible poor patient tolerance and low compliance. Special care is required in children and adolescents, as well as patients with PRL levels >50ng/ml (moderate hyperprolactinaemia). A possible prolactinoma should be investigated in patients with PRL levels >150ng/ml, with special attention to patients with breast/endometrial cancer history. Densitometry should be prescribed for males >50 years old, amenorrhea>6 months, or early menopause to avoid fracture risk. PMID- 26927538 TI - Efficacy of sodium and stannous fluoride mouthrinses when used before single and multiple erosive challenges. AB - BACKGROUND: Application of fluoride mouthrinse before an acidic challenge may decrease enamel erosion. This paper compares the efficacy of stannous (SnF2 ) and sodium (NaF) fluoride when facing single and multiple erosive cycles in vitro. METHODS: Human enamel samples (N = 60) were randomly assigned to groups testing SnF2 and NaF mouthrinses (225 p.p.m.) and a water control. Samples were allocated into subgroups testing one or five erosive cycles. Samples were immersed in test solution for 1 min prior to citric acid immersion (0.3%, pH 3.2, 10 min), and the cycle repeated either one or five times. Analysis was done using profilometry and microhardness change. RESULTS: After one cycle, SnF2 resulted in least step height followed by NaF and water (1.3 MUm (0.63), 2.3 MUm (0.39), 4.3 MUm (0.41) respectively; P < 0.0001). After five cycles SnF2 continued to reduce step height but pre-application of NaF was no different to water (4.6 MUm (0.7), 10.5 MUm (1.1) and 11.1 MUm (0.38) respectively; P < 0.0001). There were no statistical differences in microhardness change between fluorides. After one erosive cycle, fluoride application resulted in statistically softer enamel compared with water. CONCLUSIONS: Both SnF2 and NaF reduced erosion after one cycle. After five cycles, SnF2 continued to offer protection whereas NaF was statistically comparable with water. Softening of enamel may not imply less erosion has occurred. PMID- 26927540 TI - Selection Shapes Transcriptional Logic and Regulatory Specialization in Genetic Networks. AB - BACKGROUND: Living organisms need to regulate their gene expression in response to environmental signals and internal cues. This is a computational task where genes act as logic gates that connect to form transcriptional networks, which are shaped at all scales by evolution. Large-scale mutations such as gene duplications and deletions add and remove network components, whereas smaller mutations alter the connections between them. Selection determines what mutations are accepted, but its importance for shaping the resulting networks has been debated. METHODOLOGY: To investigate the effects of selection in the shaping of transcriptional networks, we derive transcriptional logic from a combinatorially powerful yet tractable model of the binding between DNA and transcription factors. By evolving the resulting networks based on their ability to function as either a simple decision system or a circadian clock, we obtain information on the regulation and logic rules encoded in functional transcriptional networks. Comparisons are made between networks evolved for different functions, as well as with structurally equivalent but non-functional (neutrally evolved) networks, and predictions are validated against the transcriptional network of E. coli. PRINCIPAL FINDINGS: We find that the logic rules governing gene expression depend on the function performed by the network. Unlike the decision systems, the circadian clocks show strong cooperative binding and negative regulation, which achieves tight temporal control of gene expression. Furthermore, we find that transcription factors act preferentially as either activators or repressors, both when binding multiple sites for a single target gene and globally in the transcriptional networks. This separation into positive and negative regulators requires gene duplications, which highlights the interplay between mutation and selection in shaping the transcriptional networks. PMID- 26927539 TI - Ambient air pollution and years of life lost in Ningbo, China. AB - To evaluate the burden of air pollution on years of life lost (YLL) in addition to mortality, we conducted a time series analysis based on the data on air pollution, meteorological conditions and 163,704 non-accidental deaths of Ningbo, China, 2009-2013. The mean concentrations of particulate matter with aerodynamic diameter <10 MUm, particulate matter with aerodynamic diameter <2.5 MUm, sulfur dioxide and nitrogen dioxide were 84.0 MUg/m(3), 60.1 MUg/m(3), 25.1 MUg/m(3) and 41.7 MUg/m(3), respectively. An increase of 10-MUg/m(3) in particulate matter with aerodynamic diameter <10 MUm, particulate matter with aerodynamic diameter <2.5 MUm, sulfur dioxide and nitrogen dioxide was associated with 4.27 (95% confidence interval [CI] 1.17-7.38), 2.97 (95% CI -2.01-7.95), 29.98 (95% CI 19.21-40.76) and 16.58 (95% CI 8.19-24.97) YLL, respectively, and 0.53% (95% CI 0.29-0.76%), 0.57% (95% CI 0.20-0.95%), 2.89% (95% CI 2.04-3.76%), and 1.65% (95% CI 1.01-2.30%) increase of daily death counts, respectively. The impact of air pollution lasted for four days (lag 0-3), and were more significant in the elderly than in the young population for both outcomes. These findings clarify the burden of air pollution on YLL and highlight the importance and urgency of air pollution control in China. PMID- 26927541 TI - Vincenc Alexandr Bohdalek (1801-1883): Czech anatomist and neuroscientist of the nineteenth century. AB - Vincenc Alexandr Bohdalek (Vincenz Alexander Bochdalek) was a well-known anatomist and pathologist in the nineteenth century. Today, however, his name is all but forgotten. Bohdalek described a number of anatomical structures; some of them became eponyms. Unfortunately, his findings concerning the innervation of the eye, upper jaw, hard palate, auditory system, and meninges are little known today. This current overview is based on available archival sources and provides an insight into his results in the field of nervous system research, which account for almost half his work. Bohdalek can clearly be considered a pioneer in the field we now call functional anatomy, as he tried to find a physiological explanation for the anatomical and pathological findings he observed. The work and results of this truly outstanding neuroscientist of his time are thus again available to current and future generations of neuroscientists and neuroanatomists. PMID- 26927542 TI - nagZ Triggers Gonococcal Biofilm Disassembly. AB - Bacterial-bacterial interactions play a critical role in promoting biofilm formation. Here we show that NagZ, a protein associated with peptidoglycan recycling, has moonlighting activity that allows it to modulate biofilm accumulation by Neisseria gonorrhoeae. We characterize the biochemical properties of NagZ and demonstrate its ability to function as a dispersing agent for biofilms formed on abiotic surfaces. We extend these observations to cell culture and tissue explant models and show that in nagZ mutants, the biofilms formed in cell culture and on human tissues contain significantly more biomass than those formed by a wild-type strain. Our results demonstrate that an enzyme thought to be restricted to peptidoglycan recycling is able to disperse preformed biofilms. PMID- 26927543 TI - [Blocking p38MAPK pathway inhibits the proliferation of OT-II cells mediated by splenic dendritic cells]. AB - OBJECTIVE: To investigate the effect of blocking p38 mitogen-activated protein kinase (p38MAPK) pathway on the proliferation of OT-II cells mediated by splenic dendritic cells (DCs). METHODS: Splenic DCs of C57BL/6 mice were purified with anti-CD11c immunomagnetic beads, and OT-II cells were isolated from the splenic of CD4(+)-ovalbumin transgenic mice (OT-IItransgenic mice) by mouse CD4 T cell isolation kits. After being pretreated with SB203580, an inhibitor of p38MAPK, DCs were stimulated with lipopolysaccharides (LPS). Then the expression levels of co-stimulatory molecules (CD80, CD86) and MHCII in DCs, and antigen-presenting ability of DCs treated with the 52-68 fragment of the E alpha-chain of I-E class II molecules (Ealpha52-68 peptide) were detected by flow cytometry. The protein levels of tumor necrosis factor alpha (TNF-alpha), interleukin 1alpha (IL 1alpha), interleukin 6 (IL-6) and transforming growth factor beta (TGF-beta) in the culture supernatants were measured by ELISA. The proliferation of OT-II cells which were co-cultured with OVA323-339-treated DCs was analyzed by flow cytometry. RESULTS: The purity of both DCs and OT-II cells reached over 90% after isolation. SB203580 downregulated the expressions of CD80, CD86 and MHC II, and suppressed the antigen-presenting ability of DCs. The expressions of TNF-alpha, IL-1alpha and IL-6 were downregulated, while the expression of TGF-beta was raised. Finally, SB203580 inhibited DCs-mediated proliferation of OT-II cells. CONCLUSION : Blocking p38MAPK pathway with SB203580 could inhibit DCs-mediated proliferation of OT-II cells, which might be involved in modulating the expressions of CD80, CD86 and MHC II, the antigen-presenting ability, as well as the expressions of pro-inflammatory and anti-inflammatory cytokines. PMID- 26927544 TI - [Increased circulating Ly6Chigh monocyte subsets are correlated with cerebral infarct size in cerebral ischemia/reperfusion mouse models]. AB - OBJECTIVE: To investigate the dynamic changes of monocyte subsets after cerebral ischemia/reperfusion in mice and their correlations with infarct size and neurological defects. METHODS: Thirty male C57BL/6 mice were randomly divided into two groups: middle cerebral artery occlusion/reperfusion (MCAO/R) group and Sham group. MCAO/R mouse models were induced via the intraluminal suture technique (so called filament or suture model). The modified Neurological Severity Scores (mNSS) was used to assess neurological function 6, 12 hours, 1, 2, 3 days after MCAO/R. Blood samples were collected 1, 2 and 3 days after surgery to determine the dynamic changes of Ly6C(high) and Ly6C(low) subsets by flow cytometry. Triphenyltetrazolium chloride (TTC) staining and HE staining of the brains were also performed on day 1, 2 and 3. The relationships between the changes of monocyte subsets and the cerebral infarct size and neurological scores were studied by correlation analysis. RESULTS: Compared with the baseline, the proportion of Ly6C(high) monocytes significantly increased 1 day after MCAO/R surgery, reached the peak level on the following day and then declined. Compared with the Sham group, the proportion of Ly6C(high) monocytes went up obviously at each time point. TTC staining revealed that the infarct size increased markedly 2 days after surgery. The proportion of Ly6C(high) monocytes in the MCAO/R group was positively associated with the percentage of cerebral infarct size, and it also showed a positive correlation with neurological function deficit scores. CONCLUSION: The dynamic changes of monocyte subsets after MCAO/R modeling revealed that Ly6C(high) subset peaked on day 2 after the operation and was correlated with cerebral infarct size. PMID- 26927545 TI - [miR-101 inhibits the proliferation and migration of breast cancer cells via downregulating the expression of DNA methyltransferase 3a]. AB - OBJECTIVE: To investigate the effect of microRNA-101 (miR-101) on the proliferation and migration of breast cancer cells and its possible mechanism. METHODS: The expressions of miR-101 and DNA methyltransferase 3a (DNMT3a) in breast cancer tissues, corresponding normal breast tissues, breast cancer cells and normal breast cells were detected by real-time quantitative PCR. The lentiviral vectors containing miR-101 and shRNA-DNMT3a sequences were transfected into MDA-MB-231 cells to regulate the expressions of miR-101 and DNMT3a. The expressions of DNMT3a and E-cadherin were determined by Western blotting. The proliferation and migration abilities of MDA-MB-231 cells were evaluated by MTT assay and wound healing assay, respectively. RESULTS: Breast cancer tissues and breast cancer cell lines (MCF-7, MDA-MB-231, MDA-MB-361, HCC70) showed lower miR 101 expression and higher DNMT3a expression than the adjacent normal breast tissues and normal breast cell line. The overexpression of miR-101 resulted in downregulation of DNMT3a and restoration of E-cadherin. Besides, knockdown of DNMT3a by shRNA increased E-cadherin expression. MTT assay and would healing assay showed that miR-101 overexpression significantly inhibited the proliferation and migration abilities of MDA-MB-231 cells. CONCLUSION: miR-101 may inhibit MDA-MB-231 cell proliferation and migration by repressing DNMT3a expression and up-regulating E-cadherin expression. PMID- 26927547 TI - [Cloning and expression of human octamer-binding protein-4 (Oct4) cDNA in Escherichia coli and HEK293T cells]. AB - OBJECTIVE: To clone and express human octamer-binding protein-4 (Oct4) cDNA in Escherichia coli and HEK293T cells. METHODS: Primers were designed based on the coding sequence for the human Oct4 cDNA. The fragment containing Oct4 gene, amplified by reverse transcription PCR (RT-PCR) from human HeLa cell cDNA as the template, was subcloned into pET-22b(+) and pcDNA3.1(+) vectors to construct the gene recombinant prokaryotic expression vector pET-22b(+)-Oct4 and eukaryotic expression vector pcDNA3.1(+)-his-Oct4, respectively. Thereafter, the double enzymes digestion and the target gene sequencing were performed for identification. The prokaryotic expression vector pET-22b(+)-Oct4 and eukaryotic expression vector pcDNA3.1(+)- his-Oct4 from the positive clones were respectively transformed into E.coli BL21 (DE3) and the embryo HEK293T cells for protein expression. RESULTS: DNA fragments (1100 bp) containing the coding region of Oct4 gene were obtained from RT-PCR. The recombinant expression plasmids were confirmed by enzymes digestion identification and sequencing analysis, proving both of the expression vectors were successfully constructed. SDS-PAGE analysis showed that the molecular mass of OCT4 expressed in the host E.coli BL21 (DE3) was 38 000, which was consistent with the theoretical prediction. Western blotting confirmed the expression of pcDNA3.1(+)-his-Oct4 transfected into HEK293T. CONCLUSION: Human Oct4 cDNA was cloned and its protein was successfully expressed in E.coli and HEK293T cells. PMID- 26927546 TI - [Combined simulated weightlessness and noise affect cell cycles and composition in rat thymocytes]. AB - OBJECTIVE: To observe the combined effects of simulated weightlessness and noise on the cell cycles of thymocytes and cell compositions of thymus in rats and to explore the possible mechanism of immune function depression in space flight. METHODS: SD rats were stimulated by simulated weightlessness and/or noise. On the 3rd, 7th and 14th day, the rats were weighed and then killed. The thymuses were taken, weighed and cell suspensions were made. Cell cycles and compositions in thymocytes were analyzed by flow cytometry. RESULTS: Compared with control group, the weights of rats were reduced in combined group and simulated weightlessness group, but the weights of rats increased or did not change in noise group. Rats in the three groups showed thymus atrophy. The ratio of cells increased in G0/G1 phase and decreased in S and G2/M phases. The ratios of CD4(-) CD8(-), CD4(+) CD8(-) and CD4(-) CD8(+) T lymphocytes increased and CD4(+) CD8(+) T lymphocytes decreased. However, these changes occurred at different time points in different groups. CONCLUSION: Simulated weightlessness and noise have significant effects on thymus, but the severity are different. The combined factors have superimposed effects. Maybe this is one of the reasons for depressed functions of T lymphocytes in space flight. PMID- 26927548 TI - [The activation of microglia caused by lead and manganese co-exposure induces activation of astrocytes and decrease of glutamine synthetase activity]. AB - OBJECTIVE: To establish microglia and astrocyte co-culture cell model and investigate the effects of lead and manganese alone or co-exposure on different glia cells and the effect of microglia activation on astrocytes' function. METHODS: MTT assay was performed to select the appropriate dose and time of lead and manganese exposure that didn't affect C6 cell growth. Then with BV2 microglia and C6 astrocytes, cell models were established through lead acetate and manganese chloride alone and co-exposure. The cell models were further divided into three types: direct stimulation, conditioned medium and co-culture. In the direct stimulation method, C6 cells were directly treated with complete medium or complete medium containing lead acetate and/or manganese chloride for 24 hours. In conditioned medium method, BV2 cells were cultured in the complete medium or complete medium containing lead acetate and/or manganese chloride for 24 hours, and then the supernatants were centrifuged and used to treat C6 cells for another 24 hours. In co-culture method, BV2 cells were seeded in semipermeable membrane inserts and the inserts were put in a normal 12-well plate; C6 cells were seeded in another 12-well plate; complete medium or complete medium containing lead acetate and/or manganese chloride was added in the wells to culture BV2 cells for 24 hours; the culture medium was abandoned, the cells seeded in the inserts were gently rinsed with complete medium and then the inserts were put into the 12-well plate where C6 were seeded before; the BV2 cells and C6 cells were co-cultured for another 24 hours. The effects of lead and manganese alone or co-exposure on different glia cells were analyzed through CR3/CD11b/OX42 and glial fibrillary acidic protein (GFAP) expression detection by Western blotting; the effect of microglia activation on astrocyte glutamate-glutamine cycle loop was studied through glutamine synthetase (GS) level detected by Western blotting. RESULTS: In direct stimulation method, 10 MUmol/L lead acetate and 100 MUmol/L manganese chloride alone and co-exposure for 24 hours did not affect astrocyte activity and its GS expression. In conditioned medium method, 10 MUmol/L lead acetate and 100 MUmol/L manganese chloried alone and co-exposure for 24 hours significantly induced microglia activation. After C6 cells were cultured with astrocyte normal culture medium for another 24 hours, GFAP level was significantly higher in the exposure groups than in the control group. On the contrary, GS level was significantly lower in the exposure groups than in the control group. In co culture methods, 10 MUmol/L lead acetate and 100 MUmol/L manganese chloride alone and co-exposure for 24 hours significantly induced microglia activation. Then the BV2 cells were rinsed gently and co-cultured with C6 cells for 24 hours, GFAP level were significantly higher in the exposure groups than in the control group. On the contrary, GS level was significantly lower in the exposure groups than in the control group. CONCLUSION: Low-level lead or manganese alone or their co exposure can cause microglia activation. The activated microglia can induce astrocyte activation and reduce its GS expression. Furthermore, compared with exposure alone, co-exposure had a synergistic effect. PMID- 26927549 TI - [Picosecond pulsed electric field inhibits the proliferation and migration, induces G2/M phase arrest and promotes apoptosis in human umbilical venous endothelial cells]. AB - OBJECTIVE: To study the impact of intense picosecond pulsed electric field (psPEF) on the biological behaviors of human umbilical venous endothelial cells (HUVECs) in vitro. METHODS: Intense psPEF with constant parameters (pulse duration, 800 ps; recurrence rate, 3 Hz; the number of pulses, 2000) and three level electric field strength (200, 300 and 400 KV/cm) were performed on HUVECs. CCK-8 assay was used to detect the cell proliferation of HUVECs treated with psPEF for 2, 4, 6, 8, 10, 12, 14, 16 hours. The effect of psPEF on HUVEC migration was measured by wound healing method and Transwell(TM) assay. The apoptosis and cell cycle were detected by flow cytometry. RESULTS: The death rate of HUVECs went up with the increase of the amount of pulses, and the maximum inhibitory rate was at 12 hours after the treatment with psPEF. Intense psPEF inhibited dose-dependently the migration of HUVECs. What's more, the treatment with psPEF arrested cell cycle in G2/M phase and increased the apoptosis rate. CONCLUSION: Intense psPEF inhibits the migration and proliferation of HUVECs as well as induces cell apoptosis and arrests the cell cycle in G2/M phase. PMID- 26927550 TI - [B7-H3 monoclonal antibody attenuates the inflammation and tissue injury in mice with cerulein-induced acute pancreatitis]. AB - OBJECTIVE: To explore the effect of B7-H3 monoclonal antibody (mAb) on cerulein induced acute pancreatitis (AP). METHODS: Mice were randomly divided into three groups: control group, AP group and B7-H3 mAb treatment group. AP was induced in mice by intraperitoneal injections of cerulein. B7-H3 mAb was administered to the mice by subcutaneous injection 1 hour before the injections of cerulein. The blood, pancreas and lung tissues of the mice were collected 6, 12 and 24 hours after cerulein induction. Expression of B7-H3 protein was detected in the pancreas tissues of the control and AP groups by Western blotting and immunohistochemistry. Serum activities of amylase and lipase were tested by VITROS 5600 Integrated System. The pancreas wet-dry mass ratio was used to value the edema of pancreas. Pathological changes of pancreas and lung tissues were evaluated by HE staining. Serum levels of tumor necrosis factor-alpha (TNF alpha), interleukin-6 (IL-6), and IL-1beta were detected by ELISA in all groups. RESULTS: The level of B7-H3 protein increased in the pancreas tissues of the AP group after successful induction of cerulein, and reached the peak at 12 hours. Serum activities of amylase and lipase in the AP group were significantly higher than those in the control group, while decreased obviously after the intervention of B7-H3 mAb. H&E staining showed that evident inflammation appeared in pancreas and lung tissues of the AP group, and the inflammation and wet-dry mass ratio were markedly reduced in the treatment group. The levels of proinflammatory factors TNF-alpha, IL-6 and IL-1beta in the AP group showed a time-dependent increase, and peaked at 12 hours, while in the treatment group were relatively lower. CONCLUSION: B7-H3 is over-expressed in cerulein-induced AP. Anti-B7-H3 mAb can attenuate the inflammation and alleviate the injury of pancreas and lung tissues. PMID- 26927551 TI - [Isolation, culture and identification of human umbilical vein endothelial cells]. AB - OBJECTIVE: To establish a simple, reliable and efficient isolation and culture method of human umbilical vein endothelial cells (HUVECs) in vitro. METHODS: Type 2 collagenase was used to digest umbilical cord and separate HUVECs. The cells were cultured in the endothelial cell culture medium (ECM). The cell morphology was observed under an inverted phase-contrast microscope. Immunofluorescence technique was applied to detect the expression of von Willebrand factor (vWF). Cell purity was determined by detecting CD31 level on cell surface with flow cytometry. Tube formation assay was used to test the function of the endothelial cells after cryopreservation in vitro. RESULTS: HUVECs successfully isolated were proved with high purity and good activity. HUVECs of primary generation could merge into a single layer one week after isolation. The cells showed a typical cobblestone-like arrangement. Immunofluorescence technique validated that the cells could widely express vWF and the expression frequency of CD31 was 93.1%. The cells were still capable of forming the lumen structure after cryopreservation, indicating that the standardized cryopreservation method could well maintain the cell function. CONCLUSION: This is a simple, reliable and efficient method of isolating and culturing HUVECs in vitro. PMID- 26927552 TI - [Adipose-derived stem cells promote the polarization from M1 macrophages to M2 macrophages]. AB - OBJECTIVE: To investigate the effects of adipose-derived stem cells (ADSCs) on M1/M2 macrophages and whether ADSCs are able to promote the polarization from M1 macrophages to M2 macrophages. METHODS: M1 macrophages were induced from J774.1 macrophages by 24-hour stimulation of lipopolysaccharide (LPS) and interferon gamma (IFN-gamma), and M2 macrophages were induced from J774.1 macrophages by interleukin 4 (IL-4) for another 24 hours. Then M1/M2 macrophages were separately cultured in the presence of ADSCs for 24 hours. The M1/M2 macrophages and their corresponding supernatants were collected for further analysis. The expressions of IL-6, tumor necrosis factor alpha (TNF-alpha), inducible nitric oxide synthase (iNOS), CC chemokine ligand 2 (CCL2), CD86, arginase 1 (Arg1), mannose receptors/CD206 (MR/CD206), IL-10, found in inflammatory zone 1 (FIZZ1), chitinase 3-like 3 (Ym-1) were detected by real-time PCR and ELISA. RESULTS: ADSCs significantly decreased the levels of IL-6, TNF-alpha, iNOS, CCL2 and CD86, and increased the levels of Arg1, CD206 and IL-10 in M1 macrophages. In the supernatant of M1 macrophages, the expressions of IL-6 and TNF-alpha were reduced, while those of CD206 were enhanced. In M2 macrophages, ADSCs resulted in down-regulation of IL-6, TNF-alpha, iNOS, CD86 and up-regulation of Arg1, CD206, FIZZ-1, Ym-1 and IL-10. In the supernatant of M2 macrophages, the expression levels of IL-6 and TNF-alpha were down-regulated and those of CD206 were up regulated. CONCLUSION: ADSCs can inhibit the gene expression of M1 macrophages and promote the gene expression of M2 macrophages, as well as mediate the polarization from M1 macrophages to M2 macrophages. PMID- 26927553 TI - [Tubacin promotes Foxp3 expression and suppressive function of mouse CD4+;CD25+; regulatory T cells]. AB - OBJECTIVE: To observe the changes of fork head transcription factor (Foxp3) expressions and suppressive functions of mouse regulatory T cells (Tregs) after stimulated by tubacin (histone deacetylase 6 inhibitor) in vitro. METHODS: CD4(+) CD25(+) T and CD4(+) CD25(-) T cells were gained from C57BL/6J mouse spleen lymphocytes by double positive magnetic bead sorting method. Natural Tregs (nTregs) and transforming growth factor beta1 (TGF-beta1)-induced Tregs (iTregs) were stimulated by tubacin in vitro. Foxp3 expression of each group was identified by reverse transcription PCR, and immunosuppressive activities of each group were tested by the mixed lymphocyte culture (MLC). RESULTS: Foxp3 expression of nTregs and iTregs were significantly enhanced after stimulated with tubacin. The tubacin induced CD4(+) CD25(+) Foxp3(high) Tregs significantly inhibited syngeneic CD4(+) CD25(-) T cell activation. CONCLUSION: Tubacin can upregulate Foxp3 expression of CD4(+) CD25(+) Tregs and enhances their cellular immunosuppressive capability. PMID- 26927554 TI - [Curcumin improves learning and memory function through decreasing hippocampal TNF-alpha and iNOS levels after subarachnoid hemorrhage in rats]. AB - OBJECTIVE: To investigate the effect of curcumin on learning and memory function of rats with subarachnoid hemorrhage (SAH) and the possible mechanism. METHODS: A total of 30 male Sprague-Dawley rats were randomly divided into three groups: Sham group, SAH group and curcumin (Cur) therapy group. Experimental SAH rat models were established by injecting autologous blood into the cisterna magna. Neurological deficits of rats were examined at different time points. Spatial learning and memory abilities were tested by Morris water maze test. The hippocampal tumor necrosis factor-alpha (TNF-alpha) and inducible nitric oxide synthase (iNOS) were detected by ELISA. RESULTS Experimental SAH rat models were established successfully. Neurological scores of the SAH rats were significantly lower than those of the sham group. Curcumin therapy obviously improved the neurological deficits of rats compared with the SAH rats. Morris water maze test showed that SAH caused significant cognitive impairment with longer escape latency compared with the sham group. After treatment with curcumin for 4 weeks, the escape latency decreased significantly. The levels of TNF-alpha and iNOS in the curcumin-treated group were significantly lower than those of the SAH group. CONCLUSION: SAH can cause learning and memory impairment in rats. Curcumin can recover learning and memory function through down-regulating hippocampal TNF alpha and iNOS levels. PMID- 26927555 TI - [miR-126 knockdown enhances the activity of murine CD4+ T cells in vivo and promotes their differentiation into Th1 cells]. AB - OBJECTIVE: To investigate the change of CD4(+) T cell activity in microRNA-126 (miR-126) knockdown (KD) mice and explore its significance. METHODS: The expression level of mature miR-126 in CD4(+) CD62L(+) T cells purified by magnetic-activated cell sorting (MACS) was analyzed by real-time PCR using specific probe. Furthermore, the expression levels of CD69, CD62L and CD44 molecules, as well as intracellular proliferating nuclear antigen Ki-67, in CD4(+) T cells in miR-126 KD mice were detected by fluorescence-activated cell sorting (FACS). Moreover, the apoptosis of CD4(+) T cells was analyzed by annexin V/PI staining assay combined with flow cytometry. Finally, the relative expressions of function-related cytokines including interleukine 4 (IL-4), IL-10, IL-12, transforming growth factor (TGF-beta), interferon (IFN-gamma) and tumor necrosis factor (TNF-alpha) in CD4(+) T cells were determined by real-time PCR. RESULTS: Compared with wild-type (WT) mice, the expression level of mature miR 126 in CD4(+) T cells in miR-126 KD mice was dramatically reduced. Furthermore, the proportion of CD62L(+) in CD4(+) T cells also decreased significantly, while the proportions of CD69(+), CD44(+) and Ki-67(+) cells were remarkably elevated. Meanwhile, the apoptosis proportion of CD4(+) T cells in vivo dropped dramatically in miR-126 KD mice. Finally, the mRNA expressions of IL-4 and IL-10 in CD4(+)T cells were significantly downregulated, but IL-12, TGF-beta, TNF-alpha and IFN-gamma mRNAs were obviously up-regulated. CONCLUSION: miR-126 knockdown could significantly enhance the functional activity of CD4(+) T cells in vivo and promote cell differentiation into Th1 cells. PMID- 26927556 TI - [The expression of IDH1 (R132H) is positively correlated with cell proliferation and angiogenesis in glioma samples]. AB - OBJECTIVE: To explore the correlations of the expression of mutant isocitrate dehydrogenase (IDH1) (R132H) protein with angiogenesis and cell proliferation in glioma. METHODS: We performed polymerase chain reaction-based IDH gene mutation screening in 385 glioma samples, and the subcellular localization and expression levels of IDH1 (R132H) was examined by immunohistochemistry (IHC). Ki-67 labeling index was introduced to determine the proliferation of glioma cells, and the microvessel density was measured through CD34 staining. Statistical analyses were performed to show the correlations of IDH1 mutation with cell proliferation and microvessel density. RESULTS: The mutant rates of IDH1 were about 50%-60% in grade II-III gliomas and secondary glioblastomas, which were significantly higher than those in pilocytic astrocytoma (grade I) and primary glioblastoma (grade IV). Moreover, the level of IDH1 (R132H) protein was positively correlated with Ki-67 labeling index and microvessel density. CONCLUSION: IDH mutation was common in grade II-III glioma and secondary glioblastoma, and the mutant IDH1 (R132H) might play a critical role in the cell proliferation and angiogenesis of glioma. PMID- 26927557 TI - [Hypercoagulable state is associated with NF-kappa B activation and increased inflammatory factors in patients with rheumatoid arthritis]. AB - OBJECTIVE: To investigate the mechanism of hypercoagulable state based on nuclear factor kappaB (NF-kappaB) pathway in patients with rheumatoid arthritis (RA). METHODS: Thirty-five RA patients were enrolled as well as 20 healthy volunteers as a control group. Interleukin-10 (IL-10), IL-6, IL-4, IL-17, NF-kappaB activator 1 (Act1), p50, p65, IkappaBalpha, platelet activating factor (PAF), PAF acetylhydrolase (PAF-AH) and anti-cyclic citrullinated peptide (CCP) were detected using ELISA. The number of platelet (PLT) was detected using Sysmex XT 2000i automated hematology analyzer. The levels of D-dimer (D-D), fibrinogen (FBG), thrombin time (TT), prothrombin time (PT), and partial thromboplastin time (APTT) were detected using Sysmex CA-1500 automatic coagulation analyzer. Erythrocyte sedimentation rate (ESR) was detected using Westergren method. C reactive protein and rheumatoid factor (RF) were detected using Hitachi 7060 automatic biochemical analyzer. Meanwhile, the mRNA expressions of Act1, p65, p50, IkappaBalpha and IkappaB kinase alpha (IKKalpha) were detected using semi quantitative reverse transcription PCR. The expressions of p65, p50 and IkappaBalpha proteins were examined using Western blotting. The correlations of the above indexes were analyzed by Spearman correlation test. RESULTS: Compared with the normal group, the levels of DD, FBG, PLT significantly increased in the peripheral blood of RA patients, TT decreased, while APTT and PT were not significantly changed. IL-4, IL-10 and PAF-AH were significantly reduced in the sera of RA patients, while IL-6, IL-17, Act1, p50, p65, IkappaBalpha, IKKalpha and PAF were significantly elevated. Spearman correlation analysis showed that coagulant and fibrinolytic indexes were significantly correlated with cytokines, NF-kappaB, activity indexes and clinical symptoms and signs. CONCLUSION: The hypercoagulable state is common in the peripheral blood of RA patients, and it is closely related to inflammatory factors, activity indexes and abnormal activation of NF-kappaB. PMID- 26927558 TI - [Decreased expression levels of LAG-3 and CD49b on CD14+ cells in peripheral blood of patients with recurrent spontaneous abortion]. AB - OBJECTIVE: To investigate the expression levels of adhesion molecule CD49b and negative regulation molecule LAG-3 (CD223) on peripheral blood CD14(+) cells in patients with recurrent spontaneous abortion (RSA). METHODS: Peripheral blood samples were collected from 7 normal female individuals and 12 patients with RSA, and then peripheral blood mononuclear cells (PBMCs) and plasma were separated from the peripheral blood via centrifugation. The expression levels of CD49b and LAG-3 on CD14(+) cells in PBMCs were detected by flow cytometry and the levels of interleukin 10 (IL-10) and transforming growth factor beta (TGF-beta) in plasma were detected by ELISA. RESULTS: In the RSA patient group, there was no significant difference in the percentage of monocytes compared with that of the normal female group. The numbers of CD14(+) CD49b(+), CD14(+) LAG-3(+) and CD14(+) CD49b(+) LAG-3(+) cells in the RSA patient group were lower than those of the normal female group. The plasma level of TGF-beta in the RSA patient group was lower than that of the normal female group. However, there was no significant difference in the plasma level of IL-10 between the two groups. CONCLUSION: In RSA patients, the expression levels of CD49b and LAG-3 on CD14(+) monocytes and the plasma level of TGF-beta decreased obviously compared with that of the normal females. PMID- 26927559 TI - [RANKL increases on peripheral blood T lymphocytes and serum Dickkopf1 decreases in rheumatoid arthritis]. AB - OBJECTIVE: To explore the roles of bone metabolism-related molecules in bone metabolic disturbance and disease progression of patients with rheumatoid arthritis (RA). METHODS: A total of 66 RA patients and 20 healthy controls were included, and their relevant clinical information was gathered. Electrochemiluminescence immunoassay (ECLIA) was used to detect the levels of osteocalcin N-terminal middle (OC-N-MID) and C-terminal cross-linked telopeptides of type 1 collagen (CTX) in serum. The serum levels of Wnt inhibitory factor Dickkopf1 (DKK1) and receptor activator of nuclear factor-kappaB ligand (RANKL) were determined by magnetic luminex assays. Flow cytometry was used to detect the RANKL level on peripheral blood T cells. RESULTS: Compared with healthy controls, the levels of OC-N-MID and CTX in the sera of the RA patients showed no significant difference. Level of RANKL in the sera of the RA patients was higher than that in the controls, while level of DKK1 was lower. The level of RANKL on peripheral blood T cells increased in the RA patients, especially on CD3(+) T cells. CONCLUSION: In RA patients, level of RANKL on T cells is elevated, and the serum level of RANKL increases, but DKK1 decreases. PMID- 26927560 TI - [The number of peripheral blood CD11c+ antigen presenting cells increases and their function strengthens in the patients with active pulmonary tuberculosis]. AB - OBJECTIVE: To detect the percentage of CD11c positive antigen presenting cells (CD11c(+) APCs) in peripheral blood from patients with active pulmonary tuberculosis (APT) and the levels of HLA-DR and CD86. Methods Fifty-two APT patients were enrolled in the study and 15 healthy volunteers served as controls. The frequencies of CD11c(+) APCs and the expressions of HLA-DR and CD86 in CD11c(+) APCs in the peripheral blood were determined by flow cytometry. RESULTS: The percentage of CD11c(+) APCs in the peripheral blood in the patients with APT was much higher than that in the controls. Interestingly, CD11c(+) APCs frequency in post-treatment patients was even higher compared with that in the pre treatment patients. Furthermore, both HLA-DR(+) CD11c(+) APC frequency and the mean fluorescence intensity (MFI) of HLA-DR in APT patients were higher than those in the controls. Similarly, the percentage of CD86(+) CD11c(+) APCs in the APT patients was also higher than that in the controls. CONCLUSION: The increase of CD11c(+) APCs with high levels of HLA-DR and CD86 in APT patients suggests that the antigen presenting capacity of APCs is at a high level in APT patients. PMID- 26927561 TI - [Selection of storage time, temperature and anticoagulants of peripheral blood samples for culturing cytokine-induced killer cells]. AB - OBJECTIVE: To investigate the effects of anticoagulants, preservation time and temperature of peripheral blood samples on the culture of cytokine-induced killer (CIK) cells so as to provide the experimental evidences for peripheral blood storage in autologous immunotherapy. METHODS: Four samples of 60 mL peripheral blood were collected. After being added with heparin sodium, cell preservation liquid (sodium citrate) and EDTA solution, they were separately stored under 4 degrees C, 22 degrees C, and 30 degrees C for 0, 4, 8, 24 hours. We divided the orthogonal experiments into 12 groups, and then separated mononuclear cells and induced them into CIK cells. The proliferation efficiency and IFN-gamma secretion were compared in the 12 groups. RESULTS: The proliferation of CIK cells was not obvious in EDTA group, but obvious in heparin sodium group and sodium citrate group, especially better in sodium citrate group. The storage time of blood did not have a significant impact on CIK cell culture, however the longer storage time, the lower cell proliferation efficiency. The proliferation efficiency decreased apparently after 16-day culture if preservation time exceeded 8 hours. After the culture period of 16 days, the efficiency of CIK cell proliferation was the highest at 22 degrees C, followed by that at 4 degrees C, and the lowest was at 30 degrees C. It was not apparent that the temperature of blood storage affected CIK cell proliferation within 16-day culture period. CONCLUSION: Both heparin sodium and sodium citrate can be used in blood sample anticoagulation for CIK cell culture. Blood samples are suitable for CIK cell culture which are stored within 24 hours between 4 degrees C and 30 degrees C. PMID- 26927563 TI - [Preparation of rabbit polyclonal antibody against mouse ADAMTS2]. AB - OBJECTIVE: To obtain recombinant mouse collagenase ADAMTS2 (ADAM metallopeptidase with thrombospondin type 1 motif, 2) C terminal (1109-1213), and prepare the corresponding rabbit anti-ADAMTS2 polyclonal antibodies. METHODS: The recombinant expression plasmid pGEX-6p-1-ADAMTS2 (1109-1213) was transformed into E.coli. The target protein was induced by IPTG and identified by mass spectrometry following affinity purification. The expressed and purified ADAMTS2 (1109-1213) protein was used to immunize New Zealand rabbits to prepare anti-ADAMTS2 polyclonal antibodies. The antibody titers were detected by ELISA and the antibody specificity by Western blotting. RESULTS: The protein ADAMTS2 (1109-1213) was expressed in E.coli after IPTG induction, and with the purified protein, we prepared antiserum in the immunized rabbits. The titer of the antiserum reached over 1:160 000. The antiserum showed a good specificity. CONCLUSION: The high titer and specific rabbit anti-ADAMTS2 antibody has been prepared successfully. PMID- 26927562 TI - [The expression and clinopathological significance of miR-130b in human hepatocellular carcinoma]. AB - OBJECTIVE: To investigate the expression of miR-130b in human hepatocellular carcinoma (HCC) and its correlations with clinical-pathological features. METHODS: Real-time quantitative PCR (qRT-PCR) was applied to detect the expression of miR-130b in HCC tissues (n=86), matched normal tumor-adjacent tissues and 5 HCC cell lines (LO2 human normal hepatocytes, HepG2, Hep3B, SMMC 7721, Hu7 cells). The expressions of peroxisome proliferator-activated receptor gamma (PPARgamma), E-cadherin and vimentin were measured by immunohistochemistry. miR-130b inhibitor synthesized artificially was transfected into SMMC-7721 cells in vitro. Cell invasion was analyzed by Transwell(TM) assay. The expressions of PPARgamma, E-cardhern and vimentin in SMMC-7721 cells after transfected with miR 130b inhibitor and PPARgamma siRNA were detected by qRT-PCR and Western blotting. RESULTS: The expression of miR-130b mRNA in HCC tissues was significantly higher than that in matched normal tumor-adjacent tissues. Clinical analysis indicated that high expression of miR-130b was prominently correlated with venous infiltration, high Edmondson-Steiner grading and advanced tumor node metastasis (TNM) stage. Elevated miR-130b expression was observed in all HCC cell lines (HepG2, SMMC-7721, Huh7 and Hep3B) as compared with that in LO2 nontransformed hepatic cell line. Furthermore, there was an inverse correlation between miR-130b and E-cadherin as well as between miR-130b and PPARgamma, and a positive correlation between miR-130b and vimentin was demonstrated in HCC tissues. miR 130b inhibitor could significantly increase the expression of PPARgamma and E cadherin, but decrease the expression of vimentin in SMMC-7721 cells, meanwhile it suppressed the migration and invasion of SMMC-7721 cells. In addition, the down-regulation of PPARgamma expression by PPARgamma siRNA partially abrogated the above effect of miR-130b on HCC cells. CONCLUSION: The expression of miR-130b in HCC tissues is significantly higher than that in tumor-adjacent tissues. The increased expression of miR-130b is related with the malignant manifestations of HCC. miR-130b may promote HCC cell invasion by inhibiting PPARgamma expression and inducing epithelial-mesenchymal transition. PMID- 26927564 TI - [Preparation and characterization of polyclonal antibody against 5-fluorouracil]. AB - OBJECTIVE: To prepare 5-fluorouracil (5-FU) immunogen and develop polyclonal antibodies against 5-FU. METHODS: The derivant of 5-FU (5-fluorouracil-1-yl-aceto amino acid, 5-FUAA) was synthesized, and then conjugated with bovine serum albumin (BSA) or ovalbumin (OVA) by carbodiimide (CDI) method. 5-FUAA conjugating BSA (5-FUAA-BSA) was used to immunize BALB/c mice to produce antiserum, and 5 FUAA conjugating OVA (5-FUAA-OVA) was used as coating antigen to detect the titer of the antiserum by indirect ELISA. Furthermore, specificity of the polyclonal antiserum was identified by ELISA and Western blotting. RESULTS: 5-FU derivant 5 FUAA was successfully synthesized and conjugated with BSA or OVA. Indirect ELISA showed that the titer of the antiserum from BALB/c mice immunized with 5-FUAA-BAS reached 1:1 280 000. Moreover, ELISA and Western blotting proved that the anti serum could combine 5-FU specifically. CONCLUSION: The experiment has prepared high-specific and high-titer polyclonal antibody against 5-FU. PMID- 26927565 TI - Are the interarytenoid muscles supplied by branches of both the recurrent and superior laryngeal nerves? AB - OBJECTIVES/HYPOTHESIS: It has been generally accepted that the branches of the internal branch of the superior laryngeal nerve to the interarytenoid muscle are exclusively sensory. However, some experimental studies have suggested that these branches may contain motor axons, and therefore that the interarytenoid muscle is supplied by both the superior and recurrent laryngeal nerves. The aim of this work was to determine whether motor axons to the interarytenoid muscles are present in both laryngeal nerves. STUDY DESIGN: Basic research. METHODS: Twelve human internal branches of the superior laryngeal nerve were dissected, and its branches to the interarytenoid muscle were removed and processed for choline acetyltransferase immunohistochemistry, a method not used previously in studying the nerve fiber composition of the laryngeal nerves. RESULTS: The internal branch of the superior laryngeal nerve divided into two to five branches to the interarytenoid muscle. All branches contained motor axons, with the proportion of motor axons varying from 6% to 31%. CONCLUSION: The present study confirms that the internal branch of the superior laryngeal nerve provides a motor innervation to the interarytenoid muscles. LEVEL OF EVIDENCE: N/A. Laryngoscope, 126:1117 1122, 2016. PMID- 26927567 TI - Illegal captive lemurs in Madagascar: Comparing the use of online and in-person data collection methods. AB - Although it is illegal to capture, sell, and trade lemurs, the live capture of lemurs in Madagascar is ongoing and may have impacted over 28,000 lemurs between 2010 and 2013. Only one study has examined this trade and did so using in-person interviews in northern Madagascar. The current study sought to expand this existing dataset and examine the comparability of online surveys to more traditional on-location data collection methods. In this study, we collected data through a web-based survey resulting in 302 sightings of 685 captive lemurs. We also collected data from 171 hotel and 43 restaurant websites and social media profiles. Survey submissions included sightings of 30 species from 10 genera, nearly twice as many species as identified via the in-person interviews. Lemur catta, Varecia variegata, and Eulemur fulvus were the most common species sighted in captivity. Captive lemurs were reported in 19 of Madagascar's 22 administrative regions and most were seen in urban areas near their habitat ranges. This represents a wider geographic distribution of captive lemurs than previously found through in-person interviews. The online survey results were broadly similar to those of the in-person surveys though greater in species and geographic diversity demonstrating advantages to the use of online surveys. The online research methods were low in cost (USD $100) compared to on-location data collection (USD $12,000). Identified disadvantages included sample bias; most of the respondents to the online survey were researchers and many captive sightings were near study sites. The results illustrate the benefits of incorporating a social science approach using online surveys as a complement to traditional fieldwork. Am. J. Primatol. 79:e22541, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 26927568 TI - Biomarkers in Ocular Chronic Graft Versus Host Disease: Tear Cytokine- and Chemokine-Based Predictive Model. AB - PURPOSE: To develop a tear molecule level-based predictive model based on a panel of tear cytokines and their correlation with clinical features in ocular chronic graft versus host disease (cGVHD). METHODS: Twenty-two ocular cGVHD patients and 21 healthy subjects were evaluated in a controlled environmental research laboratory (CERLab). Clinical parameters were recorded, and tears were collected. Levels of 15 molecules (epidermal growth factor [EGF], IL receptor antagonist [IL 1Ra], IL-1beta, IL-2, IL-6, IL-8/CXCL8, IL-10, IL-12p70, IL-17A, interferon inducible protein [IP]-10/CXCL10, IFN-gamma, VEGF, TNF-alpha, eotaxin 1, and regulated on activation normal T cell expressed and secreted [RANTES]) were measured by multiplex-bead assay and correlated with clinical parameters. Logistic regression was used to develop a predictive model. Leave-one-out cross validation was applied. Classification capacity was evaluated in a cohort of individuals with dry eye (DE) of other etiologies different from GVHD. RESULTS: Epidermal growth factor and IP-10/CXCL10 levels were significantly decreased in ocular cGVHD, positively correlating with tear production and stability and negatively correlating with symptoms, hyperemia, and vital staining. Interleukin 1Ra, IL-8/CXCL8, and IL-10 were significantly increased in ocular cGVHD, and the first two correlated positively with symptoms, hyperemia, and ocular surface integrity while negatively correlating with tear production and stability. Predictive models were generated, and the best panel was based on IL-8/CXCL8 and IP-10/CXCL10 tear levels along with age and sex, with an area under the receiving operating curve of 0.9004, sensitivity of 86.36%, and specificity of 95.24%. CONCLUSIONS: A predictive model based on tear levels of IL-8/CXCL8 and IP 10/CXCL10 resulted in optimal sensitivity and specificity. These results add further knowledge to the search for potential biomarkers in this devastating ocular inflammatory disease. PMID- 26927569 TI - In Vivo Imaging of Fluorescent Probes Linked to Antibodies Against Human and Rat Vascular Endothelial Growth Factor. AB - PURPOSE: Anti-VEGF therapy has improved functional outcome for many patients with neovascular AMD. A particular challenge in routine clinical application is to find the best treatment regimen as a high degree of interindividual variability of disease activity has been noted. The aim of the study was to investigate fluorescent probes linked to antibodies against VEGF for in vivo imaging in an animal model. METHODS: Bevacizumab, B20-4.1.1 and AF564 were covalently attached to the novel dye 6S-indocyanine green (ICG) maleimide. Binding and proliferation properties were assessed. In a rat model of laser-induced choroidal neovascularization, retinal uptake and topographic localization of antibody conjugates were analyzed. Distribution and accumulation of the probes were determined by immunohistochemistry and flow cytometry analysis. RESULTS: Antibody conjugates retained target binding affinity and showed no toxicity. In vivo imaging showed a strong fluorescence immediately following an intravenous or intravitreal injection. While accumulation within the laser lesions was visualized for all three antibody conjugates, the signal strength and the duration of fluorescence varied. In addition, distinct fluorescent spots were also recognized. Patterning and in-depth analyses including histology and flow cytometry data strongly suggest that the fluorescent spots represent labeled microglial cells and/or macrophages. CONCLUSIONS: Pharmacokinetics of fluorescent labeled bevacizumab, B20-4.1.1 and AF564 can be investigated in vivo. In this model, interpretation of long-term in vivo observations is difficult because of a possible rat-specific immune response and challenges to image localized binding of soluble VEGF. Further investigations in a primate model and the use of appropriate antibodies directed against the VEGF-receptor may represent alternative approaches. PMID- 26927570 TI - Transforming Growth Factor Beta Switch in Aqueous Humor of Patients With Fuchs' Endothelial Corneal Dystrophy. PMID- 26927571 TI - Author Response: Transforming Growth Factor Beta Switch in Aqueous Humor of Patients With Fuchs' Endothelial Corneal Dystrophy. PMID- 26927572 TI - Recovery-Oriented Practice in Mental Health Inpatient Settings: A Literature Review. AB - OBJECTIVE: Implementation of recovery-oriented practice has proven to be challenging, and little is known about the extent to which recovery-oriented principles are integrated into mental health inpatient settings. This review of the literature examined the extent to which a recovery-oriented approach is an integrated part of mental health inpatient settings. METHODS: A systematic search (2000-2014) identified quantitative and qualitative studies that made explicit reference to the concept of recovery and that were conducted in adult mental health inpatient settings or that used informants from such settings. The quality and relevance of the studies were assessed with the Critical Appraisal Skills Program, and a text-driven content analysis identified three organizing themes: definitions and understandings, current practice, and challenges. RESULTS: Eight studies from Canada, the United Kingdom, the United States, Australia, and Ireland were included. The results highlight the limited number of studies of recovery-oriented practice in mental health inpatient settings and the limited extent to which such an approach is integrated into these settings. Findings raise the question of whether recovery-oriented practice can or should be an approach used in these settings, which are primarily aimed at stabilization and symptom relief. CONCLUSIONS: Research is needed to clarify the concept of recovery and how it applies to mental health inpatient settings. The challenges to recovery-oriented practice posed by the current organization of such settings should be examined. PMID- 26927573 TI - Quality of Diabetes Care Among Adult Medicaid Enrollees With Mental Disorders. AB - OBJECTIVE: In light of the national trend toward integrating mental and general medical care, this study examined disparities in diabetes treatment among Medicaid recipients in a nonintegrated, managed care behavioral health carve-out system. METHODS: A retrospective study of Medicaid claims (July 2009-June 2010) compared quality of diabetes treatment among 21,015 patients with and without mental disorders. RESULTS: Presence of a mental disorder was associated with higher use of outpatient and primary care services for diabetes, lower rates of hospitalizations for diabetes, and higher odds of receiving three or more quality measures for diabetes care. Patients with serious mental illness had better diabetes care compared with patients with other mental disorders and patients with no mental disorders. CONCLUSIONS: Findings suggest that managed care behavioral health carve-out systems should be considered among the range of approaches for improving treatment for diabetes among persons with comorbid mental disorders, particularly serious mental disorders. PMID- 26927574 TI - Mental Health Service Use Among Firefighters With Suicidal Thoughts and Behaviors. AB - OBJECTIVE: This study aimed to characterize rates and correlates of mental health service use, as well as barriers to care, among a sample of firefighters reporting a history of suicide ideation, plans, or attempts during their firefighting careers. METHODS: Participants (N=483) completed a Web-based survey assessing history of suicidal thoughts and behaviors, prior mental health service utilization, and barriers to treatment. RESULTS: Overall, 77% of participants reported receipt of mental health services during their firefighting careers (attempt history, 93%; plan but no attempt, 77%; and ideation only 68%). Firefighters with fewer years of service were less likely than those with more years to have accessed treatment. Service nonusers were more likely than service users to report concerns regarding reputation and embarrassment as barriers to care. CONCLUSIONS: Findings from this preliminary investigation suggest that the majority of firefighters with a history of elevated suicide risk have received mental health services. PMID- 26927575 TI - State Laws on Emergency Holds for Mental Health Stabilization. AB - OBJECTIVE: Psychiatric emergency hold laws permit involuntary admission to a health care facility of a person with an acute mental illness under certain circumstances. This study documented critical variation in state laws, identified important questions for evaluation research, and created a data set of laws to facilitate the public health law research of emergency hold laws' impact on mental health outcomes. METHODS: The research team built a 50-state, open-source data set of laws currently governing emergency holds. A protocol and codebook were developed so that the study may be replicated and extended longitudinally, allowing future research to accurately capture changes to current laws. RESULTS: Although every state and the District of Columbia have emergency hold laws, state law varies on the duration of emergency holds, who can initiate an emergency hold, the extent of judicial oversight, and the rights of patients during the hold. The core criterion justifying an involuntary hold is mental illness that results in danger to self or others, but many states have added further specifications. Only 22 states require some form of judicial review of the emergency hold process, and only nine require a judge to certify the commitment before a person is hospitalized. Five states do not guarantee assessment by a qualified mental health professional during the emergency hold. CONCLUSIONS: The article highlights variability in state law for emergency holds of persons with acute mental illness. How this variability affects the individual, the treatment system, and law enforcement behavior is unknown. Research is needed to guide policy making and implementation on these issues. PMID- 26927576 TI - Severe Mental Illness in LGBT Populations: A Scoping Review. AB - OBJECTIVE: There is increasing attention to diversity in psychiatric services and widespread recognition of the mental health implications of stigma for individuals from sexual or gender minority groups. However, these areas remain markedly underdeveloped in the area of severe mental illness. The aim of this review was to map out the existing base of knowledge in these areas to help inform future research, practice, and policy directions. METHODS: A review of the literature was conducted to answer the following question: What factors and strategies need to be considered when developing services for individuals from sexual or gender minority groups who are experiencing severe mental illness? A comprehensive search of MEDLINE, PsycINFO, and Google Scholar was completed by using Arksey and O'Malley's methodological framework for scoping reviews. RESULTS: A total of 27 publications were identified for review. Mental health services research indicated generally lower levels of service satisfaction among lesbian, gay, bisexual, transgender, and transsexual (LGBT) individuals and minimal evidence regarding specific interventions. Descriptive research suggested an increased risk of severe mental illness in LGBT populations, an association between this increased risk and discrimination, and the potential benefit of cultivating spaces where individuals can be "out" in all aspects of themselves. CONCLUSIONS: There is a pressing need for research into interventions for LGBT populations with severe mental illness as well as descriptive studies to inform efforts to reduce illness morbidity linked to discrimination. PMID- 26927577 TI - Trends in Health Care Utilization Among Adults With Serious Psychological Distress: 2003-2014. AB - OBJECTIVE: The purpose of this study was to assess trends in health care utilization among adults with serious psychological distress (SPD) from 2003 to 2014 and compare utilization patterns between adults with and without SPD. METHODS: The study sample came from the 2003-2014 National Health Interview Survey series. SPD was measured by the six-item Kessler Psychological Distress Scale. Logistic regressions were performed to test the overall trends in health care utilization stratified by SPD status. Postestimation methods were used to obtain predicted changes in the percentages of adults with and without SPD who utilized health care services. RESULTS: Adjusted analyses showed that from 2003 through 2014, the percentage of adults with four or more outpatient office visits per year decreased by .4% each year among adults without SPD and by .5% among adults with SPD. The percentage of adults with a hospital admission each year decreased by .1% among adults without SPD and .3% among adults with SPD. The percentage of adults with two or more emergency department (ED) visits each year decreased by .1% among adults without SPD and increased significantly by .2% among adults with SPD. Supplementary analyses suggested that the increasing trends in ED utilization among adults with SPD had leveled off since 2011. CONCLUSIONS: Adults with SPD utilized outpatient, inpatient, and emergency care at higher rates compared with adults without SPD. In particular, utilization of ED visits increased significantly over the past decade among adults with SPD, indicating a widening gap in the adequacy of services for this population. PMID- 26927578 TI - Medicaid Coverage for Methadone Maintenance and Use of Opioid Agonist Therapy in Specialty Addiction Treatment. AB - OBJECTIVE: This study examined differences in opioid agonist therapy (OAT) utilization among Medicaid-enrolled adults receiving public-sector opioid use disorder treatment in states with Medicaid coverage of methadone maintenance, states with block grant funding only, and states without public coverage of methadone. METHODS: Person-level treatment admission data, which included information on reason for treatment and use of OAT from 36 states were linked to state-level Medicaid policies collected in a 50-state survey. Probabilities of OAT use among Medicaid enrollees in opioid addiction treatment were calculated, with adjustment for demographic characteristics and patterns of substance use. RESULTS: In adjusted analysis, 45.0% of Medicaid-enrolled individuals in opioid addiction treatment in states with Medicaid coverage for methadone maintenance used OAT, compared with 30.1% in states with block grant coverage only and 17.0% in states with no coverage. Differences were widest in nonintensive outpatient settings. CONCLUSIONS: Medicaid methadone maintenance coverage is critical for encouraging OAT among individuals with opioid use disorders. PMID- 26927579 TI - Independent Contractors in Public Mental Health Clinics: Implications for Use of Evidence-Based Practices. AB - OBJECTIVES: Community mental health clinics are increasingly utilizing independent contractors to provide clinical services. At the same time, many organizations are participating in initiatives intended to increase implementation of evidence-based practices (EBPs). The primary aim of this study was to understand the associations of utilizing independent contractors with clinician knowledge and attitudes toward EBPs and organizational culture and climate. The study also sought to understand the potential impact of using independent contractors on mental health services delivery from the perspective of organizational leadership. METHODS: Quantitative data were collected from 130 therapists in 23 organizations; qualitative data were collected from executive administrators in nine of the 16 organizations participating in EBP initiatives sponsored by the City of Philadelphia. Regression with random effects was used to estimate the associations between worker status (contractor or employee) and clinician attitudes toward EBPs, knowledge of EBPs, and organizational culture and climate. Qualitative inquiry was used to understand the impact of reliance on independent contractors on organizational participation in EBP initiatives. RESULTS: Independent contractors endorsed less positive attitudes toward EBPs and scored lower on knowledge of EBPs. Interviews revealed four main themes: reasons for using independent contractors, general consequences of using independent contractors, specific impact of independent contractors on participation in EBP initiatives, and suggestions for alternatives. CONCLUSIONS: A growing number of community mental health clinics rely on independent contractors. There may be consequences of this shift that deserve exploration. PMID- 26927580 TI - Proximal Risk Factors for Short-Term Community Violence Among Adults With Mental Illnesses. AB - OBJECTIVE: This study examined the role of static indicators and proximal, clinically relevant indicators in the prediction of short-term community violence in a large, heterogeneous sample of adults with mental illnesses. METHODS: Data were pooled from five studies of adults with mental illnesses (N=4,484). Follow up data were available for 2,579 participants. A hierarchical linear regression assessed the incremental validity of a series of variable clusters in the prediction of violence risk at six months: static characteristics (age, sex, race ethnicity, and primary diagnosis), substance use (alcohol use and drug use at baseline), clinical functioning (psychiatric symptoms at baseline and recent hospitalization), recent violence, and recent victimization. RESULTS: Results demonstrated improved prediction with each step of the model, indicating that proximal indicators contributed to the prediction of short-term community violence above and beyond static characteristics. When all variables were entered, current alcohol use, recent violence, and recent victimization were positive predictors of subsequent violence, even after the analysis controlled for participant characteristics. CONCLUSIONS: This study provides empirical evidence for three proximal, clinically relevant indicators in the assessment and management of short-term violence risk among adults with mental illnesses: current alcohol use, recent violence, and recent victimization. Consideration of these indicators in clinical practice may assist in the identification of adults with mental illnesses who are at heightened risk of short-term community violence. PMID- 26927581 TI - Implementing the Collaborative Care Model as Part of a Countywide Initiative. AB - This column describes the planning and implementation of an integrated behavioral health project which was facilitated and endorsed by a developing accountable health community, the Washtenaw Health Initiative (WHI). The WHI is a voluntary countywide coalition of academic, community, health system, and county government agencies dedicated to improving access to high-quality health care for low income, uninsured, and Medicaid populations. When lack of access to mental health services was identified as a pressing concern, the WHI endorsed pilot testing of collaborative care, an evidence-based treatment model, in county safety-net clinics. Challenges, outcomes, and relevance of this initiative to other counties or regional entities are discussed. PMID- 26927582 TI - Malaria: fluid therapy in severe disease. AB - INTRODUCTION: Severe malaria mainly affects children aged under 5 years, non immune travellers, migrants to malarial areas, and people living in areas with unstable or seasonal malaria. Cerebral malaria, causing encephalopathy and coma, is fatal in around 20% of children and adults, and may lead to neurological sequelae in survivors. Severe malarial anaemia may have a mortality rate of over 13%. The role of fluid resuscitation in severe malaria is complex and controversial. Volume expansion could help to improve impaired organ perfusion and correct metabolic acidosis. However, rapid volume expansion could aggravate intracranial hypertension associated with cerebral malaria, leading to an increased risk of cerebral herniation. METHODS AND OUTCOMES: We conducted a systematic overview, aiming to answer the following clinical question: What is the optimal method of fluid resuscitation in patients with severe malaria? We searched: Medline, Embase, The Cochrane Library, and other important databases up to December 2014 (Clinical Evidence overviews are updated periodically; please check our website for the most up-to-date version of this overview). RESULTS: At this update, searching of electronic databases retrieved 187 studies. After deduplication and removal of conference abstracts, 93 records were screened for inclusion in the overview. Appraisal of titles and abstracts led to the exclusion of 82 studies and the further review of 11 full publications. Of the 11 full articles evaluated, two systematic reviews and three RCTs were added at this update. We performed a GRADE evaluation for seven PICO combinations. CONCLUSIONS: In this systematic overview, we categorised the efficacy for three interventions based on information about the effectiveness and safety of human albumin, intravenous fluids, and whole blood or plasma. PMID- 26927583 TI - Estimating covariate-adjusted measures of diagnostic accuracy based on pooled biomarker assessments. AB - There is a need for epidemiological and medical researchers to identify new biomarkers (biological markers) that are useful in determining exposure levels and/or for the purposes of disease detection. Often this process is stunted by high testing costs associated with evaluating new biomarkers. Traditionally, biomarker assessments are individually tested within a target population. Pooling has been proposed to help alleviate the testing costs, where pools are formed by combining several individual specimens. Methods for using pooled biomarker assessments to estimate discriminatory ability have been developed. However, all these procedures have failed to acknowledge confounding factors. In this paper, we propose a regression methodology based on pooled biomarker measurements that allow the assessment of the discriminatory ability of a biomarker of interest. In particular, we develop covariate-adjusted estimators of the receiver-operating characteristic curve, the area under the curve, and Youden's index. We establish the asymptotic properties of these estimators and develop inferential techniques that allow one to assess whether a biomarker is a good discriminator between cases and controls, while controlling for confounders. The finite sample performance of the proposed methodology is illustrated through simulation. We apply our methods to analyze myocardial infarction (MI) data, with the goal of determining whether the pro-inflammatory cytokine interleukin-6 is a good predictor of MI after controlling for the subjects' cholesterol levels. PMID- 26927584 TI - Spanish version of SPADI (shoulder pain and disability index) in musculoskeletal shoulder pain: a new 10-items version after confirmatory factor analysis. AB - BACKGROUND: The Shoulder Pain and Disability Index (SPADI) is a tool designed to evaluate the impact of shoulder pathology. The aim of this study was to cross culturally adapt a Spanish version of the SPADI for Spanish population with a musculoskeletal shoulder pain, and to determine the psychometric properties of this instrument using confirmatory factor analysis (CFA). METHODS: Cross-cultural adaptation was performed according to the international guidelines. To assess factor structure, a confirmatory factor analysis was done. Internal consistency was measured using Cronbach's alpha. Item-total and inter-item correlations were assessed. Pearson and Spearman correlations were calculated to assess the convergent validity between SPADI and quick-DASH. RESULTS: A new Spanish version of SPADI was achieved. The original SPADI factor structure was tested by CFA, obtaining a poor fit: relative chi-square (chi2/df) 3.16, CFI 0.89, NFI 0.92, and RMSEA 0.10 (90 % CI 0.08 to 0.12). An additional model was tested, after deleting items which have had a poor adjustment in the model (1, 11, and 12), obtaining the best fit: relative chi-square (chi2/df) of 1.94, CFI 0.98, NFI 0.95, GFI 0,95, and RMSEA 0.06 (90 % CI 0.04 to 0.09). The analysis confirmed the bidimensional structure (pain and disability subscales). A correlation Spearman's Rho coefficient of 0.752 (p < 0.0001) and a Cronbach's alpha of 0.90 were obtained. CONCLUSIONS: This study validated a new 10-items version of SPADI for Spanish population with musculoskeletal shoulder pain providing a patient reported outcome measure that could be used in both clinical practice and research. PMID- 26927585 TI - Non-physician Clinicians in Sub-Saharan Africa and the Evolving Role of Physicians. AB - Responding to critical shortages of physicians, most sub-Saharan countries have scaled up training of non-physician clinicians (NPCs), resulting in a gradual but decisive shift to NPCs as the cornerstone of healthcare delivery. This development should unfold in parallel with strategic rethinking about the role of physicians and with innovations in physician education and in-service training. In important ways, a growing number of NPCs only renders physicians more necessary - for example, as specialized healthcare providers and as leaders, managers, mentors, and public health administrators. Physicians in sub-Saharan Africa ought to be trained in all of these capacities. This evolution in the role of physicians may also help address known challenges to the successful integration of NPCs in the health system. PMID- 26927586 TI - Preferred Primary Healthcare Provider Choice Among Insured Persons in Ashanti Region, Ghana. AB - BACKGROUND: In early 2012, National Health Insurance Scheme (NHIS) members in Ashanti Region were allowed to choose their own primary healthcare providers. This paper investigates the factors that enrolees in the Ashanti Region considered in choosing preferred primary healthcare providers (PPPs) and direction of association of such factors with the choice of PPP. METHODS: Using a cross-sectional study design, the study sampled 600 NHIS enrolees in Kumasi Metro area and Kwabre East district. The sampling methods were a combination of simple random and systematic sampling techniques at different stages. Descriptive statistics were used to analyse demographic information and the criteria for selecting PPP. Multinomial logistic regression technique was used to ascertain the direction of association of the factors and the choice of PPP using mission PPPs as the base outcome. RESULTS: Out of the 600 questionnaires administered, 496 were retained for further analysis. The results show that availability of essential drugs (53.63%) and doctors (39.92%), distance or proximity (49.60%), provider reputation (39.52%), waiting time (39.92), additional charges (37.10%), and recommendations (48.79%) were the main criteria adopted by enrolees in selecting PPPs. In the regression, income (-0.0027), availability of doctors ( 1.82), additional charges (-2.14) and reputation (-2.09) were statistically significant at 1% in influencing the choice of government PPPs. On the part of private PPPs, availability of drugs (2.59), waiting time (1.45), residence ( 2.62), gender (-2.89), and reputation (-2.69) were statistically significant at 1% level. Presence of additional charges (-1.29) was statistically significant at 5% level. CONCLUSION: Enrolees select their PPPs based on such factors as availability of doctors and essential drugs, reputation, waiting time, income, and their residence. Based on these findings, there is the need for healthcare providers to improve on their quality levels by ensuring constant availability of essential drugs, doctors, and shorter waiting time. However, individual enrolees may value each criterion differently. Thus, not all enrolees may be motivated by same concerns. This requires providers to be circumspect regarding the factors that may attract enrolees. The National Health Insurance Authority (NHIA) should also ensure timely release of funds to help providers procure the necessary medical supplies to ensure quality service. PMID- 26927587 TI - Improving Fraud and Abuse Detection in General Physician Claims: A Data Mining Study. AB - BACKGROUND: We aimed to identify the indicators of healthcare fraud and abuse in general physicians' drug prescription claims, and to identify a subset of general physicians that were more likely to have committed fraud and abuse. METHODS: We applied data mining approach to a major health insurance organization dataset of private sector general physicians' prescription claims. It involved 5 steps: clarifying the nature of the problem and objectives, data preparation, indicator identification and selection, cluster analysis to identify suspect physicians, and discriminant analysis to assess the validity of the clustering approach. RESULTS: Thirteen indicators were developed in total. Over half of the general physicians (54%) were 'suspects' of conducting abusive behavior. The results also identified 2% of physicians as suspects of fraud. Discriminant analysis suggested that the indicators demonstrated adequate performance in the detection of physicians who were suspect of perpetrating fraud (98%) and abuse (85%) in a new sample of data. CONCLUSION: Our data mining approach will help health insurance organizations in low-and middle-income countries (LMICs) in streamlining auditing approaches towards the suspect groups rather than routine auditing of all physicians. PMID- 26927588 TI - Decentralisation of Health Services in Fiji: A Decision Space Analysis. AB - BACKGROUND: Decentralisation aims to bring services closer to the community and has been advocated in the health sector to improve quality, access and equity, and to empower local agencies, increase innovation and efficiency and bring healthcare and decision-making as close as possible to where people live and work. Fiji has attempted two approaches to decentralisation. The current approach reflects a model of deconcentration of outpatient services from the tertiary level hospital to the peripheral health centres in the Suva subdivision. METHODS: Using a modified decision space approach developed by Bossert, this study measures decision space created in five broad categories (finance, service organisation, human resources, access rules, and governance rules) within the decentralised services. RESULTS: Fiji's centrally managed historical-based allocation of financial resources and management of human resources resulted in no decision space for decentralised agents. Narrow decision space was created in the service organisation category where, with limited decision space created over access rules, Fiji has seen greater usage of its decentralised health centres. There remains limited decision space in governance. CONCLUSION: The current wave of decentralisation reveals that, whilst the workload has shifted from the tertiary hospital to the peripheral health centres, it has been accompanied by limited transfer of administrative authority, suggesting that Fiji's deconcentration reflects the transfer of workload only with decision-making in the five functional areas remaining largely centralised. As such, the benefits of decentralisation for users and providers are likely to be limited. PMID- 26927589 TI - Health Insecurity and Social Protection: Pathways, Gaps, and Their Implications on Health Outcomes and Poverty. AB - Health insecurity has emerged as a major concern among health policy-makers particularly in low- and middle-income countries (LMICs). It includes the inability to secure adequate healthcare today and the risk of being unable to do so in the future as well as impoverishing healthcare expenditure. The increasing health insecurity among 150 million of the world's poor has moved social protection in health (SPH) to the top of the agenda among health policy-makers globally. This paper aims to provide a debate on the potential of social protection contribution to addressing health insecurity, poverty, and vulnerability brought by healthcare expenditure in low-income countries, to explore the gaps in current and proposed social protection measures in healthcare and provide suggestions on how social protection intervention aimed at addressing health insecurity, poverty, and vulnerability may be effectively implemented. PMID- 26927590 TI - Whistleblowing: Don't Encourage It, Prevent It Comment on "Cultures of Silence and Cultures of Voice: The Role of Whistleblowing in Healthcare Organisations". AB - In a recent article, Mannion and Davies argue that there are a multitude of ways in which organizations (such as the National Health Service [NHS]) can deal with wrongdoing or ethical problems, including the formation of policies that encourage and protect would-be whistleblowers. However, it is important to distinguish internal reporting about wrongdoing from whistleblowing proper, because the two are morally quite different and should not be dealt with in the same way. This article argues that we should not understand the authors' conclusions to apply to "whistleblowing" proper, because their recommended approach would be both unfeasible and undesirable for addressing whistleblowing defined in this way. PMID- 26927591 TI - Policies and Processes for Social Inclusion: Using EquiFrame and EquIPP for Policy Dialogue Comment on "Are Sexual and Reproductive Health Policies Designed for All? Vulnerable Groups in Policy Documents of Four European Countries and Their Involvement in Policy Development". AB - The application of EquiFrame in the analysis of sexual and reproductive health policies by Ivanova et al to a new thematic area, their selection of only some of the Core Concepts of human rights in health service provision and the addition of new vulnerable groups relevant to the purpose of their analysis, are all very welcome developments. We also applaud their application of EquiFrame to policies in countries where it has not previously been used, along with their use of interviews with policy-makers to produce a deeper understanding of policy processes. We argue that clear justification for the inclusion of additional, or replacement of some exiting vulnerable groups within EquiFrame should be accompanied by clear definitions of such groups, along with the evidence-base that justifies their classification as a vulnerable or marginalised group. To illustrate the versatility of EquiFrame, we summarise a range of ways in which it has been used across a number of regions; including a brief Case Study of its use to develop the National Health Policy of Malawi. While EquiFrame focuses on policy content, we preview a new policy analysis tool - Equity and Inclusion in Policy Processes (EquIPP) - which assesses the extent of equity and inclusion in broader policy processes. Together, EquiFrame and EquIPP can be used to help governments and civil society ensure that policies are addressing the much stronger emphasis on social inclusion, now apparent in the Sustainable Development Goals (SDGs). PMID- 26927592 TI - The Ghost Is the Machine: How Can We Visibilize the Unseen Norms and Power of Global Health? Comment on "Navigating Between Stealth Advocacy and Unconscious Dogmatism: The Challenge of Researching the Norms, Politics and Power of Global Health". AB - In his recent commentary, Gorik Ooms argues that "denying that researchers, like all humans, have personal opinions ... drives researchers' personal opinion underground, turning global health science into unconscious dogmatism or stealth advocacy, avoiding the crucial debate about the politics and underlying normative premises of global health." These 'unconscious' dimensions of global health are as Ooms and others suggest, rooted in its unacknowledged normative, political and power aspects. But why would these aspects be either unconscious or unacknowledged? In this commentary, I argue that the 'unconscious' and 'unacknowledged' nature of the norms, politics and power that drive global health is a direct byproduct of the processes through which power operates, and a primary mechanism by which power sustains and reinforces itself. To identify what is unconscious and unacknowledged requires more than broadening the disciplinary base of global health research to those social sciences with deep traditions of thought in the domains of power, politics and norms, albeit that doing so is a fundamental first step. I argue that it also requires individual and institutional commitments to adopt reflexive, humble and above all else, equitable practices within global health research. PMID- 26927593 TI - Politics or Technocracy - What Next for Global Health? Comment on "Navigating Between Stealth Advocacy and Unconscious Dogmatism: The Challenge of Researching the Norms, Politics and Power of Global Health". AB - Politics play a central part in determining health and development outcomes as Gorik Ooms highlights in his recent commentary. As health becomes more global and more politicized the need grows to better understand the inherently political processes at all levels of governance, such as ideological positions, ideas, value judgments, and power. I agree that global health research should strengthen its contribution to generating such knowledge by drawing more on political science, such research is gaining ground. Even more important is - as Ooms indicates - that global health scholars better understand their own role in the political process. It is time to acknowledge that expert-based technocratic approaches are no less political. We will need to reflect and analyse the role of experts in global health governance to a greater extent and in that context explore the links between politics, expertise and democracy. PMID- 26927594 TI - How Can a Global Social Support System Hope to Achieve Fairer Competiveness? Comment on "A Global Social Support System: What the International Community Could Learn From the United States' National Basketball Association". AB - Ooms et al sets out some good general principles for a global social support system to improve fairer global competitiveness as a result of redistribution. This commentary sets out to summarize some of the conditions that would need to be satisfied for it to level up gradients in inequality through such a social support system, using the National Basketball Association (NBA) example as a point of reference. From this, the minimal conditions are described that would be required for the support system, proposed in the article by Ooms et al, to succeed. PMID- 26927595 TI - Global Health Warning: Definitions Wield Power Comment on "Navigating Between Stealth Advocacy and Unconscious Dogmatism: The Challenge of Researching the Norms, Politics and Power of Global Health". AB - Gorik Ooms recently made a strong case for considering the centrality of normative premises to analyzing and understanding the underappreciated importance of the nexus of politics, power and process in global health. This critical commentary raises serious questions for the practice and study of global health and global health governance. First and foremost, this commentary underlines the importance of the question of what is global health, and why as well as how does this definition matter? This refocuses discussion on the importance of definitions and how they wield power. It also re-affirms the necessity of a deeper analysis and understanding of power and how it affects and shapes the practice of global health. PMID- 26927596 TI - Single Versus Multi-Faceted Implementation Strategies - Is There a Simple Answer to a Complex Question? A Response to Recent Commentaries and a Call to Action for Implementation Practitioners and Researchers. PMID- 26927597 TI - Future Challenges and Opportunities in Online Prescription Drug Promotion Research Comment on "Trouble Spots in Online Direct-to-Consumer Prescription Drug Promotion: A Content Analysis of FDA Warning Letters". AB - Despite increased availability of online promotional tools for prescription drug marketers, evidence on online prescription drug promotion is far from settled or conclusive. We highlight ways in which online prescription drug promotion is similar to conventional broadcast and print advertising and ways in which it differs. We also highlight five key areas for future research: branded drug website influence on consumer knowledge and behavior, interactive features on branded drug websites, mobile viewing of branded websites and mobile advertisements, online promotion and non-US audiences, and social media and medication decisions. PMID- 26927598 TI - The Pill Really Can Be Mightier Than the Sword: A Response to Recent Commentaries. AB - We appreciate the four commentaries that add new material and fresh perspectives to our article "The pill is mightier than the sword." In emphasizing the role of voluntary family planning and girls' education as achievable strategies with a potential to make the world a more peaceable place, we did not mean to oversimplify or disregard the intrinsic complexity of human conflict. On the whole, the commentators support and add to our thesis, although we question Pillai and Ya-Chien Wang's suggestion that we may have overstated the unique human predisposition to kill our own species. We present additional data on male team aggression. PMID- 26927599 TI - Verrucous lichen planus following contact sensitivity to implanted gentamicin polymethylmethacrylate bead chains. PMID- 26927600 TI - Cross-Sectional Associations of Computed Tomography (CT)-Derived Adipose Tissue Density and Adipokines: The Framingham Heart Study. AB - BACKGROUND: Excess accumulation of abdominal subcutaneous (SAT) and visceral adipose tissue (VAT) is associated with adverse levels of adipokines and cardiovascular disease risk. Whether fat quality is associated with adipokines has not been firmly established. This study examined the association between abdominal SAT and VAT density, an indirect measure of fat quality, with a panel of metabolic regulatory biomarkers secreted by adipose tissue or the liver independently of absolute fat volumes. METHODS AND RESULTS: We evaluated 1829 Framingham Heart Study participants (44.9% women). Abdominal SAT and VAT density was estimated indirectly by adipose tissue attenuation using computed tomography. Adipokines included adiponectin, leptin receptor, leptin, fatty acid-binding protein 4 (FABP-4), retinol-binding protein 4 (RBP-4), and fetuin-A. Fat density was associated with all the biomarkers evaluated, except fetuin-A. Lower fat density (ie, more-negative fat attenuation) was associated with lower adiponectin and leptin receptor, but higher leptin and FABP-4 levels (all P<0.0001). SAT density was inversely associated with RPB-4 in both sexes, whereas the association between VAT density and RPB-4 was only observed in men (P<0.0001). In women, after additional adjustment for respective fat volume, SAT density retained the significant associations with adiponectin, leptin, FABP-4, and RBP 4; and VAT density with adiponectin only (all P<0.0001). In men, significant associations were maintained upon additional adjustment for respective fat volume (P<0.005). CONCLUSIONS: Lower abdominal fat density was associated with a profile of biomarkers suggestive of greater cardiometabolic risk. These observations support that fat density may be a valid biomarker of cardiometabolic risk. PMID- 26927601 TI - International prospective study of distal intestinal obstruction syndrome in cystic fibrosis: Associated factors and outcome. AB - BACKGROUND: Distal intestinal obstruction syndrome (DIOS) is a specific complication of cystic fibrosis. METHODS: A study was performed in 10 countries to prospectively evaluate the incidence, associated factors, and treatment modalities in children and adults. RESULTS: 102 patients presented 112 episodes. The incidence of DIOS was similar in children and adults. Medical treatment failed only in cases of complete DIOS (11%). Children with meconium ileus had a higher rate of surgery for DIOS (15% vs. 2%, p=0.02). Complete DIOS entailed longer hospitalisation (4 [3; 7] days vs. 3 [1; 4], p=0.002). Delayed arrival at hospital and prior weight loss had a significant impact on the time needed for DIOS resolution. Associated CF co-morbidities for DIOS included meconium ileus (40% vs. 18%, p<0.0001), exocrine pancreatic insufficiency (92% vs. 84%, p=0.03), liver disease (22% vs. 12%, p=0.004), diabetes mellitus (49% vs. 25%, p=0.0003), and Pseudomonas aeruginosa (68% vs. 52%, p=0.01); low fibre intake and insufficient hydration were frequently observed. Female gender was associated with recurrent DIOS (75% vs. 52%, p=0.04), constipation with incomplete episodes (39% vs. 11%, p=0.03), and poor patient compliance in taking pancreatic enzyme therapy during complete episodes (25% vs. 3%, p=0.02). CONCLUSION: DIOS is a multifactorial condition having a similar incidence in children and adults. We show that delayed arrival at hospital after the initial symptoms causes significant morbidity. Early recognition and treatment would improve the prognosis. PMID- 26927602 TI - Bilateral midshaft femoral fractures in an adolescent baseball player. AB - Bone disease, specifically low bone mineral density, is a common and undertreated complication that begins during childhood in patients with cystic fibrosis (CF). This case describes a male baseball player, aged 14years, with undiagnosed CF who sustained a left midshaft femoral fracture while running toward base; 8months later, he sustained a right midshaft femoral fracture under similar conditions. After the second fracture, further evaluation revealed low bone mineral density and CF. There is no previously published report of pathologic fractures occurring in the femoral shaft in an athlete with undiagnosed CF. Patients with CF have a higher fracture rate. Low-energy fractures of major bones in athletically active individuals should be viewed with suspicion for an underlying process. PMID- 26927603 TI - A case which further refines the critical region for 15q25.2 microduplication phenotypes. PMID- 26927604 TI - Anterior spinal artery aneurysm in a case of Moyamoya disease. PMID- 26927605 TI - Phospholipid and Hydrocarbon Interactions with a Charged Electrode Interface. AB - Using a combination of molecular dynamics simulations and experiments we examined the interactions of alkanes and phospholipids at charged interfaces in order to understand how interfacial charge densities affect the association of these two representative molecules with electrodes. Consistent with theory and experiment, these model systems reveal interfacial associations mediated through a combination of Coulombic and van der Waals forces. van der Waals forces, in particular, mediate rapid binding of decane to neutral electrodes. No decane binding was observed at high surface charge densities because of interfacial water polarization, which screens hydrophobic attractions. The positively charged choline moiety of the phospholipid palmitoyloleoylphosphatidylcholine (POPC) is primarily responsible for POPC attraction by a moderately negatively charged electrode. The hydrocarbon tails of POPC interact with the hydrophobic electrode interface similarly to decane. Previously reported electrochemical results confirm these findings by demonstrating bipolar displacement currents from PC vesicles adhering to moderately negatively charged interfaces, originating from the choline interactions observed in simulations. At more negatively charged interfaces, choline-to-surface binding was stronger. In both simulations and experiments the maximal interaction of anionic PS occurs with a positively charged interface, provided that the electrostatic forces outweigh local Lennard Jones interactions. Direct comparisons between the binding affinities measured in experiments and those obtained in simulations reveal previously unobserved atomic interactions that facilitate lipid vesicle adhesion to charged interfaces. Moreover, the implementation of a charged interface in molecular dynamics simulations provides an alternative method for the generation of large electric fields across phospholipid bilayers, especially for systems with periodic boundary conditions, and may be useful for simulations of membrane electropermeabilization. PMID- 26927606 TI - The Index of Microcirculatory Resistance as a Predictor of Echocardiographic Left Ventricular Performance Recovery in Patients With ST-Elevation Acute Myocardial Infarction Undergoing Successful Primary Angioplasty. AB - BACKGROUND: This study aims to evaluate the relationship between IMR (Index of Microcirculatory Resistance) and the echocardiographic evolution of left ventricular (LV) systolic and diastolic performance after ST-elevation acute myocardial infarction (STEMI), undergoing primary angioplasty (P-PCI). METHODS: IMR was evaluated immediately after P-PCI. Echocardiograms were performed within the first 24 hours (Echo1) and at 3 months (Echo2): LV volumes, ejection fraction (LVEF), wall motion score index (WMSI), E/e ratio, global longitudinal strain (GLS), and left atrial volume were measured. RESULTS: Forty STEMI patients were divided in 2 groups according to median IMR: Group 1 (IMR < 26), with less microvascular dysfunction, and Group 2 (IMR > = 26), with more microvascular dysfunction. In Echo1 GLS was significantly better in Group 1 (-14.9 vs. -12.9 in Group 2, P = 0.005). However, there were no significant differences between the two groups in LV systolic volume, LVEF and WMS. Between Echo1 and Echo2, there were significant improvements in LVEF (0.48 +/- 0.06 vs. 0.55 +/- 0.06, P < 0.0001), GLS (-14.9 +/- 1.3 vs. -17.3 +/- 7.6, P = 0.001), and E/e ratio (9.3 +/- 3.4 vs. 8.2 +/- 2.0, P = 0.037) in Group 1, but not in Group 2: LVEF (0.49 +/- 0.06 vs. 0.50 +/- 0.05, P = 0.47), GLS (-12.9 +/- 2.4 vs. -14.4 +/- 3.2, P = 0.052), and E/e ratio (8.8 +/- 2.4 vs. 10.0 +/- 4.7, P = 0.18). WMSI improved significantly more in Group 1 (reduction of -17.1% vs. -6.8% in Group 2, P = 0.015). CONCLUSION: Lower IMR was associated with better myocardial GLS acutely after STEMI, and with a significantly higher recovery of the LVEF, WMSI, E/E' ratio and GLS, suggesting that IMR is an early marker of cardiac recovery, after acute myocardial infarction. PMID- 26927607 TI - A Scoping Review of Behavioral Weight Management Interventions in Overweight/Obese African American Females. AB - African American females are adversely affected by overweight and obesity and accompanying physical, psychosocial, and economic consequences. Behavioral weight management interventions are less effective in addressing the needs of overweight and obese African American females. The objective of this scoping review was to explore weight management research in this population to identify key concepts, gaps in the literature, and implications for future research. Analyses revealed a broad array in purpose, theoretical frameworks, settings, study designs, interventions, intervention strategies, and outcome variables, making comparison difficult. Many of the articles included in this review did not provide a rich description of methods, which hinder their use in the development of future studies. Consistent application of a combined theory may address the gaps identified in this review by providing a reliable method for assessing needs, developing interventions, and evaluating the effectiveness and fidelity of behavioral weight management interventions in overweight and obese African American females. PMID- 26927609 TI - Strong orbital interaction in a weak CH-pi hydrogen bonding system. AB - For the first time, the intermolecular orbital interaction between benzene and methane in the benzene-methane complex, a representative of weak interaction system, has been studied by us using ab initio calculations based on different methods and basis sets. Our results demonstrate obvious intermolecular orbital interaction between benzene and methane involving orbital overlaps including both occupied and unoccupied orbitals. Similar to interatomic orbital interaction, the intermolecular interaction of orbitals forms "bonding" and "antibonding" orbitals. In the interaction between occupied orbitals, the total energy of the complex increases because of the occupation of the antibonding orbital. The existence of the CH-pi hydrogen bond between benzene and methane causes a decrease in rest energy level, leading to at least -1.51 kcal/mol intermolecular interaction energy. Our finding extends the concept of orbital interaction from the intramolecular to the intermolecular regime and gives a reliable explanation of the deep orbital reformation in the benzene-methane complex. PMID- 26927608 TI - Perioperative blood management programme reduces the use of allogenic blood transfusion in patients undergoing total hip and knee arthroplasty. AB - BACKGROUND: Optimisation of blood management in total hip (THA) and knee arthroplasty (TKA) is associated with improved patient outcomes. This study aimed to establish the effectiveness of a perioperative blood management programme in improving postoperative haemoglobin (Hb) and reducing the rate of allogenic blood transfusion. METHODS: This retrospective before and after study involves 200 consecutive patients undergoing elective TKA and THA before (Usual Care group) and after (Intervention group) the introduction of a blood management programme in an Australian teaching hospital. Patients in the Intervention group underwent preoperative treatment for anaemia and received intraoperative tranexamic acid (15 mg/kg). The primary outcomes were to compare postoperative Hb levels and the rate of blood transfusion. Secondary outcomes included measurements of total amount of allogenic blood transfused, transfusion-related complications, postoperative complications, need for inpatient rehabilitation and duration of hospital stay. RESULTS: There were no differences between baseline characteristics between groups. The mean (SD) preoperative Hb was higher in the Intervention group compared to that in the Usual Care group: 138.7 (13.9) vs. 133.4 (13.9) g/L, p = 0.008, respectively. The postoperative day 1 Hb, lowest postoperative Hb and discharge Hb were all higher in the Intervention group (p < 0.001). Blood transfusion requirements were lower in the Intervention group compared to the Usual Care group (6 vs. 20 %, p = 0.003). There were no differences in any of the secondary outcomes measured. Patients who were anaemic preoperatively and who underwent Hb optimisation had higher Hb levels postoperatively (odds ratio 5.7; 95 % CI 1.3 to 26.5; p = 0.024). CONCLUSIONS: The introduction of a perioperative blood optimisation programme improved postoperative Hb levels and reduced the rate of allogenic blood transfusion. PMID- 26927610 TI - A Wiskott-Aldrich syndrome protein is involved in endocytosis in Aspergillus nidulans. AB - Endocytosis is vital for hyphal tip growth in filamentous fungi and is involved in the tip localization of various membrane proteins. To investigate the function of a Wiskott-Aldrich syndrome protein (WASP) in endocytosis of filamentous fungi, we identified a WASP ortholog-encoding gene, wspA, in Aspergillus nidulans and characterized it. The wspA product, WspA, localized to the tips of germ tubes during germination and actin rings in the subapical regions of mature hyphae. wspA is essential for the growth and functioned in the polarity establishment and maintenance during germination of conidia. We also investigated its function in endocytosis and revealed that endocytosis of SynA, a synaptobrevin ortholog that is known to be endocytosed at the subapical regions of hyphal tips in A. nidulans, did not occur when wspA expression was repressed. These results suggest that WspA plays roles in endocytosis at hyphal tips and polarity establishment during germination. PMID- 26927612 TI - Bag and loop small bowel contouring strategies differentially estimate small bowel dose for post-hysterectomy women receiving pencil beam scanning proton therapy. AB - Background Small bowel (SB) dose-volume relationships established during initial computed tomography (CT) simulations may change throughout therapy due to organ displacement and motion. We investigated the impact of organ motion on SB dose volume histograms (DVHs) in women with gynecologic malignancies treated with pencil beam scanning (PBS) proton therapy and compared PBS SB DVHs to intensity modulated radiation therapy (IMRT). Material and methods Post-hysterectomy patients (n = 11) treated for gynecologic cancers were enrolled on an image guided proton therapy protocol involving CT simulation with full (CTF) and empty (CTE) bladders and weekly/biweekly on-treatment scans. IMRT plans were generated for comparative analysis. SB was contoured as bowel loops or bowel bag. Wilcoxon signed-rank tests were used for matched-pair comparisons of SB, bladder, and rectum dose-volumes between CT scans and between PBS and IMRT plans. Results In PBS loops analysis, on-treatment DVH was significantly higher than CTF for doses <45 Gy (p < 0.05), and not significantly different than CTE. Specifically, V15 for loops was higher on-treatment (median 240 cm(3)) compared to CTF (median 169 cm(3), p = 0.03). In PBS bag analysis, on-treatment DVH was not significantly different from CTF across all dose ranges. Bowel bag V45 was not significantly different between on-treatment (median 540 cm(3)) and CTF (median 499 cm(3), p = 0.53). Decreasing bladder volume was associated with increasing V15 for loops and V45 for bowel bag (p < 0.005, both). Comparing PBS and IMRT, PBS resulted in significantly lower DVHs at low dose regions (<38 Gy) and higher DVHs at high dose regions (42.5-45.5 Gy) in both loops and bag analysis. IMRT plans demonstrated higher on-treatment SB loop DVHs and only minimal differences in bowel bag DVHs compared to CTF. Conclusions SB DVHs were well estimated by CTF bowel bag and underestimated by CTF loops in the setting of inconsistent bladder filling. Verifying bladder filling prior to treatment or using CTE for planning may more conservatively estimate SB dose-volume relationships. PMID- 26927611 TI - Targeting constitutively active androgen receptor splice variants in castration resistant prostate cancer. PMID- 26927613 TI - In vitro and ex vivo antitubercular activity of diarylheptanoids from the rhizomes of Alpinia officinarum Hance. AB - Phytochemical investigation of methanol extract of the rhizomes of Alpinia officinarum Hance afforded four known diarylheptanoids 1,7-diphenylhept-4-en-3 one (1), 5-hydroxy-1,7-diphenyl-3-heptanone (2), 5-hydroxy-7-(4"-hydroxy-3" methoxyphenyl)-1-phenyl-3-heptanone (3), and 7-(4"-hydroxy-3"-methoxyphenyl)-1 phenyl heptan-3-one (4).The acetate derivative of (4), 7-(4"-actetate-3"-methoxy phenyl)-1-phenyl heptan-3-one (5), was prepared. These diarylheptanoids exhibited promising in vitro and ex vivo antitubercular activity for the first time against dormant Mycobacterium tuberculosis H37Ra with the IC50 values between 0.34-47.69 and 0.13-22.91 MUM, respectively. All compounds showed comparable activity against Mycobacterium bovis BCG (dormant phage) and did not show any activity against two gram + ve and two gram -ve bacterial strains. These compounds were also weakly cytotoxic up to 300 MUM against three human cancer cell lines THP-1, Panc-1 and A549. PMID- 26927614 TI - Curcumin-albumin conjugates as an effective anti-cancer agent with immunomodulatory properties. AB - Curcumin (diferuloylmethane) is an active ingredient in turmeric (Curcuma longa) with anti-inflammatory, antioxidant, chemopreventive, chemosensitization, and radiosensitization properties. Conjugation of curcumin (Curc) to albumin (Alb) has been found to increase the aqueous solubility of the drug. The current study aimed to prove the safe use of the Curc-Alb conjugate in animals and to demonstrate that it retains drug action both in vitro and in vivo. Dalton's lymphoma ascites (DLA) cell viability was inhibited by the Curc-Alb conjugate in a dose dependent manner in vitro, as evidenced by the MTT assay. Administration of up to 11.4 mg of conjugated curcumin per kg body weight to healthy animals was non-toxic both in terms of lethality and weight loss. Histological analysis of vital organs (kidney, liver and spleen) also did not show toxic effects. Favorable immuno-modulatory activity was observed after continuous administration of sub-acute doses of the conjugate which caused increase in total leukocyte count, platelet count, and viable cell count in bone marrow, and enhanced proliferation of lymphocyte in vitro upon culture. In vivo studies in the DLA tumor model in mice demonstrated that conjugated drug induces tumor reduction and prevention. Significant tumor reduction was observed when the Curc-Alb conjugate was administered intraperitoneally in DLA-induced mice after 1 day (prevention therapy) and 7 days (reduction therapy) of tumor induction. There was significant reduction in both tumor volume and tumor cell numbers in the treated animals as well as a marked increase in their mean survival time and percent increase in life span. The effect was greater when the conjugate was administered soon after inducing the tumor as compared to when treatment was started after allowing tumor to grow for 7 days. Thus, the results of the present study suggest that curcumin albumin conjugate has immunomodulatory and tumor growth inhibition properties. The study postulates the drug form has the potential to be used as an anticancer agent in affected human subjects. PMID- 26927615 TI - Effect of vitamin D3 on chemokine levels and regulatory T-cells in pulmonary tuberculosis. AB - 1,25-Dihydroxyvitamin D3 [1,25(OH)2D3] the active form of vitamin D3 acts as an immunomodulator in various immune cells. The present study is aimed to study the effect of 1,25(OH)2D3 on chemokine levels and regulatory T-cells in 51 healthy controls (HCs) and 50 pulmonary tuberculosis (PTB) patients. Peripheral blood mononuclear cells were cultured with culture filtrate antigen (CFA) of Mycobacterium tuberculosis in the presence or absence of 1,25(OH)2D3 at 10(-7) M concentration for 72 h and the percentage positive regulatory T-cell subsets were studied using flow cytometry. The chemokine levels were estimated in the culture supernatants by ELISA. 1,25(OH)2D3 significantly upregulated the frequency of regulatory T-cell subsets while suppressed the production of chemokine levels in CFA stimulated cultures of HCs and PTB patients (p<0.05). Correlation analysis revealed a significant negative correlation between CD4+Foxp3+ regulatory T-cells and MCP-1, MIP-1beta and IP-10 in CFA stimulated with 1,25(OH)2D3 treated cells (p<0.05). The results suggested that 1,25(OH)2D3 upregulated regulatory T-cells and act as anti-inflammatory by downregulating chemokine levels which could be beneficial to protect the host from inflammation and tissue damage during infection. PMID- 26927616 TI - Automatic molecular structure perception for the universal force field. AB - The Universal Force Field (UFF) is a classical force field applicable to almost all atom types of the periodic table. Such a flexibility makes this force field a potential good candidate for simulations involving a large spectrum of systems and, indeed, UFF has been applied to various families of molecules. Unfortunately, initializing UFF, that is, performing molecular structure perception to determine which parameters should be used to compute the UFF energy and forces, appears to be a difficult problem. Although many perception methods exist, they mostly focus on organic molecules, and are thus not well-adapted to the diversity of systems potentially considered with UFF. In this article, we propose an automatic perception method for initializing UFF that includes the identification of the system's connectivity, the assignment of bond orders as well as UFF atom types. This perception scheme is proposed as a self-contained UFF implementation integrated in a new module for the SAMSON software platform for computational nanoscience (http://www.samson-connect.net). We validate both the automatic perception method and the UFF implementation on a series of benchmarks. PMID- 26927617 TI - Importance of Amino Acids, Gln-119 and Tyr-376, in the S1 Pocket of Escherichia coli Peptidase N in Determining Substrate Specificity. AB - Peptidase N (PepN) is a broad specific metallo-peptidase and the sole member of the M1 class encoded by Escherichia coli. Comparative analysis of residues present in the S1 subsite of E. coli PepN with other family members revealed that Tyr-381 is conserved whereas Glu-121, Gln-119 and Tyr-376 are partially conserved. The functional importance of these amino acids was investigated by protein engineering studies. The change in Glu-121 to Gln and Tyr-381 to Phe led to catalytically inactive PepN. At the same time, the change in Gln-119 to His (Q119H) and Tyr-376 to Phe (Y376F) led to alterations in substrate specificity. Kinetic studies revealed that purified PepN variants, Q119H and Y376F, cleaved some substrates (e.g. Arg) similar to wild type PepN. However, these variants displayed lower efficacy with other substrates (e.g. Tyr, AAF and Suc-AAF). Q119H or Y376F, cleave a natural peptide (insulin B chain) and a loosely folded protein (casein) with greatly reduced efficacy. The double mutant, i.e. harboring both Q119H and Y376F, displays greatly reduced catalytic activity with respect to all substrates studied. The in vivo significance was addressed by expressing these variants in DeltapepN during nutritional downshift and high temperature (NDHT) stress. Compared to wild type PepN, the Y376F and Q119H variants display lower intracellular amounts of free N-terminal amino acids and reduction in growth during NDHT stress. Finally, structural modeling, using the crystal structure of E. coli PepN bound to substrates, Arg or Tyr, shed insights into the roles of Q119H and Y376F in determining substrate preferences. PMID- 26927618 TI - Ferroelectric/Dielectric Double Gate Insulator Spin-Coated Using Barium Titanate Nanocrystals for an Indium Oxide Nanocrystal-Based Thin-Film Transistor. AB - Barium titanate nanocrystals (BT NCs) were prepared under solvothermal conditions at 200 degrees C for 24 h. The shape of the BT NCs was tuned from nanodot to nanocube upon changing the polarity of the alcohol solvent, varying the nanosize in the range of 14-22 nm. Oleic acid-passivated NCs showed good solubility in a nonpolar solvent. The effect of size and shape of the BT NCs on the ferroelectric properties was also studied. The maximum polarization value of 7.2 MUC/cm(2) was obtained for the BT-5 NC thin film. Dielectric measurements of the films showed comparable dielectric constant values of BT NCs over 1-100 kHz without significant loss. Furthermore, the bottom gate In2O3 NC thin film transistors exhibited outstanding device performance with a field-effect mobility of 11.1 cm(2) V(-1) s(-1) at a low applied gate voltage with BT-5 NC/SiO2 as the gate dielectric. The low-density trapped state was observed at the interface between the In2O3 NC semiconductor and the BT-5 NCs/SiO2 dielectric film. Furthermore, compensation of the applied gate field by an electric dipole-induced dipole field within the BT-5 NC film was also observed. PMID- 26927619 TI - Mental health improves after transition from comprehensive school to vocational education or employment in England: A national cohort study. AB - Underpinned by stage-environment fit and job demands-resources theories, this study examined how adolescents' anxiety, depressive symptoms, and positive functioning developed as they transferred from comprehensive school to further education, employment or training, or became NEET (not in education, employment, or training), at age 16 years, in the longitudinal English national cohort study Next Steps (N = 13,342). Controlling for childhood achievement, socioeconomic status, ethnicity, and gender, we found that NEET adolescents had the largest losses in mental health. This pattern was similar to adolescents staying on at school who had increased anxiety and depression, and decreased positive functioning, after transition. In comparison, adolescents transferring to full time work, apprenticeships, or vocational college experienced gains in mental health. PMID- 26927620 TI - Effect of Sulfated Chitooligosaccharides on Wheat Seedlings (Triticum aestivum L.) under Salt Stress. AB - In this study, sulfated chitooligosaccharide (SCOS) was applied to wheat seedlings to investigate its effect on the plants' defense response under salt stress. The antioxidant enzyme activities, chlorophyll contents, and fluorescence characters of wheat seedlings were determined at a certain time. The results showed that treatment with exogenous SCOS could decrease the content of malondialdehyde, increase the chlorophyll contents, and modulate fluorescence characters in wheat seedlings under salt stress. In addition, SCOS was able to regulate the activities of antioxidant enzymes containing superoxide dismutase, catalase, peroxidase, ascorbate peroxidase, glutathione reductase, and dehydroascorbate reductase. Similarly, the mRNA expression levels of several antioxidant enzymes were efficiently modulated by SCOS. The results indicated that SCOS could alleviate the damage of salt stress by adjusting the antioxidant enzyme activities of plant. The effect of SCOS on the photochemical efficiency of wheat seedlings was associated with its enhanced capacity for antioxidant enzymes, which prevented structure degradation of the photosynthetic apparatus under NaCl stress. Furthermore, the effective activities of alleviating salt stress indicated the activities of SCOS were closely related with the sulfate group. PMID- 26927621 TI - A scale-down mimic for mapping the process performance of centrifugation, depth and sterile filtration. AB - In the production of biopharmaceuticals disk-stack centrifugation is widely used as a harvest step for the removal of cells and cellular debris. Depth filters followed by sterile filters are often then employed to remove residual solids remaining in the centrate. Process development of centrifugation is usually conducted at pilot-scale so as to mimic the commercial scale equipment but this method requires large quantities of cell culture and significant levels of effort for successful characterization. A scale-down approach based upon the use of a shear device and a bench-top centrifuge has been extended in this work towards a preparative methodology that successfully predicts the performance of the continuous centrifuge and polishing filters. The use of this methodology allows the effects of cell culture conditions and large-scale centrifugal process parameters on subsequent filtration performance to be assessed at an early stage of process development where material availability is limited. Biotechnol. Bioeng. 2016;113: 1934-1941. (c) 2016 The Authors. Biotechnology and Bioengineering Published by Wiley Periodicals, Inc. PMID- 26927622 TI - Service Dogs in the Hospital: Helpful or Harmful? A Case Report and Clinical Recommendations. PMID- 26927623 TI - The Effect of Pretransplant Depression and Anxiety on Survival Following Lung Transplant: A Meta-analysis. AB - BACKGROUND: Current lung transplant allocation guidelines recommend considering psychological function when assessing candidacy despite limited data on whether patients with conditions, such as anxiety and depression, have reduced benefit from transplant because of decreased survival after transplant. OBJECTIVE: The aim of this article was to determine whether pretransplant depression and anxiety are associated with worse posttransplant survival. METHODS: We searched Medline, Journal Storage, and Embase for original articles that assessed the effect of pretransplant depression and anxiety on survival following lung transplant published up to November 2015. We calculated a summary estimate of hazard ratios for death using a random effects model. RESULTS: In total, 6 prospective longitudinal cohort studies were included in the meta-analysis, 4 of which used continuous scores on validated instruments to measure anxiety and depression. There were 711 patients of whom 345 (48.5%) died during the available follow-up time (mean = 7.8 years). Pretransplant anxiety and depression were not associated with posttransplant survival (hazard ratio = 1.009; 95% CI: 0.998-1.019). Heterogeneity was not detected (I(2) = 0.00%, Q = 5.87, p = 0.66) and the results did not differ whether anxiety or depression was treated as the exposure of interest. CONCLUSIONS: There is sufficient evidence to conclude that scores on indices of depression and anxiety pretransplant are not associated with worse survival following lung transplant. PMID- 26927624 TI - A New Methodology for Assessing Macromolecular Click Reactions and Its Application to Amine--Tertiary Isocyanate Coupling for Polymer Ligation. AB - Click reactions have provided access to an array of remarkably complex polymer architectures. However, the term "click" is often applied inaccurately to polymer ligation reactions that fail to respect the criteria that typify a true "click" reaction. With the purpose of providing a universal way to benchmark polymer polymer coupling efficiency at equimolarity and thus evaluate the fulfilment of click criteria, we report a simple one-pot methodology involving the homodicoupling of alpha-end-functionalized polymers using a small-molecule bifunctional linker. A combination of SEC analysis and chromatogram deconvolution enables straightforward quantification of the coupling efficiency. We subsequently employ this methodology to evaluate an overlooked candidate for the click reaction family: the addition of primary amines to alpha-tertiary isocyanates (alpha-(t)NCO). Using our bifunctional linker coupling strategy, we show that the amine-(t)NCO reaction fulfills the criteria for a polymer-polymer click reaction, achieving rapid, chemoselective, and quantitative coupling at room temperature without generating any byproducts. We demonstrate that amine (t)NCO coupling is faster and more efficient than the more common amine-tertiary active ester coupling under equivalent conditions. Additionally, we show that the alpha-(t)NCO end group is unprecedentedly stable in aqueous media. Thus, we propose that the amine-(t)NCO ligation is a powerful new click reaction for efficient macromolecular coupling. PMID- 26927625 TI - Indirect Standardization Matching: Assessing Specific Advantage and Risk Synergy. AB - OBJECTIVE: To develop a method to allow a hospital to compare its performance using its entire patient population to the outcomes of very similar patients treated elsewhere. DATA SOURCES/SETTING: Medicare claims in orthopedics and common general, gynecologic, and urologic surgery from Illinois, New York, and Texas from 2004 to 2006. STUDY DESIGN: Using two example "focal" hospitals, each hospital's patients were matched to 10 very similar patients selected from 619 other hospitals. DATA COLLECTION/EXTRACTION METHODS: All patients were used at each focal hospital, and we found the 10 closest matched patients from control hospitals with exactly the same principal procedure as each focal patient. PRINCIPAL FINDINGS: We achieved exact matches on all procedures and very close matches for other patient characteristics for both hospitals. There were few to no differences between each hospital's patients and their matched control patients on most patient characteristics, yet large and significant differences were observed for mortality, failure-to-rescue, and cost. CONCLUSION: Indirect standardization matching can produce fair audits of quality and cost, allowing for a comprehensive, transparent, and relevant assessment of all patients at a focal hospital. With this approach, hospitals will be better able to benchmark their performance and determine where quality improvement is most needed. PMID- 26927626 TI - Thrombospondin-1 levels correlate with macrophage activity and disease progression in dysferlin deficient mice. AB - Dysferlinopathy is associated with accumulation of thrombospondin (TSP)-1 and macrophages, both of which may contribute to the pathogenesis of the disease. The purpose of this study was to determine whether TSP-1 levels can predict macrophage activity and disease progression in dysferlin deficient BlaJ mice, focusing on the early disease process. In 3 month-old BlaJ mice, muscle TSP-1 levels exhibited strong positive correlations with both accumulation of F4/80hi macrophages and with their in vivo phagocytic activity in psoas muscles as measured by magnetic resonance imaging and flow cytometry. Muscle TSP-1 levels also exhibited a strong negative correlation with muscle mass and strong positive correlations with histological measurements of muscle fiber infiltration and regeneration. Over the course of disease progression from 3 to 12 months of age, muscle TSP-1 levels showed more complicated relationships with macrophage activity and an inverse relationship with muscle mass. Importantly, blood TSP-1 levels showed strong correlations with macrophage activity and muscle degeneration, particularly early in disease progression in BlaJ mice. These data indicate that TSP-1 may contribute to a destructive macrophage response in dysferlinopathy and pose the intriguing possibility that TSP-1 levels may serve as a biomarker for disease progression. PMID- 26927627 TI - Photophysics of GFP-related chromophores imposed by a scaffold design. AB - In this paper, a rigid scaffold imposes the photophysics of chromophores with a benzylidene imidazolidinone core by mimicking the beta-barrel structure of the green fluorescent protein (GFP) and its analogs. The designed artificial frameworks maintain fluorescence responses and, therefore, conformational rigidity of typically non-emissive GFP-related chromophores. To replicate a small weight percent of the chromophore inside the natural GFP, two synthetic approaches were utilized: coordinative immobilization and non-coordinative inclusion. Despite low chromophore loading in the rigid matrix, both approaches resulted in formation of photoluminescent hybrid materials. Furthermore, the rigid scaffold dictates chromophore fluorescence by replicating its behavior in solution or the solid state. The presented results open an avenue for utilization of rigid scaffolds in the engineering of materials with tunable photoluminescence profiles for a variety of practical applications. PMID- 26927628 TI - Physical fighting, fighting-related injuries and family affluence among Canadian youth. AB - BACKGROUND: Physical fighting is an assaultive behaviour that can lead to injury. Family affluence is a health determinant that can influence injury. This study examines the relationship between family affluence and two outcomes: physical fighting and fighting-related injury in Canadian adolescents. Three measurements were used to represent family affluence and assess whether these measures demonstrated different associations with these outcomes. METHODS: Canadian data from the 2009/2010 Health Behaviour in School-aged Children Study were used. It consists of a nationally representative sample of 26,078 grade 6-10 students. A subset analysis of 10,429 grade 9-10 students was conducted to account for additional confounders. Modified Poisson regression was used to compare the risk of physical fighting and fighting-related injury in youth from different levels of family affluence. Three indicators were used to represent family affluence: self-perceived affluence, a family affluence scale (FAS), and area-level average household income. RESULTS: The overall prevalence was 35.6% for physical fighting and 2.7% for fighting-related injuries. Both outcomes were more frequent in males than females. An inverse gradient was present where risk for both outcomes increased with decreasing levels of affluence irrespective of the affluence measurement. The self-perceived affluence variable showed a significantly stronger gradient in girls than boys for both outcomes. For both outcomes, FAS showed a similar inverse gradient within females, but a threshold effect in males where there was a strong effect in the low FAS group, but a null effect in the moderate FAS group. The area-level income variable presented a significantly higher likelihood for physical fighting only in females (p = 0.001-0.075). For fighting-related injury, none of the area-level income models showed significant risk estimates with the exception of the bivariate association where low income females were twice as likely to report a fighting-related injury compared to higher income groups (p = 0.030). Post hoc power calculations indicate that there was not sufficient power to detect injury effects associated with the area level income measure. CONCLUSION: It appears that a socioeconomic gradient exists where lower affluence is associated with a higher risk of reporting a physical fight and fighting-related injury irrespective of the measure used. While the patterns were generally the same with all three measurements, the strength of this gradient varied across measures. This demonstrates that each indicator may measure different aspects of affluence. Further analyses are needed to explore concepts and mechanisms underlying each affluence measure. PMID- 26927629 TI - Factors that may be influencing the rise in prescription testosterone replacement therapy in adult men: a qualitative study. AB - OBJECTIVE: To explore and describe the factors that may be influencing the rise of prescribing and use of testosterone replacement therapy (TRT) in adult men. DESIGN: A rapid qualitative research design using semi-structured interviews with providers and patients. SETTING: Ontario, Canada. PARTICIPANTS: Nine men who have used TRT (referred to as "patients"), and six primary care clinicians and seven specialists (collectively referred to as "providers") who prescribed or administered TRT. METHOD: Patients' and providers' perspectives were investigated through semi-structured interviews. A purposive sampling approach was used to recruit all participants. We conducted qualitative analysis using the framework approach for applied health research. MAIN FINDINGS: Participants perceived the following factors to have influenced TRT prescriptions and use in adult men: provider factors (diagnostic ambiguity of age-related hypogonadism and beliefs about appropriateness of TRT) and patient factors (access to information on TRT and drug seeking behavior). They perceived that these factors have perpetuated a rise in prescription in the absence of clear clinical guidelines and unclear research evidence on the safety and efficacy of TRT. CONCLUSION: The findings of this study highlight that much work still needs to be done to improve diagnostic accuracy and encourage appropriate TRT prescription in adult men. In addition, both patients and providers need more information about the risks and long-term effects of TRT in men. PMID- 26927631 TI - Midurethral sling: is there an optimal choice? AB - PURPOSE OF REVIEW: Midurethral slings (MUS) are the most common procedure performed for female stress urinary incontinence (SUI). Several variations have been introduced and evidence supporting the optimal approach for outcomes is necessary. RECENT FINDINGS: The bottom-up approach to the retropubic MUS may have higher subjective cure rates and lower rates of bladder puncture, voiding dysfunction, and vaginal extrusion compared to the top-bottom approach. Short term and medium-term cure after retropubic and transobturator approaches are similar, whereas the retropubic approach may have better outcomes in the long term. The transobturator approach, however, appears to be associated with less bladder puncture, vascular injury, and postoperative voiding dysfunction, albeit at the expense of greater groin pain. De-novo storage symptoms and impact on sexual function are similar. The single incision mini sling (SIMS) may offer similar cure rates as the transobturator approach, with lower rates of early postoperative pain. SIMS offers inferior cure rates compared with the retropubic MUS. SUMMARY: The bottom-up retropubic MUS may currently be the 'optimal' MUS procedure; however, the transobturator MUS should also be considered. Long-term results are currently emerging and detailed informed consent is required regardless of the approach. PMID- 26927630 TI - Underactive bladder in women: is there any evidence? AB - PURPOSE OF REVIEW: Underactive bladder (UAB) is a clinical symptom complex only recently gaining recognition as a clinical diagnosis. Lack of consensus agreement on a definition of UAB has limited its recognition and diagnosis in clinical practice. The purposes of this review are to: present existing definitions of UAB, review recent data regarding clinical and urodynamic diagnosis of the condition, and examine up-to-date hypotheses regarding its pathophysiology, with a focus on women. RECENT FINDINGS: The process to develop a consensus definition for UAB as a clinical symptom complex is ongoing. Symptoms associated with UAB, such as weak stream, straining to void, and history of urinary retention are well correlated to detrusor underactivity on urodynamics, which frequently develops in elderly women. In addition to aging, UAB may be the end stage of a variety of contributing pathologic conditions such as diabetes and ischemic disease. In some women, UAB may result from a progression from overactive bladder to UAB. SUMMARY: Existing evidence supports UAB in women as a symptom complex with a clinical and pathophysiologic profile distinguishable from other lower urinary tract associated clinical conditions. Consensus definitions of clinical and urodynamic diagnostic parameters will be essential to more widespread recognition of UAB. PMID- 26927632 TI - Is There Any Effect on Smell and Taste Functions with Levothyroxine Treatment in Subclinical Hypothyroidism? AB - Subclinical hypothyroidism has been accused for coronary heart disease, lipid metabolism disorders, neuropsychiatric disorders, infertility or pregnancy related problems with various strength of evidence. Currently there is insufficient knowledge about olfaction and taste functions in subclinical hypothyroidism. Aim of the present study is to investigate the degree of smell and taste dysfunction in patients with subclinical hypothyroidism. 28 subclinical hypothyroid patients, and 31 controls enrolled in the prospective study in Istanbul, Turkey. Subclinical hypothyroid patients were treated with L-thyroxine for 3 months. Psychophysiological olfactory testing was performed using odor dispensers similar to felt-tip pens ("Sniffin' Sticks", Burghart, Wedel, Germany). Taste function tests were made using "Taste Strips" (Burghart, Wedel, Germany) which are basically tastant adsorbed filter paper strip. Patients scored lower on psychophysical olfactory tests than controls (odor thresholds:8.1+/-1.0 vs 8.9+/-1.1, p = 0.007; odor discrimination:12.4+/-1.3 vs 13.1+/-0.9, p = 0.016; odor identification:13.1+/-0.9 vs 14.0+/-1.1, p = 0.001; TDI score: 33.8+/-2.4 vs 36.9+/-2.1, p = 0.001). In contrast, results from psychophysical gustatory tests showed only a decreased score for "bitter" in patients, but not for other tastes (5.9+/-1.8 vs 6.6+/-1.0, p = 0.045). Three month after onset of treatment olfactory test scores already indicated improvement (odor thresholds:8.1+/-1.0 vs 8.6+/-0.6, p<0.001; odor discrimination:12.4+/-1.31 vs 12.9+/-0.8, p = 0.011; odor identification:13.1+/-0.9 vs 13.9+/-0.8, p<0.001; TDI scores:33.8+/-2.4 vs 35.5+/-1.7, p<0.001) respectively. Taste functions did not differ between groups for sweet, salty and, sour tastes but bitter taste was improved after 3 months of thyroxin substitution (patients:5.9+/-1.8 vs 6.6+/-1.2, p = 0.045). Correlation of changes in smell and taste, with thyroid function test were also evaluated. TSH, fT4 were found have no correlation with smell and taste changes with treatment. However bitter taste found positively correlated with T3 with treatment(r: 0.445, p: 0.018). Subclinical hypothyroid patients exhibited a significantly decreased olfactory sensitivity; in addition, bitter taste was significantly affected. Most importantly, these deficits can be remedied on average within 3 months with adequate treatment. PMID- 26927633 TI - Effects of Different Doses of Levetiracetam on Aquaporin 4 Expression in Rats with Brain Edema Following Fluid Percussion Injury. AB - BACKGROUND This study was designed to investigate the effects of different doses of levetiracetam on aquaporin 4 (AQP4) expression in rats after fluid percussion injury. MATERIAL AND METHODS Sprague-Dawley rats were randomly divided into 4 groups: sham operation group, traumatic brain injury group, low-dose levetiracetam group, and high-dose levetiracetam group. Brain edema models were established by fluid percussion injury, and intervened by the administration of levetiracetam. Samples from the 4 groups were collected at 2, 6, 12, and 24 h, and at 3 and 7 days after injury. Histological observation was performed using hematoxylin-eosin staining and immunohistochemical staining. AQP4 and AQP4 mRNA expression was detected using Western blot assay and RT-PCR. Brain water content was measured by the dry-wet method. RESULTS Compared with the traumatic brain injury group, brain water content, AQP4 expression, and AQP4 mRNA expression were lower in the levetiracetam groups at each time point and the differences were statistically significant (P<0.05). The intervention effects of high-dose levetiracetam were more apparent. CONCLUSIONS Levetiracetam can lessen brain edema from fluid percussion injury by down-regulating AQP4 and AQP4 mRNA expression. There is a dose-effect relationship in the preventive effect of levetiracetam within a certain extent. PMID- 26927634 TI - Effect of breast feeding time on physiological, immunological and microbial parameters of weaned piglets in an intensive breeding farm. AB - The aim of this work was to study the long-lasting consequences of different weaning age on physiological, immunological and microbiological parameters of weaned piglets. Piglets were weaned at 14 days (14W) or 21 days (21W). Blood samples were taken for IgG and cortisol determination on preweaning day and at 4; 20 and 40 post-weaning days. Three animals of each group were sacrificed. Small intestines for morphometric studies and secretory-IgA determination in fluid were taken. The cecum was obtained for enterobacteria, lactobacilli and total anaerobes enumeration. A significant decrease in piglet's plasma IgG concentrations was observed immediately after weaning and no differences were found between 14W and 21W. An increase in intestinal S-IgA was observed according to piglet's age. This increase was significantly higher in piglets 14W compared to piglets 21W. Animals from 14W group showed a decrease in villus length and in the number of goblet cells and intraepithelial lymphocytes. Other parameters were not affected by the weaning age. A short-term increase in cortisol was observed after weaning in both experimental groups. Enterobacteria decreased significantly after weaning in both groups, reaching values of weaning after 40 days. Lactobacilli counts decreased in both groups after weaning; however their counts were always higher than those obtained for enterobacteria. No differences were observed between 14W and 21W with regards to counts of anaerobes. The shortening of breast feeding time would favor an early synthesis of intestinal S-IgA after weaning. The changes observed in the microbiota could decrease postweaning enteric infections. However, early weaning induced negative effects on the cells of gut innate immunity and villi atrophy. This work provides knowledge about advantages and disadvantages at different weaning and long-lasting consequences on pig health. It is critical that swine producers become aware of the biological impacts of weaning age, so as to be able to decide the appropriate management strategies according to their facilities and rearing environment. PMID- 26927635 TI - Mitogen-activated protein kinase pathways are required for melatonin-mediated defense responses in plants. AB - Melatonin enhances pathogen resistance by inducing the expression of a number of plant defense-related genes. To examine whether the melatonin-mediated pathogen resistance is associated with mitogen-activated protein kinase (MAPK) cascades, Arabidopsis and tobacco leaves were treated with melatonin and investigated for MAPK activation using an antiphospho-p44/42 MAPK (Erk1/2) monoclonal antibody. Two MAPKs, MPK3 and MPK6, were activated rapidly and transiently by 1 MUm melatonin treatment in Arabidopsis. Its tobacco ortholog MAPKs were also activated. The activation of MPK3 and MPK6 by 2-hydroxymelatonin and N acetylserotonin was also observed, albeit to a lesser degree than that by melatonin. Furthermore, MAPK activation by melatonin was uncoupled from G-protein signaling, because melatonin efficiently activated two MAPKs in a G-protein beta knockout mutant (agb1). Suppression of both MPK3 and MPK6 in transgenic Arabidopsis exhibited significant decreases in the induction of defense-related gene expression and pathogen resistance relative to wild-type plants. Using an array of MAP kinase kinase (MKK) knockout mutants, we found that four MKKs, namely MKK4, MKK5, MKK7, and MKK9, are responsible for the activation of MPK3 and MPK6 by melatonin, indicating that melatonin-mediated innate immunity is triggered by MAPK signaling through MKK4/5/7/9-MPK3/6 cascades. PMID- 26927637 TI - [The academization of primary care]. PMID- 26927636 TI - SOX5 is involved in balanced MITF regulation in human melanoma cells. AB - BACKGROUND: Melanoma is a cancer with rising incidence and new therapeutics are needed. For this, it is necessary to understand the molecular mechanisms of melanoma development and progression. Melanoma differs from other cancers by its ability to produce the pigment melanin via melanogenesis; this biosynthesis is essentially regulated by microphthalmia-associated transcription factor (MITF). MITF regulates various processes such as cell cycling and differentiation. MITF shows an ambivalent role, since high levels inhibit cell proliferation and low levels promote invasion. Hence, well-balanced MITF homeostasis is important for the progression and spread of melanoma. Therefore, it is difficult to use MITF itself for targeted therapy, but elucidating its complex regulation may lead to a promising melanoma-cell specific therapy. METHOD: We systematically analyzed the regulation of MITF with a novel established transcription factor based gene regulatory network model. Starting from comparative transcriptomics analysis using data from cells originating from nine different tumors and a melanoma cell dataset, we predicted the transcriptional regulators of MITF employing ChIP binding information from a comprehensive set of databases. The most striking regulators were experimentally validated by functional assays and an MITF promoter reporter assay. Finally, we analyzed the impact of the expression of the identified regulators on clinically relevant parameters of melanoma, i.e. the thickness of primary tumors and patient overall survival. RESULTS: Our model predictions identified SOX10 and SOX5 as regulators of MITF. We experimentally confirmed the role of the already well-known regulator SOX10. Additionally, we found that SOX5 knockdown led to MITF up-regulation in melanoma cells, while double knockdown with SOX10 showed a rescue effect; both effects were validated by reporter assays. Regarding clinical samples, SOX5 expression was distinctively up-regulated in metastatic compared to primary melanoma. In contrast, survival analysis of melanoma patients with predominantly metastatic disease revealed that low SOX5 levels were associated with a poor prognosis. CONCLUSION: MITF regulation by SOX5 has been shown only in murine cells, but not yet in human melanoma cells. SOX5 has a strong inhibitory effect on MITF expression and seems to have a decisive clinical impact on melanoma during tumor progression. PMID- 26927638 TI - [The use of alternative or complementary treatment in pediatric oncologic patients: Survey of 100 cases in a level III attention institute]. AB - INTRODUCTION: Alternative medicine is well accepted and widely used in Mexico, so we researched the frequency and causes of the use of alternative or complementary treatment (ACT) in pediatric oncologic patients at the Instituto Nacional de Pediatria (INP). METHODS: One hundred questionnaires were applied to caregivers of children with cancer in a course of 100 hundred consecutive patients. RESULTS: Fifty-one percent of caregivers interviewed accepted the use of some kind of ACT; biologic therapies were the most frequent treatments used, and 73% felt satisfied with the results. Caregivers told their physicians they were using ACT in 35% of the questionnaires analyzed, and only 2% of the physicians asked directly about its use. None of the caregivers substituted or stopped allopathic treatment. ANALYSIS: These questionnaires reveal that more than a half of the caregivers use ACT. We believe superstitious and cultural beliefs, as well as the desire of the caregivers to participate actively in their patient's treatment, are the main causes of the use of ACT; nevertheless, some do not notify their physicians and this may affect chemotherapy treatment in ways not investigated yet. CONCLUSIONS: The wide use of ACT in Mexico obliges every physician to enquire into it intentionally; it is therefore necessary to establish a stratification risk according to the combination of ACT and allopathic treatment used. PMID- 26927639 TI - [Assessment of the concentrations of carbonylated proteins and carbonyl reductase enzyme in mexican women with breast cancer: A pilot study]. AB - Oxidative stress could promote the development of cancer and implicate carbonylated proteins in the carcinogenic process. The goal of this study was to assess the concentrations of carbonylated proteins and carbonyl reductase enzyme in women with breast cancer and determine whether these markers were possible indicators of tissue damage caused by the disease. A total of 120 healthy women and 123 women with a diagnosis of breast cancer were included. The concentration of carbonylated proteins in plasma and the concentration of carbonyl reductase enzyme in leukocytes were determined using the ELISA assay. There was a 3.76-fold increase in the amount of carbonylated proteins in the plasma from the patient group compared with healthy control group (5+/-3.27 vs. 1.33+/-2.31 nmol carbonyls/mg protein; p<0.05). Additionally, a 60% increase in the carbonyl reductase enzyme was observed in the patient group compared with the healthy control group (3.27+/-0.124 vs. 2.04+/-0.11 ng/mg protein; p<0.05). A positive correlation (r=0.95; p<0.001) was found between both measurements. These results suggest the presence of tissue damage produced by cancer; therefore, these parameters could be used to indicate tissue damage in cancer patients. PMID- 26927640 TI - [Economic impact of hemophilia type A and B in Mexico]. AB - BACKGROUND: The treatment of hemophilia generates a disproportionally large economic impact relative to its prevalence. OBJECTIVE: To determine the economic impact of hemophilia A and B in Mexico in 2011 from the perspective of public health institutions. METHODS: Hemophilia was epidemiologically characterized in Mexico during the year of interest, direct costs (diagnosis, monitoring or follow up, care of bleeding events, and consumption of hemostatic factors), as well as absenteeism associated with illness (indirect costs) were estimated. Records, surveys and official data were supplemented by expert opinion to assess costs. RESULTS: The investment in hemostatic factors is the primary source of cost: 68.6 and 74.3% of total investment in hemophilia A and B, respectively. Sensitivity analysis showed that the most decisive variable is the cost of acquisition of hemostatic factors, including bypass agents. The second most important source of cost is the attention to bleeding events, being significantly higher in patients receiving on-demand treatment compared with those receiving prophylaxis. CONCLUSION: In Mexico, hemophilia is a condition whose treatment requires a large amount of financial resources associated with the cost of hemostatic factors and care of hemorrhage, the latter being lower in patients on prophylaxis relative to on-demand. PMID- 26927641 TI - [Characterization of adolescents and reason for the visit when attending the pediatric emergency department of the General Hospital Dr. Manuel Gea Gonzalez]. AB - RATIONALE: Emergency health care demanded by adolescents has increased due to a variety of specific disorders. AIMS: (1) Describe the frequency of emergency services utilization by adolescents; (2) Identify the reason for the visit; (3) Describe psychosocial and health features of patients; and (4) Describe information related to informed assent. MATERIAL AND METHODS: Observational, descriptive, and prospective study carried out in patients aged 12 to 18 years, treated in the emergency department of General Hospital "Dr. Manuel Gea Gonzalez ", between 2008 and 2009. Survey data as well as the HEADSS sociodemographic questionnaire was used. RESULTS: A total of 170 patients were included in the study. The average age was 14.1 years; 55% were female. The main reasons for consultation were trauma (32.9%), followed by non-surgical gastrointestinal pathologies (12.4%), acute abdomen (11.8%), psychiatric emergencies (10.6%), neurological (8.8%), infectious or gynecologic obstetrical (both 8.2%). In 81% of cases, relatives (mostly parents) were the ones who decided to take the patient to the emergency room. It is noteworthy that in 64% of cases the patients had previously gone to the emergency room. Of the patients, 72.4% reported not having regular medical care and the remaining reported that medical care was referred to once or twice a year. CONCLUSIONS: Among patients seeking emergency care, a significant proportion are teenagers. The causes are varied, with care ranging from posttraumatic aspects to psycho-behavioral disorders. There is minimal culture in this age group to agree about their own treatment through informed consent. PMID- 26927642 TI - [Depressive disorder in Mexican pediatric patients with systemic lupus erythematosus (SLE)]. AB - OBJECTIVE: To identify the prevalence of depression in Mexican pediatric patients with systemic lupus erythematosus. MATERIALS AND METHODS: Analytical transversal study including patients aged 7-16 years with a diagnosis of systemic lupus erythematosus seen at the Pediatric Rheumatology Consultation Service. The disease was classified by means of the MEX-SLEDAI questionnaire. Descriptive statistics with central tendency and dispersion and comparative measurements with chi-squared and Mann-Whitney U tests. Logistic regression and association with odds ratios. SPSS v.21.0 statistical software package. RESULTS: We evaluated 45 patients who presented depression, n=9 (20%), including eight females (89%) and one male (11%), median age 13 years (range, 7-16) in children with depression vs. 13 years (range, 9-14) p=0.941, depression more frequent in schoolchildren. Habitual residence, disease evolution time, and duration of the immunosuppressor did not show a significant difference between both groups. Divorced parents p=0.037. Neuropsychiatric manifestations of lupus presented in 2.2% of all patients and in 100% of patients with depression. Disease activity index (MEX SLEDAI) did not demonstrate a relationship with the presence of depression. CONCLUSION: Prevalences in pediatric populations are less that that reported in adults, association with disease activity, evolution time, and immunosuppressor use and duration not found. PMID- 26927643 TI - [Construction and validation of an instrument to assess primary care level patient satisfaction]. AB - OBJECTIVE: To develop an instrument to assess the satisfaction of patients using health services at the first care level of the city of Mexico (SSA), adapted to the socio-cultural characteristics of the population, and to examine its reliability and validity. METHODS: The instrument reagents were designed using the natural semantic networks technique. The dimensions used have been determined from the literature. Participants included 230 adults with type 2 diabetes attending eight SSA health centers. Subsequently, intelligibility was determined by conducting a pilot, then the construct validity of the instrument by means of exploratory factor analysis was evaluated and its internal consistency was determined by calculating Cronbach's alpha. RESULTS: The questionnaire is composed of six factors with a Likert-type scale. Its consistency showed a Crombach's alpha of 0.94. The factor structure included 29 reagents that correlated with the six dimensions with factorial loads>0.581 that explained 66.8% of the total variance. CONCLUSIONS: The patient satisfaction questionnaire incorporates the sociocultural characteristics of the target population and has an adequate level of validity and reliability and is quick and easy in application. PMID- 26927644 TI - [Clinical and periodontal predictive factors of severity in gingival recession (GR)]. AB - INTRODUCTION: Gingival recession is an unsightly condition due to root exposure. It can lead to dental hypersensitivity, root caries, and tooth loss. OBJECTIVE: To determine the influence of different clinical and periodontal parameters on the severity of gingival recession evaluated at four periods: initial, 6, 12, and 18 months of follow-up. MATERIAL AND METHODS: Forty patients with gingival recession were included in the study. Sociodemographic data, systemic diseases, harmful habits, dental hygiene habits, parafunctional habits, and orthodontic treatment were collected. Periodontal status (plaque index, gingival bleeding index, attached gingiva loss, pocket probing depth, and attachment loss) was also measured. RESULTS: None of the clinical parameters studied influenced the number of teeth with gingival recession. Smokers showed a higher number of teeth with attached gingiva loss (p=0.03). A direct relationship between the severity of gingival recession and plaque index (p=0.02) or 4-6 mm attachment loss (p=0.04) was observed. At six months of follow-up, gingival index was the only parameter that influenced the severity of gingival recession (p=0.01). PMID- 26927646 TI - [The association between red cell distribution width (RDW) and short-term mortality risk in patients with acute coronary syndrome (ACS)]. AB - OBJECTIVE: To demonstrate the association between red cell distribution width and short-term mortality risk in patients with acute coronary syndrome. METHODS: We prospectively recruited 78 patients with acute coronary syndrome. The study population was classified according to quartiles of the red cell distribution width at hospital admission. A high red cell distribution width was defined as a value in the upper fourth quartile (>15) and a low red cell distribution width was defined as any value set in the lower three quartiles (<=15). After discharge, all patients were followed for three months. RESULTS: The short-term cardiovascular mortality was 47.2% in the high red cell distribution width group vs. 10.2% in the low red cell distribution width group (p<0.001). In the receiver operating characteristic curve analysis, a red cell distribution width value of more than 15% yielded a sensitivity of 66.7%, a specificity of 83%, and a positive predictive value of 79.7% for cardiac mortality. After multivariate analysis, high levels of red cell distribution width were independent predictors for three-month mortality (p=0.001). CONCLUSION: We demonstrated that red cell distribution width is an accessible parameter associated with short-term cardiovascular mortality in patients with acute coronary syndrome. PMID- 26927645 TI - [Clinical characteristics and treatment response in adult patients with non Hodgkin's chronic lymphocytic leukemia (CLL)]. AB - OBJECTIVE: To determine comorbidities, clinical characteristics, and treatment response in adult patients with chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), and follicular lymphoma (FL). METHODS: The design was observational from reviewing the medical records of patients seen in outpatient and inpatient settings. It included >=50 subjects who demanded attention during the period 2008-2012 and that met specific inclusion/exclusion criteria. The main measures were: comorbidity (population group), clinical stage, patient treatment, response to treatment, overall survival, progression-free survival, and mortality. STATISTICAL ANALYSIS: p<0.05. RESULTS: 270 patients (CLL=90, DLBCL=81, FL=99) were recruited, with a mean age of 72.5, 65.5, and 62.4 years, respectively. These groups of neoplasms, compared with the general population, showed a higher percentage of men (60.0, 56.8 and 52.6 vs. 46.2%) and morbidity (Charlson Comorbidity Index: 1.6, 1.5, 1.4 vs. 0.4, respectively; p<0.05). The administration of chemotherapy treatment was 28.9 vs. 86.4 and 90.9%, respectively (p<0.001). Overall survival at five years was 84.4, 45.0 and 68.5%, respectively (p=0.027), while mortality rates were 17.0 vs. 35.3 and 20.6%, respectively (p=0.041). Compared with other treatments, with administered rituximab the median progression-free survival was 6.8 vs. 4.2 years (p<0.001). These differences were maintained for the three neoplasms. CONCLUSIONS: Comorbidity associated with hematological malignancies is high. The chronic lymphocytic leukemia group showed increased survival with lower mortality rate. Rituximab showed a higher progression-free survival in these neoplasms. PMID- 26927647 TI - [Hyperleptinemia associated with ischemic stroke]. AB - INTRODUCTION: The major risk factors for stroke are obesity, diabetes mellitus, systemic arterial hypertension (SAH) and dyslipidemia. In 1994 leptin was identifies as adipokine produced by adipose tissue. Its main action is the regulation of energy balance. Currently, hyperleptinemia is associated with cardiovascular disease. OBJECTIVE: To determine the association between serum leptin and stroke in patients with SAH. METHODS: We determined serum leptin in subjects with stroke and SAH, and compared this with patients with SAH without stroke. We calculated Student t, chi2, and odds ratio (OR) for quantitative and qualitative variables. RESULTS: 60 subjects were recruited, 30 subjects per group. Considering a value>3.93 ng/ml as hyperleptinemia, it also was found a t=2.8 (p=0.007), and chi2 with one degree of freedom of 10.82 (p=0.001), obtaining an OR of 3.05 for the development of stroke in the presence of elevated leptin (95% CI: 0.9-9.6; p=0.05). CONCLUSIONS: Hyperleptinemia is more common in patients with stroke than in those without this condition. But the question remains whether hyperleptinemia is a stroke risk factor or protective factor. PMID- 26927648 TI - [Biomarkers in high-grade gliomas: A systematic review]. AB - BACKGROUND: Biomarkers are a subcategory of clinical signs that can be measured and reproduced with precision and influence to predict outcome. Tissue, cells, and fluid conform the biological process. Biomarker usefulness is to determine and specify illness predisposition counting with variability and validity. Process systematization can reduce operative costs. To date, four major biomarkers have been described for high-grade gliomas: 1p/19q deletion, O6 methylguanine-DNA methyltransferase (MGMT) promoter mutation, IDH1/IDH2 mutation, and microRNA. In this manuscript we present a systematic review according to the MOOSE protocol to establish the bases to describe the utility of biomarkers in high-grade tumors. MATERIALS AND METHODS: We conducted a systematic review of the literature according to the PRISMA and MOOSE guides of all the published data from January 2004 to November 2014 with the key words: "biological markers" and "glioblastoma" that included OR and 95% CI. One researcher performed data extraction and analysis. RESULTS: A total of 169 articles were found in three major medical search engines: PubMed (42), Embase (30) and Ovid (96). CONCLUSION: Biomarkers are tools designed for early detection of specific illnesses such as high-grade glioma. Lack of methodological standardization slows down the speed of progress. PMID- 26927649 TI - [Isoforms of the human histamine H3 receptor: Generation, expression in the central nervous system and functional implications]. AB - Histamine plays a significant role as a neuromodulator in the human central nervous system. Histamine-releasing neurons are exclusively located in the tuberomammillary nucleus of the hypothalamus, project to all major areas of the brain, and participate in functions such as the regulation of sleep/wakefulness, locomotor activity, feeding and drinking, analgesia, learning, and memory. The functional effects of histamine are exerted through the activation of four G protein-coupled receptors (H1, H2, H3 and H4), and in the central nervous system the first three receptors are widely expressed. The H3 receptor (H3R) is found exclusively in neuronal cells, where it functions as auto- and hetero-receptor. One remarkable characteristic of the H3R is the existence of isoforms, generated by alternative splicing of the messenger RNA. For the human H3R, 20 isoforms have been reported; although a significant number lack those regions required for agonist binding or receptor signaling, at least five isoforms appear functional upon heterologous expression. In this work we review the evidence for the generation of human H3R isoforms, their expression, and the available information regarding the functionality of such receptors. PMID- 26927650 TI - [Frontal fibrosing alopecia (FFA): Report on four cases and review of the literature]. AB - Frontal fibrosing alopecia was recently described by Kossard, et al. as a progressive symmetrical recession of the frontal-temporal-parietal hairline affecting particularly postmenopausal women. Besides affecting the scalp, there are some cases in the literature with partial or total loss of the eyebrows, also involving the trunk, and superior extremities. Because the clinical, histological, and immunochemical findings are indistinguishable from those seen in lichen planopilaris, frontal fibrosing alopecia is now considered a localized variant of lichen planopilaris. We report four cases of Mexican postmenopausal women with this kind of dermatosis evaluated at the Dermatological Center Dr. Ladislao de la Pascua. PMID- 26927651 TI - [Trabecular hyalinizing adenoma of the thyroid (HAT): A report of two cases]. AB - The hyalinizing trabecular adenoma is a rare lesion of the thyroid. There is controversy in the literature about the correct name for this disease. Dr. Carney defended the benign nature of this condition and therefore continues calling it adenoma, the World Health Organization calls for the potential of tumor malignancy, and others qualify it as a variant of papillary carcinoma based on the presence of rearranged in transformation/papillary thyroid carcinoma (RET/PTC) rearrangements. In Latin America there are few reported cases. Two cases of hyalinizing trabecular adenoma are reported. The first is a 40-year-old woman with a thyroid nodule of 3x3 cm. The immunohistochemistry was positive for thyroglobulin and calcitonin and negative for cytokeratin 19 and chromogranin. The second case is a 36-year-old patient with a thyroid nodule of 4x4 cm with an immunohistochemical pattern identical to the first case. Trabecular hyalinizing adenoma is a benign disease, easily confused with papillary or medullary thyroid carcinoma. Awareness of this entity will allow a better classification and management of thyroid conditions. PMID- 26927652 TI - [Anomalous origin of the right pulmonary artery from the ascending aorta associated with aortopulmonary window]. AB - Anomalous origin of one pulmonary artery from the aorta is rare. We report a case of a three-month-old infant with aortopulmonary window and anomalous origin of the right pulmonary artery from the ascending aorta. He underwent surgery with anastomosis of the right pulmonary artery, ligation of the aortopulmonary window and the patent duct. He was released under medical treatment and had no signs of pulmonary hypertension or heart failure. PMID- 26927653 TI - [Tissue engineering applied to the trachea as a graft]. AB - Tissue engineering offers, through new technologies, an ex vivo generation of organs and functional tissues as grafts for transplants, for the improvement and substitution of biological functions, with an absence of immunological response. The treatment of extended tracheal lesions is a substitution of the affected segment; nevertheless, the allogeneic transplant has failed and the use of synthetic materials has not had good results. New tissue engineering technology is being developed to offer a tracheal graft for a posterior implantation. The purpose of this article is to review all the methods and components used by the engineering of tissue for tracheal grafts. PMID- 26927654 TI - [The Medical Movement in Mexico 1964-1965: What's happening half a century later?]. AB - We reviewed the literature covering the medical movement in 1964-1965, which began on November 26, 1964 with the ISSSTE November 20 Hospital scholarship protest and the emergence of the Mexican Resident Interns Physicians Association (Asociacion Mexicana de Medicos Residentes e Internos, AMMRI) and the Mexican Medical Alliance (Alianza de Medicos Mexicanos, AMM). We describe four work stoppages, two protest marches, the takeover of hospitals by the police, four interviews with Licenciado Gustavo Diaz Ordaz and his first presidential report. After that, attacks in the press, harassment, and repression provoked the weakening of the movement that ended in the AMM assembly on January 18, 1966. PMID- 26927655 TI - [Family medicine in Mexico: Present and future]. AB - Analyzing the challenges and the future scenario of Family Medicine is a priority to address challenges such as the reduction of benefits granted by social security; to adapt their practice to the changing health profile; and to curb demand for specialized services and contain the high costs of care in the second and third level. The program is aimed at three professional roles: medical care, research, and education. It is imperative review these in the light of changing demographic conditions, the type of health needs arising from new social determinants, the public expectations for greater participation in their care, and the evolution of the health system itself with the advancement of technology and a variety of organizational options with frequently limited resources. For primary care, as the core of a health system that covers principles of equity, solidarity, universality, participation, decentralization, and intra- and inter sectorial coordination, it is necessary to put at the center of the primary care team the family doctor and not an administrator, who plays an important role in supporting the care team, but can not take the lead. PMID- 26927656 TI - [Semblance of Dr. Luis Benitez Bribiesca]. PMID- 26927657 TI - Eco-toxicological effects of two kinds of lead compounds on forest tree seed in alkaline soil. AB - In order to compare the different eco-toxicological effects of lead nitrate and lead acetate on forest tree seed, a biological incubation experiment was conducted to testify the inhibition effects of two lead compounds on rates of seed germination, root and stem elongation, and seedling fresh weight for six plants (Amaorpha fruticosa L., Robinia psedoacacia L., Pinus tabuliformis Carr., Platycladus orientalis L., Koelreuteria paniculata Laxm., Hippophae rhamnoides L.) in soil. The results indicate that the inhibition effects of the two lead compounds on the rates of root elongation of plants were greater than other indices; root elongation can possibly be used as indices to investigate the relationship between lead toxicity and plant response. The response of trees to lead toxicity varied significantly, and the order of tolerance to lead pollution was as follows: Amaorpha fruticosa L. > Platycladus orientalis L. > Koelreuteria paniculata Laxm. > Robinia psedoacacia L. > Pinus tabuliformis Carr. > Hippophae rhamnoides L. Therefore, we suggest that Amaorpha fruticosa L. and Platycladus orientalis L. be used as tolerant plants for soil phytoremediation and Hippophae rhamnoides L. as an indicative plant to diagnose the toxicity of lead pollution on soil quality. Lead nitrate and lead acetate differentially restrain seeds, with seeds being more sensitive to lead nitrate than lead acetate in the soil. Thus, the characteristics of lead compounds should be taken into full consideration to appraise its impact on the environment. PMID- 26927658 TI - Involvement of Cold Inducible RNA-Binding Protein in Severe Hypoxia-Induced Growth Arrest of Neural Stem Cells In Vitro. AB - Neonatal hypoxia is the leading cause of brain damage with birth complications. Many studies have reported proliferation-promoting effect of mild hypoxia on neural stem cells (NSCs). However, how severe hypoxia influences the behavior of NSCs has been poorly explored. In the present study, we investigated the effects of 5, 3, and 1 % oxygen exposure on NSCs in vitro. MTT, neurosphere assay, and 5 ethynyl-2'-deoxyuridine (EdU) incorporation revealed a quick growth arrest of C17.2 cells and primary NSCs induced by 1 % oxygen exposure. Cell cycle analysis showed that this hypoxia exposure caused a significant increase of cells in G0/G1 phase and decrease of cells in S phase that is associated with decrease of Cyclin D1. Interestingly, the expression of cold inducible RNA-binding protein (CIRBP), a cold responsive gene reacting to multiple cellular stresses, was decreased in parallel with the 1 % oxygen-induced proliferation inhibition. Forced expression of CIRBP under hypoxia could restore the proliferation of NSCs, as showed by EdU incorporation and cell cycle analysis. Furthermore, the expression of Cyclin D1 under hypoxia was also restored by CIRBP overexpression. Taken together, these data suggested a growth-suppressing effect of severe hypoxia on NSCs and, for the first time, revealed a novel role of CIRBP in hypoxia-induced cell cycle arrest, suggesting that modulating CIRBP may be utilized for preventing hypoxia-induced neonatal brain injury. PMID- 26927661 TI - Multiscale Materials Modeling in an Industrial Environment. AB - In this review, we sketch the materials modeling process in industry. We show that predictive and fast modeling is a prerequisite for successful participation in research and development processes in the chemical industry. Stable and highly automated workflows suitable for handling complex systems are a must. In particular, we review approaches to build and parameterize soft matter systems. By satisfying these prerequisites, efficiency for the development of new materials can be significantly improved, as exemplified here for formulation polymer development. This is in fact in line with recent Materials Genome Initiative efforts sponsored by the US government. Valuable contributions to product development are possible today by combining existing modeling techniques in an intelligent fashion, provided modeling and experiment work hand in hand. PMID- 26927659 TI - Exendin-4 Reverses Biochemical and Functional Alterations in the Blood-Brain and Blood-CSF Barriers in Diabetic Rats. AB - Diabetes mellitus (DM) is a metabolic disorder associated with micro- and macrovascular alterations that contribute to the cognitive impairment observed in diabetic patients. Signs of breakdown of the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB) have been found in patients and animal models of DM. Breakdown of the BBB and BCSFB can lead to disruptions in cerebral homeostasis and eventually neural dysfunction and degeneration. However, our understanding of the biochemistry underlying barrier protein modifications is incomplete. Herein, we evaluated changes in the levels of specific proteins in the BBB (occludin, claudin-5, ZO-1, and aquaporin-4) and BCSFB (claudin-2 and aquaporin-1) in the hippocampus of diabetic rats, and we also investigated the functional alterations in these barriers. In addition, we evaluated the ability of exendin-4 (EX-4), a glucagon-like peptide-1 agonist that can cross the BBB to reverse the functional and biochemical modifications observed in these animals. We observed a decrease in BBB proteins (except ZO-1) in diabetic rats, whereas the EX-4 treatment recovered the occludin and aquaporin-4 levels. Similarly, we observed a decrease in BCSFB proteins in diabetic rats, whereas EX-4 reversed such changes. EX-4 also reversed alterations in the permeability of the BBB and BCSFB in diabetic rats. Additionally, altered cognitive parameters in diabetic rats were improved by EX-4. These data further our understanding of the alterations in the central nervous system caused by DM, particularly changes in the proteins and permeability of the brain barriers, as well as cognitive dysfunction. Furthermore, these data suggest a role for EX-4 in therapeutic strategies for cognitive dysfunction in DM. PMID- 26927662 TI - A Phase III Clinical Trial of the Epidermal Growth Factor Vaccine CIMAvax-EGF as Switch Maintenance Therapy in Advanced Non-Small Cell Lung Cancer Patients. AB - PURPOSE: EGFR is a well-validated target for patients with non-small cell lung cancer (NSCLC). CIMAvax-EGF is a therapeutic cancer vaccine composed of human recombinant EGF conjugated to a carrier protein and Montanide ISA51 as adjuvant. The vaccine is intended to induce antibodies against self EGFs that block EGF EGFR interaction. EXPERIMENTAL DESIGN: To evaluate overall survival, safety, immunogenicity, and EGF concentration in serum after CIMAvax-EGF, a randomized phase III trial was done in patients with advanced NSCLC. Four to 6 weeks after first-line chemotherapy, 405 patients with stage IIIB/IV NSCLC were randomly assigned to a vaccine group, which received CIMAvax-EGF or a control group, treated with best supportive care. RESULTS: Long-term vaccination was very safe. Most frequent adverse reactions were grade 1 or 2 injection-site pain, fever, vomiting, and headache. Vaccination induced anti-EGF antibodies and decreased serum EGF concentration. In the safety population, median survival time (MST) was 10.83 months in the vaccine arm versus 8.86 months in the control arm. These differences were not significant according the standard log rank (HR, 0.82; P = 0.100), but according a weighted log rank (P = 0.04) that was applied once the nonproportionality of the HR was verified. Survival benefit was significant (HR, 0.77; P = 0.036) in the per-protocol setting (patients receiving at least four vaccine doses): MST was 12.43 months for the vaccine arm versus 9.43 months for the control arm. MST was higher (14.66 months) for vaccinated patients with high EGF concentration at baseline. CONCLUSIONS: Switch maintenance with CIMAvax-EGF was well tolerated and significantly increased MST of patients that completed induction vaccination. Baseline EGF concentration predicted survival benefit. Clin Cancer Res; 22(15); 3782-90. (c)2016 AACR. PMID- 26927660 TI - Analysis of the Role of CX3CL1 (Fractalkine) and Its Receptor CX3CR1 in Traumatic Brain and Spinal Cord Injury: Insight into Recent Advances in Actions of Neurochemokine Agents. AB - CX3CL1 (fractalkine) is the only member of the CX3C (delta) subfamily of chemokines which is unique and combines the properties of both chemoattractant and adhesion molecules. The two-form ligand can exist either in a soluble form, like all other chemokines, and as a membrane-anchored molecule. CX3CL1 discloses its biological properties through interaction with one dedicated CX3CR1 receptor which belongs to a family of G protein-coupled receptors (GPCR). The CX3CL1/CX3CR1 axis acts in many physiological phenomena including those occurring in the central nervous system (CNS), by regulating the interactions between neurons, microglia, and immune cells. Apart from the role under physiological conditions, the CX3CL1/CX3CR1 axis was implied to have a role in different neuropathologies such as traumatic brain injury (TBI) and spinal cord injury (SCI). CNS injuries represent a serious public health problem, despite improvements in therapeutic management. To date, no effective treatment has been determined, so they constitute a leading cause of death and severe disability. The course of TBI and SCI has two consecutive poorly demarcated phases: the initial, primary injury and secondary injury. Recent evidence has implicated the role of the CX3CL1/CX3CR1 axis in neuroinflammatory processes occurring after CNS injuries. The importance of the CX3CL1/CX3CR1 axis in the pathophysiology of TBI and SCI in the context of systemic and direct local immune response is still under investigation. This paper, based on a review of the literature, updates and summarizes the current knowledge about CX3CL1/CX3CR1 axis involvement in TBI and SCI pathogenesis, indicating possible molecular and cellular mechanisms with a potential target for therapeutic intervention. PMID- 26927664 TI - Haploidentical versus Matched-Sibling Transplant in Adults with Philadelphia Negative High-Risk Acute Lymphoblastic Leukemia: A Biologically Phase III Randomized Study. AB - PURPOSE: Although matched-sibling donor (MSD) hematopoietic stem-cell transplantation (HSCT) has an established role in the management of adults with acute lymphoblastic leukemia (ALL) in first complete remission (CR1), the effect of haploidentical donor (HID) HSCT as post-remission treatment for this portion of patients is not defined. EXPERIMENTAL DESIGN: Transplantation outcomes from HIDs or MSDs were compared in a disease-specific, biologically phase III randomized, multicenter study. Between July 2010 and December 2013, 210 patients with Philadelphia-negative high-risk ALL in CR1 were assigned to undergo unmanipulated HIDs (121 patients) or MSDs HSCT (89 patients) according to donor availability on an intent-to-treat (ITT) basis. RESULTS: Overall, 24 of the 210 patients had lost transplant eligibility. Therefore, 186 of 210 (88%) patients were finally transplanted from MSD (n = 83) or HID (n = 103). Based on the ITT principle, the 3-year disease-free survival (DFS) did not differ between HID and MSD groups [61%, 95% confidence interval (CI), 52%-70%; vs. 60%, CI, 49%-71%; P = 0.91] from CR, neither did DFS differ between the two groups (68%, CI, 58%-78%; vs. 64%, CI, 52%-76%; P = 0.56) from time of the graft, with cumulative incidence of nonrelapse mortality of 13% (CI, 7%-19%) and 11% (CI, 4%-18%; P = 0.84) and relapse rates of 18% (CI, 10%-26%) and 24% (CI, 14%-34%; P = 0.30), respectively. CONCLUSIONS: Haploidentical HSCT achieves outcomes similar to those of MSD-HSCT for Philadelphia-negative high-risk ALL patients in CR1. Such transplantation could be a valid alternative as post-remission treatment for high-risk ALL patients in CR1 lacking an identical donor. Clin Cancer Res; 22(14); 3467-76. (c)2016 AACR. PMID- 26927663 TI - Inhibition of FoxM1-Mediated DNA Repair by Imipramine Blue Suppresses Breast Cancer Growth and Metastasis. AB - PURPOSE: The approaches aimed at inhibiting the ability of cancer cells to repair DNA strand breaks have emerged as promising targets for treating cancers. Here, we assessed the potential of imipramine blue (IB), a novel analogue of antidepressant imipramine, to suppress breast cancer growth and metastasis by inhibiting the ability of breast cancer cells to repair DNA strand breaks by homologous recombination (HR). EXPERIMENTAL DESIGN: The effect of IB on breast cancer growth and metastasis was assessed in vitro as well as in preclinical mouse models. Besides, the therapeutic efficacy and safety of IB was determined in ex vivo explants from breast cancer patients. The mechanism of action of IB was evaluated by performing gene-expression, drug-protein interaction, cell cycle, and DNA repair studies. RESULTS: We show that the systemic delivery of IB using nanoparticle-based delivery approach suppressed breast cancer growth and metastasis without inducing toxicity in preclinical mouse models. Using ex vivo explants from breast cancer patients, we demonstrated that IB inhibited breast cancer growth without affecting normal mammary epithelial cells. Furthermore, our mechanistic studies revealed that IB may interact and inhibit the activity of proto-oncogene FoxM1 and associated signaling that play critical roles in HR mediated DNA repair. CONCLUSIONS: These findings highlight the potential of IB to be applied as a safe regimen for treating breast cancer patients. Given that FoxM1 is an established therapeutic target for several cancers, the identification of a compound that inhibits FoxM1- and FoxM1-mediated DNA repair has immense translational potential for treating many aggressive cancers. Clin Cancer Res; 22(14); 3524-36. (c)2016 AACR. PMID- 26927667 TI - Blended sea level anomaly fields with enhanced coastal coverage along the U.S. West Coast. AB - We form a new 'blended' data set of sea level anomaly (SLA) fields by combining gridded daily fields derived from altimeter data with coastal tide gauge data. Within approximately 55-70 km of the coast, the altimeter data are discarded and replaced by a linear interpolation between the tide gauge and remaining offshore altimeter data. To create a common reference height for altimeter and tide gauge data, a 20-year mean is subtracted from each time series (from each tide gauge and altimeter grid point) before combining the data sets to form a blended mean sea level anomaly (SLA) data set. Daily mean fields are produced for the 22-year period 1 January 1993-31 December 2014. The primary validation compares geostrophic velocities calculated from the height fields and velocities measured at four moorings covering the north-south range of the new data set. The blended data set improves the alongshore (meridional) component of the currents, indicating an improvement in the cross-shelf gradient of the mean SLA data set. PMID- 26927665 TI - Clinical and Biologic Significance of MYC Genetic Mutations in De Novo Diffuse Large B-cell Lymphoma. AB - PURPOSE: MYC is a critical driver oncogene in many cancers, and its deregulation in the forms of translocation and overexpression has been implicated in lymphomagenesis and progression of diffuse large B-cell lymphoma (DLBCL). The MYC mutational profile and its roles in DLBCL are unknown. This study aims to determine the spectrum of MYC mutations in a large group of patients with DLBCL, and to evaluate the clinical significance of MYC mutations in patients with DLBCL treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) immunochemotherapy. EXPERIMENTAL DESIGN: We identified MYC mutations in 750 patients with DLBCL using Sanger sequencing and evaluated the prognostic significance in 602 R-CHOP-treated patients. RESULTS: The frequency of MYC mutations was 33.3% at the DNA level (mutations in either the coding sequence or the untranslated regions) and 16.1% at the protein level (nonsynonymous mutations). Most of the nonsynonymous mutations correlated with better survival outcomes; in contrast, T58 and F138 mutations (which were associated with MYC rearrangements), as well as several mutations occurred at the 3' untranslated region, correlated with significantly worse survival outcomes. However, these mutations occurred infrequently (only in approximately 2% of DLBCL). A germline SNP encoding the Myc-N11S variant (observed in 6.5% of the study cohort) was associated with significantly better patient survival, and resulted in reduced tumorigenecity in mouse xenografts. CONCLUSIONS: Various types of MYC gene mutations are present in DLBCL and show different impact on Myc function and clinical outcomes. Unlike MYC gene translocations and overexpression, most MYC gene mutations may not have a role in driving lymphomagenesis. Clin Cancer Res; 22(14); 3593-605. (c)2016 AACR. PMID- 26927666 TI - Genetic polymorphisms in circadian negative feedback regulation genes predict overall survival and response to chemotherapy in gastric cancer patients. AB - Circadian negative feedback loop (CNFL) genes play important roles in cancer development and progression. To evaluate the effects of single nucleotide polymorphisms (SNPs) in CNFL genes on the survival of GC patients, 13 functional SNPs from 5 CNFL genes were genotyped in a cohort of 1030 resected GC patients (704 in the training set, 326 in the validation set) to explore the association of SNPs with overall survival (OS). Among the 13 SNPs, three SNPs (rs1056560 in CRY1, rs3027178 in PER1 and rs228729 in PER3) were significantly associated with OS of GC in the training set, and verified in the validation set and pooled analysis. Furthermore, a dose-dependent cumulative effect of these SNPs on GC survival was observed, and survival tree analysis showed higher order interactions between these SNPs. In addition, protective effect conferred by adjuvant chemotherapy (ACT) on GC was observed in patients with variant alleles (TG/GG) of rs1056560, but not in those with homozygous wild (TT) genotype. Functional assay suggested rs1056560 genotypes significantly affect CRY1 expression in cancer cells. Our study presents that SNPs in the CNFL genes may be associated with GC prognosis, and provides the guidance in selecting potential GC patients most likely responsive to ACT. PMID- 26927668 TI - Thymic stromal lymphopoietin blocks early stages of breast carcinogenesis. AB - Advances in the field of cancer immunology, including studies on tumor infiltrating CD8+ cytotoxic T lymphocytes (CTLs), have led to new immunotherapeutics with proven efficacy against late-stage cancers. However, the antitumor potential of the immune system in targeting early-stage cancers remains uncertain. Here, we demonstrated that both genetic and chemical induction of thymic stromal lymphopoietin (TSLP) at a distant site leads to robust antitumor immunity against spontaneous breast carcinogenesis in mice. Breast tumors exposed to high circulating levels of TSLP were arrested at an early adenoma-like stage and were prevented from advancing to late carcinoma and metastasis. Additionally, CD4+ Th2 cells mediated the antitumor effects of TSLP, challenging the notion that Th2 cells only promote cancer. We also discovered that TSLP is expressed by the breast tumor cells themselves and acts to block breast cancer promotion. Moreover, TSLP-induced immunity also blocked early stages of pancreatic cancer development. Together, our findings demonstrate that TSLP potently induces immunity directed against early stages of breast cancer development without causing inflammation in the normal breast tissue. Moreover, our results highlight a previously unappreciated function of the immune system in controlling the early development of cancer and establish a fundamental role for TSLP and Th2 cells in tumor immunity against early-stage cancers. PMID- 26927669 TI - Endogenous transmembrane protein UT2 inhibits pSTAT3 and suppresses hematological malignancy. AB - Regulation of STAT3 activation is critical for normal and malignant hematopoietic cell proliferation. Here, we have reported that the endogenous transmembrane protein upstream-of-mTORC2 (UT2) negatively regulates activation of STAT3. Specifically, we determined that UT2 interacts directly with GP130 and inhibits phosphorylation of STAT3 on tyrosine 705 (STAT3Y705). This reduces cytokine signaling including IL6 that is implicated in multiple myeloma and other hematopoietic malignancies. Modulation of UT2 resulted in inverse effects on animal survival in myeloma models. Samples from multiple myeloma patients also revealed a decreased copy number of UT2 and decreased expression of UT2 in genomic and transcriptomic analyses, respectively. Together, these studies identify a transmembrane protein that functions to negatively regulate cytokine signaling through GP130 and pSTAT3Y705 and is molecularly and mechanistically distinct from the suppressors of cytokine signaling (SOCS) family of genes. Moreover, this work provides evidence that perturbations of this activation dampening molecule participate in hematologic malignancies and may serve as a key determinant of multiple myeloma pathophysiology. UT2 is a negative regulator shared across STAT3 and mTORC2 signaling cascades, functioning as a tumor suppressor in hematologic malignancies driven by those pathways. PMID- 26927670 TI - Renal epithelium regulates erythropoiesis via HIF-dependent suppression of erythropoietin. AB - The adult kidney plays a central role in erythropoiesis and is the main source of erythropoietin (EPO), an oxygen-sensitive glycoprotein that is essential for red blood cell production. Decreases of renal pO2 promote hypoxia-inducible factor 2 mediated (HIF-2-mediated) induction of EPO in peritubular interstitial fibroblast like cells, which serve as the cellular site of EPO synthesis in the kidney. It is not clear whether HIF signaling in other renal cell types also contributes to the regulation of EPO production. Here, we used a genetic approach in mice to investigate the role of renal epithelial HIF in erythropoiesis. Specifically, we found that HIF activation in the proximal nephron via induced inactivation of the von Hippel-Lindau tumor suppressor, which targets the HIF-alpha subunit for proteasomal degradation, led to rapid development of hypoproliferative anemia that was associated with a reduction in the number of EPO-producing renal interstitial cells. Moreover, suppression of renal EPO production was associated with increased glucose uptake, enhanced glycolysis, reduced mitochondrial mass, diminished O2 consumption, and elevated renal tissue pO2. Our genetic analysis suggests that tubulointerstitial cellular crosstalk modulates renal EPO production under conditions of epithelial HIF activation in the kidney. PMID- 26927672 TI - Dose-escalation study of octanoic acid in patients with essential tremor. AB - BACKGROUND: Recently, 1-octanol has been shown to have efficacy in treating patients with essential tremor (ET). The primary metabolite of 1-octanol is octanoic acid (OA), which is now thought to be the active substance that mediates tremor suppression. Our aim was to describe the maximum tolerated dose (MTD) of oral OA in patients with ET and assess the pharmacokinetics (PK) and pharmacodynamics (PD) profile of OA. METHODS: The MTD was studied using an open label, single-ascending 3 + 3 dose-escalation design. Predefined single doses ranged from 8 to 128 mg/kg, with grade 2 adverse events (AEs) defined as dose limiting toxicity. Tremor was assessed using accelerometry, digital spiral analysis, and a standard clinical rating scale at baseline and up to 600 minutes after intake. Safety assessments and PK sampling were also performed. RESULTS: Dose-limiting toxicity was not reached. The most frequent AE was mild abdominal discomfort. Exposure (AUC) increased linearly with the dose. Secondary efficacy measures suggested a dose-dependent reduction of tremor. Accordingly, a single unified PK/PD model with an effect compartment and sigmoid maximum effect (Emax) response could be built that accounted well for the time profiles of plasma concentrations as well as effects on tremor severity across the 5 dose levels. CONCLUSION: Although our trial did not reach an MTD, a dose-dependent effect was demonstrated in the PK/PD model as well as in secondary efficacy outcomes. Future studies are needed to explore the safety in higher dose ranges and to confirm dose-dependent efficacy in a placebo-controlled design. TRIAL REGISTRATION: Clinicaltrials.gov NCT01468948FUNDING. NINDS Intramural Research Program; TG Therapeutics Inc. PMID- 26927671 TI - Disabled homolog 2 controls macrophage phenotypic polarization and adipose tissue inflammation. AB - Acute and chronic tissue injury results in the generation of a myriad of environmental cues that macrophages respond to by changing their phenotype and function. This phenotypic regulation is critical for controlling tissue inflammation and resolution. Here, we have identified the adaptor protein disabled homolog 2 (DAB2) as a regulator of phenotypic switching in macrophages. Dab2 expression was upregulated in M2 macrophages and suppressed in M1 macrophages isolated from both mice and humans, and genetic deletion of Dab2 predisposed macrophages to adopt a proinflammatory M1 phenotype. In mice with myeloid cell-specific deletion of Dab2 (Dab2fl/fl Lysm-Cre), treatment with sublethal doses of LPS resulted in increased proinflammatory gene expression and macrophage activation. Moreover, chronic high-fat feeding exacerbated adipose tissue inflammation, M1 polarization of adipose tissue macrophages, and the development of insulin resistance in DAB2-deficient animals compared with controls. Mutational analyses revealed that DAB2 interacts with TNF receptor associated factor 6 (TRAF6) and attenuates IkappaB kinase beta-dependent (IKKbeta dependent) phosphorylation of Ser536 in the transactivation domain of NF-kappaB p65. Together, these findings reveal that DAB2 is critical for controlling inflammatory signaling during phenotypic polarization of macrophages and suggest that manipulation of DAB2 expression and function may hold therapeutic potential for the treatment of acute and chronic inflammatory disorders. PMID- 26927675 TI - [Guideline-adherent psychiatric and psychotherapeutic inpatient treatment: How much qualified personnel is needed?]. PMID- 26927673 TI - Exosomes and tumor-mediated immune suppression. AB - Tumor-derived exosomes (TEX) are harbingers of tumor-induced immune suppression: they carry immunosuppressive molecules and factors known to interfere with immune cell functions. By delivering suppressive cargos consisting of proteins similar to those in parent tumor cells to immune cells, TEX directly or indirectly influence the development, maturation, and antitumor activities of immune cells. TEX also deliver genomic DNA, mRNA, and microRNAs to immune cells, thereby reprogramming functions of responder cells to promote tumor progression. TEX carrying tumor-associated antigens can interfere with antitumor immunotherapies. TEX also have the potential to serve as noninvasive biomarkers of tumor progression. In the tumor microenvironment, TEX may be involved in operating numerous signaling pathways responsible for the downregulation of antitumor immunity. PMID- 26927674 TI - MLL1 and DOT1L cooperate with meningioma-1 to induce acute myeloid leukemia. AB - Meningioma-1 (MN1) overexpression is frequently observed in patients with acute myeloid leukemia (AML) and is predictive of poor prognosis. In murine models, forced expression of MN1 in hematopoietic progenitors induces an aggressive myeloid leukemia that is strictly dependent on a defined gene expression program in the cell of origin, which includes the homeobox genes Hoxa9 and Meis1 as key components. Here, we have shown that this program is controlled by two histone methyltransferases, MLL1 and DOT1L, as deletion of either Mll1 or Dot1l in MN1 expressing cells abrogated the cell of origin-derived gene expression program, including the expression of Hoxa cluster genes. In murine models, genetic inactivation of either Mll1 or Dot1l impaired MN1-mediated leukemogenesis. We determined that HOXA9 and MEIS1 are coexpressed with MN1 in a subset of clinical MN1hi leukemia, and human MN1hi/HOXA9hi leukemias were sensitive to pharmacologic inhibition of DOT1L. Together, these data point to DOT1L as a potential therapeutic target in MN1hi AML. In addition, our findings suggest that epigenetic modulation of the interplay between an oncogenic lesion and its cooperating developmental program has therapeutic potential in AML. PMID- 26927676 TI - [Spinal tract of the trigeminal nerve : Zoster of the trigeminal nerve]. PMID- 26927678 TI - [Patients, physicians and nursing personnel in intensive care units: Psychological and psychotherapeutic interventions]. AB - During intensive care treatment patients suffer from various forms of stress. Certain psychological and psychotherapeutic interventions (e. g. cognitive behavior therapy, hypnotherapy and psychoeducation) can provide relief. Even patients with a severely reduced ability to communicate can benefit from an early psychological intervention as supportive treatment. The aim of these interventions is to reduce psychological impairments and burdens, provide strategies for coping with physical handicaps or necessary treatment and avoid long-term negative psychological impacts. Organizational and institutional constraints as well as emotional stress are a specific challenge for intensive care personnel. In order to guarantee an efficient collaboration within an interdisciplinary team it is vital to follow clearly defined methods of communication exchange, such as daily ward rounds, regular multidisciplinary meetings and team or case-focused supervision. Properly functioning teamwork increases job satisfaction and is the key to an optimal therapy for the patients. PMID- 26927677 TI - [Monitoring of blood parameters under course-modified MS therapy : Substance specific relevance and current recommendations for action]. AB - With the approval of various substances for the immunotherapy of multiple sclerosis (MS), treatment possibilities have improved significantly over the last few years. Indeed, the choice of individually tailored preparations and treatment monitoring for the treating doctor is becoming increasingly more complex. This is particularly applicable for monitoring for a treatment-induced compromise of the immune system. The following article by members of the German Multiple Sclerosis Skills Network (KKNMS) and the task force "Provision Structures and Therapeutics" summarizes the practical recommendations for approved immunotherapy for mild to moderate and for (highly) active courses of MS. The focus is on elucidating the substance-specific relevance of particular laboratory parameters with regard to the mechanism of action and the side effects profile. To enable appropriate action to be taken in clinical practice, any blood work changes that can be expected, in addition to any undesirable laboratory findings and their causes and relevance, should be elucidated. PMID- 26927679 TI - [Guideline-oriented inpatient psychiatric psychotherapeutic/psychosomatic treatment of anxiety disorders : How many personnel are need?]. AB - BACKGROUND/OBJECTIVES: The reimbursement of inpatient psychiatric psychotherapeutic/psychosomatic hospital treatment in Germany is regulated by the German personnel ordinance for psychiatric hospitals (Psych-PV), which has remained unchanged since 1991. The aim of this article was to estimate the personnel requirements for guideline-adherent psychiatric psychotherapeutic hospital treatment. METHODS: A normative concept for the required psychotherapeutic "dose" for anxiety disorders was determined based on a literature review. The required staffing contingent was compared to the resources provided by the Psych-PV based on category A1. RESULTS: According to the German policy guidelines for outpatient psychotherapy, a quota of 25 sessions of 50 min each (as a rule plus 5 probatory sessions) is reimbursed. This approach is supported by studies on dose-response relationships. As patients undergoing inpatient treatment for anxiety disorders are usually more severely ill than outpatients, a contingent of 30 sessions for the average treatment duration of 5 weeks seems appropriate in order to fully exploit the costly inpatient treatment time (300 min per patient and week). In contrast, only 70 min are reimbursed according to the Psych-PV. The total personnel requirement for the normative concept is 624 min per patient and week. The Psych-PV only covers 488 min (78 %). CONCLUSION: Currently, the time contingents for evidence-based psychiatric psychotherapeutic/psychosomatic hospital care are nowhere near sufficient. In the development of future reimbursement systems this needs to be corrected. PMID- 26927680 TI - [Impact of early benefit assessment on patients with epilepsy in Germany: Current healthcare provision and therapeutic needs]. AB - Epilepsy is one of the most common chronic neurological diseases and represents a significant burden for patients, their families and society. In more than 75 % of patients anticonvulsant therapy consists of valproate, carbamazepine, lamotrigine or levetiracetam. There is a need for polytherapy in drug-refractory patients and they suffer from negative effects on quality of life and employment that is associated with high indirect costs. To allow a comprehensive treatment in this patient group, access to new anticonvulsants with novel modes of action is needed; however, all applications for new antiepileptic drugs failed to prove added benefits during the Pharmaceutical Market Restructuring Act (AMNOG) in Germany. One of the main reasons is the mandatory definition of a standard comparative therapy. It remains unclear whether there will be studies in the future which will fulfill the requirements of the current version of AMNOG. Observational studies after approval and marketing of new antiepileptic drugs could be better alternatives to prove added benefits for individual patients in the current German healthcare system. PMID- 26927681 TI - The Cost-Effectiveness of Using Platelet-Rich Plasma During Rotator Cuff Repair: A Markov Model Analysis. AB - PURPOSE: To perform a cost-utility analysis to determine if the use of platelet rich plasma (PRP) products during arthroscopic rotator cuff repair (RCR) is cost effective. METHODS: A cost-utility analysis was conducted using a Markov decision model. Model inputs including health utility values, retear rates, and transition probabilities were derived from the best evidence available in the literature regarding full-thickness rotator cuff tears and their repair, as well as the augmentation of their repair with PRP. Costs were determined by examining the typical patient undergoing treatment for a full-thickness rotator cuff tear in a private orthopaedic clinic and outpatient surgery center. RESULTS: The cost per quality-adjusted life-year ($/QALY) of RCR with and without PRP was $6,775/QALY and $6,612/QALY, respectively. In our base case, the use of PRP to augment RCR was not cost-effective because it had exactly the same "effectiveness" as RCR without PRP augmentation while being associated with a higher cost (additional $750). Sensitivity analysis showed that to achieve a willingness-to-pay threshold of $50,000/QALY, the addition of PRP would need to be associated with a 9.1% reduction in retear rates. If the cost of PRP were increased to $1,000, the retear rate would need to be reduced by 12.1% to reach this same threshold. This compared with a necessary reduction of only 6.1% if the additional cost of PRP was $500. CONCLUSIONS: This cost-utility analysis shows that, currently, the use of PRP to augment RCR is not cost-effective. Sensitivity analysis showed that PRP augmented repairs would have to show a reduced retear rate of at least 9.1% before the additional cost would be considered cost-effective. LEVEL OF EVIDENCE: Level III, analysis of Level I, II, and III studies. PMID- 26927682 TI - Discovery of Potent and Orally Active Lipoprotein-Associated Phospholipase A2 (Lp PLA2) Inhibitors as a Potential Therapy for Diabetic Macular Edema. AB - Lipoprotein-associated phospholipase A2 (Lp-PLA2) is considered to be a promising therapeutic target for several inflammation-associated diseases. Herein, we describe the discovery of a series of pyrimidone derivatives as Lp-PLA2 inhibitors. Systematic structural modifications led to the identification of several pyrimidone compounds with promising in vitro inhibitory potency and pharmacokinetic properties. Compound 14c, selected for in vivo evaluation, demonstrated decent pharmacokinetic profiles and robust inhibitory potency against Lp-PLA2 in Sprague-Dawley (SD) rats. Furthermore, 14c significantly inhibited retinal thickening in STZ-induced diabetic SD rats as a model of diabetic macular edema (DME) after oral dosing for 4 weeks. Taken together, these results suggested that 14c can serve as a valuable lead in the search for new Lp PLA2 inhibitors for prevention and/or treatment of DME. PMID- 26927683 TI - Improving the Performance of High-Precision qNMR Measurements by a Double Integration Procedure in Practical Cases. AB - Quantitative (1)H NMR (qNMR) is a widely applied technique for compound concentration and purity determinations. The NMR spectrum will display signals from all species in the sample, and this is generally a strength of the method. The key spectral determination is the full and accurate determination of one or more signal areas. Accurate peak integration can be an issue when unrelated peaks resonate in an important integral region. We describe a "hybrid" approach to signal integration that provides an accurate estimation of signal area, removing the component(s) that may arise from unrelated peaks. This is achieved by using the most accurate integration method for the region and removing unwanted contributions. The key to this performing well, and in almost all cases, is the use of areas from deconvolved peaks. We describe this process and show that it can be very successfully applied to cases where the highest precision is required and for more common cases of NMR-based quantitation. PMID- 26927684 TI - Optoelectronic properties of atomically thin ReSSe with weak interlayer coupling. AB - Rhenium dichalcogenides, such as ReS2 and ReSe2, have attracted a lot of interests due to the weak interlayered coupling in these materials. Studies of rhenium based dichalcogenide alloys will help us understand the differences between binary rhenium dichalcogenides. They will also extend the applications of two-dimensional (2D) materials through alloying. In this work, we studied the optoelectronic properties of ReSSe with a S and Se ratio of 1 : 1. The band gap of the ReSSe alloy is investigated by optical absorption spectra as well as theoretical calculations. The alloy shows weak interlayered coupling, as evidenced by the Raman spectrum. A field-effect transistor based on ReSSe shows typical n-type behavior with a mobility of about 3 cm(2) V(-1) s(-1) and an on/off ratio of 10(5), together with the in-plane anisotropic conductivity. The device also shows good photoresponse properties, with a photoresponsivity of 8 A W(-1). The results demonstrated here will provide new avenues for the study of 2D materials with weak interlayer interactions and in-plane anisotropy. PMID- 26927685 TI - Concise total synthesis of water soluble metatacarboline A, C, D, E and F and its anticancer activity. AB - The simple, concise, protecting group free and first total synthesis of Metatacarboline alkaloids (abbreviated as Mc) Mc A, C, D, E and F are reported. The core structure of metatacarboline alkaloids has been constructed by the classical Wittig reaction as key step from easily accessible starting materials with 40-75% overall yields. These synthesized compounds have been subjected to evaluate for their anticancer activity using C6 glioma cell lines. Mc D and Mc F showed significant antiproliferative activity, which was confirmed by MTT and Clonogenic assay. FACS analysis showed that Mc D and Mc F arrested the cell cycle at sub G0/G1 and G2/M phase of cell cycle respectively. Further, Western blot analysis and immunohistochemistry of Mc D treated cells revealed activation of caspase dependent downstream signaling which led to apoptosis. PMID- 26927686 TI - Indomethacin based new triazolothiadiazine derivatives: Synthesis, evaluation of their anticancer effects on T98 human glioma cell line related to COX-2 inhibition and docking studies. AB - In the current work, new 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazine derivatives (1 8) were synthesized via the ring closure reaction of 2-bromoacetophenone derivatives with 4-amino-5-[(5-methoxy-2-methyl-1-(4-chlorobenzoyl)-1H-indol-3 yl)methyl]-2,4-dihydro-3H-1,2,4-triazol-3-thione, which was obtained via the solvent-free reaction of indomethacin with thiocarbohydrazide. MTT assay was carried out to determine the cytotoxic effects of the compounds on T98 human glioma cell line. Among these compounds, 3-[5-methoxy-2-methyl-1-(4 chlorobenzoyl)-1H-indole-3-yl)methyl]-6-(4-methylphenyl)-7H-1,2,4-triazolo[3,4-b] 1,3,4-thiadiazine (8) was found to be the most effective compound and therefore flow cytometric method was performed to investigate the apoptotic effect of compound 8. The apoptosis stimulating percentages of compound 8 in comparison with the control group at 50 and 100 MUM doses were calculated as 11% and 12%, respectively. Besides, real-time PCR assay was carried out to determine the effects of compound 8 on COX-2, caspase 3, 8 and 9, cytochrome c mRNA levels. According to the real-time PCR analysis, compound 8 reduced COX-2 mRNA levels significantly when compared with the control group, whereas the compound did not cause any significant change in other parameters (Caspase 3, 8, 9, cytochrome c). The docking study suggested that the COX-2 inhibitory effects of compound 8 and indomethacin were similar in the catalytic active site of COX-2. These results indicated that compound 8 showed dose-dependent anticancer activity via the inhibition of COX-2 pathway. PMID- 26927687 TI - Fitness consequences of altered feeding behavior in immune-challenged mosquitoes. AB - BACKGROUND: Malaria-infected mosquitoes have been reported to be more likely to take a blood meal when parasites are infectious than when non-infectious. This change in feeding behavior increases the likelihood of malaria transmission, and has been considered an example of parasite manipulation of host behavior. However, immune challenge with heat-killed Escherichia coli induces the same behavior, suggesting that altered feeding behavior may be driven by adaptive responses of hosts to cope with an immune response, rather than by parasite specific factors. Here we tested the alternative hypothesis that down-regulated feeding behavior prior to infectiousness is a mosquito adaptation that increases fitness during infection. METHODS: We measured the impact of immune challenge and blood feeding on the fitness of individual mosquitoes. After an initial blood meal, Anopheles stephensi Liston mosquitoes were experimentally challenged with heat-killed E. coli at a dose known to mimic the same temporal changes in mosquito feeding behavior as active malaria infection. We then tracked daily egg production and survivorship of females maintained on blood-feeding regimes that either mimicked down-regulated feeding behaviors observed during early malaria infection, or were fed on a four-day feeding cycle typically associated with uninfected mosquitoes. RESULTS: Restricting access to blood meals enhanced mosquito survival but lowered lifetime reproduction. Immune-challenge did not impact either fitness component. Combining fecundity and survival to estimate the population-scale intrinsic rate of increase (r), we found that, contrary to the mosquito adaptation hypothesis, mosquito fitness decreased if blood feeding was delayed following an immune challenge. CONCLUSIONS: Our data provide no support for the idea that malaria-induced suppression of blood feeding is an adaptation by mosquitoes to reduce the impact of immune challenge. Alternatively, the behavioral alterations may be neither host nor parasite adaptations, but rather a consequence of constraints imposed on feeding by activation of the mosquito immune response, i.e. non-adaptive illness-induced anorexia. Future work incorporating field conditions and different immune challenges could further clarify the effect of altered feeding on mosquito and parasite fitness. PMID- 26927688 TI - The distinct effects of internalizing weight bias: An experimental study. AB - Both experiencing and internalizing weight bias are associated with negative mental and physical health outcomes, but internalization may be a more potent predictor of these outcomes. The current study aimed to differentiate between causal effects of experiencing versus internalizing weight bias on emotional responses and psychological well-being. Adults with overweight/obesity (N=260) completed an online experiment in which they were randomly assigned to focus on either the experience or internalization of weight bias, and completed measures of affect, self-esteem, and body dissatisfaction. Results indicated that the Internalization condition led to more negative affect, less positive affect, and lower self-esteem than the Experience condition. The Internalization condition also led to heightened body dissatisfaction among men, but not women. These findings suggest that weight bias internalization may be a stronger predictor of poor mental and physical health than experiences alone, and carry implications for developing weight bias interventions. PMID- 26927689 TI - Syncope and Motor Vehicle Crash Risk: A Danish Nationwide Study. AB - IMPORTANCE: Syncope may have serious consequences for traffic safety. Current clinical guideline recommendations on driving following syncope are primarily based on expert consensus. OBJECTIVE: To identify whether there is excess risk of motor vehicle crashes among patients with syncope compared with the general population. DESIGN, SETTING, AND PARTICIPANTS: Danish nationwide cohort study from January 1, 2008, to December 31, 2012. Through individual-level linkage of nationwide administrative registers, all Danish residents 18 years or older were identified. Of 4 265 301 eligible Danish residents, we identified 41 039 individuals with a first-time diagnosis of syncope from emergency department or hospital. MAIN OUTCOMES AND MEASURES: Rate of motor vehicle crashes (including nonfatal and fatal crashes), based on multivariate Poisson regression models, using the total Danish population as reference. RESULTS: The 41 039 patients with syncope had a median age of 66 years (interquartile range [IQR], 47-78 years); 51.0% were women; and 34.8% had cardiovascular disease. Through a median follow up of 2.0 years (IQR, 0.8-3.3 years), 1791 patients with syncope (4.4%) had a motor vehicle crash, 78.1% of which led to injury (n = 1398) and 0.3% to death (n = 6). The crude incidence rate of motor vehicle crashes was almost doubled among patients with syncope (20.6 per 1000 person-years; 95% CI, 19.7-21.6) compared with the general population (12.1; 95% CI, 12.0-12.1), with a rate ratio (RR) of 1.83 (95% CI, 1.74-1.91) after adjustment for age, sex, socioeconomic position, and relevant comorbidities and pharmacotherapy. Men had a relatively higher rate of motor vehicle crashes (RR, 1.91; 95% CI, 1.79-2.03) than women (RR, 1.74; 95% CI, 1.63-1.87). The excess risk of motor vehicle crashes persisted throughout the follow-up period. The 5-year crash risk following syncope was 8.2% (95% CI, 7.5% 8.8%) among the population aged 18 to 69 years compared with 5.1% (95% CI, 4.7% 5.4%) in the general population. CONCLUSIONS AND RELEVANCE: Prior hospitalization for syncope was associated with increased risk of motor vehicle crashes throughout the follow-up period. This study suggests that syncope should be considered as one of several factors in a broad assessment of fitness to drive. PMID- 26927690 TI - Analysis of Serum Endothelial Cell-Specific Molecule 1 (Endocan) Level in Type 2 Diabetes Mellitus With Acute ST-Segment Elevation Myocardial Infarction and its Correlation: A Pilot Study. AB - Endothelial cell-specific molecule 1 (ESM-1; endocan) is expressed by endothelial cells, and it can be overexpressed in diabetic patients. However, little is known concerning diabetic patients with acute ST-segment elevation myocardial infarction (STEMI). Therefore, we assessed serum ESM-1 level in patients having type 2 diabetes mellitus (T2DM) STEMI; 72 patients with DM (38 with and 34 without vascular disease) and 33 individuals as a control group were included. There was a significant difference in serum ESM-1 level between the T2DM group and the control group (P = .03). There was also a significant difference in serum ESM-1 level between the T2DM with STEMI group and newly diagnosed T2DM group without vascular disease (P = .01). In patients with T2DM, serum ESM-1 levels correlated positively with high-sensitivity C-reactive protein levels and the neutrophil to lymphocyte ratio (r = .321, P = .006 and r = .320, P = .006). Our findings suggest that serum ESM-1 level may be a novel endothelial dysfunction biomarker and it may be related to vascular disease in T2DM. PMID- 26927692 TI - Fraud is going unchecked, says US agency. PMID- 26927691 TI - A few of our favorite things: Pairing, the bouquet, crossover interference and evolution of meiosis. AB - Meiosis presents many important mysteries that await elucidation. Here we discuss two such aspects. First, we consider how the current meiotic program might have evolved. We emphasize the central feature of this program: how homologous chromosomes find one another ("pair") so as to create the connections required for their regular segregation at Meiosis I. Points of emphasis include the facts that: (i) the classical "bouquet stage" is not required for initial homolog contacts in the current evolved meiotic program; and (ii) diverse observations point to commonality between molecules that mediate meiotic inter-homolog interactions and molecules that are integral to centromeres and/or to microtubule organizing centers (a.k.a. spindle pole bodies or centrosomes). Second, we provide an overview of the classical phenomenon of crossover (CO) interference in an effort to bridge the gap between description on the one hand versus logic and mechanism on the other. PMID- 26927694 TI - Organic ferroelectric/semiconducting nanowire hybrid layer for memory storage. AB - Ferroelectric materials are important components of sensors, actuators and non volatile memories. However, possible device configurations are limited due to the need to provide screening charges to ferroelectric interfaces to avoid depolarization. Here we show that, by alternating ferroelectric and semiconducting nanowires over an insulating substrate, the ferroelectric dipole moment can be stabilized by injected free charge carriers accumulating laterally in the neighboring semiconducting nanowires. This lateral electrostatic coupling between ferroelectric and semiconducting nanowires offers new opportunities to design new device architectures. As an example, we demonstrate the fabrication of an elementary non-volatile memory device in a transistor-like configuration, of which the source-drain current exhibits a typical hysteretic behavior with respect to the poling voltage. The potential for size reduction intrinsic to the nanostructured hybrid layer offers opportunities for the development of strongly miniaturized ferroelectric and piezoelectric devices. PMID- 26927693 TI - Embryonic survival at day 9, 21 and 35 of pregnancy in intact and unilaterally oviduct ligated multiparous sows. AB - To investigate the effect of uterine space on timing of embryonic mortality, multiparous sows were left intact (CTR; n=42) or subjected to unilateral oviduct ligation (LIG; n=23), after their first post wean oestrus. Intact sows were killed at day 9 (n=10), day 21 (n=15), or day 35 (n=17), and LIG sows were killed at day 21 (n=11) or day 35 (n=12) of gestation. At day 9, 92% of ovulations were represented by an embryo. At day 21, embryonic mortality was 24% and was not altered by increasing uterine space. At day 35, space per embryo was twice as large in LIG sows (30+/-3 v. 16+/-0.8 cm), and implantation length tended to be larger (19.0+/-1.2 v. 15.5+/-1.3 cm). Between day 21 and day 35, CTR sows lost another 8% to 14% of their embryos, whereas LIG sows lost none. Embryos tended to be heavier (4.9+/-0.2 v. 4.3+/-0.3 g) in LIG sows. In conclusion, embryonic loss in multiparous sows is 24% by day 21 and is not related to space, whereas after day 21 limited space causes additional 8% to 14% embryonic mortality in intact sows only. PMID- 26927695 TI - Significant impact of miRNA-target gene networks on genetics of human complex traits. AB - The impact of microRNA (miRNA) on the genetics of human complex traits, especially in the context of miRNA-target gene networks, has not been fully assessed. Here, we developed a novel analytical method, MIGWAS, to comprehensively evaluate enrichment of genome-wide association study (GWAS) signals in miRNA-target gene networks. We applied the method to the GWAS results of the 18 human complex traits from >1.75 million subjects, and identified significant enrichment in rheumatoid arthritis (RA), kidney function, and adult height (P < 0.05/18 = 0.0028, most significant enrichment in RA with P = 1.7 * 10(-4)). Interestingly, these results were consistent with current literature based knowledge of the traits on miRNA obtained through the NCBI PubMed database search (adjusted P = 0.024). Our method provided a list of miRNA and target gene pairs with excess genetic association signals, part of which included drug target genes. We identified a miRNA (miR-4728-5p) that downregulates PADI2, a novel RA risk gene considered as a promising therapeutic target (rs761426, adjusted P = 2.3 * 10(-9)). Our study indicated the significant impact of miRNA-target gene networks on the genetics of human complex traits, and provided resources which should contribute to drug discovery and nucleic acid medicine. PMID- 26927698 TI - Intensifying the response of distributed optical fibre sensors using 2D and 3D image restoration. AB - Distributed optical fibre sensors possess the unique capability of measuring the spatial and temporal map of environmental quantities that can be of great interest for several field applications. Although existing methods for performance enhancement have enabled important progresses in the field, they do not take full advantage of all information present in the measured data, still giving room for substantial improvement over the state-of-the-art. Here we propose and experimentally demonstrate an approach for performance enhancement that exploits the high level of similitude and redundancy contained on the multidimensional information measured by distributed fibre sensors. Exploiting conventional image and video processing, an unprecedented boost in signal-to noise ratio and measurement contrast is experimentally demonstrated. The method can be applied to any white-noise-limited distributed fibre sensor and can remarkably provide a 100-fold improvement in the sensor performance with no hardware modification. PMID- 26927696 TI - Endothelial Cell Redox Regulation of Ischemic Angiogenesis. AB - The endothelium produces and responds to reactive oxygen and nitrogen species (RONS), providing important redox regulation to the cardiovascular system in physiology and disease. In no other situation are RONS more critical than in the response to tissue ischemia. Here, tissue healing requires growth factor-mediated angiogenesis that is in part dependent on low levels of RONS, which paradoxically must overcome the damaging effects of high levels of RONS generated as a result of ischemia. Although the generation of endothelial cell RONS in hypoxia/reoxygenation is acknowledged, the mechanism for their role in angiogenesis is still poorly understood. During ischemia, the major low molecular weight thiol glutathione (GSH) reacts with RONS and protein cysteines, producing GSH-protein adducts. Recent data indicate that GSH adducts on certain proteins are essential to growth factor responses in endothelial cells. Genetic deletion of the enzyme glutaredoxin-1, which selectively removes GSH protein adducts, improves, whereas its overexpression impairs revascularization of the ischemic hindlimb of mice. Ischemia-induced GSH adducts on specific cysteine residues of several proteins, including p65 NF-kB and the sarcoplasmic reticulum calcium ATPase 2, evidently promote ischemic angiogenesis. Identifying the specific proteins in the redox response to ischemia has provided therapeutic opportunities to improve clinical outcomes of ischemia. PMID- 26927697 TI - Presence and Persistence of Ebola or Marburg Virus in Patients and Survivors: A Rapid Systematic Review. AB - BACKGROUND: The 2013-15 Ebola outbreak was unprecedented due to sustained transmission within urban environments and thousands of survivors. In 2014 the World Health Organization stated that there was insufficient evidence to give definitive guidance about which body fluids are infectious and when they pose a risk to humans. We report a rapid systematic review of published evidence on the presence of filoviruses in body fluids of infected people and survivors. METHODS: Scientific articles were screened for information about filovirus in human body fluids. The aim was to find primary data that suggested high likelihood of actively infectious filovirus in human body fluids (viral RNA). Eligible infections were from Marburg virus (MARV or RAVV) and Zaire, Sudan, Tai Forest and Bundibugyo species of Ebola. Cause of infection had to be laboratory confirmed (in practice either tissue culture or RT-PCR tests), or evidenced by compatible clinical history with subsequent positivity for filovirus antibodies or inflammatory factors. Data were extracted and summarized narratively. RESULTS: 6831 unique articles were found, and after screening, 33 studies were eligible. For most body fluid types there were insufficient patients to draw strong conclusions, and prevalence of positivity was highly variable. Body fluids taken >16 days after onset were usually negative. In the six studies that used both assay methods RT-PCR tests for filovirus RNA gave positive results about 4 times more often than tissue culture. CONCLUSIONS: Filovirus was reported in most types of body fluid, but not in every sample from every otherwise confirmed patient. Apart from semen, most non-blood, RT-PCR positive samples are likely to be culture negative and so possibly of low infectious risk. Nevertheless, it is not apparent how relatively infectious many body fluids are during or after illness, even when culture-positive, not least because most test results come from more severe cases. Contact with blood and blood-stained body fluids remains the major risk for disease transmission because of the known high viral loads in blood. PMID- 26927699 TI - Zika Virus Update. PMID- 26927701 TI - T-cell large granular lymphocyte proliferation in myelodysplastic syndromes: Clinicopathological features and prognostic significance. AB - Inflammatory and immune dysregulation are crucial in the initiation and development of myelodysplastic syndromes (MDS). It is noted that clonal T-cell large granular lymphocyte (T-LGL) proliferation associated with MDS is not uncommon. However, clinicopathological features, and prognostic and predictive value of presence of T-LGL proliferation in MDS patients is not very clear. This study compared 35 MDS patients with T-LGL proliferation with 36 MDS patients without T-LGL proliferation and summarized clinicopathologic features, including peripheral blood LGL cell counts, immunophenotype, T cell receptor gene rearrangement, bone marrow hematopoietic status, and adjuvant immunosuppressive therapy. The peripheral blood CD3+/CD57+ cell counts were significantly different (p<0.01) between the two groups. Notably, on examination of the bone marrow, MDS patients with T-LGL proliferation showed more frequent hypocellularity and/or lineage hypoplasia, particularly erythroid hypoplasia. On survival analysis, no overall difference was noted between MDS patients with T-LGL proliferation and those without T-LGL proliferation, and between the patients who received therapy for LGL and those who did not receive adjuvant therapy for LGL in the same risk group. In conclusion, T-LGL proliferation present in MDS patients can be associated with bone marrow hypocellularity and lineage hypoplasia. Although immunosuppressive therapy to eliminate T-LGL cells is potentially beneficial to the MDS patients with associated T-LGL proliferation, there is no overall survival benefit to the patients who received such treatment. PMID- 26927700 TI - Retinoid and carotenoid status in serum and liver among patients at high-risk for liver cancer. AB - BACKGROUND: Approximately 2.7 million Americans are chronically infected with hepatitis C virus (HCV). HCV patients with cirrhosis form the largest group of persons at high risk for hepatocellular carcinoma (HCC). Increased oxidative stress is regarded as a major mechanism of HCV-related liver disease progression. Deficiencies in retinoid and carotenoid antioxidants may represent a major modifiable risk factor for disease progression. This study aims to identify key predictors of serum antioxidant levels in patients with HCV, to examine the relationship between retinoid/carotenoid concentrations in serum and hepatic tissue, to quantify the association between systemic measures of oxidative stress and antioxidant status, and to examine the relationship between retinoids and stellate cell activation. METHODS: Patients undergoing liver biopsy (n = 69) provided fasting blood, fresh tissue, urine and completed a diet history questionnaire. Serum and questionnaire data from healthy volunteers (n = 11), normal liver tissue from public repositories and patients without liver disease (n = 11) were also collected. Urinary isoprostanes, serum and tissue retinoid concentrations were obtained by UHPLC-MS-MS. Immunohistochemistry for alphaSMA was performed on FFPE sections and subsequently quantified via digital image analysis. Associations between urinary isoprostanes, alphaSMA levels, and retinoids were assessed using Spearman correlation coefficients and non parametric tests were utilized to test differences among disease severity groups. RESULTS: There was a significant inverse association between serum retinol, lycopene, and RBP4 concentrations with fibrosis stage. Serum beta-carotene and lycopene were strongly associated with their respective tissue concentrations. There was a weak downward trend of tissue retinyl palmitate with increasing fibrosis stage. Tissue retinyl palmitate was inversely and significantly correlated with hepatic alphaSMA expression, a marker for hepatic stellate cell activation (r = -0.31, P < 0.02). Urinary isoprostanes levels were inversely correlated with serum retinol, beta-carotene, and RBP4. CONCLUSIONS: A decrease in serum retinol, beta-carotene, and RBP4 is associated with early stage HCV. Retinoid and carotenoid levels decline as disease progresses, and our data suggest that this decline occurs early in the disease process, even before fibrosis is apparent. Measures of oxidative stress are associated with fibrosis stage and concurrent antioxidant depletion. Vitamin A loss is accompanied by stellate cell activation in hepatic tissue. PMID- 26927703 TI - Ethnomedicinal uses of plants in the treatment of paediatric geohelminth infections in Kalat district of Northern Balochistan, Pakistan. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Infection by intestinal parasitic worms (soil transmitted helminths or geohelminths) is prevalent in many parts of the world, and poses a particular health risk to children. This paper presents findings from a preliminary study with the primary aim to document indigenous knowledge about the use of herbal medicines in the treatment of intestinal worm infections in children among the local communities of Kalat district of northern Balochistan, Pakistan. MATERIALS AND METHODS: Ethnomedicinal data were collected through a triangulation approach, that included participant-observation and rapid appraisal methods. Prior-informed consent (PIC) was obtained from participants before conducting structured and semi-structured interviews and delivering an open ended questionnaire. A total of 94 participants, including 28 men (of whom 7 were traditional healers), and 66 women of four different age groups were interviewed. Results were analyzed using quantitative indices of Use Value citations (UVC) and Disease-Consensus Index (DCI). RESULTS: Fewer men than women agreed to be interviewed, thus overall women in the area appeared to have more ethnomedicinal knowledge. The majority of study participants belonged to the older age group (>55 years). A total of 49 plant species, belonging to 47 genera, distributed in 30 families were reported. The families Asteraceae and Lamiaceae were most frequently represented, with four species each. Trees were the most common life form, with seeds the most frequently cited plant part used (29%). Nearly a third (31%) of plant-based remedies reported in the treatment of intestinal worms were administered as a decoction. The highest UVC and DCI was reported for the species Ferula assa-foetida sL. (UVC 0.51, DCI 0.46). CONCLUSIONS: This study provides previously unreported data on the use of medicinal plants in the treatment of geohelminth infections in children of Kalat. Eight species, Acacia modesta Wall., Asparagus capitatus Baker, Microcephala lamellata (Bunge) Pobed., Nepeta praetervisa Rech.f., Plantago ciliata Desf., Pistacia atlantica Desf., Seriphidium quettense (Podlech) Y.R.Ling and Thymus linearis Benth. are reported here as anthelmintics for the first time. Detailed studies on the anthelmintic activity of chemical constituents of these species are lacking from existing literature. Further phytochemical, pharmacological and toxicity studies are required in order to evaluate the efficacy and safety of these newly reported anthelmintic species. These plants may provide a source of novel anthelmintic drug leads, which are urgently required due to the problem of global anthelmintic resistance. PMID- 26927704 TI - Development of an improved reverse genetics system for Akabane bunyavirus. AB - Akabane disease, caused by the insect-transmitted Akabane virus (AKAV), affects livestock by causing life-threatening deformities or mortality of fetuses. Therefore, Akabane disease has led to notable economic losses in numerous countries, including Japan. In this short communication, a new T7 RNA polymerase based AKAV reverse genetics system was developed. Using this system, in which three plasmids transcribing antigenomic RNAs were transfected into cells stably expressing T7 polymerase, we successfully reconstituted the live attenuated vaccine TS-C2 strain (named rTTT), and also generated a mutant AKAV (rTTTDeltaNSs) that lacked the gene encoding the nonstructural NSs protein, which is regarded as a virulence factor. Analysis of growth kinetics revealed that rTTTDeltaNSs grew at a much slower rate than the rTTT and TS-C2 virus. These results suggest that our established reverse genetics system is a powerful tool that can be used for AKAV vaccine studies with gene-manipulated viruses. PMID- 26927705 TI - Purification and immuno-gold labeling of lily mottle virus from lily leaves. AB - Lily mottle virus (LMoV) is prevalent in Lilium species worldwide causing dwarfing, flower breaking, and reduced bulb yield. In this paper, an easy to use and efficient procedure is described for purification of LMoV from lily leaves. The resulting sample is characterized by a 260/280 nm absorbance ratio of 1.20 at a concentration of 1.27 mg/ml. The procedure results in high protein purity and particle integrity as shown by UV-spectrophotometry, polyacrylamide gel electrophoresis (PAGE), Western blotting, reverse transcriptase (RT)-PCR and transmission electron microscopy (TEM) in combination with immuno-gold labeling. This is the first time that an immuno-gold labeling (IGL) assay was performed to identify a virus of lily. Purified products can be used as a source of antigen in the preparation of antibodies against LMoV and may assist in the development of a diagnostic test for LMoV and in epidemiological surveys. PMID- 26927706 TI - Microfluidic colloid filtration. AB - Filtration of natural and colloidal matter is an essential process in today's water treatment processes. The colloidal matter is retained with the help of micro- and nanoporous synthetic membranes. Colloids are retained in a "cake layer"--often coined fouling layer. Membrane fouling is the most substantial problem in membrane filtration: colloidal and natural matter build-up leads to an increasing resistance and thus decreasing water transport rate through the membrane. Theoretical models exist to describe macroscopically the hydrodynamic resistance of such transport and rejection phenomena; however, visualization of the various phenomena occurring during colloid retention is extremely demanding. Here we present a microfluidics based methodology to follow filter cake build up as well as transport phenomena occuring inside of the fouling layer. The microfluidic colloidal filtration methodology enables the study of complex colloidal jamming, crystallization and melting processes as well as translocation at the single particle level. PMID- 26927707 TI - Impact of thyroidectomy on cardiac manifestations of Graves' disease. AB - OBJECTIVES/HYPOTHESIS: Graves' disease (GD) has multiple adverse effects on the cardiovascular system. We aimed to examine the outcome of thyroidectomy in patients with cardiac manifestations of GD and evaluate their associated postoperative complications. STUDY DESIGN: Retrospective analysis using a prospectively collected database. METHODS: A retrospective analysis of our prospectively collected thyroid surgery database was performed. Forty patients with hyperthyroidism due to GD were identified, and each was appropriately age matched to a euthyroid patient with multinodular goiter (MNG). All patients underwent total thyroidectomy. Data relating to cardiac comorbidities were collected from preoperative and postoperative clinic notes, hospital admissions, electrocardiograms, echocardiograms, and blood work. Perioperative biochemical, cardiovascular, and postoperative outcomes were analyzed. RESULTS: Twenty-four (60%) GD patients and 14 (35.0%) MNG patients had cardiac manifestations (P = .001). Hypertension resolved in 41.7% of GD patients and 7.7% of MNG patients (P = .00002). Two of the three GD patients with congestive heart failure (CHF) had resolution of CHF with significant improvement in ejection fraction, whereas the one MNG patient with CHF saw no change. Additionally, the majority of GD patients saw a resolution of their tachycardia (68.8%) and atrial fibrillation (100%). Four postoperative complications occurred in both the GD and MNG groups (4/40, 10%). CONCLUSIONS: Surgical treatment of GD in patients with cardiac manifestations offers rapid clinical improvement of hypertension, impaired left ventricular systolic function, and arrhythmias. When performed by a high-volume surgeon, the complication rate is similar to thyroidectomy for other benign disease. LEVEL OF EVIDENCE: 4. Laryngoscope, 126:1256-1259, 2016. PMID- 26927709 TI - Roles of intracellular ice formation, vitrification of cell water, and recrystallisation of intracellular ice on the survival of mouse embryos and oocytes. AB - Mazur and collaborators began examining the validity of initial views regarding mouse oocyte and embryo vitrification and found that most are partially or fully wrong. First, the relative effects of warming and cooling rates on the survival of mouse oocytes subjected to a vitrification procedure were determined. The high sensitivity to warming rate strongly suggests that the lethality of slow warming is a consequence of either the crystallisation of intracellular glassy water during warming or the recrystallisation during slow warming of small intracellular crystals that had formed during cooling. Warming rates of 107 degrees C min-1 were achieved in 0.1-uL drops of ethylene glycol-acetamide-Ficoll sucrose (EAFS) solution plus a small amount of India ink on Cryotops warmed using an infrared laser pulse. Under these conditions, survival rates of 90% were obtained even when mouse oocytes were suspended in 0.3* EAFS, a concentration that falls in the range that many cells can tolerate. A second important finding was that the survival of oocytes is more dependent on the osmotic withdrawal of much of the intracellular water before vitrification than it is on the penetration of cryoprotective solutes into the cells. Herein we review the roles of internal ice formation, vitrification and recrystallisation. It remains to be seen how widely these findings will be applicable to other types of cells and tissues from other species. PMID- 26927710 TI - A novel form of macrothrombocytopenia in Akita dogs. AB - Blood samples from 3 unrelated Akita dogs with a common history of persistent macrothrombocytopenia in the absence of clinical bleeding were sent to the Auburn University College of Veterinary Medicine (AUCVM) Clinical Pathology Laboratory for evaluation. Due to low platelet counts, one Akita dog had been treated with corticosteroids for presumed immune-mediated platelet destruction, and one Akita dog was treated with doxycycline for one month for presumed infection by a tick borne agent. In spite of treatment, platelet counts remained low in both dogs. Given the absence of abnormal bleeding in all 3 dogs and lack of response to treatment in 2, congenital macrothrombocytopenia was suspected. Interestingly, platelets from all 3 dogs exhibited a consistent elongated platelet morphology. There were no morphologic abnormalities observed in other cell lines. While there have been anecdotal reports of a possible inherited macrothrombocytopenia in Akita dogs, scientific studies have not been done to verify these reports. This manuscript represents the first case report describing what is likely a congenital macrothrombocytopenia in Akita dogs based on persistently low platelet counts in the absence of clinical signs, and characterized by a unique platelet morphology. PMID- 26927711 TI - Performance in Measurement of Serum Cystatin C by Laboratories Participating in the College of American Pathologists 2014 CYS Survey. PMID- 26927712 TI - In Reply. PMID- 26927713 TI - The Archives of Pathology & Laboratory Medicine's Nonagintennial. PMID- 26927714 TI - Twenty Years of the Pulmonary Pathology Society. PMID- 26927715 TI - Ex Vivo Artifacts and Histopathologic Pitfalls in the Lung. AB - CONTEXT: Surgical and pathologic handling of lung physically affects lung tissue. This leads to artifacts that alter the morphologic appearance of pulmonary parenchyma. OBJECTIVE: To describe and illustrate mechanisms of ex vivo artifacts that may lead to diagnostic pitfalls. DESIGN: In this study 4 mechanisms of ex vivo artifacts and corresponding diagnostic pitfalls are described and illustrated. RESULTS: The 4 patterns of artifacts are: (1) surgical collapse, due to the removal of air and blood from pulmonary resections; (2) ex vivo contraction of bronchial and bronchiolar smooth muscle; (3) clamping edema of open lung biopsies; and (4) spreading of tissue fragments and individual cells through a knife surface. Morphologic pitfalls include diagnostic patterns of adenocarcinoma, asthma, constrictive bronchiolitis, and lymphedema. CONCLUSION: Four patterns of pulmonary ex vivo artifacts are important to recognize in order to avoid morphologic misinterpretations. PMID- 26927716 TI - Update on Pulmonary Fibrosis: Not All Fibrosis Is Created Equally. AB - CONTEXT: Three distinct patterns of pulmonary fibrosis, including usual interstitial pneumonia, fibrotic nonspecific interstitial pneumonia, and airway centered fibrosis, can be identified on surgical lung biopsies. OBJECTIVES: To compare the pathologic definitions, clinical and radiographic presentations, etiologies and differential diagnoses, treatments, and prognoses of usual interstitial pneumonia, fibrotic nonspecific interstitial pneumonia, and airway centered fibrosis patterns, and to address the challenges and controversies related to pulmonary fibrosis. DATA SOURCES: Data were derived from published literature and clinical experience. CONCLUSIONS: Although there may be overlap, identification of the dominant form of fibrosis in a particular case can provide a general category of disease and assist in identifying an etiology. PMID- 26927717 TI - Pulmonary Langerhans Cell Histiocytosis: An Update From the Pathologists' Perspective. AB - CONTEXT: Pulmonary Langerhans cell histiocytosis (PLCH) is a rare histiocytic disorder that almost exclusively affects the lungs of smokers. PLCH is characterized by bronchiolocentric nodules and/or cysts in an upper and mid lung distribution with sparing of the costophrenic angles. The diagnosis can be challenging and often requires transbronchial biopsy or surgical lung biopsy. Pulmonary hypertension is a relatively common and sometimes severe complication of PLCH. The pathogenesis of PLCH is still debated. Recently, BRAF V600E mutation and BRAF expression have been identified in some patients with PLCH, suggesting that at least a subset of PLCH has a clonal proliferation. While smoking cessation is the first-line treatment of PLCH, some patients might require additional treatment and eventually transplant. Given that the lesional cells of PLCH express BRAF in some patients, MAPKinase pathway-targeted treatment might be useful for therapy-resistant patients. OBJECTIVE: To present the more recently recognized clinical and pathologic aspects of PLCH, including pulmonary hypertension in PLCH, pathogenesis, and treatment, as well as the basic diagnostic approach to PLCH. DATA SOURCES: Authors' own research, and search of literature database (PubMed) and UpToDate. CONCLUSIONS: Despite the recent progress, more studies are needed to elucidate the biology of PLCH for identification of prognostic factors and appropriate treatment options, especially for therapy-refractory PLCH cases. PMID- 26927718 TI - Lung Transplantation: The State of the Airways. AB - CONTEXT: Lung transplantation has become a viable option for definitive treatment of several end-stage lung diseases for which there are no other options available. However, long-term survival continues to be limited by chronic lung allograft dysfunction, which primarily affects the airways. OBJECTIVE: To highlight the complications occurring mainly in the airways of the lung transplant recipient from the early to late posttransplant periods. DATA SOURCES: Review literature focusing on the airways in patients with lung transplants and clinical experience of the authors. CONCLUSIONS: Postsurgical complications and infections of the airways have decreased because of better techniques and management. Acute cellular rejection of the airways can be distinguished from infection pathologically and on cultures. Separating small from large airways need not be an issue because both are risk factors for bronchiolitis obliterans. Grading of airway rejection needs to be standardized. Chronic lung allograft dysfunction consists of both bronchiolitis obliterans and restrictive allograft syndrome, neither of which can be treated very effectively at present. PMID- 26927719 TI - Next-Generation Sequencing and Immunotherapy Biomarkers: A Medical Oncology Perspective. AB - The two most important scientific developments of the past decade regarding therapies for patients with non-small cell lung cancer are the ability to exploit particular genetic mutations with targeted therapies and the discovery of drugs that can help the patient's own immune system attack the cancer. Despite these advances, many patients do not yet benefit from either approach. To maximize patient benefit, clinicians and pathologists will need to rationally apply the growing scientific knowledge to best characterize a patient's tumor and possible driver mutations. A growing understanding of host-tumor immune interactions will hopefully help expand our therapeutic options. Lastly, the still elusive identification of immunotherapy biomarkers will hopefully help identify patients most likely to derive a therapeutic response to immune checkpoint inhibitors, and promises to be an important field of study for years to come. PMID- 26927721 TI - Abstracts From the Pulmonary Pathology Society 2015 Biennial Meeting. PMID- 26927720 TI - Non-Small Cell Lung Cancer, PD-L1, and the Pathologist. AB - CONTEXT: Although most primary cancers of the lung carry a heavy mutational load and will potentially present many "nonself" antigens to the immune system, there are a wide range of possible mechanisms for tumors to avoid so-called immune surveillance. One such mechanism is the adoption of immune checkpoints to inhibit the host immune response. Immune checkpoint inhibitors show great promise in the treatment of advanced non-small cell lung cancer. OBJECTIVE: To discuss the possibility of biomarker selection of patients for these therapies. This is becoming a much debated issue, and the immunohistochemical detection of Programmed Death Ligand 1 (PD-L1), the ligand for the inhibitory Programmed Death receptor 1 (PD-1) checkpoint, is one possible biomarker. Data so far available show some conflicting results, but PD-L1 immunohistochemistry looks likely to be introduced into clinical use for selecting patients for treatment with anti-PD-1 or anti-PD-L1 therapies. Given that there are 4 such drugs rapidly approaching regulatory approval, each with its own independent PD-L1 immunohistochemistry biomarker test, both oncologists and pathologists face some significant challenges. DATA SOURCES: Peer-reviewed literature and meeting proceedings, especially during the last 12 months, were used. CONCLUSIONS: The biology of PD 1/PD-L1 is complex, the clinical data for these drugs show considerable variation, the selection performance of the PD-L1 biomarker test is not perfect, and the existence of 4 drug/test combinations adds significantly to the problems faced. This article addresses some of the background to this therapeutic problem and discusses some of the issues ahead. PMID- 26927722 TI - Impact of a Rapid Blood Culture Assay for Gram-Positive Identification and Detection of Resistance Markers in a Pediatric Hospital. AB - CONTEXT: Molecular diagnostics allow for rapid identification and detection of resistance markers of bloodstream infection, with a potential for accelerated antimicrobial optimization and improved patient outcomes. Although the impact of rapid diagnosis has been reported, studies in pediatric patients are scarce. OBJECTIVE: To determine the impact of a molecular blood-culture assay that identifies a broad-spectrum of pathogens and resistance markers in pediatric patients with gram-positive bloodstream infections. DESIGN: Data on the time to antimicrobial optimization, the length of hospitalization, and the hospital cost following implementation of a rapid assay were prospectively collected and compared with corresponding preimplementation data. RESULTS: There were 440 episodes from 383 patients included, 221 preimplementation episodes and 219 postimplementation episodes. Overall time to antimicrobial optimization was shortened by 12.5 hours (P = .006), 11.9 hours (P = .005) for bloodstream infections of Staphylococcus aureus specifically. Duration of antibiotics for those with probable blood-culture contamination with coagulase-negative staphylococci was reduced by 36.9 hours (P < .001). Median length of stay for patients admitted to general pediatric units was 1.5 days shorter (P = .04), and median hospital cost was $3757 (P = .03) less after implementation. For S aureus bloodstream infections, median length of stay and hospital cost were decreased by 5.6 days (P = .01) and $13,341 (P = .03), respectively. CONCLUSIONS: Implementation of molecular assay for the detection of gram-positive pathogens and resistance markers significantly reduced time to identification and resistance detection, resulting in accelerated optimization of therapy, shorter length of stay, and decreased health care cost. PMID- 26927723 TI - Clinical Validation of Anyplex II HPV HR Detection Test for Cervical Cancer Screening in Korea. AB - CONTEXT: The Anyplex II HPV HR detection kit (Seegene Inc, Seoul, Korea) is a new, multiplex, real-time polymerase chain reaction assay to detect individual 14 high-risk (HR) human papillomavirus (HPV) types in a single tube. OBJECTIVE: To evaluate the clinical performance of the HPV HR kit in predicting high-grade squamous intraepithelial lesions and cervical intraepithelial lesions grade 2 or worse in cervical cancer screening. DESIGN: We analyzed 1137 cervical samples in Huro Path medium (CelltraZone, Seoul, Korea) from Korean women. The clinical performance of the HPV HR kit was compared with Hybrid Capture 2 (Qiagen, Valencia, California) using the noninferiority score test in a routine cervical cancer screening setting. The intralaboratory and interlaboratory agreements of HPV HR were also evaluated. RESULTS: Overall agreement between the 2 assays was 92.4% (1051 of 1137) with a kappa value of 0.787. Clinical sensitivity of HPV HR for high-grade squamous intraepithelial lesions and cervical intraepithelial lesions grade 2 or worse was 94.4% (95% confidence interval [CI], 89.2-99.7) and 92.5% (95% CI, 84.3-100.0), respectively. The respective values for Hybrid Capture 2 were 93.1% (95% CI, 87.2-98.9) and 87.5% (95% CI, 77.3-99.7). Clinical sensitivity and specificity of HPV HR were not inferior to those of Hybrid Capture 2 (P = .005 and P = .04, respectively). The HPV HR showed good intralaboratory and interlaboratory reproducibility at 98.0% (kappa = 0.953) and 97.4% (kappa = 0.940), respectively. CONCLUSIONS: The HPV HR demonstrates comparable performance to the Hybrid Capture 2 test and can be useful for HPV based cervical cancer screening testing. PMID- 26927724 TI - Ewing Sarcoma/Primitive Neuroectodermal Tumor of the Kidney: A Rare and Lethal Entity. AB - Ewing sarcoma/primitive neuroectodermal tumor represents a spectrum of undifferentiated tumors with similar biology that together represent the second most common sarcoma in the pediatric-young adult age range. Very rarely, this tumor presents as a primary neoplasm of the kidney. The clinical presentation of this tumor is not specific, and other renal tumors may present with a similar histologic appearance. Establishing the correct diagnosis is critical because renal Ewing sarcoma/primitive neuroectodermal tumor carries a strikingly dismal prognosis and thus dictates a specific treatment strategy. A low threshold for the use of ancillary molecular tests is recommended, particularly in diagnostically problematic cases. Important considerations with regards to morphology, immunohistochemistry, and molecular alterations will be reviewed here and should be taken into account before rendering this rare and lethal diagnosis. PMID- 26927725 TI - Uterine Adenosarcoma. AB - Mullerian adenosarcoma is an uncommon biphasic tumor composed of malignant stromal and benign epithelial components. Morphologically, adenosarcoma is characterized by a broad leaflike architecture, reminiscent of phyllodes tumors of the breast. Periglandular cuffing of the stromal cells around the compressed or cystically dilated glands is characteristic. The mesenchymal component is typically a low-grade spindle cell sarcoma, whereas the epithelial counterpart is commonly endometrioid with frequent squamous or mucinous metaplasia and may, in some circumstances, show mild to moderate atypia. In all cases, it is important to assess for the presence of sarcomatous overgrowth and myometrial invasion, which are the prognostic factors. In this brief review, we present the clinical, histopathologic, and immunohistochemical features of adenosarcoma, as well as updates on the molecular biology of this neoplasm. PMID- 26927726 TI - Altered resting-state whole-brain functional networks of neonates with intrauterine growth restriction. AB - The feasibility to use functional MRI (fMRI) during natural sleep to assess low frequency basal brain activity fluctuations in human neonates has been demonstrated, although its potential to characterise pathologies of prenatal origin has not yet been exploited. In the present study, we used intrauterine growth restriction (IUGR) as a model of altered neurodevelopment due to prenatal condition to show the suitability of brain networks to characterise functional brain organisation at neonatal age. Particularly, we analysed resting-state fMRI signal of 20 neonates with IUGR and 13 controls, obtaining whole-brain functional networks based on correlations of blood oxygen level-dependent (BOLD) signal in 90 grey matter regions of an anatomical atlas (AAL). Characterisation of the networks obtained with graph theoretical features showed increased network infrastructure and raw efficiencies but reduced efficiency after normalisation, demonstrating hyper-connected but sub-optimally organised IUGR functional brain networks. Significant association of network features with neurobehavioral scores was also found. Further assessment of spatiotemporal dynamics displayed alterations into features associated to frontal, cingulate and lingual cortices. These findings show the capacity of functional brain networks to characterise brain reorganisation from an early age, and their potential to develop biomarkers of altered neurodevelopment. PMID- 26927727 TI - Impact of HLA-Mismatch in Unrelated Donor Hematopoietic Stem Cell Transplantation: A Meta-Analysis. AB - The magnitude of risk associated with 9/10 mismatched unrelated donor (MMURD) hematopoietic stem cell transplantation and that of mismatches at the individual HLA loci remain unclear. We performed a meta-analysis to assess the difference in clinical outcomes between matched unrelated donor (MUD) and MMURD transplantation. A comprehensive search of Medline and Embase for manuscripts regarding transplantation outcomes in primarily adult patients with hematologic malignancies was performed. The pooled effect estimates were calculated using DerSimonian-Laird random effects models. A total of 13 studies were included, reporting on 13,446 transplants. 9/10 MMURD transplantation was associated with worse overall survival compared to 10/10 MUD transplantation (pooled HR: 1.27, 95% CI: 1.12-1.45; n = 7 studies). Mismatch at HLA-A, -B, or -C was associated with significantly worse overall survival compared to MUD transplantation, while there was no significant difference associated with -DQ or -DPB1 mismatch. Inferior survival associated with HLA-DRB1 mismatch could not be ruled out. Data on acute and chronic graft-versus-host disease were scarce but favored MUD transplantation. In summary, this meta-analysis of the available literature favored MUD over MMURD transplantation in hematologic malignancies and further quantifies the risks associated with specific HLA-allele mismatches. Am. J. Hematol. 91:551-555, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26927728 TI - Restriction of dietary protein does not promote hepatic lipogenesis in lean or fatty pigs. AB - The influence of genotype (lean v. fatty) and dietary protein level (normal v. reduced) on plasma metabolites, hepatic fatty acid composition and mRNA levels of lipid-sensitive factors is reported for the first time, using the pig as an experimental model. The experiment was conducted on forty entire male pigs (twenty lean pigs of Large White*Landrace*Pietrain cross-breed and twenty fatty pigs of Alentejana purebreed) from 60 to 93 kg of live weight. Each pig genotype was divided into two subgroups, which were fed the following diets: a normal protein diet (NPD) equilibrated for lysine (17.5 % crude protein and 0.7 % lysine) and a reduced protein diet (RPD) not equilibrated for lysine (13.1 % crude protein and 0.4 % lysine). The majority of plasma metabolites were affected by genotype, with lean pigs having higher contents of lipids, whereas fatty pigs presented higher insulin, leptin and urea levels. RPD increased plasma TAG, free fatty acids and VLDL-cholesterol compared with NPD. Hepatic total lipids were higher in fatty pigs than in the lean genotype. RPD affected hepatic fatty acid composition but had a slight influence on gene expression levels in the liver. Sterol regulatory element-binding factor 1 was down-regulated by RPD, and fatty acid desaturase 1 (FADS1) and fatty acid binding protein 4 (FABP4) were affected by the interaction between genotype and diet. In pigs fed RPD, FADS1 was up regulated in the lean genotype, whereas FABP4 increased in the fatty genotype. Although there is a genotype-specific effect of dietary protein restriction on hepatic lipid metabolism, lipogenesis is not promoted in the liver of lean or fatty pigs. PMID- 26927729 TI - Hearing protection devices: Use at work predicts use at play. AB - Use of hearing protection devices (HPDs) at work is widespread and well researched, but less is known about HPD use in high-noise leisure activities. We investigated HPD use of 8,144 Australians in leisure settings. An online survey asked questions about HPD use at work and leisure and examined whether age, gender, HPD use at work, and tinnitus predicted HPD use in leisure activities. Leisure-based HPD use was most common during high-risk work-related activities. Use of HPDs at work was the most significant predictor of leisure-based use, with workplace users up to 5 times more likely to use HPDs at leisure. Men were significantly more likely than women to use HPDs in 10/20 leisure activities, and those with tinnitus were more likely than those without to use HPDs in 8/20 activities. Older participants were more likely to use HPDs at nightclubs and concerts, but younger participants were more likely to use HPDs playing e-games and musical instruments. PMID- 26927731 TI - Stochastic Analysis and Forecasts of the Patterns of Speed, Acceleration, and Levels of Material Stock Accumulation in Society. AB - The recent acceleration of urbanization and industrialization of many parts of the developing world, most notably in Asia, has resulted in a fast-increasing demand for and accumulation of construction materials in society. Despite the importance of physical stocks in society, the empirical assessment of total material stock of buildings and infrastructure and reasons for its growth have been underexplored in the sustainability literature. We propose an innovative approach for explaining material stock dynamics in society and create a country typology for stock accumulation trajectories using the ARIMA (Autoregressive Integrated Moving Average) methodology, a stochastic approach commonly used in business studies and economics to inspect and forecast time series. This enables us to create scenarios for future demand and accumulation of building materials in society, including uncertainty estimates. We find that the so-far overlooked aspect of acceleration trends of material stock accumulation holds the key to explaining material stock growth, and that despite tremendous variability in country characteristics, stock accumulation is limited to only four archetypal growth patterns. The ability of nations to change their pattern will be a determining factor for global sustainability. PMID- 26927730 TI - Psychophysiological arousal and inter- and intraindividual differences in risk sensitive decision making. AB - The current study assessed peripheral responses during decision making under explicit risk, and tested whether intraindividual variability in choice behavior can be explained by fluctuations in peripheral arousal. Electrodermal activity (EDA) and heart rate (HR) were monitored in healthy volunteers (N = 68) during the Roulette Betting Task. In this task, participants were presented with risky gambles to bet on, with the chances of winning varying across trials. Hierarchical Bayesian analyses demonstrated that EDA and HR acceleration responses during the decision phase were sensitive to the chances of winning. Interindividual differences in this peripheral reactivity during risky decision making were related to trait sensitivity to punishment and trait sensitivity to reward. Moreover, trial-by-trial variation in EDA and HR acceleration responses predicted a small portion of intraindividual variability in betting choices. Our results show that psychophysiological responses are sensitive to explicit risk and can help explain intraindividual heterogeneity in choice behavior. PMID- 26927732 TI - Anhydrous Proton Conducting Polymer Electrolyte Membranes via Polymerization Induced Microphase Separation. AB - Solid-state polymer electrolyte membranes (PEMs) exhibiting high ionic conductivity coupled with mechanical robustness and high thermal stability are vital for the design of next-generation lithium-ion batteries and high temperature fuel cells. We present the in situ preparation of nanostructured PEMs incorporating a protic ionic liquid (IL) into one of the domains of a microphase separated block copolymer created via polymerization-induced microphase separation. This facile, one-pot synthetic strategy transforms a homogeneous liquid precursor consisting of a poly(ethylene oxide) (PEO) macro-chain-transfer agent, styrene and divinylbenzene monomers, and protic IL into a robust and transparent monolith. The resulting PEMs exhibit a bicontinuous morphology comprising PEO/protic IL conducting pathways and highly cross-linked polystyrene (PS) domains. The cross-linked PS mechanical scaffold imparts thermal and mechanical stability to the PEMs, with an elastic modulus approaching 10 MPa at 180 degrees C, without sacrificing the ionic conductivity of the system. Crucially, the long-range continuity of the PEO/protic IL conducting nanochannels results in an outstanding ionic conductivity of 14 mS/cm at 180 degrees C. We posit that proton conduction in the protic IL occurs via the vehicular mechanism and the PEMs exhibit an average proton transference number of 0.7. This approach is very promising for the development of high-temperature, robust PEMs with excellent proton conductivities. PMID- 26927734 TI - Constructing Novel Si@SnO2 Core-Shell Heterostructures by Facile Self-Assembly of SnO2 Nanowires on Silicon Hollow Nanospheres for Large, Reversible Lithium Storage. AB - Developing an industrially viable silicon anode, featured by the highest theoretical capacity (4200 mA h g(-1)) among common electrode materials, is still a huge challenge because of its large volume expansion during repeated lithiation delithiation as well as low intrinsic conductivity. Here, we expect to address these inherent deficiencies simultaneously with an interesting hybridization design. A facile self-assembly approach is proposed to decorate silicon hollow nanospheres with SnO2 nanowires. The two building blocks, hand in hand, play a wonderful duet by bridging their appealing functionalities in a complementary way: (1) The silicon hollow nanospheres, in addition to the major role as a superior capacity contributor, also act as a host material (core) to partially accommodate the volume expansion, thus alleviating the capacity fading by providing abundant hollow interiors, void spaces, and surface areas. (2) The SnO2 nanowires serve as a conductive coating (shell) to enable efficient electron transport due to a relatively high conductivity, thereby improving the cyclability of silicon. Compared to other conductive dopants, the SnO2 nanowires with a high theoretical capacity (790 mA h g(-1)) can contribute outstanding electrochemical reaction kinetics, further adding value to the ultimate electrochemical performances. The resulting novel Si@SnO2 core-shell heterostructures exhibit remarkable synergy in large, reversible lithium storage, delivering a reversible capacity as high as 1869 mA h g(-1)@500 mA g(-1) after 100 charging-discharging cycles. PMID- 26927735 TI - Preoperative Clinics. AB - Preoperative evaluation clinics have been shown to enhance operating room efficiency, decrease day-of-surgery cancellations, reduce hospital costs, and improve the quality of patient care. Although programs differ in staffing, structure, financial support, and daily operations, they share the common goal of preoperative risk reduction in order for patients to proceed safely through the perioperative period. Effective preoperative evaluation occurs if processes are standardized to ensure clinical, regulatory, and accreditation guidelines are met while keeping medical optimization and patient satisfaction at the forefront. Although no universally accepted standard model exists, there are key components to a successful preoperative process. PMID- 26927733 TI - Downregulating Aberrant Motor Evoked Potential Synergies of the Lower Extremity Post Stroke During TMS of the Contralesional Hemisphere. AB - BACKGROUND: Growing evidence demonstrates unique synergistic signatures in the lower limb (LL) post-stroke, with specific across-plane and across-joint representations. While the inhibitory role of the ipsilateral hemisphere in the upper limb (UL) has been widely reported, examination of the contralesional hemisphere (CON-H) in modulating LL expressions of synergies following stroke is lacking. OBJECTIVE: We hypothesize that stimulation of lesioned and contralesional motor cortices will differentially regulate paretic LL motor outflow. We propose a novel TMS paradigm to identify synergistic motor evoked potential (MEP) patterns across multiple muscles. METHODS: Amplitude and background activation matched adductor MEPs were elicited using single pulse TMS of L-H and CON-H (control ipsilateral) during an adductor torque matching task from 11 stroke and 10 control participants. Associated MEPs of key synergistic muscles were simultaneously observed. RESULTS: By quantifying CON-H/L-H MEP ratios, we characterized a significant targeted inhibition of aberrant MEP coupling between ADD and VM (p = 0.0078) and VL (p = 0.047) exclusive to the stroke group (p = 0.028) that was muscle dependent (p = 0.039). We find TA inhibition in both groups following ipsilateral hemisphere stimulation (p = 0.0014; p = 0.015). CONCLUSION: We argue that ipsilaterally mediated attenuation of abnormal synergistic activations post stroke may reflect an adaptive intracortical inhibition. The predominance of sub 3ms interhemispheric MEP latency differences implicates LL ipsilateral corticomotor projections. These findings provide insight into the association between CON-H reorganization and post-stroke LL recovery. While a prevailing view of driving L-H disinhibition for UL recovery seems expedient, presuming analogous LL neuromodulation may require further examination for rehabilitation. This study provides a step toward this goal. PMID- 26927736 TI - Preoperative Consultations. AB - Preoperative consultation is an important intervention that likely has most benefits for intermediate-risk to high-risk patients undergoing major surgery. Consultation rates are likely increasing and there is significant practice variation in the use of consultation. Consultations should be available within a well-organized and coordinated process of preoperative assessment. Preoperative consults should be accessible to anesthesia and surgical teams involved in the procedure and to the providers involved in postoperative care. The role of preoperative consultation should evolve as a rational approach and emerge as a value-based service. New payment methodologies are likely to facilitate appropriate use of this important resource. PMID- 26927737 TI - Perioperative Ethical Issues. AB - Shared decision-making is a paradigm of patient engagement that is assuming greater importance in the era of value-based health care. The basic tenets include patient engagement on clinical decisions, taking into account multiple factors that influence physician and patient decision-making. Understanding and reconciling diametrically opposed views of care are important tenets of shared decision-making. Because many decisions are made preoperatively, the applicability of these principles may be useful especially in the situation of a higher risk surgical candidate. Many patients with Do-Not-Resuscitate (DNR) orders are undergoing procedures to improve quality of life. This article explores shared decision-making and DNR. PMID- 26927738 TI - Preoperative Laboratory Testing. AB - Routine preoperative testing is not cost-effective, because it is unlikely to identify significant abnormalities. Abnormal findings from routine testing are more likely to be false positive, are costly to pursue, introduce a new risk, increase the patient's anxiety, and are inconvenient to the patient. Abnormal findings rarely alter the surgical or anesthetic plan, and there is usually no association between perioperative complications and abnormal laboratory results. Incidental findings and false positive results may lead to increased hospital visits and admissions. Preoperative testing needs to be done based on a targeted history and physical examination and the type of surgery. PMID- 26927739 TI - Preoperative Assessment of the Patient with Cardiac Disease Undergoing Noncardiac Surgery. AB - The American College of Cardiology/American Heart Association has published Guidelines on Perioperative Evaluation. Preoperative evaluation should focus on identifying patients with symptomatic and asymptomatic coronary artery disease. The guidelines advocate using the American College of Surgeons National Surgical Quality Improvement Project Risk Index to determine perioperative risk. Diagnostic testing should be reserved for those at increased risk with poor exercise capacity. Indications for coronary interventions are the same in the perioperative period as in the nonoperative setting. In patients with a prior coronary stent, optimal antiplatelet therapy and timing of elective noncardiac surgery is evolving. PMID- 26927740 TI - Preoperative Evaluation: Estimation of Pulmonary Risk. AB - Postoperative pulmonary complications (PPCs) are common after major non-thoracic surgery and associated with significant morbidity and high cost of care. A number of risk factors are strong predictors of PPCs. The overall goal of the preoperative pulmonary evaluation is to identify these potential, patient and procedure-related risks and optimize the health of the patients before surgery. A thorough clinical examination supported by appropriate laboratory tests will help guide the clinician to provide optimal perioperative care. PMID- 26927741 TI - Stratification and Risk Reduction of Perioperative Acute Kidney Injury. AB - Perioperative acute kidney injury (AKI) is associated with an increased morbidity and mortality. The incidence of AKI varies depending on preoperative risk factors and the surgical setting. Preoperative risk stratification is critical for informed consent and perioperative planning. Perioperative renal protection strategies are potentially invaluable in the prevention of AKI. Current advances in the development of biomarkers may offer the opportunity for early diagnosis and the implementation of therapeutic strategies. Increased awareness and concerted efforts by all perioperative physicians are needed to provide an improved outcome for surgical patients. PMID- 26927742 TI - Perioperative Approach to Anticoagulants and Hematologic Disorders. AB - Hematologic disorders and patients on anticoagulants or at risk for venous thromboembolism encompass a broad array of diagnoses, which can potentially complicate perioperative planning and management. This article addresses both bleeding and clotting concerns as well as special hematologic issues. PMID- 26927743 TI - Preoperative Anemia: Evaluation and Treatment. AB - Previously undiagnosed anemia is often identified during routine assessment of surgical patients. Although studies suggest that perioperative anemia is associated with worse outcomes and a strong predictor for postoperative red cell transfusions, anemia is frequently ignored. Preoperative optimization of patients undergoing elective surgical procedures associated with significant blood loss, along with strategies to minimize intraoperative blood loss, shows promise for reducing postoperative transfusions and improving outcomes. In most situations, anemia can be corrected prior to elective surgeries and interventions. Future research should assess the timing and methods of optimization of preoperative anemia in surgery and which patients are best candidates for therapy. PMID- 26927744 TI - Preoperative Nutrition and Prehabilitation. AB - Enhanced recovery after surgery is the natural evolution of what were previously referred to as fast track programs and seeks to implement a series of interventions to improve and enhance recovery after major surgical procedures. Two important preoperative aspects are nutrition and prehabilitation. Identifying nutritionally deficient patients allows preoperative intervention to optimize their nutritional status. The contribution of cardiopulmonary exercise testing to the evaluation of perioperative risk, subsequent development of a training program, and the use of indices to risk stratify and measure improvement after a training program allow a personalized preoperative program to be developed for each patient. PMID- 26927745 TI - Preoperative Evaluation of Patients with Diabetes Mellitus. AB - There are more than 29 million people in the United States with diabetes; it is estimated that by 2050, one in 3 individuals will have the disease. At least 50% of patients with diabetes are expected to undergo surgery in their lifetime. Complications from uncontrolled diabetes can impact multiple organ systems and affect perioperative risk. In this review, the authors discuss principles in diabetes management that will assist the perioperative clinician in caring for patients with diabetes. PMID- 26927746 TI - Preoperative Assessment of Geriatric Patients. AB - Geriatric patients are over-represented in hospitalizations, surgeries, and perioperative complications. Special consideration is required for this patient group in the perioperative period because of the prevalence of comorbid diseases, functional impairments, and other deficits. A comprehensive preoperative evaluation strategy is recommended to identify and address these issues. Systematic, multidomain assessments should be performed and paired with risk reduction efforts. A shared understanding of patient function and long-term health goals is also important for providing patient-centered care of the geriatric surgical patient. PMID- 26927747 TI - Implantable Devices: Assessment and Perioperative Management. AB - Technology is the prominent feature of the twenty-first century, including in medicine. There are very few organs that cannot be stimulated, shocked, or infused. With more and more implantable devices being approved for clinical use, anesthesiologists have to regularly take care of patients who have these devices. An understanding of the devices, the associated comorbidities, and the perioperative risks is crucial for safe management of these patients. Cardiac devices are discussed in some detail; neurostimulators and other implantable devices are briefly described. The principles of assessment and management are similar for all patients with implanted devices. PMID- 26927748 TI - Preoperative Evaluation of the Patient with Substance Use Disorder and Perioperative Considerations. AB - The patient with a current or former history of substance use disorder can be challenging to adequately care for in the perioperative period. A thorough preoperative evaluation is essential. In addition to drug abuse screening, the evaluation should include an assessment of the effects of the substance abuse, associated diseases, end-organ damage, and an awareness of the potential perioperative risks so appropriate plans are developed to minimize the risks. Intraoperatively, anesthetic management needs to be appropriately modified. Signs and symptoms of withdrawal should be monitored for postoperatively. Pain management is particularly challenging. After discharge, this patient population is vulnerable and requires close follow-up and early referral to appropriate specialists when needed. PMID- 26927749 TI - The Pregnant Patient: Assessment and Perioperative Management. AB - Pathologic changes can occur during pregnancy requiring diagnostic tests and procedures. A preoperative assessment and perioperative planning are essential. Normal physiologic changes include increased cardiac output and decreased functional residual capacity. Perioperative care should follow American Congress of Obstetricians and Gynecologists guidelines. Anesthetic concerns include desaturation during periods of apnea, aspiration, difficult intubation, friable nasal tissue, decreased MAC, and hypotension and/or decreased uterine perfusion from the uterus. Anesthesia and medications must be individualized and given only as needed. Limit exposure to multiple drugs and monitor for fetal wellbeing and premature labor per consultation and guidelines. PMID- 26927750 TI - Non-operating Room Anesthesia: The Principles of Patient Assessment and Preparation. AB - A significant number of anesthetics are performed outside of the operating room (OR). Despite the increased requirement for anesthesia services, the framework to perform the necessary preprocedural anesthesia assessments to optimize patients has not been uniformly developed. Performing anesthesia in non-OR locations poses significant and distinct challenges compared with the procedures in the OR. Anesthesiologists are faced with patients with increasingly complicated comorbidities undergoing novel, complex interventional procedures. With unique training in preoperative triaging, and an expertise in intraoperative and postoperative management of complex patients, anesthesiologists can contribute to greater efficiency and patient safety in the non-OR setting. PMID- 26927754 TI - Astaxanthin ameliorates aluminum chloride-induced spatial memory impairment and neuronal oxidative stress in mice. AB - Aluminum chloride induces neurodegenerative disease in animal model. Evidence suggests that aluminum intake results in the activation of glial cells and generation of reactive oxygen species. By contrast, astaxanthin is an antioxidant having potential neuroprotective activity. In this study, we investigate the effect of astaxanthin on aluminum chloride-exposed behavioral brain function and neuronal oxidative stress (OS). Male Swiss albino mice (4 months old) were divided into 4 groups: (i) control (distilled water), (ii) aluminum chloride, (iii) astaxanthin+aluminum chloride, and (iv) astaxanthin. Two behavioral tests; radial arm maze and open field test were conducted, and OS markers were assayed from the brain and liver tissues following 42 days of treatment. Aluminum exposed group showed a significant reduction in spatial memory performance and anxiety like behavior. Moreover, aluminum group exhibited a marked deterioration of oxidative markers; lipid peroxidation (MDA), nitric oxide (NO), glutathione (GSH) and advanced oxidation of protein products (AOPP) in the brain. To the contrary, co-administration of astaxanthin and aluminum has shown improved spatial memory, locomotor activity, and OS. These results indicate that astaxanthin improves aluminum-induced impaired memory performances presumably by the reduction of OS in the distinct brain regions. We suggest a future study to determine the underlying mechanism of astaxanthin in improving aluminum-exposed behavioral deficits. PMID- 26927753 TI - Inhibition of voltage-gated potassium channels mediates uncarboxylated osteocalcin-regulated insulin secretion in rat pancreatic beta cells. AB - Insulin secretion from pancreatic beta cells is important to maintain glucose homeostasis and is regulated by electrical activities. Uncarboxylated osteocalcin, a bone-derived protein, has been reported to regulate glucose metabolism by increasing insulin secretion, stimulating beta cell proliferation and improving insulin sensitivity. But the underlying mechanisms of uncarboxylated osteocalcin-modulated insulin secretion remain unclear. In the present study, we investigated the relationship of uncarboxylated osteocalcin regulated insulin secretion and voltage-gated potassium (KV) channels, voltage gated calcium channels in rat beta cells. Insulin secretion was measured by radioimmunoassay. Channel currents and membrane action potentials were recorded using the conventional whole-cell patch-clamp technique. Calcium imaging system was used to analyze intracellular Ca(2+) concentration ([Ca(2+)]i). The data show that under 16.7mmol/l glucose conditions uncarboxylated osteocalcin alone increased insulin secretion and [Ca(2+)]i, but with no such effects on insulin secretion and [Ca(2+)]i in the presence of a KV channel blocker, tetraethylammonium chloride. In the patch-clamp experiments, uncarboxylated osteocalcin lengthened action potential duration and significantly inhibited KV currents, but had no influence on the characteristics of voltage-gated calcium channels. These results indicate that KV channels are involved in uncarboxylated osteocalcin-regulated insulin secretion in rat pancreatic beta cells. By inhibiting KV channels, uncarboxylated osteocalcin prolongs action potential duration, increases intracellular Ca(2+) concentration and finally promotes insulin secretion. This finding provides new insight into the mechanisms of osteocalcin-modulated insulin secretion. PMID- 26927755 TI - Effects of aspirin-triggered resolvin D1 on peripheral blood mononuclear cells from patients with Chagas' heart disease. AB - Chagas disease is caused by Trypanosoma cruzi (T. cruzi). In some patients with Chagas disease, symptoms progress to chronic chagasic cardiomyopathy. Endogenously, inflammation is resolved in the presence of lipid mediators such as aspirin-triggered RvD1 (AT-RvD1) which has anti-inflammatory and pro-resolution effects. Here, we demonstrated, for the first time, the effects of AT-RvD1 on T. cruzi antigen-stimulated peripheral blood mononuclear cells (PBMCs) from patients with Chagas heart disease. The levels of IFN-gamma, TNF-alpha, IL-10, and IL-13 increased in PBMCs from cardiac-form Chagas patients in stage B1 (patients with fewer heart abnormalities) stimulated with T. cruzi antigen compared to those in non-stimulated PBMCs. AT-RvD1 reduced the IFN-gamma concentrations in PBMCs from patients with Chagas disease stimulated with T. cruzi antigen compared to stimulated with T. cruzi antigen cells. AT-RvD1 treatment resulted in no observable changes in TNF-alpha, IL-10, and IL-13 levels. AT-RvD1 significantly decreased the percentage of necrotic cells and caused a significant reduction in the proliferation rate of T. cruzi antigen-stimulated PBMCs from patients with Chagas disease. These findings demonstrate that AT-RvD1 modulates the immune response in Chagas disease patients and might have potential to be used as an alternative approach for slowing the development of further heart damage. PMID- 26927756 TI - Immune responses to Mycobacterial heat shock protein 70 accompany self-reactivity to human BiP in rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is an autoimmune disease, and a member of human heat shock protein (HSP) 70 protein family, Binding Immunoglobulin Protein (BiP), has been identified as an important autoantigen for T and B cells. We herein focused on Mycobacterial (Myc) HSPs and immune responses to MycHSPs in RA patients. Serum titers of antibodies against MycHSP70 were significantly elevated in RA patients and correlated with serum anti-BiP antibody titers. A MycHSP70-derived HLA-DR4 major epitope was identified using the proliferative capacity of RA PBMCs as an indicator. The major epitope, MycHSP70287-306, was located at the corresponding position in the major epitope for human BiP336-355, and a strong correlation was found between the proliferation of PBMCs in response to MycHSP70287-306 and BiP336-355. The immunization of HLA-DR4 transgenic mice with MycHSP70 induced the proliferation of T cells and development of anti-BiP antibodies. In contrast, the oral administration of MycHSP70287-306 resulted in the amelioration of collagen induced arthritis, serum antibody responses, and T cell proliferation. In conclusion, immune responses to MycHSP70 were associated with adaptive immunity against BiP in RA, and could be an important mechanism underlying the development of autoimmunity. PMID- 26927757 TI - Readmissions after major gynecologic oncology surgery. AB - OBJECTIVES: To examine the underlying indications, timing, and risk factors associated with unplanned hospital readmissions after major surgery for a gynecologic malignancy. METHODS: This is a retrospective database cohort study utilizing the National Surgical Quality Improvement Program database (NSQIP). The association between risk factors with respect to 30-day unplanned readmission was modeled using logistic regression. Timing of readmission and the primary reason of readmission was abstracted from the database. RESULTS: Overall, the unplanned readmission rate was 6.5% (832/12,804). On multivariate analysis, operative time>=3h (OR 1.39, p<0.001), open abdominal surgery (OR 2.2, p<0.001), any complication prior to discharge (OR 1.6, p<0.001), two or more additional surgical procedures (OR 1.34, p=0.003), or cervical cancer as the site of primary disease (OR 1.30, p=0.05) were noted to be independent predictors of readmission. To provide a convenient calculation of overall probability of readmission, we developed a nomogram of factors significantly predicting readmission. Overall, infections were a cause of 45% of the readmissions. Surgical Site Infections were the most common reason, accounting for 29.2% of all readmissions. A majority of the readmissions (approximately 75%) were within two weeks of discharge from the hospital. CONCLUSIONS: Efforts to reduce readmission rates should focus on identifying patients at a high risk of readmission and reducing surgical site infections. Additionally, prospective evaluation of interventions targeted at reducing readmissions should focus on the first two weeks after discharge from the hospital. PMID- 26927758 TI - Temporal Malignant Solitary Fibrous Tumor. PMID- 26927759 TI - Iatrogenic Phenol Injury Causing Facial Paralysis With Tympanic Membrane and Ossicular Necrosis. AB - OBJECTIVE: To describe a serious iatrogenic injury and propose means of reducing the risk of its reoccurrence. PATIENTS: A 21-year-old man who suffered facial paralysis, complete necrosis of the tympanic membrane, and ossicular discontinuity because of chemical burn from accidental application of copious amounts of topical anesthetic phenol into the ear. INTERVENTIONS: Conservative management of facial paralysis and delayed reconstruction of the tympanic membrane and ossicular chain. MAIN OUTCOME MEASURES: Gradual recovery to grade 1/6 facial function, successful repair of the tympanic membrane, but persistent 30-dB conductive hearing loss after partial ossicular replacement prosthesis presumably because of scarring. CONCLUSION: Phenol is a highly toxic chemical, topically to both skin and eyes. Absorbed through the skin it can have lethal cardiotoxicity. It is also potent neurotoxin at concentrations much lower (4-7%) than used for tympanic membrane anesthesia (89%) and has long been used therapeutically to destroy nerves in patients of contractions or intractable pain. Otologists need to have a healthy respect for the dangers of using phenol. As only a minute quantity is needed for tympanic anesthesia, commercially available prepackaged applicators are preferred. Storage of stock bottles of 89% phenol solutions in clinical settings risks injury to both patients and practitioners. PMID- 26927760 TI - Parallel-transmit-accelerated 2D Selective RF Excitation MR of the Temporal Bone: Enhanced Resolution of Labyrinthine and IAC Structures. AB - RATIONALE AND OBJECTIVES: The purpose of this study was to compare a standard T2 SPACE sequence (standard-SPACE) used in temporal bone imaging at 3 T with a new parallel-transmit-accelerated 2D-selective radio frequency excitation technique for SPACE which was either time-improved or resolution-improved. MATERIALS AND METHODS: Thirty-two consecutive patients were examined in this IRB-approved study using a standard T2 SPACE sequence, and then a time-improved zoomed SPACE sequence (short z-SPACE) with identical resolution but accelerated image acquisition and a resolution-improved zoomed SPACE sequence (high-resolution z SPACE) with identical acquisition time but higher resolution at a 3-T magnetic resonance imaging system. Signal-to-noise ratio (SNR) was measured within selected regions of interest. Image quality of anatomic temporal bone structures was determined by two independent readers using a four-point visual scale. RESULTS: Significant image quality improvement (p < 0.05) was observed in short z SPACE and high-resolution z-SPACE, especially in structures of the cochlea and also regarding the delineation of the cranial nerves within the internal auditory canal. SNR measurements showed a lower SNR in the short z-SPACE and high resolution z-SPACE sequences compared with standard-SPACE. CONCLUSION: At 3 T parallel transmission using the zoomed SPACE sequences improves the delineation of small anatomical structures within the temporal bone significantly. It is especially helpful in depicting cochlear and internal auditory canal anatomy and can therefore improve imaging in patients with temporal bone pathologies. PMID- 26927762 TI - Why we must value bank nurses. PMID- 26927764 TI - Number of higher-band nurses in the NHS is falling, figures show. PMID- 26927761 TI - MPR-CT Imaging for Stapes Prosthesis: Accuracy and Clinical Significance. AB - OBJECTIVES: The aims of this article are: 1) to re-evaluate the accuracy of multiple planar reconstruction computed tomography (MPR-CT) imaging on stapes prosthesis parameters, and 2) to clarify possible relationships between prosthesis intravestibular depth and postoperative hearing outcomes. PATIENTS: Seventy patients (46 women and 24 men; 32 right and 38 left sides) with the mean age of 40 years (range, 19-62 yr) with clinical otosclerosis. INTERVENTION(S): All patients underwent stapedotomy and were implanted with the same type of titanium piston prosthesis by the same surgeon. MAIN OUTCOME MEASURE(S): Postoperative MPR-CTs were obtained at patients' follow-up visits. The length and intravestibular depth of the stapes prosthesis (including absolute and relative depth) were calculated from the MPR-CT imaging. Relationships between the intravestibular depth of the prosthesis and hearing outcomes (pre- and postoperative audiograms) were analyzed using Spearman correlation analyses. RESULTS: The length of the prosthesis was overestimated by 1.8% (0.1 mm) by the MPR-CT imaging. Axial and coronal measurements were significantly correlated (p < 0.05). There was great intersubject variability in hearing outcomes differed insignificantly, regardless of intravestibular depth within the security range. No relationships were found between the intravestibular depth of the stapes prosthesis, as measured with MPR-CT, and postoperative hearing results. CONCLUSIONS: MPR-CT can provide an accurate estimation of stapes prosthesis parameters. However, the prosthesis intravestibular depth did not seem to affect postoperative hearing outcomes. PMID- 26927765 TI - Nursing associates' role distinct from nurses', says government. PMID- 26927767 TI - Hospital hygiene and handwashing still not good enough, say MPs. PMID- 26927768 TI - Stronger leadership needed to reverse staff shortfall. PMID- 26927769 TI - College manifesto calls for recognition of senior nurses. PMID- 26927770 TI - Council to modernise pre-registration education standards. PMID- 26927771 TI - Efficiency drive in NHS must not reduce safety, says RCN. PMID- 26927772 TI - Productivity still 'not good enough' says Carter review. PMID- 26927773 TI - Redesigning the health service in real time. PMID- 26927775 TI - Vantage point - Unity or chaos. PMID- 26927777 TI - Cultural sensibility. PMID- 26927778 TI - Susan Williams - International outlook. PMID- 26927781 TI - Matching skills with needs. PMID- 26927789 TI - Managing reliance on temporary agency staff. AB - Amid spiralling agency staff costs, in November 2015 Monitor and the Trust Development Authority placed caps on the hourly rate that NHS trusts can pay agency staff, and informed all NHS and foundation trusts that they are required to procure agency staff through approved frameworks. This article suggests ways in which management can maintain these requirements while ensuring safe staffing levels and high-quality care delivery. PMID- 26927790 TI - Evaluation of a nurse leadership development programme. AB - The challenge for nursing leaders responsible for workforce planning is to predict the knowledge, skills and abilities required to lead future healthcare delivery systems effectively. Succession planning requires a constant, competitive pool of qualified nursing leader candidates, and retention of those interested in career growth. Formal nursing leadership education in the United States is available through graduate education and professional nursing organisation programmes, such as the Emerging Nurse Leader Institute of the American Organization of Nurse Executives. However, there is also a need for local development programmes tailored to the needs of individual organisations. Leaders at Geisinger Health System, one of the largest rural health systems in the US, identified the need for an internal professional development scheme for nurses. In 2013 the Nurses Emerging as Leaders programme was developed to prepare nurse leaders for effective leadership and successful role transition. This article describes the programme and an evaluation of its effectiveness. PMID- 26927791 TI - Social network of an internationally connected nurse leader. AB - Over the past decade, there has been a proliferation of social media sites offering the opportunity for colleagues to connect with each other locally, nationally and internationally. Meanwhile, nurses have been increasingly using social network analytical techniques to look at team functioning and communication pathways. This article uses the author's LinkedIn social network to illustrate how analysis can offer insights into the connections, and how the results can be used to professional advantage. PMID- 26927792 TI - Leading by learning. PMID- 26927793 TI - Half of 23 Belgian dog breeds has a compromised genetic diversity, as revealed by genealogical and molecular data analysis. AB - The genetic diversity in 23 dog breeds raised in Belgium was investigated using both genealogical analysis and microsatellite markers. Some of these breeds are native breeds, with only small populations maintained. Pedigree and molecular data, obtained from the Belgian kennel club, were used to calculate the inbreeding coefficients, realised effective population size as well as probabilities of gene origin and average observed heterozygosity. Inbreeding coefficients ranged from 0.8 to 44.7% and realised effective population size varied between 3.2 and 829.1, according to the used method and breed. Mean observed heterozygosity ranged from 0.47 to 0.73. Both pedigree and molecular methods reveal low genetic diversity and presence of bottlenecks, especially in native Belgian breeds with small population sizes. Furthermore, principal component analysis on the set of investigated diversity parameters revealed no groups of breeds that could be identified in which similar breeding strategies could be applied to maintain genetic diversity. PMID- 26927794 TI - The combination therapy of high-intensity focused ultrasound with radiotherapy in locally advanced pancreatic carcinoma. AB - BACKGROUND: The aim of the present study is to evaluate the effectiveness of the combined application of high-intensity focused ultrasound (HIFU) and radiotherapy in the treatment of locally advanced pancreatic carcinoma (LAPC). METHODS: A total number of sixteen patients with LAPC started treatment beginning with HIFU and radiotherapy 1 week after the HIFU treatment. Evaluation of the effectiveness of treatment was performed using main clinical symptoms, serum levels of CA-19-9, Response Evaluation Criteria in Solid Tumors (RECIST) guidelines, and the Kaplan Meier method for estimating median overall survival (OS). The occurrence of adverse reactions was recorded. RESULTS: The main clinical symptoms including abdominal pain and lower back pain were alleviated, and the mean visual analog scale (VAS) pain score declined from 5.1 points to just 3.3 points immediately after the HIFU treatment. The median pain relief time was 5.6 months after radiotherapy, serum CA-19-9 levels began to decrease significantly 1 week after the HIFU treatment, from 102.1 to 60.8 U/ml, and the median continuous decline time was 4.3 months after radiotherapy. Partial response (PR) was observed in seven of sixteen patients, with stable disease (SD) in four patients, and progressive disease (PD) in the remaining five patients at 6 months after radiotherapy. Serum levels of amylopsin and lipase were not elevated to abnormal levels. The median OS was 14 months. No serious adverse reactions occurred. CONCLUSIONS: Treatment with both HIFU and radiotherapy can quickly improve symptoms and the quality of life and prolong survival lengths. This combination might be a promising therapeutic treatment for patients with LAPC. PMID- 26927795 TI - Metagenomic Characterisation of the Viral Community of Lough Neagh, the Largest Freshwater Lake in Ireland. AB - Lough Neagh is the largest and the most economically important lake in Ireland. It is also one of the most nutrient rich amongst the world's major lakes. In this study, 16S rRNA analysis of total metagenomic DNA from the water column of Lough Neagh has revealed a high proportion of Cyanobacteria and low levels of Actinobacteria, Acidobacteria, Chloroflexi, and Firmicutes. The planktonic virome of Lough Neagh has been sequenced and 2,298,791 2*300 bp Illumina reads analysed. Comparison with previously characterised lakes demonstrates that the Lough Neagh viral community has the highest level of sequence diversity. Only about 15% of reads had homologs in the RefSeq database and tailed bacteriophages (Caudovirales) were identified as a major grouping. Within the Caudovirales, the Podoviridae and Siphoviridae were the two most dominant families (34.3% and 32.8% of the reads with sequence homology to the RefSeq database), while ssDNA bacteriophages constituted less than 1% of the virome. Putative cyanophages were found to be abundant. 66,450 viral contigs were assembled with the largest one being 58,805 bp; its existence, and that of another 34,467 bp contig, in the water column was confirmed. Analysis of the contigs confirmed the high abundance of cyanophages in the water column. PMID- 26927796 TI - POU2AF1 Functions in the Human Airway Epithelium To Regulate Expression of Host Defense Genes. AB - In the process of seeking novel lung host defense regulators by analyzing genome wide RNA sequence data from normal human airway epithelium, we detected expression of POU domain class 2-associating factor 1 (POU2AF1), a known transcription cofactor previously thought to be expressed only in lymphocytes. Lymphocyte contamination of human airway epithelial samples obtained by bronchoscopy and brushing was excluded by immunohistochemistry staining, the observation of upregulation of POU2AF1 in purified airway basal stem/progenitor cells undergoing differentiation, and analysis of differentiating single basal cell clones. Lentivirus-mediated upregulation of POU2AF1 in airway basal cells induced upregulation of host defense genes, including MX1, IFIT3, IFITM, and known POU2AF1 downstream genes HLA-DRA, ID2, ID3, IL6, and BCL6. Interestingly, expression of these genes paralleled changes of POU2AF1 expression during airway epithelium differentiation in vitro, suggesting POU2AF1 helps to maintain a host defense tone even in pathogen-free condition. Cigarette smoke, a known risk factor for airway infection, suppressed POU2AF1 expression both in vivo in humans and in vitro in human airway epithelial cultures, accompanied by deregulation of POU2AF1 downstream genes. Finally, enhancing POU2AF1 expression in human airway epithelium attenuated the suppression of host defense genes by smoking. Together, these findings suggest a novel function of POU2AF1 as a potential regulator of host defense genes in the human airway epithelium. PMID- 26927797 TI - Alternatively Activated Macrophages Boost Induced Regulatory T and Th17 Cell Responses during Immunotherapy for Colitis. AB - Induced regulatory T (iTreg) and Th17 cells promote mucosal homeostasis. We used a T cell transfer model of colitis to compare the capacity of iTreg and Th17 cells to develop in situ following the transfer of naive CD4(+)CD45RB(hi)T cells intoRag1(-/-)C57BL/6 or BALB/c mice, the prototypical Th1/M1- and Th2/M2-prone strains. We found that the frequency and number of Foxp3(+)iTreg cells and Th17 cells were significantly reduced in C57BL/6 mice compared with the BALB/c strain. C57BL/6 mice with colitis were also resistant to natural Treg cell immunotherapy. Pretreatment of C57BL/6Rag1(-/-)mice with IL-4 plus IL-13, or with M2a but not M1 macrophages, dramatically increased the generation of iTreg and Th17 cells. Importantly, M2a transfers, either as a pretreatment or in mice with established colitis, allowed successful immunotherapy with natural Treg cells. M2a macrophages also reduced the generation of pathogenic iTreg cells that lost Foxp3 expression, suggesting that they stabilize the expression of Foxp3. Thus, polarized M2a macrophages drive a directionally concordant expansion of the iTreg Th17 cell axis and can be exploited as a therapeutic adjuvant in cell-transfer immunotherapy to re-establish mucosal tolerance. PMID- 26927798 TI - Cutting Edge: CLEC5A Mediates Macrophage Function and Chronic Obstructive Pulmonary Disease Pathologies. AB - Chronic obstructive pulmonary disease (COPD) is a devastating disease with no effective therapies. We investigated the role of the C-type lectin receptor, CLEC5A, in macrophage activation and pulmonary pathogenesis in a mouse model of COPD. We demonstrate that CLEC5A is expressed on alveolar macrophages in mice exposed long-term to cigarette smoke (CS), as well as in human smokers. We also show that CLEC5A-mediated activation of macrophages enhanced cytokine elaboration alone, as well as in combination with LPS or GM-CSF in CS-exposed mice. Furthermore, usingClec5a-deficient mice, we demonstrate that CS-induced macrophage responsiveness is mediated by CLEC5A, and CLEC5A is required for the development of inflammation, proinflammatory cytokine expression, and airspace enlargement. These findings suggest a novel mechanism that promotes airway inflammation and pathologies in response to CS exposure and identifies CLEC5A as a novel target for the therapeutic control of COPD pathogenesis. PMID- 26927801 TI - Self-Propelled Vesicles Induced by the Mixing of Two Polymeric Aqueous Solutions through a Vesicle Membrane Far from Equilibrium. AB - This study describes the development of self-propelled vesicles using transient interfacial energy in an aqueous two-phase system composed of polyethylene glycol (PEG), dextran (DEX), and water. The transient interfacial energy was generated at the mixing boundary between the PEG and DEX solutions when the two miscible liquids were in contact with each other far from equilibrium. Vesicles encapsulating 20 wt % DEX solution traveled spontaneously when the PEG concentration in the environmental media was >15 wt %. The motility of the vesicles varied with the permeability of the vesicle membrane. The permeability increased significantly when the concentration of PEG was >15 wt %. PEG had a profound effect not only on mass transfer through the membrane but also on the motility of the vesicles. PMID- 26927799 TI - HIV Skews the Lineage-Defining Transcriptional Profile of Mycobacterium tuberculosis-Specific CD4+ T Cells. AB - HIV-infected persons are at greater risk of developing tuberculosis (TB) even before profound CD4 loss occurs, suggesting that HIV alters CD4(+) T cell functions capable of containing bacterial replication. An effective immune response to Mycobacterium tuberculosis most likely relies on the development of a balanced CD4 response, in which distinct CD4(+) Th subsets act in synergy to control the infection. To define the diversity of M. tuberculosis-specific CD4(+) Th subsets and determine whether HIV infection impacts such responses, the expression of lineage-defining transcription factors T-bet, Gata3, RORgammat, and Foxp3 was measured in M. tuberculosis-specific CD4(+) T cells in HIV-uninfected (n = 20) and HIV-infected individuals (n = 20) with latent TB infection. Our results show that, upon 5-d restimulation in vitro, M. tuberculosis-specific CD4(+) T cells from healthy individuals have the ability to exhibit a broad spectrum of Th subsets, defined by specific patterns of transcription factor coexpression. These transcription factor profiles were skewed in HIV-infected individuals where the proportion of T-bet(high)Foxp3(+) M. tuberculosis-specific CD4(+) T cells was significantly decreased (p = 0.002) compared with HIV uninfected individuals, a change that correlated inversely with HIV viral load (p = 0.0007) and plasma TNF-alpha (p = 0.027). Our data demonstrate an important balance in Th subset diversity defined by lineage-defining transcription factor coexpression profiles that is disrupted by HIV infection and suggest a role for HIV in impairing TB immunity by altering the equilibrium of M. tuberculosis specific CD4(+) Th subsets. PMID- 26927800 TI - Antagonism of the STING Pathway via Activation of the AIM2 Inflammasome by Intracellular DNA. AB - Recent evidence has indicated that innate immune sensing of cytosolic DNA in dendritic cells via the host STING pathway is a major mechanism leading to spontaneous T cell responses against tumors. However, the impact of the other major pathway triggered by intracellular DNA, the absent in melanoma 2 (AIM2) inflammasome, on the functional output from the stimulator of IFN genes (STING) pathway is poorly understood. We found that dendritic cells and macrophages deficient in AIM2, apoptosis-associated specklike protein, or caspase-1 produced markedly higher IFN-beta in response to DNA. Biochemical analyses showed enhanced generation of cyclic GMP-AMP, STING aggregation, and TANK-binding kinase 1 and IFN regulatory factor 3 phosphorylation in inflammasome-deficient cells. Induction of pyroptosis by the AIM2 inflammasome was a major component of this effect, and inhibition of caspase-1 reduced cell death, augmenting phosphorylation of TANK-binding kinase 1/IFN regulatory factor 3 and production of IFN-beta. Our data suggest that in vitro activation of the AIM2 inflammasome in murine macrophages and dendritic cells leads to reduced activation of the STING pathway, in part through promoting caspase-1-dependent cell death. PMID- 26927802 TI - Anti-EGFR Therapy for Metastatic Colorectal Cancer in the Era of Extended RAS Gene Mutational Analysis. AB - Colorectal cancer (CRC) is one of the leading causes of cancer-related mortality worldwide. In the past 2 decades, advances in cancer therapeutics allowed for a remarkable improvement in terms of survival for patients with metastatic CRC. The advent of targeted therapy, coupled with more efficient chemotherapy regimens, was the pillar achievement that contributed to the success of CRC therapy. Cetuximab and panitumumab, monoclonal antibodies targeting the epidermal growth factor receptor pathway, are the focus of this review since their mechanism of action and efficiency are closely related to the mutational status of a predictive biomarker, the Kristen rat Sarcoma viral oncogene (KRAS). More recently, another biomarker, the neuroblastoma rat sarcoma viral oncogene (NRAS), was found to be as valuable for the refinement of this targeted therapy. The arguments for the use of extended analysis of the RAS gene are thoroughly reviewed because they directly affect the choice of targeted agents and potentially the choice of backbone chemotherapy. PMID- 26927803 TI - Management of Multiple Myeloma with Second-Generation Antibody-Drug Conjugates. AB - The antibody-drug conjugate (ADC) is a combination of a cytotoxic agent and monoclonal antibodies (mAbs) through a stable specialized chemical linker. After ADC binds to the target antigen, the conjugate is internalized and toxin is released, leading to the death of a target cell. Lorvotuzumab mertansine, indatuximab ravtansine, and milatuzumab-doxorubicin are currently under clinical development for use in multiple myeloma (MM). Preliminary data from recent studies indicate that these agents induce responses in patients with relapsed and/or refractory MM and have an acceptable safety profile. PMID- 26927804 TI - Long-Term Clinical Outcomes of a Biodegradable Polymer-Based Biolimus-Eluting Stent. AB - OBJECTIVES: To investigate the long-term clinical outcomes of biolimus-eluting stents with biodegradable polymers in real-world clinical practice. BACKGROUND: Long-term clinical outcomes of biolimus-eluting stents have not been clearly established. METHODS: A total of 824 all-comer patients (971 lesions) treated with unrestricted implantation of a biolimus-eluting stent with a biodegradable polymer were prospectively enrolled. Patients were divided into complex (413 patients) versus noncomplex (411 patients) groups according to the complexity of coronary lesions. Long-term clinical outcomes for stent efficacy (target lesion revascularization) and safety (composite of cardiac death, target lesion-related myocardial infarction, and definite or probable stent thrombosis) were compared between the two groups during 5 years of follow-up. RESULTS: The complex group showed higher rates of decreased left ventricular ejection fraction, impaired renal function, previous history of myocardial infarction, and diabetes mellitus compared to the noncomplex group. In the overall population, the 5-year cumulative rate of target lesion revascularization was 4.8% (8.3% in the complex group vs 1.6% in the noncomplex group, P < 0.001). For stent safety, the 5-year cumulative rate for a composite of cardiac death, target lesion-related myocardial infarction, and stent thrombosis was 2.5% overall (3.9% in the complex group vs 1.1% in the noncomplex group, P = 0.010). Overall 5-year cumulative rate of stent thrombosis was 0.4% (0.5% in the complex vs 0.2% in the noncomplex group, P = 0.561) with no very late stent thrombosis (VLST). CONCLUSIONS: Biodegradable polymer-based biolimus-eluting stents showed favorable efficacy and safety in all-comer patients during 5 years of follow-up. PMID- 26927805 TI - The Role of Aldosterone in Obesity-Related Hypertension. AB - Obese subjects often have hypertension and related cardiovascular and renal diseases, and this has become a serious worldwide health problem. In obese subjects, impaired renal-pressure natriuresis causes sodium retention, leading to the development of salt-sensitive hypertension. Physical compression of the kidneys by visceral fat and activation of the sympathetic nervous system, renin angiotensin systems (RAS), and aldosterone/mineralocorticoid receptor (MR) system are involved in this mechanism. Obese subjects often exhibit hyperaldosteronism, with increased salt sensitivity of blood pressure (BP). Adipose tissue excretes aldosterone-releasing factors, thereby stimulating aldosterone secretion independently of the systemic RAS, and aldosterone/MR activation plays a key role in the development of hypertension and organ damage in obesity. In obese subjects, both salt sensitivity of BP, enhanced by obesity-related metabolic disorders including aldosterone excess, and increased dietary sodium intake are closely related to the incidence of hypertension. Some salt sensitivity-related gene variants affect the risk of obesity, and together with salt intake, its combination is possibly associated with the development of hypertension in obese subjects. With high salt levels common in modern diets, salt restriction and weight control are undoubtedly important. However, not only MR blockade but also new diagnostic modalities and therapies targeting and modifying genes that are related to salt sensitivity, obesity, or RAS regulation are expected to prevent obesity and obesity-related hypertension. PMID- 26927806 TI - Molecular characterization of HIV-1 Nef and ACOT8 interaction: insights from in silico structural predictions and in vitro functional assays. AB - HIV-1 Nef interacts with several cellular proteins, among which the human peroxisomal thioesterase 8 (ACOT8). This interaction may be involved in the endocytosis regulation of membrane proteins and might modulate lipid composition in membrane rafts. Nef regions involved in the interaction have been experimentally characterized, whereas structural details of the ACOT8 protein are unknown. The lack of structural information hampers the comprehension of the functional consequences of the complex formation during HIV-1 infection. We modelled, through in silico predictions, the ACOT8 structure and we observed a high charge complementarity between Nef and ACOT8 surfaces, which allowed the identification of the ACOT8 putative contact points involved in the interaction. The predictions were validated by in vitro assays through the development of ACOT8 deletion mutants. Coimmunoprecipitation and immunofluorescence analyses showed that ACOT8 Arg(45)-Phe(55) and Arg(86)-Pro(93) regions are involved in Nef association. In addition, K91S mutation abrogated the interaction with Nef, indicating that Lys(91) plays a key role in the interaction. Finally, when associated with ACOT8, Nef may be preserved from degradation. These findings improve the comprehension of the association between HIV-1 Nef and ACOT8, helping elucidating the biological effect of their interaction. PMID- 26927807 TI - Inhibitory effects of geranium essential oil and its major component, citronellol, on degranulation and cytokine production by mast cells. AB - We investigated the effects of geranium essential oil (GEO) on anaphylaxis. GEO can exert antioxidant and anti-inflammatory effects, but its roles in allergic reactions are incompletely understood. Here, we used mouse cells to show that GEO inhibited the degranulation of cultured mast cells (CMCs). Citronellol is the major component of GEO and inhibited CMC degranulation. The l-enantiomer of citronellol more effectively suppressed CMC degranulation than did d-citronellol. We also examined whether citronellol could inhibit the immunoglobulin (Ig) E induced production of tumor necrosis factor (TNF)-alpha. Treatment with various concentrations of citronellol before CMC activation with IgE significantly inhibited the induction of TNF-alpha in a dose-dependent manner. Mechanistically, citronellol suppressed the phosphorylation of mitogen-activated protein kinase (ERK), which is critical for ERK activation and the production of inflammatory cytokines in mast cells. These findings suggest that citronellol may represent a candidate compound for the effective treatment of allergic diseases. PMID- 26927809 TI - Laser-Induced Photic Injury Phenocopies Macular Dystrophy. AB - OBJECTIVE: To describe the phenotypes associated with laser-induced retinal damage in children. METHODS: Five patients with maculopathy and reduced visual acuity associated with laser pointer use were evaluated. Best-corrected visual acuity, retinal structure, and function were monitored with color fundus, infrared (IR), and red-free images, fundus autofluorescence (AF), spectral domain optical coherence tomography (SD-OCT), and full-field electroretinography (ERG). RESULTS: All five laser pointer injury patients had retinal lesions resembling a macular dystrophy (one bilateral and four unilateral). These lesions were irregular in shape but all had a characteristic dendritic appearance with linear streaks radiating from the lesion. Photoreceptor damage was present in all patients, but serial OCT monitoring showed that subsequent photoreceptor recovery occurred over time in the eyes of at least four patients. One patient also had bilateral pigment epithelial detachments (PED). Both hyper- and hypoautofluorecence were observed in the laser damage area. CONCLUSIONS: In general, OCT and IR images are quite useful to diagnose laser damage, but AF is not as sensitive. Laser pointer damage in children can occasionally be misdiagnosed as a macular dystrophy disease, but the distinctive lesions and OCT features are helpful for differentiating laser damage from other conditions. PMID- 26927810 TI - Vici syndrome: a review. AB - Vici syndrome [OMIM242840] is a severe, recessively inherited congenital disorder characterized by the principal features of callosal agenesis, cataracts, oculocutaneous hypopigmentation, cardiomyopathy, and a combined immunodeficiency. Profound developmental delay, progressive failure to thrive and acquired microcephaly are almost universal, suggesting an evolving (neuro) degenerative component. In most patients there is additional variable multisystem involvement that may affect virtually any organ system, including lungs, thyroid, liver and kidneys. A skeletal myopathy is consistently associated, and characterized by marked fibre type disproportion, increase in internal nuclei, numerous vacuoles, abnormal mitochondria and glycogen storage. Life expectancy is markedly reduced.Vici syndrome is due to recessive mutations in EPG5 on chromosome 18q12.3, encoding ectopic P granules protein 5 (EPG5), a key autophagy regulator in higher organisms. Autophagy is a fundamental cellular degradative pathway conserved throughout evolution with important roles in the removal of defective proteins and organelles, defence against infections and adaptation to changing metabolic demands. Almost 40 EPG mutations have been identified to date, most of them truncating and private to individual families.The differential diagnosis of Vici syndrome includes a number of syndromes with overlapping clinical features, neurological and metabolic disorders with shared CNS abnormalities (in particular callosal agenesis), and primary neuromuscular disorders with a similar muscle biopsy appearance. Vici syndrome is also the most typical example of a novel group of inherited neurometabolic conditions, congenital disorders of autophagy.Management is currently largely supportive and symptomatic but better understanding of the underlying autophagy defect will hopefully inform the development of targeted therapies in future. PMID- 26927811 TI - Three-month risk-benefit profile of anticoagulation after stroke with atrial fibrillation: The SAMURAI-Nonvalvular Atrial Fibrillation (NVAF) study. AB - AIMS: This study was performed to determine the short-term risk-benefit profiles of patients treated with oral anticoagulation for acute ischemic stroke or transient ischemic attack using a multicenter, prospective registry. METHODS: A total of 1137 patients (645 men, 77 +/- 10 years old) with acute ischemic stroke/transient ischemic attack taking warfarin (662 patients) or non-vitamin K antagonist oral anticoagulants (dabigatran in 205, rivaroxaban in 245, apixaban in 25 patients) for nonvalvular atrial fibrillation who completed a three-month follow-up survey were studied. Choice of anticoagulants was not randomized. Primary outcome measures were stroke/systemic embolism and major bleeding. RESULTS: Both warfarin and non-vitamin K antagonist oral anticoagulants were initiated within four days after stroke/transient ischemic attack onset in the majority of cases. Non-vitamin K antagonist oral anticoagulant users had lower ischemia- and bleeding-risk indices (CHADS2, CHA2DS2-VASc, HAS-BLED) and milder strokes than warfarin users. The three-month cumulative rate of stroke/systemic embolism was 3.06% (95% CI 1.96%-4.74%) in warfarin users and 2.84% (1.65%-4.83%) in non-vitamin K antagonist oral anticoagulant users (adjusted HR 0.96, 95% CI 0.44-2.04). The rate of major bleeding was 2.61% (1.60%-4.22%) and 1.11% (0.14% 1.08%), respectively (HR 0.63, 0.19-1.78); that for intracranial hemorrhage was marginally significantly lower in non-vitamin K antagonist oral anticoagulant users (HR 0.17, 0.01-1.15). Major bleeding did not occur in non-vitamin K antagonist oral anticoagulant users with a CHADS2 score <4 or those with a discharge modified Rankin Scale score <=2. CONCLUSIONS: Stroke or systemic embolism during the initial three-month anticoagulation period after stroke/transient ischemic attack was not frequent as compared to previous findings regardless of warfarin or non-vitamin K antagonist oral anticoagulants were used. Intracranial hemorrhage was relatively uncommon in non-vitamin K antagonist oral anticoagulant users, although treatment assignment was not randomized. Early initiation of non-vitamin K antagonist oral anticoagulants during the acute stage of stroke/transient ischemic attack in real-world clinical settings seems safe in bleeding-susceptible Japanese population. PMID- 26927812 TI - Molecular Double Ionization Using Strong Field Few-Cycle Laser Pulses. AB - We study strong field double ionization of a series of organic molecules by making use of coincidence detection of fragment ions. We measure the double ionization yield as a function of pulse duration, intensity, polarization, and molecular conjugation. For conjugated molecules we find strong enhancement in the double ionization rate over what one would expect on the basis of tunneling or multiphoton ionization rates. Calculations reveal a correlation between the electronic structure of the different molecules and the observed double ionization yields, highlighting the removal of electrons from inner orbitals. PMID- 26927814 TI - Expanding the social media presence of the Journal of Neurointerventional Surgery: editor's report. AB - The use of social media is pervasive throughout society and serves many purposes. Traditional forms of advertising are being upended as vendors recognize the unique abilities of social media platforms to target their messages to specific customers. Peer reviewed medical and professional journals are beginning to develop their own initiatives using social media to advertize unique content. We present the nascent Journal of NeuroInterventional Surgery experience. PMID- 26927813 TI - Novel universal influenza virus vaccine approaches. AB - Seasonal influenza virus vaccines have to be re-formulated and re-administered on an annual basis due to antigenic drift of the influenza virus surface glycoproteins. In addition, seasonal vaccines show limited efficacy against novel pandemic influenza virus strains, and producing tailored vaccines for these strains in a timely manner is challenging. Several novel broadly protective vaccine candidates targeting the conserved stalk domain of the viral hemagglutinin have been developed. Here we review these novel constructs and discuss several important findings and considerations regarding the protective efficacy of stalk-based vaccines. PMID- 26927815 TI - Flexibility-rigidity index for protein-nucleic acid flexibility and fluctuation analysis. AB - Protein-nucleic acid complexes are important for many cellular processes including the most essential functions such as transcription and translation. For many protein-nucleic acid complexes, flexibility of both macromolecules has been shown to be critical for specificity and/or function. The flexibility-rigidity index (FRI) has been proposed as an accurate and efficient approach for protein flexibility analysis. In this article, we introduce FRI for the flexibility analysis of protein-nucleic acid complexes. We demonstrate that a multiscale strategy, which incorporates multiple kernels to capture various length scales in biomolecular collective motions, is able to significantly improve the state of art in the flexibility analysis of protein-nucleic acid complexes. We take the advantage of the high accuracy and O(N) computational complexity of our multiscale FRI method to investigate the flexibility of ribosomal subunits, which are difficult to analyze by alternative approaches. An anisotropic FRI approach, which involves localized Hessian matrices, is utilized to study the translocation dynamics in an RNA polymerase. PMID- 26927816 TI - Pharmacodynamics of alacepril in healthy cats. AB - Objectives The aims of this study were to investigate the pharmacodynamics of alacepril and to determine the appropriate dose for clinical usage in cats. Methods Six experimental cats were used. Each cat received alacepril orally at a single dose of 1 mg/kg, 2 mg/kg and 3 mg/kg. Blood samples were collected before administration and at 2, 4, 6, 8, 12, 24, 36, 48 and 72 h after administration to measure serum angiotensin converting enzyme (ACE) activity. Systolic blood pressure was also measured at the same time point. Results Dose-dependent inhibition of ACE activity was observed. Doses of 2 mg/kg and 3 mg/kg alacepril were considered to effectively inhibit ACE activity. There were no significant differences in systolic blood pressue among groups at any time point. Conclusions and relevance Alacepril 2-3 mg/kg q24h may be an appropriate dosage for clinical use in cats. PMID- 26927817 TI - Decontamination of carpet exposed to Microsporum canis hairs and spores. AB - Objectives The objective of this study was to evaluate the efficacy of vacuuming and three carpet cleaning methods for the removal of Microsporum canis spores and hairs from experimentally contaminated carpets. Methods Sterile Berber carpeting was artificially contaminated with naturally infective M canis hairs and spores. Carpet swatches were vacuumed for 10 s, 30 s and 60 s, and then cultured. Three carpet cleaning methods were evaluated on area rugs experimentally contaminated with infective material: a beater brush carpet shampooing, beater brush carpet shampooing post-disinfectant application and hot water extraction. Home cleaning products labeled as having efficacy against Trichophyton species were used in addition to 1% potassium peroxymonosulfate. Carpets were cultured at 24 h, 48 h and 7 days after cleaning. Good efficacy was no detectable spores at post cleaning culture. Results All pretreatment carpet samples were culture positive for M canis (>300 colony-forming units [cfu]/site). Vacuuming did not decontaminate carpets but did remove intact hairs. Spores were not detected by wipe samples after two washings with an upright beater brush carpet shampooer or pretreatment with a disinfectant prior to carpet shampooing. Carpets cleaned with one hot water extraction technique had a decrease from 300 cfu/site to a mean of 5.5 cfu/site at 24 and 48 h post-cleaning and 2 cfu/site at day 7. The use of disinfectants was associated with odor, even when dry, and permanent discoloration. Hot water extraction cleaning was associated with the fastest drying time and no discoloration. Conclusions and relevance Carpets exposed to M canis can be disinfected via carpet shampooing or hot water extraction cleaning. Vacuuming of carpets is recommended to remove infective hairs. For homes, exposed carpeting can be decontaminated by routine washing with a carpet shampooer (twice) or hot water extraction. Use of pretreatment with a disinfectant is recommended when a high level of overall decontamination is needed in an animal facility with necessary carpeted surfaces (eg, entryway carpet mats). PMID- 26927818 TI - Evaluation of two raw diets vs a commercial cooked diet on feline growth. AB - Objectives The objective of this study was to determine if two raw feline diets were nutritionally adequate for kittens. Methods Twenty-four 9-week-old kittens underwent an Association of American Feed Control Officials' (AAFCO) 10 week growth feeding trial with two raw diet groups and one cooked diet group (eight kittens in each). Morphometric measurements (weight, height and length), complete blood counts, serum chemistry, whole blood taurine and fecal cultures were evaluated. Results Overall, the growth parameters were similar for all diet groups, indicating the two raw diets used in this study supported feline growth, within the limitations of an AAFCO growth feeding trial. Kittens fed the raw diets had lower albumin ( P = 0.010) and higher globulin ( P = 0.04) levels than the kittens fed the cooked diet. These lower albumin levels were not clinically significant, as all groups were still within normal age reference intervals. A red cell microcytosis ( P = 0.001) was noted in the combination raw diet group. Increases in fecal Clostridium perfringens were noted in all groups, along with positive fecal Salmonella serovar Heidelberg and Clostridium difficile toxin in the combination raw diet group. Conclusions and relevance The majority of the parameters for feline growth were similar among all groups, indicating the two raw diets studied passed an AAFCO growth trial. In theory, it is possible to pass an AAFCO growth trial but still have nutrient deficiencies in the long term due to liver and fat storage depots. Some of the raw feeders had elevated globulin and microcytosis, likely associated with known enteropathogenic exposure. Disease risks to both pets and owners are obvious. Additional research in this area is needed to investigate the impact of raw diets on the health of domestic cats. PMID- 26927819 TI - Detection of Leptospira DNA in urine and presence of specific antibodies in outdoor cats in Germany. AB - Objectives Clinical manifestation of infection with Leptospira species in cats is rare. Nevertheless, cats can develop specific antibodies against the spirochetes after infection. In Canada, Taiwan and the USA it was recently demonstrated that naturally infected cats can also shed DNA from pathogenic Leptospira species in their urine, but the zoonotic potential of infected cats is still unclear. The objective of this study was to demonstrate if outdoor cats in Germany shed DNA from pathogenic Leptospira species in their urine. As a second aim, antibody prevalence was determined. Methods Two hundred and fifteen outdoor cats were prospectively recruited. Urine samples were tested by real-time PCR targeting the lipL32 gene of pathogenic Leptospira species. Antibody titres against eight serovars (Australis, Autumnalis, Bratislava, Canicola, Copenhageni, Grippotyphosa, Pomona, Saxkoebing) belonging to seven serogroups (Australis, Autumnalis, Canicola, Grippotyphosa, Icterohaemorrhagiae, Pomona, Sejroe) were determined by microscopic agglutination test. Results Urine samples from 7/215 cats (3.3%; 95% confidence interval [CI] 0.9-5.7) were PCR-positive. Specific antibodies were detected in 35/195 cats (17.9%; 95% CI: 12.5-23.3) with titres ranging from 1:100 to 1:6400. Australis, Bratislava and Grippotyphosa were the most common serovars. Conclusions and relevance Outdoor cats in Germany can shed DNA from pathogenic Leptospira species. Therefore, outdoor cats should be considered as a possible source of infection for dogs or humans. Further studies are needed to determine the role of Leptospira species as a cause of disease in cats. PMID- 26927820 TI - Morphology Effect of Vertical Graphene on the High Performance of Supercapacitor Electrode. AB - Graphene and its composites are widely investigated as supercapacitor electrodes due to their large specific surface area. However, the severe aggregation and disordered alignment of graphene sheets hamper the maximum utilization of its surface area. Here we report an optimized structure for supercapacitor electrode, i.e., the vertical graphene sheets, which have a vertical structure and open architecture for ion transport pathway. The effect of morphology and orientation of vertical graphene on the performance of supercapacitor is examined using a combination of model calculation and experimental study. Both results consistently demonstrate that the vertical graphene electrode has a much superior performance than that of lateral graphene electrode. Typically, the areal capacitances of a vertical graphene electrode reach 8.4 mF/cm(2) at scan rate of 100 mV/s; this is about 38% higher than that of a lateral graphene electrode and about 6 times higher than that of graphite paper. To further improve its performance, a MnO2 nanoflake layer is coated on the surface of graphene to provide a high pseudocapacitive contribution to the overall areal capacitance which increases to 500 mF/cm(2) at scan rate of 5 mV/s. The reasons for these significant improvements are studied in detail and are attributed to the fast ion diffusion and enhanced charge storage capacity. The microscopic manipulation of graphene electrode configuration could greatly improve its specific capacitance, and furthermore, boost the energy density of supercapacitor. Our results demonstrate that the vertical graphene electrode is more efficient and practical for the high performance energy storage device with high power and energy densities. PMID- 26927821 TI - Dietary Fiber-Induced Changes in the Structure and Thermal Properties of Gluten Proteins Studied by Fourier Transform-Raman Spectroscopy and Thermogravimetry. AB - Interactions between gluten proteins and dietary fiber supplements at the stage of bread dough formation are crucial in the baking industry. The dietary fiber additives are regarded as a source of polysaccharides and antioxidants, which have positive effects on human health. The fiber enrichment of bread causes a significant reduction in its quality, which is connected with changes in the structure of gluten proteins. Changes in the structure of gluten proteins and their thermal properties induced by seven commercial dietary fibers (fruit, vegetable, and cereal) were studied by FT-Raman spectroscopy and thermogravimetry (TGA), respectively. For this aim the bread dough at 500 FU consistency was made of a blend of wheat starch and wheat gluten as well as the fiber, the content of which ranged from 3 to 18% w/w. The obtained results revealed that all dietary fibers apart from oat caused similar changes in the secondary structure of gluten proteins. The most noticeable changes were observed in the regions connected with hydrogen-bonded beta-sheets (1614 and 1684 cm(-1)) and beta-turns (1640 and 1657 cm(-1)). Other changes observed in the gluten structure, concerning other beta structures, conformation of disulfide bridges, and aromatic amino acid microenvironment, depend on the fibers' chemical composition. The results concerning structural changes suggested that the observed formation of hydrogen bonds in the beta-structures can be connected with aggregation or abnormal folding. This hypothesis was confirmed by thermogravimetric results. Changes in weight loss indicated the formation of a more complex and strong gluten network. PMID- 26927822 TI - Discrete distributional differential expression (D3E)--a tool for gene expression analysis of single-cell RNA-seq data. AB - BACKGROUND: The advent of high throughput RNA-seq at the single-cell level has opened up new opportunities to elucidate the heterogeneity of gene expression. One of the most widespread applications of RNA-seq is to identify genes which are differentially expressed between two experimental conditions. RESULTS: We present a discrete, distributional method for differential gene expression (D(3)E), a novel algorithm specifically designed for single-cell RNA-seq data. We use synthetic data to evaluate D(3)E, demonstrating that it can detect changes in expression, even when the mean level remains unchanged. Since D(3)E is based on an analytically tractable stochastic model, it provides additional biological insights by quantifying biologically meaningful properties, such as the average burst size and frequency. We use D(3)E to investigate experimental data, and with the help of the underlying model, we directly test hypotheses about the driving mechanism behind changes in gene expression. CONCLUSION: Evaluation using synthetic data shows that D(3)E performs better than other methods for identifying differentially expressed genes since it is designed to take full advantage of the information available from single-cell RNA-seq experiments. Moreover, the analytical model underlying D(3)E makes it possible to gain additional biological insights. PMID- 26927823 TI - The relationship between income, economic freedom, and BMI. AB - OBJECTIVES: What explains increases in BMI (and obesity) over time and across countries? Although many microeconomic forces are likely explanations, increasingly scholars are arguing that macroeconomic forces such as market liberalism and globalization are root causes of the obesity epidemic. The purpose of this paper is to examine the impact of economic freedom on obesity conditional on the level of income and other factors. STUDY DESIGN: We use an unbalanced pooled cross section of up to 135 countries for 1995 and 2000-2009. METHODS: Our statistical model specifications include pooled OLS and fixed effects. RESULTS: First, we find that controlling for fixed effects siphons off much of the relationship previously documented between economic freedom and BMI. Second, economic freedom is associated with slightly higher BMIs but only for men in developing nations. Lastly, we show that economic freedom increases life expectancy for both men and women in developing countries. CONCLUSION: Therefore, policies aimed at reducing obesity that limit economic liberalism may come at the expense of life expectancy in the developing world. PMID- 26927824 TI - Access to care in sign language: the French experience. PMID- 26927825 TI - Association between age at first sexual intercourse and knowledge, attitudes and practices regarding reproductive health and unplanned pregnancy: a cross sectional study. AB - BACKGROUND: Age at first sexual intercourse (AFSI) is decreasing among adolescents in developed nations. An early sexual debut has been associated, to some extent, with multiple sexual partners, infrequent use of condoms, unplanned pregnancy, unsafe abortion, and sexually transmitted disease and human immunodeficiency virus infection. Unplanned pregnancy among adolescents has both physical and social adverse effects. METHODS: In total, 78,400 self-administered anonymous questionnaires were distributed to college students in seven cities in China to determine the age at which Chinese college students first engage in sexual activity, and the association between AFSI and knowledge, attitudes and practices (KAP) regarding reproductive health and unplanned pregnancy. RESULTS: Approximately 10,164 students reported that they were sexually active, and most reported that they had engaged in sexual intercourse for the first time during college. The average AFSI was 20.14 [standard deviation (SD) 2.98] years, and the average AFSI by gender was 19.97 (SD 2.97) years for males and 20.41 (SD 2.97) years for females. The unplanned pregnancy rate among the participants was 34.03%. Participants lacked knowledge about contraception and reproductive health, although most believed that it is necessary to have this knowledge. Participants' attitudes towards premarital sex were varied. Factors that were found to be associated with unplanned pregnancy were AFSI, contraceptive methods used for first sexual act, and whether contraceptive methods were used for every sexual act. CONCLUSIONS: The college period is a key time for Chinese students in terms of becoming sexually active. As such, comprehensive and informative reproductive health education should be provided before and during the college period. Furthermore, reproductive health education should include appropriate sexual morality education and comprehensive sex education. Gender traits and needs should be considered in sex education. PMID- 26927826 TI - [Lenalidomide nephrotoxicity]. AB - The introduction of lenalidomide into the therapeutic arsenal of hematologic malignancies has represented an important step forward in the management of multiple myeloma. However, its use is associated with several toxicities including kidney injury. The present review examines the drug's pharmacokinetics, discusses the main adverse renal effects that are associated with lenalidomide treatment, and makes recommendations for dosage adjustment in patients with underlying renal impairment. PMID- 26927827 TI - [Clear cell sarcoma of kidney in children]. AB - Clear cell sarcoma of the kidney (CCSK) is a rare tumor that is diagnosed most often in children between 2- and 4-years-old of age. Usually, patients with CCSK are treated in international study for intrarenal tumors, preferentially Wilms tumor, according to bad histopronostic group. The purpose of this paper is to review the most important features in 2015 about epidemiology, radiology, anatomopathology and genetic of CCSK, and above all a synthesis about successive treatment strategies with their results. Second most common pediatric renal tumor in children less than 5-years-old, its prognosis has improved dramatically in recent years with the use of anthracyclines. PMID- 26927828 TI - Abnormal Current-Voltage Hysteresis Induced by Reverse Bias in Organic-Inorganic Hybrid Perovskite Photovoltaics. AB - In this study, reverse bias (RB)-induced abnormal hysteresis is investigated in perovskite solar cells (PVSCs) with nickel oxide (NiOx)/methylammonium lead iodide (CH3NH3PbI3) interfaces. Through comprehensive current-voltage (I-V) characterization and bias-dependent external quantum efficiency (EQE) measurements, we demonstrate that this phenomenon is caused by the interfacial ion accumulation intrinsic to CH3NH3PbI3. Subsequently, via systematic analysis we discover that the abnormal I-V behavior is remarkably similar to tunnel diode I-V characteristics and is due to the formation of a transient tunnel junction at NiOx/CH3NH3PbI3 interfaces under RB. The detailed analysis navigating the complexities of I-V behavior in CH3NH3PbI3-based solar cells provided here ultimately illuminates possibilities in modulating ion motion and hysteresis via interfacial engineering in PVSCs. Furthermore, this work shows that RB can alter how CH3NH3PbI3 contributes to the functional nature of devices and provides the first steps toward approaching functional perovskite interfaces in new ways for metrology and analysis of complex transient processes. PMID- 26927830 TI - Mitigation of ammonia inhibition by internal dilution in high-rate anaerobic digestion of food waste leachate and evidences of microbial community response. AB - A high-rate anaerobic digestion of food waste leachate were tested using intermittent continuously stirred tank reactors (iCSTRs) to evaluate how severe ammonia inhibition could be mitigated with internal dilution strategy, and to identify how bacterial and archaeal community respond in genus and species level. Experimental results show that the digestion performance was well maintained up to hydraulic retention time (HRT) of 40 days but could not keep steady-state as HRT decreased to 30 days due to severe free ammonia (FA) inhibition. Coupling internal dilution was the key to relieve the inhibition since it reduced FA concentration as low as 62 mg/L even at HRT 30 days, which corresponds to organic loading rate of 5 g COD/L/d, demonstrating CH4 yield of 0.32 L CH4 /g CODadded . It was confirmed that the dilution offers iCTSRs manage severe ammonia inhibition with the balanced community structure between bacteria and archaea in this high rate anaerobic digestion. Genus and species level pyrosequencing evidence that FA inhibition to community dynamics of Methanosarcina and Methanosaeta is strongly connected to methanogenesis, and Methanosarcina plays a key role in an iCSTR with the dilution. Biotechnol. Bioeng. 2016;113: 1892-1901. (c) 2016 Wiley Periodicals, Inc. PMID- 26927829 TI - Characterization of Cardiac Glycoside Natural Products as Potent Inhibitors of DNA Double-Strand Break Repair by a Whole-Cell Double Immunofluorescence Assay. AB - Small-molecule inhibitors of DNA repair pathways are being intensively investigated as primary and adjuvant chemotherapies. We report the discovery that cardiac glycosides, natural products in clinical use for the treatment of heart failure and atrial arrhythmia, are potent inhibitors of DNA double-strand break (DSB) repair. Our data suggest that cardiac glycosides interact with phosphorylated mediator of DNA damage checkpoint protein 1 (phospho-MDC1) or E3 ubiquitin-protein ligase ring finger protein 8 (RNF8), two factors involved in DSB repair, and inhibit the retention of p53 binding protein 1 (53BP1) at the site of DSBs. These observations provide an explanation for the anticancer activity of this class of compounds, which has remained poorly understood for decades, and provide guidance for their clinical applications. This discovery was enabled by the development of the first high-throughput unbiased cellular assay to identify new small-molecule inhibitors of DSB repair. Our assay is based on the fully automated, time-resolved quantification of phospho-SER139-H2AX (gammaH2AX) and 53BP1 foci, two factors involved in the DNA damage response network, in cells treated with small molecules and ionizing radiation (IR). This primary assay is supplemented by robust secondary assays that establish lead compound potencies and provide further insights into their mechanisms of action. Although the cardiac glycosides were identified in an evaluation of 2366 small molecules, the assay is envisioned to be adaptable to larger compound libraries. The assay is shown to be compatible with small-molecule DNA cleaving agents, such as bleomycin, neocarzinostatin chromophore, and lomaiviticin A, in place of IR. PMID- 26927831 TI - Understanding Consumer Perceptions and Awareness of Hospital-Based Maternity Care Quality Measures. AB - OBJECTIVE: To explore factors that may influence use of comparative public reports for hospital maternity care. DATA SOURCES: Four focus groups conducted in 2013 with 41 women and preintervention survey data collected in 2014 to 2015 from 245 pregnant women in North Carolina. STUDY DESIGN: As part of a larger randomized controlled trial, we conducted qualitative formative research to develop an intervention that will be evaluated through pre- and postintervention surveys. DATA EXTRACTION METHODS: Analysis of focus group transcripts examined participants' perceptions of high-quality maternity care and the importance of different quality measures. Quantitative analysis included descriptive results of the preintervention survey and subgroup analyses to examine the impact of race, education, and being a first-time mom on outcomes. PRINCIPAL FINDINGS: When describing high-quality maternity care, participants focused on interactions with providers, including respect for preferences and communication. The importance of quality measures was influenced by the extent to which they focused on babies' health, were perceived as the hospital's responsibility, and were perceived as representing "standard care." At baseline, 28 percent of survey respondents had used quality information to choose a hospital. Survey respondents were more aware of some quality measures (e.g., breastfeeding support) than others (e.g., episiotomy rates). CONCLUSIONS: Public reporting efforts could help increase relevance of maternity care quality measures by creating measures that reflect women's concerns, clearly explaining the hospital's role in supporting quality care, and showing how available quality measures can inform decisions about childbirth. PMID- 26927833 TI - The effect of testosterone treatment on prostate histology and apoptosis in men with late-onset hypogonadism. AB - OBJECTIVES: To investigate the effect of testosterone replacement therapy (TRT) on prostate histology and apoptosis in men with late-onset hypogonadism (LOH). METHODS: The study included 25 men, having LOH with prostate-specific antigen (PSA) level of 4 ng/ml or less. All patients underwent transrectal ultrasound guided prostate biopsy at baseline, and received testosterone undecanoate treatment for 1 year. Prostate biopsy was repeated at the end of 1 year of testosterone therapy. In addition to clinical and biochemical parameters, prostate histology and apoptotic index (AI) were compared before and after the TRT. RESULTS: The mean serum total testosterone significantly increased from 178.04 +/- 51.92 to 496.28 +/- 103.73 ng/dl (p = 0.001). No significant differences were observed in serum total and free PSA level, prostate volume and maximal urinary flow rate. There were also no significant differences in AI, stroma/epithelial cells ratio, Ki-67 positive cells and atrophy score of prostate tissue before and after the TRT. CONCLUSIONS: This study demonstrated that TRT did not affect serum PSA level, prostate volume and maximal urinary flow rate. This study also suggests that TRT does not cause the risk for prostate cancer development, because of no significant differences in prostate histology after TRT. PMID- 26927832 TI - Monitoring cardiorespiratory instability: Current approaches and implications for nursing practice. AB - Unrecognised in-hospital cardiorespiratory instability (CRI) risks adverse patient outcomes. Although step down unit (SDU) patients have continuous non invasive physiologic monitoring of vital signs and a ratio of one nurse to four to six patients, detection of CRI is still suboptimal. Telemedicine provides additional surveillance but, due to high costs and unclear investment returns, is not routinely used in SDUs. Rapid response teams have been tested as possible approaches to support CRI patients outside the intensive care unit with mixed outcomes. Technology-enabled early warning scores, though rigorously studied, may not detect subtle instability. Efforts to utilise nursing intuition as a means to promote early identification of CRI have been explored, but the problem still persists. Monitoring systems hold promise, but nursing surveillance remains the key to reliable early detection and recognition. Research directed towards improving nursing surveillance and facilitating decision-making is needed to ensure safe patient outcomes and prevent CRI. PMID- 26927835 TI - Effect of ELP Sequence and Fusion Protein Design on Concentrated Solution Self Assembly. AB - Fusion proteins provide a facile route for the purification and self-assembly of biofunctional protein block copolymers into complex nanostructures; however, the use of biochemical synthesis techniques introduces unexplored variables into the design of the structures. Using model fusion constructs of the red fluorescent protein mCherry and the coil-like protein elastin-like polypeptide (ELP), it is shown that the molar mass and hydrophobicity of the ELP sequence have a large effect on the propensity of a fusion to form well-ordered nanostructures, even when the ELP is in the low temperature, highly solvated state. In contrast, the presence of a 6xHis purification tag has little effect on self-assembly, and the order of blocks in the construct (N-terminal vs C-terminal) only has a significant effect on the nanostructure when the conjugates are heated above the transition temperature of the ELP block. These results indicate that for a sufficiently hydrophobic and high molar mass ELP block, there is a great deal of design latitude in the construction of fusion protein block copolymers for self assembling nanomaterials. PMID- 26927834 TI - Effects of thromboprophylaxis on mesenchymal stromal cells during osteogenic differentiation: an in-vitro study comparing enoxaparin with rivaroxaban. AB - BACKGROUND: Low-molecular-weight heparins (e.g. Enoxaparin) are widely used to prevent venous thromboembolism after orthopaedic surgery, but there are reports about serious side effects including reduction in bone density and strength. In recent years new oral antithrombotic drugs (e.g. direct Factor Xa-inhibitor, Rivaroxaban) have been used to prevent venous thromboembolism. However, there is lack of information on the effects of these new drugs on human mesenchymal stromal cells during osteogenic differentiation and, therefore, effects during postoperative bone healing. METHODS: We evaluated the effects of Rivaroxaban and Enoxaparin on the proliferation, mRNA and surface receptor expression as well as differentiation capacity of primary human mesenchymal stromal cells during their osteogenic differentiation. RESULTS: Enoxaparin, but not Rivaroxaban treatment significantly increased human mesenchymal stromal cell (hMSC) proliferation during the first week of osteogenic differentiation while suppressing osteogenic marker genes, surface receptor expression and calcification. CONCLUSIONS: This is the first paper to demonstrate that Rivaroxaban had no significant influence on hMSC differentiation towards the osteogenic lineage, indicating a less affected bone healing process compared with Enoxaparin in vitro. Based on these findings Rivaroxaban seems to be superior to Enoxaparin in early stages of bone healing in vitro. PMID- 26927836 TI - Can Molecular Gradients Wire the Brain? AB - Concentration gradients are believed to play a key role in guiding axons to their appropriate targets during neural development. However, there are fundamental physical constraints on gradient detection, and these strongly limit the fidelity with which axons can respond to gradient cues. I discuss these constraints and argue they suggest that many axon guidance events in vivo cannot be explained solely in terms of gradient-based mechanisms. Rather, precise wiring requires the collaboration of gradients with other types of guidance cues. Since we know relatively little about how this might work, I argue that our understanding of how the brain becomes wired up during development is still at an early stage. PMID- 26927837 TI - Evaluation of the Activity of the Essential Oil from an Ornamental Flower against Aedes aegypti: Electrophysiology, Molecular Dynamics and Behavioral Assays. AB - Dengue fever has spread worldwide and affects millions of people every year in tropical and subtropical regions of Africa, Asia, Europe and America. Since there is no effective vaccine against the dengue virus, prevention of disease transmission depends entirely on regulating the vector (Aedes aegypti) or interrupting human-vector contact. The aim of this study was to assess the oviposition deterrent activity of essential oils of three cultivars of torch ginger (Etlingera elatior, Zingiberaceae) against the dengue mosquito. Analysis of the oils by gas chromatography (GC)-mass spectrometry revealed the presence of 43 constituents, of which alpha-pinene, dodecanal and n-dodecanol were the major components in all cultivars. Solutions containing 100 ppm of the oils exhibited oviposition deterrent activities against gravid Ae. aegypti females. GC analysis with electroantennographic detection indicated that the oil constituents n decanol, 2-undecanone, undecanal, dodecanal, trans-caryophyllene, (E)-beta farnesene, alpha-humulene, n-dodecanol, isodaucene and dodecanoic acid were able to trigger antennal depolarization in Ae. aegypti females. Bioassays confirmed that solutions containing 50 ppm of n-dodecanol or dodecanal exhibited oviposition deterrent activities, while a solution containing the alcohol and aldehyde in admixture at concentrations representative of the oil presented an activity similar to that of the 100 ppm oil solution. Docking and molecular dynamics simulations verified that the interaction energies of the long-chain oil components and Ae. aegypti odorant binding protein 1 were quite favorable, indicating that the protein is a possible oviposition deterrent receptor in the antenna of Ae. aegypti. PMID- 26927839 TI - Exploring the barriers to rigorous monitoring and evaluation of health systems strengthening activities: qualitative evidence from international development partners. AB - The number of health systems strengthening (HSS) programs has increased in the last decade. However, a limited number of studies providing robust evidence for the value and impact of these programs are available. This study aims to identify knowledge gaps and challenges that impede rigorous monitoring and evaluation (M&E) of HSS, and to ascertain the extent to which these efforts are informed by existing technical guidance. Interviews were conducted with HSS advisors at United States Agency for International Development-funded missions as well as senior M&E advisors at implementing partner and multilateral organizations. Findings showed that mission staff do not use existing technical resources, either because they do not know about them or do not find them useful. Barriers to rigorous M&E included a lack suitable of indicators, data limitations, difficulty in demonstrating an impact on health, and insufficient funding and resources. Consensus and collaboration between international health partners and local governments may mitigate these challenges. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26927840 TI - Editorial. PMID- 26927838 TI - Entacapone is an Antioxidant More Potent than Vitamin C and Vitamin E for Scavenging of Hypochlorous Acid and Peroxynitrite, and the Inhibition of Oxidative Stress-Induced Cell Death. AB - BACKGROUND Entacapone (ENT), a clinical drug for the treatment of Parkinson's disease, has been shown to have antioxidant effects, but little is known about its antioxidant mechanisms. The objective of the current study was to determine the antioxidant activity of ENT against different species of oxidants and compared it with that of vitamin C and vitamin E. We also determined the effect of ENT on oxidative stress-induced cell death in human umbilical vein endothelial cells (HUVECs). MATERIAL AND METHODS The total antioxidant activities of ENT, vitamin C and vitamin E were determined with a standard DPPH-scavenging assay. Specific assays to determine ENT's scavenging activity on hypochlorous acid (HOCl), peroxynitrite (ONOO-), and hydrogen peroxide (H2O2), and the chelating effect on Fe(II) were used. H2O2-induced cell death in HUVECs was determined with the MTT assay. RESULTS ENT (10 and 20 uM) scavenged 60% and 83% of DPPH activity, respectively. These percentages were greater than those resulting from using the same concentrations of vitamin C and vitamin E. ENT's HOCl-scavenging activity was concentration-dependent and 8 to 20 times stronger than those of vitamin C and vitamin E. ENT's ONOO--scavenging activity was 8% to 30% stronger than that of vitamin C. However, ENT, vitamin C, and vitamin E were not able to directly scavenge H2O2, and did not show any chelating effect on Fe(II). Importantly ENT, but not vitamin C or vitamin E, inhibited H2O2-induced cell death in HUVECs. CONCLUSIONS ENT is an antioxidant that can scavenge toxic HOCl and ONOO- species and inhibit oxidative stress-induced cell death more effectively than vitamin C and vitamin E. ENT may have new clinical applications as an antioxidant in the treatment of ROS-induced diseases including cardiovascular disease, cancer, and neurodegenerative diseases. PMID- 26927841 TI - Setting environmental exposure standards: Current concepts and controversies. AB - In the 1990s there will be a heightened emphasis on controlling environmental health hazards. This paper examines the nature and role of environmental standards. The process of setting exposure limits (i.e. standards) is discussed, with particular reference to quantitative risk assessment and to the complex scientific-social-political process of deciding on 'acceptable' levels of risk. The need for closer integration between epidemiology and toxicology is explored, as is the need for incorporation of biological markers in epidemiological research, particularly in order to improve the detection and quantification of small increases in risks to health caused by low-level exposures to environmental toxins. PMID- 26927842 TI - Cleaning and disinfection of blenders used in hospital kitchens. AB - The efficiency of a range of methods used to clean and disinfect blenders was compared. Blenders with metal, plastic and glass goblets were experimentally contaminated with Klebsiella aerogenes after which they were cleaned and disinfected by (a) cold water rinse, (b) detergent wash, (c) detergent wash and disinfectant soak, (d) detergent wash and boiling water rinse and (e) autoclaving. Autoclaving was the only procedure that sterilized the blenders but this could only be used for blenders with metal goblets. A detergent wash with or without chemical disinfection followed by a boiling water rinse was found to be the most effective method of cleaning and disinfecting all three types of blender. PMID- 26927843 TI - Health effects of swimmers and nonpoint sources of contaminated water. AB - Microbiological contamination from nonpoint sources of pollution is usually related to animal faecal wastes through urban, pastureland and forest run-off of stormwater. Currently-used bacterial water quality indicators cannot discriminate between human and animal faecal contamination and, therefore, it is common practice to treat the risk associated with exposure to water polluted by animal or human wastes as equally hazardous. The purpose of this study was to determine if there is a risk of gastrointestinal illness after a swimming exposure to water contaminated with animal faecal wastes. The health status and swimming activity of volunteer study participants was followed for 49 days during June, July and August. Multiple bacterial indicators of water quality were monitored daily during the course of the study. Swimming-associated symptomatic gastrointestinal illness was observed in individuals who swam in animal nonpoint source contaminated water. Swimmer illness was not associated with high densities of common faecal indicator bacteria or high volume rainy days. Swimmer illness was associated with high numbers of swimmers per day and high densities of staphylococci. The observed illnesses appeared to be caused by a swimmer to swimmer transmission via the water. PMID- 26927844 TI - Travel: A health hazard? AB - Since 1973 surveillance of returning travellers and visitors to Scotland has been undertaken. A total of 14227 persons were surveyed and of these 37% reported illness, mostly alimentary disorders. It is estimated that over L11 million is spent on the subsequent treatment of travellers' illnesses, many of which are preventable. The hazards associated with travel are not new but we have failed to benefit from experience. PMID- 26927845 TI - Correlation between mutagenicity of airborne particles and air pollution parameters in eleven Italian towns. AB - Organic extracts from airborne particles collected in 11 Italian towns between February and April, 1988, were tested for mutagenicity on TA98 and TA100 (+/- S9), and their nitroreductase (NR) deficient Salmonella strains, by the use of the Ames plate incorporation assay. Mutagenic responses were fitted by an equation which takes into account toxic effects on tester organisms. Generally parallel responses were obtained with the two Salmonella strains, but the TA98 gave, mostly, higher increases of revertants over the control level. No dramatic decreases in mutagenicity were observed with the NR derivative strains, except in a few cases with TA98NR and, more frequently, with TA100NR strains. During air sampling, temperature, atmospheric pressure, light, wind strength and direction, SO2, CO, NO2, O3 and non-methanic hydrocarbons (NMHC) concentrations were continuously monitored. Meteorological variables seem not to be significantly correlated with mutagenicity variations, while the highest correlation (r = 0.91) was observed between induced reversion in TA98 (+ S9) and NMHC concentration in air. Therefore, in spite of the wide range of different types of towns included in the study, air NMHC concentration can be considered a good predictor for the mutagenicity of the total organic material extracted from particles of urban air. PMID- 26927846 TI - Frequency of isolation of campylobacter spp., Yersinia spp. and salmonella spp. from small mammals from two sites in Southern Britain. AB - Small wild mammals were trapped at two sites in the United Kingdom: Skomer Island, Dyfed and a farm in Dorset. Faecal samples were collected from 43 rodents of two species on Skomer and tested for the presence of Yersinia. Samples of faeces and of material from the terminal ileum were collected from 141 animals of eight species in Dorset and tested for Campylobacter, Yersinia and Salmonella. In addition some samples of spleens from the Dorset animals were tested for Campylobacter. Four typable isolates of Campylobacter were obtained from the Dorset site, two from spleens from shrews and two from intestinal contents from a bank vole. Nineteen isolations of Yersinia were made from the Skomer animals and seventeen from animals in Dorset. No isolations of Salmonella were made from any of the animals sampled. PMID- 26927848 TI - CXCL13 in idiopathic pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension. AB - BACKGROUND: Chemokine CXC ligand 13 (CXCL13) has been implicated in perivascular inflammation and pulmonary vascular remodeling in patients with idiopathic pulmonary artery hypertension (IPAH). We wondered whether CXCL13 may also play a role in chronic thromboembolic pulmonary hypertension (CTEPH) and whether serum levels of CXCL13 might serve as biomarkers in these conditions. METHODS: Lung tissue from patients with IPAH or CTEPH was immunostained for CXCL13. Serum samples were obtained from patients with IPAH (n = 42) or CTEPH (n = 50) and from healthy controls (n = 13). Serum CXCL13 concentrations were measured by enzyme linked immunosorbent assay technology and were evaluated for associations with markers of disease severity and survival. RESULTS: CXCL13 was expressed in pulmonary vascular lesions and lymphocytes of patients with IPAH and inoperable CTEPH, respectively. Serum CXCL13 was elevated in patients compared to healthy controls [median, interquartile range, 83 (55,114) pg/ml versus 40 (28, 48) pg/ml; p < 0.001]. Serum CXCL13 showed only weak and inconsistent correlations with markers of inflammation or disease severity. In both populations, patients with serum CXCL13 above the median of the respective groups did not have a higher risk of death than patients with lower serum CXCL13. CONCLUSIONS: CXCL13 was overexpressed in pulmonary vascular lesions of patients with IPAH and CTEPH, and increased serum concentrations were found in patients with IPAH and CTEPH, suggesting a potential pathogenic role of CXCL13 in both diseases. However, given the weak associations between serum CXCL13 and markers of disease severity and outcome, CXCL13 is unlikely to become a promising biomarker in these patient populations. PMID- 26927849 TI - Social Evolution Selects for Redundancy in Bacterial Quorum Sensing. AB - Quorum sensing is a process of chemical communication that bacteria use to monitor cell density and coordinate cooperative behaviors. Quorum sensing relies on extracellular signal molecules and cognate receptor pairs. While a single quorum-sensing system is sufficient to probe cell density, bacteria frequently use multiple quorum-sensing systems to regulate the same cooperative behaviors. The potential benefits of these redundant network structures are not clear. Here, we combine modeling and experimental analyses of the Bacillus subtilis and Vibrio harveyi quorum-sensing networks to show that accumulation of multiple quorum sensing systems may be driven by a facultative cheating mechanism. We demonstrate that a strain that has acquired an additional quorum-sensing system can exploit its ancestor that possesses one fewer system, but nonetheless, resume full cooperation with its kin when it is fixed in the population. We identify the molecular network design criteria required for this advantage. Our results suggest that increased complexity in bacterial social signaling circuits can evolve without providing an adaptive advantage in a clonal population. PMID- 26927850 TI - Using a Topological Model in Psychology: Developing Sense and Choice Categories. AB - A duality of sense categories and choice categories is introduced to map two distinct but co-operating ways in which we as humans are relating actively to the world. We are sensing similarities and differences in our world of objects and persons, but we are also as bodies moving around in this world encountering, selecting, and attaching to objects beyond our sensory interactions and in this way also relating to the individual objects' history. This duality is necessary if we shall understand man as relating to the historical depth of our natural and cultural world, and to understand our cognitions and affections. Our personal affections and attachments, as well as our shared cultural values are centered around objects and persons chosen as reference points and landmarks in our lives, uniting and separating, not to be understood only in terms of sensory selections. The ambition is to bridge the gap between psychology as part of Naturwissenschaft and of Geisteswissenschaft, and at the same time establish a common frame for understanding cognition and affection, and our practical and cultural life (Mammen and Mironenko 2015). The duality of sense and choice categories can be described formally using concepts from modern mathematics, primarily topology, surmounting the reductions rooted in the mechanistic concepts from Renaissance science and mathematics. The formal description is based on 11 short and simple axioms held in ordinary language and visualized with instructive figures. The axioms are bridging psychology and mathematics and not only enriching psychology but also opening for a new interpretation of parts of the foundation of mathematics and logic. PMID- 26927851 TI - Identification of Loci Modulating the Cardiovascular and Skeletal Phenotypes of Marfan Syndrome in Mice. AB - Marfan syndrome (MFS) is an autosomal dominant disease of the connective tissue, affecting mostly the skeletal, ocular and cardiovascular systems, caused by mutations in the FBN1 gene. The existence of modifier genes has been postulated based on the wide clinical variability of manifestations in patients, even among those with the same FBN1 mutation. Although isogenic mouse models of the disease were fundamental in dissecting the molecular mechanism of pathogenesis, they do not address the effect of genetic background on the disease phenotype. Here, we use a new mouse model, mg(DeltaloxPneo), which presents different phenotype severity dependent on the genetic backgrounds, to identify genes involved in modulating MFS phenotype. F2 heterozygotes showed wide phenotypic variability, with no correlations between phenotypic severities of the different affected systems, indicating that each has its specific set of modifier genes. Individual analysis of the phenotypes, with SNP microarrays, identified two suggestive QTL each to the cardiovascular and skeletal, and one significant QTL to the skeletal phenotype. Epistatic interactions between the QTL account for 47.4% and 53.5% of variation in the skeletal and cardiovascular phenotypes, respectively. This is the first study that maps modifier loci for MFS, showing the complex genetic architecture underlying the disease. PMID- 26927852 TI - A global bionomic database for the dominant vectors of human malaria. AB - Anopheles mosquitoes were first recognised as the transmitters of human malaria in the late 19th Century and have been subject to a huge amount of research ever since. Yet there is still much that is unknown regarding the ecology, behaviour (collectively 'bionomics') and sometimes even the identity of many of the world's most prominent disease vectors, much less the within-species variation in their bionomics. Whilst malaria elimination remains an ambitious goal, it is becoming increasingly clear that knowledge of vector behaviour is needed to effectively target control measures. A database of bionomics data for the dominant vector species of malaria worldwide has been compiled from published peer-reviewed literature. The data identification and collation processes are described, together with the geo-positioning and quality control methods. This is the only such dataset in existence and provides a valuable resource to researchers and policy makers in this field. PMID- 26927853 TI - Incomplete and Misleading Table Used for Reappraisal of Statin Therapy. PMID- 26927854 TI - The Extracellular Matrix Signature in Vein Graft Disease. AB - BACKGROUND: Vein graft disease is a major and yet unsolved problem in cardiac revascularization surgery. Although accumulation of extracellular matrix is characteristic for vein graft disease, detailed analysis of the fibrotic material is lacking. Because alterations of collagen cross-links are typical for organ fibrosis, we performed a comprehensive analysis of collagen and elastin in vein graft disease. METHODS: Collagen, elastin, and their respective cross-links were analyzed using histology and amino acid analysis. The expression of collagen modifying enzymes was analyzed using SYBR Green quantitative real-time polymerase chain reaction. Fibrillin expression was analyzed by immunohistochemistry and quantitative real-time polymerase chain reaction. RESULTS: Diseased vein grafts showed a marked increase of collagen and of intermediate collagen cross-links, which are markers for newly synthesized collagen. Furthermore, we identified in vein graft disease increased levels of mature hydroxylysine aldehyde-derived cross-links typical for skeletal tissues. This was accompanied by upregulation of lysyl hydroxylase 2 and lysyl oxidase expression. Furthermore, vein graft disease showed a reduction of the elastin/collagen ratio, using elastin cross-links as a marker of elastin content, which was accompanied by an increase of fibrillin-1. CONCLUSIONS: Vein graft disease was accompanied by marked alterations in the composition of the extracellular matrix. The altered collagen cross-link pattern and the reduced elastin/collagen ratio might synergistically increase the stiffness in diseased vein grafts. Furthermore, hydroxylysine aldehyde-derived cross-links can cause a decreased degradability of collagens by matrix metalloproteinases. Our data suggest collagen cross-links as a therapeutic target in vein graft disease. PMID- 26927855 TI - Time in Therapeutic Range and Percentage of International Normalized Ratio in the Therapeutic Range as a Measure of Quality of Anticoagulation Control in Patients With Atrial Fibrillation. AB - BACKGROUND: Time in therapeutic range (TTR), albeit the standard measure of quality of anticoagulation control for warfarin, is underused in everyday clinical practice because of its tedious calculation. In contrast, the percentage of international normalized ratio measurements in range (PINRR) is a convenient alternative. Our objective was to investigate the correlation between PINRR and TTR and whether PINRR has clinical utility for prediction of ischemic stroke and intracranial hemorrhage in a "real-world" atrial fibrillation (AF) cohort. METHODS: This is an observational study based on a hospital-based AF registry. RESULTS: Among 1428 Chinese patients with AF who were taking warfarin (76.2 +/- 8.7 years; mean CHA2DS2-VASc, 4.2 +/- 1.6 and HAS-BLED, 2.3 +/- 0.9), mean and median TTR values were 38.2% +/- 24.4% and 38.8% (interquartile range, 17.9% and 56.2%), respectively. Patients with TTR >= 65% (14.8%) had a lower annual risk of ischemic stroke (3.04% per year) than did those with TTR < 65% (5.35% per year). Mean and median PINRR were 34.3% +/- 17.1% and 34.2% (interquartile range, 22.7% and 46.0%), respectively. TTR significantly correlated with PINRR in a linear fashion (r = 0.81; P < 0.0001). A cutoff of PINRR <= 56.1% was a good discriminator of TTR < 65%, with a high sensitivity (98.3%) and positive predictive value (91.9%). The annual ischemic stroke risk in patients with PINRR > 56.1% was 2.56% per year, lower than those with TTR >= 65% (3.04% per year). Patients with PINRR > 56.1% had an annual incidence of intracranial hemorrhage comparable to those with TTR >= 65% (0.49% per year vs 0.68% per year). CONCLUSIONS: Among patients with AF who are taking warfarin, the PINRR is a user friendly alternative to TTR, having a high sensitivity and positive predictive value in predicting TTR. As with TTR, PINRR is associated with clinical adverse events, ie, ischemic stroke and intracranial hemorrhage. PMID- 26927856 TI - Impact of Hemoglobin Drop, Bleeding Events, and Red Blood Cell Transfusions on Long-term Mortality in Patients Undergoing Transaortic Valve Implantation. AB - BACKGROUND: Despite the minimally invasive nature of transcatheter aortic valve implantation (TAVI), the procedure is associated with several complications. We aimed to analyze the individual impact of bleeding events, hemoglobin (Hb) drop, and red blood cell (RBC) transfusions on prognosis and to evaluate the temporal trends in bleeding and RBC transfusions since the initiation of the TAVI program in our centre and onward. METHODS: Consecutive patients (n = 597) undergoing transfemoral TAVI were prospectively enrolled. Periprocedural Hb levels, RBC transfusions, and major/life-threatening bleeding events were documented and analyzed. RESULTS: In the entire cohort, mean Hb level decreased after TAVI (11.8 +/- 1.4 to 9.5 +/- 1.3 g/dL; P < 0.001). Major/life threatening bleeding occurred in 66 (10.1%) patients, and 179 (30%) patients received RBC transfusions. Major/life threatening bleeding was not independently associated with mortality when adjusted for Hb drop and RBC transfusion. Among patients with an Hb drop of < 3 g/dL, those who received RBC transfusions had a higher mortality (hazard ratio [HR], 1.9; confidence interval [CI], 95% CI, 1.2-2.9; P = 0.004). Among patients with an Hb drop of >= 3 g/dL, the Hb drop had no significant impact on survival (HR, 1.5; 95% CI, 0.7-2.9; P = 0.2); however, patients who received RBC transfusions had a significantly higher mortality (HR, 4.1; 95% CI, 2.2-7.7; P < 0.001). The use of RBC transfusions decreased gradually over the duration of the study. CONCLUSIONS: An Hb drop is frequently observed after TAVI. RBC transfusions are strongly associated with increased long-term mortality in these patients, regardless of the degree of Hb drop or major bleeding. PMID- 26927857 TI - NT-proBNP Indicates Left Ventricular Impairment and Adverse Clinical Outcome in Patients With Tetralogy of Fallot and Pulmonary Regurgitation. AB - BACKGROUND: The goal of this study was to interrelate N-terminal B-type natriuretic peptide (NT-proBNP) levels and cardiac magnetic resonance imaging derived ventricular function, mass, and volumes in adults with pulmonary regurgitation after Fallot repair and to evaluate the prognostic relevance of these parameters regarding adverse clinical outcome. METHODS: Eighty-one patients (aged 26.3 +/- 7.4 years; male sex, 45.7%; New York Heart Association class I, 72.8%; pulmonary valve velocity, < 3 m/s) were included. At baseline cardiac magnetic resonance imaging and NT-proBNP measurements were performed. RESULTS: During a mean observation time of 6.9 +/- 2.6 years, 13 patients (16.1%) had sustained supraventricular arrhythmias or heart failure (2.4 per 100 patient years). Multivariate Cox analysis identified NT-proBNP, left ventricular (LV) end systolic volume index and LV ejection fraction, right ventricular (RV) end diastolic volume index, and tricuspid regurgitation as independent predictors of adverse events. NT-proBNP correlated with LV but not with RV parameters. In receiver operating characteristic curve analysis using significant variables of the multivariate analysis, NT-proBNP was superior to all other parameters to detect patients at risk (area under the curve [AUC], 0.873; 95% confidence interval, 0.772-0.974). LV end-systolic volume index (AUC, 0.734), RV end diastolic volume index (AUC, 0.645) und tricuspid regurgitation (AUC, 0.747) showed lower diagnostic accuracy. CONCLUSIONS: Even in mildly symptomatic patients with pulmonary regurgitation after Fallot repair NT-proBNP is a strong predictor of adverse outcome. It is rather associated with LV but not with RV impairment. In severe pulmonary regurgitation an increase in the level of NT proBNP and LV impairment seem to provide additional useful information for the timing of pulmonary valve replacement. PMID- 26927858 TI - First Autopsy Description of Changes 1 Year After Implantation of a Leadless Cardiac Pacemaker: Unexpected Ingrowth and Severe Chronic Inflammation. PMID- 26927859 TI - Acute Arterial Hypertension in Acute Pulmonary Edema: Mostly a Trigger or an Associated Phenomenon? AB - BACKGROUND: The role of acute arterial hypertension in acute pulmonary edema (APE) as an associated or triggering phenomenon has been poorly investigated and is relevant to patient management. METHODS: This was a prospective observational study of clinical, electrocardiographic, and echocardiographic characteristics of patients with APE. Potential triggers, including acute coronary syndrome (ACS), rapid atrial fibrillation (AF) (>= 120 bpm in AF), fever > 38 degrees C or volume overload, isolated acute hypertension (systolic blood pressure >= 170 mm Hg), and unknown factors were investigated. RESULTS: There were 742 patients, 578 with coronary artery disease (78%), 116 with valvular heart disease or cardiomyopathy (16%), and 47 without identifiable heart disease (6%). ACS was present in 482 (65%) patients (silent in 154 of them), AF was present in 76 (10%) patients, fever/volume overload was present in 62 (8%) patients, acute hypertension was present in 50 (7%) patients, and no apparent trigger was seen in 72 (10%) patients. Admission hypertension occurred in 260 patients (35%): 155 (60%) with ACS (silent in 49 [32%]), 36 (14%) with AF, 19 (7%) with fever/volume overload, and 59 (19%) as an isolated trigger. Similar results were obtained when analyzing patients using coronary angiography (467 patients [63%]). Acute hypertension was present more frequently in patients with severe hypoventilation (arterial Pco2 > 60 mm Hg) than in those without (57% vs 29%; P < 0.001) and in those without moderate-severe mitral regurgitation than in those with (51% vs 30%; P < 0.001). CONCLUSIONS: In patients with APE, with or without ACS, acute hypertension is often present but mainly as an associated/reactive phenomenon and seems favoured by severe hypoventilation. Silent myocardial ischemia/necrosis deserves systematic investigation because it is not rare that it may be the underlying cause of APE. PMID- 26927860 TI - Acute Pulmonary Edema and Acute Coronary Syndrome: Mostly a Trigger or an Associated Phenomenon? PMID- 26927861 TI - Anticoagulation Regimens During Pregnancy in Patients With Mechanical Heart Valves: A Systematic Review and Meta-analysis. AB - BACKGROUND: Managing anticoagulation in pregnant women with mechanical heart valves remains challenging. Our aim was to evaluate the effectiveness and safety of 4 regimens in these women. METHODS: Relevant studies published before June 2015 were collected in several databases and analyzed with RevMan version 5.3 and SPSS version 19.0. Four regimens were defined as follows: a regimen of a vitamin K antagonist (VKA) throughout pregnancy; a heparin (H)/VKA regimen using VKAs except for unfractionated heparin (UFH) or low molecular weight heparin (LMWH) during 6-12 weeks of pregnancy; a LMWH regimen of adjusted LMWH doses throughout pregnancy; and a UFH regimen of adjusted UFH doses throughout pregnancy. The low warfarin dose in the VKA regimen was defined as 5 mg/d or less. RESULTS: Fifty one studies comprising 2113 pregnancies in 1538 women were included. The rate of fetal wastage was significantly higher in the high warfarin dose subgroup than in the low dose one. Compared with the H/VKA regimen, the rate of maternal major thromboembolic event in the low-dose VKA regimen group was significantly lower, although the fetal outcomes were similar. Compared with the H/VKA regimen, the rate of fetal wastage in the LMWH regimen group was significantly lower, and the maternal outcomes were similar. The UFH regimen presented the worst maternal and fetal outcomes. CONCLUSIONS: In the absence of large prospective trials, this meta-analysis showed that the VKA regimen should be best for pregnant women with a low warfarin dose, and the H/VKA regimen might be reasonable for those with a high warfarin dose. The LMWH regimen could be used for those who refuse VKA. PMID- 26927862 TI - Coronary Artery Disease in French Canadians-Investigation of a Suggested Vulnerable Population. AB - BACKGROUND: There is a perception among Canadian physicians that coronary artery disease (CAD) and adverse cardiac events are more common in those of French Canadian heritage. We sought to compare the prevalence of CAD using coronary computed tomographic angiography (CCTA) in French Canadians and non-French white Canadians. METHODS: Consecutive patients were prospectively enrolled in our institutional CCTA registry. Of 10,868 CCTA examinations, we analyzed white patients who identified themselves as French Canadian or non-French Canadian. These 2 groups were compared for baseline characteristics, cardiovascular risk factors, and routine markers for CAD on CTCA. Propensity score adjustments were also made to account for differences in demographics. RESULTS: We identified 1683 French Canadians (mean age, 58.5 +/- 10.7 years; 54.2% men) and 5077 non-French white Canadians (mean age, 59.4 +/- 11.4 years; 57.3% men). French Canadians were more likely to have a smoking history (64.1% vs 56.1%), diabetes (15.6% vs 13.6%), and a family history of premature CAD (53.3% vs 44.6%) (P < 0.05 for all). There was no significant difference in measures of CAD between French Canadians and non-French white Canadians in obstructive CAD (32.5% vs 32.2%; P = 0.997), total plaque score (4.6 +/- 4.3 vs 4.5 +/- 4.4; P = 0.616) and Agatston score (168.1 +/- 319.8 vs 183.6 +/- 433.7; P = 0.371). After propensity score adjustment, there was still no significant difference between the groups. CONCLUSIONS: Our study suggests that French Canadians in the Champlain region have a greater prevalence of cardiovascular risk factors compared with non-French Canadians; however, they do not appear to have a greater prevalence or severity of coronary atherosclerosis as assessed by CCTA. PMID- 26927863 TI - Comparison of Different Forms of Exercise Training in Patients With Cardiac Disease: Where Does High-Intensity Interval Training Fit? AB - In this review, we discuss the most recent forms of exercise training available to patients with cardiac disease and their comparison or their combination (or both) during short- and long-term (phase II and III) cardiac rehabilitation programs. Exercise training modalities to be discussed include inspiratory muscle training (IMT), resistance training (RT), continuous aerobic exercise training (CAET), and high-intensity interval training (HIIT). Particular emphasis is placed on HIIT compared or combined (or both) with other forms such as CAET or RT. For example, IMT combined with CAET was shown to be superior to CAET alone for improving functional capacity, ventilatory function, and quality of life in patients with chronic heart failure. Similarly, RT combined with CAET was shown to optimize benefits with respect to functional capacity, muscle function, and quality of life. Furthermore, in recent years, HIIT has emerged as an alternative or complementary (or both) exercise modality to CAET, providing equivalent if not superior benefits to conventional continuous aerobic training with respect to aerobic fitness, cardiovascular function, quality of life, efficiency, safety, tolerance, and exercise adherence in both short- and long-term training studies. Finally, short-interval HIIT was shown to be useful in the initiation and improvement phases of cardiac rehabilitation, whereas moderate- or longer interval (or both) HIIT protocols appear to be more appropriate for the improvement and maintenance phases because of their high physiological stimulus. We now propose progressive models of exercise training (phases II-III) for patients with cardiac disease, including a more appropriate application of HIIT based on the scientific literature in the context of a multimodal cardiac rehabilitation program. PMID- 26927864 TI - Exercise and Inherited Arrhythmias. AB - Sudden cardiac death (SCD) in an apparently healthy individual is a tragedy that prompts a series of investigations to identify the cause of death and to prevent SCD in potentially at-risk family members. Several inherited channelopathies and cardiomyopathies, including long QT syndrome (LQTS), catecholaminergic polymorphic ventricular cardiomyopathy (CPVT), hypertrophic cardiomyopathy (HCM), and arrhythmogenic right ventricular cardiomyopathy (ARVC) are associated with exercise-related SCD. Exercise restriction has been a historical mainstay of therapy for these conditions. Syncope and cardiac arrest occur during exercise in LQTS and CPVT because of ventricular arrhythmias, which are managed with beta blockade and exercise restriction. Exercise may provoke hemodynamic or ischemic changes in HCM, leading to ventricular arrhythmias. ARVC is a disease of the desmosome, whose underlying disease process is accelerated by exercise. On this basis, expert consensus has erred on the side of caution, recommending rigorous exercise restriction for all inherited arrhythmias. With time, as familiarity with inherited arrhythmia conditions has increased and patients with milder forms of disease are diagnosed, practitioners have questioned the historical rigorous restrictions advocated for all. This change has been driven by the fact that these are often children and young adults who wish to lead active lives. Recent evidence suggests a lower risk of exercise-related arrhythmias in treated patients than was previously assumed, including those with previous symptoms managed with an implantable cardioverter-defibrillator. In this review, we emphasize shared decision making, monitored medical therapy, individual and team awareness of precautions and emergency response measures, and a more permissive approach to recreational and competitive exercise. PMID- 26927865 TI - Reply to Letter From Ganga and Jantz-Identifying Frailty in Elderly Patients With Acute Coronary Syndrome. PMID- 26927867 TI - Shape-controlled continuous synthesis of metal nanostructures. AB - A segmented flow-based microreactor is used for the continuous production of faceted nanocrystals. Flow segmentation is proposed as a versatile tool to manipulate the reduction kinetics and control the growth of faceted nanostructures; tuning the size and shape. Switching the gas from oxygen to carbon monoxide permits the adjustment in nanostructure growth from 1D (nanorods) to 2D (nanosheets). CO is a key factor in the formation of Pd nanosheets and Pt nanocubes; operating as a second phase, a reductant, and a capping agent. This combination confines the growth to specific structures. In addition, the segmented flow microfluidic reactor inherently has the ability to operate in a reproducible manner at elevated temperatures and pressures whilst confining potentially toxic reactants, such as CO, in nanoliter slugs. This continuous system successfully synthesised Pd nanorods with an aspect ratio of 6; thin palladium nanosheets with a thickness of 1.5 nm; and Pt nanocubes with a 5.6 nm edge length, all in a synthesis time as low as 150 s. PMID- 26927866 TI - 3-Hydroxypyrimidine-2,4-diones as Selective Active Site Inhibitors of HIV Reverse Transcriptase-Associated RNase H: Design, Synthesis, and Biochemical Evaluations. AB - Human immunodeficiency virus (HIV) reverse transcriptase (RT) associated ribonuclease H (RNase H) remains an unvalidated antiviral target. A major challenge of specifically targeting HIV RNase H arises from the general lack of selectivity over RT polymerase (pol) and integrase (IN) strand transfer (ST) inhibitions. We report herein the synthesis and biochemical evaluations of three novel 3-hydroxypyrimidine-2,4-dione (HPD) subtypes carefully designed to achieve selective RNase H inhibition. Biochemical studies showed the two subtypes with an N-1 methyl group (9 and 10) inhibited RNase H in low micromolar range without significantly inhibiting RT polymerase, whereas the N-1 unsubstituted subtype 11 inhibited RNase H in submicromolar range and RT polymerase in low micromolar range. Subtype 11 also exhibited substantially reduced inhibition in the HIV-1 INST assay and no significant cytotoxicity in the cell viability assay, suggesting that it may be amenable to further structure-activity relationship (SAR) for identifying RNase H inhibitors with antiviral activity. PMID- 26927868 TI - A role for genetic susceptibility in sporadic focal segmental glomerulosclerosis. PMID- 26927869 TI - Measurement of Antioxidant Capacity by Electron Spin Resonance Spectroscopy Based on Copper(II) Reduction. AB - A new method is proposed for measuring the antioxidant capacity by electron spin resonance spectroscopy based on the loss of electron spin resonance signal after Cu(2+) is reduced to Cu(+) with antioxidant. Cu(+) was removed by precipitation in the presence of SCN(-). The remaining Cu(2+) was coordinated with diethyldithiocarbamate, extracted into n-butanol and determined by electron spin resonance spectrometry. Eight standards widely used in antioxidant capacity determination, including Trolox, ascorbic acid, ferulic acid, rutin, caffeic acid, quercetin, chlorogenic acid, and gallic acid were investigated. The standard curves for determining the eight standards were plotted, and results showed that the linear regression correlation coefficients were all high enough (r > 0.99). Trolox equivalent antioxidant capacity values for the antioxidant standards were calculated, and a good correlation (r > 0.94) between the values obtained by the present method and cupric reducing antioxidant capacity method was observed. The present method was applied to the analysis of real fruit samples and the evaluation of the antioxidant capacity of these fruits. PMID- 26927870 TI - Ultrastructural observations of the attachment organs of the monogenean Rajonchocotyle emarginata (Olsson, 1876) (Polyopisthocotylea: Hexabothriidae), a gill parasite of rays. AB - The present study uses scanning and transmission electron microscopical observations to examine the haptoral features of the hexabothriid polyopisthocotylean monogenean Rajonchocotyle emarginata from the gills of the elasmobranch Amblyraja radiata. The haptor possesses six equal, pedunculate suckers, each armed with a large, curved, hooked sclerite, and an appendix bearing two small, terminal suckers and a pair of minute hamuli. The outer side of the distal region of the hooked sclerite forms a large bulge along the antero lateral side of each sucker and the proximal region forms a small bulge on the opposite postero-lateral side; part of the large bulge, which covers the small sclerite hook, surmounts the sucker rim. The sucker sclerite is situated outside the main sucker muscle complex of the sucker wall and is surrounded by its own muscular envelope; close to the sclerite itself, long, tightly packed lamella like processes of sarcoplasm are present. A muscular sphincter surrounds the distal region of the sclerite shaft. The sclerite consists of three heterogeneous layers, but its hook region is distinguished from the shaft by the presence of an additional homogeneous layer. Hamuli within the appendix consist of three distinct layers loosely surrounded by sarcoplasmic lamellae. The luminal surface of the appendicular suckers is covered with unusual, long, thin, interconnected surface protrusions. In all other regions of the haptor, the tegumental surface is smooth, with numerous shallow pores penetrating the "terminal web" of the syncytial cytoplasm. Unicellular gland cells are localized close to the base of the appendix, with their ducts, containing non-homogenous secretory bodies, opening onto the anterior haptoral surface. Two types of sense receptors are visible on the haptoral surface. The ultrastructural features of the haptor are discussed in relation to our understanding of their function and the evolutionary relationships of the basal polyopisthocotylean monogenean groups Hexabothriidae and Chimaericolidae. PMID- 26927871 TI - [Treatment of metastatic castration-resistant prostate cancer : Drug interaction potentials of abiraterone acetate and enzalutamide]. AB - With an ageing population and associated increasing multimorbidity and polypharmacy, the potential for drug-drug interactions (DDIs) becomes increasingly important. In general, DDIs are more likely to be clinically significant for drugs with a narrow therapeutic index, necessitating dosage adjustments or replacement of co-administered drugs. Many DDIs are a result of pharmacokinetic interactions of the cytochrome P450 enzymes. In particular, the CYP3A4 isoenzyme is involved in the metabolism of about 50 % of currently used drugs. Accordingly, many commonly used drugs in patients with prostate cancer are substrates of Cyp3A4. Hence enzalutamide, a strong Cyp3A4 inductor, has the potential to substantially decrease plasma concentrations and the effects of many co-medications in this patient population, whereas abiraterone acetate, a strong Cyp2D6 inhibitor, is less of a concern with respect to Cyp450 inhibition, since the Cyp2D6-mediated metabolism is much smaller and Cyp2D6 substrates are prescribed to a lesser extent in patients with prostate cancer. PMID- 26927872 TI - The Challenge of New Legislation on Physician-Assisted Death. PMID- 26927873 TI - Determination of Leptospira borgpetersenii serovar Javanica and Leptospira interrogans serovar Bataviae as the persistent Leptospira serovars circulating in the urban rat populations in Peninsular Malaysia. AB - BACKGROUND: Leptospirosis is an emerging infectious disease of global significance, and is endemic in tropical countries, including Malaysia. Over the last decade, a dramatic increase of human cases was reported; however, information on the primary vector, the rat, and the Leptospira serovars circulating among the rat population is limited. Therefore, the present study was undertaken to isolate Leptospira and characterise the serovars circulating in the urban rat populations from selected main cities in Peninsular Malaysia. METHODS: Rat trappings were carried out between October 2011 to February 2014 in five urban cities which were chosen as study sites to represent different geographical locations in Peninsular Malaysia. Microscopic agglutination test (MAT) and PCR were carried out to identify the Leptospiral serogroup and determine the pathogenic status of the isolates, respectively while pulsed-field gel electrophoresis (PFGE) and random amplified polymorphic DNA (RAPD)-PCR were used to characterize the isolates. RESULTS: Three rat species were identified from the three hundred and fifty seven rats captured with Rattus rattus, being the dominant rat species (285, 80 %) followed by Rattus norgevicus (53, 15 %) and Rattus exulans (19, 5 %). Only 39 samples (11.0 %) were positive by culture and further confirmed as pathogenic Leptospira by PCR. Significant associations were shown between host infection with locality, season, host-age and species. Based on MAT, two serogroups were identified in the population namely; L. borgpetersenii serogroup Javanica (n = 16) and L. interrogans serogroup Bataviae (n = 23). Pulsed-field gel electrophoresis (PFGE) distinguished the two serovars in the urban rat populations: L. borgpetersenii serovar Javanica (41 %), and L. interrogans serovar Bataviae (59 %). RAPD-PCR yielded 14 distinct patterns and was found to be more discriminative than PFGE. CONCLUSIONS: This study confirms two Leptospira serovars circulating among the urban rats population in Peninsular Malaysia namely; L. borgpetersenii serovar Javanica and L. interrogans serovars Bataviae. Despite the low number of isolates obtained from the rat population, this study suggests that rodent control programs and disease surveillance may help to reduce the possible risk of disease transmission. PMID- 26927874 TI - Validated UPLC/MS/MS assay for quantitative bioanalysis of elbasvir in rat plasma and application to pharmacokinetic study. AB - Rapid, sensitive, selective and accurate ultra performance liquid chromatography with tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for the quantification of elbasvir (ELB) in rat plasma with deuterated elbasvir (ELB D6) as internal standard (IS).Sample preparation was done by protein precipitation using acetonitrile containing 50 ng/mL IS. Chromatographic separation was achieved by an UPLC BEH C18 column (2.1 mm * 50 mm, 1.7 MUm) column with a gradient mobile phase consisting of acetonitrile-water (containing 5.0mM ammonium acetate with 0.01% acetic acid, pH 4.5) as mobile phase at a flow rate of 0.3 mL/min for 3 min. ELB was monitored using positive electrospray triple quadrupole mass spectrometer (Waters Xevo TQ-S) via multiple reaction monitoring (MRM) mode. The monitored transitions were set at m/z 882.51->656.42 and m/z 888.49->662.43 for ELB and ELB-D6, respectively. The achieved lower limit of quantification was 1.0 ng/mL. The validated method had an excellent linearity in the range of 1.0-2000 ng/mL (r(2)>0.996). Recovery efficiency at three levels QC concentrations of 2.0 (low), 160 (medium) and 1600 (high) ng/mLwas in the range of 98.29-106.40% for ELB. Matrix effect was found to be minimal. The intra- and inter-day precisions were less than 7.01%. The intra- and inter-day accuracies were determined to be within +/-6.23% for all accuracy measurements. The validated simple and rapid UPLC-MS/MS method was successfully used to the pharmacokinetics study of ELB in rats, providing its applicability in relevant preclinical studies. PMID- 26927875 TI - A lateral flow immunosensor for direct, sensitive, and highly selective detection of hemoglobin A1c in whole blood. AB - An immunosensor that operates based on the principles of lateral flow was developed for direct detection of hemoglobin A1c (HbA1c) in whole blood. We utilized colloidal gold-functionalized antibodies to transduce the specific signal generated when sandwich immuno-complexes were formed on the strip in the presence of HbA1c. The number and intensity of the test lines on the strips indicate normal, under control, and elevated levels of HbA1c. In addition, a linear relationship between HbA1c levels and immunosensor signal intensity was confirmed, with a dynamic range of 4-14% (20-130 mmol mol(-1)) HbA1c. Using this linear relationship, we determined the HbA1c levels in blood as a function of the signal intensity on the strips. Measurements were validated using the Bio-Rad Variant II HPLC and DCA Vantage tests. Moreover, the immunosensor was verified to be highly selective for detection of HbA1c against HbA0, glycated species of HbA0, and HbA2. The limit of detection was found to be 42.5 MUg mL(-1) (1.35 mmol mol(-1)) HbA1c, which is reasonably sensitive compared to the values reported for microarray immunoassays. The shelf life of the immunosensor was estimated to be 1.4 months when stored at ambient temperature, indicating that the immunoassay is stable. Thus, the lateral flow immunosensor developed here was shown to be capable of performing selective, accurate, rapid, and stable detection of HbA1c in human blood samples. PMID- 26927876 TI - Determination of macrocyclic lactones in bovine liver using QuEChERS and HPLC with fluorescence detection. AB - A method for the determination of the macrocyclic lactones Abamectin (ABA), Ivermectin (IVER), Doramectin (DORA) and Moxidectin (MOXI) in liver using HPLC with fluorescence detection is presented. The analytes were extracted and purified using a QuEChERS method. Prior to injection into an HPLC system the sample extracts were reacted with a mixture of 1-methylimidazole, triethylamine, and trifluoroacetic anhydride to obtain the fluorescent derivatives of the analytes. The method has been validated according to EU Decision 2002/657. Recovery for the analytes ranged from 85 to 90%. Repeatibility and Trueness varied between 8-18% and -6 to 6%, respectively and were compliant with the requirements stated in EU Decision 2002/657. Limit of Decision (CCalpha) were: 22.8 MUg kg(-1) (ABA), 126.3 MUg kg(-1) (DORA), 118.3 MUg kg(-1) (MOXI) and 126.9 MUg kg(-1) (IVER). PMID- 26927877 TI - Chiral analysis of carvedilol and its metabolites hydroxyphenyl carvedilol and O desmethyl carvedilol in human plasma by liquid chromatography-tandem mass spectrometry: Application to a clinical pharmacokinetic study. AB - Carvedilol is an antihypertensive drug, which is available in clinical practice as a racemic mixture. (S)-(-)-carvedilol is a beta- and alpha1-adrenergic antagonist, while (R)-(+)-carvedilol only acts as an alpha1-adrenergic antagonist. Carvedilol is metabolized mainly by glucuronidation and, to a lesser extent, by CYP2D6 to hydroxyphenyl carvedilol (OHC) and by CYP2C9 to O-desmethyl carvedilol (DMC). This study describes the development and validation of a method for the sequential analysis of the enantiomers of carvedilol, OHC and DMC in plasma using a Chirobiotic((r)) V chiral-phase column coupled to an LC-MS/MS system. The method was linear in the range of 0.05-100, 0.05-10 and 0.02-10 ng/mL for the carvedilol, OHC and DMC enantiomers, respectively. Application of the method to the investigation of a patient with type 2 diabetes mellitus treated with a single oral dose of 25mg racemic carvedilol showed plasma accumulation of the (R)-(+)-carvedilol, (R)-(+)-DMC and (R)-(+)-OHC enantiomers. These results suggest that plasma accumulation of (R)-(+)-carvedilol cannot be explained by its oxidative metabolism. PMID- 26927878 TI - Recovery and purification of a Kluyvermyces lactis beta-galactosidase by Mixed Mode Chromatography. AB - Mixed Mode Chromatography (MMC) is a potential separation technique that allows simultaneous ionic and hydrophobic interactions between the adsorbent and the adsorbate. The aim of this work was to assess the recovery and purification of a Kluyveromyces lactis beta-galactosidase employing MMC. Protein precipitation and dialysis were performed in order to concentrate the enzyme of interest and eliminate cell debris and other interferences inherent in the fermentation medium. The best conditions for both adsorption and desorption were attained by a non-factorial Central Composite Experimental Design and employed in the chromatographic runs with resin CAPTO MMC. Fermentation yielded mean values of total enzyme concentration of 0.44 mg/mL, enzymatic activity (employing lactose as a substrate) of 74 U/mL and specific activity of 168 U/mg. The Purification Factor (PF) obtained was of 1.17. After precipitation and dialysis, the subsequent chromatographic run resulted in recovery values of 41.0 and 48.2% of total protein concentration and enzymatic activity, respectively. SDS-PAGE electrophoresis confirmed the purification evolution throughout the unit operations employed, attesting the feasibility of the technique to obtain enzymes with not only considerable degree of purity but also possessing high-added value. PMID- 26927879 TI - Development of a readily applied method to quantify ractopamine residue in meat and bone meal by QuEChERS-LC-MS/MS. AB - A QuEChERS method of ractopamine (RCT) residue detection in swine meat and bone meal (MBM) samples was demonstrated. Samples were hydrolyzed with protease and beta-glucuronidase prior to QuEChERS (Quick, Easy, Cheap, Effective, Rugged and Safe) extraction and clean-up. Samples were analyzed in a Liquid Chromatography (equipped with ACE 5 C18 column under gradient elution) coupled with a triple quadrupole mass spectrometer operating in positive electrospray ionization mode (using multiple reaction monitoring, MRM). The method was validated for its specificity, decision limit (CCalpha), detection capability (CCbeta), recovery, repeatability, reproducibility, linearity, limits of detection (LODs), quantification (LOQs), and stability according to international guidelines (European Commission Decision 2002/657/EC). Recoveries ranged from 96.3 to 107.0%. Repeatability and reproducibility showed both RSD<5.7% and 3.1%, respectively. LODs and LOQs were 1.91 and 6.36 ppb, respectively. CCalpha and CCbeta values were 1.91 and 2.37 ppb, respectively. RCT showed good stability for spiked samples and real samples when the concentration was higher, otherwise at lower concentration stability was lower. The proposed method can be successfully applied on a regular basis for the determination of RCT in MBM, demonstrating the usefulness of the method as a tool for compliance monitoring in regulatory laboratories. PMID- 26927880 TI - Proglucagons in vertebrates: Expression and processing of multiple genes in a bony fish. AB - In contrast to mammals, where a single proglucagon (PG) gene encodes three peptides: glucagon, glucagon-like peptide 1 and glucagon-like peptide 2 (GLP-1; GLP-2), many non-mammalian vertebrates carry multiple PG genes. Here, we investigate proglucagon mRNA sequences, their tissue expression and processing in a diploid bony fish. Copper rockfish (Sebastes caurinus) express two independent genes coding for distinct proglucagon sequences (PG I, PG II), with PG II lacking the GLP-2 sequence. These genes are differentially transcribed in the endocrine pancreas, the brain, and the gastrointestinal tract. Alternative splicing identified in rockfish is only one part of this complex regulation of the PG transcripts: the system has the potential to produce two glucagons, four GLP-1s and a single GLP-2, or any combination of these peptides. Mass spectrometric analysis of partially purified PG-derived peptides in endocrine pancreas confirms translation of both PG transcripts and differential processing of the resulting peptides. The complex differential regulation of the two PG genes and their continued presence in this extant teleostean fish strongly suggests unique and, as yet largely unidentified, roles for the peptide products encoded in each gene. PMID- 26927881 TI - Molecular evidence for the existence of an aryl hydrocarbon receptor pathway in scallops Chlamys farreri. AB - The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that controls the expression of a diverse set of genes. In this study we cloned full-length cDNAs encoding an AhR homologue (designated CfAhR, Accession number: FJ588640) from scallop Chlamys farreri. The CfAhR sequence was constituted by an open reading frame (ORF) of 2466bp encoding 821 amino acids. The predicted molecular weight was 93.0kDa. The CfAhR showed a high conservation of the residues and domains essential to the function of AhR, including basic helix-loop helix (bHLH) and Per-ARNT-Sim (PAS) domains. Phylogenetic analysis demonstrated that it was clustered within the invertebrate AhR branch. CfAhR expression was detected in gill, digestive gland, ovary, spermary, mantle and adductor, and the highest transcription level was observed in gill. Recombinant plasmid CfAhR pET32a (designated rCfAhR) was successfully expressed in Escherichia coli BL21. To investigate the molecular detoxification mechanism of benzo(a)pyrene (BaP) detoxification-related genes (AhR; aryl hydrocarbon receptor nuclear translocator, ARNT; heat shock protein 90, HSP90; cytochrome P450 1A1, CYP1A1; glutathione S-transferase pi, GST-pi and P glycoprotein, Pgp) in C. farreri gill, real-time quantitative PCR analysis revealed that the mRNA expression level of CfAhR, xenobiotic-metabolizing enzymes and efflux transporters was induced by BaP and was sensitive to BaP exposure time and concentration, suggesting that BaP influenced the expression of a putative AhR/ARNT signaling pathway in scallops. Our results support the possibility that CfAhR genes are early molecular indicators of BaP through a putative CYP signaling pathway in marine bivalves. PMID- 26927882 TI - National Differences in Regional Emergency Department Boarding Times: Are US Emergency Departments Prepared for a Public Health Emergency? AB - OBJECTIVES: Boarding admitted patients decreases emergency department (ED) capacity to accommodate daily patient surge. Boarding in regional hospitals may decrease the ability to meet community needs during a public health emergency. This study examined differences in regional patient boarding times across the United States and in regions at risk for public health emergencies. METHODS: A retrospective cross-sectional analysis was performed by using 2012 ED visit data from the American Hospital Association (AHA) database and 2012 hospital ED boarding data from the Centers for Medicare and Medicaid Services Hospital Compare database. Hospitals were grouped into hospital referral regions (HRRs). The primary outcome was mean ED boarding time per HRR. Spatial hot spot analysis examined boarding time spatial clustering. RESULTS: A total of 3317 of 4671 (71%) hospitals were included in the study cohort. A total of 45 high-boarding-time HRRs clustered along the East/West coasts and 67 low-boarding-time HRRs clustered in the Midwest/Northern Plains regions. A total of 86% of HRRs at risk for a terrorist event had high boarding times and 36% of HRRs with frequent natural disasters had high boarding times. CONCLUSIONS: Urban, coastal areas have the longest boarding times and are clustered with other high-boarding-time HRRs. Longer boarding times suggest a heightened level of vulnerability and a need to enhance surge capacity because these regions have difficulty meeting daily emergency care demands and are at increased risk for disasters. (Disaster Med Public Health Preparedness. 2016;10:576-582). PMID- 26927884 TI - Word learning under infinite uncertainty. AB - Language learners must learn the meanings of many thousands of words, despite those words occurring in complex environments in which infinitely many meanings might be inferred by the learner as a word's true meaning. This problem of infinite referential uncertainty is often attributed to Willard Van Orman Quine. We provide a mathematical formalisation of an ideal cross-situational learner attempting to learn under infinite referential uncertainty, and identify conditions under which word learning is possible. As Quine's intuitions suggest, learning under infinite uncertainty is in fact possible, provided that learners have some means of ranking candidate word meanings in terms of their plausibility; furthermore, our analysis shows that this ranking could in fact be exceedingly weak, implying that constraints which allow learners to infer the plausibility of candidate word meanings could themselves be weak. This approach lifts the burden of explanation from 'smart' word learning constraints in learners, and suggests a programme of research into weak, unreliable, probabilistic constraints on the inference of word meaning in real word learners. PMID- 26927885 TI - Pressure-driven opening of carbon nanotubes. AB - The closing and opening of carbon nanotubes (CNTs) is essential for their applications in nanoscale chemistry and biology. We report reactive molecular dynamics simulations of CNT opening triggered by internal pressure of encapsulated gas molecules. Confined argon generates 4000 bars of pressure inside capped CNT and lowers the opening temperature by 200 K. Chemical interactions greatly enhance the efficiency of CNT opening: fluorine-filled CNTs open by fluorination of carbon bonds at temperature and pressure that are 700 K and 1000 bar lower than for argon-filled CNTs. Moreover, pressure induced CNT opening by confined gases leaves the CNT cylinders intact and removes only the fullerene caps, while the empty CNT decomposes completely. In practice, the increase in pressure can be achieved by near-infrared light, which penetrates through water and biological tissues and is absorbed by CNTs, resulting in rapid local heating. Spanning over a thousand of bars and Kelvin, the reactive and non-reactive scenarios of CNT opening represent extreme cases and allow for a broad experimental control over properties of the CNT interior and release conditions of the confined species. The detailed insights into the thermodynamic conditions and chemical mechanisms of the pressure-induced CNT opening provide practical guidelines for the development of novel nanoreactors, catalysts, photo-catalysts, imaging labels and drug delivery vehicles. PMID- 26927886 TI - Improved estimation of hydraulic conductivity by combining stochastically simulated hydrofacies with geophysical data. AB - Hydraulic conductivity is a major parameter affecting the output accuracy of groundwater flow and transport models. The most commonly used semi-empirical formula for estimating conductivity is Kozeny-Carman equation. However, this method alone does not work well with heterogeneous strata. Two important parameters, grain size and porosity, often show spatial variations at different scales. This study proposes a method for estimating conductivity distributions by combining a stochastic hydrofacies model with geophysical methods. The Markov chain model with transition probability matrix was adopted to re-construct structures of hydrofacies for deriving spatial deposit information. The geophysical and hydro-chemical data were used to estimate the porosity distribution through the Archie's law. Results show that the stochastic simulated hydrofacies model reflects the sedimentary features with an average model accuracy of 78% in comparison with borehole log data in the Chaobai alluvial fan. The estimated conductivity is reasonable and of the same order of magnitude of the outcomes of the pumping tests. The conductivity distribution is consistent with the sedimentary distributions. This study provides more reliable spatial distributions of the hydraulic parameters for further numerical modeling. PMID- 26927887 TI - Social amoebae trap and kill bacteria by casting DNA nets. AB - Extracellular traps (ETs) from neutrophils are reticulated nets of DNA decorated with anti-microbial granules, and are capable of trapping and killing extracellular pathogens. Various phagocytes of mammals and invertebrates produce ETs, however, the evolutionary history of this DNA-based host defence strategy is unclear. Here we report that Sentinel (S) cells of the multicellular slug stage of the social amoeba Dictyostelium discoideum produce ETs upon stimulation with bacteria or lipopolysaccharide in a reactive oxygen species-dependent manner. The production of ETs by S cells requires a Toll/Interleukin-1 receptor domain containing protein TirA and reactive oxygen species-generating NADPH oxidases. Disruption of these genes results in decreased clearance of bacterial infections. Our results demonstrate that D. discoideum is a powerful model organism to study the evolution and conservation of mechanisms of cell-intrinsic immunity, and suggest that the origin of DNA-based ETs as an innate immune defence predates the emergence of metazoans. PMID- 26927888 TI - Diagnostic Utility of Orthopedia Homeobox (OTP) in Pulmonary Carcinoid Tumors. AB - Recently, Orthopedia Homeobox (OTP) was described as a prognostic marker for pulmonary carcinoid tumors; however, little is known about the function and distribution pattern of this transcription factor in normal organs/tissues and in tumors. Consequently, OTP expression was investigated in a variety of tumors, with special interest in pulmonary and nonpulmonary neuroendocrine tumors (NETs) and high-grade neuroendocrine carcinomas. OTP immunohistochemical analysis was performed on a total of 162 pulmonary carcinoid tumors, 31 pulmonary neuroendocrine hyperplasias, 104 pulmonary high-grade neuroendocrine carcinomas (large cell neuroendocrine and small cell neuroendocrine), 102 nonpulmonary NETs (G1/G2 NETs, small cell and large cell neuroendocrine carcinomas, and Merkel cell carcinomas), 150 endocrine tumors (thyroid, parathyroid, adrenocortical, and pheochromocytomas/paragangliomas), 279 adenocarcinomas, and 88 squamous cell carcinomas of various organs, including those of the lungs and others. In addition, normal tissues from various organs were studied. OTP nuclear expression was seen in 80% of lung carcinoid tumors. Among other tumors, 4 small-cell carcinomas showed focal expression (2 pulmonary and 2 bladder), but all other tumors were completely negative. Overall, the sensitivity and specificity of OTP were 80.2% and 99.4%, respectively. All TTF1-positive lung carcinoid tumors were diffusely positive for OTP, but none of the OTP-negative carcinoid tumors was positive for TTF1. OTP expression was not seen in any normal tissues/organs. OTP was also negative in neuroendocrine cells of the normal bronchus/bronchiole. However, OTP was strongly expressed in neuroendocrine hyperplasia, including reactive and preneoplastic hyperplasia. Our results suggest that OTP may serve as a useful diagnostic marker for lung carcinoid tumors. PMID- 26927889 TI - Histologic Features Associated With Columnar-lined Esophagus in Distal Esophageal and Gastroesophageal Junction (GEJ) Biopsies From GERD Patients: A Community based Population Study. AB - There are inherent problems with the endoscopic and pathologic criteria for columnar-lined esophagus (CLE). Furthermore, the clinical and biological significance of an irregular squamocolumnar junction (SCJ) is unclear. The aim of this study was to evaluate the association between histologic features in SCJ biopsies and CLE and to gain insight into the significance of an irregular SCJ. The study was a cross-sectional analysis of 2176 mucosal biopsies of the SCJ from 544 patients in a large prospective community clinic-based study of gastroesophageal reflux disease in Washington State. Biopsy samples were evaluated blindly for a wide variety of histologic features, such as the presence and type of mucosal glands, submucosal glands and ducts, goblet cells, multilayered epithelium (ME), inflammation, and buried columnar epithelium. Histologic findings were correlated with the endoscopic findings (normal Z-line, irregular Z-line, or CLE) and evaluated by logistic regression and receiver operating characteristic analysis.Five histologic features were associated with CLE: pure mucous glands, ME, presence of goblet cells, >=50% of crypts with goblet cells, and buried columnar epithelium. Pure oxyntic glands were inversely associated with CLE. The features most strongly related to CLE included biopsies with >=50% of crypts with goblet cells, ME, and mucosal gland type (area under the curve=0.71; 95% confidence interval=0.66-0.76). Patients with an irregular Z line were histologically similar to those with CLE. Certain histologic features in biopsies of the SCJ are associated with the presence of CLE. Irregularity of the Z-line is probably indicative of ultrashort segment CLE, instead of being a potential variation of normal. PMID- 26927890 TI - Clinical Relevance of Different Papillary Growth Patterns of Pulmonary Adenocarcinoma. AB - Growth patterns of pulmonary adenocarcinoma (ADC) have high prognostic impact and are accepted as a novel classification system for this entity. However, specifically for the papillary pattern, divergent data with respect to prevalence, clinical associations, and prognostic impact have been reported. By evaluating 674 resected pulmonary ADCs containing 308 cases with a papillary component and 101 papillary predominant cases, we documented differences in the morphologic composition of papillary growth patterns and delineated 3 different types. The different types were correlated with pathologic and clinical data including survival. Type 3 papillary cases with any or predominant papillary growth were associated with extensive spread through alveolar spaces, high proliferation, higher stage, low rates of EGFR mutations, and smoking, whereas type 1 papillary tumors showed the opposite associations. The subclassification of papillary growth revealed type-specific associations for overall and disease free survival (disease-free survival type 1: 67.1 mo, type 2: 56.8 mo, type 3: 49.9 mo, P=0.025). The presence of any papillary type 3 pattern was a predominant pattern independent predictor of worse overall survival (hazard ratio=2.5, P=0.02). For a future grading system of lung ADC, categorization of papillary growth in 1 single category might not be adequate, as this pattern contains a heterogenous mix of tumors with a divergent prognosis. We suggest that papillary pattern types should be separated to further improve the prognostic power of ADC growth pattern analysis. PMID- 26927891 TI - Immunostains Used to Subtype Hepatic Adenomas Do Not Distinguish Hepatic Adenomas From Hepatocellular Carcinomas. AB - Immunostains are used to subtype hepatic adenomas to stratify for the risk of malignant transformation. The most common panel of immunostains used for this purpose includes liver fatty acid-binding protein (LFABP), serum amyloid A (SAA) protein, C-reactive protein (CRP), and glutamine synthetase (GS). Importantly, some pathologists use these stains in an attempt to distinguish hepatocellular carcinomas (HCC) from hepatic adenomas. However, there are limited data on the performance of these stains in HCCs. To investigate the staining characteristics of HCCs, we studied 159 HCCs (92 well-differentiated, 67 moderately differentiated, and 7 poorly differentiated) and 7 fibrolamellar carcinomas for the expression of LFABP, SAA, CRP, and GS. All of the stains were positive in at least a subset of HCCs: SAA was positive in 27 of 159 (17%), CRP in 86 of 159 (54%), and GS in 23 of 47 (49%) cases; LFABP showed loss of staining in 36 of 159 (23%) cases. Fibrolamellar carcinomas were consistently CRP positive (7 of 7 cases) and frequently showed loss of LFABP (4 of 7 cases). There was no association between expression of SAA, CRP, and GS as well as loss of LFABP expression and other clinicopathologic features. HCCs with loss of LFABP were more frequently associated with negative GS expression (11 of 14 cases, P=0.02). These data show that immunostains used to subtype hepatic adenomas are not useful for distinguishing HCCs from hepatic adenomas and should be used only after a diagnosis of hepatic adenoma has been made using other criteria. PMID- 26927892 TI - Analysis of NAB2-STAT6 Gene Fusion in 17 Cases of Meningeal Solitary Fibrous Tumor/Hemangiopericytoma: Review of the Literature. AB - Solitary fibrous tumor/hemangiopericytoma (SFT/HPC) is a mesenchymal tumor that can affect virtually any region of the body. SFT/HPC of the thoracic cavity and soft tissue has been histologically considered a single biological entity termed SFT; in fact, NAB2-STAT6 gene fusion was recently identified in both diseases. In contrast, meningeal SFT and HPC still need to be investigated in detail with regard to gene fusion variants. The aim of this study was to verify the frequency of NAB2-STAT6 fusion and the relationship between fusion variants and clinicopathologic findings of SFT/HPC, especially meningeal SFT/HPC. We examined the NAB2-STAT6 fusion by reverse transcription polymerase chain reaction with 4 cases of meningeal SFT and 13 cases of meningeal HPC. NAB2-STAT6 fusion transcripts were identified in 12 of 17 cases, including NAB2ex6-STAT6ex17 (4/17, 24%), NAB2ex6-STAT6ex16 and NAB2ex4-STAT6ex2 (3/17, 18%, respectively), and NAB2ex5-STAT6ex16 (2/17, 12%). Three cases showed a pseudopapillary pattern, and 2 of them carried NAB2ex6-STAT6ex17. In addition, our meta-analysis revealed that the major fusion variant in meningeal SFT/HPC was NAB2ex6-STAT6ex16/17 (29/54, 54%), which was also common in soft tissue and intraperitoneum/retroperitoneum but rare in thoracic SFT. Fusion variant significantly correlated with age and histologic diagnosis in meningeal SFT/HPC but not with prognosis. Our results represented that meningeal SFT and HPC were in a single biological spectrum with NAB2-STAT6 gene fusion as was nonmeningeal SFT and further confirmed the organ specific tumorigenic process and morphologic differences on the basis of fusion variants in meningeal SFT/HPC. PMID- 26927893 TI - Clinical analysis of 26 patients with histologically proven placental chorioangiomas. AB - OBJECTIVES: The purpose of this study was to evaluate the clinical characteristics, imaging features, pregnancy complications, prenatal management of patients with placenta chorioangioma. METHODS: This was a retrospective study of 26 cases with histologically proven placenta chorioangima, in which the natural history, pregnancy complications, and clinical characteristics including ultrasonography were evaluated. RESULTS: Twelve of the twenty-six cases had a wide range of maternal-fetal complications including polyhydramnios (7), fetal growth restriction (3), fetal distress (2), pre-eclampsia (3), fetal anemia thrombocytopenia (2), congestive heart failure (1) and fetal abnormality (1). CONCLUSIONS: Placenta chorioangioma was associated with series of pregnancy complications such as polyhytramnios, premature delivery, maternal pre-eclampsia, fetal growth restriction, fetal distress, even fetal anemia and cardiomegaly. With regular prenatal examination, necessary treatment, and timely delivery, the majority had a good pregnancy outcome. PMID- 26927894 TI - The sFlt-1/PlGF ratio associates with prolongation and adverse outcome of pregnancy in women with (suspected) preeclampsia: analysis of a high-risk cohort. AB - OBJECTIVE: To evaluate the additive value of the sFlt-1/PlGF ratio for diagnosing preeclampsia (PE) and predicting prolongation of pregnancy and adverse outcome in a cohort of women with PE or at high risk of PE. STUDY DESIGN: Patients with suspected or confirmed clinical PE were recruited. At time of inclusion blood for measurement of sFlt-1and PlGF was taken. Values were determined after delivery. A cut-off ratio of >=85 was defined as a positive test. RESULTS: A total of 107 patients were included. Of the patients, 62 (58%) met the clinical criteria of PE at time of blood sampling. In 10% of these patients (n=6) the ratio was <85 (false negative), whereas in 7% (n=3) of patients without clinical PE the ratio was >=85 (false positive), resulting in positive and negative predictive values of 95% and 88% respectively. One patient with false positive ratio developed superimposed PE and 2 developed gestational hypertension, and adverse outcome occurred in all three. An adverse pregnancy outcome was only encountered in 1 of the 6 patients with a false negative ratio. Using a binary regression model with adjustment for gestational age <34 weeks, the adverse outcome risk was 11 times increased on the basis of clinical PE, and 30 times on the basis of an elevated ratio (P=0.036). CONCLUSION: The additive value of an increased ratio for diagnosing PE is limited since most patients with clinical PE also have a positive ratio. However, an elevated ratio is superior to the clinical diagnosis of PE for predicting an adverse pregnancy outcome. Furthermore, irrespective of clinical PE, a low ratio is inversely correlated with prolongation of pregnancy. PMID- 26927895 TI - Reduced spontaneous platelet aggregation: a novel risk factor for adverse pregnancy outcome. AB - OBJECTIVE: Spontaneous platelet aggregation has not been adequately assessed as a potential risk factor for adverse outcomes in pregnancy. Therefore the objective of this study was to assess spontaneous platelet aggregation (SPA), measured via a novel functional assay, as a risk factor for hypertensive disease and intra uterine growth restriction (IUGR). STUDY DESIGN: This was a prospective longitudinal study. Spontaneous platelet aggregation was assessed as a marker of platelet reactivity using a modification of light transmission aggregometry. Platelet reactivity was assessed in four groups: non-pregnant healthy female volunteers (n=30), longitudinally in normal uncomplicated pregnancy (n=50), hypertensive disorder (n=40) and IUGR (n=30). The mean percentage SPA was plotted and compared across all groups. RESULTS: Spontaneous platelet aggregation was significantly reduced in the first trimester compared to the non-pregnant group (p-value=0.003). The mean aggregation for the hypertensive group was 1.9%, (95% CI -0.08 to 4.02) and for the IUGR group was 1.6%, (95% CI -0.6 to 3.72). Platelet aggregation in the hypertensive group was significantly reduced compared to the normal pregnant group (p<0.05). Spontaneous platelet aggregation was also reduced in the IUGR group compared to normal pregnancy (p<0.05). CONCLUSION: This study demonstrates that a reduction of spontaneous platelet aggregation may be a novel risk factor for adverse pregnancy outcomes such as pre-eclampsia and IUGR. The most clinically significant finding is that SPA is significantly lower in pregnancies complicated by hypertension and IUGR compared to those who had a normal pregnancy outcome. Further studies should be carried out to asses if spontaneous platelet aggregation may be a clinically useful tool for the prediction of pre-eclampsia and IUGR. PMID- 26927896 TI - Timing of ovarian stimulation in patients prior to gonadotoxic therapy: an analysis of 684 stimulations. AB - OBJECTIVE: Time to therapy initiation in patients requiring gonadotoxic therapy is crucial. This article evaluates the efficiency of random start ovarian stimulation in affected women. STUDY DESIGN: Retrospective anonymous registry data analysis from 85 university and non-university fertility centres participating in the international network FertiPROTEKT. The study comprised 684 women undergoing ovarian stimulation for fertility preservation from 2007 to 2013. According to the time of stimulation initiation, days of ovarian stimulation, total dose of gonadotropins used, gonadotropin dose used per day, number of oocytes retrieved and incidence of ovarian hyperstimulation syndrome were analysed. Statistical analysis was performed using analysis of variance in case of continuous outcome variables and chi-square tests in case of categorical variables. RESULTS: Among 684 women who underwent ovarian stimulation prior to gonadotoxic therapy 472 (69.0%) started ovarian stimulation between menstrual cycle day 1-5 (group A), 109 (15.9%) between day 6-14 (group B) and 103 (15.1%) after day 14 (group C). The days of stimulation (A: 10.8+/-2.4, B: 10.6+/-2.7, C: 11.5+/-2.2) and total dose of gonadotropins (A: 2496IU+/-980, B: 2529IU+/-940, C: 2970IU+/-1145) were significantly increased in group C. Numbers of obtained oocytes (Group A: 11.6+/-7.7, B: 13.9+/-9.1, C: 13.6+/-7.9) were significantly increased in group B and C, while the overall incidence of ovarian hyperstimulation syndrome III degrees was 0.15%. CONCLUSION: The outcome of ovarian stimulation is similar after stimulation initiation during any phase of the menstrual cycles, supporting the concept of random-start ovarian stimulation before gonadotoxic therapy without disadvantage for the patient concerning later fertility preservation. PMID- 26927897 TI - A non-invasive method to determine the pluripotent status of stem cells by culture medium microRNA expression detection. AB - To precisely determine the type and status of cells is an important prerequisite for basic researches and regenerative medicine involving stem cells or differentiated cells. However, the traditional destructive cell status examination methods have many limitations, mainly due to the heterogeneity of cells under the reprogramming or differentiation/trans-differentiation process. Here we present a new method to non-destructively determine the pluripotent level of embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), or the types of differentiated cells. The method is achieved by examining the expression profiles of microRNAs (miRNAs) in cell culture medium, which show consistent abundance trend as those of the cellular miRNAs. Therefore, the method enables status examination and afterward application being achieved on the same population of cells, which will greatly facilitate cell reprogramming or differentiation/trans-differentiation related based research and clinical therapy. PMID- 26927898 TI - Intraoperative use of fibrin glue dyed with methylene blue in surgery for branchial cleft anomalies. AB - OBJECTIVES/HYPOTHESIS: We present a new method of optimizing the results of surgery for branchial cleft anomalies based on the intraoperative injection of fibrin glue combined with methylene blue dye. STUDY DESIGN: Retrospective single center cohort study. METHODS: The method was applied in 17 patients suffering from branchial anomalies. Six (35.29%) had a preauricular lesion; three (17.65%) had lesions derived from the first arch/pouch/groove (type I), four (23.53%) had lesions derived from the first (type II), one (5.88%) had lesions derived from the second, one (5.88%) had lesions derived from the third, and two (11.76%) had lesions derived from the fourth. The median and mean age at surgery were 10 and 10.6 years, respectively. All patients were followed by periodic clinical and ultrasonographic examination. RESULTS: The combination of fibrin glue with methylene blue facilitated the correct assessment of the extension of the lesions and their intraoperative manipulation. After a mean follow-up of 47.8 months, all patients were free of disease. CONCLUSIONS: Intraoperative injection of branchial fistulae and cysts by a mixture of fibrin glue and methylene blue is an effective, easy, and safe tool to track lesions and achieve radical resection. The technique requires a definitive validation on a large cohort with adequate stratification of patients. LEVEL OF EVIDENCE: 4 Laryngoscope, 126:2147-2150, 2016. PMID- 26927900 TI - A Randomized Noninferiority Trial of Intravenous Iron Isomaltoside versus Oral Iron Sulfate in Patients with Nonmyeloid Malignancies and Anemia Receiving Chemotherapy: The PROFOUND Trial. AB - STUDY OBJECTIVE: A safe alternative to erythropoiesis-stimulating agents to treat anemia is warranted in patients with cancer and anemia; thus the objective of this trial was to compare the efficacy and safety of intravenous (IV) iron isomaltoside with oral iron in patients with cancer and anemia by testing the noninferiority of IV versus oral iron. DESIGN: Phase III, prospective, open label, comparative, randomized, noninferiority, multicenter trial. SETTING: Forty seven hospitals or private cancer clinics in Asia, the United States, and Europe. PATIENTS: A total of 350 patients with cancer and anemia. INTERVENTION: Patients were randomized in a 2:1 ratio to either intravenous iron isomaltoside or oral iron sulfate. Patients in the iron isomaltoside group were then randomized into an infusion subgroup (single intravenous infusions of a maximum dose of 1000 mg over 15 min) or a bolus injection subgroup (bolus injections of 500 mg over 2 min). MEASUREMENTS AND MAIN RESULTS: The primary efficacy outcome was change in hemoglobin concentration from baseline to week 4. Changes in other relevant hematology variables, effect on quality of life, and safety outcomes were also assessed. The primary efficacy outcome was tested for noninferiority, whereas the remaining outcomes were tested for superiority. Iron isomaltoside was noninferior to oral iron in change in hemoglobin concentration from baseline to week 4 (difference estimate 0.016, 95% confidence interval -0.26 to 0.29, p<0.001). A faster onset of the hemoglobin response was observed with infusion of iron isomaltoside (superiority test: p=0.03 at week 1), and a sustained effect on hemoglobin level was shown in both the iron isomaltoside and oral iron treatment groups until week 24. A significant mean decrease in fatigue score was observed from baseline to week 12 in the iron isomaltoside group (p<0.001) but not in the oral iron group (p=0.057). A higher proportion of patients treated with oral iron experienced adverse drug reactions (18.8% vs 6.6%, p<0.001) and discontinued the trial due to intolerance (8.0% vs 0.9%, p=0.001). Transient hypophosphatemia (phosphate level less than 2 mg/dl) was reported at similar low frequencies among the groups: 7.1% in the iron isomaltoside infusion subgroup versus 8.5% in the iron isomaltoside bolus injection subgroup versus 5.4% in the oral iron group. CONCLUSION: This trial demonstrated comparable sustained increases in hemoglobin concentration over time with both iron isomaltoside and oral iron. Iron isomaltoside was better tolerated than oral iron, and fatigue was significantly decreased with iron isomaltoside. Low rates of clinically insignificant hypophosphatemia were reported in patients receiving both treatments. PMID- 26927901 TI - Laboratory-Enhanced Dengue Sentinel Surveillance in Colombo District, Sri Lanka: 2012-2014. AB - INTRODUCTION: Dengue has emerged as a significant public health problem in Sri Lanka. Historically surveillance was passive, with mandatory dengue notifications based on clinical diagnosis with only limited laboratory confirmation. To obtain more accurate data on the disease burden of dengue, we set up a laboratory-based enhanced sentinel surveillance system in Colombo District. Here we describe the study design and report our findings of enhanced surveillance in the years 2012 2014. METHODS: Three outpatient clinics and three government hospitals in Colombo District that covered most of the Colombo metropolitan area were selected for the sentinel surveillance system. Up to 60 patients per week presenting with an undifferentiated fever were enrolled. Acute blood samples from each patient were tested by dengue specific PCR, NS1 ELISA and IgM ELISA. A sub-set of samples was sent to Duke-NUS Singapore for quality assurance, virus isolation and serotyping. Trained medical research assistants used a standardized case report form to record clinical and epidemiological data. Clinical diagnoses by the clinicians-in charge were recorded for hospitalized cases. RESULTS: Of 3,127 febrile cases, 43.6% were PCR and/or NS1 positive for dengue. A high proportion of lab confirmed dengue was observed from inpatients (IPD) (53.9%) compared to outpatient (clinics in hospitals and general practice) (7.6%). Dengue hemorrhagic fever (DHF) was diagnosed in 11% of patients at the time of first contact, and the median day of illness at time of presentation to the sentinel sites was 4. Dengue serotype 1 was responsible for 85% of the cases and serotype 4 for 15%. The sensitivity and specificity of the clinicians' presumptive diagnosis of dengue was 84% and 34%, respectively. CONCLUSION: DENV-1, and to a lesser degree DENV-4, infection were responsible for a high proportion of febrile illnesses in Colombo in the years 2012 to 2014. Clinicians' diagnoses were associated with high sensitivity, but laboratory confirmation is required to enhance specificity. PMID- 26927902 TI - Dissociative symptoms are associated with reduced neuropsychological performance in patients with recurrent depression and a history of trauma exposure. AB - BACKGROUND: Although preliminary work suggests that dissociative symptoms may impact neuropsychological performance in trauma-exposed populations, the relation between dissociation and cognitive performance has not been explored in patients with depression. OBJECTIVE: The present study examined dissociative symptoms in relation to neuropsychological performance in participants with a primary diagnosis of recurrent major depressive disorder (MDD) and a history of trauma exposure. METHOD: Twenty-three participants with MDD and 20 healthy controls who did not differ in age, sex, education, or IQ were assessed. In addition to a standardized neuropsychological battery assessing frontotemporally mediated cognitive processes, participants completed clinical measures assessing dissociative symptoms, illness severity, and past history of trauma exposure. RESULTS: Among participants with MDD, greater severity of derealization was associated with reduced performance on measures of delayed visuospatial recall and recognition on a task of verbal memory recognition. In addition, more severe depersonalization was associated with slower processing speed and a response style lending itself toward better performance in a less active environment. CONCLUSIONS: These findings point toward dissociative symptoms as a transdiagnostic factor associated with neuropsychological dysfunction in patients with depression and a history of trauma. Limitations and recommendations for future research are discussed. PMID- 26927904 TI - Biosynthesis of the Plant Cell Wall Matrix Polysaccharide Xyloglucan. AB - Xyloglucan (XyG) is a matrix polysaccharide that is present in the cell walls of all land plants. It consists of a beta-1,4-linked glucan backbone that is further substituted with xylosyl residues. These xylosyl residues can be further substituted with other glycosyl and nonglycosyl substituents that vary depending on the plant family and specific tissue. Advances in plant mutant isolation and characterization, functional genomics, and DNA sequencing have led to the identification of nearly all transferases and synthases necessary to synthesize XyG. Thus, in terms of the molecular mechanisms of plant cell wall polysaccharide biosynthesis, XyG is the most well understood. However, much remains to be learned about the molecular mechanisms of polysaccharide assembly and the regulation of these processes. Knowledge of the XyG biosynthetic machinery allows the XyG structure to be tailored in planta to ascertain the functions of this polysaccharide and its substituents in plant growth and interactions with the environment. PMID- 26927903 TI - The effects of Rpd3 on fly metabolism, health, and longevity. AB - The epigenetic regulation of DNA structure and function is essential for changes in gene expression involved in development, growth, and maintenance of cellular function. Epigenetic changes include histone modifications such as methylation, acetylation, ubiquitination, and phosphorylation. Histone deacetylase (HDAC) proteins have a major role in epigenetic regulation of chromatin structure. HDACs are enzymes that catalyze the removal of acetyl groups from lysine residues within histones, as well as a range of other proteins including transcriptional factors. HDACs are highly conserved proteins divided into two families and based on sequence similarity in four classes. Here we will discuss the roles of Rpd3 in physiology and longevity with emphasis on its role in flies. Rpd3, the Drosophila HDAC1 homolog, is a class I lysine deacetylase and a member of a large family of HDAC proteins. Rpd3 has multiple functions including control of proliferation, development, metabolism, and aging. Pharmacological and dietary HDAC inhibitors have been used as therapeutics in psychiatry, cancer, and neurology. PMID- 26927906 TI - Research Into Osteopathic Manipulative Medicine: Steps on the Evidence Pyramid. PMID- 26927905 TI - Physiological Functions of Cyclic Electron Transport Around Photosystem I in Sustaining Photosynthesis and Plant Growth. AB - The light reactions in photosynthesis drive both linear and cyclic electron transport around photosystem I (PSI). Linear electron transport generates both ATP and NADPH, whereas PSI cyclic electron transport produces ATP without producing NADPH. PSI cyclic electron transport is thought to be essential for balancing the ATP/NADPH production ratio and for protecting both photosystems from damage caused by stromal overreduction. Two distinct pathways of cyclic electron transport have been proposed in angiosperms: a major pathway that depends on the PROTON GRADIENT REGULATION 5 (PGR5) and PGR5-LIKE PHOTOSYNTHETIC PHENOTYPE 1 (PGRL1) proteins, which are the target site of antimycin A, and a minor pathway mediated by the chloroplast NADH dehydrogenase-like (NDH) complex. Recently, the regulation of PSI cyclic electron transport has been recognized as essential for photosynthesis and plant growth. In this review, we summarize the possible functions and importance of the two pathways of PSI cyclic electron transport. PMID- 26927907 TI - Osteopathic Manipulative Treatment for Older Patients: A National Survey of Osteopathic Physicians. AB - CONTEXT: The mission of the American Academy of Osteopathy (AAO) emphasizes "the integration of osteopathic principles, practices and manipulative treatment in patient care." Osteopathic manipulative treatment (OMT) can be used to address serious conditions affecting older persons (>=65 years). However, the percentage of osteopathic physicians who use OMT in older patients, the differences in conditions for which OMT is used, and the OMT techniques used in older patients compared with younger patients are unknown. OBJECTIVE: To determine the use of OMT by osteopathic physicians in older patients compared with younger patients. METHODS: Members of the AAO were invited, via 3 e-mail messages sent over the course of a 4-month period, to participate in an anonymous online survey. The survey asked physicians to report the percentage of patients by age group (<65 years, 65-79 years, and >=80 years) to whom they provided OMT, the types of musculoskeletal and system-based conditions for which OMT was used, and the specific OMT techniques used. RESULTS: A total of 197 of 629 AAO members (31.3%) responded to the survey. Respondents indicated that OMT was used at approximately the same rate in all patients in the 3 age groups. Osteopathic manipulative treatment was frequently used to manage a variety of musculoskeletal conditions, with the exception of osteoporosis, in all patients in the 3 age groups. The system-based conditions most often managed with OMT were respiratory and neurologic conditions. Various OMT techniques were used to treat patients in the 3 age groups; however, high-velocity, low-amplitude (HVLA) was usually avoided in patients aged 65 years or older. CONCLUSION: Osteopathic physicians who used OMT in their practice administered OMT for a variety of musculoskeletal and system based conditions in patients of all ages. Various OMT techniques were used by these physicians for patients of all ages, with the exception of HVLA, which was mainly used in patients younger than 65 years. PMID- 26927908 TI - Recovery From Chronic Low Back Pain After Osteopathic Manipulative Treatment: A Randomized Controlled Trial. AB - CONTEXT: Little is known about recovery after spinal manipulation in patients with low back pain (LBP). OBJECTIVE: To assess recovery from chronic LBP after a short regimen of osteopathic manipulative treatment (OMT) in a responder analysis of the OSTEOPAThic Health outcomes In Chronic low back pain (OSTEOPATHIC) Trial. METHODS: A randomized double-blind, sham-controlled trial was conducted to determine the efficacy of 6 OMT sessions over 8 weeks. Recovery was assessed at week 12 using a composite measure of pain recovery (10 mm or less on a 100-mm visual analog scale) and functional recovery (2 or less on the Roland-Morris Disability Questionnaire for back-specific functioning). The RRs and numbers needed-to-treat (NNTs) for recovery with OMT were measured, and corresponding cumulative distribution functions were plotted according to baseline LBP intensity and back-specific functioning. Multiple logistic regression was used to compute the OR for recovery with OMT while simultaneously controlling for potential confounders. Sensitivity analyses were performed to corroborate the primary results. RESULTS: There were 345 patients who met neither of the recovery criteria at baseline in the primary analyses and 433 patients who met neither or only 1 of these criteria in the sensitivity analyses. There was a large treatment effect for recovery with OMT (RR, 2.36; 95% CI, 1.31-4.24; P=.003), which was associated with a clinically relevant NNT (8.9; 95% CI, 5.4-25.5). This significant finding persisted after adjustment for potential confounders (OR, 2.92; 95% CI, 1.43-5.97; P=.003). There was also a significant interaction effect between OMT and comorbid depression (P=.02), indicating that patients without depression were more likely to recover from chronic LBP with OMT (RR, 3.21; 95% CI, 1.59-6.50; P<.001) (NNT, 6.5; 95% CI, 4.2-14.5). The cumulative distribution functions demonstrated optimal RR and NNT responses in patients with moderate to severe levels of LBP intensity and back-specific dysfunction at baseline. Similar results were observed in the sensitivity analyses. CONCLUSIONS: The OMT regimen was associated with significant and clinically relevant measures for recovery from chronic LBP. A trial of OMT may be useful before progressing to other more costly or invasive interventions in the medical management of patients with chronic LBP. (ClinicalTrials.gov number NCT00315120). PMID- 26927909 TI - Targeting Patient Subgroups With Chronic Low Back Pain for Osteopathic Manipulative Treatment: Responder Analyses From a Randomized Controlled Trial. AB - CONTEXT: Osteopathic manipulative treatment (OMT) is often used to treat patients with low back pain (LBP). OBJECTIVE: To identify subgroups of patients with chronic LBP who achieve medium to large treatment effects with OMT based on responder analyses involving pain and functioning outcomes from the OSTEOPAThic Health outcomes In Chronic low back pain (OSTEOPATHIC) Trial. METHODS: This randomized, double-blind, sham-controlled trial involving 455 patients in Dallas Fort Worth was conducted from 2006 to 2011. A 100-mm visual analog scale (VAS) for LBP intensity and the Roland-Morris Disability Questionnaire (RMDQ) for back specific functioning were used to assess primary and secondary outcomes, respectively. Substantial improvement was defined as 50% or greater reduction at week 12 compared with baseline. Cumulative distribution functions for the RR and number-needed-to-treat (NNT) were used to assess response. RESULTS: Medium treatment effects for LBP intensity were observed overall (RR, 1.41; 95% CI, 1.13 1.76; P=.002; NNT, 6.9; 95% CI, 4.3-18.6). However, large treatment effects were observed in patients with baseline VAS scores of 35 mm or greater. Although OMT was not associated with overall substantial improvement in back-specific functioning, patients with baseline RMDQ scores of 7 or greater experienced medium effects, and patients with baseline scores 16 or greater experienced large effects that were significant. The OMT effects for LBP intensity and back specific functioning were independent of baseline patient demographic characteristics, comorbid medical conditions, and medication use for LBP during the trial. CONCLUSIONS: Subgrouping according to baseline levels of chronic LBP intensity and back-specific functioning appears to be a simple strategy for identifying sizeable numbers of patients who achieve substantial improvement with OMT and may thereby be less likely to use more costly and invasive interventions. (ClinicalTrials.gov number NCT00315120). PMID- 26927910 TI - The Glymphatic-Lymphatic Continuum: Opportunities for Osteopathic Manipulative Medicine. AB - The brain has long been thought to lack a lymphatic drainage system. Recent studies, however, show the presence of a brain-wide paravascular system appropriately named the glymphatic system based on its similarity to the lymphatic system in function and its dependence on astroglial water flux. Besides the clearance of cerebrospinal fluid and interstitial fluid, the glymphatic system also facilitates the clearance of interstitial solutes such as amyloid beta and tau from the brain. As cerebrospinal fluid and interstitial fluid are cleared through the glymphatic system, eventually draining into the lymphatic vessels of the neck, this continuous fluid circuit offers a paradigm shift in osteopathic manipulative medicine. For instance, manipulation of the glymphatic lymphatic continuum could be used to promote experimental initiatives for nonpharmacologic, noninvasive management of neurologic disorders. In the present review, the authors describe what is known about the glymphatic system and identify several osteopathic experimental strategies rooted in a mechanistic understanding of the glymphatic-lymphatic continuum. PMID- 26927911 TI - Concussions and Osteopathic Manipulative Treatment: An Adolescent Case Presentation. AB - Concussions commonly occur in adolescents. Although the majority of adolescent patients' symptoms resolve, about 11% continue to experience symptoms at 3 months. Standard treatment options for prolonged symptoms are not available, and the role of osteopathic manipulative treatment in the management of adolescent concussions is unclear. The authors describe a case of a 16-year-old girl with a history of 3 head injuries who presented with concussion symptoms. After 6 weekly osteopathic manipulative treatment sessions, the patient was able to return to her normal activities. Further research on the role of osteopathic manipulative treatment to manage concussions is needed. PMID- 26927912 TI - Resolution of New Daily Persistent Headache After Osteopathic Manipulative Treatment. AB - New daily persistent headache is a refractory headache with an elusive cause and treatment. Limited available data suggest that abnormalities in the musculoskeletal system may increase vulnerability to this type of headache. Osteopathic manipulative treatment has been used successfully to manage primary headache disorders. In this case report, a patient with new daily persistent headache and severe somatic dysfunction had resolution of her pain after osteopathic manipulative treatment. This case suggests that osteopathic manipulative treatment may be useful in patients with this typically treatment resistant disorder. PMID- 26927913 TI - Acquired Tracheoesophageal Fistula Due to Battery Ingestion. PMID- 26927914 TI - Resolution of Concussion Symptoms After Osteopathic Manipulative Treatment: A Case Report. AB - A concussion is the result of a biomechanical force directed toward the head, causing neurologic dysfunction. The inflammatory response and the production of reactive oxygen species are proposed mechanisms for the symptoms and long-term sequelae of concussion. Osteopathic manipulative treatment (OMT) may help reduce inflammation by improving glymphatic flow. The authors describe the effect of OMT on a patient with mild concussion symptoms, including nausea, dizziness, tinnitus, and imbalance. The patient was evaluated with the Sensory Organization Test before and after undergoing a 25-minute session of OMT. After the session, the patient reported resolution of symptoms, and his sensory organization test score improved by 6 points. The role of OMT must be further investigated as an essential and cost-effective tool in the management of concussions. PMID- 26927915 TI - Envisioning Zero Suicide. PMID- 26927917 TI - Reported Versus Actual Assault Rates: In Reply. PMID- 26927918 TI - Reported Versus Actual Assault Rates. PMID- 26927919 TI - The Need for National Data on "Boarding" Psychiatric Patients in Emergency Departments. PMID- 26927920 TI - Spirituality and Religion: Initiating a Discussion With Patients. PMID- 26927922 TI - Phytosterolemia. PMID- 26927923 TI - Enhancing the developmental competence of the early embryo using secretory leukocyte peptidase inhibitor. AB - Secretory leukocyte peptidase inhibitor (SLPI) plays a role in proliferation and differentiation via the autocrine and paracrine systems. SLPI's expression is well-documented in the reproductive tract, but it remains unclear whether it is active during early embryonic development. In this study, the expression and role of Slpi in the early embryo were evaluated. In vitro embryo cultures in chemically defined simple medium resulted in a reduction in developmental speed from the 8-cell stage, as well as implantation rate compared with in vivo embryos. SLPI protein was localized to the membrane or submembrane cytoplasm in an embryonic stage-dependent manner. In vitro cultured embryos exhibited lower levels of Slpi mRNA expression than in vivo embryos. Slpi knockdown by antisense oligonucleotides attenuated the developmental speed and implantation rate compared with Slpi sense oligonucleotide-transfected embryos and in vitro controls. The critical period for the attenuation of developmental speed occurred after the 8-cell stage. SLPI treatment accelerated development, increased implantation rate, and ameliorated the suppressive effects of Slpi knockdown. Slpi knockdown did not induce changes in the total cell number or inner cell number in blastocysts. Meanwhile, SLPI upregulated the expression of the developmental factors matrix metalloproteinase-14, neutrophil elastase, and tissue inhibitor of metalloproteinase-1. Together, these results suggest that SLPI is an effective regulator of developmental speed and implantation competence in an autocrine and paracrine manner, respectively, and plays a role in controlling the expression of embryonic development factors, such as MMP family members. PMID- 26927926 TI - The effects of stress on brain and adrenal stem cells. PMID- 26927924 TI - Psychometric properties of multicomponent tools designed to assess frailty in older adults: A systematic review. AB - BACKGROUND: Frailty is widely recognised as a distinct multifactorial clinical syndrome that implies vulnerability. The links between frailty and adverse outcomes such as death and institutionalisation have been widely evidenced. There is currently no gold standard frailty assessment tool; optimizing the assessment of frailty in older people therefore remains a research priority. The objective of this systematic review is to identify existing multi-component frailty assessment tools that were specifically developed to assess frailty in adults aged >=60 years old and to systematically and critically evaluate the reliability and validity of these tools. METHODS: A systematic literature review was conducted using the standardised COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) checklist to assess the methodological quality of included studies. RESULTS: Five thousand sixty-three studies were identified in total: 73 of which were included for review. 38 multi-component frailty assessment tools were identified: Reliability and validity data were available for 21 % (8/38) of tools. Only 5 % (2/38) of the frailty assessment tools had evidence of reliability and validity that was within statistically significant parameters and of fair-excellent methodological quality (the Frailty Index-Comprehensive Geriatric Assessment [FI-CGA] and the Tilburg Frailty Indicator [TFI]). CONCLUSIONS: The TFI has the most robust evidence of reliability and validity and has been the most extensively examined in terms of psychometric properties. However, there is insufficient evidence at present to determine the best tool for use in research and clinical practice. Further in depth evaluation of the psychometric properties of these tools is required before they can fulfil the criteria for a gold standard assessment tool. PMID- 26927927 TI - Potential Environmental Impacts and Antimicrobial Efficacy of Silver- and Nanosilver-Containing Textiles. AB - For textiles containing nanosilver, we assessed benefit (antimicrobial efficacy) in parallel with potential to release nanosilver (impact) during multiple life cycle stages. The silver loading and method of silver attachment to the textile highly influenced the silver release during washing. Multiple sequential simulated household washing experiments for fabric swatches in deionized water with or without detergent showed a range of silver release. The toxicity of washing experiment supernatants to zebrafish (Danio rerio) embryos was negligible, with the exception of the very highest Ag releases (~1 mg/L Ag). In fact, toxicity tests indicated that residual detergent exhibited greater adverse response than the released silver. Although washing the fabrics did release silver, it did not affect their antimicrobial efficacy, as demonstrated by >99.9% inhibition of E. coli growth on the textiles, even for textiles that retained as little as 2 MUg/g Ag after washing. This suggests that very little nanosilver is required to control bacterial growth in textiles. Visible light irradiation of the fabrics reduced the extent of Ag release for textiles during subsequent washings. End-of-life experiments using simulated landfill conditions showed that silver remaining on the textile is likely to continue leaching from textiles after disposal in a landfill. PMID- 26927928 TI - Psychophysiological responses to auditory change. AB - A comprehensive characterization of autonomic and somatic responding within the auditory domain is currently lacking. We studied whether simple types of auditory change that occur frequently during music listening could elicit measurable changes in heart rate, skin conductance, respiration rate, and facial motor activity. Participants heard a rhythmically isochronous sequence consisting of a repeated standard tone, followed by a repeated target tone that changed in pitch, timbre, duration, intensity, or tempo, or that deviated momentarily from rhythmic isochrony. Changes in all parameters produced increases in heart rate. Skin conductance response magnitude was affected by changes in timbre, intensity, and tempo. Respiratory rate was sensitive to deviations from isochrony. Our findings suggest that music researchers interpreting physiological responses as emotional indices should consider acoustic factors that may influence physiology in the absence of induced emotions. PMID- 26927929 TI - Morphology-Driven High-Performance Polymer Transistor-based Ammonia Gas Sensor. AB - Developing high-performance gas sensors based on polymer field-effect transistors (PFETs) requires enhancing gas-capture abilities of polymer semiconductors without compromising their high charge carrier mobility. In this work, cohesive energies of polymer semiconductors were tuned by strategically inserting buffer layers, which resulted in dramatically different semiconductor surface morphologies. Elucidating morphological and structural properties of polymer semiconductor films in conjunction with FET studies revealed that surface morphologies containing large two-dimensional crystalline domains were optimal for achieving high surface areas and creating percolation pathways for charge carriers. Ammonia molecules with electron lone pairs adsorbed on the surface of conjugated semiconductors can serve as efficient trapping centers, which negatively shift transfer curves for p-type PFETs. Therefore, morphology optimization of polymer semiconductors enhances their gas sensing abilities toward ammonia, leading to a facile method of manufacturing high-performance gas sensors. PMID- 26927930 TI - Axitinib inhibits retinal and choroidal neovascularization in in vitro and in vivo models. AB - Age-related Macular Degeneration (AMD) is the leading cause of visual impairment and blindness in the elderly in developed countries. Neovascular/exudative (wet) AMD is the aggressive form of AMD and can involve choroidal neovascularization and vascular leakage. Anti-vascular endothelial growth factor (anti-VEGF) medications have significantly improved treatment of wet-AMD. However, only approximately 40% of patients obtain full benefit from anti-VEGF therapy and the medications are given by intravitreal injection. Axitinib, a small molecule multi receptor tyrosine kinase inhibitor used for the treatment of advanced renal cell carcinoma, is taken orally and inhibits VEGF activity by blocking VEGF receptors. Axitinib also has the advantage of blocking platelet derived growth factor (PDGF) receptors which play a role in neovascularization. Using in vitro human retinal microvascular endothelial cells (HRMVECs), human brain vascular pericytes (HBVRs), 3D co-culture vessel sprout assay, and in vivo laser induced rat choroidal neovascularization (CNV) models, the effect of axitinib on neovascularization was evaluated. Axitinib inhibited neovascularization better than anti-VEGF and/or anti-hPDGF-B mAb in the in vitro models demonstrating that combined inhibition of both VEGF and PDGF pathways may be synergistic in treating wet-AMD. Additionally, axitinib showed good efficacy at a low dose (0.875 mg/day) in laser-induced CNV model in rats. In conclusion our data shows that axitinib, an inhibitor of VEGF and PDGF-B pathways may be useful in ameliorating wet-AMD therapy. PMID- 26927931 TI - Live cell imaging of actin dynamics in dexamethasone-treated porcine trabecular meshwork cells. AB - The regulation of the actin cytoskeleton in trabecular meshwork (TM) cells is important for controlling outflow of the aqueous humor. In some reports, dexamethasone (DEX) increased the aqueous humor outflow resistance and induced unusual actin structures, such as cross-linked actin networks (CLAN), in TM cells. However, the functions and dynamics of CLAN in TM cells are not completely known, partly because actin stress fibers have been observed only in fixed cells. We conducted live-cell imaging of the actin dynamics in TM cells with or without DEX treatment. An actin-green fluorescent protein (GFP) fusion construct with a modified insect virus was transfected into porcine TM cells. Time-lapse imaging of live TM cells treated with 25 MUM Y-27632 and 100 nM DEX was performed using an inverted fluorescence microscope. Fluorescent images were recorded every 15 s for 30 min after Y-27632 treatment or every 30 min for 72 h after DEX treatment. The GFP-actin was expressed in 22.7 +/- 10.9% of the transfected TM cells. In live TM cells, many actin stress fibers were observed before the Y-27632 treatment. Y-27632 changed the cell shape and decreased stress fibers in a time dependent manner. In fixed cells, CLAN-like structures were seen in 26.5 +/- 1.7% of the actin-GFP expressed PTM cells treated with DEX for 72 h. In live imaging, there was 28% CLAN-like structure formation at 72 h after DEX treatment, and the lifetime of CLAN-like structures increased after DEX treatment. The DEX-treated cells with CLAN-like structures showed less migration than DEX-treated cells without CLAN-like structures. Furthermore, the control cells (without DEX treatment) with CLAN-like structures also showed less migration than the control cells without CLAN-like structures. These results suggested that CLAN-like structure formation was correlated with cell migration in TM cells. Live cell imaging of the actin cytoskeleton provides valuable information on the actin dynamics in TM cells. PMID- 26927932 TI - Adult Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia in Daily Practice: A Multicenter Experience. AB - BACKGROUND: The prognosis of Philadelphia-positive acute lymphoblastic leukemia (Ph(+) ALL) is generally poor. Currently, allogeneic hematopoietic cell transplantation (allo-HCT) is the only accepted therapy with curative potential. PATIENTS AND METHODS: Herein, we report our multicenter, retrospective experience with 46 (23 female; 23 male) Ph(+) ALL patients, who were treated off-study between 2005 and 2012. RESULTS: The median age of the patients was 46 years (range, 19-73 years). During induction, 30 (65%), 13 (28%), and 3 (7%) patients received tyrosine kinase inhibitors (TKIs) concurrent with chemotherapy (TKIs/chemotherapy), chemotherapy only, and TKIs only, respectively. Following induction, rates of complete remission (CR) of the study population were 85% (n = 39). CR rate in patients receiving TKIs during induction (n = 33) was significantly higher compared with patients who received chemotherapy only (n = 13; P = .011). Taking TKIs during induction significantly reduced induction mortality (3.3% vs. 38%; P = .01). Allo-HCT was performed subsequently in 21 (46%) patients. More patients who received TKIs with or without chemotherapy (19/33; 58%) during induction were able to undergo to allo-HCT compared with patients who received chemotherapy only (2/13; 15%; P = .005). Median overall survival of patients who were treated with TKIs during induction and received allo-HCT (not reached; NR) was significantly prolonged compared with patients who received allo-HCT but without TKIs during induction (23.2 months) and to the rest of the cohort (21.2 months; P = .019). CONCLUSIONS: Current state-of-the art management of Ph(+) ALL in real-life seems to be incorporation of TKIs to chemotherapy regimens and proceeding to allo-HCT, whenever possible. PMID- 26927934 TI - Inhibitory effects of Enteromorpha linza polysaccharide on micronucleus of Allium sativum root cells. AB - In this study, the antimutagenic function of the polysaccharide from Enteromorpha linza with the micronucleus test of Allium sativum root cells induced by sulfur dioxide and ultraviolet was studied. The concentration-effect relation of the two inducers was firstly evaluated. The results showed that an increase of genotoxicity damage was demonstrated and micronuclei frequency induced by sulfur dioxide and ultraviolet displayed dose dependent increases. All the doses of polysaccharide did affect the micronuclei frequency formation compared with the negative control. And also, the significant increase in inhibition rate of micronuclei frequency was observed with the increase of the dose of polysaccharide. It was showed maximum inhibition of micronuclei frequency cells (71.74% and 66.70%) at a concentration of 200g/mL in three experiments. The low molecular weight polysaccharide showed higher inhibition rate than raw polysaccharide at the higher concentration (50g/mL) in the absence of sulfur dioxide and ultraviolet. It was confirmed to be a good mutant inhibitor. PMID- 26927933 TI - HCV induces transforming growth factor beta1 through activation of endoplasmic reticulum stress and the unfolded protein response. AB - HCV replication disrupts normal endoplasmic reticulum (ER) function and activates a signaling network called the unfolded protein response (UPR). UPR is directed by three ER transmembrane proteins including ATF6, IRE1, and PERK. HCV increases TGF-beta1 and oxidative stress, which play important roles in liver fibrogenesis. HCV has been shown to induce TGF-beta1 through the generation of reactive oxygen species (ROS) and p38 MAPK, JNK, ERK1/2, and NFkappaB-dependent pathways. However, the relationship between HCV-induced ER stress and UPR activation with TGF-beta1 production has not been fully characterized. In this study, we found that ROS and JNK inhibitors block HCV up-regulation of ER stress and UPR activation. ROS, JNK and IRE1 inhibitors blocked HCV-activated NFkappaB and TGF beta1 expression. ROS, ER stress, NFkappaB, and TGF-beta1 signaling were blocked by JNK specific siRNA. Knockdown IRE1 inhibited JFH1-activated NFkappaB and TGF beta1 activity. Knockdown of JNK and IRE1 blunted JFH1 HCV up-regulation of NFkappaB and TGF-beta1 activation. We conclude that HCV activates NFkappaB and TGF-beta1 through ROS production and induction of JNK and the IRE1 pathway. HCV infection induces ER stress and the UPR in a JNK-dependent manner. ER stress and UPR activation partially contribute to HCV-induced NF-kappaB activation and enhancement of TGF-beta1. PMID- 26927935 TI - The enhanced anti-tissue adhesive effect of injectable pluronic-HA hydrogel by poly(gamma-glutamic acid). AB - The stability of tissue barrier in physiological condition is a key factor to isolate the damaged site from adjacent tissue for anti-tissue adhesion. Although pluronic or pluronic-hyaluronic acid (HA) hydrogel as an injectable formulation can prevent tissue adhesion at the injection site, the anti-tissue adhesion effect is limited due to its poor stability. Herein, we prepared tissue barrier formulations composed of pluronic F127 (F127) and HA mixture (F127-HA) and the effect of the addition of poly(gamma-glutamic acid) (PGA) was characterized. All of F127, HA, and F127-HA mixture showed the poor in vitro residence stability less than 3 days. However, by adding PGA into F127-HA mixture, their stability was significantly enhanced by the control of the molecular weight and concentration of PGA. Thus, F127-HA with 10wt% PGA (2000kDa) showed the long-term stability over 10 days. Similarly, the enhanced stability of F127-HA with PGA resulted in the enhanced and excellent in vivo anti-tissue adhesion effect, evidenced by histological analysis and grading of tissue adhesion. Therefore, F127-HA containing PGA could be applied as an efficient injectable tissue barrier for anti-tissue adhesion. PMID- 26927936 TI - Use of dextran nanoparticle: A paradigm shift in bacterial exopolysaccharide based biomedical applications. AB - This review is a concise compilation of all the major researches on dextran nanoparticle based biomedical applications. Dextran is a highly biocompatible and biodegradable neutral bacterial exopolysaccharide with simple repeating glucose subunits. It's simple yet unique biopolymeric nature made it highly suitable as nanomedicine, nanodrug carrier, and cell imaging system or nanobiosensor. Most importantly, it is extremely water soluble and shows no post drug delivery cellular toxicity. Complete metabolism of dextran is possible inside body thus possibility of renal failure is minimum. Dextran based nanoparticles have superior aqueous solubility, high cargo capacity and intrinsic viscosity, and short storage period. The main focus area of this review is- past and present of major biomedical applications of dextran based nanomaterials thus showing a paradigm shift in bacterial exopolysaccharide based nanobiotechnology. PMID- 26927938 TI - Modes of Death in a Pediatric Cardiac ICU. AB - OBJECTIVE: To determine epidemiology and proximate causes of death in a pediatric cardiac ICU in Southern Europe. DESIGN: Retrospective chart review. SETTING: Single-center institution. PATIENTS: We concurrently identified 57 consecutive patients who died prior to discharge from the cardiac ICU. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Over the study period, there were 57 deaths for a combined mortality rate of 2.4%. Four patients (7%) were declared brain dead, 25 patients (43.8%) died after a failed resuscitation attempt, and 28 patients (49.1%) died after withholding or withdrawal of life-sustaining treatment. Cardiorespiratory failure was the most frequent proximate cause of death (39, 68.4%) followed by brain injury (14, 24.6%) and septic shock (4, 7%). Older age at admission, presence of mechanical ventilation and/or device-dependent nutrition support, patients on a left-ventricular assist device and longer cardiac ICU stay were more likely to have life support withheld or withdrawn. CONCLUSIONS: Almost half of the deaths in the cardiac ICU are predictable, and they are anticipated by the decision to limit life-sustaining treatments. Brain injuries play a direct role in the death of 25% of patients who die in the cardiac ICU. Patients with left-ventricular assist device are associated with withdrawal of treatment. PMID- 26927937 TI - Simultaneous determination of neutral and uronic sugars based on UV-vis spectrometry combined with PLS. AB - A method using partial least squares (PLS) for simultaneous determination of neutral and uronic sugars was developed in this paper. This method is based on the development of the reaction between the analytes and anthrone. The calibration set was built with 25 binary solutions at the concentrations ranging from 20 to 100MUg/mL for glucose and from 10 to 50MUg/mL for glucuronic acid. An independent prediction set was utilized to check the robustness of the PLS calibration model. The root-mean-square error of prediction (RMSEP) values for neutral and uronic sugars are 1.2233 and 1.9367, respectively. The correlation coefficient for the prediction set (Rp(2)) values for them are 0.9971 and 0.9767, respectively. Compared with the univariate method, the proposed method improves detection accuracy. In addition, it was also applied to commercial polysaccharides and Glycyrrhiza uralensis polysaccharides (GUPs), and the results indicated that the PLS model was suitable for simultaneous determination of neutral and uronic sugars. PMID- 26927939 TI - Risk Factors for Longer Hospital Stay Following the Fontan Operation. AB - OBJECTIVES: Children with functional single ventricle undergoing the Fontan operation consume considerable resources. The purpose of this study is to evaluate pre- and intraoperative risk factors for longer hospital stay and to describe the perioperative course at a single institution over a 15-year period. DESIGN: Retrospective cohort study. SETTING: A single pediatric cardiac ICU. PATIENTS: All consecutive patients undergoing a first-time Fontan operation from 2000 to 2014. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Prolonged length of stay was defined as hospital stay greater than 75 percentile at our institution after surgery. Of 218 patients who met inclusion criteria, median length of stay was 10 days (interquartile range, 8-14 d); prolonged length of stay was defined greater than or equal to 15 days. Independent pre- and intraoperative risk factors for prolonged length of stay included higher hemoglobin (odds ratio, 1.29; p = 0.003), higher mean pulmonary artery pressure (odds ratio, 1.14; p = 0.037), and lower aortic saturation (odds ratio, 0.92; p = 0.008) in the entire group. When patients with hepatic vein inclusion (following previous Kawashima) were excluded, higher hemoglobin (odds ratio, 1.24; p = 0.027), lower aortic saturation (odds ratio, 0.92; p = 0.017), and placement of a fenestration (odds ratio, 2.438; p = 0.021) were associated with prolonged length of stay. Fifty-eight patients (26.6%) had major complications defined by Pediatric Cardiac Critical Care Consortium. Placement of a fenestration (odds ratio, 2.297; p = 0.014) and longer aortic cross-clamp time (odds ratio, 1.015; p = 0.003) were independently associated with Pediatric Cardiac Critical Care Consortium major complications. CONCLUSIONS: In this series, 75% of patients had a postoperative length of stay less than or equal to 2 weeks. Preoperative factors suggesting worse hypoxemia/decreased pulmonary blood flow (higher hemoglobin and lower oxygen saturation) and increased pulmonary artery pressure were associated with prolonged length of stay. These findings may help risk stratify this complex patient population, provide more accurate family counseling, and provide preliminary data for changes in preoperative timing of the Fontan and/or changes to postoperative management strategies for those at high risk for increased ICU morbidity. PMID- 26927940 TI - Cognitive neuropsychological analysis of differential reading and spelling disorder mechanisms in a patient with aphasia. AB - The purpose of this study was to determine if differential reading and spelling mechanisms were involved in a Japanese patient with aphasia. In our case, the patient scored low on all of the administered reading tasks, suggesting that both the reading lexical and non-lexical routes were impaired. In contrast, his writing-to-dictation score for Kana nonwords was high, suggesting that the spelling non-lexical route was intact. However, the patient scored low on a writing-to-dictation task comprised of high-familiarity Kanji words. The spelling lexical route was thought to be impaired. Therefore, the mechanism(s) involved in reading and spelling may differ in this case. PMID- 26927941 TI - Vascularized composite allograft-specific characteristics of immune responses. AB - Vascularized composite allograft (VCA) transplantation, or reconstructive transplantation, has revolutionized the treatment of complex tissue and functional defects. Despite arriving during an age in which the immunology of solid organ transplant rejection has been investigated in much detail, these transplants have offered new perspectives from which to explore the immunobiology of transplantation. VCAs have a number of unique molecular, cellular, and architectural features which alter the character and intensity of the rejection response. While much is yet to be clarified, an understanding of these distinct mechanisms affords new possibilities for the control of immune responses in an effort to improve outcomes after VCA transplantation. PMID- 26927943 TI - Primates, computation, and the path to language: Reply to comments on "Towards a Computational Comparative Neuroprimatology: Framing the language-ready brain". PMID- 26927944 TI - Multisensory mechanisms underlying embodiment: Insights from and for spinal cord injury patients: Comment on "The embodiment of assistive devices-from wheelchair to exoskeleton" by M. Pazzaglia and M. Molinari. PMID- 26927942 TI - Gemcitabine plus cisplatin versus gemcitabine alone in the treatment of pancreatic cancer: a meta-analysis. AB - BACKGROUND: Pancreatic cancer ranks as the fourth leading cause of cancer-related mortality in the USA. And gemcitabine has been the standard of care for advanced pancreatic cancer. However, a combined use of gemcitabine plus cisplatin (GemCis) has shown promising efficacies in pancreatic cancer patients. Here, system review and meta-analysis were performed to compare the efficacy and safety of GemCis versus gemcitabine (Gem) alone in the treatment of pancreatic cancer. METHODS: The databases of MEDLINE (PubMed), EMBASE, and Cochrane Library were systematically searched for retrieving the relevant publications prior to 31 September 2014. The primary end point was overall survival (OS) and secondary end points included 6-month survival, 1 year survival, overall response rate (ORR), clinical benefit rate (CBR), time to progression/progression-free survival (TTP/PFS), and toxicities. RESULTS: A total of nine randomized controlled trials involving 1354 patients were included for systematic evaluations. Overall, as compared with Gem alone, GemCis significantly improved the 6-month survival rate (relative risk (RR) = 1.303, 95% confidence interval (CI) 1.090-1.558, P = 0.004), ORR (RR = 1.482, 95% CI 1.148-1.913, P = 0.003), PFS/TTP (hazard ratio (HR) = 0.87; 95% CI 0.78-0.93, P = 0.022), and the overall toxicities (RR = 2.164, 95% CI 1.837-2.549, P = 0.000). However, no significance difference existed in overall survival (HR = 0.90, 95% CI 0.80-1.42, P = 1.02), 1-year survival rate (RR = 0.956, 95% CI 0.770-1.187, P = 0.684), and CBR (RR = 0.854, 95% CI 0.681-1.072, P = 0.175). As for grade III/IV toxicity, seven kinds of toxicities were higher in the GemCis group. However, no significant inter-group statistical differences existed in the incidence of leukopenia, thrombocytopenia, or diarrhea. CONCLUSIONS: Despite a higher incidence of three-fourths toxicity, GemCis offers better outcomes of ORR, PFS/TTP, and 6-month survival, which indicates GemCis may be a promising therapy for pancreatic cancer. PMID- 26927945 TI - Mid-Term Outcomes after Percutaneous Closure of the Secundum Atrial Septal Defect with the Figulla-Occlutech Device. AB - OBJECTIVES: To evaluate the mid-term outcomes after percutaneous closure of the secundum atrial septal defects (ASD) using the Figulla-Occlutech device (FOD). BACKGROUND: Transcatheter closure has become the method of choice for most patients with ASD. Although the FOD may have some advantageous characteristics there is a paucity of data on later outcomes after the use of this relatively new device. METHODS: Observational, single arm study including 200 non-consecutive patients who underwent ASD closure between 04/09 and 07/15 in 2 centers. Device performance, deployment technique, and immediate and mid-term outcomes were assessed. RESULTS: Median age and weight were 24 years (4-72) and 58 kg (15-92), respectively. Single defects were observed in 171 patients (median size of 19 mm). The remainder had multiple or multifenestrated defects. Implantation of FOD (median size of 24 mm) was successful in all (99%), but 2 patients (1 with deficient postero-inferior rim; 1 with a large ASD for the size of the child). Embolization with device retrieval occurred in 2 (1%). Median follow-up of 36 months was obtained in 172 patients. Serial echocardiographic assessment showed complete closure in all but 2 patients, in whom an additional small non significant posterior defect was purposely left untouched. There have been no episodes of late arrhythmias, device embolization, cardiac erosion, endocarditis, thromboembolism, wire fracture, or death. CONCLUSIONS: Transcatheter closure of ASDs in older children, adolescents, and adults using the FOD was highly successful in a wide range of anatomical scenarios with high closure rates and no complications in mid-term follow-up. PMID- 26927946 TI - Phylogenetic Analysis of a 'Jewel Orchid' Genus Goodyera (Orchidaceae) Based on DNA Sequence Data from Nuclear and Plastid Regions. AB - A molecular phylogeny of Asiatic species of Goodyera (Orchidaceae, Cranichideae, Goodyerinae) based on the nuclear ribosomal internal transcribed spacer (ITS) region and two chloroplast loci (matK and trnL-F) was presented. Thirty-five species represented by 132 samples of Goodyera were analyzed, along with other 27 genera/48 species, using Pterostylis longifolia and Chloraea gaudichaudii as outgroups. Bayesian inference, maximum parsimony and maximum likelihood methods were used to reveal the intrageneric relationships of Goodyera and its intergeneric relationships to related genera. The results indicate that: 1) Goodyera is not monophyletic; 2) Goodyera could be divided into four sections, viz., Goodyera, Otosepalum, Reticulum and a new section; 3) sect. Reticulum can be further divided into two subsections, viz., Reticulum and Foliosum, whereas sect. Goodyera can in turn be divided into subsections Goodyera and a new subsection. PMID- 26927947 TI - Structural basis for the regulation of enzymatic activity of Regnase-1 by domain domain interactions. AB - Regnase-1 is an RNase that directly cleaves mRNAs of inflammatory genes such as IL-6 and IL-12p40, and negatively regulates cellular inflammatory responses. Here, we report the structures of four domains of Regnase-1 from Mus musculus-the N-terminal domain (NTD), PilT N-terminus like (PIN) domain, zinc finger (ZF) domain and C-terminal domain (CTD). The PIN domain harbors the RNase catalytic center; however, it is insufficient for enzymatic activity. We found that the NTD associates with the PIN domain and significantly enhances its RNase activity. The PIN domain forms a head-to-tail oligomer and the dimer interface overlaps with the NTD binding site. Interestingly, mutations blocking PIN oligomerization had no RNase activity, indicating that both oligomerization and NTD binding are crucial for RNase activity in vitro. These results suggest that Regnase-1 RNase activity is tightly controlled by both intramolecular (NTD-PIN) and intermolecular (PIN-PIN) interactions. PMID- 26927948 TI - Inositol's and other nutraceuticals' synergistic actions counteract insulin resistance in polycystic ovarian syndrome and metabolic syndrome: state-of-the art and future perspectives. AB - The incidence of metabolic syndrome (MetS), type II diabetes (T2D) and polycystic ovarian syndrome (PCOS) has been progressively increasing. Insulin resistance (InsR) seems to play a key role in a majority of phenotypes of these conditions, altering metabolic homeostasis, within muscle, liver, adipose and other tissues. Hyperinsulinemia is often associated with InsR and causes hormonal imbalances especially within ovaries and adrenals. Inositol is a polyalcohol, naturally occurring as nine stereoisomers, including D-chiro-inositol (DCI) and myo inositol (MI), which have prominent roles in the metabolism of glucose and free fatty acids. MI and DCI have been classified as insulin-sensitizers and seem to adequately counteract several InsR-related metabolic alterations with a safe nutraceutical profile. Based on our analysis of selected studies that investigated MI and/or DCI, we conclude that supplementation with MI and/or DCI complement each other in their metabolic actions and act in synergy with other insulin sensitizing drugs and/or nutraceuticals. Nevertheless, considering the possible severe bias due to different methodologies across published studies, we conclude that there is a need for further studies on larger cohorts and with greater statistical power. These should further clarify outcomes and suitable therapeutic dosages of MI and DCI, possibly based on each patient's clinical status. PMID- 26927949 TI - Redox regulation of ascorbate and glutathione by a chloroplastic dehydroascorbate reductase is required for high-light stress tolerance in Arabidopsis. AB - Chloroplasts are a significant site for reactive oxygen species production under illumination and, thus, possess a well-organized antioxidant system involving ascorbate. Ascorbate recycling occurs in different manners in this system, including a dehydroascorbate reductase (DHAR) reaction. We herein investigated the physiological significance of DHAR3 in photo-oxidative stress tolerance in Arabidopsis. GFP-fused DHAR3 protein was targeted to chloroplasts in Arabidopsis leaves. A DHAR3 knockout mutant exhibited sensitivity to high light (HL). Under HL, the ascorbate redox states were similar in mutant and wild-type plants, while total ascorbate content was significantly lower in the mutant, suggesting that DHAR3 contributes, at least to some extent, to ascorbate recycling. Activation of monodehydroascorbate reductase occurred in dhar3 mutant, which might compensate for the lack of DHAR3. Interestingly, glutathione oxidation was consistently inhibited in dhar3 mutant. These findings indicate that DHAR3 regulates both ascorbate and glutathione redox states to acclimate to HL. PMID- 26927952 TI - Inhibiting the Thermal Gelation of Copolymer Stabilized Nonaqueous Dispersions and the Synthesis of Full Color PMMA Particles. AB - Polymeric particle dispersions have numerous potential applications; currently one of the most relevant is their use as inks in electrophoretic displays. These colloidal particles are synthesized from the appropriate monomer using nonaqueous dispersion (NAD) polymerization in a nonpolar solvent, which requires a stabilizer to control particle size and morphology. We have previously reported the facile synthesis of poly(methyl methacrylate)-block-poly(octadecyl acrylate) (PMMA-b-PODA) by atom transfer radical polymerization (ATRP), and its use in the NAD polymerization of MMA in hexane/dodecane solvent mixtures. Here we report the synthesis of monodisperse PMMA particles in dodecane following a standard "industrial" procedure using these PMMA-b-PODA stabilizers. However, it was observed that the particle suspensions solidified when they were left at temperatures below ~18 degrees C yet redispersed upon being heated. Differential scanning calorimetry, dynamic light scattering, and rheological studies demonstrated that this thermoresponsive behavior was due to a liquid-gel transition occurring at 17.5 degrees C as a consequence of the upper critical solution temperature of PODA in dodecane being traversed. Consequently, new copolymers were synthesized by ATRP with an ethylhexyl acrylate (EHA) co-monomer incorporated into the lyophilic (dodecane compatible) block. Dispersions stabilized by these PMMA-b-P(ODA-co-EHA) polymers with high EHA contents exhibited lower gelation temperatures because of the greater solvent compatibility with dodecane. The use of a PMMA65-b-(ODA10-co-EHA45) copolymer stabilizer (with the highest EHA content) gave PMMA dispersions that showed no gelation down to 4 degrees C and monodisperse cross-linked PMMA particles containing organic dyes (cyan, magenta, red, and black) giving colored particles across the size range of approximately 100-1300 nm. PMID- 26927950 TI - The Role of mTOR Inhibitors in the Treatment of Patients with Tuberous Sclerosis Complex: Evidence-based and Expert Opinions. AB - Tuberous sclerosis complex (TSC) is a genetic disorder arising from mutations in the TSC1 or TSC2 genes. The resulting over-activation of the mammalian target of rapamycin (mTOR) signalling pathway leaves patients with TSC susceptible to the growth of non-malignant tumours in multiple organs. Previously, surgery was the main therapeutic option for TSC. However, pharmacological therapy with mTOR inhibitors such as everolimus and sirolimus is now emerging as an alternate approach. Everolimus and sirolimus have already been shown to be effective in treating subependymal giant cell astrocytoma (SEGA) and renal angiomyolipoma (AML), and everolimus is currently being evaluated in treating TSC-related epilepsy. In November 2013 a group of European experts convened to discuss the current options and practical considerations for treating various manifestations of TSC. This article provides evidence-based recommendations for the treatment of SEGA, TSC-related epilepsy and renal AML, with a focus on where mTOR inhibitor therapy may be considered alongside other treatment options. Safety considerations regarding mTOR inhibitor therapy are also reviewed. With evidence of beneficial effects in neurological and non-neurological TSC manifestations, mTOR inhibitors may represent a systemic treatment for TSC. PMID- 26927951 TI - Antipsychotic Management of Schizoaffective Disorder: A Review. AB - Schizoaffective disorder (SAD) is an incapacitating illness that presents clinicians with challenges in terms of both its diagnosis and its psychopharmacological management. Most studies conducted on the psychopharmacological treatment of SAD also include patients with schizophrenia or other psychotic illnesses, thereby providing an unspecific view to the clinician as to the best way of treating patients with SAD. The objective of this article is to review studies on evidence-based treatment of patients with SAD. We conducted a systematic literature search in MEDLINE/PubMed for full-text studies in the English language using the terms 'Schizoaffective and treatment' or 'antipsychotic schizoaffective'. Our review found relatively few studies with either an active comparator or placebo that examined the efficacy of antipsychotics for patients with SAD without an admixture of patients with schizophrenia. Only oral paliperidone extended release (ER), paliperidone long acting injection (LAI), and risperidone have been shown to be effective and safe in reducing psychotic as well as affective components in acutely ill SAD patients in controlled studies. Paliperidone ER and LAI have also been shown to be efficacious in the maintenance treatment phase of SAD patients. While no supportive data exist, it is possible that other atypical antipsychotics may have similar efficacy to the two mentioned above. We conclude with a number of research recommendations for the study of treatment options for patients with SAD. First, there is a need for studies with patients specifically diagnosed with SAD for both the acute and the maintenance phase. The sample size needs to be adequate to allow a primary analysis of efficacy and to allow for analysis of the SAD subtypes: depressed and bipolar. Another recommendation is the need for studies of patients with SAD stratified into patients with and without mood stabilizers or antidepressants to allow the examination of the adjunctive role of these psychotropic medications. A third recommendation is to focus on specific co morbid aspects of patients with SAD, such as suicidality and substance use disorders. Data from such studies will fill the gap of evidence-based treatment approaches and help clinicians in making important treatment decisions for patients with this complex condition. PMID- 26927953 TI - Orbital angioleiomyoma: A rare orbital neoplasm. AB - A 44-year-old male patient presented with painless progressive proptosis of left eye for the last 20 years. Examination revealed a purplish vascular mass extending from the medial orbital region to the surface of the globe. He underwent complete excision of the mass via an anterior orbitotomy approach. Histopathology and immunohistochemistry revealed a diagnosis of angioleiomyoma. No recurrence was noted at 1 year of follow-up. Angioleiomyomas are benign smooth muscle tumors with an additional vascular component. Their occurrence in the orbit is extremely rare with only three cases reported in literature till date. We report a fourth case of angioleiomyoma of the orbit with the longest duration of presentation of 20 years. PMID- 26927955 TI - A Localized Molecular Orbital Study of the Halogen Substitution Effect on (103)Rh NMR Shielding in [Cp*RhX2]2, Where X = Cl, Br, or I. AB - (103)Rh NMR parameters and the bonding structure of three complexes of [Cp*RhX2]2, where X = Cl, Br, or I, have been studied with the help of natural bond orbitals (NBOs) and natural localized molecular orbitals (NLMOs). The complexes of [Cp*RhX2]2, where X = Cl, Br, or I, have similar bonding structures, with the major difference being in the degree of covalency of the Rh-X bonds. The decomposition of (103)Rh NMR shielding into diamagnetic, paramagnetic, and spin orbit terms shows that normal halogen dependence (NHD) of the (103)Rh NMR shift is defined mostly by the paramagnetic term, with the spin-orbit term being significantly smaller. The decomposition of (103)Rh shielding into spin-free NBO and NLMO contributions shows that (103)Rh shielding is dominated by Rh d-orbital deshielding contributions. We explain the NHD of the (103)Rh NMR shift with the increase in the energies of the virtual antibonding Rh-X orbitals along the X = Cl, Br, and I series. PMID- 26927954 TI - Risk factors for canine cognitive dysfunction syndrome in Slovakia. AB - BACKGROUND: Increasing prevalence of cognitive impairment in an aging canine population poses a serious health problem. Identifying risk factors, which may influence the onset of cognitive decline, is becoming increasingly important. Here we investigated whether age, sex, weight, nutrition, dogs' housing and reproductive state were associated with increased risk of canine cognitive dysfunction syndrome (CCDS) in Slovakia. RESULTS: Age was associated with cognitive decline and nutrition emerged as a significant predictor variable. Dogs fed controlled diets had 2.8 times lower odds of developing CCDS when compared with dogs fed uncontrolled diets. Sex, weight, reproductive state and dogs' housing were not significantly associated with cognitive decline. Further, the prevalence of CCDS was similar in both small and medium/large sized dogs aged 8 11 years, but differed in dogs at an age of 11-13 years. CONCLUSION: Age was found to be the most prominent risk factors of CCDS. Nutrition may influence the cognitive state of dogs. This finding suggests that nutritional interventions may modify canine cognitive functions. PMID- 26927956 TI - Collagen implant with gentamicin sulphate as an option to treat a neuroischaemic diabetic foot ulcer: Case report. AB - INTRODUCTION: The ischaemic diabetic foot is associated with a faster evolving atherosclerosis affecting preferentially the bellow knee arteries. This distal ischemia associated with a wide distribution of multiple stenosis and occlusions throughout lower limb arteries, makes revascularization very hard or even impossible. This represents a major factor responsible for non-healing diabetic foot ulcer. In these cases all efforts should be made to find treatment alternatives that can promote ulcer healing. CASE PRESENTATION: Male patient with neuroischaemic diabetic foot ulcer with exposure tendon, without possibility for endovascular or surgical revascularization, was treated unsuccessfully with prostaglandin and several types of dressings for 7 months. Skin graft failed. Weekly dressings with collagen implant impregnated with gentamicin sulphate were then started and continued in an outpatient setting. Evolution was very positive, with 99% of epithelisation in 9 months. No pain or infection since the beginning of this treatment. DISCUSSION: Successful treatment of a neuroischaemic diabetic foot ulcer rests with the possibility of increasing the perfusion to the foot. Whether or not a revascularization procedure is possible will set the tone for the ensuing treatment. Using collagen implant with gentamicin sulphate, collagen is delivered to the wound bed helping in the granulation tissue formation, will increase microcirculation, and topic gentamicin will decrease bacterial load, exudate and proteases production, increasing cicatrisation. CONCLUSION: In neuroischaemic diabetic foot ulcer weekly dressings with collagen implant impregnated with gentamicin sulphate can be a good option for ulcer healing. PMID- 26927957 TI - Phosphorylated Peptide Functionalization of Lanthanide Upconversion Nanoparticles for Tuning Nanomaterial-Cell Interactions. AB - Peptide modification of nanoparticles with high efficiency is critical in determining the properties and bioapplications of nanoparticles, but the methodology remains a challenging task. Here, by using the phosphorylated linear and cyclic peptide with the arginine-glycine-aspartic acid (RGD) targeting motifs as typical examples, the peptides binding efficiency for the inorganic metal compound nanoparticles was increased significantly after the phosphorylation treatment, and the modification allowed for improving the selectivity and signal to-noise ratio for cancer targeting and reduced the toxicity derived from nonspecific interactions of nanoparticles with cells owing to the higher amount of phosphopeptide binding. In addition, molecular dynamics (MD) simulations of various peptides on inorganic metal compound surfaces revealed that the peptide adsorption on the surface is mainly driven by electrostatic interactions between phosphate oxygen and the polarized interfacial water layer, consistent with the experimental observation of the strong binding propensity of phosphorylated peptides. Significantly, with the RGD phosphopeptide surface modification, these nanoparticles provide a versatile tool for tuning material-cell interactions to achieve the desired level of autophagy and may prove useful for various diagnostic and therapeutic applications. PMID- 26927958 TI - Who cares and who is careless? Insufficient effort responding as a reflection of respondent personality. AB - Insufficient effort responding (IER) to surveys, which occurs when respondents fail to carefully read questionnaire instructions or item content, has recently gained attention as a source of inaccuracy in self-report data (Huang, Curran, Keeney, Poposki, & DeShon, 2012; Johnson, 2005; Maniaci & Rogge, 2014; Meade & Craig, 2012). Whereas previous studies have focused on IER as a methodological nuisance, the current studies examined IER as a substantive variable. Specifically, we hypothesized that IER is a reflection of enduring individual differences. In Study 1, we found that IER displayed rank-order consistency over the course of 13 months; in Studies 2 and 3, we found that IER displayed rank order consistency across multiple research situations; in Study 4, we found that acquaintance-reported conscientiousness, agreeableness, extraversion, and emotional stability were each negatively related to IER; and in Study 5, we found that IER was related to college grade point average and class absences. Together, these 5 studies suggest that IER is in part a manifestation of enduring individual differences. (PsycINFO Database Record PMID- 26927959 TI - Fragmented Lactic Acid Bacterial Cells Activate Peroxisome Proliferator-Activated Receptors and Ameliorate Dyslipidemia in Obese Mice. AB - Recent studies suggest that peroxisome proliferator-activated receptor (PPAR) activation ameliorates metabolic disorders, including dyslipidemia. To identify an effective PPAR agonist, we screened the in vitro PPARalpha/gamma activation ability of organic solvent extracts from food-oriented bacterial strains belonging to 5 genera and 32 species, including lactic acid bacteria, and of these, Lactobacillus amylovorus CP1563 demonstrated the highest PPARalpha/gamma agonist activity. We also found that physical fragmentation of the strain could substitute organic solvent extraction for the expression of CP1563 activity in vitro. For functional food manufacturing, we selected the fragmented CP1563 and conducted subsequent animal experiments. In an obese mouse model, we found that treatment with fragmented CP1563 for 12 weeks decreased the levels of low-density lipoprotein (LDL)-cholesterol and triglyceride in plasma, significantly decreased the atherosclerosis index, and increased the plasma high-density lipoprotein (HDL)-cholesterol level. Thus, we conclude that fragmented CP1563 may be a candidate for the prevention and treatment of dyslipidemia. PMID- 26927960 TI - Gene Tree Discordance Causes Apparent Substitution Rate Variation. AB - Substitution rates are known to be variable among genes, chromosomes, species, and lineages due to multifarious biological processes. Here, we consider another source of substitution rate variation due to a technical bias associated with gene tree discordance. Discordance has been found to be rampant in genome-wide data sets, often due to incomplete lineage sorting (ILS). This apparent substitution rate variation is caused when substitutions that occur on discordant gene trees are analyzed in the context of a single, fixed species tree. Such substitutions have to be resolved by proposing multiple substitutions on the species tree, and we therefore refer to this phenomenon as Substitutions Produced by ILS (SPILS). We use simulations to demonstrate that SPILS has a larger effect with increasing levels of ILS, and on trees with larger numbers of taxa. Specific branches of the species trees are consistently, but erroneously, inferred to be longer or shorter, and we show that these branches can be predicted based on discordant tree topologies. Moreover, we observe that fixing a species tree topology when performing tests of positive selection increases the false positive rate, particularly for genes whose discordant topologies are most affected by SPILS. Finally, we use data from multiple Drosophila species to show that SPILS can be detected in nature. Although the effects of SPILS are modest per gene, it has the potential to affect substitution rate variation whenever high levels of ILS are present, particularly in rapid radiations. The problems outlined here have implications for character mapping of any type of trait, and for any biological process that causes discordance. We discuss possible solutions to these problems, and areas in which they are likely to have caused faulty inferences of convergence and accelerated evolution. PMID- 26927961 TI - Impacts of climate change, land-use change and phosphorus reduction on phytoplankton in the River Thames (UK). AB - Potential increases of phytoplankton concentrations in river systems due to global warming and changing climate could pose a serious threat to the anthropogenic use of surface waters. Nevertheless, the extent of the effect of climatic alterations on phytoplankton concentrations in river systems has not yet been analysed in detail. In this study, we assess the impact of a change in precipitation and temperature on river phytoplankton concentration by means of a physically-based model. A scenario-neutral methodology has been employed to evaluate the effects of climate alterations on flow, phosphorus concentration and phytoplankton concentration of the River Thames (southern England). In particular, five groups of phytoplankton are considered, representing a range of size classes and pigment phenotypes, under three different land-use/land management scenarios to assess their impact on phytoplankton population levels. The model results are evaluated within the framework of future climate projections, using the UK Climate Projections 09 (UKCP09) for the 2030s. The results of the model demonstrate that an increase in average phytoplankton concentration due to climate change is highly likely to occur, with the magnitude varying depending on the location along the River Thames. Cyanobacteria show significant increases under future climate change and land use change. An expansion of intensive agriculture accentuates the growth in phytoplankton, especially in the upper reaches of the River Thames. However, an optimal phosphorus removal mitigation strategy, which combines reduction of fertiliser application and phosphorus removal from wastewater, can help to reduce this increase in phytoplankton concentration, and in some cases, compensate for the effect of rising temperature. PMID- 26927962 TI - Soil respiration dynamics in fire affected semi-arid ecosystems: Effects of vegetation type and environmental factors. AB - Soil respiration (Rs) is the second largest carbon flux in terrestrial ecosystems and therefore plays a crucial role in global carbon (C) cycling. This biogeochemical process is closely related to ecosystem productivity and soil fertility and is considered as a key indicator of soil health and quality reflecting the level of microbial activity. Wildfires can have a significant effect on Rs rates and the magnitude of the impacts will depend on environmental factors such as climate and vegetation, fire severity and meteorological conditions post-fire. In this research, we aimed to assess the impacts of a wildfire on the soil CO2 fluxes and soil respiration in a semi-arid ecosystem of Western Australia, and to understand the main edaphic and environmental drivers controlling these fluxes for different vegetation types. Our results demonstrated increased rates of Rs in the burnt areas compared to the unburnt control sites, although these differences were highly dependent on the type of vegetation cover and time since fire. The sensitivity of Rs to temperature (Q10) was also larger in the burnt site compared to the control. Both Rs and soil organic C were consistently higher under Eucalyptus trees, followed by Acacia shrubs. Triodia grasses had the lowest Rs rates and C contents, which were similar to those found under bare soil patches. Regardless of the site condition (unburnt or burnt), Rs was triggered during periods of higher temperatures and water availability and environmental factors (temperature and moisture) could explain a large fraction of Rs variability, improving the relationship of moisture or temperature as single factors with Rs. This study demonstrates the importance of assessing CO2 fluxes considering both abiotic factors and vegetation types after disturbances such as fire which is particularly important in heterogeneous semi-arid areas with patchy vegetation distribution where CO2 fluxes can be largely underestimated. PMID- 26927963 TI - Vegetation cover and species richness after recurrent forest fires in the Eastern Mediterranean ecosystem of Mount Carmel, Israel. AB - Fire is a common disturbance in Mediterranean ecosystems, and can have a destructive, influential, and even essential, effect on vegetation and wildlife. In recent decades there has been a general increase in the number of fires in the Mediterranean Basin, including in Mount Carmel, Israel. The effects of recurrent forest fires on vegetation cover and species richness were determined in the spring of 2009 and 2010 by field surveys. The results of this study showed that the vegetation cover changes after recurrent forest fires, and can serve as a good indicator of the influence of fire and the resulting ecosystem rehabilitation. The dominant cover in most fire-damaged areas was composed of shrubs and dwarf-shrubs, especially Cistus salviifolius and Calicotome villosa. Tree cover was severely damaged after recurrent fires, and in those areas there was a drastic decrease of the total plant cover. Species richness increased mainly in the first decade after the recurrent fires, and decreased when the forest canopy began to close. Fire recurrence with short intervals (4-6years) between fires may lower the rehabilitated processes of the ecosystem and change its equilibrium. PMID- 26927964 TI - Post-fire recovery of soil organic matter in a Cambisol from typical Mediterranean forest in Southwestern Spain. AB - Wildfire is a recurrent phenomenon in Mediterranean ecosystems and contributes to soil degradation and desertification, which are partially caused by alterations to soil organic matter (SOM). The SOM composition from a Cambisol under a Mediterranean forest affected by a wildfire is studied in detail in order to assess soil health status and better understand of soil recovery after the fire event. The soil was sampled one month and twenty-five months after the wildfire. A nearby unburnt site was taken as control soil. Soil rehabilitation actions involving heavy machinery to remove burnt vegetation were conducted sixteen months after the wildfire. Immediately after fire the SOM increased in topsoil due to inputs from charred vegetation, whereas a decrease was observed in the underlying soil layer. Twenty-five months after fire soil-pH increased in fire affected topsoil due to the presence of ashes, a decrease in SOM content was recorded for the burnt topsoil and similar trend was observed for the water holding capacity. The pyro-chromatograms of burned soils revealed the formation of additional aromatic compounds. The thermal cracking of long-chain n-alkanes was also detected. Solid-state 13C NMR spectroscopy supported the increase of aromatic compounds in the fire-affected topsoil due to the accumulation of charcoal, whereas the deeper soil sections were not affected by the fire. Two years later, soil parameters for the unburnt and burnt sites showed comparable values. The reduction of the relative intensity in the aromatic C region of the NMR spectra indicated a decrease in the charcoal content of the topsoil. Due to the negligible slope in the sampling site, the loss of charcoal was explained by the post-fire restoration activity, degradation, leaching of pyrogenic SOM into deeper soil horizons or wind erosion. Our results support that in the Mediterranean region, fire-induced alteration of the SOM is not lasting in the long-term. PMID- 26927966 TI - Electron-Phonon Coupling Strength at Metal Surfaces Directly Determined from the Helium Atom Scattering Debye-Waller Factor. AB - A new quantum-theoretical derivation of the elastic and inelastic scattering probability of He atoms from a metal surface, where the energy and momentum exchange with the phonon gas can occur only through the mediation of the surface free-electron density, shows that the Debye-Waller exponent is directly proportional to the electron-phonon mass coupling constant lambda. The comparison between the values of lambda extracted from existing data on the Debye-Waller factor for various metal surfaces and the lambda values known from literature indicates a substantial agreement, which opens the possibility of directly extracting the electron-phonon coupling strength in quasi-2D conducting systems from the temperature or incident energy dependence of the elastic helium atom scattering intensities. PMID- 26927965 TI - Integration of the subsurface and the surface sectors for a more holistic approach for sustainable redevelopment of urban brownfields. AB - This paper presents a holistic approach to sustainable urban brownfield redevelopment where specific focus is put on the integration of a multitude of subsurface qualities in the early phases of the urban redevelopment process, i.e. in the initiative and plan phases. Achieving sustainability in brownfield redevelopment projects may be constrained by a failure of engagement between two key expert constituencies: urban planners/designers and subsurface engineers, leading to missed opportunities and unintended outcomes in the plan realisation phase. A more integrated approach delivers greater benefits. Three case studies in the Netherlands, Belgium and Sweden were used to test different sustainability assessment instruments in terms of the possibility for knowledge exchange between the subsurface and the surface sectors and in terms of cooperative learning among experts and stakeholders. Based on the lessons learned from the case studies, a generic decision process framework is suggested that supports holistic decision making. The suggested framework focuses on stakeholder involvement, communication, knowledge exchange and learning and provides an inventory of instruments that can support these processes. PMID- 26927967 TI - MEPE Localization in the Craniofacial Complex and Function in Tooth Dentin Formation. AB - Matrix extracellular phosphoglycoprotein (MEPE) is an extracellular matrix protein found in dental and skeletal tissues. Although information regarding the role of MEPE in bone and disorders of phosphate metabolism is emerging, the role of MEPE in dental tissues remains unclear. We performed RNA in situ hybridization and immunohistochemistry analyses to delineate the expression pattern of MEPE during embryonic and postnatal development in craniofacial mineralizing tissues. Mepe RNA expression was seen within teeth from cap through root formation in association with odontoblasts and cellular cementoblasts. More intense expression was seen in the alveolar bone within the osteoblasts and osteocytes. MEPE immunohistochemistry showed biphasic dentin staining in incisors and more intense staining in alveolar bone matrix and in forming cartilage. Analysis of Mepe null mouse molars showed overall mineralized tooth volume and density of enamel and dentin comparable with that of wild-type samples. However, Mepe(-/-) molars exhibited increased thickness of predentin, dentin, and enamel over controls and decreased gene expression of Enam, Bsp, Dmp1, Dspp, and Opnby RT-PCR. In vitro Mepe overexpression in odontoblasts led to significant reductions in Dspp reporter activity. These data suggest MEPE may be instrumental in craniofacial and dental matrix maturation, potentially functioning in the maintenance of non mineralized matrix. PMID- 26927968 TI - Computational modeling of phagocyte transmigration for foreign body responses to subcutaneous biomaterial implants in mice. AB - BACKGROUND: Computational modeling and simulation play an important role in analyzing the behavior of complex biological systems in response to the implantation of biomedical devices. Quantitative computational modeling discloses the nature of foreign body responses. Such understanding will shed insight on the cause of foreign body responses, which will lead to improved biomaterial design and will reduce foreign body reactions. One of the major obstacles in computational modeling is to build a mathematical model that represents the biological system and to quantitatively define the model parameters. RESULTS: In this paper, we considered quantitative inter connections and logical relationships among diverse proteins and cells, which have been reported in biological experiments and literature. Based on the established biological discovery, we have built a mathematical model while unveiling the key components that contribute to biomaterial-mediated inflammatory responses. For the parameter estimation of the mathematical model, we proposed a global optimization algorithm, called Discrete Selection Levenberg-Marquardt (DSLM). This is an extension of Levenberg-Marquardt (LM) algorithm which is a gradient-based local optimization algorithm. The proposed DSLM suggests a new approach for the selection of optimal parameters in the discrete space with fast computational convergence. CONCLUSIONS: The computational modeling not only provides critical clues to recognize current knowledge of fibrosis development but also enables the prediction of yet-to-be observed biological phenomena. PMID- 26927969 TI - Hypotension associated with ingestion of cannabinoids in two children with cancer. PMID- 26927970 TI - Public solicitation for organ donors: a time for direction in Canada. PMID- 26927972 TI - Not just justice: inquiry into missing and murdered Aboriginal women needs public health input from the start. PMID- 26927971 TI - Active surveillance in Canadian men with low-grade prostate cancer. AB - BACKGROUND: Recent guidelines recommend against routine screening for prostate cancer, partly because of the risks associated with overtreatment of clinically indolent tumours. We aimed to determine the proportion of patients whose low grade prostate cancer was managed by active surveillance instead of immediate treatment. METHODS: We reviewed data for patients who were referred to the Ottawa regional Prostate Cancer Assessment Clinic with abnormal results for prostate specific antigen (PSA) or prostate examination between Apr. 1, 2008, and Jan. 31, 2013. Patients with subsequent biopsy-proven low-grade (Gleason score 6) cancer were included. Active surveillance was defined a priori as monitoring by means of PSA, digital rectal examination and repeat biopsies, with the potential for curative-intent treatment in the event of disease progression. RESULTS: Of 477 patients with low-grade cancer, active surveillance was used for 210 (44.0%), and the annual proportion increased from 32% (11/34) in 2008 to 67% (20/30) in 2013. Factors associated with immediate treatment were palpable tumour, PSA density above 0.2 ng/mL(2) and more than 2 positive biopsy cores. Factors associated with surveillance were age over 70 years and higher Charlson comorbidity index. Of 173 men who received immediate surgical treatment, 103 (59.5%) had higher-grade or advanced-stage disease on final pathologic examination. Of the 210 men with active surveillance, 62 (29.5%) received treatment within a median of 1.3 years, most commonly (52 [84%]) because of upgrading of disease on the basis of surveillance biopsy. INTERPRETATION: Active surveillance has become the most common management strategy for men with low-grade prostate cancer at our regional diagnostic centre. Factors associated with immediate treatment reflected those that increase the risk of higher-grade tumours. PMID- 26927973 TI - Mycoplasma pneumoniae-associated mucositis. PMID- 26927974 TI - Taskforce aims to bolster rural physicians. PMID- 26927975 TI - Petition calls for federal funds for Cochrane. PMID- 26927976 TI - Advocates seek $100 million for youth suicide prevention. PMID- 26927977 TI - Modulating Enzyme Catalysis through Mutations Designed to Alter Rapid Protein Dynamics. AB - The relevance of sub-picosecond protein motions to the catalytic event remains a topic of debate. Heavy enzymes (isotopically substituted) provide an experimental tool for bond-vibrational links to enzyme catalysis. A recent transition path sampling study with heavy purine nucleoside phosphorylase (PNP) characterized the experimentally observed mass-dependent slowing of barrier crossing (Antoniou, D.; Ge, X.; Schramm, V. L.; Schwartz, S. D. J. Phys. Chem. Lett. 2012, 3, 3538). Here we computationally identify second-sphere amino acid residues predicted to influence the freedom of the catalytic site vibrational modes linked to heavy enzyme effects in PNP. We mutated heavy and light PNPs to increase the catalytic site vibrational freedom. Enzymatic barrier-crossing rates were converted from mass-dependent to mass-independent as a result of the mutations. The mutagenic uncoupling of femtosecond motions between catalytic site groups and reactants decreased transition state barrier crossing by 2 orders of magnitude, an indication of the femtosecond dynamic contributions to catalysis. PMID- 26927978 TI - Development of a fully integrated falling film microreactor for gas-liquid-solid biotransformation with surface immobilized O2 -dependent enzyme. AB - Microstructured flow reactors are powerful tools for the development of multiphase biocatalytic transformations. To expand their current application also to O2 -dependent enzymatic conversions, we have implemented a fully integrated falling film microreactor that provides controllable countercurrent gas-liquid phase contacting in a multi-channel microstructured reaction plate. Advanced non invasive optical sensing is applied to measure liquid-phase oxygen concentrations in both in- and out-flow as well as directly in the microchannels (width: 600 MUm; depth: 200 MUm). Protein-surface interactions are designed for direct immobilization of catalyst on microchannel walls. Target enzyme (here: d-amino acid oxidase) is fused to the positively charged mini-protein Zbasic2 and the channel surface contains a negatively charged gamma-Al2 O3 wash-coat layer. Non covalent wall attachment of the chimeric Zbasic2 _oxidase resulted in fully reversible enzyme immobilization with fairly uniform surface coverage and near complete retention of biological activity. The falling film at different gas and liquid flow rates as well as reactor inclination angles was shown to be mostly wavy laminar. The calculated film thickness was in the range 0.5-1.3 * 10(-4) m. Direct O2 concentration measurements at the channel surface demonstrated that the liquid side mass transfer coefficient (KL ) for O2 governed the overall gas/liquid/solid mass transfer and that the O2 transfer rate (>=0.75 mM . s(-1) ) vastly exceeded the maximum enzymatic reaction rate in a wide range of conditions. A value of 7.5 (+/-0.5) s(-1) was determined for the overall mass transfer coefficient KL a, comprising a KL of about 7 * 10(-5) m . s(-1) and a specific surface area of up to 10(5) m(-1) . Biotechnol. Bioeng. 2016;113: 1862 1872. (c) 2016 Wiley Periodicals, Inc. PMID- 26927979 TI - Assessing Differences between Early and Later Adopters of Accountable Care Organizations Using Taxonomic Analysis. AB - OBJECTIVE: To compare early and later adopters of the accountable care organization (ACO) model, using the taxonomy of larger, integrated system; smaller, physician-led; and hybrid ACOs. DATA SOURCES: The National Survey of ACOs, Waves 1 and 2. STUDY DESIGN: Cluster analysis using the two-step clustering approach, validated using discriminant analysis. Wave 2 data analyzed separately to assess differences from Wave 1 and then data pooled across waves. FINDINGS: Compared to early ACOs, later adopter ACOs included a greater breadth of provider group types and a greater proportion self-reported as integrated delivery systems. When data from the two time periods were combined, a three-cluster solution similar to the original cluster solution emerged. Of the 251 ACOs, 31.1 percent were larger, integrated system ACOs; 45.0 percent were smaller physician led ACOs; and 23.9 percent were hybrid ACOs-compared to 40.1 percent, 34.0 percent, and 25.9 percent from Wave 1 clusters, respectively. CONCLUSIONS: While there are some differences between ACOs formed prior to August 2012 and those formed in the following year, the three-cluster taxonomy appears to best describe the types of ACOs in existence as of July 2013. The updated taxonomy can be used by researchers, policy makers, and health care organizations to support evaluation and continued development of ACOs. PMID- 26927980 TI - Device-related pressure ulcers from a biomechanical perspective. AB - Pressure ulcers (PUs) in the pediatric population are inherently different from those in adults, in their risk factors and etiology, with more than 50% of the cases related to contact with medical equipment at the care setting. The aims of this study were to: (i) Determine the mechanical loads in the scalp of a newborn lying supine, near a wedged encephalogram electrode or wire, which is deforming the scalp at the occiput. (ii) Evaluate the effect of a doughnut-shaped headrest on the mechanical state of tissues at the same site. We used finite element computational modeling to simulate a realistic three-dimensional head of a newborn interacting with the above devices. We examined effective (von Mises) stresses, shear stresses and strain energy density (SED) in the fat and skin tissues at the occipital region. The interfering wire resulted in the worse mechanical conditions in the soft tissues, compared to the lodged electrode and use of a doughnut-shaped headrest, with 345% and 50% increase in effective stresses in skin and fat tissues, respectively. Considering that elevated and localized tissue deformations, stresses and SED indicate a risk for PUs, our simulations suggest that misplaced medical devices, and using a doughnut-shaped headrest, impose an actual risk for developing device-related PUs. We conclude that guidelines for pediatric clinical care should recommend routine inspection of the medical device placement to prevent harmful contact conditions with the patient. Furthermore, improved design of medical equipment for pediatric settings is needed in order to protect these fragile young patients from PUs. PMID- 26927981 TI - Methionine sulfoxide profiling of milk proteins to assess the influence of lipids on protein oxidation in milk. AB - Thermal treatment of milk and milk products leads to protein oxidation, mainly the formation of methionine sulfoxide. Reactive oxygen species, responsible for the oxidation, can be generated by Maillard reaction, autoxidation of sugars, or lipid peroxidation. The present study investigated the influence of milk fat on methionine oxidation in milk. For this purpose, quantitative methionine sulfoxide profiling of all ten methionine residues of beta-lactoglobulin, alpha lactalbumin, and alphas1-casein was carried out by ultrahigh-performance liquid chromatography-electrospray ionization tandem mass spectrometry with scheduled multiple reaction monitoring (UHPLC-ESI-MS/MS-sMRM). Analysis of defatted and regular raw milk samples after heating for up to 8 min at 120 degrees C and analysis of ultrahigh-temperature milk samples with 0.1%, 1.5%, and 3.5% fat revealed that methionine oxidation of the five residues of the whey proteins and of residues M 123, M 135, and M 196 of alphas1-casein was not affected or even suppressed in the presence of milk fat. Only the oxidation of residues M 54 and M 60 of alphas1-casein was promoted by lipids. In evaporated milk samples, formation of methionine sulfoxide was hardly influenced by the fat content of the samples. Thus, it can be concluded that lipid oxidation products are not the major cause of methionine oxidation in milk. PMID- 26927982 TI - Pharmacokinetics, distribution, metabolism, and excretion of the dual reuptake inhibitor [(14)C]-nefopam in rats. AB - 1. This study examined the pharmacokinetics, distribution, metabolism, and excretion of [(14)C] nefopam in rats after a single oral administration. Blood, plasma, and excreta were analyzed for total radioactivity, nefopam, and metabolites. Metabolites were profiled and identified. Radioactivity distribution was determined by quantitative whole-body autoradiography. 2. The pharmacokinetic profiles of total radioactivity and nefopam were similar in male and female rats. Radioactivity partitioned approximately equally between plasma and red blood cells. A majority of the radioactivity was excreted in urine within 24 hours and mass balance was achieved within 7 days. 3. Intact nefopam was a minor component in plasma and excreta. Numerous metabolites were identified in plasma and urine generated by multiple pathways including: hydroxylation/oxidation metabolites (M11, M22a and M22b, M16, M20), some of which were further glucuronidated (M6a to M6c, M7a to M7c, M8a and M8b, M3a to M3d); N-demethylation of nefopam to metabolite M21, which additionally undergoes single or multiple hydroxylations or sulfation (M9, M14, M23), with some of the hydroxylated metabolites further glucuronidated (M2a to M2d). 4. Total radioactivity rapidly distributed with highest concentrations found in the urinary bladder, stomach, liver, kidney medulla, small intestine, uveal tract, and kidney cortex without significant accumulation or persistence. Radioactivity reversibly associated with melanin containing tissues. PMID- 26927983 TI - Correlating rrs and eis promoter mutations in clinical isolates of Mycobacterium tuberculosis with phenotypic susceptibility levels to the second-line injectables. AB - OBJECTIVE/BACKGROUND: The in vitro drug-susceptibility testing of Mycobacterium tuberculosis reports isolates as resistant or susceptible on the basis of single critical concentrations. It is evident that drug resistance in M. tuberculosis is quite heterogeneous, and involves low level, moderate level, and high level of drug-resistant phenotypes. Thus, the aim of our study was to correlate rrs (X52917) and eis (AF144099) promoter mutations, found in M. tuberculosis isolates, with corresponding minimum inhibitory concentrations of amikacin, kanamycin, and capreomycin. METHODS: Ninety M. tuberculosis clinical isolates were analyzed in this study. The minimum inhibitory concentrations were determined by MGIT 960 for 59 isolates with resistance-associated mutations in the rrs and eis promoter gene regions, and 31 isolates with wild-type sequences, as determined by the GenoType MTBDRsl (version 1) assay. RESULTS: The rrs A1401G mutation was identified in 48 isolates resistant to the second-line injectables. The eis promoter mutations C-14T (n=3), G-10C (n=3), G-10A (n=3), and C-12T (n=2) were found within 11 isolates with various resistance profiles to the second-line injectables. Thirty-one isolates had wild-type sequences for the rrs and eis promoter gene regions of interest, one of which was amikacin, kanamycin, and capreomycin resistant. The isolates with the rrs A1401G mutation had amikacin, kanamycin, and capreomycin minimum inhibitory concentrations of >40mg/L, >20mg/L, and 5-15mg/L, respectively. The isolates with eis promoter mutations had amikacin, kanamycin, and capreomycin minimum inhibitory concentrations of 0.25 1.0mg/L, 0.625-10mg/L, and 0.625-2.5mg/L, respectively. CONCLUSION: This study provides a preliminary basis for the prediction of phenotypic-resistance levels to the second-line injectables based upon the presence of genetic mutations associated with amikacin, kanamycin, and capreomycin resistance. The results suggest that isolates with eis promoter mutations have consistently lower resistance levels to amikacin, kanamycin, and capreomycin than isolates with the rrs A1401G mutation. PMID- 26927984 TI - Cellular and humoral immunogenicity of recombinant Mycobacterium smegmatis expressing Ag85B epitopes in mice. AB - OBJECTIVE/BACKGROUND: The search for new vaccines more efficacious than bacille Calmette-Guerin for tuberculosis prevention is of paramount importance for the control of the disease. The expression of Mycobacterium tuberculosis antigens in Mycobacterium smegmatis is one of the current strategies for the development of new-generation vaccines against tuberculosis. The objective of this study was to evaluate the immunogenicity in mice of M. smegmatis expressing epitopes from Ag85B antigen. METHODS: M. smegmatis expressing three T cell epitopes from M. tuberculosis Ag85B (P21, P26, and P53) was constructed (rMs064). rMs064 was used to immunize BALB/C mice for immunogenicity evaluation. The present study investigates the capacity of rMs064 to induce specific cellular and humoral immune responses against the expressed epitopes. Cytokine production upon stimulation with Ag85B peptides and specific total immunoglobulin G and immunoglobulin G subclasses were determined. RESULTS: The results showed a significant production of interleukin-12 and interleukin-23 when splenocytes were stimulated with P21, P26, and P53 peptides, and interferon-gamma after stimulation with P21 in animals immunized with rMs064 compared with controls. The total immunoglobulin G and its subclasses showed significant increases against the Ag85B epitopes in the sera of rMs064-immunized mice compared with the control groups. CONCLUSION: The results of this study support the future evaluation of rMs064 as a vaccine candidate against tuberculosis in challenge experiments. PMID- 26927985 TI - Incidence of antituberculosis-drug-induced hepatotoxicity and associated risk factors among tuberculosis patients in Dawro Zone, South Ethiopia: A cohort study. AB - BACKGROUND: Antituberculosis drugs cause hepatotoxicity in some individuals leading to acute liver failure, which results in death. Such phenomena limit the clinical use of drugs, contributing to treatment failure that possibly causes drug resistance. Furthermore, associated risk factors for the development of antituberculosis-drug-induced hepatotoxicity (anti-TB-DIH) are found to be controversial among different study findings. METHODS: A prospective cohort study was conducted from May 2014 to October 2014 in Dawro Zone, Tercha District Hospital Laboratory, South Ethiopia. One hundred and twenty-four new tuberculosis positive individuals available from Tercha Hospital and five health centers during data collection were consecutively included. The sociodemographic data and anthropometric measurement were obtained. Then, 5mL of venous blood was drawn from each individual, and the alanine transaminase, aspartate transaminase, and total bilirubin were measured photometrically at baseline, and then continuously monitored by measuring these liver enzymes every 2weeks for 2months. Data were analyzed with SPSS version 20 for Windows (SPSS Inc., Chicago, IL, USA). RESULTS: The incidence of anti-TB-DIH was found to be 8% (10 patients out of 124). Raised serum transaminase and bilirubin level, as well as signs and symptoms of hepatotoxicity (nausea, anorexia, vomiting, malaise, and jaundice), were observed in the cases. The onset of hepatotoxicity ranged from 13days to 58days (median, 26days) after treatment was initiated. Of the various risk factors analyzed, only high alcohol intake was associated with the incidence of anti-TB-DIH (odds ratio=9.3, 95% confidence interval 1.8-47, p<.007). Age, gender, extent of tuberculosis disease, and malnutrition were not significantly associated with anti-TB-DIH. CONCLUSION: The incidence of anti-TB-DIH in Dawro Zone was high. The drug responsible for the hepatotoxicity was not known. However, chronic high alcohol intake was associated with the development of anti-TB-DIH. PMID- 26927986 TI - Antituberculosis drugs and hepatotoxicity among hospitalized patients in Jos, Nigeria. AB - BACKGROUND: Tuberculosis (TB) could be fatal if left untreated, however, adverse effects of anti-TB medications (anti-TBs) themselves may limit treatment. We determined the incidence and clinical characteristics of hepatotoxicity in hospitalized patients receiving first-line anti-TB treatment. METHODS: A retrospective cohort study of patients aged ?18years seen at the medical wards of the Jos University Teaching Hospital from January 2013 to June 2013 was carried out. Data were retrieved for 110 patients who were prescribed anti-TBs. Their demographic and clinical characteristics were described, and the incidence of symptomatic hepatotoxicity determined. The incidence of hepatotoxicity by strict American Thoracic Society criteria (symptomatic hepatotoxicity plus alanine transaminase in IU/L levels >3*upper limit of normal) was also determined. RESULTS: Twenty patients developed symptomatic hepatotoxicity, giving an incidence of 18.2%. Furthermore, 18 (16.4%) patients had hepatotoxicity according to the American Thoracic Society criteria. Those with symptomatic hepatotoxicity unexpectedly had lower baseline alanine transaminase interquartile range (IQR) (35 [16-63] vs. 67 [4-226]; p=.04) and bilirubin (MUmol/L): total IQR (15.3 [10.2 74.8] vs. 20.4 [20.4-20.4]; p=.01) and conjugated IQR (7.6 [5.1-34.8] vs. 10.2 [10.2-10.2]; p=.004). However, there were no significant differences in age, sex, body mass index, and duration of anti-TB treatment, human immunodeficiency virus infection status, antiretroviral therapy status, alcohol consumption, and the presence of hepatitis B surface antigen or hepatitis C virus antibody. CONCLUSION: Hepatotoxicity due to first-line anti-TBs, whether based on clinical features alone or backed by liver chemistry, is common among hospitalized patients in our environment. Studies to determine the predictors of hepatotoxicity to guide clinical interventions aimed at the prevention or timely identification of cases are needed. PMID- 26927987 TI - Interferon-gamma release assays and tuberculin skin testing for diagnosing latent Mycobacterium tuberculosis infection in at-risk groups in Poland. AB - OBJECTIVE/BACKGROUND: The diagnostics of latent tuberculosis infection in Poland using the tuberculin skin test is challenging due to the obligatory Bacillus Calmette-Guerin vaccinations. Interferon-gamma release assays are still very rarely used for diagnostics. We compared the tuberculin skin test and the QuantiFERON-TB Gold In-Tube test to evaluate the degree of latent tuberculosis infection in at-risk groups for tuberculosis (homeless, close contacts, periodic contacts, nursing-home attendees) and in healthy individuals. METHODS: QuantiFERON-TB Gold In-Tube tests were carried out on 785 individuals from the homeless (n=150), close contacts (n=171), periodic contacts (n=163), nursing-home attendees (n=152), and healthy individuals (n=149). The tuberculin skin test was performed on 129, 156, 147, 148, and 121 participants, respectively. We evaluated the (a) correlation between serum concentrations of interferon gamma and the tuberculin-skin-test induration diameter; (b) between the number of QuantiFERON TB Gold In-Tube-positive results and the tuberculin-skin-test diameter in the studied groups; and (c) agreement between both tests and the kappa coefficient using the tuberculin-skin-test diameters of 5, 10, and 15mm. RESULTS: Larger tuberculin-skin-test induration diameters were associated with elevated serum concentrations of interferon gamma. We found a positive correlation between the number of positive QuantiFERON-TB Gold In-Tube screening results and the tuberculin-skin-test induration diameter. The agreement between QuantiFERON-TB Gold In-Tube and tuberculin-skin-test screening results improved with increasing tuberculin-skin-test induration diameter. CONCLUSION: Based on measures of tuberculin-skin-test induration diameter alone, it is difficult to diagnose latent tuberculosis infection with certainty. The agreement of the QuantiFERON-TB Gold In-Tube test increases with the tuberculin-skin-test diameter. Tuberculin skin-test diameters larger than 15mm are more likely to be associated with active infection. PMID- 26927988 TI - Analysis of the DosR regulon genes to select cytotoxic T lymphocyte epitope specific vaccine candidates using a reverse vaccinology approach. AB - OBJECTIVE/BACKGROUND: There is an urgent need for a more effective vaccine against Mycobacterium tuberculosis (Mtb). Although CD4+ T cells play a central role in host immunity to Mtb, recent evidence suggests a critical role of CD8+ T cells in combating Mtb. In the present study, we have predicted HLA antigen class I binding peptides of DosR operon using an in-silico approach. This method is useful as an initial computational filtration of probable epitopes based on their binding ability and antigenicity. METHODS: CD8+ epitopes were predicted by software NetMHC 3.4 and BIMAS. Self-peptides were found and excluded by indigenously developed Perl script. Antigenicity of promiscuous peptides was predicted using a VaxiJen server. The top VaxiJen scoring antigenic peptides were docked to globally relevant HLA allele using CABS dock and Hex program. RESULTS: A total of 1436 overlapping nonamer peptides were generated which gave 46 promiscuous epitopes, 25 were predicted to be antigenic. Rv2627 epitope "SAFRPPLV" which gave the highest Vaxijen score of 1.9157 and showed binding to all the three HLA loci. The top VaxiJen scoring antigenic peptides were docked and had significant interactions with residues of the HLA class I molecule indicating them to be good cytotoxic T lymphocyte epitopes. CONCLUSION: Our study has generated several promiscuous antigenic peptides capable of binding to major histocompatibility complex class I with high affinity. These epitopes can become part of a postexposure multivalent subunit vaccine upon experimental validation. PMID- 26927989 TI - Does intensified case finding increase tuberculosis case notification among children in resource-poor settings? A report from Nigeria. AB - OBJECTIVE/BACKGROUND: Tuberculosis (TB) is a major cause of morbidity and mortality in developing countries. Passive case detection in national TB programmes is associated with low case notification, especially in children. This study was undertaken to improve detection of childhood TB in resource-poor settings through intensified case-finding strategies. METHODS: A community-based intervention was carried out in six states in Nigeria. The creation of TB awareness was undertaken, and work aids, guidelines, and diagnostic charts were produced, distributed, and used. Various cadres of health workers and ad hoc project staff were trained. Child contacts with TB patients were screened in their homes, and children presenting at various hospital units were screened for TB. Baseline and intervention data were collected for evaluation populations and control populations. RESULTS: Detection of childhood TB increased in the evaluation population during the intervention, with a mean quarterly increase of 4.0% [new smear positive (NSP), although the increasing trend was not statistically significant (chi(2)=1.8; p<.179)]. Additionally, there was a mean quarterly increase of 3% for all forms of TB, although the trend was not statistically significant (chi(2)=1.48; p<.224). Conversely, there was a decrease in case notification in the control population, with a mean decline of 3% (all forms). Compared to the baseline, there was an increase of 31% (all forms) and 22% (NSP) in the evaluation population. CONCLUSION: Intensified case finding combined with capacity building, provision of work aids/guidelines, and TB health education can improve childhood-TB notification. PMID- 26927990 TI - Previous treatment, sputum-smear nonconversion, and suburban living: The risk factors of multidrug-resistant tuberculosis among Malaysians. AB - The number of multidrug-resistant tuberculosis patients is increasing each year in many countries all around the globe. Malaysia has no exception in facing this burdensome health problem. We aimed to investigate the factors that contribute to the occurrence of multidrug-resistant tuberculosis among Malaysian tuberculosis patients. An unmatched case-control study was conducted among tuberculosis patients who received antituberculosis treatments from April 2013 until April 2014. Cases are those diagnosed as pulmonary tuberculosis patients clinically, radiologically, and/or bacteriologically, and who were confirmed to be resistant to both isoniazid and rifampicin through drug-sensitivity testing. On the other hand, pulmonary tuberculosis patients who were sensitive to all first-line antituberculosis drugs and were treated during the same time period served as controls. A total of 150 tuberculosis patients were studied, of which the susceptible cases were 120. Factors found to be significantly associated with the occurrence of multidrug-resistant tuberculosis are being Indian or Chinese (odds ratio 3.17, 95% confidence interval 1.04-9.68; and odds ratio 6.23, 95% confidence interval 2.24-17.35, respectively), unmarried (odds ratio 2.58, 95% confidence interval 1.09-6.09), living in suburban areas (odds ratio 2.58, 95% confidence interval 1.08-6.19), are noncompliant (odds ratio 4.50, 95% confidence interval 1.71-11.82), were treated previously (odds ratio 8.91, 95% confidence interval 3.66-21.67), and showed positive sputum smears at the 2nd (odds ratio 7.00, 95% confidence interval 2.46-19.89) and 6th months of treatment (odds ratio 17.96, 95% confidence interval 3.51-91.99). Living in suburban areas, positive sputum smears in the 2nd month of treatment, and was treated previously are factors that independently contribute to the occurrence of multidrug-resistant tuberculosis. Those with positive smears in the second month of treatment, have a history of previous treatment, and live in suburban areas are found to have a higher probability of becoming multidrug resistant. The results presented here may facilitate improvements in the screening and detection process of drug resistant patients in Malaysia in the future. PMID- 26927991 TI - Molecular epidemiology of Mycobacterium avium subspecies paratuberculosis in ruminants in different parts of India. AB - OBJECTIVE/BACKGROUND: Paratuberculosis is an economically important, chronic, and incurable disease in ruminants, caused by Mycobacterium avium subspecies paratuberculosis (MAP). Understanding the genetic variability of MAP strains is important in diagnosis, epidemiological investigation, and the formation of strategies for prevention and control of the disease. METHODS: In the present study, a total of 61 MAP isolates obtained from different parts and species of India were typed using IS1311 polymerase chain reaction-restriction endonuclease analysis (PCR-REA) to analyze the genetic difference(s), if any, between them and the host adaptation. RESULTS: Based on PCR-REA results, bison B type was detected in 54 (87%) MAP isolates obtained from cattle, sheep, and goats. Of these, 19 were from sheep of the Rajasthan (n=17) and Bareilly (n=2), North India regions, 28 were from cattle of Chennai, South India (n=3), Bareilly, North India (n=3), and Nagpur, West India (n=22), and seven goat isolates from Bareilly, North India region. The 'C' type strain was detected in only seven cattle isolates obtained from the Bareilly region. CONCLUSION: The study revealed that in India, bison B type MAP strains were prevalent in most of the ruminant species. These results have important epidemiological implications with regard to control and prevention of paratuberculosis in India. PMID- 26927993 TI - Genetic diversity of Mycobacterium tuberculosis complex strains isolated from patients with pulmonary tuberculosis in Anambra State, Nigeria. AB - In this study, we analyzed Mycobacterium tuberculosis complex (MTC) genetic diversity in Anambra State, Nigeria based on spoligotyping followed by 5-loci exact tandem repeats (ETRs). Spoligotyping of 180 MTC strains isolated in 2009 2011 from pulmonary tuberculosis (TB) patients led to a total of 31 distinct patterns. A comparison with the SITVIT2 international database showed that all the 31 patterns could be classified as Shared-types (SITs) in this database; briefly, 26/31 SITs (n=174 isolates) matched a preexisting shared-type in the database, whereas 5/31 SITs (n=6 isolates) were newly created due to 2 or more strains belonging to an identical new pattern within this study (SIT3396) or after a match with an orphan in the database (SIT3397, SIT3398, SIT3399 and SIT3400). A total of 18/31 SITs containing 167 or 92.8% isolates were clustered within this study (2-89 isolates per cluster) while 13/31 SITs contained unique strains. Using VNTR typing, a total of 36 distinct patterns were identified; 27 patterns (n=157 isolates) matched a pattern already reported in the SITVIT2 database. Combination of both the methods generated 47 combined patterns for the 180 strains: 17 belonged to clustered isolates (n=127 isolates or 70.5%) while 30 corresponded to as many unique strains (note 23 strains could not be typed using 5-loci ETRs). No correlation was found between the spoligotyping pattern and the HIV status of the patient or drug sensitivity of the strain. This study showed that the LAM10-CAM prototype SIT61 accounted for highest number of isolates (n=89) in Anambra State, showing its relative contribution to the TB burden in the study. PMID- 26927992 TI - Populations of latent Mycobacterium tuberculosis lack a cell wall: Isolation, visualization, and whole-genome characterization. AB - OBJECTIVE/BACKGROUND: Mycobacterium tuberculosis (MTB) causes active tuberculosis (TB) in only a small percentage of infected people. In most cases, the infection is clinically latent, where bacilli can persist in human hosts for years without causing disease. Surprisingly, the biology of such persister cells is largely unknown. This study describes the isolation, identification, and whole-genome sequencing (WGS) of latent TB bacilli after 782days (26months) of latency (the ability of MTB bacilli to lie persistent). METHODS: The in vitro double-stress model of latency (oxygen and nutrition) was designed for MTB culture. After 26months of latency, MTB cells that persisted were isolated and investigated under light and atomic force microscopy. Spoligotyping and WGS were performed to verify the identity of the strain. RESULTS: We established a culture medium in which MTB bacilli arrest their growth, reduce their size (0.3-0.1MUm), lose their acid fastness (85-90%) and change their shape. Spoligopatterns of latent cells were identical to original H37Rv, with differences observed at spacers two and 14. WGS revealed only a few genetic changes relative to the already published H37Rv reference genome. Among these was a large 2064-bp insertion (RvD6), which was originally detected in both H37Ra and CDC1551, but not H37Rv. CONCLUSION: Here, we show cell-wall free cells of MTB bacilli in their latent state, and the biological adaptation of these cells was more phenotypic in nature than genomic. These cell-wall free cells represent a good model for understanding the nature of TB latency. PMID- 26927994 TI - A case of tuberculosis and adenocarcinoma coexisting in the same lung lobe. AB - Tuberculosis and lung cancer rarely coincide together but have been proven to have a definitive link. In this case we describe tuberculosis and adenocarcinoma diagnosed together in the same lobe of the lung. The patient was found to have an epidermal growth factor receptor exon 19 deletion, which has been shown to have an association with tuberculosis. PMID- 26927995 TI - Interaction of antimicrobial peptide with mycolyl transferase in Mycobacterium tuberculosis. AB - It is estimated that about 40% of the Indian population are infected with tuberculosis (TB) and that ~3,000,000 people die as a result of TB annually. TB is caused by Mycobacterium tuberculosis. In 2011, the World Health Organization declared India as having the highest TB burden worldwide. An important criteria for pathogenicity is the presence of mycolic acid linked to the protective outer membrane of bacteria. Mycolyl transferase catalyzes the transfer of mycolic acid and promotes cell wall synthesis. This is also considered as a novel target for drug-mediated intervention strategies. Here, we have attempted to understand the interaction between the antimicrobial peptide (AMP), dermcidin, and mycolyl transferase in M. tuberculosis using a computational approach. The present study was undertaken in order to elucidate the capability of AMPs to treat this bacteria, which is less sensitive to available antibiotics, and to design a novel method for new therapies. PMID- 26927996 TI - First detection of Mycobacterium triplex in Latin America. AB - In this study we describe the first isolation of Mycobacterium triplex in Latin America. This species causes infections in humans, with very few reports from around the world. We isolated two sputum specimens of a patient with a 6-year history of human immunodeficiency and tuberculosis treatment failure. All tests used confirmed M. triplex and the patient responded well to drug therapy for 18months. PMID- 26927997 TI - Use of an adipocyte model to study the transcriptional adaptation of Mycobacterium tuberculosis to store and degrade host fat. AB - During its persistence in the infected host, Mycobacterium tuberculosis (Mtb) accumulates host-derived fatty acids in intracytoplasmic lipid inclusions as triacylglycerols which serve primarily as carbon and energy reserves. The Mtb genome codes for more than 15 triacylglycerol synthases, 24 lipase/esterases, and seven cutinase-like proteins. Hence, we looked at the expression of the corresponding genes in intracellular bacilli persisting amidst the host triacylglycerols. We used the Mtb infected murine adipocyte model to ensure persistence and transcripts were quantified using real-time reverse transcriptase polymerase chain reaction. Dormancy and glyoxylate metabolism was confirmed by the upregulated expression of dosR and icl, respectively, by intra-adipocyte bacilli compared with in vitro growing bacilli. The study revealed that tgs1, tgs2, Rv3371, and mycolyltransferase Ag85A are the predominant triacylglycerol synthases, while lipF, lipH, lipJ, lipK, lipN, lipV, lipX, lipY, culp5, culp7, and culp6 are the predominant lipases/esterases used by Mtb for the storage and degradation of host-derived fat. Moreover, it was observed that many of these enzymes are used by Mtb during active replication rather than during nonreplicating persistence, indicating their probable function in cell wall synthesis. PMID- 26927998 TI - Pseudotumoral form of soft-tissue tuberculosis of the wrist. AB - Tuberculosis is a major public health problem in developing countries. Hand and wrist is a rare localization for extra-pulmonary tuberculosis, a pseudotumoral form of soft tissue tuberculosis of the wrist is exceptional. We report the case of a 45-year-old male presenting with a painful swelling of the dorsal aspect of the right wrist evolving for six months. Clinical study was evoking a ganglion cyst of the wrist. Intraoperatively a pseudotumoral mass with rice bodies was found, suggesting tuberculous tenosynovitis. The histopathological study revealed caseating giant cell granulomas with epithelioid cells. Cultures on Lowenstein Jensen medium detected Mycobacterium tuberculosis. Synovectomy with removal of all the rice bodies followed by anti-tuberculous chemotherapy provided uneventful recovery. PMID- 26927999 TI - Primary oral tuberculosis in a patient with lepromatous leprosy: Diagnostic dilemma. AB - Pulmonary tuberculosis (TB) is the most common form of TB. Primary infection can also affect the pharynx, cervical lymph node, intestine, or oral mucosa. Historically, the observed incidence of concomitant infection with leprosy and TB is high. However, reports of concomitant infection in modern literature remain scarce. Most cases reported in the literature had borderline/lepromatous leprosy and pulmonary tuberculosis. Extrapulmonary tuberculosis is reported in only 3.2% of leprosy cases. To the best of our knowledge, this is the first case report of primary oral tuberculosis of the tongue in a patient with lepromatous leprosy with Type 2 lepra reaction. The patient was referred to Directly Observed Treatment, Short-Course clinic and started on Category I treatment. She received oral prednisolone for lepra reaction, which was subsequently tapered and stopped, however, she continued to receive other antileprotic drugs (thalidomide and clofazimine). The patient's general condition improved and she is on regular follow up. PMID- 26928000 TI - Selective immunoglobulin M deficiency in an adult with miliary tuberculosis: A clinically interesting coexistence. A case report and review of the literature. AB - Selective immunoglobulin M (SIgM) deficiency is a rare form of dysgammaglobulinemia. Here we are reporting a 31year old man with multiple cervical and testicular abscesses who was investigated and found to have miliary tuberculosis (MTB) with primary SIgM deficiency (Serum IgM: 17.4mg/dL) and was treated aggressively with anti-tuberculous treatment. PMID- 26928001 TI - A Comparison of Alternating Polarity and Forward Masking Artifact-Reduction Methods to Resolve the Electrically Evoked Compound Action Potential. AB - OBJECTIVE: Cochlear implant manufacturers utilize different artifact-reduction methods to measure electrically evoked compound action potentials (ECAPs) in the clinical software. Two commercially available artifact-reduction techniques include forward masking (FwdMsk) and alternating polarity (AltPol). AltPol assumes that responses to the opposing polarities are equal, which is likely problematic. On the other hand, FwdMsk can yield inaccurate waveforms if the masker does not effectively render all neurons into a refractory state. The goal of this study was to compare ECAP thresholds, amplitudes, and slopes of the amplitude growth functions (AGFs) using FwdMsk and AltPol to determine whether the two methods yield similar results. DESIGN: ECAP AGFs were obtained from three electrode regions (basal, middle, and apical) across 24 ears in 20 Cochlear Ltd. recipients using both FwdMsk and AltPol methods. AltPol waveforms could not be resolved for recipients of devices with the older-generation chip (CI24R(CS); N = 6). RESULTS: Results comparing FwdMsk and AltPol in the CI24RE- and CI512 generation devices showed significant differences in threshold, AGF slope, and amplitude between methods. FwdMsk resulted in lower visual-detection thresholds (p < 0.001), shallower slopes (p = 0.004), and larger amplitudes (p = 0.03) compared with AltPol. CONCLUSIONS: Results from this study are consistent with recent findings showing differences in ECAP amplitude and latency between polarities for human CI recipients. When averaged, these differences likely result in a reduced ECAP response with AltPol. The next step will be to separate the effects of artifact-reduction method and stimulus polarity to determine the relative effects of each. PMID- 26928002 TI - Neural Correlates of Phonetic Learning in Postlingually Deafened Cochlear Implant Listeners. AB - OBJECTIVE: The present training study aimed to examine the fine-scale behavioral and neural correlates of phonetic learning in adult postlingually deafened cochlear implant (CI) listeners. The study investigated whether high variability identification training improved phonetic categorization of the /ba/-/da/ and /wa/-/ja/ speech contrasts and whether any training-related improvements in phonetic perception were correlated with neural markers associated with phonetic learning. It was hypothesized that training would sharpen phonetic boundaries for the speech contrasts and that changes in behavioral sensitivity would be associated with enhanced mismatch negativity (MMN) responses to stimuli that cross a phonetic boundary relative to MMN responses evoked using stimuli from the same phonetic category. DESIGN: A computer-based training program was developed that featured multitalker variability and adaptive listening. The program was designed to help CI listeners attend to the important second formant transition cue that categorizes the /ba/-/da/ and /wa/-/ja/ contrasts. Nine adult CI listeners completed the training and 4 additional CI listeners that did not undergo training were included to assess effects of procedural learning. Behavioral pre-post tests consisted of identification and discrimination of the synthetic /ba/-/da/ and /wa/-/ja/ speech continua. The electrophysiologic MMN response elicited by an across phoneme category pair and a within phoneme category pair that differed by an acoustically equivalent amount was derived at pre-post test intervals for each speech contrast as well. RESULTS: Training significantly enhanced behavioral sensitivity across the phonetic boundary and significantly altered labeling of the stimuli along the /ba/-/da/ continuum. While training only slightly altered identification and discrimination of the /wa/-/ja/ continuum, trained CI listeners categorized the /wa/-/ja/ contrast more efficiently than the /ba/-/da/ contrast across pre-post test sessions. Consistent with behavioral results, pre-post EEG measures showed the MMN amplitude to the across phoneme category pair significantly increased with training for both the /ba/-/da/ and /wa/-/ja/ contrasts, but the MMN was unchanged with training for the corresponding within phoneme category pairs. Significant brain-behavior correlations were observed between changes in the MMN amplitude evoked by across category phoneme stimuli and changes in the slope of identification functions for the trained listeners for both speech contrasts. CONCLUSIONS: The brain and behavior data of the present study provide evidence that substantial neural plasticity for phonetic learning in adult postlingually deafened CI listeners can be induced by high variability identification training. These findings have potential clinical implications related to the aural rehabilitation process following receipt of a CI device. PMID- 26928003 TI - Effects of Modified Hearing Aid Fittings on Loudness and Tone Quality for Different Acoustic Scenes. AB - OBJECTIVE: To compare loudness and tone-quality ratings for sounds processed via a simulated five-channel compression hearing aid fitted using NAL-NL2 or using a modification of the fitting designed to be appropriate for the type of listening situation: speech in quiet, speech in noise, music, and noise alone. DESIGN: Ratings of loudness and tone quality were obtained for stimuli presented via a loudspeaker in front of the participant. For normal-hearing participants, levels of 50, 65, and 80 dB SPL were used. For hearing-impaired participants, the stimuli were processed via a simulated hearing aid with five-channel fast-acting compression fitted using NAL-NL2 or using a modified fitting. Input levels to the simulated hearing aid were 50, 65, and 80 dB SPL. All participants listened with one ear plugged. For speech in quiet, the modified fitting was based on the CAM2B method. For speech in noise, the modified fitting used slightly (0 to 2 dB) decreased gains at low frequencies. For music, the modified fitting used increased gains (by 5 to 14 dB) at low frequencies. For noise alone, the modified fitting used decreased gains at all frequencies (by a mean of 1 dB at low frequencies increasing to 8 dB at high frequencies). RESULTS: For speech in quiet, ratings of loudness with the NAL-NL2 fitting were slightly lower than the mean ratings for normal-hearing participants for all levels, while ratings with CAM2B were close to normal for the two lower levels, and slightly greater than normal for the highest level. Ratings of tone quality were close to the optimum value ("just right") for both fittings, except that the CAM2B fitting was rated as very slightly boomy for the 80-dB SPL level. For speech in noise, the ratings of loudness were very close to the normal values and the ratings of tone quality were close to the optimal value for both fittings and for all levels. For music, the ratings of loudness were close to the normal values for NAL-NL2 and slightly above normal for the modified fitting. The tone quality was rated as very slightly tinny for NAL-NL2 and very slightly boomy for the modified fitting. For noise alone, the NAL-NL2 fitting was rated as slightly louder than normal for all levels, while the modified fitting was rated as close to normal. Tone quality was rated as slightly sharper for the NAL-NL2 fitting than for the modified fitting. CONCLUSIONS: Loudness and tone quality can sometimes be made slightly closer to "normal" by modifying gains for different listening situations. The modification for music required to achieve "normal" tone quality appears to be less than used in this study. PMID- 26928004 TI - Intelligibility of the Patient's Speech Predicts the Likelihood of Cochlear Implant Success in Prelingually Deaf Adults. AB - OBJECTIVES: The objective of this study was to determine the validity and clinical applicability of intelligibility of the patient's own speech, measured via a Vowel Identification Test (VOW), as a predictor of speech perception for prelingually deafened adults after 1 year of cochlear implant use. Specifically, the objective was to investigate the probability that a prelingually deaf patient, given a VOW score above (or below) a chosen cutoff point, reaches a postimplant speech perception score above (or below) a critical value. High predictive values for VOW could support preimplant counseling and implant candidacy decisions in individual patients. DESIGN: One hundred and fifty-two adult cochlear implant candidates with prelingual hearing impairment or deafness took part as speakers in a VOW; 149 speakers completed the test successfully. Recordings of the speech stimuli, consisting of nonsense words of the form [h]-V [t], where V represents one of 15 vowels/diphthongs ([(Equation is included in full-text article.)]), were presented to two normal-hearing listeners. VOW score was expressed as the percentage of vowels identified correctly (averaged over the 2 listeners). Subsequently, the 149 participants enrolled in the cochlear implant selection procedure. Extremely poor speakers were excluded from implantation, as well as patients who did not meet regular selection criteria as developed for postlingually deafened patients. From the 149 participants, 92 were selected for implantation. For the implanted group, speech perception data were collected at 1 year postimplantation. RESULTS: Speech perception score at 1-year postimplantation (available for 77 of the 92 implanted participants) correlated positively with preimplant intelligibility of the patient's speech, as represented by VOW (r = 0.79, p < 0.00001): the more intelligible the patient's speech, the higher the predicted postimplant speech perception score. This correlation is explained by the hypothesis that the two variables have a common driving force, i.e., (in)adequacy of auditory speech input in the earliest years of life. With a 60% cutoff point, VOW can discriminate between individuals with "above-chance" postimplant speech perception and those with "chance level" postimplant speech perception with sensitivity and specificity of 0.84 and 0.86, respectively. The probability that a patient with a VOW score >= 60% achieves "above-chance" speech perception after implantation is 0.91. Conversely, the probability that a patient with VOW < 60% reaches "above-chance" speech perception is 0.25. CONCLUSIONS: For prelingually deaf adults, intelligibility of the patient's speech-as represented by VOW-is a valid predictor of postimplant speech perception. A patient with a VOW score above a preset cutoff is much more likely to develop acceptable speech perception after implantation than a patient with a VOW score below that cutoff. The binary classification based on VOW and the associated probabilities of cochlear implant success in terms of speech perception can be used-in addition to existing criteria-to support the clinician in guiding patient expectations and in considering implant candidacy for individual patients. PMID- 26928005 TI - A tool to include gamma analysis software into a quality assurance program. AB - PURPOSE: To provide a tool to enable gamma analysis software algorithms to be included in a quality assurance (QA) program. METHODS: Four image sets were created comprising two geometric images to independently test the distance to agreement (DTA) and dose difference (DD) elements of the gamma algorithm, a clinical step and shoot IMRT field and a clinical VMAT arc. The images were analysed using global and local gamma analysis with 2 in-house and 8 commercially available software encompassing 15 software versions. The effect of image resolution on gamma pass rates was also investigated. RESULTS: All but one software accurately calculated the gamma passing rate for the geometric images. Variation in global gamma passing rates of 1% at 3%/3mm and over 2% at 1%/1mm was measured between software and software versions with analysis of appropriately sampled images. CONCLUSION: This study provides a suite of test images and the gamma pass rates achieved for a selection of commercially available software. This image suite will enable validation of gamma analysis software within a QA program and provide a frame of reference by which to compare results reported in the literature from various manufacturers and software versions. PMID- 26928006 TI - Body composition in males with adolescent idiopathic scoliosis: a case-control study with dual-energy X-ray absorptiometry. AB - BACKGROUND: In contrast to the well-characterized body growth and development of females with adolescent idiopathic scoliosis (AIS), the pubertal growth pattern of male patients has not been well-documented. Recently, significantly lower body weight (BW) and body mass index (BMI) were reported in males with AIS, and were thought to be related to curve progression. A case-control study was carried out to characterize the body composition and bone status of males with AIS, with the aim of gaining a better understanding of lower BW among these patients. METHODS: Forty-seven males with AIS and forty age- and gender-matched healthy controls were recruited. Standing height (SH) and BW were measured. The SH of the males who had AIS was corrected using Bjure's equation, and then the BMI was calculated. Body composition, including subcranial fat mass (FM), lean mass (LM), and bone mineral content (BMC), and bone mineral density (BMD) were analyzed using dual-energy X-ray absorptiometry. The LM index (LMi) and the FM index (FMi) were calculated by dividing the FM and LM by the square of the SH. Logistic regression analysis was employed for comparison between AIS and controls. RESULTS: The AIS patients had comparable age and Tanner staging for pubic hair as the controls. After adjustment for age, the AIS patients showed comparable SH but significantly lower BW and BMI than that of the controls. The LM, LMi, BMC and BMD were also significantly lower in the AIS patients than in the controls. However, the difference in BMC between two groups was not significant by adjusting for age, FM and LM. CONCLUSION: The male AIS patients showed abnormal body composition, presenting as significantly lower LM than the controls. The lower BMC observed in the patients might due to the abnormal body composition. PMID- 26928007 TI - To be or not to be better pollinated: Differences between sex morphs in marginal gynodioecious populations. AB - PREMISE OF THE STUDY: Changes in the pollinator communities of marginal plant populations can affect their pollination quantity or quality. Geographic variation in pollination success can alter the reproductive advantage that female plants require to persist within gynodioecious populations. Particularly valuable is determining the pollination success at the prezygotic stage in self-compatible gynodioecious species whose females do not exhibit enhanced seed production. METHODS: In core and marginal populations of Daphne laureola, we analyzed the differences between hermaphrodites and females in the proportion of flowers visited, the stigma pollen loads, and the quantity of pollen tubes in styles. We also examined the relationship between the number of pollen tubes in styles vs. the number of pollen grains on stigmas using piecewise regression and binomial generalized linear mixed models. KEY RESULTS: Pollinators deposited larger pollen loads on flowers in marginal populations. In marginal populations, female flowers received more pollinator visits and more pollen grains on their stigmas, and they had more pollen tubes in their styles than did female flowers in core populations. Both piecewise regression and binomial GLMM analyses showed that females in marginal populations had a lower proportion of grains that developed tubes than females in the core populations, which suggests decreased pollination quality. CONCLUSIONS: More efficient pollination services in marginal populations decreased the overall differences in the prezygotic pollination success between the sex morphs. Our results also suggest that pollination quality is lower in females of marginal populations, which could be counteracting the increased pollination in females in marginal populations. PMID- 26928008 TI - Pollen performance traits reveal prezygotic nonrandom mating and interference competition in Arabidopsis thaliana. AB - PREMISE: The lack of ability to measure pollen performance traits in mixed pollinations has been a major hurdle in understanding the mechanisms of differential success of compatible pollen donors. In previous work, we demonstrated that nonrandom mating between two accessions of Arabidopsis thaliana, Columbia (Col) and Landsberg (Ler), is mediated by the male genotype. Despite these genetic insights, it was unclear at what stage of reproduction these genes were acting. Here, we used an experimental strategy that allowed us to differentiate different pollen populations in mixed pollinations to ask: (1) What pollen performance traits differed between Col and Ler accessions that direct nonrandom mating? (2) Is there evidence of interference competition? METHODS: We used genetically marked pollen that can be visualized colorimetrically to quantify pollen performance of single populations of pollen in mixed pollinations. We used this and other assays to measure pollen viability, germination, tube growth, patterns of fertilization, and seed abortion. Finally, we assessed interference competition. RESULTS: In mixed pollinations on Col pistils, Col pollen sired significantly more seeds than Ler pollen. Col pollen displayed higher pollen viability, faster and greater pollen germination, and faster pollen tube growth. We saw no evidence of nonrandom seed abortion. Finally, we found interference competition occurs in mixed pollinations. CONCLUSION: The lack of differences in postzygotic processes coupled with direct observation of pollen performance traits indicates that nonrandom mating in Arabidopsis thaliana is prezygotic, due mostly to differential pollen germination and pollen tube growth rates. Finally, this study unambiguously demonstrates the existence of interference competition. PMID- 26928010 TI - miR-100 Inhibits the Growth and Migration of Burn-Denatured Fibroblasts. AB - BACKGROUND Burn-denatured dermis is able to regain the function and shape of normal dermis; however, the potential mechanisms are still vague. The aim of this study was to investigate roles of miR-100 involved in the growth and migration of burn-denatured fibroblasts. MATERIAL AND METHODS Quantitative real-time polymerase chain reaction(qRT-PCR) was used to assess the expression of miR-100. Transient transfection of miR-100 mimics and inhibitor was used to up-regulate or down-regulate the expression of miR-100. Cell proliferation and colony formation assay were used to test the cell growth, and wound healing assay and transwell migration assay were used to evaluate the cell migration. RESULTS miR-100 expression was notably downregulated in the burn-denatured fibroblasts compared to normal controls. Functionally, transfection of miR-100 inhibitors improved the growth and migration abilities of burn-denatured fibroblasts. In contrast, upregulation of miR-100 inhibits the growth and migration of burn-denatured fibroblasts. CONCLUSIONS Based on these observations, we concluded that miR-100 can inhibit the growth and migration of burn-denatured fibroblasts. PMID- 26928009 TI - Mapping Antimicrobial Stewardship in Undergraduate Medical, Dental, Pharmacy, Nursing and Veterinary Education in the United Kingdom. AB - OBJECTIVES: To investigate the teaching of antimicrobial stewardship (AS) in undergraduate healthcare educational degree programmes in the United Kingdom (UK). PARTICIPANTS AND METHODS: Cross-sectional survey of undergraduate programmes in human and veterinary medicine, dentistry, pharmacy and nursing in the UK. The main outcome measures included prevalence of AS teaching; stewardship principles taught; estimated hours apportioned; mode of content delivery and teaching strategies; evaluation methodologies; and frequency of multidisciplinary learning. RESULTS: 80% (112/140) of programmes responded adequately. The majority of programmes teach AS principles (88/109, 80.7%). 'Adopting necessary infection prevention and control precautions' was the most frequently taught principle (83/88, 94.3%), followed by 'timely collection of microbiological samples for microscopy, culture and sensitivity' (73/88, 82.9%) and 'minimisation of unnecessary antimicrobial prescribing' (72/88, 81.8%). The 'use of intravenous administration only to patients who are severely ill, or unable to tolerate oral treatment' was reported in ~50% of courses. Only 32/88 (36.3%) programmes included all recommended principles. DISCUSSION: Antimicrobial stewardship principles are included in most undergraduate healthcare and veterinary degree programmes in the UK. However, future professionals responsible for using antimicrobials receive disparate education. Education may be boosted by standardisation and strengthening of less frequently discussed principles. PMID- 26928011 TI - Isolation and characterization of lactobacilli from human faeces and indigenous fermented foods for their potential application as probiotics. AB - This study was conducted to select Lactobacillus strains from various sources on the basis of their probiotic attributes, such as acid and bile tolerance, binding to intestinal cells, and antimicrobial activity. Twelve isolates were obtained from human and food sources and were evaluated against standard probiotic Lactobacillus rhamnosus GG (LGG). Isolates were also studied for their antibiotic susceptibility. Isolate Lactobacillus fermentum GPI-6 showed the best survival profile at 0.3% and 1% bile salt, as compared with LGG. Isolates Lactobacillus plantarum GRI-2 and Lactobacillus salivarius GPI-4 showed no reduction in survival rate at pH 2.5. As expected, isolates showed strain-specific differences when comparing various attributes. Isolates GPI-4, GPI-7, and FA-5 showed better adhesion to HT-29, while isolate GPI-4 adhered better to Caco-2 cells than did LGG. However, when studying their ability to compete with Escherichia coli O26:H11, isolates GPI-6 and GPI-7 significantly inhibited E. coli adhesion to both HT-29 and Caco-2 cells compared with LGG. In conclusion, isolates GPI-4, GPI 7, and FA-5 showed excellent binding ability and antagonistic activity and better tolerance to acidic pH (pH 2.5) and to different bile salt concentrations in comparison with LGG, and hence, they could be considered as potential probiotic candidates. PMID- 26928012 TI - Hard Transparent Arrays for Polymer Pen Lithography. AB - Patterning nanoscale features across macroscopic areas is challenging due to the vast range of length scales that must be addressed. With polymer pen lithography, arrays of thousands of elastomeric pyramidal pens can be used to write features across centimeter-scales, but deformation of the soft pens limits resolution and minimum feature pitch, especially with polymeric inks. Here, we show that by coating polymer pen arrays with a ~175 nm silica layer, the resulting hard transparent arrays exhibit a force-independent contact area that improves their patterning capability by reducing the minimum feature size (~40 nm), minimum feature pitch (<200 nm for polymers), and pen to pen variation. With these new arrays, patterns with as many as 5.9 billion features in a 14.5 cm(2) area were written using a four hundred thousand pyramid pen array. Furthermore, a new method is demonstrated for patterning macroscopic feature size gradients that vary in feature diameter by a factor of 4. Ultimately, this form of polymer pen lithography allows for patterning with the resolution of dip-pen nanolithography across centimeter scales using simple and inexpensive pen arrays. The high resolution and density afforded by this technique position it as a broad-based discovery tool for the field of nanocombinatorics. PMID- 26928013 TI - NO2 inhalation promotes Alzheimer's disease-like progression: cyclooxygenase-2 derived prostaglandin E2 modulation and monoacylglycerol lipase inhibition targeted medication. AB - Air pollution has been reported to be associated with increased risks of cognitive impairment and neurodegenerative diseases. Because NO2 is a typical primary air pollutant and an important contributor to secondary aerosols, NO2 induced neuronal functional abnormalities have attracted greater attention, but the available experimental evidence, modulating mechanisms, and targeting medications remain ambiguous. In this study, we exposed C57BL/6J and APP/PS1 mice to dynamic NO2 inhalation and found for the first time that NO2 inhalation caused deterioration of spatial learning and memory, aggravated amyloid beta42 (Abeta42) accumulation, and promoted pathological abnormalities and cognitive defects related to Alzheimer's disease (AD). The microarray and bioinformation data showed that the cyclooxygenase-2 (COX-2)-mediated arachidonic acid (AA) metabolism of prostaglandin E2 (PGE2) played a key role in modulating this aggravation. Furthermore, increasing endocannabinoid 2-arachidonoylglycerol (2 AG) by inhibiting monoacylglycerol lipase (MAGL) prevented PGE2 production, neuroinflammation-associated Abeta42 accumulation, and neurodegeneration, indicating a therapeutic target for relieving cognitive impairment caused by NO2 exposure. PMID- 26928014 TI - Female and male life tables for seven wild primate species. AB - We provide male and female census count data, age-specific survivorship, and female age-specific fertility estimates for populations of seven wild primates that have been continuously monitored for at least 29 years: sifaka (Propithecus verreauxi) in Madagascar; muriqui (Brachyteles hypoxanthus) in Brazil; capuchin (Cebus capucinus) in Costa Rica; baboon (Papio cynocephalus) and blue monkey (Cercopithecus mitis) in Kenya; chimpanzee (Pan troglodytes) in Tanzania; and gorilla (Gorilla beringei) in Rwanda. Using one-year age-class intervals, we computed point estimates of age-specific survival for both sexes. In all species, our survival estimates for the dispersing sex are affected by heavy censoring. We also calculated reproductive value, life expectancy, and mortality hazards for females. We used bootstrapping to place confidence intervals on life-table summary metrics (R0, the net reproductive rate; lambda, the population growth rate; and G, the generation time). These data have high potential for reuse; they derive from continuous population monitoring of long-lived organisms and will be invaluable for addressing questions about comparative demography, primate conservation and human evolution. PMID- 26928015 TI - We need more data to determine the significance of NT-proBNP and troponin I levels in high-risk patients. PMID- 26928016 TI - [Clinical and economic consequences of using dabigatran or rivaroxaban in patients with non-valvular atrial fibrillation]. AB - INTRODUCTION AND OBJECTIVES: Atrial fibrillation is a supraventricular arrhythmia that increases the risk of ischemic stroke and other thromboembolic events. Recently new treatment options have emerged whose cost-effectiveness relative to conventional therapy (warfarin) is well demonstrated. This study compares the clinical benefits and economic costs associated with the new oral anticoagulants most used in Portugal: dabigatran and rivaroxaban. METHODS: The results of an indirect comparison of the RE-LY and ROCKET AF trials, which enabled differences in the efficacy of dabigatran and rivaroxaban to be determined, were used in a Markov model simulating patient outcomes in terms of ischemic and hemorrhagic stroke, transient ischemic attack, systemic embolism, acute myocardial infarction and intra- and extracranial bleeding. RESULTS: The use of dabigatran is associated with better clinical results. The reduction in events is reflected in longer survival (8.41 vs. 8.26 years) and more quality-adjusted life years (5.87 vs. 5.74), while the lower daily treatment cost and the reduction in event related costs lead to a saving of 367 euros per patient from a societal perspective. CONCLUSIONS: The results show that dabigatran is a dominant alternative, i.e., it produces better clinical results at a lower cost. Sensitivity analysis demonstrates that the results are robust even considering the uncertainty inherent in an indirect comparison. It can thus be concluded that in clinical practice in Portugal the use of dabigatran is to be preferred to the use of rivaroxaban. PMID- 26928017 TI - [Isolated left ventricular noncompaction causing refractory heart failure]. AB - Left ventricular noncompaction is a rare congenital anomaly characterized by excessive left ventricular trabeculation, deep intertrabecular recesses and a thin compacted layer due to the arrest of compaction of myocardial fibers during embryonic development. We report the case of a young patient with isolated left ventricular noncompaction, leading to refractory heart failure that required extracorporeal membrane oxygenation followed by emergency heart transplantation. PMID- 26928018 TI - Birt-Hogg-Dube syndrome: a large single family cohort. AB - BACKGROUND: Birt-Hogg-Dube (BHD) syndrome is an autosomal dominant condition characterized by dermatologic lesions, pulmonary manifestations, and renal tumors. The syndrome arises from germline mutations in the folliculin (FLCN) gene. We present findings from the single largest family BHD cohort described to date. Primary objectives were to characterize cystic lung changes on computed tomography (CT) chest scanning and identify features that stratify patients at higher risk of pneumothorax. Secondary objectives entailed description of the following: type and natural history of BHD-associated pneumothorax, pulmonary function characteristics, and relationship between cystic lung changes and pulmonary function. METHODS: The study was a retrospective chart review for a case series of a single family. Over 70 family members of a proband with documented BHD were identified, 68 of which consented to genetic testing. All those with confirmed BHD were offered a clinical assessment by the Medical Genetics and Pulmonary services which included a history, physical exam, complete pulmonary function tests, and computed tomography (CT) scan of the chest and abdomen. RESULTS: Thirty-six individuals had a heterozygous mutation in the FLCN gene (c.59delT). Of these, 100 % (28/28) had pulmonary cysts, 41 % (13/32) had spontaneous pneumothoraces, 26 % (8/31) had kidney cysts, 3 % (1/31) had renal tumors, and 53 % (18/34) had dermatologic manifestations. Recurrent pneumothoraces were common (40 %). Cyst size (OR 3.23, 95 % CI 1.35-7.73) and extent of lower lung zone disease (OR 6.43, 95 % CI 1.41-29.2) were the only findings associated with pneumothorax. The size or extent of cystic disease did not correlate with lung function results. CONCLUSIONS: This is the largest single family cohort of patients with BHD syndrome documented to date. We found that all individuals had pulmonary cysts, pneumothoraces were common, and cyst size and lower lobe predominant disease were associated with pneumothorax. Lung function was generally preserved and not affected by a high cyst burden. PMID- 26928019 TI - Discovery of a Potent Free Fatty Acid 1 Receptor Agonist with Low Lipophilicity, Low Polar Surface Area, and Robust in Vivo Efficacy. AB - The free fatty acid receptor 1 (FFA1 or GPR40) is established as an interesting potential target for treatment of type 2 diabetes. However, to obtain optimal ligands, it may be necessary to limit both lipophilicity and polar surface area, translating to a need for small compounds. We here describe the identification of 24, a potent FFA1 agonist with low lipophilicity and very high ligand efficiency that exhibit robust glucose lowering effect. PMID- 26928020 TI - Acculturation Strategies Among South Asian Immigrants: The Mediators of Atherosclerosis in South Asians Living in America (MASALA) Study. AB - In the past, epidemiologic research on acculturation and health has been criticized for its conceptual ambiguity and simplistic measurement approaches. This study applied a widely-used theoretical framework from cross-cultural psychology to identify acculturation strategies among South Asian immigrants in the US and to examine sociodemographic correlates of acculturation strategies. Data were from the Mediators of Atherosclerosis in South Asians Living in America study. We used latent class analysis to identify groups of individuals that were similar based on cultural attitudes and behaviors. We used latent class regression analysis to examine sociodemographic correlates of acculturation strategies. We found that South Asian immigrants employed three acculturation strategies, including separation (characterized by a relatively high degree of preference for South Asian culture over US culture), assimilation (characterized by a relatively high degree of preference for US culture over South Asian culture), and integration (characterized by a similar level of preference for South Asian and US cultures). Respondents with no religious affiliation, those with higher levels of income, those who lived a greater percentage of their lives in the US, and those who spoke English well or very well were less likely to use the separation strategy than the assimilation or integration strategies. Using epidemiologic cohort data, this study illustrated a conceptual and methodological approach that addresses limitations of previous research on acculturation and health. More work is needed to understand how the acculturation strategies identified in this study affect the health of South Asian immigrants in the US. PMID- 26928022 TI - Enhancing light emission efficiency without color change in post-transition metal chalcogenides. AB - Two-dimensional (2D) materials can take a large amount of mechanical deformation before reaching the fracture limit due to their high Young's modulus, and this in return, provides a way to tune the properties of 2D materials by strain engineering. Previous works have shown that the optical band gap of transition metal chalcogenides (TMDs) can be modulated by strain, resulting in a drift of the photoluminescence (PL) peak position and a decrease (or little change) in PL intensity. Here, we report a member of the post-transition metal chalcogenides (PTMCs), 2D-GaSe sheets, displaying vastly different phenomena under strain. Strained 2D-GaSe emits photons at almost the same wavelength as unstrained material but appears an order of magnitude brighter. In contrast to TMDs, optical spectroscopy measurements reveal that changes in the optical properties are mostly related to the colossal optical absorption anisotropy of GaSe, instead of commonly accepted strain-induced band renormalization. Results suggest that the light-matter interaction and the optical properties of 2D-GaSe can be controlled at will by manipulating the optical absorption. PMID- 26928021 TI - The Helicobacter pylori cytotoxin CagA is essential for suppressing host heat shock protein expression. AB - Bacterial infections typically elicit a strong Heat Shock Response (HSR) in host cells. However, the gastric pathogen Helicobacter pylori has the unique ability to repress this response, the mechanism of which has yet to be elucidated. This study sought to characterize the underlying mechanisms by which H. pylori down modulates host HSP expression upon infection. Examination of isogenic mutant strains of H. pylori defective in components of the type IV secretion system (T4SS), identified the secretion substrate, CagA, to be essential for down modulation of the HSPs HSPH1 (HSP105), HSPA1A (HSP72), and HSPD1 (HSP60) upon infection of the AGS gastric adenocarcinoma cell line. Ectopic expression of CagA by transient transfection was insufficient to repress HSP expression in AGS or HEK293T cells, suggesting that additional H. pylori factors are required for HSP repression. RT-qPCR analysis of HSP gene expression in AGS cells infected with wild-type H. pylori or isogenic cagA-deletion mutant found no significant change to account for reduced HSP levels. In summary, this study identified CagA to be an essential bacterial factor for H. pylori-mediated suppression of host HSP expression. The novel finding that HSPH1 is down-modulated by H. pylori further highlights the unique ability of H. pylori to repress the HSR within host cells. Elucidation of the mechanism by which H. pylori achieves HSP repression may prove to be beneficial in the identification of novel mechanisms to inhibit the HSR pathway and provide further insight into the interactions between H. pylori and the host gastric epithelium. PMID- 26928023 TI - Growth-Blocking Peptides As Nutrition-Sensitive Signals for Insulin Secretion and Body Size Regulation. AB - In Drosophila, the fat body, functionally equivalent to the mammalian liver and adipocytes, plays a central role in regulating systemic growth in response to nutrition. The fat body senses intracellular amino acids through Target of Rapamycin (TOR) signaling, and produces an unidentified humoral factor(s) to regulate insulin-like peptide (ILP) synthesis and/or secretion in the insulin producing cells. Here, we find that two peptides, Growth-Blocking Peptide (GBP1) and CG11395 (GBP2), are produced in the fat body in response to amino acids and TOR signaling. Reducing the expression of GBP1 and GBP2 (GBPs) specifically in the fat body results in smaller body size due to reduced growth rate. In addition, we found that GBPs stimulate ILP secretion from the insulin-producing cells, either directly or indirectly, thereby increasing insulin and insulin-like growth factor signaling activity throughout the body. Our findings fill an important gap in our understanding of how the fat body transmits nutritional information to the insulin producing cells to control body size. PMID- 26928024 TI - Effect of obesity on cognition in adults with and without a mood disorder: study design and methods. AB - INTRODUCTION: Obesity is a common medical illness that is increasingly recognised as conferring risk of decline in cognitive performance, independent of other comorbid medical conditions. Individuals with mood disorders (bipolar disorder (BD) or major depressive disorder (MDD)) display an increased prevalence of both obesity and risk factors for cardiovascular diseases. Moreover, BD and MDD are associated with impairment in cognitive functioning across multiple domains. The independent contribution of obesity to cognitive decline in this population has not been explored. This study examines the impact of obesity on cognition by comparing neuropsychological performance in obese individuals, with or without a mood disorder before and after undergoing bariatric surgery. METHODS AND ANALYSIS: This study compares measures of declarative memory, executive functioning and attention in obese individuals (body mass index >35 kg/m(2)) with BD or MDD, and 2 control populations (obese individuals without a psychiatric illness and healthy non-obese controls) prior to and following bariatric surgery. Participants (ages 18-60) receive a psychiatric diagnosis via the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV; SCID). Mood ratings, physical measurements, nutritional and health questionnaires are also administered. A standardised battery of neuropsychological tests aimed at establishing performance in areas of declarative memory, executive functioning and attention are administered. Warrington's Recognition Memory Task (RMT) and an N-Back Task are performed in a 3 T functional MRI to investigate patterns of neural activation during cognitive performance. Additionally, anatomical MRI data are obtained to investigate potential changes in neural structures. Baseline data will be analysed for between-group differences and later compared with postsurgical data to investigate cognitive change. ETHICS AND DISSEMINATION: This study has been approved by the Hamilton Integrated Research Ethics Board (09-3254). Results will be available in peer-reviewed scientific publications and scientific meetings presentations, and released in lay form to media. PMID- 26928025 TI - Community pharmacy-delivered interventions for public health priorities: a systematic review of interventions for alcohol reduction, smoking cessation and weight management, including meta-analysis for smoking cessation. AB - OBJECTIVES: To systematically review the effectiveness of community pharmacy delivered interventions for alcohol reduction, smoking cessation and weight management. DESIGN: Systematic review and meta-analyses. 10 electronic databases were searched from inception to May 2014. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: STUDY DESIGN: randomised and non-randomised controlled trials; controlled before/after studies, interrupted times series. INTERVENTION: any relevant intervention set in a community pharmacy, delivered by the pharmacy team. No restrictions on duration, country, age, or language. RESULTS: 19 studies were included: 2 alcohol reduction, 12 smoking cessation and 5 weight management. Study quality rating: 6 'strong', 4 'moderate' and 9 'weak'. 8 studies were conducted in the UK, 4 in the USA, 2 in Australia, 1 each in 5 other countries. Evidence from 2 alcohol-reduction interventions was limited. Behavioural support and/or nicotine replacement therapy are effective and cost-effective for smoking cessation: pooled OR was 2.56 (95% CI 1.45 to 4.53) for active intervention vs usual care. Pharmacy-based interventions produced similar weight loss compared with active interventions in other primary care settings; however, weight loss was not sustained longer term in a range of primary care and commercial settings compared with control. Pharmacy-based weight management interventions have similar provider costs to those delivered in other primary care settings, which are greater than those delivered by commercial organisations. Very few studies explored if and how sociodemographic or socioeconomic variables moderated intervention effects. Insufficient information was available to examine relationships between effectiveness and behaviour change strategies, implementation factors, or organisation and delivery of interventions. CONCLUSIONS: Community pharmacy-delivered interventions are effective for smoking cessation, and demonstrate that the pharmacy is a feasible option for weight management interventions. Given the potential reach, effectiveness and associated costs of these interventions, commissioners should consider using community pharmacies to help deliver public health services. PMID- 26928027 TI - Multidisciplinary approach to the management of children with female genital mutilation (FGM) or suspected FGM: service description and case series. AB - OBJECTIVE: To describe the first dedicated clinic in the UK for children with suspected or confirmed female genital mutilation (FGM) including referral patterns, clinical findings and subsequent management. DESIGN AND SETTING: A prospective study of all children seen in a dedicated multidisciplinary FGM clinic for children over a 1-year period. POPULATION: Patients aged under 18 years referred for clinical assessment or for a second opinion on Digital Versatile Disc (DVD) images. METHODS AND MAIN OUTCOME MEASURES: Data were collected on reasons for referral, demography, genital examination findings including FGM type, and clinical recommendations. RESULTS: 38 children were referred of whom 18 (47%) had confirmed FGM; most frequently type 4 (61%). Social care and police referred 78% of cases. According to UK law FGM had been performed illegally in three cases. Anonymous information given to the police led to the referral of six children, none of whom had had FGM. CONCLUSIONS: Mandatory reporting and increased media attention may increase the numbers of referrals of children with suspected FGM. This patient group have complex needs and management in a dedicated multidisciplinary service is essential. Paediatricians and gynaecologists should have the skills to carry out the consultation and detect all types of FGM including type 4 which was the most common type seen in this series. This is the first dedicated FGM service for children in the UK and similar clinics in high-prevalence areas should be established. PMID- 26928026 TI - Evaluating the impacts of screening and smoking cessation programmes on lung cancer in a high-burden region of the USA: a simulation modelling study. AB - OBJECTIVE: While the US Preventive Services Task Force has issued recommendations for lung cancer screening, its effectiveness at reducing lung cancer burden may vary at local levels due to regional variations in smoking behaviour. Our objective was to use an existing model to determine the impacts of lung cancer screening alone or in addition to increased smoking cessation in a US region with a relatively high smoking prevalence and lung cancer incidence. SETTING: Computer based simulation model. PARTICIPANTS: Simulated population of individuals 55 and older based on smoking prevalence and census data from Northeast Pennsylvania. INTERVENTIONS: Hypothetical lung cancer control from 2014 to 2050 through (1) screening with CT, (2) intensified smoking cessation or (3) a combination strategy. PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcomes were lung cancer mortality rates. Secondary outcomes included number of people eligible for screening and number of radiation-induced lung cancers. RESULTS: Combining lung cancer screening with increased smoking cessation would yield an estimated 8.1% reduction in cumulative lung cancer mortality by 2050. Our model estimated that the number of screening-eligible individuals would progressively decrease over time, indicating declining benefit of a screening-only programme. Lung cancer screening achieved a greater mortality reduction in earlier years, but was later surpassed by smoking cessation. CONCLUSIONS: Combining smoking cessation programmes with lung cancer screening would provide the most benefit to a population, especially considering the growing proportion of patients ineligible for screening based on current recommendations. PMID- 26928028 TI - Cognitive decline in dementia with Lewy bodies: a 5-year prospective cohort study. AB - OBJECTIVES: We report the cognitive decline in persons diagnosed with mild dementia with Lewy bodies (DLB) and mild Alzheimer's disease (AD) during 5 years of annual follow-ups. METHODS: Patients were recruited into the study from geriatric, psychiatric and neurology clinics in Western Norway during 2005-2013. They were diagnosed according to clinical consensus criteria, based on standardised clinical rating scales. Autopsy-based diagnoses were available for 20 cases. Cognitive decline for up to 5 years was assessed using the Clinical Dementia Rating (CDR) scale and the Mini-Mental State Examination (MMSE). Survival analysis including Cox regression (time to reach severe dementia) and linear mixed-effects (lme) modelling were used to model the decline on MMSE. RESULTS: At least one follow-up assessment was available for 67 patients with DLB and 107 patients with AD, with a median follow-up time of 4.3 years. The time to reach severe dementia was significantly shorter in DLB (median 1793 days) compared with AD (1947 days; p=0.033), and the difference remained significant in the multiple Cox regression analysis (HR=2.0, p<0.02). In the adjusted lme model, MMSE decline was faster in DLB (annual decline 4.4 points) compared with AD (3.2 points; p<0.008). CONCLUSIONS: Our findings show that from the mild dementia stage, patients with DLB have a more rapid cognitive decline than in AD. Such prognostic information is vital for patients and families and crucial for planning clinical trials and enabling health economic modelling. PMID- 26928029 TI - Systematic review of adherence rates by medication class in type 2 diabetes: a study protocol. AB - INTRODUCTION: Treatment options for type 2 diabetes are becoming increasingly complex with people often prescribed multiple medications, and may include both oral and injectable therapies. There is ongoing debate about which drug classes provide the optimum second-line and third-line treatment options. In the real world, patient adherence and persistence determines medication effectiveness. A better understanding of adherence may help inform the choice of second-line and third-line drug classes. METHODS AND ANALYSIS: This systematic review will compare adherence and persistence rates across the different classes of medication available to people with type 2 diabetes. It will include all identified studies comparing medication adherence or persistence between two or more glucose-lowering medications in people with type 2 diabetes. Research databases (MEDLINE, EMBASE, The Cochrane Library, The Register of Controlled Trials, PsychINFO and CINAHL) will be searched for relevant articles, using a comprehensive search strategy. All identified medication trials and observational studies will be included which compare adherence or persistence across classes of diabetes medication. The characteristics and outcomes of all the included studies will be reported along with a study quality grade, assessed using the Cochrane Risk Assessment Tool. The quality of adjustment for confounders of adherence or persistence will be reported for each study. Where multiple (n >= 3) studies provide compare adherence or persistence across the same 2 medication classes, a meta-analysis will be performed. ETHICS AND DISSEMINATION: No ethics approval is required. This review and meta-analysis (where possible) will provide important information on the relative patient adherence and persistence, with the different classes of diabetes therapies. Once complete, the results will be made available by peer-reviewed publication. TRIAL REGISTRATION NUMBER: CRD42015027865. PMID- 26928030 TI - Polypeptide Functional Surface for the Aptamer Immobilization: Electrochemical Cocaine Biosensing. AB - Electroanalytical technologies as a beneficial subject of modern analytical chemistry can play an important role for abused drug analysis which is crucial for both legal and social respects. This article reports a novel aptamer-based biosensing procedure for cocaine analysis by combining the advantages of aptamers as selective recognition elements with the well-known advantages of biosensor systems such as the possibility of miniaturization and automation, easy fabrication and modification, low cost, and sensitivity. In order to construct the aptasensor platform, first, polythiophene bearing polyalanine homopeptide side chains (PT-Pala) was electrochemically coated onto the surface of an electrode and then cocaine aptamer was attached to the polymer via covalent conjugation chemistry. The stepwise modification of the surface was confirmed by electrochemical characterization. The designed biosensing system was applied for the detection of cocaine and its metabolite, benzoylecgonine (BE), which exhibited a linear correlation in the range from 2.5 up to 10 nM and 0.5 up to 50 MUM for cocaine and BE, respectively. In order to expand its practical application, the proposed method was successfully tested for the analysis of synthetic biological fluids. PMID- 26928031 TI - The Search for Treatment of Bronchopulmonary Dysplasia. PMID- 26928032 TI - A conversation with Huda Zoghbi. PMID- 26928033 TI - Beyond antigens and adjuvants: formulating future vaccines. AB - The need to optimize vaccine potency while minimizing toxicity in healthy recipients has motivated studies of the formulation of vaccines to control how, when, and where antigens and adjuvants encounter immune cells and other cells/tissues following administration. An effective subunit vaccine must traffic to lymph nodes (LNs), activate both the innate and adaptive arms of the immune system, and persist for a sufficient time to promote a mature immune response. Here, we review approaches to tailor these three aspects of vaccine function through optimized formulations. Traditional vaccine adjuvants activate innate immune cells, promote cell-mediated transport of antigen to lymphoid tissues, and promote antigen retention in LNs. Recent studies using nanoparticles and other lymphatic-targeting strategies suggest that direct targeting of antigens and adjuvant compounds to LNs can also enhance vaccine potency without sacrificing safety. The use of formulations to regulate biodistribution and promote antigen and inflammatory cue co-uptake in immune cells may be important for next generation molecular adjuvants. Finally, strategies to program vaccine kinetics through novel formulation and delivery strategies provide another means to enhance immune responses independent of the choice of adjuvant. These technologies offer the prospect of enhanced efficacy while maintaining high safety profiles necessary for successful vaccines. PMID- 26928037 TI - Effects of magnesium supplementation on the incidence of acute kidney injury in critically ill patients presenting with hypomagnesemia. PMID- 26928036 TI - Everybody loves sugar: first report of plant feeding in triatomines. AB - BACKGROUND: Triatomines, which are the vectors of Trypanosoma cruzi, have been considered to be exclusive blood feeders for more than 100 years, since the discovery of Chagas disease. METHODS: We offered artificial sugar meals to the laboratory model-insect Rhodnius prolixus, which is considered a strict haematophagous insect. We registered feeding by adding colorant to sugar meals. To assess putative phytophagy, fruits of the tomato Solanum lycopersicum were offered to R. prolixus and the presence of tomato DNA was assessed in the insects using PCR. We also assessed longevity, blood feeding and urine production of fruit-exposed triatomines and control insects. RESULTS: All instars of R. prolixus ingested sugar from artificial sugar meals in laboratory conditions. First instar R. prolixus ingested plant tissue from S. lycopersicum fruits, and this increased the amount of blood ingested and urine excreted. Decreased mortality was also observed after blood feeding. Exposure to S. lycopersicum increased longevity and reduced weight loss caused by desiccation. CONCLUSIONS: We describe here the first report of sugar feeding and phytophagy in a species that was considered to be a strict blood-feeder for over a century. We suggest that local plants might be not merely shelters for insects and vertebrate hosts as previously described, but may have a nutritional role for the maintenance of the triatomine vectors. The description of sugar and plant meals in triatomines opens new perspectives for the study and control of Chagas Disease. PMID- 26928035 TI - Endothelial fluid shear stress sensing in vascular health and disease. AB - Endothelial cells transduce the frictional force from blood flow (fluid shear stress) into biochemical signals that regulate gene expression and cell behavior via specialized mechanisms and pathways. These pathways shape the vascular system during development and during postnatal and adult life to optimize flow to tissues. The same pathways also contribute to atherosclerosis and vascular malformations. This Review covers recent advances in basic mechanisms of flow signaling and the involvement of these mechanisms in vascular physiology, remodeling, and these diseases. We propose that flow sensing pathways that govern normal morphogenesis can contribute to disease under pathological conditions or can be altered to induce disease. Viewing atherosclerosis and vascular malformations as instances of pathological morphogenesis provides a unifying perspective that may aid in developing new therapies. PMID- 26928034 TI - Mitochondria in lung disease. AB - Mitochondria are a distinguishing feature of eukaryotic cells. Best known for their critical function in energy production via oxidative phosphorylation (OXPHOS), mitochondria are essential for nutrient and oxygen sensing and for the regulation of critical cellular processes, including cell death and inflammation. Such diverse functional roles for organelles that were once thought to be simple may be attributed to their distinct heteroplasmic genome, exclusive maternal lineage of inheritance, and ability to generate signals to communicate with other cellular organelles. Mitochondria are now thought of as one of the cell's most sophisticated and dynamic responsive sensing systems. Specific signatures of mitochondrial dysfunction that are associated with disease pathogenesis and/or progression are becoming increasingly important. In particular, the centrality of mitochondria in the pathological processes and clinical phenotypes associated with a range of lung diseases is emerging. Understanding the molecular mechanisms regulating the mitochondrial processes of lung cells will help to better define phenotypes and clinical manifestations associated with respiratory disease and to identify potential diagnostic and therapeutic targets. PMID- 26928038 TI - ARDS: what experimental models have taught us. PMID- 26928039 TI - BIS monitoring in sedated, mechanically ventilated patients: right tool in the wrong patients? A meta-analysis. PMID- 26928040 TI - Long-distance air transfer on commercial long-haul flights for patients on extracorporeal life support. PMID- 26928041 TI - A novel culture system for adult porcine intestinal crypts. AB - Porcine models are useful for investigating therapeutic approaches to short bowel syndrome and potentially to intestinal stem cell (ISC) transplantation. Whereas techniques for the culture and genetic manipulation of ISCs from mice and humans are well established, similar methods for porcine stem cells have not been reported. Jejunal crypts were isolated from murine, human, and juvenile and adult porcine small intestine, suspended in Matrigel, and co-cultured with syngeneic intestinal subepithelial myofibroblasts (ISEMFs) or cultured without feeder cells in various culture media. Media containing epidermal growth factor, noggin, and R spondin 1 (ENR medium) were supplemented with various combinations of Wnt3a- or ISEMF-conditioned medium (CM) and with glycogen synthase kinase 3 inhibitor (GSK3i), and their effects were studied on cultured crypts. Cell lineage differentiation was assessed by immunohistochemistry and quantitative polymerase chain reaction. Cultured porcine cells were serially passaged and transduced with a lentiviral vector. Whereas ENR medium supported murine enteroid growth, it did not sustain porcine crypts beyond 5 days. Supplementation of Wnt3a-CM and GSK3i resulted in the formation of complex porcine enteroids with budding extensions. These enteroids contained a mixture of stem and differentiated cells and were successfully passaged in the presence of GSK3i. Crypts grown in media supplemented with porcine ISEMF-CM formed spheroids that were less well differentiated than enteroids. Enteroids and spheroids were transfected with a lentivirus with high efficiency. Thus, our method maintains juvenile and adult porcine crypt cells long-term in culture. Porcine enteroids and spheroids can be successfully passaged and transduced by using lentiviral vectors. PMID- 26928042 TI - Expression of vascular endothelial growth factor (VEGF)-B and its receptor (VEGFR1) in murine heart, lung and kidney. AB - Metabolic diseases, such as obesity and diabetes, are a serious burden for the health system. Vascular endothelial growth factor (VEGF)-B has been shown to regulate tissue uptake and accumulation of fatty acids and is thus involved in these metabolic diseases. However, the cell-type-specific expression pattern of Vegfb and its receptor (VEGFR1, gene Flt1) remains unclear. We explore the expression of Vegfb and Flt1 in the murine heart, lung and kidney by utilizing beta-galactosidase knock-in mouse models and combining the analysis of reporter gene expression and immunofluorescence microscopy. Furthermore, Flt1 heterozygous mice were analyzed with regard to muscular fatty acid accumulation and peripheral insulin sensitivity. Throughout the heart, Vegfb expression was found in cardiomyocytes with a postnatal ventricular shift corresponding to known changes in energy requirements. Vegfb expression was also found in the pulmonary myocardium of the lung and in renal epithelial cells of the thick ascending limb of Henle's loop, the connecting tubule and the collecting duct. In all analyzed organs, VEGFR1 expression was restricted to endothelial cells. We also show that reduced expression of VEGFR1 resulted in decreased cardiac fatty acid accumulation and increased peripheral insulin sensitivity, possibly as a result of attenuated VEGF-B/VEGFR1 signaling. Our data therefore support a tightly controlled, paracrine signaling mechanism of VEGF-B to VEGFR1. The identified cell-specific expression pattern of Vegfb and Flt1 might form the basis for the development of cell-type-targeted research models and contributes to the understanding of the physiological and pathological role of VEGF-B/VEGFR1 signaling. PMID- 26928043 TI - High acetone-butanol-ethanol production in pH-stat co-feeding of acetate and glucose. AB - We previously reported the metabolic analysis of butanol and acetone production from exogenous acetate by (13)C tracer experiments (Gao et al., RSC Adv., 5, 8486 8495, 2015). To clarify the influence of acetate on acetone-butanol-ethanol (ABE) production, we first performed an enzyme assay in Clostridium saccharoperbutylacetonicum N1-4. Acetate addition was found to drastically increase the activities of key enzymes involved in the acetate uptake (phosphate acetyltransferase and CoA transferase), acetone formation (acetoacetate decarboxylase), and butanol formation (butanol dehydrogenase) pathways. Subsequently, supplementation of acetate during acidogenesis and early solventogenesis resulted in a significant increase in ABE production. To establish an efficient ABE production system using acetate as a co-substrate, several shot strategies were investigated in batch culture. Batch cultures with two substrate shots without pH control produced 14.20 g/L butanol and 23.27 g/L ABE with a maximum specific butanol production rate of 0.26 g/(g h). Furthermore, pH-controlled (at pH 5.5) batch cultures with two substrate shots resulted in not only improved acetate consumption but also a further increase in ABE production. Finally, we obtained 15.13 g/L butanol and 24.37 g/L ABE at the high specific butanol production rate of 0.34 g/(g h) using pH-stat co-feeding method. Thus, in this study, we established a high ABE production system using glucose and acetate as co-substrates in a pH-stat co-feeding system with C. saccharoperbutylacetonicum N1-4. PMID- 26928044 TI - Adequacy of Rifampin Absorption after Jejunostomy Tube Administration. AB - It is not always possible to administer antituberculosis pharmacotherapy orally for reasons that may be a direct consequence of tuberculosis itself. To our knowledge, no published literature is available regarding antituberculosis drug absorption via feeding tube. We present the case of a patient with tuberculosis meningitis who required medication administration via percutaneous endoscopic jejunostomy (PEJ) tube. Blood samples were collected during the continuation phase of antituberculosis therapy, immediately before dose administration, and then at 1, 2, 4, and 6 hours after dose administration for quantification of serum rifampin concentrations. Assaying these concentrations by high-pressure liquid chromatography demonstrated a peak serum rifampin level (C(max)) of 18 MUg/ml and total rifampin exposure (area under the curve from 0-6 hours [AUC(0 6)]) of 50.1 MUg/ml. These are high compared with rifampin C(max) and AUC(0-6) values reported in patients after oral rifampin administration; C(max) tends to range between 4.0-10.5 MUg/ml and AUC(0-6) 7.0-52.9 MUg/ml after oral administration of 600 mg at steady state. Based on our patient's results, therefore, rifampin administered by PEJ tube appears to be well absorbed, with preservation of adequate C(max) and AUC values. It is worth noting that this was in the context of drug administration in the fasted state. In the absence of any published evidence of adequate absorption via jejunal feeding tube in the nonfasted state, it would seem prudent to ensure that patients are fasted when rifampin is administered via PEJ tube, just as patients are when oral rifampin is administered. This report represents the first documented evidence, to our knowledge, of adequate rifampin absorption when administered via PEJ tube and provides important reassurance for health care providers, patients, and families facing similar clinical scenarios. PMID- 26928045 TI - Ratiometric fluorescent paper sensor utilizing hybrid carbon dots-quantum dots for the visual determination of copper ions. AB - A simple and effective ratiometric fluorescence nanosensor for the selective detection of Cu(2+) has been developed by covalently connecting the carboxyl modified red fluorescent cadmium telluride (CdTe) quantum dots (QDs) to the amino functionalized blue fluorescent carbon nanodots (CDs). The sensor exhibits the dual-emissions peaked at 437 and 654 nm, under a single excitation wavelength of 340 nm. The red fluorescence can be selectively quenched by Cu(2+), while the blue fluorescence is a internal reference, resulting in a distinguishable fluorescence color change from pink to blue under a UV lamp. The detection limit of this highly sensitive ratiometric probe is as low as 0.36 nM, which is lower than the U.S. Environmental Protection Agency (EPA) defined limit (20 MUM). Moreover, a paper-based sensor has been prepared by printing the hybrid carbon dots-quantum dots probe on a microporous membrane, which provides a convenient and simple approach for the visual detection of Cu(2+). Therefore, the as synthesized probe shows great potential application for the determination of Cu(2+) in real samples. PMID- 26928046 TI - Oxidative stress pathways involved in cytotoxicity and genotoxicity of titanium dioxide (TiO2) nanoparticles on cells constitutive of alveolo-capillary barrier in vitro. AB - The health risks of nanoparticles remain a serious concern given their prevalence from industrial and domestic use. The primary route of titanium dioxide nanoparticle exposure is inhalation. The extent to which nanoparticles contribute to cellular toxicity is known to associate induction of oxidative stress. To investigate this problem further, the effect of titanium dioxide nanoparticles was examined on cell lines representative of alveolo-capillary barrier. The present study showed that all nanoparticle-exposed cell lines displayed ROS generation. Macrophage-like THP-1 and HPMEC-ST1.6R microvascular cells were sensitive to endogenous redox changes and underwent apoptosis, but not alveolar epithelial A549 cells. Genotoxic potential of titanium dioxide nanoparticles was investigated using the activation of gammaH2AX, activation of DNA repair proteins and cell cycle arrest. In the sensitive cell lines, DNA damage was persistent and activation of DNA repair pathways was observed. Moreover, western blot analysis showed that specific pathways associated with cellular stress response were activated concomitantly with DNA repair or apoptosis. Nanoparticles-induced oxidative stress is finally signal transducer for further physiological effects including genotoxicity and cytotoxicity. Within activated pathways, HSP27 and SAPK/JNK proteins appeared as potential biomarkers of intracellular stress and of sensitivity to endogenous redox changes, respectively, enabling to predict cell behavior. PMID- 26928047 TI - Dental metal-induced innate reactivity in keratinocytes. AB - In their paper that is published in Toxicology in Vitro, Rachmawati et al. have recently claimed that in spite of the growing concern about the safety of amalgam, negative reports about the health effects of dental amalgam are still scarce or controversial. Substantial evidence indicates that mercury release from dental amalgam fillings may adversely affect human health. Over the past years, we have shown that exposure to electromagnetic fields (EMFs) can increase the release of mercury from dental amalgam fillings. It is worth mentioning that the results of investigations on the microleakage of amalgam fillings following MRI have confirmed our results. Furthermore, exposure to X-rays as a part of the electromagnetic spectrum has also been linked to increased mercury release from dental amalgam fillings. Considering the explosive rise in human exposure to electromagnetic fields, the role of human exposure to EMF as a key factor in increasing the release of mercury from dental amalgam restorations cannot be simply ignored. PMID- 26928048 TI - Pretreatment of cultured preadipocytes with arachidonic acid during the differentiation phase without a cAMP-elevating agent enhances fat storage after the maturation phase. AB - Arachidonic acid (AA) and the related prostanoids exert complex effects on the adipocyte differentiation depending on the culture conditions and life stages. Here, we investigated the effect of the pretreatment of cultured 3T3-L1 preadipocytes with exogenous AA during the differentiation phase without 3 isobutyl-1-methylxanthine (IBMX), a cAMP-elevating agent, on the storage of fats after the maturation phase. This pretreatment with AA stimulated appreciably adipogenesis after the maturation phase as evident with the up-regulated gene expression of adipogenic markers. The stimulatory effect of the pretreatment with AA was attenuated by the co-incubation with each of cyclooxygenase (COX) inhibitors. Among exogenous prostanoids and related compounds, the pretreatment with MRE-269, a selective agonist of the IP receptor for prostaglandin (PG) I2, strikingly stimulated the storage of fats in adipocytes. The gene expression analysis of arachidonate COX pathway revealed that the transcript levels of inducible COX-2, membrane-bound PGE synthase-1, and PGF synthase declined more greatly in cultured preadipocytes treated with AA. By contrast, the expression levels of COX-1, cytosolic PGE synthase, and PGI synthase remained constitutive. The treatment of cultured preadipocytes with AA resulted in the decreased synthesis of PGE2 and PGF2alpha serving as anti-adipogenic PGs although the biosynthesis of pro-adipogenic PGI2 was up-regulated during the differentiation phase. Moreover, the gene expression levels of EP4 and FP, the respective prostanoid receptors for PGE2 and PGF2alpha, were gradually suppressed by the supplementation with AA, whereas that of IP for PGI2 remained relatively constant. Collectively, these results suggest the predominant role of endogenous PGI2 in the stimulatory effect of the pretreatment of cultured preadipoccytes with AA during the differentiation phase without IBMX on adipogenesis after the maturation phase. PMID- 26928049 TI - Sub-patterns of food consumption and hyperglycemia in Mexican young people: a study by factor analysis. AB - BACKGROUND: The student population that is admitted to the University Juarez of Tabasco has poor healthy eating habits. Fasting glucose >=5.6 mmol/L was found in 10% of the students. OBJECTIVE: We wanted to identify the sub-pattern of their eating habits that could explain the hyperglycemia. DESIGN: A questionnaire on the feeding habits was applied to 3,559 first-year students, who were subjected to a blood analysis to determine biochemical markers in 2011. Based on the obtained questionnaire data, the factorial analysis was used for the statistical analysis. The Kaiser-Meyer-Olkin measure for sampling adequacy was used for validation. To determine eating habits, Varimax normalization with Kaiser was used. RESULTS: The number of students with euglycemia was 3,138, including 366 with values for prediabetes, and 55 with values for diabetes. After normalization using Varimax rotation with Kaiser, component 1 of participants with euglycemia included eight foods. The number of foods in component 1 of those participants with prediabetes was seven, and it diminished to four in those with fasting glucose >7 mmol/L. CONCLUSIONS: It was found that glucose levels increase in direct relation to the diminution in the number of selected foods. PMID- 26928050 TI - High Resolution Melting Analysis Targeting hsp70 as a Fast and Efficient Method for the Discrimination of Leishmania Species. AB - BACKGROUND: Protozoan parasites of the genus Leishmania cause a large spectrum of clinical manifestations known as Leishmaniases. These diseases are increasingly important public health problems in many countries both within and outside endemic regions. Thus, an accurate differential diagnosis is extremely relevant for understanding epidemiological profiles and for the administration of the best therapeutic protocol. METHODS/PRINCIPAL FINDINGS: Exploring the High Resolution Melting (HRM) dissociation profiles of two amplicons using real time polymerase chain reaction (real-time PCR) targeting heat-shock protein 70 coding gene (hsp70) revealed differences that allowed the discrimination of genomic DNA samples of eight Leishmania species found in the Americas, including Leishmania (Leishmania) infantum chagasi, L. (L.) amazonensis, L. (L.) mexicana, L. (Viannia) lainsoni, L. (V.) braziliensis, L. (V.) guyanensis, L. (V.) naiffi and L. (V.) shawi, and three species found in Eurasia and Africa, including L. (L.) tropica, L. (L.) donovani and L. (L.) major. In addition, we tested DNA samples obtained from standard promastigote culture, naturally infected phlebotomines, experimentally infected mice and clinical human samples to validate the proposed protocol. CONCLUSIONS/SIGNIFICANCE: HRM analysis of hsp70 amplicons is a fast and robust strategy that allowed for the detection and discrimination of all Leishmania species responsible for the Leishmaniases in Brazil and Eurasia/Africa with high sensitivity and accuracy. This method could detect less than one parasite per reaction, even in the presence of host DNA. PMID- 26928052 TI - TAK1 is involved in the autophagy process in retinal pigment epithelial cells. AB - Autophagy is an evolutionarily conserved mechanism for degrading long-lived or malfunctioning proteins and organelles, such as those resulting from oxidative stress. Several publications have demonstrated the importance of the autophagy process in the pathophysiology of dry age-related macular degeneration (AMD). Still, the mechanism underlying this process and its involvement in dry AMD are not fully characterized. Investigating the autophagy process in retinal pigment epithelial (RPE) cells, we identified transforming growth factor beta activated kinase 1 (TAK1) as a key player in the process. We found increased TAK1 phosphorylation in ARPE-19 and D407 cells treated with different inducers of autophagy, such as oxidative stress and rapamycin. Moreover, utilizing TAK1 specific inhibitor prior to oxidative stress or rapamycin treatment, we found significant reduction in LC3A/B-II expression. These results point at the involvement of TAK1 in the regulation of autophagy in RPE cells. This study suggests that aberrant activity of this kinase impairs autophagy and subsequently leads to alterations in the vitality of RPE cells. Proper activity of TAK1 may be essential for efficient autophagy, and crucial for the ability of RPE cells to respond to stress and dispose of damaged organelles, thus preventing or delaying retinal pathologies. PMID- 26928053 TI - General immunity and superadditivity of two-way Gaussian quantum cryptography. AB - We consider two-way continuous-variable quantum key distribution, studying its security against general eavesdropping strategies. Assuming the asymptotic limit of many signals exchanged, we prove that two-way Gaussian protocols are immune to coherent attacks. More precisely we show the general superadditivity of the two way security thresholds, which are proven to be higher than the corresponding one way counterparts in all cases. We perform the security analysis first reducing the general eavesdropping to a two-mode coherent Gaussian attack, and then showing that the superadditivity is achieved by exploiting the random on/off switching of the two-way quantum communication. This allows the parties to choose the appropriate communication instances to prepare the key, accordingly to the tomography of the quantum channel. The random opening and closing of the circuit represents, in fact, an additional degree of freedom allowing the parties to convert, a posteriori, the two-mode correlations of the eavesdropping into noise. The eavesdropper is assumed to have no access to the on/off switching and, indeed, cannot adapt her attack. We explicitly prove that this mechanism enhances the security performance, no matter if the eavesdropper performs collective or coherent attacks. PMID- 26928054 TI - Psychometric validation of the Italian version of the Reported and Intended Behaviour Scale (RIBS). AB - BACKGROUND: Many instruments have been developed and validated to assess the stigma associated with mental disorders and its various domains across different populations. To our knowledge, the Reported and Intended Behaviour Scale (RIBS) is the only validated questionnaire to analyse the presence of reported and intended stigmatising/discriminatory behaviours towards people with mental health problems in the general population. The aims of the study presented herein are to translate and validate the RIBS in Italian language and to adapt it to the Italian socio-cultural background (RIBS-I). METHOD: The RIBS considers reported and intended behaviours across four different domains: (1) living with, (2) working with, (3) living nearby and (4) continuing a relationship with someone with a mental health problem. The validation process included four phases: (1) translation/back translation of the questionnaire from English to Italian and vice versa; (2,3) face validity and reliability of RIBS-I; (4) description of model fit through confirmatory factor analysis. The questionnaire was administered to a sample of the general public via distribution in public places such as shopping centres, markets, squares, cinemas and other gathering places. Questionnaires were administered by trained mental health professionals. RESULTS: A total of 447 lay respondents were recruited. The mean age was 38.08 (s.d. = +/ 14.74) years. Fifty-seven per cent of the sample (n = 257) were female. The Cronbach alpha of RIBS-I was 0.83. All indices of model fit were above the reference values: Goodness of Fit Index (GFI) = 0.987 (GFI > 0.9); Adjusted Goodness of Fit Index (AGFI) = 0.975 (AGFI > 0.9); Comparative Fit Index (CFI) = 0.994 (CFI > 0.9); and Root-Mean-Square Error of Approximation (RMSEA) = 0.023 (RMSEA < 0.05). The chi 2 = 23.60 (df = 19; p = 0.21) and chi 2/df = 1.24 supported the model. CONCLUSIONS: The RIBS-I demonstrated good psychometric properties and it can be considered a useful tool to: (1) assess stigmatising (actual or potential) behaviours in the general population; (2) test the efficacy of anti-stigma campaigns and actions; (3) design further studies to better understand the relationship between the three different components of stigmatisation: knowledge, attitudes and behaviours. PMID- 26928051 TI - Astrocytic Ephrin-B1 Regulates Synapse Remodeling Following Traumatic Brain Injury. AB - Traumatic brain injury (TBI) can result in tissue alterations distant from the site of the initial injury, which can trigger pathological changes within hippocampal circuits and are thought to contribute to long-term cognitive and neuropsychological impairments. However, our understanding of secondary injury mechanisms is limited. Astrocytes play an important role in brain repair after injury and astrocyte-mediated mechanisms that are implicated in synapse development are likely important in injury-induced synapse remodeling. Our studies suggest a new role of ephrin-B1, which is known to regulate synapse development in neurons, in astrocyte-mediated synapse remodeling following TBI. Indeed, we observed a transient upregulation of ephrin-B1 immunoreactivity in hippocampal astrocytes following moderate controlled cortical impact model of TBI. The upregulation of ephrin-B1 levels in hippocampal astrocytes coincided with a decline in the number of vGlut1-positive glutamatergic input to CA1 neurons at 3 days post injury even in the absence of hippocampal neuron loss. In contrast, tamoxifen-induced ablation of ephrin-B1 from adult astrocytes in ephrin B1(loxP/y)ERT2-Cre(GFAP) mice accelerated the recovery of vGlut1-positive glutamatergic input to CA1 neurons after TBI. Finally, our studies suggest that astrocytic ephrin-B1 may play an active role in injury-induced synapse remodeling through the activation of STAT3-mediated signaling in astrocytes. TBI-induced upregulation of STAT3 phosphorylation within the hippocampus was suppressed by astrocyte-specific ablation of ephrin-B1 in vivo, whereas the activation of ephrin-B1 in astrocytes triggered an increase in STAT3 phosphorylation in vitro. Thus, regulation of ephrin-B1 signaling in astrocytes may provide new therapeutic opportunities to aid functional recovery after TBI. PMID- 26928056 TI - Reverse engineering the face space: Discovering the critical features for face identification. AB - How do we identify people? What are the critical facial features that define an identity and determine whether two faces belong to the same person or different people? To answer these questions, we applied the face space framework, according to which faces are represented as points in a multidimensional feature space, such that face space distances are correlated with perceptual similarities between faces. In particular, we developed a novel method that allowed us to reveal the critical dimensions (i.e., critical features) of the face space. To that end, we constructed a concrete face space, which included 20 facial features of natural face images, and asked human observers to evaluate feature values (e.g., how thick are the lips). Next, we systematically and quantitatively changed facial features, and measured the perceptual effects of these manipulations. We found that critical features were those for which participants have high perceptual sensitivity (PS) for detecting differences across identities (e.g., which of two faces has thicker lips). Furthermore, these high PS features vary minimally across different views of the same identity, suggesting high PS features support face recognition across different images of the same face. The methods described here set an infrastructure for discovering the critical features of other face categories not studied here (e.g., Asians, familiar) as well as other aspects of face processing, such as attractiveness or trait inferences. PMID- 26928057 TI - Toxic Epidermal Necrolysis Related to Paliperidone Palmitate: First Case Report. PMID- 26928055 TI - Pooling of continuous features provides a unifying account of crowding. AB - Visual crowding refers to phenomena in which the perception of a peripheral target is strongly affected by nearby flankers. Observers often report seeing the stimuli as "jumbled up," or otherwise confuse the target with the flankers. Theories of visual crowding contend over which aspect of the stimulus gets confused in peripheral vision. Attempts to test these theories have led to seemingly conflicting results, with some experiments suggesting that the mechanism underlying crowding operates on unbound features like color or orientation (Parkes, Lund, Angelucci, Solomon, & Morgan, 2001), while others suggest it "jumbles up" more complex features, or even objects like letters (Korte, 1923). Many of these theories operate on discrete features of the display items, such as the orientation of each line or the identity of each item. By contrast, here we examine the predictions of the Texture Tiling Model, which operates on continuous feature measurements (Balas, Nakano, & Rosenholtz, 2009). We show that the main effects of three studies from the crowding literature are consistent with the predictions of Texture Tiling Model. This suggests that many of the stimulus-specific curiosities surrounding crowding are the inherent result of the informativeness of a rich set of image statistics for the particular tasks. PMID- 26928058 TI - A novel polar-modified post-cross-linked resin and its enhanced adsorption to salicylic acid: Equilibrium, kinetics and breakthrough studies. AB - Improving the surface polarity is of significance for the post-cross-linked resins to enhance their adsorption to polar aromatic compounds. In the present study, we prepared a novel polar-modified post-cross-linked PDEpc_D by the Friedel-Crafts alkylation reaction and the amination reaction, the Brunauer Emmett-Teller (BET) surface area and pore volume increased significantly after the Friedel-Crafts alkylation reaction and the surface polarity improved greatly after the amination reaction. Batch adsorption showed that PDEpc_D possessed a much enhanced adsorption to salicylic acid as compared the precursors PDE and PDEpc as well as the non-polar post-cross-linked PDVBpc. The equilibrium data was characterized by the Freundlich model, pi-pi stacking, hydrogen bonding and static interaction were the possible driving forces. The adsorption was a fast process and the kinetic data obeyed the micropore diffusion model. Column adsorption-desorption experiments suggested that PDEpc_D was a potential candidate for adsorptive removal of salicylic acid from aqueous solution. PMID- 26928059 TI - Enhanced photoactivities of TiO2 particles induced by bio-inspired micro nanoscale substrate. AB - A silicon substrate with bio-inspired micro-nanoscale structure has been fabricated by wet etching, which is used as TiO2 particles supporting substrate and makes them recovery more easily. It has been shown that the structure facilitates TiO2 with large surface area and suppresses light reflection more effectively, which results in a high photocatalytic performance. The photocatalytic and stable performance has been applied on degrading methyl orange (MO). PMID- 26928060 TI - Sensitive analysis of simazine based on platinum nanoparticles on polyoxometalate/multi-walled carbon nanotubes. AB - In this report, a novel molecular imprinted voltammetric sensor based on glassy carbon electrode (GCE) modified with platinum nanoparticles (PtNPs) involved in a polyoxometalate (H3PW12O40, POM) functionalized multi-walled carbon nanotubes (MWCNs) sheets was prepared for the determination of simazine (SIM). The developed surfaces were characterized by using scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS) and X-ray diffraction (XRD) method. SIM imprinted GCE was prepared via electropolymerization process of 100mM pyrrole as monomer in the presence of 0.1M acetate buffer (pH 4.0) containing 25mM SIM. The linearity range and the detection limit of the developed method were calculated as 1.0*10(-10)-5.0*10( 9)M and 2.0*10(-11)M, respectively. In addition, the voltammetric sensor was applied to wastewater samples. The stability and reproducibility of the voltammetric sensor were also reported. PMID- 26928061 TI - The dynamic spreading of nanofluids on solid surfaces - Role of the nanofilm structural disjoining pressure. AB - Nanofluids comprising nanoparticle suspensions in liquids have significant industrial applications. Prior work performed in our laboratory on the spreading of an aqueous film containing nanoparticles displacing an oil droplet has clearly revealed that the structural disjoining pressure arises due to the layering of the nanoparticles normal to the confining plane of the film with the wedge profile. The pressure drives the nanofluid in the wedge film and the nanofluid spreads. We observed two distinct contact lines: the inner contact line, where the structural disjoining pressure dominates the Laplace capillary pressure, and the outer contact line, given by the Laplace equation prediction extrapolated to the solid substrate where the structural disjoining pressure contribution is negligible. We report here our results of the effects of several parameters, such as the nanoparticle concentration, liquid salinity, temperature, and the substrate contact angle, on the motion of the two contact lines and their effects on the detachment of the oil droplet. We also studied the equilibrated and non equilibrated oil/nanofluid phases, the time of adhesion of the oil droplet on the solid substrate and the drying time of the substrate. We employed the frictional model to predict the outer contact line velocity and our previous theoretical model (based on the structural disjoining pressure) to predict the inner contact line velocity. The theoretical predictions agreed quite well with the experimentally measured values of the velocities. Our experimental results showed that the motion of the inner contact line was accelerated by the increase in the nanoparticle concentration, temperature, and hydrophilicity of the substrate for the pre-equilibrated oil/nanofluid phases, which resulted in the faster detachment of the oil droplet. The speed of the two contact lines decreased upon the increase in the drying time of the substrate and the oil adhesion time on the substrate. The present results provide new insights into the complex spreading behavior of nanofluids on solid substrates. PMID- 26928062 TI - Polymer grafted hard carbon microspheres at an oil/water interface. AB - Pickering emulsions offer an established method of stabilizing oil-in-water emulsions as either an alternative to surfactants or as an additive together with surfactants, providing greater colloidal stability even at low particle concentrations. This work presents a novel experimental approach to study the influence of several system parameters on the effectiveness of Pickering emulsion systems. Specifically, a dodecane oil drop stabilized by hard carbon microspheres in an aqueous saline solution is used as a model system to obtain both quantitative and qualitative information on the effectiveness of the microspheres as a function of their surface wetting properties. The test setup, in which a macroscopic oil drop is brought into contact with a test surface in a controlled motion and environment, allows for several aspects of the test (for e.g., oil drop size, approach velocity, normal force, solution ionic strength, temperature, pH, and presence of surfactants) to be potentially controlled and studied precisely. To demonstrate the capabilities of the experimental set-up, hard carbon microspheres are modified with a poly(styrenesulfonate) shell through ATRP in order to tune the wettability of the particles through choice of polymer, which are then used to stabilize a dodecane oil drop in an aqueous saline solution. The particles effectively form a steric barrier preventing the spreading of an oil drop on hydrophobic surfaces and also preventing the coalescence of stabilized oil drops. PMID- 26928063 TI - Asymmetry of Drosophila ON and OFF motion detectors enhances real-world velocity estimation. AB - The reliable estimation of motion across varied surroundings represents a survival-critical task for sighted animals. How neural circuits have adapted to the particular demands of natural environments, however, is not well understood. We explored this question in the visual system of Drosophila melanogaster. Here, as in many mammalian retinas, motion is computed in parallel streams for brightness increments (ON) and decrements (OFF). When genetically isolated, ON and OFF pathways proved equally capable of accurately matching walking responses to realistic motion. To our surprise, detailed characterization of their functional tuning properties through in vivo calcium imaging and electrophysiology revealed stark differences in temporal tuning between ON and OFF channels. We trained an in silico motion estimation model on natural scenes and discovered that our optimized detector exhibited differences similar to those of the biological system. Thus, functional ON-OFF asymmetries in fly visual circuitry may reflect ON-OFF asymmetries in natural environments. PMID- 26928064 TI - Early hyperactivity and precocious maturation of corticostriatal circuits in Shank3B(-/-) mice. AB - Some autistic individuals exhibit abnormal development of the caudate nucleus and associative cortical areas, suggesting potential dysfunction of cortico-basal ganglia (BG) circuits. Using optogenetic and electrophysiological approaches in mice, we identified a narrow postnatal period that is characterized by extensive glutamatergic synaptogenesis in striatal spiny projection neurons (SPNs) and a concomitant increase in corticostriatal circuit activity. SPNs during early development have high intrinsic excitability and respond strongly to cortical afferents despite sparse excitatory inputs. As a result, striatum and corticostriatal connectivity are highly sensitive to acute and chronic changes in cortical activity, suggesting that early imbalances in cortical function alter BG development. Indeed, a mouse model of autism with deletions in Shank3 (Shank3B(-/ )) shows early cortical hyperactivity, which triggers increased SPN excitatory synapse and corticostriatal hyperconnectivity. These results indicate that there is a tight functional coupling between cortex and striatum during early postnatal development and suggest a potential common circuit dysfunction that is caused by cortical hyperactivity. PMID- 26928065 TI - Circadian rhythms in neuronal activity propagate through output circuits. AB - Twenty-four hour rhythms in behavior are organized by a network of circadian pacemaker neurons. Rhythmic activity in this network is generated by intrinsic rhythms in clock neuron physiology and communication between clock neurons. However, it is poorly understood how the activity of a small number of pacemaker neurons is translated into rhythmic behavior of the whole animal. To understand this, we screened for signals that could identify circadian output circuits in Drosophila melanogaster. We found that leucokinin neuropeptide (LK) and its receptor (LK-R) were required for normal behavioral rhythms. This LK/LK-R circuit connects pacemaker neurons to brain areas that regulate locomotor activity and sleep. Our experiments revealed that pacemaker neurons impose rhythmic activity and excitability on LK- and LK-R-expressing neurons. We also found pacemaker neuron-dependent activity rhythms in a second circadian output pathway controlled by DH44 neuropeptide-expressing neurons. We conclude that rhythmic clock neuron activity propagates to multiple downstream circuits to orchestrate behavioral rhythms. PMID- 26928067 TI - Dual-Energy CT-based Display of Bone Marrow Edema in Osteoporotic Vertebral Compression Fractures: Impact on Diagnostic Accuracy of Radiologists with Varying Levels of Experience in Correlation to MR Imaging. AB - Purpose To evaluate whether a dual-energy (DE) computed tomographic (CT) virtual noncalcium technique can improve the detection rate of acute thoracolumbar vertebral compression fractures in patients with osteoporosis compared with that at magnetic resonance (MR) imaging depending on the level of experience of the reading radiologist. Materials and Methods This retrospective study was approved by the institutional ethics committee. Informed consent was obtained from all patients. Forty-nine patients with osteoporosis who were suspected of having acute vertebral fracture underwent DE CT and MR imaging. Conventional linear blended CT scans and corresponding virtual noncalcium reconstructions were obtained. Five radiologists with varying levels of experience evaluated gray scale CT scans for the presence of fractures and their suspected age. Then, virtual noncalcium images were evaluated to detect bone marrow edema. Findings were compared with those from MR imaging (the standard of reference). Sensitivity and specificity analyses for diagnostic performance and matched pair analyses were performed on vertebral fracture and patient levels. Results Sixty-two fractures were classified as fresh and 52 as old at MR imaging. The diagnostic performance of all readers in the detection of fresh fractures improved with the addition of virtual noncalcium reconstructions compared with that with conventional CT alone. Although the diagnostic accuracy of the least experienced reader with virtual noncalcium CT (accuracy with CT alone, 61%; accuracy with virtual noncalcium technique, 83%) was within the range of that of the most experienced reader with CT alone, the latter improved his accuracy with the noncalcium technique (from 81% to 95%), coming close to that with MR imaging. The number of vertebrae rated as unclear decreased by 59%-90% or from 15-53 to 2-13 in absolute numbers across readers. The number of patients potentially referred to MR imaging decreased by 36%-87% (from 11-23 to 2-10 patients). Considering the gain in true decisions with the virtual noncalcium technique on a patient level, between 12 (most experienced reader) and 17 (least experienced reader) MR examinations could have been avoided. Conclusion The DE CT-based virtual noncalcium technique may enable depiction of bone marrow edema in thoracolumbar vertebral compression fractures in patients with osteoporosis, with good accordance with MR imaging when images are read by experienced radiologists. Although less experienced readers improved their diagnostic performance to some degree, the experienced reader's diagnostic performance approached that with MR imaging. ((c)) RSNA, 2016. PMID- 26928068 TI - Meta-analysis of the Correlation Between Interleukin-6 Promoter Polymorphism 174G/C and Interferon Regulatory Factor 4 rs12203592 Polymorphism With Skin Cancer Susceptibility. AB - Inflammation is a process whereby the immune system responds to a disease or injury. Chronic inflammation, however, has been linked to several types of cancers such as skin cancer. Molecular epidemiological studies were carried out in recent years evaluating interferon regulatory factor 4 (IRF4) rs12203592 and interleukin-6 (IL-6) gene -174G/C polymorphism associated with skin cancer risk for different groups of people. However, the results are still conflicting, not conclusive. We performed a meta-analysis to investigate the association between cancer susceptibility and IL-6 -174G/C (1130 cases and 1260 controls from 7 studies) and IRF4 rs12203592 polymorphisms (3879 cases and 6759 controls from 9 studies) in different inheritance models. We assess the strength of association of odds ratio (ORs), 95% confidence interval (CI). Overall, significantly elevated skin cancer risk was found when all studies were pooled into the meta analysis of IL-6 -174G/C (For GC vs. GG: OR = 1.28, 95% CI, 1.06-1.54, I = 0, Pheterogeneity = 0.816; for CC/GC vs. GG: OR = 1.26, 95% CI, 1.05-1.50, I = 0, Pheterogeneity = 0.618). However, for IRF4 rs12203592 polymorphism, significantly increased risk of skin cancer was observed in TT versus CC (OR = 1.99, 95% CI, 1.30-3.07, I = 76.7%, Pheterogeneity < 0.001) and in recessive model (OR = 1.91, 95% CI, 1.31-2.77, I = 69.9%, Pheterogeneity < 0.001). This meta-analysis indicates that the IL-6 gene -174G/C and IRF4 rs12203592 polymorphisms may be associated with an increased skin cancer risk. PMID- 26928069 TI - Review of Research Reporting Guidelines for Radiology Researchers. AB - Prior articles have reviewed reporting guidelines and study evaluation tools for clinical research. However, only some of the many available accepted reporting guidelines at the Enhancing the QUAlity and Transparency Of health Research Network have been discussed in previous reports. In this paper, we review the key Enhancing the QUAlity and Transparency Of health Research reporting guidelines that have not been previously discussed. The study types include diagnostic and prognostic studies, reliability and agreement studies, observational studies, analytical and descriptive, experimental studies, quality improvement studies, qualitative research, health informatics, systematic reviews and meta-analyses, economic evaluations, and mixed methods studies. There are also sections on study protocols, and statistical analyses and methods. In each section, there is a brief overview of the study type, and then the reporting guideline(s) that are most applicable to radiology researchers including radiologists involved in health services research are discussed. PMID- 26928066 TI - Chd7 cooperates with Sox10 and regulates the onset of CNS myelination and remyelination. AB - Mutations in CHD7, encoding ATP-dependent chromodomain helicase DNA-binding protein 7, in CHARGE syndrome lead to multiple congenital anomalies, including craniofacial malformations, neurological dysfunction and growth delay. Mechanisms underlying the CNS phenotypes remain poorly understood. We found that Chd7 is a direct transcriptional target of oligodendrogenesis-promoting factors Olig2 and Smarca4/Brg1 and is required for proper onset of CNS myelination and remyelination. Genome-occupancy analyses in mice, coupled with transcriptome profiling, revealed that Chd7 interacted with Sox10 and targeted the enhancers of key myelinogenic genes. These analyses identified previously unknown Chd7 targets, including bone formation regulators Osterix (also known as Sp7) and Creb3l2, which are also critical for oligodendrocyte maturation. Thus, Chd7 coordinates with Sox10 to regulate the initiation of myelinogenesis and acts as a molecular nexus of regulatory networks that account for the development of a seemingly diverse array of lineages, including oligodendrocytes and osteoblasts, pointing to previously uncharacterized Chd7 functions in white matter pathogenesis in CHARGE syndrome. PMID- 26928070 TI - Insulating phase at low temperature in ultrathin La0.8Sr0.2MnO3 films. AB - Metal-insulator transition is observed in the La0.8Sr0.2MnO3 thin films with thickness larger than 5 unit cells. Insulating phase at lower temperature appeared in the ultrathin films with thickness ranging from 6 unit cells to 10 unit cells and it is found that the Mott variable range hopping conduction dominates in this insulating phase at low temperature with a decrease of localization length in thinner films. A deficiency of oxygen content and a resulting decrease of the Mn valence have been observed in the ultrathin films with thickness smaller than or equal to 10 unit cells by studying the aberration corrected scanning transmission electron microscopy and electron energy loss spectroscopy of the films. These results suggest that the existence of the oxygen vacancies in thinner films suppresses the double-exchange mechanism and contributes to the enhancement of disorder, leading to a decrease of the Curie temperature and the low temperature insulating phase in the ultrathin films. In addition, the suppression of the magnetic properties in thinner films indicates stronger disorder of magnetic moments, which is considered to be the reason for this decrease of the localization length. PMID- 26928071 TI - White light generation using Forster resonance energy transfer between 3 hydroxyisoquinoline and Nile Red. AB - Simple composite films consisting of a polymer blended with organic emitters have the potential for broad-band "white" light emission that can be used for general lighting applications. In the present work, a simple mixture of 3 hydroxyisoquinoline (HIQ) with Nile Red (NR) in a polymeric matrix of polyvinyl alcohol (PVA) is used to generate white light through a non-radiative excitation energy transfer (NREET) mechanism. NREET between HIQ and NR doped in PVA films is investigated using a combination of steady state and time resolved fluorescence spectroscopic methods. It is observed that NR has very weak fluorescence in the PVA film upon excitation at 400 nm, but upon mixing NR with HIQ, sensitized emission of NR is observed with decreased emission of HIQ. The behavior of the sensitized emission of NR is consistent with Forster resonance energy transfer (FRET) between the donor HIQ and acceptor NR. By adjusting the relative fractions of HIQ and NR in the films, the extent of FRET could be regulated and the overall film emission color could be manipulated to enable overall "white" (CIE color coordinates 0.34, 0.38) emission. The films showed excellent photostability with 405 nm diode illumination, along with mechanical flexibility, suggesting good potential utility as a down converting element for lighting applications. PMID- 26928072 TI - Leaching potential of geogenic nickel in serpentine soils from Taiwan and Austria. AB - Serpentine soils may be natural sources of metal leaching and pollution. In this study, two contrasting serpentine soils from Taiwan and Austria were selected to evaluate the leaching potential of geogenic nickel (Ni). We applied selective sequential extractions and dissolution kinetics with three inorganic acids (HCl, HNO3, and H2SO4) and three organic acids (citric, acetic, and oxalic acids) in concentrations ranging from 0.05 to 10 mM to determine the release rate of Ni in the soils with respect to pH and acid types. Chlorite and serpentine were the major Ni-bearing minerals in the studied soils. Ni was dominantly bound in unavailable forms within these silicate minerals, but smaller fractions of acid soluble, Fe-Mn oxide-bound, and organically bound Ni represented more labile Ni sources in the soils. The release rate of Ni from the soils increased with decreasing pH in all acids. However, the organic acids caused stronger pH dependences than the inorganic acids, likely because of ligand-promoted dissolution. The maximum total rate of Ni dissolution occurred with citric acid in both soils. The dissolution of Ni strongly increased when the ionic strength in the background solutions increased. We observed marked differences in dissolution rates and ligand effects between the Austrian and Taiwanese soils, which reflect differences in labile Ni pools, especially in the organically bound fraction. Our results demonstrate that labile fractions control the leaching potential of Ni in serpentine soils and that Ni associated with soil organic matter may contribute to leaching at moderately acidic pH levels. PMID- 26928073 TI - Knowledge and attitudes about Ebola vaccine among the general population in Sierra Leone. AB - BACKGROUND: Clinical trials of Ebola vaccine are ongoing. Before it becomes commercially available, understanding the Ebola vaccine-related knowledge and attitude of the general population is imperative to developing an effective vaccine coverage strategy. METHODS: We conducted a survey including 400 participants from general communities of the West Area Rural District, Sierra Leone. Knowledge and attitudes about Ebola vaccine were investigated, and the determinants of having knowledge and a positive attitude toward accepting vaccination were identified. RESULTS: Over half (55.8%) of the participants were aware of Ebola vaccine. About 60% of the participants were willing to be study subjects if the Ebola vaccine clinical trial were conducted in their communities. Most of the participants (72.5%) were willing to take Ebola vaccination if it was free of charge. Given that the vaccination was not free, the proportion willing to pay a fee to take the vaccination declined dramatically to 26.6%. Using a forward step-wise logistic model, monthly salary was identified as the single determinant (OR for every 100,000 Leones increase: 1.17, 95%CI: 1.04-1.31) for awareness of Ebola vaccine, which was identified as the determinant (OR: 1.88, 95%CI: 1.17-3.02) for free vaccination uptake willingness. The combination of monthly salary, monthly average income of family members and their interaction was found to be associated with charged vaccination uptake willingness. DISCUSSION: Measures are still needed to promote the Ebola vaccine awareness and knowledge updating. Free or low-priced vaccine could increase the vaccination acceptability of the general community population significantly. PMID- 26928074 TI - A randomized, observer-blind Phase Ib study to identify formulations and vaccine schedules of a trivalent Group B Streptococcus vaccine for use in non-pregnant and pregnant women. AB - BACKGROUND: Group B streptococcus (GBS) is a leading cause of sepsis and meningitis in early infancy. Substantial data demonstrate that women with higher levels of circulating antibody against the capsular polysaccharide (CPS) deliver infants at reduced risk of GBS infection, which serves as the basis for vaccine design. This study evaluates two different dosages, two injection schedules and three formulations of an investigational trivalent (serotypes Ia, Ib and III) CRM197-glycoconjugate GBS vaccine in healthy, non-pregnant women. METHODS: 678 healthy non-pregnant women received one or two injections of one of two dosages (5/5/5 MUg or 20/20/20 MUg) of the investigational vaccine, formulated with or without aluminum hydroxide (Enrollment Group 1), or with full or half dosages of MF59((r)) (Enrollment Group 2); or a placebo (Enrollment Groups 1 and 2). Geometric mean serotype-specific antibody concentrations (GMCs) at Days 61 (Enrollment Group 1) and 361 (both Groups) were analyzed to select a formulation suitable for pregnant or non-pregnant women, respectively. Solicited adverse reactions were recorded up to Day 7 and adverse events (AEs) were recorded throughout the study. RESULTS: Rates of reported AEs were similar across all groups. Higher rates of local reactogenicity were seen in adjuvanted vaccine groups compared with non-adjuvanted vaccine (or placebo) groups. All vaccine groups elicited higher GMCs than placebo; differences between treatments were not statistically significant, indicating no additional potential benefit of higher antigen content, addition of adjuvant, or a second dose. CONCLUSIONS: All GBS vaccine formulations induced a persistent antibody response and showed similar immunogenicity profiles (NCT01150123). PMID- 26928075 TI - Characterizing a psychiatric symptom dimension related to deficits in goal directed control. AB - Prominent theories suggest that compulsive behaviors, characteristic of obsessive compulsive disorder and addiction, are driven by shared deficits in goal-directed control, which confers vulnerability for developing rigid habits. However, recent studies have shown that deficient goal-directed control accompanies several disorders, including those without an obvious compulsive element. Reasoning that this lack of clinical specificity might reflect broader issues with psychiatric diagnostic categories, we investigated whether a dimensional approach would better delineate the clinical manifestations of goal-directed deficits. Using large-scale online assessment of psychiatric symptoms and neurocognitive performance in two independent general-population samples, we found that deficits in goal-directed control were most strongly associated with a symptom dimension comprising compulsive behavior and intrusive thought. This association was highly specific when compared to other non-compulsive aspects of psychopathology. These data showcase a powerful new methodology and highlight the potential of a dimensional, biologically-grounded approach to psychiatry research. PMID- 26928077 TI - Elective central node dissection: Comparison of open to minimally invasive video assisted approach. AB - OBJECTIVES/HYPOTHESIS: Compare outcomes of concomitant primary thyroidectomy with elective central neck dissection (CND) by the standard open versus minimally invasive video-assisted (MIVA) approach. STUDY DESIGN: Case series chart review, single institution, tertiary referral center. METHODS: Current Procedural Terminology code 60252 was used to identify patients undergoing CND from February 2005 through June 2012. Therapeutic CND and revision cases were excluded. The MIVA approach was performed in patients with low-risk thyroid carcinoma (cT1 or 2, cN0). Primary outcomes included nodal yield and complications, and secondary outcomes included recurrence. RESULTS: Of 87 eligible patients, 38 were open and 49 were MIVA. The MIVA group was more likely female (88% vs. 68%, P = .03), but groups were similar in age (46.0 vs. 48.6 mean years, P = .37) and percentage of unilateral dissection (69.4% vs. 71.0%, P = .86). The MIVA group was more often pT1 or 2 (86.9% vs. 76.4%, P = .02). Pathological node positivity was 40% overall and not significantly different between groups (43.5% vs. 35.3%, P = .46). Nodal yield was similar between groups (6.4 vs. 6.8, P = .73). Transient recurrent laryngeal nerve paralysis rates were similar (4.1% vs. 2.6%, P = .71). Transient hypoparathyroidism (postanesthesia care unit parathyroid hormone <=15 pg/mL) was lower in the MIVA group but not statistically significant (29.2% vs. 45.2%, P = .15). No patients experienced permanent hypoparathyroidism or developed clinically detectable structural recurrence. Rates of biochemical response were similar (any thyroglobulin >1 ng/dL) (13.8% vs. 8.0%, P = .86). CONCLUSIONS: Concomitant MIVA thyroidectomy with elective CND appears to be a safe and effective alternative to the open approach for low-risk thyroid carcinoma with similar nodal yield, complications, and recurrence. LEVEL OF EVIDENCE: 4 Laryngoscope, 126:1715-1718, 2016. PMID- 26928076 TI - Translational control of nicotine-evoked synaptic potentiation in mice and neuronal responses in human smokers by eIF2alpha. AB - Adolescents are particularly vulnerable to nicotine, the principal addictive component driving tobacco smoking. In a companion study, we found that reduced activity of the translation initiation factor eIF2alpha underlies the hypersensitivity of adolescent mice to the effects of cocaine. Here we report that nicotine potentiates excitatory synaptic transmission in ventral tegmental area dopaminergic neurons more readily in adolescent mice compared to adults. Adult mice with genetic or pharmacological reduction in p-eIF2alpha-mediated translation are more susceptible to nicotine's synaptic effects, like adolescents. When we investigated the influence of allelic variability of the Eif2s1 gene (encoding eIF2alpha) on reward-related neuronal responses in human smokers, we found that a single nucleotide polymorphism in the Eif2s1 gene modulates mesolimbic neuronal reward responses in human smokers. These findings suggest that p-eIF2alpha regulates synaptic actions of nicotine in both mice and humans, and that reduced p-eIF2alpha may enhance susceptibility to nicotine (and other drugs of abuse) during adolescence. PMID- 26928078 TI - Argatroban monitoring: aPTT versus chromogenic assay. PMID- 26928079 TI - Fused coarse-grained model of aromatic ionic liquids and their behaviour at electrodes. AB - A fused coarse-grained model of aromatic ionic liquids 1-alkyl-3 methylimidazoliums tetrafluoroborate ([CnMIM(+)][BF4(-)]) has been constructed. Structural and dynamical properties calculated from our model are compared with experimental data as well as with corresponding results from simulations of other suggested models. Specifically, we adopt a fused-sphere coarse-grained model for cations and anions. This model is utilized to study structure and differential capacitance in models of flat and porous carbon electrodes. We find that the capacitance varies with pore size, in a manner that is related to the packing of ions inside the pore. For very narrow pores, diffusion is slow and the establishment of thermodynamic equilibrium may exceed the practical limits for our molecular dynamics simulations. PMID- 26928080 TI - Validation of a Dutch version of the Geriatric Oral Health Assessment Index (GOHAI-NL) in care-dependent and care-independent older people. AB - BACKGROUND: The GOHAI is a frequently used instrument to measure oral health related quality of life (OHRQoL) of adults, in particular older people. The aim of this study was to translate the original English version of the GOHAI into a Dutch version (GOHAI-NL), and to test the validity and reliability of the GOHAI NL in care-independent and care-dependent older people. METHODS: The GOHAI questionnaire was translated into Dutch, discussed by an expert panel, back translated to the original, pilot-tested and assessed for cognitive and conceptual equivalence. The resulting GOHAI-NL was tested in a groups of care independent (Group A, n = 109, mean age 73.1 +/- 5.4 years) and care-dependent (Group B, n = 118, mean age 85.6 +/- 7.0. years) cognitively alert people of 65 years and over. Psychometric properties including reliability (internal consistency, item-total, item-dimension, dimension-total, inter-item correlation, and test-retest stability), and validity (convergent, discriminant, known-group), and floor and ceiling effects were assessed. RESULTS: Internal consistency was confirmed by Cronbach's alphas of 0.86 (group A) and 0.80 (group B). Item-total score correlations were between 0.4 and 0.7 except for item 3 in group A (0.34) and B (0.08) and for item 12 in group A (0.20). Item-dimension and dimension total correlations were between 0.30 and 0.78 and around 0.7 respectively for the dimensions 'physical functioning' and 'psychosocial functioning', but lower for the dimension 'pain and discomfort' with item-dimension correlations between 0.13 and 0.44. Average inter-item correlations were 0.34 +/- 0.11 (group A) and 0.33 +/- 0.08 (group B). Test-retest correlation of the total score (GOHAI-ADD) was 0.88 in group A (ICCs: 0.62 - 0.88) and 0.93 in group B (ICCs: 0.64 - 0.91). Significant correlations in the expected direction were found between GOHAI and most oral health-related variables except for presence of caries in group A, and perceived general health, prosthodontic status and number of natural teeth in group B. No floor or ceiling effects were detected at GOHAI-ADD level; however ceiling effects did occur at dimension level. CONCLUSION: The GOHAI-NL has satisfactory reliability and validity and can be used to measure OHRQoL in Dutch care-dependent and care-independent older people. PMID- 26928082 TI - Research Enhances and Informs Gerontology and Geriatrics Education and Practice. PMID- 26928081 TI - Toxoplasma gondii infection in pork produced in France. AB - The aim of this study was to assess the seroprevalence of the Toxoplasma gondii parasite in pork produced in France, and to determine infection risk factors. An innovative survey was designed based on annual numbers of slaughtered pigs from intensive and outdoor farms in France. A total of 1549 samples of cardiac fluids were collected from pig hearts to determine seroprevalence using a Modified Agglutination Test. Of those, 160 hearts were bio-assayed in mice to isolate live parasites. The overall seroprevalence among fattening pigs was 2.9%. The adjusted seroprevalence in pigs from intensive farms was 3.0%; the highest in sows (13.4%); 2.9% in fattening pigs and 2.6% in piglets. Adjusted seroprevalence in fattening animals from outdoor farms was 6.3%. Strains were isolated from 41 animals and all were genotyped by Restriction Fragment Length Polymorphism as type II. Risk-factor analysis showed that the risk of infection was more than three times higher for outdoor pigs, and that sows' risk was almost five times higher than that of fattening animals. This study provides further evidence of extensive pork infection with T. gondii regardless of breeding systems, indicating that farm conditions are still insufficient to guarantee 'Toxoplasma free pork'. PMID- 26928084 TI - Aggregation Kinetics of Higher-Order Fullerene Clusters in Aquatic Systems. AB - The aggregation kinetics of nC60 and higher-order fullerene (HOF) clusters, i.e., nC70, nC76, and nC84, was systematically studied under a wide range of mono- (NaCl) and divalent (CaCl2) electrolytes and using time-resolved dynamic light scattering. Suwanee River Humic Acid (SRHA) was also used to determine the effect of natural macromolecules on nHOF aggregation. An increase in electrolyte concentration resulted in electrical double-layer compression of the negatively charged fullerene clusters, and the nC60s and nHOFs alike displayed classical Derjaguin-Landau-Verwey-Overbeek (DLVO) type interaction. The critical coagulation concentration (CCC) displayed a strong negative correlation with the carbon number in fullerenes and was estimated as 220, 150, 100, and 70 mM NaCl and 10, 12, 6, and 7.5 mM CaCl2 for nC60, nC70, nC76, and nC84, respectively. The aggregation mechanism (i.e., van der Waals interaction domination) was enumerated via molecular dynamics simulation and modified DLVO model. The presence of SRHA (2.5 mg TOC/L) profoundly influenced the aggregation behavior by stabilizing all fullerene clusters, even at a 100 mM NaCl concentration. The results from this study can be utilized to predict aggregation kinetics of nHOF clusters other than the ones studied here. The scaling factor for van der Waals interaction can also be used to model nHOF cluster interaction. PMID- 26928085 TI - Multiple neural signatures of social proof and deviance during the observation of other people's preferences. AB - Detecting one's agreement with or deviation from other people, a key principle of social cognition, relies on neurocognitive mechanisms involved in reward processing, mismatch detection, and attentional orienting. Previous studies have focused on explicit depictions of the (in)congruency of individual and group judgments. Here, we report data from a novel experimental paradigm in which participants first rated a set of images and were later simply confronted with other individuals' ostensible preferences. Participants strongly aligned their judgments in the direction of other people's deviation from their own initial rating, which was neither an effect of regression toward the mean nor of evaluative conditioning (Experiment 1). Most importantly, we provide neurophysiological evidence of the involvement of fundamental cognitive functions related to social comparison (Experiment 2), even though our paradigm did not overly boost this process. Mismatches, as compared to matches, of preferences were associated with an amplitude increase of a broadly distributed N400-like deflection, suggesting that social deviance is represented in the human brain in a similar way as conflicts or breaches of expectation. Also, both early (P2) and late (LPC) signatures of attentional selection were significantly modulated by the social (mis)match of preferences. Our data thus strengthen and valuably extend previous findings on the neurocognitive principles of social proof. PMID- 26928086 TI - Fabrication of Semiordered Nanopatterned Diamond-like Carbon and Titania Films for Blood Contacting Applications. AB - Biomaterials with the ability to interface with, but not activate, blood components are essential for a multitude of medical devices. Diamond-like carbon (DLC) and titania (TiO2) have shown promise for these applications; however, both support platelet adhesion and activation. This study explored the fabrication of nanostructured DLC and TiO2 thin film coatings using a block copolymer deposition technique that produced semiordered nanopatterns with low surface roughness (5-8 nm Rrms). These surfaces supported fibrinogen and plasma protein adsorption that predominantly adsorbed between the nanofeatures and reduced the overall surface roughness. The conformation of the adsorbed fibrinogen was altered on the nanopatterned surfaces as compared with the planar surfaces to reveal higher levels of the platelet binding region. Planar DLC and TiO2 coatings supported less platelet adhesion than nanopatterned DLC and TiO2. However, platelets on the nanopatterned DLC coatings were less spread indicating a lower level of platelet activation on the nanostructured DLC coatings compared with the planar DLC coatings. These data indicated that nanostructured DLC coatings may find application in blood contacting medical devices in the future. PMID- 26928087 TI - Expression of galanin and its receptors are perturbed in a rodent model of mild, blast-induced traumatic brain injury. AB - The symptomatology, mood and cognitive disturbances seen in post-traumatic stress disorder (PTSD) and mild blast-induced traumatic brain injury (mbTBI) overlap considerably. However the pathological mechanisms underlying the two conditions are currently unknown. The neuropeptide galanin has been suggested to play a role in the development of stress and mood disorders. Here we applied bio- and histochemical methods with the aim to elucidate the nature of any changes in the expression of galanin and its receptors in a rodent model of mbTBI. In situ hybridization and quantitative polymerase chain reaction studies revealed significant, injury-induced changes, in some cases lasting at least for one week, in the mRNA levels of galanin and/or its three receptors, galanin receptor 1-3 (GalR1-3). Such changes were seen in several forebrain regions, and the locus coeruleus. In the ventral periaqueductal gray GalR1 mRNA levels were increased, while GalR2 were decreased. Analysis of galanin peptide levels using radioimmunoassay demonstrated an increase in several brain regions including the locus coeruleus, dorsal hippocampal formation and amygdala. These findings suggest a role for the galanin system in the endogenous response to mbTBI, and that pharmacological studies of the effects of activation or inhibition of different galanin receptors in combination with functional assays of behavioral recovery may reveal promising targets for new therapeutic strategies in mbTBI. PMID- 26928088 TI - Towards a patient-oriented treatment of COPD. PMID- 26928089 TI - Mathematical Modeling of Therapy-induced Cancer Drug Resistance: Connecting Cancer Mechanisms to Population Survival Rates. AB - Drug resistance significantly limits the long-term effectiveness of targeted therapeutics for cancer patients. Recent experimental studies have demonstrated that cancer cell heterogeneity and microenvironment adaptations to targeted therapy play important roles in promoting the rapid acquisition of drug resistance and in increasing cancer metastasis. The systematic development of effective therapeutics to overcome drug resistance mechanisms poses a major challenge. In this study, we used a modeling approach to connect cellular mechanisms underlying cancer drug resistance to population-level patient survival. To predict progression-free survival in cancer patients with metastatic melanoma, we developed a set of stochastic differential equations to describe the dynamics of heterogeneous cell populations while taking into account micro environment adaptations. Clinical data on survival and circulating tumor cell DNA (ctDNA) concentrations were used to confirm the effectiveness of our model. Moreover, our model predicted distinct patterns of dose-dependent synergy when evaluating a combination of BRAF and MEK inhibitors versus a combination of BRAF and PI3K inhibitors. These predictions were consistent with the findings in previously reported studies. The impact of the drug metabolism rate on patient survival was also discussed. The proposed model might facilitate the quantitative evaluation and optimization of combination therapeutics and cancer clinical trial design. PMID- 26928091 TI - A novel ubiquitin-protein ligase E3 functions as a modulator of immune response against lipopolysaccharide in Pacific oyster, Crassostrea gigas. AB - Ubiquitination is an important post-translational protein modification and plays a crucial role in various processes such as cell cycle, signal transduction, and transcriptional regulation. In the present study, a novel ubiquitin (Ub)-protein ligase E3 (designed as CgE3Rv1) was identified from Crassostrea gigas, and its ubiquitination regulation in the immune response against lipopolysaccharide (LPS) stimulation was investigated. The open reading frame of CgE3Rv1 gene was of 1455 bp encoding a polypeptide of 484 amino acids with the predicted molecular mass of 54.89 kDa. There were two transmembrane regions and a RING-variant (RINGv) domain identified in CgE3Rv1. CgE3Rv1 shared similar C4HC3 zinc-finger-like motif with those RINGv domain Ub-protein ligases E3s identified from vertebrates and invertebrates, and it was closely clustered with the membrane-associated RING-CH2 (MARCH2) Ub-protein ligases E3s in the phylogenetic tree. The mRNA transcript of CgE3Rv1 was highest expressed in gonads and hemolymph (p < 0.05), and its mRNA expression level in hemocytes was significantly increased at 6 h (p < 0.01) after the stimulation of LPS, while the up-regulated mRNA expression was significantly decreased (p < 0.01) after acetylcholine stimulation. No significant changes of CgE3Rv1 expression were observed after peptidoglycan or mannan stimulation. Immunohistochemistry and in situ hybridization assays revealed that CgE3Rv1 protein and mRNA were dominantly distributed in the gonad. In the hemocytes, CgE3Rv1 was mainly located around the nucleus, and slightly distributed in the cytoplasm and on the cell membrane. Recombinant CgE3Rv1 RINGv domain protein (rCgE3Rv1-RINGv) was confirmed to activate the Ub reaction system in vitro with the aid of Ub-activating enzyme E1 and Ub-conjugating enzyme E2. These results demonstrated that CgE3Rv1 was an Ub-protein ligase E3, which was involved in the immune response against LPS and the interaction with cell surface signal molecules of neuroendocrine-immune system in oysters. PMID- 26928092 TI - Association Between Patient and Emergency Department Operational Characteristics and Patient Satisfaction Scores in a Pediatric Population. AB - BACKGROUND: Emergency departments (EDs) are seeing an increase in the importance of patient satisfaction scores, yet little is known about their association with patient and operational characteristics. OBJECTIVES: This study aimed to identify patient and operational characteristics associated with patient satisfaction scores. METHODS: This was a retrospective analysis of data from Press Ganey patient satisfaction surveys of pediatric patients (<18 years) and their families, discharged from the ED of a single, academic, pediatric ED from December 2009 to May 2013. A linear mixed-effects regression model was used to identify significant associations while taking the clustering within patients and physicians into account. Outcome variables included scores for overall experience (0-10), wait time to be seen by a provider (0-100), and likelihood to recommend (0-100). The ED characteristics considered included daily census, proportion of left without being seen, average length of stay (LOS), and total boarding hours, as well as time of day by shift, door-to-room time, and discharge LOS. Patient characteristics included patient age, sex, race, person completing survey, survey language, survey method (mailed or online), payer type, mode of arrival, distance to hospital, weekend or weekday visit, and difference of patient-reported LOS to actual LOS. Only statistically significant variables were included in the final model. RESULTS: A total of 810 pediatric surveys were included for analysis. The overall mean (SD) was 8.7 (2.0) for overall experience, 84.0 (23.5) for waiting time to be seen by a provider, and 90.1 (22.2) for likelihood to recommend. The score for overall experience was highly correlated with likelihood to recommend (r = 0.90) and less strongly correlated with score for waiting time (r = 0.58). In the final models, increased door-to-room time was associated with a significant decrease in scores for all 3 outcome variables. In addition, a difference between perceived and actual LOS (>2 hours) was significantly associated with lower scores in overall experience and likelihood to recommend, whereas surveys completed online had higher scores for waiting time to see a provider compared with mailed. CONCLUSIONS: Emergency departments looking to increase satisfaction scores should focus efforts on decreasing door-to-room times. PMID- 26928090 TI - Increased susceptibility to metabolic dysregulation in a mouse model of Alzheimer's disease is associated with impaired hypothalamic insulin signaling and elevated BCAA levels. AB - INTRODUCTION: Epidemiologic studies have demonstrated an association between diabetes and dementia. Insulin signaling within the brain, in particular within the hypothalamus regulates carbohydrate, lipid, and branched chain amino acid (BCAA) metabolism in peripheral organs such as the liver and adipose tissue. We hypothesized that cerebral amyloidosis impairs central nervous system control of metabolism through disruption of insulin signaling in the hypothalamus, which dysregulates glucose and BCAA homeostasis resulting in increased susceptibility to diabetes. METHODS: We examined whether APP/PS1 mice exhibit increased susceptibility to aging or high-fat diet (HFD)-induced metabolic impairment using metabolic phenotyping and insulin-signaling studies. RESULTS: APP/PS1 mice were more susceptible to high-fat feeding and aging-induced metabolic dysregulation including disrupted BCAA homeostasis and exhibited impaired hypothalamic insulin signaling. DISCUSSION: Our data suggest that AD pathology increases susceptibility to diabetes due to impaired hypothalamic insulin signaling, and that plasma BCAA levels could serve as a biomarker of hypothalamic insulin action in patients with AD. PMID- 26928093 TI - After-Hours Call Center Triage of Pediatric Head Injury: Outcomes After a Concussion Initiative. AB - OBJECTIVE: The aim of the study was to characterize referral patterns and medical outcomes of children with head injury triaged by an after-hours call center of a large urban pediatric network, both before and after an institutional concussion initiative. The initiative included a revised call center triage algorithm referring patients with a suspected concussion to see a primary care provider (PCP) within 24 hours, concussion-specific continuing education for medical providers, and a new concussion information Web site. METHODS: Patients aged 5 to 18 years with head injury using the after-hours call center were identified by retrospective review of electronic medical records before (2011) and after (2012) the initiative. A random 50% sample was taken from each year for further analysis. RESULTS: A total of 127 and 159 eligible patient encounters were randomly selected from 2011 to 2012, respectively. From 2011 to 2012, PCP referrals significantly increased from 7% (95% confidence interval [CI], 4%-13%) to 38% (95% CI, 31%-45%), P < 0.001. Concussion diagnoses also significantly increased from 35% (95% CI, 27%-44%) to 58% (95% CI, 50%-66%), P < 0.001. Emergency department referrals and head computed tomography scans decreased but the differences were not statistically significant. No patients had intracranial injury on computed tomography. Most injuries were not sports related. CONCLUSIONS: After an institutional concussion initiative including implementation of a revised head trauma telephone triage algorithm, more head injuries were evaluated by PCPs and more concussions were ultimately diagnosed without an increase in emergency department referrals. Clinicians can benefit from continuing education and infrastructure to aid in initial concussion diagnosis and management. PMID- 26928095 TI - Circulating Endothelial Cells and Endothelial Progenitor Cells in Pediatric Sepsis. AB - OBJECTIVES: The aim of the study was to measure the number of circulating endothelial cells (CECs) and circulating endothelial progenitor cells (CEPs) in pediatric patients with sepsis and correlating it with the severity of the disease and its outcome. METHODS: The study included 19 children with sepsis, 26 with complicated sepsis, and 30 healthy controls. The patients were investigated within 48 hours of pediatric intensive care unit admission together with flow cytometric detection of CECs and CEPs. RESULTS: The levels of both CECs and CEPs were significantly higher in patient with sepsis and complicated sepsis than the controls. The levels of CECs were higher in patients with complicated sepsis, whereas the levels of CEPs were lower in patients with complicated sepsis. Comparing the survival and nonsurvival septic patients, the levels of CEPs were significantly higher in the survival than in nonsurvival patients, whereas the levels of CECs were significantly lower in the survival than in nonsurvival patients. Serum albumin was higher in survival than in nonsurvival patients. CONCLUSIONS: Estimation of CECs and CEPs and their correlation with other parameters such as serum albumen could add important information regarding prognosis in septic pediatric patients. PMID- 26928094 TI - Oral Ambulatory Treatment of Acute Osteomyelitis in Children: A Case-Control Study. AB - The treatment of acute hematogenous osteomyelitis has evolved in recent years to a shorter parenteral treatment with an early switch to the oral route. Current publications recommend a 2- to 4-day parenteral treatment before the oral switch. We retrospectively analyzed a series of 45 children aged 1 to 11 years and treated in our department for acute osteomyelitis without severity criterion. Nineteen of 45 patients were treated by an exclusive ambulatory oral treatment by amoxicillin and clavulanic acid. Twenty six of 45 patients had a 2- to 4-day parenteral treatment before the oral switch. The minimum follow-up was 6 months. The primary endpoint was a clinical, radiographic, and biologic healing, 6 months after the beginning of the treatment. The secondary endpoints evaluated were the length of hospitalization, the total duration of treatment, and the type of antibiotic used. On the primary endpoint, we did not find any significant difference between the 2 treatments (P = 0.38). On the duration of treatment, we found a significant difference (P = 0.049) in favor of oral treatment. The ambulatory oral treatment by amoxicillin and clavulanic acid seems to be a valid alternative to the classical parenteral then oral sequence in the treatment of acute hematogenous osteomyelitis in children without severity criterion. PMID- 26928097 TI - Traumatic Rupture of Choledochal Cyst in Children: Use of Computed Tomography in the Emergency Department. AB - The case of an 11-year-old girl who developed acute abdomen after an accidental fall over an iron bar is reported to discuss the diagnostic features and treatment options for traumatic rupture of a choledochal cyst (CC) in children. The patient was admitted to the emergency department with complaints of vomiting and abdominal pain. Physical examination revealed tenderness at the right upper quadrant of the abdomen. Computed tomography findings revealed a rupture of a type IV CC and laceration of the liver. Cholecystectomy, total excision of the cyst, and hepaticojejunostomy were performed. Traumatic rupture of a CC is extremely rare in children, and only 2 cases have been reported. Because patients can be misdiagnosed as experiencing liver hematoma, computed tomography should be performed for all patients with free fluid in the abdomen and cystic mass on the initial evaluation. PMID- 26928096 TI - Assessment of 17 Pediatric Cases With Colchicine Poisoning in a 2-Year Period. AB - AIM: The aim of the study is to discuss clinical effects, treatments, and outcomes of pediatric colchicine poisoning. METHOD: This study was designed as an observational case series study. The medical records of children aged between 0 and 18 years, who were hospitalized for colchicine poisoning at the Department of Pediatric Intensive Care Unit, Cumhuriyet University Faculty of Medicine, between January 2010 and January 2012, were retrospectively evaluated. RESULTS: We presented 17 children with colchicine poisoning. The mean (SD, range) age of patients was 71.5 (69.19, 18-204) months. The period to apply to the hospital after taking the medications was 7.3 hours (7.97, 30 minutes-26 hours) on average. The use of colchicine was due to diagnosis of Familial Mediterranean fever (FMF) in the families of 8 patients, diagnosis of Behcet disease in 1 patient's father, diagnosis of Behcet disease in 1 patient herself, and diagnosis of FMF in 6 patients themselves. Thirteen patients had taken colchicine at the dose of less than 0.5 mg/kg known as subtoxic and 1 patient had taken colchicine at the dose of greater than 0.8 mg/kg, and doses taken by 3 patients were not known. Fourteen patients (82.4%) had involuntary drug intake. Fifty percent of them were symptomatic at the moment of application and all had gastrointestinal complaints. All patients were observed in intensive care unit upon first admission and received supportive care. One of patients showed total alopecia, one showed leucocytosis, and another one showed acute abdomen picture. None of the patients showed mortality. CONCLUSIONS: Mortality of colchicine toxicity is high and quick assessment is absolutely required. In regions where FMF is common and the use of colchicine is high, clinicians should pay attention to symptoms and findings related to colchicine intoxication and keep them in mind in differential diagnosis. PMID- 26928098 TI - An Unexpected Guest: A Case of Cutaneous Furuncular Myiasis: The 2013 PEMpix Photo Competition Winner. AB - Dermatobia hominis, also known as the botfly, is a parasitic infestation commonly found in Central and South America. In humans, this usually presents as cutaneous furuncular myiasis, after the larvae become embedded in the skin. This produces a local inflammatory reaction, which may mimic cellulitis; however, definitive treatment requires removal of the botfly larvae. This infestation is uncommon in the United States but should remain high on the differential diagnosis of returning travelers presenting with cutaneous lesions, as seen in the reported case of a teenager after return from Central America. PMID- 26928099 TI - Complex Regional Pain Type 1. AB - Complex regional pain syndrome is increasingly recognized in the pediatric population. Owing to the nature of presentation with pain, many of these children present to the emergency setting at different stages of the syndrome with or without numerous prior interactions with health professionals. Complex regional pain syndrome type 1 (CRPS1) is a clinical syndrome characterized by amplified musculoskeletal limb pain that is out of proportion to the history and physical findings, or pain due to non-noxious stimuli (allodynia/hyperalgesia), and accompanied by one or more signs of autonomic dysfunction. Differential diagnosis may include significant trauma (eg, fractures), inflammatory conditions, malignancies, and systemic illness. The diagnosis is clinical. The treatment goals for CRPS1 are restoration of function and relief of pain. Education, physical, and occupational therapy with psychotherapy and defined goals of achievement with reward are the mainstay of treatment for this population. Most children with CRPS1 will have a favorable outcome. PMID- 26928101 TI - Femur Fracture Diagnosis and Management Aided by Point-of-Care Ultrasonography. AB - We describe a point-of-care ultrasonography to facilitate diagnosis of a femur fracture in a 13-year-old adolescent boy. Rapid detection of the fracture, which was not possible by physical examination alone, permitted immediate stabilization of the leg with traction, rapid communication with orthopedic surgeons, and facilitated analgesic therapy before transport and movement to obtain radiographs. PMID- 26928102 TI - Pediatric Resuscitation: Do We Maintain Adequate Skills? AB - Adequate skills and knowledge is necessary in pediatric cardiopulmonary resuscitation. We conducted a study to evaluate the current status of resuscitation knowledge and skills among the pediatric medical and nursing staff at the Royal London Hospital, London. PMID- 26928103 TI - A 17-Year-Old Girl With Cough--Pulseless After Drug Overdose. Sodium benzonatate overdose. PMID- 26928104 TI - Perforated Duodenal Ulcer. PMID- 26928105 TI - ECGs in the ED. PMID- 26928107 TI - Caution When Using the Term and Diagnosis of Agitated Delirium. PMID- 26928106 TI - Tracheobronchial Foreign Bodies in Infants in Serbia: Five-Year Study. PMID- 26928108 TI - Open Airway, Neutral Cervical Spine. PMID- 26928109 TI - The longevity transporter mIndy (Slc13a5) as a target for treating hepatic steatosis and insulin resistance. PMID- 26928112 TI - A Near-Infrared Laser-Activated "Nanobomb" for Breaking the Barriers to MicroRNA Delivery. PMID- 26928117 TI - Callosal apraxia: a 34-year follow-up study. AB - Loss of ability of the left upper limb (LUL) to correctly produce spatial and temporal components of skilled purposeful movements was reported 34 years ago in a woman with a callosal infarction. To learn about recovery, we recently reexamined this woman. This woman was tested for ideomotor apraxia by asking her to pantomime to command and to seeing pictures of tools. Whereas she performed normally with her right upper limb, her LUL remained severely apraxic, making many spatial (postural and movement) errors. Initially, she did not reveal loss of finger-hand deftness (limb-kinetic apraxia), and when tested again with the coin rotation task, her left hand performance was normal. Without vision, she could name objects placed in her left hand but not name numbers written in this hand. Since this woman had a callosal lesion, failure to recover cannot be accounted for by left hemisphere inhibition of her right hemisphere. Although failure for her LUL to improve may have been related to not using her LUL for skilled actions, her right hemisphere was able to observe transitive actions, and this failure of her LUL to produce skilled purposeful movements suggests her right hemisphere may have not had the capacity to learn these movement representations. Without vision, her ability to recognize objects with her left hand, but not numbers written on her left palm, suggests graphesthesia may require that her left hand did not have access to movement representations important for programming these numbers when writing. PMID- 26928118 TI - Effectiveness of Left Judkins Catheter as a Single Multipurpose Catheter in Transradial Coronary Angiography From Right Radial Artery: A Randomized Comparison With Conventional Two-Catheter Strategy. AB - OBJECTIVES: To investigate safety and efficacy of left Judkins (JL) catheter as a single multipurpose catheter in transradial coronary angiography (TRA). BACKGROUND: Most operators use standard femoral catheters instead of special multipurpose transradial catheters during TRA. METHODS: Patients undergoing TRA through right radial artery (RRA) were randomized into single-catheter approach with JL3.5 and two-catheter approach with JL3.5 and right Judkins 4.0 catheters. Primary outcome measures were rate of success in selective and stable engagement of both coronary arteries with JL catheter, procedure and fluoroscopy times. RESULTS: Of 314 patients enrolled, 206 patients (aged 60.3 +/- 12.4 years, 36.9% female) were randomized. JL3.5 was successful in 66.0% of patients as a single catheter. Additional catheter was needed more frequently in single-catheter group (34 vs. 0.97%, P < 0.001). Single-catheter approach reduced procedure time significantly (6.7 +/- 2.1 vs. 7.9 +/- 3.3 minutes, P = 0.002). However on average there was 19.7% relative increase in fluoroscopy time (2.61 +/- 1.38 vs. 2.18 +/- 1.54 minutes, P = 0.035) with single-catheter approach. Radial artery spasm tended to develop more frequently in two-catheter group (22.3 vs. 12.6%, P = 0.067). In nearly half of the patients, procedure had been completed successfully with JL3.5 catheter within a fluoroscopy time similar to that of two catheter group. CONCLUSION: In TRA from RRA, JL3.5 catheter can be very effective when dedicated multipurpose catheter is not available. As a single multipurpose catheter, JL works perfectly in nearly half of procedures without prolonging procedure and fluoroscopy times. However insisting on a single-catheter approach with JL could unnecessarily increase fluoroscopy time and, hence, radiation exposure. (J Interven Cardiol 2016;29:257-264). PMID- 26928120 TI - Tubal pregnancy after clomiphene treatment: are you sure is not bilateral? AB - The estimated prevalence of ectopic pregnancy (EP) is 1-2% worldwide. Bilateral tubal pregnancies represent the rarest form of heterotopic pregnancy, and spontaneously conceived are extremely unusual, as many cases are derived from assisted reproductive techniques. We describe a case of bilateral tubal pregnancy after clomiphene therapy and sexual intercourse in which the second EP was not contemporarily revealed. PMID- 26928121 TI - Kinetics of Photocontrollable Micelles: Light-Induced Self-Assembly and Disassembly of Azobenzene-Based Surfactants Revealed by TR-SAXS. AB - The kinetics of micelles involving photosensitive surfactants is still not well understood. In this work, we unravel the mechanistic pathways involved in the micelle formation and dissolution of photocontrollable micelles. We focus on the fast self-assembly processes of photosensitive cationic azobenzene-containing surfactants (AzoTMA) that display a change in hydrophobicity induced by a reversible cis-trans conformational transition upon exposure to light. By combining both in situ time-resolved small-angle X-ray scattering (SAXS) and light scattering, we characterized the detailed structure and phase behavior of AzoTMA in mixtures of water and dimethylformamide (DMF). Time-resolved synchrotron SAXS with monochromatic light as a trigger enabled us to observe the nonequilibrium formation and dissolution process of micelles (demicellization) directly on the nanoscale with a time resolution starting from milliseconds. The structural results show that in pure water UV-light illumination leads to a 12% reduction of the aggregation number of the micelles and more than a 50% increase in the critical micelle concentration (CMC). Close to the CMC, adjusted by the addition of DMF, UV light illumination leads to a complete dissolution of the micelles, while shining blue light reverses the process and leads to the reformation of micelles. The UV-triggered dissolution follows a two-step mechanism; the first and rapid (second time scale) release of unimers is followed by a slower decomposition of the micelles (over tens of seconds) as a result of an increase in temperature due to optical absorption. Similarly, the reverse process, i.e., micelle formation, occurs rapidly upon photoconversion to trans conformers under blue light, and micelles are disrupted at long exposure time due to the optical absorption and corresponding increase in temperature. Interestingly, the coexistence of unimers with regular micelles is found at all times, and no other transient assemblies could be detected by SAXS. PMID- 26928119 TI - NAD(+) regulates Treg cell fate and promotes allograft survival via a systemic IL 10 production that is CD4(+) CD25(+) Foxp3(+) T cells independent. AB - CD4(+) CD25(+) Foxp3(+) Tregs have been shown to play a central role in immune homeostasis while preventing from fatal inflammatory responses, while Th17 cells have traditionally been recognized as pro-inflammatory mediators implicated in a myriad of diseases. Studies have shown the potential of Tregs to convert into Th17 cells, and Th17 cells into Tregs. Increasing evidence have pointed out CD25 as a key molecule during this transdifferentiation process, however molecules that allow such development remain unknown. Here, we investigated the impact of NAD(+) on the fate of CD4(+) CD25(+) Foxp3(+) Tregs in-depth, dissected their transcriptional signature profile and explored mechanisms underlying their conversion into IL-17A producing cells. Our results demonstrate that NAD(+) promotes Treg conversion into Th17 cells in vitro and in vivo via CD25 cell surface marker. Despite the reduced number of Tregs, known to promote homeostasis, and an increased number of pro-inflammatory Th17 cells, NAD(+) was able to promote an impressive allograft survival through a robust systemic IL-10 production that was CD4(+) CD25(+) Foxp3(+) independent. Collectively, our study unravels a novel immunoregulatory mechanism of NAD(+) that regulates Tregs fate while promoting allograft survival that may have clinical applications in alloimmunity and in a wide spectrum of inflammatory conditions. PMID- 26928122 TI - The direct and indirect effects of lurasidone monotherapy on functional improvement among patients with bipolar depression: results from a randomized placebo-controlled trial. AB - BACKGROUND: Bipolar depression is characterized by depressive symptoms and impairment in many areas of functioning, including work, family, and social life. The objective of this study was to assess the independent, direct effect of lurasidone treatment on functioning improvement, and examine the indirect effect of lurasidone treatment on functioning improvement, mediated through improvements in depression symptoms. METHODS: Data from a 6-week placebo-controlled trial assessing the effect of lurasidone monotherapy versus placebo in patients with bipolar depression was used. Patient functioning was measured using the Sheehan disability scale (SDS). Descriptive statistics were used to assess the effect of lurasidone on improvement on the SDS total and domain scores (work/school, social, and family life), as well as number of days lost and unproductive due to symptoms. Path analyses evaluated the total effect (beta1), as well as the indirect effect (beta2*beta3) and direct effect (beta4) of lurasidone treatment on SDS total score change, using standardized beta path coefficients and baseline scores as covariates. The direct effect of treatment on SDS total score change and indirect effects accounting for mediation through depression improvement were examined for statistical significance and magnitude using MPlus. RESULTS: In this 6-week trial (N = 485), change scores from baseline to 6-weeks were significantly larger for both lurasidone treatment dosage groups versus placebo on the SDS total and all three SDS domain scores (p < 0.05). Through path analyses, lurasidone treatment predicted improvement in depression (beta2 = -0.33, p = 0.009), subsequently predicting improvement in functional impairment (beta3 = 0.70, p < 0.001; indirect effect = -0.23). The direct effect was of medium magnitude (beta4 = -0.17, p = 0.04), indicating lurasidone had a significant and direct effect on improvement in functional impairment, after accounting for depression improvement. CONCLUSIONS: Results demonstrated statistically significant improvement in functioning among patients on lurasidone monotherapy compared to placebo. Improvement in functioning among patients on lurasidone was largely mediated through a reduction in depression symptoms, but lurasidone also had a medium and statistically significant independent direct effect in improving functioning. PMID- 26928123 TI - Development and validation of the BD SX: a brief measure of mood and symptom variability for use with adults with bipolar disorder. AB - OBJECTIVES: Ecological momentary sampling in BD research requires brief symptom measures with low cognitive demands to maximize data collection across the range of BD symptomatology. We developed the BD Sx cognizant of the challenges inherent in scale development with low prevalence populations and the limitations of existing measures (e.g., over-reliance on patients in acute states recruited from psychiatric settings). In order to be generalizable across the full spectrum of the illness, we also included those currently euthymic and those who avoid clinical contact. METHODS: We recruited a global sample of 1010 adults with BD over 19 days using socio-demographically targeted, social media advertising and online data collection. At follow-up, 428 participants provided responses 67 days later on average. This enabled us to develop the BD Sx and replicate initial findings across multiple samples over time. RESULTS: Both exploratory and confirmatory factor analyses support a 4-factor BD Sx model. Goodness of fit indices indicate good model fit across samples and over time. We labeled these factors: elation/loss of insight, affrontive symptoms of mania, cognitive/depressive, and somatic/depressive symptoms. Affrontive symptoms correlate positively with cognitive and somatic depression factors, which may suggest mixed-state symptom clusters in accord with DSM 5. CONCLUSIONS: Responses to the BD Sx reliably measure both depressive and hypo/manic symptoms. Temporal invariance analyses indicate that the 4-factor structure is consistent over time. Future research should compare BD Sx responses to clinical diagnoses of hypo/mania and major depressive episodes. PMID- 26928124 TI - Robotic versus laparoscopic low anterior resection for rectal cancer: a meta analysis. AB - BACKGROUND: The objective of this meta-analysis was to compare the clinical and oncologic outcomes of robotic low anterior resection (R-LAR) with conventional laparoscopic low anterior resection (L-LAR). METHODS: A search in the MEDLINE, Embase, and Ovid databases was performed for studies published before July 2014 that compared the clinical and oncologic outcomes of R-LAR and L-LAR. The methodological quality of the selected studies was assessed. Depending on statistical heterogeneity, a fixed or random effects model was used for the meta analysis. The clinical and oncologic outcomes evaluated included operative time, estimated blood loss, length of hospital stay, rate of conversion to open surgery, post-operative complications, circumferential margin status, and number of lymph nodes collected. RESULTS: Eight studies, including 324 R-LAR cases and 268 conventional L-LAR cases, were analyzed. The meta-analysis showed that R-LAR was associated with a shorter hospital stay (mean difference (MD) = -1.03; 95% confidence interval (CI) = -1.78, -0.28; P = 0.007), lower conversion rate (odds ratio (OR) = 0.08; 95% CI = 0.02, 0.31; P = 0.0002), lower rate of circumferential margin involvement (OR = 0.5; 95% CI = 0.25, 1.01; P = 0.05), and lower overall complication rate (MD = 0.65; 95% CI = 0.43, 0.99; P = 0.04) compared with L-LAR. There was no difference in operative time (MD = 28.4; 95% CI = -3.48, 60.27; P = 0.08), the number of lymph nodes removed (MD = -0.63; 95% CI = -0.78, 2.05; P = 0.38), and days to return of bowel function (MD = -0.15; 95% CI = -0.37, 0.06; P = 0.17). CONCLUSIONS: R-LAR was shown to be associated with a shorter hospital stay, lower conversion rate, lower rate of circumferential margin involvement, and lower overall complication rate compared with L-LAR. There were no differences in operative time, the number of lymph nodes removed, and days to return of bowel function. PMID- 26928126 TI - Zinc Sensitizes Lung Cancer Cells to Anoikis through Down-Regulation of Akt and Caveolin-1. AB - Anoikis is a particular type of apoptosis induced by the loss of cell attachment from extracellular matrix. It has been shown to play a critical role in the inhibition of cancer metastasis. Herein, we report for the first time that zinc, an essential trace element, has anoikis sensitizing activity against lung cancer cells. An anoikis assay showed that zinc treatment at the concentrations of 0-50 uM enhanced the anoikis response in human lung cancer H460 cells with significant decreased cell viability and increased number of apoptosis cells detected with Hoechst 33342 and PI co-staining assay. Moreover, zinc significantly inhibited the growth of cancer cells in an anchorage-independent condition. This is mediated through the zinc-induced decrease in prosurvival active protein kinase B (Akt) and metastasis-regulating caveolin-1 (Cav-1) protein expression. Taken together, our results indicate that zinc sensitizes non-small cell lung cancer cells to anoikis and may play a role in the prevention of cancer metastasis. PMID- 26928125 TI - Relationships between Head Circumference, Brain Volume and Cognition in Children with Prenatal Alcohol Exposure. AB - Head circumference is used together with other measures as a proxy for central nervous system damage in the diagnosis of fetal alcohol spectrum disorders, yet the relationship between head circumference and brain volume has not been investigated in this population. The objective of this study is to characterize the relationship between head circumference, brain volume and cognitive performance in a large sample of children with prenatal alcohol exposure (n = 144) and healthy controls (n = 145), aged 5-19 years. All participants underwent magnetic resonance imaging to yield brain volumes and head circumference, normalized to control for age and sex. Mean head circumference, brain volume, and cognitive scores were significantly reduced in the prenatal alcohol exposure group relative to controls, albeit with considerable overlap between groups. Males with prenatal alcohol exposure had reductions in all three measures, whereas females with prenatal alcohol exposure had reduced brain volumes and cognitive scores, but no difference in head circumference relative to controls. Microcephaly (defined here as head circumference <= 3rd percentile) occurred more often in prenatal alcohol exposed participants than controls, but 90% of the exposed sample had head circumferences above this clinical cutoff indicating that head circumference is not a sensitive marker of prenatal alcohol exposure. Normalized head circumference and brain volume were positively correlated in both groups, and subjects with very low head circumference typically had below-average brain volumes. Conversely, over half of the subjects with very low brain volumes had normal head circumferences, which may stem from differential effects of alcohol on the skeletal and nervous systems. There were no significant correlations between head circumference and any cognitive score. These findings confirm group-level reductions in head circumference and increased rates of microcephaly in children with prenatal alcohol exposure, but raise concerns about the predictive value of this metric at an individual-subject level. PMID- 26928127 TI - Ypq3p-dependent histidine uptake by the vacuolar membrane vesicles of Saccharomyces cerevisiae. AB - The vacuolar membrane proteins Ypq1p, Ypq2p, and Ypq3p of Saccharomyces cerevisiae are known as the members of the PQ-loop protein family. We found that the ATP-dependent uptake activities of arginine and histidine by the vacuolar membrane vesicles were decreased by ypq2Delta and ypq3Delta mutations, respectively. YPQ1 and AVT1, which are involved in the vacuolar uptake of lysine/arginine and histidine, respectively, were deleted in addition to ypq2Delta and ypq3Delta. The vacuolar membrane vesicles isolated from the resulting quadruple deletion mutant ypq1Deltaypq2Deltaypq3Deltaavt1Delta completely lost the uptake activity of basic amino acids, and that of histidine, but not lysine and arginine, was evidently enhanced by overexpressing YPQ3 in the mutant. These results suggest that Ypq3p is specifically involved in the vacuolar uptake of histidine in S. cerevisiae. The cellular level of Ypq3p-HA(3) was enhanced by depletion of histidine from culture medium, suggesting that it is regulated by the substrate. PMID- 26928128 TI - Effect of optic nerve sheath fenestration for idiopathic intracranial hypertension on retinal nerve fiber layer thickness. AB - The objective of the study was to evaluate whether optic nerve sheath fenestration in patients with idiopathic intracranial hypertension was associated with improvement in visual field pattern deviation and optical coherence tomography retinal nerve fiber layer thickness.The records of 13 eyes of 11 patients who underwent optic nerve sheath fenestration were reviewed. The subjects were patients of a clinical practice in Dallas, Texas. Charts were reviewed for pre- and postoperative visual field pattern deviation (PD) and retinal nerve fiber layer thickness (RNFL).PD and RNFL significantly improved after surgery. Average PD preoperatively was 8.51 DB and postoperatively was 4.80 DB (p = 0.0002). Average RNFL preoperatively was 113.63 and postoperatively was 102.70 (p = 0.01). The preoperative PD and RNFL did not correlate strongly.Our results demonstrate that PD and RNFL are improved after optic nerve sheath fenestration. The pre- and postoperative RNFL values were compared to the average RNFL value of healthy optic nerves obtained from the literature. Post-ONSF RNFL values were significantly closer to the normal value than preoperative. RNFL is an objective parameter for monitoring the optic nerve after optic nerve sheath fenestration. This study adds to the evidence that OCT RNFL may be an effective monitoring tool for patients with IIH and that it continues to be a useful parameter after ONSF. PMID- 26928129 TI - Distinguishing Epimers Through Raman Optical Activity. AB - The Raman optical activity spectra of the epimers beta-D-glucose and beta-D galactose, two monosaccharides of biological importance, have been calculated using molecular dynamics combined with a quantum mechanics/molecular mechanics approach. Good agreement between theoretical and experimental spectra is observed for both monosaccharides. Full band assignments have been carried out, which has not previously been possible for carbohydrate epimers. For the regions where the spectral features are opposite in sign, the differences in the vibrational modes have been noted and ascribed to the band sign changes. PMID- 26928130 TI - An epigenetic resolution of the lek paradox. AB - Female choice for traits signaling male genetic quality is expected to erode heritable variation in fitness, undermining the benefits of choice. Known as the lek paradox, this contradiction has motivated extensive population genetic theory, yet remains unresolved. Recent modeling by Bonduriansky and Day concludes that costly female preference is best maintained when male condition is determined by environmentally induced factors transmitted across single generations. Here, we reformulate their model in explicitly epigenetic terms, and review evidence that environmentally induced paternal effects are mediated through epigenetic changes in sperm. Noncoding RNA expression, DNA methylation and histone modifications are highly sensitive to diet, stress, toxicants and stochastic events. Epigenetic variation renews each generation and cannot be exhausted by selection. By choosing well-endowed males that produce gametes in epigenetically good states, females can increase their fitness directly through increased fertilization success or indirectly through epigenetic effects on the fitness of offspring and potentially subsequent generations. Also watch the video abstract. PMID- 26928131 TI - Structural and Electrical Properties of EOT HfO2 (<1 nm) Grown on InAs by Atomic Layer Deposition and Its Thermal Stability. AB - We report on changes in the structural, interfacial, and electrical characteristics of sub-1 nm equivalent oxide thickness (EOT) HfO2 grown on InAs by atomic layer deposition. When the HfO2 film was deposited on an InAs substrate at a temperature of 300 degrees C, the HfO2 was in an amorphous phase with an sharp interface, an EOT of 0.9 nm, and low preexisting interfacial defect states. During post deposition annealing (PDA) at 600 degrees C, the HfO2 was transformed from an amorphous to a single crystalline orthorhombic phase, which minimizes the interfacial lattice mismatch below 0.8%. Accordingly, the HfO2 dielectric after the PDA had a dielectric constant of ~24 because of the permittivity of the well-ordered orthorhombic HfO2 structure. Moreover, border traps were reduced by half than the as-grown sample due to a reduction in bulk defects in HfO2 dielectric during the PDA. However, in terms of other electrical properties, the characteristics of the PDA-treated sample were degraded compared to the as-grown sample, with EOT values of 1.0 nm and larger interfacial defect states (Dit) above 1 * 10(14) cm(-2) eV(-1). X-ray photoelectron spectroscopy data indicated that the diffusion of In atoms from the InAs substrate into the HfO2 dielectric during the PDA at 600 degrees C resulted in the development of substantial midgap states. PMID- 26928132 TI - Induction of mitochondrial reactive oxygen species production by GSH mediated S glutathionylation of 2-oxoglutarate dehydrogenase. AB - 2-Oxoglutarate dehydrogenase (Ogdh) is an important mitochondria redox sensor that can undergo S-glutathionylation following an increase in H2O2 levels. Although S-glutathionylation is required to protect Ogdh from irreversible oxidation while simultaneously modulating its activity it remains unknown if glutathione can also modulate reactive oxygen species (ROS) production by the complex. We report that reduced (GSH) and oxidized (GSSG) glutathione control O2(?-)/H2O2 formation by Ogdh through protein S-glutathionylation reactions. GSSG (1mM) induced a modest decrease in Ogdh activity which was associated with a significant decrease in O2(?-)/H2O2 formation. GSH had the opposite effect, amplifying O2(?-)/H2O2 formation by Ogdh. Incubation of purified Ogdh in 2.5mM GSH led to significant increase in O2(?-)/H2O2 formation which also lowered NADH production. Inclusion of enzymatically active glutaredoxin-2 (Grx2) in reaction mixtures reversed the GSH-mediated amplification of O2(?-)/H2O2 formation. Similarly pre-incubation of permeabilized liver mitochondria from mouse depleted of GSH showed an approximately ~3.5-fold increase in Ogdh-mediated O2(?-)/H2O2 production that was matched by a significant decrease in NADH formation which could be reversed by Grx2. Taken together, our results demonstrate GSH and GSSG modulate ROS production by Ogdh through S-glutathionylation of different subunits. This is also the first demonstration that GSH can work in the opposite direction in mitochondria-amplifying ROS formation instead of quenching it. We propose that this regulatory mechanism is required to modulate ROS emission from Ogdh in response to variations in glutathione redox buffering capacity. PMID- 26928133 TI - Direct spectrophotometric measurement of supra-physiological levels of ascorbate in plasma. AB - BACKGROUND: Supra-physiological concentrations of ascorbate, vitamin C, in blood, greater than 1mM, achieved through intravenous administration (IV), are being tested in clinical trials to treat human disease, e.g. cancer. These trials need information on the high levels of ascorbate achieved in blood upon IV administration of pharmacological ascorbate so appropriate clinical decisions can be made. METHODS: Here we demonstrate that in the complex matrix of human blood plasma supra-physiological levels of ascorbate can be quantified by direct UV spectroscopy with use of a microvolume UV-vis spectrophotometer. RESULTS: Direct quantitation of ascorbate in plasma in the range of 2.9mM, lower limit of detection, up to at least 35mM can be achieved without any sample processing, other than centrifugation. CONCLUSIONS: This approach is rapid, economical, and can be used to quantify supraphysiological blood levels of ascorbate associated with the use of IV administration of pharmacological ascorbate to treat disease. PMID- 26928134 TI - A space-time analysis of Mycoplasma bovis: bulk tank milk antibody screening results from all Danish dairy herds in 2013-2014. AB - BACKGROUND: Mycoplasma bovis is an important pathogen causing severe disease outbreaks in cattle farms. Since 2011, there has been an apparent increase in M. bovis outbreaks among Danish dairy cattle herds. The dairy cattle industry performed cross-sectional antibody screening for M. bovis on four occasions, using the indirect BIO K 302 M. bovis enzyme-linked immunosorbent assay (ELISA) (Bio-X, Belgium) in bulk tank milk from all dairy herds between June 2013 and July 2014. The objective of this study was to investigate the evolution of the spatial distribution of M. bovis in the Danish dairy herd population throughout the study period. Repeated bulk tank milk samples were used as a proxy for the herd-level diagnosis. Descriptive and spatial analyses were performed for the four screening rounds. Based on a previous diagnostic test evaluation study, the M. bovis status for each herd was determined as test-positive or test-negative using a cut-off of 50 optical density coefficient %. The spatial global clustering was evaluated through a modified K-function method, and local clusters were identified by scan statistics. RESULTS: The results showed that M. bovis test-positive herds had a dynamic pattern in space. The global clustering analysis showed that M. bovis test-positive herds were spatially correlated in rounds one, three and four. These findings were supported to some extent by the local clustering analysis, which found significant high- and low-risk spatial clusters in rounds one and three in the north and south of the mainland. CONCLUSION: The clusters with a high risk of observing test-positive herds did not remain between sampling rounds, indicating that M. bovis did not tend to persist upon emergence in dairy herds. In contrast, the clusters with a low risk of observing test-positive herds persisted in the same area throughout the study period. PMID- 26928135 TI - Help-seeking among airmen in distressed relationships: Promoting relationship well-being. AB - Although a substantial proportion of service members returning from a combat deployment report individual emotional and behavioral disorders as well as intimate relationship difficulties, previous studies indicate that only a minority actually seek mental health services. Little is known about factors that predict help-seeking in this population. We first review key findings from the literature on help-seeking in military and veteran populations, including mixed findings regarding the role of perceived stigma and attitudes toward mental health treatment. We then present data from a longitudinal study of United States Air Force Security Forces following a year-long high-risk deployment to Iraq including findings regarding who seeks help, for what problems, and from which providers. We also examine whether these findings differ for Airmen in a married or committed relationship versus nonpartnered Airmen and, for the former group, whether findings differ for those in a distressed versus nondistressed relationship. Finally, we discuss implications of these findings for extending couple-based interventions to service members and veterans, and describe a multitiered "stepped" approach for promoting relationship resiliency. PMID- 26928137 TI - Pilot trial of gender-based motivational interviewing for increasing mental health service use in college men. AB - Men are considerably less likely to seek professional and nonprofessional help for mental disorders. Prior findings indicate that adherence to masculine norms contributes to stigma about internalizing disorders and help seeking. There are currently no empirically supported interventions for increasing help seeking in men with internalizing symptoms. To address this need, we conducted a pilot study of gender-based motivational interviewing (GBMI) for men with internalizing symptoms. GBMI is a single session of assessment and feedback integrating gender based and motivational interviewing principles (Addis, 2012). College men (N = 35) with significant internalizing symptoms and no recent help seeking were randomized to either GBMI or a no-treatment control and were followed for 2 months. GBMI had a significant effect on seeking help from parents and a trend for seeking professional help, but did not have a significant effect on seeking help from friends or partners. The size of the effect of GBMI on professional and nonprofessional help seeking ranged from small to medium. GBMI shows promise for improving men's help-seeking behaviors and warrants further development and investigation. PMID- 26928136 TI - Development of a treatment protocol for Puerto Rican adolescents with suicidal behaviors. AB - Adolescents in Puerto Rico are at an increased risk for suicide attempts, though evidence-based treatments specifically for this group have not been tested. The current study was designed to develop and pilot test a culturally sensitive, manualized outpatient treatment for Puerto Rican adolescents who have experienced a suicidal crisis. The study was divided into phases. Phase 1 consisted of developing a socio-cognitive behavioral treatment for suicidal behavior. Phase 2 tested the treatment protocol in an open trial with 11 (6 male and 5 female) Puerto Rican adolescents. Active treatment had an approximate duration of 3-6 months. An initial assessment, process measures, and posttreatment assessment were completed with each participant to measure treatment feasibility as well as suicidality, symptoms, and risk factors. Participants were very satisfied with treatment and reported relevant clinical benefits. The retention rate was 73% (8 out of 11). For those who completed the treatment protocol, the goal of reducing further suicide risk was achieved; 2 showed reliable clinical changes in suicidal ideation, while 6 maintained low levels during treatment. All treatment completers had either a partial or total remission of their pretreatment diagnosis and half had reliable improvements in at least 1 risk factor. A theory driven treatment protocol was developed according to patient's needs, but further research is needed to continue its development and to explore its efficacy. PMID- 26928138 TI - Simple and Fast Extraction-Coupled UPLC-MS/MS Method for the Determination of Mequindox and Its Major Metabolites in Food Animal Tissues. AB - This research described a sensitive and rapid UPLC-MS/MS method for the determination of mequindox and its six major metabolites in chicken muscle, chicken liver, swine muscle, and swine liver. Among the metabolites, carbonyl reduction-1,4-bisdesoxy-mequindox is novel. Target analytes could be extracted by ethyl acetate without any acidolysis or enzymolysis steps. After purification by a Bond Elut C18 cartridge, analysis was carried out by UPLC-MS/MS using positive ion multiple reaction monitoring (MRM) mode. Validation was performed in spiked samples, and mean recoveries ranged from 64.3 to 114.4%, with intraday and interday variations of less than 14.7 and 19.2%, respectively. The limit of detection (LOD) was <1.0 MUg kg(-1), whereas the limit of quantification (LOQ) was <4.0 MUg kg(-1). This procedure will help monitor mequindox residues in animal-derived food, and it will also facilitate further pharmacokinetics of mequindox. PMID- 26928139 TI - Hemostatic alteration during coronary artery bypass grafting: Which is the target? PMID- 26928140 TI - Demand on-demand testing for the diagnosis of heparin-induced thrombocytopenia. PMID- 26928143 TI - Identical Binding Energies and Work Functions for Distinct Adsorption Structures: Olympicenes on the Cu(111) Surface. AB - Reliability is one of the major concerns and challenges in designing organic/inorganic interfaces for (opto)electronic applications. Even small structural differences for molecules on substrates can result in a significant variation in the interface functionality, due to the strong correlation between geometry, stability, and electronic structure. Here, we employed state-of-the-art first-principles calculations with van der Waals interactions, in combination with atomic force microscopy experiments, to explore the interaction mechanism for three structurally related olympicene molecules adsorbed on the Cu(111) surface. The substitution of a single atom in the olympicene molecule switches the nature of adsorption from predominantly physisorptive character [olympicene on Cu(111)], to an intermediate state [olympicene-derived ketone on Cu(111)], then to chemisorptive character [olympicene radical on Cu(111)]. Despite the remarkable difference in adsorption structures (by up to 0.9 A in adsorption height) and different nature of bonding, the olympicene, its ketone, and its radical derivatives have essentially identical binding energies and work functions upon interaction with the metal substrate. Our findings suggest that the stability and work functions of molecular adsorbates could be rendered insensitive to their adsorption structures, which could be a useful property for (opto)electronic applications. PMID- 26928142 TI - From Suicide Enzyme to Catalyst: The Iron-Dependent Sulfide Transfer in Methanococcus jannaschii Thiamin Thiazole Biosynthesis. AB - Bacteria and yeast utilize different strategies for sulfur incorporation in the biosynthesis of the thiamin thiazole. Bacteria use thiocarboxylated proteins. In contrast, Saccharomyces cerevisiae thiazole synthase (THI4p) uses an active site cysteine as the sulfide source and is inactivated after a single turnover. Here, we demonstrate that the Thi4 ortholog from Methanococcus jannaschii uses exogenous sulfide and is catalytic. Structural and biochemical studies on this enzyme elucidate the mechanistic details of the sulfide transfer reactions. PMID- 26928144 TI - Always ask why! PMID- 26928141 TI - Immune polarization by hookworms: taking cues from T helper type 2, type 2 innate lymphoid cells and alternatively activated macrophages. AB - Cellular and molecular investigation of parasitic helminth infections has greatly accelerated the understanding of type 2 immune responses. However, there remains considerable debate regarding the specific leucocytes that kill parasites and whether these mechanisms are distinct from those responsible for tissue repair. Herein, we chronicle discoveries over the past decade highlighting current paradigms in type 2 immunity with a particular emphasis upon how CD4(+) T helper type 2 cells, type 2 innate lymphoid cells and alternatively activated macrophages coordinately control helminth-induced parasitism. Primarily, this review will draw from studies of the murine nematode parasite Nippostrongylus brasiliensis, which bears important similarities to the human hookworms Ancylostoma duodenale and Necator americanus. Given that one or more hookworm species currently infect millions of individuals across the globe, we propose that vaccine and/or pharmaceutical-based cure strategies targeting these affected human populations should incorporate the conceptual advances outlined herein. PMID- 26928145 TI - 17 Alpha-hydroxyprogesterone caproate for preterm prevention: issues in subgroup analysis. PMID- 26928146 TI - Delivery of vertex/nonvertex twins: did the horses already leave the barn? PMID- 26928147 TI - Seeing double: a nation of twins from sea to shining sea. PMID- 26928148 TI - Randomized controlled trial of prolonged second stage: extending the time limit vs usual guidelines. AB - BACKGROUND: Guidelines for management of the second stage have been proposed since the 1800s and were created largely by expert opinion. Current retrospective data are mixed regarding differences in maternal and neonatal outcomes with a prolonged second stage. There are no randomized controlled trials that have evaluated whether extending the second stage of labor beyond current American College of Obstetricians and Gynecologists recommendations is beneficial. OBJECTIVE: The purpose of this study was to evaluate whether extending the length of labor in nulliparous women with prolonged second stage affects the incidence of cesarean delivery and maternal and neonatal outcomes. STUDY DESIGN: We conducted a randomized controlled trial of nulliparous women with singleton gestations at 36 0/7 to 41 6/7 weeks gestation who reached the American College of Obstetricians and Gynecologists definition of prolonged second stage of labor, which is 3 hours with epidural anesthesia or 2 hours without epidural anesthesia. Women were assigned randomly to extended labor for at least 1 additional hour, or to usual labor, which was defined as expedited delivery via cesarean or operative vaginal delivery. The exclusion criteria were intrauterine fetal death, planned cesarean delivery, age <18 years, and suspected major fetal anomaly. Primary outcome was incidence of cesarean delivery. Maternal and neonatal outcomes were compared secondarily. Statistical analysis was done by intention-to-treat. RESULTS: Seventy-eight nulliparous women were assigned randomly. All of the women had epidural anesthesia. Maternal demographics were not significantly different. The incidence of cesarean delivery was 19.5% (n = 8/41 deliveries) in the extended labor group and 43.2% (n = 16/37 deliveries) in the usual labor group (relative risk, 0.45; 95% confidence interval, 0.22-0.93). The number needed-to treat to prevent 1 cesarean delivery was 4.2. There were no statistically significant differences in maternal or neonatal morbidity outcomes. CONCLUSION: Extending the length of labor in nulliparous women with singleton gestations, epidural anesthesia, and prolonged second stage decreased the incidence of cesarean delivery by slightly more than one-half, compared with usual guidelines. Maternal or neonatal morbidity were not statistically different between the groups; however, our study was underpowered to detect small, but potentially clinical important, differences. PMID- 26928149 TI - Induction of labor before 40 weeks is associated with lower rate of cesarean delivery in women with gestational diabetes mellitus. AB - BACKGROUND: In women with gestational diabetes mellitus, it is not clear whether routine induction of labor at <40 weeks of gestation is beneficial to mother and newborn infant. OBJECTIVE: The purpose of this study was to compare outcomes among women with gestational diabetes mellitus who had induction of labor at either 38 or 39 weeks with those whose pregnancy was managed expectantly. STUDY DESIGN: We included all women in Ontario, Canada, with diagnosed gestational diabetes mellitus who had a singleton hospital birth at >=38 + 0 weeks of gestation between April 2012 and March 2014. Data were obtained from the Better Outcomes Registry & Network Ontario, which is a province-wide registry of all births in Ontario, Canada. Women who underwent induction of labor at 38 + 0 to 38 + 6 weeks of gestation (38-IOL; n = 1188) were compared with those who remained undelivered until 39 + 0 weeks of gestation (38-Expectant; n = 5229). Separately, those women who underwent induction of labor at 39 + 0 to 39 + 6 weeks of gestation (39-IOL; n = 1036) were compared with women who remained undelivered until 40 + 0 weeks of gestation (39-Expectant; n = 2162). Odds ratios and 95% confidence intervals were adjusted for maternal age, parity, insulin treatment, and prepregnancy body mass index. RESULTS: Of 281,480 women who gave birth during the study period, 14,600 women (5.2%) had gestational diabetes mellitus; of these, 8392 women (57.5%) met all inclusion criteria. Compared with the 38 Expectant group, those women in the 38-IOL group had lower odds for cesarean delivery (adjusted odds ratio, 0.73; 95% confidence interval, 0.52-0.90), higher odds for neonatal intensive care unit admission (adjusted odds ratio, 1.36; 95% confidence interval, 1.09-1.69), and no difference in other maternal-newborn infant outcomes. Compared with the 39-Expectant group, women in the 39-IOL group likewise had lower odds for cesarean delivery (adjusted odds ratio, 0.73; 95% confidence interval, 0.58-0.93) but no difference in neonatal intensive care unit admission (adjusted odds ratio, 0.83; 95% confidence interval, 0.61-1.11). CONCLUSION: In women with gestational diabetes mellitus, the routine induction of labor at 38 or 39 weeks is associated with a lower risk of cesarean delivery compared with expectant management but may increase the risk of neonatal intensive care unit admission when done at <39 weeks of gestation. PMID- 26928150 TI - A universal mid-trimester transvaginal cervical length screening program and its associated reduced preterm birth rate. AB - BACKGROUND: Mid-trimester transvaginal cervical length assessment can identify women who are at risk of preterm birth and afford opportunities for preterm birth prevention. However, the incidence of a short cervix is low, and some physicians have questioned whether a universal screening program among women without a previous preterm birth would be beneficial. OBJECTIVE: The purpose of this study was to examine whether the introduction of a universal transvaginal cervical length screening program is associated with a reduction in the preterm birth rate. STUDY DESIGN: This is a cohort study of women with singleton gestations and without any previous preterm births who underwent an obstetric sonogram at 18-24 weeks of gestation and who had their delivery at a single tertiary institution from January 2007 to January 2014. In July 2011, a program was implemented in which all pregnant women who had a sonogram at 18-24 weeks of gestation were to receive a transvaginal cervical length measurement. The preterm birth rates were compared before and after the implementation of the universal cervical length screening program. Multivariable analysis was used to identify whether the universal cervical length screening program was associated independently with the frequency of preterm birth. The Breslow-Day test for homogeneity was used to assess whether any interaction existed in the association based on parity. RESULTS: Of 64,207 eligible women, 46,598 underwent their mid-trimester sonogram before the universal cervical length screening program, and 17,609 underwent a sonogram after implementation of the program. Of the 17,590 women (99.9%) who agreed to cervical length measurement, 157 (0.89%) had a measurement of <=25 mm. The introduction of the cervical length program was associated with a significant decrease in the frequency of preterm birth at <37 weeks of gestation (6.7% vs 6.0%; adjusted odds ratio, 0.82 [95% confidence interval, 0.76-0.88]), <34 weeks of gestation (1.9% vs 1.7%; adjusted odds ratio, 0.74 [95% confidence interval, 0.64-0.85]), and <32 weeks of gestation (1.1% vs 1.0%; adjusted odds ratio, 0.74 (95% confidence interval, 0.62-0.90]). This reduction in frequency of preterm birth primarily was due to a change in spontaneous (and not medically indicated) preterm births. The effect size for the reduction in preterm birth was similar in nulliparous and multiparous women with previous term births. CONCLUSION: The introduction of a universal transvaginal cervical length screening program in women without a history of preterm birth is associated with a reduction in the frequency of preterm birth. PMID- 26928151 TI - Quantitative assessment of placental perfusion by contrast-enhanced ultrasound in macaques and human subjects. AB - BACKGROUND: The uteroplacental vascular supply is a critical determinant of placental function and fetal growth. Current methods for the in vivo assessment of placental blood flow are limited. OBJECTIVE: We demonstrate the feasibility of the use of contrast-enhanced ultrasound imaging to visualize and quantify perfusion kinetics in the intervillous space of the primate placenta. STUDY DESIGN: Pregnant Japanese macaques were studied at mid second trimester and in the early third trimester. Markers of injury were assessed in placenta samples from animals with or without contrast-enhanced ultrasound exposure (n = 6/group). Human subjects were recruited immediately before scheduled first-trimester pregnancy termination. All studies were performed with maternal intravenous infusion of lipid-shelled octofluoropropane microbubbles with image acquisition with a multipulse contrast-specific algorithm with destruction-replenishment analysis of signal intensity for assessment of perfusion. RESULTS: In macaques, the rate of perfusion in the intervillous space was increased with advancing gestation. No evidence of microvascular hemorrhage or acute inflammation was found in placental villous tissue and expression levels of caspase-3, nitrotyrosine and heat shock protein 70 as markers of apoptosis, nitrative, and oxidative stress, respectively, were unchanged by contrast-enhanced ultrasound exposure. In humans, placental perfusion was visualized at 11 weeks gestation, and preliminary data reveal regional differences in intervillous space perfusion within an individual placenta. By electron microscopy, we demonstrate no evidence of ultrastructure damage to the microvilli on the syncytiotrophoblast after first trimester ultrasound studies. CONCLUSIONS: Use of contrast-enhanced ultrasound did not result in placental structural damage and was able to identify intervillous space perfusion rate differences within a placenta. Contrast enhanced ultrasound imaging may offer a safe clinical tool for the identification of pregnancies that are at risk for vascular insufficiency; early recognition may facilitate intervention and improved pregnancy outcomes. PMID- 26928152 TI - Neonatal and maternal outcome after blastocyst transfer: a population-based registry study. AB - BACKGROUND: Previous studies have shown a higher risk of birth defects and preterm birth (PTB) in singletons born after blastocyst transfer as compared to singletons born after cleavage-stage transfer. Few studies have investigated the maternal outcomes. OBJECTIVE: We sought to analyze the neonatal and maternal outcome after blastocyst transfer (day 5-6) compared to transfer of cleavage stage embryos (day 2-3) and spontaneous conception. STUDY DESIGN: This was a population-based retrospective registry study including all singleton deliveries after blastocyst transfer in Sweden from 2002 through 2013. The in vitro fertilization register was cross-linked with the Swedish Medical Birth Register, the Register of Birth Defects, and the National Patient Register. Deliveries after blastocyst transfer were compared with deliveries after cleavage-stage transfer and deliveries after spontaneous conception. Outcome measures included birth defects, PTB, low birthweight, small for gestational age, large for gestational age, perinatal mortality, placenta previa, placental abruption, and preeclampsia. Crude and adjusted odds ratios (AOR) with 95% confidence interval (CI) were calculated. Adjustment was made for year of birth of child, maternal age, parity, smoking, body mass index, years of involuntary childlessness, and child's sex and, for cleavage stage, also for number of oocytes retrieved, number of embryos transferred, and fresh/frozen embryo transfer. RESULTS: There were 4819 singletons born after blastocyst transfer, 25,747 after cleavage-stage transfer, and 1,196,394 after spontaneous conception. Singletons born after blastocyst transfer had no increased risk of birth defects compared to singletons born after cleavage-stage transfer (AOR, 0.94; 95% CI, 0.79-1.13) or spontaneous conception (AOR, 1.09; 95% CI, 0.92-1.28). Perinatal mortality was higher in the blastocyst vs the cleavage-stage group (AOR, 1.61; 95% CI, 1.14-2.29). When comparing singletons born after blastocyst transfer to singletons born after spontaneous conception, a higher risk of PTB (<37 weeks) was seen (AOR, 1.17; 95% CI, 1.05-1.31). Singletons born after blastocyst transfer had a lower rate of low birthweight (AOR, 0.83; 95% CI, 0.71-0.97) as compared to cleavage-stage transfer. The rate of being small for gestational age was lower in singletons born after blastocyst transfer as compared to both cleavage-stage and spontaneous conception (AOR, 0.71; 95% CI, 0.56-0.88 and AOR, 0.70; 95% CI, 0.57-0.87, respectively). The risk of placenta previa and placental abruption was higher in pregnancies after blastocyst transfer as compared to pregnancies after cleavage stage (AOR, 2.08; 95% CI, 1.70-2.55 and AOR, 1.62; 95% CI, 1.15-2.29, respectively) and spontaneous conception (AOR, 6.38; 95% CI, 5.31-7.66 and AOR, 2.31; 95% CI, 1.70-3.13, respectively). CONCLUSION: No increased risk of birth defects was found in singletons born after blastocyst transfer. Perinatal mortality and risk of placental complications were higher in the blastocyst group as compared to the cleavage-stage group, observations that need further investigations. PMID- 26928153 TI - Group B streptococcus alters properties of vaginal epithelial cells in pregnant women. AB - BACKGROUND: Group B streptococcus (GBS) infection in pregnancy is a major cause of maternal and neonatal morbidity. An understanding of the mechanisms responsible for GBS persistence in the genital tract, as well as recognition of host defenses employed to combat its presence, are crucial to our efforts to reduce maternal GBS colonization and prevent the acquisition of neonatal infections. However, alterations in vaginal immunity in response to GBS colonization in pregnant women remain incompletely defined. Whether GBS modulates autophagy, a major host defense mechanism and contributor to the control of intracellular microbial infections, also remains unclear. OBJECTIVE: We sought to identify differences in the extent of autophagy as well as in the concentration of biomarkers previously shown to be involved in vaginal innate immunity between GBS-positive and GBS-negative pregnant women. STUDY DESIGN: We performed a prospective cohort study of healthy pregnant women, who had vaginal secretions obtained at 35-37 weeks of gestation, just prior to the standard GBS rectovaginal sample collection. The contents of the swabs were released into tubes containing 1 mL of sterile phosphate-buffered saline. Samples were centrifuged, and supernatant and cell pellet fractions were collected and stored separately at -80 degrees C until used for analysis. Epithelial cells were then lysed, and the extent of autophagy was determined by measuring the residual level of p62 remaining in the cytoplasm. p62 is a protein that is consumed during autophagy, and so its concentration detectable in the cytoplasm is inversely related to the extent of autophagy induction. The intracellular level of the inducible 70-kDa heat shock protein (hsp70), an inhibitor of autophagy, was also measured. The cell-free fraction was assayed for D- and L-lactic acid, neutrophil gelatinase associated lipocalin, extracellular matrix metalloproteinase inducer (EMMPRIN), matrix metalloproteinase (MMP)-8, alpha amylase, hyaluronan, and total protein. Laboratory personnel were blinded to all clinical data. RESULTS: There were 145 women included in the study, of which 45 (31%) were culture-positive for GBS. Vaginal cells from GBS-positive women had elevated intracellular levels of p62 (2.1 vs 0.7 pg/mL, P < .01) and hsp70 (16.9 vs 9.6 ng/mL, P = .03) as compared to GBS-negative women. The p62 and hsp70 levels were highly correlated in both groups of subjects (P < .01). In vaginal fluid, concentrations of neutrophil gelatinase-associated lipocalin (1.1 vs 0.7 ng/MUg total protein, P = .01), MMP-8 (21.9 vs 11.1 pg/MUg total protein, P = .01), and extracellular MMP inducer (8.8 vs 7.2 pg/MUg total protein, P = .03) were highest in GBS-positive women. There were no differences in the concentrations of D- and L-lactic acid, alpha amylase, or hyaluronan between the 2 groups of women. CONCLUSION: The inhibition of autophagy in vaginal epithelial cells by GBS-induced hsp70 production is associated with its persistence. Concurrently, alterations in components known to influence vaginal bacterial colonization or facilitate microbial passage to the upper genital tract also occur in relation to GBS carriage. PMID- 26928155 TI - Cellulose chain binding free energy drives the processive move of cellulases on the cellulose surface. AB - Processivity is essential for cellulases in their catalysis of cellulose hydrolysis. But what drives the processive move is not well understood. In this work, we use Trichoderma reesei Cel7B as a model system and show that its processivity is directly correlated to the binding free energy difference of a cellulose chain occupying the binding sites -7 to +2 and that occupying sites -7 to -1. Several mutants that have stronger interactions with glycosyl units in sites +1 and +2 than the wild type enzyme show higher processivity. The results suggest that after the release of the product cellobiose located in sites +1 and +2, the enzyme pulls the cellulose chain to fill the vacant sites, which propels its processive move on the cellulose surface. Biotechnol. Bioeng. 2016;113: 1873 1880. (c) 2016 Wiley Periodicals, Inc. PMID- 26928154 TI - Integrase inhibitors in late pregnancy and rapid HIV viral load reduction. AB - BACKGROUND: Minimizing time to HIV viral suppression is critical in pregnancy. Integrase strand transfer inhibitors (INSTIs), like raltegravir, are known to rapidly suppress plasma HIV RNA in nonpregnant adults. There are limited data in pregnant women. OBJECTIVE: We describe time to clinically relevant reduction in HIV RNA in pregnant women using INSTI-containing and non-INSTI-containing antiretroviral therapy (ART) options. STUDY DESIGN: We conducted a retrospective cohort study of pregnant HIV-infected women in the United States from 2009 through 2015. We included women who initiated ART, intensified their regimen, or switched to a new regimen due to detectable viremia (HIV RNA >40 copies/mL) at >=20 weeks gestation. Among women with a baseline HIV RNA permitting 1-log reduction, we estimated time to 1-log RNA reduction using the Kaplan-Meier estimator comparing women starting/adding an INSTI in their regimen vs other ART. To compare groups with similar follow-up time, we also conducted a subgroup analysis limited to women with <=14 days between baseline and follow-up RNA data. RESULTS: This study describes 101 HIV-infected pregnant women from 11 US clinics. In all, 75% (76/101) of women were not taking ART at baseline; 24 were taking non INSTI containing ART, and 1 received zidovudine monotherapy. In all, 39% (39/101) of women started an INSTI-containing regimen or added an INSTI to their ART regimen. Among 90 women with a baseline HIV RNA permitting 1-log reduction, the median time to 1-log RNA reduction was 8 days (interquartile range [IQR], 7-14) in the INSTI group vs 35 days (IQR, 20-53) in the non-INSTI ART group (P < .01). In a subgroup of 39 women with first and last RNA measurements <=14 days apart, median time to 1-log reduction was 7 days (IQR, 6-10) in the INSTI group vs 11 days (IQR, 10-14) in the non-INSTI group (P < .01). CONCLUSION: ART that includes INSTIs appears to induce more rapid viral suppression than other ART regimens in pregnancy. Inclusion of an INSTI may play a role in optimal reduction of HIV RNA for HIV-infected pregnant women presenting late to care or failing initial therapy. Larger studies are urgently needed to assess the safety and effectiveness of this approach. PMID- 26928156 TI - Clinical and radiologic comparison of dynamic cervical implant arthroplasty and cervical total disc replacement for single-level cervical degenerative disc disease. AB - Anterior cervical discectomy and fusion, to date the most successful spine procedure for the surgical treatment of cervical radiculopathy, has limitations that have led to the development of non-fusion cervical procedures, such as cervical total disc replacement (TDR) and dynamic cervical implant (DCI) arthroplasty. We compared the clinical and radiological results of DCI and cervical TDR for the treatment of single-level cervical degenerative disc disease in Chinese patients. A retrospective review of 179 patients with cervical spondylotic myelopathy who underwent DCI or TDR between April 2010 and October 2012 was conducted, and 152 consecutive patients (67 patients single-level DCI and 85 single-level TDR) who completed at least 2years of follow-up were included. Clinical and radiological assessments were performed preoperatively and at 1week and 3, 6, 12, and 24months postoperatively. The most common operative level was C5/C6 (49.3%). The differences in blood loss, duration of surgery, and duration of hospitalization were not statistically significant. The Japanese Orthopaedic Association scale, Visual Analog Scale, Neck Disability Index, and Short Form-36 scores improved significantly after surgery in both the DCI and TDR groups (P<0.05), but the differences were not statistically significant at the final follow-up. The rate of occurrence of heterotopic ossification was 22.4% and 28.2% in the DCI and TDR groups, respectively. As an effective non-fusion technique, DCI is a more economical procedure. Further prospective, randomized studies with long-term follow-up periods are needed to determine the long-term effects. PMID- 26928157 TI - International benchmarking for acute thrombolytic therapy implementation in Australia and Japan. AB - Although a wide range of strategies have been established to improve intravenous tissue plasminogen activator (IV-tPA) treatment rates, international benchmarking has not been regularly used as a systems improvement tool. We compared acute stroke codes (ASC) between two hospitals in Australia and Japan to study the activation process and potentially improve the implementation of thrombolysis. Consecutive patients who were admitted to each hospital via ASC were prospectively collected. We compared IV-tPA rates, factors contributing to exclusion from IV-tPA, and pre- and in-hospital process of care. IV-tPA treatment rates were significantly higher in the Australian hospital than in the Japanese (41% versus 25% of acute ischaemic stroke patients, p=0.0016). In both hospitals, reasons for exclusion from IV-tPA treatment were intracerebral haemorrhage, mild symptoms, and stroke mimic. Patients with baseline National Institutes of Health Stroke Scale score?5 were more likely to be excluded from IV-tPA in the Japanese hospital. Of patients treated with IV-tPA, the door-to-needle time (median, 63 versus 54minutes, p=0.0355) and imaging-to-needle time (34 versus 27minutes, p=0.0220) were longer in the Australian hospital. Through international benchmarking using cohorts captured under ASC, significant differences were noted in rates of IV-tPA treatment and workflow speed. This variation highlights opportunity to improve and areas to focus targeted practice improvement strategies. PMID- 26928158 TI - Independent predictors of mortality following spine surgery. AB - We investigated the effect of preoperative patient demographics and operative factors on mortality in the 30day postoperative period after spine surgery. Postoperative mortality from surgical interventions has significantly decreased with progressive improvement in surgical techniques and patient selection. Well studied preoperative risk factors include age, obesity, emphysema, clotting disorders, renal failure, and cardiovascular disease. However, the prognostic implications of such risk factors after spine surgery specifically remain unknown. The medical records of all consecutive patients undergoing spine surgery from 2008-2010 at our institution were reviewed. Patient demographics, comorbidities, indication for operation, surgical details, postoperative complications, and mortalities were collected. The association between preoperative demographics or surgical details and postoperative mortality was assessed via logistic regression analysis. All 1344 consecutive patients (1153 elective, 191 emergency) met inclusion criteria for the study; 19 (1.4%) patients died in the 30days following surgery. Multivariable logistic regression found several predictive factors of mortality for all spine surgery patients: operation in the cervical area (odds ratio [OR]: 7.279, 95% confidence interval [CI]: 1.37 42.83, p=0.02), postoperative sepsis (OR: 5.75, 95% CI: 1.16-26.38, p=0.03), operation for neoplastic (OR: 7.68, 95% CI: 1.53-42.71, p=0.01) or traumatic (OR: 13.76, 95% CI: 2.40-88.68, p=0.03) etiology, and age as defined as a continuous variable (OR: 1.05, 95% CI: 1.01-1.10, p=0.03). This study demonstrates predictive factors to help identify and evaluate patients who are at higher risk for mortality from spinal surgery, and potentially devise methods to reduce this risk. PMID- 26928159 TI - Reconsidering the role of hypothermia in management of severe traumatic brain injury. AB - Over the past two decades there has been considerable interest in the use of hypothermia in the management of severe traumatic brain injury. However despite promising experimental evidence, results from clinical studies have failed to demonstrate benefit. Indeed recent studies have shown a tendency to worse outcomes in those patients randomised to therapeutic hypothermia. In this narrative review the pathophysiological rationale behind hypothermia and the clinical evidence for efficacy are examined. There would still appear to be a role for hypothermia in the management of intractable intracranial hypertension. However optimising therapeutic time frames and better management of strategies for complications will be required if experimental evidence for neuroprotection is to be translated into clinical benefit. PMID- 26928160 TI - A case of aneurysmal lymphoma of the small intestine. PMID- 26928162 TI - Photochemical Synthesis of Shape-Controlled Nanostructured Gold on Zinc Oxide Nanorods as Photocatalytically Renewable Sensors. AB - Biosensors always suffer from passivation that prevents their reutilization. To address this issue, photocatalytically renewable sensors composed of semiconductor photocatalysts and sensing materials have emerged recently. In this work, we developed a robust and versatile method to construct different kinds of renewable biosensors consisting of ZnO nanorods and nanostructured Au. Via a facile and efficient photochemical reduction, various nanostructured Au was obtained successfully on ZnO nanorods. As-prepared sensors concurrently possess excellent sensing capability and desirable photocatalytic cleaning performance. Experimental results demonstrate that dendritic Au/ZnO composite has the strongest surface-enhanced Raman scattering (SERS) enhancement, and dense Au nanoparticles (NPs)/ZnO composite has the highest electrochemical activity, which was successfully used for electrochemical detection of NO release from cells. Furthermore, both of the SERS and electrochemical sensors can be regenerated efficiently for renewable applications via photodegrading adsorbed probe molecules and biomolecules. Our strategy provides an efficient and versatile method to construct various kinds of highly sensitive renewable sensors and might expand the application of the photocatalytically renewable sensor in the biosensing area. PMID- 26928163 TI - Amorphous Phosphorus/Nitrogen-Doped Graphene Paper for Ultrastable Sodium-Ion Batteries. AB - As the most promising anode material for sodium-ion batteries (SIBs), elemental phosphorus (P) has recently gained a lot of interest due to its extraordinary theoretical capacity of 2596 mAh/g. The main drawback of a P anode is its low conductivity and rapid structural degradation caused by the enormous volume expansion (>490%) during cycling. Here, we redesigned the anode structure by using an innovative methodology to fabricate flexible paper made of nitrogen doped graphene and amorphous phosphorus that effectively tackles this problem. The restructured anode exhibits an ultrastable cyclic performance and excellent rate capability (809 mAh/g at 1500 mA/g). The excellent structural integrity of the novel anode was further visualized during cycling by using in situ experiments inside a high-resolution transmission electron microscope (HRTEM), and the associated sodiation/desodiation mechanism was also thoroughly investigated. Finally, density functional theory (DFT) calculations confirmed that the N-doped graphene not only contributes to an increase in capacity for sodium storage but also is beneficial in regards to improved rate performance of the anode. PMID- 26928161 TI - Conserved roles for cytoskeletal components in determining laterality. AB - Consistently-biased left-right (LR) patterning is required for the proper placement of organs including the heart and viscera. The LR axis is especially fascinating as an example of multi-scale pattern formation, since here chiral events at the subcellular level are integrated and amplified into asymmetric transcriptional cascades and ultimately into the anatomical patterning of the entire body. In contrast to the other two body axes, there is considerable controversy about the earliest mechanisms of embryonic laterality. Many molecular components of asymmetry have not been widely tested among phyla with diverse bodyplans, and it is unknown whether parallel (redundant) pathways may exist that could reverse abnormal asymmetry states at specific checkpoints in development. To address conservation of the early steps of LR patterning, we used the Xenopus laevis (frog) embryo to functionally test a number of protein targets known to direct asymmetry in plants, fruit fly, and rodent. Using the same reagents that randomize asymmetry in Arabidopsis, Drosophila, and mouse embryos, we show that manipulation of the microtubule and actin cytoskeleton immediately post fertilization, but not later, results in laterality defects in Xenopus embryos. Moreover, we observed organ-specific randomization effects and a striking dissociation of organ situs from effects on the expression of left side control genes, which parallel data from Drosophila and mouse. Remarkably, some early manipulations that disrupt laterality of transcriptional asymmetry determinants can be subsequently "rescued" by the embryo, resulting in normal organ situs. These data reveal the existence of novel corrective mechanisms, demonstrate that asymmetric expression of Nodal is not a definitive marker of laterality, and suggest the existence of amplification pathways that connect early cytoskeletal processes to control of organ situs bypassing Nodal. Counter to alternative models of symmetry breaking during neurulation (via ciliary structures absent in many phyla), our data suggest a widely-conserved role for the cytoskeleton in regulating left-right axis formation immediately after fertilization of the egg. The novel mechanisms that rescue organ situs, even after incorrect expression of genes previously considered to be left-side master regulators, suggest LR patterning as a new context in which to explore multi-scale redundancy and integration of patterning from the subcellular structure to the entire bodyplan. PMID- 26928164 TI - Do manual therapy techniques have a positive effect on quality of life in people with tension-type headache? A randomized controlled trial. AB - BACKGROUND: Controversy exists regarding the effectiveness of manual therapy for the relief of tension-type headache (TTH). However most studies have addressed the impact of therapy on the frequency and intensity of pain. No studies have evaluated the potentially significant effect on the patient's quality of life. AIM: To assess the quality of life of patients suffering from TTH treated for 4 weeks with different manual therapy techniques. DESIGN: Factorial, randomized, single-blinded, controlled clinical trial. SETTING: Specialized center for the treatment of headache. POPULATION: Seventy-six (62 women) patients aged between 18 and 65 years (age: 39.9+/-10.9) with either episodic or chronic TTH. METHODS: Patients were divided into four groups: suboccipital inhibitory pressure; suboccipital spinal manipulation; a combination of the two treatments; control. Quality of life was assessed using the SF-12 questionnaire (considering both the overall score and the different dimensions) at the beginning and end of treatment, and after a one month follow-up. RESULTS: Compared to baseline, the suboccipital inhibition treatment group showed a significant improvement in their overall quality of life at the one month follow-up and also showed specific improvement in the dimensions related to moderate physical activities, and in their emotional role. All the treatment groups, but not the control group, showed improvements in their physical role, bodily pain, and social functioning at the one month follow-up. Post treatment and at the one month follow-up, the combined treatment group showed improved vitality and the two treatment groups that involved manipulation showed improved mental health. CONCLUSIONS: All three treatments were effective at changing different dimensions of quality of life, but the combined treatment showed the most change. The results support the effectiveness of treatments applied to the suboccipital region for patients with TTH. CLINICAL REHABILITATION IMPACT: Manual therapy techniques applied to the suboccipital region, for as little as four weeks, offered a positive improvement in some aspects of quality of life of patient's suffering with TTH. PMID- 26928165 TI - Bronchiolitis and Pulse Oximetry: Choosing Wisely With a Technological Pandora's Box. PMID- 26928166 TI - Assessing anaesthesia practice in the vulnerable age group: NECTARINE: A European prospective multicentre observational study. PMID- 26928167 TI - Local anaesthesia for carotid endarterectomy: Pro: protect the brain. PMID- 26928168 TI - Local anaesthesia for carotid endarterectomy: Con: decrease the stress for all. PMID- 26928169 TI - Regional or general anaesthesia for carotid endarterectomy: Does it matter? PMID- 26928170 TI - Oligomers of Heat-Shock Proteins: Structures That Don't Imply Function. AB - Most proteins must remain soluble in the cytosol in order to perform their biological functions. To protect against undesired protein aggregation, living cells maintain a population of molecular chaperones that ensure the solubility of the proteome. Here we report simulations of a lattice model of interacting proteins to understand how low concentrations of passive molecular chaperones, such as small heat-shock proteins, suppress thermodynamic instabilities in protein solutions. Given fixed concentrations of chaperones and client proteins, the solubility of the proteome can be increased by tuning the chaperone-client binding strength. Surprisingly, we find that the binding strength that optimizes solubility while preventing irreversible chaperone binding also promotes the formation of weakly bound chaperone oligomers, although the presence of these oligomers does not significantly affect the thermodynamic stability of the solution. Such oligomers are commonly observed in experiments on small heat-shock proteins, but their connection to the biological function of these chaperones has remained unclear. Our simulations suggest that this clustering may not have any essential biological function, but rather emerges as a natural side-effect of optimizing the thermodynamic stability of the proteome. PMID- 26928171 TI - Antinociceptive fatty acid patterns differ in children with psychosomatic recurrent abdominal pain and healthy controls. AB - AIM: Stress is considered to trigger psychosomatic recurrent abdominal pain (RAP), but the mechanism behind the pain is unclear. Because the essential fatty acids, omega-6 and omega-3, are involved in pain, by regulating lipid mediators, we analysed the fatty acid patterns in children with RAP compared to healthy children. METHODS: This was a cross-sectional study of plasma phospholipid fatty acids in 22 consecutively included children with RAP, aged six to 16 years, at an outpatient clinic specialising in RAP. The controls were 100 healthy children previously reported on and analysed in the same laboratory. RESULTS: The children with psychosomatic RAP showed higher mean concentrations of saturated fatty acids than the controls (49.0 mol% versus 47.4 mol%) but lower mean levels of polyunsaturated fatty acids (38.6 mol% versus 39.9 mol%). Omega-3 fatty acids were lower in children with psychosomatic RAP, resulting in higher ratios of linoleic to alpha-linolenic acids (p < 0.001) and arachidonic to eicosapentaenoic acids (p = 0.01), despite a lower concentration of arachidonic acid in children with RAP (p < 0.01). CONCLUSION: The results suggested an imbalance between nociceptive omega-6 fatty acids and antinociceptive omega-3 fatty acids in psychosomatic RAP. Further studies, including lipid mediators and oxidative products, are necessary to confirm an association. PMID- 26928172 TI - Analysis of secondary structural elements in human microRNA hairpin precursors. AB - BACKGROUND: MicroRNAs (miRNAs) regulate gene expression by targeting complementary mRNAs for destruction or translational repression. Aberrant expression of miRNAs has been associated with various diseases including cancer, thus making them interesting therapeutic targets. The composite of secondary structural elements that comprise miRNAs could aid the design of small molecules that modulate their function. RESULTS: We analyzed the secondary structural elements, or motifs, present in all human miRNA hairpin precursors and compared them to highly expressed human RNAs with known structures and other RNAs from various organisms. Amongst human miRNAs, there are 3808 are unique motifs, many residing in processing sites. Further, we identified motifs in miRNAs that are not present in other highly expressed human RNAs, desirable targets for small molecules. MiRNA motifs were incorporated into a searchable database that is freely available. We also analyzed the most frequently occurring bulges and internal loops for each RNA class and found that the smallest loops possible prevail. However, the distribution of loops and the preferred closing base pairs were unique to each class. CONCLUSIONS: Collectively, we have completed a broad survey of motifs found in human miRNA precursors, highly expressed human RNAs, and RNAs from other organisms. Interestingly, unique motifs were identified in human miRNA processing sites, binding to which could inhibit miRNA maturation and hence function. PMID- 26928173 TI - Using routine data to improve palliative and end of life care. AB - Palliative and end of life care is essential to healthcare systems worldwide, yet a minute proportion of research funding is spent on palliative and end of life care research. Routinely collected health and social care data provide an efficient and useful opportunity for evaluating and improving care for patients and families. There are excellent examples of routine data research in palliative and end of life care, but routine data resources are widely underutilised. We held four workshops on using routinely collected health and social care data in palliative and end of life care. Researchers presented studies from the UK, USA and Europe. The aim was to highlight valuable examples of work with routine data including work with death registries, hospital activity records, primary care data and specialist palliative care registers. This article disseminates that work, describes the benefits of routine data research and identifies major challenges for the future use of routine data, including; access to data, improving data linkage, and the need for more palliative and end of life care specific data. PMID- 26928174 TI - Eremophilane-Type Sesquiterpenoids from an Acremonium sp. Fungus Isolated from Deep-Sea Sediments. AB - Chemical examination of an EtOAc extract of a cultured Acremonium sp. fungus from deep-sea sediments resulted in the isolation of 15 new eremophilane-type sesquiterpenoids, namely, acremeremophilanes A-O (1-15), together with seven known analogues. The structures of new compounds were determined through extensive spectroscopic analyses, in association with chemical conversions and ECD calculations for configurational assignments. The PKS-derived 4-hexenoic acid unit in 2-6 is rarely found in nature. All compounds were evaluated for inhibitory effects toward nitric oxide production induced by lipopolysaccharide in RAW 264.7 macrophage cells. Compounds 2-6 and 14 exhibited inhibitory effects with IC50 values ranging from 8 to 45 MUM. PMID- 26928175 TI - Gemcitabine-Induced Subacute Cutaneous Lupus Erythematosus: A Case Report. AB - Subacute cutaneous lupus erythematosus (SCLE) is a rare eruption related to several pharmacological and chemotherapy agents. We present a 63-year-old female with recurrent epithelial ovarian cancer who developed SCLE after administration of gemcitabine. Following discontinuation of gemcitabine and after oral steroid treatment, all skin lesions disappeared. In view of the extensive use of gemcitabine in recurrent ovarian cancer, it is important to be aware of the possibility of SCLE occurrence in these patients. PMID- 26928176 TI - High inbreeding, limited recombination and divergent evolutionary patterns between two sympatric morel species in China. AB - As highly prized, popular mushrooms, morels are widely distributed in the northern hemisphere, with China as a modern centre of speciation and diversity. Overharvesting of morels has caused concern over how to effectively preserve their biological and genetic diversity. However, little is known about their population biology and life cycle. In this study, we selected two sympatric phylogenetic species, Mel-13 (124 collections from 11 geographical locations) and Morchella eohespera (156 collections from 14 geographical locations), using fragments of 4 DNA sequences, to analyse their genetic structure. Our results indicated significant differentiation among geographic locations in both species, whereas no obvious correlation between genetic and geographic distance was identified in either species. M. eohespera exhibited a predominantly clonal population structure with limited recombination detected in only 1 of the 14 geographic locations. In contrast, relatively frequent recombination was identified in 6 of the 11 geographic locations of Mel-13. Our analysis indicated that the sympatric species Mel-13 and M. eohespera might have divergent evolutionary patterns, with the former showing signatures of recent population expansion and the latter being relatively stable. Interestingly, we found no heterozygosity but strong evidence for genealogical incongruence, indicating a high level of inbreeding and hybridisation among morel species. PMID- 26928177 TI - Tricks to rapidly terminate episodes of cataplexy in narcolepsy. PMID- 26928178 TI - Reversible central sleep events in type I Chiari malformation. PMID- 26928179 TI - Sleepiness in sleepwalking and sleep terrors: a higher sleep pressure? AB - OBJECTIVE: To identify the determinants of excessive daytime sleepiness in adults with sleepwalking or sleep terrors (SW/ST). METHODS: We collected the charts of all consecutive adult patients admitted from 2012 to 2014 for SW/ST. They had completed the Paris Arousal Disorders Severity Scale and the Epworth Sleepiness Scale, and had undergone one (n = 34) or two consecutive (n = 124) nocturnal videopolysomnographies. The demographic, clinical, and sleep determinants of excessive daytime sleepiness (defined as an Epworth Sleepiness Scale score of greater than 10) were analyzed. RESULTS: Almost half (46.8%) of the 158 adult patients with SW/ST reported excessive daytime sleepiness. They had shorter sleep onset latencies (in night 1 and night 2), shorter REM sleep latencies, longer total sleep time, and higher REM sleep percentages in night 2, but no greater clinical severity of the parasomnia than patients without sleepiness. The level of sleepiness correlated with the same measures (sleep onset latency on both nights, REM sleep onset latency, and total sleep time in night 2), plus the latency to N3. In the regression model, higher sleepiness was determined by shorter sleep onset latency on night 1, lower number of awakenings in N3 on night 1, and higher total sleep time on night 2. CONCLUSION: Daytime sleepiness in patients with SW/ST is not the consequence of disturbed sleep but is associated with a specific polygraphic phenotype (rapid sleep onset, long sleep time, lower numbers of awakenings on N3) that is suggestive of a higher sleep pressure that may contribute to incomplete arousal from N3. PMID- 26928180 TI - Catathrenia in a four-year-old boy: a first case report. PMID- 26928181 TI - Geographic variation in the response of Culex pipiens life history traits to temperature. AB - BACKGROUND: Climate change is predicted to alter the transmission of many vector borne pathogens. The quantitative impact of climate change is usually estimated by measuring the temperature-performance relationships for a single population of vectors, and then mapping this relationship across a range of temperatures or locations. However, life history traits of different populations often differ significantly. Specifically, performance across a range of temperatures is likely to vary due to local adaptation to temperature and other factors. This variation can cause spatial variation in pathogen transmission and will influence the impact of climate change on the transmission of vector-borne pathogens. METHODS: We quantified variation in life history traits for four populations of Culex pipiens (Linnaeus) mosquitoes. The populations were distributed along altitudinal and latitudinal gradients in the eastern United States that spanned ~3 degrees C in mean summer temperature, which is similar to the magnitude of global warming expected in the next 3-5 decades. We measured larval and adult survival, development rate, and biting rate at six temperatures between 16 and 35 degrees C, in a common garden experiment. RESULTS: Temperature had strong and consistent non-linear effects on all four life history traits for all four populations. Adult female development time decreased monotonically with increasing temperature, with the largest decrease at cold temperatures. Daily juvenile and adult female survival also decreased with increasing temperature, but the largest decrease occurred at higher temperatures. There was significant among-population variation in the thermal response curves for the four life history traits across the four populations, with larval survival, adult survival, and development rate varying up to 45, 79, and 84 % among populations, respectively. However, variation was not correlated with local temperatures and thus did not support the local thermal adaptation hypothesis. CONCLUSION: These results suggest that the impact of climate change on vector-borne disease will be more variable than previous predictions, and our data provide an estimate of this uncertainty. In addition, the variation among populations that we observed will shape the response of vectors to changing climates. PMID- 26928182 TI - Predictors of Subjective Outcome After Medial Unicompartmental Knee Arthroplasty. AB - BACKGROUND: Unexplainable pain after medial unicompartmental knee arthroplasty (UKA) remains a leading cause for revision surgery. Therefore, the aim of this study is to identify the patient-specific variables that may influence subjective outcomes after medial UKA to optimize results. METHODS: Retrospectively, we analyzed 104 consecutive medial UKA patients. The evaluated parameters consisted of age, body mass index, gender, preoperative radiographic severity of the various knee compartments, and preoperative and postoperative mechanical axis alignments. RESULTS: At an average of 2.3-year follow-up, our data demonstrate that body mass index, gender, and preoperative severity among the various knee compartments do not influence Western Ontario and McMaster Universities Arthritis Index (WOMAC) results. Preoperatively, patients aged <65 years had inferior WOMAC stiffness (4.6 vs 2.9, P = .001), pain (9.7 vs 7.6, P = .041), and total (37.2 vs 47.6, P = .028) scores vs patients aged >=65 years. Postoperatively, only the difference on the WOMAC stiffness subscale remained significant between both age groups, in favor of patients aged >=65 years (1.0 vs 1.5, P = .035). A postoperative varus mechanical axis alignment of 1 degrees -4 degrees correlated to significantly superior WOMAC pain (P = .03), function (P = .04), and total (P = .04) scores compared to a varus of <=1 degrees or >=4 degrees . CONCLUSION: Our data suggest that greater pain relief can be expected in patients aged <65 years and that a postoperative lower limb alignment of 1 degrees -4 degrees varus should be pursued. Taking these factors into consideration will help to maximize clinical outcomes, fulfill patient expectations after medial UKA, and subsequently minimize revision rates. PMID- 26928183 TI - Letter to the Editor Regarding Ben Lulu O, Rubin G, Krasnyansky S, et al. Measuring the Femoral Head Size-An Additional Real-Time Intraoperative Monitoring Tool for the Accuracy of the Preoperative Process and Implant Selection. J Arthroplasty 2015;30(12):2201. PMID- 26928184 TI - Reply to the Letter to the Editor Regarding Ben Lulu O, Rubin G, Krasnyansky S, et al. Measuring the Femoral Head Size-An Additional Real-Time Intraoperative Monitoring Tool for the Accuracy of the Preoperative Process and Implant Selection. J Arthroplasty 2015;30(12):2201. PMID- 26928185 TI - Preemptive Femoral Nerve Block Could Reduce the Rebound Pain After Periarticular Injection in Total Knee Arthroplasty. AB - BACKGROUND: We evaluated the effectiveness of postoperative pain management using intraoperative periarticular injection (PAI) and/or electromyography-guided preoperative femoral nerve block (FNB) in knees undergoing total knee arthroplasty (TKA). METHODS: This study included 90 patients (90 knees) who underwent primary TKA. Thirty patients received a single injection of electromyography-guided FNB, 30 received intraoperative PAI, and 30 received both. Pain at rest and while moving was evaluated by a visual analog scale (VAS) at 0, 4, 8, 24, and 48 hours. Postoperative range of motion, time to walking, amount of opioid consumption, and complications were analyzed. RESULTS: VAS immediately after surgery was significantly higher in the FNB group than in the PAI and combined groups, but did not differ significantly in the latter 2 groups. VAS after 4 and 8 hours showed similar results. VAS after 24 hours was significantly higher in the PAI than in the FNB and combined groups. After 48 hours, there were no differences among the 3 groups. Total opioid consumption was lower in the combined than in the FNB and PAI groups. Postoperative range of motion and time to walking were similar in the 3 groups. CONCLUSION: PAI was more effective than FNB during the early (0-8 hours) postoperative period after TKA. Patients treated with PAI, however, experienced rebound pain at 24 hours. The combination of PAI and FNB may provide greater postoperative pain management than either alone for the first 24 hours after TKA. PMID- 26928186 TI - Medication therapy for attention deficit/hyperactivity disorder is associated with lower risk of fracture: a retrospective cohort study. AB - The impact of pharmacotherapy for attention deficit/hyperactivity disorder on fracture risk has not been well studied. In this retrospective cohort study, medication therapy was associated with lower fracture incidence. Further studies are needed to better characterize the short-term and long-term effects of these medications on bone health and fracture risk. INTRODUCTION: Attention deficit/hyperactivity disorder (ADHD) is associated with increased risk of bone fractures. The impact of pharmacotherapy with either stimulant or non-stimulant medications on fracture risk has not been well characterized. We performed a study to compare fracture incidence in ADHD patients treated with stimulant or non-stimulant medications vs. no pharmacotherapy. METHODS: In this retrospective cohort study, data were extracted from a large electronic medical record. A total of 10,066 subjects with ADHD, 40 years or younger, were included. We extracted data regarding stimulant and non-stimulant ADHD medications, corticosteroids, fracture data, demographic data, and diabetes history. RESULTS: A total of 1015 patients (10 %) sustained fractures. Multivariable Cox proportional hazard analysis indicated that compared to those with two or more prescriptions for an ADHD medication, individuals without documented medication therapy had a significantly increased hazard of fracture (hazard ratio [HR] 3.9, 95 % confidence interval [CI] 2.6-5.9). However, the hazard ratio for stimulant vs. non-stimulant medication (HR 0.92, 95 % CI 0.60-1.4) was not statistically significant. CONCLUSIONS: Three times as many patients with no documented ADHD medication prescriptions suffer a fracture compared to patients with a history of two or more prescriptions for an ADHD medication. Treatment and adherence are thus important to prevent fracture in this population. PMID- 26928187 TI - Management of patients with complex regional pain syndrome type I. AB - Complex regional pain syndrome type I (CRPS-I) includes different conditions characterized by regional pain and sensory, motor, sudomotor, vasomotor, and/or trophic findings, affecting a peripheral limb usually after a noxious event, such as a trauma or surgery. The pathophysiology is still poorly understood. Limited data are available on the incidence of CRPS-I, and the disease is underestimated and under-diagnosed. The disease shows a female preponderance approximately 3:1 with a peak age of incidence around the 5th and 6th decade. The available diagnostic criteria for CRPS-I rely on clinical criteria that are unfortunately focused on the signs and symptoms of the chronic and late disease, while little emphasis is given to the typical imaging (X-rays, bone scintigraphy, MRI) findings of the early phase. Over the last decades, several therapies have been proposed but the few studies available are often too small to be conclusive and rarely evolved to randomized controlled trials (RCTs). On the basis of the results of a few RCTs, only short courses of high bisphosphonate doses appear to provide substantial benefits. The best results are seen in patients in the early phase of the disease, often with the persistent remission or complete healing of the conditions. Since the only accredited mechanism of action of bisphosphonates is the suppression of osteoclastic bone resorption, it is likely the initial dramatic bone loss plays a role in the maintenance and evolution of CRPS-I. Short courses of high doses of bisphosphonates should be considered the treatment of choice for patients with CRPS-I. PMID- 26928188 TI - Stability and degradation of fibroblast growth factor 23 (FGF23): the effect of time and temperature and assay type. AB - There is growing need for a reliable assay for measuring fibroblast growth factor 23 (FGF23), a regulator of phosphorus and vitamin D. In this work, we analyze and compare the performance of three available assays, including the effect of temperature and time. This knowledge will allow for better understanding of FGF23 in the future. INTRODUCTION: Intact and C-terminal FGF23 (iFGF23 and cFGF23) concentrations are important in the diagnosis of hypo- and hyperphosphatemic diseases. The effects of temperature, storage, and specimen handling on FGF23 levels are not well known. We investigated the effects of various factors on plasma and serum measurement of FGF23 using three different assays. METHODS: Serum and plasma FGF23 were measured using three commercially available ELISA assays-two measuring iFGF23 and one measuring cFGF23. Samples from subjects with known FGF23 disorders were stored at 4, 22, and 37 degrees C and analyzed at different intervals up to 48 hours (h). A subset of samples underwent repeated freeze-thaw cycles, and samples frozen at -80 degrees C for up to 60 months were reanalyzed. The effect of adding a furin convertase inhibitor on FGF23 degradation was investigated using samples stored at 37 degrees C for 48 h. Intact FGF23 levels were measured from plasma samples of four different groups to test the correlation of the two assays. RESULTS: Plasma FGF23 levels were stable when stored at 4 and 22 degrees C for 48 h. Both plasma and serum FGF23 levels demonstrated relative stability after five freeze-thaw cycles. Long-term storage at -80 degrees C for 40 months induced some variability in FGF23 levels. The addition of a furin inhibitor did not affect FGF23 degradation. Intact FGF23 levels showed good correlation only at the upper limit of the assay range when comparing the two assays. CONCLUSIONS: Sample type, handling, and choice of assay are factors that affect FGF23 levels and should be considered when measuring this hormone. PMID- 26928189 TI - Laparoscopic versus open surgical management of small bowel obstruction: an analysis of clinical outcomes. AB - BACKGROUND: Laparotomy is the standard surgical approach for treatment of small bowel obstruction (SBO). Laparoscopic management could be beneficial in terms of less complications and shorter hospital stay. As the minimal invasive approach is gaining more acceptances in the treatment of SBO, there is an increased need of studies to analyze outcomes. The aim of the present study was to compare the short-term clinical outcomes of laparoscopy versus laparotomy in the surgical management of non-bariatric, non-malignant SBO. METHODS: A retrospective analysis of patients treated for SBO during 2010-2015 was made by a comprehensive search of medical records. A matched-pair review was performed on patients managed surgically for non-bariatric, non-malignant SBO at Danderyd University Hospital, Stockholm, Sweden. Completed laparoscopic surgeries were matched against patients treated with open surgery. RESULTS: Laparoscopy for SBO was initiated in 71 patients. Conversion to open surgery was performed in 42 %. Results from the matched-pair analysis showed that post-operative length of stay was reduced by 60 % (P < 0.001) in the laparoscopic cohort. Additionally, less major complications were reported and duration of surgery was reduced by 50 % (P < 0.001). CONCLUSIONS: Laparoscopic management is a safe and feasible alternative to laparotomy. Hospital length of stay was significantly shorter and morbidity rate acceptable. PMID- 26928192 TI - Proton-conducting Micro-solid Oxide Fuel Cells with Improved Cathode Reactions by a Nanoscale Thin Film Gadolinium-doped Ceria Interlayer. AB - An 8 nm-thick gadolinium-doped ceria (GDC) layer was inserted as a cathodic interlayer between the nanoscale proton-conducting yttrium-doped barium zirconate (BZY) electrolyte and the porous platinum cathode of a micro-solid oxide fuel cell (MU-SOFC), which has effectively improved the cathode reaction kinetics and rendered high cell power density. The addition of the GDC interlayer significantly reduced the cathodic activation loss and increased the peak power density of the MU-SOFC by 33% at 400 degrees C. The peak power density reached 445 mW/cm(2) at 425 degrees C, which is the highest among the reported MU-SOFCs using proton-conducting electrolytes. The impressive performance was attributed to the mixed protonic and oxygen ionic conducting properties of the nano-granular GDC, and also to the high densities of grain boundaries and lattice defects in GDC interlayer that favored the oxygen incorporation and transportation during the oxygen reduction reaction (ORR) and the water evolution reaction at cathode. PMID- 26928191 TI - Implementation of adaptive methods in early-phase clinical trials. AB - There has been constant development of novel statistical methods in the design of early-phase clinical trials since the introduction of model-based designs, yet the traditional or modified 3+3 algorithmic design remains the most widely used approach in dose-finding studies. Research has shown the limitations of this traditional design compared with more innovative approaches yet the use of these model-based designs remains infrequent. This can be attributed to several causes including a poor understanding from clinicians and reviewers into how the designs work, and how best to evaluate the appropriateness of a proposed design. These barriers are likely to be enhanced in the coming years as the recent paradigm of drug development involves a shift to more complex dose-finding problems. This article reviews relevant information that should be included in clinical trial protocols to aid in the acceptance and approval of novel methods. We provide practical guidance for implementing these efficient designs with the aim of augmenting a broader transition from algorithmic to adaptive model-guided designs. In addition we highlight issues to consider in the actual implementation of a trial once approval is obtained. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26928190 TI - Endoluminal vacuum therapy for gastrojejunal anastomotic leaks after Roux-en-Y gastric bypass: a pilot study in a swine model. AB - BACKGROUND: Roux-en-Y gastric bypass (RYGB) consistently produces the most sustainable weight loss among common interventions for morbid obesity. Anastomotic leaks at the gastrojejunal (GJ) connection result in severe morbidity. We apply endoluminal negative pressure vacuum devices (EVD) to heal anastomotic leaks in a swine model. METHODS: RYGB was performed in 10 pigs (3 control, 7 experimental). GJ anastomoses were fashioned, and a 2-cm defect was made across the staple line. In controls, the defects remained open. In experimental pigs, the EVD was placed across the defect and kept at continuous 50 mmHg suction. All pigs were euthanized on postoperative day seven unless they displayed signs of peritonitis or sepsis. Fluoroscopy and necropsy were performed to assess a persistent leak, and tissue specimens were sent to histology to evaluate for degree of inflammation and ischemia. RESULTS: All three control pigs' GJ anastomoses demonstrated evidence of a persistent leak. All seven experimental pigs with the EVD in place showed evidence that their leak had sealed at time of fluoroscopy (p value 0.008). CONCLUSIONS: Endoluminal vacuum therapy is well tolerated in a swine model. GJ anastomotic leaks were consistently sealed with our device in place compared to controls. This therapy shows promise as a method to address GJ leaks in the bariatric population, and thus, we believe additional evaluation is warranted. PMID- 26928193 TI - A discrete event simulation tool to support and predict hospital and clinic staffing. AB - We demonstrate how to develop a simulation tool to help healthcare managers and administrators predict and plan for staffing needs in a hospital neonatal intensive care unit using administrative data. We developed a discrete event simulation model of nursing staff needed in a neonatal intensive care unit and then validated the model against historical data. The process flow was translated into a discrete event simulation model. Results demonstrated that the model can be used to give a respectable estimate of annual admissions, transfers, and deaths based upon two different staffing levels. The discrete event simulation tool model can provide healthcare managers and administrators with (1) a valid method of modeling patient mix, patient acuity, staffing needs, and costs in the present state and (2) a forecast of how changes in a unit's staffing, referral patterns, or patient mix would affect a unit in a future state. PMID- 26928194 TI - Association of soluble tumor necrosis factor receptors 1 and 2 with nephropathy, cardiovascular events, and total mortality in type 2 diabetes. AB - AIMS/HYPOTHESIS: Soluble tumor necrosis factor receptors 1 and 2 (sTNFR1 and sTNFR2) contribute to experimental diabetic kidney disease, a condition with substantially increased cardiovascular risk when present in patients. Therefore, we aimed to explore the levels of sTNFRs, and their association with prevalent kidney disease, incident cardiovascular disease, and risk of mortality independently of baseline kidney function and microalbuminuria in a cohort of patients with type 2 diabetes. In pre-defined secondary analyses we also investigated whether the sTNFRs predict adverse outcome in the absence of diabetic kidney disease. METHODS: The CARDIPP study, a cohort study of 607 diabetes patients [mean age 61 years, 44 % women, 45 cardiovascular events (fatal/non-fatal myocardial infarction or stroke) and 44 deaths during follow-up (mean 7.6 years)] was used. RESULTS: Higher sTNFR1 and sTNFR2 were associated with higher odds of prevalent kidney disease [odd ratio (OR) per standard deviation (SD) increase 1.60, 95 % confidence interval (CI) 1.32-1.93, p < 0.001 and OR 1.54, 95 % CI 1.21-1.97, p = 0.001, respectively]. In Cox regression models adjusting for age, sex, glomerular filtration rate and urinary albumin/creatinine ratio, higher sTNFR1 and sTNFR2 predicted incident cardiovascular events [hazard ratio (HR) per SD increase, 1.66, 95 % CI 1.29 2.174, p < 0.001 and HR 1.47, 95 % CI 1.13-1.91, p = 0.004, respectively]. Results were similar in separate models with adjustments for inflammatory markers, HbA1c, or established cardiovascular risk factors, or when participants with diabetic kidney disease at baseline were excluded (p < 0.01 for all). Both sTNFRs were associated with mortality. CONCLUSIONS/INTERPRETATIONS: Higher circulating sTNFR1 and sTNFR2 are associated with diabetic kidney disease, and predicts incident cardiovascular disease and mortality independently of microalbuminuria and kidney function, even in those without kidney disease. Our findings support the clinical utility of sTNFRs as prognostic markers in type 2 diabetes. PMID- 26928195 TI - Molecular cloning and characterization of an ADP-ribosylation factor 6 gene (ptARF6) from Pisolithus tinctorius. AB - ADP-ribosylation factor 6 (ARF6) is an evolutionarily conserved molecule that has an essential function in intracellular trafficking and organelle structure. To better understand its role during presymbiosis between plant roots and compatible filamentous fungi, the full-length cDNA sequence of ARF6 from Pisolithus tinctorius was cloned and a variety of bioinformatics analyses performed. The full-length sequence was 849 bp long and contained a 549 bp open reading frame encoding a protein of 182 amino acids. A phylogenetic analysis showed that ptARF6 was the ortholog of the ADP ribosylation factor 6/GTPase SAR1 gene from the white rot basidiomycete Trametes versicolor. A domain architecture analysis of the ARF6 protein revealed a repeat region, which is a common feature of ARF6 in other species. Recombinant ARF6 protein was expressed with an N-terminal 6*His tag and purified using Ni(2+)-NTA affinity chromatography. The molecular mass of the recombinant protein was estimated by SDS-PAGE to be 25 kDa. The recombinant ARF6 protein bound strongly to 18:1 and 18:2 phosphatidic acids. Thus, ARF6 may participate in the signaling pathways involved in membrane phospholipid composition. The intracellular distribution of ptADP6 in HEK239T cells also indicates that ptADP6 may function not only in plasma membrane events but also in endosomal membranes events. Real-time quantitative PCR revealed that the differential expression of ptARF6 was associated with the presymbiotic stage. ptARF6 may be induced by presymbiosis during the regulation of mycorrhizal formation. PMID- 26928197 TI - NLRP3 inflammasome activation mediates estrogen deficiency-induced depression- and anxiety-like behavior and hippocampal inflammation in mice. AB - Decline of estrogen level is associated with an increase in mood disturbances such as depression and anxiety. Our previous study showed that increased levels of inflammatory cytokines in hippocampus contribute to estrogen deficiency induced depression-like behavior in rodents. Since the nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome plays a critical role in various inflammatory diseases, we explored whether NLRP3 inflammasome is involved in affective disorders caused by estrogen deficiency. It was found that ovariectomy increased the levels of IL-1beta and IL 18, NLRP3 expression and active caspase-1 in hippocampus of female mice. Ovariectomy also resulted in an increase in the level of TLR-2 and TLR-4, active NF-kappaB, pro-IL-1beta and pro-IL-18. Treatment of ovariectomized (OVX) mice with inflammasome inhibitor VX-765 ameliorated depression- and anxiety-like behavior and reversed increased levels of IL-1beta and IL-18 in hippocampus. Ovariectomy-induced depression- and anxiety-like behavior and increased inflammatory indicators were reversed by administration of 17beta-estradiol (E2) and estrogen receptor (ER)beta agonist but not ERalpha agonist. In addition, ovariectomy led to increased expression of P2X7 receptor (P2X7R), which was also reversed by E2 and ERbeta agonist. Our study suggests that estrogen deficiency results in NLRP3 inflammasome activation, thereby leading to neuroinflammation in hippocampus and depression and anxiety. Estrogen modulation of inflammation in hippocampus and depression- and anxiety-like behavior is ERbeta dependent. NLRP3 inflammasome could be the potential therapeutic target for estrogen deficiency related affective disorders. PMID- 26928196 TI - Habitual physical activity is associated with the maintenance of neutrophil migratory dynamics in healthy older adults. AB - BACKGROUND: Dysfunctional neutrophils with advanced age are a hallmark of immunosenescence. Reduced migration and bactericidal activity increase the risk of infection. It remains unclear why neutrophil dysfunction occurs with age. Physical activity and structured exercise have been suggested to improve immune function in the elderly. The aim of this study was to assess a comprehensive range of neutrophil functions and determine their association with habitual physical activity. METHOD: Physical activity levels were determined in 211 elderly (67+/-5years) individuals by 7-days of accelerometry wear. Twenty of the most physically active men and women were matched for age and gender to twenty of the least physically active individuals. Groups were compared for neutrophil migration, phagocytosis, oxidative burst, cell surface receptor expression, metabolic health parameters and systemic inflammation. Groups were also compared against ten young participants (23+/-4years). RESULTS: The most active group completed over twice as many steps/day as the least active group (p<0.001), had lower BMI's (p=0.007) and body fat percentages (p=0.029). Neutrophils migrated towards IL-8 better in the most active group compared to the least active (p<0.05) and was comparable to that of the young (p>0.05). These differences remained after adjusting for BMI, body fat and plasma metabolic markers which were different between groups. Correlations revealed that steps/day, higher adiponectin and lower insulin were positively associated with migratory ability (p<0.05). There was no difference in expression of the chemokine receptors CXCR1 or CXCR2 (p>0.05 for both). CD11b was higher in the most active group compared to the least active (p=0.048). No differences between activity groups or young controls were observed for neutrophil phagocytosis or oxidative burst in response to Escherichia coli (p>0.05). The young group had lower concentrations of IL-6, IL-8, MCP-1, CRP, IL-10 and IL-13 (p<0.05 for all) with no differences between the two older groups. CONCLUSION: These data suggest that impaired neutrophil migration, but not bactericidal function, in older adults may be, in part, the result of reduced physical activity. A 2-fold difference in physical activity is associated with better preserved neutrophil migratory dynamics in healthy older people. As a consequence increasing habitual physical activity may be beneficial for neutrophil mediated immunity. PMID- 26928198 TI - Clenbuterol activates the central IL-1 system via the beta2-adrenoceptor without provoking inflammatory response related behaviours in rats. AB - The long-acting, highly lipophilic, beta2-adrenoceptor agonist clenbuterol may represent a suitable therapeutic agent for the treatment of neuroinflammation as it drives an anti-inflammatory response within the CNS. However, clenbuterol is also known to increase the expression of IL-1beta in the brain, a potent neuromodulator that plays a role in provoking sickness related symptoms including anxiety and depression-related behaviours. Here we demonstrate that, compared to the immunological stimulus lipopolysaccharide (LPS, 250MUg/kg), clenbuterol (0.5mg/kg) selectively up-regulates expression of the central IL-1 system resulting in a mild stress-like response which is accompanied by a reduction in locomotor activity and food consumption in rats. We provide further evidence that clenbuterol-induced activation of the central IL-1 system occurs in a controlled and selective manner in tandem with its negative regulators IL-1ra and IL-1RII. Furthermore, we demonstrate that peripheral beta2-adrenoceptors mediate the suppression of locomotor activity and food consumption induced by clenbuterol and that these effects are not linked to the central induction of IL-1beta. Moreover, despite increasing central IL-1beta expression, chronic administration of clenbuterol (0.03mg/kg; twice daily for 21days) fails to induce anxiety or depressive-like behaviour in rats in contrast to reports of the ability of exogenously administered IL-1 to induce these symptoms in rodents. Overall, our findings suggest that clenbuterol or other selective beta2-adrenoceptor agonists could have the potential to combat neuroinflammatory or neurodegenerative disorders without inducing unwanted symptoms of depression and anxiety. PMID- 26928199 TI - Mechanical force-induced polymerization and depolymerization of F-actin at water/solid interfaces. AB - Actin molecules are among the three main cytoskeleton proteins of cells and undergo rapid cycling to regulate critical processes such as endocytosis, cytokinesis, cell polarity, and cell morphogenesis. Although extensive studies have been carried out on the dynamics as well as biological functions of actin polymerization and depolymerization both in vivo and in vitro, the molecular mechanisms by which cells sense and respond to mechanical signals are not fully understood. In particular, little attention has been paid to the effect of a physical force that is exerted directly on the actin cytoskeleton. In this paper, we have explored how the mechanical force affects the actin polymerization and depolymerization behaviors at water/solid interfaces using an atomic force microscope (AFM) operated in liquid. By raster scanning an AFM probe on a substrate surface with a certain load, it was found that actin monomers could polymerize into filaments without the help of actin related proteins (ARPs). Further study indicated that actin monomers were inclined to form filaments only under a small scanning load. The polymerized actin filaments would be depolymerized when the mechanical force was stronger. A possible mechanism has been suggested to explain the mechanical force induced actin polymerization. PMID- 26928200 TI - Alcohol hand rub consumption objectives in European hospitals need to be revisited. PMID- 26928201 TI - Is initial serum (1,3)-beta-d-glucan truly associated with mortality in patients with candidaemia? PMID- 26928202 TI - Epidemiologic and laboratory surveillance of the measles outbreak in the Federation of Bosnia and Herzegovina, February 2014-April 2015. AB - A measles outbreak with two epidemic waves involving 4649 probable and laboratory confirmed cases was recorded in six out of ten cantons of the Federation of Bosnia and Herzegovina between February 2014 and April 2015. The majority of the patients had never received measles vaccination (3115/4649, 67.00%), and the vaccination status of another 23% was unknown (1066/4649). A total of 281 blood samples were tested serologically. Virus detection was performed using 44 nasopharyngeal swabs. About 57% (161/281) of the laboratory-investigated sera were immunoglobulin M positive, and 95% (42/44) of the swabs were reverse transcriptase-PCR positive. Phylogenetic analysis of sequences obtained from 30 swab samples showed circulation of two variants of genotype D8, but no genotype D4 strains as detected in 2007. Similar involvement of all age groups indicates a problem with vaccine refusal resulting from antivaccination activities in addition to gaps in immunization coverage during the war and postwar period (1992 1998). Differences in ethnicity, vaccine coverage, compliance with review policies of vaccination records and potentially also travel habits may partially explain why only six of ten cantons were affected by the outbreak. The second epidemic wave may in part be due to large-scale migrations due to catastrophic floods in 2014. As a result of the epidemic, 6- to 12-month-old children may now be vaccinated against measles during outbreaks, and public health recommendations for interventions have been strengthened. Additional efforts are required to implement the measures throughout the cantons. PMID- 26928203 TI - Magnesium treatment palliates noise-induced behavioral deficits by normalizing DAergic and 5-HTergic metabolism in adult male rats. AB - Magnesium (Mg) is the fourth most abundant biological mineral essential for good health. Neuroprotective, anxiolytic and antidepressant effects of magnesium following stress and brain injuries are well established. In present study, we analyzed the protective effects of magnesium in rats exposed to sub-chronic noise stress. Magnesium Chloride (MgCl2, 100 mg/kg) was administered intraperitoneally once daily for 15 days prior exposure to noise stress. Rats were exposed to noise stress for 4 h after administration of magnesium for 15 days. At the end of treatment behavioral alterations were assessed. Animals were decapitated following behavioral testing and the brains were dissected out for neurochemical estimations by HPLC-EC. Improvement in noise-induced memory deficits as assessed by novel object recognition (NOR) test and elevated plus maze (EPM) test was found in magnesium treated rats. This improvement in noise-induced behavioral deficits following treatment with magnesium may be attributed to a significant decrease (p < 0.01) in dopamine (DA) and serotonin (5-hydroxytryptamine; 5-HT) turnover as compared to control rats observed in present work. These results suggest that treatment with magnesium can attenuate the noise-induced deficits and may be used as a therapy against noise-induced neurodegeneration. Moreover an adequate amount of magnesium in daily diet may help to develop the ability to resist against or cope up with stressful conditions encountered in daily life. PMID- 26928205 TI - Randomised controlled trial evaluation of Tweet2Quit: a social network quit smoking intervention. AB - BACKGROUND: We evaluated a novel Twitter-delivered intervention for smoking cessation, Tweet2Quit, which sends daily, automated communications to small, private, self-help groups to encourage high-quality, online, peer-to-peer discussions. DESIGN: A 2-group randomised controlled trial assessed the net benefit of adding a Tweet2Quit support group to a usual care control condition of nicotine patches and a cessation website. PARTICIPANTS: Participants were 160 smokers (4 cohorts of 40/cohort), aged 18-59 years, who intended to quit smoking, used Facebook daily, texted weekly, and had mobile phones with unlimited texting. INTERVENTION: All participants received 56 days of nicotine patches, emails with links to the smokefree.gov cessation website, and instructions to set a quit date within 7 days. Additionally, Tweet2Quit participants were enrolled in 20-person, 100-day Twitter groups, and received daily discussion topics via Twitter, and daily engagement feedback via text. MEASURES: The primary outcome was sustained abstinence at 7, 30 and 60 days post-quit date. RESULTS: Participants (mean age 35.7 years, 26.3% male, 31.2% college degree, 88.7% Caucasian) averaged 18.0 (SD=8.2) cigarettes per day and 16.8 (SD=9.8) years of smoking. Participants randomised to Tweet2Quit averaged 58.8 tweets/participant and the average tweeting duration was 47.4 days/participant. Tweet2Quit doubled sustained abstinence out to 60 days follow-up (40.0%, 26/65) versus control (20.0%, 14/70), OR=2.67, CI 1.19 to 5.99, p=0.017. Tweeting via phone predicted tweet volume, and tweet volume predicted sustained abstinence (p<0.001). The daily autocommunications caused tweeting spikes accounting for 24.0% of tweets. CONCLUSIONS: Tweet2Quit was engaging and doubled sustained abstinence. Its low cost and scalability makes it viable as a global cessation treatment. TRIAL REGISTRATION NUMBER: NCT01602536. PMID- 26928204 TI - Uni-axial stretch induces actin stress fiber reorganization and activates c-Jun NH2 terminal kinase via RhoA and Rho kinase in human bladder smooth muscle cells. AB - BACKGROUND: Excessive mechanical overload may be involved in bladder wall remodelling. Since the activity of Rho kinase is known to be upregulated in the obstructed bladder, we investigate the roles of the RhoA/Rho kinase pathway in mechanical overloaded bladder smooth muscle cells. METHODS: Human bladder smooth muscle cells were stimulated on silicon culture plates by 15 % elongated uni axial cyclic stretch at 1 Hz. The activity of c-Jun NH2-terminal kinase was measured by western blotting and actin stress fibers were observed by stained with phallotoxin conjugated with Alexa-Fluor 594. RESULTS: The activity of c-Jun NH2-terminal kinase 1 peaked at 30 min (4.7-fold increase vs. before stretch) and this activity was partially abrogated by the RhoA inhibitor, C3 exoenzoyme or by the Rho kinase inhibitor, Y-27632. Stretch induced the strong formation of actin stress fibers and these fibers re-orientated in a direction that was perpendicular to the stretch direction. The average angle of the fibers from the perpendicular to the direction of stretch was significantly different between before, and 4 h after, stretch. Actin stress fibers reorganization was also suppressed by the C3 exoenzyme or Y-27632. CONCLUSIONS: Bladder smooth muscle cells appear to have elaborate mechanisms for sensing mechanical stress and for adapting to mechanical stress overload by cytoskeletal remodeling and by activating cell growth signals such as c-Jun NH2-terminal kinase via RhoA/Rho kinase pathways. PMID- 26928207 TI - Effects of quercetin on pharmacokinetics of cefprozil in Chinese-Han male volunteers. AB - 1. The primary objective of this study was to evaluate the effects of quercetin on the pharmacokinetics of cefprozil. The secondary objective was to evaluate the safety of the combined use of cefprozil and quercetin. 2. An open-label, two period, crossover phase I trial among 24 Han Chinese male subjects was conducted. Participants were given 500 mg of quercetin orally once daily for 15 d followed by single dose of cefprozil (500 mg) on day 15. Serum concentrations of cefprozil were then measured in all participants on day 15. A 15-d washout period was then assigned after which a 500 mg dose of cefprozil was administered and measured in the serum on day 36. 3. All subjects completed the trial, and no serious adverse events were reported. We measured mean serum concentrations of cefprozil in the presence and absence of quercetin in all participants. The maximum serum concentration of cefprozil in the presence of quercetin was 8.18 ug/ml (95% CI: 7.55-8.81) versus a maximum cefprozil concentration of 8.35 ug/ml (95% CI: 7.51 9.19) in the absence of quercetin. We conclude that the concurrent use of quercetin has no substantial effect on serum concentrations of orally administered cefprozil. 4. Co-administration of quercetin showed no statistically significant effects on the pharmacokinetics of cefprozil in healthy Chinese subjects. PMID- 26928206 TI - Adverse Effects of Plant Food Supplements Self-Reported by Consumers in the PlantLIBRA Survey Involving Six European Countries. AB - BACKGROUND: The use of food supplements containing botanicals is increasing in European markets. Although intended to maintain the health status, several cases of adverse effects to Plant Food Supplements (PFS) have been described. OBJECTIVES: To describe the self-reported adverse effects collected during the European PlantLIBRA PFS Consumer Survey 2011-2012, with a critical evaluation of the plausibility of the symptomatology reported using data from the literature and from the PlantLIBRA Poisons Centers' survey. SUBJECTS/SETTING: From the total sample of 2359 consumers involved in the consumers' survey, 82 subjects reported adverse effects due to a total of 87 PFS. RESULTS: Cases were self-reported, therefore causality was not classified on the basis of clinical evidence, but by using the frequency/strength of adverse effects described in scientific papers: 52 out of 87 cases were defined as possible (59.8%) and 4 as probable (4.6%). Considering the most frequently cited botanicals, eight cases were due to Valeriana officinalis (garden valerian); seven to Camellia sinensis (tea); six to Ginkgo biloba (Maidenhair tree) and Paullinia cupana (guarana). Most adverse events related to the gastrointestinal tract, nervous and cardiovascular systems. CONCLUSIONS: Comparing the data from this study with those published in scientific papers and obtained by the PlantLIBRA Poisons Centers' survey, some important conclusions can be drawn: severe adverse effects to PFS are quite rare, although mild or moderate adverse symptoms can be present. Data reported in this paper can help health professionals (and in particular family doctors) to become aware of possible new problems associated with the increasing use of food supplements containing botanicals. PMID- 26928208 TI - Microfluidics for High-Throughput Quantitative Studies of Early Development. AB - Developmental biology has traditionally relied on qualitative analyses; recently, however, as in other fields of biology, researchers have become increasingly interested in acquiring quantitative knowledge about embryogenesis. Advances in fluorescence microscopy are enabling high-content imaging in live specimens. At the same time, microfluidics and automation technologies are increasing experimental throughput for studies of multicellular models of development. Furthermore, computer vision methods for processing and analyzing bioimage data are now leading the way toward quantitative biology. Here, we review advances in the areas of fluorescence microscopy, microfluidics, and data analysis that are instrumental to performing high-content, high-throughput studies in biology and specifically in development. We discuss a case study of how these techniques have allowed quantitative analysis and modeling of pattern formation in the Drosophila embryo. PMID- 26928209 TI - Innovative Tools and Technology for Analysis of Single Cells and Cell-Cell Interaction. AB - Heterogeneity in single-cell responses and intercellular interactions results from complex regulation of cell-intrinsic and environmental factors. Single-cell analysis allows not only detection of individual cellular characteristics but also correlation of genetic content with phenotypic traits in the same cell. Technological advances in micro- and nanofabrication have benefited single-cell analysis by allowing precise control of the localized microenvironment, cell manipulation, and sensitive detection capabilities. Additionally, microscale techniques permit rapid, high-throughput, multiparametric screening that has become essential for -omics research. This review highlights innovative applications of microscale platforms in genetic, proteomic, and metabolic detection in single cells; cell sorting strategies; and heterotypic cell-cell interaction. We discuss key design aspects of single-cell localization and isolation in microfluidic systems, dynamic and endpoint analyses, and approaches that integrate highly multiplexed detection of various intracellular species. PMID- 26928212 TI - Proton NMR for detection, identification and quantification of adulterants in 160 herbal food supplements marketed for weight loss. AB - One hundred and sixty food supplements (FS) marketed for weight loss and mainly purchased on the Internet were analyzed. All the FS were claimed as 100% natural containing only natural compounds, plant extracts and/or vitamins and the presence of an active pharmaceutical ingredient (API) was never mentioned. (1)H NMR spectroscopy was used for detecting the presence of adulterants and for their identification and quantification. Mass spectrometry was used as a complementary method for supporting their identification. Among the 164 samples considered because capsules from 5 different blisters of the same FS were analyzed, 56% were tainted with six API. Forty three contained sibutramine as single adulterant (26%), 9 phenolphthalein (6%) and 23 a mixture of these API (14%) that were both withdrawn from the market several years ago because of toxicity concerns. Sildenafil was found in 12 samples, either as a single adulterant (n=5) or in combination with sibutramine (n=3), phenolphthalein (n=3) and both sibutramine and phenolphthalein (n=1). Fluoxetine was present in 4 formulations, alone (n=3) or in combination with sibutramine and orlistat (n=1). At last, lorcaserine was detected in one FS. The content of sibutramine per dosage unit was comprised between 0.1 and 22 mg and that of phenolphthalein between 0.05 and 56 mg. The study also highlights poor manufacturing practices as evidenced for instance by the variability of API in capsules from different blisters of the same box. This paper demonstrates the need for more effective quality control of weight loss FS and the efficiency of (1)H NMR spectroscopy for the detection of tainted FS. PMID- 26928213 TI - Quantitative performance of a quadrupole-orbitrap-MS in targeted LC-MS determinations of small molecules. AB - High-resolution mass spectrometry (HRMS) has been associated with qualitative and research analysis and QQQ-MS with quantitative and routine analysis. This view is now challenged and for this reason, we have evaluated the quantitative LC-MS performance of a new high-resolution mass spectrometer (HRMS), a Q-orbitrap-MS, and compared the results obtained with a recent triple-quadrupole MS (QQQ-MS). High-resolution full-scan (HR-FS) and MS/MS acquisitions have been tested with real plasma extracts or pure standards. Limits of detection, dynamic range, mass accuracy and false positive or false negative detections have been determined or investigated with protease inhibitors, tyrosine kinase inhibitors, steroids and metanephrines. Our quantitative results show that today's available HRMS are reliable and sensitive quantitative instruments and comparable to QQQ-MS quantitative performance. Taking into account their versatility, user friendliness and robustness, we believe that HRMS should be seen more and more as key instruments in quantitative LC-MS analyses. In this scenario, most targeted LC-HRMS analyses should be performed by HR-FS recording virtually "all" ions. In addition to absolute quantifications, HR-FS will allow the relative quantifications of hundreds of metabolites in plasma revealing individual's metabolome and exposome. This phenotyping of known metabolites should promote HRMS in clinical environment. A few other LC-HRMS analyses should be performed in single-ion-monitoring or MS/MS mode when increased sensitivity and/or detection selectivity will be necessary. PMID- 26928210 TI - Implications of Lymphatic Transport to Lymph Nodes in Immunity and Immunotherapy. AB - Adaptive immune response consists of many highly regulated, multistep cascades that protect against infection while preserving the health of autologous tissue. The proper initiation, maintenance, and resolution of such responses require the precise coordination of molecular and cellular signaling over multiple time and length scales orchestrated by lymphatic transport. In order to investigate these functions and manipulate them for therapy, a comprehensive understanding of how lymphatics influence immune physiology is needed. This review presents the current mechanistic understanding of the role of the lymphatic vasculature in regulating biomolecule and cellular transport from the interstitium, peripheral tissue immune surveillance, the lymph node stroma and microvasculature, and circulating lymphocyte homing to lymph nodes. This review also discusses the ramifications of lymphatic transport in immunity as well as tolerance and concludes with examples of how lymphatic-mediated targeting of lymph nodes has been exploited for immunotherapy applications. PMID- 26928211 TI - Immune Tolerance for Autoimmune Disease and Cell Transplantation. AB - The undesired destruction of healthy cells, either endogenous or transplanted, by the immune system results in the loss of tissue function or limits strategies to restore tissue function. Current therapies typically involve nonspecific immunosuppression that may prevent the appropriate response to an antigen, thereby decreasing humoral immunity and increasing the risks of patient susceptibility to opportunistic infections, viral reactivation, and neoplasia. The induction of antigen-specific immunological tolerance to block undesired immune responses to self- or allogeneic antigens, while maintaining the integrity of the remaining immune system, has the potential to transform the current treatment of autoimmune disease and serve as a key enabling technology for therapies based on cell transplantation. PMID- 26928215 TI - The Mexican experience in monitoring and evaluation of public policies addressing social determinants of health. AB - Monitoring and evaluation (M&E) have gradually become important and regular components of the policy-making process in Mexico since, and even before, the World Health Organization (WHO) Commission on Social Determinants of Health (CSDH) called for interventions and policies aimed at tackling the social determinants of health (SDH). This paper presents two case studies to show how public policies addressing the SDH have been monitored and evaluated in Mexico using reliable, valid, and complete information, which is not regularly available. Prospera, for example, evaluated programs seeking to improve the living conditions of families in extreme poverty in terms of direct effects on health, nutrition, education and income. Monitoring of Prospera's implementation has also helped policy-makers identify windows of opportunity to improve the design and operation of the program. Seguro Popular has monitored the reduction of health inequalities and inequities evaluated the positive effects of providing financial protection to its target population. Useful and sound evidence of the impact of programs such as Progresa and Seguro Popular plus legal mandates, and a regulatory evaluation agency, the National Council for Social Development Policy Evaluation, have been fundamental to institutionalizing M&E in Mexico. The Mexican experience may provide useful lessons for other countries facing the challenge of institutionalizing the M&E of public policy processes to assess the effects of SDH as recommended by the WHO CSDH. PMID- 26928216 TI - Moving forward monitoring of the social determinants of health in a country: lessons from England 5 years after the Marmot Review. AB - BACKGROUND: England has a long history of government-commissioned reviews of national inequalities. The latest review, the Marmot Review, was commissioned by a government headed by the same party (the Labour Party) that had introduced the National Health Service in 1948, but the review was implemented by a coalition of different parties (Conservatives and Liberal Democrats). At the same time, a government reform of health services took place, and the monitoring of the existing inequality strategy was changed. OBJECTIVES: This paper examines the lessons that can be learned about indicators for monitoring social determinants of health inequalities from the Marmot Review and recent health inequality strategies in England. DESIGN: The paper provides a narrative review of key findings on the collection, presentation, and analysis of routine data in England in the past 5 years, comparing what has been learned from the Marmot Review and other evaluations of the first health inequality strategy in England. RESULTS: The emphasis on monitoring has progressively shifted from monitoring a small number of targets and supporting information to frameworks that monitor across a wide range of determinants of both the causes of ill-health and of health service performance. As these frameworks become ever larger, some consideration is being given to the key indicators. CONCLUSIONS: Although the frameworks used in England for monitoring health inequality strategies have developed considerably since the first strategy began, lessons continue to be learned about how monitoring could be improved. Many of these are applicable to countries initiating or reviewing their strategies. PMID- 26928214 TI - Early cerebral volume reductions and their associations with reduced lupus disease activity in patients with newly-diagnosed systemic lupus erythematosus. AB - We examined if cerebral volume reduction occurs very early during the course of systemic lupus erythematosus (SLE), and observed prospectively whether gray (GMV) and white matter volumes (WMV) of the brain would improve with lowered SLE disease activity. T1-weighted MRI brain images were obtained from 14 healthy controls (HC) and 14 newly-diagnosed SLE patients within 5 months of diagnosis (S1) and after achieving low disease activity (S2). Whole brain voxel-based morphometry was used to detect differences in the GMV and WMV between SLE patients and HC and those between SLE patients at S1 and S2. SLE patients were found to have lower GMV than HC in the middle cingulate cortex, middle frontal gyrus and right supplementary motor area, and lower WMV in the superior longitudinal fasciculus, cingulum cingulate gyrus and inferior fronto-occipital fasciculus at both S1 and S2. Whole-brain voxel-wise analysis revealed increased GMV chiefly in the prefrontal regions at S2 compared to S1 in SLE patients. The GMV increase in the left superior frontal gyrus was significantly associated with lowered SLE disease activity. In conclusion, GMV and WMV reduced very early in SLE patients. Reduction of SLE disease activity was accompanied by region specific GMV improvement in the prefrontal regions. PMID- 26928217 TI - The path to impact of operational research on tuberculosis control policies and practices in Indonesia. AB - BACKGROUND: Operational research is currently one of the pillars of the global strategy to control tuberculosis. Indonesia initiated capacity building for operational research on tuberculosis over the last decade. Although publication of the research in peer-reviewed journals is an important indicator for measuring the success of this endeavor, the influence of operational research on policy and practices is considered even more important. However, little is known about the process by which operational research influences tuberculosis control policy and practices. OBJECTIVE: We aimed to investigate the influence of operational research on tuberculosis control policy and practice in Indonesia between 2004 and 2014. DESIGN: Using a qualitative study design, we conducted in-depth interviews of 50 researchers and 30 policy makers/program managers and performed document reviews. Transcripts of these interviews were evaluated while applying content analysis. RESULTS: Operational research contributed to tuberculosis control policy and practice improvements, including development of new policies, introduction of new practices, and reinforcement of current program policies and practices. However, most of these developments had limited sustainability. The path from the dissemination of research results and recommendations to policy and practice changes was long and complex. The skills, interests, and political power of researchers and policy makers, as well as health system response, could influence the process. CONCLUSIONS: Operational research contributed to improving tuberculosis control policy and practices. A systematic approach to improve the sustainability of the impact of operational research should be explored. PMID- 26928218 TI - Fragmented implementation of maternal and child health home-based records in Vietnam: need for integration. AB - BACKGROUND: Home-based records (HBRs) are globally implemented as the effective tools that encourage pregnant women and mothers to timely and adequately utilise maternal and child health (MCH) services. While availability and utilisation of nationally representative HBRs have been assessed in several earlier studies, the reality of a number of HBRs subnationally implemented in a less coordinated manner has been neither reported nor analysed. OBJECTIVES: This study is aimed at estimating the prevalence of HBRs for MCH and the level of fragmentation of and overlapping between different HBRs for MCH in Vietnam. The study further attempts to identify health workers' and mothers' perceptions towards HBR operations and utilisations. DESIGN: A self-administered questionnaire was sent to the provincial health departments of 28 selected provinces. A copy of each HBR available was collected from them. A total of 20 semi-structured interviews with health workers and mothers were conducted at rural communities in four of 28 selected provinces. RESULTS: Whereas HBRs developed exclusively for maternal health and exclusively for child health were available in four provinces (14%) and in 28 provinces (100%), respectively, those for both maternal health and child health were available in nine provinces (32%). The mean number of HBRs in 28 provinces (=5.75) indicates over-availability of HBRs. All 119 minimum required items for recording found in three different HBRs under nationwide scale up were also included in the Maternal and Child Health Handbook being piloted for nationwide scaling-up. Implementation of multiple HBRs is likely to confuse not only health workers by requiring them to record the same data on several HBRs but also mothers about which HBR they should refer to and rely on at home. CONCLUSIONS: To enable both health workers and pregnant women to focus on only one type of HBR, province-specific HBRs for maternal and/or child health need to be nationally standardised. Moreover, to ensure a continuum of maternal, newborn, and child health care, the HBRs currently fragmented into different MCH stages (i.e. pregnancy, delivery, child immunisation, child growth, and child development) should be integrated. Standardisation and integration of HBRs will help increase technical efficiency and financial sustainability of HBR operations. PMID- 26928219 TI - The Development of Surveillance Systems. AB - Surveillance systems in public health practice have increased in number and sophistication with advances in data collection, analysis, and communication. When the Communicable Disease Center (now the Centers for Disease Control and Prevention) was founded some 70 years ago, surveillance referred to the close observation of individuals with suspected smallpox, plague, or cholera. Alexander Langmuir, head of the Epidemiology Branch, redefined surveillance as the epidemiology-based critical factor in infectious disease control. I joined Langmuir as assistant chief in 1955 and was appointed chief of the Surveillance Section in 1961. In this paper, I describe Langmuir's redefinition of surveillance. Langmuir asserted that its proper use in public health meant the systematic reporting of infectious diseases, the analysis and epidemiologic interpretation of data, and both prompt and widespread dissemination of results. I outline the Communicable Disease Center's first surveillance systems for malaria, poliomyelitis, and influenza. I also discuss the role of surveillance in the global smallpox eradication program, emphasizing that the establishment of systematic reporting systems and prompt action based on results were critical factors of the program. PMID- 26928220 TI - Optical and neural anisotropy in peripheral vision. AB - Optical blur in the peripheral retina is known to be highly anisotropic due to nonrotationally symmetric wavefront aberrations such as astigmatism and coma. At the neural level, the visual system exhibits anisotropies in orientation sensitivity across the visual field. In the fovea, the visual system shows higher sensitivity for cardinal over diagonal orientations, which is referred to as the oblique effect. However, in the peripheral retina, the neural visual system becomes more sensitive to radially-oriented signals, a phenomenon known as the meridional effect. Here, we examined the relative contributions of optics and neural processing to the meridional effect in 10 participants at 0 degrees , 10 degrees , and 20 degrees in the temporal retina. Optical anisotropy was quantified by measuring the eye's habitual wavefront aberrations. Alternatively, neural anisotropy was evaluated by measuring contrast sensitivity (at 2 and 4 cyc/deg) while correcting the eye's aberrations with an adaptive optics vision simulator, thus bypassing any optical factors. As eccentricity increased, optical and neural anisotropy increased in magnitude. The average ratio of horizontal to vertical optical MTF (at 2 and 4 cyc/deg) at 0 degrees , 10 degrees , and 20 degrees was 0.96 +/- 0.14, 1.41 +/- 0.54 and 2.15 +/- 1.38, respectively. Similarly, the average ratio of horizontal to vertical contrast sensitivity with full optical correction at 0 degrees , 10 degrees , and 20 degrees was 0.99 +/- 0.15, 1.28 +/- 0.28 and 1.75 +/- 0.80, respectively. These results indicate that the neural system's orientation sensitivity coincides with habitual blur orientation. These findings support the neural origin of the meridional effect and raise important questions regarding the role of peripheral anisotropic optical quality in developing the meridional effect and emmetropization. PMID- 26928221 TI - Effects of Expanded Coverage for Chiropractic Services on Medicare Costs in a CMS Demonstration. AB - BACKGROUND: Moderately convincing evidence supports the benefits of chiropractic manipulations for low back pain. Its effectiveness in other applications is less well documented, and its cost-effectiveness is not known. These questions led the Centers for Medicaid and Medicare Services (CMS) to conduct a two-year demonstration of expanded Medicare coverage for chiropractic services in the treatment of beneficiaries with neuromusculoskeletal (NMS) conditions affecting the back, limbs, neck, or head. METHODS: The demonstration was conducted in 2005 2007 in selected counties of Illinois, Iowa, and Virginia and the entire states of Maine and New Mexico. Medicare claims were compiled for the preceding year and two demonstration years for the demonstration areas and matched comparison areas. The impact of the demonstration was analyzed through multivariate regression analysis with a difference-in-difference framework. RESULTS: Expanded coverage increased Medicare expenditures by $50 million or 28.5% in users of chiropractic services and by $114 million or 10.4% in all patients treated for NMS conditions in demonstration areas during the two-year period. Results varied widely among demonstration areas ranging from increased costs per user of $485 in Northern Illinois and Chicago counties to decreases in costs per user of $59 in New Mexico and $178 in Scott County, Iowa. CONCLUSION: The demonstration did not assess possible decreases in costs to other insurers, out-of-pocket payments by patients, the need for and costs of pain medications, or longer term clinical benefits such as avoidance of orthopedic surgical procedures beyond the two-year period of the demonstration. It is possible that other payers or beneficiaries saved money during the demonstration while costs to Medicare were increased. PMID- 26928223 TI - Evaluating the Molecular Interaction of Organic Liquid Mixtures Using Near Infrared Spectroscopy. AB - The near-infrared transmission spectra of two organic liquid three-component systems of variable compositions were investigated in detail. To evaluate the interaction of the different components in the two systems the experimental spectra of the pure components were compared to mathematically constructed "pure component" spectra. Though usually the correlation coefficient (CC) and Manhattan distance (MD) are used to measure the similarity of spectra, in the present investigations principal component analysis (PCA) was found to be a more effective tool to investigate the difference between these spectra and derive parameters characterizing the interaction between the different components. Thus, PC scores for the two types of spectra established some distinct patterns which clearly expressed their differences. For a three-dimensional coordinate system of selected principal components, the Euclidean distances between the mathematically constructed and the experimental spectra of the pure components were calculated. Finally, the mean values of the distances for each component provided indices to rank the interaction of the components in the mixtures. Thus, the results offer a convenient approach that can quantitatively evaluate the molecular interactions of the individual components in organic liquid mixtures by various spectroscopies. PMID- 26928222 TI - Synergistic association of combined glycemic and blood pressure level with risk of complications in US veterans with diabetes. AB - OBJECTIVES: Hemoglobin A1c levels less than 7.0% and systolic blood pressure (SBP) less than 140 mmHg are each associated with lower risk of vascular complications in patients with diabetes mellitus. Associations between combined A1c level and SBP categories and risk of mortality and morbidity in diabetic patients are not well characterized. METHODS: We examined 891 670 US diabetic veterans with baseline estimated glomerular filtration rates more than 60 ml/min per 1.73 m (mean age 67 +/- 11 years, 97% men, 17% African-Americans). The associations of mutually exclusive combined categories of A1c (<6.5, 6.5-6.9, 7.0 7.9, 8.0-8.9, 9.0-9.9, and >=10%) and SBP (<100, 100-119, 120-139, 140-159, 160 179, and >=180 mmHg) with the risk of all-cause mortality and incident chronic kidney disease (CKD), coronary heart disease, and stroke were examined in Cox models adjusted for baseline characteristics using patients with concomitant A1c 6.5-6.9% and SBP of 120-139 mmHg as the referent group. RESULTS: A total of 221 529 (25%) patients died, and 178 588 (20%), 43 373 (5%) and 36 935 (4%) developed CKD, coronary heart disease and stroke, respectively, during a median follow-up of 7.4 years. SBP displayed a J-shaped association with each outcome except CKD risk that was linearly associated with SBP across all A1c categories. A1c above 7.0% was associated with monotonically worse outcomes for all end points in all SBP categories. Patients with the combined highest A1c and SBP levels experienced the worst outcomes. CONCLUSION: SBP greater than 120-139 mmHg and A1c greater than 7.0% are associated with higher mortality and vascular complications in diabetic patients, independent of each other. Combined efforts to improve both glycemic and blood pressure control may synergistically improve outcomes in patients with normal kidney function. PMID- 26928224 TI - The impact of causal attribution on stigmatizing attitudes toward a person who stutters. AB - PURPOSE: This study investigated the impact of providing low control (biological) and high control (psychobehavioral) causal explanations for stuttering on a variety of stigma related variables including blame, anger, social distance, stereotypes, dislike, sympathy, willingness to help, and perceptions of potential for recovery for a hypothetical person who stutters. METHOD: One hundred and sixty-five university students read one of three vignettes describing a person who stutters with different descriptions about the cause of stuttering (low control, high control, and a control group in which no explanation was given) and answered a series of self-report measures assessing stigmatizing attitudes and perceived potential for recovery. RESULTS: The controllable explanation for stuttering led to more blame compared to the uncontrollable explanation and no explanation. The controllable explanation resulted in higher levels of anger and stereotypes compared to no explanation. There were no significant differences between uncontrollable explanations and no explanation on any of the stigma related variables of interest. Uncontrollable explanations increased prognostic pessimism compared to controllable explanations. Self-reported familiarity and closeness with people who stutter was significantly related to more positive attitudes toward a hypothetical person who stutters. CONCLUSIONS: Reducing the belief that stuttering is ultimately caused by psychobehavioral factors will reduce blame toward people who stutter. However, providing biological explanations for stuttering is not effective for reducing stigma compared to no explanation at all, and could increase prognostic pessimism. Biological explanations for stuttering should be provided to inform clients and society about current research findings, however this information must be given carefully and be balanced with evidence that people who stutter can make great progress with appropriate, personalized therapy that addresses the multidimensionality of the disorder. LEARNING OUTCOMES: As a result of reading this paper, readers should be able to: (1) describe how causal attributions impact attitudes toward individuals with disabilities (2) summarize the effects of providing a biological explanation for stuttering on stigmatizing attitudes toward a person who stutters (3) summarize the effects of providing a psychobehavioral explanation for stuttering on stigmatizing attitudes toward a person who stutters, (4) discuss how familiarity and closeness toward people who stutter relates to stigmatizing attitudes toward a person who stutters. PMID- 26928225 TI - WITHDRAWN: Psychological interventions to improve adherence to oral hygiene instructions in adults with periodontal diseases. PMID- 26928226 TI - Active DNA demethylation at enhancers during the vertebrate phylotypic period. AB - The vertebrate body plan and organs are shaped during a conserved embryonic phase called the phylotypic stage. However, the mechanisms that guide the epigenome through this transition and their evolutionary conservation remain elusive. Here we report widespread DNA demethylation of enhancers during the phylotypic period in zebrafish, Xenopus tropicalis and mouse. These enhancers are linked to developmental genes that display coordinated transcriptional and epigenomic changes in the diverse vertebrates during embryogenesis. Binding of Tet proteins to (hydroxy)methylated DNA and enrichment of 5-hydroxymethylcytosine in these regions implicated active DNA demethylation in this process. Furthermore, loss of function of Tet1, Tet2 and Tet3 in zebrafish reduced chromatin accessibility and increased methylation levels specifically at these enhancers, indicative of DNA methylation being an upstream regulator of phylotypic enhancer function. Overall, our study highlights a regulatory module associated with the most conserved phase of vertebrate embryogenesis and suggests an ancient developmental role for Tet dioxygenases. PMID- 26928229 TI - Posttraumatic Stress Disorder: Structural Characterization with 3-T MR Imaging. AB - Purpose To explore cerebral alterations related to the emergence of posttraumatic stress disorder (PTSD) by using three-dimensional T1-weighted imaging and also to explore the relationship of gray and white matter abnormalities and the anatomic changes with clinical severity and duration of time since the trauma. Materials and Methods Informed consent was provided, and the prospective study was approved by the ethics committee of the West China Hospital. Recruited were 67 patients with PTSD and 78 adult survivors without PTSD 7-15 months after a devastating earthquake in western China. All participants underwent magnetic resonance (MR) imaging with a 3-T imager to obtain anatomic images. Cortical thickness and volumes of 14 subcortical gray matter structures and five subregions of the corpus callosum were analyzed with software. Statistical differences between patients with PTSD and healthy survivors were evaluated with a general linear model. Averaged data from the regions with volumetric or cortical thickness differences between groups were extracted in each individual to examine correlations between morphometric measures and clinical profiles. Results Patients with PTSD showed greater cortical thickness in the right superior temporal gyrus, inferior parietal lobule, and left precuneus (P < .05; Monte Carlo null-z simulation corrected) and showed reduced volume in the posterior portion of the corpus callosum (F = 6.167; P = .014) compared with healthy survivors of the earthquake. PTSD severity was positively correlated with cortical thickness in the left precuneus (r = 0.332; P = .008). The volumes of posterior corpus callosum were negatively correlated with PTSD ratings in all survivors (r = -0.210; P = .013) and with cortical thickness of the left precuneus in patients with PTSD (r = -0.302; P = .017). Conclusion Results indicate that patients with PTSD had alterations in both cerebral gray matter and white matter compared with individuals who experienced similar psychologic trauma from the same stressor. Importantly, early in the course of PTSD, gray matter changes were in the form of increased, not decreased, cortical thickness, which may have resulted from neuroinflammatory or other trophic process related to endocrine changes or functional compensation. ((c)) RSNA, 2016. PMID- 26928227 TI - Comprehensive genomic analysis of malignant pleural mesothelioma identifies recurrent mutations, gene fusions and splicing alterations. AB - We analyzed transcriptomes (n = 211), whole exomes (n = 99) and targeted exomes (n = 103) from 216 malignant pleural mesothelioma (MPM) tumors. Using RNA-seq data, we identified four distinct molecular subtypes: sarcomatoid, epithelioid, biphasic-epithelioid (biphasic-E) and biphasic-sarcomatoid (biphasic-S). Through exome analysis, we found BAP1, NF2, TP53, SETD2, DDX3X, ULK2, RYR2, CFAP45, SETDB1 and DDX51 to be significantly mutated (q-score >= 0.8) in MPMs. We identified recurrent mutations in several genes, including SF3B1 (~2%; 4/216) and TRAF7 (~2%; 5/216). SF3B1-mutant samples showed a splicing profile distinct from that of wild-type tumors. TRAF7 alterations occurred primarily in the WD40 domain and were, except in one case, mutually exclusive with NF2 alterations. We found recurrent gene fusions and splice alterations to be frequent mechanisms for inactivation of NF2, BAP1 and SETD2. Through integrated analyses, we identified alterations in Hippo, mTOR, histone methylation, RNA helicase and p53 signaling pathways in MPMs. PMID- 26928230 TI - Comparison of slaughter value for once-calved heifers and heifers of Polish Holstein-Friesian*Limousine crossbreds. AB - The study compared the slaughter value and meat quality of heifers and once calved heifers slaughtered at the age of 18 and 28months, respectively. The once calved heifers at the age of 15months, were bred with semen of Limousine bulls and following the calving they fed their offspring and then they were slaughtered. There were no differences in the carcass conformation and fatness between the treatments. Once-calved heifers' carcasses had a higher proportion (P<0.05) of 5 most valuable primal cuts as compared with heifers. Meat of once calved heifers contained more (P<0.05) intramuscular fat, was darker (P<0.01), and exhibited a higher water-holding capacity and lower cooking loss (P<0.05) as compared with heifers' meat. In conclusion, due to the possibility for obtaining additional offspring and a heavier pre-slaughter weight without reducing the slaughter value of the carcass and meat quality, it is recommended to use heifers originating from commercial crossbreeding as the once-calved ones. PMID- 26928232 TI - Prediction of Non-invasive Mechanical Ventilation Response. Moving from Art to Science? AB - Predicting the outcome from NIV is important and the study by Martin-Gonzalez and colleagues applies data mining techniques to improve our understanding of the field. Nevertheless, the predictor variables must be robust and reliably available before NIV is applied. A predictive model must be generalisable in other clinical settings. Until models such as this are extremely robust in their predictive ability and have been shown to positively influence patient centered outcomes, they may be able to assist decision making but cannot replace clinical judgement by an experienced bedside clinician. PMID- 26928231 TI - Reciprocal Changes of Circulating Long Non-Coding RNAs ZFAS1 and CDR1AS Predict Acute Myocardial Infarction. AB - This study sought to evaluate the potential of circulating long non-coding RNAs (lncRNAs) as biomarkers for acute myocardial infarction (AMI). We measured the circulating levels of 15 individual lncRNAs, known to be relevant to cardiovascular disease, using the whole blood samples collected from 103 AMI patients, 149 non-AMI subjects, and 95 healthy volunteers. We found that only two of them, Zinc finger antisense 1 (ZFAS1) and Cdr1 antisense (CDR1AS), showed significant differential expression between AMI patients and control subjects. Circulating level of ZFAS1 was significantly lower in AMI (0.74 +/- 0.07) than in non-AMI subjects (1.0 +/- 0.05, P < 0.0001), whereas CDR1AS showed the opposite changes with its blood level markedly higher in AMI (2.18 +/- 0.24) than in non AMI subjects (1.0 +/- 0.05, P < 0.0001). When comparison was made between AMI and non-AMI, the area under ROC curve was 0.664 for ZFAS1 alone or 0.671 for CDR1AS alone, and 0.691 for ZFAS1 and CDR1AS combination. Univariate and multivariate analyses identified these two lncRNAs as independent predictors for AMI. Similar changes of circulating ZFAS1 and CDR1AS were consistently observed in an AMI mouse model. Reciprocal changes of circulating ZFAS1 and CDR1AS independently predict AMI and may be considered novel biomarkers of AMI. PMID- 26928233 TI - Comparison of Different Methods of Valsalva Maneuver for Right-to-left Shunt Detection by Contrast-Enhanced Transcranial Doppler. AB - We evaluated 298 patients for right-to-left shunt (RLS) detection by contrast enhanced transcranial Doppler at rest state (RS), during the conventional Valsalva maneuver (CM), and during the modified Valsalva maneuver (BM: blowing into the connecting tube of a sphygmomanometer at 40 mm Hg for 10 s) in random order, and the degree of RLS along the time of the first microbubble occurrence was recorded. The positive rates were 21.8%, 36.9% and 47.3% for RS, CM and BM, respectively (p < 0.001). BM resulted in a significantly higher positive rate (p = 0.010), and there was a significant difference between the two different methods of VM in terms of the degree of RLS detection (p < 0.001). Further, the first microbubble occurred later during BM than CM (10.22 +/- 3.77 s vs. 9.44 +/- 4.36 s, p < 0.05). This modified maneuver is an alternative to the conventional one, especially for those who cannot perform the conventional maneuver adequately, but are highly suspected of having RLS. PMID- 26928235 TI - A Gene Gun-mediated Nonviral RNA trans-splicing Strategy for Col7a1 Repair. AB - RNA trans-splicing represents an auspicious option for the correction of genetic mutations at RNA level. Mutations within COL7A1 causing strong reduction or absence of type VII collagen are associated with the severe skin blistering disease dystrophic epidermolysis bullosa. The human COL7A1 mRNA constitutes a suitable target for this RNA therapy approach, as only a portion of the almost 9 kb transcript has to be delivered into the target cells. Here, we have proven the feasibility of 5' trans-splicing into the Col7a1 mRNA in vitro and in vivo. We designed a 5' RNA trans-splicing molecule, capable of replacing Col7a1 exons 1-15 and verified it in a fluorescence-based trans-splicing model system. Specific and efficient Col7a1 trans-splicing was confirmed in murine keratinocytes. To analyze trans-splicing in vivo, we used gene gun delivery of a minicircle expressing a FLAG-tagged 5' RNA trans-splicing molecule into the skin of wild-type mice. Histological and immunofluorescence analysis of bombarded skin sections revealed vector delivery and expression within dermis and epidermis. Furthermore, we have detected trans-spliced type VII collagen protein using FLAG-tag antibodies. In conclusion, we describe a novel in vivo nonviral RNA therapy approach to restore type VII collagen expression for causative treatment of dystrophic epidermolysis bullosa. PMID- 26928234 TI - Translational control by eIF2alpha phosphorylation regulates vulnerability to the synaptic and behavioral effects of cocaine. AB - Adolescents are especially prone to drug addiction, but the underlying biological basis of their increased vulnerability remains unknown. We reveal that translational control by phosphorylation of the translation initiation factor eIF2alpha (p-eIF2alpha) accounts for adolescent hypersensitivity to cocaine. In adolescent (but not adult) mice, a low dose of cocaine reduced p-eIF2alpha in the ventral tegmental area (VTA), potentiated synaptic inputs to VTA dopaminergic neurons, and induced drug-reinforced behavior. Like adolescents, adult mice with reduced p-eIF2alpha-mediated translational control were more susceptible to cocaine-induced synaptic potentiation and behavior. Conversely, like adults, adolescent mice with increased p-eIF2alpha became more resistant to cocaine's effects. Accordingly, metabotropic glutamate receptor-mediated long-term depression (mGluR-LTD)-whose disruption is postulated to increase vulnerability to drug addiction-was impaired in both adolescent mice and adult mice with reduced p-eIF2alpha mediated translation. Thus, during addiction, cocaine hijacks translational control by p-eIF2alpha, initiating synaptic potentiation and addiction-related behaviors. These insights may hold promise for new treatments for addiction. PMID- 26928237 TI - Green apatites: hydride ions, electrons and their interconversion in the crystallographic channel. AB - Hydride (H(-)) ions and electrons in channel sites of the lattice of calcium phosphate apatites are characterized. Solid-state chemical reduction using TiH2 is effective for doping of H(-) ions into apatites. Irradiation of the H(-) ion doped apatite with ultraviolet (UV) light induces green coloration. Electron paramagnetic resonance (EPR) reveals that this colour centre is attributed to electrons captured at a vacant anion site in the crystallographic channel, forming F(+) centres. Transient H(0) atoms are detected at low temperatures by EPR. The concentration of UV-induced electrons in the apatite at room temperature decays according to second-order kinetics because of the chemical reactions involving two electrons; overall, electron generation and thermal decay can be described as: H(-) + O(2-) <-> 2e(-) + OH(-). (1)H magic angle spinning nuclear magnetic resonance spectroscopy is used to identify H(-) ions in the apatite, which are characterized by a chemical shift of +3.4 ppm. Various types of O-H groups including OH(-) ions in the channel and protons bound to phosphate groups are concurrently formed, and are identified by considering the relationship between the O-H stretching frequency and the (1)H chemical shift. The complementary results obtained by EPR and NMR reveal that the H(-) ions and transient H(0) atoms are located at the centre of Ca3 triangles in the apatite, while the electrons are located in the centre of Ca6 octahedra. These findings provide an effective approach for identifying new classes of mixed-oxide-hydride or -electride crystals. PMID- 26928236 TI - DNA as Tunable Adaptor for siRNA Polyplex Stabilization and Functionalization. AB - siRNA and microRNA are promising therapeutic agents, which are engaged in a natural mechanism called RNA interference that modulates gene expression posttranscriptionally. For intracellular delivery of such nucleic acid triggers, we use sequence-defined cationic polymers manufactured through solid phase chemistry. They consist of an oligoethanamino amide core for siRNA complexation and optional domains for nanoparticle shielding and cell targeting. Due to the small size of siRNA, electrostatic complexes with polycations are less stable, and consequently intracellular delivery is less efficient. Here we use DNA oligomers as adaptors to increase size and charge of cargo siRNA, resulting in increased polyplex stability, which in turn boosts transfection efficiency. Extending a single siRNA with a 181-nucleotide DNA adaptor is sufficient to provide maximum gene silencing aided by cationic polymers. Interestingly, this simple strategy was far more effective than merging defined numbers (4-10) of siRNA units into one DNA scaffolded construct. For DNA attachment, the 3' end of the siRNA passenger strand was beneficial over the 5' end. The impact of the attachment site however was resolved by introducing bioreducible disulfides at the connection point. We also show that DNA adaptors provide the opportunity to readily link additional functional domains to siRNA. Exemplified by the covalent conjugation of the endosomolytic influenza peptide INF-7 to siRNA via a DNA backbone strand and complexing this construct with a targeting polymer, we could form a highly functional polyethylene glycol-shielded polyplex to downregulate a luciferase gene in folate receptor-positive cells. PMID- 26928238 TI - Seric and hepatic NTPDase and 5' nucleotidase activities of rats experimentally infected by Fasciola hepatica. AB - The enzymatic activities of NTPDase and 5'nucleotidase are important to regulate the concentration of adenine nucleotides, known molecules involved in many physiological functions. Therefore, the objective of this study was to evaluate the activity of NTPDase and 5'nucleotidase in serum and liver tissue of rats infected by Fasciola hepatica. Rats were divided into two groups: uninfected control and infected. NTPDase activity for adenosine triphosphate (ATP) and ADP substrates in the liver was higher compared with the control group at 15 days post-infection (PI), while seric activity was lower. In addition, seric and hepatic samples did not show changes for 5'nucleotidase activity at this time. On the other hand, either NTPDase or 5'nucleotidase activities in liver homogenate and serum were higher at 87 days PI. Early in the infection, low NTPDase activity maintains an increase of ATP in the bloodstream in order to activate host immune response, while in hepatic tissue it decreases extracellular ATP to maintain a low inflammatory response in the tissue. As stated, higher NTPDase and 5'nucleotidase activities 87 days after infection in serum and tissue, probably results on an increased concentration of adenosine molecule which stimulates a Th2 immune response. Thus, it is possible to conclude that F. hepatica infections lead to different levels of nucleotide degradation when considering the two stages of infection studied, which influences the inflammatory and pathological processes developed by the purinergic system. PMID- 26928239 TI - Relationships among measures of physical activity and hearing in African Americans: The Jackson Heart Study. AB - OBJECTIVES/HYPOTHESIS: To evaluate the relationships among measures of physical activity and hearing in the Jackson Heart Study. STUDY DESIGN: Prospective cohort study. METHODS: We assessed hearing on 1,221 Jackson Heart Study participants who also had validated physical activity questionnaire data on file. Hearing thresholds were measured across frequency octaves from 250 to 8,000 Hz, and various frequency pure-tone averages (PTAs) were constructed, including PTA4 (average of 500, 1,000, 2,000, and 4,000 Hz), PTA-high (average of 4,000 and 8,000 Hz), PTA-mid (average of 1,000 and 2,000 Hz), and PTA-low (average of 250 and 500 Hz). Hearing loss was defined for pure tones and pure-tone averages as >25 dB HL in either ear and averaged between the ears. Associations between physical activity and hearing were estimated using linear regression, reporting changes in decibel hearing level, and logistic regression, reporting odds ratios (OR) of hearing loss. RESULTS: Physical activity exhibited a statistically significant but small inverse relationship with PTA4, -0.20 dB HL per doubling of activity (95% confidence interval [CI]: -0.35, -0.04; P = .016), as well as with PTA-low and pure tones at 250, 2,000, and 4,000 Hz in adjusted models. Multivariable logistic regression modeling supported a decrease in the odds of high-frequency hearing loss among participants who reported at least some moderate weekly physical activity (PTA-high, OR: 0.69 [95% CI: 0.52, 0.92]; P = .011 and 4000 Hz, OR: 0.75 [95% CI: 0.57, 0.99]; P = .044). CONCLUSIONS: Our study provides further evidence that physical activity is related to better hearing; however, the clinical significance of this relationship cannot be estimated given the nature of the cross-sectional study design. LEVEL OF EVIDENCE: 2b Laryngoscope, 126:2376-2381, 2016. PMID- 26928240 TI - Elderly patients > 65 years of age with acute myeloid leukemia and normal karyotype benefit from intensive therapeutic programs. PMID- 26928242 TI - Improving the Performance of Lithium-Sulfur Batteries by Employing Polyimide Particles as Hosting Matrixes. AB - Sulfur cathodes with four polyimide (PI) compounds as hosting matrixes have been prepared through a simple one-step approach. These four PIs-S composites exhibited higher sulfur utilization and better cycling stability than pure sulfur. At a current rate of 300 mA g(-1), the initial discharge capacities of PI 1S, PI-2S, PI-3S, and BBLS reached 1120, 1100, 1150, and 1040 mAh g(-1), respectively. After the 30th cycle, PI-1S, PI-2S, PI-3S, BBLS and pristine sulfur powder still remained discharge capacities of 715, 673, 729, 643, and 550 mAh g( 1). Especially, PI-1S and PI-3S cathodes exhibit excellent cycling stability with the discharge capacities of 522 and 574 mAh g(-1) at the 450th cycle, respectively. PMID- 26928244 TI - A high-performance supercapacitor cell based on ZIF-8-derived nanoporous carbon using an organic electrolyte. AB - Low-cost supercapacitors have the ability to rapidly store a large amount of charge, which makes them the best alternative to batteries in portable electronics. Here, we demonstrate the fabrication of all-carbon supercapacitors using an organic electrolyte. By using ZIF-derived nanoporous carbon electrodes, we have realized a high-performance supercapacitor cell using 2 M NEt4BF4/PC as the electrolyte. Our device shows good energy storage capacity that is comparable to the other previously reported supercapacitors. PMID- 26928241 TI - Regulation of long-term repopulating hematopoietic stem cells by EPCR/PAR1 signaling. AB - The common developmental origin of endothelial and hematopoietic cells is manifested by coexpression of several cell surface receptors. Adult murine bone marrow (BM) long-term repopulating hematopoietic stem cells (LT-HSCs), endowed with the highest repopulation and self-renewal potential, express endothelial protein C receptor (EPCR), which is used as a marker to isolate them. EPCR/protease-activated receptor-1 (PAR1) signaling in endothelial cells has anticoagulant and anti-inflammatory roles, while thrombin/PAR1 signaling induces coagulation and inflammation. Recent studies define two new PAR1-mediated signaling cascades that regulate EPCR(+) LT-HSC BM retention and egress. EPCR/PAR1 signaling facilitates LT-HSC BM repopulation, retention, survival, and chemotherapy resistance by restricting nitric oxide (NO) production, maintaining NO(low) LT-HSC BM retention with increased VLA4 expression, affinity, and adhesion. Conversely, acute stress and clinical mobilization upregulate thrombin generation and activate different PAR1 signaling that overcomes BM EPCR(+) LT-HSC retention, inducing their recruitment to the bloodstream. Thrombin/PAR1 signaling induces NO generation, TACE-mediated EPCR shedding, and upregulation of CXCR4 and PAR1, leading to CXCL12-mediated stem and progenitor cell mobilization. This review discusses new roles for factors traditionally viewed as coagulation related, which independently act in the BM to regulate PAR1 signaling in bone- and blood-forming progenitor cells, navigating their fate by controlling NO production. PMID- 26928245 TI - Detection of locally radio-recurrent prostate cancer at multiparametric MRI: Can dynamic contrast-enhanced imaging be omitted? AB - OBJECTIVE: The goal of this study was to assess the added value of dynamic contrast-enhanced (DCE) imaging in detecting locally radio-recurrent prostate cancer using multiparametric magnetic resonance imaging (mpMRI) at 3Tesla (T). MATERIALS AND METHODS: We retrospectively analyzed 45 patients with rising prostate-specific antigen level after prostate radiotherapy who underwent mpMRI [T2-weighted (T2w), diffusion-weighted (Dw) and DCE imaging] at 3T before prostate biopsy. Four readers assigned a 5-level Likert score of cancer likelihood in 8 prostate sectors (6 sextants, 2 seminal vesicles) on T2w+Dw and T2w+Dw+DCE images. Biopsy results were used as the standard of reference. RESULTS: T2w+Dw and T2w+Dw+DCE imaging had similar areas under the receiver operating characteristic curves on per-sector (0.87-0.89 vs. 0.87-0.89; P=0.19 0.78) and per-lobe (0.82-0.94 vs. 0.80-0.91; P=0.21-0.84) analysis. Using a Likert score>=2/5 for diagnosis threshold, T2w+Dw+DCE imaging showed non significantly higher sensitivities on per-sector (0.56-0.72 vs. 0.52-0.73, P=0.34 0.69) and per-lobe (0.80-0.90 vs. 0.73-0.88; P=0.63-0.99) analysis. It also showed non-significantly lower specificities on per-sector (0.74-0.89 vs. 0.82 0.89; P=0.09-0.99) and per-lobe (0.48-0.81 vs. 0.61-0.84; P=0.10-0.99) analysis. Weighted kappa values were respectively 0.57-0.70 and 0.55-0.66 for T2w+Dw and T2w+Dw+DCE imaging at the sector level, and 0.66-0.83 and 0.58-0.85 at the lobe level. CONCLUSION: The use of DCE MR imaging tends to increase sensitivity and decrease specificity for all readers, but the differences are not significant. PMID- 26928228 TI - Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1, RMND1 and CCDC170. AB - We analyzed 3,872 common genetic variants across the ESR1 locus (encoding estrogen receptor alpha) in 118,816 subjects from three international consortia. We found evidence for at least five independent causal variants, each associated with different phenotype sets, including estrogen receptor (ER(+) or ER(-)) and human ERBB2 (HER2(+) or HER2(-)) tumor subtypes, mammographic density and tumor grade. The best candidate causal variants for ER(-) tumors lie in four separate enhancer elements, and their risk alleles reduce expression of ESR1, RMND1 and CCDC170, whereas the risk alleles of the strongest candidates for the remaining independent causal variant disrupt a silencer element and putatively increase ESR1 and RMND1 expression. PMID- 26928243 TI - Pathogenesis of Nonalcoholic Steatohepatitis. AB - Nonalcoholic steatohepatitis (NASH) is a necro-inflammatory response that ensues when hepatocytes are injured by lipids (lipotoxicity). NASH is a potential outcome of nonalcoholic fatty liver (NAFL), a condition that occurs when lipids accumulate in hepatocytes. NASH may be reversible, but it can also result in cirrhosis and primary liver cancer. We are beginning to learn about the mechanisms of progression of NAFL and NASH. NAFL does not inevitably lead to NASH because NAFL is a heterogeneous condition. This heterogeneity exists because different types of lipids with different cytotoxic potential accumulate in the NAFL, and individuals with NAFL differ in their ability to defend against lipotoxicity. There are no tests that reliably predict which patients with NAFL will develop lipotoxicity. However, NASH encompasses the spectrum of wound healing responses induced by lipotoxic hepatocytes. Differences in these wound healing responses among individuals determine whether lipotoxic livers regenerate, leading to stabilization or resolution of NASH, or develop progressive scarring, cirrhosis, and possibly liver cancer. We review concepts that are central to the pathogenesis of NASH. PMID- 26928246 TI - Innovation in the prognostication of chronic lymphocytic leukemia: how far beyond TP53 gene analysis can we go? PMID- 26928247 TI - Securing reimbursement for patient centered haemophilia care: major collaborative efforts are needed. PMID- 26928250 TI - Dietary and pharmacological factors affecting iron absorption in mice and man (Comment for a Letter to the editor). PMID- 26928249 TI - Consensus expert recommendations for identification and management of asparaginase hypersensitivity and silent inactivation. AB - L-asparaginase is an integral component of therapy for acute lymphoblastic leukemia. However, asparaginase-related complications, including the development of hypersensitivity reactions, can limit its use in individual patients. Of considerable concern in the setting of clinical allergy is the development of neutralizing antibodies and associated asparaginase inactivity. Also problematic in the use of asparaginase is the potential for the development of silent inactivation, with the formation of neutralizing antibodies and reduced asparaginase activity in the absence of a clinically evident allergic reaction. Here we present guidelines for the identification and management of clinical hypersensitivity and silent inactivation with Escherichia coli- and Erwinia chrysanthemi- derived asparaginase preparations. These guidelines were developed by a consensus panel of experts following a review of the available published data. We provide a consensus of expert opinions on the role of serum asparaginase level assessment, indications for switching asparaginase preparation, and monitoring after change in asparaginase preparation. PMID- 26928248 TI - Epigenetic regulators and their impact on therapy in acute myeloid leukemia. AB - Genomic studies of hematologic malignancies have identified a spectrum of recurrent somatic alterations that contribute to acute myeloid leukemia initiation and maintenance, and which confer sensitivities to molecularly targeted therapies. The majority of these genetic events are small, site-specific alterations in DNA sequence. In more than two thirds of patients with de novo acute myeloid leukemia mutations epigenetic modifiers are detected. Epigenetic modifiers encompass a large group of proteins that modify DNA at cytosine residues or cause post-translational histone modifications such as methylations or acetylations. Altered functions of these epigenetic modifiers disturb the physiological balance between gene activation and gene repression and contribute to aberrant gene expression regulation found in acute myeloid leukemia. This review provides an overview of the epigenetic modifiers mutated in acute myeloid leukemia, their clinical relevance and how a deeper understanding of their biological function has led to the discovery of new specific targets, some of which are currently tested in mechanism-based clinical trials. PMID- 26928252 TI - Comment on Lipsky et al.: Incidence and Risk Factors of Bleeding-Related Adverse Events in Patients with Chronic Lymphocytic Leukemia Treated with Ibrutinib. PMID- 26928251 TI - Response to: Dietary and pharmacological factors affecting iron absorption in mice and man. PMID- 26928253 TI - Response to Comment on Incidence and Risk Factors of Bleeding-Related Adverse Events in Patients with Chronic Lymphocytic Leukemia Treated with Ibrutinib. PMID- 26928255 TI - Multiple classifier systems for automatic sleep scoring in mice. AB - BACKGROUND: Electroencephalogram (EEG) and electromyogram (EMG) recordings are often used in rodents to study sleep architecture and sleep-associated neural activity. These recordings must be scored to designate what sleep/wake state the animal is in at each time point. Manual sleep-scoring is very time-consuming, so machine-learning classifier algorithms have been used to automate scoring. NEW METHOD: Instead of using single classifiers, we implement a multiple classifier system. The multiple classifier is built from six base classifiers: decision tree, k-nearest neighbors, naive Bayes, support vector machine, neural net, and linear discriminant analysis. Decision tree and k-nearest neighbors were improved into ensemble classifiers by using bagging and random subspace. Confidence scores from each classifier were combined to determine the final classification. Ambiguous epochs can be rejected and left for a human to classify. RESULTS: Support vector machine was the most accurate base classifier, and had error rate of 0.054. The multiple classifier system reduced the error rate to 0.049, which was not significantly different from a second human scorer. When 10% of epochs were rejected, the remaining epochs' error rate dropped to 0.018. COMPARISON WITH EXISTING METHOD(S): Compared with the most accurate single classifier (support vector machine), the multiple classifier reduced errors by 9.4%. The multiple classifier surpassed the accuracy of a second human scorer after rejecting only 2% of epochs. CONCLUSIONS: Multiple classifier systems are an effective way to increase automated sleep scoring accuracy. Improvements in autoscoring will allow sleep researchers to increase sample sizes and recording lengths, opening new experimental possibilities. PMID- 26928254 TI - Social cognition and prefrontal hemodynamic responses during a working memory task in schizophrenia. AB - Social cognition is an important determinant of functional impairment in schizophrenia, but its relationship with the prefrontal functional abnormalities associated with the condition is still unclear. The present study aimed to explore the relationship between social cognition and prefrontal function in patients with schizophrenia using 52-channel near-infrared spectroscopy (NIRS). Twenty-six patients with schizophrenia and 26 age-, gender-, and intelligence quotient-matched healthy controls (HCs) participated in the study. Hemodynamic responses in the prefrontal and superior temporal cortical regions were assessed during a working memory task using NIRS. Social cognition was assessed using the Social Cognition Screening Questionnaire (SCSQ). The observed hemodynamic responses were significantly reduced in the lateral prefrontal cortex (PFC), the frontopolar cortex, and temporal regions in subjects with schizophrenia compared to HCs. Additionally, lateral PFC hemodynamic responses assessed during the working memory task demonstrated a strong positive correlation with the SCSQ theory of mind (ToM) subscale score even after controlling for working memory performance. These results suggest that ToM integrity is closely related to lateral PFC functional abnormalities found in patients with schizophrenia. In addition, this study provides evidence to suggest that NIRS could be used to identify biomarkers of social cognition function in subjects with schizophrenia. PMID- 26928256 TI - Measuring complex behaviors of local oscillatory networks in deep brain local field potentials. AB - BACKGROUND: Multiple oscillations emerging from the same neuronal substrate serve to construct a local oscillatory network. The network usually exhibits complex behaviors of rhythmic, balancing and coupling between the oscillations, and the quantification of these behaviors would provide valuable insight into organization of the local network related to brain states. NEW METHOD: An integrated approach to quantify rhythmic, balancing and coupling neural behaviors based upon power spectral analysis, power ratio analysis and cross-frequency power coupling analysis was presented. Deep brain local field potentials (LFPs) were recorded from the thalamus of patients with neuropathic pain and dystonic tremor. t-Test was applied to assess the difference between the two patient groups. RESULTS: The rhythmic behavior measured by power spectral analysis showed significant power spectrum difference in the high beta band between the two patient groups. The balancing behavior measured by power ratio analysis showed significant power ratio differences at high beta band to 8-20 Hz, and 30-40 Hz to high beta band between the patient groups. The coupling behavior measured by cross-frequency power coupling analysis showed power coupling differences at (theta band, high beta band) and (45-55 Hz, 70-80 Hz) between the patient groups. COMPARISON WITH EXISTING METHOD: The study provides a strategy for studying the brain states in a multi-dimensional behavior space and a framework to screen quantitative characteristics for biomarkers related to diseases or nuclei. CONCLUSIONS: The work provides a comprehensive approach for understanding the complex behaviors of deep brain LFPs and identifying quantitative biomarkers for brain states related to diseases or nuclei. PMID- 26928257 TI - An automatic experimental apparatus to study arm reaching in New World monkeys. AB - BACKGROUND: Several species of the New World monkeys have been used as experimental models in biomedical and neurophysiological research. However, a method for controlled arm reaching tasks has not been developed for these species. NEW METHOD: We have developed a fully automated, pneumatically driven, portable, and reconfigurable experimental apparatus for arm-reaching tasks suitable for these small primates. RESULTS: We have utilized the apparatus to train two owl monkeys in a visually-cued arm-reaching task. Analysis of neural recordings demonstrates directional tuning of the M1 neurons. COMPARISON WITH EXISTING METHOD(S): Our apparatus allows automated control, freeing the experimenter from manual experiments. CONCLUSION: The presented apparatus provides a valuable tool for conducting neurophysiological research on New World monkeys. PMID- 26928258 TI - Optimizing the 3D-reconstruction technique for serial block-face scanning electron microscopy. AB - BACKGROUND: Elucidating the anatomy of neuronal circuits and localizing the synaptic connections between neurons, can give us important insights in how the neuronal circuits work. We are using serial block-face scanning electron microscopy (SBEM) to investigate the anatomy of a collision detection circuit including the Lobula Giant Movement Detector (LGMD) neuron in the locust, Locusta migratoria. For this, thousands of serial electron micrographs are produced that allow us to trace the neuronal branching pattern. NEW METHOD: The reconstruction of neurons was previously done manually by drawing cell outlines of each cell in each image separately. This approach was very time consuming and troublesome. To make the process more efficient a new interactive software was developed. It uses the contrast between the neuron under investigation and its surrounding for semi automatic segmentation. RESULTS: For segmentation the user sets starting regions manually and the algorithm automatically selects a volume within the neuron until the edges corresponding to the neuronal outline are reached. Internally the algorithm optimizes a 3D active contour segmentation model formulated as a cost function taking the SEM image edges into account. This reduced the reconstruction time, while staying close to the manual reference segmentation result. COMPARISON WITH EXISTING METHODS: Our algorithm is easy to use for a fast segmentation process, unlike previous methods it does not require image training nor an extended computing capacity. CONCLUSION: Our semi-automatic segmentation algorithm led to a dramatic reduction in processing time for the 3D reconstruction of identified neurons. PMID- 26928260 TI - Phototransformation-Induced Aggregation of Functionalized Single-Walled Carbon Nanotubes: The Importance of Amorphous Carbon. AB - Single-walled carbon nanotubes (SWCNTs) with proper functionalization are desirable for applications that require dispersion in aqueous and biological environments, and functionalized SWCNTs also serve as building blocks for conjugation with specific molecules in these applications. In this study, we examined the phototransformation of carboxylated SWCNTs and associated amorphous carbon impurities in the presence or absence of H2O2 under simulated sunlight conditions. We found that while carboxylated SWCNTs were rather unreactive with respect to direct solar photolysis, they photoreacted in the presence of H2O2, forming CO2 and strongly aggregated SWCNT products that precipitated. Photoreaction caused SWCNTs to lose oxygen-containing functionalities, and interestingly, the resulting photoproducts had spectral characteristics similar to those of parent carboxylated SWCNTs whose amorphous carbon was removed by base washing. These results indicated that photoreaction of the amorphous carbon was likely involved. The removal of amorphous carbon after indirect photoreaction was confirmed with thermogravimetric analysis (TGA). Further studies using carboxylated SWCNTs with and without base washing indicate that amorphous carbon reduced the extent of aggregation caused by photoreaction. The second-order rate constant for carboxylated SWCNTs reacting with (*)OH was estimated to be in the range of 1.7-3.8 * 10(9) MC(-1) s(-1). The modeled phototransformation half-lives fall in the range of 2.8-280 days in typical sunlit freshwaters. Our study indicates that photosensitized reactions involving (*)OH may be a transformation and removal pathway of functionalized SWCNTs in the aquatic environment, and that the residual amorphous carbon associated with SWCNTs plays a role in SWCNT stabilization. PMID- 26928259 TI - Benefits/risks of sodium-glucose co-transporter 2 inhibitor canagliflozin in women for the treatment of Type 2 diabetes. AB - Sodium-glucose co-transporter 2 (SGLT2) inhibitors, such as canagliflozin, are used in patients with Type 2 diabetes mellitus (T2DM). In clinical studies, canagliflozin significantly reduced A1C, bodyweight and blood pressure, and was generally well tolerated with no increased risk of hypoglycemia. Most common adverse effects observed were genital mycotic infections and urinary tract infections, and increased urination. Approximately 10% of women treated with canagliflozin experienced a genital mycotic infection compared with 3% treated with placebo; those with a prior history were at greater risk. Approximately 9% of women treated with canagliflozin reported a urinary tract infection compared with 7% treated with placebo. Most adverse events were considered mild to moderate in intensity and responded to standard therapy. Treatment with canagliflozin was effective and generally well tolerated in both women (and men) with T2DM. PMID- 26928261 TI - Dendrimer-mediated approaches for the treatment of brain tumor. AB - Worldwide, the cancer appeared as one of the most leading cause of morbidity and mortality. Among the various cancer types, brain tumors are most life threatening with low survival rate. Every year approximately 238,000 new cases of brain and other central nervous system tumors are diagnosed. The dendrimeric approaches have a huge potential for diagnosis and treatment of brain tumor with targeting abilities of molecular cargoes to the tumor sites and the efficiency of crossing the blood brain barrier and penetration to brain after systemic administration. The various generations of dendrimers have been designed as novel targeted drug delivery tools for new therapies including sustained drug release, gene therapy, and antiangiogenic activities. At present era, various types of dendrimers like PAMAM, PPI, and PLL dendrimers validated them as milestones for the treatment and diagnosis of brain tumor as well as other cancers. This review highlights the recent research, opportunities, advantages, and challenges involved in development of novel dendrimeric complex for the therapy of brain tumor. PMID- 26928262 TI - Quantum Nuclear Dynamics Pumped and Probed by Ultrafast Polarization Controlled Steering of a Coherent Electronic State in LiH. AB - The quantum wave packet dynamics following a coherent electronic excitation of LiH by an ultrashort, polarized, strong one-cycle infrared optical pulse is computed on several electronic states using a grid method. The coupling to the strong field of the pump and the probe pulses is included in the Hamiltonian used to solve the time-dependent Schrodinger equation. The polarization of the pump pulse allows us to control the localization in time and in space of the nonequilibrium coherent electronic motion and the subsequent nuclear dynamics. We show that transient absorption, resulting from the interaction of the total molecular dipole with the electric fields of the pump and the probe, is a very versatile probe of the different time scales of the vibronic dynamics. It allows probing both the ultrashort, femtosecond time scale of the electronic coherences as well as the longer dozens of femtoseconds time scales of the nuclear motion on the excited electronic states. The ultrafast beatings of the electronic coherences in space and in time are shown to be modulated by the different periods of the nuclear motion. PMID- 26928263 TI - Porous and nonporous orbital implants for treating the anophthalmic socket: A meta-analysis of case series studies. AB - PURPOSE: To assess the efficacy and safety of porous and nonporous implants for management of the anophthalmic socket. METHODS: Case series meta-analysis was conducted with no language restriction, including studies from: PUBMED, EMBASE and LILACS. Study eligibility criteria were case series design with more than 20 cases reported, use of porous and/or nonporous orbital implants, anophthalmic socket and, treatment success defined as no implant exposure or extrusion. Complications rates from each included study were quantified. Proportional meta analysis was performed on both outcomes with a random-effects model and the 95% confidential intervals were calculated. RESULTS: A total of 35 case series studies with a total of 3,805 patients were included in the meta-analysis. There are no studies comparing porous and nonporous implants in the anophthalmic socket treatment. There was no statistically significant difference between porous polyethylene (PP) and hydroxyapatite (HA) on implant exposure: 0.026 (0.012 0.045) vs 0.054 (0.041-0.070), respectively and, neither on implant extrusion: 0.0042 (0.0008-0.010) vs. 0.018 (0.004-0.042), respectively. However, there was a significant difference supporting the use of PP when compared to bioceramic implant: 0.026 (0.012 -0.045) vs. 0.12 (0.06-0.20), respectively, on implant exposure. CONCLUSION: PP implants showed lower chance of exposure than bioceramic implant for anophthalmic socket reconstruction, although we cannot rule out the possibility of heterogeneity bias due to the nature and level of evidence of the included studies. Clinical trials are necessary to expand the knowledge of porous and nonporous orbital implants in the anophthalmic socket management. PMID- 26928264 TI - Induction of trap formation in nematode-trapping fungi by bacteria-released ammonia. AB - A total of 11 bacterial strains were assayed for bacteria-induced trap formation in the nematode-trapping fungus Arthrobotrys oligospora YMF1.01883 with two compartmented Petri dish. These strains were identified on the basis of their 16S rRNA gene sequences. Volatile organic compounds (VOCs) of eight isolates were extracted using solid-phase micro-extraction (SPME) and their structures were identified based on gas chromatography-mass spectrometry (GC-MS). At the same time, all isolates were used for quantitative measurement of ammonia by the indophenol blue method. The effects of pure commercial compounds on inducement of trap formation in A. oligospora were tested. Taken together, results demonstrated that the predominant bacterial volatile compound inducing trap formation was ammonia. Meanwhile, ammonia also played a role in other nematode-trapping fungi, including Arthrobotrys guizhouensis YMF1.00014, producing adhesive nets; Dactylellina phymatopaga YMF1.01474, producing adhesive knobs; Dactylellina cionopaga YMF1.01472, producing adhesive columns and Drechslerella brochopaga YMF1.01829, producing constricting rings. PMID- 26928266 TI - Antibody responses to influenza vaccine in pre- and post-lung transplant patients. AB - BACKGROUND: Although pre-transplant immunization is routinely recommended, this recommendation is based on little data. The primary objective of this study was to compare antibody responses in lung transplant patients who received influenza vaccine before the transplant, within the first six months of transplant, between 13 and 60 months post-transplant, and 110 months or beyond transplant. METHODS: This prospective cohort study included 357 total immunization events performed over five yr to measure H1N1, H3N2, and B antibody responses to the influenza vaccine in pre- and post-lung transplant patients. Geometric mean titers, seroprotection (antibody titer at least 1:40), seroconversion (fourfold increase between pre and post), and mean fold increases were compared. RESULTS: The geometric mean titer distributions were different for H3N2 and B (ANOVA; p = 0.002 for both). Pre-transplant antibody concentrations were higher compared to the 13- to 60-month group for H3N2 (corrected p = 0.002) and the healthy group for B (corrected p = 0.001). The >=110-month group had higher seroconversion rates compared to the 13- to 60-month group for H3N2 and B viruses. CONCLUSION: Lung pre-transplant patients and the long-term survivors have higher responses to the influenza vaccine than early post-transplant and the transplant control groups. PMID- 26928265 TI - Prognostic implications of dynamic serum lactate dehydrogenase assessments in nasopharyngeal carcinoma patients treated with intensity-modulated radiotherapy. AB - The prognostic value of dynamic serum lactate dehydrogenase (LDH) levels in patients with nasopharyngeal carcinoma (NPC) treated with intensity-modulated radiotherapy (IMRT) hasn't been explored. We retrospectively analyzed 1,428 cases of NPC treated with IMRT with or without chemotherapy. Elevated pre- and/or post treatment LDH levels were found to be associated with unfavorable overall survival (OS), disease-free survival (DFS) and distant metastasis-free survival (DMFS), but not with local relapse-free survival (LRFS). The dynamic variations in LDH levels were prognostic factors for OS, DFS and DMFS, but not for LRFS. Multivariate analysis revealed that the N category, T category, post-treatment serum LDH level and age were independent prognostic factors for OS. Our results demonstrated that dynamic variations in LDH levels were associated with risk of distant failure and death, which may shed light on the dynamics of the disease and the response to therapy. We consider that LDH measurements will be of great clinical importance in the management of NPC, especially, when considering "decision points" in treatment algorithms. Therefore, we strongly recommend that LDH levels should be determined before and after treatment in NPC patients and the results integrated into decisions regarding treatment strategies. PMID- 26928267 TI - Retinal Tissue Thickness is Reduced in Diabetic Peripheral Neuropathy. AB - AIM: To investigate the relationship between diabetic peripheral neuropathy (DPN) and retinal tissue thickness. METHODS: Full retinal thickness in the central retinal, parafoveal, and perifoveal zones and thickness of the ganglion cell complex and retinal nerve fiber layer (RNFL) were assessed in 193 individuals (84 with type 1 diabetes, 67 with type 2 diabetes, and 42 healthy controls) using spectral domain optical coherence tomography. Among those with diabetes, 44 had neuropathy defined using a modified neuropathy disability score recorded on a 0 10 scale. Multiple regression analysis was performed to investigate the relationship between diabetic neuropathy and retinal tissue thickness, adjusted for the presence of diabetic retinopathy (DR), age, sex, duration of diabetes, and HbA1c levels. RESULTS: In individuals with diabetes, perifoveal thickness was inversely related to the severity of neuropathy (p < 0.05), when adjusted for age, sex, duration of diabetes, and HbA1c levels. DR was associated with reduced thickness in parafovea (p < 0.01). The RNFL was thinner in individuals with greater degrees of neuropathy (p < 0.04). CONCLUSIONS: DPN is associated with structural compromise involving several retinal layers. This compromise may represent a threat to visual integrity and therefore warrants examination of functional correlates. PMID- 26928268 TI - A Selective and Purification-Free Strategy for Labeling Adherent Cells with Inorganic Nanoparticles. AB - Cellular labeling with inorganic nanoparticles such as magnetic iron oxide nanoparticles, quantum dots, and fluorescent silica nanoparticles is an important method for the noninvasive visualization of cells using various imaging modalities. Currently, this is mainly achieved through the incubation of cultured cells with the nanoparticles that eventually reach the intracellular compartment through specific or nonspecific internalization. This classic method is advantageous in terms of simplicity and convenience, but it suffers from issues such as difficulties in fully removing free nanoparticles (suspended in solution) and the lack of selectivity on cell types. This article reports an innovative strategy for the specific labeling of adherent cells without the concern of freely suspended nanoparticles. This method relies on a nanocomposite film that is prepared by homogeneously dispersing nanoparticles within a biodegradable polymeric film. When adherent cells are seeded on the film, they adhere, spread, and filtrate into the film through the micropores formed during the film fabrication. The pre-embedded nanoparticles are thus internalized by the cells during this infiltration process. As an example, fluorescent silica nanoparticles were homogeneously distributed within a polycaprolactone film by utilizing cryomilling and heat pressing. Upon incubation within physiological buffer, no silica nanoparticles were released from the nanocomposite film even after 20 d of incubation. However, when adherent cells (e.g., human mesenchymal stem cells) were grown on the film, they became fluorescent after 3 d, which suggests internalization of silica nanoparticles by cells. In comparison, the suspension cells (e.g., monocytes) in the medium remained nonfluorescent no matter whether there was the presence of adherent cells or not. This strategy eventually allowed the selective and concomitant labeling of mesenchymal stem cells during their harvest from bone marrow aspiration. PMID- 26928269 TI - Gender differences in memory processing of female facial attractiveness: evidence from event-related potentials. AB - High rates of agreement in the judgment of facial attractiveness suggest universal principles of beauty. This study investigated gender differences in recognition memory processing of female facial attractiveness. Thirty-four Chinese heterosexual participants (17 females, 17 males) aged 18-24 years (mean age 21.63 +/- 1.51 years) participated in the experiment which used event-related potentials (ERPs) based on a study-test paradigm. The behavioral data results showed that both men and women had significantly higher accuracy rates for attractive faces than for unattractive faces, but men reacted faster to unattractive faces. Gender differences on ERPs showed that attractive faces elicited larger early components such as P1, N170, and P2 in men than in women. The results indicated that the effects of recognition bias during memory processing modulated by female facial attractiveness are greater for men than women. Behavioral and ERP evidences indicate that men and women differ in their attentional adhesion to attractive female faces; different mating-related motives may guide the selective processing of attractive men and women. These findings establish a contribution of gender differences on female facial attractiveness during memory processing from an evolutionary perspective. PMID- 26928270 TI - Replication of a genetic variant in ACYP2 associated with cisplatin-induced hearing loss in patients with osteosarcoma. AB - OBJECTIVE: Irreversible hearing loss is a frequent side effect of the chemotherapeutic agent cisplatin and shows considerable interpatient variability. The variant rs1872328 in the ACYP2 gene was recently identified as a risk factor for the development of cisplatin-induced ototoxicity in children with brain tumors. We aimed to replicate this finding in patients with osteosarcoma. METHODS: An independent cohort of 156 patients was genotyped for the rs1872328 variant and evaluated for the presence of cisplatin-induced ototoxicity. RESULTS: A significant association was observed between carriership of the A allele and cisplatin-induced ototoxicity after the end of treatment (P=0.027). CONCLUSION: This is the first study replicating the association of ACYP2 variant rs1872328 with cisplatin-induced ototoxicity in patients with osteosarcoma who did not receive potentially ototoxic cranial irradiation. Hence, the ACYP2 variant should be considered a predictive pharmacogenetic marker for hearing loss, which may be used to guide therapies for patients treated with cisplatin. PMID- 26928271 TI - "In patient" medical abortion versus surgical abortion: patient's satisfaction. AB - OBJECTIVE: To compare patients' satisfaction with medical and surgical abortion, implementing the Italian guidelines on medical abortion entailing an "in patient" procedure. METHODS: A total of 1832 pregnant chose between surgical (vacuum aspiration) or medical abortion (mifepristone p.o. followed after 3 days by sublingual misoprostol) and expressed their expected satisfaction on a visual analog scale (VAS). A total of 885 women chose surgical and 947 medical abortion. The primary end-point was satisfaction VAS score 20 days after the procedure. Secondary end-points were: difference between pre- and post-abortion VAS score; difference in satisfaction VAS scores according to parity and previous abortion; incidence of side effects. RESULTS: VAS score was high in each group but significantly higher for the 1-day surgical than for the 3-day medical abortion procedure (7.9 +/- 1.0 versus 7.2 +/- 1.2; p < 0.0001). In the surgical group the VAS score increased after the treatment (6.9 +/- 1.6 versus 7.9 +/- 1.0, p < 0.0001), while it decreased in the medical group (7.5 +/- 1.0 versus 7.2 +/- 1.2; p < 0.0001). Multiparous women reported higher satisfaction with medical abortion; women with a previous abortion preferred surgical abortion. CONCLUSIONS: Both procedures are considered satisfactory by the patients. Performing medical abortion as a 3-day "in patient" procedure, decreased women's satisfaction scores from their baseline expectations. PMID- 26928272 TI - DNA methylation levels at individual age-associated CpG sites can be indicative for life expectancy. AB - DNA-methylation (DNAm) levels at age-associated CpG sites can be combined into epigenetic aging signatures to estimate donor age. It has been demonstrated that the difference between such epigenetic age-predictions and chronological age is indicative for of all-cause mortality in later life. In this study, we tested alternative epigenetic signatures and followed the hypothesis that even individual age-associated CpG sites might be indicative for life-expectancy. Using a 99-CpG aging model, a five-year higher age-prediction was associated with 11% greater mortality risk in DNAm profiles of the Lothian Birth Cohort 1921 study. However, models based on three CpGs, or even individual CpGs, generally revealed very high offsets in age-predictions if applied to independent microarray datasets. On the other hand, we demonstrate that DNAm levels at several individual age-associated CpGs seem to be associated with life expectancy - e.g., at CpGs associated with the genesPDE4C and CLCN6. Our results support the notion that small aging signatures should rather be analysed by more quantitative methods, such as site-specific pyrosequencing, as the precision of age predictions is rather low on independent microarray datasets. Nevertheless, the results hold the perspective that simple epigenetic biomarkers, based on few or individual age-associated CpGs, could assist the estimation of biological age. PMID- 26928273 TI - How much therapy is enough? Comparing dose-effect and good-enough models in two different settings. AB - The Dose-Effect model holds that longer therapy leads to better outcome, although increasing treatment length will yield diminishing returns, as additional sessions lead to progressively less change in a negatively accelerating fashion. In contrast, the Good-Enough-Level (GEL) model proposes that patients, therapists, or patients-with-therapists decide on ending treatment when treatment outcome is satisfactory, meaning that patients who change faster will have shorter treatments. If true, this means that aggregating among patients with different treatment lengths would yield biased results. Most previous research has shown that symptom change rate depends on treatment length, but all of these studies used data from University counseling centers in the United States. There is a need to test if previous results hold in different settings. Two datasets from Swedish community-based primary care (n = 640) and psychiatric care (n = 284) were used. Patients made session-wise ratings on the Clinical Outcomes in Routine Evaluation-Outcome Measure (CORE-OM). Multilevel models indicated better fit for a model in which treatment length moderated symptom change rate. In the primary care sample, patients in longer treatments achieved more symptom change from pre- to posttreatment, despite having slower rate of improvement. The most important aspect of the GEL model was supported, and no evidence was found for a negatively accelerating Dose-Effect curve. Results cannot be generalized beyond about 12 sessions, due to scarcity of data for longer treatments. PMID- 26928274 TI - Oxidized Ni/Au Transparent Electrode in Efficient CH3 NH3 PbI3 Perovskite/Fullerene Planar Heterojunction Hybrid Solar Cells. AB - The successful application of a Ni/Au transparent electrode for fabricating efficient perovskite-based solar cells is demonstrated. Through interdiffusion of the Ni/Au bilayer, Au forms an interconnected metallic network structure as the transparent electrode. Ni diffuses to the bilayer surface and oxidizes into NiOx becoming an appropriate electrode interlayer. These ITO- and PEDOT: PSS-free devices have potential applications in the design of future cost-effective, low weight, and stable solar cells. PMID- 26928275 TI - Case finding for sarcopenia in geriatric inpatients: performance of bioimpedance analysis in comparison to dual X-ray absorptiometry. AB - BACKGROUND: Sarcopenia is a common geriatric syndrome associated with serious adverse health outcomes. The European Working Group on Sarcopenia in Older People (EWGSOP) suggests different methods for case finding for sarcopenia. However, data comparing the different methodological options are scarce for geriatric inpatients. METHODS: On the basis of the recommendations of the EWGSOP sixty geriatric inpatients underwent measurement of gait speed, hand grip strength and muscle mass by both, dual X-ray absorptiometry (DXA) and bioimpedance analysis (BIA). By linear regression analysis and Bland-Altman plots muscle mass measurements of DXA and BIA were compared. Outcomes of the DXA- and BIA-based approaches for classifying participants as having normal or reduced muscle mass and sarcopenia according to the EWGSOP case finding algorithm were compared by raw agreement and kappa statistics. Finally, on the hypothetical assumption that the DXA-based approach can be set as reference, the performance of the BIA-based approach is illustrated. RESULTS: Muscle mass measured by BIA was highly correlated to DXA (r > 0.9), but BIA systematically overestimated muscle mass. The mean difference between DXA and BIA was -1.30 kg (p < 0.001) for appendicular and -2.33 kg (p < 0.001) for total muscle mass. The raw agreement between the DXA and BIA-based approaches for classifying participants as having normal or reduced muscle mass was at best 80 % depending on the BIA cut-offs used. Functional prescreening according to the sarcopenia case finding algorithm of the EWGSOP reduced the need for muscle mass measurement by 37 %, but only marginally changed the agreement between the DXA- and BIA-based approaches. CONCLUSION: Clinicians should be aware that in geriatric inpatients the BIA-based approaches resulted in highly different subgroups of sarcopenic/non-sarcopenic subjects compared to the DXA-based approach following the EWGSOP case finding algorithm. In this pilot-study the BIA-based approach misclassified nearly 1 out of 6 patients if the DXA-based approach is taken as reference. PMID- 26928276 TI - From Nanowires to Nanopores: A Versatile Method for Electroless Deposition of Nanostructures on Micropatterned Organic Substrates. AB - We demonstrate a fast, flexible, parallel, and highly controllable method by which to synthesize a variety of nanoscale and mesoscale structures. This method addresses one of the most significant challenges in nanoscience: the in situ parallel placement and synthesis of nano-objects over the mesoscale. The method is based on electroless nanowire deposition on micropatterned substrates (ENDOM). In ENDOM nanostructures are produced at the boundary between two unlike materials if two conditions are met: (a) deposition is kinetically preferred on one of the materials while (b) transport of reactants is favored on the other. In this study, copper structures were deposited on patterned -OH/-CH3-terminated alkanethiolate self-assembled monolayers (SAMs) by exploiting the different reaction rates of electroless deposition on these using the reducing agent dimethylamine borane (DMAB). We demonstrate production of nanowires (width < 100 nm), mesowires (100 nm < width < ~3000 nm), nanorings, nanopores, and nanochannels. We show that a variety of experimental conditions can be employed, making this method compatible with many substrates. We have also studied the nucleation and growth kinetics of the ENDOM process. The width of the deposit grows exponentially with deposition time and can be modeled using classical nucleation theory. Although the deposit width increases, the height and grain size of the copper deposit is constant (to within experimental uncertainty) with deposition time. These observations indicate that the minimum deposit width is controlled by the nanoparticle dimensions and so can be controlled using the reaction conditions. PMID- 26928277 TI - [ADH/D and impulsiveness: Prevalence of impulse control disorders and other comorbidities, in 81 adults with attention deficit/hyperactivity disorder (ADH/D)]. AB - Attention deficit hyperactivity disorder (ADH/D) is a neuropsychological developmental disorder characterized by pervasive and impairing symptoms of inattention, hyperactivity, and impulsivity. Whereas it is well known in children, there is still little information about ADH/D in adults, including prevalence. Indeed, there are actually no epidemiological studies in France, despite the considerable impact of this disorder in a patient's professional and affective life. Moreover, ADH/D rarely stays isolated, and many comorbidities often complicate the diagnostic investigation. It is well known that the so called ADH/D is composed of two main categories of symptoms (Attentional Disorder/Hyperactiviy Disorder), but Impulsiveness also remains a major symptom. OBJECTIVE: The aim of this study was to evaluate not only the prevalence of Impulse Control Disorders (ICD) but also psychological and addictive comorbidities among adult patients with ADH/D. A total of 100 patients from specialized consultations of adult ADH/D were evaluated in this study, but only 81 were included after presenting all the clinical criteria of ADH/D. METHOD: We used the DSM IV-T-R for ADH/D, the Minnesota Impulsive Disorders Interview a semi structured clinical interview assessing impulse control disorders (ICD) (compulsive buying, trichotillomania, compulsive sexual behaviour, kleptomania, pyromania and intermittent explosive disorder), and the Mini International Neuropsychiatric Interview in order to evaluate psychiatric and addictive comorbidities. RESULTS: More than 90 % of the patients met the early apparition criteria of ADH/D (before 7years). More than half of the patients presented a mixed type of ADH/D (both inattentive and hyperactive-impulsive forms): 55.6 % vs 44.4 % for the inattentive type. The vast majority of patients showed a complete form (with a total of 6 or more symptoms out of 9, of inattentive and/or impulsive-hyperactivity category): 93.8 % and only 6.2 % presented a sub syndromic form of ADH/D (with 3 symptoms at least of one and/or the other category). Regarding the ICDs, we found a proportion of 66 % of patients manifesting at least one, the most frequent ICD being the Intermittent Explosive Disorder (IED): 29.6 %, followed by Compulsive Buying (CB): 23.4 %, Pathological Gambling (PG): 7.4 %, Kleptomania and Compulsive Sexual Behaviour: 2.4 %, and Trichotillomania: 1.2 %. Among the psychiatric comorbidities evaluated, generalized anxiety disorder: 61.7 %, followed by dysthymia: 44.4 %, major depressive episode: 28.3 %, Agoraphobia: 22.2 %, panic disorder: 17.2 %, hypomanic episode: 16 %, social phobia: 11.1 %, bulimia nervosa: 8.6 %, and antisocial personality disorder and obsessive-compulsive disorder: 3.7 %. Regarding the addictive comorbidities, we found a prevalence of 14.8 % of substance abuse (non-alcohol), followed by 7.4 % of alcohol abuse, 6.1 % of substance dependence (non-alcohol), and 3.7 % of alcohol dependence. CONCLUSION: ADH/D in adults continues to be unrecognized in France. The aim of this study was to evaluate the prevalence of impulse control disorders, psychiatric and addictive comorbidities in adults with ADH/D. The results enable us to appreciate quantitative and qualitative data for 81 French adults with ADH/D. This disorder rarely remains isolated and is often associated with many others, especially anxiety and mood disorders. We also observed that impulsivity stays at the heart of the ADH/D, either through impulsive behaviours or addictive disorders. Considering the lack of studies with ADH/D adults, it is difficult to compare our data. The diagnosis of ADH/D is complex and stays controversial, moreover the strong prevalence of comorbidities points out the importance of differential diagnosis. PMID- 26928280 TI - Correction to "Quantitative Profiling for Substrates of the Mitochondrial Presequence Processing Protease Reveals a Set of Nonsubstrate Proteins Increased upon Proteotoxic Stress". PMID- 26928278 TI - Specific cytoarchitectureal changes in hippocampal subareas in daDREAM mice. AB - BACKGROUND: Transcriptional repressor DREAM (downstream regulatory element antagonist modulator) is a Ca(2+)-binding protein that regulates Ca(2+) homeostasis through gene regulation and protein-protein interactions. It has been shown that a dominant active form (daDREAM) is implicated in learning-related synaptic plasticity such as LTP and LTD in the hippocampus. Neuronal spines are reported to play important roles in plasticity and memory. However, the possible role of DREAM in spine plasticity has not been reported. RESULTS: Here we show that potentiating DREAM activity, by overexpressing daDREAM, reduced dendritic basal arborization and spine density in CA1 pyramidal neurons and increased spine density in dendrites in dentate gyrus granule cells. These microanatomical changes are accompanied by significant modifications in the expression of specific genes encoding the cytoskeletal proteins Arc, Formin 1 and Gelsolin in daDREAM hippocampus. CONCLUSIONS: Our results strongly suggest that DREAM plays an important role in structural plasticity in the hippocampus. PMID- 26928279 TI - Molecular Mechanism of Processive 3' to 5' RNA Translocation in the Active Subunit of the RNA Exosome Complex. AB - Recent experimental studies revealed structural details of 3' to 5' degradation of RNA molecules, performed by the exosome complex. ssRNA is channeled through its multisubunit ring-like core into the active site tunnel of its key exonuclease subunit Rrp44, which acts both as an enzyme and a motor. Even in isolation, Rrp44 can pull and sequentially cleave RNA nucleotides, one at a time, without any external energy input and release a final 3-5 nucleotide long product. Using molecular dynamics simulations, we identify the main factors that control these processes. Our free energy calculations reveal that RNA transfer from solution into the active site of Rrp44 is highly favorable, but dependent on the length of the RNA strand. While RNA strands formed by 5 nucleotides or more correspond to a decreasing free energy along the translocation coordinate toward the cleavage site, a 4-nucleotide RNA experiences a free energy barrier along the same direction, potentially leading to incomplete cleavage of ssRNA and the release of short (3-5) nucleotide products. We provide new insight into how Rrp44 catalyzes a localized enzymatic reaction and performs an action distributed over several RNA nucleotides, leading eventually to the translocation of whole RNA segments into the position suitable for cleavage. PMID- 26928281 TI - Eating breakfast, fruit and vegetable intake and their relation with happiness in college students. AB - PURPOSE: Nutrition plays a major role in physical and mental health. The aim of this study was to evaluate the relationships between happiness and fruit and vegetable intake as well as eating breakfast in students. METHODS: In this cross sectional web-based study, all students of Qazvin University of Medical Sciences in Iran who attended course classes were invited to participate in the study. Five hundred forty-one students filled out the web-based questionnaire which included questions related to measurement of happiness, breakfast, fruit and vegetable consumption and socio-economic and demographic information. Analysis of covariance was used to assess the relationship between happiness and breakfast, fruit and vegetable consumption by adjustments for covariates. RESULTS: Measure of happiness was positively associated with eating breakfast, number of meals eaten daily and the amount of fruit and vegetable consumption (P values were <0.001, 0.008, 0.02, and 0.045 respectively). Students who ate breakfast every day, more than 8 servings of fruit and vegetables daily, and had 3 meals in addition to 1-2 snacks per day had the highest happiness score. CONCLUSION: Healthier behavior pattern was associated with higher happiness scores among medical students. PMID- 26928282 TI - Validation of the SCOFF questionnaire for screening of eating disorders among Mexican university students. AB - PURPOSE: To evaluate the criterion validity and diagnostic utility of the SCOFF, a brief eating disorder (ED) screening instrument, in a Mexican sample. METHODS: The study was conducted in two phases in 2012. Phase I involved the administration of self-report measures [the SCOFF and the Eating Disorder Inventory-2, (EDI-2)] to 1057 students aged 17-56 years (M age = 21.0, SD = 3.4; 67 % female) from three colleges at the Universidad Autonoma de San Luis Potosi, Mexico. In Phase II, a random subsample of these students (n = 104) participated in the eating disorder examination, a structured interview that yields ED diagnoses. Analyses were conducted to evaluate the SCOFF's criterion validity by examining (a) correlations between scores on the SCOFF and the EDI-2 and (b) the SCOFF's ability to differentiate diagnosed ED cases and non-cases. RESULTS: EDI-2 subscales showed high correlations with the SCOFF scores proving initial evidence of criterion validity. A score of two points on the SCOFF optimized the sensitivity (78 %) and specificity (84 %). With this cutoff, the SCOFF correctly classified over half the cases (PPV = 58 %) and screened out the majority of non cases (NPV = 93 %) providing further evidence of criterion validity. Analyses were repeated separately for men and women, yielding gender-specific information on the SCOFF's performance. CONCLUSIONS: Taken as a whole, results indicated that the SCOFF can be a useful tool for identifying Mexican university students who are at risk of eating disorders. PMID- 26928283 TI - Unhealthy weight control behaviors mediate the association between weight status and weight-specific health-related quality of life in treatment-seeking youth who are obese. AB - PURPOSE: Examine whether unhealthy and extreme weight control behaviors (WCBs) mediate the relationship between youth weight status and disease-specific health related quality of life (HRQOL) in treatment-seeking youth who are overweight and obese (OV/OB). METHOD: 82 youth 10-17 years of age who were OV/OB and attending an outpatient obesity-related medical appointment completed measures assessing unhealthy and extreme WCBs and disease-specific HRQOL. Parents completed a demographic questionnaire and medical staff measured youth height and weight. RESULTS: Regression analyses revealed that unhealthy WCBs mediated the associations between youth weight status and emotional and social avoidance disease-specific HRQOL, such that higher body mass index (BMI) predicted unhealthy WCBs, which were ultimately associated with poorer emotional and social HRQOL. Mediation analyses were not significant for total, physical, teasing/marginalization, and positive attributes disease-specific HRQOL. In addition, extreme WCBs did not mediate the association between youth weight status and any subscales of the disease-specific HRQOL measure. DISCUSSION: Weight status is an important predictor of disease-specific HRQOL in OV/OB youth; however, the association with emotional and social HRQOL is partially accounted for by youth engagement in unhealthy WCBs. Clinicians and researchers should assess WCBs and further research should explore and evaluate appropriate intervention strategies to address unhealthy WCBs in pediatric weight management prevention and treatment efforts. PMID- 26928284 TI - A cell engineering strategy to enhance supercoiled plasmid DNA production for gene therapy. AB - With the recent revival of the promise of plasmid DNA vectors in gene therapy, a novel synthetic biology approach was used to enhance the quantity, (yield), and quality of the plasmid DNA. Quality was measured by percentage supercoiling and supercoiling density, as well as improving segregational stability in fermentation. We examined the hypothesis that adding a Strong Gyrase binding Site (SGS) would increase DNA gyrase-mediated plasmid supercoiling. SGS from three different replicons, (the Mu bacteriophage and two plasmids, pSC101 and pBR322) were inserted into the plasmid, pUC57. Different sizes of these variants were transformed into E. coli DH5alpha, and their supercoiling properties and segregational stability measured. A 36% increase in supercoiling density was found in pUC57-SGS, but only when SGS was derived from the Mu phage and was the larger sized version of this fragment. These results were also confirmed at fermentation scale. Total percentage supercoiled monomer was maintained to 85 90%. A twofold increase in plasmid yield was also observed for pUC57-SGS in comparison to pUC57. pUC57-SGS displayed greater segregational stability than pUC57-cer and pUC57, demonstrating a further potential advantage of the SGS site. These findings should augment the potential of plasmid DNA vectors in plasmid DNA manufacture. Biotechnol. Bioeng. 2016;113: 2064-2071. (c) 2016 The Authors. Biotechnology and Bioengineering Published by Wiley Periodicals, Inc. PMID- 26928285 TI - Sedentary behavior and subclinical atherosclerosis in African Americans: cross sectional analysis of the Jackson heart study. AB - BACKGROUND: Previous studies have reported conflicting results as to whether an association exists between sedentary time and cardiovascular disease (CVD) risk among African Americans. These studies, however, were limited by lack of consideration of sedentary behavior in leisure versus non-leisure settings. To elucidate this relation, we investigated the associations of television (TV) viewing time and occupational sitting with carotid intima-media thickness (CIMT), a subclinical atherosclerosis measure, in a community-based sample of African Americans. METHODS: We studied 3410 participants from the Jackson Heart Study, a single-site, community-based study of African Americans residing in Jackson, MS. CIMT was assessed by ultrasonography and represented mean far-wall thickness across right and left sides of the common carotid artery. TV viewing time, a measure of leisure sedentary behavior, and occupational sitting, a measure of non leisure sedentary behavior, were assessed by questionnaire. RESULTS: In a multivariable regression model that included physical activity and CVD risk factors, longer TV viewing time (2-4 h/day and >4 h/day) was associated with greater CIMT (adjusted mean +/- SE difference from referent [<2 h/day] of 0.009 +/- 0.008 mm for 2-4 h/day, and 0.028 +/- 0.009 mm for >4 h/day; P-trend =0.001). In contrast, more frequent occupational sitting ('sometimes' and 'often/always') was associated with lower CIMT (adjusted mean +/- SE difference from referent ['never/seldom']:-0.021 +/- 0.009 mm for 'sometimes', and-0.018 +/- 0.008 mm for 'often/always'; P-trend = 0.042). CONCLUSIONS: Longer TV viewing time was associated with greater CIMT, while occupational sitting was associated with lower CIMT. These findings suggest the role of sedentary behaviors in the pathogenesis of CVD among African Americans may vary by whether individuals engage in leisure versus non-leisure sedentary behaviors. PMID- 26928286 TI - Anti-inflammatory neolignans from the roots of Magnolia officinalis. AB - Nine neolignan derivatives (1-9) were characterized from the roots of Magnolia officinalis, and their structures were elucidated based on spectroscopic and physicochemical analyses. Among them, houpulins E (1) and M (9) possess novel homo- and trinor-neolignan skeletons. In addition, 15 known compounds (10-24) were identified by comparison of their spectroscopic and physical data with those reported in the literature. Some of the purified constituents were examined for anti-inflammatory activity and, among the tested compounds, houpulins G (3), I (5), J (6), and 2,2'-dihydroxy-3-methoxy-5,5'-di-(2-propenylbiphenyl) (19) significantly inhibited superoxide anion generation and elastase release with IC50 values ranging from 3.54 to 5.48 MUM and 2.16 to 3.39 MUM, respectively. Therefore, these neolignan derivatives have tremendous potential to be explored as anti-inflammatory agents. PMID- 26928287 TI - Anticancer drug released from near IR-activated prodrug overcomes spatiotemporal limits of singlet oxygen. AB - Photodynamic therapy (PDT) is a cancer treatment modality where photosensitizer (PS) is activated by visible and near IR light to produce singlet oxygen ((1)O2). However, (1)O2 has a short lifetime (<40 ns) and cannot diffuse (<20 nm) beyond the cell diameter (e.g., ~ 1800 nm). Thus, (1)O2 damage is both spatially and temporally limited and does not produce bystander effect. In a heterogeneous tumor, cells escaping (1)O2 damage can regrow after PDT treatment. To overcome these limitations, we developed a prodrug concept (PS-L-D) composed of a photosensitizer (PS), an anti-cancer drug (D), and an (1)O2-cleavable linker (L). Upon illumination of the prodrug, (1)O2 is generated, which damages the tumor and also releases anticancer drug. The locally released drug could cause spatially broader and temporally sustained damage, killing the surviving cancer cells after the PDT damage. In our previous report, we presented the superior activity of our prodrug of CA4 (combretastatin A-4), Pc-(L-CA4)2, compared to its non-cleavable analog, Pc-(NCL-CA4)2, that produced only PDT effects. Here, we provide clear evidence demonstrating that the released anticancer drug, CA4, indeed damages the surviving cancer cells over and beyond the spatial and temporal limits of (1)O2. In the limited light illumination experiment, cells in the entire well were killed due to the effect of released anti-cancer drug, whereas only a partial damage was observed in the pseudo-prodrug treated wells. A time-dependent cell survival study showed more cell death in the prodrug-treated cells due to the sustained damage by the released CA4. Cell cycle analysis and microscopic imaging data demonstrated the typical damage patterns by CA4 in the prodrug treated cells. A time-dependent histological study showed that prodrug-treated tumors lacked mitotic bodies, and the prodrug caused broader and sustained tumor size reduction compared to those seen in the tumors treated with the pseudo-prodrug. This data consistently support that the released CA4 overcomes the spatiotemporal limitations of (1)O2, providing far superior antitumor effect. PMID- 26928289 TI - Recent developments in nanowires for bio-applications from molecular to cellular levels. AB - This review highlights the most promising applications of nanowires for bioanalytical chemistry and medical diagnostics. The materials discussed here are metal oxide and Si semiconductors, which are integrated with various microfluidic systems. Nanowire structures offer desirable advantages such as a very small diameter size with a high aspect ratio and a high surface-to-volume ratio without grain boundaries; consequently, nanowires are promising tools to study biological systems. This review starts with the integration of nanowire structures into microfluidic systems, followed by the discussion of the advantages of nanowire structures in the separation, manipulation and purification of biomolecules (DNA, RNA and proteins). Next, some representative nanowire devices are introduced for biosensors from molecular to cellular levels based on electrical and optical approaches. Finally, we conclude the review by highlighting some bio-applications for nanowires and presenting the next challenges that must be overcome to improve the capabilities of nanowire structures for biological and medical systems. PMID- 26928288 TI - Tribulus terrestris Alters the Expression of Growth Differentiation Factor 9 and Bone Morphogenetic Protein 15 in Rabbit Ovaries of Mothers and F1 Female Offspring. AB - Although previous research has demonstrated the key role of the oocyte-derived factors, bone morphogenetic protein (BMP) 15 and growth differentiation factor (GDF) 9, in follicular development and ovulation, there is a lack of knowledge on the impact of external factors, which females are exposed to during folliculogenesis, on their expression. The present study investigated the effect of the aphrodisiac Tribulus terrestris on the GDF9 and BMP15 expression in the oocytes and cumulus cells at mRNA and protein levels during folliculogenesis in two generations of female rabbits. The experiment was conducted with 28 New Zealand rabbits. Only the diet of the experimental mothers group was supplemented with a dry extract of T. terrestris for the 45 days prior to insemination. The expression of BMP15 and GDF9 genes in the oocytes and cumulus cells of mothers and F1 female offspring was analyzed using real-time polymerase chain reaction (RT-PCR). The localization of the GDF9 and BMP15 proteins in the ovary tissues was determined by immunohistochemical analysis. The BMP15 and GDF9 transcripts were detected in the oocytes and cumulus cells of rabbits from all groups. T. terrestris caused a decrease in the BMP15 mRNA level in the oocytes and an increase in the cumulus cells. The GDF9 mRNA level increased significantly in both oocytes and cumulus cells. The downregulated expression of BMP15 in the treated mothers' oocytes was inherited in the F1 female offspring born to treated mothers. BMP15 and GDF9 show a clearly expressed sensitivity to the bioactive compounds of T. terrestris. PMID- 26928290 TI - Methodological development for selection of significant predictors explaining fatal road accidents. AB - Identification of the most relevant factors for explaining road accident occurrence is an important issue in road safety research, particularly for future decision-making processes in transport policy. However model selection for this particular purpose is still an ongoing research. In this paper we propose a methodological development for model selection which addresses both explanatory variable and adequate model selection issues. A variable selection procedure, TIM (two-input model) method is carried out by combining neural network design and statistical approaches. The error structure of the fitted model is assumed to follow an autoregressive process. All models are estimated using Markov Chain Monte Carlo method where the model parameters are assigned non-informative prior distributions. The final model is built using the results of the variable selection. For the application of the proposed methodology the number of fatal accidents in Spain during 2000-2011 was used. This indicator has experienced the maximum reduction internationally during the indicated years thus making it an interesting time series from a road safety policy perspective. Hence the identification of the variables that have affected this reduction is of particular interest for future decision making. The results of the variable selection process show that the selected variables are main subjects of road safety policy measures. PMID- 26928291 TI - An explanatory analysis of driver injury severity in rear-end crashes using a decision table/Naive Bayes (DTNB) hybrid classifier. AB - Rear-end crashes are a major type of traffic crashes in the U.S. Of practical necessity is a comprehensive examination of its mechanism that results in injuries and fatalities. Decision table (DT) and Naive Bayes (NB) methods have both been used widely but separately for solving classification problems in multiple areas except for traffic safety research. Based on a two-year rear-end crash dataset, this paper applies a decision table/Naive Bayes (DTNB) hybrid classifier to select the deterministic attributes and predict driver injury outcomes in rear-end crashes. The test results show that the hybrid classifier performs reasonably well, which was indicated by several performance evaluation measurements, such as accuracy, F-measure, ROC, and AUC. Fifteen significant attributes were found to be significant in predicting driver injury severities, including weather, lighting conditions, road geometry characteristics, driver behavior information, etc. The extracted decision rules demonstrate that heavy vehicle involvement, a comfortable traffic environment, inferior lighting conditions, two-lane rural roadways, vehicle disabled damage, and two-vehicle crashes would increase the likelihood of drivers sustaining fatal injuries. The research limitations on data size, data structure, and result presentation are also summarized. The applied methodology and estimation results provide insights for developing effective countermeasures to alleviate rear-end crash injury severities and improve traffic system safety performance. PMID- 26928293 TI - Use of Mobile Technology to Calm Upset Children: Associations With Social Emotional Development. PMID- 26928292 TI - 23 years of toxicology testing fatally injured pilots: Implications for aviation and other modes of transportation. AB - Use of over-the-counter, prescription, and illicit drugs is increasing in the United States (US). Many of these drugs are psychoactive and can affect the user's ability to safely operate a vehicle. However, data about drug use by vehicle operators is typically limited to a small proportion of operators and a short list of drugs. For instance, required testing for commercial vehicle operators following most accidents is limited to a urine test for 11 drugs. By comparison, the Federal Aviation Administration (FAA), routinely tests fatally injured pilots' blood and tissues for hundreds of compounds. This study used the results from these tests to assess drug use in aviation. METHODS: Using matched data from the FAA's Civil Aerospace Medical Institute toxicology database and the National Transportation Safety Board's (NTSB's) aviation accident database, this study examined trends in the prevalence of over-the-counter, prescription, and illicit drugs identified in toxicology tests of fatally injured pilots between 1990 and 2012. Cases that failed to match or where toxicology testing had not been performed were excluded. Pilots identified by the NTSB investigation as being the "flying pilot" at the time of the accident and results from blood or tissues were included. Toxicology results for ethanol and other alcohols were not included. Positive test results were categorized by drug type and potential for causing impairment. Analysis used SPSS Version 19.1 to perform linear by linear chi-squared statistics. RESULTS: The study included 6677 pilots or 87% of the eligible subjects. The large majority were male (98%) and flying general aviation operations (96%) at the time of their fatal accident. There were increasing trends in pilots' use of all drugs, potentially impairing drugs, drugs used to treat potentially impairing conditions, drugs designated as controlled substances, and illicit drugs. The most common potentially impairing drug pilots had used was diphenhydramine, a sedating antihistamine that is an active ingredient in many over-the-counter allergy formulations, cold medicines, and sleep aids in the US. Although evidence of illicit drug use was found only in a small number of cases, the percentage of pilots testing positive for marijuana use increased during the study period, mostly in the last 10 years. PMID- 26928294 TI - TIER competency-based training course for the first receivers of CBRN casualties: a European perspective. AB - INTRODUCTION: Education and training are key elements of health system preparedness vis-a-vis chemical, biological, radiological and nuclear (CBRN) emergencies. Medical respondents need sufficient knowledge and skills to manage the human impact of CBRN events. OBJECTIVE: The current study was designed to determine which competencies are needed by hospital staff when responding to CBRN emergencies, define educational needs to develop these competencies, and implement a suitable delivery method. METHODS: This study was carried out from September 2014 to February 2015, using a three-step modified Delphi method. On the basis of international experiences, publications, and experts' consensus, core competencies for hospital staff - as CBRN casualty receivers - were determined, and training curricula and delivery methods were defined. RESULTS: The course consists of 10 domains. These are as follows: threat identification; health effects of CBRN agents; planning; hospital incident command system; information management; safety, personal protective equipment and decontamination; medical management; essential resources; psychological support; and ethical considerations. Expected competencies for each domain were defined. A blended approach was chosen. CONCLUSION: By identifying a set of core competencies, this study aimed to provide the specific knowledge and skills required by medical staff to respond to CRBN emergencies. A blended approach may be a suitable delivery method, allowing medical staff to attend the same training sessions despite different time zones and locations. The study output provides a CBRN training scheme that may be adapted and used at the European Union level. PMID- 26928295 TI - Usefulness of a multiplying factor in predicting the final number of victims during a mass casualty incident. AB - OBJECTIVE: Whenever a mass casualty incident (MCI) occurs, it is essential to anticipate the final number of victims to dispatch the adequate number of ambulances. In France, the custom is to multiply the initial number of prehospital victims by 2-4 to predict the final number. However, no one has yet validated this multiplying factor (MF) as a predictive tool. We aimed to build a statistical model to predict the final number of victims from their initial count. METHODS: We observed retrospectively over 30 years of MCIs triggered in a large urban area. We considered three types of events: explosions, fires, and road traffic accidents. We collected the initial and final numbers of victims, with distinction between deaths, critical victims (T1), and delayed or minimal victims (T2-T3). The MF was calculated for each category of victims according to each type of event. Using a Poisson multivariate regression, we calculated the incidence risk ratio (IRR) of the final number of T1 as a function of the initial deaths and the initial T2-T3 counts, while controlling for potential confounding variables. RESULTS: Sixty-eight MCIs were included. The final number of T1 increased with the initial incidence of deaths [IRR: 1.8 (1.4-2.2)], the initial number of T2-T3 being greater than 12 [IRR: 1.6 (1.3-2.1)], and the presence of one or more explosion [IRR: 1.4 (1.1-1.8)]. CONCLUSION: The MF seems to be an appealing decision-making tool to anticipate the need for ambulance resources. In explosive MCIs, we recommend multiplying T1 by 1.4 to estimate final count and the need for supplementary advanced life support teams. PMID- 26928296 TI - Combination of Ruscus aculeatus extract, hesperidin methyl chalcone and ascorbic acid: a comprehensive review of their pharmacological and clinical effects and of the pathophysiology of chronic venous disease. AB - This paper focuses on Ruscus aculeatus extract (Ruscus extract) and its combination with hesperidin methyl chalcone (HMC) and ascorbic acid (AA), which have been safely and effectively used in CVD treatment for more than 50 years in some European countries. It presents the effects of that drug on veins and on venous hypertension, its effect on microcirculation and on lymphatics demonstrated by preclinical studies and the clinical evidence issued from clinical trials supporting its use to relieve the symptoms of venous disease. In addition to its venoconstrictive effect on veins, its pharmacological action is on the microcirculation impairment caused by venous hypertension that is at the heart of the pathophysiological mechanism underlying venous disease. PMID- 26928297 TI - Using text messaging to obtain weekly data on infant feeding in a Danish birth cohort resulted in high participation rates. AB - AIM: Our aim was to use text message questions to obtain prospective, real-time data on exclusive and partial breastfeeding and introduction to complementary foods in a Danish birth cohort. We also wanted to identify factors influencing breastfeeding initiation and cessation. METHODS: This study formed part of the Odense Child Cohort and focused on mothers who gave birth to full-term singletons between April and October 2012. They received the same three to five questions, about breastfeeding, infant formula and introduction to complementary food, three days after birth and then at weekly intervals. RESULTS: We recruited 499 mothers, and the response rate to the first of the weekly questions was >=89.4% during the study. Three days after birth, 96.7% of mothers were breastfeeding, 61.2% exclusively and 30.2% partially, and 26 weeks after birth 60.2% of mothers were breastfeeding, 1.1% exclusively. Complementary food was introduced at an average age of 20 weeks. Breastfeeding cessation was associated with maternal smoking, lower maternal age and supplementation with infant formula in the first days after birth (all p < 0.05). CONCLUSION: Most mothers initiated breastfeeding, but only 1.1% were exclusively breastfeeding at 26 weeks. Text messaging resulted in high response rates and was a feasible data collection method. PMID- 26928298 TI - A Multi-Method Approach for Proteomic Network Inference in 11 Human Cancers. AB - Protein expression and post-translational modification levels are tightly regulated in neoplastic cells to maintain cellular processes known as 'cancer hallmarks'. The first Pan-Cancer initiative of The Cancer Genome Atlas (TCGA) Research Network has aggregated protein expression profiles for 3,467 patient samples from 11 tumor types using the antibody based reverse phase protein array (RPPA) technology. The resultant proteomic data can be utilized to computationally infer protein-protein interaction (PPI) networks and to study the commonalities and differences across tumor types. In this study, we compare the performance of 13 established network inference methods in their capacity to retrieve the curated Pathway Commons interactions from RPPA data. We observe that no single method has the best performance in all tumor types, but a group of six methods, including diverse techniques such as correlation, mutual information, and regression, consistently rank highly among the tested methods. We utilize the high performing methods to obtain a consensus network; and identify four robust and densely connected modules that reveal biological processes as well as suggest antibody-related technical biases. Mapping the consensus network interactions to Reactome gene lists confirms the pan-cancer importance of signal transduction pathways, innate and adaptive immune signaling, cell cycle, metabolism, and DNA repair; and also suggests several biological processes that may be specific to a subset of tumor types. Our results illustrate the utility of the RPPA platform as a tool to study proteomic networks in cancer. PMID- 26928299 TI - 18beta-Glycyrrhetinic Acid Derivatives Possessing a Trihydroxylated A Ring Are Potent Gram-Positive Antibacterial Agents. AB - The oleanane-type triterpene 18beta-glycyrrhetinic acid (1) was modified chemically through the introduction of a trihydroxylated A ring and an ester moiety at C-20 to enhance its antibacterial activity. Compounds 22, 23, 25, 28, 29, 31, and 32 showed more potent inhibitory activity against Streptomyces scabies than the positive control, streptomycin. Additionally, the inhibitory activity of the most potent compound, 29, against Bacillus subtilis, Staphylococcus aureus, and methicillin-resistant Staphylococcus aureus was greater than that of the positive controls. The antibacterial mode of action of the active derivatives involved the regulation of the expression of genes associated with peptidoglycans, the respiratory metabolism, and the inherent virulence factors found in bacteria, as determined through a quantitative real time reverse transcriptase PCR assay. PMID- 26928300 TI - Ligand-dependent responses of the silkworm prothoracicotropic hormone receptor, Torso, are maintained by unusual intermolecular disulfide bridges in the transmembrane region. AB - The insect membrane-protein, Torso, is a member of the receptor-tyrosine-kinase family, and is activated by its ligand, prothoracicotropic hormone (PTTH). Although PTTH is one of the most important regulators of insect development, the mechanism of Torso activation by the hormone has remained elusive. In this study, using heterologous expression in cultured Drosophila S2 cells, we detected ligand independent dimerization of silkworm Torso, and found that the receptor molecules in the dimer were linked by intermolecular disulfide bridges. By examining the oligomerization states of several truncation and substitution mutants of Torso, atypical cysteine residues in the transmembrane region were identified as being responsible for the intermolecular linkage in the dimer. The replacement of all of the cysteines in the region with phenylalanines abolished the disulfide-bond mediated dimerization; however, non-covalent dimerization of the mutant was detected using a cross-linking reagent, both with and without ligand stimulation. This non-covalent dimerization caused apparent receptor autophosphorylation independently of the ligand stimulation, but did not promote the ERK phosphorylation in the downstream signaling pathway. The unique Torso structure with the intermolecular disulfide bridges in the transmembrane region is necessary to maintain the ligand-dependent receptor functions of autophosphorylation and downstream activation. PMID- 26928301 TI - Endothelial Function and Cardiovascular Autonomic Activity in Neurally Mediated Syncope. AB - OBJECTIVES: The aim of this study was to investigate endothelial function and cardiovascular autonomic activity in patients with neurally mediated syncope (NMS). METHODS: Patients with a typical history of NMS were divided according to the result of a head-up tilt (HUT) test. There were 25 patients each in the HUT positive (HUT+), HUT-negative (HUT-) and control groups. Flow-mediated dilation (FMD) and 24-hour ambulatory electrocardiography (AECG) were performed before the HUT tests. RESULTS: The HUT+ group had a significantly higher FMD than that of the HUT- group and the control group (8.8 +/- 3.3 vs. 6.4 +/- 2.9%, p = 0.006, and 8.8 +/- 3.3 vs. 5.7 +/- 2.2%, p = 0.001, respectively). On a 24-hour AECG, the parasympathetic indexes of time domain, such as rMSSD and the pNN50, were significantly higher in the HUT+ group than in the HUT- group (39.0 +/- 9.6 vs. 31.6 +/- 9.6 ms, p = 0.016, and 16.5 +/- 8.1 vs. 10.2 +/- 7.2%, p = 0.002, respectively) and the control group (39.0 +/- 9.6 vs. 28.9 +/- 9.6%, p = 0.001 and 16.5 +/- 8.1 vs. 8.7 +/- 6.7%, p = 0.001, respectively). High-frequency spectra (parasympathetic activity) of the frequency domain showed similar results. CONCLUSIONS: Not only parasympathetic activity, but also endothelial function may affect the results of HUT tests in patients with NMS. PMID- 26928302 TI - ADEPT, a dynamic next generation sequencing data error-detection program with trimming. AB - BACKGROUND: Illumina is the most widely used next generation sequencing technology and produces millions of short reads that contain errors. These sequencing errors constitute a major problem in applications such as de novo genome assembly, metagenomics analysis and single nucleotide polymorphism discovery. RESULTS: In this study, we present ADEPT, a dynamic error detection method, based on the quality scores of each nucleotide and its neighboring nucleotides, together with their positions within the read and compares this to the position-specific quality score distribution of all bases within the sequencing run. This method greatly improves upon other available methods in terms of the true positive rate of error discovery without affecting the false positive rate, particularly within the middle of reads. CONCLUSIONS: ADEPT is the only tool to date that dynamically assesses errors within reads by comparing position-specific and neighboring base quality scores with the distribution of quality scores for the dataset being analyzed. The result is a method that is less prone to position-dependent under-prediction, which is one of the most prominent issues in error prediction. The outcome is that ADEPT improves upon prior efforts in identifying true errors, primarily within the middle of reads, while reducing the false positive rate. PMID- 26928303 TI - Prolonged suppression of monocytic human leukocyte antigen-DR expression correlates with mortality in pediatric septic patients in a pediatric tertiary Intensive Care Unit. AB - INTRODUCTION: Immunoparalysis is a syndrome with no clinical symptoms that occurs in some septic patients. Monocytic human leukocyte antigen-DR (mHLA-DR) expression has been used to identify patients in immunoparalysis and prolonged periods of reduced mHLA-DR expression have been correlated with a poor prognosis in sepsis. However, there is a lack of studies investigating mHLA-DR expression in pediatric septic patients. AIM: To determine if mHLA-DR expression correlates with mortality in pediatric septic patients using the QuantiBRITE Anti HLA DR/Anti-Monocyte,a Bechton Dickinson novel reagent that standardizes flow cytometry values. METHODS: We determined mHLA-DR expression in 30 patients with severe sepsis or septic shock admitted to the pediatric intensive care unit at Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo, Brazil, between January 2013 and February 2015. mHLA-DR expression was quantified between days 3 to 5 and 5 to 7 after the onset of sepsis and the DeltamHLA-DR (mHLA-DR2 - mHLA-DR1) was calculated. We also measured mHLA-DR levels in 21 healthy control patients. RESULTS: Mean mHLA-DR expression was significantly lower in septic patients than in controls (P = .0001). Mortality was 46% in patients with negative DeltaHLA-DR or <1000 mAb/cell and 7% in patients with positive DeltaHLA-DR or >1000 mAb/cell. Mean DeltamHLA-DR levels were significantly different between survivors and non-survivors (P = .023). CONCLUSION: DeltaHLA-DR correlates with mortality in pediatric patients with septic shock or severe sepsis. This is the first study to have used the QuantiBRITE Anti HLA-DR/Anti-Monocyte reagent to quantify monocyte HLA-DR expression in pediatric septic patients. PMID- 26928304 TI - A high-volume trauma intensive care unit can be successfully staffed by advanced practitioners at night. AB - PURPOSE: It remains unknown whether critically ill trauma patients can be successfully managed by advanced practitioners (APs). The purpose of this study was to examine the impact of night coverage by APs in a high-volume trauma intensive care unit (ICU) on patient outcomes and care processes. MATERIALS AND METHODS: During the study period, our ICU was staffed by APs during the night shift (7 pm-7 am) from Sunday to Wednesday and by resident physicians (RPs) from Thursday to Saturday. On-call trauma fellows and attending surgeons in house supervised both APs and RPs. Patient outcomes and care processes by APs was compared with those admitted by RPs. RESULTS: A total of 289 patients were identified between July 2013 and February 2014. Median lactate clearance rate within 24 hours of admission was similar between study groups (10.0% vs 9.1%; P = .39). Advanced practitioners and RPs transfused patients requiring massive transfusion with a similar blood product ratio (packed red blood cell:fresh frozen plasma) (2.1:1 vs 1.7:1; P = .32). In a multiple logistic regression analysis, AP coverage was not associated with any clinical outcome differences. CONCLUSIONS: Our data suggest that, with adequate supervision, a high-volume trauma ICU can be safely staffed by APs overnight. PMID- 26928305 TI - Supplementation with a new trypsin inhibitor from peanut is associated with reduced fasting glucose, weight control, and increased plasma CCK secretion in an animal model. AB - Ingestion of peanuts may have a beneficial effect on weight control, possibly due to the satietogenic action of trypsin inhibitors. The aim of this study was to isolate a new trypsin inhibitor in a typical Brazilian peanut sweet (pacoca) and evaluate its effect in biochemical parameters, weight gain and food intake in male Wistar rats. The trypsin inhibitor in peanut pacoca (AHTI) was isolated. Experimental diets were prepared with AIN-93G supplemented with AHTI. Animals had their weight and food intake monitored. Animals were anesthetized, euthanized, and their bloods collected by cardiac puncture for dosage of cholecystokinin (CCK) and other biochemical parameters. Supplementation with AHTI significantly decreased fasting glucose, body weight gain, and food intake. These effects may be attributed to increased satiety, once supplemented animals showed no evidence of impaired nutritional status and also because AHTI increased CCK production. Thus, our results indicate that AHTI, besides reducing fasting glucose, can reduce weight gain via food intake reduction. PMID- 26928306 TI - Tumor-reactive immune cells protect against metastatic tumor and induce immunoediting of indolent but not quiescent tumor cells. AB - Two major barriers to cancer immunotherapy include tumor-induced immune suppression mediated by myeloid-derived suppressor cells and poor immunogenicity of the tumor-expressing self-antigens. To overcome these barriers, we reprogrammed tumor-immune cell cross-talk by combined use of decitabine and adoptive immunotherapy, containing tumor-sensitized T cells and CD25(+) NKT cells. Decitabine functioned to induce the expression of highly immunogenic cancer testis antigens in the tumor, while also reducing the frequency of myeloid derived suppressor cells and the presence of CD25(+) NKT cells rendered T cells, resistant to remaining myeloid-derived suppressor cells. This combinatorial therapy significantly prolonged survival of animals bearing metastatic tumor cells. Adoptive immunotherapy also induced tumor immunoediting, resulting in tumor escape and associated disease-related mortality. To identify a tumor target that is incapable of escape from the immune response, we used dormant tumor cells. We used Adriamycin chemotherapy or radiation therapy, which simultaneously induce tumor cell death and tumor dormancy. Resultant dormant cells became refractory to additional doses of Adriamycin or radiation therapy, but they remained sensitive to tumor-reactive immune cells. Importantly, we discovered that dormant tumor cells contained indolent cells that expressed low levels of Ki67 and quiescent cells that were Ki67 negative. Whereas the former were prone to tumor immunoediting and escape, the latter did not demonstrate immunoediting. Our results suggest that immunotherapy could be highly effective against quiescent dormant tumor cells. The challenge is to develop combinatorial therapies that could establish a quiescent type of tumor dormancy, which would be the best target for immunotherapy. PMID- 26928307 TI - Forecasting Chikungunya spread in the Americas via data-driven empirical approaches. AB - BACKGROUND: Chikungunya virus (CHIKV) is endemic to Africa and Asia, but the Asian genotype invaded the Americas in 2013. The fast increase of human infections in the American epidemic emphasized the urgency of developing detailed predictions of case numbers and the potential geographic spread of this disease. METHODS: We developed a simple model incorporating cases generated locally and cases imported from other countries, and forecasted transmission hotspots at the level of countries and at finer scales, in terms of ecological features. RESULTS: By late January 2015, >1.2 M CHIKV cases were reported from the Americas, with country-level prevalences between nil and more than 20 %. In the early stages of the epidemic, exponential growth in case numbers was common; later, however, poor and uneven reporting became more common, in a phenomenon we term "surveillance fatigue." Economic activity of countries was not associated with prevalence, but diverse social factors may be linked to surveillance effort and reporting. CONCLUSIONS: Our model predictions were initially quite inaccurate, but improved markedly as more data accumulated within the Americas. The data-driven methodology explored in this study provides an opportunity to generate descriptive and predictive information on spread of emerging diseases in the short-term under simple models based on open-access tools and data that can inform early-warning systems and public health intelligence. PMID- 26928309 TI - The bivariate combined model for spatial data analysis. AB - To describe the spatial distribution of diseases, a number of methods have been proposed to model relative risks within areas. Most models use Bayesian hierarchical methods, in which one models both spatially structured and unstructured extra-Poisson variance present in the data. For modelling a single disease, the conditional autoregressive (CAR) convolution model has been very popular. More recently, a combined model was proposed that 'combines' ideas from the CAR convolution model and the well-known Poisson-gamma model. The combined model was shown to be a good alternative to the CAR convolution model when there was a large amount of uncorrelated extra-variance in the data. Less solutions exist for modelling two diseases simultaneously or modelling a disease in two sub populations simultaneously. Furthermore, existing models are typically based on the CAR convolution model. In this paper, a bivariate version of the combined model is proposed in which the unstructured heterogeneity term is split up into terms that are shared and terms that are specific to the disease or subpopulation, while spatial dependency is introduced via a univariate or multivariate Markov random field. The proposed method is illustrated by analysis of disease data in Georgia (USA) and Limburg (Belgium) and in a simulation study. We conclude that the bivariate combined model constitutes an interesting model when two diseases are possibly correlated. As the choice of the preferred model differs between data sets, we suggest to use the new and existing modelling approaches together and to choose the best model via goodness-of-fit statistics. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26928308 TI - Multiparameter toxicity assessment of novel DOPO-derived organophosphorus flame retardants. AB - Halogen-free organophosphorus flame retardants are considered as replacements for the phased-out class of polybrominated diphenyl ethers (PBDEs). However, toxicological information on new flame retardants is still limited. Based on their excellent flame retardation potential, we have selected three novel 9,10 dihydro-9-oxa-10-phosphaphenanthrene-10-oxide (DOPO) derivatives and assessed their toxicological profile using a battery of in vitro test systems in order to provide toxicological information before their large-scale production and use. PBDE-99, applied as a reference compound, exhibited distinct neuro-selective cytotoxicity at concentrations >=10 uM. 6-(2-((6-oxido-6H dibenzo[c,e][1,2]oxaphosphinin-6-yl)amino)ethoxy)-6H dibenzo[c,e][1,2]oxaphosphinine 6-oxide (ETA-DOPO) and 6,6'-(ethane-1,2 diylbis(oxy))bis(6H-dibenzo[c,e][1,2]oxaphosphinine-6-oxide) (EG-DOPO) displayed adverse effects at concentrations >10 uM in test systems reflecting the properties of human central and peripheral nervous system neurons, as well as in a set of non-neuronal cell types. DOPO and its derivative 6,6'-(ethane-1,2 diylbis(azanediyl))bis(6H-dibenzo[c,e][1,2]oxaphosphinine-6-oxide) (EDA-DOPO) were neither neurotoxic, nor did they exhibit an influence on neural crest cell migration, or on the integrity of human skin equivalents. The two compounds furthermore displayed no inflammatory activation potential, nor did they affect algae growth or daphnia viability at concentrations <=400 uM. Based on the superior flame retardation properties, biophysical features suited for use in polyurethane foams, and low cytotoxicity of EDA-DOPO, our results suggest that it is a candidate for the replacement of currently applied flame retardants. PMID- 26928311 TI - Association of C1q-fixing DSA with late graft failure in pediatric renal transplant recipients. AB - BACKGROUND: We investigated the prognostic value of overall and complement binding donor-specific HLA antibodies (DSA) in pediatric patients undergoing clinically indicated graft biopsies and their association with graft outcome and specific histological lesions. METHODS: Sera of 62 patients at time of indication biopsy >=1 year posttransplant were assessed for DSA and C1q-fixing DSA by single antigen bead (SAB) technology. RESULTS: Twenty-six patients (42 %) were DSA positive at time of indication biopsy and nine (15 %) were C1q-positive. At 4 years postbiopsy, patients with C1q-positivity had a low graft survival (11 %) compared to DSA-positive, C1q-negative patients (82 %, p = 0.001) and to DSA negative patients (88 %, p < 0.001). The majority (89 %) of C1q-positive patients were diagnosed with active chronic antibody-mediated rejection (ABMR). C1q DSA positivity [adjusted hazard ratio (HR) 6.35], presence of transplant glomerulopathy (HR 9.54), and estimated glomerular filtration rate (eGFR) at the time of indication biopsy (HR 0.91) were risk factors for subsequent graft loss. CONCLUSIONS: The presence of C1q-positive DSA in the context of an indication biopsy identifies a subgroup of pediatric renal transplant recipients with a markedly increased risk of subsequent graft loss. Because a fraction of DSA positive patients escape rejection or graft dysfunction, the C1q assay increases the specificity of a positive DSA result regarding unfavorable transplant outcome. PMID- 26928310 TI - Anti-VEGF-related thrombotic microangiopathy in a child presenting with nephrotic syndrome. AB - BACKGROUND: Targeting the vascular endothelial growth factor (VEGF) signaling pathway has become an important approach to current cancer therapy. Anti-VEGF therapy-related renal adverse effects may present as hypertension, non-nephrotic proteinuria, and rarely as nephrotic syndrome (NS) and acute kidney injury. CASE DIAGNOSIS/TREATMENT: In this report, we present a 15-year-old boy who had developed nephrotic syndrome and thrombotic microangiopathy 26 months after administration of anti-VEGF therapy. Treatment was discontinued and nephrotic syndrome remitted spontaneously within 3 months. CONCLUSIONS: Nephrologists should be aware of the side effects of anti-VEGF therapy. Early diagnosis and prompt management with withdrawal of the agents will result in spontaneous remission. PMID- 26928312 TI - Na-ion Storage Performances of FeSe(x) and Fe2O3 Hollow Nanoparticles-Decorated Reduced Graphene Oxide Balls prepared by Nanoscale Kirkendall Diffusion Process. AB - Uniquely structured FeSe(x)-reduced graphene oxide (rGO) composite powders, in which hollow FeSe(x) nanoparticles are uniformly distributed throughout the rGO matrix, were prepared by spray pyrolysis applying the nanoscale Kirkendall diffusion process. Iron oxide-rGO composite powders were transformed into FeSe(x) rGO composite powders by a two-step post-treatment process. Metallic Fe nanocrystals formed during the first-step post-treatment process were transformed into hollow FeSe(x) nanoparticles during the selenization process. The FeSe(x) rGO composite powders had mixed crystal structures of FeSe and FeSe2 phases. A rGO content of 33% was estimated from the TG analysis of the FeSe(x)-rGO composite powders. The FeSe(x)-rGO composite powders had superior sodium-ion storage properties compared to those of the Fe2O3-rGO composite powders with similar morphological characteristics. The discharge capacities of the FeSe(x)- and Fe2O3-rGO composite powders for the 200(th) cycle at a constant current density of 0.3 A g(-1) were 434 and 174 mA h g(-1), respectively. The FeSe(x)-rGO composite powders had a high discharge capacity of 311 mA h g(-1) for the 1000(th) cycle at a high current density of 1 A g(-1). PMID- 26928313 TI - PD-1hi Identifies a Novel Regulatory B-cell Population in Human Hepatoma That Promotes Disease Progression. AB - B cells often constitute abundant cellular components in human tumors. Regulatory B cells that are functionally defined by their ability to produce IL10 downregulate inflammation and control T-cell immunity. Here, we identified a protumorigenic subset of B cells that constitutively expressed higher levels of programmed cell death-1 (PD-1) and constituted ~10% of all B cells in advanced stage hepatocellular carcinoma (HCC). These PD-1(hi) B cells exhibited a unique CD5(hi)CD24(-/+)CD27(hi/+)CD38(dim) phenotype different from the phenotype of conventional CD24(hi)CD38(hi) peripheral regulatory B cells. TLR4-mediated BCL6 upregulation was crucial for PD-1(hi) B-cell induction by HCC environmental factors, and that effect was abolished by IL4-elicited STAT6 phosphorylation. Importantly, upon encountering PD-L1(+) cells or undergoing PD-1 triggering, PD 1(hi) B cells acquired regulatory functions that suppressed tumor-specific T-cell immunity and promoted cancer growth via IL10 signals. Our findings provide significant new insights for human cancer immunosuppression and anticancer therapies regarding PD-1/PD-L1. SIGNIFICANCE: We identify a novel protumorigenic PD-1(hi) B-cell subset in human HCC that exhibits a phenotype distinct from that of peripheral regulatory B cells. TLR4-mediated BCL6 upregulation is critical for induction of PD-1(hi) B cells, which operate via IL10-dependent pathways upon interacting with PD-L1 to cause T-cell dysfunction and foster disease progression. Cancer Discov; 6(5); 546-59. (c)2016 AACR.See related commentary by Ren et al., p. 477This article is highlighted in the In This Issue feature, p. 461. PMID- 26928314 TI - Potential Therapy for Refractory Colon Cancer. AB - The drug MM-1151 may overcome resistance to cetuximab and panitumumab caused by some mutations in the extracellular domain of EGFR. The drug slowed disease progression in a colorectal cancer cell line that carried some of the mutations and curbed growth of cells derived from a cetuximab-resistant patient tumor. In a phase I trial, tumors shrank or stabilized in patients who carried the mutations and received the drug. PMID- 26928315 TI - A leading role for NADPH oxidase in an in-vitro study of experimental autoimmune encephalomyelitis. AB - Myelin oligodendrocyte glycoprotein peptide fragment 35-55 (MOG35-55) is a major autoantigen inducing experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis that is characterized by blood-brain barrier (BBB) disruption. Various experimental approaches have employed MOG35-55 in vivo; however, in vitro BBB models using MOG35-55 are rarely reported. We investigated MOG35-55 exposure effects with complete Freund's adjuvant (CFA) and pertussis toxin (PTX) on brain endothelial cells and elucidated the relationships among NADPH oxidase, MMP-9, ICAM-1, and VCAM-1. These 4 factors significantly increased in MOG35-55+CFA+PTX-exposed endothelial cells compared with the control cells. NADPH oxidase inhibition using apocynin reduced MMP-9 activity, ICAM-1, and VCAM 1. MMP-9 inhibitor I decreased expression of ICAM-1 and VCAM-1, and both anti ICAM-1 and anti-VCAM-1 inhibited MMP-9 activity. Inhibitions of MMP-9, ICAM-1, and VCAM-1 did not change NADPH oxidase activity. Although inhibition of these 4 factors decreased BBB permeability in cells, inhibition of NADPH oxidase exhibited the highest decrease among these. NADPH oxidase directly influenced MMP 9, ICAM-1, and VCAM-1, but not vice versa. MMP-9 and the cell adhesion molecules reversibly affected each other. In conclusion, NADPH oxidase-derived superoxide elevated expression of MMP-9, ICAM-1, and VCAM-1, and these interactions can finally result in increases of BBB permeability in MOG35-55+CFA+PTX-exposed endothelial cells. PMID- 26928316 TI - Unraveling the effects of static magnetic field stress on cytosolic proteins of Salmonella by using a proteomic approach. AB - The present study investigated the adaptation of Salmonella enterica subsp. enterica serovar Hadar to static magnetic field (SMF) exposure (200 mT, 9 h). The proteomic analysis provides an overview of potentially important cytosolic proteins that Salmonella needs to regulate to survive and adapt to magnetic stress. Via 2-dimensional electrophoresis and liquid chromatography tandem mass spectrometry, we compared cytosolic proteomes before and after exposure to magnetic field. A total of 35 proteins displaying more than a 2-fold change were differentially expressed in exposed cells, among which 25 were upregulated and 10 were downregulated. These proteins can be classified mainly into 6 categories: (i) proteins involved in metabolic pathways of carbohydrates, (ii) chaperones and proteins produced in response to oxidative stress, (iii) proteins involved in energy homeostasis, (iv) elongation factors (EF-Tu and EF-Ts), (v) proteins involved in motility, and (vi) proteins involved in molecules transport. Many of the presented observations could be explained, while some represent still-unknown mechanisms. In addition, this study reveals 5 hypothetical proteins. It seems that the stress response to SMF (200 mT) is essentially set up to avoid oxidative damages, with the overexpression of proteins directly involved in oxidative stress response and metabolic switches to counteract oxidative stress. Interestingly, several proteins induced under SMF exposure are found to overlap with those induced by other stresses, such as heat shock and starvation. PMID- 26928317 TI - Effects of environmental endocrine disruptors, including insecticides used for malaria vector control on reproductive parameters of male rats. AB - The male reproductive system is sensitive to endocrine disrupting chemicals (EDCs) during critical developmental windows. Male Sprague-Dawley rats were exposed in utero-, during lactation- and directly to 1,1,1-trichloro-2,2-bis(p chlorophenyl)ethane (DDT), 1,1,-dichloro-2,2-bis(p-chlorophenyl)ethylene (DDE) and a mixture of DDT, deltamethrin (DM), p-nonylphenol (p-NP) and phytoestrogens, at concentrations found in a malaria-area. After dosing for 104 days, histological assessments and reproductive-endpoints were assessed. The anogenital distance (AGD) (P=0.005) was shorter in the mixture-exposed group, while the prostate mass (P=0.018) was higher in the DDT-exposed group. A higher testicular mass and abnormal histology was observed in the DDT-(P=0.019), DDE-(P=0.047) and mixture-exposed (P<0.005) groups. This study shows that in utero-, lactational- and direct exposure to EDCs present in a malaria-area negatively affects male reproductive parameters in rats. These findings raise concerns to EDC-exposures to mothers living in malaria-areas and the reproductive health of their male offspring. PMID- 26928319 TI - Ultrasound Imaging of Breastfeeding--A Window to the Inside: Methodology, Normal Appearances, and Application. AB - Ultrasound imaging has been employed as a noninvasive technique to explore the sucking dynamics of the breastfeeding infant over the past 40 years. Recent improvements in the resolution of ultrasound images have allowed a more detailed description of the tongue movements during sucking, identification of oral structures, and measurements of nipple position and tongue motion. Several different scanning planes can be used and each show sucking from a different perspective. Ultrasound techniques and image anatomy are described in detail in this review and provide the basis for implementation in the objective assessment of breastfeeding. PMID- 26928318 TI - Analysis of maternal polymorphisms in arsenic (+3 oxidation state) methyltransferase AS3MT and fetal sex in relation to arsenic metabolism and infant birth outcomes: Implications for risk analysis. AB - Arsenic (+3 oxidation state) methyltransferase (AS3MT) is the key enzyme in the metabolism of inorganic arsenic (iAs). Polymorphisms of AS3MT influence adverse health effects in adults, but little is known about their role in iAs metabolism in pregnant women and infants. The relationships between seven single nucleotide polymorphisms (SNPs) in AS3MT and urinary concentrations of iAs and its methylated metabolites were assessed in mother-infant pairs of the Biomarkers of Exposure to ARsenic (BEAR) cohort. Maternal alleles for five of the seven SNPs (rs7085104, rs3740400, rs3740393, rs3740390, and rs1046778) were associated with urinary concentrations of iAs metabolites, and alleles for one SNP (rs3740393) were associated with birth outcomes/measures. These associations were strongly dependent upon the male sex of the fetus but independent of fetal genotype for AS3MT. These data highlight a potential sex-dependence of the relationships among maternal genotype, iAs metabolism and infant health outcomes. PMID- 26928320 TI - Quantum Mechanical Studies on the Photophysics and the Photochemistry of Nucleic Acids and Nucleobases. AB - The photophysics and photochemistry of DNA is of great importance due to the potential damage of the genetic code by UV light. Quantum mechanical studies have played a key role in interpretating the results of modern time-resolved pump probe spectroscopy, and in elucidating the main photoactivated reactive paths. This review provides a concise, complete picture of the computational studies carried out, approximately, in the past decade. We start with an overview of the photophysics of the nucleobases in the gas phase and in solution. We discuss the proposed mechanisms for ultrafast decay to the ground state, that involve conical intersections, consider the role of triplet states, and analyze how the solvent modulates the photophysics. Then we move to larger systems, from dinucleotides to single- and double-stranded oligonucleotides. We focus on the possible role of charge transfer and delocalized or excitonic states in the photophysics of these systems and discuss the main photochemical paths. We finish with an outlook on the current challenges in the field and future directions of research. PMID- 26928322 TI - Erratum to: Expression pattern of hTERT telomerase subunit gene in different stages of chronic myeloid leukemia. PMID- 26928321 TI - Bed net use among school-aged children after a universal bed net campaign in Malawi. AB - BACKGROUND: Recent data from Malawi suggest that school-aged children (SAC), aged 5-15 years, have the highest prevalence of Plasmodium falciparum infection among all age groups. They are the least likely group to utilize insecticide-treated nets (ITNs), the most commonly available intervention to prevent malaria in Africa. This study examined the effects of a universal ITN distribution campaign, and their durability over time in SAC in Malawi. This study identified factors that influence net usage among SAC and how these factors changed over time. METHODS: Cross-sectional surveys using cluster random sampling were conducted at the end of each rainy and dry season in southern Malawi from 2012 to 2014; six surveys were done in total. Mass net distribution occurred between the first and second surveys. Data were collected on household and individual net usage as well as demographic information. Statistical analyses used generalized linear mixed models to account for clustering at the household and neighbourhood level. RESULTS: There were 7347 observations from SAC and 14,785 from young children and adults. SAC used nets significantly less frequently than the rest of the population (odds ratio (OR) from 0.14 to 0.38). The most important predictors of net usage among SAC were a lower ratio of people to nets in a household and higher proportion of nets that were hanging at the time of survey. Older SAC (11 15 years) were significantly less likely to use nets than younger SAC (5-10 years) [OR = 0.24 (95 % CI: 0.21, 0.28)]. The universal bed net campaign led to a statistically significant population-wide increase in net use, however net use returned to near baseline within 3 years. CONCLUSIONS: This study suggests that a single universal net distribution campaign, in combination with routine distribution through health clinics is not sufficient to cause a sustained increase in net usage among SAC. Novel approaches to ITN distribution, such as school-based distribution, may be needed to address the high prevalence of infection in SAC. PMID- 26928324 TI - Charge effects and nanoparticle pattern formation in electrohydrodynamic NanoDrip printing of colloids. AB - Advancing open atmosphere printing technologies to produce features in the nanoscale range has important and broad applications ranging from electronics to photonics, plasmonics and biology. Recently an electrohydrodynamic printing regime has been demonstrated in a rapid dripping mode (termed NanoDrip), where the ejected colloidal droplets from nozzles of diameters of O (1 MUm) can controllably reach sizes an order of magnitude smaller than the nozzle and can generate planar and out-of-plane structures of similar sizes. Despite the demonstrated capabilities, our fundamental understanding of important aspects of the physics of NanoDrip printing needs further improvement. Here we address the topics of charge content and transport in NanoDrip printing. We employ quantum dot and gold nanoparticle dispersions in combination with a specially designed, auxiliary, asymmetric electric field, targeting the understanding of charge locality (particles vs. solvent) and particle distribution in the deposits as indicated by the dried nanoparticle patterns (footprints) on the substrate. We show that droplets of alternating charge can be spatially separated when applying an ac field to the nozzle. The nanoparticles within a droplet are distributed asymmetrically under the influence of the auxiliary lateral electric field, indicating that they are the main carriers. We also show that the ligand length of the nanoparticles in the colloid affects their mobility after deposition (in the sessile droplet state). PMID- 26928325 TI - The hyperdense basilar artery sign: a case of locked-in syndrome. AB - BACKGROUND: Locked-in syndrome, although a notoriously famous clinical entity, the rarity of the condition coupled with the variability of clinical features on acute presentation represents a potential diagnostic pitfall for the emergency physician. CASE: A previously healthy 25-year-old female was brought to our Emergency Department after being found unresponsive. On examination, she was conscious and alert with a Glasgow Coma Score of 9; on neurological examination, the patient was quadriplegic and unable to speak but was able to move her eyes and blink. Non-contrast brain computed tomography (CT) revealed a hyperdense basilar artery, and CT cerebral angiography confirmed basilar artery thrombosis. CONCLUSION: This case highlights the need for a high index of suspicion to make a diagnosis of locked-in syndrome in the Emergency Department, especially in young patients with no apparent risk factors for an ischemic stroke. The hyperdense basilar artery sign is one of the earliest signs on non-contrast CT imaging and may be the only clue to guide further management in a patient with basilar artery occlusion. PMID- 26928326 TI - Mechanism-based inactivation of human cytochrome P450 1A2 and 3A4 isoenzymes by anti-tumor triazoloacridinone C-1305. AB - 1. 5-Dimethylaminopropylamino-8-hydroxytriazoloacridinone, C-1305, is a promising anti-tumor therapeutic agent with high activity against several experimental tumors. 2. It was determined to be a potent and selective inhibitor of liver microsomal and human recombinant cytochrome P450 (CYP) 1A2 and 3A4 isoenzymes. Therefore, C-1305 might modulate the effectiveness of other drugs used in multidrug therapy. 3. The objective of this study was to investigate the mechanism of the observed C-1305-mediated inactivation of CYP1A2 and CYP3A4. 4. Our findings indicated that C-1305 produced a time- and concentration-dependent decrease in 7-ethoxycoumarin O-deethylation (CYP1A2, KI = 10.8 +/- 2.14 MUM) and testosterone 6beta-hydroxylation (CYP3A4, KI = 9.1 +/- 2.82 MUM). The inactivation required the presence of NADPH, was unaffected by a nucleophilic trapping agent (glutathione) and a reactive oxygen species scavenger (catalase), attenuated by a CYP-specific substrate (7-ethoxycoumarin or testosterone), and was not reversed by potassium ferricyanide. The estimated partition ratios of 1086 and 197 were calculated for the inactivation of CYP1A2 and CYP3A4, respectively. 5. In conclusion, C-1305 inhibited human recombinant CYP1A2 and CYP3A4 isoenzymes by mechanism-based inactivation. The obtained knowledge about specific interactions between C-1305 and/or its metabolites, and CYP isoforms would be useful for predicting the possible drug-drug interactions in potent multidrug therapy. PMID- 26928323 TI - Global expression of AMACR transcripts predicts risk for prostate cancer - a systematic comparison of AMACR protein and mRNA expression in cancerous and noncancerous prostate. AB - BACKGROUND: The high false negative rates for initial prostate biopsies refer a large number of the men for repeat biopsies each year. Therefore, biomarkers associated with high risk of the presence of malignancy in histologically benign biopsies could provide a tool to discriminate the patients who need repeat biopsy or intensive follow-up from those who do not. Here we examined the diagnostic applicability of alpha-methylacyl CoA racemase (AMACR) and androgen receptor (AR) mRNA expression and AMACR protein levels in benign and cancerous prostatic tissue. METHODS: AMACR and AR mRNA levels were measured with quantitative, reverse-transcription PCR (qRT-PCR) assays in 79 radical prostatectomy (RP) cases (including 69 benign (RP-Be) and 69 cancerous (RP-PCa) samples) and 19 benign prostate samples obtained from cystoprostatectomies. To further determine the detailed areas of altered AMACR expression, AMACR mRNA level measurement and protein staining were performed for three cross-sectioned RP cases. RESULTS: The median AMACR and AR expression levels were 194.6 (p < 0.0001) and 6.6 (p = 0.0004) times higher in RP-PCa samples than in the benign cystoprostatectomy (CP) samples, respectively. There was no statistically significant difference between RP-PCa and RP-Be samples, except for AMACR/KLK3 (Kallikrein-Related Peptidase 3) ratio, which was significantly higher in RP-PCa samples than in RP-Be samples (p = 0.016). In the systematic study of cross-sections, AMACR mRNA was detected in all of the studied areas including histologically benign tissue, but at significantly higher levels in carcinoma areas (p < 0.001). AMACR protein expression was detected in 80 % (28/35) of the areas that contained carcinoma and in 37 % (44/119) of the benign and PIN areas from the same patients. CONCLUSIONS: AMACR transcripts were detected in all RP-PCa and RP-Be samples but not in non cancerous CP samples, which suggest a global increase of AMACR expression in cancerous prostates. Therefore patients with false negative biopsies might benefit from an AMACR mRNA measurement when assessing their cancer risk. PMID- 26928327 TI - Leprosy classification methods: a comparative study in a referral center in Brazil. AB - OBJECTIVES: Different methods for the classification of leprosy have been proposed since the 1930s. The aim of this study was to compare the current methods at a referral center in Brazil. METHODS: The World Health Organization (WHO) operational classification was compared to the Ridley and Jopling classification, the Madrid classification, and a classification based on the number of body areas affected by skin and/or neural lesions (NBAA). The correlation between the clinical and histopathological components of the Ridley and Jopling classification was assessed. RESULTS: The agreement between the WHO operational classification and the Ridley and Jopling classification was 77.6% (kappa = 0.53). The WHO operational classification tended to overestimate the number of multibacillary patients. The WHO operational classification showed its best agreement with the NBAA. There was perfect agreement between the clinical and histopathological Ridley and Jopling classification in 46.9% of the patients. CONCLUSIONS: The agreement between the WHO operational classification and the Ridley and Jopling classification was better than any other purely clinical classification, reinforcing the importance and simplicity of the operational method. Although major disagreement between the clinical and histopathological Ridley and Jopling classification was uncommon, perfect agreement occurred in less than half of the cases, and was even lower for the borderline lepromatous and tuberculoid forms. Possible reasons for the differences are discussed; these showed that there may be room for improvement in the Ridley and Jopling classification histopathological criteria. PMID- 26928328 TI - Coordinated Activation of Toll-Like Receptor8 (TLR8) and NLRP3 by the TLR8 Agonist, VTX-2337, Ignites Tumoricidal Natural Killer Cell Activity. AB - VTX-2337 (USAN: motolimod) is a selective toll-like receptor 8 (TLR8) agonist, which is in clinical development as an immunotherapy for multiple oncology indications, including squamous cell carcinoma of the head and neck (SCCHN). Activation of TLR8 enhances natural killer cell activation, increases antibody dependent cell-mediated cytotoxicity, and induces Th1 polarizing cytokines. Here, we show that VTX-2337 stimulates the release of mature IL-1beta and IL-18 from monocytic cells through coordinated actions on both TLR8 and the NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome complex. In vitro, VTX 2337 primed monocytic cells to produce pro-IL-1beta, pro-IL-18, and caspase-1, and also activated the NLRP3 inflammasome, thereby mediating the release of mature IL-1beta family cytokines. Inhibition of caspase-1 blocked VTX-2337 mediated NLRP3 inflammasome activation, but had little impact on production of other TLR8-induced mediators such as TNFalpha. IL-18 activated natural killer cells and complemented other stimulatory pathways, including FcgammaRIII and NKG2D, resulting in IFNgamma production and expression of CD107a. NLRP3 activation in vivo was confirmed by a dose-related increase in plasma IL-1beta and IL-18 levels in cynomolgus monkeys administered VTX-2337. These results are highly relevant to clinical studies of combination VTX-2337/cetuximab treatment. Cetuximab, a clinically approved, epidermal growth factor receptor-specific monoclonal antibody, activates NK cells through interactions with FcgammaRIII and facilitates ADCC of tumor cells. Our preliminary findings from a Phase I open label, dose-escalation, trial that enrolled 13 patients with recurrent or metastatic SCCHN show that patient NK cells become more responsive to stimulation by NKG2D or FcgammaRIII following VTX-2337 treatment. Together, these results indicate that TLR8 stimulation and inflammasome activation by VTX-2337 can complement FcgammaRIII engagement and may augment clinical responses in SCCHN patients treated with cetuximab. TRIAL REGISTRATION: ClinicalTrials.gov NCT01334177. PMID- 26928329 TI - Low internal pressure in femtoliter water capillary bridges reduces evaporation rates. AB - Capillary bridges are usually formed by a small liquid volume in a confined space between two solid surfaces. They can have a lower internal pressure than the surrounding pressure for volumes of the order of femtoliters. Femtoliter capillary bridges with relatively rapid evaporation rates are difficult to explore experimentally. To understand in detail the evaporation of femtoliter capillary bridges, we present a feasible experimental method to directly visualize how water bridges evaporate between a microsphere and a flat substrate in still air using transmission X-ray microscopy. Precise measurements of evaporation rates for water bridges show that lower water pressure than surrounding pressure can significantly decrease evaporation through the suppression of vapor diffusion. This finding provides insight into the evaporation of ultrasmall capillary bridges. PMID- 26928330 TI - Changes in Rumen Microbial Community Composition during Adaption to an In Vitro System and the Impact of Different Forages. AB - This study examined ruminal microbial community composition alterations during initial adaption to and following incubation in a rumen simulation system (Rusitec) using grass or corn silage as substrates. Samples were collected from fermenter liquids at 0, 2, 4, 12, 24, and 48 h and from feed residues at 0, 24, and 48 h after initiation of incubation (period 1) and on day 13 (period 2). Microbial DNA was extracted and real-time qPCR was used to quantify differences in the abundance of protozoa, methanogens, total bacteria, Fibrobacter succinogenes, Ruminococcus albus, Ruminobacter amylophilus, Prevotella bryantii, Selenomonas ruminantium, and Clostridium aminophilum. We found that forage source and sampling time significantly influenced the ruminal microbial community. The gene copy numbers of most microbial species (except C. aminophilum) decreased in period 1; however, adaption continued through period 2 for several species. The addition of fresh substrate in period 2 led to increasing copy numbers of all microbial species during the first 2-4 h in the fermenter liquid except protozoa, which showed a postprandial decrease. Corn silage enhanced the growth of R. amylophilus and F. succinogenes, and grass silage enhanced R. albus, P. bryantii, and C. aminophilum. No effect of forage source was detected on total bacteria, protozoa, S. ruminantium, or methanogens or on total gas production, although grass silage enhanced methane production. This study showed that the Rusitec provides a stable system after an adaption phase that should last longer than 48 h, and that the forage source influenced several microbial species. PMID- 26928331 TI - Applying multivariate analysis as decision tool for evaluating sediment-specific remediation strategies. AB - Multivariate methodology was employed for finding optimum remediation conditions for electrodialytic remediation of harbour sediment from an Arctic location in Norway. The parts of the experimental domain in which both sediment- and technology-specific remediation objectives were met were identified. Objectives targeted were removal of the sediment-specific pollutants Cu and Pb, while minimising the effect on the sediment matrix by limiting the removal of naturally occurring metals while maintaining low energy consumption. Two different cell designs for electrochemical remediation were tested and final concentrations of Cu and Pb were below background levels in large parts of the experimental domain when operating at low current densities (<0.12 mA/cm(2)). However, energy consumption, remediation times and the effect on naturally occurring metals were different for the 2- and 3-compartment cells. PMID- 26928332 TI - Pure anatase and rutile + anatase nanoparticles differently affect wheat seedlings. AB - TiO2-nanoparticles (TiO2-NPs) are increasingly released to the environment. The present work investigates the cytotoxicity, genotoxicity and uptake of TiO2-NPs in Triticum aestivum. Wheat seeds were exposed to 5-150 mg L(-1) of anatase (ana) or rutile + anatase (rut + ana) TiO2-NPs for 5 d. After exposure, germination and growth rates were determined. Cytotoxic effects were evaluated by changes in the cell cycle dynamics and in the membrane integrity. Genotoxicity was assessed by ploidy mutations and DNA-damage, and by mitotic abnormalities. NP uptake was analyzed by Energy Dispersive X-ray Spectroscopy (EDS). Ana-TiO2 revealed higher toxicity regarding the rate of germination, but no negative effects were detected concerning growth. Although roots and shoots showed no EDS-detectable levels of Ti, despite cyto- and genotoxicity was observed in ana and rut + ana-NPs exposed roots. Cell cycle profile was formulation dependent with rut + ana presenting a higher capability to induce a cell cycle arrest at G0/G1. Both formulations induced genotoxic effects by increasing micronucleated cells: for rut + ana a dose-dependent response is evident and seems to be more genotoxic than ana at lower concentrations. Rut + ana also increased membrane permeability. The observed higher cytotoxicity of rut + ana may be explained by the higher photoactivity of this mixture. Overall, these data indicate that during germination, TiO2-NPs induce severe cyto/genotoxic effects, which are dependent on the TiO2-NP formulation. PMID- 26928333 TI - Effects of di-n-butyl phthalate and di (2-ethylhexyl) phthalate on the growth, photosynthesis, and chlorophyll fluorescence of wheat seedlings. AB - Phthalates are commonly used man-made chemicals that can be released into soil, water, and the atmosphere. The potential toxicity of phthalates on wheat seedlings has not been well studied. To better understand the deleterious effects of di-n-butyl phthalate (DBP) and di (2-ethylhexyl) phthalate (DEHP) on wheat seedlings, their influences on the following were investigated: plant growth, net photosynthetic rate (Pn), stomatal conductance (Gs), transpiration rate (Tr), intercellular CO2 concentration (Ci), chlorophyll content, initial fluorescence (F0), maximal photochemical efficiency (Fv/Fm), photochemical quenching (qP), non photochemical quenching (qN), effective quantum yield of photosystem II (PhiPSII), and photosynthetic electron transport rate (ETR). Compared with the control, the growth indices (plant height, fresh and dry weights of shoots, fresh and dry weights of roots), Pn, Gs, Tr, Ci, chlorophyll content, Fv/Fm, qP, PhiPSII, and ETR decreased in the 5 MUg mL(-1) and 10 MUg mL(-1) DBP and DEHP treatments, whereas F0 and qN increased. When wheat seedlings were treated with 20 MUg mL(-1) of DBP and DEHP, the growth indices, Pn, Gs, Tr, chlorophyll content, Fv/Fm, qP, qN, PhiPSII, and ETR decreased significantly, whereas Ci and F0 increased. A decrease in the Pn of wheat seedlings was mainly caused by stomatal limitation in the 5 MUg mL(-1) and 10 MUg mL(-1) DBP and DEHP treatments. However, stomatal and non-stomatal limitations may have caused the reduction in Pn in the 20 MUg mL(-1) DBP and DEHP treatments. Notably, the noxious effect of DBP on the wheat seedlings was significantly greater than that of DEHP. PMID- 26928334 TI - Release of arsenic from metal oxide sorbents under simulated mature landfill conditions. PMID- 26928335 TI - Unusual Presentation of Refractory Autonomic Dysreflexia During General Anesthesia. PMID- 26928336 TI - Effects of emphasising opposition and cooperation on collective movement behaviour during football small-sided games. AB - Optimizing collective behaviour helps to increase performance in mutual tasks. In team sports settings, the small-sided games (SSG) have been used as key context tools to stress out the players' awareness about their in-game required behaviours. Research has mostly described these behaviours when confronting teams have the same number of players, disregarding the frequent situations of low and high inequality. This study compared the players' positioning dynamics when manipulating the number of opponents and teammates during professional and amateur football SSG. The participants played 4v3, 4v5 and 4v7 games, where one team was confronted with low-superiority, low- and high-inferiority situations, and their opponents with low-, medium- and high-cooperation situations. Positional data were used to calculate effective playing space and distances from each player to team centroid, opponent team centroid and nearest opponent. Outcomes suggested that increasing the number of opponents in professional teams resulted in moderate/large decrease in approximate entropy (ApEn) values to both distance to team and opponent team centroid (i.e., the variables present higher regularity/predictability pattern). In low-cooperation game scenarios, the ApEn in amateurs' tactical variables presented a moderate/large increase. The professional teams presented an increase in the distance to nearest opponent with the increase of the cooperation level. Increasing the number of opponents was effective to overemphasise the need to use local information in the positioning decision-making process from professionals. Conversely, amateur still rely on external informational feedback. Increasing the cooperation promoted more regularity in spatial organisation in amateurs and emphasise their players' local perceptions. PMID- 26928337 TI - Contribution of comorbid conditions to the association between diabetes and disability pensions: a population-based nationwide cohort study. AB - OBJECTIVES: Using Swedish population-based register data, we examined the extent to which comorbid conditions contribute to the risk of disability pension among people with diabetes. METHODS: We carried out Cox proportional hazard analyses with comorbid conditions as time-dependent covariates among 14 198 people with newly diagnosed diabetes in 2006, and 39 204 people free from diabetes during the follow-up from 2007-2010. The average follow-up times were 46 and 48 months for those with and without diabetes, respectively. RESULTS: For those with diabetes only, the incidence of all-cause disability pension was 9.5 per 1000 person years. The highest incidence of disability pension were for those with: diabetes and depression (23.6); diabetes and musculoskeletal disorder (30.6), and those with diabetes and more than one comorbid condition (36.5). The incidence rate was 5.8 for those without diabetes. Diabetes was associated with a 2.30 times [95% confidence interval (95% CI) 2.09-2.54] higher risk of disability pension (adjusted for sociodemographic factors). This association attenuated by 41% after further adjustment for comorbid chronic conditions. While diabetes was a risk factor for disability pension due to musculoskeletal disorders and diseases of the circulatory system, even after accounting for the above-mentioned conditions, the association between disability pension due to mental disorders and diabetes was diluted after adjustment for mental disorders. CONCLUSIONS: Although diabetes is an independent risk factor for disability pension, comorbid conditions contribute to this risk to a large degree. PMID- 26928338 TI - Incidence of and Factors Associated With the Decision to Undergo Anterior Cruciate Ligament Reconstruction 1 to 10 Years After Injury. AB - BACKGROUND: Among patients treated nonoperatively for 1 year after anterior cruciate ligament (ACL) disruption, little is known about the frequency of ACL reconstruction within the first year of injury and the effect of age range, sex, and meniscal tears on the incidence of ACL reconstruction between 1 and 10 years after injury. PURPOSE: To (1) define the rate of delayed ACL reconstruction (between 1 and 10 years after injury) in a population-based cohort of isolated ACL tears and (2) evaluate predictive factors associated with delayed reconstruction. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: The study included a population-based cohort of 1841 patients with new-onset, isolated ACL tears that occurred between January 1, 1990, and December 31, 2010. The complete medical records were reviewed to confirm diagnosis and collect data on clinical characteristics and details of subsequent ACL surgery. To evaluate the incidence of ACL reconstruction between 1 and 10 years after injury, landmark survival analysis was performed with a landmark set at 1 year after injury. Early and late predictors of ACL reconstruction were analyzed using Cox proportional hazards regression. RESULTS: A total of 661 patients were treated nonoperatively for the first year after ACL tears. Over a mean 10 years of follow-up, 213 patients (32%) underwent ACL reconstruction between 1 and 10 years after injury. Young age (hazard ratio [HR], 0.55 per decade increase in age; 95% CI, 0.48-0.62) and meniscal tear at injury (HR, 1.48; 95% CI, 1.12-1.95) were significant predictors of undergoing delayed reconstruction. The rate of delayed ACL reconstruction decreased significantly over the study period (P < .03). There was no association between sex (HR, 0.89; 95% CI, 0.67-1.16) and delayed ACL reconstruction. Among patients who had delayed ACL reconstruction, 40% experienced a secondary meniscal tear before surgery. CONCLUSION: In this study population of 1841 patients, 62% of patients received ACL reconstruction within 1 year of injury. Of patients treated nonoperatively for 1 year after ACL tears, 32% underwent delayed ACL reconstruction. Predictors of reconstruction beyond 1 year were young age (50% reduction in reconstruction per decade increased age) and baseline meniscal tear. Sex was not predictive for reconstruction beyond 1 year from injury. PMID- 26928340 TI - The relevance of professionals' attachment style, expectations and job attitudes for therapeutic relationships with young people who experience psychosis. AB - BACKGROUND: Therapeutic relationships are a central component of community treatment for psychosis and thought to influence clinical and social outcomes, yet there is limited research regarding the potential influence of professional characteristics on positive therapeutic relationships in community care. It was hypothesised that professionals' relating style and attitudes toward their work might be important, and thus this exploratory study modelled associations between these characteristics and therapeutic relationships developed in community psychosis treatment. METHODS: Dyads of professionals and young patients with psychosis rated their therapeutic relationships with each other. Professionals also completed measures of attachment style, therapeutic optimism, outcome expectancy, and job attitudes regarding working with psychosis. RESULTS: Professionals' anxious attachment predicted less positive professional therapeutic relationship ratings. In exploratory directed path analysis, data also supported indirect effects, whereby anxious professional attachment predicts less positive therapeutic relationships through reduced professional therapeutic optimism and less positive job attitudes. CONCLUSIONS: Professional anxious attachment style is directly associated with the therapeutic relationship in psychosis, and indirectly associated through therapeutic optimism and job attitudes. Thus, intervening in professional characteristics could offer an opportunity to limit the impact of insecure attachment on therapeutic relationships in psychosis. PMID- 26928339 TI - The kinase CK1E controls the antiviral immune response by phosphorylating the signaling adaptor TRAF3. AB - The signaling adaptor TRAF3 is a highly versatile regulator of both innate immunity and adaptive immunity, but how its phosphorylation is regulated is still unknown. Here we report that deficiency in or inhibition of the conserved serine threonine kinase CK1E suppressed the production of type I interferon in response to viral infection. CK1E interacted with and phosphorylated TRAF3 at Ser349, which thereby promoted the Lys63 (K63)-linked ubiquitination of TRAF3 and subsequent recruitment of the kinase TBK1 to TRAF3. Consequently, CK1E-deficient mice were more susceptible to viral infection. Our findings establish CK1E as a regulator of antiviral innate immune responses and indicate a novel mechanism of immunoregulation that involves CK1E-mediated phosphorylation of TRAF3. PMID- 26928341 TI - Mismatch negativity: Alterations in adults from the general population who report subclinical psychotic symptoms. AB - BACKGROUND: Deficits of mismatch negativity (MMN) in schizophrenia and individuals at risk for psychosis have been replicated many times. Several studies have also demonstrated the occurrence of subclinical psychotic symptoms within the general population. However, none has yet investigated MMN in individuals from the general population who report subclinical psychotic symptoms. METHODS: The MMN to duration-, frequency-, and intensity deviants was recorded in 217 nonclinical individuals classified into a control group (n=72) and three subclinical groups: paranoid (n=44), psychotic (n=51), and mixed paranoid-psychotic (n=50). Amplitudes of MMN at frontocentral electrodes were referenced to average. Based on a three-source model of MMN generation, we conducted an MMN source analysis and compared the amplitudes of surface electrodes and sources among groups. RESULTS: We found no significant differences in MMN amplitudes of surface electrodes. However, significant differences in MMN generation among the four groups were revealed at the frontal source for duration deviant stimuli (P=0.01). We also detected a trend-level difference (P=0.05) in MMN activity among those groups for frequency deviants at the frontal source. CONCLUSIONS: Individuals from the general population who report psychotic symptoms are a heterogeneous group. However, alterations exist in their frontal MMN activity. This increased activity might be an indicator of more sensitive perception regarding changes in the environment for individuals with subclinical psychotic symptoms. PMID- 26928342 TI - Non-pharmacological interventions for reducing aggression and violence in serious mental illness: A systematic review and narrative synthesis. AB - BACKGROUND: For people with mental illness that are violent, a range of interventions have been adopted with the aim of reducing violence outcomes. Many of these interventions have been borrowed from other (offender) populations and their evidence base in a Serious Mental Illness (SMI) population is uncertain. AIMS: To aggregate the evidence base for non-pharmacological interventions in reducing violence amongst adults with SMI and PD (Personality Disorder), and to assess the efficacy of these interventions. We chose to focus on distinct interventions rather than on holistic service models where any element responsible for therapeutic change would be difficult to isolate. METHODS: We performed a systematic review and narrative synthesis of non-pharmacological interventions intended to reduce violence in a SMI population and in patients with a primary diagnosis of PD. Five online databases were searched alongside a manual search of seven relevant journals, and expert opinion was sourced. Eligibility of all returned articles was independently assessed by two authors, and quality of studies was appraised via the Cochrane Collaboration Tool for Assessing Risk of Bias. RESULTS: We included 23 studies of diverse psychological and practical interventions, with a range of experimental and quasi-experimental study designs that included 7 Randomised Controlled Trials (RCTs). The majority were studies of Mentally Disordered Offenders. The stronger evidence existed for patients with a SMI diagnosis receiving Cognitive Behavioural Therapy or modified Reasoning & Rehabilitation (R&R). For patients with a primary diagnosis of PD, a modified version of R&R appeared tolerable and Enhanced Thinking Skills showed some promise in improving attitudes over the short-term, but studies of Dialectical Behaviour Therapy in this population were compromised by high risk of experimental bias. Little evidence could be found for non-pharmacological, non psychological interventions. CONCLUSIONS: The evidence for non-pharmacological interventions for reducing violence in this population is not conclusive. Long term outcomes are lacking and good quality RCTs are required to develop a stronger evidence base. PMID- 26928343 TI - Physical health comorbidities in women with personality disorder: Data from the Geelong Osteoporosis Study. AB - BACKGROUND: Associations between common psychiatric disorders, psychotic disorders and physical health comorbidities are frequently investigated. The complex relationship between personality disorders (PDs) and physical health is less understood, and findings to date are varied. This study aims to investigate associations between PDs with a number of prevalent physical health conditions. METHODS: This study examined data collected from women (n=765;>= 25 years) participating in a population-based study located in south-eastern Australia. Lifetime history of psychiatric disorders was assessed using the semi-structured clinical interviews (SCID-I/NP and SCID-II). The presence of physical health conditions (lifetime) were identified via a combination of self-report, medical records, medication use and clinical data. Socioeconomic status, and information regarding medication use, lifestyle behaviors, and sociodemographic information was collected via questionnaires. Logistic regression models were used to investigate associations. RESULTS: After adjustment for sociodemographic variables (age, socioeconomic status) and health-related factors (body mass index, physical activity, smoking, psychotropic medication use), PDs were consistently associated with a range of physical health conditions. Novel associations were observed between Cluster A PDs and gastro-oesophageal reflux disease (GORD); Cluster B PDs with syncope and seizures, as well as arthritis; and Cluster C PDs with GORD and recurrent headaches. CONCLUSIONS: PDs were associated with physical comorbidity. The current data contribute to a growing evidence base demonstrating associations between PDs and a number of physical health conditions independent of psychiatric comorbidity, sociodemographic and lifestyle factors. Longitudinal studies are now required to investigate causal pathways, as are studies determining pathological mechanisms. PMID- 26928344 TI - Dysfunctional default mode network and executive control network in people with Internet gaming disorder: Independent component analysis under a probability discounting task. AB - BACKGROUND: The present study identified the neural mechanism of risky decision making in Internet gaming disorder (IGD) under a probability discounting task. METHODS: Independent component analysis was used on the functional magnetic resonance imaging data from 19 IGD subjects (22.2 +/- 3.08 years) and 21 healthy controls (HC, 22.8 +/- 3.5 years). RESULTS: For the behavioral results, IGD subjects prefer the risky to the fixed options and showed shorter reaction time compared to HC. For the imaging results, the IGD subjects showed higher task related activity in default mode network (DMN) and less engagement in the executive control network (ECN) than HC when making the risky decisions. Also, we found the activities of DMN correlate negatively with the reaction time and the ECN correlate positively with the probability discounting rates. CONCLUSIONS: The results suggest that people with IGD show altered modulation in DMN and deficit in executive control function, which might be the reason for why the IGD subjects continue to play online games despite the potential negative consequences. PMID- 26928345 TI - Screening of Egyptian toddlers for autism spectrum disorder using an Arabic validated version of M-CHAT; report of a community-based study (Stage I). AB - BACKGROUND: Although there is a recommendation that toddlers be screened for Autism spectrum disorder (ASD) during their 18- and 24-month well-care child visits, diagnosis often occurs well after the child turns 4 years old. Such delayed diagnosis hinders the implementation of early intervention thus worsens the long-term prognosis of ASD. OBJECTIVE: The current community-based study in its stage I aimed at early screening of Egyptian toddlers for ASD using an Arabic validated version of Modified Checklist for Autism in Toddlers (M-CHAT). METHODOLOGY: A cross-sectional community-based descriptive study was carried out enrolling 5546 Egyptian toddlers. They were randomly recruited from those attending Primary Health Care Units in six Egyptian governorates with a fair representation of the urban, semi-urban, and rural Egyptian populations. An Arabic validated version of M-CHAT was used as a screening tool for ASD. RESULTS: The current study revealed failure of M-CHAT (suspected to have ASD and needs further evaluation) in 1320 out of the enrolled 5546 Egyptian toddlers (23.8%). CONCLUSION: M-CHAT as a screening tool for ASD has flagged a considerable percent of the enrolled toddlers that necessitates referral for further evaluation (stage II) to settle the diagnosis of ASD in the true positive cases. Perfecting the delicate balance between sensitivity and specificity for ASD screening tools is crucial in order not to miss early detection of ASD cases and at the same time, to avoid over-diagnosis with subsequent abuse of the limited healthcare resources in developing countries. PMID- 26928346 TI - Spousal resemblance in psychopathology: A comparison of parents of children with and without psychopathology. AB - BACKGROUND: Spouses resemble each other for psychopathology, but data regarding spousal resemblance in externalizing psychopathology, and data regarding spousal resemblance across different syndromes (e.g. anxiety in wives and attention deficit/hyperactivity disorder [ADHD] in husbands) are limited. Moreover, knowledge is lacking regarding spousal resemblance in parents of children with psychiatric disorders. We investigated and compared spousal resemblance within and across internalizing and externalizing symptom domains in parents of children with and without psychopathology. METHODS: Symptoms of depression, anxiety, avoidant personality, ADHD, and antisocial personality were assessed with the Adult Self Report in 728 mothers and 544 fathers of 778 children seen in child and adolescent psychiatric outpatient clinics and in 2075 mothers and 1623 fathers of 2784 children from a population-based sample. Differences in symptom scores and spousal correlations between the samples were tested. RESULTS: Parents in the clinical sample had higher symptom scores than in the population-based sample. In both samples, correlations within and across internalizing and externalizing domains of psychopathology were significant. Importantly, correlations were significantly higher in the clinical sample (P=0.03). Correlations, within and across symptoms, ranged from 0.14 to 0.30 in the clinical sample and from 0.05 to 0.23 in the population-based sample. CONCLUSIONS: This large study shows that spousal resemblance is not only present within but also across symptom domains. Especially in the clinical sample, ADHD symptoms in fathers and antisocial personality symptoms in mothers were correlated with a range of psychiatric symptoms in their spouses. Clinicians need to be alert of these multiple affected families. PMID- 26928347 TI - Evaluation of the Foundation for Anesthesia Education and Research Medical Student Anesthesia Research Fellowship Program Participants' Scholarly Activity and Career Choices. AB - BACKGROUND: The Foundation for Anesthesia Education and Research Medical Student Anesthesia Research Fellowship (MSARF) program is an 8-week program that pairs medical students with anesthesiologists performing anesthesia-related research. This study evaluated the proportion of students who published an article from their work, as well as the percentage of students who entered anesthesiology residency programs. METHODS: A list of previous MSARF participants (2005 to 2012), site, and project information was obtained. Searches for publications were performed using PubMed. The primary outcome was the publication rate for MSARF projects. The MSARF abstract-to-publication ratio was compared with the percentage of abstracts presented at biomedical meetings that resulted in publication as estimated by a Cochrane review (44%). For students who had graduated from medical school, match lists from the students' medical schools were reviewed for specialty choice. RESULTS: Forty-two percent of the 346 MSARF projects were subsequently published. There was no difference between the MSARF abstract-to-publication ratio and the publication rate of articles from abstracts presented at scientific meetings (P = 0.57). Thirty percent (n = 105; 95% CI, 25 to 35%) of all the MSARF students were authors on a publication. Fifty-eight percent of the students for whom residency match data (n = 255) were available matched into anesthesiology residencies (95% CI, 52 to 64%). CONCLUSIONS: The MSARF program resulted in many students being included as a co-author on a published article; the majority of these students entered anesthesiology residency programs. Future research should determine whether the program has a long-term impact on the development of academic anesthesiologists. PMID- 26928350 TI - Ensuring the Future of the Specialty: What Is the Best Strategy to Ensure a Pipeline of Physician-scientists? PMID- 26928351 TI - Population-specific toxicity of six insecticides to the trematode Echinoparyphium sp. AB - The ubiquitous use of pesticides has increased concerns over their direct and indirect effects on disease dynamics. While studies examining the effects of pesticides on host-parasite interactions have largely focused on how pesticides influence the host, few studies have considered the effects of pesticides on parasites. We investigated the toxicity of six common insecticides at six environmentally-relevant concentrations to cercariae of the trematode Echinoparyphium from two populations. All six insecticides reduced the survival of cercariae (overall difference between mortality in control vs pesticide exposure = 86.2 +/- 8.7%) but not in a predictable dose-dependent manner. These results suggest that Echinoparyphium are sensitive to a broad range of insecticides commonly used in the USA. The lack of a clear dose-dependent response in Echinoparyphium highlights the potential limitations of toxicity assays in predicting pesticide toxicity to parasites. Finally, population-level variation in cercarial susceptibility to pesticides underscores the importance of accounting for population variation as overlooking this variation can limit our ability to predict toxicity in nature. Collectively, this work demonstrates that consideration of pesticide toxicity to parasites is important to understanding how pesticides ultimately shape disease dynamics in nature. PMID- 26928352 TI - Exploring intergenerational changes in perceptions of gender roles and sexuality among Indigenous women in Oaxaca. AB - The south of Mexico has traditionally faced disproportionate social, health and economic disadvantage relative to the rest of the country, due in part to lower levels of economic and human development, and barriers faced by Indigenous populations. The state of Oaxaca, in particular, has one of the highest proportions of Indigenous people and consistently displays high rates of maternal mortality, sexually transmitted infections and teenage pregnancy. This study examines how social values and norms surrounding sexuality have changed between two generations of women living in Indigenous communities in Oaxaca. We conducted semi-structured in-depth interviews with 19 women from two generational cohorts in 12 communities. Comparison views of these two cohorts suggest that cultural gender norms continue to govern how women express and experience their sexuality. In particular, feelings of shame and fear permeate the expression of sexuality, virginity continues be a determinant of a woman's worth and motherhood remains the key attribute to womanhood. Evidence points to a transformation of norms, and access to information and services related to sexual health is increasing. Nonetheless, there is still a need for culturally appropriate sex education programmes focused on female empowerment, increased access to sexual health services, and a reduction in the stigma surrounding women's expressions of sexuality. PMID- 26928353 TI - Orbital volume augmentation using expandable hydrogel implants in acquired anophthalmia and phthisis bulbi. AB - The purpose of this study is to describe our experience using expandable spherical hydrogel implants and injectable hydrogel pellets for orbital volume augmentation in cases of post-enucleation socket syndrome after acquired anophthalmia or phthisis bulbi. We retrospectively reviewed the clinical records of all adult patients who received an expandable hydrogel implant for orbital volume loss following enucleation or phthisis bulbi at the Emory Eye Center between 2004 and January 2007 and the Yale Eye Center between 2009 and 2011. The study included 9 women and 5 men with a mean age of 51.2 years old (range 35-76 years old). Follow-up spanned 6 to 71 months (median of 18.5 months). Four patients received spherical hydrogel implants and 10 patients received hydrogel pellet injections. On average, nine pellets (range 5-16) were placed in each patient over an average of 1.7 injections (range 1-3). Most commonly, five pellets were injected per session, as was the case for 13 of the 17 treatment sessions. Post-operative complications included 2 cases of pellet migration, one subcutaneously and one anteriorly due to insufficiently posterior implant placement, and 1 hospital admission for pain after injection of 10 pellets in one visit. All patients experienced an overall subjective improvement in cosmesis. Self-expandable hydrogel implants appear to offer several advantages over other existing options for orbital volume augmentation, as they are easy to place, generally well-tolerated, volume-titratable, and to the extent that our follow-up shows, may be a safe and durable means of treating orbital volume loss in patients with acquired anophthalmia and phthisis bulbi. PMID- 26928354 TI - Dynamic Reaction Mechanisms of ClO(-) with CH3Cl: Comparison Between Direct Dynamics Trajectory Simulations and Experiment. AB - We have investigated the dynamic reaction mechanisms of *ClO- with CH3Cl (the asterisk is utilized to label a different Cl atom). Ab initio molecular dynamics simulations at the MP2/6-31+G(d,p) level of theory have been employed to compute the dynamic trajectories. On the basis of our simulations, the dynamic reaction pathways for the bimolecular nucleophilic substitution (SN2) reaction channel and SN2-induced elimination reaction channel are clearly illustrated. For the SN2 reaction channel, some trajectories directly dissociate to the final products of CH3O*Cl and Cl-, whereas the others involve the dynamic Cl-...CH3O*Cl intermediate complex. As to the SN2-induced elimination reaction channel, the trajectories lead to the final products of CH2O, HCl, and *Cl- through the dynamic Cl-...CH3O*Cl intermediate complex. More significantly, the product branching ratios of Cl- and *Cl- predicted by our simulations are basically consistent with previous experimental results (Villano et al. J. Am. Chem. Soc. 2009, 131, 8227-8233). PMID- 26928355 TI - Disruption of DNA Damage-Response by Propyl Gallate and 9-Aminoacridine. AB - The DNA-damage response (DDR) protects the genome from various types of endogenous and exogenous DNA damage, and can itself be a target of certain chemicals that give rise to chromosomal aberrations. Here, we developed a screening method to detect inhibition of Mediator of DNA damage Checkpoint 1 (MDC1) foci formation (the Enhanced Green Fluorescent Protein (EGFP)-MDC1 foci formation-inhibition assay) using EGFP-MDC1-expressing human cells. The assay identified propyl gallate (PG) and 9-aminoacridine (9-AA) as inhibitors of camptothecin (CPT)-induced MDC1 foci formation. We demonstrated that the inhibition of CPT-induced MDC1 foci formation by PG was caused by the direct suppression of histone H2AX phosphorylation at Ser139 (gammaH2AX), which is required for MDC1 foci formation, by quantifying gammaH2AX in cells and in vitro 9-AA also directly suppressed H2AX Ser139-phosphorylation in vitro but the concentration was much higher than that required to suppress CPT-induced MDC1 foci formation in cells. Consistent with these findings, PG and 9-AA both suppressed CPT-induced G2/M cell-cycle arrest and increased the number of abnormal nuclei. Our results suggest that early DDR-inhibitory effects of PG and 9-AA contribute to their chromosome-damaging potential, and that the EGFP-MDC1 foci formation-inhibition assay is useful for detection of and screening for H2AX Ser139-phosphorylation-inhibitory effects of chemicals. PMID- 26928356 TI - Involvement of Mouse Constitutive Androstane Receptor in Acifluorfen-Induced Liver Injury and Subsequent Tumor Development. AB - Acifluorfen (ACI), a protoporphyrinogen oxidase (PROTOX) inhibitor herbicide, promotes the accumulation of protoporphyrin IX (PPIX), and induces tumors in the rodent liver. Porphyria is a risk factor for liver tumors in humans; however, the specific mechanisms through which ACI induces hepatocarcinogenesis in rodents are unclear. Here, we investigated the mode of action of ACI-induced hepatocarcinogenesis, focusing on constitutive androstane receptor (CAR, NR1I3), which is essential for the development of rodent liver tumors in response to certain cytochrome P450 (CYP) 2B inducers. Dietary treatment with 2500 ppm ACI for up to 13 weeks increased Cyp2b10 expression in the livers of wild-type (WT) mice, but not in CAR-knockout (CARKO) mice. Microscopically, ACI treatment induced cytotoxic changes, including hepatocellular necrosis and inflammation, and caused regenerative changes accompanied by prolonged increases in the numbers of proliferating cell nuclear antigen-positive hepatocytes in WT mice. In contrast, these cytotoxic and regenerative changes in hepatocytes were significantly attenuated, but still observed, in CARKO mice. ACI treatment also increased liver PPIX levels similarly in both genotypes; however, no morphological evidence of porphyrin deposition was found in hepatocytes from either genotype. Treatment with 2500 ppm ACI for 26 weeks after initiation with diethylnitrosamine increased the incidence and multiplicities of altered foci and adenomas in hepatocytes from WT mice; these effects were significantly reduced in CARKO mice. These results indicated that prolonged cytotoxicity in the liver was a key factor for ACI-induced hepatocarcinogenesis, and that CAR played an important role in ACI-induced liver injury and tumor development in mice. PMID- 26928357 TI - Distribution of Dekkera bruxellensis in a sugarcane-based fuel ethanol fermentation plant. AB - We investigated the presence of the yeast Dekkera bruxellensis in samples collected at three points surrounding the industrial alcoholic fermentation plants of two distilleries where there are often cases of contamination caused by this yeast: this involved sugar cane wash water, feeding sugar cane juice and vinasse from the treatment pond. Total yeast was isolated in WLN medium with bromocresol green and cycloheximide and further selected on the basis of its ability to grow in synthetic medium containing nitrate. Following this, colonies were selected from the distribution on nitrate plates and identified by amplification with species-specific primers and DNA sequencing of the 26S-D1/D2 locus. The results showed that D. bruxellensis is introduced through the feeding substrate, which suggests that its cells originated with the harvested cane. Subsequently, its population circulates as a result of the reuse of water for washing the cane, in a continuous re-inoculation of the plant with yeasts. Furthermore, the yeast population is formed in the vinasse by the addition of wash water into the treatment ponds and then reintroduced to the culture fields by fertigation, so that the process can be renewed in the following season. It is now possible to adopt sanitation procedures that can prevent the entry of the contamination to the fermentation process. SIGNIFICANCE AND IMPACT OF THE STUDY: The presence of the yeast Dekkera bruxellensis is sometimes attributed to a decline in the industrial productivity of ethanol since it has a more limited fermentation capacity than Saccharomyces cerevisiae. Although its adaptability to the industrial environment has been noted, so far, there has been no evidence to determine the source of this contamination. In this study, we provide evidence to show that D. bruxellensis comes from the fields together with the harvested cane and is then accumulated and recirculated. It might be possible to prevent the accumulation of this yeast by carrying out sanitation controls during the harvesting season. PMID- 26928358 TI - A human quadrupedal gait following poliomyelitis: From the Dercum-Muybridge collaboration (1885). AB - BACKGROUND: Beginning in the late 1870s, before the invention of movie cameras or projectors, pioneering English American photographer Eadweard Muybridge photographed iconic image sequences of people and animals in motion using arrays of sequentially triggered single-image cameras. In 1885, Philadelphia neurologist Francis Dercum initiated a collaborative relationship with Muybridge at the University of Pennsylvania to photograph sequential images of patients with various neurologic disorders of movement, including an acquired pathologic quadrupedal gait in a young boy that developed as a consequence of poliomyelitis. METHODS: This pathologic human quadrupedal gait was compared with other quadrupedal gaits filmed by Muybridge, including a toddler girl and an adult woman crawling on hands and knees, an adult woman bear crawling on hands and feet, and a baboon walking. RESULTS: All of the human quadrupedal gaits were lateral sequence gaits, whereas the baboon's walking gait was a diagonal sequence gait. Modern studies have confirmed the nonpathologic quadrupedal gait sequences of humans and nonhuman primates. CONCLUSION: Despite Dercum's assertion to the contrary, the limb placement pattern of the boy with a pathologic quadrupedal gait after poliomyelitis was not the typical gait of a primate quadruped, but rather was the typical gait sequence for normal human developmental and volitional quadrupedal gaits. PMID- 26928359 TI - Miliary cerebral calcifications: A rare presentation of breast cancer metastasis. PMID- 26928360 TI - Natural course of total mismatch and predictors for tissue infarction. PMID- 26928361 TI - Cerebral microbleeds and postthrombolysis intracerebral hemorrhage risk: Updated meta-analysis. PMID- 26928362 TI - Clinical Reasoning: A 71-year-old man with rapidly progressive dementia. PMID- 26928363 TI - Teaching Video NeuroImages: Alternating skew deviation with abducting hypertropia following superior colliculus infarction. PMID- 26928364 TI - Teaching NeuroImages: Optic radiation hemorrhage: A rare complication of extracorporeal membrane oxygenation. PMID- 26928365 TI - MiR-1180 promotes apoptotic resistance to human hepatocellular carcinoma via activation of NF-kappaB signaling pathway. AB - Apoptosis resistance in human hepatocellular carcinoma (HCC) is a significant factor in carcinogenesis. Therefore, understanding the molecular mechanisms involved in apoptosis resistance is crucial for developing anticancer therapies. Importantly, small non-coding microRNAs (miRNAs) have been reported as key biomarkers for detecting tumour onset and progression. In the present study, we demonstrate that miR-1180 is upregulated in HCC. Ectopic expression of miR-1180 has an anti-apoptotic effect in HCC, while miR-1180 inhibition increases cell apoptosis, both in vitro and in vivo. Moreover, our results show that miR-1180 directly targets key inhibitors of the nuclear factor (NF)-kappaB signaling pathway (i.e., OTUD7B and TNIP2) and the pro-apoptotic Bcl-2 associated death promoter (BAD) protein by post-transcriptional downregulation. Therefore, the anti-apoptotic function of miR-1180 in HCC may occur through NF-kappaB pathway activation via downregulation of its negative regulators. In conclusion, our study reveals the critical role of miR-1180 during apoptosis resistance in HCC. PMID- 26928366 TI - Comparison of live donor pre-transplant and recipient post-transplant renal volumes. AB - BACKGROUND: Live donor pre-transplant and recipient post-transplant kidney volumes based on three-dimensional computed tomography (3DCT) have been related to post-transplant renal function. We examined this association and the effect of sex/size differences between donor and recipient on kidney growth rate. METHODS: We retrospectively reviewed 30 live donors who underwent pre-transplant and post transplant 3DCT. We determined donor (Dvol) and recipient renal volumes (Rvol) based on 3DCT and calculated changes in graft volume after transplantation (Vol ratio). We also divided Dvol by recipient body weight (Dvol/RWgt) and compared the correlations between Vol-ratio and Dvol/RWgt and post-transplant renal function after one yr. We determined the rates of change in kidney volume and renal function according to the sexes of the donor and recipient. RESULTS: The mean Dvol and Rvol were 141.7 and 178.4 mL, respectively. The mean Vol-ratio was 127.3%. Dvol/RWgt showed a significant linear correlation with remaining renal function after one yr (r = 0.6745, p < 0.0001). The combination of female donor and male recipient resulted in the fastest increase in kidney volume (p < 0.001) and highest level of proteinuria (p < 0.001). CONCLUSIONS: Pre-transplant and post-transplant kidney volumes are correlated with post-transplant graft function, and graft growth is affected by the relative sexes of the recipient and donor. PMID- 26928367 TI - Retrospective comparison of ephedrine and phenylephrine for the treatment of spinal anesthesia induced hypotension in pre-eclamptic patients. AB - OBJECTIVE: To compare neonatal acid base status in parturients who underwent cesarean delivery and received either ephedrine or phenylephrine boluses for the treatment of spinal anesthesia induced hypotension. RESEARCH DESIGN AND METHODS: After institutional review board approval, the perioperative database of the University of Iowa Hospitals and Clinics was used to identify all women diagnosed with pre-eclampsia and had cesarean delivery under spinal anesthesia for the period 1 January 2005 to 31 July 2014. Data retrieved included patient demographics, indication for cesarean delivery, severity of pre-eclampsia, dose of vasopressor, neonatal umbilical artery pH and Apgar scores. MAIN OUTCOME MEASURES: Primary outcome was umbilical artery pH. RESULTS: Data for 146 patients was included in the analysis. Ephedrine was used in 57 patients (group E) and phenylephrine in 89 (group PE) patients. The median umbilical artery pH was 7.30 (IQR 7.20-7.30) and 7.30 (IQR 7.20-7.30) in the ephedrine and phenylephrine groups respectively (P = 0.41). Non-reassuring fetal heart trace was the only factor significantly associated with lower umbilical artery pH on multivariable regression analysis (beta = -0.09, P = 0.002). CONCLUSIONS: We found no difference in neonatal umbilical artery pH between ephedrine and phenylephrine when used to treat spinal anesthesia induced hypotension during cesarean delivery in pre-eclamptic patients. Limitations of the study include its retrospective single center design and the fact that the choice of vasopressor was not randomized. PMID- 26928368 TI - Mesoporogen-Free Synthesis of Hierarchically Structured Zeolites with Variable Si/Al Ratios via a Steam-Assisted Crystallization Process. AB - In the absence of additional mesoporous template, hierarchically structured zeolites (HSZs) with variable Si/Al ratios (30-150) have been successfully synthesized via a newly developed steam-assisted crystallization process. The synthesized materials were characterized with powder X-ray diffraction, nitrogen sorption measurement, scanning electron microscopy, transmission electron microscopy, inductively coupled plasma optical emission spectrometry, solid-state nuclear magnetic resonance, and ammonia temperature-programmed desorption. All these results prove that the synthesized materials feature high crystallinity (microporous framework) and auxiliary mesoporous structure. In the model reactions of isopropylbenzene and 1,3,5-triisopropylbenzene cracking, compared to purely microporous ZSM-5 counterparts, here synthesized HSZs exhibited markedly enhanced catalytic performances resulting from their enlarged external surface area and shortened diffusion length in the microporous system. PMID- 26928369 TI - Beverage consumption in an Alaska Native village: a mixed-methods study of behaviour, attitudes and access. AB - BACKGROUND: American Indians/Alaska Natives (AI/AN) have the highest prevalence of obesity for any racial/ethnic group. Previous studies examining risk factors for obesity have identified excessive sugar-sweetened beverage (SSB) and inadequate water consumption as major risk factors for this population group. The historical scarcity of water in rural Alaska may explain consumption patterns including reliance on SSBs and other packaged drinks. METHODS: Our study was designed to assess SSB, water and other beverage consumption and attitudes towards consumption in Alaska Native children and adults residing in rural Alaska. During summer 2014, 2 focus groups were conducted employing community members in a small rural village more than 200 air miles west of Fairbanks, Alaska. Interviews were completed with shop owners, Early Head Start and Head Start program instructors (n=7). SSB and total beverage intakes were measured using a modified version of the BEVQ-15, (n=69). RESULTS: High rates of SSB consumption (defined as sweetened juice beverages, soda, sweet tea, energy drink or sports drinks) and low rates of water consumption were reported for all age groups in the village. All adolescents and 81% of children reported drinking SSBs at least once per week in the last month, and 48% of adolescents and 29% of younger children reported daily consumption. Fifty-two per cent of adults reported consuming SSBs at least once per week and 20% reported daily consumption. Twenty-five per cent of adolescents reported never drinking water in the past month, and 19% of younger children and 21% of adults did not consume water daily. CONCLUSION: Alaska Native children and adults living in the Interior Alaska consume high amounts of SSBs including energy drinks and insufficient amounts of water. Interventions targeting beverage consumption are urgently needed for the Alaska Native population in rural Alaska. PMID- 26928370 TI - A survey of knowledge, attitudes, and practices towards skin and soft tissue infections in rural Alaska. AB - BACKGROUND: Community-acquired methicillin-resistant Staphylococcus aureus and methicillin-sensitive S. aureus infections are common to south-western Alaska and have been associated with traditional steambaths. More than a decade ago, recommendations were made to affected communities that included preventive skin care, cleaning methods for steambath surfaces, and the use of protective barriers while in steambaths to reduce the risk of S. aureus infection. OBJECTIVE: A review of community medical data suggested that the number of skin infection clinical encounters has increased steadily over the last 3 years and we designed a public health investigation to seek root causes. STUDY DESIGN: Using a mixed methods approach with in-person surveys, a convenience sample (n=492) from 3 rural communities assessed the range of knowledge, attitudes and practices concerning skin infections, skin infection education messaging, prevention activities and home self-care of skin infections. RESULTS: We described barriers to implementing previous recommendations and evaluated the acceptability of potential interventions. Prior public health messages appear to have been effective in reaching community members and appear to have been understood and accepted. We found no major misconceptions regarding what a boil was or how someone got one. Overall, respondents seemed concerned about boils as a health problem and reported that they were motivated to prevent boils. We identified current practices used to avoid skin infections, such as the disinfection of steambaths. We also identified barriers to engaging in protective behaviours, such as lack of access to laundry facilities. CONCLUSIONS: These findings can be used to help guide public health strategic planning and identify appropriate evidence-based interventions tailored to the specific needs of the region. PMID- 26928371 TI - Fluconazole induces rapid high-frequency MTL homozygosis with microbiological polymorphism in Candida albicans. AB - BACKGROUND: Candida albicans, a common fungal pathogen that can cause opportunistic infections, is regarded as an apparently asexual, diploid fungus. A parasexual cycle was previously found between homozygotes with opposite mating type-like loci (MTLa/alpha). Fluconazole-resistant strains had a higher proportion of MTL homozygotes, whereas MTL homozygous C. albicans was found in only about 3.2% of clinical strains. MTL heterozygotes had a low frequency (1.4 * 10-4) of white-opaque switching to MTL homozygotes in nature. METHODS: Here, a reference C. albicans strain (SC5314) was used in a fluconazole-induced assay to obtain standard opaque MTL homozygous strains and first-generation daughter strains from the fluconazole inhibition zone. Further separation methods were employed to produce second- and third-generation daughter strains. Polymerase chain reaction analysis based on MTL genes was used to define MTL genotypes, and microscopic observations, a flow-cytometric assay, and an antifungal E-test were used to compare microbiological characteristics. RESULTS: MTL homozygotes were found at a high frequency (17 of 35; 48.6%) in fluconazole-induced first generation daughter strains, as were morphological polymorphisms, decreased DNA content, and modified antifungal drug susceptibility. High-frequency MTL homozygosity was identified inside the fluconazole inhibition zone within 24 hours. The DNA content of fluconazole-induced daughter strains was reduced compared with their progenitor SC5314 and standard MTL homozygous strains. CONCLUSION: Treatment with fluconazole, commonly used to treat invasive candidiasis, inhibited the growth of C. albicans and altered its microbiological characteristics. Our results suggest that fluconazole treatment induces the high frequency of loss of heterozygosity and microbiological polymorphism in C. albicans. PMID- 26928372 TI - Narrow-band Imaging International Colorectal Endoscopic Classification to predict polyp histology: REDEFINE study (with videos). AB - BACKGROUND AND AIMS: The Narrow-band Imaging International Colorectal Endoscopic (NICE) Classification has been validated for differentiating hyperplastic from adenomatous polyps. This classification system was based on narrow-band imaging (NBI) technology, leaving uncertainty regarding its applicability to other systems. The aim of this study was to assess accuracy and reliability of histologic predictions for polyps <1 cm by applying the NICE classification to the Fujinon Spectral Imaging Color Enhancement (FICE) System. METHODS: A video library of 55 polyps <1 cm histologically verified with FICE was prospectively created, including polyps that fulfilled inclusion criteria (morphology, size, histology) in consecutive colonoscopies. Six endoscopists with experience in electronic chromoendoscopy independently reviewed the polyp images, scored the polyps as adenomatous or hyperplastic, and assigned a level of confidence to the predictions. Twenty videos were reassessed at 6 months. The diagnostic performances of the endoscopists was calculated both combined and individually according to the histopathology of the polyps. A mixed-effect logistic regression model, in which polyps were considered as random effects, and polyp histology, confidence level, and readers were considered as fixed effects, was used. Results were expressed as odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: Of the 55 polyps (mean size 4.6 mm), 29 (53%) were adenomas, and 26 (47%) were hyperplastic. Across all the readers and observations, the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), accuracy, and area under the curve (AUC) were 77%, 75%, 88%, 75%, 77%, and 0.82, respectively. Individual rater accuracy ranged from 66% to 96%, being <90% in 5 of 6 cases. Overall, 68.5% of predictions (226/330) were made with high confidence, although there was high variability (Fleiss kappa, 0.15; 95% CI, 0.08 0.22). Sensitivity, specificity, PPV, NPV, accuracy, and AUC for predictions made with high confidence were 81%, 80.5%, 80%, 77%, 82%, and 0.88 being significantly more accurate as compared with a low confidence of diagnosis (OR 2.4; 95% CI, 1.2 4.7). Regarding the performance of the individual NICE criteria, the odds of adenoma detection were 3.4 (95% CI, 1.8-6.3) and 4.0 (95% CI, 2.1-7.5) by using surface and vessels patterns alone, as compared with the color criterion. Interrater and intrarater agreement with the NICE was only moderate (interrater: Fleiss kappa, 0.51; 95% CI, 0.44-0.56; intrarater: kappa, 0.40; 95% CI, 0.20 0.60). CONCLUSIONS: The application of the NICE classification to FICE resulted in suboptimal accuracy and only moderate interobserver agreement. PMID- 26928373 TI - Methotrexate is not associated with increased liver cirrhosis in a population based cohort of rheumatoid arthritis patients with chronic hepatitis B. AB - A few studies showed that long-term methotrexate (MTX) use exacerbates liver fibrosis and even leads to liver cirrhosis in rheumatoid arthritis (RA) patients. We therefore conducted a population-based cohort study to investigate the impact of long-term MTX use on the risk of chronic hepatitis B (CHB)-related cirrhosis among RA patients. We analyzed data from the National Health Insurance Research Database in Taiwan and identified 631 incident cases of RA among CHB patients (358 MTX users and 273 MTX non-users) from January 1, 1998 to December 31, 2007. After a median follow-up of more than 6 years since the diagnosis of CHB, a total of 41 (6.5%) patients developed liver cirrhosis. We did not find an increased risk of liver cirrhosis among CHB patients with long-term MTX use for RA. Furthermore, there was no occurrence of liver cirrhosis among 56 MTX users with a cumulative dose ?3 grams after 97 months' treatment. In conclusion, our data showed that long-term MTX use is not associated with an increased risk for liver cirrhosis among RA patients with CHB. However, interpretation of the results should be cautious due to potential bias in the cohort. PMID- 26928374 TI - Preliminary experiences in trachea scaffold tissue engineering with segmental organ decellularization. AB - OBJECTIVES/HYPOTHESIS: Ideal methods for reconstructing the tracheal structure and restoring tracheal function following damage to the trachea or removal of the trachea have not been developed. The purpose of this study is to evaluate the feasibility of using a whole segment decellularized tracheal scaffold to reconstruct the trachea. STUDY DESIGN: Prospective experimental design. SETTING: In vivo rabbit model. METHODS: Trachea scaffolds were created using our previously developed freeze-dry-sonication-sodium dodecyl sulfate (SDS), [FDSS] decellularization process. After histological and mechanical testing, the scaffolds were transplanted orthotopically into segmental defects in New Zealand White Rabbits (n = 9). Another three rabbits receiving the sham operation with autologous trachea transplantations served as the control group. Two weeks after transplantation, the grafts were evaluated endoscopically and histologically. RESULTS: The mechanical properties of the decellularized trachea segment did not differ significantly from the fresh native trachea. After transplantation, whereas the autograft in the control group showed full integration and functional recovery, all of the rabbits in the decellularized scaffold transplantation group died within 7~24 days. Although significant collapse of the tracheal tubular structures was noted, full respiratory epithelium regeneration was observed in the rabbits that survived more than 2 weeks. CONCLUSION: The FDSS decellularization process is effective in creating whole-segment, subtotally decellularized trachea scaffolds. However, although the respiratory epithelium regeneration on the inner surface appeared to be satisfactory, the tubular structures were not able to be maintained after transplantation, which ultimately led to the death of the animals. LEVEL OF EVIDENCE: NA Laryngoscope, 126:2520 2527, 2016. PMID- 26928375 TI - Essential fatty acid-rich diets protect against striatal oxidative damage induced by quinolinic acid in rats. AB - Essential fatty acids have an important effect on oxidative stress-related diseases. The Huntington's disease (HD) is a hereditary neurologic disorder in which oxidative stress caused by free radicals is an important damage mechanism. The HD experimental model induced by quinolinic acid (QUIN) has been widely used to evaluate therapeutic effects of antioxidant compounds. The aim of this study was to test whether the fatty acid content in olive- or fish-oil-rich diet prevents against QUIN-related oxidative damage in rats. Rats were fed during 20 days with an olive- or a fish-oil-rich diet (15% w/w). Posterior to diet period, rats were striatally microinjected with QUIN (240 nmol/ul) or saline solution. Then, we evaluated the neurological damage, oxidative status, and gamma isoform of the peroxisome proliferator-activated receptor (PPARgamma) expression. Results showed that fatty acid-rich diet, mainly by fish oil, reduced circling behavior, prevented the fall in GABA levels, increased PPARgamma expression, and prevented oxidative damage in striatal tissue. In addition none of the enriched diets exerted changes neither on triglycerides or cholesterol blood levels, nor or hepatic function. This study suggests that olive- and fish-oil-rich diets exert neuroprotective effects. PMID- 26928376 TI - The identification of novel genetic variants associated with antipsychotic treatment response outcomes in first-episode schizophrenia patients. AB - BACKGROUND: Although antipsychotics are integral to the treatment of schizophrenia, drug efficacy varies between patients. Although it has been shown that antipsychotic treatment response outcomes are heritable, our understanding of the genetic factors that are involved remains incomplete. Therefore, this study aims to use an unbiased scan of the genome to identify the genetic variants contributing toward antipsychotic treatment response outcomes. MATERIALS AND METHODS: This study utilized whole-exome sequencing of patients on extreme ends of the treatment response spectrum (n=11) in combination with results from previous antipsychotic studies to design a panel of variants that were genotyped in two well-characterized first-episode schizophrenia cohorts (n=103 and 87). Association analyses were carried out to determine whether these variants were significantly associated with antipsychotic treatment response outcomes. RESULTS: Association analyses in the discovery cohort identified two nonsynonymous variants that were significantly associated with antipsychotic treatment response outcomes (P<2.7 * 10(-5)), which were also significantly associated with the corresponding treatment response outcome in an independent replication cohort. Computational approaches showed that both of these nonsynonymous variants- rs13025959 in MYO7B (E1647D) and rs10380 in MTRR (H622Y)--were predicted to impair the functioning of their corresponding protein products. CONCLUSION: The use of whole-exome sequencing in a subset of patients from a well-characterized cohort of first-episode schizophrenia patients, for whom longitudinal depot treatment response data were available, allowed for (i) the removal of confounding factors related to treatment progression and compliance and (ii) the identification of two genetic variants that have not been associated previously with antipsychotic treatment response outcomes and whose results were applicable across different classes of antipsychotics. Although the genes that are affected by these variants are involved in pathways that have been related previously to antipsychotic treatment outcomes, the identification of these novel genes will play an important role in improving our understanding of the specific variants involved in antipsychotic treatment response outcomes. PMID- 26928377 TI - Associations between HLA class I and cytochrome P450 2C9 genetic polymorphisms and phenytoin-related severe cutaneous adverse reactions in a Thai population. AB - BACKGROUND: Phenytoin is one of the most common causative drugs of several types of severe cutaneous adverse reactions (SCAR) such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reactions with eosinophilia and systemic symptoms (DRESS). Genetic polymorphisms of the human leukocyte antigens (HLA) and cytochromes P450 (CYP) have been proposed as key elements for the susceptibility to phenytoin-related SCAR in certain ethnicities. This study investigated the associations between the genetic polymorphisms of HLA class I and CYP2C9 and phenytoin-related SCAR in a Thai population. MATERIALS AND METHODS: Sixty phenytoin-related SCAR (i.e. 39 SJS/TEN and 21 DRESS) and 92 phenytoin-tolerant patients were enrolled in the study. The genotypes of HLA class I and CYP2C9 were determined. RESULTS: Six HLA alleles including HLA A*33:03, HLA-B*38:02, HLA-B*51:01, HLA-B*56:02, HLA-B*58:01, and HLA-C*14:02 were significantly associated with phenytoin-related SJS/TEN, whereas only the HLA B*51:01 was significantly associated with phenytoin-related DRESS. The odds ratios of phenytoin-related SJS/TEN in the patients who carried one of these alleles ranged from 4- to 10-fold. The frequencies of patients who carried the HLA-B*15:02 in the SJS/TEN (12.82%) or the DRESS (9.52%) groups were not significantly different from that of the controls (14.13%). The higher risk of phenytoin-related SJS/TEN was observed in the patients with CYP2C9*3 (odds ratio=4.30, 95% confidence interval=1.41-13.09, P<0.05). CONCLUSION: Neither SJS/TEN nor DRESS caused by phenytoin was significantly associated with the HLA B*15:02. The CYP2C9*3 variant was significantly associated with phenytoin-related SJS/TEN, but not DRESS. Certain alleles of HLA, particularly HLA-B*56:02, were significantly associated with phenytoin-related SCAR in the study population. PMID- 26928378 TI - Laparoscopic Management of Ureteroileal Anastomosis Strictures: Initial Experience. AB - BACKGROUND: A ureteroileal anastomosis stricture (UAS) is one of the most frequent complications after radical cystectomy. Open surgical repair is the treatment of choice but is associated with morbidity. OBJECTIVE: To describe the efficacy and safety of laparoscopic management for benign secondary UAS. DESIGN, SETTING, AND PARTICIPANTS: A review was performed of the 11 initial procedures performed at our academic center from December 2010 to December 2014, with mean follow-up of 38 mo (range 12-169). Patients included had benign ureteroileal strictures longer than 1cm. SURGICAL PROCEDURE: A pure laparoscopic approach was systematically used, involving a two-step procedure for left and a one-step procedure for right ureteral stenosis. MEASUREMENTS: Perioperative data were collected and complications were assessed using the Clavien-Dindo grading system. Outcomes and follow-up data were analyzed. RESULTS AND LIMITATIONS: A descriptive statistical analysis was performed for 11 surgeries in ten patients. The median stricture length was 2.4cm. No conversion to open surgery was required. The mean blood loss was 180ml and the mean hospital stay was 10 d. Early complications included limited lymphorrhea (n=1), limited anastomotic leakage (n=2), and accidental descent of a ureteral catheter (n=1) that was replaced with radiologic intervention. The mean follow-up was 38 mo (range 12-169). No late complications were reported. After 1 yr of follow-up, six patients had good glomerular filtration rates, all patients were asymptomatic, and no stenotic relapses were detected. CONCLUSIONS: This laparoscopic technique for the management of benign secondary UAS is feasible, with good results and without long-term complications. This minimally invasive approach reduces the morbidity associated with open surgery while retaining good success rates. PATIENT SUMMARY: We describe a novel laparoscopic approach for patients with a ureteroileal anastomosis stricture after radical cystectomy to avoid the complications associated with open surgery. The surgery was found to be viable and safe with good long-term results. PMID- 26928379 TI - Re: Christopher J.D. Wallis, Refik Saskin, Richard Choo, et al. Surgery Versus Radiotherapy for Clinically-localized Prostate Cancer: A Systematic Review and Meta-analysis. Eur Urol 2016;70:21-30. PMID- 26928380 TI - Re: Christopher J.D. Wallis, Refik Saskin, Richard Choo, et al. Surgery Versus Radiotherapy for Clinically-localized Prostate Cancer: A Systematic Review and Meta-analysis. Eur Urol 2016;70:21-30. PMID- 26928381 TI - Hodgkin lymphoma post-transplant lymphoproliferative disorder: A comparative analysis of clinical characteristics, prognosis, and survival. AB - Hodgkin lymphoma post-transplant lymphoproliferative disorder (HL-PTLD) is an uncommon PTLD with unclear prognosis and differences between HL-PTLD and immunocompetent HL are not well defined. Patient characteristics were compared among 192 patients with HL-PTLD from the Scientific Registry of Transplant Recipients and 13,847 HL patients in SEER (HL-SEER). Overall survival (OS) and disease-specific survival (DSS) were compared after exact matching. Additionally, multivariable analyses were used to identify prognostic markers of survival and associations between treatment and survival. Median time from transplant to HL PTLD diagnosis was 88 months. When compared with HL-SEER, patients with HL-PTLD were older (median age, 52 vs. 36 years, P = 0.001), more likely male (73% vs. 54%, P < 0.001), Caucasian (81% vs. 70%, P = 0.02), and had extranodal disease (42% vs. 3%, P < 0.001). Five-year OS for patients with HL-PTLD was 57% versus 80% for HL-SEER (P < 0.001); DSS was also inferior (P < 0.001). For patients with HL-PTLD, the use of any chemotherapy was associated with decreased hazard of death (HR = 0.36, P < 0.001). Furthermore, patients who received no chemotherapy or nontraditional HL regimens had increased hazard of death (aHR = 2.94, P = 0.001 and 2.01, P = 0.04) versus HL-specific chemotherapy regimens. In multivariable analysis, advanced age and elevated creatinine were associated with inferior OS (aHR = 1.26/decade P < 0.001 and 1.64/0.1 mg/dL increase P = 0.02). A prognostic score based on the number of these adverse factors (0, 1, 2) was associated with 10-year OS rates of 79%, 53%, and 11%, respectively (P < 0.001). Altogether, HL-PTLD patients have inferior survival when compared with HL-SEER. Furthermore, treatment with HL-specific chemotherapy was associated with improved OS, whereas age and creatinine identified patients with markedly divergent survival. Am. J. Hematol. 91:560-565, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26928382 TI - Hemorrhagic bullous dermatosis: a rare heparin-induced cutaneous manifestation. AB - Heparin is one of the most widely prescribed medications. Cutaneous reactions distant to the injection site are rare and under-reported in the literature. We present an elderly man with history of CNS lymphoma who underwent treatment of a deep venous thrombosis with enoxaparin and subsequently developed well demarcated bullous lesions within days of heparin initiation. The exact pathophysiology is not well understood. Hemorrhagic bullous dermatosis is a rare cutaneous reaction that is temporally associated with the initiation of heparin products. The handful of cases thus far suggest that regression of these seemingly benign lesions may or may not be associated with dose reduction or discontinuation of heparin products and typically occur within a few weeks. Elderly age appears to be one potential risk factor for development of these rare asymptomatic lesions. Malignancy may have some contributing factor and differentiation between this rare cutaneous manifestation from heparin products and other dermatological findings in patients with malignancy is key. Because of the asymptomatic and self limiting nature of hemorrhagic bullous dermatoses in the setting of heparin product use, we presume that the reported incidence does not reflect true clinical practice. PMID- 26928383 TI - Experimental and theoretical studies of Si-Cl and Ge-Cl sigma-bond activation reactions by iridium-hydride. AB - We report the iridium hydride-mediated Si-Cl and Ge-Cl sigma-bond activation in a low-polarity toluene solution owing to diphosphine-chelation, in which the Si-Cl and Ge-Cl sigma-bonds are readily cleaved through an SN2-type pathway via the formation of a free chloride anion. PMID- 26928384 TI - Individual gene expression and personalised medicine in sepsis. PMID- 26928385 TI - Photophysical Properties and Adsorption Behaviors of Novel Tri-Cationic Boron(III) Subporphyrin on Anionic Clay Surface. AB - Two types of +3-charged subporphyrin derivatives with m- and p-methylpyridinium as the meso-aryl substituents were designed and synthesized. Their photophysical properties with and without anionic saponite clay were investigated. These cationic subporphyrins were suitably designed for adsorption on the saponite nanosheet surface with their photoactivity. Absorption and emission spectra of these subporphyrin-saponite complexes exhibited strong bathochromic shifts due to the flattening of the molecules on the nanosheet. This behavior was observed as drastic visual changes in their luminescence colors. Additionally, aggregation behaviors were not observed in the saponite complexes even at high dye loading levels for both subporphyrins. Moreover, under such condition, their fluorescence properties on the saponite surface were not only maintained but also enhanced without unexpected deactivations despite the dye molecules are densely introduced on the solid surface. These findings are beneficial for applications of the dye clay complexes to photofunctional materials such as strongly luminescent materials, highly sensitive clay sensors and artificial photosynthesis systems. PMID- 26928386 TI - Copper that cancer with lysosomal love! PMID- 26928387 TI - Classification accuracy and acceptability of the Integrated Screening and Intervention System Teacher Rating Form. AB - This study examines the classification accuracy and teacher acceptability of a problem-focused screener for academic and disruptive behavior problems, which is directly linked to evidence-based intervention. Participants included 39 classroom teachers from 2 public school districts in the Northeastern United States. Teacher ratings were obtained for 390 students in Grades K-6. Data from the screening instrument demonstrate favorable classification accuracy, and teacher ratings of feasibility and acceptability support the use of the measure for universal screening in elementary school settings. Results indicate the novel measure should facilitate classroom intervention for problem behaviors by identifying at-risk students and informing targets for daily behavior report card interventions. (PsycINFO Database Record PMID- 26928388 TI - Graphene Oxide Liquid Crystals: Discovery, Evolution and Applications. AB - The discovery and relevant research progress in graphene oxide liquid crystals (GOLCs), the latest class of 2D nanomaterials exhibiting colloidal liquid crystallinity arising from the intrinsic disc-like shape anisotropy, is highlighted. GOLC has conferred a versatile platform for the development of novel properties and applications based on the facile controllability of molecular scale alignment. The first part of this review offers a brief introduction to LCs, including the theoretical background. Particular attention has been paid to the different types of LC phases that have been reported thus far, such as nematic, lamellar and chiral phases. Several key parameters governing the ultimate stability of GOLC behavior, including pH and ionic strength of aqueous dispersions are highlighted. In a relatively short span of time since its discovery, GOLCs have proved their remarkable potential in a broad spectrum of applications, including highly oriented wet-spun fibers, self-assembled nanocomposites, and architectures for energy storage devices. The second part of this review is devoted to an exclusive overview of the relevant applications. Finally, an outlook is provided into this newly emerging research field, where two well established scientific communities for carbon nanomaterials and liquid crystals are ideally merged. PMID- 26928389 TI - Triiodothyronine Attenuates Prostate Cancer Progression Mediated by beta Adrenergic Stimulation. AB - Prostate cancer cells are responsive to adrenergic and thyroid stimuli. It is well established that beta-adrenergic activation (protein kinase A [PKA]/cAMP response element binding protein [CREB]) promotes cancer progression, but the role of thyroid hormones is poorly understood. We analyzed the effects of beta adrenergic stimulation (isoproterenol [ISO]) and/or thyroid hormone on neuroendocrine (NE) differentiation and cell invasion, using in vivo (LNCaP tumor) and in vitro models (LNCaP and DU145 human cells). Nude mice were inoculated with LNCaP cells and were treated for 6 wks with ISO (200 MUg/d), triiodothyronine (T3, 2.5 MUg/d) or both. ISO alone reduced tumor growth but increased tumor expression of cAMP response element (CRE)-dependent genes (real time polymerase chain reaction, chromogranin A, neuron-specific enolase, survivin, vascular endothelial growth factor [VEGF], urokinase plasmin activator [uPA] and metalloproteinase-9 [MMP-9]) and some proteins related to NE differentiation and/or invasiveness (synaptophysin, VEGF, pCREB). T3 reduced tumor growth and prevented the overexpression of ISO-stimulated factors through a pCREB-independent mechanism. In low invasive LNCaP cells, 50 MUmol/L ISO or 100 nmol/L thyroxine (T4) induced the acquisition of NE-like morphology (phase contrast microscopy), increased VEGF secretion (ELISA) and invasive capacity (Transwell assay), but no synergistic effects were observed after the coadministration of ISO + T4. In contrast, 10 nmol/L T3 alone had no effect, but it prevented the NE-like morphology and invasiveness stimulated by ISO. None of these treatments had any effect on highly invasive DU145 cells. In summary, this study showed that ISO and T4 increase cancer progression, and T3 attenuates ISO stimulated progression. Further studies are required to determine if changes in the ratio of T4/T3 could be relevant for prostate cancer progression. PMID- 26928390 TI - Increased Risk of Interstitial Lung Disease in Children with a Single R288K Variant of ABCA3. AB - The ABCA3 gene encodes a lipid transporter in type II pneumocytes critical for survival and normal respiratory function. The frequent ABCA3 variant R288K increases the risk for neonatal respiratory distress syndrome among term and late preterm neonates, but its role in children's interstitial lung disease has not been studied in detail. In a retrospective cohort study of 228 children with interstitial lung disease related to the alveolar surfactant system, the frequency of R288K was assessed and the phenotype of patients carrying a single R288K variant further characterized by clinical course, lung histology, computed tomography and bronchoalveolar lavage phosphatidylcholine PC 32:0. Cell lines stably transfected with ABCA3-R288K were analyzed for intracellular transcription, processing and targeting of the protein. ABCA3 function was assessed by detoxification assay of doxorubicin, and the induction and volume of lamellar bodies. We found nine children with interstitial lung disease carrying a heterozygous R288K variant, a frequency significantly higher than in the general Caucasian population. All identified patients had neonatal respiratory insufficiency, recovered and developed chronic interstitial lung disease with intermittent exacerbations during early childhood. In vitro analysis showed normal transcription, processing, and targeting of ABCA3-R288K, but impaired detoxification function and smaller lamellar bodies. We propose that the R288K variant can underlie interstitial lung disease in childhood due to reduced function of ABCA3, demonstrated by decelerated detoxification of doxorubicin, reduced PC 32:0 content and decreased lamellar body volume. PMID- 26928391 TI - Phase Transfer and Surface Functionalization of Hydrophobic Nanoparticle using Amphiphilic Poly(amino acid). AB - Functionalization of nanoparticles with chemical and biochemical is essential for their biomedical and other application. However, most of the high quality nanoparticles are hydrophobic in nature due to surfactant capping and their conversion into water-soluble functional nanoparticle via appropriate coating and conjugation chemistry is extremely critical issue. Here we report amphiphilic poly(amino acid)-based one-pot coating and conjugation approach that can transform hydrophobic nanoparticle into water-soluble nanoparticle functionalized with primary amine, thiol, and biomolecule. We have designed amphiphilic polyaspartimide that can anchor hydrophobic nanoparticle through octadecyl groups, leaving the polar polyethylene glycol and aspartimide groups exposed outwards. The aspartimide group is then reacted with primary amine containing chemical/biomolecule with the formation of water-soluble functional nanoparticle. This approach has been extended to different hydrophobic nanoparticles and biomolecules. The present approach has advantages over existing approaches as coating and functionalization can be performed in one pot and functional nanoparticles have <12 nm hydrodynamic size, high colloidal stability, and biocompartibility. This developed approach can be used to derive biocompatible nanobioconjugates for various biomedical applications. PMID- 26928392 TI - Moderate dose melatonin for the abatement and treatment of delirium in elderly general medical inpatients: study protocol of a placebo controlled, randomised, double blind trial. AB - BACKGROUND: Delirium is a frequent, costly and morbid problem. No agent has been shown to modify the natural history of the condition, and current treatments have significant side effects. Prophylactic melatonin in low doses has been shown to prevent delirium developing. This trial then aims to determine the feasibility of a trial to assess if melatonin at a moderate dose effectively treats the symptoms of delirium and modifies the natural history, including abating symptoms after treatment cessation. METHODS/DESIGN: Elderly (>=70 years of age) patients admitted to the Royal Melbourne Hospital with delirium, and not requiring surgery, will be identified from the current practice of the investigators and through referral by other general medical unit staff. To facilitate this, other staff will be briefed on the project by investigators. Patients will be recruited with suitable informed and documented consent (person responsible) by the study investigators. They will receive orally either 5 mg melatonin (18 patients) or placebo (18 patients) nightly for 5 nights (or until discharged). During treatment, participants will be assessed by study staff using a validated scale of delirium severity (the Memorial Delirium Assessment Scale), and a validated measure of delirium state (Confusion Assessment Method) to determine if melatonin decreases the severity or the duration of delirium. Assessment will continue for a further two days after treatment has ceased, to determine if the treatment causes persisting abatement of symptoms, and to assess for adverse events. DISCUSSION: The on-going study described herein will contribute to our knowledge of available treatment options for elderly inpatients with delirium, where current pharmacological interventions show weak or no effect on hastening the resolution of delirium. As melatonin is safe, cheap, and potentially effective, it would be easily implementable in routine practice and could lead to significant outcome benefits for delirious inpatients. TRIAL REGISTRATION: The trial is registered with the Australia New Zealand Clinical Trials Registry (trial ID: ACTRN12614000101684 ) (registered 28/01/2014). PMID- 26928393 TI - Offline Versus Online Suicide-Related Help Seeking: Changing Domains, Changing Paradigms. AB - OBJECTIVE: Suicidal individuals are among the most reluctant help-seekers, which limits opportunities for treating and preventing unnecessary suffering and self inflicted deaths. This study aimed to assist outreach, prevention, and treatment efforts by elucidating relationships between suicidality and both online and offline help seeking. METHOD: An anonymous online survey provided data on 713 participants, aged 18-71 years. Measures included an expanded General Help Seeking Questionnaire and the Suicidal Affect-Behavior-Cognition Scale. RESULTS: General linear modeling results showed that, as predicted, face-to-face help seeking willingness decreased as risk level increased. However, for emerging adults help-seeking likelihood increased with informal online sources as risk increased, while other online help-seeking attitudes differed little by risk level. Linear regression modeling determined that, for suicidal individuals, willingness to seek help from online mental health professionals and online professional support sites was strongly related (ps < .001). Help seeking from social networking sites and anonymous online forums was also interrelated, but more complex, demonstrating the importance of age and social support factors (ps < .001). CONCLUSION: These findings show that the Internet has altered the suicide-related help-seeking paradigm. Online help seeking for suicidality was not more popular than face-to-face help seeking, even for emerging adults. However, treatment and prevention professionals have good reasons to increase their online efforts, because that is where some of the highest risk individuals are going for help with their most severe personal problems. PMID- 26928394 TI - Pharmaceutical-Oriented Selective Synthesis of Mononitriles and Dinitriles Directly from Methyl(hetero)arenes: Access to Chiral Nitriles and Citalopram. AB - A pharmaceutical-oriented, transition-metal-free, cyanide-free one-step direct transformation of methylarenes to aryl nitriles is described. For the dimethylarenes, the selectivity can be well-controlled to form mononitriles or dinitriles. Enantioenriched nitriles can also be synthesized by this method. As a pharmaceutically practical method, the antidepressant drug citalopram was synthesized from cheap and commercially abundant m-xylene on a gram scale in high yield, avoiding transition-metal residues and toxic cyanides. PMID- 26928395 TI - Exploring the Plant-Microbe Interface by Profiling the Surface-Associated Proteins of Barley Grains. AB - Cereal grains are colonized by a microbial community that actively interacts with the plant via secretion of various enzymes, hormones, and metabolites. Microorganisms decompose plant tissues by a collection of depolymerizing enzymes, including beta-1,4-xylanases, that are in turn inhibited by plant xylanase inhibitors. To gain insight into the importance of the microbial consortia and their interaction with barley grains, we used a combined gel-based (2-DE coupled to MALDI-TOF-TOF MS) and gel-free (LC-MS/MS) proteomics approach complemented with enzyme activity assays to profile the surface-associated proteins and xylanolytic activities of two barley cultivars. The surface-associated proteome was dominated by plant proteins with roles in defense and stress-responses, while the relatively less abundant microbial (bacterial and fungal) proteins were involved in cell-wall and polysaccharide degradation and included xylanases. The surface-associated proteomes showed elevated xylanolytic activity and contained several xylanases. Integration of proteomics with enzyme assays is a powerful tool for analysis and characterization of the interaction between microbial consortia and plants in their natural environment. PMID- 26928396 TI - Thermal Conductivity of Wurtzite Zinc-Oxide from First-Principles Lattice Dynamics--a Comparative Study with Gallium Nitride. AB - Wurtzite Zinc-Oxide (w-ZnO) is a wide bandgap semiconductor that holds promise in power electronics applications, where heat dissipation is of critical importance. However, large discrepancies exist in the literature on the thermal conductivity of w-ZnO. In this paper, we determine the thermal conductivity of w-ZnO using first-principles lattice dynamics and compare it to that of wurtzite Gallium Nitride (w-GaN)--another important wide bandgap semiconductor with the same crystal structure and similar atomic masses as w-ZnO. However, the thermal conductivity values show large differences (400 W/mK of w-GaN vs. 50 W/mK of w ZnO at room temperature). It is found that the much lower thermal conductivity of ZnO originates from the smaller phonon group velocities, larger three-phonon scattering phase space and larger anharmonicity. Compared to w-GaN, w-ZnO has a smaller frequency gap in phonon dispersion, which is responsible for the stronger anharmonic phonon scattering, and the weaker interatomic bonds in w-ZnO leads to smaller phonon group velocities. The thermal conductivity of w-ZnO also shows strong size effect with nano-sized grains or structures. The results from this work help identify the cause of large discrepancies in w-ZnO thermal conductivity and will provide in-depth understanding of phonon dynamics for the design of w ZnO-based electronics. PMID- 26928397 TI - Potential medications for the treatment of alcohol use disorder: An evaluation of clinical efficacy and safety. AB - Alcohol use disorder (AUD), as currently defined in the Diagnostic and Statistical Manual, 5th Edition (DSM-5), is a heterogeneous disorder stemming from a complex interaction of neurobiological, genetic, and environmental factors. As a result of this heterogeneity, there is no one treatment for AUD that will work for everyone. During the past 2 decades, efforts have been made to develop a menu of medications to give patients and clinicians more choices when seeking a therapy that is both effective and which has limited side effects. To date, 3 medications have been approved by the US Food and Drug Administration (FDA) to treat alcohol dependence: disulfiram, naltrexone, and acamprosate. In addition to these approved medications, researchers have identified new therapeutic targets and, as a result, a number of alternative medications are now being evaluated for treatment of AUD in human studies. Although not approved by the FDA for the treatment of AUD, in some cases, these alternative medications are being used off-label by clinicians for this purpose. These potential medications are reviewed here. They include nalmefene, varenicline, gabapentin, topiramate, zonisamide, baclofen, ondansetron, levetiracetam, quetiapine, aripiprazole, and serotonin reuptake inhibitors. The effectiveness of these medications has been mixed-some show good efficacy with side effects that are mild to moderate in intensity; others have mixed or promising results but are awaiting findings from ongoing studies; and still others show poor efficacy, despite promising preliminary results. Medications development remains a high priority. Key initiatives for the National Institute on Alcohol Abuse and Alcoholism (NIAAA) include supporting the discovery and development of more effective and safer medications, advancing the field of personalized medicine, and forging public and private partnerships to investigate new and more effective compounds. PMID- 26928398 TI - Maximizing Productivity and Reducing Environmental Impacts of Full-Scale Algal Production through Optimization of Open Pond Depth and Hydraulic Retention Time. AB - The ability to dynamically control algal raceway ponds to maximize biomass productivity and reduce environmental impacts (e.g., land and water use) with consideration of local constraints (e.g., water availability and climatic conditions) is an important consideration in algal biotechnology. This paper presents a novel optimization strategy that seeks to maximize growth (i.e., optimize land use), minimize respiration losses, and minimize water demand through regular adjustment of pond depth and hydraulic retention time (HRT) in response to seasonal changes. To evaluate the efficiency of this strategy, algal productivity and water demand were simulated in five different climatic regions. In comparison to the standard approach (constant and location-independent depth and HRT), dynamic control of depth and HRT was shown to increase productivity by 0.6-9.9% while decreasing water demand by 10-61% depending upon the location considered (corresponding to a decrease in the water footprint of 19-62%). Interestingly, when the fact that the water demand was limited to twice the local annual rainfall was added as a constraint, higher net productivities were predicted in temperate and tropical climates (15.7 and 16.7 g m(-2) day(-1), respectively) than in Mediterranean and subtropical climates (13.0 and 9.7 g m( 2) day(-1), respectively), while algal cultivation was not economically feasible in arid climates. Using dynamic control for a full-scale operation by adjusting for local climatic conditions and water constraints can notably affect algal productivity. It is clear that future assessments of algal cultivation feasibility should implement locally optimized dynamic process control. PMID- 26928399 TI - Comparison of Posttranslational Modification and the Functional Impairment of Human Serum Albumin in Commercial Preparations. AB - On account of its long circulating half-life, human serum albumin (HSA) is susceptible to posttranslational modifications that can alter its functions. Here, we comprehensively compared the degree of posttranslational modifications with the functional impairment of HSA derived from 5 different commercially available albumin preparations and clarified their relationships. We used electrospray ionization-time of flight mass spectrometry to evaluate the degree of posttranslational modification of the entire HSA molecule that was associated with disease development and found that the fraction of Cys34-cysteinylated HSA (Cys-Cys34-HSA), a major form of oxidative modification, varied substantially among the albumin preparations. Meanwhile, no remarkable difference was found in the degree of glycated or N-terminal truncated HSA among the preparations tested. The nonosmotic pressure maintenance functions of HSA, such as its antioxidative and ligand-binding activities significantly differed among the preparations. Interestingly, the alternations of these functions showed a significantly negative correlation only with the Cys-Cys34-HSA fraction. These findings suggest that the Cys-Cys34-HSA fraction, as estimated by electrospray ionization-time of flight mass spectrometry can be used as a predictive marker for the functional impairment of albumin preparations and that it would be preferable to use albumin preparations with higher contents of functionally effective albumin that correspond to a lower degree of cysteinylation of Cys34 in clinical practice. PMID- 26928400 TI - Relating Protein-Protein Interactions and Aggregation Rates From Low to High Concentrations. AB - At low protein concentrations (c2), non-native protein aggregation rates are known to be sensitive to changes in conformational stability and "weak" or "colloidal" protein-protein interactions. Protein-protein interactions are also known to be strong functions of c2. In the present work, protein-protein interactions and rates of aggregation were quantified systematically for a monoclonal antibody (MAb) across a broad range of c2 at pH 5.1 and 6.5, with or without 5 wt/wt % sucrose or 100 mM NaCl present. Aggregation rates were determined from initial-rate analysis with size-exclusion chromatography, and interactions were quantified with static and dynamic laser light scattering. A number of hypotheses were tested regarding whether changes in protein-protein interactions can be predictive of changes in aggregation rates versus c2. Hypotheses were based on (i) changes in thermodynamic activity; (ii) statistical mechanical fluctuation theory; and (iii) surface-contact probabilities. Arguments based on (i) and (ii) were qualitatively inconsistent with experimental rates and scattering. Hypothesis (iii) was reasonably successful and resulted in a semiquantitative correlation between rates and protein-protein interactions across almost 2 orders of magnitude in c2. However, (iii) requires one to assume that the concentration-dependent protein-protein Kirkwood-Buff integral is a reasonable surrogate for contact probabilities. PMID- 26928401 TI - Transdermal Delivery of Iron Using Soluble Microneedles: Dermal Kinetics and Safety. AB - Currently, the iron compounds are administered via oral and parenteral routes in patients of all ages, to treat iron deficiency. Despite continued efforts to supplement iron via these conventional routes, iron deficiency still remains the most prevalent nutritional disorder all over the world. Transdermal replenishment of iron is a novel, potential approach of iron replenishment. Ferric pyrophosphate (FPP) was found to be a suitable source of iron for transdermal replenishment. The safety of FPP was assessed in this project by challenging the dermal fibroblast cells with high concentration of FPP. The cell viability assay and reactive oxygen species assay were performed. The soluble microneedle array was developed, incorporated with FPP and the kinetics of free iron in the skin; extracellular fluid following dermal administration of microneedle array was investigated in hairless rats. From the cell based assays, FPP was selected as one of the potential iron sources for transdermal delivery. The microneedles were found to dissolve in the skin fluid within 3 hours of administration. The FPP concentration in the dermal extracellular fluid declined after complete dissolution of the microneedle array. Overall, the studies demonstrated the safety of FPP for dermal delivery and the feasibility of soluble microneedle approach for transdermal iron replenishment therapy. PMID- 26928403 TI - Microfluidic bubbler facilitates near complete mass transfer for sustainable multiphase and microbial processing. AB - A microfluidic device (channels <70 MUm) was utilized to create micro-scale bubbles to significantly increase mass transfer efficiency at low flow rates. The convergence of one gas and two liquid channels at a Y-junction generates bubbles via cyclic changes in pressure. At low flow rates, the bubbles had an average diameter of 110 MUm, corresponding to a volumetric mass transfer KL a of 1.43 h( 1) . Values of KL a normalized per flow rate showed that the microbubbler had a 100-fold increased transfer efficiency compared to four other commonly used bubblers. The calculated percentage of oxygen transferred was approximately 90%, which was consistent with a separate off-gas analysis. The improved mass transfer was also tested in an algae bioreactor in which the microbubbler absorbed approximately 90% of the CO2 feed compared to 2% in the culture with an alternative needle bubbling method. The microbubbler yielded a cell density 82% of the cell density for the alternative needle tip with an 800-fold lower flow rate (0.5 mL/min versus 400 mL/min) and a 700-fold higher ratio of biomass to fed carbon dioxide. The application of microfluidics may transform interfacial processing in order to increase mass transfer efficiencies, minimize gas feeding, and provide for more sustainable multiphase processes. Biotechnol. Bioeng. 2016;113: 1924-1933. (c) 2016 Wiley Periodicals, Inc. PMID- 26928402 TI - CD146 promotes metastasis and predicts poor prognosis of hepatocellular carcinoma. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is the third leading cause of cancer related mortality worldwide. Recurrence and metastasis after curative resection remain critical obstacles in HCC treatment. CD146 predicted poor prognosis of a variety of cancers including melanoma, breast tumors, prostate cancer, and gastric cancer. However, the role of CD146 in HCC has not yet been systematically explored. METHODS: To investigate the role of CD146 in HCC, we evaluated its expression in HCC tissues and HCC cell lines using real-time PCR and western blotting (WB). Second, we established HCC cell lines that stably overexpressed and interfered CD146 and explored the function of CD146 in HCC in vitro and in vivo. Third, we conducted microarray analysis to investigate the potential mechanism by identifying differentially expressed genes. Last, follow ups were conducted to help uncover the connection of CD146 expression and the prognosis of HCC patients. RESULTS: We found that CD146 was overexpressed in HCC tissues and that high CD146 expression predicted poor overall survival time and shorter recurrence period in HCC patients. In vitro and in vivo experiments indicated that CD146 promoted migration and invasion of HCC cell lines. Further study indicated that CD146 promoted epithelial mesenchymal transition (EMT), IL-8 upregulation, and STAT1 downregulation. CD146 was upregulated in HCC tissues and cell lines. CONCLUSIONS: CD146 promoted metastasis of HCC cells and predicted poor prognosis of HCC patients. CD146 induced EMT, and IL-8 upregulation and STAT1 downregulation may be the potential underlying mechanism. The exact mechanism still needs further investigation. PMID- 26928404 TI - Association of autoimmune thyroid diseases, chronic atrophic gastritis and gastric carcinoid: experience from a single institution. AB - PURPOSE: Autoimmune polyendocrine syndromes (APS) type III are characterized by the association of autoimmune thyroid disease (ATD) with other autoimmune diseases such as diabetes, alopecia, pernicious anemia, vitiligo and chronic atrophic gastritis. A strong association between ATD and atrophic gastritis (AG) has been demonstrated. Moreover 10 % of patients affected by AG have a predisposition to develop gastric carcinoid and adenocarcinoma as a result of chronic hypergastrinemia caused by achlorhydria and subsequent ELC cells neoplastic transformation. METHODS: The aim of the study is to evaluate, in a consecutive series of patients followed for ATD in our outpatients clinic, the prevalence of AG. In the period 2004-2014, 242 patients with ATD underwent a screening performing APCA, Vitamin B12, ferritin, iron, and hemoglobin and red cells count measurements with subsequent gastroscopy in case of APCA positivity. RESULTS: We found 57/242 (23.5 %) patients with APCA positivity. Of these patients 33/57 (57.8 %), 31 F and 2 M, were affected by Graves disease; 24/57 (42.1 %) 21 F and 3 M by Hashimoto thyroiditis; 10/57 (17.5 %) presented with anemia, 14/57 (24.5 %) with vitamin B12 deficiency, 9/57 (15.7 %) with iron deficiency. In 2/57 a gastric carcinoid was found. CONCLUSIONS: Our data confirm the high association rate of AG in ATD which frequently is not an isolated disease but configure the picture of APS type III and need to be followed accordingly. An early diagnosis may be useful for diagnosis of gastric carcinoids and to explain and treat a gastric related L-thyroxine malabsorption and presence of chronic unexplained anemia. PMID- 26928405 TI - A chip assisted immunomagnetic separation system for the efficient capture and in situ identification of circulating tumor cells. AB - The detection of circulating tumor cells (CTCs), a kind of "liquid biopsy", represents a potential alternative to noninvasive detection, characterization and monitoring of carcinoma. Many previous studies have shown that the number of CTCs has a significant relationship with the stage of cancer. However, CTC enrichment and detection remain notoriously difficult because they are extremely rare in the bloodstream. Herein, aided by a microfluidic device, an immunomagnetic separation system was applied to efficiently capture and in situ identify circulating tumor cells. Magnetic nanospheres (MNs) were modified with an anti-epithelial-cell adhesion-molecule (anti-EpCAM) antibody to fabricate immunomagnetic nanospheres (IMNs). IMNs were then loaded into the magnetic field controllable microfluidic chip to form uniform IMN patterns. The IMN patterns maintained good stability during the whole processes including enrichment, washing and identification. Apart from its simple manufacture process, the obtained microfluidic device was capable of capturing CTCs from the bloodstream with an efficiency higher than 94%. The captured cells could be directly visualized with an inverted fluorescence microscope in situ by immunocytochemistry (ICC) identification, which decreased cell loss effectively. Besides that, the CTCs could be recovered completely just by PBS washing after removal of the permanent magnets. It was observed that all the processes showed negligible influence on cell viability (viability up to 93%) and that the captured cells could be re-cultured for more than 5 passages after release without disassociating IMNs. In addition, the device was applied to clinical samples and almost all the samples from patients showed positive results, which suggests it could serve as a valuable tool for CTC enrichment and detection in the clinic. PMID- 26928406 TI - A comparison of the dietary patterns derived by principal component analysis and cluster analysis in older Australians. AB - BACKGROUND: Despite increased use of dietary pattern methods in nutritional epidemiology, there have been few direct comparisons of methods. Older adults are a particularly understudied population in the dietary pattern literature. This study aimed to compare dietary patterns derived by principal component analysis (PCA) and cluster analysis (CA) in older adults and to examine their associations with socio-demographic and health behaviours. METHODS: Men (n = 1888) and women (n = 2071) aged 55-65 years completed a 111-item food frequency questionnaire in 2010. Food items were collapsed into 52 food groups and dietary patterns were determined by PCA and CA. Associations between dietary patterns and participant characteristics were examined using Chi-square analysis. The standardised PCA derived dietary patterns were compared across the clusters using one-way ANOVA. RESULTS: PCA identified four dietary patterns in men and two dietary patterns in women. CA identified three dietary patterns in both men and women. Men in cluster 1 (fruit, vegetables, wholegrains, fish and poultry) scored higher on PCA factor 1 (vegetable dishes, fruit, fish and poultry) and factor 4 (vegetables) compared to factor 2 (spreads, biscuits, cakes and confectionery) and factor 3 (red meat, processed meat, white-bread and hot chips) (mean, 95% CI; 0.92, 0.82-1.02 vs. 0.74, 0.63-0.84 vs. -0.43, -0.50- -0.35 vs. 0.60 0.46-0.74, respectively). Women in cluster 1 (fruit, vegetables and fish) scored highest on PCA factor 1 (fruit, vegetables and fish) compared to factor 2 (processed meat, hot chips cakes and confectionery) (1.05, 0.97-1.14 vs. -0.14, -0.21- -0.07, respectively). Cluster 3 (small eaters) in both men and women had negative factor scores for all the identified PCA dietary patterns. Those with dietary patterns characterised by higher consumption of red and processed meat and refined grains were more likely to be Australian-born, have a lower level of education, a higher BMI, smoke and did not meet physical activity recommendations (all P < 0.05). CONCLUSIONS: PCA and CA identified comparable dietary patterns within older Australians. However, PCA may provide some advantages compared to CA with respect to interpretability of the resulting dietary patterns. Older adults with poor dietary patterns also displayed other negative lifestyle behaviours. Food-based dietary pattern methods may inform dietary advice that is understood by the community. PMID- 26928407 TI - A Comparison of Visual Assessment and Automated Digital Image Analysis of Ki67 Labeling Index in Breast Cancer. AB - BACKGROUND: Ki67 labeling index (LI) is critical for treatment options and prognosis evaluation in breast cancer. Visual assessment (VA) is widely used to assess Ki67 LI, but has some limitations. In this study, we compared the consistency between VA and automated digital image analysis (DIA) of Ki67 LI in breast cancer, and to evaluate the application value of DIA in Ki67 LI assessment. METHODS: Ki67 immunostained slides of 155 cases of primary invasive breast cancer were eyeballing assessed by five breast pathologists and automated digital image analyzed by one breast pathologist respectively. Two score methods, hot-spot score and average score, were used to choose score areas. The intra class correlation coefficient (ICC) was used to analyze the consistency between VA and DIA, and Wilcoxon signed-rank test was used to compare the median of paired-difference between VA and DIA values. RESULTS: (1) A perfect agreement was demonstrated between VA and DIA of Ki67 LI by ICC analysis (P<0.0001) in the whole cohort. A perfect agreement between VA and DIA of Ki67 LI was also showed in G2-G3, ER positive/HER2 negative cases. Average score and hot-spot score methods both demonstrated a perfect concordance between VA and DIA of Ki67 LI. (2) All cases were classified into three groups by VA values (<=10%, 11%-30% and >30% Ki67 LI). The concordance was relatively lower in intermediate Ki67 LI group (11%-30%) compared with high (>30%) Ki67 LI groups according to both methods. (3) All cases were classified into three groups by paired-difference (d) between VA values of hot-spot score and average score (d<5, 5<=d<10, d>=10) to evaluate the correlation between Ki67 staining distribution (heterogeneous or homogenous) and reproducibility of assessment. A perfect agreement was all demonstrated in three groups, and a slightly better Ki67 LI agreement between VA and DIA was indicated in homogenous staining slides than in heterogeneous staining ones. (4) VA values were relatively smaller than DIA values (average score: median of paired difference -3.72; hot-spot score: median of paired-difference -9.12). CONCLUSIONS: An excellent agreement between VA and DIA of Ki67 LI in breast cancer was demonstrated in the whole mixed cohort, suggesting that VA and DIA both could be used to assess Ki67 LI in clinical practice. Average score and hot spot score methods both demonstrated a perfect concordance between VA and DIA of Ki67 LI. The almost perfect agreement between VA and DIA was observed in high Ki67 LI cases, displaying a homogenous staining pattern. The consistency between VA and DIA was relatively low in intermediate Ki67 LI group. The heterogeneity of tumors may slightly affect the concordance between VA and DIA of Ki67 LI. Assessment of VA provides lower Ki67 values than DIA, the biological importance of these values are not known at the moment. PMID- 26928408 TI - All types of atrial fibrillation in the setting of myocardial infarction are associated with impaired outcome. AB - OBJECTIVES: To evaluate 90-day cardiovascular outcome in patients after myocardial infarction (MI) in relation to different subtypes of atrial fibrillation (AF) and MI. METHODS: We studied 155 071 hospital survivors of MI between 2000 and 2009 in Swedish registries. AF subtypes were defined according to history of AF and in-hospital ECG recordings. Clinical outcomes were evaluated with multivariable Cox models. RESULTS: AF was documented in 24 023 (15.5%) cases. The AF subtypes were new-onset AF with sinus rhythm at discharge (3.7%), new-onset AF with AF at discharge (3.9%), paroxysmal AF (4.9%) and chronic AF (3.0%). The event rate per 100 person-years for the composite cardiovascular outcome (all-cause mortality, MI or ischaemic stroke) was 90.9 in patients with any type of AF versus 45.2 in patients with sinus rhythm, adjusted hazard ratio with 95% CI (HR) 1.28 (1.19 to 1.37). There were no significant differences in the composite cardiovascular outcome between AF subtypes. AF was associated with higher risk of mortality, HR 1.59 (1.41 to 1.80), reinfarction, HR 1.14 (1.05 to 1.24), and ischaemic stroke, HR 2.29 (1.92 to 2.74), respectively. In subgroup analysis, AF was associated with a higher risk of composite cardiovascular outcome in the non-ST-elevation myocardial infarction (NSTEMI) and ST-elevation myocardial infarction (STEMI) cohort, HR 1.24 (1.13 to 1.36) and HR 1.34 (1.21 to 1.48), respectively, with p value for interaction=0.23. CONCLUSIONS: AF is common in the setting of MI and is associated with a higher risk of composite cardiovascular outcome and the individual components; mortality, reinfarction and ischaemic stroke, respectively. No major difference in outcome was observed between AF subtypes. No difference in outcome for AF was observed between the NSTEMI and STEMI cohort. PMID- 26928410 TI - Building Capacity for Trauma-Informed Care in the Child Welfare System: Initial Results of a Statewide Implementation. AB - Exposure to childhood trauma is a major public health concern and is especially prevalent among children in the child welfare system (CWS). State and tribal CWSs are increasingly focusing efforts on identifying and serving children exposed to trauma through the creation of trauma-informed systems. This evaluation of a statewide initiative in Connecticut describes the strategies used to create a trauma-informed CWS, including workforce development, trauma screening, policy change, and improved access to evidence-based trauma-focused treatments during the initial 2-year implementation period. Changes in system readiness and capacity to deliver trauma-informed care were evaluated using stratified random samples of child welfare staff who completed a comprehensive assessment prior to (N = 223) and 2 years following implementation (N = 231). Results indicated significant improvements in trauma-informed knowledge, practice, and collaboration across nearly all child welfare domains assessed, suggesting system wide improvements in readiness and capacity to provide trauma-informed care. Variability across domains was observed, and frontline staff reported greater improvements than supervisors/managers in some domains. Lessons learned and recommendations for implementation and evaluation of trauma-informed care in child welfare and other child-serving systems are discussed. PMID- 26928409 TI - A 10-year prognostic model for patients with suspected angina attending a chest pain clinic. AB - BACKGROUND AND OBJECTIVE: Diagnostic models used in the management of suspected angina provide no explicit information about prognosis. We present a new prognostic model of 10-year coronary mortality in patients presenting for the first time with suspected angina to complement the Diamond-Forrester diagnostic model of disease probability. METHODS AND RESULTS: A multicentre cohort of 8762 patients with suspected angina was followed up for a median of 10 years during which 233 coronary deaths were observed. Developmental (n=4412) and validation (n=4350) prognostic models based on clinical data available at first presentation showed good performance with close agreement and the final model utilised all 8762 patients to maximise power. The prognostic model showed strong associations with coronary mortality for age, sex, chest pain typicality, smoking status, diabetes, pulse rate, and ECG findings. Model discrimination was good (C statistic 0.83), patients in the highest risk quarter accounting for 173 coronary deaths (10-year risk of death: 8.7%) compared with a total of 60 deaths in the three lower risk quarters. When the model was simplified to incorporate only Diamond-Forrester factors (age, sex and character of symptoms) it underestimated coronary mortality risk, particularly in patients with reversible risk factors. CONCLUSIONS: For the first time in patients with suspected angina, a prognostic model is presented based on simple clinical factors available at the initial cardiological assessment. The model discriminated powerfully between patients at high risk and lower risk of coronary death during 10-year follow-up. Clinical utility was reflected in the prognostic value it added to the updated Diamond Forrester diagnostic model of disease probability. PMID- 26928411 TI - Development and Implementation of a Child Welfare Workforce Strategy to Build a Trauma-Informed System of Support for Foster Care. AB - Effective strategies that increase the extent to which child welfare professionals engage in trauma-informed case planning are needed. This study evaluated two approaches to increase trauma symptom identification and use of screening results to inform case planning. The first study evaluated the impact of training on trauma-informed screening tools for 44 child welfare professionals who screen all children upon placement into foster care. The second study evaluated a two-stage approach to training child welfare workers on case planning for children's mental health. Participants included (a) 71 newly hired child welfare professionals who received a 3-hr training and (b) 55 child welfare professionals who participated in a full-day training. Results from the first study indicate that training effectively increased knowledge and skills in administering screening tools, though there was variability in comfort with screening. In the second study, participants self-reported significant gains in their competency in identifying mental health needs (including traumatic stress) and linking children with evidence-based services. These findings provide preliminary evidence for the viability of this approach to increase the extent to which child welfare professionals are trauma informed, aware of symptoms, and able to link children and youth with effective services designed to meet their specific needs. PMID- 26928414 TI - Hysteroscopic myomectomy: techniques and preoperative assessment. AB - Even if usually asymptomatic, uterine myomas have been associated with a number of clinical issues such as abnormal uterine bleeding (AUB), heavy menstrual bleeding (HMB), infertility, recurrent pregnancy loss, especially when these masses are submucous. Golden standard treatment for symptomatic submucous fibroids has long been considered their laparotomic removal or a total hysterectomy. The development of endoscopy has made these fibroids accessible and removable from the inner surface of uterus. Hysteroscopy arose as a diagnostic technique, but then it also became an alternative surgical technique for many diseases, offering therapeutic and irreplaceable possibilities of treatment, avoiding major surgery on the one hand, and allowing the correction of pathologies specifically related to female fertility, on the other hand. Excision by slicing has been described as traditional resectoscopic submucosal myomectomy, but today there are new procedures among which the operator can choose, that allow overcoming the initial limitations of the traditional resectoscopic myomectomy in clinical practice. PMID- 26928413 TI - Parent-Reported Errors and Adverse Events in Hospitalized Children. AB - IMPORTANCE: Limited data exist regarding the incidence and nature of patient- and family-reported medical errors, particularly in pediatrics. OBJECTIVE: To determine the frequency with which parents experience patient safety incidents and the proportion of reported incidents that meet standard definitions of medical errors and preventable adverse events (AEs). DESIGN, SETTING, AND PARTICIPANTS: We conducted a prospective cohort study from May 2013 to October 2014 within 2 general pediatric units at a children's hospital. Included in the study were English-speaking parents (N = 471) of randomly selected inpatients (ages 0-17 years) prior to discharge. Parents reported via written survey whether their child experienced any safety incidents during hospitalization. Two physician reviewers classified incidents as medical errors, other quality issues, or exclusions (kappa = 0.64; agreement = 78%). They then categorized medical errors as harmful (ie, preventable AEs) or nonharmful (kappa = 0.77; agreement = 89%). We analyzed errors/AEs using descriptive statistics and explored predictors of parent-reported errors using bivariate statistics. We subsequently reviewed patient medical records to determine the number of parent-reported errors that were present in the medical record. We obtained demographic/clinical data from hospital administrative records. MAIN OUTCOMES AND MEASURES: Medical errors and preventable AEs. RESULTS: The mean (SD) age of the 383 parents surveyed was 36.6 (8.9) years; most respondents (n = 266) were female. Of 383 parents surveyed (81% response rate), 34 parents (8.9%) reported 37 safety incidents. Among these, 62% (n = 23, 6.0 per 100 admissions) were determined to be medical errors on physician review, 24% (n = 9) were determined to be other quality problems, and 14% (n = 5) were determined to be neither. Thirty percent (n = 7, 1.8 per 100 admissions) of medical errors caused harm (ie, were preventable AEs). On bivariate analysis, children with medical errors appeared to have longer lengths of stay (median [interquartile range], 2.9 days [2.2-6.9] vs 2.5 days [1.9-4.1]; P = .04), more often had a metabolic (14.3% vs 3.0%; P = .04) or neuromuscular (14.3% vs 3.6%; P = .05) condition, and more often had an annual household income greater than $100,000 (38.1% vs 30.1%; P = .06) than those without errors. Fifty seven percent (n = 13) of parent-reported medical errors were also identified on subsequent medical record review. CONCLUSIONS AND RELEVANCE: Parents frequently reported errors and preventable AEs, many of which were not otherwise documented in the medical record. Families are an underused source of data about errors, particularly preventable AEs. Hospitals may wish to consider incorporating family reports into routine safety surveillance systems. PMID- 26928412 TI - A panel study of the acute effects of personal exposure to household air pollution on ambulatory blood pressure in rural Indian women. AB - BACKGROUND: Almost half the world's population is exposed to household air pollution from biomass and coal combustion. The acute effects of household air pollution on the cardiovascular system are poorly characterized. We conducted a panel study of rural Indian women to assess whether personal exposures to black carbon during cooking were associated with acute changes in blood pressure. METHODS: We enrolled 45 women (ages 25-66 years) who cooked with biomass fuels. During cooking sessions in winter and summer, we simultaneously measured their personal real-time exposure to black carbon and conducted ambulatory blood pressure measurements every 10min. We recorded ambient temperature and participants' activities while cooking. We assessed body mass index, socioeconomic status, and salt intake. Multivariate mixed effects regression models with random intercepts were used to estimate the associations between blood pressure and black carbon exposure, e.g., average exposure in the minutes preceding blood pressure measurement, and average exposure over an entire cooking session. RESULTS: Women's geometric mean (GM) exposure to black carbon during cooking sessions was lower in winter (GM: 40MUg/m(3); 95% CI: 30, 53) than in summer (GM: 56MUg/m(3); 95% CI: 42, 76). Interquartile range increases in black carbon were associated with changes in systolic blood pressure from -0.4mm Hg (95% CI: -2.3, 1.5) to 1.9mm Hg (95% CI: -0.8, 4.7), with associations increasing in magnitude as black carbon values were assessed over greater time periods preceding blood pressure measurement. Interquartile range increases in black carbon were associated with small decreases in diastolic blood pressure from 0.9mm Hg (95% CI: -1.7, -0.1) to -0.4mm Hg (95% CI: -1.6, 0.8). Associations of a similar magnitude were estimated for cooking session-averaged values. CONCLUSIONS: We found some evidence of an association between exposure to black carbon and acute increases in systolic blood pressure in Indian women cooking with biomass fuels, which may have implications for the development of cardiovascular diseases. PMID- 26928415 TI - The use of bipolar technology in hysteroscopy. AB - Bipolar technology was introduced in the hysteroscopic clinical use in 1999, by the design of both loop electrodes addressed to resectoscopic surgery and miniaturized electrodes adaptable to small-size hysteroscopes. The need of an electrolytic solution as distension medium and the spatial relationships between the active and return bipolar electrode avoid, by definition, the risks of severe electrolyte imbalance syndromes and unpredictable electrical burns, sometimes complicating monopolar surgery. The true revolution in the hysteroscopy care has achieved through the availability of mini-hysteroscopes not requiring cervical dilatation, thus limiting uterine wall damages and allowing surgeons to manage several endometrial pathologies by mini-invasive procedures using an effective electrosurgical bipolar instrumentation. Many surgical interventions, traditionally accomplished by the resectoscope in a surgical room theatre, can be now carried out in an outpatient setting without any support from anesthesia. The patients' avoidance of surgical room access and the quick return to daily activities lead to an obvious - but not fully demonstrated - improvement in the medical and social costs associated to outpatient operative hysteroscopy. In the field of resectoscopy, bipolar electrodes are clinically as effective as monopolar devices. Randomized trials showed that bipolar resectoscopic technology prevents the electrolyte imbalance observed after monopolar surgery. However, in daily clinical practice the assumedly safer profile of bipolar with respect to monopolar resectoscopy has not been demonstrated yet. PMID- 26928416 TI - Fertility-enhancing hysteroscopic surgery. AB - Anatomical uterine element and functional components play a fundamental role in the enhancing of fertility are the major actors. Uterine pathologies, including congenital or acquired lesions, have been reported in 21 to 47% of patients undergoing in vitro fertilization cycles. Hysteroscopy is an important procedure in the study of one of the most important element of fertility: the uterus, even if its use in the world of infertility is discussed. There are many studies on safety and feasibility of the procedure and on patient compliance, but there is no consensus on its systemic use. This study, thanks to the wide literature about the use of hysteroscopic surgery to enhance fertility in most of the congenital and acquired problems affecting women in fertility age, allows defining that diagnostic and operative hysteroscopy is a rapid and safety technology to improve fertility. PMID- 26928417 TI - Laparoscopic myomectomy. AB - The gold standard access for myomectomy is laparoscopy in selected cases, including intramural and sub-serous symptomatic leiomyomas. The main contraindications concern inexperience of the surgeon, severe necrobiosis, suspected leiomyosarcoma and excessive size. The tips and tricks of the laparoscopic technique are described, specially enucleation, myometrium suture and prevention adhesions. PMID- 26928418 TI - Office myomectomy. AB - Small myomas have a high potential to grow and either to become symptomatic or to cause complications in women of reproductive age. Furthermore, although the risk of malignancy is rare, even the most experienced operator cannot replace the histological analysis to exclude malignancy or premalignant lesions. Such small symptomatic and asymptomatic totally or partially intracavitary myomas may be treated effectively and safety in office setting. The aim of this paper is to describe the currently available hysteroscopic techniques to treat myomas <1.5 cm also with a minimal intramural component without anaesthesia or analgesia in ambulatory setting reducing patient's discomfort. PMID- 26928419 TI - Pharmacoprevention for hereditary breast and ovarian cancer. AB - Hereditary breast and ovarian cancer (HBOC) syndrome is an important women's health condition characterized by an increased susceptibility to the development of cancer, in particular breast and ovarian neoplasms, and is caused by an inherited germline genetic mutation in one or both tumor suppressor genes named BRCA1 and BRCA2. This monographic issue provides an update on our knowledge of this syndrome with particular emphasis on the risk reduction strategies through a pharmacopreventive approach. PMID- 26928420 TI - Endometrial ablation: first- vs. second-generation techniques. AB - INTRODUCTION: Endometrial ablation is a procedure that surgically destroys (ablates) the lining of the uterus (endometrium). The goal of endometrial ablation is to reduce menstrual flow. In some women, menstrual flow may stop completely. In some cases, endometrial ablation may be an alternative to hysterectomy. There are several techniques used to perform endometrial ablation, including electrical or electrocautery ablation, in which an electric current travels through a wire loop or rollerball is applied to the endometrial lining to cauterize the tissue; hydrothermal ablation, in which heated fluid is pumped into the uterus and destroys the endometrial lining via high temperatures; balloon therapy ablation, in which a balloon at the end of a catheter is inserted into the uterus and filled with fluid, which is then heated to the point that the endometrial tissues are eroded away; radiofrequency ablation in which a triangular mesh electrode is expanded to fill the uterine cavity, at which point the electrode delivers an electrical current and destroys the endometrial lining; cryoablation (freezing), in which a probe uses extremely low temperatures to freeze and destroy the endometrial tissues; and microwave ablation, in which microwave energy is delivered through a slender probe inserted into the uterus and destroys the endometrial lining. EVIDENCE ACQUISITION: The purpose of this systematic review was to evaluate the feasibility, safety, and efficacy of endometrial ablation performed with first- and second-generation techniques. A literature search in PubMed from January 2000 to September 2015 was performed using the keywords endometrial ablation, menorrhagia, and heavy menstrual bleeding. Results were restricted to systematic reviews, randomized control trials (RCT)/controlled clinical trials, and observational studies written in English from January 2000 to September 2015. EVIDENCE SYNTHESIS: There is no evidence that either broad category is more effective than the other in reducing HMB, and there is no evidence that rates of satisfaction differ significantly. CONCLUSIONS: The overall results of the presented studies suggest that endometrial ablation is an effective therapy for menorrhagia in women with bleeding disorders. PMID- 26928421 TI - Dealing with premature menopause in women at high-risk for hereditary genital and breast cancer. AB - Risk-reducing salpingo-oophorectomy is the mainstay of ovarian cancer prevention in BRCA mutation carriers. However, premature menopause exerts many short and long-term consequences on the individual health that are preventable with a tailored approach. Even though our level of knowledge on BRCA1 and -2 mutation carriers is still in its infancy, the basic principles governing the management of menopausal symptomatology and the prevention of diseases should be applied, including the use of hormone replacement therapy (HRT), approximately until the age of 50. Indeed, short-term HRT significantly ameliorate quality of life and symptoms associated to vulvo-vaginal atrophy, without displaying an adverse effect on oncologic outcomes in BRCA1 and BRCA2 mutation carriers without a personal history of breast cancer. Premature menopause affects significantly also bone health, cardiovascular parameters and cognition. A standard of care is required in order to identify those women at higher risk of developing chronic conditions at midlife and beyond. Appropriate counseling on both hormonal and non hormonal treatments is an essential part of a shared decision on the most effective management of women at high-risk for hereditary genital and breast cancer. PMID- 26928422 TI - The OPPIuM technique: office hysteroscopic technique for the preparation of partially intramural leiomyomas. AB - Uterine fibroids, also known as leiomyomas, represent the most common benign tumors of the female genital tract. Submucosal leiomyomas are classified into three grades: G0, GI, GII according to the degree of their intramural proportion. A recently developed technique enables the preparation of G1 and G2 leiomyomas for their subsequent successful resection in a second step. The OPPIuM (office preparation of partially intramural leiomyomas) technique aims to downgrade type I and II leiomyomas, in order to facilitate a subsequent easier and safer resectoscopy. Hysteroscopic resection of large GI or GII submucosal fibroids is a complex procedure. OPPIuM technique has been invented and seems to achieve the downgrading of these types of leiomyomas in approximately 93% of cases, without any significant surgical complications or the need of hormonal agents' administration. In this way, the safer and quicker subsequent complete myomectomy is facilitated. PMID- 26928423 TI - Antimalarial Oxoprotoberberine Alkaloids from the Leaves of Miliusa cuneata. AB - Five new oxoprotoberberine alkaloids, miliusacunines A-E (1-5), along with nine known compounds, 6-14, were isolated from an acetone extract of the leaves and twigs of Miliusa cuneata. Their structures were elucidated by spectroscopic analysis. All isolated compounds were evaluated for their cytotoxicities against the KB and Vero cell lines and for antimalarial activities against the Plasmodium falciparum strains TM4 and K1 (a sensitive and a multi-drug-resistant strain, respectively). Compound 1 showed in vitro antimalarial activity against the TM4 strain, with an IC50 value of 19.3 +/- 3.4 MUM, and compound 2 demonstrated significant activity against the K1 strain, with an IC50 value of 10.8 +/- 4.1 MUM. Both compounds showed no discernible cytotoxicity to the Vero cell line at the concentration levels evaluated. PMID- 26928425 TI - The maintenance of totally implanted venous access device: When the difference is made by the nursing practice. Reply to the Letter to the Editor. PMID- 26928424 TI - Deletion of AS87_03730 gene changed the bacterial virulence and gene expression of Riemerella anatipestifer. AB - Riemerella anatipestifer is an important pathogen of waterfowl, which causes septicemia anserum exsudativa in ducks. In this study, an AS87_03730 gene deletion R. anatipestifer mutant Yb2DeltaAS87_03730 was constructed to investigate the role of AS87_03730 on R. anatipestifer virulence and gene regulation. By deleting a 708-bp fragment from AS87_03730, the mutant Yb2DeltaAS87_03730 showed a significant decreased growth rate in TSB and invasion capacity in Vero cells, compared to wild-type strain Yb2. Moreover, the median lethal dose (LD50) of Yb2DeltaAS87_03730 was 1.24 * 10(7) colony forming units (CFU), which is about 80-fold attenuated than that of Yb2 (LD50 = 1.53 * 10(5) CFU). Furthermore, RNA-Seq analysis and Real-time PCR indicated 19 up-regulated and two down-regulated genes in Yb2DeltaAS87_03730. Functional analysis revealed that 12 up-regulated genes were related to "Translation, ribosomal structure and biogenesis", two were classified into "Cell envelope biogenesis, outer membrane", one was involved in "Amino acid transport and metabolism", and the other four had unknown functions. Polymerase chain reaction and sequence analysis indicated that the AS87_03730 gene is highly conserved among R. anatipestifer strains, as the percent sequence identity was over 93.5%. This study presents evidence that AS87_03730 gene is involved in bacterial virulence and gene regulation of R. anatipestifer. PMID- 26928426 TI - Inhibitory effects of isatin Mannich bases on carbonic anhydrases, acetylcholinesterase, and butyrylcholinesterase. AB - The effects of isatin Mannich bases incorporating (1-[piperidin-1-yl (P1)/morpholin-4-yl (P2)/N-methylpiperazin-1-yl (P3)]methyl)-1H-indole-2,3-dione) moieties against human (h) carbonic anhydrase (CA, EC 4.2.1.1) isoenzymes hCA I and hCA II, acetylcholinesterase (AChE), and butyrylcholinesterase (BChE) enzymes were evaluated. P1-P3 demonstrated impressive inhibition profiles against AChE and BChE and also inhibited both CAs at nanomolar level. These inhibitory effects were more powerful in all cases than the reference compounds used for all these enzymes. This study suggests that isatin Mannich bases P1-P3 are good candidate compounds especially for the development of new cholinesterase inhibitors since they were 2.2-5.9 times better inhibitors than clinically used drug Tacrine. PMID- 26928427 TI - HbA1c Levels and Long-Term Mortality in Patients Undergoing Coronary Angiography. AB - OBJECTIVES: Previous studies investigating the prognostic value of HbA1c in patients undergoing coronary angiography reported a mixed pattern of results. Therefore, we aimed to better define the prognostic power of HbA1c among coronary catheterized patients. METHODS: Patients undergoing coronary angiography (n = 3,749) were divided into four groups according to HbA1c levels (<5, 5-6, 6-7 and >7%). Cox regression models assessed long-term mortality after adjusting for multiple covariates. RESULTS: Baseline clinical profiles differed in HbA1c groups, with a higher prevalence of comorbidities in the groups with higher HbA1c levels. Median follow-up was 1,745 days (interquartile range 1,007-2,171). A J shaped association curve was observed between HbA1c levels and all-cause mortality rates, with patients in the lowest and highest HbA1c groups suffering from significantly higher mortality rates compared to in-between groups (hazard ratio 1.9, 95% CI 1.32-2.74, p = 0.001, and hazard ratio 1.58, 95% CI 1.29-1.95, p < 0.001, for the lowest and highest HbA1c groups, respectively). This association persisted after adjustment for anemia, nutritional status, renal function, cardiovascular risk factors and inflammatory biomarkers. CONCLUSIONS: HbA1c levels <5 or >7% are predictors of all-cause mortality in patients undergoing coronary angiography. PMID- 26928428 TI - Evolution of Cooperation in Social Dilemmas on Complex Networks. AB - Cooperation in social dilemmas is essential for the functioning of systems at multiple levels of complexity, from the simplest biological organisms to the most sophisticated human societies. Cooperation, although widespread, is fundamentally challenging to explain evolutionarily, since natural selection typically favors selfish behavior which is not socially optimal. Here we study the evolution of cooperation in three exemplars of key social dilemmas, representing the prisoner's dilemma, hawk-dove and coordination classes of games, in structured populations defined by complex networks. Using individual-based simulations of the games on model and empirical networks, we give a detailed comparative study of the effects of the structural properties of a network, such as its average degree, variance in degree distribution, clustering coefficient, and assortativity coefficient, on the promotion of cooperative behavior in all three classes of games. PMID- 26928430 TI - Besnoitia besnoiti lytic cycle in vitro and differences in invasion and intracellular proliferation among isolates. AB - BACKGROUND: Bovine besnoitiosis, caused by the protozoan Besnoitia besnoiti, reduces productivity and fertility of affected herds. Besnoitiosis continues to expand in Europe and no effective control tools are currently available. Experimental models are urgently needed. Herein, we describe for the first time the kinetics of standardised in vitro models for the B. besnoiti lytic cycle. This will aid to study the pathogenesis of the disease, in the screening for vaccine targets and drugs potentially useful for the treatment of besnoitiosis. METHODS: We compared invasion and proliferation of one B. tarandi (from Finland) and seven B. besnoiti isolates (Bb-Spain1, Bb-Spain2, Bb-Israel, Bb-Evora03, Bb Ger1, Bb-France, Bb-Italy2) in MARC-145 cell culture. Host cell invasion was studied at 4, 6, 8 and 24 h post infection (hpi), and proliferation characteristics were compared at 24, 48, 72, 96, 120, and 144 hpi. RESULTS: In Besnoitia spp., the key parameters that determine the sequential adhesion invasion, proliferation and egress steps are clearly distinct from those in the related apicomplexans Toxoplasma gondii and Neospora caninum. Besnoitia spp. host cell invasion is a rather slow process, since only 50 % of parasites were found intracellular after 3-6 h of exposure to host cells, and invasion still took place after 24 h. Invasion efficacy was significantly higher for Bb-France, Bb Evora03 and Bb-Israel. In addition, the time span for endodyogeny to take place was as long as 18-35 h. Bb-Israel and B. tarandi isolates were most prolific, as determined by the tachyzoite yield at 72 hpi. The total tachyzoite yield could not be predicted neither by invasion-related parameters (velocity and half time invasion) nor by proliferation parameters (lag phase and doubling time (dT)). The lytic cycle of Besnoitia was asynchronous as evidenced by the presence of three different plaque-forming tachyzoite categories (lysis plaques, large and small parasitophorous vacuoles). CONCLUSIONS: This study provides first insights into the lytic cycle of B. besnoiti isolates and a standardised in vitro model that allows screening of drug candidates for the treatment of besnoitiosis. PMID- 26928431 TI - Evidence for spatial tuning of movement inhibition. AB - The time to initiate a movement can, even implicitly, be influenced by the environment. All primates, including humans, respond faster and with greater accuracy to stimuli that are brighter, louder or associated with larger reward, than to neutral stimuli. Whether this environment also modulates the executive functions which allow ongoing actions to be suppressed remains an issue of debate. In this study, we investigated the implicit learning of spatial selectivity of movement inhibition in humans and macaque monkeys performing a saccade-countermanding task. The occurrence of stop trials, in which subjects were visually instructed to cancel a prepared movement, was manipulated according to the target location. One visual target was associated with higher probability of stop signal appearance (e.g., 80 %), while the second target was associated with low fraction of stop (e.g., 20 %). The absolute occurrence of stop trials across the two targets (50 %) remains constant. The results show that human and macaque monkeys can selectively adapt their behaviors according to the implicit probability of stopping. Behavioral adjustments were larger when targets were in different hemifields and for larger distances between targets. Reduced selective inhibitory behaviors were observed when 15 degrees of visual angle separated the targets, and this effect vanished when targets were separated by only 2 degrees . Overall, our study shows that both response and inhibition times can be modulated by the relative spatial occurrence of stop signals. We speculate that beyond the particular effect we observed in the context of the saccade paradigm, selective motor execution may imply a disinhibitory mechanism that modulates the motor pathways associated with the fronto-median cortex and basal ganglia circuits. PMID- 26928432 TI - Arousal facilitates involuntary eye movements. AB - Attention plays a critical role in action selection. However, the role of attention in eye movements is complicated as these movements can be either voluntary or involuntary, with, in some circumstances (antisaccades), these two actions competing with each other for execution. But attending to the location of an impending eye movement is only one facet of attention that may play a role in eye movement selection. In two experiments, we investigated the effect of arousal on voluntary eye movements (antisaccades) and involuntary eye movements (prosaccadic errors) in an antisaccade task. Arousal, as caused by brief loud sounds and indexed by changes in pupil diameter, had a facilitation effect on involuntary eye movements. Involuntary eye movements were both significantly more likely to be executed and significantly faster under arousal conditions (Experiments 1 and 2), and the influence of arousal had a specific time course (Experiment 2). Arousal, one form of attention, can produce significant costs for human movement selection as potent but unplanned actions are benefited more than planned ones. PMID- 26928433 TI - Macrophage inflammatory protein 1 alpha (MIP-1alpha) may be associated with poor outcome in patients with extranodal NK/T-cell lymphoma. AB - The macrophage inflammatory protein 1alpha (MIP-1alpha) is anticipated to have a role in extranodal natural killer (NK)/T-cell lymphoma (ENKTL) because the expression of MIP-1alpha is related to Epstein-Barr virus (EBV) latency in EBV related non-Hodgkin lymphoma cells. Thus, we measured the serum level of MIP 1alpha in 69 patients with ENKTL using frozen serum samples that were archived at diagnosis. As serum level of MIP-1alpha was not detectable in 19 patients (range: 0-24.37 pg/mL), patients were dichotomized into positive (n = 50) and negative (n = 19) MIP-1alpha groups according to the presence of detectable level of MIP 1alpha in serum. MIP-1alpha-positive group showed a significantly poor overall survival (OS) in comparison with the MIP-1alpha-negative group (p = 0.004). In the subgroup analysis, the positivity of MIP-1alpha was significantly associated with OS in patients with stage IIIE/IV and a detectable level of EBV DNA (p = 0.002 and 0.032, respectively). Multivariate analysis also showed that the positivity of MIP-1alpha was independently associated with worse OS together with bone marrow involvement (p = 0.002). An in vitro study with patient-derived ENKTL tumour cells showed the expression of CCR1 and CCR5 on the surface of tumour cells (28% and 14%, respectively) , and the addition of MIP-1alpha to the culture media of tumour cells increased cell growth supporting the negative impact of MIP 1alpha on the prognosis of ENKTL patients. In conclusion, serum levels of MIP 1alpha could predict survival outcomes in patients with ENKTL. Therefore, MIP 1alpha should be considered for prognostication and a potential therapeutic target. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26928434 TI - Ultrasensitive Profiling of Metabolites Using Tyramine-Functionalized Graphene Quantum Dots. AB - Graphene quantum dots (GQDs) are emerging fluorescence reporters attractive for optical sensing, owing to their high photostability, highly tunable photoluminescence, molecular size, atomically thin structure, biocompatibility, and ease of functionalization. Herein, we present a fluorometric sensing platform based on tyramine-functionalized GQDs, which is able to detect a spectrum of metabolites with high sensitivity and specificity. Furthermore, multiparametric blood analysis (glucose, cholesterol, L-lactate, and xanthine) is demonstrated. This convenient metabolite profiling technique could be instrumental for diagnosis, study, and management of metabolic disorders and associated diseases, such as diabetes, obesity, lactic acidosis, gout, and hypertension. PMID- 26928435 TI - Comparative transcriptome analysis among parental inbred and crosses reveals the role of dominance gene expression in heterosis in Drosophila melanogaster. AB - We observed heteroses for body weight in Drosophila melanogaster after generating hybrids from three inbred lines. To better understand the mechanism for this phenomenon at the mRNA level, we compared the mRNA profiles of the parental and hybrid lines using high-throughput RNA-seq. A total of 5877 differentially expressed genes (DEGs) were found and about 92% of these exhibited parental expression level dominance. Genes in the dominance category were functionally characterized using the Kyoto Encyclopedia of Genes and Genomes (KEGG) and the gene classifications offered by the Gene Ontology (GO) Consortium. The analysis identified genes associated with crucial processes such as development and growth in all three crosses. Functional assignments involving aminoglycan metabolism, starch and sucrose metabolism, and galactose metabolism are significantly overrepresented amongst the 215 common dominance DEGs. We conclude that dominance DEGs are important in heteroses in Drosophila melanogaster and contribute specifically to body weight heterosis. PMID- 26928437 TI - Innovation in the pharmaceutical industry: New estimates of R&D costs. AB - The research and development costs of 106 randomly selected new drugs were obtained from a survey of 10 pharmaceutical firms. These data were used to estimate the average pre-tax cost of new drug and biologics development. The costs of compounds abandoned during testing were linked to the costs of compounds that obtained marketing approval. The estimated average out-of-pocket cost per approved new compound is $1395 million (2013 dollars). Capitalizing out-of-pocket costs to the point of marketing approval at a real discount rate of 10.5% yields a total pre-approval cost estimate of $2558 million (2013 dollars). When compared to the results of the previous study in this series, total capitalized costs were shown to have increased at an annual rate of 8.5% above general price inflation. Adding an estimate of post-approval R&D costs increases the cost estimate to $2870 million (2013 dollars). PMID- 26928436 TI - Prevalence of BRCA1/2 germline mutations in 21 401 families with breast and ovarian cancer. AB - PURPOSE: To characterise the prevalence of pathogenic germline mutations in BRCA1 and BRCA2 in families with breast cancer (BC) and ovarian cancer (OC) history. PATIENTS AND METHODS: Data from 21 401 families were gathered between 1996 and 2014 in a clinical setting in the German Consortium for Hereditary Breast and Ovarian Cancer, comprising full pedigrees with cancer status of all individual members at the time of first counselling, and BRCA1/2 mutation status of the index patient. RESULTS: The overall BRCA1/2 mutation prevalence was 24.0% (95% CI 23.4% to 24.6%). Highest mutation frequencies were observed in families with at least two OCs (41.9%, 95% CI 36.1% to 48.0%) and families with at least one breast and one OC (41.6%, 95% CI 40.3% to 43.0%), followed by male BC with at least one female BC or OC (35.8%; 95% CI 32.2% to 39.6%). In families with a single case of early BC (<36 years), mutations were found in 13.7% (95% CI 11.9% to 15.7%). Postmenopausal unilateral or bilateral BC did not increase the probability of mutation detection. Occurrence of premenopausal BC and OC in the same woman led to higher mutation frequencies compared with the occurrence of these two cancers in different individuals (49.0%; 95% CI 41.0% to 57.0% vs 31.5%; 95% CI 28.0% to 35.2%). CONCLUSIONS: Our data provide guidance for healthcare professionals and decision-makers to identify individuals who should undergo genetic testing for hereditary breast and ovarian cancer. Moreover, it supports informed decision-making of counselees on the uptake of genetic testing. PMID- 26928438 TI - Assaults, murders and walkers: The impact of violent crime on physical activity. AB - We investigate an underexplored externality of crime: the impact of violent crime on individuals' participation in walking. For many adults walking is the only regular physical activity. We use a sample of nearly 1 million people in 323 small areas in England between 2005 and 2011 matched to quarterly crime data at the small area level. Within area variation identifies the causal effect of local violent crime on walking and a difference-in-difference analysis of two high profile crimes corroborates our results. We find a significant deterrent effect of violent crime on walking that translates into a drop in overall physical activity. PMID- 26928439 TI - Equilibrium and kinetic studies on biosorption of Pb(II) by common edible macrofungi: a comparative study. AB - In this work, we studied the natural bioaccumulation and biosorption of Pb(II) in several common edible macrofungi. The macrofungi include the following species: Lentinus edodes, Pleurotus eryngii, Flammulina velutipes, Hypsizygus marmoreus, and Agrocybe cylindracea. The present analysis of Pb(II) revealed distinct capabilities of metal accumulation among individual species. Moreover, the natural concentrations of lead did not reach a health risk level when cultivated in uncontaminated soil. In the biosorption experiment by edible macrofungi, we found that the equilibrium data of living sporocarp (P. eryngii and H. marmoreus) and the homogenate of L. edodes and F. velutipes fit the Freundlich model well. Other data samples exhibited a better fit to the Langmuir model. The edible macrofungi showed a higher lead removal capacity than did other biosorbents. Furthermore, the pseudo-second-order kinetics model exhibited the best fit to the biosorption processes. The effectiveness of edible macrofungi as biosorbents for Pb(II) was confirmed. PMID- 26928440 TI - Identification of crucial regulatory relationships between long non-coding RNAs and protein-coding genes in lung squamous cell carcinoma. AB - PURPOSE: This study aimed to analyze the relationships of long non-coding RNAs (lncRNAs) and protein-coding genes in lung squamous cell carcinoma (LUSC). METHODS: RNA-seq data of LUSC deposited in the TCGA database were used to identify differentially expressed protein-coding genes (DECGs) and differentially expressed lncRNA genes (DE-lncRNAs) between LUSC samples and normal samples. Functional enrichment analysis of DECGs was then performed. Subsequently, the target genes and regulators of DE-lncRNAs were predicted from the DECGs. Additionally, expression levels of target genes of DE-lncRNAs were validated by RT-qPCR after the silence of DE-lncRNAs. RESULTS: In total, 5162 differentially expressed genes (DEGs) were screened from the LUSC samples, and there were seven upregulated lncRNA genes in the DEGs. The upregulated DECGs were enriched in GO terms like RNA binding and metabolic process. Meanwhile, the downregulated DECGs were enriched in GO terms like cell cycle. Furthermore, the lncRNAs PVT1 and TERC targeted multiple DECGs. PVT1 targeted genes related to cell cycle (e.g. POLA2, POLD1, MCM4, MCM5 and MCM6), and reduced expression of PVT1 decreased expression of the genes. TERC regulated several genes (e.g. NDUFAB1, NDUFA11 and NDUFB5), and reduced expression of TERC increased expression of the genes. Additionally, PVT1 was regulated by multiple transcription factors (TFs) identified from DECGs, such as HSF1; and TERC was modulated by TFs, such as PIR. CONCLUSION: A set of regulatory relationships between PVT1 and its targets and regulators, as well as TERC and its targets and regulators, may play crucial roles in the progress of LUSC. PMID- 26928441 TI - Understanding psychological distress among pediatric cancer caregivers. AB - PURPOSE: Few studies have examined distress in caregivers of pediatric cancer patients. We evaluated the association of socioeconomic, demographic, and patient clinical factors on caregivers' self-reported psychological distress associated with having a child with cancer. METHODS: N = 366 pediatric cancer caregivers completed a self-administered questionnaire from July 2010 to July 2012. The Impact of Event Scale (IES), along with two subscales "intrusion" and "avoidance" measured caregiver cancer-specific distress, with higher scores indicating greater distress. Multivariable linear regression models were used to calculate coefficients (beta) and 95 % confidence intervals (95 % CI) of IES by socioeconomic, demographic, and clinical factors. RESULTS: Average caregiver IES score was 31.2 (standard deviation (SD) = 16.9, range 0-75). Mean intrusion score was 18.1 (SD 9.8, range 0-35) and avoidance score was 12.8 (SD 9.0, range 0-40). Caregivers with household incomes <$40,000 reported higher mean distress scores than those with incomes ranging from $40,000 to $79,999 (beta = 4.45, 95 % CI 0.04-8.87, p = 0.05). Infrequently or never attending religious services, younger child age, and a diagnosis of AML were associated with higher intrusion (all p < 0.05). Caregivers with a child currently receiving therapy reported higher overall IES (beta = 5.9, 95 % CI 2.15-9.7, p < 0.01) and intrusion (beta = 4.1, 95 % CI 1.9-6.3, p < 0.001) scores compared to those off therapy (beta = 3.13, 95 % CI 0.93-5.33, p < 0.01). CONCLUSIONS: Our findings identify socioeconomic and clinical factors that influence psychological distress for caregivers of pediatric oncology patients. These findings underscore the importance of developing and testing interventions aimed at evaluating and addressing the psychosocial needs for high-risk caregivers in addition to those of patients. PMID- 26928442 TI - Mood states in long-term cancer survivors: an Italian descriptive survey. AB - PURPOSE: Since long-term survivorship is now a reality for an increasing number of people with cancer, understanding their mood states (i.e., transient subjective emotional states) can inform health-care policy as well as help support individual patients. This study described the mood states of Italian long term cancer survivors, compared them with normative data, and tested their association with the main clinical and socio-demographic sample's characteristics. METHODS: One hundred and fifty-eight Italian adults free from cancer and its treatments for at least 5 years were administered the Profile of Mood States (POMS) and two ad hoc 0-10-point visual-analogue scales on personal health-related worry and risk perception for a personal relapse, respectively. RESULTS: In comparison with the Italian normative sample, the current sample displayed a higher score in Vigor-Activity (p = 0.003) and a lower score in Confusion-Bewilderment (p = 0.008). In Tension-Anxiety, Confusion-Bewilderment, Depression-Dejection, Anger-Hostility, Fatigue-Inertia, and Vigor-Activity, 14.6, 15.9, 17.1, 17.8, 19.7, and 13.3 % of the sample, respectively, displayed meaningful scores (i.e., scores above or below 1 standard deviation from the normative mean score). The mood state profile POMS-provided was associated with gender (p = 0.002), occupational status (p = 0.003), reported health issues (p < 0.001), and quality of sleep (p < 0.001). In personal health-related worry and risk perception for a personal relapse, the average scores were 4.8 (SD = 3.0) and 4.1 (SD = 2.9), respectively. CONCLUSIONS: These data encourage a multidimensional assessment of emotional functioning of this specific population. PMID- 26928445 TI - Acknowledging rural context, local and generalist care. PMID- 26928443 TI - Permanent catheters for recurrent ascites-a critical and systematic review of study methodology. AB - PURPOSE: Management of refractory ascites traditionally includes medical treatment with diuretics or intermittent paracentesis. Patients with recurrent ascites may benefit from the use of permanent intra-abdominal catheters with more frequent drainage without hospitalization. The objective was to systematically asses the methodology of factors and endpoints reported in studies investigating permanent catheters for recurrent ascites treatment. METHODS: Using a systematic search strategy, we critically assessed the methodology when treating refractory ascites using a permanent catheter. Studies critically assessed included both retro- and prospective studies. RESULTS: A total of 715 unique articles were found via PubMed, The Cochrane Library and Embase. Twenty-nine studies (tunnelled catheter = 12, peritoneal ports = 6 and peritoneovenous shunts = 11) with three distinct types of permanent catheters fulfilled the inclusion criteria. Only three studies reported technical success less than 100 %. Data on complications and treatment were not available in all papers; peritonitis (48 %), cellulitis (41 %), prophylactic antibiotics (48 %) and complications to catheter insertion were difficult to distinguish from advanced co-morbidity of patients. Thirteen studies (45 %) reported some type of evaluating patient experience or functional outcome, but only three studies used validated reproducible scales when assessing outcomes. Fifteen of the 29 studies included 30 patients or less. CONCLUSION: Knowledge is limited because complications and outcomes are poorly defined. The expected increase in catheter treatment of refractory ascites necessitates comparative studies, using validated patient-related outcomes, and the reporting of unambiguous complications. A proposal of variables to include in future studies is presented. PMID- 26928446 TI - Acknowledging rural context, local and generalist care. PMID- 26928447 TI - Exciton energy recycling from ZnO defect levels: towards electrically driven hybrid quantum-dot white light-emitting-diodes. AB - An electrically driven quantum-dot hybrid white light-emitting diode is fabricated via spin coating CdSe quantum dots onto a GaN/ZnO nanorod matrix. For the first time, quantum dots are excited by fluorescence resonance energy transfer from the carriers trapped at surface defect levels. The prototype device exhibits achromatic emission, with a chromaticity coordinate of (0.327, 0.330), and correlated color temperature similar to sunlight. PMID- 26928449 TI - Effects of salinity on nest-building behaviour in a marine fish. AB - BACKGROUND: Parental allocation and reproductive success are often strongly influenced by environmental factors. In this respect, salinity is a key factor influencing species distributions and community structure in aquatic animals. Nevertheless, the effects of salinity on reproductive behaviours are not well known. Here, we used the sand goby (Pomatoschistus minutus), a small fish inhabiting a range of different salinities, to experimentally assess the effects of changes in salinity on nesting behaviour, a key component of reproduction in sand gobies and many other taxa. RESULTS: We found that salinity levels influenced some aspects of male nesting behaviour (i.e. nest entrance size) but not others (i.e. latency to build a nest, choice of nest site, sand on top of nest) and that small and large individuals were differently affected. In particular, the importance of body size in adjustment of nest entrance depended on the salinity level. CONCLUSION: The results support the prediction that geographically widespread aquatic species, such as sand gobies, are able to perform well under a range of salinity levels. The phenotype by environment interaction found between male size and behavioural responses to salinity can, in turn, help to explain the notable variation observed in nest-building (and other) behaviours closely linked to reproduction. PMID- 26928448 TI - Population pharmacokinetics of a three-day chloroquine treatment in patients with Plasmodium vivax infection on the Thai-Myanmar border. AB - BACKGROUND: A three-day course of chloroquine remains a standard treatment of Plasmodium vivax infection in Thailand with satisfactory clinical efficacy and tolerability although a continuous decline in in vitro parasite sensitivity has been reported. Information on the pharmacokinetics of chloroquine and its active metabolite desethylchloroquine are required for optimization of treatment to attain therapeutic exposure and thus prevent drug resistance development. METHODS: The study was conducted at Mae Tao Clinic for migrant worker, Tak province, Thailand. Blood samples were collected from a total of 75 (8 Thais and 67 Burmeses; 36 males and 39 females; aged 17-52 years) patients with mono infection with P. vivax malaria [median (95 % CI) admission parasitaemia 4898 (1206-29,480)/uL] following treatment with a three-day course of chloroquine (25 mg/kg body weight chloroquine phosphate over 3 days). Whole blood concentrations of chloroquine and desethylchloroquine were measured using high performance liquid chromatography with UV detection. Concentration-time profiles of both compounds were analysed using a population-based pharmacokinetic approach. RESULTS: All patients showed satisfactory response to standard treatment with a three-day course of chloroquine with 100 % cure rate within the follow-up period of 42 days. Neither recurrence of P. vivax parasitaemia nor appearance of P. falciparum occurred. A total of 1045 observations from 75 participants were included in the pharmacokinetic analysis. Chloroquine disposition was most adequately described by the two-compartment model with one transit compartment absorption model into the central compartment and a first-order transformation of chloroquine into desethylchloroquine with an additional peripheral compartment added to desethylchloroquine. First-order elimination from the central compartment of chloroquine and desethylchloroquine was assumed. The model exhibited a strong predictive ability and the pharmacokinetic parameters were estimated with adequate precision. CONCLUSION: The developed population-based pharmacokinetic model could be applied for future prediction of optimal dosage regimen of chloroquine in patients with P. vivax infection. PMID- 26928450 TI - Regulatory Perspectives on Strength-Dependent Dissolution Profiles and Biowaiver Approaches for Immediate Release (IR) Oral Tablets in New Drug Applications. AB - Dissolution profile comparisons are used by the pharmaceutical industry to assess the similarity in the dissolution characteristics of two formulations to decide whether the implemented changes, usually minor/moderate in nature, will have an impact on the in vitro/in vivo performance of the drug product. When similarity testing is applied to support the approval of lower strengths of the same formulation, the traditional approach for dissolution profile comparison is not always applicable for drug products exhibiting strength-dependent dissolution and may lead to incorrect conclusions about product performance. The objective of this article is to describe reasonable biopharmaceutic approaches for developing a biowaiver strategy for low solubility, proportionally similar/non proportionally similar in composition immediate release drug products that exhibit strength-dependent dissolution profiles. The paths highlighted in the article include (1) approaches to address biowaiver requests, such as the use of multi-unit dissolution testing to account for sink condition differences between the higher and lower strengths; (2) the use of a single- vs. strength-dependent dissolution method; and (3) the use of single- vs. strength-dependent dissolution acceptance criteria. These approaches are cost- and time-effective and can avoid unnecessary bioequivalence studies. PMID- 26928452 TI - Therapeutic potential of mesenchymal stem cells for pulmonary complications associated with preterm birth. AB - Preterm infants frequently suffer from pulmonary complications resulting in significant morbidity and mortality. Physiological and structural lung immaturity impairs perinatal lung transition to air breathing resulting in respiratory distress. Mechanical ventilation and oxygen supplementation ensure sufficient oxygen supply but enhance inflammatory processes which might lead to the establishment of a chronic lung disease called bronchopulmonary dysplasia (BPD). Current therapeutic options to prevent or treat BPD are limited and have salient side effects, highlighting the need for new therapeutic approaches. Mesenchymal stem cells (MSCs) have demonstrated therapeutic potential in animal models of BPD. This review focuses on MSC-based therapeutic approaches to treat pulmonary complications and critically compares results obtained in BPD models. Thereby bottlenecks in the translational systems are identified that are preventing progress in combating BPD. Notably, current animal models closely resemble the so called "old" BPD with profound inflammation and injury, whereas clinical improvements shifted disease pathology towards a "new" BPD in which arrest of lung maturation predominates. Future studies need to evaluate the utility of MSC based therapies in animal models resembling the "new" BPD though promising in vitro evidence suggests that MSCs do possess the potential to stimulate lung maturation. Furthermore, we address the mode-of-action of MSC-based therapies with regard to lung development and inflammation/fibrosis. Their therapeutic efficacy is mainly attributed to an enhancement of regeneration and immunomodulation due to paracrine effects. In addition, we discuss current improvement strategies by genetic modifications or precondition of MSCs to enhance their therapeutic efficacy which could also prove beneficial for BPD therapies. PMID- 26928453 TI - One University Making a Difference in Graduate Education: Caring in the Online Learning Environment. AB - As online education gains momentum, strategies to promote student engagement, develop social presence, and create a virtual community are essential for students' successful learning. A university with a philosophy grounded in caring developed two strategies for the graduate online education setting. These two strategies intentionally promote caring for self and others as a means to foster engagement, social presence, and a vibrant online community. One strategy was online Caring Groups, that is, small groups of four to five nursing students created each semester in one of the students' required courses in the online setting. The second strategy was the creation of two Caring Connections online sites, one for master of science in nursing students and one for doctorate in education nursing students. The sites were developed external to required courses to provide support for the online students throughout the graduate programs. Each site provides an ongoing space for students and faculty to post and discuss inspirational quotes, self-care tips, music, and photographs. The online Caring Groups and Caring Connections sites will be described, including how they were created, how they are used by students, how faculty support students, lessons learned, and how Caring Groups are integrated into the curriculum. PMID- 26928454 TI - Oral anticoagulant therapy interruption in children: A single centre experience. AB - BACKGROUND: The use of anticoagulant therapy in paediatrics is common, with vitamin K antagonists remaining the most commonly prescribed therapy. There is a weak evidence base behind many of the recommendations for anticoagulant therapy in paediatric patients. One of the areas requiring further research is the management of anticoagulant therapy interruption. Interruption to anticoagulation is the period surrounding a planned invasive procedure whereby long term anticoagulation is ceased, and recommenced post procedure. The word bridging refers to the use of low molecular weight heparin or unfractionated heparin to anticoagulate during the period of sub therapeutic INR. To date institutional protocols for bridging anticoagulation are based on adult guidelines. However, there are currently no studies validating the extrapolation of these guidelines to paediatrics. This study seeks to review the clinical outcomes associated with current bridging practices employed at a tertiary metropolitan children's hospital. METHODS: The patient population was selected from the warfarin management registry of a Clinical Haematology service of a major metropolitan children's hospital. The admission history of these patients was queried to identify admissions where anticoagulation interruption would typically be required. Namely, these were dental extraction, cerebral or cardiac angiography, or cardiac catheterization. Data relating to demographics, anticoagulant therapy interruption plan, and clinical outcomes were recorded. RESULTS: A total of 61 admissions for children aged between 1 year and 17 years and 11 months were analysed for this study. Congenital heart disease (CHD) was the primary underlying disease for which long-term oral anticoagulation with warfarin was indicated. Children with Moyamoya in this cohort were treated more consistently compared to the other disease groups. There were no instances of major bleeding (n=0) or thrombotic events (n=0). CONCLUSION: This study describes the current practices and outcomes associated with anticoagulant therapy interruption at one institution thereby filling an evidence gap in the paediatric anticoagulant management. It achieved this by analysing the largest and most representative cohort to date. This project is a stepping stone from which future studies of safety and efficacy of paediatric anticoagulation interruption management can be developed. PMID- 26928451 TI - Regulator of G Protein Signaling 17 as a Negative Modulator of GPCR Signaling in Multiple Human Cancers. AB - Regulators of G protein signaling (RGS) proteins modulate G protein-coupled receptor (GPCR) signaling networks by terminating signals produced by active Galpha subunits. RGS17, a member of the RZ subfamily of RGS proteins, is typically only expressed in appreciable amounts in the human central nervous system, but previous works have shown that RGS17 expression is selectively upregulated in a number of malignancies, including lung, breast, prostate, and hepatocellular carcinoma. In addition, this upregulation of RGS17 is associated with a more aggressive cancer phenotype, as increased proliferation, migration, and invasion are observed. Conversely, decreased RGS17 expression diminishes the response of ovarian cancer cells to agents commonly used during chemotherapy. These somewhat contradictory roles of RGS17 in cancer highlight the need for selective, high-affinity inhibitors of RGS17 to use as chemical probes to further the understanding of RGS17 biology. Based on current evidence, these compounds could potentially have clinical utility as novel chemotherapeutics in the treatment of lung, prostate, breast, and liver cancers. Recent advances in screening technologies to identify potential inhibitors coupled with increasing knowledge of the structural requirements of RGS-Galpha protein-protein interaction inhibitors make the future of drug discovery efforts targeting RGS17 promising. This review highlights recent findings related to RGS17 as both a canonical and atypical RGS protein, its role in various human disease states, and offers insights on small molecule inhibition of RGS17. PMID- 26928457 TI - False Hyperchloremia During Anesthesia in 2 Patients Treated With Potassium Bromide for Refractory Epilepsy. PMID- 26928455 TI - Understanding Specific Contexts of Antiretroviral Therapy Adherence in Rural South Africa: A Thematic Analysis of Digital Stories from a Community with High HIV Prevalence. AB - Near-perfect adherence to antiretroviral therapy (ART) is required to achieve the best possible prevention and treatment outcomes. Yet, there have been particular concerns about the challenges of adherence among patients living in resource limited settings in sub-Saharan Africa. The primary objective of this study was to explore adherence in a low-resourced, rural community of high HIV prevalence in South Africa and to identify specific individual and structural factors that can either challenge or support adherence in this context. We applied digital stories as a qualitative research tool to gain insights into personal contexts of HIV and ART adherence. Through an inductive thematic analysis of twenty story texts, soundtracks and drawings, we explored experiences, understandings, and contexts of the participants and identified potential barriers and facilitators for those on lifelong treatment. We found that many of the stories reflected a growing confidence in the effectiveness of ART, which should be viewed as a key facilitator to successful adherence since this attitude can promote disclosure and boost access to social support. Nevertheless, stories also highlighted the complexity of the issues that individuals and households face as they deal with HIV and ART in this setting and it is clear that an overburdened local healthcare system has often struggled to meet the demands of a rapidly expanding epidemic and to provide the necessary medical and emotional support. Our analysis suggests several opportunities for further research and the design of novel health interventions to support optimal adherence. Firstly, future health promotion campaigns should encourage individuals to test together, or at least accompany each other for testing, to encourage social support from the outset. Additionally, home-based testing and ART club interventions might be recommended to make it easier for individuals to adhere to their treatment regimens and to provide a sense of support and solidarity. PMID- 26928458 TI - Validity and repeatability of a depth camera-based surface imaging system for thigh volume measurement. AB - Complex anthropometrics such as area and volume, can identify changes in body size and shape that are not detectable with traditional anthropometrics of lengths, breadths, skinfolds and girths. However, taking these complex with manual techniques (tape measurement and water displacement) is often unsuitable. Three-dimensional (3D) surface imaging systems are quick and accurate alternatives to manual techniques but their use is restricted by cost, complexity and limited access. We have developed a novel low-cost, accessible and portable 3D surface imaging system based on consumer depth cameras. The aim of this study was to determine the validity and repeatability of the system in the measurement of thigh volume. The thigh volumes of 36 participants were measured with the depth camera system and a high precision commercially available 3D surface imaging system (3dMD). The depth camera system used within this study is highly repeatable (technical error of measurement (TEM) of <1.0% intra-calibration and ~2.0% inter-calibration) but systematically overestimates (~6%) thigh volume when compared to the 3dMD system. This suggests poor agreement yet a close relationship, which once corrected can yield a usable thigh volume measurement. PMID- 26928459 TI - Psoriasis and Psoriatic Arthritis: Flip Sides of the Coin? AB - Presence (current or past) of psoriasis of the skin is a major criterion to establish the diagnosis of psoriatic arthritis. However, in individual patients, the course of psoriasis and psoriatic arthritis do not seem to correlate. This raises the issue of whether psoriasis and psoriatic arthritis are distinct entities, or parts of the spectrum of a "psoriatic disease". Arguments in favour of both concepts, derived from clinical observations, animal experiments, genetic approaches, and therapeutic studies are reviewed, and the implications for scientists and practicing dermatologists highlighted. PMID- 26928456 TI - Google Glass-Directed Monitoring and Control of Microfluidic Biosensors and Actuators. AB - Google Glass is a recently designed wearable device capable of displaying information in a smartphone-like hands-free format by wireless communication. The Glass also provides convenient control over remote devices, primarily enabled by voice recognition commands. These unique features of the Google Glass make it useful for medical and biomedical applications where hands-free experiences are strongly preferred. Here, we report for the first time, an integral set of hardware, firmware, software, and Glassware that enabled wireless transmission of sensor data onto the Google Glass for on-demand data visualization and real-time analysis. Additionally, the platform allowed the user to control outputs entered through the Glass, therefore achieving bi-directional Glass-device interfacing. Using this versatile platform, we demonstrated its capability in monitoring physical and physiological parameters such as temperature, pH, and morphology of liver- and heart-on-chips. Furthermore, we showed the capability to remotely introduce pharmaceutical compounds into a microfluidic human primary liver bioreactor at desired time points while monitoring their effects through the Glass. We believe that such an innovative platform, along with its concept, has set up a premise in wearable monitoring and controlling technology for a wide variety of applications in biomedicine. PMID- 26928460 TI - Non-Interpenetrated Metal-Organic Frameworks Based on Copper(II) Paddlewheel and Oligoparaxylene-Isophthalate Linkers: Synthesis, Structure, and Gas Adsorption. AB - Two metal-organic framework materials, MFM-130 and MFM-131 (MFM = Manchester Framework Material), have been synthesized using two oligoparaxylene (OPX) tetracarboxylate linkers containing four and five aromatic rings, respectively. Both fof-type non-interpenetrated networks contain Kagome lattice layers comprising [Cu2(COO)4] paddlewheel units and isophthalates, which are pillared by the OPX linkers. Desolvated MFM-130, MFM-130a, shows permanent porosity (BET surface area of 2173 m(2)/g, pore volume of 1.0 cm(3)/g), high H2 storage capacity at 77 K (5.3 wt% at 20 bar and 2.2 wt% at 1 bar), and a higher CH4 adsorption uptake (163 cm(3)(STP)/cm(3) (35 bar and 298 K)) compared with its structural analogue, NOTT-103. MFM-130a also shows impressive selective adsorption of C2H2, C2H4, and C2H6 over CH4 at room temperature, indicating its potential for separation of C2 hydrocarbons from CH4. The single-crystal structure of MFM-131 confirms that the methyl substituents of the paraxylene units block the windows in the Kagome lattice layer of the framework, effectively inhibiting network interpenetration in MFM-131. This situation is to be contrasted with that of the doubly interpenetrated oligophenylene analogue, NOTT 104. Calculation of the mechanical properties of these two MOFs confirms and explains the instability of MFM-131 upon desolvation in contrast to the behavior of MFM-130. The incorporation of paraxylene units, therefore, provides an efficient method for preventing network interpenetration as well as accessing new functional materials with modified and selective sorption properties for gas substrates. PMID- 26928461 TI - Autoimmune Bullous Skin Disorders with Immune Checkpoint Inhibitors Targeting PD 1 and PD-L1. AB - Monoclonal antibodies (mAb) targeting immune checkpoint pathways such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed death 1 (PD 1) may confer durable disease control in several malignancies. In some patients, immune checkpoint mAbs cause cutaneous immune-related adverse events. Although the most commonly reported cutaneous toxicities are mild, a subset may persist despite therapy and can lead to severe or life-threatening toxicity. Autoimmune blistering disorders are not commonly associated with immune checkpoint mAb therapy. We report a case series of patients who developed bullous pemphigoid (BP), an autoimmune process classically attributed to pathologic autoantibody formation and complement deposition. Three patients were identified. Two patients developed BP while receiving the anti-PD-1 mAb nivolumab, and one while receiving the anti-PD-L1 mAb durvalumab. The clinicopathologic features of each patient and rash, and corresponding radiologic findings at the development of the rash and after its treatment, are described. Patients receiving an anti-PD-1/PD-L1 mAb may develop immune-related BP. This may be related to both T-cell- and B-cell mediated responses. Referral to a dermatologist for accurate diagnosis and management is recommended. Cancer Immunol Res; 4(5); 383-9. (c)2016 AACR. PMID- 26928462 TI - IFNgamma-Dependent Interactions between ICAM-1 and LFA-1 Counteract Prostaglandin E2-Mediated Inhibition of Antitumor CTL Responses. AB - Tumor-expressed ICAM-1 interaction with LFA-1 on naive tumor-specific CD8(+) T cells not only stabilizes adhesion, but, in the absence of classical B7-mediated costimulation, is also able to provide potent alternative costimulatory signaling resulting in the production of antitumor cytotoxic T lymphocyte (CTL) responses. This study shows that overproduction of prostaglandin (PG) E2 by metastatic murine renal carcinoma (Renca) cells inhibited direct priming of tumor-specific CTL responses in vivo by preventing the IFNgamma-dependent upregulation of ICAM-1 that is vital during the initial priming of naive CD8(+) T cells. The addition of exogenous IFNgamma during naive CD8(+) T-cell priming abrogated PGE2-mediated suppression, and overexpression of ICAM-1 by tumor cells restored IFNgamma production and proliferation among PGE2-treated tumor-specific CD8(+) T cells; preventing tumor growth in vivo These findings suggest that novel anticancer immunotherapies, which increase expression of ICAM-1 on tumor cells, could help alleviate PGE2-mediated immunosuppression of antitumor CTL responses. Cancer Immunol Res; 4(5); 400-11. (c)2016 AACR. PMID- 26928463 TI - Substantial interindividual and limited intraindividual genomic diversity among tumors from men with metastatic prostate cancer. AB - Tumor heterogeneity may reduce the efficacy of molecularly guided systemic therapy for cancers that have metastasized. To determine whether the genomic alterations in a single metastasis provide a reasonable assessment of the major oncogenic drivers of other dispersed metastases in an individual, we analyzed multiple tumors from men with disseminated prostate cancer through whole-exome sequencing, array comparative genomic hybridization (CGH) and RNA transcript profiling, and we compared the genomic diversity within and between individuals. In contrast to the substantial heterogeneity between men, there was limited diversity among metastases within an individual. The number of somatic mutations, the burden of genomic copy number alterations and aberrations in known oncogenic drivers were all highly concordant, as were metrics of androgen receptor (AR) activity and cell cycle activity. AR activity was inversely associated with cell proliferation, whereas the expression of Fanconi anemia (FA)-complex genes was correlated with elevated cell cycle progression, expression of the E2F transcription factor 1 (E2F1) and loss of retinoblastoma 1 (RB1). Men with somatic aberrations in FA-complex genes or in ATM serine/threonine kinase (ATM) exhibited significantly longer treatment-response durations to carboplatin than did men without defects in genes encoding DNA-repair proteins. Collectively, these data indicate that although exceptions exist, evaluating a single metastasis provides a reasonable assessment of the major oncogenic driver alterations that are present in disseminated tumors within an individual, and thus may be useful for selecting treatments on the basis of predicted molecular vulnerabilities. PMID- 26928465 TI - Surgical Risk Preoperative Assessment System (SURPAS): III. Accurate Preoperative Prediction of 8 Adverse Outcomes Using 8 Predictor Variables. AB - OBJECTIVE: To develop accurate preoperative risk prediction models for multiple adverse postoperative outcomes applicable to a broad surgical population using a parsimonious common set of risk variables and outcomes. SUMMARY BACKGROUND DATA: Currently, preoperative assessment of surgical risk is largely based on subjective clinician experience. We propose a paradigm shift from the current postoperative risk adjustment for cross-hospital comparison to patient-centered quantitative risk assessment during the preoperative evaluation. METHODS: We identify the most common and important predictor variables of postoperative mortality, overall morbidity, and 6 complication clusters from previously published prediction analyses that used forward selection stepwise logistic regression. We then refit the prediction models using only the 8 most common and important predictor variables, and compare the discrimination and calibration of these models to the original full-variable models using the c-index, Hosmer Lemeshow analysis, and Brier scores. RESULTS: Accurate risk models for 30-day outcomes of mortality, overall morbidity, and 6 clusters of complications were developed using a set of 8 preoperative risk variables. C-indexes of the 8 variable models are between 97.9% and 99.2% of those of the full models containing up to 28 variables, indicating excellent discrimination using fewer predictor variables. Hosmer-Lemeshow analyses showed observed to expected event rates to be nearly identical between parsimonious models and full models, both showing good calibration. CONCLUSIONS: Accurate preoperative risk assessment of postoperative mortality, overall morbidity, and 6 complication clusters in a broad surgical population can be achieved with as few as 8 preoperative predictor variables, improving feasibility of routine preoperative risk assessment for surgical patients. PMID- 26928464 TI - Major histocompatibility complex class I molecules protect motor neurons from astrocyte-induced toxicity in amyotrophic lateral sclerosis. AB - Astrocytes isolated from individuals with amyotrophic lateral sclerosis (ALS) are toxic to motor neurons (MNs) and play a non-cell autonomous role in disease pathogenesis. The mechanisms underlying the susceptibility of MNs to cell death remain unclear. Here we report that astrocytes derived from either mice bearing mutations in genes associated with ALS or human subjects with ALS reduce the expression of major histocompatibility complex class I (MHCI) molecules on MNs; reduced MHCI expression makes these MNs susceptible to astrocyte-induced cell death. Increasing MHCI expression on MNs increases survival and motor performance in a mouse model of ALS and protects MNs against astrocyte toxicity. Overexpression of a single MHCI molecule, HLA-F, protects human MNs from ALS astrocyte-mediated toxicity, whereas knockdown of its receptor, the killer cell immunoglobulin-like receptor KIR3DL2, on human astrocytes results in enhanced MN death. Thus, our data indicate that, in ALS, loss of MHCI expression on MNs renders them more vulnerable to astrocyte-mediated toxicity. PMID- 26928466 TI - Growth factors-loaded stents modified with hyaluronic acid and heparin for induction of rapid and tight re-endothelialization. AB - Rapid re-endothelialization of damaged vessel lining efficiently prevents restenosis and thrombosis and restores original vascular functions. In this study, we designed a novel metallic stent with a heparin-modified surface and used different methods, including 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and divinyl sulfone (DVS), to load growth factors. First we loaded heparin into a dopamine-conjugated hyaluronic acid (HA) coating to serve as a growth factor reservoir. In a second step, we took advantage of the heparin-binding domain of vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) to gain advanced re-endothelialization capabilities. We demonstrated that DVS technique offered higher amount of growth factor loading. In vitro assessment also showed better capillary-like structure formation and localized gap junctions when DVS coating was employed. This study suggested that growth factor loaded stent modified by HA and heparin provided the advantage to rapid and tight restoration of endothelium. PMID- 26928467 TI - Deciphering Mode of Action of Functionally Important Regions in the Intrinsically Disordered Paxillin (Residues 1-313) Using Its Interaction with FAT (Focal Adhesion Targeting Domain of Focal Adhesion Kinase). AB - Intrinsically disordered proteins (IDPs) play a major role in various cellular functions ranging from transcription to cell migration. Mutations/modifications in such IDPs are shown to be associated with various diseases. Current strategies to study the mode of action and regulatory mechanisms of disordered proteins at the structural level are time consuming and challenging. Therefore, using simple and swift strategies for identifying functionally important regions in unstructured segments and understanding their underlying mechanisms is critical for many applications. Here we propose a simple strategy that employs dissection of human paxillin (residues 1-313) that comprises intrinsically disordered regions, followed by its interaction study using FAT (Focal adhesion targeting domain of focal adhesion kinase) as its binding partner to retrace structural behavior. Our findings show that the paxillin interaction with FAT exhibits a masking and unmasking effect by a putative intra-molecular regulatory region. This phenomenon suggests how cancer associated mutations in paxillin affect its interactions with Focal Adhesion Kinase (FAK). The strategy could be used to decipher the mode of regulations and identify functionally relevant constructs for other studies. PMID- 26928468 TI - Effect of Toxoplasma gondii infection on the junctional complex of retinal pigment epithelial cells. AB - Ocular toxoplasmosis is the most frequent cause of uveitis, leading to partial or total loss of vision, with the retina the main affected structure. The cells of the retinal pigment epithelium (RPE) play an important role in the physiology of the retina and formation of the blood-retinal barrier. Several pathogens induce barrier dysfunction by altering tight junction (TJ) integrity. Here, we analysed the effect of infection by Toxoplasma gondii on TJ integrity in ARPE-19 cells. Loss of TJ integrity was demonstrated in T. gondii-infected ARPE-19 cells, causing increase in paracellular permeability and disturbance of the barrier function of the RPE. Confocal microscopy also revealed alteration in the TJ protein occludin induced by T. gondii infection. Disruption of junctional complex was also evidenced by scanning and transmission electron microscopy. Cell-cell contact loss was noticed in the early stages of infection by T. gondii with the visualization of small to moderate intercellular spaces. Large gaps were mostly observed with the progression of the infection. Thus, our data suggest that the alterations induced by T. gondii in the structural organization of the RPE may contribute to retinal injury evidenced by ocular toxoplasmosis. PMID- 26928470 TI - Development and validation of an LC-MS/MS method for simultaneous quantification of levodopa and MD01 in rat plasma and its application to a pharmacokinetic study of mucuna pruriens extract. AB - Mucuna pruriens, an ancient Indian herbal medicine containing levodopa, is widely used for Parkinson's disease. In order to simultaneously determine levodopa and 1,1-dimethyl-3-carboxy-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (MD01) in rat plasma, an improved LC-MS/MS method was developed and validated for a pharmacokinetic study in rats orally administered levodopa or Mucuna pruriens extract (MPE). Elimination of matrix effect and improvement of extraction recovery were achieved through systematic optimization of reversed-phase and hydrophilic interaction chromatographic conditions together with sample clean-up procedures. A satisfactory chromatographic performance was obtained with a Thermo Aquasil C18 column (50 * 2.1 mm, 3 um) using acetonitrile and water containing 0.2% formic acid as mobile phases. Futhermore, sodium metabisulfite and formic acid were used as stabilizers in neat solutions as well as rat plasma. The method was validated in a dynamic range of 20.0-10,000 ng/mL for levodopa and MD01; the intra- and inter-day precision and accuracy were acceptable. The method was successfully utilized to determine the levodopa level in plasma samples of rats administered levodopa or MPE. Pharmacokinetic results showed that an increase in the AUC of levodopa was observed in rats following oral administration of multiple doses of MPE. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26928471 TI - A patient navigator and education program for increasing potential living donors: a comparative observational study. AB - BACKGROUND AND OBJECTIVES: Person-centered clinical environments may promote living donation for patients with end-stage renal disease (ESRD). We implemented an observational study design to explore whether a patient navigator (PN) program with person-centered education in nephrology practice settings could increase potential living donors (PLDs) and, subsequently, increase living transplantation. DESIGN, SETTING, PARTICIPANTS, AND MEASURES: Patients referred to (N = 4621) and/or transplanted at (N = 950) our transplant center during 2007 2012 were eligible for inclusion. Two analytical study populations were derived from propensity score matched patient groups. Outcomes comprised total PLDs per candidate and living vs. deceased transplantation for recipients. RESULTS: Multivariable generalized estimating equations logistic regression showed that PN practice candidates were significantly more likely to have an initial inquiry PLD (odds ratio [OR] = 1.21, 95% confidence interval [CI] = 1.01-1.44) and a preliminary screening PLD (OR = 1.27, 95% CI = 1.05-1.54), while there were no significant differences observed in evaluated PLD (OR = 0.94, 95% CI = 0.61 1.45). CONCLUSIONS: Our results suggest that our person-centered PN program stimulated willingness to seek living transplantation and was associated with a trend toward increased LD. PMID- 26928473 TI - Neuropeptide evolution: Chelicerate neurohormone and neuropeptide genes may reflect one or more whole genome duplications. AB - Four genomes and two transcriptomes from six Chelicerate species were analyzed for the presence of neuropeptide and neurohormone precursors and their GPCRs. The genome from the spider Stegodyphus mimosarum yielded 87 neuropeptide precursors and 120 neuropeptide GPCRs. Many neuropeptide transcripts were also found in the transcriptomes of three other spiders, Latrodectus hesperus, Parasteatoda tepidariorum and Acanthoscurria geniculata. For the scorpion Mesobuthus martensii the numbers are 79 and 93 respectively. The very small genome of the house dust mite, Dermatophagoides farinae, on the other hand contains a much smaller number of such genes. A few new putative Arthropod neuropeptide genes were discovered. Thus, both spiders and the scorpion have an achatin gene and in spiders there are two different genes encoding myosuppressin-like peptides while spiders also have two genes encoding novel LGamides. Another finding is the presence of trissin in spiders and scorpions, while neuropeptide genes that seem to be orthologs of Lottia LFRYamide and Platynereis CCRFamide were also found. Such genes were also found in various insect species, but seem to be lacking from the Holometabola. The Chelicerate neuropeptide and neuropeptide GPCR genes often have paralogs. As the large majority of these are probably not due to local gene duplications, is plausible that they reflect the effects of one or more ancient whole genome duplications. PMID- 26928472 TI - Attenuated Leishmania induce pro-inflammatory mediators and influence leishmanicidal activity by p38 MAPK dependent phagosome maturation in Leishmania donovani co-infected macrophages. AB - Promastigote form of Leishmania, an intracellular pathogen, delays phagosome maturation and resides inside macrophages. But till date limited study has been done to manipulate the phagosomal machinery of macrophages to restrict Leishmania growth. Attenuated Leishmania strain exposed RAW 264.7 cells showed a respiratory burst and enhanced production of pro-inflammatory mediators. The augmentation of pro-inflammatory activity is mostly attributed to p38 MAPK and p44/42 MAPK. In our study, these activated macrophages are found to induce phagosome maturation when infected with pathogenic Leishmania donovani. Increased co-localization of carboxyfluorescein succinimidyl ester labeled pathogenic L. donovani with Lysosome was found. Moreover, increased co-localization was observed between pathogenic L. donovani and late phagosomal markers viz. Rab7, Lysosomal Associated Membrane Protein 1, Cathepsin D, Rab9, and V-ATPase which indicate phagosome maturation. It was also observed that inhibition of V-type ATPase caused significant hindrance in attenuated Leishmania induced phagosome maturation. Finally, it was confirmed that p38 MAPK is the key player in acidification and maturation of phagosome in attenuated Leishmania strain pre exposed macrophages. To our knowledge, this study for the first time reported an approach to induce phagosome maturation in L. donovani infected macrophages which could potentiate short-term prophylactic response in future. PMID- 26928474 TI - Hyperthermia and radiotherapy in the management of head and neck cancers: A systematic review and meta-analysis. AB - PURPOSE: A systematic review and meta-analysis was conducted to evaluate the outcome of controlled clinical trials in head and neck cancers (HNCs) using hyperthermia and radiotherapy versus radiotherapy alone. MATERIAL AND METHODS: A total of 498 abstracts were screened from four databases and hand searched as per the PRISMA guidelines. Only two-arm studies treating HNCs with either radiotherapy alone, or hyperthermia and radiotherapy without concurrent chemotherapy or surgery were considered. The evaluated end point was complete response (CR). RESULTS: Following a detailed screening of the titles, abstracts and full text papers, six articles fulfilling the above eligibility criteria were considered. In total 451 clinical cases from six studies were included in the meta-analysis. Five of six trials were randomised. The overall CR with radiotherapy alone was 39.6% (92/232) and varied between 31.3% and 46.9% across the six trials. With thermoradiotherapy, the overall CR reported was 62.5% (137/219), (range 33.9-83.3%). The odds ratio was 2.92 (95% CI: 1.58-5.42, p = 0.001); the risk ratio was 1.61 (95% CI: 1.32-1.97, p < 0.0001) and the risk difference was 0.25 (95% CI: 0.12-0.39, p < 0.0001), all in favour of combined treatment with hyperthermia and radiotherapy over radiotherapy alone. Acute and late grade III/IV toxicities were reported to be similar in both the groups. CONCLUSIONS: Hyperthermia along with radiotherapy enhances the likelihood of CR in HNCs by around 25% compared to radiotherapy alone with no significant additional acute and late morbidities. This level I evidence should justify the integration of hyperthermia into the multimodality therapy of HNCs. PMID- 26928475 TI - Bimetallic Cu(I) complex with a pyridine-bridged bis(1,2,3-triazole-5-ylidene) ligand. AB - A dinuclear copper(i) complex bearing a mesoionic carbene ligand has been prepared from the corresponding silver analogue and its structure determined spectroscopically. The results revealed that two Cu(i) halide salt molecules were bound to the carbon atoms of the pyridine-bridged bis(triazolylidene) moieties rather than the pyridine. Cyclic voltammogram measurements revealed that the two Cu(i) centres underwent a stepwise oxidation, suggesting that both the triazolylidene rings of the ligand could be on the same expanded pi-conjugated system. The catalytic hydroboration of styrene derivatives with bis(pinacolato)diborane in the presence of this complex allowed for the beta selective formation of the corresponding alkylboronate esters. PMID- 26928476 TI - [Surgical approaches of tumors of the posterior cone of the orbit]. AB - The surgical management of posterior orbital tumors is complex because it is an anatomical area located at the borders between the face and the skull base. The goal of the procedures carried-out in this area is to resect the tumor while preserving vision by using the safest possible approach. The aim of our work was to determine, in the light of our experience and of a review of the literature, the advantages and drawbacks of the numerous approaches described. PMID- 26928477 TI - Emissive Polyelectrolytes As Interlayer for Color Tuning and Electron Injection in Solution-Processed Light-Emitting Devices. AB - Herein we present a solution-processed hybrid device architecture combining organic light-emitting diodes (OLEDs) and light-emitting electrochemical cells (LECs) in a bilayer architecture. The LEC interlayer promotes the charge injection from an air-stable Ag cathode as well as permits the color tuning of the device emission. To this end, we used an alcohol-soluble anionic polyfluorene derivative, the properties of which were investigated by absorption and photoluminescence spectroscopy as well as by cyclic voltammetry. The bilayer device exhibited operating voltages ~6 V and a color tuning of the emission spectrum dependent on the LEC interlayer thickness. The hybrid devices presented a color emission ranging from the yellow (x = 0.39, y = 0.47) toward the green region (x = 0.29, y = 0.4) of the Commission Internationale de I'Eclairage (CIE) 1931 chromaticity diagram. PMID- 26928478 TI - Mitochondria operate as signaling platforms in yeast aging. PMID- 26928480 TI - Modality, probability, and mental models. AB - We report 3 experiments investigating novel sorts of inference, such as: A or B or both. Therefore, possibly (A and B). Where the contents were sensible assertions, for example, Space tourism will achieve widespread popularity in the next 50 years or advances in material science will lead to the development of antigravity materials in the next 50 years, or both. Most participants accepted the inferences as valid, though they are invalid in modal logic and in probabilistic logic too. But, the theory of mental models predicts that individuals should accept them. In contrast, inferences of this sort-A or B but not both. Therefore, A or B or both-are both logically valid and probabilistically valid. Yet, as the model theory also predicts, most reasoners rejected them. The participants' estimates of probabilities showed that their inferences tended not to be based on probabilistic validity, but that they did rate acceptable conclusions as more probable than unacceptable conclusions. We discuss the implications of the results for current theories of reasoning. PMID- 26928481 TI - Enhanced Charge Collection with Passivation Layers in Perovskite Solar Cells. AB - The Al2 O3 passivation layer is beneficial for mesoporous TiO2 -based perovskite solar cells when it is deposited selectively on the compact TiO2 surface. Such a passivation layer suppressing surface recombination can be formed by thermal decomposition of the perovskite layer during post-annealing. PMID- 26928479 TI - Using Electrophysiological Measures to Assess the Consumer Acceptability of Smokeless Tobacco Products. AB - INTRODUCTION: Adequate evaluation of novel tobacco products must include investigation of consumers' psychological response to such products. Traditionally, subjective scales of product liking have been used to assess consumer acceptability of tobacco products. However, subjective scales may miss cognitive changes that can only be captured by direct neurophysiological assessment. The present investigation explored the viability of using electroencephalography (EEG), in combination with traditional subjective measures, to assess consumer acceptability of five smokeless tobacco products. Given previous work linking product liking to arousal/attentional (executive function) enhancement, we focused on EEG measures of attention/arousal to objectively characterize cognitive changes associated with tobacco product use. METHODS: During five separate laboratory visits, smokeless tobacco users used Verve discs, Ariva dissolvables, Skoal snuff, Camel snus, or Nicorette lozenges. The N2 and P3b event-related potential components elicited by an oddball task were used to index attentional changes before/after product usage. Additionally, resting state alpha band EEG activity was analyzed before/after product usage to index cortical arousal. RESULTS: Although analyses of the subjective results provided limited inference, analyses of the electrophysiological measures, particularly the alpha suppression measure, revealed robust differences between products. Skoal elicited significantly enhanced alpha suppression compared to all four other products tested. Additionally, alpha suppression was found to correlate positively with subjective measures of satisfaction and psychological reward, but was unrelated to perceived aversion. CONCLUSIONS: The present results provide evidence that electrophysiological measures can yield important insights into consumer acceptability of novel tobacco products and are a valuable complement to subjective measures. IMPLICATIONS: This study is the first to employ a combination of electrophysiological measures and traditional subjective assays in order to assess the consumer acceptability of smokeless tobacco products. The results highlight the importance of adopting a multidimensional/multi-method approach to studying the consumer acceptability of tobacco products. PMID- 26928482 TI - The National Medical Association: True North Toward Health Care Equity. PMID- 26928483 TI - Prime Time Sister Circles((r))II: Evaluating a Culturally Relevant Intervention to Decrease Psychological and Physical Risk Factors for Chronic Disease in Mid Life African American Women. AB - PURPOSE: This article presents the results of two evaluation studies of the Prime Time Sister Circles((r)) (PTSC). The PTSC is a gender, cultural, and age specific, curriculum-based, low-cost, short-term, replicable support group approach aimed at reducing key modifiable health risk factors for chronic illnesses in midlife African American women. METHODS: Study 1 includes an evaluation of 31 PTSCs (N=656 women) documenting changes in psychological and attitudinal outcomes (health satisfaction, health locus of control), behavioral outcomes (healthy eating patterns, physical activity, stress management), and clinical outcomes (weight, BMI, blood pressure, non-fasting blood sugar). Study 2 includes evaluation of a subset of the PTSC sites (N=211 women) with comparison (N=55 women) data from those same locations. RESULTS: Study 1 showed significant changes (p<.0001) in the PTSC women's reports of (lower) stress, (higher) health locus of control, (increased) health satisfaction, (increased) physical activity, and (healthier) eating patterns. The PTSC women demonstrated a significant weight reduction at posttest (p <.0001) and had slightly better clinical outcomes in BMI, hypertension, and non-fasting blood sugar. Results document the sustainability of selected changes over a six-month period. Findings from the Study 2 strengthen the effectiveness claims of the PTSC intervention with significant changes for the PTSC women on selected outcomes and little changes for the comparison women. CONCLUSIONS: Results reaffirm findings regarding the effectiveness of the PTSC, as originally reported in Gaston, Porter, and Thomas (2007) and extends the credibility of findings by examining participants' clinical outcomes in addition to self-reports. PMID- 26928484 TI - Higher Prevalence of Human Papillomavirus-Related Cervical Precancerous Abnormalities in HIV-Infected Compared to HIV-Uninfected Women. AB - INTRODUCTION: Persistent high risk human papillomavirus (hrHPV) has been associated with cervical abnormalities and cancer. There are few studies comparing HIV-infected with uninfected African American women from the Southern U.S. We evaluated medical records of a women's cohort in an urban clinic in Tennessee to assess the prevalence of hrHPV and cytology correlates, as well as HPV vaccination rates. METHODS: We reviewed medical records of 50 HIV infected and 304 HIV uninfected women, including Pap smears and hrHPV. RESULTS: HIV infected women were older than HIV-uninfected women (p<0.0001) and were more likely to have hrHPV (p=<0.0001) and LGSIL/HGSIL (p=0.006). Within the HIV uninfected group, Hispanic women were younger than non-Hispanic African American women (p=0.04) and non-Hispanic white women (p=0.0002). Non-Hispanic African American women were younger (p=0.004) than non-Hispanic white women. Both HIV uninfected and HIV-infected women had an 11-fold and 5-fold odds, respectively, of having precancerous lesions when harboring hrHPV, compared to hrHPV-uninfected women. Of the 125 HIV-uninfected women, only 17% had received at least one dose of the HPV vaccine. None of the 21 vaccine recipients had evidence of SILs compared to 9% of vaccine non-recipients (p=0.35, Fisher's exact test). CONCLUSION: HIV-infected women remained at significantly higher risk for developing cervical precancerous lesions when exposed to hrHPV than their uninfected counterparts. Hispanic women were least likely to have been vaccinated. Missed HPV vaccination trended towards being associated with a higher odds of precancerous lesions. Routine HPV vaccination should be reinforced for adolescents and young women using public hospital facilities of all races and ethnic backgrounds. PMID- 26928485 TI - A Systematic Review of Race and Ethnicity in Hepatitis C Clinical Trial Enrollment. AB - The African American/Black population in the United States (US) is disproportionately affected by hepatitis C virus (HCV) and has lower response rates to current treatments. This analysis evaluates the participation of African American/Blacks in North American and European HCV clinical trials. The data source for this analysis was the PubMed database. Randomized controlled clinical trials (RCT) on HCV treatment with interferon 2a or 2b between January 2000 and December 2011 were reviewed. Inclusion criteria included English language and participants 18 years or older with chronic HCV. Exclusion criteria included non randomized trials, case reports, cohort studies, ethnic specific studies, or studies not using interferon-alfa or PEG-interferon. Of the 588 trials identified, 314 (53.4%) fit inclusion criteria. The main outcome was the rate of African American/ Black participation in North American HCV clinical trials. A meta-analysis comparing the expected and observed rates was performed. Of the RCT's that met search criteria, 123 (39.2%) reported race. Clinical trials in North America were more likely to report racial data than European trials. Racial reporting increased over time. There was a statistically significant difference among the expected and observed participation of African Americans in HCV clinical trials in North America based on the prevalence of this disease within the population. The burden of HCV among African Americans in North America is not reflected in those clinical trials designed to treat HCV. Research on minority participation in clinical trials and how to increase minority participation in clinical trials is needed. PMID- 26928486 TI - Mortality in African-Americans Following Cardiac Resynchronization Therapy: A Single Center Experience. AB - BACKGROUND: Cardiac resynchronization therapy (CRT) improves clinical outcomes and reduces mortality in heart failure patients who remain symptomatic despite optimal medical therapy. CRT trials have reported significant hemodynamic benefits, improvement in functional status, and reduced mortality and heart failure hospitalizations. However, African-American patient representation in these studies is limited thus the results may not be applicable to them. We described baseline clinical characteristics of African-American patients undergoing CRT and determined their outcomes relative to those reported in clinical trials. METHODS: We evaluated 131 African-American patients with New York Heart Association functional class II-IV heart failure undergoing CRT and determined predictors of all-cause mortality. Kaplan-Meier survival estimates and a Cox proportional hazards model determined mortality and risk of death. RESULTS: The mean age was 65 +/- 12 years. Over a 6-year period, total mortality in African-Americans was 23% as compared with 29% in the MADIT-CRT trial. Increased mortality was associated with older age (hazard rate (HR) 1.04, 95% confidence interval (CI) 1.01-1.07, P=.01), ischemic cardiomyopathy (HR 2.86, 95% CI 1.36 6.04, P=.006), and absence of treatment with either an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker (HR 2.75, 95% CI 1.30-5.80, P=.008), or beta-blocker (HR 2.56, 95% CI 0.98-6.69, P=.05). Hydralazine plus nitrate therapy was used in a small number of patients and did not influence mortality outcomes. CONCLUSION: African-Americans experience the same survival benefits from CRT as Caucasian patients reported in major clinical trials. Publication indices used to find publications listed in references: PubMed. PMID- 26928487 TI - Cardiovascular Health Practices Among Black Patients in an Urban Underserved Clinic. AB - BACKGROUND: An understanding of cardiovascular health practices among black patients can provide more comprehensive patient-centered care and reduce health disparities. We studied home blood pressure monitoring in our underserved patient population to determine feasibility of providing automatic blood pressure monitors to our hypertensive patients. We believed that if we provided blood pressure monitors for home use, our patients would increase home blood pressure assessments, frequency of blood pressure assessments, and provide more data on managing their hypertension. METHODS: Forty patients were selected based on their individually scheduled clinic appointments and were randomized to the experimental arm or the control arm. Patients in the experimental arm of the study received an automatic blood pressure monitor for the duration of the study, while the control group received their automatic blood pressure monitor at the end of the study period. All participants received evidence- based patient education upon enrollment in addition to phone calls to collect blood pressure readings every two weeks. After six months, patients completed an exit interview and survey to determine the effects of the study on enrollee health practices. RESULTS: Of the 40 people enrolled, 13 participants completed the study. Of those who completed, 87% of the experimental group checked their blood pressure more often outside of the healthcare setting compared to 60% of the control group. There was no increase in the control group's pre-survey blood pressure monitoring metrics but a 50 percentage point increase in the experimental group's blood pressure monitoring metrics. Telephone data demonstrated that participants who received an automatic blood pressure monitor for home use were more than three times more likely to check their blood pressure outside of the healthcare setting than those who did not have a home monitor. CONCLUSIONS: Home accessible automatic blood pressure monitoring can increase frequency of blood pressure assessment among black patients. PMID- 26928488 TI - The Epidemiology of Infant Mortality in the Greater Newark, New Jersey Area: A New Look at an Old Problem. AB - REVIEW: This research had institutional review board approval from the University of Medicine and Dentistry of New Jersey and the State of New Jersey Department of Health and Senior Services. IRB #0120110286 BACKGROUND: The death rate during the first year of life, or infant mortality rate (IMR), is a key indicator of a nation's health. Many factors affect IMR in the United States, including race and ethnicity. The 2020 U.S. Healthy People IMR target goal has been revised to 6.0 deaths per 1,000 births. In 2006, the IMR in New Jersey was 5.5 deaths per 1,000 births, ranging from 4.4 for Caucasians, to 11.5 for African Americans. OBJECTIVE: This study is designed to determine whether IMRs vary by zip code in the greater Newark region and identify maternal/infant characteristics associated with elevated IMRs. METHODS: A descriptive study was conducted using New Jersey Department of Health (NJDOH) birth certificate data and U.S. Census data by zip code in the greater Newark area. IMRs were analyzed by zip code and by characteristics of mothers and infants. RESULTS: IMRs vary by zip code of residence. The lowest and highest IMRs were in zip codes 07105 and 07102, respectively, both located within the city of Newark. Maternal characteristics associated with high IMR, in multivariable analysis, include: lack of prenatal care, single marital status, and non-Hispanic black race. Demographic characteristics associated with high IMRs were: low mean household income and a large percentage of the population living below poverty level. CONCLUSIONS: Race/ethnicity, marital status, and zip code of residence show significant impact upon infant mortality. Poverty and race/ethnicity are associated with increased IMRs and track to ZIP code. PMID- 26928489 TI - Effectiveness of Interventions to Increase Physical Activity Among Minority Populations: An Umbrella Review. AB - PURPOSE: Numerous interventions have been tested to increase physical activity (PA) among minority adults, and several review papers have examined the results from these studies. The primary purpose of this umbrella review is to summarize evidence from existing reviews regarding effectiveness of PA interventions in minority populations. PROCEDURES: Searches were conducted in five electronic databases to identify English-language articles reviewing the effects of interventions to increase PA in minority adults living in the United States. Reviews that met the inclusion criteria were critically assessed using umbrella review procedures. Review quality was assessed using the PRISMA statement and checklist. FINDINGS: Twenty-two reviews fulfilled inclusion criteria. The sample included one meta-analysis, 11 integrated reviews, and 10 narrative reviews published between 1998 and 2012. The reviews documented modest improvements in PA with considerable variation in intervention effectiveness across primary studies. Integrative reviews generally were of higher overall quality than narrative reviews with regard to fulfilling PRISMA criteria. CONCLUSIONS: Integrated and narrative reviews were unable to validly determine the characteristics of effective interventions. Future reviews should employ meta-analytic methods in order to quantitatively identify those intervention characteristics that are most likely to increase PA behavior in minority adults. PMID- 26928490 TI - Respondent-Driven Sampling in a Multi-Site Study of Black and Latino Men Who Have Sex with Men. AB - PURPOSE: Respondent-driven sampling (RDS) was used to recruit four samples of Black and Latino men who have sex with men (MSM) in three metropolitan areas to measure HIV prevalence and sexual and drug use behaviors. We compared demographic and behavioral risk characteristics of participants across sites, assessed the extent to which the RDS statistical adjustment procedure provides estimates that differ from the crude results, and summarized our experiences using RDS. METHODS: From June 2005 to March 2006 a total of 2,235 MSM were recruited and interviewed: 614 Black MSM and 516 Latino MSM in New York City, 540 Black MSM in Philadelphia, and 565 Latino MSM in Los Angeles County. Crude point estimates for demographic characteristics, behavioral risk factors and HIV prevalence were calculated for each of the four samples. RDS Analysis Tool was used to obtain population-based estimates of each sampled population's characteristics. RESULTS: RDS adjusted estimates were similar to the crude estimates for each study sample on demographic characteristics such as age, income, education and employment status. Adjusted estimates of the prevalence of risk behaviors were lower than the crude estimates, and for three of the study samples, the adjusted HIV prevalence estimates were lower than the crude estimates. However, even the adjusted HIV prevalence estimates were higher than what has been previously estimated for these groups of MSM in these cities. Each site faced unique circumstances in implementing RDS. CONCLUSIONS: Our experience in using RDS among Black and Latino MSM resulted in diverse recruitment patterns and uncertainties in the estimated HIV prevalence and risk behaviors by study site. PMID- 26928491 TI - Overweight and Physical Inactivity Among African American Students at a Historically Black University. AB - BACKGROUND: Little is known about correlates of overweight, obesity, and physical inactivity among African American students at historically Black colleges and universities. OBJECTIVE: To assess overweight, obesity, and physical inactivity among African American college students at a historically Black university in Maryland in the USA. METHODS: Data were collected from 268 African American college students in 2013. Data were analyzed with percentage difference z-tests, chi-square tests, and multiple logistic regression. DESIGN: Cross-sectional survey (student response rate = 49.9%). RESULTS: The overweight/obesity rate of participants was 47.5%, which was higher than that of the U.S. college student population overall (34.1%) and a representative sample of African American college students (38.3%). When age and sex were controlled, a family history of obesity, skipping breakfast, drinking caffeinated drinks, lower family income, and smoking a pipe, cigars, or cigarettes daily were significant correlates of overweight (obesity included). The percentage of physical inactivity was 68.3, and physical inactivity was higher among women and overweight or obese students. CONCLUSION: Given the high overweight and obesity prevalence among African American college students, historically Black colleges and universities in the USA should increase health promotion efforts targeting weight-related behaviors, particularly physical activity. PMID- 26928492 TI - Acute Blood Loss Anemia in the Octogenarian Total Knee Arthroplasty, Estimated Blood Loss and Transfusions Rates. AB - INTRODUCTION: Acute blood loss anemia is an expected morbidity after a total knee replacement. The purpose of this study is to quantify the rates of blood transfusions in the octogenarian population after a total knee replacement and its association with the surgeon's estimated blood loss (EBL). METHODS: This is a retrospective review of the senior orthopedic surgeon's charts. All patients were 80 years of age, or older at the time of surgical intervention. All patients with the diagnosis of primary osteoarthritis where included. RESULTS: A total 74 total knee arthroplasties were considered, in a total of 64 patients. Overall, 53% patients had an uneventful stay without a blood transfusion. The rates of transfusions increased with EBLs of 200, 250, and >250 ml with rates of 43%, 80%, and 55 % respectively. The average hematocrit of all patients that were transfused was 33.98, compared to 38.20 for the patients that were not transfused. CONCLUSION: 47% of patients required a blood transfusion during their hospital course regardless of the EBL estimated by the surgeon during surgery. The average hematocrit was found to be lower in the group that was transfused. PUBLICATION INDICES: Pubmed. PMID- 26928494 TI - Association of State Laws and Healthcare Workers' Influenza Vaccination Rates. AB - State laws are being used to increase healthcare worker (HCW) influenza vaccine uptake. Approximately 40% of states have enacted such laws but their effectiveness has been infrequently studied. Data sources for this study were the 2000-2011 U.S. National Health Interview Survey Adult Sample File and a summary of U.S. state HCW influenza vaccination laws. Hierarchical linear modeling was used for two time periods: 1) 2000-2005 (before enactment of many state laws) and 2) 2006-2011 (a time of increased enactment of state HCW influenza vaccination legislation). During 2000-2005, two states had HCW influenza vaccination laws and HCW influenza vaccination rates averaged 22.5%. In 2006-2011, 19 states had such laws and vaccination rates averaged 50.9% (p < 0.001). The likelihood of HCW vaccination increased with the scope and breadth, measured by a law score. Although laws varied widely in scope and applicability, states with HCW influenza vaccination laws reported higher HCW vaccination rates. PMID- 26928493 TI - Relationship Between Chronic Conditions and Disability in African American Men and Women. AB - BACKGROUND: Race differences in chronic conditions and disability are well established; however, little is known about the association between specific chronic conditions and disability in African Americans. This is important because African Americans have higher rates and earlier onset of both chronic conditions and disability than white Americans. METHODS: We examined the relationship between chronic conditions and disability in 602 African Americans aged 50 years and older in the Baltimore Study of Black Aging. Disability was measured using self-report of difficulty in activities of daily living (ADL). Medical conditions included diagnosed self-reports of asthma, depressive symptoms, arthritis, cancer, diabetes, cardiovascular disease (CVD), stroke, and hypertension. RESULTS: After adjusting for age, high school graduation, income, and marital status, African Americans who reported arthritis (women: odds ratio (OR)=4.87; 95% confidence interval(CI): 2.92-8.12; men: OR=2.93; 95% CI: 1.36-6.30) had higher odds of disability compared to those who did not report having arthritis. Women who reported major depressive symptoms (OR=2.59; 95% CI: 1.43-4.69) or diabetes (OR=1.83; 95% CI: 1.14-2.95) had higher odds of disability than women who did not report having these conditions. Men who reported having CVD (OR=2.77; 95% CI: 1.03-7.41) had higher odds of disability than men who did not report having CVD. CONCLUSIONS: These findings demonstrate the importance of chronic conditions in understanding disability in African Americans and how it varies by gender. Also, these findings underscore the importance of developing health promoting strategies focused on chronic disease prevention and management to delay or postpone disability in African Americans. PUBLICATION INDICES: Pubmed, Pubmed Central, Web of Science database. PMID- 26928496 TI - [Cotrimoxazole in bone-related infections: toxicity and clinical and economic impact]. AB - BACKGROUND: Cotrimoxazole is a therapeutic option for bone-related infections but is associated to hyperkalemia and renal failure. Tolerance to this drug may reduce length of stay (LOS) and hospital charges. AIMS: To evaluate renal, potassium toxicity, clinical outcome, and use of hospital resources in patients treated with cotrimoxazole for bone-related infections. METHODS: Retrospective analysis of adult patients with bone-related infections confirmed by culture and treated with this drug. Serum potassium and creatinine levels were analyzed during follow-up and risk factors for hyperkalemia were searched. Length of stay (LOS) and hospital charges were compared. Clinical outcome was evaluated as a secondary endpoint. RESULTS: From 2011 to 2014, 23 patients were identified (mean age 64.7 years). Diabetes mellitus, peripheral vascular disease, and previous amputations prevalence were high (82.6%, 47.8%, and 43.5%, respectively). Median serum potassium concentration increased significantly at first control (4.35 mEq/L to 4.9 mEq/L; p < 0.001), and also creatinine serum concentration (0.9 to 1.1 mg/dL; p < 0.05). Seven patients developed hyperkalemia. Cotrimoxazole was discontinued in 10 patients (43.5%), and in 6, discharge was postponed. Drugs active against the renin-angiotensin system (DAARAS) were associated with kyperkalemia (OR 10.8 IC95 1.37-85; p < 0.05). LOS was higher among patients with cotrimoxazole toxicity (median LOS 56 versus 30 days, p < 0.05). Patients with no cotrimoxazole interruption had less drug-related hospital charges (median values of 563 versus 2820 USD, respectively; p < 0.01). CONCLUSIONS: Cotrimoxazole use must be monitored in order to detect hyperkalemia or renal toxicity and suspend its prescription. Patients that use DAARAS have a higher risk of kyperkalemia. LOS and drug-related hospital charges are reduced when patients can tolerate cotrimoxazole. PMID- 26928495 TI - Gene dysregulation is restored in the Parkinson's disease MPTP neurotoxic mice model upon treatment of the therapeutic drug Cu(II)(atsm). AB - The administration of MPTP selectively targets the dopaminergic system resulting in Parkinsonism-like symptoms and is commonly used as a mice model of Parkinson's disease. We previously demonstrated that the neuroprotective compound Cu(II)(atsm) rescues nigral cell loss and improves dopamine metabolism in the MPTP model. The mechanism of action of Cu(II)(atsm) needs to be further defined to understand how the compound promotes neuronal survival. Whole genome transcriptomic profiling has become a popular method to examine the relationship between gene expression and function. Substantia nigra samples from MPTP-lesioned mice were evaluated using whole transcriptome sequencing to investigate the genes altered upon Cu(II)(atsm) treatment. We identified 143 genes affected by MPTP lesioning that are associated with biological processes related to brain and cognitive development, dopamine synthesis and perturbed synaptic neurotransmission. Upon Cu(II)(atsm) treatment, the expression of 40 genes involved in promoting dopamine synthesis, calcium signaling and synaptic plasticity were restored which were validated by qRT-PCR. The study provides the first detailed whole transcriptomic analysis of pathways involved in MPTP-induced Parkinsonism. In addition, we identify key therapeutic pathways targeted by a potentially new class of neuroprotective agents which may provide therapeutic benefits for other neurodegenerative disorders. PMID- 26928497 TI - [Seroprevalence of dengue infection in a district of the Paraguayan Chaco: Population based study]. AB - BACKGROUND: Dengue is an infection of great global importance with different clinical presentations. OBJECTIVE: To establish the seroprevalence of infection by the dengue virus in a district of the Paraguayan Chaco. MATERIAL AND METHODS: Cross-sectional study in 418 inhabitants of three villages in the district of Villa Hayes, Paraguay, using a probabilistic household sampling, a questionnaire and blood sampling. Antibodies were determined by the ELISA capture IgG anti dengue method and factors associated with seroprevalence were evaluated. RESULTS: The overall seroprevalence for dengue virus infection was 24,2% (CI95%: 20,2% 28,6%); 34% (n: 142) of respondents reported history of dengue in the previous 10 year period. Of the 276 people (66%) who reported no history of dengue infection, 37 (13%) tested positive, which points out asymptomatic individuals. The main factors associated with infection were: males with significantly higher prevalence than women (31%); to be over 60 years of age (44%), be residents of Villa Hayes (31,1%). No association with educational level or monthly income of the participants, nor housing condition, drinking water source or type of bathroom were observed. The larval infestation rate was 0,51%. CONCLUSIONS: The relatively low seroprevalence of infection by the dengue virus is consistent with the small size of the district and highlights the potential risk of infection in future epidemics. PMID- 26928498 TI - [Seroprevalence of leptospirosis and associated factors in workers of the urban cleaning service of the Municipality of Asuncion, Paraguay]. AB - INTRODUCTION: Leptospirosis is a serious infectious disease that has been linked to occupational activities such as farmers, sewer workers, garbage collectors, butchers and veterinarians. It is acquired through contact with major reservoirs like rodents, pets, or the environment contaminated by their urine. In Paraguay, there are no published reports on the seroprevalence of leptospirosis related to work activity. OBJECTIVE: To determine the seroprevalence and factors associated with transmission of leptospirosis in urban sanitation workers. METHODOLOGY: Descriptive transversal study. The study included workers from the Department of Urban Cleanliness of the City of Asuncion, who had completed at least one month on the job and who agreed to participate in the study. Sampling was stratified and proportional to the number of workers. After informed consent was obtained, participants were surveyed and a blood sample was taken for detection of Leptospira IgG antibodies by ELISA. RESULTS: Leptospirosis seroprevalence was 8.6% (29/339), all positive cases were male and prevalence was statistically higher in workers of the collection area than in those of other work areas. CONCLUSION: We found a lower than expected seroprevalence. However, conditions observed at work and at home are conducive to transmission of infection. We recommend the improvement of prevention strategies and health promotion in this population. PMID- 26928499 TI - [Cost evaluation of catheter-related bloodstream infections in adult patients in Chile]. AB - BACKGROUND: Nosocomial infections are common adverse events associated with increased morbidity, mortality, and costs of patient care. Catheter-related bloodstream infections (CR-BSI) are nosocomial infections associated with higher medical costs. AIMS: To evaluate CR-BSI associated costs in the Hospital Militar of Santiago, Chile, during year 2013. METHODS: Comparative study between cases (CR-BSI) and matched controls using the Pan American Health Organization protocol. Variables were excess in length of stay (LOS), antimicrobial use according to daily defined doses (DDD), and total number of microbial cultures per hospitalization which were compared with non-parametric tests. RESULTS: We included 10 cases and 10 matched controls. Mean LOS among cases was 40 days vs. 20.3 among controls (excess 20.3 days per event; p < 0.05). Antimicrobial consumption was higher among cases (DDD 36 vs. 10.5; p < 0.05) and there was a trend to an increased number of bacterial cultures among cases (9 vs. 5; p = 0.057). The additional cost for the 10 subjects was 38 Chilean million pesos (USD 72,869) with a mean of 7,286 USD per event. CONCLUSIONS: During one year, CR-BSI generated an excess in LOS, antimicrobial consumption, and costs (7,286 USD per event of CR-BSI). PMID- 26928500 TI - [Antimicrobial susceptibility patterns of Gram-negative bacteria isolated in urinary tract infections in Venezuela: Results of the SMART study 2009-2012]. AB - INTRODUCTION: Antimicrobial resistance of pathogens causing urinary tract infection (UTI) is a growing problem, which complicates their effective treatment. Surveillance is needed to guide appropriate empiric therapy. AIM: to describe the susceptibility patterns of Gram-negative bacteria isolated of patients with UTI to twelve antibiotics as part of the Study for Monitoring Antimicrobial Resistance Trends in Venezuela. MATERIALS AND METHODS: Between 2009 2012 a total of 472 Gram-negative bacteria were isolated from hospitalized patients with UTI. The isolates were sent to Central Laboratory (Central Laboratory of International Health Management Associates) to confirm their identification, and to make susceptibility testing as recommended by the Clinical and Laboratory Standards Institute. Enterobacteriacea comprised 96.6% of the total, where Escherichia coli (76.9%) and Klebsiella pneumoniae (10.6%) were the most frequent. Extended-spectrum beta-lactamases (ESBL) was detected in 21.6% of isolates. Top antimicrobial activity were ertapenem, imipenem, and amikacin (> 90.0%), slightly lower for amikacin (85.1%) in ESBL-producing strains. Resistance rates to fluoroquinolones and ampicillin/sulbactam were high (40 y 64%, respectively). CONCLUSIONS: These data suggest a necessary revision of the therapeutic regimens for the empirical treatment of UTI in Venezuela. PMID- 26928501 TI - [Enteric parasitic disease in children under 5 years of age, indigenous and non indigenous, from rural communities in Paraguay]. AB - BACKGROUND: Official figures of mortality in children under five years of age in the Americas, report that infectious and parasitic diseases caused most of the deaths. OBJECTIVE: To evaluate the frequency of intestinal parasites in vulnerable children, indigenous and non-indigenous, and their socio-environmental characteristics. PATIENTS AND METHODS: We evaluated 247 children under five years of age, of both sexes. Descriptive study with an analytical component, transverse cutting. Copro-parasitological examinations were carried out and semi-structured interviews to collect socio-demographic data were conducted. RESULTS: The frequency of intestinal parasitic diseases was 56.1% and 35.5% in indigenous and non-indigenous children, respectively. In both populations, the most common pathogens were Blastocystis hominis and Giardia lamblia. CONCLUSION: We found a high frequency of parasitism in indigenous children at the expense of protozoa. Non-indigenous children still present the same parasitic species found in previous studies, suggesting the need to implement more control and prevention. The poor conditions in which they live favor the development of these diseases. PMID- 26928502 TI - [Clinical and epidemiological aspects of toxoplasmosis in patients with vision problems]. AB - INTRODUCTION: Toxoplasmosis is a worldwide disease; it can cause decreased vision or even blindness. The route of transmission in humans may vary according to the habits of the region; probably the ingestion of raw or undercooked meat is the main source of infection. OBJECTIVE: To determine the seroprevalence of toxoplasmosis in an eye clinic, the frequency of ocular toxoplasmosis (OT) and risk habits for acquiring the infection. MATERIALS AND METHODS: Adult patients consulting in the Retina Department of the Teaching Hospital of the National University of Asuncion, Paraguay between August and September, 2014 were included. Prior informed consent, socio-demographic and epidemiological data related to T. gondii infection were obtained. In addition a blood sample for the determination of anti T. gondii IgG antibodies by the ELISA method was taken and ophthalmologic evaluation for the diagnosis of OT was made. RESULTS: A total of 80 patients with mean +/- SD age of 53 +/- 20 years were studied, with slight predominance of women (55%). The seroprevalence of toxoplasmosis was 84% (67/80) and OT was detected in 8.9% of the 67 seropositive persons. The habit of not washing vegetables with sodium hypochlorite and eat meat from wild animals was related to higher risk of infection in this population. CONCLUSION: It is important to conduct research at the population level to establish the epidemiology of toxoplasmosis in our country. Information on prophylactic measures to prevent infection by T. gondii should be given to the population. PMID- 26928503 TI - [Antigenemia and real time polymerase chain reaction for diagnosis of cytomegalovirus disease in HIV infected adults]. AB - BACKGROUND: Cytomegalovirus (CMV) infection is frequent in HIV adults. It is unknown usefulness of quantitative methods for diagnosing the CMV disease in Chilean patients. AIM: To determine the performance of antigenemia and real time polymerase chain reaction (rtPCR) in the diagnosis of CMV disease in Chilean HIV adults. METHOD: Detection of CMV by viral isolation (AVR), antigenemia and quantitative rtPCR in HIV adults. RESULTS: The 102 adults with suspected CMV disease had lower LTCD4 count and higher HIV viral load than 77 patients without suspicion (p < 0.05). Antigenemia and PCR were positive in 47 (46.1%) and 37 (36.3%) adults with clinical suspicion and in 2 (2.6%) and 4 (5.2%) of 77 without suspicion. The sensitivity, specificity, positive and negative predictive value of antigenemia and RPCtr were 92%, 80%, 72% and 95% and 72%, 95%, 92% and 80%, respectively. The cutoff values were >= lcell (+) and >= 5.5 log10 copies/2 x 10(6) cells. CMV was isolated in 6/179 patients (3.4%), all symptomatic. CONCLUSION: Positivity of antigenemia and rtPCR are similar for diagnosing CMV disease in Chilean HIV adults. AVR is inappropriate as a gold standard for its low performance. PMID- 26928504 TI - [Incidence of cancer in Chilean HIV-infected children]. AB - BACKGROUND: Pediatric HIV (+) patients have a 100 times greater risk of cancer than HIV (-) children. OBJECTIVE: To describe in Chilean HIV (+) children, cancer types, its appearance in relation to the stages of HIV disease and mortality. METHODS: A protocol was created to know some characteristics of these patients from the point of view of their HIV infection and cancer pathology. RESULTS: Of 360 HIV (+) children confirmed by the Institute of Public Health to May 2014, 9 patients with neoplastic disease (2.5%) were diagnosed. All the children were on ART, had more than three years of evolution of HIV infection and were in moderate to severe clinical/immunological stages. Lymphoma was the most common cancer. Five children, has received therapy according to Programa Infantil Nacional de Drogas Antineoplasicas (PINDA). There was no interaction between cancer treatment and antiretroviral therapy. Mortality was 13.8 x 1000 (5 cases). CONCLUSIONS: The incidence and type of neoplasia is consistent with the international literature, with less survival than HIV (+) children without tumors. The occurrence of cancer was observed in children with moderate to severe clinical and immunological compromise. PMID- 26928505 TI - [The challenge of controlling foodborne diseases: bacteriophages as a new biotechnological tool]. AB - Foodborne diseases are an increasing public health issue, in which bacterial pathogens have a transcendental role. To face this situation, the food industry has implemented several control strategies, using in the last decade some biotechnological tools, such as direct application of bacteriophages on food, to effectively control bacterial pathogens. Their bactericidal and safe properties to humans and animals have been widely described in the literature, being nowadays some bacteriophage-based products commercially available. Despite this, there are so many factors that can interfere in their biocontrol effectiveness on food, therefore is essential to consider these factors before their application. Thus, the optimal bacterial reduction will be achieved, which would produce a safer food. This review discusses some factors to consider in the use of bacteriophages as biocontrol agents of foodborne pathogens, including historical background, taxonomy and biological description of bacteriophages, and also advantages, disadvantages, and considerations of food applications. PMID- 26928506 TI - [Reference values of antistreptolysin O and asymptomatic carriers of beta hemolytic streptococci in adolescents and adults at Municipality Francisco Linares Alcantara, Venezuela]. AB - INTRODUCTION: beta-hemolytic streptococci (Streptococcus pyogenes) groups A, C or G, secretes streptolysin O, toxin which causes in the infected individual an adaptive humoral immune response with production of serum antibodies called anti streptolysin O (ASO). OBJECTIVES: To determine the reference value of ASO in a sample of 159 individuals aged 16-72 years from municipality Francisco Linares Alcantara, Aragua state, applying indirect (passive) agglutination test. By using a throat swab sample which was sown in blood agar 5% the frequency of asymptomatic carriers of beta-hemolytic streptococci was also determined. RESULTS AND DISCUSSION: As reference value for determining ASO by agglutination method a title of up to 200 IU/mL was obtained, this reference value differs from that recommended by the commercial equipment. Asymptomatic carriers frequency was 21.2% (n = 34). The distribution of beta-hemolytic streptococci isolated were: group A (17.6%), group B (32.3%), group C (20.5%), group D (2.9%), group F (8.8%), group G (14.7%) and unclusterable (2.9%). CONCLUSIONS: The new ASO reference value for teens and adults of the mentioned municipality is up to 200 IU/mL. beta-hemolytic Streptococcus group B was the most frequently isolated. PMID- 26928507 TI - [Human respiratory syncytial virus, genotype Ontario]. PMID- 26928508 TI - [A tribute to the gender: Devoted wives of intrepid investigators]. AB - Starting from the unfortunate words of Nobel Prize Tim Hunt about the presence of women in laboratories, we remember the stories of some devoted wives of intrepid investigators. Surely, more of someone, like Fanny Eilshemius or Mary Elizabeth Steele, never received the merited acknowledgement, working side by side with her husband in the house and in the lab; in a better stage, another one investigated as well as him, in the same or in a different field, like Mary Ethel Hayter Reed or Rebecca Craighill; and, finally and undoubtedly, most of them, being only simple housekeepers, like Emilie de La Salle, Win Warren or Adrienne Marshall, gave moral and kindly support to their men or... making an awful exception, betrayed these bored genius running away with an artist, with or without justification. PMID- 26928509 TI - [Inflammatory pseudotumor by Fasciola hepatica: a case report]. AB - INTRODUCTION: Fasciola hepatica is a parasite of the class Trematoda. It commonly has been found in developing countries. When it infects humans is characterized by a triad of fever, pain in right upper quadrant and peripheral eosinophilia. We present a 67-year-old female from a rural town of the north of Lima, Peru, it was found abdominal pain, eosinophilia and focal hepatic lesions. For this reason, a hepatic mass was the initial suspicion. The hepatic biopsy was performed and one of the findings was eosinophilia. Fasciola hepatica infection should be considered as part of differential diagnosis in hepatic tumors with eosinophilia when the origin of the patient is from endemic areas of F. hepatica. PMID- 26928510 TI - [Spondilodyscitis with medullary and spinal abscess caused by Bacillus Calmette Guerin (BCG)]. AB - Intravesical therapy with live-attenuated Mycobacterium bovis strain have demonstrated to be effective in the treatment of recurrent and high-grade superficial bladder tumors. The use of this therapy is widely extended; however spreading of bacillus from the injection site could be one rare complication that may cause infection in different locations. An appropriate anamnesis is very important to establish an etiological diagnostic of possible infections caused by M. bovis BCG. Laboratory diagnosis at species level is difficult because of the high genetic similarity (99.9%) with the other member of Mycobacterium tuberculosis complex. We present a case report who developed tuberculous spondylodiscitis by M. bovis BCG, which had a history of intravesical instillation for treatment of bladder cancer. PMID- 26928511 TI - [Study of hand carriage of potential pathogens by neonatal ICU healthcare personnel]. PMID- 26928512 TI - [WHO and UNAIDS call to control the epidemic of HIV/AIDS]. PMID- 26928514 TI - Relationship between leaf optical properties, chlorophyll fluorescence and pigment changes in senescing Acer saccharum leaves. AB - The ability of plants to sequester carbon is highly variable over the course of the year and reflects seasonal variation in photosynthetic efficiency. This seasonal variation is most prominent during autumn, when leaves of deciduous tree species such as sugar maple (Acer saccharum Marsh.) undergo senescence, which is associated with downregulation of photosynthesis and a change of leaf color. The remote sensing of leaf color by spectral reflectance measurements and digital repeat images is increasingly used to improve models of growing season length and seasonal variation in carbon sequestration. Vegetation indices derived from spectral reflectance measurements and digital repeat images might not adequately reflect photosynthetic efficiency of red-senescing tree species during autumn due to the changes in foliar pigment content associated with autumn phenology. In this study, we aimed to assess how effectively several widely used vegetation indices capture autumn phenology and reflect the changes in physiology and photosynthetic pigments during autumn. Chlorophyll fluorescence and pigment content of green, yellow, orange and red leaves were measured to represent leaf senescence during autumn and used as a reference to validate and compare vegetation indices derived from leaf-level spectral reflectance measurements and color analysis of digital images. Vegetation indices varied in their suitability to track the decrease of photosynthetic efficiency and chlorophyll content despite increasing anthocyanin content. Commonly used spectral reflectance indices such as the normalized difference vegetation index and photochemical reflectance index showed major constraints arising from a limited representation of gradual decreases in chlorophyll content and an influence of high foliar anthocyanin levels. The excess green index and green-red vegetation index were more suitable to assess the process of senescence. Similarly, digital image analysis revealed that vegetation indices such as Hue and normalized difference index are superior compared with the often-used green chromatic coordinate. We conclude that indices based on red and green color information generally represent autumn phenology most efficiently. PMID- 26928513 TI - Into the future with little past: exploring mental time travel in a patient with damage to the mammillary bodies/fornix. AB - OBJECTIVE: Remembering the past and imaging the future are both manifestations of 'mental time travel'. These processes have been found to be impaired in patients with bilateral hippocampal lesions. Here, we examined the question of whether future thinking is affected by other Papez circuit lesions, namely: damage to the mammillary bodies/fornix. METHOD: Case (SL) was a 43-year-old woman who developed dense anterograde and retrograde amnesia suddenly, as a result of Wernicke Korsakoff's syndrome. A region of interest volumetric Magnetic resonance imaging (MRI) analysis was performed. We assessed past and future thinking in SL and 11 control subjects of similar age and education with the adapted Autobiographical Interview (AI). Participants also completed a battery of neuropsychological tests. RESULTS: Volumetric MRI analyses revealed severely reduced fornix and mammillary body volumes, but intact hippocampi. SL showed substantial, albeit temporally graded retrograde memory deficits on the adapted AI. Strikingly, whilst SL could not provide any specific details of events from the past two weeks or past two years and had impaired recall of events from her late 30s, her descriptions of potential future events were normal in number of event details and plausibility. CONCLUSIONS: This dissociation of past and future events' performance after mammillary body and fornix damage is at odds with the findings of the majority of patients with adult onset hippocampal amnesia. It suggests that these non-hippocampal regions of the Papez circuit are only critical for past event retrieval and not for the generation of possible future events. PMID- 26928515 TI - High precision tracking control of a servo gantry with dynamic friction compensation. AB - This paper is concerned with the tracking control problem of a voice coil motor (VCM) actuated servo gantry system. By utilizing an adaptive control technique combined with a sliding mode approach, an adaptive sliding mode control (ASMC) law with friction compensation scheme is proposed in presence of both frictions and external disturbances. Based on the LuGre dynamic friction model, a dual observer structure is used to estimate the unmeasurable friction state, and an adaptive control law is synthesized to effectively handle the unknown friction model parameters as well as the bound of the disturbances. Moreover, the proposed control law is also implemented on a VCM servo gantry system for motion tracking. Simulations and experimental results demonstrate good tracking performance, which outperform traditional control approaches. PMID- 26928516 TI - Fractional active disturbance rejection control. AB - A fractional active disturbance rejection control (FADRC) scheme is proposed to improve the performance of commensurate linear fractional order systems (FOS) and the robust analysis shows that the controller is also applicable to incommensurate linear FOS control. In FADRC, the traditional extended states observer (ESO) is generalized to a fractional order extended states observer (FESO) by using the fractional calculus, and the tracking differentiator plus nonlinear state error feedback are replaced by a fractional proportional derivative controller. To simplify controller tuning, the linear bandwidth parameterization method has been adopted. The impacts of the observer bandwidth omegao and controller bandwidth omegac on system performance are then analyzed. Finally, the FADRC stability and frequency-domain characteristics for linear single-input single-output FOS are analyzed. Simulation results by FADRC and ADRC on typical FOS are compared to demonstrate the superiority and effectiveness of the proposed scheme. PMID- 26928517 TI - Robust disturbance rejection control of a biped robotic system using high-order extended state observer. AB - This study addressed the problem of robust control of a biped robot based on disturbance estimation. Active disturbance rejection control was the paradigm used for controlling the biped robot by direct active estimation. A robust controller was developed to implement disturbance cancelation based on a linear extended state observer of high gain class. A robust high-gain scheme was proposed for developing a state estimator of the biped robot despite poor knowledge of the plant and the presence of uncertainties. The estimated states provided by the state estimator were used to implement a feedback controller that was effective in actively rejecting the perturbations as well as forcing the trajectory tracking error to within a small vicinity of the origin. The theoretical convergence of the tracking error was proven using the Lyapunov theory. The controller was implemented by numerical simulations that showed the convergence of the tracking error. A comparison with a high-order sliding-mode observer-based controller confirmed the superior performance of the controller using the robust observer introduced in this study. Finally, the proposed controller was implemented on an actual biped robot using an embedded hardware-in the-loop strategy. PMID- 26928518 TI - Multi-thresholds for fault isolation in the presence of uncertainties. AB - Monitoring of the faults is an important task in mechatronics. It involves the detection and isolation of faults which are performed by using the residuals. These residuals represent numerical values that define certain intervals called thresholds. In fact, the fault is detected if the residuals exceed the thresholds. In addition, each considered fault must activate a unique set of residuals to be isolated. However, in the presence of uncertainties, false decisions can occur due to the low sensitivity of certain residuals towards faults. In this paper, an efficient approach to make decision on fault isolation in the presence of uncertainties is proposed. Based on the bond graph tool, the approach is developed in order to generate systematically the relations between residuals and faults. The generated relations allow the estimation of the minimum detectable and isolable fault values. The latter is used to calculate the thresholds of isolation for each residual. PMID- 26928519 TI - Impact of adenotonsillectomy on nocturnal enuresis in children with sleep disordered breathing: A prospective study. AB - OBJECTIVES/HYPOTHESIS: To investigate the relationship between sleep-disordered breathing (SDB) and nocturnal enuresis (NE) in children and to prospectively evaluate the effectiveness of adenotonsillectomy on resolving enuresis in indicated SDB patients with NE. METHODS: We prospectively collected data from 183 children (121 males, mean age 8.17 +/- 2.84 years) who underwent adenotonsillectomy to treat SDB between July 2011 and July 2013, and analyzed the prevalence of NE. Before and 3 months after surgery, all parents were requested to answer a self-reported SDB scale questionnaire (22 questions, 0-22 points) and a NE questionnaire (episodes of enuresis per month). Paired t test, Student t test, and Chi-square test were used to analyze the data. RESULTS: Overall prevalence of NE was 9.3% (17 patients) preoperatively and 1.5% postoperatively (four patients). After adenotonsillectomy, prevalence of NE and the mean SDB scale were significantly decreased (both P values < 0.001). After adenotonsillectomy, 13 of the 17 NE patients (76.5%) showed complete resolution. There was significantly higher prevalence of NE in patients with obstructive sleep apnea (OSA) than those without OSA (13.1%, 14 of 107 vs. 3.9%, 3 of 76; P = 0.036). CONCLUSION: There is strong association between NE and SDB, and adenotonsillectomy can markedly improve enuresis in the majority of children with NE and SDB. LEVELS OF EVIDENCE: 4. Laryngoscope, 126:1241-1245, 2016. PMID- 26928520 TI - Fever, palmoplantar pustules and oligoarthritis in a young woman. PMID- 26928521 TI - Five-year Antibody Persistence and Booster Response After 1 or 2 Doses of Meningococcal A, C, W and Y Tetanus Toxoid Conjugate Vaccine in Healthy Children. AB - BACKGROUND: We evaluated antibody persistence up to 5 years postvaccination with a quadrivalent meningococcal serogroups A, C, W and Y tetanus toxoid conjugate vaccine (MenACWY-TT), and subsequent booster responses to MenACWY-TT in healthy US children. METHODS: In the initial phase II, open, multicenter study (NCT00471081), 349 infants were randomized (1:1) to receive MenACWY-TT (1 or 2 doses). In the follow-up study (NCT00718666), we evaluated antibody persistence at years 1, 3 and 5 by serum bactericidal assay using human complement (hSBA). At year 5, children received a booster dose of MenACWY-TT. We compared their immune responses at 1 month postbooster with those from 100 age-matched, meningococcal naive children, who received a primary MenACWY-TT dose. We recorded solicited adverse events for 4 days and unsolicited adverse events for 31 days, followed by an additional 5-month extended safety follow-up. RESULTS: At year 5, >=64.0% of 1 dose and >=74.6% of 2-dose recipients had hSBA titers >=8 for MenC, MenW and MenY. For MenA, 31.7% of 1-dose and 38.0% of 2-dose recipients had hSBA titers >=8. One month postvaccination, all booster dose recipients and >=78.5% of primary dose recipients exhibited hSBA titers >=8 for all serogroups. Geometric mean titers were higher in primed than in naive children. MenACWY-TT had a clinically acceptable safety profile. CONCLUSIONS: With the exception of serogroup W, antibody persistence 5 years after MenACWY-TT vaccination did not differ substantially between children who received 1 or 2 doses in infancy. A booster dose of MenACWY-TT elicited robust anamnestic responses and was well tolerated. PMID- 26928522 TI - Sofosbuvir and Simeprevir Treatment of a Stem Cell Transplanted Teenager With Chronic Hepatitis C Infection. AB - There have been no previous reports on the use of interferon-free combinations in pediatric patients with chronic hepatitis C infection. An infected adolescent with severe sickle cell disease underwent stem cell transplantation and subsequent treatment with sofosbuvir and simeprevir during ongoing immunosuppression. Despite the emergence of peripheral edema as a side effect, treatment was continued with sustained antiviral response. PMID- 26928523 TI - Metabolomic Modeling To Monitor Host Responsiveness to Gut Microbiota Manipulation in the BTBR(T+tf/j) Mouse. AB - The microbiota, the entirety of microorganisms residing in the gut, is increasingly recognized as an environmental factor in the maintenance of health and the development of disease. The objective of this analysis was to model in vivo interactions between gut microbiota and both serum and liver metabolites. Different genotypic models (C57BL/6 and BTBR(T+tf/j) mice) were studied in combination with significant dietary manipulations (chow vs ketogenic diets) to perturb the gut microbiota. Diet rather than genotype was the primary driver of microbial changes, with the ketogenic diet diminishing total bacterial levels. Fecal but not cecal microbiota profiles were associated with the serum and liver metabolomes. Modeling metabolome-microbiota interactions showed fecal Clostridium leptum to have the greatest impact on host metabolism, significantly correlating with 10 circulating metabolites, including 5 metabolites that did not correlate with any other microbes. C. leptum correlated negatively with serum ketones and positively with glucose and glutamine. Interestingly, microbial groups most strongly correlated with host metabolism were those modulating gut barrier function, the primary site of microbe-host interactions. These results show very robust relationships and provide a basis for future work wherein the compositional and functional associations of the microbiome can be modeled in the context of the metabolome. PMID- 26928524 TI - Intracranial extension of orbital inflammatory pseudotumor: a case report and literature review. AB - BACKGROUND: Orbital inflammatory pseudotumor is a rare inflammatory condition of unknown cause that may extend intracranially, usually as a dural-based infiltrate. Here we report the first case of orbital pseudotumor presenting with intra-axial Magnetic Resonance Imaging (MRI) changes. CASE PRESENTATION: A 57 year-old white female, with a 3-month history of headache and right palpebral edema, presented with marked right temporal lobe edema with ominous MRI appearance, and ipsilateral alterations of orbital and periorbital structures. Following steroid therapy, both intracranial and orbital involvement dramatically improved. CONCLUSION: Orbital inflammatory pseudotumor with chronic inflammation may infrequently present with intracranial involvement, mimicking more aggressive diseases, even showing intra-axial enhancement after i.v. contrast administration in brain MRI. Awareness of this possibility may help neurologists to choose the appropriate therapeutic approach. PMID- 26928525 TI - Using an Old Drug to Target a New Drug Site: Application of Disulfiram to Target the Zn-Site in HCV NS5A Protein. AB - In viral proteins, labile Zn-sites, where Zn(2+) is crucial for maintaining the native protein structure but the Zn-bound cysteines are reactive, are promising drug targets. Here, we aim to (i) identify labile Zn-sites in viral proteins using guidelines established from our previous work and (ii) assess if clinically safe Zn-ejecting agents could eject Zn(2+) from the predicted target site and thus inhibit viral replication. As proof-of-concept, we identified a labile Zn site in the hepatitis C virus (HCV) NS5A protein and showed that the antialcoholism drug, disulfiram, could inhibit HCV replication to a similar extent as the clinically used antiviral agent, ribavirin. The discovery of a novel viral target and a new role for disulfiram in inhibiting HCV replication will enhance the therapeutic armamentarium against HCV. The strategy presented can also be applied to identify labile sites in other bacterial or viral proteins that can be targeted by disulfiram or other clinically safe Zn-ejectors. PMID- 26928526 TI - Fecundity regulation by atresia in turbot Scophthalmus maximus in the Baltic Sea. AB - Down-regulation of fecundity through oocyte resorption was assessed in Baltic Sea turbot Scophthalmus maximus at three locations in the period from late vitellogenesis in April to spawning during June to July. The mean +/- s.d. total length of the sampled fish was 32.7 +/- 3.1 cm and mean +/- s.d. age was 6.2 +/- 1.5 years. Measurements of atresia were performed using the 'profile method' with the intensity of atresia adjusted according to the 'dissector method' (10.6% adjustment; coefficient of determination was 0.675 between methods). Both prevalence (portion of fish with atresia) and intensity (calculated as the average proportion of atretic cells in fish displaying atresia) of atresia were low in prespawning fish, but high from onset of spawning throughout the spawning period. Atretic oocytes categorized as in early alpha and in late alpha state occurred irrespective of maturity stage from late prespawning individuals up to late spawning fish, showing that oocytes may become atretic throughout the spawning period. Observed prevalence of atresia throughout the spawning period was almost 40% with an intensity of c. 20%. This indicates extensive down regulation, i.e. considerably lower realized (number of eggs spawned) v. potential fecundity (number of developing oocytes), suggesting significant variability in reproductive potential. The extent of fecundity regulation in relation to fish condition (Fulton's condition factor) is discussed, suggesting an association between levels of atresia and fish condition. PMID- 26928527 TI - Drastic underestimation of amphipod biodiversity in the endangered Irano Anatolian and Caucasus biodiversity hotspots. AB - Biodiversity hotspots are centers of biological diversity and particularly threatened by anthropogenic activities. Their true magnitude of species diversity and endemism, however, is still largely unknown as species diversity is traditionally assessed using morphological descriptions only, thereby ignoring cryptic species. This directly limits evidence-based monitoring and management strategies. Here we used molecular species delimitation methods to quantify cryptic diversity of the montane amphipods in the Irano-Anatolian and Caucasus biodiversity hotspots. Amphipods are ecosystem engineers in rivers and lakes. Species diversity was assessed by analysing two genetic markers (mitochondrial COI and nuclear 28S rDNA), compared with morphological assignments. Our results unambiguously demonstrate that species diversity and endemism is dramatically underestimated, with 42 genetically identified freshwater species in only five reported morphospecies. Over 90% of the newly recovered species cluster inside Gammarus komareki and G. lacustris; 69% of the recovered species comprise narrow range endemics. Amphipod biodiversity is drastically underestimated for the studied regions. Thus, the risk of biodiversity loss is significantly greater than currently inferred as most endangered species remain unrecognized and/or are only found locally. Integrative application of genetic assessments in monitoring programs will help to understand the true magnitude of biodiversity and accurately evaluate its threat status. PMID- 26928528 TI - SOD1 nanozyme with reduced toxicity and MPS accumulation. AB - We previously developed a "cage"-like nano-formulation (nanozyme) for copper/Zinc superoxide dismutase (SOD1) by polyion condensation with a conventional block copolymer poly(ethylene glycol)-b-poly(L-lysine) (PEG-PLL) followed by chemical cross-linking. Herein we report a new SOD1 nanozyme based on PEG-b-poly(aspartate diethyltriamine) (PEG-PAsp(DET), or PEG-DET for short) engineered for chronic dosing. This new nanozyme was spherical (Rg/Rh=0.785), and hollow (60% water composition) nanoparticles with colloidal properties similar to PLL-based nanozyme. It was better tolerated by brain microvessel endothelial/neuronal cells, and accumulated less in the liver and spleen. This formulation reduced the infarct volumes by more than 50% in a mouse model of ischemic stroke. However, it was not effective at preventing neuromuscular junction denervation in a mutant SOD1(G93A) mouse model of amyotrophic lateral sclerosis (ALS). To our knowledge, this work is the first report of using PEG-DET for protein delivery and a direct comparison between two cationic block copolymers demonstrating the effect of polymer structure in modulating the mononuclear phagocyte system (MPS) accumulation of polyion complexes. PMID- 26928529 TI - Injectable polypeptide micelles that form radiation crosslinked hydrogels in situ for intratumoral radiotherapy. AB - Intratumoral radiation therapy - 'brachytherapy' - is a highly effective treatment for solid tumors, particularly prostate cancer. Current titanium seed implants, however, are permanent and are limited in clinical application to indolent malignancies of low- to intermediate-risk. Attempts to develop polymeric alternatives, however, have been plagued by poor retention and off-target toxicity due to degradation. Herein, we report on a new approach whereby thermally sensitive micelles composed of an elastin-like polypeptide (ELP) are labeled with the radionuclide (131)I to form an in situ hydrogel that is stabilized by two independent mechanisms: first, body heat triggers the radioactive ELP micelles to rapidly phase transition into an insoluble, viscous coacervate in under 2 min; second, the high energy beta-emissions of (131)I further stabilize the depot by introducing crosslinks within the ELP depot over 24h. These injectable brachytherapy hydrogels were used to treat two aggressive orthotopic tumor models in athymic nude mice: a human PC-3 M-luc-C6 prostate tumor and a human BxPc3-luc2 pancreatic tumor model. The ELP depots retained greater than 52% and 70% of their radioactivity through 60 days in the prostate and pancreatic tumors with no appreciable radioactive accumulation (<= 0.1% ID) in off-target tissues after 72h. The (131)I-ELP depots achieved >95% tumor regression in the prostate tumors (n=8); with a median survival of more than 60 days compared to 12 days for control mice. For the pancreatic tumors, ELP brachytherapy (n=6) induced significant growth inhibition (p=0.001, ANOVA) and enhanced median survival to 27 days over controls. PMID- 26928530 TI - Combining disulfiram and poly(l-glutamic acid)-cisplatin conjugates for combating cisplatin resistance. AB - A poly(l-glutamic acid) graft polyethylene glycol-cisplatin complex (PGA-CisPt) performs well in reducing the toxicity of free cisplatin and greatly enhances the accumulation and retention of cisplatin in solid tumors. However, there is a lack of effective treatment options for cisplatin-resistant tumors. A major reason for this is the dense PEG shell, which ensures that the PGA-CisPt maintains a long retention time in the blood that may result in it bypassing the tumor cells or failing to be endocytosed within the tumor microenvironment. Consequently, the cisplatin from PGA-CisPt is released to the extracellular space in the presence of cisplatin-resistant tumor cells and the resistant problem to free cisplatin still valid. Therefore, we devised a strategy to combat the resistance of cisplatin in the tumor microenvironment using nanoparticles-loaded disulfiram (NPs-DSF) as a modulator. In vitro, cisplatin, in combination with DSF, had a synergistic effect and decreased cell survival rate of cisplatin-resistant A549DDP cells. This effect was also observed when combining PGA-CisPt with NPs DSF. Similarly, in Balb/C nude mice with A549DDP xenografts, NPs-DSF improved PGA CisPt effectiveness in inhibiting tumor growth while maintaining low toxicity. Our data demonstrate that DSF reduces intracellular glutathione (GSH) levels, inhibits NFkappaB activity, and modulates the expression of apoptosis-related proteins Bcl-2 and Bax, thereby improves the effectiveness of cisplatin in resistant cell lines. Here, we provide a promising method for overcoming cisplatin resistance in tumors, while maintaining the in vivo benefits of the PGA CisPt complex. PMID- 26928531 TI - conSSert: Consensus SVM Model for Accurate Prediction of Ordered Secondary Structure. AB - Accurate prediction of protein secondary structure remains a crucial step in most approaches to the protein-folding problem, yet the prediction of ordered secondary structure, specifically beta-strands, remains a challenge. We developed a consensus secondary structure prediction method, conSSert, which is based on support vector machines (SVM) and provides exceptional accuracy for the prediction of beta-strands with QE accuracy of over 0.82 and a Q2-EH of 0.86. conSSert uses as input probabilities for the three types of secondary structure (helix, strand, and coil) that are predicted by four top performing methods: PSSpred, PSIPRED, SPINE-X, and RAPTOR. conSSert was trained/tested using 4261 protein chains from PDBSelect25, and 8632 chains from PISCES. Further validation was performed using targets from CASP9, CASP10, and CASP11. Our data suggest that poor performance in strand prediction is likely a result of training bias and not solely due to the nonlocal nature of beta-sheet contacts. conSSert is freely available for noncommercial use as a webservice: http://ares.tamu.edu/conSSert/. PMID- 26928532 TI - Light-Induced Synthesis of Heterojunctioned Nanoparticles on a Semiconductor as Durable Cocatalysts for Hydrogen Evolution. AB - This work attempted to synthesize heterojunctioned nanoparticles consisting of a transition metal and Cr on powdered SrTiO3, an n-type semiconductor exhibiting photocatalytic activity for overall water splitting. This was performed via band gap irradiation of SrTiO3 (lambda > 300 nm) in an aqueous methanol solution containing a transition metal precursor and K2CrO4. The resulting multicomponent nanoparticles were examined as promoters for photocatalytic overall water splitting. Among the transition metals examined, Au and Pd became effective promoters for overall water splitting upon codeposition of Cr. In the case of Au, which is stable in its metallic state, the resulting (Au+Cr) nanoparticles had a core/shell structure consisting of metallic Au (the core) and amorphous Cr2O3 (the shell), similar to Au/Cr2O3 prepared by a stepwise photodeposition method. However, when using a core transition metal with a tendency to form an oxide, such as Pd, the nanoparticles had different morphologies and electronic states, depending on the proportion of Cr. In the case of a combination of Pd and Cr, the photocatalytic activity for overall water splitting was strongly dependent on the structure and electronic state of the (Pd+Cr) multicomponent cocatalyst. Increasing the proportion of Cr was found to suppress the reverse reaction (that is, H2-O2 recombination), an effect that is not realized when employing a conventional impregnation method. PMID- 26928533 TI - Clinical course of patients with incidental finding of 20q- in the bone marrow without a morphologic evidence of myeloid neoplasm. AB - Deletion of the long arm of chromosome 20 (20q-) is a frequent finding in bone marrow karyotypes, mainly associated with myeloid neoplasms (MNs). Its clinical significance in the setting of normal bone marrow morphology is unclear. We described the clinical characteristics, cytogenetic findings, and outcome of 102 such patients seen at our institution from 2000-2014. Their median age was 66 years. The indication for bone marrow biopsy was either unexplained cytopenias (48%) or hematologic cancer staging/reevaluation (52%). In 88 (86%) patients, 20q was an isolated finding. Thirty-nine (38%) patients previously received chemotherapy and 88 (86%) had cytopenias at the time of 20q- finding. After a median of 35 months, 12 (13%) patients developed MNs: 10 myelodysplastic syndromes, one acute myeloid leukemia and one myeloproliferative neoplasm. None of 14 patients with normal blood counts, but 7 of 35 (20%) with mild cytopenias, and 5 of 53 (9%) with moderate/severe cytopenias developed MNs. We did not find an association between the number of metaphases with 20q- and the development of MN. The incidental finding of 20q- in the bone marrow generally does not portend an early stage MN. Particularly, those without cytopenias at the time of diagnosis may have a good prognosis. Am. J. Hematol. 91:556-559, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26928534 TI - Interconversion between Methoxylated and Hydroxylated Polychlorinated Biphenyls in Rice Plants: An Important but Overlooked Metabolic Pathway. AB - To date, there is limited knowledge on the methoxylation of polychlorinated biphenyls (PCBs) and the relationship between hydroxylated polychlorinated biphenyls (OH-PCBs) and methoxylated polychlorinated biphenyls (MeO-PCBs) in organisms. In this study, rice (Oryza sativa L.) was chosen as the model organism to determine the metabolism of PCBs in plants. Limited para-substituted 4'-OH-CB 61 (major metabolite) and 4'-MeO-CB-61 (minor metabolite) were found after a 5 day exposure to CB-61, while ortho- and meta-substituted products were not detected. Interconversion between OH-PCBs and MeO-PCBs in organisms was observed for the first time. The demethylation ratio of 4'-MeO-CB-61 was 18 times higher than the methylation ratio of 4'-OH-CB-61, indicating that formation of OH-PCBs was easier than formation of MeO-PCBs. The transformation products were generated in the roots after 24 h of exposure. The results of in vivo and in vitro exposure studies show that the rice itself played a key role in the whole transformation processes, while endophytes were jointly responsible for hydroxylation of PCBs and demethylation of MeO-PCBs. Metabolic pathways of PCBs, OH-PCBs, and MeO-PCBs in intact rice plants are proposed. The findings are important in understanding the fate of PCBs and the source of OH-PCBs in the environment. PMID- 26928536 TI - Localization and signaling of GPCRs in lipid rafts. AB - The understanding of how biological membranes are organized and how they function has evolved. Instead of just serving as a medium in which certain proteins are found, portions of the lipid bilayer have been demonstrated to form specialized platforms that foster the assembly of signaling complexes by providing a microenvironment that is conducive for effective protein-protein interactions. G protein-coupled receptors (GPCRs) and relevant signaling molecules, including the heterotrimeric G proteins, key enzymes such as kinases and phosphatases, trafficking proteins, and secondary messengers, preferentially partition to these highly organized cell membrane microdomains, called lipid rafts. As such, lipid rafts are crucial for the trafficking and signaling of GPCRs. The study of GPCR biology in the context of lipid rafts involves the localization of the GPCR of interest in lipid rafts, at the basal state and upon receptor agonism, and the evaluation of the biological functions of the GPCR in appropriate cell lines. The lack of standardized methodology to study lipid rafts, in general, and of the workings of GPCRs in lipid rafts, in particular, and the inherent drawbacks of current methods have hampered the complete understanding of the underlying molecular mechanisms. Newer methodologies that allow the study of GPCRs in their native form are needed. The use of complementary approaches that produce mutually supportive results appear to be the best way for drawing conclusions with regards to the distribution and activity of GPCRs in lipid rafts. PMID- 26928535 TI - Liver biochemistry and associations with alcohol intake, hepatitis B virus infection and Inuit ethnicity: a population-based comparative epidemiological survey in Greenland and Denmark. AB - BACKGROUND: Hepatitis B virus (HBV) infection is common in Arctic populations and high alcohol intake has been associated with an increased risk of a number of diseases. Yet, a description of the influence of alcohol intake in persons with HBV infection on liver biochemistry is lacking. OBJECTIVE: We aimed to describe the association between reported alcohol intake and liver biochemistry taking into account also HBV infection, ethnicity, Inuit diet, body mass index (BMI), gender and age in an Arctic population. DESIGN AND METHODS: Population-based investigation of Inuit (n=441) and non-Inuit (94) in Greenland and Inuit living in Denmark (n=136). Participants filled in a questionnaire on alcohol intake and other life style factors. Blood samples were tested for aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP), bilirubin, albumin, hepatitis B surface antigen, hepatitis B surface antibody and hepatitis B core antibody. We also performed physical examinations. RESULTS: Participation rate was 95% in Greenland and 52% in Denmark. An alcohol intake above the recommended level was reported by 12.9% of non-Inuit in Greenland, 9.1% of Inuit in East Greenland, 6.1% of Inuit migrants and 3.4% of Inuit in the capital of Greenland (p=0.035). Alcohol intake was associated with AST (p<0.001) and GGT (p=0.001), and HBV infection was associated with ALP (p=0.001) but not with AST, GGT, bilirubin or albumin in the adjusted analysis. Inuit had higher AST (p<0.001), GGT (p<0.001) and ALP (p=0.001) values than non Inuit after adjustment for alcohol, diet, BMI and HBV exposure. Ethnic origin modified the association between alcohol and AST, while HBV infection did not modify the associations between alcohol and liver biochemistry. CONCLUSIONS: Non Inuit in Greenland reported a higher alcohol intake than Inuit. Ethnic origin was more markedly associated with liver biochemistry than was alcohol intake, and Greenlandic ethnicity modified the effect of alcohol intake on AST. HBV infection was slightly associated with ALP but not with other liver biochemistry parameters. PMID- 26928538 TI - Trafficking of ciliary G protein-coupled receptors. AB - In the last decade highly conserved cellular appendages called cilia have enjoyed a renewed interest from basic, biomedical scientists, and clinicians alike. This interest has grown upon the elucidation that cilia throughout the body serve as important sensory and signaling centers in both development and adult homeostasis. Furthermore, the identification of several rare genetic disorders associated with cilia dysfunction has broadened the field. However, even though their potential role in human health and disease is now recognized many basic questions about their functions remain. This chapter seeks to explore the trafficking of cilia-specific G protein-coupled receptors (GPCRs) and discusses several model systems in which this has been explored. We open the chapter by briefly discussing cilia and GPCRs then begin discussing some aspects of rhodopsin trafficking, arguably the most well studied of cilia GPCRs. We continue with sections on neuronal cilia and olfactory cilia receptor trafficking. Finally, we conclude with the emerging area of dynamic ciliary GPCR trafficking and speculate about future directions and some of the questions that remain for ciliary GPCRs. PMID- 26928537 TI - Imaging GPCRs trafficking and signaling with total internal reflection fluorescence microscopy in cultured neurons. AB - Total internal reflection fluorescence (TIRF) microscopy allows probing the cellular events occurring close and at the plasma membrane. Over the last decade, we have seen a significant increase in the number of publications applying TIRF microscopy to unravel some of the fundamental biological questions regarding G protein-coupled receptors (GPCRs) function such as the mechanisms controlling receptor trafficking, quaternary structure, and signaling among others. Most of the published work has been performed in heterologous systems such as HEK293 and CHO cells, where the imaging surface available is higher and smoother when compared with the narrow processes or the smaller cell bodies of neurons. However, some publications have expanded our understanding of these events to primary cell cultures, mostly rat hippocampal and striatal neuronal cultures. Results from these cells provide a bona fide model of the complex events controlling GPCR function in living cells. We believe more work needs to be performed in primary cultures and eventually in intact tissue to complement the knowledge obtained from heterologous cell models. Here, we described a step-by step protocol to investigate the surface trafficking and signaling from GPCRs in rat hippocampal and striatal primary cultures. PMID- 26928539 TI - Single-molecule resolution of G protein-coupled receptor (GPCR) complexes. AB - The organization of G protein-coupled receptors (GPCRs) into dimers and higher order oligomers has provided a potential mechanistic system in defining complex GPCR responses. Despite being studied for nearly 20 years it has, and still is, been an area of controversy. Although technology has developed to quantitatively measure these associations in real time, identify the structural interfaces and even systems to understand the physiological significance of di/oligomerization, key questions remain outstanding including the role of each individual complex from the monomer to the higher-order oligomer, in their native system. Recently, single-molecule microscopy approaches have provided the tools to directly visualize individual GPCRs in dimers and oligomers, though as with any technological development each have their advantages and limitations. This chapter will describe these recent developments in single-molecule fluorescent microscopy, focusing on our recent application of super-resolution imaging of the GPCR for the luteinizing hormone/chorionic gonadotropin to quantify GPCR monomers and formation of protomers in to dimers and distinct oligomeric forms. We present our approach, considerations, strategy, and challenges to visualize this receptor beyond the light diffraction limit via photoactivated localization microscopy with photoactivatable dyes. The addition of super-resolution approaches to the GPCR "nano-tool kit" will pave the way for novel avenues to answer outstanding questions regarding the existence and significance of these complexes to GPCR signaling. PMID- 26928540 TI - Quantification of the mRNA expression of G protein-coupled receptors in human adipose tissue. AB - G protein-coupled receptors (GPCRs) are important regulators of human physiology and therefore the targets of a large number of modern therapeutics. Although GPCRs are important regulators of adipose tissue endocrine and energy storage functions, the expression and function of a majority of GPCRs in adipose tissue is poorly characterized. A first step in the functional characterization of adipose tissue GPCRs is to accurately quantify the expression of GPCRs in adipose tissue. In this methods chapter, a detailed, step-by-step protocol is presented for the isolation of adipose tissue total RNA, its conversion into cDNA and the real-time PCR quantification of human GPCR mRNA expression relative to the mRNA expression of the stable adipose tissue housekeeping gene peptidylprolyl isomerase A (PPIA). A comprehensive list of 377 manually validated, commercially available GPCR qPCR primers allows facilitated swift quantification of either the entire human GPCRome or individual GPCRs, thus providing a sensitive, flexible, and cost-effective means of determining the mRNA expression of GPCRs in adipose tissue. PMID- 26928541 TI - Studying the regulation of endosomal cAMP production in GPCR signaling. AB - We describe methods based on live cell fluorescent microscopy and mass spectrometry to characterize the mechanism of endosomal cAMP production and its regulation using the parathyroid hormone (PTH) type 1 receptor as a prime example. These methods permit to measure rapid changes of cAMP levels in response to PTH, kinetics of endosomal ligand-receptor interaction, pH changes associated with receptor trafficking, and to identify the endosomal receptor interactome. PMID- 26928542 TI - Olfactory receptor signaling. AB - The guanine nucleotide protein (G protein)-coupled receptors (GPCRs) superfamily represents the largest class of membrane protein in the human genome. More than a half of all GPCRs are dedicated to interact with odorants and are termed odorant receptors (ORs). Linda Buck and Richard Axel, the Nobel Prize laureates in physiology or medicine in 2004, first cloned and characterized the gene family that encode ORs, establishing the foundations to the understanding of the molecular basis for odor recognition. In the last decades, a lot of progress has been done to unravel the functioning of the sense of smell. This chapter gives a general overview of the topic of olfactory receptor signaling and reviews recent advances in this field. PMID- 26928543 TI - Assessing Smoothened-mediated Hedgehog signaling in zebrafish. AB - Smoothened belongs to the class of atypical G protein-coupled receptors and serves as the transducing molecule in Hedgehog (Hh) signaling. Hh proteins comprise a family of secreted, cholesterol-modified ligands, which act both as morphogens and as signaling molecules. Binding of Hh proteins to their direct receptor, the transmembrane protein Patched-1, relieves Smoothened from tonal inhibition by Patched-1 and causes the translocation of Smoothened into the cilium. Here, the Hh signaling cascade is initiated and results in transcriptional activation of Hh target genes such as gli1 or patched-1. This induces a plethora of physiological outcomes including normal embryonic development, but also cancer, which is the reason why scientists aim to develop strategies to manipulate as well as monitor Smoothened-mediated Hh signaling. The zebrafish has emerged as a valuable tool for the assessment of Smoothened mediated Hh signaling. In this chapter we thus describe how Smoothened-mediated Hh signaling can be monitored and also quantified using zebrafish embryos. PMID- 26928544 TI - GPCRs and actin-cytoskeleton dynamics. AB - A multitude of physiological processes regulated by G protein-coupled receptors (GPCRs) signaling are accomplished by the participation of active rearrangements of the cytoskeleton. In general, it is common that a cross talk occurs among networks of microfilaments, microtubules, and intermediate filaments in order to reach specific cell responses. In particular, actin-cytoskeleton dynamics regulate processes such as cell shape, cell division, cell motility, and cell polarization, among others. This chapter describes the current knowledge about the regulation of actin-cytoskeleton dynamic by diverse GPCR signaling pathways, and also includes some protocols combining immunofluorescence and confocal microscopy for the visualization of the different rearrangements of the actin cytoskeleton. We report how both the S1P-GPCR/G12/13/Rho/ROCK and glucagon GPCR/Gs/cAMP axes induce differential actin-cytoskeleton rearrangements in epithelial cells. We also show that specific actin-binding molecules, like phalloidin and LifeAct, are very useful to analyze F-actin reorganization by confocal microscopy, and also that both molecules show similar results in fixed cells, whereas the anti-actin antibody is useful to detect both the G- and F actin, as well as their compartmentalization. Thus, it is highly recommended to utilize different approaches to investigate the regulation of actin dynamics by GPCR signaling, with the aim to get a better picture of the phenomenon under study. PMID- 26928545 TI - GPCR-radioligand binding assays. AB - Radioligand binding assays provide sensitive and quantitative information about guanine nucleotide protein G protein-coupled receptor (GPCR) expression and affinity for a wide variety of ligands, making them essential for drug structure activity studies and basic GPCR research. Three basic radioligand binding protocols, saturation, indirect (competition, displacement, or modulation), and kinetic binding assays, are used to assess GPCR expression (Bmax), equilibrium dissociation constants for radioligands (Kd) and nonradioactive ligands (Ki), association and dissociation rates, and to distinguish competitive and allosteric mechanisms of GPCR-ligand interactions. Nonspecific radioligand binding may be mitigated by appropriate choices of reaction conditions. Radioligand depletion (bound radioactivity >10% of total radioligand), which compromises accuracy of Kd and Ki measurements, can be limited by adjusting receptor concentration and appropriate radioligand choice. Accurate Kd and Ki values in saturation and indirect binding assays depend on binding equilibrium. Equilibration time for high-affinity ligands, with slow dissociation rates, may require much extended incubation times or increased incubation temperature. PMID- 26928546 TI - Tracking GPCR biosynthesis and degradation using a nonradioactive pulse chase methodology. AB - The beta2-adrenergic receptor (beta2AR) is a prototypical member of the G protein coupled receptor (GPCR) superfamily of proteins and is one of the best characterized GPCRs due to its role in several important physiological systems. Because of limited availability of high quality antibodies against GPCRs, much of the work done on beta2AR took advantage of heterologous expression systems. Overexpressed proteins may overwhelm the cellular regulatory machinery leading potentially to responses distinct from the native protein. To address this issue we generated a stable cell line with a tetracycline-inducible beta2AR tagged with a FLAG epitope, such that we are able to control the quantity of receptor produced. This allows us to induce a discrete pulse of FLAG-beta2AR transcription and translation allowing us to follow the complete life cycle of the protein from synthesis as an immature protein to degradation. We show that such limited pulses of receptor expression lead to signaling phenotypes that more closely reflect endogenous signaling events. PMID- 26928547 TI - Tango assay for ligand-induced GPCR-beta-arrestin2 interaction: Application in drug discovery. AB - G protein-coupled receptors (GPCRs) are widely known to modulate almost all physiological functions and have been demonstrated over the time as therapeutic targets for wide gamut of diseases. The design and implementation of high throughput GPCR-based assays that permit the efficient screening of large compound libraries to discover novel drug candidates are essential for a successful drug discovery endeavor. Usually, GPCR-based functional assays depend primarily on the measurement of G protein-mediated second messenger generation. However, with advent of advanced molecular biology tools and increased understanding of GPCR signal transduction, many G protein-independent pathways such as beta-arrestin translocation are being utilized to detect the activity of GPCRs. These assays provide additional information on functional selectivity (also known as biased agonism) of compounds that could be harnessed to develop pathway-selective drug candidates to reduce the adverse effects associated with given GPCR target. In this chapter, we describe the basic principle, detailed methodologies and assay setup, result analysis and data interpretations of the beta-arrestin2 Tango assay, and its comparison with cell-based G protein dependent GPCR assays, which could be employed in a simple academic setup to facilitate GPCR-based drug discovery. PMID- 26928548 TI - Resonance Energy Transfer-Based Approaches to Study GPCRs. AB - Since their discovery, G protein-coupled receptors (GPCRs) constitute one of the most studied proteins leading to important discoveries and perspectives in terms of their biology and implication in physiology and pathophysiology. This is mostly linked to the remarkable advances in the development and application of the biophysical resonance energy transfer (RET)-based approaches, including bioluminescence and fluorescence resonance energy transfer (BRET and FRET, respectively). Indeed, BRET and FRET have been extensively applied to study different aspects of GPCR functioning such as their activation and regulation either statically or dynamically, in real-time and intact cells. Consequently, our view on GPCRs has considerably changed opening new challenges for the study of GPCRs in their native tissues in the aim to get more knowledge on how these receptors control the biological responses. Moreover, the technological aspect of this field of research promises further developments for robust and reliable new RET-based assays that may be compatible with high-throughput screening as well as drug discovery programs. PMID- 26928549 TI - Quantitative analysis of G-protein-coupled receptor internalization using DnaE intein-based assay. AB - G-protein-coupled receptors (GPCRs), the largest family of cell surface receptors, are involved in many physiological processes. They represent highly important therapeutic targets for drug discovery. Currently, there are numerous cell-based assays developed for the pharmacological profiling of GPCRs and the identification of novel agonists and antagonists. However, the development of new, faster, easier, and more cost-effective approaches to detect GPCR activity remains highly desirable. beta-arrestin-dependent internalization has been demonstrated to be a common mechanism for most GPCRs. Here we describe a novel assay for quantitative analysis of GPCR internalization based on DnaE intein mediated reconstitution of fragmented Renilla luciferase or Firefly luciferase when activated GPCRs interact with beta-arrestin2 or Rab5. Further validation, using functionally divergent GPCRs, showed that EC50 values obtained for the known agonists and antagonists were in close agreement with the results of previous reports. This suggests that this assay is sensitive enough to permit quantification of GPCR internalization. Compared with conventional assays, this novel assay system is cost-effective, rapid, and easy to manipulate. These advantages may allow this assay to be used universally as a functional cell-based system for GPCR characterization and in the screening process of drug discovery. PMID- 26928550 TI - Cellular and subcellular context determine outputs from signaling biosensors. AB - The use of biosensors either individually or as part of panels has now become a common technique to capturing signaling events in living cells. Such biosensors have become particularly important for probing biased signaling and allostery in G protein-coupled receptor drug screening efforts. However, assumptions about the portability of such biosensors between cell types may lead to misinterpretation of drug effects on specific signaling pathways in a given cellular context. Further, the output of a particular biosensor may be different depending on where it is localized in a cell. Here, we discuss strategies to mitigate these concerns which should feed into future biosensor design and usage. PMID- 26928551 TI - Protease-activated receptors (PARs) in cancer: Novel biased signaling and targets for therapy. AB - Despite the fact that G protein-coupled receptors (GPCRs) mediate numerous physiological processes and represent targets for therapeutics for a vast array of diseases, their role in tumor biology is under appreciated. Protease-activated receptors (PARs) form a family which belongs to GPCR class A. PAR1&2 emerge with a central role in epithelial malignancies. Although the part of PAR1&2 in cancer is on the rise, their underlying signaling events are poorly understood. We review hereby past, present, and future cancer-associated PAR biology. Mainly, their role in physiological (placenta-cytotophobalst) and patho-physiological invasion processes. The identification and characterization of signal pleckstrin homology (PH)-domain-binding motifs established critical sites for breast cancer growth in PAR1&2. Among the proteins found to harbor important PH-domains and are involved in PAR biology are Akt/PKB as also Etk/Bmx and Vav3. A point mutation in PAR2, H349A, but not R352A, abrogated PH-protein association and is sufficient to markedly reduce PAR2-instigated breast tumor growth in vivo as also placental extravillous trophoblast (EVT) invasion in vitro is markedly reduced. Similarly, the PAR1 mutant hPar1-7A, which is unable to bind PH-domain, inhibits mammary tumors and EVT invasion, endowing these motifs with physiological significance and underscoring the importance of these previously unknown PAR1 and PAR2 PH domain-binding motifs in both pathological and physiological invasion processes. PMID- 26928552 TI - Computational methods for studying G protein-coupled receptors (GPCRs). AB - The functioning of GPCRs is classically described by the ternary complex model as the interplay of three basic components: a receptor, an agonist, and a G protein. According to this model, receptor activation results from an interaction with an agonist, which translates into the activation of a particular G protein in the intracellular compartment that, in turn, is able to initiate particular signaling cascades. Extensive studies on GPCRs have led to new findings which open unexplored and exciting possibilities for drug design and safer and more effective treatments with GPCR targeting drugs. These include discovery of novel signaling mechanisms such as ligand promiscuity resulting in multitarget ligands and signaling cross-talks, allosteric modulation, biased agonism, and formation of receptor homo- and heterodimers and oligomers which can be efficiently studied with computational methods. Computer-aided drug design techniques can reduce the cost of drug development by up to 50%. In particular structure- and ligand-based virtual screening techniques are a valuable tool for identifying new leads and have been shown to be especially efficient for GPCRs in comparison to water soluble proteins. Modern computer-aided approaches can be helpful for the discovery of compounds with designed affinity profiles. Furthermore, homology modeling facilitated by a growing number of available templates as well as molecular docking supported by sophisticated techniques of molecular dynamics and quantitative structure-activity relationship models are an excellent source of information about drug-receptor interactions at the molecular level. PMID- 26928553 TI - Comparing Class A GPCRs to bitter taste receptors: Structural motifs, ligand interactions and agonist-to-antagonist ratios. AB - G protein-coupled receptors (GPCRs) are seven transmembrane (TM) proteins that play a key role in human physiology. The GPCR superfamily comprises about 800 members, classified into several classes, with rhodopsin-like Class A being the largest and most studied thus far. A huge component of the human repertoire consists of the chemosensory GPCRs, including ~400 odorant receptors, 25 bitter taste receptors (TAS2Rs), which are thought to guard the organism from consuming poisons, and sweet and umami TAS1R heteromers, which indicate the nutritive value of food. The location of the binding site of TAS2Rs is similar to that of Class A GPCRs. However, most of the known bitter ligands are agonists, with only a few antagonists documented thus far. The agonist-to-antagonist ratios of Class A GPCRs vary, but in general are much lower than for TAS2Rs. For a set of well studied GPCRs, a gradual change in agonists-to-antagonists ratios is observed when comparing low (10 MUM)- and high (10 nM)-affinity ligand sets from ChEMBL and the DrugBank set of drugs. This shift reflects pharmaceutical bias toward the therapeutically desirable pharmacology for each of these GPCRs, while the 10 MUM sets possibly represent the native tendency of the receptors toward either agonists or antagonists. Analyzing ligand-GPCR interactions in 56 X-ray structures representative of currently available structural data, we find that the N-terminus, TM1 and TM2 are more involved in binding of antagonists than of agonists. On the other hand, ECL2 tends to be more involved in binding of agonists. This is of interest, since TAS2Rs harbor variations on the typical Class A sequence motifs, including the absence of the ECL2-TM3 disulfide bridge. This suggests an alternative mode of regulation of conformational states for TAS2Rs, with potentially less stabilized inactive state. The comparison of TAS2Rs and Class A GPCRs structural features and the pharmacology of the their ligands highlights the intricacies of GPCR architecture and provides a framework for rational design of new ligands. PMID- 26928554 TI - What can simulations tell us about GPCRs: Integrating the scales. AB - The functional dynamics of G protein-coupled receptors (GPCRs) encompasses multiple spatiotemporal scales, ranging from femtoseconds to seconds and Angstroms to micrometers. Computational approaches, often in close collaboration with experimental methods, have been invaluable in unraveling GPCR structure and dynamics at these various hierarchical levels. The binding of natural and synthetic ligands to the wild-type and naturally occurring variant receptors have been analyzed by several computational methods. The activation of receptors from the inactive to the active state has been investigated by atomistic simulations and ongoing work on several receptors will help uncover general and receptor specific mechanisms. The interaction of GPCRs with complex membranes that contain phospholipids and cholesterol have been probed by coarse-grain methods and shown to directly influence receptor association. In this chapter, we discuss computational approaches that have been successful in analyzing each scale of GPCR dynamics. An overview of these approaches will allow a more judicious choice of the appropriate method. We hope that an appreciation of the power of current computational approaches will encourage more critical collaborations. A comprehensive integration of the different approaches over the entire spatiotemporal scales promises to unravel new facets of GPCR function. PMID- 26928555 TI - The epidemiology of childhood psoriasis: a scoping review. AB - Psoriasis is an inflammatory noncommunicable skin disease that affects both adults and children. At present, the epidemiology and natural history of psoriasis are not widely understood. This scoping review aimed to map the existing literature on the epidemiology of childhood psoriasis, identify research gaps for future studies and provide a comprehensive, clinically useful review. Search strategies were developed for Ovid Medline, Ovid Embase, Google Scholar and hand searching. In total, 131 articles met the inclusion criteria and were mapped; 107 articles were included for data extraction. Over the last 25 years there has been a dramatic increase in the volume of published observational epidemiological studies on childhood psoriasis. The majority were case series or cross-sectional studies, concentrated in Europe, Asia and North America. The prevalence of childhood psoriasis was found to be higher in European countries, older children and girls. Up to 48.8% of children had a family history of psoriasis in a first-degree relative. The most frequent subtype was plaque psoriasis and the most common initial sites of presentation were the scalp, limbs and trunk. Specific genetic differences have been found between child-onset and adult-onset populations. Case-control and cohort studies investigating risk factors for psoriasis onset, comorbidities and long-term health outcomes were extremely limited. The choice of study design and heterogeneity in methodology limit the validity and generalizability of the information, consistency of the results, and comparability of the studies. Well-designed epidemiological studies are needed to provide precise and consistent information about the frequency and clinical presentation, risk factors, associated diseases and long-term outcomes in childhood psoriasis. PMID- 26928557 TI - Prenatal Counseling, Ultrasound Diagnosis, and the Role of Maternal-Fetal Medicine of the Cleft Lip and Palate Patient. AB - A multidisciplinary team is the standard of care and the cornerstone of management of cleft patients. With readily improving advanced diagnostic modalities, early prenatal diagnosis of cleft lip and palate increasingly becomes a topic of importance for both the team caring for and families of cleft patients. Maternal-fetal medicine is a fellowship subspecialty of obstetrics that can offer high-quality care and coordination to the cleft team. Both 3-D and 4-D sonography lead to early prenatal diagnosis of cleft patients; however, differences in training result in variations in its diagnostic accuracy. PMID- 26928556 TI - WAP four-disulfide core domain protein 2 gene(WFDC2) is a target of estrogen in ovarian cancer cells. AB - BACKGROUND: WAP four-disulfide core domain protein 2 (WFDC2) shows a tumor restricted upregulated pattern of expression in ovarian cancer. METHODS: We investigated the role of estradiol (E2) on cell growth in estrogen-sensitive or estrogen-insensitive ovarian cancer cell lines. Real-time (RT)-PCR and western blotting were used to examine the expression of WFDC2 at RNA and protein levels. Growth traits of cells transfected with WFDC2-shRNA or blank control were assessed using MMT arrays. Cell apoptosis was analyzed using annexin V-FITC/PI and flow cytometry. Estrogen receptor expression was evaluated using RT-PCR and flow cytometry. Apoptosis-related proteins induced by E2 directly and indirectly were determined using an antibody array comparing cells transfected with WFDC2- shRNA or a blank control. RESULTS: High-dose (625 ng/ml) E2 increased the expression of WFDC2 in HO8910 cells at both the mRNA and protein levels. However, E2 had no effect on WFDC2 expression in estrogen-insensitive SKOV3 cells. Of interest, knockdown of WFDC2 enabled a considerable estrogen response in SKOV3 cells in terms of proliferation, similar to estrogen-responsive HO8910 cells. This transformation of SKOV3 cells into an estrogen-responsive phenotype was accompanied by upregulation of estrogen receptor beta (ERbeta) and an effect on cell apoptosis under E2 treatment by regulating genes related to cell proliferation and apoptosis. CONCLUSIONS: We postulate that increased WFDC2 expression plays an important role in altering the estrogen pathway in ovarian cancer, and the identification of WFDC2 as a new player in endocrine-related cancer encourages further studies on the significance of this gene in cancer development and therapy. PMID- 26928558 TI - Qualitative and quantitative measurement of the anterior and posterior meniscal root attachments of the New Zealand white rabbit. AB - BACKGROUND: The purpose of this study was to quantify the meniscal root anatomy of the New Zealand white rabbit to better understand this animal model for future in vitro and in vivo joint degeneration studies. METHODS: Ten non-paired fresh frozen New Zealand white rabbit knee stifle joints were carefully disarticulated for this study. Measurements were made for all bony landmarks and ligamentous structure attachment sites on the tibial plateau. The following soft tissue structures were consistently identified in the rabbit stifle joint: the anterior root attachment of the lateral meniscus, the anterior root attachment of the medial meniscus, the anterior cruciate ligament, the posterior root attachment of the medial meniscus, the ligament of Wrisberg, the posterior cruciate ligament, and the posterior meniscotibial ligament. The following bony landmarks were consistently identified: the extensor digitorum longus groove, the medial tibial eminence, the center of the tibial tuberosity, and the lateral tibial eminence. RESULTS: The center of the anterior cruciate ligament and the medial tibial eminence apex were found to be 3.4 +/- 0.3 mm (2.9-3.6) and 6.1 +/- 0.6 mm (5.1 7.0) respectively from the center of the medical anterior root attachment. The center of the anterior cruciate ligament and the lateral tibial eminence apex were found to be 2.1 +/- 0.5 mm (1.2-2.7) and 7.0 +/- 0.6 mm (6.4-8.2) respectively from the center of the lateral anterior root attachment. The center of the posterior cruciate ligament and the medial tibial eminence apex were found to be 2.0 +/- 0.7 mm (0.5-2.6) and 1.8 +/- 0.4 mm (1.2-2.4) respectively from the center of the medial posterior root attachment. CONCLUSIONS: This study augments our understanding of the comparative anatomy of the rabbit stifle joint. This information will be useful for future biomechanical, surgical, and in vitro studies utilizing the rabbit stifle as a model for human knee joint degenerative diseases. PMID- 26928559 TI - A New Theoretical Insight Into ZnO NWs Memristive Behavior. AB - Resistive switching memory operation is generally described in terms of formation and rupture of a conductive filament connecting two metal electrodes. Although this model was reported for several device types, its applicability is not guaranteed to all of them. On the basis of density functional theory calculations, we propose a novel switching mechanism suitable to nanowire-based resistive switching memories. For thick devices in particular, the current is highly unlikely to flow through a metallic filament connecting the electrodes. We demonstrate that in the case of ZnO nanowires metal adatoms, spread on the nanowire surface, locally dope the insulating oxide allowing surface conductance even for small metal concentrations. PMID- 26928560 TI - Dual Electrical-Behavior Regulation on Electrocatalysts Realizing Enhanced Electrochemical Water Oxidation. AB - Dual electrical-behavior regulation on electrocatalysts is proven to be an effective strategy for realizing enhanced electrochemical water oxidation. Electrical-behavior regulation opens up a promising avenue to design advanced electrocatalysts. PMID- 26928561 TI - Places where preschoolers are (in)active: an observational study on Latino preschoolers and their parents using objective measures. AB - BACKGROUND: To combat the disproportionately higher risk of childhood obesity in Latino preschool-aged children, multilevel interventions targeting physical (in) activity are needed. These require the identification of environmental and psychosocial determinants of physical (in) activity for this ethnic group. The objectives were to examine differences in objectively-measured physical activity and sedentary behavior across objectively-determined types of locations in Latino preschool-aged children; and determine whether the differences in physical activity by location were greater in children of parents with higher neighborhood safety perceptions and physical activity-supportive parenting practices. METHODS: An observational field study was conducted in Houston (Texas, USA) from August 2011 to April 2012. A purposive sample of Latino children aged 3-5 years and one of their parents (n = 84) were recruited from Census block groups in Houston (Texas) stratified by objectively-assessed high vs. low traffic and crime safety. Seventy-three children provided valid data. Time spent outdoors/indoors tagged with geographic locations was coded into location types based on objective data collected using Global Positioning Systems units that children wore >8 hr/day for a week. Physical activity parenting practices, perceived neighborhood-safety, and demographics were reported by parents. Time spent in sedentary behavior and moderate-to-vigorous physical activity was measured based on objective data collected using accelerometers (motion sensors) that children wore >8 hr/day for a week. RESULTS: The odds of children engaging in moderate-to-vigorous physical activity were 43% higher when outdoors than indoors (95% confidence interval: 1.30, 1.58), and the odds of being sedentary were 14% lower when outdoors compared to indoors (95% confidence intervals: 0.81, 0.91). This difference depended on parental neighborhood-safety perceptions and parenting practices. Children were most active in parks/playgrounds (30% of the time spent in moderate to-vigorous physical activity) and least active in childcare/school settings (8% of the time spent in moderate-to-vigorous physical activity). CONCLUSIONS: Objectively-assessed time spent in specific locations is correlated with physical activity and sedentary behavior in Latino preschoolers. Interventions and policies should identify ways to engage Latino preschool-aged children in more physical activity and less sedentary behavior while in childcare, and encourage parents to spend more time with their young children in parks/playgrounds and other safe outdoor places. PMID- 26928562 TI - Contrasting Role of Temperature in Structuring Regional Patterns of Invasive and Native Pestilential Stink Bugs. AB - OBJECTIVES: Assessment and identification of spatial structures in the distribution and abundance of invasive species is important for unraveling the underlying ecological processes. The invasive agricultural insect pest Halyomorpha halys that causes severe economic losses in the United States is currently expanding both within United States and across Europe. We examined the drivers of H. halys invasion by characterizing the distribution and abundance patterns of H. halys and native stink bugs (Chinavia hilaris and Euschistus servus) across eight different spatial scales. We then quantified the interactive and individual influences of temperature, and measures of resource availability and distance from source populations, and their relevant spatial scales. We used Moran's Eigenvector Maps based on Gabriel graph framework to quantify spatial relationships among the soybean fields in mid-Atlantic Unites States surveyed for stink bugs. FINDINGS: Results from the multi-spatial scale, multivariate analyses showed that temperature and its interaction with resource availability and distance from source populations structures the patterns in H. halys at very broad spatial scale. H. halys abundance decreased with increasing average June temperature and distance from source population. H. halys were not recorded at fields with average June temperature higher than 23.5 degrees C. In parts with suitable climate, high H. halys abundance was positively associated with percentage developed open area and percentage deciduous forests at 250m scale. Broad scale patterns in native stink bugs were positively associated with increasing forest cover and, in contrast to the invasive H. halys, increasing mean July temperature. Our results identify the contrasting role of temperature in structuring regional patterns in H. halys and native stink bugs, while demonstrating its interaction with resource availability and distance from source populations for structuring H. halys patterns. CONCLUSION: These results help predicting the pest potential of H. halys and vulnerability of agricultural systems at various regions, given the climatic conditions, and its interaction with resource availability and distance from source populations. Monitoring and control efforts within parts of the United States and Europe with more suitable climate could focus in areas of peri-urban developments with deciduous forests and other host plants, along with efforts to reduce propagule pressure. PMID- 26928563 TI - Determination of viable legionellae in engineered water systems: Do we find what we are looking for? AB - In developed countries, legionellae are one of the most important water-based bacterial pathogens caused by management failure of engineered water systems. For routine surveillance of legionellae in engineered water systems and outbreak investigations, cultivation-based standard techniques are currently applied. However, in many cases culture-negative results are obtained despite the presence of viable legionellae, and clinical cases of legionellosis cannot be traced back to their respective contaminated water source. Among the various explanations for these discrepancies, the presence of viable but non-culturable (VBNC) Legionella cells has received increased attention in recent discussions and scientific literature. Alternative culture-independent methods to detect and quantify legionellae have been proposed in order to complement or even substitute the culture method in the future. Such methods should detect VBNC Legionella cells and provide a more comprehensive picture of the presence of legionellae in engineered water systems. However, it is still unclear whether and to what extent these VBNC legionellae are hazardous to human health. Current risk assessment models to predict the risk of legionellosis from Legionella concentrations in the investigated water systems contain many uncertainties and are mainly based on culture-based enumeration. If VBNC legionellae should be considered in future standard analysis, quantitative risk assessment models including VBNC legionellae must be proven to result in better estimates of human health risk than models based on cultivation alone. This review critically evaluates current methods to determine legionellae in the VBNC state, their potential to complement the standard culture-based method in the near future, and summarizes current knowledge on the threat that VBNC legionellae may pose to human health. PMID- 26928564 TI - Multi-dimensional water quality assessment of an urban drinking water source elucidated by high resolution underwater towed vehicle mapping. AB - Spatial surveys of Ramsey Lake, Sudbury, Ontario water quality were conducted using an innovative underwater towed vehicle (UTV) equipped with a multi parameter probe providing real-time water quality data. The UTV revealed underwater vent sites through high resolution monitoring of different spatial chemical characteristics using common sensors (turbidity, chloride, dissolved oxygen, and oxidation/reduction sensors) that would not be feasible with traditional water sampling methods. Multi-parameter probe vent site identification is supported by elevated alkalinity and silica concentrations at these sites. The identified groundwater vent sites appear to be controlled by bedrock fractures that transport water from different sources with different contaminants of concern. Elevated contaminants, such as, arsenic and nickel and/or nutrient concentrations are evident at the vent sites, illustrating the potential of these sources to degrade water quality. PMID- 26928565 TI - Factors associated with anxiety and depressive symptoms in colorectal cancer survivors. AB - BACKGROUND: Up to 37% of colorectal cancer (CRC) survivors report depressive and anxiety symptoms. The identification of risk factors for depressive or anxiety symptoms might help focus supportive care resources on those patients most in need. The present study aims to explore which factors are associated with heightened anxiety or depression symptom severity. METHODS: In this cross sectional study, individuals diagnosed with CRC 3.5 to 6 years ago completed questionnaires on sociodemographic information, medical comorbidities, anxiety symptoms (Beck Anxiety Inventory), and depressive symptoms (Inventory of Depressive Symptomatology). The general linear model analysis of covariance was used to identify factors associated with heightened anxiety or depressive symptom severity. RESULTS: The sample included 91 CRC survivors, 40.7% women, mean age 69.1 years. A minority of CRC survivors had moderate (3.4%) or severe (2.3%) anxiety symptoms, and moderate (7.7%) or severe (0%) depressive symptoms. Shorter time since diagnosis and higher number of comorbid diseases were associated with higher anxiety symptom severity. Female sex and higher number of comorbid diseases were associated with higher depressive symptom severity. CONCLUSION: From this explorative study, it follows that survivors with multiple comorbid diseases, shorter time since diagnosis, and female survivors might be at risk for higher anxiety and/or depressive symptom severity. Survivors with these characteristics might need extra monitoring. PMID- 26928566 TI - Pilot evaluation of a web-based intervention targeting sexual health service access. AB - Sexual health service access is fundamental to good sexual health, yet interventions designed to address this have rarely been implemented or evaluated. In this article, pilot evaluation findings for a targeted public health behavior change intervention, delivered via a website and web-app, aiming to increase uptake of sexual health services among 13-19-year olds are reported. A pre-post questionnaire-based design was used. Matched baseline and follow-up data were identified from 148 respondents aged 13-18 years. Outcome measures were self reported service access, self-reported intention to access services and beliefs about services and service access identified through needs analysis. Objective service access data provided by local sexual health services were also analyzed. Analysis suggests the intervention had a significant positive effect on psychological barriers to and antecedents of service access among females. Males, who reported greater confidence in service access compared with females, significantly increased service access by time 2 follow-up. Available objective service access data support the assertion that the intervention may have led to increases in service access. There is real promise for this novel digital intervention. Further evaluation is planned as the model is licensed to and rolled out by other local authorities in the United Kingdom. PMID- 26928567 TI - Late Surfactant Administration in Very Preterm Neonates With Prolonged Respiratory Distress and Pulmonary Outcome at 1 Year of Age: A Randomized Clinical Trial. AB - IMPORTANCE: Although immature neonate survival has improved, there is an increased risk of developing bronchopulmonary dysplasia, leading to significant respiratory morbidity. Measures to reduce bronchopulmonary dysplasia are not always effective or have important adverse effects. OBJECTIVE: To evaluate the effect of late surfactant administration in infants with prolonged respiratory distress on ventilation duration, respiratory outcome at 36 weeks' postmenstrual age, and at 1 year postnatal age. DESIGN, SETTING, AND PARTICIPANTS: Double-blind randomized clinical trial at 13 level III French perinatal centers. Participants included 118 neonates at less than 33 weeks' gestation who still required mechanical ventilation on day 14 (SD, 2) with fraction of inspired oxygen of more than 0.30. All survivors were eligible for follow-up. We performed an intent-to treat analysis. INTERVENTIONS: Infants received 200 mg/kg of poractant alfa (surfactant) or air after randomization. At 1 year, after parents' interview, infants underwent physical examination by pediatricians not aware of the randomization. MAIN OUTCOMES AND MEASURES: The duration of ventilation was the primary outcome. The combined outcome of death or bronchopulmonary dysplasia at 36 weeks' postmenstrual age and respiratory morbidity at 1 year of age were the main secondary outcome measures. RESULTS: Of the 118 infants who participated in the study, 65 (55%) were male. Fraction of inspired oxygen requirements dropped after surfactant, but not air, for up to 24 hours after instillation (0.36 [0.11] vs 0.43 [0.18]; P < .005). Severe bronchopulmonary dysplasia/death rates at 36 weeks' postmenstrual age were similar (27.1% vs 35.6%; P = .32). Less surfactant treated infants needed rehospitalization for respiratory problems after discharge (28.3% vs 51.1%; P = .03); 39.5% vs 50% needed respiratory physical therapy (P = .35). No difference was observed for weight (7.8 [1.2] kg vs 7.6 [1.1] kg), height (69 [5] cm vs 69 [3] cm), and head circumference (44.4 [1.7] cm vs 44.2 [1.7] cm) measured at follow-up, nor for neurodevelopment outcome. CONCLUSIONS AND RELEVANCE: Late surfactant administration did not alter the early course of bronchopulmonary dysplasia. However, surfactant-treated infants had reduced respiratory morbidity prior to 1 year of age. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01039285. PMID- 26928568 TI - Chinese and Caucasian ocular topography and soft contact lens fit. AB - BACKGROUND: The aim was to evaluate the effect of ocular topography on soft contact lens fit in Chinese and Caucasians. METHOD: This study evaluated 547 subjects from two ethnic groups, Caucasian (n = 250) and Chinese (n = 297), at investigational sites in three locations: Wenzhou, China, Melbourne, Australia and Jacksonville, USA. Subjects underwent measurement of a range of ocular topographic variables using identical equipment and protocols, including: apical corneal radius (CR), corneal shape factor (CSF) in the two principal meridians, horizontal visible iris diameter (HVID), vertical palpebral aperture (PA), upper lid angle (ULA) and inter-canthal angle (ICA). Subjects were fitted with a spherical lens in two base curves (BCs) (1.Day ACUVUE, 8.50, 9.00 mm) and a toric soft lens (Accelerated Stabilization Design). RESULTS: The steeper base curve (8.50 mm) spherical lenses gave an acceptable overall lens fit with 98 per cent or more of subjects in both groups, while the flatter lens (9.00 mm) was acceptable in a significantly higher proportion of the Chinese compared to Caucasian group (96 versus 82 per cent, p < 0.0001) . The main difference in fit between groups was for centration; there was significantly less decentration with the Chinese group (8.50 BC: 39 versus 72 per cent, p < 0.0001; 9.0 BC: 63 versus. 85 per cent, p = 0.02). The 8.5 mm base curve showed good centration (none or slight decentration) for 97 per cent of Caucasian eyes and 96 per cent of Chinese eyes. With both groups, there were some significant correlations between lens fit and ocular topographic variables, most notable between upper lid angle and toric lens orientation with the Chinese subjects. Regression analysis also showed key predictive values relating to lens fit. CONCLUSIONS: Detailed ocular measurements suggest anatomical differences between Chinese and Caucasian populations that should be considered in soft lens design. The spherical and toric lenses tested in this study fitted a large proportion of both Chinese and Caucasian eyes and are robust to the ocular differences noted. PMID- 26928569 TI - The Use of Pediatrician Interventions to Increase Smoking Cessation Counseling Among Smoking Caregivers: A Systematic Review. PMID- 26928571 TI - Distance-based microfluidic quantitative detection methods for point-of-care testing. AB - Equipment-free devices with quantitative readout are of great significance to point-of-care testing (POCT), which provides real-time readout to users and is especially important in low-resource settings. Among various equipment-free approaches, distance-based visual quantitative detection methods rely on reading the visual signal length for corresponding target concentrations, thus eliminating the need for sophisticated instruments. The distance-based methods are low-cost, user-friendly and can be integrated into portable analytical devices. Moreover, such methods enable quantitative detection of various targets by the naked eye. In this review, we first introduce the concept and history of distance-based visual quantitative detection methods. Then, we summarize the main methods for translation of molecular signals to distance-based readout and discuss different microfluidic platforms (glass, PDMS, paper and thread) in terms of applications in biomedical diagnostics, food safety monitoring, and environmental analysis. Finally, the potential and future perspectives are discussed. PMID- 26928570 TI - CaCDPK15 positively regulates pepper responses to Ralstonia solanacearum inoculation and forms a positive-feedback loop with CaWRKY40 to amplify defense signaling. AB - CaWRKY40 is a positive regulator of pepper (Capsicum annum) response to Ralstonia solanacearum inoculation (RSI), but the underlying mechanism remains largely unknown. Here, we functionally characterize CaCDPK15 in the defense signaling mediated by CaWRKY40. Pathogen-responsive TGA, W, and ERE boxes were identified in the CaCDPK15 promoter (pCaCDPK15), and pCaCDPK15-driven GUS expression was significantly enhanced in response to RSI and exogenously applied salicylic acid, methyl jasmonate, abscisic acid, and ethephon. Virus-induced gene silencing (VIGS) of CaCDPK15 significantly increased the susceptibility of pepper to RSI and downregulated the immunity-associated markers CaNPR1, CaPR1, and CaDEF1. By contrast, transient CaCDPK15 overexpression significantly activated hypersensitive response associated cell death, upregulated the immunity associated marker genes, upregulated CaWRKY40 expression, and enriched CaWRKY40 at the promoters of its targets genes. Although CaCDPK15 failed to interact with CaWRKY40, the direct binding of CaWRKY40 to pCaCDPK15 was detected by chromatin immunoprecipitation, which was significantly potentiated by RSI in pepper plants. These combined results suggest that RSI in pepper induces CaCDPK15 and indirectly activates downstream CaWRKY40, which in turn potentiates CaCDPK15 expression. This positive-feedback loop would amplify defense signaling against RSI and efficiently activate strong plant immunity. PMID- 26928572 TI - Predicting occult lymph node-positive disease at the time of radical cystectomy: a systematic review. AB - INTRODUCTION: The aim of this paper is to provide a systematic examination of the available evidence identifying factors that predict the detection of occult nodal metastatic disease at the time of radical cystectomy in patients with urothelial cancer of the bladder (BCa). EVIDENCE ACQUISITION: A systematic literature search of the PubMed database was performed in August 2015 using medical subject headings and free-text protocol. The search was conducted by applying keywords: bladder cancer, urothelial cancer, lymph node metastasis, node positive, micrometastasis and occult metastasis. EVIDENCE SYNTHESIS: High-quality evidence assessing clinical factors that predict the discovery of occult nodal disease at the time of radical cystectomy is sparse. Despite the large number of studies examining this topic, there is a vast heterogeneity across the publications in patient selection, extent of lymph node dissection, and pathological assessment. The majority of studies reporting clinical and molecular characteristics associated with positive nodal status are based on univariable analysis and not corrected for known markers of tumor biology (stage, grade, lymphovascular invasion). CONCLUSIONS: Identifying BCa with occult lymph node metastasis holds the promise of facilitating patient selection for neoadjuvant medical therapy and tailoring surgical interventions, potentially improving clinical outcomes for BCa patients. Molecular markers need to be externally validated in prospectively well designed trials and need to prove clinical utility. Image-guided surgical technologies need further development before being adopted in routine practice. PMID- 26928573 TI - The Clinical Relevance of the IBD-Associated Variation within the Risk Gene Locus Encoding Protein Tyrosine Phosphatase Non-Receptor Type 2 in Patients of the Swiss IBD Cohort. AB - BACKGROUND/AIMS: The single nucleotide polymorphism (SNP) rs1893217 within the gene locus encoding protein tyrosine phosphatase non-receptor type 2 (PTPN2) results in a dysfunctional PTPN2 protein is associated with Crohn's disease (CD) and exists in perfect linkage disequilibrium with the CD- and ulcerative colitis (UC)-associated PTPN2 SNP rs2542151. We investigated associations of PTPN2 SNP rs1893217 and clinical characteristics of inflammatory bowel disease (IBD) patients. METHODS: One thousand seventy three patients with CD and 734 patients with UC from the Swiss IBD Cohort Study (SIBDCS) were included. Epidemiologic, disease and treatment characteristics were analysed for an association with the presence of one of the rs1893217 genotypes 'homozygous wild-type' (TT), 'heterozygous' (CT) and 'homozygous variant' (CC). RESULTS: About 2.88% of IBD patients were identified with CC, 26.8% with CT and 70.4% with TT genotype. The CC-genotype was associated with the existence of gallstones in CD and pancolitis in UC patients. The presence of the C-allele (i.e. either CC or CT genotype) was associated with the onset of uveitis, but protected from aphthous oral ulcers in CD patients. UC patients carrying a C-allele were diagnosed at an older age but required intestinal surgery more often. The presence of the C-allele was associated with a successful treatment with anti-TNF antibodies in both CD and UC patients. CONCLUSION: IBD patients carrying the C-allele of PTPN2 SNP rs1893217 are at greater risk for developing a severe disease course but are more likely to respond to treatment with anti-TNF antibodies. These findings demonstrate a clinical relevance of this PTPN2 risk variant in IBD patients. PMID- 26928574 TI - Clinical outcomes of percutaneous coronary intervention for acute coronary syndrome between hospitals with and without onsite cardiac surgery backup. AB - BACKGROUND: Based on the 2011 American College of Cardiology/American Heart Association percutaneous coronary intervention (PCI) guideline, it is recommended that PCI should be performed at hospital with onsite cardiac surgery. But, data suggest that there is no significant difference in clinical outcomes following primary or elective PCI between the two groups. We examined the impact of with or without onsite cardiac surgery on clinical outcomes following PCI for acute coronary syndrome (ACS). METHODS AND RESULTS: From August 2008 to March 2011, subjects (n=3241) were enrolled from the Kumamoto Intervention Conference Study (KICS). Patients were assigned to two groups treated in hospitals with (n=2764) or without (n=477) onsite cardiac surgery. Clinical events were followed up for 12 months. Primary endpoint was in-hospital death, cardiovascular death, myocardial infarction, and stroke. And we monitored in-hospital events, non cardiovascular deaths, bleeding complications, revascularizations, and emergent coronary artery bypass grafting (CABG). There was no overall significant difference in primary endpoint between hospitals with and without onsite cardiac surgery [ACS, 7.6% vs. 8.0%, p=0.737; ST-segment elevation myocardial infarction (STEMI), 10.4% vs. 7.5%, p=0.200]. There was also no significant difference when events in primary endpoint were considered separately. In other events, revascularization was more frequently seen in hospitals with onsite surgery (ACS, 20.0% vs. 13.0%, p<0.001; STEMI, 21.9% vs. 14.5%, p=0.009). We performed propensity score matching analysis to correct for the disparate patient numbers between the two groups, and there was also no significant difference for primary endpoint (ACS, 8.6% vs. 7.5%, p=0.547; STEMI, 11.2% vs. 7.5%, p=0.210). CONCLUSIONS: There is no significant difference in clinical outcomes following PCI for ACS between hospitals with and without onsite cardiac surgery backup in Japan. PMID- 26928575 TI - Feedbacks, Bifurcations, and Cell Fate Decision-Making in the p53 System. AB - The p53 transcription factor is a regulator of key cellular processes including DNA repair, cell cycle arrest, and apoptosis. In this theoretical study, we investigate how the complex circuitry of the p53 network allows for stochastic yet unambiguous cell fate decision-making. The proposed Markov chain model consists of the regulatory core and two subordinated bistable modules responsible for cell cycle arrest and apoptosis. The regulatory core is controlled by two negative feedback loops (regulated by Mdm2 and Wip1) responsible for oscillations, and two antagonistic positive feedback loops (regulated by phosphatases Wip1 and PTEN) responsible for bistability. By means of bifurcation analysis of the deterministic approximation we capture the recurrent solutions (i.e., steady states and limit cycles) that delineate temporal responses of the stochastic system. Direct switching from the limit-cycle oscillations to the "apoptotic" steady state is enabled by the existence of a subcritical Neimark Sacker bifurcation in which the limit cycle loses its stability by merging with an unstable invariant torus. Our analysis provides an explanation why cancer cell lines known to have vastly diverse expression levels of Wip1 and PTEN exhibit a broad spectrum of responses to DNA damage: from a fast transition to a high level of p53 killer (a p53 phosphoform which promotes commitment to apoptosis) in cells characterized by high PTEN and low Wip1 levels to long-lasting p53 level oscillations in cells having PTEN promoter methylated (as in, e.g., MCF-7 cell line). PMID- 26928577 TI - Engraftment and outcomes following autologous stem cell transplantation in Hodgkin lymphoma patients mobilized with plerixafor. AB - Plerixafor has been used to improve peripheral blood stem cell (PBSC) mobilization in multiple myeloma, non-Hodgkin lymphoma, and very recently in Hodgkin lymphoma (HL) patients. Because prior studies have suggested that mobilization with plerixafor affects the composition of mobilized cells, there are concerns that this may in turn adversely impact the immune reconstitution and longer term outcomes of transplanted patients. However, data on the engraftment characteristics and long-term post-transplant outcomes in patients transplanted with plerixafor-mobilized PBSCs are lacking. This retrospective study examined the post-transplant outcomes of 105 consecutive adult HL patients, and compared the post-transplant outcomes of 21 patients who received plerixafor in addition to G-CSF +/- chemotherapy because of poor mobilization with those of 84 patients who mobilized well without plerixafor. Despite collecting significantly lower CD34+ cell doses (median of 3.41 vs. 6.05 * 106 /kg, p < 0.0001) than control patients and requiring more collection days, plerixafor-mobilized patients showed comparable early engraftment characteristics, except for slightly delayed neutrophil engraftment (median: 11 vs.10 days, p = 0.002) and lower median neutrophil counts (2.1 vs. 2.6 * 109 /L, p = 0.04) at one month after transplant. No significant differences were observed in longer term post-transplant outcomes, including cell counts at 3, 6, and 12 months, RBC and platelet transfusion support during the first 120 days, relapse incidence, overall and progression free survival rates up to two years post transplant. The use of plerixafor not only enabled poorly mobilizing HL patients to collect enough PBSCs to proceed to ASCT, but also to have similar post-transplant outcomes compared to patients who mobilized well with conventional regimens. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26928576 TI - Identification of a Latin American-specific BabA adhesin variant through whole genome sequencing of Helicobacter pylori patient isolates from Nicaragua. AB - BACKGROUND: Helicobacter pylori (H. pylori) is one of the most common bacterial infections in humans and this infection can lead to gastric ulcers and gastric cancer. H. pylori is one of the most genetically variable human pathogens and the ability of the bacterium to bind to the host epithelium as well as the presence of different virulence factors and genetic variants within these genes have been associated with disease severity. Nicaragua has particularly high gastric cancer incidence and we therefore studied Nicaraguan clinical H. pylori isolates for factors that could contribute to cancer risk. METHODS: The complete genomes of fifty-two Nicaraguan H. pylori isolates were sequenced and assembled de novo, and phylogenetic and virulence factor analyses were performed. RESULTS: The Nicaraguan isolates showed phylogenetic relationship with West African isolates in whole-genome sequence comparisons and with Western and urban South- and Central American isolates using MLSA (Multi-locus sequence analysis). A majority, 77 % of the isolates carried the cancer-associated virulence gene cagA and also the s1/i1/m1 vacuolating cytotoxin, vacA allele combination, which is linked to increased severity of disease. Specifically, we also found that Nicaraguan isolates have a blood group-binding adhesin (BabA) variant highly similar to previously reported BabA sequences from Latin America, including from isolates belonging to other phylogenetic groups. These BabA sequences were found to be under positive selection at several amino acid positions that differed from the global collection of isolates. CONCLUSION: The discovery of a Latin American BabA variant, independent of overall phylogenetic background, suggests hitherto unknown host or environmental factors within the Latin American population giving H. pylori isolates carrying this adhesin variant a selective advantage, which could affect pathogenesis and risk for sequelae through specific adherence properties. PMID- 26928579 TI - Evaluation of (124)I PET/CT and (124)I PET/MRI in the management of patients with differentiated thyroid cancer. PMID- 26928580 TI - (18)F-FDG PET/CT in patients with idiopathic retroperitoneal and mediastinal fibrosis. PMID- 26928578 TI - BMS-754807 is cytotoxic to non-small cell lung cancer cells and enhances the effects of platinum chemotherapeutics in the human lung cancer cell line A549. AB - BACKGROUND: Despite advances in targeted therapy for lung cancer, survival for patients remains poor and lung cancer remains the leading cause of cancer-related deaths worldwide. The type I insulin-like growth factor receptor (IGF-IR) has emerged as a potential target for lung cancer treatment, however, clinical trials to date have provided disappointing results. Further research is needed to identify if certain patients would benefit from IGF-IR targeted therapies and the ideal approach to incorporate IGF-IR targeted agents with current therapies. METHODS: The dual IGF-IR/insulin receptor inhibitor, BMS-754807, was evaluated alone and in combination with platinum-based chemotherapeutics in two human non small cell lung cancer (NSCLC) cell lines. Cell survival was determined using WST 1 assays and drug interaction was evaluated using Calcusyn software. Proliferation and apoptosis were determined using immunofluorescence for phospho histone H3 and cleaved caspase 3, respectively. RESULTS: Treatment with BMS 754807 alone reduced cell survival and wound closure while enhancing apoptosis in both human lung cancer cell lines. These effects appear to be mediated through IGF-IR/IR signaling and, at least in part, through the PI3K/AKT pathway as administration of BMS-754807 to A549 or NCI-H358 cells significantly suppressed IGF-IR/IR and AKT phosphorylation. In addition of BMS-754807 enhanced the cytotoxic effects of carboplatin or cisplatin in a synergistic manner when given simultaneously to A549 cells. CONCLUSIONS: BMS-754807 may be an effective therapeutic agent for the treatment of NSCLC, particularly in lung cancer cells expressing high levels of IGF-IR. PMID- 26928582 TI - Confined Synthesis of Organometallic Chains and Macrocycles by Cu-O Surface Templating. AB - The bottom-up construction of low-dimensional macromolecular nanostructures directly on a surface is a promising approach for future application in molecular electronics and integrated circuit production. However, challenges still remain in controlling the formation of these nanostructures with predetermined patterns (such as linear or cyclic) or dimensions (such as the length of one-dimensional (1D) chains). Here, we demonstrate that a high degree of structural control can be achieved by employing a Cu(110)-(2*1)O nanotemplate for the confined synthesis of organometallic chains and macrocycles. This template contains ordered arrays of alternating stripes of Cu-O chains and bare Cu, the widths of which are controllable. Using scanning tunneling microscopy and low-energy electron diffraction, we show that well-defined, ordered 1D zigzag organometallic oligomeric chains with uniform lengths can be fabricated on the Cu stripes (width >5.6 nm) of the Cu(110)-(2*1)O surface. In addition, the lengths of the meta terphenyl (MTP)-based chains can be adjusted by controlling the widths of the Cu stripes within a certain range. When reducing the widths of Cu stripes to a range of 2.6 to 5.6 nm, organometallic macrocycles including tetramer (MTP-Cu)4, hexamer (MTP-Cu)6, and octamer (MTP-Cu)8 species are formed due to the spatial confinement effect and attraction to the Cu-O chains. An overview of all formed organometallic macrocycles on the Cu stripes with different widths reveals that the origin of the formation of these macrocycles is the cis-configured organometallic dimer (MTP)2Cu3, which was observed on the extremely narrow Cu stripe with a width of 1.5 nm. PMID- 26928581 TI - Mapping brain morphological and functional conversion patterns in predementia late-onset bvFTD. AB - PURPOSE: The diagnosis of behavioural variant frontotemporal dementia (bvFTD) is challenging during the predementia stage when symptoms are subtle and confounding. Morphological and functional neuroimaging can be particularly helpful during this stage but few data are available. METHODS: We retrospectively selected 25 patients with late-onset probable bvFTD. Brain structural MRI and FDG PET were performed during the predementia stage (mean MMSE score 27.1 +/- 2.5) on average 2 years before. The findings with the two imaging modalities were compared (SPM8) with those in a group of 20 healthy subjects. The bvFTD patients were divided into two subgroups: those with predominant disinhibition (bvFTD+) and those with apathy (bvFTD-). RESULTS: Hypometabolism exceeded grey matter (GM) density reduction in terms of both extension and statistical significance in all comparisons. In the whole bvFTD group, hypometabolism involved the bilateral medial, inferior and superior lateral frontal cortex, anterior cingulate, left temporal and right parietal cortices and the caudate nuclei. GM density reduction was limited to the right frontal cortex and the left medial temporal lobe. In bvFTD+ patients hypometabolism was found in the bilateral medial and basal frontal cortex, while GM reduction involved the left anterior cingulate and left inferior frontal cortices, and the right insula. In bvFTD- patients, atrophy and mainly hypometabolism involved the lateral frontal cortex and the inferior parietal lobule. CONCLUSION: These findings suggest that hypometabolism is more extensive than, and thus probably precedes, atrophy in predementia late-onset bvFTD, underscoring different topographic involvement in disinhibited and apathetic presentations. If confirmed in a larger series, these results should prompt biomarker operationalization in bvFTD, especially for patient selection in therapeutic clinical trials. PMID- 26928583 TI - Interfacial Properties of Monolayer and Bilayer MoS2 Contacts with Metals: Beyond the Energy Band Calculations. AB - Although many prototype devices based on two-dimensional (2D) MoS2 have been fabricated and wafer scale growth of 2D MoS2 has been realized, the fundamental nature of 2D MoS2-metal contacts has not been well understood yet. We provide a comprehensive ab initio study of the interfacial properties of a series of monolayer (ML) and bilayer (BL) MoS2-metal contacts (metal = Sc, Ti, Ag, Pt, Ni, and Au). A comparison between the calculated and observed Schottky barrier heights (SBHs) suggests that many-electron effects are strongly suppressed in channel 2D MoS2 due to a charge transfer. The extensively adopted energy band calculation scheme fails to reproduce the observed SBHs in 2D MoS2-Sc interface. By contrast, an ab initio quantum transport device simulation better reproduces the observed SBH in 2D MoS2-Sc interface and highlights the importance of a higher level theoretical approach beyond the energy band calculation in the interface study. BL MoS2-metal contacts generally have a reduced SBH than ML MoS2 metal contacts due to the interlayer coupling and thus have a higher electron injection efficiency. PMID- 26928585 TI - Transit of H2O2 across the endoplasmic reticulum membrane is not sluggish. AB - Cellular metabolism provides various sources of hydrogen peroxide (H2O2) in different organelles and compartments. The suitability of H2O2 as an intracellular signaling molecule therefore also depends on its ability to pass cellular membranes. The propensity of the membranous boundary of the endoplasmic reticulum (ER) to let pass H2O2 has been discussed controversially. In this essay, we challenge the recent proposal that the ER membrane constitutes a simple barrier for H2O2 diffusion and support earlier data showing that (i) ample H2O2 permeability of the ER membrane is a prerequisite for signal transduction, (ii) aquaporin channels are crucially involved in the facilitation of H2O2 permeation, and (iii) a proper experimental framework not prone to artifacts is necessary to further unravel the role of H2O2 permeation in signal transduction and organelle biology. PMID- 26928586 TI - Child injury: Does home matter? AB - This study examined the relationship between home risk and hospital treated injury in Australian children up to five years old. Women with children between two and four years of age enrolled in the Environments for Healthy Living (EFHL): Griffith Birth Cohort Study were invited to complete a Home Injury Prevention Survey from March 2013 to June 2014. A total home risk score (HRS) was calculated and linked to the child's injury related state-wide hospital emergency and admissions data and EFHL baseline demographic surveys. Data from 562 households relating to 566 child participants were included. We found an inverse relationship between home risk and child injury, with children living in homes with the least injury risk (based on the absence of hazardous structural features of the home and safe practices reported) having 1.90 times the injury rate of children living in high risk homes (95% CI 1.15-3.14). Whilst this appears counter-intuitive, families in the lowest risk homes were more likely to be socio economically disadvantaged than families in the highest risk homes (more sole parents, lower maternal education levels, younger maternal age and lower income). After adjusting for demographic and socio-economic factors, the relationship between home risk and injury was no longer significant (p > 0.05). Our findings suggest that children in socio-economically deprived families have higher rates of injury, despite living in a physical environment that contains substantially fewer injury risks than their less deprived counterparts. Although measures to reduce child injury risk through the modification of the physical environment remain an important part of the injury prevention approach, our study findings support continued efforts to implement societal-wide, long term policy and practice changes to address the socioeconomic differentials in child health outcomes. PMID- 26928584 TI - Redox regulation of epidermal growth factor receptor signaling during the development of pulmonary hypertension. AB - The development of pulmonary hypertension (PH) involves the uncontrolled proliferation of pulmonary smooth muscle cells via increased growth factor receptor signaling. However, the role of epidermal growth factor receptor (EGFR) signaling is controversial, as humans with advanced PH exhibit no changes in EGFR protein levels and purpose of the present study was to determine whether there are post-translational mechanisms that enhance EGFR signaling in PH. The EGFR inhibitor, gefinitib, significantly attenuated EGFR signaling and prevented the development of PH in monocrotaline (MCT)-exposed rats, confirming the contribution of EGFR activation in MCT induced PH. There was an early MCT mediated increase in hydrogen peroxide, which correlated with the binding of the active metabolite of MCT, monocrotaline pyrrole, to catalase Cys377, disrupting its multimeric structure. This early oxidative stress was responsible for the oxidation of EGFR and the formation of sodium dodecyl sulfate (SDS) stable EGFR dimers through dityrosine cross-linking. These cross-linked dimers exhibited increased EGFR autophosphorylation and signaling. The activation of EGFR signaling did not correlate with pp60(src) dependent Y845 phosphorylation or EGFR ligand expression. Importantly, the analysis of patients with advanced PH revealed the same enhancement of EGFR autophosphorylation and covalent dimer formation in pulmonary arteries, while total EGFR protein levels were unchanged. As in the MCT exposed rat model, the activation of EGFR in human samples was independent of pp60(src) phosphorylation site and ligand expression. This study provides a novel molecular mechanism of oxidative stress stimulated covalent EGFR dimerization via tyrosine dimerization that contributes into development of PH. PMID- 26928587 TI - Stigma of persons with disabilities in Afghanistan: Examining the pathways from stereotyping to mental distress. AB - Despite evidence that stigma of disability is frequently reflected through stereotyping and often results in mental distress, very limited literature demonstrates the pathways through which stereotyping has an impact on mental health. Drawing from a large sample of 1449 participants interviewed between December 2012 and September 2013 from an Afghan community-based rehabilitation program, we examined the structure of stigma associated with disability in Afghanistan. Labeling and negative stereotypes, associated with a specific cause of disability, result in social exclusion that in turn impacts mental health. Using structural equation modeling with latent variables, we examined the mediation effect of stereotypes associated with disability on mental distress and anxiety. We found a mediating role of social exclusion between stereotypes and mental distress but only in the case of persons with disabilities from birth. Comparing the total effect of 'disabled at birth' and mental distress 0.195 (95% CI: 0.018-0.367) the effect size of this mediation effect was 0.293 (95% CI: 0.173-0.415). There was no significant direct effect between 'disabled at birth' and mental distress once mediation effect was accounted for in our model. These findings suggest that a multipronged policy approach that recognizes the driving forces of stigma and promotes social participation directly alongside psychosocial interventions on mental distress of persons with disabilities is necessary to achieve wellbeing for a group that has been historically and systematically excluded from development interventions. PMID- 26928588 TI - Identification of a serum transglutaminase threshold value for the noninvasive diagnosis of symptomatic adult celiac disease patients: a retrospective study. AB - BACKGROUND: A celiac disease (CD) diagnosis is based on duodenal histology, with the exception of children showing anti-tissue transglutaminase (anti-tTG) serum levels exceeding ten times the cut-off. Our aim was to reproduce this simplified approach in adults, identifying an anti-tTG threshold value useful to diagnose CD without endoscopic procedures. METHODS: A total of 671 adult CD patients were subjected to blood sampling to determine anti-tTG serum levels, as well as to endoscopy with biopsy to perform duodenal histology. The anti-tTG serum levels/cut-off ratio was compared with the degree of duodenal lesions. RESULTS: Anti-tTG serum levels/cut-off ratio determined in patients with type IIIc was significantly higher than that measured in patients with type IIIb (p < 0.001), IIIa (p < 0.001), II (p < 0.05) and 0 (p < 0.001) of Marsh-Oberhuber histological classification. A significant correlation (r = 0.297, p < 0.0001) was found between the anti-tTG serum levels/cut-off ratio and the degree of duodenal lesions. The anti-tTG serum levels/cut-off ratio was classified as an accurate parameter (AUC = 0.715, p < 0.0001), with the best diagnostic performance obtained considering the threshold value >3.6 (sensitivity = 76.8 %, PPV = 97.2 %). CONCLUSIONS: The anti-tTG serum levels/cut-off ratio correlates with the degree of duodenal lesions and, if used with the threshold value >3.6, could avoid endoscopy with biopsy in about 75 % of seropositive adults waiting for CD diagnosis. However, since this procedure could also imply CD diagnosis in almost 3 % of seropositive patients with normal villous architecture, a consensus opinion is needed to suggest its use in the diagnosis of adult CD. PMID- 26928589 TI - The effect of moderate-intensity exercise on the expression of HO-1 mRNA and activity of HO in cardiac and vascular smooth muscle of spontaneously hypertensive rats. AB - The objective of this study was to observe the effects of moderate-intensity training on the activity of heme oxygenase (HO) and expression of HO-1 mRNA in the aorta and the cardiac muscle of spontaneously hypertensive rats (SHRs). After 9 weeks of swimming exercise, the activity of HO and expression of HO-1 mRNA in the SHRs were measured. The resting blood pressure in the exercise group was increased by 1.7% (P > 0.05), whereas it was significantly elevated by 10.3% (P < 0.01) in the SHR rats. Compared with animals in the control and sedentary groups, the expression level of HO-1 mRNA of aorta and cardiac muscle in the exercise group was significantly enhanced (P < 0.01). The HO activity and the content of plasma carbon monoxide (CO) in the sedentary group were dramatically decreased (P < 0.05 and P < 0.01, respectively) compared with the control group. HO activity and content of plasma CO in the exercise group were significantly higher compared with those in the sedentary group (P < 0.05 and P < 0.01, respectively). The HO/CO metabolic pathway might be involved in the regulation of blood pressure of the SHR models. PMID- 26928590 TI - Lipids in plant-microbe interactions. AB - Bacteria and fungi can undergo symbiotic or pathogenic interactions with plants. Membrane lipids and lipid-derived molecules from the plant or the microbial organism play important roles during the infection process. For example, lipids (phospholipids, glycolipids, sphingolipids, sterol lipids) are involved in establishing the membrane interface between the two organisms. Furthermore, lipid derived molecules are crucial for intracellular signaling in the plant cell, and lipids serve as signals during plant-microbial communication. These signal lipids include phosphatidic acid, diacylglycerol, lysophospholipids, and free fatty acids derived from phospholipase activity, apocarotenoids, and sphingolipid breakdown products such as ceramide, ceramide-phosphate, long chain base, and long chain base-phosphate. Fatty acids are the precursors for oxylipins, including jasmonic acid, and for azelaic acid, which together with glycerol-3 phosphate are crucial for the regulation of systemic acquired resistance. This article is part of a Special Issue titled "Plant Lipid Biology," guest editors Kent Chapman and Ivo Feussner. PMID- 26928592 TI - The counterflow transport of sterols and PI4P. AB - Cholesterol levels in intracellular membranes are constantly adjusted to match with specific organelle functions. Cholesterol is kept high in the plasma membrane (PM) because it is essential for its barrier function, while low levels are found in the endoplasmic reticulum (ER) where cholesterol mediates feedback control of its own synthesis by sterol-sensor proteins. The ER->Golgi->PM concentration gradient of cholesterol in mammalian cells, and ergosterol in yeast, appears to be sustained by specific intracellular transport processes, which are mostly mediated by lipid transfer proteins (LTPs). Here we review a recently described function of two LTPs, OSBP and its yeast homolog Osh4p, which consists in creating a sterol gradient between membranes by vectorial transport. OSBP also contributes to the formation of ER/Golgi membrane contact sites, which are important hubs for the transfer of several lipid species. OSBP and Osh4p organize a counterflow transport of lipids whereby sterols are exchanged for the phosphoinositide PI4P, which is used as a fuel to drive sterol transport. This article is part of a Special Issue entitled: The cellular lipid landscape edited by Tim P. Levine and Anant K. Menon. PMID- 26928593 TI - Oncogenic MicroRNAs Biogenesis as a Drug Target: Structure-Activity Relationship Studies on New Aminoglycoside Conjugates. AB - MicroRNAs (miRNAs) are a recently discovered category of small RNA molecules that regulate gene expression at the post-transcriptional level. Accumulating evidence indicates that miRNAs are aberrantly expressed in a variety of human cancers and that the inhibition of these oncogenic miRNAs could find application in the therapy of different types of cancer. Herein, we describe the synthesis and biological evaluation of new small-molecule drugs that target oncogenic miRNAs production. In particular, we chose to target two miRNAs (i.e., miRNA-372 and 373) implicated in various types of cancer, such as gastric cancer. Their precursors (pre-miRNAs) are overexpressed in cancer cells and lead to mature miRNAs after cleavage of their stem-loop structure by the enzyme Dicer in the cytoplasm. Some of the newly synthesized conjugates can inhibit Dicer processing of the targeted pre-miRNAs in vitro with increased efficacy relative to our previous results (D.D. Vo et al., ACS Chem. Biol. 2014, 9, 711-721) and, more importantly, to inhibit proliferations of adenocarcinoma gastric cancer (AGS) cells overexpressing these miRNAs, thus representing promising leads for future drug development. PMID- 26928591 TI - Peroxidase activation of cytoglobin by anionic phospholipids: Mechanisms and consequences. AB - Cytoglobin (Cygb) is a hexa-coordinated hemoprotein with yet to be defined physiological functions. The iron coordination and spin state of the Cygb heme group are sensitive to oxidation of two cysteine residues (Cys38/Cys83) and/or the binding of free fatty acids. However, the roles of redox vs lipid regulators of Cygb's structural rearrangements in the context of the protein peroxidase competence are not known. Searching for physiologically relevant lipid regulators of Cygb, here we report that anionic phospholipids, particularly phosphatidylinositolphosphates, affect structural organization of the protein and modulate its iron state and peroxidase activity both conjointly and/or independently of cysteine oxidation. Thus, different anionic lipids can operate in cysteine-dependent and cysteine-independent ways as inducers of the peroxidase activity. We establish that Cygb's peroxidase activity can be utilized for the catalysis of peroxidation of anionic phospholipids (including phosphatidylinositolphosphates) yielding mono-oxygenated molecular species. Combined with the computational simulations we propose a bipartite lipid binding model that rationalizes the modes of interactions with phospholipids, the effects on structural re-arrangements and the peroxidase activity of the hemoprotein. PMID- 26928594 TI - Human malaria diagnosis using a single-step direct-PCR based on the Plasmodium cytochrome oxidase III gene. AB - BACKGROUND: Nested PCRs based on the Plasmodium 18s-rRNA gene have been extensively used for human malaria diagnosis. However, they are not practical when large quantities of samples need to be processed, further there have been challenges in the performance and when interpreting results, especially when submicroscopic infections are analysed. Here the use of "direct PCR" was investigated with the aim of improving diagnosis in the malaria elimination era. METHODS: The performance of the Plasmodium cytochrome oxidase III gene (COX-III) based novel malaria detection strategies (direct nested PCR and direct single PCR) were compared using a 18s-rRNA direct nested PCR as a reference tool. Evaluations were based on sensitivity, specificity and the ability to detect mixed infections using control blood spot samples and field collected blood samples with final species diagnosis confirmation by sequencing. RESULTS: The COX III direct PCR (limit of detection: 0.6-2 parasites/MUL) was more sensitive than the 18s-rRNA direct nested PCR (limit of detection: 2-10 parasites/MUL). The COX III direct PCR identified all 21 positive controls (no mixed infections detected) while the 18s-rRNA direct nested PCR identified 18/21 (including four mixed infections). Different concentrations of simulated mixed infections (Plasmodium vivax and Plasmodium falciparum) suggest that the COX-III direct PCR detects only the predominant species. When the 18s-rRNA direct nested PCR was used to detect Plasmodium in field collected bloods spots (n = 3833), there was discrepancy in the results from the genus PCR (16 % positive) and the species-specific PCR (5 % positive). Further, a large portion of a subset of these positive samples (93 % for genus and 60 % for P. vivax), did not align with Plasmodium sequences. In contrast, the COX-III direct PCR clearly identified (single bands confirmed with sequencing) 2 % positive Plasmodium samples including P. vivax, P. falciparum, Plasmodium malariae and Plasmodium ovale wallikeri. CONCLUSIONS: The COX-III single direct PCR is an alternative method for accurate detection of Plasmodium microscopic and submicroscopic infections in humans, especially when a large number of samples require screening. This PCR does not require DNA isolation, is sensitive, quick, produces confident/clear results, identifies all the Plasmodium species infecting humans, and is cost-effective. PMID- 26928595 TI - Microscale characterization of the viscoelastic properties of hydrogel biomaterials using dual-mode ultrasound elastography. AB - Characterization of the microscale mechanical properties of biomaterials is a key challenge in the field of mechanobiology. Dual-mode ultrasound elastography (DUE) uses high frequency focused ultrasound to induce compression in a sample, combined with interleaved ultrasound imaging to measure the resulting deformation. This technique can be used to non-invasively perform creep testing on hydrogel biomaterials to characterize their viscoelastic properties. DUE was applied to a range of hydrogel constructs consisting of either hydroxyapatite (HA)-doped agarose, HA-collagen, HA-fibrin, or preosteoblast-seeded collagen constructs. DUE provided spatial and temporal mapping of local and bulk displacements and strains at high resolution. Hydrogel materials exhibited characteristic creep behavior, and the maximum strain and residual strain were both material- and concentration-dependent. Burger's viscoelastic model was used to extract characteristic parameters describing material behavior. Increased protein concentration resulted in greater stiffness and viscosity, but did not affect the viscoelastic time constant of acellular constructs. Collagen constructs exhibited significantly higher modulus and viscosity than fibrin constructs. Cell-seeded collagen constructs became stiffer with altered mechanical behavior as they developed over time. Importantly, DUE also provides insight into the spatial variation of viscoelastic properties at sub-millimeter resolution, allowing interrogation of the interior of constructs. DUE presents a novel technique for non-invasively characterizing hydrogel materials at the microscale, and therefore may have unique utility in the study of mechanobiology and the characterization of hydrogel biomaterials. PMID- 26928596 TI - Caspase-1 Plays a Critical Role in Accelerating Chronic Kidney Disease-Promoted Neointimal Hyperplasia in the Carotid Artery. AB - To determine whether caspase-1 is critical in chronic kidney disease (CKD) mediated arterial neointimal hyperplasia (NH), we utilized caspase(-/-) mice and induced NH in carotid artery in a CKD environment, and uremic sera-stimulated human vascular smooth muscle cells (VSMC). We made the following findings: (1) Caspase-1 inhibition corrected uremic sera-mediated downregulation of VSMC contractile markers, (2) CKD-promoted NH was attenuated in caspase(-/-) mice, (3) CKD-mediated downregulation of contractile markers was rescued in caspase null mice, and (4) expression of VSMC migration molecule alphavbeta3 integrin was reduced in caspase(-/-) tissues. Our results suggested that caspase-1 pathway senses CKD metabolic danger signals. Further, CKD-mediated increase of contractile markers in VSMC and increased expression of VSMC migration molecule alphavbeta3 integrin in NH formation were caspase-1 dependent. Therefore, caspase 1 is a novel therapeutic target for the suppression of CKD-promoted NH. PMID- 26928599 TI - Thirteen-And-A-Half Syndrome. AB - We describe a 50-year-old man who developed eight-and-a-half syndrome associated with an ipsilateral trigeminal nerve palsy because of a post-transplant lymphoproliferative disorder. This case widens the spectrum of eight-and-a-half syndrome to include a thirteen-and-a-half syndrome. PMID- 26928597 TI - The concomitant administration of systemic amoxicillin and metronidazole compared to scaling and root planing alone in treating periodontitis: =a systematic review=. AB - BACKGROUND: The treatment of periodontitis begins with a non-surgical phase that includes scaling and root planing(SRP) and on occasion the use of systemic antibiotics. The goal was to systematically evaluate in systemic healthy adults the effect of the concomitant administration of amoxicillin (amx) and metronidazole (met) adjunctive to SRP compared to SRP alone. METHODS: The PubMed MEDLINE, Cochrane-CENTRAL and EMBASE databases were searched up to November 2014 to identify appropriate studies. Probing Pocket Depth (PD), Clinical Attachment Level (CAL), Bleeding on Pocket Probing(BOP) and Plaque Indices(PI) were selected as outcome variables. Based on the extracted data a meta-analysis was conducted. RESULTS: A total of 526 unique articles were found, 20 studies met the eligibility criteria. A meta-analysis showed that SRP + amx + met provided significantly better effects overall and more pronounced PD reduction in periodontal pockets initially measuring >=6 mm (DiffM:-0.86 mm, p < 0.00001) and gain in CAL(DiffM:+0.75 mm, p = 0.0001). The meta-analysis for the secondary inflammatory parameter BOP showed that SRP + amx + met provided full mouth significantly greater reduction in BOP than SRP alone (DiffM:-6.98 %, p = 0.0001). CONCLUSION: Adjunctive systemic amoxicillin and metronidazole medication to SRP significantly improved the clinical outcomes with respect to mean PD, CAL and BOP compared to SRP alone. There is moderate to strong evidence in support of the recommendation that adjunctive amx + met therapy to SRP significantly improves the clinical outcomes, with respect to mean PD and CAL compared to SRP alone especially in initially deep (>=6 mm) pockets. No major side effects associated with the intake of amx + met were reported. This treatment regimen is an efficacious, minimally invasive, practical and inexpensive approach for periodontitis therapy. The key components are mechanical tooth and pocket debridement, supportive treatment of the disease with systemic antibiotics and attention to proper self-care. PMID- 26928598 TI - Metabolic Trade-offs in Yeast are Caused by F1F0-ATP synthase. AB - Intermediary metabolism provides living cells with free energy and precursor metabolites required for synthesizing proteins, lipids, RNA and other cellular constituents, and it is highly conserved among living species. Only a fraction of cellular protein can, however, be allocated to enzymes of intermediary metabolism and consequently metabolic trade-offs may take place. One such trade-off, aerobic fermentation, occurs in both yeast (the Crabtree effect) and cancer cells (the Warburg effect) and has been a scientific challenge for decades. Here we show, using flux balance analysis combined with in vitro measured enzyme specific activities, that fermentation is more catalytically efficient than respiration, i.e. it produces more ATP per protein mass. And that the switch to fermentation at high growth rates therefore is a consequence of a high ATP production rate, provided by a limited pool of enzymes. The catalytic efficiency is also higher for cells grown on glucose compared to galactose and ethanol, which may explain the observed differences in their growth rates. The enzyme F1F0-ATP synthase (Complex V) was found to have flux control over respiration in the model, and since it is evolutionary conserved, we expect the trade-off to occur in organisms from all kingdoms of life. PMID- 26928600 TI - Orbital Apex Syndrome Secondary to Herpes Zoster Ophthalmicus. AB - Orbital apex syndrome is a rare complication of herpes zoster ophthalmicus. In addition to our case, we review the clinical presentation, imaging findings, treatment options, and prognosis of 14 other reported cases. Magnetic resonance imaging of our patient demonstrated diffuse enhancement of the orbit involving the orbital apex, optic nerve and/or nerve sheath, extraocular muscles, and orbital soft tissues. There was significant clinical improvement with acyclovir and systemic corticosteroids, which seems to be preferred treatment for this disorder. PMID- 26928601 TI - Identifying profiles of actual and perceived motor competence among adolescents: associations with motivation, physical activity, and sports participation. AB - The present study identified adolescents' motor competence (MC)-based profiles (e.g., high actual and low perceived MC), and accordingly investigated differences in motivation for physical education (PE), physical activity (PA) levels, and sports participation between profiles by using regression analyses. Actual MC was measured with the Korperkoordinationstest fur Kinder. Adolescents (n = 215; 66.0% boys; mean age = 13.64 +/- .58 years) completed validated questionnaires to assess perceived MC, motivation for PE, PA-levels, and sports participation. Actual and perceived MC were only moderately correlated and cluster analyses identified four groups. Two groups of overestimators (low - overestimation, average - overestimation) were identified (51%), who particularly displayed better motivation for PE when compared to their peers who accurately estimated themselves (low - accurate, average - accurate). Moreover, adolescents with low actual MC, but high perceived MC were significantly more active than adolescents with low actual MC who accurately estimated themselves. Results pointed in the same direction for organised sports participation. Underestimators were not found in the current sample, which is positive as underestimation might negatively influence adolescents' motivation to achieve and persist in PA and sports. In conclusion, results emphasise that developing perceived MC, especially among adolescents with low levels of actual MC, seems crucial to stimulate motivation for PE, and engagement in PA and sports. PMID- 26928602 TI - Is the inhibition of the liver uptake and biliary excretion, via transporters, the likely mechanism for the increased exposure of vitexin-2''-O-rhamnoside with bile salts in rats? PMID- 26928603 TI - Circulating Th17 cytokine levels are altered in Hashimoto's thyroiditis. AB - The disrupted autoimmune response in Hashimoto's thyroiditis (HT) has long been considered to be dominantly T helper type 1 (Th1) mediated. Recent advances in the field of immunology have introduced a new class of effector T cells, named 'Th17', which plays important roles in autoimmune disorders once thought to be merely Th1 mediated. We aimed to examine the levels of major Th17 cytokines in patients with HT in this study. We studied serum interleukin 17 (IL-17) and interleukin 23 (IL-23) levels in 46 newly diagnosed, untreated patients with HT (40 women and 6 men, aged 40.0 +/- 11.8 years) divided into euthyroid (n=22) and hypothyroid (n=24) groups and compared them with age and sex matched 26 healthy euthyroid controls without HT (21 women and 5 men; aged 36.0 +/- 12.9 years). Serum IL-17 and IL-23 levels were significantly different among euthyroid and hypothyroid HT patients and controls, with highest levels obtained in the euthyroid HT group (p=0.041 for IL-17 and p<0.001 for IL-23). TSH was negatively and FT4 was positively correlated with IL-17 (p=0.016 for TSH and p=0.004 for FT4) and IL-23 (p<0.001 for TSH and p=0.003 for FT4) levels. There were no correlations between thyroid volumes calculated on thyroid ultrasonography and IL 17 (p=0.630) or IL-23 (p=0.321) levels. In conclusion, the levels of IL-17, one of the major effector cytokines of the Th17 system, and IL-23, which had been implicated in the generation, survival and expansion of Th17 cells, are altered in HT. How thyroid hormone status and the course of disease affect Th17 system in chronic autoimmune thyroiditis needs to be determined with further studies. PMID- 26928604 TI - Plasma levels of TGF-beta1 in homeostasis of the inflammation in sickle cell disease. AB - Sickle cell disease (SCD) represents a chronic inflammatory condition with complications triggered by the polymerization of hemoglobin S (Hb S), resulting in a series of cellular interactions mediated by inflammatory cytokines, as the transforming growth factor beta (TGF-beta), which plays an important role in inflammation resolution. This study assessed the relation between SCD inflammation and the plasma concentration of TGF-beta1, and also checked the influence of the presence of -509C/T polymorphism in TGFB1 gene on TGF-beta1 plasma values. The plasma levels of TGF-beta1 were quantified by ELISA in 115 patients with SCD (genotypes SS, SD-Los Angeles, Sbeta-thalassemia and SC) and in 58 individuals with no hemoglobinopathies (Hb AA), as the control group. The 509C/T polymorphism in TGFB1 gene was screened by PCR-RFLP. The correlation between TGF-beta1 plasma levels and the inflammation was based on its association with the count of platelets, total white blood cells (WBC) and neutrophils in the peripheral blood. Patients with SCD showed plasma levels of TGF-beta1 higher than the control group, especially the Hb SS genotype, followed by the group with Hb SD. Polymorphism investigation showed no interference in the values obtained for the cytokine in the groups evaluated. All SCD groups showed TGF-beta1 levels positively correlated to the platelets and WBC counts. The original data obtained in this study for SCD support the involvement of TGF-beta1 in regulating of the inflammatory response and suggest that this marker possibly may become a potential therapeutic target in the treatment of the disease. PMID- 26928606 TI - Ultrahigh Detective Heterogeneous Photosensor Arrays with In-Pixel Signal Boosting Capability for Large-Area and Skin-Compatible Electronics. AB - An ultra-thin and large-area skin-compatible heterogeneous organic/metal-oxide photosensor array is demonstrated which is capable of sensing and boosting signals with high detectivity and signal-to-noise ratio. For the realization of ultra-flexible and high-sensitive heterogeneous photosensor arrays on a polyimide substrate having organic sensor arrays and metal-oxide boosting circuitry, solution-processing and room-temperature alternating photochemical conversion routes are applied. PMID- 26928605 TI - A functional NMR for membrane proteins: dynamics, ligand binding, and allosteric modulation. AB - By nature of conducting ions, transporting substrates and transducing signals, membrane channels, transporters and receptors are expected to exhibit intrinsic conformational dynamics. It is therefore of great interest and importance to understand the various properties of conformational dynamics acquired by these proteins, for example, the relative population of states, exchange rate, conformations of multiple states, and how small molecule ligands modulate the conformational exchange. Because small molecule binding to membrane proteins can be weak and/or dynamic, structural characterization of these effects is very challenging. This review describes several NMR studies of membrane protein dynamics, ligand-induced conformational rearrangements, and the effect of ligand binding on the equilibrium of conformational exchange. The functional significance of the observed phenomena is discussed. PMID- 26928607 TI - Granzyme M and K release in human experimental endotoxemia. AB - Granzymes are serine proteases involved in killing of tumor cells and virally infected cells. However, granzymes are also upregulated in blood under inflammatory conditions and contribute to cytokine release and processing. Here, we show that granzyme M (GrM) and to a lesser extent GrK are transiently elevated in the circulation following LPS administration in humans. GrM is released upon stimulation of whole blood with LPS or the gram-negative bacteria Escherichia coli BL21, Pseudomonas aeruginosa, and Neisseria meningitidis. GrK is only released upon stimulation with P. aeruginosa. Thus, GrM and GrK are differentially released in response to LPS and gram-negative bacteria. PMID- 26928608 TI - Root-associated fungi of Vaccinium carlesii in subtropical forests of China: intra- and inter-annual variability and impacts of human disturbances. AB - Ericoid mycorrhiza (ERM) are expected to facilitate establishment of ericaceous plants in harsh habitats. However, diversity and driving factors of the root associated fungi of ericaceous plants are poorly understood. In this study, hair root samples of Vaccinium carlesii were taken from four forest types: old growth forests (OGF), secondary forests with once or twice cutting (SEC I and SEC II), and Cunninghamia lanceolata plantation (PLF). Fungal communities were determined using high-throughput sequencing, and impacts of human disturbances and the intra and inter-annual variability of root-associated fungal community were evaluated. Diverse fungal taxa were observed and our results showed that (1) Intra- and inter-annual changes in root-associated fungal community were found, and the Basidiomycota to Ascomycota ratio was related to mean temperature of the sampling month; (2) Human disturbances significantly affected structure of root-associated fungal community of V. carlesii, and two secondary forest types were similar in root-associated fungal community and were closer to that of the old growth forest; (3) Plant community composition, edaphic parameters, and geographic factors significantly affected root-associated fungal communities of V. carlesii. These results may be helpful in better understanding the maintenance mechanisms of fungal diversity associated with hair roots of ERM plants under human disturbances. PMID- 26928609 TI - Induction of Autophagy interferes the tachyzoite to bradyzoite transformation of Toxoplasma gondii. AB - Autophagy process in Toxoplasma gondii plays a vital role in regulating parasite survival or death. Thus, once having an understanding of certain effects of autophagy on the transformation of tachyzoite to bradyzoite this will allow us to elucidate the function of autophagy during parasite development. Herein, we used three TgAtg proteins involved in Atg8 conjugation system, TgAtg3, TgAtg7 and TgAtg8 to evaluate the autophagy level in tachyzoite and bradyzoite of Toxoplasma in vitro based on Pru TgAtg7-HA transgenic strains. We showed that both TgAtg3 and TgAtg8 were expressed at a significantly lower level in bradyzoites than in tachyzoites. Importantly, the number of parasites containing fluorescence labelled TgAtg8 puncta was significantly reduced in bradyzoites than in tachyzoites, suggesting that autophagy is downregulated in Toxoplasma bradyzoite in vitro. Moreover, after treatment with drugs, bradyzoite-specific gene BAG1 levels decreased significantly in rapamycin-treated bradyzoites and increased significantly in 3-MA-treated bradyzoites in comparison with control bradyzoites, indicating that Toxoplasma autophagy is involved in the transformation of tachyzoite to bradyzoite in vitro. Together, it is suggested that autophagy may serve as a potential strategy to regulate the transformation. PMID- 26928610 TI - [Intensive chemotherapy for Burkitt lymphoma in HIV positive patients]. AB - BACKGROUND: Burkitt lymphoma has a low incidence, is highly aggressive, may be endemic, sporadic or associated with immunodeficiency and it has a high frequency of extranodal involvement. Overall and relapse free survival in HIV patients is 72 and 71% respectively. However, the current protocol in Chile considers a positive HIV serology as an exclusion criterion for intensive chemotherapy. AIM: To analyze the response to Burkitt lymphoma treatment among HIV positive patients. MATERIAL AND METHODS: All HIV positive patients with a Burkitt lymphoma treated using PANDA protocol in a public hospital were analyzed. RESULTS: Eight male patients aged between 25 and 43 years, 63% in stage IV, were analyzed. All patients received an intensified chemotherapy regime, three of them without Rituximab. Complete remission was achieved in 87%. One patient was refractory to treatment and one patient relapsed at 5 months and died. Overall and relapse free survival were 58 and 60% respectively. All patients had episodes of high risk febrile neutropenia, but it did not cause deaths. CONCLUSIONS: In this group of HIV patients, intensive chemotherapy for Burkitt lymphoma had a high degree of effectiveness with a low relapse rate and high cure rate. PMID- 26928611 TI - [Transcatheter aortic valve implantation.Experience in 26 patients]. AB - BACKGROUND: Aortic valve stenosis (AS) is the most common valvular disease. Its surgical indication is undisputed in symptomatic severe AS, however, 30% of patients are at high surgical risk or inoperable. Transcatheter Valve Implantation (TAVI) is an alternative for this group of patients. AIM: To describe the clinical outcomes of TAVI in a group of patients treated at the Instituto Nacional del Torax, Santiago, Chile. PATIENTS AND METHODS: Prospective study including all patients referred for TAVI due to their high surgical risk or being inoperable. All-cause mortality, secondary stroke, permanent pacemaker implantation, vascular complications, prosthetic and periprosthetic regurgitation, Karnosfky test and Functional Capacity (FC) were assessed as endpoints. RESULTS: We evaluated 26 patients with a mean age of 82 years (74% women) in whom 27 procedures were done. The mean Society of Thoracic Surgeons score was 8.8%. Overall mortality at 30 days, one and two years was 11.1, 18.5 and 29.6% respectively. Karnofsky score increased significantly from 62.3% at baseline to 83.9; 88.6 and 88.8% at six months, one and two years, respectively. Prior to the procedure, FC was 3.1 +/- 0.6, decreasing significantly to 1.2; 1.3 and 1 at six months, one and two years of follow up. CONCLUSIONS: TAVI is an effective alternative treatment for patients with severe symptomatic AS and high surgical risk. PMID- 26928612 TI - [Active search of celiac disease among first degree relatives of known celiac patients]. AB - BACKGROUND: Active search of celiac disease (CD) among risk groups has significantly increased the scope of known clinical variants. AIM: To measure the frequency and clinical characteristics of CD among first degree relatives (FDR) of known celiac cases. MATERIAL AND METHODS: Between January 2012-August 2013, 37 patients with celiac disease brought 113 FDR for assessment. Their clinical data was recorded and a blood sample was obtained to measure serum Immunoglobulin A (IgA) levels, anti-transglutaminase (tTG) and anti-endomisial (EMA) antibodies. Cases with positive serology were advised to have an intestinal biopsy. RESULTS: Fourteen relatives (12.4%) had positive serological results and none had IgA deficiency. Among IgA-tTG (-) cases, measurement of IgA/IgG-tTG identified an additional case. Two of the 14 relatives were EMA positive. All 14 cases were advised to have an intestinal biopsy, but only 6 accepted the procedure. In two, the intestinal lesion was classified Marsh >= 2 and active CD was diagnosed. Histology in the remaining four was Marsh 0/1 and were diagnosed potential CD, remaining under control, without gluten free diet. CONCLUSIONS: Serological prevalence of CD among first degree relatives of known celiac cases was 15 fold greater than in THE general Chilean population, strongly supporting the idea of implementing active search to customary clinical practice. Determination of IgA/IgG-tTG may be useful to improve the yield of active search. Intestinal biopsies were crucial to differentiate active classic CD from potential CD. PMID- 26928613 TI - [Typologies and arguments about the use of assisted reproductive technologies among people living in Santiago, Chile]. AB - BACKGROUND: Assisted reproductive technologies still generate debate about ethical moral and religious issues. AIM: To analyze the opinions of the general public about the use of assisted reproduction technology (ART). MATERIAL AND METHODS: This analysis used the information gathered in a survey about human reproduction and modern reproduction technologies applied to a random sample of 1,500 volunteers aged 18 to 65 years, living in Santiago, Chile. Also, data from 25 structured interviews and six focal groups of eight participants each was used. To typify opinions concerning the use of assisted reproductive technologies (ART), a multiple correspondence analysis was undertaken. RESULTS: People that support ART are non-religious young people of medium-high socioeconomic level. The arguments most commonly used by people to justify their positions about ART are the right to have children, the protection of kinship, that ART implies commercialization and manipulation of human life, the need to obey God's will, and the autonomy of informed and educated adults. CONCLUSIONS: The study allows us to understand in more complex ways the positions about ART. Chile does not have a legislation that regulates the use of ART. Generating information on the public opinion about these techniques we hope to contribute to the debate about the access and regulation of new reproductive technologies in Chile. PMID- 26928614 TI - [Predictive value of breast imaging report and database system (BIRADS) to detect cancer in a reference regional hospital]. AB - BACKGROUND: To validate the BIRADS in mammography, the calculation of its predictive value in each center is required, as recommended by the American College of Radiology. AIM: To determine the predictive value of the BIRADS system in our center. MATERIAL AND METHODS: All ultrasound guided needle percutaneous biopsies, performed at our center between 2006 and 2010 were reviewed. Predictive value, sensitivity, specificity and diagnostic accuracy of BIRADS were calculated, with a confidence interval of 95%. RESULTS: Of 1,313 biopsies available, 1,058 met the inclusion criteria. Fifty eight percent of biopsies were performed to women with mammographies classified as BIRADS 4 or 5. The presence of cancer in mammographies classified as BIRADS 0 was 4%. The prevalence of cancer for mammographies BIRADS 1, 2, 3, 4 and 5 were 0, 3, 2.7, 17.7 and 72.4% respectively. The positive and negative predictive values of BIRADS classification were 55 and 92 % respectively. CONCLUSIONS: In our institution BIRADS classification 4 and 5 has a high positive predictive value for detecting cancer as in developed countries. PMID- 26928615 TI - [Frequency and severity of periodontitis among patients with rheumatoid arthritis]. AB - BACKGROUND: Periodontitis may have a triggering and aggravating role of various medical conditions, including rheumatoid arthritis. AIM: To evaluate the periodontal status in Chilean patients with rheumatoid arthritis (RA), treated in a public hospital. PATIENTS AND METHODS: A trained professional conducted a periodontal examination in 40 patients with RA aged 23 to 73 years (85% women). When present, the severity of periodontitis and its relationship with gender, smoking, age, corticosteroids dose and AR activity were assessed. AR activity was evaluated using the Disease Activity Score Calculator for Rheumatoid Arthritis (DAS 28). RESULTS: Thirty five of the 40 patients had periodontitis and in 13, it was severe. Men, smokers, and older patients had more severe stages. Patients using higher doses of corticosteroids had lower severity of periodontitis. No relationship between the severity of periodontitis and AR activity was found. CONCLUSIONS: Periodontitis is common and severe in patients with RA, and is influenced by gender, age, smoking and corticosteroid dose. PMID- 26928616 TI - [Causes for consultation in the emergency room among patients with systemic autoimmune diseases]. AB - BACKGROUND: The causes of acute decompensations of patients with systemic autoimmune diseases are not well known. AIM: To describe the causes for consultation in an emergency room of patients with systemic autoimmune diseases. MATERIAL AND METHODS: Review of medical records of patients with systemic autoimmune diseases, aged over 14 years, consulting in an emergency room of a general hospital during three months. RESULTS: In the study period, 166 patients with systemic autoimmune diseases consulted in the emergency room, of a total of 18,153 consultations (0.9%). Patients with rheumatoid arthritis were those that consulted with higher frequency (37%) followed by patients with systemic lupus erythematosus (21%). The most common causes for consultation were cardiovascular diseases in 25%, followed by digestive disorders in 15%. The most common diagnosis was chest pain with suspected ischemic heart disease in 36%. No differences in cardiovascular risk factors were observed between those patients consulting for cardiovascular diseases and those consulting for other causes. CONCLUSIONS: The most common cause of consultation in the emergency room of patients with systemic autoimmune diseases is cardiovascular. PMID- 26928617 TI - [Hip fracture. Experience in 647 Chilean patients aged 60 years or more]. AB - BACKGROUND: Hip fractures (HFx) are an important geriatric syndrome, with a high incidence in developing countries. AIM: To describe characteristics of a group of Chilean patients with HFx. PATIENTS AND METHODS: In a cross-sectional study we included patients aged 60 years or more with a HF admitted to an orthopedic service along three years. Age, incidence, location, seasonality, hospital stay, time between HFx and surgery, mortality, prior treatment for osteoporosis, anatomical location, etiology and type of surgery were evaluated. RESULTS: We reviewed 647 patients with a median age of 81 years (76% women). The calculated incidence of hip fracture for people aged >= 65 years was 177/100,000. Sixty six percent of fractures were extracapsular. Mean hospital stay was 17 days and the mean lapse between the fracture and surgery was 19 days. Eighty four percent of patients had osteoporosis and only 5% were receiving treatment. Eighty three percent of patients were operated. Osteosynthesis was mainly used for extracapsular fractures and arthroplasty for intracapsular lesions. Intracapsular HFx tended to occur more commonly during warm seasons (Odds ratio = 1.534). Mortality at one year was 24%. It was higher among non-operated patients in whom the proportion of males and number of comorbidities were significantly higher. CONCLUSIONS: A high proportion of patients with HFx have osteoporosis albeit a reduced number is receiving treatment. Non-operated patients had a higher risk profile and higher mortality. PMID- 26928619 TI - [A consensus of the Chilean Nephrology and Rheumatology Societies on renal involvement in systemic lupus erythematosus]. AB - Renal involvement affects over one half of patients with Systemic Lupus Erythematosus increasing their mortality and morbidity, including chronic renal disease and the need of renal replacement therapies. Aiming to achieve a consensus in the most relevant topics on diagnosis, therapy and follow-up of patients with lupus renal disease, the Chilean Societies of Nephrology and Rheumatology constituted a workgroup that, based on a critical review of the available literature and their experience, raised and answered by consensus a set of relevant questions. This document includes aspects related to the clinical diagnosis, the importance of a suitable histological classification, therapeutic alternatives to induce and maintain disease remission, strategies for follow-up, additional therapies and gynecological-obstetric issues. PMID- 26928618 TI - Familial Mediterranean Fever is associated with abnormal ventricular repolarization indices. AB - BACKGROUND: Cardiac arrhythmias can be a part of cardiovascular involvement in some rheumatic diseases, but data about familial Mediterranean fever (FMF) are conflicting. AIM: To search for abnormalities in ventricular repolarization indices in FMF patients. PATIENTS AND METHODS: Seventy seven FMF patients and 30 age/gender comparable healthy controls were included. All patients were attack free and subjects with disease or drugs that are known to alter cardiac electrophysiology were excluded. Electrocardiographic data were obtained and analyzed. RESULTS: Twelve FMF patients had amyloidosis. QT and QTc intervals were within the normal ranges and similar between FMF patients and healthy controls. QT dispersion, peak to end interval of T wave (Tpe), Tpe/QT and Tpe/QTc ratios were significantly higher in FMF patients than in healthy controls. Patients with amyloidosis had significantly higher QT dispersion, Tpe, Tpe/QT and Tpe/QTc than their counterparts without FMF. Levels of proteinuria were moderately correlated with QT dispersion, Tpe, Tpe/QT and Tpe/QTc. CONCLUSIONS: FMF patients may have an increased risk for arrhythmias. PMID- 26928620 TI - [Learning strategies of autonomous medical students]. AB - BACKGROUND: Understanding how autonomous students are capable of regulating their own learning process is essential to develop self-directed teaching methods. AIM: To understand how self-directed medical students approach learning in medical schools at University of Concepcion, Chile. MATERIAL AND METHODS: A qualitative and descriptive study, performed according to Grounded Theory guidelines, following Strauss & Corbin was performed. Twenty medical students were selected by the maximum variation sampling method. The data collection technique was carried out by a semi-structured thematic interview. Students were interviewed by researchers after an informed consent procedure. Data were analyzed by the open coding method using Atlas-ti 7.5.2 software. RESULTS: Self-directed learners were characterized by being good planners and managing their time correctly. Students performed a diligent selection of contents to study based on reliable literature sources, theoretical relevance and type of evaluation. They also emphasized the discussion of clinical cases, where theoretical contents can be applied. This modality allows them to gain a global view of theoretical contents, to verbalize knowledge and to obtain a learning feedback. CONCLUSIONS: The learning process of autonomous students is intentional and planned. PMID- 26928621 TI - [A survey about quality of care and user?s' rights in Chilean psychiatric services]. AB - BACKGROUND: Quality of care and respect for the rights of users are critical to achieve positive health outcomes and respond appropriately to the expectations of people, particularly if they have mental illnesses. AIM: To carry out a baseline diagnosis of quality of care and respect for rights in public outpatient psychiatric services. MATERIAL AND METHODS: Quality of care and respect for patients'? rights was assessed by a mental health professional and a trained psychiatric service user in 15 ambulatory psychiatric services. The WHO QualityRights instrument was used, reviewing documentation and making observations in each facility, as well as interviewing 146 patients, 148 health care workers and 64 relatives of patients. RESULTS: A high level of achievement was accomplished in terms of discrimination-free health care, availability of psychotropic medications, lack of abuse or neglect and use of informed consents. A low level of achievement was found in terms of user support to cope with community living, access to education or work and participation in community activities, respect for user treatment preferences and preventive measures to avoid maltreatment and cruelty. CONCLUSIONS: Chile could improve the performance of psychiatry services having laws based on the ?Convention of Rights of Persons with Disabilities? and standards of the World Health Organization, having national policies about quality of care and rights of users, reinforcing the community work of mental health care teams, reinforcing and informing users about their rights and promoting research on interventions to improve the respect of their rights. PMID- 26928622 TI - The controversial experiments on the intravenous administration of drugs (and air!) during the cholera epidemic of 1867 in Italy. AB - Cholera ravaged many American and European cities in the nineteenth century. Likewise, Italy was struck by six epidemics since the morbus first appeared in 1835-1837. After the International Sanitary Conferences held in Paris in 1851, there was a decrease of the cases due to consolidation of the city in terms of public and private health. Nevertheless, due to the lack of alternative and innovative remedies, the mortality remained unchanged, affecting more than 60 percent of patients. The city of Brescia in Northern Italy was severely hit by the epidemic of 1867. Not being able to implement effective therapeutic strategies, the administration of drugs like quinine and strychnine was proposed to be done intravenously. The results of intravenous injections were ominous, and all the patients died of "?sudden death"?. Although the academic authorities forbade further experiments, some physicians carried on a long trial using test animals and mental patients as ?"guinea pigs"?. PMID- 26928623 TI - [Infective endocarditis caused by Erysipelothrix rhusiopathie. Report of one case]. AB - Erysipelothrix rhusiopathie is an immobile, not sporulated, gram positive bacillus. Man is an accidental host. Infection is acquired through wounds on contact with sick animals or carriers, their products or objects contaminated with their waste. We report a 40 years old tannery male worker, presenting in the emergency room with fever lasting one month. An echocardiogram showed a vegetation and perforation of the aortic valve with severe aortic regurgitation. Blood cultures gave growth to E. rhusiopathiae. The patient was treated with penicillin. After three weeks of treatment an aortic valve replacement with a mechanical valve was performed. At six weeks, he was discharged from the hospital. PMID- 26928624 TI - [Cayetano Heredia: A contemporary view]. PMID- 26928625 TI - [Exploring HIV denial in Spanish, in the internet]. PMID- 26928626 TI - Space Maintenance Using Tenting Screws in Atrophic Extraction Sockets. PMID- 26928627 TI - An Efficient Soft Set-Based Approach for Conflict Analysis. AB - Conflict analysis has been used as an important tool in economic, business, governmental and political dispute, games, management negotiations, military operations and etc. There are many mathematical formal models have been proposed to handle conflict situations and one of the most popular is rough set theory. With the ability to handle vagueness from the conflict data set, rough set theory has been successfully used. However, computational time is still an issue when determining the certainty, coverage, and strength of conflict situations. In this paper, we present an alternative approach to handle conflict situations, based on some ideas using soft set theory. The novelty of the proposed approach is that, unlike in rough set theory that uses decision rules, it is based on the concept of co-occurrence of parameters in soft set theory. We illustrate the proposed approach by means of a tutorial example of voting analysis in conflict situations. Furthermore, we elaborate the proposed approach on real world dataset of political conflict in Indonesian Parliament. We show that, the proposed approach achieves lower computational time as compared to rough set theory of up to 3.9%. PMID- 26928628 TI - Correction to: "Using the BacMam Baculovirus System to Study Expression and Function of Recombinant Efflux Drug Transporters in Polarized Epithelial Cell Monolayers". PMID- 26928629 TI - Neoplastic Cells of Primary Cutaneous CD4+ Small/Medium-sized Pleomorphic T-cell Lymphoma Lack the Expression of Follicular T-helper Cell Defining Chemokine Receptor CXCR5. PMID- 26928630 TI - Equity and achievement in access to contraceptives in East Africa between 2000 and 2010. AB - OBJECTIVE: To examine trends in equity in contraceptive use, and in contraceptive prevalence rates in six East African countries. METHODS: In this repeated cross sectional study, Demographic and Health Surveys Program data from women aged 15 49 years in Ethiopia, Kenya, Malawi, Rwanda, Tanzania, and Uganda between 2000 and 2010 were analyzed. Individuals were ranked according to wealth quintile, stratified urban/rural populations, and calculated concentration index-a statistic integrating information from all wealth quintiles to analyze disparities. RESULTS: Equity and contraceptive-prevalence rates increased in most country regions over the study period. Notably, in rural Rwanda, contraceptive prevalence rates increased from 3.9 to 44.0, and urban Kenya became the most equitable country region, with a concentration index of 0.02. The Pearson correlation coefficient between improvements in concentration index and contraceptive-prevalence rates was 0.52 (P=0.011). CONCLUSION: The results indicate that countries seeking to increase contraceptive use should prioritize equity in access to services and contraceptives. PMID- 26928631 TI - Cross-generational transmission from drug abuse in parents to attention deficit/hyperactivity disorder in children. AB - BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) predisposes to drug abuse (DA) and twin studies suggest shared genetic effects. We here seek to determine, using adoption and adoption-like samples, the magnitude of the cross generational transmission from DA in parents to ADHD in their children and clarify the degree to which this arises from genetic v. rearing effects. METHOD: We ascertained ADHD and DA from multiple Swedish registries. Statistical analysis was performed by Cox and path models. RESULTS: Risk for ADHD was significantly and similarly increased in the offspring of biological mothers and fathers with DA who did v. did not rear their offspring. Risk for ADHD was not elevated in the offspring of adoptive or step-parents with DA. CONCLUSIONS: Cross-generational transmission was observed from DA in parents to ADHD in their children. An analysis of adoptive and adoptive-like parent-offspring relationships suggested that this transmission results from genetic and not from rearing effects. PMID- 26928632 TI - Naringenin ameliorates streptozotocin-induced diabetic rat renal impairment by downregulation of TGF-beta1 and IL-1 via modulation of oxidative stress correlates with decreased apoptotic events. AB - CONTEXT: Naringenin, a flavonone and a nutritive antioxidant which is mostly obtained from grapefruit, orange or tomato skin, has been extensively studied due to its radical scavenging activity. OBJECTIVE: The present study investigates the protective effect of naringenin on rat kidney after streptozotocin-induced diabetes. MATERIALS AND METHODS: Sixty male Wistar rats were divided into six groups. Diabetes was induced by a single intraperitoneal injection of streptozotocin (50 mg/kg) in groups II, III and IV. Naringenin 5 mg/kg body weight was given to groups III and V, but 10 mg/kg was given to groups IV and VI, orally once a day for 10 weeks. After which all animals were sacrificed, and the biochemical, histopathological, immunohistochemical and apoptotic assays were conducted. RESULTS: Naringenin treatment with 5 and 10 mg/kg significantly decreased (p < 0.05) the serum biochemical parameters, elevated tissue malondialdehyde levels and increased (p < 0.01) the reduced superoxide dismutase, catalase and reduced glutathione enzyme activities in the diabetic kidney. Diabetes-induced naringenin-treated groups showed an improved histology and revealed a significant reduction in apoptosis activity (7.2 +/- 0.01 and 1.8 +/- 0.05) and in expression of TGF-beta1 (18.9 +/- 3.4 and 10.2 +/- 2.1) at a dose of 5 and 10 mg/kg, respectively. Similarly, in contrast to the diabetic group, a significant difference was observed in the IL-1 expression (15.68 +/- 4.3) in 5 mg/kg and (9.85 +/- 2.1) in 10 mg/kg naringenin-treated groups. CONCLUSION: Naringenin acts as a protective agent in diabetic renal impairment by altering oxidative stress, modulation of cytokines expression and apoptotic events. PMID- 26928633 TI - Impact of pre-operative statin use on risk of mortality and early atrial fibrillation after heart transplantation. AB - BACKGROUND: Pre-operative statin use has shown to reduce the incidence of post operative atrial fibrillation (AF), but not mortality in patients undergoing cardiac surgery. This association, however, has not been examined in a heart transplant (HT) cohort. METHODS: Adults (>=18 yr) who underwent HT between 1997 and 2007 at the University of Minnesota were retrospectively identified. Primary outcome was 30-d mortality after HT. Secondary outcomes were 30-d incidence of AF and time to all-cause mortality. RESULTS: Data from 259 patients (mean age 52.0 +/- 11.7 yr, 81% males) were analyzed. Total of 133 (51%) patients were on statin pre-operatively at the time of HT and constituted the statin group. During a mean follow-up of 6.7 +/- 3.7 yr, 82 (32%) deaths occurred, 21 (8%) of which occurred within 30 d of HT. The incidence of 30-d mortality was not significantly different between the statin and no-statin groups (9% vs. 7%, p = 0.58). Further, cumulative long-term survival after HT was not significantly different between the study groups (log-rank p = 0.49). Pre-transplant statin use did not impact the 30-d incidence of post-transplant AF (16% vs. 19%, p = 0.59). CONCLUSIONS: Pre-operative statin therapy does not seem to influence the risk of mortality or early post-operative AF after HT. Future large-scale studies are required to validate these preliminary findings. PMID- 26928634 TI - Analysis of Transpulmonary Thermodilution Data Confirms the Influence of Renal Replacement Therapy on Thermodilution Hemodynamic Measurements. AB - BACKGROUND: Transpulmonary thermodilution (TPTD) is used frequently in the intensive care unit to determine cardiac index (CI), intrathoracic blood volume index (ITBVI), and extravascular lung volume index (EVLWI). Renal replacement therapy (RRT) influences TPTD results, but the underlying mechanisms are not completely understood. We hypothesized that RRT blood flow induces errors in TPTD measurements. METHODS: We analyzed TPTD data available from the PiCCO(r) plus hemodynamic measurement device on a personal computer using a proprietary Pulsion Medical Systems software. By using the dialysis catheter to inject the thermal indicator, 20 measurement series were performed in 12 intensive care unit patients determining CI, ITBVI, and EVLWI during RRT with the blood pump stopped, and at flows of 100 and 200 mL/min, respectively. RESULTS: Data export was successful in 17 measurement series and showed a significant decrease in measured CI (6.5 +/- 2.5 vs 5.4 +/- 1.9 L/min/m, P < 0.001) and ITBVI (1358.8 +/- 274.5 vs 1132.8 +/- 218.3 mL/m, P < 0.001) with RRT and a significant increase in EVLWI (8.6 +/- 4.4, 10.2 +/- 4.5 mL/kg, P < 0.001). Blood temperature before and the temperature decrease after injection of the thermal indicator were unchanged by RRT. Mean transit time and downslope time of the thermodilution curve, however, were both increased with the RRT blood pump running (P <= 0.001). CONCLUSIONS: Analysis of TPTD data shows that thermodilution curve forms are modified with RRT, resulting in an erroneous calculation of thermodilution-derived hemodynamic parameters. PMID- 26928635 TI - Structural insights into Cydia pomonella pheromone binding protein 2 mediated prediction of potentially active semiochemicals. AB - Given the advantages of behavioral disruption application in pest control and the damage of Cydia pomonella, due progresses have not been made in searching active semiochemicals for codling moth. In this research, 31 candidate semiochemicals were ranked for their binding potential to Cydia pomonella pheromone binding protein 2 (CpomPBP2) by simulated docking, and this sorted result was confirmed by competitive binding assay. This high predicting accuracy of virtual screening led to the construction of a rapid and viable method for semiochemicals searching. By reference to binding mode analyses, hydrogen bond and hydrophobic interaction were suggested to be two key factors in determining ligand affinity, so is the length of molecule chain. So it is concluded that semiochemicals of appropriate chain length with hydroxyl group or carbonyl group at one head tended to be favored by CpomPBP2. Residues involved in binding with each ligand were pointed out as well, which were verified by computational alanine scanning mutagenesis. Progress made in the present study helps establish an efficient method for predicting potentially active compounds and prepares for the application of high-throughput virtual screening in searching semiochemicals by taking insights into binding mode analyses. PMID- 26928636 TI - Probing disorder in isometric pyrochlore and related complex oxides. AB - There has been an increased focus on understanding the energetics of structures with unconventional ordering (for example, correlated disorder that is heterogeneous across different length scales). In particular, compounds with the isometric pyrochlore structure, A2B2O7, can adopt a disordered, isometric fluorite-type structure, (A, B)4O7, under extreme conditions. Despite the importance of the disordering process there exists only a limited understanding of the role of local ordering on the energy landscape. We have used neutron total scattering to show that disordered fluorite (induced intrinsically by composition/stoichiometry or at far-from-equilibrium conditions produced by high energy radiation) consists of a local orthorhombic structural unit that is repeated by a pseudo-translational symmetry, such that orthorhombic and isometric arrays coexist at different length scales. We also show that inversion in isometric spinel occurs by a similar process. This insight provides a new basis for understanding order-to-disorder transformations important for applications such as plutonium immobilization, fast ion conduction, and thermal barrier coatings. PMID- 26928638 TI - Complex oxides: Intricate disorder. PMID- 26928637 TI - In situ hydrodynamic spectroscopy for structure characterization of porous energy storage electrodes. AB - A primary atomic-scale effect accompanying Li-ion insertion into rechargeable battery electrodes is a significant intercalation-induced change of the unit cell volume of the crystalline material. This generates a variety of secondary multiscale dimensional changes and causes a deterioration in the energy storage performance stability. Although traditional in situ height-sensing techniques (atomic force microscopy or electrochemical dilatometry) are able to sense electrode thickness changes at a nanometre scale, they are much less informative concerning intercalation-induced changes of the porous electrode structure at a mesoscopic scale. Based on a electrochemical quartz-crystal microbalance with dissipation monitoring on multiple overtone orders, herein we introduce an in situ hydrodynamic spectroscopic method for porous electrode structure characterization. This new method will enable future developments and applications in the fields of battery and supercapacitor research, especially for diagnostics of viscoelastic properties of binders for composite electrodes and probing the micromechanical stability of their internal electrode porous structure and interfaces. PMID- 26928639 TI - Thermal resistance at a solid/superfluid helium interface. AB - Kapitza in 1941 discovered that heat flowing across a solid in contact with superfluid helium (<2 K) encounters a strong thermal resistance at the interface. Khalatnikov demonstrated theoretically that this constitutes a general phenomenon related to all interfaces at all temperatures, given the dependence of heat transmission on the acoustic impedance (sound velocity * density) of each medium. For the solid/superfluid interface, the measured transmission of heat is almost one hundred times stronger than the Khalatnikov prediction. This discrepancy could be intuitively attributed to diffuse scattering of phonons at the interface but, despite several attempts, a detailed quantitative comparison between theoretical and experimental findings to explain the occurrence of scattering and its contribution to heat transmission had been lacking. Here we show that when the thermal wavelength lambda of phonons of the less dense medium (liquid (4)He) becomes comparable to the r.m.s. surface roughness sigma, the heat flux crossing the interface is amplified; in particular when sigma ~ 0.33lambda, a spatial resonant mechanism occurs, as proposed by Adamenko and Fuks. We used a silicon single crystal whose surface roughness was controlled and characterized. The thermal boundary resistance measurements were performed from 0.4 to 2 K at different superfluid pressures ranging from saturated vapour pressure (SVP) to above (4)He solidification, to eliminate all hypothetical artefact mechanisms. Our results demonstrate the physical conditions necessary for resonant phonon scattering to occur at all interfaces, and therefore constitute a benchmark in the design of nanoscale devices for heat monitoring. PMID- 26928640 TI - Observation of room-temperature magnetic skyrmions and their current-driven dynamics in ultrathin metallic ferromagnets. AB - Magnetic skyrmions are topologically protected spin textures that exhibit fascinating physical behaviours and large potential in highly energy-efficient spintronic device applications. The main obstacles so far are that skyrmions have been observed in only a few exotic materials and at low temperatures, and fast current-driven motion of individual skyrmions has not yet been achieved. Here, we report the observation of stable magnetic skyrmions at room temperature in ultrathin transition metal ferromagnets with magnetic transmission soft X-ray microscopy. We demonstrate the ability to generate stable skyrmion lattices and drive trains of individual skyrmions by short current pulses along a magnetic racetrack at speeds exceeding 100 m s(-1) as required for applications. Our findings provide experimental evidence of recent predictions and open the door to room-temperature skyrmion spintronics in robust thin-film heterostructures. PMID- 26928641 TI - In response to Tympanic membrane repair using silk fibroin and acellular collagen scaffolds. PMID- 26928642 TI - Glucose Levels in Patients With Acute Respiratory Failure Requiring Mechanical Ventilation. AB - BACKGROUND: Recent studies suggest that patients with acute exacerbations of chronic obstructive pulmonary disease (COPD) frequently develop hyperglycemia, which has been linked to adverse outcomes. METHODS: We retrospectively collected information about patient demographics, admission diagnosis, comorbidities, use of insulin, and glucose levels and related tests in 174 patients who required mechanical ventilation for acute respiratory failure. RESULTS: These patients had a mean age of 57.8 +/- 16.8 years, a mean Acute Physiology and Chronic Health Evaluation (APACHE II) score of 13.8 +/- 6.1, and an overall mortality of 32.2%. The mean number of ventilator days was 7.5 +/- 7.1. The mean highest glucose level was 239.3 +/- 88.9 mg/dL in patients with COPD (n = 41) and 259.1 +/- 131.7 mg/dL in patients without COPD (n =133). Patients with diabetes had higher glucose levels than patients without this diagnosis ( P < .05). Patients receiving corticosteroids did not have increased glucose levels ( P > .05). The mortality rate was higher in patients with glucose levels >140 mg/dL than in patients below 140 mg/dL (35.1% vs 10.5%, P < .05 unadjusted analysis). CONCLUSION: In this study, hyperglycemia occurred in 89% of the patients with acute respiratory failure requiring mechanical ventilation. The most important risk factor for this was a premorbid diagnosis of diabetes. PMID- 26928643 TI - Acute Parotitis as a Complication of Noninvasive Ventilation. AB - Several conditions, including oropharyngeal dryness, pressure sores, ocular irritation, epistaxis, or gastric distension, have been described during noninvasive ventilation (NIV). Although this technique has been widely used in intensive care units and emergency wards, acute swelling of the parotid gland remains a scarcely reported complication. We describe herein the case of an 82 year-old man who developed unilateral parotitis during prolonged NIV for acute heart failure. Intravenous antibiotics, corticosteroids, and adjusting the mask laces' position allowed rapid resolution of clinical symptoms. PMID- 26928644 TI - Circulating progesterone dynamics after intravaginal instillation of prostaglandin-F2alpha to lactating dairy cows. AB - Our objectives were to evaluate circulating progesterone (P4) concentration dynamics and test the feasibility of inducing luteal regression after intravaginal (IVG) instillation of the PGF2alpha analogue dinoprost (PGF) in lactating dairy cows. In two experiments, cows were synchronized using the Ovsynch protocol to induce the formation of a corpus luteum (CL). Cows with at least one functional (P4 >=1 ng/mL) CL >=15 mm 7.5 days after Ovsynch remained in the studies. In experiment 1, cows (n = 31) were stratified by parity group and received 5 mL of saline IVG (SAL-IVG, n = 6), 25 mg of PGF intramuscular (IM) (PGF25-IM, n = 7), 25 mg of PGF IVG (PGF25-IVG, n = 6), 50 mg of PGF IVG (PGF50 IVG, n = 6), and 125 mg of PGF IVG (PGF125-IVG, n = 6). Experiment 2 was conducted to test the hypothesis that IVG instillation of two 25 mg doses of PGF 12 hours apart would be more effective than a 25- or 50-mg dose in a single application. Cows (n = 32) were stratified by parity and received SAL-IVG (n = 7), PGF25-IM (n = 7), PGF25-IVG (n = 6), and PGF50-IVG (n = 6) as in experiment 1, whereas another group received two IVG instillations of 25 mg of PGF 12 hours apart (PGF25-2X-IVG, n = 6). Blood was collected at -1 hour, every 6 hours from 0 hour to 24 hours, and every 12 hours up to 96 hours after treatment (trt). In experiment 1, there was an effect of trt (P < 0.01), time (P < 0.001), and an interaction between trt and time on P4 concentrations (P < 0.001). All PGF treated groups had lower (P < 0.05) concentrations of P4 than cows in the SAL-IVG group from 12 to 96 hours after trt. Although an initial decline in P4 concentrations was induced in all PGF-treated cows, some cows in the IVG-treated groups presented a rebound in plasma P4, indicating CL recovery. More cows in the PGF25-IVG and PGF125-IVG groups than in the PGF50-IVG and PGF25-IM groups presented CL recovery, suggesting that greater doses of PGF may not necessarily improve CL regression. In experiment 2, there was an effect of trt (P < 0.001), time (P < 0.001), and an interaction between trt and time on P4 concentrations (P < 0.001). All PGF-treated groups had lower (P < 0.05) P4 than the SAL-IVG group from 12 to 96 hours after trt. Cows in the PGF25-2X-IVG group had a P4 profile that was similar to that of cows in the PGF25-IM group and the lowest P4 concentrations after treatment among the IVG-treated groups, and all cows presented complete CL regression (defined as P4 <0.4 ng/mL). We conclude that CL regression can be induced through IVG instillation of PGF in lactating dairy cows and that instillation of two IVG doses of 25 mg of PGF 12 hours apart was the most effective strategy. PMID- 26928645 TI - Use of bovine pregnancy-associated glycoproteins to predict late embryonic mortality in postpartum Nelore beef cows. AB - The primary objective was to determine if circulating concentration of bovine pregnancy-associated glycoproteins (bPAGs) on Day 30 after artificial insemination (AI) may serve as a marker of late embryonic mortality in Bos indicus (Nelore) beef cows. In experiment 1, postpartum Nelore beef cows (n = 56) were artificially inseminated at a fixed time (Day 0) after synchronization of ovulation. Serum samples were collected on Days 0, 21, 24, 27, and 30 after AI. The first significant increase (P < 0.0001) in serum bPAGs after insemination occurred on Day 24 of gestation. In experiment 2, ovulation was synchronized in postpartum Nelore beef cows (n = 1460) and AI was received at a fixed time. Pregnancy diagnosis and blood sample collection were carried out on Days 28 to 30 after insemination. Cows that maintained a pregnancy from Days 28 to 100 of gestation (n = 714) had significantly (P < 0.0001) higher circulating concentrations of bPAGs on Day 28 compared with cows that did not maintain a pregnancy (embryonic mortality [EM]) until Day 100 (n = 89). When Day 28 bPAG concentration was included in a logistic regression model to predict pregnancy maintenance until Day 100 of gestation, there was an increase (P < 0.0001) in the probability of maintaining pregnancy as maternal concentrations of bPAGs increased. A receiver operating characteristic curve was generated to determine bPAG concentrations on Day 28 that should predict embryonic survival or mortality with an accuracy of 95% or more. On the basis of the positive and negative predicative value analysis, at Day 28 of gestation a circulating concentration of bPAGs greater than 7.9 ng/mL was 95% accurate in predicting embryonic maintenance (to Day 100); a concentration of bPAGs less than 0.72 ng/mL was 95% accurate in predicting EM by Day 100. In experiment 3, the preceding model was tested in a separate set of Nelore beef cows to validate whether bPAGs would serve as an accurate measure of late embryonic mortality. Ovulation was synchronized in 650 Nelore cows and received AI at a fixed time. Pregnancy diagnosis and bPAG sampling were performed at Day 28 of gestation. Only pregnant cows were included in the analysis. On the basis of the previously reported bPAG cutoff values, the test was 95% accurate in predicting late embryonic mortality at Day 28 of gestation. In summary, bPAGs seem to be a good marker for predicting EM between Days 28 and 100 of gestation and suggest that this model could help dissect the molecular mechanisms leading to late EM. PMID- 26928646 TI - Behavioral indicators to detect ovarian phase in the dromedary she-camel. AB - This pilot study was conducted to test the hypothesis that female camels behave differently in various ovarian phases in the presence of a restrained male camel. The aim was to identify behavioral patterns which could be used as indicators to detect ovulatory phase by visual observation in the presence of a restrained virile bull. Twenty-four healthy, nonpregnant, and nonlactating adult females were used. Transrectal ultrasonography was performed for each animal once a week over a 3-week period to determine the phase of the ovarian cycle. Females were considered to be in the ovulatory phase (O) when there was at least one preovulatory follicle (12 0.05) for embryo recovery, embryos recovered, embryo quality, embryo stage, or cells per embryo. Methylation of the DNA had a TRT by GRP interaction (P = 0.01). Embryos from cows in CON-CNT had greater (P = 0.04) methylation (0.87 +/- 0.09 arbitrary units [AU]) than embryos from cows in MET-CNT (0.44 +/- 0.07 AU). The cytoplasmic lipid content was not affected (P > 0.05) by TRT or their interaction, but lipid content was greater (P = 0.04) for SMT (7.02 +/- 1.03 AU) than that in CNT (3.61 +/- 1.20 AU). In conclusion, cows in MET-CNT had embryos with lower methylation, and SMT cows had a higher lipid content than CNT. Methionine supplementation seems to impact the preimplantation embryo in a way that enhances its capacity for survival because there is strong evidence that endogenous lipid reserves serve as an energy substrate. PMID- 26928649 TI - A PET-based fluorometric chemosensor for the determination of mercury(II) and pH, and hydrolysis reaction-based colorimetric detection of hydrogen sulfide. AB - A simple fluorescent chemosensor 1 for the detection of Hg(2+) and pH was developed by a combination of 2-aminoethyl piperazine and 4-chloro-7-nitrobenz-2 oxa-1,3-diazole. The sensor 1 showed OFF-ON behavior for different colors of fluorescence in the presence of Hg(2+) and under acidic conditions, respectively, in a near-perfect aqueous solution. The turn-on fluorescence caused by inhibition of photoinduced electron transfer was explained by theoretical calculations. 1 could be used to quantify Hg(2+) in water samples, and its in vitro studies with HeLa cells showed fluorescence in the presence of Hg(2+). In addition, 1 could selectively detect S(2-) by changing its color from orange to pink in a near perfect aqueous solution. Moreover, 1 could be used as a practical, visible test kit for S(2-). PMID- 26928650 TI - Perivascular fat in human muscle. PMID- 26928648 TI - Serological diagnosis of pneumococcal infection in children with pneumonia using protein antigens: A study of cut-offs with positive and negative controls. AB - The etiological diagnosis of infection by Streptococcus pneumoniae in children is difficult, and the use of indirect techniques is frequently warranted. We aimed to study the use of pneumococcal proteins for the serological diagnosis of pneumococcal infection in children with pneumonia. We analyzed paired serum samples from 13 Brazilian children with invasive pneumococcal pneumonia (positive control group) and 23 Finnish children with viral pharyngitis (negative control group), all aged <5years-old. Children with pharyngitis were evaluated for oropharyngeal colonization, and none of them carried S. pneumoniae. We used a multiplex bead-based assay with eight proteins: Ply, CbpA, PspA1 and 2, PcpA, PhtD, StkP and PcsB. The optimal cut-off for increase in antibody level for the diagnosis of pneumococcal infection was determined for each antigen by ROC curve analysis. The positive control group had a significantly higher rate of >=2-fold rise in antibody levels against all pneumococcal proteins, except Ply, compared to the negative controls. The cut-off of >=2-fold increase in antibody levels was accurate for pneumococcal infection diagnosis for all investigated antigens. However, there was a substantial increase in the accuracy of the test with a cut off of >=1.52-fold rise in antibody levels for PcpA. When using the investigated protein antigens for the diagnosis of pneumococcal infection, the detection of response against at least one antigen was highly sensitive (92.31%) and specific (91.30%). The use of serology with pneumococcal proteins is a promising method for the diagnosis of pneumococcal infection in children with pneumonia. The use of a >=2-fold increase cut-off is adequate for most pneumococcal proteins. PMID- 26928651 TI - Childhood obesity and education. PMID- 26928652 TI - An active life is a sweet life. PMID- 26928653 TI - Superparamagnetic Fe3O4 Nanoparticles: Synthesis by Thermal Decomposition of Iron(III) Glucuronate and Application in Magnetic Resonance Imaging. AB - Monodisperse superparamagnetic Fe3O4 nanoparticles coated with oleic acid were prepared by thermal decomposition of Fe(III) glucuronate. The shape, size, and particle size distribution were controlled by varying the reaction parameters, such as the reaction temperature, concentration of the stabilizer, and type of high-boiling-point solvents. Magnetite particles were characterized by transmission electron microscopy (TEM), as well as electron diffraction (SAED), X ray diffraction (XRD), dynamic light scattering (DLS), and magnetometer measurements. The particle coating was analyzed by atomic absorption spectroscopy (AAS) and attenuated total reflection (ATR) Fourier transform infrared spectroscopy (FTIR) spectroscopy. To make the Fe3O4 nanoparticles dispersible in water, the particle surface was modified with alpha-carboxyl-omega-bis(ethane-2,1 diyl)phosphonic acid-terminated poly(3-O-methacryloyl-alpha-D-glucopyranose) (PMG P). For future practical biomedical applications, nontoxicity plays a key role, and the PMG-P&Fe3O4 nanoparticles were tested on rat mesenchymal stem cells to determine the particle toxicity and their ability to label the cells. MR relaxometry confirmed that the PMG-P&Fe3O4 nanoparticles had high relaxivity but rather low cellular uptake. Nevertheless, the labeled cells still provided visible contrast enhancement in the magnetic resonance image. In addition, the cell viability was not compromised by the nanoparticles. Therefore, the PMG P&Fe3O4 nanoparticles have the potential to be used in biomedical applications, especially as contrast agents for magnetic resonance imaging. PMID- 26928654 TI - Population biology of an endangered species: the common guitarfish Rhinobatos rhinobatos in Lebanese marine waters of the eastern Mediterranean Sea. AB - This study focuses on the population biology of the common guitarfish Rhinobatos rhinobatos, a cartilaginous fish listed as Endangered in the International Union for the Conservation of Nature (IUCN) Red List. Between December 2012 and January 2014, 67 individuals were collected by bottom longlining in coastal Lebanese marine waters at different ports at depths ranging from 10 to 110 m. The total length (L(T)) of the specimens ranged from 50 to 143 cm, and the mean +/- s.d. was 76.2 +/- 19.7 cm. The most common L(T) classes were between 60 and 70 cm. The total mass of the specimens ranged from 410 to 10,000 g, and the mean +/- s.d. was 1841 +/- 1987 g. A total of 34 males and 33 females were collected, and the sex ratio was not significantly different from 1:1. The mass and L(T) relationship showed positive allometric growth (b = 3.096 and r(2) = 0.99), and the mean +/- s.d. L(T) at which 50% of the individuals were sexually mature was 84.73 +/- 5.81 cm for females and 78.57 +/- 4.88 cm for males. The gonado-somatic and hepato-somatic indices were determined along with a condition factor, and parturition appeared to occur in winter. The primary prey items found in the fish stomachs during the autumn and winter seasons were Penaeidae. The results of this study will help to parameterize models of the population dynamics for this exploited fish stock to ensure the long-term sustainability of its fishery. PMID- 26928656 TI - Extracellular vesicles for drug delivery. AB - Extracellular vesicles (EVs) are cell-derived membrane vesicles, and represent an endogenous mechanism for intercellular communication. Since the discovery that EVs are capable of functionally transferring biological information, the potential use of EVs as drug delivery vehicles has gained considerable scientific interest. EVs may have multiple advantages over currently available drug delivery vehicles, such as their ability to overcome natural barriers, their intrinsic cell targeting properties, and stability in the circulation. However, therapeutic applications of EVs as drug delivery systems have been limited due to a lack of methods for scalable EV isolation and efficient drug loading. Furthermore, in order to achieve targeted drug delivery, their intrinsic cell targeting properties should be tuned through EV engineering. Here, we review and discuss recent progress and remaining challenges in the development of EVs as drug delivery vehicles. PMID- 26928655 TI - Sirtuin 3 (SIRT3) maintains bone homeostasis by regulating AMPK-PGC-1beta axis in mice. AB - The mitochondrial sirtuin 3 (SIRT3) is involved in suppressing the onset of multiple pathologies, including cardiovascular disease, fatty liver, age-related hearing loss, and breast cancer. But a physiological role of SIRT3 in bone metabolism is not known. Here we show that SIRT3 is a key regulatory molecule to maintain bone homeostasis. Mice deficient in SIRT3 exhibited severe osteopenia owing to increased numbers of osteoclasts. Osteoclast precursors from Sirt3-/- mice underwent increased osteoclastogenesis in response to receptor activator of nuclear factor-kappaB ligand (RANKL), an essential cytokine for osteoclast differentiation. SIRT3 expression from RANKL induction depended on the transcription coactivator PGC-1beta (peroxisome proliferator-activated receptor gamma co-activator-1beta) and the nuclear receptor ERRalpha (estrogen receptor related receptor alpha), and that SIRT3 inhibited the differentiation by interfering with the RANKL-induced expression of PGC-1beta. Thus an auto regulatory feedback mechanism operates to induce its own inhibitor SIRT3 by PGC 1beta. Moreover, Sirt3-/- osteoclast precursors reduced AMP-activated protein kinase (AMPK) phosphorylation through down-regulating the expression of AMPK. Our results suggest that a mitochondrial SIRT3 is an intrinsic inhibitor for RANKL mediated osteoclastogenesis. PMID- 26928657 TI - Computational prediction of formulation strategies for beyond-rule-of-5 compounds. AB - The physicochemical properties of some contemporary drug candidates are moving towards higher molecular weight, and coincidentally also higher lipophilicity in the quest for biological selectivity and specificity. These physicochemical properties move the compounds towards beyond rule-of-5 (B-r-o-5) chemical space and often result in lower water solubility. For such B-r-o-5 compounds non traditional delivery strategies (i.e. those other than conventional tablet and capsule formulations) typically are required to achieve adequate exposure after oral administration. In this review, we present the current status of computational tools for prediction of intestinal drug absorption, models for prediction of the most suitable formulation strategies for B-r-o-5 compounds and models to obtain an enhanced understanding of the interplay between drug, formulation and physiological environment. In silico models are able to identify the likely molecular basis for low solubility in physiologically relevant fluids such as gastric and intestinal fluids. With this baseline information, a formulation scientist can, at an early stage, evaluate different orally administered, enabling formulation strategies. Recent computational models have emerged that predict glass-forming ability and crystallisation tendency and therefore the potential utility of amorphous solid dispersion formulations. Further, computational models of loading capacity in lipids, and therefore the potential for formulation as a lipid-based formulation, are now available. Whilst such tools are useful for rapid identification of suitable formulation strategies, they do not reveal drug localisation and molecular interaction patterns between drug and excipients. For the latter, Molecular Dynamics simulations provide an insight into the interplay between drug, formulation and intestinal fluid. These different computational approaches are reviewed. Additionally, we analyse the molecular requirements of different targets, since these can provide an early signal that enabling formulation strategies will be required. Based on the analysis we conclude that computational biopharmaceutical profiling can be used to identify where non-conventional gateways, such as prediction of 'formulate-ability' during lead optimisation and early development stages, are important and may ultimately increase the number of orally tractable contemporary targets. PMID- 26928658 TI - Efficacy and safety of a novel oral isoxazoline, sarolaner (SimparicaTM), for the treatment of sarcoptic mange in dogs. AB - The efficacy of the novel isoxazoline, sarolaner (SimparicaTM) was investigated in dogs with clinical signs consistent with sarcoptic mange and harbouring natural infestations of Sarcoptes scabiei. One placebo-controlled laboratory study and one multi-centred field study with a commercial comparator containing imidacloprid/moxidectin (Advocate((r)) spot-on) were conducted. Oral or topical treatments were administered on Days 0 and 30. Up to 10 skin scrapings were taken for the assessment of S. scabiei infestations from each dog before treatment and on Days 14, 30, 44 and 60 in the laboratory study, and on Days 30 and 60 in the field study. In the laboratory study, efficacy was calculated based on the percent reduction of mean live mite counts compared to the placebo group. In the field study parasitological cure rate (% dogs free of mites) was determined and non-inferiority of sarolaner to the control product was assessed. In the laboratory study 44 mixed breed dogs were enrolled in four batches. Due to decreasing mite counts in the placebo treated dogs, immunosuppression with dexamethasone (0.4mg/kg three times per week for two weeks) was initiated in all dogs on study at that time (n=6) and those subsequently enrolled (n=14). In the field study, dogs were enrolled in a 2:1 ratio (sarolaner:comparator); 79 dogs were assessed for efficacy and safety, and an additional 45 dogs were assessed for safety only. There were no treatment related adverse events in either study. In the laboratory study, no mites were found on any sarolaner-treated dogs 14 days after the first treatment except for one dog that had a single mite on Day 44. In the field study, the parasitological cure rate was 88.7% and 100% in the sarolaner group and 84.6% and 96.0% in the imidacloprid/moxidectin group, on Days 30 and 60, respectively. Statistical analysis showed that sarolaner was non inferior to imidacloprid/moxidectin at both time points. The clinical signs of sarcoptic mange, including hair loss, papules, pruritus, erythema, and scaling/crusting improved throughout the study. Sarolaner was safe, achieved 100% reduction in the numbers of S. scabiei detected and resulted in marked improvement of the clinical signs of sarcoptic mange in dogs following two monthly oral administrations. PMID- 26928659 TI - Evaluation of the speed of kill of sarolaner (SimparicaTM) against induced infestations of three species of ticks (Amblyomma maculatum, Ixodes scapularis, Ixodes ricinus) on dogs. AB - The rapid speed of kill of sarolaner (SimparicaTM, Zoetis), a novel isoxazoline compound, was demonstrated against three tick species known to infest dogs in Europe or the United States. Efficacy was measured against an existing infestation and against subsequent weekly re-infestations for 35 days after treatment. Dogs were randomly allocated to treatment with a single oral dose of either placebo or sarolaner (2mg/kg) based on pre-treatment host-suitability tick counts. Dogs were infested with approximately 50 unfed adult Ixodes scapularis, Ixodes ricinus or Amblyomma maculatum ticks on Days-2, 7, 14, 21, 28 and 35. Tick counts were conducted at 4 (I. scapularis only), 8, 12 and 24h after treatment on Day 0 and after each subsequent re-infestation. No treatment-related adverse reactions occurred during any of these studies. Dogs in the placebo-treated groups maintained adequate tick infestations (recovery of 20-70% of applied ticks) throughout the duration of the studies. Following treatment, live tick counts were significantly reduced relative to placebo at the 8h post treatment counts indicating that sarolaner started killing existing infestations of ticks rapidly after treatment. Efficacy was 90.1% against I. ricinus, 98.8% against I. scapularis, and 99.2% against A. maculatum within 12h, and 100% efficacy was achieved at 24h after treatment against all three tick species. This speed of kill was maintained throughout the month with >=95.7%, >=98.7% and >=89.6% efficacy against I. scapularis, I. ricinus, and A. maculatum, respectively, at 24h after re-infestation at least through Day 28. PMID- 26928660 TI - "Is it realistic?" the portrayal of pregnancy and childbirth in the media. AB - BACKGROUND: Considerable debate surrounds the influence media have on first-time pregnant women. Much of the academic literature discusses the influence of (reality) television, which often portrays birth as risky, dramatic and painful and there is evidence that this has a negative effect on childbirth in society, through the increasing anticipation of negative outcomes. It is suggested that women seek out such programmes to help understand what could happen during the birth because there is a cultural void. However the impact that has on normal birth has not been explored. METHODS: A scoping review relating to the representation of childbirth in the mass media, particularly on television. RESULTS: Three key themes emerged: (a) medicalisation of childbirth; (b) women using media to learn about childbirth; and (c) birth as a missing everyday life event. CONCLUSION: Media appear to influence how women engage with childbirth. The dramatic television portrayal of birth may perpetuate the medicalisation of childbirth, and last, but not least, portrayals of normal birth are often missing in the popular media. Hence midwives need to engage with television producers to improve the representation of midwifery and maternity in the media. PMID- 26928661 TI - Analysis of Mitochondrial Respiratory Chain Supercomplexes Using Blue Native Polyacrylamide Gel Electrophoresis (BN-PAGE). AB - Mitochondria are cellular organelles that harvest energy in the form of ATP through a process termed oxidative phosphorylation (OXPHOS), which occurs via the protein complexes of the electron transport chain (ETC). In recent years it has become unequivocally clear that mitochondrial complexes of the ETC are not static entities in the inner mitochondrial membrane. These complexes are dynamic and in mammals they aggregate in different stoichiometric combinations to form supercomplexes (SCs) or respirasomes. It has been proposed that the net respiration is more efficient via SCs than via isolated complexes. However, it still needs to be determined whether the activity of a particular SC is associated with a disease etiology. Here we describe a simplified method to visualize and assess in-gel activity of SCs and the individual complexes with good resolution using blue native polyacrylamide gel electrophoresis (BN-PAGE). PMID- 26928663 TI - Generating Mouse Models Using CRISPR-Cas9-Mediated Genome Editing. AB - The CRISPR-Cas9 system in bacteria and archaea has recently been exploited for genome editing in various model organisms, including mice. The CRISPR-Cas9 reagents can be delivered directly into the mouse zygote to derive a mutant animal carrying targeted genetic modifications. The major components of the system include the guide RNA, which provides target specificity, the Cas9 nuclease that creates the DNA double-strand break, and the donor oligonucleotide or plasmid carrying the intended mutation flanked by sequences homologous to the target site. Here we describe the general considerations and experimental protocols for creating genetically modified mice using the CRISPR-Cas9 system. PMID- 26928662 TI - Cardiovascular Imaging in Mice. AB - The mouse is the mammalian model of choice for investigating cardiovascular biology, given our ability to manipulate it by genetic, pharmacologic, mechanical, and environmental means. Imaging is an important approach to phenotyping both function and structure of cardiac and vascular components. This review details commonly used imaging approaches, with a focus on echocardiography and magnetic resonance imaging and brief overviews of other imaging modalities. We also briefly outline emerging imaging approaches but caution that reliability and validity data may be lacking. PMID- 26928664 TI - Analysis of Mouse Growth Plate Development. AB - To investigate skeletal development, pathophysiological mechanisms of cartilage and bone disease, and eventually assess innovative treatments, the mouse is a very important resource. During embryonic development, mesenchymal condensations are formed, and cells within these mesenchymal condensations either directly differentiate into osteoblasts and give origin to intramembranous bone, or differentiate into chondrocytes and form a cartilaginous anlage. The cartilaginous anlage or fetal growth plate is then replaced with bone. This process is also called endochondral bone development, and it is responsible for the generation of most of our skeleton. Here we discuss in detail the most common in vivo and in vitro techniques our laboratory is currently using for the analysis of the mouse fetal growth plate during development. PMID- 26928665 TI - Outcome and recurrence 1 year after pediatric arterial ischemic stroke in a population-based cohort. AB - OBJECTIVE: Arterial ischemic stroke (AIS) is an important cause of acquired brain injury in children. Few prospective population-based studies of childhood AIS have been completed. We aimed to investigate the outcome of childhood AIS 12 months after the event in a population-based cohort. METHODS: Children aged 29 days to < 16 years with radiologically confirmed AIS occurring over a 1-year period residing in southern England (population = 5.99 million children) were eligible for inclusion. Outcome was assessed during a home visit using the Pediatric Stroke Outcome Measure (PSOM). Parental impressions of recovery were assessed using the Pediatric Stroke Recurrence and Recovery Questionnaire. PSOM score was estimated via telephone interview or clinician interview whenever home visit was not possible. RESULTS: Ninety-six children with AIS were identified. Two children were lost to follow-up. Nine of 94 (10%) children died before the 12 month follow-up. One child had an AIS recurrence. PSOM scores were available for 78 of 85 living children at follow-up. Thirty-nine of 78 (50%) had a good outcome (total PSOM score < 1), and 39 of 78 (50%) had a poor outcome. Seizures at onset of AIS were associated with a poor outcome (odds ratio = 3.5, 95% confidence interval = 1.16-10.6). Twenty-eight of 73 (38%) children were judged by their carers to have fully recovered. Ten of 84 (12%) children had recurrent seizures, and 17 of 84 (20%) reported recurrent headaches. INTERPRETATION: AIS carries a significant risk of mortality and long-term neurological deficit. However, the rates of mortality, recurrence, and neurological impairment were markedly lower in this study than previously published figures in the United Kingdom. Ann Neurol 2016;79:784-793. PMID- 26928666 TI - Relationship of Self-Rated Health to Stroke Incidence and Mortality in Older Individuals with and without a History of Stroke: A Longitudinal Study of the MRC Cognitive Function and Ageing (CFAS) Population. AB - INTRODUCTION: Poor self-rated health (SRH) has been associated with increased risk of death and poor health outcomes even after adjusting for confounders. However its' relationship with disease-specific mortality and morbidity has been less studied. SRH may also be particularly predictive of health outcomes in those with pre-existing conditions. We studied whether SRH predicts new stroke in older people who have never had a stroke, or a recurrence in those with a prior history of stroke. METHODS: MRC CFAS I is a multicentre cohort study of a population representative sample of people in their 65th year and older. A comprehensive interview at baseline included questions about presence of stroke, self-rated health and functional disability. Follow-up at 2 years included self-report of stroke and stroke death obtained from death certificates. Multiple logistical regression determined odds of stroke at 2 years adjusting for confounders including disability and health behaviours. Survival analysis was performed until June 2014 with follow-up for up to 13 years. RESULTS: 11,957 participants were included, of whom 11,181 (93.8%) had no history of stroke and 776 (6.2%) one or more previous strokes. Fewer with no history of stroke reported poor SRH than those with stroke (5 versus 21%). In those with no history of stroke, poor self rated health predicted stroke incidence (OR 1.5 (1.1-1.9)), but not stroke mortality (OR 1.2 (0.8-1.9)) at 2 years nor for up to 13 years (OR 1.2(0.9-1.7)). In those with a history of stroke, self-rated health did not predict stroke incidence (OR 0.9(0.6-1.4)), stroke mortality (OR 1.1(0.5-2.5)), or survival (OR 1.1(0.6-2.1)). CONCLUSIONS: Poor self-rated health predicts risk of stroke at 2 years but not stroke mortality among the older population without a previous history of stroke. SRH may be helpful in predicting who may be at risk of developing a stroke in the near future. PMID- 26928667 TI - Effect of Nanoparticle Surface on the HPLC Elution Profile of Liposomal Nanoparticles. AB - PURPOSE: Nanoparticles have been used in diverse areas, and even broader applications are expected in the future. Since surface modification can influence the configuration and toxicity of nanoparticles, a rapid screening method is important to ensure nanoparticle quality. METHODS: We examined the effect of the nanoparticle surface morphology on the HPLC elution profile using two types of 100-nm liposomal nanoparticles (AmBisome(R) and DOXIL(R)). RESULTS: These 100-nm sized nanoparticles eluted before the holdup time (about 4 min), even when a column packed with particles with a relatively large pore size (30 nm) was used. The elution time of the nanoparticles increased with pegylation of the nanoparticles and protein adsorption to the nanoparticles; however, the nanoparticles still eluted before the holdup time. CONCLUSIONS: The results of this study indicate that HPLC is a suitable tool for rapid evaluation of the surface of liposomal nanoparticles. PMID- 26928668 TI - Production of Inhalation Phage Powders Using Spray Freeze Drying and Spray Drying Techniques for Treatment of Respiratory Infections. AB - PURPOSE: The potential of aerosol phage therapy for treating lung infections has been demonstrated in animal models and clinical studies. This work compared the performance of two dry powder formation techniques, spray freeze drying (SFD) and spray drying (SD), in producing inhalable phage powders. METHOD: A Pseudomonas podoviridae phage, PEV2, was incorporated into multi-component formulation systems consisting of trehalose, mannitol and L-leucine (F1 = 60:20:20 and F2 = 40:40:20). The phage titer loss after the SFD and SD processes and in vitro aerosol performance of the produced powders were assessed. RESULTS: A significant titer loss (~2 log) was noted for droplet generation using an ultrasonic nozzle employed in the SFD method, but the conventional two-fluid nozzle used in the SD method was less destructive for the phage (~0.75 log loss). The phage were more vulnerable during the evaporative drying process (~0.75 log further loss) compared with the freeze drying step, which caused negligible phage loss. In vitro aerosol performance showed that the SFD powders (~80% phage recovery) provided better phage protection than the SD powders (~20% phage recovery) during the aerosolization process. Despite this, higher total lung doses were obtained for the SD formulations (SD-F1 = 13.1 +/- 1.7 * 10(4) pfu and SD-F2 = 11.0 +/- 1.4 * 10(4) pfu) than from their counterpart SFD formulations (SFD-F1 = 8.3 +/- 1.8 * 10(4) pfu and SFD-F2 = 2.1 +/- 0.3 * 10(4) pfu). CONCLUSION: Overall, the SD method caused less phage reduction during the powder formation process and the resulted powders achieved better aerosol performance for PEV2. PMID- 26928669 TI - Experimental Model System to Study pH Shift-Induced Aggregation of Monoclonal Antibodies Under Controlled Conditions. AB - PURPOSE: To present a convenient screening method for evaluating additive effects on the renaturation of an acid-exposed monoclonal antibody (mAb). METHODS: The assay involves brief incubation of a mAb at acidic pH and subsequent neutralization in the absence or presence of additive to induce mainly aggregation. An increase in absorbance depicted aggregation. The recorded aggregation data traces were fitted with a nucleation-autocatalytic growth model for the extraction of kinetic parameters. RESULTS: All kinetic data traces were fitted successfully with the selected model and the adjusted R square values were greater than 0.99. Trehalose had strongly stabilizing, proline mildly stabilizing and trimethylamine oxide had destabilizing effects on both the nucleation and growth phase of the reaction. Histidine was strongly stabilizing but was limited by its poor solubility. CONCLUSION: The results demonstrate the suitability of the experimental mAb aggregation system and the nucleation-autocatalytic growth fit in the screening and quantification of additive effects on the renaturation of an acid-exposed mAb respectively. This will aid the investigation and derivation of quantitative structure-activity relationships of additive effects on mAb solubility. PMID- 26928670 TI - A Randomized, Placebo-Controlled, Phase II, Presurgical Biomarker Trial of Celecoxib Versus Exemestane in Postmenopausal Breast Cancer Patients. AB - In breast cancer presurgical trials, the Ki-67 labeling index predicts disease outcome and offers clues to the preventive potential of drugs. We conducted a placebo-controlled trial to evaluate the activity of exemestane and celecoxib before surgery. The main endpoint was the change in Ki-67. Secondary endpoints were the modulation of circulating biomarkers. Postmenopausal women with histologically confirmed estrogen receptor-positive breast cancer were randomly assigned to exemestane 25 mg/day (n = 50), or celecoxib 800 mg/day (n = 50), or placebo (n = 25) for 6 weeks before surgery. Changes in biomarkers were analyzed through an ANCOVA model adjusting for baseline values. Exemestane showed a median absolute 10% reduction in Ki-67 [from 22 (interquartile range, IQR, 16-27), to 8 (IQR 5-18)], and a 15% absolute reduction in PgR expression [from 50 (IQR 3-90) to 15 (IQR -0-30)] after 6 weeks of treatment. Exemestane significantly increased testosterone [median change 0.21 ng/mL, (IQR 0.12-0.35)], decreased SHBG [median change -14.6 nmol/L, (IQR -23.1 to -8.6)], decreased total and HDL cholesterol by -10 mg/dL (IQR -21-2) and -7 mg/dL, (IQR -14 to -2), respectively. Triglycerides were reduced by both agents [median change -0.5 mg/dL (IQR -17.5-13.5) and -8 mg/dL (IQR -28-9) for celecoxib and exemestane, respectively]. Exemestane showed a remarkable antiproliferative effect on breast cancer, whereas celecoxib did not affect breast cancer proliferation. Given the proven preventive efficacy of exemestane, these findings support the use of Ki-67 to explore the optimal exemestane dose and schedule in the prevention setting. Cancer Prev Res; 9(5); 349-56. (c)2016 AACR. PMID- 26928671 TI - The G-protein biased partial kappa opioid receptor agonist 6'-GNTI blocks hippocampal paroxysmal discharges without inducing aversion. AB - BACKGROUND AND PURPOSE: With a prevalence of 1-2%, epilepsies belong to the most frequent neurological diseases worldwide. Although antiepileptic drugs are available since several decades, the incidence of patients that are refractory to medication is still over 30%. Antiepileptic effects of kappa opioid receptor (kappa receptor) agonists have been proposed since the 1980s. However, their clinical use was hampered by dysphoric side effects. Recently, G-protein biased kappa receptor agonists were developed, suggesting reduced aversive effects. EXPERIMENTAL APPROACH: We investigated the effects of the kappa receptor agonist U-50488H and the G-protein biased partial kappa receptor agonist 6'-GNTI in models of acute seizures and drug-resistant temporal lobe epilepsy and in the conditioned place avoidance (CPA) test. Moreover, we performed slice electrophysiology to understand the functional mechanisms of 6'-GNTI. KEY RESULTS: As previously shown for U-50488H, 6'-GNTI markedly increased the threshold for pentylenetetrazole-induced seizures. All treated mice displayed reduced paroxysmal activity in response to U-50488H (20 mg.kg(-1) ) or 6'-GNTI (10-30 nmoles) treatment in the mouse model of intra-hippocampal injection of kainic acid. Single cell recordings on hippocampal pyramidal cells revealed enhanced inhibitory signalling as potential mechanisms causing the reduction of paroxysmal activity. Effects of 6'-GNTI were blocked in both seizure models by the kappa receptor antagonist 5'-GNTI. Moreover, 6'-GNTI did not induce CPA, a measure of aversive effects, while U-50488H did. CONCLUSIONS AND IMPLICATIONS: Our data provide the proof of principle that anticonvulsant/antiseizure and aversive effects of kappa receptor activation can be pharmacologically separated in vivo. PMID- 26928673 TI - The 2nd United Kingdom Extracellular Vesicle Forum Meeting Abstracts: 15 December 2015, Hadyn Ellis Building, Cardiff University. AB - The UK Extracellular Vesicles (UKEV) Forum meetings were born of the realization that there were a number of UK laboratories studying extracellular vesicle biology and using similar techniques but without a regular national meeting dedicated to EVs at which to share their findings. This was compounded by the fact that many of these labs were working in different fields and thus networking and sharing of ideas and best practice was sometimes difficult. The first workshop was organized in 2013 by Dr Charlotte Lawson, under the auspices of the Society for Endocrinology, led to the founding of the UKEV Forum and the organization of a British Heart Foundation sponsored 1-day conference held in London in December 2014. Although growing in size every year, the central aims of these workshops have remained the same: to provide a forum for discussion and exchange of ideas, to allow young scientists to present their data in the form of short talks and poster presentations and to discuss their work with more established scientists in the field. Here we include the presented abstracts for the 2015 1-day conference hosted by Cardiff University. This meeting was attended by approximately 130 delegates throughout the United Kingdom, but also attended by delegates from Belgium, Netherlands, France, Ireland and other nations. The day composed of plenary presentations from Prof Matthias Belting, Lund University, Sweden and Dr Guillaume van Niel, Institut Curie, Paris together with 10 short presentations from submitted abstracts. The topics covered were broad, with sessions on Mechanisms of EV production, EVs in Infection, EVs in Cancer and in Blood and Characterizing EVs in Biological fluids. This hopefully gives a reflection of the range of EV-related studies being conducted currently in the UK. There were also 33 poster presentations equally broad in subject matter. The organizers are grateful to the Life Science Research Network Wales - a Welsh government-funding scheme that part-sponsored the conference. We are also grateful to commercial sponsors, and 3 paid-presentations are included in the abstracts. The UK EV Forum is expected to become an established annual event held at different Universities across the UK and continue to attract increasing delegate numbers and abstract submissions. We look forward to the next planned conference, which will be hosted by David Carter and his colleagues at Oxford Brookes University on 13th December 2016. PMID- 26928672 TI - MSC secretes at least 3 EV types each with a unique permutation of membrane lipid, protein and RNA. AB - Mesenchymal stem cell (MSC), a widely used adult stem cell candidate for regenerative medicine, has been shown to exert some of its therapeutic effects through the secretion of extracellular vesicles (EVs). These homogenously sized EVs of 100-150 etam exhibited many exosome-like biophysical and biochemical properties and carry both proteins and RNAs. Recently, exosome-associated proteins in this MSC EV preparation were found to segregate primarily to those EVs that bind cholera toxin B chain (CTB), a GM1 ganglioside-specific ligand, and pulse-chase experiments demonstrated that these EVs have endosomal origin and carried many of the exosome-associated markers. Here, we report that only a fraction of the MSC EV proteome was found in CTB-bound EVs. Using Annexin V (AV) and Shiga toxin B subunit (ST) with affinities for phosphatidylserine and globotriaosylceramide, respectively, AV- and a ST-binding EV were identified. CTB , AV- and ST-binding EVs all carried actin. However, the AV-binding EVs carried low or undetectable levels of the exosome-associated proteins. Only the ST binding EVs carried RNA and EDA-containing fibronectin. Proteins in AV-binding EVs were also different from those released by apoptotic MSCs. CTB- and AV binding activities were localized to the plasma membrane and cytoplasm of MSCs, while ST-binding activity was localized to the nucleus. Together, this study demonstrates that cells secrete many types of EVs. Specifically, MSCs secrete at least 3 types. They can be differentially isolated based on their affinities for membrane lipid-binding ligands. As the subcellular sites of the binding activities of these ligands and cargo load are different for each EV type, they are likely to have a different biogenesis pathway and possibly different functions. PMID- 26928674 TI - Genetic modification of bone-marrow mesenchymal stem cells and hematopoietic cells with human coagulation factor IX-expressing plasmids. AB - Ex-vivo gene therapy of hemophilias requires suitable bioreactors for secretion of hFIX into the circulation and stem cells hold great potentials in this regard. Viral vectors are widely manipulated and used to transfer hFIX gene into stem cells. However, little attention has been paid to the manipulation of hFIX transgene itself. Concurrently, the efficacy of such a therapeutic approach depends on determination of which vectors give maximal transgene expression. With this in mind, TF-1 (primary hematopoietic lineage) and rat-bone marrow mesenchymal stem cells (BMSCs) were transfected with five hFIX-expressing plasmids containing different combinations of two human beta-globin (hBG) introns inside the hFIX-cDNA and Kozak element and hFIX expression was evaluated by different methods. In BMSCs and TF-1 cells, the highest hFIX level was obtained from the intron-less and hBG intron-I,II containing plasmids respectively. The highest hFIX activity was obtained from the cells that carrying the hBG intron I,II containing plasmids. BMSCs were able to produce higher hFIX by 1.4 to 4.7 fold increase with activity by 2.4 to 4.4-fold increase compared to TF-1 cells transfected with the same constructs. BMSCs and TF-1 cells could be effectively bioengineered without the use of viral vectors and hFIX minigene containing hBG introns could represent a particular interest in stem cell-based gene therapy of hemophilias. PMID- 26928675 TI - Energy Transfer from Quantum Dots to Graphene and MoS2: The Role of Absorption and Screening in Two-Dimensional Materials. AB - We report efficient nonradiative energy transfer (NRET) from core-shell, semiconducting quantum dots to adjacent two-dimensional sheets of graphene and MoS2 of single- and few-layer thickness. We observe quenching of the photoluminescence (PL) from individual quantum dots and enhanced PL decay rates in time-resolved PL, corresponding to energy transfer rates of 1-10 ns(-1). Our measurements reveal contrasting trends in the NRET rate from the quantum dot to the van der Waals material as a function of thickness. The rate increases significantly with increasing layer thickness of graphene, but decreases with increasing thickness of MoS2 layers. A classical electromagnetic theory accounts for both the trends and absolute rates observed for the NRET. The countervailing trends arise from the competition between screening and absorption of the electric field of the quantum dot dipole inside the acceptor layers. We extend our analysis to predict the type of NRET behavior for the near-field coupling of a chromophore to a range of semiconducting and metallic thin film materials. PMID- 26928676 TI - Enhanced Stability and Controllability of an Ionic Diode Based on Funnel-Shaped Nanochannels with an Extended Critical Region. AB - The enhanced stability and controllability of an ionic diode system based on funnel-shaped nanochannels with a much longer critical region is reported. The polarity of ion transport switching from anion/cation-selective to ambipolar can be controlled by tuning the length and charge of the critical region. This nanofluidic structure anticipates potential applications in single-molecule biosensing, water resource monitoring, and healthcare. PMID- 26928677 TI - Prophylactic salpingo-oophorectomy in BRCA1 mutation carriers and postoperative incidence of peritoneal and breast cancers. AB - BACKGROUND: There are no effective methods of diagnosis of early-stage ovarian cancer. Conservative care over patients at high risk of ovarian and breast cancers is ineffective. Prophylactic surgery is considered the best prophylaxis among BRCA1/BRCA2 carriers. METHODS: One hundred ninety-five patients, carriers of one of three most common mutations of the BRCA1 gene (Am J Hum Genet: 66: (6)1963-1968, 2000) in the Polish population (5382insC, 4153delA and C61G), who undergone prophylactic salpingo-oophorectomy. The study group consisted of consecutive mutation carriers living in Poland, in the West Pomeranian province. Histopathological examination of the surgical material failed to reveal presence of malignancy. RESULTS: During follow-up we diagnosed two peritoneal cancers and 14 breast cancers. Diagnosis of breast cancer before prophylactic surgery increased the risk of peritoneal cancer almost three times. Time from diagnosis of breast cancer to prophylactic surgery increased the risk of peritoneal cancer after prophylactic surgery. This was strongly expressed (HR = 5.0; p = 0.030) in cases of over five-year-long delay in prophylactic surgery. Diagnosis of breast cancer before prophylactic surgery correlated with the risk of death (p = 0.00010). Presence of 5382insC mutation decreased and C61G mutation increased the risk of peritoneal cancer (p = 0.049 vs. p = 0.013). CONCLUSIONS: Occurrence of primary peritoneal cancer after prophylactic surgery is similar to that reported in international literature. Primary breast cancer occurred less often than in international literature. We suspect that the risk of development of breast cancer among BRCA1 carriers undergoing prophylactic surgery can differ in a population. The next goal should be to study the molecular basis for the risk of development of malignancies in any population. Carriers of BRCA1 gene diagnosed with breast cancer should undergo prophylactic surgery within five years from the diagnosis of breast cancer. PMID- 26928679 TI - [Not Available]. PMID- 26928680 TI - [Not Available]. AB - This article presents the guidelines for the treatment of epistaxis in an out patient setting in Sweden. Nasal hemorrhage from the anterior part of the nasal cavity is best treated with silver nitrate cauterization or electrocautery. Bleeding from the posterior part of the nasal cavity often requires treatment with a pneumatic nasal tamponade, RapidRhino, or a posterior nasal packing with a Foley catheter. When a patient requires treatment with posterior nasal packing it is recommended that a contact be taken with the nearest ENT clinic. The guidelines described are used by otorhinolaryngologists at Karolinska University Hospital, Stockholm, Sahlgrenska University Hospital, Gothenburg, Lund University Hospital, Lund and District Hospital Sundsvall-Harnosand, Sundsvall. PMID- 26928681 TI - [Not Available]. PMID- 26928682 TI - [Not Available]. PMID- 26928683 TI - [Not Available]. AB - Early or delayed onset of oral anticoagulant therapy in patients with acute ischemic stroke with atrial fibrillation is an unsolved issue. Retrospectively, 294 patient records at two hospitals were scrutinized according to a protocol consisting of 20 items regarding choice of therapy (warfarin or NOAC), time for onset of therapy, CT findings of bleeding, capacity to swallow, and occurrence of clinical deterioration during the acute phase. Out of 249 patients who survived the acute phase, 116 (47%) patients were given a new prescription of warfarin or NOAC at discharge, while 43 (17 %) continued with anticoagulant therapy already prescribed before the onset of stroke. The median value for new prescriptions in relation to stroke admission was 5 days. The pattern was similar for warfarin and NOAC. Patients in whom anticoagulant therapy was started early were characterized by good capacity to swallow and no signs of bleeding on initial CT. The question "early or delayed onset of oral anticoagulant therapy after acute ischemic stroke with atrial fibrillation" needs to be tested in a randomized clinical trial. PMID- 26928684 TI - [Not Available]. PMID- 26928685 TI - [Not Available]. AB - Cogans syndrome is a rare systemic inflammatory disease characterized by a combination of audiovestibular and ocular symptoms. In some cases, systemic complications occur with vascular inflammation. Aortitis and large vessel vasculitis are the most common forms, but medium-sized and small vessel involvement has also been described. The autoimmune reaction can lead to blindness, deafness and in worst case death, if these patients remain untreated or if treatment is delayed. There is no specific blood test or imaging method available and the diagnosis is clinical. It should be suspected in patients presenting with both inflammatory eye symptoms and audiovestibular dysfunction, when more common autoimmune and infectious diseases have been excluded. The treatment consists of high dose systemic steroids, topical steroids for the affected eye and in some cases addition of immunosuppressive drugs. Treatment is based on the severity of the symptoms and how well the patient responds to initial systemic corticosteroids. Here we present a case of suspected Cogan's syndrome where diagnosis was considered after exclusion of other possible autoimmune and infectious diseases. PMID- 26928678 TI - Adult height, nutrition, and population health. AB - In this review, the potential causes and consequences of adult height, a measure of cumulative net nutrition, in modern populations are summarized. The mechanisms linking adult height and health are examined, with a focus on the role of potential confounders. Evidence across studies indicates that short adult height (reflecting growth retardation) in low- and middle-income countries is driven by environmental conditions, especially net nutrition during early years. Some of the associations of height with health and social outcomes potentially reflect the association between these environmental factors and such outcomes. These conditions are manifested in the substantial differences in adult height that exist between and within countries and over time. This review suggests that adult height is a useful marker of variation in cumulative net nutrition, biological deprivation, and standard of living between and within populations and should be routinely measured. Linkages between adult height and health, within and across generations, suggest that adult height may be a potential tool for monitoring health conditions and that programs focused on offspring outcomes may consider maternal height as a potentially important influence. PMID- 26928686 TI - [Not Available]. AB - Leakage of cerebrospinal fluid (CSF) from a cranio-orbital fistula, i.e. oculorrhea, is rare after skull trauma with fewer than 30 patients reported in Western literature. Here, we for the first time report a Swedish patient. A 75 year-old male sustained a mid-facial injury due to a bicycle accident. The CT scan showed, among other things, a fracture in the orbital roof, involving lamina cribrosa and lamina papyracea. The patient had epiphora and laboratory analysis showed CSF leakage. This diagnosis should be kept in mind when excessive tearing appears in mid-facial trauma and treatment should be considered, otherwise serious complications may occur. PMID- 26928687 TI - [Seeing the same physician continuously promotes compliance to prescriptions]. PMID- 26928688 TI - [Not Available]. PMID- 26928689 TI - [Extend the rehabilitation process for patients with chronic pain]. PMID- 26928690 TI - [Not Available]. PMID- 26928691 TI - [Not Available]. PMID- 26928692 TI - [Valve surgery and prestige]. PMID- 26928693 TI - [Death on prescription]. PMID- 26928694 TI - [Not Available]. PMID- 26928695 TI - [Not Available]. PMID- 26928696 TI - [Not Available]. PMID- 26928697 TI - [Not Available]. PMID- 26928699 TI - [Not Available]. PMID- 26928698 TI - [Not Available]. PMID- 26928701 TI - [Not Available]. PMID- 26928700 TI - [Not Available]. PMID- 26928702 TI - [Not Available]. PMID- 26928704 TI - Effect of Oxygen Desaturations on Subsequent Medical Visits in Infants Discharged From the Emergency Department With Bronchiolitis. AB - IMPORTANCE: Reliance on pulse oximetry has been associated with increased hospitalizations, prolonged hospital stay, and escalation of care. OBJECTIVE: To examine whether there is a difference in the proportion of unscheduled medical visits within 72 hours of emergency department discharge in infants with bronchiolitis who have oxygen desaturations to lower than 90% for at least 1 minute during home oximetry monitoring vs those without desaturations. DESIGN, SETTING, AND PARTICIPANTS: Prospective cohort study conducted from February 6, 2008, to April 30, 2013, at a tertiary care pediatric emergency department in Toronto, Ontario, Canada, among 118 otherwise healthy infants aged 6 weeks to 12 months discharged home from the emergency department with a diagnosis of acute bronchiolitis. MAIN OUTCOMES AND MEASURES: The primary outcome was unscheduled medical visits for bronchiolitis, including a visit to any health care professional due to concerns about respiratory symptoms, within 72 hours of discharge in infants with and without desaturations. Secondary outcomes included examination of the severity and duration of the desaturations, delayed hospitalizations within 72 hours of discharge, and the effect of activity on desaturations. RESULTS: A total of 118 infants were included (mean [SD] age, 4.5 [2.1] months; 69 male [58%]). During a mean (SD) monitoring period of 19 hours 57 minutes (10 hours 37 minutes), 75 of 118 infants (64%) had at least 1 desaturation event (median continuous duration, 3 minutes 22 seconds; interquartile range, 1 minute 54 seconds to 8 minutes 50 seconds). Among the 118 infants, 59 (50%) had at least 3 desaturations, 12 (10%) had desaturation for more than 10% of the monitored time, and 51 (43%) had desaturations lasting 3 or more minutes continuously. Of the 75 infants who had desaturations, 59 (79%) had desaturation to 80% or less for at least 1 minute and 29 (39%) had desaturation to 70% or less for at least 1 minute. Of the 75 infants with desaturations, 18 (24%) had an unscheduled visit for bronchiolitis as compared with 11 of the 43 infants without desaturation (26%) (difference, -1.6%; 95% CI, -0.15 to infinity; P = .66). One of the 75 infants with desaturations (1%) and 2 of the 43 infants without desaturations (5%) were hospitalized within 72 hours (difference, -3.3%; 95% CI, -0.04 to 0.10; P = .27). Among the 62 infants with desaturations who had diary information, 48 (77%) experienced them during sleep or while feeding. CONCLUSIONS AND RELEVANCE: The majority of infants with mild bronchiolitis experienced recurrent or sustained desaturations after discharge home. Children with and without desaturations had comparable rates of return for care, with no difference in unscheduled return medical visits and delayed hospitalizations. PMID- 26928703 TI - Human lung adenocarcinoma cell cultures derived from malignant pleural effusions as model system to predict patients chemosensitivity. AB - BACKGROUND: Lung cancer is the leading cause of cancer related deaths and Malignant Pleural Effusion (MPE) is a frequent complication. Current therapies suffer from lack of efficacy in a great percentage of cases, especially when cancer is diagnosed at a late stage. Moreover patients' responses vary and the outcome is unpredictable. Therefore, the identification of patients who will benefit most of chemotherapy treatment is important for accurate prognostication and better outcome. In this study, using malignant pleural effusions (MPE) from non-small cell lung cancer (NSCLC) patients, we established a collection of patient-derived Adenocarcinoma cultures which were characterized for their sensitivity to chemotherapeutic drugs used in the clinical practice. METHODS: Tumor cells present in MPEs of patients with NSCLC were isolated by density gradient centrifugation, placed in culture and genotyped by next generation sequencing. In a subset of cases patient derived xenografts (PDX) were obtained upon tumor cell inoculation in rag2/IL2 knock-out mice. Isolated primary cultures were characterized and tested for drug sensitivity by in vitro proliferation assays. Additivity, antagonism or synergy for combinatorial treatments were determined by analysis with the Calcusyn software. RESULTS: We have optimized isolation procedures and culture conditions to expand in vitro primary cultures from Malignant Pleural Effusions (MPEs) of patients affected by lung adenocarcinomas, the most frequent form of non small cell lung cancer. Using this approach we have been able to establish 16 primary cultures from MPEs. Cells were banked at low passages and were characterized for their mutational pattern by next generation sequencing for most common driver mutations in lung cancer. Moreover, amplified cultures were shown to engraft with high efficiency when injected in immunocompromised mice. Cancer cell sensitivity to drugs used in standard chemotherapy regimens was assessed either individually or in combination. Differential chemosensitivity and different mutation profiles were observed which suggests that this isolation method could provide a platform for predicting the efficacy of chemotherapy in the clinical setting. Most importantly for six patients it was possible to establish a correlation between drug response in vitro and response to therapy in the clinic. CONCLUSIONS: Results obtained using primary cultured cells from MPEs underscore the heterogeneity of NSCLC in advanced stage as indicated by drug response and mutation profile. Comparison of data obtained from in vitro assays with patients' responses to therapy leads to the conclusion that this strategy may provide a potentially useful approach for evaluating individual chemosensitivity profile and tailor the therapy accordingly. Furthermore, combining MPE-derived primary cultures with their genomic testing allows to identify patients eligible to trials with novel targeted agents. PMID- 26928705 TI - Assessment of Heart Transplant Waitlist Time and Pre- and Post-transplant Failure: A Mixed Methods Approach. AB - BACKGROUND: Over the past two decades, there have been increasingly long waiting times for heart transplantation. We studied the relationship between heart transplant waiting time and transplant failure (removal from the waitlist, pretransplant death, or death or graft failure within 1 year) to determine the risk that conservative donor heart acceptance practices confer in terms of increasing the risk of failure among patients awaiting transplantation. METHODS: We studied a cohort of 28,283 adults registered on the United Network for Organ Sharing heart transplant waiting list between 2000 and 2010. We used Kaplan-Meier methods with inverse probability censoring weights to examine the risk of transplant failure accumulated over time spent on the waiting list (pretransplant). In addition, we used transplant candidate blood type as an instrumental variable to assess the risk of transplant failure associated with increased wait time. RESULTS: Our results show that those who wait longer for a transplant have greater odds of transplant failure. While on the waitlist, the greatest risk of failure is during the first 60 days. Doubling the amount of time on the waiting list was associated with a 10% (1.01, 1.20) increase in the odds of failure within 1 year after transplantation. CONCLUSIONS: Our findings suggest a relationship between time spent on the waiting list and transplant failure, thereby supporting research aimed at defining adequate donor heart quality and acceptance standards for heart transplantation. PMID- 26928706 TI - Commentary: Selection Bias in Clinical Epidemiology: Causal Thinking to Guide Patient-centered Research. PMID- 26928708 TI - Property Values as a Measure of Neighborhoods: An Application of Hedonic Price Theory. AB - BACKGROUND: Researchers measuring relationships between neighborhoods and health have begun using property appraisal data as a source of information about neighborhoods. Economists have developed a rich tool kit to understand how neighborhood characteristics are quantified in appraisal values. This tool kit principally relies on hedonic (implicit) price models and has much to offer regarding the interpretation and operationalization of property appraisal data derived neighborhood measures, which goes beyond the use of appraisal data as a measure of neighborhood socioeconomic status. METHODS: We develop a theoretically informed hedonic-based neighborhood measure using residuals of a hedonic price regression applied to appraisal data in a single metropolitan area. We describe its characteristics, reliability in different types of neighborhoods, and correlation with other neighborhood measures (i.e., raw neighborhood appraisal values, census block group poverty, and observed property characteristics). We examine the association between all neighborhood measures and body mass index. RESULTS: The hedonic-based neighborhood measure was correlated in the expected direction with block group poverty rate and observed property characteristics. The neighborhood measure and average raw neighborhood appraisal value, but not census block group poverty, were associated with individual body mass index. CONCLUSION: We draw theoretically consistent methodology from the economics literature on hedonic price models to demonstrate how to leverage the implicit valuation of neighborhoods contained in publicly available appraisal data. Consistent measurement and application of the hedonic-based neighborhood measures in epidemiology will improve understanding of the relationships between neighborhoods and health. Researchers should proceed with a careful use of appraisal values utilizing theoretically informed methods such as this one. PMID- 26928709 TI - Carcinogenicity of some industrial chemicals. PMID- 26928711 TI - Correction: The NLRP3 Inflammasome and IL-1beta Accelerate Immunologically Mediated Pathology in Experimental Viral Fulminant Hepatitis. PMID- 26928710 TI - Strain-Engineered Graphene Grown on Hexagonal Boron Nitride by Molecular Beam Epitaxy. AB - Graphene grown by high temperature molecular beam epitaxy on hexagonal boron nitride (hBN) forms continuous domains with dimensions of order 20 MUm, and exhibits moire patterns with large periodicities, up to ~30 nm, indicating that the layers are highly strained. Topological defects in the moire patterns are observed and attributed to the relaxation of graphene islands which nucleate at different sites and subsequently coalesce. In addition, cracks are formed leading to strain relaxation, highly anisotropic strain fields, and abrupt boundaries between regions with different moire periods. These cracks can also be formed by modification of the layers with a local probe resulting in the contraction and physical displacement of graphene layers. The Raman spectra of regions with a large moire period reveal split and shifted G and 2D peaks confirming the presence of strain. Our work demonstrates a new approach to the growth of epitaxial graphene and a means of generating and modifying strain in graphene. PMID- 26928707 TI - Review Article: The Role of Molecular Pathological Epidemiology in the Study of Neoplastic and Non-neoplastic Diseases in the Era of Precision Medicine. AB - Molecular pathology diagnostics to subclassify diseases based on pathogenesis are increasingly common in clinical translational medicine. Molecular pathological epidemiology (MPE) is an integrative transdisciplinary science based on the unique disease principle and the disease continuum theory. While it has been most commonly applied to research on breast, lung, and colorectal cancers, MPE can investigate etiologic heterogeneity in non-neoplastic diseases, such as cardiovascular diseases, obesity, diabetes mellitus, drug toxicity, and immunity related and infectious diseases. This science can enhance causal inference by linking putative etiologic factors to specific molecular biomarkers as outcomes. Technological advances increasingly enable analyses of various -omics, including genomics, epigenomics, transcriptomics, proteomics, metabolomics, metagenomics, microbiome, immunomics, interactomics, etc. Challenges in MPE include sample size limitations (depending on availability of biospecimens or biomedical/radiological imaging), need for rigorous validation of molecular assays and study findings, and paucities of interdisciplinary experts, education programs, international forums, and standardized guidelines. To address these challenges, there are ongoing efforts such as multidisciplinary consortium pooling projects, the International Molecular Pathological Epidemiology Meeting Series, and the Strengthening the Reporting of Observational Studies in Epidemiology-MPE guideline project. Efforts should be made to build biorepository and biobank networks, and worldwide population-based MPE databases. These activities match with the purposes of the Big Data to Knowledge (BD2K), Genetic Associations and Mechanisms in Oncology (GAME-ON), and Precision Medicine Initiatives of the United States National Institute of Health. Given advances in biotechnology, bioinformatics, and computational/systems biology, there are wide open opportunities in MPE to contribute to public health. PMID- 26928712 TI - Effects of novel acylhydrazones derived from 4-quinolone on the acetylcholinesterase activity and Abeta42 peptide fibrils formation. AB - Acetylcholinesterase inhibitors and compounds that trigger Abeta amyloid oligomerization and fibrillization represent an opportunity to discover new drug candidates to treat Alzheimer's disease. In this work, we synthesized nine new acylhydrazones and a known one, both employing 3-carboethoxy-4-quinolone derivatives as starting materials with chemical yields ranging from 63% to 90%. We evaluated the effect of these compounds on the acetylcholinesterase (AChE) activity and the fibrillization of Abeta42 peptide. Except for one acylhydrazone, the compounds exhibited good inhibitory effect on AChE (1.2 MUM < IC50 values < 17 MUM). They also showed a significant decrease in the thioflavin-T fluorescence emission, suggesting an inhibitory effect on the Abeta42 fibril formation. PMID- 26928714 TI - 3-Ketosphinganine provokes the accumulation of dihydroshingolipids and induces autophagy in cancer cells. AB - Although several reports describe the metabolic fate of sphingoid bases and their analogs, as well as their action and that of their phosphates as regulators of sphingolipid metabolizing-enzymes, similar studies for 3-ketosphinganine (KSa), the product of the first committed step in de novo sphingolipid biosynthesis, have not been reported. In this article we show that 3-ketosphinganine (KSa) and its dideuterated analog at C4 (d2KSa) are metabolized to produce high levels of dihydrosphingolipids in HGC27, T98G and U87MG cancer cells. In contrast, either direct C1 O-phosphorylation or N-acylation of d2KSa to produce dideuterated ketodihydrosphingolipids does not occur. We also show that cells respond to d2KSa treatment with induction of autophagy. Time-course experiments agree with sphinganine, sphinganine 1-phosphate and dihydroceramides being the mediators of autophagy stimulated by d2KSa. Enzyme inhibition studies support that inhibition of Des1 by 3-ketobases is caused by their dihydroceramide metabolites. However, this effect contributes to increasing dihydrosphingolipid levels only at short incubation times, since cells respond to long time exposure to 3-ketobases with Des1 overexpression. The translation of these overall effects into cell fate is discussed. PMID- 26928715 TI - Unusual metastases of lung cancer: bulbus oculi and maxillary sinus. AB - Lung adenocarcinoma often makes metastasis to the brain, liver, kidneys, bone, bone marrow and adrenal glands. It can also make metastasis to other parts of the body rarely for example eye, nose, parotid gland and paranasal sinus. We did not encounter with combined ocular bulbus and the maxillary sinus metastases of lung cancer in the accessible literature. In this case report, a patient who was combined ocular bulbus and the maxillary sinus metastases of lung adenocarcinoma will be discussed. PMID- 26928716 TI - Recovery of adrenal function after chronic secondary adrenal insufficiency in patients with hypopituitarism. AB - OBJECTIVE: Previous studies have reported recovery of secondary adrenal insufficiency (SAI) in patients with pituitary disorders, generally immediately after pituitary surgery; however, data regarding recovery of long-term SAI are lacking. We conducted a study to assess the longer term recovery rate of SAI in patients with pituitary disorders. METHODS: We identified all SAI patients in the Halifax Neuropituitary Database from 1 November 2005 to 30 September 2014, who had required glucocorticoid therapy for >=3 months, and had a minimum follow-up of 6 months. Patients with ACTH-secreting adenomas, those receiving glucocorticoids only in the routine peri-operative period for pituitary surgery and those on glucocorticoids for nonpituitary conditions were excluded. SAI was defined as either basal serum cortisol < 130 nm and/or a subnormal cortisol response to ACTH-(1-24) stimulation test or insulin tolerance test response. RESULTS: Fifty-one patients fulfilled the criteria. Nine (17.6%) patients had complete recovery of SAI over a median of 20 months (range: 8-51) after initiating glucocorticoid replacement. Patients with smaller tumour size had increased likelihood of hypothalamic-pituitary-adrenal (HPA) axis recovery, whereas those with secondary hypogonadism or growth hormone deficiency were less likely to recover. Those with initial cortisol >175 nm had an almost one in two chance of recovery. CONCLUSION: Results from our study show that approximately one in six patients with SAI recover adrenal function, even up to 5 years after diagnosis. We recommend that patients with SAI undergo regular testing to assess recovery in order to prevent unnecessary glucocorticoid therapy. PMID- 26928717 TI - Identifying Robertsonian Translocation Carriers by Microarray-Based DNA Analysis. AB - OBJECTIVE: To develop a noninvasive prenatal testing improvement that allows identification of Robertsonian translocation carriers. METHODS: Blood samples from 191 subjects, including 7 pregnant and 9 non-pregnant Robertsonian translocation carriers, were analyzed for fetal trisomy and Robertsonian translocation status. Digital Analysis of Selected Regions (DANSRTM) assays targeting sequences common to the p arms of 5 acrocentric chromosomes were developed and added to existing DANSR assays. DANSR products were hybridized onto a custom DNA microarray for DNA analysis. The Fetal-Fraction Optimized Risk of Trisomy Evaluation (FORTETM) algorithm measures the fraction of fetal DNA and accounts for both the fetal and maternal fractions in the cell-free DNA sample to determine Robertsonian risk. The expectation in a Robertsonian translocation carrier is that DANSR assays on acrocentric p arms should have a concentration 20% less than that of controls. RESULTS: The FORTE algorithm correctly classified the fetal trisomy status and maternal Robertsonian translocation status in all 191 samples. Sixteen samples had a Robertsonian risk score above 99%, while 175 samples had a Robertsonian risk score below 0.01%. CONCLUSIONS: Robertsonian translocations are the most common chromosomal translocations and can have significant reproductive consequences. A maternal screen for Robertsonian translocation carriers would provide women valuable information regarding the risk of fetal trisomy. PMID- 26928719 TI - A new type of vanadium carbide V5C3 and its hardening by tuning Fermi energy. AB - Transition metal compounds usually have various stoichiometries and crystal structures due to the coexistence of metallic, covalent, and ionic bonds in them. This flexibility provides a lot of candidates for materials design. Taking the V C binary system as an example, here we report the first-principles prediction of a new type of vanadium carbide, V5C3, which has an unprecedented stoichiometry in the V-C system, and is energetically and mechanically stable. The material is abnormally much harder than neighboring compounds in the V-C phase diagram, and can be further hardened by tuning the Fermi energy. PMID- 26928718 TI - Training Excitatory-Inhibitory Recurrent Neural Networks for Cognitive Tasks: A Simple and Flexible Framework. AB - The ability to simultaneously record from large numbers of neurons in behaving animals has ushered in a new era for the study of the neural circuit mechanisms underlying cognitive functions. One promising approach to uncovering the dynamical and computational principles governing population responses is to analyze model recurrent neural networks (RNNs) that have been optimized to perform the same tasks as behaving animals. Because the optimization of network parameters specifies the desired output but not the manner in which to achieve this output, "trained" networks serve as a source of mechanistic hypotheses and a testing ground for data analyses that link neural computation to behavior. Complete access to the activity and connectivity of the circuit, and the ability to manipulate them arbitrarily, make trained networks a convenient proxy for biological circuits and a valuable platform for theoretical investigation. However, existing RNNs lack basic biological features such as the distinction between excitatory and inhibitory units (Dale's principle), which are essential if RNNs are to provide insights into the operation of biological circuits. Moreover, trained networks can achieve the same behavioral performance but differ substantially in their structure and dynamics, highlighting the need for a simple and flexible framework for the exploratory training of RNNs. Here, we describe a framework for gradient descent-based training of excitatory-inhibitory RNNs that can incorporate a variety of biological knowledge. We provide an implementation based on the machine learning library Theano, whose automatic differentiation capabilities facilitate modifications and extensions. We validate this framework by applying it to well-known experimental paradigms such as perceptual decision making, context-dependent integration, multisensory integration, parametric working memory, and motor sequence generation. Our results demonstrate the wide range of neural activity patterns and behavior that can be modeled, and suggest a unified setting in which diverse cognitive computations and mechanisms can be studied. PMID- 26928720 TI - Using a multilocus phylogeny to test morphology-based classifications of Polystichum (Dryopteridaceae), one of the largest fern genera. AB - BACKGROUND: Polystichum (Dryopteridaceae) is probably the third largest fern genus in the world and contains ca. 500 species. Species of Polystichum occur on all continents except Antarctica, but its highest diversity is found in East Asia, especially Southwest China and adjacent regions. Previous studies typically had sparse taxon sampling and used limited DNA sequence data. Consequently, the majority of morphological hypotheses/classifications have never been tested using molecular data. RESULTS: In this study, DNA sequences of five plastid loci of 177 accessions representing ca. 140 species of Polystichum and 13 species of the closely related genera were used to infer a phylogeny using maximum likelihood, Bayesian inference, and maximum parsimony. Our analyses show that (1) Polystichum is monophyletic, this being supported by not only molecular data but also morphological features and distribution information; (2) Polystichum is resolved into two strongly supported monophyletic clades, corresponding to the two subgenera, P. subg. Polystichum and P. subg. Haplopolystichum; (3) Accessions of P. subg. Polystichum are resolved into three major clades: clade K (P. sect. Xiphophyllum), clade L (P. sect. Polystichum), and the HYMASO superclade dominated by accessions of P. sect. Hypopeltis, P. sect. Macropolystichum, and P. sect. Sorolepidium, while those of P. subg. Haplopolystichum are resolved into eight major clades; and (4) The monophyly of the Afra clade (weakly supported), the Australasian clade (weakly supported), and the North American clade (strongly supported) is confirmed. CONCLUSIONS: Of the 23 sections of Polystichum recognized in a recent classification of the genus, four (P. sect. Hypopeltis, P. sect. Neopolystichum, P. sect. Sorolepidium, P. sect. Sphaenopolystichum) are resolved as non-monophyletic, 16 are recovered as monophyletic, and three are monospecific. Of the 16 monophyletic sections, two (P. sect. Adenolepia, P. sect. Cyrtogonellum) are weakly supported and 14 are strongly supported as monophyletic. The relationships of 11 sections (five in P. subg. Haplopolystichum; six in P. subg. Polystichum) are well resolved. PMID- 26928721 TI - Applicability of refractometry for fast routine checking of hospital preparations. AB - Quality control of hospital pharmacy formulations is of the utmost importance to ensure constant quality and to avoid potential mistakes before administration to the patient. In this study we investigated the applicability of refractometry as a fast, inexpensive and easy-to-use quality control measurement. Refractive indices (RI) of a multitude of different hospital formulations with varying concentrations of active compound were measured. The samples consisted of a number of binary aqueous solutions (one compound in water), complex aqueous solutions (multiple compounds in water or in a constant matrix), two suspensions and one emulsion. For all these formulations, linear regression analysis was performed, quality control limits determined and accuracy and repeatability were checked. Subsequently, actual hospital pharmacy samples were analyzed to check whether they were within the specified limits. For both binary and complex aqueous formulations, repeatability was good and a linear correlation for all samples could be observed on condition that the concentration of the active compound was sufficiently high. The refractometer was not sensitive enough for solutions of folic acid and levothyroxine, which had too low a concentration of active compound. Due to lack of homogeneity and light scattering, emulsions and suspensions do not seem suitable for quality control by refractometry. A mathematical equation was generated to predict the refractive index of an aqueous solution containing clonidine HCl as active compound. Values calculated from the equation were compared with measured values and deviations of all samples were found to be lower than 1.3%. In order to use refractometry in a hospital pharmacy for quality control of multicomponent samples, additional intermediate measurements would be required, to overcome the fact that refractometry is not compound specific. In conclusion, we found that refractometry could potentially be useful for daily, fast quality measurements of relatively concentrated binary and more complex aqueous solutions in the hospital pharmacy. PMID- 26928722 TI - Unbiased profiling of volatile organic compounds in the headspace of Allium plants using an in-tube extraction device. AB - BACKGROUND: Plants produce and emit important volatile organic compounds (VOCs), which have an essential role in biotic and abiotic stress responses and in plant plant and plant-insect interactions. In order to study the bouquets from plants qualitatively and quantitatively, a comprehensive, analytical method yielding reproducible results is required. RESULTS: We applied in-tube extraction (ITEX) and solid-phase microextraction (SPME) for studying the emissions of Allium plants. The collected HS samples were analyzed by gas chromatography-time-of flight-mass spectrometry (GC-TOF-MS), and the results were subjected to multivariate analysis. In case of ITEX-method Allium cultivars released more than 300 VOCs, out of which we provisionally identified 50 volatiles. We also used the VOC profiles of Allium samples to discriminate among groups of A. fistulosum, A. chinense (rakkyo), and A. tuberosum (Oriental garlic). As we found 12 metabolite peaks including dipropyl disulphide with significant changes in A. chinense and A. tuberosum when compared to the control cultivar, these metabolite peaks can be used for chemotaxonomic classification of A. chinense, tuberosum, and A. fistulosum. CONCLUSIONS: Compared to SPME-method our ITEX-based VOC profiling technique contributes to automatic and reproducible analyses. Hence, it can be applied to high-throughput analyses such as metabolite profiling. PMID- 26928723 TI - How to best measure femoral length and lateralisation after total hip arthroplasty on antero-posterior pelvic radiographs. AB - PURPOSE: Various methods exist for measuring limb length and lateralisation after total hip arthroplasty. Most of them utilise standard anteroposterior (AP) pelvic radiographs, but their results can be affected by patient position during imaging and thus the position of the lower limb on the coronal plane. The aim of this study is to evaluate how commonly used measuring methods of limb lengthening and femoral offset are affected by the position of the lower limb in the coronal plane. METHODS: A standing pelvic AP radiograph post implantation of a right total hip prosthesis was digitised. The right femur and its femoral stem were digitally segmented, such that they could be positioned orthogonal to the pelvis horizontal reference, with 10 degrees of adduction, and with 10 degrees of abduction, with respect to the centre of rotation. Various limb lengths and implant lateralisation were also digitised. We obtained nine x-rays differing one to three variables. Twice four independent surgeons performed three femoral length measurement methods and femoral offset measurement methods. Intra and inter-observer error as well as the effect of the femoral position on the measurements were studied. RESULTS: With respect to length measurements, the distance between the centre of rotation (C) and the tip of the lesser trochanter (LT) increased by 3 mm per cm of lateralisation. This measurement was not affected by the hip position in abduction or adduction. The distance between the tip of the lesser or greater trochanter (GT) and the horizontal passing through the centre of rotation was strongly affected by the hip position in abduction or adduction. With respect to offset, the distance between the centre of rotation and the greater trochanter (C-GT) was the most consistent and was not affected by variations in lengths or femoral axis. At the level of the lesser trochanter, the distance of the femoral anatomical axis and to Perkin's line was heavily influenced by the femoral position. CONCLUSION: The C-LT distance was consistent in measuring limb length and the C-GT distance was reliable in determining femoral offset regardless of the relative position of the femur. PMID- 26928724 TI - Local transplantation of bone marrow concentrated granulocytes precursors can cure without antibiotics infected nonunion of polytraumatic patients in absence of bone defect. AB - PURPOSE: Infected, long bone non-unions present a significant clinical challenge. New and alternative therapies are needed to address this problem. The purposes of this study were to compare the number of circulating granulocyte-macrophage colony-forming units (CFU-GM) in the peripheral blood of polytraumatic patients with infected tibial non-unions and in the peripheral blood of control patients with the hypothesis that their number was decreased in polytraumatic patients; and to treat their infection without antibiotics and with local transplantation of bone marrow concentrated granulocytes precursors. METHODS: Thirty (18 atrophic and 12 hyperthrophic ) infected tibial non-unions (without bone defect) that occurred after open fractures in polytraumatic patients were treated without antibiotics and with percutaneous injection of autologous bone marrow concentrate (BMC) containing granulocytes precursors (CFU-GM). CFU-GM progenitors were assessed in the bone marrow aspirate, peripheral blood, and fracture site of these patients. The number of these progenitors was compared with the CFU-GM progenitors of control patient samples (healthy donors matched for age and gender). Outcome measures were: timing of union, callus formation (radiographs and CT scan), and recurrence of clinical infection. RESULTS: As compared to control patients, the number of CFU GM derived colonies was lower at peripheral blood in patients with infected nonunions. The bone marrow graft injected in nonunions contained after concentration 42 621 +/- 20 350 CFU-GM-derived colonies/cc. Healing and cure of infection was observed at six months for 25 patients and at one year follow up for 30 patients. At the median ten year follow up (range: 5 to 15), only one patient had clinical recurrent infection after healing (between 6 months and last follow-up). CONCLUSION: The peripheral blood of these polytraumatic patients with infected nonunions had a remarkable decrease in CFU-GM-derived colonies as compared with normal controls. Local transplantation of concentrated CFU-GM-derived colonies aspirated from bone marrow allowed cure of infection and healing without antibiotics. PMID- 26928725 TI - Beyond the Fold: Emerging Biological Applications of DNA Origami. AB - The use of DNA as a material for nanoscale construction has blossomed in the past decade. This is largely attributable to the DNA origami technique, which has enabled construction of nanostructures ranging from simple two-dimensional sheets to complex three-dimensional objects with defined curves and edges. These structures are amenable to site-specific functionalization with nanometer precision, and have been shown to exhibit cellular biocompatibility and permeability. The DNA origami technique has already found widespread use in a variety of emerging biological applications such as biosensing, enzyme cascades, biomolecular analysis, biomimetics, and drug delivery. We highlight a few of these applications and comments on the prospects for this rapidly expanding field of research. PMID- 26928726 TI - Cystatin C, chronic kidney disease and retinopathy in adults without diabetes. AB - BACKGROUND: Serum cystatin C, a novel marker of renal function has been shown to be superior to serum creatinine in predicting renal function decline and adverse outcomes of chronic kidney disease (CKD). Our aim was to investigate the association between cystatin C and retinopathy in adults without diabetes. METHODS: We examined 1725 Indian adults, aged 40-80 years who participated in the Singapore Indian Eye Study (2007-2009) and were free of diabetes mellitus. CKD was defined as an estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m(2) determined from serum cystatin C (CKD-eGFRcys, n = 199), and serum creatinine (CKD-eGFRcr, n = 81). Retinopathy was assessed from digital fundus photographs of both eyes by trained graders using the modified Airlie House classification. The associations of CKD defined by the two markers alone and in combination (confirmed CKD, eGFRcr <60 and eGFRcys <60, n = 58) with retinopathy were examined using logistic regression models adjusted for potential confounding factors including preexisting cardiovascular disease and albuminuria. RESULTS: The prevalence of retinopathy among those with CKD-eGFRcr and CKD-eGFRcys was 9.9% and 8.5%, respectively. In separate models, the associations of retinopathy with both CKD-eGFRcys (odds ratio (OR) (95% confidence interval (CI)) = 2.18 (1.14-4.16)) and CKD-eGFRcr were significant (OR (95% CI) = 2.63 (1.10-6.28)). In models including both markers, compared to optimal kidney function (eGFRcr >=60 and eGFRcys >=60), confirmed CKD was associated with a fourfold higher odds of retinopathy (OR (95% CI) = 4.01 (1.52-10.60)). CONCLUSIONS: In a population-based sample of Indian adults without diabetes, CKD defined by both cystatin C and creatinine was strongly associated with retinopathy. PMID- 26928727 TI - Polypill-based therapy likely to reduce ethnic inequities in use of cardiovascular preventive medications: Findings from a pragmatic randomised controlled trial. AB - OBJECTIVE: The purpose of this study was to investigate the consistency of the proportional effect of fixed-dose combination therapy (the 'polypill') on the use of recommended cardiovascular preventative medications among indigenous Maori and non-indigenous adults in New Zealand. METHODS: We randomised Maori and non-Maori primary care patients at high risk of cardiovascular disease (either because of a prior event or with an estimated 5-year risk of a first event of at least 15%) to a polypill (containing aspirin, statin and two antihypertensives) or usual care for a minimum of 12 months. All patients had indications for all polypill components according to their general practitioner, and all medications (including the polypill) were prescribed by the patient's general practitioner and dispensed at community pharmacies. The main outcome for this study was the use of all recommended medications (antiplatelet, statin and two antihypertensives) at 12 months. Heterogeneity in the effect of polypill-based care compared with usual care on this outcome by ethnicity was assessed by logistic regression. RESULTS: Baseline use of recommended medications was 36% (93/257) among Maori and 51% (130/156) among non-Maori participants. Polypill based care was associated with an increase in the use of recommended medications among Maori (relative risk [RR]: 1.87; 95% confidence interval [CI]: 1.50-2.34) and non-Maori (RR: 1.66; 95% CI: 1.37-2.00) when compared with usual care at 12 months, and there was no statistically significant heterogeneity in this outcome by ethnicity (p = 0.92). CONCLUSION: Polypill-based care is likely to reduce absolute inequities between Maori and non-Maori in the use of recommended cardiovascular preventative medications given baseline absolute differences and the consistency of the proportional effect of this intervention by ethnicity in this pragmatic trial in primary care. PMID- 26928728 TI - Current practice of external ventricular drainage: a survey among neurosurgical departments in Germany. AB - BACKGROUND: There are various recommendations, but no generally accepted guidelines, to reduce the risk of external ventricular drainage (EVD)-associated infections. The primary objective of the present study was to evaluate the current practice of EVD in a European country and to set the results in perspective to published data. METHOD: A standardised questionnaire prepared by the Commission of Technical Standards and Norms of the German Society of Neurosurgery was sent to 127 neurosurgical units in Germany. RESULTS: Data were analysed from 99 out of 127 neurosurgical units which had been contacted. Overall, more than 10,000 EVD procedures appear to be performed in Germany annually. There is disagreement about the location where the EVD is inserted, and most EVDs are still inserted in the operation theatre. Most units apply subcutaneous tunnelling. Impregnated EVD catheters are used regularly in only about 20 % of units. Single-shot antibiotic prophylaxis is given in more than half of the units, while continued antibiotic prophylaxis is installed in only 15/99 units at a regular basis. There are discrepancies in the management of prolonged EVD use with regard to replacement policies. Regular cerebrospinal fluid (CSF) sampling is still performed widely. There were no statistical differences in policies with regard to academic versus non-academic units. CONCLUSIONS: This survey clearly shows that some newer recommendations drawn from published studies penetrate much slower into clinical routine, such as the use of impregnated catheters, for example. It remains unclear how different policies actually impact quality and outcome in daily routine. PMID- 26928729 TI - The effect of dopaminergic therapy on intraoperative microelectrode recordings for subthalamic deep brain stimulation under GA: Letter to the editor. PMID- 26928730 TI - Effect of weekend admission on in-hospital mortality and functional outcomes for patients with acute subarachnoid haemorrhage (SAH). AB - BACKGROUND: Aneurysmal subarachnoid haemorrhage (aSAH) is an acute cerebrovascular event with high socioeconomic impact as it tends to affect younger patients. The recent NCEPOD study looking into management of aSAH has recommended that neurovascular units in the United Kingdom should aim to secure cerebral aneurysms within 48 h and that delays because of weekend admissions can increase the mortality and morbidity attributed to aSAH. METHOD: We used data from a prospective audit of aSAH patients admitted between January 2009 and December 2011. The baseline demographic and clinical features of the weekend and weekday groups were compared using the chi-squared test and T-test. Cox proportional hazards models (Proc Phreg in SAS) were used to calculate the adjusted overall hazard of in-hospital death associated with admission on weekend, adjusting for age, sex, baseline WFNS grade, type of treatment received and time from scan to treatment. Sliding dichotomy analysis was used to estimate the difference in outcomes after SAH at 3 months in weekend and weekday admissions. RESULTS: Those admitted on weekends had a significantly higher scan to treatment time (83.05 +/- 83.4 h vs 40.4 +/- 53.4 h, P < 0.0001) and admission to treatment (71.59 +/- 79.8 h vs 27.5 +/- 44.3 h, P < 0.0001) time. After adjustments for adjusted for relevant covariates weekend admission was statistically significantly associated with excess in-hospital mortality (HR = 2.1, CL [1.13-4.0], P = 0.01). After adjustments for all the baseline covariates, the sliding dichotomy analysis did not show effects of weekend admission on long term outcomes on the good, intermediate and worst prognostic bands. CONCLUSIONS: This study provides important data showing excess in-hospital mortality of patients with SAH on weekend admissions served by the United Kingdom's National Health Service.; However, there were no effects of weekend admission on long-term outcomes. PMID- 26928731 TI - Comments on "Intraforaminal ozone therapy and particular side effects: preliminary results and early warning". PMID- 26928732 TI - Improving the Reporting of Studies Using Routinely Collected Health Data in Physical Therapy. AB - Reporting guidelines have been developed to improve the reporting of research, with the explicit aims that readers of research should understand what was planned, what was done, and what was found. The Strengthening of Reporting of Observational Studies in Epidemiology (STROBE) reporting guidelines were created to improve the transparency of reporting of observational studies, such as cohort, case-control, and cross-sectional studies, and recommend minimum reporting standards for observational studies. However, the unique elements of routinely collected health data highlight the need to develop a new reporting tool as an extension to STROBE. This need has been addressed by the REporting of studies Conducted using Observational Routinely collected Data (RECORD) initiative. The Journal of Orthopaedic & Sports Physical Therapy has decided to endorse the RECORD guidelines for relevant manuscripts and aims to maximize the implementation of, and benefit from, the RECORD guidelines in terms of completeness and transparency of reporting to ultimately help patients undergoing physical therapy. PMID- 26928733 TI - Perspectives for Practice: A New JOSPT Feature to Facilitate Translation of Research Into Practice. AB - In this month's issue, we introduce a new feature, Perspectives for Practice, which aims to interpret new research in the context of established best practice. This 2-page feature is designed to offer clinicians insight into the state of the art: what was known before, what research was done before, what new evidence the present study found, and how we should interpret this new evidence in light of what was known before. The second page of the Perspectives for Practice will provide additional material useful for teaching and discussion. The structure and content of these features will undergo continued development in response to reader feedback, which we welcome. PMID- 26928734 TI - Reporting Guidelines and Checklists Improve the Reliability and Rigor of Research Reports. AB - The Journal of Orthopaedic & Sports Physical Therapy (JOSPT) requires the use of robust research reporting guidelines for all research report submissions, including the newly adopted RECORD (REporting of studies Conducted using Observational Routinely-collected health Data) statement. We remind authors submitting research to JOSPT to identify the appropriate guideline and checklist for their study design, and to submit a completely and accurately completed checklist with their manuscript. J Orthop Sports Phys Ther 2016;46(3):130. doi:10.2519/jospt.2016.0105. PMID- 26928735 TI - Know Pain, Know Gain? A Perspective on Pain Neuroscience Education in Physical Therapy. AB - Chronic pain is incredibly complex, and so are decisions as to its treatment. During physical therapy care, pain neuroscience education (PNE) aims to help patients understand more about their pain from a biological and physiological perspective. Accompanying the growing evidence for the ability of PNE to reduce pain and disability in patients with chronic pain is an increased interest in PNE from scientists, educators, clinicians, and conference organizers. However, the rise in popularity of PNE has highlighted a historical paradox of increased knowledge not necessarily corresponding with improved care. This Viewpoint discusses the growth and popularity of PNE as well as critical future considerations such as clinical application, clinical research, appropriate outcome measures, and the blending of pain education with exercise and manual therapy. PMID- 26928736 TI - Mechanical Lumbar Traction: What Is Its Place in Clinical Practice? AB - Summary evidence concludes that mechanical lumbar traction is not effective for treating acute or chronic nonspecific low back pain (LBP). However, many physical therapists continue to use it, primarily as an additional modality. Indeed, expert clinical opinion, theoretical models, and some research evidence suggest that certain patients with LBP respond positively to traction. A study published in the March 2016 issue of JOSPT investigates the effectiveness of traction in prone as an adjunct to an extension-oriented exercise program in patients with LBP and leg pain and explores whether a previously identified set of patient characteristics is associated with better outcomes from traction. In this Perspectives for Practice, the authors explain the impact of their findings for clinicians treating these patients. PMID- 26928737 TI - Use of Ultrasonography for Assessing Treatment Efficacy in a Case With Ankylosis of the Temporomandibular Joint. AB - The patient was a 32-year-old university lecturer with limited mouth opening for 15 years. The patient was diagnosed with right temporomandibular joint ankylosis 10 years prior. Ultrasonography was employed to assess capsule-condyle distance before and after physical therapy. A treatment plan aiming at mobilizations and exercises was implemented, and the patient reported improvements in eating and speaking. PMID- 26928738 TI - ALTITUDE (IF YOU CAN CALL IT THAT) HAS NO BEARING ON THE RATES OF CONCUSSIONS IN ATHLETES. PMID- 26928739 TI - A role for plasma cell targeting agents in immune tolerance induction in autoimmune disease and antibody responses to therapeutic proteins. AB - Antibody responses to life saving therapeutic protein products, such as enzyme replacement therapies (ERT) in the setting of lysosomal storage diseases, have nullified product efficacy and caused clinical deterioration and death despite treatment with immune-suppressive therapies. Moreover, in some autoimmune diseases, pathology is mediated by a robust antibody response to endogenous proteins such as is the case in pulmonary alveolar proteinosis, mediated by antibodies to Granulocyte Macrophage-Colony Stimulating Factor (GM-CSF). In this work, we make the case that in such settings, when the antibody response is high titered, sustained, and refractory to immune suppressive treatments, the antibody response is mediated by long-lived plasma cells which are relatively unperturbed by immune suppressants including rituximab. However, long-lived plasma cells can be targeted by proteasome inhibitors such as bortezomib. Recent reports of successful reversal of antibody responses with bortezomib in the settings of ERT and Thrombotic Thrombocytopenic Purpura (TTP) argue that the safety and efficacy of such plasma cell targeting agents should be evaluated in larger scale clinical trials to delineate the risks and benefits of such therapies in the settings of antibody-mediated adverse effects to therapeutic proteins and autoantibody mediated pathology. PMID- 26928740 TI - Direct Olefination of Alcohols with Sulfones by Using Heterogeneous Platinum Catalysts. AB - Carbon-supported Pt nanoparticles (Pt/C) were found to be effective heterogeneous catalysts for the direct Julia olefination of alcohols in the presence of sulfones and KOtBu under oxidant-free conditions. Primary alcohols, including aryl, aliphatic, allyl, and heterocyclic alcohols, underwent olefination with dimethyl sulfone and aryl alkyl sulfones to give terminal and internal olefins, respectively. Secondary alcohols underwent methylenation with dimethyl sulfone. Under 2.5 bar H2, the same reaction system was effective for the transformation of alcohol OH groups to alkyl groups. Structural and mechanistic studies of the terminal olefination system suggested that Pt(0) sites on the Pt metal particles are responsible for the rate-limiting dehydrogenation of alcohols and that KOtBu may deprotonate the sulfone reagent. The Pt/C catalyst was reusable after the olefination, and this method showed a higher turnover number (TON) and a wider substrate scope than previously reported methods, which demonstrates the high catalytic efficiency of the present method. PMID- 26928741 TI - Lithostratigraphic analysis of a new stromatolite-thrombolite reef from across the rise of atmospheric oxygen in the Paleoproterozoic Turee Creek Group, Western Australia. AB - This study describes a previously undocumented dolomitic stromatolite-thrombolite reef complex deposited within the upper part (Kazput Formation) of the c. 2.4-2.3 Ga Turee Creek Group, Western Australia, across the rise of atmospheric oxygen. Confused by some as representing a faulted slice of the younger c. 1.8 Ga Duck Creek Dolomite, this study describes the setting and lithostratigraphy of the 350 m-thick complex and shows how it differs from its near neighbour. The Kazput reef complex is preserved along 15 km of continuous exposure on the east limb of a faulted, north-west-plunging syncline and consists of 5 recognisable facies associations (A-E), which form two part regressions and one transgression. The oldest facies association (A) is characterised by thinly bedded dololutite dolarenite, with local domical stromatolites. Association B consists of interbedded columnar and stratiform stromatolites deposited under relatively shallow-water conditions. Association C comprises tightly packed columnar and club-shaped stromatolites deposited under continuously deepening conditions. Clotted (thrombolite-like) microbialite, in units up to 40 m thick, dominates Association D, whereas Association E contains bedded dololutite and dolarenite, and some thinly bedded ironstone, shale and black chert units. Carbon and oxygen isotope stratigraphy reveals a narrow range in both delta(13) Ccarb values, from 0.22 to 0.970/00 (VPDB: average = 0.680/00), and delta(18) O values, from -14.8 to -10.30/00 (VPDB), within the range of elevated fluid temperatures, likely reflecting some isotopic exchange. The Kazput Formation stromatolite-thrombolite reef complex contains features of younger Paleoproterozoic carbonate reefs, yet is 300-500 Ma older than previously described Proterozoic examples worldwide. Significantly, the microbial fabrics are clearly distinct from Archean stromatolitic marine carbonate reefs by way of containing the first appearance of clotted microbialite and large columnar stromatolites with complex branching arrangements. Such structures denote a more complex morphological expression of growth than previously recorded in the geological record and may link to the rise of atmospheric oxygen. PMID- 26928742 TI - Improved secondary caries resistance via augmented pressure displacement of antibacterial adhesive. AB - The present in vitro study evaluated the secondary caries resistance potential of acid-etched human coronal dentin bonded using augmented pressure adhesive displacement in conjunction with an experimental antibacterial adhesive. One hundred and twenty class I cavities were restored with a commercial non antibacterial etch-and-rinse adhesive (N) or an experimental antibacterial adhesive (A) which was displaced by gentle air-blow (G) or augmented pressure air blow (H). After bonding and restoration with resin composite, the resulted 4 groups (N-G, N-H, A-G and A-H) were exposed to Streptococcus mutans biofilm for 4, 8, 15, 20 or 25 days. The development of secondary caries in the bonding interface was then examined by confocal laser scanning microscopy (CLSM) and scanning electron microscopy (SEM). Data acquired from 15, 20 and 25 days of artificial caries induction were analyzed with three-way ANOVA at alpha = 0.05. The depth of the artificial carious lesions was significantly affected by "adhesive type" (Single Bond 2 vs experimental antibacterial adhesive p = 0.003), "intensity of adhesive displacement" (gentle vs augmented-pressure adhesive displacement; p < 0.001), as well as "artificial caries induction time" (p < 0.001). The combined use of augmented pressure adhesive displacement and experimental antibacterial adhesive reduces the progression of secondary caries. PMID- 26928743 TI - Two new benzylisoquinoline alkaloids from Thalictrum foliolosum and their antioxidant and in vitro antiproliferative properties. AB - Two novel rare chloro-containing benzylisoquinoline alkaloids, thalfoliolosumines A (1) and B (2), along with eight known isoquinoline alkaloids (3-10) were isolated from the whole plant of Thalictrum foliolosum. The structures of these compounds were elucidated by spectral analyses, including 1D and 2D NMR (COSY, HSQC, HMBC and NOESY) experiments. The antiproliferative effects of all the isolated compounds were evaluated by MTT method against MCF-7, PC-3, and U937 cells, and trypan blue method against HL-60 cells. New compounds 1 and 2 exhibited moderate in vitro antiproliferative activity against MCF-7, PC-3, and HL-60 cells, and good inhibitory effects against U937 cells with IC50 values of 7.50 and 6.97 MUM, respectively. Compounds 7 and 10 showed the strongest in vitro antiproliferative with IC50 values of 0.93 and 1.69 MUM against HL-60 cell line. The antioxidant properties were also measured, bisbenzyltetrahydroisoquinoline alkaloids 3-6 showed the strongest antioxidant activities in ABTS assay. PMID- 26928744 TI - Optic Neuropathy due to Chronic Lymphocytic Leukemia Proven With Optic Nerve Sheath Biopsy and Chronic Myelogenous Leukemia Relapse Presenting With Central Nervous System Blast Crisis and Bilateral Optic Nerve Infiltration: Comment. PMID- 26928745 TI - Integrating patient reported measures as predictive parameters into decisionmaking about palliative chemotherapy: a pilot study. AB - BACKGROUND: Systemic treatment has proven to improve physical symptoms in patients with advanced cancer. Relationship between quality of life (QoL) or symptom burden (SYB) and treatment efficacy (tumour response and survival) is poorly described. Therefore, we evaluated the predictive value of pretreatment QoL and SYB on treatment outcomes. METHODS: Eligible patients had metastatic gastrointestinal cancers and were about to receive 1st/2nd line palliative chemotherapy. 47 patients were consecutively enrolled. QoL and SYB were assessed by EORTC QLQ-C30 and MSKCC MSAS questionnaires before treatment and after first response evaluation after 8-12 weeks. Logistic regression analysis of QoL and SYB for prediction of objective treatment efficacy was performed. Patients were categorized according to response rate (RR) based on RECIST1.1 and progression free survival (PFS). PFS was categorized by a ratio (individual PFS/expected PFS) in above median (ratio >= 1) or below median PFS (ratio < 1). QoL and SYB were analysed for RR groups (partial response, stable or progressive disease) and PFS ratio (PFSR). RESULTS: Objective response to chemotherapy and increase in PFS were associated with better pretreatment QoL and less SYB. Patients with future objective treatment efficacy (PFSR >= 1) evidenced clinically relevant better role/emotional/cognitive/social functioning and less fatigue and appetite loss at baseline in comparison to PFSR < 1 (>10 points difference). Lowest scores in all functioning scales at treatment start were seen in patients with future PFSR < 1. Global health status (EORTC), PSYCH subscale and global distress index (MSAS) predicted PFSR, even if adjusted for gender, age, cancer type, ECOG and line of treatment (p < 0.05). Interestingly, improved QoL and SYB (subjective benefit) were noted even in patients with worse pretreatment status and no objective tumour response. CONCLUSION: Future non-responders seem to show distinct QoL patterns before chemotherapy. This may facilitate early detection of patients deriving less or even no benefit from treatment regarding prolongation of survival. Even in patients with primarily progressive disease QoL and SYB may improve during treatment. Integration of QoL and SYB assessment into decision making about palliative chemotherapy seem to be an important approach to improve patient outcome and should be further evaluated. PMID- 26928746 TI - Physiological responses at the lactate-minimum-intensity with and without prior high-intensity exercise. AB - This study examined the physiological responses during exercise-to-exhaustion at the lactate-minimum-intensity with and without prior high-intensity exercise. Eleven recreationally trained males performed a graded exercise test, a lactate minimum test and two constant-load tests at lactate-minimum-intensity until exhaustion, which were applied with or without prior hyperlactatemia induction (i.e., 30-s Wingate test). The physiological responses were significantly different (P < 0.05) between constant-load tests for pulmonary ventilation ([Formula: see text]), blood-lactate-concentration ([La(-)]), pH, bicarbonate concentration ([HCO3]) and partial pressure of carbon dioxide during the initial minutes. The comparisons within constant-load tests showed steady state behaviour for oxygen uptake and the respiratory exchange ratio, but heart rate and rating of perceived exertion increased significantly during both exercise conditions, while the [Formula: see text] increased only during constant-load effort. During effort performed after high-intensity exercise: [Formula: see text], [La(-)], pH and [HCO3] differed at the start of exercise compared to another condition but were similar at the end (P > 0.05). In conclusion, the constant-load exercises performed at lactate-minimum-intensity with or without prior high-intensity exercise did not lead to the steady state of all analysed parameters; however, variables such as [La(-)], pH and [HCO3] - altered at the beginning of effort performed after high-intensity exercise - were reestablished after approximately 30 min of exercise. PMID- 26928747 TI - Steatosis and liver stiffness measurements using transient elastography. PMID- 26928748 TI - The invasive bighead goby Ponticola kessleri displays large-scale genetic similarities and small-scale genetic differentiation in relation to shipping patterns. AB - Colonization events, range expansions and species invasions leave genetic signatures in the genomes of invasive organisms and produce intricate special patterns. Predictions have been made as to how those patterns arise, but only very rarely, genetic processes can be monitored in real time during range expansions. In an attempt to change that, we track a very recently established invasive population of a fish species, the bighead goby Ponticola kessleri, with high temporal and spatial resolution through 2 years to identify patterns over time. We then compare Swiss and German samples of bighead goby along the river Rhine using microsatellites, mitochondrial D-loop sequences and geometric morphometrics to investigate geographic patterns. We detect weak temporal and strong geographic patterns in the data, which are inconsistent with isolation by distance and indicate long range transport. In search of an explanation for our observations, we analyse the vector properties and travel patterns of commercial vessels on the river Rhine. We present evidence that freshwater cargo ships and tankers are plausible vectors for larvae of invasive goby species. We also present indications that cargo ships and tankers act as differential vectors for this species. In summary, we present genetic data at unique temporal resolution from a vertebrate invasion front and substantiate the paramount role of commercial shipping in freshwater fish translocations. PMID- 26928749 TI - Musculoskeletal MRI. AB - MRI has the unique ability to detect abnormal fluid content, and is therefore unparalleled in its role of detection, diagnosis, prognosis, treatment planning and follow-up evaluation of musculoskeletal disease. MRI in companion animals should be considered in the following circumstances: a definitive diagnosis cannot be made on radiographs; a patient is nonresponsive to medical or surgical therapy; prognostic information is desired; assessing surgical margins and traumatic and/or infectious joint and bone disease; ruling out subtle developmental or early aggressive bone lesions. The MRI features of common disorders affecting the shoulder, elbow, stifle, carpal, and tarsal joints are included in this chapter. PMID- 26928750 TI - Supramolecular Approaches to Graphene: From Self-Assembly to Molecule-Assisted Liquid-Phase Exfoliation. AB - Graphene, a one-atom thick two-dimensional (2D) material, is at the core of an ever-growing research effort due to its combination of unique mechanical, thermal, optical and electrical properties. Two strategies are being pursued for the graphene production: the bottom-up and the top-down. The former relies on the use of covalent chemistry approaches on properly designed molecular building blocks undergoing chemical reaction to form 2D covalent networks. The latter occurs via exfoliation of bulk graphite into individual graphene sheets. Amongst the various types of exfoliations exploited so far, ultrasound-induced liquid phase exfoliation (UILPE) is an attractive strategy, being extremely versatile, up-scalable and applicable to a variety of environments. In this review, we highlight the recent developments that have led to successful non-covalent functionalization of graphene and how the latter can be exploited to promote the process of molecule-assisted UILPE of graphite. The functionalization of graphene with non-covalently interacting molecules, both in dispersions as well as in dry films, represents a promising and modular approach to tune various physical and chemical properties of graphene, eventually conferring to such a 2D system a multifunctional nature. PMID- 26928752 TI - Assessing rhinitis symptoms in children--a need for action. PMID- 26928753 TI - Efficacy of MP-AzeFlu in children with seasonal allergic rhinitis: Importance of paediatric symptom assessment. AB - BACKGROUND: This study aimed to assess the efficacy of MP-AzeFlu (a novel intranasal formulation of azelastine hydrochloride and fluticasone propionate in a single spray) in children with seasonal allergic rhinitis (SAR) and explore the importance of child symptom severity assessment in paediatric allergic rhinitis (AR) trials. METHODS: A total of 348 children (4-11 years) with moderate/severe SAR were randomized into a double-blind, placebo-controlled, 14-day, parallel group trial. Efficacy was assessed by changes from baseline in reflective total nasal symptom score (rTNSS), reflective total ocular symptom score (rTOSS) and individual symptom scores over 14 days (children 6-11 years; n = 304), recorded by either children or caregivers. To determine whether a by-proxy effect existed, efficacy outcomes were assessed according to degree of child/caregiver rating. Moreover, total Paediatric Rhinitis Quality of Life Questionnaire (PRQLQ) score was compared between the groups. RESULTS: A statistically superior, clinically relevant efficacy signal of MP-AzeFlu versus placebo was apparent for PRQLQ overall score (diff: -0.29, 95% CI -0.55, -0.03; p = 0.027), but not for rTNSS (diff: -0.80; 95% CI: -1.75; 0.15; p = 0.099). However, as the extent of children's self-rating increased, so too did the treatment difference between MP AzeFlu and placebo; MP-AzeFlu provided significantly better relief than placebo for rTNSS (p = 0.002), rTOSS (p = 0.009) and each individual nasal and ocular symptom assessed (except rhinorrhoea; p = 0.064) when children mostly rated their own symptoms. CONCLUSIONS: MP-AzeFlu is an effective treatment for AR in childhood. Caregivers are less able than children to accurately assess response to treatment with available tools. A simple paediatric-specific tool to assess efficacy in AR trials in children is needed. PMID- 26928754 TI - Prescription patterns, adherence and characteristics of non-adherence in children with asthma in primary care. AB - Adherence to treatment remains important for successful asthma management. Knowledge about asthma medication use and adherence in real-life offers opportunities to improve asthma treatment in children. OBJECTIVE: To describe prescription patterns, adherence and factors of adherence to drugs in children with asthma. METHODS: Population-based cohort study in a Dutch primary care database (IPCI), containing medical records of 176,516 children, aged 5-18 years, between 2000 and 2012. From asthma medication prescriptions, age, gender, seasonal and calendar year rates were calculated. Adherence was calculated using medication possession ratio (MPR) and ratio of controller to total asthma drug (CTT). Characteristics of children with high-vs.-low adherence were compared. RESULTS: The total asthma cohort (n = 14,303; 35,181 person-years (PY) of follow up) was mainly treated with short-acting beta2-agonists (SABA; 40 users/100 PY) and inhaled corticosteroids (ICS; 32/100 PY). Median MPR for ICS was 56%. Children with good adherence (Q4 = MPR > 87%) were younger at start of ICS, more often visited specialists and had more exacerbations during follow-up compared to children with low adherence (Q1 = MPR < 37%). CONCLUSION: In Dutch primary care children with asthma were mainly prescribed SABA, and ICS. Adherence to ICS was relatively low. Characteristics of children with good adherence were compatible with more severe asthma, suggesting that adherence is driven by treatment need or intensity of medical follow-up. PMID- 26928755 TI - DRESS syndrome developed related to acetylsalicylic acid use. PMID- 26928757 TI - Editorial: Recent Progress in Algal Biotechnology. PMID- 26928758 TI - Flotation: A promising microalgae harvesting and dewatering technology for biofuels production. AB - Microalgal biomass as renewable energy source is believed to be of great potential for reliable and sustainable biofuels production. However, microalgal biomass production is pinned by harvesting and dewatering stage thus hindering the developing and growing microalgae biotechnology industries. Flotation technology applied in mineral industry could be potentially applied in microalgae harvesting and dewatering, however substantial knowledge on different flotation units is essential. This paper presents an overview on different flotation units as promising cost-effective technologies for microalgae harvesting thus bestowing for further research in development and commercialization of microalgae based biofuels. Dispersed air flotation was found to be less energy consuming. Moreover, Jameson cell flotation and dispersed ozone flotation are believed to be energy efficient microalgae flotation approaches. Microalgae harvesting and dewatering by flotation is still at embryonic stage, therefore extended studies with the focus on life cycle assessment, sustainability of the flotation unit, optimization of the operating parameters using different algal species is imperative. Though there are a number of challenges in microalgae harvesting and dewatering, with well designed and developed cultivation, harvesting/dewatering, extraction and conversion technologies, progressively, microalgae technology will be of great potential for biological carbon sequestration, biofuels and biochemicals production. PMID- 26928759 TI - New type of Al-based decagonal quasicrystal in Al60Cr20Fe10Si10 alloy. AB - A new kind of decagonal quasicrystal (DQC) with a periodicity of 1.23 nm was observed in the as-cast quaternary Al60Cr20Fe10Si10 alloy. The intensity distribution of some spots in the selected-area electron diffraction pattern along the tenfold zone axis was found to be different from other Al-based DQCs. High-angle annular dark-field scanning transmission electron microscopy was adopted to reveal the structural features at an atomic level. Both the tenfold symmetry and symmetry-broken decagonal (D) clusters of 1.91 nm in diameter were found, but with structural characteristics different from the corresponding D clusters in the other Al-based DQCs. The neighboring D clusters are connected by sharing one edge rather than covering, suggesting the tiling model is better than the covering model for structural description. PMID- 26928760 TI - Capnographic Parameters in Ventilated Patients: Correspondence with Airway and Lung Tissue Mechanics. AB - BACKGROUND: Although the mechanical status of the lungs affects the shape of the capnogram, the relations between the capnographic parameters and those reflecting the airway and lung tissue mechanics have not been established in mechanically ventilated patients. We, therefore, set out to characterize how the mechanical properties of the airways and lung tissues modify the indices obtained from the different phases of the time and volumetric capnograms and how the lung mechanical changes are reflected in the altered capnographic parameters after a cardiopulmonary bypass (CPB). METHODS: Anesthetized, mechanically ventilated patients (n = 101) undergoing heart surgery were studied in a prospective consecutive cross-sectional study under the open-chest condition before and 5 minutes after CPB. Forced oscillation technique was applied to measure airway resistance (Raw), tissue damping (G), and elastance (H). Time and volumetric capnography were performed to assess parameters reflecting the phase II (SII) and phase III slopes (SIII), their transition (D2min), the dead-space indices according to Fowler, Bohr, and Enghoff and the intrapulmonary shunt. RESULTS: Before CPB, SII and D2min exhibited the closest (P = 0.006) associations with H (0.65 and -0.57; P < 0.0001, respectively), whereas SIII correlated most strongly (P < 0.0001) with Raw (r = 0.63; P < 0.0001). CPB induced significant elevations in Raw and G and H (P < 0.0001). These adverse mechanical changes were reflected consistently in SII, SIII, and D2min, with weaker correlations with the dead space indices (P < 0.0001). The intrapulmonary shunt expressed as the difference between the Enghoff and Bohr dead-space parameters was increased after CPB (95% +/- 5% [SEM] vs 143% +/- 6%; P < 0.001). CONCLUSIONS: In mechanically ventilated patients, the capnographic parameters from the early phase of expiration (SII and D2min) are linked to the pulmonary elastic recoil, whereas the effect of airway patency on SIII dominates over the lung tissue stiffness. However, severe deterioration in lung resistance or elastance affects both capnogram slopes. PMID- 26928761 TI - SuReSim: simulating localization microscopy experiments from ground truth models. AB - Super-resolution fluorescence microscopy has become a widely used tool in many areas of research. However, designing and validating super-resolution experiments to address a research question in a technically feasible and scientifically rigorous manner remains a fundamental challenge. We developed SuReSim, a software tool that simulates localization data of arbitrary three-dimensional structures represented by ground truth models, allowing users to systematically explore how changing experimental parameters can affect potential imaging outcomes. PMID- 26928763 TI - Using species distribution modeling to delineate the botanical richness patterns and phytogeographical regions of China. AB - The millions of plant specimens that have been collected and stored in Chinese herbaria over the past ~110 years have recently been digitized and geo referenced. Here we use this unique collection data set for species distribution modeling exercise aiming at mapping &explaining the botanical richness; delineating China's phytogeographical regions and investigating the environmental drivers of the dissimilarity patterns. We modeled distributions of 6,828 woody plants using MaxEnt and remove the collection bias using null model. The continental China was divided into different phytogeographical regions based on the dissimilarity patterns. An ordination and Getis-Ord Gi* hotspot spatial statistics were used to analysis the environmental drivers of the dissimilarity patterns. We found that the annual precipitation and temperature stability were responsible for observed species diversity. The mechanisms causing dissimilarity pattern seems differ among biogeographical regions. The identified environmental drivers of the dissimilarity patterns for southeast, southwest, northwest and northeast are annual precipitation, topographic &temperature stability, water deficit and temperature instability, respectively. For effective conservation of China's plant diversity, identifying the historical refuge and protection of high diversity areas in each of the identified floristic regions and their subdivisions will be essential. PMID- 26928762 TI - One library to make them all: streamlining the creation of yeast libraries via a SWAp-Tag strategy. AB - The yeast Saccharomyces cerevisiae is ideal for systematic studies relying on collections of modified strains (libraries). Despite the significance of yeast libraries and the immense variety of available tags and regulatory elements, only a few such libraries exist, as their construction is extremely expensive and laborious. To overcome these limitations, we developed a SWAp-Tag (SWAT) method that enables one parental library to be modified easily and efficiently to give rise to an endless variety of libraries of choice. To showcase the versatility of the SWAT approach, we constructed and investigated a library of ~1,800 strains carrying SWAT-GFP modules at the amino termini of endomembrane proteins and then used it to create two new libraries (mCherry and seamless GFP). Our work demonstrates how the SWAT method allows fast and effortless creation of yeast libraries, opening the door to new ways of systematically studying cell biology. PMID- 26928764 TI - In reference to Tympanic membrane repair using silk fibroin and acellular collagen scaffolds. PMID- 26928765 TI - Error in Table 1. PMID- 26928766 TI - A Novel Technique for Immediate Loading Single Root Form Implants With an Interim CAD/CAM Milled Screw-Retained Crown. AB - A technique is described where an interim abutment and crown are fabricated in the laboratory by utilizing computer-aided design/computer-aided manufacturing (CAD/CAM) technology and placed the day of dental implant surgery. The design and contours of the interim crown are designed by the computer software to be identical to the contours of the tentatively designed definitive prosthesis. The interim crown satisfies esthetics immediately after dental implant surgery while allowing the tissue to heal and obtain contours similar to the contours of the definitive prosthesis. The interim crown can be either cement retained or screw retained. The presented technique describes fabrication of a screw-retentive interim crown. After osseointegration is confirmed, a definitive impression is made with a CAD/CAM impression coping. The definitive prosthesis is then fabricated. PMID- 26928768 TI - Biometrical issues in the analysis of adverse events within the benefit assessment of drugs. AB - The analysis of adverse events plays an important role in the benefit assessment of drugs. Consequently, results on adverse events are an integral part of reimbursement dossiers submitted by pharmaceutical companies to health policy decision-makers. Methods applied in the analysis of adverse events commonly include simple standard methods for contingency tables. However, the results produced may be misleading if observations are censored at the time of discontinuation due to treatment switching or noncompliance, resulting in unequal follow-up periods. In this paper, we present examples to show that the application of inadequate methods for the analysis of adverse events in the reimbursement dossier can lead to a downgrading of the evidence on a drug's benefit in the subsequent assessment, as greater harm from the drug cannot be excluded with sufficient certainty. Legal regulations on the benefit assessment of drugs in Germany are presented, in particular, with regard to the analysis of adverse events. Differences in safety considerations between the drug approval process and the benefit assessment are discussed. We show that the naive application of simple proportions in reimbursement dossiers frequently leads to uninterpretable results if observations are censored and the average follow-up periods differ between treatment groups. Likewise, the application of incidence rates may be misleading in the case of recurrent events and unequal follow-up periods. To allow for an appropriate benefit assessment of drugs, adequate survival time methods accounting for time dependencies and duration of follow-up are required, not only for time-to-event efficacy endpoints but also for adverse events. (c) 2016 The Authors. Pharmaceutical Statistics published by John Wiley & Sons Ltd. PMID- 26928770 TI - 'It's a matter of your personality more than anything else'. AB - The impact on full-time carers of children with intellectual disabilities who exhibit challenging behaviour has been well researched (e.g. Lach et al., 2009; Shah et al., 2010; Wodehouse and McGill, 2009), however, there is to date no published research into the impact of behaviour that challenges on seasonal carers. Five participants who had been employed in summer playschemes for children and young people (up to the age of 18) were interviewed about their experiences of behaviour that challenges. The transcripts were analysed using interpretative phenomenological analysis, which revealed six superordinate themes: the belief in and sanctuary of temporary work, emotional impact, personality and gender, strength through knowledge, communication difficulties and the belief in integration. Seasonal workers discussed suppressing their emotions in order to stay in control of a challenging situation, using coping styles developed through experience or based on personal skills; it is suggested that formalized training, particularly regarding non-verbal communication, would support playscheme workers in the management of and adaption to challenging behaviour. PMID- 26928769 TI - High-throughput identification of genotype-specific cancer vulnerabilities in mixtures of barcoded tumor cell lines. AB - Hundreds of genetically characterized cell lines are available for the discovery of genotype-specific cancer vulnerabilities. However, screening large numbers of compounds against large numbers of cell lines is currently impractical, and such experiments are often difficult to control. Here we report a method called PRISM that allows pooled screening of mixtures of cancer cell lines by labeling each cell line with 24-nucleotide barcodes. PRISM revealed the expected patterns of cell killing seen in conventional (unpooled) assays. In a screen of 102 cell lines across 8,400 compounds, PRISM led to the identification of BRD-7880 as a potent and highly specific inhibitor of aurora kinases B and C. Cell line pools also efficiently formed tumors as xenografts, and PRISM recapitulated the expected pattern of erlotinib sensitivity in vivo. PMID- 26928771 TI - Interaction of extracellular S100A4 with RAGE prompts prometastatic activation of A375 melanoma cells. AB - S100A4, a member of the S100 protein family of EF-hand calcium-binding proteins, is overexpressed in various tumour entities, including melanoma, and plays an important role in tumour progression. Several studies in epithelial and mesenchymal tumours revealed a correlation between extracellular S100A4 and metastasis. However, exact mechanisms how S100A4 stimulates metastasis in melanoma are still unknown. From a pilot experiment on baseline synthesis and secretion of S100A4 in human melanoma cell lines, which are in broad laboratory use, A375 wild-type cells and, additionally, newly generated A375 cell lines stably transfected with human S100A4 (A375-hS100A4) or human receptor for advanced glycation endproducts (A375-hRAGE), were selected to investigate the influence of extracellular S100A4 on cell motility, adhesion, migration and invasion in more detail. We demonstrated that A375 cells actively secrete S100A4 in the extracellular space via an endoplasmic reticulum-Golgi-dependent pathway. S100A4 overexpression and secretion resulted in prometastatic activation of A375 cells. Moreover, we determined the influence of S100A4-RAGE interaction and its blockade on A375, A375-hS100A4, A375-hRAGE cells, and showed that interaction of RAGE with extracellular S100A4 contributes to the observed activation of A375 cells. This investigation reveals additional molecular targets for therapeutic approaches aiming at blockade of ligand binding to RAGE or RAGE signalling to inhibit melanoma metastasis. PMID- 26928772 TI - The TRPA1 Activator Allyl Isothiocyanate (AITC) Contracts Human Jejunal Muscle: Pharmacological Analysis. AB - The contractile effect of AITC (300 MUM) on human jejunal longitudinal strips was inhibited by the TRPA1 antagonist HC 030031 and atropine or scopolamine, but was insensitive to tetrodotoxin, purinoceptor antagonists or capsaicin desensitization. It is concluded that TRPA1 activation stimulates a cholinergic mechanism in a tetrodotoxin-resistant manner. PMID- 26928773 TI - Transgender Surgery in Denmark From 1994 to 2015: 20-Year Follow-Up Study. AB - INTRODUCTION: Gender dysphoria is a mismatch between a person's biological sex and gender identity. The best treatment is believed to be hormonal therapy and gender-confirming surgery that will transition the individual toward the desired gender. Treatment in Denmark is covered by public health care, and gender confirming surgery in Denmark is centralized at a single-center with few specialized plastic surgeons conducting top surgery (mastectomy or breast augmentation) and bottom surgery (vaginoplasty or phalloplasty and metoidioplasty). AIMS: To report the first nationwide single-center review on transsexual patients in Denmark undergoing gender-confirming surgery performed by a single surgical team and to assess whether age at time of gender-confirming surgery decreased during a 20-year period. METHODS: Electronic patient databases were used to identify patients diagnosed with gender identity disorders from January 1994 through March 2015. Patients were excluded from the study if they were pseudohermaphrodites or if their gender was not reported. MAIN OUTCOME MEASURES: Gender distribution, age trends, and surgeries performed for Danish patients who underwent gender-confirming surgery. RESULTS: One hundred fifty eight patients referred for gender-confirming surgery were included. Fifty-five cases (35%) were male-to-female (MtF) and 103 (65%) were female-to-male (FtM). In total, 126 gender-confirming surgeries were performed. For FtM cases, top surgery (mastectomy) was conducted in 62 patients and bottom surgery (phalloplasty and metoidioplasty) was conducted in 17 patients. For MtF cases, 45 underwent bottom surgery (vaginoplasty), 2 of whom received breast augmentation. The FtM:MtF ratio of the referred patients was 1.9:1. The median age at the time of surgery decreased from 40 to 27 years during the 20-year period. CONCLUSION: Gender confirming surgery was performed on 65 FtM and 40 MtF cases at our hospital, and 21 transsexuals underwent surgery abroad. Mastectomy was performed in 62 FtM and bottom surgery in 17 FtM cases. Vaginoplasty was performed in 45 MtF and breast augmentation in 2 MtF cases. There was a significant decrease in age at the time of gender-confirming surgery during the course of the study period. PMID- 26928774 TI - Active Polysubstance Abuse Concurrent With Surgery as a Possible Newly Identified Infection Risk Factor in Inflatable Penile Prosthesis Placement Based on a Retrospective Analysis of Health and Socioeconomic Factors. AB - INTRODUCTION: Since the introduction of inflatable penile prostheses (IPPs), risk of infection has decreased. However, concurrent substance abuse has not been investigated in prosthetic urology. AIMS: To determine whether substance abuse would stand out as a relevant risk factor for infection in patients undergoing IPP implantation. METHODS: This retrospective study was conducted on charts from the past 12 years at our institution, where a single surgeon completed 602 primary IPP surgeries, with only 12 cases (2%) resulting in postoperative infection. Five of these patients (42%) were actively misusing at least one substance at the time of operation (ie, alcohol, marijuana, cocaine, heroin, other illicit substances, and prescription narcotics). Substance abuse was identified in the medical chart by International Classification of Diseases, Ninth Revision code or by clear documentation by a provider. Multivariate logistic regression analysis was used to estimate the probability of infection as a function of demographic, physical, and treatment variables. MAIN OUTCOME MEASURES: Logistic regression analysis was used to determine statistically significant correlations between risk factors and IPP infection. RESULTS: Polysubstance abuse, poorly controlled blood sugar, and homelessness at the time of procedure positively correlated with postoperative infection. Use of the mummy wrap correlated with decreased infection. CONCLUSION: Active polysubstance abuse, poor glycemic control, and homelessness increase infection risk at IPP implantation. We encourage other implanters to discuss active polysubstance abuse with their patients and to tread cautiously because of the increased risk of infection. PMID- 26928776 TI - Cutaneous B-cell Pseudolymphoma in a Psoriatic Patient Treated with Cyclosporine. PMID- 26928775 TI - Long-Term Follow-Up of Transgender Women After Secondary Intestinal Vaginoplasty. AB - INTRODUCTION: Intestinal vaginoplasty with a sigmoid colon or ileal segment is an established surgical technique for vaginal reconstruction. Little has been reported on long-term (functional) outcome and postoperative quality of life. AIMS: To assess the surgical and long-term psychological outcomes of secondary intestinal vaginoplasty performed from 1970 through 2000 in transgender women. METHODS: Transgender women who underwent intestinal vaginoplasty from 1970 through 2000 were identified from our hospital registry. Demographics, surgical characteristics, complications, and reoperations were recorded. Traceable women were invited to fill out a set of questionnaires (quality-of-life questionnaire, Female Sexual Function Index, Amsterdam Hyperactive Pelvic Floor Scale for Women, Female Genital Self-Imaging Scale, and self-evaluation of vaginoplasty questionnaire) and attend the outpatient clinic for physical, endoscopic, and histologic examination of the neovagina. MAIN OUTCOME MEASURES: Primary outcomes were complications, reoperations, self-perceived quality of life, and functional and esthetic self-evaluation. RESULTS: Twenty-four transgender women were identified who underwent intestinal vaginoplasty as a secondary procedure from 1970 through 2000. There were no intraoperative complications. Three intestinal neovaginas were surgically removed because of postoperative complications. Nineteen women (79%) underwent at least one genital reoperation, most commonly introitus plasty (n = 13, 54%). Five women were deceased at time of analysis. Nine women consented to partake in the study (median age = 58 years, range = 50 73; median postoperative time = 29.6 years, range = 17.2-34.3). They were generally satisfied with life and scored 5.9 of 7 on a subjective happiness scale. Neovaginal functionality was rated as 7.3 and appearance as 7.4 of 10. CONCLUSION: In our institution, intestinal vaginoplasty before 2000 was always performed as a revision procedure after a previous vaginoplasty had failed. Although surgical corrections were frequently necessary, women reported satisfaction with the surgical outcome and with life in general. PMID- 26928777 TI - A cross-bridge based model of force depression: Can a single modification address both transient and steady-state behaviors? AB - Force depression (FD), the reduction of isometric force following active shortening, is a phenomenon of skeletal muscle that has received significant attention in biomechanical and physiological literature, yet the mechanisms underlying FD remain unknown. Recent experiments identified a slower rate of force redevelopment with increasing amounts of steady-state FD, suggesting that FD may be caused, at least in part, by a decrease in cross-bridge binding rate (Corr and Herzog, 2005; Koppes et al., 2014). Herein, we develop a cross-bridge based model of FD in which the binding rate function, f, decreases with the mechanical work performed during shortening. This modification incorporates a direct relationship between steady-state FD and muscle mechanical work (Corr and Herzog, 2005; Herzog et al., 2000; Kosterina et al., 2008), and is consistent with a proposed mechanism attributing FD to stress-induced inhibition of cross bridge attachments (Herzog, 1998; Marechal and Plaghki, 1979). Thus, for an increase in mechanical work, the model should predict a slower force redevelopment (decreased attachment rate) to a more depressed steady-state force (fewer attached cross-bridges), and a reduction in contractile element stiffness (Ford et al., 1981). We hypothesized that since this modification affects the cross-bridge kinetics, a corresponding model would be able to account for both transient and steady-state FD behaviors. Comparisons to prior experiments (Corr and Herzog, 2005; Herzog et al., 2000; Kosterina et al., 2008) show that both steady-state and transient aspects of FD, as well as the relationship of FD with respect to speed and amplitude of shortening, are well captured by this model. Thus, this relatively simple cross-bridge based model of FD lends support to a mechanism involving the inhibition of cross-bridge binding, and indicates that cross-bridge kinetics may play a critical role in FD. PMID- 26928778 TI - Association of TERT promoter mutations with telomerase expression in melanoma. PMID- 26928780 TI - Pyogenic Ventriculitis as Clinical Presentation of Diverticulitis. PMID- 26928779 TI - Depression of Complement Regulatory Factors in Rat and Human Renal Grafts Is Associated with the Progress of Acute T-Cell Mediated Rejection. AB - BACKGROUND: The association of complement with the progression of acute T cell mediated rejection (ATCMR) is not well understood. We investigated the production of complement components and the expression of complement regulatory proteins (Cregs) in acute T-cell mediated rejection using rat and human renal allografts. METHODS: We prepared rat allograft and syngeneic graft models of renal transplantation. The expression of Complement components and Cregs was assessed in the rat grafts using quantitative real-time PCR (qRT-PCR) and immunofluorescent staining. We also administered anti-Crry and anti-CD59 antibodies to the rat allograft model. Further, we assessed the relationship between the expression of membrane cofactor protein (MCP) by immunohistochemical staining in human renal grafts and their clinical course. RESULTS: qRT-PCR results showed that the expression of Cregs, CD59 and rodent-specific complement regulator complement receptor 1-related gene/protein-y (Crry), was diminished in the rat allograft model especially on day 5 after transplantation in comparison with the syngeneic model. In contrast, the expression of complement components and receptors: C3, C3a receptor, C5a receptor, Factor B, C9, C1q, was increased, but not the expression of C4 and C5, indicating a possible activation of the alternative pathway. When anti-Crry and anti-CD59 mAbs were administered to the allograft, the survival period for each group was shortened. In the human ATCMR cases, the group with higher MCP expression in the grafts showed improved serum creatinine levels after the ATCMR treatment as well as a better 5-year graft survival rate. CONCLUSIONS: We conclude that the expression of Cregs in allografts is connected with ATCMR. Our results suggest that controlling complement activation in renal grafts can be a new strategy for the treatment of ATCMR. PMID- 26928781 TI - Needle-like ion-doped hydroxyapatite crystals influence osteogenic properties of PCL composite scaffolds. AB - Surface topography and chemistry both play a crucial role on influencing cell response in 3D porous scaffolds in terms of osteogenesis. Inorganic materials with peculiar morphology and chemical functionalities may be proficiently used to improve scaffold properties-in the bulk and along pore surface-promoting in vitro and in vivo osseous tissue in-growth. The present study is aimed at investigating how bone regenerative properties of composite scaffolds made of poly(E caprolactone) (PCL) can be augmented by the peculiar properties of Mg(2+) ion doped hydroxyapatite (dHA) crystals, mainly emphasizing the role of crystal shape on cell activities mediated by microstructural properties. At the first stage, the study of mechanical response by crossing experimental compression tests and theoretical simulation via empirical models, allow recognizing a significant contribution of dHA shape factor on scaffold elastic moduli variation as a function of the relative volume fraction. Secondly, the peculiar needle-like shape of dHA crystals also influences microscopic (i.e. crystallinity, adhesion forces) and macroscopic (i.e. roughness) properties with relevant effects on biological response of the composite scaffold: differential scanning calorimetry (DSC) analyses clearly indicate a reduction of crystallization heat-from 66.75 to 43.05 J g(-1)-while atomic force microscopy (AFM) ones show a significant increase of roughness-from (78.15 +/- 32.71) to (136.13 +/- 63.21) nm-and of pull-off forces-from 33.7% to 48.7%. Accordingly, experimental studies with MG-63 osteoblast-like cells show a more efficient in vitro secretion of alkaline phosphatase (ALP) and collagen I and a more copious in vivo formation of new bone trabeculae, thus suggesting a relevant role of dHA to support the main mechanisms involved in bone regeneration. PMID- 26928782 TI - DTB Select: 3 | March 2016. AB - Reports of rare adverse effect with bisphosphonates ? Variation in uptake of bowel cancer screening ? New diagnostic test for dry eye disease ? New guidelines for the care of dying adults ? Changes in health expectancy in England ? More doubts over ? nalmefene for alcohol dependence ? Nurse-led drug titration beneficial in heart failure ? Warfarin, sulfonylureas and serious hypoglycaemic events. PMID- 26928783 TI - Aliidiomarina iranensis sp. nov., a haloalkaliphilic bacterium from a coastal marine wetland. AB - A novel Gram-stain-negative, straight rod-shaped, non-pigmented, slightly halophilic and alkaliphilic bacterium, designated strain GBPy7T, was isolated from a sample of the coastal-marine wetland Gomishan in Iran. Cells of strain GBPy7T were motile. Growth occurred on media with 1-15 % (w/v) NaCl (optimum 3 %), at pH 7-10 (optimum pH 8.5) and at 4-45 degrees C (optimum 37 degrees C). Phylogenetic analysis based on 16S rRNA gene sequence comparison indicated that strain GBPy7T belonged to the family Idiomarinaceae. Its closest relatives were Aliidiomarina shirensis AIST (98.1 % 16S rRNA gene sequence similarity) and other Aliidiomarina species (95.9-94.2 %), together with Idiomarina seosinensis CL SP19T (94.3 %) and Idiomarina fontislapidosi F23T (94.3 %). The major cellular fatty acids of the isolate were iso-C15 : 0, iso-C17 : 0, iso-C17 : 1omega9c and C18 : 1omega7c and its polar lipid profile comprised phosphatidylglycerol, diphosphatidylglycerol, phosphatidylethanolamine, one unknown phospholipid and one unknown aminophospholipid. Cells of strain GBPy7T contained ubiquinone Q-8. The G+C content of the genomic DNA of this strain was 51.6 mol%. The level of DNA DNA relatedness between strain GBPy7T and A. shirensis IBRC-M 10414T was 21 %. The physiological, biochemical, genotypic and phylogenetic differences between strain GBPy7T and other previously described taxa indicate that the strain represents a novel species of the genus Aliidiomarina within the family Idiomarinaceae, for which the name Aliidiomarina iranensis sp. nov. is proposed. The type strain is GBPy7T ( = IBRC-M 10763T = CECT 8339T). PMID- 26928786 TI - Looking Inside Food. PMID- 26928784 TI - Sex differences in hippocampal response to endocannabinoids after exposure to severe stress. AB - Women are more vulnerable to stress-related mental disorders than men and the naturally occurring fluctuation in estrogen that occur across the estrus cycle can dramatically influence the pathophysiology observed following traumatic events. It has been demonstrated that the endocannabinoid (eCB) system could represent a therapeutic target for the treatment of post-traumatic stress disorder (PTSD) in males. The current study aimed to examine the effects of exposure to a traumatic event and acute enhancement of eCB signaling on hippocampal-dependent learning and plasticity in male and female rats. Males and females were exposed to the single prolonged stress (SPS) model of PTSD (restraint, forced swim, and sedation) followed by acute administration of the fatty acid amide hydrolase (FAAH) inhibitor URB597 (0.3 mg/kg). Females were in diestrus during SPS exposure. SPS exposure impaired extinction and hippocampal plasticity tested a week later in males and females. Sex differences were observed in the effects of URB597 on hippocampal plasticity of SPS-exposed rats. Also, URB597 normalized the SPS-induced upregulation in CB1 receptor levels in the amygdala, prefrontal cortex (PFC), and hippocampus in males. In females, URB597 normalized the SPS-induced up regulation in CB1 receptors in the amygdala and PFC, but not hippocampus. Our findings support the eCB system as a therapeutic target for the treatment of disorders associated to inefficient fear coping in males and females. There are differences in the hippocampal response of males and females to the enhancement of eCB signaling after intense stress suggesting sex differences in treatment efficacy. (c) 2016 Wiley Periodicals, Inc. PMID- 26928788 TI - Energy scavenging based on a single-crystal PMN-PT nanobelt. AB - Self-powered nanodevices scavenging mechanical energy require piezoelectric nanostructures with high piezoelectric coefficients. Here we report the fabrication of a single-crystal (1 - x)Pb(Mg1/3Nb2/3)O3 - xPbTiO3 (PMN-PT) nanobelt with a superior piezoelectric constant (d33 = ~550 pm/V), which is approximately ~150%, 430%, and 2100% of the largest reported values for previous PMN-PT, PZT and ZnO nanostructures, respectively. The high d33 of the single crystalline PMN-PT nanobelt results from the precise orientation control during its fabrication. As a demonstration of its application in energy scavenging, a piezoelectric nanogenerator (PNG) is built on the single PMN-PT nanobelt, generating a maximum output voltage of ~1.2 V. This value is ~4 times higher than that of a single-CdTe PNG, ~13 times higher than that of a single-ZnSnO3 PNG, and ~26 times higher than that of a single-ZnO PNG. The profoundly increased output voltage of a lateral PNG built on a single PMN-PT nanobelt demonstrates the potential application of PMN-PT nanostructures in energy harvesting, thus enriching the material choices for PNGs. PMID- 26928789 TI - The effects of increased serving sizes on consumption. AB - The US Food and Drug Administration recently revealed that it is considering modifying the Nutrition Facts Panels required on packaged foods. One proposed change is increasing serving sizes included on labels, which has two potential implications. Larger serving sizes could increase consumption if consumers use the serving sizes displayed as a reference point for their own consumption (McFerran et al., 2010). Alternatively, larger serving sizes that depict increased values of negative nutrients (e.g. calories) could lead consumers to perceive foods as less healthy, thereby reducing consumption (Russo et al., 1986). In study 1 (Online sample, N = 208, Mage = 32, SDage = 12), participants saw pictures of packaged food items and nutrition labels. The labels, depicted either the existing or larger serving size. Across all foods, larger serving sizes led to lower health perceptions. Labels with larger serving sizes were rated as more representative of typical consumption. Study 2 (Online sample, N = 347, Mage = 31, SDage = 10) used the same design as study 1, but required participants to virtually portion foods. While serving sizes did not impact the amount of food consumers portioned, those who saw labels with larger serving sizes estimated that they portioned out more calories. In study 3 (Student sample, N = 198, Mage = 20, SDage = 1), participants were given M&Ms to eat, paired with a nutritional label depicting either the current or a larger serving size, while participating in unrelated surveys. Participants presented with the larger serving size label consumed less than those presented with the current serving size label. Together, the results suggest that the proposed increase in serving sizes on Nutrition Facts Panels could lower consumption of high-calorie foods. PMID- 26928790 TI - Food neophobia in German adolescents: Determinants and association with dietary habits. AB - Food neophobia (FN) is described as the rejection to eat unknown foods. Because only little is known about the role of FN in adolescence the aim of this study was to examine potential determinants of FN and associations with dietary habits of DONALD study participants. FN was measured with Pliner's and Hobden's Food Neophobia Scale (FN Score (FNS): range 10-70) in 166 10-18-year-old adolescents. Participants' age, sex, body weight status and duration of breast-feeding as well as parents' FN and educational status were considered as determinants. Energy intake, distribution of macronutrients and two variety scores were calculated from 3-day weighed dietary records. Multivariable general linear models were performed for data analyses. Boys and girls did not differ in their FNS (median (Min-Max): boys 31 (10-58), girls 32 (14-59)). Increasing age (p = 0.010) and duration of total breast-feeding (p = 0.006) were associated with decreasing FNS in girls only. FN was further positively associated with parental FN in the total sample (p = 0.004). FN was negatively associated with protein intake in the total sample (p = 0.017). The overall low level of FN in the DONALD study can be ascribed to the low level of FN in adolescence in general. Congruently with other studies, age and breast-feeding duration were identified as determinants of girls' FN and parental FN was identified as determinant of FN in the total sample. Further, our results indicate that FN leads to reduced protein intakes. Dietary variety was not strongly affected, possibly because of a broad variety of food supply in Germany. PMID- 26928791 TI - Sorting the Alphabet Soup of Renal Pathology: A Review. AB - Diseases of the kidney often have their names shortened, creating an arcane set of acronyms which can be confusing to both radiologists and clinicians. This review of renal pathology aims to explain some of the most commonly used acronyms within the field. For each entity, a summary of the clinical features, pathophysiology, and radiological findings is included to aid in the understanding and differentiation of these entities. Discussed topics include acute cortical necrosis, autosomal dominant polycystic kidney disease, angiomyolipoma, autosomal recessive polycystic kidney disease, acute tubular necrosis, localized cystic renal disease, multicystic dysplastic kidney, multilocular cystic nephroma, multilocular cystic renal cell carcinoma, medullary sponge kidney, paroxysmal nocturnal hemoglobinuria, renal papillary necrosis, transitional cell carcinoma, and xanthogranulomatous pyelonephritis. PMID- 26928792 TI - Evidence on the use of tranexamic acid at cesarean delivery. PMID- 26928793 TI - Caesarean section by maternal age group among singleton deliveries and primiparous Japanese women: a secondary analysis of the WHO Global Survey on Maternal and Perinatal Health. AB - BACKGROUND: The rising caesarean section rate is an important public health concern that in turn increases maternal and perinatal risks of adverse effects, unnecessary medical consumption, and inequities in worldwide access. The aim of this study was to investigate caesarean section indications by maternal age group and examine the association between age and caesarean section in primiparous Japanese women with singleton births. METHODS: We analyzed the Japanese data of primiparous women with singleton births from the WHO Global Survey on Maternal and Perinatal Health to compare maternal and neonatal characteristics and outcomes between groups with and without caesarean section. Women were divided into 3 maternal age groups (<=29, 30 to 34 and >=35 years). We performed multivariable logistic-regression analysis to identify characteristics associated with caesarean section. RESULTS: Of the 3245 women with singleton births were included in the Japanese data, 610 women (18.8%) delivered by caesarean section, half of whom (n = 305) were nulliparous. We included singleton nulliparous women (1747 deliveries) in our analysis. The maternal age 35 years old was associated with higher risks for all caesarean section (adjusted odds ratio [AOR] 1.89, 95% CI 1.28-2.78) and emergency antepartum caesarean section (AOR 2.26, 95% CI 1.49 3.40). Intrapartum caesarean section, which is mainly performed for obstetric indications, was not higher among the older maternal age group. CONCLUSION: In Japan, advanced maternal age significantly increased the risk for caesarean section; however, intrapartum caesarean section was not higher risk among the older age group. Management of maternal complications would help to reduce the rate of caesarean sections and associated unnecessary medical consumption. PMID- 26928794 TI - Lipogenic Enzymes Complexes and Cytoplasmic Lipid Droplet Formation During Adipogenesis. AB - Lipid droplets are dynamic organelles that store triglycerides and participate in their mobilization in adipose cells. These organelles require the reorganization of some structural components, the cytoskeleton, and the activation of lipogenic enzymes. Using confocal microscopy, we analyzed the participation of cytoskeletal components and two lipogenic enzymes, fatty acid synthase and glycerophosphate dehydrogenase, during lipid droplet biogenesis in differentiating 3T3-F442A cells into adipocytes. We show that subcortical actin microfilaments are extended at the basal side of the cells in parallel arrangement to the culture dish substrate, and that the microtubule network traverses the cytoplasm as a scaffold that supports the round shape of the mature adipocyte. By immunoprecipitation, we show that vimentin and perilipin1a associate during the early stages of the differentiation process for lipid droplet formation. We also report that the antibody against perilipin1 detected a band that might correspond to a modified form of the molecule. Finally, the cytosolic distribution and punctate organization of lipogenic enzymes and their co-localization in the proximity of lipid droplets suggest the existence of dynamic protein complexes involved in synthesis and storage of triglycerides. J. Cell. Biochem. 117: 2315-2326, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26928795 TI - Level of use and safety of botanical products for itching vulvar dermatoses. Are patch tests useful? AB - BACKGROUND: Topical remedies based on botanical ingredients are popular. OBJECTIVES: To assess: (i) the usage of botanical substances in subjects affected with itching and chronic vulvar complaints; (ii) the incidence of side-effects associated with their use and the frequency of contact allergy; (iii) the diagnostic usefulness of patch testing. METHODS: Sixty-six patients were provided with a questionnaire to assess the prevalence and type of topical botanical preparations used and the occurrence of adverse reactions. Patients were patch tested with (i) the Italian baseline series, (ii) a topical medicament series, and (iii) a botanical series. RESULTS: Forty-two patients (63.6%) reported the use of natural topical products on the vulva. Seven (16.7%) noted adverse reactions; 27 showed positive reactions with the baseline series; 14 (21.2%) had at least one relevant reaction, mainly to allergens in topical products and cosmetics; and 2 (3%) showed positive reactions to the botanical series. Of the 7 patients complaining of adverse effects of botanical products, 3 (42.8%) showed relevant sensitization. CONCLUSIONS: The use of natural topical products is widespread among women affected with itching vulvar diseases. Contact dermatitis is a possible adverse effect. Botanical series are of questionable usefulness, owing to the wide variety of botanical ingredients. PMID- 26928796 TI - Changes in First Postoperative Night Bispectral Index After Daytime Sedation Induced by Dexmedetomidine or Midazolam Under Regional Anesthesia: A Randomized Controlled Trial. AB - BACKGROUND AND OBJECTIVES: Supplementation of spinal anesthesia with various sedatives is a standard protocol to alleviate patient anxiety associated with the surgical procedure. We hypothesized that, compared with dexmedetomidine, midazolam might have a subtle influence on sleep quality after surgery following elective transurethral prostatic resection (TURP) in elderly male patients. METHODS: A randomized, double-blind, controlled trial was conducted at the First Hospital of China Medical University from July 2014 to January 2015. One hundred eleven patients undergoing TURP were enrolled and received intravenous saline infusion (control group), dexmedetomidine (dexmedetomidine group), or midazolam (midazolam group) for sedation during the spinal anesthesia procedure. The intraoperative sedative state and postoperative sleep quality were evaluated using a Bispectral Index (BIS)-Vista monitor. The primary outcome was postoperative sleep quality, as measured by the BIS-Vista monitor on the first night after surgery. RESULTS: The intraoperative BIS area under the curve value was significantly lower in the dexmedetomidine group (54.1%) compared with those in the other 2 groups (control group, 94.1%; midazolam group, 77.2%).The postoperative BIS area under the curve value was highest in the dexmedetomidine group at 88.7%. The BIS sleep efficiency index showed a significant 33.1% increase in the midazolam group compared with the dexmedetomidine group. The duration of sleep in the midazolam group was 237.8 minutes longer than that in the dexmedetomidine group. CONCLUSIONS: We conclude that midazolam combined with spinal anesthesia might preserve the sleep quality of elderly male patients immediately after TURP. PMID- 26928797 TI - Are Cure Rates for Breast Cancer Improved by Local and Regional Anesthesia? AB - BACKGROUND AND OBJECTIVES: Recent preclinical basic science studies suggest that patient tumor immunity is altered by general anesthesia (GA), potentially worsening cancer outcomes. A single retrospective review concluded that breast cancer patients receiving paravertebral block and GA had better cancer outcomes compared with patients receiving GA alone. This study has not been validated. We hypothesized that local or regional anesthesia (LRA) would be associated with better cancer outcomes compared with GA. METHODS: We retrospectively reviewed a prospectively collected database to identify all stage 0-III breast cancer patients undergoing surgery in a single center during a 9-year period ending January 1, 2010. Patients were divided into 2 groups: those who received only LRA and those who received GA. Overall survival (OS), disease-free survival (DFS), and local regional recurrence (LRR) were calculated using the Kaplan-Meier method with log-rank comparison before and after propensity score matching. RESULTS: Median age of the 1107 patients who met study criteria was 64 years (range, 24-97 years). Median and longest follow-up were 5.5 and 12.5 years, respectively. General anesthesia was used for 461 patients (42%), and 646 (58%) received LRA. The point estimates of cumulative OS, DFS, and LRR "free" rates at 5 years for the GA and LRA groups were 85.5% and 87.1%, 94.2% and 96.1%, and 96.3% and 95.8%, respectively. Cox regression showed no significant differences between the 2 groups (GA and LRA) for the 3 outcomes: OS (hazard ratio [HR], 0.81; 95% confidence interval [CI], 0.59-1.10; P = 0.17), DFS (HR, 0.91; 95% CI, 0.55-1.76; P = 0.87), and LRR (HR, 1.73; 95% CI, 0.83-3.63; P = 0.15). CONCLUSIONS: Breast cancer OS, DFS, and LRR were not affected by type of anesthesia in our institution. This result differs from that of the only prior published clinical report on this topic and does not provide clinical corroboration of the basic science studies that suggest oncologic benefits to LRA. PMID- 26928798 TI - Correction: What Do We Learn from Spheroid Culture Systems? Insights from Tumorspheres Derived from Primary Colon Cancer Tissue. PMID- 26928799 TI - Accessing a Biologically Relevant Benzofuran Skeleton by a One-Pot Tandem Heck Alkynylation/Cyclization Reaction Using Well-Defined Palladium N-Heterocyclic Carbene Complexes. AB - Well-defined palladium N-heterocyclic carbene (NHC) complexes were employed in the one-pot tandem Heck alkynylation/cyclization sequence for preparing biologically relevant benzofuran compounds under copper-free conditions in a time efficient step-reduced fashion. In particular, a series of binuclear palladium complexes, 1b-1e and 2b-2e, of the alkyl-bridged NHC ligands, namely, {1,1'-di-R1 4,4'-R2-di-1,2,4-triazoline-5,5'-diylid-2-ene] (R1 = i-Pr; R2 = -(CH2)2-, -(CH2)3 ), and their mononuclear analogues, trans-(NHC)PdBr2(pyridine) (3b) and cis (NHC)PdBr2(PPh3) (3c), successfully catalyzed the one-pot tandem Heck alkynylation/cyclization reaction of 2-iodophenol with a variety of terminal alkyne substrates, yielding 2-substituted benzofuran derivatives. The mononuclear complexes 3b and 3c were nearly half as active as the representative dinuclear analogue 1c under analogous reaction conditions, thereby implying that, at the same mole percent of the palladium loading, the monometallic 3b and 3c and the bimetallic 1c complexes were equally effective as catalysts. The two sites of the bimetallic complex 1c performed as two separate independent catalytic sites, displaying no cooperativity effect in the catalysis. Finally, the practical utility of the aforementioned catalysts was demonstrated for a representative catalyst 1c through the convenient synthesis of a key intermediate, 3-[2 (benzo[d][1,3]dioxol-5-yl)-7-methoxybenzofuran-5-yl]propan-1-ol, in a total synthesis protocol of the natural product Egonol. PMID- 26928800 TI - Cytochrome P450 CYP71AT96 catalyses the final step of herbivore-induced phenylacetonitrile biosynthesis in the giant knotweed, Fallopia sachalinensis. AB - The giant knotweed Fallopia sachalinensis (Polygonaceae) synthesizes phenylacetonitrile (PAN) from L-phenylalanine when infested by the Japanese beetle Popillia japonica or treated with methyl jasmonate (MeJA). Here we identified (E/Z)-phenylacetaldoxime (PAOx) as the biosynthetic precursor of PAN and identified a cytochrome P450 that catalysed the conversion of (E/Z)-PAOx to PAN. Incorporation of deuterium-labelled (E/Z)-PAOx into PAN emitted from the leaves of F. sachalinensis was detected using gas chromatography-mass spectrometry. Further, using liquid chromatography-tandem mass spectrometry, we detected the accumulation of (E/Z)-PAOx in MeJA-treated leaves. These results showed that (E/Z)-PAOx is the biosynthetic precursor of PAN. MeJA-induced mRNAs were analysed by differential expression analysis using a next-generation sequencer. Of the 74,329 contigs obtained from RNA-seq and de novo assembly, 252 contigs were induced by MeJA treatment. Full-length cDNAs encoding MeJA-induced cytochrome P450s CYP71AT96, CYP82AN1, CYP82D125 and CYP715A35 were cloned using 5'- and 3'-RACE and were expressed using a baculovirus expression system. Among these cytochrome P450s, CYP71AT96 catalysed the conversion of (E/Z)-PAOx to PAN in the presence of NADPH and a cytochrome P450 reductase. It also acted on (E/Z) 4-hydroxyphenylacetaldoxime and (E/Z)-indole-3-acetaldoxime. The broad substrate specificity of CYP71AT96 was similar to that of aldoxime metabolizing cytochrome P450s. Quantitative RT-PCR analysis showed that CYP71AT96 expression was highly induced because of treatment with MeJA as well as feeding by the Japanese beetle. These results indicate that CYP71AT96 likely contributes the herbivore-induced PAN biosynthesis in F. sachalinensis. PMID- 26928802 TI - Reprogramming Essential Hypertension: The Role of Resveratrol. PMID- 26928801 TI - Transient Receptor Potential Melastatin 7 Cation Channel Kinase: New Player in Angiotensin II-Induced Hypertension. AB - Transient receptor potential melastatin 7 (TRPM7) is a bifunctional protein comprising a magnesium (Mg(2+))/cation channel and a kinase domain. We previously demonstrated that vasoactive agents regulate vascular TRPM7. Whether TRPM7 plays a role in the pathophysiology of hypertension and associated cardiovascular dysfunction is unknown. We studied TRPM7 kinase-deficient mice (TRPM7Deltakinase; heterozygous for TRPM7 kinase) and wild-type (WT) mice infused with angiotensin II (Ang II; 400 ng/kg per minute, 4 weeks). TRPM7 kinase expression was lower in heart and aorta from TRPM7Deltakinase versus WT mice, effects that were further reduced by Ang II infusion. Plasma Mg(2+) was lower in TRPM7Deltakinase versus WT mice in basal and stimulated conditions. Ang II increased blood pressure in both strains with exaggerated responses in TRPM7Deltakinase versus WT groups (P<0.05). Acetylcholine-induced vasorelaxation was reduced in Ang II-infused TRPM7Deltakinase mice, an effect associated with Akt and endothelial nitric oxide synthase downregulation. Vascular cell adhesion molecule-1 expression was increased in Ang II-infused TRPM7 kinase-deficient mice. TRPM7 kinase targets, calpain, and annexin-1, were activated by Ang II in WT but not in TRPM7Deltakinase mice. Echocardiographic and histopathologic analysis demonstrated cardiac hypertrophy and left ventricular dysfunction in Ang II treated groups. In TRPM7 kinase-deficient mice, Ang II-induced cardiac functional and structural effects were amplified compared with WT counterparts. Our data demonstrate that in TRPM7Deltakinase mice, Ang II-induced hypertension is exaggerated, cardiac remodeling and left ventricular dysfunction are amplified, and endothelial function is impaired. These processes are associated with hypomagnesemia, blunted TRPM7 kinase expression/signaling, endothelial nitric oxide synthase downregulation, and proinflammatory vascular responses. Our findings identify TRPM7 kinase as a novel player in Ang II-induced hypertension and associated vascular and target organ damage. PMID- 26928803 TI - Perinatal Resveratrol Supplementation to Spontaneously Hypertensive Rat Dams Mitigates the Development of Hypertension in Adult Offspring. AB - This study was undertaken to determine whether perinatal maternal resveratrol (Resv)--a phytoalexin known to confer cardiovascular protection--could prevent the development of hypertension and improve vascular function in adult spontaneously hypertensive rat offspring. Dams were fed either a control or Resv supplemented diet (4 g/kg diet) from gestational day 0.5 until postnatal day 21. Indwelling catheters were used to assess blood pressure and vascular function in vivo; wire myography was used to assess vascular reactivity ex vivo. Perinatal Resv supplementation in dams had no effect on fetal body weights, albeit continued maternal treatment postnatally resulted in growth restriction in offspring by postnatal day 21; growth restriction was no longer evident after 5 weeks of age. Maternal perinatal Resv supplementation prevented the onset of hypertension in adult offspring (-18 mm Hg; P=0.007), and nitric oxide synthase inhibition (with L-NG-nitroarginine methyl ester) normalized these blood pressure differences, suggesting improved nitric oxide bioavailability underlies the hemodynamic alterations in the Resv-treated offspring. In vivo and ex vivo, vascular responses to methylcholine were not different between treatment groups, but prior treatment with L-NG-nitroarginine methyl ester attenuated the vasodilation in untreated, but not Resv-treated adult offspring, suggesting a shift toward nitric oxide-independent vascular control mechanisms in the treated group. Finally, bioconversion of the inactive precursor big endothelin-1 to active endothelin-1 in isolated mesenteric arteries was reduced in Resv-treated offspring (-28%; P<0.05), and this difference could be normalized by L-NG nitroarginine methyl ester treatment. In conclusion, perinatal maternal Resv supplementation mitigated the development of hypertension and causes persistent alterations in vascular responsiveness in spontaneously hypertensive rats. PMID- 26928804 TI - 6beta-Hydroxytestosterone, a Cytochrome P450 1B1-Testosterone-Metabolite, Mediates Angiotensin II-Induced Renal Dysfunction in Male Mice. AB - 6beta-Hydroxytestosterone, a cytochrome P450 1B1-derived metabolite of testosterone, contributes to the development of angiotensin II-induced hypertension and associated cardiovascular pathophysiology. In view of the critical role of angiotensin II in the maintenance of renal homeostasis, development of hypertension, and end-organ damage, this study was conducted to determine the contribution of 6beta-hydroxytestosterone to angiotensin II actions on water consumption and renal function in male Cyp1b1(+/+) and Cyp1b1(-/-) mice. Castration of Cyp1b1(+/+) mice or Cyp1b1(-/-) gene disruption minimized the angiotensin II-induced increase in water consumption, urine output, proteinuria, and sodium excretion and decreases in urine osmolality. 6beta-Hydroxytestosterone did not alter angiotensin II-induced increases in water intake, urine output, proteinuria, and sodium excretion or decreases in osmolality in Cyp1b1(+/+) mice, but restored these effects of angiotensin II in Cyp1b1(-/-) or castrated Cyp1b1(+/+) mice. Cyp1b1 gene disruption or castration prevented angiotensin II induced renal fibrosis, oxidative stress, inflammation, urinary excretion of angiotensinogen, expression of angiotensin II type 1 receptor, and angiotensin converting enzyme. 6beta-Hydroxytestosterone did not alter angiotensin II-induced renal fibrosis, inflammation, oxidative stress, urinary excretion of angiotensinogen, expression of angiotensin II type 1 receptor, or angiotensin converting enzyme in Cyp1b1(+/+)mice. However, in Cyp1b1(-/-) or castrated Cyp1b1(+/+) mice, it restored these effects of angiotensin II. These data indicate that 6beta-hydroxytestosterone contributes to increased thirst, impairment of renal function, and end-organ injury associated with angiotensin II induced hypertension in male mice and that cytochrome P450 1B1 could serve as a novel target for treating renal disease and hypertension in male mice. PMID- 26928805 TI - On the Origin of Urinary Renin: A Translational Approach. AB - Urinary angiotensinogen excretion parallels albumin excretion, which is not the case for renin, while renin's precursor, prorenin, is undetectable in urine. We hypothesized that renin and prorenin, given their smaller size, are filtered through the glomerulus in larger amounts than albumin and angiotensinogen, and that differences in excretion rate are because of a difference in reabsorption in the proximal tubule. To address this, we determined the glomerular sieving coefficient of renin and prorenin and measured urinary renin/prorenin 1) after inducing prorenin in Cyp1a1-Ren2 rats and 2) in patients with Dent disease or Lowe syndrome, disorders characterized by defective proximal tubular reabsorption. Glomerular sieving coefficients followed molecular size (renin>prorenin>albumin). The induction of prorenin in rats resulted in a >300 fold increase in plasma prorenin and doubling of blood pressure but did not lead to the appearance of prorenin in urine. It did cause parallel rises in urinary renin and albumin, which losartan but not hydralazine prevented. Defective proximal tubular reabsorption increased urinary renin and albumin 20- to 40-fold, and allowed prorenin detection in urine, at ~50% of its levels in plasma. Taken together, these data indicate that circulating renin and prorenin are filtered into urine in larger amounts than albumin. All 3 proteins are subsequently reabsorbed in the proximal tubule. For prorenin, such reabsorption is ~100%. Minimal variation in tubular reabsorption (in the order of a few %) is sufficient to explain why urinary renin and albumin excretion do not correlate. Urinary renin does not reflect prorenin that is converted to renin in tubular fluid. PMID- 26928806 TI - Estrogen Receptor alpha Is Required for Maintaining Baseline Renin Expression. AB - Enzymatic cleavage of angiotensinogen by renin represents the critical rate limiting step in the production of angiotensin II, but the mechanisms regulating the initial expression of the renin gene remain incomplete. The purpose of this study is to unravel the molecular mechanism controlling renin expression. We identified a subset of nuclear receptors that exhibited an expression pattern similar to renin by reanalyzing a publicly available microarray data set. Expression of some of these nuclear receptors was similarly regulated as renin in response to physiological cues, which are known to regulate renin. Among these, only estrogen receptor alpha (ERalpha) and hepatic nuclear factor alpha have no known function in regulating renin expression. We determined that ERalpha is essential for the maintenance of renin expression by transfection of small interfering RNAs targeting Esr1, the gene encoding ERalpha, in renin-expressing As4.1 cells. We also observed that previously characterized negative regulators of renin expression, Nr2f2 and vitamin D receptor, exhibited elevated expression in response to ERalpha inhibition. Therefore, we tested whether ERalpha regulates renin expression through an interaction with Nr2f2 and vitamin D receptor. Renin expression did not return to baseline when we concurrently suppressed both Esr1 and Nr2f2 or Esr1 and vitamin D receptor mRNAs, strongly suggesting that Esr1 regulates renin expression independent of Nr2f2 and vitamin D receptor. ERalpha directly binds to the hormone response element within the renin enhancer region. We conclude that ERalpha is a previously unknown regulator of renin that directly binds to the renin enhancer hormone response element sequence and is critical in maintaining renin expression in renin-expressing As4.1 cells. PMID- 26928808 TI - Meta-analysis of antibiotics for simple hand injuries requiring surgery. AB - BACKGROUND: Simple hand trauma is very common, accounting for 1.8 million emergency department visits annually in the USA alone. Antibiotics are used widely as postinjury prophylaxis, but their efficacy is unclear. This meta analysis assessed the effect of antibiotic prophylaxis versus placebo or no treatment on wound infection rates in hand injuries managed surgically. METHODS: Embase, MEDLINE, PubMed, Cochrane Central, ClinicalTrials.gov and the World Health Organization International Clinical Trials Portal were searched for published and unpublished studies in any language from inception to September 2015. The primary outcome was the effect of antibiotic prophylaxis on wound infection rates. Open fractures, crush injuries and bite wounds were excluded. Study quality was assessed using the Cochrane risk-of-bias tool. Data were pooled using random-effects meta-analysis, and risk ratios (RRs) and 95 per cent c.i. obtained. RESULTS: Thirteen studies (2578 patients) were included, comprising five double-blind randomized clinical trials, five prospective trials and three cohort studies. There was no significant difference in infection rate between the antibiotic and placebo/no antibiotic groups (RR 0.89, 95 per cent c.i. 0.65 to 1.23; P = 0.49). Subgroup analysis of the five double-blind randomized clinical trials (864 patients) again found no difference in infection rates (RR 0.66, 0.36 to 1.21; P = 0.18). CONCLUSION: There was moderate-quality evidence that routine use of antibiotics does not reduce the infection rate in simple hand wounds that require surgery. PMID- 26928807 TI - Intrarenal Renin-Angiotensin System: Locally Synthesized or Taken up Via Endocytosis? PMID- 26928809 TI - Tailoring LaAlO3/SrTiO3 Interface Metallicity by Oxygen Surface Adsorbates. AB - We report an oxygen surface adsorbates induced metal-insulator transition at the LaAlO3/SrTiO3 interfaces. The observed effects were attributed to the terminations of surface Al sites and the resultant electron-accepting surface states. By controlling the local oxygen adsorptions, we successfully demonstrated the nondestructive patterning of the interface two-dimensional electron gas (2DEG). The obtained 2DEG structures are stable in air and also robust against general solvent treatments. This study provides new insights into the metal insulator transition mechanism at the complex oxide interfaces and also a highly efficient technique for tailoring the interface properties. PMID- 26928810 TI - In the interests of time: improving HIV allocative efficiency modelling via optimal time-varying allocations. AB - INTRODUCTION: International investment in the response to HIV and AIDS has plateaued and its future level is uncertain. With many countries committed to ending the epidemic, it is essential to allocate available resources efficiently over different response periods to maximize impact. The objective of this study is to propose a technique to determine the optimal allocation of funds over time across a set of HIV programmes to achieve desirable health outcomes. METHODS: We developed a technique to determine the optimal time-varying allocation of funds (1) when the future annual HIV budget is pre-defined and (2) when the total budget over a period is pre-defined, but the year-on-year budget is to be optimally determined. We use this methodology with Optima, an HIV transmission model that uses non-linear relationships between programme spending and associated programmatic outcomes to quantify the expected epidemiological impact of spending. We apply these methods to data collected from Zambia to determine the optimal distribution of resources to fund the right programmes, for the right people, at the right time. RESULTS AND DISCUSSION: Considering realistic implementation and ethical constraints, we estimate that the optimal time-varying redistribution of the 2014 Zambian HIV budget between 2015 and 2025 will lead to a 7.6% (7.3% to 7.8%) decrease in cumulative new HIV infections compared with a baseline scenario where programme allocations remain at 2014 levels. This compares to a 5.1% (4.6% to 5.6%) reduction in new infections using an optimal allocation with constant programme spending that recommends unrealistic programmatic changes. Contrasting priorities for programme funding arise when assessing outcomes for a five-year funding period over 5-, 10- and 20-year time horizons. CONCLUSIONS: Countries increasingly face the need to do more with the resources available. The methodology presented here can aid decision-makers in planning as to when to expand or contract programmes and to which coverage levels to maximize impact. PMID- 26928811 TI - Response to "Oral PrEP for young African women and men". PMID- 26928815 TI - A New Path to Primary Care. AB - The University of North Texas Health Science Center and the Texas College of Osteopathic Medicine are partnering with Midland College and Midland Memorial Hospital to keep their own crop of future doctors in the area. The Primary Care Pathway identifies interested, high-achieving community college students likely to be successful in medical school and guarantees them an accelerated pathway to a doctor of osteopathic medicine degree, focusing earlier and more intensely on primary care. PMID- 26928813 TI - Flexible n-Type High-Performance Thermoelectric Thin Films of Poly(nickel ethylenetetrathiolate) Prepared by an Electrochemical Method. AB - Flexible thin films of poly(nickel-ethylenetetrathiolate) prepared by an electrochemical method display promising n-type thermoelectric properties with the highest ZT value up to 0.3 at room temperature. Coexistence of high electrical conductivity and high Seebeck coefficient in this coordination polymer is attributed to its degenerate narrow-bandgap semiconductor behavior. PMID- 26928812 TI - Cyclin E Associates with the Lipogenic Enzyme ATP-Citrate Lyase to Enable Malignant Growth of Breast Cancer Cells. AB - Cyclin E is altered in nearly a third of invasive breast cancers where it is a powerful independent predictor of survival in women with stage I-III disease. Full-length cyclin E is posttranslationally cleaved into low molecular weight (LMW-E) isoforms, which are tumor-specific and accumulate in the cytoplasm because they lack a nuclear localization sequence. We hypothesized that aberrant localization of cytosolic LMW-E isoforms alters target binding and activation ultimately contributing to LMW-E-induced tumorigenicity. To address this hypothesis, we used a retrovirus-based protein complementation assay to find LMW E binding proteins in breast cancer, identifying ATP-citrate lyase (ACLY), an enzyme in the de novo lipogenesis pathway, as a novel LMW-E-interacting protein in the cytoplasm. LMW-E upregulated ACLY enzymatic activity, subsequently increasing lipid droplet formation, thereby providing cells with essential building blocks to support growth. ACLY was also required for LMW-E-mediated transformation, migration, and invasion of breast cancer cells in vitro along with tumor growth in vivo In clinical specimens of breast cancer, the absence of LMW-E and low expression of adipophilin (PLIN2), a marker of lipid droplet formation, associated with favorable prognosis, whereas overexpression of both proteins correlated with a markedly worse prognosis. Taken together, our findings establish a novel relationship between LMW-E isoforms of cyclin E and aberrant lipid metabolism pathways in breast cancer tumorigenesis, warranting further investigation in additional malignancies exhibiting their expression. Cancer Res; 76(8); 2406-18. (c)2016 AACR. PMID- 26928816 TI - Real-Time Revolution? AB - Austin Regional Clinic (ARC) physicians and officials know patient feedback is important, but getting patients to provide it can be a challenge. A pilot program of a new, real-time feedback system provided ARC patients a high-tech convenience previous attempts lacked and produced participation numbers dwarfing those past efforts. ARC's initial results with the system, in which patients answer five to seven questions on a computer tablet and can leave free-text comments, were so successful the clinic is already planning to expand it to all of its locations by the end of June. PMID- 26928817 TI - Conversation Counts. AB - Informed consent is a hallmark of good old-fashioned patient care. But some Texas physicians and hospitals are finding ways to use the process as an opportunity to improve patient safety and patient-centered care. The Texas Medical Disclosure Panel - the state regulatory body overseeing informed consent for medical treatments - is taking steps to make state forms even more understandable for patients at a time when health literacy rates are low. PMID- 26928818 TI - A Needling Controversy. AB - Acupuncture licensing requires thousands of hours of training, but the Texas Board of Chiropractic Examiners' (TBCE's) rules allow chiropractors to perform the procedure and to do so with considerably less training. The Texas Association of Acupuncture and Oriental Medicine (TAAOM) is challenging those rules in a lawsuit, saying acupuncture is beyond the chiropractic scope of practice, and TBCE's inclusion of it constitutes a public health risk. The Texas Medical Association filed an amicus curiae brief to support TAAOM's case, citing the limitations on acupuncture practice in the Texas Occupations Code and the large disparity in required training hours between licensed acupuncturists and chiropractors who perform the technique. PMID- 26928819 TI - Strengthening the Fight Against HCC. AB - Primary care physicians have the resources they need to screen for a cancer that's growing in prevalence and hitting Texas harder than almost any other state. What's missing is awareness of what physicians can do to facilitate early detection of hepatocellular carcinoma (HCC), the most common form of primary liver cancer. That's what a TMA Foundation-funded workgroup, Texas HepCA, is trying to change as HCC rates in the state continue to rise, particularly among the Hispanic population in South Texas. PMID- 26928820 TI - PQRS Mess. AB - One-quarter of physicians who participate in the Physician Quality Reporting System and the value modifier program risked payment cuts stemming from difficulties the Centers for Medicare & Medicaid Services had with collecting and analyzing 2014 quality data. PMID- 26928821 TI - Consumer Perceptions of Interactions With Primary Care Providers After Direct-to Consumer Personal Genomic Testing. AB - BACKGROUND: Direct-to-consumer (DTC) personal genomic testing (PGT) allows individuals to learn about their genetic makeup without going through a physician, but some consumers share their results with their primary care provider (PCP). OBJECTIVE: To describe the characteristics and perceptions of DTC PGT consumers who discuss their results with their PCP. DESIGN: Longitudinal, prospective cohort study. SETTING: Online survey before and 6 months after results. PARTICIPANTS: DTC PGT consumers. MEASUREMENTS: Consumer satisfaction with the DTC PGT experience; whether and, if so, how many results could be used to improve health; how many results were not understood; and beliefs about the PCP's understanding of genetics. Participants were asked with whom they had discussed their results. Genetic reports were linked to survey responses. RESULTS: Among 1026 respondents, 63% planned to share their results with a PCP. At 6-month follow-up, 27% reported having done so, and 8% reported sharing with another health care provider only. Common reasons for not sharing results with a health care provider were that the results were not important enough (40%) or that the participant did not have time to do so (37%). Among participants who discussed results with their PCP, 35% were very satisfied with the encounter, and 18% were not at all satisfied. Frequently identified themes in participant descriptions of these encounters were actionability of the results or use in care (32%), PCP engagement or interest (25%), and lack of PCP engagement or interest (22%). LIMITATION: Participants may not be representative of all DTC PGT consumers. CONCLUSION: A comprehensive picture of DTC PGT consumers who shared their results with a health care provider is presented. The proportion that shares results is expected to increase with time after testing as consumers find opportunities for discussion at later appointments or if results become relevant as medical needs evolve. PRIMARY FUNDING SOURCE: National Institutes of Health. PMID- 26928822 TI - Antithrombotic prophylaxis in a patient with nephrotic syndrome and congenital protein S deficiency. AB - BACKGROUND: Nephrotic syndrome confers an acquired prothrombotic phenotype due to the urinary loss of anticoagulant proteins.Patients with reactivation of nephrotic syndrome may develop thrombosis. CASE PRESENTATION: We report the case of a life-threatening cerebral venous thrombosis in a 13 year-old boy affected by a relapse of nephrotic syndrome during a P. aeruginosa otitis/mastoiditis. Due to the worsening general conditions and the severe neurological impairment, a course of systemic thrombolysis was successfully administered, followed by anticoagulant therapy. In the present case severe inherited thrombophilia (inherited dysfunctional protein S deficiency) was identified as an important additional risk factors for thrombosis. CONCLUSIONS: A careful evalutaion of risk factos for thrombosi during reactivation of nephrotic syndrome include measurement of plasma anticaogulant proteins. When low, antithrombotic prophylaxis with heparin should be considered to prevent thrombotic episodes. PMID- 26928823 TI - Development and evaluation of an online, interactive information and advice tool for pre-registration nursing students. AB - Attrition rates for student nurses on academic programmes is a challenge for UK Higher Education Institutions. Reasons for leaving a programme of study include personal, financial issues or practice placement experiences. Research has shown systematic and integrated support mechanisms may improve attrition rates and student experience. This project explored the sources of, and support needs of nursing and allied health students, develop and evaluate and interactive online tool: 'SignpOSt'. Enabling students to access 'the right support, at the right time, from the right place'. Focus groups were carried out with 14, 3rd year students and 8 academic staff including personal tutors, programme/module leaders. Thematic analysis of transcribed data under four key themes for support and advice: 1. Financial 2. Programme 3. Personal 4. Study/academic, found poor student knowledge and little clarity of responsibilities of academic staff and services leads to students sourcing support from the wrong place at the wrong time. Students valued the speed and accessibility of information from informal, programme specific Facebook groups. Conversely, there were also concerns about the accuracy of these. Further research into the use of informal Facebook groups may be useful along with additional evaluation of the SOS tool. PMID- 26928824 TI - Collaborative learning in gerontological clinical settings: The students' perspective. AB - This study deals with student nurses' experiences of collaborative learning in gerontological clinical settings where aged people are involved as age-experts in students' learning processes. The data were collected in 2012 using the contents of students' reflective writing assignments concerning elderly persons' life history interviews and the students' own assessments of their learning experiences in authentic elder care settings. The results, analyzed using qualitative content analysis, revealed mostly positive learning experiences. Interaction and collaborative learning activities in genuine gerontological clinical settings contributed to the students' understanding of the multiple age related and disease-specific challenges as well as the issues of functional decline that aged patients face. Three types of factors influenced the students' collaborative learning experiences in gerontological clinical settings: student related, patient-related and learning environment-related factors. According to the results, theoretical studies in combination with collaboration, in an authentic clinical environment, by student nurses, elderly patients, representatives of the elder care staff and nurse educators provide a feasible method for helping students transform their experiences with patients into actual skills. Their awareness of and sensitivity to the needs of the elderly increase as they learn. PMID- 26928825 TI - Inhibition of miR-154 Protects Against Cardiac Dysfunction and Fibrosis in a Mouse Model of Pressure Overload. AB - Expression of miR-154 is upregulated in the diseased heart and was previously shown to be upregulated in the lungs of patients with pulmonary fibrosis. However, the role of miR-154 in a model of sustained pressure overload-induced cardiac hypertrophy and fibrosis had not been assessed. To examine the role of miR-154 in the diseased heart, adult male mice were subjected to transverse aortic constriction for four weeks, and echocardiography was performed to confirm left ventricular hypertrophy and cardiac dysfunction. Mice were then subcutaneously administered a locked nucleic acid antimiR-154 or control over three consecutive days (25 mg/kg/day) and cardiac function was assessed 8 weeks later. Here, we demonstrate that therapeutic inhibition of miR-154 in mice with pathological hypertrophy was able to protect against cardiac dysfunction and attenuate adverse cardiac remodelling. The improved cardiac phenotype was associated with attenuation of heart and cardiomyocyte size, less cardiac fibrosis, lower expression of atrial and B-type natriuretic peptide genes, attenuation of profibrotic markers, and increased expression of p15 (a miR-154 target and cell cycle inhibitor). In summary, this study suggests that miR-154 may represent a novel target for the treatment of cardiac pathologies associated with cardiac fibrosis, hypertrophy and dysfunction. PMID- 26928827 TI - Use of Three-Dimensional Arterial Models To Predict the In Vivo Behavior of Nanoparticles for Drug Delivery. AB - Nanomaterials have been widely used for applications in biomedical fields and could become indispensable in the near future. However, since it is difficult to optimize in vivo biological behavior in a 3D environment by using a single cell in vitro, there have been many failures in animal models. In vitro prediction systems using 3D human-tissue models reflecting the 3D location of cell types may be useful to better understand the biological characteristics of nanomaterials for optimization of their function. Herein we demonstrate the potential ability of 3D engineered human-arterial models for in vitro prediction of the in vivo behavior of nanoparticles for drug delivery. These models enabled optimization of the composition and size of the nanoparticles for targeting and treatment efficacy for atherosclerosis. In vivo experiments with atherosclerotic mice suggested excellent biological characteristics and potential treatment effects of the nanoparticles optimized in vitro. PMID- 26928826 TI - Salmonella Typhi-specific multifunctional CD8+ T cells play a dominant role in protection from typhoid fever in humans. AB - BACKGROUND: Typhoid fever, caused by the human-restricted organism Salmonella Typhi (S. Typhi), is a major public health problem worldwide. Development of novel vaccines remains imperative, but is hampered by an incomplete understanding of the immune responses that correlate with protection. METHODS: Recently, a controlled human infection model was re-established in which volunteers received ~10(3) cfu wild-type S. Typhi (Quailes strain) orally. Twenty-one volunteers were evaluated for their cell-mediated immune (CMI) responses. Ex vivo PBMC isolated before and up to 1 year after challenge were exposed to three S. Typhi-infected targets, i.e., autologous B lymphoblastoid cell-lines (B-LCL), autologous blasts and HLA-E restricted AEH B-LCL cells. CMI responses were evaluated using 14-color multiparametric flow cytometry to detect simultaneously five intracellular cytokines/chemokines (i.e., IL-17A, IL-2, IFN-g, TNF-a and MIP-1b) and a marker of degranulation/cytotoxic activity (CD107a). RESULTS: Herein we provide the first evidence that S. Typhi-specific CD8+ responses correlate with clinical outcome in humans challenged with wild-type S. Typhi. Higher multifunctional S. Typhi-specific CD8+ baseline responses were associated with protection against typhoid and delayed disease onset. Moreover, following challenge, development of typhoid fever was accompanied by decreases in circulating S. Typhi-specific CD8+ T effector/memory (TEM) with gut homing potential, suggesting migration to the site(s) of infection. In contrast, protection against disease was associated with low or no changes in circulating S. Typhi-specific TEM. CONCLUSIONS: These studies provide novel insights into the protective immune responses against typhoid disease that will aid in selection and development of new vaccine candidates. PMID- 26928828 TI - Can Rapid Diagnostic Testing for Malaria Increase Adherence to Artemether Lumefantrine?: A Randomized Controlled Trial in Uganda. AB - Most patients with suspected malaria do not receive diagnostic confirmation before beginning antimalarial treatment. We investigated the extent to which uncertainty about malaria diagnosis contributes to patient nonadherence to artemether-lumefantrine (AL) treatment through a randomized controlled trial in central Uganda. Among 1,525 patients purchasing a course of AL at private drug shops, we randomly offered 37.6% a free malaria rapid diagnostic test (RDT) and then assessed adherence through home visits 3 days later. Of these subjects, 68.4% tested positive for malaria and 65.8% adhered overall. Patients who tested positive did not have significantly higher odds of adherence than those who were not offered the test (adjusted odds ratio [OR]: 1.07, 95% confidence interval [CI]: 0.734-1.57,P= 0.719). Patients who received a positive malaria test had 0.488 fewer pills remaining than those not offered the test (95% CI: -1.02 to 0.043,P= 0.072). We found that patients who felt relatively healthy by the second day of treatment had lower odds of completing treatment (adjusted OR: 0.532, 95% CI: 0.394-0.719,P< 0.001). Our results suggest that diagnostic testing may not improve artemisinin-based combination therapy adherence unless efforts are made to persuade patients to continue taking the full course of drugs even if symptoms have resolved. PMID- 26928829 TI - Amebic Liver Abscess in Israeli Travelers: A Retrospective Study. AB - Amebic liver abscess (ALA) is endemic in developing countries. The epidemiology and clinical characteristics of the disease in developing countries are well described. Travelers from nonendemic countries can serve as a model for the natural history of ALA. Currently, the available literature on travelers is limited. This is a retrospective observational study on Israeli travelers diagnosed with ALA. Data regarding travel history, clinical presentation, imaging, and treatment were collected and analyzed. Among 6,867 ill returning Israeli travelers, amebiasis was diagnosed in 53 travelers (0.77%), of whom 14 were with ALA (0.2%). Twelve ALA cases (86%) had an exposure in the Indian subcontinent. The male to female ratio was 1:1, with no significant clinical differences between the sexes. The average lag period between exposure and onset of symptoms was 17.1 months. The lack of male predominance and the prolonged lag period may imply that behavioral factors are pivotal in the development of ALA. Larger case series of travelers are required. PMID- 26928830 TI - Seroprevalence and Risk Factors of Inkoo Virus in Northern Sweden. AB - The mosquito-borne Inkoo virus (INKV) is a member of the California serogroup in the family Bunyaviridae, genus Orthobunyavirus These viruses are associated with fever and encephalitis, although INKV infections are not usually reported and the incidence is largely unknown. The aim of the study was to determine the prevalence of anti-INKV antibodies and associated risk factors in humans living in northern Sweden. Seroprevalence was investigated using the World Health Organization Monitoring of Trends and Determinants in Cardiovascular Disease study, where a randomly selected population aged between 25 and 74 years (N = 1,607) was invited to participate. The presence of anti-INKV IgG antibodies was determined by immunofluorescence assay. Seropositivity for anti-INKV was significantly higher in men (46.9%) than in women (34.8%; P < 0.001). In women, but not in men, the prevalence increased somewhat with age (P = 0.06). The peak in seropositivity was 45-54 years for men and 55-64 years for women. Living in rural areas was associated with a higher seroprevalence. In conclusion, the prevalence of anti-INKV antibodies was high in northern Sweden and was associated with male sex, older age, and rural living. The age distribution indicates exposure to INKV at a relatively early age. These findings will be important for future epidemiological and clinical investigations of this relatively unknown mosquito-borne virus. PMID- 26928831 TI - Molecular Identification of Q Fever in Patients with a Suspected Diagnosis of Dengue in Brazil in 2013-2014. AB - Q fever is an important cause of undifferentiated fever that is rarely recognized or reported in Brazil. The objective of this study was to look for the presence of Coxiella burnetii during a dengue fever outbreak in the municipality of Itaborai, Rio de Janeiro, Brazil, where this bacterium had previously infected humans and domesticated animals. Blood samples from clinically suspected dengue fever patients were tested by polymerase chain reaction (PCR) for C. burnetii; the DNA was detected in nine (3.3%) of 272 patients. One was coinfected with dengue virus, which was also detected in another 166 (61.3%) patients. The nucleotide sequence of PCR amplification and DNA sequencing of the IS1111 transposase elements in the genome of C. burnetii exhibited 99% identity with the sequence in GenBank. The detection of C. burnetii in patients suspected of dengue fever indicates that awareness and knowledge of Q fever should be strengthened and that this bacterium is present in Brazil. Finally, because a negative molecular result does not completely rule out the diagnosis of Q fever and the serological assay based on seroconversion was not available, the actual number of this zoonosis is likely to be much higher than that reported in this study. PMID- 26928832 TI - Refractory and/or Relapsing Cryptococcosis Associated with Acquired Immune Deficiency Syndrome: Clinical Features, Genotype, and Virulence Factors of Cryptococcus spp. Isolates. AB - Refractory and relapsing crytocococcosis in acquired immune deficiency syndrome (AIDS) patients have a poor prognosis. The risk factors for this complicated infection course were evaluated by comparing refractory and/or relapsing cryptococcosis in human immunodeficiency virus-coinfected patients (cohort 1) with another group of AIDS patients who adequately responded to antifungals (cohort 2). Except for one isolate of Cryptococcus gattii from a cohort 2 case, all other isolates were identified as Cryptococcus neoformans var. grubii, sex type alpha, genotype VNI, including Cryptococcus reisolated from the relapse or in the refractory state. No differences were observed with respect to Cryptococcus capsule size and in the melanin and phospholipase production. The cohort 1 patients presented higher prevalence of cryptococcemia, cerebral dissemination, chronic liver disease, and leucopenia, and have increased death rate. Apparently, the refractory and/or relapsing cryptococcosis in the AIDS patients were more related to the host and the extent of the infection than to the fungal characteristics. PMID- 26928833 TI - The Relationship Between Distance to Water Source and Moderate-to-Severe Diarrhea in the Global Enterics Multi-Center Study in Kenya, 2008-2011. AB - In the developing world, fetching water for drinking and other household uses is a substantial burden that affects water quantity and quality in the household. We used logistic regression to examine whether reported household water fetching times were a risk factor for moderate-to-severe diarrhea (MSD) using case-control data of 3,359 households from the Global Enterics Multi-Center Study in Kenya in 2009-2011. We collected additional global positioning system (GPS) data for a subset of 254 randomly selected households and compared GPS-based straight line and actual travel path distances to fetching times reported by respondents. GPS based data were highly correlated with respondent-provided times (Spearman correlation coefficient = 0.81, P < 0.0001). The median estimated one-way distance to water source was 200 m for cases and 171 for controls (Wilcoxon rank sums/Mann-Whitney P = 0.21). A round-trip fetching time of > 30 minutes was reported by 25% of cases versus 15% of controls and was significantly associated with MSD where rainwater was not used in the last 2 weeks (odds ratio = 1.97, 95% confidence interval = 1.56-2.49). These data support the United Nations definition of access to an improved water source being within 30 minutes total round-trip travel time. PMID- 26928834 TI - The Burden of Dengue and the Financial Cost to Colombia, 2010-2012. AB - Data on the burden of dengue and its economic costs can help guide health policy decisions. However, little reliable information is available for Colombia. We therefore calculated the burden of the disease, expressed in disability-adjusted life years (DALYs), for two scenarios: endemic years (average number of cases in non-epidemic years 2011 and 2012) and an epidemic year (2010, when the highest number of dengue cases was reported in the study period). We also estimated the total economic cost of the disease (U.S. dollars at the average exchange rate for 2012), including indirect costs to households derived from expenses such as preventing entry of mosquitos into the home and costs to government arising from direct, indirect, and prevention and monitoring activities, as well as the direct medical and non-medical costs. In the epidemic year 2010, 1,198.73 DALYs were lost per million inhabitants versus 83.88 in endemic years. The total financial cost of the disease in Colombia from a societal perspective was US$167.8 million for 2010, US$129.9 million for 2011, and US$131.7 million for 2012. The cost of mosquito prevention borne by households was a major cost driver (accounting for 46% of the overall cost in 2010, 62% in 2011, and 64% in 2012). PMID- 26928835 TI - Knowledge of Hepatitis B Transmission Risks Among Health Workers in Tanzania. AB - Healthcare workers are at increased risk of contracting hepatitis B virus (HBV), particularly in settings of high HBV seroprevalence, such as sub-Saharan Africa. We evaluated HBV knowledge among health-care workers in rural Tanzania by distributing an HBV paper survey in two northern Tanzanian hospitals. There were 114 participants (mean age 33 years, 67% female). Of the participants, 91% were unaware of their HBV status and 89% indicated they had never received an HBV vaccine, with lack of vaccine awareness being the most common reason (34%), whereas 70% were aware of HBV complications and 60% understood routes of transmission. There was a significant difference in knowledge of HBV serostatus and vaccination between participants with a medical background and others, P = 0.01 and 0.001, respectively. However, only 33% of consultants (senior medical staff) knew their HBV serostatus. There was no significant difference between knowledge of HBV transmission routes and occupation. Our study reveals low knowledge of HBV serostatus and vaccination status among hospital workers in Tanzania. PMID- 26928836 TI - Diversity and Evolutionary Histories of Human Coronaviruses NL63 and 229E Associated with Acute Upper Respiratory Tract Symptoms in Kuala Lumpur, Malaysia. AB - The human alphacoronaviruses HCoV-NL63 and HCoV-229E are commonly associated with upper respiratory tract infections (URTI). Information on their molecular epidemiology and evolutionary dynamics in the tropical region of southeast Asia however is limited. Here, we analyzed the phylogenetic, temporal distribution, population history, and clinical manifestations among patients infected with HCoV NL63 and HCoV-229E. Nasopharyngeal swabs were collected from 2,060 consenting adults presented with acute URTI symptoms in Kuala Lumpur, Malaysia, between 2012 and 2013. The presence of HCoV-NL63 and HCoV-229E was detected using multiplex polymerase chain reaction (PCR). The spike glycoprotein, nucleocapsid, and 1a genes were sequenced for phylogenetic reconstruction and Bayesian coalescent inference. A total of 68/2,060 (3.3%) subjects were positive for human alphacoronavirus; HCoV-NL63 and HCoV-229E were detected in 45 (2.2%) and 23 (1.1%) patients, respectively. A peak in the number of HCoV-NL63 infections was recorded between June and October 2012. Phylogenetic inference revealed that 62.8% of HCoV-NL63 infections belonged to genotype B, 37.2% was genotype C, while all HCoV-229E sequences were clustered within group 4. Molecular dating analysis indicated that the origin of HCoV-NL63 was dated to 1921, before it diverged into genotype A (1975), genotype B (1996), and genotype C (2003). The root of the HCoV 229E tree was dated to 1955, before it diverged into groups 1-4 between the 1970s and 1990s. The study described the seasonality, molecular diversity, and evolutionary dynamics of human alphacoronavirus infections in a tropical region. PMID- 26928837 TI - Molecular Diagnosis of Human Taenia martis Eye Infection. AB - Taenia martis, a tapeworm harbored in the intestine of mustelids, is a rarely encountered zoonotic cysticercosis pathogen. The larval stage closely resembles the Taenia solium cysticercus, but the natural host and thus the epidemiology of the disease is different. We here report a human eye infection diagnosed molecularly in a previously healthy female German patient. The case represents the third human infection described worldwide; the two previous cases were also European, involving eye and brain. PMID- 26928838 TI - Effectiveness of Oral Cholera Vaccine in Haiti: 37-Month Follow-Up. AB - The first oral cholera vaccine (OCV) campaign, since its prequalification by the World Health Organization, in response to an ongoing cholera epidemic (reactive vaccination) was successfully conducted in a poor urban slum of approximately 70,000 inhabitants in Port-au-Prince, Haiti, in 2012. Vaccine coverage was 75% of the target population. This report documents the impact of OCV in reducing the number of culture-confirmed cases of cholera admitted to the Groupe Haitien d'Etude du Sarcome de Kaposi et des Infections Opportunistes (GHESKIO) cholera treatment center from that community in the 37 months postvaccination (April 2012 April 30, 2015). Of 1,788 patients with culture-confirmed cholera, 1,770 (99%) were either from outside the vaccine area (1,400 cases) or from the vaccinated community who had not received OCV (370 cases). Of the 388 people from the catchment area who developed culture-confirmed cholera, 370 occurred among the 17,643 people who had not been vaccinated (2.1%) and the remaining 18 occurred among the 52,357 people (0.034%) who had been vaccinated (P < 0.001), for an efficacy that approximates 97.5%. Despite not being designed as a randomized control trial, the very high efficacy is a strong evidence for the effectiveness of OCV as part of an integrated package for the control of cholera in outbreak settings. PMID- 26928839 TI - Retrospective Analysis of the 2014-2015 Ebola Epidemic in Liberia. AB - The 2014-2015 Ebola epidemic has been the most protracted and devastating in the history of the disease. To prevent future outbreaks on this scale, it is imperative to understand the reasons that led to eventual disease control. Here, we evaluated the shifts of Ebola dynamics at national and local scales during the epidemic in Liberia. We used a transmission model calibrated to epidemiological data between June 9 and December 31, 2014, to estimate the extent of community and hospital transmission. We found that despite varied local epidemic patterns, community transmission was reduced by 40-80% in all the counties analyzed. Our model suggests that the tapering of the epidemic was achieved through reductions in community transmission, rather than accumulation of immune individuals through asymptomatic infection and unreported cases. Although the times at which this transmission reduction occurred in the majority of the Liberian counties started before any large expansion in hospital capacity and the distribution of home protection kits, it remains difficult to associate the presence of interventions with reductions in Ebola incidence. PMID- 26928840 TI - First Isolates of Leptospira spp., from Rodents Captured in Angola. AB - Rodents play an important role in the transmission of pathogenic Leptospira spp. However, in Angola, neither the natural reservoirs of these spirochetes nor leptospirosis diagnosis has been considered. Regarding this gap, we captured rodents in Luanda and Huambo provinces to identify circulating Leptospira spp. Rodent kidney tissue was cultured and DNA amplified and sequenced. Culture isolates were evaluated for pathogenic status and typing with rabbit antisera; polymerase chain reaction (PCR) and sequencing were also performed. A total of 37 rodents were captured: Rattus rattus (15, 40.5%), Rattus norvegicus (9, 24.3%), and Mus musculus (13, 35.2%). Leptospiral DNA was amplified in eight (21.6%) kidney samples. From the cultures, we obtained four (10.8%) Leptospira isolates belonging to the Icterohaemorrhagiae and Ballum serogroups of Leptospira interrogans and Leptospira borgpetersenii genospecies, respectively. This study provides information about circulating leptospires spread by rats and mice in Angola. PMID- 26928842 TI - Use of Balanced Scorecard Methodology for Performance Measurement of the Health Extension Program in Ethiopia. AB - In 2004, Ethiopia introduced a community-based Health Extension Program to deliver basic and essential health services. We developed a comprehensive performance scoring methodology to assess the performance of the program. A balanced scorecard with six domains and 32 indicators was developed. Data collected from 1,014 service providers, 433 health facilities, and 10,068 community members sampled from 298 villages were used to generate weighted national, regional, and agroecological zone scores for each indicator. The national median indicator scores ranged from 37% to 98% with poor performance in commodity availability, workforce motivation, referral linkage, infection prevention, and quality of care. Indicator scores showed significant difference by region (P < 0.001). Regional performance varied across indicators suggesting that each region had specific areas of strength and deficiency, with Tigray and the Southern Nations, Nationalities and Peoples Region being the best performers while the mainly pastoral regions of Gambela, Afar, and Benishangul-Gumuz were the worst. The findings of this study suggest the need for strategies aimed at improving specific elements of the program and its performance in specific regions to achieve quality and equitable health services. PMID- 26928841 TI - Domestic Pig (Sus scrofa) as an Animal Model for Experimental Trypanosoma cruzi Infection. AB - Pigs were infected with a Bolivian strain of Trypanosoma cruzi (genotype I) and evaluated up to 150 days postinoculation (dpi) to determine the use of pigs as an animal model of Chagas disease. Parasitemia was observed in the infected pigs during the acute phase (15-40 dpi). Anti-T. cruzi immunoglobulin M was detected during 15-75 dpi; high levels of anti-T. cruzi immunoglobulin G were detected in all infected pigs from 75 to 150 dpi. Parasitic DNA was observed by western blot (58%, 28/48) and polymerase chain reaction (27%, 13/48) in urine samples, and in the brain (75%, 3/4), spleen (50%, 2/4), and duodenum (25%, 1/4), but no parasitic DNA was found in the heart, colon, and kidney. Parasites were not observed microscopically in tissues samples, but mild inflammation, vasculitis, and congestion was observed in heart, brain, kidney, and spleen. This pig model was useful for the standardization of the urine test because of the higher volume that can be obtained as compared with other small animal models. However, further experiments are required to observe pathological changes characteristic of Chagas disease in humans. PMID- 26928843 TI - Association Between Causal Beliefs and Shoe Wearing to Prevent Podoconiosis: A Baseline Study. AB - Podoconiosis is a neglected tropical disease caused by long-term barefoot exposure to volcanic clay soil. Our previous qualitative research identified various domains of beliefs about the causes of podoconiosis held by members of the community. This cross-sectional survey, conducted in southern Ethiopia, aimed to quantitatively evaluate the prevalence of these beliefs and to assess their association with observed shoe-wearing behavior. A total of 1,800 adult respondents (600 from affected families and 1,200 from unaffected families of an index child aged between 3 and 6 years) took part in the survey. Two standardized versions of an enumerator-administered survey were created, with "all day, everyday" shoe-wearing status of the index child assessed in parallel for the affected and unaffected household respondents. Associations between measures were assessed using logistic regression. Accuracy of understanding about podoconiosis was significantly lower among respondents from unaffected than affected households (P < 0.001). Among affected respondents, beliefs about heredity were negatively associated with reported shoe wearing of the index child (odds ratio = 0.67, 95% confidence interval = 0.55-0.83). In both groups, associations of causal beliefs with shoe wearing were moderated by risk perceptions. Interventions aimed at preventing podoconiosis and improving shoe wearing should consider family-oriented education on hereditary susceptibility that targets affected and unaffected families in resource-limited settings. PMID- 26928844 TI - Influenza Virus Targets Class I MHC-Educated NK Cells for Immunoevasion. AB - The immune response to influenza virus infection comprises both innate and adaptive defenses. NK cells play an early role in the destruction of tumors and virally-infected cells. NK cells express a variety of inhibitory receptors, including those of the Ly49 family, which are functional homologs of human killer cell immunoglobulin-like receptors (KIR). Like human KIR, Ly49 receptors inhibit NK cell-mediated lysis by binding to major histocompatibility complex class I (MHC-I) molecules that are expressed on normal cells. During NK cell maturation, the interaction of NK cell inhibitory Ly49 receptors with their MHC-I ligands results in two types of NK cells: licensed ("functional"), or unlicensed ("hypofunctional"). Despite being completely dysfunctional with regard to rejecting MHC-I-deficient cells, unlicensed NK cells represent up to half of the mature NK cell pool in rodents and humans, suggesting an alternative role for these cells in host defense. Here, we demonstrate that after influenza infection, MHC-I expression on lung epithelial cells is upregulated, and mice bearing unlicensed NK cells (Ly49-deficient NKCKD and MHC-I-deficient B2m-/- mice) survive the infection better than WT mice. Importantly, transgenic expression of an inhibitory self-MHC-I-specific Ly49 receptor in NKCKD mice restores WT influenza susceptibility, confirming a direct role for Ly49. Conversely, F(ab')2 mediated blockade of self-MHC-I-specific Ly49 inhibitory receptors protects WT mice from influenza virus infection. Mechanistically, perforin-deficient NKCKD mice succumb to influenza infection rapidly, indicating that direct cytotoxicity is necessary for unlicensed NK cell-mediated protection. Our findings demonstrate that Ly49:MHC-I interactions play a critical role in influenza virus pathogenesis. We suggest a similar role may be conserved in human KIR, and their blockade may be protective in humans. PMID- 26928846 TI - Coherent phonon control via electron-lattice interaction in ferromagnetic Co/Pt multilayers. AB - The manipulation of coherent phonons in condensed systems has attracted fundamental interest, particularly for its applications to future devices. We demonstrate that a coherent phonon in Co/Pt nano-multilayer can be quantitatively controlled via electron-lattice coupling, specifically by changing the multilayer repeat number. To that end, systematic measurement of the time-resolved reflectivity and magneto-optical Kerr effect in Co/Pt multilayers was performed. The coherent phonon frequency was observed to be shifted with the change of the multilayer repeat number. This shift could be clearly explained based on the two temperature model. Detailed analysis indicated that the lattice heat capacity and electron-lattice coupling strength are linearly dependent on the repeat number of the periodic multilayer structures. Accessing the control of coherent phonons using nanostructures opens a new avenue for advanced phonon-engineering applications. PMID- 26928845 TI - Effects of testosterone replacement on metabolic and inflammatory markers in men with opioid-induced androgen deficiency. AB - OBJECTIVE: Symptomatic androgen deficiency is common in patients taking opioid analgesics, and testosterone replacement in these men improves libido, quality of life and body composition. However, the effects of testosterone replacement on metabolic and inflammatory markers in this setting have not been evaluated. This is important as opiate use itself has been associated with metabolic abnormalities. The objective of this investigation was to determine the effects of testosterone administration on metabolic and inflammatory markers in adult men with opioid-induced androgen deficiency. METHODS: Sixty-four nondiabetic men aged 18 to 64 years using opioid analgesics for chronic noncancer pain with total testosterone levels <12 nmol/l were randomized to 14 weeks of transdermal testosterone gel or placebo gel daily. Total testosterone levels were measured by liquid chromatography mass spectrometry, and free testosterone was calculated using the law-of-mass-action equation. Metabolic parameters, inflammatory markers and oral glucose tolerance test (OGTT) were evaluated at baseline and 14 weeks. RESULTS: Baseline characteristics were similar between the two groups. Testosterone concentrations increased from 7.7 +/- 3.0 to 27 +/- 19 nmol/l in the testosterone group, but did not meaningfully change in placebo group. Mean changes in metabolic and inflammatory markers during intervention did not differ significantly between groups and were not related to changes in on-treatment serum testosterone concentrations. Glucose and insulin response to the 75 g OGTT also did not differ between groups. CONCLUSION: In this 14-week trial, testosterone administration in men with opioid-induced androgen deficiency was not associated with worsening of metabolic and inflammatory markers. PMID- 26928847 TI - The "pi-Clamp" Offers a New Strategy for Site-Selective Protein Modification. AB - Pentelute and co-workers have identified a small encodable cysteine-containing peptide sequence that allows selective modification with perfluoroaryl probes. This pi-clamp requires no external catalyst and is not limited to certain positions within a protein. PMID- 26928848 TI - Radiofrequency Ablation with an Internally Cooled Electrode for Twin Reversed Arterial Perfusion Sequence. AB - OBJECTIVE: The study aims to evaluate the efficacy of radiofrequency ablation (RFA) with an internally cooled electrode for twin reversed arterial perfusion (TRAP) sequence. METHODS: From April 2008 through December 2014, we retrospectively reviewed all patients who underwent RFA with an internally cooled electrode for TRAP sequence at 3 tertiary referral centers in Japan. RESULTS: Twenty-five monochorionic diamniotic twin pregnancies underwent RFA with an internally cooled electrode for TRAP sequence at 16-27 weeks of gestation. In all cases, umbilical cord blood flow cessation in the acardiac twin was confirmed by ultrasonography with color Doppler. There were 2 cases of procedure-related complications: 1 case of unintentional septostomy and 1 case of anemia in a pump twin. Fetal demise of the pump twin occurred in 3 (12%) cases. Twenty-two (88%) of 25 pump twins were delivered alive. The median gestational age at delivery was 36 + 3 weeks (range 25 + 2-40 + 5 weeks). There were 14 cases (64%) of premature deliveries before 37 weeks and 5 (23%) before 32 weeks. CONCLUSION: RFA with an internally cooled electrode is a feasible and effective procedure for the treatment of TRAP sequence. PMID- 26928849 TI - Correction: ClassTR: Classifying Within-Host Heterogeneity Based on Tandem Repeats with Application to Mycobacterium tuberculosis Infections. PMID- 26928850 TI - Robustness of Ant Colony Optimization to Noise. AB - Recently, ant colony optimization (ACO) algorithms have proven to be efficient in uncertain environments, such as noisy or dynamically changing fitness functions. Most of these analyses have focused on combinatorial problems such as path finding. We rigorously analyze an ACO algorithm optimizing linear pseudo-Boolean functions under additive posterior noise. We study noise distributions whose tails decay exponentially fast, including the classical case of additive Gaussian noise. Without noise, the classical [Formula: see text] EA outperforms any ACO algorithm, with smaller [Formula: see text] being better; however, in the case of large noise, the [Formula: see text] EA fails, even for high values of [Formula: see text] (which are known to help against small noise). In this article, we show that ACO is able to deal with arbitrarily large noise in a graceful manner; that is, as long as the evaporation factor [Formula: see text] is small enough, dependent on the variance [Formula: see text] of the noise and the dimension n of the search space, optimization will be successful. We also briefly consider the case of prior noise and prove that ACO can also efficiently optimize linear functions under this noise model. PMID- 26928851 TI - Identifying Features of Fitness Landscapes and Relating Them to Problem Difficulty. AB - Complex combinatorial problems are most often optimised with heuristic solvers, which usually deliver acceptable results without any indication of the quality obtained. Recently, predictive diagnostic optimisation was proposed as a means of characterising the fitness landscape while optimising a combinatorial problem. The scalars produced by predictive diagnostic optimisation appear to describe the difficulty of the problem with relative reliability. In this study, we record more scalars that may be helpful in determining problem difficulty during the optimisation process and analyse these in combination with other well-known landscape descriptors by using exploratory factor analysis on four landscapes that arise from different search operators, applied to a varied set of quadratic assignment problem instances. Factors are designed to capture properties by combining the collinear variances of several variables. The extracted factors can be interpreted as the features of landscapes detected by the variables, but disappoint in their weak correlations with the result quality achieved by the optimiser, which we regard as the most reliable indicator of difficulty available. It appears that only the prediction error of predictive diagnostic optimisation has a strong correlation with the quality of the results produced, followed by a medium correlation of the fitness distance correlation of the local optima. PMID- 26928852 TI - Homoleptic gold(i) N-heterocyclic allenylidene complexes: excited-state properties and lyotropic chromonics. AB - A series of phosphorescent Au(i) bis(N-heterocyclic allenylidene) complexes, namely [Au(=C=C=CR(1)R(2))2](+)X(-), were synthesized and structurally characterized. These organometallic complexes exhibit panchromatic transient absorption upon electronic photo-excitation and can self-organize into lyotropic chromonic mesophases in aqueous solutions. PMID- 26928853 TI - Spinal extradural angiolipoma manifested after normal vaginal delivery. AB - BACKGROUND: Extradural spinal angiolipomas are extremely rare benign neoplasms made up of mature lipocytes with abnormal blood vessels. Spinal angiolipomas represent only 0.14-1.2% of all spinal axis tumours. CASE PRESENTATION: A case of thoracic spinal extradural angiolipoma producing acute spinal cord compression in a 35-year old housewife is presented. Patient presented with sudden onset of lower limbs paralysis and urinary incontinence for 1 month after vaginal delivery. Patient was diagnosed as dorsal spine angiolipoma which was treated surgically with excellent outcome. CONCLUSIONS: Spinal angiolipomas are rare tumours but it is mandatory to include it in the differential diagnosis of the spinal extradural space occupying lesions. Pregnancy and vaginal delivery may suddenly exacerbate the condition. The best investigation to choose to diagnose these lesions is definitely magnetic resonance imaging of the spine. The aim of treatment of extradural angiolipomas of the spine is to resect the tumour in Toto surgically with no need of adjuvant therapy, surgery alone can lead to excellent outcome. PMID- 26928854 TI - Implementation of Enhanced Recovery After Surgery (ERAS) Across a Provincial Healthcare System: The ERAS Alberta Colorectal Surgery Experience. AB - BACKGROUND: Enhanced recovery after surgery (ERAS) colorectal guideline implementation has occurred primarily in standalone institutions worldwide. We implemented the guideline in a single provincial healthcare system, and our study examined the effect of the guideline on patient outcomes [length of stay (LOS), complications, and 30-day post-discharge readmissions] across a healthcare system. METHODS: We compared pre- and post-guideline implementation in consecutive elective colorectal patients, >= 18 years, from six Alberta hospitals between February 2013 and December 2014. Participants were followed up to 30 days post discharge. We used summary statistics, to assess the LOS and complications, and multivariate regression methods to assess readmissions and to estimate cost impacts. RESULTS: A total of 1333 patients (350 pre- and 983 post-ERAS) were analysed. Of this number, 55 % were males. Median overall guideline compliance was 39 % in pre- and 60 % in post-ERAS patients. Median LOS was 6 days for pre ERAS compared to 4.5 days in post-ERAS patients with the longest implementation (p value <0.0001). Adjusted risk ratio (RR) was 1.71, 95 % CI 1.09-2.68 for 30 day readmission, comparing pre- to post-ERAS patients. The proportion of patients who developed at least one complication was significantly reduced, from pre- to post-ERAS, difference in proportions = 11.7 %, 95 % CI 2.5-21.0, p value: 0.0139. The net cost savings attributable to guideline implementation ranged between $2806 and $5898 USD per patient. CONCLUSION: The findings in our study have shown that ERAS colorectal guideline implementation within a healthcare system resulted in patient outcome improvements, similar to those obtained in smaller standalone implementations. There was a significant beneficial impact of ERAS on scarce health system resources. PMID- 26928855 TI - Clinicopathological Characteristics and Prognostic Factors of Patients with Siewert Type II Esophagogastric Junction Carcinoma: A Retrospective Multicenter Study. AB - BACKGROUND: The incidence of esophagogastric junction (EGJ) carcinoma is increasing, but its optimal surgical management remains controversial. METHODS: We retrospectively reviewed the database of 400 patients with Siewert type II EGJ carcinoma who were treated surgically at 7 institutions between March 1986 and October 2010. We examined the clinicopathological characteristics, prognostic factors, and risk factors associated with each recurrence pattern. RESULTS: The 5 year overall survival rate of all patients with Siewert type II EGJ carcinoma was 58.4 %. Multivariate analysis showed that T and N stages were independent prognostic factors. We also found that the incidence of lower mediastinal lymph node metastasis (17.7 %) and para-aortic lymph node metastasis (16.1 %) was relatively high. In addition, the para-aortic lymph nodes (N = 39, 9.8 %) were the most frequent node recurrence site, followed by the mediastinal lymph nodes (N = 23, 5.8 %). Lung recurrence was more common than was peritoneal recurrence. Considering each type of recurrence, multivariate analysis showed that the differentiated type was associated with a higher risk of lung recurrence than was the undifferentiated type, and N stage (pN2-3) and positive venous invasion were independent risk factors for liver recurrence. CONCLUSIONS: This study is one of the largest retrospective studies to evaluate patients with Siewert type II EGJ carcinoma. Para-aortic and mediastinal lymph node metastasis and recurrence rates were relatively high. During the postoperative follow-up of patients with differentiated Siewert type II EGJ carcinoma, patients should be monitored for lung recurrence more closely than that for peritoneal recurrence. PMID- 26928857 TI - Factors affecting finger and hand pain in workers with HAVS. AB - BACKGROUND: Pain and its management are important aspects of hand-arm vibration syndrome (HAVS). AIMS: To determine the factors associated with finger and hand pain in workers with HAVS and, specifically, to assess the impact of several neurological variables as well as the vascular component of HAVS, grip strength and age. METHODS: We assessed men with HAVS at a hospital occupational medicine clinic over 2 years. Subjects scored finger and hand pain separately using the Borg Scale (0-10). The possible predictors we evaluated included the Stockholm Neurological Scale (SNS) and Stockholm Vascular Scale (SVS) stages, current perception threshold (CPT), carpal tunnel syndrome (CTS), ulnar neuropathy, grip strength and age. We carried out nerve conduction testing to confirm the presence of CTS and ulnar neuropathy and measured CPT in the fingers at 2000 Hz, 250 Hz and 5 Hz corresponding to A-beta (large myelinated), A-delta (small myelinated) and C (unmyelinated) fibres, respectively. We calculated Spearman rank correlations to examine the relation between finger and hand pain and possible predictor variables. RESULTS: Among the 134 subjects, the median (25th-75th percentile) pain scores were 6 (4-8) for the fingers and 5 (1-7) for the hands. We found statistically significant correlations with finger pain for the SVS stage (r = 0.239; P < 0.01) and CTS (r = 0.184; P < 0.05). The only statistically significant correlation identified for hand pain was a negative correlation with grip strength (r = -0.185; P < 0.05). CONCLUSIONS: Management of finger and hand pain in HAVS should focus on the correlates we have identified. PMID- 26928856 TI - Evaluation of platelet-rich plasma and fibrin matrix to assist in healing and repair of rotator cuff injuries: a systematic review and meta-analysis. AB - OBJECTIVE: To perform a meta-analysis examining the effectiveness of platelet rich plasma and platelet-rich fibrin matrix for improving healing of rotator cuff injuries. Data sources/design: A meta-analysis of eligible studies was performed after searching Medline, Cochrane, and EMBASE on 14 December 2015. SETTING: University hospital. PARTICIPANTS: Patients with rotator cuff injuries. Review methods/intervention: Databases were searched using the keywords "PRP or platelet rich plasma," "PRFM or platelet-rich fibrin matrix," "rotator cuff," and "platelet-rich" for studies comparing outcomes of patients with rotator cuff injuries that did and did not receive a platelet-rich product. MAIN MEASURES: The primary outcome was a functional score change from pre- to post-treatment (Scorepost-Scorepre). The secondary outcome was a visual analogue scale (VAS) pain score change from pre- to post-treatment (VASpost-VASpre). RESULTS: A total of 11 studies were included in the meta-analysis. The total number of patients that received platelet-rich plasma or platelet-rich fibrin matrix was 320 and the number of control patients was 318. The standard difference in means of the functional scores was similar between patients administered platelet-rich plasma/fibrin matrix and patients in the control group (standard difference in means for functional scores = 0.029; 95% confidence interval (CI): -0.132 to 0.190; p = 0.725). The standard difference in means was similar between patients administered platelet-rich plasma and the controls (standard difference in means = 0.142; 95% CI: -0.080 to 0.364; p = 0.209). CONCLUSION: The results of this meta-analysis do not support the use of platelet-rich plasma/platelet-rich fibrin matrix in patients with rotator cuff injuries. PMID- 26928858 TI - Trends in NHS doctor and dentist referrals to occupational health. AB - BACKGROUND: Ill-health in doctors can affect performance and fitness to practice, and consequently patient care and safety, placing an important responsibility on National Health Service (NHS) occupational health (OH) services. Anecdotal discussions amongst NHS occupational physicians suggest an increase in the number of doctor attendances over time, with continuing focus on mental illness. AIMS: To analyse OH referrals in doctors and dentists over 3 years. METHODS: A retrospective evaluation of all doctor and dentist referrals to the OH service in one Scottish NHS board from April 2011 to March 2014, comparing this to management-reported sickness absence (SA) data held by the organization. RESULTS: We found no significant change in overall OH referrals for doctors and dentists during the evaluation period. Mental illness was the commonest referral reason in all 3 years at 32, 38 and 30%, respectively, but no significant change in mental health referrals was demonstrated within the study period. SA events significantly increased during the three study years (356, 426 and 469, respectively; P < 0.05). OH referrals for those absent from work increased significantly between Years 1 and 3 (16 and 30, respectively; P < 0.05). CONCLUSIONS: SA events and OH referrals for those absent from work significantly increased between April 2011 and March 2014, but there was no commensurate (statistically significant) increase in overall OH referrals. These findings do not support anecdotal suggestions of increasing OH (or mental ill-health) attendances but can be used as a benchmark for other NHS organizations and for future trend comparisons. PMID- 26928859 TI - Extraversion, neuroticism and secondary trauma in Internet child abuse investigators. AB - BACKGROUND: Working with victims and perpetrators of child sexual abuse has been shown to cause secondary traumatic stress (STS) in child protection professionals. AIMS: To examine the role of gender and personality on the development of secondary trauma responses. METHODS: A study of Internet child abuse investigators (ICAIs) from two UK police forces. Participants completed a personality test together with tests for anxiety, depression, burnout, STS and post-traumatic stress disorder to assess secondary trauma. The data were normally distributed and the results were analysed using an independent t-test, Pearson correlation and linear regression. RESULTS: Among 126 study subjects (50 females and 75 males), there was a higher incidence of STS in investigators who were female, introverted and neurotic. However, there were lower levels of STS in the participants in this study than those found in other studies. CONCLUSIONS: Psychological screening and surveillance of ICAI teams can help to identify risk factors for the development of STS and identify where additional support may be required. PMID- 26928861 TI - Water Disinfection Byproducts Induce Antibiotic Resistance-Role of Environmental Pollutants in Resistance Phenomena. AB - The spread of antibiotic resistance represents a global threat to public health, and has been traditionally attributed to extensive antibiotic uses in clinical and agricultural applications. As a result, researchers have mostly focused on clinically relevant high-level resistance enriched by antibiotics above the minimal inhibitory concentrations (MICs). Here, we report that two common water disinfection byproducts (chlorite and iodoacetic acid) had antibiotic-like effects that led to the evolution of resistant E. coli strains under both high (near MICs) and low (sub-MIC) exposure concentrations. The subinhibitory concentrations of DBPs selected strains with resistance higher than those evolved under above-MIC exposure concentrations. In addition, whole-genome analysis revealed distinct mutations in small sets of genes known to be involved in multiple drug and drug-specific resistance, as well as in genes not yet identified to play role in antibiotic resistance. The number and identities of genetic mutations were distinct for either the high versus low sub-MIC concentrations exposure scenarios. This study provides evidence and mechanistic insight into the sub-MIC selection of antibiotic resistance by antibiotic-like environmental pollutants such as disinfection byproducts in water, which may be important contributors to the spread of global antibiotic resistance. The results from this study open an intriguing and profound question on the roles of large amount and various environmental contaminants play in selecting and spreading the antibiotics resistance in the environment. PMID- 26928860 TI - Sex-specific differences in adrenocortical attunement in mothers with a history of childhood abuse and their 5-month-old boys and girls. AB - Recent evidence points to the existence of a neurobiological attunement between mother and child, e.g., associations between maternal and child hypothalamic pituitary-adrenal (HPA) axis functioning. As maternal history of abuse (HoA) has been shown to negatively affect mother-child interaction and HPA-axis functioning, we theorized those experiences to exert an influence on cortisol attunement, and we examined the role of infant gender in this context. Shortly after birth of their first child, a community sample of women was screened using the Childhood Trauma Questionnaire. Mothers reporting moderate or severe sexual and/or physical abuse were included in the maltreatment group (n = 41; MG) and compared with a non-maltreated comparison group (n = 47; CG). At the child's age of 5 months, mother and infant baseline salivary cortisol was collected on two consecutive days between 11 and 1 o'clock. Correlation analyses confirmed an association between maternal and infant salivary cortisol levels for the complete sample. However, hierarchical regression models revealed a moderating role of maternal HoA and infant gender: in the CG, cortisol attunement was only significant in mother-daughter dyads, whereas in the MG, we found cortisol levels to be associated only in mother-son dyads. Consequently, alterations of neurobiological attunement between mother and child might compose a mechanism for the transgenerational transmission of adverse childhood experiences. PMID- 26928862 TI - The influence of the biological pump on ocean chemistry: implications for long term trends in marine redox chemistry, the global carbon cycle, and marine animal ecosystems. AB - The net export of organic matter from the surface ocean and its respiration at depth create vertical gradients in nutrient and oxygen availability that play a primary role in structuring marine ecosystems. Changes in the properties of this 'biological pump' have been hypothesized to account for important shifts in marine ecosystem structure, including the Cambrian explosion. However, the influence of variation in the behavior of the biological pump on ocean biogeochemistry remains poorly quantified, preventing any detailed exploration of how changes in the biological pump over geological time may have shaped long-term shifts in ocean chemistry, biogeochemical cycling, and ecosystem structure. Here, we use a 3-dimensional Earth system model of intermediate complexity to quantitatively explore the effects of the biological pump on marine chemistry. We find that when respiration of sinking organic matter is efficient, due to slower sinking or higher respiration rates, anoxia tends to be more prevalent and to occur in shallower waters. Consequently, the Phanerozoic trend toward less bottom water anoxia in continental shelf settings can potentially be explained by a change in the spatial dynamics of nutrient cycling rather than by any change in the ocean phosphate inventory. The model results further suggest that the Phanerozoic decline in the prevalence ocean anoxia is, in part, a consequence of the evolution of larger phytoplankton, many of which produce mineralized tests. We hypothesize that the Phanerozoic trend toward greater animal abundance and metabolic demand was driven more by increased oxygen concentrations in shelf environments than by greater food (nutrient) availability. In fact, a lower-than modern ocean phosphate inventory in our closed system model is unable to account for the Paleozoic prevalence of bottom-water anoxia. Overall, these model simulations suggest that the changing spatial distribution of photosynthesis and respiration in the oceans has exerted a first-order control on Earth system evolution across Phanerozoic time. PMID- 26928863 TI - Low T3 syndrome is a strong predictor of poor outcomes in patients with community acquired pneumonia. AB - Low T3 syndrome was previously reported to be linked to poor clinical outcomes in critically ill patients. The aim of this study was to evaluate the predictive power of low T3 syndrome for clinical outcomes in patients with community acquired pneumonia (CAP). Data for 503 patients were analyzed retrospectively, and the primary end point was 30-day mortality. The intensive care unit (ICU) admission rate and 30-day mortality were 8.3% and 6.4% respectively. The prevalence of low T3 syndrome differed significantly between survivors and nonsurvivors (29.1% vs 71.9%, P < 0.001), and low T3 syndrome was associated with a remarkable increased risk of 30-day mortality and ICU admission in patients with severe CAP. Multivariate logistic regression analysis produced an odds ratio of 2.96 (95% CI 1.14-7.76, P = 0.025) for 30-day mortality in CAP patients with low T3 syndrome. Survival analysis revealed that the survival rate among CAP patients with low T3 syndrome was lower than that in the control group (P < 0.01). Adding low T3 syndrome to the PSI and CURB-65 significantly increased the areas under the ROC curves for predicting ICU admission and 30-day mortality. In conclusion, low T3 syndrome is an independent risk factor for 30-day mortality in CAP patients. PMID- 26928865 TI - Predicting Early Recurrent Stroke With the Recurrence Risk Estimator. PMID- 26928864 TI - Brachytherapy for radiotherapy-resistant head and neck cancer: A review of a single center experience. AB - OBJECTIVES/HYPOTHESIS: Despite advances in radiotherapy and chemotherapy treatments for head and neck cancers, the local failure rate is high. In most radiotherapy-resistant cases, surgery is performed; however, some cases are considered unresectable. No standard treatment for these situations has been established. In this study, we review our experience with brachytherapy (BT), which has a different biological mechanism than standard radiotherapy. METHODS: All patients received prior radiation to the recurrence area. Median high-dose radiation BT dose was 50 Gy, administered in 5 to 10 Gy fractions twice daily for 5 days. High-dose radiation was given via four to 10 catheters inserted under local anesthesia (3 patients) or general anesthesia with preventive tracheostomy (10 patients). RESULTS: Thirteen patients received BT from 2010 to 2014. Male:female ratio was 1.6:1, and median age was 66 years (range 23-89). Of those 13 patients, 10 patients were diagnosed with squamous cell carcinoma (SCC) of the oral cavity, two patients with SCC of the nasal mucosa, and one patient with eccrine duct carcinoma. Prior radiation dose ranged from 60 to 70 Gy. Local control was achieved in 11 of 13 patients; only 15.3% (2 of 13) had in-field recurrence. Five patients developed local out-of-field recurrence, and two developed distant metastases. Five patients are alive with no evidence of disease. No major toxicities were encountered. Two patients had severe mucositis and recovered within several weeks. CONCLUSION: Brachytherapy for radiotherapy resistant head and neck cancers is feasible with minor adverse events, which enables good local control. However, many advanced head and neck cancers develop regional or distant metastases; therefore, additional treatment should be suggested. LEVEL OF EVIDENCE: 4. Laryngoscope, 126:2246-2251, 2016. PMID- 26928866 TI - Parasitological, Pathological, and Immunological Parameters Associated with Schistosoma mansoni Infection and Reinfection in BALB/c AND C57BL/6 Mice. AB - Schistosome-host interaction is influenced by multiple factors, such as the type of immune response developed by the host, host genetic background, intensity, and number of infections. Those factors not only affect the development and elimination of Schistosoma mansoni , but also the pathology triggered by infection with this parasite. In the present study, we assessed the parasitological, pathological, and immunological aspects elicited by infection and reinfection in 2 different mouse strains commonly used as models in studies on schistosomiasis: BALB/c and C57BL/6. No differences in worm burden recovery or in the number of eggs per gram of intestine or feces were observed between the strains or between infected and reinfected mice from the same strain. However, the number of eggs trapped in the liver of the reinfected mice was significantly higher than the number of eggs in the liver of the infected animals. But, the granulomatous area was significantly lower in reinfected animals than in infected ones. Additionally, granuloma in the infected BALB/c mice was greater than in infected C57BL/6 animals. Regarding the cytokine profile, spleen cells from the infected/reinfected C57BL/6 mice produced higher interleukin 10 (IL-10) levels against egg antigens than BALB/c-infected/reinfected mice. BALB/c mice, in contrast, produced significantly higher IL-4 and IL-13 cytokines after infection/reinfection than the C57BL/6 mice, with the highest levels of IL-13 being observed after reinfection. Our results demonstrate that, although different host backgrounds did not impact resistance to S. mansoni , they result in different immunological profiles that suggest different pathological impacts on the liver. PMID- 26928867 TI - Central Diabetes Insipidus and Cisplatin-Induced Renal Salt Wasting Syndrome: A Challenging Combination. AB - We describe a 2-year-old female with a suprasellar primitive neuroectodermal tumor and central diabetes insipidus (DI) who developed polyuria with natriuresis and subsequent hyponatremia 36 hr after cisplatin administration. The marked urinary losses of sodium in combination with a negative sodium balance led to the diagnosis of cisplatin-induced renal salt wasting syndrome (RSWS). The subsequent clinical management is very challenging. Four weeks later she was discharged from ICU without neurological sequela. The combination of cisplatin-induced RSWS with DI can be confusing and needs careful clinical assessment as inaccurate diagnosis and management can result in increased neurological injury. PMID- 26928869 TI - A Case of Sphenoid Sinus Metastasis in Hepatocellular Carcinoma. AB - Sphenoid sinus metastasis from hepatocellular carcinoma (HCC) has been reported only rarely. We present a case of solitary sphenoid sinus metastasis of a 2.7 * 2.3 cm single HCC lesion. (Hepatology 2016;63:2050-2053). PMID- 26928868 TI - Blood flow drives lumen formation by inverse membrane blebbing during angiogenesis in vivo. AB - How vascular tubes build, maintain and adapt continuously perfused lumens to meet local metabolic needs remains poorly understood. Recent studies showed that blood flow itself plays a critical role in the remodelling of vascular networks, and suggested it is also required for the lumenization of new vascular connections. However, it is still unknown how haemodynamic forces contribute to the formation of new vascular lumens during blood vessel morphogenesis. Here we report that blood flow drives lumen expansion during sprouting angiogenesis in vivo by inducing spherical deformations of the apical membrane of endothelial cells, in a process that we have termed inverse blebbing. We show that endothelial cells react to these membrane intrusions by local and transient recruitment and contraction of actomyosin, and that this mechanism is required for single, unidirectional lumen expansion in angiogenic sprouts. Our work identifies inverse membrane blebbing as a cellular response to high external pressure. We show that in the case of blood vessels such membrane dynamics can drive local cell shape changes required for global tissue morphogenesis, shedding light on a pressure driven mechanism of lumen formation in vertebrates. PMID- 26928870 TI - Neto2 Influences on Kainate Receptor Pharmacology and Function. AB - Neuropilin tolloid-like protein 2 (Neto2) is an auxiliary subunit of kainate receptors (KARs). It specifically regulates KARs, for example slows desensitization and deactivation, increases the rate of recovery from desensitization, promotes modal gating and increases agonist sensitivity. Although the mechanism of Neto2 modulation is still unclear, gain-of-function results from the characterization of GluK1-GluA2 chimeras indicate that the GluK1 sequences included in these chimeras (part or all of the TMD and part of the linkers between the TMDs and LBD) play a key role in Neto2 modulation of KAR. In addition, GluK2 M3-S2 linkers and the D1-D1 dimer interface were also recently identified to be important for Neto2 modulation, and some studies suggested that Neto2's N-terminal regions, LDLa domain and the C-terminal regions are important for its modulation of KARs. Although more studies are needed to confirm the roles of these domains and to identify all the domains and residues essential for KAR modulation, these results facilitate our understanding of Neto2 modulation at the structural level, which could potentially aid the development of novel therapies for the treatment of diseases that are associated with KARs, for example epilepsies, non-syndromic autosomal recessive mental retardation, schizophrenia and bipolar disorder. PMID- 26928871 TI - Highly selective and sensitive fluorescence detection of Zn(2+) and Cd(2+) ions by using an acridine sensor. AB - Fluorescence spectroscopy investigations of the new acridine derivative bis(N,N dimethylaminemethylene)acridine (3) show remarkable selectivity and sensitivity towards Zn(2+) and Cd(2+) ions in methanol and for the latter even in water. Through the chelation of the metal ions the present PET effect is quenched, significantly enhancing the emission intensity of the fluorophore. In solution, the bonding situation is studied by fluorescence and NMR spectroscopy, as well as ESI-TOF mass-spectrometry measurements. The solid state environment is investigated by X-ray diffraction and computational calculations. Here, we can show the complexation of the zinc and cadmium ions by the methylene bridged amine receptors as well as by the nitrogen atom of the acridine system. PMID- 26928873 TI - Trimethylsilyl speciations of cathine, cathinone and norephedrine followed by gas chromatography mass spectrometry: Direct sample preparation and analysis of khatamines. AB - A literature criticism is given on methods using currently gas chromatography mass spectrometry (GC/MS) to determine cathine (CAT), cathinone (CTN) and norephedrine (NE), jointly khatamines. In this study, khatamines' oximation, trimethylsilylation and mass fragmentation properties-applying N-Methyl-N (trimethylsilyl)trifluoroacetamide (MSTFA), its trimethyliodosilane (TMIS) catalyst containing version (MSTFA(TMIS)), N,O bis(trimethylsilyl)trifluoroacetamide (BSTFA) and hexamethyldisilazane (HMDS)-was highlighted, at first. Derivatization, mass fragmentation and quantitation related, optimized model investigations have been carried out as a function of the reaction times and conditions. Special emphasis was put (i) on the stability of the primarily formed (CAT-2TMS, NE-2TMS, CTN-TMS(TMS-oximes)1,2), then transformed, fully derived (CAT-3TMS, NE-3MTS, CTN-2TMS(TMS-oximes)1,2) species, and, (ii) on the proportionally formed stable products, suitable to selective quantitation of all three natural amines, simultaneously. Results, as novelty to the field confirmed that (i) TMIS catalyzed trimethylsilyation triggers to form fully derivatized species unfortunately, in part only; while, (ii) khatamines' simultaneous quantitation needs to be carried out in a two steps derivatization process consisting of oximation (1st step, hydroxylamine in pyridine) and trimethylsilylation (2nd step, MSTFA), to the CAT-2TMS, NE-2TMS, CTN-TMS(TMS oximes)1,2. These species were characterized with their retention, mass fragmentation and analytical performance properties, in model solutions and in the presence of plant tissues, as well: R(2), limit of quantitation (LOQ) data, expressed in pg/1MUL injection basis, proved to be 62.5pg (CAT), 20pg (NE) and 62.5pg (CTN), respectively. The practical utility of proposal was enormously enhanced by the novel, direct sample preparation method. In this process, the freshly harvested, freeze-dried, then pulverized leaves of Catha edulis FORKS were directly derivatized, in the presence of the matrix. Reproducibility (in average 2.07 RSD% varying between 0.15 and 5.5 RSD%), linearity (0.9990-0.9994) and recovery (95.7-99.1%) values of the new sample preparation protocol was confirmed by the standard addition method for CAT, NE and CTN equally. From plant leaf, 0.061w/w% CAT and 0.014w/w% NE contents were obtained. In this tissue CTN was not found. Very likely attributable to the unfavorable climate for the plant: grown in Hungary of temperate zone and naturalized in the tropical Africa. PMID- 26928872 TI - Divergence in gene expression within and between two closely related flycatcher species. AB - Relatively little is known about the character of gene expression evolution as species diverge. It is for instance unclear if gene expression generally evolves in a clock-like manner (by stabilizing selection or neutral evolution) or if there are frequent episodes of directional selection. To gain insights into the evolutionary divergence of gene expression, we sequenced and compared the transcriptomes of multiple organs from population samples of collared (Ficedula albicollis) and pied flycatchers (F. hypoleuca), two species which diverged less than one million years ago. Ordination analysis separated samples by organ rather than by species. Organs differed in their degrees of expression variance within species and expression divergence between species. Variance was negatively correlated with expression breadth and protein interactivity, suggesting that pleiotropic constraints reduce gene expression variance within species. Variance was correlated with between-species divergence, consistent with a pattern expected from stabilizing selection and neutral evolution. Using an expression PST approach, we identified genes differentially expressed between species and found 16 genes uniquely expressed in one of the species. For one of these, DPP7, uniquely expressed in collared flycatcher, the absence of expression in pied flycatcher could be associated with a ~20-kb deletion including 11 of 13 exons. This study of a young vertebrate speciation model system expands our knowledge of how gene expression evolves as natural populations become reproductively isolated. PMID- 26928875 TI - Highly Reversible and Recyclable Absorption under Both Hydrophobic and Hydrophilic Conditions using a Reduced Bulk Graphene Oxide Material. AB - A 3D crosslinked reduced bulk graphene oxide material with switchable absorption capability between hydrophobicity and hydrophilicity is achieved by a simple O3 and annealing treatment. PMID- 26928876 TI - Prevalence and associations of central serous chorioretinopathy in elderly Chinese. The Beijing Eye Study 2011. AB - PURPOSE: To determine the prevalence and associations of central serous chorioretinopathy (CSC) in elderly Chinese. METHODS: The population-based cross sectional Beijing Eye Study 2011 included 3468 individuals (age: 64.6 +/- 9.8 years; range: 50-93 years), who underwent enhanced depth imaging of spectral domain optical coherence tomography (SD-OCT). CSC was defined as serous detachment of the retina in the macular region without signs of haemorrhages or signs of polypoidal choroidal vasculopathy, exudative age-related macular degeneration or other retinal vascular disorders, both on fundus photographs and on optical coherence tomography (OCT) images. RESULTS: Central serous chorioretinopathy was diagnosed in 10 eyes (prevalence rate: 0.15 +/- 0.05%; 95% confidence interval (CI):0.06%, 0.25%) of 10 subjects (prevalence rate: 0.31 +/- 0.10%; 95% CI: 0.12%, 0.50%). In five subjects, CSC was located foveally, and in five subjects, CSC was located extrafoveally. All subjects affected by foveal CSC were men, and three of the five individuals with extrafoveal CSC were men. In univariate analysis, subjects with CSC were significantly younger than the remaining study participants, and foveal CSC showed a significant (p = 0.02) predilection for men. After adjusting for age and gender, individuals with foveal CSC (383 +/- 112 MUm versus 270 +/- 47 MUm; p = 0.02) and the whole group of subjects with CSC had a significantly thicker subfoveal choroid. In a parallel manner, eyes contralateral to eyes with foveal CSC showed a significantly thicker subfoveal choroid than the age-adjusted control group (413 +/- 74 MUm versus 270 +/- 47 MUm; p = 0.001). CONCLUSIONS: In Chinese aged 50+ years, the prevalence of CSC was 0.14% per subject. The choroid in the CSC affected eyes and in the contralateral unaffected eyes was significantly thicker than in an age- and gender-adjusted control population-based group. PMID- 26928874 TI - Comprehensive untargeted lipidomic analysis using core-shell C30 particle column and high field orbitrap mass spectrometer. AB - The goal of untargeted lipidomics is to have high throughput, yet comprehensive and unambiguous identification and quantification of lipids. Novel stationary phases in LC separation and new mass spectrometric instruments capable of high mass resolving power and faster scanning rate are essential to achieving this goal. In this work, 4 reversed phase LC columns coupled with a high field quadrupole orbitrap mass spectrometer (Q Exactive HF) were thoroughly compared using complex lipid standard mixture and rat plasma and liver samples. A good separation of all lipids was achieved in 24min of gradient. The columns compared include C30 and C18 functionalization on either core-shell or totally porous silica particles, with size ranging from 1.7 to 2.6MUm. Accucore C30 column showed the narrowest peaks and highest theoretical plate number, and excellent peak capacity and retention time reproducibility (<1% standard deviation). As a result, it resulted in 430 lipid species identified from rat plasma and rat liver samples with highest confidence. The high resolution offered by the up-front RPLC allowed discrimination of cis/trans isomeric lipid species, and the high field orbitrap mass spectrometer afforded the clear distinction of isobaric lipid species in full scan MS and the unambiguous assignment of sn-positional isomers for lysophospholipids in MS/MS. Taken together, the high efficiency LC separation and high mass resolving MS analysis are very promising tools for untargeted lipidomics analysis. PMID- 26928877 TI - Control of Perovskite Crystal Growth by Methylammonium Lead Chloride Templating. AB - State-of-the-art solar cells based on methylammonium lead iodide (MAPbI3 ) now reach efficiencies over 20 %. This fast improvement was possible with intensive research in perovskite processing. In particular, chloride-based precursors are known to have a positive influence on the crystallization of the perovskite. Here, we used a combination of in-situ X-ray diffraction and charge-transport measurements to understand the influence of chloride during perovskite crystallization in planar heterojunction solar cells. We show that MAPbCl3 crystallizes directly after the deposition of the starting solution and acts as a template for the formation of MAPbI3 . Additionally, we show that the charge carrier mobility doubles by extending the time for the template formation. Our results give a deeper understanding of the influence of chloride in the synthesis of MAPbI3 and illustrate the importance of carefully controlling crystallization for reproducible, high-efficiency solar cells. PMID- 26928878 TI - A Variational Bayes Approach to the Analysis of Occupancy Models. AB - Detection-nondetection data are often used to investigate species range dynamics using Bayesian occupancy models which rely on the use of Markov chain Monte Carlo (MCMC) methods to sample from the posterior distribution of the parameters of the model. In this article we develop two Variational Bayes (VB) approximations to the posterior distribution of the parameters of a single-season site occupancy model which uses logistic link functions to model the probability of species occurrence at sites and of species detection probabilities. This task is accomplished through the development of iterative algorithms that do not use MCMC methods. Simulations and small practical examples demonstrate the effectiveness of the proposed technique. We specifically show that (under certain circumstances) the variational distributions can provide accurate approximations to the true posterior distributions of the parameters of the model when the number of visits per site (K) are as low as three and that the accuracy of the approximations improves as K increases. We also show that the methodology can be used to obtain the posterior distribution of the predictive distribution of the proportion of sites occupied (PAO). PMID- 26928879 TI - Severe thoracic fracture dislocation. PMID- 26928880 TI - Osteoid osteoma at the posterior element of lumbar spinal column in a young boy. PMID- 26928881 TI - Effects of ultrasonication on increased germination and improved seedling growth of aged grass seeds of tall fescue and Russian wildrye. AB - The effects of ultrasonic treatments on the germination and seedling growth of aged tall fescue (Festuca arundinacea) and Russian wild rye (Psathyrostaehys juncea Nevski) seeds were determined using orthogonal matrix experimental design with four ultrasonic factors. The multivariate analysis of variance detected significant differences and coupling effects of the pair-wise factors. The activities of Superoxide Dismutase (SOD) and Peroxidase (POD) and the Malondialdehyde (MDA) content were affected. The ultrasonic treatments had positive effects on the germination percentage (GP) of the aged seeds and the growth of the seedlings (GS) and therefore we provided a basic evidence for the application of ultrasonic treatment to pretreat aged grass seeds. For the four ultrasonic factors, the optimal conditions were a sonication time of 36.7 min, a sonication temperature of 35 degrees C, an output power of 367 W and a seed soaking time 4.1 h after binary quadratic regressions analyses. The ultrasonic treatment has the potential to improve seedling growth. Moreover, the longevity of the tall fescue and the Russian wild rye seeds was approximately 9.5 and 11.5 years, respectively, under natural conditions of storage. The physiological mechanisms that might contribute to the improved GP and GS were discussed. PMID- 26928882 TI - Hydrogel-encapsulated 3D microwell array for neuronal differentiation. AB - We developed a photo-crosslinkable hydrogel-encapsulated three-dimensional (3D) microwell array for studying embryonic stem (ES) cell-derived neuronal differentiation. ES cells were cultured for 5 d in microwells and were subsequently encapsulated by photo-crosslinkable gelatin methacrylate (GelMA) and polyethylene glycol (PEG) hydrogels for an additional 7 d. We observed that ES cells cultured in PEG microwells became uniform-sized embryoid bodies (EBs) compared to those in GelMA microwells. Although ES cells were encapsulated by photo-crosslinkable GelMA and PEG hydrogels, they were highly viable. We demonstrated that uniform-sized EBs encapsulated by GelMA hydrogels in PEG microwells are largely differentiated into neuronal cells. It was revealed that neurites at the periphery of EBs in PEG microwells largely extended into the interface between GelMA hydrogels and PEG microwells for generating neuronal networks. Therefore, this photo-crosslinkable GelMA hydrogel-encapsulated PEG microwell array could be a potentially powerful tool for neurodegenerative disease applications. PMID- 26928883 TI - Evaluation of thiol levels, thiol/disulfide homeostasis and their relation with inflammation in cardiac syndrome X. AB - OBJECTIVES: Cardiac syndrome X (CSX) is characterized by the presence of myocardial ischemia in the absence of coronary artery stenosis on angiograms. Its relation to oxidative stress and inflammation is well known. There are no data on thiols and their relation with inflammation in CSX. The aim of this study was to investigate thiol levels and thiol/disulfide homeostasis in CSX patients. MATERIALS AND METHODS: Fifty consecutive patients who had documented myocardial ischemia and normal coronary angiogram (CSX group), and 45 age-matched and sex matched consecutive patients who had normal coronary angiogram without myocardial ischemia (control group) were enrolled in this study. C-reactive protein (CRP), neutrophil/lymphocyte ratio (NLR), native thiol, total thiol, and disulfide levels were measured and disulfide/thiol ratios were calculated in all patients. RESULTS: Demographic, clinical, basic laboratory, and echocardiographic characteristics were similar in the two groups (P>0.05). Serum total thiol, native thiol, and disulfide levels decreased significantly in the CSX group compared with the control group (P<0.001). CRP and NLR increased significantly in the CSX group compared with the control group (P<0.001). Although disulfide/native thiol levels increased in the CSX group, this reduction did not reach statistical significance (5.8 vs. 5.5, P>0.05). The reduction of thiols was correlated negatively with CRP and NLR (P<0.001). Although univariate logistic regression analyses showed that serum total and native thiol levels, CRP and NLR were independent predictors for CSX estimation, stepwise multivariate logistic regression analysis showed only total thiol levels as an independent predictor for CSX (odds ratio=0.966, 95% confidence interval: 0.950-0.982, P<0.001). Also, receiver operating characteristic curve analysis showed that serum total thiol values of 338.4 or below could predict the CSX with 86% sensitivity and 84% specificity (area under curve=0.903; 95% confidence interval: 0.842-0.965). CONCLUSION: Serum total thiol levels decreased significantly in CSX and this reduction independently predicted CSX with strong sensitivity and specificity. This suggests that the reduction in thiols along with increased inflammation may play a pathophysiological role in the development of CSX. PMID- 26928885 TI - Efficacy of Some Essential Oils Against Aspergillus flavus with Special Reference to Lippia alba Oil an Inhibitor of Fungal Proliferation and Aflatoxin B1 Production in Green Gram Seeds during Storage. AB - During mycofloral analysis of green gram (Vigna radiata (L.) R. Wilczek) seed samples taken from different grocery stores by agar and standard blotter paper methods, 5 fungal species were identified, of which Aspergillus flavus exhibited higher relative frequency (75.20% to 80.60%) and was found to produce aflatoxin B1 . On screening of 11 plant essential oils against this mycotoxigenic fungi, Lippia alba essential oil was found to be most effective and showed absolute inhibition of mycelia growth at 0.28 MUL/mL. The oil of L. alba was fungistatic and fungicidal at 0.14 and 0.28 MUL/mL, respectively. Oil had broad range of fungitoxicity at its MIC value and was absolutely inhibited the AFB1 production level at 2.0 MUL/mL. Chemical analysis of this oil revealed geranial (36.9%) and neral (29.3%) as major components followed by myrcene (18.6%). Application of a dose of 80 MUL/0.25 L air of Lippia oil in the storage system significantly inhibited the fungal proliferation and aflatoxin production without affecting the seed germination rate. By the virtue of fungicidal, antiaflatoxigenic nature and potent efficacy in storage food system, L. alba oil can be commercialized as botanical fungicide for the protection of green gram seeds during storage. PMID- 26928884 TI - The Role of Medial Temporal Lobe Regions in Incidental and Intentional Retrieval of Item and Relational Information in Aging. AB - Considerable neuropsychological and neuroimaging work indicates that the medial temporal lobes are critical for both item and relational memory retrieval. However, there remain outstanding issues in the literature, namely the extent to which medial temporal lobe regions are differentially recruited during incidental and intentional retrieval of item and relational information, and the extent to which aging may affect these neural substrates. The current fMRI study sought to address these questions; participants incidentally encoded word pairs embedded in sentences and incidental item and relational retrieval were assessed through speeded reading of intact, rearranged, and new word-pair sentences, while intentional item and relational retrieval were assessed through old/new associative recognition of a separate set of intact, rearranged, and new word pairs. Results indicated that, in both younger and older adults, anterior hippocampus and perirhinal cortex indexed incidental and intentional item retrieval in the same manner. In contrast, posterior hippocampus supported incidental and intentional relational retrieval in both age groups and an adjacent cluster in posterior hippocampus was recruited during both forms of relational retrieval for older, but not younger, adults. Our findings suggest that while medial temporal lobe regions do not differentiate between incidental and intentional forms of retrieval, there are distinct roles for anterior and posterior medial temporal lobe regions during retrieval of item and relational information, respectively, and further indicate that posterior regions may, under certain conditions, be over-recruited in healthy aging. (c) 2016 Wiley Periodicals, Inc. PMID- 26928886 TI - Robust Benzo[g, h, i]perylenetriimide Dye-Sensitized Electrodes in Air-Saturated Aqueous Buffer Solution. AB - Highly electron deficient benzo[ghi]perylenetriimide (BPTI) chromophores were persistently anchored to a metal oxide electrode surface and reversible formation of their radical anions was shown in air-saturated aqueous buffer solution. Our results show a very low reaction-rate constant of BPTI(.-) with O2 (k=1.92 +/- 0.05 * 10(-2) s(-1)). BPTI is a robust chromophore that can be used as the electron acceptor in molecule-based artificial photosynthetic devices for direct water splitting in aqueous phase. PMID- 26928888 TI - Orbital ossifying fibroma: A case report. AB - CLINICAL CASE: The case concerns a 34 year-old man, who presented with pain in the medial canthus in his left eye, with proptosis and diplopia. The examination showed exophthalmus and a palpable mass at the inner canthus. The computed tomography revealed a lesion, which was confirmed by biopsy to be a ossifying fibroma. DISCUSSION: Ossifying fibroma is a benign fibro-osseous lesion that mostly affects the jaw. Clinical presentation and complications vary according to its location. Clinical examination, imaging, and histopathology are essential for definitive diagnosis. Surgical treatment is multidisciplinary and long-term follow up is needed. PMID- 26928887 TI - Family conflict and lower morning cortisol in adolescents and adults: modulation of puberty. AB - We aimed to explore the association between family conflict and HPA axis activity, especially with respect to the potential modulating effect of puberty. A total of 205 adolescents and 244 adult parents were recruited. Family conflict was assessed by the family conflict subscale of the Family Environmental Scale and serial salivary cortisol was measured in all participants. A marginally lower AUCg at 30 minutes after wake up in the morning and a significant lower AUCg at 60 minutes and 90 minutes in adult parents with high family conflict was found when compared to those with low family conflict. In adolescents, there were significant interaction effects between pubertal status and family conflict on AUCg (interaction p values <0.05). Among the adolescents with low family conflict, those at late/post pubertal status had higher AUCg than their pre/early pubertal counterparts but this difference was not observed in the adolescents with high family conflict. Adverse family environment is associated with HPA axis dysfunction in adults and late/post pubertal adolescents and pubertal maturation plays a critical role in modulating the association between family environment and HPA axis function. PMID- 26928889 TI - Keratolimbal autograft transplantation as a possible new treatment of Lisch epithelial corneal dystrophy. AB - CASE REPORT: The case concerns 64-year-old woman with visual acuity of 20/40 in the right eye. Slit-lamp examination revealed a grey, feathery corneal opacification with intraepithelial microcysts compatible with Lisch epithelial corneal dystrophy (LECD). It was treated with epithelial debridements, contact lenses and mitomycin C, but the opacification recurred within months. The removal of limbus sector and autologous limbal transplantation (KLAT) were used successfully without recurrence. CONCLUSIONS: After removal of damaged limbus, KLAT should be considered as a treatment option for asymmetric LECD when other treatments have failed. PMID- 26928890 TI - Neuropsychological Profile and Dementia Symptom Recognition in Help-Seekers in a Community Early-Detection Program in Hong Kong. AB - OBJECTIVES: To examine the neuropsychological and clinical profile of help seekers in an early-detection community dementia program and to explore any relationship between profiles and time to seek help. DESIGN: Cross-sectional. SETTING: Early-detection community dementia program. PARTICIPANTS: Help-seekers (N = 1,005) with subjective cognitive complaints or complaints from an informant. MEASUREMENTS: Neurocognitive testing, including the Cantonese Mini-Mental State Examination (MMSE), Clock Drawing Test, Digit Span, and Fuld Object Memory Evaluation and other clinical and functioning assessments, including the Clinical Dementia Rating (CDR), activities of daily living (ADLs), instrumental ADLs (IADLs), and depressive symptoms. Time since the person or an informant reported that they first noticed symptoms. RESULTS: Eighty-six percent of help-seekers had at least very mild dementia (CDR score >=0.5). Cognitive performance was moderately impaired (mean MMSE score 18.4 +/- 6.1). They required some assistance with IADLs, had very mild ADL impairments, and had few depressive symptoms. Median time to seek assessment was 12 months (interquartile range 7-30 months) according to the person or the informant (an adult child in 75% of the sample). Using the median-split method, time to seek assessment was classified as early (0 12 months) and late (>12 months). Worse cognitive and IADL performance but not ADL performance or depressive symptoms were observed in late than in early help seekers. Longer time intervals between symptom recognition and early assessment showed a trend of further impairments on all measures except ADLs. CONCLUSION: A time interval of more than 12 months between symptom recognition and early assessment appears to be associated with worse cognitive function upon presentation. PMID- 26928891 TI - Planktosalinus lacus gen. nov., sp. nov., a member of the family Flavobacteriaceae isolated from a salt lake. AB - A Gram-staining-negative bacterium, strain X14M-14T, was isolated from a salt lake (Lake Xiaochaidan) in Qaidam basin, Qinghai Province, China. Its taxonomic position was determined by using a polyphasic approach. Cells of strain X14M-14T were non-spore-forming, non-motile rods. Strain X14M-14T was strictly heterotrophic and aerobic, catalase-positive and oxidase-negative. Phylogenetic analyses based on 16S rRNA gene sequences showed that strain X14M-14T belonged to the family Flavobacteriaceae and formed a distinct lineage that was independent of the most closely related genera: Aequorivita (16S rRNA gene sequence similarities, 91.8-93.1 %) and Salinimicrobium (91.5-92.4 %). Strain X14M-14T contained MK-6 as the major respiratory quinone, and phosphatidylethanolamine and two unknown lipids as the major polar lipids. The major cellular fatty acids were iso-C15 : 0, iso-C15 : 1 G and iso-C17 : 0 3-OH. The presence of iso-C15 : 1 G as a predominant fatty acid could distinguish this strain clearly from the most closely related genera in the family Flavobacteriaceae. The DNA G+C content was 36.6 mol%. On the basis of phenotypic, chemotaxonomic and phylogenetic data, strain X14M-14T represents a novel genus and species of the family Flavobacteriaceae, for which the name Planktosalinus lacus gen. nov., sp. nov. is proposed. The type strain is X14M-14T ( = CGMCC 1.12924T = KCTC 42675T). PMID- 26928892 TI - Direct Free Energy Calculation in the Continuous Fractional Component Gibbs Ensemble. AB - A new formulation of the Gibbs ensemble (GE) combined with the continuous fractional component Monte Carlo method is presented. In the proposed formulation, only a single fractional molecule per component is used instead of two in the original formulation by Shi and Maginn ( J. Comput. Chem. 2008 , 29 , 2520 - 2530 ). This has the following advantages: (1) one directly obtains chemical potentials, without using test particles. We show analytically that the expressions for the chemical potential are identical to those in the conventional Gibbs ensemble; (2) biasing is applied to each simulation box independently; (3) maximum allowed changes in the scaling parameter of intermolecular interactions can be chosen differently in each simulation box. Obtaining chemical potentials directly facilitates thermodynamic modeling using equations of state, and it can be used as an independent check to ensure that chemical equilibrium is achieved. As a proof of principle, our method is tested for Lennard-Jones (LJ) particles and the TIP3P-Ew water model. Results are compared with the conventional GE. Excellent agreement was found both for average densities and chemical potentials. In our new approach, the acceptance probability for molecule exchanges between the boxes is much higher (typically larger than 40% for LJ particles) than for the conventional GE (typically lower than 2% for LJ particles). It is also shown that the contribution of the fractional molecule should be disregarded when computing ensemble averages such as the average energy per molecule and the average densities. The algorithm can be easily extended to mixtures and molecules with intramolecular interactions. PMID- 26928893 TI - A mechanistic study of the addition of alcohol to a five-membered ring silene via a photochemical reaction. AB - The mechanism for the photochemical rearrangement of a cyclic divinyldisilane (1 Si) in its first excited state ((1)pi -> (1)pi*) is determined using the CAS/6 311G(d) and MP2-CAS/6-311++G(3df,3pd) levels of theory. The photoproduct, a cyclic silene, reacts with various alcohols to yield a mixture of cis- and trans- adducts. The two reaction pathways are denoted as the cis- addition path (path A) and the trans-addition path (path B). These model studies demonstrate that conical intersections play a crucial role in the photo-rearrangements of cyclic divinyldisilanes. The theoretical evidence also demonstrates that the addition of alcohol to a cyclic divinyldisilane follows the reaction path: cyclic divinyldisilane -> Franck-Condon region -> conical intersection -> photoproduct (cyclic silene) -> local intermediate (with alcohol) -> transition state -> cis- or trans-adduct. The theoretical studies demonstrate that the steric effects as well as the concentrations of CH3OH must have a dominant role in determining the yields of the final adducts by stereochemistry. The same mechanism for the carbon derivative (1-C) is also considered in this work. However, the theoretical results indicate that 1-C does not undergo a methanol addition reaction via the photochemical reaction pathway, since its energy of conical intersection (S1/S0 CI-C) is more than that of its FC (FC-C). The reason for these phenomena could be that the atomic radius of carbon is much smaller than that of silicon (77 and 117 pm, respectively). As a result, the conformation for 1-C is more sterically congested than that for 1-Si, along the 1,3-silyl-migration pathway. PMID- 26928894 TI - Colchicine modulates calcium homeostasis and electrical property of HL-1 cells. AB - Colchicine is a microtubule disruptor that reduces the occurrence of atrial fibrillation (AF) after an operation or ablation. However, knowledge of the effects of colchicine on atrial myocytes is limited. The aim of this study was to determine if colchicine can regulate calcium (Ca(2+) ) homeostasis and attenuate the electrical effects of the extracellular matrix on atrial myocytes. Whole-cell clamp, confocal microscopy with fluorescence, and western blotting were used to evaluate the action potential and ionic currents of HL-1 cells treated with and without (control) colchicine (3 nM) for 24 hrs. Compared with control cells, colchicine-treated HL-1 cells had a longer action potential duration with smaller intracellular Ca(2+) transients and sarcoplasmic reticulum (SR) Ca(2+) content by 10% and 47%, respectively. Colchicine-treated HL-1 cells showed a smaller L-type Ca(2+) current, reverse mode sodium-calcium exchanger (NCX) current and transient outward potassium current than control cells, but had a similar ultra-rapid activating outward potassium current and apamin-sensitive small-conductance Ca(2+) -activated potassium current compared with control cells. Colchicine treated HL-1 cells expressed less SERCA2a, total, Thr17-phosphorylated phospholamban, Cav1.2, CaMKII, NCX, Kv1.4 and Kv1.5, but they expressed similar levels of the ryanodine receptor, Ser16-phosphorylated phospholamban and Kv4.2. Colchicine attenuated the shortening of the collagen-induced action potential duration in HL-1 cells. These findings suggest that colchicine modulates the atrial electrical activity and Ca(2+) regulation and attenuates the electrical effects of collagen, which may contribute to its anti-AF activity. PMID- 26928895 TI - Ethics of Online Assent: Comparing Strategies to Ensure Informed Assent Among Youth. AB - Individuals, including youth, often participate in online research without understanding the characteristics of studies they have agreed to be part of. We assessed the impact of including questions as part of the assent process by randomizing 568 youth to one of three groups: (a) asking youth to only read study information and then indicate their willingness to participate, (b) requiring youth to answer two questions about the study's risks and voluntary nature as part of the assent process, and (c) requiring youth to answer seven questions. Participants in the two- and seven-question groups, compared with the no-question group, were less likely to complete the assent process but, among those who did complete it, were more likely to read and understand study information. PMID- 26928896 TI - Participants and Study Decliners' Perspectives About the Risks of Participating in a Clinical Trial of Whole Genome Sequencing. AB - An increasing number of individuals are being recruited to whole genome sequencing (WGS) research. When asked hypothetically, the majority of the public express willingness to participate in this type of research, yet little is known about how many individuals will actually consent to research participation or what they perceive the risks to be. The MedSeq Project is a clinical trial exploring WGS in clinical care. We documented primary reason(s) for declining participation and reviewed audio-recorded informed consent sessions to identify participants' concerns. Of 514 individuals recruited, 173 (34%) actively declined, 205 (40%) enrolled, and the remaining 136 (26%) were ineligible, unresponsive or waitlisted. Although the majority of active decliners cited logistical barriers, 40% cited risks related to the ethical, legal, and social implications (ELSI) of WGS research. Participants similarly discussed ELSI related concerns but felt the potential benefits of participation outweighed the risks. Findings provide insight into the perspectives of potential WGS research participants and identify potential barriers to participation. PMID- 26928897 TI - Ethics Review for a Multi-Site Project Involving Tribal Nations in the Northern Plains. AB - Increasingly, Tribal Nations are forming ethics review panels, which function separately from institutional review boards (IRBs). The emergence of strong community representation coincides with a widespread effort supported by the U.S. Department of Health & Human Services and other federal agencies to establish a single IRB for all multi-site research. This article underscores the value of a tribal ethics review board and describes the tribal oversight for the Safe Passage Study-a multi-site, community-based project in the Northern Plains. Our experience demonstrates the benefits of tribal ethics review and makes a strong argument for including tribal oversight in future regulatory guidance for multi site, community-based research. PMID- 26928899 TI - Urinary tract infections, urologic surgery, and renal dysfunction in a contemporary cohort of traumatic spinal cord injured patients. AB - AIMS: The objective of this study was to measure the incidence of urinary tract infections (UTIs), urologic reconstruction/urinary diversion, and renal dysfunction after a traumatic spinal cord injury (TSCI). METHODS: Retrospective cohort study using administrative data from Ontario, Canada. All incident adult TSCI patients (2002-2013) admitted to a rehabilitation center were included. The impact of lesion level on each outcome was assessed. The rate of outcomes was further compared to an age and sex matched sample from the general population. RESULTS: A total of 2,023 incident TSCI patients were identified (median follow up of 4.8 years). Most patients (73%) were male and median age was 50 years. Lesion level included cervical (39%), thoracolumbar (44%), and unknown (17%). The incidence of serious UTIs (requiring emergency room visit or hospital admission) was 40%. Thoracolumbar lesion TSCI patients had significantly greater risk of serious UTIs (HR 1.3, 95%CI 1.1-1.7, P < 0.01) compared to those with a cervical lesion. Urologic reconstruction/urinary diversion was carried out on 2.4% of patients. New onset renal dysfunction was identified in 4.2% (84) TSCI patients. The rate ratios for serious UTIs (10.59, 95%CI 8.71-12.89), urologic reconstruction/urinary diversion (6.48, 95%CI 3.07-13.68), and renal dysfunction (2.55, 95%CI 1.70-3.83) were significantly increased among TSCI patients compared to matched controls. CONCLUSIONS: Urologic disease is still an important source of morbidity for contemporary TSCI patients, and is more common compared to the general population. Neurourol. Urodynam. 36:640-647, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 26928900 TI - A Welcomed Addition. PMID- 26928898 TI - Web-based interventions for prevention and treatment of perinatal mood disorders: a systematic review. AB - BACKGROUND: Perinatal depression is strikingly common with a prevalence of 10 15%. The adverse effects of perinatal depression on maternal and child health are profound with considerable costs. Despite this, few women seek medical attention. E-health, providing healthcare via the Internet is an accessible and effective solution for the treatment of depression in the general population. We aimed to conduct a systematic review of web-based interventions for the prevention and treatment of mood disorders in the perinatal period, defined as the start of pregnancy to 1 year post-partum. METHODS: Six databases were searched until 26(th) March 2015. Two researchers independently screened articles for eligibility. Of the 547 screened articles, four met the inclusion criteria. These included three randomised-controlled trials and one feasibility trial, with total data from 1274 participants. MOOSE and PRISMA guidelines were adhered to for the conduct and reporting of the systematic review. RESULTS: All studies were conducted in the post-partum period. All reported an improvement in maternal mood following intervention. A significant improvement in depressive symptoms was measured using validated rating scales, such as the Edinburgh Postnatal Depression Scale (EPDS), either at post-treatment or follow-up which ranged from 3 to 12 months post study completion. For the two RCTs utilising the EPDS, the EPDS score reductions were (mean +/- SEM) 8.52 +/- 0.22 (Range 19.46 to10.94) and 9.19 +/- 0.63 (Range, 20.24 to 11.05) for treatment groups and 5.16 +/- 0.25 (Range 19.44 to 14.28) and 6.81 +/- 0.71 (Range 21.07 to 14.26) for comparator groups. However attrition within studies ranged from 13 to 61%. One study was rated as 'good' quality. CONCLUSIONS: Preliminary data suggests web-based therapies for perinatal depression delivered in the post-partum period may play a role in improving maternalmood but more studies are needed, particularly with interventions delivered antenatally. Further research is needed to address the limitations of the existing evidence base. PMID- 26928901 TI - Cytotoxic cell involvement in human cutaneous leishmaniasis: assessments in active disease, under therapy and after clinical cure. AB - Cutaneous leishmaniasis (CL) is an important public health issue worldwide. The control of Leishmania infection depends on cellular immune mechanisms, and the inflammatory response may contribute to pathogenesis. A beneficial role of CD8(+) T lymphocytes has been proposed; nevertheless, other studies suggest a cytotoxic role of CD8(+) T lymphocytes involved in tissue damage, showing controversial role of these cells. The goal of the current study was to understand the immunopathology of CL and determine the profile of cytotoxic cells--such as CD4(+) T, natural killer and natural killer T cells--that might be involved in triggering immunological mechanisms, and may lead to cure or disease progression. The frequencies of cytotoxic cell populations in peripheral blood, obtained from patients with active disease, during treatment and after clinical healing, were assessed by flow cytometry. Cytotoxicity could not be related to a deleterious role in Leishmania braziliensis infection, as patients with active CL showed similar percentages of degranulation to healthy individuals (HI). Cured patients exhibited a lower percentage of degranulating cells, which may be due to a downregulation of the immune response. The understanding of the immunopathological mechanisms involved in CL and the commitment of cytotoxic cells enables improvements in therapeutic strategies. PMID- 26928902 TI - Tail-like anther crest aids pollination by manipulating pollinator's behaviour in a wild ginger. AB - Innovative floral organs are widely distributed taxonomically in angiosperms, and some of them are conspicuous and curious in morphology. Floral organs have long been supposed to play a crucial role in fertilization by pollinators. However, why innovative organs occur, how they are adapted for pollinators and what sexual roles they play are still puzzling. Here we focused on a wild ginger (Zingiber densissimum, Zingiberaceae) and tested the function of the curious anther crest, an innovative floral structure widely distributed in Zingiberaceae. The anther crest is a specialized anther appendage that extends up from the top of the anther to form a tail-like structure, about 150% as long as the anther. We found this structure promoted both the male and the female functions of plants by manipulating its pollinators and causing pollinators to adopt a position ideal for pollen removal and receipt. This study provides a novel example of structure adaptation in which both the male and the female functions are enhanced by resource allocation on a male organ, expanding the knowledge of the sexual roles of the anther appendage. PMID- 26928903 TI - Single amino acid insertions in extracellular loop 2 of Bombyx mori ABCC2 disrupt its receptor function for Bacillus thuringiensis Cry1Ab and Cry1Ac but not Cry1Aa toxins. AB - In a previous report, seven Cry1Ab-resistant strains were identified in the silkworm, Bombyx mori; these strains were shown to have a tyrosine insertion at position 234 in extracellular loop 2 of the ABC transporter C2 (BmABCC2). This insertion was confirmed to destroy the receptor function of BmABCC2 and confer the strains resistance against Cry1Ab and Cry1Ac. However, these strains were susceptible to Cry1Aa. In this report, we examined the mechanisms of the loss of receptor function of the transporter by expressing mutations in Sf9 cells. After replacement of one or two of the five amino acid residues in loop 2 of the susceptible BmABCC2 gene [BmABCC2_S] with alanine, cells still showed susceptibility, retaining the receptor function. Five mutants with single amino acid insertions at position 234 in BmABCC2 were also generated, resulting in loop 2 having six amino acids, which corresponds to replacing the tyrosine insertion in the resistant BmABCC2 gene [BmABCC2_R(+(234)Y)] with another amino acid. All five mutants exhibited loss of function against Cry1Ab and Cry1Ac. These results suggest that the amino acid sequence in loop 2 is less important than the loop size (five vs. six amino acids) or loop structure for Cry1Ab and Cry1Ac activity. Several domain-swapped mutant toxins were then generated among Cry1Aa, Cry1Ab, and Cry1Ac, which are composed of three domains. Swapped mutants containing domain II of Cry1Ab or Cry1Ac did not kill Sf9 cells expressing BmABCC2_R(+(234)Y), suggesting that domain II of the Cry toxin is related to the interaction with the receptor function of BmABCC2. This also suggests that different reactions against Bt-toxins in some B. mori strains, that is, Cry1Ab resistance or Cry1Aa susceptibility, are attributable to structural differences in domain II of Cry1A toxins. PMID- 26928904 TI - Research protocol: effect of natural S-equol on blood pressure and vascular function--a six-month randomized controlled trial among equol non-producers of postmenopausal women with prehypertension or untreated stage 1 hypertension. AB - BACKGROUND: Although higher habitual soy intake is associated with lower blood pressure (BP) and stroke incidence, clinical trials using soy protein or isoflavones on cardiovascular risks yielded inconsistent results. The discrepancies are hypothesized to be due to the individuals' intestinal bacterial capacity to metabolite isoflavones daidzein into equol. Animal and in vitro studies have revealed that equol has stronger estrogen-like and anti-oxidative activity than isoflavones and possesses natriuretic and vasorelaxant properties which may play an important role in the prevention of hypertension. However, no clinical trial has examined the effect of equol on BP. We thus propose a 24-week randomized controlled trial to test the effectiveness of natural S-equol on BP and vascular function among equol non-producers. METHODS/DESIGN: This will be a 6 month double-blind, randomized, placebo-controlled trial among 207 non-equol producing postmenopausal women with prehypertension or early untreated hypertension. Eligible participants who have completed a 2-week run-in will be randomized to either one of the 3 groups: placebo group, low-equol group (10 mg/d) and high equol group (20 mg/d). The outcome measures will be conducted at baseline and at the end of the trial including 24 h ambulatory BP, endothelial function (by ultrasound determined brachial flow mediated dilation), arterial stiffness (by pulse wave analysis) and other cardiovascular risk factors (lipid profile, glycemic control and inflammatory biomarkers). Urinary isoflavones will be tested for compliance assessment. One way analysis of variance will be applied to compare the 6-month changes in ambulatory BP or parameters of vascular function among the 3 treatment groups. DISCUSSION: This study will be performed in community subjects. If the antihypertensive effect of equol is proven, the provision of natural equol to those high risk adults who are unable to produce equol will have enormous public health implications for the primary and secondary prevention of hypertension and cardiovascular diseases on a population basis. The research efforts will also have significant implications for industry in the provision of suitable soy products for the prevention of hypertension and its related complications. TRIAL REGISTRATION: The trial was registered in ClinicalTrials.gov with identifier of NCT02515682 . PMID- 26928906 TI - Electrolyte-Gated Graphene Ambipolar Frequency Multipliers for Biochemical Sensing. AB - In this Letter, the ambipolar properties of an electrolyte-gated graphene field effect transistor (GFET) have been explored to fabricate frequency-doubling biochemical sensor devices. By biasing the ambipolar GFETs in a common-source configuration, an input sinusoidal voltage at frequency f applied to the electrolyte gate can be rectified to a sinusoidal wave at frequency 2f at the drain electrode. The extraordinary high carrier mobility of graphene and the strong electrolyte gate coupling provide the graphene ambipolar frequency doubler an unprecedented unity gain, as well as a detection limit of ~4 pM for 11-mer single strand DNA molecules in 1 mM PBS buffer solution. Combined with an improved drift characteristics and an enhanced low-frequency 1/f noise performance by sampling at doubled frequency, this good detection limit suggests the graphene ambipolar frequency doubler a highly promising biochemical sensing platform. PMID- 26928907 TI - Thermal Expansion and Second Harmonic Generation Response of the Tungsten Bronze Pb2AgNb5O15. AB - The incorporation of transition metal element Ag was performed to explore negative thermal expansion (NTE) materials with tetragonal tungsten bronze (TTB) structures. In this study, the structure and thermal expansion behaviors of a polar TTB oxide, Pb2AgNb5O15 (PAN), were systematically investigated by high resolution synchrotron powder diffraction, high-resolution neutron powder diffraction, transmission electron microscope (TEM), and high-temperature X-ray diffractions. The TEM and Rietveld refinements revealed that the compound PAN displays (?2a(TTB), ?2b(TTB), 2c(TTB))-type superstructure. This superstructure within the a-b plane is caused by the ordering of A-site cations, while the doubling of the c axis is mainly induced by a slight tilt distortion of the NbO6 octahedra. The transition metal Ag has larger spontaneous polarization displacements than Pb, but the Pb-O covalence seems to be weakened compared to the potassium counterpart Pb2KNb5O15 (PKN), which may account for the similar Curie temperature and uniaxial NTE behavior for PAN and PKN. Powder second harmonic generation (SHG) measurement indicates that PAN displays a moderate SHG response of ~0.2 * LiNbO3 (or ~100 * alpha-SiO2) under 1064 nm laser radiation. The magnitudes of the local dipole moments in NbO6 and PbOx polyhedra were quantified using bond-valence approach. We show that the SHG response stems from the superposition of dipole moments of both the PbO(x) and NbO6 polyhedra. PMID- 26928905 TI - Genetic alterations in salivary gland cancers. AB - Salivary gland cancers are an incredibly heterogeneous group of tumors that include 24 histologically distinct tumor types. The use of new genetic methods has paved the way for promising advancements in our understanding of the molecular biology underlying each type of tumor. The objective of this review was to highlight common oncogenes, tumor suppressor genes, and cytogenetic and epigenetic changes associated with the most common tumor types: mucoepidermoid carcinoma, adenoid cystic carcinoma, salivary duct carcinoma, mammary analogue secretory carcinoma, hyalinizing clear cell carcinoma, carcinoma ex pleomorphic adenoma, and acinic cell carcinoma. Recent insights into the pathogenesis of each cancer subtype have helped better define and classify these tumors. Further research in salivary gland cancers should focus on determining the key genes involved in the tumorigenesis of each distinct malignancy and identifying individualized chemotherapies directed at these targets. Cancer 2016;122:1822-31. (c) 2016 American Cancer Society. PMID- 26928908 TI - Transcranial Non-Invasive Brain Stimulation in Parkinson's Disease Patients with Dyskinesias. Where is the Optimal Target? PMID- 26928909 TI - Asymmetric-Indenothiophene-Based Copolymers for Bulk Heterojunction Solar Cells with 9.14% Efficiency. AB - The first two asymmetric-indenothiophene-based donor-acceptor copolymers (PITBT and PITFBT) are prepared through Stille coupling reactions between distannyl indenothiophene and brominated benzothiadiazole derivatives. The best performing solar cell fabricated from PITFBT exhibits a power conversion efficiency of 9.14% which demonstrates a great potential of the asymmetric indenothiophene for high performance copolymers. PMID- 26928910 TI - Development and validation of the nasopharyngeal cancer scale among the system of quality of life instruments for cancer patients (QLICP-NA V2.0): combined classical test theory and generalizability theory. AB - OBJECTIVES: This research was designed to develop a nasopharyngeal cancer (NPC) scale based on quality of life (QOL) instruments for cancer patients (QLICP-NA). This scale was developed by using a modular approach and was evaluated by classical test and generalizability theories. METHODS: Programmed decision procedures and theories on instrument development were applied to create QLICP-NA V2.0. A total of 121 NPC inpatients were assessed using QLICP-NA V2.0 to measure their QOL data from hospital admission until discharge. Scale validity, reliability, and responsiveness were evaluated by correlation, factor, parallel, multi-trait scaling, and t test analyses, as well as by generalizability (G) and decision (D) studies of the generalizability theory. RESULTS: Results of multi trait scaling, correlation, factor, and parallel analyses indicated that QLICP-NA V2.0 exhibited good construct validity. The significant difference of QOL between the treated and untreated NPC patients indicated a good clinical validity of the questionnaire. The internal consistency (alpha) and test-retest reliability coefficients (intra-class correlations) of each domain, as well as the overall scale, were all >0.70. Ceiling effects were not found in all domains and most facets, except for common side effects (24.8 %) in the domain of common symptoms and side effects, tumor early symptoms (27.3 %) and therapeutic side effects (23.2 %) in specific domain, whereas floor effects did not exist in each domain/facet. The overall changes in the physical and social domains were significantly different between pre- and post-treatments with a moderate effective size (standard response mean) ranging from 0.21 to 0.27 (p < 0.05), but these changes were not obvious in the other domains, as well as in the overall scale. Scale reliability was further confirmed by G coefficients and index of dependability, with more exact variance components based on generalizability theory. CONCLUSIONS: QLICP-NA V2.0 exhibited reasonable degrees of validity, reliability, and responsiveness. However, this scale must be further improved before it can be used as a practical instrument to evaluate the QOL of NPC patients in China. PMID- 26928912 TI - Diagnosis and Management of Diabetes: Synopsis of the 2016 American Diabetes Association Standards of Medical Care in Diabetes. AB - DESCRIPTION: The American Diabetes Association (ADA) published the 2016 Standards of Medical Care in Diabetes (Standards) to provide clinicians, patients, researchers, payers, and other interested parties with the components of diabetes care, general treatment goals, and tools to evaluate the quality of care. METHODS: The ADA Professional Practice Committee performed a systematic search on MEDLINE to revise or clarify recommendations based on new evidence. The committee assigns the recommendations a rating of A, B, or C, depending on the quality of evidence. The E rating for expert opinion is assigned to recommendations based on expert consensus or clinical experience. The Standards were reviewed and approved by the Executive Committee of the ADA Board of Directors, which includes health care professionals, scientists, and laypersons. Feedback from the larger clinical community was incorporated into the 2016 revision. RECOMMENDATIONS: The synopsis focuses on 8 key areas that are important to primary care providers. The recommendations highlight individualized care to manage the disease, prevent or delay complications, and improve outcomes. PMID- 26928911 TI - Xenotransplantation elicits salient tumorigenicity of adult T-cell leukemia derived cells via aberrant AKT activation. AB - The transplantation of human cancer cells into immunodeficient NOD/SCID/IL 2Rgammac(null) (NOG) mice often causes highly malignant cell populations like cancer stem cells to emerge. Here, by serial transplantation in NOG mice, we established two highly tumorigenic adult T-cell leukemia-derived cell lines, ST1 N6 and TL-Om1-N8. When transplanted s.c., these cells formed tumors significantly earlier and from fewer initial cells than their parental lines ST1 and TL-Om1. We found that protein kinase B (AKT) signaling was upregulated in ST1-N6 and TL-Om1 N8 cells, and that this upregulation was due to the decreased expression of a negative regulator, INPP5D. Furthermore, the introduction of a constitutively active AKT mutant expression vector into ST1 cells augmented the tumorigenicity of the cells, whereas treatment with the AKT inhibitor MK-2206 attenuated the progression of tumors induced by ST1-N6 cells. Collectively, our results reveal that the AKT signaling pathway plays a critical role in the malignancy of adult T cell leukemia-derived cells. PMID- 26928914 TI - Cardioprotective Properties of Aerobic and Resistance Training Against Myocardial Infarction. AB - We evaluated the effects of aerobic and resistance exercise training on ventricular morphometry and function, physical capacity, autonomic function, as well as on ventricular inflammatory status in trained rats prior to myocardial infarction. Male Wistar rats were divided into the following groups: sedentary+Sham, sedentary+myocardial infarction, aerobic trained+myocardial infarction, and resistance trained+myocardial infarction. Sham and myocardial infarction were performed after training periods. In the days following the surgeries, evaluations were performed. Aerobic training prevents aerobic (to a greater extent) and resistance capacity impairments, ventricular dysfunction, baroreflex sensitivity and autonomic disorders (vagal tonus decrease and sympathetic tonus increase) triggered by myocardial infarction. Resistance training was able to prevent negative changes to aerobic and resistance capacity (to a greater extent) but not to ventricular dysfunction, and it prevented cardiovascular sympathetic increments. Additionally, both types of training reduced left ventricle inflammatory cytokine concentration. Our results suggest that aerobic and, for the first time, dynamic resistance training were able to reduce sympathetic tonus to the heart and vessels, as well as preventing the increase in pro-inflammatory cytokine concentrations in the left ventricle of trained groups. These data emphasizes the positive effects of aerobic and dynamic resistance training on the prevention of the negative changes triggered by myocardial infarction. PMID- 26928913 TI - Actinorhizal Alder Phytostabilization Alters Microbial Community Dynamics in Gold Mine Waste Rock from Northern Quebec: A Greenhouse Study. AB - Phytotechnologies are rapidly replacing conventional ex-situ remediation techniques as they have the added benefit of restoring aesthetic value, important in the reclamation of mine sites. Alders are pioneer species that can tolerate and proliferate in nutrient-poor, contaminated environments, largely due to symbiotic root associations with the N2-fixing bacteria, Frankia and ectomycorrhizal (ECM) fungi. In this study, we investigated the growth of two Frankia-inoculated (actinorhizal) alder species, A. crispa and A. glutinosa, in gold mine waste rock from northern Quebec. Alder species had similar survival rates and positively impacted soil quality and physico-chemical properties in similar ways, restoring soil pH to neutrality and reducing extractable metals up to two-fold, while not hyperaccumulating them into above-ground plant biomass. A. glutinosa outperformed A. crispa in terms of growth, as estimated by the seedling volume index (SVI), and root length. Pyrosequencing of the bacterial 16S rRNA gene for bacteria and the ribosomal internal transcribed spacer (ITS) region for fungi provided a comprehensive, direct characterization of microbial communities in gold mine waste rock and fine tailings. Plant- and treatment-specific shifts in soil microbial community compositions were observed in planted mine residues. Shannon diversity and the abundance of microbes involved in key ecosystem processes such as contaminant degradation (Sphingomonas, Sphingobium and Pseudomonas), metal sequestration (Brevundimonas and Caulobacter) and N2-fixation (Azotobacter, Mesorhizobium, Rhizobium and Pseudomonas) increased over time, i.e., as plants established in mine waste rock. Acetate mineralization and most probable number (MPN) assays showed that revegetation positively stimulated both bulk and rhizosphere communities, increasing microbial density (biomass increase of 2 orders of magnitude) and mineralization (five-fold). Genomic techniques proved useful in investigating tripartite (plant-bacteria-fungi) interactions during phytostabilization, contributing to our knowledge in this field of study. PMID- 26928915 TI - Reliability of Trunk Muscle Electromyography in the Loaded Back Squat Exercise. AB - Trunk muscle activation (TMA) has been reported during back squat exercise, however reliability and sensitivity to different loads alongside kinematic measures has not. Hence the aim was to determine the interday reliability and load sensitivity of TMA and kinematics during back squats. 10 males performed 3 test sessions: 1) back squat 1RM, 2) and 3) 3 reps at 65, 75, 85 and 95% of system mass max (SMmax). Kinematics were measured from an electrogoniometer and linear transducer, and surface electromyography (sEMG) recorded 4 muscles of the trunk: rectus abdominis (RA), external oblique (EO), upper lumbar erector spinae (ULES) and lumbar sacral erector spinae (LSES), and a reference leg muscle, the vastus lateralus (VL). sEMG amplitude was root mean squared (RMS). No differences (p>0.05) found between tests for any kinematic and RMS data. CV demonstrated moderate interday reliability (~16.1%) for EO, LSES and ULES but not RA (29.4%) during the velocity-controlled eccentric phase; whereas it was moderately acceptable for just LSES and ULES (~17.8%) but not RA and EO (27.9%) during the uncontrolled concentric phase. This study demonstrated acceptable interday reliability for kinematic data while sEMG for most trunk muscle sites was moderately acceptable during controlled contraction. sEMG responded significantly to load. PMID- 26928916 TI - Within-day and between-day Reproducibility of Baroreflex Sensitivity in Healthy Adult Males. AB - Within-day and between-day reproducibility of supine and tilt baroreflex sensitivity were investigated utilising sequence and spectral indices in 46 healthy adult males employing 3 repeat measures; baseline, +60 min and +24 h. Reproducibility was assessed via the 95% limits of agreement and by the technical error of the measurement. For spectral parameters, the limits of agreement indicated same day was marginally better than between-day reproducibility. For sequence parameters, between-day had marginally better agreement than same-day reproducibility. Tilt markedly improved reproducibility across all outcome measures. Precision expressed by the technical error of the measurement for all spectral outcomes was good in both supine and tilt baroreflex sensitivity (<6%). Precision was lower, but acceptable, for sequence baroreflex sensitivity outcomes in both positions (<11%). Baroreflex sensitivity transfer gain provided the best agreement and reproducibility during supine and tilt conditions. These findings suggest time and spectral techniques may be employed to assess within-day and between-day baroreflex sensitivity changes in healthy individuals. The inclusion of a tilt manoeuvre may improve the reproducibility of the outcome measure, which may aid in the detection of modest baroreflex sensitivity changes in studies employing limited sample sizes. PMID- 26928917 TI - Life-Long Wheel Running Attenuates Age-Related Fiber Loss in the Plantaris Muscle of Mice: a Pilot Study. AB - The purpose of this study was to investigate whether long-term wheel running would attenuate age-related loss of muscle fiber. Male ICR mice were divided into young (Y, n=12, aged 3 months), old-sedentary (OS, n=5, aged 24 months), and old exercise (OE, n=6, aged 24 months) groups. The OE group started spontaneous wheel running at 3 months and continued until 24 months of age. Soleus and plantaris muscles were fixed in 4% paraformaldehyde buffer. The fixed muscle was digested in a 50% NaOH solution to isolate single fiber and then fiber number was quantified. The masses of the soleus and plantaris muscles were significantly lower at 24 months than at 3 months of age, and this age-related difference was attenuated by wheel running (P<0.05). Soleus muscle fiber number did not differ among the groups. In the plantaris muscle, the fiber number in the OS group (1 288+/-92 fibers) was significantly lower than in the Y group (1 874+/-93 fibers), and this decrease was attenuated in the OE group (1 591+/-80 fibers) (P<0.05). These results suggest that age-related fiber loss occurs only in the fast-twitch fiber-rich muscle of mice, and that life-long wheel running exercise can prevent this fiber loss. PMID- 26928918 TI - Lessons learned from transfusion audits. AB - BACKGROUND: In times of patient blood management, studies focus on appropriate transfusion strategies to improve patient's outcome. Little is known about the quality assurance in preparation of blood transfusion and thereafter. In the present study, the indication, informed consent, mandatory immunohematology tests and documentation of blood transfusions were evaluated using assessed self inspection forms approved by the hospital transfusion committee. MATERIALS AND METHODS: 47 medical records of transfused patients were retrospectively reviewed by a clinical transfusion audit team in six hospital facilities from 2012 to 2015. Self-inspection forms were used to classify the physicians' documentation of transfusion into 3 groups: adequately, intermediately, and inadequately documented. RESULTS: Adequate documented records were only found in 5 cases (10.6%), followed by intermediate (51.1%) and inadequate documentation (38.3%). Informed consent was identified most often as inappropriate, and this was a critical point with respect to medico legal aspects. CONCLUSION: Continuous education of physicians defining parameters to be documented is almost essential in daily transfusion medicine routine. The use of a check list with physician's documentation of transfusion is strongly recommended. PMID- 26928919 TI - A strategical re-thinking on National Blood Donor Pool: Anti-HBc positivity related re-entry mechanisms. AB - BACKGROUND AND OBJECTIVES: Screening of blood donations for antibodies against hepatitis B core antigen (anti-HBc) is used to prevent transfusion transmitted hepatitis B virus (HBV) infection. In this study, we studied the magnitude of blood donor gain by using a re-entry mechanism in our Blood Bank of Gulhane Military Academy of Medicine. MATERIALS AND METHODS: Between January and May 2013, 5148 voluntary blood donors were screened by ELISA method for HBsAg, anti HBc total and other screening markers, prospectively. Samples with repeated reactivity for the presence of anti-HBc were further tested with four supplemental assays. RESULTS: We detected 515 (10%) anti-HBc positive and 4612 (90%) anti-HBc negative cases in 5127 HBsAg negative serum samples. A total of 461 (89.5%) blood units were reactive for at least one additional serologic parameter and 54 were (10.5%) negative. Isolated anti-HBc positivity rate was 1.3% (69/5127). In the isolated anti-HBc positive samples, 54 were also anti-HBe and HBeAg negative. HBV DNA was not detected in any of the samples. CONCLUSION: Applying the EDQM criteria would decrease our blood donor loss from 10% to 5.4%. As alternative re-entry mechanisms have already been presented in the literature, institution of a new policy is needed to enhance the limited blood donor pool in our system. PMID- 26928920 TI - Cross-talk on quality/safety of blood derived serum eye drops. PMID- 26928921 TI - Micro solid oxide fuel cell fabricated on porous stainless steel: a new strategy for enhanced thermal cycling ability. AB - Miniaturized solid oxide fuel cells (micro-SOFCs) are being extensively studied as a promising alternative to Li batteries for next generation portable power. A new micro-SOFC is designed and fabricated which shows enhanced thermal robustness by employing oxide-based thin-film electrode and porous stainless steel (STS) substrate. To deposit gas-tight thin-film electrolyte on STS, nano-porous composite oxide is proposed and applied as a new contact layer on STS. The micro SOFC fabricated on composite oxide- STS dual layer substrate shows the peak power density of 560 mW cm(-2) at 550 degrees C and maintains this power density during rapid thermal cycles. This cell may be suitable for portable electronic device that requires high power-density and fast thermal cycling. PMID- 26928922 TI - Optometry Australia - Guidelines on the examination and management of patients with diabetes. PMID- 26928924 TI - Correction: Structural Based Analyses of the JC Virus T-Antigen F258L Mutant Provides Evidence for DNA Dependent Conformational Changes in the C-Termini of Polyomavirus Origin Binding Domains. PMID- 26928923 TI - Mutations in the MTHFR gene are not associated with Methotrexate intolerance in patients with juvenile idiopathic arthritis. AB - BACKGROUND: Methotrexate (MTX) intolerance is a frequent problem of long-term treatment in juvenile idiopathic arthritis (JIA). Mutations in the methylentetrahydrofolate reductase (MTHFR) gene may increase toxicity of MTX, potentially constituting an initial stimulus for this conditioned response. The objective of this study was to investigate the relationship of common MTHFR gene mutations and occurrence of MTX intolerance in pediatric patients with JIA treated with MTX. METHODS: Consecutive JIA patients on at least 3 months of MTX treatment were included in this study. Intolerance to MTX was determined using the Methotrexate Intolerance Severity Score (MISS) questionnaire, and MTX intolerance was defined as MISS values of >= 6. Presence of the two most common mutations in the MTHFR gene (C677T and A1298C) was tested using a PCR assay. Results were analyzed using descriptive and non-parametric statistics. RESULTS: 196 patients were included (73 % female). Of those, 93 (46 %) showed MTX intolerance. 168 patients were genotyped for C677T and A1298C. MTX intolerance was not found to be significantly more frequent among patients with hetero- and homozygous or homozygous mutations C677T or A1298C compared to wild type or heterozygous mutations. Analysis of the correlation between numbers of mutations in these two loci to the MISS score did not yield a statistically significant correlation. CONCLUSION: Mutations in the MTHFR gene were not found to be significantly more frequent in JIA patients intolerant to MTX. Toxicity associated with the MTHFR gene seems to result from mechanisms different to those involved in clinical MTX intolerance. PMID- 26928925 TI - Spectroscopic Monitoring of Mechanical Forces during Protein Folding by using Molecular Force Probes. AB - Detailed folding pathways of proteins are still largely unknown. Real-time monitoring of mechanical forces acting in proteins during structural transitions would provide deep insights into these highly complex processes. Here, we propose two molecular force probes that can be incorporated into the protein backbone to gain insight into the magnitude and direction of mechanical forces acting in proteins during natural folding and unfolding through their optical spectroscopic response. In fact, changes in the infrared and Raman spectra are proportional to the mechanical force deforming the force probes, and the relevant bands can be intensified and shifted to a transparent window in the protein spectrum by isotopic substitution. As a result, the proposed molecular force probes can act as "force rulers", allowing the spectroscopic observation and measurement of mechanical forces acting within the proteins under natural conditions without external perturbation. PMID- 26928926 TI - Ultrasound Features and Management of Body Stalk Anomaly. AB - OBJECTIVES: This study describes the prenatal diagnosis of body stalk anomaly (BSA) in a large series of affected pregnancies and proposes an algorithm for the differential diagnosis of abdominal wall defects in the first trimester. METHODS: This was a retrospective study of all the cases of BSA diagnosed in our tertiary unit between 2009 and 2015. In all cases, we performed a detailed ultrasound examination with particular emphasis on the appearance of the amniotic membrane and content of the amniotic sac and the coelomic cavity. RESULTS: The study included 17 cases of BSA (15 singleton pregnancies, one dichorionic-diamniotic twin pregnancy discordant for BSA and one case of conjoined twins) at a median gestational age of 12+3 (range 11+0 to 16+6) weeks. In all cases, the liver and bowel were herniated into the coelomic cavity and the amniotic sac was intact containing the rest of the fetus with a normal amount of amniotic fluid; additionally, there was severe kyphoscoliosis and positional abnormalities of the lower limbs. The umbilical cord was absent, but umbilical vessels were seen with color Doppler running from the placenta to the fetus marginally to the eviscerated abdominal content. CONCLUSION: BSA can be easily diagnosed from 11 weeks' gestation. Examination of the amniotic membrane continuity, content of both the amniotic sac and coelomic cavity and a short umbilical cord help in differentiating this condition from other abdominal wall defects. PMID- 26928928 TI - Prenatal Diagnosis of Berry Syndrome by Fetal Echocardiography. PMID- 26928927 TI - Treatment adherence and virological response rates in hepatitis C virus infected persons treated with sofosbuvir-based regimens: results from ERCHIVES. AB - BACKGROUND & AIMS: Role of non-adherence upon virological success with newer oral regimens is unknown. We sought to determine the impact of treatment adherence upon virological outcomes in hepatitis C virus (HCV) infected persons on sofosbuvir (SOF)-based regimens, using pharmacy prescription data as a measure of adherence. METHODS: We analysed HCV infected persons in Electronically Retrieved Cohort of HCV Infected Veterans, who were initiated on SOF-based regimens, excluding those with human immunodeficiency virus, positive hepatitis-B surface antigen, hepatocellular carcinoma and missing HCV RNA. RESULTS: The final dataset included following regimens: SOF+simeprevir (SIM) (n = 1050), SOF+ledipasvir (LDV) (n = 974), SOF+ribavirin (RBV) (n = 663, genotype 2 or 3), and SOF+pegylated interferon (PEG)+RBV (n = 519, genotype 1 or 4). Those treated with a SOF-based regimen were older and more likely to have cirrhosis, diabetes, chronic kidney disease, higher HCV RNA levels, higher body mass index, compared with 1652 controls receiving a boceprevir-based (BOC) regimen. Sustained virological response (SVR12) rates for the SOF+SIM and SOF+LDV groups did not decline significantly even when as low as 50% of the full course was prescribed (except SOF+LDV, 90-99% prescriptions had SVR12 of 84.6%; n = 13). SOF+RBV for genotype 2/3 who received 50-80% of the prescriptions, 23/34 (67.6%) achieved SVR12. For persons with genotype 1/4 infection treated with SOF+PEG+RBV, no declines in SVR12 were seen with lower rates of prescriptions (40/43, or 93% SVR12 rate). CONCLUSIONS: Sofosbuvir-based treatment regimens are highly effective in achieving SVR12. This efficacy is not significantly affected when treated persons receive less than a full prescribed course of treatment. PMID- 26928929 TI - Sonographic Analysis of Changes in Skull Shape After Cranial Molding Helmet Therapy in Infants With Deformational Plagiocephaly. AB - OBJECTIVES: -The purpose of this study was to investigate the changes in skull shape on sonography after cranial molding helmet therapy in infants with deformational plagiocephaly. METHODS: -Twenty-six infants who were treated with cranial molding helmet therapy were recruited. Caliper and sonographic measurements were performed. The lateral length of the affected and unaffected sides of the skull and cranial vault asymmetry index were measured with calipers. The occipital angle, defined as the angle between lines projected along the lambdoid sutures of the skull, was calculated by sonography. The occipital angle difference and occipital angle ratio were also measured. All caliper and sonographic measurements were performed in each infant twice before and twice after treatment. RESULTS: -The study group included 12 male and 14 female infants with a mean age +/- SD of 6.2 +/- 3.5 months. The mean treatment duration was 6.0 +/- 2.5 months. The difference in lateral length before and after helmet therapy was significantly greater on the affected skull than the unaffected skull (16.7 +/- 12.7 versus 9.0 +/- 13.4 mm; P < .01). The difference in the occipital angle before and after helmet therapy was significantly greater on the affected skull than the unaffected skull (-5.7 degrees +/- 7.3 degrees versus 4.2 degrees +/- 7.9 degrees ; P < .01). The cranial vault asymmetry index and occipital angle ratio were significantly reduced after helmet therapy (cranial vault asymmetry index, 9.3% +/- 2.3% versus 3.5% +/- 3.0%; occipital angle ratio, 1.07 +/- 0.05 versus 1.01 +/- 0.01; P < .05). CONCLUSIONS: -These results suggest that occipital angle measurements using sonography, combined with cephalometry, could provide a better understanding of the therapeutic effects of cranial molding helmet therapy in infants with deformational plagiocephaly. PMID- 26928930 TI - New instrumentation in endoscopic medial orbital decompression. PMID- 26928931 TI - Identification of candidate diagnostic biomarkers for adolescent idiopathic scoliosis using UPLC/QTOF-MS analysis: a first report of lipid metabolism profiles. AB - Adolescent idiopathic scoliosis (AIS) is a complex spine deformity, affecting approximately 1-3% adolescents. Earlier diagnosis could increase the likelihood of successful conservative treatment and hence reduce the need for surgical intervention. We conducted a serum metabonomic study to explore the potential biomarkers of AIS for early diagnosis. Serum metabolic profiles were firstly explored between 30 AIS patients and 31 healthy controls by ultra high performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry. Then, the candidate metabolites were validated in an independent cohort including 31 AIS patients and 44 controls. The results showed that metabolic profiles of AIS patients generally deviated from healthy controls in both the discovery set and replication set. Seven differential metabolites were identified as candidate diagnostic biomarkers, including PC(20:4), 2 hexenoylcarnitine, beta-D-glucopyranuronicacid, DG(38:9), MG(20:3), LysoPC(18:2) and LysoPC(16:0). These candidate metabolites indicated disrupted lipid metabolism in AIS, including glycerophospholipid, glycerolipid and fatty acid metabolism. Elevated expressions of adipose triglyceride lipase and hormone sensitive lipase in adipose tissue further corroborated our findings of increased lipid metabolism in AIS. Our findings suggest that differential metabolites discovered in AIS could be used as potential diagnostic biomarkers and that lipid metabolism plays a role in the pathogenesis of AIS. PMID- 26928932 TI - Three-Dimensional Imaging of Plant Organs Using a Simple and Rapid Transparency Technique. AB - Clearing techniques eliminate factors that interfere with microscopic observation, including light scattering and absorption by pigments and cytoplasmic components. The techniques allow fluorescence-based detailed analyses of materials and characterization of the three-dimensional structure of organs. We describe a simple and rapid clearing and imaging method, termed 'TOMEI' (Transparent plant Organ MEthod for Imaging), which enables microscopic observation of intact plant organs. This method involves a clearing reagent containing 2,2'-thiodiethanol. Conveniently, transparent plant organs were prepared within only 3-6 h. We detected fluorescent stains at a depth of approximately 200 um using confocal laser scanning microscopy and analyzed fluorescent proteins in internal tissues of transparent organs cleared using TOMEI. We adapted TOMEI for various plant organs of Arabidopsis thaliana and Oryza sativa, including leaves, flower buds, flower stalks, root and nematode infected root-knots. We visualized whole leaves of A. thaliana from the adaxial epidermis to the abaxial epidermis as well as protoxylem and metaxylem vessels of vascular bundles embedded in spongy mesophyll cells. Inner floral organs were observed in flower buds cleared using TOMEI without the need to prepare sections or remove sepals. Multicolor imaging of fluorescent proteins and dyes, and analyses of the three-dimensional structure of plant organs based on optical sections are possible using TOMEI. We analyzed root-knots cleared using TOMEI and revealed that nematodes induce giant cell expansion in a DNA content-dependent manner. The TOMEI method is applicable to analysis of fluorescent proteins and dyes quantitatively with cell morphological characteristics in whole plant organs. PMID- 26928934 TI - Motor proteins: Kinesin's gait captured. PMID- 26928933 TI - Evaluation and Management of Hearing Loss in Survivors of Childhood and Adolescent Cancers: A Report From the Children's Oncology Group. AB - Hearing loss (HL) is common in childhood cancer survivors exposed to platinum chemotherapy and/or cranial radiation and can severely impact quality of life. Early detection and appropriate management can mitigate academic, speech, language, social, and psychological morbidity resulting from hearing deficits. This review is targeted as a resource for providers involved in aftercare of childhood cancers. The goal is to promote early identification of survivors at risk for HL, appropriate evaluation and interpretation of diagnostic tests, timely referral to an audiologist when indicated, and to increase knowledge of current therapeutic options. PMID- 26928936 TI - Direct observation of intermediate states during the stepping motion of kinesin 1. AB - The dimeric motor protein kinesin-1 walks along microtubules by alternatingly hydrolyzing ATP and moving two motor domains ('heads'). Nanometer-precision single-molecule studies demonstrated that kinesin takes regular 8-nm steps upon hydrolysis of each ATP; however, the intermediate states between steps have not been directly visualized. Here, we employed high-temporal resolution dark-field microscopy to directly visualize the binding and unbinding of kinesin heads to or from microtubules during processive movement. Our observations revealed that upon unbinding from microtubules, the labeled heads were displaced rightward and underwent tethered diffusive movement. Structural and kinetic analyses of wild type and mutant kinesins with altered neck linker lengths provided evidence that rebinding of the unbound head to the rear-binding site is prohibited by a tension increase in the neck linker and that ATP hydrolysis by the leading head is suppressed when both heads are bound to the microtubule, thereby explaining how the two heads coordinate to move in a hand-over-hand manner. PMID- 26928935 TI - The molecular basis of polysaccharide cleavage by lytic polysaccharide monooxygenases. AB - Lytic polysaccharide monooxygenases (LPMOs) are copper-containing enzymes that oxidatively break down recalcitrant polysaccharides such as cellulose and chitin. Since their discovery, LPMOs have become integral factors in the industrial utilization of biomass, especially in the sustainable generation of cellulosic bioethanol. We report here a structural determination of an LPMO-oligosaccharide complex, yielding detailed insights into the mechanism of action of these enzymes. Using a combination of structure and electron paramagnetic resonance spectroscopy, we reveal the means by which LPMOs interact with saccharide substrates. We further uncover electronic and structural features of the enzyme active site, showing how LPMOs orchestrate the reaction of oxygen with polysaccharide chains. PMID- 26928939 TI - Innocent BN bond substitution in anthracene derivatives. AB - Extended azaborine heterocycles are promising biomedical and electronic materials. Herein we report the synthesis of a novel family of azaborine anthracene derivatives and their structural, electrochemical and spectroscopic characterization. We observe that the properties of these materials are remarkably similar to the parent hydrocarbons, suggesting the innocence of the CC to BN bond substitution. Our results support the prospective stability to long term usage of extended azaborines and the feasibility of using such materials in device applications. PMID- 26928937 TI - Probes of ubiquitin E3 ligases enable systematic dissection of parkin activation. AB - E3 ligases represent an important class of enzymes, yet there are currently no chemical probes for profiling their activity. We develop a new class of activity based probe by re-engineering a ubiquitin-charged E2 conjugating enzyme and demonstrate the utility of these probes by profiling the transthiolation activity of the RING-in-between-RING (RBR) E3 ligase parkin in vitro and in cellular extracts. Our study provides valuable insight into the roles, and cellular hierarchy, of distinct phosphorylation events in parkin activation. We also profile parkin mutations associated with patients with Parkinson's disease and demonstrate that they mediate their effect largely by altering transthiolation activity. Furthermore, our probes enable direct and quantitative measurement of endogenous parkin activity, revealing that endogenous parkin is activated in neuronal cell lines (>=75%) in response to mitochondrial depolarization. This new technology also holds promise as a novel biomarker of PINK1-parkin signaling, as demonstrated by its compatibility with samples derived from individuals with Parkinson's disease. PMID- 26928938 TI - Human intrahepatic regulatory T cells are functional, require IL-2 from effector cells for survival, and are susceptible to Fas ligand-mediated apoptosis. AB - Regulatory T cells (Treg ) suppress T effector cell proliferation and maintain immune homeostasis. Autoimmune liver diseases persist despite high frequencies of Treg in the liver, suggesting that the local hepatic microenvironment might affect Treg stability, survival, and function. We hypothesized that interactions between Treg and endothelial cells during recruitment and then with epithelial cells within the liver affect Treg stability, survival, and function. To model this, we explored the function of Treg after migration through human hepatic sinusoidal-endothelium (postendothelial migrated Treg [PEM Treg ]) and the effect of subsequent interactions with cholangiocytes and local proinflammatory cytokines on survival and stability of Treg . Our findings suggest that the intrahepatic microenvironment is highly enriched with proinflammatory cytokines but deficient in the Treg survival cytokine interleukin (IL)-2. Migration through endothelium into a model mimicking the inflamed liver microenvironment did not affect Treg stability; however, functional capacity was reduced. Furthermore, the addition of exogenous IL-2 enhanced PEM Treg phosphorylated STAT5 signaling compared with PEMCD8. CD4 and CD8 T cells are the main source of IL-2 in the inflamed liver. Liver-infiltrating Treg reside close to bile ducts and coculture with cholangiocytes or their supernatants induced preferential apoptosis of Treg compared with CD8 effector cells. Treg from diseased livers expressed high levels of CD95, and their apoptosis was inhibited by IL-2 or blockade of CD95. CONCLUSION: Recruitment through endothelium does not impair Treg stability, but a proinflammatory microenvironment deficient in IL-2 leads to impaired function and increased susceptibility of Treg to epithelial cell-induced Fas-mediated apoptosis. These results provide a mechanism to explain Treg dysfunction in inflamed tissues and suggest that IL-2 supplementation, particularly if used in conjunction with Treg therapy, could restore immune homeostasis in inflammatory and autoimmune liver disease. (Hepatology 2016;64:138-150). PMID- 26928940 TI - Association Between Preadmission Functional Status and Use and Effectiveness of Secondary Prevention Medications in Elderly Survivors of Acute Myocardial Infarction. AB - OBJECTIVES: To determine whether function-related indicators (FRIs), derived from preadmission claims data, help explain the frequent practice of forgoing secondary prevention medications observed in Medicare. DESIGN: Retrospective cohort. SETTING: National Medicare data. PARTICIPANTS: Elderly Medicare beneficiaries discharged alive from an acute myocardial infarction (AMI) hospitalization in 2007-2008 (N = 184,156). MEASUREMENTS: Study outcomes were number of guideline-recommended secondary prevention medications (statins, beta blockers, and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers) used after discharge and 12-month survival. Preadmission data (FRIs, cardiovascular conditions, comorbid conditions), type of AMI (non-ST-elevation myocardial infarction, anterior, other), and procedures and complications during the hospitalization were from claims data. RESULTS: Function-related indicators (FRIs) were common before admission; 50% of individuals had at least one (range 0 11). After discharge, 85.8% used at least one class of guideline medication, and 30.2% used all three; 19.6% died within 12 months. Each additional FRI reduced the likelihood of receiving all three medication classes by 5% (adjusted odds ratio = 0.95, 95% confidence interval (CI) = 0.94-0.96) and increased 12-month mortality by 20% (adjusted hazard ratio (aHR) = 1.20, 95% CI = 1.19-1.21). Individuals taking all three classes of medication were 30% less likely to die within 12 months than those not taking guideline medications (aHR = 0.70, 95% CI = 0.67-0.73). Similar survival benefit was observed in individuals with and without functional impairments. CONCLUSION: Greater impairment in preadmission functional status, using a measure derived from claims data, was associated with less use of secondary prevention medications after AMI. Survival benefits of taking these medications were consistent across functional impairment levels. PMID- 26928941 TI - Comparison of Methods To Reweight from Classical Molecular Simulations to QM/MM Potentials. AB - We examine methods to reweight classical molecular mechanics solvation calculations to more expensive QM/MM energy functions. We first consider the solvation free energy difference between ethane and methanol in a QM/MM Hamiltonian from configurations generated in a cheaper MM potential. The solute molecules in the QM/MM Hamiltonian are treated with B3LYP/6-31G*, and the solvent water molecules are treated classically. The free energy difference in the QM/MM Hamiltonian is estimated using Boltzmann reweighting with both the non-Boltzmann Bennett method (NBB) and the multistate Bennett acceptance ratio (MBAR), and the variance of each method is directly compared for an identical data set. For this system, MBAR-derived methods are found to produce smaller overall uncertainties than NBB-based methods. Additionally, we show that to reduce the variance in the overall free energy difference estimate in this system for a fixed amount of QM/MM calculations, the energy re-evaluations in the Boltzmann reweighting step should be concentrated on the physical MM states with the highest overlap to the QM/MM states, rather than allocated equally over all sampled MM states. We also show that reallocating the QM/MM re-evaluations can be used to diagnose poor overlap between the sampled and target state. The solvation free energies for molecules in the SAMPL4 solvation data set are also calculated in the QM/MM Hamiltonian with NBB and MBAR, and the variances are marginally smaller for MBAR. Overall, NBB and MBAR produce similar variances for systems with poor sampling efficiency, and MBAR provides smaller variances than NBB in systems with high sampling efficiency. Both NBB and MBAR converge to identical solvation free energy estimates in the QM/MM Hamiltonian, and the RMSD to experimental values for molecules in the SAMPL4 solvation data set decreases by approximately 28% when switching from the MM Hamiltonian to the QM/MM Hamiltonian. PMID- 26928942 TI - Consensus Conference on North American Training in Hepatopancreaticobiliary Surgery: A Review of the Conference and Presentation of Consensus Statements. AB - The findings and recommendations of the North American consensus conference on training in hepatopancreaticobiliary (HPB) surgery held in October 2014 are presented. The conference was hosted by the Society for Surgical Oncology (SSO), the Americas Hepato-Pancreatico-Biliary Association (AHPBA), and the American Society of Transplant Surgeons (ASTS). The current state of training in HPB surgery in North America was defined through three pathways-HPB, surgical oncology, and solid organ transplant fellowships. Consensus regarding programmatic requirements included establishment of minimum case volumes and inclusion of quality metrics. Formative assessment, using milestones as a framework and inclusive of both operative and nonoperative skills, must be present. Specific core HPB cases should be defined and used for evaluation of operative skills. The conference concluded with a focus on the optimal means to perform summative assessment to evaluate the individual fellow completing a fellowship in HPB surgery. Presentations from the hospital perspective and the American Board of Surgery led to consensus that summative assessment was desired by the public and the hospital systems and should occur in a uniform but possibly modular manner for all HPB fellowship pathways. A task force composed of representatives of the SSO, AHPBA, and ASTS are charged with implementation of the consensus statements emanating from this consensus conference. PMID- 26928943 TI - Molecular Simulations of Human and Mouse Abeta1-16 at Different pH Values: Structural Characteristics toward Understanding Cu(2+) -Coordinated Amyloid Beta Spheres. AB - As the main sequence responsible for metal ion coordination in the amyloid beta (Abeta) peptide, Abeta1-16 plays a key role in the understanding of the aggregation of Abeta induced by Cu(2+) ions. There is no consensus on the nature of the coordination sphere of the Cu(2+) -Abeta complex so far due to the amorphous conformation of the Abeta1-16 peptide itself and the pH dependence of Cu(2+) -Abeta coordination. The simulation reported here reveals that human Abeta1-16 monomer has a U-shape morphology, which is preserved at any pH. This morphology accommodates Cu(2+) ions with several binding sites and is also the basis for establishing a center-distance statistical method (CDSM). Based on this CDSM, specific histidine residues for a Cu(2+) -coordinated sphere are identified and the corresponding accurate pH range is established, indicating that the CDSM can be used as a reference to predict the potential coordination sites of metal ions in other amorphous peptides. By contrast, mouse Abeta1-16 monomer has a more open and random morphology than human Abeta1-16 due to the differences of three sequence positions. These mutations not only reduce the number of binding sites required by a stable Cu(2+) -binding sphere but also diminish the capacity to generate salt bridges compared to the human peptide. These observations offer insights into the roles of three residues that differ in the mouse Abeta1-16 and perhaps into the reasons mice seldom develop Alzheimer's disease. PMID- 26928944 TI - Development and physicochemical characterization of clindamycin resinate for taste masking in pediatrics. AB - PURPOSE: To evaluate the physicochemical characteristics of clindamycin HCl in a complex form (resinate) with ion exchange resin (IER) (Amberlite IRP69). METHODS: Drug-resin complex was prepared by simple aqueous binding method. Drug binding study was carried out at different drug and resin concentrations. Several physicochemical characterization studies were conducted to evaluate the resinate complex. These studies included flow properties, in vitro drug release in SGF and SIF, DSC, TGA, mass spectroscopy and XPRD evaluations. In addition, stability study of resinate complex was conducted at 25 and 40 degrees C for up to 1 month. RESULTS: Clindamycin and Amberlite IRP69 have formed a complex (resinate) and have shown good flow properties, good thermal properties and chemical stability (short term over 4 weeks) at 25 and 40 degrees C. Clindamycin release profiles from resinate in SGF and SIF have shown immediate release characteristics and release in simulated saliva has shown dependence on water volume. CONCLUSION: The clindamycin stable complex with IER (Amberlite IRP69) has the potential for further development as a compatible pediatric liquid formulation (suspension) or a fast disintegrating tablet. PMID- 26928946 TI - Trunk Muscle Coordination During Upward and Downward Reaching in Stroke Survivors. AB - In this study, we investigated deficits in coordination of trunk muscle modes involved in the stabilization of the trunk's trajectory for reaching upward and downward beyond functional arm length. Trunk muscle activity from 10 stroke survivors (8 men, 2 women; 64.1 +/- 10.5 years old) and 9 healthy control subjects (7 men, 2 women; 59.3 +/- 9.3 years old) was analyzed. Coordination of trunk muscle modes to stabilize the trunk trajectory was investigated using the uncontrolled manifold (UCM) analysis. The UCM analysis decomposes the variability of muscle modes into good and bad variability. The good variability does not affect the control of trunk motion, whereas the bad variability does. In stroke survivors, deficits in the ability to flexibly combine trunk muscle modes was associated with reduced ability to minimize those combinations of trunk muscle modes that led to an error in trunk trajectory (bad variability), and this had a greater effect on reaching upward. This reduced coordination of trunk muscle modes during reaching was correlated with a clinical measure of trunk impairment. PMID- 26928945 TI - Stapled Peptides with gamma-Methylated Hydrocarbon Chains for the Estrogen Receptor/Coactivator Interaction. AB - "Stapled" peptides are typically designed to replace two non-interacting residues with a constraining, olefinic staple. To mimic interacting leucine and isoleucine residues, we have created new amino acids that incorporate a methyl group in the gamma-position of the stapling amino acid S5. We have incorporated them into a sequence derived from steroid receptor coactivator 2, which interacts with estrogen receptor alpha. The best peptide (IC50 =89 nm) replaces isoleucine 689 with an S-gamma-methyl stapled amino acid, and has significantly higher affinity than unsubstituted peptides (390 and 760 nm). Through X-ray crystallography and molecular dynamics studies, we show that the conformation taken up by the S-gamma methyl peptide minimizes the syn-pentane interactions between the alpha- and gamma-methyl groups. PMID- 26928947 TI - Photodissociation dynamics of propyne at 193 nm: a trajectory surface hopping study. AB - Photodissociation dynamics of propyne at 193 nm are studied using the fewest switches nonadiabatic trajectory surface hopping method on its first excited singlet electronic state (1(1)A''). The trajectories are propagated based on potential energies, gradients and nonadiabatic couplings calculated at the MRCIS(6,7) level with the 6-31++G(d,p) basis set. Our trajectory calculations have revealed that H + H3CCC is the major dissociation channel, which has also been predicted experimentally. For the primary photodissociation channel H + H3CCC we demonstrate that nonadiabatic dynamics do not play a significant role. This observation is however contradictory to most of the previously reported experimental predictions. The calculated product translation energy distribution for the acetylenic H atom elimination peaked at ~ 18 kcal mol(-1), indicating that the dissociation occurs adiabatically on a moderately repulsive excited surface that correlates with the ground state products (CH3C = C + H). The H atom elimination process from the methyl fragment involving a transition state, which has to compete with the acetylenic H atom dissociation channel with no barrier in the excited singlet surface, was found to be too less probable to make a contribution to product branching. We observed that a fewer but significant number of trajectories led to CH3 + CCH product formation which has not been observed experimentally when propyne is excited at 193 nm. PMID- 26928948 TI - Cobalt(II)-Catalyzed C-H Amination of Arenes with Simple Alkylamines. AB - A new method of cobalt-catalyzed amination of arylamides with simple alkylamines is reported through C(sp(2))-H bond functionalization. For the first time, inexpensive cobalt is exploited as the catalyst in the amination of C(sp(2))-H bond using simple alkylamines. PMID- 26928949 TI - Hyperhomocysteinemia activates the aryl hydrocarbon receptor/CD36 pathway to promote hepatic steatosis in mice. AB - Hyperhomocysteinemia (HHcy) is associated with liver diseases such as fatty liver and hepatic fibrosis; however, the underlying mechanism is still largely unknown. The current study aimed to explore the signaling pathway involved in HHcy-induced hepatic steatosis (HS). C57BL/6 mice were fed a high-methionine diet (HMD) for 4 and 8 weeks to establish the HHcy mouse model. Compared to a chow diet, the HMD induced hepatic steatosis and elevated hepatic expression of CD36, a fatty acid transport protein. The increased CD36 expression was associated with activation of the aryl hydrocarbon receptor (AHR). In primary cultured hepatocytes, high levels of homocysteine (Hcy) treatment up-regulated CD36 and increased subsequent lipid uptake; both were significantly attenuated by small interfering RNA (siRNA) knockdown of CD36 and AHR. Chromatin immunoprecipitation assay revealed that Hcy promoted binding of AHR to the CD36 promoter, and transient transfection assay demonstrated markedly increased activity of the AHR response element by Hcy, which was ligand dependent. Mass spectrometry revealed significantly increased hepatic content of lipoxin A4 (LXA4 ), a metabolite of arachidonic acid, in HMD fed mice. Furthermore, overexpression of 15-oxoprostaglandin 13-reductase 1, a LXA4 inactivation enzyme, inhibited Hcy-induced AHR activation, lipid uptake, and lipid accumulation. Moreover, LXA4 -induced up-regulation of CD36 and lipid uptake was inhibited by AHR siRNA in vitro in hepatocytes. Finally, treatment with an AHR antagonist reversed HHcy-induced lipid accumulation by inhibiting the AHR-CD36 pathway in mice. CONCLUSION: HHcy activates the AHR-CD36 pathway by increasing hepatic LXA4 content, which results in hepatic steatosis. (Hepatology 2016;64:92-105). PMID- 26928950 TI - Influence of the rearing system on yolk corticosterone concentration in captive Greater Rheas (Rhea americana). AB - Many environmental conditions elevate plasma corticosterone in laying birds, leading to elevated hormone accumulation in the egg. We investigated whether maternal yolk corticosterone levels in Greater Rheas differ between fresh eggs collected from an intensive (IRS) and a semi-extensive (SRS) rearing system. After HPLC validation, yolk corticosterone was measured using a corticosterone (125) I radio-immunoassay kit. Results (mean +/- SE) showed that eggs collected from the IRS exhibited a significantly higher corticosterone concentration than eggs from SRS (89.88 +/- 8.93 vs. 45.41 +/- 5.48 ng/g yolk, respectively). Our findings suggest that rearing conditions under an intensive scheme (e.g., small pens with bare ground, no direct foraging and handling) might be perceived as more stressful for Greater Rhea females than semi-extensive rearing conditions (e.g., low animal density distributed in extensive areas and direct foraging), which would result in the transfer of higher yolk corticosterone levels. A better understanding of environmental conditions and female traits that affect yolk corticosterone deposition provides a background for future studies concerning the roles of maternal corticosterone on offspring development. Zoo Biol. 35:246-250, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26928951 TI - Cost analysis and outcomes of a second-look tympanoplasty-mastoidectomy strategy for cholesteatoma. AB - OBJECTIVES/HYPOTHESIS: To analyze cost and compare cholesteatoma recidivism and hearing outcomes with single-stage and second-look operative strategies. STUDY DESIGN: Retrospective review and cost analysis. METHODS: Adult and pediatric patients who underwent a tympanoplasty with mastoidectomy for cholesteatoma with a single-stage or second-look operative strategy were identified. Variables included procedure approach, residual or recurrent cholesteatoma, ossicular chain reconstruction frequency, and operative complications. Audiologic outcomes included pre-/postoperative air bone gap (ABG) and word recognition score (WRS). Cost analysis included charges for consultation and follow-up visits, surgical procedures, computed tomography temporal bone scans, and audiology visits. RESULTS: One hundred and six patients had a tympanoplasty with mastoidectomy for cholesteatoma, with 80 canal wall-up procedures (CWU) as initial approach. Of these, 46 (57.5%) CWU patients had a planned second look. Two (4.3%) CWU patients had recurrent cholesteatoma and 20 (43.4%) had residual identified at second look. Four (11.7%) single-stage CWU strategy patients developed recurrent cholesteatoma. There was no significant difference in pre-/postoperative ABG and WRS between second look and single stage (P > 0.05). Compared to second-look patients, single-stage patients had significantly fewer postoperative visits (6.32 vs. 10.4; P = 0.007), and significantly lower overall charges for care ($23,529. vs. $41.411; P < 0.0001). CONCLUSION: The goal of cholesteatoma surgery is to produce a safe ear, and a second-look strategy after CWU has historically been used to evaluate for recurrent or residual disease. The cholesteatoma recurrence rate at a second look after a CWU tympanoplasty-mastoidectomy is low. Costs of operative procedures are a significant proportion of healthcare resource expenditures. Considering the low rate of cholesteatoma recurrence and relatively high cost of care, implementation of a second-look strategy should be individually tailored and not universally performed. LEVEL OF EVIDENCE: 4. Laryngoscope, 126:2574-2579, 2016. PMID- 26928953 TI - DNA Methylation Adds Prognostic Value to Minimal Residual Disease Status in Pediatric T-Cell Acute Lymphoblastic Leukemia. AB - BACKGROUND: Despite increased knowledge about genetic aberrations in pediatric T cell acute lymphoblastic leukemia (T-ALL), no clinically feasible treatment stratifying marker exists at diagnosis. Instead patients are enrolled in intensive induction therapies with substantial side effects. In modern protocols, therapy response is monitored by minimal residual disease (MRD) analysis and used for postinduction risk group stratification. DNA methylation profiling is a candidate for subtype discrimination at diagnosis and we investigated its role as a prognostic marker in pediatric T-ALL. PROCEDURE: Sixty-five diagnostic T-ALL samples from Nordic pediatric patients treated according to the Nordic Society of Pediatric Hematology and Oncology ALL 2008 (NOPHO ALL 2008) protocol were analyzed by HumMeth450K genome wide DNA methylation arrays. Methylation status was analyzed in relation to clinical data and early T-cell precursor (ETP) phenotype. RESULTS: Two distinct CpG island methylator phenotype (CIMP) groups were identified. Patients with a CIMP-negative profile had an inferior response to treatment compared to CIMP-positive patients (3-year cumulative incidence of relapse (CIR3y ) rate: 29% vs. 6%, P = 0.01). Most importantly, CIMP classification at diagnosis allowed subgrouping of high-risk T-ALL patients (MRD >=0.1% at day 29) into two groups with significant differences in outcome (CIR3y rates: CIMP negative 50% vs. CIMP positive 12%; P = 0.02). These groups did not differ regarding ETP phenotype, but the CIMP-negative group was younger (P = 0.02) and had higher white blood cell count at diagnosis (P = 0.004) compared with the CIMP-positive group. CONCLUSIONS: CIMP classification at diagnosis in combination with MRD during induction therapy is a strong candidate for further risk classification and could confer important information in treatment decision making. PMID- 26928952 TI - Identification of clusters of individuals relevant to temporomandibular disorders and other chronic pain conditions: the OPPERA study. AB - The classification of most chronic pain disorders gives emphasis to anatomical location of the pain to distinguish one disorder from the other (eg, back pain vs temporomandibular disorder [TMD]) or to define subtypes (eg, TMD myalgia vs arthralgia). However, anatomical criteria overlook etiology, potentially hampering treatment decisions. This study identified clusters of individuals using a comprehensive array of biopsychosocial measures. Data were collected from a case-control study of 1031 chronic TMD cases and 3247 TMD-free controls. Three subgroups were identified using supervised cluster analysis (referred to as the adaptive, pain-sensitive, and global symptoms clusters). Compared with the adaptive cluster, participants in the pain-sensitive cluster showed heightened sensitivity to experimental pain, and participants in the global symptoms cluster showed both greater pain sensitivity and greater psychological distress. Cluster membership was strongly associated with chronic TMD: 91.5% of TMD cases belonged to the pain-sensitive and global symptoms clusters, whereas 41.2% of controls belonged to the adaptive cluster. Temporomandibular disorder cases in the pain sensitive and global symptoms clusters also showed greater pain intensity, jaw functional limitation, and more comorbid pain conditions. Similar results were obtained when the same methodology was applied to a smaller case-control study consisting of 199 chronic TMD cases and 201 TMD-free controls. During a median 3 year follow-up period of TMD-free individuals, participants in the global symptoms cluster had greater risk of developing first-onset TMD (hazard ratio = 2.8) compared with participants in the other 2 clusters. Cross-cohort predictive modeling was used to demonstrate the reliability of the clusters. PMID- 26928954 TI - Large Magnetization and Reversible Magnetocaloric Effect at the Second-Order Magnetic Transition in Heusler Materials. AB - In contrast to rare-earth-based materials, cheaper and more environmentally friendly candidates for cooling applications are found within the family of Ni-Mn Heusler alloys. Initial interest in these materials is focused on the first-order magnetostructural transitions. However, large hysteresis makes a magnetocaloric cycle irreversible. Alternatively, here it is shown how the Heusler family can be used to optimize reversible second-order magnetic phase transitions for magnetocaloric applications. PMID- 26928955 TI - Early operative outcomes and learning curve of robotic assisted giant paraesophageal hernia repair. AB - BACKGROUND: We have previously described our technique of robotic-assisted giant paraesophageal hernia repair (RA-GPEHR). The purpose of this study was to report our initial experience, early outcomes and learning curve with RA-GPEHR using a four-arm robotic platform. METHODS: 24 consecutive patients presenting with symptomatic giant paraesophageal hernias (GPEH) underwent RA-GPEHR from April 2011 to February 2014. Peri-operative data and short-term patient outcomes were assessed by retrospective review of a prospectively maintained database. RESULTS: Median age was 62 years (range 44-84). 15 (63%) patients underwent fundoplication and 9 (37%) gastropexy. Median procedure time was 277 min (range: 185-485) and decreased steadily over the experience. There were no intra-operative complications or surgical mortality. No patients experienced dysphagia in the early post-operative period. CONCLUSIONS: RA-GPEHR is safe, with reported short term operative and functional outcomes similar to conventional laparoscopic approaches. The initial learning curve appears relatively short for experienced minimally invasive esophageal surgeons. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26928957 TI - A Versatile One-Pot Access to Cyanoarenes from ortho- and para-Quinones: Paving the Way for Cyanated Functional Materials. AB - A generally applicable direct synthesis of cyanoarenes from quinones is presented. Particular emphasis is placed on the preparation of precursors and target molecules relevant for organic materials, including halogenated cyanoarenes and larger cyanated acenes. The reaction and work-up protocols are adjusted for the challenges presented by the different substrates and products. Screening results of the initial reaction optimization are given to further facilitate adaptation to other synthetic problems. The universality of the reaction is finally highlighted by successful substitution of para-quinones by an ortho-quinone as the starting material. PMID- 26928956 TI - Brucella vulpis sp. nov., isolated from mandibular lymph nodes of red foxes (Vulpes vulpes). AB - Two slow-growing, Gram-negative, non-motile, non-spore-forming, coccoid bacteria (strains F60T and F965), isolated in Austria from mandibular lymph nodes of two red foxes (Vulpes vulpes), were subjected to a polyphasic taxonomic analysis. In a recent study, both isolates were assigned to the genus Brucella but could not be attributed to any of the existing species. Hence, we have analysed both strains in further detail to determine their exact taxonomic position and genetic relatedness to other members of the genus Brucella. The genome sizes of F60T and F965 were 3 236 779 and 3 237 765 bp, respectively. Each genome consisted of two chromosomes, with a DNA G+C content of 57.2 %. A genome-to-genome distance of >80 %, an average nucleotide identity (ANI) of 97 % and an average amino acid identity (AAI) of 98 % compared with the type species Brucella melitensis confirmed affiliation to the genus. Remarkably, 5 % of the entire genetic information of both strains was of non-Brucella origin, including as-yet uncharacterized bacteriophages and insertion sequences as well as ABC transporters and other genes of metabolic function from various soil-living bacteria. Core-genome-based phylogenetic reconstructions placed the novel species well separated from all hitherto-described species of the genus Brucella, forming a long-branched sister clade to the classical species of Brucella. In summary, based on phenotypic and molecular data, we conclude that strains F60T and F965 are members of a novel species of the genus Brucella, for which the name Brucella vulpis sp. nov. is proposed, with the type strain F60T ( = BCCN 09-2T = DSM 101715T). PMID- 26928958 TI - Mothers' Employment Attributes and Use of Preventive Child Health Services. AB - This study examines whether paid sick leave and hours worked per week are associated with receipt of recommended well-child visits, preventive dental care, influenza vaccines, obesity screening, and vision screening among U.S. children aged 0 to 17 years whose mothers were employed using data from the Medical Expenditure Panel Survey. Residual inclusion instrumental variables methods were used to address unobserved confounding related to maternal employment and child health care use. Instruments were the industry-specific mean of paid leave and hours worked. Fewer than half of children received the recommended number of well child visits and dental care; only 14% of children received an influenza vaccine in the past year. Paid sick leave was associated with increased adherence to recommended well-child visits (marginal probability, 0.12; 95% confidence interval [CI] = 0.23, 0.01), preventive dental care (marginal probability, 0.28; 95% CI = 0.34, 0.33), and receipt of the influenza vaccine (marginal probability, 0.09; 95% CI = 0.13, 0.05 ). PMID- 26928959 TI - Immunological Differences between Lymphocytic and Collagenous Colitis. AB - BACKGROUND: Lymphocytic (LC) and collagenous (CC) colitis are the two major forms of microscopic colitis (MC). The aim of this study was to identify similarities and differences in their mucosal immune characteristics. METHODS: Colonic biopsies from 15 CC, 8 LC, and 10 healthy controls were collected. Mucosal lymphocytes were assessed by flow cytometry. Tissue gene expression and protein levels were determined by real-time PCR and ELISA, respectively. RESULTS: LC patients had lower numbers of CD4(+) and double-positive CD4(+)CD8(+)mucosal T lymphocytes, and higher numbers of CD8(+) and CD4(+)TCRgammadelta(+) mucosal T cells, compared with controls and CC patients. Regulatory Treg (CD4(+)CD25(+)FOXP3(+)) and double-negative (CD3(+)CD4(-)CD8(-)) T cell percentages were higher in both CC and LC compared with controls, coupled with higher levels of the anti-inflammatory IL-10, both at mRNA and protein levels. By contrast, Th1 and Th17 cells were lower in both CC and LC, although gene expression of Th1/Th17 cytokines was higher in both. CONCLUSION: CC and LC share some regulatory and effector mechanisms, but not others. Higher IL-10 levels and higher Treg and double-negative T cell percentages, found in both CC and LC, could be responsible for the lack of progression of structural damage and the blockade of proinflammatory cytokine production. However, CC and LC are revealed as separate, independent entities, as they show clearly different mucosal lymphocyte profiles, which could be caused by different luminal triggers of the two diseases. Hence, CC and LC are two closely related but independent intestinal disorders. PMID- 26928960 TI - EHealth Technologies in Inflammatory Bowel Disease: A Systematic Review. AB - BACKGROUND AND AIMS: Electronic-health technologies (eHealth) such as Web-based interventions, virtual clinics, smart-phone applications, and telemedicine are being used to manage patients with inflammatory bowel disease (IBD). We aimed to: (1) Evaluate the impact of eHealth technologies on conventional clinical indices and patient-reported outcome measures (PROs) in IBD; (2) assess the effectiveness, cost-effectiveness and feasibility of using eHealth technologies to facilitate the self-management of individuals with IBD, and; (3) provide recommendations for their design and optimal use for patient care. METHODS: Relevant publications were identified via a literature search, and 17 publications were selected based on predefined quality parameters. RESULTS: Six randomized controlled trials and nine observational studies utilizing eHealth technologies in IBD were identified. Compared with standard outpatient-led care, eHealth technologies have led to improvements in: Relapse duration [(n = 1) 18 days vs 77 days, p < 0.001]; disease activity (n = 2); short-term medication adherence (n = 3); quality of life (n = 4); IBD knowledge (n = 2); healthcare costs (n = 4); the number of acute visits to the outpatient clinic due to IBD symptoms (n = 1), and; facilitating the remote management of up to 20% of an IBD cohort (n = 2). Methodological shortcomings of eHealth studies include heterogeneity of outcome measures, lack of clinician/patient input, lack of validation against conventional clinical indices and PROs, and limited cost benefit analyses. CONCLUSIONS: EHealth technologies have the potential for promoting self-management and reducing the impact of the growing burden of IBD on health care resource utilization. A theoretical framework should be applied to the development, implementation, and evaluation of eHealth interventions. PMID- 26928961 TI - European Crohn's and Colitis Organisation Topical Review on Prediction, Diagnosis and Management of Fibrostenosing Crohn's Disease. AB - This ECCO topical review of the European Crohn's and Colitis Organisation [ECCO] focused on prediction, diagnosis, and management of fibrostenosing Crohn's disease [CD]. The objective was to achieve evidence-supported, expert consensus that provides guidance for clinical practice. PMID- 26928962 TI - Sci-B-VacTM Vs ENGERIX-B Vaccines for Hepatitis B Virus in Patients with Inflammatory Bowel Diseases: A Randomised Controlled Trial. AB - BACKGROUND AND AIMS: Response rate to second-generation hepatitis B virus vaccines is relatively low in patients with inflammatory bowel diseases compared with the general healthy population. We compared the efficacy and safety of a third- vs a second-generation hepatitis B virus vaccine in a group of patients with inflammatory bowel diseases treated with immunosuppressive medications. METHODS: Prospective, randomised, single-blind, controlled study. Eligible patients were randomly assigned to receive one of two vaccines, ENGERIX-B or Sci B-Vac. The vaccines were administered in three doses at 0, 1, and 6 months. The primary endpoint was defined as the titre of anti-hepatitis B S [HBs] antibodies following the standard three-dose hepatitis B virus vaccination schedule. RESULTS: A total of 72 patients complied with study protocol [37 and 35 patients in the ENGERIX-B and Sci-B-Vac groups, respectively]. Overall, 75% of the cohort seroconverted. The primary endpoint was met in 81.1% in the ENGERIX-B group and 68.6% in the Sci-B-Vac group [p = 0.22]. Patients in the Sci-B-Vac group showed a statistically significant decreased seroconversion rate compared with the ENGERIX B group, with use of tumour necrosis factor [TNF] alpha inhibitors [p = 0.03], and higher degree of disease activity [p = 0.03]. CONCLUSIONS: Overall seroconversion rate in our cohort was higher than in previous reports in the literature, possibly due to a low disease activity state in the majority of participants. Third-generation hepatitis B virus vaccines showed no apparent advantage over standard of care vaccine in this patient group. PMID- 26928963 TI - Eosinophils Contribute to Intestinal Inflammation via Chemoattractant Receptor homologous Molecule Expressed on Th2 Cells, CRTH2, in Experimental Crohn's Disease. AB - BACKGROUND AND AIMS: Prostaglandin [PG] D2 activates two receptors, DP and CRTH2. Antagonism of CRTH2 has been shown to promote anti-allergic and anti-inflammatory effects. We investigated whether CRTH2 may play a role in Crohn's disease [CD], focusing on eosinophils which are widely present in the inflamed mucosa of CD patients and express both receptors. METHODS: Using the 2,4,6 trinitrobenzenesulfonic acid [TNBS]-induced colitis model, involvement of CRTH2 in colitis was investigated by pharmacological antagonism, immunohistochemistry, Western blotting, immunoassay, and leukocyte recruitment. Chemotactic assays were performed with isolated human eosinophils. Biopsies and serum samples of CD patients were examined for presence of CRTH2 and ligands, respectively. RESULTS: High amounts of CRTH2-positive cells, including eosinophils, are present in the colonic mucosa of mice with TNBS colitis and in human CD. The CRTH2 antagonist OC 459, but not the DP antagonist MK0524, reduced inflammation scores and decreased TNF-alpha, IL-1beta, and IL-6 as compared with control mice. OC-459 inhibited recruitment of eosinophils into the colon and also inhibited CRTH2-induced chemotaxis of human eosinophils in vitro. Eosinophil-depleted DeltadblGATA knockout mice were less sensitive to TNBS-induced colitis, whereas IL-5 transgenic mice with lifelong eosinophilia were more severely affected than wild types. In addition, we show that serum levels of PGD2 and Delta(12)-PGJ2 were increased in CD patients as compared with control individuals. CONCLUSIONS: CRTH2 plays a pro-inflammatory role in TNBS-induced colitis. Eosinophils contribute to the severity of the inflammation, which is improved by a selective CRTH2 antagonist. CRTH2 may, therefore, represent an important target in the pharmacotherapy of CD. PMID- 26928964 TI - Tetrahydrobiopterin Attenuates DSS-evoked Colitis in Mice by Rebalancing Redox and Lipid Signalling. AB - BACKGROUND AND AIMS: Guanosine triphosphate cyclohydrolase [GCH1] governs the production of the enzyme cofactor tetrahydrobiopterin [BH4] which is essential for biogenic amine synthesis, lipid metabolism via alkylglycerol monooxygenase [AGMO], and redox coupling of nitric oxide synthases [NOSs]. Inflammation-evoked unequal regulation of GCH1 and NOS or AGMO may cause redox stress and lipid imbalances. METHODS: The present study assessed potential therapeutic effects of rebalancing these systems with BH4 in experimental colitis in mice. RESULTS: Oral treatment with BH4 as a suspension of crushed tablets attenuated colitis, whereas inhibition of its production had opposite effects: aggravated weight loss, epithelial haemorrhages and ulcers, neutrophil infiltrates, production of reactive oxygen species, and unfavourable profile changes of endocannabinoids, ceramides, and lysophosphatidic acids. Conversely, oral BH4 normalised biopterin, reduced in vivo activity of oxidases and peroxidases in the inflamed gut, favoured nitric oxide over hydrogen peroxide, and maintained normal levels of lipid signalling molecules. BH4 favoured thereby resident CD3+CD8+ and regulatory CD3+CD25+ intraepithelial T cells that are important for epithelial integrity. CONCLUSIONS: BH4 protected against colitis in mice via two major pathways: [i] by reduction of oxidative stress; and [ii] by re-orchestration of alkyl- and acylglycerolipid signalling via AGMO. Oral treatment with BH4 is a safe approved supplementary therapy for genetic BH4 deficiency and did not excessively increase systemic BH4 levels. Therefore, one may consider repurposing of oral BH4 as an adjunctive treatment for colitis. PMID- 26928965 TI - Systematic Review and Meta-analysis: Phenotype and Clinical Outcomes of Older onset Inflammatory Bowel Disease. AB - BACKGROUND: Little is known of the clinical outcome of patients with older-onset inflammatory bowel disease [IBD]. We performed a systematic review to determine phenotype and outcomes of older-onset IBD compared with younger-onset subjects. METHODS: A systematic search of Embase and Medline up to June 2015 identified studies investigating phenotype and outcomes of older-onset [diagnosed at age >= 50 years] Crohn's disease [CD] and ulcerative colitis [UC] subjects. Pooled analyses of disease phenotype, medication use, and disease-related surgery were calculated. RESULTS: We analysed findings from 43 studies comprising 8274 older onset and 34641 younger-onset IBD subjects. Compared with younger-onset patients, older-onset CD patients were more likely to have colonic disease (odds ratio [OR] 2.56, 95% confidence interval [CI] 1.88 - 3.48) and inflammatory behaviour [OR 1.19, 95% CI 1.07 - 1.33], and less likely to have penetrating disease or perianal involvement. More older-onset UC patients had left-sided colitis [OR 1.49, 95% CI 1.18 - 1.88]. Although fewer older-onset IBD patients received immunomodulators [CD: OR 0.44; UC: OR 0.60] or biologicals [CD: OR 0.34; UC: OR 0.41], older-onset CD was similar in the need for surgery [OR 0.70, 95% CI 0.40 - 1.22] whereas more older-onset UC patients underwent surgery [OR 1.36, 95% CI 1.18 - 1.57]. CONCLUSIONS: Elderly IBD patients present with less complicated disease, but have similar or higher rates of surgery than non-elderly patients. Whether this reflects a non-benign disease course, physicians' reluctance to employ immunomodulators, or both, merits further study which is essential for improving the care of IBD in the elderly. PMID- 26928967 TI - Cationic Silica-Supported N-Heterocyclic Carbene Tungsten Oxo Alkylidene Sites: Highly Active and Stable Catalysts for Olefin Metathesis. AB - Designing supported alkene metathesis catalysts with high activity and stability is still a challenge, despite significant advances in the last years. Described herein is the combination of strong sigma-donating N-heterocyclic carbene ligands with weak sigma-donating surface silanolates and cationic tungsten sites leading to highly active and stable alkene metathesis catalysts. These well-defined silica-supported catalysts, [(=SiO)W(=O)(=CHCMe2 Ph)(IMes)(OTf)] and [(=SiO)W(=O)(=CHCMe2 Ph)(IMes)(+) ][B(Ar(F) )4 (-) ] [IMes=1,3-bis(2,4,6 trimethylphenyl)-imidazol-2-ylidene, B(Ar(F) )4 =B(3,5-(CF3 )2 C6 H3 )4 ] catalyze alkene metathesis, and the cationic species display unprecedented activity for a broad range of substrates, especially for terminal olefins with turnover numbers above 1.2 million for propene. PMID- 26928966 TI - Delayed Cytotoxic T Lymphocyte-Associated Protein 4-Immunoglobulin Treatment Reverses Ongoing Alloantibody Responses and Rescues Allografts From Acute Rejection. AB - Antibody-mediated rejection has emerged as the leading cause of late graft loss in kidney transplant recipients, and inhibition of donor-specific antibody production should lead to improved transplant outcomes. The fusion protein cytotoxic T lymphocyte-associated protein 4-immunoglobulin (CTLA4-Ig) blocks T cell activation and consequently inhibits T-dependent B cell antibody production, and the current paradigm is that CTLA4-Ig is effective with naive T cells and less so with activated or memory T cells. In this study, we used a mouse model of allosensitization to investigate the efficacy of continuous CTLA4-Ig treatment, initiated 7 or 14 days after sensitization, for inhibiting ongoing allospecific B cell responses. Delayed treatment with CTLA4-Ig collapsed the allospecific germinal center B cell response and inhibited alloantibody production. Using adoptively transferred T cell receptor transgenic T cells and a novel approach to track endogenous graft-specific T cells, we demonstrate that delayed CTLA4-Ig minimally inhibited graft-specific CD4(+) and T follicular helper responses. Remarkably, delaying CTLA4-Ig until day 6 after transplantation in a fully mismatched heart transplant model inhibited alloantibody production and prevented acute rejection, whereas transferred hyperimmune sera reversed the effects of delayed CTLA4-Ig. Collectively, our studies revealed the unexpected efficacy of CTLA4-Ig for inhibiting ongoing B cell responses even when the graft-specific T cell response was robustly established. PMID- 26928968 TI - Is wounding aggression in zoo-housed chimpanzees and ring-tailed lemurs related to zoo visitor numbers? AB - Chimpanzees in laboratory colonies experience more wounds on weekdays than on weekends, which has been attributed to the increased number of people present during the week; thus, the presence of more people was interpreted as stressful. If this were also true for primates in zoos, where high human presence is a regular feature, this would clearly be of concern. Here we examine wounding rates in two primate species (chimpanzees Pan troglodytes and ring-tailed lemurs Lemur catta) at three different zoos, to determine whether they correlate with mean number of visitors to the zoo. Wounding data were obtained from a zoo electronic record keeping system (ZIMSTM). The pattern of wounds did not correlate with mean gate numbers for those days for either species in any group. We conclude that there is no evidence that high visitor numbers result in increased woundings in these two species when housed in zoos. Zoo Biol. 35:205-209, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26928969 TI - Diagnostic Accuracy of Rating Scales for Attention-Deficit/Hyperactivity Disorder: A Meta-analysis. AB - CONTEXT: The Child Behavior Checklist-Attention Problem (CBCL-AP) scale and Conners Rating Scale-Revised (CRS-R) are commonly used behavioral rating scales for diagnosing attention-deficit/hyperactivity disorder (ADHD) in children and adolescents. OBJECTIVE: To evaluate and compare the diagnostic performance of CBCL-AP and CRS-R in diagnosing ADHD in children and adolescents. DATA SOURCES: PubMed, Ovid Medline, and other relevant electronic databases were searched for articles published up to May 2015. STUDY SELECTION: We included studies evaluating the diagnostic performance of either CBCL-AP scale or CRS-R for diagnosing ADHD in pediatric populations in comparison with a defined reference standard. DATA EXTRACTION: Bivariate random effects models were used for pooling and comparing diagnostic performance. RESULTS: We identified and evaluated 14 and 11 articles on CBCL-AP and CRS-R, respectively. The results revealed pooled sensitivities of 0.77, 0.75, 0.72, and 0.83 and pooled specificities of 0.73, 0.75, 0.84, and 0.84 for CBCL-AP, Conners Parent Rating Scale-Revised, Conners Teacher Rating Scale-Revised, and Conners Abbreviated Symptom Questionnaire (ASQ), respectively. No difference was observed in the diagnostic performance of the various scales. Study location, age of participants, and percentage of female participants explained the heterogeneity in the specificity of the CBCL-AP. CONCLUSIONS: CBCL-AP and CRS-R both yielded moderate sensitivity and specificity in diagnosing ADHD. According to the comparable diagnostic performance of all examined scales, ASQ may be the most effective diagnostic tool in assessing ADHD because of its brevity and high diagnostic accuracy. CBCL is recommended for more comprehensive assessments. PMID- 26928970 TI - Improving Care for Children With ADHD: The Information is Just a Rating Scale Away. PMID- 26928971 TI - Evolution of Renal Cysts to Anaplastic Sarcoma of Kidney in a Child With DICER1 Syndrome. AB - Anaplastic sarcoma of kidney (ASK) is a rare neoplasm recently associated with DICER1 mutations. We report a child with germline DICER1 mutation who developed ASK in preexisting septated renal cysts, which were likely cystic nephroma. From age 2.5 to 6 years, sonographic imaging illustrated changes in the size and number of renal cysts, followed at age 8.8 years by a mass, pathologically an ASK. Lung cysts resected in infancy were diagnosed retrospectively as pleuropulmonary blastoma. Both tumors had acquired somatic DICER1 mutations. Ultrasonographic evolution of renal cysts to ASK has not previously been documented. Children with both pulmonary and renal cysts are candidates for DICER1 mutation testing. PMID- 26928973 TI - The Effectiveness and Acceptability of Pipelle Endometrial Sampling versus Classical Dilatation and Curettage: A Three-Year Observational Study. AB - OBJECTIVE: To assess the effectiveness and acceptability of Pipelle endometrial sampling in comparison to dilatation and curettage (D&C). METHODS: This was a prospective observational study including a total of 538 patients with abnormal uterine bleeding who were allocated to be treated using 2 sampling techniques: Pipelle sampler (n = 270) and D&C (n = 268). The primary outcome was the adequacy of both methods and concordance rate with hysterectomy specimens. The secondary outcome included drawbacks and patients' acceptability. RESULTS: There was no significant difference between the 2 methods regarding adequacy and concordance rate with hysterectomy (p > 0.05). There was a statistically significant difference between the 2 groups regarding the requirement of analgesia and overall discomfort (p < 0.001), which was higher in the Pipelle group. No significant statistical difference was recognized between the study groups regarding the occurrence of cervical lacerations, fever or the rate of inadequate intrauterine sampling (p > 0.05). In addition, no significant statistical difference between both procedures was recognized concerning the overall satisfaction rate and the advisability of the procedure to other women (p > 0.05). CONCLUSION: Under the conditions of this study, Pipelle endometrial sampling is comparable to D&C biopsy in terms of adequacy and concordance rate with hysterectomy except that more pain and a higher overall discomfort rate were associated with it. PMID- 26928972 TI - Multimodal-Imaging-Guided Cancer Phototherapy by Versatile Biomimetic Theranostics with UV and gamma-Irradiation Protection. AB - A versatile biomimetic theranostic agent based on magnetic melanin nanoparticles is developed for positron-emission tomography/magnetic resonance/photoacoustic/photothermal multimodal-imaging-guided cancer photothermal therapy and UV and gamma-irradiation protection. PMID- 26928974 TI - Outcomes of a virtual-reality simulator-training programme on basic surgical skills in robot-assisted laparoscopic surgery. AB - BACKGROUND: The utility of the virtual-reality robotic simulator in training programmes has not been clearly evaluated. Our aim was to evaluate the impact of a virtual-reality robotic simulator-training programme on basic surgical skills. METHODS: A simulator-training programme in robotic surgery, using the da Vinci Skills Simulator, was evaluated in a population including junior and seasoned surgeons, and non-physicians. Their performances on robotic dots and suturing skin pod platforms before and after virtual-simulation training were rated anonymously by surgeons experienced in robotics. RESULTS: 39 participants were enrolled: 14 medical students and residents in surgery, 14 seasoned surgeons, 11 non-physicians. Junior and seasoned surgeons' performances on platforms were not significantly improved after virtual-reality robotic simulation in any of the skill domains, in contrast to non-physicians. CONCLUSIONS: The benefits of virtual-reality simulator training on several tasks to basic skills in robotic surgery were not obvious among surgeons in our initial and early experience with the simulator. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26928975 TI - The effects of framework dynamics on the behavior of water adsorbed in the [Zn(l L)(Cl)] and Co-MOF-74 metal-organic frameworks. AB - The effects of framework flexibility on the structural and dynamical properties of water adsorbed in two prototypical metal-organic frameworks are investigated through molecular dynamics simulations. It is found that water molecules in the pores of a flexible model of [Zn(l-L)(Cl)] exhibit slower dynamics than when the framework is artificially held rigid in the simulations. In contrast, the water dynamics in Co-MOF-74 is predicted to be accelerated by the framework vibrations. The origin of this different behavior directly relates to how water interacts with the two frameworks, which, in turn, determines different hydrogen-bond patterns in the pores. While the first water molecules adsorbed in [Zn(l-L)(Cl)] donate a single hydrogen bond to the Zn-Cl groups and point the other hydrogen atom towards the center of the pore, water molecules adsorbed in Co-MOF-74 initially bind to the cobalt atoms of the framework via their oxygen atoms, thus leaving each molecule free to form two hydrogen bonds with additional molecules adsorbed at higher loading. The simulation results indicate that taking into account the framework flexibility in computer simulations is necessary for a quantitative modeling of adsorption and transport processes in metal-organic frameworks. PMID- 26928977 TI - Criteria for phytoplasma 16Sr group/subgroup delineation and the need of a platform for proper registration of new groups and subgroups. AB - As phytoplasmas are discovered at an ever-increasing pace in emerging and re emerging plant diseases worldwide, the scheme for classification of phytoplasmas into 16S rRNA gene RFLP (16Sr) groups and subgroups is experiencing an ongoing rapid expansion. Improper delineation or designation of new groups and subgroups can open potential conflicts in classifying newly identified phytoplasma strains. To maintain the integrity of the classification scheme, criteria for the delineation of new groups and subgroups must be followed, and proper registration should be required to track established groups and subgroups. PMID- 26928976 TI - Microneedles Integrated with Pancreatic Cells and Synthetic Glucose-Signal Amplifiers for Smart Insulin Delivery. AB - An innovative microneedle (MN)-based cell therapy is developed for glucose responsive regulation of the insulin secretion from exogenous pancreatic beta cells without implantation. One MN patch can quickly reduce the blood-sugar levels (BGLs) of chemically induced type-1 diabetic mice and stabilize BGLs at a reduced level for over 10 h. PMID- 26928978 TI - Improving visual prognosis of the diabetic patients during the past 30 years based on the data of the Finnish Register of Visual Impairment. AB - PURPOSE: To evaluate changes in visual impairment (VI) due to diabetic retinopathy (DR) recorded in the Finnish Register of Visual Impairment (RVI) during the past 30 years. METHODS: Data from the visually impaired diabetic persons included in the RVI were analysed using three 10-year cohorts (1982-90, 1991-2000, 2001-10). Information on the age at the time of the first VI registration, severity of VI determined according to the World Health Organisation (WHO) definition, and the age at death was collected. VI due to proliferative (PDR) and non-proliferative (NPDR) DR were analysed separately. RESULTS: Data of 4080 patients whose primary cause for VI was DR were analysed. The median age at the time of notification of VI for the three cohorts was 39, 62 and 59 years in the PDR group and 71, 73 and 73 in the NPDR group, respectively. The proportion of blind persons was 42%, 22% and 15% in the PDR group and 10%, 9% and 4% in the NPDR group, respectively. The median age at death in the three cohorts was 54, 73 and 72 years in PDR group and 76, 79 and 80 years in the NPDR group, respectively. The standardized mortality ratio (SMR) compared with the general population was 8.3, 2.9 and 1.4 in persons with PDR and 3.4, 2.0 and 1.2 in those with NPDR, respectively. CONCLUSIONS: A significant change in the profile of the VI in the PDR group has taken place in Finland. It was characterized by increased age at the time of VI notification, decreased severity of VI and higher age at death. Most evidently these improvements took place in the 1990s. The profile of VI in the NPDR group has changed only modestly. Compared with the general population, SMRs improved both in NPDR and PDR groups continuously. PMID- 26928979 TI - Reply To: How Does Substitutional Doping Affect Visible Light Absorption in a Series of Homodisperse Ti11 Polyoxotitanate Nanoparticles--A Comment on the Band Gap Determination of the Fe(II) Cages. AB - A summary of the evidence based on spectroscopy, calculated density of states (DOS) and photo-electrochemistry, for electron transfer from the occupied Fe(2+) (d)-beta orbital located within the band gap of the [Ti4 O(OEt)15 (FeBr)] cluster, to its unoccupied Ti(d) orbitals is presented. The importance of the distinction between the concepts of band gap and HOMO-LUMO gap is emphasized. PMID- 26928980 TI - Facile Conversion of Red Phosphorus into Soluble Polyphosphide Anions by Reaction with Potassium Ethoxide. AB - Soluble polyphosphide anions were successfully generated in a number of organic solvents by the reaction between shelf-stable red phosphorus and potassium ethoxide. The species were identified by (31)P NMR spectroscopy in solution and by X-ray crystal-structure determination of (Bu4N)2P16 in the solid state. The reaction was scaled up to gram quantities by using a flow-chemistry process. PMID- 26928981 TI - Pregnancy-associated spontaneous coronary artery dissection: insights from a case series of 13 patients. AB - AIMS: We sought to present a series of 13 pregnancy-associated spontaneous coronary artery dissection (P-SCAD), their angiographic and multimodal imaging findings, acute phase treatment, and outcomes. METHODS AND RESULTS: Between 2005 and 2015, 13 cases of P-SCAD were collected from a database of 11 tertiary hospitals. The mean age was 33.8 +/- 3.7 years; most patients had no risk factors for coronary artery disease, and the majority were multiparous. P-SCAD occurred during the puerperium in 12 patients with a median time of 10 days. Only one patient presented with P-SCAD in the 37th week of pregnancy, and she was the only patient who died in this series. Six patients (46%) presented with ST-segment elevation acute myocardial infarction (STEMI), six (46%) presented with non STEMI, and one presented with unstable angina; one-third of women had cardiogenic shock. In 12 patients, the dissection involved the left anterior descending or circumflex artery, and it extended to the left main coronary artery in 6 patients. Intravascular ultrasound or optical coherence tomography helped to confirm diagnosis and guide treatment in 46% of cases. Seven women were managed clinically; percutaneous coronary intervention was performed in five cases, and coronary artery bypass grafting was performed in one patient. CONCLUSION: In these 13 cases of P-SCAD, clinical presentation commonly included acute myocardial infarction and cardiogenic shock. Multivessel dissections and involvement of the left coronary artery and left main coronary artery were highly prevalent. Clinicians must be aware of angiographic appearances of P-SCAD for prompt diagnosis and management in these high-risk patients. PMID- 26928982 TI - A zero phase adaptive fuzzy Kalman filter for physiological tremor suppression in robotically assisted minimally invasive surgery. AB - BACKGROUND: Hand physiological tremor of surgeons can cause vibration at the surgical instrument tip, which may make it difficult for the surgeon to perform fine manipulations of tissue, needles, and sutures. METHODS: A zero phase adaptive fuzzy Kalman filter (ZPAFKF) is proposed to suppress hand tremor and vibration of a robotic surgical system. The involuntary motion can be reduced by adding a compensating signal that has the same magnitude and frequency but opposite phase with the tremor signal. RESULTS: Simulations and experiments using different filters were performed. Results show that the proposed filter can avoid the loss of useful motion information and time delay, and better suppress minor and varying tremor. CONCLUSIONS: The ZPAFKF can provide less error, preferred accuracy, better tremor estimation, and more desirable compensation performance, to suppress hand tremor and decrease vibration at the surgical instrument tip. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26928983 TI - Investigating the Experiences of Childhood Cancer Patients and Parents Participating in Optional Nontherapeutic Clinical Research Studies in the UK. AB - BACKGROUND: While the majority of childhood cancer clinical trials are treatment related, additional optional research investigations may be carried out that do not directly impact on treatment. It is essential that these studies are conducted ethically and that the experiences of families participating in these studies are as positive as possible. METHODS: A questionnaire study was carried out to investigate the key factors that influence why families choose to participate in optional nontherapeutic research studies, the level of understanding of the trials involved, and the experiences of participation. RESULTS: A total of 100 participants from six UK centers were studied; 77 parents, 10 patients >16 years, and 13 patients aged 8-15 years. Ninety-seven percent of parents and 90% of patients felt that information provided prior to study consent was of the right length, with 52% of parents and 65% of patients fully understanding the information provided. Seventy-four percent of parents participated in research studies in order to "do something important", while 74% of patients participated "to help medical staff". Encouragingly, <5% of participants felt that their clinical care would be negatively affected if they did not participate. Positive aspects of participation included a perception of increased attention from medical staff. Negative aspects included spending longer periods in hospital and the requirement for additional blood samples. Ninety-six percent of parents and 87% of patients would participate in future studies. CONCLUSIONS: The study provides an insight into the views of childhood cancer patients and their parents participating in nontherapeutic clinical research studies. Overwhelmingly, the findings suggest that participation is seen as a positive experience. PMID- 26928984 TI - High-Energy Long-Lived Mixed Frenkel-Charge-Transfer Excitons: From Double Stranded (AT)n to Natural DNA. AB - The electronic excited states populated upon absorption of UV photons by DNA are extensively studied in relation to the UV-induced damage to the genetic code. Here, we report a new unexpected relaxation pathway in adenine-thymine double stranded structures (AT)n . Fluorescence measurements on (AT)n hairpins (six and ten base pairs) and duplexes (20 and 2000 base pairs) reveal the existence of an emission band peaking at approximately 320 nm and decaying on the nanosecond time scale. Time-dependent (TD)-DFT calculations, performed for two base pairs and exploring various relaxation pathways, allow the assignment of this emission band to excited states resulting from mixing between Frenkel excitons and adenine-to thymine charge-transfer states. Emission from such high-energy long-lived mixed (HELM) states is in agreement with their fluorescence anisotropy (0.03), which is lower than that expected for pi-pi* states (>=0.1). An increase in the size of the system quenches pi-pi* fluorescence while enhancing HELM fluorescence. The latter process varies linearly with the hypochromism of the absorption spectra, both depending on the coupling between pi-pi* and charge-transfer states. Subsequently, we identify the common features between the HELM states of (AT)n structures with those reported previously for alternating (GC)n : high emission energy, low fluorescence anisotropy, nanosecond lifetimes, and sensitivity to conformational disorder. These features are also detected for calf thymus DNA in which HELM states could evolve toward reactive pi-pi* states, giving rise to delayed fluorescence. PMID- 26928985 TI - First-principles Study on the Charge Transport Mechanism of Lithium Sulfide (Li2 S) in Lithium-Sulfur Batteries. AB - The lithium-sulfur chemistry is regarded as a promising candidate for next generation battery systems because of its high specific energy (1675 mA h g(-1) ). Although issues such as low cycle stability and power capability of the system remain to be addressed, extensive research has been performed experimentally to resolve these problems. Attaining a fundamental understanding of the reaction mechanism and its reaction product would further spur the development of lithium sulfur batteries. Here, we investigated the charge transport mechanism of lithium sulfide (Li2 S), a discharge product of conventional lithium-sulfur batteries using first-principles calculations. Our calculations indicate that the major charge transport is governed by the lithium-ion vacancies among various possible charge carriers. Furthermore, the large bandgap and low concentration of electron polarons indicate that the electronic conduction negligibly contributes to the charge transport mechanism in Li2 S. PMID- 26928986 TI - Selection of the effect size for sample size determination for a continuous response in a superiority clinical trial using a hybrid classical and Bayesian procedure. AB - BACKGROUND: When designing studies that have a continuous outcome as the primary endpoint, the hypothesized effect size ([Formula: see text]), that is, the hypothesized difference in means ([Formula: see text]) relative to the assumed variability of the endpoint ([Formula: see text]), plays an important role in sample size and power calculations. Point estimates for [Formula: see text] and [Formula: see text] are often calculated using historical data. However, the uncertainty in these estimates is rarely addressed. METHODS: This article presents a hybrid classical and Bayesian procedure that formally integrates prior information on the distributions of [Formula: see text] and [Formula: see text] into the study's power calculation. Conditional expected power, which averages the traditional power curve using the prior distributions of [Formula: see text] and [Formula: see text] as the averaging weight, is used, and the value of [Formula: see text] is found that equates the prespecified frequentist power ([Formula: see text]) and the conditional expected power of the trial. This hypothesized effect size is then used in traditional sample size calculations when determining sample size for the study. RESULTS: The value of [Formula: see text] found using this method may be expressed as a function of the prior means of [Formula: see text] and [Formula: see text], [Formula: see text], and their prior standard deviations, [Formula: see text]. We show that the "naive" estimate of the effect size, that is, the ratio of prior means, should be down-weighted to account for the variability in the parameters. An example is presented for designing a placebo-controlled clinical trial testing the antidepressant effect of alprazolam as monotherapy for major depression. CONCLUSION: Through this method, we are able to formally integrate prior information on the uncertainty and variability of both the treatment effect and the common standard deviation into the design of the study while maintaining a frequentist framework for the final analysis. Solving for the effect size which the study has a high probability of correctly detecting based on the available prior information on the difference [Formula: see text] and the standard deviation [Formula: see text] provides a valuable, substantiated estimate that can form the basis for discussion about the study's feasibility during the design phase. PMID- 26928987 TI - Commentary on McRae et al. PMID- 26928988 TI - Red light of the visual spectrum attenuates cell death in culture and retinal ganglion cell death in situ. AB - PURPOSE: To ascertain whether red light, known to enhance mitochondrial function, can blunt chemical insults to cell cultures and ischaemic insults to the rat retina. METHODS: Raised intraocular pressure (IOP, 140 mmHg, 60 min) or ischaemia was delivered in complete darkness or in the presence of low intensity red light (16.5 watts/m(2) , 3000 lux, 625-635 nm) to one eye of each rat. Animals were killed at specific times after ischemia and retinas analysis for ganglion cell numbers, the localization of specific antigens or for changes in defined RNAs. RGC-5 cell cultures were also exposed to various chemical insults in the presence or absence of red light. Significant differences were determined by t-test and anova. RESULTS: Elevation of IOP causes changes in the localization of glial fibrillary acid protein (GFAP), calretinin, calbindin, choline acetyltransferase, ganglion cell numbers and an elevation (GFAP, vimentin, HO-1 and mTORC1) or reduction (Thy-1 and Brn3a) of mRNAs in the rat retina. These negative effects to the rat retina caused by ischaemia are reduced by red light. Moreover, chemical insults to cell cultures are blunted by red light. CONCLUSIONS: Low, non-toxic levels of red light focussed on the retina for a short period of time are sufficient to attenuate an insult of raised IOP to the rat retina. Since mitochondrial dysfunctions are thought to play a major role in ganglion cell death in glaucoma, we propose the potential use of red light therapy for the treatment of the disease. PMID- 26928989 TI - Reliability of Orientational Order Parameters Determined from Two-dimensional X ray Diffraction Patterns: A Simulation Study. AB - The orientational order parameter S2 is one of the most important quantities to describe the degree of long-range orientational ordering of liquid crystals. There are several approaches to experimentally measure this order parameter of liquid crystalline phases but every method includes substantial simplifications and assumptions. We present a simulation-based approach to elucidate the reliability of the method of Davidson, Petermann and Levelut to measure S2 via 2D X-ray experiments. We have found that this method slightly underestimates S2 by an absolute value of only 0.05 and thus provides reliable measures of S2 by X-ray diffraction. PMID- 26928990 TI - Structural and biochemical characterization of EDTA monooxygenase and its physical interaction with a partner flavin reductase. AB - Ethylenediaminetetraacetate (EDTA) is currently the most abundant organic pollutant due to its recalcitrance and extensive use. Only a few bacteria can degrade it, using EDTA monooxygenase (EmoA) to initiate the degradation. EmoA is an FMNH2 -dependent monooxygenase that requires an NADH:FMN oxidoreductase (EmoB) to provide FMNH2 as a cosubstrate. Although EmoA has been identified from Chelativorans (ex. Mesorhizobium) sp. BNC1, its catalytic mechanism is unknown. Crystal structures of EmoA revealed a domain-like insertion into a TIM-barrel, which might serve as a flexible lid for the active site. Docking of MgEDTA(2-) into EmoA identified an intricate hydrogen bond network connected to Tyr(71) , which should potentially lower its pKa. Tyr(71) , along with nearby Glu(70) and a peroxy flavin, facilitates a keto-enol transition of the leaving acetyl group of EDTA. Further, for the first time, the physical interaction between EmoA and EmoB was observed by ITC, molecular docking and enzyme kinetic assay, which enhanced both EmoA and EmoB activities probably through coupled channelling of FMNH2 . PMID- 26928993 TI - Envisioning the Future of Nanotechnology Platforms for Biomedicine. PMID- 26928999 TI - Chemoreactive Natural Products that Afford Resistance Against Disparate Antibiotics and Toxins. AB - Microorganisms use chemical inactivation strategies to circumvent toxicity caused by many types of antibiotics. Yet in all reported cases, this approach is limited to enzymatically facilitated mechanisms that each target narrow ranges of chemically related scaffolds. The fungus-derived shikimate analogues, pericoxide and pericosine A, were identified as chemoreactive natural products that attenuate the antagonistic effects of several synthetic and naturally derived antifungal agents. Experimental and computational studies suggest that pericoxide and pericosine A readily react via SN 2' mechanisms against a variety of nucleophilic substances under both in vitro aqueous and in situ co-culture conditions. Many of the substitution products from this reaction were highly stable and exhibited diminished toxicities against environmental fungal isolates, including the Tolypocladium sp. strain that produced pericoxide and pericosine A. PMID- 26929000 TI - Telmisartan ameliorates carbon tetrachloride-induced acute hepatotoxicity in rats. AB - This study assessed the potential hepatoprotective effect of telmisartan (TLM), a selective angiotensin II type 1 (AT1 ) receptor blocker, on carbon tetrachloride (CCl4 )-induced acute hepatotoxity in rats. Intraperitoneal injection of male Wistar rats with CCl4 1 mL kg-1 , 1:1 mixture with corn oil for 3 days increased serum alanine transaminase, aspartate transaminase, and alkaline phosphatase activities as well as total bilirubin, triglycerides and total cholesterol levels. This is in addition to the disrupted histological architecture in the CCl4 group. Rats receiving CCl4 and co-treated with TLM (3 and 10 mg kg-1 , orally) showed ameliorated serum biochemical and histological changes almost to the control level. Nevertheless, rats treated with TLM (1 mg kg-1 ) didn't show any significant changes compared to CCl4 intoxicated group. In addition, TLM rectified oxidative status disrupted by CCl4 intoxication. Interestingly, TLM protected against CCl4 -induced expressions of nuclear factor-kappaB, inducible nitric oxide synthase and cyclooxygenase-II, in a dose related manner. Moreover, TLM (3 and 10 mg kg-1 ) significantly modified CCl4 -induced elevation in tumor necrosis factor-alpha and nitric oxide levels. Furthermore, TLM showed a marked decline in CD68+ cells stained areas and reduced activity of myeloperoxidase enzyme compared to CCl4 -intoxicated group. In conclusion, both doses of TLM (3 and 10 mg kg-1 ) showed significant hepato-protective effects. However, TLM at a dose of 10 mg kg-1 didn't show significant efficacy above 3 mg kg-1 which is nearly equivalent to the human anti-hypertensive dose of 40 mg. Thus, may be effective in guarding against several hepatic complications due to its antioxidant and anti-inflammatory activities. (c) 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 359-370, 2017. PMID- 26929001 TI - Is it True That the Normal Valence-Length Correlation Is Irrelevant for Metal Metal Bonds? AB - The most intriguing feature of metal-metal bonds in inorganic compounds is an apparent lack of correlation between the bond order and the bond length. In this study, we combine a variety of literature data obtained by quantum chemistry and our results based on the empirical bond valence model (BVM), to confirm for the first time the existence of a normal exponential correlation between the effective bond order (EBO) and the length of the metal-metal bonds. The difference between the EBO and the formal bond order is attributed to steric conflict between the (TM)n cluster (TM=transition metal) and its environment. This conflict, affected mainly by structural type, should cause high lattice strains, but electron redistribution around TM atoms, evident from the BVM calculations, results in a full or partial strain relaxation. PMID- 26929002 TI - Psychometric validation of Chinese Health Assessment Questionnaire for use in rheumatoid arthritis patients in China. AB - BACKGROUND: To validate the psychometric properties of the Chinese Health Assessment Questionnaire (HAQ) for use in rheumatoid arthritis (RA) patients in China. METHODS: The psychometric properties of the HAQ were validated by interviewing subjects with a questionnaire battery containing the HAQ, EQ-5D, and Short Form 12 (SF-12). Reliability was assessed by Cronbach's alpha, construct validity by assessing a priori hypotheses, and discriminative validity by discriminating subjects in different groups, respectively. To assess the applicability of HAQ in different regions, subgroup analyses were conducted for south and north China, respectively. RESULTS: Questionnaires were administered to a consecutive sample of 133 RA patients. Cronbach's alpha showed a strong reliability among all the items. In particular, the internal reliability was higher when excluding the items about the use of aids and devices: 0.987 when excluding versus 0.963 when including. Construct validity was supported by achieving both of the a priori hypotheses based on correlations between the HAQ scores and scales of EQ-5D and SF-12. Overall, HAQ scores were important inferential factors for Global Functional Status in RA, which indicated good discriminative validity. The validation results are generally consistent between subgroups from north and south China. CONCLUSIONS: The Chinese HAQ demonstrated good acceptability and psychometric properties in RA patients from China. Two possible improvements for better use and interpretation of the patient-reported outcomes of RA patients in China could be to cross-culturally adapt the items about the use of aids and devices and joint use of mental health measurements together with HAQ in future studies. PMID- 26929003 TI - Polygonum aviculare L. and its active compounds, quercitrin hydrate, caffeic acid, and rutin, activate the Wnt/beta-catenin pathway and induce cutaneous wound healing. AB - Polygonum aviculare L. is a member of the Polygonaceae family of plants, which has been known for its antioxidant and anti-obesity effects. However, the wound healing function of P. aviculare extract has not been assessed. In this study, we identified a novel property of P. aviculare extract as a Wnt/beta-catenin pathway activator based on a screen of 350 plant extracts using HEK293-TOP cells retaining the Wnt/beta-catenin signaling reporter gene. P. aviculare extract accelerated the migration of HaCaT keratinocytes without showing significant cytotoxicity. Moreover, P. aviculare extract efficiently re-epithelized wounds generated on mice. Additionally, ingredients of P. aviculare extract, such as quercitrin hydrate, caffeic acid, and rutin, also accelerated the motility of HaCaT keratinocytes with the activation of Wnt/beta-catenin signaling. Therefore, based on our findings, P. aviculare extract and its active ingredients could be potential therapeutic agents for wound healing. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26929004 TI - Coexisting cryptic species of the Litoditis marina complex (Nematoda) show differential resource use and have distinct microbiomes with high intraspecific variability. AB - Differences in resource use or in tolerances to abiotic conditions are often invoked as potential mechanisms underlying the sympatric distribution of cryptic species. Additionally, the microbiome can provide physiological adaptations of the host to environmental conditions. We determined the intra- and interspecific variability of the microbiomes of three cryptic nematode species of the Litoditis marina species complex that co-occur, but show differences in abiotic tolerances. Roche 454 pyrosequencing of the microbial 16S rRNA gene revealed distinct bacterial communities characterized by a substantial diversity (85-513 OTUs) and many rare OTUs. The core microbiome of each species contained only very few OTUs (2-6), and four OTUs were identified as potentially generating tolerance to abiotic conditions. A controlled experiment in which nematodes from two cryptic species (Pm1 and Pm3) were fed with either an E. coli suspension or a bacterial mix was performed, and the 16S rRNA gene was sequenced using the MiSeq technology. OTU richness was 10-fold higher compared to the 454 data set and ranged between 1118 and 7864. This experiment confirmed the existence of species specific microbiomes, a core microbiome with few OTUs, and high interindividual variability. The offered food source affected the bacterial community and illustrated different feeding behaviour between the cryptic species, with Pm3 exhibiting a higher degree of selective feeding than Pm1. Morphologically similar species belonging to the same feeding guild (bacterivores) can thus have substantial differences in their associated microbiomes and feeding strategy, which in turn may have important ramifications for biodiversity-ecosystem functioning relationships. PMID- 26929005 TI - Increase in the length of superficial temporal artery biopsy over 14 years. AB - BACKGROUND: Giant cell arteritis is a systemic inflammatory vasculitis of large sized and medium-sized arteries. Superficial temporal artery biopsy of at least 20 mm has traditionally been the standard length for histopathology to accurately diagnose giant cell arteritis. Recent studies suggest than a post-fixation superficial temporal artery biopsy length of 7 to 10 mm is adequate for diagnosing giant cell arteritis. DESIGN: This is a retrospective observational study. PARTICIPANTS OR SAMPLES: The participants were all patients who underwent superficial temporal artery biopsy at Royal Prince Alfred Hospital, a large tertiary teaching hospital in Sydney, Australia, from 2008 to 2014. METHODS: Patients were identified using computerized hospital databases. Superficial temporal artery biopsy lengths were obtained from the histopathology reports. MAIN OUTCOME MEASURES: We aimed to compare the superficial temporal artery biopsy lengths performed at a large tertiary hospital over the past 7 years, to those performed from 2000 to 2005, and to determine the frequency of diagnosis of giant cell arteritis over the two time periods. RESULTS: There was a total of 96 superficial temporal artery biopsies performed from 2008 to 2014. The superficial temporal artery biopsy mean (standard deviation) length was 16.0(7.3) mm. This represented a significant (P = 0.015) increase in mean superficial temporal artery biopsy length when compared with a previous audit performed from 2000 to 2005 where the mean (standard deviation) superficial temporal artery biopsy was 11.7(6.2) mm. Of the 96 TABs, 20 (20.8%) were positive for giant cell arteritis, compared with a giant cell arteritis positivity rate of 20.4% for the previous audit period from 2000 to 2005. CONCLUSION: There has been a significant improvement in the length of superficial temporal artery biopsy performed at a tertiary hospital. Despite the increase in superficial temporal artery biopsy lengths, the giant cell arteritis positivity rate has remained stable. PMID- 26929006 TI - Carbon Nanotube Yarn-Based Glucose Sensing Artificial Muscle. AB - Boronic acid (BA), known to be a reversible glucose-sensing material, is conjugated to a nanogel (NG) derived from hyaluronic acid biopolymer and used as a guest material for a carbon multiwalled nanotube (MWNT) yarn. By exploiting the swelling/deswelling of the NG that originates from the internal anionic charge changes resulting from BA binding to glucose, a NG MWNT yarn artificial muscle is obtained that provides reversible torsional actuation that can be used for glucose sensing. This actuator shows a short response time and high sensitivity (in the 5-100 * 10(-3) m range) for monitoring changes in glucose concentration in physiological buffer, without using any additional auxiliary substances or an electrical power source. It may be possible to apply the glucose-sensing MWNT yarn muscles as implantable glucose sensors that automatically release drugs when needed or as an artificial pancreas. PMID- 26929007 TI - Bioinformatics analysis of gene expression profile in callus tissues of osteoporotic phenotype mice induced by osteoblast-specific Krm2 overexpression. AB - PURPOSE: The aim of this study was to explore the molecular mechanism of fracture healing in osteoporotic mice. METHODS: The gene expression profiles of callus tissues of osteoporotic mice and controls were obtained from Gene Expression Omnibus database. The differentially expressed genes (DEGs) and their related biological function and pathways were investigated. In addition, the protein protein interaction (PPI) network was constructed for DEG encoding proteins and the differentially expressed transcriptional factor was screened. RESULTS: There were 275 up-regulated genes and 347 down-regulated genes. The collagen metabolic process biological function was significantly enriched by down-regulated genes. Extracellular matrix (ECM)-receptor interaction was a significant pathway that was enriched by differentially expressed genes. In PPI (protein-protein interaction) network, Pcna was the significant node with highest connective degrees. Other hub nodes, such as Ccnb2 and Rrm2, were closely associated with the p53 signaling pathway. Tal1 and Smad6 were found to be differentially expressed transcription factors. CONCLUSION: The dysregulated collagen metabolic process, ECM-receptor interaction and p53 signaling pathway may be responsible for impaired fracture healing of osteoporotic mice. The hub nodes (such as Ccnb2 and Rrm2) and differentially expressed TFs (such as Tal1 and Smad6) play a critical role in bone remodeling of osteoporotic individuals. PMID- 26929008 TI - Diastereoselective Synthesis of and Mechanistic Understanding for the Formation of 2-Piperidinones from Imines and Cyano-Substituted Anhydrides. AB - 2-Piperidinones are synthesized in a single step from imines and 2-cyano glutaric anhydrides. The reaction provides the products in good diastereoselectivity and generates a quaternary stereogenic center. Substitutions on the anhydride skeleton are well tolerated to provide 2-piperidinones with three stereogenic centers from a single transformation. The pertinent transition structures have also been computed using quantum mechanics and reveal the key interactions controlling the stereochemical outcome of the reaction. PMID- 26929009 TI - Multicenter Cohort Study Comparing U.S. Management of Inpatient Pediatric Immune Thrombocytopenia to Current Treatment Guidelines. AB - BACKGROUND: Recent pediatric immune thrombocytopenia (ITP) guidelines have significantly altered and are encouraging an observational approach for patients without significant bleeding regardless of their platelet count. PROCEDURE: This retrospective multicenter cohort study utilized the Pediatric Health Information Systems (PHIS) administrative database. Subjects were 6 months to 18 years of age, admitted to a PHIS hospital between January 1, 2008 and September 30, 2014, with a primary diagnosis code for ITP. International Classification of Disease, Ninth Revision, Clinical Modification Code (ICD-9-CM) discharge codes identified significant bleeding. Pharmaceutical billing codes identified the use of pharmacologic therapy for ITP. Clinical management during preguideline admissions (January 1, 2008 to August 31, 2011) was compared to postguideline admissions (September 1, 2011 to September 30, 2014). RESULTS: A total of 4,937 subjects met inclusion criteria with a mean age of 6.2 (SD 5) years; 93.4% (4,613/4,937) received pharmacologic treatment for ITP but only 14.2% (699/4,937) had ICD-9-CM codes for significant bleeding; 11.5% (570/4,937) of subjects were readmitted. In comparing pre- versus postguideline time periods, the proportion of subjects receiving ITP pharmacologic treatment did not change (92.9% vs. 94.1%; P = 0.26). A decrease was found in the proportion of bone marrows performed (9.7% vs. 6.4%; P < 0.001) and length of stay (2.3 vs. 2 days; P < 0.001). The proportion of ITP admissions from 2012 to 2014 was modestly decreased when compared to 2008-2010 (12.9 vs. 14.5/10,000 PHIS admissions, P < 0.001). CONCLUSIONS: Despite guidelines and evidence that supports a watchful waiting approach for pediatric patients with ITP, a large proportion of inpatients without significant bleeding are still receiving pharmacologic therapy. Continued efforts are needed to address why inpatient U.S. practice patterns are so discrepant from current treatment guidelines. PMID- 26929010 TI - Molecular Imaging of Biological Samples on Nanophotonic Laser Desorption Ionization Platforms. AB - Mass spectrometry imaging (MSI) is a comprehensive tool for the analysis of a wide range of biomolecules. The mainstream method for molecular MSI is matrix assisted laser desorption ionization, however, the presence of a matrix results in spectral interferences and the suppression of some analyte ions. Herein we demonstrate a new matrix-free MSI technique using nanophotonic ionization based on laser desorption ionization (LDI) from a highly uniform silicon nanopost array (NAPA). In mouse brain and kidney tissue sections, the distributions of over 80 putatively annotated molecular species are determined with 40 MUm spatial resolution. Furthermore, NAPA-LDI-MS is used to selectively analyze metabolites and lipids from sparsely distributed algal cells and the lamellipodia of human hepatocytes. Our results open the door for matrix-free MSI of tissue sections and small cell populations by nanophotonic ionization. PMID- 26929011 TI - CPAP promotes timely cilium disassembly to maintain neural progenitor pool. AB - A mutation in the centrosomal-P4.1-associated protein (CPAP) causes Seckel syndrome with microcephaly, which is suggested to arise from a decline in neural progenitor cells (NPCs) during development. However, mechanisms ofNPCs maintenance remain unclear. Here, we report an unexpected role for the cilium inNPCs maintenance and identifyCPAPas a negative regulator of ciliary length independent of its role in centrosome biogenesis. At the onset of cilium disassembly,CPAPprovides a scaffold for the cilium disassembly complex (CDC), which includes Nde1, Aurora A, andOFD1, recruited to the ciliary base for timely cilium disassembly. In contrast, mutatedCPAPfails to localize at the ciliary base associated with inefficientCDCrecruitment, long cilia, retarded cilium disassembly, and delayed cell cycle re-entry leading to premature differentiation of patientiPS-derivedNPCs. AberrantCDCfunction also promotes premature differentiation ofNPCs in SeckeliPS-derived organoids. Thus, our results suggest a role for cilia in microcephaly and its involvement during neurogenesis and brain size control. PMID- 26929013 TI - Concerns regarding "2015 ACR/ACC/AHA/AATS/ACEP/ASNC/NASCI/SAEM/SCCT/SCMR/SCPC/SNMMI/STR/STS: Appropriate utilization of cardiovascular imaging in emergency department patients with chest Pain". PMID- 26929012 TI - How to make a synaptic ribbon: RIBEYE deletion abolishes ribbons in retinal synapses and disrupts neurotransmitter release. AB - Synaptic ribbons are large proteinaceous scaffolds at the active zone of ribbon synapses that are specialized for rapid sustained synaptic vesicles exocytosis. A single ribbon-specific protein is known, RIBEYE, suggesting that ribbons may be constructed from RIBEYE protein. RIBEYE knockdown in zebrafish, however, only reduced but did not eliminate ribbons, indicating a more ancillary role. Here, we show in mice that full deletion of RIBEYE abolishes all presynaptic ribbons in retina synapses. Using paired recordings in acute retina slices, we demonstrate that deletion of RIBEYE severely impaired fast and sustained neurotransmitter release at bipolar neuron/AII amacrine cell synapses and rendered spontaneous miniature release sensitive to the slow Ca(2+)-buffer EGTA, suggesting that synaptic ribbons mediate nano-domain coupling of Ca(2+) channels to synaptic vesicle exocytosis. Our results show that RIBEYE is essential for synaptic ribbons as such, and may organize presynaptic nano-domains that position release ready synaptic vesicles adjacent to Ca(2+) channels. PMID- 26929014 TI - Antioxidant and Physicochemical Properties of Hydrogen Peroxide-Treated Sugar Beet Dietary Fibre. AB - The aim of the present work was to examine if hydrogen peroxide treatment of sugar beet fibre that aimed at improving its physicochemical properties would impair its antioxidant potential. Three different sugar beet fibres were obtained from sugar beet - non-treated fibre (NTF) from sugar beet cossettes extracted with sulphurous acid, treated fibre (TF) from NTF treated with hydrogen peroxide in alkaline solution and commercially available Fibrex((r)) . The antioxidant activity of extractable and non-extractable fibre fractions in ethanol/water mixture (80:20, v/v) of three fibre samples was estimated. Non-extractable fractions obtained after alkaline treatment of investigated fibres were much higher in phenolic compounds and possessed higher antioxidant potential than extractable fractions. Ferulic acid was proven to be the dominant phenolic acid. Regarding both extractable and non-extractable fractions, Fibrex((r)) had the highest antioxidant activity in chemical tests, while NTF was superior in comparison with TF. Based on the results of Caco-2 cells-based test, all non extractable fractions possessed potential for reactive oxygen species inhibition. Regarding the extractable fractions, only the TF manifested this effect.Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26929015 TI - A Transparent and Flexible Graphene-Piezoelectric Fiber Generator. AB - Piezoelectric fiber-based generators are prepared by combining two distinctive materials - poly(vinlyidene fluoride) fibers and monolayer/bilayer graphene. Novelty lies in the replacement of opaque metal electrodes with transparent graphene electrodes which enable the graphene-piezoelectric fiber generator to exhibit high flexibility and transparency as well as a great performance with an achievable output of voltage/current about 2 V/200 nA. PMID- 26929016 TI - Changing patterns in paediatric optic atrophy aetiology: 1979 to 2015. AB - BACKGROUND: To evaluate the aetiology of paediatric optic atrophy in an Australian population. DESIGN: Retrospective review of medical records was conducted at The Children's Hospital at Westmead, Sydney, Australia. PARTICIPANTS: Two hundred twenty-seven subjects <16 years who were diagnosed with optic atrophy on fundoscopic examination between 1979 and 2015 were included in the study. METHODS: Subjects were obtained from the hospital database, which codes diagnoses for all admissions, as well as the orthoptic department database, which codes diagnoses for ophthalmology department outpatients. MAIN OUTCOME MEASURES: The predominant cause for optic atrophy was assigned to each patient. Clinical presentation was defined as the principal reason for evaluation. Demographic data included gender, affected eye and age at diagnosis. Data on medical comorbidities (cerebral palsy, developmental delay, microcephaly and seizures) and ocular comorbidities (strabismus and nystagmus) were collected. RESULTS: The mean age at initial eye review was 4.7 +/- 4.4 years. There was bilateral optic atrophy in 81.5% of cases. Unilateral optic atrophy was largely due to tumours. When analysing over the three time periods, (1979-1990, 1991-2003 and 2004-2015), perinatal events (3.0%, 22.7% and 22.6%) and neurodegenerative disease (3.0%, 14.9% and 15.1%) are slowly replacing tumours (39.4%, 24.8% and 15.1%) as the top causes for paediatric optic atrophy. The incidence of other causes has remained fairly stable over time, albeit an increase in idiopathic causes. CONCLUSIONS: There has been shift in the etiological profile of optic atrophy. Whilst tumours are still an important cause of paediatric optic atrophy for an Australian population, perinatal events and neurodegenerative disease are becoming more significant. PMID- 26929017 TI - High-Performance Lithium-Air Battery with a Coaxial-Fiber Architecture. AB - The lithium-air battery has been proposed as the next-generation energy-storage device with a much higher energy density compared with the conventional lithium ion battery. However, lithium-air batteries currently suffer enormous problems including parasitic reactions, low recyclability in air, degradation, and leakage of liquid electrolyte. Besides, they are designed into a rigid bulk structure that cannot meet the flexible requirement in the modern electronics. Herein, for the first time, a new family of fiber-shaped lithium-air batteries with high electrochemical performances and flexibility has been developed. The battery exhibited a discharge capacity of 12,470 mAh g(-1) and could stably work for 100 cycles in air; its electrochemical performances were well maintained under bending and after bending. It was also wearable and formed flexible power textiles for various electronic devices. PMID- 26929018 TI - Prevalence of Metastasis at Diagnosis of Osteosarcoma: An International Comparison. AB - BACKGROUND: Osteosarcoma (OS) is the most common primary malignant bone tumor in many countries, with metastatic disease responsible for most patient deaths. This study compares the prevalence of metastatic OS at diagnosis across countries to inform the critical question of whether diagnostic delay or tumor biology drives metastases development prior to diagnosis. PROCEDURE: A literature search of the PubMed database was conducted to compare the prevalence of metastatic disease at the time of OS diagnosis between countries. A pooled prevalence with 95% confidence intervals was calculated for each study meeting inclusion criteria. Studies were grouped for analysis based on human development index (HDI) scores. RESULTS: Our analysis found an 18% (95% confidence interval [CI]: 15%, 20%) average global pooled proportion of metastasis at OS diagnosis. The average prevalence of metastasis at diagnosis increased as HDI groupings decreased, with very high HDI, high HDI, and medium/low HDI groups found to be 15% (95% CI: 13%, 17%), 20% (95% CI: 14%, 28%), and 31% (95% CI: 15%, 52%), respectively. CONCLUSIONS: Our evidence suggests there is a biological baseline for metastatic OS at diagnosis, which is observed in countries with very high HDI. In countries with medium/low HDI, where there are more barriers to accessing healthcare, the higher prevalence of metastasis may result from treatment delay or an artificial prevalence inflation due to patients with less severe symptoms not presenting to clinic. Additional research in countries with medium/low HDI may reveal that earlier detection and treatment could improve patient outcomes in those countries. PMID- 26929019 TI - Efficacy and safety of minodronic acid hydrate in patients with steroid-induced osteoporosis. AB - OBJECTIVES: Minodronic acid hydrate, an oral bisphosphonate, has a greater inhibitory effect on bone resorption than do other approved drugs; however, this has been studied only in patients with primary osteoporosis. Here, we administered minodronic acid hydrate to patients with steroid-induced osteoporosis who have been treated with steroids for rheumatoid arthritis or other collagen diseases, and the efficacy and safety of minodronic acid hydrate were prospectively investigated. METHODS: Twenty-five patients treated in our rheumatology clinic received minodronic acid hydrate 1 mg/day. The changes in bone mineral density (BMD) and bone turnover markers were investigated at 3 and 6 months, and adverse events, including the presence or absence of an incident osteoporotic fracture, were examined over a period of 6 months. RESULTS: Percent changes in BMD of the lumbar spine and femur significantly increased. The values of bone turnover markers significantly decreased. There were no patients with a radiographically apparent incident fracture. Adverse events included toothache for which the patient discontinued the treatment and three cases of gastrointestinal disorder that did not lead to discontinuation, and thus minodronic acid hydrate was well tolerated. CONCLUSIONS: Here, we show that minodronic acid hydrate is effectively and safely used for treatment of steroid induced osteoporosis. PMID- 26929021 TI - Iridium(I)-catalyzed C-H Borylation of alpha,beta-Unsaturated Esters with Bis(pinacolato)diboron. AB - A new process has been developed for the iridium(I)-catalyzed vinylic C-H borylation of alpha,beta-unsaturated esters with bis(pinacolato)diboron (B2 pin2 ). These reactions proceeded in octane at temperatures in the range of 80-120 degrees C to afford the corresponding alkenylboronic compounds in high yields with excellent regio- and stereoselectivities. The presence of an aryl ester led to significant improvements in the yields of the acyclic alkenylboronates. Crossover experiments involving deuterated substrates as well as a mixture of stereoisomers confirmed that this reaction proceeds via a 1,4-addition/beta hydride elimination mechanism. Notably, this reaction was also used to develop a one-pot borylation/Suzuki-Miyaura cross-coupling procedure. PMID- 26929020 TI - Clinical psychologists' attitudes towards the biology and 'new genetics' of intellectual and developmental disabilities: a pilot study using Q-methodology. AB - BACKGROUND: The current study investigated how ideas and models from the 'New Genetics' and associated fields of developmental neuroscience and behavioural phenotypes are perceived by clinical psychologists working with people with intellectual and developmental disabilities (IDD). As well as examining the take up and influence of such ideas, it also examines barriers, both personal and institutional, to the widespread adoption of such concepts and research findings in services for people with IDD. METHODS: A Q-methodology study was undertaken with 31 qualified and 16 trainee clinical psychologists in the North West of England using a specifically developed 81-item Q set. RESULTS: Three factors were identified and labelled Integration of social and medical models, Social model of disability is more helpful and Genetic advances in conflict with recognising the value of people with IDD. CONCLUSION: There was a lack of consensus in clinical psychologists working with people with IDD, with amount and type of professional experience affecting the factor loadings, which may need to be considered in developing clinical applications of genetic IDD research. PMID- 26929022 TI - A Personalized Framework for Dynamic Modeling of Disease Trajectories in Chronic Lymphocytic Leukemia. AB - Chronic lymphocytic leukemia (CLL) is the most common peripheral blood and bone marrow cancer in the developed world. This manuscript proposes mathematical model equations representing the disease dynamics of B-cell CLL. We interconnect delay differential cell cycle models in each of the tumor-involved disease centers using physiologically relevant cell migration. We further introduce five hypothetical case studies representing CLL heterogeneity commonly seen in clinical practice and demonstrate how the proposed CLL model framework may capture disease pathophysiology across patient types. We conclude by exploring the capacity of the proposed temporally- and spatially distributed model to capture the heterogeneity of CLL disease progression. By using global sensitivity analysis, the critical parameters influencing disease trajectory over space and time are: 1) the initial number of CLL cells in peripheral blood, the number of involved lymph nodes, the presence and degree of splenomegaly; 2) the migratory fraction of nonproliferating as well as proliferating CLL cells from bone marrow into blood and of proliferating CLL cells from blood into lymph nodes; and 3) the parameters inducing nonproliferative cells to proliferate. The proposed model offers a practical platform that may be explored in future personalized patient protocols once validated. PMID- 26929023 TI - Characterization of an HEM-Mode Dielectric Resonator for 7-T Human Phosphorous Magnetic Resonance Imaging. AB - GOAL: To design and characterize a new set-up for dual nuclei MRI combining an annular dielectric resonator filled with high permittivity material for phosphorous (31P) and a traveling wave antenna for proton imaging. METHODS: Recent studies have shown that an annular cylinder filled with water can serve as dielectric resonator for proton MRI of the extremities at 7 T. Using a very high permittivity material such as BaTiO3, this type of dielectric resonator can potentially be designed for lower gyromagnetic ratio nuclei. Combining this with a remote antenna for proton imaging, an alternative method for dual frequency imaging at ultrahigh field has been implemented. RESULTS: 3D electromagnetic simulations were performed to examine the efficiency of the dielectric resonator. The new dielectric resonator was constructed for 31P acquisition at 121 MHz on a human 7 T MRI system. Phantom and in vivo scans demonstrated the feasibility of the setup, although the current sensitivity of the dielectric resonator is only half that of an equivalently sized birdcage. CONCLUSION: The new approach offers a simple implementation for dual nuclei imaging at ultrahigh field, with several possibilities for further increases in sensitivity. SIGNIFICANCE: Utilizing high permittivity materials enables very simple designs for high field RF coils: in the current configuration the interactions between the proton and phosphorous resonators are very low. PMID- 26929024 TI - A Novel Sparse Dictionary Learning Separation (SDLS) Model With Adaptive Dictionary Mutual Incoherence Constraint for fMRI Data Analysis. AB - OBJECTIVE: Many studies have shown that the independence assumption in the widely used ICAs is not adaptive enough for brain functional networks (BFN) detection due to the complex brain hemodynamics, functional integration, artifacts embedded in functional magnetic resonance imaging (fMRI) data, etc. In this paper, inspired by sparse coding behavior of human brain, we propose an effective BFNs detection model, called sparse dictionary learning separation (SDLS). METHODS: In the SDLS, facing the dilemma of huge training samples in sparse learning, an efficient spatial-domain data reduction algorithm was first designed to sharply alleviate the training cost and suppress noise. Then, an improved K singular value decomposition was proposed to speed up the correct convergence of the dictionary learning process. Furthermore, considering the variant degrees of functional integration and sparsity of BFNs across different fMRI datasets, a minimum description length-based framework was proposed to formulate two key factors, i.e., the dictionary mutual incoherence level and sparsity level, self adaptively resulting in effective temporal dynamics model. Finally, a least square-based functional network reconstruction was presented to extract the final BFNs. RESULTS: The simulated and real data experiments demonstrated that SDLS had the superiority in the spatial/temporal sources identification, and stronger spatial robustness against the variant smoothing kernels, in contrast to ICAs. CONCLUSION: SDLS was a novel data-driven BFN separation model, which had an overall consideration of multiple factors, e.g., huge samples dilemma, artifacts removal, and variant degrees of functional integration and sparsity of BFNs. SIGNIFICANCE: SDLS as an extension to current fMRI analysis methods was a promising model, which declared the advantage of sparsity. PMID- 26929025 TI - Data Processing in Cellular Microphysiometry. AB - GOAL: This contribution points out the need for well-defined and documented data processing protocols in microphysiometry, an evolving field of label-free cell assays. The sensitivity of the obtained cell metabolic rates toward different routines of raw data processing is evaluated. METHODS: A standard microphysiometric experiment structured in discrete measurement intervals was performed on a platform with a pH- and O 2-sensor readout. It is evaluated using three different data evaluation protocols, based on A) fast Fourier transformation of such dynamics, B) linear regression (LIN) of pH(t) and O2(t) dynamics, and C) numerical simulation (SIM) with a subsequent fitting of dynamics for parameter estimation. RESULTS: We propose a sequence of well documented steps for an organized processing of raw sensor data. Figures of merit for the quality of raw data and the performance of data processing are provided. To estimate metabolic rates, a reaction-diffusion modeling approach is recommended if the necessary model input parameters such as the distribution of the active biomass, sensor response time, and material properties are available. CONCLUSION: The information about cellular metabolic activity contained by measured sensor data dynamics is superimposed by manifold sources of error. Careful consideration of data processing is necessary to eliminate these errors as much as possible and to avoid an incorrect interpretation of data. PMID- 26929026 TI - Palmitoylethanolamide Exerts Antiproliferative Effect and Downregulates VEGF Signaling in Caco-2 Human Colon Carcinoma Cell Line Through a Selective PPAR alpha-Dependent Inhibition of Akt/mTOR Pathway. AB - Palmitoylethanolamide (PEA) is a nutraceutical compound that has been demonstrated to improve intestinal inflammation. We aimed at evaluating its antiproliferative and antiangiogenic effects in human colon adenocarcinoma Caco-2 cell line. Caco-2 cells were treated with increasing concentrations of PEA (0.001, 0.01 and 0.1 MUM) in the presence of peroxisome proliferator-activated receptor-a (PPAR-alpha) or PPAR-gamma antagonists. Cell proliferation was evaluated by performing a MTT assay. Vascular endothelial growth factor (VEGF) release was estimated by ELISA, while the expression of VEGF receptor and the activation of the Akt/mammalian target of rapamycin (mTOR) pathway were evaluated by western blot analysis. PEA caused a significant and concentration-dependent decrease of Caco-2 cell proliferation at 48 h. PEA administration significantly reduced in a concentration-dependent manner VEGF secretion and VEGF receptor expression. Inhibition of Akt phosphorylation and a downstream decrease of phospho-mTOR and of p-p70S6K were observed as compared with untreated cells. PPAR alpha, but not PPAR-gamma antagonist, reverted all effects of PEA. PEA is able to decrease cell proliferation and angiogenesis. The antiangiogenic effect of PEA depends on the specific inhibition of the AkT/mTOR axis, through the activation of PPAR-alpha pathway. If supported by in vivo models, our data pave the way to PEA co-administration to the current chemotherapeutic regimens for colon carcinoma. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26929028 TI - Emergence of an imaging biomarker for amyotrophic lateral sclerosis: is the end point near? PMID- 26929027 TI - A subpopulation of itch-sensing neurons marked by Ret and somatostatin expression. AB - Itch, the unpleasant sensation that elicits a desire to scratch, is mediated by specific subtypes of cutaneous sensory neuron. Here, we identify a subpopulation of itch-sensing neurons based on their expression of the receptor tyrosine kinase Ret. We apply flow cytometry to isolate Ret-positive neurons from dorsal root ganglia and detected a distinct population marked by low levels of Ret and absence of isolectin B4 binding. We determine the transcriptional profile of these neurons and demonstrate that they express neuropeptides such as somatostatin (Sst), the NGF receptor TrkA, and multiple transcripts associated with itch. We validate the selective expression of Sst using an Sst-Cre driver line and ablated these neurons by generating mice in which the diphtheria toxin receptor is conditionally expressed from the sensory neuron-specific Avil locus. Sst-Cre::Avil(iDTR) mice display normal nociceptive responses to thermal and mechanical stimuli. However, scratching behavior evoked by interleukin-31 (IL-31) or agonist at the 5HT1F receptor is significantly reduced. Our data provide a molecular signature for a subpopulation of neurons activated by multiple pruritogens. PMID- 26929030 TI - Tetraphenylethene-Based Conjugated Fluoranthene: A Potential Fluorescent Probe for Detection of Nitroaromatic Compounds. AB - This study reports the synthesis and photophysical properties of a star-shaped, novel, fluoranthene-tetraphenylethene (TFPE) conjugated luminogen, which exhibits aggregation-induced blue-shifted emission (AIBSE). The bulky fluoranthene units at the periphery prevent intramolecular rotation (IMR) of phenyl rings and induces a blueshift with enhanced emission. The AIBSE phenomenon was investigated by solvatochromic and temperature-dependent emission studies. Nanoaggregates of TFPE, formed by varying the water/THF ratio, were investigated by SEM and TEM and correlated with optical properties. The TFPE conjugate was found to be a promising fluorescent probe towards the detection of nitroaromatic compounds (NACs), especially for 2,4,6-trinitrophenol (PA) with high sensitivity and a high Stern-Volmer quenching constant. The study reveals that nanoaggregates of TFPE formed at 30 and 70% water in THF showed unprecedented sensitivity with detection limits of 0.8 and 0.5 ppb, respectively. The nanoaggregates formed at water fractions of 30 and 70% exhibit high Stern-Volmer constants (Ksv=79,998 and 51,120 M(-1), respectively) towards PA. Fluorescence quenching is ascribed to photoinduced electron transfer between TFPE and NACs with a static quenching mechanism. Test strips coated with TFPE luminogen demonstrate fast and ultra-low level detection of PA for real-time field analysis. PMID- 26929031 TI - Minimum Entropy Rate Simplification of Stochastic Processes. AB - We propose minimum entropy rate simplification (MERS), an information-theoretic, parameterization-independent framework for simplifying generative models of stochastic processes. Applications include improving model quality for sampling tasks by concentrating the probability mass on the most characteristic and accurately described behaviors while de-emphasizing the tails, and obtaining clean models from corrupted data (nonparametric denoising). This is the opposite of the smoothing step commonly applied to classification models. Drawing on rate distortion theory, MERS seeks the minimum entropy-rate process under a constraint on the dissimilarity between the original and simplified processes. We particularly investigate the Kullback-Leibler divergence rate as a dissimilarity measure, where, compatible with our assumption that the starting model is disturbed or inaccurate, the simplification rather than the starting model is used for the reference distribution of the divergence. This leads to analytic solutions for stationary and ergodic Gaussian processes and Markov chains. The same formulas are also valid for maximum-entropy smoothing under the same divergence constraint. In experiments, MERS successfully simplifies and denoises models from audio, text, speech, and meteorology. PMID- 26929029 TI - Multiparametric Biomechanical and Biochemical Phenotypic Profiling of Single Cancer Cells Using an Elasticity Microcytometer. AB - Deep phenotyping of single cancer cells is of critical importance in the era of precision medicine to advance understanding of relationships between gene mutation and cell phenotype and to elucidate the biological nature of tumor heterogeneity. Existing microfluidic single-cell phenotyping tools, however, are limited to phenotypic measurements of 1-2 selected morphological and physiological features of single cells. Herein a microfluidic elasticity microcytometer is reported for multiparametric biomechanical and biochemical phenotypic profiling of free-floating, live single cancer cells for quantitative, simultaneous characterizations of cell size, cell deformability/stiffness, and surface receptors. The elasticity microcytometer is implemented for measurements and comparisons of four human cell lines with distinct metastatic potentials and derived from different human tissues. An analytical model is developed from first principles for the first time to convert cell deformation and adhesion information of single cancer cells encapsulated inside the elasticity microcytometer to cell deformability/stiffness and surface protein expression. Together, the elasticity microcytometer holds great promise for comprehensive molecular, cellular, and biomechanical phenotypic profiling of live cancer cells at the single cell level, critical for studying intratumor cellular and molecular heterogeneity using low-abundance, clinically relevant human cancer cells. PMID- 26929032 TI - Do physicians correctly calculate thromboembolic risk scores? A comparison of concordance between manual and computer-based calculation of CHADS2 and CHA2 DS2 VASc scores. AB - BACKGROUND: Clinical risk scores, CHADS2 and CHA2 DS2 -VASc scores, are the established tools for assessing stroke risk in patients with atrial fibrillation (AF). AIM: The aim of this study is to assess concordance between manual and computer-based calculation of CHADS2 and CHA2 DS2 -VASc scores, as well as to analyse the patient categories using CHADS2 and the potential improvement on stroke risk stratification with CHA2 DS2 -VASc score. METHODS: We linked data from Atrial Fibrillation Spanish registry FANTASIIA. Between June 2013 and March 2014, 1318 consecutive outpatients were recruited. We explore the concordance between manual scoring and computer-based calculation. We compare the distribution of embolic risk of patients using both CHADS2 and CHA2 DS2 -VASc scores RESULTS: The mean age was 73.8 +/- 9.4 years, and 758 (57.5%) were male. For CHADS2 score, concordance between manual scoring and computer-based calculation was 92.5%, whereas for CHA2 DS2 -VASc score was 96.4%. In CHADS2 score, 6.37% of patients with AF changed indication on antithrombotic therapy (3.49% of patients with no treatment changed to need antithrombotic treatment and 2.88% of patients otherwise). Using CHA2 DS2 -VASc score, only 0.45% of patients with AF needed to change in the recommendation of antithrombotic therapy. CONCLUSION: We have found a strong concordance between manual and computer-based score calculation of both CHADS2 and CHA2 DS2 -VASc risk scores with minimal changes in anticoagulation recommendations. The use of CHA2 DS2 -VASc score significantly improves classification of AF patients at low and intermediate risk of stroke into higher grade of thromboembolic score. Moreover, CHA2 DS2 -VASc score could identify 'truly low risk' patients compared with CHADS2 score. PMID- 26929033 TI - Controlled Core-Modification of a Porphyrin into an Antiaromatic Isophlorin. AB - Partial core-modification of a porphyrin can be employed to synthesize the 20pi antiaromatic isophlorin. Unlike the tetra-, tri-, and dipyrrole derivatives of a porphyrin, a monopyrrole porphyrin exhibits antiaromatic characteristics. It undergoes a two-electron reversible ring oxidation to yield the 18pi aromatic dication. (1) H NMR analysis provides distinct evidence of the altered electronic characteristics through typical paratropic and diatropic ring current effects for the 4n and the (4n+2) pi-electron systems, respectively. PMID- 26929034 TI - Mammalian Target of Rapamycin Inhibitor Induced Complete Remission of a Recurrent Subependymal Giant Cell Astrocytoma in a Patient Without Features of Tuberous Sclerosis Complex. AB - The majority of patients with subependymal giant cell astrocytoma (SEGA) have tuberous sclerosis complex (TSC). In such patients, the mammalian target of rapamycin (mTOR) inhibitor everolimus has been shown to induce responses. Isolated SEGA have been reported in patients without clinical or genetic features of TSC. The treatment of these patients with everolimus has not previously been reported. We treated a patient with a recurrent isolated SEGA with an mTOR inhibitor. The patient tolerated therapy well and had a sustained complete remission. MTOR inhibitors may be useful for the treatment of isolated SEGA. Further study is warranted. PMID- 26929035 TI - What led health professionals to study and practise acupuncture in Spain? AB - Acupuncture is the most widespread practice of Traditional Chinese Medicine in the Western world. This confers special relevance to the experiences and circumstances of life to explain the health-illness process. Recent research has reported an increasing interest of Western health professionals in its practice. The aim of this study was to map and understand the motivation of health professionals to study and practise acupuncture in Spain. A total of 27 in-depth interviews were conducted with Spanish health professionals trained in acupuncture. Participants were selected following a theoretical sampling. Grounded theory dimensional analysis guided this research in order to obtain a theoretical explanation of the motivations of health professionals to study and practise acupuncture. Their motivations were focused on six categories: humanisation of medicine, acquiring additional therapeutic resources, efficacy and far-reaching healing potential of acupuncture, attraction to acupuncture philosophy, external influences (other professionals and relevant sources of information) and work-related motivation. Our results show that health professionals were attracted to acupuncture because of the Traditional Chinese Medicine worldview (a philosophical approach) and therapeutic benefits of acupuncture (a practical approach). Acupuncture offers the possibility to improve the healthcare assistance by transcending the reification of human beings resulting from the pre-eminence of the biomedical paradigm and facilitating cooperation between disciplines. Participants consider acupuncture as a complete medicine, not merely as a technique, and highlight the importance of traditional Chinese concepts to practise it. PMID- 26929036 TI - Central pontine myelinolysis in Sjogren's syndrome with hypokalemia. PMID- 26929037 TI - Validity of a condition specific outcome measure for fragile X syndrome: the Aberrant Behaviour Checklist-utility index. AB - BACKGROUND: The purpose of this study was to assess the construct validity of the Aberrant Behaviour Checklist-utility index (ABC-UI) by examining the relationship between healthcare resource utilisation by patients with fragile X syndrome (FXS) as well as burden experienced by their caregivers. METHOD: In 2011, a total of 350 US caregivers of individuals with FXS completed a questionnaire that captured information on FXS-related burden as well as the ABC-Community. Using the ABC-UI, a condition-specific outcome measure derived from the ABC-Community, five utility index categories were created: very low (0.00-0.33); low (0.34-0.66); moderate (0.67-0.77); high (0.78-0.89); and very high (0.90-1.00). Multivariable regression models examined the association between the utility value and nine burden-related outcomes. RESULTS: Approximately 2% of individuals with FXS were in the very low utility index category, 31% low, 27% moderate, 38% high and 3% very high. The median utility value was 0.74. Women with FXS and adults 18 years and older had higher values. Regression results indicate that individuals with higher utility values were more likely to have fewer specialist visits, use fewer prescription medications, need fewer hours of unpaid caregiving, inflict fewer caregiver injuries and have caregivers with fewer mental health provider visits. CONCLUSIONS: The ABC-UI appears to function well as condition-specific outcome measure, and as an indicator of health-related quality-of-life and economic burden in individuals with FXS. Among patients with FXS in the US and their caregivers, significant differences in health care resource utilisation and burden exist across health state utility categories. PMID- 26929038 TI - Asymmetric P-C Bond Formation: Diastereoselective Synthesis of Adjacent P,C Stereogenic Allylic Phosphorus Compounds. AB - A novel catalytic asymmetric P-C bond formation between phosphinates/phosphine oxide and allylic carbonates was developed. This methodology could not only afford a variety of functionalized adjacent P,C-stereogenic phosphorus compounds in high yields with high regio- and diastereoselectivities but also provide an alternative strategy to access enantiomerically enriched (SP )-phosphinates through kinetic resolution. PMID- 26929039 TI - An Investigation of Lateral Modes in FBAR Resonators. AB - Using first principles and the constitutive equations for a piezoelectric, we solve the 2D acoustic wave inside a single, infinite, piezoelectric membrane in order to study the dispersion of Thin Film Bulk Acoustic Resonator (FBAR) lateral modes, with and without infinitely-thin electrodes. The acoustic eigenfunction is a dual wave, composed of longitudinal and shear components, able to satisfy the 2D acoustic boundary conditions at the vacuum interfaces. For the single piezoelectric slab we obtain analytical expressions of the dispersion for frequencies near the longitudinal resonant frequency (Fs) of the resonator. These expressions are more useful for the understanding of dispersion in FBARs and more elegant than numerical methods like Finite Element Modeling (FEM) and various matrix methods. We additionally find that the interaction between the resonator's electrodes and the acoustic wave modifies the lateral mode dispersion when compared to the case with no electrodes. When correctly accounting for these interactions the dispersion zero is placed clearly at Fs, unlike what is calculated from a 2D model without electrodes where the dispersion zero is placed at Fp. This is important since all experimental evidence of measures FBAR resonators shows that the dispersion zero is at Fs. Furthermore, we introduce an electrical current flow model for the propagating acoustic wave inside the electroded piezoelectric and based on this model we can discuss an electrode-loss mechanism for FBAR lateral modes which depends on dispersion. From our model it results that lateral modes with real kx have higher electrode dissipation if they are closer to the resonant frequency. This is consistent with the typical behavior of measured FBAR filters where the maximum lateral mode damage on the insertion loss takes place for frequencies immediately below Fs. PMID- 26929040 TI - Structural and resting-state MRI detects regional brain differences in young and mid-age healthy APOE-e4 carriers compared with non-APOE-e4 carriers. AB - The presence of the e4 allele of the apolipoprotein E (APOE) gene is the best known genetic risk factor for Alzheimer's disease. In this study, we investigated the link between functional and behavioural differences and regional brain volume and cortical thickness differences in those who carry the e4 allele (e4+) and those who only carry the e3 allele (e3/e3). We studied these genotype populations in two age groups: a young group (average age, 21 years) and a mid-age group (average age, 50 years). High-resolution T1 -weighted MRI scans were analysed with Freesurfer to measure regional white matter brain volume and cortical thickness differences between genotype groups at each age. These data were correlated with behavioural findings in the same cohort. Resting-state MRI was also conducted to identify differences in underlying brain functional connectivity. We found that there was a positive correlation between the thickness of the parahippocampal cortex in young e4+ individuals and performance on an episodic memory task. Young e4+ individuals also showed a positive correlation between white matter volume in the left anterior cingulate and performance on a covert attention task. At mid-age, e4+ individuals had structural differences relative to e3/e3 individuals in these areas: the parahippocampal cortex was thicker and white matter volume in the left anterior cingulate was greater than in e3/e3 individuals. We discuss the possibility that an over-engagement with these regions by e4+ individuals in youth may have a neurogenic effect that is observable later in life. The cuneus appears to be an important region for APOE-driven differences in the brain, with greater functional connectivity among young e3/e3 individuals and greater white matter volume in young e4+ individuals. PMID- 26929041 TI - Chemical modification of a phenoxyfuranone-type strigolactone mimic for selective effects on rice tillering or Striga hermonthica seed germination. AB - BACKGROUND: We previously reported that a series of phenoxyfuranone compounds, designated 'debranones', mimic strigolactone (SL) activity. 4-Bromodebranone (4BD) is a functionally selective SL mimic that reduces the number of shoot branches on rice more potently than GR24, a typical synthetic SL analogue, but does not induce seed germination in the root-parasitic plant Striga hermonthica. To enhance the selective activity of debranones in stimulating the seed germination of root-parasitic plants, we prepared several analogues of 4BD in which the chlorine atom was substituted with an H atom at the o-, m- or p position on the phenyl ring (designated 2-, 3-, or 4-chlorodebranone, respectively) or had a bicyclic group instead of the phenyl ring. We evaluated the biological activities of the compounds with rice tillering assays and S. hermonthica seed germination assays. RESULTS: Both assays showed that the substituent position affected debranone efficiency, and among the monochlorodebranones, 2-chlorodebranone was more effective than the other two isomers in both assays. When the activities of the bicyclic debranones were compared in the same two assays, one was more active than GR24 in the rice tillering assay. This debranone also stimulated the germination of S. hermonthica seeds. Thus, some debranone derivatives induced the germination of S. hermonthica seeds, although their activities were still ~1/20 that of GR24. CONCLUSION: These results strongly suggest that further and rigorous structure-activity relationship studies of the debranones will identify derivatives that more potently stimulate the suicidal germination of S. hermonthica seeds. (c) 2016 Society of Chemical Industry. PMID- 26929042 TI - Oxygen Evolution Assisted Fabrication of Highly Loaded Carbon Nanotube/MnO2 Hybrid Films for High-Performance Flexible Pseudosupercapacitors. AB - To date, it has been a great challenge to design high-performance flexible energy storage devices for sufficient loading of redox species in the electrode assemblies, with well-maintained mechanical robustness and enhanced electron/ionic transport during charge/discharge cycles. An electrochemical activation strategy is demonstrated for the facile regeneration of carbon nanotube (CNT) film prepared via floating catalyst chemical vapor deposition strategy into a flexible, robust, and highly conductive hydrogel-like film, which is promising as electrode matrix for efficient loading of redox species and the fabrication of high-performance flexible pseudosupercapacitors. The strong and conductive CNT films can be effectively expanded and activated by electrochemical anodic oxygen evolution reaction, presenting greatly enhanced internal space and surface wettability with well-maintained strength, flexibility, and conductivity. The as-formed hydrogel-like film is quite favorable for electrochemical deposition of manganese dioxide (MnO2 ) with loading mass up to 93 wt% and electrode capacitance kept around 300 F g(-1) (areal capacitance of 1.2 F cm(-2) ). This hybrid film was further used to assemble a flexible symmetric pseudosupercapacitor without using any other current collectors and conductive additives. The assembled flexible supercapacitors exhibited good rate performance, with the areal capacitance of more than 300 mF cm(-2) , much superior to other reported MnO2 based flexible thin-film supercapacitors. PMID- 26929043 TI - Design of an Os Complex-Modified Hydrogel with Optimized Redox Potential for Biosensors and Biofuel Cells. AB - Multistep synthesis and electrochemical characterization of an Os complex modified redox hydrogel exhibiting a redox potential ~+30 mV (vs. Ag/AgCl 3 M KCl) is demonstrated. The careful selection of bipyridine-based ligands bearing N,N-dimethylamino moieties and an amino-linker for the covalent attachment to the polymer backbone ensures the formation of a stable redox polymer with an envisaged redox potential close to 0 V. Most importantly, the formation of an octahedral N6-coordination sphere around the Os central atoms provides improved stability concomitantly with the low formal potential, a low reorganization energy during the Os(3+/2+) redox conversion and a negligible impact on oxygen reduction. By wiring a variety of enzymes such as pyrroloquinoline quinone (PQQ) dependent glucose dehydrogenase, flavin adenine dinucleotide (FAD)-dependent glucose dehydrogenase and the FAD-dependent dehydrogenase domain of cellobiose dehydrogenase, low-potential glucose biosensors could be obtained with negligible co-oxidation of common interfering compounds such as uric acid or ascorbic acid. In combination with a bilirubin oxidase-based biocathode, enzymatic biofuel cells with open-circuit voltages of up to 0.54 V were obtained. PMID- 26929044 TI - Scene Parsing With Integration of Parametric and Non-Parametric Models. AB - We adopt convolutional neural networks (CNNs) to be our parametric model to learn discriminative features and classifiers for local patch classification. Based on the occurrence frequency distribution of classes, an ensemble of CNNs (CNN Ensemble) are learned, in which each CNN component focuses on learning different and complementary visual patterns. The local beliefs of pixels are output by CNN Ensemble. Considering that visually similar pixels are indistinguishable under local context, we leverage the global scene semantics to alleviate the local ambiguity. The global scene constraint is mathematically achieved by adding a global energy term to the labeling energy function, and it is practically estimated in a non-parametric framework. A large margin-based CNN metric learning method is also proposed for better global belief estimation. In the end, the integration of local and global beliefs gives rise to the class likelihood of pixels, based on which maximum marginal inference is performed to generate the label prediction maps. Even without any post-processing, we achieve the state-of the-art results on the challenging SiftFlow and Barcelona benchmarks. PMID- 26929045 TI - A survey of Australian and New Zealand clinical practice with neoadjuvant systemic therapy for breast cancer. AB - BACKGROUND: Neoadjuvant systemic therapy (NAST) has become an established treatment option for women with operable breast cancer. AIM: We aimed to better understand NAST treatment patterns, barriers and facilitators in Australia and New Zealand. METHODS: We undertook a cross-sectional survey of the current clinical practice of Australian and New Zealand breast cancer specialists. Questions included referral patterns for NAST, patient selection, logistics, decision making and barriers. RESULTS: Of 207 respondents, 162 (78%) reported routinely offering NAST to selected patients with operable breast cancer (median 9% of patients offered NAST). Specialty, location, practice type, gender or years of experience did not predict for offering NAST. In all, 45 and 58% wanted to increase the number of patients who receive NAST in routine care and in clinical trials respectively. Facilitators included the multidisciplinary team meeting and access to NAST clinical trials. Specialist-reported patient barriers included: patient desire for immediate surgery (63% rated as important/very important); lack of awareness of NAST (50%); concern about progression (43%) and disinterest in downstaging (32%). Forty-three per cent of participants experienced system related barriers to the use of NAST, including other clinicians' lack of interest (27%); lack of clinical trials (24%) and unacceptable wait for a medical oncology appointment (37%). CONCLUSION: This group of Australian and New Zealand clinicians are interested in NAST for operable breast cancer in routine care and clinical trials. Patient- and system-related barriers that prevent the optimal uptake of this treatment approach will need to be systematically addressed if NAST is to become a more common approach. PMID- 26929046 TI - A family is born. PMID- 26929047 TI - Successful treatment of PR3-ANCA positive vasculitis with pancreatitis as the first manifestation with rituximab. PMID- 26929048 TI - Efficient Synthesis of the Disialylated Tetrasaccharide Motif in N-Glycans through an Amide-Protection Strategy. AB - A disialylated tetrasaccharide, Neu5Ac(alpha2,3)Gal(beta1,3)[Neu5Ac(alpha2,6)]GlcNAc (1), which is found at the termini of some N-glycans, has been synthesized. Compound 1 was obtained through an alpha-sialylation reaction between a sialic acid donor and a trisaccharide that was synthesized from the glycosylation of a sialylated disaccharide with a glucosaminyl donor. This synthetic route enabled the synthesis of the as described disialylated structure. A more-convergent route based on the glycosylation of two sialylated disaccharides was also established to scale up the synthesis. Protection of the amide groups in the sialic acid residues significantly increased the yield of the glycosylation reaction between the two sialylated disaccharides, thus suggesting that the presence of hydrogen bonds on the sialic acid residues diminished their reactivity. PMID- 26929050 TI - Apparent exchange rate for breast cancer characterization. AB - Although diffusion MRI has shown promise for the characterization of breast cancer, it has low specificity to malignant subtypes. Higher specificity might be achieved if the effects of cell morphology and molecular exchange across cell membranes could be disentangled. The quantification of exchange might thus allow the differentiation of different types of breast cancer cells. Based on differences in diffusion rates between the intra- and extracellular compartments, filter exchange spectroscopy/imaging (FEXSY/FEXI) provides non-invasive quantification of the apparent exchange rate (AXR) of water between the two compartments. To test the feasibility of FEXSY for the differentiation of different breast cancer cells, we performed experiments on several breast epithelial cell lines in vitro. Furthermore, we performed the first in vivo FEXI measurement of water exchange in human breast. In cell suspensions, pulsed gradient spin-echo experiments with large b values and variable pulse duration allow the characterization of the intracellular compartment, whereas FEXSY provides a quantification of AXR. These experiments are very sensitive to the physiological state of cells and can be used to establish reliable protocols for the culture and harvesting of cells. Our results suggest that different breast cancer subtypes can be distinguished on the basis of their AXR values in cell suspensions. Time-resolved measurements allow the monitoring of the physiological state of cells in suspensions over the time-scale of hours, and reveal an abrupt disintegration of the intracellular compartment. In vivo, exchange can be detected in a tumor, whereas, in normal tissue, the exchange rate is outside the range experimentally accessible for FEXI. At present, low signal-to-noise ratio and limited scan time allows the quantification of AXR only in a region of interest of relatively large tumors. PMID- 26929051 TI - Determinants for Tight and Selective Binding of a Medicinal Dicarbene Gold(I) Complex to a Telomeric DNA G-Quadruplex: a Joint ESI MS and XRD Investigation. AB - The dicarbene gold(I) complex [Au(9-methylcaffein-8-ylidene)2 ]BF4 is an exceptional organometallic compound of profound interest as a prospective anticancer agent. This gold(I) complex was previously reported to be highly cytotoxic toward various cancer cell lines in vitro and behaves as a selective G quadruplex stabilizer. Interactions of the gold complex with various telomeric DNA models have been analyzed by a combined ESI MS and X-ray diffraction (XRD) approach. ESI MS measurements confirmed formation of stable adducts between the intact gold(I) complex and Tel 23 DNA sequence. The crystal structure of the adduct formed between [Au(9-methylcaffein-8-ylidene)2 ](+) and Tel 23 DNA G quadruplex was solved. Tel 23 maintains a characteristic propeller conformation while binding three gold(I) dicarbene moieties at two distinct sites. Stacking interactions appear to drive noncovalent binding of the gold(I) complex. The structural basis for tight gold(I) complex/G-quadruplex recognition and its selectivity are described. PMID- 26929052 TI - Survey of indigenous entomopathogenic fungi and evaluation of their pathogenicity against the carmine spider mite, Tetranychus cinnabarinus (Boisd.), and the whitefly, Bemisia tabaci (Genn.) biotype B. AB - BACKGROUND: The carmine spider mite, Tetranychus cinnabarinus, and the silverleaf whitefly, Bemisia tabaci, are serious pests of both field- and greenhouse-grown crops in south-western Turkey. Control of these pests has been heavily dependent upon chemical pesticides. The objectives of this study were to investigate the occurrence of indigenous entomopathogenic fungi (EPF) in field populations of T. cinnabarinus and B. tabaci, and to evaluate their pathogenicity against these pests. For this purpose, a survey of EPF isolated from field-collected samples of both pests was carried out in Antalya in 2010 and 2011 using the dilution plating method. RESULTS: Four indigenous Beauveria bassiana isolates (TUR1-B, TUR2-B, FIN1-B, FIN2-B) were recovered. In pathogenicity bioassays with T. cinnabarinus and B. tabaci biotype B, all the isolates tested were pathogenic to some of the biological stages of both pests to varying degrees. FIN1-B and TUR1-B caused mortalities of up to 50 and 45%, respectively, in adults of T. cinnabarinus, and of over 79 and 37%, respectively, in pupae of B. tabaci with 107 conidia mL-1 suspensions under laboratory conditions 10 days after inoculation. FIN2-B and TUR2-B had mortalities of 19.45 and 12.28%, respectively, in adults of T. cinnabarinus, and of 6.78 and 8.18%, respectively, in pupae of B. tabaci. None of the isolates had an effect on eggs of either species and larvae of the mite. CONCLUSION: Overall results suggest that isolates FIN1-B and TUR1-B have potential for management of T. cinnabarinus and B. tabaci. (c) 2016 Society of Chemical Industry. PMID- 26929054 TI - Missing Sample Recovery for Wireless Inertial Sensor-Based Human Movement Acquisition. AB - This paper presents a novel, practical, and effective routine to reconstruct missing samples from a time-domain sequence of wirelessly transmitted IMU data during high-level mobility activities. Our work extends previous approaches involving empirical mode decomposition (EMD)-based and auto-regressive (AR) model based interpolation algorithms in two aspects: 1) we utilized a modified sifting process for signal decomposition into a set of intrinsic mode functions with missing samples, and 2) we expand previous AR modeling for recovery of audio signals to exploit the quasi-periodic characteristics of lower-limb movement during the modified Edgren side step test. To verify the improvements provided by the proposed extensions, a comparison study of traditional interpolation methods, such as cubic spline interpolation, AR model-based interpolations, and EMD-based interpolation is also made via simulation with real inertial signals recorded during high-speed movement. The evaluation was based on two performance criteria: Euclidian distance and Pearson correlation coefficient between the original signal and the reconstructed signal. The experimental results show that the proposed method improves upon traditional interpolation methods used in recovering missing samples. PMID- 26929053 TI - Flexible Octopus-Shaped Hydrogel Particles for Specific Cell Capture. AB - Multiarm hydrogel microparticles with varying geometry are fabricated to specifically capture cells expressing epithelial cell adhesion molecule. Results show that particle shape influences cell-capture efficiency due to differences in surface area, hydrodynamic effects, and steric constraints. These findings can lead to improved particle design for cell separation and diagnostic applications. PMID- 26929055 TI - Assistive Control System for Upper Limb Rehabilitation Robot. AB - This paper presents an assistive control system with a special kinematic structure of an upper limb rehabilitation robot embedded with force/torque sensors. A dynamic human model integrated with sensing torque is used to simulate human interaction under three rehabilitation modes: active mode, assistive mode, and passive mode. The hereby proposed rehabilitation robot, called NTUH-ARM, provides 7 degree-of- freedom (DOF) motion and runs subject to an inherent mapping between the 7 DOFs of the robot arm and the 4 DOFs of the human arm. The Lyapunov theory is used to analyze the stability of the proposed controller design. Clinical trials have been conducted with six patients, one of which acts as a control. The results of these experiments are positive and STREAM assessment by physical therapists also reveals promising results. PMID- 26929056 TI - MIT-Skywalker: A Novel Gait Neurorehabilitation Robot for Stroke and Cerebral Palsy. AB - The MIT-Skywalker is a novel robotic device developed for the rehabilitation or habilitation of gait and balance after a neurological injury. It represents an embodiment of the concept exhibited by passive walkers for rehabilitation training. Its novelty extends beyond the passive walker quintessence to the unparalleled versatility among lower extremity devices. For example, it affords the potential to implement a novel training approach built upon our working model of movement primitives based on submovements, oscillations, and mechanical impedances. This translates into three distinct training modes: discrete, rhythmic, and balance. The system offers freedom of motion that forces self directed movement for each of the three modes. This paper will present the technical details of the robotic system as well as a feasibility study done with one adult with stroke and two adults with cerebral palsy. Results of the one month feasibility study demonstrated that the device is safe and suggested the potential advantages of the three modular training modes that can be added or subtracted to tailor therapy to a particular patient's need. Each participant demonstrated improvement in common clinical and kinematic measurements that must be confirmed in larger randomized control clinical trials. PMID- 26929057 TI - Discriminating Between Patients With Parkinson's and Neurological Diseases Using Cepstral Analysis. AB - In this paper, we wanted to discriminate between two groups of patients (patients who suffer from Parkinson's disease and patients who suffer from other neurological disorders). We collected a variety of voice samples from 50 subjects using different recording devices in different conditions. Subsequently, we analyzed and extracted features from these samples using three different Cepstral techniques; Mel frequency cepstral coefficients (MFCC), perceptual linear prediction (PLP), and ReAlitive SpecTrAl PLP (RASTA-PLP). For classification we used leave one subject out validation scheme along with five different supervised learning classifiers. The best obtained result was 90% using the first 11 coefficients of the PLP and linear SVM kernels. PMID- 26929058 TI - How Does Substitutional Doping Affect Visible Light Absorption in a Series of Homodisperse Ti11 Polyoxotitanate Nanoparticles--A Comment on the Band Gap Determination of the Fe(II) Cages (Chem. Eur. J. 2015, 21, 11538). AB - There is no experimental support for the conclusion by Coppens and Chen in a recent paper that the (HOMO-LUMO) band gaps in a series of Fe(II) polyoxotitanate cages are in the range 1.43-1.59 eV. PMID- 26929059 TI - Asking better questions about clinical skills training. PMID- 26929060 TI - Laser Speckle Imaging to Monitor Microvascular Blood Flow: A Review. AB - Laser speckle is a complex interference phenomenon that can easily be understood, in concept, but is difficult to predict mathematically, because it is a stochastic process. The use of laser speckle to produce images, which can carry many types of information, is called laser speckle imaging (LSI). The biomedical applications of LSI started in 1981 and, since then, many scientists have improved the laser speckle theory and developed different imaging techniques. During this process, some inconsistencies have been propagated up to now. These inconsistencies should be clarified in order to avoid errors in future works. This review presents a review of the laser speckle theory used in biomedical applications. Moreover, we also make a review of the practical concepts that are useful in the construction of laser speckle imagers. This study is not only an exposition of the concepts that can be found in the literature but also a critical analysis of the investigations presented so far. Concepts like scatterers velocity distribution, effect of static scatterers, optimal speckle size, light penetration angle, and contrast computation algorithms are discussed in detail. PMID- 26929061 TI - Methamphetamine-associated cardiomyopathy: patterns and predictors of recovery. AB - BACKGROUND: Methamphetamine abuse is a growing public health problem, and increasing numbers of patients are admitted with methamphetamine-associated cardiomyopathy (MAC). AIM: We sought to characterise the patterns of this disease and identify predictors of recovery. METHODS: We retrospectively studied consecutive patients diagnosed with MAC between January 2006 and July 2015. RESULTS: We identified 20 patients (14 males, 6 females) with mean age 35 +/- 9 years. Most had very severe systolic dysfunction (mean left ventricular ejection fraction (LVEF) 19.7 +/- 11.4%) at presentation with 14 requiring inotropes and 5 requiring mechanical support. The pattern of systolic dysfunction was global in 14 patients, while 6 patients had a 'reverse Takotsubo' (RT) pattern with severely hypokinetic basal-mid segments and apical preservation. RT patients were predominantly female, had a short history of methamphetamine abuse and had higher cardiac enzyme levels. Patients with global dysfunction tended to have mid-wall fibrosis on cardiac magnetic resonance imaging. On follow-up transthoracic echocardiography, 6 out of 19 (32%) had normalisation of LVEF (LVEF >= 50%) within 6 weeks. Smaller left ventricular and left atrial size, shorter duration of methamphetamine use and RT pattern appeared to predict early recovery. CONCLUSION: A subset of MAC patients, particularly those with a RT pattern and lesser ventricular dilatation have the potential for early recovery of ventricular function. By contrast, those with evidence of myocardial fibrosis and ventricular enlargement have limited scope for recovery. PMID- 26929063 TI - Is plasmapheresis a potential treatment for familial Mediterranean fever patients resistant or intolerant to colchicine? PMID- 26929064 TI - Modeling Disease Progression via Multisource Multitask Learners: A Case Study With Alzheimer's Disease. AB - Understanding the progression of chronic diseases can empower the sufferers in taking proactive care. To predict the disease status in the future time points, various machine learning approaches have been proposed. However, a few of them jointly consider the dual heterogeneities of chronic disease progression. In particular, the predicting task at each time point has features from multiple sources, and multiple tasks are related to each other in chronological order. To tackle this problem, we propose a novel and unified scheme to coregularize the prior knowledge of source consistency and temporal smoothness. We theoretically prove that our proposed model is a linear model. Before training our model, we adopt the matrix factorization approach to address the data missing problem. Extensive evaluations on real-world Alzheimer's disease data set have demonstrated the effectiveness and efficiency of our model. It is worth mentioning that our model is generally applicable to a rich range of chronic diseases. PMID- 26929062 TI - Predicting all-cause readmissions using electronic health record data from the entire hospitalization: Model development and comparison. AB - BACKGROUND: Incorporating clinical information from the full hospital course may improve prediction of 30-day readmissions. OBJECTIVE: To develop an all-cause readmissions risk-prediction model incorporating electronic health record (EHR) data from the full hospital stay, and to compare "full-stay" model performance to a "first day" and 2 other validated models, LACE (includes Length of stay, Acute [nonelective] admission status, Charlson Comorbidity Index, and Emergency department visits in the past year), and HOSPITAL (includes Hemoglobin at discharge, discharge from Oncology service, Sodium level at discharge, Procedure during index hospitalization, Index hospitalization Type [nonelective], number of Admissions in the past year, and Length of stay). DESIGN: Observational cohort study. SUBJECTS: All medicine discharges between November 2009 and October 2010 from 6 hospitals in North Texas, including safety net, teaching, and nonteaching sites. MEASURES: Thirty-day nonelective readmissions were ascertained from 75 regional hospitals. RESULTS: Among 32,922 admissions (validation = 16,430), 12.7% were readmitted. In addition to many first-day factors, we identified hospital acquired Clostridium difficile infection (adjusted odds ratio [AOR]: 2.03, 95% confidence interval [CI]: 1.18-3.48), vital sign instability on discharge (AOR: 1.25, 95% CI: 1.15-1.36), hyponatremia on discharge (AOR: 1.34, 95% CI: 1.18 1.51), and length of stay (AOR: 1.06, 95% CI: 1.04-1.07) as significant predictors. The full-stay model had better discrimination than other models though the improvement was modest (C statistic 0.69 vs 0.64-0.67). It was also modestly better in identifying patients at highest risk for readmission (likelihood ratio +2.4 vs. 1.8-2.1) and in reclassifying individuals (net reclassification index 0.02-0.06). CONCLUSIONS: Incorporating clinically granular EHR data from the full hospital stay modestly improves prediction of 30-day readmissions. Given limited improvement in prediction despite incorporation of data on hospital complications, clinical instabilities, and trajectory, our findings suggest that many factors influencing readmissions remain unaccounted for. Further improvements in readmission models will likely require accounting for psychosocial and behavioral factors not currently captured by EHRs. Journal of Hospital Medicine 2016;11:473-480. (c) 2016 Society of Hospital Medicine. PMID- 26929065 TI - LIF and Simplified SRM Neurons Encode Signals Into Spikes via a Form of Asynchronous Pulse Sigma-Delta Modulation. AB - We show how two spiking neuron models encode continuous-time signals into spikes (action potentials, time-encoded pulses, or point processes) using a special form of sigma-delta modulation (SDM). In particular, we show that the well-known leaky integrate-and-fire (LIF) neuron and the simplified spike response model (SRM0) neuron encode the continuous-time signals into spikes via a proposed asynchronous pulse SDM (APSDM) scheme. The encoder is clock free using level-crossing sampling with a single-level quantizer, unipolar signaling, differential coding, and pulse shaping filters. The decoder, in the form of a low-pass filter or bandpass smoothing filter, can be fed with the spikes to reconstruct an estimate of the signal. The density of the spikes reflects the amplitude of the encoded signal. Numerical examples illustrating the concepts and the signaling efficiency of APSDM vis-a-vis SDM for comparable reconstruction accuracies are presented. We anticipate these results will facilitate the design of spiking neurons and spiking neural networks as well as cross fertilizations between the fields of neural coding and the SDM. PMID- 26929066 TI - A Note on the Unification of Adaptive Online Learning. AB - In online convex optimization, adaptive algorithms, which can utilize the second order information of the loss function's (sub)gradient, have shown improvements over standard gradient methods. This paper presents a framework Follow the Bregman Divergence Leader that unifies various existing adaptive algorithms from which new insights are revealed. Under the proposed framework, two simple adaptive online algorithms with improvable performance guarantee are derived. Furthermore, a general equation derived from a matrix analysis generalizes the adaptive learning to nonlinear case with kernel trick. PMID- 26929067 TI - A Robust Regularization Path Algorithm for $?nu $ -Support Vector Classification. AB - The nu -support vector classification has the advantage of using a regularization parameter nu to control the number of support vectors and margin errors. Recently, a regularization path algorithm for nu -support vector classification ( nu -SvcPath) suffers exceptions and singularities in some special cases. In this brief, we first present a new equivalent dual formulation for nu -SVC and, then, propose a robust nu -SvcPath, based on lower upper decomposition with partial pivoting. Theoretical analysis and experimental results verify that our proposed robust regularization path algorithm can avoid the exceptions completely, handle the singularities in the key matrix, and fit the entire solution path in a finite number of steps. Experimental results also show that our proposed algorithm fits the entire solution path with fewer steps and less running time than original one does. PMID- 26929068 TI - Synthesis of Aryldifluoroamides by Copper-Catalyzed Cross-Coupling. AB - A copper-catalyzed coupling of aryl, heteroaryl, and vinyl iodides with alpha silyldifluoroamides is reported. The reaction forms alpha,alpha-difluoro-alpha aryl amides from electron-rich, electron-poor, and sterically hindered aryl iodides in high yield and tolerates a variety of functional groups. The aryldifluoroamide products can be transformed further to provide access to a diverse array of difluoroalkylarenes, including compounds of potential biological interest. PMID- 26929070 TI - Metabolic and molecular regulation of dietary polyunsaturated fatty acids on prostate cancer. AB - PURPOSE: The aim of this study is to investigate the role of n-3 and n-9 fatty acids in crucial processes involved in prostate cancer cell growth through a large-scale proteomic analysis. EXPERIMENTAL DESIGN: We used a label-free protein quantification method to profile global protein expression of fish oil and oleic acid treated PCa cells and validated a panel of differentially expressed proteins by either Western blot or multiple reaction monitoring. Bioinformatic analysis was also performed to uncover the pathways involved in fatty acid metabolism. RESULTS: Fish oil, not oleic acid, suppresses prostate cancer cell viability. Assessment of fatty acid synthesis pathway activity also shows that oleic acid is a more potent inhibitor than fish oil on de novo fatty acid synthesis. Although fatty acid synthase activity decreases with fish oil treatment, the inhibition of its activity occurs over time while reduction in viability occurs within 24 h. Bioinformatic analysis revealed the pathways altered by these fatty acid treatments. CONCLUSIONS AND CLINICAL RELEVANCE: This study suggests that suppression of cell viability by fish oil is independent of fatty acid synthase and fish oil regulates prostate cancer cells through activation of other pathways depending upon length of exposure to fish oil. PMID- 26929073 TI - Sharing of mitotic pre-ribosomal particles between daughter cells. AB - Ribosome biogenesis is a fundamental multistep process initiated by the synthesis of 90S pre-ribosomal particles in the nucleoli of higher eukaryotes. Even though synthesis of ribosomes stops during mitosis while nucleoli disappear, mitotic pre ribosomal particles persist as observed in pre-nucleolar bodies (PNBs) during telophase. To further understand the relationship between the nucleolus and the PNBs, the presence and the fate of the mitotic pre-ribosomal particles during cell division were investigated. We demonstrate that the recently synthesized 45S precursor ribosomal RNAs (pre-rRNAs) as well as the 32S and 30S pre-rRNAs are maintained during mitosis and associated with the chromosome periphery together with pre-rRNA processing factors. Maturation of the mitotic pre-ribosomal particles, as assessed by the stability of the mitotic pre-rRNAs, is transiently arrested during mitosis by a cyclin-dependent kinase (CDK)1-cyclin-B-dependent mechanism and can be restored by CDK inhibitor treatments. At the M-G1 transition, the resumption of mitotic pre-rRNA processing in PNBs does not induce the disappearance of PNBs; this only occurs when functional nucleoli reform. Strikingly, during their maturation process, mitotic pre-rRNAs localize in reforming nucleoli. PMID- 26929075 TI - Covalent Reactions on Chemical Vapor Deposition Grown Graphene Studied by Surface Enhanced Raman Spectroscopy. AB - Graphene is a material of unmatched properties and eminent potential in disciplines ranging from physics, to chemistry, to biology. Its advancement to applications with a specific function requires rational design and fine tuning of its properties, and covalent introduction of various substituents answers this requirement. We challenged the obstacle of non-trivial and harsh procedures for covalent functionalization of pristine graphene and developed a protocol for mild nucleophilic introduction of organic groups in the gas phase. The painstaking analysis problem of monolayered materials was addressed by using surface-enhanced Raman spectroscopy, which allowed us to monitor and characterize in detail the surface composition. These deliverables provide a toolbox for reactivity of fluorinated graphene under mild reaction conditions, providing structural freedom of the species to-be-grafted to the single-layer graphene. PMID- 26929074 TI - HSPB7 interacts with dimerized FLNC and its absence results in progressive myopathy in skeletal muscles. AB - HSPB7 belongs to the small heat-shock protein (sHSP) family, and its expression is restricted to cardiac and skeletal muscles from embryonic stages to adulthood. Here, we found that skeletal-muscle-specific ablation of the HspB7 does not affect myogenesis during embryonic stages to postnatal day 1 (P1), but causes subsequent postnatal death owing to a respiration defect, with progressive myopathy phenotypes in the diaphragm. Deficiency of HSPB7 in the diaphragm muscle resulted in muscle fibrosis, sarcomere disarray and sarcolemma integrity loss. We identified dimerized filamin C (FLNC) as an interacting partner of HSPB7. Immunofluorescence studies demonstrated that the aggregation and mislocalization of FLNC occurred in the muscle of HspB7 mutant adult mice. Furthermore, the components of dystrophin glycoprotein complex, gamma- and delta-sarcoglycan, but not dystrophin, were abnormally upregulated and mislocalized in HSPB7 mutant muscle. Collectively, our findings suggest that HSPB7 is essential for maintaining muscle integrity, which is achieved through its interaction with FLNC, in order to prevent the occurrence and progression of myopathy. PMID- 26929076 TI - Cautionary tales regarding the dissemination of motivational interviewing. PMID- 26929077 TI - Recent treatment advances in Hodgkin lymphoma: a concise review. AB - The majority of patients with Hodgkin lymphoma enjoy durable remissions following front-line treatment. This typically involves combination chemotherapy with or without radiotherapy. A significant minority of patients experience relapsed/refractory disease, of whom only approximately half can be 'salvaged' with conventional second-line treatments. Until recently, for those patients either failing or who are not fit for salvage, there have been few curative alternatives. Furthermore, there is a significant risk of delayed treatment complications to conventional therapies, including secondary malignancies and cardiac disease. However, novel targeted therapies are producing excellent results in clinical trials. They provide additional treatment options for those with relapsing/refractory disease; they may have potential in front-line therapy. The anti-CD30 antibody brentuximab vedotin (BV) has been tested as monotherapy and in combination in a variety of clinical settings, including in relapsed/refractory patients and as consolidative therapy following standard second-line therapy. Nivolumab and pembrolizumab, currently used in other malignancies that are known to utilise the programmed death pathway for survival, have shown outstanding results when used as single agents in heavily pre-treated (including BV refractory) patients. Individualising and adapting a patient's treatment course, whether augmenting or rationalising therapy, based on an interim positron emission tomography/computed tomography response is an important strategy currently under exploration to minimise toxicity while maximising response. Further work is needed to explore clinical and biological factors associated with improved outcomes. Knowledge of these factors combined with the movement of novel therapies into the front-line setting will enable individualised therapy to enhance clinical responses and minimise toxicities. PMID- 26929079 TI - How often are hospitalized patients and providers on the same page with regard to the patient's primary recovery goal for hospitalization? AB - BACKGROUND: To deliver high-quality, patient-centered care during hospitalization, healthcare providers must correctly identify the patient's primary recovery goal. OBJECTIVE: To determine the degree of concordance between patients and key hospital providers. DESIGN: A validated questionnaire administered to a random sample of hospitalized patients alongside their nurse and physician provider. Goals included: "be cured," "live longer," "improve/maintain health," "be comfortable," "accomplish a particular life goal," or "other." SETTING: Major academic hospital in Boston, Massachusetts. PARTICIPANTS: Adult patients admitted for more than 48 hours from November 2013 to May 2014 were eligible. When a patient was incapacitated, a legal proxy was interviewed. The nurse and physician provider were then interviewed within 24 hours. MEASUREMENTS: Frequencies of responses for each recovery goal and the rate of concordance among the patient, nurse, and physician provider were measured. The frequency of responses across groups were compared using adjusted chi(2) analyses. Inter-rater agreement was measured using 2-way Kappa tests. RESULTS: All 3 participants were interviewed in 109 of the 181 (60.2%) patients approached (or with proxy available). Significant differences in selected goals were observed across respondent groups (P < 0.001). Patients frequently chose "be cured" (46.8%). Nurses and physician providers frequently selected "improve or maintain health" (38.5% and 46.8%, respectively). All 3 participants selected the same goal in 22 cases (20.2%). Inter-rater agreement was poor to slight for all pairs (kappa 0.09 [-0.03-0.19], 0.19 [0.08-0.30], and 0.20 [0.08-0.32] for patient-physician, patient-nurse, and nurse-physician, respectively). CONCLUSIONS: We observed poor to slight concordance among hospitalized patients and key medical team members with regard to the patient's primary recovery goal. Journal of Hospital Medicine 2016;11:615-619. (c) 2016 Society of Hospital Medicine. PMID- 26929080 TI - Optimal Control-Based Adaptive NN Design for a Class of Nonlinear Discrete-Time Block-Triangular Systems. AB - In this paper, we propose an optimal control scheme-based adaptive neural network design for a class of unknown nonlinear discrete-time systems. The controlled systems are in a block-triangular multi-input-multi-output pure-feedback structure, i.e., there are both state and input couplings and nonaffine functions to be included in every equation of each subsystem. The design objective is to provide a control scheme, which not only guarantees the stability of the systems, but also achieves optimal control performance. The main contribution of this paper is that it is for the first time to achieve the optimal performance for such a class of systems. Owing to the interactions among subsystems, making an optimal control signal is a difficult task. The design ideas are that: 1) the systems are transformed into an output predictor form; 2) for the output predictor, the ideal control signal and the strategic utility function can be approximated by using an action network and a critic network, respectively; and 3) an optimal control signal is constructed with the weight update rules to be designed based on a gradient descent method. The stability of the systems can be proved based on the difference Lyapunov method. Finally, a numerical simulation is given to illustrate the performance of the proposed scheme. PMID- 26929081 TI - Fuzzy Adaptive Tracking Control of Constrained Nonlinear Switched Stochastic Pure Feedback Systems. AB - In this paper, the fuzzy adaptive control problem for a class of switched stochastic nonlinear systems in pure feedback form with output constraint is addressed. By proposing a nonlinear mapping, the constrained system is transformed into an unconstrained one, with equivalent control objective. All signals in the closed-loop system are proved to be semiglobally uniformly ultimately bounded. Meanwhile, the output constraint is satisfied and the output tracking error converges to an arbitrarily small neighborhood of zero. Finally, the applicability of the proposed controller is verified by a simulation example. PMID- 26929082 TI - An Event-Triggered ADP Control Approach for Continuous-Time System With Unknown Internal States. AB - This paper proposes a novel event-triggered adaptive dynamic programming (ADP) control method for nonlinear continuous-time system with unknown internal states. Comparing with the traditional ADP design with a fixed sample period, the event triggered method samples the state and updates the controller only when it is necessary. Therefore, the computation cost and transmission load are reduced. Usually, the event-triggered method is based on the system entire state which is either infeasible or very difficult to obtain in practice applications. This paper integrates a neural-network-based observer to recover the system internal states from the measurable feedback. Both the proposed observer and the controller are aperiodically updated according to the designed triggering condition. Neural network techniques are applied to estimate the performance index and help calculate the control action. The stability analysis of the proposed method is also demonstrated by Lyapunov construct for both the continuous and jump dynamics. The simulation results verify the theoretical analysis and justify the efficiency of the proposed method. PMID- 26929078 TI - A structurally plastic ribonucleoprotein complex mediates post-transcriptional gene regulation in HIV-1. AB - HIV replication requires the nuclear export of essential, intron-containing viral RNAs. To facilitate export, HIV encodes the viral accessory protein Rev which binds unspliced and partially spliced viral RNAs and creates a ribonucleoprotein complex that recruits the cellular Chromosome maintenance factor 1 export machinery. Exporting RNAs in this manner bypasses the necessity for complete splicing as a prerequisite for mRNA export, and allows intron-containing RNAs to reach the cytoplasm intact for translation and virus packaging. Recent structural studies have revealed that this entire complex exhibits remarkable plasticity at many levels of organization, including RNA folding, protein-RNA recognition, multimer formation, and host factor recruitment. In this review, we explore each aspect of plasticity from structural, functional, and possible therapeutic viewpoints. WIREs RNA 2016, 7:470-486. doi: 10.1002/wrna.1342 For further resources related to this article, please visit the WIREs website. PMID- 26929083 TI - Template Deformation-Based 3-D Reconstruction of Full Human Body Scans From Low Cost Depth Cameras. AB - Full human body shape scans provide valuable data for a variety of applications including anthropometric surveying, clothing design, human-factors engineering, health, and entertainment. However, the high price, large volume, and difficulty of operating professional 3-D scanners preclude their use in home entertainment. Recently, portable low-cost red green blue-depth cameras such as the Kinect have become popular for computer vision tasks. However, the infrared mechanism of this type of camera leads to noisy and incomplete depth images. We construct a stereo full-body scanning environment composed of multiple depth cameras and propose a novel registration algorithm. Our algorithm determines a segment constrained correspondence for two neighboring views, integrating them using rigid transformation. Furthermore, it aligns all of the views based on uniform error distribution. The generated 3-D mesh model is typically sparse, noisy, and even with holes, which makes it lose surface details. To address this, we introduce a geometric and topological fitting prior in the form of a professionally designed high-resolution template model. We formulate a template deformation optimization problem to fit the high-resolution model to the low-quality scan. Its solution overcomes the obstacles posed by different poses, varying body details, and surface noise. The entire process is free of body and template markers, fully automatic, and achieves satisfactory reconstruction results. PMID- 26929084 TI - A Unified Treatment of the Relationship Between Ligand Substituents and Spin State in a Family of Iron(II) Complexes. AB - The influence of ligands on the spin state of a metal ion is of central importance for bioinorganic chemistry, and the production of base-metal catalysts for synthesis applications. Complexes derived from [Fe(bpp)2 ](2+) (bpp=2,6 di{pyrazol-1-yl}pyridine) can be high-spin, low-spin, or spin-crossover (SCO) active depending on the ligand substituents. Plots of the SCO midpoint temperature (T1/2 ) in solution vs. the relevant Hammett parameter show that the low-spin state of the complex is stabilized by electron-withdrawing pyridyl ("X") substituents, but also by electron-donating pyrazolyl ("Y") substituents. Moreover, when a subset of complexes with halogeno X or Y substituents is considered, the two sets of compounds instead show identical trends of a small reduction in T1/2 for increasing substituent electronegativity. DFT calculations reproduce these disparate trends, which arise from competing influences of pyridyl and pyrazolyl ligand substituents on Fe-L sigma and pi bonding. PMID- 26929085 TI - Longitudinal functional connectivity changes correlate with mood improvement after regular exercise in a dose-dependent fashion. AB - Exercise increases wellbeing and improves mood. It is however unclear how these mood changes relate to brain function. We conducted a randomized controlled trial investigating resting-state modifications in healthy adults after an extended period of aerobic physical exercise and their relationship with mood improvements. We aimed to identify novel functional networks whose activity could provide a physiological counterpart to the mood-related benefits of exercise. Thirty-eight healthy sedentary volunteers were randomised to either the aerobic exercise group of the study or a control group. Participants in the exercise group attended aerobic sessions with a physiotherapist twice a week for 16 weeks. Resting-state modifications using magnetic resonance imaging were assessed before and after the programme and related to mood changes. An unbiased approach using graph metrics and network-based statistics was adopted. Exercise reduced mood disturbance and improved emotional wellbeing. It also induced a decrease in local efficiency in the parahippocampal lobe through strengthening of the functional connections from this structure to the supramarginal gyrus, precentral area, superior temporal gyrus and temporal pole. Changes in mood disturbance following exercise were correlated with those in connectivity between parahippocampal gyrus and superior temporal gyrus as well as with the amount of training. No changes were detected in the control group. In conclusion, connectivity from the parahippocampal gyrus to motor, sensory integration and mood regulation areas was strengthened through exercise. These functional changes might be related to the benefits of regular physical activity on mood. PMID- 26929086 TI - Subcellular measurements of mechanical and chemical properties using dual Raman Brillouin microspectroscopy. AB - Brillouin microspectroscopy is a powerful technique for noninvasive optical imaging. In particular, Brillouin microspectroscopy uniquely allows assessing a sample's mechanical properties with microscopic spatial resolution. Recent advances in background-free Brillouin microspectroscopy make it possible to image scattering samples without substantial degradation of the data quality. However, measurements at the cellular- and subcellular-level have never been performed to date due to the limited signal strength. In this report, by adopting our recently optimized VIPA-based Brillouin spectrometer, we probed the microscopic viscoelasticity of individual red blood cells. These measurements were supplemented by chemically specific measurements using Raman microspectroscopy. PMID- 26929087 TI - Naphthalene-Functionalized, Photoluminescent Room Temperature Ionic Liquids Bearing Small Counterions. AB - Obtaining pi-conjugated room temperature ionic liquids (RTILs) is difficult because of the relatively strong pi-pi interaction among the pi-moieties. Existing strategies by using bulky counterions greatly hindered further property optimization and potential applications of these intriguing functional fluids through simple ion exchange. Herein, four naphthalene-functionalized, pi conjugated RTILs with small counterions (Br(-) ) have been facilely synthesized with high yields. Our strategy is to attach branched alkyl chains to the cationic backbone of the target compounds (2 a-d), which effectively tune inter- and intramolecular interactions. Compounds 2 a-d have satisfactory thermal stability (up to 300 degrees C) and low melting points (<-19 degrees C). Rheological measurements revealed the fluid character of 2 a-d, whose viscosity decrease with the increase of the alkyl chain length and temperature. The presence of the pi conjugated naphthalene moiety imparts 2 a-d photoluminescent properties in bulk solutions. Moreover, the absence of strong pi-pi stacking among the naphthalene units in solvent-free states enables them to be used as a new generation of photoluminescent inks. PMID- 26929088 TI - M. Weinstein and M. A. Lane, Sociality, Hierarchy, Health: Comparative Biodemography: A Collection of Papers. PMID- 26929089 TI - Stephen C. Stearns and Ruslan Medzhitov, Evolutionary Medicine. PMID- 26929091 TI - Training in vain? PMID- 26929090 TI - Borderline Personality Disorder: Why 'fast and furious'? AB - The term 'Borderline Personality Disorder' (BPD) refers to a psychiatric syndrome that is characterized by emotion dysregulation, impulsivity, risk-taking behavior, irritability, feelings of emptiness, self-injury and fear of abandonment, as well as unstable interpersonal relationships. BPD is not only common in psychiatric populations but also more prevalent in the general community than previously thought, and thus represents an important public health issue. In contrast to most psychiatric disorders, some symptoms associated with BPD may improve over time, even without therapy, though impaired social functioning and interpersonal disturbances in close relationships often persist. Another counterintuitive and insufficiently resolved question is why depressive symptoms and risk-taking behaviors can occur simultaneously in the same individual. Moreover, there is an ongoing debate about the nosological position of BPD, which impacts on research regarding sex differences in clinical presentation and patterns of comorbidity.In this review, it is argued that many features of BPD may be conceptualized within an evolutionary framework, namely behavioral ecology. According to Life History Theory, BPD reflects a pathological extreme or distortion of a behavioral 'strategy' which unconsciously aims at immediate exploitation of resources, both interpersonal and material, based on predictions shaped by early developmental experiences. Such a view is consistent with standard medical conceptualizations of BPD, but goes beyond classic 'deficit'-oriented models, which may have profound implications for therapeutic approaches. PMID- 26929092 TI - Density fluctuations represent a key process maintaining personality variation in a wild passerine bird. AB - Heritable personality variation is subject to fluctuating selection in many animal taxa; a major unresolved question is why this is the case. A parsimonious explanation must involve a general ecological process: a likely candidate is the omnipresent spatiotemporal variation in conspecific density. We tested whether spatiotemporal variation in density within and among nest box plots of great tits (Parus major) predicted variation in selection acting on exploratory behaviour (n = 48 episodes of selection). We found viability selection favouring faster explorers under lower densities but slower explorers under higher densities. Temporal variation in local density represented the primary factor explaining personality-related variation in viability selection. Importantly, birds did not anticipate changes in selection by means of adaptive density-dependent plasticity. This study thereby provides an unprecedented example of the key importance of the interplay between fluctuating selection and lack of adaptive behavioural plasticity in maintaining animal personality variation in the wild. PMID- 26929093 TI - Stenotrophomonas maltophilia biofilm reduction by Bdellovibrio exovorus. AB - Stenotrophomonas maltophilia, a bacterium ubiquitous in the environment, is also an opportunistic, multidrug-resistant human pathogen that colonizes tissues and medical devices via biofilm formation. We investigated the ability of an isolate from sewage of the bacterial predator Bdellovibrio exovorus to disrupt preformed biofilms of 18 strains of S. maltophilia isolated from patients, hospital sink drains and water fountain drains. B. exovorus FFRS-5 preyed on all S. maltophilia strains in liquid co-cultures and was able to significantly disrupt the biofilms of 15 of the S. maltophilia strains tested, decreasing as much as 76.7% of the biofilm mass. The addition of ciprofloxacin and kanamycin in general reduced S. maltophilia biofilms but less than that of B. exovorus alone. Furthermore, when antibiotics and B. exovorus were used together, B. exovorus was still effective in the presence of ciprofloxacin whereas the addition of kanamycin reduced the effectiveness of B. exovorus. Overall, B. exovorus was able to decrease the mass of preformed biofilms of S. maltophilia in the presence of clinically relevant antibiotics demonstrating that the predator may prove to be a beneficial tool to reduce S. maltophilia environmental or clinically associated biofilms. PMID- 26929094 TI - Relationship between hospital financial performance and publicly reported outcomes. AB - BACKGROUND: Hospitals that have robust financial performance may have improved publicly reported outcomes. OBJECTIVES: To assess the relationship between hospital financial performance and publicly reported outcomes of care, and to assess whether improved outcome metrics affect subsequent hospital financial performance. DESIGN: Observational cohort study. SETTING AND PATIENTS: Hospital financial data from the Office of Statewide Health Planning and Development in California in 2008 and 2012 were linked to data from the Centers for Medicare and Medicaid Services Hospital Compare website. MEASUREMENTS: Hospital financial performance was measured by net revenue by operations, operating margin, and total margin. Outcomes were 30-day risk-standardized mortality and readmission rates for acute myocardial infarction (AMI), congestive heart failure (CHF), and pneumonia (PNA). RESULTS: Among 279 hospitals, there was no consistent relationship between measures of financial performance in 2008 and publicly reported outcomes from 2008 to 2011 for AMI and PNA. However, improved hospital financial performance (by any of the 3 measures) was associated with a modest increase in CHF mortality rates (ie, 0.26% increase in CHF mortality rate for every 10% increase in operating margin [95% confidence interval: 0.07%-0.45%]). Conversely, there were no significant associations between outcomes from 2008 to 2011 and subsequent financial performance in 2012 (P > 0.05 for all). CONCLUSIONS: Robust financial performance is not associated with improved publicly reported outcomes for AMI, CHF, and PNA. Financial incentives in addition to public reporting, such as readmissions penalties, may help motivate hospitals with robust financial performance to further improve publicly reported outcomes. Reassuringly, improved mortality and readmission rates do not necessarily lead to loss of revenue. Journal of Hospital Medicine 2016;11:481 488. (c) 2016 Society of Hospital Medicine. PMID- 26929095 TI - Effect of the Web-Based Intervention MyPlan 1.0 on Self-Reported Fruit and Vegetable Intake in Adults Who Visit General Practice: A Quasi-Experimental Trial. AB - BACKGROUND: Web-based interventions typically have small intervention effects on adults' health behavior because they primarily target processes leading to an intention to change leaving individuals in an intention-behavior gap, they often occur without contact with health care providers, and a limited amount of feedback is provided only at the beginning of these interventions, but not further on in the behavior change process. Therefore, we developed a Web-based intervention ("MyPlan 1.0") to promote healthy behavior in adults. The intervention was based on a self-regulation perspective that also targets postintentional processes and guides individuals during all phases of behavior change. OBJECTIVE: The study investigated the effectiveness of MyPlan1.0 on fruit and vegetable intake of Flemish adults visiting general practice (3 groups: control group, intervention group recruited by researchers, and intervention group recruited and guided by general practitioners [GPs]). Second, it examined whether there was a larger intervention effect for the intervention group guided by GPs compared to the intervention group recruited by researchers. METHODS: Adults (>= 18 years) were recruited in 19 Flemish general practices. In each general practice, patients were systematically allocated by a researcher either for the intervention group (researchers' intervention group) or the waiting-list control group that received general advice. In a third group, the GP recruited adults for the intervention (GPs intervention group). The two intervention groups filled in evaluation questionnaires and received MyPlan 1.0 for a behavior of choice (fruit, vegetable, or physical activity). The waiting-list control group filled in the evaluation questionnaires and received only general information. Self-reported fruit and vegetable intake were assessed at baseline (T0), 1 week (T1), and 1 month (T2) postbaseline. Three-level (general practice, adults, time) linear regression models were conducted in MLwiN. RESULTS: A total of 426 adults initially agreed to participate (control group: n=149; GPs' intervention group: n=41; researchers' intervention group: n=236). A high attrition rate was observed in both intervention groups (71.8%, 199/277) and in the control group (59.1%, 88/149). In comparison to no change in the control group, both the GPs' intervention group (fruit: chi(2)1=10.9, P=.004; vegetable: chi(2)1=5.3, P=.02) and the researchers' intervention group (fruit: chi(2)1=18.0, P=.001; vegetable: chi(2)1=12.8, P<.001) increased their intake of fruit and vegetables. CONCLUSIONS: A greater increase in fruit and vegetable intake was found when the Web-based intervention MyPlan 1.0 was used compared to usual care of health promotion in general practice (ie, flyers with general information). However, further investigation on which (or combinations of which) behavior change techniques are effective, how to increase response rates, and the influence of delivery mode in routine practice is required. TRIAL REGISTRATION: ClinicalTrials.gov NCT02211040; https://clinicaltrials.gov/ct2/show/NCT02211040 (Archived by WebCite(r) at http://www.webcitation.org/6f8yxTRii). PMID- 26929096 TI - A psbA mutation (Val219 to Ile) causes resistance to propanil and increased susceptibility to bentazon in Cyperus difformis. AB - BACKGROUND: Propanil-resistant (R) Cyperus difformis populations were recently confirmed in California rice fields. To date, propanil resistance in other weed species has been associated with enhanced aryl acylamidase (AAA)-mediated propanil conversion into 3,4-dichloroaniline. Our objectives were to determine the level of propanil resistance and cross-resistance to other PSII inhibitors in C. difformis lines, and to elucidate the mechanism of propanil resistance. RESULTS: The propanil-R line had a 14-fold propanil resistance and increased resistance to bromoxynil, diuron and metribuzin, but not to atrazine. The R line, however, displayed a fourfold increased susceptibility to bentazon. Interestingly, susceptible (S) plants accumulated more 3,4-dichloroaniline and were more injured by propanil and carbaryl (AAA-inhibitor) applications than R plants, suggesting that propanil metabolism is not the resistance mechanism. psbA gene sequence analysis indicated a valine-219-isoleucine (Val219 Ile) amino acid exchange in the propanil-R chloroplast D1 protein. CONCLUSION: The D1 Val219 Ile modification in C. difformis causes resistance to propanil, diuron, metribuzin and bromoxynil but increased susceptibility to bentazon, suggesting that the Val219 residue participates in binding of these herbicides. This is the first report of a higher plant exhibiting target-site propanil resistance. Tank mixing of bentazon and propanil, where permitted, can control both propanil-R and propanil-S C. difformis and prevent the spread of the resistant phenotype. (c) 2016 Society of Chemical Industry. PMID- 26929097 TI - Guided Self-Propelled Leaping of Droplets on a Micro-Anisotropic Superhydrophobic Surface. AB - By introducing anisotropic micropatterns on a superhydrophobic surface, we demonstrate that water microdroplets can coalesce and leap over the surface spontaneously along a prescribed direction. This controlled behavior is attributed to anisotropic liquid-solid adhesion. An analysis relating the preferential leaping probability to the geometrical parameters of the system is presented with consistent experimental results. Surfaces with this rare quality demonstrate many unique characteristics, such as self-powered, and relatively long-distance transport of microdroplets by "relay" coalescence-induced leaping. PMID- 26929098 TI - Sleep is in for Summer: Patterns of Sleep and Physical Activity in Urban Minority Girls. AB - OBJECTIVE: Urban minority girls are at risk for summertime weight gain, and may also experience insufficient summertime sleep. Few studies have objectively measured sleep in this population or examined correlates, including physical activity (PA). This study is the first to objectively describe summertime sleep among urban minority girls. METHODS: Data were collected at a community-based summer program that promoted PA (n = 60 girls, ages 10-14 years), at two time points: before beginning programming (T1; unstructured context) and during the final week of programming (T2; structured context). RESULTS: At both time points, participants experienced shorter nighttime sleep than the recommended amount for girls their age. African American girls recorded significantly less sleep than Latina girls in the unstructured context. Findings also suggest that sleep schedules have an influential role in youths' abilities to obtain adequate sleep. CONCLUSION: Overall, summertime sleep is an understudied health behavior that may be important to consider among minority youth. PMID- 26929099 TI - A key challenge for motivational interviewing: training in clinical practice. PMID- 26929100 TI - Severe alcoholic relapse after liver transplantation: What consequences on the graft? A study based on liver biopsies analysis. AB - Alcoholic liver disease (ALD) is a major indication for liver transplantation (LT), but up to 20% of patients experience severe alcoholic relapse. The aims of this study were to evaluate the impact of severe alcoholic relapse on the graft (based on histological examination) and to identify predictive factors associated with recurrent alcoholic cirrhosis (RAC). From 1990 to 2010, 369 patients underwent LT for ALD at Edouard Herriot Hospital (Lyon, France) and survived more than 1 year. All patients who presented severe alcoholic relapse and histological follow-up were included. Liver biopsies were performed at 1 and 5 years and at every 5 years after LT, and when clinically indicated. The median follow-up after LT was 11 years (range, 3-18 years). Severe alcoholic relapse was observed in 73 (20%) of the 369 patients, from whom 56 patients with histological evaluation were included. RAC was diagnosed in 18 (32%) of the 56 patients included, which represents 5% of the 369 patients transplanted for ALD. The median delay between LT and RAC was 6 years (range, 3-10 years) and 4.5 years (range, 2-8 years) after severe alcoholic relapse. The median cumulated years of alcohol use before RAC was 3.5 years (range, 2-7 years). The cumulative risk for F4 fibrosis was 15% at 3 years, 32% at 5 years, and 54% at 10 years after severe alcoholic relapse. A young age at LT (<=50 years old) and an early onset of heavy drinking (within the first 3 years after LT) were associated with RAC. In conclusion, severe alcoholic relapse usually occurs in the first years after LT and is responsible for accelerated severe graft injury. Liver Transplantation 22 773-784 2016 AASLD. PMID- 26929102 TI - Virus-host interplay in high salt environments. AB - Interaction of viruses and cells has tremendous impact on cellular and viral evolution, nutrient cycling and decay of organic matter. Thus, viruses can indirectly affect complex processes such as climate change and microbial pathogenicity. During recent decades, studies on extreme environments have introduced us to archaeal viruses and viruses infecting extremophilic bacteria or eukaryotes. Hypersaline environments are known to contain strikingly high numbers of viruses (~10(9) particles per ml). Halophilic archaea, bacteria and eukaryotes inhabiting hypersaline environments have only a few cellular predators, indicating that the role of viruses is highly important in these ecosystems. Viruses thriving in high salt are called haloviruses and to date more than 100 such viruses have been described. Virulent, temperate, and persistent halovirus life cycles have been observed among the known isolates including the recently described SNJ1-SNJ2 temperate virus pair which is the first example of an interplay between two haloviruses in one host cell. In addition to direct virus and cell isolations, metagenomics have provided a wealth of information about virus-host dynamics in hypersaline environments suggesting that halovirus populations and halophilic microorganisms are dynamic over time and spatially distributed around the highly saline environments on the Earth. PMID- 26929101 TI - Direction selectivity of neurons in the visual cortex is non-linear and lamina dependent. AB - Neurons in the visual cortex are generally selective to direction of movement of a stimulus. Although models of this direction selectivity (DS) assume linearity, experimental data show stronger degrees of DS than those predicted by linear models. Our current study was intended to determine the degree of non-linearity of the DS mechanism for cells within different laminae of the cat's primary visual cortex. To do this, we analysed cells in our database by using neurophysiological and histological approaches to quantify non-linear components of DS in four principal cortical laminae (layers 2/3, 4, 5, and 6). We used a DS index (DSI) to quantify degrees of DS in our sample. Our results showed laminar differences. In layer 4, the main thalamic input region, most neurons were of the simple type and showed high DSI values. For complex cells in layer 4, there was a broad distribution of DSI values. Similar features were observed in layer 2/3, but complex cells were dominant. In deeper layers (5 and 6), DSI value distributions were characterized by clear peaks at high values. Independently of specific lamina, high DSI values were accompanied by narrow orientation tuning widths. Differences in orientation tuning for non-preferred vs. preferred directions were smallest in layer 4 and largest in layer 6. These results are consistent with a non-linear process of intra-cortical inhibition that enhances DS by selective suppression of neuronal firing for non-preferred directions of stimulus motion in a lamina-dependent manner. Other potential mechanisms are also considered. PMID- 26929103 TI - Flexible Near-Infrared Photovoltaic Devices Based on Plasmonic Hot-Electron Injection into Silicon Nanowire Arrays. AB - The development of flexible near-infrared (NIR) photovoltaic (PV) devices containing silicon meets the strong demands for solar utilization, portability, and sustainable manufacture; however, improvements in the NIR light absorption and conversion efficiencies in ultrathin crystalline Si are required. We have developed an approach to improve the quantum efficiency of flexible PV devices in the NIR spectral region by integrating Si nanowire arrays with plasmonic Ag nanoplates. The Ag nanoplates can directly harvest and convert NIR light into plasmonic hot electrons for injection into Si, while the Si nanowire arrays offer light trapping. Taking the wavelength of 800 nm as an example, the external quantum efficiency has been improved by 59 % by the integration Ag nanoplates. This work provides an alternative strategy for the design and fabrication of flexible NIR PVs. PMID- 26929104 TI - Layered MoS2 Hollow Spheres for Highly-Efficient Photothermal Therapy of Rabbit Liver Orthotopic Transplantation Tumors. AB - Combining photothermal therapy (PTT) with clinical technology to kill cancer via overcoming the low tumor targeting and poor therapy efficiency has great potential in basic and clinical researches. A brand-new MoS2 nanostructure is designed and fabricated, i.e., layered MoS2 hollow spheres (LMHSs) with strong absorption in near-infrared region (NIR) and high photothermal conversion efficiency via a simple and fast chemical aerosol flow method. Owing to curving layered hollow spherical structure, the as-prepared LMHSs exhibit unique electronic properties comparing with MoS2 nanosheets. In vitro and in vivo studies demonstrate their high photothermal ablation of cell and tumor elimination rate by single NIR light irradiation. Systematic acute toxicity study indicates that these LMHSs have negligible toxic effects to normal tissues and blood. Remarkably, minimally invasive interventional techniques are introduced to improve tumor targeting of PTT agents for the first time. To explore PTT efficiency on orthotopic transplantation tumors, New Zealand white rabbits with VX2 tumor in liver are used as animal models. The effective elimination of tumors is successfully realized by PTT under the guidance of digital subtraction angiography, computed tomography, and thermal imaging, which provides a new way for tumor-targeting delivery and cancer theranostic application. PMID- 26929105 TI - Planar Chiral, Ferrocene-Stabilized Silicon Cations. AB - The preparation of a series of planar chiral, ferrocenyl-substituted hydrosilanes as precursors of ferrocene-stabilized silicon cations is described. These molecules also feature stereogenicity at the silicon atom. The generation and (29)Si NMR spectroscopic characterization of the corresponding silicon cations is reported, and problems arising from interactions of the electron-deficient silicon atom and adjacent C(sp(3))-H bonds or aromatic pi donors are discussed. These issues are overcome by tethering another substituent at the silicon atom to the ferrocene backbone. The resulting annulation also imparts conformational rigidity and steric hindrance in such a way that the central chirality at the silicon atom is set with complete diastereocontrol. These chiral Lewis acid catalysts were then tested in difficult Diels-Alder reactions, but no enantioinduction was seen. PMID- 26929106 TI - A comparative evaluation of diffuse reflectance and Raman spectroscopy in the detection of cervical cancer. AB - Optical spectroscopic techniques show improved diagnostic accuracy for non invasive detection of cervical cancers. In this study, sensitivity and specificity of two in vivo modalities, i.e diffuse reflectance spectroscopy (DRS) and Raman spectroscopy (RS), were compared by utilizing spectra recorded from the same sites (67 tumor (T), 22 normal cervix (C), and 57 normal vagina (V)). Data was analysed using principal component - linear discriminant analysis (PC-LDA), and validated using leave-one-out-cross-validation (LOOCV). Sensitivity, specificity, positive predictive value and negative predictive value for classification between normal (N) and tumor (T) sites were 91%, 96%, 95% and 93%, respectively for RS and 85%, 95%, 93% and 88%, respectively for DRS. Even though DRS revealed slightly lower diagnostic accuracies, owing to its lower cost and portability, it was found to be more suited for cervical cancer screening in low resource settings. On the other hand, RS based devices could be ideal for screening patients with centralised facilities in developing countries. PMID- 26929107 TI - Addressing sex and gender inequities in scientific research and publishing. PMID- 26929108 TI - The utility of pulmonary function testing in predicting outcomes following liver transplantation. AB - Although pulmonary function tests (PFTs) are routinely performed in patients during the evaluation period before liver transplantation (LT), their utility in predicting post-LT mortality and morbidity outcomes is not known. The aim of this study was to determine the impact of obstructive and/or restrictive lung disease on post-LT outcomes. We conducted a retrospective analysis of patients who had pre-LT PFTs and underwent a subsequent LT (2007-2013). We used statistical analyses to determine independent associations between PFT parameters and outcomes (graft/patient survival, time on ventilator, and hospital/intensive care unit [ICU] length of stay [LOS]). A total of 415 LT recipients with available PFT data were included: 65% of patients had normal PFTs; 8% had obstructive lung disease; and 27% had restrictive lung disease. There was no difference in patient and graft survival between patients with normal, obstructive, and restrictive lung disease. However, restrictive lung disease was associated with longer post LT time on ventilator and both ICU and hospital LOS (P < 0.05). More specific PFT parameters (diffusing capacity of the lungs for carbon monoxide, total lung capacity, and residual volume) were all significant predictors of ventilator time and both ICU and hospital LOS (P < 0.05). Although pre-LT PFT parameters may not predict post-LT mortality, restrictive abnormalities correlate with prolonged post-LT ventilation and LOS. Efforts to identify and minimize the impact of restrictive abnormalities on PFTs might improve such outcomes. Liver Transplantation 22 805-811 2016 AASLD. PMID- 26929110 TI - A single dose of lorazepam reduces paired-pulse suppression of median nerve evoked somatosensory evoked potentials. AB - Paired-pulse behaviour in the somatosensory cortex is an approach to obtain insights into cortical processing modes and to obtain markers of changes of cortical excitability attributable to learning or pathological states. Numerous studies have demonstrated suppression of the response to the stimulus that follows a first one after a short interval, but the underlying mechanisms remain elusive, although there is agreement that GABAergic mechanisms seem to play a crucial role. We therefore aimed to explore the influence of the GABAA agonist lorazepam on paired-pulse somatosensory evoked potentials (SEPs). We recorded and analysed SEPs after paired median nerve stimulation in healthy individuals before and after they had received a single dose of 2.5 mg of lorazepam as compared with a control group receiving placebo. Paired-pulse suppression was expressed as a ratio of the amplitudes of the second and the first peaks. We found that, after lorazepam application, paired-pulse suppression of the cortical N20 component remained unchanged, but suppression of the N20-P25 complex was significantly reduced, indicative of GABAergic involvement in intracortical processing. Our data suggest that lorazepam most likely enhances inhibition within the cortical network of interneurons responsible for creating paired-pulse suppression, leading to reduced inhibitory drive with a subsequently reduced amount of suppression. The results provide further evidence that GABAA -mediated mechanisms are involved in the generation of median nerve evoked paired-pulse suppression. PMID- 26929109 TI - Preparedness for hospital discharge and prediction of readmission. AB - BACKGROUND, OBJECTIVE: Patients' self-reported preparedness for discharge has been shown to predict readmission. It is unclear what differences exist in the predictive abilities of 2 available discharge preparedness measures. To address this gap, we conducted a comparison of these measures. DESIGN, SETTING, PATIENTS: Adults hospitalized for cardiovascular diagnoses were enrolled in a prospective cohort. MEASUREMENTS: Two patient-reported preparedness measures assessed during postdischarge calls: the 11-item Brief Prescriptions, Ready to re-enter community, Education, Placement, Assurance of safety, Realistic expectations, Empowerment, Directed to appropriate services (B-PREPARED) and the 3-item Care Transitions Measure (CTM-3). Cox proportional hazard models analyzed the relationship between preparedness and time to first readmission or death at 30 and 90 days, adjusted for readmission risk using the administrative database derived Length of stay, Acuity, Comorbidity, and Emergency department use (LACE) index and other covariates. RESULTS: Median preparedness scores were: B-PREPARED 21 (interquartile range [IQR] 18-22) and CTM-3 77.8 (IQR 66.7-100). In individual Cox models, a 4-point increase in B-PREPARED score was associated with a 16% decrease in time to readmission or death at 30 and 90 days. A 10-point increase in CTM-3 score was not associated with readmission or death at 30 days, but was associated with a 6% decrease in readmission or death at 90 days. In models with both preparedness scores, B-PREPARED retained an association with readmission or death at both 30 and 90 days. However, neither preparedness score was as strong a predictor as the LACE index when all were included in the model predicting 30- and 90-day readmission or death. CONCLUSION: The B-PREPARED score was more strongly associated with readmission or death than the more widely adopted CTM-3, but neither predicted readmission as well as the LACE index. Journal of Hospital Medicine 2016;11:603-609. (c) 2016 Society of Hospital Medicine. PMID- 26929112 TI - Cyanobacterial gardens: the liverwort Frullania asagrayana acts as a reservoir of lichen photobionts. AB - Cyanobacteria are important mediators of unrelated lichen species, which form epiphytic communities that share the same cyanobiont. No study to date, however, has considered the role of cyanobacteria as mediator between lichens and bryophytes. In the present study, DNA barcoding (16S rDNA, rbcLX) was used to identify filamentous cyanobacteria living in close association with members of an epiphytic liverwort-lichen community on balsam fir in Newfoundland. This study is the first to confirm the presence of Rhizonema strains in boreal forests where they are associated with the liverwort Frullania asagrayana and several lichen species. The majority of cyanobacterial haplotypes can associate with the liverwort, however, some lichen species appear to be more selective for single or closely related haplotypes. Some Rhizonema strains were found exclusively in association with boreal lichens, while others seem to be globally distributed and involved in different lichen symbioses of unrelated fungal lineages and of varying ecological traits. Complex biological interactions in a cyanobacteria mediated guild are proposed here, which explains composition and dynamics in bryophyte and lichen-dominated epiphytic communities. PMID- 26929111 TI - Is baseline aerobic fitness associated with illness and attrition rate in military training? AB - BACKGROUND: Respiratory illnesses are a leading cause of morbidity and medical discharge in the military. This study aimed to investigate the effects of baseline aerobic fitness on haematological, salivary and mood variables, and simultaneously, in a novel approach, to identify factors precipitating illness and attrition rate in recruits during military training. METHODS: Thirty-five healthy male recruits from an Army Training Regiment undertaking 12 weeks of training were prospectively investigated. Their 2.4 km run time (RT) was used as a surrogate of baseline aerobic fitness. Saliva and venous blood samples were analysed for secretory IgA, full blood counts and cell cytokine production (interleukin (IL) 6 and IL-8), respectively. Each recruit completed questionnaires on mood profile, and gastrointestinal and upper respiratory tract symptoms (URTS). RESULTS: Significant salivary and haematological perturbations were observed and coincided with increased duration of URTS/week and mood disturbance over this military training period. From Start to End: leucocyte count decreased by 28% (p<0.001); neutrophil percentage (%) decreased by 13% (p<0.01); lymphocyte % increased by 17% (p<0.05); the neutrophil:lymphocyte ratio decreased by 22% (p<0.01); eosinophil% increased by 71% (p<0.01). From Start to Mid to End: monocyte% increased by 68% at Mid (p<0.01) but only by 30% at End (p<0.01); IL-6 increased by 39% at Mid (p<0.01) and a further 61% by End. The 2.4 km RT was significantly associated with URTS duration (p<0.01). In addition, a 1 min increase in 2.4 km RT increased a recruit's risk 9.8-fold of developing URTS lasting, on average, 3.36 days/week. In recruits ranked with high-URTS duration their RT was 48 s slower (p<0.01) than those with low-URTS, and their attrition rate reached 45%. CONCLUSIONS: The least fit recruits may have found training more physically demanding as reflected in the higher URTS duration, which may have led to a high attrition rate from the Army. It is worth considering that baseline aerobic fitness might be an important factor in illness development and attrition rate in recruits during this type of military training. PMID- 26929113 TI - A Symmetric Recognition Motif between Vicinal Diols: The Fourfold Grip in Ethylene Glycol Dimer. AB - Ethylene glycol has a transiently chiral, asymmetric global minimum structure, but it favors a highly symmetric, achiral dimer arrangement which has not been considered or found in previous quantum-chemical studies. Complementary FTIR and Raman spectroscopy in supersonic jets allows for the detection and straightforward assignment of this four-fold hydrogen-bonded dimer, which introduces an interesting supramolecular binding motif for vicinal diols and provides a strong case for transient chirality synchronization. PMID- 26929114 TI - A Highly Active System for the Metal-Free Aerobic Photocyanation of Tertiary Amines with Visible Light: Application to the Synthesis of Tetraponerines and Crispine A. AB - A highly efficient metal-free catalytic system for the aerobic photocyanation of tertiary amines with visible light is reported. The use of air as terminal oxidant offers an improved safety profile compared with pure oxygen, the used compact fluorescent lamp (CFL) light sources are highly economical, and no halogenated solvents are required. This system not only proves to be effective for a wide variety of trialkylamines, pharmaceuticals, and alkaloids but remarkably also allows the lowest catalyst loading (0.00001 mol% or 0.1 ppm) ever reported for an organic dye. Bruylants reactions and C-alkylation/decyanations were performed on the obtained alpha-aminonitriles to demonstrate the postfunctionalization of complex molecules. The catalytic system is furthermore applied in the short and effective syntheses of the alkaloids (+/-)-crispine A and the tetraponerines T7 and T8. PMID- 26929115 TI - Comparing isogenic strains of Beijing genotype Mycobacterium tuberculosis after acquisition of Isoniazid resistance: A proteomics approach. AB - We determined differences in the protein abundance among two isogenic strains of Mycobacterium tuberculosis (Mtb) with different Isoniazid (INH) susceptibility profiles. The strains were isolated from a pulmonary tuberculosis patient before and after drug treatment. LC-MS/MS analysis identified 46 Mtb proteins with altered abundance after INH resistance acquisition. Protein abundance comparisons were done evaluating the different bacterial cellular fractions (membrane, cytosol, cell wall and secreted proteins). MS data have been deposited to the ProteomeXchange with identifier PXD002986. PMID- 26929116 TI - Is setting a criterion for 'clinically significant weight loss' necessary? PMID- 26929117 TI - Better options than self-report of consumption. PMID- 26929118 TI - An Electronic Wellness Program to Improve Diet and Exercise in College Students: A Pilot Study. AB - BACKGROUND: In transitioning from adolescence to adulthood, college students are faced with significant challenges to their health habits. Independence, stress, and perceived lack of time by college students have been known to result in poor eating and exercise habits, which can lead to increased disease risk. OBJECTIVE: To assess the feasibility and to determine preliminary efficacy of an electronic wellness program in improving diet and physical activity in college students. METHODS: A 24-week diet and physical activity program was delivered via email to 148 college students. The intervention involved weekly, tailored, and interactive diet and physical activity goals. The control group received nondiet and nonexercise-related health fact sheets. Anthropometric and blood pressure measurements, as well as food frequency and physical activity surveys were conducted at baseline, week 12, and week 24. Students' choice of fruit as a snack was also monitored at study visits. RESULTS: Students were 18-20 years old, 69% female, and from a diverse college campus (46% Caucasian, 23% Asian, 20% African American, 11% other). At week 24, 84% of students reported reading at least half of all emails. Mean change (standard error [SE]) from baseline of saturated fat intake was marginally significant between the treatment groups at week 24, 0.7 (SE 0.42) % kcal for control and -0.3 (SE 0.30) % kcal for intervention (P=0.048). A significant difference in percent of snacks chosen that were fruit (chi(2)1, N=221 = 11.7, P<0.001) was detected between the intervention and control group at week 24. CONCLUSIONS: Use of an electronic wellness program is feasible in college students and resulted in a decrease in saturated fat intake and an increase in observed fruit intake compared to a control group. PMID- 26929120 TI - Can the identification of an idle line facilitate its removal? A comparison between a proposed guideline and clinical practice. AB - BACKGROUND: There are 250,000 cases of central line-associated blood stream infections in the United States annually, some of which may be prevented by the removal of lines that are no longer needed. OBJECTIVE: To test the performance of criteria to identify an idle line as a guideline to facilitate its removal. METHODS: Patients with central lines on the wards were identified. Criteria for justified use were defined. If none were met, the line was considered "idle." We proposed the guideline that a line may be removed the day following the first idle day and compared actual practice with our proposed guideline. RESULTS: One hundred twenty-six lines in 126 patients were observed. Eighty-three (65.9%) were peripherally inserted central catheters. Twenty-seven percent (n= 34) were placed for antibiotics. Seventy-six patients had lines removed prior to discharge. In these patients, the line was in place for 522 days, of which 32.7% were idle. The most common reasons to justify the line included parenteral antibiotics and meeting systemic inflammatory response (SIRS) criteria. In 11 (14.5%) patients, the line was removed prior to the proposed guideline. Most (n = 36, 47.4%) line removals were observed to be in accordance with our guideline. In another 29 (38.2%), line removal was delayed compared to our guideline. CONCLUSIONS: Idle days are common. Central line days may be reduced by the consistent daily reevaluation of a line's justification using defined criteria. The practice of routine central line placement for prolonged antibiotics and the inclusion of SIRS criteria to justify the line may need to be reevaluated. Journal of Hospital Medicine 2016;11:489-493. (c) 2016 Society of Hospital Medicine. PMID- 26929119 TI - Preferential accumulation of T helper cells but not cytotoxic T cells characterizes benign subclinical rejection of human liver allografts. AB - Subclinical rejection (SCR) is a common event in protocol biopsies after liver transplantation (LT). So far the interpretation of the underlying histological changes and clinical significance is limited. Previous studies were restricted to SCR manifestations within the first weeks after transplantation with limited follow-up. We analyzed clinical data from our prospective protocol biopsy program and found late SCR (at least 3 months after transplantation) to be a common event (41/94 patients). SCR manifested much later than acute cellular rejection (ACR). In the second year after transplantation, the SCR incidence in protocol biopsies reached a plateau of approximately 25% and remained at this level until the latest observed manifestations more than 5 years after transplantation. During a median follow-up of 32 months after SCR, no acute or chronic rejection, relevant graft fibrosis, graft loss, or liver-related death occurred even without specific therapy for SCR. Immunophenotyping of liver biopsies during SCR showed that similar to ACR, the composition of intrahepatic T cells depended on the severity of histological rejection. However, SCR showed a different pattern of infiltrating T cells with a stronger accumulation of CD4(+) cells, an increasing CD4(+) /CD8(+) ratio, and an increasing CD4(+) forkhead box P3 (FOXP3)(+) regulatory T cell (Treg)/CD8(+) ratio, which was not seen in ACR. These intrahepatic T cell patterns were not reflected in the peripheral blood. In conclusion, late SCR after LT has a good clinical prognosis, and it seems safe to leave it untreated. This benign clinical course compared to ACR is associated with intrahepatic T cell infiltration patterns showing less cytotoxic T cells and more CD4(+) FOXP3(+) Tregs. Liver Transplantation 22 943-955 2016 AASLD. PMID- 26929121 TI - High Oestradiol Replacement Reverses Response Memory Bias in Ovariectomised Female Rats Regardless of Dopamine Levels in the Dorsal Striatum. AB - Oestrogens influence memory system bias in female rats such that high levels of oestrogen are associated with place (or spatial) memory use, and low oestrogen levels with response (or habitual) memory use. Moreover, striatal-dependent response memory is sensitive to dopamine transmission in the dorsal striatum, and oestrogens have been shown to affect dopamine release in that brain area. In the present study, the effects of oestrogens and dopamine transmission on multiple memory system bias were explored in ovariectomised rats receiving low or high 17beta-oestradiol replacement under saline, autoreceptor-activating doses of the dopamine D2 receptor agonist, apomorphine (50 and 80 MUg/kg), or amphetamine (0.5 mg/kg) administration. Furthermore, dorsal striatal dopamine release was measured after administration of the same drug conditions using in vivo microdialysis. As expected, high oestradiol rats predominantly used place memory, whereas the opposite pattern was observed in low oestradiol rats. However, the high apomorphine dose statistically significantly altered memory bias in high oestradiol rats from predominant place to predominant response memory, with a similar trend in the low apomorphine dose and the amphetamine group. There was no effect of drugs on memory bias in low oestradiol rats. Rats with high oestradiol replacement receiving amphetamine exhibited greater dorsal striatal dopamine release than low oestradiol replacement rats, and this difference was amplified in the right hemisphere. Furthermore, a logistic regression analysis revealed that oestradiol, but not dorsal striatal dopamine levels, significantly predicted response memory bias. These findings provide further evidence that oestradiol modulates memory system bias, and also that memory bias is changed by systemic apomorphine administration. However, although oestradiol affects dopamine transmission in the dorsal striatum in a lateralised manner, this does not predict memory system bias. PMID- 26929122 TI - Filamentous phage SW1 is active and influences the transcriptome of the host at high-pressure and low-temperature. AB - As the most abundant biological entities on the planet, viruses are involved in global biogeochemical cycles, and they have been shown to play an important role in the overall functioning of the deep-sea ecosystem. Nevertheless, little is known about whether and how deep-sea viruses affect the physiology of their bacterial hosts. Previously, the filamentous phage SW1 was identified in the bathypelagic bacterium Shewanella piezotolerans WP3, which was isolated from the upper sediment of West Pacific ocean. In this study, phage SW1 was shown to be active under in situ environmental conditions (20 MPa and 4 degrees C) by transmission electron microscopy and reverse-transcription quantitative polymerase chain reaction. Further comparative analysis showed that SW1 had a significant influence on the growth and transcriptome of its host. The transcription of genes responsible for basic cellular activities, including the transcriptional/translational apparatus, arginine synthesis, purine metabolism and the flagellar motor, were down-regulated by the phage. Our results present the first characterization of a phage-host interaction under high-pressure and low-temperature conditions, which indicated that the phage adjusted the energy utilization strategy of the host for improved survival in deep-sea environments. PMID- 26929123 TI - Stretchable Electrochemical Sensor for Real-Time Monitoring of Cells and Tissues. AB - Stretchable electrochemical sensors are conceivably a powerful technique that provides important chemical information to unravel elastic and curvilinear living body. However, no breakthrough was made in stretchable electrochemical device for biological detection. Herein, we synthesized Au nanotubes (NTs) with large aspect ratio to construct an effective stretchable electrochemical sensor. Interlacing network of Au NTs endows the sensor with desirable stability against mechanical deformation, and Au nanostructure provides excellent electrochemical performance and biocompatibility. This allows for the first time, real-time electrochemical monitoring of mechanically sensitive cells on the sensor both in their stretching free and stretching states as well as sensing of the inner lining of blood vessels. The results demonstrate the great potential of this sensor in electrochemical detection of living body, opening a new window for stretchable electrochemical sensor in biological exploration. PMID- 26929124 TI - Labeling and Selective Inactivation of Gram-Positive Bacteria Employing Bimodal Photoprobes with Dual Readouts. AB - Carbohydrate-conjugated silicon(IV) phthalocyanines with bimodal photoactivity were developed as probes with both fluorescent labeling and photosensitizing capabilities, and the concomitant fluorescent labeling and photoinduced inactivation of Gram-positive and Gram-negative models was explored. The maltohexaose-conjugated photoprobe provides a dual readout to distinguish between both groups of pathogens, as only the Gram-positive species was inactivated, even though both appeared labeled with near-infrared luminescence. Antibiotic resistance did not hinder the phototoxic effect, as even the methicillin resistant pathogen Staphylococcus aureus (MRSA) was completely photoinactivated. Time-resolved confocal fluorescence microscopy analysis suggests that the photoprobe sticks onto the outer rim of the microorganisms, explaining the resistance of Gram-negative species on the basis of their membrane constitution. The mannose-conjugated photoprobe yields a different readout because it is able to label and to inactivate only the Gram-positive strain. PMID- 26929125 TI - Determining synthesis rates of individual proteins in zebrafish (Danio rerio) with low levels of a stable isotope labelled amino acid. AB - The zebrafish is a powerful model organism for the analysis of human cardiovascular development and disease. Understanding these processes at the protein level not only requires changes in protein concentration to be determined but also the rate at which these changes occur on a protein-by-protein basis. The ability to measure protein synthesis and degradation rates on a proteome-wide scale, using stable isotope labelling in conjunction with mass spectrometry is now a well-established experimental approach. With the advent of more selective and sensitive mass spectrometers, it is possible to accurately measure lower levels of stable isotope incorporation, even when sample is limited. In order to challenge the sensitivity of this approach, we successfully determined the synthesis rates of over 600 proteins from the cardiac muscle of the zebrafish using a diet where either 30% or 50% of the L-leucine was replaced with a stable isotope labelled analogue ([(2) H7 ]L-leucine]. It was possible to extract sufficient protein from individual zebrafish hearts to determine the incorporation rate of the label into hundreds of proteins simultaneously, with the two labelling regimens showing a good correlation of synthesis rates. PMID- 26929126 TI - Should the BK polyomavirus cytopathic effect be best classified as atypical or benign in urine cytology specimens? AB - BACKGROUND: According to The Paris System for Reporting Urinary Cytology (TPS), the category of atypical urothelial cells (AUC) should not be applied to specimens in which cellular changes can be entirely attributed to the polyoma (BK) virus cytopathic effect (CPE). Until recently, cases with BK CPE at The Johns Hopkins Hospital were categorized as atypical urothelial cells of uncertain significance (AUC-US), which is equivalent to the TPS AUC category. This study was performed to determine how significantly the rate of AUC-US specimens would decrease if specimens with only BK CPE were classified as benign. METHODS: Two reviewers and 1 adjudicator re-evaluated urinary tract specimens to determine whether sufficient cytological atypia justified an AUC-US diagnosis independent of the presence of BK CPE. For patients with surgical follow-up, the rate of high grade urothelial carcinoma (HGUC) on tissue biopsy was tracked over a 5-year period. RESULTS: The reclassification rate of AUC-US cases with BK CPE as benign was 62.6%. The rate of subsequent HGUC was 6.0% for cases reclassified as benign and 10.0% for cases still classified as AUC-US. These rates were not significantly elevated in comparison with control cohorts among all-comers. However, for patients without a history of HGUC, the rate of HGUC on follow-up was significantly elevated in comparison with the rate for a benign control cohort and was similar to the rate for the AUC-US control cohort. CONCLUSIONS: Reclassification as benign would have decreased the rate of AUC-US from 24.8% to 20.7% during the study year. However, the high rate of subsequent HGUC among nonsurveillance patients suggests that the reclassification of specimens with BK CPE in these patients may be inappropriate. Cancer Cytopathol 2016;124:436-42. (c) 2016 American Cancer Society. PMID- 26929127 TI - Settling the score: moving beyond the 5/4 criterion debate. PMID- 26929128 TI - A confirmed rabies case in a French resident in Cambodia, June 2015. AB - A case of confirmed rabies in a French resident is a wake-up call for improved access to timely and adequate rabies post-exposure prophylaxis for all those living in Cambodia, as well as for improved pre-exposure prevention in travellers to Cambodia and other highly endemic settings. PMID- 26929129 TI - Effect of Early Overfeeding on Palatable Food Preference and Brain Dopaminergic Reward System at Adulthood: Role of Calcium Supplementation. AB - Rats raised in small litters (SL) are obese and hyperphagic. In the present study, we evaluated whether obesity is associated with changes in the mesocorticolimbic dopaminergic reward system in these animals at adulthood. We also assessed the anti-obesity effects of dietary calcium supplementation. To induce early overfeeding, litters were adjusted to three pups on postnatal day (PN)3 (SL group). Control litters were kept with 10 pups each until weaning (NL group). On PN120, SL animals were subdivided into two groups: SL (standard diet) and SL-Ca [SL with calcium supplementation (10 g calcium carbonate/kg rat chow) for 60 days]. On PN175, animals were subjected to a food challenge: animals could choose between a high-fat (HFD) or a high-sugar diet (HSD). Food intake was recorded after 30 min and 12 h. Euthanasia occurred on PN180. SL rats had higher food intake, body mass and central adiposity. Sixty days of dietary calcium supplementation (SL-Ca) prevented these changes. Only SL animals preferred the HFD at 12 h. Both SL groups had lower tyrosine hydroxylase content in the ventral tegmental area, lower dopaminergic transporter content in the nucleus accumbens, and higher type 2 dopamine receptor (D2R) content in the hypothalamic arcuate nucleus (ARC). They also had higher neuropeptide Y (NPY) and lower pro opiomelanocortin contents in the ARC. Calcium treatment normalised only D2R and NPY contents. Precocious obesity induces long-term effects in the brain dopaminergic system, which can be associated with an increased preference for fat at adulthood. Calcium treatment prevents this last alteration, partially through its actions on ARC D2R and NPY proteins. PMID- 26929130 TI - Molecular Design for Cryogenic Magnetic Coolants. AB - The area of molecular magnetic coolants has developed rapidly in recent years. A large number of competitive candidates have been reported, with the cooling performances chasing each other. In this account, four explicit strategies, namely, increasing ground-state spin, reducing magnetic anisotropy, weakening magnetic interactions, and lowering the molecular weight, are proposed from the theoretical viewpoint towards improving the magnetocaloric effect (MCE). According to this guidance, these successful strategies are discussed to pursue excellent magnetic coolants. This is accompanied by a discussion of the representative examples reported by our group. The magnetic entropy change increases from one compound to another, which in the most pronounced cases is suggestive of being the largest MCE in magnetic coolants. PMID- 26929131 TI - High signal intensity in dentate nucleus and globus pallidus on unenhanced T1 weighted MR images in three patients with impaired renal function and vascular calcification. AB - Gadolinium-based contrast agents (primarily those with linear chelates) are associated with a dose-dependent signal hyperintensity in the dentate nucleus and the globus pallidus on unenhanced T1-weighted MRI following administration to selected patients with normal renal function. The accumulation of gadolinium has also been reported in the skin, heart, liver, lung, and kidney of patients with impaired renal function suffering from nephrogenic systemic fibrosis (NSF). Here we report on three patients with impaired renal function and vascular calcification (two with confirmed NSF) whose unenhanced T1-weighted MRIs showed conspicuous high signal intensity in the dentate nucleus and the globus pallidus after they had been exposed to relatively low doses of linear gadolinium-based contrast agents (0.27, 0.45, and 0.68 mmol/kg). Signal ratios between dentate nucleus and pons and between globus pallidus and thalamus were comparable with previously reported measurements in subjects without renal impairment. Of note, all three analysed patients suffered from transient signs of neurological disorders of undetermined cause. In conclusion, the exposure to 0.27-0.68 mmol/kg of linear gadolinium-based contrast agent was associated with probable gadolinium accumulation in the brain of three patients suffering from impaired renal function and vascular calcification. (c) 2016 The Authors. Contrast Media & Molecular Imaging published by John Wiley & Sons Ltd. PMID- 26929132 TI - Dissection of the sensor domain of the copper-responsive histidine kinase CorS from Myxococcus xanthus. AB - Myxococcus xanthus CorSR is a two-component system responsible for maintaining the response of this bacterium to copper. In the presence of this metal it upregulates, among others, the genes encoding the multicopper oxidase CuoA and the P1B -ATPase CopA. Dissection of the periplasmic sensor domain of the histidine kinase CorS by the analysis of a series of in-frame deletion mutants generated in this portion of the protein has revealed that copper sensing requires a region of 28 residues in the N terminus and another region of nine residues in the C terminus. Point mutations at His34, His38 and His171 demonstrate that they are essential for the ability of CorS to sense copper. Furthermore, the use of a bacterial two-hybrid system has revealed dimerization between monomers of CorS even in the absence of any metal, and that copper enhances this interaction. When dimerization was tested with proteins mutated at the three essential His residues, it was observed that these proteins maintain the intrinsic dimerization ability in the absence of metal. In contrast to the wild-type protein, copper did not strengthen the interaction, corroborating that copper binding to the three His residues of CorS is required for enhancing dimerization and transmitting the signal. PMID- 26929134 TI - Formation of N-Heterocyclic Carbenes by Tautomerization of Mesomeric Betaines: Cyclic Boron Adducts and Palladium Complexes From 2-(Imidazolium-1-yl)phenolates. AB - 2-(Imidazolium-1-yl)phenolates are conjugated heterocyclic mesomeric betaines in tautomeric equilibrium with the corresponding N-heterocyclic carbenes (NHCs), 3 (2-hydroxyphenyl)-imidazol-2-ylidenes. The carbene tautomers can be trapped as thiones (X-ray analysis). Moreover, bis(triphenylphosphine)palladium(II) dichloride in THF trapped the carbene tautomer as a palladium complex without participation of the phenolate group (X-ray analysis). The corresponding anionic NHCs, 2-phenolate-substituted imidazol-2-ylidenes, can be trapped by triethylborane or triphenylborane to form 4,4-diethyl- or 4,4-diphenyl-4H benzo[e]imidazo[2,1-c][1,4,2]oxaza-borininium-4-ides, respectively (two X-ray analyses). These tricyclic systems are the first representatives of a new heterocyclic ring system. The results of DFT calculations concerning the HOMO/LUMO profiles and partial charges are also presented. PMID- 26929135 TI - Spatially-resolved protein surface microsampling from tissue sections using liquid extraction surface analysis. AB - Tissue microenvironment characterization presents a challenge for a better understanding of the full complexity of a pathology. Unfortunately, making a precise "picture" of the disease needs an efficient microsampling method coupled to an accurate localization for performing region-dependent proteomics. Here, we present a method that enables rapid and reproducible extraction of proteins from a tissue section to analyze a specific region at a millimeter scale. The method used a liquid-microjunction extraction with conventional detergent solution for proteomics analysis. We successfully performed immunoblotting experiments and showed the possibility to retrieve and identify more than 1400 proteins from a 1 mm diameter spot size on tissue sections with a high degree of reproducibility both qualitatively and quantitatively. Moreover, the small size of the extracted region achieved by this sampling method allows the possibility to perform multiple extractions on different tissue section points. Ten points on a sagittal rat brain tissue section were analyzed and the measured proteins clearly distinguished the different parts of the brain, thus permitting precise functional mapping. We thus demonstrate that with this technology, it is possible to map the tissue microenvironment and gain an understanding of the molecular mechanisms at millimeter resolution. PMID- 26929136 TI - One size should not fit all, so use the right tool for the job. PMID- 26929137 TI - Efficacy of medical grade honey in the management of canine otitis externa - a pilot study. AB - BACKGROUND: The high prevalence of antimicrobial resistance within otic pathogens has created a need for alternative therapies of otitis externa (OE). Evidence suggests that medical grade honey (MGH) may be effective against drug-resistant pathogens. HYPOTHESIS/OBJECTIVES: The efficacy of a commercial MGH compound was assessed in an open clinical trial. We hypothesized that it would be an effective alternative to conventional treatments. ANIMALS: Client-owned dogs (n = 15) with a confirmed diagnosis of infectious OE were enrolled in this pilot study. METHODS: Dogs were prescribed MGH (1 mL daily per ear) until cure was achieved or for a maximum of 21 d. Evaluation was based on weekly clinical scores, cytological progression and owner assessments of pruritus. Swab samples were submitted for culture and susceptibility testing. MGH was tested for biocidal activity against the bacterial isolates. RESULTS: Medical grade honey promoted rapid clinical progress, with 70% of dogs achieving clinical cure between days 7 and 14 and over 90% having resolved by Day 21. There was a decrease in clinical scores throughout the duration of the trial (P < 0.001) and owner-assessed pruritus also decreased significantly (P < 0.05). In vitro assays of the biocidal activity of MGH showed activity against all bacterial isolates, including meticillin-resistant strains of Staphylococcus pseudintermedius (MRSP) and other species of drug-resistant bacteria. CONCLUSION AND CLINICAL IMPORTANCE: Medical grade honey was successful in both clinical and laboratory settings, thus demonstrating its potential of becoming an alternative treatment for canine OE. PMID- 26929138 TI - Are Pregnancy Intentions Associated with Transitions Into and Out of Marriage? AB - CONTEXT: In addition to having associations with health outcomes, pregnancy intentions may be associated with social outcomes, including marital transitions. METHODS: Linked data from the 2004-2008 Oklahoma Pregnancy Risk Assessment Monitoring System and The Oklahoma Toddler Survey for 2006-2010 on 3,617 women who were married and 2,123 who were unmarried at conception were used to examine the relationship between pregnancy intention status (intended, mistimed by less than two years, mistimed by two or more years, or unwanted) and marital formation or dissolution by the time of the birth and two years later. Logistic regression analyses were conducted, and propensity score methods were used to adjust for confounding characteristics. RESULTS: Intention status was associated with marital transition two years after the birth, but not between conception and birth. In adjusted models, among women married at conception, those with a birth resulting from an unwanted pregnancy were more likely than those with a birth resulting from an intended pregnancy to transition out of marriage by the time their child was two years old (odds ratio, 2.2). Among women unmarried at conception, those with a birth following an unwanted pregnancy were less likely than those with a birth following an intended pregnancy to marry by the time their child was two (0.5). Births following mistimed pregnancies were not associated with marital transition. CONCLUSIONS: The findings should motivate researchers to broaden the scope of research on the consequences of unintended childbearing. Future research should distinguish between mistimed and unwanted births. PMID- 26929139 TI - Evaluating the effectiveness of transferrin receptor-1 (TfR1) as a magnetic resonance reporter gene. AB - Magnetic resonance (MR) reporter genes have the potential for tracking the biodistribution and fate of cells in vivo, thus allowing the safety, efficacy and mechanisms of action of cell-based therapies to be comprehensively assessed. In this study, we evaluate the effectiveness of the iron importer transferrin receptor-1 (TfR1) as an MR reporter gene in the model cell line CHO-K1. Overexpression of the TfR1 transgene led to a reduction in the levels of endogenous TfR1 mRNA, but to a 60-fold increase in total TfR1 protein levels. Although the mRNA levels of ferritin heavy chain-1 (Fth1) did not change, Fth1 protein levels increased 13-fold. The concentration of intracellular iron increased significantly, even when cells were cultured in medium that was not supplemented with iron and the amount of iron in the extracellular environment was thus at physiological levels. However, we found that, by supplementing the cell culture medium with ferric citrate, a comparable degree of iron uptake and MR contrast could be achieved in control cells that did not express the TfR1 transgene. Sufficient MR contrast to enable the cells to be detected in vivo following their administration into the midbrain of chick embryos was obtained irrespective of the reporter gene. We conclude that TfR1 is not an effective reporter and that, to track the biodistribution of cells with MR imaging in the short term, it is sufficient to simply culture cells in the presence of ferric citrate. Copyright (c) 2016 The Authors Contrast Media & Molecular Imaging Published by John Wiley & Sons Ltd. PMID- 26929141 TI - Phylogenetic diversity and biogeography of the Mamiellophyceae lineage of eukaryotic phytoplankton across the oceans. AB - High-throughput diversity amplicon sequencing of marine microbial samples has revealed that members of the Mamiellophyceae lineage are successful phytoplankton in many oceanic habitats. Indeed, these eukaryotic green algae can dominate the picoplanktonic biomass, however, given the broad expanses of the oceans, their geographical distributions and the phylogenetic diversity of some groups remain poorly characterized. As these algae play a foundational role in marine food webs, it is crucial to assess their global distribution in order to better predict potential changes in abundance and community structure. To this end, we analyzed the V9-18S small subunit rDNA sequences deposited from the Tara Oceans expedition to evaluate the diversity and biogeography of these phytoplankton. Our results show that the phylogenetic composition of Mamiellophyceae communities is in part determined by geographical provenance, and do not appear to be influenced - in the samples recovered - by water depth, at least at the resolution possible with the V9-18S. Phylogenetic classification of Mamiellophyceae sequences revealed that the Dolichomastigales order encompasses more sequence diversity than other orders in this lineage. These results indicate that a large fraction of the Mamiellophyceae diversity has been hitherto overlooked, likely because of a combination of size fraction, sequencing and geographical limitations. PMID- 26929142 TI - The coat protein of Alfalfa mosaic virus interacts and interferes with the transcriptional activity of the bHLH transcription factor ILR3 promoting salicylic acid-dependent defence signalling response. AB - During virus infection, specific viral component-host factor interaction elicits the transcriptional reprogramming of diverse cellular pathways. Alfalfa mosaic virus (AMV) can establish a compatible interaction in tobacco and Arabidopsis hosts. We show that the coat protein (CP) of AMV interacts directly with transcription factor (TF) ILR3 of both species. ILR3 is a basic helix-loop-helix (bHLH) family member of TFs, previously proposed to participate in diverse metabolic pathways. ILR3 has been shown to regulate NEET in Arabidopsis, a critical protein in plant development, senescence, iron metabolism and reactive oxygen species (ROS) homeostasis. We show that the AMV CP-ILR3 interaction causes a fraction of this TF to relocate from the nucleus to the nucleolus. ROS, pathogenesis-related protein 1 (PR1) mRNAs, salicylic acid (SA) and jasmonic acid (JA) contents are increased in healthy Arabidopsis loss-of-function ILR3 mutant (ilr3.2) plants, which implicates ILR3 in the regulation of plant defence responses. In AMV-infected wild-type (wt) plants, NEET expression is reduced slightly, but is induced significantly in ilr3.2 mutant plants. Furthermore, the accumulation of SA and JA is induced in Arabidopsis wt-infected plants. AMV infection in ilr3.2 plants increases JA by over 10-fold, and SA is reduced significantly, indicating an antagonist crosstalk effect. The accumulation levels of viral RNAs are decreased significantly in ilr3.2 mutants, but the virus can still systemically invade the plant. The AMV CP-ILR3 interaction may down regulate a host factor, NEET, leading to the activation of plant hormone responses to obtain a hormonal equilibrium state, where infection remains at a level that does not affect plant viability. PMID- 26929143 TI - Reproductive biology of Syzygiella rubricaulis (Nees) Steph. (Adelanthaceae, Marchantiophyta), a liverwort disjunctly distributed in high-altitude Neotropical mountains. AB - Syzygiella rubricaulis is a dioecious leafy liverwort disjunctly distributed and restricted to high-altitude mountains in the Neotropics and the Azores. This study is part of a larger project examining the phylogeography of S. rubricaulis in the Neotropics, and our main goals were to understand its reproductive biology, where sex expression occurs, if vegetative propagules are frequently found, how the sexes are distributed in populations, how frequently sporophytes are formed and what environmental conditions influence sexual expression. S. rubricaulis patches are mostly female, but all patches also contain non sex expressing shoots. Out of 42 patches examined, 29 (69%) were sex-expressing: 25 were unisexual (21 female and four male) and four of mixed sex (two male-biased and two unbiased). At shoot level, out of 4200 shoots 18% were female and 7% male; among sex-expressing shoots, 73% were female, representing a sex ratio of 0.8 (female-biased). We encountered a total of 33 sporophytes in six patches (in Brazil, Venezuela and Ecuador). Leaf regenerants were found in one patch in Mexico. Low rates of sporophytes were likely related to low frequencies of male shoots and large distances between the sexes. As 25% of S. rubricaulis shoots expressed sex (occasionally producing sporophytes), we suggest that short distance (and rarely long-distance) spore dispersal events occur in mountainous areas on a short-term basis. On a long-term basis, however, these events likely contribute to dynamic exchanges among populations in the Neotropics. PMID- 26929144 TI - Questions about the validity of the binge or heavy drinking criterion have implications for more than just treatment evaluation. AB - Commentary to: Questioning the validity of the 4+/5+ binge or heavy drinking criterion in college and clinical populations. PMID- 26929145 TI - Stem cell therapy: a promising biological strategy for tendon-bone healing after anterior cruciate ligament reconstruction. AB - Tendon-bone healing after anterior cruciate ligament (ACL) reconstruction is a complex process, impacting significantly on patients' prognosis. Natural tendon bone healing usually results in fibrous scar tissue, which is of inferior quality compared to native attachment. In addition, the early formed fibrous attachment after surgery is often not reliable to support functional rehabilitation, which may lead to graft failure or unsatisfied function of the knee joint. Thus, strategies to promote tendon-bone healing are crucial for prompt and satisfactory functional recovery. Recently, a variety of biological approaches, including active substances, gene transfer, tissue engineering and stem cells, have been proposed and applied to enhance tendon-bone healing. Among these, stem cell therapy has been shown to have promising prospects and draws increasing attention. From commonly investigated bone marrow-derived mesenchymal stem cells (bMSCs) to emerging ACL-derived CD34+ stem cells, multiple stem cell types have been proven to be effective in accelerating tendon-bone healing. This review describes the current understanding of tendon-bone healing and summarizes the current status of related stem cell therapy. Future limitations and perspectives are also discussed. PMID- 26929146 TI - Highly Active Cobalt Sulfide/Carbon Nanotube Catalyst for Hydrogen Evolution at Soft Interfaces. AB - Hydrogen evolution at polarized liquid-liquid interfaces [water/1,2 dichloroethane (DCE)] by the electron donor decamethylferrocene (DMFc) is catalyzed efficiently by the fabricated cobalt sulfide (CoS) nanoparticles and nanocomposites of CoS nanoparticles formed on multi-walled carbon nanotubes (CoS/CNT). The suspended CoS/CNT nanocomposite catalysts at the interface show a higher catalytic activity for the hydrogen evolution reaction (HER) than the CoS nanoparticles due to the high dispersity and conductivity of the CNT materials, which can serve as the main charge transport pathways for the injection of electrons to attain the catalytic sites of the nanoparticles. The reaction rate increased more than 1000-fold and 300-fold by using CoS/CNT and CoS catalysts, respectively, when compared to a non-catalyzed reaction. PMID- 26929149 TI - Impact of introduction of blended learning in gross anatomy on student outcomes. AB - Blended learning has become increasingly common, in a variety of disciplines, to take advantage of new technology and potentially increase the efficiency and flexibility of delivery. This study aimed to describe blended delivery of a gross anatomy course and to evaluate the effectiveness of the delivery in terms of student outcomes. A gross anatomy course for second-year physiotherapy students across two campuses was delivered in traditional face-to-face teaching mode in 2013 (n = 150 students), some online content was introduced in 2014 (n = 160) and the subject was fully blended in 2015 (n = 151). The final 'blend' consisted of one lecture per week with most content delivered using online video resources (prepared by staff using a structured peer-reviewed process) and retention of face-to-face practical classes. Outcomes evaluated included student grades, student engagement with content through online discussion forums and student feedback using both quantitative and qualitative analysis. Grades were higher in 2014 and 2015 than in 2013 (P < 0.01). There were no differences in student engagement with online discussion forums. Student feedback identified some negative comments and lower levels of intellectual stimulation (P < 0.05) with the initial introduction of online content in 2014. The fully blended version in 2015 resulted in more balanced comments about online content but higher perceived workload (P < 0.05). All cohorts listed practical classes as a major factor contributing to learning. Blended learning appears to be well-suited to gross anatomy teaching on the proviso that face-to-face practical classes are maintained, but may result in higher perceived workloads. Anat Sci Educ 9: 422 430. (c) 2016 American Association of Anatomists. PMID- 26929147 TI - Platelet signaling: a complex interplay between inhibitory and activatory networks. AB - The role of platelets in hemostasis and thrombosis is dependent on a complex balance of activatory and inhibitory signaling pathways. Inhibitory signals released from the healthy vasculature suppress platelet activation in the absence of platelet receptor agonists. Activatory signals present at a site of injury initiate platelet activation and thrombus formation; subsequently, endogenous negative signaling regulators dampen activatory signals to control thrombus growth. Understanding the complex interplay between activatory and inhibitory signaling networks is an emerging challenge in the study of platelet biology, and necessitates a systematic approach to utilize experimental data effectively. In this review, we will explore the key points of platelet regulation and signaling that maintain platelets in a resting state, mediate activation to elicit thrombus formation, or provide negative feedback. Platelet signaling will be described in terms of key signaling molecules that are common to the pathways activated by platelet agonists and can be described as regulatory nodes for both positive and negative regulators. PMID- 26929148 TI - MEAN inhibits hepatitis C virus replication by interfering with a polypyrimidine tract-binding protein. AB - MEAN (6-methoxyethylamino-numonafide) is a small molecule compound, and here, we report that it effectively inhibits hepatitis C virus (HCV) infection in an HCV cell culture system using a JC1-Luc chimeric virus, with a 50% effective concentration (EC50) of 2.36 +/- 0.29 MUM. Drug combination usage analyses demonstrated that MEAN was synergistic with interferon alpha, ITX5061 and ribavirin. In addition, MEAN effectively inhibits N415D mutant virus and G451R mutant viral infections. Mechanistic studies show that the treatment of HCV infected hepatocytes with MEAN inhibits HCV replication but not translation. Furthermore, treatment with MEAN significantly reduces polypyrimidine tract binding protein (PTB) levels and blocks the cytoplasmic redistribution of PTB upon infection. In the host cytoplasm, PTB is directly associated with HCV replication, and the inhibition of HCV replication by MEAN can result in the sequestration of PTB in treated nuclei. Taken together, these results indicate that MEAN is a potential therapeutic candidate for HCV infection, and the targeting of the nucleo-cytoplasmic translocation of the host PTB protein could be a novel strategy to interrupt HCV replication. PMID- 26929150 TI - Geographically conserved microbiomes of four temperate water tunicates. AB - Tunicates are useful models for exploring microbiomes because they have an innate immune system resembling that of chordates. Automated ribosomal RNA intergenic spacer analysis and High-Throughput Sequencing were used to compare the tunic microbiomes of Ciona robusta (formerly Ciona intestinalis type A), Ciona savignyi, Botrylloides leachi and Botryllus schlosseri sampled from three distinct locations with limited genetic connectivity. Bacterial phylotype profiles were conserved within each species, and there were no detectable differences between tunic and tunic + cuticle subsamples from an individual. Bacterial operational taxonomic unit (OTU) diversity was lowest for C. savignyi (320 +/- 190 OTUs) and highest for B. schlosseri (1260 +/- 190 OTUs). Each species had a distinct set of bacterial OTUs (pseudo-F = 3.0, p > 0.001), with the exception of B. leachi and B. schlosseri from one sampling location (t = 1.2, p = 0.09). Of note were OTUs assigned to Alphaproteobacteria from C. robusta plus Phyllobacteriaceae and Endozoicomonas from C. savignyi. These OTUs contributed 51, 22 and 10% of sequence reads, respectively, and are related to known bacterial symbionts. The within-species conservation of core OTUs across three distinct and co-occurring populations of tunicates provides compelling evidence that these tunicates foster defined microbiomes. PMID- 26929152 TI - Development of Anionically Decorated Caged Neurotransmitters: In Vitro Comparison of 7-Nitroindolinyl- and 2-(p-Phenyl-o-nitrophenyl)propyl-Based Photochemical Probes. AB - Neurotransmitter uncaging, especially that of glutamate, has been used to study synaptic function for over 30 years. One limitation of caged glutamate probes is the blockade of gamma-aminobutyric acid (GABA)-A receptor function. This problem comes to the fore when the probes are applied at the high concentrations required for effective two-photon photolysis. To mitigate such problems one could improve the photochemical properties of caging chromophores and/or remove receptor blockade. We show that addition of a dicarboxylate unit to the widely used 4 methoxy-7-nitroindolinyl-Glu (MNI-Glu) system reduced the off-target effects by about 50-70 %. When the same strategy was applied to an electron-rich 2-(p-Phenyl o-nitrophenyl)propyl (PNPP) caging group, the pharmacological improvements were not as significant as in the MNI case. Finally, we used very extensive biological testing of the PNPP-caged Glu (more than 250 uncaging currents at single dendritic spines) to show that nitro-biphenyl caging chromophores have two-photon uncaging efficacies similar to that of MNI-Glu. PMID- 26929151 TI - Cell wall targeted in planta iron accumulation enhances biomass conversion and seed iron concentration in Arabidopsis and rice. AB - Conversion of nongrain biomass into liquid fuel is a sustainable approach to energy demands as global population increases. Previously, we showed that iron can act as a catalyst to enhance the degradation of lignocellulosic biomass for biofuel production. However, direct addition of iron catalysts to biomass pretreatment is diffusion-limited, would increase the cost and complexity of biorefinery unit operations and may have deleterious environmental impacts. Here, we show a new strategy for in planta accumulation of iron throughout the volume of the cell wall where iron acts as a catalyst in the deconstruction of lignocellulosic biomass. We engineered CBM-IBP fusion polypeptides composed of a carbohydrate-binding module family 11 (CBM11) and an iron-binding peptide (IBP) for secretion into Arabidopsis and rice cell walls. CBM-IBP transformed Arabidopsis and rice plants show significant increases in iron accumulation and biomass conversion compared to respective controls. Further, CBM-IBP rice shows a 35% increase in seed iron concentration and a 40% increase in seed yield in greenhouse experiments. CBM-IBP rice potentially could be used to address iron deficiency, the most common and widespread nutritional disorder according to the World Health Organization. PMID- 26929153 TI - Synthesis and Evaluation of a 2,11-Cembranoid-Inspired Library. AB - The 2,11-cembranoid family of natural products has been used as inspiration for the synthesis of a structurally simplified, functionally diverse library of octahydroisobenzofuran-based compounds designed to augment a typical medicinal chemistry library screen. Ring-closing metathesis, lactonisation and SmI2 mediated methods were exemplified and applied to the installation of a third ring to mimic the nine-membered ring of the 2,11-cembranoids. The library was assessed for aqueous solubility and permeability, with a chemical-space analysis performed for comparison to the family of cembranoid natural products and a sample set of a screening library. Preliminary investigations in cancer cells showed that the simpler scaffolds could recapitulate the reported anti-migratory activity of the natural products. PMID- 26929154 TI - BMP7 enhances the effect of BMSCs on extracellular matrix remodeling in a rabbit model of intervertebral disc degeneration. AB - Intervertebral discs (IVDs) provide stability and flexibility to the spinal column; however, IVDs, and in particular the nucleus pulposus (NP), undergo a degenerative process characterized by changes in the disc extracellular matrix (ECM), decreased cell viability, and reduced synthesis of proteoglycan and type II collagen. Here, we investigated the efficacy and feasibility of stem cell therapy using bone marrow mesenchymal stem cells (BMSCs) over-expressing bone morphogenetic protein 7 (BMP7) to promote ECM remodeling of degenerated IVDs. Lentivirus-mediated BMP7 over-expression induced differentiation of BMSCs into an NP phenotype, as indicated by expression of the NP markers collagen type II, aggrecan, SOX9 and keratins 8 and 19, increased the content of glycosaminoglycan, and up-regulated beta-1,3-glucuronosyl transferase 1, a regulator of chondroitin sulfate synthesis in NP cells. These effects were suppressed by Smad1 silencing, indicating that the effect of BMP7 on ECM remodeling was mediated by the Smad pathway. In vivo analysis in a rabbit model of disc degeneration showed that implantation of BMSCs over-expressing BMP7 promoted cell differentiation and proliferation in the NP, as well as their own survival, and these effects were mediated by the Smad pathway. The results of the present study indicate the beneficial effects of BMP7 on restoring ECM homeostasis in NP cells, and suggest potential strategies for improving cell therapy for the treatment of disc diseases. PMID- 26929155 TI - Travel-related health risks in moderately and severely immunocompromised patients: a case-control study. AB - BACKGROUND: The number of immunocompromised persons travelling to tropical countries is increasing. The hypothesis is that this population is at increased risk of travel-related health problems but there are few data to support it. The objective was to assess the risk of travel-related health problems in immunocompromised persons when compared with the general population of travellers. METHODS: A retrospective matched case-control study was performed. Cases were moderately or severely immunocompromised persons travelling to tropical countries and controls were non-immunocompromised persons, matched for demographic and travel characteristics. All participants responded to a phone questionnaire, asking them about any health problem they may have encountered while travelling or during the month following their return. The primary outcome was the incidence of a significant clinical event defined as repatriation, hospitalization during the travel or during the month following the return if due to a travel-related health problem and medical consultations during the trip. RESULTS: One hundred and sixteen moderately or severely immunocompromised cases [HIV infection (15), active cancer (25), splenectomized (20), solid organ transplant recipients (4) and use of systemic immunosuppressive medication (52)] and 116 controls were included. Incidence rates of significant clinical events were higher in immunocompromised travellers (9/116, 7.8%) than in controls (2/116, 1.7%) [OR = 4.8 , 95% CI 1.01-22.70; P = 0.048]. Most cases were related to infectious diseases (5/9, 55.5%), others were pulmonary embolism (2/9, 22%), inflammatory disease and trauma (1/9, 11.1% each). There was no significant difference between the two groups regarding common health problems. CONCLUSION: Moderately and severely immunocompromised travellers are at increased risk of developing a serious health problem during or after a trip in a tropical country. They should be well informed about the specific risks they are particularly prone to. Travel medicine health professionals should favour effective preventive measures for immunocompromised travellers and envisage stand-by antibiotic treatment. PMID- 26929156 TI - Dengue fever among Israeli expatriates in Delhi, 2015: implications for dengue incidence in Delhi, India. AB - We present the data of 13 dengue cases diagnosed between 1 August and 15 September 2015 among 240 Israeli expatriates residing in Delhi. Attack rates were similar between adults (6/128, 4.7%) and children (7/112, 6.3%). dengue virus (DENV-2) was identified in two and DENV-1 in one dengue-seropositive sample. Another febrile patient was diagnosed with chikungunya virus infection. The reported incidence of dengue fever among people living in Delhi was lower than 0.1% as of September 2015. Based on our results, we hypothesize that the incidence of dengue fever in Delhi is grossly underestimated. PMID- 26929157 TI - International Society on Thrombosis and Haemostasis core curriculum project: core competencies in clinical thrombosis and hemostasis: comment. PMID- 26929158 TI - Relationship Between Pathological Findings and Cholinesterase Activity and Nitric Oxide Levels in Cattle Infected Naturally by Eurytrema coelomaticum. AB - The aim of this study was to evaluate the role of butyrylcholinesterase (BChE) (in the serum and pancreas), acetylcholinesterase (AChE) (in the whole blood and pancreas) and nitric oxide (NO) (in the serum and pancreas) in cattle infected naturally by Eurytrema coelomaticum. Fifty-one cattle were studied, including 33 infected by E. coelomaticum and 18 uninfected animals. Significantly greater AChE activity was found in the pancreas of infected animals (P <0.01); however, these cattle had lower AChE activity in whole blood. BChE activity was greater in the sera of infected animals (P = 0.05), but was less in pancreatic samples. NO levels were significantly higher in the sera (P <0.05) and pancreas (P <0.001) of infected cattle compared with uninfected animals. A positive correlation was found between AChE activity in the pancreas and parasite load, but there was negative correlation between pancreatic BChE activity and parasitic load. Expression of AChE, BChE and NO is therefore linked to the inflammation caused by E. coelomaticum in cattle. PMID- 26929160 TI - Method for the quantification of rupture probability in soft collagenous tissues. AB - A computational method is presented for the assessment of rupture probabilities in soft collagenous tissues. This may in particular be important for the quantitative analysis of medical diseases such as atherosclerotic arteries or abdominal aortic aneurysms, where an unidentified rupture has in most cases fatal consequences. The method is based on the numerical minimization and maximization of probabilities of failure, which arise from random input quantities, for example, tissue properties. Instead of assuming probability distributions for these quantities, which are typically unknown especially for soft collagenous tissues, only restricted knowledge of these distributions is taken into account. Given this limited statistical input data, the minimized/maximized probabilities represent optimal bounds on the rupture probability, which enable a quantitative estimation of potential risks of performing or not performing medical treatment. Although easily extendable to all kinds of mechanical rupture criteria, the approach presented here incorporates stretch-based and damage-based criteria. These are evaluated based on numerical simulations of loaded tissues, where continuum mechanical material formulations are considered, which capture the supra-physiological behavior of soft collagenous tissues. Numerical examples are provided demonstrating the applicability of the method in an overstretched atherosclerotic artery. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26929159 TI - MiR-134-Mbd3 axis regulates the induction of pluripotency. AB - MicroRNAs (miRNAs) are post-transcriptional modulators of gene expression and play an important role in reprogramming process; however, relatively little is known about the underlying regulatory mechanism of miRNAs on how they epigenetically modulate reprogramming and pluripotency. Here, we report that the expression level of microRNA-134 (miR-134) was low in mouse embryonic stem cells (mESCs) but significantly up-regulated during neural differentiation, while down regulated during the induction of induced pluripotent stem cells (iPSCs) from neural progenitor cells (NPCs). Inhibition of miR-134 by miR-134 sponge promoted the efficiency of reprogramming which also was highly similar to mESCs. On the contrary, up-regulation of miR-134 repressed iPSCs induction. We also found that inhibition of miR-134 promoted the maturation of pre-iPSCs and increased its pluripotency. We also showed that miR-134 can directly target to the pluripotency related factor Methyl-CpG-binding domain protein 3 (Mdb3) 3' untranslated regions (3' UTR) to down-regulate its expression. And Mbd3 was found to promote the induction of iPSCs and could block the repression of reprogramming caused by overexpression of miR-134. This work revealed the critical function of miR-134 Mbd3 axis on regulating reprogramming and pluripotency of iPSCs derived from the NPCs, and might provide an insight into the miR-134-Mbd3 axis on regulating the iPSCs quality for further clinical treatment. PMID- 26929161 TI - Remnants of marine bacterial communities can be retrieved from deep sediments in lakes of marine origin. AB - Some bacteria can be preserved over time in deep sediments where they persist either in dormant or slow-growing vegetative stages. Here, we hypothesized that such cells can be revived when exposed to environmental conditions similar to those before they were buried in the sediments. To test this hypothesis, we collected bacteria from sediment samples of different ages (140-8500 calibrated years before present, cal BP) from three lakes that differed in the timing of their physical isolation from the Baltic Sea following postglacial uplift. After these bacterial communities were grown in sterile water from the Baltic Sea, we determined the proportion of 16S rRNA sequence reads associated with marine habitats by extracting the environment descriptive terms of homologous sequences retrieved from public databases. We found that the proportion of reads associated with marine descriptive term was significantly higher in cultures inoculated with sediment layers formed under Baltic conditions and where salinities were expected to be similar to current levels. Moreover, a similar pattern was found in the original sediment layers. Our study, therefore, suggests that remnants of marine bacterial communities can be preserved in sediments over thousands of years and can be revived from deep sediments in lakes of marine origin. PMID- 26929162 TI - Low dose aspirin and pregnancy: how important is aspirin resistance? AB - Antiplatelet agents are pivotal for prevention of coronary artery disease and cerebrovascular disease worldwide. Individual patient data meta-analysis indicates that low-dose aspirin causes a 10% risk reduction in pre-eclampsia for women at high individual risk. However, in the last 15 years it has emerged that a significant proportion of aspirin-treated individuals exhibit suboptimal platelet response, determined biochemically and clinically, termed 'aspirin non responsiveness', 'aspirin resistance' and 'aspirin treatment failure'. More recently, investigation of aspirin responsiveness has begun in pregnant women. This review explores the history and clinical relevance of 'aspirin resistance' applied to high-risk obstetric populations. TWEETABLE ABSTRACT: Is 'aspirin resistance' clinically relevant in high-risk obstetrics? PMID- 26929164 TI - Expected Value of Sample Information with Imperfect Implementation: Improving Practice and Reducing Uncertainty with Appropriate Counterfactual Consideration. PMID- 26929165 TI - Adjusting Expected Value of Sample Information Using Realistic Expectations around Implementation. PMID- 26929166 TI - Brief report of virtual clinician research tools for tobacco dependence or dyslipidemia. AB - Health avatars were created to deliver previously tested live interventions for tobacco dependence and cholesterol management. The exploratory aims were to develop and test whether the avatar can be reliably assessed for autonomy supportiveness using the Health Care Climate Questionnaire and estimate the mean changes in motivation variables and correlate the avatars' autonomy supportiveness with the motivation variables and health outcomes. The avatars were found to be reliably assessed for autonomy supportiveness on the Health Care Climate Questionnaire. Autonomy support was positively correlated with the change in motivations and reduction in low-density lipoprotein. These findings suggest that health avatars may be tested in clinical trials. PMID- 26929167 TI - Barriers and facilitators of obesity management in families of youth with emotional and behavioral disorders. AB - While youth with emotional and behavioral disorders experience increased rates of obesity, few obesity interventions exist that are tailored to their needs. Qualitative methods were employed to elucidate obesity management practices in this population. In all, 56 participants (i.e. 21 youths with emotional and behavioral disorders, 20 caregivers of youth with emotional and behavioral disorders, and 15 mental health providers) were recruited from community mental health centers. Participants completed a demographic form and semi-structured interview regarding obesity-related behaviors. Barriers (e.g. psychiatric symptoms) and facilitators (e.g. social support) to obesity management were identified. These results highlight preferred intervention components for this unique population. PMID- 26929168 TI - Illness perceptions and coping with disease in chronic obstructive pulmonary disease: Effects on health-related quality of life. AB - This study investigated the effects of illness perceptions and coping with disease on health-related quality of life in chronic obstructive pulmonary disease. Therefore, participants ( N = 444) completed online questionnaires assessing illness severity (chronic obstructive pulmonary disease stage), Illness Perceptions Questionnaire, coping with disease (Essener Coping Questionnaire), and health-related quality of life (short form-12). Hierarchical regression and moderation analyses were conducted. The results showed that health-related quality of life was predicted by illness perceptions and several aspects of coping with disease. The association between illness perceptions and health related quality of life was mediated by the corresponding coping with disease subscales. It is concluded that in order to prevent decreasing health-related quality of life in chronic obstructive pulmonary disease, treatment may be adjusted by promoting coping with disease and functional illness perceptions. PMID- 26929169 TI - The role of familism in weight loss treatment for Mexican American women. AB - Mexican American women are disproportionately affected by overweight/obesity and the health complications accompanying them, but weight loss treatments are less successful in this ethnic group. High levels of familism, a value reflecting obligation to family that supersedes attention to oneself, interfere with weight loss for Mexican American women. This mixed methods study investigated overweight Mexican American women's beliefs about how familism, and Mexican American culture, might hinder weight loss success, and how treatments might be culturally adapted. Results suggest a need to support women in their commitment to family while also helping them make changes. Recommendations for culturally adapted treatments are made. PMID- 26929170 TI - Voluntariness of consent to HIV clinical research: A conceptual and empirical pilot study. AB - Obtaining voluntary informed consent for research participation is an ethical imperative, yet there appears to be little consensus regarding what constitutes a voluntary consent decision. An instrument to assess influences on participants' consent decision and perceived voluntariness was developed and piloted in two South African HIV clinical trials. The pilot study found high levels of perceived voluntariness. The feeling of having no choice but to participate was significantly associated with lower perceived voluntariness. Overall the data suggest that it is possible to obtain voluntary and valid consent for research participants in ethically complex HIV clinical trials in a developing country context. PMID- 26929171 TI - Body dissatisfaction and psychological distress in adolescents: Is self-esteem a mediator? AB - This brief report tests the mediating effect of self-esteem in the relationship between body dissatisfaction and symptoms of depression and anxiety. A sample of 409 adolescents (females = 58.4%) aged between 14 and 18 years completed the Rosenberg Self-Esteem Scale, the Contour Drawing Rating Scale, the Multidimensional Anxiety Scale for Children, and the Center for Epidemiologic Studies Depression Scale. Overall, results for the indirect effects analysis were significant for both anxiety and depression, which confirmed the mediating role of self-esteem. Thus, a negative perception of one's body image has the effect of lowering self-esteem, which in turn increases psychological distress. PMID- 26929172 TI - Health behaviors in older adults: Considering age, affect, and attitudes. AB - Identifying psychological factors associated with engagement in healthy behaviors in later life is a key to effective behavior interventions. In all, 204 adults ( Mage = 80) took a questionnaire assessing objective and perceived health, positive affect and negative affect, aging attitudes, and three classes of health behaviors: eating/nutrition, exercise, and general health behavior. Regression models found better eating behavior was best explained by older age, more exercise was best explained by more positive affect, and better general lifestyle behavior was best explained by worse perceived health. Programs promoting health behaviors in older adults can utilize the findings to tailor interventions to the health behavior of interest. PMID- 26929173 TI - "That would be good but most men are afraid of coming to the clinic": Men and women's perspectives on strategies to increase male involvement in women's reproductive health services in rural Uganda. AB - In Uganda, increasing male involvement in reproductive health services may improve women's access to care. The purpose of this study was to explore factors influencing male support for women's reproductive health services and to elicit suggestions for strategies to increase male involvement. In 2008-2009, focus groups ( N = 76) were conducted with men and women in a rural hospital in Uganda. A content analysis approach was used for data analysis. Our findings point to the need for multi-level approaches that educate and mobilize men, while improving quality of care at the facility level to increase male involvement in reproductive health services. PMID- 26929174 TI - Sociocultural experiences, body image, and indoor tanning among young adult women. AB - The purpose of this survey study was to evaluate a model of body image influences on indoor tanning behavior. Participants were 823 young adult women recruited from a probability-based web panel in the United States. Consistent with our hypothesized model, tanning-related sociocultural experiences were indirectly associated with lifetime indoor tanning use and intentions to tan as mediated through tan surveillance and tan dissatisfaction. Findings suggest the need for targeting body image constructs as mechanisms of behavior change in indoor tanning behavioral interventions. PMID- 26929176 TI - Psyched Down. PMID- 26929177 TI - Erratum. PMID- 26929175 TI - Functional and structural characterization of a potent GH74 endo-xyloglucanase from the soil saprophyte Cellvibrio japonicus unravels the first step of xyloglucan degradation. AB - The heteropolysaccharide xyloglucan (XyG) comprises up to one-quarter of the total carbohydrate content of terrestrial plant cell walls and, as such, represents a significant reservoir in the global carbon cycle. The complex composition of XyG requires a consortium of backbone-cleaving endo-xyloglucanases and side-chain cleaving exo-glycosidases for complete saccharification. The biochemical basis for XyG utilization by the model Gram-negative soil saprophytic bacterium Cellvibrio japonicus is incompletely understood, despite the recent characterization of associated side-chain cleaving exo-glycosidases. We present a detailed functional and structural characterization of a multimodular enzyme encoded by gene locus CJA_2477. The CJA_2477 gene product comprises an N-terminal glycoside hydrolase family 74 (GH74) endo-xyloglucanase module in train with two carbohydrate-binding modules (CBMs) from families 10 and 2 (CBM10 and CBM2). The GH74 catalytic domain generates Glc4 -based xylogluco-oligosaccharide (XyGO) substrates for downstream enzymes through an endo-dissociative mode of action. X ray crystallography of the GH74 module, alone and in complex with XyGO products spanning the entire active site, revealed a broad substrate-binding cleft specifically adapted to XyG recognition, which is composed of two seven-bladed propeller domains characteristic of the GH74 family. The appended CBM10 and CBM2 members notably did not bind XyG, nor other soluble polysaccharides, and instead were specific cellulose-binding modules. Taken together, these data shed light on the first step of xyloglucan utilization by C. japonicus and expand the repertoire of GHs and CBMs for selective biomass analysis and utilization. DATABASE: Structural data have been deposited in the RCSB protein database under the Protein Data Bank codes: 5FKR, 5FKS, 5FKT and 5FKQ. PMID- 26929178 TI - Reducing Intra-articular Hemarthrosis After Arthroscopic ACL Reconstruction: Letter to the Editor. PMID- 26929179 TI - Reducing Intra-articular Hemarthrosis After Arthroscopic ACL Reconstruction: Response. PMID- 26929180 TI - Statistical issues in the analysis of adverse events in time-to-event data. AB - The aim of this work is to shed some light on common issues in the statistical analysis of adverse events (AEs) in clinical trials, when the main outcome is a time-to-event endpoint. To begin, we show that AEs are always subject to competing risks. That is, the occurrence of a certain AE may be precluded by occurrence of the main time-to-event outcome or by occurrence of another (fatal) AE. This has raised concerns on 'informative' censoring. We show that, in general, neither simple proportions nor Kaplan-Meier estimates of AE occurrence should be used, but common survival techniques for hazards that censor the competing event are still valid, but incomplete analyses. They must be complemented by an analogous analysis of the competing event for inference on the cumulative AE probability. The commonly used incidence rate (or incidence density) is a valid estimator of the AE hazard assuming it to be time constant. An estimator of the cumulative AE probability can be derived if the incidence rate of AE is combined with an estimator of the competing hazard. We discuss less restrictive analyses using non-parametric and semi-parametric approaches. We first consider time-to-first-AE analyses and then briefly discuss how they can be extended to the analysis of recurrent AEs. We will give a practical presentation with illustration of the methods by a simple example. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26929181 TI - Outcomes of unplanned sarcoma excision: impact of residual disease. AB - This study aimed to compare the oncological results between unplanned excision (UE) and planned excision (PE) of malignant soft tissue tumor and to examine the impact of residual tumor (ReT) after UE. Nonmetastatic soft tissue sarcomas surgically treated in 1996-2012 were included in this study. Disease-specific survival (DSS), metastasis-free survival (MFS), and local-recurrence-free survival (LRFS) were stratified according to the tumor location and American Joint Committee on Cancer Classification 7th edition stage. Independent prognostic parameters were identified by Cox proportional hazard models. Two hundred and ninety PEs and 161 UEs were identified. Significant difference in oncological outcome was observed only for LRFS probability of retroperitoneal sarcomas (5-year LRFS: 33.0% [UE] vs. 71.0% [PE], P = 0.018). Among the 142 UEs of extremity and trunk, ReT in re-excision specimen were found in 75 cases (53%). UEs with ReT had significantly lower survival probabilities and a higher amputation rate than UEs without ReT (5-year DSS: 68.8% vs. 92%, P < 0.001; MFS: 56.1% vs. 90.9%, P < 0.001; LRFS: 75.8% vs. 98.4%, P = <0.001; amputation rate 18.5% vs. 1.8%, P = 0.003). The presence of ReT was an independent poor prognostic predictor for DSS, MFS, and LRFS with hazard ratios of 2.02 (95% confidence interval (CI), 1.25-3.26), 1.62 (95% CI, 1.05-2.51) and 1.94 (95% CI, 1.05-3.59), respectively. Soft tissue sarcomas should be treated in specialized centers and UE should be avoided because of its detrimental effect especially when ReT remains after UE. PMID- 26929183 TI - Habitat partitioning of marine benthic denitrifier communities in response to oxygen availability. AB - Denitrification is of global significance for the marine nitrogen budget and the main process for nitrogen loss in coastal sediments. This facultative anaerobic respiratory pathway is modular in nature and the final step, the reduction of nitrous oxide (N2 O), is performed by microorganisms with a complete denitrification pathway as well as those only capable of N2 O reduction. Fluctuating oxygen availability is a significant driver of denitrification in sediments, but the effects on the overall N2 O-reducing community that ultimately controls the emission of N2 O from marine sediments is not well known. To investigate the effects of different oxygen regimes on N2 O reducing communities, coastal marine surface sediment was incubated in microcosms under oxic, anoxic or oscillating oxygen conditions in the overlying water for 137 days. Quantification of the genetic potential for denitrification, anammox and respiratory ammonification indicated that denitrification supported nitrogen removal in these sediments. Furthermore, denitrifiers with a complete pathway were identified as the dominant community involved in N2 O reduction, rather than organisms that are only N2 O reducers. Specific lineages within each group were associated with different oxygen regimes suggesting that oxygen availability in the overlying water is associated with habitat partitioning of N2 O reducers in coastal marine surface sediments. PMID- 26929184 TI - Speciation in peripheral populations: effects of drift load and mating systems. AB - Speciation in peripheral populations has long been considered one of the most plausible scenarios for speciation with gene flow. In this study, however we identify two additional problems of peripatric speciation, as compared to the parapatric case, that may impede the completion of the speciation process for most parameter regions. First, with (predominantly) unidirectional gene flow, there is no selection pressure to evolve assortative mating on the continent. We discuss the implications of this for different mating schemes. Second, genetic load can build up in small populations. This can lead to extinction of the peripheral species, or generate selection pressure for lower assortative mating to avoid inbreeding. In this case, either a stable equilibrium with intermediate assortment evolves or there is cycling between phases of hybridization and phases of complete isolation. PMID- 26929182 TI - O-GlcNAcylation: a bridge between glucose and cell differentiation. AB - Glucose is the major energy supply and a critical metabolite for most cells and is especially important when cell is differentiating. High or low concentrations of glucose enhances or inhibits the osteogenic, chondrogenic and adipogenic differentiation of cell via the insulin, transforming growth factor-beta and peroxisome proliferator-activated receptor gamma pathways, among others. New evidence implicates the hexosamine biosynthetic pathway as a mediator of crosstalk between glucose flux, cellular signalling and epigenetic regulation of cell differentiation. Extracellular glucose flux alters intracellular O GlcNAcylation levels through the hexosamine biosynthetic pathway. Signalling molecules that are important for cell differentiation, including protein kinase C, extracellular signal-regulated kinase, Runx2, CCAAT/enhancer-binding proteins, are modified by O-GlcNAcylation. Thus, O-GlcNAcylation markedly alters cell fate during differentiation via the post-transcriptional modification of proteins. Furthermore, O-GlcNAcylation and phosphorylation show complex interactions during cell differentiation: they can either non-competitively occupy different sites on a substrate or competitively occupy a single site or proximal sites. Therefore, the influence of glucose on cell differentiation via O-GlcNAcylation offers a potential target for controlling tissue homoeostasis and regeneration in ageing and disease. Here, we review recent progress establishing an emerging relationship among glucose concentration, O-GlcNAcylation levels and cell differentiation. PMID- 26929185 TI - MicroRNA-493 regulates angiogenesis in a rat model of ischemic stroke by targeting MIF. AB - MicroRNA-493 (miR-493) is known to suppress tumour metastasis and angiogenesis and its expression is decreased in stroke patients. In the present study, we investigated a role for miR-493 in regulating post-stroke angiogenesis. We found decreased expression of miR-493 in the ischemic boundary zone (IBZ) of rats subjected to middle cerebral artery occlusion (MCAO), and in rat brain microvascular endothelial cells (RBMECs) exposed to oxygen glucose deprivation. Down-regulating miR-493 with a lateral ventricular injection of antagomir-493, a synthetic miR-493 inhibitor, increased capillary density in the IBZ, decreased focal infarct volume and ameliorated neurologic deficits in rats subjected to MCAO. Intriguingly, MCAO also increased the expression of macrophage migration inhibitory factor (MIF) in the IBZ of rats; MIF expression was also increased in RBMECs exposed to oxygen glucose deprivation. We found that miR-493 directly targeted MIF, and that the protective effect of miR-493 inhibition in angiogenesis was attenuated by knocking down MIF. This effect could then be rescued by administration of recombinant MIF. Our findings highlight the importance of miR-493 in regulating angiogenesis after MCAO, and indicate that miR-493 is a potential therapeutic target in the treatment of stroke. PMID- 26929186 TI - Glasgow prognostic score is an independent marker for poor prognosis with all cases of epithelial ovarian cancer. AB - Inflammatory markers are important prognostic factors in various cancers. This study investigated whether inflammatory markers of the Glasgow prognostic score (GPS) predicted progression-free survival (PFS) and overall survival (OS) for patients with all cases of epithelial ovarian cancer (OC). Pretreatment GPS was examined for the correlations with PFS and OS in 216 patients in all stages of epithelial OC. Statistical analyses were performed using the Mann-Whitney U-test. PFS and OS were analyzed using the Kaplan-Meier method. Cox's proportional hazard regression was used for univariate and multivariate analyses. For all patients, the median PFS was 35.1 months, and median OS was 46.7 months; follow-up range was 1-162 months. Kaplan-Meier analysis revealed that patients with high GPS (GPS 2) at pretreatment had a shorter PFS and OS than did patients with lower GPS (GPS 0 + 1) in for early, advanced, and all-stages of OC (PFS: P < 0.001 for early-, advanced- and all-stages; OS; P < 0.001 for early- and all-stage, P = 0.015 for advanced-stage). GPS (GPS 2) was also found to be an independent predictor of both recurrence (P = 0.002) and survival (P = 0.001) of all cases of epithelial OC by a multivariate analysis. GPS can serve as an indicator of poor prognosis in patients with all stages of epithelial OC, including early-stage disease and regardless of histology. PMID- 26929187 TI - Combinatorial incorporation of fluoride and cobalt ions into calcium phosphates to stimulate osteogenesis and angiogenesis. AB - Bone healing requires two critical mechanisms, angiogenesis and osteogenesis. In order to improve bone graft substitutes, both mechanisms should be addressed simultaneously. While the individual effects of various bioinorganics have been studied, an understanding of the combinatorial effects is lacking. Cobalt and fluoride ions, in appropriate concentrations, are known to individually favor the vascularization and mineralization processes, respectively. This study investigated the potential of using a combination of fluoride and cobalt ions to simultaneously promote osteogenesis and angiogenesis in human mesenchymal stromal cells (hMSCs). Using a two-step biomimetic method, wells of tissue culture plates were coated with a calcium phosphate (CaP) layer without or with the incorporation of cobalt, fluoride, or both. In parallel, hMSCs were cultured on uncoated well plates, and cultured with cobalt and/or fluoride ions within the media. The results revealed that cobalt ions increased the expression of angiogenic markers, with the effects being stronger when the ions were added as a dissolved salt in cell medium as compared to incorporation into CaP. Cobalt ions generally suppressed the ALP activity, the expression of osteogenic genes, and the level of mineralization, regardless of delivery method. Fluoride ions, individually or in combination with cobalt, significantly increased the expression of many of the selected osteogenic markers, as well as mineral deposition. This study demonstrates an approach to simultaneously target the two essential mechanisms in bone healing: angiogenesis and osteogenesis. The incorporation of cobalt and fluoride into CaPs is a promising method to improve the biological performance of fully synthetic bone graft substitutes. PMID- 26929189 TI - Pre-reconstruction of cervical-to-petrous internal carotid artery: An improved technique for treatment of vascular lesions involving internal carotid artery at the lateral skull base. AB - BACKGROUND: Reconstruction of the internal carotid artery (ICA) is an operative challenge for lesions involving the lateral skull base because of excessive blood loss, intraoperative cranial nerve injury, and difficulties in cerebral protection. METHODS: Between January 2010 and October 2014, 9 patients with vascular lesions at the lateral skull base were treated with a "pre reconstruction" technique, which means reconstruction of the ICA in advance of excising the lesions. RESULTS: All operations were technically successful with no mortality or strokes. The mean blood loss was 921 +/- 210 mL. The mean total clamping time was 18 +/- 5 minutes. Among the 5 patients without invasion of specific cranial nerves, no long-term sequelae occurred during the follow-up period ranging from 11 to 54 months. CONCLUSION: With less blood loss, slighter cranial nerve injuries, and shorter clamping time, the "pre-reconstruction" technique was safe and effective for the treatment of vascular lesions at the lateral skull base. (c) 2016 Wiley Periodicals, Inc. Head Neck 38: E1562-E1567, 2016. PMID- 26929188 TI - Being hit twice: The psychological consequences of the economic crisis and an earthquake. AB - BACKGROUND: The Great Recession has caused worldwide tangible costs in terms of cuts in employment and income, which have been widely recognised also as major social determinants of mental health. Italy has not been spared from the financial crisis with severe societal and mental health consequences. In addition, a strong earthquake hit the province of Modena, Italy, in 2012, that is, amid the crisis. AIMS: In this study, we explored and investigated the possible additional impact of concurrent events such as economic crisis and a natural disaster. METHODS: Our analysis elaborated data from two local surveys, ICESmo2 (2006) and ICESmo3 (2012), and a national survey carried out in 2013 by the Italian National Institute of Statistics (Istituto Nazionale di Statistica (ISTAT)). A regression model was adopted to distinguish the effect of the crisis and the earthquake. RESULTS: Our analysis confirmed the negative effect of the economic crisis on psychological wellbeing, but within the province of Modena such an effect resulted as even stronger compared with the rest of Italy, particularly within those areas struck by the earthquake. CONCLUSION: Being hit by a combination of two major negative events might have a significantly increased negative effect on psychological health. The higher repercussion observed is not only attributable to the occurrence of a natural disaster but can be reasonably related to the additional effect of unemployment on psychological dimensions. PMID- 26929190 TI - Use of serum lactate levels to predict survival for patients with out-of-hospital cardiac arrest: A cohort study. AB - OBJECTIVES: We examined the association of serum lactate levels and early lactate clearance with survival to hospital discharge for patients suffering an out-of hospital cardiac arrest (OHCA). METHODS: A retrospective cohort analysis was performed of patients with OHCA transported by ambulance to two adult tertiary hospitals in Perth, Western Australia. Exclusion criteria were traumatic cardiac arrest, return of spontaneous circulation prior to the arrival of the ambulance, age less than 18 years and no serum lactate levels recorded. Serum lactate levels recorded for up to 48 h post-arrest were obtained from the hospital clinical information system, and lactate clearance over 48 h was calculated. Descriptive and logistic regression analyses were conducted. RESULTS: There were 518 patients with lactate values, of whom 126 (24.3%) survived to hospital discharge. Survivors and non-survivors had different mean initial lactate levels (mean +/- SD 6.9 +/- 4.7 and 12.2 +/- 5.5 mmol/L, respectively; P < 0.001). Lactate clearance was higher in survivors. Lactate levels for non-survivors did not decrease below 2 mmol/L until at least 30 h after the ambulance call. CONCLUSION: In OHCA patients who had serum lactate levels measured, both lower initial serum lactate and early lactate clearance in the first 48 h following OHCA were associated with increased likelihood of survival. However, the use of lactate in isolation as a predictor of survival or neurological outcome is not recommended. Prospective studies that minimise selection bias are required to determine the clinical utility of serum lactate levels in OHCA patients. PMID- 26929192 TI - Usefulness of MR elastography for detecting clinical progression of cirrhosis from child-pugh class A to B in patients with type C viral hepatitis. AB - PURPOSE: To evaluate the usefulness of magnetic resonance elastography (MRE) in detecting the clinical progression of cirrhosis from Child-Pugh class A to B in patients with hepatitis C. MATERIALS AND METHODS: We reviewed the data of 101 consecutive patients with type C viral hepatitis and clinically suspected cirrhosis who fulfilled the all following criteria: available MRE at 1.5 Tesla (T) or 3.0T and laboratory tests within a month, Child-Pugh class A, platelet count less than 155 * 10(3) /MUL, no clinical history of hepatocellular carcinoma, and >=6 months of follow-up after MRE. We longitudinally analyzed the incidence of cirrhosis progression as defined by the clinical progression from Child-Pugh class A to B at two subsequent follow-up points. Risk of cirrhosis progression was assessed by Cox analyses and Kaplan-Meyer methods. RESULTS: Cirrhosis progression was noted in 25 patients during the follow-up period. Liver stiffness (hazard ratio [HR] by 1 kPa increase = 1.397; P = 0.0074), Child-Pugh score of 6 versus score 5 (HR of 3.085; P = 0.0276), and treatment responses to anti-viral therapy versus nonresponse (HR of <0.001, P = 0.0006) were independent risk factors of cirrhosis progression. The 1-year risk (0.7%; 95% confidence interval, 0.1-4.2%) of cirrhosis progression was negligible in patients with liver stiffness of <3.3 kPa or response to anti-viral treatment. CONCLUSION: MRE is useful to stratify the risk of cirrhosis progression in patients with hepatitis C. J. Magn. Reson. Imaging 2016;44:715-722. PMID- 26929191 TI - Functional Status in ICU Survivors and Out of Hospital Outcomes: A Cohort Study. AB - OBJECTIVES: Functional status at hospital discharge may be a risk factor for adverse events among survivors of critical illness. We sought to examine the association between functional status at hospital discharge in survivors of critical care and risk of 90-day all-cause mortality after hospital discharge. DESIGN: Single-center retrospective cohort study. SETTING: Academic Medical Center. PATIENTS: Ten thousand three hundred forty-three adults who received critical care from 1997 to 2011 and survived hospitalization. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The exposure of interest was functional status determined at hospital discharge by a licensed physical therapist and rated based on qualitative categories adapted from the Functional Independence Measure. The main outcome was 90-day post hospital discharge all-cause mortality. A categorical risk-prediction score was derived and validated based on a logistic regression model of the function grades for each assessment. In an adjusted logistic regression model, the lowest quartile of functional status at hospital discharge was associated with an increased odds of 90-day postdischarge mortality compared with patients with independent functional status (odds ratio, 7.63 [95% CI, 3.83-15.22; p < 0.001]). In patients who had at least 7 days of physical therapy treatment prior to hospital discharge (n = 2,293), the adjusted odds of 90-day postdischarge mortality in patients with marked improvement in functional status at discharge was 64% less than patients with no change in functional status (odds ratio, 0.36 [95% CI, 0.24-0.53]; p < 0.001). CONCLUSIONS: Lower functional status at hospital discharge in survivors of critical illness is associated with increased postdischarge mortality. Furthermore, patients whose functional status improves before discharge have decreased odds of postdischarge mortality. PMID- 26929193 TI - alpha-Defensins and bacterial/permeability-increasing protein as new markers of childhood obesity. AB - OBJECTIVES: The aim of this paper is to test whether alpha-defensins and bacterial/permeability-increasing protein were related to obesity and cardiovascular risk factors in prepubertal children. METHODS: Plasma alpha defensins and bacterial/permeability-increasing protein, body mass index (BMI), waist circumference, systolic blood pressure (SBP), carotid intima media thickness (cIMT), HOMA-IR and HMW-adiponectin were assessed. RESULTS: In a cross sectional study (N = 250), higher alpha-defensins concentrations were positively associated with BMI, waist, SBP, cIMT, HOMA-IR and negative correlated with HMW adiponectin (all between r = 0.191 and r = 0.377, p <= 0.01 and p <= 0.0001). Conversely, plasma bacterial/permeability-increasing protein concentrations presented inversed associated with the same parameters (all between r = -0.124 and r = -0.329; p <= 0.05 and p <= 0.0001). In a longitudinal study (N = 91), alpha-defensins at age 7 were associated with BMI (beta = 0.189, p = 0.002; model R2 = 0.847) and waist (beta = 0.241, pthinsp;= 0.001; model R2 = 0.754) at age 10. CONCLUSIONS: alpha-Defensins and bacterial/permeability-increasing protein may be the markers of childhood obesity. Increased concentrations of alpha defensins may predict BMI and abdominal fat deposition in children. PMID- 26929194 TI - Cytotoxic and adhesion-associated response of NIH-3T3 fibroblasts to COOH functionalized multi-walled carbon nanotubes. AB - As novel, promising, man-made nanomaterials with extraordinary properties, carbon nanotubes have been attracting massive attention in regenerative medicine. However, published reports on their potential cytotoxic effects are not concordant and are even conflicting. In the current study, the cytotoxic effects of carboxyl-modified multi-walled carbon nanotubes (COOH-MWCNTs), as well as their influences on the cell adhesion of NIH-3T3 fibroblasts, were thoroughly investigated. Live/dead cell viability assay and cell counting kit-8 assay both indicated that the viability of the NIH-3T3 cells exposed to COOH-MWCNTs in the culture medium was dependent on the latter's concentration. Cell viability increased at COOH-MWCNT concentrations below 50 MUg ml(-1) and then decreased with increasing concentration. Scanning electron microscopy and immunofluorescent staining of the NIH-3T3 cells revealed that the cells were well adherent to the substrate after exposure to the COOH-MWCNTs for 48 h. Western blot demonstrated that COOH-MWCNT exposure enhanced the expression of adhesion-associated proteins compared with normal cells, peaking at an intermediate concentration. Our study showed that the cytotoxicity of COOH-MWCNTs, as well as their effects on NIH-3T3 fibroblast adhesion, was dose dependent. Therefore, COOH-MWCNT concentrations in the cell culture medium should be considered in the biomedical application of COOH-MWCNTs. PMID- 26929195 TI - Rapid breath-hold assessment of myocardial velocities using spiral UNFOLD-ed SENSE tissue phase mapping. AB - PURPOSE: To develop and validate a rapid breath-hold tissue phase mapping (TPM) sequence. MATERIALS AND METHODS: The sequence was based on an efficient uniform density spiral acquisition, combined with data acceleration. A novel acquisition and reconstruction strategy enabled combination of UNFOLD (2*) and SENSE (3*): UNFOLD-ed SENSE. The sequence was retrospectively cardiac-gated, and a graphics processing unit (GPU) was used for rapid "online" reconstruction. The optimal UNFOLD parameters for the data were calculated using an in silico model. The technique was validated on a 1.5T MR scanner in 15 patients with known aortic valve disease, against a respiratory self-navigated free-breathing TPM technique. Quantitative image quality measures (velocity-to-noise and edge sharpness) were made as well as calculation of longitudinal, radial, and tangential myocardial velocities in the left ventricle. RESULTS: The proposed breath-hold TPM data took eight heartbeats to acquire. The breath-hold TPM images had significantly higher edge sharpness (P = 0.0014) than the self-navigated TPM images, but with significantly lower velocity-to-noise ratio (P < 0.0001). There was excellent agreement (r > 0.94) in the longitudinal, radial, and tangential velocities between the self-navigated data and the proposed breath-hold TPM sequence. CONCLUSION: We demonstrate the feasibility of using spiral UNFOLD-ed SENSE to measure myocardial velocities using a rapid breath-hold spiral TPM sequence. This novel technique might enable accurate measurement of myocardial velocities, in a short scan time, which is especially important in a busy clinical workflow. J. MAGN. RESON. IMAGING 2016;44:1003-1009. PMID- 26929196 TI - Global emergence of enterovirus D68: a systematic review. AB - Since its discovery in California in 1962, reports of enterovirus D68 have been infrequent. Before 2014, infections were confirmed in only 699 people worldwide. In August, 2014, two paediatric hospitals in the USA reported increases in the number of patients with severe respiratory illness, with an over-representation in children with asthma. Shortly after, the authorities recognised a nationwide outbreak, which then spread to Canada, Europe, and Asia. In 2014, more than 2000 cases of enterovirus D68 were reported in 20 countries. Concurrently, clusters of children with acute flaccid paralysis of unknown cause were reported in several US states and in Europe. Enterovirus D68 infection was confirmed in some of the paralysed children, but not all. Complications in patients who were severely neurologically affected resemble those caused by poliomyelitis. In this paper we systematically review reports on enterovirus D68 to estimate its global epidemiology and its ability to cause respiratory infections and neurological damage in children. We extracted data from 70 papers to report on prevalence, symptoms, hospitalisation and mortality, and complications of enterovirus D68, both before and during the large outbreak of 2014. The magnitude and severity of the enterovirus D68 outbreak underscores a need for improved diagnostic work-up of paediatric respiratory illness, not only to prevent unnecessary use of antibiotics, but also to ensure better surveillance of diseases. Existing surveillance systems should be assessed in terms of capacity and ability to detect and report any upsurge of respiratory viruses such as enterovirus D68 in a timely manner, and focus should be paid to development of preventive measures against these emerging enteroviruses that have potential for severe disease. PMID- 26929197 TI - Design considerations and challenges for mechanical stretch bioreactors in tissue engineering. AB - With the increase in average life expectancy and growing aging population, lack of functional grafts for replacement surgeries has become a severe problem. Engineered tissues are a promising alternative to this problem because they can mimic the physiological function of the native tissues and be cultured on demand. Cyclic stretch is important for developing many engineered tissues such as hearts, heart valves, muscles, and bones. Thus a variety of stretch bioreactors and corresponding scaffolds have been designed and tested to study the underlying mechanism of tissue formation and to optimize the mechanical conditions applied to the engineered tissues. In this review, we look at various designs of stretch bioreactors and common scaffolds and offer insights for future improvements in tissue engineering applications. First, we summarize the requirements and common configuration of stretch bioreactors. Next, we present the features of different actuating and motion transforming systems and their applications. Since most bioreactors must measure detailed distributions of loads and deformations on engineered tissues, techniques with high accuracy, precision, and frequency have been developed. We also cover the key points in designing culture chambers, nutrition exchanging systems, and regimens used for specific tissues. Since scaffolds are essential for providing biophysical microenvironments for residing cells, we discuss materials and technologies used in fabricating scaffolds to mimic anisotropic native tissues, including decellularized tissues, hydrogels, biocompatible polymers, electrospinning, and 3D bioprinting techniques. Finally, we present the potential future directions for improving stretch bioreactors and scaffolds. (c) 2016 American Institute of Chemical Engineers Biotechnol. Prog., 32:543-553, 2016. PMID- 26929198 TI - New Regulatory Roles of Galectin-3 in High-Affinity IgE Receptor Signaling. AB - Aggregation of the high-affinity receptor for IgE (FcepsilonRI) in mast cells initiates activation events that lead to degranulation and release of inflammatory mediators. To better understand the signaling pathways and genes involved in mast cell activation, we developed a high-throughput mast cell degranulation assay suitable for RNA interference experiments using lentivirus based short hairpin RNA (shRNA) delivery. We tested 432 shRNAs specific for 144 selected genes for effects on FcepsilonRI-mediated mast cell degranulation and identified 15 potential regulators. In further studies, we focused on galectin-3 (Gal3), identified in this study as a negative regulator of mast cell degranulation. FcepsilonRI-activated cells with Gal3 knockdown exhibited upregulated tyrosine phosphorylation of spleen tyrosine kinase and several other signal transduction molecules and enhanced calcium response. We show that Gal3 promotes internalization of IgE-FcepsilonRI complexes; this may be related to our finding that Gal3 is a positive regulator of FcepsilonRI ubiquitination. Furthermore, we found that Gal3 facilitates mast cell adhesion and motility on fibronectin but negatively regulates antigen-induced chemotaxis. The combined data indicate that Gal3 is involved in both positive and negative regulation of FcepsilonRI-mediated signaling events in mast cells. PMID- 26929199 TI - Phosphorylation-Dependent Regulation of the DNA Damage Response of Adaptor Protein KIBRA in Cancer Cells. AB - Multifunctional adaptor proteins encompassing various protein-protein interaction domains play a central role in the DNA damage response pathway. In this report, we show that KIBRA is a physiologically interacting reversible substrate of ataxia telangiectasia mutated (ATM) kinase. We identified the site of phosphorylation in KIBRA as threonine 1006, which is embedded within the serine/threonine (S/T) Q consensus motif, by site-directed mutagenesis, and we further confirmed the same with a phospho-(S/T) Q motif-specific antibody. Results from DNA repair functional assays such as the gamma-H2AX assay, pulsed field gel electrophoresis (PFGE), Comet assay, terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL) assay, and clonogenic cell survival assay using stable overexpression clones of wild type (wt.) KIBRA and active (T1006E) and inactive (T1006A) KIBRA phosphorylation mutants showed that T1006 phosphorylation on KIBRA is essential for optimal DNA double-strand break repair in cancer cells. Further, results from stable retroviral short hairpin RNA-mediated knockdown (KD) clones of KIBRA and KIBRA knockout (KO) model cells generated by a clustered regularly interspaced short palindromic repeat (CRISPR)-Cas9 system showed that depleting KIBRA levels compromised the DNA repair functions in cancer cells upon inducing DNA damage. All these phenotypic events were reversed upon reconstitution of KIBRA into cells lacking KIBRA knock-in (KI) model cells. All these results point to the fact that phosphorylated KIBRA might be functioning as a scaffolding protein/adaptor protein facilitating the platform for further recruitment of other DNA damage response factors. In summary, these data demonstrate the imperative functional role of KIBRAper se(KIBRA phosphorylation at T1006 site as a molecular switch that regulates the DNA damage response, possibly via the nonhomologous end joining [NHEJ] pathway), suggesting that KIBRA could be a potential therapeutic target for modulating chemoresistance in cancer cells. PMID- 26929201 TI - How do secretory products cross the plant cell wall to be released? A new hypothesis involving cyclic mechanical actions of the protoplast. AB - BACKGROUND: In plants, the products of secretory activity leave the protoplast and cross the plasma membrane by means of transporters, fusion with membranous vesicles or, less commonly, as result of disintegration of the cell. These mechanisms do not address an intriguing question: How do secretory products cross the cell wall? Furthermore, how do these substances reach the external surface of the plant body? Such diverse substances as oils, polysaccharides or nectar are forced to cross the cell wall and, in fact, do so. How are chemical materials that are repelled by the cell wall or that are sufficiently viscous to not cross passively released from plant cells? SCOPE AND CONCLUSIONS: I propose a cell cycle model developed based on observations of different secreting systems, some unpublished results and an extensive literature review, aiming to understand the processes involved in both the secretory process and the release of secretion products. In the absence of facilitated diffusion, a mechanical action of the protoplast is necessary to ensure that some substances can cross the cell wall. The mechanical action of the protoplast, in the form of successive cycles of contraction and expansion, causes the material accumulated in the periplasmic space to cross the cell wall and the cuticle. This action is particularly relevant for the release of lipids, resins and highly viscous hydrophilic secretions. The proposed cell-cycle model and the statements regarding exudate release will also apply to secretory glands not elaborated upon here. Continuous secretion of several days, as observed in extrafloral nectaries, salt glands and some mucilage-producing glands, is only possible because the process is cyclical. PMID- 26929200 TI - NR4A1 Antagonists Inhibit beta1-Integrin-Dependent Breast Cancer Cell Migration. AB - Overexpression of the nuclear receptor 4A1 (NR4A1) in breast cancer patients is a prognostic factor for decreased survival and increased metastasis, and this has been linked to NR4A1-dependent regulation of transforming growth factor beta (TGF beta) signaling. Results of RNA interference studies demonstrate that basal migration of aggressive SKBR3 and MDA-MB-231 breast cancer cells is TGF-beta independent and dependent on regulation of beta1-integrin gene expression by NR4A1 which can be inhibited by the NR4A1 antagonists 1,1-bis(3'-indolyl)-1-(p hydroxyphenyl)methane (DIM-C-pPhOH) and a related p-carboxymethylphenyl [1,1 bis(3'-indolyl)-1-(p-carboxymethylphenyl)methane (DIM-C-pPhCO2Me)] analog. The NR4A1 antagonists also inhibited TGF-beta-induced migration of MDA-MB-231 cells by blocking nuclear export of NR4A1, which is an essential step in TGF-beta induced cell migration. We also observed that NR4A1 regulates expression of both beta1- and beta3-integrins, and unlike other beta1-integrin inhibitors which induce prometastatic beta3-integrin, NR4A1 antagonists inhibit expression of both beta1- and beta3-integrin, demonstrating a novel mechanism-based approach for targeting integrins and integrin-dependent breast cancer metastasis. PMID- 26929202 TI - Pure species in a continuum of genetic and morphological variation: sympatric oaks at the edge of their range. AB - BACKGROUND AND AIMS: Studies on oaks (Quercus spp.) have often been hampered by taxonomic confusion, a situation further compounded by the occurrence of extensive interspecific hybridization. In the present study, a combination of genetic and morphological analyses was used to examine sympatric populations of Q. petraea and Q. robur at the north-western edge of their ranges in Northern Ireland, since it had previously been suggested that hybridization could facilitate the apparent rapid, long-distance dispersal of oaks following the glaciations. METHODS: Samples were collected from 24 sites across Northern Ireland that had been previously designated as ancient or semi-natural woodland. Genotypes were obtained from a total of 950 trees using 12 nuclear microsatellite loci, and admixture coefficients were calculated based on a Bayesian clustering approach. Individuals were also classified as Q. petraea,Q. robur or hybrids based on two objective morphometric characters shown previously to delineate pure individuals effectively. Genetically 'pure' individuals of both species, as defined by the Bayesian clustering, were also genotyped for five chloroplast microsatellites. KEY RESULTS: Genetic and morphological analyses both indicated the presence of pure individuals of both species, as well as a continuum of intermediates. There was a good agreement between the molecular and morphological classification, with a generally clear separation between pure individuals. CONCLUSIONS: Despite millennia of hybridization and introgression, genetically and morphologically pure individuals of both Q. petraea and Q. robur can be found at the edge of their range, where both species occur sympatrically. The high proportion of individuals exhibiting introgression compared with previous studies may reflect the historical role of hybridization in facilitating dispersal following the glaciations. This is further supported by the significantly higher chloroplast diversity in Q. robur compared with Q. petraea. PMID- 26929203 TI - The gelatinous extracellular matrix facilitates transport studies in kelp: visualization of pressure-induced flow reversal across sieve plates. AB - BACKGROUND AND AIMS: In vascular plants, important questions regarding phloem function remain unanswered due to problems with invasive experimental procedures in this highly sensitive tissue. Certain brown algae (kelps; Laminariales) also possess sieve tubes for photoassimilate transport, but these are embedded in large volumes of a gelatinous extracellular matrix which isolates them from neighbouring cells. Therefore, we hypothesized that kelp sieve tubes might tolerate invasive experimentation better than their analogues in higher plants, and sought to establish Nereocystis luetkeana as an experimental system. METHODS: The predominant localization of cellulose and the gelatinous extracellular matrix in N. luetkeana was verified using specific fluorescent markers and confocal laser scanning microscopy. Sieve tubes in intact specimens were loaded with fluorescent dyes, either passively (carboxyfluorescein diacetate; CFDA) or by microinjection (rhodamine B), and the movement of the dyes was monitored by fluorescence microscopy. KEY RESULTS: Application of CFDA demonstrated source to sink bulk flow in N. luetkeana sieve tubes, and revealed the complexity of sieve tube structure, with branches, junctions and lateral connections. Microinjection into sieve elements proved comparatively easy. Pulsed rhodamine B injection enabled the determination of flow velocity in individual sieve elements, and the direct visualization of pressure-induced reversals of flow direction across sieve plates. CONCLUSIONS: The reversal of flow direction across sieve plates by pressurizing the downstream sieve element conclusively demonstrates that a critical requirement of the Munch theory is satisfied in kelp; no such evidence exists for tracheophytes. Because of the high tolerance of its sieve elements to experimental manipulation, N. luetkeana is a promising alternative to vascular plants for studying the fluid mechanics of sieve tube networks. PMID- 26929207 TI - Abstracts of the 13th Annual Conference of the American Psychosocial Oncology Society, 3-5 March 2016, San Diego, California. PMID- 26929204 TI - Performance of Facepiece Respirators and Surgical Masks Against Surgical Smoke: Simulated Workplace Protection Factor Study. AB - OBJECTIVE: Surgical smoke generated during electrocautery contains toxins which may cause adverse health effects to operating room (OR) personnel. The objective of this study was to investigate the performance of surgical masks (SMs), which are routinely used in ORs, more efficient N95 surgical mask respirator (SMRs) and N100 filtering facepiece respirator (FFRs), against surgical smoke. METHODS: Ten subjects were recruited to perform surgical dissections on animal tissue in a simulated OR chamber, using a standard electrocautery device, generating surgical smoke. Six respiratory protective devices (RPDs) were tested: two SMs, two SMRs, and two N100 FFRs [including a newly developed faceseal (FS) prototype]. Fit testing was conducted before the experiment. Each subject was then exposed to the surgical smoke while wearing an RPD under the tests. Concentrations inside (C in) and outside (C out) of the RPD were measured by a particle size spectrometer. The simulated workplace protection factor (SWPF) was determined by the ratio of C out and C in for each RPD-wearing subject. RESULTS: For the SMs, the geometric means of SWPFtotal (based on the total aerosol concentration) were 1.49 and 1.76, indicating minimal protection. The SWPFtotal values of the SMRs and N100 FFRs were significantly higher than those of the SMs: for the two SMRs, the SWPFtotal were 208 and 263; for the two N100s, the SWPFtotal values were 1,089 and 2,199. No significant difference was observed between either the two SMs or the two SMRs. The SWPFtotal for the novel FS prototype N100 FFR was significantly higher than the conventional N100 FFR. The correlation between SWPFtotal and fit factor (FF) determined for two N95 SMRs was not significant. CONCLUSIONS: SMs do not provide measurable protection against surgical smoke. SMRs offer considerably improved protection versus SMs, while the N100 FFRs showed significant improvement over the SMRs. The FS prototype offered a higher level of protection than the standard N100 FFR, due to a tighter seal. While we acknowledge that conventional N100 FFRs (equipped with exhalation valves) are not practical for human OR use, the results obtained with the FS prototype demonstrate the potential of the new FS technology for implementation on various types of respirators. PMID- 26929208 TI - FRACTURE OF THE CENTRAL TARSAL BONE IN NONRACEHORSES: FOUR CASES. AB - Fractures of the central tarsal bone are a rarely recognized cause of acute severe hind limb lameness in nonracehorses. Diagnosis of these fractures can be challenging and little is known about their configuration or outcome. The objectives of this retrospective case series study were to describe the clinical features, imaging findings, and outcomes of fractures of the central tarsal bone in a sample of nonracehorses. Medical records from 2001 to 2014 were searched for cases of central tarsal bone fractures in nonracehorses. All available imaging findings including radiography, ultrasound, computed tomography (CT), and/or nuclear scintigraphy were reviewed. History, clinical presentation, and outcome were collected from the records. Four horses met the inclusion criteria. All had a similar configuration as a simple nondisplaced slab fracture in a dorsomedial to plantarolateral orientation. Initial radiographs failed to reveal the fracture in three of four cases. When additional plantarolateral-dorsomedial oblique radiographic views were obtained, the fracture could be identified in all cases. Fractures of the central tarsal bone seemed to occur in a consistent dorsomedial to plantarolateral orientation in this sample of nonracehorses, which is different from the configuration previously reported in racehorses. While CT can be used for detection and assessment of these fractures, authors propose that radiography can also identify these fractures with the appropriate view. Authors recommend the use of several plantarolateral to dorsomedial radiographic projections at varying degrees of obliquity for horses with a suspected central tarsal bone fracture. PMID- 26929210 TI - Extra! Extra! Read All About It! PMID- 26929209 TI - Germline Chromothripsis Driven by L1-Mediated Retrotransposition and Alu/Alu Homologous Recombination. AB - Chromothripsis (CTH) is a phenomenon where multiple localized double-stranded DNA breaks result in complex genomic rearrangements. Although the DNA-repair mechanisms involved in CTH have been described, the mechanisms driving the localized "shattering" process remain unclear. High-throughput sequence analysis of a familial germline CTH revealed an inserted SVAE retrotransposon associated with a 110-kb deletion displaying hallmarks of L1-mediated retrotransposition. Our analysis suggests that the SVAE insertion did not occur prior to or after, but concurrent with the CTH event. We also observed L1-endonuclease potential target sites in other breakpoints. In addition, we found four Alu elements flanking the 110-kb deletion and associated with an inversion. We suggest that chromatin looping mediated by homologous Alu elements may have brought distal DNA regions into close proximity facilitating DNA cleavage by catalytically active L1 endonuclease. Our data provide the first evidence that active and inactive human retrotransposons can serve as endogenous mutagens driving CTH in the germline. PMID- 26929211 TI - Science Over Stigma: Saving Lives--Implementation of Naloxone Use in the School Setting. AB - Unintentional drug overdose is a leading cause of preventable death in the United States. Administration of naloxone hydrochloride ("naloxone") can reverse a potentially fatal opioid overdose and save lives. The school nurse is an essential part of the school team responsible for developing emergency response procedures and should facilitate access to naloxone for the management of opioid related overdose in the school setting. Delaware has been leading efforts to provide education, increase awareness, and help erase the stigma of substance use disorder through school nurse collaboration with a grassroots organization and state stakeholders. This article discusses the successful implementation of naloxone use in the school setting in Delaware public high schools. PMID- 26929212 TI - Naloxone Use in the School Setting--The Role of the School Nurse: Position Statement. PMID- 26929213 TI - Automated discrimination of dicentric and monocentric chromosomes by machine learning-based image processing. AB - Dose from radiation exposure can be estimated from dicentric chromosome (DC) frequencies in metaphase cells of peripheral blood lymphocytes. We automated DC detection by extracting features in Giemsa-stained metaphase chromosome images and classifying objects by machine learning (ML). DC detection involves (i) intensity thresholded segmentation of metaphase objects, (ii) chromosome separation by watershed transformation and elimination of inseparable chromosome clusters, fragments and staining debris using a morphological decision tree filter, (iii) determination of chromosome width and centreline, (iv) derivation of centromere candidates, and (v) distinction of DCs from monocentric chromosomes (MC) by ML. Centromere candidates are inferred from 14 image features input to a Support Vector Machine (SVM). Sixteen features derived from these candidates are then supplied to a Boosting classifier and a second SVM which determines whether a chromosome is either a DC or MC. The SVM was trained with 292 DCs and 3135 MCs, and then tested with cells exposed to either low (1 Gy) or high (2-4 Gy) radiation dose. Results were then compared with those of 3 experts. True positive rates (TPR) and positive predictive values (PPV) were determined for the tuning parameter, sigma. At larger sigma, PPV decreases and TPR increases. At high dose, for sigma = 1.3, TPR = 0.52 and PPV = 0.83, while at sigma = 1.6, the TPR = 0.65 and PPV = 0.72. At low dose and sigma = 1.3, TPR = 0.67 and PPV = 0.26. The algorithm differentiates DCs from MCs, overlapped chromosomes and other objects with acceptable accuracy over a wide range of radiation exposures. PMID- 26929214 TI - Proteomic Analysis of the Mammalian Katanin Family of Microtubule-severing Enzymes Defines Katanin p80 subunit B-like 1 (KATNBL1) as a Regulator of Mammalian Katanin Microtubule-severing. AB - The Katanin family of microtubule-severing enzymes is critical for remodeling microtubule-based structures that influence cell division, motility, morphogenesis and signaling. Katanin is composed of a catalytic p60 subunit (A subunit, KATNA1) and a regulatory p80 subunit (B subunit, KATNB1). The mammalian genome also encodes two additional A-like subunits (KATNAL1 and KATNAL2) and one additional B-like subunit (KATNBL1) that have remained poorly characterized. To better understand the factors and mechanisms controlling mammalian microtubule severing, we have taken a mass proteomic approach to define the protein interaction module for each mammalian Katanin subunit and to generate the mammalian Katanin family interaction network (Katan-ome). Further, we have analyzed the function of the KATNBL1 subunit and determined that it associates with KATNA1 and KATNAL1, it localizes to the spindle poles only during mitosis and it regulates Katanin A subunit microtubule-severing activity in vitro Interestingly, during interphase, KATNBL1 is sequestered in the nucleus through an N-terminal nuclear localization signal. Finally KATNB1 was able to compete the interaction of KATNBL1 with KATNA1 and KATNAL1. These data indicate that KATNBL1 functions as a regulator of Katanin A subunit microtubule-severing activity during mitosis and that it likely coordinates with KATNB1 to perform this function. PMID- 26929215 TI - Human Leukocyte Antigen (HLA) B27 Allotype-Specific Binding and Candidate Arthritogenic Peptides Revealed through Heuristic Clustering of Data-independent Acquisition Mass Spectrometry (DIA-MS) Data. AB - Expression of HLA-B27 is strongly associated with ankylosing spondylitis (AS) and other spondyloarthropathies. While this is true for the majority of HLA-B27 allotypes, HLA-B*27:06 and HLA-B*27:09 are not associated with AS. These two subtypes contain polymorphisms that are ideally positioned to influence the bound peptide repertoire. The existence of disease-inducing peptides (so-called arthritogenic peptides) has therefore been proposed that are exclusively presented by disease-associated HLA-B27 allotypes. However, we have recently demonstrated that this segregation of allotype-bound peptides is not the case and that many peptides that display sequence features predicted to favor binding to disease-associated subtypes are also capable of being presented naturally by protective alleles. To further probe more subtle quantitative changes in peptide presentation, we have used a combination of data-independent acquisition (DIA) and multiple reaction monitoring (MRM) mass spectrometry to quantify the abundance of 1646 HLA-B27 restricted peptides across the eight most frequent HLA B27 allotypes (HLA-B*27:02-HLA-B*27:09). We utilized K means cluster analysis to group peptides with similar allelic binding preferences across the eight HLA-B27 allotypes, which enabled us to identify the most-stringent binding characteristics for each HLA-B27 allotype and further refined their existing consensus-binding motifs. Moreover, a thorough analysis of this quantitative dataset led to the identification of 26 peptides, which are presented in lower abundance by HLA-B*27:06 and HLA-B*27:09 compared with disease-associated HLA-B27 subtypes. Although these differences were observed to be very subtle, these 26 peptides might encompass the sought-after arthritogenic peptide(s). PMID- 26929217 TI - Evidence for Differential Glycosylation of Trophoblast Cell Types. AB - Human placental villi are surfaced by the syncytiotrophoblast (STB), with a layer of cytotrophoblasts (CTB) positioned just beneath the STB. STB in normal term pregnancies is exposed to maternal immune cells in the placental intervillous space. Extravillous cytotrophoblasts (EVT) invade the decidua and spiral arteries, where they act in conjunction with natural killer (NK) cells to convert the spiral arteries into flaccid conduits for maternal blood that support a 3-4 fold increase in the rate of maternal blood flow into the placental intervillous space. The functional roles of these distinct trophoblast subtypes during pregnancy suggested that they could be differentially glycosylated. Glycomic analysis of these trophoblasts has revealed the expression of elevated levels of biantennary N-glycans in STB and CTB, with the majority of them bearing a bisecting GlcNAc. N-glycans terminated with polylactosamine extensions were also detected at low levels. A subset of the N-glycans linked to these trophoblasts were sialylated, primarily with terminal NeuAcalpha2-3Gal sequences. EVT were decorated with the same N-glycans as STB and CTB, except in different proportions. The level of bisecting type N-glycans was reduced, but the level of N-glycans decorated with polylactosamine sequences were substantially elevated compared with the other types of trophoblasts. The level of triantennary and tetraantennary N-glycans was also elevated in EVT. The sialylated N-glycans derived from EVT were completely susceptible to an alpha2-3 specific neuraminidase (sialidase S). The possibility exists that the N-glycans associated with these different trophoblast subpopulations could act as functional groups. These potential relationships will be considered. PMID- 26929216 TI - Maturing Glycoproteomics Technologies Provide Unique Structural Insights into the N-glycoproteome and Its Regulation in Health and Disease. AB - The glycoproteome remains severely understudied because of significant analytical challenges associated with glycoproteomics, the system-wide analysis of intact glycopeptides. This review introduces important structural aspects of protein N glycosylation and summarizes the latest technological developments and applications in LC-MS/MS-based qualitative and quantitative N-glycoproteomics. These maturing technologies provide unique structural insights into the N glycoproteome and its synthesis and regulation by complementing existing methods in glycoscience. Modern glycoproteomics is now sufficiently mature to initiate efforts to capture the molecular complexity displayed by the N-glycoproteome, opening exciting opportunities to increase our understanding of the functional roles of protein N-glycosylation in human health and disease. PMID- 26929218 TI - Single Chain Antibodies as Tools to Study transforming growth factor-beta Regulated SMAD Proteins in Proximity Ligation-Based Pharmacological Screens. AB - The cellular heterogeneity seen in tumors, with subpopulations of cells capable of resisting different treatments, renders single-treatment regimens generally ineffective. Accordingly, there is a great need to increase the repertoire of drug treatments from which combinations may be selected to efficiently target sets of pathological processes, while suppressing the emergence of resistance mutations. In this regard, members of the TGF-beta signaling pathway may furnish new, valuable therapeutic targets. In the present work, we developed in situ proximity ligation assays (isPLA) to monitor the state of the TGF-beta signaling pathway. Moreover, we extended the range of suitable affinity reagents for this analysis by developing a set of in-vitro-derived human antibody fragments (single chain fragment variable, scFv) that bind SMAD2 (Mothers against decapentaplegic 2), 3, 4, and 7 using phage display. These four proteins are all intracellular mediators of TGF-beta signaling. We also developed an scFv specific for SMAD3 phosphorylated in the linker domain 3 (p179 SMAD3). This phosphorylation has been shown to inactivate the tumor suppressor function of SMAD3. The single chain affinity reagents developed in the study were fused tocrystallizable antibody fragments (Fc-portions) and expressed as dimeric IgG-like molecules having Fc domains (Yumabs), and we show that they represent valuable reagents for isPLA.Using these novel assays, we demonstrate that p179 SMAD3 forms a complex with SMAD4 at increased frequency during division and that pharmacological inhibition of cyclin-dependent kinase 4 (CDK4)(1) reduces the levels of p179SMAD3 in tumor cells. We further show that the p179SMAD3-SMAD4 complex is bound for degradation by the proteasome. Finally, we developed a chemical screening strategy for compounds that reduce the levels of p179SMAD3 in tumor cells with isPLA as a read-out, using the p179SMAD3 scFv SH544-IIC4. The screen identified two kinase inhibitors, known inhibitors of the insulin receptor, which decreased levels of p179SMAD3/SMAD4 complexes, thereby demonstrating the suitability of the recombinant affinity reagents applied in isPLA in screening for inhibitors of cell signaling. PMID- 26929220 TI - Response to: 'Effects of colchicine on risk of cardiovascular events among patients with gout: as evidence accrues, is it time for a randomized trial?' by Giannopoulos and Deftereos. PMID- 26929219 TI - Efficacy of first-line tocilizumab therapy in early polymyalgia rheumatica: a prospective longitudinal study. AB - BACKGROUND: Glucocorticoids are the cornerstone treatment of polymyalgia rheumatica (PMR) but induce adverse events. OBJECTIVES: To evaluate the efficacy and safety of first-line tocilizumab in PMR. METHODS: In a prospective open-label study (ClinicalTrials.gov: NCT01713842), 20 glucocorticoid-free patients fulfilling Chuang's PMR criteria, with symptom onset within the last 12 months and a PMR activity score (PMR-AS) >10, each received three tocilizumab infusions at 4-week intervals, without glucocorticoids, followed by oral prednisone from weeks 12 to 24 (0.15 mg/kg if PMR-AS <=10 and 0.30 mg/kg otherwise). The primary end point was the proportion of patients with PMR-AS<=10 at week 12. RESULTS: Baseline median PMR-AS was 36.6 (IQR 30.4-43.8). At week 12, all patients had PMR AS<=10 and received the low prednisone dosage. Median PMR-AS at weeks 12 and 24 was 4.5 (3.2-6.8) and 0.95 (IQR 0.4-2), respectively (p<0.001 vs baseline for both time points). No patient required rescue treatment. Positron emission tomography-CT showed significant improvements. The most common adverse events were transient neutropenia (n=3) and leucopenia (n=5); in one patient, the second tocilizumab infusion was omitted due to leucopenia. CONCLUSIONS: Tocilizumab monotherapy is effective in recent-onset PMR. Randomised controlled trials are warranted. TRIAL REGISTRATION NUMBER: NCT01713842. PMID- 26929221 TI - Combining tract- and atlas-based analysis reveals microstructural abnormalities in early Tourette syndrome children. AB - Tourette syndrome (TS) is a neurological disorder that causes uncontrolled repetitive motor and vocal tics in children. Examining the neural basis of TS churned out different research studies that advanced our understanding of the brain pathways involved in its development. Particularly, growing evidence points to abnormalities within the fronto-striato-thalamic pathways. In this study, we combined Tract-Based Spatial Statistics (TBSS) and Atlas-based regions of interest (ROI) analysis approach, to investigate the microstructural diffusion changes in both deep and superficial white matter (SWM) in TS children. We then characterized the altered microstructure of white matter in 27 TS children in comparison with 27 age- and gender-matched healthy controls. We found that fractional anisotropy (FA) decreases and radial diffusivity (RD) increases in deep white matter (DWM) tracts in cortico-striato-thalamo-cortical (CSTC) circuit as well as SWM. Furthermore, we found that lower FA values and higher RD values in white matter regions are correlated with more severe tics, but not tics duration. Besides, we also found both axial diffusivity and mean diffusivity increase using Atlas-based ROI analysis. Our work may suggest that microstructural diffusion changes in white matter is not only restricted to the gray matter of CSTC circuit but also affects SWM within the primary motor and somatosensory cortex, commissural and association fibers. Hum Brain Mapp 37:1903 1919, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26929222 TI - Infantile intracranial aneurysm of the superior cerebellar artery. AB - Intracranial aneurysms in the pediatric population are rare. We report a case of a 3-month-old infant who presented with inconsolable crying, vomiting, and sunset eye sign. CT revealed a subarachnoid hemorrhage, with CT angiogram revealing a superior cerebellar artery aneurysm. An external ventricular drain was placed for acute management of hydrocephalus, with definitive treatment by endovascular technique with a total of six microcoils to embolize the aneurysm. Serial transcranial Dopplers revealed no subsequent vasospasm. Although aneurysms in the pediatric population are rare, once the diagnosis is established, early treatment results in better outcomes. PMID- 26929223 TI - Something old, something new: a successful case of meprobamate withdrawal. AB - Meprobamate, a benzodiazepine-like drug, was commonly prescribed for anxiety in the 1960s and 1970s, but fell out of favour, at least in part, due to the risk of dependence, for which there is little published evidence to guide clinical management. We discuss a 70-year-old man with a 45-year history of meprobamate dependency and multiple failed previous withdrawal attempts who was successfully withdrawn from meprobamate using diazepam during a 2-week inpatient stay on a specialist Addictions ward. An appropriate diazepam dose was established using the Clinical Institute Withdrawal Assessment scale for benzodiazepines (CIWA-B). This dose was then slowly reduced over 12 days. Multidisciplinary input, especially psychological therapy tackling his underlying anxiety disorder during his admission, was thought to be particularly helpful. PMID- 26929224 TI - Congenital genitourinary malformation in a woman with three primary gynaecological tumours: synchronous findings never before described. PMID- 26929225 TI - Perforation of the gastric remnant in a patient post-Roux-en-Y gastric bypass. AB - With the dramatic increase in obesity surgery and the subsequent increase in ageing post-gastric bypass patients, early recognition of possible and serious complications is of the utmost importance. We present a case of a 33-year-old woman who presented to the emergency room, with progressive epigastric pain. The patient had undergone laparoscopic Roux-en-Y gastric bypass surgery 14 months earlier. Diagnostic laparoscopy was performed and showed a prepyloric perforation of the gastric remnant. The defect was closed and omentoplasty was performed. The patient was put on lifelong proton pump inhibitors. PMID- 26929226 TI - Granulomatosis with polyangiitis affecting the skull base and manifesting as spontaneous skull base osteomyelitis. AB - A 53-year-old woman presented with right-sided otalgia radiating to the temporal region, angle of the mandible and upper neck. Otoscopy was unremarkable on examination and there were no signs of otitis externa. MRI revealed an infiltrative soft tissue mass to the right lateral aspect of the clivus. Transnasal and CT-guided biopsies were performed, however, these showed either inconclusive or benign tissue. Following multidisciplinary team assessment a diagnosis of spontaneous skull base osteomyelitis was made and treatment with intravenous antibiotics started. Failure to respond to antimicrobials and the development of cranial nerve palsies raised the possibility of a vasculitis. Subsequently, a clinical diagnosis of granulomatosis with polyangiitis (GPA) was made. Remission has now been maintained with cyclophosphamide and prednisolone. We discuss the rare presentation of GPA mimicking that of spontaneous skull base osteomyelitis as well as its management and related primary otolaryngological manifestations. PMID- 26929227 TI - Isolated case of left ventricular diverticulum; other aneurysmal structures of the left ventricle. PMID- 26929228 TI - Experience Needed for Psychiatric Nursing. PMID- 26929229 TI - Psychometric Properties of Responses to an Arabic Version of the Hamilton Depression Rating Scale (HAM-D6). AB - BACKGROUND: Among existing instruments, the Hamilton Depression Rating Scale has become the gold standard for assessing depressive symptoms. An Arabic version of this instrument is lacking. OBJECTIVE: This study examines the psychometric properties of responses to an abridged Arabic version of the Hamilton Depression Rating Scale (HAM-D6). DESIGN: A total of 125 Bedouin Arabs completed a questionnaire consisting of the HAM-D6 and other Well-Being measures. The HAM-D6 was assessed using confirmatory factor analysis. Concurrent validity was also examined. RESULTS: Responses to the HAM-D6 suggest that this instrument measures a unidimensional construct with each of the scales' six items contributing significantly to the measurement. Concurrent validity was established by the scale's negative association with well-being and positive associations with emotional exhaustion and caregiving burden. CONCLUSION: The findings suggest that this abridged Arabic version of the HAM-D6 is appropriate for use for evaluating depressive symptoms. PMID- 26929230 TI - "No Right Place to Die": Nursing Attitudes and Needs in Caring for People With Serious Mental Illness at End-of-Life. AB - BACKGROUND: Approximately 6% of the U.S. population suffer from a serious mental illness (SMI). People with SMI reportedly die 20 to 25 years earlier than the general population. OBJECTIVES: To explore both hospice/palliative care nurses' and psychiatric/mental health nurses' attitudes and needs toward people with SMI at the end-of-life. DESIGN: A qualitative study following a phenomenological approach was used to interview hospice/palliative care nurses and psychiatric nurses about the experience of caring for people with SMI at the end-of-life; a total of 20 nurses were interviewed. Interviews were analyzed and coded, and themes were identified. RESULTS: Six themes were identified: stigma of mental illness, effect of SMI symptoms on communication and trust, chaotic family systems, advocacy issues around pain and comfort, need for formal support, no right place to die. CONCLUSIONS: Participants discussed the need for better education and collaboration between psychiatric and palliative care nurses as well as the need for ongoing support. PMID- 26929231 TI - The 10-Item Connor-Davidson Resilience Scale: Factorial Structure, Reliability, Validity, and Correlates Among Student Nurses in Southwestern Nigeria. AB - BACKGROUND: The 10-item Connor-Davidson Resilience Scale (CD-RISC) has demonstrated satisfactory psychometric properties as a measure of resilience in all the previous studies conducted in developed countries. OBJECTIVE: The objective of this study was to explore the psychometric characteristics of the 10 item CD-RISC among students nurses in southwestern Nigeria. DESIGN: This descriptive cross-sectional study involved a total of 449 student nurses who completed the 10-item CD-RISC in addition to measures of self-esteem, depression, religiosity, and psychological distress. RESULTS: The scale demonstrated adequate reliability (Cronbach's alpha = .81) and satisfactory validity with significant correlations with the measures of self-esteem, depression, religiosity, and psychological distress. Factor analyses revealed that resilience was best explained by a two-factor construct. CONCLUSIONS: The scale is a valid measure of resilience among Nigerian student nurses. PMID- 26929232 TI - Ethically Relevant Differences in Advance Directives for Psychiatric and End-of Life Care. AB - BACKGROUND: Psychiatric advance directives (PADs) represent a shift from more coercive to more recovery-oriented care and hold the promise of empowering patients while helping fill the gap in treatment of non-dangerous patients lacking decision-making capacity. Advance directives for end-of-life and psychiatric care share an underlying rationale of extending respect for patient autonomy and preventing the harm of unwanted treatment for patients lacking the decision-making capacity to participate meaningfully in planning their care. OBJECTIVE: Ethically relevant differences in applying advance directives to end of-life and psychiatric care are discussed. DESIGN: These differences fall into three categories: (1) patient factors, including decision-making capacity, ability to communicate, and prior experience; (2) decisional factors, including expected outcome and the nature of the decisions; and (3) historical-legal precedent. RESULTS: Specific recommendations are offered. CONCLUSIONS: Clinicians need to appreciate the ethical implications of these differences to effectively invoke PADs or assist patients in creating PADs. PMID- 26929233 TI - Unleash Your Inner Leader. PMID- 26929234 TI - Collaborating in an Evolving Health Care System: Opportunities for Redesigning Health Care Delivery. PMID- 26929235 TI - An International Congress on Violence in Clinical Psychiatry: Reflections and Takeaways. AB - Psychiatric-mental health nurses are lifelong learners and reflective practitioners. In this brief article, the authors share their professional reflections and pearls on innovative mental health nursing practice from a recent international conference on violence in clinical psychiatry. PMID- 26929237 TI - Preoperative MRI. PMID- 26929238 TI - Minimally invasive extracorporeal circulation resuscitation in hypothermic cardiac arrest. AB - Current guidelines for the treatment of hypothermic cardiocirculatory arrest recommend extracorporeal life support and rewarming, using cardiopulmonary bypass or extracorporeal membrane oxygenation circuits. Both have design-related shortcomings which may result in prolonged reperfusion time or insufficient oxygen delivery to vital organs. This article describes clear advantages of minimally invasive extracorporeal circulation systems during emergency extracorporeal life support in hypothermic arrest. The technique of minimally invasive extracorporeal circulation for reperfusion and rewarming is represented by the case of a 59-year-old patient in hypothermic cardiocirculatory arrest at 25.3 degrees C core temperature, with multiple trauma. With femoro-femoral cannulation performed under sonographic and echocardiographic guidance, extracorporeal life support was initiated using a minimally invasive extracorporeal circulation system. Perfusing rhythm was restored at 28 degrees C. During rewarming on the mobile circuit, trauma surveys were completed and the treatment initiated. Normothermic weaning was successful on the first attempt, trauma surgery was completed and the patient survived neurologically intact. For extracorporeal resuscitation from hypothermic arrest, minimally invasive extracorporeal circulation offers all the advantages of conventional cardiopulmonary bypass and extracorporeal membrane oxygenation systems without their shortcomings. PMID- 26929236 TI - Functional Connectivity of the Infant Human Brain: Plastic and Modifiable. AB - Infancy is a critical and immensely important period in human brain development. Subtle changes during this stage may be greatly amplified with the unfolding of different developmental processes, exerting far-reaching consequences. Studies of the structure and behavioral manifestations of the infant brain are fruitful. However, the specific functional brain mechanisms that enable the execution of different behaviors remained elusive until the advent of functional connectivity fMRI (fcMRI), which provides an unprecedented opportunity to probe the infant functional brain development in vivo. Since its inception, a burgeoning field of infant brain functional connectivity study has emerged and thrived during the past decade. In this review, we describe (1) findings of normal development of functional connectivity networks and their relationships to behaviors and (2) disruptions of the normative functional connectivity development due to identifiable genetic and/or environmental risk factors during the first 2 years of human life. Technical considerations of infant fcMRI are also provided. It is our hope to consolidate previous findings so that the field can move forward with a clearer picture toward the ultimate goal of fcMRI-based objective methods for early diagnosis/identification of risks and evaluation of early interventions to optimize developing functional connectivity networks in this critical developmental window. PMID- 26929240 TI - The Increasing Role of Lymphedema Screening, Diagnosis and Management as Part of Evidence-Based Guidelines for Breast Cancer Care. PMID- 26929241 TI - Chiral recognition in amyloid fiber growth. AB - Insoluble amyloid fibers represent a pathological signature of many human diseases. To treat such diseases, inhibition of amyloid formation has been proposed as a possible therapeutic strategy. d-Peptides, which possess high proteolytic stability and lessened immunogenicity, are attractive candidates in this context. However, a molecular understanding of chiral recognition phenomena for d-peptides and l-amyloids is currently incomplete. Here we report experiments on amyloid growth of individual enantiomers and their mixtures for two distinct polypeptide systems of different length and structural organization: a 44-residue covalently-linked dimer derived from a peptide corresponding to the [20-41] fragment of human beta2-microglobulin (beta2m) and the 99-residue full-length protein. For the dimeric [20-41]beta2m construct, a combination of electron paramagnetic resonance of nitroxide-labeled constructs and (13) C-isotope edited FT-IR spectroscopy of (13) C-labeled preparations was used to show that racemic mixtures precipitate as intact homochiral fibers, i.e. undergo spontaneous Pasteur-like resolution into a mixture of left- and right-handed amyloids. In the case of full-length beta2m, the presence of the mirror-image d-protein affords morphologically distinct amyloids that are composed largely of enantiopure domains. Removal of the l-component from hybrid amyloids by proteolytic digestion results in their rapid transformation into characteristic long straight d-beta2m amyloids. Furthermore, the full-length d-enantiomer of beta2m was found to be an efficient inhibitor of l-beta2m amyloid growth. This observation highlights the potential of longer d-polypeptides for future development into inhibitors of amyloid propagation. Copyright (c) 2016 European Peptide Society and John Wiley & Sons, Ltd. PMID- 26929239 TI - Resting state connectivity and cognitive performance in adults with cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy. AB - Cognitive impairment is an inevitable feature of cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), affecting executive function, attention and processing speed from an early stage. Impairment is associated with structural markers such as lacunes, but associations with functional connectivity have not yet been reported. Twenty-two adults with genetically-confirmed CADASIL (11 male; aged 49.8 +/- 11.2 years) underwent functional magnetic resonance imaging at rest. Intrinsic attentional/executive networks were identified using group independent components analysis. A linear regression model tested voxel-wise associations between cognitive measures and component spatial maps, and Pearson correlations were performed with mean intra-component connectivity z-scores. Two frontoparietal components were associated with cognitive performance. Voxel-wise analyses showed an association between one component cluster and processing speed (left middle temporal gyrus; peak -48, -18, -14; ZE = 5.65, pFWE corr = 0.001). Mean connectivity in both components correlated with processing speed (r = 0.45, p = 0.043; r = 0.56, p = 0.008). Mean connectivity in one component correlated with faster Trailmaking B minus A time (r = -0.77, p < 0.001) and better executive performance (r = 0.56, p = 0.011). This preliminary study provides evidence for associations between cognitive performance and attentional network connectivity in CADASIL. Functional connectivity may be a useful biomarker of cognitive performance in this population. PMID- 26929242 TI - Overtreatment and Cost-Effectiveness of the See-and-Treat Strategy for Managing Cervical Precancer. AB - BACKGROUND: See-and-treat using loop electrosurgical excision procedure (LEEP) has been recommended as an alternative in managing high-grade cervical squamous intraepithelial lesions, but existing literature lacks evidence of the strategy's cost-effectiveness. We evaluated the overtreatment and cost-effectiveness of the see-and-treat strategy compared with usual care. METHODS: We modeled a hypothetical cohort of 40-year-old females who had not been screened for cervical cancer and followed them through their lifetimes using a Markov model. From a U.S. health-system perspective, the analysis was conducted in 2012 dollars and measured effectiveness in quality-adjusted life-years (QALY). We estimated incremental cost-effectiveness ratios (ICER) using a willingness-to-pay threshold of $50,000/QALY. The robustness of the see-and-treat strategy's cost effectiveness and its overtreatment rates were further examined in various sensitivity analyses. RESULTS: In the base-case, the see-and-treat strategy yielded an ICER of $70,774/QALY compared with usual care. For most scenarios in the deterministic sensitivity analysis, this strategy had ICERs larger than $50,000/QALY, and its cost-effectiveness was sensitive to the disutility of LEEP treatment and biopsy-directed treatment adherence under usual care. Probabilistic sensitivity analysis showed that the see-and-treat strategy had a 50.1% chance to be cost-effective. It had an average overtreatment rate of 7.1% and a 78.8% chance to have its overtreatment rate lower than the 10% threshold. CONCLUSION: The see-and-treat strategy induced an acceptable overtreatment rate. Its cost effectiveness, compared with usual care, was indiscriminating at the chosen willingness-to-pay threshold but much improved when the threshold increased. IMPACT: The see-and-treat strategy was reasonable for particular settings, that is, those with low treatment adherence. Cancer Epidemiol Biomarkers Prev; 25(5); 807-14. (c)2016 AACR. PMID- 26929244 TI - Efficiencies of the NJp, Maximum Likelihood, and Bayesian Methods of Phylogenetic Construction for Compositional and Noncompositional Genes. AB - At the present time it is often stated that the maximum likelihood or the Bayesian method of phylogenetic construction is more accurate than the neighbor joining (NJ) method. Our computer simulations, however, have shown that the converse is true if we use p distance in the NJ procedure and the criterion of obtaining the true tree (Pc expressed as a percentage) or the combined quantity (c) of a value of Pc and a value of Robinson-Foulds' average topological error index (dT). This c is given by Pc (1 - dT/dTmax) = Pc (m - 3 - dT/2)/(m - 3), where m is the number of taxa used and dTmax is the maximum possible value of dT, which is given by 2(m - 3). This neighbor joining method with p distance (NJp method) will be shown generally to give the best data-fit model. This c takes a value between 0 and 1, and a tree-making method giving a high value of c is considered to be good. Our computer simulations have shown that the NJp method generally gives a better performance than the other methods and therefore this method should be used in general whether the gene is compositional or it contains the mosaic DNA regions or not. PMID- 26929243 TI - Predicting Barrett's Esophagus in Families: An Esophagus Translational Research Network (BETRNet) Model Fitting Clinical Data to a Familial Paradigm. AB - BACKGROUND: Barrett's esophagus is often asymptomatic and only a small portion of Barrett's esophagus patients are currently diagnosed and under surveillance. Therefore, it is important to develop risk prediction models to identify high risk individuals with Barrett's esophagus. Familial aggregation of Barrett's esophagus and esophageal adenocarcinoma, and the increased risk of esophageal adenocarcinoma for individuals with a family history, raise the necessity of including genetic factors in the prediction model. Methods to determine risk prediction models using both risk covariates and ascertained family data are not well developed. METHODS: We developed a Barrett's Esophagus Translational Research Network (BETRNet) risk prediction model from 787 singly ascertained Barrett's esophagus pedigrees and 92 multiplex Barrett's esophagus pedigrees, fitting a multivariate logistic model that incorporates family history and clinical risk factors. The eight risk factors, age, sex, education level, parental status, smoking, heartburn frequency, regurgitation frequency, and use of acid suppressant, were included in the model. The prediction accuracy was evaluated on the training dataset and an independent validation dataset of 643 multiplex Barrett's esophagus pedigrees. RESULTS: Our results indicate family information helps to predict Barrett's esophagus risk, and predicting in families improves both prediction calibration and discrimination accuracy. CONCLUSIONS: Our model can predict Barrett's esophagus risk for anyone with family members known to have, or not have, had Barrett's esophagus. It can predict risk for unrelated individuals without knowing any relatives' information. IMPACT: Our prediction model will shed light on effectively identifying high-risk individuals for Barrett's esophagus screening and surveillance, consequently allowing intervention at an early stage, and reducing mortality from esophageal adenocarcinoma. Cancer Epidemiol Biomarkers Prev; 25(5); 727-35. (c)2016 AACR. PMID- 26929246 TI - Sheffield Hallam Staff Wellness service: Four-year follow-up of the impact on health indicators. AB - AIMS: Alongside the increasing prevalence of chronic health conditions such as cardiovascular disease and diabetes has been an increase in interventions to reverse these ill-health trends. The aim of this study was to examine the longitudinal impact of the Sheffield Hallam University Staff Wellness Service on health indicators over a five-year period. METHODS: The Sheffield Hallam Staff Wellness Service was advertised to university employees. Of 2651 employees who have attended the service, 427 respondents (male = 162, female = 265) aged 49.86 +/- 12.26 years attended for five years (4 years follow-up). Each year, participants were assessed on a range of health measures (i.e. cardio-respiratory fitness, body mass index, blood pressure, total cholesterol, high-density lipoproteins, lung function and percentage body fat). Participants also received lifestyle advice (based on motivational interviewing) as part of the intervention to either improve, or in some cases maintain, their current health behaviours (e.g. increased physical activity and diet change). RESULTS: The wellness service improved staff health for those with an 'at risk' health profile from baseline. These improvements were maintained in subsequent follow-up assessments. Improvement from baseline to 1-year follow-up was observed for all health indicators as was the maintenance of this improvement in years 2, 3 and 4. CONCLUSIONS: The service demonstrates that a university-based wellness service using a combination of motivational interviewing and health screening to elicit behaviour change (and subsequent improvements in health-related outcomes) was successful in improving the health of employees with an 'at risk' profile. PMID- 26929247 TI - Biodistribution of the cyclotide MCoTI-II, a cyclic disulfide-rich peptide drug scaffold. AB - Disulfide-rich macrocyclic peptides are promising templates for drug design because of their unique topology and remarkable stability. However, little is known about their pharmacokinetics. In this study, we characterize the biodistribution in mice of Momordica cochinchinensis trypsin inhibitor-II (MCoTI II), a cyclic three-disulfide-containing peptide that has been used in a number of studies as a drug scaffold. The distribution of MCoTI-II was compared with that of chlorotoxin, which is a four-disulfide-containing peptide that has been used to develop brain tumor imaging agents; dermorphin, which is a disulfide-less peptide; and bovine serum albumin, a large protein. Both MCoTI-II and chlorotoxin distributed predominantly to the serum and kidneys, confirming that they are stable in serum and suggesting that they are eliminated from the blood through renal clearance. Although cell-penetrating peptides have been reported to be able to transport across the blood-brain barrier, MCoTI-II, which is a cell penetrating peptide, showed no uptake into the brain. The uptake of chlorotoxin was higher than that of MCoTI-II but lower than that of dermorphin, which is considered to have low uptake into the brain. This study provides insight into the behavior of disulfide-rich peptides in vivo. Copyright (c) 2016 European Peptide Society and John Wiley & Sons, Ltd. PMID- 26929245 TI - Widespread Impact of Chromosomal Inversions on Gene Expression Uncovers Robustness via Phenotypic Buffering. AB - The nonrandom gene organization in eukaryotes plays a significant role in genome evolution and function. Chromosomal structural changes impact meiotic fitness and, in several organisms, are associated with speciation and rapid adaptation to different environments. Small sized chromosomal inversions, encompassing few genes, are pervasive in Saccharomyces "sensu stricto" species, while larger inversions are less common in yeasts compared with higher eukaryotes. To explore the effect of gene order on phenotype, reproductive isolation, and gene expression, we engineered 16 Saccharomyces cerevisiae strains carrying all possible paracentric and pericentric inversions between Ty1 elements, a natural substrate for rearrangements. We found that 4 inversions were lethal, while the other 12 did not show any fitness advantage or disadvantage in rich and minimal media. At meiosis, only a weak negative correlation with fitness was seen with the size of the inverted region. However, significantly lower fertility was seen in heterozygote invertant strains carrying recombination hotspots within the breakpoints. Altered transcription was observed throughout the genome rather than being overrepresented within the inversions. In spite of the large difference in gene expression in the inverted strains, mitotic fitness was not impaired in the majority of the 94 conditions tested, indicating that the robustness of the expression network buffers the deleterious effects of structural changes in several environments. Overall, our results support the notion that transcriptional changes may compensate for Ty-mediated rearrangements resulting in the maintenance of a constant phenotype, and suggest that large inversions in yeast are unlikely to be a selectable trait during vegetative growth. PMID- 26929248 TI - Effects of Naringenin on Oxidative Stress and Histopathological Changes in the Liver of Lead Acetate Administered Rats. AB - Lead has several adverse effects on the body due to one of the environmental pollutants. We aimed to determine the effects of naringenin on the oxidative stress and the hepatic damage against lead acetate treatment in the liver of male rats. Naringenin was administered by orogastric gavage (50 mg/kg) and lead acetate was given as daily 500 parts per million in drinking water for 4 weeks. Lead and antioxidant activities were measured, and histopathological evaluation was performed in the liver. Lead concentrations, malondialdehyde, and antioxidant activity were restored by the naringenin. The grade of necrosis, hydropic degeneration, and hepatic cord disorganization was decreased by the naringenin. However, there were no differences in the degree of sinusoidal congestion, hepatic steatosis, and capsular fibrosis between lead acetate and naringenin + lead acetate groups. We can suggest that naringenin has antioxidant and chelating effects in the liver. Nevertheless, this effect is not enough against the lead acetate induced hepatic injury. PMID- 26929249 TI - Chikusetsusaponin IVa Butyl Ester (CS-IVa-Be), a Novel IL6R Antagonist, Inhibits IL6/STAT3 Signaling Pathway and Induces Cancer Cell Apoptosis. AB - The activation of IL6/STAT3 signaling is associated with the pathogenesis of many cancers. Agents that suppress IL6/STAT3 signaling have cancer-therapeutic potential. In this study, we found that chikusetsusaponin IVa butyl ester (CS-IVa Be), a triterpenoid saponin extracted from Acanthopanas gracilistylus W.W.Smith, induced cancer cell apoptosis. CS-IVa-Be inhibited constitutive and IL6-induced STAT3 activation, repressed STAT3 DNA-binding activity, STAT3 nuclear translocation, IL6-induced STAT3 luciferase reporter activity, IL6-induced STAT3 regulated antiapoptosis gene expression in MDA-MB-231 cells, and IL6-induced TF-1 cell proliferation. Surprisingly, CS-IVa-Be inhibited IL6 family cytokines rather than other cytokines induced STAT3 activation. Further studies indicated that CS IVa-Be is an antagonist of IL6 receptor via directly binding to the IL6Ralpha with a Kd of 663 +/- 74 nmol/L and the GP130 (IL6Rbeta) with a Kd of 1,660 +/- 243 nmol/L, interfering with the binding of IL6 to IL6R (IL6Ralpha and GP130) in vitro and in cancer cells. The inhibitory effect of CS-IVa-Be on the IL6 IL6Ralpha-GP130 interaction was relatively specific as CS-IVa-Be showed higher affinity to IL6Ralpha than to LIFR (Kd: 4,910 +/- 1,240 nmol/L) and LeptinR (Kd: 4,990 +/- 915 nmol/L). We next demonstrated that CS-IVa-Be not only directly induced cancer cell apoptosis but also sensitized MDA-MB-231 cells to TRAIL induced apoptosis via upregulating DR5. Our findings suggest that CS-IVa-Be as a novel IL6R antagonist inhibits IL6/STAT3 signaling pathway and sensitizes the MDA MB-231 cells to TRAIL-induced cell death. Mol Cancer Ther; 15(6); 1190-200. (c)2016 AACR. PMID- 26929250 TI - Application of HIF-1alpha by gene therapy enhances angiogenesis and osteogenesis in alveolar bone defect regeneration. AB - BACKGROUND: A successful clinical outcome for implanted tissue-engineered bone is dependent on the establishment of a functional vascular network. Gene-enhanced tissue engineering represents a promising approach for vascularization and osteogenesis. In the present study, we tested the angiogenesis and osteogenesis efficacy of gelatin as the scaffold carrier in combination with a virus encoding the HIF-1alpha gene in a rat alveolar bone defect model. METHODS: Three groups of 10 rats each were either left untreated, treated with adenovirus encoding hypoxia inducible factor-1alpha (AdHIF-1alpha)/gelatin sponge or treated with gelatin sponge with adenovirus encoding red fluorescence protein, respectively. At 4 weeks, all samples were determined by micro-computed tomography, histological analyses and immunohistochemical studies. RESULTS: Scaffolds loaded with AdHIF 1alpha were able to sustain the release of AdHIF-1alpha for up to 21 days and alveolar bone defects treated with scaffolds containing AdHIF-1alpha significantly induced new bone and new vessel formation in vivo. CONCLUSIONS: Overexpression of HIF-1alpha by gene therapy may be a useful method for enhancing alveolar bone defect osteogenesis and angiogenesis. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26929251 TI - Prevalence of sleep-disordered breathing in a multiethnic Asian population in Singapore: A community-based study. AB - BACKGROUND AND OBJECTIVE: Limited data exist on the prevalence variation in sleep disordered breathing (SDB) across different Asian ethnicities. This population study aimed to estimate the prevalence of SDB in Singapore, a multiethnic nation, and to quantify the prevalence variation among Chinese, Malays and Indians. METHODS: The Singapore Health Study 2012 was a cross-sectional population study conducted on adults aged 21-79 years. Among 2329 participants who completed baseline examination, a sample of 242 subjects completed home-based sleep testing with an Embletta device (type 3 monitor). Moderate-to-severe SDB, defined as an apnoea-hypopnoea index (AHI) of >=15 events/h, was used to estimate prevalence. RESULTS: The weighted estimates of the population prevalence of moderate-to severe SDB and sleep apnoea syndrome were 30.5% and 18.1%, respectively. Of subjects with AHI >=15, 91.0% were previously undiagnosed. Moderate-to-severe SDB prevalence varied across the Chinese (32.1%), Malays (33.8%) and Indians (16.5%). The mean body mass index (BMI) was lowest in Chinese (23.3 kg/m(2) ) and highest among Malays (26.0 kg/m(2) ) and Indians (25.4 kg/m(2) ). Compared with Chinese, Indians had lower odds of moderate-to-severe SDB after adjustment for age, sex and BMI (odds ratio 0.82, 95% CI: 0.70-0.96, P = 0.02). CONCLUSION: Sleep disordered breathing is prevalent but mostly undiagnosed among Asians in Singapore. There was a lower prevalence of SDB among Indians compared with Chinese that remained after adjustment for age, sex and BMI. Strategies are needed to optimize diagnosis and recognize ethnic differences in SDB prevalence. PMID- 26929252 TI - CENTRE: creating psychological safety in groups. AB - BACKGROUND: Ten years of clinical and teaching experience has shown us that when teams or groups come together, it is often for a commonly understood and agreed upon purpose, but often without an agreed upon process of how to work together. Explicit guidelines in this regard promote psychological safety. CONTEXT: This article presents a method of developing agreements that can be used in a variety of settings to create psychological safety and cohesion. In our experience, agreements about how people join together seem to be developed implicitly. Assumption-based and implicit agreements can engender friction because unspoken or unclear agreements are not easily addressed because they are not universally understood. INNOVATION: A literature review helped to identify key factors contributing to psychological safety and led to creating 'CENTRE' to help clinical teams apply these factors. We are now starting to evaluate its impact. We believe a tool such as CENTRE facilitates the development of explicitly articulated group formation and maintenance guidelines, thus reducing the risk of interpersonal discord. IMPLICATIONS: We propose that a tool such as CENTRE be considered for a range of group situations, including clinical family meetings, teaching, professional teams and Balint-type groups. We are currently using this approach in clinical, academic and other professional environments. Findings from a survey of groups where CENTRE was used suggested that participants find the process useful. We believe a tool such as CENTRE can be used to help address relational issues, promote psychological safety, inclusion and trust among members, and reduce the risk of undeclared expectations and assumptions from dictating how groups function. Assumption-based and implicit agreements can engender friction because unspoken or unclear agreements are not easily addressed. PMID- 26929253 TI - Simulated ward round: reducing costs, not outcomes. AB - BACKGROUND: Distractions and interruptions on the ward pose substantial patient safety risks, but medical students receive little training on their management. Although there is some evidence that medical students can be taught how to manage distractions and interruptions in a simulated ward environment, the only model to date is based on individual feedback, which is resource-expensive, mitigating curricular integration. Our aim was to assess the educational utility of a cost efficient approach to a patient safety-focused simulated ward round. METHODS: Twenty-three of 55 final-year medical students took part in a cost-reduced simulated ward round. Costs were minimised by providing group rather than individualised feedback, thereby shortening the duration of each simulation and reducing the number of interruptions. The utility of the simulation was assessed via student evaluation and performance on a patient safety station of an objective structured clinical examination (OSCE). FINDINGS: The direct costs of the simulation were more than 50 per cent lower per student compared with the original study, mostly as a result of a reduction in the time that faculty members took to give feedback. Students managed distractions better and received higher scores in the OSCE station than those who had not undergone the ward round. Group feedback was evaluated positively by most participants: 94 per cent of those who provided feedback agreed or strongly agreed that the simulation would make them a safer doctor and would improve their handling of distractions. Our aim was to assess the educational utility of a cost-efficient approach to a patient safety-focused simulated ward round DISCUSSION: The costs of a simulated ward round can be significantly reduced whilst maintaining educational utility. These findings should encourage medical schools to integrate ward simulation into curricula. PMID- 26929254 TI - The Predictive Value of Platelet/Lymphocyte Ratio in Hemodialysis Patients With Erythropoietin Resistance. AB - The most important cause of anemia in CKD is relative deficiency of erythropoietin (EPO) secretion from the diseased kidney and EPO therapy has become the standard treatment for anemia of CKD. However, some patients do not respond well to erythropoiesis stimulating agent (ESA), so-called ESA resistance. One of the most important causes of ESA resistance is chronic inflammation in hemodialysis (HD) patients. ESA hyporesponsiveness index (EHRI), calculated as the weekly dose of EPO divided by kilograms of body weight divided by the hemoglobin level, and has been considered useful to assess the EPO resistance. Neutrophil/lymphocyte (NLR) ratio and platelet/lymphocyte ratio (PLR) were also found to be associated with inflammation in HD patients. However, the relationship between NLR, PLR and EHRI has not been investigated before. HD patients underwent medical history taking, physical examination, calculation of dialysis adequacy and biochemical analysis and calculation of EHRI. Logarithmically converted EHRI (logEHRI) was correlated only with hemoglobin (r 0.381, P < 0.0001) and PLR (r = 0.227, P = 0.021) but not with NLR. Comparison of PLR among 25th, 50th and 75th percentile of EHRI showed that PLR levels increased going from the 25th to 75(th) percentile (P = 0.032). Posthoc analysis revealed that 25-75th percentile (P = 0.014) and 50-75th percentile (P = 0.033) were different with respect to PLR. In linear regression analysis, PLR (standardized beta = 0.296, confidence interval: 0.000-0.001, P = 0.003) was independently associated with logEHRI. We found that PLR was independently associated with EHRI in HD patients. PLR, which is quite a simple and cheap method, may guide clinicians for detecting EPO resistance. PMID- 26929255 TI - Liver Support With Albumin Dialysis Reduces Hepatitis C Virus Viremia and Facilitates Antiviral Treatment of Severe Hepatitis C Virus Recurrence After Liver Transplantation. AB - Patients with severe hepatitis C virus (HCV) recurrence after liver transplantation (LT) present an ominous prognosis, rarely achieving sustained virological response (SVR). Dialysis procedures may transiently decrease the HCV viral load, but the effect of albumin dialysis is currently unknown. Here, we evaluated the impact of albumin dialysis using the Molecular Adsorbent Recirculating System (MARS) used as a co-adjuvant antiviral treatment for severe HCV recurrence after LT. Thirteen patients (11 males, median age 48 years) with fibrosing cholestatic hepatitis or METAVIR fibrosis score >= F3 with severe portal hypertension underwent three consecutive MARS sessions. Antiviral therapy was initiated in 11 patients within 24 h after the MARS sessions. A contemporary cohort of seven patients who did not follow the MARS protocol is shown for comparison. MARS treatment resulted in consistent decreases of viral load from 7.59 log10 IU/mL [6.15-8.90] to 6.79 log10 IU/mL [5.18-7.84] (P = 0.003) as well as in decreases of serum bilirubin, gamma-glutamyl transpeptidase, alanine aminotransferase and aspartate aminotransferase (all P < 0.05). The overall rate of SVR was 0% in the Control group and 54.6% in patients initiating antiviral therapy within 24 h after MARS. Survival at 1 and 3 years was, respectively, 93% and 70% in patients undergoing MARS, compared with 29% and 14% in the Control group (P = 0.001). No major adverse events related to MARS treatment were observed. In conclusion, the use of MARS may facilitate the achievement of SVR and improve the prognosis of patients with severe HCV-recurrence after LT by reducing viral load and improving liver function prior to antiviral therapy. PMID- 26929256 TI - Effects of Icodextrin and Glucose Bicarbonate/Lactate-Buffered Peritoneal Dialysis Fluids on Effluent Cell Population and Biocompatibility Markers IL-6 and CA125 in Incident Peritoneal Dialysis Patients. AB - Icodextrin peritoneal dialysis (PD) solution has been shown to increase interleukin-6 (IL-6) levels in PD effluent as well as leukocyte and mesothelial cell count. Mesothelial cells release cancer antigen 125 (CA125), which is used as a marker of mesothelial cell mass. This 1-year prospective study was designed to compare peritoneal effluent cell population, its inflammatory phenotype and biocompatibility biomarkers IL-6 and CA125 between icodextrin (E) and glucose bicarbonate/lactate (P) based PD solutions. Using baseline peritoneal ultrafiltration capacity, 19 stable incident PD patients were allocated either to P only (N = 8) or to P plus E for the overnight dwell (N = 11). Flow cytometry was used to measure white blood cell count and differential and the expression of inflammatory molecules on peritoneal cells isolated from timed overnight peritoneal effluents. Compared to P, E effluent showed higher leukocyte (10.9 vs. 7.9), macrophages (6.1 vs. 2.5) and mesothelial cells (0.3 vs. 0.1)*10(6) /L count, as well as expression of HLA DR on mesothelial cells and IL-6 (320.5 vs. 141.2 pg/min) on mesothelial cells and CA125 appearance rate (159.6 vs. 84.3 IU/min), all P < 0.05. In the E group, correlation between IL-6 and CA125 effluent levels (r = 0.503, P < 0.05) as well as appearance rates (r = 0.774, P < 0.001) was demonstrated. No effect on systemic inflammatory markers or peritoneal permeability was found. Icodextrin PD solution activates local inflammation without systemic consequences so the clinical relevance of this observation remains obscure. Correlation between effluent IL-6 and CA125 suggests that CA125 might be upregulated due to inflammation and thus is not a reliable marker of mesothelial cell mass and/or biocompatibility. PMID- 26929257 TI - Impact of Lanthanum Carbonate on Prognosis of Chronic Hemodialysis Patients: A Retrospective Cohort Study (Kawashima Study). AB - In hemodialysis patients, mineral and bone disorder is an important risk factor for cardiovascular disease and subsequent death through the progression of vascular calcification. Serum phosphorus plays a major role in this process. In the present study, we retrospectively analyzed the effects of oral phosphate binder, lanthanum carbonate (LC), on the mortality in hemodialysis patients. Among a total of 841 patients who underwent maintenance hemodialysis on 1 July 2010, patients who were treated with LC (LC group, N = 324) and those who were treated without LC (NLC group, N = 517) were compared with respect to their all cause mortality for a long-term observation period of up to 36 months. The mortality rate was compared using the Cox proportional hazard model adjusted by the propensity score. The adjusted hazard ratio for mortality in the LC group versus NLC group was 0.515 (95% confidence interval, 0.328-0.807), suggesting that the use of LC is associated with an almost 50% reduction in the mortality rate. The present retrospective study including all hemodialysis patients demonstrated, for the first time, an association between the use of LC and improved prognosis in hemodialysis patients. Randomized controlled trials should be done in the future to validate our present findings. PMID- 26929259 TI - Fatigue in transportation: NTSB investigations and safety recommendations. AB - OBJECTIVE: We aim to place into the scientific literature information on the prevalence of operator fatigue as a factor in causing transportation mishaps, and the categories of improvements identified to address fatigue in transportation. METHODS: We analyzed the number of major National Transportation Safety Board (NTSB) investigations that identified fatigue as a probable cause, contributing factor, or a finding. We divided all NTSB recommendations addressing fatigue issued since the agency was founded into 7 subject categories, and placed each recommendation into the appropriate category. This information was then analyzed to determine the number of recommendations in each category, both overall and by transportation mode. Analysis was also performed regarding the types of organizations that received the recommendations, whether the recommended actions have been taken, and the NTSB's evaluation of whether the action taken satisfied a given recommendation. RESULTS: We reviewed 182 major NTSB investigations completed between 1 January 2001 and 31 December 2012 and found that 20% of these investigations identified fatigue as a probable cause, contributing factor, or a finding. The presence of fatigue varied between among the modes of transportation, ranging from 40% of highway investigations to 4% of marine investigations. The first NTSB recommendation to address the safety risks associated with human fatigue was issued over 40 years ago, in 1972. Since then, the NTSB has issued 205 separate fatigue-specific recommendations. Scheduling policies and practices was the most common subject category accounting for 40% of all recommendations issued. Federal agencies received 54% of all recommendations, with 22% to transportation operators, and 16% to associations. Of all NTSB fatigue recommendations, 24% were open ranging from a low of 9% in highway to 39% in aviation. Overall, only 3% of open recommendations were classified "unacceptable," whereas 16% of all closed recommendations were classified "unacceptable." CONCLUSIONS: Although there has been over 100 years of progress in recognizing and addressing the safety risk posed by human fatigue in transportation, 20% of recent NTSB investigations have identified fatigue as a probable cause, contributing factor or finding. This analysis represents the first-ever examination of fatigue identified in major NTSB investigations across modes and of the focus, recipients, and classification status of fatigue-related safety recommendations. It demonstrates that fatigue remains a significant transportation safety risk. PMID- 26929260 TI - A review of stroller-related and pram-related injuries to children in Singapore. AB - Prams and strollers are commonly used in daily childcare. We aim to study the type and severity of injuries associated with prams and strollers in an Asian population. We performed a retrospective review of children below the age of 6 who presented to a tertiary paediatric hospital in Singapore, from January 2012 to June 2015, with such injuries. There were 248 pram-related and stroller related injuries. The median age was 12.5 months old. 69 (27.8%) sustained open wounds, 17 (6.9%) suffered fractures or dislocations and 2 children had significant head injuries. 29 patients (11.7%) sustained injuries while on stairs or escalators. Most of the injuries (197 cases, 79.4%) occurred despite adult supervision. The need for intervention was associated with older age and entrapment injuries (p<0.001). Only appropriately sized prams and strollers without exposed hinges should be used. These should not be deployed on stairs and escalators. PMID- 26929261 TI - Correlation of obstructive sleep apnoea and laryngopharyngeal reflux: phmetry study. AB - OBJECTIVE: To study the correlation of obstructive sleep apnoea (OSA) and laryngopharyngeal reflux (LPR). DESIGN: A descriptive study. SETTING: Suez Canal University Hospital, Ismailia, Egypt. PATIENTS: 62 patients with polysomnography confirmed OSA. INTERVENTION: Patients were evaluated with ambulatory 24-h double channel pH monitoring. RESULTS: Mean reflux symptom index in the study group was 9 +/- 5.5, and it was > 13 in all patients with severe OSA. Signs of LPR reflux were present in 34 (55%) patients. Abnormal reflux was detected in the distal oesophagus in 41 patients (66%) and in the proximal oesophagus in 21 patients (34%). Patients with severe OSA had significantly higher nocturnal LPR reflux episodes compared to patients with mild disease (P < .05). Number of reflux episodes and total duration of reflux during sleep are significantly correlated to degree of OSA (P < .05). No difference was found in relation to age or sex. Daytime reflux was not related to the degree of obstructive sleep apnoea (P > .05). CONCLUSION: LPR is common in patients with OSA. Patients with severe OSA have significantly higher nocturnal LPR. This should be considered when treating this group of patients. PMID- 26929262 TI - Long-term quality-of-life outcomes following treatment for adult obstructive sleep apnoea: comparison of upper airway surgery, continuous positive airway pressure and mandibular advancement splints. AB - OBJECTIVE: Long-term quality-of-life (QOL) outcomes, complications and clinical effectiveness in patients undergoing treatment with upper airway surgery (UAS), continuous positive airway pressure (CPAP) and mandibular advancement splints (MAS) for adult obstructive sleep apnoea (OSA). DESIGN: Retrospective cohort study. SETTING: Multidisciplinary OSA clinic in University teaching hospital. PARTICIPANTS: Consecutive, simultaneously treated patients with OSA undergoing UAS (n = 83), CPAP (n = 83) and MAS (n = 79). MAIN OUTCOME MEASURES: Glasgow Benefit Inventory (GBI), Snoring Severity Scale (SSS), Epworth Sleepiness Score (ESS) and side-effects in all three groups were recorded at a mean of 34.5 months following start of treatment and compared via anova with Bonferroni's adjustment for pairwise comparisons. RESULTS: Upper airway surgery demonstrated a statistically significant QOL benefit over MAS. All three groups showed a significant improvement in SSS with CPAP significantly better than MAS, but equivalent to UAS. Uncomplicated UAS provided a greater QOL outcome than compliant MAS, non-compliant CPAP (P < 0.05) and comparable to compliant CPAP. Patients undergoing UAS with recorded complications still reported equivalent QOL outcomes to compliant CPAP and MAS, suggesting these surgical complications are relatively minor compared to the QOL benefit of OSA treatment. CONCLUSION: Upper airway surgery showed a significant improvement in QOL outcomes compared to non compliant CPAP or MAS and equivalent benefit to compliant CPAP. This study strongly supports the role for contemporary UAS in OSA when CPAP is not or no longer an option. PMID- 26929263 TI - Risk factors for Barrett's esophagus. AB - Barrett's esophagus (BE) is a well-recognized precursor of esophageal adenocarcinoma (EAC) and is defined as >=1 cm segment of salmon-colored mucosa extending above the gastroesophageal junction into the tubular esophagus with biopsy confirmation of metaplastic replacement of the normal squamous epithelium by intestinal-type columnar epithelium. The incidence of both BE and EAC has been increasing over the past few decades. As a result, preventing the development of BE by identifying and understanding its modifiable and non-modifiable risk factors may help reduce the incidence of EAC. Over the recent past, a tremendous amount of progress has been made towards improving our knowledge of risk factors and pathogenesis of BE. This article reviews the evidence for the various risk factors for developing BE. PMID- 26929264 TI - Temporal trends in ischemic stroke and anticoagulation therapy for non-valvular atrial fibrillation: effect of diabetes. AB - BACKGROUND: Diabetes is an important risk factor for ischemic stroke in non valvular atrial fibrillation (AF). The aim of the present study was to evaluate temporal trends in ischemic stroke and warfarin use among US Medicare patients with and without diabetes. METHODS: In this retrospective cohort study, 1-year cohorts of patients with Medicare as the primary payer over the period 1992-2010 were created using the Medicare 5% sample (excluding patients with valvular disease and end-stage renal disease). International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes were used to identify AF, ischemic and hemorrhagic stroke, and diabetes; three or more consecutive prothrombin time claims were used to identify warfarin use. RESULTS: Demographic characteristics of subjects in 1992 (n = 40 255) and 2010 (n = 80 314), respectively, were as follows: age 65-74 years, 37% and 32%; age >85 years, 20% and 25%; White, 94% and 93%; hypertension, 46% and 80%; diabetes, 20% and 32%; and chronic kidney disease, 5% and 18%. Among Medicare AF patients with diabetes, ischemic stroke decreased by 71% (1992-2010) from 65 to 19 per 1000 patient years; warfarin use increased from 28% to 62%. Among patients without diabetes, ischemic stroke decreased by 68% from 44 to 14 per 1000 patient-years, whereas warfarin use increased from 26% to 59%. Approximately 38% of Medicare AF patients with diabetes did not receive anticoagulation in 2010. CONCLUSIONS: Ischemic stroke declined and warfarin use increased similarly in Medicare patients with and without diabetes. Ischemic stroke rates were consistently higher in diabetes patients, validating the inclusion of diabetes in risk calculators. The population of Medicare patients with diabetes who did not receive warfarin deserves future attention. PMID- 26929265 TI - New resources for genetic studies in Populus nigra: genome-wide SNP discovery and development of a 12k Infinium array. AB - Whole genome resequencing of 51 Populus nigra (L.) individuals from across Western Europe was performed using Illumina platforms. A total number of 1 878 727 SNPs distributed along the P. nigra reference sequence were identified. The SNP calling accuracy was validated with Sanger sequencing. SNPs were selected within 14 previously identified QTL regions, 2916 expressional candidate genes related to rust resistance, wood properties, water-use efficiency and bud phenology and 1732 genes randomly spread across the genome. Over 10 000 SNPs were selected for the construction of a 12k Infinium Bead-Chip array dedicated to association mapping. The SNP genotyping assay was performed with 888 P. nigra individuals. The genotyping success rate was 91%. Our high success rate was due to the discovery panel design and the stringent parameters applied for SNP calling and selection. In the same set of P. nigra genotypes, linkage disequilibrium throughout the genome decayed on average within 5-7 kb to half of its maximum value. As an application test, ADMIXTURE analysis was performed with a selection of 600 SNPs spread throughout the genome and 706 individuals collected along 12 river basins. The admixture pattern was consistent with genetic diversity revealed by neutral markers and the geographical distribution of the populations. These newly developed SNP resources and genotyping array provide a valuable tool for population genetic studies and identification of QTLs through natural-population based genetic association studies in P. nigra. PMID- 26929266 TI - Identification of CR1 retroposons in Arborophila rufipectus and their application to Phasianidae phylogeny. AB - Chicken repeat 1 (CR1), a member of non-LTR retroposon, is an important phylogenetic marker in avian systematics. In this study, we reported several characteristics of CR1 elements in a draft genome of Arborophila rufipectus (Sichuan partridge). According to the analyses of RepeatMasker, approximately 254 966 CR1 elements were identified in A. rufipectus, covering 6.7% of the genome. Subsequently, we selected eighteen novel CR1 elements by comparing the chicken genome, turkey genome and assembled A. rufipectus scaffolds. Here, a combined data set comprising of 22 CR1 loci, mitochondrial genomes and eight unlinked introns was analysed to infer the evolutionary relationships of twelve Phasianidae species. The applicability of CR1 sequences for inferring avian phylogeny relative to mtDNA and intron sequences was investigated as well. Our results elucidated the position of A. rufipectus in Phasianidae with robust supports that it presented a sister clade to Arborophila ardens/Arborophila brunneopectus, and implied that genus Arborophila was in a basal phylogenetic position within Phasianidae and a phylogenetic affinity between Meleagris gallopavo and Pucrasia macrolopha. Therefore, this work not only resolved some of the confounding relationships among Phasianidae, but also suggested CR1 sequences could provide powerful complementary data for phylogeny reconstruction. PMID- 26929267 TI - Simultaneous drug resistance detection and genotyping of Mycobacterium tuberculosis using a low-density hydrogel microarray. AB - BACKGROUND: Nucleic acid amplification tests are widely used in TB diagnostics. Priority tasks in their development consist of increasing the specificity and sensitivity of the detection of resistance to a wide spectrum of anti-TB drugs. METHODS: We developed a multiplexed assay allowing the detection of 116 drug resistance-determining mutations in the rpoB, katG, inhA, ahpC, gyrA, gyrB, rrs, eis and embB genes in the Mycobacterium tuberculosis complex genome and six SNPs to identify the main lineages circulating in Russia. The assay is based on the amplification of 17 fragments of the genome using the universal primer adapter technique and heat pulses at the elongation step, followed by hybridization on a microarray. RESULTS: The method was evaluated using 264 pairs of clinical samples and corresponding isolates. A significant proportion (25%) of smear-negative samples were correctly analysed by microarray analysis in addition to 96% of smear-positive samples. The sensitivity and specificity of the assay exceeded 90% for rifampicin, isoniazid, ofloxacin and second-line injection drugs. In agreement with previous studies, the specificity of ethambutol resistance was as low as 57%, while the sensitivity was 89.9%. Strong association of the Beijing lineage with a resistant phenotype was observed. Euro-American lineage strains, excluding Ural and LAM, were predominantly associated with the susceptible phenotype. CONCLUSIONS: The developed test has a high sensitivity and specificity and can be directly applied to clinical samples. The combination of mutation based drug resistance profiling and basic genotyping could be useful for clinical microbiology studies and epidemiological surveillance of the M. tuberculosis complex. PMID- 26929268 TI - Bactericidal and intracellular activity of beta-lactams against Mycobacterium abscessus. AB - OBJECTIVES: Cefoxitin and imipenem are the sole recommended beta-lactams for the treatment of Mycobacterium abscessus pulmonary infections. Here, we investigated whether one of these drugs displays superiority in terms of killing and intracellular activity. We have also evaluated whether the use of a beta lactamase inhibitor could improve their activity. METHODS: The impact of the beta lactamase BlaMab on the activity of beta-lactams was assessed by comparing M. abscessus CIP104536 and its beta-lactamase-deficient DeltablaMab derivative, as well as by using the beta-lactamase inhibitor avibactam. The activity of cefoxitin, imipenem, amoxicillin and ceftaroline, alone and in various combinations including amikacin, was compared based on determination of time-kill curves and of intracellular proliferation in human macrophages. RESULTS: Imipenem was superior to cefoxitin in both the time-kill and macrophage assays. Production of BlaMab limited the activity of imipenem. The combination of imipenem and amikacin was bactericidal against the DeltablaMab mutant. Deletion of blaMab extended the spectrum of beta-lactams active against M. abscessus to include amoxicillin and ceftaroline. In the absence of BlaMab, amoxicillin was as active as imipenem. These drugs were more active than ceftaroline and cefoxitin was the least active. Avibactam increased the intracellular activity of ceftaroline, but inhibition of BlaMab was only partial, as previously reported for amoxicillin. CONCLUSIONS: Evaluation of the killing and intracellular activities of beta lactams indicates that imipenem is superior to cefoxitin at clinically achievable drug concentrations. Inhibition of BlaMab could improve the efficacy of imipenem and extend the spectrum of drugs potentially useful to treat pulmonary infections. PMID- 26929269 TI - Sharp increase in rates of HIV transmitted drug resistance at antenatal clinics in Botswana demonstrates the need for routine surveillance. AB - OBJECTIVES: The aim of the study was to evaluate for the presence of drug resistance to HIV medications in treatment-naive individuals in Botswana. METHODS: Two different populations were evaluated for evidence of HIV drug resistance at three different geographical locations in Botswana. In the first study population, consisting of pregnant females diagnosed with HIV during pregnancy, participants were enrolled at the time of their HIV diagnosis. The second population included pre-ART enrollees at Infectious Diseases Care Clinics (IDCCs) who had a CD4 T cell count >350 cells/MUL. RESULTS: A total of 422 genotypes were determined: 234 for samples from antenatal clinic (ANC) participants and 188 for samples from IDCC participants. Between 2012 and 2014, 6 of 172 (3.5%) genotypes from ANC participants exhibited transmitted drug resistance (TDR), with 3 (1.7%) showing resistance to first-line ART. In a subset of samples from Gaborone, Botswana's capital and largest city, the TDR rate was 3 in 105 (2.9%), but only 1 in 105 (1.0%) showed first-line ART resistance. Between December 2014 and April 2015, the rate of resistance to any ART in Gaborone was 6 in 62 (9.7%), with 5 (8.1%) exhibiting first-line ART resistance. CONCLUSIONS: These data demonstrate that TDR rates for HIV differ geographically and temporally in Botswana, with significant increases in TDR observed at ANCs in Gaborone between 2012 and 2015. These findings stress the importance of continued testing for TDR, particularly as access to HIV treatment increases and guidelines recommend treatment at the time of HIV diagnosis. PMID- 26929271 TI - Cryptic diversity revealed by DNA barcoding in Colombian illegally traded bird species. AB - Colombia is the country with the largest number of bird species worldwide, yet its avifauna is seriously threatened by habitat degradation and poaching. We built a DNA barcode library of nearly half of the bird species listed in the CITES appendices for Colombia, thereby constructing a species identification reference that will help in global efforts for controlling illegal species trade. We obtained the COI barcode sequence of 151 species based on 281 samples, representing 46% of CITES bird species registered for Colombia. The species analysed belong to nine families, where Trochilidae and Psittacidae are the most abundant ones. We sequenced for the first time the DNA barcode of 47 species, mainly hummingbirds endemic of the Northern Andes region. We found a correct match between morphological and genetic identification for 86-92% of the species analysed, depending on the cluster analysis performed (BIN, ABGD and TaxonDNA). Additionally, we identified eleven cases of high intraspecific divergence based on K2P genetic distances (up to 14.61%) that could reflect cryptic diversity. In these cases, the specimens were collected in geographically distant sites such as different mountain systems, opposite flanks of the mountain or different elevations. Likewise, we found two cases of possible hybridization and incomplete lineage sorting. This survey constitutes the first attempt to build the DNA barcode library of endangered bird species in Colombia establishing as a reference for management programs of illegal species trade, and providing major insights of phylogeographic structure that can guide future taxonomic research. PMID- 26929270 TI - Importance of selection and duration of antibiotic regimen in prosthetic joint infections treated with debridement and implant retention. AB - OBJECTIVES: Early prosthetic joint infections (PJIs) are managed with debridement, implant retention and antibiotics (DAIR). Our aim was to evaluate risk factors for failure after stopping antibiotic treatment. METHODS: From 1999 to 2013, early PJIs managed with DAIR were prospectively collected and retrospectively reviewed. The main variables potentially associated with outcome were gathered, and the minimum follow-up was 2 years. For the present study, only patients who were in remission after one debridement and without long-term antibiotic suppression were included. The primary endpoint was implant removal or the need to reintroduce antibiotic treatment due to failure. RESULTS: One-hundred and-forty-three patients met the inclusion criteria. The failure rate after a median duration of oral antibiotic treatment of 69 days (IQR 45-95 days) was 11.8%. In 92 cases, PJI was due to Gram-positive microorganisms, in 21 cases PJI was due to Gram-negative microorganisms and in 30 cases PJI was due to a polymicrobial infection with both Gram-positive and Gram-negative microorganisms. In Gram-positive infections, rifampicin administered in combination with linezolid, co-trimoxazole or clindamycin was associated with a higher failure rate (27.8%, P = 0.026) than that in patients receiving a combination of rifampicin with levofloxacin, ciprofloxacin or amoxicillin (8.3%) or monotherapy with linezolid or co-trimoxazole (0%). Among patients with a Gram-negative infection, the use of fluoroquinolones was associated with a lower failure rate (7.1% versus 37.5%, P = 0.044). CONCLUSIONS: The only factor associated with failure was the oral antibiotic selection, not the duration of treatment. Linezolid, co-trimoxazole and clindamycin, but not levofloxacin, serum concentrations are reduced by rifampicin; a fact that could explain our findings. Further studies monitoring serum concentration could help to improve the efficacy of these antibiotics when administered in combination with rifampicin. PMID- 26929272 TI - High rates of phasing errors in highly polymorphic species with low levels of linkage disequilibrium. AB - Short read sequencing of diploid individuals does not permit the direct inference of the sequence on each of the two homologous chromosomes. Although various phasing software packages exist, they were primarily tailored for and tested on human data, which differ from other species in factors that influence phasing, such as SNP density, amounts of linkage disequilibrium (LD) and sample sizes. Despite becoming increasingly popular for other species, the reliability of phasing in non-human data has not been evaluated to a sufficient extent. We scrutinized the phasing accuracy for Drosophila melanogaster, a species with high polymorphism levels and reduced LD relative to humans. We phased two D. melanogaster populations and compared the results to the known haplotypes. The performance increased with size of the reference panel and was highest when the reference panel and phased individuals were from the same population. Full genomic SNP data and inclusion of sequence read information also improved phasing. Despite humans and Drosophila having similar switch error rates between polymorphic sites, the distances between switch errors were much shorter in Drosophila with only fragments <300-1500 bp being correctly phased with >=95% confidence. This suggests that the higher SNP density cannot compensate for the higher recombination rate in D. melanogaster. Furthermore, we show that populations that have gone through demographic events such as bottlenecks can be phased with higher accuracy. Our results highlight that statistically phased data are particularly error prone in species with large population sizes or populations lacking suitable reference panels. PMID- 26929273 TI - Cholesterol in platelet biogenesis and activation. AB - Hypercholesterolemia is a risk factor for atherothrombotic disease, largely attributed to its impact on atherosclerotic lesional cells such as macrophages. Platelets are involved in immunity and inflammation and impact atherogenesis, primarily by modulating immune and inflammatory effector cells. There is evidence that hypercholesterolemia increases the risk of atherosclerosis and thrombosis by modulating platelet biogenesis and activity. This review highlights recent findings on the impact of aberrant cholesterol metabolism on platelet biogenesis and activity and their relevance in atherosclerosis and thrombosis. PMID- 26929276 TI - Hybridization relics complicate barcode-based identification of species in earthworms. AB - Introgressive hybridization results in mito-nuclear discordance which could obscure the delimitation of closely related taxa. Although such events are increasingly reported, they have been poorly studied in earthworms. Here, we propose a method for investigating the degree of introgressive hybridization between three taxa of the Allolobophora chlorotica aggregate within two field populations (N = 67 and N = 105) using a reference data set including published DNA barcoding and microsatellite data of all known A. chlorotica lineages (N = 85). For this, we used both molecular phylogenetic and population genetic approaches. The test of correspondence between mitochondrial cytochrome c oxidase I (COI) lineages and clusters of nuclear microsatellite genotypes allowed individuals to be sorted in three categories (matching, admixed and nonmatching) and additional markers (mitochondrial NADH dehydrogenase subunit 1, nuclear Histone 3 and Internal transcribed Spacer Region 2) were used for phylogenetic reconstructions in order to check assignments. Although 15 admixed individuals were observed, no early-generation hybrids were detected within the two populations. Interestingly, 14 nonmatching individuals (i.e. with a mtDNA haplotype that did not correspond to their nuclear cluster) were detected, a pattern that would result after multiple generations of unidirectional hybridization of female from one taxon to male of the other taxon. Because earthworms are simultaneous hermaphrodites, these events of unidirectional hybridization suggest sterility of the male function in several crosses and highlight that some individuals can be misidentified if reliance is placed on COI barcodes alone. These findings could improve the use of these barcodes in earthworms for species delineation. PMID- 26929275 TI - ADAMTS13-mediated thrombolysis of t-PA-resistant occlusions in ischemic stroke in mice. AB - Rapid vascular recanalization forms the basis for successful treatment of cerebral ischemia. Currently, tissue plasminogen activator (t-PA) is the only approved thrombolytic drug for ischemic stroke. However, t-PA does not always result in efficient thrombus dissolution and subsequent blood vessel recanalization. To better understand thrombus composition, we analyzed thrombi retrieved from ischemic stroke patients and found a distinct presence of von Willebrand factor (VWF) in various samples. Thrombi contained on average 20.3% +/ 10.1% VWF, and this was inversely correlated with thrombus red blood cell content. We hypothesized that ADAMTS13 can exert a thrombolytic effect in VWF containing thrombi in the setting of stroke. To test this, we generated occlusive VWF-rich thrombi in the middle cerebral artery (MCA) of mice. Infusion of t-PA did not dissolve these MCA occlusions. Interestingly, administration of ADAMTS13 5 minutes after occlusion dose-dependently dissolved these t-PA-resistant thrombi resulting in fast restoration of MCA patency and consequently reduced cerebral infarct sizes (P < .005). Delayed ADAMTS13 administration 60 minutes after occlusion was still effective but to a lesser extent (P < .05). These data show for the first time a potent thrombolytic activity of ADAMTS13 in the setting of stroke, which might become useful in treatment of acute ischemic stroke. PMID- 26929274 TI - The level of blast CD33 expression positively impacts the effect of gemtuzumab ozogamicin in patients with acute myeloid leukemia. PMID- 26929277 TI - A quarter of patients with rarer cancers see GPs several times before referral. PMID- 26929278 TI - Melanocytes in psoriasis: convicted culprit or bullied bystander? PMID- 26929279 TI - Aflibercept is better drug for diabetic macular oedema, study finds. PMID- 26929280 TI - Three-Year Results of a Single-Centre Single-Blinded Randomised Study Evaluating the Impact of Mesh Pore Size on Chronic Pain after Lichtenstein Hernioplasty. AB - BACKGROUND AND AIMS: The aim of the present study was to determine whether usage of mesh with larger pores, compared with mesh with smaller pores, would result in a decreased rate of chronic pain at 3-year follow-up. According to earlier published short-term results, differences in mesh pore size do not influence the rate of chronic pain. MATERIAL AND METHODS: The patients were randomized into two study groups for which meshes with similar weight but different pore size were used: the UM group received Ultrapro mesh (pore size 3-4 mm) and the OM group received Optilene LP mesh (pore size 1 mm). Pain scores were measured on a visual analog scale. The feeling of a foreign body was a yes-or-no question. RESULTS: A total of 65 patients in the UM group and 63 patients in the OM group were included in analysis. Of the patients, 33.9% in the UM group and 15.9% in the OM group reported having experienced pain during different activities at 3-year follow-up (P = 0.025). Comparison with the results of 6-month follow-up (46.3% in the UM group, 34.3% in the OM group) showed that the rate of chronic pain had decreased significantly in the OM group (P = 0.009) but not in the UM group (P = 0.113). The feeling of a foreign body in the inguinal region was experienced by 23.1% of the patients in the UM group and by 15.9% in the OM group (P = 0.375). There was one hernia recurrence in the OM group. Severe preoperative pain and younger age were identified as risk factors for development of chronic pain. CONCLUSIONS: Mesh with larger pores, compared with mesh with smaller pores, has no advantages in reducing the rate of chronic pain. We speculate that the reason for the higher rate of chronic pain in the study group where the mesh with larger pores was used might have been the different composition of the meshes at implantation. Also, it is possible as development of chronic pain after inguinal hernia repair is multifactorial, we failed to find a plausible explanation for this difference. Low recurrence rates were achieved with both meshes used in our study. PMID- 26929281 TI - Ultrasound Screening of Men with Coronary Artery Disease for Abdominal Aortic Aneurysms: A Prospective Dual Center Study. AB - BACKGROUND AND AIMS: According to the heterogeneous results of previous studies, the prevalence of abdominal aortic aneurysm seems high among men with coronary artery disease. The associating risk factors for abdominal aortic aneurysm in this population require clarification. Our objective was to assess the prevalence of non-diagnosed abdominal aortic aneurysms in men with angiographically verified coronary artery disease and to document the associated co-morbidities and risk factors. MATERIAL AND METHODS: Altogether, 407 men with coronary artery disease were screened after invasive coronary angiography in two series at independent centers. Risk factor data were recorded and analyzed. RESULTS AND CONCLUSION: The mean age of the study cohort was 70.0 years (standard deviation: 11.0). The prevalence of previously undiagnosed abdominal aortic aneurysms in the whole screened population of 407 men was 6.1% (n = 25/407). In a multivariate analysis of the whole study population, the only significant risk factors for abdominal aortic aneurysm were age (odds ratio: 1.04, 95% confidence interval: 1.00-1.09) and history of smoking (odds ratio: 3.13, 95% confidence interval: 1.26-7.80). Non-smokers with abdominal aortic aneurysm were significantly older than smokers (mean age: 80.7 (standard deviation: 8.0) vs 68.0 (standard deviation: 11.1), p = 0.003), and age was a significant risk factor only among non-smokers (p = 0.011; p = 0.018 for interaction). Among smokers, the prevalence of abdominal aortic aneurysm was 8.8%, and 72% (n = 18/25) of all diagnosed abdominal aortic aneurysm patients were smokers. Prevalence of undiagnosed abdominal aortic aneurysms among patients with coronary artery disease is high, and history of smoking is the most significant risk factor for abdominal aortic aneurysm. Effectiveness of selective screening of abdominal aortic aneurysm in male patients with coronary artery disease warrants further studies. PMID- 26929282 TI - Does the Introduction of Laparoscopic Distal Pancreatectomy Jeopardize Patient Safety and Well-Being? AB - BACKGROUND/PURPOSE: Despite retrospective data indicating short-term superiority for laparoscopic distal pancreatectomy compared to open distal pancreatectomy, the implementation of the procedure has been slow. The aim of this study was to investigate whether patients operated with laparoscopic distal pancreatectomy during the early phase of introduction are at higher risk for complications than patients operated with open distal pancreatectomy. METHODS: A retrospective single-center analysis of patients operated with laparoscopic distal pancreatectomy (n = 37) from the introduction of the procedure and comparison regarding demographic data, preoperative data, operative factors, and postoperative outcomes to patients operated with open distal pancreatectomy was done. RESULTS: Operation duration shortened (195 vs 143 min, p = 0.04) and severe complications reduced (37% vs 6%, p = 0.02) significantly in the laparoscopic distal pancreatectomy group between the first half of the study and the second half. Blood loss was significantly (p < 0.001) lower in the laparoscopic distal pancreatectomy group (75 mL) than in the open distal pancreatectomy group (550 mL), while complication rate and hospital stay as well as the percentage of radical resections were the same. CONCLUSION: Laparoscopic distal pancreatectomy can be introduced without jeopardizing patient safety and well-being during the early learning curve. The procedures should be compared in a prospective randomized manner. PMID- 26929283 TI - Do Treatment Policies for Proximal Humerus Fractures Differ among Three Nordic Countries and Estonia? Results of a Survey Study. AB - BACKGROUND AND PURPOSE: Proximal humerus fractures are common fragility injuries. The incidence of these fractures has been estimated to be 82-105 per 105 person years. Treatment of this fracture, especially in the elderly, is controversial. Our study group published a systematic review of the available literature and concluded that non-operative methods are favored over operative methods in three- and four-part fractures. The aim of this multinational study was to compare treatment policies for proximal humerus fractures among the Nordic countries and Estonia. MATERIALS AND METHODS: The study was conducted as a questionnaire-based survey, using the Internet-based program, Webropol((r)) (webropol.com). The questionnaire link was sent to the surgeons responsible for treating proximal humerus fractures in major public hospitals in Estonia, Finland, Norway, and Sweden. Questionnaire included questions regarding the responder's hospital, patient characteristics, and examinations taken before decision making. Clinical part included eight example patient cases with treatment options. RESULTS: Of the 77 recipients of the questionnaire, 59 responded; consequently, the response rate was 77%. Based on the eight presented displaced fracture examples, in both Estonia and Norway and in Finland, 41% and 38%, respectively, preferred surgical treatment with locking plate. In Sweden, the percentage was 28%. The pre- and post-operative protocols showed a similarity in all participant countries. CONCLUSION: Our survey revealed a remarkable uniformity in the current practice of operative treatments and rehabilitation for proximal humerus fractures in the participant countries. PMID- 26929284 TI - Reconstruction of Vertebral Bone Defects using an Expandable Replacement Device and Bioactive Glass S53P4 in the Treatment of Vertebral Osteomyelitis: Three Patients and Three Pathogens. AB - BACKGROUND AND AIMS: Bioactive glass S53P4 is an antibacterial bone substitute with bone-bonding and osteostimulative properties. The bone substitute has been successfully used clinically in spine; trauma; orthopedic; ear, nose, and throat; and cranio-maxillofacial surgeries. Bioactive glass S53P4 significantly reduces the amount of bacteria in vitro and possesses the capacity to kill both planktonic bacteria and bacteria in biofilm. Three patients with severe spondylodiscitis caused by Mycobacterium tuberculosis, Candida tropicalis, or Staphylococcus aureus were operatively treated due to failed conservative treatment. The vertebral defects were reconstructed using bioactive glass S53P4 and an expandable replacement device. MATERIAL AND METHODS: Decompression and a posterolateral spondylodesis, using transpedicular fixation, were performed posteriorly in combination with an anterior decompression and reconstruction using an expandable vertebral body replacement device. For patients 1 and 2, the expander was covered with bioactive glass S53P4 only, and for patient 3, the glass was mixed with autograft bone. RESULTS: The patients healed well with complete neurological recovery. Fusion was observed for all patients. The total follow-up was 4 years for patient 1, 1 year and 8 months for patient 2, and 2 years and 2 months for patient 3. No relapses or complications were observed. CONCLUSION: The antibacterial properties of bioactive glass S53P4 also make it a suitable bone substitute in the treatment of severe spondylodiscitis. PMID- 26929285 TI - Improved Survival in Male Melanoma Patients in the Era of Sentinel Node Biopsy. AB - BACKGROUND AND AIMS: Sentinel node biopsy is a standard method for nodal staging in patients with clinically localized cutaneous melanoma, but the survival advantage of sentinel node biopsy remains unsolved. The aim of this case-control study was to investigate the survival benefit of sentinel node biopsy. MATERIALS AND METHODS: A total of 305 prospective melanoma patients undergoing sentinel node biopsy were compared with 616 retrospective control patients with clinically localized melanoma whom have not undergone sentinel node biopsy. Survival differences were calculated with the median follow-up time of 71 months in sentinel node biopsy patients and 74 months in control patients. Analyses were calculated overall and separately in males and females. RESULTS: Overall, there were no differences in relapse-free survival or cancer-specific survival between sentinel node biopsy patients and control patients. Male sentinel node biopsy patients had significantly higher relapse-free survival ( P = 0.021) and cancer specific survival ( P = 0.024) than control patients. In females, no differences were found. Cancer-specific survival rates at 5 years were 87.8% in sentinel node biopsy patients and 85.2% in controls overall with 88.3% in male sentinel node biopsy patients and 80.6% in male controls and 87.3% in female sentinel node biopsy patients and 89.8% in female controls. CONCLUSION: Sentinel node biopsy did not improve survival in melanoma patients overall. While females had no differences in survival, males had significantly improved relapse-free survival and cancer-specific survival following sentinel node biopsy. PMID- 26929286 TI - Amended Classification of the Open Abdomen. AB - BACKGROUND: In 2009, a classification system for the open abdomen was introduced. The aim of such a classification is to aid the (1) description of the patient's clinical course; (2) standardization of clinical guidelines for guiding open abdomen management; and (3) facilitation of comparisons between studies and heterogeneous patient populations, thus serving as an aid in clinical research. METHODS: As part of the revision of the definitions and clinical guidelines performed by the World Society of the Abdominal Compartment Syndrome, this 2009 classification system was amended following a review of experiences in teaching and research and published as part of updated consensus statements and clinical practice guidelines in 2013. Among 29 articles citing the 2009 classification system, nine were cohort studies. They were reviewed as part of the classification revision process. A total of 542 patients (mean: 60, range: 9-160) had been classified. Two problems with the previous classification system were identified: the definition of enteroatmospheric fistulae, and that an enteroatmospheric fistula was graded less severe than a frozen abdomen. RESULTS: The following amended classification was proposed: Grade 1, without adherence between bowel and abdominal wall or fixity of the abdominal wall (lateralization), subdivided as follows: 1A, clean; 1B, contaminated; and 1C, with enteric leak. An enteric leak controlled by closure, exteriorization into a stoma, or a permanent enterocutaneous fistula is considered clean. Grade 2, developing fixation, subdivided as follows: 2A, clean; 2B, contaminated; and 2C, with enteric leak. Grade 3, frozen abdomen, subdivided as follows: 3A clean and 3B contaminated. Grade 4, an established enteroatmospheric fistula, is defined as a permanent enteric leak into the open abdomen, associated with granulation tissue. CONCLUSIONS: The authors believe that, with these changes, the requirements on a functional and dynamic classification system, useful in both research and training, will be fulfilled. We encourage future investigators to apply the system and report on its merits and constraints. PMID- 26929287 TI - Hemorrhage after Major Pancreatic Resection: Incidence, Risk Factors, Management, and Outcome. AB - BACKGROUND AND AIMS: Hemorrhage is a rare but dreaded complication after pancreatic surgery. The aim of this study was to examine the incidence, risk factors, management, and outcome of postpancreatectomy hemorrhage in a tertiary care center. MATERIALS AND METHODS: A retrospective observational study was conducted on 500 consecutive patients undergoing major pancreatic resections at our institution. Postpancreatectomy hemorrhage was defined according to the International Study Group of Pancreatic Surgery criteria. RESULTS: A total of 68 patients (13.6%) developed postpancreatectomy hemorrhage. Thirty-four patients (6.8%) had a type A, 15 patients (3.0%) had a type B, and the remaining 19 patients (3.8%) had a type C bleed. Postoperative pancreatic fistula Grades B and C and bile leakage were significantly associated with severe postpancreatectomy hemorrhage on multivariable logistic regression. For patients with postpancreatectomy hemorrhage Grade C, the onset of bleeding was in median 13 days after the index operation, ranging from 1 to 85 days. Twelve patients (63.2%) had sentinel bleeds. Surgery lead to definitive hemostatic control in six of eight patients (75.0%). Angiography was able to localize the bleeding source in 8/10 (80.0%) cases. The success rate of angiographic hemostasis was 8/8. (100.0%). The mortality rate among patients with postpancreatectomy hemorrhage Grade C was 2/19 (10.5%), and both fatalities occurred late as a consequence of eroded vessels in association with pancreaticogastrostomy. CONCLUSION: Delayed hemorrhage is a serious complication after major pancreatic surgery.Sentinel bleed is an early warning sign. Postoperative pancreatic fistula and bile leakage are important risk factors for severe postpancreatectomy hemorrhage. PMID- 26929288 TI - Intraoperatively Testing the Anastomotic Integrity of Esophagojejunostomy Using Methylene Blue. AB - BACKGROUND: Intraoperative testing of gastrointestinal anastomosis effectively ensures anastomotic integrity. This study investigated whether the routine use of methylene blue intraoperatively identified leaks to reduce the postoperative proportion of clinical leaks. METHODS: This study retrospectively analyzed consecutive total gastrectomies performed from January 2007 to December 2014 in a university hospital setting by a general surgical group that exclusively used the methylene blue test. All surgeries were performed for gastric or junctional cancers (n = 198). All reconstructions (Roux-en Y esophagojejunostomy) were performed using a stapler. The methylene blue test was used in 108 cases (group 1) via a nasojejunal tube. No test was performed for the other 90 cases (group 2). Intraoperative leakage rate, postoperative clinical leakage rate, length of hospitalization, and mortality rate were the outcome measures. RESULTS: The intraoperative leakage rate was 7.4% in group 1. The postoperative clinical leakage rate was 8.6%. The postoperative clinical leakage rate was 3.7% in group 1 and 14.4% in group 2 (p = 0.007). There were no postoperative clinical leaks when an intraoperative leak led to concomitant intraoperative repair. The median length of hospital stay was 6 days in group 1 and 8 days in group 2 (p < 0.001). One death occurred in each group. No test-related complications were observed. CONCLUSION: The methylene blue test for esophagojejunostomy is a safe and reliable method for the assessment of anastomosis integrity, especially in cases with difficult esophagojejunostomic construction. PMID- 26929289 TI - Comparison Between Minimally Invasive and Open Gastrectomy for Gastric Cancer in Europe: A Systematic Review and Meta-analysis. AB - AIMS: We compared laparoscopic and robotic gastrectomies with open gastrectomies and with each other that were held for gastric cancer in Europe. METHODS: We searched for studies conducted in Europe and published up to 20 February 2015 in the PubMed database that compared laparoscopic or robotic with open gastrectomies for gastric cancer and with each other. RESULTS: We found 18 original studies (laparoscopic vs open: 13; robotic vs open: 3; laparoscopic vs robotic: 2). Of these, 17 were non-randomized trials and only 1 was a randomized controlled trial. Only four studies had more than 50 patients in each arm. No significant differences were detected between minimally invasive and open approaches regarding the number of retrieved lymph nodes, anastomotic leakage, duodenal stump leakage, anastomotic stenosis, postoperative bleeding, reoperation rates, and intraoperative/postoperative mortality. Nevertheless, laparoscopic procedures provided higher overall morbidity rates when compared with open ones, but robotic approaches did not differ from open ones. On the contrary, blood loss was less and hospital stay was shorter in minimally invasive than in open approaches. However, the results were controversial concerning the duration of operations when comparing minimally invasive with open gastrectomies. Additionally, laparoscopic and robotic procedures provided equivalent results regarding resection margins, duodenal stump leakage, postoperative bleeding, intraoperative/postoperative mortality, and length of hospital stay. On the contrary, robotic operations had less blood loss, but lasted longer than laparoscopic ones. Finally, there were relatively low conversion rates in laparoscopic (0%-6.7%) and robotic gastrectomies (0%-5.6%) in most studies. CONCLUSION: Laparoscopic and robotic gastrectomies may be considered alternative approaches to open gastrectomies for treating gastric cancer. Minimally invasive operations are characterized by less blood loss and shorter hospital stay than open ones. In addition, robotic procedures have less blood loss, but last longer than laparoscopic ones. PMID- 26929290 TI - Tumor Size of Invasive Breast Cancer on Magnetic Resonance Imaging and Conventional Imaging (Mammogram/Ultrasound): Comparison with Pathological Size and Clinical Implications. AB - BACKGROUND AND AIM: In Landspitali University Hospital, magnetic resonance imaging is used non-selectively in addition to mammogram and ultrasound in the preoperative assessment of breast cancer patients. The aim of this study was to assess invasive tumor size on imaging, compare with pathological size and evaluate the impact of magnetic resonance imaging on the type of surgery performed. MATERIAL AND METHODS: All women with invasive breast cancer, diagnosed in Iceland, between 2007 and 2009 were reviewed retrospectively. In all, 438 of 641 (68%) patients diagnosed had preoperative magnetic resonance imaging. Twelve patients treated with neoadjuvant chemotherapy were excluded and 65 patients with multifocal or contralateral disease were assessed separately. RESULTS: Correlations between microscopic and radiologic tumor sizes were relatively weak. All imaging methods were inaccurate especially for large tumors, resulting in an overall underestimation of tumor size for these tumors. Magnetic resonance imaging under- and overestimated pathological tumor size by more than 10 mm in 16/348 (4.6%) and 26/348 patients (7.5%), respectively. In 19 patients (73%), overestimation of size was seen exclusively on magnetic resonance imaging. For tumors under- or overestimated by magnetic resonance imaging, the mastectomy rates were 56% and 65%, respectively, compared to an overall mastectomy rate of 43%. Of 51 patients diagnosed with multifocal disease on pathology, 19 (37%) were diagnosed by mammogram or ultrasound and 40 (78%) by magnetic resonance imaging resulting in a total detection rate of 84% (43 patients). Fourteen (3%) patients were diagnosed preoperatively with contralateral disease. Of those tumors, all were detected on magnetic resonance imaging but seven (50%) were also detected on mammogram or ultrasound or both. CONCLUSION: Our results suggest that routine use of magnetic resonance imaging may result in both under- and overestimation of tumor size and increase mastectomy rates in a small proportion of patients. Magnetic resonance imaging aids in the diagnosis of contralateral and multifocal disease. PMID- 26929291 TI - The Use of Blood Products in Adult Patients with Burns. AB - INTRODUCTION: Burn anemia represents a common complication following a burn injury. Burn anemia etiology carries distinct features occurring at each stage of the post-injury and treatment periods resulting from different causes. We aimed to analyze the use of blood components in Finnish burn victims and to identify patient- and injury-related factors influencing their use. METHODS: To study the use of blood products in burn patients, we used data collected from the Optimal Use of Blood registry, developed through co-operation between 10 major hospital districts and the Finnish Red Cross Blood Service. Burn patients ?18 years treated at the Helsinki University Hospital between 2005 and 2011 with an in hospital stay ?1 day who received at least one transfusion during their hospital stay were included in this study. RESULTS: Among all 558 burn patients, 192 (34%) received blood products during their hospital stay. The transfused cohort comprised 192 burn patients. The study cohort received a total of 6087 units of blood components, 2422 units of leukoreduced red blood cells, 1728 units of leukoreduced platelets, and 420 units of single-donor fresh frozen plasma or, after 2007, 1517 units of Octaplas((r)) frozen plasma. All three types of blood components were administered to 29% of patients, whereas 45% received only red blood cells and 6% received only Octaplas. Transfused patients were significantly older (p < 0.001), experienced fire-/flame-related accidents and burns to multiple locations (p < 0.001), and their in-hospital mortality exceeded that for non-transfused burn patients fivefold (p < 0.05). DISCUSSION: We show that Finnish adult burn patients received ample transfusions. The number of blood components transfused varied according to the anatomical location of the injury and patient survival. Whether the additional mortality is related directly to transfusions or is merely a manifestation of the more severe burn injury remains unknown. PMID- 26929292 TI - Missed Injuries in Polytrauma Patients after Trauma Tertiary Survey in Trauma Intensive Care Unit. AB - BACKGROUND AND AIMS: Injuries are often missed during the primary and secondary surveys in trauma patients. Studies have suggested that a formal tertiary survey protocol lowers the number of missed injuries. Our aim was to determine the number, severity, and consequences of injuries missed by a non-formalized trauma tertiary survey, but detected within 3 months from the date of injury in trauma patients admitted to a trauma intensive care unit. MATERIAL AND METHODS: We conducted a cohort study of trauma patients admitted to a trauma intensive care unit between 1 January and 17 October 2013. We reviewed the electronic medical records of patients admitted to the trauma intensive care unit in order to register any missed injuries, their delay, and possible consequences. We classified injuries into four types: Type 0, injury detected prior to trauma tertiary survey; Type I, injury detected by trauma tertiary survey; Type II, injury missed by trauma tertiary survey but detected prior to discharge; and Type III, injury missed by trauma tertiary survey and detected after discharge. RESULTS: During the study period, we identified a total of 841 injuries in 115 patients. Of these injuries, 93% were Type 0 injuries, 3.9% were Type I injuries, 2.6% were Type II injuries, and 0,1% were Type III injuries. Although most of the missed injuries in trauma tertiary survey (Type II) were fractures (50%), only 2 of the 22 Type II injuries required surgical intervention. Type II injuries presumably did not cause extended length of stay in the intensive care unit or in hospital and/or morbidity. CONCLUSION: In conclusion, the missed injury rate in trauma patients admitted to trauma intensive care unit after trauma tertiary survey was very low in our system without formal trauma tertiary survey protocol. These missed injuries did not lead to prolonged hospital or trauma intensive care unit stay and did not contribute to mortality. Most of the missed injuries received non-surgical treatment. PMID- 26929293 TI - Multivisceral Resection in Patients with Advanced Abdominal Tumors. AB - BACKGROUND/AIM: Multivisceral resection for advanced tumors can result in prolonged survival but may also increase the risk of postoperative morbidity and mortality. The primary aim of this study was to investigate whether extensive resections increase the severity of postoperative complications. MATERIALS AND METHODS: A retrospective study was conducted between 2009 and 2014 at the Linkoping University Hospital surgical department. All patients with a confirmed or presumed malignant disease who underwent a non-standardized surgical procedure requiring a multivisceral resection were included. The primary endpoint was 90 day complications according to the Clavien-Dindo score. RESULTS: Forty-eight patients were included, with an age range of 17-77 years. A median of three organs was resected. The most common diagnoses were neuroendocrine tumor (n = 8), gastric cancer (n = 7), and gastrointestinal stromal tumor (n = 6). One patient died during surgery. Complications ? grade 3b according to Clavien-Dindo score occurred in 10 patients. R0 resection was achieved in 32 patients. No correlation was observed between the number of anastomoses, perioperative blood loss, operative time, and complications. Only postoperative blood transfusion was correlated with severe complications (p = 0.046); however, a tendency toward more complications with an increasing number of resected organs was observed (p = 0.06). CONCLUSION: Multivisceral resection can result in R0, potentially curing patients with advanced tumors. Here, no correlation between extensive resections and complications was observed. Only postoperative blood transfusion was correlated with severe complications. PMID- 26929294 TI - Intracranial Suppurative Complications of Sinusitis. AB - BACKGROUND: Intracranial complications of paranasal sinusitis have become rare due to widespread and early use of antibiotics. Potentially life-threatening intracranial complications of sinusitis include subdural empyema, epidural and intracerebral abscess, meningitis, and sinus thrombosis. Patients with intracranial complication of sinusitis can present without neurological signs, which may delay diagnosis and correct treatment. AIMS: Our aim was to evaluate the diagnostics, treatment, and outcome of sinusitis-related intracranial infections at our tertiary referral hospital with a catchment area of 1.9 million people. MATERIALS AND METHODS: We retrospectively collected data on all patients diagnosed and treated with an intracranial infection at the Helsinki University Hospital, Helsinki, Finland, during a 10-year period between 2003 and 2013. RESULTS: Six patients were diagnosed to have a sinusitis-related intracranial infection. Four patients had an epidural abscess, one both an epidural abscess and a subdural empyema and one a subdural empyema. The most common presenting complaint was headache (100%) followed by fever (83%), vomiting (50%), nasal congestion (50%), forehead lump (34%), and neck stiffness (17%). All patients were managed surgically. Most (83%) patients recovered to premorbid state without neurological sequelae. One patient died intraoperatively. CONCLUSION: Patients with a sinusitis-related intracranial suppuration typically present with signs of raised intracranial pressure rather than signs of sinusitis. Most are likely to need neurosurgical intervention and evacuation of the abscess without delay. PMID- 26929295 TI - Surgical Management of Renal Cell Cancer Liver Metastases. AB - BACKGROUND AND AIMS: There is an increasing trend toward performing liver resections in the setting of metastatic disease. Renal cell cancer liver metastases are associated with poor survival. The indications for and the short- and long-term outcomes of liver resection for renal cell cancer liver metastases remain not well defined. MATERIAL AND METHODS: A focused, structured literature review on PubMed, EMBASE, and Google Scholar was performed to identify primary research articles, on short- and long-term outcomes and prognostic factors of patients undergoing liver resection for renal cell cancer liver metastases. Only studies with a sample size equal or larger than 10 patients were included. RESULTS AND CONCLUSION: A total of 10 studies met inclusion criteria. Median overall survival ranged between 16 and 142 months. Major morbidity was rare while 30-day postoperative mortality was less than 5%. A disease-free interval of more than 2 years from nephrectomy to evidence of liver metastases and a radical, microscopically negative surgical resection (R0) were the most consistent prognostic factors that, in turn, could be used as potential selection criteria to identify patients who can benefit the most from liver-directed surgery. Liver surgery for renal cell cancer liver metastases can be performed with low mortality, acceptable morbidity, and promising survival benefit in carefully selected patients. Studies that can assess the impact of modern, targeted regimens in the preoperative setting and liver-directed surgery and in turn shape new selection criteria are warranted. PMID- 26929296 TI - Associating Liver Partition and Portal Vein Ligation for Primary Hepatobiliary Malignancies and Non-Colorectal Liver Metastases. AB - BACKGROUND AND AIMS: Associating liver partition and portal vein ligation for staged hepatectomy may increase the possibility of radical resection in the case of liver malignancy. Concerns have been raised about the high morbidity and mortality associated with the procedure, particularly when applied for diagnoses other than colorectal liver metastases. The aim of this study was to analyze the initial experience with associating liver partition and portal vein ligation for staged hepatectomy in cases of non-colorectal liver metastases and primary hepatobiliary malignancies in Scandinavia. MATERIALS AND METHODS: A retrospective analysis of all associating liver partition and portal vein ligation for staged hepatectomy procedures performed at two Swedish university hospitals for non colorectal liver metastases and primary hepatobiliary malignancies was performed. The primary focus was on the safety of the procedure. RESULTS AND CONCLUSION: Ten patients were included: four had hepatocellular cancer, three had intrahepatic cholangiocarcinoma, one had a Klatskin tumor, one had ocular melanoma metastasis, and one had a metastasis from a Wilms' tumor. All patients completed both operations, and the highest grade of complication (according to the Clavien-Dindo classification) was 3A, which was observed in one patient. No 90-day mortality was observed. Radical resection (R0) was achieved in nine patients, while the resection was R2 in one patient. The low morbidity and mortality observed in this cohort compared with those of earlier reports on associating liver partition and portal vein ligation for staged hepatectomy for diagnoses other than colorectal liver metastases may be related to the selection of patients with limited comorbidity. In addition, procedures other than associating liver partition and portal vein ligation for staged hepatectomy had been avoided in most of the patients. In conclusion, associating liver partition and portal vein ligation for staged hepatectomy can be applied to primary hepatobiliary malignancies and non colorectal liver metastases with acceptable rates of morbidity and mortality. PMID- 26929297 TI - Use of Laparoscopy in Gastrointestinal Surgery in Sweden 1998-2014: A Nationwide Study. AB - BACKGROUND AND AIMS: One by one, minimally invasive alternatives to established gastrointestinal procedures have become clinical routine. We have studied the use of laparoscopy in four common procedures-cholecystectomy, appendectomy, reflux surgery, and bariatric surgery-as well as in major resectional gastrointestinal surgery in Sweden. MATERIALS AND METHODS: The National Patient Registry was used to identify all in-hospital procedures performed in patients above the age of 15 during 1998-2014, meeting our inclusion criteria. For each group, the annual number of procedures and proportion of laparoscopic surgery were studied, as well as applicable subgroups. Differences in age, gender, as well as geographical differences were evaluated in the most recent 3-year period (2012-2014). RESULTS: In total, 537,817 procedures were studied, 43% by laparoscopic approach. In 2012 2014, the proportion of laparoscopic surgery ranged from high rates in the four common procedures (cholecystectomy 81%, appendectomy 47%, reflux surgery 72%, and bariatric surgery 97%) to rather low numbers in resectional surgery (4%-10%), however, increasing in the last years. In appendectomy and cholecystectomy, men were less likely to have laparoscopic surgery (42% versus 51% and 74% versus 85%, respectively, p < 0.001). Substantial geographical differences in the use of laparoscopy were also noted, for example, the proportion of laparoscopic appendectomy varied from 11% to 76% among the 21 different Swedish counties. CONCLUSION: The proportion of laparoscopy was high in the four common procedures and low, but rising, in major resectional surgery. A large variation in the proportion of laparoscopic surgery by age, gender, and place of residence was noted. PMID- 26929298 TI - Functional Role of N- and C-Terminal Amino Acids in the Structural Subunits of Colonization Factor CS6 Expressed by Enterotoxigenic Escherichia coli. AB - CS6 is a common colonization factor expressed by enterotoxigenic Escherichia coli It is a two-subunit protein consisting of CssA and CssB in an equal stoichiometry, assembled via the chaperone-usher pathway into an afimbrial, oligomeric assembly on the bacterial cell surface. A recent structural study has predicted the involvement of the N- and C-terminal regions of the CS6 subunits in its assembly. Here, we identified the functionally important residues in the N- and C-terminal regions of the CssA and CssB subunits during CS6 assembly by alanine scanning mutagenesis. Bacteria expressing mutant proteins were tested for binding with Caco-2 cells, and the results were analyzed with respect to the surface expression of mutant CS6. In this assay, many mutant proteins were not expressed on the surface while some showed reduced expression. It appeared that some, but not all, of the residues in both the N and C termini of CssA and CssB played an important role in the intermolecular interactions between these two structural subunits, as well as chaperone protein CssC. Our results demonstrated that T20, K25, F27, S36, Y143, and V147 were important for the stability of CssA, probably through interaction of CssC. We also found that I22, V29, and I33 of CssA and G154, Y156, L160, V162, F164, and Y165 of CssB were responsible for CssA CssB intermolecular interactions. In addition, some of the hydrophobic residues in the C terminus of CssA and the N terminus of CssB were involved in the stabilization of higher-order complex formation. Overall, the results presented here might help in understanding the pathway used to assemble CS6 and predict its structure. IMPORTANCE: Unlike most other colonization factors, CS6 is nonfimbrial, and in a sense, its subunit composition and assembly are also unique. Here we report that both the N- and C-terminal amino acid residues of CssA and CssB play a critical role in the intermolecular interactions between them and assembly proteins. We found mainly that alternate hydrophobic residues present in these motifs are essential for the interaction between the structural subunits, as well as the chaperone and usher assembly proteins. Our results indicate the involvement of the side chains of identified amino acids in CS6 assembly. This study adds a step toward understanding the interactions between structural subunits of CS6 and assembly proteins during CS6 biogenesis. PMID- 26929299 TI - Carbon Fixation Driven by Molecular Hydrogen Results in Chemolithoautotrophically Enhanced Growth of Helicobacter pylori. AB - A molecular hydrogen (H2)-stimulated, chemolithoautotrophic growth mode for the gastric pathogen Helicobacter pylori is reported. In a culture medium containing peptides and amino acids, H2-supplied cells consistently achieved 40 to 60% greater growth yield in 16 h and accumulated 3-fold more carbon from [(14)C]bicarbonate (on a per cell basis) in a 10-h period than cells without H2 Global proteomic comparisons of cells supplied with different atmospheric conditions revealed that addition of H2 led to increased amounts of hydrogenase and the biotin carboxylase subunit of acetyl coenzyme A (acetyl-CoA) carboxylase (ACC), as well as other proteins involved in various cellular functions, including amino acid metabolism, heme synthesis, or protein degradation. In agreement with this result, H2-supplied cells contained 3-fold more ACC activity than cells without H2 Other possible carbon dioxide (CO2) fixation enzymes were not up-expressed under the H2-containing atmosphere. As the gastric mucus is limited in carbon and energy sources and the bacterium lacks mucinase, this new growth mode may contribute to the persistence of the pathogen in vivo This is the first time that chemolithoautotrophic growth is described for a pathogen. IMPORTANCE: Many pathogens must survive within host areas that are poorly supplied with carbon and energy sources, and the gastric pathogen Helicobacter pylori resides almost exclusively in the nutritionally stringent mucus barrier of its host. Although this bacterium is already known to be highly adaptable to gastric niches, a new aspect of its metabolic flexibility, whereby molecular hydrogen use (energy) is coupled to carbon dioxide fixation (carbon acquisition) via a described carbon fixation enzyme, is shown here. This growth mode, which supplements heterotrophy, is termed chemolithoautotrophy and has not been previously reported for a pathogen. PMID- 26929300 TI - Vfr Directly Activates exsA Transcription To Regulate Expression of the Pseudomonas aeruginosa Type III Secretion System. AB - The Pseudomonas aeruginosa cyclic AMP (cAMP)-Vfr system (CVS) is a global regulator of virulence gene expression. Regulatory targets include type IV pili, secreted proteases, and the type III secretion system (T3SS). The mechanism by which CVS regulates T3SS gene expression remains undefined. Single-cell expression studies previously found that only a portion of the cells within a population express the T3SS under inducing conditions, a property known as bistability. We now report that bistability is altered in avfr mutant, wherein a substantially smaller fraction of the cells express the T3SS relative to the parental strain. Since bistability usually involves positive-feedback loops, we tested the hypothesis that virulence factor regulator (Vfr) regulates the expression of exsA ExsA is the central regulator of T3SS gene expression and autoregulates its own expression. Although exsA is the last gene of the exsCEBA polycistronic mRNA, we demonstrate that Vfr directly activates exsA transcription from a second promoter (PexsA) located immediately upstream of exsA PexsA promoter activity is entirely Vfr dependent. Direct binding of Vfr to a PexsA promoter probe was demonstrated by electrophoretic mobility shift assays, and DNase I footprinting revealed an area of protection that coincides with a putative Vfr consensus-binding site. Mutagenesis of that site disrupted Vfr binding and PexsA promoter activity. We conclude that Vfr contributes to T3SS gene expression through activation of the PexsA promoter, which is internal to the previously characterized exsCEBA operon. IMPORTANCE: Vfr is a cAMP-dependent DNA-binding protein that functions as a global regulator of virulence gene expression in Pseudomonas aeruginosa Regulation by Vfr allows for the coordinate production of related virulence functions, such as type IV pili and type III secretion, required for adherence to and intoxication of host cells, respectively. Although the molecular mechanism of Vfr regulation has been defined for many target genes, a direct link between Vfr and T3SS gene expression had not been established. In the present study, we report that Vfr directly controls exsA transcription, the master regulator of T3SS gene expression, from a newly identified promoter located immediately upstream of exsA. PMID- 26929303 TI - Taking aspirin before coronary artery surgery does not increase deaths or bleeding, study shows. PMID- 26929301 TI - Friendly Fire: Biological Functions and Consequences of Chromosomal Targeting by CRISPR-Cas Systems. AB - Clustered regularly interspaced short palindromic repeat (CRISPR)-associated (Cas) systems in bacteria and archaea target foreign elements, such as bacteriophages and conjugative plasmids, through the incorporation of short sequences (termed spacers) from the foreign element into the CRISPR array, thereby allowing sequence-specific targeting of the invader. Thus, CRISPR-Cas systems are typically considered a microbial adaptive immune system. While many of these incorporated spacers match targets on bacteriophages and plasmids, a noticeable number are derived from chromosomal DNA. While usually lethal to the self-targeting bacteria, in certain circumstances, these self-targeting spacers can have profound effects in regard to microbial biology, including functions beyond adaptive immunity. In this minireview, we discuss recent studies that focus on the functions and consequences of CRISPR-Cas self-targeting, including reshaping of the host population, group behavior modification, and the potential applications of CRISPR-Cas self-targeting as a tool in microbial biotechnology. Understanding the effects of CRISPR-Cas self-targeting is vital to fully understanding the spectrum of function of these systems. PMID- 26929304 TI - Neurological services need urgent attention, say MPs. PMID- 26929302 TI - A Membrane-Embedded Amino Acid Couples the SpoIIQ Channel Protein to Anti-Sigma Factor Transcriptional Repression during Bacillus subtilis Sporulation. AB - SpoIIQ is an essential component of a channel connecting the developing forespore to the adjacent mother cell during Bacillus subtilis sporulation. This channel is generally required for late gene expression in the forespore, including that directed by the late-acting sigma factor sigma(G) Here, we present evidence that SpoIIQ also participates in a previously unknown gene regulatory circuit that specifically represses expression of the gene encoding the anti-sigma factor CsfB, a potent inhibitor of sigma(G) The csfB gene is ordinarily transcribed in the forespore only by the early-acting sigma factor sigma(F) However, in a mutant lacking the highly conserved SpoIIQ transmembrane amino acid Tyr-28, csfB was also aberrantly transcribed later by sigma(G), the very target of CsfB inhibition. This regulation of csfB by SpoIIQ Tyr-28 is specific, given that the expression of other sigma(F)-dependent genes was unaffected. Moreover, we identified a conserved element within the csfB promoter region that is both necessary and sufficient for SpoIIQ Tyr-28-mediated inhibition. These results indicate that SpoIIQ is a bifunctional protein that not only generally promotes sigma(G)activity in the forespore as a channel component but also specifically maximizes sigma(G)activity as part of a gene regulatory circuit that represses sigma(G)-dependent expression of its own inhibitor, CsfB. Finally, we demonstrate that SpoIIQ Tyr-28 is required for the proper localization and stability of the SpoIIE phosphatase, raising the possibility that these two multifunctional proteins cooperate to fine-tune developmental gene expression in the forespore at late times. IMPORTANCE: Cellular development is orchestrated by gene regulatory networks that activate or repress developmental genes at the right time and place. Late gene expression in the developing Bacillus subtilis spore is directed by the alternative sigma factor sigma(G) The activity of sigma(G)requires a channel apparatus through which the adjacent mother cell provides substrates that generally support gene expression. Here we report that the channel protein SpoIIQ also specifically maximizes sigma(G)activity as part of a previously unknown regulatory circuit that prevents sigma(G)from activating transcription of the gene encoding its own inhibitor, the anti-sigma factor CsfB. The discovery of this regulatory circuit significantly expands our understanding of the gene regulatory network controlling late gene expression in the developing B. subtilis spore. PMID- 26929305 TI - Afatinib in the first-line treatment of epidermal-growth-factor-receptor mutation positive non-small cell lung cancer: a review of the clinical evidence. AB - First-line afatinib significantly improved progression-free survival, patient reported outcomes, and quality of life compared with chemotherapy regimens in patients with advanced epidermal-growth-factor-receptor (EGFR) mutation-positive non-small cell lung cancer, based on results of the LUX-Lung 3 and LUX-Lung 6 trials. When the analysis of these trials was restricted to patients with common EGFR mutations only (exon 19 deletions and L858R), the advantage over chemotherapy was even more pronounced. A significant overall survival advantage was firstly demonstrated versus chemotherapy in patients with non-small cell lung cancer-harboring EGFR exon 19 deletion (del19) mutations. First-line afatinib was also effective in patients with certain uncommon EGFR mutation and patients with central nervous system metastasis. So far, these data are not sufficient to conclude that afatinib is better than first-generation EGFR inhibitors. In addition, the toxicity profile of afatinib was somewhat worse than that observed with either erlotinib or gefitinib. In the absence of direct comparisons, for each patient the choice among the available EGFR inhibitors should take into account all the clinically relevant endpoints, including disease control, survival prolongation, tolerability, and quality of life. PMID- 26929307 TI - The Experience of Cancer in American Indians Living in Oklahoma. AB - Many cancers in American Indians (AIs) are not diagnosed early leading to effects on physical, social, and emotional well-being or quality of life (QOL). Little research has been done on QOL of AIs in Oklahoma. This study examined the experience of living with cancer of AIs in Oklahoma to gain greater understanding of QOL issues and provide a basis for interventions to improve QOL. Twenty AIs diagnosed with cancer and receiving care in Oklahoma participated in this pilot study through semistructured interviews. Data were analyzed using thematic analysis. Themes identified included circles of support, finding meaning in the experience, and facing personal challenges such as health care-related issues, including mental health needs and fragmented care. The findings from this pilot study provide insights into the cancer experience of AIs in Oklahoma and demonstrate that care navigation and social support are important aspects to address in intervention development. PMID- 26929308 TI - The European Respiratory Society evaluates its 2013-2018 strategic plan implementation. PMID- 26929309 TI - Accuracy of diagnostic testing in primary ciliary dyskinesia: are we there yet? PMID- 26929310 TI - Clinical significance and management of right heart thrombi: more questions than answers. PMID- 26929311 TI - Diagnostics for latent TB infection: incremental, not transformative progress. PMID- 26929306 TI - Novel approaches to the management of noneosinophilic asthma. AB - Noneosinophilic airway inflammation occurs in approximately 50% of patients with asthma. It is subdivided into neutrophilic or paucigranulocytic inflammation, although the proportion of each subtype is uncertain because of variable cut-off points used to define neutrophilia. This article reviews the evidence for noneosinophilic inflammation being a target for therapy in asthma and assesses clinical trials of licensed drugs, novel small molecules and biologics agents in noneosinophilic inflammation. Current symptoms, rate of exacerbations and decline in lung function are generally less in noneosinophilic asthma than eosinophilic asthma. Noneosinophilic inflammation is associated with corticosteroid insensitivity. Neutrophil activation in the airways and systemic inflammation is reported in neutrophilic asthma. Neutrophilia in asthma may be due to corticosteroids, associated chronic pulmonary infection, altered airway microbiome or delayed neutrophil apoptosis. The cause of poorly controlled noneosinophilic asthma may differ between patients and involve several mechanism including neutrophilic inflammation, T helper 2 (Th2)-low or other subtypes of airway inflammation or corticosteroid insensitivity as well as noninflammatory pathways such as airway hyperreactivity and remodelling. Smoking cessation in asthmatic smokers and removal from exposure to some occupational agents reduces neutrophilic inflammation. Preliminary studies of 'off-label' use of licensed drugs suggest that macrolides show efficacy in nonsmokers with noneosinophilic severe asthma and statins, low-dose theophylline and peroxisome proliferator activated receptor gamma (PPARgamma) agonists may benefit asthmatic smokers with noneosinophilic inflammation. Novel small molecules targeting neutrophilic inflammation, such as chemokine (CXC) receptor 2 (CXCR2) antagonists reduce neutrophils, but do not improve clinical outcomes in studies to date. Inhaled phosphodiesterase (PDE)4 inhibitors, dual PDE3 and PDE4 inhibitors, p38MAPK (mitogen-activated protein kinase) inhibitors, tyrosine kinase inhibitors and PI (phosphoinositide) 3kinase inhibitors are under development and these compounds may be of benefit in noneosinophilic inflammation. The results of clinical trials of biological agents targeting mediators associated with noneosinophilic inflammation, such as interleukin (IL)-17 and tumor necrosis factor (TNF)-alpha are disappointing. Greater understanding of the mechanisms of noneosinophilic inflammation in asthma should lead to improved therapies. PMID- 26929312 TI - Specific antigen(s) in sarcoidosis: a link to autoimmunity? PMID- 26929313 TI - Catch-up alveolar development into adulthood: also in those born prematurely? PMID- 26929314 TI - A model for active and healthy ageing with a rare genetic disease: cystic fibrosis. PMID- 26929315 TI - Histological grading in lung cancer: one system for all or separate systems for each histological type? PMID- 26929316 TI - Practical tools for implementing early palliative care in advanced lung cancer. PMID- 26929317 TI - Paradoxical decrease in isoprostane and increase in superoxide dismutase following CPAP withdrawal in OSA. PMID- 26929318 TI - Paradoxical decrease in isoprostane and increase in superoxide dismutase following CPAP withdrawal in OSA. PMID- 26929320 TI - Unnatural paradigm calls into question whether macaques' social decisions represent empathy. PMID- 26929323 TI - Correction for Baggen et al., Enterovirus D68 receptor requirements unveiled by haploid genetics. PMID- 26929321 TI - High-throughput small molecule screen identifies inhibitors of aberrant chromatin accessibility. AB - Mutations in chromatin-modifying proteins and transcription factors are commonly associated with a wide variety of cancers. Through gain- or loss-of-function, these mutations may result in characteristic alterations of accessible chromatin, indicative of shifts in the landscape of regulatory elements genome-wide. The identification of compounds that reverse a specific chromatin signature could lead to chemical probes or potential therapies. To explore whether chromatin accessibility could serve as a platform for small molecule screening, we adapted formaldehyde-assisted isolation of regulatory elements (FAIRE), a chemical method to enrich for nucleosome-depleted genomic regions, as a high-throughput, automated assay. After demonstrating the validity and robustness of this approach, we applied this method to screen an epigenetically targeted small molecule library by evaluating regions of aberrant nucleosome depletion mediated by EWSR1-FLI1, the chimeric transcription factor critical for the bone and soft tissue tumor Ewing sarcoma. As a class, histone deacetylase inhibitors were greatly overrepresented among active compounds. These compounds resulted in diminished accessibility at targeted sites by disrupting transcription of EWSR1 FLI1. Capitalizing on precise differences in chromatin accessibility for drug discovery efforts offers significant advantages because it does not depend on the a priori selection of a single molecular target and may detect novel biologically relevant pathways. PMID- 26929324 TI - Mushrooms use convectively created airflows to disperse their spores. AB - Thousands of basidiomycete fungal species rely on mushroom spores to spread across landscapes. It has long been thought that spores depend on favorable winds for dispersal--that active control of spore dispersal by the parent fungus is limited to an impulse delivered to the spores to carry them clear of the gill surface. Here we show that evaporative cooling of the air surrounding the pileus creates convective airflows capable of carrying spores at speeds of centimeters per second. Convective cells can transport spores from gaps that may be only 1 cm high and lift spores 10 cm or more into the air. This work reveals how mushrooms tolerate and even benefit from crowding and explains their high water needs. PMID- 26929322 TI - Novel genomic island modifies DNA with 7-deazaguanine derivatives. AB - The discovery of ~20-kb gene clusters containing a family of paralogs of tRNA guanosine transglycosylase genes, called tgtA5, alongside 7-cyano-7-deazaguanine (preQ0) synthesis and DNA metabolism genes, led to the hypothesis that 7 deazaguanine derivatives are inserted in DNA. This was established by detecting 2'-deoxy-preQ0 and 2'-deoxy-7-amido-7-deazaguanosine in enzymatic hydrolysates of DNA extracted from the pathogenic, Gram-negative bacteria Salmonella enterica serovar Montevideo. These modifications were absent in the closely related S. enterica serovar Typhimurium LT2 and from a mutant of S Montevideo, each lacking the gene cluster. This led us to rename the genes of the S. Montevideo cluster as dpdA-K for 7-deazapurine in DNA. Similar gene clusters were analyzed in ~150 phylogenetically diverse bacteria, and the modifications were detected in DNA from other organisms containing these clusters, including Kineococcus radiotolerans, Comamonas testosteroni, and Sphingopyxis alaskensis Comparative genomic analysis shows that, in Enterobacteriaceae, the cluster is a genomic island integrated at the leuX locus, and the phylogenetic analysis of the TgtA5 family is consistent with widespread horizontal gene transfer. Comparison of transformation efficiencies of modified or unmodified plasmids into isogenic S. Montevideo strains containing or lacking the cluster strongly suggests a restriction-modification role for the cluster in Enterobacteriaceae. Another preQ0 derivative, 2'-deoxy-7-formamidino-7-deazaguanosine, was found in the Escherichia coli bacteriophage 9 g, as predicted from the presence of homologs of genes involved in the synthesis of the archaeosine tRNA modification. These results illustrate a deep and unexpected evolutionary connection between DNA and tRNA metabolism. PMID- 26929325 TI - Immunoproteasome deficiency is a feature of non-small cell lung cancer with a mesenchymal phenotype and is associated with a poor outcome. AB - The immunoproteasome plays a key role in generation of HLA peptides for T cell mediated immunity. Integrative genomic and proteomic analysis of non-small cell lung carcinoma (NSCLC) cell lines revealed significantly reduced expression of immunoproteasome components and their regulators associated with epithelial to mesenchymal transition. Low expression of immunoproteasome subunits in early stage NSCLC patients was associated with recurrence and metastasis. Depleted repertoire of HLA class I-bound peptides in mesenchymal cells deficient in immunoproteasome components was restored with either IFNgamma or 5-aza-2' deoxycytidine (5-aza-dC) treatment. Our findings point to a mechanism of immune evasion of cells with a mesenchymal phenotype and suggest a strategy to overcome immune evasion through induction of the immunoproteasome to increase the cellular repertoire of HLA class I-bound peptides. PMID- 26929327 TI - Pressure-induced superconductivity in a three-dimensional topological material ZrTe5. AB - As a new type of topological materials, ZrTe5 shows many exotic properties under extreme conditions. Using resistance and ac magnetic susceptibility measurements under high pressure, while the resistance anomaly near 128 K is completely suppressed at 6.2 GPa, a fully superconducting transition emerges. The superconducting transition temperature Tc increases with applied pressure, and reaches a maximum of 4.0 K at 14.6 GPa, followed by a slight drop but remaining almost constant value up to 68.5 GPa. At pressures above 21.2 GPa, a second superconducting phase with the maximum Tc of about 6.0 K appears and coexists with the original one to the maximum pressure studied in this work. In situ high pressure synchrotron X-ray diffraction and Raman spectroscopy combined with theoretical calculations indicate the observed two-stage superconducting behavior is correlated to the structural phase transition from ambient Cmcm phase to high pressure C2/m phase around 6 GPa, and to a mixture of two high-pressure phases of C2/m and P-1 above 20 GPa. The combination of structure, transport measurement, and theoretical calculations enable a complete understanding of the emerging exotic properties in 3D topological materials under extreme environments. PMID- 26929326 TI - Actomyosin dynamics drive local membrane component organization in an in vitro active composite layer. AB - The surface of a living cell provides a platform for receptor signaling, protein sorting, transport, and endocytosis, whose regulation requires the local control of membrane organization. Previous work has revealed a role for dynamic actomyosin in membrane protein and lipid organization, suggesting that the cell surface behaves as an active composite composed of a fluid bilayer and a thin film of active actomyosin. We reconstitute an analogous system in vitro that consists of a fluid lipid bilayer coupled via membrane-associated actin-binding proteins to dynamic actin filaments and myosin motors. Upon complete consumption of ATP, this system settles into distinct phases of actin organization, namely bundled filaments, linked apolar asters, and a lattice of polar asters. These depend on actin concentration, filament length, and actin/myosin ratio. During formation of the polar aster phase, advection of the self-organizing actomyosin network drives transient clustering of actin-associated membrane components. Regeneration of ATP supports a constitutively remodeling actomyosin state, which in turn drives active fluctuations of coupled membrane components, resembling those observed at the cell surface. In a multicomponent membrane bilayer, this remodeling actomyosin layer contributes to changes in the extent and dynamics of phase-segregating domains. These results show how local membrane composition can be driven by active processes arising from actomyosin, highlighting the fundamental basis of the active composite model of the cell surface, and indicate its relevance to the study of membrane organization. PMID- 26929328 TI - Biophysical principles predict fitness landscapes of drug resistance. AB - Fitness landscapes of drug resistance constitute powerful tools to elucidate mutational pathways of antibiotic escape. Here, we developed a predictive biophysics-based fitness landscape of trimethoprim (TMP) resistance for Escherichia coli dihydrofolate reductase (DHFR). We investigated the activity, binding, folding stability, and intracellular abundance for a complete set of combinatorial DHFR mutants made out of three key resistance mutations and extended this analysis to DHFR originated from Chlamydia muridarum and Listeria grayi We found that the acquisition of TMP resistance via decreased drug affinity is limited by a trade-off in catalytic efficiency. Protein stability is concurrently affected by the resistant mutants, which precludes a precise description of fitness from a single molecular trait. Application of the kinetic flux theory provided an accurate model to predict resistance phenotypes (IC50) quantitatively from a unique combination of the in vitro protein molecular properties. Further, we found that a controlled modulation of the GroEL/ES chaperonins and Lon protease levels affects the intracellular steady-state concentration of DHFR in a mutation-specific manner, whereas IC50 is changed proportionally, as indeed predicted by the model. This unveils a molecular rationale for the pleiotropic role of the protein quality control machinery on the evolution of antibiotic resistance, which, as we illustrate here, may drastically confound the evolutionary outcome. These results provide a comprehensive quantitative genotype-phenotype map for the essential enzyme that serves as an important target of antibiotic and anticancer therapies. PMID- 26929329 TI - Ablation of sensory neurons in a genetic model of pancreatic ductal adenocarcinoma slows initiation and progression of cancer. AB - Pancreatic ductal adenocarcinoma (PDAC) is characterized by an exuberant inflammatory desmoplastic response. The PDAC microenvironment is complex, containing both pro- and antitumorigenic elements, and remains to be fully characterized. Here, we show that sensory neurons, an under-studied cohort of the pancreas tumor stroma, play a significant role in the initiation and progression of the early stages of PDAC. Using a well-established autochthonous model of PDAC (PKC), we show that inflammation and neuronal damage in the peripheral and central nervous system (CNS) occurs as early as the pancreatic intraepithelial neoplasia (PanIN) 2 stage. Also at the PanIN2 stage, pancreas acinar-derived cells frequently invade along sensory neurons into the spinal cord and migrate caudally to the lower thoracic and upper lumbar regions. Sensory neuron ablation by neonatal capsaicin injection prevented perineural invasion (PNI), astrocyte activation, and neuronal damage, suggesting that sensory neurons convey inflammatory signals from Kras-induced pancreatic neoplasia to the CNS. Neuron ablation in PKC mice also significantly delayed PanIN formation and ultimately prolonged survival compared with vehicle-treated controls (median survival, 7.8 vs. 4.5 mo; P = 0.001). These data establish a reciprocal signaling loop between the pancreas and nervous system, including the CNS, that supports inflammation associated with oncogenic Kras-induced neoplasia. Thus, pancreatic sensory neurons comprise an important stromal cell population that supports the initiation and progression of PDAC and may represent a potential target for prevention in high-risk populations. PMID- 26929330 TI - Junctophilin-4, a component of the endoplasmic reticulum-plasma membrane junctions, regulates Ca2+ dynamics in T cells. AB - Orai1 and stromal interaction molecule 1 (STIM1) mediate store-operated Ca(2+) entry (SOCE) in immune cells. STIM1, an endoplasmic reticulum (ER) Ca(2+) sensor, detects store depletion and interacts with plasma membrane (PM)-resident Orai1 channels at the ER-PM junctions. However, the molecular composition of these junctions in T cells remains poorly understood. Here, we show that junctophilin-4 (JP4), a member of junctional proteins in excitable cells, is expressed in T cells and localized at the ER-PM junctions to regulate Ca(2+) signaling. Silencing or genetic manipulation of JP4 decreased ER Ca(2+) content and SOCE in T cells, impaired activation of the nuclear factor of activated T cells (NFAT) and extracellular signaling-related kinase (ERK) signaling pathways, and diminished expression of activation markers and cytokines. Mechanistically, JP4 directly interacted with STIM1 via its cytoplasmic domain and facilitated its recruitment into the junctions. Accordingly, expression of this cytoplasmic fragment of JP4 inhibited SOCE. Furthermore, JP4 also formed a complex with junctate, a Ca(2+)-sensing ER-resident protein, previously shown to mediate STIM1 recruitment into the junctions. We propose that the junctate-JP4 complex located at the junctions cooperatively interacts with STIM1 to maintain ER Ca(2+) homeostasis and mediate SOCE in T cells. PMID- 26929332 TI - Structural basis for DNA cleavage by the potent antiproliferative agent (-) lomaiviticin A. AB - (-)-Lomaiviticin A (1) is a complex antiproliferative metabolite that inhibits the growth of many cultured cancer cell lines at low nanomolar-picomolar concentrations. (-)-Lomaiviticin A (1) possesses a C2-symmetric structure that contains two unusual diazotetrahydrobenzo[b]fluorene (diazofluorene) functional groups. Nucleophilic activation of each diazofluorene within 1 produces vinyl radical intermediates that affect hydrogen atom abstraction from DNA, leading to the formation of DNA double-strand breaks (DSBs). Certain DNA DSB repair deficient cell lines are sensitized toward 1, and 1 is under evaluation in preclinical models of these tumor types. However, the mode of binding of 1 to DNA had not been determined. Here we elucidate the structure of a 1:1 complex between 1 and the duplex d(GCTATAGC)2 by NMR spectroscopy and computational modeling. Unexpectedly, we show that both diazofluorene residues of 1 penetrate the duplex. This binding disrupts base pairing leading to ejection of the central AT bases, while placing the proreactive centers of 1 in close proximity to each strand. DNA binding may also enhance the reactivity of 1 toward nucleophilic activation through steric compression and conformational restriction (an example of shape dependent catalysis). This study provides a structural basis for the DNA cleavage activity of 1, will guide the design of synthetic DNA-activated DNA cleavage agents, and underscores the utility of natural products to reveal novel modes of small molecule-DNA association. PMID- 26929331 TI - Crosstalk between the lipopolysaccharide and phospholipid pathways during outer membrane biogenesis in Escherichia coli. AB - The outer membrane of gram-negative bacteria is composed of phospholipids in the inner leaflet and lipopolysaccharides (LPS) in the outer leaflet. LPS is an endotoxin that elicits a strong immune response from humans, and its biosynthesis is in part regulated via degradation of LpxC (EC 3.5.1.108) and WaaA (EC 2.4.99.12/13) enzymes by the protease FtsH (EC 3.4.24.-). Because the synthetic pathways for both molecules are complex, in addition to being produced in strict ratios, we developed a computational model to interrogate the regulatory mechanisms involved. Our model findings indicate that the catalytic activity of LpxK (EC 2.7.1.130) appears to be dependent on the concentration of unsaturated fatty acids. This is biologically important because it assists in maintaining LPS/phospholipids homeostasis. Further crosstalk between the phospholipid and LPS biosynthetic pathways was revealed by experimental observations that LpxC is additionally regulated by an unidentified protease whose activity is independent of lipid A disaccharide concentration (the feedback source for FtsH-mediated LpxC regulation) but could be induced in vitro by palmitic acid. Further experimental analysis provided evidence on the rationale for WaaA regulation. Overexpression of waaA resulted in increased levels of 3-deoxy-d-manno-oct-2-ulosonic acid (Kdo) sugar in membrane extracts, whereas Kdo and heptose levels were not elevated in LPS. This implies that uncontrolled production of WaaA does not increase the LPS production rate but rather reglycosylates lipid A precursors. Overall, the findings of this work provide previously unidentified insights into the complex biogenesis of the Escherichia coli outer membrane. PMID- 26929334 TI - Gold surfaces and nanoparticles are protected by Au(0)-thiyl species and are destroyed when Au(I)-thiolates form. AB - The synthetic chemistry and spectroscopy of sulfur-protected gold surfaces and nanoparticles is analyzed, indicating that the electronic structure of the interface is Au(0)-thiyl, with Au(I)-thiolates identified as high-energy excited surface states. Density-functional theory indicates that it is the noble character of gold and nanoparticle surfaces that destabilizes Au(I)-thiolates. Bonding results from large van der Waals forces, influenced by covalent bonding induced through s-d hybridization and charge polarization effects that perturbatively mix in some Au(I)-thiolate character. A simple method for quantifying these contributions is presented, revealing that a driving force for nanoparticle growth is nobleization, minimizing Au(I)-thiolate involvement. Predictions that Brust-Schiffrin reactions involve thiolate anion intermediates are verified spectroscopically, establishing a key feature needed to understand nanoparticle growth. Mixing of preprepared Au(I) and thiolate reactants always produces Au(I)-thiolate thin films or compounds rather than monolayers. Smooth links to O, Se, Te, C, and N linker chemistry are established. PMID- 26929333 TI - Critical role for Epac1 in inflammatory pain controlled by GRK2-mediated phosphorylation of Epac1. AB - cAMP signaling plays a key role in regulating pain sensitivity. Here, we uncover a previously unidentified molecular mechanism in which direct phosphorylation of the exchange protein directly activated by cAMP 1 (EPAC1) by G protein kinase 2 (GRK2) suppresses Epac1-to-Rap1 signaling, thereby inhibiting persistent inflammatory pain. Epac1(-/-) mice are protected against inflammatory hyperalgesia in the complete Freund's adjuvant (CFA) model. Moreover, the Epac specific inhibitor ESI-09 inhibits established CFA-induced mechanical hyperalgesia without affecting normal mechanical sensitivity. At the mechanistic level, CFA increased activity of the Epac target Rap1 in dorsal root ganglia of WT, but not of Epac1(-/-), mice. Using sensory neuron-specific overexpression of GRK2 or its kinase-dead mutant in vivo, we demonstrate that GRK2 inhibits CFA induced hyperalgesia in a kinase activity-dependent manner. In vitro, GRK2 inhibits Epac1-to-Rap1 signaling by phosphorylation of Epac1 at Ser-108 in the Disheveled/Egl-10/pleckstrin domain. This phosphorylation event inhibits agonist induced translocation of Epac1 to the plasma membrane, thereby reducing Rap1 activation. Finally, we show that GRK2 inhibits Epac1-mediated sensitization of the mechanosensor Piezo2 and that Piezo2 contributes to inflammatory mechanical hyperalgesia. Collectively, these findings identify a key role of Epac1 in chronic inflammatory pain and a molecular mechanism for controlling Epac1 activity and chronic pain through phosphorylation of Epac1 at Ser-108. Importantly, using the Epac inhibitor ESI-09, we validate Epac1 as a potential therapeutic target for chronic pain. PMID- 26929335 TI - Human DNMT1 transition state structure. AB - Human DNA methyltransferase 1 (DNMT1) maintains the epigenetic state of DNA by replicating CpG methylation signatures from parent to daughter strands, producing heritable methylation patterns through cell divisions. The proposed catalytic mechanism of DNMT1 involves nucleophilic attack of Cys(1226) to cytosine (Cyt) C6, methyl transfer from S-adenosyl-l-methionine (SAM) to Cyt C5, and proton abstraction from C5 to form methylated CpG in DNA. Here, we report the subangstrom geometric and electrostatic structure of the major transition state (TS) of the reaction catalyzed by human DNMT1. Experimental kinetic isotope effects were used to guide quantum mechanical calculations to solve the TS structure. Methyl transfer occurs after Cys(1226) attack to Cyt C6, and the methyl transfer step is chemically rate-limiting for DNMT1. Electrostatic potential maps were compared for the TS and ground states, providing the electronic basis for interactions between the protein and reactants at the TS. Understanding the TS of DNMT1 demonstrates the possibility of using similar analysis to gain subangstrom geometric insight into the complex reactions of epigenetic modifications. PMID- 26929336 TI - Two distinct cytokinesis pathways drive trypanosome cell division initiation from opposite cell ends. AB - Cytokinesis in Trypanosoma brucei, an early branching protozoan, occurs along its longitudinal axis uni-directionally from the anterior tip of the new flagellum attachment zone filament toward the cell's posterior end. However, the underlying mechanisms remain elusive. Here we report that cytokinesis in T. brucei is regulated by a concerted action of Polo-like kinase, Aurora B kinase, and a trypanosome-specific protein CIF1. Phosphorylation of CIF1 by Polo-like kinase targets it to the anterior tip of the new flagellum attachment zone filament, where it subsequently recruits Aurora B kinase to initiate cytokinesis. Consistent with its role, CIF1 depletion inhibits cytokinesis initiation from the anterior end of the cell, but, surprisingly, triggers cytokinesis initiation from the posterior end of the cell, suggesting the activation of an alternative cytokinesis from the opposite cell end. Our results reveal the mechanistic roles of CIF1 and Polo-like kinase in cytokinesis initiation and elucidate the mechanism underlying the recruitment of Aurora B kinase to the cytokinesis initiation site at late anaphase. These findings also delineate a signaling cascade controlling cytokinesis initiation from the anterior end of the cell and uncover a backup cytokinesis that is initiated from the posterior end of the cell when the typical anterior-to-posterior cytokinesis is compromised. PMID- 26929339 TI - Correction for Chreifi et al., Crystal structure of the pristine peroxidase ferryl center and its relevance to proton-coupled electron transfer. PMID- 26929337 TI - Mechanisms of backtrack recovery by RNA polymerases I and II. AB - During DNA transcription, RNA polymerases often adopt inactive backtracked states. Recovery from backtracks can occur by 1D diffusion or cleavage of backtracked RNA, but how polymerases make this choice is unknown. Here, we use single-molecule optical tweezers experiments and stochastic theory to show that the choice of a backtrack recovery mechanism is determined by a kinetic competition between 1D diffusion and RNA cleavage. Notably, RNA polymerase I (Pol I) and Pol II recover from shallow backtracks by 1D diffusion, use RNA cleavage to recover from intermediary depths, and are unable to recover from extensive backtracks. Furthermore, Pol I and Pol II use distinct mechanisms to avoid nonrecoverable backtracking. Pol I is protected by its subunit A12.2, which decreases the rate of 1D diffusion and enables transcript cleavage up to 20 nt. In contrast, Pol II is fully protected through association with the cleavage stimulatory factor TFIIS, which enables rapid recovery from any depth by RNA cleavage. Taken together, we identify distinct backtrack recovery strategies of Pol I and Pol II, shedding light on the evolution of cellular functions of these key enzymes. PMID- 26929338 TI - Global change and terrestrial plant community dynamics. AB - Anthropogenic drivers of global change include rising atmospheric concentrations of carbon dioxide and other greenhouse gasses and resulting changes in the climate, as well as nitrogen deposition, biotic invasions, altered disturbance regimes, and land-use change. Predicting the effects of global change on terrestrial plant communities is crucial because of the ecosystem services vegetation provides, from climate regulation to forest products. In this paper, we present a framework for detecting vegetation changes and attributing them to global change drivers that incorporates multiple lines of evidence from spatially extensive monitoring networks, distributed experiments, remotely sensed data, and historical records. Based on a literature review, we summarize observed changes and then describe modeling tools that can forecast the impacts of multiple drivers on plant communities in an era of rapid change. Observed responses to changes in temperature, water, nutrients, land use, and disturbance show strong sensitivity of ecosystem productivity and plant population dynamics to water balance and long-lasting effects of disturbance on plant community dynamics. Persistent effects of land-use change and human-altered fire regimes on vegetation can overshadow or interact with climate change impacts. Models forecasting plant community responses to global change incorporate shifting ecological niches, population dynamics, species interactions, spatially explicit disturbance, ecosystem processes, and plant functional responses. Monitoring, experiments, and models evaluating multiple change drivers are needed to detect and predict vegetation changes in response to 21st century global change. PMID- 26929340 TI - Tungsten isotopic constraints on the age and origin of chondrules. AB - Chondrules may have played a critical role in the earliest stages of planet formation by mediating the accumulation of dust into planetesimals. However, the origin of chondrules and their significance for planetesimal accretion remain enigmatic. Here, we show that chondrules and matrix in the carbonaceous chondrite Allende have complementary (183)W anomalies resulting from the uneven distribution of presolar, stellar-derived dust. These data refute an origin of chondrules in protoplanetary collisions and, instead, indicate that chondrules and matrix formed together from a common reservoir of solar nebula dust. Because bulk Allende exhibits no (183)W anomaly, chondrules and matrix must have accreted rapidly to their parent body, implying that the majority of chondrules from a given chondrite group formed in a narrow time interval. Based on Hf-W chronometry on Allende chondrules and matrix, this event occurred ~2 million years after formation of the first solids, about coeval to chondrule formation in ordinary chondrites. PMID- 26929341 TI - Paracrine Wnt/beta-catenin signaling mediates proliferation of undifferentiated spermatogonia in the adult mouse testis. AB - Spermatogonial stem cells (SSCs) fuel the production of male germ cells but the mechanisms behind SSC self-renewal, proliferation, and differentiation are still poorly understood. Using the Wnt target gene Axin2 and genetic lineage-tracing experiments, we found that undifferentiated spermatogonia, comprising SSCs and transit amplifying progenitor cells, respond to Wnt/beta-catenin signals. Genetic elimination of beta-catenin indicates that Wnt/beta-catenin signaling promotes the proliferation of these cells. Signaling is likely initiated by Wnt6, which is uniquely expressed by neighboring Sertoli cells, the only somatic cells in the seminiferous tubule that support germ cells and act as a niche for SSCs. Therefore, unlike other stem cell systems where Wnt/beta-catenin signaling is implicated in self-renewal, the Wnt pathway in the testis specifically contributes to the proliferation of SSCs and progenitor cells. PMID- 26929342 TI - Type VI secretion system sheaths as nanoparticles for antigen display. AB - The bacterial type 6 secretion system (T6SS) is a dynamic apparatus that translocates proteins between cells by a mechanism analogous to phage tail contraction. T6SS sheaths are cytoplasmic tubular structures composed of stable VipA-VipB (named for ClpV-interacting protein A and B) heterodimers. Here, the structure of the VipA/B sheath was exploited to generate immunogenic multivalent particles for vaccine delivery. Sheaths composed of VipB and VipA fused to an antigen of interest were purified from Vibrio cholerae or Escherichia coli and used for immunization. Sheaths displaying heterologous antigens generated better immune responses against the antigen and different IgG subclasses compared with soluble antigen alone. Moreover, antigen-specific antibodies raised against sheaths presenting Neisseria meningitidis factor H binding protein (fHbp) antigen were functional in a serum bactericidal assay. Our results demonstrate that multivalent nanoparticles based on the T6SS sheath represent a versatile scaffold for vaccine applications. PMID- 26929343 TI - Material heterogeneity in cancellous bone promotes deformation recovery after mechanical failure. AB - Many natural structures use a foam core and solid outer shell to achieve high strength and stiffness with relatively small amounts of mass. Biological foams, however, must also resist crack growth. The process of crack propagation within the struts of a foam is not well understood and is complicated by the foam microstructure. We demonstrate that in cancellous bone, the foam-like component of whole bones, damage propagation during cyclic loading is dictated not by local tissue stresses but by heterogeneity of material properties associated with increased ductility of strut surfaces. The increase in surface ductility is unexpected because it is the opposite pattern generated by surface treatments to increase fatigue life in man-made materials, which often result in reduced surface ductility. We show that the more ductile surfaces of cancellous bone are a result of reduced accumulation of advanced glycation end products compared with the strut interior. Damage is therefore likely to accumulate in strut centers making cancellous bone more tolerant of stress concentrations at strut surfaces. Hence, the structure is able to recover more deformation after failure and return to a closer approximation of its original shape. Increased recovery of deformation is a passive mechanism seen in biology for setting a broken bone that allows for a better approximation of initial shape during healing processes and is likely the most important mechanical function. Our findings suggest a previously unidentified biomimetic design strategy in which tissue level material heterogeneity in foams can be used to improve deformation recovery after failure. PMID- 26929344 TI - Inactivation of 3-hydroxybutyrate dehydrogenase 2 delays zebrafish erythroid maturation by conferring premature mitophagy. AB - Mitochondria are the site of iron utilization, wherein imported iron is incorporated into heme or iron-sulfur clusters. Previously, we showed that a cytosolic siderophore, which resembles a bacterial siderophore, facilitates mitochondrial iron import in eukaryotes, including zebrafish. An evolutionarily conserved 3-hydroxy butyrate dehydrogenase, 3-hydroxy butyrate dehydrogenase 2 (Bdh2), catalyzes a rate-limiting step in the biogenesis of the eukaryotic siderophore. We found that inactivation of bdh2 in developing zebrafish embryo results in heme deficiency and delays erythroid maturation. The basis for this erythroid maturation defect is not known. Here we show that bdh2 inactivation results in mitochondrial dysfunction and triggers their degradation by mitophagy. Thus, mitochondria are prematurely lost in bdh2-inactivated erythrocytes. Interestingly, bdh2-inactivated erythroid cells also exhibit genomic alterations as indicated by transcriptome analysis. Reestablishment of bdh2 restores mitochondrial function, prevents premature mitochondrial degradation, promotes erythroid development, and reverses altered gene expression. Thus, mitochondrial communication with the nucleus is critical for erythroid development. PMID- 26929345 TI - Cyclic nucleotide-gated channel 18 is an essential Ca2+ channel in pollen tube tips for pollen tube guidance to ovules in Arabidopsis. AB - In flowering plants, pollen tubes are guided into ovules by multiple attractants from female gametophytes to release paired sperm cells for double fertilization. It has been well-established that Ca(2+) gradients in the pollen tube tips are essential for pollen tube guidance and that plasma membrane Ca(2+) channels in pollen tube tips are core components that regulate Ca(2+) gradients by mediating and regulating external Ca(2+) influx. Therefore, Ca(2+) channels are the core components for pollen tube guidance. However, there is still no genetic evidence for the identification of the putative Ca(2+) channels essential for pollen tube guidance. Here, we report that the point mutations R491Q or R578K in cyclic nucleotide-gated channel 18 (CNGC18) resulted in abnormal Ca(2+) gradients and strong pollen tube guidance defects by impairing the activation of CNGC18 in Arabidopsis. The pollen tube guidance defects of cngc18-17 (R491Q) and of the transfer DNA (T-DNA) insertion mutant cngc18-1 (+/-) were completely rescued by CNGC18. Furthermore, domain-swapping experiments showed that CNGC18's transmembrane domains are indispensable for pollen tube guidance. Additionally, we found that, among eight Ca(2+) channels (including six CNGCs and two glutamate receptor-like channels), CNGC18 was the only one essential for pollen tube guidance. Thus, CNGC18 is the long-sought essential Ca(2+) channel for pollen tube guidance in Arabidopsis. PMID- 26929346 TI - Regulation of seminiferous tubule-associated stem Leydig cells in adult rat testes. AB - Testicular Leydig cells are the primary source of testosterone in males. Adult Leydig cells have been shown to arise from stem cells present in the neonatal testis. Once established, adult Leydig cells turn over only slowly during adult life, but when these cells are eliminated experimentally from the adult testis, new Leydig cells rapidly reappear. As in the neonatal testis, stem cells in the adult testis are presumed to be the source of the new Leydig cells. As yet, the mechanisms involved in regulating the proliferation and differentiation of these stem cells remain unknown. We developed a unique in vitro system of cultured seminiferous tubules to assess the ability of factors from the seminiferous tubules to regulate the proliferation of the tubule-associated stem cells, and their subsequent entry into the Leydig cell lineage. The proliferation of the stem Leydig cells was stimulated by paracrine factors including Desert hedgehog (DHH), basic fibroblast growth factor (FGF2), platelet-derived growth factor (PDGF), and activin. Suppression of proliferation occurred with transforming growth factor beta (TGF-beta). The differentiation of the stem cells was regulated positively by DHH, lithium- induced signaling, and activin, and negatively by TGF-beta, PDGFBB, and FGF2. DHH functioned as a commitment factor, inducing the transition of stem cells to the progenitor stage and thus into the Leydig cell lineage. Additionally, CD90 (Thy1) was found to be a unique stem cell surface marker that was used to obtain purified stem cells by flow cytometry. PMID- 26929347 TI - Risk assessment of radioisotope contamination for aquatic living resources in and around Japan. AB - Food contamination caused by radioisotopes released from the Fukushima Dai-ichi nuclear power plant is of great public concern. The contamination risk for food items should be estimated depending on the characteristics and geographic environments of each item. However, evaluating current and future risk for food items is generally difficult because of small sample sizes, high detection limits, and insufficient survey periods. We evaluated the risk for aquatic food items exceeding a threshold of the radioactive cesium in each species and location using a statistical model. Here we show that the overall contamination risk for aquatic food items is very low. Some freshwater biota, however, are still highly contaminated, particularly in Fukushima. Highly contaminated fish generally tend to have large body size and high trophic levels. PMID- 26929349 TI - Impacts of nonstate, market-driven governance on Chilean forests. AB - Global markets for agricultural products, timber, and minerals are critically important drivers of deforestation. The supply chains driving land use change may also provide opportunities to halt deforestation. Market campaigns, moratoria, and certification schemes have been promoted as powerful tools to achieve conservation goals. Despite their promise, there have been few opportunities to rigorously quantify the ability of these nonstate, market-driven (NSMD) governance regimes to deliver conservation outcomes. This study analyzes the impacts of three NSMD governance systems that sought to end the conversion of natural forests to plantations in Chile at the start of the 21st century. Using a multilevel, panel dataset of land use changes in Chile, we identify the impact of participation within each of the governance regimes by implementing a series of matched difference-in-differences analyses. Taking advantage of the mosaic of different NSMD regimes adopted in Chile, we explore the relative effectiveness of different policies. NSMD governance regimes reduced deforestation on participating properties by 2-23%. The NSMD governance regimes we studied included collaborative and confrontational strategies between environmental and industry stakeholders. We find that the more collaborative governance systems studied achieved better environmental performance than more confrontational approaches. Whereas many government conservation programs have targeted regions with little likelihood of conversion, we demonstrate that NSMD governance has the potential to alter behavior on high-deforestation properties. PMID- 26929348 TI - Efficient delivery of genome-editing proteins using bioreducible lipid nanoparticles. AB - A central challenge to the development of protein-based therapeutics is the inefficiency of delivery of protein cargo across the mammalian cell membrane, including escape from endosomes. Here we report that combining bioreducible lipid nanoparticles with negatively supercharged Cre recombinase or anionic Cas9:single guide (sg)RNA complexes drives the electrostatic assembly of nanoparticles that mediate potent protein delivery and genome editing. These bioreducible lipids efficiently deliver protein cargo into cells, facilitate the escape of protein from endosomes in response to the reductive intracellular environment, and direct protein to its intracellular target sites. The delivery of supercharged Cre protein and Cas9:sgRNA complexed with bioreducible lipids into cultured human cells enables gene recombination and genome editing with efficiencies greater than 70%. In addition, we demonstrate that these lipids are effective for functional protein delivery into mouse brain for gene recombination in vivo. Therefore, the integration of this bioreducible lipid platform with protein engineering has the potential to advance the therapeutic relevance of protein based genome editing. PMID- 26929350 TI - Correction for Mitchener et al., Competition and allostery govern substrate selectivity of cyclooxygenase-2. PMID- 26929351 TI - Correction for Lavine et al., Distinct macrophage lineages contribute to disparate patterns of cardiac recovery and remodeling in the neonatal and adult heart. PMID- 26929352 TI - Early signaling dynamics of the epidermal growth factor receptor. AB - Despite extensive study of the EGF receptor (EGFR) signaling network, the immediate posttranslational changes that occur in response to growth factor stimulation remain poorly characterized; as a result, the biological mechanisms underlying signaling initiation remain obscured. To address this deficiency, we have used a mass spectrometry-based approach to measure system-wide phosphorylation changes throughout the network with 10-s resolution in the 80 s after stimulation in response to a range of eight growth factor concentrations. Significant changes were observed on proteins far downstream in the network as early as 10 s after stimulation, indicating a system capable of transmitting information quickly. Meanwhile, canonical members of the EGFR signaling network fall into clusters with distinct activation patterns. Src homology 2 domain containing transforming protein (Shc) and phosphoinositol 3-kinase (PI3K) phosphorylation levels increase rapidly, but equilibrate within 20 s, whereas proteins such as Grb2-associated binder-1 (Gab1) and SH2-containing tyrosine phosphatase (SHP2) show slower, sustained increases. Proximity ligation assays reveal that Shc and Gab1 phosphorylation patterns are representative of separate timescales for physical association with the receptor. Inhibition of phosphatases with vanadate reveals site-specific regulatory mechanisms and also uncovers primed activating components in the network, including Src family kinases, whose inhibition affects only a subset of proteins within the network. The results presented highlight the complexity of signaling initiation and provide a window into exploring mechanistic hypotheses about receptor tyrosine kinase (RTK) biology. PMID- 26929353 TI - Economic irrationality is optimal during noisy decision making. AB - According to normative theories, reward-maximizing agents should have consistent preferences. Thus, when faced with alternatives A, B, and C, an individual preferring A to B and B to C should prefer A to C. However, it has been widely argued that humans can incur losses by violating this axiom of transitivity, despite strong evolutionary pressure for reward-maximizing choices. Here, adopting a biologically plausible computational framework, we show that intransitive (and thus economically irrational) choices paradoxically improve accuracy (and subsequent economic rewards) when decision formation is corrupted by internal neural noise. Over three experiments, we show that humans accumulate evidence over time using a "selective integration" policy that discards information about alternatives with momentarily lower value. This policy predicts violations of the axiom of transitivity when three equally valued alternatives differ circularly in their number of winning samples. We confirm this prediction in a fourth experiment reporting significant violations of weak stochastic transitivity in human observers. Crucially, we show that relying on selective integration protects choices against "late" noise that otherwise corrupts decision formation beyond the sensory stage. Indeed, we report that individuals with higher late noise relied more strongly on selective integration. These findings suggest that violations of rational choice theory reflect adaptive computations that have evolved in response to irreducible noise during neural information processing. PMID- 26929356 TI - Correction for Mesquita et al., Genome of Rhodnius prolixus, an insect vector of Chagas disease, reveals unique adaptations to hematophagy and parasite infection. PMID- 26929354 TI - Importin-7 mediates memory consolidation through regulation of nuclear translocation of training-activated MAPK in Drosophila. AB - Translocation of signaling molecules, MAPK in particular, from the cytosol to nucleus represents a universal key element in initiating the gene program that determines memory consolidation. Translocation mechanisms and their behavioral impact, however, remain to be determined. Here, we report that a highly conserved nuclear transporter, Drosophila importin-7 (DIM-7), regulates import of training activated MAPK for consolidation of long-term memory (LTM). We show that silencing DIM-7 functions results in impaired LTM, whereas overexpression of DIM 7 enhances LTM. This DIM-7-dependent regulation of LTM is confined to a consolidation time window and in mushroom body neurons. Image data show that bidirectional alteration in DIM-7 expression results in proportional changes in the intensity of training-activated MAPK accumulated within the nuclei of mushroom body neurons during LTM consolidation. Such DIM-7-regulated nuclear accumulation of activated MAPK is observed only in the training specified for LTM induction and determines the amplitude, but not the time course, of memory consolidation. PMID- 26929355 TI - Acetylcholine receptors from human muscle as pharmacological targets for ALS therapy. AB - Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting motor neurons that leads to progressive paralysis of skeletal muscle. Studies of ALS have revealed defects in expression of acetylcholine receptors (AChRs) in skeletal muscle that occur even in the absence of motor neuron anomalies. The endocannabinoid palmitoylethanolamide (PEA) modified the clinical conditions in one ALS patient, improving muscle force and respiratory efficacy. By microtransplanting muscle membranes from selected ALS patients into Xenopus oocytes, we show that PEA reduces the desensitization of acetylcholine-evoked currents after repetitive neurotransmitter application (i.e., rundown). The same effect was observed using muscle samples from denervated (non-ALS) control patients. The expression of human recombinant alpha1beta1gammadelta (gamma-AChRs) and alpha1beta1epsilondelta AChRs (epsilon-AChRs) in Xenopus oocytes revealed that PEA selectively affected the rundown of ACh currents in epsilon-AChRs. A clear up-regulation of the alpha1 subunit in muscle from ALS patients compared with that from non-ALS patients was found by quantitative PCR, but no differential expression was found for other subunits. Clinically, ALS patients treated with PEA showed a lower decrease in their forced vital capacity (FVC) over time as compared with untreated ALS patients, suggesting that PEA can enhance pulmonary function in ALS. In the present work, data were collected from a cohort of 76 ALS patients and 17 denervated patients. Our results strengthen the evidence for the role of skeletal muscle in ALS pathogenesis and pave the way for the development of new drugs to hamper the clinical effects of the disease. PMID- 26929358 TI - Measures with locally finite support and spectrum. AB - The goal of this paper is the construction of measures MU on R(n)enjoying three conflicting but fortunately compatible properties: (i) MU is a sum of weighted Dirac masses on a locally finite set, (ii) the Fourier transform MU f MU is also a sum of weighted Dirac masses on a locally finite set, and (iii) MU is not a generalized Dirac comb. We give surprisingly simple examples of such measures. These unexpected patterns strongly differ from quasicrystals, they provide us with unusual Poisson's formulas, and they might give us an unconventional insight into aperiodic order. PMID- 26929357 TI - Role of bacteriophage T4 baseplate in regulating assembly and infection. AB - Bacteriophage T4 consists of a head for protecting its genome and a sheathed tail for inserting its genome into a host. The tail terminates with a multiprotein baseplate that changes its conformation from a "high-energy" dome-shaped to a "low-energy" star-shaped structure during infection. Although these two structures represent different minima in the total energy landscape of the baseplate assembly, as the dome-shaped structure readily changes to the star shaped structure when the virus infects a host bacterium, the dome-shaped structure must have more energy than the star-shaped structure. Here we describe the electron microscopy structure of a 3.3-MDa in vitro-assembled star-shaped baseplate with a resolution of 3.8 A. This structure, together with other genetic and structural data, shows why the high-energy baseplate is formed in the presence of the central hub and how the baseplate changes to the low-energy structure, via two steps during infection. Thus, the presence of the central hub is required to initiate the assembly of metastable, high-energy structures. If the high-energy structure is formed and stabilized faster than the low-energy structure, there will be insufficient components to assemble the low-energy structure. PMID- 26929359 TI - Disrupted iron homeostasis causes dopaminergic neurodegeneration in mice. AB - Disrupted brain iron homeostasis is a common feature of neurodegenerative disease. To begin to understand how neuronal iron handling might be involved, we focused on dopaminergic neurons and asked how inactivation of transport proteins affected iron homeostasis in vivo in mice. Loss of the cellular iron exporter, ferroportin, had no apparent consequences. However, loss of transferrin receptor 1, involved in iron uptake, caused neuronal iron deficiency, age-progressive degeneration of a subset of dopaminergic neurons, and motor deficits. There was gradual depletion of dopaminergic projections in the striatum followed by death of dopaminergic neurons in the substantia nigra. Damaged mitochondria accumulated, and gene expression signatures indicated attempted axonal regeneration, a metabolic switch to glycolysis, oxidative stress, and the unfolded protein response. We demonstrate that loss of transferrin receptor 1, but not loss of ferroportin, can cause neurodegeneration in a subset of dopaminergic neurons in mice. PMID- 26929360 TI - Structure of an endogenous yeast 26S proteasome reveals two major conformational states. AB - The eukaryotic proteasome mediates degradation of polyubiquitinated proteins. Here we report the single-particle cryoelectron microscopy (cryo-EM) structures of the endogenous 26S proteasome from Saccharomyces cerevisiae at 4.6- to 6.3-A resolution. The fine features of the cryo-EM maps allow modeling of 18 subunits in the regulatory particle and 28 in the core particle. The proteasome exhibits two distinct conformational states, designated M1 and M2, which correspond to those reported previously for the proteasome purified in the presence of ATP gammaS and ATP, respectively. These conformations also correspond to those of the proteasome in the presence and absence of exogenous substrate. Structure-guided biochemical analysis reveals enhanced deubiquitylating enzyme activity of Rpn11 upon assembly of the lid. Our structures serve as a molecular basis for mechanistic understanding of proteasome function. PMID- 26929362 TI - Correction for Plamont et al., Small fluorescence-activating and absorption shifting tag for tunable protein imaging in vivo. PMID- 26929361 TI - Insights into global diatom distribution and diversity in the world's ocean. AB - Diatoms (Bacillariophyta) constitute one of the most diverse and ecologically important groups of phytoplankton. They are considered to be particularly important in nutrient-rich coastal ecosystems and at high latitudes, but considerably less so in the oligotrophic open ocean. The Tara Oceans circumnavigation collected samples from a wide range of oceanic regions using a standardized sampling procedure. Here, a total of ~12 million diatom V9-18S ribosomal DNA (rDNA) ribotypes, derived from 293 size-fractionated plankton communities collected at 46 sampling sites across the global ocean euphotic zone, have been analyzed to explore diatom global diversity and community composition. We provide a new estimate of diversity of marine planktonic diatoms at 4,748 operational taxonomic units (OTUs). Based on the total assigned ribotypes, Chaetoceros was the most abundant and diverse genus, followed by Fragilariopsis, Thalassiosira, and Corethron We found only a few cosmopolitan ribotypes displaying an even distribution across stations and high abundance, many of which could not be assigned with confidence to any known genus. Three distinct communities from South Pacific, Mediterranean, and Southern Ocean waters were identified that share a substantial percentage of ribotypes within them. Sudden drops in diversity were observed at Cape Agulhas, which separates the Indian and Atlantic Oceans, and across the Drake Passage between the Atlantic and Southern Oceans, indicating the importance of these ocean circulation choke points in constraining diatom distribution and diversity. We also observed high diatom diversity in the open ocean, suggesting that diatoms may be more relevant in these oceanic systems than generally considered. PMID- 26929363 TI - Excitatory synapses are stronger in the hippocampus of Rett syndrome mice due to altered synaptic trafficking of AMPA-type glutamate receptors. AB - Deficits in long-term potentiation (LTP) at central excitatory synapses are thought to contribute to cognitive impairments in neurodevelopmental disorders associated with intellectual disability and autism. Using the methyl-CpG-binding protein 2 (Mecp2) knockout (KO) mouse model of Rett syndrome, we show that naive excitatory synapses onto hippocampal pyramidal neurons of symptomatic mice have all of the hallmarks of potentiated synapses. Stronger Mecp2 KO synapses failed to undergo LTP after either theta-burst afferent stimulation or pairing afferent stimulation with postsynaptic depolarization. On the other hand, basal synaptic strength and LTP were not affected in slices from younger presymptomatic Mecp2 KO mice. Furthermore, spine synapses in pyramidal neurons from symptomatic Mecp2 KO are larger and do not grow in size or incorporate GluA1 subunits after electrical or chemical LTP. Our data suggest that LTP is occluded in Mecp2 KO mice by already potentiated synapses. The higher surface levels of GluA1-containing receptors are consistent with altered expression levels of proteins involved in AMPA receptor trafficking, suggesting previously unidentified targets for therapeutic intervention for Rett syndrome and other MECP2-related disorders. PMID- 26929365 TI - Spectral gap optimization of order parameters for sampling complex molecular systems. AB - In modern-day simulations of many-body systems, much of the computational complexity is shifted to the identification of slowly changing molecular order parameters called collective variables (CVs) or reaction coordinates. A vast array of enhanced-sampling methods are based on the identification and biasing of these low-dimensional order parameters, whose fluctuations are important in driving rare events of interest. Here, we describe a new algorithm for finding optimal low-dimensional CVs for use in enhanced-sampling biasing methods like umbrella sampling, metadynamics, and related methods, when limited prior static and dynamic information is known about the system, and a much larger set of candidate CVs is specified. The algorithm involves estimating the best combination of these candidate CVs, as quantified by a maximum path entropy estimate of the spectral gap for dynamics viewed as a function of that CV. The algorithm is called spectral gap optimization of order parameters (SGOOP). Through multiple practical examples, we show how this postprocessing procedure can lead to optimization of CV and several orders of magnitude improvement in the convergence of the free energy calculated through metadynamics, essentially giving the ability to extract useful information even from unsuccessful metadynamics runs. PMID- 26929364 TI - Partial connectivity increases cultural accumulation within groups. AB - Complex technologies used in most human societies are beyond the inventive capacities of individuals. Instead, they result from a cumulative process in which innovations are gradually added to existing cultural traits across many generations. Recent work suggests that a population's ability to develop complex technologies is positively affected by its size and connectedness. Here, we present a simple computer-based experiment that compares the accumulation of innovations by fully and partially connected groups of the same size in a complex fitness landscape. We find that the propensity to learn from successful individuals drastically reduces cultural diversity within fully connected groups. In comparison, partially connected groups produce more diverse solutions, and this diversity allows them to develop complex solutions that are never produced in fully connected groups. These results suggest that explanations of ancestral patterns of cultural complexity may need to consider levels of population fragmentation and interaction patterns between partially isolated groups. PMID- 26929366 TI - Dynamics inside the cancer cell attractor reveal cell heterogeneity, limits of stability, and escape. AB - The observed intercellular heterogeneity within a clonal cell population can be mapped as dynamical states clustered around an attractor point in gene expression space, owing to a balance between homeostatic forces and stochastic fluctuations. These dynamics have led to the cancer cell attractor conceptual model, with implications for both carcinogenesis and new therapeutic concepts. Immortalized and malignant EBV-carrying B-cell lines were used to explore this model and characterize the detailed structure of cell attractors. Any subpopulation selected from a population of cells repopulated the whole original basin of attraction within days to weeks. Cells at the basin edges were unstable and prone to apoptosis. Cells continuously changed states within their own attractor, thus driving the repopulation, as shown by fluorescent dye tracing. Perturbations of key regulatory genes induced a jump to a nearby attractor. Using the Fokker Planck equation, this cell population behavior could be described as two virtual, opposing influences on the cells: one attracting toward the center and the other promoting diffusion in state space (noise). Transcriptome analysis suggests that these forces result from high-dimensional dynamics of the gene regulatory network. We propose that they can be generalized to all cancer cell populations and represent intrinsic behaviors of tumors, offering a previously unidentified characteristic for studying cancer. PMID- 26929368 TI - Continued emissions of carbon tetrachloride from the United States nearly two decades after its phaseout for dispersive uses. AB - National-scale emissions of carbon tetrachloride (CCl4) are derived based on inverse modeling of atmospheric observations at multiple sites across the United States from the National Oceanic and Atmospheric Administration's flask air sampling network. We estimate an annual average US emission of 4.0 (2.0-6.5) Gg CCl4 y(-1) during 2008-2012, which is almost two orders of magnitude larger than reported to the US Environmental Protection Agency (EPA) Toxics Release Inventory (TRI) (mean of 0.06 Gg y(-1)) but only 8% (3-22%) of global CCl4 emissions during these years. Emissive regions identified by the observations and consistently shown in all inversion results include the Gulf Coast states, the San Francisco Bay Area in California, and the Denver area in Colorado. Both the observation derived emissions and the US EPA TRI identified Texas and Louisiana as the largest contributors, accounting for one- to two-thirds of the US national total CCl4 emission during 2008-2012. These results are qualitatively consistent with multiple aircraft and ship surveys conducted in earlier years, which suggested significant enhancements in atmospheric mole fractions measured near Houston and surrounding areas. Furthermore, the emission distribution derived for CCl4 throughout the United States is more consistent with the distribution of industrial activities included in the TRI than with the distribution of other potential CCl4 sources such as uncapped landfills or activities related to population density (e.g., use of chlorine-containing bleach). PMID- 26929367 TI - Functional and topological diversity of LOV domain photoreceptors. AB - Light-oxygen-voltage sensitive (LOV) flavoproteins are ubiquitous photoreceptors that mediate responses to environmental cues. Photosensory inputs are transduced into signaling outputs via structural rearrangements in sensor domains that consequently modulate the activity of an effector domain or multidomain clusters. Establishing the diversity in effector function and sensor-effector topology will inform what signaling mechanisms govern light-responsive behaviors across multiple kingdoms of life and how these signals are transduced. Here, we report the bioinformatics identification of over 6,700 candidate LOV domains (including over 4,000 previously unidentified sequences from plants and protists), and insights from their annotations for ontological function and structural arrangements. Motif analysis identified the sensors from ~42 million ORFs, with strong statistical separation from other flavoproteins and non-LOV members of the structurally related Per-aryl hydrocarbon receptor nuclear translocator (ARNT) Sim family. Conserved-domain analysis determined putative light-regulated function and multidomain topologies. We found that for certain effectors, sensor effector linker length is discretized based on both phylogeny and the preservation of alpha-helical heptad repeats within an extended coiled-coil linker structure. This finding suggests that preserving sensor-effector orientation is a key determinant of linker length, in addition to ancestry, in LOV signaling structure-function. We found a surprisingly high prevalence of effectors with functions previously thought to be rare among LOV proteins, such as regulators of G protein signaling, and discovered several previously unidentified effectors, such as lipases. This work highlights the value of applying genomic and transcriptomic technologies to diverse organisms to capture the structural and functional variation in photosensory proteins that are vastly important in adaptation, photobiology, and optogenetics. PMID- 26929369 TI - Redox-coupled proton transfer mechanism in nitrite reductase revealed by femtosecond crystallography. AB - Proton-coupled electron transfer (PCET), a ubiquitous phenomenon in biological systems, plays an essential role in copper nitrite reductase (CuNiR), the key metalloenzyme in microbial denitrification of the global nitrogen cycle. Analyses of the nitrite reduction mechanism in CuNiR with conventional synchrotron radiation crystallography (SRX) have been faced with difficulties, because X-ray photoreduction changes the native structures of metal centers and the enzyme substrate complex. Using serial femtosecond crystallography (SFX), we determined the intact structures of CuNiR in the resting state and the nitrite complex (NC) state at 2.03- and 1.60-A resolution, respectively. Furthermore, the SRX NC structure representing a transient state in the catalytic cycle was determined at 1.30-A resolution. Comparison between SRX and SFX structures revealed that photoreduction changes the coordination manner of the substrate and that catalytically important His255 can switch hydrogen bond partners between the backbone carbonyl oxygen of nearby Glu279 and the side-chain hydroxyl group of Thr280. These findings, which SRX has failed to uncover, propose a redox-coupled proton switch for PCET. This concept can explain how proton transfer to the substrate is involved in intramolecular electron transfer and why substrate binding accelerates PCET. Our study demonstrates the potential of SFX as a powerful tool to study redox processes in metalloenzymes. PMID- 26929371 TI - Autoinhibition and relief mechanism by the proteolytic processing of Toll-like receptor 8. AB - Toll-like receptor 8 (TLR8) senses single-stranded RNA (ssRNA) and initiates innate immune responses. TLR8 requires proteolytic cleavage at the loop region (Z loop) between leucine-rich repeat (LRR) 14 and LRR15 for its activation. However, the molecular basis of Z-loop processing remains unknown. To elucidate the mechanism of Z-loop processing, we performed biochemical and structural studies of how the Z-loop affects the function of TLR8. TLR8 with the uncleaved Z-loop is unable to form a dimer, which is essential for activation, irrespective of the presence of agonistic ligands. Crystallographic analysis revealed that the uncleaved Z-loop located on the ascending lateral face prevents the approach of the dimerization partner by steric hindrance. This autoinhibition mechanism of dimerization by the Z-loop might be occurring in the proteins of the same subfamily, TLR7 and TLR9. PMID- 26929370 TI - The retrovirus HTLV-1 inserts an ectopic CTCF-binding site into the human genome. AB - Human T-lymphotropic virus type 1 (HTLV-1) is a retrovirus that causes malignant and inflammatory diseases in ~10% of infected people. A typical host has between 10(4) and 10(5) clones of HTLV-1-infected T lymphocytes, each clone distinguished by the genomic integration site of the single-copy HTLV-1 provirus. The HTLV-1 bZIP (HBZ) factor gene is constitutively expressed from the minus strand of the provirus, whereas plus-strand expression, required for viral propagation to uninfected cells, is suppressed or intermittent in vivo, allowing escape from host immune surveillance. It remains unknown what regulates this pattern of proviral transcription and latency. Here, we show that CTCF, a key regulator of chromatin structure and function, binds to the provirus at a sharp border in epigenetic modifications in the pX region of the HTLV-1 provirus in T cells naturally infected with HTLV-1. CTCF is a zinc-finger protein that binds to an insulator region in genomic DNA and plays a fundamental role in controlling higher order chromatin structure and gene expression in vertebrate cells. We show that CTCF bound to HTLV-1 acts as an enhancer blocker, regulates HTLV-1 mRNA splicing, and forms long-distance interactions with flanking host chromatin. CTCF binding sites (CTCF-BSs) have been propagated throughout the genome by transposons in certain primate lineages, but CTCF binding has not previously been described in present-day exogenous retroviruses. The presence of an ectopic CTCF BS introduced by the retrovirus in tens of thousands of genomic locations has the potential to cause widespread abnormalities in host cell chromatin structure and gene expression. PMID- 26929372 TI - Pten loss promotes MAPK pathway dependency in HER2/neu breast carcinomas. AB - Loss of the tumor suppressor gene PTEN is implicated in breast cancer progression and resistance to targeted therapies, and is thought to promote tumorigenesis by activating PI3K signaling. In a transgenic model of breast cancer, Pten suppression using a tetracycline-regulatable short hairpin (sh)RNA cooperates with human epidermal growth factor receptor 2 (HER2/neu), leading to aggressive and metastatic disease with elevated signaling through PI3K and, surprisingly, the mitogen-activated protein kinase (MAPK) pathway. Restoring Pten function is sufficient to down-regulate both PI3K and MAPK signaling and triggers dramatic tumor regression. Pharmacologic inhibition of MAPK signaling produces similar effects to Pten restoration, suggesting that the MAPK pathway contributes to the maintenance of advanced breast cancers harboring Pten loss. PMID- 26929375 TI - Long-ranged contributions to solvation free energies from theory and short-ranged models. AB - Long-standing problems associated with long-ranged electrostatic interactions have plagued theory and simulation alike. Traditional lattice sum (Ewald-like) treatments of Coulomb interactions add significant overhead to computer simulations and can produce artifacts from spurious interactions between simulation cell images. These subtle issues become particularly apparent when estimating thermodynamic quantities, such as free energies of solvation in charged and polar systems, to which long-ranged Coulomb interactions typically make a large contribution. In this paper, we develop a framework for determining very accurate solvation free energies of systems with long-ranged interactions from models that interact with purely short-ranged potentials. Our approach is generally applicable and can be combined with existing computational and theoretical techniques for estimating solvation thermodynamics. We demonstrate the utility of our approach by examining the hydration thermodynamics of hydrophobic and ionic solutes and the solvation of a large, highly charged colloid that exhibits overcharging, a complex nonlinear electrostatic phenomenon whereby counterions from the solvent effectively overscreen and locally invert the integrated charge of the solvated object. PMID- 26929373 TI - Endolysosomal trafficking of viral G protein-coupled receptor functions in innate immunity and control of viral oncogenesis. AB - The ubiquitin-proteasome system degrades viral oncoproteins and other microbial virulence factors; however, the role of endolysosomal degradation pathways in these processes is unclear. Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi's sarcoma, and a constitutively active viral G protein coupled receptor (vGPCR) contributes to the pathogenesis of KSHV-induced tumors. We report that a recently discovered autophagy-related protein, Beclin 2, interacts with KSHV GPCR, facilitates its endolysosomal degradation, and inhibits vGPCR-driven oncogenic signaling. Furthermore, monoallelic loss of Becn2 in mice accelerates the progression of vGPCR-induced lesions that resemble human Kaposi's sarcoma. Taken together, these findings indicate that Beclin 2 is a host antiviral molecule that protects against the pathogenic effects of KSHV GPCR by facilitating its endolysosomal degradation. More broadly, our data suggest a role for host endolysosomal trafficking pathways in regulating viral pathogenesis and oncogenic signaling. PMID- 26929374 TI - Functional requirements of AID's higher order structures and their interaction with RNA-binding proteins. AB - Activation-induced cytidine deaminase (AID) is essential for the somatic hypermutation (SHM) and class-switch recombination (CSR) of Ig genes. Although both the N and C termini of AID have unique functions in DNA cleavage and recombination, respectively, during SHM and CSR, their molecular mechanisms are poorly understood. Using a bimolecular fluorescence complementation (BiFC) assay combined with glycerol gradient fractionation, we revealed that the AID C terminus is required for a stable dimer formation. Furthermore, AID monomers and dimers form complexes with distinct heterogeneous nuclear ribonucleoproteins (hnRNPs). AID monomers associate with DNA cleavage cofactor hnRNP K whereas AID dimers associate with recombination cofactors hnRNP L, hnRNP U, and Serpine mRNA binding protein 1. All of these AID/ribonucleoprotein associations are RNA dependent. We propose that AID's structure-specific cofactor complex formations differentially contribute to its DNA-cleavage and recombination functions. PMID- 26929376 TI - Quantifying dispersal from hydrothermal vent fields in the western Pacific Ocean. AB - Hydrothermal vent fields in the western Pacific Ocean are mostly distributed along spreading centers in submarine basins behind convergent plate boundaries. Larval dispersal resulting from deep-ocean circulations is one of the major factors influencing gene flow, diversity, and distributions of vent animals. By combining a biophysical model and deep-profiling float experiments, we quantify potential larval dispersal of vent species via ocean circulation in the western Pacific Ocean. We demonstrate that vent fields within back-arc basins could be well connected without particular directionality, whereas basin-to-basin dispersal is expected to occur infrequently, once in tens to hundreds of thousands of years, with clear dispersal barriers and directionality associated with ocean currents. The southwest Pacific vent complex, spanning more than 4,000 km, may be connected by the South Equatorial Current for species with a longer than-average larval development time. Depending on larval dispersal depth, a strong western boundary current, the Kuroshio Current, could bridge vent fields from the Okinawa Trough to the Izu-Bonin Arc, which are 1,200 km apart. Outcomes of this study should help marine ecologists estimate gene flow among vent populations and design optimal marine conservation plans to protect one of the most unusual ecosystems on Earth. PMID- 26929378 TI - Composite lithium metal anode by melt infusion of lithium into a 3D conducting scaffold with lithiophilic coating. AB - Lithium metal-based battery is considered one of the best energy storage systems due to its high theoretical capacity and lowest anode potential of all. However, dendritic growth and virtually relative infinity volume change during long-term cycling often lead to severe safety hazards and catastrophic failure. Here, a stable lithium-scaffold composite electrode is developed by lithium melt infusion into a 3D porous carbon matrix with "lithiophilic" coating. Lithium is uniformly entrapped on the matrix surface and in the 3D structure. The resulting composite electrode possesses a high conductive surface area and excellent structural stability upon galvanostatic cycling. We showed stable cycling of this composite electrode with small Li plating/stripping overpotential (<90 mV) at a high current density of 3 mA/cm(2) over 80 cycles. PMID- 26929377 TI - Mean deformation metrics for quantifying 3D cell-matrix interactions without requiring information about matrix material properties. AB - Mechanobiology relates cellular processes to mechanical signals, such as determining the effect of variations in matrix stiffness with cell tractions. Cell traction recorded via traction force microscopy (TFM) commonly takes place on materials such as polyacrylamide- and polyethylene glycol-based gels. Such experiments remain limited in physiological relevance because cells natively migrate within complex tissue microenvironments that are spatially heterogeneous and hierarchical. Yet, TFM requires determination of the matrix constitutive law (stress-strain relationship), which is not always readily available. In addition, the currently achievable displacement resolution limits the accuracy of TFM for relatively small cells. To overcome these limitations, and increase the physiological relevance of in vitro experimental design, we present a new approach and a set of associated biomechanical signatures that are based purely on measurements of the matrix's displacements without requiring any knowledge of its constitutive laws. We show that our mean deformation metrics (MDM) approach can provide significant biophysical information without the need to explicitly determine cell tractions. In the process of demonstrating the use of our MDM approach, we succeeded in expanding the capability of our displacement measurement technique such that it can now measure the 3D deformations around relatively small cells (~10 micrometers), such as neutrophils. Furthermore, we also report previously unseen deformation patterns generated by motile neutrophils in 3D collagen gels. PMID- 26929379 TI - Disruption of lipid homeostasis in the Gram-negative cell envelope activates a novel cell death pathway. AB - Gram-negative bacteria balance synthesis of the outer membrane (OM), cell wall, and cytoplasmic contents during growth via unknown mechanisms. Here, we show that a dominant mutation (designated mlaA*, maintenance of lipid asymmetry) that alters MlaA, a lipoprotein that removes phospholipids from the outer leaflet of the OM of Escherichia coli, increases OM permeability, lipopolysaccharide levels, drug sensitivity, and cell death in stationary phase. Surprisingly, single-cell imaging revealed that death occurs after protracted loss of OM material through vesiculation and blebbing at cell-division sites and compensatory shrinkage of the inner membrane, eventually resulting in rupture and slow leakage of cytoplasmic contents. The death of mlaA* cells was linked to fatty acid depletion and was not affected by membrane depolarization, suggesting that lipids flow from the inner membrane to the OM in an energy-independent manner. Suppressor analysis suggested that the dominant mlaA* mutation activates phospholipase A, resulting in increased levels of lipopolysaccharide and OM vesiculation that ultimately undermine the integrity of the cell envelope by depleting the inner membrane of phospholipids. This novel cell-death pathway suggests that balanced synthesis across both membranes is key to the mechanical integrity of the Gram-negative cell envelope. PMID- 26929381 TI - Reply to Cronin: Consistency between decision-making, gaze, and natural social behavior validates inferences on macaque social cognition. PMID- 26929380 TI - Mitochondrial Hsp90 is a ligand-activated molecular chaperone coupling ATP binding to dimer closure through a coiled-coil intermediate. AB - Heat-shock protein of 90 kDa (Hsp90) is an essential molecular chaperone that adopts different 3D structures associated with distinct nucleotide states: a wide open, V-shaped dimer in the apo state and a twisted, N-terminally closed dimer with ATP. Although the N domain is known to mediate ATP binding, how Hsp90 senses the bound nucleotide and facilitates dimer closure remains unclear. Here we present atomic structures of human mitochondrial Hsp90N (TRAP1N) and a composite model of intact TRAP1 revealing a previously unobserved coiled-coil dimer conformation that may precede dimer closure and is conserved in intact TRAP1 in solution. Our structure suggests that TRAP1 normally exists in an autoinhibited state with the ATP lid bound to the nucleotide-binding pocket. ATP binding displaces the ATP lid that signals the cis-bound ATP status to the neighboring subunit in a highly cooperative manner compatible with the coiled-coil intermediate state. We propose that TRAP1 is a ligand-activated molecular chaperone, which couples ATP binding to dramatic changes in local structure required for protein folding. PMID- 26929382 TI - Classic Spotlight: Crowd Sourcing Provided Penicillium Strains for the War Effort. PMID- 26929383 TI - Classic Spotlight: When Phenotypic Heterogeneity Met Carbon Catabolite Repression. PMID- 26929386 TI - Using lessons from breast, cervical, and colorectal cancer screening to inform the development of lung cancer screening programs. AB - Multiple advisory groups now recommend that high-risk smokers be screened for lung cancer by low-dose computed tomography. Given that the development of lung cancer screening programs will face many of the same issues that have challenged other cancer screening programs, the National Cancer Institute-funded Population based Research Optimizing Screening through Personalized Regimens (PROSPR) consortium was used to identify lessons learned from the implementation of breast, cervical, and colorectal cancer screening that should inform the introduction of lung cancer screening. These lessons include the importance of developing systems for identifying and recruiting eligible individuals in primary care, ensuring that screening centers are qualified and performance is monitored, creating clear communication standards for reporting screening results to referring physicians and patients, ensuring follow-up is available for individuals with abnormal test results, avoiding overscreening, remembering primary prevention, and leveraging advances in cancer genetics and immunology. Overall, this experience emphasizes that effective cancer screening is a multistep activity that requires robust strategies to initiate, report, follow up, and track each step as well as a dynamic and ongoing oversight process to revise current screening practices as new evidence regarding screening is created, new screening technologies are developed, new biological markers are identified, and new approaches to health care delivery are disseminated. Cancer 2016;122:1338-1342. (c) 2016 American Cancer Society. PMID- 26929387 TI - Avian responses to an extreme ice storm are determined by a combination of functional traits, behavioural adaptations and habitat modifications. AB - The extent to which species' traits, behavior and habitat synergistically determine their response to extreme weather events (EWE) remains poorly understood. By quantifying bird and vegetation assemblages before and after the 2008 ice storm in China, combined with interspecific interactions and foraging behaviours, we disentangled whether storm influences avian reassembly directly via functional traits (i.e. behavioral adaptations), or indirectly via habitat variations. We found that overall species richness decreased, with 20 species detected exclusively before the storm, and eight species detected exclusively after. These shifts in bird relative abundance were linked to habitat preferences, dietary guild and flocking behaviours. For instance, forest specialists at higher trophic levels (e.g. understory-insectivores, woodpeckers and kingfishers) were especially vulnerable, whereas open-habitat generalists (e.g. bulbuls) were set to benefit from potential habitat homogenization. Alongside population fluctuations, we found that community reassembly can be rapidly adjusted via foraging plasticity (i.e. increased flocking propensity and reduced perching height). And changes in preferred habitat corresponded to a variation in bird assemblages and traits, as represented by intact canopy cover and high density of large trees. Accurate predictions of community responses to EWE are crucial to understanding ecosystem disturbances, thus linking species oriented traits to a coherent analytical framework. PMID- 26929389 TI - Pyrodiversity begets plant-pollinator community diversity. AB - Fire has a major impact on the structure and function of many ecosystems globally. Pyrodiversity, the diversity of fires within a region (where diversity is based on fire characteristics such as extent, severity, and frequency), has been hypothesized to promote biodiversity, but changing climate and land management practices have eroded pyrodiversity. To assess whether changes in pyrodiversity will have impacts on ecological communities, we must first understand the mechanisms that might enable pyrodiversity to sustain biodiversity, and how such changes might interact with other disturbances such as drought. Focusing on plant-pollinator communities in mixed-conifer forest with frequent fire in Yosemite National Park, California, we examine how pyrodiversity, combined with drought intensity, influences those communities. We find that pyrodiversity is positively related to the richness of the pollinators, flowering plants, and plant-pollinator interactions. On average, a 5% increase in pyrodiversity led to the gain of approximately one pollinator and one flowering plant species and nearly two interactions. We also find that a diversity of fire characteristics contributes to the spatial heterogeneity (beta-diversity) of plant and pollinator communities. Lastly, we find evidence that fire diversity buffers pollinator communities against the effects of drought-induced floral resource scarcity. Fire diversity is thus important for the maintenance of flowering plant and pollinator diversity and predicted shifts in fire regimes to include less pyrodiversity compounded with increasing drought occurrence will negatively influence the richness of these communities in this and other forested ecosystems. In addition, lower heterogeneity of fire severity may act to reduce spatial turnover of plant-pollinator communities. The heterogeneity of community composition is a primary determinant of the total species diversity present in a landscape, and thus, lower pyrodiversity may negatively affect the richness of plant-pollinator communities across large spatial scales. PMID- 26929388 TI - Evidence for AKT-independent regulation of FOXO1 and FOXO3 in haematopoietic stem and progenitor cells. AB - Transcription factors FOXOs (1, 3, 4) are essential for the maintenance of haematopoietic stem cells. FOXOs are evolutionary conserved substrates of the AKT serine threonine protein kinase that are also phosphorylated by several kinases other than AKT. Specifically, phosphorylation by AKT is known to result in the cytosolic localization of FOXO and subsequent inhibition of FOXO transcriptional activity. In addition to phosphorylation, FOXOs are regulated by a number of other post-translational modifications including acetylation, methylation, redox modulation, and ubiquitination that altogether determine these factors' output. Cumulating evidence raises the possibility that in stem cells, including in haematopoietic stem cells, AKT may not be the dominant regulator of FOXO. To address this question in more detail, we examined gene expression, subcellular localization, and response to AKT inhibition of FOXO1 and FOXO3, the main FOXO expressed in HSPCs (haematopoietic stem and progenitor cells). Here we show that while FOXO1 and FOXO3 transcripts are expressed at similar levels, endogenous FOXO3 protein is mostly nuclear compared to the cytoplasmic localization of FOXO1 in HSPCs. Furthermore, inhibition of AKT does not enhance nuclear localization of FOXO1 nor FOXO3. Nonetheless AKT inhibition in the context of loss of NAD dependent SIRT1 deacetylase modulates FOXO3 localization in HSPCs. Together, these data suggest that FOXO3 is more active than FOXO1 in primitive haematopoietic stem and multipotent progenitor cells. In addition, they indicate that upstream regulators other than AKT, such as SIRT1, maintain nuclear FOXO localization and activity in HSPCs. PMID- 26929391 TI - Simulation-based training: the missing link to lastingly improved patient safety and health? PMID- 26929390 TI - Elevated atmospheric [CO2 ] can dramatically increase wheat yields in semi-arid environments and buffer against heat waves. AB - Wheat production will be impacted by increasing concentration of atmospheric CO2 [CO2 ], which is expected to rise from about 400 MUmol mol(-1) in 2015 to 550 MUmol mol(-1) by 2050. Changes to plant physiology and crop responses from elevated [CO2 ] (e[CO2 ]) are well documented for some environments, but field level responses in dryland Mediterranean environments with terminal drought and heat waves are scarce. The Australian Grains Free Air CO2 Enrichment facility was established to compare wheat (Triticum aestivum) growth and yield under ambient (~370 MUmol(-1) in 2007) and e[CO2 ] (550 MUmol(-1) ) in semi-arid environments. Experiments were undertaken at two dryland sites (Horsham and Walpeup) across three years with two cultivars, two sowing times and two irrigation treatments. Mean yield stimulation due to e[CO2 ] was 24% at Horsham and 53% at Walpeup, with some treatment responses greater than 70%, depending on environment. Under supplemental irrigation, e[CO2 ] stimulated yields at Horsham by 37% compared to 13% under rainfed conditions, showing that water limited growth and yield response to e[CO2 ]. Heat wave effects were ameliorated under e[CO2 ] as shown by reductions of 31% and 54% in screenings and 10% and 12% larger kernels (Horsham and Walpeup). Greatest yield stimulations occurred in the e[CO2 ] late sowing and heat stressed treatments, when supplied with more water. There were no clear differences in cultivar response due to e[CO2 ]. Multiple regression showed that yield response to e[CO2 ] depended on temperatures and water availability before and after anthesis. Thus, timing of temperature and water and the crop's ability to translocate carbohydrates to the grain postanthesis were all important in determining the e[CO2 ] response. The large responses to e[CO2 ] under dryland conditions have not been previously reported and underscore the need for field level research to provide mechanistic understanding for adapting crops to a changing climate. PMID- 26929392 TI - The impact of gestational weight gain in different trimesters of pregnancy on glucose challenge test and gestational diabetes. AB - PURPOSE: Assessing the effects of excessive weight gain before pregnancy, in the first and second trimesters and in the month preceding glucose challenge test (GCT) on GCT results and gestational diabetes mellitus (GDM). STUDY DESIGN: This prospective cohort study evaluated 1279 pregnant women who were referred for their first prenatal visit in 2012-2015. Mother's body mass index (BMI) was recorded before pregnancy, during the first visit and every 4 weeks until 28 gestational weeks. All mothers underwent GCT at 28 weeks and when 1 h glucose >=140 mg/dL (>=7.8 mmol/L), they were referred for a 100 g fasting glucose 3 h glucose tolerance test. RESULTS: Obesity and being overweight prior to pregnancy were associated with 2.8-fold and 1.5-fold higher rates of developing GDM (p<0.001, p=0.04) and 1.9-fold and 1.8-fold higher rates of having false-positive GCT results (p<0.001). First-trimester excessive weight gain was significantly associated with false-positive GCT in women who were lean, overweight and obese before pregnancy (all p<0.001). When these women kept gaining excessive weight during the subsequent period the risk of developing GDM was significantly increased regardless of their pre-pregnancy BMI (p=0.03). When these women adhered to the recommended weight gain during the subsequent period, the risk of developing GDM was not increased, however the risk of having false-positive GCT remained high (p<0.001). CONCLUSIONS: Elevated pre-pregnancy BMI independently increases the risk of GDM and false-positive GCT. First trimester weight gain is the most important predictor of GCT and GDM regardless of pre-pregnancy BMI. The weight gain during the subsequent period affects the risk of developing GDM only in women with excessive first-trimester weight gain. PMID- 26929393 TI - Drought survival is a threshold function of habitat size and population density in a fish metapopulation. AB - Because smaller habitats dry more frequently and severely during droughts, habitat size is likely a key driver of survival in populations during climate change and associated increased extreme drought frequency. Here, we show that survival in populations during droughts is a threshold function of habitat size driven by an interaction with population density in metapopulations of the forest pool dwelling fish, Neochanna apoda. A mark-recapture study involving 830 N. apoda individuals during a one-in-seventy-year extreme drought revealed that survival during droughts was high for populations occupying pools deeper than 139 mm, but declined steeply in shallower pools. This threshold was caused by an interaction between increasing population density and drought magnitude associated with decreasing habitat size, which acted synergistically to increase physiological stress and mortality. This confirmed two long-held hypotheses, firstly concerning the interactive role of population density and physiological stress, herein driven by habitat size, and secondly, the occurrence of drought survival thresholds. Our results demonstrate how survival in populations during droughts will depend strongly on habitat size and highlight that minimum habitat size thresholds will likely be required to maximize survival as the frequency and intensity of droughts are projected to increase as a result of global climate change. PMID- 26929394 TI - Conversion from forests to pastures in the Colombian Amazon leads to contrasting soil carbon dynamics depending on land management practices. AB - Strategies to mitigate climate change by reducing deforestation and forest degradation (e.g. REDD+) require country- or region-specific information on temporal changes in forest carbon (C) pools to develop accurate emission factors. The soil C pool is one of the most important C reservoirs, but is rarely included in national forest reference emission levels due to a lack of data. Here, we present the soil organic C (SOC) dynamics along 20 years of forest-to-pasture conversion in two subregions with different management practices during pasture establishment in the Colombian Amazon: high-grazing intensity (HG) and low grazing intensity (LG) subregions. We determined the pattern of SOC change resulting from the conversion from forest (C3 plants) to pasture (C4 plants) by analysing total SOC stocks and the natural abundance of the stable isotopes (13) C along two 20-year chronosequences identified in each subregion. We also analysed soil N stocks and the natural abundance of (15) N during pasture establishment. In general, total SOC stocks at 30 cm depth in the forest were similar for both subregions, with an average of 47.1 +/- 1.8 Mg C ha(-1) in HG and 48.7 +/- 3.1 Mg C ha(-1) in LG. However, 20 years after forest-to-pasture conversion SOC in HG decreased by 20%, whereas in LG SOC increased by 41%. This net SOC decrease in HG was due to a larger reduction in C3-derived input and to a comparatively smaller increase in C4-derived C input. In LG both C3- and C4 derived C input increased along the chronosequence. N stocks were generally similar in both subregions and soil N stock changes during pasture establishment were correlated with SOC changes. These results emphasize the importance of management practices involving low-grazing intensity in cattle activities to preserve SOC stocks and to reduce C emissions after land-cover change from forest to pasture in the Colombian Amazon. PMID- 26929395 TI - Revealing turning points in ecosystem functioning over the Northern Eurasian agricultural frontier. AB - The collapse of the Soviet Union in 1991 has been a turning point in the World history that left a unique footprint on the Northern Eurasian ecosystems. Conducting large scale mapping of environmental change and separating between naturogenic and anthropogenic drivers is a difficult endeavor in such highly complex systems. In this research a piece-wise linear regression method was used for breakpoint detection in Rain-Use Efficiency (RUE) time series and a classification of ecosystem response types was produced. Supported by earth observation data, field data, and expert knowledge, this study provides empirical evidence regarding the occurrence of drastic changes in RUE (assessment of the timing, the direction and the significance of these changes) in Northern Eurasian ecosystems between 1982 and 2011. About 36% of the study area (3.4 million km(2) ) showed significant (P < 0.05) trends and/or turning points in RUE during the observation period. A large proportion of detected turning points in RUE occurred around the fall of the Soviet Union in 1991 and in the following years which were attributed to widespread agricultural land abandonment. Our study also showed that recurrent droughts deeply affected vegetation productivity throughout the observation period, with a general worsening of the drought conditions in recent years. Moreover, recent human-induced turning points in ecosystem functioning were detected and attributed to ongoing recultivation and change in irrigation practices in the Volgograd region, and to increased salinization and increased grazing intensity around Lake Balkhash. The ecosystem-state assessment method introduced here proved to be a valuable support that highlighted hotspots of potentially altered ecosystems and allowed for disentangling human from climatic disturbances. PMID- 26929396 TI - Non-invasive Ventilation as Airway Clearance Technique in Cystic Fibrosis. AB - BACKGROUND AND PURPOSE: For patients with cystic fibrosis, chest physiotherapy is crucial for evacuating airway secretions. Because chest physiotherapy increases energy expenditure, fatigue and dyspnoea, non-invasive ventilation (NIV) could be beneficial for severely ill patients during airway clearance. The aim of the study is to evaluate and compare the effects between NIV and positive expiratory pressure (PEP) on airway clearance. METHODS: Prospective, randomized trial compares PEP to NIV. Thirty-two subjects, mean age 31 years, mean forced expiratory volume in 1 second 47% (+/-14) and mean forced vital capacity 69% (+/ 13), completed a 3-month randomized trial comparing NIV with standard PEP treatment as airway clearance technique. Lung functions testing, 6-minute walk test, blood gases, sputum culture and inflammatory parameters were measured before and after the treatment period. RESULTS: There was a significant reduction in lung clearance index (LCI) following NIV compared with PEP (p = 0.01). LCI is performed within the lung function testing. DISCUSSION: Non-invasive ventilation was shown to be a good alternative to PEP in chest physiotherapy for patients with cystic fibrosis who are severely ill. PMID- 26929398 TI - The GGDEF-domain protein GdpX1 attenuates motility, exopolysaccharide production and virulence in Xanthomonas oryzae pv. oryzae. AB - AIMS: Cyclic di-GMP (c-di-GMP), a ubiquitous bacterial second messenger that is synthesized by diguanylate cyclase (DGC) with the GGDEF-domain, regulates diverse virulence phenotypes in pathogenic bacteria. Although 11 genes encoding GGDEF domain proteins have been shown in the genome of Xanthomonas oryzae pv. oryzae (Xoo) strain PXO99(A) , the causal pathogen of bacterial blight of rice, however, little is known about their roles in the c-di-GMP regulation of virulence in the pathogen. GdpX1, one of the GGDEF-domain proteins in Xoo was investigated in this study to reveal its regulatory function of bacterial virulence expression through genetic analysis. METHODS AND RESULTS: GdpX1 was functionally characterized in virulence expression through deletion and overexpression analysis. Bioinformatics analysis revealed the GGDEF-domain in GdpX1 was well conserved, indicating it is a putative DGC. Deletion of gdpX1 resulted in significant increases in virulence, exopolysaccharide (EPS) production and flagellar motility. In contrast, overexpression of gdpX1 dramatically reduced these virulence phenotypes. qRT-PCR analysis showed genes related to the type III secretion system (T3SS), EPS synthesis, and flagellar motility, were up-regulated in ?gdpX1 and down-regulated in the gdpX1-overexpressed strains. In addition, overexpression of gdpX1 promoted biofilm formation and xylanase activity. CONCLUSION: GdpX1 is the first GGDEF domain protein functionally characterized in Xoo, which functions as a negative regulator of bacterial virulence via suppression of virulence-related gene transcription. SIGNIFICANCE AND IMPACT OF THE STUDY: Identification and functional characterization of GdpX1 provided additional insights into molecular mechanisms of c-di-GMP regulation of bacterial virulence expression. PMID- 26929399 TI - Comparison of DNA-based techniques for differentiation of production strains of ale and lager brewing yeast. AB - AIMS: Brewing yeasts are classified into two species-Saccharomyces pastorianus and Saccharomyces cerevisiae. Most of the brewing yeast strains are natural interspecies hybrids typically polyploids and their identification is thus often difficult giving heterogenous results according to the method used. We performed genetic characterization of a set of the brewing yeast strains coming from several yeast culture collections by combination of various DNA-based techniques. The aim of this study was to select a method for species-specific identification of yeast and discrimination of yeast strains according to their technological classification. METHODS AND RESULTS: A group of 40 yeast strains were characterized using PCR-RFLP analysis of ITS-5.8S, NTS, HIS4 and COX2 genes, multiplex PCR, RAPD-PCR of genomic DNA, mtDNA-RFLP and electrophoretic karyotyping. Reliable differentiation of yeast to the species level was achieved by PCR-RFLP of HIS4 gene. Numerical analysis of the obtained RAPD-fingerprints and karyotype revealed species-specific clustering corresponding with the technological classification of the strains. Taxonomic position and partial hybrid nature of strains were verified by multiplex PCR. Differentiation among species using the PCR-RFLP of ITS-5.8S and NTS region was shown to be unreliable. Karyotyping and RFLP of mitochondrial DNA evinced small inaccuracies in strain categorization. CONCLUSIONS: PCR-RFLP of HIS4 gene and RAPD-PCR of genomic DNA are reliable and suitable methods for fast identification of yeast strains. RAPD PCR with primer 21 is a fast and reliable method applicable for differentiation of brewing yeasts with only 35% similarity of fingerprint profile between the two main technological groups (ale and lager) of brewing strains. SIGNIFICANCE AND IMPACT OF THE STUDY: It was proved that PCR-RFLP method of HIS4 gene enables precise discrimination among three technologically important Saccharomyces species. Differentiation of brewing yeast to the strain level can be achieved using the RAPD-PCR technique. PMID- 26929400 TI - Slow-binding inhibition of acetylcholinesterase by an alkylammonium derivative of 6-methyluracil: mechanism and possible advantages for myasthenia gravis treatment. AB - Inhibition of human AChE (acetylcholinesterase) and BChE (butyrylcholinesterase) by an alkylammonium derivative of 6-methyluracil, C-547, a potential drug for the treatment of MG (myasthenia gravis) was studied. Kinetic analysis of AChE inhibition showed that C-547 is a slow-binding inhibitor of type B, i.e. after formation of the initial enzyme.inhibitor complex (Ki=140 pM), an induced-fit step allows establishment of the final complex (Ki*=22 pM). The estimated koff is low, 0.05 min(-1) On the other hand, reversible inhibition of human BChE is a fast-binding process of mixed-type (Ki=1.77 MUM; Ki'=3.17 MUM). The crystal structure of mouse AChE complexed with C-547 was solved at 3.13 A resolution. The complex is stabilized by cation-pi, stacking and hydrogen-bonding interactions. Molecular dynamics simulations of the binding/dissociation processes of C-547 and C-35 (a non-charged analogue) to mouse and human AChEs were performed. Molecular modelling on mouse and human AChE showed that the slow step results from an enzyme conformational change that allows C-547 to cross the bottleneck in the active-site gorge, followed by formation of tight complex, as observed in the crystal structure. In contrast, the related non-charged compound C-35 is not a slow-binding inhibitor. It does not cross the bottleneck because it is not sensitive to the electrostatic driving force to reach the bottom of the gorge. Thus C-547 is one of the most potent and selective reversible inhibitors of AChE with a long residence time, tau=20 min, longer than for other reversible inhibitors used in the treatment of MG. This makes C-547 a promising drug for the treatment of this disease. PMID- 26929401 TI - Identification of ferrichrome- and ferrioxamine B-mediated iron uptake by Aspergillus fumigatus. AB - Aspergillus fumigatus is an opportunistic fungal pathogen for immunocompromised patients, and genes involved in siderophore metabolism have been identified as virulence factors. Recently, we identified the membrane transporters sit1 and sit2, which are putative virulence factors of A. fumigatus; sit1 and sit2 are homologous to yeast Sit1, and sit1 and sit2 gene expression was up-regulated after iron depletion. When expressed heterologously in Saccharomyces cerevisiae, sit1 and sit2 were localized to the plasma membrane; sit1 efficiently complemented ferrichrome (FC) and ferrioxamine B (FOB) uptake in yeast cells, whereas sit2 complemented only FC uptake. Deletion of sit1 resulted in a decrease in FOB and FC uptake, and deletion of sit2 resulted in a decrease in FC uptake in A. fumigatus It is of interest that a sit1 and sit2 double-deletion mutant resulted in a synergistic decrease in FC uptake activity. Both sit1 and sit2 were localized to the plasma membrane in A. fumigatus The expression levels of the sit1 and sit2 genes were dependent on hapX under low-but not high-iron conditions. Furthermore, mirB, and sidA gene expression was up-regulated and sreA expression down-regulated when sit1 and sit2 were deleted. Although sit1 and sit2 failed to affect mouse survival rate, these genes affected conidial killing activity. Taken together, our results suggest that sit1 and sit2 are siderophore transporters and putative virulence factors localized to the plasma membrane. PMID- 26929402 TI - Human 3alpha-hydroxysteroid dehydrogenase type 3: structural clues of 5alpha-DHT reverse binding and enzyme down-regulation decreasing MCF7 cell growth. AB - Human 3alpha-HSD3 (3alpha-hydroxysteroid dehydrogenase type 3) plays an essential role in the inactivation of the most potent androgen 5alpha-DHT (5alpha dihydrotestosterone). The present study attempts to obtain the important structure of 3alpha-HSD3 in complex with 5alpha-DHT and to investigate the role of 3alpha-HSD3 in breast cancer cells. We report the crystal structure of human 3alpha-HSD3.NADP(+).A-dione (5alpha-androstane-3,17-dione)/epi-ADT (epiandrosterone) complex, which was obtained by co-crystallization with 5alpha DHT in the presence of NADP(+) Although 5alpha-DHT was introduced during the crystallization, oxidoreduction of 5alpha-DHT occurred. The locations of A-dione and epi-ADT were identified in the steroid-binding sites of two 3alpha-HSD3 molecules per crystal asymmetric unit. An overlay showed that A-dione and epi-ADT were oriented upside-down and flipped relative to each other, providing structural clues for 5alpha-DHT reverse binding in the enzyme with the generation of different products. Moreover, we report the crystal structure of the 3alpha HSD3.NADP(+).4-dione (4-androstene-3,17-dione) complex. When a specific siRNA (100 nM) was used to suppress 3alpha-HSD3 expression without interfering with 3alpha-HSD4, which shares a highly homologous active site, the 5alpha-DHT concentration increased, whereas MCF7 cell growth was suppressed. The present study provides structural clues for 5alpha-DHT reverse binding within 3alpha HSD3, and demonstrates for the first time that down-regulation of 3alpha-HSD3 decreases MCF7 breast cancer cell growth. PMID- 26929403 TI - Structural plasticity and in vivo activity of Cas1 from the type I-F CRISPR-Cas system. AB - CRISPR-Cas systems are adaptive immune systems in prokaryotes that provide protection against viruses and other foreign DNA. In the adaptation stage, foreign DNA is integrated into CRISPR (clustered regularly interspaced short palindromic repeat) arrays as new spacers. These spacers are used in the interference stage to guide effector CRISPR associated (Cas) protein(s) to target complementary foreign invading DNA. Cas1 is the integrase enzyme that is central to the catalysis of spacer integration. There are many diverse types of CRISPR Cas systems, including type I-F systems, which are typified by a unique Cas1-Cas2 3 adaptation complex. In the present study we characterize the Cas1 protein of the potato phytopathogen Pectobacterium atrosepticum, an important model organism for understanding spacer acquisition in type I-F CRISPR-Cas systems. We demonstrate by mutagenesis that Cas1 is essential for adaptation in vivo and requires a conserved aspartic acid residue. By X-ray crystallography, we show that although P. atrosepticum Cas1 adopts a fold conserved among other Cas1 proteins, it possesses remarkable asymmetry as a result of structural plasticity. In particular, we resolve for the first time a flexible, asymmetric loop that may be unique to type I-F Cas1 proteins, and we discuss the implications of these structural features for DNA binding and enzymatic activity. PMID- 26929404 TI - Co-occurrence of analogous enzymes determines evolution of a novel (betaalpha)8 isomerase sub-family after non-conserved mutations in flexible loop. AB - We investigate the evolution of co-occurring analogous enzymes involved in L tryptophan and L-histidine biosynthesis in Actinobacteria Phylogenetic analysis of trpF homologues, a missing gene in certain clades of this lineage whose absence is complemented by a dual-substrate HisA homologue, termed PriA, found that they fall into three categories: (i) trpF-1, an L-tryptophan biosynthetic gene horizontally acquired by certain Corynebacterium species; (ii) trpF-2, a paralogue known to be involved in synthesizing a pyrrolopyrrole moiety and (iii) trpF-3, a variable non-conserved orthologue of trpF-1 We previously investigated the effect of trpF-1 upon the evolution of PriA substrate specificity, but nothing is known about the relationship between trpF-3 and priA After in vitro steady-state enzyme kinetics we found that trpF-3 encodes a phosphoribosyl anthranilate isomerase. However, mutation of this gene in Streptomyces sviceus did not lead to auxothrophy, as expected from the biosynthetic role of trpF-1 Biochemical characterization of a dozen co-occurring TrpF-2 or TrpF-3, with PriA homologues, explained the prototrophic phenotype, and unveiled an enzyme activity trade-off between TrpF and PriA. X-ray structural analysis suggests that the function of these PriA homologues is mediated by non-conserved mutations in the flexible L5 loop, which may be responsible for different substrate affinities. Thus, the PriA homologues that co-occur with TrpF-3 represent a novel enzyme family, termed PriB, which evolved in response to PRA isomerase activity. The characterization of co-occurring enzymes provides insights into the influence of functional redundancy on the evolution of enzyme function, which could be useful for enzyme functional annotation. PMID- 26929405 TI - The METTL20 Homologue from Agrobacterium tumefaciens Is a Dual Specificity Protein-lysine Methyltransferase That Targets Ribosomal Protein L7/L12 and the beta Subunit of Electron Transfer Flavoprotein (ETFbeta). AB - Human METTL20 is a mitochondrial, lysine-specific methyltransferase that methylates the beta-subunit of electron transfer flavoprotein (ETFbeta). Interestingly, putative METTL20 orthologues are found in a subset of alpha proteobacteria, including Agrobacterium tumefaciens Using an activity-based approach, we identified in bacterial extracts two substrates of recombinant METTL20 from A. tumefaciens (AtMETTL20), namely ETFbeta and the ribosomal protein RpL7/L12. We show that AtMETTL20, analogous to the human enzyme, methylates ETFbeta on Lys-193 and Lys-196 both in vitro and in vivo ETF plays a key role in mediating electron transfer from various dehydrogenases, and we found that its electron transferring ability was diminished by AtMETTL20-mediated methylation of ETFbeta. Somewhat surprisingly, AtMETTL20 also catalyzed monomethylation of RpL7/L12 on Lys-86, a common modification also found in many bacteria that lack METTL20. Thus, we here identify AtMETTL20 as the first enzyme catalyzing RpL7/L12 methylation. In summary, here we have identified and characterized a novel bacterial lysine-specific methyltransferase with unprecedented dual substrate specificity within the seven beta-strand class of lysine-specific methyltransferases, as it targets two apparently unrelated substrates, ETFbeta and RpL7/L12. Moreover, the present work establishes METTL20-mediated methylation of ETFbeta as the first lysine methylation event occurring in both bacteria and humans. PMID- 26929406 TI - Loss of Interdependent Binding by the FoxO1 and FoxA1/A2 Forkhead Transcription Factors Culminates in Perturbation of Active Chromatin Marks and Binding of Transcriptional Regulators at Insulin-sensitive Genes. AB - FoxO1 binds to insulin response elements located in the promoters of insulin-like growth factor-binding protein 1 (IGFBP1) and glucose-6-phosphatase (G6Pase), activating their expression. Insulin-mediated phosphorylation of FoxO1 promotes cytoplasmic translocation, inhibiting FoxO1-mediated transactivation. We have previously demonstrated that FoxO1 opens and remodels chromatin assembled from the IGFBP1 promoter via a highly conserved winged helix motif. This finding, which established FoxO1 as a "pioneer" factor, suggested a model whereby FoxO1 chromatin remodeling at regulatory targets facilitates binding and recruitment of additional regulatory factors. However, the impact of FoxO1 phosphorylation on its ability to bind chromatin and the effect of FoxO1 loss on recruitment of neighboring transcription factors at its regulatory targets in liver chromatin is unknown. In this study, we demonstrate that an amino acid substitution that mimics insulin-mediated phosphorylation of a serine in the winged helix DNA binding motif curtails FoxO1 nucleosome binding. We also demonstrate that shRNA mediated loss of FoxO1 binding to the IGFBP1 and G6Pase promoters in HepG2 cells significantly reduces binding of RNA polymerase II and the pioneer factors FoxA1/A2. Knockdown of FoxA1 similarly reduced binding of RNA polymerase II and FoxO1. Reduction in acetylation of histone H3 Lys-27 accompanies loss of FoxO1 and FoxA1/A2 binding. Interdependent binding of FoxO1 and FoxA1/A2 possibly entails cooperative binding because FoxO1 and FoxA1/A2 facilitate one another's binding to IGFPB1 promoter DNA. These results illustrate how transcription factors can nucleate transcriptional events in chromatin in response to signaling events and suggest a model for regulation of hepatic glucose metabolism through interdependent FoxO/FoxA binding. PMID- 26929407 TI - Promoter-Terminator Gene Loops Affect Alternative 3'-End Processing in Yeast. AB - Many eukaryotic genes undergo alternative 3'-end poly(A)-site selection producing transcript isoforms with 3'-UTRs of different lengths and post-transcriptional fates. Gene loops are dynamic structures that juxtapose the 3'-ends of genes with their promoters. Several functions have been attributed to looping, including memory of recent transcriptional activity and polarity of transcription initiation. In this study, we investigated the relationship between gene loops and alternative poly(A)-site. Using the KlCYC1 gene of the yeast Kluyveromyces lactis, which includes a single promoter and two poly(A) sites separated by 394 nucleotides, we demonstrate in two yeast species the formation of alternative gene loops (L1 and L2) that juxtapose the KlCYC1 promoter with either proximal or distal 3'-end processing sites, resulting in the synthesis of short and long forms of KlCYC1 mRNA. Furthermore, synthesis of short and long mRNAs and formation of the L1 and L2 loops are growth phase-dependent. Chromatin immunoprecipitation experiments revealed that the Ssu72 RNA polymerase II carboxyl-terminal domain phosphatase, a critical determinant of looping, peaks in early log phase at the proximal poly(A) site, but as growth phase advances, it extends to the distal site. These results define a cause-and-effect relationship between gene loops and alternative poly(A) site selection that responds to different physiological signals manifested by RNA polymerase II carboxyl-terminal domain phosphorylation status. PMID- 26929409 TI - Asymmetric Functional Conversion of Eubacterial Light-driven Ion Pumps. AB - In addition to the well-known light-driven outward proton pumps, novel ion pumping rhodopsins functioning as outward Na(+) and inward Cl(-) pumps have been recently found in eubacteria. They convert light energy into transmembrane electrochemical potential difference, similar to the prototypical archaeal H(+) pump bacteriorhodopsin (BR) and Cl(-) pump halorhodopsin (HR). The H(+), Na(+), and Cl(-) pumps possess the conserved respective DTE, NDQ, and NTQ motifs in the helix C, which likely serve as their functional determinants. To verify this hypothesis, we attempted functional interconversion between selected pumps from each category by mutagenesis. Introduction of the proton-pumping motif resulted in successful Na(+) -> H(+) functional conversion. Introduction of the respective characteristic motifs with several additional mutations leads to successful Na(+) -> Cl(-) and Cl(-) -> H(+) functional conversions, whereas remaining conversions (H(+) -> Na(+), H(+) -> Cl(-), Cl(-) -> Na(+)) were unsuccessful when mutagenesis of 4-6 residues was used. Phylogenetic analysis suggests that a H(+) pump is the common ancestor of all of these rhodopsins, from which Cl(-) pumps emerged followed by Na(+) pumps. We propose that successful functional conversions of these ion pumps are achieved exclusively when mutagenesis reverses the evolutionary amino acid sequence changes. Dependence of the observed functional conversions on the direction of evolution strongly suggests that the essential structural mechanism of an ancestral function is retained even after the gain of a new function during natural evolution, which can be evoked by a few mutations. By contrast, the gain of a new function needs accumulation of multiple mutations, which may not be easily reproduced by limited mutagenesis in vitro. PMID- 26929408 TI - Structural and Functional Analysis of a Novel Interaction Motif within UFM1 activating Enzyme 5 (UBA5) Required for Binding to Ubiquitin-like Proteins and Ufmylation. AB - The covalent conjugation of ubiquitin-fold modifier 1 (UFM1) to proteins generates a signal that regulates transcription, response to cell stress, and differentiation. Ufmylation is initiated by ubiquitin-like modifier activating enzyme 5 (UBA5), which activates and transfers UFM1 to ubiquitin-fold modifier conjugating enzyme 1 (UFC1). The details of the interaction between UFM1 and UBA5 required for UFM1 activation and its downstream transfer are however unclear. In this study, we described and characterized a combined linear LC3-interacting region/UFM1-interacting motif (LIR/UFIM) within the C terminus of UBA5. This single motif ensures that UBA5 binds both UFM1 and light chain 3/gamma aminobutyric acid receptor-associated proteins (LC3/GABARAP), two ubiquitin (Ub) like proteins. We demonstrated that LIR/UFIM is required for the full biological activity of UBA5 and for the effective transfer of UFM1 onto UFC1 and a downstream protein substrate both in vitro and in cells. Taken together, our study provides important structural and functional insights into the interaction between UBA5 and Ub-like modifiers, improving the understanding of the biology of the ufmylation pathway. PMID- 26929410 TI - Regulation of Piezo2 Mechanotransduction by Static Plasma Membrane Tension in Primary Afferent Neurons. AB - The Piezo2 channel is a newly identified mammalian mechanical transducer that confers rapidly adapting mechanically activated (RA-MA) currents in primary afferent neurons. The Piezo2 channels sense rapid membrane displacement, but it is not clear whether they are sensitive to osmotic swelling, which slowly increases static plasma membrane tension (SPMT). Here, we show that SPMT exerts a profound impact on the mechanical sensitivity of RA-MA channels in primary afferent neurons. RA-MA currents are greatly enhanced, and the mechanical threshold was reduced in both primary afferent neurons of rat dorsal root ganglia (DRG) and HEK293 cells heterologously expressing Piezo2 when these cells undergo osmotic swelling to increase SPMT. Osmotic swelling switches the kinetics of RA MA currents to the slowly adapting type in both cultured DRG neurons and HEK293 cells heterologously expressing Piezo2. The potentiation of RA-MA currents is abolished when cultured DRG neurons are treated with cytochalasin D, an actin filament disruptor that prevents SPMT of cultured DRG neurons from an increase by osmotic swelling. Osmotic swelling significantly increases DRG neuron mechano excitability such that a subthreshold mechanical stimulus can result in action potential firing. Behaviorally, the mechanical hind paw withdrawal threshold in rats is reduced following the injection of a hypotonic solution, but this osmotic effect is abolished when cytochalasin D or Gd(3+) is co-administered with the hypo-osmotic solution. Taken together, our findings suggest that Piezo2-mediated mechanotransduction is regulated by SPMT in primary afferent neurons. Because SPMT can be changed by multiple biological factors, our findings may have broad implications in mechanical sensitivity under physiological and pathological conditions. PMID- 26929411 TI - A Novel Function of Pet54 in Regulation of Cox1 Synthesis in Saccharomyces cerevisiae Mitochondria. AB - Cytochrome c oxidase assembly requires the synthesis of the mitochondria-encoded core subunits, Cox1, Cox2, and Cox3. In yeast, Pet54 protein is required to activate translation of the COX3 mRNA and to process the aI5beta intron on the COX1 transcript. Here we report a third, novel function of Pet54 on Cox1 synthesis. We observed that Pet54 is necessary to achieve an efficient Cox1 synthesis. Translation of the COX1 mRNA is coupled to the assembly of cytochrome c oxidase by a mechanism that involves Mss51. This protein activates translation of the COX1 mRNA by acting on the COX1 5'-UTR, and, in addition, it interacts with the newly synthesized Cox1 protein in high molecular weight complexes that include the factors Coa3 and Cox14. Deletion of Pet54 decreased Cox1 synthesis, and, in contrast to what is commonly observed for other assembly mutants, double deletion of cox14 or coa3 did not recover Cox1 synthesis. Our results show that Pet54 is a positive regulator of Cox1 synthesis that renders Mss51 competent as a translational activator of the COX1 mRNA and that this role is independent of the assembly feedback regulatory loop of Cox1 synthesis. Pet54 may play a role in Mss51 hemylation/conformational change necessary for translational activity. Moreover, Pet54 physically interacts with the COX1 mRNA, and this binding was independent of the presence of Mss51. PMID- 26929414 TI - The goal is to go further and do better: but how? PMID- 26929413 TI - Nutritional effects on the mycelial growth and enzymatic activity of Isaria farinosa, and Hepialus larvae growth. AB - AIMS: To investigate the nutritional requirements of the mycelial growth and pathogenesis-related enzymatic activity on Isaria farinosa and the nutritional effect of fungus on its host Hepialus larvae. METHODS AND RESULTS: Sixteen carbon sources, 16 nitrogen sources and 9 vitamin combinations were tested. The nutritional conditions that significantly prevented I. farinosa pathogenesis were selected as feed additives for rearing Hepialus larvae. Citric acid significantly inhibited the growth of I. farinosa and the activity of three enzymes. l histidine and l-aspartic acid significantly reduced the dry weights of mycelia and their protease and lipase activities. Vitamin combination that lacked VB 1 significantly increased the growth of I. farinosa and enhanced its chitinase and lipase activities. l-aspartic acid, VB 1 or a combination of them were beneficial for maintaining the larvae survival rate and decreasing the disease rate. The result provides new insight to develop a nutrition-based strategy to control fungal epidemics during insect rearing. CONCLUSIONS: The ability of some specific nutrients to inhibit mycelial growth and enzymatic activity can prevent epidemics of fungal disease. SIGNIFICANCE AND IMPACT OF THE STUDY: These results will aid in the development of nutrition-based strategies to control entomopathogenic fungal epidemics during the large-scale rearing of insects. PMID- 26929412 TI - Structural Basis for Substrate Preference of SMYD3, a SET Domain-containing Protein Lysine Methyltransferase. AB - SMYD3 is a SET domain-containing N-lysine methyltransferase associated with multiple cancers. Its reported substrates include histones (H3K4 and H4K5), vascular endothelial growth factor receptor 1 (VEGFR1 Lys(831)) and MAP3 kinase kinase (MAP3K2 Lys(260)). To reveal the structural basis for substrate preference and the catalytic mechanism of SMYD3, we have solved its co-crystal structures with VEGFR1 and MAP3K2 peptides. Our structural and biochemical analyses show that MAP3K2 serves as a robust substrate of SMYD3 because of the presence of a phenylalanine residue at the -2 position. A shallow hydrophobic pocket on SMYD3 accommodates the binding of the phenylalanine and promotes efficient catalytic activities of SMYD3. By contrast, SMYD3 displayed a weak activity toward a VEGFR1 peptide, and the location of the acceptor lysine in the folded kinase domain of VEGFR1 requires drastic conformational rearrangements for juxtaposition of the acceptor lysine with the enzymatic active site. Our results clearly revealed structural determinants for the substrate preference of SMYD3 and provided mechanistic insights into lysine methylation of MAP3K2. The knowledge should be useful for the development of SMYD3 inhibitors in the fight against MAP3K2 and Ras-driven cancer. PMID- 26929415 TI - Pulmonary hypertension. AB - In 2015, more than 800 papers were published in the field of pulmonary hypertension. A Clinical Year in Review article cannot possibly incorporate all this work and needs to be selective. The recently published European guidelines for the diagnosis and treatment of pulmonary hypertension contain an inclusive summary of all published clinical studies conducted until very recently. Here, we provide an overview of papers published after the finalisation of the guideline. In addition, we summarise recent advances in pulmonary vasculature science. The selection we made from the enormous amount of published work undoubtedly reflects our personal views and may not include all papers with a significant impact in the near or more distant future. The focus of this paper is on the diagnosis of pulmonary arterial hypertension, understanding the success of combination therapy on the right ventricle and scientific breakthroughs. PMID- 26929416 TI - Sleep apnoea. AB - Sleep apnoea is a disorder characterised by repetitive pauses in breathing during sleep caused by airway occlusion (obstructive sleep apnoea) or altered control of breathing (central sleep apnoea). In this Clinical Year in Review, we summarise high-impact research from the past year pertaining to management, diagnosis and cardio-metabolic consequences of sleep apnoea. PMID- 26929417 TI - The role of moxifloxacin in tuberculosis therapy. AB - Tuberculosis (TB) remains a global threat with more than 9 million new infections. Treatment remains difficult and there has been no change in the duration of the standard regimen since the early 1980s. Moreover, many patients are unable to tolerate this treatment and discontinue therapy, increasing the risk of resistance. There is a growing tide of multidrug resistance and few effective antibiotics to tackle the problem. Since the turn of the millennium there has been a surge in interest in developing new therapies for TB and a number of new drugs have been developed. In this review the repurposing of moxifloxacin, an 8-methoxy-fluoroquinolone, for TB treatment is discussed. The evidence that underpins the development of this agent is reviewed. The results of the recently completed phase III trials are summarised and the reasons for the unexpected outcome are explored. Finally, the design of new trials that incorporate moxifloxacin, and that address both susceptible disease and multidrug resistance, is described. PMID- 26929419 TI - Paediatric respiratory infections. AB - Pulmonary infections remain a major cause of infant and child mortality worldwide and are responsible for a substantial burden of morbidity. During the 2015 European Respiratory Society International Congress in Amsterdam, some of the main findings from peer-reviewed articles addressing this topic that were published in the preceding 12 months were reviewed in a Paediatric Clinical Year in Review session. The following article highlights some of the insights provided by these articles into the complex interactions of the human host with the extensive and dynamic populations of microorganisms that call an individual "home". PMID- 26929418 TI - Short-course treatment for multidrug-resistant tuberculosis: the STREAM trials. AB - Multidrug-resistant (MDR) tuberculosis (TB) is a threat to global TB control, as suboptimal and poorly tolerated treatment options have resulted in largely unfavourable outcomes for these patients. The last of six cohort studies conducted in Bangladesh which assessed a new shorter regimen using currently available TB drugs showed promising results and offered the possibility of a more acceptable and more effective regimen than the one recommended by the World Health Organization (WHO). The aims of stage 1 of the STREAM (Evaluation of a Standardised Treatment Regimen of Anti-tuberculosis Drugs for Patients with Multidrug-resistant Tuberculosis) trial are to evaluate the efficacy and safety of this regimen, compared to the current WHO-recommended standard of care. Stage 2 evaluates two new bedaquiline-containing regimens: one an all-oral regimen and the second a further shortened and simplified version of the stage 1 study regimen, comparing the efficacy and safety of each to that of the stage 1 study regimen and also to the WHO-recommended standard of care. Success of the stage 1 study regimen would in all probability provide a new standard of care for MDR-TB patients, while positive results from the bedaquiline-containing regimens in stage 2 may allow for even greater progress in the management of this difficult population. PMID- 26929421 TI - Sleep disordered breathing in childhood. AB - Sleep disordered breathing (SDB) in childhood is linked with significant end organ dysfunction across various systems, particularly with cardiovascular, neurocognitive and metabolic consequences. If we understand the pathophysiology of SDB, diagnose it promptly and treat appropriately, we may be able to prevent morbidity associated with SDB and also save health resources around the world. In this article, we highlight articles on this topic published in medical journals in the past year. PMID- 26929420 TI - Asthma in childhood. AB - Several topics on childhood asthma were addressed in the Paediatric Clinical Year in Review session at the 2015 European Respiratory Society International Congress. With regard to the relationship between lower respiratory tract infections and asthma, it emerges that is the number of respiratory episodes in the first years of life, but not the particular viral trigger, to be associated with later asthma development. Understanding which characteristics of individual patients are associated with an increased risk for asthma exacerbation is a critical step to implement strategies preventing these seasonal events. Recent data suggest the possibility that exhaled volatile organic compounds may qualify as biomarkers in detecting early signs of asthma. Adding information of exhaled volatile organic compounds and expression of inflammation genes to a clinical tool significantly improves asthma prediction in preschool wheezy children. Personal communication with children and adolescents is likely more important than the tools actually used for monitoring asthma. Systemic corticosteroids do not affect the long-term prognosis in children with first viral-induced wheezing episode and should be used cautiously during acute episodes. Finally, stress and a polymorphism upstream of a specific gene are both associated with reduced bronchodilator response in children with asthma. PMID- 26929422 TI - Long-acting muscarinic antagonists: a potential add-on therapy in the treatment of asthma? AB - Asthma is a chronic inflammatory disorder of the airways that is a major global burden on both individuals and healthcare systems. Despite guideline-directed treatment, a significant proportion of patients with asthma do not achieve control. This review focuses on the potential use of long-acting anticholinergics as bronchodilators in the treatment of asthma, with results published from clinical trials of glycopyrrolate, umeclidinium and tiotropium. The tiotropium clinical trial programme is the most advanced, with data available from a number of phase II and III studies of tiotropium as an add-on to inhaled corticosteroid maintenance therapy, with or without a long-acting beta2-agonist, in patients across asthma severities. Recent studies using the Respimat Soft Mist inhaler have identified 5 ug once daily as the preferred dosing regimen, which has shown promising results in adults, adolescents and children with asthma. Tiotropium Respimat has recently been incorporated into the Global Initiative for Asthma 2015 treatment strategy as a recommended alternative therapy at steps 4 and 5 in adult patients with a history of exacerbations. The increasing availability of evidence from ongoing and future clinical trials will be beneficial in determining where long-acting anticholinergic agents fit in future treatment guidelines across a variety of patient populations and disease severities. PMID- 26929423 TI - Radio(chemo)therapy in locally advanced nonsmall cell lung cancer. AB - Definitive radiochemotherapy is the standard treatment for many patients with locally advanced nonsmall cell lung cancer (NSCLC). Treatment outcomes have improved over the last decades. Several treatment regimens have been shown effective and safe. This review summarises the results of significant studies between 1996 and 2015 on concomitant and sequential radiochemotherapy regimens and radiation dose per fraction. Beside therapy regimens, optimised radiotherapy planning is indispensable to improve outcome and minimise radiation-induced toxicity. An insight into the rationale of radiotherapy planning for stage III NSCLC is also provided. PMID- 26929424 TI - KRAS oncogene in lung cancer: focus on molecularly driven clinical trials. AB - KRAS mutations are the most frequent molecular abnormalities found in one out of four nonsmall cell lung cancers (NSCLC). Their incidence increases in cases of adenocarcinoma, smokers and Caucasian patients. Their negative value in terms of prognosis and responsiveness to both standard chemotherapy and targeted therapies remains under debate. Many drugs have been developed specifically for KRAS mutated NSCLC patients. Direct inhibition of RAS activation failed to show any clinical efficacy. Inhibition of downstream targets of the mitogen-activated protein kinase (MEK) pathway is a promising strategy: phase II combinations of MEK 1/2 kinase inhibitors with chemotherapy doubled patients' clinical outcomes. One phase III trial in such a setting is ongoing. Double inhibition of MEK and epidermal growth factor receptor proteins is currently being assessed in early phase trials. The association with mammalian target of rapamycin pathway inhibition leads to non-manageable toxicity. Other strategies, such as inhibition of molecular heat-shock proteins 90 or focal adhesion kinase are currently assessed. Abemaciclib, a cyclin-dependent kinase 4/6 inhibitor, showed promising results in a phase I trial, with a 54% disease control rate. Results of an ongoing phase III trial are warranted. Immunotherapy might be the next relevant step in KRAS-mutated NSCLC management due to the high burden of associated mutations and neo-antigens. PMID- 26929425 TI - Future treatment for asthma. AB - The landscape of asthma has considerably changed after 40 years of inhaled corticosteroid development and nearly 20 years since the first monoclonal antibodies (mAbs) were approved. New members of pharmacological families and more effective drug-delivery devices have been designed but the proportion of uncontrolled patients, unfortunately, remains stable. The most promising treatments now rely on targeted therapies that encourage the improvement of the characterisation of our patients. These clinical (phenotype) or new biological (endotype) tools lead to palpable personalised medicine. This review examines not only the future of mAbs and other new ways of treating asthma but also describes futuristic views based on the paradigm shifts that are ready to occur. PMID- 26929426 TI - A rare case of sarcoidosis-associated pulmonary hypertension in a patient exposed to silica. PMID- 26929427 TI - Pulmonary tuberculosis masquerading as metastatic lung disease. PMID- 26929428 TI - "Recent advances in targeting the prostacyclin pathway in pulmonary arterial hypertension." Irene M. Lang and Sean P. Gaine. Eur Respir Rev 2015; 24: 630-641. PMID- 26929429 TI - Entrapment of anaerobic thermophilic and hyperthermophilic marine micro-organisms in a gellan/xanthan matrix. AB - AIMS: The aims of this study were (i) to develop a protocol for the entrapment of anaerobic (hyper)thermophilic marine micro-organisms; (ii) to test the use of the chosen polymers in a range of physical and chemical conditions and (iii) to validate the method with batch cultures. METHODS AND RESULTS: The best conditions for immobilization were obtained at 80 degrees C with gellan and xanthan gums. After 5-week incubation, beads showed a good resistance to all tested conditions except those simultaneously including high temperature (100 degrees C), low NaCl (<0?5 mol l(-1) ) and extreme pH (4/8). To confirm the method efficiency, batch cultures with immobilized Thermosipho sp. strain AT1272 and Thermococcus kodakarensis strain KOD1 showed an absence of detrimental effect on cell viability and a good growth within and outside the beads. CONCLUSION: This suggests that entrapment in a gellan-xanthan matrix could be employed for the culture of anaerobic (hyper)thermophilic marine micro-organisms. SIGNIFICANCE AND IMPACT OF THE STUDY: (Hyper)thermophilic marine micro-organisms possess a high biotechnological potential. Generally microbial cells are grown as free-cell cultures. The use of immobilized cells may offer several advantages such as protection against phage attack, high cell biomass and better production rate of desired metabolites. PMID- 26929431 TI - Listening to the consumer voice: developing multilingual cancer information resources for people affected by liver cancer. AB - BACKGROUND: In Australia, liver cancer incidence is rising, particularly among people born in hepatitis B-endemic countries. We sought to build an understanding of the information needs of people affected by liver cancer, to inform the design of in-language consumer information resources. METHODS: We searched the World Wide Web for available in-language consumer information and conducted a literature search on consumers' information needs and their preferred means of accessing it. Qualitative data collection involved bilingual researchers conducting focus group discussions (26 participants) and in-depth interviews (22 participants) with people affected by liver cancer in English, Vietnamese, Cantonese and Mandarin. Sessions were audio-recorded, transcribed, translated and thematically analysed. The key themes and salient findings informed the development of in-language multimedia information resources. RESULTS: Many consumer resources did not cater for people with low literacy levels. The participants wanted more information on cancer diagnostic and treatment options, nutrition and Chinese Medicine and experienced communication challenges speaking to health professionals. While Vietnamese speakers relied entirely on information provided by their doctors, other participants actively searched for additional treatment information and commonly used the Internet to source it. We developed multilingual, multimedia consumer information resources addressing identified consumer information needs through an iterative process, in collaboration with our multilingual consumer panel. These resources are available in four languages, as separate modules accessible online and in DVD format. CONCLUSION: This process enabled the development of user-friendly patient resources, which complement health-care provider information and supports informed patient decision making. PMID- 26929430 TI - 'Who is on your health-care team?' Asking individuals with heart failure about care team membership and roles. AB - BACKGROUND: Complex, chronically ill patients require interprofessional teams to address their multiple health needs; heart failure (HF) is an iconic example of this growing problem. While patients are the common denominator in interprofessional care teams, patients have not explicitly informed our understanding of team composition and function. Their perspectives are crucial for improving quality, patient-centred care. OBJECTIVES: To explore how individuals with HF conceptualize their care team, and perceive team members' roles. SETTING AND PARTICIPANTS: Individuals with advanced HF were recruited from five cities in three Canadian provinces. DESIGN: Individuals were asked to identify their HF care team during semi-structured interviews. Team members' titles and roles, quotes pertaining to team composition and function, and frailty criteria were extracted and analysed using descriptive statistics and content analysis. RESULTS: A total of 62 individuals with HF identified 2-19 team members. Caregivers, nurses, family physicians and cardiologists were frequently identified; teams also included dentists, foot care specialists, drivers, housekeepers and spiritual advisors. Most individuals met frailty criteria and described participating in self-management. DISCUSSION: Individuals with HF perceived being active participants, not passive recipients, of care. They identified teams that were larger and more diverse than traditional biomedical conceptualizations. However, the nature and importance of team members' roles varied according to needs, relationships and context. Patients' degree of agency was negotiated within this context, causing multiple, sometimes conflicting, responses. CONCLUSION: Ignoring the patient's role on the care team may contribute to fragmented care. However, understanding the team through the patient's lens - and collaborating meaningfully among identified team members - may improve health-care delivery. PMID- 26929432 TI - Topical minoxidil and tretinoin combined with an oral vitamin D analog as a treatment for woolly hair. PMID- 26929433 TI - Inhibitory action of gonadotropin-inhibitory hormone on the signaling pathways induced by kisspeptin and vasoactive intestinal polypeptide in GnRH neuronal cell line, GT1-7. AB - Gonadotropin-inhibitory hormone (GnIH) acts as a negative regulator of reproduction by acting on gonadotropes and gonadotropin-releasing hormone (GnRH) neurons. Despite its functional significance, the molecular mechanism of GnIH action in the target cells has not been fully elucidated. To expand our previous study on GnIH actions in gonadotropes, we investigated the potential signal transduction pathway that conveys the inhibitory action of GnIH in GnRH neurons by using the GnRH neuronal cell line, GT1-7. We examined whether GnIH inhibits the action of kisspeptin and vasoactive intestinal polypeptide (VIP), positive regulators of GnRH neurons. Although GnIH significantly suppressed the stimulatory effect of kisspeptin on GnRH release in hypothalamic culture, GnIH had no inhibitory effect on kisspeptin stimulation of serum response element and nuclear factor of activated T-cell response element activities and ERK phosphorylation, indicating that GnIH may not directly inhibit kisspeptin signaling in GnRH neurons. On the contrary, GnIH effectively eliminated the stimulatory effect of VIP on p38 and ERK phosphorylation, c-Fos mRNA expression, and GnRH release. The use of pharmacological modulators strongly demonstrated the specific inhibitory action of GnIH on the adenylate cyclase/cAMP/protein kinase A pathway, suggesting a common inhibitory mechanism of GnIH action in GnRH neurons and gonadotropes.-Son, Y. L., Ubuka, T., Soga, T., Yamamoto, K., Bentley, G. E., Tsutsui, K. Inhibitory action of gonadotropin-inhibitory hormone on the signaling pathways induced by kisspeptin and vasoactive intestinal polypeptide in GnRH neuronal cell line, GT1-7. PMID- 26929434 TI - Loss of mitochondrial DNA-encoded protein ND1 results in disruption of complex I biogenesis during early stages of assembly. AB - Mitochondrial complex I (NADH:ubiquinone oxidoreductase) must be assembled precisely from 45 protein subunits for it to function correctly. One of its mitochondrial DNA (mtDNA) encoded subunits, ND1, is incorporated during the early stages of complex I assembly. However, little is known about how mutations in ND1 affect this assembly process. We found that in human 143B cybrid cells carrying a homoplasmic MT-ND1 mutation, ND1 protein could not be translated. As a result, the early stages of complex I assembly were disrupted, with mature complex I undetectable and complex I-linked respiration severely reduced to 2.0% of control levels. Interestingly, complex IV (ferrocytochrome c:oxygen oxidoreductase) steady-state levels were also reduced to 40.3%, possibly due to its diminished stability in the absence of respiratory supercomplex formation. This was in comparison with 143B cybrid controls (that contained wild-type mtDNA on the same nuclear background), which exhibited normal complex I, complex IV, and supercomplex assembly. We conclude that the loss of ND1 stalls complex I assembly during the early stages of its biogenesis, which not only results in the loss of mature complex I but also disrupts the stability of complex IV and the respiratory supercomplex to cause mitochondrial dysfunction.-Lim, S. C., Hroudova, J., Van Bergen, N. J., Lopez Sanchez, M. I. G., Trounce, I. A., McKenzie, M. Loss of mitochondrial DNA-encoded protein ND1 results in disruption of complex I biogenesis during early stages of assembly. PMID- 26929435 TI - Severe cryptococcal-associated neurological immune reconstitution inflammatory syndrome in a renal transplant recipient treated with adalimumab. AB - Cryptococcosis is a major concern in organ transplant recipients. A decrease in immunosuppressants following the initiation of antifungal therapy is currently recommended, but can occasionally be complicated by the onset of immune reconstitution inflammatory syndrome (IRIS). We report on a case of cryptococcosis in a kidney transplant recipient, compounded by severe neurological IRIS, the outcome of which was unfavorable despite the use of anti tumor necrosis factor-alpha monoclonal antibodies. PMID- 26929438 TI - Determining threshold values for barcoding fungi: lessons from Cortinarius (Basidiomycota), a highly diverse and widespread ectomycorrhizal genus. AB - Different distance-based threshold selection approaches were used to assess and compare use of the internal transcribed spacer (ITS) region to distinguish among 901 Cortinarius species represented by >3000 collections. Sources of error associated with genetic markers and selection approaches were explored and evaluated using MOTUs from genus and lineage based-alignments. Our study indicates that 1%-2% more species can be distinguished by using the full-length ITS barcode as compared to either the ITS1 or ITS2 regions alone. Optimal threshold values for different picking approaches and genetic marker lengths inferred from a subset of species containing major lineages ranged from 97.0% to 99.5% sequence similarity using clustering optimization and UNITE SH, and from 1% to 2% sequence dissimilarity with CROP. Errors for the optimal cutoff ranged from 0% to 70%, and these can be reduced to a maximum of 22% when excluding species lacking a barcode gap. A threshold value of 99% is suitable for distinguishing species in the majority of lineages in the genus using the entire ITS region but only 90% of the species could be identified using just the ITS1 or ITS2 region. Prior identification of species, lacking barcode gaps and their subsequent separate analyses, maximized the accuracy of threshold approaches. PMID- 26929437 TI - High-fat diet increases O-GlcNAc levels in cerebral arteries: a link to vascular dysfunction associated with hyperlipidaemia/obesity? AB - Obesity and high fat intake induce alterations in vascular function and structure. Aberrant O-GlcNAcylation (O-GlcNAc) of vascular proteins has been implicated in vascular dysfunction associated with cardiovascular and metabolic diseases. In the present study, we tested the hypothesis that high-fat diet (HFD) mediated increases in O-GlcNAc-modified proteins contribute to cerebrovascular dysfunction. O-GlcNAc-protein content was increased in arteries from male Wistar rats treated with a HFD (45% fat) for 12 weeks compared with arteries from rats on control diet (CD). HFD augmented body weight [(g) 550+/-10 compared with 502+/ 10 CD], increased plasma triacylglycerols [(mg/dl) 160+/-20 compared with 95+/-15 CD] and increased contractile responses of basilar arteries to serotonin [5 hydroxytryptamine (5-HT)] [(pD2) 7.0+/-0.1 compared with 6.7+/-0.09 CD] and the thromboxane analogue 9,11-dideoxy-9alpha,11alpha-methanoepoxy prostaglandin F2alpha (U-46619) [(pD2) 7.2+/-0.1 compared with 6.8+/-0.09 CD]. Of importance, increased levels of O-GlcNAc [induced by 24 h-incubation of vessels with a potent inhibitor of O-GlcNAcase (OGA), O-(2-acetamido-2-deoxy-D glucopyranosylidene)amino-N-phenylcarbamate (PugNAc)] increased basilar artery contractions in response to U-46619 [(pD2) 7.4+/-0.07 compared with 6.8+/-0.08 CD] and 5-HT [(pD2) 7.5+/-0.06 compared with 7.1+/-0.1 CD]. Vessels from rats on the HFD for 12 weeks and vessels treated with PugNAc displayed increased phosphorylation of p38 (Thr(180/182)) and extracellular signal-regulated kinase 1/2 (Erk1/2) (Ser(180/221)). Increased 5HT-induced contractions in arteries from rats on the HFD or in arteries incubated with PugNAc were abrogated by mitogen activated protein kinase (MAPK) inhibitors. Our data show that HFD augments cerebrovascular O-GlcNAc and this modification contributes to increased contractile responses and to the activation of the MAPK pathway in the rat basilar artery. PMID- 26929439 TI - Expression and characterization of a new esterase with GCSAG motif from a permafrost metagenomic library. AB - As a result of construction and screening of a metagenomic library prepared from a permafrost-derived microcosm, we have isolated a novel gene coding for a putative lipolytic enzyme that belongs to the hormone-sensitive lipase family. It encodes a polypeptide of 343 amino acid residues whose amino acid sequence displays maximum likelihood with uncharacterized proteins from Sphingomonas species. A putative catalytic serine residue of PMGL2 resides in a new variant of a recently discovered GTSAG sequence in which a Thr residue is replaced by a Cys residue (GCSAG). The recombinant PMGL2 was produced in Escherichia coli cells and purified by Ni-affinity chromatography. The resulting protein preferably utilizes short-chain p-nitrophenyl esters (C4 and C8) and therefore is an esterase. It possesses maximum activity at 45 degrees C in slightly alkaline conditions and has limited thermostability at higher temperatures. Activity of PMGL2 is stimulated in the presence of 0.25-1.5 M NaCl indicating the good salt tolerance of the new enzyme. Mass spectrometric analysis demonstrated that N-terminal methionine in PMGL2 is processed and cysteine residues do not form a disulfide bond. The results of the study demonstrate the significance of the permafrost environment as a unique genetic reservoir and its potential for metagenomic exploration. PMID- 26929440 TI - A case of cystinuria presenting with cerebellar ataxia and dementia. AB - Cystinuria normally manifests as recurrent urinary stones and renal dysfunction, but can present to neurologists with ataxia, posterior column impairment, intellectual deficiency and pyramidal and extrapyramidal signs; the neuroradiological features include cerebellar, brainstem and cerebral atrophy. It is an autosomal recessive disease caused by a transport disorder of cystine and dibasic amino acids in renal proximal tubules. Most cases have an SLC3A1 and/or SLC7A9 gene mutation but some recent Japanese patients have had distinct heterozygous gene mutations. We report a patient with cystinuria with a heterozygous P482L mutation in the SLC7A9 gene, presenting with atrophy in the cerebellum, brainstem and cerebrum and with no urinary stones. Cystine, an amino acid comprising two cysteine molecules, is transported into cells via a cystine transporter. It is essential for producing hydrogen sulfate and the cellular antioxidant glutathione: these exert neuroprotection in astrocytes and cerebellar Purkinje cells. Although cystinuria is a metabolic disorder associated with renal dysfunction, we suspect that a trafficking defect of transporter rBAT-BAT1 in brain might cause neuronal degeneration, leading to cerebellar and cerebral atrophy. PMID- 26929441 TI - Topiramate-induced acute glaucoma. PMID- 26929436 TI - Kinetic Adaptations of Myosins for Their Diverse Cellular Functions. AB - Members of the myosin superfamily are involved in all aspects of eukaryotic life. Their function ranges from the transport of organelles and cargos to the generation of membrane tension, and the contraction of muscle. The diversity of physiological functions is remarkable, given that all enzymatically active myosins follow a conserved mechanoenzymatic cycle in which the hydrolysis of ATP to ADP and inorganic phosphate is coupled to either actin-based transport or tethering of actin to defined cellular compartments. Kinetic capacities and limitations of a myosin are determined by the extent to which actin can accelerate the hydrolysis of ATP and the release of the hydrolysis products and are indispensably linked to its physiological tasks. This review focuses on kinetic competencies that - together with structural adaptations - result in myosins with unique mechanoenzymatic properties targeted to their diverse cellular functions. PMID- 26929442 TI - Mobilising a team for the WHO Surgical Safety Checklist: a qualitative video study. AB - BACKGROUND: One challenge identified in the Surgical Safety Checklist literature is the inconsistent participation of operating teams in the safety checks. Less is known about how teams move from preparatory activities into a huddle, and how communication underpins this gathering. The objective of this study is to examine the ways of mobilising teams and the level of participation in the safety checks. METHODS: Team participation in time-out and sign-out was examined from a video corpus of 20 elective surgical operations. Teams included surgeons, nurses and anaesthetists in a UK teaching hospital, scheduled to work in the operations observed. Qualitative video analysis of team participation was adapted from the study of social interaction. RESULTS: The key aspects of team mobilisation were the timing of the checklist, the distribution of personnel in the theatre and the instigation practices used. These were interlinked in bringing about the participation outcomes, the number of people huddling up for time-out and sign out. Timing seemed appropriate when most personnel were present in the theatre suite; poor timing was marked by personnel dispersed through the theatre. Participation could be managed using the instigation practices, which included or excluded participation within teams. The factors hindering full-team participation at time-out and sign-out were the overlapping (eg, anaesthetic and nursing) responsibilities and the use of exclusive instigation practices. CONCLUSIONS: The implementation of the Surgical Safety Checklist represents a global concern in patient safety research. Yet how teams huddle for the checks has to be acknowledged as an issue in its own right. Appropriate mobilisation practices can help bringing fuller teams together, which has direct relevance to team training. PMID- 26929443 TI - Response to the letter to the editor by Drs Merchant and Federman. PMID- 26929444 TI - Patient-centred bedside rounds-exploring patient preferences before patient centred care. PMID- 26929446 TI - Jessica Feldman: Microtubule-organizing function dives off centrosomes. PMID- 26929445 TI - Tofacitinib or adalimumab versus placebo: patient-reported outcomes from a phase 3 study of active rheumatoid arthritis. AB - OBJECTIVE: To evaluate effects of tofacitinib or adalimumab on patient-reported outcomes (PROs) in patients with moderate to severe RA and inadequate responses to MTX. METHODS: In this 12-month, phase 3, randomized controlled trial (ORAL Standard), patients (n = 717) receiving background MTX were randomized to tofacitinib 5 or 10 mg twice daily (BID), adalimumab 40 mg once every 2 weeks or placebo. PROs included HAQ-Disability Index, Patient Global Assessment of Arthritis, Patient Assessment of Arthritis Pain, health-related quality of life (Short Form-36 [SF-36]), fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue) and sleep (Medical Outcomes Study-Sleep). RESULTS: At month 3, tofacitinib 10 mg BID treatment resulted in significant changes from baseline vs placebo across all PROs, sustained to month 12, with the highest number of patients reporting improvements ?minimum clinically important differences vs placebo (P < 0.05). Changes from baseline at month 3 with tofacitinib 5 mg BID and adalimumab were similar and statistically significant vs placebo across most PROs, excluding SF-36 Mental Component Score and Social Functioning, Role Emotional, and Mental Health domains, with significantly more patients reporting improvements ?minimum clinically important differences. Numbers Needed to Treat were lowest for tofacitinib 10 mg BID and similar between tofacitinib 5 mg BID and adalimumab. CONCLUSION: Patients with moderate to severe RA and inadequate responses to MTX reported improvements across a broad range of PROs with tofacitinib 5 and 10 mg BID and adalimumab that were significantly superior to placebo. PMID- 26929447 TI - Burning cellular bridges: Two pathways to the big breakup. AB - During cytokinetic abscission, the endosomal sorting complex required for transport (ESCRT) proteins are recruited to the midbody and direct the severing of the intercellular bridge. In this issue, Christ et al. (2016. J. Cell Biol. http://dx.doi.org/10.1083/jcb.201507009) demonstrate that two separate but redundant pathways exist to recruit ESCRT-III proteins to the midbody. PMID- 26929448 TI - Mosaic cellular patterning in the nose: Adhesion molecules give their two scents. AB - The sense of smell is mediated by the olfactory epithelium, which is composed of a mosaic pattern of olfactory sensory cells surrounded by supporting cells. In this issue, Katsunuma et al. (2016. J. Cell Biol. http://dx.doi.org/10.1083/jcb.201509020) show that the differential expression of nectins and cadherins establishes this pattern. PMID- 26929449 TI - ALIX and ESCRT-I/II function as parallel ESCRT-III recruiters in cytokinetic abscission. AB - Cytokinetic abscission, the final stage of cell division where the two daughter cells are separated, is mediated by the endosomal sorting complex required for transport (ESCRT) machinery. The ESCRT-III subunit CHMP4B is a key effector in abscission, whereas its paralogue, CHMP4C, is a component in the abscission checkpoint that delays abscission until chromatin is cleared from the intercellular bridge. How recruitment of these components is mediated during cytokinesis remains poorly understood, although the ESCRT-binding protein ALIX has been implicated. Here, we show that ESCRT-II and the ESCRT-II-binding ESCRT III subunit CHMP6 cooperate with ESCRT-I to recruit CHMP4B, with ALIX providing a parallel recruitment arm. In contrast to CHMP4B, we find that recruitment of CHMP4C relies predominantly on ALIX. Accordingly, ALIX depletion leads to furrow regression in cells with chromosome bridges, a phenotype associated with abscission checkpoint signaling failure. Collectively, our work reveals a two pronged recruitment of ESCRT-III to the cytokinetic bridge and implicates ALIX in abscission checkpoint signaling. PMID- 26929450 TI - Assembly, molecular organization, and membrane-binding properties of development specific septins. AB - Septin complexes display remarkable plasticity in subunit composition, yet how a new subunit assembled into higher-order structures confers different functions is not fully understood. Here, this question is addressed in budding yeast, where during meiosis Spr3 and Spr28 replace the mitotic septin subunits Cdc12 and Cdc11 (and Shs1), respectively. In vitro, the sole stable complex that contains both meiosis-specific septins is a linear Spr28-Spr3-Cdc3-Cdc10-Cdc10-Cdc3-Spr3-Spr28 hetero-octamer. Only coexpressed Spr3 and Spr28 colocalize with Cdc3 and Cdc10 in mitotic cells, indicating that incorporation requires a Spr28-Spr3 protomer. Unlike their mitotic counterparts, Spr28-Spr3-capped rods are unable to form higher-order structures in solution but assemble to form long paired filaments on lipid monolayers containing phosphatidylinositol-4,5-bisphosphate, mimicking presence of this phosphoinositide in the prospore membrane. Spr28 and Spr3 fail to rescue the lethality of a cdc11Delta cdc12Delta mutant, and Cdc11 and Cdc12 fail to restore sporulation proficiency to spr3Delta/spr3Delta spr28Delta/spr28Delta diploids. Thus, specific meiotic and mitotic subunits endow septin complexes with functionally distinct properties. PMID- 26929451 TI - Elevated p62/SQSTM1 determines the fate of autophagy-deficient neural stem cells by increasing superoxide. AB - Autophagy plays important roles in many biological processes, but our understanding of the mechanisms regulating stem cells by autophagy is limited. Interpretations of earlier studies of autophagy using knockouts of single genes are confounded by accumulating evidence for other functions of many autophagy genes. Here, we show that, in contrast to Fip200 deletion, inhibition of autophagy by deletion of Atg5, Atg16L1, or Atg7 does not impair the maintenance and differentiation of postnatal neural stem cells (NSCs). Only Fip200 deletion, but not Atg5, Atg16L1, or Atg7 deletion, caused p62/sequestome1 aggregates to accumulate in NSCs. Fip200 and p62 double conditional knockout mice demonstrated that p62 aggregate formation triggers aberrant superoxide increases by impairing superoxide dismutase functions. By comparing the inhibition of autophagy by deletion of Atg5, Atg16L1, or Atg7 with Fip200 deletion, we revealed a critical role of increased p62 in determining the fate of autophagy-deficient NSCs through intracellular superoxide control. PMID- 26929452 TI - Synergistic action of nectins and cadherins generates the mosaic cellular pattern of the olfactory epithelium. AB - In the olfactory epithelium (OE), olfactory cells (OCs) and supporting cells (SCs), which express different cadherins, are arranged in a characteristic mosaic pattern in which OCs are enclosed by SCs. However, the mechanism underlying this cellular patterning is unclear. Here, we show that the cellular pattern of the OE is established by cellular rearrangements during development. In the OE, OCs express nectin-2 and N-cadherin, and SCs express nectin-2, nectin-3, E-cadherin, and N-cadherin. Heterophilic trans-interaction between nectin-2 on OCs and nectin 3 on SCs preferentially recruits cadherin via alpha-catenin to heterotypic junctions, and the differential distributions of cadherins between junctions promote cellular intercalations, resulting in the formation of the mosaic pattern. These observations are confirmed by model cell systems, and various cellular patterns are generated by the combinatorial expression of nectins and cadherins. Collectively, the synergistic action of nectins and cadherins generates mosaic pattern, which cannot be achieved by a single mechanism. PMID- 26929453 TI - Prevalence and sonographic changes compatible with fatty liver disease in patients referred for abdominal ultrasound examination in Aracaju, SE. AB - OBJECTIVE: To estimate the prevalence and evaluate sonographic findings compatible with changes consistent with hepatic steatosis in patients referred for abdominal ultrasonography at four reference centers in Aracaju, SE, Brazil. MATERIALS AND METHODS: Prospective, descriptive survey, with analytical and quantitative approach, comprising abdominal ultrasonography scans performed with a convex, dynamic 3.75 MHz transducer. Liver dimensions and parenchymal echotexture were evaluated, classifying hepatic steatosis into grades (1, 2 or 3). The SPSS((r)) 22.0 software was used for statistical analysis, adopting p < 0.05 as significance level. RESULTS: A total of 800 individuals (561 women and 239 men) were evaluated. The prevalence of steatosis was 29.1%, and the male patients were most affected, presenting with more advanced grades of disease (p = 0.021), as follows: 119 grade 1 (51.0%); 94 grade 2 (40.4%); and 20 grade 3 (8.6%). The median age patients' was 46 years. CONCLUSION: In the present study sample, the prevalence of hepatic steatosis was high, particularly in the male patients. Ultrasonography is suggested as a first choice for the diagnosis of this condition, considering its wide availability, low cost and absence of side effects or risks to the patient. PMID- 26929454 TI - Diagnostic underestimation of atypical ductal hyperplasia and ductal carcinoma in situ at percutaneous core needle and vacuum-assisted biopsies of the breast in a Brazilian reference institution. AB - OBJECTIVE: To determine the rates of diagnostic underestimation at stereotactic percutaneous core needle biopsies (CNB) and vacuum-assisted biopsies (VABB) of nonpalpable breast lesions, with histopathological results of atypical ductal hyperplasia (ADH) or ductal carcinoma in situ (DCIS) subsequently submitted to surgical excision. As a secondary objective, the frequency of ADH and DCIS was determined for the cases submitted to biopsy. MATERIALS AND METHODS: Retrospective review of 40 cases with diagnosis of ADH or DCIS on the basis of biopsies performed between February 2011 and July 2013, subsequently submitted to surgery, whose histopathological reports were available in the internal information system. Biopsy results were compared with those observed at surgery and the underestimation rate was calculated by means of specific mathematical equations. RESULTS: The underestimation rate at CNB was 50% for ADH and 28.57% for DCIS, and at VABB it was 25% for ADH and 14.28% for DCIS. ADH represented 10.25% of all cases undergoing biopsy, whereas DCIS accounted for 23.91%. CONCLUSION: The diagnostic underestimation rate at CNB is two times the rate at VABB. Certainty that the target has been achieved is not the sole determining factor for a reliable diagnosis. Removal of more than 50% of the target lesion should further reduce the risk of underestimation. PMID- 26929455 TI - Receiver operating characteristic (ROC) curve for classification of (18)F-NaF uptake on PET/CT. AB - OBJECTIVE: To assess the cutoff values established by ROC curves to classify (18)F-NaF uptake as normal or malignant. MATERIALS AND METHODS: PET/CT images were acquired 1 hour after administration of 185 MBq of (18)F-NaF. Volumes of interest (VOIs) were drawn on three regions of the skeleton as follows: proximal right humerus diaphysis (HD), proximal right femoral diaphysis (FD) and first vertebral body (VB1), in a total of 254 patients, totalling 762 VOIs. The uptake in the VOIs was classified as normal or malignant on the basis of the radiopharmaceutical distribution pattern and of the CT images. A total of 675 volumes were classified as normal and 52 were classified as malignant. Thirty five VOIs classified as indeterminate or nonmalignant lesions were excluded from analysis. The standardized uptake value (SUV) measured on the VOIs were plotted on an ROC curve for each one of the three regions. The area under the ROC (AUC) as well as the best cutoff SUVs to classify the VOIs were calculated. The best cutoff values were established as the ones with higher result of the sum of sensitivity and specificity. RESULTS: The AUCs were 0.933, 0.889 and 0.975 for UD, FD and VB1, respectively. The best SUV cutoffs were 9.0 (sensitivity: 73%; specificity: 99%), 8.4 (sensitivity: 79%; specificity: 94%) and 21.0 (sensitivity: 93%; specificity: 95%) for UD, FD and VB1, respectively. CONCLUSION: The best cutoff value varies according to bone region of analysis and it is not possible to establish one value for the whole body. PMID- 26929457 TI - Locally advanced hypopharyngeal squamous cell carcinoma: single-institution outcomes in a cohort of patients curatively treated either with or without larynx preservation. AB - OBJECTIVE: The present study was aimed at describing a single-institution experience in the curative treatment of patients diagnosed with locally advanced hypopharyngeal squamous cell carcinoma. MATERIALS AND METHODS: Data concerning all patients treated for locally advanced hypopharyngeal squamous cell carcinoma between January 2006 and June 2012 were reviewed. RESULTS: A total of 144 patients were included in the present study. The median follow-up period was 36.6 months. Median survival was 26 months, and 2-year and 5-year overall survival rates were, 51% and 30.5%, respectively. Median recurrence-free survival was 18 months and 2-year and 5-year recurrence-free survival rates were 42.8% and 28.5%, respectively. CONCLUSION: The outcomes in the present series are in line with the literature. PMID- 26929456 TI - Strategies to evaluate the impact of rectal volume on prostate motion during three-dimensional conformal radiotherapy for prostate cancer. AB - OBJECTIVE: To evaluate the rectal volume influence on prostate motion during three-dimensional conformal radiotherapy (3D-CRT) for prostate cancer. MATERIALS AND METHODS: Fifty-one patients with prostate cancer underwent a series of three computed tomography scans including an initial planning scan and two subsequent scans during 3D-CRT. The organs of interest were outlined. The prostate contour was compared with the initial CT images considering the anterior, posterior, superior, inferior and lateral edges of the organ. Variations in the anterior limits and volume of the rectum were assessed and correlated with prostate motion in the anteroposterior direction. RESULTS: The maximum range of prostate motion was observed in the superoinferior direction, followed by the anteroposterior direction. A significant correlation was observed between prostate motion and rectal volume variation (p = 0.037). A baseline rectal volume superior to 70 cm(3) had a significant influence on the prostate motion in the anteroposterior direction (p = 0.045). CONCLUSION: The present study showed a significant interfraction motion of the prostate during 3D-CRT with greatest variations in the superoinferior and anteroposterior directions, and that a large rectal volume influences the prostate motion with a cutoff value of 70 cm(3). Therefore, the treatment of patients with a rectal volume > 70 cm(3) should be re-planned with appropriate rectal preparation. PMID- 26929458 TI - Cardiac magnetic resonance imaging and computed tomography in ischemic cardiomyopathy: an update. AB - Ischemic cardiomyopathy is one of the major health problems worldwide, representing a significant part of mortality in the general population nowadays. Cardiac magnetic resonance imaging (CMRI) and cardiac computed tomography (CCT) are noninvasive imaging methods that serve as useful tools in the diagnosis of coronary artery disease and may also help in screening individuals with risk factors for developing this illness. Technological developments of CMRI and CCT have contributed to the rise of several clinical indications of these imaging methods complementarily to other investigation methods, particularly in cases where they are inconclusive. In terms of accuracy, CMRI and CCT are similar to the other imaging methods, with few absolute contraindications and minimal risks of adverse side-effects. This fact strengthens these methods as powerful and safe tools in the management of patients. The present study is aimed at describing the role played by CMRI and CCT in the diagnosis of ischemic cardiomyopathies. PMID- 26929459 TI - Solitary pulmonary nodule and (18)F-FDG PET/CT. Part 1: epidemiology, morphological evaluation and cancer probability. AB - Solitary pulmonary nodule corresponds to a common radiographic finding, which is frequently detected incidentally. The investigation of this entity remains complex, since characteristics of benign and malignant processes overlap in the differential diagnosis. Currently, many strategies are available to evaluate solitary pulmonary nodules with the main objective of characterizing benign lesions as best as possible, while avoiding to expose patients to the risks inherent to invasive methods, besides correctly detecting cases of lung cancer so as the potential curative treatment is not delayed. This first part of the study focuses on the epidemiology, the morfological evaluation and the methods to determine the likelihood of cancer in cases of indeterminate solitary pulmonary nodule. PMID- 26929460 TI - Hyperechoic breast lesions: anatomopathological correlation and differential sonographic diagnosis. AB - Hyperechoic lesions are not a frequent finding at breasts ultrasonography, and most of times are associated with benign pathologies that do not require further evaluation. However, some neoplasms such as invasive breast carcinomas and metastases may present with hyperechogenicity. Thus, the knowledge about differential diagnoses and identification of signs of lesion aggressiveness are of great relevance to avoid unnecessary procedures or underdiagnosis, and to support the correct clinical/surgical approach. On the basis of such concepts, the present essay describes and illustrates the main features of hyperechoic lesions at breast ultrasonography in different cases, with anatomopathological correlation. PMID- 26929461 TI - Multidetector computed tomography angiography of the celiac trunk and hepatic arterial system: normal anatomy and main variants. AB - Although digital angiography remains as the gold standard for imaging the celiac arterial trunk and hepatic arteries, multidetector computed tomography in association with digital images processing by software resources represents a useful tool particularly attractive for its non invasiveness. Knowledge of normal anatomy as well as of its variations is helpful in images interpretation and to address surgical planning on a case-by-case basis. The present essay illustrates several types of anatomical variations of celiac trunk, hepatic artery and its main branches, by means of digitally reconstructed computed tomography images, correlating their prevalence in the population with surgical implications. PMID- 26929462 TI - Glenohumeral interposition of rotator cuff stumps: a rare complication of traumatic rotator cuff tear. AB - The present report describes a case where typical findings of traumatic glenohumeral interposition of rotator cuff stumps were surgically confirmed. This condition is a rare complication of shoulder trauma. Generally, it occurs in high energy trauma, frequently in association with glenohumeral joint dislocation. Radiography demonstrated increased joint space, internal rotation of the humerus and coracoid process fracture. In addition to the mentioned findings, magnetic resonance imaging showed massive rotator cuff tear with interposition of the supraspinatus, infraspinatus and subscapularis stumps within the glenohumeral joint. Surgical treatment was performed confirming the injury and the rotator cuff stumps interposition. It is important that radiologists and orthopedic surgeons become familiar with this entity which, because of its rarity, might be neglected in cases of shoulder trauma. PMID- 26929463 TI - Tracheobronchopathia osteochondroplastica: computed tomography, bronchoscopy and histopathological findings. PMID- 26929464 TI - Giant pedunculated hemangioma of the liver. PMID- 26929465 TI - Posterior reversible encephalopathy syndrome following immunoglobulin therapy in a patient with Miller-Fisher syndrome. PMID- 26929466 TI - Pulmonary paracoccidioidomycosis showing reversed halo sign with nodular/coarse contour. PMID- 26929467 TI - Bilateral elastofibroma dorsi. PMID- 26929468 TI - Endometrial osseous metaplasia: sonographic, radiological and histopathological findings. PMID- 26929469 TI - Mesothelioma of the tunica vaginalis in a patient with giant hydrocele. PMID- 26929470 TI - Fine-needle aspiration of axillary lymph nodes: a change of paradigm in the approach to axillary compromise? PMID- 26929472 TI - Cardiac MRI and CT: the eyes to visualize coronary arterial disease and their effect on the prognosis explained by the Schrodinger's cat paradox. PMID- 26929471 TI - Imaging evaluation in metabolic syndrome: beyond steatosis. PMID- 26929473 TI - Exposure to a combination of heat and hyperoxia during cycling at submaximal intensity does not alter thermoregulatory responses. AB - In this study, we tested the hypothesis that breathing hyperoxic air (FinO2 = 0.40) while exercising in a hot environment exerts negative effects on the total tissue level of haemoglobin concentration (tHb); core (Tcore) and skin (Tskin) temperatures; muscle activity; heart rate; blood concentration of lactate; pH; partial pressure of oxygen (PaO2) and carbon dioxide; arterial oxygen saturation (SaO2); and perceptual responses. Ten well-trained male athletes cycled at submaximal intensity at 21 degrees C or 33 degrees C in randomized order: first for 20 min while breathing normal air (FinO2 = 0.21) and then 10 min with FinO2 = 0.40 (HOX). At both temperatures, SaO2 and PaO2, but not tHb, were increased by HOX. Tskin and perception of exertion and thermal discomfort were higher at 33 degrees C than 21 degrees C (p < 0.01), but independent of FinO2. Tcore and muscle activity were the same under all conditions (p > 0.07). Blood lactate and heart rate were higher at 33 degrees C than 21 degrees C. In conclusion, during 30 min of submaximal cycling at 21 degrees C or 33 degrees C, Tcore, Tskin and Tbody, tHb, muscle activity and ratings of perceived exertion and thermal discomfort were the same under normoxic and hyperoxic conditions. Accordingly, breathing hyperoxic air (FinO2 = 0.40) did not affect thermoregulation under these conditions. PMID- 26929474 TI - Determination of metabolic equivalents during low- and high-intensity resistance exercise in healthy young subjects and patients with type 2 diabetes. AB - The purpose of this study was to quantify the metabolic equivalents (METs) of resistance exercise in obese patients with type 2 diabetes (T2DM) and healthy young subjects and to evaluate whether there were differences between sessions executed at low- versus high-intensity resistance exercise. Twenty obese patients with T2DM (62.9+/-6.1 years) and 22 young subjects (22.6+/-1.9 years) performed two training sessions: one at vigorous intensity (80% of 1-repetition maximum (1RM)) and one at moderate intensity (60% of 1RM). Both groups carried out three strength exercises with a 2-day recovery between sessions. Oxygen consumption was continuously measured 15 min before, during and after each training session. Obese T2DM patients showed lower METs values compared with young healthy participants at the baseline phase (F= 2043.86; P<0.01), during training (F=1140.59; P<0.01) and in the post-exercise phase (F=1012.71; P<0.01). No effects were detected in the group x intensity analysis of covariance. In this study, at both light-moderate and vigorous resistance exercise intensities, the METs value that best represented both sessions was 3 METs for the obese elderly T2DM patients and 5 METs for young subjects. PMID- 26929476 TI - Comparison of effects of static, proprioceptive neuromuscular facilitation and Mulligan stretching on hip flexion range of motion: a randomized controlled trial. AB - The aim of this study was to compare the effects of static stretching, proprioceptive neuromuscular facilitation (PNF) stretching and Mulligan technique on hip flexion range of motion (ROM) in subjects with bilateral hamstring tightness. A total of 40 students (mean age: 21.5+/-1.3 years, mean body height: 172.8+/-8.2 cm, mean body mass index: 21.9+/-3.0 kg . m(-2)) with bilateral hamstring tightness were enrolled in this randomized trial, of whom 26 completed the study. Subjects were divided into 4 groups performing (I) typical static stretching, (II) PNF stretching, (III) Mulligan traction straight leg raise (TSLR) technique, (IV) no intervention. Hip flexion ROM was measured using a digital goniometer with the passive straight leg raise test before and after 4 weeks by two physiotherapists blinded to the groups. 52 extremities of 26 subjects were analyzed. Hip flexion ROM increased in all three intervention groups (p<0.05) but not in the no-intervention group after 4 weeks. A statistically significant change in initial-final assessment differences of hip flexion ROM was found between groups (p<0.001) in favour of PNF stretching and Mulligan TSLR technique in comparison to typical static stretching (p=0.016 and p=0.02, respectively). No significant difference was found between Mulligan TSLR technique and PNF stretching (p=0.920). The initial-final assessment difference of hip flexion ROM was similar in typical static stretching and no intervention (p=0.491). A 4-week stretching intervention is beneficial for increasing hip flexion ROM in bilateral hamstring tightness. However, PNF stretching and Mulligan TSLR technique are superior to typical static stretching. These two interventions can be alternatively used for stretching in hamstring tightness. PMID- 26929477 TI - Greetings!! PMID- 26929475 TI - Sclerostin as a novel marker of bone turnover in athletes. AB - Sclerostin is a protein secreted by osteocytes that acts as an inhibitor of bone formation. It has been shown that physical activity affects sclerostin concentration and thus bone remodelling. The aim of the study was to evaluate serum concentrations of sclerostin, selected bone turnover markers (PTH, P1NP), 25(OH)D3 and the intake of calcium and vitamin D in physically active versus sedentary men. A total of 59 healthy men aged 17-37 were enrolled in the study (43 athletes and 16 non-athletes). The mean sclerostin concentration in the group of athletes (A) was significantly higher than in non-athletes (NA) (35.3+/-8.9 vs 28.0+/-5.6 pmol.l(-1), p= 0.004). A compared with NA had higher concentrations of P1NP (145.6+/-77.5 vs 61.2+/-22.3 ng.ml(-1), p= <0.0001) and 25(OH)D3 (16.9+/-8.4 vs 10.3+/-4.3 ng.ml(-1), p= 0.004) and lower concentrations of PTH (25.8+/-8.3 vs 38.2+/-11.5 pg.ml(-1), p= <0.0001). Vitamin D deficiency was found in 77% of A and 100% of NA. A and NA had similar daily energy intake. They did not differ as to the intake of calcium and vitamin D. We observed a negative correlation between the serum concentrations of sclerostin and calcium in the studied subjects. Our results suggest that regular, long-lasting physical training may be associated with higher concentration of sclerostin. It seems that increased sclerostin is not related to other bone turnover markers (PTH, P1NP). PMID- 26929478 TI - Internal derangements of the temporomandibular joint: A review of the anatomy, diagnosis, and management. AB - Internal derangements of the temporomandibular joint are conditions in which the articular disc has become displaced from its original position the condylar head. Relevant anatomic structures and their functional relationships are briefly discussed. The displacement of the disc can result in numerous presentations, with the most common being disc displacement with reduction (with or without intermittent locking), and disc displacement without reduction (with or without limited opening). These are described in this article according to the standardized Diagnostic Criteria for Temporomandibular Disorders, as well as the less common posterior disc displacement. Appropriate management usually ranges from patient education and monitoring to splints, physical therapy, and medications. In rare and select cases, surgery may be necessary. However, in for the majority of internal derangements, the prognosis is good, particularly with conservative care. PMID- 26929479 TI - Fundamentals of cone beam computed tomography for a prosthodontist. AB - Cone beam computed tomography (CBCT, also referred to as C-arm computed tomography [CT], cone beam volume CT, or flat panel CT) is a medical imaging technique of X-ray CT where the X-rays are divergent, forming a cone.[1] CBCT systems have been designed for imaging hard tissues of the maxillofacial region. CBCT is capable of providing sub-millimeter resolution in images of high diagnostic quality, with short scanning times (10-70 s) and radiation dosages reportedly up to 15-100 times lower than those of conventional CT scans. Increasing availability of this technology provides the dental clinician with an imaging modality capable of providing a three-dimensional representation of the maxillofacial skeleton with minimal distortion. The aim of this article is to sensitize the Prosthodontist to CBCT technology, provide an overview of currently available maxillofacial CBCT systems and review the specific application of various CBCT display modes to clinical Prosthodontic practice. A MEDLINE search for relevant articles in this specific area of interest was conducted. The selected articles were critically reviewed and the data acquired were systematically compiled. PMID- 26929480 TI - A novel technique using arti-spot coated on fleximeter strips to determine the clearance during tooth preparation in fixed partial denture. AB - The amount of occlusal clearance during tooth preparation for fixed partial denture is more crucial and critical phase of fixed prosthodontics. Improper tooth reduction leads to compromise in structural durability and failure of the restoration. Over reduction affects the biological principles of tooth preparation. This article uses color coded fleximeter strips coated with arti spot to determine the amount of clearance during tooth preparation in fixed partial denture. PMID- 26929481 TI - Oral care needs, barriers and challenges among elderly in India. AB - OBJECTIVE: This paper presents an approach to the assessment of oral health needs of elderly and barriers to receive oral care in the life course. BACKGROUND: The dental needs of the elderly are changing and growing day by day. The management of older patients requires not only an understanding of the medical and dental aspects of ageing but also provide them good oral health service. In the life course of elderly there are many hurdles to receive proper oral care. The use of an assessment of oral health need will be essential in the development of care pathways to the elderly. METHODS: The proportion of older people is growing faster than that of any other age group. There is no sound database regarding the oral disease burden and treatment needs of the elderly in India. Physical and biological barriers with age can also affect oral health care either directly or indirectly. CONCLUSION: Oral care guidelines designed to assist elderly should consider not only prevention and treatment modalities but also the means of implementing such therapies in varying settings and utilizing the whole dental team. PMID- 26929482 TI - Comparative evaluation of surface topography of tooth prepared using erbium, chromium: Yttrium, scandium, gallium, garnet laser and bur and its clinical implications. AB - BACKGROUND: Erbium, chromium: Yttrium, scandium, gallium, garnet (Er, Cr: YSGG) laser has been successfully used in the ablation of dental hard and soft tissues. It has been reported that this system is also useful for preparing tooth surfaces and etching, but no consensus exist in the literature regarding the advantage of lasers over conventional tooth preparation technique. MATERIALS AND METHODS: Labial surfaces of 25 extracted human maxillary central incisors were divided into two halves. Right half was prepared with diamond bur and left half with Er, Cr; YSGG laser and a reduction of 0.3-0.5 mm was carried out. Topography of prepared surfaces of five teeth were examined under scanning electron microscope (SEM). The remaining samples were divided into 4 groups of 10 specimens each based on the surface treatment received: One group was acid etched and other was nonetched. Composite resin cylinders were bonded on prepared surfaces and shear bond strength was assessed using a universal testing machine. RESULTS: The SEM observation revealed that the laser prepared surfaces were clean, highly irregular and devoid of a smear layer. Bur prepared surfaces were relatively smooth but covered with smear layer. Highest bond strength was shown by laser prepared acid etched group, followed by bur prepared the acid etched group. The bur prepared nonacid etched group showed least bond strength. CONCLUSIONS: Er, Cr: YSGG laser can be used for preparing tooth and bond strength value achieved by laser preparation alone without surface treatment procedure lies in the range of clinical acceptability. PMID- 26929483 TI - Prevalence of Candida spp. among healthy denture and nondenture wearers with respect to hygiene and age. AB - Dentures are inert and nonshading surfaces and therefore get easily colonized by Candida species. Subsequent biofilm produced by them lead to denture stomatitis and candidiasis. This study was aimed to understand the prevalence of Candida species among healthy denture and nondenture wearers with respect to their age and hygiene status. Swabs were collected from 50 complete dentures and 50 non denture wearers and processed on Sabouraud's dextrose agar. Identification of Candida species was done by staining and a battery of biochemical tests. Data obtained was correlated with age & oral hygiene and statistical analysis was performed. Candida was isolated from both denture and nondenture wearers. Prevalence of different Candida species was significantly higher in denture wearers and found predominated by C. albicans, C. tropicalis, C. dubliensis and C. glabrata. Among nondenture wearers, C. albicans and C. tropicalis were isolated. Prevalence of Candida increased with increasing age among denture wearers. Men presented declining denture hygiene compared to women with increasing age. In comparison to nondenture wearers, multispecies of Candida colonized the dentures thus presenting higher risk of candidiasis especially with increasing age. PMID- 26929484 TI - A comparative study to evaluate the osteoblastic cell behavior of two nano coated titanium surfaces with NAFION stabilized the membrane. AB - AIM: The aim of the study was to comparatively analyze the in vitro cell adhesion between nano coated titanium dioxide, and calcium hydroxyapatite (HA) coated titanium samples. MATERIALS AND METHODS: Nano coated titanium dioxide, and calcium HA were coated onto the titanium samples by drop casting with NAFION membrane and cell culture was done by seeding human osteoblastic sarcoma cells on the coated samples. RESULTS AND CONCLUSION: There was marked cell adhesion seen in the samples coated by titanium dioxide nano particles and more cells spreading as compared to calcium HA nano particles. PMID- 26929485 TI - Effect of oral prophylactic instrumentation on the surface texture of all metal restorative materials. AB - INTRODUCTION: In the inaccessible areas on the crown the removal of calculus and stains by hand and ultrasonic instrumentation is the method for cleaning to preserve and increase the longevity of the restoration. However, when oral prophylaxis is performed on restorative crowns, it may produce some surface alterations and may favour plaque accumulation. STATEMENT OF PROBLEM: Many patients may have restored their teeth with artificial crowns and would come to the dental office for oral prophylaxis. If a routine oral prophylaxis is followed, its effect on the restorative materials and the plaque accumulation can be studied. MATERIALS AND METHODS: A total of 15 disc shaped wax patterns were invested and casted for cast titanium (Group A) and the remaining 15 disk shaped for nickel-chromium (Group B). The obtained castings were finished and polished. All the specimens were subjected to hand and ultrasonic scaling for 15 s. Profilometer and scanning electron microscopic was used to analyze and evaluate the surface roughness. Specimens of each group were embedded on the anterior lingual aspects of the removable lower retention plates. 5 volunteers were asked to wear it in the mouth for 24 h for 7 days. After 7 days, the specimens were stained with plaque disclosing solutions and the photomicrographs were taken by the optical stereomicroscope and the plaque accumulations were assessed in percentage. RESULTS: The difference in average surface roughness (MUm) of the polished test specimens was maximum for ultrasonic scaling than hand scaling and maximum for Group A than Group B. Plaque accumulation in percentage on the treated specimens was found to be nonsignificant but, mean plaque accumulation was maximum on ultrasonic scaling surface than hand scaling and maximum for Group A than Group B. Surface roughness was found to be statistically significant after hand scaling (F = 9.377, P = 0.000) and ultrasonic scaling (F = 5.373, P = 0.0000) by Student t-test. CONCLUSION: The Surface roughness and plaque accumulation on the specimens were more for Group A than Group B and maximum produced by ultrasonic scaling than hand scaling. PMID- 26929486 TI - Comparative evaluation of effects of bleaching on color stability and marginal adaptation of discolored direct and indirect composite laminate veneers under in vivo conditions. AB - STATEMENT OF PROBLEM: Change in color and loss of marginal adaptation of tooth colored restorative materials is not acceptable. Bleaching is commonly used for treating discolored teeth. However, the literature is scanty regarding its effect on color and marginal adaptation of direct and indirect composite laminate veneers (CLVs) under in vivo conditions. PURPOSE: Purpose of the study was to determine the effect of bleaching on color change and marginal adaptation of direct and indirect CLVs over a period of time when exposed to the oral environment. MATERIALS AND METHODS: For this purpose, a total of 14 subjects irrespective of age and sex indicated for CLV restorations on maxillary anterior teeth were selected following the inclusion and exclusion criteria. For each subject, indirect CLVs were fabricated and looted in the first quadrant (Group 1) and direct CLV's (Group 2), were given in the second quadrant. Color change was assessed clinically using intra-oral digital spectrophotometer and marginal adaptation was assessed on epoxy resin replica of the tooth-restoration interface under scanning electron microscope. After 6 months, the subjects underwent a home bleaching regimen for 14 days using 10% carbamide peroxide. The assessment of color change and marginal adaptation was done at 6 months after veneering (0-180 days), immediately after the bleaching regimen (0-194 days) and 3 months after the bleaching regimen (0-284 days). RESULTS: The difference in median color change (DeltaE) between the groups was tested using Wilcoxon rank sum test while the median color change with time within the groups was tested using Wilcoxon signed rank test. The difference in the rates of marginal adaptation was tested between the groups using Chi-square/Fisher's exact test. Bleaching led to statistically significant color change at cervical (CE), middle and incisal (IE) regions when direct and indirect composites were compared (P < 0.05). During intra-group comparison, direct CLV's showed significant color change at CE and IE regions when DeltaE was compared at 180 days and 284 days (CE 10 vs. CE 30, P = 0.008, IE 10 vs. IE 30, P = 0.003). No significant differences were found when within group comparison was made for indirect laminates. Intergroup comparison between the groups showed significant difference in marginal adaptation at CE margin at all.time points (at baseline, P = 0.005; at 180 days, P = 0.007; 194 days, P = 0.025; at 284 days, P = 0.067). CONCLUSION: After bleaching, indirect CLVs performed better in terms of color stability whereas direct CLVs performed better in terms of marginal adaptation. CLINICAL SIGNIFICANCE: Indirect composites should be preferred to direct composites as veneering materials as they have better color stability. Special attention should be given to their marginal adaptation especially in the CE region. Bleaching should be avoided in patients with composite restorations in the mouth. PMID- 26929487 TI - A comparative evaluation of bond strength of feldspathic porcelain to nickel chromium alloy, when subjected to various surface treatments: An in vitro study. AB - PURPOSE OF THE STUDY: The purpose was to evaluate the effect of various surface treatments and sandblasting with different particle size on the bond strength of feldspathic porcelain with predominantly base metal alloys, using a universal testing machine. MATERIALS AND METHODS: Totally, 40 specimen of nickel-chromium alloy were prepared in an induction casting machine. The groups divided were as follows: Group I-sandblasted with 50 MU Al2O3, Group II-sandblasted with 110 MU Al2O3, Group III-sandblasted with 250 MU Al2O3 and Group IV-sandblasted with 250 MU Al2O3, followed by oxidation and again sandblasted with 250 MU Al2O3. The dimensions of each specimen were adjusted so as to maintain the thickness of ceramic at 1 mm. The specimen were loaded on the assembly of the universal testing machine, and a cross head speed of 0.5 mm/min was used to apply a compressive force at the junction of metal and feldspathic porcelain. The force application continued until adhesive fracture occurred, and the readings of the load applied to that particular specimen were recorded. RESULTS: The means for shear bond strength for Group I, II, III and IV were found to be (226.92 +/- 1.67), (233.16 +/- 3.85), (337.81 +/- 16.97) and (237.08 +/- 4.33), respectively. Means of shear bond strength among the groups were compared using one-way analysis of variance test. Comparison between individual groups were made with Tukey's Honestly Significant Difference post-hoc test. CONCLUSION: Different particle size and surface treatment have an important role on the bond strength of ceramic-metal interface. Greater particle size demonstrated higher bond strength. PMID- 26929488 TI - Marginal accuracy of nickel chromium copings fabricated by conventional and accelerated casting procedures, produced with ringless and metal ring investment procedures: A comparative in vitro study. AB - BACKGROUND: Conventional investing and casting techniques are time-consuming and usually requires 2-4 h for completion. Accelerated nonstandard, casting techniques have been reported to achieve similar quality results in significantly less time, namely, in 30-40 min. During casting, it is essential to achieve compensation for the shrinkage of solidifying alloy by investment expansion. The metal casting ring restricts the thermal expansion of investment because the thermal expansion of the ring is lesser than that of the investment. The use of casting ring was challenged with the introduction of the ringless technique. MATERIALS AND METHODS: A total of 40 test samples of nickel chromium (Ni-Cr) cast copings were obtained from the patterns fabricated using inlay casting wax. The 20 wax patterns were invested using metal ring and 20 wax patterns were invested using the ringless investment system. Of both the groups, 10 samples underwent conventional casting, and the other 10 underwent accelerated casting. The patterns were casted using the induction casting technique. All the test samples of cast copings were evaluated for vertical marginal gaps at four points on the die employing a stereo optical microscope. RESULTS: The vertical marginal discrepancy data obtained were tabulated. Mean and standard deviations were obtained. Vertical discrepancies were analyzed using analysis of variance and Tukey honestly significantly different. The data obtained were found to be very highly significant (P < 0.001). Mean vertical gap was the maximum for Group II (53.64 MUm) followed by Group IV (47.62 MUm), Group I (44.83 MUm) and Group III (35.35 MUm). CONCLUSION: The Ni-Cr cast copings fabricated with the conventional casting using ringless investment system showed significantly better marginal fit than that of cast copings fabricated from conventional and accelerated casting with metal ring investment and accelerated casting using ringless investment since those copings had shown the least vertical marginal discrepancies among the four methods evaluated in this study. PMID- 26929489 TI - Intervention for replacing missing teeth: Partially absent dentition-Evidence summary of Cochrane review. AB - Cochrane reviews are systematic reviews with meta analysis published by the Cochrane collaboration, in the Cochrane Database of Systematic Reviews (CDSR). These reviews provide the clinicians with the highest level of evidence as they use a highly structured and transparent systematic review model to address a specific research question. The management of partially absent dentition is routinely under taken by general dentist and Prosthodontist but clinical practice guidelines based on evidence to this common problem is yet to be summarized. This Cochrane systematic review aims to address the effect of different prosthesis for the treatment of partially absent dentition in the terms of, Long-term success, function, morbidity, and patient satisfaction. All randomized controlled trials were searched till March 18, 2011, based on the inclusion and exclusion criteria, 21 trials were included and 32 trials were excluded and, it was critically appraised using the Cochrane methodology for interventions. The summary of evidence from the study concludes that there is insufficient evidence to state the effectiveness of removable and fixed prosthesis in partially edentulous subjects in the following four outcomes. There were insufficient trials to perform a meta-analysis and sensitivity analysis. This evidence-based summary emphasizes and reinforces the need to reassess the quality of research currently pursued in our profession, to address the need to provide higher level of evidence for common conditions like partial edentulousness. The included studies are basically not from our population too, hence the urgency to address this critical issue. PMID- 26929490 TI - Rehabilitation of a missing ear with an implant retained auricular prosthesis. AB - Burns can leave a patient with a severely debilitating disability even after treatment. The objectives of burn rehabilitation are to minimize the adverse effects caused by the injury while rehabilitating the patient's physical and psychological well-being, maximizing social integration. Long-term success of maxillofacial prostheses mainly depends on the retention. Extra oral implant retained prostheses have proved to be a predictable treatment option for maxillofacial rehabilitation. Replacement of a severely deformed external ear with burned tissues may be satisfactorily accomplished by a cosmetic prosthesis anchored by implants integrated in the skull. The use of such implants is now a well-recognized method for creating a stable result in maxillofacial rehabilitation. This case report describes a safe, simple and economical method for the rehabilitation of a patient with missing right auricle using an implant supported silicone prosthesis. The implant was placed in the mastoid region of the temporal bone. Reconstruction of the ear was done with auricular silicone prosthesis, retained using magnets incorporated in an autopolymerizing resin shim to decrease the weight of the prosthesis on a single implant. This method eliminates the need of tedious laboratory procedures and exact casting and fitting requirements of a metal substructure while minimizing the overall weight and cost of the prosthesis while maintaining adequate support, esthetics and retention of the prosthesis. PMID- 26929492 TI - Start something new. PMID- 26929491 TI - A new and simple method of fabrication of tracheostomal prosthesis. AB - Patients with a tracheostomy stoma experience compromised speech and function due to the associated changes in airflow patterns. Rehabilitation of a patient with tracheal stoma is a highly challenging task. The main objective is to design an inexpensive, easily fabricated stomal prosthesis for postlaryngectomy patients who require prolonged tracheotomy. This clinical case report describes a 29-year old male patient who underwent for tracheotomy 3 months before for respiratory distress following a suicidal attempt. Hence tracheotomy was done, and the patient has been with the tracheostomal tube since surgery for the past 3 months. Laryngoscopy examination reported as restricted bilateral vocal cord movements, and the cords were in the adducted position with minimal glottic chink. No history of difficulty in swallowing. On examination, no scar or ulceration is seen around the stoma. The skin around the stoma is healthy. The patient was referred to the oral and maxillofacial Prosthodontics Department from the Department of ENT. The patient's old tracheostomal tube was used as the dimensions of the custom made tracheal prosthesis without making a functional impression of the mature stoma. A tracheal button was made with 2 mm polyethylene urethane sheet to maintain the airway patency of the mature stoma. Width and length of the old tracheostomal tube were measured and customized with polyurethane sheet by directly flaming over heat. The finished product was thin, flexible, maintains enhanced tear strength, require no tapes or adhesives and less technique sensitive. These properties of the prosthesis make more advantageous than the commercially available tracheal buttons. The result in this patient was excellent with no postoperative complications. An innovative approach for fabrication of tracheostomal prosthesis was discussed to increase its successful use in tracheostomal patients. The patient's old tracheostomal tube was used as the dimensions of the custom made tracheal prosthesis without making a functional impression of the mature stoma. The finished product was thin, flexible, maintains enhanced tear strength, require no tapes or adhesives and less technique sensitive. These properties of the prosthesis makes more advantageous than the commercially available tracheal buttons. The result in this patient was excellent with no postoperative complications. PMID- 26929493 TI - The relationship between innercanthal dimension and interalar width to the intercanine width of maxillary anterior teeth in central Indian population. AB - STATEMENT OF PROBLEM: Selection of proper sized maxillary anterior teeth is one of the difficult clinical steps in complete denture esthetics. Several studies have been reported to establish methods of estimating the combined width of maxillary anterior teeth. PURPOSE: The aim of this study was to determine whether a relationship exists between the innercanthal distance (ICD) and interalar width (IAW) with the combined width of maxillary anterior teeth. MATERIAL AND METHODS: The maxillary anterior teeth of 600 adult subjects were examined. ICD was measured between the median angles of the palpebral fissure. IAW was measured between the ala of the nose at their widest point. The mean combined width of the maxillary anterior teeth was determined intraorally at their widest dimension. Pearson's correlation coefficients were calculated to determine the relationship between ICD, IAW and the combined width of maxillary anterior teeth (alpha =0.05). RESULTS: Although the Pearson correlation coefficients were relatively small, a significant relationship existed between innercanthal dimension and IAW (P < 0001). CONCLUSION: Within the limitations of this study, the results suggest that ICD and IAW cannot be used as a preliminary method for determining the width of the maxillary anterior teeth for edentulous patients. PMID- 26929494 TI - Innovative dual impression technique for patients with atrophia idiopathica mucosa oris. AB - Atrophia idiopathica mucosa oris is an oral fibrosing disease resulting in marked rigidity and an eventual inability to open the mouth or had limited mouth opening. Patients with limited mouth opening are a common occurrence in prosthodontic practice. The majority of these patients can be treated with exercise and stretching movements before impressions are made. Some will not respond to these procedures because of facial scarring and surgical manipulation of the facial muscles. This article presents an impression procedure for overcoming difficulties encountered in such reduced mouth opening patients that can be assembled intraorally, disassembled intraorally, and reassembled extraorally. PMID- 26929495 TI - Comparative evaluation of reproducibility of peripheral tissues produced by different border molding materials in edentulous patients: An in vivo study. AB - AIM: The aim of the study is to analyze the effect of different materials and techniques in current use on peripheral shaping of complete denture impression. METHODS: The present study was conducted to compare and evaluate the maxillary border morphology produced using tissue conditioner as control and low fusing impression compound, Polyether, Pattern resin and periphery wax as border molding materials. The study was carried out on 15 denture wearer patients with well formed, rounded edentulous maxillary arch with adequate width and height. On each patient, border moldings were done, with tissue conditioner which was loaded on the borders of previous maxillary denture of the patient (control group), low fusing impression compound (Group 1), polyether (Group 2), Pattern resin (Group 3) and Peripheral wax (Group 4), respectively on special tray made for the patient. Sulcus width height and area was then measured for each group using stereomicroscope. RESULTS AND CONCLUSIONS: Based on the study it is concluded that the polyether was the best material for border molding which will give most accurate borders to a denture. PMID- 26929496 TI - An evaluation of wear of human enamel opposed by ceramics of different surface finishes. AB - STATEMENT OF PROBLEM: Surface of porcelain restoration is a matter of clinical concern because of its abrasive action on the opposing enamel. PURPOSE: This study comparatively evaluated wear of enamel when opposed by three different surface finishes of ceramic. MATERIALS AND METHODS: A total of 60 metal-ceramic discs (10 mm * 2 mm) with different surface finishes were fabricated. They were divided into four groups of autoglazed ceramic surface, over glazed ceramic surface, ceramic surface polished with Shofu polishing kit and ceramic surface polished with DFS polishing wheels and paste. Each group comprised of 15 discs. Sixty human teeth samples were prepared from freshly extracted, unrestored, caries free, nonattrited maxillary first premolars. Each tooth sample was weighed before wear testing using AT200 Mettler Toledo electronic analytical balance of 0.0001 g accuracy. Occlusal surfaces of these teeth were then abraded against the substrates in a wear machine for a total of 10,000 cycles. Each tooth sample was weighed after 5000 cycles and after the total of 10,000 cycles, respectively, using the same balance. Differences in weight of tooth samples before and after wear testing were evaluated statistically using one-way analysis of variance and Bonferroni's correction for multiple group comparisons. RESULTS: The values obtained for percentage weight loss after 10,000 cycles for over glazed ceramic surface were marginally higher than values obtained for autoglazed surface. It was observed that values obtained for percentage weight loss by polished ceramic after 10,000 cycles were statistically less as compared to the values obtained with autoglazed and over glazed ceramic surface (P < 0.001). There was no statistically significant difference between the values obtained by polished ceramic surfaces of two different groups. CONCLUSION: Enamel wear produced by polished porcelain is substantially less than autoglazed and over glazed porcelain. No significant difference was found in enamel wear when opposed by ceramic surfaces polished by two different methods. This study indicates the potential damage porcelain can inflict upon enamel and suggests that porcelain should be polished instead of over glazed. PMID- 26929497 TI - Does periodical department audit really works to make things fall in place: A Geriatric/General Oral Health Assessment Index based audit in prosthodontics. AB - PURPOSE: The purpose was to assess the outcome of improved staff supervision on the efficiency and quality of complete dentures delivered by clinical students. MATERIALS AND METHODS: The audit was performed in two parts. In the first cycle, retrospective analysis for complete dentures delivered by clinical students was undertaken, and patient's satisfaction was graded using Geriatric/General Oral Health Assessment Index (GOHAI). All the impeding factors encountered in the first cycle were identified, and corrective measures were implemented. Subsequently, a prospective analysis for the dentures delivered under strict staff supervision was undertaken in the second cycle. Patient satisfaction was graded again using GOHAI. RESULTS: Improved staff supervision increased the patient satisfaction significantly. CONCLUSIONS: The quality of care had improved in leaps and bounds compared to the first cycle due to increased level of supervision and strict adherence to the recommendations made at the end of the first cycle. PMID- 26929498 TI - Vertical and horizontal proportions of the face and their correlation to phi among Indians in Moradabad population: A survey. AB - PURPOSE: The purpose was to examine the existence of divine proportions among the Indian faces in Moradabad population. MATERIALS AND METHODS: Totally, 100 patients (50 males; 50 females) aged 25-45 years were selected for the study. All facial photographs were analyzed based on the method of Ricketts assessing the divine proportions in vertical and transverse facial planes. Six horizontal and seven vertical ratios were determined, which were then compared with the phi ratio. RESULTS: The horizontal ratio results showed that three male and female ratios were not significantly different from each other (P > 0.05), and interchilion/nose width ratio was highly significant (P < 0.001). The horizontal mean ratios for females as well as males were highly significant from the phi ratio (P < 0.001) except for interchilion/interdacryon ratio, which was significant (P < 0.05) for females and not significant (P > 0.05) for males. The vertical ratio results showed that there was a highly significant difference (P < 0.001) for forehead height/stomion-soft menton ratio and no significant difference for two ratios between the mean ratios of males and females. All the vertical mean ratios for both the groups were highly significant (P < 0.001), except for the intereye-soft menton/intereye-stomion ratio, which was significant (P < 0.05) for female group and not significant (P > 0.05) for the male group. CONCLUSION: Although, the golden proportion is a prominent and recurring theme in esthetics, it should not be embraced as the only method by which human beauty is measured to the exclusion of others factors. PMID- 26929499 TI - An in vitro study to evaluate the effect on dimensional changes of elastomers during cold sterilization. AB - OBJECTIVES: This study was planned to evaluate the dimensional stability of elastomers during cold sterilization or immersion disinfection and also to evaluate the same, along with acrylic resin trays which are used in clinical practice. MATERIALS AND METHODS: A study mold according to revised American Dental Association. Specification no. 19 was used. Polyether, polyvinyl siloxane (PVS) (heavy body), PVS (regular body) and Hydrophilic addition reaction silicon (medium body) were selected for study. 2% glutaraldehyde and 0.525% sodium hypochlorite were the disinfectants used. The study was divided into group-I and group-II. In group-I study, 24 specimens of each impression material were prepared. Eight immersed in 2% glutaraldehyde, eight in 0.525% sodium hypochlorite and rest eight allowed to dry bench cure. After 16 h, the specimens measured under Leica WILD stereomicroscope and dimensions compared with master die. In group II study, 24 specimens of the material with the least dimensional changes were prepared and adhered to 24 acrylic resin disks using tray adhesive. Same immersion procedure was followed as in group I. The data were analyzed by one-way ANOVA and Tukey's multiple tests. RESULTS: Of four impression materials used, PVS (heavy body) was the most dimensionally stable, and Polyether was the least dimensionally stable in both the groups. INTERPRETATION AND CONCLUSION: Within the limitation of the study, PVS (heavy body) was most stable, and polyether was least stable of all the impression materials. PMID- 26929500 TI - Differences in tooth shade value according to age, gender and skin color: A pilot study. AB - PURPOSE OF THE STUDY: The purpose was to investigate the differences in tooth shade value according to age, gender and skin color among a sample of the local population in Bengaluru, India. METHODOLOGY: The study comprised 100 subjects belonging to both gender between the age groups of 16 years to 55 years. Tooth shade values of permanent maxillary left or right central incisors were recorded using the Vitapan 3D-Master shade guide. Skin color was matched using the Radiance compact makeup shades as a guide. RESULTS: Chi-square statistical test demonstrated that younger subjects have lighter tooth shade values. No statistically significant differences were recorded in tooth shade value according to gender or skin color. CONCLUSION: Within the limitations of the current study, it can be concluded that tooth shade value is significantly influenced by age. Gender and skin color appear not to have a significant relation to tooth shade value. PMID- 26929501 TI - Comparison of fiber reinforcement placed at different locations of pontic in interim fixed partial denture to prevent fracture: An in vitro study. AB - BACKGROUND: The interim restoration is an important phase in fixed prosthodontic therapy. It should provide sufficient durability to withstand the forces of mastication. A fractured interim restoration is damaging to the prosthodontic care and may lead to an unscheduled appointment for repair. Several attempts have been made to reinforce interim fixed partial dentures (FPDs). These have included the use of metal wire, a lingual cast metal reinforcement, a processed acrylic resin interim restoration, and different types of fibers, e.g., carbon, polyethylene, nylon and glass. These fibers can be placed in the occlusal, middle or cervical thirds in the FPD. There is no scientific data to evaluate the effect of fiber placement methods on the fracture resistance of clinical interim FPDs. PURPOSE OF THE STUDY: Hence this study was designed to evaluate fracture load values of interim FPDs with different locations of fiber reinforcement. MATERIALS AND METHODS: 30 interim FPD samples with polymethyl methacrylate (PMMA) reinforced with fibers at three different locations mainly occlusal, cervical and middle (10 samples each) were fabricated using a metal FPD on a master die. They were tested for fracture resistance in universal testing machine. RESULTS: The fracture resistance was recorded and is tabulated and analyzed statistically. The results showed that the placement of the reinforcement in the occlusal third of the pontic resulted in higher fracture resistance which was significantly higher (P < 0.05) than all other locations. CONCLUSION: The occlusal third of the pontic region from mesial to the distal end of the connector is the best site of placement of the fiber for reinforcing the PMMA interim restorative resin. PMID- 26929502 TI - Investigation of the relationship between psychosocial stress and temporomandibular disorder in adults by measuring salivary cortisol concentration: A case-control study. AB - BACKGROUND/PURPOSE OF THE STUDY: Psychological factors, particularly psychosocial stress, have been implicated as risk indicators for temporomandibular disorder (TMD). The aim of this study was to assess any differences in salivary cortisol concentration, scores of perceived stress scale (PSS), and scores of depression and distress between TMD patients and matched controls. MATERIALS AND METHODS: This case-control study comprised two groups; the patient group consisted of 60 patients attending the Department of Fixed Prosthodontics at the Faculty of Dentistry who met the inclusion criteria (42 females and 18 males aged 19-44), whereas the control group was selected to match the patient group in number, age and sex. Two questionnaires were used for stress assessment: The PSS 10 and the psychosocial measure of Research Diagnostic Criteria (RDC) for TMD axis II. Salivary cortisol levels were measured by a competitive immunoenzymatic colorimetric method. Data were analyzed using SPSS 17. Descriptive statistics, one-way ANOVA test, and independent t-test were used. RESULTS: This study showed statistically significant differences between the patient group and the control group at the three measures of psychosocial stress (P < 0.05). Increased occurrence of this disorder in women has been observed. CONCLUSION: Psychosocial stress plays an important role in the etiopathogenesis of TMD. Women are at increased risk of TMD when compared to men. Sub-types TMD patients approximately have the same level of stress. Muscle disorders were the most common. PMID- 26929503 TI - Change in color of a maxillofacial prosthetic silicone elastomer, following investment in molds of different materials. AB - PURPOSE: In the authors' experience, the color of silicone elastomer following polymerization in molds made of gypsum products is slightly different from the color that was matched in the presence of the patient, before the silicone is packed. It is hypothesized that the investing materials and separating media have an effect on the color during the polymerization process of the silicone. MATERIALS AND METHODS: This study compares and evaluates the change in color of silicone elastomer packed in three commonly used investing materials - Dental stone (white color), dental stone (green color), and die stone (orange color); coated with three different separating media - Alginate-based medium, soap solution and a resin-based die hardening material. Pigmented silicone samples of dimensions 1.5 cm * 2 cm * 0.5 cm were made from the elastomer in the above mentioned mold materials using combinations of the mentioned separating media. These served as test group samples. Control group samples were made by packing a mix of the same pigmented elastomer in stainless steel molds. The L*, a*, b* values of the test and control group samples were determined using a spectrophotometer. The change in color (Delta E) was calculated between the control and test groups. RESULTS: The mean L, a, b values for the control group were, 31.8, 26.2, and 36.3, respectively. Average values of change in color (Delta E) for samples packed utilizing alginate-based medium, die hardener, and soap solution, respectively in white dental stone (2.70, 2.74, and 2.88), green dental stone (2.19, 2.23, 2.42), and orange die stone (3.19, 2.72, 2.80) were tabulated. CONCLUSION: Among the investing materials studied, die stone showed the most color change (3.19), which was statistically significant. Among the separating media, die hardener showed the least color change (2.23). The best combination of an investing material and separating media as per this investigation is a dental stone (green) and alginate-based separating medium. PMID- 26929504 TI - Development and evaluation of learning module on clinical decision-making in Prosthodontics. AB - PURPOSE: Best practice strategies for helping students learn the reasoning skills of problem solving and critical thinking (CT) remain a source of conjecture, particularly with regard to CT. The dental education literature is fundamentally devoid of research on the cognitive components of clinical decision-making. AIM: This study was aimed to develop and evaluate the impact of blended learning module on clinical decision-making skills of dental graduates for planning prosthodontics rehabilitation. METHODOLOGY: An interactive teaching module consisting of didactic lectures on clinical decision-making and a computer assisted case-based treatment planning software was developed Its impact on cognitive knowledge gain in clinical decision-making was evaluated using an assessment involving problem-based multiple choice questions and paper-based case scenarios. RESULTS: Mean test scores were: Pretest (17 +/- 1), posttest 1 (21 +/- 2) and posttest 2 (43 +/- 3). Comparison of mean scores was done with one-way ANOVA test. There was overall significant difference in between mean scores at all the three points (P < 0.001). A pair-wise comparison of mean scores was done with Bonferroni test. The mean difference is significant at the 0.05 level. The pair-wise comparison shows that posttest 2 score is significantly higher than posttest 1 and posttest 1 is significantly higher than pretest that is, pretest 2 > posttest 1 > pretest. CONCLUSION: Blended teaching methods employing didactic lectures on the clinical decision-making as well as computer assisted case-based learning can be used to improve quality of clinical decision-making in prosthodontic rehabilitation for dental graduates. PMID- 26929505 TI - Evaluation of three different tooth preparation techniques for metal ceramic crowns by comparing preparation depths: An in vitro study. AB - AIM: To determine the effect of three different tooth preparation techniques had on operator's ability to appropriately and consistently prepare teeth for metal ceramic crowns. MATERIALS AND METHODS: Ninety maxillary left central incisor typodont teeth were allocated to three equal groups (A, B and C) of thirty and mounted in standard working model one at a time. A freehand approach was used to prepare the teeth in Group A, which acted as a control. Groups B and C were prepared with the assistance of silicon index and suitable depth gauge burs, respectively. A silicon index of unprepared teeth, into which contrasting colored silicon injected to occupy the space created by tooth preparation, was sectioned in the midline. Images of sectioned index were captured with optical microscope attached to a personal computer. A calibrated image analysis software was used to measure the depth of preparation (in millimeters) at five points (labial cervical, mid-labial, incisal, mid-palatal and palatal cervical) on two occasions. These results were pooled and averaged to give a mean labial, incisal and palatal preparation depths in mm. The data were analyzed by one-way analysis of variance and Scheffe's post-hoc statistical test. RESULTS: The mean depth of labial and incisal preparation for Groups A, B and C was 1.23 and 1.72 mm, 1.45 and 1.96 mm, 1.47 and 1.95 mm, respectively. The difference between the groups' labial preparation depth was significant as well as the difference between groups' incisal preparation depth. The mean palatal preparation was 0.46 mm for Group A, 0.54 mm for Group B and 0.59 mm for Group C. CONCLUSION: Teeth preparation for metal ceramic crowns without any assistance can lead to under preparation of labial and incisal surface. CLINICAL SIGNIFICANCE: Whenever possible, considerable importance should be given to the use of index or depth gauge burs for preparing teeth for receiving metal ceramic crowns. PMID- 26929506 TI - An evaluation of relation between the relative parallelism of occlusal plane to ala-tragal line and variation in the angulation of Po-Na-ANS angle in dentulous subjects: A cephalometric study. AB - AIMS: The aim was to evaluate if any correlation exists between variation in angulation of Po-Na-ANS angle and relative parallelism of the occlusal plane to the different tragal levels of the ear in dentulous subjects. METHODOLOGY: A total of 200 subjects were selected for the study. A custom made occlusal plane analyzer was used to determine the posterior point of the ala-tragal line. The lateral cephalogram was shot for each of the subjects. The points Porion, Nasion, and Anterior Nasal Spine were located and the angle formed between these points was measured. STATISTICAL ANALYSIS USED: Fischer's exact test was used to find the correlation between Po-Na-ANS angle and relative parallelism of the occlusal plane to the ala-tragal line at different tragal levels. RESULTS: Statistical analysis showed no significant correlation between Po-Na-ANS angle and relative parallelism of an occlusal plane at different tragal levels, and an inferior point on the tragus was the most common. CONCLUSION: Irrespective of variations in the Po-Na-ANS angle, no correlation exists between the variation in the angulations of Po-Na-ANS angle and the relative parallelism of occlusal plane to the ala-tragal line at different tragal levels. Furthermore, in a large number of subjects (54%), the occlusal plane was found parallel to a line joining the inferior border of the ala of the nose and the inferior part of the tragus. PMID- 26929507 TI - Evaluation of marginal fit and internal adaptation of zirconia copings fabricated by two CAD - CAM systems: An in vitro study. AB - STATEMENT OF PROBLEM: Three main factors which determine the success of an All ceramic restoration are esthetic value, resistance to fracture and third being the marginal fit. Marginal fit and internal adaptation are crucial factors in increasing the longevity of the restoration. Newer and economical CAD CAM systems have been introduced claiming better marginal fit and adaptation of All ceramic crowns. CAD CAM systems involves scanning of the die or the tooth preparation and milling of the restoration, which may have variations among the systems available. AIM OF THE STUDY: Our study intended to check the marginal fit and internal adaptation of commonly used CAD CAM systems namely CERAMILL and CEREC In Lab MC XL. MATERIALS AND METHODS: Two groups of typodont teeth (n = 10) were prepared using a standardized protocol to receive All ceramic copings. 10 samples of Group A were used for fabrication of copings using CERAMILL system and 10 samples of Group B were used for fabrication of copings using CEREC -In Lab MC XL system. They were then luted with glass ionomer cement under mild finger pressure. Samples were embedded in resin and sliced longitudinally. They were then viewed under stereomicroscope and readings were measured along 15 points using ImageScope software. The P value was set at 0.05 at 95% confidence interval with 80% power. The data were checked for normality and unpaired t-test was used to evaluate the results of the two groups. RESULTS: The overall internal adaptation was 61.5 +/- 5.2 MUm for CERAMILL and 56.9 +/- 5.7 MUm for CEREC -In Lab MC XL (P < 0.05). The marginal fit for CERAMILL was 83 MUm and for CEREC -In Lab MC XL was 68 MUm (P < 0.05). CONCLUSION: The marginal adaptation of CEREC -In Lab MC XL (68 MUm) was found to be superior to CERAMILL (83 MUm) (P < 0.05). Both the CEREC -In Lab MC XL and CERAMILL copings demonstrated internal adaptation and marginal fit within acceptable discrepancy range. When corroborating both the internal adaptation and marginal fit, CEREC -In Lab MC XL was found to be better than CERAMILL. PMID- 26929508 TI - Interventions for replacing missing teeth: Antibiotics in dental implant placement to prevent complications: Evidence summary of Cochrane review. AB - The failure of dental implant can occurs at the preoperative planning stage, at the surgical stage, and at the postoperative stage. The success of this treatment can be increased if the clinical implant practice guidelines are prepared based on the recommendations from the highest level of research evidence (i.e.,) from systematic review of randomized controlled trials (RCTs) with meta-analysis. The Cochrane reviews of interventions are basically systematic reviews of RCTs with meta-analysis but follow a systematic methodological approach following the guidelines from Cochrane handbook for Systematic Reviews of Intervention. They give the current best evidence as they are updated every 2 years which is being the minimum period for an update. This evidence summary recommends the use of antibiotics, single dose of 2 g of amoxicillin 1 h prior to implant surgery to prevent implant failure, based on the body of evidence from the Cochrane review that was first published in 2003, 2008, and then updated twice in 2010 and 2013. The included studies are not from our population for the research question asked in this updated Cochrane review; hence, the need to do primary research in our population to support the available evidence is mandatory. PMID- 26929509 TI - Enhancing the zone of keratinized tissue around implants. AB - Presence or absence of a minimal zone of keratinized tissue around dental implants has been a matter of controversy. However, a consensus exists that a thick zone of keratinized zone around implants provides a prosthetic friendly environment, facilitates precise prosthetic procedures, allows oral hygiene maintenance, resists recession, and enhances esthetic blending. The aim of the present case series was to increase the zone of keratinized soft tissue around dental implants supporting overdentures. Three different surgical techniques modified palatal roll technique with and without apical positioning and connective tissue graft (CTG) were used to achieve this goal. There was a significant gain of keratinized soft tissue with all the three techniques, which remained stable over a period of 6 months. Modified palatal roll technique with and without apical positioning and CTG are simpler surgical techniques, which can be successfully and predictably used for increasing the zone of keratinized tissue around implants. PMID- 26929510 TI - Magnet retained lip prosthesis in a geriatric patient. AB - Surgical resection of lips is a relatively rare procedure. A defective lip may cause the patient to feel socially vulnerable as well as functionally handicapped and the defect will influence the patient's self-esteem and body image. Patients with labial defects also experience speech problems along with drying and crusting of the tissues in the area of defect. The lip and cheek provide a valve mechanism for speech. Rehabilitation of patients with this type of surgery creates numerous challenges for both the surgical and the maxillofacial prosthetic teams. The goals of prosthetic treatment include regaining favorable speech and restoration of esthetics. This case report presents a 65-year-old woman who was referred for restoration of her lost lip. This case paper describes a quick and simple method of positioning magnets with lip prosthesis attached to maxillary denture and thus esthetics and speech of the patient is restored. Use of retention magnets simplify the clinical and laboratory phase retains the denture and makes it stable and comfortable for the patient. The advent of magnets has enhanced the dental practitioner's capabilities with a remarkably improved potential for increasing prosthesis stability and preserving tissue. PMID- 26929511 TI - Are implants the ONLY solution to replacement of missing teeth?? PMID- 26929513 TI - Concepts of occlusion in prosthodontics: A literature review, part I. AB - Occlusion and its relationship to the function of the stomatognathic system have been widely studied in dentistry since many decades. This series of articles describe about occlusion in the complete denture, fixed partial denture, and implants. Part I and II of this articles series describe concepts and philosophies of occlusion in complete denture. So far, available research has not concluded a superior tooth form or occlusal scheme to satisfy the requirements of completely edentulous patients with respect to comfort, mastication, phonetics, and esthetics. Since then, several balanced and nonbalanced articulation concepts were proposed in the literature. A balanced articulation appears to be most appropriate because of tooth contacts observed during nonfunctional activities of patients. This article discusses about evolution of different concepts of occlusion and occlusal schemes in complete denture occlusion. PMID- 26929514 TI - Quantitative analysis of leaching of different metals in human saliva from dental casting alloys: An in vivo study. AB - BACKGROUND: The issue of biomaterial-derived ionic release in various sites of the human body has attracted the interest of many investigators because of the possibility that debris or degradation products elicit a foreign body reaction or have a role in the induction of pathological processes. PURPOSE: The purpose was to evaluate the saliva of denture wearers after insertion of the prosthesis for leaching of metals from metallic denture. MATERIALS AND METHODS: Total 20 subjects of age group of 40-60 years including both males (10) and females (10) were selected for the study. Total subjects were divided into 2 groups each containing 10 subjects, Group I (control group): Subjects having dentition intact up to second molar and free of any dental restoration; Group II (study group): Partially edentulous subjects rehabilitated with cast-metal removable partial denture. Saliva samples were taken at three stages that is, 1 h, 24 h and 72 h after the denture insertion from subjects of study group as well as from the control group. Atomic absorption spectroscopy (AAS) was used to estimate the concentration of elemental ions. Obtained data's were analyzed using SPSS (Statistical Package for Social Sciences) version 15.0 statistical analysis software. The values were represented in a number (%) and mean +/- standard deviation. RESULTS: At 1 h, 24 h and 72 h after the denture insertion in study group, chromium (Cr) had statistically significant higher mean concentration as compared to manganese (Mn) (P < 0.001). Cr had maximum concentration (0.1479 + 0.0052) immediately after denture insertion while maximum concentration of Mn (0.1479 + 0.0052) was found 24 h after denture insertion. CONCLUSION: Metal-based dentures show maximum leaching immediately after wearing of the prosthesis which decreased significantly over the period of 3 days. Cr and Mn were the metal ions mainly found in saliva of cast partial denture wearer. No concentration of cobalt, molybdenum (Mo) and iron (Fe) was found in saliva of metal base denture wearer. There was a significant change in concentration of elutes in saliva in first 72 h/3 days making time an effective variable was observed. PMID- 26929512 TI - Clinical evaluation of osseointegration using resonance frequency analysis. AB - The stability of the implant at the time of placement and during the development of the osseointegration process are the two major issues governing the implant survival. Implant stability is a mechanical phenomenon related to local factors such as bone quality, quantity, type of placement technique and type of implant used. The application of a user-friendly, clinically reliable, non-invasive method to assess implant stability and the osseointegration process is considered highly desirable. Resonance frequency analysis (RFA) is one such method which shows almost perfect reproducibility and repeatability after statistical analysis. The aim of this paper is to review the various methods used to assess implant stability and on the currently used RFA method which is being highly accepted in the recent times. PMID- 26929515 TI - The dimensional accuracy of polyvinyl siloxane impression materials using two different impression techniques: An in vitro study. AB - AIM OF THE STUDY: To evaluate and compare the linear dimensional changes of the three representative polyvinyl siloxane (PVS) impression materials and to compare the accuracy of single mix with double mix impression technique. METHODOLOGY: A study mold was prepared according to revised American Dental Association specification number 19 for nonaqueous elastic dental impression materials. Three PVS impression materials selected were Elite-HD, Imprint(TM) II Garant, Aquasil Ultra Heavy. Two impression techniques used were single mix and double mix impression technique. A total of 60 specimens were made and after 24 h the specimens were measured using profile projector. STATISTICAL ANALYSIS: The data were analyzed using one-way analyses of variance analysis and significant differences were separated using Student's Newman-Keul's test. RESULTS: When all the three study group impression materials were compared for double mix technique, the statistically significant difference was found only between Imprint(TM) II Garantand Elite-HD (P < 0.05). Similarly, using single mix technique, statistically significant difference were found between Elite-HD and Imprint(TM) II Garant (P < 0.05) and also between Aquasil Ultra Heavy and Elite HD (P < 0.05). When the linear dimensional accuracy of all three impression material in double mix impression technique and single mix impression technique were compared with the control group, Imprint(TM) II Garant showed the values more nearing to the values of master die, followed by Aquasil Ultra Heavy and Elite-HD respectively. CONCLUSION: Among the impression materials Imprint(TM) II Garant showed least dimensional change. Among the impression techniques, double mix impression technique showed the better results. PMID- 26929516 TI - The influence of immediate complete anterior guidance development technique on subjective symptoms in Myofascial pain patients: Verified using digital analysis of occlusion (Tek-scan) for analysing occlusion: A 3 years clinical observation. AB - OBJECTIVES: The purpose of this study is to evaluate the effect of occlusal equilibration using immediate complete anterior guidance development (ICAGD) technique by Kerstein and Farrell on the subjective symptoms of myofascial pain. This technique is the most advanced verifiable and measurable way of digitally analyzing the occlusion using T-scan technology. The primary objective is to reduce the anterior disclusion time to <0.4 s and the secondary objective is to reduce the signs and symptoms of myofascial pain. MATERIALS AND METHODS: This study is to assess the reducing effects of subjective symptoms of 100 patients diagnosed as myofascial pain patients treated by ICAGD technique as described by Kerstein and Farrell. The common complaints of the patients were a pain in the masseter and temporal muscles, jaw tiredness in the mornings, night bruxing and difficulty in chewing. In this technique occlusal equilibration involves removal of posterior interferences and establish anterior guidance. The patients were treated over three visits 1-week apart and followed for 3 years with an interval of 3 months for the subsequent visits. A visual analog ordinal scale is used to rate the symptoms. The symptoms reduction occurred for all the patients after the first correction in about 5-10 days. In about a period of 3 years review, no recurrence was seen of the chronic myofascial symptoms. RESULTS: In spite of the chronic nature of the patient's symptoms, symptom reduction occurred in a week's time. This was assessed by the results of the ordinal scale values. This agrees with the studies of Kerstein and Farrell. CONCLUSION: Equilibration of occlusion using digital analysis by T-scan in which force is quantified against time, should be done to establish free functional movements without any interference; otherwise the disturbances in the excursive movements may lead to muscle dysfunction at later years. PMID- 26929517 TI - Effect of sandblasting on fracture load of titanium ceramic crowns. AB - PURPOSE OF THE STUDY: It is difficult to achieve a reliable bond between the titanium and veneering porcelain. The aim of this study was to evaluate the bond strength between titanium ceramic crowns. MATERIALS AND METHODS: The surfaces of titanium copings were divided in two groups. Group A sandblasted with 250 um (n = 10) and Group B without sandblasting (n = 10). Low-fusing porcelain was bonded over copings. A universal testing machine was used to determine the fracture load (N) of the crowns. All data were compared using Student's t-test. RESULTS: There was a significant difference in fracture toughness between two groups (P = 0.05). The mean value of fracture strength for Group A was 721.66 N and for Group B was 396.39 N. CONCLUSIONS: Sandblasting improves the bond strength between titanium, and ceramic, mechanical bonding plays a crucial role in the bonding between titanium and ceramic. PMID- 26929518 TI - A three-dimensional finite element analysis of a passive and friction fit implant abutment interface and the influence of occlusal table dimension on the stress distribution pattern on the implant and surrounding bone. AB - AIMS: The aim of the study was to evaluate the stress distribution pattern in the implant and the surrounding bone for a passive and a friction fit implant abutment interface and to analyze the influence of occlusal table dimension on the stress generated. MATERIALS AND METHODS: CAD models of two different types of implant abutment connections, the passive fit or the slip-fit represented by the Nobel Replace Tri-lobe connection and the friction fit or active fit represented by the Nobel active conical connection were made. The stress distribution pattern was studied at different occlusal dimension. Six models were constructed in PRO ENGINEER 05 of the two implant abutment connection for three different occlusal dimensions each. The implant and abutment complex was placed in cortical and cancellous bone modeled using a computed tomography scan. This complex was subjected to a force of 100 N in the axial and oblique direction. The amount of stress and the pattern of stress generated were recorded on a color scale using ANSYS 13 software. RESULTS: The results showed that overall maximum Von Misses stress on the bone is significantly less for friction fit than the passive fit in any loading conditions stresses on the implant were significantly higher for the friction fit than the passive fit. The narrow occlusal table models generated the least amount of stress on the implant abutment interface. CONCLUSION: It can thus be concluded that the conical connection distributes more stress to the implant body and dissipates less stress to the surrounding bone. A narrow occlusal table considerably reduces the occlusal overload. PMID- 26929519 TI - A study of the emotional effects of tooth loss in an edentulous Gujarati population and its association with depression. AB - CONTEXT: To fully estimate the burden of illness due to edentulism and establish valid treatment outcomes measures in this regard, it is equally important to study its psychosocial repercussions. AIMS: The aim was to conduct a study to explore the emotional reactions to tooth loss, screen for current depressive symptoms and test for association between the two; among an edentulous Gujarati population. SETTINGS AND DESIGN: A total of 147 edentulous people visiting the Prosthodontics Department were surveyed. SUBJECTS AND METHODS: A questionnaire (based on previous studies) to test the emotional reactions to tooth loss and Nine Item-Patient Health Questionnaire to test for depression were used. STATISTICAL ANALYSIS USED: The data were analyzed using the Chi-square (chi (2)) test with the help of SPSS v. 18.0 (IBM Corp., Armonk, NY, USA). RESULTS: Totally, 100 out of 147 edentulous people returned the questionnaire of which 58% experienced difficulties in accepting tooth loss and 37% felt unprepared for its effects. Those with difficulties accepting tooth loss had a greater effect on self esteem and social life, had more reservation about discussing tooth loss and was more likely to experience depression. Both groups were satisfied with dentures, had no problem meeting their friends or partners without dentures and leaving out dentures at night. CONCLUSION: About 58% of edentulous people had difficulties accepting tooth loss, which was unrelated to denture satisfaction. Respondents appeared to be restricted in social activities mainly due to functional limitations. Those with difficulties accepting tooth loss were more likely to experience depression. PMID- 26929520 TI - Bridging the gap in 1(st) year dental material curriculum: A 3 year randomized cross over trial. AB - BACKGROUND: Case-oriented small group discussions (COSGDs) can help students to correlate and integrate the basic science of dental materials into clinical application. We used COSGDs along with didactic lectures in dental material curriculum and hypothesized that case-oriented group discussions would be more effective than traditional lecture alone in terms of performance of students, student perception on the above two teaching methodologies and the feasibility in classes of 2010, 2011 and 2012. METHODS: A total of 170 students were taught using both COSGD and didactic lecture in a randomized controlled crossover trial design. Their performance was assessed through multiple-choice questions (MCQs) as part of the formative assessment, and their perception was assessed through Likert scale questionnaire. RESULTS: The mean difference in the scores between case-oriented group discussions with lecture and didactic lecture showed significant difference only in few topics. Around 94-96% of students perceived COSGD with didactic lecture help them understand theory better; 76-92% of students feel more comfortable asking questions in a group discussion; 89-98% of students feel such discussions motivate them and 91-100% of students agree that discussions make the subject interesting in the respective years of 2010, 2011 and 2012. CONCLUSION: Effectiveness of COSGD in terms of scores through MCQs is comparable to traditional lecture. However, most of the students perceive COSGD help them understand the theory better; co-relate clinically; more motivating and interesting than a traditional lecture. Feasibility in institution needs more time and resources to conduct COSGD within the dental material curriculum. PMID- 26929521 TI - Stress distribution patterns of implant supported overdentures-analog versus finite element analysis: A comparative in-vitro study. AB - AIMS AND OBJECTIVES: The aim of this study was to asses & compare the load transfer characteristics of Ball/O-ring and Bar/Clip attachment systems in implant supported overdentures using analog and finite element analysis models. METHODOLOGY: For the analog part of the study, castable bar was used for the bar and clip attachment and a metallic housing with a rubber O-ring component was used for the ball/O-ring attachment. The stress on the implant surface was measured using the strain-gauge technique. For the finite element analysis, the model were fabricated and load applications were done in a similar manner as in analog study. RESULTS: The difference between both the attachment systems was found to be statistically significant (P<0.001). CONCLUSION: Ball/O-ring attachment system transmitted lesser amount of stresses to the implants on the non-loading side, as compared to the Bar-Clip attachment system. When overall stress distribution is compared, the Bar-Clip attachment seems to perform better than the Ball/O-ring attachment, because the force was distributed better. PMID- 26929522 TI - The effect of microwave processing and use of antimicrobial agent on porosity of conventional heat cured denture base resin: An in vitro study. AB - STATEMENT OF PROBLEM: The occurrence porosity in polymethyl methacrylate, the most commonly used denture base material is a problem. The occurrence of oral candidiasis and other infections has also been reported in denture users. PURPOSE: The aim of this study was to evaluate the effect of addition of an antimicrobial agent, silver zeolite on the porosity of denture base resin, which will be an effective tool in the prevention of oral candidiasis among denture wearers. This study also aims to analyze the effect of polymerization technique on porosity in zeolite incorporated dentures to develop a denture base resin which will be easy to process with optimal mechanical and antimicrobial properties. MATERIALS AND METHODS: Eighty rectangular resin specimens (65 mm * 40 mm * 5 mm) were divided into one control group (A) and three experimental groups (B - Microwave cured denture base resin specimens, C - Conventionally cured denture base resin incorporated with antibacterial zeolites, D - Microwave cured denture base resin incorporated with antibacterial zeolites) porosity was calculated by measurement of the specimen volume before and after its immersion in water. Data were analyzed using one-way analysis of variance. RESULTS: The mean values of the percent mean porosity were: A = 0.9555%, B = 0.9590%, C = 0.9630%, D = 0.9695%. No significant differences were found in mean porosity among the groups evaluated. CONCLUSION: Within the limitations of this study, it could be concluded that the addition of zeolites did not result in significant porosity and that the use of microwave processing is a viable option for denture processing. PMID- 26929523 TI - The effect of spraying different disinfectants on condensational silicone impressions; an in vitro study. AB - BACKGROUND: Dentistry equipment are exposed to different types of pathogenic microorganisms. The aim of this study was to investigate the effect of spraying three different types of disinfectants on condensational silicones after 5 and 10 min. MATERIALS AND METHODS: Totally, 66 circular samples of condensational silicone impression materials of 1 cm diameter and 2 mm thickness were contaminated by Staphylococcus aureus, Pseudomonas aeruginosa, and Candida albicans fungus. Except for control samples, all of them were disinfected with sodium hypochlorite (NaOCl) 0.525%, Deconex and Epimax by spraying method. Afterward, they kept in plastic bags with humid rolled cotton for 5 and 10 min. In order to isolate microbiotas, the samples were immersed in 2% trypsin for 1 h and diluted with normal saline in a portion of 1, 1/2, and 1/4. The trypsin suspensions were transferred to culture plates for incubation and colony-forming unit assay. The data were analyzed by Mann-Whitney test and SPSS software version 16 at a significant level of 0.05. RESULTS: There was a meaningful difference between disinfection effects of Epimax-Deconex for all mentioned microorganisms after 5 min (P = 0.034), and between disinfection effects of NaOCl 0.525%-Epimax for S. aureus (P = 0.043) and P. aeruginosa (P = 0.046) after 5 min. Furthermore, there was a meaningful difference between disinfection effects of Epimax-Deconex (P = 0.034) and NaOCl 0.525%-Epimax (P = 0.034) for P. aeruginosa after 10 min. CONCLUSION: Condensational silicone can be effectively disinfected by spraying tested three disinfecting agents. More specifically, Deconex showed the best results compared to the other agents. PMID- 26929524 TI - Intervention for replacing missing teeth: Different types of implants - evidence summary of updated Cochrane review. AB - Around 1300 different types of dental implants are available worldwide and the implant manufacturers are resorting to aggressive marketing strategies; claiming their implants to provide a superior outcome. The clinician is left with a constant dilemma on which implant to choose for better clinical outcome and welfare of the patient. Moreover, in India, economical consideration is a concern too. The dentist has to select an implant that provides a good result and is economical. Cochrane systematic reviews provide the gold standard evidence for intervention, diagnosis, etc., and follow a strict quality control. A Cochrane systematic review was done to shed light on whether the different implant surface modifications, shapes or materials significantly influence clinical outcomes. All randomized controlled trials (RCTs) till January 17, 2014 were searched and out of the 81 trials, only 27 met the inclusion criteria. This evidence summary from the review concludes that based on the available literature; there is no evidence of any one type of implant being superior to another. There is weak evidence showing roughened dental implants are more prone to bone loss due to periimplantitis. This review indicated that there is a need for well-designed RCTs, with long-term follow-up and low bias. Moreover, none of the included studies was from India, which also points out the need for improving the quality of RCTs conducted in India. PMID- 26929525 TI - Prosthetic rehabilitation of large mid-facial defect with magnet-retained silicone prosthesis. AB - Rehabilitation of maxillofacial defect patients is a challenging task. The most common prosthetic treatment problem with such patients is, getting adequate retention, stability, and support. In cases of large maxillofacial defect, movement of the prosthesis is inevitable. The primary objectives in rehabilitating the maxillofacial defect patients are to restore the function of mastication, deglutition, speech, and to achieve normal orofacial appearance. This clinical report describes maxillofacial prosthetic rehabilitation of large midfacial defect including orbit along with its contents, zygoma and soft tissues including half of the nose, cheeks, upper lip of left side, accompanying postsurgical microstomia and orofacial communication, which resulted from severe fungal infection mucormycosis. The defect in this case was restored with magnet retained two piece maxillofacial prosthesis having hollow acrylic resin framework and an overlying silicone facial prosthesis. The retention of prosthesis was further enhanced with the use of spectacles. This type of combination prosthesis enhanced the cosmesis and functional acceptability of prosthesis. PMID- 26929526 TI - Alleviating speech and deglutition: Role of a prosthodontist in multidisciplinary management of velopharyngeal insufficiency. AB - Surgical resection of soft palate due to cancer affects the effective functioning of the velopharyngeal mechanism (speech and deglutition). With the loss of speech intelligibility, hyper resonance in voice and impaired function of swallowing (due to nasal regurgitation), there is a depreciation in the quality of life of such an individual. In a multidisciplinary setup, the role of a prosthodontist has been described to rehabilitate such patients by fabrication of speech aid prosthesis. The design and method of fabrication of the prosthesis are simple and easy to perform. The use of prosthesis, together with training (of speech) by a speech pathologist resulted in improvement in speech. Furthermore, an improvement in swallowing had been noted, resulting in an improved nutritional intake and general well-being of an individual. The take-home message is that in the treatment of oral cancer, feasible, and rapid rehabilitation should be endeavored in order to make the patient socially more acceptable. The onus lies on the prosthodontist to practise the same in a rapid manner before the moral of the patient becomes low due to the associated stigma of cancer. PMID- 26929528 TI - Glove over glove technique for manipulation of vinyl polysiloxane impression material with latex gloves. PMID- 26929527 TI - Achieving an esthetic smile with fixed and removal prosthesis using extracoronal castable precision attachments. AB - Satisfactory restoration in a patient with a partially edentulous situation can be challenging especially when unilateral or bilateral posterior segment of teeth is missing. Successful restoration can be done with various conventional and contemporary treatment options. One such treatment modality is attachment retained cast partial dentures. A key to success for an attachment retained cast partial denture is the strategic selection of teeth for retention. This clinical report discusses rehabilitation of a patient with the help of a combined prosthesis in the upper arch and stud retained overdenture in the lower arch. PMID- 26929529 TI - Virtual articulators and virtual facebow transfers: Digital prosthodontics!!! PMID- 26929530 TI - Relationship between removable prosthesis and some systemics disorders. AB - This article reviews the dental literature concerning the potential impact of the removable prosthesis (RP) on the health status of patients with certain systemic diseases. Literature was surveyed using Medline/PubMed database resources, as well as a manual search, up to 2015 to identify appropriate articles that addressed the aim of this review. The research used keywords about associations between RP and six pathologies: Human immunodeficiency virus infection, diabetes mellitus, pulmonary diseases, gastric-Helicobacter pylori, cancer, and cardiovascular diseases. Analysis of literature showed that in patients with dentures having one or more of the six general conditions listed, Candida albicans organism is more frequently found in the oral flora compared to healthy denture wearer. Although causality has not been established and pending further research on this topic, the hygienic practices necessary to minimize the risk of numerous pathologies should be strengthened in the case of these patients, all the more in the presence of physical or psychological disability. The relationship between the general diseases and increasing of oral candidiasis denture patients is not explained. Therefore, attention to oral hygiene and professional care for removing C. albicans may be beneficial in these medically compromised patients. PMID- 26929531 TI - Burning mouth syndrome: Current concepts. AB - Burning mouth syndrome (BMS) is a chronic pain condition. It has been described by the International Headache Society as "an intra-oral burning or dysesthetic sensation, recurring daily for more than 2 h/day for more than 3 months, without clinically evident causative lesions." BMS is frequently seen in women in the peri-menopausal and menopausal age group in an average female/male ratio of 7:1. The site most commonly affected is the anterior two-thirds of the tongue. The patient may also report taste alterations and oral dryness along with the burning. The etiopathogenesis is complex and is not well-comprehended. The more accepted theories point toward a neuropathic etiology, but the gustatory system has also been implicated in this condition. BMS is frequently mismanaged, partly because it is not well-known among healthcare providers. Diagnosis of BMS is made after other local and systemic causes of burning have been ruled out as then; the oral burning is the disease itself. The management of BMS still remains a challenge. Benzodiazepines have been used in clinical practice as the first-line medication in the pharmacological management of BMS. Nonpharmacological management includes cognitive behavioral therapy and complementary and alternative medicine (CAM). The aim of this review is to familiarize healthcare providers with the diagnosis, pathogenesis, and general characteristics of primary BMS while updating them with the current treatment options to better manage this group of patients. PMID- 26929533 TI - A comparative evaluation of the reliability of three methods of assessing gingival biotype in dentate subjects in different age groups: An in vivo study. AB - INTRODUCTION: In the modern competitive society, a pleasing appearance often dictates the difference between success and failure in both our personal and professional lives. Evaluation of gingival biotype is very important from the start of treatment plan to the final restorative placement to provide excellent esthetics. MATERIALS AND METHODOLOGY: For the study, subjects were divided into 4 groups of different ages, from 20-30, 31-40, 41-50 and 51-60 years. 30 subjects (15 men and 15 women) were selected in each group for the study. Examination of the thickness of Gingival Biotype was done in 3 different ways; - Direct visual, William's Graduated Probe and Using modified wax caliper. RESULTS: The McNemar test showed statistically significant differences in the way gingival biotype was identified when comparing visual assessment with assessment using direct measurement (P < 0.001). And there was no statistically significant difference when assessment using a periodontal probe was compared to direct measurement (P < 0.676). There is no correlation for the Biotype among the different age groups. CONCLUSION: Gingival biotype identification by visual assessment is statistically significantly different from assessment with direct measurement. Gingival biotype identification by assessment with a periodontal probe is not statistically significantly different from direct measurement. PMID- 26929532 TI - Evaluation and comparison of the effect of different surface treatment modifications on the shear bond strength of a resin cement to titanium: An in vitro study. AB - The purpose of this study was to evaluate and compare the effect of grit blasting, chemical treatment, and application of alloy primer combinations on the shear bond strength (SBS) of a self-cure resin cement to titanium surface. MATERIALS AND METHODS: Fifty cast commercially pure titanium discs (9 mm * 2 mm) were divided into five groups (n = 10), which received the following surface treatments: Control group (no surface treatment), group 1 (grit blasting using 110 um Al2O3 particles and application of alloy primer), group 2 (grit blasting using 110 um Al2O3 particles and chemical treatment using 1N HCl), group 3 (chemical treatment using 1N HCl and application of alloy primer), and group 4 (Grit blasting using 110 um Al2O3 particles, chemical treatment using 1N HCl and application of alloy primer). Superbond C and B resin cement was applied to the treated titanium surfaces including controls. SBSs were determined after thermocycling for 5000 cycles. Data (megapascal) were analyzed by ANOVA and Bonferroni test. RESULTS: Group 4 (grit blasting using 110 um Al2O3 particles, chemical treatment using 1N hydrochloric acid, and application of alloy primer) produced the highest bond strength followed by group 1, group 3, group 2, and the control group which showed the least bond strength. CONCLUSION: (1) Air-abrasion with alumina particles increases the micromechanical retention of the resin to titanium. (2) The alloy primer promotes wettability, which increases the adhesive bonding of resin cement to titanium. (3) Chemical treatment using hydrochloric acid effectively pretreats the titanium surface thereby increasing the SBS values. PMID- 26929534 TI - Comparative evaluation of bond strength of all-metal crowns with different luting agents after undergoing various modes of surface treatments: An in-vitro study. AB - AIM: This study includes a comparative evaluation of the various surface treatments of the intaglio surface of crowns in combination with various luting agents for maximal retention. MATERIALS AND METHODS: Totally, 150 dies of a standard complete crown preparation were fabricated. Wax pattern with a loop on the occlusal surface was prepared on each die using standard procedures, and then crowns were cast with nickel-chromium alloy. These crowns were randomly divided into five groups as per the surface of the intaglio surface of the metal copings. The crowns in each group were again subdivided randomly into three groups as per the luting agents used resin-modified glass ionomer cement, glass ionomer cement, and zinc phosphate cement. Retention was measured (MPa) by separating the metal crowns from the metallic die under tension on a Universal testing machine. STATISTICAL ANALYSIS USED: The data were recorded and statistically analyzed using one-way analysis of variance followed by Tukey's test. RESULTS: The retention differed both with surface treatment and type of luting agents. Untreated group showed the least bond strengths < sandblasting with 50 um alumina < sandblasting with 50 um alumina with ultrasonic cleaning < sandblasting with 110 um alumina < sandblasting with 110 um alumina along with ultrasonic cleaning. For luting agents, glass ionomer cement showed least bond strength because there was no chemical bonding present between metal crown and metallic die, followed by zinc phosphate cement and maximum bond strength were found for resin-modified glass ionomer cement. CONCLUSION: Among all types of surface treatments used in this study, maximum bond strength was yielded by sandblasting with 110 um alumina + ultrasonic cleaning and the best luting agent was resin-modified glass ionomer cement. PMID- 26929535 TI - Evaluation of Hanau's formula in determination of lateral condylar guidance: A clinical research study. AB - STATEMENT OF PROBLEM: The accuracy and reliability of the methods used for programming the semi-adjustable articulators determine the accuracy in occlusion. The current recommended average settings using the Hanau's formula commonly used by clinicians is questionable, and thus reassessment is needed. This study was carried out to evaluate and compare the lateral condylar guidance: (1) Using the Hanau's formula and the computerized jaw tracking device (Kinesiograph). (2) On the right and left sides using both these methods. MATERIALS AND METHODS: A total of 20 completely edentulous patients (14 male and 6 females) within 40-60 years of age were selected. Jaw relation was recorded followed by face bow transfer. Extraoral Gothic arch tracing was recorded; three protrusive records were obtained and condylar guidance was calculated. Lateral condylar guidance was then calculated using Hanau's formula, followed by the computerized jaw tracking device. A comparative evaluation was done of the obtained values. The same investigator worked with each of the study participants for the purpose of standardization. RESULTS: The lateral condylar guidance values obtained using the Hanau's formula ranged from 14 to 17 degrees while those obtained using the computerized K7 jaw tracking device ranged from 8 to 40 degrees . Bennett angle values, obtained using the jaw tracking device and Hanau's formula showed statistically significant differences (P < 0.05) using paired t-test (at 95% confidence interval). Bennett angle values of the right and left sides found using the Hanau's formula were almost similar. Difference in the Bennett angle values of the right and left sides were found using the jaw tracking device. However, this difference was not statistically significant (P > 0.05). CONCLUSION: Based on the results, dentist and dental technicians should consider reassessing the current recommended average settings and use of the Hanau's formula for programming the semi-adjustable articulators. PMID- 26929536 TI - Comparative evaluation of craniofacial anthropometric measurements in Indian adult patients with and without obstructive sleep apnea: A pilot study. AB - AIMS: The study aimed to compare the craniofacial features of North Indian patients suffering from obstructive sleep apnea (OSA) to that of normal North Indian population. MATERIALS AND METHODS: Selected 25 North Indian subjects (age: 18-65 years) were divided into two groups (OSA group [n = 14] and non-OSA group [n = 9]) according to the results of full night polysomnographic sleep study. Body mass index (BMI), neck circumference (NC), and lateral cephalograms were recorded for each subject in both groups and total 22 parameters of craniofacial anthropometric features were measured on lateral cephalograms for each subject. The differences in BMI, NC, and craniofacial features between the OSA and non-OSA groups were compared statistically. RESULTS: Independent sample t-test was used to compare the differences between OSA group and non-OSA group. The results showed that the BMI, NC, bulk of tongue (tongue length, tongue height, and tongue area) and length of the soft palate (PNS-U) were significantly higher in OSA group. OSA group was also found to have inferior positioning of hyoid bone (MP-H, ANS-H, PNS-H, ANS-Eb), narrower superior and middle airway space (SPAS and MAS), antero-inferior positioning of mandible (Gn-C3, ANS-Me, SNB, N-Me) and lower cranial base flexure angle (N-S-Ba). CONCLUSION: Craniofacial features, which play an important role in the pathophysiology of OSA, differ significantly between North Indian patients suffering from OSA and normal North Indian population. PMID- 26929537 TI - Maxillomandibular relationship record for implant complete mouth rehabilitation with elastomeric material and facial surface index of existing denture. AB - INTRODUCTION: The maxillomandibular relationship (MMR) record is a critical step to establish the new occlusion in implant supported complete mouth rehabilitation. Using patients existing denture for recording the MMR requires implant definitive cast to be modified extensively to completely seat the denture (with unaltered flanges) on it. This may influence the correct seating of the denture on the implant definitive cast causing faulty recording of the MMR. MATERIALS AND METHOD: Elastomeric record bases, reinforced with the resin framework, are fabricated and relined with the light body elastomeric material when all the healing abutments are in place. The MMR is recorded with these elastomeric record bases using vacuum formed facial surface index of the occluded existing dentures as a guideline. RESULTS: The elastomeric record bases with facial surface index of the existing dentures can allow clinicians to record MMR records without removing the healing abutments from the mouth with acceptable accuracy. This can save chair-side time of the procedure. The record of facial surfaces of existing complete denture in the form of vacuum formed sheet helps to set the occlusal vertical dimension. CONCLUSION: Use of facial surface index together with the elastomeric record bases can be the useful alternative technique to record the MMR in patients with implant supported full mouth rehabilitation. Further study is required to prove its routine clinical utility. PMID- 26929538 TI - Perception and knowledge of dental interns toward interdepartmental coordination for successful prosthodontic treatment: A pilot study. AB - BACKGROUND: The graduating dentist should be trained in providing treatment utilizing the interdisciplinary approach because of the rapid advancements and increase in patient expectations, which demands for collaboration between the different specialists. PURPOSE: A pilot study was undertaken with an aim to assess the perception and knowledge of dental interns toward interdepartmental coordination for successful prosthodontic treatment. SUBJECTS AND METHODS: Dental interns from two dental colleges in Sangli (India) participated in the study. A 24-item self-administered, structured closed-ended questionnaire was used to collect the data. Four questions assessed the perception and 20 questions assessed the knowledge, which were based on the four domains viz.: General, Endodontics, Orthodontics, and Prosthodontics. They were framed from case scenarios reporting to the Department of Prosthodontics, which required interdepartmental consultation. The questionnaire was validated before its application and reliability were also assessed. The final score for each question was calculated based on the correct responses. Descriptive analysis was calculated using the frequencies, percentages, and mean values by using SPSS 16 software. RESULTS: Among 117 interns who participated in the study, 79.5% reported that they lacked training in an interdisciplinary approach. Approximately, 96% reported that the curriculum should be designed to include interdisciplinary training. Nearly, 88% reported that specialist from different specialty should be posted in one interdisciplinary department. Around 60% reported that they did not have the confidence of treating the patient as a whole. When the overall mean scores were considered, the highest scores were obtained for the general domain (95.3) and the lowest for the prosthodontic domain (83.6). CONCLUSION: The dental interns perceived that they lacked training in interdisciplinary approach, and the curriculum should include interdisciplinary training. PMID- 26929539 TI - In vitro and in vivo evaluation of carbonate apatite-collagen scaffolds with some cytokines for bone tissue engineering. AB - BACKGROUND: Collagen is regarded as one of the most useful biomaterials. We tried to combine collagen and carbonate apatite (CA) with some cytokines in order to enhance bone formation ability. In this study, we found that CA-collagen sponge (CA-CS) was a possible candidate of newly graft material for bone formation. MATERIALS AND METHODS: CA-CS was fabricated by the following procedure. One wt% of pig hide collagen solution (Nippon Meat Packers. Inc., Tokyo, Japan) was neutralized with 0.1 N NaOH, and then mixed immediately 243 mg apatite powder with 0.06 M carbonate contents. After centrifugation at 1500 rpm for 10 min, excess water was removed, and the mixture was packed into Teflon molds (5.0 mm * 2.0 mm). Each 10 ug of basic fibroblast growth factor (bFGF) and recombinant human bone morphogenetic protein-2 (rh-BMP2) were involved in these sponges. Then these scaffolds frozen at -80 degrees C for 2 h and dried in a freeze dry machine for 24 h. CA-CS without cytokines were also prepared as a control. Mouse osteoblast-like cell (MC3T3-E1) proliferations in these scaffolds were investigated by 3-day in vitro cell culture using MTT assay examination. Ten New Zealand rabbits (weight: 3-3.5 kg) were used in this in vivo study. After 3 weeks of placement, the scaffolds, rabbits were sacrificed, and bone formation in the sockets was evaluated histologically and histomorphometrically. RESULTS AND CONCLUSION: By histological observation and measurement of bone area ratio, CA-CS with cytokines showed higher bone formation ability (bFGF/CA-CS: 50.7 +/- 7.3%, rh-BMP2/CA-CS: 54.2 +/- 5.0%) than other groups. From the limited results of this study, it is suggested that CA collagen scaffolds with some cytokines may become an attractive scaffold for bone regeneration. PMID- 26929540 TI - A clinical study to compare between resting and stimulated whole salivary flow rate and pH before and after complete denture placement in different age groups. AB - PURPOSE: This study compared the flow rate and pH of resting (unstimulated) and stimulated whole saliva before and after complete denture placement in different age groups. MATERIALS AND METHODS: Fifty healthy, non-medicated edentulous individuals of different age groups requiring complete denture prostheses were selected from the outpatient department. The resting (unstimulated) and stimulated whole saliva and pH were measured at three stages i.e., i)Before complete denture placement;ii)Immediately after complete denture placement; andiii)After 2 to 3 months of complete denture placement. Saliva production was stimulated by chewing paraffin wax. pH was determined by using a digital pH meter. RESULTS: Statistically significant differences were seen in resting(unstimulated) and stimulated whole salivary flow rate and pH obtained before, immediately after, and after 2 to 3 months of complete denture placement. No statistically significant differences were found between the different age groups in resting (unstimulated) as well as stimulated whole salivary flow rate and pH. CONCLUSION: Stimulated whole salivary flow rates and pH were significantly higher than resting (unstimulated) whole salivary flow rates and pH obtained before, immediately after, and after 2 to 3 months of complete denture placement. No age related variations in whole salivary flow rate and pH were observed in healthy, non-medicated individuals. CLINICAL IMPLICATIONS: The assessment of salivary flow rate, pH in different age groups is of prognostic value, which is an important aspect to be considered in the practice of removable prosthodontics. PMID- 26929541 TI - Evaluation of flexural strength and color stability of different denture base materials including flexible material after using different denture cleansers. AB - AIMS: Present study aimed at evaluating the colour stability and flexural strength of flexible denture base materials (Valplast) and Polymethyl methacrylate (PMMA) denture base material (Meliodent) processed by two different methods (Injection moulding and compression moulding) after immersing them in three different denture cleansers with acidic, basic and neutral PH. METHODS AND MATERIALS: Total 120 specimens (65 * 10 * 3 mm3), 40 specimens of each material (Valplast, Meliodent compression moulding and injection moulding) were immersed in denture cleansers having different PH; Valclean (Acidic), Clinsodent (Basic) and Polident (Neutral) as well as Distilled Water. Color changes were measured with a spectrophotometer after 1 month, 3 months and 6 months of immersion cycle. A flexural 3-point bending test was carried out by using an Instron universal testing machine after 6 months of soaking. Data were analyzed using SPSS software. RESULTS: Maximum effect on colour stability was noted with Clinsodent followed by Valclean. Least color changes were observed after immersion in Polident. Colour difference was increased significantly as the immersion time increased. For both Meliodent and Nylon resins, statistically significant change in flexural strength occurred with immersion in all denture cleansers. Clinsodent has greater effect as compared to Valclean and Polident. CONCLUSIONS: Polident and Valclean can be safely used as denture cleanser for both nylon and acrylic resin denture base materials as far as colour stability and flexural strength both are concerned. PMID- 26929542 TI - Evaluation of the surface roughness of three heat-cured acrylic denture base resins with different conventional lathe polishing techniques: A comparative study. AB - PURPOSE: Surface roughness promotes adhesion and colonization of denture plaque. Therefore, it is important to know the effects of polishing and finishing on the surface roughness of various acrylic resin materials. OBJECTIVES: To evaluate and compare the effects of different conventional lathe polishing techniques on heat cured acrylic resins in producing surface roughness. MATERIALS AND METHODS: Three different commercially available heat-cured acrylic resin materials namely DPI, Meliodent and Trevalon Hi were selected. 30 Specimens of each acrylic material (30 x 3 = 90, 10 x 60 x 2mm) were prepared and divided into 5 groups, each group consisted of 6 Nos. of specimens per material(6x3=18) and were grouped as Group A(unfinished), Group B (finished), Group C (Polishing Paste), Group D (Polishing Cake) and Group E (Pumice and Gold rouge). The resulted surface roughness (MUm) was measured using Perthometer and observed under Scanning Electron Microscope. The values obtained were subjected statistical analyses. RESULTS: Among the materials tested, better results were obtained with Trevalon Hi followed by Meliodent and DPI. Among the polishing methods used, superior results were obtained with universal polishing paste followed by polishing cake; Pumice and Gold rouge. Although Pumice and Gold rouge values produced greater roughness value, they were well within the threshold value of 0.2 mm. PMID- 26929543 TI - Intervention for replacing missing teeth: Alveolar ridge preservation techniques for dental implant site development - evidence summary of Cochrane review. AB - The Cochrane reviews have transparent reporting of the methodology to clarify the reader the methods used for writing the review; hence, each review becomes a large volume of scientific literature. This evidence summary of the Cochrane review published in 2015 for the question, what are the clinical effects (preservation of both width and height of bone, esthetic outcomes, complications, and failure of implant) for different alveolar ridge preservation techniques (ARP) and materials used in patients planning implant placement following extraction after 6 months follow-up. This review provides evidence for efficacy of different ARP techniques, materials, and superiority of one over the other. It also tries to settle the controversy of timing of placement of implant after grafting. Of the 8 included studies from 50, two trials provide moderate evidence for xenografts versus extraction favoring xenografts in preserving the width and height of bone by 1.97 mm (2.48-1.46) and 2.60 mm (3.43-1.76), respectively in pooled estimates of meta-analysis. Using different material, five-trial were found; of which, two trials provide moderate evidence for alloplast versus xenografts favoring alloplast in preserving the width by 0.44 mm (0.90-0.02) and low-grade evidence for height of bone by 0.35 mm (0.86-0.16) in pooled estimates of meta-analysis. There is a paucity of randomized controlled trial to address other primary and secondary outcomes addressed in this review. PMID- 26929544 TI - Posterior open occlusion management by registration of overlay removable partial denture: A clinical report. AB - This clinical report describes prosthetic rehabilitation of posterior open bite relationship in a patient with several missing teeth and skeletal Class III malocclusion. Primary diagnostic esthetic evaluations were performed by mounting casts in centric relation and estimating lost vertical dimension of occlusion. Exclusive treatments were designated by applying overlay removable partial denture with external attachment systems for higher retentions. PMID- 26929545 TI - Prosthetic rehabilitation of a total laryngectomy patient. AB - The fundamental objective in restoring a defect created after total laryngectomy with a custom made silicone prosthesis is to enable the patient to cope better with the difficult process of rehabilitation after a major surgery has been performed. A cosmetically acceptable prosthesis that reproduces the color and form and allows the patient to return to his/her accustomed lifestyle. A sequence of steps for construction of custom-made laryngeal prosthesis is outlined in this case report using the readily available materials and method which any prosthodontist can readily understand and deliver. PMID- 26929546 TI - Versatility of Pleuripotent Undifferentiated Stem Cells Aspirated from Bone Marrow and its Applications in Oral and Maxillofacial Surgery. AB - INTRODUCTION: Bone marrow (BM) derived pleuripotent undifferentiated stem cells represent a promising population for supporting new concepts in cellular therapy. AIM: The aim of this study is to evaluate the versatility of pleuripotent undifferentiated stem cells derived from BM aspiration and its applications in oral and maxillofacial surgical procedures. MATERIALS AND METHODS: A total of 30 patients out of which 15 were with hard tissue defects (cystic lesions n = 6, post surgical alveolar defects n = 4, peri implant defects n = 3, alveolar clefts n = 2) and 15 soft tissue lesions (leukoplakia and lichen planus n = 6, oral submucous fibrosis n = 7, post traumatic soft tissue loss n = 2) were included in the study on randomized clinical basis. The patients received autologous BM derived mononuclear cells which were being locally delivered into the lesion and followed up. The parameters used were (1) To compare and evaluate the bone regeneration by radiographic assessment at the end of 3rd and 6th month postoperatively. (2) Duration of the procedure. (3) Clinical improvement in the management of soft tissue lesions. (4) Assessment of wound healing by Vancouver burn scar assessment of wound. (5) Safety, postoperative infections and complications. RESULTS: For hard tissue lesions CT scans and OPG revealed adequate regenerated bone, bridging the defect after 3 months. Hounsfield units of regenerated bone after 6 months were more or less similar to native bone which was statistically significant (unpaired t test = p < 0.05). For soft tissue lesions (1) 7 cases of OSMF showed adequate clinical mouth opening (one way anova test = p < 0.05), reduction in burning sensation and blanching of mucosa, (2) 6 cases of leukoplakia and lichen planus and 2 cases of post traumatic soft tissue defects showed good clinical improvement by Vancouver burn scar assessment of wound index. CONCLUSION: The study shows that there is a definite beneficial effect in bone regeneration and soft tissue wound healing with the use of BM derived mononuclear cells. PMID- 26929548 TI - "Oral Submucous Fibrosis Scoring Index" to Predict the Treatment Algorithm in Oral Submucous Fibrosis. AB - PURPOSE: The main aim of the study is to propose a treatment protocol based on scoring system. MATERIALS AND METHODS: One hundred patients were selected randomly having oral submucous fibrosis. They were classified into five groups based on clinical signs and symptoms, radiological and histopathological grading and severity of fibrosis. Patients of particular group were subjected to specific treatment for each group and followed for 2 years regularly. RESULTS: We found that almost all patients got symptomatic relief and they are able to take regular diet. Patient's interincisal mouth opening increased significantly. CONCLUSION: Based on this scoring and grouping we can give definite and prompt treatment to the patients with satisfactory results. This proposed scoring and staging can play major role in controlling and treating this widespread global disease. Thus, OSMF scoring index is very effective to decide the severity of disease and progress. PMID- 26929547 TI - Long-Term Effect of Maxillary Distraction Osteogenesis (DO) on Nasal Index in Adult Patients with Cleft Lip and Palate Deformities. AB - PURPOSE: To test the hypothesis that there is no immediate and long-term effects of maxillary distraction osteogenesis (DO) on nasal index among adult subjects with cleft lip and palate deformities. MATERIALS AND METHODS: Twelve adult subjects in the age range of 17-20 years with complete unilateral cleft lip and palate underwent advancement of maxilla by DO. The immediate and long-term effects of maxillary DO on nasal index were evaluated from extra-oral full face frontal photographs recorded prior to DO (T0), at the end of active DO (T1) and at least 2-years after the DO (T2). The ANOVA, Post Hoc test (Bonferroni) and Pearson correlation coefficients were used. The probability value (P value) 0.05 was considered as statistically significant. RESULTS: SNM angle and Ptm-M distance increased significantly by DO (P < 0.001). The nasal index increased significantly (P < 0.01) by 13.85 % from T0 value of 85.15 +/- 4.49 to 99.02 +/- 11.16 % at the end of active distraction (T1) and by 12.69 to 97.84 +/- 9.14 % at the end of long-term follow-up (T2). The correlation between sagittal maxillary advancement and nasal index was statistically significant (P < 0.001). For each millimeter of maxillary advancement, the nasal index increased by 1.38 % and 1.8 % at the end of active distraction and long-term follow-up respectively. CONCLUSION: The advancement of maxilla by distraction osteogenesis among subjects with cleft lip and palate deformities increased nasal index significantly. PMID- 26929549 TI - Maxillofacial Fractures in Bhopal, India: Analytic Study of 1268 Cases. AB - PURPOSE: To ascertain the pattern, incidence, causes, age and sex distribution, types, condition and treatment of maxillofacial fractures and their interwoven relationship being practiced in Bhopal. MATERIALS AND METHODS: Retrospectively 3 year records of patients with maxillofacial fractures from 12 selected centres in Bhopal were reviewed. The following data were extracted from the medical records: age; gender; site of the fracture(s); other associated injury(ies); cause of the trauma and method of treatment(s). RESULT: In 1268 patients, a total of 2613 fractures were found of which 44.58 % patients had mandibular fractures. Parasymphysis was the most common site of fracture overall. Most patients were in the 21-30 year old age group, and the male: female ratio was 3.3:1. Road traffic accident accounted for 858 cases (67.67 %). Head injury was the highest occurring associated injury. Open surgical modalities was the most employed treatment modality in 52.60 % of cases. CONCLUSION: Preference for open surgical treatment along with increasing trend of supplemental intermaxillary fixation was found, which prompts us to check for the underlying reason behind this, which could be the increasing number of displaced and comminuted fracture cases or the decreasing efficiency of open reduction treatment rendered. Latter reason prompts to re-evaluate the existing surgical techniques and expertise of the practicing surgeons. PMID- 26929550 TI - Trends in Le Fort Fractures at a South American Trauma Care Center: Characteristics and Management. AB - PURPOSE: To assess the trends in Le Fort (maxillary) fractures in patients seen at a South American trauma care center based on the characteristics and management of these. MATERIALS AND METHODS: Of all patients with facial fractures seen at a trauma hospital during a six-year period, 50 (6.6 %) presented with Le Fort fractures. Medical charts were reviewed for characteristics presented and management performed. To improve the analyses, computed tomography and intraoperative findings were used. Statistical analyses involved descriptive statistics and the likelihood ratio test. RESULTS: The fractures were Le Fort II (52 %), Le Fort I (22 %), Le Fort type-associated (20 %) and Le Fort III (6 %). Male patients (90 %) in their third decade of life (38 %) were more frequent (p = 0.022). Traffic accidents (56 %) were the major etiologic factor (p = 0.048). There were 1.4 additional facial fractures per patient, with predominance of zygoma fractures (36.5 %). Most of the cases were managed by open reduction (60 %) (p = 0.015) with the subciliary approach (42.7 %) (p = 0.001). The 1.5-mm system was the most used fixation and the zygomaticomaxillary suture the most frequent location (p = 0.001). CONCLUSION: the most common patient with a Le Fort fracture is an adult male, with a Le Fort II fracture due to a traffic accident requiring surgical fixation on zygomaticomaxillary suture. PMID- 26929551 TI - Prevalence of Functional Problems After Oral Cavity Malignancy Treatment at a Tertiary Center: Utilizing PSS HN (Performance Status Scale for Head and Neck) Scale. AB - BACKGROUND: Oral cancer is the most common type of cancer occurring in India and it is equally important to assess morbidities after treatment for optimal utilization of resources. Utilizing PSS HN we try to identify the patient population who are severely impaired and need aggressive rehabilitation. METHOD AND MATERIAL: The PSSHN questionnaire was administered by the treating physician to 100 consecutive oral cancer patients who completed their index treatment at least 6 months prior to accrual. Functional morbidities with score <=50 were considered as significant. RESULTS: Prevalence of functional deficit of eating in public; deficit of understandability of speech and deficit of normalcy of diet were 28, 13 and 38 % respectively. CONCLUSION: Type of resection either segmental mandibulectomy or major glossectomy, had most significant impact on concerned functional deficits and surgeries involving these defects should be carefully planned to involve free flap reconstruction and proper postoperative rehabilitation. PMID- 26929552 TI - 'Y' Modification of the Transconjunctival Approach for Management of Zygomatic Complex Fractures: A Prospective Analysis. AB - PURPOSE: The purpose of this study was to clinically and radiologically evaluate reduction and fixation of isolated zygomatic complex (ZMC) fractures treated by Y modification of the transconjunctival approach. PATIENTS AND METHODS: A prospective evaluation of ten patients was undertaken for a period of 6 months using this modified approach from Jan 2012 to Jun 2013. Patients were examined preoperatively and post operatively at the end of 6 months for symmetry discrepancies involving A-P globe projection, lateral canthal level, malar projection and diplopia in direct and extreme gazes. Cosmetic outcomes were assessed by clinical assessment and examination of photographs. Quality of reduction and stability of fixation was assessed by examination of postoperative images. RESULTS: All patients underwent a three point fixation of ZMC with reconstruction of the orbital floor using titanium mesh. Patients were post surgically followed up at regular intervals of 1, 3 and 6 months. Immediate complications noted were chemosis, lid edema and lower lid retraction. Late complications included minor scleral show in two cases. All patients experienced significant improvement with excellent esthetic appearance and function. CONCLUSIONS: Y modification of transconjunctival approach provides excellent surgical exposure for ZMC fractures potentially avoiding the use of a second incision in the area of ZF suture. Although this technique provides good exposure and excellent esthetics, it requires more operating time and detailed knowledge of the anatomy of the lateral canthal region. PMID- 26929553 TI - Influence of Kinesiologic Tape on Post-operative Swelling After Orthognathic Surgery. AB - INTRODUCTION: Orthognathic surgery involves making several osteotomies that lead to varying degrees of post-operative swelling. The use of KT may be beneficial for postoperative treatment after head and neck surgery, accelerating drainage of tissue reaction or haemorrhages. The goal of this study was to find out if the application of KT prevents or improves swelling, pain and trismus after orthognathic surgery, improving patients' postoperative quality of life. MATERIALS AND METHODS: In this double-blinded, randomized, control trial, 24 patients in whom bimaxillary orthognathic surgery was indicated, were included. Before surgery each patient alternatively was randomly included in the study group (treated with K-Taping((r)) and corticosteroid) or in the control group (treated with corticosteroid). In the present study a MakerBot((r)) Digitizer 3DTM was used to assess accurate volume measurements. All swelling measurements were expressed as total 3-D area of the landmarks (cm(2) ) in T0 pre-operative, T1 fourth day after surgery. RESULTS: The differences T0-T1 are highly significant (p < 0.01) between group 1 or study group (treated with K taping((r))) and group 2 (control group). DISCUSSION: The use of KT appears promising, because it is simple to carry out, less traumatic, economical, can be performed everywhere in the world, free from side effects on the body. Even when swelling persists, KT gives patients the impression of a minor swelling detracting them from their pain and morbidity. Further studies have to be performed to find out if KT can reduce or replace the need for additional medications such as the use of steroids. PMID- 26929554 TI - Angioembolisation in Maxillofacial Trauma: An Initial Experience in a Tertiary Care Center. AB - PURPOSE: To analyze the safety, efficacy and outcome of angio-embolization in the management of refractory oro-nasal bleeding in patients of severe maxillofacial trauma. MATERIALS AND METHODS: It was a retrospective analysis of 21 patients who were managed by angio-embolisation to control refractory oro-nasal bleeding in severe maxillofacial trauma from December 2010 to December 2013. The patient population included 19 males and 2 females and the age ranged from 16 to 55 years (mean age of 29.6 years). Gelfoam pledgets and coils were used as embolising agents in branches of external carotid arteries. Embolising coils were preferably used to block actively bleeding vessels on angiography. RESULTS: Road traffic accidents were the etiology in 17 patients and fall from height (two), assault (one) and gunshot injury (one) in the rest. Twelve (52 %) patients showed active contrast extravasation on angiography. Active arterial bleeding was observed from branches of internal maxillary [11], facial [2] and lingual arteries [4]. Gel foam embolisation alone was done in 16 patients, coil embolisation alone in two patients and both coil and gel foam embolisation in three patients. The procedures were technically successful in twenty (95 %) patients. None of the patients had procedure related complications. Nine patients (42 %) succumbed to their associated injuries later, in which five patients had severe head injuries and four patients had history of hemorrhagic shock and cardiac arrest prior to the procedure. CONCLUSION: Angio-embolisation is a safe and effective technique in managing intractable bleeding in maxillofacial injuries. PMID- 26929555 TI - A Single Pre Operative Dose of Sub Mucosal Dexamethasone is Effective in Improving Post Operative Quality of Life in the Surgical Management of Impacted Third Molars: A Comparative Randomised Prospective Study. AB - OBJECTIVE: The aim of the study was to observe and compare the effects of dexamethasone on pain, swelling and trismus administered as one dose preoperatively sub mucosal (study group 2) versus intramuscular injection (study group 1) keeping control as those who received no dose of steroid in the management of third molar surgery. MATERIALS AND METHODS: The group 2 (20 patients) is the study group in which all the patients had single dose of pre operative sub mucosal dexamethasone of 4 mg/2 ml. The group 1 patients (20 patients) received single dose of pre-operative intra muscular dexamethasone of 4 mg/2 ml. The control group (20 patients) did not receive steroid in any form. The post operative pain, swelling and trismus were assessed for all the groups. RESULTS: The submucosal dexamethasone group showed marked improvement in the mouth opening in the follow ups than the intra muscular dexamethasone group. In those five cases of bilateral impaction, in study groups 1 and 2, the mouth opening was very much significant when sub mucosal dexamethasone was given. CONCLUSION: The pre operative use of submucosal dexamethasone effectively reduces the post operative pain, swelling and trismus showing statistically significant results. The number of post operative use of analgesic tablets taken by the patients in the study group 2 were less compared to the study group 1 and the control group showing clinically significant results. PMID- 26929556 TI - Orbital Infection Threatening Blindness Due to Carious Primary Molars: An Interesting Case Report. AB - INTRODUCTION: Distant spread of infection due to dental abscess in head and neck region is often reported in the literature. Orbital cellulitis or abscess although rare as a complication from decayed primary teeth in children is not an exception. The periapical infection from the maxillary primary molar spreads easily to the maxillary sinus first and followed by entry into the orbit through the orbital floor or through the ethmoidal sinuses. This if untreated may lead to orbital abscess, proptosis, progressive loss of vision, intracranial extension and even death. MATERIALS AND METHODS: A 10 year old boy presenting with severe pain, proptosis of right eyeball, ophthalmoplegia and blindness. CONCLUSION: Managed successfully with timely medical and surgical intervention with complete restoration of vision. This case presented emphasizes the primary teeth care necessary in children which if unchecked can cause fatal complications. PMID- 26929557 TI - Bone and Skin-Supported Stereolithographic Surgical Guides for Cranio-Facial Implant Placement. AB - PURPOSE: Osseointegrated skin-penetrating implants enhance the retention and stability of the craniofacial prostheses and provide the long-term comfort. However, to determine the implant locations is a great challenge facing the surgeon. Implants may either be located in conventional manner or by STL generated surgical guides. MATERIALS AND METHODS: Present study reports the CT based 3D virtual modeling, preoperative virtual planning and the implant placement by using a STL surgical guide, in an anotia case. RESULTS: Employed materials and the methods facilitated the implant surgery while improving the operational security. CONCLUSIONS: CT based 3D virtual modeling of the surgical site, determining the implant locations virtually and the STL guided placement of the craniofacial implants, were found useful applications in order to facilitating the surgical intervention and providing prevention from complications. PMID- 26929558 TI - Efficacy and Versatility of the 3-D Titanium Mesh Implant in the Closure of Large Post-Craniectomy Osseous Defects, and its Therapeutic Role in Reversing the Syndrome of the Trephined: Clinical Study of a Case Series and Review of Literature. AB - INTRODUCTION: An ideal cranioplasty material is one which adequately restores calvarial continuity, contour and esthetics, provides adequate cerebral protection, is biocompatible and corrosion resistant, lightweight yet strong, easy to manipulate and possesses long term stability. The 3-D Titanium mesh implant fulfills most of these criteria, and offers certain added advantages, as exemplified in this case series. Four patients with post craniectomy osseous defects of varying sizes and at different locations of the calvarium were studied. In addition to the obvious cosmetic deformity, the patients also exhibited various subjective and objective features of neurosensory and motor deficits characteristic of the motor trephine syndrome (MTS), that often develops secondary to large cranial defects. OBJECTIVE: There have been no documented reports so far on the effect of Titanium mesh cranioplasty on features of the MTS in patients with large cranial defects. It was the objective of this study to see if any specific therapeutic goals such as reversal of the neurological deterioration and sensorimotor deficits associated with the syndrome could be achieved by performing Titanium mesh cranioplasty to reconstruct the missing part of the cranial shield in these patients. Any added benefits of using 3-D Titanium mesh as a cranioplasty material were also recorded. MATERIALS AND METHODS: The cranial defects in all four patients were reconstructed using different dimensions of Titanium mesh implants. Two of the cases were early cranioplasties (performed within 3 months of craniectomy) and two were late cranioplasties (performed after 3 months of craniectomy), one of them even being a previous autologous bone flap cranioplasty failure. The patients were followed up for a period ranging from 3 to 4 years and observed carefully for cosmetic, functional and neurological improvements following the cranioplasty. RESULTS: There was achieved gratifying cosmetic correction of the cranial deformities, and remarkable functional recovery from the sensorimotor deficits, reversal of the neurological deterioration as well as resolution of most of the symptoms of MTS in all the four patients, following the Titanium mesh cranioplasty. Many added benefits were noted, such as quick post operative recovery, absence of any early or late complications and a ready means to aspirate any epidural collections, if they developed post operatively, through the mesh structure of the implant. CONCLUSION: Apart from the cosmetic, functional and protective roles, Titanium mesh cranioplasty demonstrated a definite therapeutic role in all the cases presented, making it preferable to even replacement with natural bone (either re implanted excised autologous bone flaps, or cortico-cancellous bone autografts). It is an extremely safe and reliable alternative to autografts, and is even preferable to them, especially when the size of the cranial defect is large. PMID- 26929559 TI - A Comparative Study of 3-Dimensional Titanium Versus 2-Dimensional Titanium Miniplates for Open Reduction and Fixation of Mandibular Parasymphysis Fracture. AB - INTRODUCTION: Three dimensional titanium plating system was developed by Farmand in 1995 to meet the requirements of semi rigid fixation with lesser complication. The purpose of this in vivo prospective study was to evaluate and compare the clinical effectiveness of three dimensional and two dimensional Titanium miniplates for open reduction and fixation of mandibular parasymphysis fracture. MATERIALS AND METHODS: Thirty patients with non-comminuted mandibular parasymphysis fractures were divided randomly into two equal groups and were treated with 2 mm 3D and 2D miniplate system respectively. All patients were systematically monitored at 1st, 2nd, 3rd, 6th week, 3rd and 6th month postoperatively. The outcome parameters recorded were severity of pain, infection, mobility, occlusion derangement, paresthesia and implant failure. The data so collected was analyzed using independent t test and Chi square test (alpha = .05). RESULTS: The results showed that one patient in each group had post-operative infection, occlusion derangement and mobility (p > .05). In Group A, one patient had paresthesia while in Group B, two patients had paresthesia (p > .05). None of the patients in both the groups had implant failure. There was no statistically significant difference between 3D and 2D miniplate system in all the recorded parameters at all the follow-ups (p > .05). CONCLUSION: 3D miniplates were found to be better than 2D miniplates in terms of cost, ease of surgery and operative time. However, 3D miniplates were unfavorable for cases where fracture line was oblique and in close proximity to mental foramen, where they were difficult to adapt and more chances for tooth-root damage and inadvertent injury to the mental nerve due to traction. PMID- 26929560 TI - A Comparative Study Between Bupivacaine with Adrenaline and Carbonated Bupivacaine with Adrenaline for Surgical Removal of Impacted Mandibular Third Molar. AB - OBJECTIVES: To compare the effectiveness of bupivacaine with adrenaline with that of carbonated bupivacaine with adrenaline on pain, onset of anesthesia and duration of anesthesia following surgical removal of impacted mandibular third molar. STUDY DESIGN: All the patients who underwent surgical removal of impacted mandibular third molar and who fulfilled our inclusion and exclusion criteria from 1st June 2013 to 30th June 2014 were included in our study. Patients who were diagnosed as having impacted mandibular third molar were randomly allocated to two groups namely group A (bupivacaine with adrenaline), group B (carbonated bupivacaine with adrenaline). Pain during deposition of local anesthetic, onset of anesthesia and duration of anesthesia were compared between the two groups. The collected data were subjected to statistical analysis by Chi Square test, Mann-Whitney U test. RESULTS AND CONCLUSION: The efficacy of carbonated bupivacaine with adrenaline is more compared with bupivacaine with adrenaline in decreasing pain on deposition of local anesthetic solution and in rapid onset of anesthesia. The duration of anesthesia for carbonated bupivacaine with adrenaline and bupivacaine with adrenaline had no significant difference. The use of carbonated bupivacaine with adrenaline will reduce the patient discomfort both intra-operatively and post-operatively. PMID- 26929561 TI - Adolescent Mandibular Central Odontoameloblastoma: A Rare Case Report. AB - Odontoameloblastoma is a rare odontogenic tumour, characterised by simultaneous occurrence of an ameloblastoma and a compound or complex odontoma in the same tumoral mass. The tumour is seen in first three decades and affects mandible or maxilla equally, commonly found posterior to the canines. The management is similar to unicystic ameloblastoma and odontoma excision. A long term follow up is a must to observe the recurrence. Here we present a rare case of odontoameloblastoma in a 17 year old male, presenting as an asymptomatic anterior mandibular swelling with chief complaint of missing lower front teeth. PMID- 26929562 TI - Complicated Giant Pilomatrixoma of the Parotid Region. AB - OBJECTIVE: Pilomatrixoma (calcifying epithelioma of Malherbe) is a benign soft tissue tumour arising from dermis or subcutaneous tissue which should be considered in differential diagnosis of preauricular lesions especially when skin fixation is present. CASE REPORT: Twenty-three year old male referred to our clinic with complaint of left preauricular swelling over 18 months which enlarged and became painful in the last 2 months. Because the lesion showed signs of infection, surgery was planned after medical therapy was completed. FNAB suggest pleomorphic adenoma as preliminary diagnosis. US or MRI showed no specific feature. TREATMENT AND PROGNOSIS: Total excision, superficial parotidectomy with facial nerve sparing was performed after regression of infectious signs. Postoperatively no recurrence was detected. CONCLUSION: Pilomatrixomas are benign tumours but have diagnostic difficulties according to clinical and cytologic findings. This rare lesion should be kept in mind to avoid misdiagnosis as malign parotid tumours, particularly in the presence of skin change. PMID- 26929563 TI - Benign Fibrous Histiocytoma: A Rare Case Report and Literature Review. AB - Fibrous histiocytoma is a benign soft tissue tumour that may present as a fibrous mass anywhere in the human body. The involvement of the oral cavity is extremely rare and very few cases have been reported in literature till date. We here report a case of benign fibrous histiocytoma localized in the oral cavity. The clinical and histological features of the lesion are discussed precisely in the light of a literature review of this pathology in oral cavity. PMID- 26929564 TI - Long-Term Follow-Up of Bimaxillary Osteomyelitis Associated with Autosomal Dominant Osteopetrosis: A Case Report. AB - Osteopetrosis (OP) is a rare metabolic bone disease characterized by a generalized increase in skeletal mass. The disease is characterized by increased susceptibility to develop osteomyelitis of the jaws. We report a case of clinical and radiological progression of bimaxillary osteomyelitis in a patient with autosomal dominant OP. The patient presented non simultaneous osteomyelitis in both upper and lower jaws with time interval of 10 years. The osteomyelitis of maxilla resulted in oroantral fistula formation and required surgical closure with Bichat fat pad flap. The mandibular osteomyelitis resulted in sequestra formation and pathological fracture and required multiple debridement procedures. Both maxillary and mandibular osteomyelitic foci were persistent and healing required more than 2 years. The case confirms the possibility of development of non simultaneous bimaxillary osteomyelitis in patients with OP. The case enhances the need of close follow- up and preventive measures in patients with OP. PMID- 26929565 TI - Successful Treatment of Postoperative Mouth Opening Limitation Following Le Fort III Distraction with Bilateral Coronoidectomies. AB - INTRODUCTION: Distraction osteogenesis is a powerful tool in craniomaxillofacial surgery, allowing for large advancements of osteotomized segments in the setting of a restrictive soft tissue envelope. Despite its benefits, distraction can have negative functional consequences. We present a case of a patient with Crouzon syndrome who developed reduced mouth opening capability after a Le Fort III midfacial advancement with rigid external distraction. TECHNIQUE: Radiographic evaluation revealed that the coronoid process was restricting the normal excursion of the mandible by contacting the posterior zygoma. The patient was subsequently treated with a bilateral coronoidectomy via an intraoral approach, which improved his interincisal opening. Maximum interincisal distance was improved from 18 mm to 33 mm following bilateral cornoid resection. CONCLUSION: We report coronoid impingement as a potential complication after Le Fort III distraction. Such a finding suggests the need for a detailed vector analysis in cases undergoing midface advancement with distraction. Post-distraction coronoidectomy is a useful surgical procedure to treat mouth opening limitation due to coronoid impingement against the zygoma after midfacial advancement. PMID- 26929566 TI - Modification of Heister Jaw Opener. AB - Heister introduced a mouth gag of incentric pattern which is still being used. Heister jaw opener has narrow blades which rest on the occlusal surface of molar teeth. The force of mouth gag is not equally distributed on all the teeth, therefore there is great risk of tooth avulsion in periodontally compromised dentition and fracture of tooth while using standard Heister appliance. To overcome this modification of Heister mouth gag is done. PMID- 26929567 TI - Questionable Ethical Clearance, Incorrect Recommendations and Indiscernible Merit. PMID- 26929568 TI - Assessment of the Efficacy of Submental Intubation in the Management of Midfacial and Panfacial Trauma Patients. PMID- 26929569 TI - Cissus quadrangularis Linn. Stem Ethanolic Extract Liberates Reactive Oxygen Species and Induces Mitochondria Mediated Apoptosis in KB Cells. AB - BACKGROUND: Cissus quadrangularis Linn. (CQ) commonly known as Hadjod (Family: Vitaceae) is usually distributed in India and Sri Lanka and contains several bioactive compounds responsible for various metabolic and physiologic effects. OBJECTIVE: In this study, the biological effects of CQ ethanolic extract were evaluated by in vitro and supported by in silico analysis on KB oral epidermoid cancer cell line. MATERIALS AND METHODS: Anti-cancer potential of ethanolic extract of CQ stem against KB oral epidermoid cancer cells was evaluated in terms of morphological analysis, nuclei staining, liberation of reactive oxygen species (ROS), cell cycle arrest, mitochondrial membrane potential (MMP) and p53 and Bcl 2 protein expression which reveal the induction of apoptosis along with supporting in silico analysis. RESULTS: Ethanolic extract of CQ stem contains various bioactive compounds responsible for cancer cell morphological alterations, liberation of ROS, G1 phase cell cycle arrest and decreased MMP along with up-regulation of p53 and down-regulation of Bcl-2. By employing in silico approach, we have also postulated that the CQ extract active constituents sequester Bcl-2 with higher affinity as compared to p53, which may be the reason for induction of growth arrest and apoptosis in KB cells. CONCLUSION: Our data indicate that the CQ extract has a remarkable apoptotic effect that suggests that it could be a viable treatment option for specific types of cancers. SUMMARY: Cissus quadrangularis stem ethanolic extract induces apoptosis and cell cycle arrest at G1 phaseIt liberates (ROS) and mitochondria mediated apoptosisIt upregulates p53 and down-regulates Bcl-2 protein expressionIn silico studies indicates that the active constituents of CQ binds Bcl-2 with higher affinity as compared to p53. PMID- 26929570 TI - Hepatoprotective Effect of A Polyherbal Extract Containing Andrographis Paniculata, Tinospora Cordifolia and Solanum Nigrum Against Paracetamol Induced Hepatotoxicity. AB - BACKGROUND: Traditionally, a number of medicinal plants are used to treat various types of hepatic disorders but few of them were pharmacologically evaluated for their safety and efficacy. The combination of Andrographis paniculata (Kalmegha), Tinospora cordifolia (Guduchi), and Solanum nigrum (Kakmachi) was traditionally used in Indian System of Medicine (Ayurveda) for the treatment of various liver related disorders. OBJECTIVE: In the present study, an attempt was made to substantiate the ethnopharmacological use of a traditional formulation in hepatoprotection against paracetamol-induced hepatotoxicity. SUBJECTS AND METHODS: Swiss albino mice (weight 20-25 g) were used for this study. Intraperitoneal injection of paracetamol (500 mg/kg body weight) was used to induce hepatotoxicity. Serum levels of alanine transaminase, aspartate aminotransferase, bilirubin, alkaline phosphatase, were used as indices of liver injury. In addition total cholesterol, triglyceride, low-density lipoprotein, high-density lipoprotein and creatinine were also assayed using the standard procedure. RESULTS: Among the two different doses, pretreatment with Polyherbal extract at 500 mg/kg body weight exhibited a significant (P < 0.05) hepatoprotective activity as compared to paracetamol group. CONCLUSION: The polyherbal extract exhibits a significant hepatoprotective effect in vivo. The study contributes to its use in traditional Ayurveda system for the management of liver diseases. SUMMARY: Traditionally, a number of medicinal plants are used to treat various types of liver disorders but few of them were pharmacologically evaluated for their safety and efficacy. Combination of Andrographis paniculata (Kalmegha), Tinospora cordifolia (Guduchi), and Solanum nigrum (Kakmachi) was traditionally used in Ayurveda for the treatment of various liver related disorders. In the present study an attempt was made to validate the ethnopharmacological use of a traditional formulation in hepatoprotection against paracetamol induced hepatotoxicity. Swiss albino mice (weight 20-25 g) were used for this study. Intraperitoneal injection (IP) of paracetamol (500 mg/kg body weight) was used to induce hepatotoxicity. Serum levels of Alanine transaminase (ALT), Aspartate Aminotransferase (AST), Bilirubin, Alkaline phosphatase (ALP),. were used as indices of liver injury. In addition total cholesterol, triglyceride, Low density lipoprotein (LDL), High density lipoprotein (HDL) and creatinine were also assayed using standard procedure. Among the two different doses, pre-treatment with Polyherbal extract at 500 mg/kg body weight exhibited a significant (P < 0.05) hepatoprotective activity as compared to paracetamol group. The polyherbal extract exhibits significant hepatoprotective effect in vivo. The study contributes to its use in traditional Ayurveda system for the management of liver diseases. PMID- 26929571 TI - Toxicogenomics of Phenylhydrazine Induced Hematotoxicity and its Attenuation by Plumbagin from Plumbago zeylanica. AB - BACKGROUND: High regenerative and proliferative capacity of blood and its components renders it to be at higher risk of adverse drug reactions (ADRs) which are manifested in several treatment regimens against various ailments such as cancers, viral diseases, and several metabolic disorders. OBJECTIVE: It is prudent to come up with some therapeutic entity that can prevent this damage and protects the blood from these ADRs. MATERIALS AND METHODS: We examined protective effects of Plumbago zeylanica (PZ) and its active constituent plumbagin (PL) on Sprague Dawley (SD) rats using a phenylhydrazine (Phz) induced hematotoxicity model. Hemoglobin (Hgb), red blood cells (RBCs), mean corpuscular volume, mean corpuscular Hgb (MCH), MCH concentration (MCHC), leukocytes and platelets were studied. Anti-oxidant enzymes superoxide dismutases 2 and 3 (SODs) and nuclear erythroid 2 p45-related factor 1 and 2 (Nfer-1 and 2) were also studied using quantitative real-time polymerase chain reaction (PCR). RESULTS: In Phz treated rats, the positive hematotoxic response was obtained in terms of deviated endpoints of blood indices. In PLtreated groups protective response was obtained in terms of normal endpoints of blood indices. In PCR studies, we observed the similar trend. Thus, it can be postulated that PL exerts its protective effects via modulation of anti-oxidant enzymes. CONCLUSION: The study proves that PL can be employed against combatting the ADRs associated with several therapeutic treatment regimens. Similar studies employing such pharmacological entities and their combinations may further prove to be effective against ADRs, especially in the context of blood cells. SUMMARY: Hematotoxicity is generally encountered in various therapeutic regimens as ADRs (Adverse Drug Reactions). Plumbagin, an active constituent of plant Plumbago zeylanica is tested for its anti-hematotoxic potential in Phenylhydrazine induced hematotoxicity model in Sprague dawley rats. In vivo, in-vitro and molecular studies confirmed the peremptory actions of PL. It was revealed in our studies that the anti-hematotoxic actions of Plumbagin are due to its capacity to modulate anti-oxidant enzyme system. PMID- 26929572 TI - Effects of 4-hydroxyisoleucine from Fenugreek Seeds on Depression-like Behavior in Socially Isolated Olfactory Bulbectomized Rats. AB - CONTEXT: Antidepressant-like effects of (2S, 3R, 4S)-4-hydroxyisoleucine (4-HI), a major amino acid from fenugreek seeds, has been reported in the animal model of acute depression. AIMS: To evaluate effects of subacute administration of 4-HI in animal model of stress-induced depression namely socially isolated olfactory bulbectomized rats. MATERIALS AND METHODS: Bilateral olfactory bulbectomy (OBX) were induced in 30 Sprague-Dawley rats. After recovery period of 14 days, rats were randomized into five groups of 6 rats each and stressed with social isolation (individual housing). The rats were orally treated with either vehicle (OBX-Iso), positive control, fluoxetine (30 mg/kg) or 4-HI (10, 30, 100 mg/kg) once a day from day 14 onward. Separate group of rats with social isolation but without OBX (Sham-Iso) was also maintained. The behavioral depression and anxiety related parameters using open field test (OFT), sucrose intake test, novelty suppressed feeding (NSF) and forced swim test (FST), and neurochemical estimation (brain monoamines viz., serotonin and nor-adrenaline, serotonin turnover, and serum cortisol) were performed. STATISTICAL ANALYSIS USED: Data was analyzed by either two-way ANOVA (OFT and FST) or one-way ANOVA (sucrose intake test, NSF, and neurochemical estimation) followed by Dunnett's multiple comparisons test. Differences were considered significant at P < 0.05. RESULTS: The significant and dose-dependent protection from behavioral and neurochemical changes were observed in 4-HI co-administrated OBX-Iso rats. CONCLUSION: 4-HI demonstrated the antidepressant and antianxiety effects in socially isolated stress-induced OBX rats with possible involvement of multiple stress relieving mechanisms. HIGHLIGHTS OF PAPER: In this study, the subacute pretreatment of 4-HI showed strong and dose-dependent prevention of isolation stress related behavioral and neurochemical responses in olfactory bulbectomized rats. The prevention of hyperactive HPA axis in OBX-Iso stress-induced rats can be envisaged as probable mechanism of antidepressant and antianxiety effects of 4-HI. SUMMARY: Effect of 4 hydroxyisoleucine (4-HI) in olfactory bulbectomized and socially isolated (Iso) rats was evaluated4-HI showed significant and dose-dependent antidepressant effects during novelty suppressed feeding (NSF) and forced swim test (FST)4-HI showed significant and dose-dependent antianxiety effects during OFT (open field test) and sucrose intake test4-HI showed protection from OBX-Iso stress-induced brain monoamines, serotonin turnover, and serum cortisol level elevation. Abbreviations used: SSRI: Selective Serotonin Reuptake Inhibitor; 4-HI: (2S, 3R, 4S)-4-hydroxyisoleucine; OBX: Olfactory bulbectomy; CPCSEA: Committee for the Purpose of Control and Supervision of Experiments on Animals; OFT: Open Field Test; NSF: Novelty Suppressed Feeding; FST: Forced Swimming Test; 5HT: 5 Hydroxytryptamine; 5-HIAA: 5-Hydroxyindoleacetic Acid; NA: Nor-adrenaline; and HPA: Hypothalamic-Pituitary Adrenal. PMID- 26929573 TI - Ultraviolet-B Protective Effect of Flavonoids from Eugenia caryophylata on Human Dermal Fibroblast Cells. AB - BACKGROUND: The exposure of skin to ultraviolet-B (UV-B) radiations leads to deoxyribonucleic acid (DNA) damage and can induce production of free radicals which imbalance the redox status of the cell and lead to increased oxidative stress. Clove has been traditionally used for its analgesic, anti-inflammatory, anti-microbial, anti-viral, and antiseptic effects. OBJECTIVE: To evaluate the UV B protective activity of flavonoids from Eugenia caryophylata (clove) buds on human dermal fibroblast cells. MATERIALS AND METHODS: Protective ability of flavonoid-enriched (FE) fraction of clove was studied against UV-B induced cytotoxicity, anti-oxidant regulation, oxidative DNA damage, intracellular reactive oxygen species (ROS) generation, apoptotic morphological changes, and regulation of heme oxygenase-1 (HO-1) gene through nuclear factor E2-related factor 2 antioxidant response element (Nrf2 ARE) pathway. RESULTS: FE fraction showed a significant antioxidant potential. Pretreatment of cells with FE fraction (10-40 MUg/ml) reversed the effects of UV-B induced cytotoxicity, depletion of endogenous enzymatic antioxidants, oxidative DNA damage, intracellular ROS production, apoptotic changes, and overexpression of Nrf2 and HO-1. CONCLUSION: The present study demonstrated for the first time that the FE fraction from clove could confer UV-B protection probably through the Nrf2-ARE pathway, which included the down-regulation of Nrf2 and HO-1. These findings suggested that the flavonoids from clove could potentially be considered as UV-B protectants and can be explored further for its topical application to the area of the skin requiring protection. SUMMARY: Pretreatment of human dermal fibroblast with flavonoid-enriched fraction of Eugenia caryophylata attenuated effects of ultraviolet-B radiationsIt also conferred protection through nuclear factor E2-related factor 2-antioxidant response pathway and increased tolerance of cells against oxidative stressFlavonoid-enriched fraction can be explored further for topical application to the skin as a ultraviolet-B protectant. Abbreviations used: ABTS: 2,2'-azino-bis-(3-ethylbenzothiazoline- 6-sulphonic acid), AO: Acridine orange, ANOVA: Analysis of variance, ARE: Antioxidant response elements, BSA: Bovine serum albumin, CAPE: Caffeic acid phenethyl ester, CAT: Catalase, DCFH-DA: 2',7'-dichlorofluorescein diacetate, DMEM: Dulbecco's Modified Eagle's Medium, DMSO: Dimethyl sulfoxide, DNA: Deoxyribonucleic acid, DPBS: Dulbecco's phosphate buffered saline, DPPH: 2,2-diphenyl-1-picrylhydrazyl, ECL: Enhanced chemiluminescence, EDTA: Ethylenediaminetetraacetic acid, ELISA: Enzyme-linked immunesorbent assay, EtBr: Ethidium bromide, FBS: Fetal bovine serum, FE fraction: Flavonoid-enriched fraction, FRAP: Ferric reducing antioxidant power, GPx: Glutathione peroxidase, GR: Glutathione reductase, GST: Glutathione-S-transferase, GSH: Reduced glutathione, GSSG: Oxidized glutathione, HDF: Human dermal fibroblast, HEPES: 4-(2-hydroxyethyl)-1 piperazineethanesulphonic acid, HRP: Horseradish peroxidase, HO-1: Heme oxygenase 1, HPTLC: High-performance thin layer chromatography, Keap-1: Kelch-like ECH associated protein-1, MTT: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, NaCl: Sodium chloride, NFDM: Nonfat dry milk, Nrf2: Nuclear factor E2 related factor 2, NQO1: NAD (P) H: Quinine oxidoreductase 1, OH: Hydroxyl ions, PBST: Phosphate buffered saline with 0.1% tween 20, PCR: Polymerase chain reaction, PMSF: Phenylmethanesulfonyl fluoride, Rf: Retention factor, ROS: Reactive oxygen species, rRNA: Ribosomal ribonucleic acid, SDS: Sodium dodecyl sulfate, SOD: Superoxide dismutase, TLC: Thin layer chromatography, TLC-DPPH: Thin layer chromatography-2,2-diphenyl-1-picrylhydrazyl, UV: Ultraviolet, UV-A: Ultraviolet-A, UV-B: Ultraviolet-B, UV-C: Ultraviolet-C, and qPCR: Quantitative polymerase chain reaction. PMID- 26929574 TI - Anti-inflammatory, Anti-estrogenic, and Anti-implantation Activity of Bergia suffruticosa (Delile) Fenzl. AB - BACKGROUND: Bergia suffruticosa (Delile) Fenzl (Syn. Bergia odorata Edgew) (Elatinaceae family) is used traditionally to repair bones and is applied as a poultice on sores. It is also used for stomach troubles and as an antidote to scorpion stings. So far, very little scientific work has been reported to validate its ethnomedical uses in the alleviation of pain, bone repair, etc. OBJECTIVE: This study was designed to explore the anti-inflammatory and anti implantation potential of n-hexane extract of B. suffruticosa whole plant in mice along with identification of its chemical constituents. MATERIALS AND METHODS: n Hexane extract of B. suffruticosa whole plant was screened for acute and chronic anti-inflammatory activity followed by an anti-estrogenic activity. Eventually, n hexane extract was tested for anti-implantation activity by exploiting markers of uterine receptivity, lipid peroxidation, and superoxide enzyme activity. The extract was administered orally at a dose of 100 mg/kg body weight in each study. RESULTS: Thin layer chromatography fingerprint profile of n-hexane extract revealed the presence of lupeol and beta-sitosterol. The n-hexane extract reduced the edema by 80% in acute inflammation, whereas it reduced edema to 75% on the 5(th) day in chronic inflammation. The n-hexane extract reduced elevated malonaldehyde level from 6 to 2.5 nmol/g * 10(-5) and increased superoxide dismutase enzyme activity from 0 to 350 units/g in treated animals on the 5(th) day of pregnancy. Moreover, extract decreased uterine weight from 0.33 to 0.2 g in estradiol treated animals. CONCLUSION: These results indicate that n-hexane extract of B. suffruticosa is having potent anti-inflammatory, anti-estrogenic, and anti-implantation activity. This is the first report of all the pharmacological activities of B. suffruticosa mentioned above. SUMMARY: TLC fingerprint profile of n-hexane extract of Bergia suffruticosa whole plant revealed the presence of lupeol and beta-sitosteroln-Hexane extract showed in vivo anti-inflammatory activity in both acute and chronic model of inflammation in ratsn-Hexane extract possess significant anti-estrogenic activityn-Hexane extract altered the levels superoxide anion radical and superoxide dismutase enzyme activity during the blastocyst implantationAnti-implantation activity of n hexane extract is attributed to its anti-inflammatory and anti-estrogenic potential. Abbreviations used: TLC: Thin layer chromatography; LPO: Lipid peroxidation; SOD: Superoxide dismutase; B. suffruticosa: Bergia suffruticosa; TNF-alpha: Tumor necrosis factor-alpha; NO: Nitric oxide; IL-1: Interleukin-1; LIF: Leukemia inhibitory factor; CSF-1: Colony-stimulating factor; COX: Cyclooxygenase; SDS: Sodium dodecyl sulfate; IAEC: Animal House Ethics Committee; CPCSEA: Committee for the Purpose of Control and Supervision of Experiments on Animals; HBSS: Hank's balanced salt solution; MDA: Malonaldehyde; and TBA: Thiobarbituric acid. PMID- 26929575 TI - Molecular Docking and Molecular Dynamics to Identify a Novel Human Immunodeficiency Virus Inhibitor from Alkaloids of Toddalia asiatica. AB - BACKGROUND: Acquired immunodeficiency syndrome caused by human immunodeficiency virus (HIV) is an immunosuppressive disease. Over the past decades, it has plagued human health due to the grave consequences in its harness. OBJECTIVE: For this reason, anti-HIV agents are imperative, and the search for the same from natural resources would assure the safety. MATERIALS AND METHODS: In this investigation we have performed molecular docking, molecular property prediction, drug-likeness score, and molecular dynamics (MD) simulation to develop a novel anti-HIV drug. We have screened 12 alkaloids from a medicinal plant Toddalia asiatica for its probabilistic binding with the active site of the HIV-1-reverse transcriptase (HIV-1-RT) domain (the major contributor to the onset of the disease). RESULTS: The docking results were evaluated based on free energies of binding (DeltaG), and the results suggested toddanol, toddanone, and toddalenone to be potent inhibitors of HIV-1-RT. In addition, the alkaloids were subjected to molecular property prediction analysis. Toddanol and toddanone with more rotatable bonds were found to have a drug-likeness score of 0.23 and 0.11, respectively. These scores were comparable with the standard anti-HIV drug zidovudine with a model score 0.28. Finally, two characteristic protein-ligand complexes were exposed to MD simulation to determine the stability of the predicted conformations. CONCLUSION: The toddanol-RT complex showed higher stability and stronger H-bonds than toddanone-RT complex. Based on these observations, we firmly believe that the alkaloid toddanol could aid in efficient HIV-1 drug discovery. SUMMARY: In the present study, the molecular docking and MD simulations are performed to explore the possible binding mode of HIV 1 RT with 12 alkaloids of T. asiatica. Molecular docking by AutoDock4 revealed three alkaloids toddanol, toddanone, and toddalenone with highest binding affinity towards HIV 1 RT. The drug likeness model score revealed a positive score for toddanol and toddanone which is comparable to the drug likeness score of the standard anti HIV drug zidovudine. Results from simulation analysis revealed that toddanol RT complex is more stable than toddanone RT complex inferring toddanol as a potential anti HIV drug molecule. Abbreviations used: HIV: Human immunodeficiency virus, HIV 1 RT: HIV 1 reverse transcriptase, RNase H: Ribonuclease H, MD: Molecular dynamics, PDB: Protein databank, RMSD: Root mean square deviation, RMSF: Root mean square fluctuation. PMID- 26929576 TI - Assessment of Pharmacodynamic and Pharmacokinetic Interaction of Aqueous Extract of Cassia auriculata L. and Metformin in Rats. AB - BACKGROUND: Cassia auriculata L. (CA) leaf extract might increase the body's production of insulin thereby suppressing the elevated blood glucose and lipid levels in diabetic rats. CA has been used as dietary supplement in India from ancient times. OBJECTIVE: The present study was to elucidate the synergistic pharmacodynamic (PD) and pharmacokinetic (PK) interaction of metformin (MT) with CA. MATERIALS AND METHODS: A simple, precise reverse phase high performance liquid chromatography - UV detection mode method was developed to quantify MT in rat plasma. In PD interaction, streptozotocin (45mg/kg, intraperitoneally) induced diabetic Wistar rats weighing 180-250 g of either sex were randomized to receive MT (90 mg/kg, MT-HD), CA (500 mg/kg) separately and in combination of MT (90 mg/kg, MT-HD) + CA (500 mg/kg), and MT (45 mg/kg, MT-LD) + CA (500 mg/kg) (all oral) along with normal and diabetic control groups for 21 days. PK of MT was carried out in normal rats with preadministration of CA (500 mg/kg) for 14 days. RESULTS: PD data showed reasonable blood glucose lowering effect of CA. The reduction of MT dose with combination of CA achieved a similar blood glucose lowering effect of MT alone. PK data showed enhanced time taken to achieve maximum plasma concentration (Cmax), area under the curve (AUC0-t), and Cmax in combination group of MT (90mg/kg) and CA (500mg/kg), and reduction of MT dose in Group III had a reduced Cmax and AUC0-t compared to MT alone treated groups. CONCLUSION: Co-administration of CA with MT at varying dose showed a synergistic herb-drug interaction. Thus using the synergistic herb-drug interaction, the dose level of MT may be reduced to produce the same therapeutic effect as when taken alone. SUMMARY: Elucidating the synergistic pharmacodynamic (PD) and pharmacokinetic (PK) interaction of metformin (MT) with Cassia auriculata L. (CA)PD data showed reasonable blood glucose lowering effect of CA. The reduction of MT dose with combination of CA achieved a similar blood glucose lowering effect of MT alonePK data showed enhanced time taken to achieve maximum plasma concentration (Cmax), area under the curve (AUC0-t), and Cmax in combination group of MT and CA, and reduction of MT dose had a reduced Cmax and AUC0-t compared to MT alone treated groupsCo-administration of CA with MT at varying dose showed a synergistic herb-drug interaction. Thus using the synergistic herb drug interaction, the dose level of MT may be reduced to produce the same therapeutic effect as when taken alone. Abbreviations used: CA: Cassia auriculata L., PD: Pharmacodynamic, PK: Pharmacokinetic, MT: Metformin, RP-HPLC-UV: Reverse phase High Performance Liquid Chromatography-UV detection mode, Tmax: Time taken to achieve maximum plasma concentration, AUC0-t: Area under the curve, Cmax: Maximum plasma concentration. PMID- 26929578 TI - The isolation, Characterization and Preclinical Studies of Metal Complex of Thespesia populnea for the Potential Peroxisome Proliferator-activated Receptors gamma Agonist Activity. AB - BACKGROUND: Diabetes mellitus is an international public health problem since ancient days. The condition is predominantly more severe in developing countries like India where, life is more sedentary due to the even changing lifestyles in this fast-paced global scenario. Thespesia populnea is widely used in the ayurvedic system of medicine for treatment of diabetes mellitus in India for years. The aim of this work is to explore the anti-diabetic activity of the isolated compound. MATERIALS AND METHODS: The sesquiterpene isolated from hexane fraction of bark of T. populnea modified synthetically then identified by using analytical techniques such as electron paramagnetic resonance spectra for confirmation and the anti-diabetic activity was evaluated by anti-hyperglycemic, hypoglycemic potential. RESULT: In the present work, we have studied the anti hyperglycemic and hypoglycemic activity of the vanadium complex in glucose loaded and normal animals were shown significantly decreased in plasma blood glucose level. The results derived from preclinical studies confirm the potential of new sesquiterpene. CONCLUSION: The findings could provide evidence regarding the anti diabetic potential of T. populnea by lowering blood glucose level. SUMMARY: Thespesia populnea is widely used in the ayurvedic system of medicine for treatment of diabetes in India. Present study aimed to explore the anti diabetic potential of isolated compound. Isolation of sesquiterpene from hexane fraction of bark of Thespesia populnea and modified synthetically then authenticated by using analytical techniques such as electron paramagnetic resonance spectra for confirmation. The modified complex was further assessed for its anti diabetic property in glucose loaded rats. Vanadium complex demonstrated significant reduction in plasma blood glucose level in glucose loaded animals. The results derived from preclinical studies confirm the potential of new sesquiterpene. The present findings conclude that anti diabetic potential of Thespesia populnea could be due to lowering blood glucose level by acting on PPAR-gamma receptor. PMID- 26929577 TI - Toxicological Evaluation of Emblica officinalis Fruit Extract and its Anti inflammatory and Free Radical Scavenging Properties. AB - BACKGROUND: Emblica officinalis (Euphorbiaceae), popularly known as Indian gooseberry or "Amla" in India, is used in Ayurveda as "rejuvenating herb" since ancient times. OBJECTIVE: This study was carried out to estimate toxicity, anti inflammatory, and antioxidative activities of the methanolic extract of Emblica officinalis fruit (MEO) in an animal model. MATERIALS AND METHODS: Antioxidative property of MEO was assessed by in vitro assays such as phosphomolybdenum assay (total antioxidant capacity), free radical scavenging assays 1,1-diphenyl-2 picrylhydrazyl and 2,2'-azino-bis and 3-ethylbenzthiazoline-6-sulphonic acid (DPPH and ABTS method) and lipid peroxidation assay (LPO). The anti-inflammatory property was evaluated by carrageenan-induced acute inflammation in rats by measuring rat paw volume at different time intervals and toxicological analysis using mice. RESULTS AND DISCUSSION: High performance liquid chromatography studies revealed the presence of gallic acid (2.10%), mucic acid (4.90%), ellagic acid (2.10%), quercetin (28.00%), rutin (3.89%), and beta-glucogallin (1.46%). MEO showed highest antioxidant activities by using DPPH (17.33-89.00%), ABTS (23.03-94.16%), nitric oxide scavenging activity (12.94-70.16%), LPO (56.54%), and phosphomolybdenum assay (142 +/- 6.09 MUg/ml). The LD50 was found to be approximately 1125 mg/kg (p.o). High dose of MEO showed significant reduction (72.71%) in the inflammation after 4 h of treatment, which was comparable to diclofenac (10 mg/kg) (61.57%) treated group. Significant reduction (P < 0.05) in the inflammatory cytokine (interleukin-1beta and tumor necrosis factor-alpha) markers were also observed (57.25% and 35.41%, respectively) in serum of MEO treated animals as compared to control. CONCLUSION: Taken together, phenolic compounds of MEO may serve as a potential herbal drug for amelioration of acute inflammation due to their modulatory action on free radicals. SUMMARY: The methanolic extract of Emblica officinalis fruit (MEO) has potent antioxidant activity as assessed by DPPH, ABTS and LPO assaysMEO has potent anti-inflammatory activity in carrageenan induced paw edema modelThe phenolic compounds of MEO might be a potential herbal drug for amelioration of acute inflammation. Abbreviations used: ROS, reactive oxygen species; RNS, reactive nitrogen species, LPO, lipid peroxidation, NO, nitric oxide, IL, interleukin; TNF alpha tumor necrosis factor alpha; NSAIDs, nonsteroidal anti inflammatory drugs; AA, ascorbic acid; MEO, methanolic extract of Emblica officinalis fruit; ABTS+; 2,2' azino bis 3 ethylbenzthiazoline 6 sulphonic acid; DPPH, 1,1 diphenyl 2 picrylhydrazyl; HPLC, high performance liquid chromatography; MDA, malondialdehyde; DMSO, dimethyl sulphoxide; ELISA, enzyme linked immunosorbent assay. PMID- 26929579 TI - Morphological and Chemoprofile (Liquid Chromatography-mass Spectroscopy and Gas Chromatography-mass Spectroscopy) Comparisons of Cyperus scariosus R. Br and Cyperus rotundus L. AB - BACKGROUND: Cyperus scariosus (CS) R.Br and Cyperus rotundus (CR) L. belongs to Cyperaceae family which is well-reputed in the traditional systems of medicine. Although they grow in different agro-climatic conditions, they are often considered to be synonymous with each other. OBJECTIVE: The present study was aimed to systematically classify both the species CS and CR through their morphological features and chemical profiling using liquid chromatography-mass spectroscopy (LC-MS), gas chromatography-mass spectroscopy (GC-MS) and thin layer chromatography patterns of the rhizome extracts. MATERIALS AND METHODS: A method (LC-MS analysis) has been developed on Agilent LC-MSD Trap SL mass spectrometer equipped with Waters HR C18 column (3.9 mm * 300 mm, 6 MUm) using isocratic elution with acetonitrile and water (70:30% v/v ratio). GC-MS analysis was performed on a Shimadzu GC-MS-QP 2010 equipped with DB-5 capillary column (30 m * 0.25 mm * 0.25 MUm). RESULTS: Chemoprofiling of CS and CR using LC-MS and GC-MS suggested that these two are different based on their deferential spectral pattern, however, some of the common peaks were found in both the species. In addition, we also performed the preliminary phytochemical investigation of hexane and chloroform extracts of these species, which led to the isolation of stigmasterol, beta-sitosterol and lupeol as major constituents in CS. CONCLUSION: In summary, we have developed optimal chromatographic conditions (LC-MS and GC MS) and morphological profiles to classify both the species, that is, CS and CR. Collectively, our analytical results coupled with the morphological data clearly suggested that CS and CR are morphologically different. SUMMARY: The huge demand for herbal medicine has put pressure on the supply of natural resources which ultimately results in use of substandard materials or substitution and adulteration. The medicinal plants, Cyperus rotundus L and Cyperus scariosus R.Br which belongs to cyperaceae family and extensively used in the traditional systems of medicine. Although these two species are grown in different soil conditions, Cyperus scariosus R.Br often treated as synonymous of Cyperus rotundus. Thus, the present study was undertaken to classify these two species systematically using the modern analytical techniques as a powerful tools. Further, we also carried out the preliminary phytochemical investigation of hexane and chloroform extracts of cyperus scariosus rhizomes, which resulted in the isolation of three compounds namely Sitosterol, Stigmasterol and Lupeol. PMID- 26929580 TI - Culture Conditions for Production of Biomass, Adenosine, and Cordycepin from Cordyceps sinensis CS1197: Optimization by Desirability Function Method. AB - BACKGROUND: Cordyceps sinensis (CS) is a traditional Chinese medicine contains potent active metabolites such as nucleosides and polysaccharides. The submerged cultivation technique is studied for the large scale production of CS for biomass and metabolites production. OBJECTIVE: To optimize culture conditions for large scale production of CS1197 biomass and metabolites production. MATERIALS AND METHODS: The CS1197 strain of CS was isolated from dead larvae of natural CS and the authenticity was assured by the presence of two major markers adenosine and cordycepin by high performance liquid chromatography and mass spectrometry. A three-level Box-Behnken design was employed to optimize process parameters culturing temperature, pH, and inoculum volume for the biomass yield, adenosine and cordycepin. The experimental results were regressed to a second-order polynomial equation by a multiple regression analysis for the prediction of biomass yield, adenosine and cordycepin production. Multiple responses were optimized based on desirability function method. RESULTS: The desirability function suggested the process conditions temperature 28 degrees C, pH 7 and inoculum volume 10% for optimal production of nutraceuticals in the biomass. The water extracts from dried CS1197 mycelia showed good inhibition for 2 diphenyl-1 picrylhydrazyl and 2,2-azinobis-(3-ethyl-benzo-thiazoline-6-sulfonic acid-free radicals. CONCLUSION: The result suggests that response surface methodology desirability function coupled approach can successfully optimize the culture conditions for CS1197. SUMMARY: Authentication of CS1197 strain by the presence of adenosine and cordycepin and culturing period was determined to be for 14 daysContent of nucleosides in natural CS was found higher than in cultured CS1197 myceliumBox-Behnken design to optimize critical cultural conditions: temperature, pH and inoculum volumeWater extract showed better antioxidant activity proving credible source of natural antioxidants. PMID- 26929581 TI - Synergistic Caseinolytic Activity and Differential Fibrinogenolytic Action of Multiple Proteases of Maclura spinosa (Roxb. ex Willd.) latex. AB - BACKGROUND: Kollamalayaali tribes of South India use latex of Maclura spinosa for milk curdling. This action is implicated to proteases which exhibit strong pharmacological potential in retardation of blood flow and acceleration of wound healing. OBJECTIVE: To validate the presence of a proteolytic enzyme(s) in Maclura spinosa latex (MSL), and to investigate their probable role in hemostasis. MATERIALS AND METHODS: Processed latex was examined for proteolytic and hemostatic activity using casein and human fibrinogen as substrates, respectively. Caseinoltyic activity was compared with two standard proteases viz., trypsin I and trypsin II. Effect of various standard protease inhibitors viz., iodoacetic acid (IAA), phenylmethylsulfonyl fluoride (PMSF), ethylene glycol tetraacetic acid, and ethylenediaminetetraacetic acid on both caseinolytic and fibrinogenolytic activities were examined. Electrophoretogram of fibrinogenolytic assays were subjected to densitometric analysis. RESULTS: Proteolytic action of MSL was found to be highly efficient over trypsin I and trypsin II in dose-dependent caseinolytic activity (P < 0.05; specific activity of 1,080 units/mg protein). The Aalpha and Bbeta bands of human fibrinogen were readily cleaved by MSL (for 1 MUg crude protein and 30 min of incubation time). Furthermore, MSL cleaved gamma subunit in dose- and time-dependent manner. Quantitative correlation of these results was obtained by densitometric analysis. The caseinolytic activity of MSL was inhibited by IAA, PMSF. While, only PMSF inhibited fibrinogenolytic activity. CONCLUSIONS: MSL contains proteolytic enzymes belonging to two distinct superfamilies viz., serine protease and cysteine proteases. The fibrinogenolytic activity of MSL is restricted to serine proteases only. The study extrapolates the use of M. spinosa latex from milk curdling to hemostasis. SUMMARY: Proteolytic enzymes present in latex of Maclura spinosa can be assigned to two different protease superfamilies viz., serine protease and cysteine protease as revealed by the inhibitory studies of caseinolytic activity. Among them, only serine protease can be considered as hemostatically significant as inhibition of fibrinogenolytic action of Maclura spinosa latex protease is shown only by PMSF, a serine protease-specific inhibitor. Abbreviations used: MSL: Maclura spinos Latex, IAA: Iodo Acetic Acid, EDTA: Ethylene Diamine Tetra Acetic Acid, EGTA: Ethylene glycol tetra acetic acid, PMSF: Phenyl methyl sulphonyl fluoride. PMID- 26929582 TI - Dosakaya Juice Assuages Development of Sucrose Induced Impaired Glucose Tolerance and Imbalance in Antioxidant Defense. AB - OBJECTIVE: The objective was to explore the effect of Dosakaya (DK) (Cucumis melo var. chito) juice on sucrose induced dysglycemia and disturbances in antioxidant defense in rats. MATERIALS AND METHODS: Rats were preconditioned with DK juice before administration of sucrose beverage continuously for 1-month. Blood glucose tolerance test and glutathione (GSH) homeostasis pathways in kidney were analyzed in different group of animals at the end of the study. RESULTS: DK juice diffused (P < 0.001) hypertriglyceridemia inducing effect of sucrose and arrested sucrose induced weight gain. It improved glucose tolerance ability by significantly reducing (P < 0.05) first-hour glycemic excursion and decreasing 2 h glycemic load (P < 0.05) following oral glucose tolerance test in sucrose fed animals. Furthermore, disturbances in antioxidant defense mechanisms in terms of GSH homeostasis in kidney were restored due to juice feeding. DK juice administration checked reduction in GSH-S-transferase and glyoxalase-I activity, thus, significantly mitigated lipid peroxidation (P < 0.05), and formation of advanced glycation end-products (P < 0.001) in kidney and serum (P < 0.01). Quantitative analysis of juice found it a rich source of protein and polyphenols. Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) analysis revealed the presence of multiple protein bands in whole fruit juice. Therefore, SDS-PAGE protein fingerprint of DK juice may serve as a quality control tool for standardization of juice. CONCLUSION: The whole fruit juice of DK may become cost effective, affordable health beverage in extenuating ill-health effects of sugar consumption. This is the first report identifying DK juice in preventing development dysglycemia, dyslipidemia, and oxidative stress induced due to chronic sucrose feeding in rats. SUMMARY: Chronic sucrose consumption induced development of dysglycemia and also impaired antioxidant defense mechanism in rats. The oral administration of Dosakaya juice prior to sucrose feeding however, mitigated the development of dysglycemia and impairment in antioxidant defense in rats. PMID- 26929583 TI - Bio Prospecting of Marine-derived Streptomyces spectabilis VITJS10 and Exploring its Cytotoxicity Against Human Liver Cancer Cell Lines. AB - BACKGROUND: Recently, numerous pathogens have developed resistance due to the indiscriminate use of commercial therapeutic drugs. OBJECTIVE: The main aim of the study was to evaluate the bioactive potential of the Streptomyces spectabilis VITJS10 crude extract. MATERIALS AND METHODS: The S. spectabilis VITJS10 ethyl acetate extract was tested for antibacterial, antioxidant, and cytotoxic properties. Genotypic characterization was done using 16S r-DNA partial gene amplification and sequencing. The authenticity of the crude chemical constitutes were determined by gas chromatography-mass spectrometry (GC-MS). RESULTS: The antibacterial potential revealed the effective activity against Shigellaflexneri (MTCC No: 1457) (22 mm), Salmonella typhi (MTCC No: 1167) (23 mm), Escherichia coli (MTCC No: 1588) (22 mm), Pseudomonas aeruginosa (MTCC No: 4676) (22 mm) at 20 mg/mL concentration. Scavenging ability of the extract was determined using 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay revealing its 95% inhibition at 5 mg/mL concentration. Hepatocellular cancer cells (HepG2) cell line was used to evaluate the cytotoxicity by 3-(4, 5-dimethyl thiazol-2yl)-2, 5-diphenyl tetrazolium bromide assay. The extract showed maximum inhibition at IC50 of 250 MUg/mL with 53.6% cell viability. The highest 16S rRNA gene sequence homogeneity was observed 99% similar with the novel strain S. spectabilis S3-1. The chemical components of the crude extract of VITJS10 were detected with 37 chemical constituents. However three major compounds were identified, namely Sulfurous acid, 2-ethylhexyl tridecyl ester, Phenol, 2,4-bis (1,1-dimethylethyl), and Trans 2-methyl-4-n-pentylthiane, S, S-Dioxide. CONCLUSION: Hence the present study justifies the overwhelming circumstantial evidence as the most bioactive metabolites from the marine origin, which has potential utilization in pharmaceutical industry. SUMMARY: The aim of this study was to explore the bioactive potential of marine Streptomyces sp. isolated from marine soil and understand the bioactive properties of the crude extracts. It is clearly evident from the study that the bioactive metabolites produced by Streptomyces sp. exhibited good antibacterial, antioxidant and anticancer activity. Our results indicated that Starch casein medium was the good base for bioactive metabolite production. The taxonomic position of Streptomyces sp. isolated revealed unique pattern of phenotypic properties that distinguished it from representatives. The molecular characterization results provided valuable data for establishing the internal taxonomic structure of the genus. Hence high mortality rates, serious side effects, deficiencies of the available chemotherapeutics, and high costs during treatment clearly underscore the need to develop new anticancer agents, With the above significant features the strain could be recommended for its use in medicinal and agricultural sectors, an extensive knowledge on the behavior of natural compounds can be gained for the benefit of health. PMID- 26929584 TI - Identity-based High-performance thin Layer Chromatography Fingerprinting Profile and Tumor Inhibitory Potential of Anisochilus carnosus (L.f.) wall Against Ehrlich Ascites Carcinoma. AB - CONTEXT: Anisochilus carnosus (L.f.) wall belonging to the family Lamiaceae is a plant that is widely used in folk medicine for treating eczema, cold, cough, and fever. OBJECTIVE: In the present study, we explored the anticancer potential of A. carnosus leaves against Ehrlich ascites carcinoma (EAC) and estimated the quantity of luteolin present in various extracts and fractions of A. carnosus by high-performance thin layer chromatography (HPTLC) fingerprinting. MATERIALS AND METHODS: Various factors such as tumor volume, tumor cell viability, tumor weight, prolongation of lifespan, and hematological parameters were assessed. RESULT: We observed a significant lowering in tumor volume, tumor weight, and cell viability in EAC-induced mice following intervention with A. carnosus extracts. Also, there was a considerable prolongation of host lifespan and restoration of hematological parameters to almost normal levels with A. carnosus treatment. HPTLC fingerprinting of various extracts and fractions of A. carnosus along with luteolin as the reference standard revealed the occurrence of luteolin in all tested extracts and fractions of A. carnosus with the highest concentration being reported in the ethanol fraction. CONCLUSION: A. carnosus exhibits potent anti-tumor potential which can most likely be attributed to the occurrence of different phytochemicals such as phytosterols, terpenoids, and flavonoids in the plant. Further studies to isolate compounds from A. carnosus and understand the mechanism of anti-tumor activity would be worthwhile. SUMMARY: EAC induced mice that received A. carnosus treatment exhibited significant reduction in tumor volume, tumor weight and tumor cell viability. Their life span was considerably prolonged. We detected luteolin in A. carnosus aqueous and ethanol extract using HPTLC. Hence, anticancer activity of A. carnosus can be partly attributed to the presence of luteolin. PMID- 26929585 TI - Selective Cytotoxicity and Pro-apoptotic Activity of Stem Bark of Wrightia tinctoria (Roxb.) R. Br. in Cancerous Cells. AB - BACKGROUND: Wrightia tinctoria (Roxb.) R. Br. is a widely available shrub in India used traditionally in various ailments, including cancer. However, the anticancer activity of the bioactive fractions has not been validated scientifically. OBJECTIVE: To investigate the anticancer potential of stem bark of W. tinctoria and establish its phytochemical basis. MATERIALS AND METHODS: The ethanol extract and subsequent fractions, petroleum ether, ethyl acetate, n butanol, and aqueous were prepared by standard methods. In vitro cytotoxicity was determined in MCF-7 (breast) and HeLa (cervical) adenocarcinoma cells, and V79 (nontumor fibroblast) cells and apoptogenic activity in MCF-7 cells by acridine orange (AO)/ethidium bromide (EB) staining. Additionally, the antioxidant potential was evaluated using suitable methods. High-performance thin layer chromatography (HPTLC) analysis was performed for identification of active phytoconstituents. RESULTS: Petroleum ether and ethyl acetate fractions were most potent with IC50 values of 37.78 and 29.69 MUg/ml in HeLa and 31.56 and 32.63 MUg/ml in MCF-7 cells respectively in the sulforhodamine B assay. Comparable results were obtained in HeLa cells in 3-(4,5-dimethylthiazolyl-2-yl)-2,5 diphenyl tetrazolium bromide assay and interestingly, the fractions were found to be safe to noncancerous fibroblast cells. Both fractions induced significant (P < 0.05) apoptotic morphological changes observed by AO/EB staining. Moreover, extract/fractions exhibited excellent inhibition of lipid peroxidation with the ethyl acetate fraction being most active (IC50:23.40 MUg/ml). HPTLC confirmed the presence of two anti-cancer triterpenoids, lupeol, and beta-sitosterol in active fractions. CONCLUSION: Extract/fractions of W. tinctoria exhibit selective cytotoxicity against cancerous cells that is mediated by apoptosis. Fractions are less toxic to noncancerous cells; hence, they can be developed as safer chemopreventive agents. SUMMARY: Petroleum ether and ethyl acetate fractions were most active and exhibited dose-dependent cytotoxicity in HeLa and MCF-7 cells.Fractions were relatively less toxic to non-tumor fibroblast cells demonstrating its selectivity to cancer cells.Fractions exhibited pro-apoptotic activity in MCF-7 cells in AO/EB staining.Lupeol and beta-sitosterol were identified as anticancer constituents by HPTLC. PMID- 26929586 TI - Reversed-phase high-performance Liquid Chromatography-ultraviolet Photodiode Array Detector Validated Simultaneous Quantification of six Bioactive Phenolic Acids in Roscoea purpurea Tubers and their In vitro Cytotoxic Potential against Various Cell Lines. AB - BACKGROUND: Roscoea purpurea or Roscoea procera Wall. (Zingiberaceae) is traditionally used for nutrition and in the treatment of various ailments. OBJECTIVE: Simultaneous reversed-phase high-performance liquid chromatography ultraviolet (RP-HPLC) photodiode array detector identification of phenolic acids (PA's) was carried out in whole extract of tuber and their cytotoxic potential was estimated along with radical scavenging action. Bioactivity guided fractionation was also done to check the response potential against the same assay. MATERIALS AND METHODS: Identification and method validation was performed on RP-HPLC column and in vitro assays were used for bioactivity. RESULTS: Protocatechuic acid, syringic acid, ferulic acid, rutin, apigenin, and kaempferol were quantified as 0.774%, 0.064%, 0.265%, 1.125%, 0.128%, and 0.528%, respectively. Validated method for simultaneous determination of PA's was found to be accurate, reproducible, and linearity was observed between peak area response and concentration. Recovery of identified PA's was within the acceptable limit of 97.40-104.05%. Significant pharmacological response was observed in whole extract against in vitro cytotoxic assay, that is, Sulforhodamine B assay, however, fractionation results in decreased action potential. Similar pattern of results were observed in the antioxidant assay, as total phenolic content and total flavonoid content were highest in whole extract and decreases with fractionation. Radical scavenging activity was prominent in chloroform fraction, exhibiting IC50 at 0.25 mg/mL. CONCLUSION: Study, thus, reveals that R. purpurea exhibit significant efficacy in cytotoxic activity with the potentiality of scavenging free radicals due the presence of PA's as reported through RP-HPLC. SUMMARY: Proto-catechuic acid, syringic acid, ferulic acid, rutin, apigenin and kaempferol were quantified as 0.774, 0.064, 0.265, 1.125, 0.128 and 0.528 %Preliminary cytotoxic activity revealed that whole extract of R. purpurea exhibit promising effect and after fractionation the potentiation of action reducesThe radical scavenging potential of whole extract and fractions are well reflected by TPC, TFC and DPPH assay. PMID- 26929587 TI - Modulatory Role of Shorea robusta Bark on Glucose-metabolizing Enzymes in Diethylnitrosamine Induced Hepatocellular Carcinoma in Rats. AB - INTRODUCTION: The modulations of glucose-metabolizing enzyme activities play a vital rolein the depletion of energy metabolism and leads to inhibition of cancer growth. OBJECTIVE: To find the effect of shorearobusta bark extract on glucose metbolizing enzymes in diethylnitrosamine (DEN) induced hepatocellular carcinoma rats. MATERIALS AND METHODS: Biochemical evaluation of glucose metabolizing enzyme were done in before and after shorearobusta bark extract (500mg/kg) treatment in DEN induced rats. RESULTS: A significant increasein the activities of the key glycolytic enzymes viz., hexokinase and phosphoglucoisomerase, with a significant decrease in the gluconeogenic enzymes glucose-6-phosphatase and fructose-1,6-bisphosphatasewere observed in HCC bearing rats, when compared with the control. Administration of shorearobusta extract caused a significant decrease in theactivities of glycolytic enzymes and an increase in the gluconeogenic enzymes activities to near normal values. CONCLUSION: The current findings suggest that the S. robusta extract has a definite modulating role on the key enzymes ofglucose-metabolism in HCC. The modulatory effect may be due to the phytoactive constituents present in the extract of S. robusta. SUMMARY: Administration of shorea robusta bark extract caused a significant decrease in the activities of glycolytic enzymes and an increase in the gluconeogenic enzymes activities to near normal values. The S. robusta extract has modulatory activity on the carbohydrate metabolism in DEN-induced HCC bearing rats through a mechanism that which does not provoke any acute biochemical disturbances in the metabolic pathways of glycolysis and gluconeogenesis. The modulatory effect of S. robusta extract may be attributed to the presence of active compounds such as polyphenols and flavonoids. Abbreviations used: HCC: Hepatocellular Carcinoma, SRBE: Shorearobusta bark extract; HEX: Hexokinase; PGI: Phosphoglucoisomerase; DEN: Diethylnitrosamine. PMID- 26929588 TI - Nitro-Group Functionalization of Dopamine and its Contribution to the Viscoelastic Properties of Catechol-Containing Nanocomposite Hydrogels. AB - Linear polyacrylamide (PAAm) is modified with dopamine or nitrodopamine (PAAm-D and PAAm-ND, respectively) to evaluate the effect of nitro-group modification on the interfacial binding properties of polymer-bound catechol. Nanocomposite hydrogels are prepared by mixing PAAm-based polymers with Laponite and the viscoelastic properties of these materials are determined using oscillatory rheometry. The incorporation of a small amount of catechol (~0.1 wt% in swollen hydrogel) drastically increases the shear moduli by 1-2 orders of magnitude over those of the catechol-free control. Additionally, PAAm-ND exhibits higher shear moduli values than PAAm-D across the whole pH range tested (pH 3.0-9.0). Based on the calculated effective crosslinking density, effective functionality, and molecular weight between crosslinks, nitro-group functionalization of dopamine results in a polymer network with increased crosslinking density and crosslinking points with higher functionality. Nitro-functionalization enhances the interfacial binding property of dopamine and increases its resistant to oxidation, which results in nanocomposite hydrogels with enhanced stiffness and a viscous dissipation property. PMID- 26929589 TI - Zwitterionic Ligands Bound to CdSe/ZnS Quantum Dots Prevent Adhesion to Mammalian Cells. AB - Zwitterionic materials are useful tools in material science and biology as they provide high water solubility while preventing non-specific interactions. Quantum dots (QDs) functionalized with zwitterionic and quaternary ammonium ligands were synthesized to investigate their interactions with the outer membrane of HeLa cells. Quaternary ammonium functionalized quantum dots adhered strongly to the cell surface while zwitterionic QDs had no cell adhesion. These results demonstrate that future non-interacting nanoparticles based on this design are possible. PMID- 26929590 TI - Cohabitation and Child Wellbeing. AB - In recent decades, writes Wendy Manning, cohabitation has become a central part of the family landscape in the United States-so much so that by age 12, 40 percent of American children will have spent at least part of their lives in a cohabiting household. Although many children are born to cohabiting parents, and cohabiting families come in other forms as well, the most common cohabiting arrangement is a biological mother and a male partner. Cohabitation, Manning notes, is associated with several factors that have the potential to reduce children's wellbeing. Cohabiting families are more likely than married families to be poor, and poverty harms children in many ways. Cohabiting parents also tend to have less formal education-a key indicator of both economic and social resources-than married parents do. And cohabiting parent families don't have the same legal protections that married parent families have. Most importantly, cohabitation is often a marker of family instability, and family instability is strongly associated with poorer outcomes for children. Children born to cohabiting parents see their parents break up more often than do children born to married parents. In this way, being born into a cohabiting family sets the stage for later instability, and children who are born to cohabiting parents appear to experience enduring deficits of psychosocial wellbeing. On the other hand, stable cohabiting families with two biological parents seem to offer many of the same health, cognitive, and behavioral benefits that stable married biological parent families provide. Turning to stepfamilies, cohabitation's effects are tied to a child's age. Among young children, living in a cohabiting stepfamily rather than a married stepfamily is associated with more negative indicators of child wellbeing, but this is not so among adolescents. Thus the link between parental cohabitation and child wellbeing depends on both the type of cohabiting parent family and the age of the child. PMID- 26929591 TI - Professor John B. Chang, MD, FACS, FICA (1935-2015). PMID- 26929594 TI - Partial posterior vitreous detachment as a classification criterion of epiretinal membrane. PMID- 26929592 TI - Teleophthalmology: improving patient outcomes? AB - Teleophthalmology is gaining importance as an effective eye care delivery modality worldwide. In many developing countries, teleophthalmology is being utilized to provide quality eye care to the underserved urban population and the unserved remote rural population. Over the years, technological innovations have led to improvement in evidence and teleophthalmology has evolved from a research tool to a clinical tool. The majority of the current teleophthalmology services concentrate on patient screening and appropriate referral to experts. Specialty care using teleophthalmology services for the pediatric group includes screening as well as providing timely care for retinopathy of prematurity (ROP). Among geriatric eye diseases, specialty teleophthalmology care is focused toward screening and referral for diabetic retinopathy (DR), glaucoma, age-related macular degeneration (ARMD), and other sight-threatening conditions. Comprehensive vision screening and refractive error services are generally covered as part of most of the teleophthalmology methods. Over the past decades, outcome assessment of health care system includes patients' assessments on their health, care, and services they receive. Outcomes, by and large, remain the ultimate validators of the effectiveness and quality of medical care. Teleophthalmology produces the same desired clinical outcome as the traditional system. Remote portals allow specialists to provide care over a larger region, thereby improving health outcomes and increasing accessibility of specialty care to a larger population. A high satisfaction level and acceptance is reported in the majority of the studies because of increased accessibility and reduced traveling cost and time. Considering the improved quality of patient care and patient satisfaction reported for these telemedicine services, this review explores how teleophthalmology helps to improve patient outcomes. PMID- 26929593 TI - Update on the evaluation of transient vision loss. AB - Transient vision loss may indicate underlying vascular disease, including carotid occlusion and thromboembolism, or it may have a more benign etiology, such as migraine or vasospasm. This review focuses on the differential diagnosis and workup of patients presenting with transient vision loss, focusing on several key areas: the relationship to thromboembolic vascular disease, hypercoagulable testing, retinal migraine, and bilateral vision loss. The objective is to provide the ophthalmologist with information on how to best manage these patients. Thromboembolic etiologies for transient vision loss are sometimes managed with medications, but when carotid surgery is indicated, earlier intervention may prevent future stroke. This need for early treatment places the ophthalmologist in the important role of expediting the management process. Hospital admission is recommended in patients presenting with transient symptoms within 72 hours who meet certain high-risk criteria. When the cause is giant cell arteritis, ocular ischemic syndrome, or a cardioembolic source, early management of the underlying condition is equally important. For nonthromboembolic causes of transient vision loss such as retinal migraine or retinal vasospasm, the ophthalmologist can provide reassurance as well as potentially give medications to decrease the frequency of vision loss episodes. PMID- 26929595 TI - Silent information regulator T1 in aqueous humor of patients with cataract. AB - PURPOSE: Silent information regulator T1 (SIRT1), a member of the sirtuin family, has a preventive role in various ocular diseases. We evaluated the relations between the aqueous humor level of SIRT1 and age, sex, systemic diseases, the severity of lens opacity, and other factors. SETTING: This study was conducted at a university teaching hospital in Tokyo, Japan. DESIGN: This study was designed based on the consecutive case series. METHODS: Aqueous humor samples were obtained from 29 eyes of the 21 consecutive patients undergoing surgery for age related cataract (ARC). SIRT1 levels were determined by enzyme-linked immunosorbent assay. RESULTS: Aqueous humor levels of SIRT1 showed a positive correlation with visual acuity (logarithm of the minimum angle of resolution) and with the severity of nuclear cataract (r=0.32 and 0.30, respectively, P<0.05). However, only visual acuity was correlated with SIRT1 according to the stepwise multiple regression analysis (P<0.05). CONCLUSION: These findings suggest that SIRT1 may have an effect on the formation of ARC, acting as a defensive factor against ARC. PMID- 26929596 TI - Safety and comfort evaluation of a new formulation of Visine((r)) lubricant eye drops containing HydroBlendTM and GentlePurTM. AB - PURPOSE: To evaluate the clinical safety and comfort of a new benzalkonium chloride-free Visine((r)) lubricant eye drop formulation (HydroblendTM and GentlePurTM) in healthy and dry eye subjects. METHODS: This was a single-site, open-label clinical study comprised of 22 healthy and 22 dry eye subjects. Subjects were instructed to instill 1-2 drops of the test product four times a day for 2 weeks and were examined at visit 1 (day 0), visit 2 (day 7), and visit 3 (day 14). Assessments at each visit included postdosing product usage comfort scores, predosing fluorescein corneal staining score, predosing visual acuity, and pre- and postdosing ocular structure change using slit-lamp biomicroscopy. Adverse events were monitored throughout the course of the study. RESULTS: Throughout the 14 days of the trial period, subjects from both healthy and dry eye groups rated the eye drops as "very comfortable". For dry eye group, the mean product usage comfort scores for the first 3 minutes postdosing ranged from 8.5 to 8.8 at visit 1 and 9.2 to 9.6 at visit 3 on a 0-10 point scale, with 0 being very uncomfortable and 10 being very comfortable. The mean corneal staining scores over five corneal regions changed from 0.65 at visit 1 to 0.39 at visit 3 for dry eye group. The individual region corneal staining scores were also decreased from visits 1 to 3 for dry eye group. All subjects maintained pretreatment means visual acuity at visits 2 and 3. Biomicroscopic examination indicated no structural changes at all visits. There were no significant adverse events reported during the course of the study. CONCLUSION: The study confirms that GentlePurTM is an appropriate choice as a preservative for ocular application. The new formulation was safe and comfortable when used four times a day in healthy and dry eye subjects. PMID- 26929597 TI - Protective effect of fucoidan from Fucus vesiculosus on liver fibrosis via the TGF-beta1/Smad pathway-mediated inhibition of extracellular matrix and autophagy. AB - Liver fibrosis is a dynamic reversible pathological process in the development of chronic liver disease to cirrhosis. However, the current treatments are not administered for a long term due to their various side effects. Autophagy is initiated to decompose damaged or excess organelles, which had been found to alter the progression of liver fibrosis. In this article, we hypothesized that fucoidan from Fucus vesiculosus may attenuate liver fibrosis in mice by inhibition of the extracellular matrix and autophagy in carbon tetrachloride- and bile duct ligation-induced animal models of liver fibrosis. The results were determined using enzyme-linked immunosorbent assay, quantitative real-time polymerase chain reaction, Western blotting, and immunohistochemical staining. Fucoidan from F. vesiculosus could inhibit the activation of hepatic stellate cells and the formation of extracellular matrix and autophagosomes, and its effect may be associated with the downregulation of transforming growth factor beta 1/Smads pathways. Fucoidan, as an autophagy and transforming growth factor beta 1 inhibitor, could be a promising potential therapeutic agent for liver fibrosis. PMID- 26929600 TI - Erratum: Treatment of osteoporosis with eldecalcitol, a new vitamin D analog: a comprehensive review and meta-analysis of randomized clinical trials [Corrigendum]. PMID- 26929599 TI - Drug-loaded erythrocytes: on the road toward marketing approval. AB - Erythrocyte drug encapsulation is one of the most promising therapeutic alternative approaches for the administration of toxic or rapidly cleared drugs. Drug-loaded erythrocytes can operate through one of the three main mechanisms of action: extension of circulation half-life (bioreactor), slow drug release, or specific organ targeting. Although the clinical development of erythrocyte carriers is confronted with regulatory and development process challenges, industrial development is expanding. The manufacture of this type of product can be either centralized or bedside based, and different procedures are employed for the encapsulation of therapeutic agents. The major challenges for successful industrialization include production scalability, process validation, and quality control of the released therapeutic agents. Advantages and drawbacks of the different manufacturing processes as well as success key points of clinical development are discussed. Several entrapment technologies based on osmotic methods have been industrialized. Companies have already achieved many of the critical clinical stages, thus providing the opportunity in the future to cover a wide range of diseases for which effective therapies are not currently available. PMID- 26929598 TI - Epigallocatechin-3-gallate attenuates apoptosis and autophagy in concanavalin A induced hepatitis by inhibiting BNIP3. AB - BACKGROUND: Epigallocatechin-3-gallate (EGCG) is the most effective compound in green tea, and possesses a wide range of beneficial effects, including anti inflammatory, antioxidant, antiobesity, and anticancer effects. In this study, we investigated the protective effects of EGCG in concanavalin A (ConA)-induced hepatitis in mice and explored the possible mechanisms involved in these effects. METHODS: Balb/C mice were injected with ConA (25 mg/kg) to induce acute autoimmune hepatitis, and EGCG (10 or 30 mg/kg) was administered orally twice daily for 10 days before ConA injection. Serum liver enzymes, proinflammatory cytokines, and other marker proteins were determined 2, 8, and 24 hours after the ConA administration. RESULTS: BNIP3 mediated cell apoptosis and autophagy in ConA induced hepatitis. EGCG decreased the immunoreaction and pathological damage by reducing inflammatory factors, such as TNF-alpha, IL-6, IFN-gamma, and IL-1beta. EGCG also exhibited an antiapoptotic and antiautophagic effect by inhibiting BNIP3 via the IL-6/JAKs/STAT3 pathway. CONCLUSION: EGCG attenuated liver injury in ConA-induced hepatitis by downregulating IL-6/JAKs/STAT3/BNIP3-mediated apoptosis and autophagy. PMID- 26929601 TI - The clinicopathological significance and ethnic difference of FHIT hypermethylation in non-small-cell lung carcinoma: a meta-analysis and literature review. AB - Emerging evidence indicates that FHIT is a candidate tumor suppressor in many types of tumors including non-small-cell lung carcinoma (NSCLC). However, the prognostic value and correlation between FHIT hypermethylation and clinicopathological characteristics of NSCLC remains unclear. In this report, we performed a meta-analysis to evaluate the effects of FHIT hypermethylation on the incidence of NSCLC and clinicopathological characteristics of human NSCLC patients. Final analysis of 1,801 NSCLC patients from 18 eligible studies was performed. FHIT hypermethylation was found to be significantly higher in NSCLC than in normal lung tissue. The pooled odds ratio (OR) from ten studies included 819 NSCLC and 792 normal lung tissues (OR =7.51, 95% confidence interval [CI] =2.98-18.91, P<0.0001). Subgroup analysis based on ethnicity implied that FHIT hypermethylation level was higher in NSCLC tissues than in normal tissues in both Caucasians (P=0.02) and Asians (P<0.0001), indicating that the difference in Asians was much more significant. FHIT hypermethylation was also correlated with sex status, smoking status, as well as pathological types. In addition, patients with FHIT hypermethylation had a lower survival rate than those without (hazard ratio =1.73, 95% CI =1.10-2.71, P=0.02). The results of this meta-analysis suggest that FHIT hypermethylation is associated with an increased risk and poor survival in NSCLC patients. FHIT hypermethylation, which induces the inactivation of FHIT gene, plays an important role in the carcinogenesis and clinical outcome and may serve as a potential diagnostic marker and drug target of NSCLC. PMID- 26929602 TI - A network pharmacology approach to discover active compounds and action mechanisms of San-Cao Granule for treatment of liver fibrosis. AB - ETHNOPHARMACOLOGICAL RELEVANCE: San-Cao Granule (SCG) has been used in patients with liver fibrosis for many years and has shown good effect. However, its mechanism of therapeutic action is not clear because of its complex chemical system. The purpose of our study is to establish a comprehensive and systemic method that can predict the mechanism of action of SCG in antihepatic fibrosis. MATERIALS AND METHODS: In this study, a "compound-target-disease" network was constructed by combining the SCG-specific and liver fibrosis-specific target proteins with protein-protein interactions, and network pharmacology was used to screen out the underlying targets and mechanisms of SCG for treatment of liver fibrosis. Then, some key molecules of the enriched pathway were chosen to verify the effects of SCG on liver fibrosis induced by thioacetamide (TAA). RESULTS: This systematic approach had successfully revealed that 16 targets related to 11 SCG compounds were closely associated with liver fibrosis therapy. The pathway enrichment analysis of them showed that the TGF-beta1/Smad signaling pathway is relatively important. Animal experiments also proved that SCG could significantly ameliorate liver fibrosis by inhibiting the TGF-beta1/Smad pathway. CONCLUSION: SCG could alleviate liver fibrosis through the molecular mechanisms predicted by network pharmacology. Furthermore, network pharmacology could provide deep insight into the pharmacological mechanisms of Chinese herbal formulas. PMID- 26929604 TI - Effects of Xuanbai Chengqi decoction on lung compliance for patients with exogenous pulmonary acute respiratory distress syndrome. AB - OBJECTIVE: To observe the effects of Xuanbai Chengqi decoction on lung compliance for patients with exogenous pulmonary acute respiratory distress syndrome. SUBJECTS AND METHODS: A total of 53 patients with exogenous pulmonary acute respiratory distress syndrome, who were admitted to the intensive care unit of the First Affiliated Hospital of Henan University of Traditional Chinese Medicine from March 2009 to February 2013, were selected. They were randomly divided into the treatment group (25 cases) and the control group (28 cases). Both the groups were treated with conventional treatment and lung-protective ventilation strategy; apart from these, enema therapy with Xuanbai Chengqi decoction was given to the treatment group. Meanwhile, static lung compliance, dynamic lung compliance, peak airway pressure, plateau pressure, and positive end-expiratory pressure (PEEP) for patients in both the groups were observed and recorded at 24, 48, and 72 hours after the drug was used. Moreover, variations in the duration of parenteral nutrition, incidence rate of complications, and case fatality rate in patients after treatment were recorded. RESULTS: For patients in the treatment group, at 48 and 72 hours after treatment, the static lung compliance and dynamic lung compliance were significantly higher than those in the control group, while plateau pressure, peak airway pressure, and PEEP were significantly lower than those before treatment. At the same time, PEEP for patients in the treatment group at 72 hours after treatment was remarkably lower than that in the control group, showing significant difference (P<0.05). The duration of parenteral nutrition in the treatment group was significantly shorter than that in the control group (P<0.05). Both the incidence rate and the fatality rate of complications, such as abdominal distension and ventilator-associated pneumonia, for patients in the treatment group were distinctly smaller than those in the control group (P<0.05). CONCLUSION: Xuanbai Chengqi decoction not only can improve the static lung compliance and dynamic compliance of patients with exogenous pulmonary distress syndrome but also can shorten the parenteral nutrition duration, as well as reducing the complication incidence rate and fatality rate. PMID- 26929603 TI - Andrographolide suppresses thymic stromal lymphopoietin in phorbol myristate acetate/calcium ionophore A23187-activated mast cells and 2,4 dinitrofluorobenzene-induced atopic dermatitis-like mice model. AB - BACKGROUND: Atopic dermatitis (AD) is one of the most common inflammatory cutaneous diseases. Thymic stromal lymphopoietin (TSLP) has been demonstrated to be an important immunologic factor in the pathogenesis of AD. The production of TSLP can be induced by a high level of intracellular calcium concentration and activation of the receptor-interacting protein 2/caspase-1/NF-kappaB pathway. Andrographolide (ANDRO), a natural bicyclic diterpenoid lactone, has been found to exert anti-inflammatory effects in gastrointestinal inflammatory disorders through suppressing the NF-kappaB pathway. OBJECTIVE: To explore the effect of ANDRO on the production of TSLP in human mast cells and AD mice model. METHODS: We utilized enzyme-linked immunosorbent assay, real-time reverse transcription polymerase chain reaction analysis, Western blot analysis, and immunofluorescence staining assay to investigate the effects of ANDRO on AD. RESULTS: ANDRO ameliorated the increase in the intracellular calcium, protein, and messenger RNA levels of TSLP induced by phorbol myristate acetate/calcium ionophore A23187, through the blocking of the receptor-interacting protein 2/caspase-1/NF-kappaB pathway in human mast cell line 1 cells. ANDRO, via oral or local administration, also attenuated clinical symptoms in 2,4-dinitrofluorobenzene-induced AD mice model and suppressed the levels of TSLP in lesional skin. CONCLUSION: Taken together, ANDRO may be a potential therapeutic agent for AD through suppressing the expression of TSLP. PMID- 26929605 TI - Identification of factors involved in medication compliance: incorrect inhaler technique of asthma treatment leads to poor compliance. AB - OBJECTIVE: To identify the impact of delivery device of inhaled corticosteroids and long-acting beta2-agonist (ICS/LABA) on asthma medication compliance, and investigate other factors associated with compliance. MATERIALS AND METHODS: We conducted a retrospective and multicenter study based on a review of medical registries of asthmatic patients treated with ICS/LABA combinations (n=2,213) whose medical devices were either dry powder inhalers (DPIs, such as Accuhaler((r)), Turbuhaler((r)), and NEXThaler((r))) or pressurized metered-dose inhalers (pMDI). Medication compliance included persistence outcomes through 18 months and medication possession ratios. Data on potential confounders of treatment compliance such as asthma exacerbations, comorbidities, demographic characteristics, and health care resource utilization were also explored. RESULTS: The probability of asthma medication compliance in case of DPIs was lower compared to pMDIs, which suggests that inhaler devices influence inhalation therapies. There were additional confounding factors that were considered as explanatory variables of compliance. A worse measure of airflow obstruction (forced expiration volume in 1 second), comorbidities and general practitioner (GP) consultations more than once per month decreased the probability of compliance. Within comorbidities, alcoholism was positively associated with compliance. Patients of 29-39, 40-50, and 51-61 age groups or suffering from more than two exacerbations during the study period were more likely to comply with their medication regime. The effects of DPIs toward compliance varied with the different DPIs. For instance, Accuhaler((r)) had a greater negative effect on compliance compared to Turbuhaler((r)) and Nexthaler((r)) in cases of patients who suffered exacerbations. We found that GP consultations reduced the probability of medication compliance for patients treated with formoterol/budesonide combination. For retired patients, visiting the GP increased the probability of medication compliance. CONCLUSION: We concluded that inhaler devices influence patients' compliance for long-term asthma medication. The impact of Accuhaler((r)), Turbuhaler((r)), and NEXThaler((r)) on medication compliance was negative. We also identified some confounders of medication compliance such as patient's age, severity of asthma, comorbidities, and health care costs. PMID- 26929606 TI - Effectiveness of stress management in patients undergoing transrectal ultrasound guided biopsy of the prostate. AB - BACKGROUND: To assess the utilization of stress management in relieving anxiety and pain among patients who undergo transrectal ultrasound (TRUS)-guided biopsy of the prostate. METHODS: Eighty-two patients admitted to a community hospital for a TRUS biopsy of the prostate participated in this case-controlled study. They were divided into an experimental group that was provided with stress management and a control group that received only routine nursing care. Stress management included music therapy and one-on-one simulation education. Before and after the TRUS biopsy, the patients' state-anxiety inventory score, pain visual analogue scale (VAS), respiratory rate, heart rate, and blood pressure were obtained. RESULTS: There were no differences in baseline and disease characteristics between the two groups. The VAS in both groups increased after the TRUS biopsy, but the difference in pre- and postbiopsy VAS scores was significantly lower in the experimental group (P=0.03). Patients in both groups experienced mild anxiety before and after the biopsy, but those in the experimental group displayed a significantly greater decrease in postbiopsy state anxiety inventory score compared to the control group (P=0.02). CONCLUSION: Stress management can alleviate anxiety and pain in patients who received a TRUS biopsy of the prostate under local anesthesia. PMID- 26929607 TI - Priorities in the primary care of persons experiencing homelessness: convergence and divergence in the views of patients and provider/experts. AB - PURPOSE: Homeless individuals face unique challenges in health care. Several US initiatives seeking to advance patient-centered primary care for homeless persons are more likely to succeed if they incorporate the priorities of the patients they are to serve. However, there has been no prior research to elicit their priorities in primary care. This study sought to identify aspects of primary care important to persons familiar with homelessness based on personal experience or professional commitment, and to highlight where the priorities of patients and professionals dedicated to their care converge or diverge. METHODS: This qualitative exercise asked 26 homeless patients and ten provider/experts to rank 16 aspects of primary care using a card sort. Patient-level respondents (n=26) were recruited from homeless service organizations across all regions of the USA and from an established board of homeless service users. Provider/expert-level respondents (n=10) were recruited from veteran and non-veteran-focused homeless health care programs with similar geographic diversity. RESULTS: Both groups gave high priority to accessibility, evidence-based care, coordination, and cooperation. Provider/experts endorsed patient control more strongly than patients. Patients ranked information about their care more highly than provider/experts. CONCLUSION: Accessibility and the perception of care based on medical evidence represent priority concerns for homeless patients and provider/experts. Patient control, a concept endorsed by experts, is not strongly endorsed by homeless patients. Understanding how to assure fluid communication, coordination, and team member cooperation could represent more worthy targets for research and quality improvement in this domain. PMID- 26929608 TI - Motivation of health workers and associated factors in public hospitals of West Amhara, Northwest Ethiopia. AB - BACKGROUND: Health professionals' motivation reflects the interaction between health professionals and their work environment. It can potentially affect the provision of health services; however, this important attribute of the workplace climate in public hospitals is not usually given serious attention to the desired level. For this reason, the authors of this study have assessed the level of motivation of health professionals and associated factors in public hospitals of West Amhara, Northwest Ethiopia. METHODS: A facility based cross-sectional study was conducted in eight public hospitals of West Amhara from June 1 to July 30, 2013. A total of 304 health professionals were included in this study. The collected data were analyzed using SPSS software version 20. The reliability of the instrument was assessed through Cronbach's alpha. Factor scores were generated for the items found to represent the scales (eigenvalue greater than one in varimax rotation) used in the measurement of the variables. The scores were further analyzed using one-way analysis of variance, t-tests, Pearson's correlation, and hierarchical multiple linear regression analyses. The cut-off point for the regression analysis to determine significance was set at beta (95% confidence interval, P<0.05). RESULTS: Mean motivation scores (as the percentage of maximum scale scores) were 58.6% for the overall motivation score, 71.0% for the conscientiousness scale, 52.8% for the organizational commitment scale, 58.3% for the intrinsic motivation scale, and 64.0% for organizational burnout scale. Professional category, age, type of the hospital, nonfinancial motivators like performance evaluation and management, staffing and work schedule, staff development and promotion, availability of necessary resources, and ease of communication were found to be strong predictors of health worker motivation. Across the hospitals and professional categories, health workers' overall level of motivation with absolute level of compensation was not significantly associated with their overall level of motivation. CONCLUSION: The strongest drivers of all motivation dimensions were found to be nonfinancial human resource management tools, so policy makers and health workforce stake holders should focus on these tools to alleviate motivation problems. PMID- 26929609 TI - Physicians' perspectives on the treatment of osteoporosis patients with bisphosphonates. AB - BACKGROUND: Noncompliance with bisphosphonate therapy among osteoporosis patients attenuates the reduction of fracture risk. The objective of this study was to assess physicians' prescribing considerations, preferences for osteoporosis treatments, and perceptions of patients' compliance with oral bisphosphonates. METHODS: This was an online survey of US physicians identified in the HealthCore Integrated Research Database (HIRD(SM)) as prescribing oral bisphosphonates to women aged >=55 years. The survey gauged physicians' prescribing considerations and preferences for various types of osteoporosis medications. The physicians were asked to predict patient persistence and compliance, and rate various reasons for noncompliance. RESULTS: Bone mineral density, long-term medication use (eg, corticosteroids), and a history of fracture were ranked as major considerations by 94.9%, 88.6%, and 86.7% of participating physicians (N=158), respectively, when deciding whether to treat an osteoporosis patient. Most physicians expressed a preference for prescribing weekly or monthly oral bisphosphonates, for both newly diagnosed patients (54.4% and 34.2%, respectively) and long-term users of oral bisphosphonates (40.5% and 36.1%, respectively). Most physicians (23.4% always, 58.9% sometimes) incorporated a drug holiday into their prescribing patterns. Although most physicians predicted that more than half of the patients would comply with the prescribed medication for at least a year, 17.7% predicted that less than half of the patients would be compliant in the 1st year, and 29.7% predicted the same result for compliance beyond 1 year. In the opinion of the majority of physicians, the major reasons for noncompliance with oral bisphosphonates were intolerance of a medication due to a gastrointestinal condition (71.5%) and medication side effects (69.6%). CONCLUSION: US physicians consider several relevant risk factors when deciding whether to prescribe pharmacotherapy and exhibit a preference for weekly or monthly regimens. The physicians estimated a substantial minority of the patients to be noncompliant with oral bisphosphonates, for reasons including primarily gastrointestinal intolerance and medication-related side effects. PMID- 26929611 TI - A retrospective analysis of safety and efficacy of weekly nab-paclitaxel as second-line chemotherapy in elderly patients with advanced squamous non-small cell lung carcinoma. AB - PURPOSE: The aim of this retrospective study was to investigate the anticancer effect and toxicity of weekly administered nab-paclitaxel as a second-line chemotherapy in elderly patients with relapsed squamous non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: We retrospectively reviewed the treatment of 42 elderly patients with relapsed squamous NSCLC, who received nab-paclitaxel monotherapy as a second-line treatment from January 2010 to March 2014. A dose of 100 mg/m(2) nab-paclitaxel was administered weekly on days 1, 8, and 15, followed by 1 week of rest. The protocol was maintained for at least two cycles. RESULTS: The overall response rate (ORR) and the disease control rate (DCR) were 21.43% (9/42) and 47.62% (20/42), respectively. The median progression-free survival (PFS) and overall survival (OS) were 6.6 and 10.9 months, respectively. In the subgroup analysis, there was no significant difference in ORR, DCR, PFS, and OS, accounting for the first-line therapy factors (taxane agent, radiotherapy, or surgery). There was a statistically significant difference in DCR for stages III and IV (62.96% vs 20%, P=0.008), but there was no such difference in either PFS or OS. The ORR of 29 patients receiving more than three cycles of treatment was higher than that of those receiving less than three cycles of treatment (31.03% vs 0%, P=0.038), and there was a significant difference in PFS (7.6 vs 4.9 months, P=0.004) and OS (11.7 vs 8.9 months, P=0.002). No hypersensitivity reactions or treatment-related grade 4 adverse events were reported. CONCLUSION: Nab-paclitaxel monotherapy administered weekly at a dose of 100 mg/m(2) is shown to be an effective and safe regimen for elderly patients with relapsed squamous NSCLC, especially for patients with stage III disease or good performance status. PMID- 26929610 TI - Recommendations for managing cutaneous disorders associated with advancing age. AB - The increasingly aged population worldwide means more people are living with chronic diseases, reduced autonomy, and taking various medications. Health professionals should take these into consideration when managing dermatological problems in elderly patients. Accordingly, current research is investigating the dermatological problems associated with the loss of cutaneous function with age. As cell renewal slows, the physical and chemical barrier function declines, cutaneous permeability increases, and the skin becomes increasingly vulnerable to external factors. In geriatric dermatology, the consequences of cutaneous aging lead to xerosis, skin folding, moisture-associated skin damage, and impaired wound healing. These problems pose significant challenges for both the elderly and their carers. Most often, nurses manage skin care in the elderly. However, until recently, little attention has been paid to developing appropriate, evidence-based, skincare protocols. The objective of this paper is to highlight common clinical problems with aging skin and provide some appropriate advice on cosmetic protocols for managing them. A review of the literature from 2004 to 2014 using PubMed was performed by a working group of six European dermatologists with clinical and research experience in dermatology. Basic topical therapy can restore and protect skin barrier function, which relieves problems associated with xerosis, prevents aggravating moisture-associated skin damage, and enhances quality of life. In conclusion, the authors provide physicians with practical recommendations to assist them in implementing basic skin care for the elderly in an integrated care approach. PMID- 26929613 TI - Impact of GOLD groups of chronic pulmonary obstructive disease on surgical complications. AB - PURPOSE: Chronic obstructive pulmonary disease (COPD) is associated with increased postoperative complications. Recently, the Global Initiative for Chronic Obstructive Lung Disease (GOLD) classified COPD patients into four groups based on spirometry results and the severity of symptoms. The objective of this study was to evaluate the impact of GOLD groups on postoperative complications. PATIENTS AND METHODS: We reviewed the medical records of COPD patients who underwent preoperative spirometry between April and August 2013 at a tertiary hospital in Korea. We divided the patients into GOLD groups according to the results of spirometry and self-administered questionnaires that assessed the symptom severity and exacerbation history. GOLD groups, demographic characteristics, and operative conditions were analyzed. RESULTS: Among a total of 405 COPD patients, 70 (17.3%) patients experienced various postoperative complications, including infection, wound, or pulmonary complications. Thoracic surgery, upper abdominal surgery, general anesthesia, large estimated blood loss during surgery, and longer anesthesia time were significant risk factors for postoperative complications. Patients in high-risk group (GOLD groups C or D) had an increased risk of postoperative complications compared to those in low-risk group (GOLD groups A or B). CONCLUSION: COPD patients in GOLD groups representing a high exacerbation risk have an increased risk of postoperative complications compared to those with low risk. PMID- 26929612 TI - Depression, body mass index, and chronic obstructive pulmonary disease - a holistic approach. AB - BACKGROUND: Several clinical studies suggest common underlying pathogenetic mechanisms of COPD and depressive/anxiety disorders. We aim to evaluate psychopathological and physical effects of aerobic exercise, proposed in the context of pulmonary rehabilitation, in a sample of COPD patients, through the correlation of some psychopathological variables and physical/pneumological parameters. METHODS: Fifty-two consecutive subjects were enrolled. At baseline, the sample was divided into two subgroups consisting of 38 depression-positive and 14 depression-negative subjects according to the Hamilton Depression Rating Scale (HAM-D). After the rehabilitation treatment, we compared psychometric and physical examinations between the two groups. RESULTS: The differences after the rehabilitation program in all assessed parameters demonstrated a significant improvement in psychiatric and pneumological conditions. The reduction of BMI was significantly correlated with fat mass but only in the depression-positive patients. CONCLUSION: Our results suggest that pulmonary rehabilitation improves depressive and anxiety symptoms in COPD. This improvement is significantly related to the reduction of fat mass and BMI only in depressed COPD patients, in whom these parameters were related at baseline. These findings suggest that depressed COPD patients could benefit from a rehabilitation program in the context of a multidisciplinary approach. PMID- 26929614 TI - Relevance of dosage in adherence to treatment with long-acting anticholinergics in patients with COPD. AB - INTRODUCTION: The aim of this study was to assess the degree of adherence for two standard regimens for administrating anticholinergic drugs (12 and 24 hours) in patients with chronic obstruction of the airflow and to establish whether the use of a once-daily dose improves the level of treatment adherence. METHODS: We used long-acting anticholinergics (LAMAs) as a study variable, and included the entire health area of Castile-La Mancha, numbering 2,100,998 inhabitants, as the study population. We analyzed a total of 16,446 patients who had been prescribed a LAMA between January 1, 2013 and December 31, 2013. The follow-up period, based on a centralized system of electronic prescription management, was extended until December 2014. RESULTS: During 2013, the medication collected was 7.4%-10.7% higher than indicated by labeling. This was very similar for all LAMAs, irrespective of the patient's sex, the molecule, the device, and the drug dosage. We did not observe seasonal variations in the consumption of LAMAs, nor did we detect differences between prescription drugs for once-daily (every 24 hours) versus twice-daily (every 12 hours) administration, between the different molecules, or between different types of inhalers for the same molecule. The results were similar in 2014. CONCLUSION: The principal conclusion of this study is that, in an area with a centralized management system of pharmacological prescriptions, adherence to treatment with LAMAs is very high, irrespective of the molecules or inhalation device. We did not find that patients who used twice daily medication had a lower adherence. PMID- 26929615 TI - Responsiveness of blood and sputum inflammatory cells in Japanese COPD patients, non-COPD smoking controls, and non-COPD nonsmoking controls. AB - PURPOSE: To compare pulmonary and systemic inflammatory mediator release, pre- and poststimulation, ex vivo, in cells from Japanese patients with chronic obstructive pulmonary disease (COPD), non-COPD smoking controls, and non-COPD nonsmoking controls (NSC). PATIENTS AND METHODS: This was a nontreatment study with ten subjects per group. Inflammatory biomarker release, including interleukin (IL)-6 and -8, matrix metalloproteinase-9, and tumor necrosis factor (TNF)-alpha, was measured in peripheral blood mononuclear cells (PBMC) and sputum cells with and without lipopolysaccharide or TNF-alpha stimulation. RESULTS: In PBMC, basal TNF-alpha release (mean +/- standard deviation) was significantly different between COPD (81.6+/-111.4 pg/mL) and nonsmoking controls (9.5+/-5.2 pg/mL) (P<0.05). No other significant differences were observed. Poststimulation biomarker release tended to increase, with the greatest changes in the COPD group. The greatest mean increases were seen in the lipopolysaccharide-induced release of matrix metalloproteinase-9, TNF-alpha, and IL-6 from PBMC. Pre- and poststimulation data from sputum samples were more variable and less conclusive than from PBMC. In the COPD group, induced sputum neutrophil levels were higher and macrophage levels were lower than in either control group. Significant correlations were seen between the number of sputum cells (macrophages and neutrophils) and biomarker levels (IL-8, IL-6, and TNF-alpha). CONCLUSION: This was the first study to compare cellular inflammatory mediator release before and after stimulation among Japanese COPD, smoking controls, and nonsmoking controls populations. Poststimulation levels tended to be higher in patients with COPD. The results suggest that PBMC are already preactivated in the circulation in COPD patients. This provides further evidence that COPD is a multicomponent disease, involving both airway and systemic inflammation. PMID- 26929616 TI - Study protocol for a randomized controlled trial of telephone-delivered cognitive behavior therapy compared with befriending for treating depression and anxiety in older adults with COPD. AB - BACKGROUND: COPD is an umbrella term to describe chronic lung diseases that cause limitations in lung airflow, including emphysema and chronic bronchitis. The prevalence of depression and anxiety in people with COPD is high, although these comorbidities are often undiagnosed, untreated, or undertreated. There is a need to identify efficacious treatments for depression and anxiety in people with COPD. Cognitive behavior therapy (CBT) for the treatment of anxiety and depression has a strong evidence base. There has been some success delivering this treatment over the telephone in limited studies. The aim of this study is to evaluate the efficacy of both telephone-administered CBT and befriending on outcomes for patients with diagnosed COPD who have at least mild levels of depression and/or anxiety. METHODS: The protocol described in this paper is of a pragmatic randomized controlled trial comparing eight sessions of telephone CBT to an active social control, referred to as befriending. Primary outcome measures will include depression and anxiety symptoms, and secondary outcome measures will include quality of life, self-efficacy, and COPD symptom severity. Participants' satisfaction with the intervention and therapeutic alliance will also be assessed. Measures will be taken pre- and postdelivery of the intervention and again at 8 weeks following the intervention. CONCLUSION: People with COPD often have limitations to their mobility because of their breathlessness. They are often already attending many medical appointments and could be reluctant to attend for face-to-face psychological treatment. The results of this study should identify the relative efficacy of CBT delivered over the telephone to this population, which, if successful, may be a cost-effective and more palatable alternative to face-to-face treatment of depression or anxiety for this population. PMID- 26929617 TI - Feasibility of spirometry in primary care to screen for COPD: a pilot study. AB - BACKGROUND: COPD is a frequent but underdiagnosed disease whose diagnosis relies on the spirometric demonstration of bronchial obstruction. Spirometry use by general practitioners could represent the first line in COPD diagnosis. OBJECTIVE: Because duration of spirometry is retarding its development in primary care, we decided to measure the time it requires in the primary-care context in France. METHODS: Ten volunteer general practitioners were trained during two 3 hour theoretical and practical continuing education sessions. Then, from October 2013 to May 2014, they included patients without any known respiratory disease but at risk of developing COPD (age: >=40 years, smoker: >=20 pack-years). The duration of spirometry and its quality were evaluated according to the following acceptability criteria: 1) expiration >=6 seconds or reaching a plateau; 2) good start with an early peak flow, curve peaked on top and not flat; 3) no artifacts; and 4) reproducibility criteria, ie, forced expiratory volume in 1 second and forced vital capacity differences between the two best spirometry curves <=0.15 L. Quality of the spirograms was defined as optimal when all the criteria were met and acceptable when all the criteria were satisfied except the reproducibility criterion, otherwise, it was unacceptable. RESULTS: For the 152 patients included, the 142 assessable spirometries lasted for 15.2+/-5.9 minutes. Acceptability criteria 1-3, respectively, were satisfied for 90.1%, 89.4%, and 91.5% of patients and reproducibility criterion 4 for 56.3%. Quality was considered optimal for 58.5% of the curves and acceptable for 30.2%. CONCLUSION: The duration of spirometry renders it poorly compatible with the current primary care practice in France other than for dedicated consultations. Moreover, the quality of spirometry needs to be improved. PMID- 26929618 TI - COPD characteristics and socioeconomic burden in Hellenic correctional institutions. AB - BACKGROUND: The high prevalence of smoking (80%) in Greek correctional institutions is anticipated to result in high prevalence of COPD in such settings. AIM: The aim of the Greek obstructive luNg disease epidemiOlogy and health economics Study In corrective institutionS (GNOSIS) is to determine the prevalence of smoking and COPD among inmates and to assess the health-related quality of life. METHODS: GNOSIS, a cross-sectional epidemiological study, was conducted between March 2011 and December 2011 in seven correctional institutions in Greece. RESULTS: A total of 552 participants, 91.3% male, median age of 43.0 years (interquartile range: 35-53), were enrolled. COPD prevalence was 6.0% and was found to increase with age (18.6% among those >=60 years), length of prison stay, and length of sentence. Of the participants diagnosed with COPD, 36.4% were diagnosed with Global initiative for chronic Obstructive Lung Disease (GOLD) stage I and 51.5% were diagnosed with stage II. Dyspnea severity was assessed as grades 0-1 on the medical research council dyspnea scale for 88.3%, while 31% reported >=2 COPD exacerbations in the past year. Seventy-nine percent of the total number of the participants were smokers, with a median smoking of 20.0 cigarettes per day, while 42.9% were assessed as having a strong addiction to nicotine. The median EuroQol visual analog scale score was 70.0 (interquartile range: 60.0-90.0). Problems in the dimension of anxiety/depression were reported by 82.8%. CONCLUSION: The results of the study support the notion that the prevalence of COPD among inmates of Greek correctional institutions may increase in the following years. The findings underscore the importance of taking actions to limit COPD prevalence and its risk factors in the Greek correctional system. PMID- 26929619 TI - Cytoprotective effect of glutaraldehyde erythropoietin on HEK293 kidney cells after silver nanoparticle exposure. AB - The toxic effects from exposure to silver nanoparticles (AgNPs), which are broadly present in many consumer products, have long raised concerns. Many studies have focused on the mechanisms of nanosilver, which cause toxicity in human cells, but little is known about prevention of this type of injury. This study investigated the in vitro effects of glutaraldehyde erythropoietin (GEPO), a cytoprotective compound derived from erythropoietin, in terms of cell protection against AgNP-induced injury. HEK293 cells were pretreated with or without GEPO before administration of AgNPs. The protective effects of GEPO in this cell line were assessed by the percentage of viable cells, alterations of cell morphology, and the proliferative capability of the cells. In addition, we assessed the role of GEPO in lowering cellular oxidative stress and regulating expression of the anti-apoptotic protein Bcl2. The results showed rescue effects on the percentage of viable and proliferative cells among GEPO pretreated cells. Pretreatment with GEPO maintained the normal cell shape and ultrastructural morphology. Moreover, GEPO reduced the generation of reactive oxygen species in cells and activated expression of Bcl2, which are the major mechanisms in protection against cellular toxicity induced by AgNPs. In conclusion, our study showed that the cytotoxic effects from exposure to AgNPs can be prevented by GEPO. PMID- 26929620 TI - Toward a general physiologically-based pharmacokinetic model for intravenously injected nanoparticles. AB - To assess the potential toxicity of nanoparticles (NPs), information concerning their uptake and disposition (biokinetics) is essential. Experience with industrial chemicals and pharmaceutical drugs reveals that biokinetics can be described and predicted accurately by physiologically-based pharmacokinetic (PBPK) modeling. The nano PBPK models developed to date all concern a single type of NP. Our aim here was to extend a recent model for pegylated polyacrylamide NP in order to develop a more general PBPK model for nondegradable NPs injected intravenously into rats. The same model and physiological parameters were applied to pegylated polyacrylamide, uncoated polyacrylamide, gold, and titanium dioxide NPs, whereas NP-specific parameters were chosen on the basis of the best fit to the experimental time-courses of NP accumulation in various tissues. Our model describes the biokinetic behavior of all four types of NPs adequately, despite extensive differences in this behavior as well as in their physicochemical properties. In addition, this simulation demonstrated that the dose exerts a profound impact on the biokinetics, since saturation of the phagocytic cells at higher doses becomes a major limiting step. The fitted model parameters that were most dependent on NP type included the blood:tissue coefficients of permeability and the rate constant for phagocytic uptake. Since only four types of NPs with several differences in characteristics (dose, size, charge, shape, and surface properties) were used, the relationship between these characteristics and the NP dependent model parameters could not be elucidated and more experimental data are required in this context. In this connection, intravenous biodistribution studies with associated PBPK analyses would provide the most insight. PMID- 26929622 TI - Development of nanoantibiotic delivery system using cockle shell-derived aragonite nanoparticles for treatment of osteomyelitis. AB - A local antibiotic delivery system (LADS) with biodegradable drug vehicles is recognized as the most effective therapeutic approach for the treatment of osteomyelitis. However, the design of a biodegradable LADS with high therapeutic efficacy is too costly and demanding. In this research, a low-cost, facile method was used to design vancomycin-loaded aragonite nanoparticles (VANPs) with the aim of understanding its potency in developing a nanoantibiotic bone implant for the treatment of osteomyelitis. The aragonite nanoparticles (ANPs) were synthesized from cockle shells by a hydrothermal approach using a zwitterionic surfactant. VANPs were prepared using antibiotic ratios of several nanoparticles, and the formulation (1:4) with the highest drug-loading efficiency (54.05%) was used for physicochemical, in vitro drug release, and biological evaluation. Physiochemical characterization of VANP was performed by using transmission electron microscopy, Fourier transform infrared spectroscopy, X-ray powder diffraction, and Zetasizer. No significant differences were observed between VANP and ANP in terms of size and morphology as both samples were cubic shaped with sizes of approximately 35 nm. The Fourier transform infrared spectroscopy of VANP indicated a weak noncovalent interaction between ANP and vancomycin, while the zeta potential values were slightly increased from -19.4+/-3.3 to -21.2+/-5.7 mV after vancomycin loading. VANP displayed 120 hours (5 days) release profile of vancomycin that exhibited high antibacterial effect against methicillin-resistant Staphylococcus aureus ATCC 29213. The cell proliferation assay showed 80% cell viability of human fetal osteoblast cell line 1.19 treated with the highest concentration of VANP (250 ug/mL), indicating good biocompatibility of VANP. In summary, VANP is a potential formulation for the development of an LADS against osteomyelitis with optimal antibacterial efficacy, good bone resorbability, and biocompatibility. PMID- 26929621 TI - Gold nanoparticles enhance the effect of tyrosine kinase inhibitors in acute myeloid leukemia therapy. AB - BACKGROUND AND AIMS: Every year, in Europe, acute myeloid leukemia (AML) is diagnosed in thousands of adults. For most subtypes of AML, the backbone of treatment was introduced nearly 40 years ago as a combination of cytosine arabinoside with an anthracycline. This therapy is still the worldwide standard of care. Two-thirds of patients achieve complete remission, although most of them ultimately relapse. Since the FLT3 mutation is the most frequent, it serves as a key molecular target for tyrosine kinase inhibitors (TKIs) that inhibit FLT3 kinase. In this study, we report the conjugation of TKIs onto spherical gold nanoparticles. MATERIALS AND METHODS: The internalization of TKI-nanocarriers was proved by the strongly scattered light from gold nanoparticles and was correlated with the results obtained by transmission electron microscopy and dark-field microscopy. The therapeutic effect of the newly designed drugs was investigated by several methods including cell counting assay as well as the MTT assay. RESULTS: We report the newly described bioconjugates to be superior when compared with the drug alone, with data confirmed by state-of-the-art analyses of internalization, cell biology, gene analysis for FLT3-IDT gene, and Western blotting to assess degradation of the FLT3 protein. CONCLUSION: The effective transmembrane delivery and increased efficacy validate its use as a potential therapeutic. PMID- 26929623 TI - Lysine-functionalized nanodiamonds as gene carriers: development of stable colloidal dispersion for in vitro cellular uptake studies and siRNA delivery application. AB - PURPOSE: Nanodiamonds (NDs) are emerging as an attractive tool for gene therapeutics. To reach their full potential for biological application, NDs should maintain their colloidal stability in biological milieu. This study describes the behavior of lysine-functionalized ND (lys-ND) in various dispersion media, with an aim to limit aggregation and improve the colloidal stability of ND gene complexes called diamoplexes. Furthermore, cellular and macromolecular interactions of lys-NDs are also analyzed in vitro to establish the understanding of ND-mediated gene transfer in cells. METHODS: lys-NDs were synthesized earlier through covalent conjugation of lysine amino acid to carboxylated NDs surface generated through re-oxidation in strong oxidizing acids. In this study, dispersions of lys-NDs were prepared in various media, and the degree of sedimentation was monitored for 72 hours. Particle size distributions and zeta potential measurements were performed for a period of 25 days to characterize the physicochemical stability of lys-NDs in the medium. The interaction profile of lys-NDs with fetal bovine serum showed formation of a protein corona, which was evaluated by size and charge distribution measurements. Uptake of lys-NDs in cervical cancer cells was analyzed by scanning transmission X-ray microscopy, flow cytometry, and confocal microscopy. Cellular uptake of diamoplexes (complex of lys-NDs with small interfering RNA) was also analyzed using flow cytometry. RESULTS: Aqueous dispersion of lys-NDs showed minimum sedimentation and remained stable over a period of 25 days. Size distributions showed good stability, remaining under 100 nm throughout the testing period. A positive zeta potential of >+20 mV indicated a preservation of surface charges. Size distribution and zeta potential changed for lys-NDs after incubation with blood serum, suggesting an interaction with biomolecules, mainly proteins, and a possible formation of a protein corona. Cellular internalization of lys-NDs was confirmed by various techniques such as confocal microscopy, soft X-ray spectroscopy, and flow cytometry. CONCLUSION: This study establishes that dispersion of lys-NDs in aqueous medium maintains long-term stability and also provides evidence that lysine functionalization enables NDs to interact effectively with the biological system to be used for RNAi therapeutics. PMID- 26929624 TI - Epilepsy and attention-deficit hyperactivity disorder: links, risks, and challenges. AB - Attention-deficit hyperactivity disorder (ADHD) has a prevalence rate of 7%-9% in the general population of children. However, in children with epilepsy, ADHD has been found to be present in 20%-50% of patients. This paper provides a review of ADHD prevalence in pediatric epilepsy populations and reviews data on specific symptom presentation and attention deficits in patients with epilepsy. This paper also reviews evidence-based treatments for ADHD and specifically the treatment of ADHD as a comorbid condition in children with epilepsy. PMID- 26929626 TI - Traumatic brain injury-induced sleep disorders. AB - Sleep disturbances are frequently identified following traumatic brain injury, affecting 30%-70% of persons, and often occur after mild head injury. Insomnia, fatigue, and sleepiness are the most frequent sleep complaints after traumatic brain injury. Sleep apnea, narcolepsy, periodic limb movement disorder, and parasomnias may also occur after a head injury. In addition, depression, anxiety, and pain are common brain injury comorbidities with significant influence on sleep quality. Two types of traumatic brain injury that may negatively impact sleep are acceleration/deceleration injuries causing generalized brain damage and contact injuries causing focal brain damage. Polysomnography, multiple sleep latency testing, and/or actigraphy may be utilized to diagnose sleep disorders after a head injury. Depending on the disorder, treatment may include the use of medications, positive airway pressure, and/or behavioral modifications. Unfortunately, the treatment of sleep disorders associated with traumatic brain injury may not improve neuropsychological function or sleepiness. PMID- 26929627 TI - A retrospective drug use evaluation of cabergoline for lactation inhibition at a tertiary care teaching hospital in Qatar. AB - BACKGROUND: Breastfeeding is considered as gold standard for infant nutrition and should be interrupted only when a compelling indication exists. Certain medical conditions such as abortion, stillbirth, HIV infection, or infant galactosemia and certain medications such as chemotherapy necessitate lactation inhibition to protect the health of mother and infant. Drug use evaluation (DUE) studies are done to explore the current practice in a setting and help to identify areas in which further information and education may be needed by clinicians. OBJECTIVE: The aim of this study was to conduct a DUE of cabergoline to assess indications for lactation inhibition, dosage regimen, and its safety. METHOD: A retrospective cross-sectional DUE study was conducted over a period of 4 months from September 1, 2013, till December 31, 2013, at the Women's Hospital, Qatar. All cabergoline prescriptions written for lactation inhibition within 10 days of delivery or abortion were included in the study. A descriptive data analysis was undertaken. RESULTS: Of the 85 patients included, stillbirth (50.6%) was considered as the main reason for lactation inhibition, followed by abortion (27.1%) and neonatal death (12.9%). The remaining 9.4% of the patients had live baby, and the majority of them were prescribed cabergoline for lactation inhibition because their maternal medical conditions required the use of drugs with insufficient safety data (n=6). Seventy-four percent of patients received cabergoline at accurate time and dose. However, 14% of the patients had preexisting hypertensive disorder and 58.3% of them were diagnosed as uncontrolled hypertension. CONCLUSION: The current DUE study found that cabergoline was mainly used to inhibit lactation for patients with stillbirth, abortion, and neonatal death. In mothers who use medications for other medical conditions, benefits and risks of breastfeeding should be carefully balanced before prescribing cabergoline. Current prescribing pattern can be further enhanced through informing health care providers regarding appropriate cabergoline dosage regimen and its safety in patients with uncontrolled hypertension. PMID- 26929628 TI - Intermittent negative pressure wound therapy with instillation for the treatment of persistent periprosthetic hip infections: a report of two cases. AB - Intermittent negative pressure wound therapy with instillation (NPWTi) is starting to be used successfully to treat early periprosthetic infections of endoprostheses. However, few articles have reported the outcome of treatment with intermittent NPWTi for late persistent periprosthetic infections of the hip. In this study, we report two cases who underwent several rounds of radical wound debridement for the treatment of a late persistent periprosthetic infection of the hip. Intermittent NPWTi was used in both cases. Patients were treated successfully and there was no recurrence after 3 and 1 years of follow-up, respectively. PMID- 26929629 TI - Optimal medical therapy for secondary prevention after an acute coronary syndrome: 18-month follow-up results at a tertiary teaching hospital in South Korea. AB - BACKGROUND: Acute coronary syndrome (ACS) is a fatal cardiovascular disease caused by atherosclerotic plaque erosion or rupture and formation of coronary thrombus. The latest guidelines for ACS recommend the combined drug regimen, comprising aspirin, P2Y12 inhibitor, angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker, beta-blocker, and statin, at discharge after ACS treatment to reduce recurrent ischemic cardiovascular events. This study aimed to examine prescription patterns of secondary prevention drugs in Korean patients with ACS after hospital discharge, to access the appropriateness of secondary prevention drug therapy for ACS, and to evaluate whether to persistently use discharge medications for 18 months. METHODS: This study was retrospectively conducted with the patients who were discharged from the tertiary hospital, located in South Korea, after ACS treatment between September 2009 and August 2013. Data were collected through electronic medical record. RESULTS: Among 3,676 patients during the study period, 494 were selected based on inclusion and exclusion criteria. The regimen of aspirin + clopidogrel + beta-blocker + angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker + statin was prescribed to 374 (75.71%) patients with ACS at discharge. Specifically, this regimen was used in 177 (69.69%) unstable angina patients, 44 (70.97%) non-ST segment elevation myocardial infarction patients, and 153 (85.96%) ST-segment elevation myocardial infarction patients. Compared with the number of ACS patients with all five guideline-recommended drugs at discharge, the number of ACS patients using them 12 (n=169, 34.21%) and 18 (n=105, 21.26%) months after discharge tended to be gradually decreased. CONCLUSION: The majority of ACS patients in this study received all five guideline-recommended medications at discharge from the hospital. However, the frequency of using all of them had been gradually decreased 3, 6, 12, and 18 months after discharge compared with that at discharge. Careful monitoring of adherence on ACS secondary prevention medications may help improve the outcomes of ACS patients in terms of recurrent ischemic cardiovascular events. PMID- 26929625 TI - Strategies to improve anxiety and depression in patients with COPD: a mental health perspective. AB - Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory lung disease characterized by progressive and only partially reversible symptoms. Worldwide, the incidence of COPD presents a disturbing continuous increase. Anxiety and depression are remarkably common in COPD patients, but the evidence about optimal approaches for managing psychological comorbidities in COPD remains unclear and largely speculative. Pharmacological treatment based on selective serotonin reuptake inhibitors has almost replaced tricyclic antidepressants. The main psychological intervention is cognitive behavioral therapy. Of particular interest are pulmonary rehabilitation programs, which can reduce anxiety and depressive symptoms in these patients. Although the literature on treating anxiety and depression in patients with COPD is limited, we believe that it points to the implementation of personalized strategies to address their psychopathological comorbidities. PMID- 26929630 TI - Intravitreal ketorolac for the treatment of chronic cystoid macular edema after cataract surgery. AB - PURPOSE: To report two cases of chronic postoperative cystoid macular edema, resistant to topical therapy, treated with consecutive intravitreal injections of ketorolac tromethamine. METHODS: Four daily intravitreal injections of 500 MUg/0.05 mL of ketorolac were given to each patient. Complete clinical examination and OCT were performed before every injection, 1, 2, 3 weeks, and 1, 3, and 6 months after the last injection. Fluorescein angiography was performed at baseline examination, 1, 3, and 6 months after the last injection. RESULTS: In both cases, the edema regressed and visual acuity increased. At 6 months after the last injection, the leakage was significantly reduced at the fluorescein angiography. DISCUSSION: Both cases responded favorably to the consecutive intravitreal administration of ketorolac tromethamine. The long-lasting remission of the macular edema in these chronic cases underlines the therapeutic potential of these agents when delivered intravitreally. PMID- 26929631 TI - Low-back pain at the emergency department: still not being managed? AB - BACKGROUND: Low-back pain (LBP) affects about 40% of people at some point in their lives. In the presence of "red flags", further tests must be done to rule out underlying problems; however, biomedical imaging is currently overused. LBP involves large in-hospital and out-of-hospital economic costs, and it is also the most common musculoskeletal disorder seen in emergency departments (EDs). PATIENTS AND METHODS: This retrospective observational study enrolled 1,298 patients admitted to the ED, including all International Classification of Diseases 10 diagnosis codes for sciatica, lumbosciatica, and lumbago. We collected patients' demographic data, medical history, lab workup and imaging performed at the ED, drugs administered at the ED, ED length of stay (LOS), numeric rating scale pain score, admission to ward, and ward LOS data. Thereafter, we performed a cost analysis. RESULTS: Mean numeric rating scale scores were higher than 7/10. Home medication consisted of no drug consumption in up to 90% of patients. Oxycodone-naloxone was the strong opioid most frequently prescribed for the home. Once at the ED, nonsteroidal anti-inflammatory drugs and opiates were administered to up to 72% and 42% of patients, respectively. Imaging was performed in up to 56% of patients. Mean ED LOS was 4 hours, 14 minutes. A total of 43 patients were admitted to a ward. The expense for each non-ward admitted patient was approximately ?200 in the ED, while the mean expense for ward-admitted patients was ?9,500, with a mean LOS of 15 days. CONCLUSION: There is not yet a defined therapeutic care process for the patient with LBP with clear criteria for an ED visit. It is to this end that we need a clinical pathway for the prehospital management of LBP syndrome and consequently for an in-hospital time-saving therapeutic approach to the patient. PMID- 26929632 TI - IgG4-related disease: current challenges and future prospects. AB - Immunoglobulin G4-related disease (IgG4-RD) represents an immune-mediated fibroinflammatory condition with a characteristic histopathological appearance that can affect various organs. Although numerous single-organ manifestations have been described more than a century ago, its systemic nature and unique features were only discovered in the last 2 decades, when IgG4-RD emerged as a new entity of disease. IgG4-RD is usually considered a rare disease, but its true epidemiology has not yet been fully clarified. Also, despite recent advances in the identification of the underlying immunological processes, its pathophysiology is only incompletely understood till now. The diagnostic workup of IgG4-RD is complex and usually requires a combination of clinical examination, imaging, histological, and serological analyses. However, no finding alone is specific for IgG4-RD. Therefore, its diagnosis requires careful interpretation of examination results in context with the patient's clinical appearance as well as the exclusion of a broad variety of differential diagnoses. The past years brought rapid advances concerning this novel disease entity: diagnostic criteria, further insights into the underlying immunological processes, new biomarkers, and novel therapeutic approaches were proposed and widened the knowledge in the field of IgG4-RD. Still, a greater number of questions remain unanswered, and many recent developments require further discussion and proof from clinical trials. This review should give an overview on current knowledge and future perspectives in epidemiology, pathophysiology, diagnosis, and therapy of IgG4-RD. PMID- 26929633 TI - Evaluation of a new tablet formulation of deferasirox to reduce chronic iron overload after long-term blood transfusions. AB - Transfusion-dependent anemia is a common feature in a wide array of hematological disorders, including thalassemia, sickle cell disease, aplastic anemia, myelofibrosis, and myelo-dysplastic syndromes. In the absence of a physiological mechanism to excrete excess iron, chronic transfusions ultimately cause iron overload. Without correction, iron overload can lead to end-organ damage, resulting in cardiac, hepatic, and endocrine dysfunction/failure. Iron chelating agents are utilized to reduce iron overload, as they form a complex with iron, leading to its clearance. Iron chelation has been proven to decrease organ dysfunction and improve survival in certain transfusion-dependent anemias, such as beta-thalassemia. Several chelating agents have been approved by the United States Food and Drug Administration for the treatment of iron overload, including deferoxamine, deferiprone, and deferasirox. A variety of factors have to be considered when choosing an iron chelator, including dosing schedule, route of administration, tolerability, and side effect profile. Deferasirox is an orally administered iron chelator with proven efficacy and safety in multiple hematological disorders. There are two formulations of deferasirox, a tablet for suspension, and a new tablet form. This paper is intended to provide an overview of iron overload, with a focus on deferasirox, and its recently approved formulation Jadenu((r)) for the reduction of transfusional iron overload in hematological disorders. PMID- 26929634 TI - New combinations in the treatment of COPD: rationale for aclidinium-formoterol. AB - The current guidelines on chronic obstructive pulmonary disease (COPD) recommend the prominent use of bronchodilators, including long-acting beta2-agonists (LABAs) and long-acting muscarinic antagonists (LAMAs), while inhaled corticosteroids are recommended only in patients with severe disease or frequent exacerbations. LABA-LAMA combinations are indicated when single bronchodilators are insufficient to control COPD. A number of LABA-LAMA combinations are available, based on twice-daily or once-daily administration according to the 12- or 24-hour duration of action, respectively. The aclidinium-formoterol combination is based on the new LAMA aclidinium bromide, which has a high selectivity for M3 muscarinic receptors and a fast onset of action, and the well known LABA formoterol. Both drugs require twice-daily administration. The fixed dose combination of aclidinium 400 MUg/formoterol 12 MUg has shown in randomized controlled trials fast and sustained bronchodilation that was greater than either monotherapy and provided clinically significant improvements in dyspnea and health status compared with placebo, also reducing the use of rescue medications. The overall incidence of adverse events was low and comparable to placebo. These data define the aclidinium-formoterol fixed-dose combination as a new treatment option for patients with COPD. The need for twice-daily administration could be an apparent disadvantage compared to the available once-daily LABA-LAMA combinations, but the immediately perceived benefit in reducing dyspnea due to the fast onset of action, as well as reported correct patient use and satisfaction with the Genuair inhaler might prove useful in favoring adherence. PMID- 26929635 TI - Influence of MDR1 methylation on the curative effect of interventional embolism chemotherapy for cervical cancer. AB - BACKGROUND: Multi-drug resistance (MDR) is the main cause of tumor failure to chemotherapy. This study aims to explore the influence of MDR1 methylation on curative effect of interventional embolism chemotherapy for cervical cancer. METHODS: Sixty-seven patients with cervical cancer receiving embolism chemotherapy were selected, and 45 normal cervical tissues were included as a control. Immunohistochemistry was used to detect the level of P-glycoprotein (P gp) in cervical cancer, and to make an analysis compared with normal tissues. The methylation status of the MDR1 gene promoter region 16 CpG units was analyzed by using kilobase-specific cracking and matrix-assisted laser desorption ionization time of flight mass spectrometry. RESULTS: The results indicated that the positive expression rates of P-gp were 0% (0/45) in normal cervical tissue, and 61.19% (41/67) and 77.61% (52/67) before and after interventional embolism chemotherapy in cervical cancer tissues, respectively. There were significant differences compared with normal cervical tissues (chi (2)=4.2523, 0.0392). The positive expression rate of P-gp before chemotherapy was negatively correlated with efficacy of chemotherapy (r=-0.340, P=0.005). Methylation rate of 13 CpG units in normal tissues was significantly greater than cervical tissues (P<0.05). In cervical cancer tissue, methylation rate of six CpG units before interventional embolism chemotherapy was higher than after chemotherapy, but that of one CpG unit was lower than after chemotherapy (P<0.05). The methylation rate of one CpG unit with effective chemotherapy before chemotherapy was significantly higher than ineffective chemotherapy (P<0.05), and the other CpG units were similar (P>0.05). CONCLUSION: P-gp expression level coded by MDR1, methylation status of partial MDR1 gene promoter regions CpG island, is closely related to the efficacy of interventional embolism chemotherapy for cervical cancer before the operation. PMID- 26929636 TI - Fingolimod for multiple sclerosis and emerging indications: appropriate patient selection, safety precautions, and special considerations. AB - Fingolimod (FTY720), an immunotherapeutic drug targeting the sphingosine-1 phosphate receptor, is a widely used medication for relapsing-remitting multiple sclerosis (MS). Apart from the pivotal Phase III trials demonstrating efficacy against placebo and interferon-beta-1a once weekly, sufficient clinical data are now available to assess its real-world efficacy and safety profile. Approved indications of fingolimod differ between countries. This discrepancy, to some extent, reflects the intermediate position of fingolimod in the expanding lineup of MS medications. With individualization of therapy, appropriate patient selection gets more important. We discuss various scenarios for fingolimod use in relapsing-remitting MS and their pitfalls: as first-line therapy, as escalation therapy after failure of previous immunotherapies, and as de-escalation therapy following highly potent immunotherapies. Potential side effects such as bradycardia, infections, macular edema, teratogenicity, and progressive multifocal leukoencephalopathy as well as appropriate safety precautions are outlined. Disease reactivation has been described upon fingolimod cessation; therefore, patients should be closely monitored for MS activity for several months after stopping fingolimod. Finally, we discuss preclinical and clinical data indicating neuroprotective effects of fingolimod, which might open the way to future indications such as stroke, Alzheimer's disease, and other neurodegenerative disorders. PMID- 26929637 TI - Considerations for long-term anticoagulant therapy in patients with venous thromboembolism in the novel oral anticoagulant era. AB - BACKGROUND: Patients who have had a venous thromboembolic event are generally advised to receive anticoagulant treatment for 3 months or longer to prevent a recurrent episode. Current guidelines recommend initial heparin and an oral vitamin K antagonist (VKA) for long-term anticoagulation. However, because of the well-described disadvantages of VKAs, including extensive food and drug interactions and the need for regular anticoagulation monitoring, novel oral anticoagulants (NOACs) have become an attractive option in recent years. These agents are given at fixed doses and do not require routine coagulation-time monitoring. The NOACs are discussed in this review with regard to the needs of patients on long-term anticoagulation. METHODS: Current guidelines from Europe and North America that refer to the treatment of deep vein thrombosis and/or pulmonary embolism are included, as well as published randomized Phase III clinical trials of NOACs. PubMed searches were used for sourcing case studies of long-term anticoagulant treatment, and results were filtered for human application and screened for relevance. CONCLUSION: NOAC-based therapy showed a similar efficacy and safety profile to heparins/VKAs but without the need for regular anticoagulation monitoring or dietary adjustments, and can be taken as a fixed-dose regimen once or twice daily. This represents a significant step forward in facilitating the management of long-term anticoagulation therapy. Furthermore, in the EINSTEIN studies, improved patient satisfaction was documented with the NOAC rivaroxaban, which may result in better adherence to therapy and an overall reduction in the incidence of recurrent venous thromboembolism. PMID- 26929638 TI - Genetic polymorphisms of CASR and cancer risk: evidence from meta-analysis and HuGE review. AB - BACKGROUND: CASR gene appears to be involved in cancer biology and physiology. However, a number of studies investigating CASR polymorphisms and cancer risks have presented inconclusive results. Thus, a systematic review and a meta analysis of the effect of CASR polymorphisms on several cancer risks were performed to suggest a statistical evidence for the association of CASR polymorphisms with cancer risks. METHODS: MEDLINE, EMBASE, Web of Science, Scopus, and the HuGE databases were searched. Nineteen articles of case-control and cohort studies were included for the final analysis. RESULTS: The colorectal cancer risk was reduced in proximal (odds ratio [OR] =0.679, P=0.001) and distal (OR =0.753, P=0.026) colon sites with GG genotype of CASR rs1042636 and increased in distal colon site (OR =1.418, P=0.039) with GG genotype of rs1801726 by additive genetic model. The rs17251221 demonstrated noticeable associations that carrying a homozygote variant increases breast and prostate cancer risk considerably. CONCLUSION: The significant association of CASR polymorphisms with several cancer risks was observed in this review. In particular, the act of CASR polymorphisms as a tumor suppressor or an oncogene differs by cancer site and can be the research target for tumorigenesis. PMID- 26929640 TI - Profile of capecitabine/temozolomide combination in the treatment of well differentiated neuroendocrine tumors. AB - Neuroendocrine tumors are a rare and heterogeneous group of tumors with a variety of primary origins and variable aggressiveness. Platinum-based chemotherapy has been the cornerstone of treatment for the poorly differentiated tumors. However, well-differentiated neuroendocrine tumors are quite chemoresistant and therapy options are limited. Octreotide analogs and tyrosine kinase inhibitors are widely acceptable treatments due to substantial efficacy and tolerable toxicity. On the contrary, monotherapy or combinations of the only approved cytotoxic agent streptozocin with other drugs have been almost abandoned because of excessive toxic events. In recent years, the combination of capecitabine and temozolomide has emerged as the most promising and efficacious treatment. The oral route of administration and the substantial improvement in the outcomes with manageable toxicity are the major advantages. We reviewed the current literature and presented the profile of the capecitabine/temozolomide combination in the management of well-differentiated neuroendocrine tumors. PMID- 26929641 TI - Exceptional response to cetuximab monotherapy in a patient with metastatic oropharyngeal squamous cell carcinoma: a molecular insight. AB - BACKGROUND: Metastatic head and neck squamous cell carcinoma (HNSCC) carries a very poor prognosis. A better understanding of the molecular driver of the disease and the identification of biomarkers of response remain paramount for an effective personalized therapy. CASE REPORT: We report an original case of a 56 year-old patient diagnosed with metastatic HNSCC to both kidneys, who experienced a long-lasting complete response to a single-agent cetuximab, a monoclonal antibody-targeting EGFR. Comprehensive multiplatform biomarker analysis of the tumor revealed the presence of phosphatidyl-inositol 3 kinase mutation, EGFR overexpression, and the absence of PD-1/PD-L1 expression. Since PI3K, a downstream effector of EGFR, is activated, the tumor regression may have occurred mainly through a cetuximab-induced immune-mediated response, rather than EGFR signal blockade. It is plausible that this effect was enhanced by the lack of PD 1 and PD-L1 expression. CONCLUSION: Our case proposes that the absence of PD-1 and PD-L1 expression in conjunction with EGFR overexpression may correlate with better response to cetuximab in HNSCC. This hypothesis needs to be examined through a large clinical trial. PMID- 26929639 TI - Long noncoding RNAs in gastric cancer: functions and clinical applications. AB - Over the last two decades, genome-wide studies have revealed that only a small fraction of the human genome encodes proteins; long noncoding RNAs (lncRNAs) account for 98% of the total genome. These RNA molecules, which are >200 nt in length, play important roles in diverse biological processes, including the immune response, stem cell pluripotency, cell proliferation, apoptosis, differentiation, invasion, and metastasis by regulating gene expression at the epigenetic, transcriptional, and posttranscriptional levels. However, the detailed molecular mechanisms underlying lncRNA function are only partially understood. Recent studies showed that many lncRNAs are aberrantly expressed in gastric cancer (GC) tissues, gastric juice, plasma, and cells, and these alterations are linked to the occurrence, progression, and outcome of GC. Here, we review the current knowledge of the biological functions and clinical aspects of lncRNAs in GC. PMID- 26929643 TI - Values of (99m)Tc-methoxyisobutylisonitrile imaging after first-time large-dose (131)I therapy in treating differentiated thyroid cancer. AB - OBJECTIVE: The aim of this study is to investigate the use of (99m)Tc methoxyisobutylisonitrile (MIBI) imaging for evaluating the treatment response of differentiated thyroid cancer (DTC) after the first administration of a high dose of (131)I. METHODS: Patients with DTC who received (131)I therapy underwent (99m)Tc-MIBI imaging after successive increases in the therapeutic dose of (131)I, and the serum levels of thyroglobulin (Tg) were measured. RESULTS: A total of 191 patients were enrolled in the final analysis, including 65 metastases and/or thyroid remnant-positive patients (22 patients with metastases and 43 patients with thyroid remnants). The sensitivity of (99m)Tc-MIBI imaging for detecting positive cases and thyroid remnants was 56.9% and 39.5%, respectively, which was significantly lower than that of (131)I imaging (92.3% and 100%, respectively, P<0.01 for both). The sensitivity of (99m)Tc-MIBI imaging for detecting metastases was 90.9%, which was slightly higher than that of (131)I imaging (77.3%, P>0.05). The Tg levels in the positive group were significantly higher than that in the negative group (P<0.01). In addition, the Tg levels in the (99m)Tc-MIBI(+)/(131)I(-) group were significantly higher than that in the (131)I(+)/(99m)Tc-MIBI group (P<0.05). CONCLUSION: After the first (131)I therapy, although (99m)Tc-MIBI imaging was able to detect the existence of metastatic lesions in patients with DTC better, its assessment for the removal efficiency of thyroid remnants was unsatisfactory. The results of (99m)Tc-MIBI imaging showed good correlations with the Tg level. PMID- 26929642 TI - Higher expression levels of the HOXA9 gene, closely associated with MLL-PTD and EZH2 mutations, predict inferior outcome in acute myeloid leukemia. AB - BACKGROUND: Although the biological insight of acute myeloid leukemia (AML) has increased in the past few years, the discovery of novel discriminative biomarkers remains of utmost value for improving outcome predictions. Systematical studies concerning the clinical implications and genetic correlations of HOXA9 aberrations in patients with AML are relatively promising. MATERIALS AND METHODS: Here, we investigated mutational status and the mRNA levels of the HOXA9 gene in 258 patients with AML. Furthermore, hematological characteristics, chromosome abnormalities, and genetic mutations associated with AML were analyzed, followed by the assessment of clinical survival. Besides, the expression level and mutational status of MEIS1, a cofactor of HOXA9, were also detected in patients with AML with the aim of a deeper understanding about the homeodomain-containing transcription factors associated with hematological characteristics. RESULTS: HOXA9 and MEIS1 mutations were detected in 4.26% and 3.49% AML cases, respectively. No correlations were detected between mutation status and clinical characteristics, cytogenetic and genetic aberrations, and clinical survival. Higher HOXA9 expression levels were correlated with white blood cell count and closely associated with unfavorable karyotype as well as MLL-PTD and EZH2 mutations, whereas, there was an inverse correlation with the French-American British M3 subtype. Compared with patients with lower HOXA9 expression levels, those with higher HOXA9 expression levels had a lower complete remission rate and inferior survivals in both AML and cytogenetically normal AML. CONCLUSION: HOXA9 expression may serve as a promising biomarker to ameliorate a prognostic model for predicting clinical outcome and consummating individualized treatment in patients with AML. PMID- 26929644 TI - Monitoring cancer stem cells: insights into clinical oncology. AB - Cancer stem cells (CSCs) are a small, characteristically distinctive subset of tumor cells responsible for tumor initiation and progression. Several treatment modalities, such as surgery, glycolytic inhibition, driving CSC proliferation, immunotherapy, and hypofractionated radiotherapy, may have the potential to eradicate CSCs. We propose that monitoring CSCs is important in clinical oncology as CSC populations may reflect true treatment response and assist with managing treatment strategies, such as defining optimal chemotherapy cycles, permitting pretreatment cancer surveillance, conducting a comprehensive treatment plan, modifying radiation treatment, and deploying rechallenge chemotherapy. Then, we describe methods for monitoring CSCs. PMID- 26929645 TI - Effects of electromagnetic radiation exposure on bone mineral density, thyroid, and oxidative stress index in electrical workers. AB - BACKGROUND: In the literature, some articles report that the incidence of numerous diseases increases among the individuals who live around high-voltage electric transmission lines (HVETL) or are exposed vocationally. However, it was not investigated whether HVETL affect bone metabolism, oxidative stress, and the prevalence of thyroid nodule. METHODS: Dual-energy X-ray absorptiometry (DEXA) bone density measurements, serum free triiodothyronine (FT3), free thyroxine (FT4), RANK, RANKL, osteoprotegerin (OPG), alkaline phosphatase (ALP), phosphor, total antioxidant status (TAS), total oxidant status (TOS), and oxidative stress index (OSI) levels were analyzed to investigate this effect. RESULTS: Bone mineral density levels of L1-L4 vertebrae and femur were observed significantly lower in the electrical workers. ALP, phosphor, RANK, RANKL, TOS, OSI, and anteroposterior diameter of the left thyroid lobe levels were significantly higher, and OPG, TAS, and FT4 levels were detected significantly lower in the study group when compared with the control group. CONCLUSION: Consequently, it was observed that the balance between construction and destruction in the bone metabolism of the electrical workers who were employed in HVETL replaced toward destruction and led to a decrease in OPG levels and an increase in RANK and RANKL levels. In line with the previous studies, long-term exposure to an electromagnetic field causes disorders in many organs and systems. Thus, it is considered that long-term exposure to an electromagnetic field affects bone and thyroid metabolism and also increases OSI by increasing the TOS and decreasing the antioxidant status. PMID- 26929646 TI - Association of polymorphisms hOGGI rs1052133 and hMUTYH rs3219472 with risk of nasopharyngeal carcinoma in a Chinese population. AB - This case-control study investigates the possible relationships between the single-nucleotide polymorphisms rs1052133 in the human 8-oxoguanine DNA glycosylase 1 (hOGG1) gene and rs3219472 in the human MutY glycosylase homologue (hMUTYH) gene and the risk of nasopharyngeal carcinoma (NPC). The two polymorphisms were genotyped in 488 unrelated NPC patients and 573 cancer-free controls. Genotype GG at rs1052133 was associated with significantly lower NPC risk than genotypes GC + CC (odds ratio [OR] 0.770, 95% confidence interval [CI] 0.595-0.996, P=0.012). In subgroup analyses, subjects with genotype GG at rs1052133 were at lower risk of NPC than those with GC or CC among individuals older than 40 years (OR 0.706, 95% CI 0.524-0.950), women (OR 0.571, 95% CI 0.337 0.968), and those with no smoking history (OR 0.634, 95% CI 0.463-0.868). No significant association was seen between polymorphisms at hMUTYH rs3219472 and the risk of NPC. However, gene-gene interaction analysis showed that subjects with genotype CC at rs1052133 and genotype AA at rs3219472 (CC/AA) were at 2.887 fold higher risk of NPC than those with GG/GG, 3.183-fold higher risk than those with GG/GA, and 3.392-fold higher risk than those with GG/AA. Our results suggest that hOGG1 rs1052133 polymorphism may play an important role in NPC pathogenesis, especially among women, >40 years old, and those with no smoking history. The hMUTYH rs3219472 polymorphism may interact with hOGG1 rs1052133 polymorphism to influence susceptibility to NPC. PMID- 26929647 TI - Expression profile analysis of long noncoding RNA in HER-2-enriched subtype breast cancer by next-generation sequencing and bioinformatics. AB - BACKGROUND: Human epidermal growth factor receptor 2 (HER-2)-enriched subtype breast cancer is associated with a more aggressive phenotype and shorter survival time. Long non-coding RNAs (LncRNAs) have essential roles in tumorigenesis and occupy a central place in cancer progression. Notably, few studies have focused on the dysregulation of LncRNAs in the HER-2-enriched subtype breast cancer. In this study, we analyzed the expression profile of LncRNAs and mRNAs in this particular subtype of breast cancer. METHODS: Seven pairs of HER-2-enriched subtype breast cancer and normal tissue were sequenced. We screened out differently expressed genes and measured the correlation of the expression levels of dysregulated LncRNAs and HER-2 by Pearson's correlation coefficient analysis. Gene ontology analysis and pathway analysis were used to understand the biological roles of these differently expressed genes. Pathway act network and coexpression network were constructed. RESULTS: More than 1,300 LncRNAs and 2,800 mRNAs, which were significantly differently expressed, were identified. Among these LncRNAs, AFAP1-AS1 was the most dysregulated LncRNA, while ORM2 was the most dysregulated mRNA. LOC100288637 had the highest positive correlation coefficient of 0.93 with HER-2, while RPL13P5 had the highest negative correlation coefficient of -0.87. The pathway act network showed that MAPK signaling pathway, PI3K-Akt signaling pathway, metabolic pathways, cell cycle, and regulation of actin cytoskeleton were highly related with HER-2-enriched subtype breast cancer. Coexpression network recognized LINC00636, LINC01405, ADARB2-AS1, ST8SIA6-AS1, LINC00511, and DPP10-AS1 as core genes. CONCLUSION: These results analyze the functions of LncRNAs and provide useful information for exploring candidate therapeutic targets and new molecular biomarkers for HER-2 enriched subtype breast cancer. PMID- 26929648 TI - Phase II trial of bevacizumab and erlotinib as a second-line therapy for advanced hepatocellular carcinoma. AB - TRIAL REGISTRY: Clinicaltrials.gov #NCT01180959. BACKGROUND: Early clinical studies of bevacizumab and erlotinib in advanced hepatocellular carcinoma (HCC) have a tolerable toxicity and a promising clinical outcome. We evaluated the efficacy and tolerability of this combination as a second-line therapy for HCC refractory to sorafenib. METHODS: For this single-arm, Phase II study, we recruited patients with Child-Pugh class A or B liver disease, Eastern Cooperative Oncology Group performance status 0-2, and advanced HCC that was not amenable to surgical or regional therapies and treatment with sorafenib had failed (disease progressed or patient could not tolerate sorafenib). Patients received 10 mg/kg intravenous bevacizumab every 14 days and 150 mg oral erlotinib daily for 28-day cycles until progression. Tumor response was evaluated every two cycles using Response Evaluation Criteria in Solid Tumors. The primary end point was the 16-week progression-free survival rate. Secondary end points included time to progression and overall survival. RESULTS: A total of 44 patients were enrolled and had a median follow-up time of 33.8 months (95% confidence interval [CI]: 23.5 months - not defined). The 16-week progression-free survival rate was 43% (95% CI: 28%-59%), median time to progression was 3.9 months (95% CI: 2.0-8.3 months), and median overall survival duration was 9.9 months (95% CI: 8.3-15.5 months). Grade 3-4 adverse events included fatigue (13%), acne (11%), diarrhea (9%), anemia (7%), and upper gastrointestinal hemorrhage (7%). CONCLUSION: Bevacizumab plus erlotinib was tolerable and showed a signal of survival benefit in the second-line setting for patients with advanced HCC. Because standard-of care options are lacking in this setting, further studies to identify predictors of response to this regimen are warranted. PMID- 26929649 TI - Association of polymorphisms in WWOX gene with risk and outcome of osteosarcoma in a sample of the young Chinese population. AB - The WW domain-containing oxidoreductase (WWOX) gene is a tumor suppressor gene, the abnormal expression of which will lead to osteosarcoma tumorigenesis. Polymorphisms of the WWOX gene are associated with the risk of several malignancies. We hypothesized that genetic variations in the WWOX gene were related to osteosarcoma risk and outcome. In this case-control study, we recruited 276 young osteosarcoma patients and 286 controls from the East Chinese population and genotyped seven tag single-nucleotide polymorphisms (SNPs) of the WWOX gene (rs10220974C>T, rs12918952G>A, rs3764340C>G, rs1074963C>G, rs383362G>T, rs1424110A>G, and rs12828A>G). We discovered that two SNPs (rs3764340C>G and rs383362G>T) were associated with osteosarcoma risk. The CG genotype and dominant model of rs3764340 indicated elevated risk of osteosarcoma, and similar results were found for rs383362. Furthermore, rs3754340C>G was also related to grade and metastasis risk of osteosarcoma. Taken together, our results provide the first evidence that WWOX gene polymorphisms have the potential to be predictive factors for assessing risk and outcome of osteosarcoma. PMID- 26929650 TI - Overexpression of eIF4E in colorectal cancer patients is associated with liver metastasis. AB - PURPOSE: Liver metastasis is one of the leading causes of death in colorectal cancer (CRC) patients. The present study aimed to evaluate the value of eIF4E as a prognostic marker of colorectal liver metastasis (CLM) and identify the functional role of eIF4E in CRC metastasis. PATIENTS AND METHODS: The expression level of eIF4E in CRC tissues was analyzed by immunohistochemical staining and Western blot. Expression of eIF4E in CRC cell lines was evaluated by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Western blot. Cell Counting Kit-8 (CCK-8) and Transwell assays were performed to assess the effects of eIF4E on cell proliferation, migration, and invasion. Western blot was further used to investigate the mechanism of eIF4E in tumor metastasis. RESULTS: The upregulation frequency of eIF4E in the CLM group (82.5%) was higher than that in the non-CLM group (65.0%). Of the 80 patients recruited for the follow-up study, 23 were in the low eIF4E group (ratio of tumor to nontumor tissue =twofold). In addition, the group exhibiting high eIF4E expression had a higher rate of liver metastasis (47.4%) than the group exhibiting low eIF4E expression (13.0%). In CRC cell lines, the expression of eIF4E was higher than in the normal cells. In vitro functional studies indicated that eIF4E knockdown inhibited the proliferation, migration, and invasion of Lovo and SW480 cells, and suppressed the expression of cyclin D1, VEGF, MMP-2, and MMP-9. CONCLUSION: The results of the present study indicated that high eIF4E levels in CRC patients predicted a high risk of liver metastasis. Knockdown of eIF4E inhibited CRC cell metastasis in part through regulating the expression of cyclin D1, VEGF, MMP-2, and MMP-9. PMID- 26929651 TI - Delineation of clinical target volume for postoperative radiotherapy in stage IIIA-pN2 non-small-cell lung cancer. AB - With the high locoregional relapse rate and the improvement of radiation technology, postoperative radiotherapy (PORT) has been widely used in the treatment of completely resected stage IIIA-pN2 non-small-cell lung cancer (NSCLC). However, there is still no definitive consensus on clinical target volume for the pN2 subgroup. This review will discuss how to delineate the clinical target volume (CTV) for pN2 subgroups of IIIA-N2 NSCLC based on the published literature and to investigate the optimal PORT CTV in this cohort of patients. Besides overall survival (OS), locoregional recurrence (LR), and radiotherapy-related toxicity of this subset of the population in the modern PORT era, selection of proper patients will also be considered in this review. In summary, it is appropriate to include involved lymph node stations and uninvolved stations at high risk in PORT CTV for patients with pN2 disease when PORT is administered. PORT can reduce LR and has the potential to improve OS. In the current era of modern radiation technology, PORT can be administered safely with well-tolerated toxicity. Clinicopathological characteristics may be helpful in selecting proper candidates for PORT. PMID- 26929652 TI - The asthma-COPD overlap syndrome: how is it defined and what are its clinical implications? AB - It is increasingly recognized that both asthma and chronic obstructive pulmonary disease (COPD) are heterogeneous diseases with a large inter-individual variability with respect to their clinical expression, disease progression, and responsiveness to the available treatments. The introduction of asthma-COPD overlap syndrome (ACOS) may lead to a better clinical characterization and improved treatment of patients with obstructive airways disease. However, it is still in its early phase and several improvements will have to be made. First, a clear definition of ACOS and preferably also its sub-phenotypes, eg, asthma-ACOS and COPD-ACOS, is urgently needed. That would also allow researchers to design clinical studies in well-defined patients. The latter is important since the interpretation of clinical studies performed so far is hampered by the use of many different definitions of ACOS. Second, future studies are needed to investigate the role of state-of-the-art techniques such as computed tomography, genetics, and genomics in the phenotyping of patients with obstructive airways disease, ie, asthma, COPD, and ACOS. Third, longitudinal studies are now needed to better define the clinical implications of ACOS with respect to the long-term outcome and treatment of ACOS and its sub-phenotypes compared to only asthma or COPD. PMID- 26929653 TI - Methicillin-resistant Staphylococcus aureus multiple sites surveillance: a systemic review of the literature. AB - PURPOSE: The objective of this study was to evaluate the optimal number of sampling sites for detection of methicillin-resistant Staphylococcus aureus (MRSA) colonization. METHODS: We performed a Medline search from January 1966 to February 2014 for articles that reported the prevalence of MRSA at different body sites. Studies were characterized by study design, country and period of the study, number of patients and/or isolates of MRSA, specimen type, sites of MRSA isolation, study population sampled, diagnostic testing method, and percentage of the MRSA isolates at each site in relation to the total number of sites. RESULTS: We reviewed 3,211 abstracts and 177 manuscripts, of which 17 met the criteria for analysis (n=52,642 patients). MRSA colonization prevalence varied from 8% to 99% at different body sites. The nasal cavity as a single site had MRSA detection sensitivity of 68% (34%-91%). The throat and nares gave the highest detection rates as single sites. A combination of two swabs improved MRSA detection rates with the best combination being groin/throat (89.6%; 62.5%-100%). A combination of three swab sites improved MRSA detection rate to 94.2% (81%-100%) with the best combination being groin/nose/throat. Certain combinations were associated with low detection rates. MRSA detection rates also varied with different culture methods. CONCLUSION: A combination of three swabs from different body sites resulted in the highest detection rate for MRSA colonization. The use of three swab sites would likely improve the recognition and treatment of MRSA colonization, which may in turn reduce infection and transmission of MRSA to other patients. PMID- 26929654 TI - Costs associated with rheumatoid arthritis in Italy: past, present, and future. AB - This literature review examines available evidence on the current and past costs associated with rheumatoid arthritis (RA) in Italy, together with the future health-economic prospects for the disease. Studies have been conducted to date on the prevalence, or the associated costs, of RA in Italy. Although future changes in the incidence of RA are a matter of debate, the impact of RA on health care costs is expected to grow in coming decades in line with projected increases in life expectancy and in the proportion of elderly people in Italy. It has been estimated that the indirect (productivity loss and informal care) and intangible (deterioration in health-related quality of life) costs of the disease will contribute to an increase in national health service expenditure, which will correspond to 1% of the total health care costs of the nation in the near future. The introduction of biological agents for the treatment of rheumatic diseases has resulted in an increase in the direct costs of RA; however, economic analyses that exclude indirect costs will underestimate the full economic impact of RA. The effectiveness of innovative therapies in preventing disease progression and functional impairment may, over time, attenuate the cost impact of RA in terms of hospitalizations and work absenteeism. Further research is needed to develop estimates of the economic impact of different therapeutic approaches in patients with RA in Italy, in order to provide tools that can drive the choice of the most cost-effective therapeutic option while maintaining high-quality care. PMID- 26929655 TI - Fracture risk in patients with type 2 diabetes under different antidiabetic treatment regimens: a retrospective database analysis in primary care. AB - AIM: Type 2 diabetes is associated with an increased risk of fractures. There are a few studies on the effects of diabetes treatment on fracture risk. The aim was to investigate the fracture risk related to various types of insulin therapy in primary care practices. METHODS: Data from 105,960 type 2 diabetes patients from 1,072 general and internal medicine practices in Germany were retrospectively analyzed (Disease Analyzer database; 01/2000-12/2013). Fracture risk of the following therapies was compared using multivariate logistic regression models adjusting for age, sex, diabetes care, comorbidity, and glycemic control (HbAlc): 1) incident insulin therapy versus oral antidiabetic drugs, 2) basal-supported oral therapy versus supplementary insulin therapy versus conventional insulin therapy, and 3) insulin glargine versus insulin detemir versus NPH insulin. RESULTS: There was a lower odds of having incident fractures in the oral antidiabetic drug group compared to incident insulin users, although not significant (odds ratio [OR]; 95% confidence interval: 0.87; 0.72-1.06). There were increased odds for conventional insulin therapy (OR: 1.59; 95% CI [confidence interval] 0.89-2.84) and supplementary insulin therapy (OR: 1.20; 0.63-2.27) compared to basal-supported oral therapy, which was not significant as well. Overall, there was no significant difference in fracture risk for basal insulins (glargine, detemir, NPH insulin). After a treatment duration >=2 years, insulin glargine showed a lower odds of having >=1 fracture compared to NPH users (OR: 0.78; 0.65-0.95) (detemir vs NPH insulin: OR: 1.03; 0.79-1.36). CONCLUSION: Long-standing therapy with insulin glargine was associated with a lower odds of having any fractures compared to NPH insulin. Further studies are required to investigate whether the lower chance is due to a reduced frequency of hypoglycemia. PMID- 26929657 TI - The macrophages in rheumatic diseases. AB - Macrophages belong to the innate immune system giving us protection against pathogens. However it is known that they are also involved in rheumatic diseases. Activated macrophages have two different phenotypes related to different stimuli: M1 (classically activated) and M2 (alternatively activated). M1 macrophages release high levels of pro-inflammatory cytokines, reactive nitrogen and oxygen intermediates killing microorganisms and tumor cells; while M2 macrophages are involved in resolution of inflammation through phagocytosis of apoptotic neutrophils, reduced production of pro-inflammatory cytokines, and increased synthesis of mediators important in tissue remodeling, angiogenesis, and wound repair. The role of macrophages in the different rheumatic diseases is different according to their M1/M2 macrophages phenotype. PMID- 26929658 TI - Class attendance and cardiology examination performance: a study in problem-based medical curriculum. AB - BACKGROUND AND AIMS: Information on the effect of students' class attendance on examination performance in a problem-based learning medical curriculum is limited. This study investigates the impact of different educational activities on students' academic performance in a problem-based learning curriculum. METHODS: This is a retrospective cohort study conducted on the cardiology block at the College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia. All students who undertook the cardiology block during the academic year 2011-2012 were included. The students' attendance was measured using their overall attendance percentage. This percentage is a product of their attendance of many activities throughout the block. The students' performance was assessed by the final mark obtained, which is a product of many assessment elements. Statistical correlation between students' attendance and performance was established. RESULTS: A total of 127 students were included. The average lecture attendance rate for the medical students in this study was found to be 86%. A significant positive correlation was noted between the overall attendance and the accumulated students' block mark (r=0.52; P<0.001). Students' attendance to different education activities was correlated to their final mark. Lecture attendance was the most significant predictor (P<0.001), that is, 1.0% increase in lecture attendance has predicted a 0.27 increase in students' final block mark. CONCLUSION: Class attendance has a positive effect on students' academic performance with stronger effect for lecture attendance compared to attendance in other teaching modalities. This suggests that lecture attendance is critical for learning even when a problem-based learning medical curriculum is applied. PMID- 26929656 TI - Optimal management of collagenous colitis: a review. AB - Collagenous colitis (CC) is an increasingly recognized cause of chronic inflammatory bowel disease characterized by watery non-bloody diarrhea. As a lesser studied inflammatory bowel disease, many aspects of the CC's natural history are poorly understood. This review discusses strategies to optimally manage CC. The goal of therapy is to induce clinical remission, <3 stools a day or <1 watery stool a day with subsequent improved quality of life (QOL). Antidiarrheal can be used as monotherapy or with other medications to control diarrhea. Budesonide therapy has revolutionized treatment and is superior to prednisone, however, the treatment is associated with high-relapse rates and the management of refractory disease is challenging. Ongoing trials will address the safety and efficacy of low-dose maintenance therapy. For those with refractory disease, case reports and case series support the role of biologic agents. Diversion of the fecal stream normalizes colonic mucosal changes and ileostomy may be considered where anti-tumor necrosis factor (TNF)-alpha agents are contraindicated. Underlying celiac disease, bile salt diarrhea, and associated thyroid dysfunction should be ruled out. The author recommends smoking cessation as well as avoidance of nonsteroidal anti-inflammatories as well as other associated medications. PMID- 26929660 TI - Erratum: Integrating complementary/alternative medicine into primary care: evaluating the evidence and appropriate implementation [Corrigendum]. AB - [This corrects the article on p. 361 in vol. 8, PMID: 26673479.]. PMID- 26929659 TI - Diagnosis and treatment of diarrhea-predominant irritable bowel syndrome. AB - Irritable bowel syndrome (IBS) is one of the most common gastrointestinal disorders worldwide. The economic impact of IBS on the health care system is substantial, as is the personal impact on patients. Patients with diarrhea predominant IBS (IBS-D) comprise a substantial proportion of the overall IBS population. Primary care providers are often the first point of contact for patients with IBS-D and can accurately diagnose IBS after a careful history and examination without extensive diagnostic tests. Several pharmacologic treatments (eg, loperamide, alosetron, and antidepressants) and non-pharmacologic treatments (eg, dietary modification and probiotics) are available for IBS-D, but restrictions on use (eg, alosetron) or the lack of controlled trial data showing reductions in both global and individual IBS-D symptoms (eg, bloating, pain and stool frequency) emphasize the need for alternative treatment options. Two newer medications (eluxadoline and rifaximin) were approved in May 2015 for the treatment of IBS-D, and represent new treatment options for this common gastrointestinal condition. PMID- 26929661 TI - Options for perioperative pain management in neurosurgery. AB - Moderate-to-severe pain following neurosurgery is common but often does not get attention and is therefore underdiagnosed and undertreated. Compounding this problem is the traditional belief that neurosurgical pain is inconsequential and even dangerous to treat. Concerns about problematic effects associated with opioid analgesics such as nausea, vomiting, oversedation, and increased intracranial pressure secondary to elevated carbon dioxide tension from respiratory depression have often led to suboptimal postoperative analgesic strategies in caring for neurosurgical patients. Neurosurgical patients may have difficulty or be incapable of communicating their need for analgesics due to neurologic deficits, which poses an additional challenge. Postoperative pain control should be a priority, because pain adversely affects recovery and patient outcomes. Inconsistent practices and the quality of current analgesic strategies for neurosurgical patients still leave room for improvement. Given the complexity of postoperative pain management for these patients, multimodal strategies are often required to optimize pain control and at the same time limit undesired side effects. PMID- 26929662 TI - The pharmacogenomics of pain management: prospects for personalized medicine. AB - Pain is a common symptom that can be complex to treat. Analgesic medications are the mainstay treatment, but there is wide interindividual variability in analgesic response and adverse effects. Pharmacogenomics is the study of inherited genetic traits that result in these individual responses to drugs. This narrative review will attempt to cover the current understanding of the pharmacogenomics of pain, examining common genes affecting metabolism of analgesic medications, their distribution throughout the body, and end organ effects. PMID- 26929663 TI - Endogenous inhibition of pain and spinal nociception in women with premenstrual dysphoric disorder. AB - PURPOSE: Premenstrual dysphoric disorder (PMDD) is characterized by severe affective and physical symptoms, such as increased pain, during the late-luteal phase of the menstrual cycle. The mechanisms underlying hyperalgesia in women with PMDD have yet to be identified, and supraspinal pain modulation has yet to be examined in this population. The present study assessed endogenous pain inhibitory processing by examining conditioned pain modulation (CPM, a painful conditioning stimulus inhibiting pain evoked by a test stimulus at a distal body site) of pain and the nociceptive flexion reflex (NFR, a spinally-mediated withdrawal reflex) during the mid-follicular, ovulatory, and late-luteal phases of the menstrual cycle. METHODS: Participants were regularly-cycling women (14 without PMDD; 14 with PMDD). CPM was assessed by delivering electrocutaneous test stimuli to the sural nerve before, during, and after a painful conditioning ischemia task. Participants rated their pain to electrocutaneous stimuli, and NFR magnitudes were measured. A linear mixed model analysis was used to assess the influence of group and menstrual phase on CPM. RESULTS: Compared with controls, women with PMDD experienced greater pain during the late-luteal phase and enhanced spinal nociception during the ovulation phase, both of which were independent of CPM. Both groups showed CPM inhibition of pain that did not differ by menstrual phase. Only women with PMDD evidenced CPM inhibition of NFR. CONCLUSION: Endogenous modulation of pain and spinal nociception is not disrupted in women with PMDD. Additionally, greater NFR magnitudes during ovulation in PMDD may be due to tonically-engaged descending mechanisms that facilitate spinal nociception, leading to enhanced pain during the premenstrual phase. PMID- 26929665 TI - A urinary test procedure for identification of cannabidiol in patients undergoing medical therapy with marijuana. AB - Marijuana is classified by the Drug Enforcement Agency (DEA) as Schedule I, drugs having no accepted medical value. Twenty-three states and the District of Columbia have legalized medical marijuana. This conflict inhibits physicians from prescribing marijuana and the systematic study of marijuana in medical care. This study concerns the use of the clinical laboratory as a resource for physicians recommending cannabidiol (CBD) to patients, or for patients using medical marijuana. Marijuana containing delta-9-tetrahydrocannabinol (THC) is psychoactive. CBD is not psychoactive. CBD is reported to have medical benefit for seizure control, neurologic disorders including multiple sclerosis, neuropathic pain and pain associated with cancer. Use of opiates leads to increasing dosage over time that may cause respiratory depression. The Medical Board of California has termed this a serious public health crisis of addiction, overdose, and death. Is it feasible that CBD might alleviate persistent, severe pain and therefore diminished opiate use? Further study is needed to determine medical effectiveness of CBD including the effect on concurrent opiate therapy due to competition for receptor sites. This study is the application of a gas chromatography mass spectrometry procedure adapted for use in our laboratory, to detect CBD in urine. The intended use is as a tool for physicians to assess that marijuana being used by a patient is of a composition likely to be medically effective. A law ensuring physicians freedom from federal prosecution would provide confidence essential to formal study of medical uses of marijuana and treatment of clinical problems. Detection of CBD in a urine sample would be a convenient test for such confirmation. PMID- 26929664 TI - The topical 5% lidocaine medicated plaster in localized neuropathic pain: a reappraisal of the clinical evidence. AB - Topical 5% lidocaine medicated plasters represent a well-established first-line option for the treatment of peripheral localized neuropathic pain (LNP). This review provides an updated overview of the clinical evidence (randomized, controlled, and open-label clinical studies, real-life daily clinical practice, and case series). The 5% lidocaine medicated plaster effectively provides pain relief in postherpetic neuralgia, and data from a large open-label controlled study indicate that the 5% lidocaine medicated plaster is as effective as systemic pregabalin in postherpetic neuralgia and painful diabetic polyneuropathy but with an improved tolerability profile. Additionally, improved analgesia and fewer side effects were experienced by patients treated synchronously with the 5% lidocaine medicated plaster, further demonstrating the value of multimodal analgesia in LNP. The 5% lidocaine medicated plaster provides continued benefit after long-term (<=7 years) use and is also effective in various other LNP conditions. Minor application-site reactions are the most common adverse events associated with the 5% lidocaine medicated plaster; there is minimal risk of systemic adverse events and drug-drug interactions. Although further well controlled studies are warranted, the 5% lidocaine medicated plaster is efficacious and safe in LNP and may have particular clinical benefit in elderly and/or medically compromised patients because of the low incidence of adverse events. PMID- 26929667 TI - Influence of core design, production technique, and material selection on fracture behavior of yttria-stabilized tetragonal zirconia polycrystal fixed dental prostheses produced using different multilayer techniques: split-file, over-pressing, and manually built-up veneers. AB - AIM: To investigate and compare the fracture strength and fracture mode in eleven groups of currently, the most commonly used multilayer three-unit all-ceramic yttria-stabilized tetragonal zirconia polycrystal (Y-TZP) fixed dental prostheses (FDPs) with respect to the choice of core material, veneering material area, manufacturing technique, design of connectors, and radii of curvature of FDP cores. MATERIALS AND METHODS: A total of 110 three-unit Y-TZP FDP cores with one intermediate pontic were made. The FDP cores in groups 1-7 were made with a split file design, veneered with manually built-up porcelain, computer-aided design-on veneers, and over-pressed veneers. Groups 8-11 consisted of FDPs with a state-of the-art design, veneered with manually built-up porcelain. All the FDP cores were subjected to simulated aging and finally loaded to fracture. RESULTS: There was a significant difference (P<0.05) between the core designs, but not between the different types of Y-TZP materials. The split-file designs with VITABLOCS((r)) (1,806+/-165 N) and e.max((r)) ZirPress (1,854+/-115 N) and the state-of-the-art design with VITA VM((r)) 9 (1,849+/-150 N) demonstrated the highest mean fracture values. CONCLUSION: The shape of a split-file designed all-ceramic reconstruction calls for a different dimension protocol, compared to traditionally shaped ones, as the split-file design leads to sharp approximal indentations acting as fractural impressions, thus decreasing the overall strength. The design of a framework is a crucial factor for the load bearing capacity of an all-ceramic FDP. The state-of-the-art design is preferable since the split-file designed cores call for a cross-sectional connector area at least 42% larger, to have the same load bearing capacity as the state-of-the-art designed cores. All veneering materials and techniques tested in the study, split-file, over-press, built-up porcelains, and glass-ceramics are, with a great safety margin, sufficient for clinical use both anteriorly and posteriorly. Analysis of the fracture pattern shows differences between the milled veneers and over-pressed or built-up veneers, where the milled ones show numerically more veneer cracks and the other groups only show complete connector fractures. PMID- 26929666 TI - Idiopathic intracranial hypertension: ongoing clinical challenges and future prospects. AB - Idiopathic intracranial hypertension (IIH) is an uncommon disorder characterized by increased intracranial pressure without radiological or laboratory evidence of intracranial pathology except empty sella turcica, optic nerve sheath with filled out cerebrospinal fluid spaces, and smooth-walled nonflow-related venous sinus stenosis or collapse. This condition typically affects obese women. The incidence of IIH is increasing with the rising prevalence of obesity. Persistent headache is the most common symptom. Visual impairment is a serious complication that may not be recognized by the patients. This paper reviews clinical manifestations, diagnostic challenges, and current treatments of IIH in adults. Various imaging modalities have been studied on their validity for detection of IIH and papilledema. This review also includes new studies on medical, surgical, and interventional management of this condition. Acetazolamide and topiramate are the only two medications that have been studied in randomized controlled trials about their efficacy in treatment of IIH. In patients who have severe visual impairment or progressive visual deterioration despite medical management, surgical or interventional treatment may be considered. The efficacy and complications of cerebrospinal fluid diversion, optic nerve sheath fenestration, and endovascular venous stenting reported in the last 3 decades have been summarized in this review. Finally, the prospective aspects of biomarkers and treatments are proposed for future research. PMID- 26929668 TI - A fatal adverse effect of cefazolin administration: severe brain edema in a patient with multiple meningiomas. AB - Cefazolin is commonly administered before surgery as a prophylactic antibiotic. Hypersensitivity to cefazolin is not uncommon, and the symptoms mostly include urticaria, skin reaction, diarrhea, vomiting, and transient neutropenia, which are rarely life threatening. We present a rare case of fatal cefazolin hypersensitivity in a female who was diagnosed with multiple meningiomas and scheduled for craniotomy and tumor removal. Immediately after cefazolin IV administration, the patient developed acute hypertensive crisis, which resolved within 10 minutes after the treatment. This was followed by unexplained metabolic acidosis. The patient then developed severe brain edema 100 minutes later. The patient had facial edema when her face was exposed for the next 30 minutes. A computed tomography scan revealed global brain edema with herniation. She was admitted to the intensive care unit for symptomatic treatment and died 10 days after surgery from multiorgan failure. The serum IgE level was very high (734 IU/mL). Single-dose administration of cefazolin for surgical prophylaxis may lead to rare, fatal adverse reaction. The warning signs are sudden, unexplained metabolic acidosis, hypertensive crisis, tachycardia, and facial angioedema predominating with or without cutaneous symptoms like urticaria. PMID- 26929669 TI - Clinical utility of dronabinol in the treatment of weight loss associated with HIV and AIDS. AB - Since the beginning of the HIV/AIDS epidemic, weight loss has been a common complaint for patients. The use of various definitions defining HIV wasting syndrome has made it difficult to determine its actual prevalence. Despite the use of highly active antiretroviral therapy, it is estimated that the prevalence of HIV wasting syndrome is between 14% and 38%. HIV wasting syndrome may stem from conditions affecting chewing, swallowing, or gastrointestinal motility, neurologic disease affecting food intake or the perception of hunger or ability to eat, psychiatric illness, food insecurity generated from psychosocial or economic concerns, or anorexia due to medications, malabsorption, infections, or tumors. Treatment of HIV wasting syndrome may be managed with appetite stimulants (megestrol acetate or dronabinol), anabolic agents (testosterone, testosterone analogs, or recombinant human growth hormone), or, rarely, cytokine production modulators (thalidomide). The goal of this review is to provide an in-depth evaluation based on existing clinical trials on the clinical utility of dronabinol in the treatment of weight loss associated with HIV/AIDS. Although total body weight gain varies with dronabinol use (-2.0 to 3.2 kg), dronabinol is a well-tolerated option to promote appetite stimulation. Further studies are needed with standardized definitions of HIV-associated weight loss and clinical outcomes, robust sample sizes, safety and efficacy data on chronic use of dronabinol beyond 52 weeks, and associated virologic and immunologic outcomes. PMID- 26929670 TI - Malignant melanoma of the nasal septum, a rare tumor, occurring in a 54-year-old patient after hereditary retinoblastoma treatment. AB - The authors report a case of a malignant melanoma of the nasal cavity that is a rare tumor and very aggressive, constituting 1% of all melanomas. It appeared in a patient 54 years after he was treated for a hereditary retinoblastoma. Its symptoms are nonspecific, and often marked by epistaxis. Its diagnosis is histological, supported by immunohistochemistry. Its prognosis is often unfavorable, and characterized by the occurrence of metastases and recurrences. Because of the risk of secondary cancer that exists in any survivor of hereditary retinoblastoma, we must think of possible mucosal melanoma of the nasal sinus in these patients in cases of chronic epistaxis. The prognosis of this tumor depends on its early diagnosis and surgical treatment. PMID- 26929671 TI - Preservation of retinal structure and function after cilioretinal artery occlusion: a case report. AB - Cilioretinal artery occlusion is a cause of sudden, often catastrophic loss of central vision. There are no established effective treatments. Recently, a patient presented 24 hours after a cilioretinal artery occlusion, following a cardiac catheterization prior to which her blood thinners had been discontinued. Lacking an effective way to address the severe retinal ischemic oxidative stress, she was offered, under compassionate use, a multivitamin complex designed to address retinal ischemia and oxidative stress. Significant components of this product are L-methylfolate and n-acetyl cysteine. The patient experienced a rapid unexpected improvement in vision and preservation of retinal structure, suggesting that marked improvement in retinal artery occlusions outcomes may be possible as late as 24 hours postocclusion. This is the third reported case of cilioretinal artery occlusion associated with cardiac catheterization. PMID- 26929672 TI - Pharmacokinetics of daclizumab high-yield process with repeated administration of the clinical subcutaneous regimen in patients with relapsing-remitting multiple sclerosis. AB - BACKGROUND: Daclizumab high-yield process (DAC HYP), a humanized immunoglobulin G1 monoclonal antibody specific for the alpha subunit (CD25) of the high-affinity interleukin-2 receptor, has demonstrated efficacy for treatment of relapsing forms of multiple sclerosis in Phase II and III clinical trials. OBJECTIVE: To characterize the pharmacokinetics (PK) of DAC HYP following repeated administration of the 150 mg subcutaneous (SC) dose every 4 weeks (q4wk), the proposed clinical regimen in patients with relapsing-remitting multiple sclerosis (RRMS). METHODS: Twenty-six patients with RRMS received DAC HYP 150 mg SC q4wk for a total of six doses. Serial PK blood samples were collected over the first and last dosing intervals and trough PK samples were collected between these doses. Blood samples for immunogenicity assessment were collected throughout the study. Serum DAC HYP levels and anti-DAC HYP antibodies were characterized using validated immunoassays. PK parameters were estimated using noncompartmental analysis. RESULTS: DAC HYP showed slow SC absorption with a median time to reach maximum observed concentration (Cmax) value of ~1 week. Steady state was reached by the fourth injection. At steady state, DAC HYP mean serum Cmax, minimum observed concentration (Cmin), and area under the concentration-time curve within a dosing interval (AUCtau) values were 29.1 ug/mL, 14.9 ug/mL, and 638 ug . day/mL, respectively, with intersubject variability of 35%-40%. The AUC accumulation ratio was ~2.5 at steady state. DAC HYP had a long elimination half life of ~22 days and low apparent clearance (0.274 L/day). Nine patients tested positive for anti-DAC HYP antibodies, with no impact on DAC HYP clearance in this limited data set. CONCLUSION: The PK of DAC HYP in patients with RRMS are consistent with those previously reported in healthy volunteers. The half-life of ~3 weeks and the low fluctuations in peak and trough concentrations of serum DAC HYP support the once-monthly SC dosing regimen. PMID- 26929673 TI - Hand hygiene knowledge and practice among university students: evidence from Private Universities of Bangladesh. AB - Hand hygiene has achieved the reputation of being a convenient means of preventing communicable diseases. Although causal links between hand hygiene and rates of infectious disease have also been established earlier, studies focusing on hand hygiene among university-going students are not adequate in number. This study evaluated handwashing knowledge, practice, and other related factors among the selected university students in the city of Dhaka, Bangladesh. A cross sectional study was conducted among 200 undergraduate students from four selected universities. A pretested, semistructured questionnaire, that included a checklist associated with handwashing practice, was applied to capture all relevant data. The mean (+/- SD) age of the participants was 20.4 (+/-1.8) years. The majority of the students washed their hands with water, but only 22.5% washed their hands effectively by maintaining the correct steps and frequency of handwashing with water, and soap or hand sanitizer. The mean (+/- SD) score of the participants' hand hygiene practice was 50.81 (+/-4.79), while the total score with all perfect answers was considered as 66. Regression coefficient demonstrated that age has a negative influence on hand hygiene practice, as older students have lower scores compared to the younger ones (P<0.01). However, the unmarried students were a significant predictor for influencing the incensement of handwashing practice compared to the married ones (P<0.01). Findings of this study designate widespread insufficient hand hygiene practice in the university going students and indicate a need for an extensive public health education program on this topic. Furthermore, availability of soap and sufficient water supply is needed within the university setting to facilitate handwashing. Therefore, supporting quantity and quality of available campus-based public health education programs along with providing health-washing equipment is suggested. PMID- 26929674 TI - Reducing the risk of music-induced hearing loss from overuse of portable listening devices: understanding the problems and establishing strategies for improving awareness in adolescents. AB - Hearing loss from the overuse of portable listening devices (PLDs), such as MP3 players or iPods, is of great concern in the popular media. This review aims to discuss the current state of scientific knowledge about music-induced hearing loss from PLD use. This report evaluates the literature on the risk to hearing from PLD use, the individual and psychological factors that influence PLD usage, and strategies for reducing exposure to music through PLDs. Specific interventions are reviewed, and several recommendations for designing interventions and for individual intervention in clinical practice are presented. Clinical recommendations suggested include the "80-90 rule" and the use of isolator-style earphones to reduce background noise. PMID- 26929675 TI - Portfolio as a tool to evaluate clinical competences of traumatology in medical students. AB - This article investigates whether a reflexive portfolio is instrumental in determining the level of acquisition of clinical competences in traumatology, a subject in the 5th year of the degree of medicine. A total of 131 students used the portfolio during their clinical rotation of traumatology. The students' portfolios were blind evaluated by four professors who annotated the existence (yes/no) of 23 learning outcomes. The reliability of the portfolio was moderate, according to the kappa index (0.48), but the evaluation scores between evaluators were very similar. Considering the mean percentage, 59.8% of the students obtained all the competences established and only 13 of the 23 learning outcomes (56.5%) were fulfilled by >50% of the students. Our study suggests that the portfolio may be an important tool to quantitatively analyze the acquisition of traumatology competences of medical students, thus allowing the implementation of methods to improve its teaching. PMID- 26929676 TI - Going beyond the situational judgment test: the true impact of the educational performance measure, publications, and extra-degree performance on the foundation program application. PMID- 26929677 TI - Use of intuition by critical care nurses: a phenomenological study. AB - BACKGROUND: Intuition is defined as an irrational unconscious type of knowing. This concept was incorporated into nursing discipline for 3 decades, but nowadays its application is uncertain and ignored by educational institutions. Therefore, this study aimed to explore critical care nurses' understanding of the use of intuition in clinical practice. MATERIALS AND METHODS: In a descriptive phenomenological study, 12 nurses employed in critical care units of the hospitals affiliated with Kermanshah University of Medical Sciences, were recruited to a study using purposive, semistructured interviews, which were then written down verbatim. The data were managed by MaxQDA 10 software and analyzed as qualitative, with Colaizzi's seven-stage approach. RESULTS: Of the 12 nurses who participated in the study, seven (58.3%) were female and married, 88.3% (ten) had a Bachelor of Nursing (BSc) degree, and the means +/- SD of age, job experience, and critical care experience were 36.66+/-7.01, 13.75+/-6.82, and 7.66+/-3.36 years, respectively. We extracted three main themes, namely "patient conditions", "nurse readiness", and "outcome", and seven subthemes - including "clinical signs", "patient behaviors", "prognosis", "being sensitive", "desire to act", "prediction", and "satisfaction" - integral to understanding the use of intuition in clinical practice by critical care nurses. CONCLUSION: The findings showed that some nurses were attracted by the patients' conditions and were more intuitive about them, and following their intuition prepared the nurses to under take more appropriate measures. The positive results that the majority of the nurses experienced convinced them to follow their intuitions more often. PMID- 26929678 TI - Using consensus methods to develop a country-specific Master of Public Health curriculum for the Republic of Maldives. AB - BACKGROUND: Over the last four decades, the health status of Maldivian people improved considerably, as reflected in child and maternal mortality indicators and the eradication or control of many communicable diseases. However, changing disease patterns are now undermining these successes, so the local public health practitioners need new skills to perform effectively in this changing environment. To address these needs, in 2013 the Faculty of Health Sciences of the Maldives National University developed the country's first Master of Public Health (MPH) program. METHODS: The process commenced with a wide scoping exercise and an analysis of the curricular structure of MPH programs of high-ranking universities. Thereafter, a stakeholder consultation using consensus methods reached agreement on overall course structure and the competencies required for local MPH graduates. Subsequently, a working group developed course descriptors and identified local public health research priorities, which could be addressed by MPH students. RESULTS: Ten semistructured interviews explored specific training needs of prospective MPH students, key public health competencies required by local employers and preferred MPH training models. The recommendations informed a nominal group meeting, where participants agreed on MPH core competencies, overall curricular structure and core subjects. The 17 public health electives put forward by the group were prioritized using an online Delphi process. Participants ranked them by their propensity to address local public health needs and the locally available teaching expertise. The first student cohort commenced their MPH studies in January 2014. CONCLUSION: Consensus methods allowed a broad stakeholder engagement with public health curriculum development and the creation of a country-specific curriculum, informed by local realities and needs. PMID- 26929679 TI - Feasibility of Spanish-language acquisition for acute medical care providers: novel curriculum for emergency medicine residencies. AB - INTRODUCTION: Language and cultural barriers are detriments to quality health care. In acute medical settings, these barriers are more pronounced, which can lead to poor patient outcomes. MATERIALS AND METHODS: We implemented a longitudinal Spanish-language immersion curriculum for emergency medicine (EM) resident physicians. This curriculum includes language and cultural instruction, and is integrated into the weekly EM didactic conference, longitudinal over the entire 3-year residency program. Language proficiency was assessed at baseline and annually on the Interagency Language Roundtable (ILR) scale, via an oral exam conducted by the same trained examiner each time. The objective of the curriculum was improvement of resident language skills to ILR level 1+ by year 3. Significance was evaluated through repeated-measures analysis of variance. RESULTS: The curriculum was launched in July 2010 and followed through June 2012 (n=16). After 1 year, 38% had improved over one ILR level, with 50% achieving ILR 1+ or above. After year 2, 100% had improved over one level, with 90% achieving the objective level of ILR 1+. Mean ILR improved significantly from baseline, year 1, and year 2 (F=55, df =1; P<0.001). CONCLUSION: Implementation of a longitudinal, integrated Spanish-immersion curriculum is feasible and improves language skills in EM residents. The curriculum improved EM-resident language proficiency above the goal in just 2 years. Further studies will focus on the effect of language acquisition on patient care in acute settings. PMID- 26929680 TI - A proposal for health care management and leadership education within the UK undergraduate medical curriculum. AB - Health care management and leadership education is an important gap in the undergraduate medical curriculum. Lack of training promotes poor decision making and may lead to inadequate health services, adversely affecting patients. We propose an integrated approach to health care management and leadership education at undergraduate level, to enable doctors to be effective leaders and manage resources appropriately and to ultimately improve patient care. PMID- 26929681 TI - Re-establishing apical patency after obturation with Gutta-percha and two novel calcium silicate-based sealers. AB - OBJECTIVE: Aim of the present study was to evaluate the retreatability and reestablishment of apical patency of two calcium silicate-based sealers, TotalFill BC Sealer (BCS) and mineral trioxide aggregate Fillapex (MTA F), versus AH Plus, when used in combination with Gutta-percha (GP). MATERIALS AND METHODS: The canals of 54 single-rooted anterior teeth were instrumented and filled with GP/AH Plus (Group A), GP/MTA F (Group B), or GP/BCS (Group C) using continuous wave obturation technique. The groups were subdivided into subgroups with the master-GP cone placed to the working length (WL) or intentionally 2 mm short. The retreatment procedures were performed using ultrasonics, chloroform, rotary, and hand files. The ability to establish the patency and reach WL was determined as well as the time taken to reach WL was calculated in minutes. Furthermore, the samples were observed under a dental, optical microscope, after vertically splitting them. RESULTS: The WL and patency were reestablished in 100% of specimens in all groups. The Mann-Whitney U-test indicated that there was a significant difference in the amount of time required to reach WL between the groups (P < 0.05) with group GP/BCS short of the WL showing the most amount of time to be retreated. CONCLUSION: The novel calcium silicate-based sealers are negotiable under simple root canal anatomy. However, the conventional retreatment techniques are not able to fully remove them. PMID- 26929682 TI - Evaluation of the effect of three supplementary oral hygiene measures on salivary mutans streptococci levels in children: A randomized comparative clinical trial. AB - OBJECTIVE: The aim of this study was to evaluate and compare the effect of tongue scraping, tongue brushing, and saturated saline on salivary MS levels. MATERIALS AND METHODS: A single-blinded, randomized, parallel group clinical trial was conducted in children aged 9-12 years. Total sample of 45 subjects were randomly assigned to three groups, that is, Group A, Group B, and Group C comprised of 15 each. Group A, Group B, and Group C were asked to do tongue scraping, tongue brushing and saturated saline rinsing twice daily, respectively for 21 days. Saliva samples, collected from the subjects on the baseline, 7(th) day and 21(st) day, were inoculated on mitis salivarius bacitracin agar and incubated at 37 degrees C for 48 h. The mean streptococcal colony forming counts were enumerated. The data were subjected to statistical analysis using Wilcoxon signed rank sum test for intragroup comparisons and Mann-Whitney U-test for intergroup comparisons. RESULTS: Intragroup comparisons showed statistically significant reduction in MS levels (P < 0.01). However, the intergroup comparisons showed no statistically significant difference (P > 0.05). CONCLUSION: The oral hygiene measures evaluated proved equal efficacy in reducing the colony counts. Hence, there is a need to emphasize the importance of incorporating supplementary oral hygiene measures in daily oral care. PMID- 26929683 TI - Effectiveness of audiovisual distraction eyewear and computerized delivery of anesthesia during pulp therapy of primary molars in phobic child patients. AB - OBJECTIVES: The aim of this study is to assess the effectiveness of audiovisual distraction technique with video eyewear and computerized delivery system intrasulcular (CDS-IS) during the application of local anesthetic in phobic pediatric patients undergoing pulp therapy of primary molars. MATERIALS AND METHODS: This randomized, crossover clinical study includes 60 children, aged between 4 and 7-year-old (31 boys and 29 girls). Children were randomly distributed equally into two groups as A and B. This study involved two treatment sessions of pulp therapy, 1-week apart. During treatment session I, group A had an audiovisual distraction with video eyewear, whereas group B had audiovisual distraction using projector display only without video eyewear. During treatment session II, group A had undergone pulp therapy without video eyewear distraction, whereas group B had the pulp treatment using video eyewear distraction. Each session involved the pulp therapy of equivalent teeth in the opposite sides of the mouth. At each visit scores on the Modified Child Dental Anxiety Scale (MCDAS) (f) were used to evaluate the level of anxiety before treatment. After the procedure, children were instructed to rate their pain during treatment on the Wong Bakers' faces pain scale. Changes in pulse oximeter and heart rate were recorded in every 10 min. RESULTS: From preoperative treatment session I (with video eyewear) to preoperative treatment session II (without video eyewear) for the MCDAS (f), a significant (P > 0.03) change in the mean anxiety score was observed for group A. Self-reported mean pain score decreases dramatically after treatment sessions' with video eyewear for both groups. CONCLUSION: The use of audiovisual distraction with video eyewear and the use of CDS-IS system for anesthetic delivery was demonstrated to be effective in improving children's cooperation, than routine psychological interventions and is, therefore, highly recommended as an effective behavior management technique for long invasive procedures of pulp therapy in young children. PMID- 26929684 TI - Root canal anatomy of mandibular first premolars in an Emirati subpopulation: A laboratory study. AB - OBJECTIVE: The purpose of this study was to determine the root canal anatomy of mandibular first premolar teeth in an Emirati subpopulation using a decalcification and clearing method. MATERIALS AND METHODS: One hundred permanent mandibular first premolar teeth extracted for orthodontic purposes from an Emirati subpopulation from the United Arab Emirates were used for this study. They were subjected to decalcification and clearing. The tooth length, the canal orifice shape, mesial invagination, canal pattern, the location of apex, presence of lateral canals, and intercanal communications were determined. RESULTS: The most common canal pattern was the Vertucci Type I (65%) followed by Type V (14%) and Type IV (13%). The most common type of canal orifice seen was the oval shape (36%) followed by the round shape (25%). Mesial invaginations were seen in 44% of the teeth. The mean tooth length was 19.9 mm, and apical deltas were seen in 24% of teeth. CONCLUSION: The Vertucci Type I canal pattern was the most prevalent in the mandibular first premolars while the occurrence of multiple canals was noted in 35% of this population. PMID- 26929686 TI - Maxillary and mandibular anterior crown width/height ratio and its relation to various arch perimeters, arch length, and arch width groups. AB - OBJECTIVE: To investigate the maxillary and mandibular anterior crown width/height ratio and its relation to various arch perimeters, arch length, and arch width (intercanine, interpremolar, and intermolar) groups. MATERIALS AND METHODS: The calculated sample size was 128 subjects. The crown width/height, arch length, arch perimeter, and arch width of the maxilla and mandible were obtained via digital calliper (Mitutoyo, Japan). A total of 4325 variables were measured. The sex differences in the crown width and height were evaluated. Analysis of variance was applied to evaluate the differences between arch length, arch perimeter, and arch width groups. RESULTS: Males had significantly larger mean values for crown width and height than females (P <= 0.05) for maxillary and mandibular arches, both. There were no significant differences observed for the crown width/height ratio in various arch length, arch perimeter, and arch width (intercanine, interpremolar, and intermolar) groups (P <= 0.05) in maxilla and mandible, both. CONCLUSIONS: Our results indicate sexual disparities in the crown width and height. Crown width and height has no significant relation to various arch length, arch perimeter, and arch width groups of maxilla and mandible. Thus, it may be helpful for orthodontic and prosthodontic case investigations and comprehensive management. PMID- 26929685 TI - Evaluation of the relationship between periodontal risk and carotid artery calcifications on panoramic radiographs. AB - OBJECTIVE: To evaluate if there is a relationship between findings of carotid artery calcification (CAC) and periodontal risk in nonsmoker subjects by using panoramic radiographs (DPR). MATERIALS AND METHODS: A total of 1146 DPRs were investigated. Gender, age, severity of bone loss, tooth loss, periodontal risk, and findings of carotid calcification were recorded. The periodontal risk was evaluated and classified according to the degree of alveolar bone loss. RESULTS: CAC was diagnosed in %13.6 (n: 156) of DPRs. Of 1146 patients, 338 (29.5%) had low, 668 (60%) had moderate, and 120 (10.5%) had high periodontal risk. A statistically significant relation was observed between carotid calcification and periodontal risk. CONCLUSION: Positive findings of carotid calcification may be related with periodontal problems. Clinicians must be careful about diagnosing CACs on DPRs during routine examinations. In the case of positive findings of CAC and periodontitis together, the patient may be consulted to a specialist for further investigation. PMID- 26929687 TI - Anatomic symmetry of root and root canal morphology of posterior teeth in Indian subpopulation using cone beam computed tomography: A retrospective study. AB - OBJECTIVE: To investigate the anatomic symmetry of maxillary and mandibular posteriors in Indian subpopulation using cone beam computed tomography (CBCT). MATERIALS AND METHODS: CBCT images of 246 patients that had at least one noncarious, posterior tooth free of restorations in each quadrant were enrolled for retrospective analysis. A total of 3015 teeth (811 maxillary premolars, 845 mandibular premolars, 738 maxillary molars, and 621 mandibular molars) were analyzed for number of roots and root canals, canal morphology and anatomic symmetry, and concurrent types between the maxilla and mandible. RESULTS: There was no difference in the percentage of symmetry for maxillary first (81.5%) and second (81.5%) premolars. Mandibular second premolars (98.3%) exhibited greater symmetry than mandibular first premolars (96.1%). First molars (77.5% and 82.1%) showed greater symmetry than second molars (70.8% and 78.6%), in both maxillary and mandibular arches, respectively. The most common anatomy observed were: maxillary first premolars - 2 roots with 2 canals, maxillary second premolars - 1 root with 2 canals, mandibular first and second premolars - 1 root with 1 canal, maxillary first and second molars - 3 roots with 4 canals, and mandibular first and second molars - 2 roots with 3 canals. When compared with any other teeth, maximum asymmetry was observed in maxillary second molar (29.2%). CONCLUSION: The percentage of symmetry observed in the present study varied from 70% to 98% with least percentage of symmetry in maxillary second molars. These data should alert the clinicians while treating homonymous teeth of the same patient. PMID- 26929688 TI - Dentinal crack formation during root canal preparations by the twisted file adaptive, Reciproc and WaveOne instruments. AB - OBJECTIVE: This study aimed to compare the frequency of dentinal microcracks after root canal shaping with 2 reciprocating (Reciproc and WaveOne) and 1 combined continuous reciprocating motion twisted files adaptive (TFA) rotary system. MATERIALS AND METHODS: Ninety molars were chosen and divided into three groups of 30 each. Root canal preparation was achieved by using Reciproc R25, Primary WaveOne and TFA systems. All the roots were horizontally sectioned at 15, 9, and 3 mm from the apex. The slices were then viewed each under a microscope at * 25 magnification to determine the presence of cracks. The absence/presence of cracks was recorded, and the data were analyzed with a Chi-square test. The significance level was set at P < 0.05. RESULTS: Instrumentation with Reciproc produced significantly more complete cracks than WaveOne and TFA (P = 0.032). The TFA system produced significantly less cracks then the Reciproc and WaveOne systems apically (P = 0.004). CONCLUSIONS: Within the limits of this study, the TFA system caused less cracks then the full reciprocating system (Reciproc and WaveOne). Single-file reciprocating files produced significantly more incomplete dentinal cracks than full-sequence adaptive rotary motion. PMID- 26929689 TI - Effect of dry cryogenic treatment on Vickers hardness and wear resistance of new martensitic shape memory nickel-titanium alloy. AB - OBJECTIVES: The aim of this study is to investigate the role of dry cryogenic treatment (CT) temperature and time on the Vickers hardness and wear resistance of new martensitic shape memory (SM) nickel-titanium (NiTi) alloy. The null hypothesis tested was that there is no difference in Vickers hardness and wear resistance between SM NiTi alloys following CT under two soaking temperatures and times. MATERIALS AND METHODS: The composition and the phase transformation behavior of the alloy were examined by X-ray energy dispersive spectroscopy and differential scanning calorimetry, respectively. Fifteen cylindrical specimens and 50 sheet specimens were subjected to different CT conditions: Deep cryogenic treatment (DCT) 24 group: -185 degrees C, 24 h; DCT six group: -185 degrees C, 6 h; shallow cryogenic treatment (SCT) 24 group: -80 degrees C, 24 h; SCT six group: -80 degrees C, 6 h; and control group. Wear resistance was assessed from weight loss before and after reciprocatory wet sliding wear. RESULTS: The as received SM NiTi alloy contained 50.8 wt% nickel and possessed austenite finish temperature (Af) of 45.76 degrees C. Reduction in Vickers hardness of specimens in DCT 24 group was highly significant (P < 0.01; Tukey's honest significant difference [HSD]). The weight loss was significantly higher in DCT 24 group (P < 0.05; Tukey's HSD). CONCLUSION: Deep dry CT with 24 h soaking period significantly reduces the hardness and wear resistance of SM NiTi alloy. PMID- 26929690 TI - Knowledge and attitude of dental trauma among dental students in Saudi Arabia. AB - OBJECTIVE: The aim of this study was to assess the level of knowledge and attitude of Saudi dental students in the management of dental trauma in children. MATERIALS AND METHODS: A self-administered questionnaire comprising 17 close ended questions was used in this survey. The questions were divided into three parts including: Personal and professional profile; knowledge assessment; attitude toward dental trauma. Data of 307 respondents were analyzed using SPSS (Statistical Package for Social Studies) version 22.0 (IBM Corporation, Chicago, IL, USA). RESULTS: The response rate was 76.8%. Around 40.3% of students reported attending additional courses about dental trauma with a significant difference between males (57.2%) and females (19.4%). The vast majority of students (95.7%) stressed the importance of dental trauma education. While 77% could correctly identify the media of transportation of an avulsed tooth, only 26.9% of the students knew the proper method of transportation. Regarding the knowledge of immediate replantation, only 67.5% of students responded correctly. CONCLUSION: The present study demonstrates an insufficient knowledge concerning dental trauma management among dental students in Saudi Arabia. This highlights the need to improve the knowledge of dental students regarding dental trauma and its management using a variety of educational methods such as problem-based learning and powering the curriculum concerning those topics of dental trauma. PMID- 26929691 TI - Efficacy of etidronic acid, BioPure MTAD and SmearClear in removing calcium ions from the root canal: An in vitro study. AB - OBJECTIVE: The purpose of this study was to quantify the amount of calcium ions removed from the root canal by etidronic acid (HEBP), BioPure MTAD, and SmearClear using atomic absorption spectrophotometer. MATERIALS AND METHODS: Fifty (n = 50) freshly extracted human mandibular premolar teeth were collected and decoronated at the cementoenamel junction. The canals were prepared in a crown down fashion using the rotary system and copiously irrigated with 1.0% sodium hypochlorite. All specimens were rinsed with the deionized water. Based on the type of chelating agent used, the samples (n = 10) were randomly divided into five (four test and one negative control) groups. Accordingly, Group I - 9% HEBP, Group II - 18% HEBP, Group III - SmearClear, Group IV - BioPure MTAD, and Group V - normal Saline. Subsequent to irrigation, the solution was collected in a test tube and subjected to atomic absorption spectrophotometer for the quantification of calcium ions removed from the root canal. RESULTS: The mean concentration of calcium ions removed from the root canal (mean +/- standard deviation) in all groups (I-V) were 13.32 +/- 0.54 MUg/ml, 16.36 +/- 0.27 MUg/ml, 20.04 +/- 0.24 MUg/ml, 18.15 +/- 0.39 MUg/ml, and 8.74 +/- 0.49 MUg/ml, respectively. CONCLUSIONS: SmearClear was the most effective agent for the removal of calcium ions from the root canal. Hence, its combined use with an organic solvent can be recommended for efficient smear layer removal. PMID- 26929692 TI - In vivo antimicrobial efficacy of 6% Morinda citrifolia, Azadirachta indica, and 3% sodium hypochlorite as root canal irrigants. AB - OBJECTIVE: To evaluate and compare the antimicrobial efficacy of 6% Morinda citrifolia, Azadirachta indica, and 3% sodium hypochlorite (NaOCl) as root canal irrigants. MATERIALS AND METHODS: Thirty nonvital maxillary anteriors were randomly assigned to one of the three groups corresponding to the irrigant to be tested; 6% Morinda citrifolia juice (MCJ) (n = 10), A. indica (n = 10) and 3% NaOCl (n = 10). After the root canal access opening a root canal culture sample was taken with two paper points and cultured under aerobic and anaerobic conditions. Cleaning and shaping were completed with irrigation by 10 mL of respective irrigants and 5 mL of final rinse. The patients were recalled after 3 days and canals were rinsed again with 5 mL of the test irrigants. This was followed by obtaining a posttreatment root canal culture sample and culturing and analyzed by counting the colony forming units (CFUs). RESULTS: Six percentage MCJ, A. indica, and 3% NaOCl showed a significant reduction (P < 0.05) in the mean CFU counts for aerobic and anaerobic bacteria between baseline and 3 days. CONCLUSION: There was no difference in the antimicrobial efficacy of 6% M. citrifolia, A. indica, and 3% NaOCl as root canal irrigants. PMID- 26929693 TI - In vitro evaluation of temperature rise during different post space preparations. AB - OBJECTIVE: The aim of this study was to evaluate temperature alterations on the outer root surface during post space preparation with six different post drills by using an infrared thermometer. MATERIALS AND METHODS: Sixty extracted single rooted human mandibular incisor teeth were used. After root canal obturation, the specimens were divided into six groups (n = 10). During post space preparation, the temperature rises were measured in the middle third of the roots using a noncontact infrared thermometer with a sensitivity of 0.1 degrees C. The temperature data were transferred from the thermometer to the computer and were observed graphically. RESULTS: The maximum temperature rise was observed in Snowpost 2 (29.95 +/- 10.2 degrees C) (P < 0.001), but there were no significant differences among Snowpost 2 (29.95 +/- 10.2 degrees C), Snowpost 1 (24.6 +/- 8.0 degrees C), and Relyx 2 (17.68 +/- 9.1 degrees C) (P > 0.05). CONCLUSIONS: Although water coolant used, the critical temperature rise was observed on the outer root surface in all post drill systems. PMID- 26929694 TI - Psychosocial determinants of dental service utilization among adults: Results from a population-based survey (Urban HEART-2) in Tehran, Iran. AB - OBJECTIVES: To evaluate the association between dental service utilization and mental health in an adult population in the context of the socioeconomic status of the participants. SUBJECTS AND METHODS: Multi-stage cluster random sampling was performed in Tehran, Iran, in 2011. Data were collected on dental service utilization, barriers of dental visit, self-perceived oral health, mental health, age, gender, education, and wealth status. The complex sample analysis method in SPSS and the survey data analysis menu in STATA were employed for statistical evaluation. RESULTS: Of 20,320 participants, 25-36% suffered from disorders in at least one of the domains of somatization, anxiety, social dysfunction, and depression. Only 56% of the participants visited a dentist at least once during the last year. The main barriers to a dental visit were "no perceived need" and "high costs." Females, the richest participants, subjects aged 25-64-year-old, and those with poor self-perceived oral health, mental health disorders, and higher education had more visits. The participants who perceived the need but did not visit a dentist due to some reasons mostly comprised females, those aged 25 44-year-old, those with a poor perceived oral health, disordered people in all domains of mental health, and poorer participants. CONCLUSION: Dental service utilization was influenced by socioeconomic factors and the mental health status of the adult population after controlling for multiple confounders. Reducing financial hardship and providing health education on the importance of preventive visits may decrease barriers to regular visits in countries with developing oral health systems. PMID- 26929695 TI - Evaluation of root morphology and root canal configuration of premolars in the Turkish individuals using cone beam computed tomography. AB - OBJECTIVE: The aim of the present study is to assess the root and root canal morphology of maxillary and mandibular premolars in a Turkish population by using cone beam computed tomography (CBCT). MATERIALS AND METHODS: In this study, CBCT images of 2134 premolars (987 maxillary, 1147 mandibular) were obtained from 404 patients. Details of gender, age, number of roots and canals, and canal configuration in each root were recorded. The canal configuration was classified and evaluated according to Vertucci's criteria. RESULTS: The majority of maxillary premolars had two separate roots; although, three roots were identified in 1% of maxillary first premolars. However, most of the mandibular premolars had a single root. The two canals (69.9%) and type I (62.6%) and type II (34.1%) configuration for upper first premolar, one canal (82.1%) and type I (77.6%) canal configuration for second premolar was the most prevalent root canal frequency. The most prevalent root canal frequency was the one canal (96.2%) and type I (94.2%) and type V (3.2%) configuration for mandibular first premolar, one canal (98.9%) and type I (98.9%) canal configuration for second premolar. There was no difference in the root canal configurations and the numbers of canals between the left and the right side of both females and males (P > 0.05). CONCLUSIONS: Recognition of morphology and anatomy of the root canal system is one of the most important factors for successful endodontic treatment. Preoperative CBCT examination allows determination of root canal configuration of premolar teeth and helps clinicians in root canal treatment. PMID- 26929696 TI - Effects of sealant, viscosity, and bonding agents on microleakage of fissure sealants: An in vitro study. AB - OBJECTIVE: The aim of this study was to evaluate the effects of enamel or dentin bonding agent (DBA) and sealant viscosity on sealant microleakage. MATERIALS AND METHODS: Sixty extracted human premolars were randomly divided into two equal groups (based on sealant viscosity) and each group was divided into three subgroups of 10 teeth. Group 1 (low viscosity sealant, Seal-Rite, Pulpdent, USA with 7.7% filler): Prophylaxis, enameloplasty, etching of occlusal surfaces with 38% of phosphoric acid gel, rinsing and drying, followed by (1) enamel bonding agent (EBA) (Margin Bond, Coltene/Whaledent AG) or (2) DBA (Excite, Ivoclar Vivadent AG, Liechtenstein) or (3) no bonding (NB) prior to sealant application. In Group 2, similar procedures were performed except for applying a high viscosity sealant (Seal-Rite, Pulpdent, The USA with 34.4% filler). Specimens were thermocycled and then immersed in a 0.5% basic fuchsine solution for 24 h next, buccolingual slices of samples were scored under a stereomicroscope. The Kruskal-Wallis and Mann-Whitney U-tests were used for data analysis. RESULTS: There was no significant difference between DBA, EBA, and NB subgroups in the microleakage scores in both groups. Low viscosity sealant had a lower microleakage than the high viscosity sealant in both DBA (P = 0.002) and NB (P = 0.041) subgroups. CONCLUSION: The results indicated that the use of low viscosity sealant reduced the microleakage of pit and fissure sealants. However, the use of a bonding agent before sealant placement didn't affect the microleakage. PMID- 26929697 TI - Awareness assessment in Turkish subpopulation with chronic oral mucosal diseases. AB - OBJECTIVES: The aim of this study was to evaluate the awareness of group Turkish patients with chronic oral mucosal diseases by chronic oral mucosal diseases questionnaires (COMDQ). MATERIALS AND METHODS: Eighty patients with chronic oral mucosal diseases were participated in the study. A detailed medical history of each patient was taken, and all the COMDQ questions, which were translated from English version, were filled out. The data were analyzed with the IBM Statistical Package for Social Sciences Statistics 22.0. RESULTS: The mean ages of patients were 48.91 +/- 13.36 years. Of the total 80 cases of chronic oral mucosal diseases identified 52 (65%) were female and 28 (35%) male. The standardized mean scores for COMDQ were 1.72 +/- 1.11 for "pain and functional limitation," 1.09 +/ 0.94 for "medication and treatment," 2.31 +/- 1.06 for "social and emotional," and 2.27 +/- 0.83 for "patient support," respectively. CONCLUSIONS: The results of this study indicate that the Turkish version of the COMDQ has the profitable psychometric peculiarity and comfortable to patients with chronic oral mucosal diseases in Turkey. PMID- 26929698 TI - Differences between centric relation and maximum intercuspation as possible cause for development of temporomandibular disorder analyzed with T-scan III. AB - OBJECTIVE: To compare subjects from the group with fixed dentures, the group who present temporomandibular disorders (TMDs) and a control group considering centric relation (CR) and maximum intercuspation (MIC)/habitual occlusion (Hab. Occl.) and to analyze the related variables also compared and analyzed with electronic system T-scan III. MATERIALS AND METHODS: A total of 54 subjects were divided into three groups; 17 subjects with fixed dentures, 14 with TMD and 23 controls-selection based on anamnesis-responded to a Fonseca questionnaire and clinical measurements analyzed with electronic system T-scan III. Occlusal force, presented by percentage (automatically by the T-scan electronic system) was analyzed in CR and in MIC. RESULTS: Data were presented as mean +/- standard deviation and differences in P < 0.05 were considered significant. After measurements of the differences between CR and MIC in the three groups were noticed varieties but the P > 0.05 it was not significant in all three groups. CONCLUSION: In our study, it was concluded that there are not statistically significant differences between CR and MIC in the group of individuals without any symptom or sign of TMD although there are noticed in the group with TMD and fixed dentures disharmonic relation between the arches with overload of the occlusal force on the one side. PMID- 26929699 TI - In vitro antimicrobial evaluation of toothpastes with natural compounds. AB - OBJECTIVES: This in vitro study evaluated the antimicrobial effects of commercial toothpastes containing natural compounds. MATERIALS AND METHODS: The study groups were divided based on the natural compound present in the toothpaste composition: Sorbitol (I), tocopherol (II), mint (III), cinnamon/mint (IV), propolis/melaleuca (V), mint/acai (VI), mint/guarana (VII), propolis (VIII), negative control (IX), and the positive control (X). The antimicrobial properties of the toothpastes were tested using the disk diffusion method against oral pathogens: Streptococcus mutans, Pseudomonas aeruginosa, and Enterococcus faecalis. The resulting inhibition halos were measured in millimeters. RESULTS: The data indicated that the bacteria responded differently to the toothpastes (P < 0.0001). The diameters of the inhibition halos against S. mutans were in decreasing order of efficacy: Propolis/melaleuca > mint/guarana > mint/acai > sorbitol > tocopherol > cinnamon/mint > propolis > mint (P < 0.001 vs. negative control). E. faecalis showed variable responses to the dentifrices in the following order of decreasing efficacy: Mint/guarana > propolis > sorbitol > mint/acai > tocopherol > cinnamon/mint > mint = propolis/melaleuca = negative control. The product with the highest antimicrobial activity was mint/guarana, which was significantly different than propolis/melaleuca, mint, cinnamon/mint, and tocopherol and negative control (P < 0.001). The statistical analysis indicated that propolis, sorbitol, and mint/acai did not show any differences compared to mint/guarana (P > 0.05) and positive control (P > 0.05). P. aeruginosa was resistant to all dental gels tested including positive control. CONCLUSION: The toothpastes with natural compounds have therapeutic potential and need more detailed searches for the correct clinic therapeutic application. The results from this study revealed differences in the antimicrobial activities of commercial toothpastes with natural compounds. PMID- 26929700 TI - Hardness and modulus of elasticity of primary and permanent teeth after wear against different dental materials. AB - OBJECTIVES: The purpose of this study was to determine the Young's modulus and the hardness of deciduous and permanent teeth following wear challenges using different dental materials. MATERIALS AND METHODS: Wear challenges were performed against four dental materials: A resin-based fissure sealant (Fluoroshield((r))), a glass ionomer based fissure sealant (Vitremer((r))), and two microhybrid composite resins (Filtek Z250 and P90((r))). Using the pin-on-plate design, a deciduous or a permanent tooth was made into a pin (4 mm * 4 mm * 2 mm) working at a 3 N vertical load, 1 Hz frequency, and 900 cycles (15 min) with Fusayama artificial saliva as a lubricant. Before and after the tribological tests, the hardness and elasticity modulus of the tooth samples were measured by creating a nanoindentation at load forces up to 50 mN and 150 mN. All of the results were statistically analyzed using ANOVA and post-hoc Duncan's tests (P < 0.05). RESULTS: No difference in hardness was encountered between deciduous and permanent teeth (P < 0.05) or modulus of elasticity (P < 0.05) before or after the wear challenges for all of the dental materials tested. CONCLUSIONS: Wear challenges against the studied dental materials did not alter the properties of permanent or deciduous teeth after the application of a 3 N load. PMID- 26929701 TI - Primary failure of eruption combined with bilateral transmigration of mandibular canines, transposition, torus palatinus, and class III incisor relationship: A rare case report. AB - Eruption disorders are numerous varying from delayed to complete failure of eruption. Primary failure of eruption (PFE) is a rare condition that involves arrested eruption of teeth with the absence of local or general contributory factors. Another rare and clinically challenging phenomenon is canine transmigration which is the intra-osseous movement of impacted canines across the midline. This report presents the first case of combined failure of eruption of multiple teeth with bilateral mandibular canine transmigration, transposition of upper canine and the first premolar, torus palatinus, and class III incisor relationship in a 33-year-old asymptomatic and nonsyndromic female patient. PMID- 26929702 TI - Dentigerous cyst in a young child. AB - Dentigerous cyst is a type of odontogenic cysts and generally occurs in the ages of twenties or thirties. Dentigerous cyst always includes a tooth which cannot complete the eruption process and occurs around the crown by the fluid accumulation between the layers of enamel organ. In rare cases, dentigerous cyst occurs in the first decade of life and develops in an immature permanent tooth as a result of a chronic inflammation of overlying nonvital primary tooth. In this report, a case of dentigerous cyst in primary dentition in a 5-year-old child patient and its treatment were presented. The dentigerous cyst was totally enucleated, and the unerupted permanent first premolar tooth was removed from the primary mandibular right premolar region. There was no recurrence observed after 18 months follow-up. PMID- 26929703 TI - Localized idiopathic root resorption in the primary dentition: Review of the literature and a case report. AB - Idiopathic root resorption (IRR) is an infrequent condition that is usually found as an accidental finding on radiography. A significant number of cases of IRR in permanent dentition have been presented but are rarely reported in primary dentition. The aim of this case report is to present a case of localized IRR in a 7-year-old boy. The patient was referred because of increased mobility of the left mandibular primary second molar. On radiographic evaluation, severe root resorption of that tooth, and mild root resorption of the right mandibular primary second molar were evident; the patient was caries-free. The left affected tooth was lost, and after placing a band and loop space maintainer, the patient was followed for 18 months. A patient with an abnormal pattern of root resorption, especially in the primary dentition, should alert the clinician to rule out the known important local and systemic factors. The exact causes of and treatments for IRR continue to be discovered. PMID- 26929704 TI - Clear double layer Bioplast feeding plate for neonates with cleft palate. AB - An infant with cleft palate was referred to cleft clinic of the Orthodontic Department. The mother was concerned to feed the child because of the escape of milk from the nose. Intraoral examination revealed a large palatal cleft extending from hard to soft palate involving uvula. The impression was taken and dental cast obtained. A 3 mm soft and afterward a 1 mm hard Bioplast plate was pressed using Biostar device (Scheu-Dental Gmbh, Iserlohn, Germany) on the model. Finally, a hole was prepared on the anterior part to put a thread through it. The infant tolerated the plate immediately and encounters no difficulties during feeding. The inlaying soft Bioplast plates eliminate the risk of tissue irritation, whereas the covering hard Bioplast plate supplies endurance. The fabrication of the clear Bioplast feeding plate is easy and less time-consuming compared with acrylic plates and may be recommended in crowded and overloaded cleft centers. PMID- 26929705 TI - Allergic effects of the residual monomer used in denture base acrylic resins. AB - Denture base resins are extensively used in dentistry for a variety of purposes. These materials can be classified as chemical, heat, light, and microwave polymerization materials depending upon the factor which starts the polymerization reaction. Their applications include use during denture base construction, relining existing dentures, and for fabrication of orthodontic removable appliances. There have been increased concerns regarding the safe clinical application of these materials as their biodegradation in the oral environment leads to harmful effects. Along with local side effects, the materials have certain occupational hazards, and numerous studies can be found in the literature mentioning those. The purpose of this article is to outline the cytotoxic consequences of denture base acrylic resins and clinical recommendations for their use. PMID- 26929707 TI - Preservation of iridescent colours in Phorinia Robineau-Desvoidy, 1830 (Diptera: Tachinidae). AB - BACKGROUND: Iridescent blue-green colours are exhibited by various organisms including several taxa in the Tachinidae (Diptera) with notable examples within the Afrotropical members of the genus Phorinia Robineau-Desvoidy, 1830. The vivid colouration observed in life quickly fades to a dull golden-yellow when a specimen is dried. Although well known, no published explanation has been given for this phenomenon. NEW INFORMATION: We illustrate the mechanism associated with this colour change. We also test and propose technical alternatives to retain the living colours in dried specimens. PMID- 26929706 TI - World checklist of hornworts and liverworts. AB - A working checklist of accepted taxa worldwide is vital in achieving the goal of developing an online flora of all known plants by 2020 as part of the Global Strategy for Plant Conservation. We here present the first-ever worldwide checklist for liverworts (Marchantiophyta) and hornworts (Anthocerotophyta) that includes 7486 species in 398 genera representing 92 families from the two phyla. The checklist has far reaching implications and applications, including providing a valuable tool for taxonomists and systematists, analyzing phytogeographic and diversity patterns, aiding in the assessment of floristic and taxonomic knowledge, and identifying geographical gaps in our understanding of the global liverwort and hornwort flora. The checklist is derived from a working data set centralizing nomenclature, taxonomy and geography on a global scale. Prior to this effort a lack of centralization has been a major impediment for the study and analysis of species richness, conservation and systematic research at both regional and global scales. The success of this checklist, initiated in 2008, has been underpinned by its community approach involving taxonomic specialists working towards a consensus on taxonomy, nomenclature and distribution. PMID- 26929709 TI - New records of chalcidid (Hymenoptera: Chalcididae) pupal parasitoids from India. AB - BACKGROUND: Chalcidids are one of the most important parasitoids of pupae of agriculturally important pests belonging to orders like Lepidoptera, Diptera, Coleoptera and Hymenoptera. Such an important group has not been studied consistently by any team of workers from any country apart from the notable contributions by Boucek, Steffan, Delvare and Narendran. (Boucek 1988, Steffan 1973, Delvare 1992 and Narendran 1989). On a personal note, Dr. John S Noyes of Natural History Museum London agrees with this view as expressed with the second author and hence we felt that we can initiate further work on this group within India. We currently hold hundreds of unidentified specimens of this family in our department collection confirming that we will have much work to do over a long period of time. NEW INFORMATION: New distribution records of Chalcididae from Andhra Pradesh (Brachymeria megaspila, B. minuta, Dirhinus anthracia and D. auratus), Bihar (B. podagrica, B. excarinata, B. hearseyi, D. anthracia, D. auratus, D. pilifer, Epitranus erythrogaster and Psilochalcis carinigena), Karnataka (B. apicicornis), Manipur (B. euploeae, D. auratus and E. erythrogaster), Mizoram (B. euploeae and D. anthracia), Nagaland (B. euploeae), Himachal Pradesh (B. alternipes), and Tamil Nadu (B. apicicornis, D. anthracia, D. deplanatus, D. pilifer, D. bakeri, E. observator, E. elongatulus, P. keralensis and P. soudanensis) and union territories Andaman & Nicobar Islands (B. podagrica, B. excarinata, E. erythrogaster and P. carinigena) and Pudhucherry (B. albicrus, D. anthracia, D. auratus, E. erythrogaster and P. kerelensis) are documented from the unidentified material mentioned above. PMID- 26929708 TI - Checklist of the subfamily Adoncholaiminae Gerlach and Riemann, 1974 (Nematoda: Oncholaimida: Oncholaimidae) of the world: genera, species, distribution, and reference list for taxonomists and ecologists. AB - BACKGROUND: Adoncholaiminae is one of the seven subfamilies in the free-living aquatic nematode family Oncholaimidae. Nematodes in Adoncholaiminae are found from various water environment of the world. However, a checklist of all Adoncholaiminae species including full literature, especially information of experimental (not taxonomic) works, has not been updated for more than 40 years. NEW INFORMATION: A revised checklist of the subfamily Adoncholaiminae of the world is provided. It contains 31 valid and 13 invalid species names in four genera with synonyms, collection records, and full literature from 1860's to 2015 for each species. A literature survey of total 477 previous papers was conducted in this work, and 362 of them are newly added to checklist. PMID- 26929710 TI - Spider diversity (Arachnida: Araneae) in Atlantic Forest areas at Pedra Branca State Park, Rio de Janeiro, Brazil. AB - BACKGROUND: There has never been any published work about the diversity of spiders in the city of Rio de Janeiro using analytical tools to measure diversity. The only available records for spider communities in nearby areas indicate 308 species in the National Park of Tijuca and 159 species in Marapendi Municipal Park. These numbers are based on a rapid survey and on an one-year survey respectively. NEW INFORMATION: This study provides a more thorough understanding of how the spider species are distributed at Pedra Branca State Park. We report a total of 14,626 spider specimens recorded from this park, representing 49 families and 373 species or morphospecies, including at least 73 undescribed species. Also, the distribution range of 45 species was expanded, and species accumulation curves estimate that there is a minimum of 388 (Bootstrap) and a maximum of 468 species (Jackknife2) for the sampled areas. These estimates indicates that the spider diversity may be higher than observed. PMID- 26929711 TI - Snake richness in urban forest fragments from Niteroi and surroundings, state of Rio de Janeiro, southeastern Brazil. AB - BACKGROUND: The Atlantic Forest is a hotspot for biodiversity, an area which houses high species richness and endemism, but with high level of threat. With reference to the herpetofauna, until recently there has been no detailed information regarding diversity of snakes recorded in the Atlantic Forest, the number of endemic species and their distribution ranges. While these basic data were missing, large areas of original forest have continued to be lost to increased urbanization and human population, representing a severe threat to the biodiversity. NEW INFORMATION: We recorded 28 snake species in our study area. Dipsadidae was the richest family with 14 species, followed by Colubridae (eight species), Boidae (two species), Viperidae (two species), and Anomalepididae, Elapidae and Typhlopidae (one species each). Most species were forest inhabitants (61%), of which 13 are endemic to the Atlantic Forest. There were no clearly defined species clusters regarding species composition. None of the species recorded in Niteroi are listed as threatened in the Brazilian Redlist. However, most of them are strongly associated with forested areas and, perhaps, are not adapted to live in small fragments. Thus, more initiatives should be implemented to evaluate the true conservation status of these species in order to better protect them. PMID- 26929712 TI - New and poorly known Holarctic species of Boletina Staeger, 1840 (Diptera, Mycetophilidae). AB - BACKGROUND: The genus Boletina is a species rich group of fungus gnats. Members of the genus are mainly known from temperate, boreal and arctic biomes. Phylogeny of the genus is still poorly resolved, dozens of species are insufficiently described and undescribed species are often discovered, especially from samples taken from the boreal zone. NEW INFORMATION: Four new species are described. Boletina valteri Salmela sp.n. (Finland), Boletina kullervoi Salmela sp.n. (Finland), B. hyperborea Salmela sp.n. (Finland, Norway, Sweden, Canada) and B. nuortti Salmela sp.n. (Finland). Boletina arctica Holmgren is redescribed and reported for the first time from the Canadian high arctic zone. Boletina borealis Zetterstedt and B. birulai Lundstrom are reported for the first time from Canada. Boletina subnitidula Sasakawa (syn. n.) is proposed as a junior synonym of B. pallidula Edwards. PMID- 26929713 TI - Abyssal fauna of the UK-1 polymetallic nodule exploration claim, Clarion Clipperton Zone, central Pacific Ocean: Echinodermata. AB - We present data from a DNA taxonomy register of the abyssal benthic Echinodermata collected as part of the Abyssal Baseline (ABYSSLINE) environmental survey cruise 'AB01' to the UK Seabed Resources Ltd (UKSRL) polymetallic-nodule exploration claim 'UK-1' in the eastern Clarion-Clipperton Zone (CCZ), central Pacific Ocean abyssal plain. Morphological and genetic data are presented for 17 species (4 Asteroidea, 4 Crinoidea, 2 Holothuroidea and 7 Ophiuroidea) identified by a combination of morphological and genetic data. No taxa matched previously published genetic sequences, but 8 taxa could be assigned to previously-described species based on morphology, although here we have used a precautionary approach in taxon assignments to avoid over-estimating species ranges. The Clarion Clipperton Zone is a region undergoing intense exploration for potential deep-sea mineral extraction. We present these data to facilitate future taxonomic and environmental impact study by making both data and voucher materials available through curated and accessible biological collections. PMID- 26929714 TI - Records of larentiine moths (Lepidoptera: Geometridae) collected at the Station Linne in Sweden. AB - BACKGROUND: The island of Oland, at the southeast of Sweden, has unique geological and environmental features. The Station Linne is a well-known Oland research station which provides facilities for effective studies and attracts researchers from all over the world. Moreover, the station remains a center for ecotourism due to extraordinary biodiversity of the area. The present paper is aimed to support popular science activities carried out on the island and to shed light on diverse geometrid moth fauna of the Station Linne. NEW INFORMATION: As an outcome of several research projects, including the Swedish Malaise Trap Project (SMTP) and the Swedish Taxonomy Initiative (STI) conducted at the Station Linne, a list of larentiine moths (Lepidoptera: Geometridae) collected on the territory of the station is presented. Images of moths from above and underside are shown. Of the totally 192 species registered for Sweden, 41 species (more than 21%) were collected in close proximity to the main building of the Station Linne. Malaise trap sampling of Lepidoptera is discussed. PMID- 26929715 TI - An online taxonomic database of the stick insect (Phasmida) egg-parasitising subfamilies Amiseginae and Loboscelidiinae (Hymenoptera: Chrysididae). AB - BACKGROUND: The wasp subfamilies Amiseginae and Loboscelidiinae (Hymenoptera: Chrysididae) were last catalogued in Kimsey and Bohart (1991). The subfamilies are considered to be obligate egg parasitoids of the Phasmida (stick insects), which are known to be pests in many areas of the world (Baker 2015). Our lack of knowledge of these wasps, in particular their host associations and host specificity, prevents studies into using them as potential control agents for pest phasmids. Phasmids are popular throughout the world with people from a wide range of backgrounds, from pet keepers to professional entomologists. NEW INFORMATION: A taxonomic database of the subfamilies Amiseginae and Loboscelidiinae has been created as the Chrysididae SpeciesFile, summarising the current state of scientific knowledge about these groups. In addition, a bibliography of works on these subfamilies has been created. In total information is provided for 187 valid species. PMID- 26929716 TI - Two newly recorded genera and species of Owlflies (Neuroptera: Ascalaphidae) from China. AB - BACKGROUND: The records of genus Bubopsis McLachlan, 1898 with species Bubopsis tancrei Weele, 1908 and the genus Nousera Navas, 1923 with species Nousera gibba Navas, 1923 have not been published in China. NEW INFORMATION: The genus Bubopsis McLachlan, 1898 with species Bubopsis tancrei Weele, 1908 and the genus Nousera Navas, 1923 with species Nousera gibba Navas, 1923 are recorded for the first time from China. We provide detailed descriptions and illlustrations of specimens and the collecting information of the specimens are also provided. PMID- 26929717 TI - First report of Tequus schrottkyi (Konow) (Hymenoptera: Pergidae) in Uruguay, and information about its host plant and biology. AB - BACKGROUND: The sawfly family Pergidae is best represented in South America, and it is the third largest family in the suborder Symphyta. Tequus is a Neotropical genus that has been reported in association with host plants of the genus Solanum (Solanaceae), with little information about the life history of its members. Tequus schrottkyi (Konow, 1906) was described from Paraguay, without any information about its biology and host plant. NEW INFORMATION: We report the first record of T. schrottkyi from Uruguay, with information on its host plant and details of its biology. The identification was based on morphology, DNA barcode is provided to allow identification using molecular characters. This sawfly species is associated with Solanum commersonii, a native plant common in Uruguay. Tequus schrottkyi presents several generations between March and July. The larvae feed on leaves and spin a silk cocoon in the soil in which they pupate. The adults exhibit sexual dimorphism, the female being larger than the male and with a different color pattern. The eggs are laid individually in the leaf margins into the leaf tissue. The larvae are unpalatable to a generalist predator, possibly due to defensive compounds sequestered from their host plant, known to contain toxic compounds. PMID- 26929718 TI - The Meristogram: a neglected tool for acanthocephalan systematics. AB - BACKGROUND: The hooks of the acanthocephalan proboscis exhibit serial variation in size and shape. The Meristogram was developed by Huffman and Bullock (1975) to provide a graphical representation of this positional variation in hook morphology. Initial studies demonstrated the ability of the Meristogram to discriminate species within the genera Echinorhynchus and Pomphorhynchus (Huffman and Bullock 1975, Huffman and Nickol 1978, Gleason and Huffman 1981). However, the reliability of the method for taxonomic work was questioned by Shostak et al. (1986) after they found intra-specific variation in two Echinorhynchus species. Uncertainty about the usefulness of the Meristogram and the absence of a readily available software implementation of the algorithm, might explain why this abstract proboscis character has yet to be adopted by acanthocephalan systematists. NEW INFORMATION: The Meristogram algorithm was implemented in the R language and a simple graphical user interface created to facilitate ease of use (the software is freely available from https://github.com/WaylandM/meristogram). The accuracy of the algorithm's formula for calculating hook cross-sectional area was validated by data collected using a digitizing tablet. Meristograms were created from data in public respositories for eight Echinorhynchus taxa: E. bothniensis, E. 'bothniensis', E. gadi spp. A, B and I, E. brayi, E. salmonis and E. truttae. In this preliminary analysis, the meristogram differentiated E. bothniensis, E. brayi, E. gadi sp. B, E. salmonis and E. truttae from each other, and from the remaining taxa in this study, but independent data will be required for validation. Sample sizes for E. 'bothniensis' and E. gadi spp. A and I were too small to identify diagnostic features with any degree of confidence. Meristogram differences among the sibling species of the E. gadi and E. bothniensis groups suggest that the 'intra-specfic' variation in meristogram previously reported for some Echinorhynchus taxa, may have actually represented morphological divergence between unrecognized cryptic species. Hierarchical clustering of taxa based on Meristogram data yielded dendrograms that were largely concordant with phylogenetic relationships inferred from DNA sequence data, indicating the presence of a strong phylogenetic signal. PMID- 26929719 TI - New records of Trichoceridae (Diptera) from the island of Mallorca . AB - BACKGROUND: The Trichoceridae are a small family distributed mainly in the Holarctic Region, most of which are associated with cold seasons and even snow. From the Iberian peninsula, 5 species have been recorded; however only a single previous occurence record exists from the Balearic islands. NEW INFORMATION: In this paper we present new records of two species from Mallorca, of which Trichocera (Saltrichocera) saltator (Harris, 1776) has not previously been recorded from the Balearic islands. Trichocera (Saltrichocera) annulata Meigen, 1818 is recorded for the first time from Mallorca. We furthermore discuss the species' distributions within the Mediterranean region and report new morphological data for the Mallorca island form of T. saltator. PMID- 26929720 TI - Two new bee-killing flies from Brazil (Insecta: Diptera: Phoridae: Melaloncha). AB - BACKGROUND: The genus Melaloncha is a large group of species of parasitoid phorid flies that attack Hymenoptera, mostly stingless bees (Meliponinae, Apidae) in the Neotropical Region. NEW INFORMATION: Two new Brazilian species, Melaloncha (Melaloncha) peacockorum sp. n. and Melaloncha (Udamochiras) nielsi sp. n., are described and their identification clarified. PMID- 26929721 TI - New records of Sylvicola (Diptera: Anisopodidae) from Romania. AB - BACKGROUND: Anisopodidae (window gnats or wood gnats) is a small family of nematocerous Diptera. Until now only Sylvicola (Anisopus) punctatus (Fabricius, 1787) and Sylvicola (Sylvicola) fenestralis (Scopoli, 1763) were reported from Romania. NEW INFORMATION: New faunistic records of Sylvicola (Diptera: Anisopodidae) are presented. Sylvicola (Sylvicola) cinctus (Fabricius, 1787) and S. (Anisopus) fuscatus (Fabricius, 1775) are recorded from Romania for the first time. An identification key and illustrations of Romanian Sylvicola species are presented. PMID- 26929722 TI - Control of type 2 diabetes in King Abdulaziz Housing City (Iskan) population, Saudi Arabia. AB - OBJECTIVE: To assess the level of control and prevalence of type 2 diabetes in King Abdulaziz Housing City (Iskan) population of Saudi Arabia. MATERIALS AND METHODS: Retrospective cross-sectional study conducted in a primary-care setting. All Type 2 diabetics referred to our diabetes center between January 2011 and January 2015 were identified, and their computerized records reviewed. Glycated hemoglobin levels (HbA1c), low-density lipoprotein (LDL), blood pressure (BP), and the albumin-creatinine ratio (ACR) were noted and the patients categorized accordingly. Demographic data (age and gender) were also documented. Inactive patients (not seen for more than 2 years) were excluded. RESULTS: The overall prevalence of type 2 diabetes for all age groups in ISKAN population was 3.25%. About 56% of the diabetics were female and 70% were aged between 18 and 59 years. The rate of uncontrolled diabetes was 59.3%. Males were more likely to have uncontrolled diabetes (odds ratio: 1.44, CI: 1.17-1.76, P = 0.0004). Forty percent of the diabetics had an LDL above target (>=2.6 mmol/l) while 25.9% had uncontrolled hypertension (BP >= 140/90). Of those who had an ACR test done within the last year (59.3%), the rate of micro- and macro-albuminuria was 8.8% and 2.5%, respectively. CONCLUSIONS: The overall prevalence of type 2 diabetes in our community seems lower than the previously reported national figures. An alarming number of diabetics in our population have an uncontrolled disease. More stringent diabetes annual review and recall program is needed to control diabetes and reduce complications. PMID- 26929723 TI - Socioeconomic factors affecting patients' utilization of primary care services at a Tertiary Teaching Hospital in Riyadh, Saudi Arabia. AB - BACKGROUND: Primary care services utilization is dependent on socioeconomic factors. It is proven that variation in socioeconomic factors result in discrepancies in the use of such services. Admittedly, research is limited on the socioeconomic factors affecting the utilization of primary care services in Saudi Arabia. OBJECTIVES: The aim of this research was to study the effect of the main socioeconomic factors affecting patients' utilization of primary care services at a tertiary teaching hospital, Riyadh, Saudi Arabia. MATERIALS AND METHODS: A cross-sectional study was conducted from January to February 2014 in a primary care clinic of a tertiary teaching hospital in Riyadh city; subjects selected using a random consecutive sampling technique. A self-administered questionnaire in Arabic was given to the participants to collect the data which comprised sociodemographic data, utilization measures, and health needs. The data were analyzed using SPSS version 21. RESULTS: A total of 358 subjects participated in the study. The main factors that best determine the utilization of primary health care clinic in a tertiary teaching hospital were the possession of a health insurance (P = 0.046, odds ratio [OR] = 8.333), and bad self-health-perception (P < 0.014, OR: 2.088). Chronic illness was also associated with higher utilization (OR = 2.003). CONCLUSION: Our results reveal that chronic health problems, self health-perception, and health insurance are the most significant socioeconomic factors affecting the utilization of primary care services. PMID- 26929724 TI - Establishing rapport: Physicians' practice and attendees' satisfaction at a Primary Health Care Center, Dammam, Saudi Arabia, 2013. AB - BACKGROUND: Establishing rapport is an important step in physician-patient communication resulting in a positive effect on patient satisfaction and overall clinical outcomes. However, there is a dearth of studies on the condition of doctor-patient relations in Saudi Arabia. This study was performed to estimate the proportion of physicians who have a good rapport with patients in their practice and the proportion of satisfied attendees. MATERIALS AND METHODS: A cross-sectional study was conducted at a Primary Health Care Center, Dammam, KSA. The data were collected through a structured self-administered questionnaire given to samples of attendees and physicians to estimate patient satisfaction and the practice of rapport by physicians. RESULTS: A total of 374 attendees and 27 physicians participated in the study. The percentage of physicians who had good rapport was 51.9%. Factors that showed significant relationship with rapport practice were: Physician's age (p = 0.016), physician's experience (p = 0.043), and professional status (p = 0.031). The attendees satisfied with their physician's rapport with them were 50.5%. Factors that showed significant relationship with satisfaction were: Attendee's age (p < 0.0001), educational level (p < 0.0001), having a chronic illness (p < 0.0001), having appointment (p < 0.0001), physicians' professional status (p < 0.0001), and a nonsurgical specialty (p < 0.0001). CONCLUSION AND RECOMMENDATION: Physicians' rapport with patients and patients' satisfaction with physicians' empathy is not high. Training is required to optimize physician-patient communication. PMID- 26929725 TI - Diabetic retinopathy and the associated risk factors in diabetes type 2 patients in Abha, Saudi Arabia. AB - OBJECTIVES: To assess the proportion and grades of retinopathy and its risk factors in diabetes type 2 patients. MATERIALS AND METHODS: This was a cross sectional study of 401 type 2 diabetic patients. A questionnaire and checklist were used to collect the data. Retinopathy was diagnosed and graded by fundus photographs and slit lamp examination. The duration of diabetes, age of patients, age at onset of diabetes, body mass index, hemoglobin A1c level, blood pressure, and complications were noted. RESULTS: The mean age of male and female patients was 54.93 and 54.25 years; 57.6% were males. The mean age of onset and mean duration of diabetes were 43.91 and 13.4 years, respectively. The proportion of retinopathy was 36.4%. Grades of retinopathy were: Mild 57.5%, moderate 19.9%, severe nonproliferative 11%, and proliferative retinopathy 11.6%; 7.2% of patients had maculopathy. Retinopathy was significantly associated with older age, younger age at onset, longer duration of disease, poorly controlled blood sugar, hypertension, insulin use; the presence of neuropathy and nephropathy appeared as a significant risk. Younger age at onset, longer duration, and insulin use appeared as the strongest predictors for diabetic retinopathy. CONCLUSIONS: More than a third (36.4%) of the diabetic patients attending a diabetic center had retinopathy. The control of the risk factors may reduce both prevalence and consequences of retinopathy. PMID- 26929726 TI - Social anxiety disorder in Saudi adolescent boys: Prevalence, subtypes, and parenting style as a risk factor. AB - BACKGROUND: Available information on social anxiety disorder (SAD) in adolescents in Saudi Arabia is limited. The objective of the study was to estimate the prevalence, severity, and subtypes of SAD, and parenting style risk factors associated with SAD in the adolescent. MATERIALS AND METHODS: This cross sectional study was conducted in two secondary schools for boys in Abha, Saudi Arabia during the Academic year 2013. To collect the data, a questionnaire eliciting information on background characteristics and parenting style as well as the Liebowitz Social Anxiety Scale Test (LSAS), for the evaluation of SAD, were used. RESULTS: A total of 454 students participated in the study. The age of the participants ranged between 15 and 20 years with a mean of 17.4 years. The prevalence of SAD was 11.7%. Around 36% and 11.4% of the students respectively had severe and more severe forms of SAD. Parenting style such as parental anger, criticism particularly in front of others, exaggerated protection, maltreatment and family provocation emerged as a significant risk factor for SAD. The independent predictors of SAD were a parental provocation and physical or emotional maltreatment by the parent (odds ratio [OR] = 3.97, 95% confidence interval [CI]: 1.90-8.31 and OR = 2.67, 95% CI: 3.17-5.19, respectively). CONCLUSION: The prevalence of SAD in secondary school students at Abha is high. Parenting style risk factors for SAD are modifiable. In this context, a national program to improve mental health in this age group is crucial. PMID- 26929727 TI - Determinants of nonimmunization of children under 5 years of age in Pakistan. AB - BACKGROUND: Child vaccination is perhaps the first line of defense to ensure a healthy society. Unfortunately, the coverage of child vaccination in Pakistan is poor resulting in unnecessary yet preventable deaths. This study investigated the determinants and reasons for not vaccinating children in Pakistan. MATERIALS AND METHODS: The study used the Pakistan Integrated Household Survey/Household Integrated Economic Survey 2001-2002 data. Demographic, distance to health facility, poverty status, literacy and education, and location of residence were used as determinants of nonimmunization of children. Descriptive statistics including frequency distribution, proportions for categorical variables and mean for continuous variables, and logistic regression analysis were done using the Stata 11.0. RESULTS: Almost 7.73% children in Pakistan were never immunized. More than 87.4% of these lived in the rural areas. Prevalence of nonimmunization was highest in Balochistan compared to other provinces. Large households appeared to have increased risk of a child not being vaccinated. Moreover, low literacy and education of the head of the household and the spouse was also associated with low vaccination coverage. Distance from the health facility was found to be another factor related to nonimmunization of children. Increase in per capita income significantly decreased the risk of missing vaccinations. CONCLUSIONS: Prevention and immunization programs should focus more on high-risk regions such as Balochistan and rural areas. Literacy, education, and economic status were among the other significant factors associated with low vaccination rates, which need a special focus in the public policy to achieve the target of a healthy society. PMID- 26929728 TI - Budding adult hypertensives with modifiable risk factors: "Catch them young". AB - BACKGROUND: Since the data of primary hypertension (HT) in children is scanty in India, this study attempted to evaluate HT by a multidimensional investigation of the various risk factors in children and adolescents. MATERIALS AND METHODS: A total of 3906 subjects were recruited, all of whom lived in Chennai, an urban area of Tamil Nadu. The children and adolescents aged from 10 to 17 years were selected by random sampling. The children/adolescents were randomized into one control and further divided into two groups. The National High Blood Pressure Education Program fourth report (2004) and anthropometric body mass index (BMI), food frequency questionnaire (PURE) were followed in the study. RESULTS: Out of 3906 children, 2107 were girls and 1799 boys. On screening, we found 9.5% to be hypertensive with the prevalence rate of boys and girls 8% and 10.8%, respectively. Overall obesity was 2.7%, (boys 2%, girls 3.32%); hypertensives and normotensives were 8.4% and 2.1%, respectively. We found that overweight (odds ratio [OR]: 2.06 [1.40-3.01] 95% confidence interval [CI]), obese children (OR: 1.21 [2.72-6.48] 95% CI), and those with a family history of HT (OR: 1.66 [1.20 2.30] 95% CI) had increased risk of hypertension. Females were 1.39 times (OR: 1.39 [1.11-1.72] 95% CI) more at risk of getting HT. Multivariate analysis showed that obese children/adolescent were four times more likely to have HT than children with normal BMI (OR: 4.67 [3.00-7.26] 95% CI]. CONCLUSION: Family history of HT, obesity, and female gender are associated with a high risk of HT. The prevalence of HT was higher among obese adolescents than among slender subjects. This may be related to their sedentary lifestyle, faulty eating habits, high fat content in the diet and little physical activity. PMID- 26929729 TI - Communication skills in pediatric training program: National-based survey of residents' perspectives in Saudi Arabia. AB - BACKGROUND: Good communication skills and rapport building are considered the cardinal tools for developing a patient-doctor relationship. A positive, healthy competition among different health care organizations in Saudi Arabia underlines an ever increasing emphasis on effective patient-doctor relationship. Despite the numerous guidelines provided and programs available, there is a significant variation in the acceptance and approach to the use of this important tool among pediatric residents in this part of the world. OBJECTIVE: To determine pediatric residents' attitude toward communication skills, their perception of important communication skills, and their confidence in the use of their communication skills in the performance of their primary duties. MATERIALS AND METHODS: A cross sectional study was conducted among all pediatrics trainee residents working in 13 different hospitals in Saudi Arabia. A standardized self-administered questionnaire developed by the Harvard Medical School was used. RESULTS: A total of 297 residents out of all trainees in these centers participated in the data collection. The 283 (95%) residents considered learning communication skills a priority in establishing a good patient-doctor relationship. Thirty four percent reported being very confident with regard to their communication skills. Few residents had the skills, and the confidence to communicate with children with serious diseases, discuss end-of-life issues, and deal with difficult patients and parents. CONCLUSION: Pediatric residents perceive the importance of communication skills and competencies as crucial components in their training. A proper comprehensive communication skills training should be incorporated into the pediatric resident training curriculum. PMID- 26929730 TI - Acute epiploic appendagitis: A rare cause of acute abdomen and a diagnostic dilemma. AB - Acute epiploic appendagitis is a relatively rare cause of lower abdominal pain that clinically mimics other acute abdomen conditions that require surgery such as acute diverticulitis or appendicitis. Here, we report a case of a 50-year-old lady who presented with an unusual lower abdominal pain. Awareness of such a clinical condition with its characteristic imaging findings is important to avoid costly hospitalization, unnecessary antibiotic courses, and the morbidity and mortality associated with surgical procedures. PMID- 26929731 TI - Should family physicians perform frenotomy for neonatal ankyloglossia? PMID- 26929732 TI - Effect of Common Faults on the Performance of Different Types of Vapor Compression Systems. AB - The effect of faults on the cooling capacity, coefficient of performance, and sensible heat ratio, was analyzed and compared for five split and rooftop systems, which use different types of expansion devices, compressors and refrigerants. The study applied multivariable polynomial and normalized performance models, which were developed for the studied systems for both fault free and faulty conditions based on measurements obtained in a laboratory under controlled conditions. The analysis indicated differences in responses and trends between the studied systems, which underscores the challenge to devise a universal FDD algorithm for all vapor compression systems and the difficulty to develop a methodology for rating the performance of different FDD algorithms. PMID- 26929733 TI - Pancreatic Cancer: Current Progress and Future Challenges. AB - Pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer, remains one of the highly lethal malignancies. The highly refractory nature of clinically advanced disease and lack of a reliable biomarker for early detection are major obstructions in improving patient outcome. The recent efforts, however, in understanding the pancreatic tumor biology have resulted in the recognition of novel addictions as well as vulnerabilities of tumor cells and are being assessed for their clinical potential. This special issue highlights some of the recent progress, complexity and challenges towards improving disease outcome in patients with this lethal malignancy. PMID- 26929734 TI - The Landscape of Pancreatic Cancer Therapeutic Resistance Mechanisms. AB - Pancreatic cancer (pancreatic ductal adenocarcinoma, PDA) is infamously moving to the top of the list as one of the most lethal cancers with an overall 5 year survival rate of 7%. Multiple genomic-based and molecular characterization studies of PDA specimens and established animal models have provided the field with multiple targets and a progression model of this disease. Still, to date, the best therapeutic options are surgery and combination cytotoxic therapies. In general, even in the best case scenario (i.e., an early stage diagnosis and a response to a specific therapy), most of these fortunate patients' PDA cells acquire or exert resistance mechanisms and eventually kill the patient. Herein, we touch on a growing field of investigation that focuses on PDA cell therapeutic resistance mechanisms. We examine extrinsic elements (i.e., the tumor microenvironment, hypoxia) to the intrinsic processes within the cell (i.e., post transcriptional gene regulation and somatic mutations) that are important for therapeutic efficacy and resistance. Even as better targeted and personalized approaches move through the clinical trial pipeline the discussed resistance mechanisms will most likely play a role in the management of this deadly disease. PMID- 26929735 TI - The Role of Gastrin and CCK Receptors in Pancreatic Cancer and other Malignancies. AB - The gastrointestinal (GI) peptide gastrin is an important regulator of the release of gastric acid from the stomach parietal cells and it also plays an important role in growth of the gastrointestinal tract. It has become apparent that gastrin and its related peptide cholecystokinin (CCK) are also significantly involved with growth of GI cancers as well as other malignancies through activation of the cholecystokinin-B (CCK-B) receptor. Of interest, gastrin is expressed in the embryologic pancreas but not in the adult pancreas; however, gastrin becomes re-expressed in pancreatic cancer where it stimulates growth of this malignancy by an autocrine mechanism. Strategies to down-regulate gastrin or interfere with its interface with the CCK receptor with selective antibodies or receptor antagonists hold promise for the treatment of pancreatic cancer and other gastrin--responsive tumors. PMID- 26929736 TI - Molecular Biomarkers of Pancreatic Intraepithelial Neoplasia and Their Implications in Early Diagnosis and Therapeutic Intervention of Pancreatic Cancer. AB - Lack of early detection and effective interventions is a major reason for the poor prognosis and dismal survival rates for pancreatic cancer. Pancreatic intraepithelial neoplasia (PanIN) is the most common precursor of invasive pancreatic ductal adenocarcinoma (PDAC). Each stage in the progression from PanIN to PDAC is well characterized by multiple significant genetic alterations affecting signaling pathways. Understanding the biological behavior and molecular alterations in the progression from PanIN to PDAC is crucial to the identification of noninvasive biomarkers for early detection and diagnosis and the development of preventive and therapeutic strategies for control of pancreatic cancer progression. This review focuses on molecular biomarkers of PanIN and their important roles in early detection and treatment of pancreatic cancer. PMID- 26929737 TI - Neutrophil-Derived Proteases in the Microenvironment of Pancreatic Cancer -Active Players in Tumor Progression. AB - A hallmark of pancreatic ductal adenocarcinoma (PDAC) is the fibro-inflammatory microenvironment, consisting of activated pancreatic stellate cells, extracellular matrix proteins, and a variety of inflammatory cells, such as T cells, macrophages, or neutrophils. Tumor-infiltrating immune cells, which are found in nearly all cancers, including PDAC, often fail to eliminate the tumor, but conversely can promote its progression by altering the tumor microenvironment. Pancreatic cancer cells are able to attract polymorphonuclear neutrophils (PMN) via tumor secreted chemokines and in human PDAC, PMN infiltrates can be observed in the vicinity of tumor cells and in the desmoplastic tumor stroma, which correlate with undifferentiated tumor growth and poor prognosis. The behavior of tumor-infiltrating neutrophils in the tumor micromilieu is not yet understood at a mechanistic level. It has been shown that PMN have the potential to kill tumor cells, either directly or by antibody dependent cell-mediated cytotoxicity, but on the other side various adverse effects of PMN, such as promotion of aggressive tumor growth with epithelial-to mesenchymal transition and increased metastatic potential, have been described. Recent therapeutic approaches for PDAC focus not only the tumor cell itself, but also elements of the tumor microenvironment. Therefore, the role of PMN and their derived products (e.g. cytokines, proteases) as a new vein for a therapeutic target should be critically evaluated in this context. This review summarizes the current understanding of the interplay between proteases of tumor-infiltrating neutrophils and pancreatic tumor cells and elements of the desmoplastic stroma. PMID- 26929738 TI - Pancreatic Cancer Genetics. AB - Although relatively rare, pancreatic tumors are highly lethal [1]. In the United States, an estimated 48,960 individuals will be diagnosed with pancreatic cancer and 40,560 will die from this disease in 2015 [1]. Globally, 337,872 new pancreatic cancer cases and 330,391 deaths were estimated in 2012 [2]. In contrast to most other cancers, mortality rates for pancreatic cancer are not improving; in the US, it is predicted to become the second leading cause of cancer related deaths by 2030 [3, 4]. The vast majority of tumors arise in the exocrine pancreas, with pancreatic ductal adenocarcinoma (PDAC) accounting for approximately 95% of tumors. Tumors arising in the endocrine pancreas (pancreatic neuroendocrine tumors) represent less than 5% of all pancreatic tumors [5]. Smoking, type 2 diabetes mellitus (T2D), obesity and pancreatitis are the most consistent epidemiological risk factors for pancreatic cancer [5]. Family history is also a risk factor for developing pancreatic cancer with odds ratios (OR) ranging from 1.7-2.3 for first-degree relatives in most studies, indicating that shared genetic factors may play a role in the etiology of this disease [6-9]. This review summarizes the current knowledge of germline pancreatic cancer risk variants with a special emphasis on common susceptibility alleles identified through Genome Wide Association Studies (GWAS). PMID- 26929740 TI - The Significance of Ras Activity in Pancreatic Cancer Initiation. AB - The genetic landscape of pancreatic cancer shows nearly ubiquitous mutations of K RAS. However, oncogenic K-Ras(mt) alone is not sufficient to lead to pancreatic ductal adenocarcinoma (PDAC) in either human or in genetically modified adult mouse models. Many stimulants, such as high fat diet, CCK, LPS, PGE2 and others, have physiological effects at low concentrations that are mediated in part through modest increases in K-Ras activity. However, at high concentrations, they induce inflammation that, in the presence of oncogenic K-Ras expression, substantially accelerates PDAC formation. The mechanism involves increased activity of oncogenic K-Ras(mt). Unlike what has been proposed in the standard paradigm for the role of Ras in oncogenesis, oncogenic K-Ras(mt) is now known to not be constitutively active. Rather, it can be activated by standard mechanisms similar to wild-type K-Ras, but its activity is sustained for a prolonged period. Furthermore, if the level of K-Ras activity exceeds a threshold at which it begins to generate its own activators, then a feed-forward loop is formed between K-Ras activity and inflammation and pathological processes including oncogenesis are initiated. Oncogenic K-Ras(mt) activation, a key event in PDAC initiation and development, is subject to complex regulatory mechanisms. Reagents which inhibit inflammation, such as the Cox2 inhibitor celecoxib, block the feed-forward loop and prevent induction of PDAC in models with endogenous oncogenic K-Ras(mt). Increased understanding of the role of activating and inhibitory mechanisms on oncogenic K-Ras(mt) activity is of paramount importance for the development of preventive and therapeutic strategies to fight against this lethal disease. PMID- 26929743 TI - Sean J. Langenfeld, MD, FACS. PMID- 26929742 TI - Moderators of intensive CBT for adolescent panic disorder: the of fear and avoidance. AB - BACKGROUND: Research supports the efficacy of intensive cognitive behavioral therapy (CBT) for the treatment of adolescent panic disorder with or without agoraphobia (PDA). However, little is known about the conditions under which intensive treatment is most effective. The current investigation examined the moderating roles of baseline fear and avoidance in the intensive treatment of adolescent PDA. METHODS: Adolescents with PDA (ages 11-17; N = 54) were randomized to either an intensive CBT treatment (n = 37) or a waitlist control condition (n = 17). PDA diagnosis, symptom severity, and number of feared and avoided situations were assessed at baseline and 6-week post-treatment/post waitlist. Hierarchical regression analyses examined the relative contributions of treatment condition, number of baseline feared or avoided situations, and their interactions in the prediction of post-treatment/waitlist PDA symptoms. RESULTS: The main effect of intensive CBT on post-treatment PDA symptoms was not uniform across participants, with larger treatment effects found among participants with lower, relative to higher, baseline levels of fear and avoidance. CONCLUSIONS: Findings help clarify which adolescents suffering with PDA may benefit most from an intensive treatment format. PMID- 26929744 TI - Approaches to Anorectal Disease. PMID- 26929741 TI - Non-DHFR-mediated effects of methotrexate in osteosarcoma cell lines: epigenetic alterations and enhanced cell differentiation. AB - BACKGROUND: Methotrexate is an important chemotherapeutic drug widely known as an inhibitor of dihydrofolate reductase (DHFR) which inhibits the reduction of folic acid. DHFR-mediated effects are apparently responsible for its primary antineoplastic action. However, other non-DHFR-mediated effects of methotrexate have been recently discovered, which might be very useful in the development of new strategies for the treatment of pediatric malignancies. The principal goal of this study was to analyze the possible impact of clinically achievable methotrexate levels on cell proliferation, mechanisms of epigenetic regulation (DNA methylation and histone acetylation), induced differentiation and the expression of differentiation-related genes in six osteosarcoma cell lines. METHODS: The Saos-2 reference cell line and five other patient-derived osteosarcoma cell lines were chosen for this study. The MTT assay was used to assess cell proliferation, DNA methylation and histone acetylation were detected using ELISA, and western blotting was used for a detailed analysis of histone acetylation. The expression of differentiation-related genes was quantified using RT-qPCR and the course of cell differentiation was evaluated using Alizarin Red S staining, which detects the level of extracellular matrix mineralization. RESULTS: Methotrexate significantly decreased the proliferation of Saos-2 cells exclusively, suggesting that this reference cell line was sensitive to the DHFR mediated effects of methotrexate. In contrast, other results indicated non-DHFR mediated effects in patient-derived cell lines. Methotrexate-induced DNA demethylation was detected in almost all of them; methotrexate was able to lower the level of 5-methylcytosine in treated cells, and this effect was similar to the effect of 5-aza-2'-deoxycytidine. Furthermore, methotrexate increased the level of acetylated histone H3 in the OSA-06 cell line. Methotrexate also enhanced all-trans retinoic acid-induced cell differentiation in three patient derived osteosarcoma cell lines, and the modulation of expression of the differentiation-related genes was also shown. CONCLUSIONS: Overall non-DHFR mediated effects of methotrexate were detected in the patient-derived osteosarcoma cell lines. Methotrexate acts as an epigenetic modifier and has a potential impact on cell differentiation and the expression of related genes. Furthermore, the combination of methotrexate and all-trans retinoic acid can be effective as a differentiation therapy for osteosarcoma. PMID- 26929739 TI - MicroRNA Targeted Therapeutic Approach for Pancreatic Cancer. AB - Pancreatic cancer remains the fourth leading cause of cancer-related death in the US and is expected to be the second leading cause of cancer-related death by 2030. Therefore, it is important to better understand the molecular pathogenesis, phenotypes and features of pancreatic cancer in order to design novel molecularly targeted therapies for achieving better therapeutic outcome of patients with pancreatic cancer. Recently, the roles of microRNAs (miRNAs) in the development and progression of pancreatic cancer became a hot topic in the scientific community of pancreatic cancer research. By conducting miRNA expression profiling, the aberrant expression of miRNAs was revealed in the serum and in cancer tissues from patients with pancreatic cancer. These aberrantly expressed miRNAs are critically correlated with the disease stage, drug resistance, and survival of pancreatic cancer patients. Hence, targeting these tiny molecules, the specific miRNAs, could provide an efficient and optimal approach in the therapy of pancreatic cancer. Indeed, the pre-clinical and in vivo experiments showed that nanoparticle delivery of synthetic oligonucleotides or treatment with natural agents could be useful to modulate the expression of miRNAs and thereby inhibit pancreatic cancer growth and progression, suggesting that targeting miRNAs combined with conventional anti-cancer therapeutics could be a novel therapeutic strategy for increasing drug sensitivity and achieving better therapeutic outcome of patients diagnosed with pancreatic cancer. PMID- 26929745 TI - Evidence-based Evaluation and Management of Anorectal Disease. PMID- 26929746 TI - Perioperative Management of the Ambulatory Anorectal Surgery Patient. AB - Ambulatory surgery is appropriate for most anorectal pathology. Ambulatory anorectal surgery can be performed at reduced cost compared with inpatient procedures with excellent safety, improved efficiency, and high levels of patient satisfaction. Several perioperative strategies are employed to control pain and avoid urinary retention, including the use of a multimodal pain regimen and restriction of intravenous fluids. Ambulatory anorectal surgery often utilizes standardized order sets and discharge instructions. PMID- 26929747 TI - Complications Following Anorectal Surgery. AB - Anorectal surgery is well tolerated. Rates of minor complications are relatively high, but major postoperative complications are uncommon. Prompt identification of postoperative complications is necessary to avoid significant patient morbidity. The most common acute complications include bleeding, infection, and urinary retention. Pelvic sepsis, while may result in dramatic morbidity and even mortality, is relatively rare. The most feared long-term complications include fecal incontinence, anal stenosis, and chronic pelvic pain. PMID- 26929748 TI - Review of Hemorrhoid Disease: Presentation and Management. AB - Symptomatic hemorrhoid disease is one of the most prevalent ailments associated with significant impact on quality of life. Management options for hemorrhoid disease are diverse, ranging from conservative measures to a variety of office and operating-room procedures. In this review, the authors will discuss the anatomy, pathophysiology, clinical presentation, and management of hemorrhoid disease. PMID- 26929749 TI - Anal Fissure. AB - Anal fissure (fissure-in-ano) is a very common anorectal condition. The exact etiology of this condition is debated; however, there is a clear association with elevated internal anal sphincter pressures. Though hard bowel movements are implicated in fissure etiology, they are not universally present in patients with anal fissures. Half of all patients with fissures heal with nonoperative management such as high fiber diet, sitz baths, and pharmacological agents. When nonoperative management fails, surgical treatment with lateral internal sphincterotomy has a high success rate. In this chapter, we will review the symptoms, pathophysiology, and management of anal fissures. PMID- 26929750 TI - Pruritus Ani. AB - Pruritus ani is a common condition with many different potential causes. Because of this, it can be difficult to treat. It is important to identify and eliminate any inciting factors, which are often unintentional consequences of the patient's attempts to alleviate symptoms. If no reversible cause is found, simple measures with diet modification and perianal hygiene are tried before using topical medications or procedures. PMID- 26929751 TI - Management of Complex Anal Fistulas. AB - Complex anal fistulas require careful evaluation. Prior to any attempts at definitive repair, the anatomy must be well defined and the sepsis resolved. Several muscle-sparing approaches to anal fistula are appropriate, and are often catered to the patient based on their presentation and previous repairs. Emerging technologies show promise for fistula repair, but lack long-term data. PMID- 26929752 TI - Rectovaginal Fistulae. AB - Rectovaginal fistulae are abnormal epithelialized connections between the rectum and vagina. Fistulae from the anorectal region to the posterior vagina are truly best characterized as anovaginal or very low rectovaginal fistulae. True rectovaginal fistulae are less common and result from inflammatory bowel disease, trauma, or iatrogenic injury. A very few patients are asymptomatic, but the symptoms of rectovaginal fistula are incredibly distressing and unacceptable. Diagnostic approach, timing, and choice of surgical intervention, including sphincteroplasty, gracilis flaps, Martius flaps, and special circumstances are discussed. PMID- 26929754 TI - Transanal Approach to Rectal Polyps and Cancer. AB - A transanal approach to rectal polyp and cancer excision is often an appropriate alternative to conventional rectal resection, and has a lower associated morbidity. There has been a steady evolution in the techniques of transanal surgery over the past 30 years. It started with traditional transanal excision and was revolutionized by introduction of transanal endoscopic microsurgery in early 1980s. Introduction of transanal minimally invasive surgery made it more accessible to surgeons around the world. Now robotic platforms are being tried in certain institutions. Concerns have been raised about recurrence rates of cancers with transanal approach and success of subsequent salvage operations. PMID- 26929753 TI - Screening, Surveillance, and Treatment of Anal Intraepithelial Neoplasia. AB - The prevalence of anal intraepithelial neoplasia has been increasing, especially in high-risk patients, including men who have sex with men, human immunodeficiency virus positive patients, and those who are immunosuppressed. Several studies with long-term follow-up have suggested that rate of progression from high-grade squamous intraepithelial lesions to invasive anal cancer is ~ 5%. This number is considerably higher for those at high risk. Anal cytology has been used to attempt to screen high-risk patients for disease; however, it has been shown to have very little correlation to actual histology. Patients with lesions should undergo history and physical exam including digital rectal exam and standard anoscopy. High-resolution anoscopy can be considered as well, although it is of questionable time and cost-effectiveness. Nonoperative treatments include expectant surveillance and topical imiquimod or 5-fluorouracil. Operative therapies include wide local excision and targeted ablation with electrocautery, infrared coagulation, or cryotherapy. Recurrence rates remain high regardless of treatment delivered and surveillance is paramount, although optimal surveillance regimens have yet to be established. PMID- 26929755 TI - Relationship between cervical dilation and time to delivery in women with preterm labor. AB - BACKGROUND: Early recognition of the signs and symptoms of preterm labor (PTL) is important in order to establish treatment. Our aim was to determine the relation between cervical dilatation and time interval from admission to delivery in women with preterm labor. MATERIALS AND METHODS: A retrospective cohort study was conducted on 83 singleton gestations admitted for preterm labor between 24 weeks and 34 weeks, who subsequently delivered preterm. Women were categorized into three groups of cervical dilatation (0-2 cm, 3-6 cm, >6 cm) and the time interval from admission to delivery was compared. Cox regression analysis was performed to assess the association between cervical dilatation and time interval from admission to delivery. The other variables examined were gestational age (GA) at admission and length of the cervix, when performed. RESULTS: The time interval from admission to delivery was significantly shorter in women with higher dilatation of the cervix (p < 0.02) and in those admitted at a more advanced gestational age (p < 0.05). Forty-eight percent of women with cervical dilatation 0-2 cm delivered in the first 48 h compared to 85% of the women with a dilatation of 3-6 cm. No significant association was found between the length of the cervix and the time interval to delivery. CONCLUSION: Dilatation of the cervix and gestational age at admission are associated with the time interval to delivery in women with preterm labor. The assessment of the length of the cervix is unlikely to add clinical information in women with an already dilated cervix. PMID- 26929757 TI - Effect of change in patient's bed angles on pain after coronary angiography according to vital signals. AB - BACKGROUND: One of the most common and important diagnostic methods for the detection of heart diseases is coronary angiography. The aim of this study was to determine the optimum angle of the bed by using vital signals to optimize the patient's position after the angiography. MATERIALS AND METHODS: This study was a randomized clinical trial (RCT) on participants after angiography who were divided into five groups. The first group was placed routinely in a supine position. In the other groups, all of the patients were placed in bed by angle 15 degrees , 30 degrees , 45 degrees , and 60 degrees upward. In each group, vital signals were measured that included blood pressure, percent of blood oxygen saturation, heart rate, respiratory rate, and temperature. All of measured data compared with the pain score has been achieved from numerical pain scale. The data were analyzed by descriptive statistics method, variance analysis, and post hoc tests in the Statistical Package for the Social Sciences (SPSS) software, version 16. Estimation of the relationship was done by MATLAB version 2011. The level of significance was considered to be 0.05. RESULTS: In various groups, there was no significance difference in demographic variables such as gender, age, height, and weight. The mean of pain score, heart rate, systolic blood pressure, and respiratory rate changed significantly (P < 0.05) but the temperature variation, blood oxygen saturation, and diastolic blood pressure in subjects were not significant (P > 0.05). It showed linear changes between pain and systolic blood pressure, respiratory rate, and heart rate changes. A dramatic reduction was also seen in systolic blood pressure, respiratory rate, heart rate, and also pain at an angle of 45( degrees ). CONCLUSION: This study showed that, 45( degrees ) was the best angle of the bed to optimize the patient's position after the procedure, based on his/her vital signs and pain score. Thus, in order to relive pain, this change in bed angle is advised to be planned by postangiography nurses in patients after coronary angiography. PMID- 26929756 TI - Self-esteem, general and sexual self-concepts in blind people. AB - BACKGROUND: People with visual disability have lower self-esteem and social skills than sighted people. This study was designed to describe self-esteem and general and sexual self-concepts in blind people. MATERIALS AND METHODS: This was a cross-sectional study, conducted in the Isfahan University of Medical Sciences in 2013-2014. In this study, 138 visually impaired people participated from Isfahan Province Welfare Organization and were interviewed for measuring of self esteem and self-concept using Eysenck self-esteem and Rogers' self-concept questionnaires. The correlation between above two variables was measured using Statistical Package for the Social Sciences (SPSS) software by Pearson correlation test. RESULTS: Mean [+/- standard deviation (SD)] age of patients was 30.9 +/- 8 years. The mean (+/-SD) of general self-concept score was 11 +/- 5.83. The mean (+/-SD) of self-esteem score was 16.62 +/- 2.85. Pearson correlation results showed a significant positive correlation between self-esteem and general self-concept (r = 0.19, P = 0.025). The mean of sexual self-concept scores in five subscales (sexual anxiety, sexual self-efficacy, sexual self-esteem, sexual fear, and sexual depression) were correspondingly 11 +/- 4.41, 19.53 +/- 4.53, 12.96 +/- 4.19, 13.48 +/- 1.76, and 5.38 +/- 2.36. Self-esteem and self-concept had significant positive correlation with sexual anxiety (r = 0.49; P < 0.001) (r = -.23; P < 0.001) and sexual fear (r = 0.25; P = 0.003) (r = 0.18; P = 0.02) and negative correlation with sexual self-efficacy (r = -0.26; P = 0.002) (r = -0.28; P = 0.001) and sexual-esteem (r = -0.34; P < 0.001) (r = -0.34; P < 0.001). CONCLUSION: Self-esteem and self-concept had significant correlation with sexual anxiety and sexual fear; and negative correlation with sexual self-efficacy and sexual-esteem. PMID- 26929758 TI - Trends of diabetic nephropathy prevalence in Isfahan, Iran, during 1992-2010. AB - BACKGROUND: Diabetes mellitus is a metabolic disorder and its subsequent complications such as retinopathy, nephropathy, ulcers, disability, and amputation increase the burden of the disease. Patient knowledge-improving programs are employed to prevent disease progression and to improve the quality of life of the patients. In this way, we need to characterize the groups of patients in urgent need for more and rich-in-content programs. In the present study, we used piecewise regression to evaluate the trends of diabetic nephropathy prevalence in patients registered in the Sedigheh-Tahereh Research Center and to identify patients who were in need of more attention. MATERIALS AND METHODS: Piecewise regression, used in this study, is a statistical method to identify change points, if any, in the trends of mortality rates, prevalence of a disease, or any other trends. Available information for 1,935 patients were retrieved from the database. Joinpoint program 3.5.3 and Statistical Package for the Social Sciences (SPSS) 20 was used to fit piecewise regression and obtain descriptive statistics, respectively. RESULTS: We assessed the trend of diabetic nephropathy in different groups of diabetic patients with respect to sex, blood pressure status, education, family history of diabetes, and age. The results showed an increasing trend in females, patients without family history of diabetes, and eover th recent years. The prevalence of diabetic nephropathy in patients with academic education was high. CONCLUSION: The groups with high prevalence or increasing trends need more preventive intervention and detailed assessment of the present trends. Exploring high-risk groups is beneficial for better policy-making in the future. However, discovering the reasons for the increased trend of the disease is really helpful in controlling diabetes complications. PMID- 26929759 TI - Efficacy of microencapsulated lactic acid bacteria in Helicobater pylori eradication therapy. AB - BACKGROUND: Probiotic delivery systems are widely used nutraceutical products for the supplementation of natural intestinal flora. These delivery systems vary greatly in the effectiveness to exert health benefits for a patient. This study focuses on providing probiotic living cells with a physical barrier against adverse environmental conditions. MATERIALS AND METHODS: Microencapsulation of the selected lactic acid bacteria (LAB) using chitosan and alginate was performed. Physical examination of the formulated LAB microcapsules was observed using phase contrast inverted microscope and scanning electron microscope (SEM). Finally, the survival of microencapsulated and noncapsulated bacteria was cheeked in the simulated human gastric tract (GT). The potential antimicrobial activity of the most potent microencapsulated LAB strain was in vivo evaluated in rabbit models. RESULTS: Microencapsulated L. plantarum, L. acidophilus, and L. bulgaricus DSMZ 20080 were loaded with 1.03 * 10(10) CFU viable bacteria/g, 1.9 * 10(10) CFU viable bacteria/g, and 5.5 * 10(9) CFU viable bacteria/g, respectively. The survival of microencapsulated cells was significantly higher than that of the free cells after exposure to simulated gastric juice (SGJ) at pH 2. Additionally, in simulated small intestine juice (SSJ), larger amounts of the selected LAB cells were found, whereas in simulated colon juice (SCJ), the released LAB reached the maximum counts. In vivo results pointed out that an 8 week supplementation with a triple therapy of a microencapsulated L. plantarum, L. acidophilus, and L. bulgaricus DSMZ 20080 might be able to reduce H. pylori. CONCLUSION: Microencapsulated probiotics could possibly compete with and downregulate H. pylori infection in humans. PMID- 26929760 TI - Effect of tetanus-diphtheria (Td) vaccine on immune response to hepatitis B vaccine in healthy individuals with insufficient immune response. AB - BACKGROUND: Hepatitis B virus (HBV) fails to produce appropriate immune responses in some healthy individuals; thus, different strategies have been adopted to promote immune responses. The current study aimed at evaluating the efficacy of HBV vaccine coadministered with tetanus-diphtheria (Td) vaccine compared with HBV vaccine in healthy individuals through measuring hepatitis B surface antibody (HBsAb) levels. MATERIALS AND METHODS: This was a randomized controlled clinical trial, which was implemented in Isfahan, Isfahan Province (Iran) in 2013. One hundred and forty healthy individuals, whose HBsAb titers were less than 10 IU/L were recruited. The subjects were randomly assigned to either in intervention or control trials. The control group received 40 MUg of recombinant HBV vaccines intramuscularly injected at 0, 1, and 6 months; however, the intervention group was simultaneously vaccinated by Td with the first dose of HBV vaccine. HBV antibody levels (titer) were measured before the vaccination and 6 months after the last vaccination. RESULTS: Antibody titers of the subjects in the intervention and control groups increased from 5.07 +/- 2.9 IU/L to 744.45 +/- 353.07 IU/L and from 4.45 +/- 3.4 IU/L to 589.94 +/- 353 IU/L, respectively (both P < 0.001). Also, the mean difference of antibody titer was significantly different between the two groups (P = 0.011). CONCLUSION: Td vaccination can be applied as a feasible approach to promote efficient and persistent immunity in healthy individuals with insufficient HBsAb titers. PMID- 26929761 TI - The association of metabolic syndrome with left ventricular mass and geometry in community-based hypertensive patients among Han Chinese. AB - BACKGROUND: The association of metabolic syndrome (MS) with left ventricular (LV) hypertrophy is controversial. The objective of our study was to investigate the influence of MS on LV mass and geometry in community-based hypertensive patients among Han Chinese. MATERIALS AND METHODS: This study included 1733 metabolic syndrome patients according to the International Diabetes Federation (IDF) definition and 2373 non-MS hypertension patients. LV hypertrophy was diagnosed by the criteria of LV mass >=49.2 g/m(2.7) for men and 46.7 g/m(2.7) for women. LV geometric patterns (normal, concentric remodeling, concentric or eccentric hypertrophy) were calculated according to LV hypertrophy and relative wall thickness. Logistic regression analysis was used to determine odds ratio (OR) and 95% confidence interval (CI) of MS for LV hypertrophy and LV geometry abnormality. RESULTS: The LV mass and LV mass index were higher in the MS group than in the non-MS group. In multiple adjusted models. LV mass index, LV mass, interventricular septum, and post wall were raised with the increased number of MS disorders. MS was associated with increased LV hypertrophy risk (unadjusted OR 1.38; 95% CI 1.21-1.57); age, sex, and blood pressure (BP; adjusted OR 1.39; 95% CI 1.22-1.59). MS was also associated with increased risk of eccentric hypertrophy in male and female patients. MS was only associated with increased risk of concentric hypertrophy in female patients; and MS was not associated with concentric remodeling. CONCLUSION: LV mass and LV mass index were associated with the increased number of MS disorders in the Chinese community-based hypertensive population. MS was not only associated with increased LV hypertrophy risk, but also associated with concentric and eccentric LV geometry abnormality, especially in females. PMID- 26929762 TI - Normal reference range of fetal nuchal translucency thickness in pregnant women in the first trimester, one center study. AB - BACKGROUND: Considering that establishment of reference value of nuchal translucency (NT)-related to the crown rump length (CRL) during the first trimester will be helpful for determining an appropriate cutoff level for screening of increased NT thickness-related abnormalities, we determined the NT thickness and investigated its relation with different chromosomal and nonchromosomal abnormalities among a large sample size of pregnant Iranian women. MATERIALS AND METHODS: In this analytic cross-sectional study, pregnant women who were in their first trimester were enrolled at their antenatal visit. Using an abdominal ultrasonography, the fetal NT thickness of the studied population was measured. Those with increased NT thickness were determined. The reference value of NT thickness (5th, 25th, 50th, 75th, and 95th percentiles) within each 5-mm range of CRL and during the 11th, 12th, and 13th gestational weeks were determined. The presences of the different chromosomal and nonchromosomal abnormalities were compared in women with different percentiles of NT thickness who underwent amniocentesis and those who did not. RESULTS: 1,614 pregnant women were evaluated. The mean NT thickness was 1.30 +/- 0.54 mm. Increased NT thickness >2 mm and >95th percentile according to their gestational age (GA) was detected in 89 (5.5%) and 58 (3.6%) pregnant women. The reference 95th percentile value range for NT was 1.8-2.35 and increased NT thickness according to our obtained values was associated significantly with chromosomal abnormalities. CONCLUSION: The obtained reference range in our studied population was different from that reported for other ethnic groups and it is suggested that using this values are more favorable for screening of chromosomal abnormalities during the first trimester of pregnancy than the recommended single cutoff value. PMID- 26929763 TI - Plumb as a cause of kidney cancer (case study: Iran from 2008-2010). AB - BACKGROUND: The main threats to human health from heavy metals are associated with exposure to plumb (Pb), cadmium, mercury, and arsenic. Some hazards that threat human health are the results of environmental factors and the relevant pollutions. Some important categories of diseases including (cancers) have considerable differences in various places, as observed in their spatial prevalence and distribution maps. The present study sets out to investigate the correlation between kidney cancer and the concentration of Pb in Iran. MATERIALS AND METHODS: In this study, the first challenge was to collect some relevant information. In this connection, the authors managed to gain access to data concerning kidney cancer in Iran. The data were collected by a health centre for the period of 2008-2010. Besides, a map of Pb distribution in soil, drawn by the Mineral Exploration Organization, and Plumb Concentration Information, collected by Agriculture Jihad Organization, were used. Using a geographic information system (GIS) software such as ArcGIS (USA), the researchers drew the map of the spatial distribution of kidney cancer in the Iran country. In the indirect methods, one measures vegetation stress caused by heavy metal soil contamination. In direct methods, target detection algorithms are used to detect a selected material on the basis of its unique spectral signature. In this research, we applied target detection algorithms on moderate resolution imaging spectroradiometer (MODIS) images to detect Pb. MODIS is a sensor placed on the Terra satellite that collects data in 35 spectral bands with 250-1,000 m special resolutions. RESULTS: The spatial distribution of kidney cancer in Iran country delineated above revealed a positive correlation between the amount of lead and the high frequency of kidney cancer. Regression analyses also confirmed this relationship (R (2) = 0.77 and R = 0.87). CONCLUSION: The findings of the current study underscore not only the importance of preventing exposure to Pb but also the importance of controlling Pb-producing industries. PMID- 26929764 TI - Evaluation of the left-to-right shift of colon tumors in Iran: Is the trend changing? AB - BACKGROUND: Colorectal cancer (CRC) is the second cause of cancer-related deaths worldwide. There have been several studies reporting the proximal tumor shift, especially in Western countries. In the present study, we investigated the clinicopathologic and anatomical distributions of colorectal tumors in Iranian CRC patients. MATERIALS AND METHODS: In this retrospective cohort study, 258 patients with CRC from 2008 to 2013 were evaluated. Comparison of variables was performed using Pearson's chi-square test and Fisher's exact test depending on the nature of the data. RESULTS: A total of 258 patients including 124 (48.1%) females and 134 (51.9%) males enrolled in this study. The majority of cancers were detected in the rectosigmoid, i.e., 98 (38%) followed by the left colon, i.e., 84 (32.6%) and the right colon, i.e., 76 (29.5%). In the present study, we observed the significant association between metastases, adjuvant therapy, family history, and history of inflammatory bowel disease (IBD) with tumor, node, and metastasis (TNM) staging (P < 0.001). In univariate analysis, there was a strong association between overall survival (OS) and stage II CRC (P = 0.03). However, the predictive value was lost in multivariate analysis (P = 0.145). CONCLUSION: Unlike the majority of previous studies on Iranian CRC patients, we observed a considerably higher occurrence of right-sided colon cancers (84 versus 76). Although this phenomenon did not reach the statistical significance rate, based on recent studies on Iranian population including the present one, the pattern of anatomical distribution of colorectal tumors has been changed toward the proximal colon. This requires an urgent need to provide other strategies and complementary detecting approaches in order to identify proximal tumors in Iranian CRC patients. PMID- 26929765 TI - Comparing of goal setting strategy with group education method to increase physical activity level: A randomized trial. AB - BACKGROUND: Designing an intervention to increase physical activity is important to be based on the health care settings resources and be acceptable by the subject group. This study was designed to assess and compare the effect of the goal setting strategy with a group education method on increasing the physical activity of mothers of children aged 1 to 5. MATERIALS AND METHODS: Mothers who had at least one child of 1-5 years were randomized into two groups. The effect of 1) goal-setting strategy and 2) group education method on increasing physical activity was assessed and compared 1 month and 3 months after the intervention. Also, the weight, height, body mass index (BMI), waist and hip circumference, and well-being were compared between the two groups before and after the intervention. RESULTS: Physical activity level increased significantly after the intervention in the goal-setting group and it was significantly different between the two groups after intervention (P < 0.05). BMI, waist circumference, hip circumference, and well-being score were significantly different in the goal setting group after the intervention. In the group education method, only the well-being score improved significantly (P < 0.05). CONCLUSION: Our study presented the effects of using the goal-setting strategy to boost physical activity, improving the state of well-being and decreasing BMI, waist, and hip circumference. PMID- 26929766 TI - A systematic review on the effects of maternal calcium supplementation on offspring's blood pressure. AB - BACKGROUND: Evidence proposes that maternal calcium (Ca) supplement during pregnancy may be inversely associated with the off spring's blood pressure (BP) level. It is suggested that increased maternal Ca intake during pregnancy may result in lower BP in the off spring. The reduction in the incidence of hypertension in mothers is documented but the effects on the off spring are uncertain. MATERIALS AND METHODS: We conducted a systematic review of the literature to summarize the evidence supporting an association between maternal dietary Ca intake during pregnancy and the BP in the off spring. In this systematic review, relevant papers were selected in three phases. After quality assessment, a reviewer extracted the data while the other one checked the extracted data. We summarized the information regarding the association of maternal Ca intake either by food or supplements with BP in the off spring. RESULTS: Four randomized trials and three observational studies were included in this review. The results were more consistent among the studies including older children (1-9 years) where a higher maternal Ca intake was associated with a reduction in the off spring's systolic BP. One large randomized trial found a clinically and statistically significant reduction in the incidence of elevated BP in 7-year-old children [relative risk (RR) = 0.59, 95% confidence interval (CI) 0.39-0.90]. CONCLUSION: Overall, our findings confirm the beneficial effects of maternal Ca intake during pregnancy for the off spring's BP level. PMID- 26929767 TI - Potential medicinal benefits of Cosmos caudatus (Ulam Raja): A scoping review. AB - Cosmos caudatus is widely used as a traditional medicine in Southeast Asia. C. caudatus has been reported as a rich source of bioactive compounds such as ascorbic acid, quercetin, and chlorogenic acid. Studies have shown that C. caudatus exhibits high anti-oxidant capacity and various medicinal properties, including anti-diabetic activity, anti-hypertensive properties, anti-inflammatory responses, bone-protective effect, and anti-microbial activity. This review aims to present the potential medicinal benefits of C. caudatus from the available scientific literature. We searched PubMed and ScienceDirect database for articles published from 1995 to January 2015. Overall, 15 articles related to C. caudatus and its medicinal benefits are reviewed. All these studies demonstrated that C. caudatus is effective, having demonstrated its anti-diabetic, anti-hypertensive, anti-inflammatory, bone-protective, anti-microbial, and anti-fungal activity in both in vitro and animal studies. None of the studies showed any negative effect of C. caudatus related to medicinal use. Currently available evidence suggests that C. caudatus has beneficial effects such as reducing blood glucose, reducing blood pressure, promoting healthy bone formation, and demonstrating anti inflammatory and anti-microbial properties. However, human clinical trial is warranted. PMID- 26929768 TI - A review on equipped hospital beds with wireless sensor networks for reducing bedsores. AB - At present, the solutions to prevent bedsore include using various techniques for movement and displacement of patients, which is not possible for some patients or dangerous for some of them while it also poses problems for health care providers. On the other hand, development of information technology in the health care system including application of wireless sensor networks (WSNs) has led to easy and quick service-providing. It can provide a solution to prevent bedsore in motionless and disabled patients. Hence, the aim of this article was first to introduce WSNs in hospital beds and second, to identify the benefits and challenges in implementing this technology. This study was a nonsystematic review. The literature was searched for WSNs to reduce and prevent bedsores with the help of libraries, databases (PubMed, SCOPUS, and EMBASE), and also searches engines available at Google Scholar including during 1974-2014 while the inclusion criteria were applied in English and Persian. In our searches, we employed the following keywords and their combinations: "wireless sensor network," "smart bed," "information technology," "smart mattress," and "bedsore" in the searching areas of titles, keywords, abstracts, and full texts. In this study, more than 45 articles and reports were collected and 37 of them were selected based on their relevance. Therefore, identification and implementation of this technology will be a step toward mechanization of traditional procedures in providing care for hospitalized patients and disabled people. The smart bed and mattress, either alone or in combination with the other technologies, should be capable of providing all of the novel features while still providing the comfort and safety features usually associated with traditional and hospital mattresses. It can eliminate the expense of bedsore in the intensive care unit (ICU) department in the hospital and save much expense there. PMID- 26929769 TI - Strengthening water, sanitation, and hygiene services in health establishments: An urgent priority of WHO. PMID- 26929770 TI - Alkaptonuric ochronosis. PMID- 26929771 TI - Which method has the most accurate measurement of daily salt intake? PMID- 26929772 TI - Symptom Burden and Functional Gains in a Cancer Rehabilitation Unit. AB - BACKGROUND/AIMS: To determine if there is a relationship between patient symptoms and functional improvement on inpatient rehabilitation. METHODS: Retrospective review of medical records at an American tertiary referral-based cancer center of all patients admitted to an inpatient rehabilitation unit between 3/1/2013 5/20/2013. Main outcome measures included the Edmonton Symptom and Assessment Scale (ESAS) and Functional Independence Measure (FIM). FINDINGS: The medical records for 71 unique cancer rehabilitation inpatients were analyzed. Statistical analysis of total admission ESAS on total FIM change found no significant relationships. The symptom burden of the patients was mild. Patients demonstrated statistically significant improvements in function and symptoms during inpatient rehabilitation. The mean change in total FIM and total ESAS were an increase of 19.20 and decrease of 7.41 respectively. Statistically significant changes occurred in fatigue, sleep, pain, and anxiety. CONCLUSION: Both symptom and functional scores improved significantly during inpatient rehabilitation. However, no significant relationships were found between symptoms at admission and improvement in FIM. PMID- 26929773 TI - Intergenerational Transmission of Aggression: Physiological Regulatory Processes. AB - Children who grow up in aggressive households are at risk of having problems with physiological regulation, but researchers have not investigated physiology as a mechanism in the intergenerational transmission of aggression. In this article, we posit that physiological regulation, particularly during stressful interpersonal interactions, may shed light on sensitivity to conflict, It can also inform our understanding of associations between childhood exposure to aggression in families of origin and aggression against partners in adolescence or adulthood. In support of this model, we highlight findings showing that childhood exposure to family aggression relates to physiological regulation across the life span, and that reactions to physiological stress concurrently relate to aggression against intimate partners. Emerging evidence from research on biological processes during stressful interpersonal interactions raises questions about what is adaptive for individuals from aggressive families, particularly as past family experiences intersect with the challenges of new relationships. PMID- 26929774 TI - Ultrasound-guided thrombin injection for treatment of superficial traumatic pseudoaneurysms and associated expanding hematomas: experience in five patients. AB - BACKGROUND: Angiography allows for excellent characterization and treatment of traumatic pseudoaneurysms. However, ultrasound-guided thrombin injection for pseudoaneurysm thrombosis allows for radiation-free treatment of superficial pseudoaneurysms and superficial expanding hematomas. METHODS: A retrospective review of 5 patient cases treated under this paradigm was performed following institutional review board approval. Outcomes following intervention were recorded and compared amongst the patient cohort. RESULTS: Ultrasound-guided closure of traumatic pseudoaneurysms allowed for reduced procedural times and procedural invasiveness. CONCLUSIONS: As demonstrated by the following cases, ultrasound guided thrombin injection is a good method of primary treatment for superficial pseudoaneurysms, or as an alternative treatment in cases where transcatheter embolization fails. PMID- 26929775 TI - EUS-guided transmural gallbladder drainage: a new era has begun. PMID- 26929776 TI - Recent advances in pancreatic cancer: updates and insights from the 2015 annual meeting of the American Society of Clinical Oncology. PMID- 26929777 TI - Cardiovascular risk assessment in the treatment of nonalcoholic steatohepatitis: a secondary analysis of the MOZART trial. AB - BACKGROUND: Nonalcoholic steatohepatitis (NASH) is associated with increased cardiovascular risk and mortality. No US Food and Drug Administration (FDA) approved therapies for NASH are available; clinical trials to date have not yet systematically assessed for changes in cardiovascular risk. This study examines the prospective utility of cardiovascular risk assessments, the Framingham risk score (FRS) and coronary artery calcium (CAC) score, as endpoints in a NASH randomized clinical trial, and assesses whether histologic improvements lead to lower cardiovascular risk. METHODS: Secondary analysis of a 24-week randomized, double-blind, placebo-controlled trial (MOZART) in which 50 biopsy-proven NASH patients received oral ezetimibe 10 mg daily (n = 25) versus placebo (n = 25). Biochemical profiling, FRS, CAC scores, liver biopsies were obtained at baseline and endpoint. RESULTS: Ezetimibe improved FRS whereas placebo did not (4.4 +/- 6.2 to 2.9 +/- 4.8, p = 0.038; 3.0 +/- 4.4 to 2.9 +/- 4.2, p = 0.794). CAC scores did not change with ezetimibe or placebo (180.4 +/- 577.2 to 194.1 +/- 623.9, p = 0.293; 151.4 +/- 448.9 to 183.3 +/- 555.7, p = 0.256). Ezetimibe improved FRS and CAC scores in more patients than placebo (48% versus 23%, p = 0.079, and 21% versus 0%, p = 0.090, respectively), though not significantly. No differences were noted in cardiovascular risk scores among histologic responders versus nonresponders. CONCLUSIONS: Ezetimibe improved FRS whereas placebo did not. FRS and CAC scores improved in a greater proportion of patients with ezetimibe; this trend did not reach significance. These findings indicate the utility and feasibility of monitoring cardiovascular risk in a NASH trial. The utility of CAC scores may be higher in trials of longer duration (?52 weeks) and with older patients (age ?45). ClinicalTrials.gov registration: NCT01766713. PMID- 26929778 TI - A novel schedule of erlotinib/capecitabine (7/7) as salvage therapy in previously treated advanced pancreatic adenocarcinoma: a case series. AB - BACKGROUND: The objective of this study was to report a case series on the efficacy and safety of capecitabine 7/7 schedule combined with erlotinib (CAP ERL) in patients with advanced pancreatic cancer (APC) who have failed prior therapies. METHODS: We retrospectively evaluated 13 patients with locally advanced or metastatic pancreatic cancer previously treated with gemcitabine or oxaliplatin-irinotecan-based first-line regimens. Treatment consisted of capecitabine (Xeloda) at a flat dose of 1000 mg orally twice daily on days 1-7 out of 14 days (7/7 schedule) and erlotinib (Tarceva) 100 mg orally once daily until unacceptable toxicity or disease progression. Tumor assessments were repeated every two cycles (8 weeks) and serum tumor markers were measured every 4 weeks. RESULTS: All patients (median age: 63 years; 7 female/3 male) had various previous lines of treatments of chemotherapies. Median number of cycles with CAP ERL was 4 (range 2-12). The overall response rate was 20%. CA19-9 was reduced more than 25% in 40% patients. The median overall survival and progression-free survival from the start of CAP-ERL were 4.5 months (range 3-7.5) and 2 months (range 1.5-4), respectively. The most common grade 3 toxicities included hand foot syndrome, nausea, vomiting, diarrhea, rash, and fatigue. CONCLUSIONS: Our result suggests that the combination of a fixed low dose of CAP-ERL 7/7 schedule was tolerated with manageable toxicity and showed encouraging activity as salvage treatment in patients with refractory APC with ECOG performance status 0-2. Further prospective studies are warranted to evaluate this combination. PMID- 26929779 TI - The safety and efficacy of single balloon enteroscopy in the elderly. AB - BACKGROUND: Single balloon enteroscopy (SBE) is an important tool in the management of small bowel disease with limited data available on its performance in the elderly. We aimed to evaluate the safety, efficacy, diagnostic and therapeutic outcomes of SBE in the elderly. METHODS: A retrospective review was performed on 366 patients undergoing 428 SBEs from 2010 to 2014. Patients were divided into different age groups: control <55, 55-64, 65-74 and ?75 years. Data on comorbidities, complications, findings, diagnostic and therapeutic yield were compared between groups. RESULTS: Anterograde and retrograde SBE were performed in 340 and 49 patients, respectively, with 63 patients requiring more than 1 procedure. Diagnostic yield was significantly higher for age ?75 years compared with <55, 66.3% versus 50%, odds ratio (OR) 1.97 [95% confidence interval (CI) 1.14-3.41]. Therapeutic yield was significantly higher in all three older age groups compared with <55 years, 20.3%: 55-64 years, 44.4%, OR 3.13(95% CI 1.7 5.78); 65-74 years, 42%, OR 2.84 (95% CI 1.59-5.06); and >75 years, 47.5%, OR 3.55 (95% CI 1.96-6.43). No significant difference was seen between age groups in complications or failures. Our overall complication rate was 2.3% with 5 minor and 5 major complications. There was a higher yield of angioectasias in the elderly. Argon plasma coagulation (APC) and multipolar electrocoagulation were used more often in older age groups. CONCLUSION: SBE is safe in elderly patients and delivers higher diagnostic and therapeutic yields compared to younger patients. The elderly are more likely to have angioectasias and undergo APC and electrocoagulation. PMID- 26929780 TI - Fully covered self-expandable metal stent in the treatment of postsurgical colorectal diseases: outcome in 29 patients. AB - BACKGROUND: Self-expandable metal stent (SEMS) placement is a minimally invasive treatment for palliation of malignant colorectal strictures and as a bridge to surgery. However, the use of SEMS for benign colorectal diseases is controversial. The purpose of this retrospective study is to evaluate the efficacy and safety of fully covered SEMS (FCSEMS) placement in postsurgical colorectal diseases. METHODS: From 2008 to 2014, 29 patients with 32 FCSEMS deployment procedures were evaluated. The indications for stent placement were: 17 anastomotic strictures (3/17 presented complete closure of the anastomosis); four anastomotic leaks; seven strictures associated with anastomotic leak; and one rectum-vagina fistula. RESULTS: Clinical success was achieved in 18 out of 29 patients (62.1%) being symptom-free at an average of 19 months. In the remaining 11 patients (37.9%), a different treatment was needed: four patients required multiple endoscopic dilations, 4 patients colostomy confection, one patient definitive ileostomy and three patients revisional surgery. The FCSEMS were kept in place for a mean period of 34 (range: 6-65) days. Major complications occurred in 12 out of 29 patients (41.4%) and consisted of stent migration. Minor complications included two cases of transient fever, eight cases of abdominal or rectal pain, and one case of tenesmus. CONCLUSION: FCSEMS are considered a possible therapeutic option for treatment of postsurgical strictures and leaks. However, their efficacy in guaranteeing long-term anastomotic patency and leak closure is moderate. A major complication is migration. The use of FCSEMS for colonic postsurgical pathologies should be carefully evaluated for each patient. PMID- 26929781 TI - Air cholangiography in endoscopic bilateral stent-in-stent placement of metallic stents for malignant hilar biliary obstruction. AB - BACKGROUND: Although endoscopic bilateral stent-in-stent (SIS) placement of self expandable metallic stents (SEMS) is one of the major palliative treatments for unresectable malignant hilar biliary obstruction, post-endoscopic retrograde cholangiopancreatography (ERCP) cholangitis can occur frequently due to inadequate drainage, especially after contrast injection into the biliary tree. The aim of this study is to evaluate the efficacy and safety of air cholangiography-assisted stenting. METHODS: This study included 47 patients with malignant hilar biliary obstruction who underwent endoscopic bilateral SEMS placement using the SIS technique. They were divided into two groups, air (n = 23) or iodine contrast (n = 24) cholangiography. We retrospectively compared comprehensive clinical and laboratory data of both groups. RESULTS: There were no significant differences found between the two groups with respect to technical success (87% versus 87.5%, air versus contrast group, respectively), functional success (95% versus 95.2%), 30-day mortality (8.3% versus 8.7%) and stent patency. Post-ERCP adverse events occurred in 5 (21.7%) of the patients in the air group and 8 (33.3%) of the patients in the contrast group. Among these, the rate of cholangitis was significantly lower in the air group (4.8% versus 29.2%, p = 0.048). In multivariate analysis, air cholangiography, technical success and a shorter procedure time were significantly associated with a lower incidence of post-ERCP cholangitis. CONCLUSIONS: Air cholangiography-assisted stenting can be a safe and effective method for endoscopic bilateral SIS placement of SEMS in patients with malignant hilar biliary obstruction. PMID- 26929782 TI - Overlapping irritable bowel syndrome and inflammatory bowel disease: less to this than meets the eye? AB - Though distinct in terms of pathology, natural history and therapeutic approach, irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD) have some features in common. These include shared symptomatology and largely similar demographics. However, in most instances, clinical presentation, together with laboratory, imaging and endoscopic findings will readily permit the differentiation of active IBD from IBS. More problematic is the situation where a subject with IBD, in apparent remission, continues to complain of symptoms which, in aggregate, satisfy commonly employed criteria for the diagnosis of IBS. Access to methodologies, such the assay for levels of calprotectin in feces, now allows identification of ongoing inflammation in some such individuals and prompts appropriate therapy. More challenging is the IBD patient with persisting symptoms and no detectable evidence of inflammation; is this coincident IBS, IBS triggered by IBD or an even more subtle level of IBD activity unrecognized by available laboratory or imaging methods? Arguments can be advanced for each of these proposals; lacking definitive data, this issue remains unresolved. The occurrence of IBS-type symptoms in the IBD patient, together with some data suggesting a very subtle level of 'inflammation' or 'immune activation' in IBS, raises other questions: is IBS a prodromal form of IBD; and are IBS and IBD part of the spectrum of the same disease? All of the available evidence indicates that the answer to both these questions should be a resounding 'no'. Indeed, the whole issue of overlap between IBS and IBD should be declared moot given their differing pathophysiologies, contrasting natural histories and divergent treatment paths. The limited symptom repertoire of the gastrointestinal tract may well be fundamental to the apparent confusion that has, of late, bedeviled this area. PMID- 26929785 TI - Prognostic significance of adverse events in patients with hepatocellular carcinoma treated with sorafenib. AB - Sorafenib is the standard treatment for patients with hepatocellular carcinoma (HCC) with advanced stage disease. Although its effectiveness has been demonstrated by randomized clinical trials and confirmed by field practice studies, reliable markers predicting therapeutic response have not yet been identified. Like other tyrosine kinase inhibitors, treatment with sorafenib is burdened by the development of adverse effects, the most frequent being cutaneous toxicity, diarrhoea, arterial hypertension and fatigue. In recent years, several studies have analysed the correlation between off-target effects and sorafenib efficacy in patients with HCC. In this review, an overview of the studies assessing the prognostic significance of sorafenib-related adverse events is provided. PMID- 26929783 TI - Diverticulosis today: unfashionable and still under-researched. AB - Diverticulosis of the colon is a widespread disease, and its prevalence is increasing especially in the developing world. The underlying pathological mechanisms that cause the formation of colonic diverticula remain unclear but are likely to be the result of complex interactions among age, diet, genetic factors, colonic motility, and changes in colonic structure. The large majority of patients remain asymptomatic throughout their life, one fifth of them become symptomatic (developing the so-called 'diverticular disease') while only a minority of these will develop acute diverticulitis. The factors predicting the development of symptoms remain to be identified. Again, it is generally recognized that diverticular disease occurrence is probably related to complex interactions among colonic motility, diet, lifestyle, and genetic features. Changes in intestinal microflora due to low-fiber diet and consequent low-grade inflammation are thought to be one of the mechanisms responsible for symptoms occurrence of both diverticular disease and acute diverticulitis. Current therapeutic approaches with rifaximin and mesalazine to treat the symptoms seem to be promising. Antibiotic treatment is currently advised only in acute complicated diverticulitis, and no treatment has currently proven effective in preventing the recurrence of acute diverticulitis. Further studies are required in order to clarify the reasons why diverticulosis occurs and the factors triggering occurrence of symptoms. Moreover, the reasons why rifaximin and mesalazine work in symptomatic diverticular disease but not in acute diverticulitis are yet to be elucidated. PMID- 26929784 TI - Fecal microbiota transplantation: in perspective. AB - There has been increasing interest in understanding the role of the human gut microbiome to elucidate the therapeutic potential of its manipulation. Fecal microbiota transplantation (FMT) is the administration of a solution of fecal matter from a donor into the intestinal tract of a recipient in order to directly change the recipient's gut microbial composition and confer a health benefit. FMT has been used to successfully treat recurrent Clostridium difficile infection. There are preliminary indications to suggest that it may also carry therapeutic potential for other conditions such as inflammatory bowel disease, obesity, metabolic syndrome, and functional gastrointestinal disorders. PMID- 26929786 TI - Efficacy and toxicity of salvage weekly paclitaxel chemotherapy in non-Asian patients with advanced oesophagogastric adenocarcinoma. AB - OBJECTIVES: Survival for oesophagogastric adenocarcinoma (OGA) patients varies globally and clinical trial results are seldom replicated in clinical practice. We sought to examine the efficacy and toxicity of salvage paclitaxel chemotherapy for patients with advanced OGA at our institution. METHODS: Advanced OGA patients treated with paclitaxel between June 2011 and February 2014 were identified from the electronic record at the Royal Marsden Hospital (RMH), London. Chart review was performed to obtain demographics, performance status (PS), laboratory parameters, radiological response and dates of progression, death and last follow up. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method. Multivariate Cox regression analysis examined the interaction between clinical and laboratory parameters and survival. RESULTS: Fifty-seven patients were identified; OS and PFS were 5.8 and 2.6 months respectively. From first-line chemotherapy, median OS was 14.3 months. Two-year and three-year survival rates from diagnosis were 26% and 13%. More than or equivalent to Grade 3 neutropenia occurred in 13% of patients. In multivariate analysis, PS more than or equal to 2, alkaline phosphatase (ALP) more than or equal to100 U/L, and previous rechallenge with platinum were independent prognostic factors for OS. CONCLUSIONS: OGA cancer patients treated at RMH with salvage paclitaxel had an OS equivalent to patients in clinical trials with more (33%) PS = 2 patients treated and less haematological toxicity than Asian patients. Eastern Cooperative Oncology Group (ECOG) PS more than or equal to 2, ALP more than or equal to 100 U/L, and prior platinum rechallenge were associated with poor survival. However, the proportion of patients surviving more than or equal to two years from diagnosis demonstrates a clinically relevant improvement from historical controls. PMID- 26929787 TI - Novel targets in the treatment of advanced gastric cancer: a perspective review. AB - Gastric cancer is responsible for a high burden of disease globally. Although more extensive use of chemotherapy together with the recent introduction of the two targeted agents trastuzumab and ramucirumab have contributed to marginal outcome prolongation, overall survival for patients with advanced stage disease remains poor. Over the last decade, a number of novel agents have been examined in clinical trials with largely disappointing results. Potential explanations for this are the absence of molecularly selected trial populations or weak predictive biomarkers within the context of a highly heterogeneous disease. In the recently published gastric cancer The Cancer Genome Atlas (TCGA) project a new classification of four different tumour subtypes according to different molecular characteristics has been proposed. With some overlap, several relatively distinct and potentially targetable pathways have been identified for each subtype. In this perspective review we match recent trial results with the subtypes described in the gastric cancer TCGA aiming to highlight data regarding novel agents under evaluation and to discuss whether this publication might provide a framework for future drug development. PMID- 26929789 TI - Phonological Awareness at 5 years of age in Children who use Hearing Aids or Cochlear Implants. AB - : Children with hearing loss typically underachieve in reading, possibly as a result of their underdeveloped phonological skills. This study addressed the questions of whether the development of phonological awareness (PA) is influenced by 1) the degree of hearing loss; and 2) whether performance of children with severe-profound hearing loss differed according to the hearing devices used. Drawing on data collected as part of the Longitudinal Outcomes of Children with Hearing Impairment (LOCHI, www. OUTCOMES: nal.gov.au) study, the authors found that sound-matching scores of children with hearing loss ranging from mild to profound degrees were, on average, within the normal range. The degree of hearing loss did not have a significant impact on scores, but there was a non-significant tendency for the proportion of children who achieved zero scores to increase with increase in hearing loss. For children with severe hearing loss, there was no significant group difference in scores among children who used bilateral hearing aids, bimodal fitting (a cochlear implant and a hearing aid in contralateral ears), and bilateral cochlear implants. Although there is a need for further prospective research, professionals have an important role in targeting PA skills for rehabilitation of young children with hearing loss. PMID- 26929788 TI - Targeting dormant micrometastases: rationale, evidence to date and clinical implications. AB - In spite of decades of research, cancer survival has increased only modestly. This is because most research is based on models of primary tumors. Slow recognition has begun that disseminated, dormant cancer cells (micrometastatic cells) that are generally resistant to chemotherapy are the culprits in recurrence, and until these are targeted effectively we can expect only slow progress in increasing overall survival from cancer. This paper reviews efforts to understand the mechanisms by which cancer cells can become dormant, and thereby identify potential targets and drugs either on the market or in clinical trials that purport to prevent metastasis. This review targets the most recent literature because several excellent reviews have covered the literature from more than two years ago. The paper also describes recent work in the authors' laboratories to develop a screening-based approach that does not require understanding of mechanisms of action or the molecular target. Success of this approach shows that targeting micrometastatic cells is definitely feasible. PMID- 26929790 TI - Draft genomic sequence of Nereida ignava CECT 5292(T), a marine bacterium of the family Rhodobacteraceae. AB - Nereida ignava strain 2SM4(T) (= CECT 5292(T) = DSM 16309(T) = CIP 108404(T) = CCUG 49433(T)) is a marine bacterium belonging to the Roseobacter group of the family Rhodobacteraceae within the class Alphaproteobacteria. The strain was isolated from sea water surrounding cultivated oysters 2-3 miles off the Mediterranean coast near Valencia (Spain) and was phylogenetically related to uncultured clones of gall symbiont bacteria of some species of Prionitis alga. Here we describe the genome sequence and annotation of this organism, the type strain of the single species of this genus. The genome comprised 2,888,349 bp, 2,872 protein-coding genes and 52 RNA genes. The annotation revealed the capacity to produce bacteriocins, vitamins and auxins. Besides, it contained sulfur cycling related genes. PMID- 26929791 TI - A PEDIATRIC AIRWAY ATLAS AND ITS APPLICATION IN SUBGLOTTIC STENOSIS. AB - Young children with upper airway problems are at risk for hypoxia, respiratory insufficiency and long term morbidity. Computational models and quantitative analysis would reveal airway growth patterns and benefit clinical care. To capture expected growth patterns we propose a method to build a pediatric airway atlas as a function of age. The atlas is based on a simplified airway model in combination with kernel regression. We show experimental results on children with subglottic stenosis to demonstrate that our method is able to track and measure the stenosis in pediatric airways. PMID- 26929792 TI - Sharpening Precision Medicine by a Thorough Interrogation of Metabolic Individuality. AB - Precision medicine is an active component of medical practice today, but aspirations are to both broaden its reach to a greater diversity of individuals and improve its "precision" by enhancing the ability to define even more disease states in combination with associated treatments. Given complexity of human phenotypes, much work is required. In this review, we deconstruct this challenge at a high level to define what is needed to move closer toward these aspirations. In the context of the variables that influence the diverse array of phenotypes across human health and disease - genetics, epigenetics, environmental influences, and the microbiome - we detail the factors behind why an individual's biochemical (metabolite) composition is increasingly regarded as a key element to precisely defining phenotypes. Although an individual's biochemical (metabolite) composition is generally regarded, and frequently shown, to be a surrogate to the phenotypic state, we review how metabolites (and therefore an individual's metabolic profile) are also functionally related to the myriad of phenotypic influencers like genetics and the microbiota. We describe how using the technology to comprehensively measure an individual's biochemical profile - metabolomics - is integrative to defining individual phenotypes and how it is currently being deployed in efforts to continue to elaborate on human health and disease in large population studies. Finally, we summarize instances where metabolomics is being used to assess individual health in instances where signatures (i.e. biomarkers) have been defined. PMID- 26929794 TI - Triangular Fixation Technique for Bicolumn Restoration in Treatment of Distal Humerus Intercondylar Fracture. AB - BACKGROUND: Distal humerus intercondylar fractures are intra-articular and comminuted fractures involving soft tissue injury. As distal humerus is triangle shaped, parallel plating coupled with articular fixation would be suitable for bicolumn restoration in treatment of distal humerus intercondylar fracture. METHODS: This study included 38 patients (15 males and 23 females) who underwent olecranon osteotomy, open reduction and internal fixation with the triangle shaped cannulated screw and parallel locking plates (triangular fixation technique). Functional results were assessed with the visual analog scale (VAS) scores, Mayo elbow performance (MEP) scores and Disabilities of the Arm, Shoulder and Hand (DASH) questionnaires. Anteroposterior and lateral elbow radiographs were assessed for reduction, alignment, fracture union, posttraumatic arthrosis, and heterotopic ossification, and computed tomography (CT) scans were used to obtain more accurate measurements of articular discrepancy. RESULTS: All fractures healed primarily with no loss of reduction. The mean VAS, MEP, and DASH scores of the affected elbow were not significantly different from those of the unaffected elbow (p = 0.140, p = 0.090, and p = 0.262, respectively). The mean degree of flexion was significantly lower in the affected elbow than in the unaffected elbow, but was still considered as functional (p = 0.001, > 100 degrees in 33 of 38 patients). Two cases of articular step-offs (> 2 mm) were seen on follow-up CT scans, but not significantly higher in the affected elbow than in the unaffected elbow (p = 0.657). Binary logistic regression analysis revealed that only Association for Osteosynthesis (AO) type C3 fractures correlated with good/excellent functional outcome (p = 0.012). Complications occurred in 12 of the 38 patients, and the overall reoperation rate for complications was 10.5% (4 of 38 patients). CONCLUSIONS: Triangular fixation technique for bicolumn restoration was an effective and reliable method in treatment of distal humerus intercondylar fracture. This technique maintained articular congruency and restored both medial and lateral columns, resulting in good elbow function. PMID- 26929793 TI - Stem Cell Therapy for the Treatment of Hip Osteonecrosis: A 30-Year Review of Progress. AB - Avascular necrosis of the femoral head is caused by a multitude of etiologic factors and is associated with collapse with a risk of hip arthroplasty in younger populations. A focus on early disease management with the use of stem cells was proposed as early as 1985 by the senior author (PH). We undertook a systematic review of the medical literature to examine the progress in cell therapy during the last 30 years for the treatment of early stage osteonecrosis. PMID- 26929795 TI - Senior Managed Care System for Hip Fracture in the United States. AB - BACKGROUND: It is debatable whether a managed care model would affect the quality of care and length of hospital stay in the treatment of hip fractures in elderly patients. METHODS: This prospective study was undertaken to determine whether or not a managed care critical pathway tool shortened hospital stay in a group of 102 senior patients with fractures of the hip during follow-up. We compared our study findings with two equivalent populations of senior hip fracture patients not treated using a critical care pathway concerning specific markers of quality. RESULTS: The managed care group had a 9% mortality rate, 95% return to prefracture living and 63% return to ambulatory status. The rates compared favorably with previous studies. The quality of care provided before and after the critical pathway was equivalent, while the post-pathway length of stay dropped 30%. CONCLUSIONS: The proposed care protocol is recommended to shorten hospital stay in elderly patients with hip fractures. PMID- 26929796 TI - The Epidemiology and National Trends of Bearing Surface Usage in Primary Total Hip Arthroplasty in Korea. AB - BACKGROUND: We analyzed the data for primary total hip arthroplasty (THA) in the Korean nationwide database to assess (1) the epidemiology and national trends of bearing surface usage in THAs and (2) the prevalence of each type of bearing surface according to age, gender, hospital type, primary payer, and hospital procedure volume. METHODS: A total of 30,881 THAs were analyzed using the Korean Health Insurance Review and Assessment Service database for 2007 through 2011. Bearing surfaces were sub-grouped according to device code for national health insurance claims and consisted of ceramic-on-ceramic (CoC), metal-on-polyethylene (MoP), ceramic-on-polyethylene (CoP), and metal-on-metal (MoM). The prevalence of each type of bearing surface was calculated and stratified by age, gender, hospital type, primary payer, and procedure volume of each hospital. RESULTS: CoC was the most frequently used bearing surface (76.7%), followed by MoP (11.9%), CoP (7.3%), and MoM (4.1%). The proportion of THAs using a CoC bearing surface increased steadily from 71.6% in 2007 to 81.4% in 2011, whereas the proportions using CoP, MoP, and MoM bearing surfaces decreased. The order of prevalence was identical to that in the general population regardless of age, gender, hospital type, primary payer, and hospital procedure volume. CONCLUSIONS: The trends and epidemiology of bearing surface usage in THAs in Korea are different from those in other countries, and the CoC bearing surface is the most prevalent articulation. In future, the results of a large-scale study using nationwide data of THAs involving a CoC bearing surface will be reported in Korea. PMID- 26929797 TI - Results of Total Hip Arthroplasty after Core Decompression with Tantalum Rod for Osteonecrosis of the Femoral Head. AB - BACKGROUND: Early stage osteonecrosis of the femoral head (ONFH) has many treatment options including core decompression with implantation of a tantalum rod. The purpose of this study was to evaluate clinical and radiological outcomes and potential complications during conversion total hip arthroplasty (THA) in such patients. METHODS: Six male patients (8 hips) underwent THA subsequent to removing a tantalum rod (group I) from April 2010 to November 2011. We retrospectively reviewed the medical records of these patients. We enrolled 12 age- and sex-matched patients (16 hips) during the same period, who had undergone primary THA without a previous operation as the control group (group II). All patients were followed for at least 3 years. We checked the Harris hip score (HHS), operative time, and volume of blood loss. Radiological results, including inclination, anteversion of the acetabular cup, presence of periprosthetic osteolysis, and subsidence of femoral stem were checked at the last follow-up. RESULTS: The mean preoperative HHS values were 56.5 (range, 50 to 62) and 59.1 (range, 42 to 70) in groups I and II, respectively. The HHS improved to 96.0 (range, 93 to 100) and 97.6 (range, 93 to 100), respectively, at the 3-year follow-up (p = 0.172). Mean operation time was 98.8 minutes (range, 70 to 120 minutes) in group I and 77.5 minutes (range, 60 to 115 minutes) in group II (p = 0.006). Total blood loss volumes were 1,193.8 mL (range, 960 to 1,360 mL) and 944.1 mL (range, 640 to 1,280 mL) in groups I and II, respectively (p = 0.004). No significant differences in inclination or anteversion of acetabular cup and no evidence of osteolysis or subsidence of the femoral stem were reported in either group in radiological follow-up results. However, one case of squeaking occurred in group I during the follow-up. CONCLUSIONS: The two groups showed no clinical or radiological differences except extended operative time and increased blood loss. However, the incidence of squeaking (1 of 8 hips) was higher, as compared to the control group or previously reported values. PMID- 26929798 TI - Radiologic Measurement of Tibial Tuberosity-Trochlear Groove (TT-TG) Distance by Lower Extremity Rotational Profile Computed Tomography in Koreans. AB - BACKGROUND: Tibial tuberosity-trochlear groove (TT-TG) distance is important in the assessment and treatment of patellofemoral disorders. However, normal and pathological TT-TG values have not been established in Koreans. The purpose of this study was to evaluate the TT-TG distance in the Korean population using lower leg rotational profile computed tomography (CT) scans. METHODS: One hundred rotational profile CT scans were retrospectively collected from patients without knee joint problems aged between 25 to 82 years. TT-TG distances were measured, and statistical analysis was performed. Each CT scan was measured twice in a blinded, randomized manner by three reviewers. Patients with pre-existing knee joint problems were excluded from the study; hence 15 of the 100 patients were excluded because of deformity or unreadable CT scans. Thus, 85 of the 100 patients were included in the study. RESULTS: Interobserver and intraobserver reliability of TT-TG distance measurements was good. The median TT-TG distance for this Korean population was 11.24 mm (mean, 10.24 +/- 0.8 mm). TT-TG distance measured nearly 2 mm less on rotational profile CT scans. CONCLUSIONS: Some of the TT-TG distances on rotational profile CT scans were significantly correlated, indicating that they could be accepted. Furthermore, the values on CT scans showed good reliability. In this study, the TT-TG distance in normal Korean people was approximately 10.24 mm without significant differences in TT-TG values between genders. PMID- 26929799 TI - Quantification of the Effect of Vertical Bone Resection of the Medial Proximal Tibia for Achieving Soft Tissue Balancing in Total Knee Arthroplasty. AB - BACKGROUND: Degenerative osteoarthritis of the knee usually shows arthritic change in the medial tibiofemoral joint with severe varus deformity. In total knee arthroplasty (TKA), the medial release technique is often used for achieving mediolateral balancing. But, in a more severe varus knee, there are more difficult technical problems. Bony resection of the medial proximal tibia (MPT) as an alternative technique for achieving soft tissue balancing was assessed in terms of its effectiveness and possibility of quantification. METHODS: TKAs were performed in 78 knees (60 patients) with vertical bone resection of the MPT for soft tissue balancing from September 2011 to March 2013. During operation, the medial and lateral gaps were measured before and after the bony resection technique. First, the correlation between the measured thickness of the resected bone and the change in medial and lateral gaps was analyzed. Second, the possibility of quantification of each parameter was evaluated by linear regression and the coefficient ratio was obtained. RESULTS: A significant correlation was identified between alteration in the medial gap change in extension and the measured thickness of the vertically resected MPT (r = 0.695, p = 0.000). In the medial gap change in flexion, there was no statistical significance (r = 0.214, p = 0.059). When the MPT was resected at an average thickness of 8.25 +/- 1.92 mm, the medial gap in extension was increased by 2.94 +/- 0.87 mm. In simple linear regression, it was predictable that MPT resection at a thickness of 2.80 mm was required to increase the medial gap by 1.00 mm in knee extension. CONCLUSIONS: The method of bone resection of the MPT can be considered effective with a predictable result for achieving soft tissue balancing in terms of quantification during TKA. PMID- 26929800 TI - Arthroscopic Bioabsorbable Screw Fixation of Unstable Osteochondritis Dissecans in Adolescents: Clinical Results, Magnetic Resonance Imaging, and Second-Look Arthroscopic Findings. AB - BACKGROUND: This study aimed to evaluate the clinical and radiological outcomes of arthroscopic bioabsorbable screw fixation in osteochondritis dissecans (OCD) in adolescent patients with unstable lesions causing pain. METHODS: The study included 11 patients (10 males and 1 female) with OCD who underwent arthroscopic bioabsorbable screw fixation between July 2007 and February 2014 and were available for follow-up for more than 12 months. The mean age at diagnosis was 16.3 years (range, 11 to 19 years), and the average follow-up period was 51 months (range, 12 to 91 months). Clinical results were evaluated using the Knee Injury and Osteoarthritis Outcome Score (KOOS), Lysholm knee score, and International Knee Documentation Committee (IKDC) score measured before surgery and at follow-up. Functional evaluation was made using the Tegner activity scale. Magnetic resonance imaging (MRI) and second-look arthroscopy were performed at the 12-month follow-up. RESULTS: Between the preoperative assessment and follow up, improvements were seen in the KOOS (range, 44.9 to 88.1), Lysholm knee score (range, 32.6 to 82.8), and IKDC score (range, 40.8 to 85.6). The Tegner activity scale also improved from 2.8 to 6.1. Based on postoperative MRI, there were eight Dipaola grade I cases and three grade II cases. No complications due to fixation failure developed in any case. Second-look arthroscopy at 12 months postoperatively revealed that the lesion was covered with cartilage in all cases. CONCLUSIONS: For unstable OCD lesions causing pain in adolescents, arthroscopic bioabsorbable screw fixation provided favorable outcomes with reduced pain and restoration of movement. Therefore, it should be considered as an effective treatment for OCD. PMID- 26929801 TI - Lumbar Lordosis of Spinal Stenosis Patients during Intraoperative Prone Positioning. AB - BACKGROUND: To evaluate the effect of spondylolisthesis on lumbar lordosis on the OSI (Jackson; Orthopaedic Systems Inc.) frame. Restoration of lumbar lordosis is important for maintaining sagittal balance. Physiologic lumbar lordosis has to be gained by intraoperative prone positioning with a hip extension and posterior instrumentation technique. There are some debates about changing lumbar lordosis on the OSI frame after an intraoperative prone position. We evaluated the effect of spondylolisthesis on lumbar lordosis after an intraoperative prone position. METHODS: Sixty-seven patients, who underwent spinal fusion at the Department of Orthopaedic Surgery of Gwangmyeong Sungae Hospital between May 2007 and February 2012, were included in this study. The study compared lumbar lordosis on preoperative upright, intraoperative prone and postoperative upright lateral X rays between the simple stenosis (SS) group and spondylolisthesis group. The average age of patients was 67.86 years old. The average preoperative lordosis was 43.5 degrees (+/- 14.9 degrees ), average intraoperative lordosis was 48.8 degrees (+/- 13.2 degrees ), average postoperative lordosis was 46.5 degrees (+/- 16.1 degrees ) and the average change on the frame was 5.3 degrees (+/- 10.6 degrees ). RESULTS: Among all patients, 24 patients were diagnosed with simple spinal stenosis, 43 patients with spondylolisthesis (29 degenerative spondylolisthesis and 14 isthmic spondylolisthesis). Between the SS group and spondylolisthesis group, preoperative lordosis, intraoperative lordosis and postoperative lordosis were significantly larger in the spondylolisthesis group. The ratio of patients with increased lordosis on the OSI frame compared to preoperative lordosis was significantly higher in the spondylolisthesis group. The risk of increased lordosis on frame was significantly higher in the spondylolisthesis group (odds ratio, 3.325; 95% confidence interval, 1.101 to 10.039; p = 0.033). CONCLUSIONS: Intraoperative lumbar lordosis on the OSI frame with a prone position was larger in the SS patients than the spondylolisthesis patients, which also produced a larger postoperative lordosis angle after posterior spinal fusion surgery. An increase in lumbar lordosis on the OSI frame should be considered during posterior spinal fusion surgery, especially in spondylolisthesis patients. PMID- 26929802 TI - More than 5-Year Follow-up Results of Two-Level and Three-Level Posterior Fixations of Thoracolumbar Burst Fractures with Load-Sharing Scores of Seven and Eight Points. AB - BACKGROUND: The development of pedicle screw-based posterior spinal instrumentation is recognized as one of the major surgical treatment methods for thoracolumbar burst fractures. However, the appropriate level in posterior segment instrumentation is still a point of debate. To assesses the long-term results of two-level and three-level posterior fixations of thoracolumbar burst fractures that have load-sharing scores of 7 and 8 points. METHODS: From January 1998 to May 2009, we retrospectively analyzed clinical and radiologic outcomes of 45 patients with thoracolumbar burst fractures of 7 and 8 points in load-sharing classification who were operated on using two-level posterior fixation (one segment above and one segment below: 28 patients, group I) or three-level posterior fixation (two segments above and one segment below: 17 patients, group II). Clinical results included the grade of the fracture using the Frankel classification, and the visual analog score was used to evaluate pain before surgery, immediately after surgery, and during follow-up period. We also evaluated pain and work status at the final follow-up using the Denis pain scale. RESULTS: In all cases, non-union or loosening of implants was not observed. There were two screw breakages in two-level posterior fixation group, but bony union was obtained at the final follow-up. There were no significant differences in loss of anterior vertebral body height, correction loss, or change in adjacent discs. Also, in clinical evaluation, there was no significant difference in the neurological deficit of any patient during the follow-up period. CONCLUSIONS: In our study, two-level posterior fixation could be used successfully in selected cases of thoracolumbar burst fractures of 7 and 8 points in the load-sharing classification. PMID- 26929803 TI - Can We Prevent a Postoperative Spinal Epidural Hematoma by Using Larger Diameter Suction Drains? AB - BACKGROUND: Epidural hematoma is a rare but serious complication. According to previous studies, it is not prevented by suction drains. This study evaluated the following alternative hypothesis: the larger the diameter of a suction drain, the less the remaining epidural hematoma after spinal surgery. METHODS: This was a randomized prospective study. Patients who underwent posterior lumbar decompression and instrumented fusion were divided into two groups: the large drain (LD, 2.8-mm-diameter tube) and small drain (SD, 1.6-mm-diameter tube) groups according to the diameter of the suction drains. All patients were consecutive and allocated alternately according to the date of operations. Suction drains were removed on day 3 and magnetic resonance imaging was performed on day 7 postoperatively. The size of remaining hematomas was measured by the degree of thecal sac compression in cross section using the following 4-point numeric scale: G1, less than one quarter; G2, between one quarter and half; G3, more than half; and G4, more than subtotal obstruction. RESULTS: There were 39 patients with LDs and 38 with SDs. They did not differ significantly in terms of sex, number of fusion segments, revision or not, antiplatelet medication, intraoperative injection of tranexamic acid. However, patient age differed significantly between the two groups (LD, 63.3 years and < SD, 68.6 years; p = 0.007). The two groups did not differ significantly in terms of prothrombin time, activated partial thromboplastin time, platelet number, blood loss, or operation duration. However, platelet function analysis exhibited a significant difference (LD, 164.7 seconds and < SD, 222.3 seconds; p = 0.002). The two blinded readers showed high consistency (Kappa value = 0.740; p = 0.000). The results of reader 1 were as follows: LD and SD had 21 and 21 cases of G1, 9 and 11 cases of G2, 6 and 6 cases of G3, and 3 and 0 cases of G4, respectively. The results of reader 2 were as follows: LD and SD had 22 and 23 cases of G1, 7 and 9 cases of G2, 7 and 6 cases of G3, and 3 and 0 cases of G4, respectively. There was no difference between the two groups (reader 1, p = 0.636; reader 2, p = 0.466). CONCLUSIONS: The alternative hypothesis was rejected. Therefore, postoperative spinal epidural hematoma would not be prevented by LD. PMID- 26929804 TI - Biomechanical Comparison of the Latarjet Procedure with and without Capsular Repair. AB - BACKGROUND: The purpose of this study was to determine if capsular repair used in conjunction with the Latarjet procedure results in significant alterations in glenohumeral rotational range of motion and translation. METHODS: Glenohumeral rotational range of motion and translation were measured in eight cadaveric shoulders in 90 degrees of abduction in both the scapular and coronal planes under the following four conditions: intact glenoid, 20% bony Bankart lesion, modified Latarjet without capsular repair, and modified Latarjet with capsular repair. RESULTS: Creation of a 20% bony Bankart lesion led to significant increases in anterior and inferior glenohumeral translation and rotational range of motion (p < 0.005). The Latarjet procedure restored anterior and inferior stability compared to the bony Bankart condition. It also led to significant increases in glenohumeral internal and external rotational range of motion relative to both the intact and bony Bankart conditions (p < 0.05). The capsular repair from the coracoacromial ligament stump to the native capsule did not significantly affect translations relative to the Latarjet condition; however it did cause a significant decrease in external rotation in both the scapular and coronal planes (p < 0.005). CONCLUSIONS: The Latarjet procedure is effective in restoring anteroinferior glenohumeral stability. The addition of a capsular repair does not result in significant added stability; however, it does appear to have the effect of restricting glenohumeral external rotational range of motion relative to the Latarjet procedure performed without capsular repair. PMID- 26929806 TI - Computer-Assisted Rotational Acetabular Osteotomy for Patients with Acetabular Dysplasia. AB - Rotational acetabular osteotomy (RAO) is a well-established surgical procedure for patients with acetabular dysplasia, and excellent long-term results have been reported. However, RAO is technically demanding and precise execution of this procedure requires experience with this surgery. The usefulness of computer navigation in RAO includes its ability to perform three-dimensional (3D) preoperative planning, enable safe osteotomy even with a poor visual field, reduce exposure to radiation from intraoperative fluoroscopy, and display the tip position of the chisel in real time, which is educationally useful as it allows staff other than the operator to follow the progress of the surgery. In our results comparing 23 hips that underwent RAO with navigation and 23 hips operated on without navigation, no significant difference in radiological assessment was observed. However, no perioperative complications were observed in the navigation group whereas one case of transient femoral nerve palsy was observed in non navigation group. A more accurate and safer RAO can be performed using 3D preoperative planning and intraoperative assistance with a computed tomography based navigation system. PMID- 26929805 TI - The Efficacy of Percutaneous Lateral Hemiepiphysiodesis on Angular Correction in Idiopathic Adolescent Genu Varum. AB - BACKGROUND: Percutaneous lateral hemiepiphysiodesis of the lower extremity is a simple and excellent method to correct the angular and length problems cosmetically. However, the efficacy of percutaneous lateral hemiepiphysiodesis is not well established in the literature. The purpose of this study was to evaluate the efficacy of percutaneous lateral hemiepiphysiodesis for angular corrections in adolescent idiopathic genu varum patients with proximal tibia vara and identify the factors affecting the amount of deformity correction of the lower limb in the coronal plane. METHODS: We retrospectively reviewed 20 patients (40 lower limbs) who had percutaneous lateral hemiepiphysiodesis on the proximal lateral tibia between 1997 and 2010. Radiographic evaluations were made using (1) the hip-knee-ankle angle and (2) the length of the tibia. Furthermore, the intercondylar distance was evaluated at the level of the knee joint. Preoperative factors (gender, age, body mass index, intercondylar distance, preoperative hip knee-ankle angle, remaining growth of tibia, and calculated correctable angle) were analyzed, as well as their correlation with the degree of the actual correction angle. RESULTS: The amount of coronal deformity of the lower limb was improved from its preoperative state. The median average of hip-knee-ankle angle improved from 8.0 degrees (interquartile range [IQR], 7.0 degrees to 10.0 degrees ) preoperatively to 3.0 degrees (IQR, 2.5 degrees to 4.0 degrees ) at the final follow-up (p < 0.001). The median percent ratio of the angular correction was 60% (IQR, 50% to 71.3%). The correlation coefficients were -0.537, 0.832, 0.791, and 0.685 for the bone age, preoperative hip-knee-ankle angle, the remaining growth of tibia, and calculated correctable angle, respectively. CONCLUSIONS: Despite the excellent cosmetic outcome of percutaneous lateral hemiepiphysiodesis on the proximal lateral tibia in adolescent idiopathic genu varum, the effect was limited in most cases. For optimum results, surgery a few months earlier is recommended, rather than at the calculated operation time. PMID- 26929807 TI - Bursectomy, Curettage, and Chemotherapy in Tuberculous Trochanteric Bursitis. AB - We presented three patients with trochanteric tuberculosis and described the clinical and imaging findings of the infection. Histology revealed a necrotizing granulomatous bursitis and microbiology confirmed tuberculosis. All cases were successfully treated with bursectomy and curettage of the trochanteric lesion and antituberculous chemotherapy including isoniazid, pyrazinamide, rifampicin, and ethambutol. PMID- 26929809 TI - Compartment Syndrome Following Arthroscopic Removal of a Bullet in the Knee Joint after a Low-Velocity Gunshot Injury. AB - Gunshot injuries are getting more frequently reported while the civilian (nongovernmental) armament increases in the world. A 42-year-old male patient presented to emergency room of Istanbul Medipol University Hospital due to a low velocity gunshot injury. We detected one entry point on the posterior aspect of the thigh, just superior to the popliteal groove. No exit wound was detected on his physical examination. There was swelling around the knee and range of motion was limited due to pain and swelling. Neurological and vascular examinations were intact. Following the initial assessment, the vascular examination was confirmed by doppler ultrasonography of the related extremity. There were no signs of compartment syndrome in the preoperative physical examination. A bullet was detected in the knee joint on the initial X-rays. Immediately after releasing the tourniquet, swelling of the anterolateral compartment of the leg and pulse deficiency was detected on foot in the dorsalis pedis artery. Although the arthroscopic removal of intra-articular bullets following gunshot injuries seems to have low morbidity rates, it should always be considered that the articular capsule may have been ruptured and the fluids used during the operation may leak into surrounding tissues and result in compartment syndrome. PMID- 26929808 TI - Injury to the Anterior Tibial Artery during Bicortical Tibial Drilling in Anterior Cruciate Ligament Reconstruction. AB - Many complications have been reported during or after anterior cruciate ligament (ACL) reconstruction, including infection, bleeding, tibial tunnel widening, arthrofibrosis, and graft failure. However, arterial injury has been rarely reported. This paper reports a case of an anterior tibial arterial injury during bicortical tibial drilling in arthroscopic ACL reconstruction, associated with an asymptomatic occlusion of the popliteal artery. The patient had a vague pain which led to delayed diagnosis of compartment syndrome and delayed treatment with fasciotomy. All surgeons should be aware of these rare but critical complications because the results may be disastrous like muscle necrosis as in this case. PMID- 26929810 TI - Is Antegrade Transmalleolar Drilling Method for Osteochondral Lesion of Talus Necessary? Iatrogenic Cystic Formation at the Tibia: A Report of Five Cases. AB - Antegrade transmalleolar drilling method is one of the options for the treatment of osteochondral lesion of talus (OLT). We present five patients who underwent tibial drilling for treatment of OLT and later developed distal tibial cystic formation induced by cartilage opening or heat necrosis during drilling. Antegrade transmalleolar drilling can be a possible option for the treatment of OLT if the lesion is not easily reachable; however, other viable treatment should be considered due to its possibility of distal tibial pathologic change. PMID- 26929811 TI - Osteochondroma Arising from Anterior Inferior Iliac Spine as a Cause of Snapping Hip. AB - Snapping hip syndrome is a relatively common problem that can be easily managed with conservative treatment. This syndrome can be divided into external, internal and intra-articular types. Internal snapping hip syndrome is the rarest amongst these and its etiology is not well understood. We report a unique case of osteochondroma arising from the anterior inferior iliac spine (AIIS), which caused the internal snapping hip syndrome with hip pain and restriction of activity. This rare case of snapping hip syndrome from the AIIS was treated surgically and the symptoms completely disappeared after excision of the tumor. PMID- 26929815 TI - Reproductive cycles and reproductive strategies among populations of the Rose bellied Lizard Sceloporus variabilis (Squamata: Phrynosomatidae) from central Mexico. AB - Species with wide distribution, generally show variations in life history characteristics, which can be attributed to environmental causes. In this study, we analyzed the reproductive cycle and reproductive characteristics from three populations (Atlapexco, San Pablo Tetlapayac, and Santa Catarina) of the lizard Sceloporus variabilis from central Mexico. The specific goal of this study was to evaluate life history characteristics such as reproductive period extent, SVL (snout-vent length) at sexual maturity, clutch size, egg mass and volume, and RCM (relative clutch mass). The San Pablo Tetlapayac population showed a larger clutch size, RCM, egg mass, and a smaller SVL, body mass and reproductive period (January-September), as well as egg volume than the Atlapexco and Santa Catarina populations. Reproductive cycle and reproductive characteristics were more similar between the Atlapexco and Santa Catarina populations. Differences found in the population of San Pablo Tetlapayac with respect to the Atlapexco and Santa Catarina populations could be attributed to environmental variations where lizard populations occur. Differences in the reproductive period and reproductive characteristics in each population could be the result of both historical (phylogenetic; e.g., reproductive mode) and nonhistorical (environmental; e.g., temperature, food availability) causes. This study showed that populations of the same species are under different selection pressures, and these affect the reproductive characteristics of populations. Our results also indicate that long term and targeted studies on predation, use and selection of food, are needed to determine the causes of these variations in populations of S. variabilis. PMID- 26929814 TI - Scaling the consequences of interactions between invaders from the individual to the population level. AB - The impact of human-induced stressors, such as invasive species, is often measured at the organismal level, but is much less commonly scaled up to the population level. Interactions with invasive species represent an increasingly common source of stressor in many habitats. However, due to the increasing abundance of invasive species around the globe, invasive species now commonly cause stresses not only for native species in invaded areas, but also for other invasive species. I examine the European green crab Carcinus maenas, an invasive species along the northeast coast of North America, which is known to be negatively impacted in this invaded region by interactions with the invasive Asian shore crab Hemigrapsus sanguineus. Asian shore crabs are known to negatively impact green crabs via two mechanisms: by directly preying on green crab juveniles and by indirectly reducing green crab fecundity via interference (and potentially exploitative) competition that alters green crab diets. I used life-table analyses to scale these two mechanistic stressors up to the population level in order to examine their relative impacts on green crab populations. I demonstrate that lost fecundity has larger impacts on per capita population growth rates, but that both predation and lost fecundity are capable of reducing population growth sufficiently to produce the declines in green crab populations that have been observed in areas where these two species overlap. By scaling up the impacts of one invader on a second invader, I have demonstrated that multiple documented interactions between these species are capable of having population level impacts and that both may be contributing to the decline of European green crabs in their invaded range on the east coast of North America. PMID- 26929813 TI - Costs of resistance and infection by a generalist pathogen. AB - Pathogen infection is typically costly to hosts, resulting in reduced fitness. However, pathogen exposure may also come at a cost even if the host does not become infected. These fitness reductions, referred to as "resistance costs", are inducible physiological costs expressed as a result of a trade-off between resistance to a pathogen and aspects of host fitness (e.g., reproduction). Here, we examine resistance and infection costs of a generalist fungal pathogen (Metschnikowia bicuspidata) capable of infecting a number of host species. Costs were quantified as reductions in host lifespan, total reproduction, and mean clutch size as a function of pathogen exposure (resistance cost) or infection (infection cost). We provide empirical support for infection costs and modest support for resistance costs for five Daphnia host species. Specifically, only one host species examined incurred a significant cost of resistance. This species was the least susceptible to infection, suggesting the possibility that host susceptibility to infection is associated with the detectability and size of resistance cost. Host age at the time of pathogen exposure did not influence the magnitude of resistance or infection cost. Lastly, resistant hosts had fitness values intermediate between unexposed control hosts and infected hosts. Although not statistically significant, this could suggest that pathogen exposure does come at some marginal cost. Taken together, our findings suggest that infection is costly, resistance costs may simply be difficult to detect, and the magnitude of resistance cost may vary among host species as a result of host life history or susceptibility. PMID- 26929812 TI - Overexpression of Homer1a in the basal and lateral amygdala impairs fear conditioning and induces an autism-like social impairment. AB - BACKGROUND: Autism spectrum disorders (ASDs) represent a heterogeneous group of disorders with a wide range of behavioral impairments including social and communication deficits. Apart from these core symptoms, a significant number of ASD individuals display higher levels of anxiety, and some studies indicate that a subset of ASD individuals have a reduced ability to be fear conditioned. Deciphering the molecular basis of ASD has been considerably challenging and it currently remains poorly understood. In this study we examined the molecular basis of autism-like impairments in an environmentally induced animal model of ASD, where pregnant rats are exposed to the known teratogen, valproic acid (VPA), on day 12.5 of gestation and the subsequent progeny exhibit ASD-like symptoms. We focused our analysis on the basal and lateral nucleus of the amygdala (BLA), a region of the brain found to be associated with ASD pathology. METHODS: We performed whole genome gene expression analysis on the BLA using DNA microarrays to examine differences in gene expression within the amygdala of VPA-exposed animals. We validated one VPA-dysregulated candidate gene (Homer1a) using both quantitative PCR (qRT-PCR) and western blot. Finally, we overexpressed Homer1a within the basal and lateral amygdala of naive animals utilizing adeno-associated viruses (AAV) and subsequently examined these animals in a battery of behavioral tests associated with ASD, including auditory fear conditioning, social interaction and open field. RESULTS: Our microarray data indicated that Homer1a was one of the genes which exhibited a significant upregulation within the amygdala. We observed an increase in Homer1a messenger RNA (mRNA) and protein in multiple cohorts of VPA-exposed animals indicating that dysregulation of Homer1a levels might underlie some of the symptoms exhibited by VPA-exposed animals. To test this hypothesis, we overexpressed Homer1a within BLA neurons utilizing a viral-mediated approach and found that overexpression of Homer1a impaired auditory fear conditioning and reduced social interaction, while having no influence on open-field behavior. CONCLUSIONS: This study indicates that dysregulation of amygdala Homer1a might contribute to some autism-like symptoms induced by VPA exposure. These findings are interesting in part because Homer1a influences the functioning of Shank3, metabotropic glutamate receptors (mGluR5), and Homer1, and these proteins have previously been associated with ASD, indicating that these differing models of ASD may have a similar molecular basis. PMID- 26929816 TI - Scorched mussels (Brachidontes spp., Bivalvia: Mytilidae) from the tropical and warm-temperate southwestern Atlantic: the role of the Amazon River in their speciation. AB - Antitropicality is a distribution pattern where closely related taxa are separated by an intertropical latitudinal gap. Two potential examples include Brachidontes darwinianus (south eastern Brazil to Uruguay), considered by some authors as a synonym of B. exustus (Gulf of Mexico and the Caribbean), and B. solisianus, distributed along the Brazilian coast with dubious records north of the intertropical zone. Using two nuclear (18S and 28S rDNA) and one mitochondrial gene (mtDNA COI), we aimed to elucidate the phylogeographic and phylogenetic relationships among the scorched mussels present in the warm temperate region of the southwest Atlantic. We evaluated a divergence process mediated by the tropical zone over alternative phylogeographic hypotheses. Brachidontes solisianus was closely related to B. exustus I, a species with which it exhibits an antitropical distribution. Their divergence time was approximately 2.6 Ma, consistent with the intensification of Amazon River flow. Brachidontes darwinianus, an estuarine species is shown here not to be related to this B. exustus complex. We suspect ancestral forms may have dispersed from the Caribbean to the Atlantic coast via the Trans-Amazonian seaway (Miocene). The third species, B rodriguezii is presumed to have a long history in the region with related fossil forms going back to the Miocene. Although scorched mussels are very similar in appearance, their evolutionary histories are very different, involving major historical contingencies as the formation of the Amazon River, the Panama Isthmus, and the last marine transgression. PMID- 26929817 TI - Sex roles in nest keeping - how information asymmetry contributes to parent offspring co-adaptation. AB - Parental food provisioning and offspring begging influence each other reciprocally. This makes both traits agents and targets of selection, which may ultimately lead to co-adaptation. The latter may reflect co-adapted parent and offspring genotypes or could be due to maternal effects. Maternal effects are in turn likely to facilitate in particular mother-offspring co-adaptation, further emphasized by the possibility that mothers are sometimes found to be more responsive to offspring need. However, parents may not only differ in their sensitivity, but often play different roles in postnatal care. This potentially impinges on the access to information about offspring need. We here manipulated the information on offspring need as perceived by parents by playing back begging calls at a constant frequency in the nest-box of blue tits (Cyanistes caeruleus). We measured the parental response in provisioning to our treatment, paying particular attention to sex differences in parental roles and whether such differences alter the perception of the intensity of our manipulation. This enabled us to investigate whether an information asymmetry about offspring need exists between parents and how such an asymmetry relates to co-adaptation between parental provisioning and offspring begging. Our results show that parents indeed differed in the frequency how often they perceived the playback due to the fact that females spent more time with their offspring in the nest box. Correcting for the effective exposure of an adult to the playback, the parental response in provisioning covaried more strongly (positive) with offspring begging intensity, independent of the parental sex, indicating coadaptation on the phenotypic level. Females were not more sensitive to experimentally increased offspring need than males, but they were exposed to more broadcasted begging calls. Therefore, sex differences in access to information about offspring need, due to different parental roles, have the potential to impinge on family conflicts and their resolution. PMID- 26929818 TI - Vitally important - does early innate immunity predict recruitment and adult innate immunity? AB - The immune system is one of the most important adaptations that has evolved to protect animals from a wide range of pathogens they encounter from early life onwards. During the early developmental period this is particularly true for the innate immunity, as other components of the immune system are, as yet, poorly developed. But innate immunity may not only be crucial for early life survival, but may also have long-lasting effects, for example if early life immunity reflects the functioning of the immune system as a whole. For this reason, we investigated the importance of four constitutive innate immune parameters (natural antibodies, complement activity, concentrations of haptoglobin, and concentrations of nitric oxide) for recruitment in free-living great tits. We compared nestling immunity of recruits with nestling immunity of their nonrecruited siblings. We also investigated within individual consistency of these innate immune parameters for those individuals that recruited, which may be taken as a measure of immune capacity. In accordance with previous studies, we found a clear effect of tarsus length and a trend for body mass on the likelihood to recruit. Nevertheless, we found no evidence that higher levels of constitutive innate immunity as a nestling facilitated local recruitment. Furthermore, individual innate immunity was not consistent across life stages, that is to say, nestling immune parameters did not determine, or respectively, reflect adult innate immune parameters. This plasticity in innate immune components may explain why we did not find long-lasting survival benefits. PMID- 26929819 TI - Spatial diversity patterns of Pristimantis frogs in the Tropical Andes. AB - Although biodiversity gradients have been widely documented, the factors governing broad-scale patterns in species richness are still a source of intense debate and interest in ecology, evolution, and conservation biology. Here, we tested whether spatial hypotheses (species-area effect, topographic heterogeneity, mid-domain null model, and latitudinal effect) explain the pattern of diversity observed along the altitudinal gradient of Andean rain frogs of the genus Pristimantis. We compiled a gamma-diversity database of 378 species of Pristimantis from the tropical Andes, specifically from Colombia to Bolivia, using records collected above 500 m.a.s.l. Analyses were performed at three spatial levels: Tropical Andes as a whole, split in its two main domains (Northern and Central Andes), and split in its 11 main mountain ranges. Species richness, area, and topographic heterogeneity were calculated for each 500-m width elevational band. Spatial hypotheses were tested using linear regression models. We examined the fit of the observed diversity to the mid-domain hypothesis using randomizations. The species richness of Pristimantis showed a hump-shaped pattern across most of the altitudinal gradients of the Tropical Andes. There was high variability in the relationship between area and species richness along the Tropical Andes. Correcting for area effects had little impact in the shape of the empirical pattern of biodiversity curves. Mid-domain models produced similar gradients in species richness relative to empirical gradients, but the fit varied among mountain ranges. The effect of topographic heterogeneity on species richness varied among mountain ranges. There was a significant negative relationship between latitude and species richness. Our findings suggest that spatial processes partially explain the richness patterns of Pristimantis frogs along the Tropical Andes. Explaining the current patterns of biodiversity in this hot spot may require further studies on other possible underlying mechanisms (e.g., historical, biotic, or climatic hypotheses) to elucidate the factors that limit the ranges of species along this elevational gradient. PMID- 26929820 TI - 'Blood doping' from Armstrong to prehabilitation: manipulation of blood to improve performance in athletes and physiological reserve in patients. AB - Haemoglobin is the blood's oxygen carrying pigment and is encapsulated in red blood corpuscles. The concentration of haemoglobin in blood is dependent on both its total mass in the circulation (tHb-mass) and the total plasma volume in which it is suspended. Aerobic capacity is defined as the maximum amount of oxygen that can be consumed by the body per unit time and is one measure of physical fitness. Observations in athletes who have undergone blood doping or manipulation have revealed a closer relationship between physical fitness (aerobic capacity) and total haemoglobin mass (tHb-mass) than with haemoglobin concentration ([Hb]). Anaemia is defined by the World Health Organisation (WHO) as a haemoglobin concentration of <130 g/L for men and <120 g/L for women. Perioperative anaemia is a common problem and is associated with increased mortality and morbidity following surgery. Aerobic capacity is also associated with outcome following major surgery, with less fit patients having a higher incidence of mortality and morbidity after surgery. Taken together, these observations suggest that targeted preoperative elevation of tHb-mass may raise aerobic capacity both directly and indirectly (by augmenting preoperative exercise initiatives- 'prehabilitation') and thus improve postoperative outcome. This notion in turn raises a number of questions. Which measure ([Hb] or tHb-mass) has the most value for the description of oxygen carrying capacity? Which measure has the most utility for targeting therapies to manipulate haemoglobin levels? Do the newer agents being used for blood manipulation (to increase tHb-mass) in elite sport have utility in the clinical environment? This review explores the literature relating to blood manipulation in elite sport as well as the relationship between perioperative anaemia, physical fitness and outcome following surgery, and suggests some avenues for exploring this area further. PMID- 26929821 TI - Towards use of MRI-guided ultrasound for treating cerebral vasospasm. AB - Cerebral vasospasm is a major cause of morbidity and mortality in patients with subarachnoid hemorrhage (SAH), causing delayed neurological deficits in as many as one third of cases. Existing therapy targets induction of cerebral vasodilation through use of various drugs and mechanical means, with a range of observed efficacy. Here, we perform a literature review supporting our hypothesis that transcranially delivered ultrasound may have the ability to induce therapeutic cerebral vasodilation and, thus, may one day be used therapeutically in the context of SAH. Prior studies demonstrate that ultrasound can induce vasodilation in both normal and vasoconstricted blood vessels in peripheral tissues, leading to reduced ischemia and cell damage. Among the proposed mechanisms is alteration of several nitric oxide (NO) pathways, where NO is a known vasodilator. While in vivo studies do not point to a specific physical mechanism, results of in vitro studies favor cavitation induction by ultrasound, where the associated shear stresses likely induce NO production. Two papers discussed the effects of ultrasound on the cerebral vasculature. One study applied clinical transcranial Doppler ultrasound to a rodent complete middle cerebral artery occlusion model and found reduced infarct size. A second involved the application of pulsed ultrasound in vitro to murine brain endothelial cells and showed production of a variety of vasodilatory chemicals, including by products of arachidonic acid metabolism. In sum, nine reviewed studies demonstrated evidence of either cerebrovascular dilation or elaboration of vasodilatory compounds. Of particular interest, all of the reviewed studies used ultrasound capable of transcranial application: pulsed ultrasound, with carrier frequencies ranging between 0.5 and 2.0 MHz, and intensities not substantially above FDA-approved intensity values. We close by discussing potential specific treatment paradigms of SAH and other cerebral ischemic disorders based on MRI guided transcranial ultrasound. PMID- 26929822 TI - Risk profiles of lipids, blood pressure, and anthropometric measures in childhood and adolescence: project heartBeat! AB - BACKGROUND: Many common risk factors for cardiovascular disease (CVD) originate in childhood and adolescence. There is a lack of literature examining variability within study populations, as well as a shortage of simultaneous analyses of CVD risk factors operating in tandem. METHODS: We used data from Project HeartBeat!-a multi-cohort longitudinal growth study of children and adolescents in the US - for assessing multiple profiles for lipids, blood pressure, and anthropometric measures. Principal component functional curve analysis methods were used to summarize trajectories of multiple measurements. Subsequently less favorable health (high risk) and more favorable (low risk) groups from both female and male cohorts were identified and compared to US national norms. RESULTS: Compared to national norms, the high risk groups have increased waist circumference, body mass index, and percent body fat as well as higher low-density lipoprotein cholesterol and triglyceride levels, and lower high-density lipoprotein cholesterol. The risk profiles also exhibit patterns of convergence and divergence across the high and low risk groups as a function of age. CONCLUSIONS: These observations may have clinical and public health implications in identifying groups of children at high risk of CVD for earlier interventions. PMID- 26929823 TI - Impact of uncontrolled hypertension on 12-month clinical outcomes following below the-knee arteries (BTK) interventions in patients with critical limb ischemia. AB - BACKGROUND: Despite intensive anti-hypertensive treatment, overall control rates of only 30 ~ 50 % have been reported in patients with hypertension (HTN). However, clinical significance and angiographic characteristics of patients with uncontrolled HTN following Below-the-knee arteries (BTK) interventions in patients with critical limb ischemia (CLI) are not clarified yet as compared to those with controlled HTN. METHODS: A total 165 consecutive hypertensive patients with BTK lesions from August 2004 to November 2012 were enrolled for this study. Uncontrolled HTN was defined as a blood pressure of > 140 mmHg systolic and 90 mmHg diastolic under anti-hypertensive treatment. A total of 112 patients (67.8 %) had uncontrolled HTN. We compared the clinical and angiographic characteristics of patients with uncontrolled HTN following BTK interventions to those with controlled HTN at 12-month follow-up. RESULTS: The baseline characteristics are well balanced between the two groups. At 12 months, there was no difference in the incidence of mortality, target lesion revascularization (TLR), target extremity revascularization (TER), and limb salvage rate in both groups. However, amputation rates were higher in patients with controlled HTN (33.9 vs. 19.6 %, P = 0.045). CONCLUSION: Regardless of blood pressure control, HTN itself was an independent risk factor for BTK lesions, suggesting more intensive medical therapy with close clinical follow up will be required for all BTK patients with HTN. PMID- 26929825 TI - Estimating Benzene Exposure Level over Time and by Industry Type through a Review of Literature on Korea. AB - The major purpose of this study is to construct a retrospective exposure assessment for benzene through a review of literature on Korea. Airborne benzene measurements reported in 34 articles were reviewed. A total of 15,729 individual measurements were compiled. Weighted arithmetic means [AM(w)] and their variance calculated across studies were summarized according to 5-year period intervals (prior to the 1970s through the 2010s) and industry type. Industries were classified according to Korea Standard Industrial Classification (KSIC) using information provided in the literature. We estimated quantitative retrospective exposure to benzene for each cell in the matrix through a combination of time and KSIC. Analysis of the AM(w) indicated reductions in exposure levels over time, regardless of industry, with mean levels prior to the 1980-1984 period of 50.4 ppm (n = 2,289), which dropped to 2.8 ppm (n = 305) in the 1990-1994 period, and to 0.1 ppm (n = 294) in the 1995-1999 period. There has been no improvement since the 2000s, when the AM(w) of 4.3 ppm (n = 6,211) for the 2005-2009 period and 4.5 ppm (n = 3,358) for the 2010-2013 period were estimated. A comparison by industry found no consistent patterns in the measurement results. Our estimated benzene measurements can be used to determine not only the possibility of retrospective exposure to benzene, but also to estimate the level of quantitative or semiquantitative retrospective exposure to benzene. PMID- 26929824 TI - Review and Evaluation of Hand-Arm Coordinate Systems for Measuring Vibration Exposure, Biodynamic Responses, and Hand Forces. AB - The hand coordinate systems for measuring vibration exposures and biodynamic responses have been standardized, but they are not actually used in many studies. This contradicts the purpose of the standardization. The objectives of this study were to identify the major sources of this problem, and to help define or identify better coordinate systems for the standardization. This study systematically reviewed the principles and definition methods, and evaluated typical hand coordinate systems. This study confirms that, as accelerometers remain the major technology for vibration measurement, it is reasonable to standardize two types of coordinate systems: a tool-based basicentric (BC) system and an anatomically based biodynamic (BD) system. However, these coordinate systems are not well defined in the current standard. Definition of the standard BC system is confusing, and it can be interpreted differently; as a result, it has been inconsistently applied in various standards and studies. The standard hand BD system is defined using the orientation of the third metacarpal bone. It is neither convenient nor defined based on important biological or biodynamic features. This explains why it is rarely used in practice. To resolve these inconsistencies and deficiencies, we proposed a revised method for defining the realistic handle BC system and an alternative method for defining the hand BD system. A fingertip-based BD system for measuring the principal grip force is also proposed based on an important feature of the grip force confirmed in this study. PMID- 26929826 TI - A Review on Mutagenicity Testing for Hazard Classification of Chemicals at Work: Focusing on in vivo Micronucleus Test for Allyl Chloride. AB - Chemical mutagenicity is a major hazard that is important to workers' health. Despite the use of large amounts of allyl chloride, the available mutagenicity data for this chemical remains controversial. To clarify the mutagenicity of allyl chloride and because a micronucleus (MN) test had not yet been conducted, we screened for MN induction by using male ICR mice bone marrow cells. The test results indicated that this chemical is not mutagenic under the test conditions. In this paper, the regulatory test battery and several assay combinations used to determine the genotoxic potential of chemicals in the workplace have been described. Further application of these assays may prove useful in future development strategies of hazard evaluations of industrial chemicals. This study also should help to improve the testing of this chemical by commonly used mutagenicity testing methods and investigations on the underlying mechanisms and could be applicable for workers' health. PMID- 26929828 TI - Factors Influencing Implementation of OHSAS 18001 in Indian Construction Organizations: Interpretive Structural Modeling Approach. AB - BACKGROUND: Construction activity has made considerable breakthroughs in the past two decades on the back of increases in development activities, government policies, and public demand. At the same time, occupational health and safety issues have become a major concern to construction organizations. The unsatisfactory safety performance of the construction industry has always been highlighted since the safety management system is neglected area and not implemented systematically in Indian construction organizations. Due to a lack of enforcement of the applicable legislation, most of the construction organizations are forced to opt for the implementation of Occupational Health Safety Assessment Series (OHSAS) 18001 to improve safety performance. METHODS: In order to better understand factors influencing the implementation of OHSAS 18001, an interpretive structural modeling approach has been applied and the factors have been classified using matrice d'impacts croises-multiplication applique a un classement (MICMAC) analysis. The study proposes the underlying theoretical framework to identify factors and to help management of Indian construction organizations to understand the interaction among factors influencing in implementation of OHSAS 18001. RESULTS: Safety culture, continual improvement, morale of employees, and safety training have been identified as dependent variables. Safety performance, sustainable construction, and conducive working environment have been identified as linkage variables. Management commitment and safety policy have been identified as the driver variables. CONCLUSION: Management commitment has the maximum driving power and the most influential factor is safety policy, which states clearly the commitment of top management towards occupational safety and health. PMID- 26929827 TI - Association Between Leisure Time Physical Activity, Cardiopulmonary Fitness, Cardiovascular Risk Factors, and Cardiovascular Workload at Work in Firefighters. AB - BACKGROUND: Overweight, obesity, and cardiovascular disease risk factors are prevalent among firefighters in some developed countries. It is unclear whether physical activity and cardiopulmonary fitness reduce cardiovascular disease risk and the cardiovascular workload at work in firefighters. The present study investigated the relationship between leisure-time physical activity, cardiopulmonary fitness, cardiovascular disease risk factors, and cardiovascular workload at work in firefighters in Hong Kong. METHODS: Male firefighters (n = 387) were randomly selected from serving firefighters in Hong Kong (n = 5,370) for the assessment of cardiovascular disease risk factors (obesity, hypertension, diabetes mellitus, dyslipidemia, smoking, known cardiovascular diseases). One third (Target Group) were randomly selected for the assessment of off-duty leisure-time physical activity using the short version of the International Physical Activity Questionnaire. Maximal oxygen uptake was assessed, as well as cardiovascular workload using heart rate monitoring for each firefighter for four "normal" 24-hour working shifts and during real-situation simulated scenarios. RESULTS: Overall, 33.9% of the firefighters had at least two cardiovascular disease risk factors. In the Target Group, firefighters who had higher leisure time physical activity had a lower resting heart rate and a lower average working heart rate, and spent a smaller proportion of time working at a moderate intensity cardiovascular workload. Firefighters who had moderate aerobic fitness and high leisure-time physical activity had a lower peak working heart rate during the mountain rescue scenario compared with firefighters who had low leisure-time physical activities. CONCLUSION: Leisure-time physical activity conferred significant benefits during job tasks of moderate cardiovascular workload in firefighters in Hong Kong. PMID- 26929829 TI - Body Sway as a Possible Indicator of Fatigue in Clerical Workers. AB - BACKGROUND: Fatigue has a strong impact on workers' performance and safety, but expedient methods for assessing fatigue on the job are not yet available. Studies discuss posturography as an indicator of fatigue, but further evidence for its use in the workplace is needed. The purpose of the study is to examine whether posturography is a suitable indicator of fatigue in clerical workers. METHODS: Thirty-six employees (O 34.8 years, standard deviation = 12.5) participated in postural tasks (eyes open, eyes closed, arm swinging, and dual task) in the morning and afternoon. Position of their center of pressure (COP) was registered using a Nintendo Wii Balance Board and commercial software. From registered COP time series, we calculated the following parameters: path length (mm), velocity (mm/s), anterior-posterior variance (mm), mediolateral variance (mm), and confidence area (mm(2)). These parameters were reduced to two orthogonal factors in a factor analysis with varimax rotation. RESULTS: Statistical analysis of the first factor (path length and velocity) showed a significant effect of time of day: COP moved along a shorter path at a lower velocity in the afternoon compared with that in the morning. There also was a significant effect of task, but no significant interaction. CONCLUSION: Data suggest that postural stability of clerical workers was comparable in the morning and afternoon, but COP movement was greater in the morning. Within the framework of dynamic systems theory, this could indicate that the postural system explored the state space in more detail, and thus was more ready to respond to unexpected perturbations in the morning. PMID- 26929830 TI - Factors Influencing Learning Satisfaction of Migrant Workers in Korea with E learning-Based Occupational Safety and Health Education. AB - BACKGROUND: E-learning-based programs have recently been introduced to the occupational safety and health (OSH) education for migrant workers in Korea. The purpose of this study was to investigate how the factors related to migrant workers' backgrounds and the instructional design affect the migrant workers' satisfaction with e-learning-based OSH education. METHODS: The data were collected from the surveys of 300 migrant workers who had participated in an OSH education program. Independent sample t test and one-way analysis of variance were conducted to examine differences in the degree of learning satisfaction using background variables. In addition, correlation analysis and multiple regression analysis were conducted to examine relationships between the instructional design variables and the degree of learning satisfaction. RESULTS: There was no significant difference in the degree of learning satisfaction by gender, age, level of education, number of employees, or type of occupation, except for nationality. Among the instructional design variables, "learning content" (beta = 0.344, p < 0.001) affected the degree of learning satisfaction most significantly, followed by "motivation to learn" (beta = 0.293, p < 0.001), "interactions with learners and instructors" (beta = 0.149, p < 0.01), and "previous experience related to e-learning" (beta = 0.095, p < 0.05). "Learning environment" had no significant influence on the degree of learning satisfaction. CONCLUSION: E-learning-based OSH education for migrant workers may be an effective way to increase their safety knowledge and behavior if the accuracy, credibility, and novelty of learning content; strategies to promote learners' motivation to learn; and interactions with learners and instructors are systematically applied during the development and implementation of e-learning programs. PMID- 26929831 TI - Trend of Occupational Injuries/Diseases in Pakistan: Index Value Analysis of Injured Employed Persons from 2001-02 to 2012-13. AB - BACKGROUND: The present study aimed to analyze the index value trends of injured employed persons (IEPs) covered in Pakistan Labour Force Surveys from 2001-02 to 2012-13. METHODS: The index value method based on reference years and reference groups was used to analyze the IEP trends in terms of different criteria such as gender, area, employment status, industry types, occupational groups, types of injury, injured body parts, and treatment received. The Pearson correlation coefficient analysis was also performed to investigate the inter-relationship of different occupational variables. RESULTS: The values of IEP increased at the end of the studied year in industry divisions such as agriculture, forestry, hunting, and fishing, followed by in manufacturing and construction industry divisions. People associated with major occupations (such as skilled agricultural and fishery workers) and elementary (unskilled) occupations were found to be at an increasing risk of occupational injuries/diseases with an increasing IEP trend. Types of occupational injuries such as sprain or strain, superficial injury, and dislocation increased during the studied years. Major injured parts of body such as upper limb and lower limb found with increasing trend. Types of treatment received, including hospitalization and no treatment, were found to decrease. Increased IEP can be justified due to inadequate health care facilities, especially in rural areas by increased IEP in terms of gender, areas, received treatment, occupational groups and employment status as results found after Pearson correlation coefficient analysis. CONCLUSION: The increasing trend in the IEP% of the total employed persons due to agrarian activities shows that there is a need to improve health care setups in rural areas of Pakistan. PMID- 26929832 TI - Surprising Incentive: An Instrument for Promoting Safety Performance of Construction Employees. AB - BACKGROUND: In comparison with other industries, the construction industry still has a higher rate of fatal injuries, and thus, there is a need to apply new and innovative approaches for preventing accidents and promoting safe conditions at construction sites. METHODS: In this study, the effectiveness of a new incentive system-the surprising incentive system-was assessed. One year after the implementation of this new incentive system, behavioral changes of employees with respect to seven types of activities were observed. RESULTS: The results of this study showed that there is a significant relationship between the new incentive system and the safety performance of frontline employees. The new incentive system had a greater positive impact in the first 6 months since its implementation. In the long term, however, safety performance experienced a gradual reduction. Based on previous studies, all activities selected in this study are important indicators of the safety conditions at workplaces. However, there is a need for a comprehensive and simple-to-apply tool for assessing frontline employees' safety performance. Shortening the intervals between incentives is more effective in promoting safety performance. CONCLUSION: The results of this study proved that the surprising incentive would improve the employees' safety performance just in the short term because the surprising value of the incentives dwindle over time. For this reason and to maintain the surprising value of the incentive system, the amount and types of incentives need to be evaluated and modified annually or biannually. PMID- 26929833 TI - Reliability and Validity of the Greek Version of the Job Content Questionnaire in Greek Health Care Workers. AB - BACKGROUND: The Job Content Questionnaire (JCQ), which is based on the Demand Control-Support model, is designed to measure the psychosocial characteristics of the respondent's work, and has been identified to predict health and psychological outcomes. The purpose of this study was to investigate the psychometric properties of this instrument and the subsequent adaptation of its scales to the population of Greek health workers. METHODS: The Greek version of the JCQ was developed by using forward- and back-translation in accordance with the JCQ policy. The reliability and validity of the measure were investigated in a sample of health workers working in a hospital in Athens, Greece. The internal consistency of the scales was examined based on Cronbach alpha coefficients, and the validity was evaluated subjecting the items of the three main scales of the JCQ (decision latitude, psychological job demands, and social support) to exploratory and confirmatory factor analysis. RESULTS: The reliability of the scales was found to be acceptable for all the scales, except for the skill discretion subscale. Confirmatory factor analysis confirmed a slightly modified version of the original construct including several items to more than one factor. CONCLUSION: Our findings suggest that the Greek JCQ is reliable and valid for investigating psychosocial job characteristics among Greek health workers. PMID- 26929834 TI - Self-Reported Recovery from 2-Week 12-Hour Shift Work Schedules: A 14-Day Follow Up. AB - BACKGROUND: Recovery from fatigue is important in maintaining night workers' health. This study compared the course of self-reported recovery after 2-week 12 hour schedules consisting of either night shifts or swing shifts (i.e., 7 night shifts followed by 7 day shifts) to such schedules consisting of only day work. METHODS: Sixty-one male offshore employees-20 night workers, 16 swing shift workers, and 25 day workers-rated six questions on fatigue (sleep quality, feeling rested, physical and mental fatigue, and energy levels; scale 1-11) for 14 days after an offshore tour. After the two night-work schedules, differences on the 1(st) day (main effects) and differences during the follow-up (interaction effects) were compared to day work with generalized estimating equations analysis. RESULTS: After adjustment for confounders, significant main effects were found for sleep quality for night workers (1.41, 95% confidence interval 1.05-1.89) and swing shift workers (1.42, 95% confidence interval 1.03-1.94) when compared to day workers; their interaction terms were not statistically significant. For the remaining fatigue outcomes, no statistically significant main or interaction effects were found. CONCLUSION: After 2-week 12-hour night and swing shifts, only the course for sleep quality differed from that of day work. Sleep quality was poorer for night and swing shift workers on the 1(st) day off and remained poorer for the 14-day follow-up. This showed that while working at night had no effect on feeling rested, tiredness, and energy levels, it had a relatively long-lasting effect on sleep quality. PMID- 26929835 TI - Does Leaders' Health (and Work-Related Experiences) Affect their Evaluation of Followers' Stress? AB - BACKGROUND: Stressed workers suffer from severe health problems which appear to have increased. Poor leadership is especially considered a source of stress. Indeed, supervisors might perceive their subordinates to be similar to them as far as stress is concerned and this might more widespread in organizations than previously thought. METHODS: The present research investigates the relationships between leaders' health, in terms of work-related stress, mental health, and workplace bullying and their evaluation of subordinates' stress. Five regression models were formulated to test our hypothesis. This is a cross-sectional study among 261 Italian leaders, using supervisor self-assessment and leaders' assessments of their subordinates. RESULTS: Leaders' health was related to their evaluation of staff stress. Job demand, lack of job control, and lack of support by colleagues and supervisors evaluated in their subordinates were particularly associated with the leaders' own health. CONCLUSION: Implications for developing healthy leaders are finally discussed. PMID- 26929836 TI - Effects of Low-Dose Aspirin Therapy on Thermoregulation in Firefighters. AB - BACKGROUND: Heart attack is the most common cause of line-of-duty death in the fire service. Daily aspirin therapy is a preventative measure used to reduce the morbidity of heart attacks but may decrease the ability to dissipate heat by reducing skin blood flow. METHODS: In this double-blind, placebo-controlled, crossover study, firefighters were randomized to receive 14 days of therapy (81 mg aspirin or placebo) before performing treadmill exercise in thermal-protective clothing in a hot room [38.8 +/- 2.1 degrees C, 24.9 +/- 9.1% relative humidity (RH)]. Three weeks without therapy was provided before crossing to the other arm. Firefighters completed a baseline skin blood-flow assessment via laser Doppler flowmetry; skin was heated to 44 degrees C to achieve maximal cutaneous vasodilation. Skin blood flow was measured before and after exercise in a hot room, and at 0 minutes, 10 minutes, 20 minutes, and 30 minutes of recovery under temperature conditions (25.3 +/- 1.2 degrees C, 40.3 +/- 13.7% RH). Platelet clotting time was assessed before drug administration, and before and after exercise. RESULTS: Fifteen firefighters completed the study. Aspirin increased clotting time before and after exercise compared with placebo (p = 0.003). There were no differences in absolute skin blood flow between groups (p = 0.35). Following exercise, cutaneous vascular conductance (CVC) was 85 +/- 42% of maximum in the aspirin and 76 +/- 37% in the placebo groups. The percentage of maximal CVC did not differ by treatment before or after recovery. Neither maximal core body temperature nor heart rate responses to exercise differed between trials. CONCLUSION: There were no differences in skin blood flow during uncompensable heat stress following exercise after aspirin or placebo therapy. PMID- 26929837 TI - The Role of Labour Inspectorates in Tackling the Psychosocial Risks at Work in Europe: Problems and Perspectives. AB - Significant changes in the past year have taken place in the world of work that are bringing new challenges with regard to employee safety and health. These changes have led to emerging psychosocial risks (PSRs) at work. The risks are primarily linked to how work is designed, organized, and managed, and to the economic and social frame of work. These factors have increased the level of work related stress and can lead to serious deterioration in mental and physical health. In tackling PSRs, the European labor inspectorates can have an important role by enforcing preventive and/or corrective interventions in the content and context of work. However, to improve working conditions, unilateral interventions in the context and content of work are insufficient and require adopting a common strategy to tackle PSRs, based on a holistic approach. The implementation of a common strategy by the European Labor Inspectorate for tackling PSRs is restricted by the lack of a common legislative frame with regard to PSR evaluation and management, the different levels of labor inspectors' training, and the different levels of employees' and employers' health and safety culture. PMID- 26929838 TI - Whole-body Vibration Exposure of Drill Operators in Iron Ore Mines and Role of Machine-Related, Individual, and Rock-Related Factors. AB - BACKGROUND: This study aimed to assess the whole-body vibration (WBV) exposure among large blast hole drill machine operators with regard to the International Organization for Standardization (ISO) recommended threshold values and its association with machine- and rock-related factors and workers' individual characteristics. METHODS: The study population included 28 drill machine operators who had worked in four opencast iron ore mines in eastern India. The study protocol comprised the following: measurements of WBV exposure [frequency weighted root mean square (RMS) acceleration (m/s(2))], machine-related data (manufacturer of machine, age of machine, seat height, thickness, and rest height) collected from mine management offices, measurements of rock hardness, uniaxial compressive strength and density, and workers' characteristics via face to-face interviews. RESULTS: More than 90% of the operators were exposed to a higher level WBV than the ISO upper limit and only 3.6% between the lower and upper limits, mainly in the vertical axis. Bivariate correlations revealed that potential predictors of total WBV exposure were: machine manufacturer (r = 0.453, p = 0.015), age of drill (r = 0.533, p = 0.003), and hardness of rock (r = 0.561, p = 0.002). The stepwise multiple regression model revealed that the potential predictors are age of operator (regression coefficient beta = -0.052, standard error SE = 0.023), manufacturer (beta = 1.093, SE = 0.227), rock hardness (beta = 0.045, SE = 0.018), uniaxial compressive strength (beta = 0.027, SE = 0.009), and density (beta = -1.135, SE = 0.235). CONCLUSION: Prevention should include using appropriate machines to handle rock hardness, rock uniaxial compressive strength and density, and seat improvement using ergonomic approaches such as including a suspension system. PMID- 26929839 TI - Measurement and Modeling of Job Stress of Electric Overhead Traveling Crane Operators. AB - BACKGROUND: In this study, the measurement of job stress of electric overhead traveling crane operators and quantification of the effects of operator and workplace characteristics on job stress were assessed. METHODS: Job stress was measured on five subscales: employee empowerment, role overload, role ambiguity, rule violation, and job hazard. The characteristics of the operators that were studied were age, experience, body weight, and body height. The workplace characteristics considered were hours of exposure, cabin type, cabin feature, and crane height. The proposed methodology included administration of a questionnaire survey to 76 electric overhead traveling crane operators followed by analysis using analysis of variance and a classification and regression tree. RESULTS: The key findings were: (1) the five subscales can be used to measure job stress; (2) employee empowerment was the most significant factor followed by the role overload; (3) workplace characteristics contributed more towards job stress than operator's characteristics; and (4) of the workplace characteristics, crane height was the major contributor. CONCLUSION: The issues related to crane height and cabin feature can be fixed by providing engineering or foolproof solutions than relying on interventions related to the demographic factors. PMID- 26929840 TI - The Type of Payment and Working Conditions. AB - BACKGROUND: The type of payment is one of the important factors that has an effect on the health of employees, as a basic working condition. In the conventional research field of occupational safety and health, only the physical, chemical, biological, and ergonomic factors are treated as the main hazardous factors. Managerial factors and basic working conditions such as working hours and the type of payment are neglected. This paper aimed to investigate the association of the type of payment and the exposure to the various hazardous factors as an heuristic study. METHODS: The third Korean Working Conditions Survey (KWCS) by the Occupational Safety and Health Research Institute in 2011 was used for this study. Among the total sample of 50,032 economically active persons, 34,788 employees were considered for analysis. This study examined the relation between the three types of payment such as basic fixed salary and wage, piece rate, and extra payment for bad and dangerous working conditions and exposure to hazardous factors like vibration, noise, temperature, chemical contact, and working at very high speeds. Multivariate regression analysis was used to measure the effect of the type of payment on working hours exposed to hazards. RESULTS: The result showed that the proportion of employees with a basic fixed salary was 94.5%, the proportion with piece rates was 38.6%, and the proportion who received extra payment for hazardous working conditions was 11.7%. CONCLUSION: The piece rate was associated with exposure to working with tight deadlines and stressful jobs. This study had some limitations because KWCS was a cross-sectional survey. PMID- 26929841 TI - Examples of Holistic Good Practices in Promoting and Protecting Mental Health in the Workplace: Current and Future Challenges. AB - BACKGROUND: While attention has been paid to physical risks in the work environment and the promotion of individual employee health, mental health protection and promotion have received much less focus. Psychosocial risk management has not yet been fully incorporated in such efforts. This paper presents good practices in promoting mental health in the workplace in line with World Health Organization (WHO) guidance by identifying barriers, opportunities, and the way forward in this area. METHODS: Semistructured interviews were conducted with 17 experts who were selected on the basis of their knowledge and expertise in relation to good practice identified tools. Interviewees were asked to evaluate the approaches on the basis of the WHO model for healthy workplaces. RESULTS: The examples of good practice for Workplace Mental Health Promotion (WMHP) are in line with the principles and the five keys of the WHO model. They support the third objective of the WHO comprehensive mental health action plan 2013-2020 for multisectoral implementation of WMHP strategies. Examples of good practice include the engagement of all stakeholders and representatives, science driven practice, dissemination of good practice, continual improvement, and evaluation. Actions to inform policies/legislation, promote education on psychosocial risks, and provide better evidence were suggested for higher WMHP success. CONCLUSION: The study identified commonalities in good practice approaches in different countries and stressed the importance of a strong policy and enforcement framework as well as organizational responsibility for WMHP. For progress to be achieved in this area, a holistic and multidisciplinary approach was unanimously suggested as a way to successful implementation. PMID- 26929842 TI - Workplace System Factors of Obstetric Nurses in Northeastern Ontario, Canada: Using a Work Disability Prevention Approach. AB - BACKGROUND: The purpose of this study was to examine the relationship nursing personal and workplace system factors (work disability) and work ability index scores in Ontario, Canada. METHODS: A total of 111 registered nurses were randomly selected from the total number of registered nurses on staff in the labor, delivery, recovery, and postpartum areas of four northeastern Ontario hospitals. Using a stratified random design approach, 51 participants were randomly selected in four northeastern Ontario cities. RESULTS: A total of 51 (45.9% response rate) online questionnaires were returned and another 60 (54.1% response rate) were completed using the paper format. The obstetric workforce in northeastern Ontario was predominately female (94.6%) with a mean age of 41.9 (standard deviation = 10.2). In the personal systems model, three variables: marital status (p = 0.025), respondent ethnicity (p = 0.026), and mean number of patients per shift (p = 0.049) were significantly contributed to the variance in work ability scores. In the workplace system model, job and career satisfaction (p = 0.026) had a positive influence on work ability scores, while work absenteeism (p = 0.023) demonstrated an inverse relationship with work ability scores. In the combined model, all the predictors were significantly related to work ability scores. CONCLUSION: Work ability is closely related to job and career satisfaction, and perceived control at work among obstetric nursing. In order to improve work ability, nurses need to work in environments that support them and allow them to be engaged in the decision-making processes. PMID- 26929843 TI - Early Liver and Kidney Dysfunction Associated with Occupational Exposure to Sub Threshold Limit Value Levels of Benzene, Toluene, and Xylenes in Unleaded Petrol. AB - BACKGROUND: Unleaded petrol contains significant amounts of monocyclic aromatic hydrocarbons such as benzene, toluene, and xylenes (BTX). Toxic responses following occupational exposure to unleaded petrol have been evaluated only in limited studies. The main purpose of this study was to ascertain whether (or not) exposure to unleaded petrol, under normal working conditions, is associated with any hepatotoxic or nephrotoxic response. METHODS: This was a cross-sectional study in which 200 employees of Shiraz petrol stations with current exposure to unleaded petrol, as well as 200 unexposed employees, were investigated. Atmospheric concentrations of BTX were measured using standard methods. Additionally, urine and fasting blood samples were taken from individuals for urinalysis and routine biochemical tests of kidney and liver function. RESULTS: The geometric means of airborne concentrations of BTX were found to be 0.8 mg m( 3), 1.4 mg m(-3), and 2.8 mg m(-3), respectively. Additionally, means of direct bilirubin, alanine aminotransferase, aspartate aminotransferase, blood urea and plasma creatinine were significantly higher in exposed individuals than in unexposed employees. Conversely, serum albumin, total protein, and serum concentrations of calcium and sodium were significantly lower in petrol station workers than in their unexposed counterparts. CONCLUSION: The average exposure of petrol station workers to BTX did not exceed the current threshold limit values (TLVs) for these chemicals. However, evidence of subtle, subclinical and prepathologic early liver and kidney dysfunction was evident in exposed individuals. PMID- 26929844 TI - Role of Headmasters, Teachers, and Supervisors in Knowledge Transfer about Occupational Health and Safety to Pupils in Vocational Education. AB - BACKGROUND: Young people are at an increased risk for illness in working life. The authorities stipulate certain goals for training in occupational health and safety (OHS) in vocational schools. A previous study concluded that pupils in vocational education had limited knowledge in the prevention of health risks at work. The aim of the current study, therefore, was to study how OHS training is organized in school and in workplace-based learning (WPL). METHODS: The study design featured a qualitative approach, which included interviews with 12 headmasters, 20 teachers, and 20 supervisors at companies in which the pupils had their WPL. The study was conducted at 10 upper secondary schools, located in Central Sweden, that were graduating pupils in four vocational programs. RESULTS: The interviews with headmasters, teachers, and supervisors indicate a staggered picture of how pupils are prepared for safe work. The headmasters generally give teachers the responsibility for how goals should be reached. Teaching is very much based on risk factors that are present in the workshops and on teachers' own experiences and knowledge. The teaching during WPL also lacks the systematic training in OHS as well as in the traditional classroom environment. CONCLUSION: Teachers and supervisors did not plan the training in OHS in accordance with the provisions of systematic work environment management. Instead, the teachers based the training on their own experiences. Most of the supervisors did not receive information from the schools as to what should be included when introducing OHS issues in WPL. PMID- 26929845 TI - Impact of Job Satisfaction on Greek Nurses' Health-Related Quality of Life. AB - BACKGROUND: Employee job satisfaction and its relationship with health and quality of life has been an issue of major concern over the past decades. Nurses experience difficult working conditions that affect their job satisfaction, health, and quality of life. METHODS: A cross-sectional study was undertaken in three general hospitals and their respective health centers. Stratified random sampling by level of education was used, and 508 nurses and nursing assistants were included. A self-administered anonymous questionnaire, which included the Measure of Job Satisfaction, the 36-item Short Form Health Survey, as well as demographic details, education, and work conditions data, was used. RESULTS: Greek nurses were found to be dissatisfied with their job according to the total score of the job satisfaction scale, although personal satisfaction and satisfaction with support had had higher scores. Their general health was reported as average, because of physical and mental health problems, low vitality, low energy, and increased physical pain. Multivariate linear regression analysis revealed that males and those wishing to stay in the job had higher physical and mental health. Increased job satisfaction was related to increased physical and mental health. CONCLUSION: Although Greek nurses are not satisfied with their work, those with high levels of job satisfaction had better health related quality of life. The findings suggest that improvement of the work environment would contribute to a healthier and more satisfied nursing workforce. PMID- 26929847 TI - Korean Emotional Laborers' Job Stressors and Relievers: Focus on Work Conditions and Emotional Labor Properties. AB - BACKGROUND: The present study aims to investigate job stressors and stress relievers for Korean emotional laborers, specifically focusing on the effects of work conditions and emotional labor properties. Emotional laborers are asked to hide or distort their real emotions in their interaction with clients. They are exposed to high levels of stress in the emotional labor process, which leads to serious mental health risks including burnout, depression, and even suicide impulse. Exploring job stressors and relieving factors would be the first step in seeking alternatives to protect emotional laborers from those mental health risks. METHODS: Using the third wave data of Korean Working Conditions Survey, logistic regression analysis was conducted for two purposes: to examine the relations of emotional labor and stress, and to find out job stressors and relievers for emotional laborers. RESULTS: The chances of stress arousal are 3.5 times higher for emotional laborers; emotional laborers experience double risk burden for stress arousal. In addition to general job stressors, emotional laborers need to bear burdens related to emotional labor properties. The effect of social support at the workplace is not significant for stress relief, unlike common assumptions, whereas subjective satisfaction (wage satisfaction and work life balance) is proven to have relieving effects on emotional laborers' job stress. CONCLUSION: From the results, the importance of a balanced understanding of emotional labor for establishing effective policies for emotional laborer protection is stressed. PMID- 26929846 TI - Work-Family Conflict, Task Interruptions, and Influence at Work Predict Musculoskeletal Pain in Operating Room Nurses. AB - BACKGROUND: The aim of this study is to examine the prevalence of musculoskeletal complaints in Swiss operating room (OR) nurses, and to investigate how work family conflict, work interruptions, and influence at work are related to lumbar and cervical back pain. METHODS: Participants in this correlational questionnaire study included 116 OR nurses from eight different hospitals in Switzerland. RESULTS: We found that 66% of the OR staff suffered from musculoskeletal problems. The most prevalent musculoskeletal complaints were lumbar (52.7%) and cervical pain (38.4%). Furthermore, 20.5% reported pain in the mid spine region, 20.5% in the knees and legs, and 9.8% in the hands and feet. Multiple linear regression analyses showed that work-family conflict (p < 0.05) and interruptions (p < 0.05) significantly predicted lumbar and cervical pain in OR nurses, while influence at work (p < 0.05) only predicted lumbar pain. CONCLUSION: These results suggest that reducing the work-family conflict and interruptions at work, as well as offering opportunities to influence one's workplace, help to promote OR nurses' health. PMID- 26929848 TI - Effectuality of Cleaning Workers' Training and Cleaning Enterprises' Chemical Health Hazard Risk Profiling. AB - BACKGROUND: Goal-oriented communication of risk of hazards is necessary in order to reduce risk of workers' exposure to chemicals. Adequate training of workers and enterprise priority setting are essential elements. Cleaning enterprises have many challenges and the existing paradigms influence the risk levels of these enterprises. METHODS: Information on organization and enterprises' prioritization in training programs was gathered from cleaning enterprises. A measure of enterprises' conceptual level of importance of chemical health hazards and a model for working out the risk index (RI) indicating enterprises' conceptual risk level was established and used to categorize the enterprises. RESULTS: In 72.3% of cases, training takes place concurrently with task performances and in 67.4% experienced workers conduct the trainings. There is disparity between employers' opinion on competence level of the workers and reality. Lower conceptual level of importance was observed for cleaning enterprises of different sizes compared with regional safety delegates and occupational hygienists. Risk index values show no difference in risk level between small and large enterprises. CONCLUSION: Training of cleaning workers lacks the prerequisite for suitability and effectiveness to counter risks of chemical health hazards. There is dereliction of duty by management in the sector resulting in a lack of competence among the cleaning workers. Instituting acceptable easily attainable safety competence level for cleaners will conduce to risk reduction, and enforcement of attainment of the competence level would be a positive step. PMID- 26929849 TI - A Case-Study of Implementation of Improved Strategies for Prevention of Laboratory-acquired Brucellosis. AB - BACKGROUND: In 2012, the Alaska Section of Epidemiology investigated personnel potentially exposed to a Brucella suis isolate as it transited through three laboratories. METHODS: We summarize the first implementation of the United States Centers for Disease Control and Prevention 2013 revised recommendations for monitoring such exposures: (1) risk classification; (2) antimicrobial postexposure prophylaxis; (3) serologic monitoring; and (4) symptom surveillance. RESULTS: Over 30 people were assessed for exposure and subsequently monitored for development of illness. No cases of laboratory-associated brucellosis occurred. Changes were made to gaps in laboratory biosafety practices that had been identified in the investigation. CONCLUSION: Achieving full compliance for the precise schedule of serologic monitoring was challenging and resource intensive for the laboratory performing testing. More refined exposure assessments could inform decision making for follow-up to maximize likelihood of detecting persons at risk while not overtaxing resources. PMID- 26929850 TI - Factors Associated With Early Functional Outcome After Hip Fracture Surgery. AB - BACKGROUND: Hip fractures are common in the elderly and are likely to become more prevalent as the US population ages. Early functional status is an indicator of longer term outcome, yet in-hospital predictors of functional recovery, particularly time of surgery and composition of support staff, after hip fracture surgery have not been well studied. METHODS: Ninety-nine consecutive patients underwent hip fracture surgery by a single surgeon between 2009 and 2013. Surgery after 48 hours was deemed as surgical delay, and surgery after 5 pm was deemed as after hours. Surgical support staff experience was determined by experts from our institution as well as documented level of training. Functional status was determined by independent ambulation on postoperative day (POD) 3. RESULTS: On POD3, 48 (79%) of 62 patients with no delay were able to ambulate, whereas only 14 (38%) of 37 patients with delayed surgery were able to ambulate (P < .001). This relationship persisted when adjusted for American Society of Anesthesiologist classification. No delay in patients older than 80 (odds ratio [OR], 6.91; 95% confidence interval [CI], 2.16-22.10) and females (OR, 7.05; 95% CI, 2.34-21.20) was associated with greater chance of early ambulation. After hours surgery was not associated with ambulation (P = .35). Anesthesiologist and circulating nurse experience had no impact on patient's ambulatory status; however, nonorthopedic scrub technicians were associated with worse functional status (OR 7.50; 95% CI, 1.46-38.44, P = .01). CONCLUSION: Surgical delay and nonorthopedic scrub technicians are associated with worse early functional outcome after hip fracture surgery. Surgical delay should be avoided in older patients and women. More work should be done to understand the impact of surgical team composition on outcome. PMID- 26929851 TI - A Nationwide Analysis of Pelvic Ring Fractures: Incidence and Trends in Treatment, Length of Stay, and Mortality. AB - BACKGROUND: Previous studies evaluating the epidemiology of pelvic ring fractures and predictors of mortality are largely based upon non-US populations, potentially limiting their generalizability. This study sought to analyze trends of pelvic ring fractures and associated complications in the United States using the largest and most recent national data set available. The specific aims of this study were to determine whether the incidence of pelvic ring fractures changed over time, whether in-hospital mortality following pelvic ring fracture changed over time, whether hospital length of stay following pelvic ring fracture changed over time, and whether there are independent predictors of in-hospital mortality, adverse events, or nonroutine discharge following pelvic fracture. METHODS: The National Hospital Discharge Survey was queried to identify all patients admitted to US hospitals with pelvic ring fractures between 1990 and 2007. A cohort representative of 1 464 458 patients was identified, and multivariable logistic regression was used to find independent predictors of mortality, adverse events, and nonroutine discharge to another inpatient facility. RESULTS: Between 1990 and 2007, the population-adjusted incidence of pelvic ring fractures increased from 27.24 to 34.30 per 100 000 capita (P < .001). Mortality declined from 4.2% to 2.8% (P < .001) paralleling an increase in the proportion of patients treated with surgical fixation (7.22%-10.36%). All forms of internal fixation were associated with decreased odds of mortality, while external fixation was associated with increased odds of mortality. Internal fixation was also associated with lower odds of adverse events and nonroutine discharge to inpatient facilities. The average in-hospital length of stay decreased from 11.2 days to 6.5 days (P < .001). CONCLUSION: This study provides the largest and most comprehensive epidemiologic analysis of pelvic ring fractures in the United States. Knowledge of the increasing incidence of pelvic fractures and prognostic factors associated with poor outcomes may improve outcomes. PMID- 26929852 TI - Do Orthogeriatric Inpatients Have a Correct Medication List? A Pharmacist-Led Assessment of 254 Patients in a Swedish University Hospital. AB - INTRODUCTION: Comorbidities and polypharmacy complicate the treatment of geriatric patients with acute orthopedic injuries. A correct medication history and an updated medication list are a prerequisite for safe treatment of these debilitated patients. Published evidence suggests favorable outcomes with comanaged care. The aim of this study was to assess the accuracy of the inpatient medication lists generated at admission and investigate the efficacy of a dedicated ward-based pharmacist to find and correct mistakes in these lists. METHODS: A total of 254 patients were enrolled. The ward-based pharmacist performed the assessment regarding the accuracy of the medication list generated at admission by the method of medication reconciliation. Number of discrepancies and types of discrepancy were noted. RESULTS: The 254 patients (176 women) had a mean age of 85 years (standard deviation 7.4 years, range 42-100 years). The most common reason for orthopedic admission was hip fracture. The mean number of discrepancies was 2.1 for all patients (range 0-13). Omission of a prescribed drug was the most common mistake. Fifty-six (22%) of the 254 assessed patients had a correct medication list. DISCUSSION: The many discrepancies in our study may have several explanations but highlight the difficulties in taking a correct medication history of patients in a stressful environment with an extremely high workload. Moreover, electronic medication lists create challenges. Implementing new electronic tools for health care requires feedback, redesign, and adaptation to meet various needs of the users. CONCLUSION: In conclusion, orthogeriatric patients have an unsatisfactory high number of discrepancies in their medication lists. Clinical pharmacists can accurately identify many of these mistakes. PMID- 26929853 TI - Can Radiocarpal-Spanning Fixation Be Made More Functional by Placing the Wrist in Extension? A Biomechanical Study Under Physiologic Loads. AB - We investigate whether applying an internal radiocarpal-spanning plate with the wrist in slight extension affects the biomechanical stability of the construct. An unstable distal radius fracture was simulated in 10 cadaveric specimens and immobilized with a radiocarpal-spanning plate holding the wrist in a neutral position. This construct was then physiologically loaded through the wrist flexor and extensor tendons. The resulting motion at the fracture was captured with a displacement sensor. The plate was then extended using an in situ bending technique, placing the wrist in extension, and the experiment was repeated. No statistically significant difference in the biomechanical stability afforded by the radiocarpal-spanning plate was detected with the wrist in extension compared to that in the traditional neutral position. The radiocarpal-spanning plate fixation was more stable when loaded through the extensor tendons. We conclude that immobilizing a distal radius fracture with an internal radiocarpal-spanning plate that holds the wrist in extension does not compromise biomechanical stability. PMID- 26929854 TI - Spontaneous Iliopsoas Tendon Tear: A Rare Cause of Hip Pain in the Elderly. AB - Hip pain is one of the most common reasons for the elderly to present to the emergency department, and the differential diagnosis spectrum is vast. Iliopsoas injury is a relatively uncommon condition that may present with hip or groin pain. It is usually seen in athletes due to trauma, particularly flexion injuries. However, spontaneous iliopsoas tendon tear is extremely rare, and only a small number of cases have been reported; it has an estimated prevalence of 0.66% in individuals from 7 to 95 years. Risk factors include aging, use of steroids, and chronic diseases. Magnetic resonance imaging (MRI) using its high soft-tissue contrast resolution remains the most valuable imaging modality. A prompt diagnosis and treatment, which is usually conservative, is important to improve the quality of life in this group of patients. We describe a case of spontaneous iliopsoas tendon tear in an elderly woman. PMID- 26929855 TI - Gait Training in Patients Discharged to a Skilled Nursing Facility Following Total Joint Arthroplasty. AB - BACKGROUND: Expenditures for postacute care in total joint arthroplasty (TJA) have risen dramatically over recent decades. Therefore, efforts are underway to better identify cost savings in postacute rehabilitation centers, such as skilled nursing facilities (SNFs). The primary purpose of this study was to analyze gait training achievements in post-TJA patients in the interval between hospital discharge and the patients' first 4 days at the SNF. Identification of potential losses in therapeutic progress may lead the way for improved patient care, outcomes, and cost savings. Our hypothesis is that patients discharged to an SNF will have a decline in gait achievements upon transfer from the hospital. METHODS: A total of 68 patients who underwent TJA were included. The total distance ambulated during physical therapy (PT) was recorded for the last day of hospital therapy and the first 4 days at the SNF as well as the reported visual analog scale (VAS) pain scores. RESULTS: There was a 73% decline in distance ambulated on SNF day 0 (Hospital: 138.6 ft vs SNF: 37.9 ft; P < .001) and a 50% decline on SNF day 1 (Hospital: 103.0 ft; SNF vs 51.1 ft; P < .001) compared to the last hospital session. There were no significant differences in distance walked on SNF days 3 and 4 relative to the last hospital session. The VAS pain scores did not significantly differ on SNF days 0 and 1 compared to the last hospital day but began to significantly decline on SNF day 3 (Hospital: 4.9; SNF: 3.3; P = .02) and day 4 (Hospital: 3.9; SNF: 2.3; P = .03). CONCLUSION: There was a significant decline in ambulatory proficiency in post-TJA patients on the day of and the day following hospital discharge to an SNF. These deficits cannot be attributed to heightened pain levels. Early and progressive ambulation is a recognized component of appropriate PT following TJA. This study therefore highlights the transition from hospital to SNF as a crucial and novel target for improvement in post-TJA care. PMID- 26929856 TI - Short-Term Complications of Distal Humerus Fractures in Elderly Patients: Open Reduction Internal Fixation Versus Total Elbow Arthroplasty. AB - BACKGROUND: The purpose of this study was to evaluate 30-day postoperative complications of open reduction and internal fixation [ORIF] and total elbow arthroplasty [TEA] for the treatment of distal humerus fractures in elderly patients using a validated national database. METHODS: Review of the National Surgical Quality Improvement Program (NSQIP) Database identified all elderly patients (>65 years) who underwent TEA or ORIF for the treatment of closed intra articular distal humerus fractures from 2007 to 2013. Bivariate and multivariate analyses of risk factors for 30-day adverse events as defined by NSQIP between ORIF and TEA groups were assessed using preoperative and intraoperative variables. RESULTS: Among the 176 patients with distal humerus fractures, there were 33 TEA and 143 ORIF. There was no difference in age, medical comorbidities, or functional status. Total elbow arthroplasty was associated with an increased odds of severe adverse event compared to ORIF (odds ratio = 1.57, P = .16), although it did not achieve statistical significance. Infection rate was 0.7% in ORIF and 0.0% in TEA (P = .99). Insulin-dependent diabetes and functional status were significant independent predictors of postoperative adverse events. Operative time (165 minutes vs 140 minutes, P = .06) and postoperative length of stay (3.6 days vs 2.3 days, P = 0.03) were longer for TEA compared to ORIF. CONCLUSION: Open reduction and internal fixation and TEA have similar 30-day postoperative complications for the treatment of distal humerus fractures among elderly patients. Despite favorable trends for TEA in recent studies, additional clinical results are needed to understand complications and limitation of TEA. LEVEL OF EVIDENCE: Level III, prognostic study. PMID- 26929858 TI - The "P3" Concept Or How to Make Secondary Fracture Prevention Become the Orthotrauma Surgeon's Baby. PMID- 26929857 TI - Parameters Pointing at an Increased Risk for Contralateral Hip Fractures: Systematic Review. AB - BACKGROUND: Early identification of hip fracture (HF) patients bearing an increased risk for a contralateral occurrence would allow providing preventive measures timely. OBJECTIVES: To summarize the available evidence describing risk scores, prognostic instruments, or (groups of) parameters predicting contralateral HFs at the time point of the first fracture. Methods/Systematic Review: Articles were identified through searches in MEDLINE and Scopus from inception to April 2014, checking of reference lists of the included studies and reviews. One reviewer assessed all articles for inclusion and abstracted the data. Uncertain cases were discussed and decided with a second reviewer. Salient study and population characteristics were abstracted for each article. Studies reporting the association of a set of risk factors for second HFs were further examined and compared. The number of studies reporting on a risk parameter was assessed. RESULTS: Searches identified 3560 records, and 47 studies were included in this review. There was a large spectrum of study designs, patient populations, and follow-up periods. Among 11 studies reporting on a set of parameters, female gender was assessed most commonly (7 times), followed by age (5) and parameters of general health, vision, and stroke (each 4 times). We were unable to depict stringent patterns of risk parameters to be used for decision making in clinical practice. CONCLUSIONS: The findings of this article call for a conjoint effort to achieve an expert consensus regarding a critical set of parameters for a risk instrument identifying patients bearing an increased risk for contralateral HFs early. PMID- 26929859 TI - Comparison of Presentation, Course, and Outcome of Congenital and Acquired Cytomegalovirus Infection in Twins. AB - Background Cytomegalovirus (CMV) is one of the most common causes of serious viral intrauterine infections. It is universally distributed among the human population with an average incidence of 0.15 to 2%. Indeed, at least half of the women in the reproductive age have evidence of prior CMV infection. Epidemiology and Pathogenicity However, it is not a usual practice to screen asymptomatic pregnant woman or neonates for CMV. Even if a mother developed a primary CMV infection during pregnancy, up to 90% of the newborns with congenital CMV will be asymptomatic at the time of birth. Only 5 to 7% of the infected babies will be acutely symptomatic, and the typical clinical presentation includes intrauterine growth restriction, microcephaly, various cutaneous manifestations (including petechiae and purpura), hematological abnormalities (particularly resistant thrombocytopenia), hepatosplenomegaly, chorioretinitis, hepatitis, etc. In contrast, acquired CMV infection is extremely unlikely to cause any serious sequelae for the infant. Cases We present a case of congenital and acquired CMV infection in twins with a focus of dissimilarity in presentation, clinical course, and outcome. PMID- 26929860 TI - A Rare Full-Term Newborn Case of Rib Osteomyelitis with Suspected Preceding Fracture. AB - Acute osteomyelitis is uncommon in full-term neonates and occurs most frequently in those with critical illnesses, often following episodes of sepsis, skin infection, umbilical catheterization, urinary tract anomalies, or a complicated delivery. Here, we report a very rare case of acute rib osteomyelitis due to Staphylococcus aureus in a 13-day-old full-term male neonate. Ultrasonography (US) enabled diagnosis and revealed a coexisting costochondral junction rib fracture, which was not detected on routine chest radiography. Following a 29-day course of intensive parenteral antibiotic therapy, the patient was discharged in good health at 42 days of age without any scar formation. Due to its accessibility and safety, US can be a promising modality for detecting acute osteomyelitis in neonates with clinically highly suspected conditions in the neonatal intensive care unit setting, particularly those involving thin and mobile bones subject to respiratory motion. However, further studies are required to assess the utility of US in these cases and negative results. In low-risk neonates with osteomyelitis, an accompanying fracture should be considered. PMID- 26929861 TI - A Sporadic Neonatal Case of Epidermolysis Bullosa Simplex Generalized Intermediate with KRT5 and KRT14 Gene Mutations. AB - Background Epidermolysis bullosa simplex (EBS) is a rare genodermatosis resulting from multiple gene mutations, including KRT5 and KRT14. The clinical expression of the mechanobullous skin fragility disease has not been fully explained by the genotype. Case Description An 11-day-old Japanese newborn infant was hospitalized because of herpetiform skin blistering on the feet, which expanded systemically after birth. There was no evidence of virus infection. The biopsied skin lesion showed a blister on the lamina densa without keratin clumps, indicating a diagnosis of EBS-generalized intermediate. We punctured the blisters to remove the contents daily, which led to no exacerbation or infection. The genetic study determined that the patient carried double substitutions of KRT5 c.1424A > G (p.E475G) and KRT14 c.1237G > A (p.A413T). The asymptomatic mother and sister carried the KRT14 substitution, but the healthy father had no substitution of the KRT gene. Conclusion This is the first report of EBS-generalized intermediate in a newborn with de novo KRT5 gene mutation and KRT14 gene polymorphism, and no familial history of epidermolysis. Neonatal blistering due to EBS requires optimal skin management after excluding infectious and immunobullous diseases. PMID- 26929862 TI - Septo-Optic Dysplasia in a Newborn Presenting with Bilateral Dilated and Fixed Pupils. AB - Introduction We describe a newborn female infant with septo-optic dysplasia (SOD) presenting with bilateral dilated and fixed pupils. Conclusion Our report is unique because the incidental finding of bilateral dilated and fixed pupils on the newborn exam was the only clinical finding which led to a prompt work-up and eventual diagnosis of SOD. PMID- 26929863 TI - Gastroschisis Complicated by Septo-Optic Dysplasia: Two Distinct Anomalies with a Common Origin. AB - Introduction Gastroschisis is considered to be an isolated abdominal wall defect that is infrequently associated with other anomalies. Case This case describes an infant with gastroschisis who developed refractory shock after an uncomplicated surgery for bowel atresia. He was found to have adrenal insufficiency secondary to septo-optic dysplasia with panhypopituitarism. Conclusion Gastroschisis and septo-optic dysplasia arise from vascular disruptions, therefore presence in the same infant can be more than just a coincidence. While this is not a common occurrence, our case illustrates the need for a high index of suspicion with an unusual clinical course. PMID- 26929864 TI - Obstetrician and Gynecologist Utilization of the Noninvasive Prenatal Testing Expanded Option. AB - Objective Noninvasive prenatal testing (NIPT) enables the detection of common fetal aneuploidies such as trisomy 21, trisomy 18, trisomy 13, and sex chromosome abnormalities via analysis of cell-free fetal DNA circulating in maternal serum. In October 2013, the option to screen for additional trisomies and select microdeletion syndromes became clinically available. The complex testing methods, oftentimes unclear clinical utility of results, and lack of professional guidelines renders it challenging for clinicians to keep abreast of evolving prenatal screening options. We undertook a survey to assess physicians' awareness of, utilization of, and attitudes toward the expanded NIPT option. Study Design Obstetricians attending hospital service meetings in the Houston Texas Medical Center completed an anonymous survey regarding the utilization patterns of expanded NIPT. Results Overall, 85 obstetricians were surveyed. While all respondents indicated awareness of NIPT in its traditional form, 75% (64/85) were aware of the expanded testing option, and 14% (12/85) reported having ordered the expanded NIPT option. A total of 91% (77/85) expressed that practitioners need more information regarding the screening. Conclusion Based on these findings and the fluid landscape of prenatal screening, education, and reeducation of health care professionals is imperative to ensure responsible patient counseling, informed consent, and appropriate posttest management. PMID- 26929865 TI - Lactobacillus Sepsis and Probiotic Therapy in Newborns: Two New Cases and Literature Review. AB - Many term and preterm infants are commonly supplemented with probiotics to prevent adverse effects of antibiotic administration and necrotizing enterocolitis and they are believed to be safe. However, the supplementation with Lactobacillus rhamnosus GG has been associated with the development of sepsis with a cause-effect relationship in six newborns and children. In this study, we report two further cases and discuss the emerging issue of probiotic supplementation safety in neonates. We conclude that physicians must be aware that supplementation with L. rhamnosus GG can cause sepsis in high-risk patients on rare occasions. PMID- 26929866 TI - Perineal Groove: A Rare Congenital Midline Defect of Perineum. AB - Perineal groove is a rare congenital malformation that is characterized by an exposed wet sulcus with nonkeratinized mucous membrane that extends from the posterior vaginal fourchette to the anterior ridge of the anal orifice. This condition is one of the uncommon anomalies of urogenital/anogenital region that is unknown to many clinicians. Although, this condition may be self-resolved before the age of 2 years, this nonepithelized mucous membrane can pose the risk of local irritation and infection, urinary tract infection, and the possibility of nonself-resolved condition that eventually needs surgical correction. Only a few reported cases (n = 23) were found in current medical literatures. This lesion could be misdiagnosed as contact dermatitis, trauma, or even sexual abuse. Therefore, recognition of the congenital perineal groove at birth is important for the health care providers to deliver an appropriate parental counseling and appropriate follow-up. PMID- 26929867 TI - Prominent Eustachian Valve in Newborns: A Report of Four Cases. AB - The Eustachian valve (EV) is an embryological remnant of the inferior vena cava that during fetal life helps divert oxygenated blood from the IVC toward the foramen ovale to escape the pulmonary circulation. This remnant usually regresses after birth and is considered a benign finding in the majority of cases. However, EV can lead to complications in the neonatal period or later in life. In this short case series, we present four newborn infants with prominent EV who were symptomatic after birth and required admission to the neonatal intensive care unit. PMID- 26929868 TI - Severe First Trimester Recurrent Intrahepatic Cholestasis of Pregnancy: A Case Report and Literature Review. AB - Background Intrahepatic cholestasis of pregnancy (ICP) is a disorder of defective bile acid transport that results in systemic accumulation of bile acids and typically presents in the third trimester of pregnancy with intense pruritus. A positive linear correlation exists between total bile acid level and poor pregnancy outcome, and labor is typically induced at 37 weeks gestation to prevent intrauterine fetal demise (IUFD). Case Study We present the most severe reported case of recurrent ICP presenting early in the first trimester. The patient was delivered by repeat cesarean section at 31 (6/7) weeks gestation resulting in a viable female infant. Conclusion Iatrogenic preterm delivery may be indicated in early-severe recurrent ICP to prevent IUFD, but more research is needed. PMID- 26929869 TI - Neonatal Thrombocytopenia as a Consequence of Maternal Preeclampsia. AB - Introduction Preeclampsia (preE) is pregnancy-induced hypertension affecting a significant proportion of pregnant women worldwide and can cause detrimental effects in the mother and newborn. Some of the effects in the newborn include neonatal thrombocytopenia. Pertaining specifically to neonatal thrombocytopenia, several questions remain unanswered. Discussion According to the current literature, neonatal thrombocytopenia due to maternal preE is highly prevalent in the general population and the incidence is reported to be around 30% worldwide. This review gives an insight into the syndrome and summarizes the possible pathological mechanisms, the diagnostic approach, complications, and therapeutic interventions of neonatal thrombocytopenia. It also identifies the involvement of other cell lines, apart from platelets in the newborns. Furthermore, we suggest a future prospective study to investigate the pathogenesis of preE and plan a study involving animal models to come up with a possible therapeutic intervention to prevent preE and its various consequences in neonates. PMID- 26929871 TI - Prenatal Diagnosis of Aorta-Porto-Umbilical Vein Fistulas with Left-Sided Inferior Vena Cava. AB - Congenital arteriovenous fistulas involved with the abdominal aorta are very rare. Left-sided subrenal inferior vena cava (IVC) with normal connection to the heart is also rare and has not been reported prenatally. In this article, we described a fetus with aorta-porto-umbilical vein fistulas combined with a left sided IVC. PMID- 26929870 TI - Secondary Increase of Lactate Levels in Asphyxiated Newborns during Hypothermia Treatment: Reflect of Suboptimal Hemodynamics (A Case Series and Review of the Literature). AB - Objective To evaluate whether a secondary increase of serum lactate levels in asphyxiated newborns during hypothermia treatment may reflect suboptimal dynamics. Methods-Retrospective case series and review of the literature. We present the clinical course of four asphyxiated newborns treated with hypothermia who presented with hypotension requiring inotropic support, and who displayed a secondary increase of serum lactate levels during hypothermia treatment. Serial serum lactate levels are correlated with blood pressure and inotropic support within the first 96 hours of life. Results Lactate levels initially decreased in the four patients. However, each of them started to present lower blood pressure, and lactate levels started to increase again. Inotropic support was started to raise blood pressure. The introduction of an epinephrine drip consistently worsened the increase of lactate levels in these newborns, whereas dopamine and dobutamine enabled the clearance of lactate in addition to raising the blood pressure. Rewarming was associated with hemodynamics perturbations (a decrease of blood pressure and/or an increase of lactate levels) in the three newborns who survived. Conclusions Lactate levels during the first 4 days of life should be followed as a potential marker for suboptimal hemodynamic status in term asphyxiated newborns treated with hypothermia, for whom the maintenance of homeostasis during hypothermia treatment is of utmost importance to alleviate brain injury. PMID- 26929873 TI - Preeclampsia as a Manifestation of New-Onset Systemic Lupus Erythematosus during Pregnancy: A Case-Based Literature Review. AB - Introduction New-onset systemic lupus erythematosus (SLE) during pregnancy is rare and difficult to diagnose, especially in cases that manifest as preeclampsia. We report a patient with new-onset SLE that manifested as preeclampsia during pregnancy and provide a review of the literature to identify factors for a rapid diagnosis. Case A 32-year-old primigravid Japanese woman was diagnosed with severe preeclampsia and underwent emergent cesarean section at 29 weeks of gestation. Her hypertension and renal disorder gradually improved after the operation, but her thrombocytopenia and anemia worsened. SLE was diagnosed on postoperative day 5 by a comprehensive autoimmune workup. She was discharged on postoperative day 34 with remission. Conclusion Our case and previous reports suggest that distinguishing underlying SLE from preeclampsia in the third trimester is particularly difficult. Helpful factors for diagnosis of suspected SLE in these cases were persistence of symptoms and new atypical symptoms for preeclampsia revealed after delivery (e.g., fever, renal disorder, and thrombocytopenia). PMID- 26929874 TI - Spontaneous Posterior Uterine Rupture in Twin-Twin Transfusion Syndrome. AB - Background The maternal and fetal risks of uterine distension in rapidly progressive twin-twin transfusion syndrome (TTTS) in the setting of prior uterine scar are poorly characterized. Case We present the case of a 42-year-old woman, G4P1201, at 21 weeks gestation with stage-1 TTTS who developed a spontaneous posterior uterine rupture necessitating emergent laparotomy and delivery of previable fetuses, possibly due to prior uterine scar from a displaced intrauterine device. Conclusion TTTS may be a risk factor for uterine rupture, including uterine rupture in atypical anatomic locations. Prior unrecognized uterine scars, including perforations, may magnify the risk for atypical uterine rupture in the setting of excessive uterine distension. PMID- 26929875 TI - Phlegmasia Cerulea Dolens and May-Thurner Syndrome in the first trimester of Pregnancy. AB - Background Venous thromboembolism in pregnancy remains one of the leading causes of morbidity and mortality. Case A young, gravid patient presented with a cyanotic, edematous left lower extremity with no distal pulses palpable. She was emergently taken to the operating room and was found to have extensive iliofemoral thrombosis requiring femoral angioplasty and embolectomy with 43.7 rad intraoperative radiation exposure. Phlegmasia cerulea dolens and May-Thurner syndrome were diagnosed. Conclusion Timely diagnosis and prompt surgical management are necessary due to the limb-threatening nature of this condition. Despite maternal radiation exposure, the nature and extent of fetal effects depends upon radiation dose and gestational age. PMID- 26929872 TI - A Systematic Review of Acquired Uterine Arteriovenous Malformations: Pathophysiology, Diagnosis, and Transcatheter Treatment. AB - Objective An acquired uterine arteriovenous malformation (AVM) is a rare cause of vaginal bleeding and, although hysterectomy is the definitive therapy, transcatheter embolization (TCE) provides an alternative treatment option. This systematic review presents the indications, technique, and outcomes for transcatheter treatment of the acquired uterine AVMs. Study Design Literature databases were searched from 2003 to 2013 for eligible clinical studies, including the patient characteristics, procedural indication, results, complications, as well as descriptions on laterality and embolic agents utilized. Results A total of 40 studies were included comprising of 54 patients (average age of 33.4 years). TCE had a primary success rate with symptomatic control of 61% (31 patients) and secondary success rate of 91% after repeated embolization. When combined with medical therapy, symptom resolution was noted in 48 (85%) patients without more invasive surgical procedures. Conclusion Low-level evidence supports the role of TCE, including in the event of persistent bleeding following initial embolization, for the treatment of acquired uterine AVMs. The variety of embolic agents and laterality of approach delineate the importance of refining procedural protocols in the treatment of the acquired uterine AVM. Condensation A review on the management of patients with acquired uterine AVMs. PMID- 26929876 TI - Neonate with VACTERL Association and a Branchial Arch Anomaly without Hydrocephalus. AB - VACTERL (vertebral anomalies, anal atresia, cardiac defect, tracheoesophageal fistula, renal anomaly, limb anomalies) is an association of anomalies with a wide spectrum of phenotypic expression. While the majority of cases are sporadic, there is evidence of an inherited component in a small number of patients as well as the potential influence of nongenetic risk factors (maternal diabetes mellitus). Presence of hydrocephalus has been reported in VACTERL patients (VACTERL-H) in the past, with some displaying branchial arch anomalies. We report the unique case of an infant of diabetic mother with VACTERL association and a branchial arch anomaly-in the absence of hydrocephalus. PMID- 26929878 TI - Uncomplicated Pregnancies and Ultrasounds for Fetal Growth Restriction: A Pilot Randomized Clinical Trial. AB - Objective The purpose of this multicenter pilot study was to determine the feasibility of randomizing uncomplicated pregnancies (UPs) to have third trimester ultrasonographic exams (USE) versus routine prenatal care (RPNC) to improve the detection of small for gestational age (SGA; birth weight < 10% for GA). Material and Methods At three referral centers, 50 UPs were randomized after gestational diabetes was ruled out. Women needed to screen, consenting, and loss to follow-up was ascertained, as was the detection rate of SGA in the two groups. Results During the study period at the three centers, there were 7,680 births, of which 64% were uncomplicated. Of the 234 women approached for randomization, 36% declined. We recruited 149 women and had follow-up delivery data on 97%. The antenatal detection rate of SGA in the intervention group was 67% (95% confidence intervals 31-91%) and 9% (0.5-43%) in control. Conclusion The pilot study provides feasibility data for a multicenter randomized clinical trial to determine if third trimester USE, compared with RPNC, improves the detection of SGA and composite neonatal morbidity. PMID- 26929879 TI - Prenatal Diagnosis of Uhl Anomaly with Autopsy Correlation. AB - Uhl anomaly is a rare form of congenital hypoplasia of the right ventricular myocardium. Here, we report, a rare finding in fetal cardiac ultrasound in a 33 year-old woman who presented at 20 weeks' of gestation. A diagnosis of Uhl anomaly was made. An autopsy was performed at 23weeks gestation after obtaining permission for medicolegal termination of pregnancy. Histopathological examination confirmed the diagnosis. Diagnosing Uhl anomaly in fetal life is essential since mortality and survival mainly depend on the severity of right ventricle dysfunction related to, the either partial or complete absence of the myocardium. Hence, surviving cases need to be followed up carefully and counselled accordingly. PMID- 26929877 TI - Low Gestational Weight Gain in Obese Women and Pregnancy Outcomes. AB - Obesity during pregnancy and excessive weight gain during this period are associated with several maternal-fetal and neonatal complications. Moreover, a significant percentage of women have weight retention in the postpartum period, especially those with excessive weight gain during pregnancy. The recommendations of the 2009 Institute of Medicine were based on observational studies that have consistently shown that women with weight gain within the recommended range had better outcomes during pregnancy. In patients with obesity, however, there is no recommendation for weight gain, according to the class of obesity. This review, therefore, aims to evaluate the evidence on key maternal and fetal complications related to low weight gain during pregnancy in obese and overweight patients. PMID- 26929880 TI - Junctional Bradycardia as Early Sign of Digoxin Toxicity in a Premature Infant with Congestive Heart Failure due to a Left to Right Shunt. AB - Introduction Congestive heart failure due to left to right cardiac shunt is usually managed medically with diuretics, angiotensin converting enzyme inhibitors, and, in some cases, with the addition of digoxin. Case We report a 31 week gestation premature male infant who did not respond to such treatment and developed hyperaldosteronism and severe hypokalemia secondary to activation of the renin angiotensin aldosterone system. The hypokalemia was not responsive to intravenous KCL supplementation and induced digoxin toxicity despite a relatively normal digoxin level. The earliest signs of digoxin toxicity in the patient were junctional rhythm and bradycardia. The discontinuation of digoxin and the administration of digoxin specific immunoglobulin fragments (Fab) reversed those changes. The addition of spironolactone (an aldosterone antagonist) had a dramatic effect, resulting in clinical improvement of the patient coupled with normalization of Q4 serum and urine electrolytes. Conclusion Serum Digoxin level alone may fail as an independent guide in the diagnosis of digoxin toxicity when hypokalemia is present. In premature infants with congestive heart failure and hypokalemia, addition of an aldosterone antagonist should be considered. PMID- 26929881 TI - Multiple Successful Angioembolizations for Refractory Cardiac Failure in a Preterm with Rapidly Involuting Congenital Hemangioma. AB - Rapidly involuting congenital hemangiomas (RICH) are the commonest variety of congenital hemangioma, often diagnosed antenatally as high-flow arteriovenous shunts causing hemodynamic compromise to the fetus. The postnatal management of such patients is often challenging. We present the case of an infant boy who was delivered prematurely at 29 weeks of gestation due to fetal compromise by a RICH, with features of high-output cardiac failure and major systemic hemodynamic steal from peripheral organs. Two early angioembolizations were required to manage his high-output cardiac failure. To our knowledge, this infant is the smallest and earliest newborn case of successful angioembolization for a complex, life threatening vascular anomaly. We discuss the interventional dilemmas regarding the optimal timing of delivery and early embolization. PMID- 26929882 TI - Volar and Dorsal Rim Fractures of the Distal Radius. PMID- 26929884 TI - The Effect of Temperature Changes in Vitreoretinal Surgery. AB - PURPOSE: Recent studies on temperature control in biology and medicine have found the temperature as a new instrument in healthcare. In this manuscript, we reviewed the effects of temperature and its potential role in pars plana vitrectomy. We also examined the relationship between intraocular pressure, viscosity, and temperature in order to determine the best balance to manipulate the tamponades during the surgery. METHODS: A literature review was performed to identify potentially relevant studies on intraocular temperature. Physics equations were applied to explain the described effects of temperature changes on the behavior of the endotamponades commonly used during vitreoretinal surgery. We also generated an operating diagram on the pressure-temperature plane for the values of both vapor-liquid equilibrium and intraocular pressure. RESULTS: The rapid circulation of fluid in the vitreous cavity reduces the heat produced by the retinal and choroidal surface, bringing the temperature toward room temperature (22 degrees C, deep hypothermia). Temperature increases with endolaser treatment, air infusion, and the presence of silicone oil. The variations in temperature during vitreoretinal surgery are clinically significant, as the rheology of tamponades can be better manipulated by modulating intraocular pressure and temperature. CONCLUSIONS: During vitreoretinal surgery, the intraocular temperature showed rapid and significant fluctuations at different steps of the surgical procedure inside the vitreous cavity. Temperature control can modulate the rheology of tamponades. TRANSLATIONAL RELEVANCE: Intraoperative temperature control can improve neuroprotection during vitreoretinal surgery, induce the vaporization of perfluorcarbon liquid, and change the shear viscosity of silicone oil. PMID- 26929883 TI - Ethical Considerations for the Return of Incidental Findings in Ophthalmic Genomic Research. AB - Whole genome and whole exome sequencing technologies are being increasingly used in research. However, they have the potential to identify incidental findings (IF), findings not related to the indication of the test, raising questions regarding researchers' responsibilities toward the return of this information to participants. In this study we discuss the ethical considerations related to the return of IF to research participants, emphasizing that the type of the study matters and describing the current practice standards. There are currently no legal obligations for researchers to return IF to participants, but some viewpoints consider that researchers might have an ethical one to return IF of clinical validity and clinical utility and that are actionable. The reality is that most IF are complex to interpret, especially since they were not the indication of the test. The clinical utility often depends on the participants' preferences, which can be challenging to conciliate and relies on participants' understanding. In summary, in the context of a lack of clear guidance, researchers need to have a clear plan for the disclosure or nondisclosure of IF from genomic research, balancing their research goals and resources with the participants' rights and their duty not to harm. PMID- 26929885 TI - Axial Length/Corneal Radius of Curvature Ratio and Myopia in 3-Year-Old Children. AB - PURPOSE: This study investigated the association of axial length (AL) to corneal radius of curvature (CRC) ratio with spherical equivalent (SE) in a 3-year old Asian cohort. METHODS: Three-hundred forty-nine 3-year old Asian children from The Growing Up in Singapore towards Healthy Outcomes (GUSTO) birth cohort study underwent AL and CRC measurements with a noncontact ocular biometer and cycloplegic refraction using an autorefractor. The ratio of AL to CRC (AL/CRC) was calculated for all the participants, and subsequently AL, CRC, and AL/CRC were analyzed in relationship to SE. RESULTS: The SE showed better correlation with AL/CRC (Spearman's correlation coefficient, rho = -0.53; 95% confidence interval [CI]: -0.66; -0.49; P < 0.001) compared to either AL or CRC alone ([rho = -0.36; 95% CI: -0.51 to 0.51; P = 0.01] and [rho = 0.05; 95% CI: -0.04 to 0.17; P = 0.34], respectively). Mean AL/CRC was 2.91 +/- 0.06 among myopes and decreased to 2.79 +/- 0.06 among hyperopes. Axial length to corneal radius of curvature was strongly correlated with SE in myopes (rho = -0.78; 95% CI: -3.76; 0.79; P = < 0.001), but not in emmetropes and hyperopes ([rho = -0.39; 95% CI: 10.73; -0.57; P = 0.01] and [rho = -0.18; 95% CI: -17.28; 12.42; P = 0.38], respectively). Linear regression adjusted for gender and ethnicity showed a 0.74 diopter shift in SE towards myopia with every 0.1 increase in AL/CRC ratio (P < 0.001, r2 = 0.33). CONCLUSION: The correlation between SE and AL/CRC is stronger than that between AL or CRC alone. This suggests that in a research setting, when cycloplegic refraction is difficult to perform on 3-year-old children, AL/CRC may be the next best reference for refractive error. TRANSLATIONAL RELEVANCE: In the research setting, AL/CRC may be the next best reference for refractive error over AL alone when cycloplegic refraction is unavailable in 3-year old children. PMID- 26929886 TI - A New Method to Visualize the Intact Subretina From Retinal Pigment Epithelium to Retinal Tissue in Whole Mount of Pigmented Mouse Eyes. AB - PURPOSE: The subretinal layer between apical retinal pigment epithelium (RPE) and the apices of the photoreceptor outer segments is important to aging and degenerative pathogenesis, but current protocols do not provide intact horizontal images of this retinal space. Thus, an RPE/retina whole mount staining protocol was developed to observe integral subretinal regions. METHODS: RPE/retina whole mounts were stained instead of separated retina or RPE whole mounts. Hydrogen peroxide (H2O2) treatment was applied in different conditions of concentration, time, and temperature for the bleaching of RPE and choroidal melanocyte pigmentation in the pigmented RPE/retina whole mounts before antibody staining. RESULTS: An RPE/retina whole mount staining protocol provided better morphology of the photoreceptor outer segment than current retina whole mount. For the pigmented eyes, 10% H2O2 pretreatment effectively bleached melanin at 55 degrees C less than 2 hours, or at 4 degrees C within 7 days, without significant effect on immunolabeling efficacy of most antibodies tested. Actually, 55 degrees C bleaching improved immunolabeling intensities compared to the nonbleaching control. This melanin bleaching RPE/retina protocol was applied further to observe macrophage/microglia extending from the sclera to outer plexiform layer in the CX3CR1+/GFP retina. CONCLUSIONS: The pigment bleaching RPE/retina whole mount allowed integral horizontal imaging between choroid to photoreceptor layers, which could not be accomplished with existing methods of separated retina or RPE whole mount. Under these procedures, antigenicity of most antibodies also was well preserved. TRANSLATIONAL RELEVANCE: This efficient protocol provides a tool to observe an integral view of subretinal structures including macrophage/microglia and transplanted cells, and further allows study of the interrelationship between the choroid and photoreceptor in models of aging, disease, and retinal degeneration. PMID- 26929887 TI - Long-term Remission Over Six Years for a Patient with Recurrent Glioblastoma Treated with Cediranib/Lomustine. AB - Cediranib is an orally available, pan-VEGFR tyrosine kinase inhibitor. A previous Phase III study of patients with recurrent glioblastoma treated with this drug did not meet the primary end of progressive-free survival (PFS). We identified one patient, a 57-year-old Caucasian female who, following surgery in October 2008 and concurrent temozolomide and radiation therapy from November 8, 2008, to January 6, 2009, developed a tumor progression of the left posterior frontal measuring 1.2 x 1.5 cm in February 2009. She was enrolled in a randomized, Phase III, placebo-controlled, partially-blinded clinical trial of cediranib as either monotherapy or in combination with lomustine (CCNU) versus CCNU. She was randomized to receive a combination therapy with 1st cycle CCNU 190 mg and cediranib 20 mg per day on April 15, 2009. However, she developed nephrotic syndrome and uncontrolled hypertension and was taken off this study in May 2010. Her six-week MRI showed a 50% tumor regression and a complete response at twenty four weeks. With no enhancement seen on MRI on June 4, 2015, she has been off therapy and in clinical remission over five years with high functional level and good quality of life (KPS-90%). This is a case report of successful therapy for recurrent glioblastoma with long-term remission despite termination of therapy greater than six years from cediranib and limited CCNU dosage. PMID- 26929888 TI - Resident-led Implementation of a Standardized Handoff System to Facilitate Transfer of Postoperative Neurosurgical Patients to the ICU. AB - Transitions in care are pivotal moments for patient safety. Although many strategies have been suggested for handoff improvement in the healthcare realm, little focus has been placed on patient safety during the transition from the operative to the postoperative setting. Many surgical trainees have received limited instruction, if any, on how to conduct comprehensive handoffs that ensure the safe transition of care and optimize continuity of care. Therefore, structured transfers of patient care can be invaluable. Here, we describe the implementation of a standardized handoff system developed by residents in an academic neurosurgery department to communicate key perioperative data via both electronic documentation and in-person discussion as a means of reinforcement. Our results are part of a comprehensive effort to strengthen the culture of safety surrounding the care and treatment of neurosurgical patients at our institution. PMID- 26929889 TI - Long-term Survival after Resection of HER2+ Infiltrating Ductal Carcinoma Metastasis to the Brainstem. AB - The central nervous system is a common site of metastatic spread from neoplasms in distant organs, including breast, bone, and lung. The decision to surgically treat these metastatic lesions is often challenging, especially in the setting of systemic disease or when eloquent brain regions are involved. Treating metastatic disease in the brainstem can be technically difficult, and in many institutions, considered a contraindication to surgical intervention, given the relatively high risk of new postoperative neurological deficits. Herein, we report a case of metastatic ductal carcinoma of the breast with spread to the pontine-medullary junction that was treated with aggressive surgical resection and chronic hormonal therapy. After surgical excision of the brainstem lesion, the patient remained asymptomatic and was maintained on trastuzumab therapy over a 10-year follow-up period, with no radiographic or clinical evidence of recurrent disease. To our knowledge, this is the first report of a patient treated for a solitary metastasis to the brainstem with long-term survival. PMID- 26929890 TI - Trauma Boot Camp: A Simulation-Based Pilot Study. AB - INTRODUCTION: Interns are often unprepared to effectively communicate in the acute trauma setting. Despite the many strengths of the Advanced Trauma Life Support (ATLS) program, the main shortcoming within the course is the deficiency of teamwork and leadership training. In this study, we describe the creation of an interdisciplinary boot camp in which interns' basic trauma knowledge, level of confidence, and teamwork skills are assessed. METHODS: We designed a one-day, boot camp curriculum for interns of various specialties with the purpose of improving communication and teamwork skills for effective management of acute trauma patients. Our curriculum consisted of a one-day, twelve-hour experience, which included trauma patient simulations, content expert lectures, group discussion of video demonstrations, and skill development workstations. Baseline and acquired knowledge were assessed through the use of confidence surveys, cognitive questionnaires, and a validated evaluation tool of teamwork and leadership skills for trauma Results: Fifteen interns entered the boot camp with an overall confidence score of 3.2 (1-5 scale) in the management of trauma cases. At the culmination of the study, there was a significant increase in the overall confidence level of interns in role delegation, leadership, Crisis Resource Management (CRM) principles, and in the performance of primary and secondary surveys. No significant changes were seen in determining and effectively using the Glasgow Coma Scale, Orthopedic splinting/reduction skills, and effective use of closed-loop communication. CONCLUSION: An intensive one-day trauma boot camp demonstrated significant improvement in self-reported confidence of CRM concepts, role delegation, leadership, and performance of primary and secondary surveys. Despite the intensive curriculum, there was no significant improvement in overall teamwork and leadership performance during simulated cases. Our boot camp curriculum offers educators a unique framework to which they can apply to their own training program as a foundation for effective leadership and teamwork training for interns. PMID- 26929891 TI - Transient Ischemic Attack in the Setting of Carotid Atheromatous Disease with a Persistent Primitive Hypoglossal Artery Successfully Treated with Stenting: A Case Report. AB - Fetal brain perfusion is supplied by the primitive dorsal aorta anteriorly, longitudinal neural arteries posteriorly, and anastomotic transverse segmentals. Most notable of these connections are the primitive trigeminal, otic, hypoglossal, and proatlantal arteries. With cranial-cervical circulatory maturation and development of the posterior communicating segments and vertebro basilar system, these primitive segmental anastomoses normally regress. Anomalous neurovascular development can result in persistence of these anastomoses. Due to its territory of perfusion, the persistent primitive hypoglossal artery (PPHA) is associated with vertebral artery and posterior communicating artery hypoplasia or aplasia. As a consequence, primary blood supply to the hindbrain comes chiefly from this single artery. Although usually clinically silent, PPHA is susceptible to common cerebrovascular disorders including athero-ischemic disease and saccular aneurysmal dilation to name a few. We present a case of transient ischemic attack in a patient with a PPHA and proximal atherosclerotic disease treated by endovascular stenting. PMID- 26929892 TI - Baastrup's Disease: An Often Missed Etiology for Back Pain. AB - Baastrup's disease is a relatively common disorder of the vertebral column, characterized by low back pain arising from the close approximation of adjacent posterior spinous processes and resultant degenerative changes, most commonly at L4-L5. Though fairly common, Baastrup's disease is overwhelmingly underdiagnosed and often missed due to a lack of knowledge and/or improper diagnostic techniques, leading to frequent mistreatment. We present a case of a 56-year-old man who presented with chronic, ongoing low back pain of several years duration. His pain was relieved by flexion of the spine, and aggravated by extension. Imaging studies revealed "kissing" posterior spinous processes, consistent with a diagnosis of Baastrup's Disease. He was treated with subcutaneous steroid injections and showed considerable clinical improvement. PMID- 26929893 TI - Is a Clinical Target Volume (CTV) Necessary in the Treatment of Lung Cancer in the Modern Era Combining 4-D Imaging and Image-guided Radiotherapy (IGRT)? AB - OBJECTIVE: We hypothesized that omission of clinical target volumes (CTV) in lung cancer radiotherapy would not compromise control by determining retrospectively if the addition of a CTV would encompass the site of failure. METHODS: Stage II III patients were treated from 2009-2012 with daily cone-beam imaging and a 5 mm planning target volume (PTV) without a CTV. PTVs were expanded 1 cm and termed CTVretro. Recurrences were scored as 1) within the PTV, 2) within CTVretro, or 3) outside the PTV. Locoregional control (LRC), distant control (DC), progression free survival (PFS), and overall survival (OS) were estimated. RESULT: Among 110 patients, Stage IIIA 57%, IIIB 32%, IIA 4%, and IIB 7%. Eighty-six percent of Stage III patients received chemotherapy. Median dose was 70 Gy (45-74 Gy) and fraction size ranged from 1.5-2.7 Gy. Median follow-up was 12 months, median OS was 22 months (95% CI 19-30 months), and LRC at two years was 69%. Fourteen local and eight regional events were scored with two CTVretro failures equating to a two-year CTV failure-free survival of 98%. CONCLUSION: Omission of a 1 cm CTV expansion appears feasible based on only two events among 110 patients and should be considered in radiation planning. PMID- 26929894 TI - Endoscopic-Assisted Middle Fossa Craniotomy for Resection of Vestibular Schwannoma. AB - Background Rates of hearing preservation following surgery via middle fossa craniotomy in patients harboring tumors with unfavorable characteristics are significantly lower than for those patients with "favorable" tumors. Objectives We will present two cases both with unfavorable conditions, which underwent endoscopic-assisted middle fossa craniotomy (MFC) resection of intracanalicular vestibular schwannomas with preserved postoperative hearing. Methods Chart reviews were conducted on both patients. Their presentation, intraoperative details, and techniques, pre- and postoperative audiograms, and facial nerve outcomes are presented. Results Patient A had 5.6 * 6.8 * 13.2 mm intracanalicular tumor with unserviceable hearing (pure tone audiometry [PTA], 41; speech determination score [SDS], 47%; class D) but was blind so hearing preservation was attempted. Postoperative hearing was preserved (PTA, 47; SDS, 60%; class B). Patient B had a 5 mm round intracanalicular tumor immediately adjacent to the vestibule and cochlea without any fundal fluid present. Preoperative audiogram showed serviceable hearing (PTA, 48; SDS, 88%; class B). Postoperatively, aidable hearing was preserved (PTA, 51; SDS, 76%; class C). Conclusion Hearing preservation surgery via MFC can be enhanced with endoscopic assisted dissection, especially in the lateral internal auditory canal. The superior optical view allows for preservation of cochlear nerve function and removal of residual tumor not otherwise seen on microscopy. PMID- 26929895 TI - En Bloc Resection of Desmoplastic Neurotropic Melanoma with Perineural Invasion of the Intracranial Trigeminal and Intraparotid Facial Nerve: Case Report and Review of the Literature. AB - Background Desmoplastic neurotropic melanoma (DNM) is a rare, highly malignant, and locally invasive form of cutaneous melanoma with a tendency for perineural invasion (PNI). Methods We report a case of a 61-year-old man presenting with right-sided trigeminal neuralgia and progressive facial paresis due to the PNI of the intracranial trigeminal nerve and the intraparotid facial nerve from DNM. We also present a review of the literature with six cases of DNM with PNI of the intracranial trigeminal nerve identified. Results The combined transtemporal infratemporal fossa approach was performed to achieve total en bloc resection of the tumor mass followed by postoperative radiotherapy (PORT). After 24 months of follow-up, the patient remains disease free with no signs of recurrence on magnetic resonance imaging. Conclusion We recommend the en bloc resection of the tumor mass followed by PORT for the management of DNM with PNI. A high index of suspicion for PNI as a cause of cranial neuropathies is essential for the early detection and treatment of patients with known melanoma. PMID- 26929896 TI - Mycotic Aneurysm Treated with Aneurysm Trapping. Case Report. AB - The authors describe a rare case of mycotic aneurysm (MA) associated with subarachnoid hemorrhage treated with aneurysm trapping. The literature on management and the surgical techniques are controversial due to lack of randomize trials. PMID- 26929897 TI - Upper Nasopharyngeal Corridor for Transnasal Endoscopic Drainage of Petroclival Cholesterol Granulomas: Alternative Access in Conchal Sphenoid Patients. AB - Background Cholesterol granulomas arising at the petrous apex can be treated via traditional open surgical, endoscopic, and endoscopic-assisted approaches. Endoscopic approaches require access to the sphenoid sinus, which is technically challenging in patients with conchal sphenoidal anatomy. Clinical Presentation A 55-year-old woman presented with intermittent headaches and tinnitus. Formal audiometry demonstrated moderately severe bilateral hearing loss. CT of the temporal bones and sella revealed a well-demarcated expansile lytic mass. MRI of the face, orbit, and neck showed a right petrous apex mass measuring 22 * 18 * 19 mm that was hyperintense on T1- and T2-weighted images without enhancement, consistent with a cholesterol granuloma. The patient had a conchal sphenoidal anatomy. Operative Technique Herein, we present an illustrative case of a low lying petroclival cholesterol granuloma in a patient with conchal sphenoidal anatomy to describe an alternative high nasopharyngeal corridor for endoscopic transnasal transclival access. Postoperative Course Postoperatively, the patient's symptoms recovered and no complications occurred. Follow-up imaging demonstrated a patent drainage tract without evidence of recurrence. Conclusion In patients with a conchal sphenoid sinus, endoscopic transnasal transclival access can be gained using a high nasopharyngeal approach. This corridor facilitates safe access to these lesions and others in this location. PMID- 26929899 TI - Paradoxical Herniation in the Postcraniectomy Syndrome: Report and Literature Update. AB - Introduction The decompressive craniectomy is a surgical strategy widely used with specific criteria to control the refractory intracranial pressure (ICP). However, it is important to warn about the presence of a postcraniectomy syndrome and analyze the risk-benefit on a long term. Case Report A 72-year-old male patient diagnosed with a subarachnoid hemorrhage secondary to the rupture of an anterior circulation aneurysm that develops vasospasm, secondary ischemia, and edema with signs of herniation that required a decompressive craniectomy on a first step. Afterwards, the aneurysm was approached and he consequently developed hydrocephaly. A ventriculoperitoneal shunt is installed, contralateral to the craniectomy, and progressive sinking of the skin flap, there is neurological deterioration and paradoxical herniation. Its association with the clinical deterioration by bronchoaspiration did not allow the cranioplasty to resolve the ICP decompensation. Conclusions The paradoxical herniation as part of the postcraniectomy syndrome is an increasingly common condition identified in adult patients with cortical atrophy, and who have also been treated with ventricular shunt systems. Timely cranioplasty represents the ideal therapeutic plan once the compromise from the mass effect has resolved to avoid complications derived from the decompressive craniectomy per se. PMID- 26929898 TI - Chondromyxoid Fibroma of the Skull Base and Calvarium: Surgical Management and Literature Review. AB - Chondromyxoid fibroma (CMF) is an exceedingly rare tumor that represents less than 1% of all primary bone neoplasms. Occurrence in the facial and cranial bones is extremely rare and frequently misdiagnosed. Case Reports We report two cases of CMF, one in the sphenoclival skull base and the other involving the parietal bone in two young female patients. Excision was performed in both cases. Presenting symptoms, treatment, and follow-up are reported. Methods A retrospective review of the literature on cranial CMF was performed. The location, demographics, presenting symptoms, and treatment of all calvarial and skull base CMF cases published since 1990 are summarized. Discussion In our literature review, we found 67 published cases of cranial CMF. Mean age of all calvarial and skull base CMFs at diagnosis was 38.2 years old. Of the cases affecting the cranium, the sinonasal structures were most commonly involved. To our knowledge we report only the second case of CMF involving the parietal bone published in an English-language journal. Total resection is the best treatment, and should be the goal of surgical intervention. Curettage results in high recurrence rates. Radiotherapy in the setting of subtotal resection or recurrence cannot be definitively recommended and needs further investigation. PMID- 26929900 TI - Sharing big biomedical data. AB - BACKGROUND: The promise of Big Biomedical Data may be offset by the enormous challenges in handling, analyzing, and sharing it. In this paper, we provide a framework for developing practical and reasonable data sharing policies that incorporate the sociological, financial, technical and scientific requirements of a sustainable Big Data dependent scientific community. FINDINGS: Many biomedical and healthcare studies may be significantly impacted by using large, heterogeneous and incongruent datasets; however there are significant technical, social, regulatory, and institutional barriers that need to be overcome to ensure the power of Big Data overcomes these detrimental factors. CONCLUSIONS: Pragmatic policies that demand extensive sharing of data, promotion of data fusion, provenance, interoperability and balance security and protection of personal information are critical for the long term impact of translational Big Data analytics. PMID- 26929901 TI - Frequencies of single-nucleotide polymorphisms and haplotypes of the SLCO1B1 gene in selected populations of the western balkans. AB - As a membrane influx transporter, organic anion-transporting polypeptide 1B1 (OATP1B1) regulates the cellular uptake of a number of endogenous compounds and drugs. The aim of this study was to characterize the diversity of the solute carrier organic anion transporter family member 1B1 (SLCO1B1) gene encoding this transporter in two ethnic groups populating the Western Balkans. The distribution of SCLO1B1 alleles was determined at seven variant sites (c.388A>G, c.521T>C, c.571T>C, c.597C>T, c.1086C>T, c.1463G>C and c.*439T>G) in 266 Macedonians and 94 Albanians using the TaqMan allelic discrimination assay. No significant difference in the frequencies of the single nucleotide polymorphisms (SNPs) was observed between these populations. The frequency of the c.521T>C SNP was the lowest (<13.7 and 12.2%, respectively), while the frequencies of all other SNP alleles were above 40.0%. Variant alleles of c.1463G>C and c.1086 C>T SNPs were not identified in either ethnic group. The haplotype analysis revealed 20 and 21 different haplotypes in the Macedonian and Albanian population, respectively. The most common haplotype in both ethnic groups, *1J/*1K/*1L, had a frequency of 39.0% and 26.6%, respectively. In both populations, the variant alleles of the functionally significant c.521T>C and c.388A>G SNPs existed in one major haplotype (*15/*16/*17), with a frequency of 8.6 and 2.4% in the Macedonian and Albanian subjects, respectively. In conclusion, sequence variations of the SLCO1B1 gene in the studied populations occur at high frequencies, which are similar to that of the Caucasian population. Further studies are needed to evaluate the clinical significance of these SNPs and/ or the major SLCO1B1 haplotypes they form for a large number of substrates and for susceptibility to certain diseases. PMID- 26929902 TI - Prevalence of chromosomal abnormalities in infertile couples in romania. AB - The purpose of this study was to establish a correlation between the presence of chromosomal abnormalities in one of the partners and infertility. This retrospective study was performed at the Department of Reproductive Medicine, Life Memorial Hospital, Bucharest, Romania, between August 2007 to December 2011. Two thousand, one hundred and ninety-five patients with reproductive problems were investigated, and the frequency of chromosomal abnormalities was calculated. The control group consisting of 87 fertile persons who had two or more children, was investigated in this retrospective study. All the patients of this study were investigated by cytogenetic techniques and the results of the two groups were compared by a two-tailed Fisher's exact test. In this study, 94.99% patients had a normal karyotype and 5.01% had chromosomal abnormalities (numerical and structural chromosomal abnormalities). In the study group, numerical chromosomal abnormalities were detected in 1.14% of infertile men and 0.62% of infertile women, and structural chromosomal abnormalities were detected in 1.38% of infertile men and 1.87% of infertile women, respectively. The correlation between the incidence of chromosomal anomalies in the two sexes in couple with reproductive problems was not statistically significant. Recently, a possible association between infertility and chromosomal abnormalities with a significant statistical association has been reported. Our study shows that there is no association between chromosomal abnormalities and infertility, but this study needs to be confirmed with further investigations and a larger control group to establish the role of chromosomal abnormalities in the etiology of infertility. PMID- 26929903 TI - Investigation of fasciculation and elongation protein zeta-1 (FEZ1) in peripheral blood reveals differences in gene expression in patients with schizophrenia. AB - Schizophrenia (SZ) is a chronic neuropsychiatric disorder characterized by affective, neuromorphological and cognitive impairment, deteriorated social functioning and psychosis with underlying molecular abnormalities, including gene expression changes. Observations have suggested that fasciculation and elongation protein zeta-1 (FEZ1) may be implicated in the pathogenesis of schizophrenia. Nevertheless, our current knowledge of the expression of FEZ1 in peripheral blood of schizophrenia patients remains unclear. The purpose of this study was to identify the characteristic gene expression patterns of FEZ1 in peripheral blood samples from schizophrenia patients. We performed quantitative reverse transcriptase (qRT-PCR) analysis using peripheral blood from drug-free schizophrenia patients (n = 29) and age and gender-matched general population controls (n = 24). For the identification of FEZ1 gene expression patterns, we applied a comparative threshold cycle (CT) method. A statistically significant difference of FEZ1 mRNA level was revealed in schizophrenia subjects compared to healthy controls (p = 0.0034). To the best of our knowledge, this study is the first describing a down-regulation of FEZ1 gene expression in peripheral blood of patients with schizophrenia. Our results suggested a possible functional role of FEZ1 in the pathogenesis of schizophrenia and confirmed the utility of peripheral blood samples for molecular profiling of psychiatric disorders including schizophrenia. The current study describes FEZ1 gene expression changes in peripheral blood of patients with schizophrenia with significantly down regulation of FEZ1 mRNA. Thus, our results provide support for a model of SZ pathogenesis that includes the effects of FEZ1 expression. PMID- 26929904 TI - The relationship between transcript expression levels of nuclear encoded (TFAM, NRF1) and mitochondrial encoded (MT-CO1) genes in single human oocytes during oocyte maturation. AB - In some cases of infertility in women, human oocytes fail to mature when they reach the metaphase II (MII) stage. Mitochondria plays an important role in oocyte maturation. A large number of mitochondrial DNA (mtDNA), copied in oocytes, is essential for providing adenosine triphosphate (ATP) during oocyte maturation. The purpose of this study was to identify the relationship between transcript expression levels of the mitochondrial encoded gene (MT-CO1) and two nuclear encoded genes, nuclear respiratory factor 1 (NRF1) and mitochondrial transcription factor A (TFAM) in various stages of human oocyte maturation. Nine consenting patients, age 21-35 years old, with male factors were selected for ovarian stimulation and intracytoplasmic sperm injection (ICSI) procedures. mRNA levels of mitochondrial-related genes were performed by singlecell TaqMan(r) quantitative real-time polymerase chain reaction (qRT-PCR). There was no significant relationship between the relative expression levels in germinal vesicle (GV) stage oocytes (p = 0.62). On the contrary, a significant relationship was seen between the relative expression levels of TFAM and NRF1 and the MT-CO1 genes at the stages of metaphase I (MI) and MII (p = 0.03 and p = 0.002). A relationship exists between the transcript expression levels of TFAM and NRF1, and MT-CO1 genes in various stages of human oocyte maturation. PMID- 26929905 TI - Clinical relevance of CHEK2 and NBN mutations in the macedonian population. AB - Clinical importance of the most common CHEK2 (IVS2+1 G>A, 1100delC, I157T and del5395) and NBN (R215W and 657del5) gene mutations for breast cancer development in Macedonian breast cancer patients is unknown. We performed a case-control study including 300 Macedonian breast cancer patients and 283 Macedonian healthy controls. Genotyping was done using a fast and highly accurate single-nucleotide primer extension method for the detection of five mutations in a single reaction. The detection of the del5395 was performed using an allele-specific duplex polymerase chain reaction (PCR) assay. We have found that mutations were more frequent in breast cancer patients (n = 13, 4.3%) than in controls (n = 5, 1.8%), although without statistical significance. Twelve patients were heterozygous for one of the analyzed mutations, while one patient had two mutations (NBN R215W and CHEK2 I157T). The most frequent variant was I157T, found in 10 patients and four controls (p = 0.176) and was found to be associated with familial breast cancer (p = 0.041). CHEK2 1100delC and NBN 657del5 were each found in one patient and not in the control group. CHEK2 IVS2+1G>A and del5395 were not found in our cohort. Frequencies of the studied mutations are low and they are not likely to represent alleles of clinical importance in the Macedonian population. PMID- 26929906 TI - KIR and HLA haplotype analysis in a family lacking the KIR 2DL1-2DP1 genes. AB - The killer cell immunoglobulin-like receptor (KIR) gene cluster exhibits extensive allelic and haplotypic diversity that is observed as presence/absence of genes, resulting in expansion and contraction of KIR haplotypes and by allelic variation of individual KIR genes. We report a case of KIR pseudogene 2DP1 and 2DL1 gene absence in members of one family with the children suffering from acute myelogenous leukemia (AML). Killer cell immunoglobulin-like receptor low resolution genotyping was performed by the polymerase chain reaction (PCR) sequence-specific primers (SSP)/sequence-specific oligonucleotide (SSO) method and haplotype assignment was done by gene content analysis. Both parents and the maternal grandfather, shared the same Cen-B2 KIR haplotype, containing KIR 3DL3, 2DS2, -2DL2 and -3DP1 genes. The second haplotype in the KIR genotype of the mother and grandfather was Tel-A1 with KIR 2DL4 (normal and deleted variant), 3DL1, -22 bp deletion variant of the 2DS4 gene and -3DL2, while the second haplotype in the KIR genotype of the father was Tel-B1 with 2DL4 (normal variant), -3DS1, -2DL5, -2DS5, -2DS1 and 3DL2 genes. Haplotype analysis in all three offsprings revealed that the children inherited the Cen-B2 haplotype with the same gene content but two of the children inherited a deleted variant of the 2DL4 gene, while the third child inherited a normal one. The second haplotype of all three offspring contained KIR 2DL4, -2DL5, -2DS1, -2DS4 (del 22bp variant), 2DS5, -3DL1 and -3DL2 genes, which was the basis of the assumption that there is a hybrid haplotype and that the present 3DL1 gene is a variant of the 3DS1 gene. Due to consanguinity among the ancestors, the results of KIR segregation analysis showed the existence of a very rare KIR genotype in the offspring. The family who is the subject of this case is even more interesting because the father was 10/10 human leukocyte antigen (HLA)-matched to his daughter, all members of the family have the "best" donor KIR-B content and the presence of a rare KIR genotype with KIR 2DP1-2DL1 genes absence. PMID- 26929907 TI - Three novel mutations of CHD7 gene in two turkish patients with charge syndrome; A double point mutation and an insertion. AB - The CHARGE (coloboma, heart defects, atresia, retardation, genital, ear) syndrome is a genetic disease characterized by ocular coloboma, choanal atresia or stenosis and semicircular canal abnormalities. Most of the patients clinically diagnosed with CHARGE syndrome have mutations in chromodomain helicase DNA binding protein 7 (CHD7) gene. The CHD7 gene is located on chromosome 8q12.1, and up to now, there are more than 500 pathogenic mutations identified in the literature. We report two patients diagnosed with CHARGE syndrome with two novel mutations in the CHD7 gene: the first patient has double consecutive novel mutations in three adjacent codons, and the other has a novel insertion. PMID- 26929908 TI - Early onset marfan syndrome: Atypical clinical presentation of two cases. AB - Early onset Marfan Syndrome (eoMFS) is a rare, severe form of Marfan Syndrome (MFS). The disease has a poor prognosis and most patients present with resistance to heart failure treatment during the newborn period. This report presents two cases of eoMFS with similar clinical features diagnosed in the newborn period and who died at an early age due to the complications related to the involvement of the cardiovascular system. PMID- 26929909 TI - Congenital hydrocephalus and hemivertebrae associated with de novo partial monosomy 6q (6q25.3->qter). AB - This study was conducted to describe a prenatal case of congenital hydrocephalus and hemivertebrae with a 6q terminal deletion and to investigate the possible correlation between the genotype and phenotype of the proband. We performed an array-based comparative genomic hybridization (aCGH) analysis on a fetus diagnosed with congenital hydrocephalus and hemivertebrae. The deletion, spanning 10.06 Mb from 6q25.3 to 6qter, was detected in this fetus. The results of aCGH, karyotype and fluorescent in situ hybridization (FISH) analyses in the healthy parents were normal, which confirmed that the proband's copy-number variant (CNV) was de novo. This deleted region encompassed 97 genes, including 28 OMIM genes. We discussed four genes (TBP, PSMB1, QKI and Pacrg) that may be responsible for hydrocephalus while the T gene may have a role in hemivertebra. We speculate that five genes in the 6q terminal deletion region were potentially associated with hemivertebrae and hydrocephalus in the proband. PMID- 26929910 TI - Report of a new case with pentasomy X and novel clinical findings. AB - Pentasomy X is an extremely rare sex chromosome abnormality, a condition that only affects females, in which three more X chromosomes are added to the normally present two chromosomes in females. We investigated the novel clinical findings in a 1-year-old female baby with pentasomy X, and determined the parental origins of the X chromosomes. Our case had thenar atrophy, postnatal growth deficiency, developmental delay, mongoloid slant, microcephaly, ear anomalies, micrognathia and congenital heart disease. A conventional cytogenetic technique was applied for the diagnosis of the polysomy X, and quantitative fluorescent polymerase chain reaction (QF-PCR) using 11 inherited short tandem repeat (STR) alleles specific to the chromosome X for the determination of parental origin of X chromosomes. A cytogenetic evaluation revealed that the karyotype of the infant was 49,XXXXX. Comparison of the infant's features with previously reported cases indicated a clinically recognizable specific pattern of malformations referred to as the pentasomy X syndrome. However, to the best of our know-ledge, this is the first report of thenar atrophy in a patient with 49,XXXXX. The molecular analysis suggested that four X chromosomes of the infant originated from the mother as a result of the non disjunction events in meiosis I and meiosis II. We here state that the clinical manifestations seen in our case were consistent with those described previously in patients with pentasomy X. The degree of early hypotonia constitutes an important early prognostic feature in this syndrome. The pathogenesis of pentasomy X is not clear at present, but it is thought to be caused by successive maternal non disjunctions. PMID- 26929911 TI - Exposure of Infants to Aflatoxin M1 from Mother's Breast Milk in Ilam, Western Iran. AB - OBJECTIVES: Aflatoxins as a highly toxic group of mycotoxins are present in the environment and foodstuff. These have been reported to cause serious health problems in humans. Since aflatoxin M1 (AFM1) is excreted into breast milk, investigating the exposure of infants to AFM1 is of special concern. METHODS: In the present study, breast milk samples were collected from 85 lactating mothers in Ilam province, Iran, and the levels of AFM1 were analyzed using the enzyme linked immunosorbent assay-based technique. AFM1 was detected in breast milk of all lactating women. The mean contamination level was 5.91 +/- 2.031 ng/L, ranging from 2 ng/L to 10 ng/L. RESULTS: Multiple regression analysis indicated no significant associations of consumption of milk and dairy products, meat, fish, legumes, grain products, fruits, and nuts with the concentration of AFM1 in breast milk. Furthermore, no significant association was observed between AFM1 concentration and anthropometric data of infants. CONCLUSION: In western parts of Iran, lactating mothers and their infants could be at risk of aflatoxin B1 and AFM1 exposure, respectively. Therefore, in Iran, the evaluation of AFM1 in human breast milk as a biomarker for postnatal exposure of infants to this carcinogen requires more attention in different regions and various seasons. PMID- 26929912 TI - Modeling Chagas Disease at Population Level to Explain Venezuela's Real Data. AB - OBJECTIVES: In this paper we present an age-structured epidemiological model for Chagas disease. This model includes the interactions between human and vector populations that transmit Chagas disease. METHODS: The human population is divided into age groups since the proportion of infected individuals in this population changes with age as shown by real prevalence data. Moreover, the age structured model allows more accurate information regarding the prevalence, which can help to design more specific control programs. We apply this proposed model to data from the country of Venezuela for two periods, 1961-1971, and 1961-1991 taking into account real demographic data for these periods. RESULTS: Numerical computer simulations are presented to show the suitability of the age-structured model to explain the real data regarding prevalence of Chagas disease in each of the age groups. In addition, a numerical simulation varying the death rate of the vector is done to illustrate prevention and control strategies against Chagas disease. CONCLUSION: The proposed model can be used to determine the effect of control strategies in different age groups. PMID- 26929913 TI - Epidemics of Norovirus GII.4 Variant in Outbreak Cases in Korea, 2004-2012. AB - Norovirus GII.4 is recognized as a worldwide cause of nonbacterial outbreaks. In particular, the GII.4 variant occurs every 2-3 years according to antigenic variation. The aim of our study was to identify GII.4 variants in outbreaks in Korea during 2004-2012. Partial VP1 sequence of norovirus GII.4-related outbreaks during 2004-2012 was analyzed. The partial VP1 sequence was detected with reverse transcription-polymerase chain reaction, seminested polymerase chain reaction, and nucleotide sequence of 312-314 base pairs for phylogenetic comparison. Nine variants emerged in outbreaks, with the Sydney variant showing predominance recently. This predominance may persist for at least 3 years, although new variants may appear in Korea. PMID- 26929914 TI - Occurrence of Norovirus GII.4 Sydney Variant-related Outbreaks in Korea. AB - Human noroviruses are major causative agents of food and waterborne outbreaks of nonbacterial acute gastroenteritis. In this study, we report the epidemiological features of three outbreak cases of norovirus in Korea, and we describe the clinical symptoms and distribution of the causative genotypes. The incidence rates of the three outbreaks were 16.24% (326/2,007), 4.1% (27/656), and 16.8% (36/214), respectively. The patients in these three outbreaks were affected by acute gastroenteritis. These schools were provided unheated food from the same manufacturing company. Two genotypes (GII.3 and GII.4) of the norovirus were detected in these cases. Among them, major causative strains of GII.4 (Hu-jeju-47 2007KR-like) were identified in patients, food handlers, and groundwater from the manufacturing company of the unheated food. In the GII.4 (Hu-jeju-47-2007KR-like) strain of the norovirus, the nucleotide sequences were identical and identified as the GII.4 Sydney variant. Our data suggests that the combined epidemiological and laboratory results were closely related, and the causative pathogen was the GII.4 Sydney variant strain from contaminated groundwater. PMID- 26929915 TI - Impact and risk factors of post-stroke bone fracture. AB - Bone fracture occurs in stroke patients at different times during the recovery phase, prolonging recovery time and increasing medical costs. In this review, we discuss the potential risk factors for post-stroke bone fracture and preventive methods. Most post-stroke bone fractures occur in the lower extremities, indicating fragile bones are a risk factor. Motor changes, including posture, mobility, and balance post-stroke contribute to bone loss and thus increase risk of bone fracture. Bone mineral density is a useful indicator for bone resorption, useful to identify patients at risk of post-stroke bone fracture. Calcium supplementation was previously regarded as a useful treatment during physical rehabilitation. However, recent data suggests calcium supplementation has a negative impact on atherosclerotic conditions. Vitamin D intake may prevent osteoporosis and fractures in patients with stroke. Although drugs such as teriparatide show some benefits in preventing osteoporosis, additional clinical trials are needed to determine the most effective conditions for post-stroke applications. PMID- 26929916 TI - Inflammatory diseases modelling in zebrafish. AB - The ingest of diets with high content of fats and carbohydrates, low or no physical exercise and a stressful routine are part of the everyday lifestyle of most people in the western world. These conditions are triggers for different diseases with complex interactions between the host genetics, the metabolism, the immune system and the microbiota, including inflammatory bowel diseases (IBD), obesity and diabetes. The incidence of these disorders is growing worldwide; therefore, new strategies for its study are needed. Nowadays, the majority of researches are in use of murine models for understand the genetics, physiopathology and interaction between cells and signaling pathways to find therapeutic solutions to these diseases. The zebrafish, a little tropical water fish, shares 70% of our genes and conserves anatomic and physiological characteristics, as well as metabolical pathways, with mammals, and is rising as a new complementary model for the study of metabolic and inflammatory diseases. Its high fecundity, fast development, transparency, versatility and low cost of maintenance makes the zebrafish an interesting option for new researches. In this review, we offer a discussion of the existing genetic and induced zebrafish models of two important Western diseases that have a strong inflammatory component, the IBD and the obesity. PMID- 26929918 TI - Hydrogels for ocular drug delivery and tissue engineering. AB - Hydrogels, as crosslinked polymeric three dimensional networks, possess unique structure and behavior in response to the internal and/or external stimuli. As a result, they offer great prospective applications in drug delivery, cell therapy and human tissue engineering. Here, we highlight the potential of hydrogels in prolonged intraocular drug delivery and ocular surface therapy using stem cells incorporated hydrogels. PMID- 26929919 TI - Stem cell therapy of cataract. AB - INTRODUCTION: Cataract is recognized as a disease of the lens resulting in many blindness cases, while the only therapeutic procedure is surgery. Thus, to tackle this disease, alternative methods are required. Stem cell therapy is one of the alternative treatment modalities. Paired lens' epithelial pieces induced by vitreous body were shown to produce lens-like structures. Here, Wharton's jelly derived stem cells are suggested as the best candidates for this purpose, as these cells have potency for the differentiation into the lens fiber cells. HYPOTHESIS: It is hypothesized that Wharton's jelly derived stem cells could be used as a novel and appropriate source for the treatment of cataract. Evaluation of HYPOTHESIS: To attain this aim, lens of an animal model of cataract can be removed. Then, the human Wharton's jelly stem cells (hWJSCs) are injected into a capsule. Finally, the expression of crystalline proteins and vision function are analyzed. CONCLUSION: It is hypothesized that the lens capsule could act as a natural scaffold and hWJSCs could be used to restore the lens structure in the empty capsule. PMID- 26929920 TI - Laboratory environment and bio-medical experience: the impact of administration technique on the quality of immune-behavior data results in stress experience. AB - INTRODUCTION: Often in an experiment, the control group and the intact group are not identified because most scientists neglect the fact that the sets of manipulation as technical administrations may be considered as an undesirable stress on the clarity of the data obtained from a scientific research specifically if it focuses on studying the effects of stress. METHODS: This study was conducted in two parts using 40 male Wistar rats. The first part aimed to treat a group of rats by repeated injections i.p route (1 mL/kg) of placebo or NaCl (0.9%) and the other by direct oral administration of NaCl (0.9%). Both groups spent 1 h of jet air stress with stressed group. Our objective was to consider the effects that these manipulations would have on the validity of behavioral results (the elevated plus maze test, the open field, the light/dark box test) and immune data (immune cell count) during this stress experience. The second part was devoted to the measurement of ACTH, IL6, and CRP in these experimental groups. RESULTS: Unlike oral administration, repeated intra peritoneal injections cause a significant increase of plasma obtained levels of the adrenocorticotropin hormone (ACTH), interleukin-6 (IL-6) and the C-reactive protein (CRP) using injections of placebo: NaCl 0.9% (1 mL/kg) and it may have side effect on significant immune and behavioral alterations data quality induced by 1 h of air jet in the animal's cage identified by the leukocyte formula and behavioral tests. CONCLUSION: In an experimental protocol conducted on animal models, it is essential to opt for painless techniques such as oral administration instead of painful injections to avoid confusion at the behavioral and immunological results from biomedical experiments specifically one that focuses on the stress study. PMID- 26929917 TI - Hepatocellular carcinoma: Where are we? AB - Hepatocellular carcinoma (HCC) is the second cause of death due to malignancy in the world, following lung cancer. The geographic distribution of this disease accompanies its principal risk factors: Chronic hepatitis B virus and hepatitis C virus infection, alcoholism, aflatoxin B1 intoxication, liver cirrhosis, and some genetic attributes. Recently, type II diabetes has been shown to be a risk factor for HCC together with obesity and metabolic syndrome. Although the risk factors are quite well known and it is possible to diagnose HCC when the tumor is less than 1 cm diameter, it remains elusive at the beginning and treatment is often unsuccessful. Liver transplantation is thus far considered the best treatment for HCC as it cures HCC and the underlying liver disease. Using the Milan criteria, overall survival after liver transplantation for HCC is about 70% after 5 years. Many attempts have been made to go beyond the Milan Criteria and according to recent works reasonably good results have been achieved by using a histochemical marker such as cytokeratine 19 and the so-called "up to seven criteria" to divide patients into categories according to their risk of relapse. In addition to liver transplantation other therapies have been proposed such as resection, tumor ablation by different means, embolization and chemotherapy. An important step in the treatment of advanced HCC has been the introduction of sorafenib, the first oral, systemic drug that has provided significant improvement in survival. Treatment of HCC patients must be multidisciplinary and by using the different approaches discussed in this review it is possible to offer prolonged survival and quite good and sometimes even excellent quality of life to many patients. PMID- 26929921 TI - Effects of folic acid supplementation on serum homocysteine and lipoprotein (a) levels during pregnancy. AB - INTRODUCTION: There are many ideas concerning the etiology and pathogenesis of preeclampsia including endothelial dysfunction, inflammation and angiogenesis. Elevated levels of total homocysteine (Hcy) and lipoprotein (a) [Lp(a)] are risk factors for endothelial dysfunction. This study aimed to evaluate the effect of high dose folic acid (FA) on serum Hcy and Lp(a) concentrations with respect to methylenetetrahydrofolate reductase (MTHFR) polymorphisms 677C->T during pregnancy. METHODS: In a prospective uncontrolled intervention, 90 pregnant women received 5 mg FA supplementation before pregnancy till 36th week of pregnancy. The MTHFR polymorphisms 677C->T, serum lactate dehydrogenase activity, urine protein and creatinine concentrations were measured before starting folic acid administration. Serum levels of Hcy and Lp(a) were determined before and after completion of folic acid supplementation period. RESULTS: Supplementation of the patients with FA for 36 week decreased the median (minimum- maximum) levels of serum Hcy from 11.40 MUmol/L (4.40-28.70) to 9.70 (1.60-20.80) MUmol/L (p=0.001). There was no significant change in serum Lp(a) after FA supplementation (p=0.17). The overall prevalence of genotypes in pregnant women that were under study for MTHFR C677T polymorphism was 53.3% CC, 26.7% CT and 20.0% TT. There was no correlation between decreasing level of serum Hcy in the patients receiving FA and MTHFR polymorphisms. CONCLUSION: Although FA supplementation decreased serum levels of Hcy in different MTHFR genotypes, serum Lp(a) was not changed by FA supplements. Our data suggests that FA supplementation effects on serum Hcy is MTHFR genotype independent in pregnant women. PMID- 26929923 TI - Spectroscopic analysis of bosentan in biological samples after a liquid-liquid microextraction. AB - INTRODUCTION: Microextraction processes with UV-Vis measurement have been developed and validated for analysis of bosentan in biological samples. METHODS: In this work, liquid-liquid microextraction procedures (DLLME & USAEME) were employed for cleanup, pre-concentration, and determination of bosentan in biological samples by UV-Vis spectroscopy at 270 nm. The method was validated and applied to the determination of bosentan in spiked serum, exhaled breath condensate and urine samples. RESULTS: Various experimental factors including type of extraction and dispersive solvents and their volumes, pH, sonication time and centrifuging time were investigated. Under the optimum conditions, the method was linear in the range of 1.0-5.0 MUg.mL(-1), with coefficient of determination (R(2)) of > 0.998. The limit of detection (LOD) was 0.07 mg.L(-1). Recovery of the target analyte in biological samples was 106.2%. The method could be easily applied for higher concentration of bosentan and needs more improvement for application in the pharmacokinetic investigations where more sensitive methods are required. CONCLUSION: A simple, low cost, precise and accurate spectrophotometric analysis of bosentan in biological samples after liquid-liquid microextraction were developed and validated for routine analyses. PMID- 26929922 TI - Detection of retinal capillary nonperfusion in fundus fluorescein angiogram of diabetic retinopathy. AB - INTRODUCTION: Retinal capillary nonperfusion (CNP) is one of the retinal vascular diseases in diabetic retinopathy (DR) patients. As there is no comprehensive detection technique to recognize CNP areas, we proposed a different method for computing detection of ischemic retina, non-perfused (NP) regions, in fundus fluorescein angiogram (FFA) images. METHODS: Whilst major vessels appear as ridges, non-perfused areas are usually observed as ponds that are surrounded by healthy capillaries in FFA images. A new technique using homomorphic filtering to correct light illumination and detect the ponds surrounded in healthy capillaries on FFA images was designed and applied on DR fundus images. These images were acquired from the diabetic patients who had referred to the Nikookari hospital and were diagnosed for diabetic retinopathy during one year. Our strategy was screening the whole image with a fixed window size, which is small enough to enclose areas with identified topographic characteristics. To discard false nominees, we also performed a thresholding operation on the screen and marked images. To validate its performance we applied our detection algorithm on 41 FFA diabetic retinopathy fundus images in which the CNP areas were manually delineated by three clinical experts. RESULTS: Lesions were found as smooth regions with very high uniformity, low entropy, and small intensity variations in FFA images. The results of automated detection method were compared with manually marked CNP areas so achieved sensitivity of 81%, specificity of 78%, and accuracy of 91%.The result was present as a Receiver operating character (ROC) curve, which has an area under the curve (AUC) of 0.796 with 95% confidence intervals. CONCLUSION: This technique introduced a new automated detection algorithm to recognize non-perfusion lesions on FFA. This has potential to assist detecting and managing of ischemic retina and may be incorporated into automated grading diabetic retinopathy structures. PMID- 26929924 TI - Network of nanomedicine researches: impact of Iranian scientists. AB - INTRODUCTION: We may define the nanomedicine as the use of nanotechnology in the health care, disease diagnoses and treatment in order to maintain and increase the health status of a population through improve pharmacotherapy. The main objective of the current study is to analyze and visualize the co-authorship network of all papers in the field of nanomedicine published throughout 2002-2014 in journals and indexed in the Web of Science database. METHODS: The Web of Science database was used to extract all papers indexed as a topic of nanomedicine through 2002-2014. The Science of Science Tool was used to map the co-authorship network of papers. RESULTS: Total number of papers extracted from the Web of Science in the field of nanomedicine was 3092 through 2002-2014. Analysis of data showed that the research activities in the field of nanomedicine increased steadily through the period of study. USA, China, and India were the most prolific countries in the field. The dominant language of publications was English. The co-authorship connection revealed a network with a density of 0.0006. CONCLUSION: Nanomedicine researches have markedly been increased in Iran. Ninety-five percent of Iranian papers were cooperated with multi-authors. The collaboration coefficient degree was 0.731. PMID- 26929925 TI - Recent advances in immunosensor for narcotic drug detection. AB - INTRODUCTION: Immunosensor for illicit drugs have gained immense interest and have found several applications for drug abuse monitoring. This technology has offered a low cost detection of narcotics; thereby, providing a confirmatory platform to compliment the existing analytical methods. METHODS: In this minireview, we define the basic concept of transducer for immunosensor development that utilizes antibodies and low molecular mass hapten (opiate) molecules. RESULTS: This article emphasizes on recent advances in immunoanalytical techniques for monitoring of opiate drugs. Our results demonstrate that high quality antibodies can be used for immunosensor development against target analyte with greater sensitivity, specificity and precision than other available analytical methods. CONCLUSION: In this review we highlight the fundamentals of different transducer technologies and its applications for immunosensor development currently being developed in our laboratory using rapid screening via immunochromatographic kit, label free optical detection via enzyme, fluorescence, gold nanoparticles and carbon nanotubes based immunosensing for sensitive and specific monitoring of opiates. PMID- 26929926 TI - Molecular Targeted Therapy for Hepatocellular Carcinoma: Where Are We Now? PMID- 26929927 TI - Integrative Biology of Diabetic Kidney Disease. AB - BACKGROUND: The leading cause of ESRD in the U.S. is diabetic kidney disease (DKD). Despite significant efforts to improve outcomes in DKD, the impact on disease progression has been disappointing. This has prompted clinicians and researchers to search for alternative approaches to identify persons at risk, and to search for more effective therapies to halt progression of DKD. Identification of novel therapies is critically dependent on a more comprehensive understanding of the pathophysiology of DKD, specifically at the molecular level. A more expansive and exploratory view of DKD is needed to complement more traditional research approaches that have focused on single molecules. SUMMARY: In recent years, sophisticated research methodologies have emerged within systems biology that should allow for a more comprehensive disease definition of DKD. Systems biology provides an inter-disciplinary approach to describe complex interactions within biological systems including how these interactions influence systems' functions and behaviors. Computational modeling of large, system-wide, quantitative data sets is used to generate molecular interaction pathways, such as metabolic and cell signaling networks. KEY MESSAGES: Importantly, interpretation of data generated by systems biology tools requires integration with enhanced clinical research data and validation using model systems. Such an integrative biological approach has already generated novel insights into pathways and molecules involved in DKD. In this review, we highlight recent examples of how combining systems biology with traditional clinical and model research efforts results in an integrative biology approach that has significantly added to the understanding of the complex pathophysiology of DKD. PMID- 26929928 TI - Meditation and Yoga can Modulate Brain Mechanisms that affect Behavior and Anxiety-A Modern Scientific Perspective. AB - Meditation and Yoga techniques are receiving increased attention throughout the world, due to the accumulation of evidence based research that proves the direct and indirect benefits of such practices. Based on studies conducted so far, it has been found that the practice of meditation triggers neurotransmitters that modulate psychological disorders such as anxiety. This paper will review the psychological effects of the practice of meditation, the role of neurotransmitters, and studies using EEG and fMRI. PMID- 26929929 TI - The Effect of Walking Speed on Gait Variability in Healthy Young, Middle-aged and Elderly Individuals. AB - Previous research with healthy young adults has suggested that the temporal structure of gait variability is not random but shows self-similarity that is dependent on speed. Specifically, the strength of the long-range correlation of stride intervals follows a quadratic relationship with the minimum values at the respective preferred walking speed (PWS). The purpose of this study was to investigate if this relationship is affected by increasing age. Ten healthy young, seven healthy, middle-aged and seven healthy, elderly adults completed five-minute walking trials at 80%, 90%, 100%, 110% and 120% of their PWS on a treadmill. We investigated the temporal structure of gait variability by using detrended fluctuation analysis. In addition, we computed the Coefficient of Variation (CV) to identify effects on amount of gait variability. Our results revealed a significant quadratic relationship between the temporal structure of gait variability and speed for all groups extending the previously reported existence of such a relationship in healthy young adults to older individuals. However, only significant negative linear relationships were found between amount of variability and speed providing support that this relationship is not quadratic but linear across individuals of different ages. In addition, we found that the examination of the temporal structure of gait variability is more sensitive in differentiating middle-age and younger individuals. If middle-age is where the aging process starts, then measures of the temporal structure of gait variability are essential as prognostic and diagnostic tools of aging. PMID- 26929930 TI - Effects of dietary fiber preparations made from maize starch on the growth and activity of selected bacteria from the Firmicutes, Bacteroidetes, and Actinobacteria phyla in fecal samples from obese children. AB - Currently, there is a search for substances that would be very well tolerated by an organism and which could contribute to the activation of the growth of Bacteroidetes and Actinobacteria strains, with simultaneous inhibition of the growth of Firmicutes. High expectations in this regard are raised with the use of fiber preparations from starch - resistant corn dextrins, branched dextrins, resistant maltodextrins and soluble corn fiber. In this paper, the influence of fiber preparations made from corn starch was evaluated on growth and activity of Bacteroidetes, Actinobacteria and Firmicutes strains isolated from obese children. It was demonstrated that in the stool of obese children Firmicutes strains predominate, while Bacteroidetes and Actinobacteria strains were in the minority. A supplementation of fecal culture with fiber preparations did not cause any significant changes in the number of strains of Bacteroidetes and Firmicutes. Addition of fiber preparations to the fecal samples of obese children increased the amount of short-chain fatty acids, especially acetic (p < 0.01), propionic, butyric (p = 0.05) and lactic acid (p < 0.01). PMID- 26929931 TI - Metagenomic 16s rRNA investigation of microbial communities in the Black Sea estuaries in South-West of Ukraine. AB - The Black Sea estuaries represent interfaces of the sea and river environments. Microorganisms that inhabit estuarine water play an integral role in all biochemical processes that occur there and form unique ecosystems. There are many estuaries located in the Southern-Western part of Ukraine and some of them are already separated from the sea. The aim of this research was to determine the composition of microbial communities in the Khadzhibey, Dniester and Sukhyi estuaries by metagenomic 16S rDNA analysis. This study is the first complex analysis of estuarine microbiota based on isolation of total DNA from a biome that was further subjected to sequencing. DNA was extracted from water samples and sequenced on the Illumina Miseq platform using primers to the V4 variable region of the 16S rRNA gene. Computer analysis of the obtained raw sequences was done with QIIME (Quantitative Insights Into Microbial Ecology) software. As the outcome, 57970 nucleotide sequences were retrieved. Bioinformatic analysis of bacterial community in the studied samples demonstrated a high taxonomic diversity of Prokaryotes at above genus level. It was shown that majority of 16S rDNA bacterial sequences detected in the estuarine samples belonged to phyla Cyanobacteria, Proteobacteria, Bacteroidetes, Actinobacteria, Verrucomicrobia, Planctomycetes. The Khadhzibey estuary was dominated by the Proteobacteria phylum, while Dniester and Sukhyi estuaries were characterized by dominance of Cyanobacteria. The differences in bacterial populations between the Khadzhibey, Dniester and Sukhyi estuaries were demonstrated through the Beta-diversity analysis. It showed that the Khadzhibey estuary's microbial community significantly varies from the Sukhyi and Dniester estuaries. The majority of identified bacterial species is known as typical inhabitants of marine environments, however, for 2.5% of microbial population members in the studied estuaries no relatives were determined. PMID- 26929932 TI - The links between hypertrophy, reproductive potential and longevity in the Saccharomyces cerevisiae yeast. AB - The yeast Saccharomyces cerevisiae has long been used as a model organism for studying the basic mechanisms of aging. However, the main problem with the use of this unicellular fungus is the unit of "longevity". For all organisms, lifespan is expressed in units of time, while in the case of yeast it is defined by the number of daughter cells produced. Additionally, in yeast the phenotypic effects of mutations often show a clear dependence on the genetic background, suggesting the need for an analysis of strains representing different genetic backgrounds. Our results confirm the data presented in earlier papers that the reproductive potential is strongly associated with an increase in cell volume per generation. An excessive cell volume results in the loss of reproductive capacity. These data clearly support the hypertrophy hypothesis. The time of life of all analysed mutants, with the exception of sch9D, is the same as in the case of the wild-type strain. Interestingly, the 121% increase of the fob1D mutant's reproductive potential compared to the sfp1D mutant does not result in prolongation of the mutant's time of life (total lifespan). PMID- 26929933 TI - An endless research for 2016. AB - In a moment of reflection of the past year of 2015, as to what we have achieved in medical research and what we need to do in the future we realize that although we have performed an enormous progress in medical research in the past we still have to do much more. In nuclear medicine there are many problems to solve like, how can we differentiate between infection, inflammation and cancer or between lymphomas and adenocarcinomas. In bone scans we need to differentiate traumatic lesions acute or chronic and lesions from another origin. Dosimetry and radiation burden is another problem. In HJNM we have previously published related papers. Not to mention radiation sickness due to modern atomic or hydrogen bombs. Labeling antibodies and genetic material is another issue. Additionally, in general medical knowledge is still unable to solve many unknown, difficult or tragic problems of our lives, like cancer, some viral infections, research in immunology, collagen diseases, genetics, radiation treatment, psychological disorders, anesthetics, the Hayflick phenomenon, hypertension, asthma, the function of the gastrointestinal tract, infectious diseases, physical exercise, all of which are briefly mentioned. We hope that even under the present financial problems and considering that almost 90% of medical truth is still unknown, our research in 2016 will be very important. In this paper we also discuss means for a more genuine and effective research. PMID- 26929934 TI - (18)F-FDG PET/CT imaging in granulomatosis with polyangiitis. AB - The paper gives an overview of the literature data on uptake of fluorine-18 fluorodeoxyglucose ((18)F-FDG) into the different tissue lesions which may occur in granulomatosis with polyangiitis (formerly called Wegener's syndrome). It discusses the cellular mechanisms of such (18)F-FDG uptake, which provide a basis for its interpretation in the context of (18)F-FDG positron emission tomography (PET) for inflammatory conditions. PMID- 26929935 TI - Causes of (18)F-FDG uptake on white adipose tissue. AB - White adipose tissue usually shows negligible fluorine-18-fluorodeoxyglucose ((18)F-FDG) uptake. In certain clinical conditions this (18)F-FDG uptake has been reported to be increased like in HIV patients under treatment, in exogenous Cushing's syndrome, in cases related to premedication and other cases. PMID- 26929937 TI - Challenges and strategies on radioiodine treatment for differentiated thyroid carcinoma. AB - OBJECTIVE: Radioiodine ((131)I) is considered an effective and low-risk therapeutic radionuclide for differentiated thyroid carcinoma (DTC); however, dilemmas exist in the optimization of indications, pre-treatment thyroid stimulating hormone (TSH) stimulation, dose decision, as well as in the treatment of (131)I-refractory disease. Refined strategies on (131)I treatment for DTC based on late evidence and novel insights are greatly needed. CONCLUSION: The indications of (131)I ablation continue to be refined with a better understanding of the risks and benefits. For pre-treatment TSH stimulation, recombinant human thyrotropin presents a better choice as it improves the quality of life, but is indicated only for ablation of the thyroid remnant and follow-up. Decreased doses of (131)I seem to be more appropriate in patients without gross residual disease or metastases, but maximal doses are suggested in patients with advanced disease. Imaging procedures contributing to decision-making for patients with advanced DTC also continue to be modified. As for the (131)I-refractory disease, there is a trend to increase (131)I uptake and retention by using additional therapeutic agents like kinase inhibitors with encouraging results. PMID- 26929936 TI - Towards tracer dose reduction in PET studies: Simulation of dose reduction by retrospective randomized undersampling of list-mode data. AB - OBJECTIVE: Optimization of tracer dose regimes in positron emission tomography (PET) imaging is a trade-off between diagnostic image quality and radiation exposure. The challenge lies in defining minimal tracer doses that still result in sufficient diagnostic image quality. In order to find such minimal doses, it would be useful to simulate tracer dose reduction as this would enable to study the effects of tracer dose reduction on image quality in single patients without repeated injections of different amounts of tracer. The aim of our study was to introduce and validate a method for simulation of low-dose PET images enabling direct comparison of different tracer doses in single patients and under constant influencing factors. METHODS: (18)F-fluoride PET data were acquired on a combined PET/magnetic resonance imaging (MRI) scanner. PET data were stored together with the temporal information of the occurrence of single events (list-mode format). A predefined proportion of PET events were then randomly deleted resulting in undersampled PET data. These data sets were subsequently reconstructed resulting in simulated low-dose PET images (retrospective undersampling of list-mode data). This approach was validated in phantom experiments by visual inspection and by comparison of PET quality metrics contrast recovery coefficient (CRC), background variability (BV) and signal-to-noise ratio (SNR) of measured and simulated PET images for different activity concentrations. In addition, reduced-dose PET images of a clinical (18)F-FDG PET dataset were simulated using the proposed approach. RESULTS: (18)F-PET image quality degraded with decreasing activity concentrations with comparable visual image characteristics in measured and in corresponding simulated PET images. This result was confirmed by quantification of image quality metrics. CRC, SNR and BV showed concordant behavior with decreasing activity concentrations for measured and for corresponding simulated PET images. Simulation of dose-reduced datasets based on clinical (18)F-FDG PET data demonstrated the clinical applicability of the proposed data. CONCLUSION: Simulation of PET tracer dose reduction is possible with retrospective undersampling of list-mode data. Resulting simulated low-dose images have equivalent characteristics with PET images actually measured at lower doses and can be used to derive optimal tracer dose regimes. PMID- 26929938 TI - Current status and future challenges of brain imaging with (18)F-DOPA PET for movement disorders. AB - OBJECTIVE: Parkinson's disease (PD) is a neurodegenerative disorder (ND) due to progressive loss of dopaminergic neurons in the basal ganglia. The correct differential diagnosis of this disease with parkinsonian syndromes (PS) or with essential tremor (ET) is a diagnostic dilemma, considering that only PD is responsive to treatment with levodopa. Traditional imaging fails to diagnose PD because morphological alterations in the brain are usually detectable only at advanced stages. Single photon emission tomography (SPET) with cocaine analogues has recently been used in the early detection of PD. The fluoro-18-deoxyphenyl alanine ((18)F-DOPA) is a positron emission tomography (PET) tracer with selective in vivo affinity to the basal ganglia, due to the specific metabolism of substantia nigra. We assessed the effective use of (18)F-DOPA PET in brain imaging in order to describe the function of presynaptic disorders of PD, PS, ET and other movement disorders compared to SPET imaging and also discussed novel radiopharmaceuticals. The role of magnetic resonance imaging (MRI) was also discussed. CONCLUSION: (18)F-DOPA PET imaging is still the best diagnostic tool for the diagnosis of PD and other movement disorders. Fluorine-18-FDG PET can play a role in the differential diagnosis between PD and other PS. The hybrid (18)F-DOPA PET/MRI seems to be able to play an important additional role in early diagnosis of the above syndromes. PMID- 26929939 TI - (18)F-FDG PET/CT imaging in systemic lupus erythematosus related autoimmune haemolytic anaemia and lymphadenopathy. AB - OBJECTIVE: We present a case of systemic lupus erythematosus (SLE) related autoimmune haemolytic anaemia (AIHA) and lymphadenopathy. AIHA as a serious complication of SLE, requiring urgent appropriate management. The timely differential diagnosis between SLE with lymphadenopathy and lymphoma, primary and SLE-related AIHA often looms as practical challenge under clinical scenario. Fluorine-18 fluorodeoxyglucose position emission tomography/computed tomography ((18)F-FDG PET/CT) performed for fever of a known origin and for possible malignancy, showed increased (18)F-FDG uptake in lymph nodes, as well as increased spleen uptake, which was probably due to lymphoma. CONCLUSIONS: A symmetrically increased (18)F-FDG uptake in small lymph nodes with multiple serous cavity effusion helped the differential diagnosis between SLE related AIHA and lymphoma. In addition, PET/CT can visualize not only the degree of disease activity or the "burden of inflammation" but also the distribution of the disease in the entire body. PMID- 26929940 TI - Missed causative tumors in diagnosing tumor-induced osteomalacia with (18)F-FDG PET/CT: a potential pitfall of standard-field imaging. AB - OBJECTIVE: We describe herein two tumor-induced osteomalacia (TIO) cases for whom the causative lesions, located in their popliteal fossa, that were not identified in the standard field of fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography ((18)F-FDG PET/CT), which usually images only the head, trunk, and proximal parts of the extremities. CLINICAL PRESENTATION AND INTERVENTION: A 47 years old Japanese man with multiple pathological fractures due to osteomalacia, accompanied by muscle weakness, hypophosphatemia, and an elevation of alkaline phosphatase (ALP) was referred to our hospital. A (18)F-FDG PET/CT scan was performed, but no (18)F-FDG uptake was detected in the standard field of imaging. Magnetic resonance imaging revealed a small subcutaneous tumor (1.9*1.2*0.6cm) of the left posteriomedial knee, displaying uniform enhancement on gadolinium-enhanced T1-weighted fat-suppression imaging. The tumor was resected widely and diagnosed as phosphaturic mesenchymal tumor, mixed connective tissue variant (PMTMCT). The other patient was a 31 years old Japanese woman with multiple pathological fractures, hypophosphatemia and elevated of ALP and was referred to our hospital on suspicion of TIO. Although the causative lesion was not identified in the standard field of (18)F-FDG PET/CT, (18)F-FDG uptake (SUVmax 2.9) was detected on the right knee in the additional whole-body (18)F FDG PET/CT. Magnetic resonance imaging revealed a soft-tissue tumor (6.4*4.1*2.9cm) in the right posterior knee. Following biopsy, the tumor was marginally resected, and was pathologically diagnosed as PMTMCT. CONCLUSION: Once patients are suspected to have TIO, a whole-body nuclear imaging study such as (18)F-FDG PET/CT should be performed, in order not to miss the hidden causative tumor, especially occurring in the distal extremities. PMID- 26929941 TI - Increased pertechnetate and radioiodine uptake in the thyroid gland with subacute thyroiditis and concurrent Graves' disease. AB - OBJECTIVE: A 61 years old woman presented with low grade fever and weight loss for a month. Thyroid function tests showed hyperthyroidism: increased technetium 99m pertechnetate ((99m)Tc O(-)4) and radioiodine ((131)I) uptake and elevated thyroid stimulating hormone receptor antibodies (TSHRAb). She also had high erythrocyte sedimentation rate. Fine-needle aspiration (FNA) biopsies of left thyroid lobe revealed subacute thyroiditis (SAT). Simultaneous occurrence of SAT and Graves' disease (GD) was diagnosed. The patient was in good physical condition after two doses of betamethasone and daily administration of low dose antithyroid drugs. CONCLUSION: This case indicated that the measurement of TSHRAb is useful in understanding the clinical course of patients with SAT when thyroid function tests including the (99m)Tc and (131)I uptake are not compatible with the diagnosis. In such cases, GD should be suspected. The mechanism of high (99m)Tc and/or (131)I uptake in patients with simultaneous SAT and GD may be due to the inflammatory process which was detected by FNA in a small part of the left thyroid lobe inducing the stimulating effects of elevated TSHRAb on the undamaged follicular cells. PMID- 26929942 TI - (18)F-FDG PET imaging of granulomatosis with polyangiitis -Wegener's Syndrome. AB - OBJECTIVE: Granulomatosis with polyangiitis (GPA), formerly called Wegener's syndrome, is a vasculitis associated with antineutrophil cytoplasmic antibody and may occur in all ages but mostly in order adults. The organs most frequently involved are the ear, nose and throat (rhinitis, sinusitus, oral ulcers, chondritis), the lungs (nodules, sometimes cavitating, infiltrates, hilar adenopathy) and the kidneys (glomerulonephritis). As patients typically present with constitutional symptoms, the diagnosis can be challenging. We report the findings on position emission tomography/computed tomography (PET/CT) with fluorine-18-fluorodeoxyglucose ((18)F-FDG) in a patient with a limited form of GPA. CONCLUSION: None of the findings on PET are specific for GPA, but in a given clinical context, they may contribute to early diagnosis. They may guide biopsy taking, and may determine the extent of the disease. During and after treatment, PET can be used to monitor disease activity. PMID- 26929943 TI - The role of PET/CT in diagnosing generalized lymphadenopathy in asymptomatic secondary syphilis. AB - OBJECTIVE: Syphilis is a well-known sexually transmitted disease, and has multiple stages and various symptoms. However, it is difficult to diagnose syphilis in patients who may have no clinical symptoms. Because of these reasons, there have been several case reports on misdiagnosis of syphilis. Generalized lymphadenopathy could be an indication of various diseases including malignancies or infections. CONCLUSION: We report a case of a secondary syphilis in a patient with generalized lymphadenopathy detected by fluorine-18-fluorodeoxy glucose positron emission tomography/computed tomography ((18)F-FDG PET/CT) images without any clinical symptom. Clinical examination found an ulcer on his penis and serologic tests set the diagnosis of an early stage of secondary syphilis. PMID- 26929944 TI - Nuclear Medicine and its promising applications in gynecological cancers. PMID- 26929945 TI - A case of intravascular large B-cell lymphoma in the left adrenal and another tumor in the right adrenal detected by (18)F-FDG PET/CT. AB - OBJECTIVE: Intravascular large B-cell lymphoma (IVLBCL) is a rare but fatal malignancy with a rapid onset, and presenting as an aggressive variant of diffuse large B-cell non-Hodgkin's lymphoma. Fluoro-18-fluorine positron emission tomography/computed tomography ((18)F-FDG PET/CT) is reported to be highly sensitive in diagnosing lymphoma. Herein, we present our (18)F-FDG PET/CT findings at an early case of IVLBCL in bilateral adrenals. The patient had no symptoms. Positron emission tomography and CT images showed irregular density on bilateral adrenals indicating malignant tumor and also another tumor on the hepatic flexure of the colon. Both adrenal tumors had a maximum standardized uptake value (SUVmax) of 11.4, whereas the colon tumor had less SUVmax value. Histopathological examination further confirmed that the bilateral adrenal was IVLBCL, whereas the colon mass was a benign tumor. CONCLUSION: We describe this case, to highlight the importance of (18)F-FDG-PET/CT in early diagnosis of IVLBCL in bilateral adrenals confirmed by pathology and in differentiating a highly malignant from a benign tumor. PMID- 26929946 TI - [Radiation treatment of head and neck carcinomas as a risk factor for thyroid carcinomas]. AB - OBJECTIVE: Cancer of the thyroid is a relatively rare malignant neoplasm with an increasing incidence in the last decades. Ionizing radiation is the best documented risk factor for thyroid malignant neoplasms, in current medical literature. An increase in the global annual per caput effective radiation dose has been described, partly as a result of medical exposure. External beam radiation therapy of the head and neck region has also been attributed. Thyroid tissue is particularly vulnerable to the carcinogenic effects of ionizing radiation because of its anatomical position and radiosensitivity. We review the relationship between external beam radiotherapy and secondary thyroid cancer and of factors influencing this correlation. Since 1950 this causal relationship has been confirmed by numerous researchers. The role of the primary disease, the administrated radiation dose, the irradiation field, sex, age and genetic background and also the time interval between radiation and the onset of thyroid cancer are the main factors that have been studied in medical literature. Developments in the field of radiotherapy, recent findings on the relationship between head and neck carcinomas and thyroid carcinomas and interactions between confounding factors, raise the need for further study on this subject. PMID- 26929947 TI - Survival, Function, and Complications of Oral Implants Placed in Bone Flaps in Jaw Rehabilitation: A Systematic Review. AB - PURPOSE: This systematic review attempted to determine the survival rate of implants placed in bone flaps in jaw rehabilitation and the functional gains and the most common complications related to these implants. MATERIALS AND METHODS: An electronic search was undertaken of PubMed, EMBASE, and CNKI records from 1990 through July 2014. Two independent examiners read the titles and abstracts of the results to identify studies that met the inclusion criteria. Subsequently, the reference lists of the selected publications were hand searched. Descriptive statistics were used to report all data related to the survival rate of implants placed in bone flaps in jaw rehabilitation, the functional gains, and complications. RESULTS: A total of 20 studies were included for systematic review without repetition. The mean follow-up time after implant placement ranged from 1.75 to 9.5 years. Within the limitations of available studies, the survival rate of implants placed in bone flaps in jaw rehabilitation ranged from 82.4% to 100%. Of the 20 included studies, 15 reported a survival rate higher than 90%. The cumulative survival rate was 93.2%, with the longest follow-up time being 12.9 years. The most common complications related to these implants were peri-implant bone resorption or peri-implant inflammation, and peri-implant soft tissue proliferation. The main factors associated with the survival rate of implants in bone flaps were reported as time of implant placement and radiotherapy. Despite some persistent soft tissue problems and implant loss, most patients reached a satisfactory functional and esthetic outcome, as evaluated by clinical examination and subjectively by the patients at interview. Implant-supported dental prosthetic rehabilitation in reconstructed jaws improved the quality of life in terms of speech, nutrition, oral competence, and facial appearance. CONCLUSION: Placement of implants in bone flaps in jaw rehabilitation was demonstrated to be a reliable technique with a high survival rate. Multicentered randomized controlled clinical trials and longer clinical studies should be undertaken in this area. PMID- 26929949 TI - Comparison of 64-Detector-Multislice and Cone Beam Computed Tomographies in the Evaluation of Linear Measurements in the Alveolar Ridge. AB - This study compared the accuracy of linear measurements of the alveolar ridge in images obtained using 64-detector-multislice computed tomography (CT) and cone beam CT (CBCT). Eight sites were selected corresponding to the regions of molars, premolars, canines, and incisors in six dry human jaws. After the completion of multislice CT and CBCT, the jaws were sectioned into specific regions. Results showed there was no statistically significant difference between the measurements obtained from the CT images and those obtained from dry jaws (actual measurements) for all the evaluated sites (molars, premolars, and anterior teeth). There was also no statistically significant difference between the measurements obtained by the two CT methods. PMID- 26929948 TI - The Retread: A Definition and Retrospective Analysis of 205 Implant-Supported Fixed Prostheses. AB - PURPOSE: Acrylic resin teeth on fixed implant prostheses are subject to time dependent wear. The purpose of this retrospective analysis is to evaluate and describe the management of such wear in the context of selected variables- patient gender and age, dental arch location, and opposing dentition. The clinical and dental laboratory process to replace the worn teeth is defined as a retread. MATERIALS AND METHODS: A retrospective database review from a single private prosthodontic practice was carried out on all patients who had undergone a retread procedure. The patient pool included 205 arches in 194 patients (70 in men, 135 in women) with a mean age of 57.4 years (range: 19.9 to 80.5 years). The retread procedure is described. RESULTS: The mean time between final prosthesis delivery and retread was 7.8 years (range: 1.1 to 22.9 years). Statistical analysis was significant according to dental arch and opposing dentition. A statistical difference was also noted in patients undergoing multiple retread procedures, with a reduction in time between the subsequent procedures. CONCLUSION: Acrylic resin components of implant-supported hybrid prostheses wear over time and are influenced by a combination of the nature of the opposing dentition and patient habits. The dental laboratory process to retread the implant-supported framework is important for long-term patient care and maintenance of an appropriate vertical dimension of occlusion. PMID- 26929950 TI - How to Find Dental Survival Articles: Using the New Search Strategies. AB - Clinicians and readers rely on accurate identification of articles to answer clinical questions and explore hypotheses. Commonly, these questions relate to the outcome and survival of dental treatments. Errors in indexing and inconsistencies in descriptions of these studies have meant that such articles are difficult to locate. To help address this problem, sensitive, precise and optimized electronic search strategies have been developed, and this article aims to explain how these new strategies can be used. These electronic search strategies have been shown to improve the identification of dental survival analyses. PMID- 26929951 TI - Predictors of Prosthodontic Treatment-Related Behavior Using the Theory of Planned Behavior Framework. AB - The Theory of Planned Behavior (TPB) was used to assess subjects' intentions and behavior to predict willingness to undergo prosthodontic care. A questionnaire was administered to 225 adults with history of teeth loss who currently were not under prosthodontic treatment. The questionnaire comprised TPB components (attitude toward behaviour [ATB], subjective norm [SN], and perceived behavioral control [PBC]) containing items with potential influence on the intentions and behavior of individuals toward prosthodontic care. Clinical and socioeconomic data were also assessed. A path regression model was constructed explaining two dependent variables simultaneously: one explained the influence of PBC on intention (R2=0.04) and another explained the influence of dental arch, position of lost teeth, socioeconomic status, and PBC on behavior (R2=0.31). It was concluded that PBC was a relevant TPB component that encompasses perception of costs, opportunity cost, perceived need, and access to dental care. Clinical and socioeconomic factors were also major determinants of behavior toward prosthodontic treatment. PMID- 26929952 TI - Screw Joint Stability in Conventional and Abutment-Free Implant-Supported Fixed Restorations. AB - PURPOSE: Procera Implant Bridges (PIBs) do not engage supporting implant shoulders and are fixed using comparably long retention screws. The aim of this in vitro clinical study was to determine the detorque values in PIBs and conventionally fabricated fixed dental prostheses (FDPs). MATERIALS AND METHODS: Two groups of screw-retained implant-supported three-unit FDPs (n=10) were fabricated by means of conventional casting or computer-aided design/computer assisted manufacture to fit an in vitro situation with two implants. Following fixation, the restorations were subjected to masticatory simulation (100,000 cycles, 100 N) and subsequent detorquing of the retention screws. In the clinical part, a total of 10 patients received PIB restorations in the premolar/molar region that were detorqued after 2, 4, and 6 months. One-sample t tests adjusted for multiple testing by the Bonferroni-Holm method were applied for statistical analysis based on percentage detorque values (alpha=.05). RESULTS: 60% of the initial torque values were maintained in screws directly retaining restorations, while the abutment screws used in the conventional restorations showed detorque levels in the range of 80%. No significant difference in detorque levels between screws retaining PIBs and conventional FDPs could be detected (P=.5186). The abutment screws showed significantly greater detorque values compared with screws directly retaining restorations (P=.0002; P=.0000). In vivo, a significant increase in detorque values ranging from 21.64 Ncm after 2 months to 27.81 Ncm after 6 months was recorded. CONCLUSION: Prosthetic screws retaining implant supported FDPs show torque loss during the initial period of service. Retightening reduces the amount of future torque loss. PMID- 26929953 TI - Clinical and Radiographic Evaluation of a Small-Diameter Dental Implant Used for the Restoration of Patients with Permanent Tooth Agenesis (Hypodontia) in the Maxillary Lateral Incisor and Mandibular Incisor Regions: A 36-Month Follow-Up. AB - PURPOSE: For patients with narrow, single-tooth edentulous ridges as a result of permanent tooth agenesis (hypodontia) in the maxillary lateral and mandibular incisor regions, dental implant treatment may present a reliable and predictable restorative treatment solution. The aim of the present study was to evaluate the clinical reliability and outcome of small-diameter dental implants placed in a one-stage procedure with early loading replacing maxillary lateral or mandibular incisor teeth. MATERIALS AND METHODS: Patients with hypodontia in the maxillary lateral incisor or mandibular incisor region analyzed in this report were selected from a larger prospective multicenter study. Small-diameter dental implants (AstraTech OsseoSpeed TX 3.0 S, Dentsply) of different lengths were placed using a one-stage surgical protocol with a 6- to 10-week healing period before loading. Probing pocket depth, bleeding on probing, and gingival zenith score were assessed after 6, 12, 24, and 36 months. Radiographic examination was assessed at 6, 12, and 36 months. RESULTS: In total, 38 patients were included in this analysis and 62 small-diameter implants were placed. The mean distance between adjacent teeth was 6.30 mm (SD: 1.36). All patients received a titanium transmucosal abutment and cement-retained ceramic crown after 6 to 10 weeks of healing. Two implants were lost during the healing period before loading, providing a total implant survival rate of 96.8%. No implant fractures were reported. Mean marginal bone level change from surgery to follow-up visits at 6, 12, and 36 months were 0.39 mm, 0.22 mm, and 0.23 mm, respectively. The condition of soft tissue was stable at all follow-up visits with clinically insignificant changes in probing depth, bleeding on probing, and gingival zenith score. CONCLUSION: This study evaluated the behavior over 36 months of AstraTech Osseospeed TX 3.0 S dental implants placed into narrow one-tooth defect edentulous ridges as a result of hypodontia. The data collected highlighted the stability of the marginal bone level and soft tissues around the dental implants in conjunction with durable mechanical function. Small-diameter implants can be considered a valid solution in the restorative treatment of hypodontia in the maxillary lateral and mandibular incisor regions. PMID- 26929954 TI - Effect of Remaining Cavity Wall, Cervical Dentin, and Post on Fracture Resistance of Endodontically Treated, Composite Restored Premolars. AB - PURPOSE: The aim of this study was to examine the effect of remaining buccal cavity wall, remaining cervical tissue, and post on the fracture strength of endodontically treated restored premolars. MATERIALS AND METHODS: Teeth were randomly allocated to 10 experimental groups (n=10) according to cavity design and presence or absence of post or to a control group. After thermal and mechanical aging, ramped loading until fracture was performed. RESULTS: A high cervical outline (417 N) and the presence of a post (189 N) increased fracture strength, but both factors together had an antagonistic effect of -218 N, resulting in a higher strength of not 606 N (417+189) but 388 N. The risk of catastrophic failure increased (OR=3.17) when a post was present. PMID- 26929955 TI - Analysis of Vertical Marginal Adaptation of Zirconia Fixed Dental Prosthesis Frameworks Fabricated by the CAD/CAM System: A Randomized, Double-Blind Study. AB - PURPOSE: The purpose of this study was to evaluate the marginal adaptation of fixed dental prosthesis frameworks fabricated by computer-aided design/computer assisted manufacture (CAD/CAM) with three different systems of data acquisition. MATERIALS AND METHODS: A total of 50 specimens were fabricated as follows: using the conventional method (Ni-Cr) (n=10); iTero/industrial milling (Group 1, n=10); Cerec Bluecam/industrial milling (Group 2, n=10); 3S/industrial milling (Group 3, n=10); and Cerec BlueCam/Sirona milling (Group 4, n=10). The specimens were numbered and randomized, and the vertical marginal discrepancy was analyzed. RESULTS: Intraobserver analysis indicated no statistically significant difference (paired t test, P=.822) between periods before and after analysis. The conventional method (321 MUm) showed greater discrepancy when compared with the CAD/CAM system (89 MUm) (P<.001). The intraoral system showed a lower rate of marginal discrepancy when compared with the extraoral system (3S) (P<.001). The closed system presented a higher marginal discrepancy (114 MUm) than the open intraoral system (iTero) at P<.001. In addition, the intraoral system when open showed statistically significant differences in mean marginal discrepancy values compared with the same system in closed condition (P>.05). CONCLUSION: The CAD/CAM systems showed less marginal discrepancy than the conventional method for the fabrication of the frameworks. PMID- 26929956 TI - Tooth Fractures in Fixed Full-Arch Implant-Supported Acrylic Resin Prostheses: A Retrospective Clinical Study. AB - PURPOSE: The aim of this study was to assess the influence of several variables in the frequency of prosthetic teeth fractures in fixed full-arch implant supported acrylic resin prostheses. MATERIALS AND METHODS: The influence of each variable was determined after analyzing the results obtained from 161 prostheses after a mean follow-up period of 39.69 months. All patients were treated with standard Nobel Biocare and Biomet 3i implants, and followed a strict prosthodontic protocol. RESULTS: A total of 155 fractures were recorded, all of which took place in 60 prostheses (40% of the total). Statistically significant differences were found among several variables: the arch the prosthesis was on, patient sex, opposing arch characteristics, length of the cantilevers, and whether the structure had mechanical retention. The prostheses that suffered a greater number of fractures were those that had been placed in men, opposing a natural arch, with cantilevers shorter than 10 mm and without mechanical retention. Patient age and presence or absence of a cantilever were not determinants. CONCLUSION: Tooth fractures in fixed full-arch implant-supported metal-acrylic prostheses are a common complication. Several factors are linked more directly with the need for mechanical maintenance. The design and indications of this type of prosthesis should be carefully considered. PMID- 26929957 TI - Impression Procedures for Metal Frame Removable Partial Dentures as Applied by General Dental Practitioners. AB - This pilot study analyzed impression procedures for conventional metal frame removable partial dentures (RPDs). Heads of RPD departments of three dental laboratories were asked to record features of all incoming impressions for RPDs during a 2-month period. Records included: (1) impression procedure, tray type (stock/custom), impression material (elastomer/alginate), use of border-molding material (yes/no); and (2) RPD type requested (distal-extension/tooth bounded/combination). Of the 132 total RPD impressions, 111 (84%) involved custom trays, of which 73 (55%) were combined with an elastomer. Impression border molding material was used in 4% of the cases. Associations between impression procedure and RPD type or dentists' year/university of graduation were not found. PMID- 26929958 TI - On Comparing Two Different Tray-Holding Techniques for Edentulous Maxillary Impressions. AB - PURPOSE: This study compared tissue three-dimensional (3D) displacements during the material setting phase of two maxillary impression tray-holding techniques: clinician manual pressure and patient occlusal pressure. MATERIALS AND METHODS: The resultant two maxillary casts for each of 10 edentulous patients were compared using an optical 3D measurement system. RESULTS: The junction between the hard and soft palates acted like a rotation center during impression making. The vertical displacements were significantly lower and posteriorly set when the impression was taken with the patient's occlusion, in contrast to being located at the anterior two-thirds during the manual impression technique. CONCLUSION: Use of patient's occlusion as a tray-holding technique may be preferred during the material setting phase of maxillary impressions. PMID- 26929959 TI - A Posterior Lingual Sulcoplasty in Implant Therapy: A Case History Report. AB - This case history report describes the deepening of a patient's posterior mandibular lingual sulcus in combination with an acrylic resin guiding device fixed to an osseointegrated dental implant to maintain the patency of the new sulcular depth. PMID- 26929960 TI - The Use of Telescopic Crowns in Removable Partial Denture Treatment for Patients with Severe Periodontal Disease: Two Patient Case History Reports. AB - Two patient case histories are described as examples of treatment of severe periodontitis in severely compromised partial dentitions. Management consisted of periodontal treatment and telescopic crown support for removable partial dentures with friction pin retention. PMID- 26929961 TI - Survival Probability of Narrow and Standard-Diameter Implants with Different Implant-Abutment Connection Designs. AB - PURPOSE: To investigate the probability of survival of different implant-abutment connection designs in narrow versus standard-diameter implants supporting anterior crowns. MATERIALS AND METHODS: A total of 108 implants of either 3.5-mm or 4.0-mm diameter (narrow and standard, respectively) (10 mm in length, Implacil de Bortoli) were divided into six groups (n=18 each) as follows: external hexagon 3.5 mm or 4.0 mm (EH3.5 or EH4.0), internal hexagon 3.5 mm or 4.0 mm (IH3.5 or IH4.0), and Morse taper 3.5 mm or 4.0 mm (MT3.5 or MT4.0). The corresponding abutments were screwed to the implants, and standardized maxillary central incisor metal crowns were cemented and subjected to step-stress accelerated life testing in water. Use-level probability Weibull curves and reliability for a mission of 50,000 and 100,000 cycles at 100 N and 150 N (90% 2-sided confidence intervals [CI]) were calculated. Polarized-light and scanning electron microscopes were used to assess the failure modes. RESULTS: The calculated reliability with 90% CI for a mission of 50,000 cycles at 100 N and 150 N showed that cumulative damage from the respective loads would lead to ~93% and ~18% implant-supported restoration survival in group EH3.5, ~99% and ~1% in group IH3.5, ~97% and ~89% in the MT3.5, ~100% and ~99% in the group EH4.0, ~100% and ~100% in group IH4.0, and ~99% and ~99% in group MT4.0. For the 100,000-cycle mission, the probability of survival estimated at 100 N and 150 N was, respectively: 0% for EH3.5 and IH3.5 at both load levels, ~96% and ~87% for the MT3.5, 100% and ~99% for EH4.0, 100% and ~99% for IH4.0, and 98% and ~92% for the MT4.0. CONCLUSION: A significant decrease in the probability of survival as a function of elapsed fatigue cycles and load increase was observed for narrow implants only with EH and IH implant-abutment connections, but not on Morse taper. PMID- 26929962 TI - Case History Report: Cone Beam Computed Tomography for Implant Insertion Guidance in the Presence of a Dense Bone Island. AB - This article describes the use of cone beam computed tomography (CBCT) to diagnose a dense bone island (DBI) to facilitate implant insertion guidance in a patient followed up for 4 years. Suitable image-directed preplanning and periodic review by CBCT scanning is recommended when a jaw DBI is encountered in treatment planning for implant placement. PMID- 26929963 TI - Checklists: You documented it, but did you do it? PMID- 26929964 TI - Introduction to the Principles of Integrative Medicine (IM). PMID- 26929965 TI - Making Whole: Applying the Principles of Integrative Medicine to Medical Education. AB - In the past few decades, the public's use of complementary and alternative medicine (CAM) has steadily increased. The term "integrative medicine" is often used to refer to the combination of CAM with conventional medicine. Many medical schools have incorporated didactic content on CAM and/or integrative medicine into their curricula. A frequently cited rationale for these course offerings is that medical students ought to be taught the basics of CAM in order to counsel patients on safe, effective therapeutic options. Schools have also offered these courses to meet the needs of students who are interested in incorporating CAM into future practices. In this article, the authors suggest that the core principles of integrative medicine--holistic worldview, centrality of the doctor patient relationship, emphasis on wellness, and inclusiveness--are aligned with the goals of contemporary medical education and serve a critical function in the development of effective, humanistic physicians. PMID- 26929966 TI - Yoga for Depression and Anxiety: A Review of Published Research and Implications for Healthcare Providers. AB - There is increasing interest in the use of yoga as way to manage or treat depression and anxiety. Yoga is afford- able, appealing, and accessible for many people, and there are plausible cognitive/affective and biologic mechanisms by which yoga could have a positive impact on depression and anxiety. There is indeed preliminary evidence that yoga may be helpful for these problems, and there are several ongoing larger-scale randomized clinical trials. The current evidence base is strongest for yoga as efficacious in reducing symptoms of unipolar depression. However, there may be risks to engaging in yoga as well. Healthcare providers can help patients evaluate whether a particular community based yoga class is helpful and safe for them. PMID- 26929967 TI - Teaching Doctors-in-Training About Nutrition: Where Are We Going in 2016? AB - Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of preventable death in the U.S., and its public health and economic burdens are rising. There is substantial evidence that dietary factors significantly reduce ASCVD-related morbidity and mortality, and that Americans, including those with established ASCVD, adhere poorly to cardio-protective diet patterns. Despite this, there continues to be a large gap in nutrition education during medical school and post-graduate training, leaving physicians poorly prepared to counsel patients on diet, nutrition, and related behavior change. The result is a massive missed opportunity to improve cardiovascular disease prevention at the health system level. However, recent calls for change by stakeholder groups, and a surprising new experiential learning model, suggest this may be changing. PMID- 26929968 TI - On Patients, Bonsai, and Orangutans: The Value of Mindfulness in the Practice of Medicine. PMID- 26929969 TI - Child Passenger Safety Training for Pediatric Interns: Does it Work? AB - OBJECTIVE: Evaluate the efficacy of a child passenger safety (CPS) educational intervention on the CPS-related knowledge, attitude and anticipatory guidance behaviors of pediatric interns. METHODS: All subjects were surveyed at baseline and 6 months. Intervention interns attended a CPS training module which included viewing an educational video, observing a car seat inspection appointment, hands on practice and completion of a post-intervention survey. RESULTS: All 16 intervention interns completed the initial survey, the intervention and the immediate-post questionnaire. Thirteen (81%) completed the 6-month follow-up. The baseline survey was completed by 27/40 (67%) of control interns, 28/40 (70%) submitted a follow-up. The proportion of intervention interns who self-reported giving CPS guidance at all well-child visits increased by 31.3% (95% CI 6.1,56.5%); the control group had no change. Similar results were seen with self reported knowledge and attitude. CONCLUSIONS: A CPS training module increases pediatric interns' knowledge, improves attitudes, and self-reported behaviors regarding CPS-related anticipatory guidance. PMID- 26929970 TI - Concordance between Activated Partial Thromboplastin Time and Antifactor Xa Assay for Monitoring Unfractionated Heparin in Hospitalized Hyperbilirubinemic Patients. AB - BACKGROUND: Activated partial thromboplastin time (aPTT) and antifactor Xa (anti Xa) monitoring methods for unfractionated heparin (UFH) often disagree. The extent of discordance for those with elevated bilirubin remains unclear. Our objective was to evaluate concordance between activated aPTT and anti-Xa methods for hyperbilirubinemic patients on UFH. METHODS: This was a retrospective cohort study of 26 patients hospitalized at Rhode Island Hospital between August 2014 and September 2014. Patients had at least one bilirubin measurement >5 mg/dL. After categorizing lab values, percent agreement and kappa were used to examine concordance between aPTT and anti-Xa. RESULTS: Overall percent agreement between aPTT and anti-Xa was 50%. A nontherapeutic aPTT and therapeutic anti-Xa accounted for 98% of all disagreement. Specifically, 76.7% of disagreement was due to a subtherapeutic aPTT and a therapeutic anti-Xa. Unweighted kappa was 0.141 (95%CI: 0.048-0.235). CONCLUSION: Concordance between aPTT and anti-Xa values was poor in hyperbilirubinemic patients. PMID- 26929971 TI - An Atypical Presentation of a Small Bowel Obstruction in a Young Woman with a Congenital Omental Defect. PMID- 26929972 TI - The Rhode Island Special Needs Emergency Registry--An Opportunity for Expanding the Healthcare Provider's Role in Health Equity. PMID- 26929973 TI - Retraction notice to "Resveratrol rescued the TNF-alpha-induced impairments of osteogenesis of bone-marrow derived mesenchymal stem cells and inhibited the TNF alpha-activated NF-kB signaling pathway" [Int Immunopharmacol 26(2) (2015) 409 415]. PMID- 26929975 TI - A tribute to Dr. Willy Burgdorfer, Medical Entomologist Extraordinaire. PMID- 26929974 TI - [Hypnotherapy of atopic dermatitis in an adult. Case report]. AB - Hypnosis is well known for its modulatory effects on immune and inflammatory processes, and it is a therapeutic option for certain diseases of such pathogenesis. The authors report treatment of an adult patient with extensive atopic dermatitis, who was only minimally responsive to conservative treatment. In a 15 session hypnotherapy the authors combined the use of direct, symptom oriented suggestive techniques with hypnotic procedures to identify and modify comorbid psychological issues. To monitor the effect of the treatment, patient diaries (quality and quantity of sleep, intensity of pain and itch) and repeated psychometric tests were used. At the end of treatment there were improvements in all measured dimensions (itch, pain, insomnia, activity, anxiety and emotional state) both clinically and psychometrically. The authors conclude, that hypnosis can be an effective adjunctive therapy in atopic dermatitis, and in certain severe cases may constitute a salvage therapy. PMID- 26929976 TI - Response. PMID- 26929977 TI - Mechanistic Investigation of Aromatic C(sp(2))-H and Alkyl C(sp(3))-H Bond Insertion by Gold Carbenes. AB - It was recently reported that the gold-carbenes have an unprecedented catalysis toward the functionalization of C(sp(2))-H bonds of aromatic compounds. However, the associated mechanisms of C(sp(2))-H bonds inserted by gold-carbenes have not been comprehensively understood. We carried out a detailed mechanistic investigation of gold-carbene insertion into the C(sp(2))-H bond of anisole by means of theoretical calculations and control experiments. It significantly reveals that the aromatic C(sp(2))-H bond activation starts with the electrophilic addition of aromatic carbon toward the carbene carbon and subsequently followed the [1,3]-proton shift to form an enol intermediate. The rearrangement of enol proceeds through the mechanisms of proton transfer assisted by water molecules or enol intermediates, which are supported by our control experiments. It was also found that the C(sp(3))-H insertions of alkanes by gold carbenes proceed through a concerted process via a three-centered transition state. The further comparison of different mechanisms provides a clear theoretical scheme to account for the difference in aromatic C(sp(2))-H and alkyl C(sp(3))-H bond activation, which is instructive for the further experimental functionalization of C-H bonds by gold-carbenes. PMID- 26929978 TI - A sense of increased living space after participating in multimodal rehabilitation. AB - PURPOSE: The aim was to explore and describe experiences of change related to multimodal rehabilitation (MMR) in participants suffering from persistent musculoskeletal-related pain, in order to increase knowledge about the impact of the rehabilitation. METHODS: Participants in MMR from an outpatient rehabilitation unit in primary care in Sweden were recruited for interviews about any kind of change they experienced that they thought were related to their participation in the MMR. Systematic text condensation according to Malterud was used to analyze the data. RESULTS: A total of 14 participants were interviewed. The interview analysis resulted in four categories in which the participants described their experience of change related to the MMR: a new desire for participation, increased embodied knowledge, a stronger sense of feeling empowered and regained hope. The categories interacted and from these categories, one theme emerged: a sense of increased living space. CONCLUSION: According to these results, it is important to have various entrances to enhance change and to be aware of how these changes interact and can reinforce each other in order to facilitate the participants' empowerment processes toward a sense of increased living space. Implications for rehabilitation The efforts in MMR should be coordinated to be mutually reinforcing as changes in one area could facilitate in others and thus facilitate the participants' empowerment processes. Participants experience change after MMR in areas that standardized assessment questionnaires do not capture and consequently it would be useful to let the participants answer an open question about perceived changes together with standardized questionnaires. PMID- 26929979 TI - In Situ Grown TiO2 Nanospindles Facilitate the Formation of Holey Reduced Graphene Oxide by Photodegradation. AB - Titanium dioxide (TiO2) nanostructures and TiO2/graphene nanocomposites are intensively studied materials for energy conversion, energy storage, and organic contaminant photodegradation. However, for TiO2/graphene composites, impermeability across the graphitic basal plane for electrolytes, metal ions, and gas molecules hinders their practical applications. Herein we report a simple, environmentally friendly synthetic route for mesoporous anatase TiO2 nanospindles, and successfully apply this method to obtain in situ grown TiO2 nanospindles/graphene oxide composite. After a thermal reduction at 400 degrees C, holes are created in the reduced graphene oxide (RGO) sheets through a photocatalytic oxidation mechanism. The formation of holes in RGO is promoted by photogenerated hydroxyl radicals that oxidize and subsequently decarboxylate the graphitic surface of RGO. The proposed mechanism was supported by photocatalytic electrochemical properties of the nanomaterials. The resulting TiO2/holey RGO composites may overcome the original impermeability of graphene sheets and find applications in catalysis, energy conversion/storage devices, and sensors. PMID- 26929981 TI - Modeling of Toxicity-Relevant Electrophilic Reactivity for Guanine with Epoxides: Estimating the Hard and Soft Acids and Bases (HSAB) Parameter as a Predictor. AB - According to the electrophilic theory in toxicology, many chemical carcinogens in the environment and/or their active metabolites are electrophiles that exert their effects by forming covalent bonds with nucleophilic DNA centers. The theory of hard and soft acids and bases (HSAB), which states that a toxic electrophile reacts preferentially with a biological macromolecule that has a similar hardness or softness, clarifies the underlying chemistry involved in this critical event. Epoxides are hard electrophiles that are produced endogenously by the enzymatic oxidation of parent chemicals (e.g., alkenes and PAHs). Epoxide ring opening proceeds through a SN2-type mechanism with hard nucleophile DNA sites as the major facilitators of toxic effects. Thus, the quantitative prediction of chemical reactivity would enable a predictive assessment of the molecular potential to exert electrophile-mediated toxicity. In this study, we calculated the activation energies for reactions between epoxides and the guanine N7 site for a diverse set of epoxides, including aliphatic epoxides, substituted styrene oxides, and PAH epoxides, using a state-of-the-art density functional theory (DFT) method. It is worth noting that these activation energies for diverse epoxides can be further predicted by quantum chemically calculated nucleophilic indices from HSAB theory, which is a less computationally demanding method than the exacting procedure for locating the transition state. More importantly, the good qualitative/quantitative correlations between the chemical reactivity of epoxides and their bioactivity suggest that the developed model based on HSAB theory may aid in the predictive hazard evaluation of epoxides, enabling the early identification of mutagenicity/carcinogenicity-relevant SN2 reactivity. PMID- 26929982 TI - Nucleation Kinetics in Mixed NaNO3/Glycerol Droplets Investigated with the FTIR ATR Technique. AB - The in situ infrared spectra of sodium nitrate (NaNO3) and mixed NaNO3/glycerol droplets with organic to inorganic molar ratio (OIR) of 1:8, 1:4, 1:2, 1:1, and 2:1 on the ZnSe substrate were collected using the Fourier transform infrared attenuated total reflection (FTIR-ATR) technique in the RH linearly decreasing process. When the efflorescence process occurred in the RH decreasing process, the stochastric transformation from NaNO3 droplets to NaNO3 solid particles resulted in gradually increasing of a new band at 836 cm(-1) and contineously decreasing of an initial band at 829 cm(-1), which were assigned to the v2-NO3(-) mode in crystal phase state and in liquid state, respectively. There were excellent isobesic points between the two bands in the transformation processes, indicating the synchronization between the disappearence of NO3(-) in solutions and the production of NaNO3 crystal. The nucleation ratio, i.e., the amount of the droplets crystallized at a given RH upon the total amount droplets, was obtained by using the absorbance of nu2-NO3(-) band at 836 cm(-1), which was used to calculate the nucleation rates of NaNO3 either for heterogeneous or for homogeneous nucleation process. While the glycerol molecules delayed the efflorescence RHs (ERH) of NaNO3 in the mixed NaNO3/glycerol droplets (OIR = 2:1) to 15%, greatly lower than the ERH for pure NaNO3 droplets at 62.5%, they also greatly suppressed the heterogeneous nucleation rate with increase of the OIR ratio. Two different kinetic mechanisms were suggested in the mixed droplets with OIR = 1:8, 1:4, 1:2, and 1:1, i.e., homogeneous nucleation at higher supersaturation and heterogeneous nucleation at lower supersaturation. For the mixed droplets with 2:1 OIR, they fell into the homogeneous nucleation region completely. PMID- 26929980 TI - Delineation of Polypharmacology across the Human Structural Kinome Using a Functional Site Interaction Fingerprint Approach. AB - Targeted polypharmacology of kinases has emerged as a promising strategy to design efficient and safe therapeutics. Here, we perform a systematic study of kinase-ligand binding modes for the human structural kinome at scale (208 kinases, 1777 unique ligands, and their complexes) by integrating chemical genomics and structural genomics data and by introducing a functional site interaction fingerprint (Fs-IFP) method. New insights into kinase-ligand binding modes were obtained. We establish relationships between the features of binding modes, the ligands, and the binding pockets, respectively. We also drive the intrinsic binding specificity and which correlation with amino acid conservation. Third, we explore the landscape of the binding modes and highlight the regions of "selectivity pocket" and "selectivity entrance". Finally, we demonstrate that Fs IFP similarity is directly correlated to the experimentally determined profile. These improve our understanding of kinase-ligand interactions and contribute to the design of novel polypharmacological therapies targeting kinases. PMID- 26929984 TI - Powders Analysis by Second Harmonic Generation Microscopy. AB - A microscopy approach is developed for quantifying second harmonic generation (SHG) activity of powders that largely decouples linear and nonlinear optical interactions. Decoupling the linear and nonlinear optical effects provides a means to independently evaluate and optimize the role of each in crystal engineering efforts and facilitates direct comparisons between experimental and computational predictions of lattice hyperpolarizabilities. In this respect, the microscopy-based approach nicely complements well-established Kurtz-Perry ( J. Appl. Phys. 1968 , 39 , 3798 ) and related methods, in which collimated sources are used for powders analysis. Using a focused fundamental beam places a controllable upper bound on the interaction length, given by the depth of field. Because measurements are performed on a per-particle basis, crystal size dependent trends can be recovered from a single powdered sample. An analytical model that includes scattering losses of a focused Gaussian beam reliably predicted several experimental observations. Specifically, the measured scattering length for SHG was in excellent agreement with the value predicted based on the particle size distribution. Additionally, histograms of the SHG intensities as functions of particle size and orientation agreed nicely with predictions from the model. PMID- 26929983 TI - Proximal placement of lateral thigh skin markers reduces soft tissue artefact during normal gait using the Conventional Gait Model. AB - A primary source of measurement error in gait analysis is soft-tissue artefact. Hip and knee angle measurements, regularly used in clinical decision-making, are particularly prone to pervasive soft tissue on the femur. However, despite several studies of thigh marker artefact it remains unclear how lateral thigh marker height affects results using variants of the Conventional Gait Model. We compared Vicon Plug-in Gait hip and knee angle estimates during gait using a proximal and distal thigh marker placement for ten healthy subjects. Knee axes were estimated by optimizing thigh rotation offsets to minimize knee varus-valgus range during gait. Relative to the distal marker, the proximal marker produced 37% less varus-valgus range and 50% less hip rotation range (p < 0.001), suggesting that it produced less soft-tissue artefact in knee axis estimates. The thigh markers also produced different secondary effects on the knee centre estimate. Using whole gait cycle optimization, the distal marker showed greater minimum and maximum knee flexion (by 6 degrees and 2 degrees respectively) resulting in a 4 degrees reduction in range. Mid-stance optimization reduced distal marker knee flexion by 5 degrees throughout, but proximal marker results were negligibly affected. Based on an analysis of the Plug-in Gait knee axis definition, we show that the proximal marker reduced sensitivity to soft-tissue artefact by decreasing collinearity between the points defining the femoral frontal plane and reducing anteroposterior movement between the knee and thigh markers. This study suggests that a proximal thigh marker may be preferable when performing gait analysis using the Plug-in Gait model. PMID- 26929988 TI - The association between osteoporosis and patient outcomes in Japan. AB - Objective To quantify the burden of osteoporosis and examine the interplay between osteoporosis and various comorbidities as it relates to patient outcomes. Methods Data from the 2011 Japan National Health and Wellness Survey (NHWS; n = 30 000), an internet health survey fielded to a nationally representative sample of the Japanese population were used. Only women between the ages of 50-90 years were included in the analyses (n = 6950). Results Compared with matched controls (n = 404), patients with osteoporosis (n = 404) had lower MCS scores (48.94 vs 51.63), PCS scores (45.57 vs 49.12) (all p < 0.05). The presence of osteoporosis was associated with worse patient outcomes among those with hypertension, high cholesterol, and insomnia, among other conditions. Conclusions The results suggest a significant quality-of-life and economic burden for patients with osteoporosis in Japan. Moreover, in a complex co-morbid environment, the presence of osteoporosis contributes more to patient outcomes than other chronic conditions. PMID- 26929989 TI - Phage Selection of Chemically Stabilized alpha-Helical Peptide Ligands. AB - Short alpha-helical peptides stabilized by linkages between constituent amino acids offer an attractive format for ligand development. In recent years, a range of excellent ligands based on stabilized alpha-helices were generated by rational design using alpha-helical peptides of natural proteins as templates. Herein, we developed a method to engineer chemically stabilized alpha-helical ligands in a combinatorial fashion. In brief, peptides containing cysteines in position i and i + 4 are genetically encoded by phage display, the cysteines are modified with chemical bridges to impose alpha-helical conformations, and binders are isolated by affinity selection. We applied the strategy to affinity mature an alpha helical peptide binding beta-catenin. We succeeded in developing ligands with Kd's as low as 5.2 nM, having >200-fold improved affinity. The strategy is generally applicable for affinity maturation of any alpha-helical peptide. Compared to hydrocarbon stapled peptides, the herein evolved thioether-bridged peptide ligands can be synthesized more easily, as no unnatural amino acids are required and the cyclization reaction is more efficient and yields no stereoisomers. A further advantage of the thioether-bridged peptide ligands is that they can be expressed recombinantly as fusion proteins. PMID- 26929985 TI - Quantitative genome-wide methylation analysis of high-grade non-muscle invasive bladder cancer. AB - High-grade non-muscle invasive bladder cancer (HG-NMIBC) is a clinically unpredictable disease with greater risks of recurrence and progression relative to their low-intermediate-grade counterparts. The molecular events, including those affecting the epigenome, that characterize this disease entity in the context of tumor development, recurrence, and progression, are incompletely understood. We therefore interrogated genome-wide DNA methylation using HumanMethylation450 BeadChip arrays in 21 primary HG-NMIBC tumors relative to normal bladder controls. Using strict inclusion-exclusion criteria we identified 1,057 hypermethylated CpGs within gene promoter-associated CpG islands, representing 256 genes. We validated the array data by bisulphite pyrosequencing and examined 25 array-identified candidate genes in an independent cohort of 30 HG-NMIBC and 18 low-intermediate-grade NMIBC. These analyses revealed significantly higher methylation frequencies in high-grade tumors relative to low intermediate-grade tumors for the ATP5G2, IRX1 and VAX2 genes (P<0.05), and similarly significant increases in mean levels of methylation in high-grade tumors for the ATP5G2, VAX2, INSRR, PRDM14, VSX1, TFAP2b, PRRX1, and HIST1H4F genes (P<0.05). Although inappropriate promoter methylation was not invariantly associated with reduced transcript expression, a significant association was apparent for the ARHGEF4, PON3, STAT5a, and VAX2 gene transcripts (P<0.05). Herein, we present the first genome-wide DNA methylation analysis in a unique HG NMIBC cohort, showing extensive and discrete methylation changes relative to normal bladder and low-intermediate-grade tumors. The genes we identified hold significant potential as targets for novel therapeutic intervention either alone, or in combination, with more conventional therapeutic options in the treatment of this clinically unpredictable disease. PMID- 26929990 TI - Application of new phenolic antioxidants for cryopreservation of sturgeon sperm. AB - Heterocyclic derivatives of butylated hydroxytoluene (BHT) were studied as cryoprotectants of the basic media for cryopreservation of the Russian sturgeon sperm. Rates of lipid peroxidation of sturgeon sperm before and after cryopreservation were reduced in the presence of the studied compounds, exceeding the effects of BHT and water-soluble analogue of vitamin E, trolox. The most efficient antioxidant has the effective concentration of 0.1 mM. Novel antioxidant agents as cryomedium supplements not only reduced the level of lipid peroxidation, but also enhanced the translational motility of the sperm of the Russian sturgeon after defrosting. PMID- 26929992 TI - Hijacking translation in addiction. AB - Two studies suggest that the reduced activity of a translation initiation factor called eIF2alpha might be partly responsible for the increased risk of drug addiction seen in adolescents. PMID- 26929993 TI - A cause for childhood ataxia. AB - Genetic studies uncover a mutation in a widely conserved protein as the cause of a neurological disorder in two brothers. PMID- 26929991 TI - A family of photoswitchable NMDA receptors. AB - NMDA receptors, which regulate synaptic strength and are implicated in learning and memory, consist of several subtypes with distinct subunit compositions and functional properties. To enable spatiotemporally defined, rapid and reproducible manipulation of function of specific subtypes, we engineered a set of photoswitchable GluN subunits ('LiGluNs'). Photo-agonism of GluN2A or GluN2B elicits an excitatory drive to hippocampal neurons that can be shaped in time to mimic synaptic activation. Photo-agonism of GluN2A at single dendritic spines evokes spine-specific calcium elevation and expansion, the morphological correlate of LTP. Photo-antagonism of GluN2A alone, or in combination with photo antagonism of GluN1a, reversibly blocks excitatory synaptic currents, prevents the induction of long-term potentiation and prevents spine expansion. In addition, photo-antagonism in vivo disrupts synaptic pruning of developing retino tectal projections in larval zebrafish. By providing precise and rapidly reversible optical control of NMDA receptor subtypes, LiGluNs should help unravel the contribution of specific NMDA receptors to synaptic transmission, integration and plasticity. PMID- 26929994 TI - Single and 14-day repeated dose inhalation toxicity studies of hexabromocyclododecane in rats. AB - Limited toxicological information is available for hexabromocyclododecane (HBCD),a widely used additive brominated flame retardant. Inhalation is a major route of human exposure to HBCD. The aim of this study was to determine the acute inhalation toxicity and potential subchronic inhalation toxicity of HBCD in Sprague-Dawley rats exposed to HBCD only through inhalation. The acute inhalation toxicity of HBCD was determined using the limit test method on five male and five female Sprague-Dawley rats at a HBCD concentration of 5000 mg/m(3). Repeated-dose toxicity tests were also performed, with 20 males and 20 females randomly assigned to four experimental groups (five rats of each sex in each group). There were three treatment groups (exposed to HBCD concentrations of 125,500, and 2000 mg/m(3)) and a blank control group (exposed to fresh air). In the acute inhalation toxicity study, no significant clinical signs were observed either immediately after exposure or during the recovery period. Gross pathology examination revealed no evidence of organ-specific toxicity in any rat. The inhalation LC50(4 h) for HBCD was higher than 5312 +/- 278 mg/m3 for both males and females. In the repeated dose inhalation study, daily head/nose-only exposure to HBCD at 132 +/- 8.8, 545.8 +/- 35.3, and 2166.0 +/- 235.9 mg/m(3) for 14 days caused no adverse effects. No treatment-related clinical signs were observed at any of the test doses. The NOAEL for 14-day repeated dose inhalation toxicity study of HBCD is 2000 mg/m(3). PMID- 26929995 TI - Genotoxicity of monosodium glutamate. AB - Monosodium glutamate (MSG) is one of the most widely used flavor enhancers throughout the world. The aim of this study is to investigate the genotoxic potential of MSG by using chromosome aberrations (CAs), sister-chromatid exchanges (SCEs), cytokinesis-blocked micronucleus (CBMN), and random amplified polymorphic DNA-polimerase chain reaction (RAPD-PCR) in cultured human lymphocytes and alkaline comet assays in isolated human lymphocytes, which were incubated with six concentrations (250, 500, 1000, 2000, 4000 and 8000 MUg/mL) of MSG. The result of this study indicated that MSG significantly and dose dependently increased the frequencies of CAs, SCE and MN in all treatments and times, compared with control. However, the replication (RI) and nuclear division indices (NDI) were not affected. In this paper, in vitro genotoxic effects of the MSG was also investigated on human peripheral lymphocytes by analysing the RAPD PCR with arbitrary 10-mer primers. The changes occurring in RAPD profiles after MSG treatment include increase or decrease in band intensity and gain or loss of bands. In the comet assay, this additive caused DNA damage at all concentrations in isolated human lymphocytes after 1-h in vitro exposure. Our results demonstrate that MSG is genotoxic to the human peripheral blood lymphocytes in vitro. PMID- 26929996 TI - Plateau-Rayleigh Crystal Growth of Nanowire Heterostructures: Strain-Modified Surface Chemistry and Morphological Control in One, Two, and Three Dimensions. AB - One-dimensional (1D) structures offer unique opportunities for materials synthesis since crystal phases and morphologies that are difficult or impossible to achieve in macroscopic crystals can be synthesized as 1D nanowires (NWs). Recently, we demonstrated one such phenomenon unique to growth on a 1D substrate, termed Plateau-Rayleigh (P-R) crystal growth, where periodic shells develop along a NW core to form diameter-modulated NW homostructures with tunable morphologies. Here we report a novel extension of the P-R crystal growth concept with the synthesis of heterostructures in which Ge (Si) is deposited on Si (Ge) 1D cores to generate complex NW morphologies in 1, 2, or 3D. Depositing Ge on 50 nm Si cores with a constant GeH4 pressure yields a single set of periodic shells, while sequential variation of GeH4 pressure can yield multimodulated 1D NWs with two distinct sets of shell periodicities. P-R crystal growth on 30 nm cores also produces 2D loop structures, where Ge (Si) shells lie primarily on the outside (inside) of a highly curved Si (Ge) core. Systematic investigation of shell morphology as a function of growth time indicates that Ge shells grow in length along positive curvature Si cores faster than along straight Si cores by an order of magnitude. Short Ge deposition times reveal that shells develop on opposite sides of 50 and 100 nm Si cores to form straight 1D morphologies but that shells develop on the same side of 20 nm cores to produce 2D loop and 3D spring structures. These results suggest that strain mediates the formation of 2 and 3D morphologies by altering the NW's surface chemistry and that surface diffusion of heteroatoms on flexible freestanding 1D substrates can facilitate this strain mediated mechanism. PMID- 26929997 TI - Use of a combined effect model approach for discriminating between ABCB1- and ABCC1-type efflux activities in native bivalve gill tissue. AB - Aquatic organisms, such as bivalves, employ ATP binding cassette (ABC) transporters for efflux of potentially toxic chemicals. Anthropogenic water contaminants can, as chemosensitizers, disrupt efflux transporter function enabling other, putatively toxic compounds to enter the organism. Applying rapid amplification of cDNA ends (RACE) PCR we identified complete cDNAs encoding ABCB1 and ABCC1-type transporter homologs from zebra mussel providing the molecular basis for expression of both transporter types in zebra mussel gills. Further, efflux activities of both transporter types in gills were indicated with dye accumulation assays where efflux of the dye calcein-am was sensitive to both ABCB1- (reversin 205, verapamil) and ABCC1- (MK571) type specific inhibitors. The assumption that different inhibitors targeted different efflux pump types was confirmed when comparing measured effects of binary inhibitor compound mixtures in dye accumulation assays with predictions from mixture effect models. Effects by the MK571/reversin 205 mixture corresponded better with independent action, whereas reversin 205/verapamil joint effects were better predicted by the concentration addition model indicating different and equal targets, respectively. The binary mixture approach was further applied to identify the efflux pump type targeted by environmentally relevant chemosensitizing compounds. Pentachlorophenol and musk ketone, which were selected after a pre-screen of twelve compounds that previously had been identified as chemosensitizers, showed mixture effects that corresponded better with concentration addition when combined with reversine 205 but with independent action predictions when combined with MK571 indicating targeting of an ABCB1-type efflux pump by these compounds. PMID- 26929998 TI - Neural circuits for sexually dimorphic and sexually divergent behaviors in Caenorhabditis elegans. AB - Increasing interest in sex differences in Caenorhabditis elegans neurobiology is resulting from several advances, including the completion of the male tail connectome and the surprising discovery of two 'new' neurons in the male head. In this species, sex-specific circuits in the hermaphrodite and male control reproductive behaviors such as egg-laying and copulation, respectively. Studies of these systems are revealing interesting similarities and contrasts, particularly in the mechanisms by which nutritional status influences reproductive behaviors. Other studies have highlighted the importance of sexual modulation of shared neurons and circuits in optimizing behavioral strategies. Together, these findings indicate that C. elegans uses intertwined, distributed sex differences in circuit structure and function to implement sex-specific as well as sexually divergent, shared behaviors. PMID- 26930000 TI - A preclinical simulated dataset of S-values and investigation of the impact of rescaled organ masses using the MOBY phantom. AB - Nuclear medicine and radiation therapy, although well established, are still rapidly evolving, by exploiting animal models, aiming to define precise dosimetry in molecular imaging protocols. The purpose of the present study was to create a dataset based on the MOBY phantom for the calculation of organ-to-organ S-values of commonly used radionuclides. S-values of most crucial organs were calculated using specific biodistributions with a whole-body heterogeneous source. In order to determine the impact of the varying organs' size on the S-values, and based on the fact that the anatomic properties of the organs are correlated with S-values, dosimetric calculations were performed by simulating the MOBY-version 2 model with different whole-body masses. The GATE Monte Carlo simulation toolkit was used for all simulations. Two mouse models of different body masses were developed to calculate the S-values of eight commonly used radioisotopes in nuclear imaging studies, namely (18)F, (68)Ga, (131)I, (111)In, (177)Lu, and (99m)Tc, (90)Y and (188)Re. The impact of modified mass of the source organs in S values was investigated with (18)F, and (90)Y in five different scalings of the source organs. Based on realistic preclinical exams, three mouse models, 22, 28 and 34 g, were used as input in the GATE simulator based on realistic preclinical exams to calculate the S-values of the six radioisotopes used. Whole body activity distributions were used as the source organ. The simulation procedure was validated in terms of extracting individual organ-to-organ S-values, and consequently in calculating the new S-values using a heterogeneous activity distribution as a source. The calculation was validated with (18)F source in a 30 g mouse model. For the generation of the new S-values with heterogeneous activity sources, four organs were used for the calculation of a single S-value. The absorbed doses per organ were compared with previously published reports. The validation procedure of (18)F indicates discrepancies, ranging from 5.32 to 7.72%. The S-values in Gy/(Bq.s), with the corresponding uncertainties of all simulated cases, are given in the developed dataset. The comparison of the dosimetric calculations on the three different phantoms highlights the impact of the mouse model size on the calculated S-values. The developed dataset can be used to improve the accuracy of the absorbed dose calculations in small animal dosimetry and depict the crucial impact the mouse size has on S-values' calculation. The generated S-values dataset for different radiopharmaceuticals contributes to the estimation of radiation dose to mice in small animal PET and SPECT exams. Finally, the detailed methodology of the procedure is provided. PMID- 26930001 TI - Health insurance and diversity of treatment. AB - We determine the optimal health policy mix when the average utility of patients increases with the supply of drugs available in a therapeutic class. Health risk coverage relies on two instruments, copayment and reference pricing, both of which affect the risk associated with health expenses and diversity of treatment. For a fixed supply of drugs, the reference pricing policy aims at minimizing expenses, in which case the equilibrium price of drugs is independent of the copayment rate. However, with an endogenous supply of drugs, diversity of treatment may susbtitute for insurance so that the reference pricing may depart from maximal cost-containment in order to promote entry. We next analyze the determinants of the optimal policy. While an increase in risk aversion, or in the side effect loss, increases diversity and decreases the copayment rate, an increase in entry cost decreases both diversity and the copayment rate. PMID- 26929999 TI - Photo-protective activity of pogostone against UV-induced skin premature aging in mice. AB - Pogostone, a chemical constituent of patchouli oil, has been confirmed to possess favorable anti-inflammatory property. In the present study, we investigated the possible anti-photoaging potential of pogostone and the underlying mechanism against UV-induced skin damage in mice. The macroscopic and histopathological lesions were significantly ameliorated by pretreatment of pogostone as compared to the VC group. Furthermore, topical application of pogostone markedly increased the activities of the antioxidant enzymes, including catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), and observably decreased malonaldehyde (MDA) level. Analysis of inflammatory cytokines showed obvious down regulation of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), interleukin-1beta (IL-1beta) and cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2) in the pogostone groups. In addition, pogostone pretreatment evidently inhibited the abnormal expression of matrix metalloproteinases (MMP-1 and MMP-3). Taken together, pogostone exhibited prominent photo-protective activity mainly by its antioxidative and anti-inflammatory properties, promising it as an effective alternative pharmaceutical therapy for photoaging. PMID- 26930002 TI - Creatine salts provide neuroprotection even after partial impairment of the creatine transporter. AB - Creatine, a compound that is critical for energy metabolism of nervous cells, crosses the blood-brain barrier (BBB) and the neuronal plasma membrane with difficulty, and only using its specific transporter. In the hereditary condition where the creatine transporter is defective (creatine transporter deficiency) there is no creatine in the brain, and administration of creatine is useless lacking the transporter. The disease is severe and incurable. Creatine-derived molecules that could cross BBB and plasma membrane independently of the transporter might be useful to cure this condition. Moreover, such molecules could be useful also in stroke and other brain ischemic conditions. In this paper, we investigated three creatine salts, creatine ascorbate, creatine gluconate and creatine glucose. Of these, creatine glucose was ineffective after transporter block with guanidine acetic acid (GPA) administration. Creatine ascorbate was not superior to creatine in increasing tissue creatine and phosphocreatine content after transporter impairment, however even after such impairment it delayed synaptic failure during anoxia. Finally, creatine gluconate was superior to creatine in increasing tissue content of creatine after transporter block and slowed down PS disappearance during anoxia, an effect that creatine did not have. These findings suggest that coupling creatine to molecules having a specific transporter may be a useful strategy in creatine transporter deficiency. In particular, creatine ascorbate has effects comparable to those of creatine in normal conditions, while being superior to it under conditions of missing or impaired creatine transporter. PMID- 26930003 TI - A novel 3-(4,5-diphenyl-1,3-oxazol-2-yl)propanal oxime compound is a potent Transient Receptor Potential Ankyrin 1 and Vanilloid 1 (TRPA1 and V1) receptor antagonist. AB - Transient Receptor Potential Ankyrin 1 and Vanilloid 1 (TRPA1, TRPV1) ion channels expressed on nociceptive primary sensory neurons are important regulators of pain and inflammation. TRPA1 is activated by several inflammatory mediators including formaldehyde and methylglyoxal that are products of the semicarbazide-sensitive amine-oxidase enzyme (SSAO). SZV-1287 is a new 3-(4,5 diphenyl-1,3-oxazol-2-yl)propanal oxime SSAO inhibitor, its chemical structure is similar to other oxime derivatives described as TRPA1 antagonists. Therefore, we investigated its effects on TRPA1 and TRPV1 receptor activation on the cell bodies and peripheral terminals of primary sensory neurons and TRPA1 or TRPV1 receptor-expressing cell lines. Calcium influx in response to the TRPA1 agonist allyl-isothiocyanate (AITC) (200 MUM) and the TRPV1 stimulator capsaicin (330 nM) in rat trigeminal neurons or TRPA1 and TRPV1 receptor-expressing cell lines was measured by microfluorimetry or radioactive (45)Ca(2+) uptake experiments. Calcitonin gene-related peptide (CGRP) release as the indicator of 100 MUM AITC - or 100 nM capsaicin-induced peripheral sensory nerve terminal activation was measured by radioimmunoassay. SZV-1287 (100, 500 and 1000 nM) exerted a concentration-dependent significant inhibition on both AITC- and capsaicin-evoked calcium influx in trigeminal neurons and TRPA1 or TRPV1 receptor-expressing cell lines. It also significantly inhibited the TRPA1, but not the TRPV1 activation induced CGRP release from the peripheral sensory nerve endings in a concentration dependent manner. In contrast, the reference SSAO inhibitor LJP 1207 with a different structure had no effect on TRPA1 or TRPV1 activation in either model system. This is the first evidence that our novel oxime compound SZV-1287 originally developed as a SSAO inhibitor has a potent dual antagonistic action on TRPA1 and TRPV1 ion channels on primary sensory neurons. PMID- 26930004 TI - hnRNP A1-mediated translational regulation of the G quadruplex-containing RON receptor tyrosine kinase mRNA linked to tumor progression. AB - The expression and role of RNA binding proteins (RBPs) controlling mRNA translation during tumor progression remains largely uncharacterized. Analysis by immunohistochemistry of the expression of hnRNP A1, hnRNPH, RBM9/FOX2, SRSF1/ASF/SF2, SRSF2/SC35, SRSF3/SRp20, SRSF7/9G8 in breast tumors shows that the expression of hnRNP A1, but not the other tested RBPs, is associated with metastatic relapse. Strikingly, hnRNP A1, a nuclear splicing regulator, is also present in the cytoplasm of tumor cells of a subset of patients displaying exceedingly worse prognosis. Expression of a cytoplasmic mutant of hnRNP A1 leads to increased translation of the mRNA encoding the tyrosine kinase receptor RON/MTS1R, known for its function in tumor dissemination, and increases cell migration in vitro. hnRNP A1 directly binds to the 5' untranslated region of the RON mRNA and activates its translation through G-quadruplex RNA secondary structures. The correlation between hnRNP A1 and RON tumoral expression suggests that these findings hold clinical relevance. PMID- 26930005 TI - 3D scanning electron microscopy applied to surface characterization of fluorosed dental enamel. AB - The enamel surfaces of fluorotic teeth were studied by scanning electron stereomicroscopy. Different whitening treatments were applied to 25 pieces to remove stains caused by fluorosis and their surfaces were characterized by stereomicroscopy in order to obtain functional and amplitude parameters. The topographic features resulting for each treatment were determined through these parameters. The results obtained show that the 3D reconstruction achieved from the SEM stereo pairs is a valuable potential alternative for the surface characterization of this kind of samples. PMID- 26930006 TI - Correlated light and electron microscopy observations of the uterine epithelial cell actin cytoskeleton using fluorescently labeled resin-embedded sections. AB - In order to perform correlative light and electron microscopy (CLEM) more precisely, we have modified existing specimen preparation protocols allowing fluorescence retention within embedded and sectioned tissue, facilitating direct observation across length scales. We detail a protocol which provides a precise correlation accuracy using accessible techniques in biological specimen preparation. By combining a pre-embedding uranyl acetate staining step with the progressive lowering of temperature (PLT) technique, a methacrylate embedded tissue specimen is ultrathin sectioned and mounted onto a TEM finder grid for immediate viewing in the confocal and electron microscope. In this study, the protocol is applied to rat uterine epithelial cells in vivo during early pregnancy. Correlative overlay data was used to track changes in filamentous actin that occurs in these cells from fertilization (Day 1) to implantation on Day 6 as part of the plasma membrane transformation, a process essential in the development of uterine receptivity in the rat. CLEM confirmed that the actin cytoskeleton is disrupted as apical microvilli are progressively lost toward implantation, and revealed the thick and continuous terminal web is replaced by a thinner and irregular actin band, with individually distinguishable filaments connecting actin meshworks which correspond with remaining plasma membrane protrusions. PMID- 26930008 TI - An Unusual Lesion Presenting as Cholangiopathy. PMID- 26930007 TI - Muscle injury in rats induces upregulation of inflammatory cytokines in injured muscle and calcitonin gene-related peptide in dorsal root ganglia innervating the injured muscle. AB - INTRODUCTION: In this study we evaluated the relationships among the behavioral changes after muscle injury, histological changes, changes in inflammatory cytokines in the injured muscle, and changes in the sensory nervous system innervating the muscle in rats. METHODS: We established a model of muscle injury in rats using a dropped weight. Behavior was assessed using the CatWalk system. Subsequently, bilateral gastrocnemius muscles and dorsal root ganglia (DRGs) were resected. Muscles were stained with hematoxylin and eosin, and inflammatory cytokines in injured muscles were assayed. DRGs were immunostained for calcitonin gene-related peptide (CGRP). RESULTS: Changes of behavior and upregulation of inflammatory cytokines in injured muscles subsided within 2 days of injury. Repaired tissue was observed 3 weeks after injury. However, upregulation of CGRP in DRG neurons continued for 2 weeks after injury. CONCLUSION: These findings may explain in part the pathological mechanism of persistent muscle pain. Muscle Nerve 54: 776-782, 2016. PMID- 26930009 TI - A 63-Year-Old Woman With Muscle Weakness and Abdominal Pain. PMID- 26930010 TI - Double Trouble in Acute Pancreatitis. PMID- 26930011 TI - A Bulky Posterior Mediastinal Tumor. PMID- 26930012 TI - Reply. PMID- 26930013 TI - An Unusual Gastric Mass. PMID- 26930014 TI - Unusual Esophageal Mass as a Cause of Dysphagia. PMID- 26930015 TI - The Burden of Gastrointestinal, Liver, and Pancreatic Diseases: The Global Scenario. PMID- 26930016 TI - Gastrointestinal Ulcerative Nodular Lesions. PMID- 26930017 TI - RE: Impaired Upper Esophageal Sphincter Reflexes in Patients With Supraesophageal Reflux Disease. PMID- 26930018 TI - Diarrhea, Ascites, and Eosinophilia. PMID- 26930019 TI - Unusual Cause of Abdominal Pain. PMID- 26930020 TI - A Stunned Esophagus. PMID- 26930021 TI - Why perimenopausal women should consider to use a levonorgestrel intrauterine system. AB - OBJECTIVE: The use of a levonorgestrel intrauterine system (LNG-IUS) is useful in preventing pregnancy and for the treatment of menstrual disturbances. A smooth or symptom-free transition to and through menopause is possible when LNG-IUS is combined with estrogen therapy. Unfortunately the majority of physicians are generally unaware of this usefulness combined hormonal therapy in the pre-, peri- and postmenopausal women. DESIGN AND METHOD: Based on long-term clinical experience with LNG-IUS in the form of Femilis(r), 104 women where followed from the premenopause through the menopausal transition into the postmenopause. These perimenopausal women received supplemental 17 beta-estradiol by gel or patch, or orally as estradiol valerate. Patients received one or two separate Femilis insertions at 5 year intervals. Main outcome measures included acceptability and continued use of the combined regimen for the treatment of climacteric symptoms and for prevention of cardiovascular disease, osteoporosis and other adverse effects caused by estrogen deprivation. RESULTS: The average age at insertion was 48 years (range 28-58) and the total duration of use was 137 months (range 80 161). The Femilis LNG-IUS was well tolerated as the number of removals for LNG IUS-related reasons was low. The LNG-IUS was well retained in the uterine cavity as no expulsions were observed. Seven women were lost to follow-up. Eighty-six women (82%) opted for replacement of an LNG-IUS at expiry after 5 years and continued with the estrogen therapy. CONCLUSION: Intrauterine progestogen delivery for endometrial suppression in combination with estrogen therapy in the symptomatic perimenopausal women is highly practical as it combines the benefits of prevention of endometrial proliferation and treatment of menorrhagia and hyperplasia, if present. In addition, the contraceptive effect of locally administered LNG is highly desirable as many perimenopausal women run considerable risk of unintended pregnancy. For these reasons, the author views this regimen as one of the most effective, safest and best accepted route resulting in high patient compliance. It is important to convey this message to general practitioners as well as women. PMID- 26930022 TI - Prevalence of Radiographic Knee Osteoarthritis After Anterior Cruciate Ligament Reconstruction, With or Without Meniscectomy: An Evidence-Based Practice Article. AB - : Reference: Claes S, Hermie L, Verdonk R, Bellemans J, Verdonk P. Is osteoarthritis an inevitable consequence of anterior cruciate ligament reconstruction? A meta-analysis. Knee Surg Sports Traumatol Arthrosc. 2013;21(9):1967-1976. CLINICAL QUESTION: What is the prevalence of radiographic knee osteoarthritis (OA) at a mean follow-up equal to or greater than 10 years after autologous anterior cruciate ligament (ACL) reconstruction, with or without meniscectomy? DATA SOURCES: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guidelines were used to conduct this meta-analysis. Studies were identified by searching PubMed, MEDLINE, EMBASE, and Cochrane Library dating from their earliest file until October 2010. Key terms applied for searching were anterior cruciate ligament or ACL, autologous, follow up, long-term, outcome, reconstruction, results, treatment, and (osteo)arthritis or osteoarthrosis. The reference lists of included studies were also manually checked to ensure that relevant articles were not omitted. STUDY SELECTION: The authors limited their search to English- and French-language journals. Included studies provided radiographic outcomes after autologous ACL reconstruction and had a mean follow-up of >=10 years. Excluded studies evaluated ACL reconstruction with major concomitant surgical procedures (eg, meniscal allograft transplantation, high tibial osteotomy). In addition, data from 2 studies completed by the same research team with identical patient populations were limited to the article with the longest follow-up. Finally, manuscripts with inaccurate or incomplete data were excluded. DATA EXTRACTION: The following key characteristics of each study were extracted: type of study (prospective or retrospective); ACL surgical procedure (eg, open or arthroscopic bone-patellar tendon-bone graft); time frame of surgery; mean follow-up (in years) post-ACL reconstruction; total number of participants with radiographs; total number of participants with radiographic OA at follow-up; and number of participants with meniscectomy before, during, or after ACL reconstruction. Although the OA diagnosis was based on radiographic criteria, the included studies used 4 OA classifications and grading scales: Ahlback, Fairbanks, Kellgren and Lawrence, and International Knee Documentation Committee. Regardless of classification or grading scale, OA was defined as the presence of joint-space narrowing: Ahlback grades 1 through 5, modified Fairbanks grades 2 and 3, Kellgren and Lawrence >=2, and International Knee Documentation Committee grades C and D. Tibiofemoral and patellofemoral OA data were collapsed due to the lack of reporting specificity among the studies. Participants were categorized into a meniscectomy or nonmeniscectomy group if this information was reported. Partial or total meniscectomies before, during, or after ACL reconstruction were collapsed regardless of location (medial or lateral compartment), and those patients who underwent a meniscal repair were grouped into the nonmeniscectomy group. Data were analyzed using odds ratios, the Cochran chi2 test, and a random-effects meta regression analysis. The DerSimonian and Laird approach was used to assess study heterogeneity. P values below .05 were considered statistically significant. MAIN RESULTS: The initial computerized database search resulted in 211 possible studies. However, after the authors applied the inclusionary and exclusionary criteria, only 16 studies were relevant. A total of 1554 participants were available at the follow-up period. Mean follow-up ranged from 10 to 24.5 years; 11 of the 16 articles had a mean follow-up between 10 and 12 years. Heterogeneity was large (I2 = 96%), which indicated that the included studies generated a wide range of knee OA prevalence (2%-79%). Almost 28% (95% confidence interval [CI] = 16.3%, 43.5%) of participants had radiographic knee OA. A total of 1264 participants were involved in studies that evaluated meniscectomies (n = 11). Among the 614 participants with either partial or total meniscectomies, 50.4% had radiographic knee OA (95% CI = 27.4%, 73.1%). In contrast, only 16.4% (95% CI = 7.0%, 33.9%) of those without a meniscectomy had radiographic knee OA. CONCLUSIONS: The findings of Claes et al reflected a radiographic knee OA prevalence at a minimum average of 10 years' postautologous ACL reconstruction that was lower than commonly perceived (up to 79%). In addition, meniscectomy was an important risk factor (3.54-fold increase) for developing OA after ACL reconstruction. PMID- 26930023 TI - Thermodynamic and Spectroscopic Studies of Trivalent f-element Complexation with Ethylenediamine-N,N'-di(acetylglycine)-N,N'-diacetic Acid. AB - The coordination behavior and thermodynamic features of complexation of trivalent lanthanides and americium by ethylenediamine-N,N'-di(acetylglycine)-N,N'-diacetic acid (EDDAG-DA) (bisamide-substituted-EDTA) were investigated by potentiometric and spectroscopic techniques. Acid dissociation constants (K(a)) and complexation constants (beta) of lanthanides (except Pm) were determined by potentiometric analysis. Absorption spectroscopy was used to determine stability constants for the binding of trivalent americium and neodymium by EDDAG-DA under similar conditions. The potentiometry revealed 5 discernible protonation constants and 3 distinct metal-ligand complexes (identified as ML(-), MHL, and MH2L(+)). Time resolved fluorescence studies of Eu-(EDDAG-DA) solutions (at varying pH) identified a constant inner-sphere hydration number of 3, suggesting that glycine functionalities contained in the amide pendant arms are not involved in metal complexation and are protonated under more acidic conditions. The thermodynamic studies identified that f-element coordination by EDDAG-DA is similar to that observed for ethylenediamine-N,N,N',N'-tetraacetic acid (EDTA). However, coordination via two amidic oxygens of EDDAG-DA lowers its trivalent f-element complex stability by roughly 3 orders of magnitude relative to EDTA. PMID- 26930025 TI - PrEP Whores and HIV Prevention: The Queer Communication of HIV Pre-Exposure Prophylaxis (PrEP). AB - HIV pre-exposure prophylaxis (PrEP) has been introduced as another biomedical tool in HIV prevention. Whereas other such tools-including post-exposure prophylaxis (PEP) and interruption of perinatal transmission-have been embraced by those impacted by HIV, PrEP has been met with more conflict, especially within the gay community and HIV organizations. The "PrEP whore" has come to designate the social value and personal practices of those taking PrEP. This study examines the "PrEP whore" discourse by using queer theory and quare theory. Within these theoretical vantage points, the study explicates four discursive areas: slut shaming, dirty/clean binaries, mourning the loss of condoms, and reclaiming the inner whore. The study illuminates possible discursive strategies that lie outside of the domains of public health and within the individual and community. PMID- 26930026 TI - Patient and clinician support for the learning healthcare system: recommendations for enhancing value. PMID- 26930024 TI - Understanding and effectively addressing breast cancer in African American women: Unpacking the social context. AB - Black women have a higher incidence of breast cancer before the age of 40 years, more severe disease at all ages, and an elevated mortality risk in comparison with white women. There is limited understanding of the contribution of social factors to these patterns. Elucidating the role of the social determinants of health in breast cancer disparities requires greater attention to how risk factors for breast cancer unfold over the lifecourse and to the complex ways in which socioeconomic status and racism shape exposure to psychosocial, physical, chemical, and other individual and community-level assaults that increase the risk of breast cancer. Research that takes seriously the social context in which black women live is also needed to maximize the opportunities to prevent breast cancer in this underserved group. Cancer 2016;122:2138-49. (c) 2016 American Cancer Society. PMID- 26930027 TI - Targeting acid sphingomyelinase reduces cardiac ceramide accumulation in the post ischemic heart. AB - Ceramide accumulation is known to accompany acute myocardial ischemia, but its role in the pathogenesis of ischemic heart disease is unclear. In this study, we aimed to determine how ceramides accumulate in the ischemic heart and to determine if cardiac function following ischemia can be improved by reducing ceramide accumulation. To investigate the association between ceramide accumulation and heart function, we analyzed myocardial left ventricle biopsies from subjects with chronic ischemia and found that ceramide levels were higher in biopsies from subjects with reduced heart function. Ceramides are produced by either de novo synthesis or hydrolysis of sphingomyelin catalyzed by acid and/or neutral sphingomyelinase. We used cultured HL-1 cardiomyocytes to investigate these pathways and showed that acid sphingomyelinase activity rather than neutral sphingomyelinase activity or de novo sphingolipid synthesis was important for hypoxia-induced ceramide accumulation. We also used mice with a partial deficiency in acid sphingomyelinase (Smpd1(+/-) mice) to investigate if limiting ceramide accumulation under ischemic conditions would have a beneficial effect on heart function and survival. Although we showed that cardiac ceramide accumulation was reduced in Smpd1(+/-) mice 24h after an induced myocardial infarction, this reduction was not accompanied by an improvement in heart function or survival. Our findings show that accumulation of cardiac ceramides in the post-ischemic heart is mediated by acid sphingomyelinase. However, targeting ceramide accumulation in the ischemic heart may not be a beneficial treatment strategy. PMID- 26930028 TI - Inhibition of Focal Adhesion Kinase Signaling by Integrin alpha6beta1 Supports Human Pluripotent Stem Cell Self-Renewal. AB - Self-renewal of human embryonic stem cells and human induced pluripotent stem cells (hiPSCs)-known as pluripotent stem cells (PSC)-is influenced by culture conditions, including the substrate on which they are grown. However, details of the molecular mechanisms interconnecting the substrate and self-renewal of these cells remain unclear. We describe a signaling pathway in hPSCs linking self renewal and expression of pluripotency transcription factors to integrin alpha6beta1 and inactivation of focal adhesion kinase (FAK). Disruption of this pathway results in hPSC differentiation. In hPSCs, alpha6beta1 is the dominant integrin and FAK is not phosphorylated at Y397, and thus, it is inactive. During differentiation, integrin alpha6 levels diminish and Y397 FAK is phosphorylated and activated. During reprogramming of fibroblasts into iPSCs, integrin alpha6 is upregulated and FAK is inactivated. Knockdown of integrin alpha6 and activation of beta1 integrin lead to FAK phosphorylation and reduction of Nanog, Oct4, and Sox2, suggesting that integrin alpha6 functions in inactivation of integrin beta1 and FAK signaling and prevention of hPSC differentiation. The N-terminal domain of FAK, where Y397 is localized, is in the nuclei of hPSCs interacting with Oct4 and Sox2, and this immunolocalization is regulated by Oct4. hPSCs remodel the extracellular microenvironment and deposit laminin alpha5, the primary ligand of integrin alpha6beta1. Knockdown of laminin alpha5 resulted in reduction of integrin alpha6 expression, phosphorylation of FAK and decreased Oct4. In conclusion, hPSCs promote the expression of integrin alpha6beta1, and nuclear localization and inactivation of FAK to supports stem cell self-renewal. Stem Cells 2016;34:1753-1764. PMID- 26930029 TI - Effect of sucrose on chemically and thermally induced unfolding of domain-I of human serum albumin: Solvation dynamics and fluorescence anisotropy study. AB - The present study is devoted to understand the effect of sucrose on the hydration dynamics and rotational relaxation dynamics within the domain-I of HSA during chemically as well as thermally induced unfolding. It has been observed that the average solvation time become slower in the presence of sucrose for the lower concentrations of GnHCl, however at higher concentrations of GnHCl the effect of sucrose is almost negligible. From the time resolved fluorescence anisotropy it has been observed that in the lower concentration region of GnHCl the sucrose induced stabilization is small as compared to the higher concentrations of GnHCl. We have concluded that the hydration dynamics plays an important role in the sucrose induced stabilization process at the low concentration region; whereas environmental restriction is responsible at the higher concentration of GnHCl. However, we have observed a negligible stabilizing effect of sucrose towards the temperature induced unfolding. PMID- 26930030 TI - Investigation of enrofloxacin residues in broiler tissues using ELISA and LC MS/MS. AB - This study investigated the efficiency of an enrofloxacin ELISA test kit to detect the presence of enrofloxacin residues in broiler tissues compared with LC MS/MS. Broiler tissues from 72 samples consisting of 60 breast muscle, six pools of livers (500 g each) and six pools of kidneys (500 g each) were obtained from six different slaughterhouses. Breast muscle from 10 carcasses and pools of livers and kidneys from approximately 200 carcasses of the same flock were collected from each slaughterhouse. ELISA and HPLC were used to identify and quantify the contamination of the samples with enrofloxacin. A total of 72% of the analysed samples contained enrofloxacin residues detected by the ELISA and 22.2% were detected by LC-MS/MS. The mean values of enrofloxacin contamination found in chicken breast by ELISA and HPLC were 8.63 and 12.25 MUg kg(-1), respectively. None of the samples exceeded the maximum limit of 100 MUg kg(-1) by both methods set by the European Union as well as the Brazilian Agriculture Ministry. All positive samples for enrofloxacin residues detected by LC-MS/MS were also positive by ELISA. These data confirm the efficiency of the ELISA test, and suggest its use as a screening method for enrofloxacin residues in poultry tissues due to its quick results, low price and ease of applicability. PMID- 26930031 TI - Growth and maturity status of elite British junior tennis players. AB - Growth and maturation impact the selection, development and progression of youth athletes. Individual differences in the growth and maturity may afford a performance advantage, clouding coaches and practitioners' perceptions regarding current ability and future potential. This may result in the exclusion of talented, yet less physically gifted athletes. Participants were 91 male (n = 47) and female (n = 44) elite British Junior tennis players, 8-17 years of age (12.5 +/- 1.9 years). Height and body mass were measured and compared to growth charts; hand-wrist radiographs were taken. Skeletal age (SA) was estimated with the Fels method and contrasted to chronological age (CA). Mean height and body mass of individual players ranged between the 50th and 90th centiles for age and sex. Females were advanced in SA relative to CA (0.3-0.89 years.) from 8 years. Males were average to delayed in maturation from 8 to 12 years, but advanced in SA from 14 to 16 years (0.75-1.23 years). Individual differences in growth and maturation appear to contribute towards the selection of elite junior tennis players, with a bias towards males and females who are advanced in maturation and comparatively tall and heavy for their age. This has important implications for talent identification and development. PMID- 26930032 TI - Improving the enzymatic hydrolysis of dilute acid pretreated wheat straw by metal ion blocking of non-productive cellulase adsorption on lignin. AB - Eleven salts were selected to screen the possible metal ions for blocking the non productive adsorption of cellulase onto the lignin of dilute acid pretreated wheat straw. Mg(2+) was screened finally as the promising candidate. The optimal concentration of MgCl2 was 1 mM, but the beneficial action was also dependent on pH, hydrolysis time and cellulase loading. Significant improvement of glucan conversion (19.3%) was observed at low cellulase loading (5 FPU/g solid). Addition of isolated lignins, tannic acid and lignin model compounds to pure cellulose hydrolysis demonstrated that phenolic hydroxyl group (Ph-OH) was the main active site blocked by Mg(2+). The interaction between Mg(2+) and Ph-OH of lignin monomeric moieties followed an order of p-hydroxyphenyl (H)>guaiacyl (G)>syringyl (S). Mg(2+) blocking made the lignin surface less negatively charged, which might weaken the hydrogen bonding and electrostatically attractive interaction between lignin and cellulase enzymes. PMID- 26930033 TI - Electricity generation from rapeseed straw hydrolysates using microbial fuel cells. AB - Rapeseed straw is an attractive fuel material for microbial fuel cells (MFCs) due to its high content of carbohydrates (more than 60% carbohydrates). This study has demonstrated that reducing sugars can be efficiently extracted from raw rapeseed straw by combination of hydrothermal pretreatment and enzymatic hydrolysis followed by utilization as a fuel in two-chamber MFCs for electrical power generation. The most efficient method of saccharification of this lignocellulosic biomass (17%) turned out hydrothermal pretreatment followed by enzymatic hydrolysis. Electricity was produced using hydrolysate concentrations up to 150 mg/dm(3). The power density reached 54 mW/m(2), while CEs ranged from 60% to 10%, corresponding to the initial reducing sugar concentrations of 10-150 mg/dm(3). The COD degradation rates based on charge calculation increased from 0.445 g COD/m(2)/d for the hydrolysate obtained with the microwave treatment to 0.602 g COD/m(2)/d for the most efficient combination of hydrothermal treatment followed by enzymatic hydrolysis. PMID- 26930034 TI - Synthesis and evaluation of cholesterol-grafted PEGylated peptides with pH triggered property as novel drug carriers for cancer chemotherapy. AB - Multifunctional core/shell micelles were self-assembled from triblock copolymers poly(ethylene glycol) methyl ether-b-peptide-g-cholesterol (mPEG-b-P-g-Chol) and used as the doxorubicin delivery carriers for cancer chemotherapy. The copolymers were designed and synthesized successfully based on peptides containing histidine residues (pH-trigger) with different topological structures. The peptides were modified by mPEG (hydrophilic) and cholesterol motifs (hydrophobic) on the terminus, resulting in pH-sensitive amphiphilic copolymers. The critical micelle concentrations (CMCs) of the micelles were determined as 4.79, 2.50 and 1.86mg/L for the linear, Y-shape and fork-shape copolymers, respectively, demonstrating the formation of micelle even at low concentration. The pKb values of three copolymers were found to be around 6.1-6.3 by potentiometric titration test, showing the satisfied pH-sensitivity. The average diameter and zeta potential of blank micelles were 170nm and +20mV at pH 7.4, and increased to 250nm and +35mV at pH 5.0. DOX was loaded into the core of polymeric micelles by dialysis method, and the drug loading capacity slightly increased when the copolymer topological structure changed from linear to Y- and fork-shape. The drug release rate from the system was obviously influencing by the pH values according to the results of in vitro DOX release experiment. Moreover, to investigate the structure-property relationship, the drug release mechanism was preliminarily explored by the semi empirical equations. Toxicity test showed that three copolymers had bare toxicity whereas the DOX-loaded micelles remained high cytotoxicity for tumor cells. The results indicate the synthesized copolymers might be a potential hydrophobic drug delivery carrier for cancer targeting therapy with controlled drug release. PMID- 26930035 TI - Biological effects of agglomerated multi-walled carbon nanotubes. AB - The physicochemical properties of nanomaterials play crucial roles in determining their biological effects. Agglomeration of nanomaterials in various systems is a common phenomenon, however, how agglomeration affects the biological consequence of nanomaterials has not been well investigated because of its complexity. Herein, we prepared variable sized agglomerates of oxidized multi-walled carbon nanotubes (O-MWCNTs) by using Ca(2+) and studied their cellular uptake and cytotoxicity in HeLa cells. We found the altered property of O-MWCNTs agglomerates could be controlled and adjusted by the amount of Ca(2+). Agglomeration remarkably facilitated the cellular uptake of O-MWCNTs at the initial contact stage, due to the easy contact of agglomerates with cells. But agglomeration did not induce evident cytotoxicity when the concentration of O MWCNTs was less than 150MUg/mL. That was assayed by cell proliferation, membrane integrity, apoptosis and ROS generation. This study suggests us that the biological behaviors of nanomaterials could be altered by their states of agglomeration. PMID- 26930036 TI - Manipulation of partially oriented hydroxyapatite building blocks to form flowerlike bundles without acid-base regulation. AB - The application of hydroxyapatite (HAP) in different fields depends greatly on its morphology, composition and structure. Besides, the main inorganic building blocks of human bones and teeth are also HAP. Therefore, accurate shape and aggregation control and of hydroxyapatite particles will be of great interest. Herein, oriented bundles of flowerlike HAP nanorods were successfully prepared through hydrothermal treatment without acid-base regulation, with the mono-alkyl phosphate (MAP) and sodium citrate as surfactant and chelating agent, respectively. The prepared samples were characterized by the X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), field emission scanning electron microscopy (FESEM), transmission electron microscopy (TEM), high resolution transmission electron microscopy (HRTEM) and zeta potential, the pH value and conductivity value of suspension were characterized by pH meter and conductivity measurement. The results showed that the MAP and citrate play an important role in assembly of HAP nanorods without acid-base regulation. Citrate calcium complex could decompose slowly and release citrate ions at hydrothermal conditions. Besides, the further decomposition of citrate ions could release aconitic acid as the reaction time prolongs. Moreover, the possible scheme for the formation process was discussed in detail. PMID- 26930037 TI - Comparison of indications of pregnancy termination and prognosis of mothers and neonates in early- and late-onset preeclampsia. AB - OBJECTIVE: To compare the indications of pregnancy termination and prognosis between early-onset preeclampsia (EOP) and late-onset preeclampsia (LOP). METHODS: In total, 100 patients diagnosed early-onset preeclampsia in our hospital from January 1, 2012, to June 30, 2014, were recruited for this retrospective cohort study. At the same time, we randomly chose another 100 late onset preeclampsia as the contrast group. Criterion distinguishing early versus late was set at week 34 of gestation. Indications for pregnancy termination and prognosis of mothers and neonates were compared between the groups. RESULTS: Significant differences were observed between the groups regarding indications for terminating pregnancy. The EOP indications to terminate the pregnancy were mainly fetal-related, while LOP were mainly maternal-related. Postpartum neonatal morbidity and mortality were significantly higher, mean gestational age onset and delivery were significantly earlier, latent period for delivery and postpartum hospitalization time were significantly longer, admission 24 h proteinuria was significantly higher in EOP than in LOP group (P < 0.05). CONCLUSION: EOP is a distinct and more severe clinical entity with earlier gestational age onset and delivery. EOP might be a fetal-related disease complicated by severe placental and perinatal injuries; LOP might be a maternal-related derived disease condition. PMID- 26930038 TI - In vivo immunomodulatory effects of adipose-derived mesenchymal stem cells conditioned medium in experimental autoimmune encephalomyelitis. AB - Mesenchymal stem cells (MSCs) are well known to possess neuroprotective and immunomodulatory effects, due to cell-to-cell interaction and their soluble factors. We conducted a comparative analysis of the immunomodulatory properties of adipose tissue mesenchymal stem cells (AT-MSCs) and their conditioned media (CM), derived from C57/BL6 mice, for mitigating the adverse clinical course of experimental autoimmune encephalomyelitis (EAE). We measure IL4, IL17 and IFNgamma production of supernatant from spleen cells. We analyzed brain cell infiltration, splenocyte proliferation and evaluated the percentage of CD4+CD25+FOXP3+splenic cell population in all EAE C57/BL6 mice. AT-MSCs and its conditioned medium induced CD4+CD25+FOXP3+regulatory T cells after in vitro co culture with naive T cells. There is no significant difference in the clinical scores and body weight of EAE mice treated with AT-MSCs and CM. The reduction in proliferative responses and brain cell infiltration was more pronounced in mice injected with CM than other groups. It is found that the percentage of splenic CD4+CD25+FOXP3+ population as well as the level of IL4 production in mice administrated with AT-MSCs is increased compared to other animals. Our results suggest that AT-MSCs-derived CM is promising in stem cell therapy, due to their neuroprotective and immunomudulatory properties. PMID- 26930039 TI - Functionalized Silica Nanoparticles As an Alternative Platform for Targeted Drug Delivery of Water Insoluble Drugs. AB - The selective action of drugs in tumor cells is a major problem in cancer therapy. Most chemotherapy drugs act nonspecifically and damage both cancer and healthy cells causing various side effects. In this study, the preparation of a selective drug delivery system, which is able to act as a carrier for hydrophobic and anticancer drugs is reported. Amino-functionalized silica nanoparticles loaded with curcumin were successfully synthesized via sol-gel approach and duly characterized. Thereafter, the targeting ligand, folate, was covalently attached to amino groups of nanoparticle surface through amide bond formation. The cytotoxic effect of nanoparticles on prostate cancer cells line was evaluated and compared to normal cells line (prostate epithelial cell). Cytotoxicity experiments demonstrated that folate-functionalized nanoparticles were significantly cytotoxic to tumor cells, whereas normal cells were much less affected by the presence of these structures. PMID- 26930040 TI - Gods, Germs, and Petri Dishes: Toward a Nonsecular Medical Anthropology. AB - This commentary calls on medical anthropology to become programmatically non secular. Despite recent anthropological critiques of secularity, within and outside of anthropology, most contemporary medical anthropologists continue to leave deities and religiosity out of their examinations of healing practices, especially in their accounts of biomedicine. Through a critical, relational constructionist lens, which traces how all entities are both constructed and real, a non-secular medical anthropology would insist that when deities are part of medical practice, they are integral to analysis. Importantly then, within the symmetrical nature of this same constructionist lens, biomedical entities like germs and petri dishes need to be accounted for just as much as deities. PMID- 26930041 TI - Myoma-associated pain frequency and intensity: a retrospective evaluation of 1548 myoma patients. AB - OBJECTIVE: To analyze the possible relation between symptoms (especially pain) reported by myoma patients and objective features of their myomas as determined by ultrasound. Specifically: (1) What is the frequency and intensity of myoma related pain? (2) Does the pain intensity depend on the number, size, or location of the myomas? (3) Is there any correlation between premenstrual pain, menstrual pain, and pain during sexual intercourse? STUDY DESIGN: A retrospective analysis of data from a patient questionnaire and ultrasound exams, collected from February 2009 until January 2013 at the myoma clinic of a university hospital in a large European city. The study analyzed data from 1548 myoma patients. Patients completed a 0-10 Likert scale questionnaire about their symptoms. The number, size, and location of myomas were determined from ultrasound exams. RESULTS: The three most frequent symptoms reported were hypermenorrhea, dysmenorrhea, and premenstrual pain. There was no statistically significant relationship between premenstrual pain or pain during sexual intercourse on the one hand and the number, size, or location of myomas on the other hand. For women with severe dysmenorrhea (Likert-scale scores of 8-10), submucosal myomas were significantly more frequent than all other myoma locations (p=0.01). Severe dysmenorrhea (Likert-scale scores of 8-10) was reported by a significantly (p<0.001) greater portion of the women whose largest myoma had a largest diameter of <5cm than by the women whose largest myoma had a diameter >=5cm. The number of myomas did not have a significant influence on the dysmenorrhea intensity. The three types of pain (premenstrual, menstrual, and/or during sexual intercourse) had moderate pairwise correlations (rho values from 0.304 to 0.542) that were all statistically highly significant (p<0.001). CONCLUSION: Myoma-associated pain is, alongside hypermenorrhea, the most frequent problem reported by the affected patients. Unlike premenstrual pain and pain during sexual intercourse, the intensity of menstrual pain is clearly dependent on the location and size of the largest myoma. Further research is needed to better understand the degree to which the pain reported by the patients is due to features of the myomas versus other possible factors. PMID- 26930042 TI - Do younger women with elevated basal follicular stimulating hormone levels undergoing gonadotropin-stimulated intrauterine insemination cycles represent compromised reproductive outcomes? AB - OBJECTIVE: To compare stimulation characteristics and reproductive outcomes in women representing elevated and normal day 3 FSH levels and to evaluate the prognostic significance of day 3 FSH on the reproductive outcomes of gonadotropin stimulated IUI (GS-IUI) cycles in women <35 years. STUDY DESIGN: A cross sectional study was designed. Unexplained infertility patients at the age <=36 years, who underwent IUI, following gonadotropin stimulation (GS), were investigated. From 105 women with a day 3 FSH>= 10U/L, 170GS/IUI cycles were assigned to Group EF; whereas a control group (Group NF, normal FSH) was constituted of 170 cycles with a day 3 FSH levels <10U/L. Demographic and stimulation characteristics as well as reproductive outcomes were compared. Primary outcome measure of this study was the biochemical, clinical and ongoing pregnancy rates. Secondary outcome measures were total gonadotropin dose, duration of gonadotropin stimulation, multiple pregnancy, miscarriage and cycle cancellation rates. RESULTS: beta-hCG positivity, clinical and ongoing pregnancy rates did not differ between women with normal and elevated FSH levels (p=0.234, 0.282 and 0.388, respectively). Total gonadotropin dose, multiple pregnancy and miscarriage rates were not significantly different between the groups (p=0,181, 0.652 and 0.415, respectively). Duration of stimulation was significantly longer and cycle cancellation rate was significantly higher in Group EF than in Group NF (p=0.005 and 0.021, respectively). CONCLUSION: Younger women with elevated day 3 FSH represent comparable reproductive outcomes in GS-IUI cycles to those with normal FSH levels, although they may require longer periods of stimulation and are at higher risk of cycle cancellation. Thus, GS-IUI could be a possible treatment option in this patient group and should not be neglected. PMID- 26930043 TI - Weekly time spent in the standing position is independently related to a better quality of life in postmenopausal women. AB - OBJECTIVES: To analyze the relationship between standing, sitting and reclining behaviors and quality of life in postmenopausal women. STUDY DESIGN: Cross sectional study composed of forty postmenopausal women (aged 59.58+/-5.32) who do not practice regular physical exercise. Body composition was measured using Dual energy X-ray absorptiometry and quality of life by the Short Form 36 Health Survey (SF-36). Physical activity level was assessed using an accelerometer (Actigraph GTX3x) and is reported as minutes per week of moderate-to-vigorous physical activity (MVPA). Inclinometer analysis was also measured using this accelerometer model and reported as a weekly percentage of time spent standing, sitting and reclining. All analyses were performed using SPSS 17.0 software with the significance level set at 5%. RESULTS: The percentage of time in the standing position was lower among women with poor quality of life (p<0.05). Adjusted analysis (age, years since menopause, percentage of fat mass, MVPA and occupation status) was used to evaluate the relationship between quality of life and accelerometer inclinometer measures. The relationship between time standing and general health status (beta=0.353; 95%CI=0.017; 0.377), social function (beta=0.429; 95%CI=0.060; 0.396) and overall score (beta=0.336; 95%CI=0.015; 0.442) were statistically significant. The relationship between the reclining position and both overall score (beta=-0.320; 95%CI=-0.492; 0.006) and emotional aspects (beta=-0.337; 95%CI=-0.191; 0.001) showed a tendency to present statistical significance. CONCLUSION: In summary, our results suggest that postmenopausal women who spend more time in the standing position have a better overall quality of life regardless of confounders. PMID- 26930044 TI - Evaluation of oxidative stress markers and intra-extracellular antioxidant activities in patients with endometriosis. AB - OBJECTIVE: The aim of the study is to evaluate alterations in intracellular and extracellular antioxidant enzymes activities and serum oxidative stress markers in patients with endometriosis. STUDY DESIGN: The current prospective study consisted of 31 female patients with endometriosis and 27 healthy controls. Serum total thiol, native thiol, disulphide, catalase, myeloperoxidase, and ceruloplasmin concentrations were measured. Laboratory and clinical data of all participants were recorded to compare the differences between the study and the control groups. RESULTS: Serum native thiol and total thiol levels in the study group were significantly lower than those in the control group [(p=0.009, p=0.03, respectively)]. Serum catalase levels are significantly higher in patients with endometriosis comparing to the control group (p=0.009). CONCLUSIONS: The finding that significant differences in serum total thiol, native thiol, and catalase levels observed in endometriotic patients supports that oxidative stress carries weigh in the pathophysiological aspects of endometriosis. Also significantly low levels of extracellular antioxidants and significantly high levels of intracellular antioxidants in endometriotic patients may arise from differences of free radicals in endometriosis and the activity levels of endometriosis. These non-invasive serum markers might give us an opportunity to monitor the disease's progress during the treatment. PMID- 26930045 TI - Abnormal thyroid function parameters in the second trimester of pregnancy are associated with breech presentation at term: a nested cohort study. AB - OBJECTIVE: Thyroid dysfunction has been described as a possible risk factor for having an abnormal fetal position at birth. In this study we aim to determine the association between thyroid function in early pregnancy and breech presentation at term. STUDY DESIGN: We used data from the Amsterdam Born Children and their Development (ABCD) cohort. 3347 pregnant women were included between January 2003 and March 2004 in Amsterdam, the Netherlands. Thyroid function tests were performed between 5 and 37 weeks gestational age (median 12.9 weeks). The main outcome measure was the association between thyroid function in early pregnancy and breech presentation at term. Univariate and multivariate analysis were performed to determine the association between thyroid function and breech presentation. RESULTS: Increased TSH in pregnancy, defined as thyroid stimulating hormone (TSH) >97.5th percentile (>3.53mIU/L), was associated with a higher risk for breech presentation at term (aOR 2.32, CI 1.1-4.8, p=0.02) compared to euthyroidism (TSH between 2.5th and 97.5th percentile). After exclusion of overt hypothyroidism and hyperthyroidism the aOR was 2.34 (CI 1.1-5.0, p=0.03). Trimester specific analysis showed a significant association of increased TSH levels (>3.68mIU/L) in the second trimester with breech presentation (aOR 3.7, CI 1.7-7.8, p=0.001). In the second trimester low free thyroxine (FT4) <2.5th percentile (<6.7pmol/L) was also associated with breech presentation (aOR 2.5, CI 1.0-6.3, p=0.04). CONCLUSIONS: Increased TSH and decreased FT4 in the second trimester of pregnancy are associated with an increased risk for breech presentation at term. The association of abnormal thyroid parameters in the first of third trimester is still unclear. PMID- 26930046 TI - Exploring the Masculine Identity in the Context of HIV Prevention in Chile. AB - PURPOSE: This study aims to describe human immunodeficiency virus (HIV)-related knowledge and beliefs, as well as understanding attitudes towards masculinity in the context of HIV prevention, held among Chilean men. DESIGN: This study reports the qualitative findings of a sequential qualitative-quantitative mixed methodology study: Bringing men into HIV Prevention in Chile, NIH R01 TW007674 03. METHODS: Twenty in-depth interviews using a qualitative, descriptive approach to elicit information for the study were conducted among men residing in two communities of low socio-economic status in Santiago, Chile. FINDINGS: Content analysis of interviews revealed three main themes regarding machismo and how it relates to HIV: sexuality and machismo, the changing nature of machismo, and violence against women. CONCLUSIONS: Addressing HIV and intimate partner violence through developing education programs tailored to meet the needs of Chilean men are needed to include men in HIV prevention efforts. CLINICAL RELEVANCE: Specifically, incorporating ideas of what men consider healthy masculinity and working to destigmatize men who have sex with men are important steps in addressing the negative aspects of machismo. PMID- 26930047 TI - Diagnosis of Coronary Heart Diseases Using Gene Expression Profiling; Stable Coronary Artery Disease, Cardiac Ischemia with and without Myocardial Necrosis. AB - Cardiovascular disease (including coronary artery disease and myocardial infarction) is one of the leading causes of death in Europe, and is influenced by both environmental and genetic factors. With the recent advances in genomic tools and technologies there is potential to predict and diagnose heart disease using molecular data from analysis of blood cells. We analyzed gene expression data from blood samples taken from normal people (n = 21), non-significant coronary artery disease (n = 93), patients with unstable angina (n = 16), stable coronary artery disease (n = 14) and myocardial infarction (MI; n = 207). We used a feature selection approach to identify a set of gene expression variables which successfully differentiate different cardiovascular diseases. The initial features were discovered by fitting a linear model for each probe set across all arrays of normal individuals and patients with myocardial infarction. Three different feature optimisation algorithms were devised which identified two discriminating sets of genes, one using MI and normal controls (total genes = 6) and another one using MI and unstable angina patients (total genes = 7). In all our classification approaches we used a non-parametric k-nearest neighbour (KNN) classification method (k = 3). The results proved the diagnostic robustness of the final feature sets in discriminating patients with myocardial infarction from healthy controls. Interestingly it also showed efficacy in discriminating myocardial infarction patients from patients with clinical symptoms of cardiac ischemia but no myocardial necrosis or stable coronary artery disease, despite the influence of batch effects and different microarray gene chips and platforms. PMID- 26930049 TI - Seasonal variation in cutaneous melanoma incidence, link with recent UV levels: a population-based study in Belgium (2006-2011). AB - Our objective was to test the hypothesis of a short-term late-promoting effect of ultraviolet (UV) exposure on the development of cutaneous melanoma as an explanation for the summer peak in melanoma incidence. Therefore, we studied seasonal variation in melanoma incidence in relation to recent UV levels by direct UV measurements. Data from the Belgian Cancer Registry on invasive cutaneous melanoma diagnosed during 2006-2011 were used for analysis. Daily data on UV measurements in Belgium were obtained from the Royal Meteorological Institute. Simple and multiple negative binomial regression models were used to investigate the influence of recent UV levels on melanoma incidence. The sum of the mean UV doses in the 2 months before diagnosis was used as a proxy for recent UV exposure in the population. To include variable sunburn risks during the year, the categorical variable 'semester' was created. The incidence of melanoma in Belgium shows a distinct seasonal variation, with peaks in June or July. We found that part of this variation could be explained by the variation in dermatologic activity and, therefore, used this as an offset in our models. We found a linear relationship between melanoma incidence and UV dose in the 2 months preceding the diagnosis. UV levels had more impact in the first semester. The effect of UV levels was not modified by sex nor age. The interaction between anatomical site and UV levels was significant (P=0.002) and showed a higher effect on the upper and lower limbs compared with the head and neck and trunk. PMID- 26930048 TI - Gamma-interferon-inducible lysosomal thiol reductase is upregulated in human melanoma. AB - T-cell-mediated immunity has the ability to produce durable antimelanoma responses, resulting in improved survival of patients with advanced melanoma. Antigen presentation is a key determinant of T-cell responses. Gamma-interferon inducible lysosomal thiol reductase (GILT) is critical for MHC class II restricted presentation of multiple melanoma antigens to CD4+ T cells. However, GILT expression in melanoma has not been defined. We evaluated GILT and MHC class II expression in human primary and metastatic melanomas and nevi using immunohistochemical analysis. GILT staining in melanocytes was observed in 70% of primary and 58% of metastatic melanomas versus 0% of nevi. When present, the GILT staining intensity in melanocytes was typically faint. Both GILT and MHC class II expression were increased in melanocytes of primary and metastatic melanomas compared with nevi. GILT staining in antigen-presenting cells (APCs) was detected in 100% of primary and metastatic melanomas versus 31% of nevi, and it was typically intense. GILT expression was increased in APCs of primary and metastatic melanomas compared with nevi, whereas MHC class II had equivalent high expression in APCs of all melanocytic lesions. GILT staining in keratinocytes was detected in 67% of primary melanomas versus 14% of nevi and 6% of metastatic melanomas. GILT, but not MHC class II, expression was increased in keratinocytes of primary melanomas compared with nevi and metastases. GILT expression is anticipated to result in improved presentation of melanoma antigens and more effective antimelanoma T-cell responses. GILT expression may be a biomarker of immune recognition of melanoma. PMID- 26930050 TI - Uncontrolled Hypertension and Its Determinants in Patients with Concomitant Type 2 Diabetes Mellitus (T2DM) in Rural South Africa. AB - BACKGROUND: Paucity of data on the prevalence, treatment and control of hypertension in individuals living with type 2 diabetes mellitus (T2DM) in the rural communities of South Africa may undermine efforts to reduce the morbidity and mortality associated with cardiovascular diseases. This study examines the socio-demographic and clinical determinants of uncontrolled hypertension among individuals living with T2DM in the rural communities of Mthatha, South Africa. METHODS: This cross-sectional study involved a serially selected sample of 265 individuals living with T2DM and hypertension at Mthatha General Hospital, Mthatha. Uncontrolled hypertension was defined as systolic blood pressure greater than or equal to 140 mmHg and diastolic blood pressure greater than or equal to 90mmHg in accordance with the Eight Joint National Committee Report (JNC 8) (2014). We performed univariate and multivariate logistic regression analyses to identify the significant determinants of uncontrolled hypertension. RESULTS: Of the total participants (n = 265), the prevalence of uncontrolled hypertension was 75.5% (n = 200). In univariate analysis of all participants, male gender (p = 0.029), age>=65 years (p = 0.016), unemployed status (p<0.0001), excessive alcohol intake (p = 0.005) and consumption of western-type diet (p<0.0001) were positively associated with uncontrolled hypertension. In multivariate logistic regression (LR method) analysis, unemployed status (p<0.0001), excessive alcohol intake (p = 0.007) and consumption of western-type diet (p<0.0001) were independently and significantly associated with uncontrolled hypertension. There is significant association between increasing number and classes of anti hypertensive drugs and uncontrolled hypertension (p = 0.05 and 0.02, respectively). CONCLUSION: Prevalence of uncontrolled hypertension was high in individuals with concomitant hypertension and T2DM in the study population. Male sex, aging, clinic inertia, unemployed status and nutritional transitions are the most important determinants of uncontrolled hypertension in T2DM in Mthatha, South Africa. Treatment to blood pressure targets, though feasible in our setting, would require concerted efforts by addressing these determinants and clinic inertia. PMID- 26930052 TI - How to Rank Journals. AB - There are now many methods available to assess the relative citation performance of peer-reviewed journals. Regardless of their individual faults and advantages, citation-based metrics are used by researchers to maximize the citation potential of their articles, and by employers to rank academic track records. The absolute value of any particular index is arguably meaningless unless compared to other journals, and different metrics result in divergent rankings. To provide a simple yet more objective way to rank journals within and among disciplines, we developed a kappa-resampled composite journal rank incorporating five popular citation indices: Impact Factor, Immediacy Index, Source-Normalized Impact Per Paper, SCImago Journal Rank and Google 5-year h-index; this approach provides an index of relative rank uncertainty. We applied the approach to six sample sets of scientific journals from Ecology (n = 100 journals), Medicine (n = 100), Multidisciplinary (n = 50); Ecology + Multidisciplinary (n = 25), Obstetrics & Gynaecology (n = 25) and Marine Biology & Fisheries (n = 25). We then cross compared the kappa-resampled ranking for the Ecology + Multidisciplinary journal set to the results of a survey of 188 publishing ecologists who were asked to rank the same journals, and found a 0.68-0.84 Spearman's rho correlation between the two rankings datasets. Our composite index approach therefore approximates relative journal reputation, at least for that discipline. Agglomerative and divisive clustering and multi-dimensional scaling techniques applied to the Ecology + Multidisciplinary journal set identified specific clusters of similarly ranked journals, with only Nature & Science separating out from the others. When comparing a selection of journals within or among disciplines, we recommend collecting multiple citation-based metrics for a sample of relevant and realistic journals to calculate the composite rankings and their relative uncertainty windows. PMID- 26930051 TI - Intra- and Interhemispheric Propagation of Electrophysiological Synchronous Activity and Its Modulation by Serotonin in the Cingulate Cortex of Juvenile Mice. AB - Disinhibition of the cortex (e.g., by GABA -receptor blockade) generates synchronous and oscillatory electrophysiological activity that propagates along the cortex. We have studied, in brain slices of the cingulate cortex of mice (postnatal age 14-20 days), the propagation along layer 2/3 as well as the interhemispheric propagation through the corpus callosum of synchronous discharges recorded extracellularly and evoked in the presence of 10 MUM bicuculline by electrical stimulation of layer 1. The latency of the responses obtained at the same distance from the stimulus electrode was longer in anterior cingulate cortex (ACC: 39.53 +/- 2.83 ms, n = 7) than in retrosplenial cortex slices (RSC: 21.99 +/- 2.75 ms, n = 5; p<0.05), which is equivalent to a lower propagation velocity in the dorso-ventral direction in ACC than in RSC slices (43.0 mm/s vs 72.9 mm/s). We studied the modulation of this propagation by serotonin. Serotonin significantly increased the latency of the intracortical synchronous discharges (18.9% in the ipsilateral hemisphere and 40.2% in the contralateral hemisphere), and also increased the interhemispheric propagation time by 86.4%. These actions of serotonin were mimicked by the activation of either 5-HT1B or 5-HT2A receptors, but not by the activation of the 5-HT1A subtype. These findings provide further knowledge about the propagation of synchronic electrical activity in the cerebral cortex, including its modulation by serotonin, and suggest the presence of deep differences between the ACC and RSC in the structure of the local cortical microcircuits underlying the propagation of synchronous discharges. PMID- 26930053 TI - Left Adrenal Gland Analysis in Lung Cancer Patients Using the Endobronchial Ultrasound Scope: A Feasibility Trial. AB - BACKGROUND: In lung cancer patients, the adrenal glands are predilection sites for distant metastases. Esophageal endoscopic ultrasound - fine-needle aspiration (EUS-FNA) is a minimally invasive and accurate method for left adrenal gland (LAG) analysis but requires a conventional gastrointestinal echoendoscope. Complete endobronchial and esophageal mediastinal nodal staging can be achieved by just a single endobronchial ultrasound (EBUS) scope, introducing it into the esophagus (EUS-B) following the endobronchial procedure. Whether the LAG can also be assessed with the EBUS scope is unknown. OBJECTIVES: The aim of the study was to investigate the feasibility of identifying the LAG with the EBUS scope. METHODS: We conducted a retrospective analysis of lung cancer patients who underwent EBUS and EUS-B for mediastinal staging and LAG assessment between January 2013 and May 2015. RESULTS: A total of 143 patients with (suspected) lung cancer were investigated by the combination of EBUS and EUS-B. In 68 of the 80 patients (85%) in whom an attempt was made to identify the LAG, it was feasible to transgastrically detect the LAG with the EBUS scope. In 9 patients with endosonographic signs of malignant involvement, diagnostic transgastric FNAs were obtained in all. In the 12 patients (15%) in whom the LAG was not detected, the contact between the ultrasound transducer and the gastric wall was suboptimal - the length of the scope was not a limiting factor. CONCLUSIONS: The EBUS scope allows identification of the LAG in the vast majority of lung cancer patients. IMPLICATION: In patients with (suspected) lung cancer, in addition to complete hilar and mediastinal staging, LAG assessment using just a single EBUS scope also seems feasible. Prospective studies are indicated. PMID- 26930054 TI - D-BRAIN: Anatomically Accurate Simulated Diffusion MRI Brain Data. AB - Diffusion Weighted (DW) MRI allows for the non-invasive study of water diffusion inside living tissues. As such, it is useful for the investigation of human brain white matter (WM) connectivity in vivo through fiber tractography (FT) algorithms. Many DW-MRI tailored restoration techniques and FT algorithms have been developed. However, it is not clear how accurately these methods reproduce the WM bundle characteristics in real-world conditions, such as in the presence of noise, partial volume effect, and a limited spatial and angular resolution. The difficulty lies in the lack of a realistic brain phantom on the one hand, and a sufficiently accurate way of modeling the acquisition-related degradation on the other. This paper proposes a software phantom that approximates a human brain to a high degree of realism and that can incorporate complex brain-like structural features. We refer to it as a Diffusion BRAIN (D-BRAIN) phantom. Also, we propose an accurate model of a (DW) MRI acquisition protocol to allow for validation of methods in realistic conditions with data imperfections. The phantom model simulates anatomical and diffusion properties for multiple brain tissue components, and can serve as a ground-truth to evaluate FT algorithms, among others. The simulation of the acquisition process allows one to include noise, partial volume effects, and limited spatial and angular resolution in the images. In this way, the effect of image artifacts on, for instance, fiber tractography can be investigated with great detail. The proposed framework enables reliable and quantitative evaluation of DW-MR image processing and FT algorithms at the level of large-scale WM structures. The effect of noise levels and other data characteristics on cortico-cortical connectivity and tractography based grey matter parcellation can be investigated as well. PMID- 26930055 TI - A Novel Brief Therapy for Patients Who Attempt Suicide: A 24-months Follow-Up Randomized Controlled Study of the Attempted Suicide Short Intervention Program (ASSIP). AB - BACKGROUND: Attempted suicide is the main risk factor for suicide and repeated suicide attempts. However, the evidence for follow-up treatments reducing suicidal behavior in these patients is limited. The objective of the present study was to evaluate the efficacy of the Attempted Suicide Short Intervention Program (ASSIP) in reducing suicidal behavior. ASSIP is a novel brief therapy based on a patient-centered model of suicidal behavior, with an emphasis on early therapeutic alliance. METHODS AND FINDINGS: Patients who had recently attempted suicide were randomly allocated to treatment as usual (n = 60) or treatment as usual plus ASSIP (n = 60). ASSIP participants received three therapy sessions followed by regular contact through personalized letters over 24 months. Participants considered to be at high risk of suicide were included, 63% were diagnosed with an affective disorder, and 50% had a history of prior suicide attempts. Clinical exclusion criteria were habitual self-harm, serious cognitive impairment, and psychotic disorder. Study participants completed a set of psychosocial and clinical questionnaires every 6 months over a 24-month follow-up period. The study represents a real-world clinical setting at an outpatient clinic of a university hospital of psychiatry. The primary outcome measure was repeat suicide attempts during the 24-month follow-up period. Secondary outcome measures were suicidal ideation, depression, and health-care utilization. Furthermore, effects of prior suicide attempts, depression at baseline, diagnosis, and therapeutic alliance on outcome were investigated. During the 24 month follow-up period, five repeat suicide attempts were recorded in the ASSIP group and 41 attempts in the control group. The rates of participants reattempting suicide at least once were 8.3% (n = 5) and 26.7% (n = 16). ASSIP was associated with an approximately 80% reduced risk of participants making at least one repeat suicide attempt (Wald chi21 = 13.1, 95% CI 12.4-13.7, p < 0.001). ASSIP participants spent 72% fewer days in the hospital during follow-up (ASSIP: 29 d; control group: 105 d; W = 94.5, p = 0.038). Higher scores of patient-rated therapeutic alliance in the ASSIP group were associated with a lower rate of repeat suicide attempts. Prior suicide attempts, depression, and a diagnosis of personality disorder at baseline did not significantly affect outcome. Participants with a diagnosis of borderline personality disorder (n = 20) had more previous suicide attempts and a higher number of reattempts. Key study limitations were missing data and dropout rates. Although both were generally low, they increased during follow-up. At 24 months, the group difference in dropout rate was significant: ASSIP, 7% (n = 4); control, 22% (n = 13). A further limitation is that we do not have detailed information of the co active follow-up treatment apart from participant self-reports every 6 months on the setting and the duration of the co-active treatment. CONCLUSIONS: ASSIP, a manual-based brief therapy for patients who have recently attempted suicide, administered in addition to the usual clinical treatment, was efficacious in reducing suicidal behavior in a real-world clinical setting. ASSIP fulfills the need for an easy-to-administer low-cost intervention. Large pragmatic trials will be needed to conclusively establish the efficacy of ASSIP and replicate our findings in other clinical settings. TRIAL REGISTRATION: ClinicalTrials.gov NCT02505373. PMID- 26930056 TI - Identification and Comparative Study of Chemosensory Genes Related to Host Selection by Legs Transcriptome Analysis in the Tea Geometrid Ectropis obliqua. AB - Host selection by female moths is fundamental to the survival of their larvae. Detecting and perceiving the non-volatile chemicals of the plant surface involved in gustatory detection determine the host preference. In many lepidopteran species, tarsal chemosensilla are sensitive to non-volatile chemicals and responsible for taste detection. The tea geometrid Ectropis obliqua is one devastating chewing pest selectively feeding on limited plants, requiring the specialized sensors to forage certain host for oviposition. In present study, we revealed the distribution of chemosensilla in the ventral side of female fifth tarsomere in E. obliqua. To investigate its molecular mechanism of gustatory perception, we performed HiSeq 2500 sequencing of the male- and female- legs transcriptome and identified 24 candidate odorant binding proteins (OBPs), 21 chemosensory proteins (CSPs), 2 sensory neuron membrane proteins (SNMPs), 3 gustatory receptors (GRs) and 4 odorant receptors (ORs). Several leg-specific or enriched chemosensory genes were screened by tissue expression analysis, and clustered with functionally validated genes from other moths, suggesting the potential involvement in taste sensation or other physiological processes. The RPKM value analysis revealed that 9 EoblOBPs showed sex discrepancy in the leg expression, 8 being up-regulated in female and only 1 being over expressed in male. These female-biased EoblOBPs indicated an ecological adaption related with host-seeking and oviposition behaviors. Our work will provide basic knowledge for further studies on the molecular mechanism of gustatory perception, and enlighten a host-selection-based control strategy of insect pests. PMID- 26930058 TI - Contact Bioassays with Phenoxybenzyl and Tetrafluorobenzyl Pyrethroids against Target-Site and Metabolic Resistant Mosquitoes. AB - BACKGROUND: Mosquito strains that exhibit increased tolerance to the chemical class of compounds with a sodium channel modulator mode of action (pyrethroids and pyrethrins) are typically described as "pyrethroid resistant". Resistance to pyrethroids is an increasingly important challenge in the control of mosquito borne diseases, such as malaria or dengue, because one of the main interventions (the distribution of large numbers of long-lasting insecticide-treated bed nets) currently relies entirely on long-lasting pyrethroids. Increasing tolerance of target insects against this class of insecticides lowers their impact in vector control. The current study suggests that the level of metabolic resistance depends on the structure of the molecule and that structurally different compounds may still be effective because detoxifying enzymes are unable to bind to these uncommon structures. METHODS: Treated surface contact bioassays were performed on susceptible Aedes aegypti, East African knockdown resistance (kdr) Anopheles gambiae (strain RSP-H) and metabolically resistant Anopheles funestus (strain FUMOZ-R) with different pyrethroids, such as cypermethrin, beta cyfluthrin, deltamethrin, permethrin and transfluthrin (alone and in combination with the synergist piperonyl butoxide). The nonfluorinated form of transfluthrin was also assessed as a single agent and in combination with piperonyl butoxide. RESULTS: Although the dosages for pyrethroids containing a phenoxybenzyl moiety have exhibited differences in terms of effectiveness among the three tested mosquito species, the structurally different transfluthrin with a polyfluorobenzyl moiety remained active in mosquitoes with upregulated P450 levels. In trials with transfluthrin mixed with piperonyl butoxide, the added synergist exhibited no efficacy-enhancing effect. CONCLUSION: The results of this study suggest that transfluthrin has the potential to control P450-mediated metabolically resistant mosquitoes because the structural formula of transfluthrin differs from that of the tested pyrethroids, which are used in vector control. The P450-detoxifying enzymes of the Anopheles funestus FUMOZ-R mosquitoes seem to bind preferably at the phenoxybenzyl moiety and appear to be unable to degrade transfluthrin with its tetrafluorobenzyl moiety. Inhibition of the class of monooxygenases by piperonyl butoxide revealed no increase of efficacy of the pure transfluthrin compound, which also indicates that the P450 enzymes potentially do not impact the efficacy of transfluthrin. PMID- 26930057 TI - Prevalence of Failure due to Adverse Reaction to Metal Debris in Modern, Medium and Large Diameter Metal-on-Metal Hip Replacements--The Effect of Novel Screening Methods: Systematic Review and Metaregression Analysis. AB - Metal-on-metal (MoM) hip replacements were used for almost a decade before adverse reactions to metal debris (ARMD) were found to be a true clinical problem. Currently, there is a paucity of evidence regarding the usefulness of systematic screening for ARMD. We implemented a systematic review and meta analysis to establish the prevalence of revision confirmed ARMD stratified by the use of different screening protocols in patients with MoM hip replacements. Five levels of screening were identified: no screening (level 0), targeted blood metal ion measurement and/or cross-sectional imaging (level 1), metal ion measurement without imaging (level 2), metal ion measurement with targeted imaging (level 3) and comprehensive screening (both metal ions and imaging for all; level 4). 122 studies meeting our eligibility criteria were included in analysis. These studies included 144 study arms: 100 study arms with hip resurfacings, 33 study arms with large-diameter MoM total hip replacements (THR), and 11 study arms with medium diameter MoM THRs. For hip resurfacing, the lowest prevalence of ARMD was seen with level 0 screening (pooled prevalence 0.13%) and the highest with level 4 screening (pooled prevalace 9.49%). Pooled prevalence of ARMD with level 0 screening was 0.29% and with level 4 screening 21.3% in the large-diameter MoM THR group. In metaregression analysis of hip resurfacings, level 4 screening was superior with regard to prevalence of ARMD when compared with other levels. In the large diameter THR group level 4 screening was superior to screening 0,2 and 3. These outcomes were irrespective of follow-up time or study publication year. With hip resurfacings, routine cross-sectional imaging regardless of clinical findings is advisable. It is clear, however, that targeted metal ion measurement and/or imaging is not sufficient in the screening for ARMD in any implant concepts. However, economic aspects should be weighed when choosing the preferred screening level. PMID- 26930059 TI - Distinct Contributions of Astrocytes and Pericytes to Neuroinflammation Identified in a 3D Human Blood-Brain Barrier on a Chip. AB - Neurovascular inflammation is a major contributor to many neurological disorders, but modeling these processes in vitro has proven to be difficult. Here, we microengineered a three-dimensional (3D) model of the human blood-brain barrier (BBB) within a microfluidic chip by creating a cylindrical collagen gel containing a central hollow lumen inside a microchannel, culturing primary human brain microvascular endothelial cells on the gel's inner surface, and flowing medium through the lumen. Studies were carried out with the engineered microvessel containing endothelium in the presence or absence of either primary human brain pericytes beneath the endothelium or primary human brain astrocytes within the surrounding collagen gel to explore the ability of this simplified model to identify distinct contributions of these supporting cells to the neuroinflammatory response. This human 3D BBB-on-a-chip exhibited barrier permeability similar to that observed in other in vitro BBB models created with non-human cells, and when stimulated with the inflammatory trigger, tumor necrosis factor-alpha (TNF-alpha), different secretion profiles for granulocyte colony-stimulating factor (G-CSF) and interleukin-6 (IL-6) were observed depending on the presence of astrocytes or pericytes. Importantly, the levels of these responses detected in the 3D BBB chip were significantly greater than when the same cells were co-cultured in static Transwell plates. Thus, as G-CSF and IL 6 have been reported to play important roles in neuroprotection and neuroactivation in vivo, this 3D BBB chip potentially offers a new method to study human neurovascular function and inflammation in vitro, and to identify physiological contributions of individual cell types. PMID- 26930060 TI - Structure of the Response Regulator NsrR from Streptococcus agalactiae, Which Is Involved in Lantibiotic Resistance. AB - Lantibiotics are antimicrobial peptides produced by Gram-positive bacteria. Interestingly, several clinically relevant and human pathogenic strains are inherently resistant towards lantibiotics. The expression of the genes responsible for lantibiotic resistance is regulated by a specific two-component system consisting of a histidine kinase and a response regulator. Here, we focused on a response regulator involved in lantibiotic resistance, NsrR from Streptococcus agalactiae, and determined the crystal structures of its N-terminal receiver domain and C-terminal DNA-binding effector domain. The C-terminal domain exhibits a fold that classifies NsrR as a member of the OmpR/PhoB subfamily of regulators. Amino acids involved in phosphorylation, dimerization, and DNA binding were identified and demonstrated to be conserved in lantibiotic resistance regulators. Finally, a model of the full-length NsrR in the active and inactive state provides insights into protein dimerization and DNA-binding. PMID- 26930061 TI - Feedback on the Rate and Depth of Chest Compressions during Cardiopulmonary Resuscitation Using Only Accelerometers. AB - BACKGROUND: Quality of cardiopulmonary resuscitation (CPR) is key to increase survival from cardiac arrest. Providing chest compressions with adequate rate and depth is difficult even for well-trained rescuers. The use of real-time feedback devices is intended to contribute to enhance chest compression quality. These devices are typically based on the double integration of the acceleration to obtain the chest displacement during compressions. The integration process is inherently unstable and leads to important errors unless boundary conditions are applied for each compression cycle. Commercial solutions use additional reference signals to establish these conditions, requiring additional sensors. Our aim was to study the accuracy of three methods based solely on the acceleration signal to provide feedback on the compression rate and depth. MATERIALS AND METHODS: We simulated a CPR scenario with several volunteers grouped in couples providing chest compressions on a resuscitation manikin. Different target rates (80, 100, 120, and 140 compressions per minute) and a target depth of at least 50 mm were indicated. The manikin was equipped with a displacement sensor. The accelerometer was placed between the rescuer's hands and the manikin's chest. We designed three alternatives to direct integration based on different principles (linear filtering, analysis of velocity, and spectral analysis of acceleration). We evaluated their accuracy by comparing the estimated depth and rate with the values obtained from the reference displacement sensor. RESULTS: The median (IQR) percent error was 5.9% (2.8-10.3), 6.3% (2.9-11.3), and 2.5% (1.2-4.4) for depth and 1.7% (0.0-2.3), 0.0% (0.0-2.0), and 0.9% (0.4-1.6) for rate, respectively. Depth accuracy depended on the target rate (p < 0.001) and on the rescuer couple (p < 0.001) within each method. CONCLUSIONS: Accurate feedback on chest compression depth and rate during CPR is possible using exclusively the chest acceleration signal. The algorithm based on spectral analysis showed the best performance. Despite these encouraging results, further research should be conducted to asses the performance of these algorithms with clinical data. PMID- 26930063 TI - Preface. PMID- 26930062 TI - Osteoinductive Effects of Free and Immobilized Bone Forming Peptide-1 on Human Adipose-Derived Stem Cells. AB - Most synthetic polymeric materials currently used for bone tissue engineering lack specific signals through which cells can identify and interact with the surface, resulting in incompatibility and compromised osteogenic activity. Soluble inductive factors also have issues including a short half-live in vivo. Bone forming peptide-1 is a truncated peptide from the immature form of bone morphogenetic protein-7 (BMP-7) that displays higher osteogenic activity than full-length, mature BMP-7. In this study, we used a mussel-inspired immobilization strategy mediated by polymerization of dopamine to introduce recently discovered stimulators of bone forming peptide-1 (BFP-1) onto the surface of poly-lactic-co-glycolic acid (PLGA) substrate to form a biomaterial that overcomes these challenges. Human adipose-derived stem cells (hASCs), being abundant and easy accessible, were used to test the osteogenic activity of BFP-1 and the novel biomaterial. Under osteoinductive conditions, cells treated with both BFP-1 alone and BFP-1-coated biomaterials displayed elevated expression of the osteogenic markers alkaline phosphatase (ALP), osteocalcin (OC), and RUNX2. Furthermore, hASCs associated with poly-dopamine-assisted BFP-1-immobilized PLGA (pDA-BFP-1-PLGA) scaffolds promoted in vivo bone formation in nude mice. Our novel materials may hold great promise for future bone tissue engineering applications. PMID- 26930064 TI - The Association between Job-Related Psychosocial Factors and Prolonged Fatigue among Industrial Employees in Taiwan. AB - BACKGROUND AND OBJECTIVES: Prolonged fatigue is common among employees, but the relationship between prolonged fatigue and job-related psychosocial factors is seldom studied. This study aimed (1) to assess the individual relations of physical condition, psychological condition, and job-related psychosocial factors to prolonged fatigue among employees, and (2) to clarify the associations between job-related psychosocial factors and prolonged fatigue using hierarchical regression when demographic characteristics, physical condition, and psychological condition were controlled. METHODS: A cross-sectional study was employed. A questionnaire was used to obtain information pertaining to demographic characteristics, physical condition (perceived physical health and exercise routine), psychological condition (perceived mental health and psychological distress), job-related psychosocial factors (job demand, job control, and workplace social support), and prolonged fatigue. RESULTS: A total of 3,109 employees were recruited. Using multiple regression with controlled demographic characteristics, psychological condition explained 52.0% of the variance in prolonged fatigue. Physical condition and job-related psychosocial factors had an adjusted R2 of 0.370 and 0.251, respectively. Hierarchical multiple regression revealed that, among job-related psychosocial factors, job demand and job control showed significant associations with fatigue. CONCLUSION: Our findings highlight the role of job demand and job control, in addition to the role of perceived physical health, perceived mental health, and psychological distress, in workers' prolonged fatigue. However, more research is required to verify the causation among all the variables. PMID- 26930066 TI - Spillover Effects of Loss of Control on Risky Decision-Making. AB - Decision making in risky situations is frequently required in our everyday lives and has been shown to be influenced by various factors, some of which are independent of the risk context. Based on previous findings and theories about the central role of perceptions of control and their impact on subsequent settings, spillover effects of subjective loss of control on risky decision making are assumed. After developing an innovative experimental paradigm for inducing loss of control, its hypothesized effects on risky decision-making are investigated. Partially supporting the hypotheses, results demonstrated no increased levels of risk perceptions but decreased risk-taking behavior following experiences of loss of control. Thus, this study makes a methodological contribution by proposing a newly developed experimental paradigm facilitating further research on the effects of subjective loss of control, and additionally provides partial evidence for the spillover effects of loss of control experiences on risky decision-making. PMID- 26930065 TI - Dynamic Modeling and Analysis of the Cross-Talk between Insulin/AKT and MAPK/ERK Signaling Pathways. AB - Feedback loops play a key role in the regulation of the complex interactions in signal transduction networks. By studying the network of interactions among the biomolecules present in signaling pathways at the systems level, it is possible to understand how the biological functions are regulated and how the diseases emerge from their deregulations. This paper identifies the key feedback loops involved in the cross-talk among the insulin-AKT and MAPK/ERK signaling pathways. We developed a mathematical model that can be used to study the steady-state and dynamic behavior of the interactions among these two important signaling pathways. Modeling analysis and simulation case studies identify the key interaction parameters and the feedback loops that determine the normal and disease phenotypes. PMID- 26930067 TI - Gtsf1l and Gtsf2 Are Specifically Expressed in Gonocytes and Spermatids but Are Not Essential for Spermatogenesis. AB - The unknown protein family 0224 (UPF0224) includes three members that are expressed in germ-line cells in mice: Gtsf1, Gtsf1l, and BC048502 (Gtsf2). These genes produce proteins with two repeats of the CHHC Zn-finger domain, a predicted RNA-binding motif, in the N terminus. We previously reported that Gtsf1 is essential for spermatogenesis and retrotransposon suppression. In this study, we investigated the expression patterns and functions of Gtsf1l and Gtsf2. Interestingly, Gtsf1l and Gtsf2 were found to be sequentially but not simultaneously expressed in gonocytes and spermatids. Pull-down experiments showed that both GTSF1L and GTSF2 can interact with PIWI-protein complexes. Nevertheless, knocking out Gtsf1, Gtsf2, or both did not cause defects in spermatogenesis or retrotransposon suppression in mice. PMID- 26930068 TI - Immunopotentiation of Different Adjuvants on Humoral and Cellular Immune Responses Induced by HA1-2 Subunit Vaccines of H7N9 Influenza in Mice. AB - In spring 2013, human infections with a novel avian influenza A (H7N9) virus were reported in China. The number of cases has increased with over 200 mortalities reported to date. However, there is currently no vaccine available for the H7 subtype of influenza A virus. Virus-specific cellular immune responses play a critical role in virus clearance during influenza infection. In this study, we undertook a side-by-side evaluation of two different adjuvants, Salmonella typhimurium flagellin (fliC) and polyethyleneimine (PEI), through intraperitoneal administration to assess their effects on the immunogenicity of the recombinant HA1-2 subunit vaccine of H7N9 influenza. The fusion protein HA1-2-fliC and HA1-2 combined with PEI could induce significantly higher HA1-2-specific IgG and hemagglutination inhibition titers than HA1-2 alone at 12 days post-boost, with superior HA1-2 specific IgG titers in the HA1-2-fliC group compared with the PEI adjuvanted group. The PEI adjuvanted vaccine induced higher IgG1/IgG2a ratio and significantly increased numbers of IFN-gamma- and IL-4-producing cells than HA1-2 alone, suggesting a mixed Th1/Th2-type cellular immune response with a Th2 bias. Meanwhile, the HA1-2-fliC induced higher IgG2a and IgG1 levels, which is indicative of a mixed Th1/Th2-type profile. Consistent with this, significant levels, and equal numbers, of IFN-gamma- and IL-4-producing cells were detected after HA1-2-fliC vaccination. Moreover, the marked increase in CD69 expression and the proliferative index with the HA1-2-fliC and PEI adjuvanted vaccines indicated that both adjuvanted vaccine candidates effectively induced antigen specific cellular immune responses. Taken together, our findings indicate that the two adjuvanted vaccine candidates elicit effective and HA1-2-specific humoral and cellular immune responses, offering significant promise for the development of a successful recombinant HA1-2 subunit vaccine for H7N9 influenza. PMID- 26930070 TI - The Arabidopsis Domain of Unknown Function 1218 (DUF1218) Containing Proteins, MODIFYING WALL LIGNIN-1 and 2 (At1g31720/MWL-1 and At4g19370/MWL-2) Function Redundantly to Alter Secondary Cell Wall Lignin Content. AB - DUF1218 is a land plant-specific innovation and has previously been shown to be associated with cell wall biology, vasculature patterning and abiotic/biotic stress response. The Arabidopsis genome encodes 15 members, two of which (At1g31720 and At4g27435) are preferentially expressed in the secondary cell wall depositing inflorescence stems. To further our understanding of the roles of DUF1218-containing proteins in secondary cell wall biology, we functionally characterized At1g31720 (herein referred to as MODIFYING WALL LIGNIN-1 or MWL-1). Since related gene family members may contribute to functional redundancy, we also characterized At4g19370 (MWL-2), the most closely related gene to MWL-1 in the protein family. Subcellular localization revealed that both Arabidopsis proteins are targeted to the cell periphery. The single T-DNA knockout lines, mwl 1 and mwl-2, and independent overexpression lines showed no significant differences in plant growth or changes in total lignin content relative to wild type (WT) control plants. However, the double homozygous mutant, mwl-1/mwl-2, had smaller rosettes with a significant decrease in rosette fresh weight and stem height relative to the WT control at four weeks and six weeks, respectively. Moreover, mwl-1/mwl-2 showed a significant reduction in total lignin content (by ca. 11% relative to WT) and an increase in syringyl/guaiacyl (S/G) monomer ratio relative to the control plants. Our study has identified two additional members of the DUF1218 family in Arabidopsis as novel contributors to secondary cell wall biology, specifically lignin biosynthesis, and these proteins appear to function redundantly. PMID- 26930071 TI - Embryonic Development of the Deer Mouse, Peromyscus maniculatus. AB - Deer mice, or Peromyscus maniculatus, are an emerging model system for use in biomedicine. P. maniculatus are similar in appearance to laboratory mice, Mus musculus, but are more closely related to hamsters than to Mus. The laboratory strains of Peromyscus have captured a high degree of the genetic variability observed in wild populations, and are more similar to the genetic variability observed in humans than are laboratory strains of Mus. The Peromyscus Genetic Stock Center at the University of South Carolina maintains several lines of Peromyscus harboring mutations that result in developmental defects. We present here a description of P. maniculatus development from gastrulation to late gestation to serve as a guide for researchers interested in pursuing developmental questions in Peromyscus. PMID- 26930072 TI - Correction: On the Viability of Conspiratorial Beliefs. PMID- 26930069 TI - Variations in Multiple Birth Rates and Impact on Perinatal Outcomes in Europe. AB - OBJECTIVE: Infants from multiple pregnancies have higher rates of preterm birth, stillbirth and neonatal death and differences in multiple birth rates (MBR) exist between countries. We aimed to describe differences in MBR in Europe and to investigate the impact of these differences on adverse perinatal outcomes at a population level. METHODS: We used national aggregate birth data on multiple pregnancies, maternal age, gestational age (GA), stillbirth and neonatal death collected in the Euro-Peristat project (29 countries in 2010, N = 5 074 643 births). We also used European Society of Human Reproduction and Embryology (ESHRE) data on assisted conception and single embryo transfer (SET). The impact of MBR on outcomes was studied using meta-analysis techniques with random-effects models to derive pooled risk ratios (pRR) overall and for four groups of country defined by their MBR. We computed population attributable risks (PAR) for these groups. RESULTS: In 2010, the average MBR was 16.8 per 1000 women giving birth, ranging from 9.1 (Romania) to 26.5 (Cyprus). Compared to singletons, multiples had a nine-fold increased risk (pRR 9.4, 95% Cl 9.1-9.8) of preterm birth (<37 weeks GA), an almost 12-fold increased risk (pRR 11.7, 95% CI 11.0-12.4) of very preterm birth (<32 weeks GA). Pooled RR were 2.4 (95% Cl 1.5-3.6) for fetal mortality at or after 28 weeks GA and 7.0 (95% Cl 6.1-8.0) for neonatal mortality. PAR of neonatal death and very preterm birth were higher in countries with high MBR compared to low MBR (17.1% (95% CI 13.8-20.2) versus 9.8% (95% Cl 9.6-11.0) for neonatal death and 29.6% (96% CI 28.5-30.6) versus 17.5% (95% CI 15.7-18.3) for very preterm births, respectively). CONCLUSIONS: Wide variations in MBR and their impact on population outcomes imply that efforts by countries to reduce MBR could improve perinatal outcomes, enabling better long-term child health. PMID- 26930073 TI - Three-Directional Evaluation of Mitral Flow in the Rat Heart by Phase-Contrast Cardiovascular Magnetic Resonance. AB - PURPOSE: Determination of mitral flow is an important aspect in assessment of cardiac function. Traditionally, mitral flow is measured by Doppler echocardiography which suffers from several challenges, particularly related to the direction and the spatial inhomogeneity of flow. These challenges are especially prominent in rodents. The purpose of this study was to establish a cardiovascular magnetic resonance (CMR) protocol for evaluation of three directional mitral flow in a rodent model of cardiac disease. MATERIALS AND METHODS: Three-directional mitral flow were evaluated by phase contrast CMR (PC CMR) in rats with aortic banding (AB) (N = 7) and sham-operated controls (N = 7). Peak mitral flow and deceleration rate from PC-CMR was compared to conventional Doppler echocardiography. The accuracy of PC-CMR was investigated by comparison of spatiotemporally integrated mitral flow with left ventricular stroke volume assessed by cine CMR. RESULTS: PC-CMR portrayed the spatial distribution of mitral flow and flow direction in the atrioventricular plane throughout diastole. Both PC-CMR and echocardiography demonstrated increased peak mitral flow velocity and higher deceleration rate in AB compared to sham. Comparison with cine CMR revealed that PC-CMR measured mitral flow with excellent accuracy. Echocardiography presented significantly lower values of flow compared to PC-CMR. CONCLUSIONS: For the first time, we show that PC-CMR offers accurate evaluation of three-directional mitral blood flow in rodents. The method successfully detects alterations in the mitral flow pattern in response to cardiac disease and provides novel insight into the characteristics of mitral flow. PMID- 26930074 TI - Comparative Epidemiology of Human Infections with Middle East Respiratory Syndrome and Severe Acute Respiratory Syndrome Coronaviruses among Healthcare Personnel. AB - The largest nosocomial outbreak of Middle East respiratory syndrome (MERS) occurred in South Korea in 2015. Health Care Personnel (HCP) are at high risk of acquiring MERS-Coronavirus (MERS-CoV) infections, similar to the severe acute respiratory syndrome (SARS)-Coronavirus (SARS-CoV) infections first identified in 2003. This study described the similarities and differences in epidemiological and clinical characteristics of 183 confirmed global MERS cases and 98 SARS cases in Taiwan associated with HCP. The epidemiological findings showed that the mean age of MERS-HCP and total MERS cases were 40 (24~74) and 49 (2~90) years, respectively, much older than those in SARS [SARS-HCP: 35 (21~68) years, p = 0.006; total SARS: 42 (0~94) years, p = 0.0002]. The case fatality rates (CFR) was much lower in MERS-HCP [7.03% (9/128)] or SARS-HCP [12.24% (12/98)] than the MERS-non-HCP [36.96% (34/92), p<0.001] or SARS-non-HCP [24.50% (61/249), p<0.001], however, no difference was found between MERS-HCP and SARS-HCP [p = 0.181]. In terms of clinical period, the days from onset to death [13 (4~17) vs 14.5 (0~52), p = 0.045] and to discharge [11 (5~24) vs 24 (0~74), p = 0.010] and be hospitalized days [9.5 (3~22) vs 22 (0~69), p = 0.040] were much shorter in MERS-HCP than SARS-HCP. Similarly, days from onset to confirmation were shorter in MERS-HCP than MERS-non-HCP [6 (1~14) vs 10 (1~21), p = 0.044]. In conclusion, the severity of MERS-HCP and SARS-HCP was lower than that of MERS-non-HCP and SARS-non-HCP due to younger age and early confirmation in HCP groups. However, no statistical difference was found in MERS-HCP and SARS-HCP. Thus, prevention of nosocomial infections involving both novel Coronavirus is crucially important to protect HCP. PMID- 26930075 TI - Can Staining of Damaged Proteins in Urine Effectively Predict Preeclampsia? AB - OBJECTIVES: To assess Congo red urine test in the first trimester for preeclampsia (PE) prediction. SAMPLE: A Congo red test was developed with a cohort of 81 pregnant women in Bnai Zion hospital, Israel, at 26-41 weeks of gestation (12 PE cases). The test was then applied to a first-trimester cohort of 642 women at King's College Hospital, UK (105 subsequently developed PE, 21 early, i.e., <34 weeks; 537 controls). METHODS: Urine samples were spotted onto nitrocellulose membranes, stained with Congo red, de-stained, dried and quantified with imager and densitometry. RESULTS: At PE signs and symptoms, the detection rate (DR) was 93% and the false-positive rate (FPR) 4%. However, with first-trimester urine samples, the DR was 33.3%, 16.1% and 20% for early, late and all PE cases, respectively, at 12.8% FPR. The odds ratio (OR) for PE by Congo red alone (including adjusted OR) was superior to body mass index and mean arterial blood pressure (MAP) but inferior to previous PE and black ethnicity. Combining all five parameters generated an adjusted OR of 13.92 for PE (p < 0.001). CONCLUSION: Congo red urine test at PE verifies the disorder. In the first trimester, it adds accuracy for PE prediction in obese, black women, who had previous PE and over-average MAP. PMID- 26930076 TI - Homology Directed Knockin of Point Mutations in the Zebrafish tardbp and fus Genes in ALS Using the CRISPR/Cas9 System. AB - The methodology for site-directed editing of single nucleotides in the vertebrate genome is of considerable interest for research in biology and medicine. The clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR associated protein 9 type II (Cas9) system has emerged as a simple and inexpensive tool for editing genomic loci of interest in a variety of animal models. In zebrafish, error-prone non-homologous end joining (NHEJ) has been used as a simple method to disrupt gene function. We sought to develop a method to easily create site-specific SNPs in the zebrafish genome. Here, we report simple methodologies for using CRISPR/Cas9-mediated homology directed repair using single-stranded oligodeoxynucleotide donor templates (ssODN) for site-directed single nucleotide editing, for the first time in two disease-related genes, tardbp and fus. PMID- 26930077 TI - Spatially Extended Relativistic Particles Out of Traveling Front Solutions of Sine-Gordon Equation in (1+2) Dimensions. AB - Slower-than-light multi-front solutions of the Sine-Gordon in (1+2) dimensions, constructed through the Hirota algorithm, are mapped onto spatially localized structures, which emulate free, spatially extended, massive relativistic particles. A localized structure is an image of the junctions at which the fronts intersect. It propagates together with the multi-front solution at the velocity of the latter. The profile of the localized structure obeys the linear wave equation in (1+2) dimensions, to which a term that represents interaction with a slower-than-light, Sine-Gordon-multi-front solution has been added. This result can be also formulated in terms of a (1+2)-dimensional Lagrangian system, in which the Sine-Gordon and wave equations are coupled. Expanding the Euler Lagrange equations in powers of the coupling constant, the zero-order part of the solution reproduces the (1+2)-dimensional Sine-Gordon fronts. The first-order part is the spatially localized structure. PACS: 02.30.Ik, 03.65.Pm, 05.45.Yv, 02.30.Ik. PMID- 26930080 TI - Trailblazers & Peacekeepers: Exhibition Review. PMID- 26930081 TI - Guest Editor. PMID- 26930079 TI - Abnormal Fixational Eye Movements in Amblyopia. AB - PURPOSE: Fixational saccades shift the foveal image to counteract visual fading related to neural adaptation. Drifts are slow eye movements between two adjacent fixational saccades. We quantified fixational saccades and asked whether their changes could be attributed to pathologic drifts seen in amblyopia, one of the most common causes of blindness in childhood. METHODS: Thirty-six pediatric subjects with varying severity of amblyopia and eleven healthy age-matched controls held their gaze on a visual target. Eye movements were measured with high-resolution video-oculography during fellow eye-viewing and amblyopic eye viewing conditions. Fixational saccades and drifts were analyzed in the amblyopic and fellow eye and compared with controls. RESULTS: We found an increase in the amplitude with decreased frequency of fixational saccades in children with amblyopia. These alterations in fixational eye movements correlated with the severity of their amblyopia. There was also an increase in eye position variance during drifts in amblyopes. There was no correlation between the eye position variance or the eye velocity during ocular drifts and the amplitude of subsequent fixational saccade. Our findings suggest that abnormalities in fixational saccades in amblyopia are independent of the ocular drift. DISCUSSION: This investigation of amblyopia in pediatric age group quantitatively characterizes the fixation instability. Impaired properties of fixational saccades could be the consequence of abnormal processing and reorganization of the visual system in amblyopia. Paucity in the visual feedback during amblyopic eye-viewing condition can attribute to the increased eye position variance and drift velocity. PMID- 26930082 TI - SI. The World War I Military Service of Paul M. Wood. PMID- 26930078 TI - Genome-Wide Association Studies of Anthracnose and Angular Leaf Spot Resistance in Common Bean (Phaseolus vulgaris L.). AB - The common bean (Phaseolus vulgaris L.) is the world's most important legume for human consumption. Anthracnose (ANT; Colletotrichum lindemuthianum) and angular leaf spot (ALS; Pseudocercospora griseola) are complex diseases that cause major yield losses in common bean. Depending on the cultivar and environmental conditions, anthracnose and angular leaf spot infections can reduce crop yield drastically. This study aimed to estimate linkage disequilibrium levels and identify quantitative resistance loci (QRL) controlling resistance to both ANT and ALS diseases of 180 accessions of common bean using genome-wide association analysis. A randomized complete block design with four replicates was performed for the ANT and ALS experiments, with four plants per genotype in each replicate. Association mapping analyses were performed for ANT and ALS using a mixed linear model approach implemented in TASSEL. A total of 17 and 11 significant statistically associations involving SSRs were detected for ANT and ALS resistance loci, respectively. Using SNPs, 21 and 17 significant statistically associations were obtained for ANT and angular ALS, respectively, providing more associations with this marker. The SSR-IAC167 and PvM95 markers, both located on chromosome Pv03, and the SNP scaffold00021_89379, were associated with both diseases. The other markers were distributed across the entire common bean genome, with chromosomes Pv03 and Pv08 showing the greatest number of loci associated with ANT resistance. The chromosome Pv04 was the most saturated one, with six markers associated with ALS resistance. The telomeric region of this chromosome showed four markers located between approximately 2.5 Mb and 4.4 Mb. Our results demonstrate the great potential of genome-wide association studies to identify QRLs related to ANT and ALS in common bean. The results indicate a quantitative and complex inheritance pattern for both diseases in common bean. Our findings will contribute to more effective screening of elite germplasm to find resistance alleles for marker-assisted selection in breeding programs. PMID- 26930083 TI - S3. The Outlook of Physician Histories: J. Marion Sims and "The Discovery of Anesthesia". PMID- 26930084 TI - S2. Medical Care During WW II in the Pacific: the Interaction and Cooperation Between New Zealand and American Armed Forces. PMID- 26930085 TI - S4. Using Paper Fold Analysis to Examine Postscripts and Marginalia Handwritten Upon a Missive that Launched the Ether Controversy. PMID- 26930086 TI - S5. The History and Evolution of Anesthetic Care in Rwanda. PMID- 26930087 TI - S6. General Anesthesia in Japan Around 1830. PMID- 26930088 TI - S7. The First Man who used a Laryngoscope in Japan. PMID- 26930089 TI - S8. American-Trained Chinese Anesthesiologists: How Are They Doing? PMID- 26930090 TI - S9. Nonanesthetic Uses of Ether During the Anesthesia Residency of Dr. Laurie Brown 1955-1957. PMID- 26930091 TI - S10. Methoxyflurane: Like a Phoenix Rising From the Ashes. PMID- 26930092 TI - S11. Pain is in the Eye of the Beholder. PMID- 26930093 TI - S12. Total Recall: the Evolution of Awake Craniotomies. PMID- 26930094 TI - S13. The History of Breathing. PMID- 26930095 TI - S14. Critical Care Medicine: Hospital Ethics Committee. PMID- 26930096 TI - S15. Beat to Beat: a Measured Look at the History of Pulse Oximetry. PMID- 26930097 TI - S16. The First Gorilla Anesthesia in the United States? PMID- 26930099 TI - S18. The History of Euthanasia and Physician-Assisted Suicide. PMID- 26930098 TI - S17. Importing Entire Anesthesia History Book to a Database Software: its Versatile Possibility for Historical Research. PMID- 26930100 TI - S19. The Professor and the Student: Their Influence on Statistical Inference. PMID- 26930102 TI - S21. Keeping Track of Audio-Video History. PMID- 26930101 TI - S20. Religious Attitudes Toward Pain and Suffering in Mid-19th Century America. PMID- 26930103 TI - S22. History of Airway Management. PMID- 26930104 TI - S24. History of Pacemakers and Anesthesia. PMID- 26930105 TI - S23. The Father (and Lawyer) of Intravenous Therapy. PMID- 26930106 TI - Reduced Graphene Oxide Nanosheet for Chemo-photothermal Therapy. AB - The protein-functionalized reduced graphene oxide (rGO) nanosheet is of great interest in stimuli-responsive drug delivery and controlled release applications. We developed doxorubicin (DOX)-loaded bovine serum albumin (BSA)-functionalized rGO (DOX-BSA-rGO) nanosheets. To investigate the reduction of BSA-functionalized GO nanosheets and drug loading efficiency, we used X-ray photoelectron spectroscopy (XPS) and UV-visible spectrophotometer analysis. DOX-BSA-rGO nanosheets exhibited dose-dependent cellular uptake without any cytotoxic effect. We also demonstrated near-infrared (NIR)-induced chemo-photothermal therapy of brain tumor cells treated with DOX-BSA-rGO nanosheets. Therefore, this DOX-BSA rGO nanosheet could be a powerful tool for chemo-photothermal therapy applications. PMID- 26930107 TI - A new benzopyrans derivatives from a mangrove-derived fungus Penicillium citrinum from the South China Sea. AB - One new benzopyran derivative (2R(*),4R(*))-3,4-dihydro-5-methoxy-2-methyl-2H-1 benzopyran-4-ol (1), together with five known compounds (2-6), were obtained from the EtOAc extract of the endophytic fungus Penicillium citrinum HL-5126 isolated from the mangrove Brguiera sexangula var. rhynchopetala collected in the South China Sea. Their structures were elucidated by the detailed analysis of comprehensive spectroscopic data. All compounds were evaluated for their antibacterial activities. Compound 6 exhibited potent inhibitory activity against Bacillus subtilis, Bacillus cereus and Micrococcus tetragenus with the same MIC values of 6.94 MUM. PMID- 26930108 TI - Evolution of Structure and Photoluminescence by Cation Cosubstitution in Eu(2+) Doped (Ca(1-x)Li(x))(Al(1-x)Si(1+x))N3 Solid Solutions. AB - Red-emitting nitride phosphors excited with blue light have great potential for the fabrication of warm white light-emitting diodes (WLEDs). Chemical composition and structural modification are generally adopted to optimize the photoluminescence behaviors of the targeted phosphors. Herein, on the basis of the famous CaAlSiN3 phosphors, Eu(2+)-doped (Ca(1-x)Li(x))(Al(1-x)Si(1+x))N3 solid solutions via the cations' cosubstitution of (CaAl)(5+) pair by (LiSi)(5+) pair are successfully synthesized by a solid state reaction, and the lattice parameters show a linear decrease with chemical compositions suggesting the formation of the isostructural phase relationship. Four types of coordinated structure models, corresponding to different coordination environments of Eu(2+), are proposed over the course of structural evolution, which induces different structural rigidity and stability, and then they are responsible for three-stage changes of emission spectra of Eu(2+) in (Ca(1-x)Li(x))(Al(1-x)Si(1+x))N3 solid solution. PMID- 26930109 TI - Consequences of Delayed Prenatal Diagnosis of beta-Thalassemia in Mainland China. AB - beta-Thalassemia (beta-thal) is one of the most common inherited single gene disorders in the world. The aim of this study was to describe the gestational age at prenatal diagnosis (PND) for beta-thal in at-risk women in mainland China. All pregnant women at-risk for beta-thal and undergoing PND at a Mainland Chinese tertiary obstetric center between January 2005 and December 2014 were included. Information required for the survey was obtained from prenatal records and delivery charts. In total, 1307 women underwent PND for beta-thal. The mean gestational age for the procedure was 18.5 weeks. There were 384 (29.0%) women with fetal diagnosis in early trimester (<14 weeks), 715 (55.0%) in early second trimester (14-24 weeks), and 208 (16.0%) in late second trimester or beyond (>24 weeks). Although the proportion of patients undergoing early PND increased along with the time span, the mean n gestational age was not decreased significantly during the study period. The delay in PND deprived couples of the opportunity to make informed decisions early in pregnancy. PMID- 26930110 TI - Effect of Hippotherapy on Motor Proficiency and Function in Children with Cerebral Palsy Who Walk. AB - AIMS: To evaluate the effects of hippotherapy on physical capacities of children with cerebral palsy. METHODS: Thirteen children (4-12 years old) with cerebral palsy classified in Gross Motor Function Classification System Level I or II were included in this prospective quasi-experimental ABA design study. Participants received 10 weeks of hippotherapy (30 min per week). Gross motor function and proficiency were measured with the Bruininks-Oseretski Motor Proficiency short form [BOT2-SF]) and the Gross Motor Function Measure-88 [GMFM-88] (Dimension D and E) twice before the program (T1 and T1'), immediately after (T2), and 10 weeks following the end of the program (T3). RESULTS: Mean scores for dimensions D and E of the GMFM-88 Dimension scores (p = .005) and three out of the eight items of the BOT2-SF (fine motor precision (p = .013), balance (p = .025), and strength (p = .012) improved between baseline and immediately after intervention; mean scores immediately following and 10 weeks following intervention did not differ. CONCLUSIONS: Hippotherapy provided by a trained therapist who applies an intense and graded session for 10 weeks can improve body functions and performance of gross motor and fine motor activities in children with cerebral palsy. PMID- 26930112 TI - ORION RESEARCH. PMID- 26930111 TI - Gaze-based assistive technology in daily activities in children with severe physical impairments-An intervention study. AB - OBJECTIVE: To establish the impact of a gaze-based assistive technology (AT) intervention on activity repertoire, autonomous use, and goal attainment in children with severe physical impairments, and to examine parents' satisfaction with the gaze-based AT and with services related to the gaze-based AT intervention. METHODS: Non-experimental multiple case study with before, after, and follow-up design. Ten children with severe physical impairments without speaking ability (aged 1-15 years) participated in gaze-based AT intervention for 9-10 months, during which period the gaze-based AT was implemented in daily activities. RESULTS: Repertoire of computer activities increased for seven children. All children had sustained usage of gaze-based AT in daily activities at follow-up, all had attained goals, and parents' satisfaction with the AT and with services was high. DISCUSSION: The gaze-based AT intervention was effective in guiding parents and teachers to continue supporting the children to perform activities with the AT after the intervention program. PMID- 26930113 TI - Photovolt Corporation. PMID- 26930115 TI - Future of breeding by genome editing is in the hands of regulators. AB - We are witnessing the timely convergence of several technologies that together will have significant impact on research, human health and in animal and plant breeding. The exponential increase in genome and expressed sequence data, the ability to compile, analyze and mine these data via sophisticated bioinformatics procedures on high-powered computers, and developments in various molecular and in-vitro cellular techniques combine to underpin novel developments in research and commercial biotechnology. Arguably the most important of these is genome editing which encompasses a suite of site directed nucleases (SDN) that can be designed to cut, or otherwise modify predetermined DNA sequences in the genome and result in targeted insertions, deletions, or other changes for genetic improvement. It is a powerful and adaptive technology for animal and plant science, with huge relevance for plant and animal breeding. But this promise will be realized only if the regulatory oversite is proportionate to the potential hazards and has broad support from consumers, researchers and commercial interests. Despite significant progress in research and development and one genome edited crop close to commercialization, in most regions of the world it still remains unclear how or whether this fledgling technology will be regulated. The various risk management authorities and biotechnology regulators have a unique opportunity to set up a logical, appropriate and workable regulatory framework for gene editing that, unlike the situation for GMOs, would have broad support from stakeholders. PMID- 26930116 TI - A new window of opportunity to reject process-based biotechnology regulation. AB - The question of whether biotechnology regulation should be based on the process or the product has long been debated, with different jurisdictions adopting different approaches. The European Union has adopted a process-based approach, Canada has adopted a product-based approach, and the United States has implemented a hybrid system. With the recent proliferation of new methods of genetic modification, such as gene editing, process-based regulatory systems, which are premised on a binary system of transgenic and conventional approaches, will become increasingly obsolete and unsustainable. To avoid unreasonable, unfair and arbitrary results, nations that have adopted process-based approaches will need to migrate to a product-based approach that considers the novelty and risks of the individual trait, rather than the process by which that trait was produced. This commentary suggests some approaches for the design of such a product-based approach. PMID- 26930114 TI - Genome editing for crop improvement: Challenges and opportunities. AB - Genome or gene editing includes several new techniques to help scientists precisely modify genome sequences. The techniques also enables us to alter the regulation of gene expression patterns in a pre-determined region and facilitates novel insights into the functional genomics of an organism. Emergence of genome editing has brought considerable excitement especially among agricultural scientists because of its simplicity, precision and power as it offers new opportunities to develop improved crop varieties with clear-cut addition of valuable traits or removal of undesirable traits. Research is underway to improve crop varieties with higher yields, strengthen stress tolerance, disease and pest resistance, decrease input costs, and increase nutritional value. Genome editing encompasses a wide variety of tools using either a site-specific recombinase (SSR) or a site-specific nuclease (SSN) system. Both systems require recognition of a known sequence. The SSN system generates single or double strand DNA breaks and activates endogenous DNA repair pathways. SSR technology, such as Cre/loxP and Flp/FRT mediated systems, are able to knockdown or knock-in genes in the genome of eukaryotes, depending on the orientation of the specific sites (loxP, FLP, etc.) flanking the target site. There are 4 main classes of SSN developed to cleave genomic sequences, mega-nucleases (homing endonuclease), zinc finger nucleases (ZFNs), transcriptional activator-like effector nucleases (TALENs), and the CRISPR/Cas nuclease system (clustered regularly interspaced short palindromic repeat/CRISPR-associated protein). The recombinase mediated genome engineering depends on recombinase (sub-) family and target-site and induces high frequencies of homologous recombination. Improving crops with gene editing provides a range of options: by altering only a few nucleotides from billions found in the genomes of living cells, altering the full allele or by inserting a new gene in a targeted region of the genome. Due to its precision, gene editing is more precise than either conventional crop breeding methods or standard genetic engineering methods. Thus this technology is a very powerful tool that can be used toward securing the world's food supply. In addition to improving the nutritional value of crops, it is the most effective way to produce crops that can resist pests and thrive in tough climates. There are 3 types of modifications produced by genome editing; Type I includes altering a few nucleotides, Type II involves replacing an allele with a pre-existing one and Type III allows for the insertion of new gene(s) in predetermined regions in the genome. Because most genome-editing techniques can leave behind traces of DNA alterations evident in a small number of nucleotides, crops created through gene editing could avoid the stringent regulation procedures commonly associated with GM crop development. For this reason many scientists believe plants improved with the more precise gene editing techniques will be more acceptable to the public than transgenic plants. With genome editing comes the promise of new crops being developed more rapidly with a very low risk of off-target effects. It can be performed in any laboratory with any crop, even those that have complex genomes and are not easily bred using conventional methods. PMID- 26930117 TI - A new strategy to tackle severe knee osteoarthritis: Combination of intra articular and intraosseous injections of Platelet Rich Plasma. AB - INTRODUCTION: Knee osteoarthritis (KOA) is a mechanically induced, cytokine and enzyme-mediated disorder involving all the joint tissue of the knee. Rebuilding a physiological-homeostatic network at the tissue level following knee organ failure, such as in severe KOA, is a daunting task with therapeutic targets encompassing the articular cartilage, synovium and subchondral bone. Intraarticular infiltration of plasma rich in growth factors (PRP) has emerged as a promising symptomatic approach, although it is insufficient to reach the subchondral bone. AREAS COVERED: This review addresses current molecular and cellular data in joint homeostasis and osteoarthritis pathophysiology. In particular, it focuses on changes that subchondral bone undergoes in knee osteoarthritis and evaluates recent observations on the crosstalk among articular cartilage, subchondral bone and synovial membrane. In addition, we review some mechanistic aspects that have been proposed and provide the rationale for using PRP intraosseously in KOA. EXPERT OPINION: The knee joint is a paradigm of autonomy and connectedness of its anatomical structures and tissues from which it is made. We propose an innovative approach to the treatment of severe knee osteoarthritis consisting of a combination of intraarticular and intraosseous infiltrations of PRP, which might offer a new therapeutic tool in KOA therapy. PMID- 26930118 TI - Better research reporting to improve the utility of routine data for making better treatment decisions. AB - The availability of routinely collected health data, such as health administrative data, electronic health records, prescription records and disease registries, has increased in the information age. This has led to an explosion of reports of comparativeness effectiveness research using such data. Guidelines for the REporting of studies Conducted using Observational Routinely-collected Data (RECORD) will improve the completeness and transparency of reporting of research using routinely collected health data. The Journal of Comparative Effectiveness Research has endorsed these guidelines. In this commentary, the RECORD checklist is reprinted and members of the RECORD working committee reflect on the importance of these reporting guidelines for the field of comparative effectiveness research. PMID- 26930119 TI - Discovery of Orally Available Prodrugs of the Glutamate Carboxypeptidase II (GCPII) Inhibitor 2-Phosphonomethylpentanedioic Acid (2-PMPA). AB - 2-Phosphonomethylpentanedioic acid (1, 2-PMPA) is a potent inhibitor of glutamate carboxypeptidase II which has demonstrated robust neuroprotective efficacy in many neurological disease models. However, 1 is highly polar containing a phosphonate and two carboxylates, severely limiting its oral bioavailability. We strategized to mask the polar groups via a prodrug approach, increasing the likelihood of passive oral absorption. Our initial strategy was to cover the phosphonate with hydrophobic moieties such as pivaloyloxymethyl (POM) and isopropyloxycarbonyloxymethyl (POC) while keeping the alpha- and gamma carboxylates unsubstituted. This attempt was unsuccessful due to the chemical instability of the bis-POC/POM derivatives. Addition of alpha,gamma-diesters and alpha-monoesters enhanced chemical stability and provided excellent oral exposure in mice, but these mixed esters were too stable in vivo, resulting in minimal release of 1. By introducing POC groups on both the phosphonate and alpha carboxylate, we synthesized Tris-POC-2-PMPA (21b), which afforded excellent release of 1 following oral administration in both mice and dog. PMID- 26930120 TI - Resilience of African migrants: An integrative review. AB - African migrant women represent a rapidly growing cohort of new arrivals in many countries. Many of these women demonstrate strength and resilience throughout the stressful migration process. In this integrative review, we explore the literature on African migrants' resilience using an ecological framework. Nine peer-reviewed journal articles and six grey literature documents were reviewed. Key internal and external factors in achieving resilience were identified, discussed, and diagrammatically represented using Bronfenbrenner's Ecological Framework under micro-, meso-, exo-, and macro-levels. Our findings show that the capacity for resilience demonstrated during migration could have implications for policy and practice. PMID- 26930121 TI - Multi-segment trunk models used to investigate the crunch factor in golf and their relationship with selected swing and launch parameters. AB - The use of multi-segment trunk models to investigate the crunch factor in golf may be warranted. The first aim of the study was to investigate the relationship between the trunk and lower trunk for crunch factor-related variables (trunk lateral bending and trunk axial rotation velocity). The second aim was to determine the level of association between crunch factor-related variables with swing (clubhead velocity) and launch (launch angle). Thirty-five high-level amateur male golfers (Mean +/- SD: age = 23.8 +/- 2.1 years, registered golfing handicap = 5 +/- 1.9) without low back pain had kinematic data collected from their golf swing using a 10-camera motion analysis system operating at 500 Hz. Clubhead velocity and launch angle were collected using a validated real-time launch monitor. A positive relationship was found between the trunk and lower trunk for axial rotation velocity (r(35) = .47, P < .01). Cross-correlation analysis revealed a strong coupling relationship for the crunch factor (R(2) = 0.98) between the trunk and lower trunk. Using generalised linear model analysis, it was evident that faster clubhead velocities and lower launch angles of the golf ball were related to reduced lateral bending of the lower trunk. PMID- 26930123 TI - Peptide Glycosylation Generates Supramolecular Assemblies from Glycopeptides as Biomimetic Scaffolds for Cell Adhesion and Proliferation. AB - Glycopeptide-based hydrogelators with well-defined molecular structures and varied contents of sugar moieties were prepared via in vitro peptide glycosylation reactions. With systematic glucose modification, these glycopeptide hydrogelators exhibited diverse self-assembling behaviors in water and formed supramolecular hydrogels with enhanced thermostability and biostability, in comparison with their peptide analogue. Moreover, because of high water content and similar structural morphology and composition to extracellular matrixes (ECM) in tissues, these self-assembled hydrogels also exhibited great potential to act as new biomimetic scaffolds for mammalian cell growth. Therefore, peptide glycosylation proved to be an effective means for peptide modification and generation of novel supramolecular hydrogelators/hydrogels with improved biophysical properties (e.g., high biostability, increased thermostability, and cell adhesion) which could promise potential applications in regenerative medicine. PMID- 26930124 TI - Oleic Acid-Induced Atomic Alignment of ZnS Polyhedral Nanocrystals. AB - Ordered two-dimensional (2D) superstructures of colloidal nanocrystals (NCs) can be tailored by the size, shape, composition, and surface chemistry of the NC building blocks, which can give directionality to the resulting superstructure geometry. The exact formation mechanism of 2D NC superstructures is however not yet fully understood. Here, we show that oleic acid (OA) ligands induce atomic alignment of wurtzite ZnS bifrustum-shaped NCs. We find that in the presence of OA ligands the {002} facets of the ZnS bifrustums preferentially adhere to the liquid-air interface. Furthermore, OA ligands induce inter-NC interactions that also orient the NCs in the plane of the liquid-air interface, resulting in atomically aligned 2D superstructures. We follow the self-assembly process in real-time with in situ grazing incidence small-angle X-ray scattering and find that the NCs form a hexagonal superstructure at early stages after which they come closer over time, resulting in a close-packed NC superstructure. Our results demonstrate the profound influence that surface ligands have on the directionality of 2D NC superstructures and highlight the importance of detailed in situ studies in order to understand the self-assembly of NCs into 2D superstructures. PMID- 26930122 TI - Vascular Endothelial Growth Factor and Podocyte Protection in Chronic Hypoxia: Effects of Endothelin-A Receptor Antagonism. AB - BACKGROUND: Podocytes are major components of the filtration barrier and a renal source of vascular endothelial growth factor (VEGF). Chronic renovascular disease (RVD) progressively degrades the renal function, accompanied by podocyte damage and a progressive reduction in VEGF. We showed that the endothelin (ET) pathway contributes to this pathological process and ET-A (but not ET-B) receptor antagonism protects the kidney in RVD. We hypothesize that ET-A-induced renoprotection is largely driven by the protection of podocyte integrity and function. METHODS: To mimic the renal environment of chronic RVD, human podocytes were incubated under chronic hypoxia for 96 h and divided in untreated or treated with an ET-A or ET-B receptor antagonist. Cells were quantified after 96 h. Cell homogenates and media were obtained after 1, 24 and 96 h to quantify production of VEGF, anti-VEGF soluble receptor s-Flt1, and the expression of apoptotic mediators. A separate set of similar experiments was performed after addition of a VEGF-neutralizing antibody (VEGF-NA). RESULTS: Hypoxia decreased podocyte number, which was exacerbated by ET-B but improved after ET-A antagonism. Production of VEGF was preserved by ET-A antagonism, whereas s-Flt1 increased in hypoxic cells after ET-B antagonism only, accompanied by a greater expression of pro-apoptotic mediators. On the other hand, treatment with VEGF-NA diminished ET A-induced protection of podocytes. CONCLUSION: ET-A antagonism preserves podocyte viability and integrity under chronic hypoxia, whereas ET-B antagonism exacerbates podocyte dysfunction and death. Enhanced bioavailability of VEGF after ET-A antagonism could be a pivotal mechanism of podocyte protection that significantly contributes to ET-A receptor blockade-induced renal recovery in chronic RVD. PMID- 26930125 TI - Association between hypertension and quality of life in pregnancy. AB - PURPOSE: To assess the association between hypertension in pregnancy and women's quality of life (QoL) and the variation in the quality of life over gestational trimesters. METHOD: A questionnaire was applied to 194 hypertensive pregnant women and 195 pregnant women without complications. The questionnaire was composed of two parts: socioeconomic profile and specifically QoL, using the instrument Ferrans & Powers Quality of Life Index. All women included underwent a physical examination. RESULTS: Blood pressure was found to be approximately 20 mmHg higher in hypertensive pregnant women compared to pregnant women without complications. All QoL domains of hypertensive pregnant women had lower scores than those of pregnant women without complications, with health/functioning rated the lowest, averaging 17.63. The least affected domain was family, having the best average score (26.0). The QoL had no significant variations in relation to gestational trimesters. CONCLUSIONS: Pregnancy causes intense changes, both physical and psychological, in women's lives and hypertension was found to be a factor of high interference in pregnant woman's QoL, causing lower scores in all QoL domains of hypertensive pregnant women, compared with pregnant woman without complications. PMID- 26930126 TI - Do faster swimmers spend longer underwater than slower swimmers at World Championships? AB - The main objectives of the present research were (1) to examine the relationships between the distances travelled underwater during the start and turn segments with swimming race performance at the elite level and (2) to determine if the individualised-distance start and turn parameters affect the overall race performance. The race parameters of the 100 and 200 m events during 2013 World Championships were measured by an innovative image-processing system (InThePool((r)) 2.0). Overall, 100 m race times were largely related to faster start velocities in men's breaststroke and freestyle events. Conversely, overall, 200 m race times were largely related to longer starting distances in the women's butterfly events, to longer turn distances in men's and women's backstroke and women's butterfly events and to shorter turn distances in women's freestyle events. Changes on the start or turn velocities could represent moderate time improvements in most of the 100 m events, whereas modifications on the start or turn distances (especially in the last turn) could provide elite swimmers with time improvements of practical importance on the 200 m events. The evaluation of races by individualised-distance parameters should be provided to elite swimmers in order to decide the most appropriate race segment configuration for each event. PMID- 26930127 TI - Long-Lived Triplet Excited States of Bent-Shaped Pentacene Dimers by Intramolecular Singlet Fission. AB - Intramolecular singlet fission (ISF) is a promising photophysical process to construct more efficient light energy conversion systems as one excited singlet state converts into two excited triplet states. Herein we synthesized and evaluated bent-shaped pentacene dimers as a prototype of ISF to reveal intrinsic characters of triplet states (e.g., lifetimes of triplet excited states). In this study, meta-phenylene-bridged TIPS-pentacene dimer (PcD-3Ph) and 2,2'-bipheynyl bridged TIPS-pentacene dimer (PcD-Biph) were newly synthesized as bent-shaped dimers. In the steady-state spectroscopy, absorption and emission bands of these dimers were fully characterized, suggesting the appropriate degree of electronic coupling between pentacene moieties in these dimers. In addition, the electrochemical measurements were also performed to check the electronic interaction between two pentacene moieties. Whereas the successive two oxidation peaks owing to the delocalization were observed in a directly linked-pentacene dimer (PcD) by a single bond, the cyclic voltammograms in PcD-Biph and PcD-3Ph implied the weaker interaction compared to that of p-phenylene-bridged TIPS pentacene dimer (PcD-4Ph) and PcD. The femtosecond and nanosecond transient absorption spectra clearly revealed the slower ISF process in bent-shaped pentacene dimers (PcD-Biph and PcD-3Ph), more notably, the slower relaxation of the excited triplet states in PcD-Biph and PcD-3Ph. Namely, the quantum yields of triplet states (PhiT) by ISF approximately remain constant (ca. 180-200%) in all dimer systems, whereas the lifetimes of the triplet excited states became much longer (up to 360 ns) in PcD-Biph as compared to PcD-4Ph (15 ns). Additionally, the lifetimes of the corresponding triplet states in PcD-Biph and PcD-3Ph were sufficiently affected by solvent viscosity. In particular, the lifetimes of PcD Biph triplet state in THF/paraffin (1.0 MUs) increased up to approximately three times as compared to that in THF (360 ns), whereas those of PcD-4Ph were quite similar in both solvent. PMID- 26930128 TI - Solanum melongena polyphenol oxidase biosensor for the electrochemical analysis of paracetamol. AB - A new strategy for the construction of a polyphenol oxidase carbon paste biosensor for paracetamol detection is reported. The eggplant (Solanum melongena) was processed to collect the polyphenol oxidase as an enzyme that was incorporated in the carbon paste sensor construction. The constructed sensor displayed high sensitivity and good selection for paracetamol detection and recognition. Optimized conditions included pH 6.0 (highest activity), pH 7.0 (highest stability), pulse amplitude of 50 mV, and 15% of vegetable extract per carbon paste. The sensor displayed a linear range from 20 to 200 uM, with a detection limit of 5 uM. Application of the sensor to paracetamol determination in tablet and oral solutions have shown satisfactory results. The efficiency of the method showed very good repeatability ranging between 1.26 and 1.72% relative standard deviation for interday analysis, while recoveries for paracetamol varied between 97.5 and 99.8% for the voltammetric determination. The strategy for a simple, low cost, and efficient eggplant polyphenol oxidase sensor showcased in this work provides an opportunity for the detection of other phenolic compounds in various matrices. PMID- 26930129 TI - Daily rhythms in the somatotropic axis of Senegalese sole (Solea senegalensis): The time of day influences the response to GH administration. AB - Growth factors in vertebrates display daily rhythms, which, while widely described in mammals, are still poorly understood in teleost fish. Here, we investigated the existence of daily rhythms in the somatotropic axis of the flatfish Solea senegalensis. In a first experiment, daily rhythms of the expression of pituitary adenylate cyclase-activating polypeptide (pacap), growth hormone (gh), insulin-like growth factor 1 (igf1) and its receptor (igf1r) were analyzed under a 12:12 h light:dark cycle. All genes displayed daily rhythms with the acrophases of pacap, gh and igf1 located in the second half of the dark phase (ZT 20:28-0:04 h), whereas the acrophase of igf1r was located around mid-light (ZT 5:33 h). In a second experiment, the influence of the time of day (mid-light, ML, versus mid-darkness, MD) of GH administration on the expression of these factors and on plasma glucose levels was tested. The response observed depended on the time of injection: the strongest effects were observed at MD, when GH administration significantly reduced pituitary gh and enhanced liver igf1 expression. These results provide the first evidence of daily rhythms and differential day/night effects in growth factors in S. senegalensis, suggesting new insights for investigating the physiology of growth and possible applications to improve fish aquaculture. PMID- 26930131 TI - Identity processes as a predictor of memory beliefs in older adults. AB - OBJECTIVES: The impact of identity processes (identity assimilation, identity accommodation, and identity balance) on memory beliefs was explored. METHOD: Individually administered questionnaires (e.g. depressive symptoms, subjective health, identity processes, memory beliefs) and a brief neuropsychological assessment of cognitive abilities were completed during a one-time interview with 82 participants aged 58-92 years-old (M = 74.68, SD = 10.95). Forty (49.4%) identified their race as White/Caucasian, 38 (46.9%) identified their race as Black/African American, and 3 (3.7%) indicated no primary racial/ethnic group. RESULTS: Hierarchical regression analyses revealed that identity processes account for differences in memory beliefs beyond established predictors. Specifically, identity accommodation and identity balance predicted memory self efficacy beyond depression and subjective health. These findings are congruent with identity process theory; however, the impact of identity assimilation in this population was unremarkable. Exploratory analyses also indicated that the identity processes have a stronger relationship to some domains of memory self efficacy (i.e. anxiety, capacity) than others (i.e. perceived change, locus of control). CONCLUSION: Beliefs about memory and their integration into an adaptable, yet consistent self-concept are an important element of identity for aging individuals. Additional research is needed to determine the unique role of identity accommodation and identity balance in understanding cognitive functioning and ultimately the impact on potential clinical applications, such as related health-seeking behavior among older adults. Tailored interventions could be developed to facilitate optimal utilization of health care services at a time when early diagnosis of memory-related disorders is critical for future planning and care decisions. PMID- 26930132 TI - Preeclampsia and superimposed preeclampsia: The same disease? The role of angiogenic biomarkers. AB - OBJECTIVE: We aimed to compare sFlt-1 and placental growth factor (PlGF) levels and the sFlt-1/PlGF ratio between women with preeclampsia and superimposed preeclampsia to, respectively, normotensive and chronic hypertensive ones. STUDY DESIGN: We performed a prospective two-armed cohort in a tertiary teaching hospital in Sao Paulo, Brazil, including 37 normotensive and 60 chronic hypertensive pregnant women. We assessed the serum levels of sFlt-1 and PlGF at 20, 26, 32, and 36 gestational weeks by enzyme-linked immunosorbent assay. MAIN OUTCOME MEASURES: Having preeclampsia and superimposed preeclampsia. RESULTS: Among normotensive and chronic hypertensive pregnancies, 4 (10.8%) and 14 (23.3%) women developed preeclampsia and superimposed preeclampsia, respectively. Compared with those who remained normotensive, the preeclampsia women presented higher sFlt-1 levels at 32 gestational weeks (4323.45 pg/mL vs. 2242.04 pg/mL, p = 0.019), lower PlGF levels at 20 (183.54 pg/mL vs. 337.38 pg/mL, p = 0.034), 32 (169.69 pg/mL vs. 792.53 pg/mL, p = 0.001), and 36 gestational weeks (252.99 pg/mL vs. 561.81 pg/mL, p = 0.029), and higher sFlt-1/PlGF ratios at 26 (9.02 vs. 1.84, p = 0.004), 32 (23.61 vs. 2.55, p = 0.001), and 36 gestational weeks (49.02 vs. 7.34, p = 0.029). On the other hand, compared with those who remained chronic hypertensive, the superimposed preeclampsia women only presented a higher sFlt 1/PlGF ratio at 32 gestational weeks (9.98 vs. 2.51, p = 0.039). CONCLUSION: Although angiogenic imbalance is clearly related to preeclampsia, it seems to play a more modest role in superimposed preeclampsia, in which other mechanisms should also be investigated. PMID- 26930130 TI - Spectroscopic and Theoretical Study of Cu(I) Binding to His111 in the Human Prion Protein Fragment 106-115. AB - The ability of the cellular prion protein (PrP(C)) to bind copper in vivo points to a physiological role for PrP(C) in copper transport. Six copper binding sites have been identified in the nonstructured N-terminal region of human PrP(C). Among these sites, the His111 site is unique in that it contains a MKHM motif that would confer interesting Cu(I) and Cu(II) binding properties. We have evaluated Cu(I) coordination to the PrP(106-115) fragment of the human PrP protein, using NMR and X-ray absorption spectroscopies and electronic structure calculations. We find that Met109 and Met112 play an important role in anchoring this metal ion. Cu(I) coordination to His111 is pH-dependent: at pH >8, 2N1O1S species are formed with one Met ligand; in the range of pH 5-8, both methionine (Met) residues bind to Cu(I), forming a 1N1O2S species, where N is from His111 and O is from a backbone carbonyl or a water molecule; at pH <5, only the two Met residues remain coordinated. Thus, even upon drastic changes in the chemical environment, such as those occurring during endocytosis of PrP(C) (decreased pH and a reducing potential), the two Met residues in the MKHM motif enable PrP(C) to maintain the bound Cu(I) ions, consistent with a copper transport function for this protein. We also find that the physiologically relevant Cu(I)-1N1O2S species activates dioxygen via an inner-sphere mechanism, likely involving the formation of a copper(II) superoxide complex. In this process, the Met residues are partially oxidized to sulfoxide; this ability to scavenge superoxide may play a role in the proposed antioxidant properties of PrP(C). This study provides further insight into the Cu(I) coordination properties of His111 in human PrP(C) and the molecular mechanism of oxygen activation by this site. PMID- 26930133 TI - Towards artificial tissue models: past, present, and future of 3D bioprinting. AB - Regenerative medicine and tissue engineering have seen unprecedented growth in the past decade, driving the field of artificial tissue models towards a revolution in future medicine. Major progress has been achieved through the development of innovative biomanufacturing strategies to pattern and assemble cells and extracellular matrix (ECM) in three-dimensions (3D) to create functional tissue constructs. Bioprinting has emerged as a promising 3D biomanufacturing technology, enabling precise control over spatial and temporal distribution of cells and ECM. Bioprinting technology can be used to engineer artificial tissues and organs by producing scaffolds with controlled spatial heterogeneity of physical properties, cellular composition, and ECM organization. This innovative approach is increasingly utilized in biomedicine, and has potential to create artificial functional constructs for drug screening and toxicology research, as well as tissue and organ transplantation. Herein, we review the recent advances in bioprinting technologies and discuss current markets, approaches, and biomedical applications. We also present current challenges and provide future directions for bioprinting research. PMID- 26930134 TI - Participation in Early Childhood Educational Environments for Young Children with and Without Developmental Disabilities and Delays: A Mixed Methods Study. AB - AIMS: This mixed methods study examined: 1) how young children with and without developmental disabilities and delays participate in daycare or preschool activities; 2) similarities and differences in environmental factors impacting daycare or preschool participation; and 3) strategies used by parents who desired a change in their child's participation. METHODS: Data were drawn from 129 parents of young children with and without developmental disabilities and delays (mean age = 49.3 months) residing in North America. Summary and item-level group differences based on disability status were assessed for participation and environmental supports to participation. Narrative data on parental strategies were content coded, transformed into numerical counts, and summarized to identify strategies commonly employed by parents to promote their child's participation. RESULTS: Moderate to large disability related group differences in participation and environmental support to participation were found even after controlling for confounding effects of child age, child gender, and family income. Parents commonly described strategies focused on "child care tasks" and "child peer groups," irrespective of the type(s) of change they desired. CONCLUSIONS: Study findings suggest that discrepancies in school participation between young children with and without disabilities and delays can be detected and intervened on during the early childhood period. PMID- 26930135 TI - Optimization Algorithms in Optimal Predictions of Atomistic Properties by Kriging. AB - The machine learning method kriging is an attractive tool to construct next generation force fields. Kriging can accurately predict atomistic properties, which involves optimization of the so-called concentrated log-likelihood function (i.e., fitness function). The difficulty of this optimization problem quickly escalates in response to an increase in either the number of dimensions of the system considered or the size of the training set. In this article, we demonstrate and compare the use of two search algorithms, namely, particle swarm optimization (PSO) and differential evolution (DE), to rapidly obtain the maximum of this fitness function. The ability of these two algorithms to find a stationary point is assessed by using the first derivative of the fitness function. Finally, the converged position obtained by PSO and DE is refined through the limited-memory Broyden-Fletcher-Goldfarb-Shanno bounded (L-BFGS-B) algorithm, which belongs to the class of quasi-Newton algorithms. We show that both PSO and DE are able to come close to the stationary point, even in high dimensional problems. They do so in a reasonable amount of time, compared to that with the Newton and quasi-Newton algorithms, regardless of the starting position in the search space of kriging hyperparameters. The refinement through L-BFGS-B is able to give the position of the maximum with whichever precision is desired. PMID- 26930136 TI - Orthogonal Assays Clarify the Oxidative Biochemistry of Taxol P450 CYP725A4. AB - Natural product metabolic engineering potentially offers sustainable and affordable access to numerous valuable molecules. However, challenges in characterizing and assembling complex biosynthetic pathways have prevented more rapid progress in this field. The anticancer agent Taxol represents an excellent case study. Assembly of a biosynthetic pathway for Taxol has long been stalled at its first functionalization, putatively an oxygenation performed by the cytochrome P450 CYP725A4, due to confounding characterizations. Here, through combined in vivo (Escherichia coli), in vitro (lipid nanodisc), and metabolite stability assays, we verify the presence and likely cause of this enzyme's inherent promiscuity. Thereby, we remove the possibility that promiscuity simply existed as an artifact of previous metabolic engineering approaches. Further, spontaneous rearrangement and the stabilizing effect of a hydrophobic overlay suggest a potential role for nonenzymatic chemistry in Taxol's biosynthesis. Taken together, this work confirms taxadiene-5alpha-ol as a primary enzymatic product of CYP725A4 and provides direction for future Taxol metabolic and protein engineering efforts. PMID- 26930137 TI - Pediatric Cardiac Arrest Due to Trauma. AB - Survival from pediatric cardiac arrest due to trauma has been reported to be 0.0% 8.8%. Some argue that resuscitation efforts in the case of trauma-related cardiac arrests are futile. We describe a successful outcome in the case of a child who suffered cardiac arrest caused by external traumatic airway obstruction. Our case illustrates how to deal with pediatric traumatic cardiac arrests in an out-of hospital environment. It also illustrates how good clinical treatment in these situations may be supported by correct treatment after hospital admission when it is impossible to ventilate the patient to provide sufficient oxygen delivery to vital organs. This case relates to a lifeless child of 3-5 years, blue, and trapped by an electrically operated garage door. The first ambulance arrived to find several men trying to bend the frame and the door apart in order to extricate the child, who was hanging in the air with head and neck squeezed between the horizontally-moving garage door and the vertical door frame. One paramedic found a car jack and used it to push the door and the frame apart, allowing the lifeless child to be extricated. Basic life support was then initiated. Intubation was performed by the anesthesiologist without drugs. With FiO2 1.0 the first documented SaO2 was <50%. Restoration of Spontaneous Circulation was achieved after thirty minutes, and she was transported to the hospital. After a few hours she was put on venous-arterial ECMO for 5.5 days and discharged home after two months. Outpatient examinations during the rest of 2013 were positive, and the child found not to be suffering from any injuries, either physical or mental. The last follow-up in October 2014 demonstrated she had made a 100% recovery and she started school in August 2014. PMID- 26930139 TI - Many names and a single disease: The plurality of the Sensory Neuronopathies. PMID- 26930138 TI - New initiatives to improve HPV vaccination rates. PMID- 26930140 TI - Low-Temperature Additive Manufacturing of Biomimic Three-Dimensional Hydroxyapatite/Collagen Scaffolds for Bone Regeneration. AB - Low-temperature additive manufacturing (AM) holds promise for fabrication of three-dimensional (3D) scaffolds containing bioactive molecules and/or drugs. Due to the strict technical limitations of current approaches, few materials are suitable for printing at low temperature. Here, a low-temperature robocasting method was employed to print biomimic 3D scaffolds for bone regeneration using a routine collagen-hydroxyapatite (CHA) composite material, which is too viscous to be printed via normal 3D printing methods at low temperature. The CHA scaffolds had excellent 3D structure and maintained most raw material properties after printing. Compared to nonprinted scaffolds, printed scaffolds promoted bone marrow stromal cell proliferation and improved osteogenic outcome in vitro. In a rabbit femoral condyle defect model, the interconnecting pores within the printed scaffolds facilitated cell penetration and mineralization before the scaffolds degraded and enhanced repair, compared to nonprinted CHA scaffolds. Additionally, the optimal printing parameters for 3D CHA scaffolds were investigated; 600-MUm diameter rods were optimal in terms of moderate mechanical strength and better repair outcome in vivo. This low-temperature robocasting method could enable a variety of bioactive molecules to be incorporated into printed CHA materials and provides a method of bioprinting biomaterials without compromising their natural properties. PMID- 26930141 TI - Exploiting the antivirulence efficacy of an ajoene-ciprofloxacin combination against Pseudomonas aeruginosa biofilm associated murine acute pyelonephritis. AB - The study investigated the in vitro, ex vivo and in vivo efficacy of ajoene and ciprofloxacin (CIP) alone and in combination against Pseudomonas aeruginosa biofilms and biofilm-associated murine acute pyelonephritis. The ajoene-CIP combination exhibited significant greater (p < 0.05) antimotility and biofilm inhibitory effects than those obtained when they were applied individually. The combined action of the agents resulted in a significant increase in serum sensitivity and phagocytic uptake and killing of P. aeruginosa (p < 0.001) compared to the untreated control. Mice groups treated with an ajoene (25 mg kg( 1)) and CIP (30 mg kg(-1) or 15 mg kg(-1)) combination showed a significantly (p < 0.001) reduced bacterial load in the kidney and bladder as compared to that of infected controls and mice treated with solo agents on the fifth day post infection. The decreased levels of biomarkers and photomicrographs of the kidney tissue of the treated mice showed a reduced severity of damage. Hence, the study highlights the antivirulent and therapeutic efficacy of the ajoene-CIP combination at the minimal dosage of CIP. PMID- 26930142 TI - Silencing of Antichondrogenic MicroRNA-221 in Human Mesenchymal Stem Cells Promotes Cartilage Repair In Vivo. AB - There is a growing demand for the development of experimental strategies for efficient articular cartilage repair. Current tissue engineering-based regenerative strategies make use of human mesenchymal stromal cells (hMSCs). However, when implanted in a cartilage defect, control of hMSCs differentiation toward the chondrogenic lineage remains a significant challenge. We have recently demonstrated that silencing the antichondrogenic regulator microRNA-221 (miR-221) was highly effective in promoting in vitro chondrogenesis of monolayered hMSCs in the absence of the chondrogenic induction factor TGF-beta. Here we investigated the feasibility of this approach first in conventional 3D pellet culture and then in an in vivo model. In pellet cultures, we observed that miR-221 silencing was sufficient to drive hMSCs toward chondrogenic differentiation in the absence of TGF-beta. In vivo, the potential of miR-221 silenced hMSCs was investigated by first encapsulating the cells in alginate and then by filling a cartilage defect in an osteochondral biopsy. After implanting the biopsy subcutaneously in nude mice, we found that silencing of miR-221 strongly enhanced in vivo cartilage repair compared to the control conditions (untreated hMSCs or alginate-only). Notably, miR-221 silenced hMSCs generated in vivo a cartilaginous tissue with no sign of collagen type X deposition, a marker of undesired hypertrophic maturation. Altogether our data indicate that silencing miR-221 has a prochondrogenic role in vivo, opening new possibilities for the use of hMSCs in cartilage tissue engineering. Stem Cells 2016;34:1801-1811. PMID- 26930143 TI - Oxa- and Azacycle Formation via Migrative Cyclization of Sulfonylalkynol and Sulfonylalkynamide with N-Heterocyclic Carbene. AB - An N-heterocyclic carbene promotes cyclization of sulfonylalkynols and sulfonylalkynamides that accompanies 1,2-migration of the sulfonyl groups. This reaction provides a novel access to oxa- and azacycles possessing a pendent vinyl sulfone functionality, which, in turn, is amenable for further transformations. PMID- 26930144 TI - Brief report: Human papillomavirus (HPV) 6, 11, 16, and 18 seroprevalence among males and females entering military service during 2011-2012. PMID- 26930145 TI - Editorial: What's old is new again: syphilis in the U.S. Army. PMID- 26930146 TI - Use of quadrivalent human papillomavirus vaccine and the prevalence of antibodies to vaccine-targeted strains among female service members before and after vaccination. AB - The quadrivalent human papillomavirus vaccine (HPV4) has been shown to generate a robust immune response among fully vaccinated individuals; however, among U.S. service members, HPV vaccine completion rates are low. This study compared the immunogenicity of HPV4 vaccine among partially and fully vaccinated service members at 4-6 years post-vaccination. A random sample was obtained of 2,091 female service members, aged 17-26 years, who received 1-3 HPV4 doses during 2006 2012, stratified by number of doses (one, two, or three). Pre- and post immunization sera from these service members were tested for antibodies to the HPV strains covered by the vaccine. Prior to immunization 42% were seropositive for HPV strain 6; 34% for strain 11; 29% for strain 16; and 16% for strain 18. Among those naive to all four strains prior to immunization, there was 100% seroconversion after one, two, or three doses. The results indicate that many service members had already been exposed to strains of HPV prior to receiving the vaccine; however, seropositivity prevalence was lower for the oncogenic HPV strains 16 and 18. The data demonstrate sustained immunogenicity after a single dose of vaccine, with modest improvement with successive doses for all strains except 18. PMID- 26930147 TI - Sexually transmitted infections in U.S. Air Force recruits in basic military training. AB - This study reports the counts, prevalence, and trends of five common sexually transmitted infections (STIs) among U.S. Air Force recruits during 2012-2014. Chlamydia and genital herpes simplex virus (HSV) were the most commonly identified STIs in females, with a prevalence of 4,841.2 and 432.3 per 100,000, respectively. Genital HSV was the most commonly identified STI in males at 133.4 per 100,000. There were 13 cases of chlamydia and gonorrhea co-infection among females and none among males. STI prevalence was lower than in a similarly aged U.S. civilian population. PMID- 26930148 TI - Incident and recurrent Chlamydia trachomatis and Neisseria gonorrhoeae infections, active component, U.S. Armed Forces, 2010-2014. AB - Chlamydia trachomatis and Neisseria gonorrhoeae infections impose a significant clinical and public health burden on the Military Health System. Repeat infections contribute significantly to that burden. This report summarizes rates and relative risks of true incident (i.e., initial or "first time ever") and recurrent (i.e., repeat) chlamydia and gonorrhea infections among active component members between 1 January 2010 and 31 December 2014. During the surveillance period, a total of 66,396 initial chlamydia and 9,138 initial gonorrhea cases were diagnosed. Annual crude rates of initial chlamydia infections increased by 23%. Crude rates of initial gonorrhea infections remained stable overall, but female rates decreased by 28.3% over the period. Among the incident cohorts, 11,699 cases of repeat chlamydia, and 1,138 cases of repeat gonorrhea were diagnosed over the period, accounting for 15.0% and 11.1% of overall cohort chlamydia and gonorrhea infections, respectively. The Army branch, those aged 17-19 years, females, non-Hispanic black service members, junior enlisted ranks, and single/never-married service members had the highest crude rates of initial chlamydia and gonorrhea infection, and (single/never-married service members excepted) highest adjusted relative risk of repeat chlamydia infection. PMID- 26930149 TI - Incidence of Chlamydia trachomatis infections and screening compliance, U.S. Army active duty females under 25 years of age, 2011-2014. AB - Reported chlamydia infection rates among active duty U.S. Army females less than 25 years old declined by 20% from 2011 to 2014 (11,028 infections per 100,000 person-years [p-yrs] to 8,793 infections per 100,000 p-yrs, respectively). An overall decline in the proportions of high-risk female soldiers tested for chlamydia occurred during the same period, declining from a high of 85% in 2011 to a low of 71% in 2012, with an increase to 80% in 2014. Chlamydia laboratory testing volume also decreased from 2011 to 2013 but the test positivity rate remained stable at 6.0%-6.4%. By using projected incidence rates based on 100% of at-risk women being screened with a stable laboratory positivity rate, there was an estimated 15% decline in chlamydia incidence from 2011 to 2014 (12,794 to 10,991 infections per 100,000 p-yrs, respectively). Surveillance for chlamydia infections must include consideration of screening program performance in addition to passive reporting. PMID- 26930150 TI - Brief report: Associations between antecedent bacterial vaginosis and incident chlamydia and gonorrhea diagnoses, U.S. Army females, 2006-2012. PMID- 26930151 TI - Social determinants of health: Social forces that shape women and men's knowledge of reproductive health in a resource-limited setting. AB - Social forces shape people's reproductive health in many ways. We examined people's knowledge about reproductive health using focus group data collected from 93 participants in rural districts of Malawi. Participants' perspectives were contextualized by explaining the socioeconomic, cultural, and gender factors that determine reproductive health for rural Malawians. Strategies to improve reproductive health care in environments lacking in health infrastructure, staff, and economic resources are then provided. We call for a reproductive health agenda to target preventive care by providing information about anatomy and biology, communicating information in culturally competent ways, and educating men and women over the life course. PMID- 26930152 TI - Relative appendicular skeletal muscle mass is associated with isokinetic muscle strength and balance in healthy collegiate men. AB - There are few studies on the relationship between skeletal muscle mass and balance in the young ages. We investigated the relationship between appendicular skeletal muscle mass, isokinetic muscle strength of lower extremity, and balance among healthy young men using relative skeletal muscle index. Thirty men were grouped according to relative appendicular skeletal muscle mass index: higher skeletal muscle group (n = 15) and lower skeletal muscle group (n = 15). Static and dynamic balance abilities were measured using the following: a test where participants stood on one leg with eyes closed, a modified Clinical Test of Sensory Interaction on Balance (mCTSIB) with eyes open and eyes closed, a stability test, and limits of stability test. The muscle strength of lower extremities was measured with an isokinetic analyser in hip, knee, and ankle joints. Participants with higher appendicular skeletal muscle mass were significantly more stable in maintaining dynamic balance than those with lower appendicular skeletal muscle mass. Moreover, appendicular skeletal muscle mass index was positively correlated with dynamic balance ability. Participants with higher appendicular skeletal muscle mass had stronger strength in the lower extremity, and there were significant differences in the isokinetic torque ratios between groups. From these results, it can be inferred that higher appendicular skeletal muscle mass relates to muscle strength and the alteration in the peak torque ratio of the lower extremity, contributing to the maintenance of balance. PMID- 26930153 TI - Integrated analysis of different microarray studies to identify candidate genes in type 1 diabetes. AB - BACKGROUND: Type 1 diabetes (T1D), an autoimmune disease, occurs most commonly in children. Identifying altered gene expression in peripheral blood mononuclear cells (PBMCs) of T1D may lead to new strategies for preserving or improving beta ell function in patients with T1D. METHODS: The Gene Expression Omnibus database was searched for microarray studies in PBMCs of T1D. Subsequently, gene expression datasets from multiple microarray studies were integrated to obtain differentially expressed genes (DEGs) between T1D and normal controls (NC). Gene function analysis was performed to determine the functions of the DEGs identified. RESULTS: Four microarray studies were available for analysis, including 199 T1D samples and 74 NC samples. Analysis revealed 695 genes that were significantly differentially expressed in PBMCs from T1D compared with NC samples, with 450 upregulated and 245 downregulated. Signal transduction (gene ontology [GO]: 0007165; false discovery rate [FDR] = 1.54 * 10-7 ) and protein binding (GO: 0005515; FDR = 2.93 * 10-24 ) were significantly enriched for the GO categories of biological processes and molecular functions, respectively. The most significant pathway in the Kyoto Encyclopedia of Genes and Genomes analysis was arachidonic acid metabolism (FDR = 1.44 * 10-3 ). Protein-protein interaction network analysis showed that the significant hub proteins contained immature colon carcinoma transcript 1 (ICT1; degree = 214; clustering coefficient [C] = 4.39 * 10-5 ), zinc finger and BTB domain containing 16 (ZBTB16; degree = 112; C = 8.04 * 10-4 ), and SERTA domain containing 1 (SERTAD1; degree = 38; C = 0.0014). CONCLUSIONS: This integrated analysis will help develop improved therapies and interventions for T1D by identifying novel drug targets. PMID- 26930154 TI - Healthcare-seeking behaviors for acute respiratory illness in two communities of Java, Indonesia: a cross-sectional survey. AB - Understanding healthcare-seeking patterns for respiratory illness can help improve estimations of disease burden and inform public health interventions to control acute respiratory disease in Indonesia. The objectives of this study were to describe healthcare-seeking behaviors for respiratory illnesses in one rural and one urban community in Western Java, and to explore the factors that affect care seeking. From February 8, 2012 to March 1, 2012, a survey was conducted in 2520 households in the East Jakarta and Bogor districts to identify reported recent respiratory illnesses, as well as all hospitalizations from the previous 12-month period. We found that 4% (10% of those less than 5years) of people had respiratory disease resulting in a visit to a healthcare provider in the past 2weeks; these episodes were most commonly treated at government (33%) or private (44%) clinics. Forty-five people (0.4% of those surveyed) had respiratory hospitalizations in the past year, and just over half of these (24/45, 53%) occurred at a public hospital. Public health programs targeting respiratory disease in this region should account for care at private hospitals and clinics, as well as illnesses that are treated at home, in order to capture the true burden of illness in these communities. PMID- 26930155 TI - Hypolipidemic Activity of Peony Seed Oil Rich in alpha-Linolenic, is Mediated Through Inhibition of Lipogenesis and Upregulation of Fatty Acid beta-Oxidation. AB - Peony seed oil (PSO) is a new resource food rich in alpha-Linolenic Acid(ALA) (38.66%). The objective of this study was to assess the modulatory effect of PSO on lipid metabolism. Lard oil, safflower oil (SFO), and PSO were fed to wistar rats with 1% cholesterol in the diet for 60 d. Serum and liver lipids showed significant decrease in total cholesterol (TC), triglyceride (TG), and low density lipoprotein-cholesterol (LDL-C) levels in PSO fed rats compared to lard oil and SFO fed rats. ALA, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), contents were significantly increased, whereas linoleic acid (LA), arachidonic acid (AA) levels decreased in serum and liver of PSO fed rats. Feeding PSO increased ALA level and decreased n-6 to n-3 polyunsaturated fatty acid (PUFA) ratio. The hypolipidemic result of PSO indicated that PSO participated in the regulation of plasma lipid concentration and cholesterol metabolism in liver. The decreased expression of sterol regulatory element binding proteins 1C (SREBP-1c), acetyl-CoA carboxylase (ACC), and fatty acid synthase (FAS)-reduced lipid synthesis; Activation of peroxisome proliferator activator receptor (PPARalpha) accompanied by increase of uncoupling protein2 (UP2) and acyl-CoA oxidase (AOX) stimulated lipid metabolism and exerted an antiobesity effect via increasing energy expenditure for prevention of obesity. PMID- 26930156 TI - Late preterm neonatal morbidity in hypertensive versus normotensive women. AB - OBJECTIVE: We estimated risks of late preterm (LP, 34 degrees (/7)-36(6/7) weeks) delivery and neonatal respiratory and non-respiratory morbidity in women with mild and severe hypertension, in both low-risk and high-risk (history of chronic hypertension, preeclampsia (PE), or insulin-dependent diabetes in current pregnancy) cohorts. STUDY DESIGN: This is a secondary analysis of two Maternal Fetal Medicine Units Network randomized trials of aspirin to prevent PE. Women with non-anomalous singleton gestations delivered at >=34 weeks were divided into three groups: normotensive, mild PE/gestational hypertension (GH), and severe PE/GH. Primary outcomes were respiratory (respiratory distress syndrome (RDS), bronchopulmonary dysplasia (BPD), or intubation) and non-respiratory (intraventricular hemorrhage, retinopathy of prematurity, small for gestational age (SGA) <10%, neonatal intensive care unit (NICU) admission, perinatal death, pulmonary hypertension, seizures, and 5 min Apgar <5) morbidity. Associations between LP delivery and risks of respiratory and non-respiratory morbidity were evaluated by fitting log-Binomial regression models before and after adjusting potential confounders. RESULTS: Of 2781 women in the low-risk trial, mild and severe hypertension were diagnosed in 8.5% (n = 235) and 3.3% (n = 92), respectively. Respiratory morbidity was similar in all groups. Risks of non respiratory morbidity were higher in the severe PE/GH group compared with normotensive women (28.3% vs. 16.8%, risk ratio 1.5, 95% confidence interval 1.1, 2.1). When restricting the analysis to late preterm infants, this risk was no longer present. Of the 1542 women in the high-risk trial, mild and severe hypertension were present in 16.6% (n = 256) and 11.9% (n = 184), respectively. Respiratory morbidity was again similar. Risks of non-respiratory morbidity were also not significantly increased in the high-risk cohort. CONCLUSION: In both low and high-risk women, mild PE/GH at >=34 weeks is not associated with an increased risk of neonatal morbidity compared with normotensive women. Increased risk of composite neonatal morbidity related to severe PE/GH is confined to the subgroup of infants with non-respiratory morbidity, and disappears when including only late preterm infants. PMID- 26930157 TI - Shh/Ptch and EGF/ErbB cooperatively regulate branching morphogenesis of fetal mouse submandibular glands. AB - The hedgehog family includes Sonic hedgehog (Shh), Desert hedgehog, and Indian hedgehog, which are well known as a morphogens that play many important roles during development of numerous organs such as the tongue, pancreas, kidney, cartilage, teeth and salivary glands (SMG). In Shh null mice, abnormal development of the salivary gland is seen after embryonic day 14 (E14). Shh also induced lobule formation and lumen formation in acini-like structures in cultured E14 SMG. In this study, we investigated the relationship between Shh and epidermal growth factor (EGF)/ErbB signaling in developing fetal mouse SMG. Administration of Shh to cultured E13 SMG stimulated branching morphogenesis (BrM) and induced synthesis of mRNAs for EGF ligands and receptors of the ErbB family. Shh also stimulated activation of ErbB signaling system such as ERK1/2. AG1478, a specific inhibitor of ErbB receptors, completely suppressed BrM and activation of EGF/ErbB/ERK1/2 cascade in E13 SMGs cultured with Shh. The expressions of mRNA for Egf in mesenchyme and mRNA for Erbb1, Erbb2 and Erbb3 in epithelium of E13 SMG were specifically induced by administration of Shh. These results show that Shh stimulates BrM of fetal mouse SMG, at least in part, through activation of the EGF/ErbB/ERK1/2 signaling system. PMID- 26930158 TI - Photodynamic activity of thiophene-derived lysosome-specific dyes. AB - The photodynamic activity occurring through the lysosome photo-damage is effective in terms of triggered synergic effects which can avoid chemo-resistance pathways. The potential photodynamic activity of two fluorescent lysosome specific probes was studied providing their interaction with human serum albumin, demonstrating their in vitro generation of singlet oxygen and investigating the resulted photo-toxic effect in human cancer cells. PMID- 26930159 TI - Low-intensity electrical muscle stimulation induces significant increases in muscle strength and cardiorespiratory fitness. AB - The aim of this study was to investigate the effect of low-intensity exercise training using belt electrode skeletal muscle electrical stimulation on muscle strength and cardiorespiratory fitness in healthy subjects. Nineteen healthy subjects were allocated into control or intervention groups; in both groups the participants kept regular physical activity while the intervention group underwent 30 min B-SES training at 3-4 METs for four weeks. Knee extensor muscle strength and cardiorespiratory endurance during incremental exercise test were measured at baseline and after four weeks for all participants. The relative change of knee extensor muscle strength in the intervention group was significantly higher than control group (p < .05). Also, oxygen uptake at ventilator threshold and peak oxygen uptake during incremental exercise test significantly increased in the intervention group when compared with control group (p < .05). This study showed that prolonged low-intensity B-SES training resulted in significant increases in muscle strength and cardiorespiratory fitness in healthy subjects. Our present work suggested that B-SES training could assist patients who might have difficulty performing adequate voluntary exercise because of excessive obesity, orthopaedic problems and chronic diseases such as cardiovascular disease and type 2 diabetes. An intervention study conducted for such patients is strongly recommended. PMID- 26930160 TI - Altered heart proteome in fructose-fed Fisher 344 rats exposed to bisphenol A. AB - Bisphenol A (BPA), is an artificial estrogen initially produced for medical purposes but is today widely used in polycarbonate plastics and epoxy resins. Exposure-related reproductive disorders have been found, but recently it has also been suggested that BPA may be involved in obesity, diabetes, myocardial hypertrophy and myocardial infarction in humans. To mimic a modern lifestyle, female rats were fed with fructose or fructose plus BPA (0.25mg/L drinking water). The myocardial left ventricle proteome of water controls, fructose-fed and fructose-fed plus BPA supplemented rats was explored. The proteome was investigated using nano-liquid chromatography tandem mass spectrometry and two dimensional gel electrophoresis followed by matrix assisted laser desorption/ionization mass spectrometry identification. In total, 41 proteins were significantly altered by BPA exposure compared to water or fructose controls. Principal component analysis and cellular process enrichment analysis of altered proteins suggested increased fatty acid transport and oxidation, increased ROS generation and altered structural integrity of the myocardial left ventricle in the fructose-fed BPA-exposed rats, indicating unfavorable effects on the myocardium. In conclusion, BPA exposure in the rats induces major alterations in the myocardial proteome. PMID- 26930161 TI - Preferential processing of self-relevant stimuli occurs mainly at the perceptual and conscious stages of information processing. AB - Self-related stimuli, such as one's own name or face, are processed faster and more accurately than other types of stimuli. However, what remains unknown is at which stage of the information processing hierarchy this preferential processing occurs. Our first aim was to determine whether preferential self-processing involves mainly perceptual stages or also post-perceptual stages. We found that self-related priming was stronger than other-related priming only because of perceptual prime-target congruency. Our second aim was to dissociate the role of conscious and unconscious factors in preferential self-processing. To this end, we compared the "self" and "other" conditions in trials where primes were masked or unmasked. In two separate experiments, we found that self-related priming was stronger than other-related priming but only in the unmasked trials. Together, our results suggest that preferential access to the self-concept occurs mainly at the perceptual and conscious stages of the stimulus processing hierarchy. PMID- 26930162 TI - The failed attribution of the Nobel Prize for Medicine or Physiology to Viktor Hamburger for the discovery of Nerve Growth Factor. AB - The announcement in October 1986 that the Nobel Prize for Physiology or Medicine was to awarded to Rita Levi Montalcini and Stanley Cohen for the discovery of nerve growth factor (NGF) and epidermal growth factor, respectively, caused many to wonder why Viktor Hamburger in whose laboratory the initial work was done had not been included in the award. This article try to reconstruct the history of the discovery of NGF with the aim to re-establish a correct dynamic of the events. PMID- 26930163 TI - Ryanodine receptors contribute to the induction of ischemic tolerance. AB - Ischemic tolerance (IT) is induced by a variety of insults to the brain (e.g., nonfatal ischemia, heat and hypoxia) and it provides a strong neuroprotective effect. Although the mechanisms are still not fully elucidated, Ca(2+) is regarded as a key mediator of IT. Ryanodine receptors (RyRs) are located in the sarcoplasmic/endoplasmic reticulum membrane and are responsible for the release of Ca(2+) from intracellular stores. In brain, neuronal RyRs are thought to play a role in various neuropathological conditions, including ischemia. The purpose of the present study was to investigate the involvement of RyRs in IT. Pretreatment with a RyR antagonist, dantrolene (25mg/kg, i.p), blocked IT in a gerbil global ischemia model, while a RyR agonist, caffeine (100mg/kg, i.p), stimulated the production of IT. In vitro, using rat hippocampal cells, short term oxygen/glucose deprivation induced preconditioning and RyR antagonists, dantrolene (50 and 100 MUM) and ryanodine (100 and 200 MUM) prevented it. RyR protein and mRNA levels were transiently decreased after induction of IT. These results suggest that RyRs are involved in the induction of ischemic tolerance. PMID- 26930164 TI - Efficacy of ferulic acid encapsulated chitosan nanoparticles against Candida albicans biofilm. AB - Candida albicans, an opportunistic fungal pathogen is a major causative agent of superficial to systemic life-threating biofilm infections on indwelling medical devices. These biofilms acts as double edge swords owing to their resistance towards antibiotics and immunological barriers. To overcome this threat ferulic acid encapsulated chitosan nanoparticles (FA-CSNPs) were formulated to assess its efficacy as an antibiofilm agent against C. albicans. These FA-CSNPs were synthesized using ionotropic gelation method and observed through field emission scanning electron microscopy (FESEM) and fluorescent microscopy. Assessment of successful encapsulation and stability of ferulic acid into chitosan nanoparticles was made using Fourier transform infrared spectrum (FTIR), (1)H NMR and thermal analyses. Synthesized FA-CSNPs, were found to be cytocompatible, when tested using Human Embryonic Kidney (HEK-293) cell lines. XTT assay revealed that FA-CSNPs reduced the cell metabolic activity of C. albicans upto 22.5% as compared to native ferulic acid (63%) and unloaded CSNPs (88%) after 24 h incubation. Disruption of C. albicans biofilm architecture was visualized by FESEM. Results highlighted the potential of FA-CSNPs to be used as an effective alternative to the conventional antifungal therapeutics. PMID- 26930165 TI - Friendship trumps neediness: The impact of social relations and others' wealth on preschool children's sharing. AB - Recent work has suggested the presence of a variety of motives and mechanisms that affect young children's sharing decisions. Yet, little is known about the relative impact of these motives. In three experiments with 3- to 6-year-old children (total N=140), the current study contrasts two important recipient characteristics that have been suggested to play a major role in early sharing; the positive social relationship between children and recipients and the differences in recipients' wealth. To this end, children could allocate resources to a friend who already possessed a lot of them and to a nonfriend (Experiments 1 and 2) or a stranger (Experiment 3) who owned only very few resources. Across age, children showed a preference to share more with their rich friend, although this tendency was stronger in the older preschool children. The findings are discussed with respect to theoretical accounts on the psychological basis of early sharing. PMID- 26930166 TI - Bilingual effects on deployment of the attention system in linguistically and culturally homogeneous children and adults. AB - We investigated the impact of early childhood and adulthood bilingualism on the attention system in a group of linguistically and culturally homogeneous children (5- and 6-year olds) and young adults. We administered the child Attention Network Test (ANT) to 63 English monolingual and Korean-English bilingual children and administered the adult ANT to 39 language- and culture-matched college students. Advantageous bilingual effects on attention were observed for both children and adults in global processing levels of inverse efficiency, response time, and accuracy at a magnitude more pronounced for children than for adults. Differential bilingualism effects were evident at the local network level of executive control and orienting in favor of the adult bilinguals only. Notably, however, bilingual children achieved an adult level of accuracy in the incongruent flanker condition, implying enhanced attentional skills to cope with interferences. Our findings suggest that although both child and adult bilinguals share cognitive advantages in attentional functioning, age-related cognitive and linguistic maturation differentially shapes the outcomes of attentional processing at a local network level. PMID- 26930167 TI - Cooperation among cancer cells as public goods games on Voronoi networks. AB - Cancer cells produce growth factors that diffuse and sustain tumour proliferation, a form of cooperation that can be studied using mathematical models of public goods in the framework of evolutionary game theory. Cell populations, however, form heterogeneous networks that cannot be described by regular lattices or scale-free networks, the types of graphs generally used in the study of cooperation. To describe the dynamics of growth factor production in populations of cancer cells, I study public goods games on Voronoi networks, using a range of non-linear benefits that account for the known properties of growth factors, and different types of diffusion gradients. The results are surprisingly similar to those obtained on regular graphs and different from results on scale-free networks, revealing that network heterogeneity per se does not promote cooperation when public goods diffuse beyond one-step neighbours. The exact shape of the diffusion gradient is not crucial, however, whereas the type of non-linear benefit is an essential determinant of the dynamics. Public goods games on Voronoi networks can shed light on intra-tumour heterogeneity, the evolution of resistance to therapies that target growth factors, and new types of cell therapy. PMID- 26930169 TI - Editorial by new Editors-in-Chief. PMID- 26930168 TI - New perspectives on rare connective tissue calcifying diseases. AB - Connective tissue calcifying diseases (CTCs) are characterized by abnormal calcium deposition in connective tissues. CTCs are caused by multiple factors including chronic diseases (Type II diabetes mellitus, chronic kidney disease), the use of pharmaceuticals (e.g. warfarin, glucocorticoids) and inherited rare genetic diseases such as pseudoxanthoma elasticum (PXE), generalized arterial calcification in infancy (GACI) and Keutel syndrome (KTLS). This review explores our current knowledge of these rare inherited CTCs, and highlights the most promising avenues for pharmaceutical intervention. Advancing our understanding of rare inherited forms of CTC is not only essential for the development of therapeutic strategies for patients suffering from these diseases, but also fundamental to delineating the mechanisms underpinning acquired chronic forms of CTC. PMID- 26930170 TI - Dysfunctional error-related processing in incarcerated youth with elevated psychopathic traits. AB - Adult psychopathic offenders show an increased propensity towards violence, impulsivity, and recidivism. A subsample of youth with elevated psychopathic traits represent a particularly severe subgroup characterized by extreme behavioral problems and comparable neurocognitive deficits as their adult counterparts, including perseveration deficits. Here, we investigate response locked event-related potential (ERP) components (the error-related negativity [ERN/Ne] related to early error-monitoring processing and the error-related positivity [Pe] involved in later error-related processing) in a sample of incarcerated juvenile male offenders (n=100) who performed a response inhibition Go/NoGo task. Psychopathic traits were assessed using the Hare Psychopathy Checklist: Youth Version (PCL:YV). The ERN/Ne and Pe were analyzed with classic windowed ERP components and principal component analysis (PCA). Using linear regression analyses, PCL:YV scores were unrelated to the ERN/Ne, but were negatively related to Pe mean amplitude. Specifically, the PCL:YV Facet 4 subscale reflecting antisocial traits emerged as a significant predictor of reduced amplitude of a subcomponent underlying the Pe identified with PCA. This is the first evidence to suggest a negative relationship between adolescent psychopathy scores and Pe mean amplitude. PMID- 26930172 TI - The influence of chronotype in the daily lives of young children. AB - Research on chronotypic differences has been conducted for many years, however, until recently, little attention has been paid to young children. The current study examined the influence of morningness-eveningness in the daily lives of 2 to 4 year olds (291 females, 230 males, 8 gender not given) via an online survey completed by 529 mothers from across the United States. The results replicated previous findings on chronotypic differences in sleep-wake patterns and the development of morningness-eveningness in early childhood. The influence of chronotype on sleep habits, daily routines and schedules was also explored. At both bed and wake times, mothers of evening type (E-type) children were more likely to report challenges. For a while, morning type (M-type) children tended to fall asleep easily and wake themselves up in the morning, E-types were more likely to show bedtime resistance, wake in a negative mood and have conflicts with their parents. In the morning, mothers of M-type children often stuck to their normal routine on days when the child had to be somewhere at 7:00 am, whereas mothers of E-type children employed different strategies to get their child up and out the door. Bedtime routines and daily schedules also differed by chronotype. Individual differences in morningness-eveningness and their impact on sleep-wake patterns and social interactions are evident early on. A greater understanding of how they affect the lives of young children and their future development is needed. PMID- 26930173 TI - Modality specificity in the cerebro-cerebellar neurocircuitry during working memory. AB - Previous studies have suggested cerebro-cerebellar circuitry in working memory. The present fMRI study aims to distinguish differential cerebro-cerebellar activation patterns in verbal and visual working memory, and employs a quantitative analysis to deterimine lateralization of the activation patterns observed. Consistent with Chen and Desmond (2005a,b) predictions, verbal working memory activated a cerebro-cerebellar circuitry that comprised left-lateralized language-related brain regions including the inferior frontal and posterior parietal areas, and subcortically, right-lateralized superior (lobule VI) and inferior cerebellar (lobule VIIIA/VIIB) areas. In contrast, a distributed network of bilateral inferior frontal and inferior temporal areas, and bilateral superior (lobule VI) and inferior (lobule VIIB) cerebellar areas, was recruited during visual working memory. Results of the study verified that a distinct cross cerebro-cerebellar circuitry underlies verbal working memory. However, a neural circuitry involving specialized brain areas in bilateral neocortical and bilateral cerebellar hemispheres subserving visual working memory is observed. Findings are discussed in the light of current models of working memory and data from related neuroimaging studies. PMID- 26930171 TI - Nitric Oxide Exerts Basal and Insulin-Dependent Anorexigenic Actions in POMC Hypothalamic Neurons. AB - The arcuate nucleus of the hypothalamus represents a key center for the control of appetite and feeding through the regulation of 2 key neuronal populations, notably agouti-related peptide/neuropeptide Y and proopimelanocortin (POMC)/cocaine- and amphetamine-regulated transcript neurons. Altered regulation of these neuronal networks, in particular the dysfunction of POMC neurons upon high-fat consumption, is a major pathogenic mechanism involved in the development of obesity and type 2 diabetes mellitus. Efforts are underway to preserve the integrity or enhance the functionality of POMC neurons in order to prevent or treat these metabolic diseases. Here, we report for the first time that the nitric oxide (NO(-)) donor, sodium nitroprusside (SNP) mediates anorexigenic actions in both hypothalamic tissue and hypothalamic-derived cell models by mediating the up-regulation of POMC levels. SNP increased POMC mRNA in a dose dependent manner and enhanced alpha-melanocortin-secreting hormone production and secretion in mHypoA-POMC/GFP-2 cells. SNP also enhanced insulin-driven POMC expression likely by inhibiting the deacetylase activity of sirtuin 1. Furthermore, SNP enhanced insulin-dependent POMC expression, likely by reducing the transcriptional repression of Foxo1 on the POMC gene. Prolonged SNP exposure prevented the development of insulin resistance. Taken together, the NO(-) donor SNP enhances the anorexigenic potential of POMC neurons by promoting its transcriptional expression independent and in cooperation with insulin. Thus, increasing cellular NO(-) levels represents a hormone-independent method of promoting anorexigenic output from the existing POMC neuronal populations and may be advantageous in the fight against these prevalent disorders. PMID- 26930175 TI - Recent advances in hyaluronic acid hydrogels for biomedical applications. AB - Hyaluronic acid (HA) is widely used in the design of engineered hydrogels, due to its biofunctionality, as well as numerous sites for modification with reactive groups. There are now widespread examples of modified HA macromers that form either covalent or physical hydrogels through crosslinking reactions such as with click chemistry or supramolecular assemblies of guest-host pairs. HA hydrogels range from relatively static matrices to those that exhibit spatiotemporally dynamic properties through external triggers like light. Such hydrogels are being explored for the culture of cells in vitro, as carriers for cells in vivo, or to deliver therapeutics, including in an environmentally responsive manner. The future will bring new examples of HA hydrogels due to the synthetic diversity of HA. PMID- 26930174 TI - Substrain and light regime effects on integrated anxiety-related behavioral z scores in male C57BL/6 mice-Hypomagnesaemia has only a small effect on avoidance behavior. AB - Magnesium (Mg) has been described to possess an anxiolytic function, but a number of studies present inconsistent results on this matter. In this study the effect of Mg deficiency on anxiety-related behavior, brain and blood plasma Mg in young adult male C57BL/6JOlaHsd and C57BL/6NCrl mice was studied. The animals were put on a control or Mg deficient diet from day 0 and significant hypomagnesaemia was evident from day 12 onwards in the test animals. Housing and test conditions were under either conventional light regime (white light behavioral test conditions) or reverse light regime (red light behavioral test conditions). The animals were tested in three tests for unconditioned anxiety: the modified Hole Board (day 14), the light-dark test (day 21) and the elevated plus maze (day 28). Overall integrated behavioral z-scores were calculated over these three behavioral tests. Mg showed a structure dependent distribution at the level of the brain, that differed between C57BL/6 substrain and light regime (conventional versus reverse), respectively. Likewise, total brain Mg did differ between substrain and light regime, but was not affected by the diet. Animals on the Mg deficient diet housed under conventional light regime had a higher final (day 28) blood plasma corticosterone level as compared to controls. Animals housed under reverse light regime exhibited no diet effect of plasma corticosterone levels. The significant hypomagnesaemia at blood plasma level resulted in an effect of Mg deficiency on avoidance, but not overall anxiety-related behavior. Significant differences regarding avoidance behavior were found between the two substrains and light regimes, respectively. PMID- 26930176 TI - Detection of circulating trophoblast particles in maternal blood using density gradient centrifugation in preeclampsia and in normotensive pregnancies. AB - OBJECTIVE: Preeclampsia (PE) is a frequent pregnancy-related disease and a major cause of maternal and fetal morbidity and mortality. Despite that, exact mechanisms of its pathophysiology remain largely unknown. In pregnancies complicated by PE, changes in the regulation of apoptosis seem to result in increased apoptotic shedding of trophoblast particles (TPs) into maternal circulation. Since the number of TP in peripheral blood is low, their detection necessitates pre-analytical enrichment. METHODS: In this prospective multicenter pilot study we aimed to analyze TP in peripheral blood of 29 women with PE and of 13 unaffected controls using the OncoQuick(r)plus system for cell enrichment. Using immunocytochemistry, slides were evaluated microscopically for TP. Statistical analyses were performed using Welch's t-test or Fisher's exact test. RESULTS: TP were detected in 10 (34.5%) women with PE and in two (15.4%) of unaffected controls. More than one TP were only found in PE. Comparing the mean counts of TP between groups, we detected significantly more TP in PE (p = 0.046). CONCLUSIONS: The OncoQuick(r)plus system can be applied to detect TP in both women with PE and in normotensive pregnancies. Longitudinal studies investigating the role of TP as a screening method for patients at risk for PE are warranted. PMID- 26930177 TI - Study protocol Implementation of the Veder contact method (VCM) in daily nursing home care for people with dementia: an evaluation based on the RE-AIM framework. AB - OBJECTIVES: People with dementia in nursing homes benefit from person-centred care methods. Studies examining the effect of these methods often fail to report about the implementation of these methods. The present study aims to describe the implementation of the Veder contact method (VCM) in daily nursing home care. METHOD: A process analysis will be conducted based on qualitative data from focus groups with caregivers and interviews with key figures. To investigate whether the implementation of VCM is reflected in the attitude and behaviour of caregivers and in the behaviour and quality of life of people with dementia, a controlled observational cohort study will be conducted. Six nursing home wards implementing VCM will be compared with six control wards providing Care As Usual. Quantitative data from caregivers and residents will be collected before (T0), and 9-12 months after the implementation (T1). Qualitative analysis and multilevel analyses will be carried out on the collected data and structured based on the constructs of the RE-AIM framework (Reach, Effectiveness, Adoption, Implementation, Maintenance). CONCLUSION: By using the RE-AIM framework this study introduces a structured and comprehensive way of investigating the implementation process and implementation effectiveness of person-centred care methods in daily dementia care. PMID- 26930178 TI - An Analysis of Intravenous Catheter Placement Among Patients in a Pediatric Emergency Department. AB - OBJECTIVES: Pediatric emergency departments (PED) are overcrowded and at times inefficient with malaligned resources, especially regarding the use of intravenous (IV) catheters which are placed frequently, yet may be underused. This study seeks to determine which pediatric patients are more likely to need IV access in a PED. METHODS: This retrospective study examined patients 3 days to 21 years seen in a tertiary PED from January 1, 2013, to February 28, 2013, who were triaged using the Emergency Severity Index, levels 1 to 3. Extracted data included age, chief complaints, chronic medical conditions, final diagnoses, evidence of venipuncture, and IV placement and usage. Patients were excluded if they entered the PED with an IV or central venous catheter, were older than 21 years, or had charts with missing data. RESULTS: Four thousand three hundred twenty-two patients were initially evaluated, and 122 patients were excluded. Mean age of the patients was 6.2 years (SD = 5.65), most common triage was level 3 (urgent), and the majority of patients (n = 2898, 69.0%) did not have a chronic medical condition. Five hundred forty-five (13%) had IVs placed, and of those, 152 (27.9%) had IVs placed and not used. Patients triaged as critical or emergent, patients older than 10 years, and those with a gastrointestinal chief complaint and chronic medical conditions involving hematology, oncology/immunology, or endocrinology were most likely to have an IV placed and used. CONCLUSIONS: Patients with higher acuities, specified systemic complaints, certain chronic medical conditions, and patients older than 10 years are more likely to need an IV. PMID- 26930179 TI - Characterisation of the surface structure of 3D printed scaffolds for cell infiltration and surgical suturing. AB - 3D printing is of great interest for tissue engineering scaffolds due to the ability to form complex geometries and control internal structures, including porosity and pore size. The porous structure of scaffolds plays an important role in cell ingrowth and nutrition infusion. Although the internal porosity and pore size of 3D printed scaffolds have been frequently studied, the surface porosity and pore size, which are critical for cell infiltration and mass transport, have not been investigated. The surface geometry can differ considerably from the internal scaffold structure depending on the 3D printing process. It is vital to be able to control the surface geometry of scaffolds as well as the internal structure to fabricate optimal architectures. This work presents a method to control the surface porosity and pore size of 3D printed scaffolds. Six scaffold designs have been printed with surface porosities ranging from 3% to 21%. We have characterised the overall scaffold porosity and surface porosity using optical microscopy and microCT. It has been found that surface porosity has a significant impact on cell infiltration and proliferation. In addition, the porosity of the surface has been found to have an effect on mechanical properties and on the forces required to penetrate the scaffold with a surgical suturing needle. To the authors' knowledge, this study is the first to investigate the surface geometry of extrusion-based 3D printed scaffolds and demonstrates the importance of surface geometry in cell infiltration and clinical manipulation. PMID- 26930180 TI - Association of Muscle Mass, Area, and Strength With Incident Diabetes in Older Adults: The Health ABC Study. AB - CONTEXT: Skeletal muscle plays a key role in glucose regulation, yet the association between muscle quantity or quality and the risk of developing type 2 diabetes has not been explored. OBJECTIVE: The objective of the study was to assess the association between muscle quantity and strength and incident diabetes and to explore whether this association differs by body mass index (BMI) category. DESIGN AND SETTING: Participants were 2166 older adults in the Health, Aging, and Body Composition Study who were free of diabetes at baseline (1997 1998). Computed tomography and dual-energy x-ray absorptiometry were used to measure abdominal and thigh muscle area and total body lean mass, respectively. Strength was quantified by grip and knee extensions. MAIN OUTCOME MEASURE: Incident diabetes, defined as fasting glucose of 126 mg/dL or greater, a physician's diagnosis, and/or the use of hypoglycemic medication were measured. RESULTS: After a median 11.3 years of follow-up, there were 265 incident diabetes cases (12.2%). In fully adjusted models, no association was found between muscle or strength measures and incident diabetes (for all, P > .05). For women, there was a significant interaction with BMI category for both abdominal and thigh muscle, such that greater muscle predicted lower risk of incident diabetes for normal-weight women (hazard ratio 0.37 [0.17-0.83] and 0.58 [0.27-1.27] per SD, respectively) and a greater risk for overweight and obese women (hazard ratio 1.23 [0.98-1.54] and 1.28 [1.00-1.64], respectively). No significant interactions by BMI category existed for strength measures or any measures for men (for all, P > .05). CONCLUSIONS: Greater muscle area is associated with a lower risk of incident diabetes for older normal-weight women but not for men or overweight women. PMID- 26930182 TI - Pediatric Thyroid Cancer: Postoperative Classifications and Response to Initial Therapy as Prognostic Factors. AB - CONTEXT: Prognostic factors for pediatric differentiated thyroid cancer (DTC) are not well established. OBJECTIVE: The objective of the study was to retrospectively compare the postoperative risk-stratification systems: American Thyroid Association (ATA) risk categories, Schneider Children's Medical Center of Israel (SCMCI) score, and the response to initial therapy as predictors for disease outcome. PATIENTS AND METHODS: Fifty-four DTC patients, median age at diagnosis 13.9 years (range 1.9-17 y), followed up for a median of 8.8 years (range 2.6-20.5 y) were stratified into prepubertal (n = 9), pubertal (n = 25), and postpubertal (n = 20) groups. All patients underwent total/near-total thyroidectomy; 48 received radioiodine therapy. The extent of DTC was evaluated by applying the ATA risk categories and the novel SCMCI score. Postoperative risk stratifications (low/intermediate/high) were determined using histopathological, laboratory, and imaging findings. Response to initial therapy (complete/acceptable/incomplete) was based on stimulated thyroglobulin and imaging results during the first 2 years of follow-up. RESULTS: The risk for recurrent/persistent disease, as assessed by the postoperative ATA risk stratification system and the SCMCI score and by the response to initial therapy, was higher in the prepubertal group (P < .001, P = .002, and P = .02, respectively). Outcome prediction by the risk-stratification systems was applicable: ATA risk categories, P = .014, R(2) = 0.247, predictive ability 80.4%; SCMCI score, P < .001, R(2) = 0.435, predictive ability 86.3%; and response to initial therapy stratification, P < .001, R(2) = 0.789, predictive ability 96.1%. The proportion of variance explained by the ATA risk categories (0.25), SCMCI score (0.44), and response to initial therapy (0.79) indicated that the latter was the most precise predictor and that the SCMCI score reflected the disease outcome better than ATA risk categories. CONCLUSIONS: Our data confirm that the postoperative pediatric ATA stratification system and the novel SCMCI score are suitable for predicting the risk of recurrent/persistent disease in this population. The response to initial therapy classification performed 1-2 years after the initial therapy may be more appropriate for guiding surveillance recommendations. PMID- 26930181 TI - Effect of Pramlintide on Postprandial Glucose Fluxes in Type 1 Diabetes. AB - CONTEXT: Early postprandial hyperglycemia and delayed hypoglycemia remain major problems in current management of type 1 diabetes (T1D). OBJECTIVE: Our objective was to investigate the effects of pramlintide, known to suppress glucagon and delay gastric emptying, on postprandial glucose fluxes in T1D. DESIGN: This was a single-center, inpatient, randomized, crossover study. PATIENTS: Twelve patients with T1D who completed the study were analyzed. INTERVENTIONS: Subjects were studied on two occasions with or without pramlintide. Triple tracer mixed-meal method and oral minimal model were used to estimate postprandial glucose turnover and insulin sensitivity (SI). Integrated liver insulin sensitivity was calculated based on glucose turnover. Plasma glucagon and insulin were measured. MAIN OUTCOME MEASURE: Glucose turnover and SI were the main outcome measures. RESULTS: With pramlintide, 2-hour postprandial glucose, insulin, glucagon, glucose turnover, and SI indices showed: plasma glucose excursions were reduced (difference in incremental area under the curve [iAUC], 444.0 mMmin, P = .0003); plasma insulin concentrations were lower (difference in iAUC, 7642.0 pMmin; P = .0099); plasma glucagon excursions were lower (difference in iAUC, 1730.6 pg/mlmin; P = .0147); meal rate of glucose appearance was lower (difference in iAUC: 1196.2 MUM/kg fat free mass [FFM]; P = .0316), endogenous glucose production was not different (difference in iAUC: -105.5 MUM/kg FFM; P = .5842), rate of glucose disappearance was lower (difference in iAUC: 1494.2 MUM/kg FFM; P = .0083). SI and liver insulin sensitivity were not different between study visits (P > .05). CONCLUSIONS: Inhibition of glucagon and gastric emptying delaying reduced 2-hour prandial glucose excursions in T1D by delaying meal rate of glucose appearance. PMID- 26930185 TI - Potential Energy Surface of the Chromium Dimer Re-re-revisited with Multiconfigurational Perturbation Theory. AB - The chromium dimer has long been a benchmark molecule to evaluate the performance of different computational methods ranging from density functional theory to wave function methods. Among the latter, multiconfigurational perturbation theory was shown to be able to reproduce the potential energy surface of the chromium dimer accurately. However, for modest active space sizes, it was later shown that different definitions of the zeroth-order Hamiltonian have a large impact on the results. In this work, we revisit the system for the third time with multiconfigurational perturbation theory, now in order to increase the active space of the reference wave function. This reduces the impact of the choice of zeroth-order Hamiltonian and improves the shape of the potential energy surface significantly. We conclude by comparing our results of the dissocation energy and vibrational spectrum to those obtained from several highly accurate multiconfigurational methods and experiment. For a meaningful comparison, we used the extrapolation to the complete basis set for all methods involved. PMID- 26930183 TI - Does Sitagliptin Affect the Rate of Osteoporotic Fractures in Type 2 Diabetes? Population-Based Cohort Study. AB - CONTEXT: Type 2 diabetes and osteoporosis are both common, chronic, and increase with age, whereas type 2 diabetes is also a risk factor for major osteoporotic fractures (MOFs). However, different treatments for type 2 diabetes can affect fracture risk differently, with metaanalyses showing some agents increase risk (eg, thiazolidinediones) and some reduce risk (eg, sitagliptin). OBJECTIVE: To determine the independent association between new use of sitagliptin and MOF in a large population-based cohort study. DESIGN, SETTING, AND SUBJECTS: A sitagliptin new user study design employing a nationally representative Unites States claims database of 72 738 insured patients with type 2 diabetes. We used 90-day time varying sitagliptin exposure windows and controlled confounding by using multivariable analyses that adjusted for clinical data, comorbidities, and time updated propensity scores. MAIN OUTCOMES: We compared the incidence of MOF (hip, clinical spine, proximal humerus, distal radius) in new users of sitagliptin vs nonusers over a median 2.2 years follow-up. RESULTS: At baseline, the median age was 52 years, 54% were men, and median A1c was 7.5%. There were 8894 new users of sitagliptin and 63 834 nonusers with a total 181 139 person-years of follow-up. There were 741 MOF (79 hip fractures), with 53 fractures (4.8 per 1000 person years) among new users of sitagliptin vs 688 fractures (4.0 per 1000 person years) among nonusers (P = .3 for difference). In multivariable analyses, sitagliptin was not associated with fracture (adjusted hazard ratio 1.1, 95% confidence interval 0.8-1.4; P = .7), although insulin (P < .001), sulfonylureas (P < .008), and thiazolidinedione (P = .019) were each independently associated with increased fracture risk. CONCLUSIONS: Even in a young population with type 2 diabetes, osteoporotic fractures were not uncommon. New use of sitagliptin was not associated with fracture, but other commonly used second-line agents for type 2 diabetes were associated with increased risk. These data should be considered when making treatment decisions for those with type 2 diabetes at particularly high risk of fractures. PMID- 26930186 TI - Hydrogel Drug Delivery System Using Self-Cleaving Covalent Linkers for Once-a Week Administration of Exenatide. AB - We have developed a unique long-acting drug-delivery system for the GLP-1 agonist exenatide. The peptide was covalently attached to Tetra-PEG hydrogel microspheres by a cleavable beta-eliminative linker; upon s.c. injection, the exenatide is slowly released at a rate dictated by the linker. A second beta-eliminative linker with a slower cleavage rate was incorporated in polymer cross-links to trigger gel degradation after drug release. The uniform 40 MUm microspheres were fabricated using a flow-focusing microfluidic device and in situ polymerization within droplets. The exenatide-laden microspheres were injected subcutaneously into the rat, and serum exenatide measured over a one-month period. Pharmacokinetic analysis showed a t1/2,beta of released exenatide of about 7 days which represents over a 300-fold half-life extension in the rat and exceeds the half-life of any currently approved long-acting GLP-1 agonist. Hydrogel-exenatide conjugates gave an excellent Level A in vitro-in vivo correlation of release rates of the peptide from the gel, and indicated that exenatide release was 3 fold faster in vivo than in vitro. Pharmacokinetic simulations indicate that the hydrogel-exenatide microspheres should support weekly or biweekly subcutaneous dosing in humans. The rare ability to modify in vivo pharmacokinetics by the chemical nature of the linker indicates that an even longer acting exenatide is feasible. PMID- 26930184 TI - Circulating Sex Steroids and Vascular Calcification in Community-Dwelling Men: The Framingham Heart Study. AB - CONTEXT: The relationship between sex steroids and atherosclerosis is poorly understood. OBJECTIVE: To describe the association of serum total T (TT), calculated free T (cFT), estrone (E1), estradiol (E2), and SHBG to vascular calcification in adult men. DESIGN: Observational study (Framingham Heart Study). Analyses are cross-sectional. TT, E1, and E2 were measured by liquid chromatography-tandem mass spectrometry, and SHBG by immunofluorometric assay. Estimates of association were obtained by Tobit regression, which acknowledges the influence of floor effects on outcomes. SETTING: General community. PARTICIPANTS: A total of 1654 community-dwelling men from the Offspring and Third Generation cohorts of the Framingham Heart Study. MAIN OUTCOME MEASURES: Coronary artery calcification (CAC), abdominal aortic calcification, and thoracic aortic calcification were measured by computed tomography. RESULTS: Mean (standard deviation [SD]) age was 49 (10) years. Mean (SD) TT, cFT, and SHBG were: 616 (224) ng/dL, 111 (45) pg/mL, and 46 (23) nmol/L, respectively. Mean (SD) E2 and E1 were 28 (10) and 39 (14) pg/mL. Vascular calcification at all sites was negatively associated with TT and cFT and positively associated with E2 and E1. A 100-ng/dL between-subjects increase in TT was associated with a mean (95% confidence interval) age-adjusted difference in CAC of -23% (-41%, -4%) (P = .02). After model adjustment for other cardiovascular risk factors, the estimated associations between T and vascular calcification scores were statistically nonsignificant. CONCLUSIONS: Decreased circulating T and E2 levels are associated with an age-adjusted increase in CAC, but these associations appear to express relationships either attributable to or mediated by established cardiovascular risk factors. PMID- 26930187 TI - Antenatal Emergency Care Provided by Paramedics: A One-Year Clinical Profile. AB - OBJECTIVE: To report on clinical and socio-demographic factors of a one-year caseload of women attended by a statewide ambulance service in Australia, who presented during pregnancy, prior to the commencement of labor. METHODS: Retrospective clinical data collected via in-field electronic patient care record (VACIS(r)) by paramedics during clinical management was provided by Ambulance Victoria. Cases were electronically extracted from the Ambulance Victoria Clinical Data Warehouse via comprehensive filtering followed by case review. RESULTS: Over a 12-month period, paramedics were called to 2,098 women with pregnancy as a primary or non-primary clinical consideration. Women's ages ranged from 14 to 48 years. The majority were multigravidas (86%). There was a greater chance that ambulance services would be required during business hours than any other time of the day. Paramedics noted pregnant women required ambulance services for a range of primary presenting symptoms both obstetric (n = 1137) and non-obstetric (n = 961). Some women had pre-existing conditions including asthma, hypertension, and diabetes potentially complicating their pregnancies. Paramedics administered analgesia to one third of the women. Paired t-tests revealed significant improvement in the pain relief and overall vital signs of the women encountered. Less than half the women (n = 986, 47%) required interventions. CONCLUSIONS: This is a unique population wide analysis of ambulance service resource use exploring the clinical profile of pregnant women requiring ambulance services in one calendar year. To manage obstetric and non-obstetric complications in this population safely and effectively, paramedics require an understanding of the unique physiological adaptions during pregnancy. This study therefore has both educational and practice implications. PMID- 26930188 TI - Myasthenia gravis in pregnancy: Experience of a portuguese center. AB - INTRODUCTION: We evaluated the clinical course during pregnancy and neonatal outcomes of a cohort of Portuguese women with myasthenia gravis (MG). METHODS: Retrospective study. RESULTS: Twenty-five patients with 30 pregnancies were included. Mean maternal age was 32.4 +/- 4.1 years. Miscarriage rate was 6.7%, with delivery of 28 newborns. Deterioration in MG during pregnancy occurred in 43.3%, and 46.4% occurred at postpartum. Eighty percent were medicated with pyridostigmine, 43.3% with corticosteroids, and 40% with intravenous immunoglobulin. There were no maternal or neonatal deaths. Mean gestational time at delivery was 38.2 weeks. No cases of fetal growth restriction, preeclampsia, preterm delivery, or fetal demise were observed. Global cesarean rate was 64.3%. Two newborns developed transient neonatal myasthenia. CONCLUSIONS: A high rate of clinical worsening of MG in the mother was observed in this retrospective study, which highlights the importance of a multidisciplinary approach for avoiding maternal adverse outcomes. Muscle Nerve 54: 715-720, 2016. PMID- 26930189 TI - On the blessing of abstraction. AB - The "blessing of abstraction" refers to the observation that acquiring abstract knowledge sometimes proceeds more quickly than acquiring more specific knowledge. This observation can be formalized and reproduced by hierarchical Bayesian models. The key notion is that more abstract layers of the hierarchy have a larger "effective" sample size, because they combine information across multiple specific instances lower in the hierarchy. This notion relies on specific variables being relatively concentrated around the abstract "overhypothesis". If the variables are highly dispersed, then the effective sample size for the abstract layers will not be appreciably larger than for the specific layers. Moreover, the blessing of abstraction is counterbalanced by the fact that data are more informative about lower levels of the hierarchy, because there is necessarily less stochasticity intervening between specific variables and the data. Thus, in certain cases abstract knowledge will be acquired more slowly than specific knowledge. This paper reports an experiment that shows how manipulating dispersion can produce both fast and slow acquisition of abstract knowledge in the same paradigm. PMID- 26930190 TI - Phenolic Compounds in Extra Virgin Olive Oil Stimulate Human Osteoblastic Cell Proliferation. AB - In this study, we aimed to clarify the effects of phenolic compounds and extracts from different extra virgin olive oil (EVOO) varieties obtained from fruits of different ripening stages on osteoblast cells (MG-63) proliferation. Cell proliferation was increased by hydroxytyrosol, luteolin, apigenin, p-coumaric, caffeic, and ferulic acids by approximately 11-16%, as compared with controls that were treated with one vehicle alone, while (+)-pinoresinol, oleuropein, sinapic, vanillic acid and derivative (vanillin) did not affect cell proliferation. All phenolic extracts stimulated MG-63 cell growth, and they induced higher cell proliferation rates than individual compounds. The most effective EVOO phenolic extracts were those obtained from the Picual variety, as they significantly increased cell proliferation by 18-22%. Conversely, Arbequina phenolic extracts increased cell proliferation by 9-13%. A decline in osteoblast proliferation was observed in oils obtained from olive fruits collected at the end of the harvest period, as their total phenolic content decreases at this late stage. Further research on the signaling pathways of olive oil phenolic compounds involved in the processes and their metabolism should be carried out to develop new interventions and adjuvant therapies using EVOO for bone health (i.e.osteoporosis) in adulthood and the elderly. PMID- 26930191 TI - Effectiveness and Cost-Effectiveness of Occupation-Based Occupational Therapy Using the Aid for Decision Making in Occupation Choice (ADOC) for Older Residents: Pilot Cluster Randomized Controlled Trial. AB - BACKGROUND: Care-home residents are mostly inactive, have little interaction with staff, and are dependent on staff to engage in daily occupations. We recently developed an iPad application called the Aid for Decision-making in Occupation Choice (ADOC) to promote shared decision-making in activities and occupation based goal setting by choosing from illustrations describing daily activities. This study aimed to evaluate if interventions based on occupation-based goal setting using the ADOC could focus on meaningful activities to improve quality of life and independent activities of daily living, with greater cost-effectiveness than an impairment-based approach as well as to evaluate the feasibility of conducting a large cluster, randomized controlled trial. METHOD: In this single (assessor)-blind pilot cluster randomized controlled trial, the intervention group (ADOC group) received occupational therapy based on occupation-based goal setting using the ADOC, and the interventions were focused on meaningful occupations. The control group underwent an impairment-based approach focused on restoring capacities, without goal setting tools. In both groups, the 20-minute individualized intervention sessions were conducted twice a week for 4 months. MAIN OUTCOME MEASURES: Short Form-36 (SF-36) score, SF-6D utility score, quality adjusted life years (QALY), Barthel Index, and total care cost. RESULTS: We randomized and analyzed 12 facilities (44 participants, 18.5% drop-out rate), with 6 facilities each allocated to the ADOC (n = 23) and control (n = 21) groups. After the 4-month intervention, the ADOC group had a significantly greater change in the BI score, with improved scores (P = 0.027, 95% CI 0.41 to 6.87, intracluster correlation coefficient = 0.14). No other outcome was significantly different. The incremental cost-effectiveness ratio, calculated using the change in BI score, was $63.1. CONCLUSION: The results suggest that occupational therapy using the ADOC for older residents might be effective and cost-effective. We also found that conducting an RCT in the occupational therapy setting is feasible. TRIAL REGISTRATION: UMIN Clinical Trials Registry UMIN000012994. PMID- 26930192 TI - Twelve-Year Cardiovascular and Mortality Risk in Relation to Smoking Habits in Type 2 Diabetic and Non-Diabetic Men: Tehran Lipid and Glucose Study. AB - INTRODUCTION: To examine the associations between smoking and cardiovascular disease (CVD) / coronary heart disease (CHD) and all-cause mortality events in men with and without type 2 diabetes (T2D) in a Middle Eastern cohort during a median follow-up of 12 years. METHODS: The study population included 2230 subjects aged >= 40 years, free from CVD, comprised of 367 participants with diabetes (21.2% current smokers) and 1863 without (27.3% current smokers). Multivariate Hazard ratios (HR) and 95% confidence intervals (CI) were calculated for smoking (considering different definitions) for those with and without diabetes. Potential confounding factors including age, body mass index, estimated Glomerular Filtration Rate, hypertension, hypercholesterolemia and educational level were entered in the multivariate analysis. RESULTS: In men with diabetes, the HR (95% CI) of comparing current and non-smokers was 1.25 (0.74-2.12) for incident CHD, 1.52 (0.96-2.40) for CVD and 2.10 (1.27-3.47) for mortality events; the corresponding values for men without diabetes were 1.65 (1.24-2.20), 1.70 (1.30-2.22) and 1.72 (1.14-2.58), respectively (all P values for interactions > 0.46). After pooling past smokers with current smokers, among diabetic individuals there was no significant risk for CVD [1.29 (0.89-1.86)] or mortality events [1.25 (0.81-1.92)]; however, among non-diabetic individuals the HRs of current/past smokers reached significant levels for CVD [1.53 (1.23-1.91)] but not for mortality outcomes (all P values for interactions > 0.51). CONCLUSIONS: The strength of the associations between smoking habits and incident CVD/CHD and mortality events from all causes did not differ significantly among diabetic and non-diabetic participants. Therefore, a comprehensive community-based smoking prevention program is important, given the increasing trend of smoking among the Iranian population regardless of diabetes status. PMID- 26930194 TI - Desynchronization of Theta-Phase Gamma-Amplitude Coupling during a Mental Arithmetic Task in Children with Attention Deficit/Hyperactivity Disorder. AB - INTRODUCTION: Theta-phase gamma-amplitude coupling (TGC) measurement has recently received attention as a feasible method of assessing brain functions such as neuronal interactions. The purpose of this electroencephalographic (EEG) study is to understand the mechanisms underlying the deficits in attentional control in children with attention deficit/hyperactivity disorder (ADHD) by comparing the power spectra and TGC at rest and during a mental arithmetic task. METHODS: Nineteen-channel EEGs were recorded from 97 volunteers (including 53 subjects with ADHD) from a camp for hyperactive children under two conditions (rest and task performance). The EEG power spectra and the TGC data were analyzed. Correlation analyses between the Intermediate Visual and Auditory (IVA) continuous performance test (CPT) scores and EEG parameters were performed. RESULTS: No significant difference in the power spectra was detected between the groups at rest and during task performance. However, TGC was reduced during the arithmetic task in the ADHD group compared with the normal group (F = 16.70, p < 0.001). The TGC values positively correlated with the IVA CPT scores but negatively correlated with theta power. CONCLUSIONS: Our findings suggest that desynchronization of TGC occurred during the arithmetic task in ADHD children. TGC in ADHD children is expected to serve as a promising neurophysiological marker of network deactivation during attention-demanding tasks. PMID- 26930193 TI - Parkinson-Related LRRK2 Mutation R1628P Enables Cdk5 Phosphorylation of LRRK2 and Upregulates Its Kinase Activity. AB - BACKGROUND: Recent studies have linked certain single nucleotide polymorphisms in the leucine-rich repeat kinase 2 (LRRK2) gene with Parkinson's disease (PD). Among the mutations, LRRK2 c.4883G>C (R1628P) variant was identified to have a significant association with the risk of PD in ethnic Han-Chinese populations. But the molecular pathological mechanisms of R1628P mutation in PD is still unknown. PRINCIPLE FINDINGS: Unlike other LRRK2 mutants in the Roc-COR-Kinase domain, the R1628P mutation didn't alter the LRRK2 kinase activity and promote neuronal death directly. LRRK2 R1628P mutation increased the binding affinity of LRRK2 with Cyclin-dependent kinase 5 (Cdk5). Interestingly, R1628P mutation turned its adjacent amino acid residue S1627 on LRRK2 protein to a novel phosphorylation site of Cdk5, which could be defined as a typical type II (+) phosphorylation-related single nucleotide polymorphism. Importantly, we showed that the phosphorylation of S1627 by Cdk5 could activate the LRRK2 kinase, and neurons ectopically expressing R1628P displayed a higher sensitivity to 1-methyl 4-phenylpyridinium, a bioactive metabolite of environmental toxin MPTP, in a Cdk5 dependent manner. CONCLUSION: Our data indicate that Parkinson-related LRRK2 mutation R1628P leads to Cdk5 phosphorylation of LRRK2 at S1627, which would upregulate the kinase activity of LRRK2 and consequently cause neuronal death. PMID- 26930195 TI - Trajectories of Symbolic and Nonsymbolic Magnitude Processing in the First Year of Formal Schooling. AB - Sensitivity to numerical magnitudes is thought to provide a foundation for higher level mathematical skills such as calculation. It is still unclear how symbolic (e.g. Arabic digits) and nonsymbolic (e.g. Dots) magnitude systems develop and how the two formats relate to one another. Some theories propose that children learn the meaning of symbolic numbers by scaffolding them onto a pre-existing nonsymbolic system (Approximate Number System). Others suggest that symbolic and nonsymbolic magnitudes have distinct and non-overlapping representations. In the present study, we examine the developmental trajectories of symbolic and nonsymbolic magnitude processing skills and how they relate to each other in the first year of formal schooling when children are becoming more fluent with symbolic numbers. Thirty Grade 1 children completed symbolic and nonsymbolic magnitude processing tasks at three time points in Grade 1. We found that symbolic and nonsymbolic magnitude processing skills had distinct developmental trajectories, where symbolic magnitude processing was characterized by greater gains than nonsymbolic skills over the one-year period in Grade 1. We further found that the development of the two formats only related to one another in the first half of the school year where symbolic magnitude processing skills influenced later nonsymbolic skills. These findings indicate that symbolic and nonsymbolic abilities have different developmental trajectories and that the development of symbolic abilities is not strongly linked to nonsymbolic representations by Grade 1. These findings also suggest that the relationship between symbolic and nonsymbolic processing is not as unidirectional as previously thought. PMID- 26930196 TI - Quantification and Assessment of Interfraction Setup Errors Based on Cone Beam CT and Determination of Safety Margins for Radiotherapy. AB - INTRODUCTION: To quantify interfraction patient setup-errors for radiotherapy based on cone-beam computed tomography and suggest safety margins accordingly. MATERIAL AND METHODS: Positioning vectors of pre-treatment cone-beam computed tomography for different treatment sites were collected (n = 9504). For each patient group the total average and standard deviation were calculated and the overall mean, systematic and random errors as well as safety margins were determined. RESULTS: The systematic (and random errors) in the superior-inferior, left-right and anterior-posterior directions were: for prostate, 2.5(3.0), 2.6(3.9) and 2.9(3.9)mm; for prostate bed, 1.7(2.0), 2.2(3.6) and 2.6(3.1)mm; for cervix, 2.8(3.4), 2.3(4.6) and 3.2(3.9)mm; for rectum, 1.6(3.1), 2.1(2.9) and 2.5(3.8)mm; for anal, 1.7(3.7), 2.1(5.1) and 2.5(4.8)mm; for head and neck, 1.9(2.3), 1.4(2.0) and 1.7(2.2)mm; for brain, 1.0(1.5), 1.1(1.4) and 1.0(1.1)mm; and for mediastinum, 3.3(4.6), 2.6(3.7) and 3.5(4.0)mm. The CTV-to-PTV margins had the smallest value for brain (3.6, 3.7 and 3.3mm) and the largest for mediastinum (11.5, 9.1 and 11.6mm). For pelvic treatments the means (and standard deviations) were 7.3 (1.6), 8.5 (0.8) and 9.6 (0.8)mm. CONCLUSIONS: Systematic and random setup-errors were smaller than 5mm. The largest errors were found for organs with higher motion probability. The suggested safety margins were comparable to published values in previous but often smaller studies. PMID- 26930197 TI - Interactions between Silicon Oxide Nanoparticles (SONPs) and U(VI) Contaminations: Effects of pH, Temperature and Natural Organic Matters. AB - The interactions between contaminations of U(VI) and silicon oxide nanoparticles (SONPs), both of which have been widely used in modern industry and induced serious environmental challenge due to their high mobility, bioavailability, and toxicity, were studied under different environmental conditions such as pH, temperature, and natural organic matters (NOMs) by using both batch and spectroscopic approaches. The results showed that the accumulation process, i.e., sorption, of U(VI) on SONPs was strongly dependent on pH and ionic strength, demonstrating that possible outer- and/or inner-sphere complexes were controlling the sorption process of U(VI) on SONPs in the observed pH range. Humic acid (HA), one dominated component of NOMs, bounded SONPs can enhance U(VI) sorption below pH~4.5, whereas restrain at high pH range. The reversible sorption of U(VI) on SONPs possibly indicated that the outer-sphere complexes were prevalent at pH 5. However, an irreversible interaction of U(VI) was observed in the presence of HA (Fig 1). It was mainly due to the ternary SONPs-HA-U(VI) complexes (Type A Complexes). After SONPs adsorbed U(VI), the particle size in suspension was apparently increased from ~240 nm to ~350 nm. These results showed that toxicity of both SONPs and U(VI) will decrease to some extent after the interaction in the environment. These findings are key for providing useful information on the possible mutual interactions among different contaminants in the environment. PMID- 26930198 TI - Detecting Selection on Temporal and Spatial Scales: A Genomic Time-Series Assessment of Selective Responses to Devil Facial Tumor Disease. AB - Detecting loci under selection is an important task in evolutionary biology. In conservation genetics detecting selection is key to investigating adaptation to the spread of infectious disease. Loci under selection can be detected on a spatial scale, accounting for differences in demographic history among populations, or on a temporal scale, tracing changes in allele frequencies over time. Here we use these two approaches to investigate selective responses to the spread of an infectious cancer--devil facial tumor disease (DFTD)--that since 1996 has ravaged the Tasmanian devil (Sarcophilus harrisii). Using time-series 'restriction site associated DNA' (RAD) markers from populations pre- and post DFTD arrival, and DFTD free populations, we infer loci under selection due to DFTD and investigate signatures of selection that are incongruent among methods, populations, and times. The lack of congruence among populations influenced by DFTD with respect to inferred loci under selection, and the direction of that selection, fail to implicate a consistent selective role for DFTD. Instead genetic drift is more likely driving the observed allele frequency changes over time. Our study illustrates the importance of applying methods with different performance optima e.g. accounting for population structure and background selection, and assessing congruence of the results. PMID- 26930199 TI - A Hybrid of the Chemical Master Equation and the Gillespie Algorithm for Efficient Stochastic Simulations of Sub-Networks. AB - Modeling stochastic behavior of chemical reaction networks is an important endeavor in many aspects of chemistry and systems biology. The chemical master equation (CME) and the Gillespie algorithm (GA) are the two most fundamental approaches to such modeling; however, each of them has its own limitations: the GA may require long computing times, while the CME may demand unrealistic memory storage capacity. We propose a method that combines the CME and the GA that allows one to simulate stochastically a part of a reaction network. First, a reaction network is divided into two parts. The first part is simulated via the GA, while the solution of the CME for the second part is fed into the GA in order to update its propensities. The advantage of this method is that it avoids the need to solve the CME or stochastically simulate the entire network, which makes it highly efficient. One of its drawbacks, however, is that most of the information about the second part of the network is lost in the process. Therefore, this method is most useful when only partial information about a reaction network is needed. We tested this method against the GA on two systems of interest in biology--the gene switch and the Griffith model of a genetic oscillator--and have shown it to be highly accurate. Comparing this method to four different stochastic algorithms revealed it to be at least an order of magnitude faster than the fastest among them. PMID- 26930200 TI - Transposon Tagging of a Male-Sterility, Female-Sterility Gene, St8, Revealed that the Meiotic MER3 DNA Helicase Activity Is Essential for Fertility in Soybean. AB - The W4 locus in soybean encodes a dihydroflavonol-4-reductase (DFR2) that regulates pigmentation patterns in flowers and hypocotyl. The mutable w4-m allele that governs variegated flowers has arisen through insertion of a CACTA-type transposable element, Tgm9, in DFR2. In the w4-m line, reversion from variegated to purple flower indicates excision of Tgm9, and its insertion at a new locus. Previously, we have identified a male-sterile, female-sterile mutant among the selfed progenies of a revertant plant carrying only purple flowers. Co segregation between Tgm9 and the sterility phenotype suggested that the mutant was generated by insertion of Tgm9 at the St8 locus. The transposon was localized to exon 10 of Glyma.16G072300 that shows high identity to the MER3 DNA helicase involved in crossing over. Molecular analysis of fertile branches from two independent revertant plants confirmed precise excision of Tgm9 from the st8 allele, which restored fertility. In soybean, the gene is expressed in flower buds, trifoliate leaves and stem. Phylogenetic analysis placed St8 in a clade with the Arabidopsis and rice MER3 suggesting that St8 is most likely the orthologous MER3 soybean gene. This study established the utility of Tgm9 in gene identification as well as in forward and reverse genetics studies. PMID- 26930201 TI - Safety of Levetiracetam in Paediatrics: A Systematic Review. AB - OBJECTIVE: To identify adverse events (AEs) associated with Levetiracetam (LEV) in children. METHODS: Databases EMBASE (1974-February 2015) and Medline (1946 February 2015) were searched for articles in which paediatric patients (<=18 years) received LEV treatment for epilepsy. All studies with reports on safety were included. Studies involving adults, mixed age population (i.e. children and adults) in which the paediatric subpopulation was not sufficiently described, were excluded. A meta-analysis of the RCTs was carried out and association between the commonly reported AEs or treatment discontinuation and the type of regimen (polytherapy or monotherapy) was determined using Chi2 analysis. RESULTS: Sixty seven articles involving 3,174 paediatric patients were identified. A total of 1,913 AEs were reported across studies. The most common AEs were behavioural problems and somnolence, which accounted for 10.9% and 8.4% of all AEs in prospective studies. 21 prospective studies involving 1120 children stated the number of children experiencing AEs. 47% of these children experienced AEs. Significantly more children experienced AEs with polytherapy (64%) than monotherapy (22%) (p<0.001). Levetiracetam was discontinued in 4.5% of all children on polytherapy and 0.9% on monotherapy (p<0.001), the majority were due to behavioural problems. CONCLUSION: Behavioural problems and somnolence were the most prevalent adverse events to LEV and the most common causes of treatment discontinuation. Children on polytherapy have a greater risk of adverse events than those receiving monotherapy. PMID- 26930202 TI - Natural Tendency towards Beauty in Humans: Evidence from Binocular Rivalry. AB - Although human preference for beauty is common and compelling in daily life, it remains unknown whether such preference is essentially subserved by social cognitive demands or natural tendency towards beauty encoded in the human mind intrinsically. Here we demonstrate experimentally that humans automatically exhibit preference for visual and moral beauty without explicit cognitive efforts. Using a binocular rivalry paradigm, we identified enhanced gender independent perceptual dominance for physically attractive persons, and the results suggested universal preference for visual beauty based on perceivable forms. Moreover, we also identified perceptual dominance enhancement for characters associated with virtuous descriptions after controlling for facial attractiveness and vigilance-related attention effects, which suggested a similar implicit preference for moral beauty conveyed in prosocial behaviours. Our findings show that behavioural preference for beauty is driven by an inherent natural tendency towards beauty in humans rather than explicit social cognitive processes. PMID- 26930203 TI - MicroRNA from Moringa oleifera: Identification by High Throughput Sequencing and Their Potential Contribution to Plant Medicinal Value. AB - Moringa oleifera is a widespread plant with substantial nutritional and medicinal value. We postulated that microRNAs (miRNAs), which are endogenous, noncoding small RNAs regulating gene expression at the post-transcriptional level, might contribute to the medicinal properties of plants of this species after ingestion into human body, regulating human gene expression. However, the knowledge is scarce about miRNA in Moringa. Furthermore, in order to test the hypothesis on the pharmacological potential properties of miRNA, we conducted a high-throughput sequencing analysis using the Illumina platform. A total of 31,290,964 raw reads were produced from a library of small RNA isolated from M. oleifera seeds. We identified 94 conserved and two novel miRNAs that were validated by qRT-PCR assays. Results from qRT-PCR trials conducted on the expression of 20 Moringa miRNA showed that are conserved across multiple plant species as determined by their detection in tissue of other common crop plants. In silico analyses predicted target genes for the conserved miRNA that in turn allowed to relate the miRNAs to the regulation of physiological processes. Some of the predicted plant miRNAs have functional homology to their mammalian counterparts and regulated human genes when they were transfected into cell lines. To our knowledge, this is the first report of discovering M. oleifera miRNAs based on high-throughput sequencing and bioinformatics analysis and we provided new insight into a potential cross-species control of human gene expression. The widespread cultivation and consumption of M. oleifera, for nutritional and medicinal purposes, brings humans into close contact with products and extracts of this plant species. The potential for miRNA transfer should be evaluated as one possible mechanism of action to account for beneficial properties of this valuable species. PMID- 26930205 TI - Reconstructing Causal Biological Networks through Active Learning. AB - Reverse-engineering of biological networks is a central problem in systems biology. The use of intervention data, such as gene knockouts or knockdowns, is typically used for teasing apart causal relationships among genes. Under time or resource constraints, one needs to carefully choose which intervention experiments to carry out. Previous approaches for selecting most informative interventions have largely been focused on discrete Bayesian networks. However, continuous Bayesian networks are of great practical interest, especially in the study of complex biological systems and their quantitative properties. In this work, we present an efficient, information-theoretic active learning algorithm for Gaussian Bayesian networks (GBNs), which serve as important models for gene regulatory networks. In addition to providing linear-algebraic insights unique to GBNs, leading to significant runtime improvements, we demonstrate the effectiveness of our method on data simulated with GBNs and the DREAM4 network inference challenge data sets. Our method generally leads to faster recovery of underlying network structure and faster convergence to final distribution of confidence scores over candidate graph structures using the full data, in comparison to random selection of intervention experiments. PMID- 26930204 TI - An Automated Treatment Plan Quality Control Tool for Intensity-Modulated Radiation Therapy Using a Voxel-Weighting Factor-Based Re-Optimization Algorithm. AB - Intensity-modulated radiation therapy (IMRT) currently plays an important role in radiotherapy, but its treatment plan quality can vary significantly among institutions and planners. Treatment plan quality control (QC) is a necessary component for individual clinics to ensure that patients receive treatments with high therapeutic gain ratios. The voxel-weighting factor-based plan re optimization mechanism has been proved able to explore a larger Pareto surface (solution domain) and therefore increase the possibility of finding an optimal treatment plan. In this study, we incorporated additional modules into an in house developed voxel weighting factor-based re-optimization algorithm, which was enhanced as a highly automated and accurate IMRT plan QC tool (TPS-QC tool). After importing an under-assessment plan, the TPS-QC tool was able to generate a QC report within 2 minutes. This QC report contains the plan quality determination as well as information supporting the determination. Finally, the IMRT plan quality can be controlled by approving quality-passed plans and replacing quality-failed plans using the TPS-QC tool. The feasibility and accuracy of the proposed TPS-QC tool were evaluated using 25 clinically approved cervical cancer patient IMRT plans and 5 manually created poor-quality IMRT plans. The results showed high consistency between the QC report quality determinations and the actual plan quality. In the 25 clinically approved cases that the TPS-QC tool identified as passed, a greater difference could be observed for dosimetric endpoints for organs at risk (OAR) than for planning target volume (PTV), implying that better dose sparing could be achieved in OAR than in PTV. In addition, the dose-volume histogram (DVH) curves of the TPS-QC tool re-optimized plans satisfied the dosimetric criteria more frequently than did the under assessment plans. In addition, the criteria for unsatisfied dosimetric endpoints in the 5 poor-quality plans could typically be satisfied when the TPS-QC tool generated re-optimized plans without sacrificing other dosimetric endpoints. In addition to its feasibility and accuracy, the proposed TPS-QC tool is also user friendly and easy to operate, both of which are necessary characteristics for clinical use. PMID- 26930206 TI - Impact of Marine Submergence and Season on Faunal Colonization and Decomposition of Pig Carcasses in the Salish Sea. AB - Pig carcasses, as human proxies, were placed on the seabed at a depth of 300 m, in the Strait of Georgia and observed continuously by a remotely operated camera and instruments. Two carcasses were deployed in spring and two in fall utilizing Ocean Network Canada's Victoria Experimental Network under the Sea (formerly VENUS) observatory. A trial experiment showed that bluntnose sixgill sharks could rapidly devour a carcass so a platform was designed which held two matched carcasses, one fully exposed, the other covered in a barred cage to protect it from sharks, while still allowing invertebrates and smaller vertebrates access. The carcasses were deployed under a frame which supported a video camera, and instruments which recorded oxygen, temperature, salinity, density, pressure, conductivity, sound speed and turbidity at per minute intervals. The spring exposed carcass was briefly fed upon by sharks, but they were inefficient feeders and lost interest after a few bites. Immediately after deployment, all carcasses, in both spring and fall, were very rapidly covered in vast numbers of lyssianassid amphipods. These skeletonized the carcasses by Day 3 in fall and Day 4 in spring. A dramatic, very localized drop in dissolved oxygen levels occurred in fall, exactly coinciding with the presence of the amphipods. Oxygen levels returned to normal once the amphipods dispersed. Either the physical presence of the amphipods or the sudden draw down of oxygen during their tenure, excluded other fauna. The amphipods fed from the inside out, removing the skin last. After the amphipods had receded, other fauna colonized such as spot shrimp and a few Dungeness crabs but by this time, all soft tissue had been removed. The amphipod activity caused major bioturbation in the local area and possible oxygen depletion. The spring deployment carcasses became covered in silt and a black film formed on them and on the silt above them whereas the fall bones remained uncovered and hence continued to be attractive to large numbers of spot shrimp. The carcass remains were recovered after 166 and 134 days respectively for further study. PMID- 26930207 TI - Preoperative Plasma Fibrinogen Level Represents an Independent Prognostic Factor in a Chinese Cohort of Patients with Upper Tract Urothelial Carcinoma. AB - BACKGROUND: Increased plasma fibrinogen is thought to contribute to tumor progression and metastasis. The association of plasma fibrinogen with clinicopathological characteristics, and the optimal cutoff with an ideal predictive value has not been fully determined in patients with upper tract urothelial carcinoma (UTUC). We aimed to investigate the clinical significance of this parameter in a Chinese cohort of patients with UTUC. METHODS: A retrospective study was conducted to analyze the clinical data of 184 operable UTUC patients in a Chinese cohort with a high incidence of chronic kidney disease (CKD). An optimal cutoff was set for further analysis according to validated web based software. The associations of plasma fibrinogen with clinicopathological characteristics and survival were assessed. Multivariate analyses were performed to determine the independent prognostic factors. RESULTS: Elevated plasma fibrinogen was significantly associated with tumor necrosis, lymph node involvement, and a higher preoperative CKD stage, pathological tumor stage and grade (all P < 0.05). Kaplan-Meier analysis showed that plasma fibrinogen >= 3.54 g/L predicted a poorer overall and cancer-specific survival than < 3.54 g/L (P < 0.001 for both). Multivariate analyses revealed that elevated preoperative plasma fibrinogen was an independent negative prognostic factor for overall survival (HR = 2.026; 95% CI: 1.226-3.349; P = 0.006) and cancer-specific survival (HR = 1.886; 95% CI: 1.019-3.490; P = 0.043). CONCLUSIONS: Increased plasma fibrinogen was an independent prognostic risk factor for poor outcomes in UTUC. This parameter may serve as an effective biomarker with easy accessibility for evaluating prognosis for patients with UTUC. PMID- 26930208 TI - Inflammatory Markers and Immune Response to Pneumococcal Vaccination in HIV Positive and -Negative Adults. AB - BACKGROUND: Members of the Tumor Necrosis Factor (TNF)-superfamily have speculated roles in the response against T-independent type II antigens (TI-II) including pneumococcal polysaccharides (PPS). Dysregulation in their expression is associated with an enhanced risk for pneumococcal disease in neonates but their expression in other high-risk populations including HIV-positive individuals remains to be elucidated. OBJECTIVE: To investigate signals that contribute towards PPS-response and identify potential anomalies that may account for diminished serological response in HIV-positive individuals post Pneumovax (PPV23) immunization. METHODS: Markers of inflammation, C-reactive protein (CRP), IL-6, sCD27 and sCD30, were assessed in HIV-positive and -negative individuals as potential predictors of PPV23 response. Serum levels of B cell activating factor (BAFF), transmembrane activator and calcium-modulator and cytophilin ligand interactor (TACI), B cell maturation antigen (BCMA) and B cell expression of BAFF R, TACI, BCMA, CD40 and CD21 were assessed in total (unselected) and PPS23F (antigen)-specific B cells of PPV23 immunized HIV-positive and -negative individuals. RESULTS: CRP, sCD27, sCD30 and BAFF were significantly elevated in the serum of HIV-positive individuals but did not adversely affect PPV23 response. Assessment of PPS-specific B cells revealed enhanced TACI and reduced BAFF-R expression compared to unselected B cells in HIV-positive and -negative individuals. Surface TACI was similar but soluble TACI was significantly lower in HIV-positive compared to HIV-negative individuals. CONCLUSION: Current studies highlight a potential role for TACI in PPV23 response based on its enhanced expression on PPS-specific B cells. Although surface levels of TACI were similar, diminished soluble TACI (sTACI) in HIV-positive compared to HIV-negative individuals could potentially decrease BAFF responsiveness and Ig response. A better understanding of the role of TNF receptors could contribute to the design of improved pneumococcal vaccines. TRIAL REGISTRATION: ClinicalTrials.gov NCT02515240. PMID- 26930209 TI - Absolute Quantification of the Host-To-Parasite DNA Ratio in Theileria parva Infected Lymphocyte Cell Lines. AB - Theileria parva is a tick-transmitted intracellular apicomplexan pathogen of cattle in sub-Saharan Africa that causes East Coast fever (ECF). ECF is an acute fatal disease that kills over one million cattle annually, imposing a tremendous burden on African small-holder cattle farmers. The pathology and level of T. parva infections in its wildlife host, African buffalo (Syncerus caffer), and in cattle are distinct. We have developed an absolute quantification method based on quantitative PCR (qPCR) in which recombinant plasmids containing single copy genes specific to the parasite (apical membrane antigen 1 gene, ama1) or the host (hypoxanthine phosphoribosyltransferase 1, hprt1) are used as the quantification reference standards. Our study shows that T. parva and bovine cells are present in similar numbers in T. parva-infected lymphocyte cell lines and that consequently, due to its much smaller genome size, T. parva DNA comprises between 0.9% and 3% of the total DNA samples extracted from these lines. This absolute quantification assay of parasite and host genome copy number in a sample provides a simple and reliable method of assessing T. parva load in infected bovine lymphocytes, and is accurate over a wide range of host-to-parasite DNA ratios. Knowledge of the proportion of target DNA in a sample, as enabled by this method, is essential for efficient high-throughput genome sequencing applications for a variety of intracellular pathogens. This assay will also be very useful in future studies of interactions of distinct host-T. parva stocks and to fully characterize the dynamics of ECF infection in the field. PMID- 26930210 TI - Making Sense of Residues on Flaked Stone Artefacts: Learning from Blind Tests. AB - Residue analysis has become a frequently applied method for identifying prehistoric stone tool use. Residues adhering to the stone tool with varying frequencies are interpreted as being the result of an intentional contact with the worked material during use. Yet, other processes during the life cycle of a stone tool or after deposition may leave residues and these residues may potentially lead to misinterpretations. We present a blind test that was designed to examine this issue. Results confirm that production, retouch, prehension, hafting, various incidental contacts during use and deposition may lead to residue depositions that significantly affect the accurateness of identifications of tool-use. All currently applied residue approaches are concerned. We therefore argue for a closer interaction with independent wear studies and a step-wise procedure in which a low magnification of wear traces is used as a first step for selecting potentially used flakes in archaeological contexts. In addition, residue concentrations on a tool's edge should be sufficiently dense before linking them with use. PMID- 26930211 TI - Respiration-Averaged CT for Attenuation Correction of PET Images - Impact on PET Texture Features in Non-Small Cell Lung Cancer Patients. AB - PURPOSE: We compared attenuation correction of PET images with helical CT (PET/HCT) and respiration-averaged CT (PET/ACT) in patients with non-small-cell lung cancer (NSCLC) with the goal of investigating the impact of respiration averaged CT on 18F FDG PET texture parameters. MATERIALS AND METHODS: A total of 56 patients were enrolled. Tumors were segmented on pretreatment PET images using the adaptive threshold. Twelve different texture parameters were computed: standard uptake value (SUV) entropy, uniformity, entropy, dissimilarity, homogeneity, coarseness, busyness, contrast, complexity, grey-level nonuniformity, zone-size nonuniformity, and high grey-level large zone emphasis. Comparisons of PET/HCT and PET/ACT were performed using Wilcoxon signed-rank tests, intraclass correlation coefficients, and Bland-Altman analysis. Receiver operating characteristic (ROC) curves as well as univariate and multivariate Cox regression analyses were used to identify the parameters significantly associated with disease-specific survival (DSS). A fixed threshold at 45% of the maximum SUV (T45) was used for validation. RESULTS: SUV maximum and total lesion glycolysis (TLG) were significantly higher in PET/ACT. However, texture parameters obtained with PET/ACT and PET/HCT showed a high degree of agreement. The lowest levels of variation between the two modalities were observed for SUV entropy (9.7%) and entropy (9.8%). SUV entropy, entropy, and coarseness from both PET/ACT and PET/HCT were significantly associated with DSS. Validation analyses using T45 confirmed the usefulness of SUV entropy and entropy in both PET/HCT and PET/ACT for the prediction of DSS, but only coarseness from PET/ACT achieved the statistical significance threshold. CONCLUSIONS: Our results indicate that 1) texture parameters from PET/ACT are clinically useful in the prediction of survival in NSCLC patients and 2) SUV entropy and entropy are robust to attenuation correction methods. PMID- 26930212 TI - MECP2 Duplication Syndrome: Evidence of Enhanced Oxidative Stress. A Comparison with Rett Syndrome. AB - Rett syndrome (RTT) and MECP2 duplication syndrome (MDS) are neurodevelopmental disorders caused by alterations in the methyl-CpG binding protein 2 (MECP2) gene expression. A relationship between MECP2 loss-of-function mutations and oxidative stress has been previously documented in RTT patients and murine models. To date, no data on oxidative stress have been reported for the MECP2 gain-of-function mutations in patients with MDS. In the present work, the pro-oxidant status and oxidative fatty acid damage in MDS was investigated (subjects n = 6) and compared to RTT (subjects n = 24) and healthy condition (subjects n = 12). Patients with MECP2 gain-of-function mutations showed increased oxidative stress marker levels (plasma non-protein bound iron, intraerythrocyte non-protein bound iron, F2 isoprostanes, and F4-neuroprostanes), as compared to healthy controls (P <= 0.05). Such increases were similar to those observed in RTT patients except for higher plasma F2-isoprostanes levels (P < 0.0196). Moreover, plasma levels of F2 isoprostanes were significantly correlated (P = 0.0098) with the size of the amplified region. The present work shows unique data in patients affected by MDS. For the first time MECP2 gain-of-function mutations are indicated to be linked to an oxidative damage and related clinical symptoms overlapping with those of MECP2 loss-of-function mutations. A finely tuned balance of MECP2 expression appears to be critical to oxidative stress homeostasis, thus shedding light on the relevance of the redox balance in the central nervous system integrity. PMID- 26930213 TI - Health Impacts of Active Transportation in Europe. AB - Policies that stimulate active transportation (walking and bicycling) have been related to heath benefits. This study aims to assess the potential health risks and benefits of promoting active transportation for commuting populations (age groups 16-64) in six European cities. We conducted a health impact assessment using two scenarios: increased cycling and increased walking. The primary outcome measure was all-cause mortality related to changes in physical activity level, exposure to fine particulate matter air pollution with a diameter <2.5 MUm, as well as traffic fatalities in the cities of Barcelona, Basel, Copenhagen, Paris, Prague, and Warsaw. All scenarios produced health benefits in the six cities. An increase in bicycle trips to 35% of all trips (as in Copenhagen) produced the highest benefits among the different scenarios analysed in Warsaw 113 (76-163) annual deaths avoided, Prague 61 (29-104), Barcelona 37 (24-56), Paris 37 (18-64) and Basel 5 (3-9). An increase in walking trips to 50% of all trips (as in Paris) resulted in 19 (3-42) deaths avoided annually in Warsaw, 11(3-21) in Prague, 6 (4 9) in Basel, 3 (2-6) in Copenhagen and 3 (2-4) in Barcelona. The scenarios would also reduce carbon dioxide emissions in the six cities by 1,139 to 26,423 (metric tonnes per year). Policies to promote active transportation may produce health benefits, but these depend of the existing characteristics of the cities. Increased collaboration between health practitioners, transport specialists and urban planners will help to introduce the health perspective in transport policies and promote active transportation. PMID- 26930214 TI - A Comparison of the ATP Generating Pathways Used by S. Typhimurium to Fuel Replication within Human and Murine Macrophage and Epithelial Cell Lines. AB - The metabolism of S. Typhimurium within infected host cells plays a fundamental role in virulence since it enables intracellular proliferation and dissemination and affects the innate immune response. An essential requirement for the intracellular replication of S. Typhimurium is the need to regenerate ATP. The metabolic route used to fulfil this requirement is the subject of the present study. For infection models we used human and murine epithelial and macrophage cell lines. The epithelial cell lines were mICc12, a transimmortalised murine colon enterocyte cell line that shows many of the characteristics of a primary epithelial cell line, and HeLa cells. The model macrophage cell lines were THP-1A human monocyte/macrophages and RAW 264.7 murine macrophages. Using a mutational approach combined with an exometabolomic analysis, we showed that neither fermentative metabolism nor anaerobic respiration play major roles in energy generation in any of the cell lines studied. Rather, we identified overflow metabolism to acetate and lactate as the foremost route by which S. Typhimurium fulfils its energy requirements. PMID- 26930215 TI - Novel Pectate Lyase Genes of Heterodera glycines Play Key Roles in the Early Stage of Parasitism. AB - Pectate lyases are known to play a key role in pectin degradation by catalyzing the random cleavage of internal polymer linkages (endo-pectinases). In this paper, four novel cDNAs, designated Hg-pel-3, Hg-pel-4, Hg-pel-6 and Hg-pel-7, that encode pectate lyases were cloned and characterized from the soybean cyst nematode, Heterodera glycines. The predicted protein sequences of HG-PEL-3, HG PEL-4 and HG-PEL-6 differed significantly in both their amino acid sequences and their genomic structures from other pectate lyases of H. glycines (HG-PEL-1, HG PEL-2 and HG-PEL-7). A phylogenetic study revealed that the pectate lyase proteins of H. glycines are clustered into distinct clades and have distinct numbers and positioning of introns, which suggests that the pectate lyase genes of H. glycines may have evolved from at least two ancestral genes. A Southern blot analysis revealed that multiple Hg-pel-6-like genes were present in the H. glycines genome. In situ hybridization showed that four novel pectate lyases (Hg pel-3, Hg-pel-4, Hg-pel-6 and Hg-pel-7) were actively transcribed in the subventral esophageal gland cells. A semi-quantitative RT-PCR assay supported the finding that the expression of these genes was strong in the egg, pre-parasitic second-stage juvenile (J2) and early parasitic J2 stages and that it declined in further developmental stages of the nematode. This expression pattern suggests that these proteins play a role in the migratory phase of the nematode life cycle. Knocking down Hg-pel-6 using in vitro RNA interference resulted in a 46.9% reduction of the number of nematodes that invaded the plants and a 61.5% suppression of the development of H. glycines females within roots compared to the GFP-dsRNA control. Plant host-derived RNAi induced the silencing of the Hg pel-6gene, which significantly reduced the nematode infection levels at 7 Days post inoculation (dpi). Similarly, this procedure reduced the number of female adults at 40 dpi, which suggests the important roles of this gene in the early stages of parasitism. Our combined data suggest that two types of pectate lyases are present in the H. glycines genome and may have different roles during infection. PMID- 26930216 TI - Self-decontaminating photocatalytic zinc oxide nanorod coatings for prevention of marine microfouling: a mesocosm study. AB - The antifouling (AF) properties of zinc oxide (ZnO) nanorod coated glass substrata were investigated in an out-door mesocosm experiment under natural sunlight (14:10 light: dark photoperiod) over a period of five days. The total bacterial density (a six-fold reduction) and viability (a three-fold reduction) was significantly reduced by nanocoatings in the presence of sunlight. In the absence of sunlight, coated and control substrata were colonized equally by bacteria. MiSeq Illumina sequencing of 16S rRNA genes revealed distinct bacterial communities on the nanocoated and control substrata in the presence and absence of light. Diatom communities also varied on nanocoated substrata in the presence and the absence of light. The observed AF activity of the ZnO nanocoatings is attributed to the formation of reactive oxygen species (ROS) through photocatalysis in the presence of sunlight. These nanocoatings are a significant step towards the production of an environmentally friendly AF coating that utilizes a sustainable supply of sunlight. PMID- 26930217 TI - Correction: Long-Term Benefits of Smoking Cessation on Gastroesophageal Reflux Disease and Health-Related Quality of Life. PMID- 26930218 TI - Two-Port Laparoscopic Reconstructive Surgery of the Urinary Tract with Reusable Umbilical System (Hybrid Less): A Proof of Concept Study. AB - OBJECTIVES: We compared perioperative results and complications of reconstructive surgery of the urinary tract performed using a multichannel platform through the umbilicus and one additional 3.5-mm with a cohort of patients simultaneously treated with conventional 4-port laparoscopy. MATERIALS AND METHODS: Matched-pair study comparing perioperative outcomes, postoperative visual analogue pain scale (VAPS) and morbidity of 2-port (n = 20) and 4-port (n = 10) laparoscopic reconstructive urological surgery. Preoperative and perioperative data compared included demographics, type of surgery, operative time, blood loss, decrease in serum hemoglobin, operative complications, length of stay and postoperative complications according to Clavien-Dindo classification. RESULTS: There was no significant difference between groups regarding age, gender, body mass index, American Society of Anesthesiologists score, type of surgery, operative time, operative complications and intraoperative or postoperative transfusion. Estimated blood loss was lower using reduced-port approach. VAPS at postoperative day one was significantly lower for 2-port approach and so was the length of stay. Patient satisfaction with the wound was higher for 2-port surgery. Differences were not observed in number and severity of postoperative complications. CONCLUSIONS: Urological reconstructive operations can be safely performed using the hybrid laparoendoscopic single-site umbilical approach, resulting in lower blood loss, higher patient satisfaction and lower postoperative pain, which also facilitate earlier hospital discharge, than the same reconstructive procedures performed through multiport conventional laparoscopy. PMID- 26930220 TI - Lithium Diffusion Pathway in Li(1.3)Al(0.3)Ti(1.7)(PO4)3 (LATP) Superionic Conductor. AB - The Al-substituted LiTi2(PO4)3 powders Li(1+x)Al(x)Ti(2-x)(PO4)3 (LATP) were successfully prepared by a water-based sol-gel process with subsequent calcination and sintering. The crystal structure of obtained samples was characterized at different temperatures using high-resolution synchrotron-based X ray and neutron powder diffraction. Possible lithium diffusion pathways were initially evaluated using the difference bond-valence approach. Experimental 3D lithium diffusion pathway in LATP was extracted from the negative nuclear density maps reconstructed by the maximum entropy method. Evaluation of the energy landscape determining the lithium diffusion process in NASICON-type superionic conductor is shown for the first time. PMID- 26930219 TI - Averting the Legacy of Kidney Disease - Focus on Childhood. AB - World Kidney Day 2016 focuses on kidney disease in childhood and the antecedents of adult kidney disease that can begin in earliest childhood. Chronic kidney disease (CKD) in childhood differs from that in adults, as the largest diagnostic group among children includes congenital anomalies and inherited disorders, with glomerulopathies and kidney disease in the setting of diabetes being relatively uncommon. In addition, many children with acute kidney injury will ultimately develop sequelae that may lead to hypertension and CKD in later childhood or in adult life. Children born early or who are small-for date newborns have relatively increased risk for the development of CKD later in life. Persons with a high-risk birth and early childhood history should be watched closely in order to help detect early signs of kidney disease in time to provide effective prevention or treatment. Successful therapy is feasible for advanced CKD in childhood; there is evidence that children fare better than adults, if they receive kidney replacement therapy including dialysis and transplantation, while only a minority of children may require this ultimate intervention. Because there are disparities in access to care, effort is needed so that those children with kidney disease, wherever they live, may be treated effectively, irrespective of their geographic or economic circumstances. Our hope is that World Kidney Day will inform the general public, policy makers and caregivers about the needs and possibilities surrounding kidney disease in childhood. PMID- 26930221 TI - Semi-dominant mutations in MFN2-related neuropathy and implications for genetic counselling. PMID- 26930222 TI - Erratum. PMID- 26930223 TI - Successful use of camelid (alpaca) antivenom to treat a potentially lethal tiger snake (Notechis scutatus) envenomation in a dog. AB - This report describes a confirmed clinical case of tiger snake (Notechis scutatus) envenomation in a domestic dog that was successfully treated with a novel polyvalent camelid (alpaca; Llama pacos) antivenom. Samples collected from the dog were assayed for tiger snake venom (TSV) using a highly sensitive and specific ELISA. The TSV concentration in serum and urine at initial presentation was 365 ng/mL and 11,640 ng/mL respectively. At the time of initial presentation whole blood collected from the dog did not clot and the Prothrombin Time was abnormally increased (>300 s). Serum was also visibly hemolysed. The dog was administered antihistamine, dexamethasone and 4000 Units (sufficient to neutralise 40 mg of TSV) of a novel polyvalent alpaca antivenom diluted in 0.9% NaCl. At 4 h post-antivenom treatment the dog's clinical condition had improved markedly with serum TSV concentrations below the limit of detection (<0.015 ng/mL), consistent with complete binding of venom antigens by the alpaca antivenom. Coagulation parameters had begun to improve by 4 h and had fully normalised by 16 h post-antivenom. Venom concentrations in both serum and urine remained undetectable at 16 h post-antivenom. The dog made a complete recovery, without complications, suggesting that the alpaca-based antivenom is both clinically safe and effective. PMID- 26930224 TI - Insertion of N-Tosylacetimidates/Acetimidamides onto Arynes via [2 + 2] Cycloaddition. AB - A novel insertion reaction of N-tosylacetimidates and N-tosylacetimidamides onto arynes via a benzocyclobutene intermediate followed by ring cleavage is developed to afford o-benzylbenzoic acid derivatives in good yields. Interestingly, the use of cyclic 2-sulfonyliminoindolines provided two distinct products such as azepanimines via [2 + 2] cycloaddition and indolamines via protonation based on solvent medium. PMID- 26930225 TI - Tear Film, Lacrimal Drainage System, and Eyelid Findings in Subjects With Anophthalmic Socket Discharge. AB - PURPOSE: To compare the results of tear film and lacrimal drainage system tests between anophthalmic socket and normal eye and assess discharge characteristics and frequency of prosthesis removal (questionnaire), eyelid function, and meibomian glad dysfunction (MGD). DESIGN: Prospective masked case control. METHODS: Subjects (>=6 years and >=6 months of wearing prosthesis) with unilateral acquired anophthalmic socket discharge were included. Excluded was ocular adnexal abnormality of any reason and incomplete tests. The subjective questionnaire was completed. Blinking rate, lagophthalmos, eyelid laxity, MGD, Schirmer test, tear meniscus height, and dye disappearance test were assessed by a masked examiner. Another masked examiner performed an irrigation test 1 week later and interpreted the scintigraphy images at the end of the study. RESULTS: Included were 50 subjects (mean age: 31.3 years, mean prosthesis wear: 96.1 months). Discharge was frequent or very frequent in 85%, mucoid or mucopurulent in 90%, and moderate to severe in 86% of the subjects. MGD in 58%, lagophthalmos in 80%, and eyelid laxity in 46% were observed. Anophthalmic socket sides showed a significantly lower tear production and higher tear drainage obstruction. Subjects with frequent prosthesis removal had a significantly (P = .02) greater lagophthalmos and blinking rate (P = .04). The blinking rate was also significantly greater in subjects with higher frequency of discharge (P = .04). CONCLUSION: Tear film impairment (aqueous and lipid) and lacrimal drainage obstruction should be considered in subjects with anophthalmic socket discharge. A significantly higher blinking rate and lagophthalmos were found in subjects with higher frequency of prosthesis removal. PMID- 26930226 TI - Influence of football match time-motion parameters on recovery time course of muscle damage and jump ability. AB - We analysed the time course of recovery of creatine kinase (CK) and countermovement jump (CMJ) parameters after a football match, and correlations between changes in these variables and match time-motion parameters (GPS accelerometry) in 15 U-19 elite male players. Plasma CK and CMJ height (CMJH), average concentric force (CMJCON) and average eccentric force (CMJECC) were assessed 2 h before and 30 min, 24 h and 48 h post-match. There were substantially higher CK levels 30 min, 24 h and 48 h (ES: 0.43, 0.62, 0.40, respectively), post-match. CMJECC (ES: -0.38), CMJH (ES: -0.35) decreased 30 min post, CMJCON (ES: -0.35), CMJECC (ES: -0.35) and CMJH (ES: -1.35) decreased 24 h post, and CMJCON (ES: -0.41) and CMJH (ES: -0.53) decreased 48 h post. We found correlations between distance covered at velocities <=21 km . h(-1) and changes in CK at 24 h (r = 0.56) and at 48 h (r = 0.54) and correlations between CK and distance covered >14 km . h(-1) (r = 0.50), accelerations (r = 0.48), and decelerations (r = 0.58) at 48 h. Changes in CMJCON 30 min and 24 h post (both r = -0.68) correlated with impacts >7.1.G. Decelerations >2 m . s(-)(2) correlated with changes CMJCON (r = -0.49) at 48 h and CMJECC (r = -0.47) at 30 min. Our results suggest that match GPS-accelerometry parameters may predict muscle damage and changes in components of neuromuscular performance immediately and 24-48 h post-match. PMID- 26930227 TI - Changes in Energy Metabolism after Continuous Positive Airway Pressure for Obstructive Sleep Apnea. AB - RATIONALE: Disrupted energy homeostasis in obstructive sleep apnea (OSA) may lead to weight gain. Paradoxically, treating OSA with continuous positive airway pressure (CPAP) may also promote weight gain, although the underlying mechanism remains unclear. OBJECTIVES: To explore the underlying mechanism by which patients with OSA gain weight after CPAP. METHODS: A comprehensive assessment of energy metabolism was performed in 63 newly diagnosed OSA study participants (51 men; 60.8 +/- 10.1 yr; apnea-hypopnea index >20 h(-1)) at baseline, CPAP initiation, and at a 3-month follow-up. Measurements included polysomnography, body weight, body composition, basal metabolic rate (BMR), hormones (norepinephrine, cortisol, leptin, ghrelin, insulin-like growth factor-1), dietary intake, eating behavior, and physical activity. MEASUREMENTS AND MAIN RESULTS: BMR significantly decreased after CPAP (1,584 kcal/d at baseline, 1,561 kcal/d at CPAP initiation, and 1,508 kcal/d at follow-up; P < 0.001), whereas physical activity and total caloric intake did not significantly change. In multivariate regression, baseline apnea-hypopnea index, Deltaurine norepinephrine, and CPAP adherence were significant predictors of DeltaBMR. The weight gainers had higher leptin levels, lower ghrelin levels, and higher eating behavior scores than the non-weight gainers, indicating a positive energy balance and disordered eating behavior among the weight gainers. Among the parameters related to energy metabolism, increased caloric intake was a particularly significant predictor of weight gain. CONCLUSIONS: Although a reduction in BMR after CPAP predisposes to a positive energy balance, dietary intake and eating behavior had greater impacts on weight change. These findings highlight the importance of lifestyle modifications combined with CPAP. Clinical trial registered with http://www.umin.ac.jp/english/ (UMIN000012639). PMID- 26930228 TI - Activation of beta1-adrenoceptor triggers oxidative stress mediated myocardial membrane destabilization in isoproterenol induced myocardial infarcted rats: 7 hydroxycoumarin and its counter action. AB - Activation of beta1-adrenoceptor stimulates myocardial membrane destabilization in isoproterenol induced rats. Male albino Wistar rats were pre and co-treated with 7-hydroxycoumarin (16mg/kg body weight) daily for 8 days. Myocardial infarction was induced into rats by the subcutaneous administration of isoproterenol (100mg/kg body weight) at an interval of 24h daily for a period of two days (7th and 8th day). The levels/activities of serum cardiac troponin-T, lactate dehydrogenase and the concentrations of heart lipid peroxidation products were significantly increased and the antioxidant status was significantly decreased in isoproterenol induced rats. Furthermore, the activity of sodium/potassium-dependent adenosine triphosphatase was significantly decreased and the activities of calcium and magnesium-dependent adenosine triphosphatases were significantly increased in the heart of isoproterenol induced myocardial infarcted rats. Isoproterenol induced rats also revealed increased concentrations of sodium and calcium and decreased concentrations of potassium in the heart. 7 hydroxycoumarin pre- and co-treatment showed considerable impact on all biochemical parameters assessed. Also, 7-HC greatly reduced the infarct size of the myocardium. The in vitro study confirmed its potent free radical scavenging activity. Thus, the present study revealed that 7-HC attenuates myocardial membrane destabilization by reinstating the activities/levels of adenosine triphosphatases and minerals in isoproterenol induced rats by inhibiting oxidative stress. These effects are attributed to the membrane stabilizing and free radical scavenging properties of 7-hydroxycoumarin. PMID- 26930229 TI - Paclitaxel inhibits cell proliferation and collagen lattice contraction via TGF beta signaling pathway in human tenon's fibroblasts in vitro. AB - As an anti-microtubule agent, paclitaxel has been widely applied clinically. However, the effects of paclitaxel on human tenon's fibroblast (HTF) proliferation and migration in vitro was still unclear. In the present study, we explored the influences of paclitaxel on HTF cell proliferation, cell viability, cell cycle phase distribution under various concentrations of paclitaxel (i.e., 0, 10(-8), 10(-7), 10(-6)mol/l) via real-time cell electronic system and flow cytometry, further determined the expression of TGF-beta1 and connective tissue growth factor (CTGF) after treatment with different concentrations of paclitaxel. Moreover, extra cellular matrix production and collagen lattice contraction assay were also explored. The results indicate that paclitaxel could apparently inhibit the cell viability, induces the elevation of S and G2/M phases of HTFs, and downregulates the expression of both TGF-beta1 and CTGF. Meanwhile, the levels of fibronectin extra domain A (EDA), collagen and collagen lattice contraction were apparently reduced after treatment with paclitaxel. Overall, paclitaxel could apparently inhibit the proliferation of HTFs and leads to cell cycle arrest at both S and G2/M phases, attenuates the generation of collagen and collagen lattice contraction, decreases the expressions of TGF-beta1, CTGF and fibronectin EDA. The inhibitory mechanism of paclitaxel on HTFs is involved in TGF-beta1 signaling pathway. PMID- 26930231 TI - Orthopedic Problems in Overweight and Obese Children. PMID- 26930230 TI - Cyclic RGDfK Peptide Functionalized Polymeric Nanocarriers for Targeting Gemcitabine to Ovarian Cancer Cells. AB - Current cancer chemotherapies commonly suffer from nonspecificity, drug resistance, poor bioavailability, and narrow therapeutic indices. To achieve the optimum drug efficacy, we designed a polymeric drug delivery system for targeted intracellular delivery of a clinically approved, water-soluble anticancer drug, gemcitabine hydrochloride (GEM). We utilized the unique ability of a cyclic pentapeptide cRGDfK to specifically target alphavbeta3 integrin receptors that are overexpressed on SKOV-3 human ovarian cancer cells. This significantly increased the effective intracellular drug concentration even at low doses, thereby remarkably improving the chemotherapeutic potential of GEM. cRGDfK conjugated, GEM-loaded nanoparticles reduced the nonspecific hemolytic cytotoxicity of the drug, simultaneously influencing intracellular processes such as mitochondrial membrane potential (DPsim), reactive oxygen species (ROS) levels, and apoptosis, thereby favorably influencing drug antiproliferative efficacy. PMID- 26930232 TI - Laparoscopic Adrenalectomy is Feasible for Suspected Adrenal Tumors in Children Younger than 24 Months of Age - But is it Always Justified? AB - INTRODUCTION: Tumors of the adrenal gland are rare in children younger than 24 months of age. While neuroblastomas are most important in this age group, adrenal hemorrhage and other tumors are sometimes difficult to distinguish. Harvesting biopsies is mandatory in these young patients to obtain information on molecular markers, namely, MYCN and 1p deletion. PATIENTS: Between 03/2012 and 10/2013, 11 patients younger than 24 months of age with suspicious adrenal tumors were operated on laparoscopically. METHODS: The diagnostic workup was coordinated by our pediatric oncologists according to the terms of the NB2004 trial protocol. RESULTS: 9 out of 11 had a diagnosis of neuroblastoma, the others were adenoma respective complete necrosis of the adrenal gland. All of the neuroblastomas were negative for both MYCN amplification and 1p deletion. A complete resection was successful in 9 out of 11 cases. 3 complications occurred, 1 major and 2 minor. DISCUSSION AND CONCLUSION: Behind the recognition that laparoscopic adrenalectomy is technically feasible, the fact that all neuroblastomas were negative for MYCN amplification and 1p deletion raises the issue of whether biopsy is mandatory for risk stratification in this age group. PMID- 26930233 TI - Image-defined Risk Factors Correlate with Surgical Radicality and Local Recurrence in Patients with Neuroblastoma. AB - BACKGROUND: Neuroblastoma is the second most common solid pediatric tumor and the most common cancer to be detected in children younger than 12 months of age. To date, 2 different staging systems describe the extent of the disease: the International Neuroblastoma Staging System (INSS) and the International Neuroblastoma Risk Group Staging System (INRGSS). The INRGSS-system is characterized by the presence or absence of so called image-defined risk factors (IDRFs), which are described as surgical risk factors. We hypothesized that IDRFs correlate with surgical complications, surgical radicality, local recurrence and overall survival (OS). PATIENTS AND METHODS: Between 2003 and 2010, 102 patients had neuroblastoma surgery performed in our department. We analyzed medical records for IDRF-status and above named data. RESULTS: 16 patients were IDRF negative, whereas 86 patients showed one or more IDRF. Intra- or postoperative complications have been reported in 21 patients (21%). 19 of them showed one or more IDRF and 2 patients were IDRF-negative (p=n.s.). Patients who suffered from intra- or postoperative complications demonstrated a decreased OS (p=0.011). Statistical analysis revealed an inverse correlation between the extent of macroscopical removal and IDRF-status (p=0.001). Furthermore, the number of IDRFs were associated with a decreased likelihood of radical tumor resection (p<0.001). 19 patients had local recurrence; all of them were IDRF-positive (p=0.037). CONCLUSIONS: Pediatric surgeons should consider IDRFs as a useful tool for risk assessment and therefore planning for neuroblastoma surgery. PMID- 26930234 TI - Association of School-Based Influenza Vaccination Clinics and School Absenteeism- Arkansas, 2012-2013. AB - BACKGROUND: Influenza is a major cause of seasonal viral respiratory illness among school-aged children. Accordingly, the Arkansas Department of Health (ADH) coordinates >800 school-based influenza immunization clinics before each influenza season. We quantified the relationship between student influenza vaccination in Arkansas public schools and school absenteeism during the 2012 2013 influenza season. METHODS: The relationship between the percent of students vaccinated in Arkansas public schools during ADH-facilitated clinics and the average daily percent of students absent from school during the 2012-2013 influenza season was quantified using linear regression modeling. The effect of increasing vaccination coverage among students on absentee days in the Arkansas public school system was estimated. RESULTS: For every 1% higher vaccination coverage, 0.027% fewer absenteeism days were predicted. Larger school size was associated with higher absenteeism and predicted decreases in absenteeism were larger in magnitude for larger schools compared with smaller schools. Extrapolation of the model showed that a 10% higher vaccination level was associated with a reduction of 16-163 student absentee days per school over a 12 week influenza season. CONCLUSIONS: Influenza vaccination is an effective tool to reduce school absenteeism. School-based clinics are a feasible way to target influenza vaccinations to school-aged children. PMID- 26930235 TI - Opening School-Based Health Centers in a Rural Setting: Effects on Emergency Department Use. AB - BACKGROUND: Previous studies of urban school-based health centers (SBHCs) have shown that SBHCs decrease emergency department (ED) utilization. This study seeks to evaluate the effect of SBHCs on ED utilization in a rural setting. METHODS: This retrospective, controlled, quasi-experimental study used an ED patient data set from the Bassett Healthcare Network in rural New York to compare ED visits between school-aged children from 12 SBHC schools before and after the SBHC opening. Time series analysis was used to determine trends in SBHC schools and 2 control schools without SBHCs over the 18-year study period. RESULTS: ED visit incidence densities for all 12 school districts combined showed a significant increase in ED visits post-SBHC (Rate ratio (RR) = 1.15; p < .0001). This increase may, in part, be explained by the upward trend of ED visits in the region, as seen in the small, but significant, positive slope (RR = 0.0033, p < .0001) for control schools. There was variation in the change in incidence density post-SBHC among school districts, with increases in 78% of schools. CONCLUSIONS: The opening of SBHCs in rural settings results in a slight, but significant, increase in ED use, which is contrary to previous cross-sectional studies in urban settings. PMID- 26930236 TI - A Statewide Profile of Frequent Users of School-Based Health Centers: Implications for Adolescent Health Care. AB - BACKGROUND: The purpose of this study is to describe patterns of care and service use among adolescent school-based health center (SBHC) users in New Mexico and contrast patterns and services between frequent and infrequent users. METHODS: Medical claims/encounter data were analyzed from 59 SBHCs located in secondary schools in New Mexico during the 2011-2012 school year. We used Pearson's chi square test to examine the differences between frequent (>= 4 visits/year) and infrequent users in their patterns of SBHC care, and we conducted logistic regression to examine whether frequent use of the SBHC predicted receipt of behavioral, reproductive, and sexual health; checkup; or acute care services. RESULTS: Most of the 26,379 adolescent SBHC visits in New Mexico were for behavioral health (42.4%) and reproductive and sexual health (22.9%). Frequent users have greater odds of receiving a behavioral, reproductive, and sexual health; and acute care visit than infrequent users (p < .001). American Indians, in particular, have higher odds of receiving behavioral health and checkup visits, compared with other races/ethnicities (p < .001). CONCLUSIONS: SBHCs deliver core health care services to adolescents, including behavioral, reproductive, and checkup services, to high need populations. American-Indian youth, more than their peers, use SBHCs for behavioral health and checkups. PMID- 26930237 TI - Sustaining Teen Pregnancy Prevention Programs in Schools: Needs and Barriers Identified by School Leaders. AB - BACKGROUND: To reduce teen pregnancy rates, prevention programs must be consistently available to large numbers of youth. However, prevention efforts have been historically conducted with little emphasis on ensuring program sustainability. This study examined the needs and barriers to sustaining teen pregnancy prevention (TPP) programming in schools after grant funding has ended, as identified by school leadership. METHODS: A total of 11 qualitative interviews were conducted between June and September 2012 with middle school leaders from 11 schools involved in current implementation of a TPP program in South Carolina. Interviews were audio-recorded, transcribed verbatim, and thematically coded. RESULTS: Identified needs and barriers to sustainability varied across schools. Common barriers to program sustainability included: lack of materials and supplies, insufficient funding (at the school and district level), lack of support and/or parental opposition, and other school/district priorities. School leaders also identified several needs to continue TPP programming, including: continued funding, trainings, outcome/effectiveness data to support the program, and regularly updated curriculum. CONCLUSION: Schools with greater perceived needs and barriers may be less likely to sustain. Knowledge gained through this research may be used to inform future interventions and sustainability planning efforts, allowing us to maximize prevention programming. PMID- 26930238 TI - School-Based First Aid Training Programs: A Systematic Review. AB - BACKGROUND: This review examines the breadth of first aid training delivered to school students and the components that are age appropriate to adolescents. METHOD: Eligible studies included school-based first aid interventions targeting students aged between 10 and 18 years. Online databases were searched, for peer reviewed publications available as at August 2014. RESULTS: A total of 20 journal articles were relevant to the review. Research supported programs with longer durations (3 hours or more). Most programs taught resuscitation alone and few included content that was context-specific and relevant to the target group. The training experience of the facilitator did not appear to impact on student outcomes. Incorporating both practical and didactic components was found to be an important factor in delivering material and facilitating the retention of knowledge. Educational resources and facilitator training were found to be common features of effective programs. CONCLUSIONS: The review supports first aid in school curriculum and provides details of key components pertinent to design of school-based first aid programs. The findings suggest that first aid training may have benefits wider than the uptake and retention of knowledge and skills. There is a need for future research, particularly randomized controlled trials to aid in identifying best practice approaches. PMID- 26930239 TI - "Can't We Just Have Some Sazon?" Student, Family, and Staff Perspectives on a New School Food Program at a Boston High School. AB - BACKGROUND: In September 2013, a Massachusetts high school launched a nutrition program in line with 2013 United States Department of Agriculture requirements. We sought to understand attitudes of stakeholders toward the new program. METHODS: We employed community-based participatory research methods in a qualitative evaluation of the food program at the school, where 98% of students are students of color and 86% qualify for free/reduced lunch. We conducted 4 student (N = 32), 2 parent (N = 10), 1 faculty/staff focus group (N = 14), and interviews with school leadership (N = 3). RESULTS: A total of 10 themes emerged from focus groups and interviews, in 3 categories--impressions of the food (insufficient portion size, dislike of the taste, appreciation of the freshness, increased unhealthy food consumption outside school), impact on learning (learning what's healthy, the program's innovativeness, control versus choice), and concerns about stakeholder engagement (lack of student/family engagement, culturally incompatible foods). A representative comment was: "You need something to hold them from 9 to 5, because if they are hungry, McDonald's is right there." CONCLUSION: Stakeholders appreciated the educational value of the program but stakeholder dissatisfaction may jeopardize its success. Action steps could include incorporating culturally appropriate recipes in the school's menus and working with local restaurants to promote healthier offerings. PMID- 26930240 TI - Extreme Weight-Control Behaviors and Suicide Risk Among High School Students. AB - BACKGROUND: Suicide is the third leading cause of death for people ages 15-19. Research has established an association across numerous risk factors and suicide, including depression, substance abuse, bullying victimization, and feelings of alienation. However, the connection between disordered eating as manifested in extreme weight-control behaviors (EWCB), and suicidal thoughts, ideation, and attempts among adolescents is less understood. Given the prevalence of adolescent suicide, this investigation examined associations between EWCB and suicide risk among high school students. METHODS: Data were collected from a convenience sample of 4178 students in grades 9-12 attending 5 public high schools using the Youth Risk Behavior Survey (YRBS) questionnaire. Logistic regressions were used to estimate associations between EWCB and suicide controlling for grade level and race, reported separately by sex. RESULTS: Students who reported seriously considering suicide had higher odds of exhibiting all 3 EWCBs [adjusted odds ratio (AOR)(male) = 3.0 (confidence interval (CI): 1.4, 6.5); AOR(female) = 4.5 (CI: 2.5, 8.3)]. Moreover, students who reported they made plans about suicide were also more likely to exhibit all EWCBs [AOR(male) = 3.7 (CI: 1.7, 7.9); AOR(female) = 4.2 (CI: 2.3, 7.7)]. CONCLUSIONS: EWCBs were significantly associated with suicide risk, furthering the evidence suggesting a link between disordered eating and suicide. Findings demonstrated the need for school health services that address disordered eating in the effort to reduce adolescent suicide. PMID- 26930241 TI - Pilot Investigation of the Katie Brown Educational Program: A School-Community Partnership. AB - BACKGROUND: Schools in the United States are increasingly being urged to address the problem of adolescent dating violence (DV) with their students. Given the limited time available to implement prevention programming during the school day, brief programs are needed. The purpose of this study was to test the efficacy of a widely disseminated, brief community-based DV prevention program in partnership with a nonprofit community agency. METHODS: We conducted a randomized waitlist control trial of a 5-session DV prevention program (active condition) compared to health class as usual (waitlist control condition). Participants were 225 10th grade students with a recent dating history in a large public school in New England. Surveys were administered at baseline, end of program, and 3 months postintervention. RESULTS: After completing the program, students in the active condition reported significantly lower approval of aggression, healthier dating attitudes, and more DV knowledge. These effects were sustained at 3-month follow up. In addition, students in the active condition reported significantly less emotional/verbal and total DV perpetration and victimization at 3-month follow up. CONCLUSIONS: These findings suggest that a brief, community-based DV prevention curriculum can promote change in behaviors, attitudes, and knowledge among high school students. PMID- 26930242 TI - Sleep Patterns and Academic Performance During Preparation for College Entrance Exam in Chinese Adolescents. AB - BACKGROUND: Deficient sleep is linked to detrimental outcomes in health and school performance for adolescents. This study characterized sleep patterns in Chinese adolescents preparing for the College Entrance Exam (CEE) and evaluated the association between sleep patterns, self-rated academic performance, and the CEE scores. METHODS: A sample of 481 Chinese adolescents in 12th grade (ages 16 19 years) completed questionnaires about sleep patterns, academic performance, academic stress, and sociodemographic factors 4-6 weeks before the CEE in June 2013. The CEE scores for each student also were obtained. RESULTS: A total of 21% of the students had bedtimes after 12:00 am, 78.3% had sleep latency longer than 30 minutes, 14.6% had wake time earlier than 6:00 am, and the vast majority (94.4%) had sleep duration less than 8 hours. After adjusting for selected confounders such as academic stress, prolonged sleep latency was associated with poorer self-reported academic performance, and late bedtime was associated with higher CEE score. CONCLUSIONS: Our findings highlight the complex association between sleep and academic performance. Assessing and monitoring sleep patterns in adolescents during periods of high academic demand and stress may yield important recommendations for their health and safety as well as establishing optimal sleep and study habits. PMID- 26930243 TI - Environmental Pollution: An Under-recognized Threat to Children's Health, Especially in Low- and Middle-Income Countries. AB - Exposures to environmental pollutants during windows of developmental vulnerability in early life can cause disease and death in infancy and childhood as well as chronic, non-communicable diseases that may manifest at any point across the life span. Patterns of pollution and pollution-related disease change as countries move through economic development. Environmental pollution is now recognized as a major cause of morbidity and mortality in low- and middle-income countries (LMICs). According to the World Health Organization, pollution is responsible for 8.9 million deaths around the world each year; of these, 94% (8.4 million) are in LMICs. Toxic chemical pollution is growing into a major threat to children's health in LMICs. The disease and disability caused by environmental pollution have great economic costs, and these costs can undercut trajectories of national development. To combat pollution, improved programs of public health and environmental protection are needed in countries at every level of development. Pollution control strategies and technologies that have been developed in high income countries must now be transferred to LMICs to assist these emerging economies to avoid the mistakes of the past. A new international clearinghouse is needed to define and track the health effects of pollution, quantify the economic costs of these effects, and direct much needed attention to environmental pollution as a risk factor for disease. PMID- 26930245 TI - Life and Death of Podocytes: Not Only a Matter of Vascular Endothelial Growth Factor. PMID- 26930244 TI - Effects of Elaeagnus angustifolia L. on Lipid Profile and Atherogenic Indices in Obese Females: A Randomized Controlled Clinical Trial. AB - In the present randomized double-blinded placebo-controlled study, the effect of Elaeagnus angustifolia L. (EA) whole fruit and medulla powders on anthropometric indices, serum lipid profile, and atherogenic indices in females with knee osteoarthritis (OA) was investigated. Ninety females with mild to moderate knee osteoarthritis were randomly assigned to one of three groups-medulla powder, whole fruit powder, or placebo. The subjects received 15 g/day of medulla powder of EA, whole fruit powder of EA, or placebo. Lipid profile, weight, and dietary intake were measured at baseline and at the end of the study. Body mass index and atherogenic indices were calculated. Statistical analysis was performed using SPSS version 13.0, and Paired t tests, analysis of variance (ANOVA), analysis of covariance (ANCOVA), and the Tukey post hoc test were used to compare within group and between-group values. After 8 weeks of supplementations, compared with the baseline, significant reductions in total cholesterol (TC), low density lipoprotein/high density lipoprotein (LDL/HDL), and TC/HDL ratios were observed in the two supplemented groups; however, the reduction of these values was not statistically significant in the placebo group. There were significant differences between the patients who received medulla powder and placebo group in the case of changes in TC/HDL and LDL/HDL ratios (p < .001). However, no significant differences were found between the two supplemented groups in the case of changes in studied values (p > .05). Generally, whole fruit and medulla powders of Elaeagnus angustifolia L. had positive effects, especially in decreasing total cholesterol and atherogenic indices in females with knee OA. PMID- 26930246 TI - Effect of high-temperature stress on microalgae at the end of the logarithmic phase for the efficient production of lipid. AB - Efficient production of microalgae lipid is significant for the production of renewable biodiesel. In the present study, the high temperature of 40 degrees C as stress environment was tested for stimulating lipid accumulation after the microalgae (Scenedesmus quadricauda) cells in suitable conditions grew to the end of the logarithmic phase. Different stress cultivation times of 1, 2, 3, 4, 5 and 6 days were studied. Interestingly, the lipid content and productivity reached 33.5% and 23.2 mg/L d after one day stress cultivation, showing substantial improvements of 39.6% and 33.3% compared with that in the untreated (day 0) microalgae cells, respectively. Longer stress time led to the decrease of biomass and lipid content compared with the untreated microalgae. However, a maximum protein content of 58.7% was obtained after six days. The stress cultivation at the end of the microalgae exponential phase for one day at a high temperature of 40 degrees C could be a very useful industrial approach for efficiently promoting lipid content and biodiesel production. PMID- 26930247 TI - Effect of aging on bioaccessibility of arsenic and lead in soils. AB - The effect of aging on the bioaccessibility of As and Pb in three soils spiked with As (40 or 400 mg kg(-1)), Pb (150 or 1500 mg kg(-1)) or As + Pb (40 mg kg( 1) As and 150 mg kg(-1) Pb) were investigated using the physiologically based extraction test (PBET). Prolonged aging in soils resulted in a decrease in As/Pb bioaccessibility, especially within the first month. After 76 weeks, As/Pb bioaccessibility in soils decreased to a stable level, with 48-84% and 8-34% for bioaccessible As and Pb respectively in the intestinal phase, illustrating that As in spiked soils was much more bioaccessible than Pb. Correlation analysis between sequential extraction data and PBET results showed that the non specifically sorbed As contributed the most to bioaccessible As, while Pb bound with carbonates and exchangeable fractions were the source for bioaccessible Pb. For future work, minerals containing As and/or Pb instead of their soluble salts can be added to uncontaminated soils to better simulate the natural aging processes. PMID- 26930248 TI - Surface acoustic wave characterization of optical sol-gel thin layers. AB - Controlling the thin film deposition and mechanical properties of materials is a major challenge in several fields of application. We are more particularly interested in the characterization of optical thin layers produced using sol-gel processes to reduce laser-induced damage. The mechanical properties of these coatings must be known to control and maintain optimal performance under various solicitations during their lifetime. It is therefore necessary to have means of characterization adapted to the scale and nature of the deposited materials. In this context, the dispersion of ultrasonic surface waves induced by a micrometric layer was studied on an amorphous substrate (fused silica) coated with a layer of ormosil using a sol-gel process. Our ormosil material is a silica-PDMS mixture with a variable polydimethylsiloxane (PDMS) content. The design and implementation of Surface Acoustic Wave InterDigital Transducers (SAW-IDT) have enabled quasi-monochromatic Rayleigh-type SAW to be generated and the dispersion phenomenon to be studied over a wide frequency range. Young's modulus and Poisson's ratio of coatings were estimated using an inverse method. PMID- 26930251 TI - Promiscuous primates engage in same-sex genital interactions. AB - Same-sex genital interactions (SSGIs) occur across the order primates, yet explaining their maintenance in evolutionary terms appears problematic; as such interactions seem to counteract reproductive goals. We hypothesised that in more promiscuous species, where sexual motivation, mating effort, and non-conceptive heterosexual behaviour are greater, SSGIs may also occur at greater frequencies without necessarily impeding reproduction. We found that the expression of both male and female SSGIs were greater in multimale systems than in unimale ones. Both male and female SSGIs were positively correlated with the degree of promiscuity (relative testes mass). As mating system confers biases in the sex ratio that may influence the expression of SSGIs, we controlled for availability of members of the same-sex. When employing this control, results were largely congruent. For males, SSGIs were expressed more frequently in multimale systems. For both sexes, SSGIs were expressed more frequently with greater relative testes mass. We suggest SSGIs in primates may be a neutral by-product of selection for increases in promiscuous sexual activity, and that in certain instances these interactions may be co-opted to facilitate adaptive social functions. PMID- 26930250 TI - Getting better, but not well: A 1.5 year follow-up of cognitive performance and cortisol levels in clinical and non-Clinical burnout. AB - The purpose was to reexamine cognitive performance and cortisol levels of initial clinical burnout patients, non-clinical burnout individuals, and healthy controls. After 1.5-years of the initial measurement, clinical burnout patients showed a reduction of burnout symptoms and general physical and psychological complaints, but these were still elevated compared with controls. Nonetheless, they continued to report cognitive problems and still showed a minor impaired cognitive test performance. However, they no longer reported larger subjective costs associated with cognitive test performance and their cortisol awakening response (CAR) returned to a normal level. Compared with controls, non-clinical burnout individuals still reported the same, elevated, level of burnout symptoms, general physical and psychological complaints, and cognitive problems. Their cognitive test performance and associated subjective costs remained normal. However, they seemed to continue to display a lowered CAR. To conclude, after 1.5 years, clinical burnout patients got better, but not 'well', and non-clinical burnout individuals remained not 'well'. PMID- 26930252 TI - Chemotherapeutic efficiency of drugs in vitro: Comparison of doxorubicin exposure in 3D and 2D culture matrices. AB - The interest in the use of 3D matrices for in vitro analysis, with a view to increasing the relevance of in vitro studies and reducing the dependence on in vivo studies, has been growing in recent years. Cells grown in a 3D in vitro matrix environment have been reported to exhibit significantly different properties to those in a conventional 2D culture environment. However, comparison of 2D and 3D cell culture models have recently been noted to result in differing responses of cytotoxic assays, without any associated change in viability. The effect was attributed to differing conversion rates and effective concentrations of the resazurin assay in 2D and 3D environments, rather than differences in cellular metabolism. In this study, the efficacy of a chemotherapeutic agent, doxorubicin, is monitored and compared in conventional 2D and 3D collagen gel exposures of immortalized human cervical cells. Viability was monitored with the aid of the Alamar Blue assay and drug internalisation was verified using confocal microscopy. Drug uptake and retention within the collagen matrix was monitored by absorption spectroscopy. The viability studies showed apparent differences between the 2D and 3D culture systems, the differences attributed in part to the physical transition from 2D to a 3D environment causing alterations to dye resazurin uptake and conversion rates. The use of 3D culture matrices has widely been interpreted to result in "reduced" toxicity or cellular "resistance" to the chemotherapeutic agent. The results of this study show that the reduced efficiency of the drug to cells grown in the 3D environment can be accounted for by a sequential reduction of the effective concentration of the test compound and assay. This is due to absorption within the collagen gel inducing a higher uptake of both drug and assay thereby influencing the toxic impact of the drug and conversion rate of resazurin, and. The increased effective surface area of the cell exposed to the drug and assay in the 3D environment. The effect was noted to be higher after shorter exposure periods and should be accounted for in in vitro 2D and 3D culture environment comparisons. PMID- 26930249 TI - Current development of targeted oligonucleotide-based cancer therapies: Perspective on HER2-positive breast cancer treatment. AB - This Review discusses the various types of non-coding oligonucleotides, which have garnered extensive interest as new alternatives for targeted cancer therapies over small molecule inhibitors and monoclonal antibodies. These oligonucleotides can target any hallmark of cancer, no longer limited to so called "druggable" targets. Thus, any identified gene that plays a key role in cancer progression or drug resistance can be exploited with oligonucleotides. Among them, small-interfering RNAs (siRNAs) are frequently utilized for gene silencing due to the robust and well established mechanism of RNA interference. Despite promising advantages, clinical translation of siRNAs is hindered by the lack of effective delivery platforms. This Review provides general criteria and consideration of nanoparticle development for systemic siRNA delivery. Different classes of nanoparticle candidates for siRNA delivery are discussed, and the progress in clinical trials for systemic cancer treatment is reviewed. Lastly, this Review presents HER2 (human epidermal growth factor receptor type 2) positive breast cancer as one example that could benefit significantly from siRNA technology. How siRNA-based therapeutics can overcome cancer resistance to such therapies is discussed. PMID- 26930253 TI - Urothelial Dysfunction, Suburothelial Inflammation and Altered Sensory Protein Expression in Men with Bladder Outlet Obstruction and Various Bladder Dysfunctions: Correlation with Urodynamics. AB - PURPOSE: We investigated urothelial integrity, suburothelial inflammation and the expression of sensory proteins in the bladder urothelium of male patients with bladder outlet obstruction and various bladder dysfunctions. MATERIALS AND METHODS: We prospectively enrolled 33 men with urodynamically proven bladder outlet obstruction as the study group. Bladder biopsies were obtained from all study patients and 10 control patients. The expression of E-cadherin, zonula occludens-1, tryptase, apoptosis, TRPV (transient receptor potential vanilloid) 1 and 4, beta3 adrenoreceptor, M2 and M3 muscarinic receptors, P2X3 receptor, and inducible/epithelial nitric oxide synthase were compared between study and control patients. RESULTS: Study patients had significantly lower expression of E cadherin, and a higher number of suburothelial mast and apoptotic cells than controls. Additionally, higher expression of P2X3 and M2 muscarinic receptors, and lower expression of M3 muscarinic receptor were detected in study patients. The detrusor underactivity subgroup was characterized by significantly higher expression of beta3 adrenoreceptors and lower expression of inducible nitric oxide synthase than in controls. In study patients a significantly positive correlation was noted between voided volume and E-cadherin expression (r = 0.372), volume at first sensation of filling and beta3 adrenoreceptor expression (r = 0.386), and detrusor pressure and M2 muscarinic receptor expression (r = 0.496) in the bladder urothelium (each p <0.05). CONCLUSIONS: Urothelial dysfunction, suburothelial inflammation, cellular apoptosis and alterations in sensory proteins are prominent in bladder dysfunction secondary to bladder outlet obstruction. Impaired urothelial signaling and sensory transduction pathways appear to reflect the pathophysiology of bladder dysfunction and detrusor underactivity in patients with bladder outlet obstruction. PMID- 26930255 TI - Analysis of Gut Microbiome Reveals Significant Differences between Men with Chronic Prostatitis/Chronic Pelvic Pain Syndrome and Controls. AB - PURPOSE: Chronic prostatitis/chronic pelvic pain syndrome is a common disorder with heterogeneous etiologies and clinical features. The gut microbiome is a metabolically active ecosystem linked to systemic conditions (gut-brain axis). We hypothesize that the gut microbiome will show alterations between patients with chronic pelvic pain syndrome and controls. MATERIALS AND METHODS: We identified patients with chronic pelvic pain syndrome and controls who were asymptomatic or only had urinary tract symptoms. After rectal examination the soiled glove tip was immersed in sterile saline and stored on ice. Symptom severity was measured with the NIH-Chronic Prostatitis Symptom Index and clinical phenotype with UPOINT. Total DNA was extracted from the pellet of samples. MiSeq sequencing of bacterial specific 16S rRNA capture was performed. Taxonomic and bioinformatic analyses were performed using principal coordinate analysis, QIIME and LEfSe algorithms. RESULTS: There were 25 patients and 25 controls with complete data. Mean age was similar (chronic pelvic pain syndrome 52.3 vs control 57.0 years, p=0.27). For patients with chronic pelvic pain syndrome median symptom duration was 48 months, mean Chronic Prostatitis Symptom Index was 26.0 and mean UPOINT domain was 3.6. Three-dimensional UniFrac principal coordinate analysis revealed tighter clustering of controls in a space distinct from the wider clustering of cases (p=0.001) with cases having decreased alpha diversity (p=0.001). Compared to controls, 3 taxa were overrepresented in cases and 12 were underrepresented, eg Prevotella. CONCLUSIONS: Patients with chronic pelvic pain syndrome have significantly less gut microbiome diversity which clusters differently from controls, and robustly lower counts of Prevotella, with separation sufficient to serve as a potential biomarker. The gut microbiome may serve as disease biomarker and potential therapeutic target in chronic pelvic pain syndrome. PMID- 26930256 TI - Cutaneous plasmacytoma adjacent to Bowenoid actinic keratosis on the scalp: Is there a link? AB - INTRODUCTION: Cutaneous extramedullary plasmacytoma without bone marrow involvement is very rare. We present a plasmacytoma on the scalp with an adjacent Bowenoid disease. PRESENTATION: An 86 year old man presented to our unit with an ulcerated lump on the vertex of the scalp. Excisional biopsy showed plasmacytoma with adjacent Bowenoid actinic keratosis. Blood tests did not show any systemic multiple myeloma. However, skeletal survey showed possible osteolytic lesions in some areas. Sixteen months afterwards, the patient remains well on follow up. DISCUSSION: As far as we know, this is the first reported case of a cutaneous plasma cell tumour next to an area of Bowenoid actinic keratosis. Relevant literature is investigated here for possible correlation. CONCLUSION: Within the limitations of this study, solitary primary cutaneous plasmacytoma can be treated surgically with a favourable outcome. A hypothesis of correlation between Bowenoid actinic keratosis and plasmacytoma is investigated here. Further research is needed to confirm this finding. PMID- 26930257 TI - Editorial: Unlocking Therapeutic Potential of Brown Fat. PMID- 26930260 TI - Daily expression of genes coding for neurotransmitters in central and peripheral tissues of redheaded bunting: Implication for circadian regulation of physiology in songbirds. AB - In birds, circadian control of tissue level communication is not well understood. The present study investigated this, by monitoring daily oscillation of genes coding for peptides (neuropeptide Y, NPY; vasoactive intestinal peptide, VIP; somatostatis, SST) and intermediary enzymes of amine and amino acid neurotransmitters (dopamine [tyrosine hydroxylase, TH]; glutamate [glutaminase, GLS; glutamate oxaloacetate transaminase 2, GOT2]; gamma amino butyric actid, GABA [glutamic acid decarboxylase 65, GAD65]) biosynthetic pathway, along with c FOS as an activation marker, in different tissues of migratory redheaded buntings, Emberiza bruniceps. We cloned a partial sequence of these genes, and measured their mRNA expression in the 'central' clock (retina, hypothalamus) and peripheral (heart, stomach, gut, liver) tissues, collected at six times (ZT 2, 6, 11, 13, 18 and 23; ZT 0 = lights on) from birds (n = 4/ ZT) in the 12 h:12 h light-dark cycle. There were daily mRNA oscillations of all genes, although with a tissue-specific expression pattern as well as with the differential phase relationships in genes within and between tissues. These results support a conserved tissue level circadian regulation of genes coding for peptide, amine and amino acid neurotransmitters, and substantiate the expression and plausible role of neurotransmitters in the peripheral tissues. We suggest a tissue-specific contribution of neurotransmitters in the circadian regulation of physiology and behaviour in a seasonal migratory species, the redheaded bunting. PMID- 26930261 TI - Further investigations of the relation between polymorphisms in sex steroid related genes and autistic-like traits. AB - Autism spectrum disorders (ASDs) are more prevalent in boys than in girls, indicating that high levels of testosterone during early development may be a risk factor. Evidence for this hypothesis comes from studies showing associations between fetal testosterone levels, as well as indirect measures of prenatal androgenization, and ASDs and autistic-like traits (ALTs). In a recent study we reported associations between ALTs and single nucleotide polymorphisms (SNPs) in the genes encoding estrogen receptor 1 (ESR1), steroid-5-alpha-reductase, type 2 (SRD5A2) and sex hormone-binding globulin (SHBG) in a subset (n=1771) from the Child and Adolescent Twin Study in Sweden (CATSS). The aim of the present study was to try to replicate these findings in an additional, larger, sample of individuals from the CATSS (n=10,654), as well as to analyze additional SNPs of functional importance in SHBG and SRD5A2. No associations between the previously associated SNPs in the genes ESR1 and SRD5A2 and ALTs could be seen in the large replication sample. Still, our results show that two non-linked SNPs (rs6259 and rs9901675) at the SHBG gene locus might be of importance for language impairment problems in boys. The results of the present study do not point toward a major role for the investigated SNPs in the genes ESR1 and SRD5A2 in ALTs, but a possible influence of genetic variation in SHBG, especially for language impairment problems in boys, cannot be ruled out. PMID- 26930262 TI - Social network centrality and hormones: The interaction of testosterone and cortisol. AB - In this study we tested whether testosterone and cortisol interacted in predicting social network centrality within a male rugby team. Using social network analysis (SNA), three measures of centrality were investigated: popularity (i.e., the number of incoming ties a participant receives), gregariousness (i.e., the number of ties leaving from a participant and reaching out to others), and betweenness (i.e., the number of times a person lies between two other individuals). In line with the idea that testosterone and cortisol jointly regulate the emergence of social status, we found that individuals with high basal testosterone and low basal cortisol were more popular and more likely to act as connectors among other individuals (i.e., betweenness). The same hormonal profile was not predictive of gregariousness. However, in line with the small literature on the topic, we found that cortisol was inversely correlated with gregariousness. Despite the cross-sectional and correlational nature of our research design, these findings represent the first empirical evidence that testosterone and cortisol interact to predict complex measures of social hierarchy position derived from social network analyses. PMID- 26930263 TI - Toward the validation of a new method (MUNIX) for motor unit number assessment. AB - INTRODUCTION: This prospectively designed study analyzed the correlation of a new, non-invasive neurophysiological method (Motor Unit Number Index - MUNIX) with two established Motor Unit Number Estimation (MUNE) methods. METHODS: MUNIX and incremental stimulation MUNE (IS-MUNE) were done in the abductor digiti minimi muscle (ADM), while MUNIX and spike-triggered averaging MUNE (STA-MUNE) were tested in the trapezius muscle. Twenty healthy subjects and 17 patients with amyotrophic lateral sclerosis (ALS) were examined. RESULTS: MUNIX and MUNE values correlated significantly (ADM: n=108; Spearman-Rho; r=0.88; p<0.01; trapezius muscle: n=49; Spearman-Rho; r=0.46; p<0.01). DISCUSSION: MUNIX indeed reflects the number of motor units in a muscle, and may sensibly be recorded from the trapezius muscle. With MUNIX being both much more patient friendly and much more rapid to assess than MUNE, the results support the use of MUNIX when motor unit number assessment is desired. PMID- 26930264 TI - A categorical recall strategy does not explain animacy effects in episodic memory. AB - Animate stimuli are better remembered than matched inanimate stimuli in free recall. Three experiments tested the hypothesis that animacy advantages are due to a more efficient use of a categorical retrieval cue. Experiment 1 developed an "embedded list" procedure that was designed to disrupt participants' ability to perceive category structure at encoding; a strong animacy effect remained. Experiments 2 and 3 employed animate and inanimate word lists consisting of tightly constrained categories (four-footed animals and furniture). Experiment 2 failed to find an animacy advantage when the categorical structure was readily apparent, but the advantage returned in Experiment 3 when the embedded list procedure was employed using the same target words. These results provide strong evidence against an organizational account of the animacy effect, indicating that the animacy effect in episodic memory is probably due to item-specific factors related to animacy. PMID- 26930265 TI - Attenuation of hyperglycemia-induced apoptotic signaling and anti-angiogenic milieu in cultured cytotrophoblast cells. AB - OBJECTIVE: Preeclampsia (preE) is a hypertensive disorder that occurs 20% in diabetic pregnancy. We have shown that hyperglycemia impairs cytotrophoblast cell (CTB) function. In this study, we assess apoptotic and anti-angiogenic signaling in excess glucose-induced CTBs. STUDY DESIGN: Human extravillous CTBs (Sw. 71) were treated with 100, 150, 200, 300, or 400 mg/dL glucose for 48 h. Some cells were pretreated with a p38 inhibitor (SB203580) or a peroxisome proliferator activated receptor gamma (PPARgamma) ligand (rosiglitazone) or with D-mannitol. Cell lysates were utilized to measure p38 MAPK phosphorylation, PPARgamma, Bcl-2 associated-X protein (Bax), anti-apoptotic Bcl-2, caspase-9, and cyclooxygenase-2 (Cox-2) expression by western blot. Levels of the vascular endothelial growth factor (VEGF), placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1), soluble endoglin (sEng), and interleukin 6 (IL-6) were measured in culture media using ELISA kits. Statistical comparisons were performed using analysis of variance with Duncan's post hoc test. RESULTS: p38 phosphorylation and PPARgamma were upregulated (p < 0.05) in CTBs treated with >=150 mg/dL glucose compared to basal (100 mg/dL). Expressions of Bax/Bcl-2, Cox-2, and caspase-9 were upregulated (p < 0.05) in CTBs treated with >=150 mg/dL glucose. Secretion of sFlt-1, sEng, and IL-6 was increased while VEGF and PIGF were decreased in CTB-treated >=150 mg/dl of glucose (*p < 0.01 for each). SB203580 or rosiglitazone pretreatment significantly attenuated hyperglycemia-induced apoptotic and anti-angiogenic signaling. D-Mannitol had no effect. CONCLUSION: Hyperglycemia induced apoptotic and anti-angiogenic signaling in CTBs. The observed diminution of hyperglycemia-induced signaling by SB203580 or rosiglitazone pretreatment suggests the involvement of apoptotic and anti angiogenic signaling in CTB dysfunction. PMID- 26930267 TI - Person-centred dementia care: moving beyond caregiving. PMID- 26930268 TI - Inkjet printing Schwann cells and neuronal analogue NG108-15 cells. AB - Porcine Schwann cells and neuronal analogue NG108-15 cells were printed using a piezoelectric-inkjet-printer with a nozzle diameter of 60 MUm, within the range of 70-230 V, with analysis of viability and quality after printing. Neuronal and glial cell viabilities of >86% and >90% were detected immediately after printing and no correlation between voltage applied and cell viability could be seen. Printed neuronal cells were shown to produce neurites earlier compared to controls, and over several days, produced longer neurites which become most evident by day 7. The number of neurites becomes similar by day 7 also, and cells proliferate with a similar viability to that of non-printed cells (controls). This method of inkjet printing cells provides a technical platform for investigating neuron-glial cell interactions with no significant difference to cell viability than standard cell seeding. Such techniques can be utilized for lab-on-a-chip technologies and to create printed neural networks for neuroscience applications. PMID- 26930266 TI - Sustained reduction of intraocular pressure by supraciliary delivery of brimonidine-loaded poly(lactic acid) microspheres for the treatment of glaucoma. AB - Although effective drugs that lower intraocular pressure (IOP) in the management of glaucoma exist, their efficacy is limited by poor patient adherence to the prescribed eye drop regimen. To replace the need for eye drops, in this study we tested the hypothesis that IOP can be reduced for one month after a single targeted injection using a microneedle for administration of a glaucoma medication (i.e., brimonidine) formulated for sustained release in the supraciliary space of the eye adjacent to the drug's site of action at the ciliary body. To test this hypothesis, brimonidine-loaded microspheres were formulated using poly(lactic acid) (PLA) to release brimonidine at a constant rate for 35 days and microneedles were designed to penetrate through the sclera, without penetrating into the choroid/retina, in order to target injection into the supraciliary space. A single administration of these microspheres using a hollow microneedle was performed in the eye of New Zealand White rabbits and was found to reduce IOP initially by 6 mmHg and then by progressively smaller amounts for more than one month. All administrations were well tolerated without significant adverse events, although histological examination showed a foreign body reaction to the microspheres. This study demonstrates, for the first time, that the highly-targeted delivery of brimonidine-loaded microspheres into the supraciliary space using a microneedle is able to reduce IOP for one month as an alternative to daily eye drops. PMID- 26930269 TI - Vast potential for using the piggyBac transposon to engineer transgenic plants at specific genomic locations. AB - The acceptance of bioengineered plants by some nations is hampered by a number of factors, including the random insertion of a transgene into the host genome. Emerging technologies, such as site-specific nucleases, are enabling plant scientists to promote recombination or mutations at specific plant loci. Off target activity of these nucleases may limit widespread use. Insertion of transgenes by transposases engineered with a specific DNA binding domain has been accomplished in a number of organisms, but not in plants. The piggyBac transposon system, originally isolated from an insect, has been utilized to transform a variety of organisms. The piggyBac transposase is amendable to structural modifications, and was able to insert a transgene at a specific human locus through fusion of a DNA binding domain to its N-terminus. Recent developments demonstrating the activity of piggyBac transposase in plants is an important first step toward the potential use of engineered versions of piggyBac transposase for site-specific transgene insertion in plants. PMID- 26930270 TI - Determining the Energetics of Small beta-Sheet Peptides using Adaptive Steered Molecular Dynamics. AB - Mechanically driven unfolding is a useful computational tool for extracting the energetics and stretching pathway of peptides. In this work, two representative beta-hairpin peptides, chignolin (PDB: 1UAO ) and trpzip1 (PDB: 1LE0 ), were investigated using an adaptive variant of the original steered molecular dynamics method called adaptive steered molecular dynamics (ASMD). The ASMD method makes it possible to perform energetic calculations on increasingly complex biological systems. Although the two peptides are similar in length and have similar secondary structures, their unfolding energetics are quite different. The hydrogen bonding profile and specific residue pair interaction energies provide insight into the differing stabilities of these peptides and reveal which of the pairs provides the most significant stabilization. PMID- 26930271 TI - An ex Vivo Model for Evaluating Blood-Brain Barrier Permeability, Efflux, and Drug Metabolism. AB - The metabolism of drugs in the brain is difficult to study in most species because of enzymatic instability in vitro and interference from peripheral metabolism in vivo. A locust ex vivo model that combines brain barrier penetration, efflux, metabolism, and analysis of the unbound fraction in intact brains was evaluated using known drugs. Clozapine was analyzed, and its major metabolites, clozapine N-oxide (CNO) and N-desmethylclozapine (NDMC), were identified and quantified. The back-transformation of CNO into clozapine observed in humans was also observed in locusts. In addition, risperidone, citalopram, fluoxetine, and haloperidol were studied, and one preselected metabolite for each drug was analyzed, identified, and quantified. Metabolite identification studies of clozapine and midazolam showed that the locust brain was highly metabolically active, and 18 and 14 metabolites, respectively, were identified. The unbound drug fraction of clozapine, NDMC, carbamazepine, and risperidone was analyzed. In addition, coadministration of drugs with verapamil or fluvoxamine was performed to evaluate drug-drug interactions in all setups. All findings correlated well with the data in the literature for mammals except for the stated fact that CNO is a highly blood-brain barrier permeant compound. Overall, the experiments indicated that invertebrates might be useful for screening of blood-brain barrier permeation, efflux, metabolism, and analysis of the unbound fraction of drugs in the brain in early drug discovery. PMID- 26930272 TI - Increased M1 Macrophages Infiltration Is Associated with Thrombogenesis in Rheumatic Mitral Stenosis Patients with Atrial Fibrillation. AB - Atrial fibrillation (AF) is the most common arrhythmia. In patients with AF, the role of macrophage subsets in thrombogenesis is unclear. In the present study, we analyzed the role of M1 and M2 macrophages and related cytokines in thrombogenesis of AF. Immunohistochemistry, Western blot, and TUNEL assay were used to detect M1/M2 macrophage infiltration, the expression pattern of IL-1beta and inflammasome components, and apoptosis of cardiomyocytes in 71 specimens obtained from the left atrial appendage of patients with rheumatic mitral stenosis (MS) with or without thrombosis. We demonstrated that proinflammatory M1 macrophages were predominant in the atrium of MS patients with AF and thrombus. NLRP3 inflammasomes and IL-1beta, which are primarily functional in macrophages, were activated in those patients. We also showed that increased cell death was associated with thrombogenesis in MS patients. These data indicate that infiltration of M1 macrophages and over-activation of NLRP3 inflammasomes may play a role in progressive atrial inflammation and thrombogenesis in rheumatic mitral stenosis patients with AF. PMID- 26930273 TI - Development of a Prehospital Tranexamic Acid Administration Protocol. AB - OBJECTIVE: Early administration of tranexamic acid (TXA) has been shown to reduce all-cause mortality and death secondary to trauma. Our objective was to develop a collaborative prehospital TXA administration protocol between a ground EMS and academic medical center. METHODS: Physicians, pharmacists, and EMS and fire department personnel developed a prehospital TXA administration protocol between a local fire and EMS center with a Midwest tertiary care health system based on results from the CRASH-2 Trial. The protocol was initiated March 27, 2013 and the first dose of TXA was administered in September 2013. RESULTS: Since September 2013, nineteen trauma patients received TXA. Survival rate was 89% (17/19); 2 patients expired immediately following arrival to the trauma bay. Seven patients did not receive the in-hospital maintenance dose due to the following: 3/7 (43%) due to miscommunication of pre-TXA administration; 2/7 (29%) did not meet inclusion criteria for TXA protocol; 1/7 (14%) due to protocol noncompliance; 1/7 (14%) due to a chaotic situation with an unstable patient. CONCLUSIONS: Prehospital TXA protocol based on the CRASH-2 trial is safe and feasible. The first dose of TXA administered under this protocol marks the first ground EMS administration in the USA. Conceivably, this will pose as a model to other trauma centers that receive patients from outlying areas without immediate access to care. Large multi-institutional analyses need to be performed to evaluate survival benefits of prehospital TXA administration protocol. PMID- 26930274 TI - Bioorthogonal Copper Free Click Chemistry for Labeling and Tracking of Chondrocytes In Vivo. AB - Establishment of an appropriate cell labeling and tracking method is essential for the development of cell-based therapeutic strategies. Here, we are introducing a new method for cell labeling and tracking by combining metabolic gylcoengineering and bioorthogonal copper-free Click chemistry. First, chondrocytes were treated with tetraacetylated N-azidoacetyl-D-mannosamine (Ac4ManNAz) to generate unnatural azide groups (-N3) on the surface of the cells. Subsequently, the unnatural azide groups on the cell surface were specifically conjugated with near-infrared fluorescent (NIRF) dye-tagged dibenzyl cyclooctyne (DBCO-650) through bioorthogonal copper-free Click chemistry. Importantly, DBCO 650-labeled chondrocytes presented strong NIRF signals with relatively low cytotoxicity and the amounts of azide groups and DBCO-650 could be easily controlled by feeding different amounts of Ac4ManNAz and DBCO-650 to the cell culture system. For the in vivo cell tracking, DBCO-650-labeled chondrocytes (1 * 10(6) cells) seeded on the 3D scaffold were subcutaneously implanted into mice and the transplanted DBCO-650-labeled chondrocytes could be effectively tracked in the prolonged time period of 4 weeks using NIRF imaging technology. Furthermore, this new cell labeling and tracking technology had minimal effect on cartilage formation in vivo. PMID- 26930275 TI - Integrated Analysis of Dysregulated ncRNA and mRNA Expression Profiles in Humans Exposed to Carbon Nanotubes. AB - BACKGROUND: As the application of carbon nanotubes (CNT) in consumer products continues to rise, studies have expanded to determine the associated risks of exposure on human and environmental health. In particular, several lines of evidence indicate that exposure to multi-walled carbon nanotubes (MWCNT) could pose a carcinogenic risk similar to asbestos fibers. However, to date the potential markers of MWCNT exposure are not yet explored in humans. METHODS: In the present study, global mRNA and ncRNA expression profiles in the blood of exposed workers, having direct contact with MWCNT aerosol for at least 6 months (n = 8), were compared with expression profiles of non-exposed (n = 7) workers (e.g., professional and/or technical staff) from the same manufacturing facility. RESULTS: Significant changes in the ncRNA and mRNA expression profiles were observed between exposed and non-exposed worker groups. An integrative analysis of ncRNA-mRNA correlations was performed to identify target genes, functional relationships, and regulatory networks in MWCNT-exposed workers. The coordinated changes in ncRNA and mRNA expression profiles revealed a set of miRNAs and their target genes with roles in cell cycle regulation/progression/control, apoptosis and proliferation. Further, the identified pathways and signaling networks also revealed MWCNT potential to trigger pulmonary and cardiovascular effects as well as carcinogenic outcomes in humans, similar to those previously described in rodents exposed to MWCNTs. CONCLUSION: This study is the first to investigate aberrant changes in mRNA and ncRNA expression profiles in the blood of humans exposed to MWCNT. The significant changes in several miRNAs and mRNAs expression as well as their regulatory networks are important for getting molecular insights into the MWCNT-induced toxicity and pathogenesis in humans. Further large-scale prospective studies are necessary to validate the potential applicability of such changes in mRNAs and miRNAs as prognostic markers of MWCNT exposures in humans. PMID- 26930276 TI - Inhibition of IKKalpha by BAY61-3606 Reveals IKKalpha-Dependent Histone H3 Phosphorylation in Human Cytomegalovirus Infected Cells. AB - Protein kinase inhibitors can be used as tools to identify proteins and pathways required for virus replication. Using virus replication assays and western blotting we found that the widely used protein kinase inhibitor BAY61-3606 inhibits replication of human cytomegalovirus (HCMV) strain AD169 and the accumulation of HCMV immediate-early proteins in AD169 infected cells, but has no effect on replication of HCMV strain Merlin. Using in vitro kinase assays we found that BAY61-3606 is a potent inhibitor of the cellular kinase IKKalpha. Infection of cells treated with siRNA targeting IKKalpha indicated IKKalpha was required for efficient AD169 replication and immediate-early protein production. We hypothesized that IKKalpha was required for AD169 immediate-early protein production as part of the canonical NF-kappaB signaling pathway. However, although BAY61-3606 inhibited phosphorylation of the IKKalpha substrate IkappaBalpha, we found no canonical or non-canonical NF-kappaB signaling in AD169 infected cells. Rather, we observed that treatment of cells with BAY61-3606 or siRNA targeting IKKalpha decreased phosphorylation of histone H3 at serine 10 (H3S10p) in western blotting assays. Furthermore, we found treatment of cells with BAY61-3606, but not siRNA targeting IKKalpha, inhibited the accumulation of histone H3 acetylation (H3K9ac, H3K18ac and H3K27ac) and tri-methylation (H3K27me3 and H3K36me3) modifications. Therefore, the requirement for IKKalpha in HCMV replication was strain-dependent and during replication of an HCMV strain requiring IKKalpha, IKKalpha-dependent H3S10 phosphorylation was associated with efficient HCMV replication and immediate-early protein production. Plus, inhibition of HCMV replication by BAY61-3606 is associated with acetylation and tri-methylation modifications of histone H3 that do not involve IKKalpha. PMID- 26930277 TI - Urinary Exosomal miRNA Signature in Type II Diabetic Nephropathy Patients. AB - MicroRNAs (miRNAs) are short non-coding RNA species which are important post transcriptional regulators of gene expression and play an important role in the pathogenesis of diabetic nephropathy. miRNAs are present in urine in a remarkably stable form packaged in extracellular vesicles, predominantly exosomes. In the present study, urinary exosomal miRNA profiling was conducted in urinary exosomes obtained from 8 healthy controls (C), 8 patients with type II diabetes (T2D) and 8 patients with type II diabetic nephropathy (DN) using Agilent's miRNA microarrays. In total, the expression of 16 miRNA species was deregulated (>2 fold) in DN patients compared to healthy donors and T2D patients: the expression of 14 miRNAs (miR-320c, miR-6068, miR-1234-5p, miR-6133, miR-4270, miR-4739, miR 371b-5p, miR-638, miR-572, miR-1227-5p, miR-6126, miR-1915-5p, miR-4778-5p and miR-2861) was up-regulated whereas the expression of 2 miRNAs (miR-30d-5p and miR 30e-5p) was down-regulated. Most of the deregulated miRNAs are involved in progression of renal diseases. Deregulation of urinary exosomal miRNAs occurred in micro-albuminuric DN patients but not in normo-albuminuric DN patients. We used qRT-PCR based analysis of the most strongly up-regulated miRNAs in urinary exosomes from DN patients, miRNAs miR-320c and miR-6068. The correlation of miRNA expression and micro-albuminuria levels could be replicated in a confirmation cohort. In conclusion, urinary exosomal miRNA content is altered in type II diabetic patients with DN. Deregulated miR-320c, which might have an impact on the TGF-beta-signaling pathway via targeting thrombospondin 1 (TSP-1) shows promise as a novel candidate marker for disease progression in type II DN that should be evaluated in future studies. PMID- 26930278 TI - Tankyrase Inhibitors Stimulate the Ability of Tankyrases to Bind Axin and Drive Assembly of beta-Catenin Degradation-Competent Axin Puncta. AB - Activation of the wnt signaling pathway is a major cause of colon cancer development. Tankyrase inhibitors (TNKSi) have recently been developed to block the wnt pathway by increasing axin levels to promote degradation of the wnt regulator beta-catenin. TNKSi bind to the PARP (poly(ADP)ribose polymerase) catalytic region of tankyrases (TNKS), preventing the PARylation of TNKS and axin that normally control axin levels through ubiquitination and degradation. TNKSi treatment of APC-mutant SW480 colorectal cancer cells can induce axin puncta which act as sites for assembly of beta-catenin degradation complexes, however this process is poorly understood. Using this model system, we found that siRNA knockdown of TNKSs 1 and 2 actually blocked the ability of TNKSi drugs to induce axin puncta, revealing that puncta formation requires both the expression and the inactivation of TNKS. Immunoprecipitation assays showed that treatment of cells with TNKSi caused a strong increase in the formation of axin-TNKS complexes, correlating with an increase in insoluble or aggregated forms of TNKS/axin. The efficacy of TNKSi was antagonized by proteasome inhibitors, which stabilized the PARylated form of TNKS1 and reduced TNKSi-mediated assembly of axin-TNKS complexes and puncta. We hypothesise that TNKSi act to stimulate TNKS oligomerization and assembly of the TNKS-axin scaffold that form puncta. These new insights may help in optimising the future application of TNKSi in anticancer drug design. PMID- 26930279 TI - Selective Efficacy of Static and Dynamic Imagery in Different States of Physical Fatigue. AB - There is compelling evidence that motor imagery contributes to improved motor performance, and recent work showed that dynamic motor imagery (dMI) might provide additional benefits by comparison with traditional MI practice. However, the efficacy of motor imagery in different states of physical fatigue remains largely unknown, especially as imagery accuracy may be hampered by the physical fatigue states elicited by training. We investigated the effect of static motor imagery (sMI) and dMI on free-throw accuracy in 10 high-level basketball athletes, both in a non-fatigued state (Experiment 1) and immediately after an incremental running test completed until exhaustion (20 m shuttle run-test Experiment 2). We collected perceived exhaustion and heart rate to quantify the subjective experience of fatigue and energy expenditure. We found that dMI brought better shooting performance than sMI, except when athletes were physically exhausted. These findings shed light on the conditions eliciting optimal use of sMI and dMI. In particular, considering that the current physical state affects body representation, performing dMI under fatigue may result in mismatches between actual and predicted body states. PMID- 26930280 TI - A combination of ellagic acid and tetracycline inhibits biofilm formation and the associated virulence of Propionibacterium acnes in vitro and in vivo. AB - Propionibacterium acnes is an opportunistic pathogen which has become notorious owing to its ability to form a recalcitrant biofilm and to develop drug resistance. The current study aimed to develop anti-biofilm treatments against clinical isolates of P. acnes under in vitro and in vivo conditions. A combination of ellagic acid and tetracycline (ETC; 250 MUg ml(-1) + 0.312 MUg ml( 1)) was determined to effectively inhibit biofilm formation by P. acnes (80-91%) without affecting its growth, therefore potentially limiting the possibility of the bacterium attaining resistance. In addition, ETC reduced the production of extracellular polymeric substances (EPS) (20-26%), thereby making P. acnes more susceptible to the human immune system and antibiotics. The anti-biofilm potential of ETC was further substantiated under in vivo conditions using Caenorhabditis elegans. This study reports a novel anti-biofilm combination that could be developed as an ideal therapeutic agent with broad cosmeceutical and pharmaceutical applicability in the era of antibiotic resistance. PMID- 26930281 TI - Spatial Variations in Vitreous Oxygen Consumption. AB - We investigated the spatial variation of vitreous oxygen consumption in enucleated porcine eyes. A custom made oxygen source was fabricated that could be localized to either the mid or posterior vitreous cavity and steady state vitreous oxygen tension was measured as a function of distance from the source using a commercially available probe. The reaction rate constant of ascorbate oxidation was estimated ex vivo by measuring the change in oxygen tension over time using vitreous harvested from porcine eyes. Vitreous ascorbate from mid and posterior vitreous was measured spectrophotometrically. When the oxygen source was placed in either the mid-vitreous (N = 6) or the posterior vitreous (N = 6), we measured a statistically significant decrease in vitreous oxygen tension as a function of distance from the oxygen source when compared to control experiments without an oxygen source; (p<0.005 for mid-vitreous and p<0.018 for posterior vitreous at all distances). The mid-vitreous oxygen tension change was significantly different from the posterior vitreous oxygen tension change at 2 and 3mm distances from the respective oxygen source (p<0.001). We also found a statistically significant lower concentration of ascorbate in the mid-vitreous as compared to posterior vitreous (p = 0.02). We determined the reaction rate constant, k = 1.61 M(-1) s(-1) +/- 0.708 M(-1) s(-1) (SE), of the oxidation of ascorbate which was modeled following a second order rate equation. Our data demonstrates that vitreous oxygen consumption is higher in the posterior vitreous compared to the mid-vitreous. We also show spatial variations in vitreous ascorbate concentration. PMID- 26930282 TI - Characterization and Vaccine Potential of Outer Membrane Vesicles Produced by Haemophilus parasuis. AB - Haemophilus parasuis is a Gram-negative bacterium that colonizes the upper respiratory tract of swine and is capable of causing a systemic infection, resulting in high morbidity and mortality. H. parasuis isolates display a wide range of virulence and virulence factors are largely unknown. Commercial bacterins are often used to vaccinate swine against H. parasuis, though strain variability and lack of cross-reactivity can make this an ineffective means of protection. Outer membrane vesicles (OMV) are spherical structures naturally released from the membrane of bacteria and OMV are often enriched in toxins, signaling molecules and other bacterial components. Examination of OMV structures has led to identification of virulence factors in a number of bacteria and they have been successfully used as subunit vaccines. We have isolated OMV from both virulent and avirulent strains of H. parasuis, have examined their protein content and assessed their ability to induce an immune response in the host. Vaccination with purified OMV derived from the virulent H. parasuis Nagasaki strain provided protection against challenge with a lethal dose of the bacteria. PMID- 26930283 TI - Use of H-Index and Other Bibliometric Indicators to Evaluate Research Productivity Outcome on Swine Diseases. AB - H-index is the most commonly applied tool to evaluate scientific productivity. In this study, the use of the H-index to evaluate scientific production in swine veterinary medicine was explored. A database of 137 pig infectious agents was constructed, including its taxonomic division, zoonotic potential, status as emerging pathogen and whether it was OIE-listed. The H-index and the total number of citations were calculated for those pathogens, the location of the affiliation of the first author of each paper included in the H-index core was registered and, for the ten pathogens with the highest H-index, evolution over time was measured. H-index values were compared to the M quotient, A-index, G-index, HG index and the G/H ratio. H-indices were found to be severely affected by search accuracy and the database was hand curated. Swine pathogen H-indexes were highly dispersed ranging from 0 to 106 and were generally higher for pathogens causing endemic diseases in large pig producing countries. Indeed, the three top pathogens were Escherichia coli, Porcine reproductive and respiratory syndrome virus and Porcine circovirus type 2 with H-indices 106, 95 and 85, respectively. H-indices of viruses and bacteria were significantly higher (P<0.001) than other pathogen types. Also, non-zoonotic pathogens had higher H-indices than zoonotic pathogens (p<0.009) while no differences could be found for being listed by the OIE. For emerging diseases, only non-emerging viruses had higher H-index (p = 0.02). The study of H-indexes over time revealed three general patterns and that they had increased mainly after the 1980's. As expected, there were strong geographic patterns in terms of authorship and North America (38%) and Europe (46%) coped the majority of the papers. Finally, in order to quantify the contribution of a subject to a specific field, a new index "Deciphering Citations Organized by Subject" (Dcos) is proposed. PMID- 26930284 TI - Fronto-Limbic Brain Dysfunction during the Regulation of Emotion in Schizophrenia. AB - Schizophrenia is characterized by significant and widespread impairments in the regulation of emotion. Evidence is only recently emerging regarding the neural basis of these emotion regulation impairments, and few studies have focused on the regulation of emotion during effortful cognitive processing. To examine the neural correlates of deficits in effortful emotion regulation, schizophrenia outpatients (N = 20) and age- and gender-matched healthy volunteers (N = 20) completed an emotional faces n-back task to assess the voluntary attentional control subprocess of emotion regulation during functional magnetic resonance imaging. Behavioral measures of emotional intelligence and emotion perception were administered to examine brain-behavior relationships with emotion processing outcomes. Results indicated that patients with schizophrenia demonstrated significantly greater activation in the bilateral striatum, ventromedial prefrontal, and right orbitofrontal cortices during the effortful regulation of positive emotional stimuli, and reduced activity in these same regions when regulating negative emotional information. The opposite pattern of results was observed in healthy individuals. Greater fronto-striatal response to positive emotional distractors was significantly associated with deficits in facial emotion recognition. These findings indicate that abnormalities in striatal and prefrontal cortical systems may be related to deficits in the effortful emotion regulatory process of attentional control in schizophrenia, and may significantly contribute to emotion processing deficits in the disorder. PMID- 26930286 TI - Children's Comprehension of Sentences with Focus Particles and the Role of Cognitive Control: An Eye Tracking Study with German-Learning 4-Year-Olds. AB - Children's interpretations of sentences containing focus particles do not seem adult-like until school age. This study investigates how German 4-year-old children comprehend sentences with the focus particle 'nur' (only) by using different tasks and controlling for the impact of general cognitive abilities on performance measures. Two sentence types with 'only' in either pre-subject or pre object position were presented. Eye gaze data and verbal responses were collected via the visual world paradigm combined with a sentence-picture verification task. While the eye tracking data revealed an adult-like pattern of focus particle processing, the sentence-picture verification replicated previous findings of poor comprehension, especially for 'only' in pre-subject position. A second study focused on the impact of general cognitive abilities on the outcomes of the verification task. Working memory was related to children's performance in both sentence types whereas inhibitory control was selectively related to the number of errors for sentences with 'only' in pre-subject position. These results suggest that children at the age of 4 years have the linguistic competence to correctly interpret sentences with focus particles, which--depending on specific task demands--may be masked by immature general cognitive abilities. PMID- 26930285 TI - A Switch in the Dynamics of Intra-Platelet VEGF-A from Cancer to the Later Phase of Liver Regeneration after Partial Hepatectomy in Humans. AB - BACKGROUND: Liver regeneration (LR) involves an early inductive phase characterized by the proliferation of hepatocytes, and a delayed angiogenic phase distinguished by the expansion of non-parenchymal compartment. The interest in understanding the mechanism of LR has lately shifted from the proliferation and growth of parenchymal cells to vascular remodeling during LR. Angiogenesis accompanied by LR exerts a pivotal role to accomplish the process. Vascular endothelial growth factor (VEGF) has been elucidated as the most dynamic regulator of angiogenesis. From this perspective, platelet derived/Intra-platelet (IP) VEGF-A should be associated with LR. MATERIAL AND METHODS: Thirty-seven patients diagnosed with hepatocellular carcinoma and undergoing partial hepatectomy (PH) were enrolled in the study. Serum and IP VEGF-A was monitored preoperatively and at four weeks of PH. Liver volumetry was determined on computer models derived from computed tomography (CT) scan. RESULTS: Serum and IP VEGF-A was significantly elevated at four weeks of PH. Preoperative IP VEGF-A was higher in patients with advanced cancer and vascular invasion. Postoperative IP VEGF-A was higher after major liver resection. There was a statistically significant correlation between postoperative IP VEGF-A and the future remnant liver volume. Moreover, the soluble vascular endothelial growth factor receptor-1 (sVEGFR1) was distinctly down-regulated suggesting a fine-tuned angiogenesis at the later phase of LR. CONCLUSION: IP VEGF-A is overexpressed during later phase of LR suggesting its implications in inducing angiogenesis during LR. PMID- 26930288 TI - Correction: Glaucoma, Alzheimer's Disease, and Parkinson's Disease: An 8-Year Population-Based Follow-Up Study. PMID- 26930287 TI - Association between Directly Observed Therapy and Treatment Outcomes in Multidrug Resistant Tuberculosis: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Multidrug-resistant tuberculosis (MDR-TB) represents a major obstacle towards successful TB control. Directly observed therapy (DOT) was recommended by WHO to improve adherence and treatment outcomes of MDR-TB patients, however, the effectiveness of DOT on treatment outcomes of MDR-TB patients was mixed in previous studies. We conducted this systematic review and meta-analysis to assess the association between DOT and treatment outcomes and to examine the impact of different DOT providers and DOT locations on successful treatment outcomes in MDR TB patients. METHODS: We searched studies published in English between January 1970 and December 2015 in major electronic databases. Two reviewers independently screened articles and extracted information of DOT, treatment success rate and other characteristics of studies. Random effects model was used to calculate the pooled treatment success rate and 95% confidence interval (CI). Sub-group analyses were conducted to access factors associated with successful treatment outcomes. RESULTS: A total of 31 articles 7,466 participants were included. Studies reporting full DOT (67.4%, 95% CI: 61.4-72.8%) had significantly higher pooled treatment success rates than those reporting self-administration therapy (46.9%, 95% CI: 41.4-52.4%). No statistically difference was found among DOT provided by healthcare providers (65.8%, 95% CI: 55.7-74.7%), family members (72.0%, 95% CI: 31.5-93.5%) and private DOT providers (69.5%, 95% CI: 57.0 79.7%); and neither did we find significantly difference on pooled treatment success rates between patients having health facility based DOT (70.5%, 95% CI: 61.5-78.1%) and home-based DOT (68.4%, 95% CI: 51.5-81.5%). CONCLUSION: Providing DOT for a full course of treatment associated with a higher treatment success rate in MDR-TB patients. PMID- 26930289 TI - Mapping National Plant Biodiversity Patterns in South Korea with the MARS Species Distribution Model. AB - Accurate information on the distribution of existing species is crucial to assess regional biodiversity. However, data inventories are insufficient in many areas. We examine the ability of Multivariate Adaptive Regression Splines (MARS) multi response species distribution model to overcome species' data limitations and portray plant species distribution patterns for 199 South Korean plant species. The study models species with two or more observations, examines their contribution to national patterns of species richness, provides a sensitivity analysis of different range threshold cutoff approaches for modeling species' ranges, and presents considerations for species modeling at fine spatial resolution. We ran MARS models for each species and tested four threshold methods to transform occurrence probabilities into presence or absence range maps. Modeled occurrence probabilities were extracted at each species' presence points, and the mean, median, and one standard deviation (SD) calculated to define data driven thresholds. A maximum sum of sensitivity and specificity threshold was also calculated, and the range maps from the four cutoffs were tested using independent plant survey data. The single SD values were the best threshold tested for minimizing omission errors and limiting species ranges to areas where the associated occurrence data were correctly classed. Eight individual species range maps for rare plant species were identified that are potentially affected by resampling predictor variables to fine spatial scales. We portray spatial patterns of high species richness by assessing the combined range maps from three classes of species: all species, endangered and endemic species, and range-size rarity of all species, which could be used in conservation planning for South Korea. The MARS model is promising for addressing the common problem of few species occurrence records. However, projected species ranges are highly dependent on the threshold and scale criteria, which should be assessed on a per project basis. PMID- 26930290 TI - Iterative Reconstruction Improves Both Objective and Subjective Image Quality in Acute Stroke CTP. AB - PURPOSE: Computed tomography perfusion (CTP) imaging in acute ischemic stroke (AIS) suffers from measurement errors due to image noise. The purpose of this study was to investigate if iterative reconstruction (IR) algorithms can be used to improve the diagnostic value of standard-dose CTP in AIS. METHODS: Twenty three patients with AIS underwent CTP with standardized protocol and dose. Raw data were reconstructed with filtered back projection (FBP) and IR with intensity levels 3, 4, 5. Image quality was objectively (quantitative perfusion values, signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR)) and subjectively (overall image quality) assessed. Ischemic core and perfusion mismatch were visually rated. Discriminative power for tissue outcome prediction was determined by the area under the receiver operating characteristic curve (AUC) resulting from the overlap between follow-up infarct lesions and stepwise thresholded CTP maps. RESULTS: With increasing levels of IR, objective image quality (SNR and CNR in white matter and gray matter, elimination of error voxels) and subjective image quality improved. Using IR, mean transit time (MTT) was higher in ischemic lesions, while there was no significant change of cerebral blood volume (CBV) and cerebral blood flow (CBF). Visual assessments of perfusion mismatch changed in 4 patients, while the ischemic core remained constant in all cases. Discriminative power for infarct prediction as represented by AUC was not significantly changed in CBV, but increased in CBF and MTT (mean (95% CI)): 0.72 (0.67-0.76) vs. 0.74 (0.70-0.78) and 0.65 (0.62-0.67) vs 0.67 (0.64-0.70). CONCLUSION: In acute stroke patients, IR improves objective and subjective image quality when applied to standard-dose CTP. This adds to the overall confidence of CTP in acute stroke triage. PMID- 26930291 TI - Progress in Reversing the HIV Epidemic through Intensified Access to Antiretroviral Therapy: Results from a Nationally Representative Population-Based Survey in Kenya, 2012. AB - BACKGROUND: In 2014, the Joint United Nations Programme on HIV/AIDS (UNAIDS) called for 90% of persons living with HIV (PLHIV) to know their status, 90% of these to be on antiretroviral therapy (ART), and 90% of these to be virally suppressed by 2020 (90-90-90). It is not clear whether planned ART scale-up in countries whose eligibility criteria for ART initiation are based on recommendations from the 2013 World Health Organization treatment guidelines will be sufficient to meet UNAIDS' new global targets. MATERIALS AND METHODS: Using data from a nationally representative population-based household survey of persons in Kenya we compared coverage and unmet need associated with HIV diagnosis, ART, and viral suppression among PLHIV aged 15-64 years in 2012 based on criteria outlined in the 2014 national ART guidelines and UNAIDS' 90-90-90 goals. Estimates were weighted to account for sampling probability and nonresponse. RESULTS: Eight in ten PLHIV aged 15-64 years needed ART based on treatment eligibility. Need for treatment based on the national treatment policy was 97.4% of treatment need based on UNAIDS' 90-90-90 goals, requiring an excess of 24,000 PLHIV to access treatment beyond those eligible for ART to achieve UNAIDS' 90-90-90 treatment target. The gap in treatment coverage was high, ranging from 43.1% nationally to 52.3% in Nyanza among treatment-eligible PLHIV and 44.6% nationally to 52.4% in Nyanza among all PLHIV. CONCLUSION: Maintaining the current pace of ART scale-up in Kenya will result in thousands of PLHIV unreached, many with high viral load and at-risk of transmitting infection to others. Careful strategies for reaching 90-90-90 will be instrumental in determining whether intensified access to treatment can be achieved to reach all who require ART. PMID- 26930292 TI - Predictors of Ibandronate Efficacy for the Management of Osteoporosis: A Meta Regression Analysis. AB - BACKGROUND: Aim of the present study was to identify the predictors of ibandronate efficacy in subjects with osteoporosis or decreased bone mineral density (BMD). METHOD: Several electronic databases were searched by using specific keywords for the acquisition of research articles reporting the efficacy of ibandronate in subjects with osteoporosis or decreased BMD. Metaregression analyses were carried out by using changes in the BMD of lumbar spine and total hip following ibandronate treatment as dependent (outcome) variables against several independent (explanatory) variables. RESULTS: Data were extracted from 34 studies (11,090 ibandronate treated subjects) which fulfilled eligibility criteria. A history of previous fracture/s was reported by 46% of these subjects. In overall population, longer treatment duration from 1 to 5 years, increasing age, history of previous fractures, lower baseline T score, and higher baseline levels of C-terminal telopeptide of type 1 collagen (CTX) predicted higher ibandronate efficacy in improving BMD of the lumbar spine as well as of the total hip. Lower baseline levels of vitamin D and higher baseline levels of bone specific alkaline phosphatase (BSAP) predicted higher efficacy of ibandronate for lumbar spine only. In postmenopausal women with osteoporosis or decreased BMD, in addition to above-mentioned predictors, better efficacy of ibandronate was also associated with increasing time since menopause for both lumbar spine and total hip and lower body weight for lumbar spine only. CONCLUSION: Longer treatment duration from 1 to 5 years, increasing age, lower baseline T scores, and higher serum CTX levels are identified as the predictors of better efficacy of ibandronate in the study subjects with osteoporosis or decreased BMD. PMID- 26930293 TI - Seeing through Musculoskeletal Tissues: Improving In Situ Imaging of Bone and the Lacunar Canalicular System through Optical Clearing. AB - In situ, cells of the musculoskeletal system reside within complex and often interconnected 3-D environments. Key to better understanding how 3-D tissue and cellular environments regulate musculoskeletal physiology, homeostasis, and health is the use of robust methodologies for directly visualizing cell-cell and cell-matrix architecture in situ. However, the use of standard optical imaging techniques is often of limited utility in deep imaging of intact musculoskeletal tissues due to the highly scattering nature of biological tissues. Drawing inspiration from recent developments in the deep-tissue imaging field, we describe the application of immersion based optical clearing techniques, which utilize the principle of refractive index (RI) matching between the clearing/mounting media and tissue under observation, to improve the deep, in situ imaging of musculoskeletal tissues. To date, few optical clearing techniques have been applied specifically to musculoskeletal tissues, and a systematic comparison of the clearing ability of optical clearing agents in musculoskeletal tissues has yet to be fully demonstrated. In this study we tested the ability of eight different aqueous and non-aqueous clearing agents, with RIs ranging from 1.45 to 1.56, to optically clear murine knee joints and cortical bone. We demonstrated and quantified the ability of these optical clearing agents to clear musculoskeletal tissues and improve both macro- and micro-scale imaging of musculoskeletal tissue across several imaging modalities (stereomicroscopy, spectroscopy, and one-, and two-photon confocal microscopy) and investigational techniques (dynamic bone labeling and en bloc tissue staining). Based upon these findings we believe that optical clearing, in combination with advanced imaging techniques, has the potential to complement classical musculoskeletal analysis techniques; opening the door for improved in situ investigation and quantification of musculoskeletal tissues. PMID- 26930294 TI - Trade-Offs between Growth Rate, Tree Size and Lifespan of Mountain Pine (Pinus montana) in the Swiss National Park. AB - A within-species trade-off between growth rates and lifespan has been observed across different taxa of trees, however, there is some uncertainty whether this trade-off also applies to shade-intolerant tree species. The main objective of this study was to investigate the relationships between radial growth, tree size and lifespan of shade-intolerant mountain pines. For 200 dead standing mountain pines (Pinus montana) located along gradients of aspect, slope steepness and elevation in the Swiss National Park, radial annual growth rates and lifespan were reconstructed. While early growth (i.e. mean tree-ring width over the first 50 years) correlated positively with diameter at the time of tree death, a negative correlation resulted with lifespan, i.e. rapidly growing mountain pines face a trade-off between reaching a large diameter at the cost of early tree death. Slowly growing mountain pines may reach a large diameter and a long lifespan, but risk to die young at a small size. Early growth was not correlated with temperature or precipitation over the growing period. Variability in lifespan was further contingent on aspect, slope steepness and elevation. The shade-intolerant mountain pines follow diverging growth trajectories that are imposed by extrinsic environmental influences. The resulting trade-offs between growth rate, tree size and lifespan advance our understanding of tree population dynamics, which may ultimately improve projections of forest dynamics under changing environmental conditions. PMID- 26930295 TI - Genetic landscape of APOE in human longevity revealed by high-throughput sequencing. AB - Apolipoprotein E (APOE) gene has been the most replicated longevity-associated gene in humans. Two common APOE alleles are either significantly depleted (epsilon4 allele) or enriched (epsilon2 allele) in long-lived individuals as compared to controls. We performed high-throughput sequencing analysis of exons and 2kb proximal promoter of APOE in 450 centenarians and 500 controls of Ashkenazi Jewish decent. We found two common regulatory variants, rs405509 (p=0.006) and rs769449 (p=0.036), that were significantly depleted in centenarians. Genotyping analysis of rs7412 and rs429358 showed significant enrichment of epsilon2 allele (p=0.003) and epsilon2/epsilon3 genotype (p=0.005), and significant depletion of epsilon3/epsilon4 genotype (p=0.005) in centenarians. Our findings support the hypothesis that variants in both coding and regulatory regions of APOE may contribute to longevity in humans. PMID- 26930296 TI - Changes in Drosophila mitochondrial proteins following chaperone-mediated lifespan extension confirm a role of Hsp22 in mitochondrial UPR and reveal a mitochondrial localization for cathepsin D. AB - Hsp22 is a small mitochondrial heat shock protein (sHSP) preferentially up regulated during aging in Drosophila melanogaster. Its developmental expression is strictly regulated and it is rapidly induced in conditions of stress. Hsp22 is one of the few sHSP to be localized inside mitochondria, and is the first sHSP to be involved in the mitochondrial unfolding protein response (UPR(MT)) together with Hsp60, mitochondrial Hsp70 and TRAP1. The UPR(MT) is a pro-longevity mechanism, and interestingly Hsp22 over-expression by-itself increases lifespan and resistance to stress. To unveil the effect of Hsp22 on the mitochondrial proteome, comparative IEF/SDS polyacrylamide 2D gels were done on mitochondria from Hsp22+ flies and controls. Among the proteins influenced by Hsp22 expression were proteins from the electron transport chain (ETC), the TCA cycle and mitochondrial Hsp70. Hsp22 co-migrates with ETC components and its over expression is associated with an increase in mitochondrial protease activity. Interestingly, the only protease that showed significant changes upon Hsp22 over expression in the comparative IEF/SDS-PAGE analysis was cathepsin D, which is localized in mitochondria in addition to lysosome in D. melanogaster as evidenced by cellular fractionation. Together the results are consistent with a role of Hsp22 in the UPR(MT) and in mitochondrial proteostasis. PMID- 26930297 TI - Species-specific lifespans: Can it be a lottery based on the mode of mitochondrial DNA replication? AB - Accumulating evidence suggests that the aging process is, in part, driven by accumulation of large deletions in mitochondrial DNA (mtDNA). Here, I present a hypothesis that significant variations in lifespans can be explained by species specific mtDNA sequence features that cause a shift in the mode of mtDNA replication and thus preclude the formation of large deletions. PMID- 26930298 TI - Computational and experimental approaches for investigating nanoparticle-based drug delivery systems. AB - Most therapeutic agents suffer from poor solubility, rapid clearance from the blood stream, a lack of targeting, and often poor translocation ability across cell membranes. Drug/gene delivery systems (DDSs) are capable of overcoming some of these barriers to enhance delivery of drugs to their right place of action, e.g. inside cancer cells. In this review, we focus on nanoparticles as DDSs. Complementary experimental and computational studies have enhanced our understanding of the mechanism of action of nanocarriers and their underlying interactions with drugs, biomembranes and other biological molecules. We review key biophysical aspects of DDSs and discuss how computer modeling can assist in rational design of DDSs with improved and optimized properties. We summarize commonly used experimental techniques for the study of DDSs. Then we review computational studies for several major categories of nanocarriers, including dendrimers and dendrons, polymer-, peptide-, nucleic acid-, lipid-, and carbon based DDSs, and gold nanoparticles. This article is part of a Special Issue entitled: Membrane Proteins edited by J.C. Gumbart and Sergei Noskov. PMID- 26930299 TI - The Experiences and Meanings That Shape Heterosexual Fathers' Relationships With Their Gay Sons in South Africa. AB - Gay men's relationships with their mothers are likely to be more positive than their relationships with their fathers, and fathers are less likely to be told, less likely to be told first, and more likely to react negatively to disclosure than mothers. Drawing on an interpretivist approach, an individual in-depth interview strategy was adopted in the study as a means of gathering data from six Afrikaans-speaking White fathers, between the ages of 53 and 61 years (median: 55.5 years), residing in Gauteng, South Africa. Interviews were audio-recorded and transcribed for later coding and analysis. Through thematic network analysis, eight organizing themes emerged and were explored. For the purpose of this article only three organizing themes are discussed, namely "subliminal awareness prior to coming out," "epistemic rupture of internal systems of ideas/beliefs," and "acceptance as a complex and ongoing dialectical and reconciliatory process." The themes support the view that most parents are neither totally rejecting nor fully accepting of their gay sons. Although the fathers may have attained a level of "loving denial" in the relationships with their gay sons, most continue to struggle with the meaning and expression of same-sex sexuality. Despite these challenges, it is recognized that the fathers are adapting to changing circumstances and are trying to find ways to tolerate, accommodate, and in some ways accept their gay sons. PMID- 26930300 TI - Synthesis, Structure, Properties, and Bioimaging of a Fluorescent Nitrogen-Linked Bisbenzothiadiazole. AB - This paper describes the synthesis, structure, photophysical properties, and bioimaging application of a novel 2,1,3-benzothiadiazole (BTD)-based rationally designed fluorophore. The capability of undergoing efficient stabilizing processes from the excited state allowed the novel BTD derivative to be used as a stable probe for bioimaging applications. No notable photobleaching effect or degradation could be observed during the experimental time period. Before the synthesis, the molecular architecture of the novel BTD derivative was evaluated by means of DFT calculations to validate the chosen design. Single-crystal X-ray analysis revealed the nearly flat characteristics of the structure in a syn conformation. The fluorophore was successfully tested as a live-cell-imaging probe and efficiently stained MCF-7 breast cancer cell lineages. PMID- 26930301 TI - High Leucine Diets Stimulate Cerebral Branched-Chain Amino Acid Degradation and Modify Serotonin and Ketone Body Concentrations in a Pig Model. AB - In addition to its role as an essential protein component, leucine (Leu) displays several other metabolic functions such as activation of protein synthesis. This property makes it an interesting amino acid for the therapy of human muscle atrophy and for livestock production. However, Leu can stimulate its own degradation via the branched-chain keto acid dehydrogenase complex (BCKDH). To examine the response of several tissues to excessive Leu, pigs were fed diets containing two- (L2) and four-fold (L4) higher Leu contents than the recommended amount (control). We found that the L4 diet led to a pronounced increase in BCKDH activity in the brain (2.5-fold, P < 0.05), liver (1.8-fold, P < 0.05) and cardiac muscle (1.7-fold, P < 0.05), whereas we found no changes in enzyme activity in the pancreas, skeletal muscle, adipose tissue and intestinal mucosa. The L2 diet had only weak effects on BCKDH activity. Both high Leu diets reduced the concentrations of free valine and isoleucine in nearly all tissues. In the brain, high Leu diets modified the amount of tryptophan available: for serotonin synthesis. Compared to the controls, pigs treated with the high Leu diets consumed less food, showed increased plasma concentrations of 3-hydroxybutyrate and reduced levels of circulating serotonin. In conclusion, excessive Leu can stimulate BCKDH activity in several tissues, including the brain. Changes in cerebral tryptophan, along with the changes in amino acid-derived metabolites in the plasma may limit the use of high Leu diets to treat muscle atrophy or to increase muscle growth. PMID- 26930302 TI - Physical activity levels during youth sport practice: does coach training or experience have an influence? AB - This study examined moderate-to-vigorous physical activity (MVPA) levels in youth during flag football practice and compared youth MVPA in practices led by trained or untrained, and by experienced or inexperienced, coaches. Boys (n = 111, mean age = 7.9 +/- 1.2 years) from 14 recreation-level flag football teams wore an accelerometer during two practices. Each team's volunteer head coach reported prior training and coaching experience. Mixed-model team-adjusted means showed the proportion of practice time spent in sedentary (13 +/- 1%), MVPA (34 +/- 2%) and vigorous (12 +/- 1%) activity. Practice contributed ~20 min of MVPA towards public health guidelines. There was no significant difference in percentage time spent in MVPA between teams with trained (mean = 33.3%, 95% CI = 29.4%, 37.2%) and untrained coaches (mean = 35.9%, 95% CI = 25.5%, 42.4%) or between experienced (mean = 34.1%, 95% CI = 30.2%, 38.0%) and inexperienced coaches (mean = 33.8, 95% CI = 27.9%, 39.7%). Although sport provides a setting for youth to accrue MVPA, two-thirds of practice was spent sedentarily or in light activity. Participation in a coach training programme was not associated with higher MVPA. Further research is needed to inform volunteer coach training programmes that provide coaches with skills necessary to increase the percentage of practice time spent in MVPA. PMID- 26930304 TI - Anion Binding by Dimetallic Nickel(II) and Nickel(III) Complexes of a Face-to Face Bicyclam: Looking for a Bimacrocyclic Effect. AB - The dinickel(II) complex of the face-to-face bicyclam ligand alpha,alpha'-bis(5,7 dimethyl-1,4,8,11-tetraazacyclotetradecan-6-yl)-o-xylene (L?L) in a dimethyl sulfoxide solution exists as a mixture of high- and low-spin forms and uptakes up to three halide and pseudohalide ions (X(-)), according to stepwise equilibria, whose constants were determined through spectrophotometric titration experiments. In the case of halides, the first anion goes into the intermetallic cavity, whereas pseudohalides first coordinate the metal center from outside. Comparison with equilibrium data for the complex with the macrocycle 5,7-dimethyl-6-benzyl 1,4,8,11-tetraazacyclotetradecane (L) shows that the dinuclear complex [Ni(II)2(L?L)](4+) displays an affinity for the first halide distinctly higher than the mononuclear complex [Ni(II)(L)](2+), thus disclosing the existence of a bimacrocyclic effect for anion binding. Differential pulse voltammetry studies typically showed a three-peak profile: the most anodic pertaining to the [Ni(II)2(L?L)](4+) -> Ni(III)2(L?L)](6+) two-electron process, then one originating from the [Ni(II)2(L?L)X](3+) -> Ni(III)2(L?L)X](5+) two-electron process, and one deriving from the two two-electron half reactions [Ni(II)2(L?L)X2](2+) -> Ni(III)2(L?L)X2](4+) and [Ni(II)2(L?L)X3](+) -> Ni(III)2(L?L)X3](3+), taking place at nearly the same potential. The crystal structure of the [Ni(II)2(L?L)(MU-NCO)(NCO)2]ClO4.2.5H2O complex salt showed a caterpillar arrangement of the three metal-bound cyanate ions. PMID- 26930303 TI - Effect of Sleep-disordered Breathing Severity on Cognitive Performance Measures in a Large Community Cohort of Young School-aged Children. AB - RATIONALE: Sleep-disordered breathing (SDB) in children is associated with cognitive challenges. However, potential associations between SDB severity and neurocognitive function, as well as the presence of an SDB cutoff, have not been fully explored. OBJECTIVES: To determine whether SDB-associated adverse changes in neurocognitive functioning are severity dependent. METHODS: A total of 1,010 snoring and nonsnoring children ages 5-7 years were prospectively recruited from public schools and underwent polysomnography and neurocognitive assessments of intellectual, attention, memory, language, and executive function development. The children were subdivided into four severity groups on the basis of apnea hypopnea index (AHI), followed by comparisons of cognitive function, with a particular focus on standardized subtests of intellectual, language, attention, memory, and executive function. MEASUREMENT AND MAIN RESULTS: Differential Ability Scales Verbal (P < 0.001) and Nonverbal (P = 0.002) performance, as well as global conceptual ability (IQ) (P < 0.001) scores, differed significantly across the groups, with individuals with higher AHI showing worse performance. Additionally, specific NEPSY (a Developmental Neuropsychological Assessment) subscores focused on attention and executive skills differed across the groups, indicating differences in levels of engagement and problem solving. Children with higher AHI (>5 per hour of total sleep time) were significantly more impaired than all three lower AHI groups, indicating a dose-response impact of SDB. CONCLUSIONS: This large community-based sample of children highlights the significant deleterious impact of SDB, particularly in children with moderate to severe obstructive sleep apnea, and also that even snoring alone affects neurocognitive function. By affecting developing capabilities, as illustrated by cognitive measures in a severity-graded manner, SDB could adversely impact children's capacity to attain academic and adaptive goals, ultimately hampering their ability to reach independence. Our findings support the need for increased awareness of SDB, with particular emphasis on children with more severe obstructive sleep apnea. PMID- 26930306 TI - Heterogeneity in leaf litter decomposition in a temporary Mediterranean stream during flow fragmentation. AB - In temporary Mediterranean streams, flow fragmentation during summer droughts originates an ephemeral mosaic of terrestrial and aquatic habitat types. The heterogeneity of habitat types implies a particular ecosystem functioning in temporary streams that is still poorly understood. We assessed the initial phases of leaf litter decomposition in selected habitat types: running waters, isolated pools and moist and dry streambed sediments. We used coarse-mesh litter bags containing Populus nigra leaves to examine decomposition rates, microbial biomass, macroinvertebrate abundance and dissolved organic carbon (DOC) release rates in each habitat type over an 11-day period in late summer. We detected faster decomposition rates in aquatic (running waters and isolated pools) than in terrestrial habitats (moist and dry streambed sediments). Under aquatic conditions, decomposition was characterized by intense leaching and early microbial colonization, which swiftly started to decompose litter. Microbial colonization in isolated pools was primarily dominated by bacteria, whereas in running waters fungal biomass predominated. Under terrestrial conditions, leaves were most often affected by abiotic processes that resulted in small mass losses. We found a substantial decrease in DOC release rates in both aquatic habitats within the first days of the study, whereas DOC release rates remained relatively stable in the moist and dry sediments. This suggests that leaves play different roles as a DOC source during and after flow fragmentation. Overall, our results revealed that leaf decomposition is heterogeneous during flow fragmentation, which has implications related to DOC utilization that should be considered in future regional carbon budgets. PMID- 26930305 TI - Trends and sources vs air mass origins in a major city in South-western Europe: Implications for air quality management. AB - This study presents a 17-years air quality database comprised of different parameters corresponding to the largest city in the south of Spain (Seville) where atmospheric pollution is frequently attributed to traffic emissions and is directly affected by Saharan dust outbreaks. We identify the PM10 contributions from both natural and anthropogenic sources in this area associated to different air mass origins. Hourly, daily and seasonal variation of PM10 and gaseous pollutant concentrations (CO, NO2 and SO2), all of them showing negative trends during the study period, point to the traffic as one of the main sources of air pollution in Seville. Mineral dust, secondary inorganic compounds (SIC) and trace elements showed higher concentrations under North African (NAF) air mass origins than under Atlantic. We observe a decreasing trend in all chemical components of PM10 under both types of air masses, NAF and Atlantic. Principal component analysis using more frequent air masses in the area allows the identification of five PM10 sources: crustal, regional, marine, traffic and industrial. Natural sources play a more relevant role during NAF events (20.6 MUg . m(-3)) than in Atlantic episodes (13.8 MUg . m(-3)). The contribution of the anthropogenic sources under NAF doubles the one under Atlantic conditions (33.6 MUg . m(-3) and 15.8 MUg . m(-3), respectively). During Saharan dust outbreaks the frequent accumulation of local anthropogenic pollutants in the lower atmosphere results in poor air quality and an increased risk of mortality. The results are relevant when analysing the impact of anthropogenic emissions on the exposed population in large cities. The increase in potentially toxic elements during Saharan dust outbreaks should also be taken into account when discounting the number of exceedances attributable to non-anthropogenic or natural origins. PMID- 26930307 TI - Characterization of water dissolved organic matter under woody vegetation patches in semi-arid Mediterranean soils. AB - Woody patches in semiarid environments favor the establishment of other plants. Facilitation may be favored by an increase in soil fertility. Dissolved organic matter (DOM), is the most active fraction of soil organic matter and may contain compounds affecting plant establishment, as allelochemicals, hormone-like substances and metal carriers. However, information on DOM contents and composition in these environments is scarce. In this paper, we study the impact of woody patches on DOM in Stipa tenacissima L. steppes and discuss its implications for community dynamics. DOM under patch- and inter-patch areas, was analyzed for elemental composition, UV-Vis indices and organic acid content. Element concentration and composition in DOM, and organic acid concentration were similar in patch- and inter-patch areas. Yet, soils under patches were richer in DOC, aromatic species and organic acids (particularly fumaric acid) than soils in inter-patch areas. Dominant species affected organic matter concentration and quality in complex ways. Thus, patches dominated by Ephedra fragilis showed higher concentrations of TOC and aromatics than those dominated by other species. Rhamnus lycioides patches showed the highest accumulation of fumaric acid, which may contribute to its successful recruitment rate and expansion in the area. Our results show substantial differences in the amount and composition of DOM and specific compounds affecting soil functionality and plant dynamics. Further studies on the effects of such changes on seedling performance are needed to increase our understanding of plant-plant interactions in semiarid environments. PMID- 26930308 TI - Consistent effects of canopy vs. understory nitrogen addition on the soil exchangeable cations and microbial community in two contrasting forests. AB - Anthropogenic N deposition has been well documented to cause substantial impacts on the chemical and biological properties of forest soils. In most studies, however, atmospheric N deposition has been simulated by directly adding N to the forest floor. Such studies thus ignored the potentially significant effect of some key processes occurring in forest canopy (i.e., nitrogen retention) and may therefore have incorrectly assessed the effects of N deposition on soils. Here, we conducted an experiment that included both understory addition of N (UAN) and canopy addition of N (CAN) in two contrasting forests (temperate deciduous forest vs. subtropical evergreen forest). The goal was to determine whether the effects on soil exchangeable cations and microbial biomass differed between CAN and UAN. We found that N addition reduced pH, BS (base saturation) and exchangeable Ca and increased exchangeable Al significantly only at the temperate JGS site, and reduced the biomass of most soil microbial groups only at the subtropical SMT site. Except for soil exchangeable Mn, however, effects on soil chemical properties and soil microbial community did not significantly differ between CAN and UAN. Although biotic and abiotic soil characteristics differ significantly and the responses of both soil exchangeable cations and microbial biomass were different between the two study sites, we found no significant interactive effects between study site and N treatment approach on almost all soil properties involved in this study. In addition, N addition rate (25 vs. 50 kg N ha(-1) yr( 1)) did not show different effects on soil properties under both N addition approaches. These findings did not support previous prediction which expected that, by bypassing canopy effects (i.e., canopy retention and foliage fertilization), understory addition of N would overestimate the effects of N deposition on forest soil properties, at least for short time scale. PMID- 26930309 TI - Drought monitoring based on TIGGE and distributed hydrological model in Huaihe River Basin, China. AB - Drought assessment is important for developing measures to reduce agricultural vulnerability and thereby secure the livelihoods of those who depend on agriculture. This study uses four global ensemble weather prediction systems: the China Meteorological Administration (CMA), the European Centre for Medium-Range Weather Forecasts (ECMWF), the UK Met Office (UKMO), and the US National Centres for Environmental Prediction (NCEP) in the THORPEX (The Observing System Research and Predictability Experiment) Interactive Grand Global Ensemble (TIGGE) archive from 2006 to 2010. Based on results from the XXT (the first X denotes Xinanjiang, the second X denotes hybrid, and the T denotes TOPMODEL) distributed hydrological model, as well as soil moisture observations and digital elevation model (DEM) data, synthesized drought grades were established in the Huaihe River Basin of China. To filter out the impact of short-term fluctuations on observed soil moisture, a 30-day moving average was calculated. Use of the moving average significantly improves the correlation between observed soil moisture and simulated soil water deficit depth. Finally, a linear regression model describing the relationship between observed soil moisture and simulated soil water deficit depth was constructed. The deterministic regression coefficient was 0.5872, the correlation coefficient was 0.77, and the regression coefficient was -154.23. The trends in drought grades calculated using soil moisture and soil water deficit depth were found to be the same, and the grades agreed to within one level. Our findings highlight the importance of synthesizing drought grading when assessing drought using different soil moisture indicators in order to obtain a more comprehensive forecast of drought conditions. PMID- 26930310 TI - Boosted regression tree model-based assessment of the impacts of meteorological drivers of hand, foot and mouth disease in Guangdong, China. AB - BACKGROUND: Hand, foot and mouth disease (HFMD) is a common childhood infection and has become a major public health issue in China. Considerable research has focused on the role of meteorological factors in HFMD development. Nonlinear relationship, delayed effects and collinearity problems are key issues for achieving robust and accurate estimations in this kind of weather-health relationship explorations. The current study was designed to address these issues and assess the impact of meteorological factors on HFMD in Guangdong, China. METHODS: Case-based HFMD surveillance data and daily meteorological data collected between 2010 and 2012 was obtained from China CDC and the National Meteorological Information Center, respectively. After a preliminary variable selection, for each dataset boosted regression tree (BRT) models were applied to determine the optimal lag for meteorological factors at which the variance of HFMD cases was most explained, and to assess the impacts of these meteorological factors at the optimal lag. RESULTS: Variance of HFMD cases was explained most by meteorological factors about 1 week ago. Younger children and those from the Pearl-River Delta Region were more sensitive to weather changes. Temperature had the largest contribution to HFMD epidemics (28.99-71.93%), followed by precipitation (6.52-16.11%), humidity (3.92-17.66%), wind speed (3.84-11.37%) and sunshine (6.21-10.36%). Temperature between 10 degrees C and 25 degrees C, as well as humidity between 70% and 90%, had a facilitating effect on the epidemic of HFMD. Sunshine duration above 9h and wind speed below 2.5m/s also contributed to an elevated risk of HFMD. The positive relationship between HFMD and precipitation reversed when the daily amount of rainfall exceeded 25 mm. CONCLUSIONS: This study indicated significantly facilitating effects of five meteorological factors within some range on the epidemic of HFMD. Results from the current study were particularly important for developing early warning and response system on HFMD in the context of global climate change. PMID- 26930311 TI - The effects of vegetation barriers on near-road ultrafine particle number and carbon monoxide concentrations. AB - Numerous studies have shown that people living in near-roadway communities (within 100 m of the road) are exposed to high ultrafine particle (UFP) number concentrations, which may be associated with adverse health effects. Vegetation barriers have been shown to affect pollutant transport via particle deposition to leaves and altering the dispersion of emission plumes, which in turn would modify the exposure of near-roadway communities to traffic-related UFPs. In this study, both stationary (equipped with a Scanning Mobility Particle Sizer, SMPS) and mobile (equipped with Fast Mobility Particle Sizer, FMPS) measurements were conducted to investigate the effects of vegetation barriers on downwind UFP (particle diameters ranging from 14 to 102 nm) concentrations at two sites in North Carolina, USA. One site had mainly deciduous vegetation while the other was primarily coniferous; both sites have a nearby open field without the vegetation barriers along the same stretch of limited access road, which served as a reference. During downwind conditions (traffic emissions transported towards the vegetation barrier) and when the wind speed was above or equal to 0.5m/s, field measurements indicated that vegetation barriers with full foliage reduced UFP and CO concentrations by 37.7-63.6% and 23.6-56.1%, respectively. When the test was repeated at the same sites during winter periods when deciduous foliage was reduced, the deciduous barrier during winter showed no significant change in UFP concentration before and after the barrier. Results from the stationary (using SMPS) and mobile (using FMPS) measurements for UFP total number concentrations generally agreed to within 20%. PMID- 26930312 TI - Study of road dust magnetic phases as the main carrier of potentially harmful trace elements. AB - Mineralogical and morphological characteristics and heavy metal content of different fractions (bulk, non-magnetic fraction-NMF and magnetic fraction-MF) of road dusts from the city of Thessaloniki (Northern Greece) were investigated. Main emphasis was given on the magnetic phases extracted from these dusts. High magnetic susceptibility values were presented, whereas the MFs content of road dust samples ranged in 2.2-14.7 wt.%. Thermomagnetic analyses indicated that the dominating magnetic carrier in all road dust samples was magnetite, while the presence of hematite and iron sulphides in the investigated samples cannot be excluded. SEM/EDX analyses identified two groups of ferrimagnetic particles: spherules with various surface morphologies and textures and angular/aggregate particles with elevated heavy metal contents, especially Cr. The road dusts (bulk samples) were dominated by calcium, while the mean concentrations of trace elements decreased in the order Zn > Mn > Cu > Pb > Cr > Ni > V > Sn > As > Sb > Co > Mo > W > Cd. MFs exhibited significantly higher concentrations of trace elements compared to NMFs indicating that these potentially harmful elements (PHEs) are preferentially enriched in the MFs and highly associated with the ferrimagnetic particles. Hazard Index (HI) obtained for both adults and children through exposure to bulk dust samples were lower or close to the safe level (=1). On the contrary, the HIs for the magnetic phases indicated that both children and adults are experiencing potential health risk since HI for Cr was significantly higher than safe level. Cancer risk due to road dust exposure is low. PMID- 26930313 TI - Spatial and seasonal variations of the chemical, mineralogical and morphological features of quasi-ultrafine particles (PM 0.49) at urban sites. AB - Combining chemical and physical-structural information of particles is a key issue in PM investigations. Chemical, mineralogical, and morphological characterization of quasi-ultrafine particles (PM 0.49) was carried out at two urban sites of varying traffic-influence (roadside and urban background) in Thessaloniki, northern Greece, during the cold and the warm period of 2013. Bulk analyses of chemical species included organic and elemental carbon (OC, EC), water soluble organic carbon (WSOC), ionic species (NO3(-), SO4(2-), Cl(-), Na(+), NH4(+), K(+), Mg(2+), Ca(2+)) and trace elements (As, Ba, Cd, Cr, Cu, Fe, Pb, Mn, Ni, Zn, Pt, Pd, Rh, Ru, and Ir). X-ray diffractometry (XRD) was employed for the mineralogical analysis of PM 0.49 in order to identify and quantify amorphous and crystalline phases. In addition, scanning electron microscopy coupled with energy dispersive spectrometry (SEM-EDS) was employed for morphological characterization and elemental microanalysis of individual particles. Findings of this work could provide the basis for designing epidemiological and toxicity studies to mitigate population exposure to UFPs. PMID- 26930314 TI - Comparative summer dynamics of surface cyanobacterial communities in two connected lakes from the west of Ireland. AB - The eutrophication of lakes is typically associated with high biomass proliferations of potentially toxic cyanobacteria. At a regional level, the sustainable management of water resources necessitates an approach that recognises the interconnectivity of multiple water systems within river catchments. This study examined the dynamics in summer diversity of planktonic cyanobacterial communities and microcystin toxin concentrations in two inter connected lakes from the west of Ireland prone to nutrient enrichment. DGGE analysis of 16S rRNA gene amplicons of genotype-I cyanobacteria (typically spherical) showed changes in the communities of both Lough Corrib and Ballyquirke Lough throughout the summer, and identified cyanobacterial genotypes both unique and shared to both lakes. Microcystin concentrations, estimated via the protein phosphatase 2A inhibition assay, were greater in August than in July and June in both lakes. This was concomitant to the increased occurrence of Microcystis as evidenced by DGGE band excision and subsequent sequencing and BLAST analysis. RFLP analysis of PCR amplified mcy-A/E genes clustered together the August samples of both lakes, highlighting a potential change in microcystin producers across the two lakes. Finally, the multiple factor analysis of the combined environmental data set for the two lakes highlighted the expected pattern opposing greater water temperature and chlorophyll concentration against macronutrient concentrations, but also indicated a negative relationship between microcystin concentration and cyanobacterial diversity, possibly underlining allelopathic interactions. Despite some element of connectivity, the dissimilarity in the composition of the cyanobacterial assemblages and the timing of community change in the two lakes likely were a reflexion of niche differences determined by meteorologically-forced variation in physico-chemical parameters in the two water bodies. PMID- 26930315 TI - "APEC blue"--The effects and implications of joint pollution prevention and control program. AB - To ensure good air quality in Beijing during Asia-Pacific Economic Cooperation (APEC) China 2014, Beijing and its neighboring five provinces and the associated cities were combined under the Joint Prevention and Control of Atmospheric Pollution (JPCAP) program, which implemented rigorous cooperative emission reduction measures. The program was a unique and large-scale artificial experiment that showed that such measures can achieve excellent results, and it led to the popular "APEC blue" catchphrase (i.e., Beijing's skies became blue as pollution levels decreased). This artificial experiment provided the means to effectively conduct JPCAP strategies in the future. Accordingly, our research focused on the characteristics of the six primary pollutants in Beijing. We found that the JPCAP measures directly reduced concentrations of all pollutants except O3. Through correlation analysis, we found that the band distribution of the cities with strong correlations in PM2.5 and PM10 concentrations was affected by wind conditions. Therefore, JPCAP measures should account for specific seasonal and climatic conditions. Based on cluster analysis using the results from the correlation analysis, we divided 13 cities within a 300-km radius of Beijing into different groups according to the similarity of their PM2.5 and PM10 correlation coefficients. For JPCAP measures relevant to PM2.5 and PM10, we found differences in the degrees of collaboration among cities. Therefore, depending upon the pollutant type, the JPCAP strategy should account for the cities involved, the scope of the core area, and the optimal cities to involve in the collaborative efforts based on cost-effectiveness and collaborative difficulty among the involved cities. PMID- 26930316 TI - Occurrence, distribution and health risk from polycyclic aromatic compounds (PAHs, oxygenated-PAHs and azaarenes) in street dust from a major West African Metropolis. AB - Scientific evidence suggests that the burden of disease on urban residents of sub Saharan African Countries is increasing, partly as a result of exposure to elevated concentrations of toxic environmental chemicals. However, characterization of the levels, composition pattern and sources of polycyclic aromatic compounds (PACs) in environmental samples from African cities is still lacking. This study measured the PAHs, oxygenated-PAHs (OPAHs) and azaarene (AZAs) content of street dusts collected from Kumasi, Ghana (a major metropolis located in the tropical forest zone of West Africa). The ?Alkyl+parent-PAHs, ?OPAHs and ?AZAs concentration in street dust averaged 2570 ng g(-1) (range: 181 7600 ng g(-1)), 833 ng g(-1) (57-4200 ng g(-1)) and 73 ng g(-1) (3.3-240 ng g( 1)), respectively. The concentrations of ?Alkyl+parent-PAHs were strongly correlated (n=25) with ?OPAHs (r=0.96, p<0.01) and ?AZAs (r=0.94, p<0.01). The ?OPAHs concentrations were also strongly correlated with ?AZAs (r=0.91, p<0.01). Concentrations of individual PAHs in these street dusts were enriched at between 12 and 836 compared to their average concentrations in background soils from same city, demonstrating the high influence of traffic emissions. Several individual OPAHs and AZAs had higher concentrations than their related and often monitored parent-PAHs. The estimated incremental lifetime cancer risks due to the parent PAHs in street dusts was >10(-6) indicating high risk of contracting cancer from exposure to street dust from Kumasi. The contribution of OPAHs, AZAs, and alkyl PAHs in street dust to cancer risk could not be quantified because of lack of toxicity equivalency factors for these compounds; however this could be significant because of their high concentration and known higher toxicity of some polar PACs and alkyl-PAHs than their related parent-PAHs. PMID- 26930317 TI - Life-history and phenotypic traits of insectivorous songbirds breeding on reclaimed mine land reveal ecological constraints. AB - Studies assessing impacts of industrial activities on wildlife typically examine population- or community-level responses. However, changes in measures such as species abundance or diversity are driven by cumulative responses of individuals to disturbance, and may take time to detect. Quantifying individual responses could allow us to foresee and mitigate future population declines resulting from industrial activities, while providing ecologically informative indices to assess quality of reclaimed land. We examined life-history and phenotypic traits of mountain bluebirds (Sialia currucoides) and tree swallows (Tachycineta bicolor) breeding on reclaimed copper mine lands in Canada over two years in comparison to a nearby undisturbed reference area. Bluebirds feed on terrestrial invertebrates, whereas swallows feed on adult forms of insects with aquatic larvae, allowing us to assess quality of both reclaimed terrestrial and aquatic systems as habitat for insectivorous birds. Supplemental feeding of bluebirds also was used to experimentally assess nutritional limitation of birds feeding on terrestrial invertebrates. Bluebirds on reclaimed land initiated clutches later, and in one year had lower fledging success compared to birds on the reference area. Tree swallows also bred later in the season on reclaimed land, but were otherwise comparable to or exceeded performance of birds on the reference area. Annual differences in responses of nestling bluebirds on the mine to supplemental feeding revealed an apparent switch in life-history strategy of parents between years, from brood reduction to brood survival, suggesting greater annual fluctuations in ecological conditions within terrestrial systems on reclaimed land. Sex differences in response of nestling bluebirds to food supplementation additionally suggested high within-brood competition for food on reclaimed land. We suggest that measures of avian life-history and phenotypic traits, particularly when assessed over multiple years using experimental approaches such as food supplementation, are informative and sensitive indices of the health of reclaimed terrestrial and aquatic systems. PMID- 26930318 TI - Distribution patterns and possible influencing factors of As speciation in ornithogenic sediments from the Ross Sea region, East Antarctica. AB - Ornithogenic sediments are rich in toxic As (arsenic) compounds, posing a potential threat to local ecosystems. Here we analyzed the distribution of As speciation in three ornithogenic sediment profiles (MB6, BI and CC) collected from the Ross Sea region, East Antarctica. The distributions of total As and total P (phosphorus) concentrations were highly consistent in all three profiles, indicating that guano input is a major factor controlling total As distribution in the ornithogenic sediments. The As found in MB6 and CC is principally As(V) (arsenate), in BI As(III) (arsenite) predominates, but the As in fresh guano is largely composed of DMA (dimethylarsinate). The significant difference of As species between fresh guano and ornithogenic sediment samples may be related to diagenetic processes after deposition by seabirds. Based on analysis of the sedimentary environment in the studied sediments, we found that the redox conditions have an obvious influence on the As speciation distribution. Moreover, the distributions of As(III) and chlorophyll a in the MB6 and BI profiles are highly consistent, demonstrating that aquatic algae abundance may also influence the distribution patterns of As speciation in the ornithogenic sediments. PMID- 26930319 TI - No association between the use of Bti for mosquito control and the dynamics of non-target aquatic invertebrates in French coastal and continental wetlands. AB - The environmental safety of Bacillus thuringiensis subsp. israelensis (Bti) is still controversial, mainly because most of the previous field studies on its undesired effects were spatially limited and did not address the relationship between community similarity and application time and frequency. No general statement can therefore be drawn on the usage conditions of Bti that insure protection of non-target organisms. The present study was conducted in eight sites distributed over the main geographical sectors where mosquito control is implemented in mainland France and Corsica. Changes in non-target aquatic invertebrates were followed at elapsed time after repeated applications of two Bti formulations (VectoBac(r) WDG or 12AS) up to four consecutive years. We examined the influence of both larvicide treatments and environmental variables on community dynamics and dissimilarity between treated and control areas. As it can be argued that chironomids are the most vulnerable group of non-target invertebrates, we scrutinised potential Bti-related effects on the dynamics of their community. The use of VectoBac(r) WDG and 12AS in coastal and continental wetlands had no immediate or long-term detectable effect on the taxonomic structure and taxa abundance of non-target aquatic invertebrate communities, including chironomids. This applied to the main habitats where mosquito larvae occur, regardless of their geographic location. Flooding, whose frequency and duration depend on local meteorological and hydrological conditions, was identified as the main environmental driver of invertebrate community dynamics. Our findings add support to the environmental safety of currently available Bti formulations when following recommended application rates and best mosquito control practices. PMID- 26930320 TI - Scale-dependent effects of river habitat quality on benthic invertebrate communities--Implications for stream restoration practice. AB - Although most stream restoration projects succeed in improving hydromorphological habitat quality, the ecological quality of the stream communities often remains unaffected. We hypothesize that this is because stream communities are largely determined by environmental properties at a larger-than-local spatial scale. Using benthic invertebrate community data as well as hydromorphological habitat quality data from 1087 stream sites, we investigated the role of local- (i.e. 100 m reach) and regional-scale (i.e. 5 km ring centered on each reach) stream hydromorphological habitat quality (LQ and RQ, respectively) on benthic invertebrate communities. The analyses showed that RQ had a greater individual effect on communities than LQ, but the effects of RQ and LQ interacted. Where RQ was either good or poor, communities were exclusively determined by RQ. Only in areas of intermediate RQ, LQ determined communities. Metacommunity analysis helped to explain these findings. Species pools in poor RQ areas were most depauperated, resulting in insufficient propagule pressure for species establishment even at high LQ (e.g. restored) sites. Conversely, higher alpha diversity and an indication of lower beta dispersion signals at mass effects occurring in high RQ areas. That is, abundant neighboring populations may help to maintain populations even at sites with low LQ. The strongest segregation in species co-occurrence was detected at intermediate RQ levels, suggesting that communities are structured to the highest degree by a habitat/environmental gradient. From these results, we conclude that when restoring riverine habitats at the reach scale, restoration projects situated in intermediate RQ settings will likely be the most successful in enhancing the naturalness of local communities. With a careful choice of sites for reach-scale restoration in settings of intermediate RQ and a strategy that aims to expand areas of high RQ, the success of reach-scale restoration in promoting the ecological quality of communities can be greatly improved. PMID- 26930321 TI - The importance of uncertainties in scenario analyses--A study on future ecosystem service delivery in Flanders. AB - Land use is rapidly changing and is significantly affecting ecosystem service delivery all around the world. The socio-economic context and political choices largely determine land use change. This land use change, driven by socio-economic pressures, will impact diverse elements of the environment including, for example, air quality, soil properties, water infiltration and food and wood production, impacts that can be linked to the provisioning of ecosystem services. To gain more insight into the effects of alternative socio-economic developments on ecosystem service delivery, land use change models are being coupled to ecosystem service delivery models to perform scenario analyses. Although the uncertainty of the results of these kind of scenario analyses are generally far from negligible, studies rarely take them into account. In this study, a cellular automaton land use change model is coupled to Bayesian belief network ecosystem service delivery models to facilitate the study of error propagation in scenario analysis. The proposed approach is applied to model the impact of alternative socio-economic developments on ecosystem service delivery in Flanders, Belgium and to assess the impact of land use allocation uncertainty on the uncertainty associated to future ecosystem service delivery. Results suggest that taking into account uncertainties may have an effect on policy recommendations that come out of the scenario analysis. However, in this study, uncertainties in the applied ecosystem service models were dominant, reducing the importance of accounting for land use allocation uncertainty. PMID- 26930322 TI - Comparative analysis of water quality and toxicity assessment methods for urban highway runoff. AB - In this study, comparative analyses of highway runoff samples obtained from seventeen storm events have been conducted between the traditional water quality assessment method and biotoxicity tests, using zebrafish (Danio rerio) embryos and luminous bacteria (Vibrio qinghaiensis. Q67) to provide useful information for ecotoxicity assessment of urban highway runoff. The study results showed that the Nemerow pollution index based on US EPA recommended Criteria Maximum Concentrations (CMC) (as traditional water quality assessment method) had no significant correlation with luminous bacteria acute toxicity test results, while significant correlation has been observed with two indicators of 72 hpf (hours post fertilization) hour hatching rate and 96 hpf abnormality rate from the toxicity test with zebrafish embryos. It is therefore concluded that the level of mixture toxicity of highway runoff could not be adequately measured by the Nemerow assessment method. Moreover, the key pollutants identified from the water quality assessment and from the biotoxicity evaluation were not consistent. For biotoxic effect evaluation of highway runoff, three indexes were found to be sensitive, i.e. 24 hpf lethality and 96 hpf abnormality of zebrafish embryos, as well as the inhibition rate for luminous bacteria Q67. It is therefore recommended that these indexes could be incorporated into the traditional Nemerow method to provide a more reasonable evaluation of the highway runoff quality and ecotoxicity. PMID- 26930323 TI - Small scale spatial gradients of outdoor and indoor benzene in proximity of an integrated steel plant. AB - Benzene is known as a human carcinogen, whose annual mean concentration exceeded the EU limit value (5 MUg/m(3)) only in very few locations in Europe during 2012. Nevertheless 10% to 12% of the EU-28 urban population was still exposed to benzene concentrations above the WHO reference level of 1.7 MUg/m(3). WHO recommended a wise choice of monitoring stations positioning in proximity of "hot spots" to define and assess the representativeness of each site paying attention to micro-scale conditions. In this context benzene and other VOCs of health concern (toluene, ethylbenzene, xylenes) concentrations have been investigated, with weekly passive sampling for one year, both in outdoor and indoor air in inhabited buildings in close proximity (180 m far up to 1100 m) of an integrated steel plant in NE of Italy. Even though the outdoor mean annual benzene concentration was below the EU limit in every site, in the site closest to the works the benzene concentration was above 5 MUg/m(3) in 14 weeks. These events were related to a benzene over toluene ratio above one, which is diagnostic for the presence of an industrial source, and to meteorological factors. These information pointed at the identification of the coke ovens of the plant as the dominant outdoor source of benzene. Benzene gradients with the increasing distance from coke ovens have been found for both outdoor and indoor air. Linear models linking outdoor to indoor benzene concentrations have been then identified, allowing to estimate indoor exposure from ambient air benzene data. In the considered period, a narrow area of about 250 m appeared impacted at a higher degree than the other sites both considering outdoor and indoor air. Passive BTEX sampling permits to collect information on both ambient air and daily life settings, allowing to assemble a valuable data support for further environmental cost-benefit analyses. PMID- 26930324 TI - Dipeptidyl peptidase 9 enzymatic activity influences the expression of neonatal metabolic genes. AB - The success of dipeptidyl peptidase 4 (DPP4) inhibition as a type 2 diabetes therapy has encouraged deeper examination of the post-proline DPP enzymes. DPP9 has been implicated in immunoregulation, disease pathogenesis and metabolism. The DPP9 enzyme-inactive (Dpp9 gene knock-in; Dpp9 gki) mouse displays neonatal lethality, suggesting that DPP9 enzyme activity is essential in neonatal development. Here we present gene expression patterns in these Dpp9 gki neonatal mice. Taqman PCR arrays and sequential qPCR assays on neonatal liver and gut revealed differential expression of genes involved in cell growth, innate immunity and metabolic pathways including long-chain-fatty-acid uptake and esterification, long-chain fatty acyl-CoA binding, trafficking and transport into mitochondria, lipoprotein metabolism, adipokine transport and gluconeogenesis in the Dpp9 gki mice compared to wild type. In a liver cell line, Dpp9 knockdown increased AMP-activated protein kinase phosphorylation, which suggests a potential mechanism. DPP9 protein levels in liver cells were altered by treatment with EGF, HGF, insulin or palmitate, suggesting potential natural DPP9 regulators. These gene expression analyses of a mouse strain deficient in DPP9 enzyme activity show, for the first time, that DPP9 enzyme activity regulates metabolic pathways in neonatal liver and gut. PMID- 26930326 TI - 2016 Oral, Head and Neck Cancer Awareness Week: April 10-16. PMID- 26930327 TI - Endoscopic view of a unilateral nasal soft-tissue obstruction. PMID- 26930325 TI - Serum Creatinine Modifies Associations between Body Mass Index and Mortality and Morbidity in Prevalent Hemodialysis Patients. AB - BACKGROUND: High body mass index (BMI) is paradoxically associated with better outcomes in hemodialysis (HD) patients. This study aimed to examine whether serum creatinine (Cr), a marker of muscle mass, could modify the association between BMI, and mortality and morbidity in prevalent HD patients. METHODS: A retrospective study was conducted using a nationwide database from the registry of the Japanese Society for Dialysis Therapy. A total of 119,099 patients were selected (age: 65+/-12 years; median time on HD: 5.6 years; male: 62%), and we examined the association of basal BMI with mortality and morbidity after a 1-year period. Patients were stratified either by BMI into 4 groups or by serum Cr levels into 3 tertiles. Odds ratio (OR) [95% confidence interval] was calculated by multivariate logistic regression analysis. RESULTS: Higher BMI did not predict a higher 1-year total mortality. However, when we stratified the patients by serum Cr levels, the risk of cardiac death became significantly higher in obese patients with the lowest Cr levels, in both males (OR 2.82 [1.51-5.27], p<0.01) and females (OR 2.00 [1.03-3.90], p<0.05). The risk of new cerebral infarction was also higher in obese male patients within the lowest Cr tertile. In contrast, there was a significantly lower risk of cardiac, cerebrovascular, and infection related death in non-obese patients with higher levels of Cr. Higher serum Cr was also related to a lower risk of cardiovascular events and hip fracture in non obese HD patients. CONCLUSIONS: The obesity paradox was found to be present in HD patients only when obesity was defined by BMI. Decreased serum Cr levels were found to be positively associated with clinical poor outcomes in all BMI groups. Thus, irrespective of BMI, the evaluation of serum Cr levels is important to predict mortality and morbidity in patients receiving regular HD. PMID- 26930328 TI - Blood flow to a hemorrhagic vocal fold mass. PMID- 26930329 TI - Novel injection technique into the interarytenoid area to treat dysphagia. PMID- 26930330 TI - Resolution of vocal fold leukoplakia during erlotinib treatment for lung cancer. AB - Treatment of vocal fold leukoplakia is complicated because it is associated with a high rate of recurrence after excision and it has the potential for progression to malignancy. Authors have presented different approaches to management, one of which is directed serial excisional biopsies. Ideally, a topical or systemic agent could be administered to eradicate this troublesome condition. We present the case of a patient with an 8-year history of vocal fold leukoplakia treated with directed serial biopsies who was subsequently diagnosed with non-small-cell lung cancer and treated with erlotinib. He experienced a complete resolution after 2 months of erlotinib therapy for his lung cancer. Immunohistochemistry confirmed that his lesion exhibited a much higher than normal expression of epidermal growth factor receptor (EGFR), which supports the idea that EGFR antagonism may combat EGFR-avid leukoplakia. However, we caution that the clinical observation made herein is an association and should not be misconstrued as a recommendation regarding the safety, efficacy, or economy of using erlotinib for the treatment of vocal fold leukoplakia. PMID- 26930331 TI - Thymoma with an incidental benign laryngeal mass mimicking laryngeal carcinoma: Case report. AB - Thymic carcinomas are rarely seen. Because of recurrent laryngeal nerve involvement, hoarseness is a common presenting symptom. Persistent hoarseness in a male smoker past his fifth decade is also a distinctive symptom for laryngeal carcinoma. Stroboscopic laryngeal examination and biopsy are required for the diagnosis. In this article we describe a case involving a patient with thymic carcinoma who, interestingly, also presented with a benign laryngeal mass with unilateral vocal fold fixation. We emphasize the importance of keeping in mind nonlaryngeal pathologies invading the recurrent laryngeal nerve in patients with persistent hoarseness and a nonspesific laryngeal mass. PMID- 26930332 TI - Methylene blue and parathyroid adenoma localization: Three new cases of a rare cutaneous complication. AB - Methylene blue has been safely used for the localization of parathyroid glands during parathyroidectomy, and only a few adverse effects have been documented. Methylene blue administration as a cause of pulse-oximetry-related skin injury is extremely rare. We describe 2 such cases in patients who developed a blister on the second digit at the pulse oximetry site after an uncomplicated excision of a parathyroid adenoma. In another case, a patient became bradycardic intraoperatively; she was successfully resuscitated, but she incurred a second degree burn at the pulse oximetry site. In all 3 cases, the burns resolved with local wound care. We publish this report to alert surgeons and anesthesiologists to the risk of skin complications with the use of high-dose intraoperative methylene blue. PMID- 26930333 TI - Risk factors for cervical lymph node metastasis in papillary thyroid microcarcinoma: A meta-analysis. AB - A number of studies of predictive factors for lymph node metastasis in papillary thyroid microcarcinoma have been published. We conducted a systematic meta analysis of some of these studies, and we present our findings herein. We searched the PubMed database and found 13 eligible studies and case series of papillary thyroid microcarcinoma that were published in the English-language literature from January 2001 through December 2012, and we analyzed their findings. The most commonly investigated tumor characteristics associated with lymph node metastasis were size, multifocality, capsular invasion, and lymphovascular invasion. With regard to the risk of developing lymph node metastasis, patients with larger tumors had a 1.93 greater chance (95% confidence interval [CI]: 1.36 to 2.73, p < 0.001), those with multifocal tumors had a 3.03 greater chance (95% CI: 2.05 to 4.47; p < 0.001), those with capsular invasion had a 4.13 greater chance (95% CI: 2.40 to 7.10; p < 0.001), and those with lymphovascular invasion had a 2.76 greater chance (95% CI: 1.50 to 5.07; p = 0.005). We conclude that patients with larger and/or multifocal papillary thyroid microcarcinomas and tumors associated with capsular or lymphovascular invasion have a significantly greater risk of developing lymph node metastasis. PMID- 26930334 TI - Ultrasonography-guided minimally invasive removal of parotid calculi: A prudent approach. AB - The trend in modern salivary calculi surgery is toward minimally invasive procedures because these benign conditions do not warrant open salivary gland surgery. Since ultrasonography is readily available, highly specific, noninvasive, and cost-effective, we have used an ultrasonography-guided technique for patients with parotid gland calculi, as both a diagnostic and a therapeutic tool for calculi removal, thus avoiding the morbidity of open surgery. We describe a case in which we used this novel technique for the peroral removal of multiple parotid calculi in a 29-year-old man. The use of ultrasonography in parotid calculi removal has been reported in the literature, but only infrequently. Our extensive search of the peer-reviewed English-language literature found no article reporting the technique that we describe here. PMID- 26930336 TI - Cavernous hemangioma of the submandibular gland with parapharyngeal extension in an adult: Case report. AB - Cavernous hemangiomas of the submandibular gland are rare. Signs and symptoms typically resemble those of sialolithiasis and chronic sialadenitis. If a lesion extends into the parapharyngeal space, otalgia and sore throat can result. Spontaneous regression is not a characteristic of cavernous hemangiomas. Surgical excision is a management option. We report the case of an adult with a submandibular gland cavernous hemangioma with parapharyngeal extension. PMID- 26930335 TI - Sinonasal glomangiopericytoma: Is anything new? AB - More than 100 cases of sinonasal hemangiopericytoma have been reported in the literature, but only a handful of cases of nasal glomangiopericytoma. In this article, we report a case of a nasal glomangiopericytoma that was treated with endonasal surgical excision. We also attempt to clarify the confusion that attends to the nomenclature surrounding the terms glomangiopericytoma and hemangiopericytoma, which are often used interchangeably. Although glomangiopericytomas are histologically similar to sinonasal hemangiopericytomas, they sometimes behave in a different clinical manner. To further enhance our understanding of nasal glomangiopericytomas, more cases need to be reported. This may improve our ability to establish specific treatment modalities for this type of neoplasm and to predict clinical outcomes. PMID- 26930337 TI - Repair of a posterior perforation of the trachea following thyroidectomy with a muscle transposition flap. AB - Tracheal perforation is a rare postoperative complication of total thyroidectomy. While previously documented cases have been reported in the anterior aspect of the trachea after a total thyroidectomy, we report what we believe is the first documented case of a perforation in the posterior aspect of the trachea. Our patient was a 29-year-old woman who presented with symptoms of tracheal impingement in the context of a right-sided goiter that subsequent investigation found to be three benign colloid nodules. Fourteen days after her total thyroidectomy, she presented with surgical emphysema surrounding the wound. Computed tomography identified a 2.5-mm defect in the right posterior lateral trachea, posterior to the cartilaginous ring. The defect failed to seal spontaneously, and after 48 hours, the patient remained symptomatic. During reexploration, the defect was successfully repaired with a myovascular transposition flap in conjunction with Tisseel tissue-bonding agent. This technique has the potential to be applied in future intraoperative and postoperative cases of tracheal perforation. PMID- 26930338 TI - A twin-center study of nasal tip numbness following septorhinoplasty or rhinoplasty. AB - Nasal tip numbness is a recognized postoperative complication after septorhinoplasty and rhinoplasty. We performed a twin-center retrospective study to determine the incidence of short- and long-term (>6 mo) nasal tip numbness after these procedures, and we studied several variables that might have been associated with this complication. Our study group was made up of 65 patients-31 males and 34 females, aged 15 to 67 years (mean: 30.5). Septorhinoplasty had been performed in 52 patients and rhinoplasty in 13; all surgeries were performed by two different surgeons at two different centers. There were 50 closed (endonasal) surgeries and 15 open surgeries. Follow-up phone calls made 6 to 37 months postoperatively revealed that 17 patients had experienced postoperative nasal tip numbness (26.2%); there were 10 cases of short-term numbness (15.4%) and 7 cases of long-term numbness (10.8%). Numbness resolved within 2 weeks in 8 of the 10 short-term patients. Of the 7 cases of long-term numbness, 6 patients reported severe numbness beyond 8 months, and 1 had mild numbness for at least a year. We found no association between the incidence of numbness and the type of surgery, the particular surgeon, or the particular center where the surgery had been performed. We did find that there was an association between long-term numbness and the open procedure, but it was not statistically significant. We discuss the possible mechanisms that might cause numbness in cases when the external nasal nerve is not cut. We believe it is important to include a discussion of the risk of nasal tip numbness during preoperative consultations and when seeking informed consent. PMID- 26930339 TI - Ganglioneuromas involving the hypoglossal nerve and the vagus nerve in a child: Surgical difficulties. AB - Ganglioneuromas are benign tumors that arise from the Schwann cells of the autonomic nervous system. They are usually seen in the posterior mediastinum and the paraspinal retroperitoneum in relation to the sympathetic chain. In the head and neck, they are usually related to the cervical sympathetic ganglia or to the ganglion nodosum of the vagus nerve or the hypoglossal nerve. We describe what we believe is the first reported case of multiple ganglioneuromas of the parapharyngeal space in which two separate cranial nerves were involved. The patient was a 10-year-old girl who presented with a 2-year history of a painless and slowly progressive swelling on the left side of her neck and a 1-year history hoarseness. She had no history of relevant trauma or surgery. Intraoperatively, we found two tumors in the left parapharyngeal space-one that had arisen from the hypoglossal nerve and the other from the vagus nerve. Both ganglioneuromas were surgically removed, but the affected nerves had to be sacrificed. Postoperatively, the patient exhibited hypoglossal nerve and vocal fold palsy, but she was asymptomatic. In addition to the case description, we discuss the difficulties we faced during surgical excision. PMID- 26930340 TI - External auditory canal stenting with nonlatex glove and Gelfoam. AB - External auditory canal stenosis, although uncommon, is a condition that is sometimes encountered by otolaryngologists. This condition has been shown to result from inflammatory changes that may be incited by many different causes. Various methods of stenting the canal open postoperatively have been described. We describe a readily accessible and inexpensive method of stenting the canal open postoperatively. The technique presented has been used effectively in all age groups at our institution, in cases ranging from trauma to postmastoidectomy procedures. PMID- 26930341 TI - The immediate use of a silicone sheet wound closure device in scar reduction and prevention. AB - Silicone has been used successfully postoperatively in the prevention of hypertrophic and other types of adverse scars. The Silicone Suture Plate (SSP) is a new, minimally invasive, sterile wound closure device that is applied intraoperatively to prevent adverse scarring. The SSP device permits immediate application of silicone while concurrently allowing for wound-edge tension redistribution. In this prospective, controlled, single-blinded clinical study, 8 consecutive patients undergoing deep-plane rhytidectomy were selected. SSP devices were placed on the patients' posterior rhytidectomy hairline incision; the mirror-image control site underwent standard suturing techniques. Three blinded, independent raters assessed the treatment and control sides at 6-week and 4-month follow-up visits, using the Objective Scar Assessment Scale (OSAS), a validated scar assessment tool. The 6-week OSAS scores revealed an 18.4% improvement on the side with the SSP device (13.3) when compared to the control side (16.3). The 4-month OSAS scores showed a 27.3% improvement on the treatment side from 12.7 (control) to 9.2 (SSP). These OSAS results were found to be statistically significant when taken as an aggregate of the observers' scores, but not when observers' scores were measured individually (p < 0.05). In our series of patients, we showed promising results with the use of the SSP device. Early silicone application and tissue tension distribution contributed to an overall more aesthetically pleasing scar compared to those seen with standard suturing techniques, although more testing is required. PMID- 26930342 TI - Concurrent chemoradiotherapy with capecitabine/cisplatin versus 5 fluorouracil/cisplatin in resectable laryngohypopharyngeal squamous cell carcinoma. AB - A combination of 5-fluorouracil and cisplatin (FP regimen) is widely used as a standard treatment for head and neck cancer. Recently, capecitabine has received increased attention. We conducted a retrospective study to compare the efficacy and safety of the FP regimen with that of the "XP regimen," which entails concurrent chemoradiotherapy (CCRT) with capecitabine and cisplatin, in patients with resectable laryngohypopharyngeal squamous cell carcinoma (SCC). We retrospectively reviewed the records of 71 patients-67 men and 4 women, mean age 63.1 years-who had undergone CCRT from August 2004 through March 2010 as a primary treatment for resectable laryngohypopharyngeal SCC. There were 19 patients in the FP group and 52 in the XP group. With regard to chemotherapy morbidity, the XP group had less need for healthcare resources and fewer delays in treatment due to toxicity. After CCRT, a higher (but not statistically significant) rate of complete response was observed in the XP group than in the FP group (71.2 vs. 57.9%; p = 0.291); the XP group also had a better, although not significant, response among patients with neck metastases (67.7 vs. 30%; p = 0.063). During follow-up (mean: 34.8 +/- 30.6 mo), recurrence rates were 25.6% in the XP group and 21.4% in the FP group-again, not a statistically significant difference (p = 0.745). At the time of the final follow-up, 20 of the 71 patients (28.2%) had died of disease. Compared with the FP group, the XP group had a significantly lower incidence of disease-specific death (21.2 vs. 47.4% respectively; p = 0.030). However, the Kaplan-Meier method identified no significant difference between the two groups in the 3-year survival rate (69.6 vs. 63.2%; p = 0.263). Overall toxicities and grade 3 or 4 toxicities (with the exception of hand-foot syndrome) were generally far less common in the XP group, with statistical significance identified for patients who experienced anemia, nausea, and vomiting. On the basis of our experience, we conclude that the results of the XP regimen were comparable to those of the FP regimen for CCRT in patients with resectable laryngohypopharyngeal SCC in terms of treatment efficacy, toxicity, and patient convenience. PMID- 26930343 TI - Changes in the nasalance of vowels within the first week following uvulopalatopharyngoplasty. AB - We conducted a retrospective study to evaluate the short-term effect of uvulopalatopharyngoplasty (UPPP) on changes in the nasalance of five vowels: /a/, /epsilon/, /i/, /o/, and /u/. Our study group was made up of 20 patients-15 males and 5 females, aged 16 to 57 years (mean: 37.3 +/- 11.5)-who had undergone UPPP as a treatment for mild to moderate obstructive sleep apnea. Nasometry was used to obtain nasalance scores in all patients on the morning of the operation (day 1) and subsequently on day 4 or 5 (mean: 4.5 +/- 0.5). Preoperatively, nasalance scores were highest for /i/ (mean: 29.8 +/- 12.6) and /a/ (mean: 24.1 +/- 10.3). After the operation, nasalance scores for all five studied vowels increased; they were highest for /i/ (mean: 40.7 +/- +17.8) and /epsilon/ (mean: 30.0 +/- 10.8). The increases in the nasalance of /i/, /epsilon/, and /u/ were statistically significant (p < 0.05). Our findings indicate that UPPP has a significant impact on nasalance immediately after surgery. PMID- 26930344 TI - Laser myringoplasty for tympanic membrane retraction. PMID- 26930345 TI - Granulomatous ulcers of the nose and oropharynx: Lupus vulgaris revisited. PMID- 26930346 TI - Swallowing frequency: Impact of accumulated oropharyngeal secretion levels and gustatory stimulation. AB - We conducted a prospective, descriptive study of 27 individuals with known or suspected dysphagia to investigate the relationship between swallowing frequency, accumulated oropharyngeal secretion levels, and gustatory stimulation. Assessment of the secretion level was quantified with the use of a previously published 5 point rating scale using endoscopy. Overall, we found a moderate relationship between the baseline swallowing frequency at rest and the accumulated oropharyngeal secretion level (Pearson correlation 0.470; p = 0.01). The study sample was divided into two groups based on their secretion level. Group 1 (n = 19; mean age 59.7 +/- 21.5 years) included patients whose accumulated oropharyngeal secretion level was rated as 1 (normal) or 2 (mild). Group 2 (n = 8; mean age 69.78 +/- 8.35 years) included patients whose accumulated oropharyngeal secretion level was rated as 4 (severe) or 5 (profound). For Group 1, swallowing frequency increased from a baseline of 1.05 to 5.26 swallows over 2 minutes, following gustatory stimulation; for Group 2 it increased from a baseline of 0.125 swallows to 3.5 swallows. These results indicate that individuals with a lower baseline swallowing frequency at rest demonstrated a higher accumulated oropharyngeal secretion level as viewed by nasal endoscopy and that, regardless of secretion level, gustatory stimulation was effective at increasing swallowing frequency. Increasing swallowing frequency may be a functional dysphagia treatment objective in efforts to improve the efficiency of the swallow and may offer better management of accumulated oropharyngeal secretions. PMID- 26930347 TI - Comment on "Effects of in Utero Exposure to Arsenic during the Second Half of Gestation on Reproductive End Points and Metabolic Parameters in Female CD-1 Mice". PMID- 26930349 TI - Orange Peel Extracts: Chemical Characterization, Antioxidant, Antioxidative Burst, and Phytotoxic Activities. AB - The search for novel drugs and alternative medicine has led to increased research in medicinal plants. Among such plants is the orange fruit. Its peels have been utilized for long as an active ingredient in most traditional medicines. This study aims at investigating the chemical properties of the hexane and dichloromethane (DCM) extracts of orange peel as well as their biological potentials. Blended peels were extracted with n-hexane and n-dichloromethane, respectively. The resulting extracts were subjected to gas chromatography mass spectrometry (GCMS) characterization. The extracts were also assayed for free radical scavenging ability against 1,1 -diphenyl -2 picrylhydrazyl (DPPH), antioxidative burst via measuring luminol -amplified chemiluminescence response in human blood, and phytotoxicity against lemna minor. GCMS analysis revealed a predominance of fatty acid methyl esters in the hexane extract, while the DCM extract had more ketone metabolites. The DCM extract had significant (p < .05) higher free radical scavenging and antioxidative burst activities compared to the hexane. Both extracts revealed a significantly (p < .05) high phytotoxicity activity. Results from this study indicated that solvent type played a vital a role in the extraction of secondary metabolites, which are responsible for the observed biological activities. The higher activities by the DCM extract can be attributed to its constituents as revealed by GCMS analysis. There is great need to explore the phytotoxicity potentials of both extracts as natural herbicides. PMID- 26930348 TI - The Accuracy of Computerized Adaptive Testing in Heterogeneous Populations: A Mixture Item-Response Theory Analysis. AB - BACKGROUND: Computerized adaptive testing (CAT) utilizes latent variable measurement model parameters that are typically assumed to be equivalently applicable to all people. Biased latent variable scores may be obtained in samples that are heterogeneous with respect to a specified measurement model. We examined the implications of sample heterogeneity with respect to CAT-predicted patient-reported outcomes (PRO) scores for the measurement of pain. METHODS: A latent variable mixture modeling (LVMM) analysis was conducted using data collected from a heterogeneous sample of people in British Columbia, Canada, who were administered the 36 pain domain items of the CAT-5D-QOL. The fitted LVMM was then used to produce data for a simulation analysis. We evaluated bias by comparing the referent PRO scores of the LVMM with PRO scores predicted by a "conventional" CAT (ignoring heterogeneity) and a LVMM-based "mixture" CAT (accommodating heterogeneity). RESULTS: The LVMM analysis indicated support for three latent classes with class proportions of 0.25, 0.30 and 0.45, which suggests that the sample was heterogeneous. The simulation analyses revealed differences between the referent PRO scores and the PRO scores produced by the "conventional" CAT. The "mixture" CAT produced PRO scores that were nearly equivalent to the referent scores. CONCLUSION: Bias in PRO scores based on latent variable models may result when population heterogeneity is ignored. Improved accuracy could be obtained by using CATs that are parameterized using LVMM. PMID- 26930350 TI - Effect of Algal Inoculation on COD and Nitrogen Removal, and Indigenous Bacterial Dynamics in Municipal Wastewater. AB - The effects of algal inoculation on chemical oxygen demand (COD) and total nitrogen (TN) removal, and indigenous bacterial dynamics were investigated in municipal wastewater. Experiments were conducted with municipal wastewater inoculated with either Chlorella vulgaris AG10032, Selenastrum gracile UTEX 325, or Scenedesmus quadricauda AG 10308. C. vulgaris and S. gracile as fast growing algae in municipal wastewater, performed high COD and TN removal in contrast to Sc. quadricauda. The indigenous bacterial dynamics revealed by 16S rRNA gene amplification showed different bacterial shifts in response to different algal inoculations. The dominant bacterial genera of either algal case were characterized as heterotrophic nitrifying bacteria. Our results suggest that selection of indigenous bacteria that symbiotically interact with algal species is important for better performance of wastewater treatment. PMID- 26930351 TI - Identification and Characterization of Trichoderma Species Damaging Shiitake Mushroom Bed-Logs Infested by Camptomyia Pest. AB - The shiitake mushroom industry has suffered from Camptomyia (gall midges) pest, which feeds on the mycelium of shiitake mushroom during its cultivation. It has been postulated that fungal damage of shiitake bed-logs is associated with infestation by the insect pest, but this is not well understood. To understand the fungal damage associated with Camptomyia pest, various Trichoderma species were isolated, identified, and characterized. In addition to two previously known Trichoderma species, T. citrinoviride and T. deliquescens, two other Trichoderma species, T. harzianum and T. atroviride, were newly identified from the pestinfested bed-log samples obtained at three mushroom farms in Cheonan, Korea. Among these four species, T. harzianum was the most evident. The results of a chromogenic media-based assay for extracellular enzymes showed that these four species have the ability to produce amylase, carboxyl-methyl cellulase, avicelase, pectinase, and beta-glucosidase, thus indicating that they can degrade wood components. A dual culture assay on PDA indicated that T. harzianum, T. atroviride, and T. citrinoviride were antagonistic against the mycelial growth of a shiitake strain (Lentinula edodes). Inoculation tests on shiitake bed-logs revealed that all four species were able to damage the wood of bed-logs. Our results provide evidence that the four green mold species are the causal agents involved in fungal damage of shiitake bed-logs infested by Camptomyia pest. PMID- 26930354 TI - Erratum. PMID- 26930352 TI - The Transmission and Antibiotic Resistance Variation in a Multiple Drug Resistance Clade of Vibrio cholerae Circulating in Multiple Countries in Asia. AB - Vibrio cholerae has caused massive outbreaks and even trans-continental epidemics. In 2008 and 2010, at least 3 remarkable cholera outbreaks occurred in Hainan, Anhui and Jiangsu provinces of China. To address the possible transmissions and the relationships to the 7th pandemic strains of those 3 outbreaks, we sequenced the whole genomes of the outbreak isolates and compared with the global isolates from the 7th pandemic. The three outbreaks in this study were caused by a cluster of V. cholerae in clade 3.B which is parallel to the clade 3.C that was transmitted from Nepal to Haiti and caused an outbreak in 2010. Pan-genome analysis provided additional evolution information on the mobile element and acquired multiple antibiotic resistance genes. We suggested that clade 3.B should be monitored because the multiple antibiotic resistant characteristics of this clade and the 'amplifier' function of China in the global transmission of current Cholera pandemic. We also show that dedicated whole genome sequencing analysis provided more information than the previous techniques and should be applied in the disease surveillance networks. PMID- 26930353 TI - Prevalence of Depression and Depression Care for Populations Registered in Primary Care in Two Remote Cities in the Brazilian Amazon. AB - BACKGROUND: The prevalence of depression has been widely studied in high-income countries and in large cities of low-income countries; however, little is known about the prevalence and treatment gap of depression in remote areas of the Amazonian region in Brazil. OBJECTIVES: The objectives of this study are to estimate the prevalence of depression in adults registered with the Family Health Strategy in two remote cities in the Brazilian Amazon and to investigate the proportion of individuals with depression that received mental health care. METHODS: This is a cross-sectional study of an adult population registered with primary care clinics in the cities of Coari and Tefe, State of Amazon, Brazil. Depression was defined as a score of >=10 on the Patient Health Questionnaire-9. Depression care was evaluated by asking participants with depression if they received antidepressants and/or had been seen by a health professional at a community mental health center in the three months prior to the interview. Poisson regression was used to examine the unadjusted and adjusted associations between depression and exposure variables. RESULTS: The overall prevalence of depression was 19.1% (95% CI: 17.2-21.1), with 22.2% (95% CI: 19.3-25.0) among women and 16.0% (95% CI: 13.4-18.5) among men. The prevalence of depression in Coari and Tefe were 18.3% (CI 95% 15.7-21.0) and 19.9% (95% CI:17.2-22.7), respectively. Being a woman, lacking social support, increasing exposure to stressful life events and having a higher number medical comorbidities were consistently associated with depression. Lower educational attainment and income, tobacco use, and risky alcohol use were also associated with depression in the unadjusted analyses. Only 11.5% of those with depression were receiving antidepressants and/or visited the mental health care facility during the three months prior to the interview. CONCLUSION: Approximately one in five adults in our sample had depression. A high proportion of participants presented indicators of social disadvantage and other risk factors previously associated with depression worldwide. There was a large treatment gap for depression in the Amazonian region, which demonstrates the need for innovative models of depression care in primary care settings in Brazil. PMID- 26930355 TI - The Influence of Learning on Host Plant Preference in a Significant Phytopathogen Vector, Diaphorina citri. AB - Although specialist herbivorous insects are guided by innate responses to host plant cues, host plant preference may be influenced by experience and is not dictated by instinct alone. The effect of learning on host plant preference was examined in the Asian citrus psyllid, Diaphorina citri; vector of the causal agent of citrus greening disease or huanglongbing. We investigated: a) whether development on specific host plant species influenced host plant preference in mature D. citri; and b) the extent of associative learning in D. citri in the form of simple and compound conditioning. Learning was measured by cue selection in a 2-choice behavioral assay and compared to naive controls. Our results showed that learned responses in D. citri are complex and diverse. The developmental host plant species influenced adult host plant preference, with female psyllids preferring the species on which they were reared. However, such preferences were subject to change with the introduction of an alternative host plant within 24-48 hrs, indicating a large degree of experience-dependent response plasticity. Additionally, learning occurred for multiple sensory modalities where novel olfactory and visual environmental cues were associated with the host plant. However, males and females displayed differing discriminatory abilities. In compound conditioning tasks, males exhibited recognition of a compound stimulus alone while females were capable of learning the individual components. These findings suggest D. citri are dynamic animals that demonstrate host plant preference based on developmental and adult experience and can learn to recognize olfactory and visual host plant stimuli in ways that may be sex specific. These experience-based associations are likely used by adults to locate and select suitable host plants for feeding and reproduction and may suggest the need for more tailored lures and traps, which reflect region-specific cultivars or predominate Rutaceae in the area being monitored. PMID- 26930356 TI - The Geography of Gender Inequality. AB - Reducing gender inequality is a major policy concern worldwide, and one of the Sustainable Development Goals. However, our understanding of the magnitude and spatial distribution of gender inequality results either from limited-scale case studies or from national-level statistics. Here, we produce the first high resolution map of gender inequality by analyzing over 689,000 households in 47 countries. Across these countries, we find that male-headed households have, on average, 13% more asset wealth and 303% more land for agriculture than do female headed households. However, this aggregate global result masks a high degree of spatial heterogeneity, with bands of both high inequality and high equality apparent in countries and regions of the world. Further, areas where inequality is highest when measured by land ownership generally are not the same areas that have high inequality as measured by asset wealth. Our metrics of gender inequality in land and wealth are not strongly correlated with existing metrics of poverty, development, and income inequality, and therefore provide new information to increase the understanding of one critical dimension of poverty across the globe. PMID- 26930357 TI - Second-Line Intraperitoneal Chemotherapy for Recurrent Epithelial Ovarian, Tubal and Peritoneal Cancer: A Propensity Score-Matching Study. AB - BACKGROUND: The superiority of frontline intraperitoneal (IP) over intravenous (IV) chemotherapy is well established in the treatment of epithelial ovarian cancer. However, the role of IP chemotherapy in the second-line setting has rarely been investigated. METHODS: Consecutive patients diagnosed with recurrent epithelial, tubal and peritoneal cancers between January 2000 and December 2012 were recruited using a propensity score-matching technique to adjust relevant risk factors. RESULTS: In total, 310 patients were included in the final analysis (94 for platinum-refractory/resistant disease and 216 for platinum-sensitive disease). IP chemotherapy demonstrated significantly longer median progression free survival than IV chemotherapy (4.9 vs. 2.4 months, p < 0.001, for platinum refractory/resistant disease, and 9.8 vs. 6.9 months, p < 0.001, for platinum sensitive disease). CONCLUSIONS: Second-line IP chemotherapy confers longer progression-free survival than IV chemotherapy. Large-scale clinical trials should be conducted to validate the true efficacy. PMID- 26930358 TI - Aminopropyltrimethoxysilane- and aminopropyltrimethoxysilane-silver-modified montmorillonite for the removal of nitrate ions. AB - A natural clay (Mn) modified with gamma-aminopropyltrimethoxysilane (Mn-S) and silver (Mn-S-Ag) were evaluated as a potential adsorption media for nitrate removal from water. These materials were characterized by Fourier transform infrared spectroscopy, X-ray diffraction, zeta-potential, thermogravimetric analysis, scanning electron microscopy and elemental analyses. First, the adsorption capacity of the Mn-S clay for Ag(+) was studied. The cation adsorption capacity was almost three times greater for Mn-S than for Mn because a metal amino group complex is favored. Second, the nitrate adsorption on Mn-S and Mn-S Ag was studied as a function of contact time, pH, temperature and adsorbent dosage using batch techniques. In the absence of Ag(+), [Formula: see text] adsorption was high at low pH and the amount of adsorbed nitrate decreased as the pH increased. For the Mn-S, the following monolayer adsorption capacities were obtained: Qmax = 0.80, 0.72 and 0.68 mmol [Formula: see text]/g at pH 3, 5 and 7, respectively, whereas for the Mn-S-Ag the values obtained were: Qmax = 0.77, 0.74 and 0.42 mmol [Formula: see text]/g at pH 3, 5 and 7, respectively. From the results obtained, [Formula: see text] adsorption occurs over [Formula: see text] surface groups without involving the Ag(+) cation in the adsorption process. PMID- 26930359 TI - Evaluation of the pentylenetetrazole seizure threshold test in epileptic mice as surrogate model for drug testing against pharmacoresistant seizures. AB - Resistance to antiepileptic drugs (AEDs) is a major problem in epilepsy therapy, so that development of more effective AEDs is an unmet clinical need. Several rat and mouse models of epilepsy with spontaneous difficult-to-treat seizures exist, but because testing of antiseizure drug efficacy is extremely laborious in such models, they are only rarely used in the development of novel AEDs. Recently, the use of acute seizure tests in epileptic rats or mice has been proposed as a novel strategy for evaluating novel AEDs for increased antiseizure efficacy. In the present study, we compared the effects of five AEDs (valproate, phenobarbital, diazepam, lamotrigine, levetiracetam) on the pentylenetetrazole (PTZ) seizure threshold in mice that were made epileptic by pilocarpine. Experiments were started 6 weeks after a pilocarpine-induced status epilepticus. At this time, control seizure threshold was significantly lower in epileptic than in nonepileptic animals. Unexpectedly, only one AED (valproate) was less effective to increase seizure threshold in epileptic vs. nonepileptic mice, and this difference was restricted to doses of 200 and 300 mg/kg, whereas the difference disappeared at 400mg/kg. All other AEDs exerted similar seizure threshold increases in epileptic and nonepileptic mice. Thus, induction of acute seizures with PTZ in mice pretreated with pilocarpine does not provide an effective and valuable surrogate method to screen drugs for antiseizure efficacy in a model of difficult-to-treat chronic epilepsy as previously suggested from experiments with this approach in rats. PMID- 26930360 TI - The application of biosensors for drip loss analysis and glycolytic potential evaluation. AB - The aim of this study was to evaluate the relationship between glucose and lactate measured by biosensors in drip loss (strip method) with muscle glycolytic potential and their compounds. On the samples taken from Longissimus dorsi of 24 pigs (pure Neckar hybrid line) the following meat quality traits were determined: pH at 24h, meat color according to CIE L(*)a(*)b(*) system and drip loss. The highest correlations were found between glucose in drip loss and glycogen (r=0.84) or glycolytic potential (r=0.81) in muscle. A significant positive relationship between lactate measured in muscle by enzymatic method and by biosensor in drip loss was established (r=0.76). Glycogen, glucose, lactate and glycolytic potential with meat quality traits as ultimate pH, lightness, b(*) value and drip loss were significantly related. Results of multiple regression between glucose as well as lactate measured in muscle drip loss with muscle glycolytic potential showed the possibility of its prediction (r=0.87 with Palpha<=0.001). PMID- 26930361 TI - Fatty acid profile of beef from immunocastrated (BOPRIVA((r))) Nellore bulls. AB - Twenty Nellore bulls (ABW=357.7+/-9.65kg) were divided into 2 groups: intact and immunocastrated - Bopriva(r). After the trial period, the cattle were slaughtered and carcass fat thickness was evaluated, ether extract and fatty acid composition of the longissimus thoracis analyses were performed, and the activity indices of relevant enzymes were calculated. The means were calculated and compared by Student's t-test and Pearson's correlation coefficients (p<0.05). The immunocastrated group showed higher back fat thickness, ether extract, monounsaturated fatty acids (MUFAs), and activity index of Delta(9) desaturase C18 and lower polyunsaturated fatty acids (PUFAs) and n-6 fatty acids when compared to the intact group. The correlations between ether extract and the saturated and monounsaturated fatty acids were positive, and negative with polyunsaturated, n-3, n-6 and PUFA/SFA. Therefore, immunocastration may improve the fatty acid profile in the longissimus thoracis by increasing MUFAs, mainly oleic acid that is the most representative fatty acid in the meat and is considered beneficial to health. PMID- 26930362 TI - Tetraspanins: Spanning from solid tumors to hematologic malignancies. AB - Tetraspanins (tetraspans or TM4SF) are a family of integral membrane proteins with four transmembrane helices, a small extracellular loop, and a large extracellular loop. Although tetraspanins are expressed in many types of cells, including immune cells, their biological roles are not fully defined. Nonetheless, recent studies have revealed the important roles of tetraspanins in solid tumors and hematologic malignancies, and expression of tetraspanins is associated with the malignancy of human tumors. Furthermore, genetic mouse models of tetraspanins highlight their contribution to tumorigenesis. In this review, we summarize the implication of tetraspanins in cancer with a special focus on tetraspanin 3 in myeloid leukemia. Our increasing knowledge of tetraspanins and the pathologies that alter their function will undoubtedly inform the rational design of novel cancer therapies. PMID- 26930363 TI - Identification of a variation in the IVSII of alpha2 gene and its frequency in the population of Guangxi. AB - OBJECTIVE: During thalassemia screening, a previously unidentified alpha2 gene variation in alpha-globin gene cluster was isolated. This variation was distinct from other variations known to confer thalassemia as assessed by conventional thalassemia genotype analysis. Because the sample in the thalassemia screening was positive (MCV=83.6fL, MCH=26.1pg/cell, Hb=11.3g/dL), further analysis was required. MATERIAL AND METHODS: MLPA (multiplex ligation-dependent probe amplification) and sequencing were used for analysis, and a qPCR system was designed for the frequency study. RESULTS: The MLPA result showed that there was a mutation or small fragment deletions between 34247 (160bp probe) and 34618 (196bp probe) in alpha-globin gene cluster (NG_000006.1). Through sequencing, this variation was identified as HBA2: c.301-24delGinsCTCGGCCC. The gene polymorphisms similar to HBA2:c.301-24delGinsCTCGGCCC are alpha121 and alpha212. Since alpha212 is unrelated to microcytosis, and the structure of HBA2: c.301 24delGinsCTCGGCCC is similar to alpha212, this change is more appropriately considered as a polymorphism. The allele frequency of HBA2: c.301 24delGinsCTCGGCCC is 0.184% in this region. CONCLUSIONS: There is a certain ratio for HBA2:c.301-24delGinsCTCGGCCC carriers among the Chinese population. The HBA2:c.301-24delGinsCTCGGCCC variant results in an abnormal result from MLPA analysis. Investigators performing thalassemia screening in Guangxi region should be aware of the HBA2:c.301-24delGinsCTCGGCCC variant to avoid misinterpretation of the MLPA results. PMID- 26930364 TI - Urotensin II induction of neonatal cardiomyocyte hypertrophy involves the CaMKII/PLN/SERCA 2a signaling pathway. AB - Although studies have shown that Urotensin II (UII) can induce cardiomyocyte hypertrophy and UII-induced cardiomyocyte hypertrophy model has been widely used for hypertrophy research, but its precise mechanism remains unknown. Recent researches have demonstrated that UII-induced cardiomyocyte hypertrophy has a relationship with the changes of intracellular Ca(2+) concentration. Therefore, the aim of this study was to investigate the mechanisms of cardiomyocyte hypertrophy induced by UII and to explore whether the calcium/calmodulin dependent protein kinase II (CaMKII)-mediated up-regulating of phospholamban (PLN) Thr17-phosphorylation signaling pathway contributed to UII-induced cardiomyocyte hypertrophy. Primary cultures of neonatal rat cardiomyocytes were stimulated for 48h with UII. Cell size, protein/DNA contents and intracellular Ca(2+) were determined. Phosphorylated and total forms of CaMKII, PLN and the total amount of serco/endo-plasmic reticulum ATPases (SERCA 2a) were quantified by western blot. The responses of cardiomyocytes to UII were also evaluated after pretreatment with the CaMKII inhibitor, KN-93. These results showed that UII increased cell size, protein/DNA ratio and intracellular Ca(2+), consistent with a hypertrophic response. Furthermore, the phosphorylation of CaMKII and its downstream target PLN (Thr17), SERCA 2a levels were up-regulated by UII treatment. Conversely, treatment with KN-93 reversed all those effects of UII. Taken together, the results suggest that UII can induce cardiomyocyte hypertrophy through CaMKII-mediated up-regulating of PLN Thr17-phosphorylation signaling pathway. PMID- 26930365 TI - LGBT health and vaccinations: Findings from a community health survey of Lexington-Fayette County, Kentucky, USA. AB - Data on adult immunization coverage at the state level and for LGBT Americans in particular are sparse. This study reports the results of a 2012 Lexington-Fayette County, Kentucky, community health assessment's results asking about eight adult vaccinations among 218 lesbian, gay, bisexual, and transgendered (LGBT) respondents. Researchers collected data using an online survey distributed through LGBT social media, posters, and LGBT print media. The LGBT sample largely matches the demographics of the county as a whole except this group reports higher level of education and fewer uninsured individuals. Among LGBT respondents, immunization prevalence reaches 68.0% (annual Influenza), 65.7% (Hepatitis B), 58.8% (Chickenpox/Varicella), 55.9% (Hepatitis A), 41.2% (Smallpox), and 25.8% (Pneumonia). Among respondents who are currently within the recommended 19-26 years age range for the Human Papillomavirus (HPV) vaccine, the LGBT females are less likely to report receiving the vaccine (15.4%) compared to the national coverage percentage of 34.5%. Males, however, are more likely to have received the vaccine (10.3%) than the national percentage of 2.3%. The small number of LGBT seniors in the study report a much higher prevalence of the Shingles (Herpes Zoster) vaccines than for U.S. seniors 60 and older (71.4% compared to 20.1% nationally). LGBT respondents report higher percentages of adult vaccination. PMID- 26930366 TI - Generation and immunogenicity of porcine circovirus type 2 chimeric virus-like particles displaying porcine reproductive and respiratory syndrome virus GP5 epitope B. AB - Virus-like particles (VLPs) can be used as transfer vehicles carrying foreign proteins or antigen epitopes to produce chimeric VLPs for bivalent or multivalent vaccines. Based on the crystal structure of porcine circovirus type 2 (PCV2) capsid protein (Cap), in addition to alignment of the Cap sequences collected from various isolates of PCV2 and PCV1, we predicted that Loop CD of the PCV2 Cap should tolerate insertion of foreign epitopes, and furthermore that such an insertion could be presented on the surface of PCV2 VLPs. To validate this, the GP5 epitope B of porcine reproductive and respiratory syndrome virus (PRRSV) was inserted into Loop CD of the PCV2 Cap. The 3D structure of the recombinant PCV2 Cap (rCap) was simulated by homology modeling; it appeared that the GP5 epitope B was folded as a relatively independent unit, separated from the PCV2 Cap backbone. Furthermore, based on transmission electron microscopy, the purified PCV2 rCap self-assembled into chimeric VLPs which entered PK-15 cells. In addition, PCV2 chimeric VLPs induced strong humoral (neutralizing antibodies against PCV2 and PRRSV) and cellular immune responses in mice. We concluded that the identified insertion site in the PCV2 Cap had great potential to develop PCV2 VLPs-based bivalent or multivalent vaccines; furthermore, it would also facilitate development of a nano-device to present a functional peptide on the surface of the VLPs that could be used for therapeutic purposes. PMID- 26930367 TI - Immune response to second vaccination series of hepatitis B virus among booster dose non-responders. AB - OBJECTIVE: To evaluate the response to second vaccination series among post booster sero-negative children who had previously received compulsory HBV vaccination. SUBJECTS AND METHODS: After given a booster dose to 1070 children, 103 of them failed to generate anamnestic response (anti-HBs <10 IU/L). Only 91/103 children received additional two doses of recombinant HBV vaccine (i.e. 2(nd) vaccination series) after 1 and 6 months post-booster. Blood sample was withdrawn aseptically one month later for quantitative assessment of anti-HBs to detect development of protective immune response (>=10 IU/L). Immunological vaccination failure was assigned to children who did not develop protective immune response after 2(nd) vaccination series. RESULTS: Protective immune response was detected among 84/91 children (92.3%). While 7/91 (7.7%) whose age were >=10 years did not respond and had post-booster undetectable anti-HBs. About 80% of children with post-booster detectable anti-HBs showed significant protective immune response (anti-HBs >=100 IU/L) and higher GMT (299.1 +/- 3.6 IU/L) compared to those with undetectable 60% and 106.2 +/- 12.9 IU/L respectively (P<0.05). No significant difference was detected as regards gender or residence, P>0.05. All children with history of rheumatic fever (7 children) or diabetes mellitus (1 child) developed immune response after 2(nd) vaccination series. CONCLUSION: A booster dose of HB vaccine may be unable to induce sufficient immunological response in children who had undetectable anti-HBs titers. Revaccination for non-responders is an important procedure to increase HBV protection rate. PMID- 26930368 TI - Evaluating the case-positive, control test-negative study design for influenza vaccine effectiveness for the frailty bias. AB - INTRODUCTION: Previous influenza vaccine effectiveness studies were criticized for their failure to control for frailty. This study was designed to see if the test-negative study design overcomes this bias. METHODS: Adults >= 50 years of age with respiratory symptoms were enrolled from November 2006 through May 2012 during the influenza season (excluding the 2009-2010 H1N1 pandemic season) to perform yearly test-negative control influenza vaccine effectiveness studies in Nashville, TN. At enrollment, both a nasal and throat swab sample were obtained and tested for influenza by RT-PCR. Frailty was calculated using a modified Rockwood Index that included 60 variables ascertained in a retrospective chart review giving a score of 0 to 1. Subjects were divided into three strata: non frail (<= 0.08), pre-frail (> 0.08 to < 0.25), and frail (>= 0.25). Vaccine effectiveness was calculated using the formula [1-adjusted odds ratio (OR)] * 100%. Adjusted ORs for individual years and all years combined were estimated by penalized multivariable logistic regression. RESULTS: Of 1023 hospitalized adults enrolled, 866 (84.7%) participants had complete immunization status, molecular influenza testing and covariates to calculate frailty. There were 83 influenza positive cases and 783 test-negative controls overall, who were 74% white, 25% black, and 59% female. The median frailty index was 0.167 (Interquartile: 0.117, 0.267). The frailty index was 0.167 (0.100, 0.233) for the influenza positive cases compared to 0.183 (0.133, 0.267) for influenza negative controls (p = 0.07). Vaccine effectiveness estimates were 55.2% (95%CI: 30.5, 74.2), 60.4% (95%CI: 29.5, 74.4), and 54.3% (95%CI: 28.8, 74.0) without the frailty variable, including frailty as a continuous variable, and including frailty as a categorical variable, respectively. CONCLUSIONS: Using the case positive test negative study design to assess vaccine effectiveness, our measure of frailty was not a significant confounder as inclusion of this measure did not significantly change vaccine effectiveness estimates. PMID- 26930370 TI - Metabolic status of patients with muscular dystrophy in early phase of the disease: In vitro, high resolution NMR spectroscopy based metabolomics analysis of serum. AB - AIMS: Proton Nuclear Magnetic Resonance (NMR) based metabolomics analysis is extensively used to explore the metabolic profiling of biofluids. This approach was used for the analysis of metabolites in serum of patients with major types of muscular dystrophy in early phase of the disease. MATERIAL AND METHODS: Proton NMR spectroscopy based qualitative (assignment of metabolites) and quantitative (quantification of metabolites) analysis of metabolites in native serum of patients with Duchenne muscular dystrophy (DMD) [n=88; n represent the number], Becker muscular dystrophy (BMD) [n=40], facioscapulohumeral dystrophy (FSHD) [n=22], limb girdle muscular dystrophy (LGMD)-2B [n=35] and myotonic dystrophy (DM) [n=21] as compared to normal subjects [n=50] were performed. KEY FINDINGS: Quantity of branched chain amino acids was elevated in serum of patients with DMD, BMD, FSHD and DM-1 as compared to normal subjects. Acetate level was elevated in serum of patients with DMD, BMD, FSHD, LGMD-2B and DM-1 as compared to normal subjects. Level of glutamine was reduced in serum of patients with DMD, BMD, LGMD-2B, FSHD and elevated in DM-1 patients as compared to normal subjects. Quantity of tyrosine was increased in serum of BMD patients as compared to normal subjects. There was a reduction in the level of lysine in serum of FSHD, LGMD-2B and DM-1 patients as compared to normal subjects. Citrate level was reduced in serum of FSHD patients, but elevated in LGMD-2B patients. Lactate level was reduced in serum of LGMD-2B patients and histidine was reduced in serum of patients with FSHD as compared to normal subjects. SIGNIFICANCE: Outcome of this study may be useful as supportive information for the existing diagnostic methods of the muscular dystrophy. PMID- 26930371 TI - Deficit of RACK1 contributes to the spatial memory impairment via upregulating BECLIN1 to induce autophagy. AB - AIMS: Deficiency of activated C kinase1 (RACK1) in the brain of aging animal and Alzheimer's disease was characterized by cognitive dementia and spatial memory impairment. However, the correlation between the RACK1 and spatial memory impairment and the mechanism involved in it remains unknown. MAIN METHODS: Spatial memory impairment was performed in mice by lateral ventricle injection of Abeta25-35 (n=16, 10MUl) and intraperitoneal injection of scopolamine (n=16, 10ml/kg). After the Morris water maze (MWM) which was performed to determine the ability of learning and memory in mice, expression of RACK1 was tested and the damage of hippocampus was confirmed by histopathology test. ShRACK1 was then used to decrease the level of RACK1 in hippocampus to test the ability of learning and memory and histopathology changes in hippocampus. To look into the mechanism of RACK1 on spatial memory impairment, we further measured the expression of autophagy proteins BECLIN1 and LC3-II/I in hippocampus of all mice. KEY FINDINGS: Both the Abeta25-35, scopolamine impaired the spatial memory in mice (for escape latency, P=0.0004, P<0.0001) and severely damaged hippocampal DG neurons (P=0.012, P=0.014). The expression of RACK1 was significantly decreased which was concomitant with elevated BECLIN1 and LC3-II/I (P<0.001). Suppression of RACK1 by ShRACK1 plasmid (shGnb2l1) significantly impaired the spatial memory in mice, damaged hippocampal DG neurons (P=0.013), and increased the proteins of BECLIN1 and LC3-II/I (P<0.005). SIGNIFICANCE: It demonstrated that the deficit of RACK1 in hippocampus impairs the ability of learning and memory in mice via up regulating autophagy. PMID- 26930372 TI - Role of low-level laser therapy on the cardiac remodeling after myocardial infarction: A systematic review of experimental studies. AB - AIMS: We systematically reviewed the role of low-level laser therapy (LLLT) in cardiac remodeling after myocardial infarction. MAIN METHODS: Literatures were systematically searched in several electronic databases. We included only studies with a well-standardized coronary occlusion model in vivo LLLT application. KEY FINDINGS: After screening, 14 studies were eligible for review. The study heterogeneity was described in terms of rationality, gender, irradiation parameters, treatment numbers and moment of LLLT application. Three studies showed a null role of LLLT on infarct size, and only one study found positive LLLT effects on the cardiac performance. The cardioprotective role of LLLT was mediated by anti-inflammatory, pro-angiogenic and anti-oxidant actions. SIGNIFICANCE: The reduction in infarct size is a major finding. The LLLT cardioprotection may be mediated by several molecular and cellular mechanisms. Although these results are exciting, there are many limitations that must be resolved before LLLT clinical trials. PMID- 26930373 TI - UPLC-MS/MS assay for the simultaneous determination of ethinyl estradiol, norgestimate and 17-Desacetyl norgestimate at low pg/mL in human plasma. AB - Previously, because of the difficulty of measuring very low levels (pg/mL) of norgestimate (NGM) due to rapid metabolism to its active and major metabolite, 17 Desacetyl norgestimate (DNGM), only DNGM and the co-administered ethinyl estradiol (EE2) were required to be analyzed in bioequivalence (BE) studies for oral contraceptive NGM/EE2 tablets. Recently, with more sensitive assays available, health authorities have requested that bioequivalence of NGM be also demonstrated in addition to DNGM and EE2. Therefore, it was important to establish a 3-in-1 method for the quantitation of EE2, NGM and DNGM in human plasma. Here a UPLC-MS/MS method for the simultaneous quantitation of EE2, NGM and DNGM in human plasma at low pg/mL range is described. EE2, NGM, DNGM and their isotopic labeled internal standards (IS) EE2-d4, NGM-d6 and DNGM-d6 in 0.4mL of human plasma were extracted with hexane/ethyl acetate. The extracts were evaporated to dryness and derivatized with dansyl chloride, to enhance the mass spec response. The derivatives were reconstituted with methanol and analyzed by UPLC-MS/MS. In order to minimize the ex-vivo conversion of NGM to DNGM, sodium fluoride/potassium oxalate was used as anti-coagulant. To achieve desirable throughput for sample analysis, UPLC-MS/MS with a run time of 4.4min was utilized. The calibration curve ranges were 5-500pg/mL for EE2 and NGM, and 25 2500pg/mL for DNGM, respectively. The chromatographic separation was achieved on a Waters Acquity UPLC HSS T3 (100*2.1mm, 1.8MUm) column with a gradient elution. Assay accuracy, precision, linearity, selectivity, sensitivity and analyte stability covering sample storage and analysis were established. This validated UPLC-MS/MS method has been applied to a BE study for the determination of EE2, NGM and DNGM concentrations in human plasma. PMID- 26930369 TI - Gait dyspraxia as a clinical marker of cognitive decline in Down syndrome: A review of theory and proposed mechanisms. AB - Down syndrome (DS) is the most common genetic cause of intellectual disability in children. With aging, DS is associated with an increased risk for Alzheimer's disease (AD). The development of AD neuropathology in individuals with DS can result in further disturbances in cognition and behavior and may significantly exacerbate caregiver burden. Early detection may allow for appropriate preparation by caregivers. Recent literature suggests that declines in gait may serve as an early marker of AD-related cognitive disorders; however, this relationship has not been examined in individuals with DS. The theory regarding gait dyspraxia and cognitive decline in the general population is reviewed, and potential applications to the population with individuals with DS are highlighted. Challenges and benefits in the line of inquiry are discussed. In particular, it appears that gait declines in aging individuals with DS may be associated with known declines in frontoparietal gray matter, development of AD related pathology, and white matter losses in tracts critical to motor control. These changes are also potentially related to the cognitive and functional changes often observed during the same chronological period as gait declines in adults with DS. Gait declines may be an early marker of cognitive change, related to the development of underlying AD-related pathology, in individuals with DS. Future investigations in this area may provide insight into the clinical changes associated with development of AD pathology in both the population with DS and the general population, enhancing efforts for optimal patient and caregiver support and propelling investigations regarding safety/quality of life interventions and disease-modifying interventions. PMID- 26930374 TI - Cognitive function alone is a poor predictor of health-related quality of life in employed patients with MS: results from a cross-sectional study. AB - OBJECTIVE: Depression, anxiety, disease severity, and cognitive functions impact on the quality of life of people with MS. However, the majority of studies were not based on multivariate models and did not target employed patients. The aim of this study was to investigate predictors of HRQoL in persons with MS in the workforce considering cognitive, psychological, disease severity, and disability related variables. METHODS: Cross-sectional study. Hierarchical block regression analyses were conducted to identify predictors of physical and mental components of HRQoL, measured with the MSQOL-54. Candidate predictors included cognitive functioning (a selection of Rao's BRB-NT), sample features (age, education, MS duration), depressive symptoms (BDI-II), anxiety (STAI-Y), disability (WHODAS 2.0), and MS severity (EDSS): those that correlated with PCS and MCS with p < .250 and those that correlated with other predictors with coefficients >.800 were excluded from regression analyses. RESULTS: In total, 181 patients (60.8% females, mean age 39.6, median EDSS 1.5) were included. In both models, cognitive variables had a poor explicative power. The models improved significantly when psychological, as well as, disease severity and disability variables were added. R(2) of complete models was 0.732 for the physical component, 0.697 for the mental one: BDI-II, STAI-State and, some WHODAS 2.0 scales were significant predictors of HRQoL. CONCLUSIONS: Monitoring anxiety, depressive symptoms, and level of disability through self-reported questionnaires may provide useful suggestions to improve the HRQoL of persons with MS in the workforce, permitting to address possible problems in the work context and plan corrective actions. PMID- 26930375 TI - Comparison of extracorporeal shock wave therapy with botulinum toxin type A in the treatment of plantar fasciitis. AB - OBJECTIVE: To compare the efficacy of extracorporeal shock wave therapy (ESWT) with botulinum toxin type A (BoNT-A) in the treatment of plantar fasciitis (PF). DESIGN: Open label, prospective, randomized study. RESULTS: A total of 72 patients were included. In all participants the median (and interquartile range) of the visual analog scale (VAS) of pain result, when taking the first steps, was 8 (6-9) points before treatment and 6 (4-8) points after treatment (p < 0.001). In the group of patients that received ESWT, the median (and interquartile range) of improvement in the VAS of pain result, when taking the first steps, was 2 (1 4) points, and in the group of patients that received BoNT-A the same result was 1 (0-2) points (p = 0.009). In the group of patients that received ESWT, the median (and interquartile range) of improvement in the Roles and Maudsley scale of pain result was 1 (0-1) points, and in the group of patients that received BoNT-A the same result was 0 (0-1) points (p = 0.006). In a multivariate analysis use of ESWT and lower weight were associated with improvement of pain with treatment in at least one of the three VAS of pain scales used in the study. CONCLUSION: ESWT was superior to BoNT-A in the control of pain in patients with PF. Implications for Rehabilitation Plantar fasciitis is characterized by pain at the calcaneal origin of the plantar fascia, exacerbated by weight bearing after prolonged periods of rest. Although studies comparing extracorporeal shock wave therapy or botulinum toxin type A to placebo suggest a superiority of the first one, no reliable data exist about it. Extracorporeal shock wave therapy was superior to botulinum toxin type A in the control of pain in patients with PF. PMID- 26930377 TI - Immune System Modifications Induced in a Mouse Model of Chronic Exposure to (90)Sr. AB - Strontium 90 ((90)Sr) remains in the environment long after a major nuclear disaster occurs. As a result, populations living on contaminated land are potentially exposed to daily ingesting of low quantities of (90)Sr. The potential long-term health effects of such chronic contamination are unknown. In this study, we used a mouse model to evaluate the effects of (90)Sr ingestion on the immune system, the animals were chronically exposed to (90)Sr in drinking water at a concentration of 20 kBq/l, for a daily ingestion of 80-100 Bq/day. This resulted in a reduced number of CD19(+) B lymphocytes in the bone marrow and spleen in steady-state conditions. In contrast, the results from a vaccine experiment performed as a functional test of the immune system showed that in response to T-dependent antigens, there was a reduction in IgG specific to tetanus toxin (TT), a balanced Th1/Th2 response inducer antigen, but not to keyhole limpet hemocyanin (KLH), a strong Th2 response inducer antigen. This was accompanied by a reduction in Th1 cells in the spleen, consistent with the observed reduction in specific IgG concentration. The precise mechanisms by which (90)Sr acts on the immune system remain to be elucidated. However, our results suggest that (90)Sr ingestion may be responsible for some of the reported effects of internal contamination on the immune system in civilian populations exposed to the Chernobyl fallout. PMID- 26930376 TI - Prediction model of RSV-hospitalization in late preterm infants: An update and validation study. AB - BACKGROUND: New vaccines and RSV therapeutics have been developed in the past decade. With approval of these new pharmaceuticals on the horizon, new challenges lie ahead in selecting the appropriate target population. We aimed to improve a previously published prediction model for prediction of RSV-hospitalization within the first year of life. METHODS: Two consecutive prospective multicenter birth cohort studies were performed from June 2008 until February 2015. The first cohort (RISK-I, n=2524, 2008-2011) was used to update the existing model. The updated model was subsequently validated in the RISK-II cohort (n=1564, 2011 2015). We used the TRIPOD criteria for transparent reporting. RESULTS: 181 infants (n=127 in RISK-I, n=54 in RISK-II) were hospitalized for RSV within their first year of life. The updated model included the following predictors; day care attendance and/or siblings (OR: 5.3; 95% CI 2.8-10.1), birth between Aug. 14th and Dec. 1st (OR: 2.4; 1.8-3.2), neonatal respiratory support (OR 2.2; 1.6-3.0), breastfeeding <=4 months (OR 1.6; 1.2-2.2) and maternal atopic constitution (OR 1.5; 1.1-2.1). The updated models' discrimination was superior to the original model in the RISK-II cohort (AUROC 0.72 95% CI 0.65-0.78 versus AUROC 0.66, 95% CI 0.60-0.73, respectively). The updated model was translated into a simple nomogram to be able to distinguish infants with high versus low risk of RSV hospitalization. CONCLUSION: We developed and validated a clinical prediction model to be able to predict RSV-hospitalization in preterm infants born within 32 35 weeks gestational age. A simple nomogram was developed to target RSV therapeutics to those children who will benefit the most. PMID- 26930378 TI - Radioprotective Efficacy of Gamma-Tocotrienol in Nonhuman Primates. AB - The search for treatments to counter potentially lethal radiation-induced injury over the past several decades has led to the development of multiple classes of radiation countermeasures. However, to date only granulocyte colony-stimulating factor (G-CSF; filgrastim, Neupogen)and pegylated G-CSF (pegfilgrastim, Neulasta) have been approved by the United States Food and Drug Administration (FDA) for the treatment of hematopoietic acute radiation syndrome (ARS). Gamma-tocotrienol (GT3) has demonstrated strong radioprotective efficacy in the mouse model, indicating the need for further evaluation in a large animal model. In this study, we evaluated GT3 pharmacokinetics (PK) and efficacy at different doses of cobalt-60 gamma radiation (0.6 Gy/min) using the nonhuman primate (NHP) model. The PK results demonstrated increased area under the curve with increasing drug dose and half-life of GT3. GT3 treatment resulted in reduced group mean neutropenia by 3-5 days and thrombocytopenia by 1-5 days. At 5.8 and 6.5 Gy total body irradiation, GT3 treatment completely prevented thrombocytopenia. The capability of GT3 to reduce severity and duration of neutropenia and thrombocytopenia was dose dependent; 75 mg/kg treatment was more effective than 37.5 mg/kg treatment after a 5.8 Gy dose. However, the higher GT3 dose (75 mg/kg) was associated with higher frequency of adverse skin effects (small abscess) at the injection site. GT3 treatment of irradiated NHPs caused no significant difference in animal survival at 60 days postirradiation, however, low mortality was observed in irradiated, vehicle-treated groups as well. The data from this pilot study further elucidate the role and pharmacokinetics of GT3 in hematopoietic recovery after irradiation in a NHP model, and demonstrate the potential of GT3 as a promising radioprotector. PMID- 26930380 TI - Advantages of Binomial Likelihood Maximization for Analyzing and Modeling Cell Survival Curves. AB - Mathematical analysis of cell survival allows parameter estimation for radiobiological models and selection of an appropriate model. To our knowledge, no rigorous comparisons on the accuracy of various methods used for such analysis have been performed. In this study we compared three methods: 1. maximization of binomial log-likelihood (BLL); 2. minimization of sum of squares (SS); and 3. method 2 using log-transformed data (SSlog). Analysis of Monte Carlo simulated data (A) generated from the linear-quadratic (LQ) model showed that model parameter estimates from the BLL method were more accurate and less affected by "noise" than those from other methods. Analysis of actual breast cancer cell data showed substantial differences among LQ parameters estimated by the three methods (B). To select among radiobiological models, we used: 1. Sample size-corrected Akaike information criterion (AICc), calculated from BLL method-generated log likelihood values; and 2. Adjusted coefficient of determination (R(2)), calculated from SS/SSlog method-generated SS values. Analysis of data simulated from the repair-misrepair (RMR) formalism (C) showed that the first approach outperformed the second approach at identifying the true data-generating model. Examples of how the first approach discriminates between several models were explored using actual mouse (H2AX-proficient and -deficient) and human [DNA dependent protein kinase (DNA-PK)-proficient and -deficient] cell data (D). Based on this work, we concluded that BLL maximization combined with AICc-based model selection constitutes an effective method for analyzing cell survival data. PMID- 26930379 TI - Effects of High-LET Radiation Exposure and Hindlimb Unloading on Skeletal Muscle Resistance Artery Vasomotor Properties and Cancellous Bone Microarchitecture in Mice. AB - Weightlessness during spaceflight leads to functional changes in resistance arteries and loss of cancellous bone, which may be potentiated by radiation exposure. The purpose of this study was to assess the effects of hindlimb unloading (HU) and total-body irradiation (TBI) on the vasomotor responses of skeletal muscle arteries. Male C57BL/6 mice were assigned to control, HU (13-16 days), TBI (1 Gy (56)Fe, 600 MeV, 10 cGy/min) and HU-TBI groups. Gastrocnemius muscle feed arteries were isolated for in vitro study. Endothelium-dependent (acetylcholine) and -independent (Dea-NONOate) vasodilator and vasoconstrictor (KCl, phenylephrine and myogenic) responses were evaluated. Arterial endothelial nitric oxide synthase (eNOS), superoxide dismutase-1 (SOD-1) and xanthine oxidase (XO) protein content and tibial cancellous bone microarchitecture were quantified. Endothelium-dependent and -independent vasodilator responses were impaired in all groups relative to control, and acetylcholine-induced vasodilation was lower in the HU-TBI group relative to that in the HU and TBI groups. Reductions in endothelium-dependent vasodilation correlated with a lower cancellous bone volume fraction. Nitric oxide synthase inhibition abolished all group differences in endothelium-dependent vasodilation. HU and HU-TBI resulted in decreases in eNOS protein levels, while TBI and HU-TBI produced lower SOD-1 and higher XO protein content. Vasoconstrictor responses were not altered. Reductions in NO bioavailability (eNOS), lower anti-oxidant capacity (SOD-1) and higher pro-oxidant capacity (XO) may contribute to the deficits in NOS signaling in skeletal muscle resistance arteries. These findings suggest that the combination of insults experienced in spaceflight leads to impairment of vasodilator function in resistance arteries that is mediated through deficits in NOS signaling. PMID- 26930382 TI - Genistein attenuates oxidative damage in preeclamptic placental trophoblast. AB - OBJECTIVE: To evaluate the effect of genistein supplementation on the oxidative/nitrative stress and antioxidant capacity of normotensive and preeclamptic placental trophoblast. METHODS: The stress status of placental trophoblast was assessed by measuring their respective markers before and after incubation with genistein. RESULTS: A significant increase in stress along with decrease in antioxidant status was observed in preeclamptic placental trophoblast, whereas genistein incubation significantly alters oxidant antioxidant status. CONCLUSION: The study revealed that genistein may play a significant role in controlling oxidative/nitrative stress during preeclampsia. Hence, genistein can be used as an effective dietary supplement for the treatment and management of preeclampsia. PMID- 26930381 TI - Ionizing Radiation Exposure and Basal Cell Carcinoma Pathogenesis. AB - This commentary summarizes studies showing risk of basal cell carcinoma (BCC) development in relationship to environmental, occupational and therapeutic exposure to ionizing radiation (IR). BCC, the most common type of human cancer, is driven by the aberrant activation of hedgehog (Hh) signaling. Ptch, a tumor suppressor gene of Hh signaling pathway, and Smoothened play a key role in the development of radiation-induced BCCs in animal models. Epidemiological studies provide evidence that humans exposed to radiation as observed among the long term, large scale cohorts of atomic bomb survivors, bone marrow transplant recipients, patients with tinea capitis and radiologic workers enhances risk of BCCs. Overall, this risk is higher in Caucasians than other races. People who were exposed early in life develop more BCCs. The enhanced IR correlation with BCC and not other common cutaneous malignancies is intriguing. The mechanism underlying these observations remains undefined. Understanding interactions between radiation-induced signaling pathways and those which drive BCC development may be important in unraveling the mechanism associated with this enhanced risk. Recent studies showed that Vismodegib, a Smoothened inhibitor, is effective in treating radiation-induced BCCs in humans, suggesting that common strategies are required for the intervention of BCCs development irrespective of their etiology. PMID- 26930383 TI - Diversity in fathers' food parenting practices: A qualitative exploration within a heterogeneous sample. AB - BACKGROUND: Food parenting practices (FPPs) are important in shaping children's dietary behaviors. However, existing FPP knowledge is largely based on research with mothers. PURPOSE: This study (1) identified fathers' FPPs; (2) described differences in FPP use by fathers' education and residential status. METHODS: Semi-structured interviews were conducted with 40 fathers (39 +/- 9.1 years; 37.5% non-residential; 40% >=college education). Interviews were audio-recorded and transcribed. NVivo 10 was used for theme detection, categorization and classification using inductive and deductive approaches. FPPs were identified and their relative distribution was examined across education and residential status. RESULTS: Twenty FPPs were identified - 13 responsive practices and 7 unresponsive practices. Having food rules was the most common responsive FPP (81.5%), followed by feeding on schedule (60%) and making healthy food accessible (60%). Common unresponsive FPPs were letting child dictate preferences (70%), incentivizing food consumption (60%) and pressuring the child to eat (35%). Compared to fathers with a college education, more fathers without a college education reported letting child dictate preferences (92% vs. 37%), educating their children about food (37% vs 12%), fewer reported feeding on schedule (50% vs. 75%), modeling healthy practices (29% vs. 50%), and using distraction to feed (4% vs. 37%). Compared to residential fathers, more non-residential fathers monitored (60% vs. 40%) or encouraged (60% vs. 36%) child food intake and let child dictate preferences (87% vs. 60%). CONCLUSIONS: Fathers used an extensive variety of FPPs, similar to those identified in mothers. Further study on the influence of fathers' education and residential status on FPP use is warranted. PMID- 26930386 TI - Enhancement of chest radiographs obtained in the intensive care unit through bone suppression and consistent processing. AB - Portable chest radiographs (CXRs) are commonly used in the intensive care unit (ICU) to detect subtle pathological changes. However, exposure settings or patient and apparatus positioning deteriorate image quality in the ICU. Chest x rays of patients in the ICU are often hazy and show low contrast and increased noise. To aid clinicians in detecting subtle pathological changes, we proposed a consistent processing and bone structure suppression method to decrease variations in image appearance and improve the diagnostic quality of images. We applied a region of interest-based look-up table to process original ICU CXRs such that they appeared consistent with each other and the standard CXRs. Then, an artificial neural network was trained by standard CXRs and the corresponding dual-energy bone images for the generation of a bone image. Once the neural network was trained, the real dual-energy image was no longer necessary, and the trained neural network was applied to the consistent processed ICU CXR to output the bone image. Finally, a gray level-based morphological method was applied to enhance the bone image by smoothing other structures on this image. This enhanced image was subtracted from the consistent, processed ICU CXR to produce a soft tissue image. This method was tested for 20 patients with a total of 87 CXRs. The findings indicated that our method suppressed bone structures on ICU CXRs and standard CXRs, simultaneously maintaining subtle pathological changes. PMID- 26930385 TI - Improving the relevance and consistency of outcomes in comparative effectiveness research. AB - Policy makers have clearly indicated--through heavy investment in the Patient Centered Outcomes Research Institute--that reporting outcomes that are meaningful to patients is crucial for improvement in healthcare delivery and cost reduction. Better interpretation and generalizability of clinical research results that incorporate patient-centered outcomes research can be achieved by accelerating the development and uptake of core outcome sets (COS). COS provide a standardized minimum set of the outcomes that should be measured and reported in all clinical trials of a specific condition. The level of activity around COS has increased significantly over the past decade, with substantial progress in several clinical domains. However, there are many important clinical conditions for which high quality COS have not been developed and there are limited resources and capacity with which to develop them. We believe that meaningful progress toward the goals behind the significant investments in patient-centered outcomes research and comparative effectiveness research will depend on a serious effort to address these issues. PMID- 26930387 TI - Hereditary non-BRCA gynecological tumors. AB - Early diagnosis and proper management of gynecologic malignancies represent a challenge in modern oncology. A growing interest has arisen around the gynecological manifestations of hereditary cancer syndromes. In particular, the discovery of the BRCA1 and BRCA2 genes in ovarian cancer and the mismatch repair genes (MMR) in endometrial carcinoma has revolutionized our approach to the diagnosis and screening of women for ovarian and uterine cancers. The clinical, genetic and pathological features of hereditary cancer syndromes with gynecological manifestations are reviewed focusing on Lynch Syndrome, also known as hereditary nonpolyposis colorectal carcinoma (HNPCC), Peutz-Jeghers Syndrome (PJS), Cowden Syndrome or multiple hamartoma syndrome, Gorlin Syndrome or nevoid basal-cell carcinoma syndrome (NBCCS) and Reed's Syndrome or hereditary leiomyomatosis and renal cell cancer (HLRCC). PMID- 26930384 TI - Transcriptome of the inner circular smooth muscle of the developing mouse intestine: Evidence for regulation of visceral smooth muscle genes by the hedgehog target gene, cJun. AB - BACKGROUND: Digestion is facilitated by coordinated contractions of the intestinal muscularis externa, a bilayered smooth muscle structure that is composed of inner circular muscles (ICM) and outer longitudinal muscles (OLM). We performed transcriptome analysis of intestinal mesenchyme tissue at E14.5, when the ICM, but not the OLM, is present, to investigate the transcriptional program of the ICM. RESULTS: We identified 3967 genes enriched in E14.5 intestinal mesenchyme. The gene expression profiles were clustered and annotated to known muscle genes, identifying a muscle-enriched subcluster. Using publically available in situ data, 127 genes were verified as expressed in ICM. Examination of the promoter and regulatory regions for these co-expressed genes revealed enrichment for cJUN transcription factor binding sites, and cJUN protein was enriched in ICM. cJUN ChIP-seq, performed at E14.5, revealed that cJUN regulatory regions contain characteristics of muscle enhancers. Finally, we show that cJun is a target of Hedgehog (Hh), a signaling pathway known to be important in smooth muscle development, and identify a cJun genomic enhancer that is responsive to Hh. CONCLUSIONS: This work provides the first transcriptional catalog for the developing ICM and suggests that cJun regulates gene expression in the ICM downstream of Hh signaling. Developmental Dynamics 245:614-626, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26930388 TI - Gynecological surveillance in high risk women. AB - In high-risk women, risk reducing surgery remains the cornerstone of prevention. However, the resulting premature menopause has led to continued efforts to develop effective screening strategies for those who wish to delay or avoid surgery. This review describes how the screening of women at risk of ovarian and endometrial cancer has evolved to its current state. Serial monitoring of CA125 is core to ovarian cancer screening and most recent studies have used the Risk of Ovarian Cancer Algorithm (ROCA) to interpret CA125 profile. The additional use of a second tumour marker, HE4, is reviewed. The results to date of key ovarian cancer screening studies in high-risk women are summarised ahead of their concluding findings due later in 2016. The role of both ultrasound and endometrial sampling in the management of women at increased risk of endometrial cancer is outlined. Exciting new methodology, which could help shape the future of screening is investigated. The article summarises the current recommendations and guidelines from recognised international bodies to aid the clinician with management of these women. PMID- 26930389 TI - Modern operative hysteroscopy. AB - Hysteroscopy is an endoscopic surgical procedure that has become an important tool to evaluate intrauterine pathology. It offers a direct visualization of the entire uterine cavity and provides the possibility of performing biopsy of suspected lesions that can be missed by dilatation and curettage (D&C). In most cases, the intrauterine pathologies can be diagnosed and treated at the same setting as office hysteroscopy ("see and treat approach"). For example, endometrial polyps can be diagnosed and removed; similarly, intrauterine adhesions can be liberated in the outpatient setting without the need for an operating theatre. Today, many hysteroscopic procedures can be performed in the office or outpatient setting. This is due to the feasibility of operative hysteroscopy using saline as a distending medium, the vaginoscopic approach of hysteroscopy and the availability of mini-hysteroscopic endoscopes. There is good evidence to suggest that hysteroscopy in an ambulatory setting is preferable for the patient, and that it avoids complications, allows a quicker recovery time and lowers cost. Advances in technology have led to miniaturization of high definition hysteroscopes without compromising optical performance, thereby making hysteroscopy a simple, safe and well-tolerated office procedure. The new surgical technology such as bipolar electrosurgery, endometrial ablation devices, hysteroscopic sterilization, and morcellators has revolutionized this surgical modality. The modern development of hysteroscopy completely transformed the approach to the uterine intracavitary pathologies moving from a blind procedure under general anesthesia to an outpatient procedure performed under direct visualization, offering therapeutic and irreplaceable possibilities of treatment that should belong to every modern gynecologist. PMID- 26930390 TI - The place of selective progesterone receptor modulators in myoma therapy. AB - Uterine fibroids are the most commonly encountered benign uterine tumors in women of reproductive age. As progesterone is known to play a key role in promoting myoma growth, the goal of the study was to analyze the efficacy of selective progesterone receptor modulators (SPRMs). From four studies, it was concluded that UPA (ulipristal acetate) treatment was able to control myoma-associated uterine bleeding in over 90% of cases and significantly reduce myoma volume in more than 80% of women. The results of long-term intermittent therapy (PEARL III and PEARL IV studies) (4 courses of 3 months) demonstrated that more than one course of UPA is able to maximize its potential benefits in terms of control of bleeding and fibroid volume reduction. The treatment was considered safe, even at the level of endometrial changes. With the advent of SPRMs, new algorithms should be discussed, as there is no doubt that there is a place for medical therapy with SPRMs in the current armamentarium of fibroid management. PMID- 26930391 TI - Challenges in ovarian stimulation. AB - In 2016, ovarian stimulation faces two main challenges: how to obtain good quality oocytes while not endangering the patients treated, but also limited by maternal age and poor ovarian responders (POR). The first IVF birth, Louise Brown, was obtained from a natural cycle. With the introduction, in the 1980s of gonadotropin releasing hormone agonists (GnRHa) and in the 2000s of GnRH antagonists (GnRHant), stimulation became plurifollicular (and source of consequences). Today, only about 50% of the transferred blastocysts after IVF lead to a pregnancy. The purpose of this review was to describe the current challenges and limits of ovarian stimulation. PMID- 26930392 TI - Constructing Optimal Coarse-Grained Sites of Huge Biomolecules by Fluctuation Maximization. AB - Coarse-grained (CG) models are valuable tools for the study of functions of large biomolecules on large length and time scales. The definition of CG representations for huge biomolecules is always a formidable challenge. In this work, we propose a new method called fluctuation maximization coarse-graining (FM CG) to construct the CG sites of biomolecules. The defined residual in FM-CG converges to a maximal value as the number of CG sites increases, allowing an optimal CG model to be rigorously defined on the basis of the maximum. More importantly, we developed a robust algorithm called stepwise local iterative optimization (SLIO) to accelerate the process of coarse-graining large biomolecules. By means of the efficient SLIO algorithm, the computational cost of coarse-graining large biomolecules is reduced to within the time scale of seconds, which is far lower than that of conventional simulated annealing. The coarse-graining of two huge systems, chaperonin GroEL and lengsin, indicates that our new methods can coarse-grain huge biomolecular systems with up to 10,000 residues within the time scale of minutes. The further parametrization of CG sites derived from FM-CG allows us to construct the corresponding CG models for studies of the functions of huge biomolecular systems. PMID- 26930393 TI - Variability in the Treatment of Prehospital Hypoglycemia: A Structured Review of EMS Protocols in the United States. AB - BACKGROUND: In many industries, limiting variability in process has been associated with a reduction in errors. Hypoglycemia is a common prehospital diabetic emergency for which most EMS systems have a treatment protocol. OBJECTIVE: To examine the treatment variability for prehospital hypoglycemia within EMS protocols in the U.S. METHODS: EMS protocols were reviewed in a structured fashion from 2 sources: the website www.emsprotocols.org and through manual identification from the 50 largest populated cities in the U.S. Data was abstracted by trained investigators regarding the concentration of glucose recommended for the parenteral reversal of hypoglycemia, clinical treatment thresholds, dose recommendations, follow-up care, and non-transport policies. Descriptive statistics were used to summarize the findings. We also reviewed these EMS protocols for the protocol's effective date, the presence of a specific hypoglycemia patient non-transport policy, the use of dilutions of hypertonic dextrose for pediatric patients, glucagon use, and CBG or GCS for patient follow up. RESULTS: Protocols were retrieved from 185 EMS agencies of a variety of sizes across the U.S. Seventy percent specified only D50 for the treatment of hypoglycemia in adult patients, 8% only D10, and 22% either D10 or D50. Most protocols (85%), which used D50, specified concentration dilutions for pediatric patients. The most frequently specified initial dose of glucose was 25 g of glucose for adults (73-78%), 0.5 g/kg for pediatric (70%), and 0.5 g/kg for neonates (45%). The median blood glucose level threshold for treatment was 60 mg/dl for patients of all ages, but the mean treatment threshold levels for adults, pediatric patients and neonates were statistically different (p < 0.0001). Nearly all protocols (97%) allowed for the use of glucagon in the absence of vascular access. Patient follow up with a repeat CBG was recommended in 32%, both CBG and GCS in 31%, GCS only in 4%, and no follow-up was specified in 33% of the protocols. A specific policy permitting the non-transport of select patients whose hypoglycemia had been corrected was noted in slightly less than half (49%) of the protocols. CONCLUSIONS: In the U.S., EMS protocols for the treatment of hypoglycemia vary significantly. Further studies are warranted to determine the factors underlying this variability and effects on patient outcomes. PMID- 26930394 TI - Design, Synthesis, and Use of MMP-2 Inhibitor-Conjugated Quantum Dots in Functional Biochemical Assays. AB - The development of chemically designed matrix metalloprotease (MMP) inhibitors has advanced the understanding of the roles of MMPs in different diseases. Most MMP probes designed are fluorogenic substrates, often suffering from photo- and chemical instability and providing a fluorescence signal of moderate intensity, which is difficult to detect and analyze when dealing with crude biological samples. Here, an inhibitor that inhibits MMP-2 more selectively than Galardin has been synthesized and used for enzyme labeling and detection of the MMP-2 activity. A complete MMP-2 recognition complex consisting of a biotinylated MMP inhibitor tagged with the streptavidin-quantum dot (QD) conjugate has been prepared. This recognition complex, which is characterized by a narrow fluorescence emission spectrum, long fluorescence lifetime, and negligible photobleaching, has been demonstrated to specifically detect MMP-2 in in vitro sandwich-type biochemical assays with sensitivities orders of magnitude higher than those of the existing gold standards employing organic dyes. The approach developed can be used for specific in vitro visualization and testing of MMP-2 in cells and tissues with sensitivities significantly exceeding those of the best existing fluorogenic techniques. PMID- 26930395 TI - Depression-Burnout Overlap in Physicians. AB - BACKGROUND: Whether burnout is a distinct phenomenon rather than a type of depression and whether it is a syndrome, limited to three "core" components (emotional exhaustion, depersonalization and low personal accomplishment) are subjects of current debate. We investigated the depression-burnout overlap, and the pertinence of these three components in a large, representative sample of physicians. METHODS: In a cross-sectional study, all Austrian physicians were invited to answer a questionnaire that included the Major Depression Inventory (MDI), the Hamburg Burnout Inventory (HBI), as well as demographic and job related parameters. Of the 40093 physicians who received an invitation, a total of 6351 (15.8%) participated. The data of 5897 participants were suitable for analysis. RESULTS: Of the participants, 10.3% were affected by major depression. Our study results suggest that potentially 50.7% of the participants were affected by symptoms of burnout. Compared to physicians unaffected by burnout, the odds ratio of suffering from major depression was 2.99 (95% CI 2.21-4.06) for physicians with mild, 10.14 (95% CI 7.58-13.59) for physicians with moderate, 46.84 (95% CI 35.25-62.24) for physicians with severe burnout and 92.78 (95% CI 62.96-136.74) for the 3% of participants with the highest HBI_sum (sum score of all ten HBI components). The HBI components Emotional Exhaustion, Personal Accomplishment and Detachment (representing depersonalization) tend to correlate more highly with the main symptoms of major depression (sadness, lack of interest and lack of energy) than with each other. A combination of the HBI components Emotional Exhaustion, Helplessness, Inner Void and Tedium (adj.R2 = 0.92) explained more HBI_sum variance than the three "core" components (adj.R2 = 0.85) of burnout combined. Cronbach's alpha for Emotional Exhaustion, Helplessness, Inner Void and Tedium combined was 0.90 compared to alpha = 0.54 for the combination of the three "core" components. CONCLUSIONS: This study demonstrates the overlap of burnout and major depression in terms of symptoms and the deficiency of the three-dimensional concept of burnout. In our opinion, it might be preferable to use multidimensional burnout inventories in combination with valid depression scales than to rely exclusively on MBI when clinically assessing burnout. PMID- 26930397 TI - Mini-review: Assessing the drivers of ship biofouling management--aligning industry and biosecurity goals. AB - Biofouling exerts a frictional and cost penalty on ships and is a direct cause of invasion by marine species. These negative consequences provide a unifying purpose for the maritime industry and biosecurity managers to prevent biofouling accumulation and transfer, but important gaps exist between these sectors. This mini-review examines the approach to assessments of ship biofouling among sectors (industry, biosecurity and marine science) and the implications for existing and emerging management of biofouling. The primary distinctions between industry and biosecurity in assessment of vessels biofouling revolve around the resolution of biological information collected and the specific wetted surface areas of primary concern to each sector. The morphological characteristics of biofouling and their effects on propulsion dynamics are of primary concern to industry, with an almost exclusive focus on the vertical sides and flat bottom of hulls and an emphasis on antifouling and operational performance. In contrast, the identity, biogeography, and ecology of translocated organisms is of highest concern to invasion researchers and biosecurity managers and policymakers, especially as it relates to species with known histories of invasion elsewhere. Current management practices often provide adequate, although not complete, provision for hull surfaces, but niche areas are well known to enhance biosecurity risk. As regulations to prevent invasions emerge in this arena, there is a growing opportunity for industry, biosecurity and academic stakeholders to collaborate and harmonize efforts to assess and manage biofouling of ships that should lead to more comprehensive biofouling solutions that promote industry goals while reducing biosecurity risk and greenhouse gas emissions. PMID- 26930396 TI - Computational Identification Raises a Riddle for Distribution of Putative NACHT NTPases in the Genome of Early Green Plants. AB - NACHT NTPases and AP-ATPases belongs to STAND (signal transduction ATPases with numerous domain) P-loop NTPase class, which are known to be involved in defense signaling pathways and apoptosis regulation. The AP-ATPases (also known as NB ARC) and NACHT NTPases are widely spread throughout all kingdoms of life except in plants, where only AP-ATPases have been extensively studied in the scenario of plant defense response against pathogen invasion and in hypersensitive response (HR). In the present study, we have employed a genome-wide survey (using stringent computational analysis) of 67 diverse organisms viz., archaebacteria, cyanobacteria, fungi, animalia and plantae to revisit the evolutionary history of these two STAND P-loop NTPases. This analysis divulged the presence of NACHT NTPases in the early green plants (green algae and the lycophyte) which had not been previously reported. These NACHT NTPases were known to be involved in diverse functional activities such as transcription regulation in addition to the defense signaling cascades depending on the domain association. In Chalmydomonas reinhardtii, a green algae, WD40 repeats found to be at the carboxyl-terminus of NACHT NTPases suggest probable role in apoptosis regulation. Moreover, the genome of Selaginella moellendorffii, an extant lycophyte, intriguingly shows the considerable number of both AP-ATPases and NACHT NTPases in contrast to a large repertoire of AP-ATPases in plants and emerge as an important node in the evolutionary tree of life. The large complement of AP-ATPases overtakes the function of NACHT NTPases and plausible reason behind the absence of the later in the plant lineages. The presence of NACHT NTPases in the early green plants and phyletic patterns results from this study raises a quandary for the distribution of this STAND P-loop NTPase with the apparent horizontal gene transfer from cyanobacteria. PMID- 26930398 TI - Evaluating the Potential of Q-Band ESR Spectroscopy for Dose Reconstruction of Fossil Tooth Enamel. AB - The potential of Q-band Electron Spin Resonance (ESR) for quantitative measurements has been scarcely evaluated in the literature and its application for dose reconstruction of fossil tooth enamel with dating purposes remains still quite unknown. Hence, we have performed a comparative study based on several Early to Middle Pleistocene fossil tooth samples using both X- and Q-band spectroscopies. Our results show that Q-band offers a significant improvement in terms of sensitivity and signal resolution: it allows not only to work with reduced amounts of valuable samples (< 4 mg), but also to identify different components of the main composite ESR signal. However, inherent precision of the ESR intensity measurements at Q-band is clearly lower than that achieved at X band, highlighting the necessity to carry out repeated measurements. All dose values derived from X- and Q-band are nevertheless systematically consistent at either 1 or 2 sigma. In summary, our results indicate that Q-band could now be considered as a reliable tool for ESR dosimetry/dating of fossil teeth although further work is required to improve the repeatability of the measurements. PMID- 26930399 TI - Biofilm Filtrates of Pseudomonas aeruginosa Strains Isolated from Cystic Fibrosis Patients Inhibit Preformed Aspergillus fumigatus Biofilms via Apoptosis. AB - Pseudomonas aeruginosa (Pa) and Aspergillus fumigatus (Af) colonize cystic fibrosis (CF) patient airways. Pa culture filtrates inhibit Af biofilms, and Pa non-CF, mucoid (Muc-CF) and nonmucoid CF (NMuc-CF) isolates form an ascending inhibitory hierarchy. We hypothesized this activity is mediated through apoptosis induction. One Af and three Pa (non-CF, Muc-CF, NMuc-CF) reference isolates were studied. Af biofilm was formed in 96 well plates for 16 h +/- Pa biofilm filtrates. After 24 h, apoptosis was characterized by viability dye DiBAc, reactive oxygen species (ROS) generation, mitochondrial membrane depolarization, DNA fragmentation and metacaspase activity. Muc-CF and NMuc-CF filtrates inhibited and damaged Af biofilm (p<0.0001). Intracellular ROS levels were elevated (p<0.001) in NMuc-CF-treated Af biofilms (3.7- fold) compared to treatment with filtrates from Muc-CF- (2.5- fold) or non-CF Pa (1.7- fold). Depolarization of mitochondrial potential was greater upon exposure to NMuc-CF (2.4-fold) compared to Muc-CF (1.8-fold) or non-CF (1.25-fold) (p<0.0001) filtrates. Exposure to filtrates resulted in more DNA fragmentation in Af biofilm, compared to control, mediated by metacaspase activation. In conclusion, filtrates from CF-Pa isolates were more inhibitory against Af biofilms than from non-CF. The apoptotic effect involves mitochondrial membrane damage associated with metacaspase activation. PMID- 26930400 TI - Comparing Tuberculosis Diagnostic Yield in Smear/Culture and Xpert(r) MTB/RIF Based Algorithms Using a Non-Randomised Stepped-Wedge Design. AB - SETTING: Primary health services in Cape Town, South Africa. STUDY AIM: To compare tuberculosis (TB) diagnostic yield in an existing smear/culture-based and a newly introduced Xpert(r) MTB/RIF-based algorithm. METHODS: TB diagnostic yield (the proportion of presumptive TB cases with a laboratory diagnosis of TB) was assessed using a non-randomised stepped-wedge design as sites transitioned to the Xpert(r) based algorithm. We identified the full sequence of sputum tests recorded in the electronic laboratory database for presumptive TB cases from 60 primary health sites during seven one-month time-points, six months apart. Differences in TB yield and temporal trends were estimated using a binomial regression model. RESULTS: TB yield was 20.9% (95% CI 19.9% to 22.0%) in the smear/culture-based algorithm compared to 17.9% (95%CI 16.4% to 19.5%) in the Xpert(r) based algorithm. There was a decline in TB yield over time with a mean risk difference of -0.9% (95% CI -1.2% to -0.6%) (p<0.001) per time-point. When estimates were adjusted for the temporal trend, TB yield was 19.1% (95% CI 17.6% to 20.5%) in the smear/culture-based algorithm compared to 19.3% (95% CI 17.7% to 20.9%) in the Xpert(r) based algorithm with a risk difference of 0.3% (95% CI 1.8% to 2.3%) (p = 0.796). Culture tests were undertaken for 35.5% of smear negative compared to 17.9% of Xpert(r) negative low MDR-TB risk cases and for 82.6% of smear-negative compared to 40.5% of Xpert(r) negative high MDR-TB risk cases in respective algorithms. CONCLUSION: Introduction of an Xpert(r) based algorithm did not produce the expected increase in TB diagnostic yield. Studies are required to assess whether improving adherence to the Xpert(r) negative algorithm for HIV-infected individuals will increase yield. In light of the high cost of Xpert(r), a review of its role as a screening test for all presumptive TB cases may be warranted. PMID- 26930401 TI - Stratification of Prognosis of Triple-Negative Breast Cancer Patients Using Combinatorial Biomarkers. AB - BACKGROUND: Triple-negative breast cancer (TNBC) is highly diverse group of cancers, and generally considered an aggressive disease associated with poor survival. Stratification of TNBC is highly desired for both prognosis and treatment decisions to identify patients who may benefit from less aggressive therapy. METHODS: This study retrieved 192 consecutive non-metastasis TNBC patients who had undergone a resection of a primary tumor from 2008 to 2012. All samples were negative for ER, PR, and HER2/neu. Disease-free-survival (DFS) and overall-survival (OS) were evaluated for expression of immunohistochemical biomarkers (P53, Ki-67, CK5/6 and EGFR), as well as clinicopathological variables including age, tumor size, grade, lymph node status, pathologic tumor and nodal stages. The cutoff values of the basal biomarkers, EGFR and CK5/6, were estimated by time-dependent ROC curves. The prognostic values of combinatorial variables were identified by univariate and multivariate Cox analysis. Patients were stratified into different risk groups based on expression status of identified prognostic variables. RESULTS: Median age was 57 years (range, 28-92 years). Patients' tumor stage and nodal stage were significantly associated with OS and DFS. EGFR and CK5/6 were significant prognostic variables at cutoff points of 15% (p = 0.001, AUC = 0.723), and 50% (p = 0.006, AUC = 0.675), respectively. Multivariate Cox analysis identified five significant variables: EGFR (p = 0.016), CK5/6 (p = 0.018), Ki-67 (p = 0.048), tumor stage (p = 0.010), and nodal stage (p = 0.003). Patients were stratified into low basal (EGFR<=15% and CK5/6<=50%) and high basal (EGFR>15% and/or CK5/6>50%) expression groups. In the low basal expression group, patients with low expressions of Ki-67, low tumor and nodal stage had significantly better survival than those with high expressions/stages of three variables, log-rank p = 0.015 (100% vs 68% at 50 months). In the high basal expression group, patient with high basal expression of both biomarkers (EGFR >15% and CK5/6 >50%) had worse survival (mean DFS = 25 months, 41.7% event rate) than those patient with high expression of either one marker (mean DFS = 34 months, 25.5% event rate). CONCLUSIONS: Immunoexpression of basal biomarkers, EGFR and CK5/6, is useful in predicting survival of TNBC patients. Integrated with Ki-67, tumor and nodal stages, combinatorial biomarker analysis provides a feasible clinical solution to stratify patient risks and help clinical decision-making with respect to selecting the appropriate therapies for individual patients. PMID- 26930402 TI - Internal Variability-Generated Uncertainty in East Asian Climate Projections Estimated with 40 CCSM3 Ensembles. AB - Regional climate projections are challenging because of large uncertainty particularly stemming from unpredictable, internal variability of the climate system. Here, we examine the internal variability-induced uncertainty in precipitation and surface air temperature (SAT) trends during 2005-2055 over East Asia based on 40 member ensemble projections of the Community Climate System Model Version 3 (CCSM3). The model ensembles are generated from a suite of different atmospheric initial conditions using the same SRES A1B greenhouse gas scenario. We find that projected precipitation trends are subject to considerably larger internal uncertainty and hence have lower confidence, compared to the projected SAT trends in both the boreal winter and summer. Projected SAT trends in winter have relatively higher uncertainty than those in summer. Besides, the lower-level atmospheric circulation has larger uncertainty than that in the mid level. Based on k-means cluster analysis, we demonstrate that a substantial portion of internally-induced precipitation and SAT trends arises from internal large-scale atmospheric circulation variability. These results highlight the importance of internal climate variability in affecting regional climate projections on multi-decadal timescales. PMID- 26930403 TI - Psychometric Properties of Translation of the Child Perception Questionnaire (CPQ11-14) in Telugu Speaking Indian Children. AB - Oral health related quality of life research among children in India is still nascent and no measures have been validated to date. Although CPQ11-14 has been previously used in studies from the Indian sub-continent, the instrument has never been tested for cross-cultural adaptability. This study aimed to assess the validity and reliability of CPQ11-14 in Telugu speaking Indian school children. Primary school children of Medak district, Telangana State, India, were recruited by a multi-stage probability sampling method. The translated questionnaire was initially pilot tested on a small subset of children (n = 40). Children with informed consent from parents (N = 1342) were then provided with questionnaires containing the Telugu translation of CPQ11-14, followed by a clinical examination conducted by a single examiner, using Basic WHO survey methods for dental caries, malocclusion, and Dean's Fluorosis index. Children (n = 161) in randomly chosen schools were re-administered the same questionnaire after a two week interval to test reliability of CPQ11-14 on repeated administrations. Internal consistency and test-retest reliability as determined by Cronbach's alpha and Intra-class correlation coefficient for overall CPQ11-14 scale were 0.925 and 0.923, respectively. CPQ11-14 discriminated between the categories of fluorosis and malocclusion while its discriminant validity with respect to dental caries was limited. CPQ11-14 also demonstrated good construct validity with both overall CPQ11-14 and its subscales having significant positive correlation with global ratings of oral health and overall wellbeing, even after adjusting for confounding variables. CPQ11-14 had a correlation of 0.405 with self-evaluated oral health and 0.407 with self-evaluated impact of oral health on overall wellbeing. In conclusion, Telugu translation of CPQ11-14 demonstrated good internal consistency and excellent reliability on repeated administrations after two weeks. It also exhibited good discriminant and construct validity. PMID- 26930404 TI - Driving following Kava Use and Road Traffic Injuries: A Population-Based Case Control Study in Fiji (TRIP 14). AB - OBJECTIVE: To investigate the association between kava use and the risk of four wheeled motor vehicle crashes in Fiji. Kava is a traditional beverage commonly consumed in many Pacific Island Countries. Herbal anxiolytics containing smaller doses of kava are more widely available. METHODS: Data for this population-based case-control study were collected from drivers of 'case' vehicles involved in serious injury-involved crashes (where at least one road user was killed or admitted to hospital for 12 hours or more) and 'control' vehicles representative of 'driving time' in the study base. Structured interviewer administered questionnaires collected self-reported participant data on demographic characteristics and a range of risk factors including kava use and potential confounders. Unconditional logistic regression models estimated odds ratios relating to the association between kava use and injury-involved crash risk. FINDINGS: Overall, 23% and 4% of drivers of case and control vehicles, respectively, reported consuming kava in the 12 hours prior to the crash or road survey. After controlling for assessed confounders, driving following kava use was associated with a four-fold increase in the odds of crash involvement (Odds ratio: 4.70; 95% CI: 1.90-11.63). The related population attributable risk was 18.37% (95% CI: 13.77-22.72). Acknowledging limited statistical power, we did not find a significant interaction in this association with concurrent alcohol use. CONCLUSION: In this study conducted in a setting where recreational kava consumption is common, driving following the use of kava was associated with a significant excess of serious-injury involved road crashes. The precautionary principle would suggest road safety strategies should explicitly recommend avoiding driving following kava use, particularly in communities where recreational use is common. PMID- 26930405 TI - The Prevalence and Incidence of Atrial Fibrillation in Patients with Acute Pulmonary Embolism. AB - BACKGROUND: Symptomatic pulmonary embolism (PE) is a major cause of cardiovascular death and morbidity. Estimated prevalence and incidence of atrial fibrillation (AF) in developed countries are between 388-661 per 100,000, and 90 123 per 100,000 person-years respectively. However, the prevalence and incidence of AF in patients presenting with an acute PE and its predictors are not clear. METHODS: Individual patient clinical details were retrieved from a database containing all confirmed acute PE presentations to a tertiary institution from 2001-2012. Prevalence and incidence of AF was tracked from a population registry by systematically searching for AF during any hospital admission (2000-2013) based on International Classification of Disease (ICD-10) code. RESULTS: Of the 1,142 patients included in this study, 935 (81.9%) had no AF during index PE admission whilst 207 patients had documented baseline AF (prevalence rate 18,126 per 100,000; age-adjusted 4,672 per 100,000). Of the 935 patients without AF, 126 developed AF post-PE (incidence rate 2,778 per 100,000 person-years; age-adjusted 984 per 100,000 person-years). Mean time from PE to subsequent AF was 3.4 +/- 2.9 years. Total mortality (mean follow-up 5.0 +/- 3.7 years) was 42% (n = 478): 35% (n = 283), 59% (n = 119) and 60% (n = 76) in the no AF, baseline AF and subsequent AF cohorts respectively. Independent predictors for subsequent AF after acute PE include age (hazard ratio [HR] 1.06, 95% confidence interval [CI] 1.04-1.08, p<0.001), history of congestive cardiac failure (HR 1.88, 95% CI 1.12 3.16, p = 0.02), diabetes (HR 1.72, 95% CI 1.07-2.77, p = 0.02), obstructive sleep apnea (HR 4.83, 1.48-15.8, p = 0.009) and day-1 serum sodium level during index PE admission (HR 0.94, 95% CI 0.90-0.98, p = 0.002). CONCLUSIONS: Patients presenting with acute PE have a markedly increased age-adjusted prevalence and subsequent incidence of AF. Screening for AF may be of importance post-PE. PMID- 26930406 TI - Early HAART Initiation May Not Reduce Actual Reproduction Number and Prevalence of MSM Infection: Perspectives from Coupled within- and between-Host Modelling Studies of Chinese MSM Populations. AB - Having a thorough understanding of the infectivity of HIV, time of initiating treatment and emergence of drug resistant virus variants is crucial in mitigating HIV infection. There are many challenges to evaluating the long-term effect of the Highly Active Antiretroviral Therapy (HAART) on disease transmission at the population level. We proposed an individual based model by coupling within-host dynamics and between-host dynamics and conduct stochastic simulation in the group of men who have sex with men (MSM). The mean actual reproduction number is estimated to be 3.6320 (95% confidence interval: [3.46, 3.80]) for MSM group without treatment. Stochastic simulations show that given relatively high (low) level of drug efficacy after emergence of drug resistant variants, early initiation of treatment leads to a less (greater) actual reproduction number, lower (higher) prevalence and less (more) incidences, compared to late initiation of treatment. This implies early initiation of HAART may not always lower the actual reproduction number and prevalence of infection, depending on the level of treatment efficacy after emergence of drug resistant virus variants, frequency of high-risk behaviors and etc. This finding strongly suggests early initiation of HAART should be implemented with great care especially in the settings where the effective drugs are limited. Coupling within-host dynamics with between-host dynamics can provide critical information about impact of HAART on disease transmission and thus help to assist treatment strategy design and HIV/AIDS prevention and control. PMID- 26930407 TI - Effect of Serum Leptin on Weight Gain Induced by Olanzapine in Female Patients with Schizophrenia. AB - BACKGROUND: Olanzapine (OLZ) treatment is associated with a high risk of weight gain, and may cause abnormalities in glycolipid metabolism. Therefore, the underlying mechanism of OLZ-related weight gain is needed to clarify but not yet been adequately determined. In recent years, adipocytokines such as leptin, adiponectin, and tumor necrosis factor (TNF)-alpha, which play important roles in energy homeostasis, have been suggested as biomarkers of weight gain. Here, we determined if baseline plasma concentrations of leptin, adiponectin, and TNF alpha predict weight gain following OLZ treatment. METHODS: We recruited 31 schizophrenia outpatients (12 men and 19 women, 28.8 +/- 10.2 years old) that were unmedicated or on another antipsychotic monotherapy medication. Baseline body mass index (BMI) and plasma levels of leptin, adiponectin, and TNF-alpha were obtained. All patients started or were switched to OLZ monotherapy for a maximum of 1 year. BMI was also obtained at the endpoint. RESULTS: Mean BMI change following OLZ treatment was 2.1 +/- 2.7 kg/m2. BMI change from baseline to endpoint negatively-correlated with baseline leptin levels in female patients (r = -0.514, P = 0.024), but not male patients. Baseline adiponectin or TNF-alpha levels were not correlated with BMI change. CONCLUSION: Baseline plasma leptin can have an effect on subsequent weight gain following OLZ treatment in female patients with schizophrenia. PMID- 26930408 TI - Association between Maternal Fish Consumption and Gestational Weight Gain: Influence of Molecular Genetic Predisposition to Obesity. AB - BACKGROUND: Studies suggest that fish consumption can restrict weight gain. However, little is known about how fish consumption affects gestational weight gain (GWG), and whether this relationship depends on genetic makeup. OBJECTIVE: To examine the association between fish consumption and GWG, and whether this relationship is dependent on molecular genetic predisposition to obesity. DESIGN: A nested case-cohort study based on the Danish National Birth Cohort (DNBC) sampling the most obese women (n = 990) and a random sample of the remaining participants (n = 1,128). Replication of statistically significant findings was attempted in the Avon Longitudinal Study of Parents and Children (ALSPAC) (n = 4,841). We included 32 body mass index (BMI) associated single nucleotide polymorphisms (SNPs) and 5 SNPs found associated with GWG. BMI associated SNPs were combined in a genetic risk score (GRS). Associations between consumption of fish, GRS or individual variants and GWG were analysed, and interactions between fish and the GRS or individual variants were examined. RESULTS: In the DNBC, each portion/week (150 g) of fatty fish was associated with a higher GWG of 0.58 kg (95% CI: 0.16, 0.99, P<0.01). For total fish and lean fish, similar patterns were observed, but these associations were not statistically significant. We found no association between GRS and GWG, and no interactions between GRS and dietary fish on GWG. However, we found an interaction between the PPARG Pro12Ala variant and dietary fish. Each additional Pro12Ala G-allele was associated with a GWG of 0.83 kg (95% CI: -1.29, -0.37, P<0.01) per portion/week of dietary fish, with the same pattern for both lean and fatty fish. In ALSPAC, we were unable to replicate these findings. CONCLUSION: We found no consistent evidence of association between fish consumption and GWG, and our results indicate that the association between dietary fish and GWG has little or no dependency on GRS or individual SNPs. PMID- 26930409 TI - Cell Sheet Transplantation for Esophageal Stricture Prevention after Endoscopic Submucosal Dissection in a Porcine Model. AB - BACKGROUND & AIMS: Extended esophageal endoscopic submucosal dissection (ESD) is highly responsible for esophageal stricture. We conducted a comparative study in a porcine model to evaluate the effectiveness of adipose tissue-derived stromal cell (ADSC) double cell sheet transplantation. METHODS: Twelve female pigs were treated with 5 cm long hemi-circumferential ESD and randomized in two groups. ADSC group (n = 6) received 4 double cell sheets of allogenic ADSC on a paper support membrane and control group (n = 6) received 4 paper support membranes. ADSC were labelled with PKH-67 fluorophore to allow probe-based confocal laser endomicroscopie (pCLE) monitoring. After 28 days follow-up, animals were sacrificed. At days 3, 14 and 28, endoscopic evaluation with pCLE and esophagography were performed. RESULTS: One animal from the control group was excluded (anesthetic complication). Animals from ADSC group showed less frequent alimentary trouble (17% vs 80%; P = 0.08) and higher gain weight on day 28. pCLE demonstrated a compatible cell signal in 4 animals of the ADSC group at day 3. In ADSC group, endoscopy showed that 1 out of 6 (17%) animals developed a severe esophageal stricture comparatively to 100% (5/5) in the control group; P = 0.015. Esophagography demonstrated a decreased degree of stricture in the ADSC group on day 14 (44% vs 81%; P = 0.017) and day 28 (46% vs 90%; P = 0.035). Histological analysis showed a decreased fibrosis development in the ADSC group, in terms of surface (9.7 vs 26.1 mm2; P = 0.017) and maximal depth (1.6 vs 3.2 mm; P = 0.052). CONCLUSION: In this model, transplantation of allogenic ADSC organized in double cell sheets after extended esophegeal ESD is strongly associated with a lower esophageal stricture's rate. PMID- 26930411 TI - Recombinant Measles AIK-C Vaccine Strain Expressing the prM-E Antigen of Japanese Encephalitis Virus. AB - An inactivated Japanese encephalitis virus (JEV) vaccine, which induces neutralizing antibodies, has been used for many years in Japan. In the present study, the JEV prM-E protein gene was cloned, inserted at the P/M junction of measles AIK-C cDNA, and an infectious virus was recovered. The JEV E protein was expressed in B95a cells infected with the recombinant virus. Cotton rats were inoculated with recombinant virus. Measles PA antibodies were detected three weeks after immunization. Neutralizing antibodies against JEV developed one week after inoculation, and EIA antibodies were detected three weeks after immunization. The measles AIK-C-based recombinant virus simultaneously induced measles and JEV immune responses, and may be a candidate for infant vaccines. Therefore, the present strategy of recombinant viruses based on a measles vaccine vector would be applicable to the platform for vaccine development. PMID- 26930410 TI - Dietary Iodine Sufficiency and Moderate Insufficiency in the Lactating Mother and Nursing Infant: A Computational Perspective. AB - The Institute of Medicine recommends that lactating women ingest 290 MUg iodide/d and a nursing infant, less than two years of age, 110 MUg/d. The World Health Organization, United Nations Children's Fund, and International Council for the Control of Iodine Deficiency Disorders recommend population maternal and infant urinary iodide concentrations >= 100 MUg/L to ensure iodide sufficiency. For breast milk, researchers have proposed an iodide concentration range of 150-180 MUg/L indicates iodide sufficiency for the mother and infant, however no national or international guidelines exist for breast milk iodine concentration. For the first time, a lactating woman and nursing infant biologically based model, from delivery to 90 days postpartum, was constructed to predict maternal and infant urinary iodide concentration, breast milk iodide concentration, the amount of iodide transferred in breast milk to the nursing infant each day and maternal and infant serum thyroid hormone kinetics. The maternal and infant models each consisted of three sub-models, iodide, thyroxine (T4), and triiodothyronine (T3). Using our model to simulate a maternal intake of 290 MUg iodide/d, the average daily amount of iodide ingested by the nursing infant, after 4 days of life, gradually increased from 50 to 101 MUg/day over 90 days postpartum. The predicted average lactating mother and infant urinary iodide concentrations were both in excess of 100 MUg/L and the predicted average breast milk iodide concentration, 157 MUg/L. The predicted serum thyroid hormones (T4, free T4 (fT4), and T3) in both the nursing infant and lactating mother were indicative of euthyroidism. The model was calibrated using serum thyroid hormone concentrations for lactating women from the United States and was successful in predicting serum T4 and fT4 levels (within a factor of two) for lactating women in other countries. T3 levels were adequately predicted. Infant serum thyroid hormone levels were adequately predicted for most data. For moderate iodide deficient conditions, where dietary iodide intake may range from 50 to 150 MUg/d for the lactating mother, the model satisfactorily described the iodide measurements, although with some variation, in urine and breast milk. Predictions of serum thyroid hormones in moderately iodide deficient lactating women (50 MUg/d) and nursing infants did not closely agree with mean reported serum thyroid hormone levels, however, predictions were usually within a factor of two. Excellent agreement between prediction and observation was obtained for a recent moderate iodide deficiency study in lactating women. Measurements included iodide levels in urine of infant and mother, iodide in breast milk, and serum thyroid hormone levels in infant and mother. A maternal iodide intake of 50 MUg/d resulted in a predicted 29-32% reduction in serum T4 and fT4 in nursing infants, however the reduced serum levels of T4 and fT4 were within most of the published reference intervals for infant. This biologically based model is an important first step at integrating the rapid changes that occur in the thyroid system of the nursing newborn in order to predict adverse outcomes from exposure to thyroid acting chemicals, drugs, radioactive materials or iodine deficiency. PMID- 26930413 TI - Correction: Focal Experimental Injury Leads to Widespread Gene Expression and Histologic Changes in Equine Flexor Tendons. PMID- 26930412 TI - DNA Damage and Repair Biomarkers in Cervical Cancer Patients Treated with Neoadjuvant Chemotherapy: An Exploratory Analysis. AB - Cervical cancer cells commonly harbour a defective G1/S checkpoint owing to the interaction of viral oncoproteins with p53 and retinoblastoma protein. The activation of the G2/M checkpoint may thus become essential for protecting cancer cells from genotoxic insults, such as chemotherapy. In 52 cervical cancer patients treated with neoadjuvant chemotherapy, we investigated whether the levels of phosphorylated Wee1 (pWee1), a key G2/M checkpoint kinase, and gamma H2AX, a marker of DNA double-strand breaks, discriminated between patients with a pathological complete response (pCR) and those with residual disease. We also tested the association between pWee1 and phosphorylated Chk1 (pChk1), a kinase acting upstream Wee1 in the G2/M checkpoint pathway. pWee1, gamma-H2AX and pChk1 were retrospectively assessed in diagnostic biopsies by immunohistochemistry. The degrees of pWee1 and pChk1 expression were defined using three different classification methods, i.e., staining intensity, Allred score, and a multiplicative score. gamma-H2AX was analyzed both as continuous and categorical variable. Irrespective of the classification used, elevated levels of pWee1 and gamma-H2AX were significantly associated with a lower rate of pCR. In univariate and multivariate analyses, pWee1 and gamma-H2AX were both associated with reduced pCR. Internal validation conducted through a re-sampling without replacement procedure confirmed the robustness of the multivariate model. Finally, we found a significant association between pWee1 and pChk1. The message conveyed by the present analysis is that biomarkers of DNA damage and repair may predict the efficacy of neoadjuvant chemotherapy in cervical cancer. Further studies are warranted to prospectively validate these encouraging findings. PMID- 26930414 TI - Women's Views and Experiences of the Triggers for Onset of Bacterial Vaginosis and Exacerbating Factors Associated with Recurrence. AB - BACKGROUND: Bacterial vaginosis (BV) is the most common vaginal infection affecting women of childbearing age. While the aetiology and transmissibility of BV remain unclear, there is strong evidence to suggest an association between BV and sexual activity. This study explored women's views and experiences of the triggers for BV onset and factors associated with recurrence. METHODS: A descriptive, social constructionist approach was chosen as the framework for the study. Thirty five women of varying sexual orientation who had experienced recurrent BV in the past five years took part in semi-structured interviews. RESULTS: The majority of women predominantly reported sexual contact triggered the onset of BV and sexual and non-sexual factors precipitated recurrence. Recurrence was most commonly referred to in terms of a 'flare-up' of symptoms. The majority of women did not think BV was a sexually transmitted infection however many reported being informed this by their clinician. Single women who attributed BV onset to sex with casual partners were most likely to display self blame tendencies and to consider changing their future sexual behaviour. Women who have sex with women (WSW) were more inclined to believe their partner was responsible for the transmission of or reinfection with BV and seek partner treatment or change their sexual practices. CONCLUSION: Findings from this study strongly suggest women believe that BV onset is associated with sexual activity, concurring with epidemiological data which increasingly suggest BV may be sexually transmitted. Exacerbating factors associated with recurrence were largely heterogeneous and may reflect the fact it is difficult to determine whether recurrence is due to persistent BV or a new infection in women. There was however evidence to suggest possible transmission and reinfection among WSW, reinforcing the need for new approaches to treatment and management strategies including male and female partner treatment trials. PMID- 26930415 TI - Increased Case Notification through Active Case Finding of Tuberculosis among Household and Neighbourhood Contacts in Cambodia. AB - BACKGROUND: Globally, there has been growing evidence that suggests the effectiveness of active case finding (ACF) for tuberculosis (TB) in high-risk populations. However, the evidence is still insufficient as to whether ACF increases case notification beyond what is reported in the routine passive case finding (PCF). In Cambodia, National TB Control Programme has conducted nationwide ACF with Xpert MTB/RIF that retrospectively targeted household and neighbourhood contacts alongside routine PCF. This study aims to investigate the impact of ACF on case notifications during and after the intervention period. METHODS: Using a quasi-experimental cluster randomized design with intervention and control arms, we compared TB case notification during the one-year intervention period with historical baseline cases and trend-adjusted expected cases, and estimated additional cases notified during the intervention period (separately for Year 1 and Year 2 implementation). The proportion of change in case notification was compared between intervention and control districts for Year 1. The quarterly case notification data from all intervention districts were consolidated, aligning different implementation quarters, and separately analysed to explore the additionality. The effect of the intervention on the subsequent case notification during the post-intervention period was also assessed. RESULTS: In Year 1, as compared to expected cases, 1467 cases of all forms (18.5%) and 330 bacteriologically-confirmed cases (9.6%) were additionally notified in intervention districts, whereas case notification in control districts decreased by 2.4% and 2.3%, respectively. In Year 2, 2737 cases of all forms (44.3%) and 793 bacteriologically-confirmed cases (38%) were additionally notified as compared to expected cases. The proportions of increase in case notifications from baseline cases and expected cases to intervention period cases were consistently higher in intervention group than in control group. The consolidated quarterly data showed sharp rises in all forms and bacteriologically-confirmed cases notified during the intervention quarter, with 64.6% and 68.4% increases (compared to baseline cases), and 46% and 52.9% increases (compared to expected cases), respectively. A cumulative reduction of case notification for five quarters after ACF reached more than -200% of additional cases. CONCLUSIONS: The Cambodia's ACF with Xpert MTB/RIF that retrospectively targeted household and neighbourhood contacts resulted in the substantial increase in case notification during the intervention period and reduced subsequent case notification during the post-intervention period. The applicability of retrospective contact investigation in other high-burden settings should be explored. PMID- 26930416 TI - Stretching Your Energetic Budget: How Tendon Compliance Affects the Metabolic Cost of Running. AB - Muscles attach to bones via tendons that stretch and recoil, affecting muscle force generation and metabolic energy consumption. In this study, we investigated the effect of tendon compliance on the metabolic cost of running using a full body musculoskeletal model with a detailed model of muscle energetics. We performed muscle-driven simulations of running at 2-5 m/s with tendon force strain curves that produced between 1 and 10% strain when the muscles were developing maximum isometric force. We computed the average metabolic power consumed by each muscle when running at each speed and with each tendon compliance. Average whole-body metabolic power consumption increased as running speed increased, regardless of tendon compliance, and was lowest at each speed when tendon strain reached 2-3% as muscles were developing maximum isometric force. When running at 2 m/s, the soleus muscle consumed less metabolic power at high tendon compliance because the strain of the tendon allowed the muscle fibers to operate nearly isometrically during stance. In contrast, the medial and lateral gastrocnemii consumed less metabolic power at low tendon compliance because less compliant tendons allowed the muscle fibers to operate closer to their optimal lengths during stance. The software and simulations used in this study are freely available at simtk.org and enable examination of muscle energetics with unprecedented detail. PMID- 26930418 TI - Association of peak factor VIII levels and area under the curve with bleeding in patients with haemophilia A on every third day pharmacokinetic-guided prophylaxis. AB - INTRODUCTION: We previously showed that pharmacokinetic-guided prophylaxis (PKP) allows the dosing interval to be extended while maintaining a specific trough level. However, the associations of peak factor VIII (FVIII) levels and area under the curve (AUC) with breakthrough bleeding have not been investigated. AIM: The aim of this study was to analyse data from the PKP arm to determine whether peak FVIII levels, AUC and time with FVIII levels in a haemostatically effective range are independent predictors of bleeding during prophylaxis. METHODS: Post hoc analysis of the association of FVIII levels and AUC with annualized bleeding rate in 34 patients on PKP. RESULTS: During 1 year of PKP, 131 bleeding episodes occurred in 24/34 patients. Average peak FVIII levels ranged from 24 to 168 IU dL(-1) , with higher values associated with a decreased risk for all bleeding (joint and non-joint; P < 0.01) and joint bleeding (P < 0.01). Following rFVIII infusion, median percent of time spent with FVIII levels >20 IU dL(-1) was 22%; median AUC was 1363. Both values were significantly associated with a lower ABR when targeting a 1% trough at 72 h. CONCLUSION: When PKP was administered every third day, higher peak FVIII levels, higher AUC and more time spent per week with FVIII levels >20 IU dL(-1) provided increased protection from joint and non-joint bleeding. These data highlight the potential impact of variability in individual pharmacokinetic and bleeding risk and support the need for high peak levels and AUC in some patients treated every third day. The findings do not necessarily apply to alternate-day or other prophylactic dosing regimens. PMID- 26930417 TI - Chemically Modifying Viruses for Diverse Applications. AB - Long fascinating to biologists, viruses offer nanometer-scale benchtops for building molecular-scale devices and materials. Viruses tolerate a wide range of chemical modifications including reaction conditions, pH values, and temperatures. Recent examples of nongenetic manipulation of viral surfaces have extended viruses into applications ranging from biomedical imaging, drug delivery, tissue regeneration, and biosensors to materials for catalysis and energy generation. Chemical reactions on the phage surface include both covalent and noncovalent modifications, including some applied in conjunction with genetic modifications. Here, we survey viruses chemically augmented with capabilities limited only by imagination. PMID- 26930419 TI - Rosuvastatin: Beyond the cholesterol-lowering effect. AB - Rosuvastatin is a fully synthetic statin wich acts by interfering with the endogenous synthesis of cholesterol through competitively inhibiting the 3 hydroxy-3-methylglutaryl coenzyme A reductase, a liver enzyme responsible of the rate-limiting step in cholesterol synthesis. When compared to other molecules of the same class, it shows high efficacy in the improvement of lipid profile, and, thanks to its non-cholesterol-lowering actions (anti-inflammatory, antioxidant and antithrombotic), represents a crucial tool for cardiovascular primary and secondary prevention. Moreover, recent data highlight rosuvastatin beneficial effects in several other fields. In this manuscript we analyzed literature sources in order to better define rosuvastatin features and discuss some critical issues. PMID- 26930421 TI - Gonadal hormone modulation of intracellular calcium as a mechanism of neuroprotection. AB - Hormones have wide-ranging effects throughout the nervous system, including the ability interact with and modulate many aspects of intracellular calcium regulation and calcium signaling. Indeed, these interactions specifically may help to explain the often opposing or paradoxical effects of hormones, such as their ability to both promote and prevent neuronal cell death during development, as well as reduce or exacerbate damage following an insult or injury in adulthood. Here, we review the basic mechanisms underlying intracellular calcium regulation-perhaps the most dynamic and flexible of all signaling molecules-and discuss how gonadal hormones might manipulate these mechanisms to coordinate diverse cellular responses and achieve disparate outcomes. Additional future research that specifically addresses questions of sex and hormone effects on calcium signaling at different ages will be critical to understanding hormone mediated neuroprotection. PMID- 26930420 TI - Assessment of resveratrol, apocynin and taurine on mechanical-metabolic uncoupling and oxidative stress in a mouse model of duchenne muscular dystrophy: A comparison with the gold standard, alpha-methyl prednisolone. AB - Antioxidants have a great potential as adjuvant therapeutics in patients with Duchenne muscular dystrophy, although systematic comparisons at pre-clinical level are limited. The present study is a head-to-head assessment, in the exercised mdx mouse model of DMD, of natural compounds, resveratrol and apocynin, and of the amino acid taurine, in comparison with the gold standard alpha-methyl prednisolone (PDN). The rationale was to target the overproduction of reactive oxygen species (ROS) via disease-related pathways that are worsened by mechanical metabolic impairment such as inflammation and over-activity of NADPH oxidase (NOX) (taurine and apocynin, respectively) or the failing ROS detoxification mechanisms via sirtuin-1 (SIRT1)-peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha) (resveratrol). Resveratrol (100mg/kg i.p. 5days/week), apocynin (38mg/kg/day per os), taurine (1g/kg/day per os), and PDN (1mg/kg i.p., 5days/week) were administered for 4-5 weeks to mdx mice in parallel with a standard protocol of treadmill exercise and the outcome was evaluated with a multidisciplinary approach in vivo and ex vivo on pathology-related end-points and biomarkers of oxidative stress. Resveratrol>=taurine>apocynin enhanced in vivo mouse force similarly to PDN. All the compounds reduced the production of superoxide anion, assessed by dihydroethidium staining, with apocynin being as effective as PDN, and ameliorated electrophysiological biomarkers of oxidative stress. Resveratrol also significantly reduced plasma levels of creatine kinase and lactate dehydrogenase. Force of isolated muscles was little ameliorated. However, the three compounds improved histopathology of gastrocnemius muscle more than PDN. Taurine>apocynin>PDN significantly decreased activated NF-kB positive myofibers. Thus, compounds targeting NOX-ROS or SIRT1/PGC-1alpha pathways differently modulate clinically relevant DMD-related endpoints according to their mechanism of action. With the caution needed in translational research, the results show that the parallel assessment can help the identification of best adjuvant therapies. PMID- 26930422 TI - Net joint moments and muscle activation in barbell squats without and with restricted anterior leg rotation. AB - Muscle utilisation in squat exercise depends on technique. The purpose of this study was to compare net joint moments (NJMs) and muscle activation during squats without and with restricted leg dorsiflexion. Experienced men (n = 5) and women (n = 4) performed full squats at 80% one repetition maximum. 3D motion analysis, force platform and (EMG) data were collected. Restricting anterior leg rotation reduced anterior leg (P = 0.001) and posterior thigh (P < 0.001) rotations, resulting in a smaller knee flexion range of motion (P < 0.001). At maximum squat depth, ankle plantar flexor (P < 0.001) and knee extensor (P < 0.001) NJM were higher in unrestricted squats. Hip extensor NJM (P = 0.14) was not different between squat types at maximum squat depth. Vastus lateralis (P > 0.05), vastus medialis (P > 0.05) and rectus femoris (P > 0.05) EMG were not different between squat types. Unrestricted squats have higher ankle plantar flexor and knee extensor NJM than previously reported from jumping and landing. However, ankle plantar flexor and knee extensor NJM are lower in restricted squats than previous studies of jumping and landing. The high NJM in unrestricted squat exercise performed through a full range of motion suggests this squat type would be more effective to stimulate adaptations in the lower extremity musculature than restricted squats. PMID- 26930424 TI - Electronic Structure and Magnetic Properties of Dioxo-Bridged Diuranium Complexes with Diamond-Core Structural Motifs: A Relativistic DFT Study. AB - Electronic structures and magnetic properties of the binuclear bis(MU-oxo) U(IV)/U(IV) K2[{(((nP,Me)ArO)3tacn)U(IV)}2(MU-O)2] and U(V)/U(V) [{(((nP,Me)ArO)3tacn)U(V)}2(MU-O)2] (tacn = triazacyclononane, nP = neopentyl) complexes, exhibiting [U(MU-O)2U] diamond-core structural motifs, have been investigated computationally using scalar relativistic Density Functional Theory (DFT) combined with the Broken Symmetry (BS) approach for their magnetic properties. Using the B3LYP hybrid functional, the BS ground state of the pentavalent [U(V)(MU-O)2U(V)] 5f(1)-5f(1) complex has been found of lower energy than the high spin (HS) triplet state, thus confirming the antiferromagnetic character in agreement with experimental magnetic susceptibility measurements. The nonmagnetic character observed for the tetravalent K2[U(IV)(MU-O)2U(IV)] 5f(2)-5f(2) species is also predicted by our DFT calculations, which led practically to the same energy for the HS and BS states. As reported for related dioxo diuranium(V) systems, superexchange is likely to be responsible for the antiferromagnetic coupling through the pi-network orbital pathway within the (MU O)2 bridge, the dissymmetrical structure of the U2O2 core playing a determining role. In the case of the U(IV) species, our computations indicate that the K(+) counterions are likely to play a role for the observed magnetic property. Finally, the MO analysis, in conjunction with NPA and QTAIM analyses, clarify the electronic structures of the studied complexes. In particular, the fact that the experimentally attempted chemical oxidation of the U(V) species does not lead straightforwardly to binuclear complexes U(VI) is clarified by the MO analysis. PMID- 26930423 TI - Clinical trial readiness in non-ambulatory boys and men with duchenne muscular dystrophy: MDA-DMD network follow-up. AB - INTRODUCTION: Outcomes sensitive to change over time in non-ambulatory boys/men with Duchenne muscular dystrophy (DMD) are not well-established. METHODS: Subjects (n = 91; 16.8 +/- 4.5 years old) were assessed at baseline and 6-month intervals for 2 years. We analyzed all subjects using an intent-to-treat model and a subset of stronger subjects with Brooke Scale score <=4, using repeated measures. RESULTS: Eight patients (12-33 years old) died during the study. Sixty six completed 12-month follow-up, and 51 completed 24-month follow-up. Those taking corticosteroids performed better at baseline, but rates of decline were similar. Forced vital capacity percent predicted (FVC% predicted) declined significantly only after 2 years. However, Brooke and Egen Klassifikation (EK) Scale scores, elbow flexion, and grip strength declined significantly over both 1 and 2 years. CONCLUSION: Brooke and EK Scale scores, elbow flexion, and grip strength were outcomes most responsive to change. FVC% predicted was responsive to change over 2 years. Corticosteroids benefited non-ambulatory DMD subjects but did not affect decline rates of measures tested here. Muscle Nerve 54: 681-689, 2016. PMID- 26930425 TI - Pediatric High-Frequency Oscillation. The End of the Road? PMID- 26930426 TI - Alterations of the Nasopharyngeal Microbiota in Infants with Cystic Fibrosis. Cystic Fibrosis Transmembrane Conductance Regulator and Antibiotic Effects. PMID- 26930427 TI - Bridge or Abyss: Extracorporeal Membrane Oxygenation for Acute Respiratory Failure in Interstitial Lung Disease. PMID- 26930428 TI - Just Say No! Smoking Abstinence Works. PMID- 26930429 TI - Screening for Lung Cancer. Improving Outcomes with Better Patient Selection. PMID- 26930430 TI - A Critical Role for Airway Microvessels in Lung Transplantation. PMID- 26930431 TI - Heart Failure and Sleep-disordered Breathing. The Chicken or the Egg? PMID- 26930432 TI - New Thoughts about the Origin of Plexiform Lesions. PMID- 26930433 TI - Intrapulmonary Bronchopulmonary Anastomoses and Plexiform Lesions in Idiopathic Pulmonary Arterial Hypertension. PMID- 26930434 TI - Positive (18)Fluorodeoxyglucose-Positron Emission Tomography/Computed Tomography Predicts Preinvasive Endobronchial Lesion Progression to Invasive Cancer. PMID- 26930435 TI - Obstructive Sleep Apnea, Sleep Duration, and Fasting Glucose. PMID- 26930436 TI - Reply: "Obstructive Sleep Apnea, Sleep Duration, and Fasting Glucose" and "The Impact of Obesity on the Association between Obstructive Sleep Apnea and Glucose Metabolism". PMID- 26930437 TI - The Impact of Obesity on the Association between Obstructive Sleep Apnea and Glucose Metabolism. PMID- 26930439 TI - Retraction: Maternal Exposure to Particulate Matter Increases Postnatal Ozone induced Airway Hyperreactivity in Juvenile Mice. PMID- 26930438 TI - Comment on Expression of Concern: c-Kit Is Essential for Alveolar Maintenance and Protection from Emphysema-like Disease in Mice. PMID- 26930441 TI - Healthy Sleep In Adults. PMID- 26930442 TI - Nucleoplasmic Lamin A/C and Polycomb group of proteins: An evolutionarily conserved interplay. AB - Nuclear lamins are the main components of the nuclear lamina at the nuclear periphery, providing mechanical support to the nucleus. However, recent findings suggest that lamins also reside in the nuclear interior, as a distinct and dynamic pool with critical roles in transcriptional regulation. In our work we found a functional and evolutionary conserved crosstalk between Lamin A/C and the Polycomb group (PcG) of proteins, this being required for the maintenance of the PcG repressive functions. Indeed, Lamin A/C knock-down causes PcG foci dispersion and defects in PcG-mediated higher order structures, thereby leading to impaired PcG mediated transcriptional repression. By using ad-hoc algorithms for image analysis and PLA approaches we hereby show that PcG proteins are preferentially located in the nuclear interior where they interact with nucleoplasmic Lamin A/C. Taken together, our findings suggest that nuclear components, such as Lamin A/C, functionally interact with epigenetic factors to ensure the correct transcriptional program maintenance. PMID- 26930443 TI - Rat intra-hippocampal NMDA infusion induces cell-specific damage and changes in expression of NMDA and GABAA receptor subunits. AB - Excessive stimulation of NMDA receptors with glutamate or other potent agonists such as NMDA leads to excitotoxicity and neural injury. In this study, we aimed to provide insight into an animal model of brain excitotoxic damage; single unilateral infusion of NMDA at mild dose into the hippocampal formation. NMDA infusion induced chronic, focal neurodegeneration in the proximity of the injection site. The lesion was accompanied by severe and progressive neuroinflammation and affected preferentially principal neurons while sparing GABAergic interneurons. Furthermore, the unilateral lesion did not cause significant impairment of spatial learning abilities. Finally, GluN1 and GluN2B subunits of NMDA receptor were significantly upregulated up to 3 days after the NMDA infusion, while GABAA alpha5 subunit was downregulated at 30 days after the lesion. Taken together, a single infusion of NMDA into the hippocampal formation represents an animal model of excitotoxicity-induced chronic neurodegeneration of principal neurons accompanied by severe neuroinflammation and subunit specific changes in NMDA and GABAA receptors. PMID- 26930444 TI - Adjusting to bodily change following stoma formation: a phenomenological study. AB - PURPOSE: Scant research has been undertaken to explore in-depth the meaning of bodily change for individuals following stoma formation. The aim of this study was to understand the experience of living with a new stoma, with a focus on bodily change. METHOD: The study adopted a longitudinal phenomenological approach. Purposeful sampling was used to recruit 12 participants who had undergone faecal stoma-forming surgery. In-depth, unstructured interviews were conducted at 3, 9 and 15 months following surgery. A five-stage framework facilitated iterative data analysis. RESULTS: Stoma formation altered the taken for-granted relationship individuals had with their bodies in terms of appearance, function and sensation, undermining the unity between body and self. Increasing familiarity with and perceived control over their stoma over time diminished awareness of their changed body, facilitating adaptation and self acceptance. CONCLUSIONS: Stoma formation can undermine an individual's sense of embodied self. A concept of embodiment is proposed to enable the experience of living with a new stoma to be understood as part of a wider process of re establishing a unity between body, self and world. In defining a framework of care, individuals with a new stoma can be assisted to adapt to and accept a changed sense of embodied self. Implications for Rehabilitation Awareness and understanding of the diverse ways in which stoma formation disrupts the unconscious relationship between body and self can help clinicians to provide responsive, person-centred care. Supporting strategies that facilitate bodily mastery following stoma formation will facilitate rehabilitation and promote adjustment and self-acceptance. A concept of embodiment can help clinicians to deepen their understanding of the experiences of people living with a new stoma and the support they may require during the rehabilitation process. This paper provides clinicians with actionable insight that allows them to better support patients to a smoother adjustment process after stoma formation. PMID- 26930445 TI - Development of an accurate molecular mechanics model for buckling behavior of multi-walled carbon nanotubes under axial compression. AB - In the present paper, an analytical solution based on a molecular mechanics model is developed to evaluate the elastic critical axial buckling strain of chiral multi-walled carbon nanotubes (MWCNTs). To this end, the total potential energy of the system is calculated with the consideration of the both bond stretching and bond angular variations. Density functional theory (DFT) in the form of generalized gradient approximation (GGA) is implemented to evaluate force constants used in the molecular mechanics model. After that, based on the principle of molecular mechanics, explicit expressions are proposed to obtain elastic surface Young's modulus and Poisson's ratio of the single-walled carbon nanotubes corresponding to different types of chirality. Selected numerical results are presented to indicate the influence of the type of chirality, tube diameter, and number of tube walls in detailed. An excellent agreement is found between the present numerical results and those found in the literature which confirms the validity as well as the accuracy of the present closed-form solution. It is found that the value of critical axial buckling strain exhibit significant dependency on the type of chirality and number of tube walls. PMID- 26930447 TI - Study of Acidithiobacillus ferrooxidans and enzymatic bio-Fenton process-mediated corrosion of copper-nickel alloy. AB - This study presents the corrosion behavior of the copper-nickel (Cu-Ni) alloy in the presence of Acidithiobacillus ferrooxidans (A. ferrooxidans) and glucose oxidase (GOx) enzyme. In both the cases ferric ions played an important role in weight loss and thereby to carry out the corrosion of the Cu-Ni alloy. A corrosion rate of 0.6 (+/-0.008), 2.11 (+/-0.05), 3.69 (+/-0.26), 0.7 (+/-0.006) and 0.08 (+/-0.002) mm/year was obtained in 72 h using 9K medium with ferrous sulfate, A. ferrooxidans culture supernatant, A. ferrooxidans cells, GOx enzyme and hydrogen peroxide (H2O2) solution respectively. The scanning electron microscopy (SEM) micrographs showed that a variable extent of corrosion was caused by 9K medium with ferrous sulfate, GOx and A. ferrooxidans cells. An arithmetic average surface roughness (Ra) of 174.78 nm was observed for the control work-piece using optical profilometer. The change in Ra was observed with the treatment of the Cu-Ni alloy using various systems. The Ra for 9K medium with ferrous sulfate, GOx and A. ferrooxidans cells was 374.54, 607.32 and 799.48 nm, respectively, after 24 h. These results suggest that A. ferrooxidans cells were responsible for more corrosion of the Cu-Ni alloy than other systems used. PMID- 26930446 TI - DFT simulations and microkinetic modelling of 1-pentyne hydrogenation on Cu20 model catalysts. AB - Adsorption and dissociation of H2 and hydrogenation of 1-pentyne on neutral and anionic Cu20 clusters have been investigated using the density functional theory and microkinetic modelling. Molecular adsorption of H2 is found to occur strictly at atop sites. The H2 dimer is activated upon adsorption, and the dissociation occurs with moderate energy barriers. The dissociated H atoms reside preferentially on 3-fold face and 2-fold edge sites. Based on these results, the reaction paths leading to the partial and total hydrogenation of 1-pentyne have been studied step-by-step. The results suggest that copper clusters can display selective activity on the hydrogenation of alkyne and alkene molecules. The hydrogenated products are more stable than the corresponding initial reactants following an energetic staircase with the number of added H atoms. Stable semi hydrogenated intermediates are formed before the partial (1-pentene) and total (pentane) hydrogenation stages of 1-pentyne. The microkinetic model analysis shows that C5H10 is the dominant product. Increasing the reactants (C5H8/H2) ratio enhances the formation of products (C5H10 and C5H12). PMID- 26930448 TI - KLF7 Regulates Satellite Cell Quiescence in Response to Extracellular Signaling. AB - Retaining muscle stem satellite cell (SC) quiescence is important for the maintenance of stem cell population and tissue regeneration. Accumulating evidence supports the model where key extracellular signals play crucial roles in maintaining SC quiescence or activation, however, the intracellular mechanisms that mediate niche signals to control SC behavior are not fully understood. Here, we reported that KLF7 functioned as a key mediator involved in low-level TGF-beta signaling and canonical Notch signaling-induced SC quiescence and myoblast arrest. The data obtained showed that KLF7 was upregulated in quiescent SCs and nonproliferating myoblasts. Silence of KLF7 promoted SCs activation and myoblasts proliferation, but overexpression of KLF7 induced myogenic cell arrest. Notably, the expression of KLF7 was regulated by TGF-beta and Notch3 signaling. Knockdown of KLF7 diminished low-level TGF-beta and canonical Notch signaling-induced SC quiescence. Investigation into the mechanism revealed that KLF7 regulation of SC function was dependent on p21 and acetylation of Lys227 and/or 231 in the DNA binding domain of KLF7. Our study provides new insights into the regulatory network of muscle stem cell quiescence. Stem Cells 2016;34:1310-1320. PMID- 26930449 TI - Determination of optimal collimation parameters for a rotating slat collimator system: a system matrix method using ML-EM. AB - Nowadays, Single Photon imaging has become an essential part of molecular imaging and nuclear medicine. Whether to establish a diagnosis or in the therapeutic monitoring, this modality presents performance that continues to improve. For over 50 years, several collimators have been proposed. Mainly governed by collimation parameters, the resolution-sensitivity trade-off is the factor determining the collimator the most suitable for an intended study. One alternative to the common approaches is the rotating slat collimator (RSC). In the present study, we are aiming at developing a preclinical system equipped with a RSC dedicated to mice and rats imaging, which requires both high sensitivity and spatial resolution. We investigated the resolution-sensitivity trade-offs obtained by varying different collimation parameters: (i) the slats height (H), and (ii) the gap between two consecutive slats (g), considering different intrinsic spatial resolutions. One system matrix was generated for each set of collimation parameters (H,g). Spatial resolutions, Signal-to-Noise Ratio (SNR) and sensitivity obtained for all the set of collimation parameters (H,g) were measured in the 2D projections reconstructed with ML-EM. According to our results, 20 mm high slats and a 1 mm gap were chosen as a good RSC candidate for a preclinical detection module. This collimator will ensure a sensitivity greater than 0.2% and a system spatial resolution below 1 mm, considering an intrinsic spatial resolution below 0.8 mm. PMID- 26930450 TI - Is birthweight associated with total and aggressive/lethal prostate cancer risks? A systematic review and meta-analysis. AB - BACKGROUND: It has been hypothesised that intrauterine exposures are important for subsequent prostate cancer risk. Prior epidemiological studies have used birthweight as a proxy of cumulative intrauterine exposures to test this hypothesis, but results have been inconsistent partly because of limited statistical power. METHODS: We investigated birthweight in relation to prostate cancer in the Medical Research Council (MRC) National Survey of Health and Development (NSHD) using Cox proportional hazards models. We then conducted a meta-analysis of birthweight in relation to total and aggressive/lethal prostate cancer risks, combining results from the NSHD analysis with 13 additional studies on this relationship identified from a systematic search in four major scientific literature databases through January 2015. RESULTS: Random-effects models found that per kg increase in birthweight was positively associated with total (OR=1.02, 95% confidence interval (95% CI)=1.00, 1.05; I(2)=13%) and aggressive/lethal prostate cancer (OR=1.08, 95% CI=0.99, 1.19; I(2)=40%). Sensitivity analyses restricted to studies with birthweight extracted from medical records demonstrated stronger positive associations with total (OR=1.11, 95% CI=1.03, 1.19; I(2)=0%) and aggressive/lethal (OR=1.37, 95% CI=1.09, 1.74; I(2)=0%) prostate cancer. These studies heavily overlapped with those based in Nordic countries. CONCLUSIONS: This study provides evidence that heavier birthweight may be associated with modest increased risks of total and aggressive/lethal prostate cancer, which supports the hypothesis that intrauterine exposures may be related to subsequent prostate cancer risks. PMID- 26930452 TI - A fatal intoxication related to MDPV and pentedrone combined with antipsychotic and antidepressant substances in Cyprus. AB - This is a case report of a fatal intoxication in Cyprus related to 3,4 methylenedioxypyrovalerone (MDPV) and 2-(methylamino)-1-phenylpentan-1-one (pentedrone) intake combined with antipsychotic and antidepressant substances. A 42- year old man with a history of serious psychiatric illness was found unresponsive in his bed. Seized materials were also found close to his body. The forensic autopsy reported myocardial infarction due to multidrug intoxication. Toxicology screening in blood and urine was applied. Biological specimens were analysed by enzyme immunoassay procedure and GC/MS. MDPV, pentedrone and etizolam detected and quantitated in blood and urine. Other drugs quantitated in blood were also olanzapine, mirtazapine, and ephedrine. This was the first fatal case reported in Cyprus associated with new psychoactive substances. Additionally, this was the first case reported to Early Warning System of the European Monitoring Center of Drugs and Drug Abuse (EMCDDA), related to multidrug intoxication, attributed to the consumption of cathinones, designer benzodiazepines, and other drugs. PMID- 26930451 TI - Androgen receptors are acquired by healthy postmenopausal endometrial epithelium and their subsequent loss in endometrial cancer is associated with poor survival. AB - BACKGROUND: Endometrial cancer (EC) is a hormone-driven disease, and androgen receptor (AR) expression in high-grade EC (HGEC) and metastatic EC has not yet been described. METHODS: The expression pattern and prognostic value of AR in relation to oestrogen (ERalpha and ERbeta) and progesterone (PR) receptors, and the proliferation marker Ki67 in all EC subtypes (n = 85) were compared with that of healthy and hyperplastic endometrium, using immunohistochemisty and qPCR. RESULTS: Compared with proliferative endometrium, postmenopausal endometrtial epithelium showed significantly higher expression of AR (P < 0.001) and ERalpha (P = 0.035), which persisted in hyperplastic epithelium and in low-grade EC (LGEC). High-grade EC showed a significant loss of AR (P < 0.0001), PR (P < 0.0001) and ERbeta (P < 0.035) compared with LGEC, whilst maintaining weak to moderate ERalpha. Unlike PR, AR expression in metastatic lesions was significantly (P = 0.039) higher than that in primary tumours. Androgen receptor expression correlated with favourable clinicopathological features and a lower proliferation index. Loss of AR, with/without the loss of PR was associated with a significantly lower disease-free survival (P < 0.0001, P < 0.0001, respectively). CONCLUSIONS: Postmenopausal endometrial epithelium acquires AR whilst preserving other steroid hormone receptors. Loss of AR, PR with retention of ERalpha and ERbeta may promote the unrestrained growth of HGEC. Androgen receptor may therefore be a clinically relevant prognostic indicator and a potential therapeutic target in EC. PMID- 26930453 TI - Determination of medicinal and illicit drugs in post mortem dental hard tissues and comparison with analytical results for body fluids and hair samples. AB - In burnt or skeletonized bodies dental hard tissue sometimes is the only remaining specimen available. Therefore, it could be used as an alternative matrix in post mortem toxicology. Additionally, analysis of dental tissues could provide a unique retrospective window of detection. For forensic interpretation, routes and rates of incorporation of different drugs as well as physicochemical differences between tooth root, tooth crown and carious material have to be taken into account. In a pilot study, one post mortem tooth each from three drug users was analyzed for medicinal and illicit drugs. The pulp was removed in two cases; in one case the tooth was root canal treated. The teeth were separated into root, crown and carious material and drugs were extracted from the powdered material with methanol under ultrasonication. The extracts were screened for drugs by LC MS(n) (ToxTyperTM) and quantitatively analyzed with LC-ESI-MS/MS in MRM mode. The findings were compared to the analytical results for cardiac blood, femoral blood, urine, stomach content and hair. In dental hard tissues, 11 drugs (amphetamine, MDMA, morphine, codeine, norcodeine, methadone, EDDP, fentanyl, tramadol, diazepam, nordazepam, and promethazine) could be detected and concentrations ranged from approximately 0.13pg/mg to 2,400pg/mg. The concentrations declined in the following order: carious material>root>crown. Only the root canal treated tooth showed higher concentrations in the crown than in the root. In post mortem toxicology, dental hard tissue could be a useful alternative matrix facilitating a more differentiated consideration of drug consumption patterns, as the window of detection seems to overlap those for body fluids and hair. PMID- 26930454 TI - Quantum Mechanics/Molecular Mechanics Method Combined with Hybrid All-Atom and Coarse-Grained Model: Theory and Application on Redox Potential Calculations. AB - We developed a new multiresolution method that spans three levels of resolution with quantum mechanical, atomistic molecular mechanical, and coarse-grained models. The resolution-adapted all-atom and coarse-grained water model, in which an all-atom structural description of the entire system is maintained during the simulations, is combined with the ab initio quantum mechanics and molecular mechanics method. We apply this model to calculate the redox potentials of the aqueous ruthenium and iron complexes by using the fractional number of electrons approach and thermodynamic integration simulations. The redox potentials are recovered in excellent accordance with the experimental data. The speed-up of the hybrid all-atom and coarse-grained water model renders it computationally more attractive. The accuracy depends on the hybrid all-atom and coarse-grained water model used in the combined quantum mechanical and molecular mechanical method. We have used another multiresolution model, in which an atomic-level layer of water molecules around redox center is solvated in supramolecular coarse-grained waters for the redox potential calculations. Compared with the experimental data, this alternative multilayer model leads to less accurate results when used with the coarse-grained polarizable MARTINI water or big multipole water model for the coarse-grained layer. PMID- 26930455 TI - Cytogenetic evaluation of mesenchymal stem/stromal cells from patients with myelodysplastic syndromes at different time-points during ex vivo expansion. AB - Mounting evidence suggests that in myelodysplastic syndromes (MDSs) bone marrow (BM) mesenchymal stem/stromal cells (MSCs) possess abnormal characteristics and are actively involved in disease pathogenesis. Nevertheless, it is controversial whether these cells harbor clonal cytogenetic aberrations. To probe more deeply into this issue, in the present study we used conventional G-banding and FISH analysis to assess the clonal chromosomal abnormalities of hematopoietic cells (HCs) and cultured MSCs, from 29 MDS patients and 25 healthy individuals, at early, intermediate and late passage. Variable clonal cytogenetic aberrations were detected in HCs from 31% and in MSCs from 34% of MDS patients. Clonal chromosomal abnormalities in MSCs were detected even in patients without aberrations in HCs. They were mostly numerical and always differed from those in HCs from the same individual. Clonal chromosomal abnormalities did not seem to confer a proliferative and/or survival advantage to MSCs. HCs from normal donors harbored no cytogenetic abnormalities, whereas trisomy of chromosome 5 was detected in MSCs from 16% of healthy individuals, in line with other studies. Our results suggest that MDS-derived BM-MSCs are genetically unstable. The significance of this observation in the biology of MSCs and MDS pathogenesis is still unknown and warrants further evaluation. PMID- 26930457 TI - Addendum. PMID- 26930456 TI - CD38+ CD58- is an independent adverse prognostic factor in paediatric Philadelphia chromosome negative B cell acute lymphoblastic leukaemia patients. AB - To explore new risk predictors for a high risk of relapse in Philadelphia chromosome negative (Ph-) B cell acute lymphoblastic leukaemia (B-ALL) patients, 196 paediatric Ph- B-ALL patients (<= 18 years) were retrospectively analysed. We mainly focus on investigating the prognostic value of CD38 and CD58 expression in leukemic blasts in these patients by four colour flow cytometry. The CD38+ CD58- group (n=16) had a higher relapse rate, a shorter 3-year event-free survival (EFS) and overall survival (OS) than the CD38+ CD58+ group (n=157; 31.3% vs 10.2%, P=0.04; 52.4% vs 92.3%, P<0.01; 32.5% vs 91.0%, P=0.01); CD38+ CD58- was an independent adverse prognostic predictor for relapse (hazard ratio [HR], 0.203; 95%CI, 0.063-0.656; P=0.01), 3-year EFS (HR, 0.091; 95%CI, 0.023-0.355; P<0.01) and OS (HR, 0.102; 95%CI, 0.026-0.3971; P<0.01) in this cohort, as determined by Cox multivariate analysis. We identified, for the first time, a higher risk population of paediatric Ph- B-ALL patients with CD38+ CD58- who had a higher relapse risk and a shorter survival. Our results may allow better risk stratification and individualized treatment. PMID- 26930458 TI - Intraperitoneal rendezvous: a mini-invasive biliary reconstruction. PMID- 26930459 TI - Unusual cause of hemobilia. PMID- 26930460 TI - Submucosal tunneling and en bloc endoscopic resection facilitates laparoscopic transgastric removal of a large GI stromal tumor at the esophagogastric junction. PMID- 26930461 TI - Response to "Comment on 'Effects of in Utero Exposure to Arsenic during the Second Half of Gestation on Reproductive End Points and Metabolic Parameters in Female CD-1 Mice'". PMID- 26930462 TI - Screening and identification of proteins interacting with IL-24 by the yeast two hybrid screen, Co-IP, and FRET assays. AB - Interleukin-24 (IL-24) is an ideal tumor-suppressor gene, but the mechanisms underlying its antitumor specificity remain to be elucidated. The best way to investigate these problems is to begin from the initiation of corresponding signaling cascades activated by IL-24 with screening and identifying those proteins that interacted with IL-24. With the aim of identifying these initial interactions, a yeast two-hybrid screening was performed by transforming AH109 cells containing PGBKT7-IL-24 with a liver cDNA plasmid library. These cells were then plated on synthetic nutrient medium (SD/-Trp/-Leu/-His) for the first screening and on quadruple dropout medium containing X-alpha-gal for the second screening. Positive colonies were further verified by repeating the MATE experiments, co-immunoprecipitation (Co-IP) analysis, and fluorescence resonance energy transfer (FRET) assays in vitro. Following the yeast two-hybrid screening, 15 genes were selected for sequencing, with two genes, HLA-C and NDUFA13, further verified using Co-IP assays and FRET assays. Both HLA-C and NDUFA13 were found to interact with IL-24. We found that HLA-C and NDUFA13 could interact with IL-24 and it may be involved in the signal induced by IL-24. Overall, this study contributes further insight into the cancer-specific apoptosis-inducing abilities of IL-24 to potentially enhance its therapeutic potential, and it also provides outlets for other biological functions of IL-24. PMID- 26930463 TI - Intraoperative frozen section analysis for the diagnosis of early stage ovarian cancer in suspicious pelvic masses. AB - BACKGROUND: Women with suspected early-stage ovarian cancer need surgical staging which involves taking samples from areas within the abdominal cavity and retroperitoneal lymph nodes in order to inform further treatment. One potential strategy is to surgically stage all women with suspicious ovarian masses, without any histological information during surgery. This avoids incomplete staging, but puts more women at risk of potential surgical over-treatment.A second strategy is to perform a two-stage procedure to remove the pelvic mass and subject it to paraffin sectioning, which involves formal tissue fixing with formalin and paraffin embedding, prior to ultrathin sectioning and multiple site sampling of the tumour. Surgeons may then base further surgical staging on this histology, reducing the rate of over-treatment, but conferring additional surgical and anaesthetic morbidity.A third strategy is to perform a rapid histological analysis on the ovarian mass during surgery, known as 'frozen section'. Tissues are snap frozen to allow fine tissue sections to be cut and basic histochemical staining to be performed. Surgeons can perform or avoid the full surgical staging procedure depending on the results. However, this is a relatively crude test compared to paraffin sections, which take many hours to perform. With frozen section there is therefore a risk of misdiagnosing malignancy and understaging women subsequently found to have a presumed early-stage malignancy (false negative), or overstaging women without a malignancy (false positive). Therefore it is important to evaluate the accuracy and usefulness of adding frozen section to the clinical decision-making process. OBJECTIVES: To assess the diagnostic test accuracy of frozen section (index test) to diagnose histopathological ovarian cancer in women with suspicious pelvic masses as verified by paraffin section (reference standard). SEARCH METHODS: We searched MEDLINE (January 1946 to January 2015), EMBASE (January 1980 to January 2015) and relevant Cochrane registers. SELECTION CRITERIA: Studies that used frozen section for intraoperative diagnosis of ovarian masses suspicious of malignancy, provided there was sufficient data to construct 2 x 2 tables. We excluded articles without an available English translation. DATA COLLECTION AND ANALYSIS: Authors independently assessed the methodological quality of included studies using the Quality Assessment of Diagnostic Accuracy Studies tool (QUADAS-2) domains: patient selection, index test, reference standard, flow and timing. Data extraction converted 3 x 3 tables of per patient results presented in articles into 2 x 2 tables, for two index test thresholds. MAIN RESULTS: All studies were retrospective, and the majority reported consecutive sampling of cases. Sensitivity and specificity results were available from 38 studies involving 11,181 participants (3200 with invasive cancer, 1055 with borderline tumours and 6926 with benign tumours, determined by paraffin section as the reference standard). The median prevalence of malignancy was 29% (interquartile range (IQR) 23% to 36%, range 11% to 63%). We assessed test performance using two thresholds for the frozen section test. Firstly, we used a test threshold for frozen sections, defining positive test results as invasive cancer and negative test results as borderline and benign tumours. The average sensitivity was 90.0% (95% confidence interval (CI) 87.6% to 92.0%; with most studies typically reporting range of 71% to 100%), and average specificity was 99.5% (95% CI 99.2% to 99.7%; range 96% to 100%).Similarly, we analysed sensitivity and specificity using a second threshold for frozen section, where both invasive cancer and borderline tumours were considered test positive and benign cases were classified as negative. Average sensitivity was 96.5% (95% CI 95.5% to 97.3%; typical range 83% to 100%), and average specificity was 89.5% (95% CI 86.6% to 91.9%; typical range 58% to 99%).Results were available from the same 38 studies, including the subset of 3953 participants with a frozen section result of either borderline or invasive cancer, based on final diagnosis of malignancy. Studies with small numbers of disease-negative cases (borderline cases) had more variation in estimates of specificity. Average sensitivity was 94.0% (95% CI 92.0% to 95.5%; range 73% to 100%), and average specificity was 95.8% (95% CI 92.4% to 97.8%; typical range 81% to 100%).Our additional analyses showed that, if the frozen section showed a benign or invasive cancer, the final diagnosis would remain the same in, on average, 94% and 99% of cases, respectively.In cases where the frozen section diagnosis was a borderline tumour, on average 21% of the final diagnoses would turn out to be invasive cancer.In three studies, the same pathologist interpreted the index and reference standard tests, potentially causing bias. No studies reported blinding pathologists to index test results when reporting paraffin sections.In heterogeneity analyses, there were no statistically significant differences between studies with pathologists of different levels of expertise. AUTHORS' CONCLUSIONS: In a hypothetical population of 1000 patients (290 with cancer and 80 with a borderline tumour), if a frozen section positive test result for invasive cancer alone was used to diagnose cancer, on average 261 women would have a correct diagnosis of a cancer, and 706 women would be correctly diagnosed without a cancer. However, 4 women would be incorrectly diagnosed with a cancer (false positive), and 29 with a cancer would be missed (false negative).If a frozen section result of either an invasive cancer or a borderline tumour was used as a positive test to diagnose cancer, on average 280 women would be correctly diagnosed with a cancer and 635 would be correctly diagnosed without. However, 75 women would be incorrectly diagnosed with a cancer and 10 women with a cancer would be missed.The largest discordance is within the reporting of frozen section borderline tumours. Investigation into factors leading to discordance within centres and standardisation of criteria for reporting borderline tumours may help improve accuracy. Some centres may choose to perform surgical staging in women with frozen section diagnosis of a borderline ovarian tumour to reduce the number of false positives. In their interpretation of this review, readers should evaluate results from studies most typical of their population of patients. PMID- 26930464 TI - Professional identity acquisition process model in interprofessional education using structural equation modelling: 10-year initiative survey. AB - The mandatory interprofessional education (IPE) programme at Gunma University, Japan, was initiated in 1999. A questionnaire of 10 items to assess the students' understanding of the IPE training programme has been distributed since then, and the factor analysis of the responses revealed that it was categorised into four subscales, i.e. "professional identity", "structure and function of training facilities", "teamwork and collaboration", and "role and responsibilities", and suggested that these may take into account the development of IPE programme with clinical training. The purpose of this study was to examine the professional identity acquisition process (PIAP) model in IPE using structural equation modelling (SEM). Overall, 1,581 respondents of a possible 1,809 students from the departments of nursing, laboratory sciences, physical therapy, and occupational therapy completed the questionnaire. The SEM technique was utilised to construct a PIAP model on the relationships among four factors. The original PIAP model showed that "professional identity" was predicted by two factors, namely "role and responsibilities" and "teamwork and collaboration". These two factors were predicted by the factor "structure and function of training facilities". The same structure was observed in nursing and physical therapy students' PIAP models, but it was not completely the same in laboratory sciences and occupational therapy students' PIAP models. A parallel but not isolated curriculum on expertise unique to the profession, which may help to understand their professional identity in combination with learning the collaboration, may be necessary. PMID- 26930465 TI - Isomer-Specific Chemistry in the Propyne and Allene Reactions with Oxygen Atoms: CH3CH + CO versus CH2CH2 + CO Products. AB - We report direct experimental and theoretical evidence that, under single collision conditions, the dominant product channels of the O((3)P) + propyne and O((3)P) + allene isomeric reactions lead in both cases to CO formation, but the coproducts are singlet ethylidene ((1)CH3CH) and singlet ethylene (CH2CH2), respectively. These data, which settle a long-standing issue on whether ethylidene is actually formed in the O((3)P) + propyne reaction, suggest that formation of CO + alkylidene biradicals may be a common mechanism in O((3)P) + alkyne reactions, in contrast to formation of CO + alkene molecular products in the corresponding isomeric O((3)P) + diene reactions, either in combustion or other gaseous environments. These findings are of fundamental relevance and may have implications for improved combustion models. Moreover, we predict that the so far neglected (1)CH3CH + CO channel is among the main reaction routes also when the C3H4O singlet potential energy surface is accessed from the OH + C3H3 (propargyl) entrance channel, which are radical species playing a key role in many combustion systems. PMID- 26930466 TI - Membrane Blebbing Is Required for Mesenchymal Precursor Migration. AB - Mesenchymal precursors (MPs) present some advantageous features, such as differentiation and migration, which make them promising candidates for cell therapy. A better understanding of MP migration characteristics would aid the development of cell delivery protocols. Traditionally, cell migration is thought to occur only through the formation of lamellipodia. More recently, contractility driven bleb formation has emerged as an alternative mechanism of motility. Here we report that MPs derived from different tissues present spontaneously dynamic cytoplasmic projections in sub-confluent culture, which appear as a combination of lamellipodia with blebs in the leading edge. Upon initial seeding, however, only bleb structures could be observed. Immunofluorescence revealed the presence of pERM, RhoA and F-actin during the blebbing process. Results from migration assays in the presence of blebbistatin, a myosin II inhibitor, showed that bleb formation correlated with migratory capacity, suggesting a functional role for blebs in migration. Bleb formation might be a useful mechanism to improve cell migration in cellular therapy protocols. PMID- 26930467 TI - Determinants of Desire for Children among HIV-Positive Women in the Afar Region, Ethiopia: Case Control Study. AB - INTRODUCTION: The desire for a child in Ethiopian society is normal. Among HIV positive women, due to the risk of MTCT, it is imperative to understand factors influencing women's desire for children. This study aimed at assessing factors associated with desire for children among HIV-positive women in two selected hospitals of Afar Regional State, Ethiopia. METHODS: A facility based case control study was conducted among 157 cases (with a desire) and 157 controls of HIV positive individuals registered in the selected health facilities. The participants were selected by random sampling technique. Data were collected using face-to-face interview and was analyzed using logistic regression. RESULT: Factors found to be independently associated with desire for children were age categories of 20-24 years (OR = 6.22, 1.29-10.87) and 25-29 years (OR = 14.6, 3.05-21.60), being married (OR = 5.51, 2.19-13.54), Afar ethnicity (OR 6.93, 1.19 12.14), having HIV-positive children (OR 0.23, 0.09-0.63), duration on ART more than one year (3.51, 1.68-9.05), CD4 count greater than 350 (OR 4.83, 1.51-7.27) and discussion of reproductive health issues with health providers (OR 0.31, 0.12 0.51). CONCLUSION: Women who were young, married, Afar, those who received ART more than one year, and had CD4 count >350 were more likely to have a desire for children. RECOMMENDATION: Health care workers at ART clinic should openly discuss about the reproductive options for the women living with HIV/AIDS. PMID- 26930468 TI - Correction: Anatomical Variations in the Sinoatrial Nodal Artery: A Meta-Analysis and Clinical Considerations. PMID- 26930469 TI - Selective disruption of disulphide bonds lowered activation energy and improved catalytic efficiency in TALipB from Trichosporon asahii MSR54: MD simulations revealed flexible lid and extended substrate binding area in the mutant. AB - TALipB (33 kDa) is a solvent stable, enantioselective lipase from Trichosporon asahii MSR54. It is cysteine-rich and shows activation in presence of thiol reducing agents. DIANNA server predicted three disulphide bridges C53-C195 (S1), C89-C228 (S2) and C164-C254 (S3) in the enzyme. Selective disruption of disulphide bonds by cysteine to alanine mutations at Cys53 and Cys89 of S1 and S2 bonds resulted in enzyme activation. Mutant mTALipB (S1+S2) showed increase in specific activity by ~4-fold (834 mM/mg) and improved Vmax of 6.27 MUmol/ml/min at 40 degrees Con pNP caprate. Temperature optima of mTALipB shifted from 50 to 40 degrees C and activation energy decreased by 0.7 kcal mol(-1). However, the mutant was less thermostable with a t1/2 of 18 min at 60 degrees C as compared to t1/2 of 38 min for the native enzyme. Mutant also displayed an improved activity on all pNP esters and higher enantiomeric excess (61%) during esterification of (+/-) 1-phenylethanol. Far-UV CD analysis showed significant changes in secondary structure after S-S bridge disruption with 7.16% decrease in alpha-helices and 1.31% increase in beta-sheets. In silico analysis predicted two lids (alpha5 and alpha9) in TALipB. Molecular dynamic simulations at 40 degrees C and 50 degrees C revealed that in the mTALipB, both the lids opened at 40 degrees C with clockwise and anticlockwise rotations in Lid1 and Lid2, respectively. In the native protein, however, the lid was only partially open even at 50 degrees C. Concomitant to lid flexibility, there was an extension of accessible catalytic triad surface area resulting in improved catalytic efficiency of the mutant enzyme. PMID- 26930471 TI - Gender Role Violations and the Sexual Double Standard. AB - The sexual double standard (SDS) suggests that women are evaluated negatively and men positively for engaging in similar sexual behaviors. According to social role theory, the SDS exists due to gender role structures. Consequently, perceived violations of women's sexual behavior are associated with the SDS. In addition to gender role violations of sexual behavior, two additional violations of gender roles exist: heterosexual sexual orientation norms and gender role characteristics. The current study aims to investigate whether the SDS persists for sexual orientation-violating and gender role characteristic-violating targets, and to examine which of the three gender role violations influence evaluations of others' sexual behavior. A U.S. sample of 483 participants evaluated target individuals who were either female or male, heterosexual/gay man or lesbian, feminine or masculine, and had 1 or 12 sexual partners. Results indicate that SDS persists for gender role-violating targets but is exhibited differently for targets violating heterosexual sexual orientation norms and gender role characteristics. PMID- 26930470 TI - Genome editing in pluripotent stem cells: research and therapeutic applications. AB - Recent progress in human pluripotent stem cell (hPSC) and genome editing technologies has opened up new avenues for the investigation of human biology in health and disease as well as the development of therapeutic applications. Gene editing approaches with programmable nucleases have been successfully established in hPSCs and applied to study gene function, develop novel animal models and perform genetic and chemical screens. Several studies now show the successful editing of disease-linked alleles in somatic and patient-derived induced pluripotent stem cells (iPSCs) as well as in animal models. Importantly, initial clinical trials have shown the safety of programmable nucleases for ex vivo somatic gene therapy. In this context, the unlimited proliferation potential and the pluripotent properties of iPSCs may offer advantages for gene targeting approaches. However, many technical and safety issues still need to be addressed before genome-edited iPSCs are translated into the clinical setting. Here, we provide an overview of the available genome editing systems and discuss opportunities and perspectives for their application in basic research and clinical practice, with a particular focus on hPSC based research and gene therapy approaches. Finally, we discuss recent research on human germline genome editing and its social and ethical implications. PMID- 26930472 TI - Dermal absorption and skin damage following hydrofluoric acid exposure in an ex vivo human skin model. AB - The wide industrial use of hydrofluoric acid (HF) poses a high risk for accidental dermal exposure. Despite local and systemic hazards associated with HF, information on percutaneous penetration and tissue damage is rare. In the present ex vivo study, the dermal absorption of HF (detected in terms of fluoride ions) was quantified and the skin damaging potential as a function of concentration and exposure duration was assessed. Percutaneous penetration of HF (c=5, 30, and 50%) at 3 exposure durations (3, 5, and 10 min) was investigated in a static diffusion cell model using freshly excised human skin. Alterations of skin were histologically evaluated. HF rapidly penetrated through skin under formation of a considerable intradermal reservoir (~ 13-67% of total absorbed fluoride). Histologically, epidermal alterations were detected already after exposure to 5% HF for 3 min. The degree of skin damage increased with rising concentration and exposure duration leading to coagulation necrosis. For HF concentrations of >= 30%, skin damage progressed into deeper skin layers. Topically applied HF concentration was the principal parameter determining HF induced skin effects. The intradermal HF retention capacity associated with progression and prolongation of HF induced skin effects must be considered in the review of skin decontamination procedures. PMID- 26930474 TI - Hyperocclusion stimulates the expression of collagen type XII in periodontal ligament. AB - OBJECTIVES: It is known that excessive mechanical force exerted by hyperocclusion induces occlusal trauma. However, the mechanism of the process remains unclear. In the present study, we employed an in vivo hyperocclusion rodent model to examine morphological and biological mechanisms of occlusal trauma in periodontal ligament tissue. DESIGN: To investigate alveolar bone resorption, tooth sections were stained to detect osteoclasts. To investigate the relationship between hyperocclusion and the regeneration of the cell matrix, we examined the effect of hyperocclusal force on the expression of collagens using immunohistochemistry and quantitative PCR methods. RESULTS: The arrangement of collagen fibers in the furcation area of the teeth was undisturbed before hyperocclusion (control). Type I collagen was localized in the extracellular area at the furcation and there was faint expression and localization of type XII collagen in the periodontal ligament. The number of osteoclasts significantly increased in the furcation and lingual cervical regions on day 4 after hyperocclusion was induced. Type XII collagens were gradually up-regulated following the induction of hyperocclusion, in a time-dependent manner. Although type I collagen mRNA expression was stable before and after hyperocclusion, type XII collagen mRNA was significantly up regulated on day 2 and day 4 after hyperocclusion treatment. CONCLUSIONS: Our findings indicate that hyperocclusal force predominantly up-regulates the expression of type XII collagen in periodontal tissue, but not type I collagen, suggesting that there is a mechanism for regeneration of periodontal tissues as a response to occlusal trauma. PMID- 26930473 TI - Expression of the ZNT1 Zinc Transporter from the Metal Hyperaccumulator Noccaea caerulescens Confers Enhanced Zinc and Cadmium Tolerance and Accumulation to Arabidopsis thaliana. AB - Prompt regulation of transition metal transporters is crucial for plant zinc homeostasis. NcZNT1 is one of such transporters, found in the metal hyperaccumulator Brassicaceae species Noccaea caerulescens. It is orthologous to AtZIP4 from Arabidopsis thaliana, an important actor in Zn homeostasis. We examined if the NcZNT1 function contributes to the metal hyperaccumulation of N. caerulescens. NcZNT1 was found to be a plasma-membrane located metal transporter. Constitutive overexpression of NcZNT1 in A. thaliana conferred enhanced tolerance to exposure to excess Zn and Cd supply, as well as increased accumulation of Zn and Cd and induction of the Fe deficiency response, when compared to non transformed wild-type plants. Promoters of both genes were induced by Zn deficiency in roots and shoots of A. thaliana. In A. thaliana, the AtZIP4 and NcZNT1 promoters were mainly active in cortex, endodermis and pericycle cells under Zn deficient conditions. In N. caerulescens, the promoters were active in the same tissues, though the activity of the NcZNT1 promoter was higher and not limited to Zn deficient conditions. Common cis elements were identified in both promoters by 5' deletion analysis. These correspond to the previously determined Zinc Deficiency Responsive Elements found in A. thaliana to interact with two redundantly acting transcription factors, bZIP19 and bZIP23, controlling the Zn deficiency response. In conclusion, these results suggest that NcZNT1 is an important factor in contributing to Zn and Cd hyperaccumulation in N. caerulescens. Differences in cis- and trans-regulators are likely to account for the differences in expression between A. thaliana and N. caerulescens. The high, constitutive NcZNT1 expression in the stele of N. caerulescens roots implicates its involvement in long distance root-to-shoot metal transport by maintaining a Zn/Cd influx into cells responsible for xylem loading. PMID- 26930475 TI - Critical Difference and Biological Variation in Biomarkers of Oxidative Stress and Nutritional Status in Athletes. AB - The longitudinal monitoring of oxidative stress (OS) in athletes may enable the identification of fatigued states and underperformance. The application of OS biomarker monitoring programs in sport are hindered by reliability and repeatability of in-the-field testing tools, the turnaround of results, and the understanding of biological variation (BV). Knowledge of BV and critical difference values (CDV) may assist with data interpretation in the individual athlete. METHODS: We aimed firstly to assess the repeatability of the clinical point of care redox test, Free Oxygen Radical Test (FORT) and the Free Oxygen Radical Defence (FORD) in trained participants and elite athletes and secondly to calculate the analytical, BV, CDV and index of individuality (II) for FORT, FORD, red blood cell glutathione, lutein, alpha and gamma-tocopherol. Part 1: Fifteen elite athletes were sampled in duplicate for calculation of the repeatability of the FORT and FORD tests. Part 2: Twelve well-trained athletes had venous samples drawn every 2 hours from 0800 to 1800 for calculation of BV, CDV, II for FORT, FORD, RBC GSH, lutein, alpha-tocopherol and gamma-tocopherol. RESULTS: Repeatability of the FORT and FORD assay was 3.9% and 3.7% respectively. Biomarker CDV ranged from 12.8% to 37%, with a circadian effect for FORT, alpha tocopherol and gamma-tocopherol (p<0.01), with all biomarker indices of individuality < 0.8 arbitrary units. CONCLUSION: We report that the use of the novel redox test in athletes is practical, and the generation of BV and CDV for biomarkers of OS enhances the interpretation of physiologically meaningful changes in individuals above the use of clinical reference ranges alone. PMID- 26930477 TI - The Kanizsa triangle illusion in foraging ants. AB - The Kanizsa triangle, wherein three Pac-Man configurations symmetrically face inwards, is a well-known illusion. By exposing foraging ants (Lasius niger) to Kanizsa-shaped honeydew solutions, we studied the origin of this illusion. More specifically, we examined whether foraging ants showed different movement reactions to local honeydew patterns formed by nestmates. This novel phenomenon could serve as an abstract model of the Kanizsa triangle illusion under the assumption that such an illusion could arise through the sum of each agent's limited global cognitions, because each agent could not perceive the entire subjective contours. Even a subjective consciousness consists of some parts which have no identical perception and could be an illusion. We succeeded in inducing foragers to move along the sides of a Kanizsa triangle when Pac-Man-shaped inducers were introduced. Furthermore, foragers appeared to form Y-shaped trajectories when dot-shaped or inverse Kanizsa inducers were used. Based on our findings, we propose an agent-based ant model that compares modelled behaviour with experimental phenomena. Our abstract model could be used to explain such cognitive phenomena for bottom-up processes, because ants cannot perceive the given subjective contours, instead simply move along the edges. PMID- 26930476 TI - Genetic depletion of glutathione peroxidase-1 potentiates nephrotoxicity induced by multiple doses of cocaine via activation of angiotensin II AT1 receptor. AB - We investigated the possible roles of angiotensin II type 1 receptor (AT1R) and oxidative stress responsive nuclear factor kappaB (NFkappaB) in renal damage caused by multiple doses of cocaine in glutathione peroxidase (GPx)-1 gene depleted mice. Treatment with cocaine resulted in significant increases in malondialdehyde, protein carbonyl, and pro-apoptotic Bax expression and decreases in the ratio of glutathione (GSH) and its oxidized form (GSSG), GSH-dependent enzymes, and anti-apoptotic factors in the kidney. These alterations were more pronounced in GPx-1 knockout (-/-) mice than in wild type (WT) mice. Notably, the AT1R antagonist losartan protected against the renal toxicity induced by cocaine, whereas the NFkappaB inhibitor pyrrolidine dithiocarbamate was not protective. The toxicity was more pronounced in GPx-1 (-/-) mice than in WT mice. The protective effect afforded by losartan against cocaine toxicity appeared to be more sensitive in GPx-1 (-/-) mice than that in WT mice. These losartan-mediated protective effects were inhibited by the phosphatidyl-inositol-3-kinase (PI3K) inhibitor LY294002, indicating that losartan provides significant protection from cocaine-induced renal toxicity through PI3K/Akt signaling. Our results suggest that genetic inhibition of GPx-1 potentiates cocaine-induced renal damage via activation of AT1R by inhibition of PI3K-Akt signaling, and that AT1R can be a therapeutic target against renal toxicity induced by cocaine. PMID- 26930478 TI - Subject-specific geometrical detail rather than cost function formulation affects hip loading calculation. AB - This study assessed the relative importance of introducing an increasing level of medical image-based subject-specific detail in bone and muscle geometry in the musculoskeletal model, on calculated hip contact forces during gait. These forces were compared to introducing minimization of hip contact forces in the optimization criterion. With an increasing level of subject-specific detail, specifically MRI-based geometry and wrapping surfaces representing the hip capsule, hip contact forces decreased and were more comparable to contact forces measured using instrumented prostheses (average difference of 0.69 BW at the first peak compared to 1.04 BW for the generic model). Inclusion of subject specific wrapping surfaces in the model had a greater effect than altering the cost function definition. PMID- 26930479 TI - Genetic and biochemical effects induced by iron ore, Fe and Mn exposure in tadpoles of the bullfrog Lithobates catesbeianus. AB - For decades, the extraction of minerals has intensified in order to meet the demand of industry. Iron ore deposits are important sources of metals, such as iron (Fe) and manganese (Mn). The particulate ores can be dispersed during extraction, transport and storage, with potential to induce biological impacts. Amphibians are very sensitive to environmental stressors. Therefore, the present study aimed to assess the effects of iron ore, Fe and Mn exposure during the metamorphosis of Lithobates catesbeianus. Endpoints analyzed included morphological (biometrical and developmental analyses), whole body Fe and Mn concentration in, plasma ferritin concentration, erythrocyte DNA damage (measured through comet assay and micronucleus test) and liver activity of enzymes involved in oxidative status [glutathione S-transferase (GST) and catalase (CAT)]. Tadpoles were kept under control condition (no contaminant addition) or exposed to iron ore (3.79mg/L as fine particulate matter); Fe (nominal concentration: 0.51mg/L Fe as C10H12FeN2NaO8; Fe-EDTA); and Mn (nominal concentration: 5.23mg/L Mn as 4H2O.MnCl2) for 30 days. Virtually, no mortality was observed, except for one tadpole found dead in the iron ore treatment. However, tadpoles exposed to iron ore had longer tail than those kept under control conditions while tadpoles exposed to manganese chloride showed higher body length than control ones. Exposure to Fe and Mn induced a delay in tadpole metamorphosis, especially when these metals are presented not as a mixture (iron ore). Tadpoles exposed to iron ore had increased whole body Fe and Mn while those exposed to Fe and Mn accumulated each metal individually. Tadpoles exposed to any of the contaminants tested showed a significant increase in erythrocyte DNA damage and frequency of micronuclei. In addition, they showed higher liver GST activity respect with those kept under control conditions. Plasma ferritin concentration and liver CAT activity were higher only in tadpoles exposed to iron ore. These findings indicated that tadpoles accumulated Fe and Mn at the whole body level after exposure to the single metals or to their mixture as iron ore. In addition, they indicate that Fe and Mn accumulation can induce oxidative stress with consequent significant developmental, genotoxic and biochemical effects in L. catesbeianus tadpoles. PMID- 26930480 TI - Activity of binary mixtures of drospirenone with progesterone and 17alpha ethinylestradiol in vitro and in vivo. AB - Despite potential exposure of aquatic organisms to mixtures of steroid hormones, very little is known on their joint activity in fish. Drospirenone (DRS) is a new synthetic progestin used in contraceptive pills in combination with 17alpha ethinylestradiol (EE2). Here we systematically analyzed effects of DRS in binary mixtures with progesterone (P4) and EE2. First, we determined the in vitro activity of single compounds in recombinant yeast assays that express the human progesterone, androgen, or estrogen receptor, followed by determination of mixture activities of DRS and P4, DRS and EE2, as well as medroxyprogesterone acetate (MPA) and dydrogesterone (DDG). Mixtures of DRS and P4, as well as of DRS and EE2 showed additive progestogenic and androgenic activities. However, DDG and MPA showed non-additive progestogenic and androgenic activities. We then analyzed the in vivo activity of single compounds and mixtures of DRS and P4, as well as DRS and EE2, by assessing transcriptional changes of up to 14 selected target genes in zebrafish embryos at 48h post fertilization (hpf), and in eleuthero embryos at 96hpf and 144hpf. DRS, P4, and EE2 led to significant transcriptional alteration of genes, including those encoding hormone receptors (pgr, esr1), a steroidogenic enzyme (hsd17b3), and estrogenic markers (vtg1, cyp19b), in particular at 144 hpf. In general, DRS showed stronger transcriptional changes than P4. In mixtures of DRS and P4, they were mainly non-additive (antagonistic interaction). In mixtures of DRS and EE2, transcriptional responses of esr1, vtg1 and cyp19b were dominated by EE2, suggesting an antagonistic interaction or independent action. Equi-effective mixtures of DRS and EE2, based on progesterone receptor transcripts, showed antagonistic interactions. Our data suggest that interactions in mixtures assessed in vitro in recombinant yeast cannot be translated to the in vivo situation. The receptor-based responses did not correspond well to the transcriptional responses in embryos which are much more complex due to the interplay between hormonal pathways, receptor crosstalk, and hormonal feedback loops. PMID- 26930481 TI - The RecA-Dependent SOS Response Is Active and Required for Processing of DNA Damage during Bacillus subtilis Sporulation. AB - The expression of and role played by RecA in protecting sporulating cells of Bacillus subtilis from DNA damage has been determined. Results showed that the DNA-alkylating agent Mitomycin-C (M-C) activated expression of a PrecA-gfpmut3a fusion in both sporulating cells' mother cell and forespore compartments. The expression levels of a recA-lacZ fusion were significantly lower in sporulating than in growing cells. However, M-C induced levels of beta-galactosidase from a recA-lacZ fusion ~6- and 3-fold in the mother cell and forespore compartments of B. subtilis sporangia, respectively. Disruption of recA slowed sporulation and sensitized sporulating cells to M-C and UV-C radiation, and the M-C and UV-C sensitivity of sporangia lacking the transcriptional repair-coupling factor Mfd was significantly increased by loss of RecA. We postulate that when DNA damage is encountered during sporulation, RecA activates the SOS response thus providing sporangia with the repair machinery to process DNA lesions that may compromise the spatio-temporal expression of genes that are essential for efficient spore formation. PMID- 26930482 TI - The Relationships between Polymorphisms in Genes Encoding the Growth Factors TGF beta1, PDGFB, EGF, bFGF and VEGF-A and the Restenosis Process in Patients with Stable Coronary Artery Disease Treated with Bare Metal Stent. AB - BACKGROUND: Neointima forming after stent implantation consists of vascular smooth muscle cells (VSMCs) in 90%. Growth factors TGF-beta1, PDGFB, EGF, bFGF and VEGF-A play an important role in VSMC proliferation and migration to the tunica intima after arterial wall injury. The aim of this paper was an analysis of functional polymorphisms in genes encoding TGF-beta1, PDGFB, EGF, bFGF and VEGF-A in relation to in-stent restenosis (ISR). MATERIALS AND METHODS: 265 patients with a stable coronary artery disease (SCAD) hospitalized in our center in the years 2007-2011 were included in the study. All patients underwent stent implantation at admission to the hospital and had another coronary angiography performed due to recurrence of the ailments or a positive result of the test assessing the coronary flow reserve. Angiographically significant ISR was defined as stenosis >50% in the stented coronary artery segment. The patients were divided into two groups-with angiographically significant ISR (n = 53) and without significant ISR (n = 212). Additionally, the assessment of late lumen loss (LLL) in vessel was performed. EGF rs4444903 polymorphism was genotyped using the PCR-RFLP method whilst rs1800470 (TGFB1), rs2285094 (PDGFB) rs308395 (bFGF) and rs699947 (VEGF-A) were determined using the TaqMan method. RESULTS: Angiographically significant ISR was significantly less frequently observed in the group of patients with the A/A genotype of rs1800470 polymorphism (TGFB1) versus patients with A/G and G/G genotypes. In the multivariable analysis, LLL was significantly lower in patients with the A/A genotype of rs1800470 (TGFB1) versus those with the A/G and G/G genotypes and higher in patients with the A/A genotype of the VEGF-A polymorphism versus the A/C and C/C genotypes. The C/C genotype of rs2285094 (PDGFB) was associated with greater LLL compared to C/T heterozygotes and T/T homozygotes. CONCLUSIONS: The polymorphisms rs1800470, rs2285094 and rs6999447 of the TGFB1, PDGFB and VEGF-A genes, respectively, are associated with LLL in patients with SCAD treated by PCI with a metal stent implantation. PMID- 26930484 TI - Using Next-Generation Sequencing to Contrast the Diet and Explore Pest-Reduction Services of Sympatric Bird Species in Macadamia Orchards in Australia. AB - Worldwide, avian communities inhabiting agro-ecosystems are threatened as a consequence of agricultural intensification. Unravelling their ecological role is essential to focus conservation efforts. Dietary analysis can elucidate bird insect interactions and expose avian pest-reduction services, thus supporting avian conservation. In this study, we used next-generation sequencing to analyse the dietary arthropod contents of 11 sympatric bird species foraging in macadamia orchards in eastern Australia. Across all species and based on arthropod DNA sequence similarities >=98% with records in the Barcode of Life Database, 257 operational taxonomy units were assigned to 8 orders, 40 families, 90 genera and 89 species. These taxa included 15 insect pests, 5 of which were macadamia pests. Among the latter group, Nezara viridula (Pentatomidae; green vegetable bug), considered a major pest, was present in 23% of all faecal samples collected. Results also showed that resource partitioning in this system is low, as most bird species shared large proportion of their diets by feeding primarily on lepidopteran, dipteran and arachnids. Dietary composition differed between some species, most likely because of differences in foraging behaviour. Overall, this study reached a level of taxonomic resolution never achieved before in the studied species, thus contributing to a significant improvement in the avian ecological knowledge. Our results showed that bird communities prey upon economically important pests in macadamia orchards. This study set a precedent by exploring avian pest-reduction services using next-generation sequencing, which could contribute to the conservation of avian communities and their natural habitats in agricultural systems. PMID- 26930483 TI - A Naturally-Derived Compound Schisandrin B Enhanced Light Sensation in the pde6c Zebrafish Model of Retinal Degeneration. AB - Retinal degeneration is often progressive. This feature has provided a therapeutic window for intervention that may extend functional vision in patients. Even though this approach is feasible, few promising drug candidates are available. The scarcity of new drugs has motivated research to discover novel compounds through different sources. One such example is Schisandrin B (SchB), an active component isolated from the five-flavor fruit (Fructus Schisandrae) that is postulated in traditional Chinese medicines to exert prophylactic visual benefit. This SchB benefit was investigated in this study in pde6cw59, a zebrafish retinal-degeneration model. In this model, the pde6c gene (phosphodiesterase 6C, cGMP-specific, cone, alpha prime) carried a mutation which caused cone degeneration. This altered the local environment and caused the bystander rods to degenerate too. To test SchB on the pde6cw59 mutants, a treatment concentration was first determined that would not cause morphological defects, and would initiate known physiological response. Then, the mutants were treated with the optimized SchB concentration before the appearance of retinal degeneration at 3 days postfertilization (dpf). The light sensation of animals was evaluated at 6 dpf by the visual motor response (VMR), a visual startle that could be initiated by drastic light onset and offset. The results show that the VMR of pde6cw59 mutants towards light onset was enhanced by the SchB treatment, and that the initial phase of the enhancement was primarily mediated through the mutants' eyes. Further immunostaining analysis indicates that the treatment specifically reduced the size of the abnormally large rods. These observations implicate an interesting hypothesis: that the morphologically-improved rods drive the observed VMR enhancement. Together, these investigations have identified a possible visual benefit of SchB on retinal degeneration, a benefit that can potentially be further developed to extend functional vision in patients. PMID- 26930485 TI - Differential Modulation of GABAA Receptors Underlies Postsynaptic Depolarization- and Purinoceptor-Mediated Enhancement of Cerebellar Inhibitory Transmission: A Non-Stationary Fluctuation Analysis Study. AB - Cerebellar GABAergic inhibitory transmission between interneurons and Purkinje cells (PCs) undergoes a long-lasting enhancement following different stimulations, such as brief depolarization or activation of purinergic receptors of postsynaptic PCs. The underlying mechanisms, however, are not completely understood. Using a peak-scaled non-stationary fluctuation analysis, we therefore aimed at characterizing changes in the electrophysiological properties of GABAA receptors in PCs of rat cerebellar cortex during depolarization-induced "rebound potentiation (RP)" and purinoceptor-mediated long-term potentiation (PM-LTP), because both RP and PM-LTP likely depend on postsynaptic mechanisms. Stimulation evoked inhibitory postsynaptic currents (eIPSCs) were recorded from PCs in neonatal rat cerebellar slices. Our analysis showed that postsynaptic membrane depolarization induced RP of eIPSCs in association with significant increase in the number of synaptic GABAA receptors without changing the channel conductance. By contrast, bath application of ATP induced PM-LTP of eIPSCs with a significant increase of the channel conductance of GABAA receptors without affecting the receptor number. Pretreatment with protein kinase A (PKA) inhibitors, H-89 and cAMPS-Rp, completely abolished the PM-LTP. The CaMKII inhibitor KN-62 reported to abolish RP did not alter PM-LTP. These results suggest that the signaling mechanism underlying PM-LTP could involve ATP-induced phosphorylation of synaptic GABAA receptors, thereby resulting in upregulation of the channel conductance by stimulating adenylyl cyclase-PKA signaling cascade, possibly via activation of P2Y11 purinoceptor. Thus, our findings reveal that postsynaptic GABAA receptors at the interneuron-PC inhibitory synapses are under the control of two distinct forms of long-term potentiation linked with different second messenger cascades. PMID- 26930486 TI - RNA Sequencing Reveals the Alteration of the Expression of Novel Genes in Ethanol Treated Embryoid Bodies. AB - Fetal alcohol spectrum disorder is a collective term representing fetal abnormalities associated with maternal alcohol consumption. Prenatal alcohol exposure and related anomalies are well characterized, but the molecular mechanism behind this phenomenon is not well characterized. In this present study, our aim is to profile important genes that regulate cellular development during fetal development. Human embryonic carcinoma cells (NCCIT) are cultured to form embryoid bodies and then treated in the presence and absence of ethanol (50 mM). We employed RNA sequencing to profile differentially expressed genes in the ethanol-treated embryoid bodies from NCCIT vs. EB, NCCIT vs. EB+EtOH and EB vs. EB+EtOH data sets. A total of 632, 205 and 517 differentially expressed genes were identified from NCCIT vs. EB, NCCIT vs. EB+EtOH and EB vs. EB+EtOH, respectively. Functional annotation using bioinformatics tools reveal significant enrichment of differential cellular development and developmental disorders. Furthermore, a group of 42, 15 and 35 transcription factor-encoding genes are screened from all of the differentially expressed genes obtained from NCCIT vs. EB, NCCIT vs. EB+EtOH and EB vs. EB+EtOH, respectively. We validated relative gene expression levels of several transcription factors from these lists by quantitative real-time PCR. We hope that our study substantially contributes to the understanding of the molecular mechanism underlying the pathology of alcohol mediated anomalies and ease further research. PMID- 26930487 TI - Perception, Price and Preference: Consumption and Protection of Wild Animals Used in Traditional Medicine. AB - A wide array of wildlife species, including many animals, are used in traditional medicines across many medicinal systems, including in Traditional Chinese Medicine (TCM). Due to over-exploitation and habitat loss, the populations of many animals commonly used in TCM have declined and are unable to meet market demand. A number of measures have been taken to try to reduce the impact that this large and growing market for TCM may have on wild animal species. Consumer preferences and behavior are known to play an important role in the consumption and protection of wild animals used in traditional medicine, and thus are likely to be an important factor in the success of many of these mechanisms- particularly given the significant percentage of TCMs that are over-the-counter products (access to which is not mediated by practitioners). In this study we conducted questionnaires and designed stated preference experiments embodying different simulation scenarios using a random sample of the population in Beijing to elicit individuals' knowledge, perceptions and preferences toward wild or farmed animal materials and their substitutes used in traditional Chinese medicine. We found that respondents had a stated preference for wild materials over farm-raised and other alternatives because they believe that the effectiveness of wild-sourced materials is more credible than that of other sources. However, we also found that, although respondents used TCM products, they had a poor understanding of the function or composition of either traditional Chinese medicines or proprietary Chinese medicines (PCM), and paid little attention to the composition of products when making purchasing decisions. Furthermore, awareness of the need for species protection, or "conservation consciousness" was found to play an important role in willingness to accept substitutions for wild animal materials, while traditional animal medicinal materials (TAMs) derived from well-known endangered species, such as bear bile and tiger bone, show relatively higher substitutability. These results suggest that there is still hope for conservation measures which seek to promote a transition to farmed animal, plant and synthetic ingredients and provide clear directions for future social marketing, education and engagement efforts. PMID- 26930488 TI - A Randomised Controlled Trial of Therapist-Assisted, Internet-Delivered Cognitive Behavior Therapy for Women with Maternal Depression. AB - Postpartum depression impacts up to 15% of Canadian women following childbirth. Remarkably, many women suffering from this disorder do not receive appropriate treatment. The aim of this study was to conduct a parallel-group randomized controlled trial to determine the efficacy of Therapist-Assisted Internet delivered Cognitive Behavior Therapy (TA-ICBT) for the treatment of postpartum depression. This study was registered with the International Standard Randomized Controlled Trials ( ISRCTN: 85456371) and received funding from Canadian Institutes of Health Research (#101526) and the Saskatchewan Health Research Foundation. Fifty women who gave birth to an infant in the past year, who scored above 10 on the Edinburgh Postnatal Depression Scale (EPDS), and who resided in Saskatchewan, Canada were eligible to participate. Participants were randomly assigned to receive either TA-ICBT (n = 25) or waitlist control (n = 25). The efficacy of the treatment was investigated at baseline and at seven- to 10-week follow-up. TA-ICBT participants were also contacted four-weeks following treatment completion. Symptoms of postpartum depression decreased more for participants in the TA-ICBT group (average reduction of 6.24 points on the EPDS; n = 21 included in analyses) compared to those participants in the waitlist control group (average reduction of 2.42 points on the EPDS; n = 20 included in analyses), and these results were clinically significant and maintained at four week follow-up. TA-ICBT participants demonstrated a reduction in postnatal anxiety, general stress, and parental distress, and an increase in psychological and environmental quality of life when compared to the waitlist control participants. Study implications, limitations, and future research directions are discussed. Trial registration: Controlled-Trials.com ISRCTN85456371. PMID- 26930489 TI - Induction of Posttranslational Modifications of Mitochondrial Proteins by ATP Contributes to Negative Regulation of Mitochondrial Function. AB - It is generally accepted that ATP regulates mitochondrial function through the AMPK signaling pathway. However, the AMPK-independent pathway remains largely unknown. In this study, we investigated ATP surplus in the negative regulation of mitochondrial function with a focus on pyruvate dehydrogenase (PDH) phosphorylation and protein acetylation. PDH phosphorylation was induced by a high fat diet in the liver of obese mice, which was associated with ATP elevation. In 1c1c7 hepatoma cells, the phosphorylation was induced by palmitate treatment through induction of ATP production. The phosphorylation was associated with a reduction in mitochondria oxygen consumption after 4 h treatment. The palmitate effect was blocked by etomoxir, which inhibited ATP production through suppression of fatty acid beta-oxidation. The PDH phosphorylation was induced by incubation of mitochondrial lysate with ATP in vitro without altering the expression of PDH kinase 2 (PDK2) and 4 (PDK4). In addition, acetylation of multiple mitochondrial proteins was induced by ATP in the same conditions. Acetyl CoA exhibited a similar activity to ATP in induction of the phosphorylation and acetylation. These data suggest that ATP elevation may inhibit mitochondrial function through induction of the phosphorylation and acetylation of mitochondrial proteins. The results suggest an AMPK-independent mechanism for ATP regulation of mitochondrial function. PMID- 26930490 TI - Type 2 Endoleaks: The Diagnostic Performance of Non-Specialized Readers on Arterial and Venous Phase Multi-Slice CT Angiography. AB - PURPOSE: To define the diagnostic precision of non-specialized readers in the detection of type 2 endoleaks (T2EL) in arterial versus venous phase acquisitions, and to evaluate an approach for radiation dose reduction. METHODS: The pre-discharge and final follow-up multi-slice CT angiographies of 167 patients were retrospectively analyzed. Image data were separated into an arterial and a venous phase reading set. Two radiology residents assessed the reading sets for the presence of a T2EL, feeding vessels, and aneurysm sac size. Findings were compared with a standard of reference established by two experts in interventional radiology. The effective dose was calculated. RESULTS: Overall, experts detected 131 T2ELs, and 331 feeding vessels in 334 examinations. Persistent T2ELs causing aneurysm sac growth > 5 mm were detected in 20 patients. Radiation in arterial and venous phases contributed to a mean of 58.6% and 39.0% of the total effective dose. Findings of reader 1 and 2 showed comparable sensitivities in arterial sets of 80.9 versus 85.5 (p = 0.09), and in venous sets of 73.3 versus 79.4 (p = 0.15), respectively. Reader 1 and 2 achieved a significant higher detection rate of feeding vessels with arterial compared to venous set (p = 0.04, p < 0.01). Both readers correctly identified T2ELs with growing aneurysm sac in all cases, independent of the acquisition phase. CONCLUSION: Arterial acquisitions enable non-specialized readers an accurate detection of T2ELs, and a significant better identification of feeding vessels. Based on our results, it seems reasonable to eliminate venous phase acquisitions. PMID- 26930492 TI - Engineering the Transformation Strain in LiMnyFe1-yPO4 Olivines for Ultrahigh Rate Battery Cathodes. AB - Alkali ion intercalation compounds used as battery electrodes often exhibit first order phase transitions during electrochemical cycling, accompanied by significant transformation strains. Despite ~30 years of research into the behavior of such compounds, the relationship between transformation strain and electrode performance, especially the rate at which working ions (e.g., Li) can be intercalated and deintercalated, is still absent. In this work, we use the LiMnyFe1-yPO4 system for a systematic study, and measure using operando synchrotron radiation powder X-ray diffraction (SR-PXD) the dynamic strain behavior as a function of the Mn content (y) in powders of ~50 nm average diameter. The dynamically produced strain deviates significantly from what is expected from the equilibrium phase diagrams and demonstrates metastability but nonetheless spans a wide range from 0 to 8 vol % with y. For the first time, we show that the discharge capacity at high C-rates (20-50C rate) varies in inverse proportion to the transformation strain, implying that engineering electrode materials for reduced strain can be used to maximize the power capability of batteries. PMID- 26930491 TI - Influence of the Biliary System on Biliary Bacteria Revealed by Bacterial Communities of the Human Biliary and Upper Digestive Tracts. AB - Biliary bacteria have been implicated in gallstone pathogenesis, though a clear understanding of their composition and source is lacking. Moreover, the effects of the biliary environment, which is known to be generally hostile to most bacteria, on biliary bacteria are unclear. Here, we investigated the bacterial communities of the biliary tract, duodenum, stomach, and oral cavity from six gallstone patients by using 16S rRNA amplicon sequencing. We found that all observed biliary bacteria were detectable in the upper digestive tract. The biliary microbiota had a comparatively higher similarity with the duodenal microbiota, versus those of the other regions, but with a reduced diversity. Although the majority of identified bacteria were greatly diminished in bile samples, three Enterobacteriaceae genera (Escherichia, Klebsiella, and an unclassified genus) and Pyramidobacter were abundant in bile. Predictive functional analysis indicated enhanced abilities of environmental information processing and cell motility of biliary bacteria. Our study provides evidence for the potential source of biliary bacteria, and illustrates the influence of the biliary system on biliary bacterial communities. PMID- 26930494 TI - Unravelling the Effects of Grain Boundary and Chemical Doping on Electron-Hole Recombination in CH3NH3PbI3 Perovskite by Time-Domain Atomistic Simulation. AB - Advancing organohalide perovskite solar cells requires understanding of carrier dynamics. Electron-hole recombination is a particularly important process because it constitutes a major pathway of energy and current losses. Grain boundaries (GBs) are common in methylammonium lead iodine CH3NH3PbI3 (MAPbI3) perovskite polycrystalline films. First-principles calculations have suggested that GBs have little effect on the recombination; however, experiments defy this prediction. Using nonadiabatic (NA) molecular dynamics combined with time-domain density functional theory, we show that GBs notably accelerate the electron-hole recombination in MAPbI3. First, GBs enhance the electron-phonon NA coupling by localizing and contributing to the electron and hole wave functions and by creating additional phonon modes that couple to the electronic degrees of freedom. Second, GBs decrease the MAPbI3 bandgap, reducing the number of vibrational quanta needed to accommodate the electronic energy loss. Third, the phonon-induced loss of electronic coherence remains largely unchanged and not accelerated, as one may expect from increased electron-phonon coupling. Further, replacing iodines by chlorines at GBs reduces the electron-hole recombination. By pushing the highest occupied molecular orbital (HOMO) density away from the boundary, chlorines restore the NA coupling close to the value observed in pristine MAPbI3. By introducing higher-frequency phonons and increasing fluctuation of the electronic gap, chlorines shorten electronic coherence. Both factors compete successfully with the reduced bandgap relative to pristine MAPbI3 and favor long excited-state lifetimes. The simulations show excellent agreement with experiment and characterize how GBs and chlorine dopants affect electron hole recombination in perovskite solar cells. The simulations suggest a route to increased photon-to-electron conversion efficiencies through rational GB passivation. PMID- 26930495 TI - Influence of Toothbrushing on the Antierosive Effect of Film-Forming Agents. AB - This study evaluated the influence of toothbrushing on the antierosive effect of solutions containing sodium fluoride (225 ppm/F), stannous chloride (800 ppm/Sn), sodium linear polyphosphate (2%/LPP), and their combinations, and deionized water as negative control (C). Solutions were tested in a 5-day erosion remineralization-abrasion cycling model, using enamel and dentin specimens (n = 8). Erosion was performed 6 times/day for 5 min, exposure to the test solutions 3 times/day for 2min, and toothbrushing (or not) with toothpaste slurry 2 times/day for 2 min (45 strokes). Surface loss (SL) was determined by noncontact profilometry. Data were analyzed using three-way ANOVA (alpha = 0.05). Brushing caused more SL than no brushing for enamel (mean +/- SD, in micrometers: 52.7 +/- 6.6 and 33.0 +/- 4.5, respectively), but not for dentin (28.2 +/- 1.9 and 26.6 +/ 1.8, respectively). For enamel without brushing, F+LPP+Sn showed the lowest SL (23.8 +/- 3.4), followed by F+Sn (30.6 +/- 4.9) and F+LPP (31.7 +/- 1.7), which did not differ from each other. No differences were found between the other groups and C (37.8 +/- 2.1). When brushing, F+LPP+Sn exhibited the lowest SL (36.7 +/- 2.4), not differing from F+LPP (39.1 +/- 1.8). F, F+Sn and LPP+Sn were similar (46.7 +/- 2.9, 42.1 +/- 2.8 and 45.3 +/- 4.6, respectively) and better than C (52.7 +/- 4.3). Sn (55.0 +/- 2.4) and LPP (51.0 +/- 4.3) did not differ from C. For dentin, neither groups differed from C, regardless of brushing. In conclusion, toothbrushing did not affect the antierosive effect of F+Sn, F+LPP and F+LPP+Sn on enamel, although overall it led to more erosion than nonbrushing. F and LPP+Sn showed a protective effect only under brushing conditions, whereas Sn and LPP did not exhibit any protection. For dentin, neither toothbrushing nor the test solutions influenced the development of erosion. PMID- 26930493 TI - Dihydrofolate-Reductase Mutations in Plasmodium knowlesi Appear Unrelated to Selective Drug Pressure from Putative Human-To-Human Transmission in Sabah, Malaysia. AB - BACKGROUND: Malaria caused by zoonotic Plasmodium knowlesi is an emerging threat in Eastern Malaysia. Despite demonstrated vector competency, it is unknown whether human-to-human (H-H) transmission is occurring naturally. We sought evidence of drug selection pressure from the antimalarial sulfadoxine pyrimethamine (SP) as a potential marker of H-H transmission. METHODS: The P. knowlesi dihdyrofolate-reductase (pkdhfr) gene was sequenced from 449 P. knowlesi malaria cases from Sabah (Malaysian Borneo) and genotypes evaluated for association with clinical and epidemiological factors. Homology modelling using the pvdhfr template was used to assess the effect of pkdhfr mutations on the pyrimethamine binding pocket. RESULTS: Fourteen non-synonymous mutations were detected, with the most common being at codon T91P (10.2%) and R34L (10.0%), resulting in 21 different genotypes, including the wild-type, 14 single mutants, and six double mutants. One third of the P. knowlesi infections were with pkdhfr mutants; 145 (32%) patients had single mutants and 14 (3%) had double-mutants. In contrast, among the 47 P. falciparum isolates sequenced, three pfdhfr genotypes were found, with the double mutant 108N+59R being fixed and the triple mutants 108N+59R+51I and 108N+59R+164L occurring with frequencies of 4% and 8%, respectively. Two non-random spatio-temporal clusters were identified with pkdhfr genotypes. There was no association between pkdhfr mutations and hyperparasitaemia or malaria severity, both hypothesized to be indicators of H-H transmission. The orthologous loci associated with resistance in P. falciparum were not mutated in pkdhfr. Subsequent homology modelling of pkdhfr revealed gene loci 13, 53, 120, and 173 as being critical for pyrimethamine binding, however, there were no mutations at these sites among the 449 P. knowlesi isolates. CONCLUSION: Although moderate diversity was observed in pkdhfr in Sabah, there was no evidence this reflected selective antifolate drug pressure in humans. PMID- 26930496 TI - The Involvement of hybrid cluster protein 4, HCP4, in Anaerobic Metabolism in Chlamydomonas reinhardtii. AB - The unicellular green algae Chlamydomonas reinhardtii has long been studied for its unique fermentation pathways and has been evaluated as a candidate organism for biofuel production. Fermentation in C. reinhardtii is facilitated by a network of three predominant pathways producing four major byproducts: formate, ethanol, acetate and hydrogen. Previous microarray studies identified many genes as being highly up-regulated during anaerobiosis. For example, hybrid cluster protein 4 (HCP4) was found to be one of the most highly up-regulated genes under anoxic conditions. Hybrid cluster proteins have long been studied for their unique spectroscopic properties, yet their biological functions remain largely unclear. To probe its role during anaerobiosis, HCP4 was silenced using artificial microRNAs (ami-hcp4) followed by extensive phenotypic analyses of cells grown under anoxic conditions. Both the expression of key fermentative enzymes and their respective metabolites were significantly altered in ami-hcp4, with nitrogen uptake from the media also being significantly different than wild type cells. The results strongly suggest a role for HCP4 in regulating key fermentative and nitrogen utilization pathways. PMID- 26930497 TI - Lumican Inhibits SNAIL-Induced Melanoma Cell Migration Specifically by Blocking MMP-14 Activity. AB - Lumican, a small leucine rich proteoglycan, inhibits MMP-14 activity and melanoma cell migration in vitro and in vivo. Snail triggers epithelial-mesenchymal transitions endowing epithelial cells with migratory and invasive properties during tumor progression. The aim of this work was to investigate lumican effects on MMP-14 activity and migration of Snail overexpressing B16F1 (Snail-B16F1) melanoma cells and HT-29 colon adenocarcinoma cells. Lumican inhibits the Snail induced MMP-14 activity in B16F1 but not in HT-29 cells. In Snail-B16F1 cells, lumican inhibits migration, growth, and melanoma primary tumor development. A lumican-based strategy targeting Snail-induced MMP-14 activity might be useful for melanoma treatment. PMID- 26930498 TI - Positive Allosteric Modulator of GABA Lowers BOLD Responses in the Cingulate Cortex. AB - Knowledge about the neural underpinnings of the negative blood oxygen level dependent (BOLD) responses in functional magnetic resonance imaging (fMRI) is still limited. We hypothesized that pharmacological GABAergic modulation attenuates BOLD responses, and that blood concentrations of a positive allosteric modulator of GABA correlate inversely with BOLD responses in the cingulate cortex. We investigated whether or not pure task-related negative BOLD responses were co-localized with pharmacologically modulated BOLD responses. Twenty healthy adults received either 5 mg diazepam or placebo in a double blind, randomized design. During fMRI the subjects performed a working memory task. Results showed that BOLD responses in the cingulate cortex were inversely correlated with diazepam blood concentrations; that is, the higher the blood diazepam concentration, the lower the BOLD response. This inverse correlation was most pronounced in the pregenual anterior cingulate cortex and the anterior mid cingulate cortex. For subjects with diazepam plasma concentration > 0.1 mg/L we observed negative BOLD responses with respect to fixation baseline. There was minor overlap between cingulate regions with task-related negative BOLD responses and regions where the BOLD responses were inversely correlated with diazepam concentration. We interpret that the inverse correlation between the BOLD response and diazepam was caused by GABA-related neural inhibition. Thus, this study supports the hypothesis that GABA attenuates BOLD responses in fMRI. The minimal overlap between task-related negative BOLD responses and responses attenuated by diazepam suggests that these responses might be caused by different mechanisms. PMID- 26930500 TI - Long-term consequences of electrical injury: neuropsychological predictors of adjustment. AB - OBJECTIVE: Electrical injury (EI) produces an assortment of consequences for individuals. Survivors perform poorly on measures of attention and mental speed, memory, and emotional functioning. Moreover, sequelae are not always reported immediately following injury and often increase over the months following injury. It remains unclear whether the observed increase in neuropsychological and emotional symptoms over time is attributable to the delayed physical effects of EI or other factors that arise subsequent to injury, such as difficulty adjusting to post-injury limitations. METHOD: The current study utilized archival data to compare the neuropsychological and emotional complaints of EI survivors at two points during recovery, hypothesizing that Time 1 data would predict participants' outcome at Time 2. Specifically, those with worse neuropsychological performance and greater depressive symptomatology at Time 1 would have worse long-term adjustment to injury and psychological symptomatology. RESULTS: Multiple regression analyses revealed a significant predictive effect of Time 1 neurocognitive performance and depressive symptomatology on Time 2 adjustment to injury, psychological distress, and return to work. Participants with greater depressive symptomatology endorsed during the initial neuropsychological evaluation had substantially more difficulty with overall psychosocial adjustment to electrical injury. Moreover, depressive symptomatology persisted or worsened over the course of recovery. CONCLUSIONS: Findings demonstrate that poor outcome 4 years after EI is largely predicated by early emotional sequelae. Early screening and specialized interventions are needed to address psychological symptomatology among EI survivors. PMID- 26930499 TI - Development of a Genus-Specific Antigen Capture ELISA for Orthopoxviruses - Target Selection and Optimized Screening. AB - Orthopoxvirus species like cowpox, vaccinia and monkeypox virus cause zoonotic infections in humans worldwide. Infections often occur in rural areas lacking proper diagnostic infrastructure as exemplified by monkeypox, which is endemic in Western and Central Africa. While PCR detection requires demanding equipment and is restricted to genome detection, the evidence of virus particles can complement or replace PCR. Therefore, an easily distributable and manageable antigen capture enzyme-linked immunosorbent assay (ELISA) for the detection of orthopoxviruses was developed to facilitate particle detection. By comparing the virus particle binding properties of polyclonal antibodies developed against surface-exposed attachment or fusion proteins, the surface protein A27 was found to be a well bound, highly immunogenic and exposed target for antibodies aiming at virus particle detection. Subsequently, eight monoclonal anti-A27 antibodies were generated and characterized by peptide epitope mapping and surface plasmon resonance measurements. All antibodies were found to bind with high affinity to two epitopes at the heparin binding site of A27, toward either the N- or C terminal of the crucial KKEP-segment of A27. Two antibodies recognizing different epitopes were implemented in an antigen capture ELISA. Validation showed robust detection of virus particles from 11 different orthopoxvirus isolates pathogenic to humans, with the exception of MVA, which is apathogenic to humans. Most orthopoxviruses could be detected reliably for viral loads above 1 * 103 PFU/mL. To our knowledge, this is the first solely monoclonal and therefore reproducible antibody-based antigen capture ELISA able to detect all human pathogenic orthopoxviruses including monkeypox virus, except variola virus which was not included. Therefore, the newly developed antibody-based assay represents important progress towards feasible particle detection of this important genus of viruses. PMID- 26930501 TI - Comparison of serum zinc, calcium, and magnesium concentrations in women with pregnancy-induced hypertension and healthy pregnant women: A meta-analysis. AB - OBJECTIVE: The relationship between serum zinc, magnesium, and calcium levels and pregnancy-induced hypertension (PIH) is controversial. The aim of our study was to determine whether or not serum zinc, magnesium, and calcium levels are associated with PIH. METHODS: In our study, we searched databases, including Wangfang, Chinese National Knowledge Infrastructure, and PubMed, to find literature regarding the relationship between PIH and serum trace elements. Meta analysis was performed using the Review Manager5.3 software. RESULTS: A total of 14 articles were included in our study. The results of the meta-analysis indicated that patients with PIH had lower serum zinc (SMD = -1.14; 95% CI] = 1.69, -0.59; P < 0.05), calcium (MD = -0.26; 95% CI = -0.36, -0.15; P < 0.05), and magnesium concentration (MD = -0.0.06; 95% CI = -0.08, -0.05; P < 0.05) than healthy gravidas. CONCLUSION: Our research suggests that serum zinc, calcium, and magnesium concentrations may have an effect on PIH. Thus, the serum zinc, calcium, and magnesium levels could be measured for PIH patients. PMID- 26930502 TI - Spiritual coping, psychosocial adjustment, and physical health in youth with chronic illness: a meta-analytic review. AB - OBJECTIVE: The current systematic review and meta-analysis aimed to assess the strength of the relationships between religious/spiritual coping strategies and psychosocial adjustment and physical health in youth with chronic illness. BACKGROUND: Faced with medical stressors and uncertainty about their illness, spiritual beliefs and behaviours are important for youth with chronic illness. Research suggests that some spiritual coping strategies are helpful (positive), while others are not (negative), and these dimensions of spiritual coping are important predictors of functioning among youth with chronic illness. METHOD: Fourteen studies, published between 1990 and 2015, met inclusion criteria for the meta-analysis and were analysed using both a fixed effects model and random effects model (REM). RESULTS: Findings revealed significant, small to moderate associations between negative spiritual coping and more concurrent internalising problems (REM r = .34), lower quality of life (REM r = -.34), and poorer health (REM r = -.08). Under the fixed, but not REM, the combined effects showed small to moderate significant relationships between positive spiritual coping and fewer internalising problems (r = -.19) and better physical health (r = .19). CONCLUSION: The results reveal that spiritual coping is an important coping strategy for paediatric patients. Consistent with findings among adults with chronic illness, negative spiritual coping puts paediatric patients at risk for psychosocial maladjustment and poorer health. Intervention research is needed to determine if targeting spiritual coping improves health and psychosocial well being. PMID- 26930503 TI - Porous Fe3O4-NCs-in-Carbon Nanofoils as High-Rate and High-Capacity Anode Materials for Lithium-Ion Batteries from Na-Citrate-Mediated Growth of Super-Thin Fe-Ethylene Glycolate Nanosheets. AB - Porous Fe3O4/C composite nanofoils, characterized by a thickness of ~20 nm and with ~8 nm open pores and ~5 nm Fe3O4 nanoparticles embedded in the carbon matrix, were prepared for the first time using Na-citrate to mediate the growth of hexagonal Fe-ethylene glycolate nanosheets and subsequently annealing them at 350 degrees C in N2. It has been found that the Fe-ethylene glycolate nanosheets can be effectively slimmed by increasing the concentration of Na-citrate, and the microstructures of Fe3O4/C nanocomposites may be tailored by the annealing temperature. When tested as the anode materials in LIBs, the Fe3O4/C nanofoils obtained after annealing at 350 degrees C were found to exhibit superior electrochemical performance due to its optimal microstructure, featured by a reversible capacity of 1314.4 mAh g(-1) at 0.4 A g(-1) over 100 cycles, 1034.2 mAh g(-1) at 1 A g(-1), and 686.4 mAh g(-1) at 5 A g(-1) after 500 cycles, whereas the annealing treatments at 450 and 550 degrees C render the Fe3O4/C nanocomposites with the inferior electrochemical performances as a result of shrinking porous microstructures and coarsening of Fe3O4 nanoparticles in the carbon matrix. With a particle-size control model proposed herein, the cycle discharging behaviors of the Fe3O4/C nanocomposites with different microstructures are well explained from the perspective of the local confinement of Fe3O4 nanoparticles inside the carbon matrix and their evolution in size and composite microstructure during the charge/discharge cycling. PMID- 26930504 TI - The never-ending struggle with laboratory testing for Clostridium difficile infection. PMID- 26930507 TI - Correction: Endothelial Dysfunction in Rheumatoid Arthritis: Mechanistic Insights and Correlation with Circulating Markers of Systemic Inflammation. PMID- 26930505 TI - Structure-Activity Relationship Studies of N- and C-Terminally Modified Secretin Analogs for the Human Secretin Receptor. AB - The pleiotropic role of human secretin (hSCT) validates its potential use as a therapeutic agent. Nevertheless, the structure of secretin in complex with its receptor is necessary to develop a suitable therapeutic agent. Therefore, in an effort to design a three-dimensional virtual homology model and identify a peptide agonist and/or antagonist for the human secretin receptor (hSR), the significance of the primary sequence of secretin peptides in allosteric binding and activation was elucidated using virtual docking, FRET competitive binding and assessment of the cAMP response. Secretin analogs containing various N- or C terminal modifications were prepared based on previous findings of the role of these domains in receptor binding and activation. These analogs exhibited very low or no binding affinity in a virtual model, and were found to neither exhibit in vitro binding nor agonistic or antagonistic properties. A parallel analysis of the analogs in the virtual model and in vitro studies revealed instability of these peptide analogs to bind and activate the receptor. PMID- 26930506 TI - Mechanisms Underpinning Increased Plasma Creatinine Levels in Patients Receiving Vemurafenib for Advanced Melanoma. AB - CONTEXT: Serum creatinine has been reported to increase in patients receiving Vemurafenib, yet neither the prevalence nor the mechanism of this adverse event are known. OBJECTIVE: We aimed to evaluate the frequency and the mechanisms of increases in plasma creatinine level in patients receiving Vemurafenib for advanced melanoma. METHODS: We performed a retrospective monocentric study including consecutive patients treated with Vemurafenib for an advanced melanoma. We collected clinical and biological data concerning renal function before introduction of Vemurafenib and in the course of monthly follow-up visits from March 2013 to December 2014. Cystatin C-derived glomerular filtration rate was evaluated before and after Vemurafenib initiation, as increase in serum cystatin C is specific to a decrease in the glomerular filtration rate. We also performed thorough renal explorations in 3 patients, with measurement of tubular secretion of creatinine before and after Vemurafenib initiation and a renal biopsy in 2 patients. RESULTS: 70 patients were included: 97% of them displayed an immediate, and thereafter stable, increase in creatinine (+22.8%) after Vemurafenib initiation. In 44/52 patients in whom Vemurafenib was discontinued, creatinine levels returned to baseline. Serum cystatin C increased, although proportionally less than serum creatinine, showing that creatinine increase under vemurafenib was indeed partly due to a renal function impairment. In addition, renal explorations demonstrated that Vemurafenib induced an inhibition of creatinine tubular secretion. CONCLUSION: Thus, Vemurafenib induces a dual mechanism of increase in plasma creatinine with both an inhibition of creatinine tubular secretion and slight renal function impairment. However, this side effect is mostly reversible when Vemurafenib is discontinued, and should not lead physicians to discontinue the treatment if it is effective. PMID- 26930508 TI - Glucagon-like peptide-1 regulates calcium homeostasis and electrophysiological activities of HL-1 cardiomyocytes. AB - Glucagon like-peptide-1 (GLP-1) is an incretin hormone with antidiabetic effects through stimulating insulin secretion, beta cell neogenesis, satiety sensation, and inhibiting glucagon secretion. Administration of GLP-1 provides cardioprotective effects through attenuating cardiac inflammation and insulin resistance. GLP-1 also modulates the heart rate and systolic pressure, which suggests that GLP-1 may have cardiac electrical effects. Therefore, the purposes of this study were to evaluate whether GLP-1 has direct cardiac effects and identify the underlying mechanisms. Patch clamp, confocal microscopy with Fluo-3 fluorescence, and Western blot analyses were used to evaluate the electrophysiological characteristics, calcium homeostasis, and calcium regulatory proteins in HL-1 atrial myocytes with and without GLP-1 (1 and 10nM) incubation for 24h. GLP-1 (1 and 10nM) and control cells had similar action potential durations. However, GLP-1 at 10nM significantly increased calcium transients and sarcoplasmic reticular Ca(2+) contents. Compared to the control, GLP-1 (10nM) treated cells significantly decreased phosphorylation of the ryanodine receptor at S2814 and total phospholamban, but there were similar protein levels of sarcoplasmic reticular Ca(2+)-ATPase and the sodium-calcium exchanger. Moreover, exendin (9-39) amide (a GLP-1 receptor antagonist, 10nM) attenuated GLP-1 mediated effects on total SR content and phosphorylated ryanodine receptor S2814. This study demonstrates GLP-1 may regulate HL-1 cell arrhythmogenesis through modulating calcium handling proteins. PMID- 26930510 TI - Microsites Matter: Improving the Success of Rare Species Reintroductions. AB - Our study was undertaken to better understand how to increase the success rates of recovery plantings of a rare hemiparasite, golden paintbrush (Castilleja levisecta-Orobanchaceae). This species is endemic to western Washington and Oregon, USA, and southwestern British Columbia, Canada. Over 5000 golden paintbrush plants were outplanted as plugs in 2007 at six different native prairie sites that were considered to be suitable habitat, based on general evaluations of vegetation and soil conditions. Outplantings were installed at regular intervals along transects up to 1 km long to include a range of conditions occurring at each site. All plantings were re-examined five years later. The patchy distribution of surviving plugs and new recruits within each reintroduction site suggested success is strongly influenced by microsite characteristics. Indicator species analysis of taxa growing in microsites around outplanted golden paintbrush identified species that were positively or negatively associated with paintbrush survival. Species such as Festuca roemeri, Eriophyllum lanatum, and Viola adunca were strong indicators at some sites; non natives such as Hypochaeris radicata and Teesdalia nudicaulis tended to be frequent negative indicators. Overall, higher richness of native perennial forbs was strongly correlated with both survival and flowering of golden paintbrush, a pattern that may reflect interactions of this hemiparasite with the immediately surrounding plant community. Topographic position also influenced outcomes, with greater survival occurring on mounds and in swales, where soils generally were deeper. Our findings suggest that assessments of site suitability based on vegetation alone, and coarser, site-level assessments that do not characterize heterogeneity at the microsite scale, may not be strong predictors of restoration success over the longer term and in sites with variability in vegetation and soils. By identifying suitable microsites to focus rare species plantings, survival and efficiency may be significantly enhanced. PMID- 26930509 TI - Fine Mapping of a QTL Associated with Kernel Row Number on Chromosome 1 of Maize. AB - The genetic factors underlying changes in ear morphology, and particularly the inheritance of kernel row number (KRN), have been broadly investigated in diverse mapping populations in maize (Zea mays L.). In this study, we mapped a region on the long arm of chromosome 1 containing a QTL for KRN. This work was performed using a set of recombinant chromosome nearly isogenic lines (RCNILs) derived from a BC2S3 population produced using the inbred maize line W22 and teosinte (Zea mays ssp. parviglumis) as the parents. A set of 48 RCNILs was evaluated in the field during the summer of 2013 in order to perform the mapping. A QTL for KRN was found that explained approximately 51% of the phenotypic variance and had a 1.5-LOD confidence interval of 203 kb. Seven genes are described in this interval. One of these candidate genes may have been the target of domestication processes in maize and contributed to the shift from two kernel row ears in teosinte to a highly polystichous ear in maize. PMID- 26930511 TI - Epithelium-Intrinsic MicroRNAs Contribute to Mucosal Immune Homeostasis by Promoting M-Cell Maturation. AB - M cells in the follicle-associated epithelium (FAE) of Peyer's patches (PPs) serve as a main portal for external antigens and function as a sentinel in mucosal immune responses. The scarcity of these cells has hampered identification of M cell-specific molecules. Recent efforts have begun to provide insight into antigen transcytosis and differentiation of M cells; however, the molecular mechanisms underlying these processes are not fully elucidated. Small non-coding RNAs including microRNA (miRNA) have been reported to regulate gene expression and control various biological processes such as cellular differentiation and function. To evaluate the expression of miRNAs in FAE, including M cells, we previously performed microarray analysis comparing intestinal villous epithelium (VE) and PP FAE. Here we confirmed FAE specific miRNA expression levels by quantitative PCR. To gain insight into miRNA function, we generated mice with intestinal epithelial cell-specific deletion of Dicer1 (DicerDeltaIEC) and analyzed intestinal phenotypes, including M-cell differentiation, morphology and function. DicerDeltaIEC mice had a marked decrease in M cells compared to control floxed Dicer mice, suggesting an essential role of miRNAs in maturation of these cells. Furthermore, transmission electron microscopic analysis revealed that depletion of miRNA caused the loss of endosomal structures in M cells. In addition, antigen uptake by M cells was impaired in DicerDeltaIEC mice. These results suggest that miRNAs play a significant role in M cell differentiation and help secure mucosal immune homeostasis. PMID- 26930512 TI - Consensus statement: Using laryngeal electromyography for the diagnosis and treatment of vocal cord paralysis. AB - INTRODUCTION: The purpose of this study was to develop an evidence-based consensus statement regarding use of laryngeal electromyography (LEMG) for diagnosis and treatment of vocal fold paralysis after recurrent laryngeal neuropathy (RLN). METHODS: Two questions regarding LEMG were analyzed: (1) Does LEMG predict recovery in patients with acute unilateral or bilateral vocal fold paralysis? (2) Do LEMG findings change clinical management in these individuals? A systematic review was performed using American Academy of Neurology criteria for rating of diagnostic accuracy. RESULTS: Active voluntary motor unit potential recruitment and presence of polyphasic motor unit potentials within the first 6 months after lesion onset predicted recovery. Positive sharp waves and/or fibrillation potentials did not predict outcome. The presence of electrical synkinesis may decrease the likelihood of recovery, based on 1 published study. LEMG altered clinical management by changing the initial diagnosis from RLN in 48% of cases. Cricoarytenoid fixation and superior laryngeal neuropathy were the most common other diagnoses observed. CONCLUSIONS: If prognostic information is required in a patient with vocal fold paralysis that is more than 4 weeks and less than 6 months in duration, then LEMG should be performed. LEMG may be performed to clarify treatment decisions for vocal fold immobility that is presumed to be caused by RLN. Muscle Nerve 53: 850-855, 2016. PMID- 26930513 TI - Younger age at initiation of the human papillomavirus (HPV) vaccination series is associated with higher rates of on-time completion. AB - Vaccination rates for human papillomavirus (HPV) have remained disappointingly low. It is critical to identify methods to increase on-time vaccine series completion rates (before 13 or 15years). To determine whether younger age (9 to 10years of age) at HPV vaccine series initiation was associated with improved on time completion rates compared to initiation at 11 to 12years, we examined the prevalence of on-time HPV vaccine series completion rates from August 2006 through December 2012 in a large, population-based cohort of children and adolescents (aged 9.5 to 27years) residing in Olmsted County, MN on December 31, 2012 (n=36,223). We compared age at vaccine initiation between individuals who successfully completed both 2 and 3 doses of the vaccination series on-time (before age 13.5 or 15.0years) using multivariate logistic regression. On-time completion of both 2 and 3 doses of the vaccine series by age 13.5 or 15.0years was significantly associated with initiation at 9 to 10years as compared to 11 to 12years after adjusting for sex, race, insurance status, frequent health care visits, and year of first vaccination (all p<.01). Interventions focused on beginning the vaccination series at 9 to 10years of age may result in higher rates of timely series completion. PMID- 26930514 TI - Intrapartum and Postpartum Transfers to a Tertiary Care Hospital from Out-of Hospital Birth Settings: A Retrospective Case Series. AB - INTRODUCTION: This study describes the reasons for and outcomes of maternal transfers from private homes and freestanding birthing suites to a large academic hospital in order to better understand and meet the needs of transferring women and their families. METHODS: The convenience sample included all adult women admitted to the labor and birth unit or emergency room within a 5-year period who: 1) had planned to give birth out-of-hospital but developed complications at term before the onset of labor and were admitted to the hospital for labor induction; 2) had planned to give birth at home or in a birthing suite but transferred to the hospital during labor; or 3) arrived at the hospital for care within 24 hours after a planned birth at home or in a birthing suite. Descriptive data for each transfer were obtained from the medical record. RESULTS: Fifty-one transfers were identified: 11 prior to labor, 38 during labor, and 2 postpartum. Only 4 transfers were considered urgent by the referring provider. The most common reasons for intrapartum transfer were prolonged labor (n = 19) and desire for epidural analgesia (n = 10). Only 25% of the medical records had documentation that the referring provider accompanied the woman to the hospital during the care transition or was involved in her hospital course; however, the prenatal and/or intrapartum records had been delivered by the referring provider, were referenced in the hospital admission note, and had become part of the permanent hospital medical record for 85% of the women. On average, one transfer per year was complicated by neonatal morbidity, and one transfer per year involved significant disagreement between hospital providers and the women presenting for care. DISCUSSION: Collecting and reviewing data about a facility's perinatal transfer events can help the local multi-stakeholder group appraise current practice and plan for quality improvement. PMID- 26930516 TI - Access to the Parent Tetrakis(pyridine)gold(III) Trication, Facile Formation of Rare Au(III) Terminal Hydroxides, and Preliminary Studies of Biological Properties. AB - In this paper we report on the use of [NO][BF4] to access tricationic tetrakis(pyridine)gold(III) from Au powder, a species inaccessible using the more traditional (tetrahydrothiophene)AuCl route. It is then demonstrated that this family of compounds can be used to access new terminal Au(III) hydroxides, a challenging class of compounds, and the first crystallographically characterized examples employing bidentate ligands. Finally, preliminary biological studies indicate good activity for derivatives featuring polydentate ligands against the HeLa and PC3 cell lines but also strong inhibition of primary HUVEC cells. PMID- 26930515 TI - Roles of Aag, Alkbh2, and Alkbh3 in the Repair of Carboxymethylated and Ethylated Thymidine Lesions. AB - Environmental and endogenous genotoxic agents can result in a variety of alkylated and carboxymethylated DNA lesions, including N3-ethylthymidine (N3 EtdT), O(2)-EtdT, and O(4)-EtdT as well as N3-carboxymethylthymidine (N3-CMdT) and O(4)-CMdT. By using nonreplicative double-stranded vectors harboring a site specifically incorporated DNA lesion, we assessed the potential roles of alkyladenine DNA glycosylase (Aag); alkylation repair protein B homologue 2 (Alkbh2); or Alkbh3 in modulating the effects of N3-EtdT, O(2)-EtdT, O(4)-EtdT, N3-CMdT, or O(4)-CMdT on DNA transcription in mammalian cells. We found that the depletion of Aag did not significantly change the transcriptional inhibitory or mutagenic properties of all five examined lesions, suggesting a negligible role of Aag in the repair of these DNA adducts in mammalian cells. In addition, our results revealed that N3-EtdT, but not other lesions, could be repaired by Alkbh2 and Alkbh3 in mammalian cells. Furthermore, we demonstrated the direct reversal of N3-EtdT by purified human Alkbh2 protein in vitro. These findings provided important new insights into the repair of the carboxymethylated and alkylated thymidine lesions in mammalian cells. PMID- 26930519 TI - Robert L. Spitzer, MD 1932-2015. PMID- 26930520 TI - Longitudinal study of low serum LDL cholesterol and depressive symptom onset in postmenopause. AB - OBJECTIVE: The aim of this study was to characterize the relationship between serum low-density lipoprotein cholesterol (LDL-c) and subsequent depressive symptoms onset in postmenopausal women. We secondarily assessed serum high density lipoprotein (HDL-c), total cholesterol, and triglycerides. METHOD: This population-based prospective cohort study utilizes data from 24,216 women between 50 and 79 years of age who were participants of the Women's Health Initiative, which originally ran from 1993 to 2005 and has since incorporated 2 extension studies, with the most recent culminating in 2015. Fasting lipids were measured for all participants at baseline and for a subset through 6 years of follow-up. Depressive symptoms were characterized using the Burnam 8-item scale for depressive disorders (Center for Epidemiologic Studies-Depression/Diagnostic Interview Schedule short form) at baseline and during follow-up, using a cut point of 0.06 to indicate presence of depressive symptoms. RESULTS: The lowest quintile of LDL-c was associated with an increased risk of subsequent depressive symptoms (hazard ratio [HR] = 1.25, 95% CI = 1.05-1.49, P = .01), and follow-up analyses demonstrated that the elevated risk appeared to be confined to the lowest decile (LDL-c < 100 mg/dL). Further, this elevated risk was moderated by lipid-lowering drug treatment. Elevated risk was demonstrated among those who reported no lipid-lowering medication use (HR = 1.23, 95% CI = 1.03-1.47, P = .02), but not among those reporting use (HR = 0.65, 95% CI = 0.18-2.29, P = .50). CONCLUSIONS: Among postmenopausal women, untreated serum LDL-c below 100 mg/dL was associated with an increased risk of developing depressive symptoms. No excess risk was observed in those attaining LDL-c < 100 mg/dL with lipid-lowering therapy. These findings have important implications for risk assessment, treatment considerations, and mechanistic insight. PMID- 26930521 TI - Risk of suicide attempt and suicide death following completion of the Patient Health Questionnaire depression module in community practice. AB - OBJECTIVE: To examine the association between thoughts of death or self-harm reported on item 9 of the Patient Health Questionnaire (PHQ) depression module and the risk of suicide attempt or suicide death over the following 2 years. METHOD: In 4 health care systems participating in the Mental Health Research Network, electronic records identified 509,945 adult outpatients completing 1,228,308 PHQ depression questionnaires during visits to primary care, specialty mental health, and other outpatient providers between January 1, 2007 and December 31, 2012. 9,203 nonfatal suicide attempts were identified using health system records of inpatient or outpatient encounters for self-inflicted injury. 484 suicide deaths were identified using cause-of-death codes from state mortality data. RESULTS: Cumulative hazard of suicide attempt during 2 years ranged from approximately 0.5% among those reporting thoughts of death or self harm "not at all" to 3.5% among those reporting such thoughts "nearly every day." Cumulative hazard of suicide death during 2 years ranged from approximately 0.04% among those responding "not at all" to 0.19% among those responding "nearly every day." The excess hazard associated with thoughts of death or self-harm declined with time, but remained 2- to 5-fold higher for at least 18 months. Nevertheless, 39% of suicide attempts and 36% of suicide deaths within 30 days of completing a PHQ occurred among those responding "not at all" to item 9. CONCLUSIONS: In community practice, response to PHQ item 9 is a strong predictor of suicide attempt and suicide death over the following 2 years. For patients reporting thoughts of death or self-harm, suicide prevention efforts must address this enduring vulnerability. PMID- 26930523 TI - Introduction. AB - When Thomas Insel announced last year that he was stepping down from his position as director of the National Institute of Mental Health to join Google Life Sciences, some surprise was expressed by my colleagues. Typically, their thinking was that individuals in his position would (should?) return to academia or perhaps work at a pharmaceutical firm developing new therapeutics. As someone familiar with both psychiatry and the technology field, I thought Dr Insel's decision was quite rational given the increasing overlap between both fields and that his move reflected this new paradigm. PMID- 26930522 TI - Residual memory impairment in remitted depression may be a predictive factor for recurrence. AB - OBJECTIVE: Memory impairment in remitted depression is reported to be related to the number of previous depressive episodes. A recent report hypothesized that each depressive episode increases the risk of memory impairment during remission, which further increases the risk of recurrence. We investigated whether the risk for recurrence increased as a function of memory impairment at remission. METHOD: One hundred ten participants with DSM-IV-TR major depressive disorder (MDD) after remission (defined as a score <= 7 on the Hamilton Depression Rating Scale) were recruited between April 2004 and March 2012 and were followed up prospectively. All patients were divided into 2 groups: those who had memory impairment and those who had no memory impairment after remission. (Memory impairment was determined with the Wechsler Memory Scale-Revised.) The time to recurrence of depression (a score >= 4 on the Clinical Global Impressions-Severity of Illness scale) was compared between the groups prospectively. Kaplan-Meier survival curves, log-rank test for trend for survivor functions, and Cox proportional hazard ratio (HR) estimates for a multivariate model were conducted to examine the risk of recurrence by presence of memory impairment after remission. RESULTS: One hundred nine participants completed this study. In the follow-up period, recurrence occurred in 25 (55.6%) of the 45 patients with memory impairment and 21 (32.8%) of the 64 patients with no memory impairment. In the Kaplan-Meier survival estimates for time to incidence of recurrence in patients with and without memory impairment, the cumulative probability of developing a recurrence for patients with memory impairment was higher than for patients with no memory impairment (log-rank test: chi(2)1 = 4.63, P = .03). Survival analysis was also performed using Cox proportional hazards regression in a multivariate model. The presence of memory impairment remained significantly associated with incidence of recurrence (HR = 2.55; 95% CI, 1.30-4.99; P = .006). CONCLUSIONS: The presence of residual memory impairment in patients with remitted MDD may increase the risk of recurrence. PMID- 26930524 TI - Evidence for an internet addiction disorder: internet exposure reinforces color preference in withdrawn problem users. AB - OBJECTIVE: This study examined whether exposure to the Internet could create a preference for colors associated with visited Web sites and explored the possible relationship with self-reported problematic Internet use and Internet deprivation. METHOD: 100 adult participants were divided into 2 groups; one was deprived access to the Internet for 4 hours, and the other was not. After this period, they were asked to choose a color and complete a series of psychometric questionnaires concerning mood (Positive and Negative Affect Schedule), anxiety (Spielberger State-Trait Anxiety Inventory), and depression (Beck Depression Inventory). They were then given a 15-minute exposure to the Internet, and the Web sites they visited were recorded. They were then asked to again choose a color, complete the same psychometric questionnaires, and complete the Internet Addiction Test. The study was conducted between November 2013 and April 2014. RESULTS: For Internet-deprived, but not nondeprived, subjects, a reduction of mood and increased anxiety was noted in the higher problematic Internet users following Web cessation. There was also a shift toward choosing the color most prominent on the visited Web sites in these participants. No shift in mood, or toward choosing the dominant Web site color, was seen in the lower problem users. CONCLUSIONS: These findings suggest that the Internet can serve as a negative reinforcer for behavior in higher problem users and that the reinforcement obtained from the alleviation of withdrawal symptoms becomes conditioned, with the color and appearance of the visited Web sites giving them a more positive value. PMID- 26930525 TI - An open-label, pilot trial of adjunctive tocilizumab in schizophrenia. PMID- 26930526 TI - Opportunities for smartphones in clinical care: the future of mobile mood monitoring. PMID- 26930528 TI - Use of acetaminophen (paracetamol) during pregnancy and the risk of autism spectrum disorder in the offspring. AB - Acetaminophen (paracetamol) is available over the counter in most countries and is widely considered to be safe for use during pregnancy; studies report gestational exposures to acetaminophen that lie in the 46%-65% range. Acetaminophen influences inflammatory and immunologic mechanisms and may predispose to oxidative stress; these and other effects are hypothesized to have the potential to compromise neurodevelopment in the fetal and infant brain. Two ecological studies suggested that population-level trends in the use of acetaminophen were associated with trends in the incidence/prevalence of autism; one of these studies specifically examined acetaminophen use during pregnancy. One large prospective observational cohort study found that gestational exposure to acetaminophen (especially when the duration of exposure was 28 days or more) was associated with motor milestone delay, gross and fine motor impairments, communication impairment, impairments in internalizing and externalizing behaviors, and hyperactivity, all at age 3 years; however, social and emotional developmental behaviors were mostly unaffected. A very recent large cohort study with a 12.7-year follow-up found that gestational exposure to acetaminophen was associated with an increased risk of autism spectrum disorder, but only when a hyperkinetic disorder was also present. In the light of existing data associating acetaminophen use during pregnancy and subsequent risk of attention deficit/hyperactivity disorder, this new finding suggests that the predisposition, if any, is toward the hyperkinetic syndrome rather than to autism. In summary, the empirical data are very limited, but whatever empirical data exist do not support the suggestion that the use of acetaminophen during pregnancy increases the risk of autism in the offspring. PMID- 26930527 TI - Baseline blood levels of omega-3 and depression remission: a secondary analysis of data from a placebo-controlled trial of omega-3 supplements. AB - OBJECTIVE: Depression is associated with low red blood cell (RBC) levels of 2 omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), suggesting that omega-3 supplements might improve depression. However, clinical trials have produced mixed results. The purpose of this secondary analysis of data from a randomized controlled trial was to determine whether baseline blood levels of omega-3, which are known to vary widely among individuals, predict depression outcomes. METHOD: The percentages of EPA, DHA, and the omega-6 arachidonic acid (AA) were measured in RBCs at baseline and posttreatment in 122 participants with DSM-IV major depression who were randomly assigned between May 2005 and December 2008 to receive either 50 mg/d of sertraline and a daily dosage of 930 mg EPA/750 mg DHA or sertraline plus placebo. Associations between baseline omega-3 RBC levels and remission of depression (17-item Hamilton Depression Rating Scale score <= 7) were analyzed by treatment arm. RESULTS: Among participants in the omega-3 arm, baseline RBC levels of EPA + DHA (P = .002) and the EPA + DHA:AA ratio (P = .003) were significantly higher among those whose depression subsequently remitted compared with those whose depression did not remit. No associations were detected in the sertraline plus placebo arm. Baseline levels of EPA (P = .03) and the EPA + DHA:AA ratio (P = .04) moderated the relationship between treatment arm and depression outcomes. CONCLUSIONS: High baseline RBC levels of EPA and DHA and a high EPA + DHA:AA ratio predict favorable depression outcomes in patients receiving omega-3 supplements. Omega-3 supplementation may be an effective treatment for depression, but the requisite dosage and duration of treatment may depend on the patient's baseline level of omega-3 fatty acids. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00116857. PMID- 26930529 TI - Prolactin Levels During Long-Term Risperidone Treatment in Children and Adolescents: a reanalysis of data. PMID- 26930534 TI - Behavioral interventions for antipsychotic medication-associated obesity: a randomized, controlled clinical trial. AB - OBJECTIVE: To demonstrate the effectiveness of a Diabetes Prevention Program inspired 12-month behavioral intervention for patients with severe mental illness (SMI) and medication-associated obesity. METHOD: This randomized, controlled, parallel, superiority study screened 225 volunteers from November 2005 to August 2008 at the VA Greater Los Angeles Healthcare System. 122 outpatients with DSM-IV diagnosed SMI taking antipsychotic medications who had >= 7% weight gain or body mass index (BMI) > 25 were randomized by computer-generated number to Lifestyle Balance treatment intervention (n = 60) or usual care control (n = 62) groups. Clinical raters were masked to randomization. Treatment intervention included weekly classes and individual counseling for 8 weeks, food and exercise diaries, rewards, caregiver consultations, and monthly booster classes and counseling for 1 year. Controls received self-help materials and visited at equivalent intervals without formal classes or counseling. Outcomes were changes in anthropometric measurements, psychiatric symptoms, health knowledge, and glucose, hemoglobin A1c, and lipid levels. RESULTS: Our intention-to-treat analysis found significant differences in predicted trajectory of mean weight change between the groups over 12 months (P < .01), with treatment participants expected to lose an average 4.6 kg, while control participants would gain an average 0.6 kg. BMI and body fat percentage followed the same pattern. Both groups demonstrated statistically significant improvements in health knowledge quiz scores over time (P = .006), without significant difference between groups. CONCLUSIONS: Treatment was more effective than usual care control in treating medication-associated obesity, independent of SMI diagnosis, antipsychotic medication, and knowledge gained, suggesting that behavioral interventions are effective in SMI patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00344500. PMID- 26930533 TI - Preschool outcomes following prenatal serotonin reuptake inhibitor exposure: differences in language and behavior, but not cognitive function. AB - OBJECTIVE: To test the hypothesis that prenatal exposure to serotonin reuptake inhibitors (SRIs) is associated with language and behavioral outcomes in preschool-aged children, while accounting for confounds such as concomitant exposures and maternal mental illness. METHOD: An observational, prospective, longitudinal study of mental illness in pregnancy was conducted at a university based women's mental health clinic (April 2010-November 2012). A sample of 178 mother-child dyads participated in a laboratory visit at preschool age (2.5-5.5 years). The majority of women (87%) received psychotropic medication during pregnancy. Psychiatric status (based on DSM-IV), other medication use, and substance use were serially assessed and tested as confounds. Primary outcome measures included standardized measures of expressive language and cognitive function and mother and alternate caregiver ratings of child behavior problems, including the Pervasive Developmental Disorders (PDD) subscale of the Child Behavior Checklist. RESULTS: Linear regression analyses revealed that, after controlling for relevant covariates, expressive language scores from the Test of Early Language Development, 3rd edition, were negatively associated with prenatal SRI exposure (beta = -0.15, t = -2.41), while the PDD behavioral problems subscales completed by alternate caregivers and mothers were positively associated with prenatal SRI exposure (beta = 0.17, t = 2.01; beta = 0.16, t = 2.00, respectively). Cognitive function, measured using the Differential Ability Scales, 2nd edition, was not associated with any medication exposures. CONCLUSIONS: The current data suggest a small but significant association between prenatal SRI exposure and preschool outcomes, including expressive language and behavior problems. These data corroborate data from recent, population-based studies, although overall, published findings are mixed. Replication and identification of moderating risk factors are needed to understand potential clinical implications. PMID- 26930536 TI - Adverse outcomes following serotonin reuptake inhibitor exposure during pregnancy. PMID- 26930535 TI - A pilot randomized clinical trial evaluating the impact of genetic counseling for serious mental illnesses. AB - OBJECTIVE: The serious mental illnesses schizophrenia, schizoaffective disorder, and bipolar disorder are complex conditions affecting 1% to 4% of the population. Individuals with serious mental illnesses express interest in genetic counseling, an intervention showing promise for increasing patient knowledge and adaptation. This trial aimed to evaluate the effects of genetic counseling for people with serious mental illnesses as compared to an educational intervention or wait list. METHOD: A pilot 3-arm (each n = 40; genetic counseling, a control intervention involving an educational booklet, or wait list), parallel-group, randomized clinical trial was conducted from September 2008 through November 2011 in Vancouver, Canada. Participants with schizophrenia, bipolar disorder, or schizoaffective disorder (DSM-IV) completed outcome measures assessing knowledge, risk perception, internalized stigma, and perceived control over illness at baseline and 1-month follow-up. The Brief Symptom Inventory was administered to control for current symptoms. Analyses included linear mixed-effects models and chi(2) tests. RESULTS: Knowledge increased for genetic counseling/educational booklet compared to wait list at follow-up (LRT1 = 19.33, Holm-adjusted P = .0003, R(2)LMM(m) = 0.17). Risk perception accuracy increased at follow-up for genetic counseling compared to wait list (Yates continuity corrected chi(2)1 = 9.1, Bonferroni P = .003) and educational booklet (Yates continuity corrected chi(2)1 = 8.2, Bonferroni P = .004). There were no significant differences between groups for stigma or perceived control scores. CONCLUSIONS: Genetic counseling and the educational booklet improved knowledge, and genetic counseling, but not the educational booklet, improved risk perception accuracy for this population. The impact of genetic counseling on internalized stigma and perceived control is worth further investigation. Genetic counseling should be considered for patients with serious mental illnesses. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00713804. PMID- 26930537 TI - The safety and regulatory process for low calorie sweeteners in the United States. AB - Low calorie sweeteners are some of the most thoroughly tested and evaluated of all food additives. Products including aspartame and saccharin, have undergone several rounds of risk assessment by the United States Food and Drug Administration (FDA) and the European Food Safety Authority (EFSA), in relation to a number of potential safety concerns, including carcinogenicity and more recently, effects on body weight gain, glycemic control and effects on the gut microbiome. The majority of the modern day sweeteners; acesulfame K, advantame, aspartame, neotame and sucralose have been approved in the United States through the food additive process, whereas the most recent sweetener approvals for steviol glycosides and lo han guo have occurred through the Generally Recognized as Safe (GRAS) system, based on scientific procedures. While the regulatory process and review time of these two types of sweetener evaluations by the FDA differ, the same level of scientific evidence is required to support safety, so as to ensure a reasonable certainty of no harm. PMID- 26930538 TI - Introduction of double amidoxime group by double post surface modification on poly(vinylbenzyl chloride) beads for higher amounts of organic dyes, As (V) and Cr (VI) removal. AB - In this study, the synthesis of micron-sized poly(vinylbenzyl chloride) (p(VBC)) beads and subsequent conversion of the reactive chloromethyl groups to double amidoxime group containing moieties by post modification is reported. The prepared beads were characterized by SEM and FT-IR spectroscopy. The amidoximated p(VBC) beads were used as adsorbent for the removal of organic dyes, such as eosin y (EY) and methyl orange (MO), and heavy metals containing complex ions such as dichromate (Cr2O7(2-)) and arsenate (HAsO4(2)(-)) from aqueous media. The effect of the adsorbent dose on the percent removal, the effect of initial concentration of adsorbates on the adsorption rate and their amounts were also investigated. The Langmuir, Freundlich and Temkin adsorption isotherms were applied to the adsorption processes. The results indicated that the adsorption of both dichromate and arsenate ions obeyed the Langmuir adsorption model. Interestingly, it was found that the prepared beads were capable of removing significant amounts of arsenate and dichromate ions from tap and river (Saricay, Canakkale-Turkey) water. PMID- 26930539 TI - Efficient drug delivery using SiO2-layered double hydroxide nanocomposites. AB - MgAl-layered double hydroxide (MgAl-LDH) nanoparticles have great potentials in drug and siRNA delivery. In this work, we used a nanodot-coating strategy to prepare SiO2 dot-coated layered double hydroxide (SiO2@MgAl-LDH) nanocomposites with good dispersibility and controllable size for drug delivery. The optimal SiO2@MgAl-LDH nanocomposite was obtained by adjusting synthetic parameters including the mass ratio of MgAl-LDH to SiO2, the mixing temperature and time. The optimal SiO2@MgAl-LDH nanocomposite was shown to have SiO2 nanodots (10-15nm in diameter) evenly deposited on the surface of MgAl-LDHs (110nm in diameter) with the plate-like morphology and the average hydrodynamic diameter of 170nm. We further employed SiO2@MgAl-LDH nanocomposite as a nanocarrier to deliver methotrexate (MTX), a chemotherapy drug, to the human osteosarcoma cell (U2OS) and found that MTX delivered by SiO2@MgAl-LDH nanocomposite apparently inhibited the U2OS cell growth. PMID- 26930540 TI - Design and preparation of a simple and effective palladium catalyst and the hydrogenation performance toward dibenzylbiotinmethylester. AB - A series of well-dispersed carbon supported Pd catalysts were prepared by a simple and effective method under mild conditions. The functionalized carbon supported Pd catalyst (Pd/AC-H) demonstrated a enhanced performance to original carbon supported Pd catalyst (Pd/AC) in the probe reaction hydrogenation of 3,4 (1',3'-Dibenzyl-2'-oxoimidazolido)-2-(4-carboxybutylidene)thiophane to dibenzylbiotinmethylester. The results of various characterization techniques revealed that the improvement of Pd dispersion on Pd/AC-H catalyst surface could be associated to the presence of abundant oxygen-containing groups available for anchorage. Furthermore, the role of the surface groups of carbon supports was indispensable since they could provide an efficient pathway for the reaction. The oxygen-containing groups located at the Pd-supports interface were able to adjust the strength of reactant adsorption/activation on the Pd active sites, which was responsible for the high yield of dibenzylbiotinmethylester. PMID- 26930542 TI - Interfacial tension measured at high expansion rates and within milliseconds using microfluidics. AB - To understand droplet formation and stabilisation, technologies are needed to measure interfacial tension at micrometer range and millisecond scale. In this paper, microtechnology is used, and that allows us to access these ranges and derive a model for surfactant free systems. The predicting power of the model was tested, and we found that it can be used to accurately (validated with >60 experiments) describe droplet size for a wide range of flow rates, interfacial tensions, and continuous phase viscosities. The model was used next to determine interfacial tensions in a system with hexadecane and sodium dodecylsulfate (SDS) solutions, and it was found that the model can be used for droplet formation times ranging from 0.4 to 9.4ms while using a wide range of process conditions. The method described here differs greatly from standard dynamic interfacial tension methods that use quiescent, mostly diffusion-limited situations. The effects that we measured are much faster due to enhanced mass transfer; this allows us to assess the typical time scales used in industrial emulsification devices. PMID- 26930541 TI - A new route to fabricate biocompatible hydrogels with controlled drug delivery behavior. AB - Hydrogels for drug delivery have attracted extensive interests since they can be used for biomaterials such as contact lenses. Here, we report that biocompatible hydrogels for contact lenses with controlled drug delivery behavior can be fabricated using copolymer hydrogels and Layer-by-Layer (LbL) surface modification technique. Methyl acrylic anhydride (MAA) modified beta-cyclodextrin (beta-CD) (MA-beta-CD) was synthesized and copolymerized with hydroxyethyl methacrylate (HEMA) to form copolymer hydrogel. The introduction of second monomer of MA-beta-CD would accelerate the polymerization of hydrogel, leading to increase of residual CC groups. The structure of copolymers was characterized by differential scanning calorimetry (DSC). Transparence, equilibrium swelling ratio and contact angle of copolymer hydrogel were also detailed discussed in the work. In vitro drug release results showed that copolymer hydrogel with higher MA-beta CD content exhibited a better drug loading capacity and drug release behaviors could be tuned by MA-beta-CD/monomer ratio. Finally, alkynyl functional hyaluronic acid (HA-BP) and nitrine functional chitosan (CS-N3) were synthesized and covalently cross-linked to copolymer hydrogel surface using LbL technique through click chemistry. The successful LbL multilayers were confirmed by X-ray Photoelectron Spectroscopy (XPS). Resultsofcytotoxicityexperiment revealed that the hydrogels were biocompatible since they could support the growth of cells. PMID- 26930543 TI - Phase behavior and interfacial properties of a switchable ethoxylated amine surfactant at high temperature and effects on CO2-in-water foams. AB - The interfacial properties for surfactants at the supercritical CO2-water (C-W) interface at temperatures above 80 degrees C have very rarely been reported given limitations in surfactant solubility and chemical stability. These limitations, along with the weak solvent strength of CO2, make it challenging to design surfactants that adsorb at the C-W interface, despite the interest in CO2-in water (C/W) foams (also referred to as macroemulsions). Herein, we examine the thermodynamic, interfacial and rheological properties of the surfactant C12 14N(EO)2 in systems containing brine and/or supercritical CO2 at elevated temperatures and pressures. Because the surfactant is switchable from the nonionic state to the protonated cationic state as the pH is lowered over a wide range in temperature, it is readily soluble in brine in the cationic state below pH 5.5, even up to 120 degrees C, and also in supercritical CO2 in the nonionic state. As a consequence of the affinity for both phases, the surfactant adsorption at the CO2-water interface was high, with an area of 207A(2)/molecule. Remarkably, the surfactant lowered the interfacial tension (IFT) down to ~5mN/m at 120 degrees C and 3400 psia (23MPa), despite the low CO2 density of 0.48g/ml, indicating sufficient solvation of the surfactant tails. The phase behavior and interfacial properties of the surfactant in the cationic form were favorable for the formation and stabilization of bulk C/W foam at high temperature and high salinity. Additionally, in a 1.2 Darcy glass bead pack at 120 degrees C, a very high foam apparent viscosity of 146 cP was observed at low interstitial velocities given the low degree of shear thinning. For a calcium carbonate pack, C/W foam was formed upon addition of Ca(2+) and Mg(2+) in the feed brine to keep the pH below 4, by the common ion effect, in order to sufficiently protonate the surfactant. The ability to form C/W foams at high temperatures is of interest for a variety of applications in chemical synthesis, separations, materials science, and subsurface energy production. PMID- 26930544 TI - Is toxicity of PMMA (paramethoxymethamphetamine) associated with cytochrome P450 pharmacogenetics? AB - In 2010-2013, 29 fatal intoxications related to the designer drug paramethoxymethamphetamine (PMMA, 4-methoxymethamphetamine) occurred in Norway. The current knowledge about metabolism and toxicity of PMMA in humans is limited. Metabolism by the polymorphic cytochrome P450 (CYP) 2D6 enzyme to the psychoactive metabolite 4-hydroxymethamphetamine (OH-MA), and possibly by additional enzymes, is suggested to be involved in its toxicity. The aim of this work was to study the association between CYP genetics, PMMA metabolism and risk of fatal PMMA toxicity in humans. The frequency distribution of clinically relevant gene variants of CYP2D6, CYP2C9, CYP2C19 and CYP3A5, and the phenotypic blood CYP2D6 metabolic ratio (OH-MA/PMMA) in particular, were compared in fatal PMMA intoxications (n=17) and nonfatal PMMA abuse controls (n=30), using non abusers (n=305) as references for the expected genotype frequencies in the Norwegian population. Our study demonstrated that the CYP2D6 enzyme and genotype are important in the metabolism of PMMA to OH-MA in humans, but that other enzymes are also involved in this biotransformation. In the fatal PMMA intoxications, the blood concentrations of PMMA were higher and the CYP2D6 metabolic ratios were lower, than in the nonfatal PMMA abuse controls (median (range) 2.1 (0.03-5.0) vs 0.3 (0.1-0.9) mg/L, and ratio 0.6 (0.0-4.6) vs 2.1 (0.2 7.4) p=0.021, respectively). Overall, our findings indicated that, in most cases, PMMA death occurred rapidly and at an early stage of PMMA metabolism, following the ingestion of large and toxic PMMA doses. We could not identify any genetic CYP2D6, CYP2C9, CYP2C19 or CYP3A5 predictive marker on fatal toxicity of PMMA in humans. The overrepresentation of the CYP2D6 poor metabolizer (PM) genotype found in the nonfatal PMMA abuse controls warrants further investigations. PMID- 26930545 TI - Photocatalytic hydrogen production from biomass-derived compounds: a case study of citric acid. AB - Highly crystalline anatase TiO2 nanoparticles with high BET surface area have been synthesized by thermal hydrolysis of titanium(IV) bis(ammoniumlactato) dihydroxide aqueous solutions. The photocatalytic H2 production from aqueous citric acid (CA) solutions over Pt-loaded TiO2 has been investigated under different experimental conditions, that is, different CA concentration, temperature, light intensity, and pH of Pt/TiO2 suspension. For comparison, the photocatalytic dehydrogenation of triethanolamine (TEA) has also been investigated. The highest H2 production rates were obtained at pH 3 and 9 for CA and TEA, respectively. This behavior is readily explained by the adsorption characteristic of the employed reagent on the surface of the charged TiO2. The effect of the photocatalyst loading and the light intensity on the H2 production rate showed the same behavior in the case of CA and TEA evincing that these parameters are catalyst dependent. The apparent activation energies have been determined to be 13.5 +/- 1.8 and 14.7 +/- 1.6 kJ mol(-1) for CA and TEA, respectively, indicating the existence of an activation energy barrier in a photocatalytic process which can be attributed to the desorption of adsorbed products. PMID- 26930546 TI - Autophagy Proteins ATG5 and ATG7 Are Essential for the Maintenance of Human CD34(+) Hematopoietic Stem-Progenitor Cells. AB - Autophagy is a highly regulated catabolic process that involves sequestration and lysosomal degradation of cytosolic components such as damaged organelles and misfolded proteins. While autophagy can be considered to be a general cellular housekeeping process, it has become clear that it may also play cell type dependent functional roles. In this study, we analyzed the functional importance of autophagy in human hematopoietic stem/progenitor cells (HSPCs), and how this is regulated during differentiation. Western blot-based analysis of LC3-II and p62 levels, as well as flow cytometry-based autophagic vesicle quantification, demonstrated that umbilical cord blood-derived CD34(+) /CD38(-) immature hematopoietic progenitors show a higher autophagic flux than CD34(+) /CD38(+) progenitors and more differentiated myeloid and erythroid cells. This high autophagic flux was critical for maintaining stem and progenitor function since knockdown of autophagy genes ATG5 or ATG7 resulted in reduced HSPC frequencies in vitro as well as in vivo. The reduction in HSPCs was not due to impaired differentiation, but at least in part due to reduced cell cycle progression and increased apoptosis. This is accompanied by increased expression of p53, proapoptotic genes BAX and PUMA, and the cell cycle inhibitor p21, as well as increased levels of cleaved caspase-3 and reactive oxygen species. Taken together, our data demonstrate that autophagy is an important regulatory mechanism for human HSCs and their progeny, reducing cellular stress and promoting survival. Stem Cells 2016;34:1651-1663. PMID- 26930548 TI - Gate-Tunable Tunneling Resistance in Graphene/Topological Insulator Vertical Junctions. AB - Graphene-based vertical heterostructures, particularly stacks incorporated with other layered materials, are promising for nanoelectronics. The stacking of two model Dirac materials, graphene and topological insulator, can considerably enlarge the family of van der Waals heterostructures. Despite good understanding of the two individual materials, the electron transport properties of a combined vertical heterojunction are still unknown. Here, we show the experimental realization of a vertical heterojunction between Bi2Se3 nanoplate and monolayer graphene. At low temperatures, the electron transport through the vertical heterojunction is dominated by the tunneling process, which can be effectively tuned by gate voltage to alter the density of states near the Fermi surface. In the presence of a magnetic field, quantum oscillations are observed due to the quantized Landau levels in both graphene and the two-dimensional surface states of Bi2Se3. Furthermore, we observe an exotic gate-tunable tunneling resistance under high magnetic field, which displays resistance maxima when the underlying graphene becomes a quantum Hall insulator. PMID- 26930549 TI - A risk index for pediatric patients undergoing diagnostic imaging with (99m)Tc dimercaptosuccinic acid that accounts for body habitus. AB - Published guidelines for administered activity to pediatric patients undergoing diagnostic nuclear medicine imaging are currently obtained through expert consensus of the minimum values as a function of body weight as required to yield diagnostic quality images. We have previously shown that consideration of body habitus is also important in obtaining diagnostic quality images at the lowest administered activity. The objective of this study was to create a series of computational phantoms that realistically portray the anatomy of the pediatric patient population which can be used to develop and validate techniques to minimize radiation dose while maintaining adequate image quality. To achieve this objective, we have defined an imaging risk index that may be used in future studies to develop pediatric patient dosing guidelines. A population of 48 hybrid phantoms consisting of non-uniform B-spline surfaces and polygon meshes was generated. The representative ages included the newborn, 1 year, 5 year, 10 year and 15 year male and female. For each age, the phantoms were modeled at their 10th, 50th, and 90th height percentile each at a constant 50th weight percentile. To test the impact of kidney size, the newborn phantoms were modeled with the following three kidney volumes: -15%, average, and +15%. To illustrate the impact of different morphologies on dose optimization, we calculated the effective dose for each phantom using weight-based (99m)Tc-DMSA activity administration. For a given patient weight, body habitus had a considerable effect on effective dose. Substantial variations were observed in the risk index between the 10th and 90th percentile height phantoms from the 50th percentile phantoms for a given age, with the greatest difference being 18%. There was a dependence found between kidney size and risk of radiation induced kidney cancer, with the highest risk indices observed in newborns with the smallest kidneys. Overall, the phantoms and techniques in this study can be used to provide data to refine dosing guidelines for pediatric nuclear imaging studies while taking into account the effects on both radiation dose and image quality. PMID- 26930551 TI - The Value of Alternatives Assessment. PMID- 26930550 TI - An antigen-specific, four-color, B-cell FluoroSpot assay utilizing tagged antigens for detection. AB - The FluoroSpot assay, a variant of ELISpot utilizing fluorescent detection, has so far been used primarily for assessment of T cells, where simultaneous detection of several cytokines has allowed a more qualitative analysis of functionally distinct T cells. The potential to measure multiple analytes also presents several advantages when analyzing B cells. Our aim was to develop a B cell FluoroSpot assay adaptable to studies of a variety of antigens. The assay utilizes anti-IgG antibodies immobilized in 96-well filter membrane plates. During cell culture, IgG antibodies secreted by antibody-secreting cells (ASCs) are captured in the vicinity of each of these cells and the specificity of single ASCs is defined using antigens for detection. The antigens were labeled with biotin or peptide tags enabling secondary detection with fluorophore-conjugated streptavidin or tag-specific antibodies. The assay, utilizing up to four different tag systems and fluorophores simultaneously, was evaluated using hybridomas and immunized splenocytes as ASCs. Assay variants were developed that could: i) identify multiple ASCs with different antigen specificities; ii) detect ASCs showing cross-reactivity with different but related antigens; and iii) define the antigen-specificity and, by including anti-IgG subclass detection reagents, simultaneously determine the IgG subclass of antibodies secreted by ASCs. As demonstrated here, the B-cell FluoroSpot assay using tag-based detection systems provides a versatile and powerful tool to investigate antibody responses by individual cells that can be readily adapted to studies of a variety of antigen-specific ASCs. PMID- 26930552 TI - From Observation to Information: Data-Driven Understanding of on Farm Yield Variation. AB - Agriculture research uses "recommendation domains" to develop and transfer crop management practices adapted to specific contexts. The scale of recommendation domains is large when compared to individual production sites and often encompasses less environmental variation than farmers manage. Farmers constantly observe crop response to management practices at a field scale. These observations are of little use for other farms if the site and the weather are not described. The value of information obtained from farmers' experiences and controlled experiments is enhanced when the circumstances under which it was generated are characterized within the conceptual framework of a recommendation domain, this latter defined by Non-Controllable Factors (NCFs). Controllable Factors (CFs) refer to those which farmers manage. Using a combination of expert guidance and a multi-stage analytic process, we evaluated the interplay of CFs and NCFs on plantain productivity in farmers' fields. Data were obtained from multiple sources, including farmers. Experts identified candidate variables likely to influence yields. The influence of the candidate variables on yields was tested through conditional forests analysis. Factor analysis then clustered harvests produced under similar NCFs, into Homologous Events (HEs). The relationship between NCFs, CFs and productivity in intercropped plantain were analyzed with mixed models. Inclusion of HEs increased the explanatory power of models. Low median yields in monocropping coupled with the occasional high yields within most HEs indicated that most of these farmers were not using practices that exploited the yield potential of those HEs. Varieties grown by farmers were associated with particular HEs. This indicates that farmers do adapt their management to the particular conditions of their HEs. Our observations confirm that the definition of HEs as recommendation domains at a small-scale is valid, and that the effectiveness of distinct management practices for specific micro recommendation domains can be identified with the methodologies developed. PMID- 26930553 TI - Development and Evaluation of a Blood Culture PCR Assay for Rapid Detection of Salmonella Paratyphi A in Clinical Samples. AB - BACKGROUND: Enteric fever remains an important cause of morbidity in many low income countries and Salmonella Paratyphi A has emerged as the aetiological agent in an increasing proportion of cases. Lack of adequate diagnostics hinders early diagnosis and prompt treatment of both typhoid and paratyphoid but development of assays to identify paratyphoid has been particularly neglected. Here we describe the development of a rapid and sensitive blood culture PCR method for detection of Salmonella Paratyphi A from blood, potentially allowing for appropriate diagnosis and antimicrobial treatment to be initiated on the same day. METHODS: Venous blood samples from volunteers experimentally challenged orally with Salmonella Paratyphi A, who subsequently developed paratyphoid, were taken on the day of diagnosis; 10 ml for quantitative blood culture and automated blood culture, and 5 ml for blood culture PCR. In the latter assay, bacteria were grown in tryptone soy broth containing 2.4% ox bile and micrococcal nuclease for 5 hours (37 degrees C) before bacterial DNA was isolated for PCR detection targeting the fliC-a gene of Salmonella Paratyphi A. RESULTS: An optimized broth containing 2.4% ox bile and micrococcal nuclease, as well as a PCR test was developed for a blood culture PCR assay of Salmonella Paratyphi A. The volunteers diagnosed with paratyphoid had a median bacterial burden of 1 (range 0.1-6.9) CFU/ml blood. All the blood culture PCR positive cases where a positive bacterial growth was shown by quantitative blood culture had a bacterial burden of >= 0.3 CFU/ ml blood. The blood culture PCR assay identified an equal number of positive cases as automated blood culture at higher bacterial loads (>=0.3 CFU/ml blood), but utilized only half the volume of specimens. CONCLUSIONS: The blood culture PCR method for detection of Salmonella Paratyphi A can be completed within 9 hours and offers the potential for same-day diagnosis of enteric fever. Using 5 ml blood, it exhibited a lower limit of detection equal to 0.3 CFU/ml blood, and it performed at least as well as automated blood culture at higher bacterial loads (>=0.3 CFU/ml blood) of clinical specimens despite using half the volume of blood. The findings warrant its further study in endemic populations with a potential use as a novel diagnostic which fills the present gap of paratyphoid diagnostics. PMID- 26930554 TI - Preparation of High-Density Fibrillar Collagen Matrices That Mimic Desmoplastic Tumor Stroma. AB - The stroma of invasive tumors becomes enriched in dense fibrillar collagen as a result of the desmoplastic reaction. This desmoplastic collagen exerts profound effects on tumor and normal cells. In view of these findings, it is important to develop novel in vitro cell systems that mimic this desmoplastic extracellular matrix in order to permit cell studies under in vivo-like conditions. This unit provides a protocol and troubleshooting guide for preparation of high-density fibrillar collagen (HDFC) matrices that closely model the desmoplastic collagenous matrix of malignant tumors. It then describes the use of this matrix for in vitro cell studies of invadopodia formation and function in extracellular matrix invasion. In addition, it provides a detailed protocol for immunolabeling of invadopodial proteins and detection of HDFC matrix degradation associated with invadopodia to permit visualization of invadopodia using fluorescence microscopy. (c) 2016 by John Wiley & Sons, Inc. PMID- 26930555 TI - Analysis of the Stromal Cellular Components of the Solid Tumor Microenvironment Using Flow Cytometry. AB - The tumor microenvironment consists of a variety of cell types. The contribution of each cell type to the tumor is an emerging subject in the field of cancer research. Here, we describe protocols for dissociating tumor tissues and Matrigel plugs into single cells for further analysis by flow cytometry. These protocols can be used for evaluating the cellular component of solid tumors from human or mouse origin or Matrigel plugs implanted in mice. The protocols describe the dissociation of tumor tissue with or without dissociation automatic devices. Subsequently, the use of flow cytometry for immunophenotypic analysis of host cells found in the tumor microenvironment, including myeloid derived suppressor cells, endothelial cells, and macrophages is provided. These methods can be used to broaden our understanding of the cross-talk between tumor and host cells in the tumor microenvironment. (c) 2016 by John Wiley & Sons, Inc. PMID- 26930556 TI - Three-Dimensional Patterning of the ECM Microenvironment Using Magnetic Nanoparticle Self Assembly. AB - This protocol describes a way to introduce topography to three-dimensional (3D) biomaterials. The self-assembling behavior of magnetic particles can be exploited to form nanoscale to microscale fibers, such that one can dissect the contribution of topography on cell behavior, which is independent of other physical properties of the biomaterial (e.g., stiffness). The magnetic particles are chemically cross-linked with several extracellular matrix (ECM) proteins and then using magnetic force-mediated assembly, one can program aligned nanofibers in a 3D hydrogel. This process allows the creation of diverse topographic patterns in 3D, including isotropic, anisotropic (fibril), or interfaced architectures, without changing the bulk stiffness of the scaffold material. This anisotropic architecture guides the dendritic protrusions of cells, which can be compared to cells grown in an isotropic architecture lacking spatial guidance cues. Several cell types, such as fibroblasts and neurons, have been cultured in this engineered 3D matrix. This technology provides an easy way to construct nano bio interfaces for various biomedical engineering applications as well as dissect the role of topography in various cell behaviors. (c) 2016 by John Wiley & Sons, Inc. PMID- 26930557 TI - Interprofessional orientation for health professionals utilising simulated learning: Findings from a pilot study. AB - We describe a novel, interprofessional educational intervention pilot used to orient new health profession employees through the simulation laboratory. Health profession employees were recruited to engage in a simulation training session that focused on communication, collaboration, and healthcare roles and responsibilities. Learners (N = 11) were divided into two groups with representation from various health disciplines. Each group participated in a simulated patient scenario while the other group actively observed in another classroom. At the end of both sessions, the group reconvened for a debriefing session. Participants were given a survey before and after the training session, to evaluate the content, experience, and value to their practice. The pre- and post-evaluation survey analysis showed improvement in all objectives with a mean (SD) pre-evaluation score of 4.10 (0.40-1.01) and mean (SD) post-evaluation score of 4.73 (0.30-0.81). Results were favourable, and plans to expand this project are under way. PMID- 26930559 TI - Mechanisms of Phenotypic Rifampicin Tolerance in Mycobacterium tuberculosis Beijing Genotype Strain B0/W148 Revealed by Proteomics. AB - The "successful" Russian clone B0/W148 of Mycobacterium tuberculosis Beijing is well-known for its capacity to develop antibiotic resistance. During treatment, resistant mutants can occur that have inheritable resistance to specific antibiotics. Next to mutations, M. tuberculosis has several mechanisms that increase their tolerance to a variety of antibiotics. Insights in the phenotypic mechanisms that contribute to drug tolerance will increase our understanding of how antibiotic resistance develops in M. tuberculosis. In this study, we examined the (phospho)proteome dynamics in M. tuberculosis Beijing strain B0/W148 when exposed to a high dose of rifampicin; one of the most potent first-line antibiotics. A total of 2,534 proteins and 191 phosphorylation sites were identified, and revealed the differential regulation of DosR regulon proteins, which are necessary for the development of a dormant phenotype that is less susceptible to antibiotics. By examining independent phenotypic markers of dormancy, we show that persisters of in vitro rifampicin exposure entered a metabolically hypoactive state, which yields rifampicin and other antibiotics largely ineffective. These new insights in the role of protein regulation and post-translational modifications during the initial phase of rifampicin treatment reveal a shortcoming in the antituberculosis regimen that is administered to 8-9 million individuals annually. PMID- 26930560 TI - Staying in the Hood: Black Lesbian and Transgender Women and Identity Management in North Philadelphia. AB - The concept Don't Ask, Don't Tell regarding Black LGBT sexuality in Black communities has been an acceptable form of identity management for Black LGBT people. In other words, Black LGBT people are accepted as long as they are not vocal about their sexuality. However, this is changing with the issue of gay marriage, which is creating a space where Black LGBT people are more open about their gender identity and sexuality in heterosexual Black spaces. This new form of openness allows Black LGBT people to "stay in" their communities, as opposed to coming out. In this article I examine how Black LGBT women in North Philadelphia stay in their communities: being politically active regarding LGBT issues, disengaging from LGBT issues, passing, and educating straight Black people about issues affecting the Black LGBT community. I conclude with implications of staying in and intersectionality among Black heterosexual and LGBT women fighting for social change. PMID- 26930558 TI - Generation and Characterization of Mice Expressing a Conditional Allele of the Interleukin-1 Receptor Type 1. AB - The cytokines IL-1alpha and IL-1beta exert powerful pro-inflammatory actions throughout the body, mediated primarily by the intracellular signaling capacity of the interleukin-1 receptor (IL-1R1). Although Il1r1 knockout mice have been informative with respect to a requirement for IL-1R1 signaling in inflammatory events, the constitutive nature of gene elimination has limited their utility in the assessment of temporal and spatial patterns of cytokine action. To pursue such questions, we have generated C57Bl/6J mice containing a floxed Il1r1 gene (Il1r1loxP/loxP), with loxP sites positioned to flank exons 3 and 4 and thereby the ability to spatially and temporally eliminate Il1r1 expression and signaling. We found that Il1r1loxP/loxP mice breed normally and exhibit no gross physical or behavioral phenotypes. Moreover, Il1r1loxP/loxP mice exhibit normal IL-1R1 receptor expression in brain and spleen, as well as normal IL-1R1-dependent increases in serum IL-6 following IL-1alpha injections. Breeding of Il1r1loxP/loxP mice to animals expressing a cytomegalovirus (CMV)-driven Cre recombinase afforded efficient excision at the Il1r1 locus. The Il1r1loxP/loxP line should be a valuable tool for the assessment of contributions made by IL-1R1 signaling in diverse cell types across development. PMID- 26930561 TI - Diminished Lipid Raft SNAP23 Increases Blood Pressure by Inhibiting the Membrane Fluidity of Vascular Smooth-Muscle Cells. AB - Synaptosomal-associated protein 23 (SNAP23) is involved in microvesicle trafficking and exocytosis in various cell types, but its functional role in blood pressure (BP) regulation has not yet been defined. Here, we found that lipid raft SNAP23 expression was much lower in vascular smooth-muscle cells (VSMCs) from spontaneously hypertensive rats (SHR) than in those from normotensive Wistar-Kyoto (WKY) rats. This led us to investigate the hypothesis that this lower expression may be linked to the spontaneous hypertension found in SHR. The expression level of lipid raft SNAP23 and the fluidity in the plasma membrane of VSMCs were lower in SHR than in WKY rats. Cholesterol content in the VSMC membrane was higher, but the secreted cholesterols found in VSMC-conditioned medium and in the blood serum were lower in SHR than in WKY rats. SNAP23 knockdown in WKY rat VSMCs reduced the membrane fluidity and increased the membrane cholesterol level. Systemic overexpression of SNAP23 in SHR resulted in an increase of cholesterol content in their serum, a decrease in cholesterol in their aorta and the reduction of their BP. Our findings suggest that the low expression of the lipid raft SNAP23 in VSMCs might be a potential cause for the characteristic hypertension of SHR. PMID- 26930562 TI - Organic acid component from Taraxacum mongolicum Hand.-Mazz alleviates inflammatory injury in lipopolysaccharide-induced acute tracheobronchitis of ICR mice through TLR4/NF-kappaB signaling pathway. AB - Inflammation plays an important role in the pathogenesis of acute tracheobronchitis. Taraxacum mongolicum Hand.-Mazz (TMHM) is a dietic herb for heat-clearing and detoxifying functions as well as swell-reducing and mass resolving effect in Traditional Chinese Medicine. Studies have shown that its major ingredient organic acid component (OAC) possesses favorable anti inflammatory activity. However, the protective effect of OAC from TMHM (TMHM-OAC) on inflammatory injury of acute tracheobronchitis and its possible mechanism remains poorly understood. In this study, HPLC-DAD was used to analyze the components of TMHM-OAC. Lipopolysaccharide of 1mg/ml was used to induce respiratory inflammation in ICR mice at the dose of 5mg/kg by intratracheally aerosol administration. Enzyme-linked immunosorbent assay (ELISA) was employed to detect the levels of inflammation factors such as interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and nitric oxide in serum and supernatant of trachea tissue. Western blotting (WB) and Immunohistochemistry analysis (IHC) were conducted in parallel to determine TNF-alpha, IL-6, inducible nitric oxide synthase (iNOS), Toll-like receptors 4(TLR4) protein expressions and nuclear factor-kappa B p65 (NF-kappaB p65) phosphorylation. Hematoxylin-Eosin staining (HE) was applied to evaluate pathological lesions of trachea tissue. Experimental results showed that TMHM-OAC significantly reduced the levels of the TNF-alpha, IL-6 and NO in serum and supernatant of tracheal of LPS-induced ICR mice. The protein expression levels of TNF-alpha, IL-6 and iNOS in tracheal tissue were also down-regulated significantly by the treatment of TMHM-OAC. Moreover, TMHM OAC downregulated phosphorylation of NF-kappaB p65 and protein expression of TLR4. Our results indicated that TMHM-OAC could improve LPS-induced histopathological damage of tracheal tissues through the regulation of TLR4/NF kappaB signaling pathway and could be beneficial for the treatment of acute tracheobronchitis. PMID- 26930563 TI - Comparative genomics for understanding the structure, function and sub-cellular localization of hypothetical proteins in Thermanerovibrio acidaminovorans DSM 6589 (tai). AB - The Thermanerovibrio acidaminovorans DSM 6589 (tai) is a unique bacterium isolated from anaerobic sludge bed reactor from sugar refinery in Netherland. The comparative genomic studies for understanding the hypothetical proteins in T. acidaminovorans DSM 6589 (tai) were carried out using different bioinformatic tools and web servers. In all 320 hypothetical proteins were screened from the total available genome. The Insilico function prediction for 320 hypothetical proteins was achieved by using different online servers like CDD-Blast, Interproscan and pfam whereas, the structure prediction for 202 hypothetical proteins were deciphered by using protein structure prediction server (PS2 server). The sub-cellular localization for the identified proteins was predicted by the use of cello v2.5 for 320. The study carried out has helped us to understand the structures and functions of unknown proteins available in T. acidaminovorans DSM 6589 (tai) through comparative genomic approach. PMID- 26930564 TI - Equilibrium and kinetic selectivity profiling on the human adenosine receptors. AB - Classical evaluation of target selectivity is usually undertaken by measuring the binding affinity of lead compounds against a number of potential targets under equilibrium conditions, without considering the kinetics of the ligand-receptor interaction. In the present study we propose a combined strategy including both equilibrium- and kinetics-based selectivity profiling. The adenosine receptor (AR) was chosen as a prototypical drug target. Six in-house AR antagonists were evaluated in a radioligand displacement assay for their affinity and in a competition association assay for their binding kinetics on three AR subtypes. One of the compounds with a promising kinetic selectivity profile was also examined in a [(35)S]-GTPgammaS binding assay for functional activity. We found that XAC and LUF5964 were kinetically more selective for the A1R and A3R, respectively, although they are non-selective in terms of their affinity. In comparison, LUF5967 displayed a strong equilibrium-based selectivity for the A1R over the A2AR, yet its kinetic selectivity thereon was less pronounced. In a GTPgammaS assay, LUF5964 exhibited insurmountable antagonism on the A3R while having a surmountable effect on the A1R, consistent with its kinetic selectivity profile. This study provides evidence that equilibrium and kinetic selectivity profiling can both be important in the early phases of the drug discovery process. Our proposed combinational strategy could be considered for future medicinal chemistry efforts and aid the design and discovery of different or even better leads for clinical applications. PMID- 26930565 TI - The Non-Specific Binding of Fluorescent-Labeled MiRNAs on Cell Surface by Hydrophobic Interaction. AB - BACKGROUND: MicroRNAs are small noncoding RNAs about 22 nt long that play key roles in almost all biological processes and diseases. The fluorescent labeling and lipofection are two common methods for changing the levels and locating the position of cellular miRNAs. Despite many studies about the mechanism of DNA/RNA lipofection, little is known about the characteristics, mechanisms and specificity of lipofection of fluorescent-labeled miRNAs. METHODS AND RESULTS: Therefore, miRNAs labeled with different fluorescent dyes were transfected into adherent and suspension cells using lipofection reagent. Then, the non-specific binding and its mechanism were investigated by flow cytometer and laser confocal microscopy. The results showed that miRNAs labeled with Cy5 (cyanine fluorescent dye) could firmly bind to the surface of adherent cells (Hela) and suspended cells (K562) even without lipofection reagent. The binding of miRNAs labeled with FAM (carboxyl fluorescein) to K562 cells was obvious, but it was not significant in Hela cells. After lipofectamine reagent was added, most of the fluorescently labeled miRNAs binding to the surface of Hela cells were transfected into intra cell because of the high transfection efficiency, however, most of them were still binding to the surface of K562 cells. Moreover, the high-salt buffer which could destroy the electrostatic interactions did not affect the above-mentioned non-specific binding, but the organic solvent which could destroy the hydrophobic interactions eliminated it. CONCLUSIONS: These results implied that the fluorescent-labeled miRNAs could non-specifically bind to the cell surface by hydrophobic interaction. It would lead to significant errors in the estimation of transfection efficiency only according to the cellular fluorescence intensity. Therefore, other methods to evaluate the transfection efficiency and more appropriate fluorescent dyes should be used according to the cell types for the accuracy of results. PMID- 26930566 TI - In vitro skin permeation of artemisone and its nano-vesicular formulations. AB - The artemisinin derivative artemisone has antitumor activity. In particular when encapsulated in solid lipid nanoparticles (SLNs) and niosomes, it is active against human melanoma A-375 cells, although such formulations have a negligible effect on human keratinocyte cells. The aim here was to determine whether these formulations could enhance the topical delivery and skin permeation of artemisone as a prelude to evaluating use of artemisone and related compounds for melanoma treatment. In vitro skin permeation studies were conducted to determine the concentration of artemisone delivered into the stratum corneum-epidermis and epidermis-dermis. Artemisone-SLNs delivered artemisone into the stratum corneum epidermis at significantly higher concentration (62.632 MUg/mL) than the artemisone-niosomes (12.792 MUg/mL). Neither of the controls delivered artemisone into the stratum corneum-epidermis. In the epidermis-dermis, artemisone (13.404 MUg/mL) was only detected after application of the SLN formulation. Overall, the excellent topical delivery of artemisone with the SLN formulation coupled with the intrinsic activity of formulated artemisone confirms potential for use in treatment of melanoma. PMID- 26930567 TI - Vitamin D improves endothelial dysfunction and restores myeloid angiogenic cell function via reduced CXCL-10 expression in systemic lupus erythematosus. AB - Patients with systemic lupus erythematosus (SLE) have accelerated cardiovascular disease and dysfunctional endothelial repair mechanisms. Myeloid angiogenic cells (MACs), derived from circulating monocytes, augment vascular repair by paracrine secretion of pro-angiogenic factors. We observed that SLE MACs are dysfunctional and secrete pro-inflammatory cytokines. We also found that the vitamin D receptor was transiently expressed during MAC differentiation and that in vitro, calcitriol increased differentiation of monocytes into MACs in both SLE and in a model using the prototypic SLE cytokine, interferon-alpha. The active form of vitamin D (calcitriol) restored the SLE MAC phenotype towards that of healthy subjects with reduced IL-6 secretion, and normalised surface marker expression. Calcitriol also augmented the angiogenic capacity of MACs via the down-regulation of CXCL-10. In SLE patients treated with cholecalciferol for 12 weeks, the improvement in endothelial function correlated with increase in serum 25(OH)D concentrations independently of disease activity. We also show that MACs were able to positively modulate eNOS expression in human endothelial cells in vitro, an effect further enhanced by calcitriol treatment of SLE MACs. The results demonstrate that vitamin D can positively modify endothelial repair mechanisms and thus endothelial function in a population with significant cardiovascular risk. PMID- 26930569 TI - Effect of NSAIDs on the aminopeptidase activity of cultured human osteoblasts. AB - Aminopeptidases (APs) are involved in various physiological and pathological processes. In tumor tissues the expression of APs, cyclooxygenase-2 and its metabolites are increased. The objective was to determine the effect of certain NSAIDs on the AP activity of osteoblasts. Primary cultures of osteoblast were treated with different concentrations of indomethacin, meloxicam, naproxen, nimesulide, and piroxicam. The AP activity was fluorimetrically determined using aminoacyl-beta-naphthylamides (aa-betaNAs) as substrates: Ala-betaNA, Arg-betaNA, Gly-betaNA, Leu-betaNA, Lys-betaNA, Met-betaNA, and Phe-betaNA. The five NSAIDs showed an inhibitory effect of AP activity against the study substrates depending on the dose tested. Meloxicam and piroxicam had the highest inhibitory effect on enzymatic activity, with an IC50 of around 70 MUM. Our results suggest that the physiological alteration of osteoblasts in the presence of NSAIDs may be a consequence of AP inhibition, suggesting a potential clinical role for these drugs against cancer in combination with chemotherapeutic agents. PMID- 26930568 TI - High Spinal Anesthesia Enhances Anti-Inflammatory Responses in Patients Undergoing Coronary Artery Bypass Graft Surgery and Aortic Valve Replacement: Randomized Pilot Study. AB - BACKGROUND: Cardiac surgery induces many physiologic changes including major inflammatory and sympathetic nervous system responses. Here, we conducted a single-centre pilot study to generate hypotheses on the potential immune impact of adding high spinal anaesthesia to general anaesthesia during cardiac surgery in adults. We hypothesized that this strategy, previously shown to blunt the sympathetic response and improve pain management, could reduce the undesirable systemic inflammatory responses caused by cardiac surgery. METHODS: This prospective randomized unblinded pilot study was conducted on 14 patients undergoing cardiac surgery for coronary artery bypass grafting and/or aortic valve replacement secondary to severe aortic stenosis. The primary outcome measures examined longitudinally were serum pro-inflammatory (IL-6, IL-1b, CCL2), anti-inflammatory (IL-10, TNF-RII, IL-1Ra), acute phase protein (CRP, PTX3) and cardiovascular risk (sST2) biomarkers. RESULTS: The kinetics of pro- and anti inflammatory biomarker was determined following surgery. All pro-inflammatory and acute phase reactant biomarker responses induced by surgical stress were indistinguishable in intensity and duration between control groups and those who also received high spinal anaesthesia. Conversely, IL-10 levels were markedly elevated in both intensity and duration in the group receiving high spinal anesthesia (p = 0.005). CONCLUSIONS: This hypothesis generating pilot study suggests that high spinal anesthesia can alter the net inflammatory response that results from cardiac surgery. In appropriately selected populations, this may add incremental benefit by dampening the net systemic inflammatory response during the week following surgery. Larger population studies, powered to assess immune, physiologic and clinical outcomes in both acute and longer term settings, will be required to better assess potential benefits of incorporating high spinal anesthesia. TRIAL REGISTRATION: ClinicalTrials.gov NCT00348920. PMID- 26930570 TI - Actin microfilaments are involved in the regulation of HVA1 transcript accumulation in drought-treated barley leaves. AB - Drought is one of the stresses that limit the yield of barley. Despite extensive studies focused on the issue, the molecular mechanism of the response to drought is still not fully understood. In our previous study, we proposed drought-induced signal perception controlled by actin filaments (AFs). To test this hypothesis, we used a chemical inhibitor of AF polarization-latrunculin B. In drought-treated barley leaves, latrunculin B induced AF depolymerization and altered gene expression (mainly those controlling AF formation), notably inhibiting the expression of HVA1, a dehydrin encoding gene whose function in drought tolerance has been widely studied. These results suggest that AFs might be involved in water-deficit signal perception in plant cells. PMID- 26930571 TI - Diagnosis of HIV-Associated Oral Lesions in Relation to Early versus Delayed Antiretroviral Therapy: Results from the CIPRA HT001 Trial. AB - Oral mucosal lesions that are associated with HIV infection can play an important role in guiding the decision to initiate antiretroviral therapy (ART). The incidence of these lesions relative to the timing of ART initiation has not been well characterized. A randomized controlled clinical trial was conducted at the GHESKIO Center in Port-au-Prince, Haiti between 2004 and 2009. 816 HIV-infected ART-naive participants with CD4 T cell counts between 200 and 350 cells/mm3 were randomized to either immediate ART initiation (early group; N = 408), or initiation when CD4 T cell count was less than or equal 200 cells/mm3 or with the development of an AIDS-defining condition (delayed group; N = 408). Every 3 months, all participants underwent an oral examination. The incidence of oral lesions was 4.10 in the early group and 17.85 in the delayed group (p-value <0.01). In comparison to the early group, there was a significantly higher incidence of candidiasis, hairy leukoplakia, herpes labialis, and recurrent herpes simplex in the delayed group. The incidence of oral warts in delayed group was 0.97 before therapy and 4.27 post-ART initiation (p-value <0.01). In the delayed group the incidence of oral warts post-ART initiation was significantly higher than that seen in the early group (4.27 versus 1.09; p-value <0.01). The incidence of oral warts increased after ART was initiated, and relative to the early group there was a four-fold increase in oral warts if ART was initiated following an AIDS diagnosis. Based upon our findings, candidiasis, hairy leukoplakia, herpes labialis, and recurrent herpes simplex indicate immune suppression and the need to start ART. In contrast, oral warts are a sign of immune reconstitution following ART initiation. PMID- 26930572 TI - Unexpectedly High Levels of Cryptic Diversity Uncovered by a Complete DNA Barcoding of Reptiles of the Socotra Archipelago. AB - Few DNA barcoding studies of squamate reptiles have been conducted. Due to the significance of the Socotra Archipelago (a UNESCO Natural World Heritage site and a biodiversity hotspot) and the conservation interest of its reptile fauna (94% endemics), we performed the most comprehensive DNA barcoding study on an island group to date to test its applicability to specimen identification and species discovery. Reptiles constitute Socotra's most important vertebrate fauna, yet their taxonomy remains under-studied. We successfully DNA-barcoded 380 individuals of all 31 presently recognized species. The specimen identification success rate is moderate to high, and almost all species presented local barcoding gaps. The unexpected high levels of intra-specific variability found within some species suggest cryptic diversity. Species richness may be under estimated by 13.8-54.4%. This has implications in the species' ranges and conservation status that should be considered for conservation planning. Other phylogenetic studies using mitochondrial and nuclear markers are congruent with our results. We conclude that, despite its reduced length (663 base pairs), cytochrome c oxidase 1, COI, is very useful for specimen identification and for detecting intra-specific diversity, and has a good phylogenetic signal. We recommend DNA barcoding to be applied to other biodiversity hotspots for quickly and cost-efficiently flagging species discovery, preferentially incorporated into an integrative taxonomic framework. PMID- 26930573 TI - Spatial Patterns of a Predator-Prey System of Leslie Type with Time Delay. AB - Time delay due to maturation time, capturing time or other reasons widely exists in biological systems. In this paper, a predator-prey system of Leslie type with diffusion and time delay is studied based on mathematical analysis and numerical simulations. Conditions for both delay induced and diffusion induced Turing instability are obtained by using bifurcation theory. Furthermore, a series of numerical simulations are performed to illustrate the spatial patterns, which reveal the information of density changes of both prey and predator populations. The obtained results show that the interaction between diffusion and time delay may give rise to rich dynamics in ecosystems. PMID- 26930574 TI - An expedient sequential one-pot four component synthesis of novel steroidal spiro pyrrolidine heterocycles in ionic liquid. AB - A facile one-pot synthesis of novel steroidal dispiro-indenoquinoxaline pyrrolidines via multicomponent-[3+2]-cycloaddition of azomethine ylides in ionic liquid is described. The structure of cycloadduct is confirmed by IR, (1)H NMR, (13)C NMR, high resolution mass spectroscopy and elemental analysis. PMID- 26930575 TI - New dimension of glucocorticoids in cancer treatment. AB - Glucocorticoids have been used in clinical oncology for over half a century. The clinical applications of glucocorticoids in oncology are mainly dependent on their pro-apoptotic action to treat lymphoproliferative disorders, and also on alleviating side effects induced by chemotherapy or radiotherapy in non hematologic cancer types. Researches in the past few years have begun to unveil the profound complexity of glucocorticoids signaling and have contributed remarkably on therapeutic strategies. However, it remains striking and puzzling how glucocorticoids use different mechanisms in different cancer types and different targets to promote or inhibit tumor progression. In this review, we provide an update on glucocorticoids and its receptor, GR-mediated signaling and highlight some of the latest findings on the actions of glucocorticoids signaling during tumor progression and metastasis. PMID- 26930576 TI - Effects of Bisphenol A on ion channels: Experimental evidence and molecular mechanisms. AB - Bisphenol A (BPA) is an endocrine-disrupting chemical (EDC) produced in huge quantities in the manufacture of polycarbonate plastics and epoxy resins. It is present in most humans in developed countries, acting as a xenoestrogen and it is considered an environmental risk factor associated to several diseases. Among the whole array of identified mechanisms by which BPA can interfere with physiological processes in living organisms, changes on ion channel activity is one of the most poorly understood. There is still little evidence about BPA regulation of ion channel expression and function. However, this information is key to understand how BPA disrupts excitable and non-excitable cells, including neurons, endocrine cells and muscle cells. This report is the result of a comprehensive literature review on the effects of BPA on ion channels. We conclude that there is evidence to say that these important molecules may be key end-points for EDCs acting as xenoestrogens. However, more research on channel mediated BPA effects is needed. Particularly, mechanistic studies to unravel the pathophysiological actions of BPA on ion channels at environmentally relevant doses. PMID- 26930577 TI - Enhanced Osteogenic Activity of TiO2 Nanorod Films with Microscaled Distribution of Zn-CaP. AB - The topography at the micro-/nanoscale level and bioactive composition of material surfaces have been thought to play vital roles in their interactions with cells. However, it is still a challenge to further modify special topography with biodegradable composition or vice versa. In this study, TiO2 nanorod films covered with microscale-distributed Zn-containing calcium phosphate (Zn-CaP) were prepared, trying to create a micro-/nanoscale topography and Zn(2+) release capability. MC3T3-E1 cells cultured on TiO2 nanorod film with sparsely distributed Zn-CaP (TiO2/S-ZCP) had significantly higher biological responses than those on the films with densely distributed Zn-CaP (TiO2/D-ZCP) and fully covered Zn-CaP (F-ZCP). TiO2/S-ZCP film was demonstrated to facilitate osteogenic differentiation much more strongly than F-ZCP and TiO2/D-ZCP films based on evaluations of ALP, related gene expressions, and extracellular matrix mineralization. The higher osteogenic differentiation on TiO2/S-ZCP film is ascribed to the micro-/nanoscale topography from Zn-CaP coverage promoting cell adhesion and filopodia extension, and inducing differentiation-orientation in the initial stage. And consequently Zn(2+) release results in enhancement of differentiation. Therefore, we believe that better organization of the micro /nanotopography and bioactive ion release on the surface would be a promising way to enhance osteogenic activity for orthopedic and dental implants. PMID- 26930578 TI - Preparation and cytotoxicity of N-modified chitosan nanoparticles applied in curcumin delivery. AB - Nanoparticles (NPs) based on N,N-dimethyl chitosan (DMC) and N,N,N-trimethyl chitosan (TMC), physical crosslinked with sodium tripolyphosphate (TPP) were successful obtained, using water/benzyl alcohol emulsion system. NPs morphologies were evaluated by Scanning Electron Microscopy and Transmission Electron Microscopy. NPs were characterized by Infrared Spectroscopy (FTIR), Thermogravimetric Analysis, Zeta Potential, Differential Scanning Calorimetry and Wide-angle X-ray Scattering. Curcumin (CUR) was loaded onto NPs and controlled release studies were evaluated in simulated intestinal fluid and in simulated gastric fluid. Cytotoxicity assays showed only loaded TMC/TPP particles containing CUR were slightly cytotoxic on human cervical tumor cells (SiHa cells), concerning unloaded TMC/TPP particles. Conversely, loaded NPs (TMC/TPP/CUR and DMC/TPP/CUR), especially TMC/TPP/CUR sample presented greater biocompatibility toward healthy VERO cells than unloaded NPs (TMC/TPP and DMC/TPP). PMID- 26930579 TI - Venom peptides cathelicidin and lycotoxin cause strong inhibition of Escherichia coli ATP synthase. AB - Venom peptides are known to have strong antimicrobial activity and anticancer properties. King cobra cathelicidin or OH-CATH (KF-34), banded krait cathelicidin (BF-30), wolf spider lycotoxin I (IL-25), and wolf spider lycotoxin II (KE-27) venom peptides were found to strongly inhibit Escherichia coli membrane bound F1Fo ATP synthase. The potent inhibition of wild-type E. coli in comparison to the partial inhibition of null E. coli by KF-34, BF-30, Il-25, or KE-27 clearly links the bactericidal properties of these venom peptides to the binding and inhibition of ATP synthase along with the possibility of other inhibitory targets. The four venom peptides KF-34, BF-30, IL-25, and KE-27, caused >=85% inhibition of wild-type membrane bound E.coli ATP synthase. Venom peptide induced inhibition of ATP synthase and the strong abrogation of wild-type E. coli cell growth in the presence of venom peptides demonstrates that ATP synthase is a potent membrane bound molecular target for venom peptides. Furthermore, the process of inhibition was found to be fully reversible. PMID- 26930580 TI - Evaluation of rapid tests for diagnosis of acute hepatitis E. AB - BACKGROUND: Hepatitis E virus diagnosis still presents difficulties due to discordant results among diagnostic tests. OBJECTIVES: The aim of this study was to evaluate the performance of two rapid tests for detection of anti-HEV IgM antibodies. STUDY DESIGN: The rapid tests were compared with three commercial anti-HEV ELISA assays and one Real-Time PCR assay on 59 sera from patients with acute viral non-AC hepatitis. RESULTS: The presence of anti-HEV IgM antibodies was evaluated by two rapid tests (Wantai and Assure) on 25 HEV RNA positive samples. Anti-HEV IgM antibodies were detected in 24/25 and 23/25 samples respectively. The sensitivity and specificity of Wantai and Assure Rapid tests were evaluated using the 25 HEV RNA positive samples and 50 HEV RNA negative samples (including sera from acute-phase HAV and HBV infections and blood donors). Overall, the sensitivity of Wantai Rapid and Assure Rapid tests was 96.1% and 92.6% respectively; the specificity of the 2 tests was 100%. CONCLUSION: Our data suggest the potential use of anti-HEV IgM rapid assays as a first line test in primary health care settings, particularly useful for patients with chronic liver disease or pregnant women who urgently need an antiviral treatment. PMID- 26930582 TI - Determination of benzophenones in lipophilic extract of Brazilian red propolis, nanotechnology-based product and porcine skin and mucosa: Analytical and bioanalytical assays. AB - Lipophilic compounds of Brazilian Red Propolis (BRP) have received increasing attention due to some interesting findings regarding their biological activities. This study was first aimed at evaluating the chemical composition of BRP n-hexane extract (HEXred) by UPLC-MS-PDA. Chemical investigation mainly resulted in the identification of polyprenylated benzophenones (PPBs) in this extract, named oblongifolin A, guttiferone E, and/or xanthochymol. After that, an isocratic HPLC UV method was validated for the determination of total content of PPBs (at 260 nm) expressed as garcinol, a commercially available guttiferone E diastereoisomer. The method showed to be specific, precise, accurate, and linear (0.1-10 MUg/mL) for the determination of PPBs in HEXred, BRP-loaded nanoemulsions, as well as, in porcine skin and mucosa samples after permeation/retention studies. The matrix effect was determined for all complex matrices, demonstrating low effect during the analysis. The stability-indicating method was verified by submitting HEXred to acidic, alkaline, oxidative, and thermal stress conditions. No interference of degradation products was detected during analysis. Therefore, the proposed analytical and bioanalytical methods proved to be simple and reliable for the determination of PPBs in the presence of different matrices. PMID- 26930581 TI - CLCA2 Interactor EVA1 Is Required for Mammary Epithelial Cell Differentiation. AB - CLCA2 is a p53-, p63-inducible transmembrane protein that is frequently downregulated in breast cancer. It is induced during differentiation of human mammary epithelial cells, and its knockdown causes epithelial-to-mesenchymal transition (EMT). To determine how CLCA2 promotes epithelial differentiation, we searched for interactors using membrane dihybrid screening. We discovered a strong interaction with the cell junctional protein EVA1 (Epithelial V-like Antigen 1) and confirmed it by co-immunoprecipitation. Like CLCA2, EVA1 is a type I transmembrane protein that is regulated by p53 and p63. It is thought to mediate homophilic cell-cell adhesion in diverse epithelial tissues. We found that EVA1 is frequently downregulated in breast tumors and breast cancer cell lines, especially those of mesenchymal phenotype. Moreover, knockdown of EVA1 in immortalized human mammary epithelial cells (HMEC) caused EMT, implying that EVA1 is essential for epithelial differentiation. Both EVA1 and CLCA2 co-localized with E-cadherin at cell-cell junctions. The interacting domains were delimited by deletion analysis, revealing the site of interaction to be the transmembrane segment (TMS). The primary sequence of the CLCA2 TMS was found to be conserved in CLCA2 orthologs throughout mammals, suggesting that its interaction with EVA1 co evolved with the mammary gland. A screen for other junctional interactors revealed that CLCA2 was involved in two different complexes, one with EVA1 and ZO 1, the other with beta catenin. Overexpression of CLCA2 caused downregulation of beta catenin and beta catenin-activated genes. Thus, CLCA2 links a junctional adhesion molecule to cytosolic signaling proteins that modulate proliferation and differentiation. These results may explain how attenuation of CLCA2 causes EMT and why CLCA2 and EVA1 are frequently downregulated in metastatic breast cancer cell lines. PMID- 26930583 TI - Application of an LC-MS/MS method for reliable determination of amodiaquine, N desethylamodiaquine, artesunate and dihydroartemisinin in human plasma for a bioequivalence study in healthy Indian subjects. AB - A sensitive and high throughput bioanalytical method has been developed for reliable determination of amodiaquine (AQ), N-desethylamodiaquine (DEAQ), artesunate (AS) and dihydroartemisinin (DHA) in human plasma by LC-MS/MS. The method employs a solid phase extraction procedure without an evaporation step and with optimum use of organic solvents to circumvent degradation of artemisinin derivatives. The analytes and their deuterated internal standards (ISs) were analyzed on Hypersil Gold (100 mm * 4.6mm, 5 MUm) column using acetonitrile and 2.0mM ammonium formate (pH 2.50) in 80:20 (v/v) ratio as the mobile phase. A triple quadrupole mass spectrometer equipped with an electrospray ionization interface was used to detect and quantify the analytes. The method was established over the concentration range of 0.250-30.0 ng/mL, 1.50-180 ng/mL, 2.00-600 ng/mL and 5.00-1400 ng/mL for AQ, DEAQ, AS and DHA respectively using 250 MUL human plasma. The intra-day and inter-day accuracy and precision (% CV) across quality controls varied from 93.3-105.0% and 1.7-8.3 respectively for all the analytes. The stability was assessed in whole blood as well as in plasma samples under different conditions. All four analytes were stable in whole blood up to 2h on melting ice. The long term stability in plasma was ascertained up to 90 days. IS-normalized matrix factors ranged from 0.988-1.023 for all the analytes. The method was successfully applied to a bioequivalence study using 50mg artesunate and 135 mg amodiaquine fixed dose formulation in 14 healthy subjects. PMID- 26930584 TI - Evidence for the recruitment of autophagic vesicles in human brain after stroke. AB - Autophagy is a homeostatic process for recycling proteins and organelles that is increasingly being proposed as a therapeutic target for acute and chronic neurodegenerative diseases, including stroke. Confirmation that autophagy is present in the human brain after stroke is imperative before prospective therapies can begin the translational process into clinical trials. Our current study using human post-mortem tissue observed an increase in staining in microtubule-associated protein 1 light chain 3 (LC3), sequestosome 1 (SQSTM1; also known as p62) and the increased appearance of autophagic vesicles after stroke. These data confirm that alterations in autophagy take place in the human brain after stroke and suggest that targeting autophagic processes after stroke may have clinical significance. PMID- 26930585 TI - Rare Copy Number Variants Identified Suggest the Regulating Pathways in Hypertension-Related Left Ventricular Hypertrophy. AB - Left ventricular hypertrophy (LVH) is an independent risk factor for cardiovascular morbidity and mortality, and a powerful predictor of adverse cardiovascular outcomes in the hypertensive patients. It has complex multifactorial and polygenic basis for its pathogenesis. We hypothesized that rare copy number variants (CNVs) contribute to the LVH pathogenesis in hypertensive patients. Copy number variants (CNV) were identified in 258 hypertensive patients, 95 of whom had LVH, after genotyping with a high resolution SNP array. Following stringent filtering criteria, we identified 208 rare, or private CNVs that were only present in our patients with hypertension related LVH. Preliminary findings from Gene Ontology and pathway analysis of this study confirmed the involvement of the genes known to be functionally involved in cardiac development and phenotypes, in line with previously reported transcriptomic studies. Network enrichment analyses suggested that the gene-set was, directly or indirectly, involved in the transcription factors regulating the "foetal cardiac gene programme" which triggered the hypertrophic cascade, confirming previous reports. These findings suggest that multiple, individually rare copy number variants altering genes may contribute to the pathogenesis of hypertension-related LVH. In summary, we have provided further supporting evidence that rare CNV could potentially impact this common and complex disease susceptibility with lower heritability. PMID- 26930586 TI - X-ray crystal structure of anhydrous chitosan at atomic resolution. AB - We determined the crystal structure of anhydrous chitosan at atomic resolution, using X-ray fiber diffraction data extending to 1.17 A resolution. The unit cell [a = 8.129(7) A, b = 8.347(6) A, c = 10.311(7) A, space group P21 21 21 ] of anhydrous chitosan contains two chains having one glucosamine residue in the asymmetric unit with the primary hydroxyl group in the gt conformation, that could be directly located in the Fourier omit map. The molecular arrangement of chitosan is very similar to the corner chains of cellulose II implying similar intermolecular hydrogen bonding between O6 and the amine nitrogen atom, and an intramolecular bifurcated hydrogen bond from O3 to O5 and O6. In addition to the classical hydrogen bonds, all the aliphatic hydrogens were involved in one or two weak hydrogen bonds, mostly helping to stabilize cohesion between antiparallel chains. (c) 2016 Wiley Periodicals, Inc. Biopolymers 105: 361-368, 2016. PMID- 26930588 TI - What is a Midwife? PMID- 26930587 TI - Evaluation of Immunophenotypic and Molecular Biomarkers for Sezary Syndrome Using Standard Operating Procedures: A Multicenter Study of 59 Patients. AB - Differentiation between Sezary syndrome and erythrodermic inflammatory dermatoses can be challenging, and a number of studies have attempted to identify characteristic immunophenotypic changes and molecular biomarkers in Sezary cells that could be useful as additional diagnostic criteria. In this European multicenter study, the sensitivity and specificity of these immunophenotypic and recently proposed but unconfirmed molecular biomarkers in Sezary syndrome were investigated. Peripheral blood CD4(+) T cells from 59 patients with Sezary syndrome and 19 patients with erythrodermic inflammatory dermatoses were analyzed for cell surface proteins by flow cytometry and for copy number alterations and differential gene expression using custom-made quantitative PCR plates. Experiments were performed in duplicate in two independent centers using standard operating procedures with almost identical results. Sezary cells showed MYC gain (40%) and MNT loss (66%); up-regulation of DNM3 (75%), TWIST1 (69%), EPHA4 (66%), and PLS3 (66%); and down-regulation of STAT4 (91%). Loss of CD26 (>=80% CD4(+) T cells) and/or CD7 (>=40% CD4(+) T cells) and combination of altered expression of STAT4, TWIST1, and DNM3 or PLS3 could distinguish, respectively, 83% and 98% of patients with Sezary syndrome from patients with erythrodermic inflammatory dermatoses with 100% specificity. These additional diagnostic panels will be useful adjuncts in the differential diagnosis of Sezary syndrome versus erythrodermic inflammatory dermatoses. PMID- 26930589 TI - State estimation for a class of artificial neural networks with stochastically corrupted measurements under Round-Robin protocol. AB - This paper is concerned with the state estimation problem for a class of artificial neural networks (ANNs) without the assumptions of monotonicity or differentiability of the activation functions. The measured outputs are corrupted by stochastic noise signal whose intensity is quantified by a nonlinear function. In order to accommodate the bandwidth limit of the communication channel between the ANN and the state estimator, an equal allocation scheme (i.e. Round-Robin protocol) of the communication resource is employed to effectively mitigate data congestions and save energies. A set of zero-order holders (ZOHs) is utilized to store the received measurements, such that the utilization of the received measurements can be maximized. An update matrix approach is developed to handle the time-varying yet periodic time-delays resulting from the adoption of the Round-Robin protocol. The aim of the proposed problem is to design a state estimator such that the error dynamics is exponentially ultimately bounded. A combination of the Lyapunov stability theory and the stochastic analysis technique is used to derive some easy-to-test conditions for the existence of the desired state estimator. The estimator gains are characterized by the solution to a convex optimization problem that is solved via the semi-definite programme method. Simulation results are given to demonstrate the effectiveness of the proposed estimation approach. PMID- 26930590 TI - lncRNA-RNA Interactions across the Human Transcriptome. AB - Long non-coding RNAs (lncRNAs) represent a numerous class of non-protein coding transcripts longer than 200 nucleotides. There is possibility that a fraction of lncRNAs are not functional and represent mere transcriptional noise but a growing body of evidence shows they are engaged in a plethora of molecular functions and contribute considerably to the observed diversification of eukaryotic transcriptomes and proteomes. Still, however, only ca. 1% of lncRNAs have well established functions and much remains to be done towards decipherment of their biological roles. One of the least studied aspects of lncRNAs biology is their engagement in gene expression regulation through RNA-RNA interactions. By hybridizing with mate RNA molecules, lncRNAs could potentially participate in modulation of pre-mRNA splicing, RNA editing, mRNA stability control, translation activation, or abrogation of miRNA-induced repression. Here, we implemented a similarity-search based method for transcriptome-wide identification of RNA-RNA interactions, which enabled us to find 18,871,097 lncRNA-RNA base-pairings in human. Further analyses showed that the interactions could be involved in processing, stability control and functions of 57,303 transcripts. An extensive use of RNA-Seq data provided support for approximately one third of the interactions, at least in terms of the two RNA components being co-expressed. The results suggest that lncRNA-RNA interactions are broadly used to regulate and diversify the human transcriptome. PMID- 26930592 TI - Overexpression of AQP5 Was Detected in Axillary Sweat Glands of Primary Focal Hyperhidrosis Patients. AB - BACKGROUND: The expression of aquaporin 5 (AQP5) in human axillary sweat glands has never been studied so far. OBJECTIVE: To detect the expression of AQP5 in axillary sweat glands of patients with primary focal hyperhidrosis (PFH) relative to control subjects. METHODS: The morphological characteristics and the number of sweat coils in axillary sweat glands were compared between two groups by using transmission electron microscopy. The expression of AQP5 was detected by immunohistochemistry, Western blot analysis, and real-time transcription polymerase chain reaction. RESULTS: There were no significant differences between the two groups in terms of morphological characteristics and the number of sweat coils in axillary sweat glands. The expressions of AQP5 protein and AQP5 mRNA were significantly higher in the patient group than in the control group. CONCLUSION: AQP5 is involved in the secretion of human axillary sweat glands. The overexpression of AQP5 in sweat glands is probably one pathogenetic mechanism underlying PFH. PMID- 26930591 TI - Community Attitude and Associated Factors towards People with Mental Illness among Residents of Worabe Town, Silte Zone, Southern Nation's Nationalities and People's Region, Ethiopia. AB - BACKGROUND: Mental illnesses worldwide are accompanied by another pandemic, that of stigma and discrimination. Public understanding about mental illnesses and attitudes towards people with mental illness play a paramount role in the prevention and treatment of mental illness and the rehabilitation of people with mental illness. OBJECTIVE: To assess community attitude and associated factors towards people with mental illness. METHODS: Community based cross-sectional study was conducted from April 28 to May 28, 2014. Quantitative data were collected through interview from 435 adults selected using simple random sampling. Data were collected using community attitude towards mentally ill (CAMI) tool to assess community attitude towards people with mental illness and associated factors. Multiple linear regression analysis was performed to identify predictors of community attitude towards people with mental illness and the level of significance association was determined by beta with 95% confidence interval and P less than 0.05. RESULTS: The highest mean score was on social restrictiveness subscale (31.55+/-5.62). Farmers had more socially restrictive view (beta = 0.291, CI [0.09, 0.49]) and have less humanistic view towards mentally ill (beta = 0.193, CI [-0.36, -0.03]). Having mental health information had significantly less socially restrictive (beta = -0.59, CI [-1.13, -0.05]) and less authoritarian (beta = -0.10, CI [-1.11, -0.06]) view towards mentally ill but respondents who are at university or college level reported to be more socially restrictive (beta = 0.298, CI [0.059, 0.54]). Respondents whose age is above 48 years old had significantly less view of community mental health ideology (beta = -0.59, CI [-1.09, -0.08]). CONCLUSION AND RECOMMENDATION: Residents of Worabe town were highly socially restrictive but less authoritarian. There was high level of negative attitude towards people with mental illness along all the subscales with relative variation indicating a need to develop strategies to change negative attitude attached to mental illness in Worabe town at community level. PMID- 26930593 TI - Evaluating the Applicability of Phi Coefficient in Indicating Habitat Preferences of Forest Soil Fauna Based on a Single Field Study in Subtropical China. AB - Phi coefficient directly depends on the frequencies of occurrence of organisms and has been widely used in vegetation ecology to analyse the associations of organisms with site groups, providing a characterization of ecological preference, but its application in soil ecology remains rare. Based on a single field experiment, this study assessed the applicability of phi coefficient in indicating the habitat preferences of soil fauna, through comparing phi coefficient-induced results with those of ordination methods in charactering soil fauna-habitat(factors) relationships. Eight different habitats of soil fauna were implemented by reciprocal transfer of defaunated soil cores between two types of subtropical forests. Canonical correlation analysis (CCorA) showed that ecological patterns of fauna-habitat relationships and inter-fauna taxa relationships expressed, respectively, by phi coefficients and predicted abundances calculated from partial redundancy analysis (RDA), were extremely similar, and a highly significant relationship between the two datasets was observed (Pillai's trace statistic = 1.998, P = 0.007). In addition, highly positive correlations between phi coefficients and predicted abundances for Acari, Collembola, Nematode and Hemiptera were observed using linear regression analysis. Quantitative relationships between habitat preferences and soil chemical variables were also obtained by linear regression, which were analogous to the results displayed in a partial RDA biplot. Our results suggest that phi coefficient could be applicable on a local scale in evaluating habitat preferences of soil fauna at coarse taxonomic levels, and that the phi coefficient-induced information, such as ecological preferences and the associated quantitative relationships with habitat factors, will be largely complementary to the results of ordination methods. The application of phi coefficient in soil ecology may extend our knowledge about habitat preferences and distribution-abundance relationships, which will benefit the understanding of biodistributions and variations in community compositions in the soil. Similar studies in other places and scales apart from our local site will be need for further evaluation of phi coefficient. PMID- 26930594 TI - TLR4 Activation Promotes Bone Marrow MSC Proliferation and Osteogenic Differentiation via Wnt3a and Wnt5a Signaling. AB - Mesenchymal stem cells (MSCs) from adult bone marrow maintain their self-renewal ability and the ability to differentiate into osteoblast. Thus, adult bone marrow MSCs play a key role in the regeneration of bone tissue. Previous studies indicated that TLR4 is expressed in MSCs and is critical in regulating the fate decision of MSCs. However, the exact functional role and underlying mechanisms of how TLR4 regulate bone marrow MSC proliferation and differentiation are unclear. Here, we found that activated TLR4 by its ligand LPS promoted the proliferation and osteogenic differentiation of MSCs in vitro. TLR4 activation by LPS also increased cytokine IL-6 and IL-1beta production in MSCs. In addition, LPS treatment has no effect on inducing cell death of MSCs. Deletion of TLR4 expression in MSCs completely eliminated the effects of LPS on MSC proliferation, osteogenic differentiation and cytokine production. We also found that the mRNA and protein expression of Wnt3a and Wnt5a, two important factors in regulating MSC fate decision, was upregulated in a TLR4-dependent manner. Silencing Wnt3a with specific siRNA remarkably inhibited TLR4-induced MSC proliferation, while Wnt5a specific siRNA treatment significantly antagonized TLR4-induced MSC osteogenic differentiation. These results together suggested that TLR4 regulates bone marrow MSC proliferation and osteogenic differentiation through Wnt3a and Wnt5a signaling. These finding provide new data to understand the role and the molecular mechanisms of TLR4 in regulating bone marrow MSC functions. These data also provide new insight in developing new therapy in bone regeneration using MSCs by modulating TLR4 and Wnt signaling activity. PMID- 26930595 TI - Evaluation of a Performance-Based Expert Elicitation: WHO Global Attribution of Foodborne Diseases. AB - For many societally important science-based decisions, data are inadequate, unreliable or non-existent, and expert advice is sought. In such cases, procedures for eliciting structured expert judgments (SEJ) are increasingly used. This raises questions regarding validity and reproducibility. This paper presents new findings from a large-scale international SEJ study intended to estimate the global burden of foodborne disease on behalf of WHO. The study involved 72 experts distributed over 134 expert panels, with panels comprising thirteen experts on average. Elicitations were conducted in five languages. Performance based weighted solutions for target questions of interest were formed for each panel. These weights were based on individual expert's statistical accuracy and informativeness, determined using between ten and fifteen calibration variables from the experts' field with known values. Equal weights combinations were also calculated. The main conclusions on expert performance are: (1) SEJ does provide a science-based method for attribution of the global burden of foodborne diseases; (2) equal weighting of experts per panel increased statistical accuracy to acceptable levels, but at the cost of informativeness; (3) performance-based weighting increased informativeness, while retaining accuracy; (4) due to study constraints individual experts' accuracies were generally lower than in other SEJ studies, and (5) there was a negative correlation between experts' informativeness and statistical accuracy which attenuated as accuracy improved, revealing that the least accurate experts drive the negative correlation. It is shown, however, that performance-based weighting has the ability to yield statistically accurate and informative combinations of experts' judgments, thereby offsetting this contrary influence. The present findings suggest that application of SEJ on a large scale is feasible, and motivate the development of enhanced training and tools for remote elicitation of multiple, internationally dispersed panels. PMID- 26930596 TI - Antimycobacterial Activity of a New Peptide Polydim-I Isolated from Neotropical Social Wasp Polybia dimorpha. AB - Mycobacterium abscessus subsp. massiliense, a rapidly growing mycobacteria (RGM) that is becoming increasingly important among human infectious diseases, is virulent and pathogenic and presents intrinsic resistance to several antimicrobial drugs that might hamper their elimination. Therefore, the identification of new drugs to improve the current treatment or lower the risk of inducing resistance is urgently needed. Wasp venom primarily comprises peptides that are responsible for most of the biological activities in this poison. Here, a novel peptide Polydim-I, from Polybia dimorpha Neotropical wasp, was explored as an antimycobacterial agent. Polydim-I provoked cell wall disruption and exhibited non-cytotoxicity towards mammalian cells. Polydim-I treatment of macrophages infected with different M. abscessus subsp. massiliense strains reduced 40 to 50% of the bacterial load. Additionally, the Polydim-I treatment of highly susceptible mice intravenously infected with M. abscessus subsp. massiliense induced 0.8 to 1 log reduction of the bacterial load in the lungs, spleen, and liver. In conclusion, this is the first study to show the therapeutic potential of a peptide derived from wasp venom in treating mycobacteria infections. Polydim-I acts on the M. abscessus subsp. massiliense cell wall and reduce 40-90% of the bacterial load both in vitro and in vivo. The presented results encourage further studies on the use of Polydim-I as one of the components for M. abscessus subsp. massiliense treatment. PMID- 26930597 TI - Quantitative Detection of the Foot-And-Mouth Disease Virus Serotype O 146S Antigen for Vaccine Production Using a Double-Antibody Sandwich ELISA and Nonlinear Standard Curves. AB - The efficacy of an inactivated foot-and-mouth disease (FMD) vaccine is mainly dependent on the integrity of the foot-and-mouth disease virus (FMDV) particles. At present, the standard method to quantify the active component, the 146S antigen, of FMD vaccines is sucrose density gradient (SDG) analysis. However, this method is highly operator dependent and difficult to automate. In contrast, the enzyme-linked immunosorbent assay (ELISA) is a time-saving technique that provides greater simplicity and sensitivity. To establish a valid method to detect and quantify the 146S antigen of a serotype O FMD vaccine, a double antibody sandwich (DAS) ELISA was compared with an SDG analysis. The DAS ELISA was highly correlated with the SDG method (R2 = 0.9215, P<0.01). In contrast to the SDG method, the DAS ELISA was rapid, robust, repeatable and highly sensitive, with a minimum quantification limit of 0.06 MUg/mL. This method can be used to determine the effective antigen yields in inactivated vaccines and thus represents an alternative for assessing the potency of FMD vaccines in vitro. But it still needs to be prospectively validated by analyzing a new vaccine preparation and determining the proper protective dose followed by an in vivo vaccination-challenge study to confirm the ELISA findings. PMID- 26930598 TI - Regional Fluctuation in the Functional Consequence of LINE-1 Insertion in the Mitf Gene: The Black Spotting Phenotype Arisen from the Mitfmi-bw Mouse Lacking Melanocytes. AB - Microphthalmia-associated transcription factor (Mitf) is a key regulator for differentiation of melanoblasts, precursors to melanocytes. The mouse homozygous for the black-eyed white (Mitfmi-bw) allele is characterized by the white-coat color and deafness with black eyes due to the lack of melanocytes. The Mitfmi-bw allele carries LINE-1, a retrotransposable element, which results in the Mitf deficiency. Here, we have established the black spotting mouse that was spontaneously arisen from the homozygous Mitfmi-bw mouse lacking melanocytes. The black spotting mouse shows multiple black patches on the white coat, with age related graying. Importantly, each black patch also contains hair follicles lacking melanocytes, whereas the white-coat area completely lacks melanocytes. RT PCR analyses of the pigmented patches confirmed that the LINE-1 insertion is retained in the Mitf gene of the black spotting mouse, thereby excluding the possibility of the somatic reversion of the Mitfmi-bw allele. The immunohistochemical analysis revealed that the staining intensity for beta catenin was noticeably lower in hair follicles lacking melanocytes of the homozygous Mitfmi-bw mouse and the black spotting mouse, compared to the control mouse. In contrast, the staining intensity for beta-catenin and cyclin D1 was higher in keratinocytes of the black spotting mouse, compared to keratinocytes of the control mouse and the Mitfmi-bw mouse. Moreover, the keratinocyte layer appears thicker in the Mitfmi-bw mouse, with the overexpression of Ki-67, a marker for cell proliferation. We also show that the presumptive black spots are formed by embryonic day 15.5. Thus, the black spotting mouse provides the unique model to explore the molecular basis for the survival and death of developing melanoblasts and melanocyte stem cells in the epidermis. These results indicate that follicular melanocytes are responsible for maintaining the epidermal homeostasis; namely, the present study has provided evidence for the link between melanocyte development and the epidermal microenvironment. PMID- 26930599 TI - RED: A Java-MySQL Software for Identifying and Visualizing RNA Editing Sites Using Rule-Based and Statistical Filters. AB - RNA editing is one of the post- or co-transcriptional processes that can lead to amino acid substitutions in protein sequences, alternative pre-mRNA splicing, and changes in gene expression levels. Although several methods have been suggested to identify RNA editing sites, there remains challenges to be addressed in distinguishing true RNA editing sites from its counterparts on genome and technical artifacts. In addition, there lacks a software framework to identify and visualize potential RNA editing sites. Here, we presented a software - 'RED' (RNA Editing sites Detector) - for the identification of RNA editing sites by integrating multiple rule-based and statistical filters. The potential RNA editing sites can be visualized at the genome and the site levels by graphical user interface (GUI). To improve performance, we used MySQL database management system (DBMS) for high-throughput data storage and query. We demonstrated the validity and utility of RED by identifying the presence and absence of C->U RNA editing sites experimentally validated, in comparison with REDItools, a command line tool to perform high-throughput investigation of RNA editing. In an analysis of a sample data-set with 28 experimentally validated C->U RNA editing sites, RED had sensitivity and specificity of 0.64 and 0.5. In comparison, REDItools had a better sensitivity (0.75) but similar specificity (0.5). RED is an easy-to-use, platform-independent Java-based software, and can be applied to RNA-seq data without or with DNA sequencing data. The package is freely available under the GPLv3 license at http://github.com/REDetector/RED or https://sourceforge.net/projects/redetector. PMID- 26930601 TI - Concurrent Codes: A Holographic-Type Encoding Robust against Noise and Loss. AB - Concurrent coding is an encoding scheme with 'holographic' type properties that are shown here to be robust against a significant amount of noise and signal loss. This single encoding scheme is able to correct for random errors and burst errors simultaneously, but does not rely on cyclic codes. A simple and practical scheme has been tested that displays perfect decoding when the signal to noise ratio is of order -18dB. The same scheme also displays perfect reconstruction when a contiguous block of 40% of the transmission is missing. In addition this scheme is 50% more efficient in terms of transmitted power requirements than equivalent cyclic codes. A simple model is presented that describes the process of decoding and can determine the computational load that would be expected, as well as describing the critical levels of noise and missing data at which false messages begin to be generated. PMID- 26930600 TI - Blocking Nuclear Factor-Kappa B Protects against Diet-Induced Hepatic Steatosis and Insulin Resistance in Mice. AB - Inflammation critically contributes to the development of various metabolic diseases. However, the effects of inhibiting inflammatory signaling on hepatic steatosis and insulin resistance, as well as the underlying mechanisms remain obscure. In the current study, male C57BL/6J mice were fed a chow diet or high fat diet (HFD) for 8 weeks. HFD-fed mice were respectively treated with p65 siRNA, non-silence control siRNA or vehicle every 4th day for the last 4 weeks. Vehicle-treated (HF) and non-silence siRNA-treated (HFNS) mice displayed overt inflammation, hepatic steatosis and insulin resistance compared with chow-diet fed (NC) mice. Upon treatment with NF-kappaB p65 siRNA, HFD-fed (HFPS) mice were protected from hepatic steatosis and insulin resistance. Furthermore, Atg7 and Beclin1 expressions and p-AMPK were increased while p-mTOR was decreased in livers of HFPS mice in relative to HF and HFNS mice. These results suggest a crosslink between NF-kappaB signaling pathway and liver AMPK/mTOR/autophagy axis in the context of hepatic steatosis and insulin resistance. PMID- 26930602 TI - Correction: Neighbourhood Characteristics and Long-Term Air Pollution Levels Modify the Association between the Short-Term Nitrogen Dioxide Concentrations and All-Cause Mortality in Paris. PMID- 26930603 TI - Creatine supplementation does not alter neuromuscular recovery after eccentric exercise. AB - INTRODUCTION: The purpose of this study was to investigate the effects of creatine (CR) supplementation on recovery after eccentric exercise (ECC). METHODS: Fourteen men were assigned randomly to ingest 0.3 g/kg of CR or placebo (PL) before and during recovery (48 hours) from 6 sets of 8 repetitions of ECC. Maximal voluntary contraction (MVC), voluntary activation (VA), muscle thickness (MT), electromyography (EMG), contractile properties, and soreness were assessed. RESULTS: MVC, evoked twitch torque, and rate of torque development decreased for both groups immediately after ECC and recovered at 48 hours. MT increased and remained elevated at 48 hours for both groups. Soreness increased similarly for both groups. EMG activation was higher for CR versus PL only at 48 hours. There were no group differences for torque, total work, or fatigue index during ECC. CONCLUSIONS: CR supplementation before and during recovery from ECC had no effect on strength, voluntary activation, or indicators of muscle damage. Muscle Nerve 54: 487-495, 2016. PMID- 26930604 TI - Impaired Inactivation of L-Type Ca2+ Current as a Potential Mechanism for Variable Arrhythmogenic Liability of HERG K+ Channel Blocking Drugs. AB - The proarrhythmic effects of new drugs have been assessed by measuring rapidly activating delayed-rectifier K+ current (IKr) antagonist potency. However, recent data suggest that even drugs thought to be highly specific IKr blockers can be arrhythmogenic via a separate, time-dependent pathway such as late Na+ current augmentation. Here, we report a mechanism for a quinolone antibiotic, sparfloxacin-induced action potential duration (APD) prolongation that involves increase in late L-type Ca2+ current (ICaL) caused by a decrease in Ca2+ dependent inactivation (CDI). Acute exposure to sparfloxacin, an IKr blocker with prolongation of QT interval and torsades de pointes (TdP) produced a significant APD prolongation in rat ventricular myocytes, which lack IKr due to E4031 pretreatment. Sparfloxacin reduced peak ICaL but increased late ICaL by slowing its inactivation. In contrast, ketoconazole, an IKr blocker without prolongation of QT interval and TdP produced reduction of both peak and late ICaL, suggesting the role of increased late ICaL in arrhythmogenic effect. Further analysis showed that sparfloxacin reduced CDI. Consistently, replacement of extracellular Ca2+ with Ba2+ abolished the sparfloxacin effects on ICaL. In addition, sparfloxacin modulated ICaL in a use-dependent manner. Cardiomyocytes from adult mouse, which is lack of native IKr, demonstrated similar increase in late ICaL and afterdepolarizations. The present findings show that sparfloxacin can prolong APD by augmenting late ICaL. Thus, drugs that cause delayed ICaL inactivation and IKr blockage may have more adverse effects than those that selectively block IKr. This mechanism may explain the reason for discrepancies between clinically reported proarrhythmic effects and IKr antagonist potencies. PMID- 26930605 TI - Using Micro-Computed Tomography to Evaluate the Dynamics of Orthodontically Induced Root Resorption Repair in a Rat Model. AB - OBJECTIVE: To observe dynamic changes in root resorption repair, tooth movement relapse and alveolar bone microstructure following the application of orthodontic force. MATERIALS AND METHODS: Forces of 20 g, 50 g or 100 g were delivered to the left maxillary first molars of fifteen 10-week-old rats for 14 days. Each rat was subjected to micro-computed tomography scanning at 0, 3, 7, 10, 14, 28 and 42 days after force removal. The root resorption crater volume, tooth movement relapse and alveolar bone microarchitecture were measured at each time point. RESULTS: From day 3 to day 14, the root resorption volume decreased significantly in each group. In the 20-g force group, the root resorption volume gradually stabilized after 14 days, whereas in the 50-g and 100-g force groups, it stabilized after 28 days. In all groups, tooth movement relapsed significantly from day 0 to day 14 and then remained stable. From day 3 to day 10, the 20-g group exhibited faster relapse than the 50-g and 100-g groups. In all groups, the structure model index and trabecular separation decreased slowly from day 0 to day 10 and eventually stabilized. Trabecular number increased slowly from day 0 to day 7 and then stabilized. CONCLUSIONS: The initial stage of root resorption repair did not change significantly and was followed by a dramatic repair period before stabilizing. The most serious tooth movement relapse occurred immediately after the appliance was removed, and then the tooth completely returned to the original position. PMID- 26930606 TI - Computational Characterization of Osteoporosis Associated SNPs and Genes Identified by Genome-Wide Association Studies. AB - OBJECTIVES: Genome-wide association studies (GWASs) have revealed many SNPs and genes associated with osteoporosis. However, influence of these SNPs and genes on the predisposition to osteoporosis is not fully understood. We aimed to identify osteoporosis GWASs-associated SNPs potentially influencing the binding affinity of transcription factors and miRNAs, and reveal enrichment signaling pathway and "hub" genes of osteoporosis GWAS-associated genes. METHODS: We conducted multiple computational analyses to explore function and mechanisms of osteoporosis GWAS associated SNPs and genes, including SNP conservation analysis and functional annotation (influence of SNPs on transcription factors and miRNA binding), gene ontology analysis, pathway analysis and protein-protein interaction analysis. RESULTS: Our results suggested that a number of SNPs potentially influence the binding affinity of transcription factors (NFATC2, MEF2C, SOX9, RUNX2, ESR2, FOXA1 and STAT3) and miRNAs. Osteoporosis GWASs-associated genes showed enrichment of Wnt signaling pathway, basal cell carcinoma and Hedgehog signaling pathway. Highly interconnected "hub" genes revealed by interaction network analysis are RUNX2, SP7, TNFRSF11B, LRP5, DKK1, ESR1 and SOST. CONCLUSIONS: Our results provided the targets for further experimental assessment and further insight on osteoporosis pathophysiology. PMID- 26930608 TI - Healthcare Burden and Costs Associated with Urinary Tract Infections in Type 2 Diabetes Mellitus Patients: An Analysis Based on a Large Sample of 456,586 German Patients. AB - OBJECTIVES: We examined the real-world treatment of urinary tract infections (UTIs) in a type 2 diabetes mellitus (T2DM) population, evaluated UTI-related healthcare resource use and direct treatment costs, and assessed factors that may predict UTI-related costs. METHODS: We analyzed an anonymized dataset from a regional German healthcare fund (2010-2012). UTI-associated resource use was described by the number of UTI-associated outpatient visits, the number and length of UTI-related acute hospital visits, and the number of UTI-related antibiotics prescriptions. UTI-related direct treatment costs were studied both based on these resource use numbers and, additionally, based on a comparison of all-cause annual healthcare costs of T2DM-patients who were or were not affected by a UTI. To identify factors that might predict direct treatment costs related to UTI treatment, we conducted generalized linear regression model analyses (based on gamma distribution) using sociodemographic and clinical characteristics of observed patients as available in the database as independent variables. RESULTS: A total of 456,586 T2DM-patients were included with a mean age of 73.8, a percentage of 56.3 female patients, and a mean Charlson comorbidity index of 7.3. In our database, we observed 48,337 UTI events. The direct mean resource based costs were ?315.90 per UTI event. Older age, higher comorbidity status, at least one previous non-UTI infection, and poorer renal function were associated with higher costs, while female gender and at least one previous UTI event were associated with lower costs. In the all-cause cost analysis, healthcare costs per patient year were ?3,916 higher in the UTI group than in the non-UTI group. CONCLUSION: Our study confirms that UTI is a common complication in patients with T2DM. Patients with T2DM who have had previous infections, who are older, and who are male, as well as patients who have more comorbidities or severe renal insufficiency, face above-average UTI treatment costs. These patient groups, therefore, should receive special attention in the real-world treatment of T2DM, which should include a regular screening of UTI risk. PMID- 26930607 TI - A Study to Investigate the Efficacy and Safety of an Anti-Interleukin-18 Monoclonal Antibody in the Treatment of Type 2 Diabetes Mellitus. AB - OBJECTIVE: Evidence suggests that chronic subclinical inflammation plays an important role in the pathogenesis of type 2 diabetes (T2DM). Circulating levels of interleukin (IL)-18 appear to be associated with a number of micro- and macrovascular comorbidities of obesity and T2DM. This study was designed to investigate whether inhibition of IL-18 had any therapeutic benefit in the treatment of T2DM. Preliminary efficacy, safety and tolerability, pharmacokinetics, and pharmacodynamics of the anti-IL-18 monoclonal antibody, GSK1070806, were assessed. RESEARCH DESIGN AND METHODS: This was a multicentre, randomized, single-blind (sponsor-unblinded), placebo-controlled, parallel-group, phase IIa trial. Obese patients of either sex, aged 18-70 years, with poorly controlled T2DM on metformin monotherapy were recruited. Patients received two doses, of placebo (n = 12), GSK1070806 0.25 mg/kg (n = 13) or GSK1070806 5 mg/kg (n = 12). The primary end-point was the change from baseline in fasting plasma glucose and weighted mean glucose area under the curve (AUC)(0-4 hours) postmixed meal test on Days 29, 57, and 85. RESULTS: Thirty-seven patients were randomized to one of the three treatment arms. There were no statistically significant effects of GSK1070806 doses on fasting plasma glucose levels, or weighted mean glucose AUC(0-4 hours) compared with placebo. CONCLUSIONS: GSK1070806 was well tolerated, and inhibition of IL-18 did not lead to any improvements in glucose control. However, because of study limitations, smaller, potentially clinically meaningful effects of IL-18 inhibition cannot be excluded. TRIAL REGISTRATION: ClinicalTrials.gov NCT01648153. PMID- 26930609 TI - Brain Radiotherapy plus Concurrent Temozolomide versus Radiotherapy Alone for Patients with Brain Metastases: A Meta-Analysis. AB - OBJECTIVE: We performed a meta-analysis of randomized clinical trials to compare the efficacy of brain radiotherapy (RT) combined with temozolomide (TMZ) versus RT alone as first-line treatment for brain metastases (BM). METHODS: Medline, Embase, and Pubmed were used to search for relevant randomized controlled trials (RCTs). Two investigators reviewed the abstracts and independently rated the quality of trials and relevant data. The primary outcome was overall survival (OS). Secondary outcomes included progression-free survival (PFS), objective response rate (ORR), and adverse events. RESULTS: Seven studies were selected from the literature search. RT plus TMZ produced significant improvement in ORR with odds ratio (OR) of 2.27 (95% CI, 1.29 to 4.00; P = 0.005) compared with RT alone. OS and PFS were not significantly different between the two arms (OS: HR, 1.00; P = 0.959; PFS: HR, 0.73; P = 0.232). However, the RT plus TMZ arm was associated with significantly more grade 3 to 4 nausea and thrombocytopenia. CONCLUSION: Concomitant RT and TMZ, compared to RT alone, significantly increases ORR in patients with BM, but yields increased toxicity and fails to demonstrate a survival advantage. PMID- 26930610 TI - Transcriptional Regulation of CYP2B6 Expression by Hepatocyte Nuclear Factor 3beta in Human Liver Cells. AB - CYP2B6 plays an increasingly important role in xenobiotic metabolism and detoxification. The constitutive androstane receptor (CAR) and the pregnane X receptor (PXR) have been established as predominant regulators for the inductive expression of CYP2B6 gene in human liver. However, there are dramatic interindividual variabilities in CYP2B6 expression that cannot be fully explained by the CAR/PXR-based modulation alone. Here, we show that expression level of CYP2B6 was correlated with that of hepatocyte nuclear factor 3beta (HNF3beta) in human primary hepatocytes prepared from 35 liver donors. Utilizing recombinant virus-mediated overexpression or knockdown of HNF3beta in HepG2 cells, as well as constructs containing serial deletion and site-directed mutation of HNF3beta binding motifs in CYP2B6 luciferase reporter assays, we demonstrated that the presence or lack of HNF3beta expression markedly correlated with CYP2B6 gene expression and its promoter activity. Novel enhancer modules of HNF3beta located upstream of the CYP2B6 gene transcription start site were identified and functionally validated as key elements governing HNF3beta-mediated CYP2B6 expression. Chromatin immunoprecipitation assays in human primary hepatocytes and surface plasmon resonance binding affinity experiments confirmed the essential role of these enhancers in the recruitment of HNF3beta to the promoter of CYP2B6 gene. Overall, these findings indicate that HNF3beta represents a new liver enriched transcription factor that is involved in the transcription of CYP2B6 gene and contributes to the large interindividual variations of CYP2B6 expression in human population. PMID- 26930611 TI - Use of Photo-Identification and Mark-Recapture Methodology to Assess Basking Shark (Cetorhinus maximus) Populations. AB - Following centuries of exploitation, basking sharks (Cetorhinus maximus) are considered by IUCN as Endangered in the Northeast Atlantic, where they have now been substantially protected for over two decades. However, the present size of this population remains unknown. We investigated the use of photo-identification of individuals' dorsal fins, combined with mark-recapture methodology, to investigate the size of populations of basking shark within the west coast of Scotland. From a total of 921 encounters photographed between 2004 and 2011, 710 sharks were found to be individually identifiable based on dorsal fin damage and natural features. Of these, only 41 individuals were re-sighted, most commonly both within days of, and close to the site of, the initial encounter. A smaller number were re-sighted after longer periods of up to two years. A comparison of the distinguishing features of individuals on first recording and subsequent re sighting showed that in almost all cases these features remained little changed, suggesting the low re-sighting rate was not due to a loss of distinguishing features. Because of the low number of re-sighting we were not able to produce reliable estimates for the long-term regional population. However, for one 50 km diameter study area between the islands of Mull, Coll and Tiree, we were able to generate closed-population estimates for 6-9 day periods in 2010 of 985 (95% CI = 494-1683), and in 2011 of 201 (95% CI = 143-340). For the same 2011 period an open-population model generated a similar estimate of 213 (95% CI = 111-317). Otherwise the low rate and temporal patterning of re-sightings support the view that such local basking shark populations are temporary, dynamic groupings of individuals drawn from a much larger regional population than previously supposed. The study demonstrated the feasibility and limitations of photo identification as a non-invasive technique for identifying individual basking sharks. PMID- 26930612 TI - Strain Specific Factors Control Effector Gene Silencing in Phytophthora sojae. AB - The Phytophthora sojae avirulence gene Avr3a encodes an effector that is capable of triggering immunity on soybean plants carrying the resistance gene Rps3a. P. sojae strains that express Avr3a are avirulent to Rps3a plants, while strains that do not are virulent. To study the inheritance of Avr3a expression and virulence towards Rps3a, genetic crosses and self-fertilizations were performed. A cross between P. sojae strains ACR10 X P7076 causes transgenerational gene silencing of Avr3a allele, and this effect is meiotically stable up to the F5 generation. However, test-crosses of F1 progeny (ACR10 X P7076) with strain P6497 result in the release of silencing of Avr3a. Expression of Avr3a in the progeny is variable and correlates with the phenotypic penetrance of the avirulence trait. The F1 progeny from a direct cross of P6497 X ACR10 segregate for inheritance for Avr3a expression, a result that could not be explained by parental imprinting or heterozygosity. Analysis of small RNA arising from the Avr3a gene sequence in the parental strains and hybrid progeny suggests that the presence of small RNA is necessary but not sufficient for gene silencing. Overall, we conclude that inheritance of the Avr3a gene silenced phenotype relies on factors that are variable among P. sojae strains. PMID- 26930613 TI - Induced neural stem cells from distinct genetic backgrounds exhibit different reprogramming status. AB - Somatic cells could be directly converted into induced neural stem cells (iNSCs) by ectopic expression of defined transcription factors. However, the underlying mechanism of direct lineage transition into iNSCs is largely unknown. In this study, we examined the effect of genetic background on the direct conversion process into an iNSC state. The iNSCs from two different mouse strains exhibited the distinct efficiency of lineage conversion as well as clonal expansion. Furthermore, the expression levels of endogenous NSC markers, silencing of transgenes, and in vitro differentiation potential were also different between iNSC lines from different strains. Therefore, our data suggest that the genetic background of starting cells influences the conversion efficiency as well as reprogramming status of directly converted iNSCs. PMID- 26930614 TI - Medial frontal negativity reflects advantageous inequality aversion of proposers in the ultimatum game: An ERP study. AB - Inequality aversion is a typical form of fairness preferences, which can explain the behaviors in many social exchange situations such as the ultimatum game (UG). There are two kinds of inequality aversion-disadvantageous inequality aversion of responders and advantageous inequality aversion of proposers in the ultimatum game. Although neuroscience research has reported neural correlates of disadvantageous inequality aversion, there are still debates about advantageous inequality aversion of proposers. In this paper, we developed a variant of ultimatum game in which participants played the UG as proposers. On each trial, first, the offer was randomly presented, then, participants as proposers decided whether to choose this offer; next, responders decided whether to accept or not. Offers that responders got 1-20% of the pie are defined as advantageous unfair offers of proposers, whereas offers that responders got 31-50% are defined as fair offers. Event-related brain potentials recorded from the participants showed that more negative-going medial frontal negativity (MFN) was elicited by advantageous unfair offers compared to fair offers in the early time window (250 350ms), which suggested that proposers were averse to advantageous inequality. PMID- 26930615 TI - Up-regulated ephrinB3/EphB3 expression in intractable temporal lobe epilepsy patients and pilocarpine induced experimental epilepsy rat model. AB - EphB family receptor tyrosine kinases, in cooperation with cell surface-bound ephrinB ligands, play a critical role in maintenance of dendritic spine morphogenesis, axons guidance, synaptogenesis, synaptic reorganization and plasticity in the central nervous system (CNS). However, the expression pattern of ephrinB/EphB in intractable temporal lobe epilepsy (TLE) and the underlying molecular mechanisms during epileptogenesis remain poorly understood. Here we investigated the expression pattern and cellular distribution of ephrinB/EphB in intractable TLE patients and lithium chloride-pilocarpine induced TLE rats using real-time quantitative polymerase chain reaction (RT-qPCR), immunohistochemistry, double-labeled immunofluorescence and Western blot analysis. Compared to control groups, ephrinB3 and EphB3 mRNA expression were significantly up-regulated in intractable TLE patients and TLE rats, while the mRNA expression trend of ephrinB1/2 and EphB1/2/4/6 in intractable TLE patients and TLE rats were inconsistent. Western blot analysis and semi-quantitative immunohistochemistry confirmed that ephrinB3 and EphB3 protein level were up-regulated in intractable TLE patients and TLE rats. At the same time, double-labeled immunofluorescence indicate that ephrinB3 was expressed mainly in the cytoplasm and protrusions of glia and neurons, while EphB3 was expressed mainly in the cytoplasm of neurons. Taken together, up-regulated expression of ephrinB3/EphB3 in intractable TLE patients and experimental TLE rats suggested that ephrinB3/EphB3 might be involved in the pathogenesis of TLE. PMID- 26930617 TI - Use of testicular versus ejaculated sperm for intracytoplasmic sperm injection among men with cryptozoospermia: a meta-analysis. AB - OBJECTIVE: To examine outcomes of intracytoplasmic sperm injection (ICSI) using testicular versus ejaculated sperm among men with cryptozoospermia. DESIGN: Meta analysis. SETTING: Not applicable. PATIENT(S): Men with cryptozoospermia undergoing consecutive ICSI cycles using ejaculated or testicular sperm. INTERVENTION(S): A systematic search was performed using PubMed (inception to August 2015). Inclusion criteria were studies comparing ICSI outcomes among men with cryptozoospermia using ejaculated and testicular sperm. MAIN OUTCOME MEASURE(S): Primary outcomes included ICSI fertilization or pregnancy rates (PRs). Secondary analysis included number of retrieved oocytes, maternal and paternal ages. Meta-analysis of weighted data using a random effects model was performed. Results are reported as relative risk or weighted mean differences (WMD) with 95% confidence intervals (CI). RESULT(S): Five cohort studies were included, encompassing 272 ICSI cycles and 4,596 injected oocytes. There were no differences in ICSI PRs (relative risk [RR] 0.53, 95% CI 0.19-1.42, I(2) = 67%) or fertilization rates (RR 0.91, 95% CI 0.78-1.06, I(2) = 73%) between testicular and ejaculated sperm groups. There was a significant trend toward increasing maternal age (WMD 1.69 years, 95% CI -2.71 to -0.66) and paternal age (WMD 2.61 years, 95% CI -4.73 to -0.48) with testicular sperm. There was no difference between numbers of oocytes retrieved (WMD 0.95, 95% CI -0.15 to 2.05). Post-hoc power analysis revealed pbeta <20% for PR analysis and pbeta <10% for fertilization rate analysis. CONCLUSION(S): The existing literature does not support a recommendation for men with cryptozoospermia to use testicular sperm in preference over ejaculated sperm for ICSI. PMID- 26930616 TI - Ocular Dominance Plasticity after Stroke Was Preserved in PSD-95 Knockout Mice. AB - Neuronal plasticity is essential to enable rehabilitation when the brain suffers from injury, such as following a stroke. One of the most established models to study cortical plasticity is ocular dominance (OD) plasticity in the primary visual cortex (V1) of the mammalian brain induced by monocular deprivation (MD). We have previously shown that OD-plasticity in adult mouse V1 is absent after a photothrombotic (PT) stroke lesion in the adjacent primary somatosensory cortex (S1). Exposing lesioned mice to conditions which reduce the inhibitory tone in V1, such as raising animals in an enriched environment or short-term dark exposure, preserved OD-plasticity after an S1-lesion. Here we tested whether modification of excitatory circuits can also be beneficial for preserving V1 plasticity after stroke. Mice lacking postsynaptic density protein-95 (PSD-95), a signaling scaffold present at mature excitatory synapses, have lifelong juvenile like OD-plasticity caused by an increased number of AMPA (alpha-amino-3-hydroxy-5 methyl-4-isoxazolepropionic acid) -silent synapses in V1 but unaltered inhibitory tone. In fact, using intrinsic signal optical imaging, we show here that OD plasticity was preserved in V1 of adult PSD-95 KO mice after an S1-lesion but not in PSD-95 wildtype (WT)-mice. In addition, experience-enabled enhancement of the optomotor reflex of the open eye after MD was compromised in both lesioned PSD-95 KO and PSD-95 WT mice. Basic V1-activation and retinotopic map quality were, however, not different between lesioned PSD-95 KO mice and their WT littermates. The preserved OD-plasticity in the PSD-95 KO mice indicates that V1-plasticity after a distant stroke can be promoted by either changes in excitatory circuitry or by lowering the inhibitory tone in V1 as previously shown. Furthermore, the present data indicate that an increased number of AMPA-silent synapses preserves OD-plasticity not only in the healthy brain, but also in another experimental paradigm of cortical plasticity, namely the long-range influence on V1-plasticity after an S1-lesion. PMID- 26930618 TI - Introduction: Examining the many potential reasons why euploid blastocysts do not always result in viable pregnancies (and deliveries): part 2. AB - To result in a viable delivery: 1) a capable embryo must be accurately deposited and retained in an optimal location of the uterine cavity; 2) the endometrium must be receptive and synchronized to the developmental stage of the embryo; 3) the uterus must be physiologically and anatomically adequate; and 4) there should not be the presence of circulating factors capable of disrupting normal implantation and placentation, nor the absence of specific factors required for endometrial receptivity. The intricate interaction between the embryo and the uterus is discussed in this series of reviews. PMID- 26930619 TI - Predictive value of sperm morphology and progressively motile sperm count for pregnancy outcomes in intrauterine insemination. AB - OBJECTIVE: To investigate the value of sperm parameters to predict an ongoing pregnancy outcome in couples treated with intrauterine insemination (IUI), during a methodologically stable period of time. DESIGN: Retrospective, observational study with logistic regression analyses. SETTING: University hospital. PATIENT(S): A total of 1,166 couples visiting the fertility laboratory for their first IUI episode, including 4,251 IUI cycles. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Sperm morphology, total progressively motile sperm count (TPMSC), and number of inseminated progressively motile spermatozoa (NIPMS); odds ratios (ORs) of the sperm parameters after the first IUI cycle and the first finished IUI episode; discriminatory accuracy of the multivariable model. RESULT(S): None of the sperm parameters was of predictive value for pregnancy after the first IUI cycle. In the first finished IUI episode, a positive relationship was found for <=4% of morphologically normal spermatozoa (OR 1.39) and a moderate NIPMS (5-10 million; OR 1.73). Low NIPMS showed a negative relation (<=1 million; OR 0.42). The TPMSC had no predictive value. The multivariable model (i.e., sperm morphology, NIPMS, female age, male age, and the number of cycles in the episode) had a moderate discriminatory accuracy (area under the curve 0.73). CONCLUSION(S): Intrauterine insemination is especially relevant for couples with moderate male factor infertility (sperm morphology <=4%, NIPMS 5-10 million). In the multivariable model, however, the predictive power of these sperm parameters is rather low. PMID- 26930620 TI - Self-acceptance of stuttering: A preliminary study. AB - PURPOSE: This study explored the relationship between self-acceptance of stuttering and (1) psychosocial factors (self-esteem, hostility towards others, emotional support, and perceived discrimination); (2) treatment history (support group participation, therapy duration, and perceived therapy success); and (3) previously reported variables in self-acceptance of stuttering, which include age and stuttering severity. METHOD: Participants were 80 adults who stutter who were recruited with assistance from the National Stuttering Association and Board Certified Specialists in Fluency Disorders. Participants completed an electronic survey composed of an acceptance of stuttering scale, psychosocial scales, and a participant information questionnaire. RESULTS: Statistical analysis identified significant correlations between participants' reports of self-acceptance of stuttering and self-esteem, perceived discrimination, hostility towards others, and perceived therapy outcome. Self-esteem was positively correlated with self acceptance, while hostility towards others and perceived discrimination was negatively correlated with self-acceptance. Participants who perceived their therapy outcome to be successful were significantly more likely to report higher levels of self-acceptance. No significant relationships were found between self acceptance of stuttering and support group participation, emotional support, stuttering severity, and participant age. CONCLUSION: This exploratory investigation has provided a foundation for future studies on the self-acceptance of stuttering. The findings indicate common psychosocial variables in self acceptance of stuttering and of other disabilities. The significant relationships between self-acceptance of stuttering and psychosocial and therapeutic variables found need to be further explored to identify its causalities and clinical implications. LEARNING OUTCOMES: The reader will be able to (1) discuss the importance of assessing self-acceptance of stuttering, (2) summarize the literature on self-acceptance of disability, and (3) describe the significant findings related to self-acceptance of stuttering and psychosocial, therapeutic variables. PMID- 26930621 TI - Nanocellulose, a tiny fiber with huge applications. AB - Nanocellulose is of increasing interest for a range of applications relevant to the fields of material science and biomedical engineering due to its renewable nature, anisotropic shape, excellent mechanical properties, good biocompatibility, tailorable surface chemistry, and interesting optical properties. We discuss the main areas of nanocellulose research: photonics, films and foams, surface modifications, nanocomposites, and medical devices. These tiny nanocellulose fibers have huge potential in many applications, from flexible optoelectronics to scaffolds for tissue regeneration. We hope to impart the readers with some of the excitement that currently surrounds nanocellulose research, which arises from the green nature of the particles, their fascinating physical and chemical properties, and the diversity of applications that can be impacted by this material. PMID- 26930622 TI - HEI-OC1 cells as a model for investigating drug cytotoxicity. AB - The House Ear Institute-Organ of Corti 1 (HEI-OC1) is one of the few, and arguable the most used, mouse auditory cell line available for research purposes. Originally proposed as an in vitro system for screening of ototoxic drugs, it has been used to investigate, among other topics, apoptotic pathways, autophagy and senescence, mechanism of cell protection, inflammatory responses, cell differentiation, effects of hypoxia, oxidative and endoplasmic reticulum stress, and expression of molecular channels and receptors. However, the use of different techniques with different goals resulted in apparent contradictions on the actual response of these cells to some specific treatments. We have now performed studies to characterize the actual response of HEI-OC1 cells to a battery of commonly used pharmacological drugs. We evaluated cell toxicity, apoptosis, viability, proliferation, senescence and autophagy in response to APAP (acetaminophen), cisplatin, dexamethasone, gentamicin, penicillin, neomycin, streptomycin, and tobramycin, at five different doses and two time-points (24 and 48 h), by flow cytometry techniques and caspase 3/7, MTT, Cytotoxicity, BrdU, Beclin1, LC3 and SA-beta-galactosidase assays. We also used HEK-293 and HeLa cells to compare some of the responses of these cells to those of HEI-OC1. Our results indicate that every cell line responds to the each drug in a different way, with HEI-OC1 cells showing a distinctive sensitivity to at least one of the mechanisms under study. Altogether, our results suggest that the HEI-OC1 might be a useful model to investigate biological responses associated with auditory cells, including auditory sensory cells, but a careful approach would be necessary at the time of evaluating drug effects. PMID- 26930623 TI - Reply to Letter to the Editor: "Effects of Different Heel Angles in Sleep Mode on Heel Interface Pressure in the Elderly". PMID- 26930624 TI - Lithium effects on circadian rhythms in fibroblasts and suprachiasmatic nucleus slices from Cry knockout mice. AB - Lithium is widely used as a treatment of bipolar disorder, a neuropsychiatric disorder associated with disrupted circadian rhythms. Lithium is known to lengthen period and increase amplitude of circadian rhythms. One possible pathway for these effects involves inhibition of glycogen synthase kinase-3beta (GSK 3beta), which regulates degradation of CRY2, a canonical clock protein determining circadian period. CRY1 is also known to play important roles in regulating circadian period and phase, although there is no evidence that it is similarly phosphorylated by GSK-3beta. In this paper, we tested the hypothesis that lithium affects circadian rhythms through CRYs. We cultured fibroblasts and slices of the suprachiasmatic nucleus (SCN), the master circadian pacemaker of the brain, from Cry1-/-, Cry2-/-, or wild-type (WT) mice bearing the PER2:LUC circadian reporter. Lithium was applied in the culture medium, and circadian rhythms of PER2 expression were measured. In WT and Cry2-/- fibroblasts, 10mM lithium increased PER2 expression and rhythm amplitude but not period, and 1mM lithium did not affect either period or amplitude. In non-rhythmic Cry1-/- fibroblasts, 10mM lithium increased PER2 expression. In SCN slices, 1mM lithium lengthened period ~1h in all genotypes, but did not affect amplitude except in Cry2-/- SCN. Thus, the amplitude-enhancing effect of lithium in WT fibroblasts was unaffected by Cry2 knockout and occurred in the absence of period lengthening, whereas the period-lengthening effect of lithium in WT SCN was unaffected by Cry1 or Cry2 knockout and occurred in the absence of rhythm amplification, suggesting that these two effects of lithium on circadian rhythms are independent of CRYs and of each other. PMID- 26930625 TI - ERP comparison study of face gender and expression processing in unattended condition. AB - This paper explores the differences within the underlying brain mechanism for facial expression and gender information processing. The study recorded Event Related Potentials (ERPs) of participants while they were performing a cross change detection task, in which the cross was peripherally surrounded by four facial stimuli. For investigating facial expression processing, either four faces with positive expressions from two females and two males were presented infrequently among four faces with negative expressions, or four faces with negative expressions from two females and two males were presented infrequently among four faces with positive expressions. For gender information processing, four female faces were presented infrequently among four male faces, or vice versa. The findings showed that the latency of facial emotion-related visual mismatch negativity (vMMN) was shorter than that of facial gender-related vMMN, and that their related brain regions presented some differences. The results can be viewed as evidence of the difference by which the human brain processes facial emotion and gender information. PMID- 26930626 TI - In Vivo Biodistribution and Anti-Tumor Efficacy Evaluation of Doxorubicin and Paclitaxel-Loaded Pluronic Micelles Decorated with c(RGDyK) Peptide. AB - The treatment of squamous carcinoma, especially multidrug resistance (MDR) tumors, represents one of the most formidable challenges in oncology. In this study, integrin-mediated Pluronic-based micellar system (c(RGDyK)-FP-DP) was proposed as a drug delivery system to enhance the in vivo anti-tumor efficacy in MDR human squamous carcinoma (KBv)-bearing. Following the recognition by integrin proteins express on the cell surface, cellular uptake and in vitro anti-tumor efficacy of c(RGDyK)-FP-DP were better than conventional PF-DP in KBv cells. The tumor homing specificity and further in vivo anticancer efficacy of c(RGDyK)-FP DP were performed using subcutaneous KBv tumor-bearing mice model, respectively. Compared with PF-DP, c(RGDyK)-FP-DP demonstrated more drug accumulation in tumor and relatively less drug accumulation in heart, and an extended median survival time in the KBv tumor-bearing mice model. Furthermore, preliminary in vivo subacute toxicity evaluation was also conducted by the measurement of histopathology, blood cell counts and clinical biochemistry parameters. Results showed that no obvious toxicity was observed to the hematological system or heart after a series of intravenous administration of c(RGDyK)-FP-DP. In conclusion, our results suggested that c(RGDyK) peptide conjugated Pluronic micelles could be a promising vehicle for enhancing the treatment of MDR human squamous carcinoma. PMID- 26930628 TI - Novel approach to automatically classify rat social behavior using a video tracking system. AB - BACKGROUND: In the past, studies in behavioral neuroscience and drug development have relied on simple and quick readout parameters of animal behavior to assess treatment efficacy or to understand underlying brain mechanisms. The predominant use of classical behavioral tests has been repeatedly criticized during the last decades because of their poor reproducibility, poor translational value and the limited explanatory power in functional terms. NEW METHOD: We present a new method to monitor social behavior of rats using automated video tracking. The velocity of moving and the distance between two rats were plotted in frequency distributions. In addition, behavior was manually annotated and related to the automatically obtained parameters for a validated interpretation. RESULTS: Inter individual distance in combination with velocity of movement provided specific behavioral classes, such as moving with high velocity when "in contact" or "in proximity". Human observations showed that these classes coincide with following (chasing) behavior. In addition, when animals are "in contact", but at low velocity, behaviors such as allogrooming and social investigation were observed. Also, low dose treatment with morphine and short isolation increased the time animals spent in contact or in proximity at high velocity. COMPARISON WITH EXISTING METHODS: Current methods that involve the investigation of social rat behavior are mostly limited to short and relatively simple manual observations. CONCLUSION: A new and automated method for analyzing social behavior in a social interaction test is presented here and shows to be sensitive to drug treatment and housing conditions known to influence social behavior in rats. PMID- 26930629 TI - Validation of neural spike sorting algorithms without ground-truth information. AB - BACKGROUND: The throughput of electrophysiological recording is growing rapidly, allowing thousands of simultaneous channels, and there is a growing variety of spike sorting algorithms designed to extract neural firing events from such data. This creates an urgent need for standardized, automatic evaluation of the quality of neural units output by such algorithms. NEW METHOD: We introduce a suite of validation metrics that assess the credibility of a given automatic spike sorting algorithm applied to a given dataset. By rerunning the spike sorter two or more times, the metrics measure stability under various perturbations consistent with variations in the data itself, making no assumptions about the internal workings of the algorithm, and minimal assumptions about the noise. RESULTS: We illustrate the new metrics on standard sorting algorithms applied to both in vivo and ex vivo recordings, including a time series with overlapping spikes. We compare the metrics to existing quality measures, and to ground-truth accuracy in simulated time series. We provide a software implementation. COMPARISON WITH EXISTING METHODS: Metrics have until now relied on ground-truth, simulated data, internal algorithm variables (e.g. cluster separation), or refractory violations. By contrast, by standardizing the interface, our metrics assess the reliability of any automatic algorithm without reference to internal variables (e.g. feature space) or physiological criteria. CONCLUSIONS: Stability is a prerequisite for reproducibility of results. Such metrics could reduce the significant human labor currently spent on validation, and should form an essential part of large-scale automated spike sorting and systematic benchmarking of algorithms. PMID- 26930630 TI - Somatic Symptoms: Prevalence, Co-Occurrence and Associations with Self-Perceived Health and Limitations Due To Physical Health - A Danish Population-Based Study. AB - A high number of somatic symptoms have been associated with poor health status and increased health care use. Previous studies focused on number of symptoms without considering the specific symptoms. The aim of the study was to investigate 1) the prevalence of 19 somatic symptoms, 2) the associations between the symptoms, and 3) the associations between the somatic symptoms, self perceived health and limitations due to physical health accounting for the co occurrence of symptoms. Information on 19 somatic symptoms, self-perceived health and limitations due to physical health was achieved from a population-based questionnaire survey of 36,163 randomly selected adults in the Capital Region of Denmark in 2006/07. Chain graph models were used to transparently identify and describe the associations between symptoms, self-perceived health and limitations due to physical health. In total, 94.9% of the respondents were bothered by one or more of the 19 somatic symptoms. The symptoms were associated in a complex structure. Still, recognisable patterns were identified within organ systems/body parts. When accounting for symptom co-occurrence; dizziness, pain in legs, respiratory distress and tiredness were all strongly directly associated with both of the outcomes (gamma>0.30). Chest pain was strongly associated with self perceived health, and other musculoskeletal symptoms and urinary retention were strongly associated with limitations due to physical health. Other symptoms were either moderate or not statistically associated with the health status outcomes. Opposite, almost all the symptoms were strongly associated with the two outcomes when not accounting for symptom co-occurrence. In conclusion, we found that somatic symptoms were frequent and associated in a complex structure. The associations between symptoms and health status measures differed between the symptoms and depended on the co-occurrence of symptoms. This indicates an importance of considering both the specific symptoms and symptom co-occurrence in further symptom research instead of merely counting symptoms. PMID- 26930632 TI - Salt-Responsive Transcriptome Profiling of Suaeda glauca via RNA Sequencing. AB - BACKGROUND: Suaeda glauca, a succulent halophyte of the Chenopodiaceae family, is widely distributed in coastal areas of China. Suaeda glauca is highly resistant to salt and alkali stresses. In the present study, the salt-responsive transcriptome of Suaeda glauca was analyzed to identify genes involved in salt tolerance and study halophilic mechanisms in this halophyte. RESULTS: Illumina HiSeq 2500 was used to sequence cDNA libraries from salt-treated and control samples with three replicates each treatment. De novo assembly of the six transcriptomes identified 75,445 unigenes. A total of 23,901 (31.68%) unigenes were annotated. Compared with transcriptomes from the three salt-treated and three salt-free samples, 231 differentially expressed genes (DEGs) were detected (including 130 up-regulated genes and 101 down-regulated genes), and 195 unigenes were functionally annotated. Based on the Gene Ontology (GO), Clusters of Orthologous Groups (COG) and Kyoto Encyclopedia of Genes and Genomes (KEGG) classifications of the DEGs, more attention should be paid to transcripts associated with signal transduction, transporters, the cell wall and growth, defense metabolism and transcription factors involved in salt tolerance. CONCLUSIONS: This report provides a genome-wide transcriptional analysis of a halophyte, Suaeda glauca, under salt stress. Further studies of the genetic basis of salt tolerance in halophytes are warranted. PMID- 26930631 TI - Chronic Drinking During Adolescence Predisposes the Adult Rat for Continued Heavy Drinking: Neurotrophin and Behavioral Adaptation after Long-Term, Continuous Ethanol Exposure. AB - Previous research has found that adolescent ethanol (EtOH) exposure alters drug seeking behaviors, cognition and neuroplasticity. Using male Sprague Dawley rats, differences in spatial working memory, non-spatial discrimination learning and behavioral flexibility were explored as a function of age at the onset (mid adolescent vs. adult) of chronic EtOH exposure (CET). Concentrations of mature brain-derived neurotrophic factor (mBDNF) and beta-nerve growth factor (beta-NGF) in the prefrontal cortex and hippocampus were also assessed at different time points: during CET, following acute abstinence (48-hrs), and after protracted abstinence (6-8 wks). Our results revealed that an adolescent onset of CET leads to increased EtOH consumption that persisted into adulthood. In both adult and adolescent onset CET groups, there were significant long-term reductions in prefrontal cortical mBDNF and beta-NGF levels. However, only adult onset CET rats displayed decreased hippocampal BDNF levels. Spatial memory, assessed by spontaneous alternation and delayed alternation, was not significantly affected by CET as a function of age of drinking onset, but higher blood-EtOH levels were correlated with lower spontaneous alternation scores. Regardless of the age of onset, EtOH exposed rats were impaired on non-spatial discrimination learning and displayed inflexible behavioral patterns upon reversal learning. Our results indicate that adolescent EtOH exposure changes long-term consumption patterns producing behavioral and neural dysfunctions that persist across the lifespan. PMID- 26930633 TI - Adhesion protein networks reveal functions proximal and distal to cell-matrix contacts. AB - Cell adhesion to the extracellular matrix is generally mediated by integrin receptors, which bind to intracellular adhesion proteins that form multi molecular scaffolding and signalling complexes. The networks of proteins, and their interactions, are dynamic, mechanosensitive and extremely complex. Recent efforts to characterise adhesions using a variety of technologies, including imaging, proteomics and bioinformatics, have provided new insights into their composition, organisation and how they are regulated, and have also begun to reveal unexpected roles for so-called adhesion proteins in other cellular compartments (for example, the nucleus or centrosomes) in diseases such as cancer. We believe this is opening a new chapter on understanding the wider functions of adhesion proteins, both proximal and distal to cell-matrix contacts. PMID- 26930636 TI - Letter: Clarifying doubt about endocrine-related science. PMID- 26930634 TI - Impact of Obstructive Sleep Apnea on the Levels of Placental Growth Factor (PlGF) and Their Value for Predicting Short-Term Adverse Outcomes in Patients with Acute Coronary Syndrome. AB - BACKGROUND: Placental growth factor (PlGF) induces angiogenesis and promotes tissue repair, and plasma PlGF levels change markedly during acute myocardial infarction (AMI). Currently, the impact of obstructive sleep apnea (OSA) in patients with AMI is a subject of debate. Our objective was to evaluate the relationships between PlGF levels and both the severity of acute coronary syndrome (ACS) and short-term outcomes after ACS in patients with and without OSA. METHODS: A total of 538 consecutive patients (312 OSA patients and 226 controls) admitted for ACS were included in this study. All patients underwent polygraphy in the first 72 hours after hospital admission. The severity of disease and short-term prognoses were evaluated during the hospitalization period. Plasma PlGF levels were measured using an electrochemiluminescence immunoassay. RESULTS: Patients with OSA were significantly older and more frequently hypertensive and had higher BMIs than those without OSA. After adjusting for age, smoking status, BMI and hypertension, PlGF levels were significantly elevated in patients with OSA compared with patients without OSA (19.9 pg/mL, interquartile range: 16.6-24.5 pg/mL; 18.5 pg/mL, interquartile range: 14.7-22.7 pg/mL; p<0.001), and a higher apnea-hypopnea index (AHI) was associated with higher PlGF concentrations (p<0.003). Patients with higher levels of PlGF had also an increased odds ratio for the presence of 3 or more diseased vessels and for a Killip score>1, even after adjustment. CONCLUSIONS: The results of this study show that in patients with ACS, elevated plasma levels of PlGF are associated with the presence of OSA and with adverse outcomes during short-term follow-up. TRIAL REGISTRATION: ClinicalTrials.gov NCT01335087. PMID- 26930635 TI - Micro-CT imaging: Developing criteria for examining fetal skeletons in regulatory developmental toxicology studies - A workshop report. AB - During the past two decades the use and refinements of imaging modalities have markedly increased making it possible to image embryos and fetuses used in pivotal nonclinical studies submitted to regulatory agencies. Implementing these technologies into the Good Laboratory Practice environment requires rigorous testing, validation, and documentation to ensure the reproducibility of data. A workshop on current practices and regulatory requirements was held with the goal of defining minimal criteria for the proper implementation of these technologies and subsequent submission to regulatory agencies. Micro-computed tomography (micro-CT) is especially well suited for high-throughput evaluations, and is gaining popularity to evaluate fetal skeletons to assess the potential developmental toxicity of test agents. This workshop was convened to help scientists in the developmental toxicology field understand and apply micro-CT technology to nonclinical toxicology studies and facilitate the regulatory acceptance of imaging data. Presentations and workshop discussions covered: (1) principles of micro-CT fetal imaging; (2) concordance of findings with conventional skeletal evaluations; and (3) regulatory requirements for validating the system. Establishing these requirements for micro-CT examination can provide a path forward for laboratories considering implementing this technology and provide regulatory agencies with a basis to consider the acceptability of data generated via this technology. PMID- 26930637 TI - Use of Renal Replacement Therapy May Influence Graft Outcomes following Liver Transplantation for Acute Liver Failure: A Propensity-Score Matched Population Based Retrospective Cohort Study. AB - INTRODUCTION: Acute kidney injury is associated with a poor prognosis in acute liver failure but little is known of outcomes in patients undergoing transplantation for acute liver failure who require renal replacement therapy. METHODS: A retrospective analysis of the United Kingdom Transplant Registry was performed (1 January 2001-31 December 2011) with patient and graft survival determined using Kaplan-Meier methods. Cox proportional hazards models were used together with propensity-score based full matching on renal replacement therapy use. RESULTS: Three-year patient and graft survival for patients receiving renal replacement therapy were 77.7% and 72.6% compared with 85.1% and 79.4% for those not requiring renal replacement therapy (P<0.001 and P = 0.009 respectively, n = 725). In a Cox proportional hazards model, renal replacement therapy was a predictor of both patient death (hazard ratio (HR) 1.59, 95% CI 1.01-2.50, P = 0.044) but not graft loss (HR 1.39, 95% CI 0.92-2.10, P = 0.114). In groups fully matched on baseline covariates, those not receiving renal replacement therapy with a serum creatinine greater than 175 MUmol/L had a significantly worse risk of graft failure than those receiving renal replacement therapy. CONCLUSION: In patients being transplanted for acute liver failure, use of renal replacement therapy is a strong predictor of patient death and graft loss. Those not receiving renal replacement therapy with an elevated serum creatinine may be at greater risk of early graft failure than those receiving renal replacement therapy. A low threshold for instituting renal replacement therapy may therefore be beneficial. PMID- 26930627 TI - Experimental Treatment with Favipiravir for Ebola Virus Disease (the JIKI Trial): A Historically Controlled, Single-Arm Proof-of-Concept Trial in Guinea. AB - BACKGROUND: Ebola virus disease (EVD) is a highly lethal condition for which no specific treatment has proven efficacy. In September 2014, while the Ebola outbreak was at its peak, the World Health Organization released a short list of drugs suitable for EVD research. Favipiravir, an antiviral developed for the treatment of severe influenza, was one of these. In late 2014, the conditions for starting a randomized Ebola trial were not fulfilled for two reasons. One was the perception that, given the high number of patients presenting simultaneously and the very high mortality rate of the disease, it was ethically unacceptable to allocate patients from within the same family or village to receive or not receive an experimental drug, using a randomization process impossible to understand by very sick patients. The other was that, in the context of rumors and distrust of Ebola treatment centers, using a randomized design at the outset might lead even more patients to refuse to seek care. Therefore, we chose to conduct a multicenter non-randomized trial, in which all patients would receive favipiravir along with standardized care. The objectives of the trial were to test the feasibility and acceptability of an emergency trial in the context of a large Ebola outbreak, and to collect data on the safety and effectiveness of favipiravir in reducing mortality and viral load in patients with EVD. The trial was not aimed at directly informing future guidelines on Ebola treatment but at quickly gathering standardized preliminary data to optimize the design of future studies. METHODS AND FINDINGS: Inclusion criteria were positive Ebola virus reverse transcription PCR (RT-PCR) test, age >= 1 y, weight >= 10 kg, ability to take oral drugs, and informed consent. All participants received oral favipiravir (day 0: 6,000 mg; day 1 to day 9: 2,400 mg/d). Semi-quantitative Ebola virus RT PCR (results expressed in "cycle threshold" [Ct]) and biochemistry tests were performed at day 0, day 2, day 4, end of symptoms, day 14, and day 30. Frozen samples were shipped to a reference biosafety level 4 laboratory for RNA viral load measurement using a quantitative reference technique (genome copies/milliliter). Outcomes were mortality, viral load evolution, and adverse events. The analysis was stratified by age and Ct value. A "target value" of mortality was defined a priori for each stratum, to guide the interpretation of interim and final analysis. Between 17 December 2014 and 8 April 2015, 126 patients were included, of whom 111 were analyzed (adults and adolescents, >=13 y, n = 99; young children, <=6 y, n = 12). Here we present the results obtained in the 99 adults and adolescents. Of these, 55 had a baseline Ct value >= 20 (Group A Ct >= 20), and 44 had a baseline Ct value < 20 (Group A Ct < 20). Ct values and RNA viral loads were well correlated, with Ct = 20 corresponding to RNA viral load = 7.7 log10 genome copies/ml. Mortality was 20% (95% CI 11.6% 32.4%) in Group A Ct >= 20 and 91% (95% CI 78.8%-91.1%) in Group A Ct < 20. Both mortality 95% CIs included the predefined target value (30% and 85%, respectively). Baseline serum creatinine was >=110 MUmol/l in 48% of patients in Group A Ct >= 20 (>=300 MUmol/l in 14%) and in 90% of patients in Group A Ct < 20 (>=300 MUmol/l in 44%). In Group A Ct >= 20, 17% of patients with baseline creatinine >=110 MUmol/l died, versus 97% in Group A Ct < 20. In patients who survived, the mean decrease in viral load was 0.33 log10 copies/ml per day of follow-up. RNA viral load values and mortality were not significantly different between adults starting favipiravir within <72 h of symptoms compared to others. Favipiravir was well tolerated. CONCLUSIONS: In the context of an outbreak at its peak, with crowded care centers, randomizing patients to receive either standard care or standard care plus an experimental drug was not felt to be appropriate. We did a non-randomized trial. This trial reaches nuanced conclusions. On the one hand, we do not conclude on the efficacy of the drug, and our conclusions on tolerance, although encouraging, are not as firm as they could have been if we had used randomization. On the other hand, we learned about how to quickly set up and run an Ebola trial, in close relationship with the community and non governmental organizations; we integrated research into care so that it improved care; and we generated knowledge on EVD that is useful to further research. Our data illustrate the frequency of renal dysfunction and the powerful prognostic value of low Ct values. They suggest that drug trials in EVD should systematically stratify analyses by baseline Ct value, as a surrogate of viral load. They also suggest that favipiravir monotherapy merits further study in patients with medium to high viremia, but not in those with very high viremia. TRIAL REGISTRATION: ClinicalTrials.gov NCT02329054. PMID- 26930639 TI - Impact of cardiac output imprecision on the clinical interpretation of haemodynamic variables in the cardiac catheterisation laboratory. PMID- 26930638 TI - Optimal medical therapy may be a better initial strategy in patients with chronic total occlusion of a single coronary artery. AB - OBJECTIVES: To compare clinical outcomes of percutaneous coronary intervention (PCI) with those of optimal medical therapy (OMT) alone in patients with chronic total occlusion (CTO) of a single coronary artery. BACKGROUND: Limited data are available on the efficacy of OMT for the treatment of single-vessel CTO. METHODS: Between March 2003 and February 2012, we enrolled 2024 CTO patients in a retrospective, observational registry and analyzed 435 patients with CTO of a single coronary artery. We divided patients into an OMT group (n=147) and PCI group (n=288) according to the initial treatment strategy. One-to-many (1:N) propensity score matching with a non-fixed matching ratio was also performed. The primary outcome measured in this study was major adverse cardiac events (MACEs) including cardiac death, myocardial infarction, and repeated coronary revascularization. RESULTS: The median follow-up duration was 47.6 (interquartile range: 22.9 to 68.9) months. Major adverse cardiac events were noted for 16 patients (10.9%) in the OMT group compared to 41 patients (14.2%) in the PCI group (p=0.38). After propensity-score matching, there were no significant differences between the OMT group and PCI group with respect to MACE frequency (10.1% vs. 16.9%, adjusted hazard ratio [HR], 2.03; 95% confidence interval [CI], 0.88-4.68, p=0.10) or cardiac death (OMT vs. PCI: 5.1% vs. 4.8%, HR, 1.14; 95% CI, 0.30-4.42, p=0.85). Subgroup analysis showed that the rate of MACEs was significantly lower in the OMT group compared to the PCI group among patients with an APPROACH score <= 18 and SYNTAX score <= 12. CONCLUSIONS: As a treatment strategy in patients with single-vessel CTO, PCI did not reduce the risk of MACE or cardiac death. These results suggest that OMT may be a better initial strategy for patients as assessed by low APPROACH and SYNTAX scores. PMID- 26930640 TI - The diagnosis of intermediate coronary artery stenosis by myocardial perfusion imaging using an ultrafast cardiac gamma camera: Comparison with fractional flow reserve. PMID- 26930641 TI - Prognostic value of new onset atrial fibrillation after transcatheter aortic valve implantation: A FRANCE 2 registry substudy. AB - BACKGROUND: The development of new onset atrial fibrillation (NOAF) post transcatheter aortic valve implantation (TAVI) is common and may be associated with an adverse prognosis. This study seeks to identify incidence, predictors, and impact of NOAF post-TAVI. METHODS: From the multicenter study of the French national transcatheter aortic valve implantation registry, FRANCE 2, a total of 1959 patients with sinus rhythm prior to TAVI were enrolled into this study. The incidence of post-TAVI NOAF, predictors of development of NOAF and impact on 30 day and 1-year-mortalities were assessed. RESULTS: Of the 1959 TAVI patients (mean-age: 82.6 +/- 7.5 years, mean-logistic-EuroSCORE: 21.8 +/- 14.3), 149 (7.6%) developed NOAF with the remaining 1810 (92.4%) control patients demonstrating no evidence of AF as defined by the Valve Academic Research Consortium (VARC). Advanced age and major and life-threatening bleeding were independent predictors of NOAF (95% CI: 0.93-0.99; p=0.006, 95% CI: 1.58-4.00; p<0.001, 95% CI: 1.09-3.75; p=0.025, respectively). A trend towards a higher incidence of major and life-threatening bleeding was observed in the patients undergoing TAVI via the transapical (TA)-approach compared with the transfemoral (TF)-approach. Both 30-day and cumulative 1-year-mortalities were significantly higher in patients with NOAF compared to patients without NOAF (3.0% vs. 7.4%; p=0.005, 9.1% vs. 20.8%; p<0.001, respectively). In addition, NOAF was an independent predictor of 30-day and 1-year-mortalities (HR: 2.16; 95% CI: 1.06 4.41; p=0.033, HR: 2.12; 95% CI: 1.42-3.15; p<0.001, respectively). CONCLUSION: Advanced age and major and life-threatening bleeding were independently associated with increased incidence of NOAF, which itself was an independent predictor of 30-day and 1-year-mortalities. With regards to the various transcatheter approaches, a trend towards a higher incidence of major and life threatening bleeding was observed only with the TA-approach. PMID- 26930642 TI - ZFHX3 knockdown increases arrhythmogenesis and dysregulates calcium homeostasis in HL-1 atrial myocytes. AB - BACKGROUND: ZFHX3 plays an important role in the genesis of atrial fibrillation. However, the atrial electrophysiological effects of ZFHX3 are not clear. This study sought to investigate roles of ZFHX3 in atrial electrophysiology and calcium homeostasis by using HL-1 atrial myocytes knocked-down with ZFHX3. METHODS: Patch clamp, confocal fluorescence microscopy and Western blot were used to study electrical activity, ionic currents, calcium homeostasis and protein expressions in stable ZFHX3 shRNA cells. RESULTS: As compared to control, ZFHX3 shRNA cells with 28% decline of ZFHX3 protein had a larger sarcoplasmic reticulum Ca(2+) content by 62%, Ca(2+) transient by 20%, and calcium leak by 75%. ZFHX3 shRNA cells (n=35) had shorter action potential duration (APD) at 50% (14.7 +/- 0.9 versus 20.3 +/- 1.4 ms, P<0.005), and 20% (6.1 +/- 0.3 versus 8.3 +/- 0.8 ms, P<0.005) repolarization than control cells (n=30). ZFHX3 shRNA cells (n=10) had larger amplitudes of isoproterenol (1 MUM)-induced delayed after depolarization (14.1 +/- 0.9 versus 7.2 +/- 0.2 mV, P<0.05) than control cells (n=10). Besides, acetylcholine (3 MUM) shortened APD at 90% repolarization to a greater extent (19 +/- 4% versus 7 +/- 2%, P<0.01) in ZFHX3 shRNA cells (n=11) than in control cells (n=12). In addition, ZFHX3 shRNA cells had increased expressions of SERCA2a, ryanodine receptor, Kv1.4, Kv1.5 and Kir3.4. Moreover, ZFHX3 shRNA cells had a larger SERCA2a activity, ultra-rapid delayed rectifier potassium currents, transient outward currents and acetylcholine-sensitive potassium currents. CONCLUSIONS: ZFHX3 knock-down in atrial myocytes dysregulated calcium homeostasis and increased atrial arrhythmogenesis, which may contribute to the occurrence of AF. PMID- 26930643 TI - Myocardial infarction associated with a "Takotsubo component": Some caveats need to be considered. PMID- 26930644 TI - Sonographic Evaluation of Fetal Conus Medullaris and Filum Terminale. AB - BACKGROUND: Sonographic evaluation of the fetal conus medullaris (CM) level is not reproducible. The objectives of this study were to determine the normal position of the fetal CM during pregnancy as well as the normal intradural filum terminale (FT) length and to evaluate their use in detecting tethered cord. METHODS: This is a prospective evaluation of normal singleton pregnancies examined by sonography from 17 weeks of gestation to term. Each sonographer had to identify the top of the first sacral vertebra (S1) to measure the distance between it and the conus extremity (CM-S1 distance). The intradural FT distance was measured with 5- to 8-MHz probes. RESULTS: 194 consecutive pregnant women were included. The CM and intradural FT were demonstrated clearly in 164 (84%) cases. The mean CM-S1 distance was 20.6 mm (range 0.5-42). The mean intradural FT distance was 27.9 mm (range 6.6-49.3). Linear regression analysis showed a significant association between both those distances and gestational age (p < 0.05). In cases of tethered cord, the mean CM-S1 distance and the mean intradural FT distance were both below the 5th percentile. CONCLUSION: Prenatal evaluation of the CM and the intradural FT is feasible and reproducible and seems useful in detecting tethered cord. PMID- 26930645 TI - The Antiviral Activity of Approved and Novel Drugs against HIV-1 Mutations Evaluated under the Consideration of Dose-Response Curve Slope. AB - OBJECTIVES: This study was designed to identify common HIV-1 mutation complexes affecting the slope of inhibition curve, and to propose a new parameter incorporating both the IC50 and the slope to evaluate phenotypic resistance. METHODS: Utilizing site-directed mutagenesis, we constructed 22 HIV-1 common mutation complexes. IC50 and slope of 10 representative approved drugs and a novel agent against these mutations were measured to determine the resistance phenotypes. The values of new parameter incorporating both the IC50 and the slope of the inhibition curve were calculated, and the correlations between parameters were assessed. RESULTS: Depending on the class of drug, there were intrinsic differences in how the resistance mutations affected the drug parameters. All of the mutations resulted in large increases in the IC50s of nucleoside reverse transcriptase inhibitors. The effects of the mutations on the slope were the most apparent when examining their effects on the inhibition of non-nucleoside reverse transcriptase inhibitors and protease inhibitors. For example, some mutations, such as V82A, had no effect on IC50, but reduced the slope. We proposed a new concept, termed IIPatoxic, on the basis of IC50, slope and the maximum limiting concentrations of the drug. The IIPatoxic values of 10 approved drugs and 1 novel agent were calculated, and were closely related to the IIPmax values (r > 0.95, p < 0.001). CONCLUSIONS: This study confirms that resistance mutations cannot be accurately assessed by IC50 alone, because it tends to underestimate the degree of resistance. The slope parameter is of very importance in the measurement of drug resistance and the effect can be applied to more complex patterns of resistance. This is the most apparent when testing the effects of the mutations on protease inhibitors activity. We also propose a new index, IIPatoxic, which incorporates both the IC50 and the slope. This new index could complement current IIP indices, thereby enabling predict the efficacy of pre-clinical drugs for which human pharmacokinetic is not available. PMID- 26930646 TI - Content and Composition of Branched-Chain Fatty Acids in Bovine Milk Are Affected by Lactation Stage and Breed of Dairy Cow. AB - Dairy products contain bioactive fatty acids (FA) and are a unique dietary source of an emerging class of bioactive FA, branched-chain fatty acids (BCFA). The objective of this study was to compare the content and profile of bioactive FA in milk, with emphasis on BCFA, among Holstein (HO), Jersey (JE), and first generation HO x JE crossbreeds (CB) across a lactation to better understand the impact of these factors on FA of interest to human health. Twenty-two primiparous cows (n = 7 HO, n = 7 CB, n = 8 JE) were followed across a lactation. All cows were fed a consistent total mixed ration (TMR) at a 70:30 forage to concentrate ratio. Time points were defined as 5 days in milk (DIM), 95 DIM, 185 DIM, and 275 DIM. HO and CB had a higher content of n-3 FA at 5 DIM than JE and a lower n-6:n 3 ratio. Time point had an effect on the n-6:n-3 ratio, with the lowest value observed at 5 DIM and the highest at 185 DIM. The content of vaccenic acid was highest at 5 DIM, yet rumenic acid was unaffected by time point or breed. Total odd and BCFA (OBCFA) were higher in JE than HO and CB at 185 and 275 DIM. Breed affected the content of individual BCFA. The content of iso-14:0 and iso-16:0 in milk was higher in JE than HO and CB from 95 to 275 DIM. Total OBCFA were affected by time point, with the highest content in milk at 275 DIM. In conclusion, HO and CB exhibited a higher content of several bioactive FA in milk than JE. Across a lactation the greatest content of bioactive FA in milk occurred at 5 DIM and OBCFA were highest at 275 DIM. PMID- 26930647 TI - Socioeconomic and Other Demographic Disparities Predicting Survival among Head and Neck Cancer Patients. AB - BACKGROUND: The Institute of Medicine (IOM) report, "Unequal Treatment," which defines disparities as racially based, indicates that disparities in cancer diagnosis and treatment are less clear. While a number of studies have acknowledged cancer disparities, they have limitations of retrospective nature, small sample sizes, inability to control for covariates, and measurement errors. OBJECTIVE: The purpose of this study was to examine disparities as predictors of survival among newly diagnosed head and neck cancer patients recruited from 3 hospitals in Michigan, USA, while controlling for a number of covariates (health behaviors, medical comorbidities, and treatment modality). METHODS: Longitudinal data were collected from newly diagnosed head and neck cancer patients (N = 634). The independent variables were median household income, education, race, age, sex, and marital status. The outcome variables were overall, cancer-specific, and disease-free survival censored at 5 years. Kaplan-Meier curves and univariate and multivariate Cox proportional hazards models were performed to examine demographic disparities in relation to survival. RESULTS: Five-year overall, cancer-specific, and disease-free survival were 65.4% (407/622), 76.4% (487/622), and 67.0% (427/622), respectively. Lower income (HR, 1.5; 95% CI, 1.1-2.0 for overall survival; HR, 1.4; 95% CI, 1.0-1.9 for cancer-specific survival), high school education or less (HR, 1.4; 95% CI, 1.1-1.9 for overall survival; HR, 1.4; 95% CI, 1.1-1.9 for cancer-specific survival), and older age in decades (HR, 1.4; 95% CI, 1.2-1.7 for overall survival; HR, 1.2; 95% CI, 1.1-1.4 for cancer specific survival) decreased both overall and disease-free survival rates. A high school education or less (HR, 1.4; 95% CI, 1.0-2.1) and advanced age (HR, 1.3; 95% CI, 1.1-1.6) were significant independent predictors of poor cancer-specific survival. CONCLUSION: Low income, low education, and advanced age predicted poor survival while controlling for a number of covariates (health behaviors, medical comorbidities, and treatment modality). Recommendations from the Institute of Medicine's Report to reduce disparities need to be implemented in treating head and neck cancer patients. PMID- 26930648 TI - JAG1 Is Associated with Poor Survival through Inducing Metastasis in Lung Cancer. AB - JAG1 is a Notch ligand that plays a critical role in multiple signaling pathways. However, the functionality of JAG1 in non-small cell lung cancer (NSCLC) has not been investigated thoroughly. By comparison of gene transcripted RNA profiles in the cell line pair with differential invasion ability, we identified JAG1 as a potential metastasis enhancer in lung cancer. Ectopic expression of JAG1 on lung cancer cells enhanced cell migration and invasion as well as metastasis in vitro and in vivo. Conversely, knockdown of JAG1 with siRNA in highly invasive cancer cells led to the reduction of migration and invasion. In clinical analysis, JAG1 mRNA expression was higher in tumors than in adjacent normal tissues in 14 of 20 patients with squamous cell carcinoma (SCC). SCC patients with higher JAG1 transcription had poor overall survival than those with low-transcripted JAG1. Microarray analysis indicated that the enforced JAG1 transcription was associated with an elevated HSPA2 RNA transcription, which played a role in promoting cancer cell migration and invasion. In conclusion, this is the first study that demonstrated that JAG1 might act as a potential prognostic marker and JAG1/HSPA2 axis mediates lung cancer malignancy at least partly. PMID- 26930649 TI - Metabolic Power Requirement of Change of Direction Speed in Young Soccer Players: Not All Is What It Seems. AB - PURPOSE: The aims of this study were to 1) compare the metabolic power demand of straight-line and change of direction (COD) sprints including 45 degrees or 90 degrees -turns, and 2) examine the relation between estimated metabolic demands and muscular activity throughout the 3 phases of COD-sprints. METHODS: Twelve highly-trained soccer players performed one 25-m and three 20-m sprints, either in straight-line or with one 45 degrees - or 90 degrees -COD. Sprints were monitored with 2 synchronized 100-Hz laser guns to assess players' velocities before, during and after the COD. Acceleration and deceleration were derived from changes in speed over time. Metabolic power was estimated based on di Prampero's approach (2005). Electromyography amplitude (RMS) of 2 lower limb muscles was measured. The expected energy expenditure during time-adjusted straight-line sprints (matching COD sprints time) was also calculated. RESULTS: Locomotor dependant metabolic demand was largely lower with COD (90 degrees , 142.1+/-13.5 J.kg(-1)) compared with time-adjusted (effect size, ES = -3.0; 193.2+/-18.6 J.kg( 1)) and non-adjusted straight-line sprints (ES = -1.7; 168.4+/-15.3 J.kg(-1)). Metabolic power requirement was angle-dependent, moderately lower for 90 degrees COD vs. 45 degrees -COD sprint (ES = -1.0; 149.5+/-10.4 J.kg(-1)). Conversely, the RMS was slightly- (45 degrees , ES = +0.5; +2.1%, 90% confidence limits (+/ 3.6) for vastus lateralis muscle (VL)) to-largely (90 degrees , ES = +1.6; +6.1 (3.3%) for VL) greater for COD-sprints. Metabolic power/RMS ratio was 2 to 4 times lower during deceleration than acceleration phases. CONCLUSION: Present results show that COD-sprints are largely less metabolically demanding than linear sprints. This may be related to the very low metabolic demand associated with the deceleration phase during COD-sprints that may not be compensated by the increased requirement of the reacceleration phase. These results also highlight the dissociation between metabolic and muscle activity demands during COD sprints, which questions the use of metabolic power as a single measure of running load in soccer. PMID- 26930650 TI - Impaired Autophagy in Adult Bone Marrow CD34+ Cells of Patients with Aplastic Anemia: Possible Pathogenic Significance. AB - Aplastic anemia (AA) is a bone marrow failure syndrome that is caused largely by profound quantitative and qualitative defects of hematopoietic stem and progenitor cells. However, the mechanisms underlying these defects remain unclear. Under conditions of stress, autophagy acts as a protective mechanism for cells. We therefore postulated that autophagy in CD34+ hematopoietic progenitor cells (HPCs) from AA patients might be impaired and play a role in the pathogenesis of AA. To test this hypothesis, we tested autophagy in CD34+ cells from AA samples and healthy controls and investigated the effect of autophagy on the survival of adult human bone marrow CD34+ cells. We found that the level of autophagy in CD34+ cells from AA patients was significantly lower than in age/sex matched healthy controls, and lower in cases of severe AA than in those with non severe AA. Autophagy in CD34+ cells improved upon amelioration of AA but, compared to healthy controls, was still significantly reduced even in AA patients who had achieved a complete, long-term response. We also showed that although the basal autophagy in CD34+ cells was low, the autophagic response of CD34+ cells to "adversity" was rapid. Finally, impaired autophagy resulted in reduced differentiation and proliferation of CD34+ cells and sensitized them to death and apoptosis. Thus, our results confirm that autophagy in CD34+ cells from AA patients is impaired, that autophagy is required for the survival of CD34+ cells, and that impaired autophagy in CD34+ HPCs may play an important role in the pathogenesis of AA. PMID- 26930652 TI - Triglyceride Glucose-Body Mass Index Is a Simple and Clinically Useful Surrogate Marker for Insulin Resistance in Nondiabetic Individuals. AB - BACKGROUND: Insulin resistance (IR) and the consequences of compensatory hyperinsulinemia are pathogenic factors for a set of metabolic abnormalities, which contribute to the development of diabetes mellitus and cardiovascular diseases. We compared traditional lipid levels and ratios and combined them with fasting plasma glucose (FPG) levels or adiposity status for determining their efficiency as independent risk factors for IR. METHODS: We enrolled 511 Taiwanese individuals for the analysis. The clinical usefulness of various parameters--such as traditional lipid levels and ratios; visceral adiposity indicators, visceral adiposity index (VAI), and lipid accumulation product (LAP); the product of triglyceride (TG) and FPG (the TyG index); TyG with adiposity status (TyG-body mass index [BMI]) and TyG-waist circumference index [WC]); and adipokine levels and ratios--was analyzed to identify IR. RESULTS: For all lipid ratios, the TG/high-density lipoprotein cholesterol (HDL-C) ratio had the highest additional percentage of variation in the homeostasis model assessment of insulin resistance (HOMA-IR; 7.0% in total); for all variables of interest, TyG-BMI and leptin adiponectin ratio (LAR) were strongly associated with HOMA-IR, with 16.6% and 23.2% of variability, respectively. A logistic regression analysis revealed similar patterns. A receiver operating characteristic (ROC) curve analysis indicated that TG/HDL-C was a more efficient IR discriminator than other lipid variables or ratios. The area under the ROC curve (AUC) for VAI (0.734) and TyG (0.708) was larger than that for TG/HDL-C (0.707). TyG-BMI and LAR had the largest AUC (0.801 and 0.801, respectively). CONCLUSION: TyG-BMI is a simple, powerful, and clinically useful surrogate marker for early identification of IR. PMID- 26930651 TI - Metformin Changes the Relationship between Blood Monocyte Toll-Like Receptor 4 Levels and Nonalcoholic Fatty Liver Disease-Ex Vivo Studies. AB - BACKGROUND: Toll-like receptor 4 (TLR4) contributes to the development of NAFLD (nonalcoholic fatty liver disease) and MetS (metabolic syndrome). It is unclear whether anti-diabetic metformin affects TLR4 expression on blood monocytes, thereby protecting or improving inflammatory parameters. Therefore, we investigated TLR4 in patients with NAFLD meeting different sets of MetS criteria and linked the results with the disease burden. METHODS: 70 subjects were characterized and divided into three groups: (I) healthy individuals, (II) nonobese with NAFLD and without MetS, and (III) prediabetic, obese with NAFLD and MetS. We determined the concentrations of IL-1beta, IL-6, TNFalpha, and monocyte TLR4 levels in fresh blood as well as in blood cultures with or without metformin supplementation. RESULTS: The characteristics of the study groups revealed a significant association between NAFLD and BMI, MetS and inflammatory parameters, and TLR4. In ex vivo studies, 100 MUM of metformin decreased the TLR4 level by 19.9% (II group) or by 35% (III group) as well as IL-1beta and TNFalpha production. A stepwise multiple regression analysis highlighted a strong effect of metformin on attenuation of the link between TLR4 and NAFLD, and TNFalpha. CONCLUSION: We concluded that, by attenuation of the blood monocyte TLR4 level, metformin reduced their inflammatory potential-critical after recruitment these cells into liver. However, this finding should be confirmed after in vivo metformin administration. PMID- 26930654 TI - Tracking Protests Using Geotagged Flickr Photographs. AB - Recent years have witnessed waves of protests sweeping across countries and continents, in some cases resulting in political and governmental change. Much media attention has been focused on the increasing usage of social media to coordinate and provide instantly available reports on these protests. Here, we investigate whether it is possible to identify protest outbreaks through quantitative analysis of activity on the photo sharing site Flickr. We analyse 25 million photos uploaded to Flickr in 2013 across 244 countries and regions, and determine for each week in each country and region what proportion of the photographs are tagged with the word "protest" in 34 different languages. We find that higher proportions of "protest"-tagged photographs in a given country and region in a given week correspond to greater numbers of reports of protests in that country and region and week in the newspaper The Guardian. Our findings underline the potential value of photographs uploaded to the Internet as a source of global, cheap and rapidly available measurements of human behaviour in the real world. PMID- 26930653 TI - HIV Impairs Lung Epithelial Integrity and Enters the Epithelium to Promote Chronic Lung Inflammation. AB - Several clinical studies show that individuals with HIV are at an increased risk for worsened lung function and for the development of COPD, although the mechanism underlying this increased susceptibility is poorly understood. The airway epithelium, situated at the interface between the external environment and the lung parenchyma, acts as a physical and immunological barrier that secretes mucins and cytokines in response to noxious stimuli which can contribute to the pathobiology of chronic obstructive pulmonary disease (COPD). We sought to determine the effects of HIV on the lung epithelium. We grew primary normal human bronchial epithelial (NHBE) cells and primary lung epithelial cells isolated from bronchial brushings of patients to confluence and allowed them to differentiate at an air- liquid interface (ALI) to assess the effects of HIV on the lung epithelium. We assessed changes in monolayer permeability as well as the expression of E-cadherin and inflammatory modulators to determine the effect of HIV on the lung epithelium. We measured E-cadherin protein abundance in patients with HIV compared to normal controls. Cell associated HIV RNA and DNA were quantified and the p24 viral antigen was measured in culture supernatant. Surprisingly, X4, not R5, tropic virus decreased expression of E-cadherin and increased monolayer permeability. While there was some transcriptional regulation of E-cadherin, there was significant increase in lysosome-mediated protein degradation in cells exposed to X4 tropic HIV. Interaction with CXCR4 and viral fusion with the epithelial cell were required to induce the epithelial changes. X4 tropic virus was able to enter the airway epithelial cells but not replicate in these cells, while R5 tropic viruses did not enter the epithelial cells. Significantly, X4 tropic HIV induced the expression of intercellular adhesion molecule-1 (ICAM-1) and activated extracellular signal-regulated kinase (ERK). We demonstrate that HIV can enter airway epithelial cells and alter their function by impairing cell-cell adhesion and increasing the expression of inflammatory mediators. These observed changes may contribute local inflammation, which can lead to lung function decline and increased susceptibility to COPD in HIV patients. PMID- 26930656 TI - Correction: A Transmembrane Domain GGxxG Motif in CD4 Contributes to Its Lck Independent Function but Does Not Mediate CD4 Dimerization. PMID- 26930655 TI - GW-Bodies and P-Bodies Constitute Two Separate Pools of Sequestered Non Translating RNAs. AB - Non-translating RNAs that have undergone active translational repression are culled from the cytoplasm into P-bodies for decapping-dependent decay or for sequestration. Organisms that use microRNA-mediated RNA silencing have an additional pathway to remove RNAs from active translation. Consequently, proteins that govern microRNA-mediated silencing, such as GW182/Gw and AGO1, are often associated with the P-bodies of higher eukaryotic organisms. Due to the presence of Gw, these structures have been referred to as GW-bodies. However, several reports have indicated that GW-bodies have different dynamics to P-bodies. Here, we use live imaging to examine GW-body and P-body dynamics in the early Drosophila melanogaster embryo. While P-bodies are present throughout early embryonic development, cytoplasmic GW-bodies only form in significant numbers at the midblastula transition. Unlike P-bodies, which are predominantly cytoplasmic, GW-bodies are present in both nuclei and the cytoplasm. RNA decapping factors such as DCP1, Me31B, and Hpat are not associated with GW-bodies, indicating that P-bodies and GW-bodies are distinct structures. Furthermore, known Gw interactors such as AGO1 and the CCR4-NOT deadenylation complex, which have been shown to be important for Gw function, are also not present in GW-bodies. Use of translational inhibitors puromycin and cycloheximide, which respectively increase or decrease cellular pools of non-translating RNAs, alter GW-body size, underscoring that GW-bodies are composed of non-translating RNAs. Taken together, these data indicate that active translational silencing most likely does not occur in GW-bodies. Instead GW-bodies most likely function as repositories for translationally silenced RNAs. Finally, inhibition of zygotic gene transcription is unable to block the formation of either P-bodies or GW-bodies in the early embryo, suggesting that these structures are composed of maternal RNAs. PMID- 26930658 TI - Computer-Aided Tomographic Analysis of Interstitial Lung Disease (ILD) in Patients with Systemic Sclerosis (SSc). Correlation with Pulmonary Physiologic Tests and Patient-Centred Measures of Perceived Dyspnea and Functional Disability. AB - OBJECTIVES: This study was designed (a) to evaluate an improved quantitative lung fibrosis score based on a computer-aided diagnosis (CaM) system in patients with systemic sclerosis (SSc),-related interstitial lung disease (SSc-ILD), (b) to investigate the relationship between physiologic parameters (forced vital capacity [FVC] and single-breath diffusing capacity for carbon monoxide [DLCO]), patient-centred measures of dyspnea and functional disability and CaM and visual reader-based (CoVR) methods, and (c) to identify potential surrogate measures from quantitative and visual HRCT measurement. METHODS: 126 patients with SSc underwent chest radiography, HRCT and PFTs. The following patient-centred measures were obtained: modified Borg Dyspnea Index (Borg score), VAS for breathing, and Health Assessment Questionnaire-Disability Index (HAQ-DI). HRCT abnormalities were scored according to the conventional visual reader-based score (CoVR) and by a CaM. The relationships among the HRCT scores, physiologic parameters (FVC and DLCO, % predicted) results and patient-centred measures, were calculated using linear regression analysis and Pearson's correlation. Multivariate regression models were performed to identify the predictor variables on severity of pulmonary fibrosis. RESULTS: Subjects with limited cutaneous SSc had lower HAQ-DI scores than subjects with diffuse cutaneous SSc (p <0.001). CaM and CoVR scores were similar in the 2 groups. In univariate analysis, a strong correlation between CaM and CoVR was observed (p <0.0001). In multivariate analysis the CaM and CoVR scores were predicted by DLco, FVC, Borg score and HAQ DI. Age, sex, disease duration, anti-topoisomerase antibodies and mRSS were not significantly associated with severity of pulmonary fibrosis on CaM- and CoVR methods. CONCLUSIONS: Although a close correlation between CaM score results and CoVR total score was found, CaM analysis showed a more significant correlation with DLco (more so than the FVC), patient-centred measures of perceived dyspnea and functional disability. Computer-aided tomographic analysis is computationally efficient, and in combination with physiologic and patient-centred measures, it could allow a means for accurately assessing and monitoring the disease progression or response to therapy. PMID- 26930657 TI - ADAM15 Is Functionally Associated with the Metastatic Progression of Human Bladder Cancer. AB - ADAM15 is a member of a family of catalytically active disintegrin membrane metalloproteinases that function as molecular signaling switches, shed membrane bound growth factors and/or cleave and inactivate cell adhesion molecules. Aberrant metalloproteinase function of ADAM15 may contribute to tumor progression through the release of growth factors or disruption of cell adhesion. In this study, we utilized human bladder cancer tissues and cell lines to evaluate the expression and function of ADAM15 in the progression of human bladder cancer. Examination of genome and transcriptome databases revealed that ADAM15 ranked in the top 5% of amplified genes and its mRNA was significantly overexpressed in invasive and metastatic bladder cancer compared to noninvasive disease. Immunostaining of a bladder tumor tissue array designed to evaluate disease progression revealed increased ADAM15 immunoreactivity associated with increasing cancer stage and exhibited significantly stronger staining in metastatic samples. About half of the invasive tumors and the majority of the metastatic cases exhibited high ADAM15 staining index, while all low grade and noninvasive cases exhibited negative or low staining. The knockdown of ADAM15 mRNA expression significantly inhibited bladder tumor cell migration and reduced the invasive capacity of bladder tumor cells through MatrigelTM and monolayers of vascular endothelium. The knockdown of ADAM15 in a human xenograft model of bladder cancer inhibited tumor growth by 45% compared to controls. Structural modeling of the catalytic domain led to the design of a novel ADAM15-specific sulfonamide inhibitor that demonstrated bioactivity and significantly reduced the viability of bladder cancer cells in vitro and in human bladder cancer xenografts. Taken together, the results revealed an undescribed role of ADAM15 in the invasion of human bladder cancer and suggested that the ADAM15 catalytic domain may represent a viable therapeutic target in patients with advanced disease. PMID- 26930659 TI - Normative Values of Retinal Oxygen Saturation in Rhesus Monkeys: The Beijing Intracranial and Intraocular Pressure (iCOP) Study. AB - OBJECTIVE: To study the normal values of the retinal oxygen saturation in Rhesus monkeys and to evaluated repeatability and reproducibility of retinal oxygen saturation measurements. METHODS: Eighteen adult Rhesus macaque monkeys were included in this experimental study. An Oxymap T1 retinal oximeter (Oxymap, Reykjavik, Iceland) was used to perform oximetry on all subjects. Global arterial (SaO2) and venous oxygen saturation (SvO2), arteriovenous difference in SO2 were measured. In the first examination, each eye was imaged three times. At the following two examinations, each eye was imaged once. All examinations were finished in one month. P values were calculated to evaluate the difference between the measurements during three visits by performing an ANOVA. Intra-visit and inter-visit intraclass correlation coefficient (ICC) was determined. RESULTS: At baseline, the average SaO2 and SvO2 were 89.48 +/- 2.64% and 54.85 +/- 2.18%, respectively. The global A-V difference was 34.63 +/- 1.91%. The difference between the three visits was not significant (p>0.05). The highest A-V difference in SO2 and lowest saturations were found in the inferotemporal quadrant. Intra session and inter-visit repeatability were both high. For all oxygen saturation parameters, the ICC values of the intra-session repeatability ranged between 0.92 and 0.96. As found previously, a relatively high ICC value for inter-visit repeatability also was found for all oxygen saturation measurements, ranging between 0.86 and 0.94, with the lowest values in the infero-nasal quadrant. CONCLUSIONS: Our study is the first to describe retinal SO2 in healthy Rhesus monkeys. In normal monkey eyes, the reproducibility and repeatability of retinal oximetry oxygen saturation measurements were high in the retinal arterioles and venules. Our results support that Oxymap T1 retinal oximetry is a suitable and reliable technique in monkey studies. PMID- 26930660 TI - Morphological Diversity of the Rod Spherule: A Study of Serially Reconstructed Electron Micrographs. AB - PURPOSE: Rod spherules are the site of the first synaptic contact in the retina's rod pathway, linking rods to horizontal and bipolar cells. Rod spherules have been described and characterized through electron micrograph (EM) and other studies, but their morphological diversity related to retinal circuitry and their intracellular structures have not been quantified. Most rod spherules are connected to their soma by an axon, but spherules of rods on the surface of the Mus musculus outer plexiform layer often lack an axon and have a spherule structure that is morphologically distinct from rod spherules connected to their soma by an axon. Retraction of the rod axon and spherule is often observed in disease processes and aging, and the retracted rod spherule superficially resembles rod spherules lacking an axon. We hypothesized that retracted spherules take on an axonless spherule morphology, which may be easier to maintain in a diseased state. To test our hypothesis, we quantified the spatial organization and subcellular structures of rod spherules with and without axons. We then compared them to the retracted spherules in a disease model, mice that overexpress Dscam (Down syndrome cell adhesion molecule), to gain a better understanding of the rod synapse in health and disease. METHODS: We reconstructed serial EM images of wild type and DscamGoF (gain of function) rod spherules at a resolution of 7 nm in the X-Y axis and 60 nm in the Z axis. Rod spherules with and without axons, and retracted spherules in the DscamGoF retina, were reconstructed. The rod spherule intracellular organelles, the invaginating dendrites of rod bipolar cells and horizontal cell axon tips were also reconstructed for statistical analysis. RESULTS: Stereotypical rod (R1) spherules occupy the outer two-thirds of the outer plexiform layer (OPL), where they present as spherical terminals with large mitochondria. This spherule group is highly uniform and composed more than 90% of the rod spherule population. Rod spherules lacking an axon (R2) were also described and characterized. This rod spherule group consists of a specific spatial organization that is strictly located at the apical OPL-facing layer of the Outer Nuclear Layer (ONL). The R2 spherule displays a large bowl-shaped synaptic terminal that hugs the rod soma. Retracted spherules in the DscamGoF retina were also reconstructed to test if they are structurally similar to R2 spherules. The misplaced rod spherules in DscamGoF have a gross morphology that is similar to R2 spherules but have significant disruption in internal synapse organization. CONCLUSION: We described a morphological diversity within Mus musculus rod spherules. This diversity is correlated with rod location in the ONL and contributes to the intracellular differences within spherules. Analysis of the DscamGoF retina indicated that their R2 spherules are not significantly different than wild type R2 spherules, but that their retracted rod spherules have abnormal synaptic organization. PMID- 26930661 TI - Respiratory Stabilization after Delivery in Term Infants after the Update of the Japan Resuscitation Council Guidelines in 2010. AB - BACKGROUND: The Japan Resuscitation Council (JRC) updated the guidelines for neonatal cardiopulmonary resuscitation in 2010, which recommended appropriate oxygen supplementation under the assessment of oximetry, with continuous positive airway pressure (CPAP) as a consideration in the delivery room. Whether this update has resulted in an improvement of respiratory stabilization in term neonates has not been well investigated to date. OBJECTIVES: The aim of this study is to evaluate the impact of the update of the JRC Guidelines in 2010 on the frequency of respiratory support for term neonates within 24 h of life in the nursery or neonatal intensive care unit (NICU). METHODS: We conducted a retrospective, single-center study using data of term neonates born between 2008 and 2009 (defined as 'group 1', before the update of the guidelines), and between 2011 and 2012 (defined as 'group 2', after the update of the guidelines). We compared resuscitation procedures in the delivery room and respiratory support in the nursery or NICU within 24 h of life between the two groups. Respiratory support included oxygen therapy, nasal CPAP and mechanical ventilation. RESULTS: A total of 5,036 infants were analyzed. In group 2, oxygen administration in the delivery room was significantly decreased (38.9 vs. 22.1%, p < 0.001) and face mask CPAP in the delivery room increased (1.7 vs. 11.1%, p < 0.001). The prevalence of respiratory support within 24 h of life in the nursery or NICU increased significantly in group 2 (group 1, 6.8% vs. group 2, 16.6%, p < 0.001). CONCLUSIONS: The update of the JRC Guidelines in 2010 resulted in an increase of respiratory support for term infants within 24 h of life. PMID- 26930662 TI - The Widespread Presence of a Multidrug-Resistant Escherichia coli ST131 Clade among Community-Associated and Hospitalized Patients. AB - BACKGROUND & AIMS: The extent of entry of multidrug-resistant Escherichia coli from the community into the hospital and subsequent clonal spread amongst patients is unclear. To investigate the extent and direction of clonal spread of these bacteria within a large teaching hospital, we prospectively genotyped multidrug-resistant E. coli obtained from community- and hospital associated patient groups and compared the distribution of diverse genetic markers. METHODS: A total of 222 E. coli, classified as multi-drug resistant according to national guidelines, were retrieved from both screening (n = 184) and non-screening clinical cultures (n = 38) from outpatients and patients hospitalized for various periods. All isolates were routinely genotyped using an amplified fragment length polymorphism (AFLP) assay and real-time PCR for CTX-M genes. Multi-locus sequence typing was additionally performed to confirm clusters. Based on demographics, patients were categorized into two groups: patients that were not hospitalized or less than 72 hours at time of strain isolation (group I) and patients that were hospitalized for at least 72 hours (group II). RESULTS: Genotyping showed that most multi-drug resistant E. coli either had unique AFLP profiles or grouped in small clusters of maximally 8 isolates. We identified one large ST131 clade comprising 31% of all isolates, containing several AFLP clusters with similar profiles. Although different AFLP clusters were found in the two patient groups, overall genetic heterogeneity was similar (35% vs 28% of isolates containing unique AFLP profiles, respectively). In addition, similar distributions of CTX-M groups, including CTX-M 15 (40% and 44% of isolates in group I and II, respectively) and ST131 (32% and 30% of isolates, respectively) were found. CONCLUSION: We conclude that multi-drug resistant E. coli from the CTX-M 15 associated lineage ST131 are widespread amongst both community- and hospital associated patient groups, with similar genetic diversity and similar distributions of genetic markers. PMID- 26930664 TI - Depositional Environment of Mio-Pliocene Siwalik Sedimentary Strata from the Darjeeling Himalayan Foothills, India: A Palynological Approach. AB - A rich and diverse palynoassemblage recovered from the Churanthi River section (26 degrees 53' 59.3" N, 88 degrees 34' 17.2" E), Darjeeling foothills Eastern Himalaya, has yielded 87 species assigned to 69 genera. The palynoassemblage is rich in angiosperm taxa (45.63%) followed by gymnosperms (0.45%), pteridophytes (18.49%) and fungal remains (23.88%). Based on their nearest living relatives, a wet evergreen to semi-evergreen forest under a humid tropical to sub-tropical environment during the Mio-Pliocene age has been suggested. A lot of angiosperms such as Palaeosantalaceaepites, Araliaceoipollenites, Malvacearampollis, Zonocostites, Neocouperipollis, Dicolpopollis, Palmidites, Palmaepollenites, isolated salt glands of mangrove plant leaves (Heliospermopsis) and Mediaverrunites type of fungal spores, along with ichnofossils like Planolites, Palaeophycus, Skolithos, Rosselia, Ophiomorpha and Teichichnus associated with rippled mudstone-siltstone suggest an environment strongly influenced by brackish water. Primary sedimentary structures in the associated strata indicate strong wave agitation common in shallow marine setting. Some high elevation components (5.14%) such as Alnipollenites, cf. Corylus (Betulaceae), Juglanspollenites, Engelhardtioipollenites (Juglandaceae), Quercoides, Cupuliferoidaepollenites, Lithocarpus, Castanopsis (Fagaceae), Abietineaepollenites (Pinaceae) represent hinterland vegetation possibly transported to the prograding deltaic coastline by the rivers. Reworked palynotaxa (Striatopodocarpites sp., Striatites sp., Faunipollenites sp., Circumstriatites sp., Crescentipollenites sp., Cuneatisporites sp., Parasaccites sp., Scheuringipollenites sp., Rhizomaspora sp., Marsupipollenites sp., Lophotriletes sp.) of Permian age have also been recorded in the palynoassemblage (11.55%) indicating the abundance of Permian Gondwana strata in the source area. PMID- 26930663 TI - Evidence for ACTN3 as a Speed Gene in Isolated Human Muscle Fibers. AB - PURPOSE: To examine the effect of alpha-actinin-3 deficiency due to homozygosity for the ACTN3 577X-allele on contractile and morphological properties of fast muscle fibers in non-athletic young men. METHODS: A biopsy was taken from the vastus lateralis of 4 RR and 4 XX individuals to test for differences in morphologic and contractile properties of single muscle fibers. The cross sectional area of the fiber and muscle fiber composition was determined using standard immunohistochemistry analyses. Skinned single muscle fibers were subjected to active tests to determine peak normalized force (P0), maximal unloading velocity (V0) and peak power. A passive stretch test was performed to calculate Young's Modulus and hysteresis to assess fiber visco-elasticity. RESULTS: No differences were found in muscle fiber composition. The cross sectional area of type IIa and IIx fibers was larger in RR compared to XX individuals (P<0.001). P0 was similar in both groups over all fiber types. A higher V0 was observed in type IIa fibers of RR genotypes (P<0.001) but not in type I fibers. The visco-elasticity as determined by Young's Modulus and hysteresis was unaffected by fiber type or genotype. CONCLUSION: The greater V0 and the larger fast fiber CSA in RR compared to XX genotypes likely contribute to enhanced whole muscle performance during high velocity contractions. PMID- 26930665 TI - Demographic and Component Allee Effects in Southern Lake Superior Gray Wolves. AB - Recovering populations of carnivores suffering Allee effects risk extinction because positive population growth requires a minimum number of cooperating individuals. Conservationists seldom consider these issues in planning for carnivore recovery because of data limitations, but ignoring Allee effects could lead to overly optimistic predictions for growth and underestimates of extinction risk. We used Bayesian splines to document a demographic Allee effect in the time series of gray wolf (Canis lupus) population counts (1980-2011) in the southern Lake Superior region (SLS, Wisconsin and the upper peninsula of Michigan, USA) in each of four measures of population growth. We estimated that the population crossed the Allee threshold at roughly 20 wolves in four to five packs. Maximum per-capita population growth occurred in the mid-1990s when there were approximately 135 wolves in the SLS population. To infer mechanisms behind the demographic Allee effect, we evaluated a potential component Allee effect using an individual-based spatially explicit model for gray wolves in the SLS region. Our simulations varied the perception neighborhoods for mate-finding and the mean dispersal distances of wolves. Simulation of wolves with long-distance dispersals and reduced perception neighborhoods were most likely to go extinct or experience Allee effects. These phenomena likely restricted population growth in early years of SLS wolf population recovery. PMID- 26930666 TI - Low Discrepancy Between Tissue Biopsy Plus Magnifying Endoscopy With Narrow-Band Imaging and Endoscopic Resection in the Diagnosis of Gastric Epithelial Neoplasia (STROBE): Erratum. AB - In the article ''Low Discrepancy Between Tissue Biopsy Plus Magnifying Endoscopy With Narrow-Band Imaging and Endoscopic Resection in the Diagnosis of Gastric Epithelial Neoplasia (STROBE)'', which appeared in Volume 94, Issue 27 of Medicine, Figure 2 originally contained Chinese characters. The article has since been corrected online. PMID- 26930667 TI - Rapid Synthesis of a Long Double-Stranded Oligonucleotide from a Single-Stranded Nucleotide Using Magnetic Beads and an Oligo Library. AB - Chemical synthesis of oligonucleotides is a widely used tool in the field of biochemistry. Several methods for gene synthesis have been introduced in the growing area of genomics. In this paper, a novel method of constructing dsDNA is proposed. Short (28-mer) oligo fragments from a library were assembled through successive annealing and ligation processes, followed by PCR. First, two oligo fragments annealed to form a dsDNA molecule. The double-stranded oligo was immobilized onto magnetic beads (solid support) via streptavidin-biotin binding. Next, single-stranded oligo fragments were added successively through ligation to form the complete DNA molecule. The synthesized DNA was amplified through PCR and gel electrophoresis was used to characterize the product. Sanger sequencing showed that more than 97% of the nucleotides matched the expected sequence. Extending the length of the DNA molecule by adding single-stranded oligonucleotides from a basis set (library) via ligation enables a more convenient and rapid mechanism for the design and synthesis of oligonucleotides on the go. Coupled with an automated dispensing system and libraries of short oligo fragments, this novel DNA synthesis method would offer an efficient and cost-effective method for producing dsDNA. PMID- 26930668 TI - Evaluation of the Permanence of Land Use Change Induced by Payments for Environmental Services in Quindio, Colombia. AB - The effectiveness of conservation interventions such as Payments for Environmental Services (PES) is often evaluated--if it is evaluated at all--only at the completion of the intervention. Since gains achieved by the intervention may be lost after it ends, even apparently successful interventions may not result in long-term conservation benefits, a problem known as that of permanence. This paper uses a unique dataset to examine the permanence of land use change induced by a short-term, asset-building PES program implemented in Quindio, Colombia, between 2003 and 2008. This the first PES program to have a control group for comparison. Under this program, PES had been found to have a positive and highly significant impact on land use. To assess the long-term permanence of these changes, both PES recipients and control households were re-surveyed in 2011, four years after the last payment was made. We find that the land use changes that had been induced by PES were broadly sustained in intervening years, with minor differences across specific practices and sub-groups of participants, indicating that these changes were in fact permanent. The patterns of change in the period after the PES program was completed also help better understand the reasons for the program's success. These results suggest that, at least in the case of productive land uses such as silvopastoral practices under conditions such as those at the study site, asset-building PES programs can be effective at encouraging land owners to adopt environmentally-beneficial land management practices and that the benefits will persist after payments cease. PMID- 26930670 TI - Refined Multiscale Hilbert-Huang Spectral Entropy and Its Application to Central and Peripheral Cardiovascular Data. AB - OBJECTIVE: Spectral entropy has been applied in variety of fields. Multiscale spectral entropy (MSSE) has also recently been proposed to take into account structures on several scales. However, MSSE has some drawbacks, such as the coarse-graining procedure performed in the time domain. In this study, we propose a new framework to compute MSSE. This framework is also adapted for nonstationary data. METHODS: Our work relies on processing steps performed directly in the frequency domain. For nonstationary signals, the evolution of entropy values with scales is observed along time. Our algorithm is herein evaluated both on synthetic time series (stationary and non-stationary signals) and on data from the cardiovascular system (CVS). For this purpose, heart rate variability (from the central CVS), laser Doppler flowmetry, and laser speckle contrast data (both from the peripheral CVS) are analyzed. RESULTS: The results show that our framework has better performances than the existing algorithms to compute MSSE, both in terms of reliability and computational cost. Moreover, it is able to reveal repetitive patterns on central and peripheral CVS signals. These patterns may be linked to physiological activities. Furthermore, from the processing of microvascular data, it is able to distinguish young from elderly subjects. CONCLUSION: Our framework outperforms other algorithms to compute MSSE. It also has the advantage of revealing physiological information. SIGNIFICANCE: By showing better performances than existing algorithms to compute MSSE, our work is a new and promising way to compute an entropy measure from the spectral domain. It also has the advantage of stressing physiologically linked phenomena. PMID- 26930669 TI - Maternal Creatine Supplementation during Pregnancy Prevents Long-Term Changes in Diaphragm Muscle Structure and Function after Birth Asphyxia. AB - Using a model of birth asphyxia, we previously reported significant structural and functional deficits in the diaphragm muscle in spiny mice, deficits that are prevented by supplementing the maternal diet with 5% creatine from mid-pregnancy. The long-term effects of this exposure are unknown. Pregnant spiny mice were fed control or 5% creatine-supplemented diet for the second half of pregnancy, and fetuses were delivered by caesarean section with or without 7.5 min of in-utero asphyxia. Surviving pups were raised by a cross-foster dam until 33+/-2 days of age when they were euthanized to obtain the diaphragm muscle for ex-vivo study of twitch tension and muscle fatigue, and for structural and enzymatic analyses. Functional analysis of the diaphragm revealed no differences in single twitch contractile parameters between any groups. However, muscle fatigue, induced by stimulation of diaphragm strips with a train of pulses (330 ms train/sec, 40 Hz) for 300 sec, was significantly greater for asphyxia pups compared with controls (p<0.05), and this did not occur in diaphragms of creatine + asphyxia pups. Birth asphyxia resulted in a significant increase in the proportion of glycolytic, fast twitch fibres and a reduction in oxidative capacity of Type I and IIb fibres in male offspring, as well as reduced cross-sectional area of all muscle fibre types (Type I, IIa, IIb/d) in both males and females at 33 days of age. None of these changes were observed in creatine + asphyxia animals. Thus, the changes in diaphragm fatigue and structure induced by birth asphyxia persist long-term but are prevented by maternal creatine supplementation. PMID- 26930671 TI - One-Day Bayesian Cloning of Type 1 Diabetes Subjects: Toward a Single-Day UVA/Padova Type 1 Diabetes Simulator. AB - OBJECTIVE: The UVA/Padova Type 1 Diabetes (T1DM) Simulator has been shown to be representative of a T1DM population observed in a clinical trial, but has not yet been identified on T1DM data. Moreover, the current version of the simulator is "single meal" while making it "single-day centric," i.e., by describing intraday variability, would be a step forward to create more realistic in silico scenarios. Here, we propose a Bayesian method for the identification of the model from plasma glucose and insulin concentrations only, by exploiting the prior model parameter distribution. METHODS: The database consists of 47 T1DM subjects, who received dinner, breakfast, and lunch (respectively, 80, 50, and 60 CHO grams) in three 23-h occasions (one open- and one closed-loop). The model is identified using the Bayesian Maximum a Posteriori technique, where the prior parameter distribution is that of the simulator. Diurnal variability of glucose absorption and insulin sensitivity is allowed. RESULTS: The model well describes glucose traces (coefficient of determination R2 = 0.962 +/- 0.027 ) and the posterior parameter distribution is similar to that included in the simulator. Absorption parameters at breakfast are significantly different from those at lunch and dinner, reflecting more rapid dynamics of glucose absorption. Insulin sensitivity varies in each individual but without a specific pattern. CONCLUSION: The incorporation of glucose absorption and insulin sensitivity diurnal variability into the simulator makes it more realistic. SIGNIFICANCE: The proposed method, applied to the increasing number of long-term artificial pancreas studies, will allow to describe week/month variability, thus further refining the simulator. PMID- 26930672 TI - A Discriminatively Trained Fully Connected Conditional Random Field Model for Blood Vessel Segmentation in Fundus Images. AB - GOAL: In this work, we present an extensive description and evaluation of our method for blood vessel segmentation in fundus images based on a discriminatively trained fully connected conditional random field model. METHODS: Standard segmentation priors such as a Potts model or total variation usually fail when dealing with thin and elongated structures. We overcome this difficulty by using a conditional random field model with more expressive potentials, taking advantage of recent results enabling inference of fully connected models almost in real time. Parameters of the method are learned automatically using a structured output support vector machine, a supervised technique widely used for structured prediction in a number of machine learning applications. RESULTS: Our method, trained with state of the art features, is evaluated both quantitatively and qualitatively on four publicly available datasets: DRIVE, STARE, CHASEDB1, and HRF. Additionally, a quantitative comparison with respect to other strategies is included. CONCLUSION: The experimental results show that this approach outperforms other techniques when evaluated in terms of sensitivity, F1-score, G mean, and Matthews correlation coefficient. Additionally, it was observed that the fully connected model is able to better distinguish the desired structures than the local neighborhood-based approach. SIGNIFICANCE: Results suggest that this method is suitable for the task of segmenting elongated structures, a feature that can be exploited to contribute with other medical and biological applications. PMID- 26930673 TI - Toward a Portable Cancer Diagnostic Tool Using a Disposable MEMS-Based Biochip. AB - GOAL: The objective of this study is to design and develop a portable tool consisting of a disposable biochip for measuring electrothermomechanical (ETM) properties of breast tissue. METHODS: A biochip integrated with a microheater, force sensors, and electrical sensors is fabricated using microtechnology. The sensor covers the area of 2 mm and the biochip is 10 mm in diameter. A portable tool capable of holding tissue and biochip is fabricated using 3-D printing. Invasive ductal carcinoma and normal tissue blocks are selected from cancer tissue bank in Biospecimen Repository Service at Rutgers Cancer Institute of New Jersey. The ETM properties of the normal and cancerous breast tissues (3-mm thickness and 2-mm diameter) are measured by indenting the tissue placed on the biochip integrated inside the 3-D printed tool. RESULTS: Integrating microengineered biochip and 3-D printing, we have developed a portable cancer diagnosis device. Using this device, we have shown a statistically significant difference between cancerous and normal breast tissues in mechanical stiffness, electrical resistivity, and thermal conductivity. CONCLUSION: The developed cancer diagnosis device is capable of simultaneous ETM measurements of breast tissue specimens and can be a potential candidate for delineating normal and cancerous breast tissue cores. SIGNIFICANCE: The portable cancer diagnosis tool could potentially provide a deterministic and quantitative information about the breast tissue characteristics, as well as the onset and disease progression of the tissues. The tool can be potentially used for other tissue-related cancers. PMID- 26930675 TI - Nuclear Norm Based Matrix Regression with Applications to Face Recognition with Occlusion and Illumination Changes. AB - Recently, regression analysis has become a popular tool for face recognition. Most existing regression methods use the one-dimensional, pixel-based error model, which characterizes the representation error individually, pixel by pixel, and thus neglects the two-dimensional structure of the error image. We observe that occlusion and illumination changes generally lead, approximately, to a low rank error image. In order to make use of this low-rank structural information, this paper presents a two-dimensional image-matrix-based error model, namely, nuclear norm based matrix regression (NMR), for face representation and classification. NMR uses the minimal nuclear norm of representation error image as a criterion, and the alternating direction method of multipliers (ADMM) to calculate the regression coefficients. We further develop a fast ADMM algorithm to solve the approximate NMR model and show it has a quadratic rate of convergence. We experiment using five popular face image databases: the Extended Yale B, AR, EURECOM, Multi-PIE and FRGC. Experimental results demonstrate the performance advantage of NMR over the state-of-the-art regression-based methods for face recognition in the presence of occlusion and illumination variations. PMID- 26930674 TI - Real-Time Model-Based Fault Detection of Continuous Glucose Sensor Measurements. AB - OBJECTIVE: Faults in subcutaneous glucose concentration readings with a continuous glucose monitoring (CGM) may affect the computation of insulin infusion rates that can lead to hypoglycemia or hyperglycemia in artificial pancreas control systems for patients with type 1 diabetes (T1D). METHODS: Multivariable statistical monitoring methods are proposed for detection of faults in glucose concentration values reported by a subcutaneous glucose sensor. A nonlinear first principle glucose/insulin/meal dynamic model is developed. An unscented Kalman filter is used for state and parameter estimation of the nonlinear model. Principal component analysis models are developed and used for detection of dynamic changes. K-nearest neighbor classification algorithm is used for diagnosis of faults. Data from 51 subjects are used to assess the performance of the algorithm. RESULTS: The results indicate that the proposed algorithm works successfully with 84.2% sensitivity. Overall, 155 (out of 184) of the CGM failures are detected with a 2.8-min average detection time. CONCLUSION: A novel algorithm that integrates data-driven and model-based methods is developed. The proposed method is able to detect CGM failures with a high rate of success. SIGNIFICANCE: The proposed fault detection algorithm can decrease the effects of faults on insulin infusion rates and reduce the potential for hypo- or hyperglycemia for patients with T1D. PMID- 26930676 TI - Weakly Supervised Object Localization with Multi-Fold Multiple Instance Learning. AB - Object category localization is a challenging problem in computer vision. Standard supervised training requires bounding box annotations of object instances. This time-consuming annotation process is sidestepped in weakly supervised learning. In this case, the supervised information is restricted to binary labels that indicate the absence/presence of object instances in the image, without their locations. We follow a multiple-instance learning approach that iteratively trains the detector and infers the object locations in the positive training images. Our main contribution is a multi-fold multiple instance learning procedure, which prevents training from prematurely locking onto erroneous object locations. This procedure is particularly important when using high-dimensional representations, such as Fisher vectors and convolutional neural network features. We also propose a window refinement method, which improves the localization accuracy by incorporating an objectness prior. We present a detailed experimental evaluation using the PASCAL VOC 2007 dataset, which verifies the effectiveness of our approach. PMID- 26930677 TI - Deep Learning Guided Partitioned Shape Model for Anterior Visual Pathway Segmentation. AB - Analysis of cranial nerve systems, such as the anterior visual pathway (AVP), from MRI sequences is challenging due to their thin long architecture, structural variations along the path, and low contrast with adjacent anatomic structures. Segmentation of a pathologic AVP (e.g., with low-grade gliomas) poses additional challenges. In this work, we propose a fully automated partitioned shape model segmentation mechanism for AVP steered by multiple MRI sequences and deep learning features. Employing deep learning feature representation, this framework presents a joint partitioned statistical shape model able to deal with healthy and pathological AVP. The deep learning assistance is particularly useful in the poor contrast regions, such as optic tracts and pathological areas. Our main contributions are: 1) a fast and robust shape localization method using conditional space deep learning, 2) a volumetric multiscale curvelet transform based intensity normalization method for robust statistical model, and 3) optimally partitioned statistical shape and appearance models based on regional shape variations for greater local flexibility. Our method was evaluated on MRI sequences obtained from 165 pediatric subjects. A mean Dice similarity coefficient of 0.779 was obtained for the segmentation of the entire AVP (optic nerve only =0.791 ) using the leave-one-out validation. Results demonstrated that the proposed localized shape and sparse appearance-based learning approach significantly outperforms current state-of-the-art segmentation approaches and is as robust as the manual segmentation. PMID- 26930678 TI - Sub-Nyquist Sampling and Fourier Domain Beamforming in Volumetric Ultrasound Imaging. AB - A key step in ultrasound image formation is digital beamforming of signals sampled by several transducer elements placed upon an array. High-resolution digital beamforming introduces the demand for sampling rates significantly higher than the signals' Nyquist rate, which greatly increases the volume of data that must be transmitted from the system's front end. In 3-D ultrasound imaging, 2-D transducer arrays rather than 1-D arrays are used, and more scan lines are needed. This implies that the amount of sampled data is vastly increased with respect to 2-D imaging. In this work, we show that a considerable reduction in data rate can be achieved by applying the ideas of Xampling and frequency domain beamforming (FDBF), leading to a sub-Nyquist sampling rate, which uses only a portion of the bandwidth of the ultrasound signals to reconstruct the image. We extend previous work on FDBF for 2-D ultrasound imaging to accommodate the geometry imposed by volumetric scanning and a 2-D grid of transducer elements. High image quality from low-rate samples is demonstrated by simulation of a phantom image composed of several small reflectors. Our technique is then applied to raw data of a heart ventricle phantom obtained by a commercial 3-D ultrasound system. We show that by performing 3-D beamforming in the frequency domain, sub Nyquist sampling and low processing rate are achievable, while maintaining adequate image quality. PMID- 26930679 TI - Multi-Viewpoint Panorama Construction With Wide-Baseline Images. AB - We present a novel image stitching approach, which can produce visually plausible panoramic images with input taken from different viewpoints. Unlike previous methods, our approach allows wide baselines between images and non-planar scene structures. Instead of 3D reconstruction, we design a mesh-based framework to optimize alignment and regularity in 2D. By solving a global objective function consisting of alignment and a set of prior constraints, we construct panoramic images, which are locally as perspective as possible and yet nearly orthogonal in the global view. We improve composition and achieve good performance on misaligned areas. Experimental results on challenging data demonstrate the effectiveness of the proposed method. PMID- 26930680 TI - Blind Image Blur Estimation via Deep Learning. AB - Image blur kernel estimation is critical to blind image deblurring. Most existing approaches exploit handcrafted blur features that are optimized for a certain uniform blur across the image, which is unrealistic in a real blind deconvolution setting, where the blur type is often unknown. To deal with this issue, we aim at identifying the blur type for each input image patch, and then estimating the kernel parameter in this paper. A learning-based method using a pre-trained deep neural network (DNN) and a general regression neural network (GRNN) is proposed to first classify the blur type and then estimate its parameters, taking advantages of both the classification ability of DNN and the regression ability of GRNN. To the best of our knowledge, this is the first time that pre-trained DNN and GRNN have been applied to the problem of blur analysis. First, our method identifies the blur type from a mixed input of image patches corrupted by various blurs with different parameters. To this aim, a supervised DNN is trained to project the input samples into a discriminative feature space, in which the blur type can be easily classified. Then, for each blur type, the proposed GRNN estimates the blur parameters with very high accuracy. Experiments demonstrate the effectiveness of the proposed method in several tasks with better or competitive results compared with the state of the art on two standard image data sets, i.e., the Berkeley segmentation data set and the Pascal VOC 2007 data set. In addition, blur region segmentation and deblurring on a number of real photographs show that our method outperforms the previous techniques even for non uniformly blurred images. PMID- 26930681 TI - Aging Face Recognition: A Hierarchical Learning Model Based on Local Patterns Selection. AB - Aging face recognition refers to matching the same person's faces across different ages, e.g., matching a person's older face to his (or her) younger one, which has many important practical applications, such as finding missing children. The major challenge of this task is that facial appearance is subject to significant change during the aging process. In this paper, we propose to solve the problem with a hierarchical model based on two-level learning. At the first level, effective features are learned from low-level microstructures, based on our new feature descriptor called local pattern selection (LPS). The proposed LPS descriptor greedily selects low-level discriminant patterns in a way, such that intra-user dissimilarity is minimized. At the second level, higher level visual information is further refined based on the output from the first level. To evaluate the performance of our new method, we conduct extensive experiments on the MORPH data set (the largest face aging data set available in the public domain), which show a significant improvement in accuracy over the state-of-the art methods. PMID- 26930682 TI - Analysis of Decorrelation Transform Gain for Uncoded Wireless Image and Video Communication. AB - An uncoded transmission scheme called SoftCast has recently shown great potential for wireless video transmission. Unlike conventional approaches, SoftCast processes input images only by a series of transformations and modulates the coefficients directly to a dense constellation for transmission. The transmission is uncoded and lossy in nature, with its noise level commensurate with the channel condition. This paper presents a theoretical analysis for an uncoded visual communication, focusing on developing a quantitative measurements for the efficiency of decorrelation transform in a generalized uncoded transmission framework. Our analysis reveals that the energy distribution among signal elements is critical for the efficiency of uncoded transmission. A decorrelation transform can potentially bring a significant performance gain by boosting the energy diversity in signal representation. Numerical results on Markov random process and real image and video signals are reported to evaluate the performance gain of using different transforms in uncoded transmission. The analysis presented in this paper is verified by simulated SoftCast transmissions. This provide guidelines for designing efficient uncoded video transmission schemes. PMID- 26930683 TI - A Feature Learning and Object Recognition Framework for Underwater Fish Images. AB - Live fish recognition is one of the most crucial elements of fisheries survey applications where the vast amount of data is rapidly acquired. Different from general scenarios, challenges to underwater image recognition are posted by poor image quality, uncontrolled objects and environment, and difficulty in acquiring representative samples. In addition, most existing feature extraction techniques are hindered from automation due to involving human supervision. Toward this end, we propose an underwater fish recognition framework that consists of a fully unsupervised feature learning technique and an error-resilient classifier. Object parts are initialized based on saliency and relaxation labeling to match object parts correctly. A non-rigid part model is then learned based on fitness, separation, and discrimination criteria. For the classifier, an unsupervised clustering approach generates a binary class hierarchy, where each node is a classifier. To exploit information from ambiguous images, the notion of partial classification is introduced to assign coarse labels by optimizing the benefit of indecision made by the classifier. Experiments show that the proposed framework achieves high accuracy on both public and self-collected underwater fish images with high uncertainty and class imbalance. PMID- 26930684 TI - 3D Geometry and Motion Estimations of Maneuvering Targets for Interferometric ISAR With Sparse Aperture. AB - In the current scenario of high-resolution inverse synthetic aperture radar (ISAR) imaging, the non-cooperative targets may have strong maneuverability, which tends to cause time-variant Doppler modulation and imaging plane in the echoed data. Furthermore, it is still a challenge to realize ISAR imaging of maneuvering targets from sparse aperture (SA) data. In this paper, we focus on the problem of 3D geometry and motion estimations of maneuvering targets for interferometric ISAR (InISAR) with SA. For a target of uniformly accelerated rotation, the rotational modulation in echo is formulated as chirp sensing code under a chirp-Fourier dictionary to represent the maneuverability. In particular, a joint multi-channel imaging approach is developed to incorporate the multi channel data and treat the multi-channel ISAR image formation as a joint-sparsity constraint optimization. Then, a modified orthogonal matching pursuit (OMP) algorithm is employed to solve the optimization problem to produce high resolution range-Doppler (RD) images and chirp parameter estimation. The 3D target geometry and the motion estimations are followed by using the acquired RD images and chirp parameters. Herein, a joint estimation approach of 3D geometry and rotation motion is presented to realize outlier removing and error reduction. In comparison with independent single-channel processing, the proposed joint multi-channel imaging approach performs better in 2D imaging, 3D imaging, and motion estimation. Finally, experiments using both simulated and measured data are performed to confirm the effectiveness of the proposed algorithm. PMID- 26930685 TI - Embedding Spatio-Temporal Information into Maps by Route-Zooming. AB - Analysis and exploration of spatio-temporal data such as traffic flow and vehicle trajectories have become important in urban planning and management. In this paper, we present a novel visualization technique called route-zooming that can embed spatio-temporal information into a map seamlessly for occlusion-free visualization of both spatial and temporal data. The proposed technique can broaden a selected route in a map by deforming the overall road network. We formulate the problem of route-zooming as a nonlinear least squares optimization problem by defining an energy function that ensures the route is broadened successfully on demand while the distortion caused to the road network is minimized. The spatio-temporal information can then be embedded into the route to reveal both spatial and temporal patterns without occluding the spatial context information. The route-zooming technique is applied in two instantiations including an interactive metro map for city tourism and illustrative maps to highlight information on the broadened roads to prove its applicability. We demonstrate the usability of our spatio-temporal visualization approach with case studies on real traffic flow data. We also study various design choices in our method, including the encoding of the time direction and choices of temporal display, and conduct a comprehensive user study to validate our embedded visualization design. PMID- 26930686 TI - Generating Ambiguous Figure-Ground Images. AB - Ambiguous figure-ground images, mostly represented as binary images, are fascinating as they present viewers a visual phenomena of perceiving multiple interpretations from a single image. In one possible interpretation, the white region is seen as a foreground figure while the black region is treated as shapeless background. Such perception can reverse instantly at any moment. In this paper, we investigate the theory behind this ambiguous perception and present an automatic algorithm to generate such images. We model the problem as a binary image composition using two object contours and approach it through a three-stage pipeline. The algorithm first performs a partial shape matching to find a good partial contour matching between objects. This matching is based on a content-aware shape matching metric, which captures features of ambiguous figure ground images. Then we combine matched contours into a compound contour using an adaptive contour deformation, followed by computing an optimal cropping window and image binarization for the compound contour that maximize the completeness of object contours in the final composition. We have tested our system using a wide range of input objects and generated a large number of convincing examples with or without user guidance. The efficiency of our system and quality of results are verified through an extensive experimental study. PMID- 26930687 TI - Analyzing Eye-Tracking Information in Visualization and Data Space: From Where on the Screen to What on the Screen. AB - Eye-tracking data is currently analyzed in the image space that gaze-coordinates were recorded in, generally with the help of overlays such as heatmaps or scanpaths, or with the help of manually defined areas of interest (AOI). Such analyses, which focus predominantly on where on the screen users are looking, require significant manual input and are not feasible for studies involving many subjects, long sessions, and heavily interactive visual stimuli. Alternatively, we show that it is feasible to collect and analyze eye-tracking information in data space. Specifically, the visual layout of visualizations with open source code that can be instrumented is known at rendering time, and thus can be used to relate gaze-coordinates to visualization and data objects that users view, in real time. We demonstrate the effectiveness of this approach by showing that data collected using this methodology from nine users working with an interactive visualization, was well aligned with the tasks that those users were asked to solve, and similar to annotation data produced by five human coders. Moreover, we introduce an algorithm that, given our instrumented visualization, could translate gaze-coordinates into viewed objects with greater accuracy than simply binning gazes into dynamically defined AOIs. Finally, we discuss the challenges, opportunities, and benefits of analyzing eye-tracking in visualization and data space. PMID- 26930688 TI - Predicting the Absorption Potential of Chemical Compounds Through a Deep Learning Approach. AB - The human colorectal carcinoma cell line (Caco-2) is a commonly used in-vitro test that predicts the absorption potential of orally administered drugs. In silico prediction methods, based on the Caco-2 assay data, may increase the effectiveness of the high-throughput screening of new drug candidates. However, previously developed in-silico models that predict the Caco-2 cellular permeability of chemical compounds use handcrafted features that may be dataset specific and induce over-fitting problems. Deep Neural Network (DNN) generates high-level features based on non-linear transformations for raw features, which provides high discriminant power and, therefore, creates a good generalized model. We present a DNN-based binary Caco-2 permeability classifier. Our model was constructed based on 663 chemical compounds with in-vitro Caco-2 apparent permeability data. Two hundred nine molecular descriptors are used for generating the high-level features during DNN model generation. Dropout regularization is applied to solve the over-fitting problem and the non-linear activation. The Rectified Linear Unit (ReLU) is adopted to reduce the vanishing gradient problem. The results demonstrate that the high-level features generated by the DNN are more robust than handcrafted features for predicting the cellular permeability of structurally diverse chemical compounds in Caco-2 cell lines. PMID- 26930689 TI - Omics Informatics: From Scattered Individual Software Tools to Integrated Workflow Management Systems. AB - Omic data analyses pose great informatics challenges. As an emerging subfield of bioinformatics, omics informatics focuses on analyzing multi-omic data efficiently and effectively, and is gaining momentum. There are two underlying trends in the expansion of omics informatics landscape: the explosion of scattered individual omics informatics tools with each of which focuses on a specific task in both single- and multi- omic settings, and the fast-evolving integrated software platforms such as workflow management systems that can assemble multiple tools into pipelines and streamline integrative analysis for complicated tasks. In this survey, we give a holistic view of omics informatics, from scattered individual informatics tools to integrated workflow management systems. We not only outline the landscape and challenges of omics informatics, but also sample a number of widely used and cutting-edge algorithms in omics data analysis to give readers a fine-grained view. We survey various workflow management systems (WMSs), classify them into three levels of WMSs from simple software toolkits to integrated multi-omic analytical platforms, and point out the emerging needs for developing intelligent workflow management systems. We also discuss the challenges, strategies and some existing work in systematic evaluation of omics informatics tools. We conclude by providing future perspectives of emerging fields and new frontiers in omics informatics. PMID- 26930691 TI - hc-OTU: A Fast and Accurate Method for Clustering Operational Taxonomic Units Based on Homopolymer Compaction. AB - To assess the genetic diversity of an environmental sample in metagenomics studies, the amplicon sequences of 16s rRNA genes need to be clustered into operational taxonomic units (OTUs). Many existing tools for OTU clustering trade off between accuracy and computational efficiency. We propose a novel OTU clustering algorithm, hc-OTU, which achieves high accuracy and fast runtime by exploiting homopolymer compaction and k-mer profiling to significantly reduce the computing time for pairwise distances of amplicon sequences. We compare the proposed method with other widely used methods, including UCLUST, CD-HIT, MOTHUR, ESPRIT, ESPRIT-TREE, and CLUSTOM, comprehensively, using nine different experimental datasets and many evaluation metrics, such as normalized mutual information, adjusted Rand index, measure of concordance, and F-score. Our evaluation reveals that the proposed method achieves a level of accuracy comparable to the respective accuracy levels of MOTHUR and ESPRIT-TREE, two widely used OTU clustering methods, while delivering orders-of-magnitude speedups. PMID- 26930690 TI - D-Map: Random Walking on Gene Network Inference Maps Towards differential Avenue Discovery. AB - Differential rewiring of cellular interaction networks between disease and healthy state is of great importance. Through a systems level approach, malfunctioned mechanisms that are absent in the normal cases, may enlighten the key-players in terms of genes and their interaction chains related to disease. We have developed D-Map, a publicly available user-friendly web application, capable of generating and manipulating advanced differential networks by combining state of-the-art inference reconstruction methods with random walk simulations. The inputs are expression profiles obtained from the Gene Expression Omnibus and a gene list under investigation. Differential networks may be visualized and interpreted through the use of D-Map interface, where display of the disease, the normal and the common state can be performed, interactively. A case study scenario concerning Alzheimer's disease, as well as breast, lung, and bladder cancer was conducted in order to demonstrate the usefulness of the proposed methodology to different disease types. Findings were consistent with the current bibliography, and the provided interaction lists may be further explored towards novel biological insights of the investigated diseases. The DMap web-application is available at: http://bioserver-3.bioacademy.gr/Bioserver/DMap/index.php. PMID- 26930692 TI - Wireless Multichannel Neural Recording With a 128-Mbps UWB Transmitter for an Implantable Brain-Machine Interfaces. AB - Simultaneous recordings of neural activity at large scale, in the long term and under bio-safety conditions, can provide essential data. These data can be used to advance the technology for brain-machine interfaces in clinical applications, and to understand brain function. For this purpose, we present a new multichannel neural recording system that can record up to 4096-channel (ch) electrocorticogram data by multiple connections of customized application specific integrated circuits (ASICs). The ASIC includes 64-ch low-noise amplifiers, analog time-division multiplexers, and 12-bit successive approximation register ADCs. Recorded data sampled at a rate of 1 kS/s are multiplexed with time division via an integrated multiplex board, and in total 51.2 Mbps of raw data for 4096 ch are generated. This system has an ultra wideband (UWB) wireless unit for transmitting the recorded neural signals. The ASICs, multiplex boards, and UWB transmitter unit are designed with the aim of implanting them. From preliminary experiments with a human body-equivalent liquid phantom, we confirmed 4096-ch UWB wireless data transmission at 128 Mbps for distances below 20 mm . PMID- 26930693 TI - Force Maintenance Accuracy Using a Tool: Effects of Magnitude and Feedback. AB - The ability to precisely produce a force via a hand-held tool is crucial in fine manipulations. In this paper, we study the error in maintaining a target force ranging from 0.5 to 5 N under two concurrent feedback conditions: pure haptic feedback (H), and visual plus haptic feedback (V + H). The results show that absolute error (AE) increases along with the increasing force magnitudes under both feedback conditions. For target forces ranging from 1.5 to 5 N, the relative error (RE) is approximately constant under both feedback conditions, while the RE significantly increases for the small target forces of 0.5 and 1 N. The effect of force magnitude on the coefficient of variation (CoV) is not significant for target forces ranging from 1.5 to 5 N. For both the RE and the CoV, the values under the H condition are significantly larger than those under the V + H condition. The effect of manipulation mode (i.e., a hand-held tool or a fingertip) on force maintenance accuracy is complex, i.e., its effect on RE is not significant while its effect on CoV is significant. Only for the magnitude of 0.5 N, the RE of using the tool was significantly greater than that of using the fingertip under both feedback conditions. For both the RE and the CoV, no interaction effect exists between manipulation mode, force magnitude and feedback condition. PMID- 26930694 TI - Fair Energy Scheduling for Vehicle-to-Grid Networks Using Adaptive Dynamic Programming. AB - Research on the smart grid is being given enormous supports worldwide due to its great significance in solving environmental and energy crises. Electric vehicles (EVs), which are powered by clean energy, are adopted increasingly year by year. It is predictable that the huge charge load caused by high EV penetration will have a considerable impact on the reliability of the smart grid. Therefore, fair energy scheduling for EV charge and discharge is proposed in this paper. By using the vehicle-to-grid technology, the scheduler controls the electricity loads of EVs considering fairness in the residential distribution network. We propose contribution-based fairness, in which EVs with high contributions have high priorities to obtain charge energy. The contribution value is defined by both the charge/discharge energy and the timing of the action. EVs can achieve higher contribution values when discharging during the load peak hours. However, charging during this time will decrease the contribution values seriously. We formulate the fair energy scheduling problem as an infinite-horizon Markov decision process. The methodology of adaptive dynamic programming is employed to maximize the long-term fairness by processing online network training. The numerical results illustrate that the proposed EV energy scheduling is able to mitigate and flatten the peak load in the distribution network. Furthermore, contribution-based fairness achieves a fast recovery of EV batteries that have deeply discharged and guarantee fairness in the full charge time of all EVs. PMID- 26930695 TI - Optimized Kernel Entropy Components. AB - This brief addresses two main issues of the standard kernel entropy component analysis (KECA) algorithm: the optimization of the kernel decomposition and the optimization of the Gaussian kernel parameter. KECA roughly reduces to a sorting of the importance of kernel eigenvectors by entropy instead of variance, as in the kernel principal components analysis. In this brief, we propose an extension of the KECA method, named optimized KECA (OKECA), that directly extracts the optimal features retaining most of the data entropy by means of compacting the information in very few features (often in just one or two). The proposed method produces features which have higher expressive power. In particular, it is based on the independent component analysis framework, and introduces an extra rotation to the eigen decomposition, which is optimized via gradient-ascent search. This maximum entropy preservation suggests that OKECA features are more efficient than KECA features for density estimation. In addition, a critical issue in both the methods is the selection of the kernel parameter, since it critically affects the resulting performance. Here, we analyze the most common kernel length-scale selection criteria. The results of both the methods are illustrated in different synthetic and real problems. Results show that OKECA returns projections with more expressive power than KECA, the most successful rule for estimating the kernel parameter is based on maximum likelihood, and OKECA is more robust to the selection of the length-scale parameter in kernel density estimation. PMID- 26930696 TI - Erratum: "Exposure to Household Air Pollution from Wood Combustion and Association with Respiratory Symptoms and Lung Function in Nonsmoking Women: Results from the RESPIRE Trial, Guatemala". PMID- 26930697 TI - Inflammatory Bowel Disease in Asia: A Second Chance at Uncovering Environmental Factors. PMID- 26930698 TI - Eating for Two: Does an Organic Diet Make a Difference? PMID- 26930699 TI - A Satellite View of Pollution on the Ground: Long-Term Changes in Global Nitrogen Dioxide. PMID- 26930700 TI - Noise and Body Fat: Uncovering New Connections. PMID- 26930701 TI - The Right Tools for the Job: Evaluating Frameworks for Chemical Alternatives Assessment. PMID- 26930702 TI - Cytotoxic and Inflammatory Responses Induced by Outer Membrane Vesicle-Associated Biologically Active Proteases from Vibrio cholerae. AB - Proteases in Vibrio cholerae have been shown to play a role in its pathogenesis. V. cholerae secretes Zn-dependent hemagglutinin protease (HAP) and calcium dependent trypsin-like serine protease (VesC) by using the type II secretion system (TIISS). Our present studies demonstrated that these proteases are also secreted in association with outer membrane vesicles (OMVs) and transported to human intestinal epithelial cells in an active form. OMV-associated HAP induces dose-dependent apoptosis in Int407 cells and an enterotoxic response in the mouse ileal loop (MIL) assay, whereas OMV-associated VesC showed a hemorrhagic fluid response in the MIL assay, necrosis in Int407 cells, and an increased interleukin 8 (IL-8) response in T84 cells, which were significantly reduced in OMVs from VesC mutant strain. Our results also showed that serine protease VesC plays a role in intestinal colonization of V. cholerae strains in adult mice. In conclusion, our study shows that V. cholerae OMVs secrete biologically active proteases which may play a role in cytotoxic and inflammatory responses. PMID- 26930703 TI - Role of the Emp Pilus Subunits of Enterococcus faecium in Biofilm Formation, Adherence to Host Extracellular Matrix Components, and Experimental Infection. AB - Enterococcus faecium is an important cause of hospital-associated infections, including urinary tract infections (UTIs), bacteremia, and infective endocarditis. Pili have been shown to play a role in the pathogenesis of Gram positive bacteria, including E. faecium We previously demonstrated that a nonpiliated DeltaempABC::cat derivative of E. faecium TX82 was attenuated in biofilm formation and in a UTI model. Here, we studied the contributions of the individual pilus subunits EmpA, EmpB, and EmpC to pilus architecture, biofilm formation, adherence to extracellular matrix (ECM) proteins, and infection. We identified EmpA as the tip of the pili and found that deletion of empA reduced biofilm formation to the same level as deletion of the empABC operon, a phenotype that was restored by reconstituting in situ the empA gene. Deletion of empB also caused a reduction in biofilm, while EmpC was found to be dispensable. Significant reductions in adherence to fibrinogen and collagen type I were observed with deletion of empA and empB, while deletion of empC had no adherence defect. Furthermore, we showed that each deletion mutant was significantly attenuated in comparison to the isogenic parental strain, TX82, in a mixed inoculum UTI model (P < 0.001 to 0.048), that reconstitution of empA restored virulence in the UTI model, and that deletion of empA also resulted in attenuation in an infective endocarditis model (P = 0.0088). Our results indicate that EmpA and EmpB, but not EmpC, contribute to biofilm and adherence to ECM proteins; however, all the Emp pilins are important for E. faecium to cause infection in the urinary tract. PMID- 26930704 TI - Involvement of NADH Oxidase in Competition and Endocarditis Virulence in Streptococcus sanguinis. AB - Here, we report for the first time that the Streptococcus sanguinis nox gene encoding NADH oxidase is involved in both competition with Streptococcus mutans and virulence for infective endocarditis. An S. sanguinis nox mutant was found to fail to inhibit the growth of Streptococcus mutans under microaerobic conditions. In the presence of oxygen, the recombinant Nox protein of S. sanguinis could reduce oxygen to water and oxidize NADH to NAD(+) The oxidation of NADH to NAD(+) was diminished in the nox mutant. The nox mutant exhibited decreased levels of extracellular H2O2; however, the intracellular level of H2O2 in the mutant was increased. Furthermore, the virulence of the nox mutant was attenuated in a rabbit endocarditis model. The nox mutant also was shown to be more sensitive to blood killing, oxidative and acid stresses, and reduced growth in serum. Thus, NADH oxidase contributes to multiple phenotypes related to competitiveness in the oral cavity and systemic virulence. PMID- 26930705 TI - Infiltrated Macrophages Die of Pneumolysin-Mediated Necroptosis following Pneumococcal Myocardial Invasion. AB - Streptococcus pneumoniae (the pneumococcus) is capable of invading the heart. Herein we observed that pneumococcal invasion of the myocardium occurred soon after development of bacteremia and was continuous thereafter. Using immunofluorescence microscopy (IFM), we observed that S. pneumoniae replication within the heart preceded visual signs of tissue damage in cardiac tissue sections stained with hematoxylin and eosin. Different S. pneumoniae strains caused distinct cardiac pathologies: strain TIGR4, a serotype 4 isolate, caused discrete pneumococcus-filled microscopic lesions (microlesions), whereas strain D39, a serotype 2 isolate, was, in most instances, detectable only using IFM and was associated with foci of cardiomyocyte hydropic degeneration and immune cell infiltration. Both strains efficiently invaded the myocardium, but cardiac damage was entirely dependent on the pore-forming toxin pneumolysin only for D39. Early microlesions caused by TIGR4 and microlesions formed by a TIGR4 pneumolysin deficient mutant were infiltrated with CD11b(+) and Ly6G-positive neutrophils and CD11b(+) and F4/80-positive (F4/80(+)) macrophages. We subsequently demonstrated that macrophages in TIGR4-infected hearts died as a result of pneumolysin-induced necroptosis. The effector of necroptosis, phosphorylated mixed-lineage kinase domain-like protein (MLKL), was detected in CD11b(+) and F4/80(+) cells associated with microlesions. Likewise, treatment of infected mice and THP-1 macrophages in vitro with the receptor-interacting protein 1 kinase (RIP1) inhibitor necrostatin-5 promoted the formation of purulent microlesions and blocked cell death, respectively. We conclude that pneumococci that have invaded the myocardium are an important cause of cardiac damage, pneumolysin contributes to cardiac damage in a bacterial strain-specific manner, and pneumolysin kills infiltrated macrophages via necroptosis, which alters the immune response. PMID- 26930706 TI - Neisseria meningitidis Polynucleotide Phosphorylase Affects Aggregation, Adhesion, and Virulence. AB - Neisseria meningitidis autoaggregation is an important step during attachment to human cells. Aggregation is mediated by type IV pili and can be modulated by accessory pilus proteins, such as PilX, and posttranslational modifications of the major pilus subunit PilE. The mechanisms underlying the regulation of aggregation remain poorly characterized. Polynucleotide phosphorylase (PNPase) is a 3'-5' exonuclease that is involved in RNA turnover and the regulation of small RNAs. In this study, we biochemically confirm that NMC0710 is the N. meningitidis PNPase, and we characterize its role in N. meningitidis pathogenesis. We show that deletion of the gene encoding PNPase leads to hyperaggregation and increased adhesion to epithelial cells. The aggregation induced was found to be dependent on pili and to be mediated by excessive pilus bundling. PNPase expression was induced following bacterial attachment to human cells. Deletion of PNPase led to global transcriptional changes and the differential regulation of 469 genes. We also demonstrate that PNPase is required for full virulence in an in vivo model of N. meningitidis infection. The present study shows that PNPase negatively affects aggregation, adhesion, and virulence in N. meningitidis. PMID- 26930707 TI - Haemophilus ducreyi Seeks Alternative Carbon Sources and Adapts to Nutrient Stress and Anaerobiosis during Experimental Infection of Human Volunteers. AB - Haemophilus ducreyi causes the sexually transmitted disease chancroid in adults and cutaneous ulcers in children. In humans, H. ducreyi resides in an abscess and must adapt to a variety of stresses. Previous studies (D. Gangaiah, M. Labandeira Rey, X. Zhang, K. R. Fortney, S. Ellinger, B. Zwickl, B. Baker, Y. Liu, D. M. Janowicz, B. P. Katz, C. A. Brautigam, R. S. MunsonJr, E. J. Hansen, and S. M. Spinola, mBio 5:e01081-13, 2014, http://dx.doi.org/10.1128/mBio.01081-13) suggested that H. ducreyi encounters growth conditions in human lesions resembling those found in stationary phase. However, how H. ducreyi transcriptionally responds to stress during human infection is unknown. Here, we determined the H. ducreyi transcriptome in biopsy specimens of human lesions and compared it to the transcriptomes of bacteria grown to mid-log, transition, and stationary phases. Multidimensional scaling showed that the in vivo transcriptome is distinct from those of in vitro growth. Compared to the inoculum (mid-log phase bacteria), H. ducreyi harvested from pustules differentially expressed ~93 genes, of which 62 were upregulated. The upregulated genes encode homologs of proteins involved in nutrient transport, alternative carbon pathways (l-ascorbate utilization and metabolism), growth arrest response, heat shock response, DNA recombination, and anaerobiosis. H. ducreyi upregulated few genes (hgbA, flp-tad, and lspB-lspA2) encoding virulence determinants required for human infection. Most genes regulated by CpxRA, RpoE, Hfq, (p)ppGpp, and DksA, which control the expression of virulence determinants and adaptation to a variety of stresses, were not differentially expressed in vivo, suggesting that these systems are cycling on and off during infection. Taken together, these data suggest that the in vivo transcriptome is distinct from those of in vitro growth and that adaptation to nutrient stress and anaerobiosis is crucial for H. ducreyi survival in humans. PMID- 26930708 TI - Lactobacilli Reduce Helicobacter pylori Attachment to Host Gastric Epithelial Cells by Inhibiting Adhesion Gene Expression. AB - The human gastrointestinal tract, including the harsh environment of the stomach, harbors a large variety of bacteria, of which Lactobacillus species are prominent members. The molecular mechanisms by which species of lactobacilli interfere with pathogen colonization are not fully characterized. In this study, we aimed to study the effect of lactobacillus strains upon the initial attachment of Helicobacter pylori to host cells. Here we report a novel mechanism by which lactobacilli inhibit adherence of the gastric pathogen H. pylori In a screen with Lactobacillus isolates, we found that only a few could reduce adherence of H. pylori to gastric epithelial cells. Decreased attachment was not due to competition for space or to lactobacillus-mediated killing of the pathogen. Instead, we show that lactobacilli act on H. pylori directly by an effector molecule that is released into the medium. This effector molecule acts on H. pylori by inhibiting expression of the adhesin-encoding gene sabA Finally, we verified that inhibitory lactobacilli reduced H. pylori colonization in an in vivo model. In conclusion, certain Lactobacillus strains affect pathogen adherence by inhibiting sabA expression and thereby reducing H. pylori binding capacity. PMID- 26930709 TI - Cigarette Smoke Attenuates the Nasal Host Response to Streptococcus pneumoniae and Predisposes to Invasive Pneumococcal Disease in Mice. AB - Streptococcus pneumoniae is a leading cause of invasive bacterial infections, with nasal colonization an important first step in disease. While cigarette smoking is a strong risk factor for invasive pneumococcal disease, the underlying mechanisms remain unknown. This is partly due to a lack of clinically relevant animal models investigating nasal pneumococcal colonization in the context of cigarette smoke exposure. We present a model of nasal pneumococcal colonization in cigarette smoke-exposed mice and document, for the first time, that cigarette smoke predisposes to invasive pneumococcal infection and mortality in an animal model. Cigarette smoke increased the risk of bacteremia and meningitis without prior lung infection. Mechanistically, deficiency in interleukin 1alpha (IL 1alpha) or platelet-activating factor receptor (PAFR), an important host receptor thought to bind and facilitate pneumococcal invasiveness, did not rescue cigarette smoke-exposed mice from invasive pneumococcal disease. Importantly, we observed cigarette smoke to attenuate nasal inflammatory mediator expression, particularly that of neutrophil-recruiting chemokines, normally elicited by pneumococcal colonization. Smoking cessation during nasal pneumococcal colonization rescued nasal neutrophil recruitment and prevented invasive disease in mice. We propose that cigarette smoke predisposes to invasive pneumococcal disease by suppressing inflammatory processes of the upper respiratory tract. Given that smoking prevalence remains high worldwide, these findings are relevant to the continued efforts to reduce the invasive pneumococcal disease burden. PMID- 26930711 TI - Integrated quantitative proteomic and transcriptomic analysis of lung tumor and control tissue: a lung cancer showcase. AB - Proteomics analysis of paired cancer and control tissue can be applied to investigate pathological processes in tumors. Advancements in data-independent acquisition mass spectrometry allow for highly reproducible quantitative analysis of complex proteomic patterns. Optimized sample preparation workflows enable integrative multi-omics studies from the same tissue specimens.We performed ion mobility enhanced, data-independent acquisition MS to characterize the proteome of 21 lung tumor tissues including adenocarcinoma and squamous cell carcinoma (SCC) as compared to control lung tissues of the same patient each. Transcriptomic data were generated for the same specimens. The quantitative proteomic patterns and mRNA abundances were subsequently analyzed using systems biology approaches.We report a significantly (p = 0.0001) larger repertoire of proteins in cancer tissues. 12 proteins were higher in all tumor tissues as compared to matching control tissues. Three proteins, CAV1, CAV2, and RAGE, were vice versa higher in all controls. We also identified characteristic SCC and adenocarcinoma protein patterns. Principal Component Analysis provided evidence that not only cancer from control tissue but also tissue from adenocarcinoma and SCC can be differentiated. Transcriptomic levels of key proteins measured from the same matched tissue samples correlated with the observed protein patterns.The applied study set-up with paired lung tissue specimens of which different omics are measured, is generally suited for an integrated multi-omics analysis. PMID- 26930710 TI - FAD-I, a Fusobacterium nucleatum Cell Wall-Associated Diacylated Lipoprotein That Mediates Human Beta Defensin 2 Induction through Toll-Like Receptor-1/2 (TLR-1/2) and TLR-2/6. AB - We previously identified a cell wall-associated protein from Fusobacterium nucleatum, a Gram-negative bacterium of the oral cavity, that induces human beta defensin 2 (hBD-2) in primary human oral epithelial cells (HOECs) and designated it FAD-I (Fusobacterium-associated defensin inducer). Here, we report differential induction of hBD-2 by different strains of F. nucleatum; ATCC 25586 and ATCC 23726 induce significantly more hBD-2 mRNA than ATCC 10953. Heterologous expression of plasmid-borne fadI from the highly hBD-2-inducing strains in a DeltafadI mutant of ATCC 10953 resulted in hBD-2 induction to levels comparable to those of the highly inducing strains, indicating that FAD-I is the principal F. nucleatum agent for hBD-2 induction in HOECs. Moreover, anti-FAD-I antibodies blocked F. nucleatum induction of hBD-2 by more than 80%. Recombinant FAD-I (rFAD I) expressed in Escherichia coli triggered levels of hBD-2 transcription and peptide release in HOECs similar to those of native FAD-I (nFAD-I) isolated from F. nucleatum ATCC 25586. Tandem mass spectrometry revealed a diacylglycerol modification at the cysteine residue in position 16 for both nFAD-I and rFAD-I. Cysteine-to-alanine substitution abrogated FAD-I's ability to induce hBD-2. Finally, FAD-I activation of hBD-2 expression was mediated via both Toll-like receptor-1/2 (TLR-1/2) and TLR-2/6 heterodimerization. Microbial molecules like FAD-I may be utilized in novel therapeutic ways to bolster the host innate immune response at mucosal surfaces. PMID- 26930712 TI - Heme oxygenase-1 nuclear translocation regulates bortezomibinduced cytotoxicity and mediates genomic instability in myeloma cells. AB - Multiple myeloma (MM) is a clonal B-cell malignancy characterized by an accumulation of clonal plasma cells in the bone marrow leading to bone destruction and bone marrow failure. Several molecular mechanisms underlie chemoresistance among which heme oxygenase-1 (HO-1) could play a major role. The aim of the present research was to evaluate the impact of HO-1 in MM following bortezomib (BTZ) treatment and how HO-1 is implicated in the mechanisms of chemoresistance. MM cells were treated for 24h with BTZ (15 nM), a boronic acid dipeptide inhibitor of the 26S proteasome used in the treatment of patients with MM as first-line therapy. We evaluated cell viability, reactive oxygen species (ROS) formation, endoplasmic reticulum (ER) stress, HO-1 expression and compartmentalization and cellular genetic instability. Results showed that BTZ significantly reduced cell viability in different MM cell lines and induced ER stress and ROS formation. Concomitantly, we observed a significant overexpression of both HO-1 gene and protein levels. This effect was abolished by concomitant treatment with 4-phenybutirric acid, a molecular chaperone, which is known to reduce ER-stress. Surprisingly, inhibition of HO activity with SnMP (10MUM) failed to increase BTZ sensitivity in MM cells whereas inhibition of HO-1 nuclear translocation by E64d, a cysteine protease inhibitor, increased sensitivity to BTZ and decreased genetic instability as measured by cytokinesis-block micronucleus assay. In conclusion, our data suggest that BTZ sensitivity depends on HO-1 nuclear compartmentalization and not on its enzymatic activity and this finding may represent an important tool to overcome BTZ chemoresistance in MM patients. PMID- 26930713 TI - Histone deacetylase 9 regulates breast cancer cell proliferation and the response to histone deacetylase inhibitors. AB - Histone lysine acetylation is an epigenetic mark regulated by histone acetyltransferases and histone deacetylases (HDAC) which plays an important role in tumorigenesis. In this study, we observed a strong overexpression of class IIa HDAC9, at the mRNA and protein levels, in the most aggressive human breast cancer cell lines (i.e. in basal breast cancer cells vs luminal ones or in malignant vs begnin MCF10A breast epithelial cell lines). HDAC9 overexpression was associated with higher rates of gene transcription and increased epigenetic marks on the HDAC9 promoter. Ectopic expression of HDAC9 in MCF7 luminal breast cancer cells led to an increase in cell proliferation and to a decrease in apoptosis. These effects were associated with a deregulated expression of several genes controlled by HDAC inhibitors such as CDKN1A, BAX and TNFRSF10A. Inversely, knock-down of HDAC9 expression in MDA-MB436 basal breast cancer cells reduced cell proliferation. Moreover, high HDAC9 expression decreased the efficacy of HDAC inhibitors to reduce cell proliferation and to regulate CDKN1A gene expression. Interestingly, the gene encoding the transcription factor SOX9 was identified by a global transcriptomic approach as an HDAC9 target gene. In stably transfected MCF7 cells, SOX9 silencing significantly decreased HDAC9 mitogenic activity. Finally, in a large panel of breast cancer biopsies, HDAC9 expression was significantly increased in tumors of the basal subtype, correlated with SOX9 expression and associated with poor prognosis. Altogether, these results indicate that HDAC9 is a key factor involved in mammary carcinogenesis and in the response to HDAC inhibitors. PMID- 26930714 TI - Epigallocatechin-3-gallate targets cancer stem-like cells and enhances 5 fluorouracil chemosensitivity in colorectal cancer. AB - Resistance to cytotoxic chemotherapy is a major cause of mortality in colorectal cancer (CRC) patients. A small subset of cancer cells, termed "cancer stem cells" (CSCs), are believed to be key contributors of chemoresistance and tumor recurrence. Recently, epigallocatechin-3-gallate (EGCG), an active catechin present in green tea, has been shown to suppress CSC growth in various cancers, but whether it can specifically target CSCs and subsequently sensitize chemoresistant CRC cells to standard of care chemotherapeutic treatments remains unknown. Herein, we investigated the chemosensitizing effects of EGCG in 5 fluorouracil (5FU)-resistant (5FUR) CRC cells and spheroid-derived CSCs (SDCSCs), and interrogated the underlying molecular mechanisms responsible for its chemopreventive activity. EGCG enhanced 5FU-induced cytotoxicity and inhibited proliferation in 5FUR cell lines through enhancement of apoptosis and cell cycle arrest. The 5FUR cells showed higher spheroid forming capacity compared to parental cells, indicating higher CSC population. EGCG treatment in these cells resulted in suppression of SDCSC formation and enhanced 5FU sensitivity to SDCSCs. Furthermore, EGCG suppressed Notch1, Bmi1, Suz12, and Ezh2, and upregulated self-renewal suppressive-miRNAs, miR-34a, miR-145, and miR-200c, which are some of the key pathways targeted in 5FUR CRC cells. These findings were validated in vivo, wherein EGCG treatment resulted in inhibited tumor growth in a SDCSC xenograft model. Collectively our data provide novel and previously unrecognized evidence for EGCG-induced sensitization to 5FU through targeting of CSCs in CRC. Our data highlight that in addition to its chemopreventive ability, EGCG may serve as an adjunctive treatment to conventional chemotherapeutic drugs in CRC patients. PMID- 26930715 TI - The prevalence and clinicopathological features of programmed death-ligand 1 (PD L1) expression: a pooled analysis of literatures. AB - BACKGROUND & AIMS: Programmed death-ligand 1 (PD-L1) has been recognized as a critical and promising target in therapies that direct immune escape of cancers. However, its association with aggressive clinicopathological features in solid tumors remains unclear. We investigated this question by synthesizing published articles. METHODS: Electronic databases were searched for relevant studies. Outcomes of interest included age, gender, tumor size, tumor size, lymph node metastasis and tumor cell differentiation. RESULTS: A total of 61 studies involving 17 types of malignancies were included. The overall expression rate of PD-L1 was 44.5% (95% CI, 37.5% to 51.6 %). Patients with regional lymph node metastases (OR 1.38; P < 0.01), large size tumor (OR 1.89; P < 0.01) or poor differentiated tumors (OR 1.71; P < 0.01) were associated with higher PD-L1 expression rate. However, no significant association was observed between young and elder patients (OR 1.04; P = 0.58), or male and female patients (OR 1.13; P = 0.06). A numerically higher PD-L1 expression rate was detected in polyclonal antibodies (57.2%) than monoclonal antibodies (39.6%). In addition, the PD-L1 expression rate reported by studies from Asian areas (52.3%) was numerically higher than those from non-Asian areas, namely Caucasians (32.7%). CONCLUSIONS: This meta-analysis indicated that patients with larger tumors, regional lymph node metastases, or poor-differentiated tumors were associated with a higher PD L1 expression rate; in addition the expression rate of PD-L1 in Asians might be higher than that of Caucasians. This information might be useful in screening candidates for relevant tests and treatments. PMID- 26930716 TI - Fatty acid amide hydrolase inhibitors confer anti-invasive and antimetastatic effects on lung cancer cells. AB - Inhibition of endocannabinoid degradation has been suggested as tool for activation of endogenous tumor defense. One of these strategies lies in blockade of fatty acid amide hydrolase (FAAH) which catalyzes the degradation of endocannabinoids (anandamide [AEA], 2-arachidonoylglycerol [2-AG]) and endocannabinoid-like substances (N-oleoylethanolamine [OEA], N palmitoylethanolamine [PEA]). This study addressed the impact of two FAAH inhibitors (arachidonoyl serotonin [AA-5HT], URB597) on A549 lung cancer cell metastasis and invasion. LC-MS analyses revealed increased levels of FAAH substrates (AEA, 2-AG, OEA, PEA) in cells incubated with either FAAH inhibitor. In athymic nude mice FAAH inhibitors were shown to elicit a dose-dependent antimetastatic action yielding a 67% and 62% inhibition of metastatic lung nodules following repeated administration of 15 mg/kg AA-5HT and 5 mg/kg URB597, respectively. In vitro, a concentration-dependent anti-invasive action of either FAAH inhibitor was demonstrated, accompanied with upregulation of tissue inhibitor of matrix metalloproteinases-1 (TIMP-1). Using siRNA approaches, a causal link between the TIMP-1-upregulating and anti-invasive action of FAAH inhibitors was confirmed. Moreover, knockdown of FAAH by siRNA was shown to confer decreased cancer cell invasiveness and increased TIMP-1 expression. Inhibitor experiments point toward a role of CB2 and transient receptor potential vanilloid 1 in conferring anti-invasive effects of FAAH inhibitors and FAAH siRNA. Finally, antimetastatic and anti-invasive effects were confirmed for all FAAH substrates with AEA and OEA causing a TIMP-1-dependent anti-invasive action. Collectively, the present study provides first-time proof for an antimetastatic action of FAAH inhibitors. As mechanism of its anti-invasive properties an upregulation of TIMP-1 was identified. PMID- 26930717 TI - Downregulation of 26S proteasome catalytic activity promotes epithelial mesenchymal transition. AB - The epithelial-mesenchymal transition (EMT) endows carcinoma cells with phenotypic plasticity that can facilitate the formation of cancer stem cells (CSCs) and contribute to the metastatic cascade. While there is substantial support for the role of EMT in driving cancer cell dissemination, less is known about the intracellular molecular mechanisms that govern formation of CSCs via EMT. Here we show that beta2 and beta5 proteasome subunit activity is downregulated during EMT in immortalized human mammary epithelial cells. Moreover, selective proteasome inhibition enabled mammary epithelial cells to acquire certain morphologic and functional characteristics reminiscent of cancer stem cells, including CD44 expression, self-renewal, and tumor formation. Transcriptomic analyses suggested that proteasome-inhibited cells share gene expression signatures with cells that have undergone EMT, in part, through modulation of the TGF-beta signaling pathway. These findings suggest that selective downregulation of proteasome activity in mammary epithelial cells can initiate the EMT program and acquisition of a cancer stem cell-like phenotype. As proteasome inhibitors become increasingly used in cancer treatment, our findings highlight a potential risk of these therapeutic strategies and suggest a possible mechanism by which carcinoma cells may escape from proteasome inhibitor-based therapy. PMID- 26930718 TI - Functional interactions of the cystine/glutamate antiporter, CD44v and MUC1-C oncoprotein in triple-negative breast cancer cells. AB - The xCT light chain of the cystine/glutamate transporter (system XC-) is of importance for the survival of triple-negative breast cancer (TNBC) cells. The MUC1-C transmembrane oncoprotein is aberrantly overexpressed in TNBC and, like xCT, has been linked to maintaining glutathione (GSH) levels and redox balance. However, there is no known interaction between MUC1-C and xCT. Here we show that silencing MUC1-C is associated with decreases in xCT expression in TNBC cells. The results demonstrate that MUC1-C forms a complex with xCT and the CD44 variant (CD44v), which interacts with xCT and thereby controls GSH levels. MUC1-C binds directly with CD44v and in turn promotes stability of xCT in the cell membrane. The interaction between MUC1-C and xCT is further supported by the demonstration that targeting xCT with silencing or the inhibitor sulfasalazine suppresses MUC1 gene transcription by increasing histone and DNA methylation on the MUC1 promoter. In terms of the functional significance of the MUC1-C/xCT interaction, we show that MUC1-C protects against treatment with erastin, an inhibitor of XC- and inducer of ferroptosis, a form of non-apoptotic cell death. These findings indicate that targeting this novel MUC1-C/xCT pathway could represent a potential therapeutic approach for promoting TNBC cell death. PMID- 26930719 TI - Cis-acting elements in its 3' UTR mediate post-transcriptional regulation of KRAS. AB - Multiple RNA-binding proteins and non-coding RNAs, such as microRNAs (miRNAs), are involved in post-transcriptional gene regulation through recognition motifs in the 3' untranslated region (UTR) of their target genes. The KRAS gene encodes a key signaling protein, and its messenger RNA (mRNA) contains an exceptionally long 3' UTR; this suggests that it may be subject to a highly complex set of regulatory processes. However, 3' UTR-dependent regulation of KRAS expression has not been explored in detail. Using extensive deletion and mutational analyses combined with luciferase reporter assays, we have identified inhibitory and stabilizing cis-acting regions within the KRAS 3' UTR that may interact with miRNAs and RNA-binding proteins, such as HuR. Particularly, we have identified an AU-rich 49-nt fragment in the KRAS 3' UTR that is required for KRAS 3' UTR reporter repression. This element contains a miR-185 complementary element, and we show that overexpression of miR-185 represses endogenous KRAS mRNA and protein in vitro. In addition, we have identified another 49-nt fragment that is required to promote KRAS 3' UTR reporter expression. These findings indicate that multiple cis-regulatory motifs in the 3' UTR of KRAS finely modulate its expression, and sequence alterations within a binding motif may disrupt the precise functions of trans-regulatory factors, potentially leading to aberrant KRAS expression. PMID- 26930721 TI - Endoplasmic reticulum stress-mediated induction of SESTRIN 2 potentiates cell survival. AB - Upregulation of SESTRIN 2 (SESN2) has been reported in response to diverse cellular stresses. In this study we demonstrate SESTRIN 2 induction following endoplasmic reticulum (ER) stress. ER stress-induced increases in SESTRIN 2 expression were dependent on both PERK and IRE1/XBP1 arms of the unfolded protein response (UPR). SESTRIN 2 induction, post ER stress, was responsible for mTORC1 inactivation and contributed to autophagy induction. Conversely, knockdown of SESTRIN 2 prolonged mTORC1 signaling, repressed autophagy and increased ER stress induced cell death. Unexpectedly, the increase in ER stress-induced cell death was not linked to autophagy inhibition. Analysis of UPR pathways identified prolonged eIF2alpha, ATF4 and CHOP signaling in SESTRIN 2 knockdown cells following ER stress. SESTRIN 2 regulation enables UPR derived signals to indirectly control mTORC1 activity shutting down protein translation thus preventing further exacerbation of ER stress. PMID- 26930722 TI - Aging is a weak but relentless determinant of dementia severity. AB - Structural Equation Models (SEM) can explicitly distinguish "dementia-relevant" variance in cognitive task performance (i.e., "delta" for dementia). In prior work, delta appears to uniquely account for dementia severity regardless of the cognitive measures used to construct it. In this study, we test delta as a mediator of age's prospective association with future cognitive performance and dementia severity in a large, ethnically diverse longitudinal cohort, the Texas Alzheimer's Research and Care Consortium (TARCC). Age had adverse effects on future cognition, and these were largely mediated through delta, independently of education, ethnicity, gender, depression ratings, serum homo-cysteine levels, hemoglobin A1c, and apolipoprotein e4 status. Age explained 4% of variance in delta, and through it, 11-18% of variance in future cognitive performance. Our findings suggest that normative aging is a dementing condition (i.e., a "senility"). While the majority of variance in dementia severity must be independent of age, age's specific effect is likely to accumulate over the lifespan. Our findings also constrain age's dementing effects on cognition to the age-related fraction of "general intelligence" (Spearman's "g"). That has broad biological and pathophysiological implications. PMID- 26930720 TI - p73 promotes glioblastoma cell invasion by directly activating POSTN (periostin) expression. AB - Glioblastoma Multiforme is one of the most highly metastatic cancers and constitutes 70% of all gliomas. Despite aggressive treatments these tumours have an exceptionally bad prognosis, mainly due to therapy resistance and tumour recurrence. Here we show that the transcription factor p73 confers an invasive phenotype by directly activating expression of POSTN (periostin, HGNC:16953) in glioblastoma cells. Knock down of endogenous p73 reduces invasiveness and chemo resistance, and promotes differentiation in vitro. Using chromatin immunoprecipitation and reporter assays we demonstrate that POSTN, an integrin binding protein that has recently been shown to play a major role in metastasis, is a transcriptional target of TAp73. We further show that POSTN overexpression is sufficient to rescue the invasive phenotype of glioblastoma cells after p73 knock down. Additionally, bioinformatics analysis revealed that an intact p73/ POSTN axis, where POSTN and p73 expression is correlated, predicts bad prognosis in several cancer types. Taken together, our results support a novel role of TAp73 in controlling glioblastoma cell invasion by regulating the expression of the matricellular protein POSTN. PMID- 26930723 TI - Personalized Medicine. PMID- 26930724 TI - Comparative study of glycated hemoglobin by ion exchange chromatography and affinity binding nycocard reader in type 2 diabetes mellitus. AB - The aim of this study was to compare the level of glycated hemoglobin (HbA1c) in type 2 Diabetes Mellitus (DM) patients by two different methods namely Ion Exchange Chromatography and Affinity Binding Nycocard Reader. This is a cross sectional study conducted on confirmed type 2 diabetes mellitus patients (n = 100) who visited Out Patients Department of the Universal College of Medical Sciences Teaching hospital, Bhairahawa, Nepal from November 2012 to March 2013. The diagnosis of diabetes mellitus was done on the basis of their fasting (164.46 +/- 45.33 mg/dl) and random (187.93 +/- 78.02 mg/dl) serum glucose level along with clinical history highly suggestive of type 2 DM. The HbA1c values of (7.8 +/ 1.9%) and (8.0 +/- 2.2%) were found in DM patients as estimated by those two different methods respectively. The highest frequency was observed in HbA1c > 8.0% indicating maximum cases were under very poor glycemic control. However, there were no significant differences observed in HbA1c value showing both methods are comparable in nature and can be used in lab for ease of estimation. The significant raised in HbA1c indicates complications associated with DM and monitoring of therapy become hard for those patients. Despite having standard reference method for HbA1c determination, the availability of report at the time of the patient visit can be made easy by using Nycocard Reader and Ion Exchange Chromatography techniques without any delay in communicating glycemic control, clinical decision-making and changes in treatment regimen. PMID- 26930725 TI - Occurrence of dental caries in primary and permanent dentition, oral health status and treatment needs among 12-15 year old school children of Jorpati VDC, Kathmandu. AB - Dental caries occurrence, distribution, oral health status and corresponding treatment needs in 12 - 15 year old children are useful tools for evaluation of oral health. Dental caries status along with its treatment needs was recorded according to World Health Organization (WHO) index (1997) in 366 children from five schools within Jorpati Village Development Committee (VDC), Kathmandu. Dental caries was diagnosed in 156 (42.6%) children, out of which 122 (78.21%) had caries in permanent teeth, 26 (16.67%) had caries in primary teeth, and 8 (5.13%) had caries in both dentition. The age wise distribution of dental caries showed the highest prevalence among 12 year old students (23.8%) and the lowest among 15 year olds (3.8%). Among the female students (177), 43.5% showed presence of dental caries, while the prevalence among male students (179) was 41.8%.Out of the total number of teeth affected by dental caries (336), 273 (81.25%) were permanent teeth and 63 (18.75%) were primary teeth. The intra arch distribution of dental caries in permanent as well as primary dentition was statistically significant (P < 0.05). Restorative treatment (89.38%) was the main need in permanent dentition, and endodontic treatment (60.32%) in primary dentition. Chronologic enamel hypoplasia was found in 14 (3.83%) of the total population, and 62 (16.94%) required oral prophylaxis. These findings are significant as they can initiate further research in this area, which may help establish reliable baseline data for implementation of preventive oral health programs. PMID- 26930726 TI - An analysis of surgical complications; a tool to improve surgical outcome. AB - Complications in surgery are an important cause of morbidity and mortality. Complications may result in an increased length of stay in hospital, repeat surgery, additional medical treatment, legal issues and increased costs. Classification and regular audit of complications is a useful tool to improve patient safety and surgical outcome. The purpose of this study is to identify and classify surgical complications and evaluate the various contributing factors. The complications were categorized by Clavein Dindo system as Grade 1:52 (29.1%), Grade II :45 (25.1%),Grade IIIa:26 (14.5%), Grade IIIB:25 (14%), Grade IVa:5 (2.8%), Grade IVb:0 and Grade V:26 (14.5%) . The complication rate was 5.3% and mortality rate was 0.8% in total 3336 surgical procedures. There was significantly higher mortality in complications due to patient related factors 23.4% (11/47), compared to technical factors 4.2% (2/48) and other factors 15.4% (13/84) (p value = 0.024). The mortality was significantly higher in the patients who required ICU care, 54% (20/37), in class B surgical procedures 22.4% (22/98) and those who developed complications after emergency procedures were 31% (14/45). The mortality was significantly higher in the patients who required medical intervention for various medical complications 30.1% (19/63) compared to those who required surgical intervention 8.4% (5/59) or were managed conservatively 3.5% (2/57) (p value = 0.0001). PMID- 26930727 TI - Understanding socio economic contexts of female sex workers in eastern Nepal. AB - The present focus is mostly laid on high risk behavior of commercial sex workers without any consideration of their location, educational status and other socio cultural norms. Thus, we designed a study to understand socio demographic characteristics, lifestyle of female sex workers and search for driving factors for prostitution in eastern Nepal. A descriptive study was conducted in three districts of Eastern Nepal in 2012 over the period of six months. The data regarding their socio demographic characteristics, income, reason for joining sex trade and future choice regarding the profession were recorded from 210 female sex workers through face-to-face interviews. Majority (53.3%) of respondents belonged to the productive age group of 20-29 years, more than one thirds (43.3%) had not received any form of formal education and were unmarried. More than half (53.80%) were presently living alone and about one thirds of the women (31.90%) were minors when they joined this profession. Major portion of the sample (94.80%) worked more than three days a week with median income of 15 thousand per month and 41 percent had sex with more than or equal to ten clients per week. Poor economic condition was the most frequent (47.6%) factor leading to joining of sex trade however, more than two thirds, (72.80%) wanted to quit the profession. Given low level of education, relatively low income, and young age among this population, empowerment and alternative employment/education opportunities should be created to develop this part of Nepalese society. PMID- 26930728 TI - Prevalence of high level gentamicin and vancomycin resistance among clinical isolates of enterococci from a tertiary care hospital in central Nepal. AB - High level aminoglycoside resistance is an established phenomenon in enterococci. With the increasing use of broad spectrum cephalosporins and glycopeptides, vancomycin resistant enterococci are being increasingly reported from different parts of the world. The objective of our study was to determine the prevalence of high level gentamicin resistant (HLAR) enterococci among the clinical isolates in our hospital and to find the minimum inhibitory concentration (MIC) of vancomycin against these isolates. The enterococci isolated over a year (n = 41) were subjected to HLAR screening by disc diffusion and MIC of vancomycin by agar dilution method. HLAR prevalence was 63%. MIC of vancomycin showed none in the resistant range. However, 4 (9.7%) isolates were in the intermediate range heralding the eminent emergence of VRE if adequate control measures are not implemented in time. PMID- 26930729 TI - Health status and related behavior of children in a private and a public school of a village in Kathmandu district. AB - Children spend around 25% of their time of 260 days in a year in school. Hence early detection of abnormalities in health enables timely corrective measures to be taken. A descriptive study related to health of primary class students was carried out from June to September 2013 in a village which lies inside Kathmandu valley. Health status and related behavior was assessed in 69 students from a public school and 125 students from a private school who belonged to class 1 to 5. The results did not show significant difference between the variables in private and public school. PMID- 26930730 TI - The impact of hearing loss in older adults: a tertiary care hospital based study. AB - Hearing loss is the most common sensory deficit in the elderly, and is becoming a severe social and health problem. Presbycusis is the result of aging which can lead to communication problems compromising the quality of life (QoL).Since the elderly population is increasing worldwide, presbycusis is showing a similar trend. This study intended to identify the impact of hearing loss in the social life of the elderly. A total of 70 elderly patients attending Nepal Medical College Teaching Hospital who were found to have sensorineural hearing loss (SNHL) on pure tone audiometry (PTA) were recruited for this study.None of the patients had used hearing aids in the past. To assess their handicap due to hearing impairment a Hearing Handicap Inventory for the Elderly (HHIE) questionnaire was used and patients were graded as: no handicap, mild to moderate handicap and significant handicap. Pure-tone averages (PTA) were calculated for the thresholds at 0.5, 1 and 2 kHz in each ear. Patients with their PTA values between 26 to 40 dBHL were interpreted as having mild SNHL, those between 41 to 55dBHL as moderate SNHL and those above 55 dBHL as severe SNHL. Out of 70 patients, 65 had some degree of handicap ranging from mild to severe. The severity of handicap was significantly associated with the degree of hearing loss in both ears. PMID- 26930731 TI - Food practices among postnatal mothers in a hilly township in Northeastern Nepal. AB - A descriptive study on food practice among postnatal mothers in a hilly township in northeastern Nepal was carried out with 50 mothers (aged 20-39 years) of different ethnic groups (Adibasi-Janajati: 46.0%, Bahun/ Chhetri: 34.0% and Dalit 20.0%). Findings show that this township was representative of a rural area in northeastern Nepal in terms of demographic characteristics like mixed ethnic composition, high illiteracy rate (especially among women), joint family structure in majority of the households (80% of the total participants) and agriculture as the more common occupation (44% of the total participants). It was seen that various factors are responsible for affecting food practices of mothers during the postnatal period in this region. Socio-cultural beliefs are contributory to the food practices followed, like the frequency of meals/day eaten by the mothers. Other factors that affected were: Lower economic status of the family (33% of Dalit women and 50% of women who work as laborers were only eating meals two times a day); Support from the family (75% of women living in joint families were eating meals four times a day while 80% of the women living in nuclear families were eating meals three times a day); It also showed more attention and care was given to younger, first-time mothers (younger mothers who were mostly first-time mothers were eating meals four times a day while experienced and older mothers were eating meals three times a day). The study also showed that there are food taboos surrounding specific food items, which were not consumed from 11 days to six months after delivery based on various socio-cultural beliefs and practices. PMID- 26930732 TI - Laparoscopic cholecystectomy under spinal anaesthesia: a prospective study. AB - Laparoscopic cholecystectomy under general anaesthesia is the present gold standard in treatment of symptomatic gall bladder disease. This study was conducted to determine the efficacy and safety of laparoscopic cholecystectomy under spinal anaesthesia which could be more cost effective. A prospective study was conducted was over a fourteen month period at a teaching hospital to evaluate efficacy, safety and cost benefit of conducting laparoscopic cholecystectomy under spinal anaesthesia(SA). Patients meeting inclusion criteria were taken up for laparoscopic cholecystectomy under spinal anaesthesia by standardized techniques. They underwent standard four port laparoscopic cholecystectomy. Mean anaesthesia time, pneumoperitoneum time and surgery time defined primary outcome measures. Intraoperative events and post operative pain score were the secondary outcomes measured. All patients underwent laparoscopic cholecystectomy without any major complications. None had to be converted to general anaesthesia in this series. The operation had to be converted to open incision in 3 patients. Commonest complaint was pain in right shoulder and anxiety at the beginning of operation/pneumoperitoneum. All patients were highly or well satisfied during follow up. Laparoscopic cholecystectomy done under spinal anaesthesia as a routine anaesthesia of choice is feasible and safe. In this study spinal anaesthesia for laparoscopic cholecystectomy was found to be safe even in patients with respiratory problems, cost-effective, with minimal postoperative pain and smooth recovery; the disadvantage being occasional right shoulder pain following pneumo-peritoneum (40%). Spinal anaesthesia can be recommended to be the anaesthesia technique of choice for conducting laparoscopic cholecystectomy in hospital setups where cost is a major factor; provided proper backup is present. PMID- 26930733 TI - In vitro Temocillin efficacy against extended spectrum beta-lactamase producing multidrug resistant gram negative bacterial isolates from Nepal. AB - Temocillin is relatively more stable against most beta-lactamases and requires re evaluation to include it in common clinical practice as a therapeutic alternative. At the National Reference Laboratory of Nepal, we evaluated multidrug resistance (MDR) and extended spectrum beta-lactamase (ESBL) phenotypes among 292 gram-negative clinical bacterial isolates of 18 different genera during 2009/2010 by Kirby-Bauer disc diffusion method following CLSI guidelines. ESBL screen positive isolates were tested for Temocillin efficacy by disc diffusion method following British Society of Antimicrobial Chemotherapy (BSAC) guidelines and other antibiotics following Clinical and Laboratory Standards Institute (CLSI) guidelines. Of the 292 isolates, 75.0% isolates were MDR, among which 61.6% were primarily screened positive for ESBL production but only 38.8% were confirmed as ESBL producers. We report relatively lower Temocillin resistance of 28.9% and 15.6% among MDR and ESBL positive populations, respectively. Among ESBL positive isolates, no Proteus mirabilis, 19.7% Escherichia coli and 33.3% Klebsiella oxytoca showed resistance to Temocillin, although such resistance was higher among Acinetobacter spp. (66.7%) and K. pneumoniae 50.0%. Among ESBL negative isolates, none of the K. oxytoca and few (13.3%) Acinetobacter spp. were resistant to Temocillin, while all Citrobacter freundii, Pseudomonas aeruginosa (85.7%) and K. pneumoniae (66.7%) showed Temocillin resistance. Only 14.8% and 3.0% of total MDR isolates were resistant to Imipenem and Meropenem, respectively. However, Imipenem resistance was remarkably high (86.7%) among ESBL negative Acinetobacter spp. than Meropenem (13.3%). Temocillin showed comparable efficacy against MDR and ESBL producing bacterial isolates and could be a next therapeutic option. PMID- 26930734 TI - Surgical site wound infection in relation to antibiotic prophylaxis given before skin incision and after cord clamping during cesarean delivery. AB - Surgical site infection is one of the most common complications following Lower Segment Cesarean Section, which accounts for prolonged hospital stay thereby increasing expense. Prophylactic antibiotics in cesarean section reduces surgical site infection significantly. The best protection is provided when tissue level of antibiotics are adequate before incision, without prejudice to neonatal infectious morbidity. The objective of this study was to compare the incidence of surgical site wound infection with prophylactic antibiotics given before skin incision and after cord clamping following delivery of baby. This was a prospective, hospital based study, in which hundred cases of cesarean deliveries who received antibiotics prophylaxis one hour before the skin incision were compared with another 100 cases where antibiotic was given after cord clamping following delivery of the baby. Surgical site infection occurred in 3% of women who received antibiotics prophylaxis before skin incision as compared to 6% in whom antibiotic was given after cord clamping. It was statistically not significant (p = 0.465). PMID- 26930735 TI - Normal fetal nasal bone length at 14 to 28 weeks of gestation. AB - The fetal nasal bone length (FNBL) is a recent sonographic marker included in second trimester genetic sonography which varies with race and ethnicity. The importance of measuring FNBL is in the prenatal diagnosis of Down's syndrome (DS), the most common chromosomal abnormality. Nasal bone hypoplasia or absence is one of the frequent features of DS. Different studies conducted in different parts of the world have established FNBL in different races. But, reference values for normal fetal nasal bone length are yet to be established for Nepalese population. So, the aim of this study was to determine normal FNBL in second trimester. Objective was to create normal reference values for fetal nasal bone in Nepalese population. A cross sectional study was carried out on 150 second trimester pregnancy cases referred for antenatal ultrasound to Department of Radiology at Nepal Medical College and Teaching Hospital between May 2014 and July 2014. Cases included all the clinically normal second trimester pregnancy in which fetal nasal bone could be visualized in midsagittal plane. Table demonstrating normal FNBL corresponding to weeks of gestation was generated using IBM SPSS Statistics Version 20. There was linear increase in mean FNBL with gestational age. Minimum mean FNBL was 2.93 mm at 14 weeks and maximum was 7.89 mm at 27 weeks. Age of patients ranged from 17 to 35 years. Normal FNBL values in Nepalese population corroborates with those published in Western literature but with variation. Hence, reference values for local population become more relevant for antenatal ultrasound practices in Nepal. PMID- 26930736 TI - Instrumentation in cervical spine injury: neurological outcome measurement using ASIA impairment scale. AB - Cervical spinal cord injuries make up more than half of all spinal cord injuries. It affects 2-3% of all trauma patients and accounts for 8.2% of all trauma related deaths. Cervical spine surgery has been evolving in terms of surgical technique, equipment, and instrumentation. We have analyzed a series of patients with cervical spine injuries stabilized with various instrumentation techniques. The objective of the study was to evaluate the outcome of instrumentation in cervical spine injury measured on ASIA Impairment Scale. We present prospective observational descriptive analysis, for 36 patients, looking at the clinical and neurological outcomes following instrumentation for cervical spine injuries from Jun 2011 to July 2013. All 36 patients underwent various instrumentation techniques for stabilization and decompression of the cervical spinal cord. The outcome was compared by the ASIA impairment scale. There were 27 (75%) males and 9 (25%) females. The mean age at presentation was 46 years (17-74 years). The most common mode of injury was fall (62%), with ASIA grade C and D, 31% each. C5/6 level was the most common level (26.2%) of injury. The timing of surgery ranged between 8 - 270 days from injury. Out of thirty-six, thirty-two patients were available for follow-up. Eighteen of these patients had spinal cord injury and improved by at least one ASIA grade. It is concluded that instrumentation in cervical spine injury is an effective surgical procedure with minimal post operative morbidity for the management of cervical injury, allowing an improved physiologic environment for maximal neurologic improvement. The post-operative outcome measured on ASIA impairment scale was comparable to international study. PMID- 26930737 TI - Bacteriological profile and associated risk factors of neonatal sepsis in Paropakar Maternity and Women's Hospital Thapathali, Kathmandu. AB - Neonatal Sepsis is one of the most common reasons for admission to neonatal units in developing countries. It is also a major cause of mortality in both developed and developing countries. Identification of the common bacteria and risk factors causing such infections and their susceptibility patterns will provide necessary information for timely intervention. This study was carried out to determine the bacteriological profile and associated risk factors of neonatal sepsis in Paropakar Maternity and Women's hospital. A cross-sectional prospective study was conducted among neonates suspected of neonatal sepsis. Blood culture was performed and organisms were identified and antibiotic susceptibility was carried out with standard microbiological methods. Data were analysed by using SPSS. Ver. 16 software. The positive yield of blood culture was 21%. The most common isolates were Staphylococcus epidermidis, E. coli, Staphylococcus aureus, Klebsiella pneumoniae and Pseudomonas spp. In Antibiotic susceptibility pattern Gentamycin showed the highest sensitivity to all types of isolated organisms. Vancomycin sensitivity was highest for Gram positive organism and Ciprofloxacin was most effective for Gram negative organisms isolated. Ampicillin and Amoxycillin were the least effective drug. Multiple drug resistance was observed in 77.15% of isolates. Prematurity, low birth weight and maternal pyrexia before delivery were found to be strongly associated with neonatal sepsis. Gram positive organisms were more prevalent than gram negative organisms. PMID- 26930738 TI - Early outcome of 212 coronary angioplasty procedures our experience at Manmohan Cardiothoracic Vascular and Transplant Centre. AB - A prospective study was carried out to evaluate safety, in-hospital clinical end points and early outcome in a consecutive series of 212 patients with coronary artery disease (CAD) who underwent coronary angioplasty in Manmohan Cardiothoracic Vascular and Transplant Centre from October 2012 to April 2014 over a period of 18 months. All patients who underwent angioplasty during the specified period were included in the study. Majority of the patients were male (84.4%). Hypertension was found in 31%, diabetes in 29%, dyslipidemia in 23% and smoking in 19%. A total of 253 stents were deployed. Patients with single vessel coronary artery disease (SVD) were 75%, double vessel coronary artery disease (DVD) 23% and triple vessel coronary artery disease (TVD) was only 1.8%. Indications for stent implantation were stable CAD in 110 (51.8%), unstable angina (UA) in 19 (8.9%), Non ST segment elevation Myocardial Infarction (NSTEMI) in 31 (14.6%) and ST segment elevation Myocardial Infarction (STEMI) in 52 (24.5%). Eighty one percent received drug eluting stent (DES); while 19% received bare metal stent (BMS). Over all procedural success was obtained in 206 (97.6%) cases. Mortality occurred in 4 cases (1.9%) during index hospitalization. All these patients were in cardiogenic shock due to acute STEMI. On follow up, one case of sub acute stent thrombosis (0.4%) and 3 cases (6.3%) of instent restenosis were observed among 47 BMS cases. Coronary Angioplasty was found to be a safe and effective method of coronary revascularization with low in-hospital morbidity and mortality even in high risk elective and emergency procedures. PMID- 26930739 TI - Retrospective study of spinal cord injury patients admitted to spinal injury rehabilitation center, Sanga, Banepa, Nepal. AB - Spinal cord injury is a serious problem that affects many facets of an individual's life. This was a retrospective study which included data from all patients admitted to the Spinal Injury Rehabilitation Center (SIRC), Sanga with spinal injuries over a 4 year period between January 2008 and January 2011. The overall objective of the study was to determine the epidemiology of spinal injury patients admitted at the center. Socio-demographic details, mechanism of injury, level of injury, ASIA score and length of hospital stay of the subjects were recorded and analyzed. An incremental pattern was observed in the number of spinal injury patients attending SIRC. In the year 2008, 81 patients of spinal injury were recorded which increased to 122 in 2011. A total of 381 spinal injury patients were included in the study out of which a majority, 73.50% were male, 30.45% belonged to the 21-30 years age group and 23.10% belonged to the 31-40 years age group. A majority of Spinal injury patients, 189 (49.60%), were from the Central region followed by 89 (23.36%) from the Western region. Fall from height (68.24%) was the predominant cause of spinal injury followed by road traffic accident (18.63%). In the study, 213 subjects (55.91%) had ASIA A scoring and thoracic injury (49.34%) was most common followed by lumbar injury (29.66%), cervical injury (17.84%) and sacral injury (3.15%). About Two-fifths (40.42%) of the spinal injury patients were conservatively managed whereas three-fifths (59.58%) underwent surgery and length of stay of patients ranged from 2 to 305 days. This study shows that the young adults, predominantly males in their most productive years of life, are prone to traumatic spinal cord injury which results in personal and family tragedies along with socioeconomic burden to the nation. Thus, recognizing the pattern of traumatic spinal cord injuries, relevant etiological factors and identification of high-risk groups is necessary in designing better methods of prevention. PMID- 26930740 TI - Variations in total facial index among students of Kathmandu University School of Medical Sciences. AB - The total facial index exhibits sexual differences and different shapes of face. Facial anthropometry has its well known implications for forensic scientists, anatomists, human biologists, criminologists and physical anthropologists. Facial index is the ratio of the morphological facial height to facial width and multiplied by 100. The present study aimed to examine the facial length, facial width, facial index and to find out the facial type in students of Kathmandu University School of Medical Sciences. The present study was conducted on 300 medical, dental and human biology students of Kathmandu University School of Medical Sciences, Dhulikhel, Nepal. Of the total 300 students 150 students were male and 150 students were female and were between the age group 18-25 years. The study had been approved by the Institutional review committee of Kathmandu University School of Medical Sciences, Dhulikhel, Nepal. The study result showed that the mean facial index of Nepalese students was 87.01. The mean facial index of Nepalese male was found to be 87.20 and female was found to be 86.81. The dominant facial type in students of Kathmandu University School of Medical Sciences was found to be mesoproscopic and least common was hyperleptoproscopic. The dominant facial type in male was euriproscopic and the dominant type in female face was mesoproscopic. PMID- 26930741 TI - Visual rehabilitation and intraocular pressure control after combined manual small incision cataract surgery and mitomycin-C augmented trabeculectomy. AB - Both cataract and glaucoma are significant public health problems. Combined cataract operation and trabeculectomy is required for visual rehabilitation and control of intraocular pressure (IOP) thereby preventing progressive optic nerve damage, in patients with coexisting cataract and glaucoma. The aim of this study was to find out the visual rehabilitation and IOP control following combined manual small incision cataract surgery (SICS) and mitomycin-C (MMC) augmented trabeculectomy. In this study 45 consecutive eyes of 45 patients who had undergone combined procedures (manual SICS+ trabeculectomy with MMC) were reviewed between September 2011 and August 2012. Postoperative visual acuity and IOP were recorded at postoperative day 1, 2nd week and 6th week to see the short term outcome of surgery and any postoperative complications were recorded. Best corrected visual acuity (BCVA) at 6th week follow-up was noted. Out of 45 patients males were 31 (68.8%) and females were 14 (31.1%). Twenty nine (64.4%) patients were Primary open angle glaucoma (POAG), 11 (24.4%) Primary angle closure glaucoma (PACG), 5 (11.1%) Normal tension glaucoma (NTG) with visually significant cataract. The mean preoperative and postoperative IOP was 23.93 mmHg +/- 0.75 mmHg and 11.2 mmHg +/- 1.5 mmHg respectively. The mean reduction in IOP was 12.73 mmHg on the 6th week of follow up. There was statistically significant reduction in IOP on the 6th week follow up (p < 0.000 1). Twenty three patients (65.7%) achieved best corrected visual acuity between 6/6 to 6/18 and 6 patients (17.1%) had 6/24 to 6/60 on the 6th week follow up. Combined SICS with MMC augmented trabeculectomy is effective in terms of IOP control and visual rehabilitation in treating glaucoma patients with cataract. PMID- 26930742 TI - Magnification error of digital x rays on the computer screen. AB - Templating x-rays of total hip and knee replacements pre-operatively are important to plan surgery. This is usually done using acetate templates of the prosthesis on hard copies of the x-ray. With the change in practice, to use digital x-rays on computer screens instead of hard copies, it is important to assess if acetate templates can be used for digital x-rays on the computer screen. This is a retrospective x-ray study of 19 hip replacements and 30 knee replacements to assess their magnification using the Patient Archiving Computerised System (PACS) software. This study was done to assess the accuracy of magnification, using acetate templates over a computer screen. In total hip replacement, the outer cup diameter was also measured using the digital measurement scale. The mean magnification was 0.59 for the acetabular cup and the femoral stem in total hip replacement and 0.48 for the femoral and tibial implant in total knee replacement. The mean difference in cup diameter comparing to the real size was an excess of 10.21 mm. The study showed over-magnified hip and knee x-rays thus suggesting that acetate templates and measurement scales on PACS was not reliable. PMID- 26930743 TI - Comparison between males and females on the effect of PNF hold relax stretching over rectus femoris flexibility. AB - The concept of stretching is to increase the range of motion of a joint. Theoretical evidence suggests that the in vivo properties of tendon are different between men and women. There exist gender differences in the viscoelastic properties of a tendon too. This suggests that stretching affects the properties of a muscle and because male and female tendons have different viscoelastic properties, the effect of stretching should also vary accordingly. However, no experimental study has been conducted till date to verify these theoretical constructs. Therefore, the objective of this study was to demonstrate any difference between male and female Rectus Femoris muscle flexibility following application of Proprioceptive Neuromuscular Facilitation hold relax stretching. An experimental comparative study was conducted among 30 students in a physiotherapy college using purposive sampling. Mean values of all the readings of active knee flexion range of motion (AKFROM) at 0, 3rd and 7th day were taken for both the groups. No significant difference was observed between 0 - 3rd and 0 - 7th day but statistically significant results were found between 3rd - 7th day. These findings were more significant among females. It was therefore concluded that the PNF hold-relax stretching has a positive effect on improving Rectus femoris muscle flexibility and this effect is more prominent in females. PMID- 26930745 TI - Opportunistic infections and clinical profile of HIV/AIDS patients: A study from eastern region of Nepal. AB - There is a wide spread availability of highly active antiretroviral treatment but opportunistic illnesses still occur and result in an increased risk of mortality among persons with HIV/AIDS. The spectrum of illness that one observes, changes as the CD4+ cell count declines. The close relationship between clinical manifestation and CD4+ cell count has made measurement of the latter a routine part of evaluation of the progress of HIV infection in individuals: The objective of this study was to reveal the clinical spectrum and explore the different types of opportunistic infections in HIV/AIDS patients. A total of 234 patients with HIV/AIDS from three ART centers of Eastern Nepal were purposively selected for this cross sectional study conducted from May 2009 to April 2010. Statistical analysis was done using SPSS version 11.5. Chi-squared test and Student's t test were applied to find the association between the variables. A p-value less than 0.05 was considered to be significant. Out of the 234 patient, 85% were found to be symptomatic. Most common presenting symptoms were weight loss (74.4%) followed by fever (59.4%). Around 64% of HIV/AIDS patients had a CD4+ cell count below 200 cells/mm3. Most common opportunistic infections were tuberculosis (51.1%) followed by oral candidiasis (21.7%). A significant relationship (p < 0.001) between decrease in CD4+ cell count and occurrence of opportunistic infections in HIV/AIDS patients was seen. PMID- 26930744 TI - Clinico-epidemiological study of low birth weight newborns in the Eastern part of Nepal. AB - Low birth weight (LBW) remains an important cause of newborn morbidity and mortality. A hospital based prospective and descriptive study was conducted at Paediatric wards, Nursery, Neonatal intensive unit (NICU) and Post natal ward during period of June to October 2010 to note the clinico-epidemiological profile of Low Birth Weight (LBW) newborns. Incidence of the LBW babies in our hospital was 14.45%; more than four fifth (82.2%) baby's mothers were primigravida. Eighty two percent mothers had unbooked pregnancies. Twenty and half percent LBW babies were twins. The mean duration of hospital stay of the subject was 7.4 (+/- 5.5) days. The mean birth weight of LBW babies was 1648 (+/- 344) grams. Clinical sepsis, non physiological jaundice and hypoglycaemia were the three most common complications of LBW babies. Antibiotics, oxygen and phototherapy were the three commonest modes of therapy. Majority of children (82.0%) improved and were discharged. Birth weight and gestational age were significantly different between survivors and babies who expired. Primigravida and lesser antenatal visits were important risk factors for Low birth weight babies. Birth weight, gestational age, apnoea and mechanical ventilation were the predictors of outcome. PMID- 26930746 TI - Cor triloculare biatriatum--A case report. AB - Cor triloculare biatriatum or double inlet single ventricle is a congenital heart defect in which both atria are connected to a common or dominant ventricle. The present report presents an index case and describes the embryological basis and clinical aspects of this extremely rare anomaly. A three months old infant presented with extreme respiratory distress without cyanosis and repeated chest infections. The patient was diagnosed to be a case of single ventricle with both atria opening in the common ventricular chamber. The common ventricular chamber (single ventricle) was connected to a rudimentary outflow tract. The great arteries were in a position of d-transposition of great arteries. However, there was no pulmonary or aortic stenosis. A clear concept and awareness regarding this condition and its clinical manifestations is bound to facilitate timely intervention with improved success rates. PMID- 26930747 TI - A unique presentation: rectus sternalis. AB - Rectus Sternalis is a rare flat slip of muscle present parasternally in the thoracic wall. During the regular dissection of pectoral region, three slips of Sternalis muscle were observed bilaterally in an adult male cadaver. On the right side there was a single slip (RS 1) while on the left side two slips (RS2 and RS3) were present. All three slips were present anterior to the Pectoralis Major muscle of respective side and each muscle had fleshy origin and tendinous insertions. RS1 had two heads arising from the aponeurosis of External Oblique and Rectus Abdominis. RS2 had a single origin from aponeurosis of Rectus Abdominis and RS3 took its origin from the aponeurosis of Pectoralis Major muscle. Indistinct tendinous intersections were noted in both RS1 and RS3 slips proximal to fusion of both Sternalis muscle (RS1 and RS3) with each other. Out of three slips, right Rectus Sternalis was largest with breadth 3.8cm near its origin while the second slip of Rectus Sternalis on the left was longest with length of 12.5cm. RS2 was smallest and shortest among the three slips. The RS1 even presented a flattened tendon running upwards which fused with the membranous origin of right Sternocleidomastoid muscle. The Rectus Sternalis when present arises from hypomeres as longitudinal group of muscles which usually disappears in the thoracic region. The knowledge about Sternalis muscle and its variations is important for anatomists and clinicians (radiologists and surgeons) to avoid any confusion and misdiagnosis as well as anthropologists. PMID- 26930748 TI - Stepping Outside the Operatory. PMID- 26930749 TI - A Cry for Help. PMID- 26930750 TI - Oral Cancer: Novel Concepts for the Oral Health Care Practitioner. PMID- 26930752 TI - Current Trends in the Incidence and Presentation of Oropharyngeal Cancer. AB - The prevalence and behavior of oropharyngeal cancers have dramatically changed over the past 30 years. It is now clear that human papillomavirus (HPV) plays a major role in the incidence of head and neck cancers in the general population and among patients with HIV infection. This article reviews the current knowledge about oropharyngeal cancers for their epidemiology, pathogenesis, clinical behavior, treatment and prevention. This review further examines the subset of oropharyngeal cancers among the HIV-seropositive patients. PMID- 26930751 TI - Managing Intraoral Lesions in Oral Cancer Patients in a General Dental Practice: An Overview. AB - As medical technology advances in the area of cancer therapeutics, dental practitioners will encounter patients with active cancer or a history of cancer. Typically, these patients may have had or are undergoing therapies such as surgery, radiation, chemotherapy or a combination of therapies. These patients may present with multiple side effects that dental practitioners can manage or prevent. We discuss some of these concerns and provide management strategies. PMID- 26930753 TI - Oral Cancer Chernoprevention: Current Status and Future Direction. AB - The aim of this study is to review the current status of cancer chemoprevention and its effectiveness in treatment of oral premalignant lesions and prevention of their progression to oral cancer. The challenges encountered in the different oral cancer chemoprevention clinical trials, including lack of surrogate endpoints, reversal of histologic premalignant changes as study endpoints, tobacco use, human papillomavirus, delivery system, adverse effects and risk of bias in clinical studies, are presented. PMID- 26930754 TI - Targeting Cancer Stem Cells in Oral Cancer. AB - The concept of tumor development driven by a unique subpopulation of cancer stem cells (CSCs), or the CSCs hypothesis, may help to explain the high mortality, low response to treatment and tendency of developing multiple tumors in oral cancer. We will review current knowledge of the CSCs hypothesis in oral cancer and the traits displayed by CSCs, focusing on the resistance to therapy and attempts being made to treat oral cancer by specifically targeting CSCs. PMID- 26930755 TI - A Chemopreventive Nanodiamond Platform for Oral Cancer Treatment. AB - Standard oral cancer therapy generally includes a combination of surgery with chemotherapy and/or radiotherapy. This treatment paradigm has not changed in some time. In this paper, we propose a chemopreventive nanodiamond platform for the delivery of celecoxib (Celebrex) to oral cancer lesions. This innovative platform allows for sustained drug release under physiological conditions, potentially enhancing chemopreventive efficacy of celecoxib without the physical and toxicological damage associated with conventional means of drug delivery. PMID- 26930756 TI - Getting the All-Clear Signal: Medical Clearance Forms and Follow-Up. PMID- 26930757 TI - Infection Control Q-and-A. PMID- 26930758 TI - AOmegaA Fellow in Leadership Award. PMID- 26930759 TI - A syllabus on healing. PMID- 26930760 TI - The physician condolence letter and the role of compassion and healing in modern medicine. PMID- 26930761 TI - First principles. PMID- 26930762 TI - On the significance of the Circle of Tugo. PMID- 26930763 TI - A recruit enters the Epidemic, Intelligene Service. PMID- 26930764 TI - Bosch and Bruegel. Disability in sixteenth-century art. PMID- 26930765 TI - 2015 Robert J. Glaser Distinguished Teacher Awards. PMID- 26930766 TI - An Orientation Program for Clinical Adjunct Faculty. AB - Having highly competent clinical faculty in an institution of higher learning is a prerequisite for graduating safe nurses in the future. The purpose of this project was to increase each clinical nurse's knowledge and skills for the new role of clinical adjunct nursing faculty. Successful implementation of this program will help promote consistency in effective job performance of clinical adjunct faculty and facilitate achievement of the projected goals and outcomes. This orientation program was presented in a one day face-to-face encounter with twelve (12) adjunct faculty members, tenured and others on the tenured track. These faculty members were hired by City Colleges of Chicago (CCC) School of Nursing Program at the Malcolm X College. Presentations were given by attendees with a lesson plan. Pre-test, post-test and evaluation forms were presented and it was agreed that an orientation program should be developed and presented to all newly hired clinical adjunct nursing faculty at CCC. PMID- 26930767 TI - Black Feminism: An Integrated Review of Literature. AB - This study presents a systematic literature review exploring the uses and potential benefits of Black Feminism in nursing research. Black Feminism may benefit knowledge development for nursing in a variety of ways, such as illuminating the multifaceted factors of Black women's identities in helping scholars move away from generalization of experiences, to improve understanding of health disparities, and making such changes by broadening the social consciousness of the nurse researchers, who are predominantly White. Discrimination in health disparities may be deconstructed if the focus is placed on asking different research questions and offering different interventions with the social structures that contributes to such actions. When Black Feminism guides the research method (including research questions and analysis), the accuracy of representing the experiences of Black women is increased. In this research, Black Feminism highlights experience, coping mechanisms, spiritual values, a tradition of strength, and a holistic view of identity. PMID- 26930768 TI - The Effectiveness and Need for Facility Based Nurse Aide Training Competency Evaluation Programs. AB - It has become crucial for nursing facilities to rapidly train future nurse aides and remove any barriers to their matriculation into the field of care. Facilities feel the organizational burden of insufficient staffing and need to lever all effective programs to train future employees. The facility-based, Nurse Aide Training Competency Evaluation Programs (NATCEP) serve as a viable option to help fill shortages in the professional medical workforce. Data were analyzed from the National Nursing Assistant Survey to provide an overview of the benefits of using facility-trained nurse aides, versus those trained elsewhere, including their own perceptions of training and abilities. These findings also show the importance of facility based training programs for nurse aides on a global level. Providing training on site increases the efficiency and proficiency of nurse aides, making the transition to caregivers an easier for students, employers and residents. PMID- 26930769 TI - [Evaluation of the quality of proximal restorations with plastic materials: radiographic study]. AB - AIM: To assess the quality of proximal coronary restorations and bring out the factors influencing this quality. MATERIAL AND METHOD: A transversal study on 160 radiographs of proximal coronary restorations was conducted at the University Center of Dental Consultation and Treatment of Rabat. Restorations were evaluated according to the modified USPHS criteria. Four variables were studied: restoration material, treated tooth, cavity type and location of treatment in order to identify the influencing factors. RESULTS: Forty five per cent of the evaluated proximal coronary restorations required replacement. The main cause of failure was recurrent caries in 36% of cases, followed by the absence of the contact point (24.4%), unacceptable proximal coronary outline (13.8%), and finally dentin exposure (6.9%). Thus, it turned out that there is a difficulty to restore correctly posterior proximal cavities especially using amalgam and a high rate of recurrent caries at both the anterior and posterior teeth. CONCLUSION: Both a clinical and a radiographic evaluation after each proximal restoration would be recommended to reduce failure. PMID- 26930770 TI - [Orthodontic correction of a Brodie syndrome case related to oral habits]. AB - Unilateral Brodie bite, called also Scissor bite, is a form of transversal malocclusion that often leads to minor facial asymmetry. The prevalence of this form of malocclusion is rare, especially met in mixed denture. We report a case of 11-year-old girl who presents unilateral scissor bite related to oral habits, with a skeletal class II. Modified activation by contraction of a bi-helix appliance was used to treat the unilateral scissor bite occlusion, before approaching the correction of the sagittal relationship. PMID- 26930771 TI - Ritual tooth modification among the Baka pygmies in Cameroon. AB - INTRODUCTION: Ritual tooth mutilation is a relatively understudied human body mutilatory practices. The purpose of the study was to examine the effects of ritual tooth modification, teeth cleaning measures and herbal medications for their oral health problems among the Baka pygmies in Cameroon. MATERIALS AND METHODS: This cross-sectional study was conducted between January and March, 2012 using semi-structured questionnaire as the tool of data collection. Intra-oral examinations were carried out to determine the dental hard tissue loss using Smith and Knight Tooth Wear Index (TWI). RESULTS: Fifty-six pygmies with ritual tooth modification made of 34 males (60.7%) and 22 females (39.3%) with a mean age of 31 years were interviewed and had oral health examination. The reported age at which the tooth modification was done was between 10 and 15 years with mean age as 12 +/- 1.66 years. More than half (58.9%) of the participants reported the tooth filing as painful and nearly two-thirds (64.3%) of the participants reported having persistent pain afterwards. The upper right central and lateral incisors were the most commonly modified teeth. A total of 42.9%, 12.5% and 7.1% of the participants had Smith and Knight TWI scores of 2, 3 and 4 respectively. All the participants reported cleaning their teeth at least once daily with about two-thirds (66.1%) of them doing so with chewing stick. The majority (67.9%) of the participants reported cleaning their teeth for cosmetic reasons [to remove dirt' (60.7%) and 'to remove stains' (7.1%)]. The oral health problems among the participants in form of tooth sensitivity, toothache and dental abscess were treated with plant-based traditional medicines from Irvingia gabonensis, Ricinodendron heudoletti, Pterocarpus soyauxii, Alchornea cordifolia and Piptadeniastrum africanum. CONCLUSION: Ritual tooth modification is a painful mutilatory practice which is culturally significant for the Baka pygmies without health benefit. There is need for intervention to stop this harmful traditional practices among the pygmies. Further studies is recommended to elucidate the medicinal and pharmaceutical benefits of plants used for tooth sensitivity and other oral health problems by the pygmies. PMID- 26930772 TI - [Transient removable dentures]. AB - Removable dentures are always transient current. The epidemiology and causes of tooth gaps demonstrate the need to master the different prosthetic treatment. This made whether to propose treatment plans that take into account psychological, physiological and technical support for this patient. Different situations may arise. A gradual transition may be considered or immediate passage to the total edentulous according to general criteria, local and desiderata of patients. After tooth extraction, the transitional prosthesis can control bone lysis thereby it is part of a complete treatment before prosthesis. It also facilitates a good psychological and physiological integration before the prosthesis use. PMID- 26930774 TI - MIDYEAR CAREER PLANNING CONFERENCE. PMID- 26930773 TI - [Accidental injection sodium hypochlorite during endodontic therapy. Better understand to better manage]. AB - The high frequency of iatrogenic incidents during endodontic treatment is a source of stress for the practitioner. These incidents may occur during the different steps of a root canal treatment. During irrigation, extrusion of sodium hypochlorite beyond the apex is a rare but impressive accident. Sodium hypochlorite, is the most common irrigant used in modern endodontics, but when it comes in contact with the periapical tissue, it can cause complications ranging from mild discomfort to serious tissue damage such as the hematoma and hemato emphysema. The aims of this article are to discuss through the presentation of two clinical cases: Etiological and predisposing factors; Signs guiding to suspicion of accidental injection of sodium hypochlorite. In this work, we focused on clinical keys that help the practitioner in better understanding this accident in order to prevent it or to manage it well when it occurs. PMID- 26930775 TI - UP CLOSE. PMID- 26930776 TI - Fact Sheet. PMID- 26930777 TI - Convention Funding: Where Do I Get It? PMID- 26930778 TI - A Nursing Student Reflects on Death and Dying. PMID- 26930779 TI - "Can I Have the Small?"--A Follow-up to the Resolution, "Increased Awareness and Education about Portion Size Estimation Aids". PMID- 26930780 TI - Being Mindful of Self-Care. PMID- 26930781 TI - HEALING the HEALERS. PMID- 26930782 TI - What You Learn as a Psychiatric Nurse: From the Moment You Step into the Profession Onwards. PMID- 26930783 TI - DEALING WITH CONFLICT AND INCIVILITY AS A NURSING STUDENT AND AS A PROFESSIONAL RN. PMID- 26930784 TI - DESPITE BENEFITS, TECHNOLOGY STILL NOT WIDELY USED TO COMBAT MULTI-MILLION DOLLAR BREACHES. PMID- 26930785 TI - Instituting an Enterprise-wide PHI Disclosure Management Strategy. PMID- 26930786 TI - LEARN MORE TO EARN MORE...HOW TO FURTHER YOUR HIM EDUCATION, AND WHAT IT GETS YOU. PMID- 26930787 TI - Clearing the HIPAA Cobwebs. PMID- 26930788 TI - Where to Begin with Cyber Defense. PMID- 26930789 TI - Issues in Accessing Foreign Personal Information for Use in US Legal Proceedings. PMID- 26930790 TI - Security, Privacy, and Safety Standards in Canadian Healthcare. PMID- 26930791 TI - Evaluating the Information Governance Principles for Healthcare: Integrity and Protection. PMID- 26930792 TI - The Implementation and Management of Patient Portals. PMID- 26930793 TI - A Call for Additional Coding Metrics. PMID- 26930794 TI - Six Months and Counting ARE YOU READY FOR ICD-10-CM/PCS IMPLEMENTATION?. PMID- 26930795 TI - Cow Manure Composting by Microbial Treatment for Using as Potting Material: An Overview. AB - Dairy industry is flourishing in Saudi Arabia for the last two decades producing milk and milk products to meet the population needs. Simultaneously, it is also producing large amount of dairy waste (animal manure) posing a serious environmental issues. Vermicomposting (conversion of animal manure into compost by bacterial treatments) is considered as one of the safest means for efficient management and to mitigate environmental pollution issues resulting from land disposal of raw dairy wastes. The main objective of this studywas to summarize different processes of vermicomposting and identified the most important bacteria species suitable for vermicomposting using animal manure especially the cowdung. The review showed that among the different bacteria species, Eisenia fetida is the most efficient and commonly used bacteria for vermicomposting to develop compost using cow dung (dairy manure). Overall,this review has highlighted the various vermicomposting technologies, various bacteria species involved in vermicomposting, effect on soil and plant growth as well as the benefits of using compost prepared by way of vermicomposting. The study showed a lot of potential for the production of compost by vermicomposting technology using appropriate bacteria species which is safe, friendly and is associated with minimum environmental issues for safe land disposal of dairy waste (animal manure) with minimum possible environmental issues for the adjacent population. PMID- 26930796 TI - Mold-Ripened Soft Cheeses Fortified with Date Palm Fruit Product as Functional Dairy Products. AB - Date fruit based products are gaining popularity among the consumers in almost all date growing countries due to its added nutritional value. Therefore, novel products were developed by combining two types of foods i.e., soft ripened cheeses and date fruit syrups or date powder. This study is the first to report the surface mold-ripened cheese production with date syrup and date powder. Model cheeses were prepared from pasteurized milk inoculated with Streptococcus thermophilus, Penicillium camemberti and Geotrichum candidum. Date syrup-1, date syrup-2, date powder or the date mixture were added at the stage of curdling. Based on the kinetic growth of the microbial groups in all the treatments, there was no change in the growth of these in various date palm product. On the contrary It may be said that addition of the date fruit product supports their growth. After 35 days, the amounts of total poly phenols were 128.3 +/- 1.01, 81.8 +/- 1.11, 33.5 +/- 2.19, 156.23 +/- 1.27 mg GAE/100 g in the cheeses support with date syrup-1, date syrup-2, date powder or the date mixture, respectively. Antioxidant activity of date fruits ranged from 80.13 IC50 (date syrup-2) to 82.23 IC50 (date syrup-1). Based on the chemical characteristics and sensory analysis, the study results showed the potential for innovative application of date products for developing new functional dairy products as an ideal medium for the delivery of biological active compounds with beneficial health effects over. PMID- 26930797 TI - Experimental Studies on Some Immunotoxicological Aspects of Aflatoxins Containing Diet and Protective Effect of Bee Pollen Dietary Supplement. AB - Aflatoxins (AFs), widely distributed food-borne mycotoxins, affect quality and safety of food and cause economic losses in livestock. In this study, the protective effect of Bee Pollen (BP) against some immunotoxic hazards elucidated from eating of AFs-containing diet was investigated in Wistar rats. Rats were randomly classified intofour groups and treated for 30 days, Group 1; control negative, Group 2; Total AFs (3 mg kg(-1) basal diet), Group 3; BP (20 g kg(-1) basal diet) and Group 4; AFs+BP in basal diet. The immunoprotective effect of BP was revealed in terms of increasing (relative to levels seen in Group 2 rats that consumed the AFs diet) serum total protein and globulin levels, restored normal neutrophil (PMN)/lymphocyte ratio, increased PMN phagocytic activity and increased lymphocyte proliferative capacity. Also, the use of the BP reduced spleen H2O2 levels and increased GSH content while maintaining normal levels of NO formation. Histopathologic analysis showed thatthe AFs caused lymphocytic depletion in the spleen; however, BP induced lymphocytic hyperplasia and reduced the levels of AFs-inducible cellular exhaustion or depletion. These results provide evidence of a protective effect of BP against some immunotoxic actions induced in situ by consumption of AFs. PMID- 26930798 TI - Propagation by Cutting of Grewia coriacea Mast. (Malvaceae). AB - Congolese forests contain important spontaneous food plants. Among these plants, there is the Grewia coriacea Mast., called in the national language "Tsui-teke", which is a tree of 4-25 m high and of 12-40 cm in diameter. Its fruits are used in several drinks making (juice, sparkling wine, syrup) and lollipops. Grewia's barks are used in pharmacopoeia to cure of stomach aches, syphilis. However, the fruits harvesting method based on branches or trees cutting as well as swidden agriculture by local people dangerously threatens the Grewia in the natural ecosystems of Congo. To insure the longevity of this species, we undertook trials of vegetative reproduction of the plant by means of propagation by cuttings for its domestication. Less woody leafless cuttings of 30 cm in length provided best results with a resumption rate of 63.3%, a good rooting production and an average duration of the apparent plastochrone of three days from the second to the fifth leaf. The study shows that domestication of the Grewia coriacea Mast. is possible today by cuttings. Its culture might allow the diversification of species which can be used in orchards. PMID- 26930799 TI - Effects of Prepubertal Acute Immobilization Stress on Serum Kisspeptin Level and Testis Histology in Rats. AB - Stress has inhibitory effect on HPG axis through increasing cortisol serum level. In this study, the effect of acute prepubertal stress on kisspeptin, which plays essential role in puberty achievement is assessed. To do this experimental study thirty immature healthy male wistar rats of 4 weeks old and without any symptoms of puberty were selected randomly. These rats were divided into three groups, randomly. Two groups were chosen as control and pretest and one as stress (test) group. Immobilization stress was applied for 10 days and serum level of cortisol, testosterone and kisspeptin were measured. Primary and secondary spermatocyte and sertoli cell evaluated and compared among groups. Mean serum level of kisspeptin in pretest group, control group and stress (test) group were 0.0381 +/- 0.0079, 91.0500 +/- 4.87430 and 15.2156 +/- 3.88135 pg mL(-1) respectively. Serum level of kisspeptin had significant differences between three groups (p < 0.001). Acute prepubertal immobilization stress led to decrease in serum level of kisspeptin and testosterone in stress (test) group compared to control groups. Also stress caused a significant decrease in the numbers of secondary spermatocytes of the test group. PMID- 26930800 TI - [Breast augmentation by autologous fat grafting: efficacy, safety and indications]. PMID- 26930801 TI - [Synchronous correction of lip and nasal deformity in complete bilateral cleft lip]. AB - OBJECTIVE: To investigate the technique and its therapeutic effect of synchronous correction of lip and nasal deformity in complete bilateral cleft lip. METHODS: 29 patients with complete bilateral cleft lip underwent synchronous correction of lip and nasal deformity with the modified Mulliken method for Asians. The philtral flap was 6-7 mm in length, and 3-4 mm in width at the collumellar-labial junction. The distance between the peaks of cupid's bow was 4-5 mm. The bilateral edge of philtral flap was de-epithelialized and advanced to form philtrum column. The lateral lip was advanced to the medial site, and the central vermilion tubercle was constructed with the bilateral vermilion-mucosal flap. Through the alar rim incision, the displaced cartilage was dissected and repositioned to raise the nasal tip. The follow-up period was 6 months to 6 years. RESULTS: Satisfactory results were achieved in all patients. The reconstructed upper lip had invisible scar with natural philtrum and column. The vermilion had good appearance with tubercle. The length of nasal column was not decreased and depression of nasal tip and alar was greatly improved. CONCLUSIONS: Our modified Mulliken method is effective in synchronous correction of lip and nasal deformity in bilateral cleft lip. PMID- 26930803 TI - [Application of double pedicle sliding skin flap in cryptotia correction]. AB - OBJECTIVE: To explor the curative effect of double pedicle sliding skin flap for correction of cryptotia. METHODS: From January 2011 to October 2014, 7 cases with cryptotia (12 ears) were treated. We designed a double pedicle sliding skin flap above the helix. The flap was slided downward to form a new auriculocephalic sulcus. The other wound was covered by skin graft. RESULTS: All wounds healed very well with no complication. The follow-up period ranged from 3 months to 1 year, with an average of (5.67 +/- 3.38) months. The ear had stable appearance with no recurrence. The result was satisfactory. CONCLUSIONS: The method is simple with reliable flap survival rates. The new auriculocephalic sulcus is stable and resistant. It's a good choice for correction of cryptotia. PMID- 26930802 TI - [Clinical analysis on characteristics of rib cartilage calcification in congenital microtia patients]. AB - OBJECTIVE: To explore the incidence, degree, and pattern of rib cartilage calcification in congenital microtia patients, in order to provide reference for harvesting the rib cartilage, sculpturing cartilage framework. METHODS: From Jun. 2013 to Nov. 2014, 383 patients (age range, 6-45 years) underwent CT scans of the chest. 11 patients with bony diseases or traumatic history were excluded. The remaining 372 patients were divided by age into four groups as 6-15, 16-25, 26 35, 36-45 years old. Twenty patients (10 male and 10 female) were selected by the order of patient identification number in each age group, thus selecting a total of 80 patients (40 male and 40 female). Retrospective study of CT scans of the chest in 80 patients and the incidence, degree, and pattern of cartilage calcification of the sixth to eighth ribs were noted. A chi-square test is conducted to test whether there are significant difference between the variables through the SPSS 19.0 software. RESULTS: Overall, 40.4% (194/480) cartilage was calcified; female patients (47.50%, 114/240) showed higher frequency of calcification than male patients (33.33%, 80/240, P = 0. 025). Calcification rates of all age groups are 1.7% (2/120), 46.7% (56/ 120), 49.2% (59/120), 64.2% (77/120). Calcification rate of 6-15 years group is lowest in all groups (P < 0.05) while other three groups have no statistical significance (P > 0.05). Calcification rates of the sixth and sevent rib cartilage were higher than those of the eighth rib cartilage in all age groups except 6-15 years group, who had a similar rate of all three ribs. Calcification rate of all three rib cartilage was significantly increased with age. Calcification rates of the amle's rib cartilage and the female's in all age groups are 3.3% (2/60) and 0.0% (0/60) (6-15 years): 33.3% (20/60) and 60.0% (36/60) (16-25 years): 40.0% (24/60) and 58.3% (35/60) (26-35 years), 56.7% (34/60) and 71.2% (43/60) (36-45 years). In 6-15 years group calcification rates of male and female had a similar rate, while female's rates were higher than male's rates in other three groups. Male and females mainly had the granular type of calcification [70.0% (56/80), 63.2% (72/114)]. CONCLUSIONS: Females who are over 16 years old should pay more attention to the possibility of middle-severe calcification before harvesting rib cartilage. These patients should take CT examination if necessary. In addition, the patients who had previous operation, or traumatic history, rib deformity, or spine deformity should select the CT examination. PMID- 26930804 TI - [Therapeutic efficacy of a modified method with splints in correction of cryptotia]. AB - OBJECTIVE: To explore the therapeutic efficacy of a modified method with splints in correction of cryptotia. METHODS: From Oct. 2012 to Jan. 2014, 3 cases with unilateral cryptotia were treated with the modified method with splints. The muscles attached to the periosteum of cartilage were dissected. The muscles between the ear and temper were cut off. Then one silicon tube was put around the ear through cranioauricular sulcus. The other tube was placed within the cavum conchae and fixed with the tube around the ear. RESULTS: No flap necrosis happened. The patients were followed up for six months to one year with satisfied and stable results. CONCLUSIONS: The modified method is easy to perform with less morbidity. It is one of the ideal correction for cryptotia. PMID- 26930805 TI - [Replantation of amputated ear with anastomosis of vessel]. AB - OBJECTIVE: To investigate the application of microsurgical technique in the replantation of amputated ear. METHODS: 7 cases of amputated ears were analyzed from June 2009 to April 2015 in our department. We used microsurgical technique to anastomose about five vessels and nerves. The blood supply of auricle was restored within three to six hours. All subjects underwent treatments including anti-freezing, anti-spasm and anti-infection treatment after the emergency surgery. RESULTS: 7 amputated ears were all survived after replantation. The patients were followed up for one month to six months ( average for 28 months). The appearances of survived ears body were fully recovered without any significant atrophy or pigmentation. The sensory function of ears recovered to normal after 1 year. CONCLUSIONS: The application of microsurgical technique in the replantation of amputated ear can expect the high success rate of ear replantation. However, skilled and high-quality anastomosis technique of small vascular are required. PMID- 26930806 TI - [Scalp expanded flap combined with IPL hair removal for large area scar on forehead]. AB - OBJECTIVE: To investigate the therapeutic effect of scalp expanded flap combined with JPL hair removal for large area scar on forehead. METHODS: From Jul. 2010 to Nov. 2012, 9 cases with large area scar on forehead received treatment of adjacent scalp expanded flap combined with JPL hair removal. One the first stage, the expander was implanted under the scalp near the forehead scar, followed hy expansion process. When the expansion was completed, the expanded flap was transferred to cover the wound after scar excision. 10 days after flap transposition, the forehead hair line was designed and extra hair on flap underwent JPL hair removal. After 3-5 treatments, the hair on flap was almost removed. RESULTS: All the scalp flaps survived completely. JPL hair removal had exact effect. The patients were followed up for 5-11 months. The hair density on the flap decreased hy more than 90%. The flap had a good match with surrounding facial skin in color, texture and thickness. The reconstructed forehead hair line was satisfactory. CONCLUSIONS: It is a good option to reconstruct large area scar on forehead with scalp expanded flap comhined with IPL hair removal. PMID- 26930807 TI - [Application of photodynamic therapy combined with compound betamethasone in treatment of hypertrophic scar]. AB - OBJECTIVE: To investigate the effect of photodynamic therapy combined with compound betamethasone in the treatment of hypertrophic scar. METHODS: 37 cases of keloid were divided into two groups, 19 cases in the treatment group, 18 cases in the control group. The patients in treatment group were treated with photodynamic therapy combined with compound betamethasone injection therapy. The patients in the control group were treated by compound betamethasone injection. The effect and recurrence rate were compared before and after treatment. RESULTS: The effective rate was 89.5% in the treatment group, 55. 6% in the control group, showing significant difference between the two groups (P = 0.029) The relapse rate in treatment group was significantly lower than that in the control group (P = 0.047) CONCLUSIONS: Photodynamic therapy combined with compound betamethasone has good effect and safety for the treatment of hypertrophic scar. The combined treatment can reduce the treatment period and side effects PMID- 26930808 TI - [The proximal crescentic osteotomy of the first metatarsal bone combined distal soft tissue reconstruction to treat severe hallux valgus]. AB - OBJECTIVE: To explore the method of the treatment for hallux valgus with the proximal crescentic osteotomy of the first metatarsal bone, combining with distal lateral soft tissue release. METHODS: From January 2008 to December 2012, 21 cases 21 hallux valgus feet were treated by operative procedure, included 1 male (1 foot) and 20 females (20 feet), with the mean age of 52 years (range, 36-68 years). Among all patients were followed up for 12 to 26 months, with the mean 16 months. The preoperative, post-operative and final follow-up X-ray films of all patients were collected. The hallux valgus angle, intermetatarsal angle and distal metatarsal articular angle were measured and analyzed. The surgical outcome was evaluated combined with the AOFAS score. RESULTS: The average hallux valgus angle decreased from 42.3 degrees +/- 1.8 degrees preoperatively to 14.5 degrees +/- 1.8 postoperatively, the average intermetatarsal angle did from 21.9 degrees +/- 1.7 to 9.1 degrees +/- 1.8 degrees , and the average distal metatarsal articular angle did from 14.9 degrees +/- 1.8 to 7.2 degrees +/- 1.5, respectively. There were significant differences between the preoperative and postoperative roentgenographic index. AOFAS score was improved from 44.0 +/- 1.8 preoperatively to 83.9 +/- 2.2 at the final follow-up. CONCLUSIONS: The proximal crescentic osteotomy of the first metatarsal bone combined distal soft tissue reconstruction obtained satisfactory results in severe hallux valgus patients with big intermetatarsal angle. PMID- 26930809 TI - [Application of embolic sclerotherapy for the treatment of painful venous malformation in limbs]. AB - OBJECTIVE: To investigate the safe and effective treatment for painful venous malformation (VM) in limbs. METHOD: (1) 97 cases with painful VM underwent MRI to detect the location of VM, as well as its size and structure, its relationship with the surrounding tissue. Statistical analysis was also performed. (2) The embolic agent (ethanol) was first injected to embolize the draining vessels of VM, then the Polidocanol plus Methotrexate (MTX) was followed to keep the embolization effect on VM. The therapeutic effect was observed and analyzed. RESULTS: From January 2010 to January 2012, 97 patients with painful VM were treated. A Spearman correlation analysis showed no significant correlation between symptoms of pain and lesion growth, volume, or MRI grades (P > 0.05). The lesions in the muscle space are more likely to have the symptoms of pain (P < 0.01), followed by the lesions in the muscle, then the lesions in the joint and subcutaneous tissue. The pain relieve percentage was 95.9% (93/97) after one time embolic sclerotherapy. No severe complication, such as distant embolization, nerve damage, or muscle atrophy happened. No pain reoccurrence happened after 0.5 1.5 years of follow-up period. CONCLUSIONS: The treatment of embolic scleratherapy is minimal invasive, safe and effective for painful VM with stable results. PMID- 26930810 TI - [Meta-analysis of steroids in reducing postoperative edema in rhinoplasty]. AB - OBJECTIVE: To investigate the clinical effect of steroids on reducing postoperative edema in rhinoplasty. METHODS: Cochrane, Medline data, Pubmed date, were searched and updated on October 2013. Randomized controlled trials(RCTS) studies were included to assess the efficacy of steroids on decreasing postoperative edema after rhinoplasty. The methodological quality of the included studies was evaluated, and date analyses were performed using the Cochrane Collaboration's software RevMan 5.2. RESULTS: A total of 4 RCTS involved 172 patients with rhinoplasty, including 87 patients in the experimental group( steroid) and 85 paitents in control group (placebo). Meta analysis results showed the edema in experimental group was significantly less than that in the control group on postoperative day 1 and 3 (P < 0.01), while the difference was not significant on postoperative day 7 (P = 0.19). CONCLUSIONS: Perioperative application of steroid in rhinoplasty can significantly reduce periorbital edema in the first postoperative day. The edema can completely be relieved after application of steroid for 3 days. It is a safe and effective way to reduce the postoperative edema. PMID- 26930811 TI - [Application of abdominal venous angio-architecture in flap thinning of deep inferior epigastric artery perforator flap]. AB - OBJECTIVE: To explore the venous angio-architecture of deep inferior epigastric artery perforator ( DIEP) flap with computed tomography angiography( CTA) and the application of venous angio-architecture in flap thinning of DIEP flap. METHODS: From February 2012 to August 2014, preoperative CTA examination of venous system of DIEP flap was performed in 11 patients to study the course, the branch and the anastomosis of the deep inferior epigastric veins, the superficial inferior epigastric veins and the perforator veins. The flap thinning of DIEP flap was based on the finding of the abdominal venous system. RESULTS: The CTA images were obtained including 22 deep inferior epigastric veins, 22 superficial inferior epigastric veins and 22 perforator veins. The distance between the superficial inferior epigastric vein and abdominal midline was 3.30 cm to 5.77 cm in the zone 3 cm above umbilicus and in the zone 15 cm below umbilicus. The superficial inferior epigastric vein was 0.29 to 0.39 in depth ratio. The superficial inferior epigastric veins were the main drainage vessels of superficial abdominal wall according to the CTA images. They were anastomosed with the deep inferior epigastric veins through perforator veins. The 11 DIEP flaps were thinned based on the structure of the superficial inferior epigastric veins and all flaps had no drainage disturbance. CONCLUSIONS: Preoperative CTA images can display the venous angio-architecture of deep inferior epigastric artery perforator flap. The superficial inferior epigastric vein can be utilized as reference architecture to guide flap thinning of DIEP flap. PMID- 26930812 TI - [The influence of estradiol on histomorphology of skin flaps with ischemia reperfusion injury]. AB - OBJECTIVE: To study the influence of estradiol on histomorphology of skin flaps with ischemia reperfusion injury. METHODS: 48 adult male Wistar rats aged 12-14 weeks old, were randomly divided into control group (group I), ischemia reperfusion group (group II), saline group (group III), estradiol group (group IV). Superficial epigastric artery axial flap, 3 cm x 6 cm in size, was made in the left lower quadrant abdominal of each rat. Flap model with ischemia reperfusion injury was established by using the nondestructive micro vascular clamp to clamp the superficial epigastric artery. The general condition of the flap was observed after operation. At 7 days after operation, the survival rate of the flap was detected, the flaps were harvested to receive histology and ultrastructural observation. The neutrophils level of the superficial epigastric vein were tested. RESULTS: 7 days after operation, the survival rate of the flap in group IV was significantly higher than that in group II, III (P < 0.05). The neutrophils level in group IV was lower than that in group II, III (P < 0.05). The histological observation showed that the degree of tissue swelling and inflammatory exudation in group IV was more slight than that in group II, III. Presence of high neutrophils density were observed in group II, III, while slight inflammation and necrosis were observed in group IV. In group I, collagen fibers in flap are regularly arranged with no significant necrosis. Oganelles structure disappeared and apoptotic bodies were shown in group II and group III, even the lysosome could be seen in the cell. Collagen fibers in flap are regularly arranged with slight swelling and no obvious ultrastructural necrocytosis was seen in the cell of group IV. CONCLUSION: The estradiol can significantly increase flap survival rate by inhibiting neutrophils infiltration and improving the pathological changes of organization structure in flap. PMID- 26930813 TI - [An ischemic postconditioning model of human dermal microvascular endothelial cells]. AB - OBJECTIVE: To establish a model of hypoxic postconditioning of dermal microvascular endothelial cells. METHODS: During reoxygenation after hypoxia, cells received three times of hypoxic/ reoxygenation alternate treatment for a certain time. The cells were seeded on 6-well plates, with one plate for one group. They were divided into 6 groups as group 1 ( Control), group 2 (8h hypoxia + 24h reoxygenation), group 3 (8h hypoxia + 2 min x 3 times post-hypoxia treatment) , group 4 (8h hypoxia + 5 min x 3 times post-hypoxia treatment), group 5 (8h hypoxia + 10 min x 3 times post-hypoxia treatment), 6 group (8h hypoxia + 20 min x 3 times post-hypoxia treatment). Each group underwent 8 h hypoxia + 24 h hypoxia Buffer and reoxygenation. Lactate dehydrogenase (LDH) was detected during the process. Apoptosis rate was calculated by staining Tunel method. Bcl-2, Bax and activated caspase-3 protein were detected by Western Blot. RESULTS: In the continuous hypoxia process, the LDH was (1563 +/- 83.35) IU/L at 8h and (582.85 +/- 58.25 ) IU/L at 0h, showing a statistical difference (P = 0.0001). Western blotting results showed that the expression of Bax/Bcl-2 in group 2 was 0.38 +/- 0.02, showing a significant difference when compared with that in group 3 (0.23 +/- 0.01) and group 4 (0.22 +/- 0.02) (P = 0.012, P = 0.005), while not when compared with that in group 5 (0.33 +/- 0.02) and 6 groups (0.34 +/- 0.01) P > 0.05). The ratio of Activated caspase-3/caspase-3 in group 2 (6.30 +/- 1.50) was significantly higher than that in group 3 (2.17 +/- 0.26) and group 4 (2.63 +/- 0.31) (P = 0.008, P = 0.019); while not in group 5 (4.36 +/- 0.29) and group 6 (4.97 +/- 0.51) (P > 0.05). CONCLUSIONS: The model of hypoxic postconditioning of human dermal microvascular endothelial cells is successfully established. PMID- 26930815 TI - Last Call: Will WIMPs Show Their Faces? PMID- 26930814 TI - Beware Prenatal Gene Screens. PMID- 26930816 TI - Talk Therapy. PMID- 26930817 TI - The Ear as Tape Measure. PMID- 26930818 TI - Poison Pot. PMID- 26930820 TI - Space Jellies. PMID- 26930819 TI - The New Crash Test Dummy. PMID- 26930821 TI - Elemental Urgency. PMID- 26930823 TI - Get Out the iVote. PMID- 26930822 TI - When Love Wins. PMID- 26930824 TI - For Sale: Your Medical Records. PMID- 26930825 TI - THE SEARCH FOR PLANET. PMID- 26930826 TI - Bitter taste bodyguards. PMID- 26930828 TI - The Quantum Hack. PMID- 26930827 TI - Collective Wisdom of Ants. PMID- 26930829 TI - Six Billion in Africa. PMID- 26930831 TI - My LIFE AS A COMET HUNTER. PMID- 26930830 TI - THE POWER OF THE INFANT BRAIN. PMID- 26930832 TI - Afterlife for Atheists. PMID- 26930833 TI - Disease Squeeze. PMID- 26930834 TI - Factors Affecting Corneal Hysteresis in Taiwanese Adults. AB - PURPOSE: To investigate the correlation of various corneal hysteresis (CH) factors in Chinese adults. METHODS: From January 2009 to November 2011, the healthy right eyes of a total of 292 adults were recruited into the study. Goldmann-correlated intraocular pressure (IOPG) and CH were measured using an ocular response analyzer (ORA). Central corneal thickness was measured using the ORA's integrated handheld ultrasonic pachymeter. The IOLMaster was used to obtain the ocular biometric measurements including axial length, anterior chamber depth, and keratometric values. The Pearson correlation coefficient was used to test correlations between CH and quantitative factors. The chi-square test was used to detect differences in categorical values. RESULTS: Longer axial length (P = 0.0001), lower IOPG (P = 0.03), older age (P = 0.003), and thinner central corneal thickness (P = 0.0001) were significantly associated with lower CH. The anterior chamber depth (P = 0.34), gender (P = 0.23), and corneal curvature (P = 0.18) had no relationship to CH. CONCLUSION: Various factors including axial length, intraocular pressure, age, and central corneal thickness can affect measurement of corneal biomechanical properties in Chinese adults. But the anterior chamber depth, gender, and corneal curvature were irrelevant to CH. PMID- 26930835 TI - Outcomes of Coaxial Micro-incision Phacoemulsification in Nanophthalmic Eyes: Report of Retrospective Case Series. AB - PURPOSE: The surgical risk and complication rate after cataract surgery are extremely high in patients with nanophthalmos. This study is designed to compare the visual and refractive outcomes before and after coaxial micro-incision phacoemulsification and evaluate postoperative complications. METHODS: Fifty nine patients (89 eyes) with axial length (AL) < 21 mm diagnosed with nanophthalmos were enrolled in this retrospective study. All patients underwent coaxial micro incision phacoemulsification and IOL implantation. The main outcome measures included anterior chamber depth (ACD), anterior chamber volume (ACV), anterior chamber angle (A CA), intraocular pressure (IOP) and best corrected visual acuity (BCVA). Wilcoxon signed rank test or Mann-Whitney test, and Chi-square test and logistic regression analysis were performed for statistical tests as appropriate. RESULTS: The median AL was 19.63 mm. Sixty-six eyes (74.16%) had a history of surgical intervention. Postoperative ACD, ACV and ACA were increased significantly (all P < 0.001), whereas postoperative IOP was decreased significantly (P < 0.001) after surgery. Previous surgical intervention was related to a reduction in the postoperative ACD and ACA (P < 0.01), and both preoperative and postoperative IOP (P < 0.001). Postoperative BCVA was improved in 94.38% of the cases. Intraoperative complications mainly included iridoschisis (6 eyes, 6.74%). Early postoperative complications included temporary corneal edema (TCE) (23 eyes, 25.84%), anterior inflammatory response (AIR) (19 eyes, 21.35%), cystoid macular edema (CME) (14 eyes, 15.73%), and uveal effusion (4 eyes, 4.49%). Late postoperative complications included CME (8 eyes, 8.99%), uveal effusion (8 eyes, 8.99%), malignant glaucoma (2 eyes, 2.25%) and posterior capsular opacification (PCO) (10 eyes, 11.24%). The majority of complications (80%) were successfully resolved by pharmacotherapy or operation. The risk of surgical complications was greater in patients with lower AL, ACD, ACV or ACA and higher nuclear hardness or mean keratometry (Km). CONCLUSION: With reasonable preoperative management, prudent selection of the lens, rigorous surgical technique and unerring cognition of potential complications, coaxial microincision phacoemulsification lens surgery can be performed in patients with nanophthalmos and yield favorable outcomes and a low incidence of complications. PMID- 26930836 TI - [Long-term Efficacy and Ocular Surface of Pterygium Excision Combined with Autologous Corneal Limbal Stem Cell Transplantation in Treatment of Pterygium]. AB - PURPOSE: To evaluate the long-term efficacy of pterygium excision combined with autologous corneal limbal stem cell transplantation in the treatment of pterygium. METHODS: Fifty five patients (57 eyes) diagnosed with primary pterygium undergoing pterygium excision combined with autologous corneal limbal stem cell transplantation between December 2003 and December 2008 were enrolled in this study. Postoperative follow-up endured for 2-8 years, 5.3 years on average. The wound healing, clinical efficacy and postoperative complications were observed. RESULTS: During early stage after surgery, all patients presented with varying degree of hyperemia, edema and sense of foreign body, which were gradually mitigated 3-5 d later and completely recovered in approximately 1 week. The corneal wound was completely epithelized within 4-7 d, 4.83 d on average. Seven patients had persistent ocular surface irritation symptoms after surgery, one case had residual fibrous tissues and four patients developed superficial corneal scars. Postoperative follow-up endured for 2-8 years, 5.3 years on average. Eight patients (8 eyes) recurred with a recurrence rate of 13.11%. In all patients, postoperative OSDI score was significantly decreased at 1-year reexamination. OSDI score and constitution ratio significantly differed between two groups (both P < 0.05). At postoperative 5 years, OSDI score was slightly lower compared with that in last year with no statistical significance (P > 0.05). At post-operative 1- and 5-year, basic tear secretion was (12.95 +/- 4.03) mm and (12.68 +/- 4.77) mm, tear film break-up time was (10.55 +/- 4.13) s and (10.03 +/- 4.64) s. Both indexes were significantly improved compared with (9.48 +/- 3.34) mm and (8.14 +/- 3.57) s before surgery (all P < 0.05). CONCLUSION: Pterygium excision combined with autologous corneal limbal stem cell transplantation is an efficacious treatment of pterygium with mild postoperative symptoms, rapid recovery, low long-term recurrence rate and high efficacy. PMID- 26930837 TI - [Analysis of the Effect of Non-phacoemulsification Cataract Operation on Corneal Endothelial Cell Nucleus Division]. AB - PURPOSE: To investigate the effect of non-phacoemulsification cataract operation in two different patterns of nucleus delivery on the quantity and morphology of corneal endothelial cells and postoperative visual acuity. METHODS: Forty patients diagnosed with cataract underwent cataract surgery and were assigned into the direct nuclear delivery and semi-nuclear delivery groups. Lens density was measured and divided into the hard and soft lenses according to Emery-little lens nucleus grading system. Non-phacoemulsification cataract operation was performed. At 3 d after surgery, the quantity and morphology of corneal endothelium were counted and observed under corneal endothelial microscope. During 3-month postoperative follow-up, the endothelial cell loss rate, morphological changes and visual acuity were compared among four groups. RESULTS: Corneal endothelial cell loss rate in the direct delivery of hard nucleus group significantly differed from those in the other three groups before and 3 months after operation (P < 0.01), whereas no statistical significance was found among the direct delivery of soft nucleus, semi-delivery of hard nucleus and semi delivery soft nucleus groups (all P > 0.05). Preoperative and postoperative 2-d visual acuity did not differ between the semi-delivery of hard nucleus and direct delivery of soft nucleus groups (P = 0.49), significantly differed from those in the semi-delivery of soft nucleus (P = 0.03) and direct delivery of hard nucleus groups (P = 0.14). Visual acuity at postoperative four months did not differ among four groups (P = 0.067). CONCLUSION: During non-phacoemulsification cataract surgery, direct delivery of hard nucleus caused severe injury to corneal endothelium and semi-delivery of soft nucleus yielded mild corneal endothelial injury. Slight corneal endothelial injury exerted no apparent effect upon visual acuity and corneal endothelial morphology at three months after surgery. PMID- 26930838 TI - [Research Progress in Measurement of Human Accommodative Amplitude]. AB - Accommodation is an important function of the human eye, which can change the parameters of ocular refractive system and also has a strong correlation with the development of myopia and presbyopia. Several subjective measurements have been applied in accommodation assessment such as push-up test, push-down test and minus-lens procedures. It can be measured objectively by measuring the change in refraction of the eye with dynamic retinoscopy or autorefractor. This article reviews the application of measurement of accommodative amplitude and research progress in accommodation, providing clinical information for further studies. PMID- 26930839 TI - [Continuing Nursing Care of Patients with Senile and Diabetic Cataract]. AB - PURPOSE: To explore the treatment and continuing nursing of patients diagnosed with senile and diabetic cataract. METHODS: In total, 142 patients diagnosed with senile and diabetic cataract admitted to Zhongshan Ophthalmic Center from January to December 2014 were randomly assigned into groups A and B. In group A, patients received conventional instruction after discharge, and those in group B additionally received continuing nursing care after discharge including ocular nursing, use of anti-diabetic drugs, psychological nursing, diet nursing, self monitoring guidance, re-examination and regular follow-up according to the patients' conditions. RESULTS: After one year of continuing nursing care, visual acuity of patients in group B was increased without complications. Body mass index, the fasting and 2h postprandial plasma glucose, and the systolic and diastolic blood pressure were decreased significantly compared with those in group A (all P < 0.05). CONCLUSION: Continuing nursing care, including knowledge education related to ocular use and diabetes mellitus, targeted psychological nursing, medication nursing and daily life guidance, play a pivotal role in enhancing the compliance rate of the patients, reducing the influence upon work and life and enhancing the quality of life to varying extent. PMID- 26930840 TI - [The Nursing of 20 Cases of High Myopia Complicated with Fixed Esotropia]. AB - To summarize the nursing experience of 20 cases of high myopia complicated with fixed esotropia. Before surgery, psychological nursing and self-care education were necessary. After the operation, ocular symptoms and complications should be closely observed and treatment in a timely manner. Explicit instructions after discharge and telephone follow-up played a pivotal role in improving clinical efficacy, preventing complications and enhancing patients' quality of life. PMID- 26930841 TI - [Management of Lamellar Keratoplasty in Day-care Unit]. AB - PURPOSE: The management and efficacy of lamellar keratoplasty of 8 patients in day-care unit were summarized. METHODS: The work flow and medical record of 8 cases undergoing corneal transplantation in day-care unit were retrospectively analyzed. RESULTS: Eight patients were fully recovered. One case with fungal keratohelcosis was re-infected at post-operative 2 months and hospitalized. CONCLUSION: During lamellar keratoplasty in day-care unit, the work flow should be explicitly established and modified. The quality of patient selection, preoperative and postoperative nursing, follow-up after discharge should be carefully assured. In addition, nursing paperwork should be simplified, psychological nursing should be strengthened, and doctors and nurses should cooperate closely to enhance work efficiency. PMID- 26930842 TI - [Establishment and Implementation of Humanistic Nursing Care in Ophthalmic Ward]. AB - PURPOSE: To discuss the role of humanistic nursing care in improving the nursing quality and patients' degree of satisfaction in ophthalmic ward. METHODS: A mode of humanistic nursing care was established, hospital environment was improved and work flow was arranged in details. Nurses received professional training of humanistic care skills. By using multiple educational approaches, nursing care with responsibility system can be delivered in a continuous and seamless manner. RESULTS: The measures of humanistic nursing care were fully implemented. The nurses' communication ability was improved and the nurses worked more actively. The quality of nursing and patients' degree of satisfaction (99%) were equally significantly improved. No mistake occurred and no complaint was received from the patients. CONCLUSION: Proper application of humanistic care in clinical nursing provides high-quality nursing for patients. PMID- 26930843 TI - [Nursing Experience of Corneal Collagen Cross-linking in Treating Keratoconus]. AB - PURPOSE: To summarize the nursing experience and clinical efficacy of corneal collagen cross-linking in treating keratoconus. METHODS: Preoperative and postoperative nursing and medical record of 30 patients (31 eyes) undergoing corneal collagen cross-linking were retrospectively analyzed. RESULTS: The the severity of diseases in all 30 patients (31 eyes) was properly controlled. All cases were fully recovered. The visual acuity at postoperative one month was improved in all cases. CONCLUSION: Assistance in terms of preoperative examination, education of health knowledge and effective psychological nursing play a pivatol role in the nursing before and after corneal collagen cross linking. Following surgery, postoperative changes in the the severity of diseases should be strictly observed. Much attention should be diverted to ease patients' pain, prevent infection and accelerate the healing of corneal epithelium. PMID- 26930844 TI - Advertising in Heroic Couplets: Laughing Gas by Dentist W.J.A. DeLancey. AB - Dr. William J.A. DeLancey moved to Illinois from New England in 1858 to practice dentistry. Renowned for his good humor and amiable personality, DeLancey penned a seven-stanza poem in heroic couplets titled "Dental Surgery." These mock-heroic verses were published in about half of the Centralia Sentinel weekly newspapers issued in 1864. Inventor of a tooth powder and an electric dental motor, DeLancey became a statewide leader of Freemasonry. Unfortunately, both his vocational dental library and his avocational Masonic one were incinerated by a house fire in 1892. As a lifelong professional dentist, DeLancey was widely regarded as a true pillar of the communities and of the Masonic Temples in which he had served- first in Illinois (Galesburg and then Centralia) and finally in Williamsport, Indiana. PMID- 26930845 TI - Baltimore and the Beginnings of the Fluoride Controversy. AB - The fluoridation of municipal water as a preventive dental health measure has proven to be a contentious issue from its very outset. In 1952, Baltimore became the first major city in the United States to artificially add fluoride to its water supply. This study draws largely on print media sources as a means of discerning public sentiment, in order to evaluate the nature of Baltimore's fluoride controversy in its infancy. Initial response was influenced by prior exposure to the substance within the context of dentistry, as well as a continued trend of conservatism within the community. Logistical issues during implementation due to the necessary upscale of established practices to accommodate Baltimore's population served to further exacerbate concerns. Much of the opposition was predicated on the breadth of the measure, as evidenced by the myriad of personal concerns put forth in objection. Personal concerns developed into demands for personal autonomy, providing a philosophical foundation for the anti-fluoridation movement that persists today. PMID- 26930846 TI - Collector's Corner: Medallic Work of Abram Belskie. PMID- 26930847 TI - Dental Items of Interest: The Case of Delphic Sibyl by Michelangelo: Solitary Median Maxillary Central Incisor or Mesiodens. AB - A case of an anomaly in the maxillary dental arch on "Delphic Sibyl," a fresco by Michelangelo is reported. An accurate analysis of this fresco shows a single incisor tooth is present precisely in the midline. We hypothesize that it may be a case of solitary median maxillary central incisor (SMMCI) and discuss the differential diagnosis with another similar anomaly--the mesiodens. PMID- 26930848 TI - Cystic Conditions of the jawbones: A Review of Early Classification Systems. AB - Cystic conditions of the jawbones were recognized long before the establishment of the American Academy of Oral Pathology (AAOP) in 1948, but it was around this time when they were studied, characterized, and classified. The history of the classification systems implemented by oral pathologists to study the cystic conditions of the maxillary bones is intimately related with the birth of oral and maxillofacial pathology as a specialty of dentistry. The purpose of this paper is to review the early classification systems proposed for the cystic conditions of the jawbones. PMID- 26930849 TI - Dental Trade Cards XLII. WADWORTH'S TOOTH POWDER. PMID- 26930850 TI - Dental Postcards LVIII. PMID- 26930852 TI - EDITORIAL. PMID- 26930851 TI - In Memoriam: Dr. Gerald "Gerry" Shklar. PMID- 26930854 TI - Comparative evaluation of five Pleurotus species for their growth behaviour and yield performance using wheat straw as a substrate. AB - Pleurotus spp. is one of the most important edible mushrooms cultivated in India. The present study was an attempt to compare five Pleurotus species in context of actual time required for each growth stage viz., spawn run period, number of days required for initiation of pin heads of sporophores, average weight of fruiting bodies in all the flushes and total yield. The spawn run period in all the five species were recorded between 18 days-21 days, similarly for initiation of pinheads 5 days -7 days were required after spawn run period. A total of 24 days to 27 days, 34 days to 37 days and 47 days to 53 days were required for harvesting the I, II and III flushes respectively. An average number of 41 to 70 sporophores per bag containing 1 kg of dry substrates were obtained from all the Pleurotus species. Maximum 14 g weight of single sporophore was recorded from P. florida, similarly, an average maximum diameter of 5.3 cm of sporophores of P. florida was observed whereas the diameter of sporophores in rest of the species ranged from 3.0 cm to 3.2 cm. The number of sporophores were obtained from P. sajor-caju (n-70) and all the species showed significant difference with respect to the number of sporophores in a bunch at probability level of P = 0.05. Maximum weight of single bunch was recorded (58 g) in P. florida and total yield of 740 gkg(-1) of dry matter was recorded in P. florida. PMID- 26930853 TI - In vitro studies on anti-obesity activity of Korean Memilmuk through AMPK activation. AB - The anti-obesity effect of Korean traditional food, Memilmuk, was examined through inhibition of differentiation of 3T3-L1 preadipocytes by buckwheat flour extract. Oil-Red O staining showed that lipid accumulation in adipocytes was reduced upon adding buckwheat flour extract, indicating effective inhibition of adipocyte differentiation. Buckwheat flour extract also inhibited the expression of adipogenic transcription factor, peroxisome proliferator-activated receptor gamma (PPARgamma), and AMP-activated protein kinase (AMPK), an intracellular regulator of energy balance. Overall, the anti-obesity effect of Korean Memilmuk might be mediated through down-regulation of PPARgamma expression via AMPK activation by buckwheat flour. PMID- 26930855 TI - Effects of root exudates of bivalent transgenic cotton (Bt+CpTI) plants on antioxidant proteins and growth of conventional cotton (Xinluhan 33). AB - A greenhouse experiment was conducted to assess the adverse impact of transgenic cotton on ecosystem and environment via effect of transgenic Bt+CpTI cotton root exudates on growth and antioxidant activity of conventional parental cotton. Results showed elevated reductive and oxidative species activities in the leaves of conventional parental cotton seedlings treated with varying concentrations of transgenic cotton root exudates. Compared to control, 14.9% to 39.9% increase in catalase, 8.8% to 114% increase in for peroxidase, 21.3% to 59.7% increase in phenylalanine ammonia-lyase and 5.8 to 19.5 fold in ascorbate specific peroxidase was observed. However, biomass and height of conventional cotton seedlings were not affected by any concentration of transgenic cotton root exudates. These results suggested that cultivation of transgenic Bt+CpTI cotton plants poses little risk to conventional parental cotton based on their root interactions. PMID- 26930856 TI - Effect of culture intensity and probiotics application on microbiological and environmental parameters in Litopenaeus vannamei culture ponds. AB - The present study examined the complex interaction among stocking density and extent of probiotic use with production and environmental parameters in Litopenaeus vannamei culture ponds to suggest suitable management strategies. The study was conducted inL. vannamei culture ponds with stocking density of 35 nos sq m(-1) (Group I) and 56 nos sq m(-1) (Group II) and probiotic application @16.5 kg ha(-1) and 157 kg ha(-1), respectively. There was no significant difference noted between the two groups of ponds in respect to ammonia oxidizing bacteria (AOB) in sediment and nitrite oxidizing bacteria (NOB) in water samples, whereas significantly higher levels of AOB in water samples of high intensity culture ponds (Group II) and NOB in sediment samples of Group I were observed. The levels of sulphur oxidizing bacteria (SOB) and sulphur reducing bacteria (SRB) in Group I pond water and in Group II sediment were significantly higher than their corresponding levels in the other group. In both the groups, ammonia, nitrite and sulphide concentrations were below toxic limits prescribed for shrimp farming. Comparing the production parameters at harvest revealed that low intensity culture ponds (Group I) had higher growth rate, average body weight and significantly lower FCR and higher survival rate than high intensity culture ponds (Group II). The results indicated that application of microbial products in higher quantities did not benefit significantly, and there is a need to regulate quantum and schedule of biological product usage for economically sustainable shrimp culture. PMID- 26930857 TI - Performance of fenugreek bioinoculated with Rhizobium meliloti strains under semi arid condition. AB - Rhizobium meliloti strains were isolated from the fields of S.D. Agricultural University (Gujarat, India) and were maintained in the Congo Red Yeast Extract Mannitol Agar medium. These strains were tested for their effectiveness for fenugreek crop grown under semi-arid condition. Among the six Rhizobium strains, FRS-7 strain showed best plant growth parameters like shoot length, shoot dry weight, shoot total nitrogen, root length, root dry weight, root total nitrogen, seed yield, 1000 grain weight, number of root nodules, and nodules fresh and dry weight. The performance of this strain was better as compared to 20 kgN ha(-1) treatment through urea and was even far better over control plot. Seed yields obtained with FRS-7 during two years were 10.14 and 9.66 q ha(-1); which was about 36.8% and 45.9% high over control. This strain resulted in saving of about 20 kgN ha(-1) accompanied with better crop yield and soil health. Results of the present experiments can be utilized in integrated nutrient management for cultivation of fenugreek in semi-arid areas to provide sustainability to agricultural productivity in such regions. PMID- 26930858 TI - Studies on influence and fate of carbamazepine in anaerobic digestion of sludge. AB - Increased consumption of pharmaceutical compounds compounded by their persistence in biological treatment processes and potential toxicity is becoming a serious concern. The aim of the present study was to investigate the fate of an antiepileptic drug, carbamazepine (CBZ), in anaerobic digestion process and its impact on methanogenic metabolism. Biochemical methane potential of CBZ with or without glucose was studied for 40 days in designed batch experiments. About 67.98% and 66.37% of spiked CBZ (about 100 MUg l(-1)) were removed during this period from glucose amended or unamended sets, respectively. Loss of CBZ through adsorption onto suspended particles, as in sterilized seed sludge control (16.98%), was significantly lower in comparison to its biotic counterparts (P = 0.002 and P = 0.003). Analysis of methane or biogas production revealed no inhibitory effect of CBZ toward methanogenic process at its tested concentration. Differences in cumulative methane yields between glucose containing sets with or without CBZ were insignificant (P = 0.885). This study suggests that any residual CBZ concentration lower than the present study, if detected in waste-water, might not significantly affect the methanogenic process. PMID- 26930859 TI - Generation of cytotoxic molecules and oxidative stress in haemolymph of pebrinised tasar silkworm Antheraea mylitta Drury. AB - The present study was carried out to investigate the effects of microsporidial infection on redox regulation mechanism and oxidative stress in tasar silkworm Antheraea mylitta. High level of superoxide radical (p < 0.05), nitric oxide (p < 0.001) and lipid peroxidation (p < 0.001) was observed in haemolymph of pebrinised larvae, which indicated the resultant generation of cytotoxic molecules and oxidative damage. Increased phenol oxidase (PO) activity in haemolymph of pebrinised larvae indicated the activation of immune defences during pathological conditions. In addition, higher level of glutathione-S tranferase (GST) activity and reduced glutathione (GSH) level observed in pebrinised larvae indicated adaptive behaviour of tissue against toxic oxyradicals (p < 0.05). Conversely, low level of ascorbic acid (ASA) content suggested that the larvae might have used these compounds to counteract stress in tissues or low uptake under microspridial infection (p < 0.05). Present findings provide new insights into the cellular and biochemical bases of host-pathogen interactions in tasar silkworm A. mylitta. PMID- 26930861 TI - Physiological properties of Scomber japonicus meat hydrolysate prepared by subcritical water hydrolysis. AB - The health-beneficial biological activities, including antioxidant and tyrosinase inhibitory activities, of Scomber japonicus muscle protein hydrolysates prepared by subcritical water hydrolysis were investigated. After 5 min of subcritical hydrolysis at 140 degrees C, 59.76% of S. japonicus muscle protein was hydrolyzed, the highest degree of hydrolysis in all the groups were tested. According to the response surface methodology results, as the reaction temperature and reaction time became lower and shorter, the yield became higher. The highest 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical-scavenging activity (90.63%) occurred in hydrolysates treated at 140 degrees C for 5 min, and the highest tyrosinase inhibitory activity (65.54%) was identified in hydrolysates treated at 200 degreesC for 15 min. Changes in the molecular weight distribution of S. japonicus muscle proteins after subcritical water hydrolysis were observed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Subcritical water hydrolysis is a suitable technique for obtaining S.japonicus muscle protein hydrolysates with useful biological activities, within a short time (5-15 min). PMID- 26930860 TI - Molecular phylogenetic analysis of mango mealybug, Drosicha mangiferae from Punjab. AB - Mealybugs (Hemiptera: Pseudococcidae) are major pests of a wide range of crops and ornamental plants worldwide. Their high degree of morphological similarity makes them difficult to identify and limits their study and management. In the present study, four Indian populations of mango mealybug (mango, litchi, guava from Gurdaspur and mango from Jalandhar) were analyzed. The mtCOI region was amplified, cloned, the nucleotide sequences were determined and analysed. All the four species were found to be D. mangiferae. The population from Litchi and Mango from Gurdaspur showed 100% homologus sequence. The population of Guava-Gurdaspur and Mango-Jalandhar showed a single mutation of 'C' instead of 'T' at 18th and 196th position, respectively. Indian populations were compared with populations from Pakistan (21) and Japan (1). The phylogenetic tree resulted in two main clusters. Cluster1 represent all the 4 populations of Punjab, India, 20 of Pakistan (Punjab, Sind, Lahore, Multan, Faisalabad and Karak districts) with homologous sequences. The two population collected from Faisalabad district of Pakistan and Japan made a separate cluster 2 because the gene sequence used in analysis was from the COI-3p region. However, all the other sequence of D. mangiferae samples under study showed a low nucleotide divergence. The homologus mtCO1 sequence of Indian and Pakistan population concluded that the genetic diversity in mealybug population was quite less over a large geographical area. PMID- 26930862 TI - Isolation of useful scented rice mutants and comparative assessment of genetic diversity. AB - A set of 36 scented rice mutants were developed through recurrent mutagenesis Pusa basmati-1, Pusa Sugandha-2 and Ketakijoha local with ethyl methane sulphonate (EMS), N-methyl N-nitro N-nitrosoguanidine (NG) and a combination of 0.4% EMS and 0.015% NG over two successive generations. ORM 256-8-10 and ORM 256 8-6 (mutants of PB-1) and ORM 228-1 (mutant of Pusa Sugandha 2) had shown significantly higher grain yield than Geetanjali (standard check), as well as, their respective parent varieties. The above test genotypes were analysed by 12 RAPD and 11 ISSR primers. RAPD and ISSR primers amplified 92 and 77 bands ranging from 4-15 and 4-12 bands per respective primer exhibiting higher level of polymorphism (86.95% and 94.80%). RAPD primer OU 1 and ISSR primer OUAT 7 produced maximum number of 15 (280-1830bp) and 12 polymorphic bands (420-1260bp), respectively. ISSR revealed higher polymorphic information content (PIC) values than RAPD primers indicating better allelic diversity. Resolving power revealed higher efficiency of RAPD primers. OU-1 with high GC content (80%) and two ISSR primers OUAT-7 (GC = 66.7%) and OUAT-15 (GC = 88.2%) produced higher number of polymorphic amplicons. ORM 228-1, Pusa Sugandha-2, ORM 256-8-10 and Ketakijoha were identified to be highly divergent genotypes based on RAPD and ISSR analyses. RAPD analysis revealed divergence of ORM 256-2 and ORM 256-8-12 while ORM 256-8-6 isolated from rest of the genotypes in case of ISSR. This could be attributed to genotype-specific RAPD and ISSR alleles. The above diverse genotypes with high yield identified in the present pursuit would enrich the basmati gene pool for further genetic improvement for grain quality and yield per se. PMID- 26930863 TI - Isolation, fingerprinting and genetic identification of indigenous PAHs degrading bacteria from oil-polluted soils. AB - In the present study, thirty five bacterial isolates were obtained from hydrocarbon-contaminated soil samples using an enrichment method. These isolates were tested to grow on mineral salt medium containing anthracene or phenanthrene as sole carbon source. Only five isolates showed the ability to degrade these compounds. RAPD-PCR fingerprinting was carried out for the five isolates, and the DNA patterns revealed that there was no similarity among the examined bacteria whenever the RFLP using four restriction enzymes HaeIII, Msp1, Hinf1 and Taq1 failed to differentiate among them. Five bacterial isolates were grown in high concentration of anthracene and phenanthrene (4% w/v). Two bacterial isolates were selected due to their high ability to grow in the presence of high concentrations of anthracene and phenanthrene. The isolates were identified as Bacillus flexus and Ochrobactrum anthropi, based on DNA sequencing of amplified 16S rRNA gene and phylogenetic analysis. Finally, the ability of these bacterial strains to tolerate and remove different PAHs looked promising for application in bioremediation technologies. PMID- 26930864 TI - Impact of organic and mineral inputs onto soil biological and metabolic activities under a long-term rice-wheat cropping system in sub-tropical Indian Inceptisols. AB - Long-term use of organic and mineral inputs has an overriding impact on soil biological and metabolic activities and crop management. Farm yard manure (FYM), paddy straw (PS) and green manure (GM, Sesbania sesban L.) were used for 24- years old rice (Oyza sativa L.) -wheat (Triticum aestivum L.) cropping system in sub-tropical India to predict whether the screened soil biological and metabolic activities are correlated with system yield. The integrated approaches viz., NPK + FYM, NPK + PS and NPK + GM significantly increased both rice and wheat yield together by 67.5, 44.4 and 55.4%, respectively over control. However, for a few exceptions both soil microbial activity and metabolic activity were remarkably enhanced under integrated treatment NPK + FYM followed by NPK + PS, and NPK + GM, respectively. Among the studied attributes fluorescein diacetate hydrolyzing, dehydrogenase, beta-glucosidase activity (beta-glu) and microbial biomass C (C(mic)) were screened through principal component (PCA) and discriminate analysis (DA) that explained nearly 89% of total variations of the entire data set. Among the four identified attributes, only beta-glu assay value could predict system yield (R2 = 0.65). Further, estimation of beta-glu activity in soil can predict other soil biological properties (R2 = 0.96). PMID- 26930865 TI - Spore population, colonization, species diversity and factors influencing the association of arbuscular mycorrhizal fungi with litchi trees in India. AB - Abundance and diversity of arbuscular mycorrhizal fungi (AMF) in association with litchi (Litchi chinensis Sonn.) trees were studied during 2012-2013, where orchard soil had high pH (7.42-9.53) and salinity (0.07- 0.39 dSm(-1)). A total of 105 rhizospheric soil and root samples were collected considering variables like location, age of tree, cultivar and production management. Results showed that spore count was in the range of 1-22 g(-1) soil. All the examined root segments had colonization of AMF, which ranged between 3.3 to 90.0%. AMF community comprised of Glomus mosseae, G. intaradices, G. constricta, G. coronatum, G. fasciculatum, G. albidum, G. hoi, G. multicauli, Acaulospora scrobiculata, A. laevis, Rhizophagus litchi and Entrophosphora infrequens. Higher spore density and AMF colonization were observed at medium level (13-28 kg ha( 1)) of available phosphorus that decreased ('r' = -0.21 for spore density, -0.48 for root colonization) with increasing soil phosphorus. While nitrogen did not influence the AMF association, a weak negative linear relationship with AMF colonization ('r' = -0.30) was apparent in the medium level (112-200 kg ha(-1)) of potash. Micronutrients (Zn, Fe, Cu, Mn and B) did not affect spore density (zero or a very weak linear correlation) but influenced root colonization ('r' = 0.53 to -0.44), the effect being more prominent above critical limits. Nutritionally sufficient, irrigated litchi orchards had greater spore count (46% samples having 5-22 spores g(-1) soil) and colonization (> 50% in 37.4% roots examined) than nutrient deficient, non-irrigated orchards, indicating essentiality of a threshold nutrients and moisture regime for the association. AMF symbiosis was influenced by cultivar (greater in 'China'), but tree age was not correlated to mycorrhizal association. A consortium of native species coupled with the understanding of nutrient effects on AMF would be useful for field application in litchi. PMID- 26930866 TI - Mycoflora and natural aflatoxin contamination in dried quince seeds from Jammu, India. AB - Eighty two samples of dried quince seeds, obtained from the markets of Jammu province, were examined for mycoflora by different isolation techniques. A total of 27 fungal species belonging to 11 genera were recovered and identified from these samples. The predominant fungal genera encountered were Aspergillus, Penicillium and Fusarium. In view of the predominance of Aspergillus flavus, a known producer of aflatoxins, screening of the fungal contaminated samples was carried out for total aflatoxin levels using high performance liquid chromatography (HPLC). Twenty one aflatoxin positive samples contained 8.07-33.45 MUg g(-1) and 0.05-3946.97 MUg g(-1) AFB1 and AFB2 respectively. These results suggest that biochemical composition of dried quince seeds, along with climatic conditions of the region seem to be very favourable for aflatoxin production by toxigenic strains of A. flavus. Therefore, monitoring of aflatoxins in dried quince seeds is recommended for this region. PMID- 26930867 TI - Effects of drought stress on growth, solute accumulation and membrane stability of leafy vegetable, huckleberry (Solanum scabrum Mill.). AB - The present study sought to investigate the factors implicated in growth impairment of huckleberry (a leafy vegetable) under water stress conditions. To achieve this, seedlings of plant were subjected to control, mild stress and severe stress conditions for 30 days. Plant growth, plant water relation, gas exchange, oxidative stress damage, electrolyte leakage rate, mineral content and osmolyte accumulation were measured. Water deficit markedly decreased leaf, stem and root growth. Leaf photosynthetic rate was tremendously reduced by decrease in stomatal conductance under stress conditions. Malondialdehyde (MDA) content markedly increased under mild (82%) and severe (131%) stress conditions, while electrolyte leakage rate (ELR) increased by 59% under mild stress and 3-fold under severe stress. Mineral content in leafwas high in stressed plants, while proline content markedly increased under mild stress (12-fold) and severe stress (15-fold), with corresponding decrease in osmotic potential at full turgor and an increase in osmotic adjustment. These results suggest that maintenance of high mineral content and osmotic adjustment constitute important adaptations in huckleberry under water deficit conditions and that growth depression under drought stress would be mainly caused by increased electrolyte leakage resulting from membrane damage induced by oxidative stress. PMID- 26930868 TI - Irrigational impact of untreated and treated brewery-distillery effluent on seed germination of marigold (Tagetes erecta L.). AB - Current study presents the effect of irrigation with different concentrations (20, 40, 60, 80 and 100%) of untreated and treated brewery-distillery effluent on germination behaviour of marigold (Tagetes erecta L. var. Pusa Basanti). The 100% untreated effluent showed acidic pH (4.80) and higher values of BOD (1500.00 mg l(-1)), COD (4000.00 mg l(-1)), chloride (1742.20 mg l(-1)), TSS (900.00 mg l( 1)) as compared to that of treated effluent. Tagetes seeds were exposed to different concentrations of effluent and the results revealed maximum values of germination parameters viz., percent germination, peak value, germination value, germination index, speed of germination and vigour index at 20% untreated and 60% treated effluent concentrations, whereas the values for negative germination parameters viz., delay index, germination period and percent inhibition were minimum at 20% untreated and 60% treated effluent concentrations. PMID- 26930869 TI - Comparative study on oviposition and larval preference of spotted bollworm, Earias vittella on Bt and non-Bt cotton. AB - Oviposition and larval preference of spotted bollworm, Earias vittella (Fabricius) was assessed on four transgenic Bt cotton hybrids, viz. MRC 6304 Bt (cry1Ac gene), JKCH 1947 Bt (modified cry1Ac gene), NCEH 6R Bt (cry1Ab/cry1Ac fused gene) and MRC 7017 BG II (cry1Ac and cry2Ab genes) in comparison to the respective isogenic cotton. The results showed that Bt toxin did not deter oviposition preference of E. vittella moths as there was no significant difference in the number of eggs laid on squares/bolls of Bt and non-Bt cotton hybrids, across different crop growth stages. There was also no behavioral change in larval preference with respect to selecting non-Bt cotton in comparison to Bt cotton. Floral bodies from Bt and the respective isogenic cotton genotypes were equally preferred by both first and third instar larvae after 24 hrs indicating that initial selection was independent of susceptibility to Bt toxin. However, E. vittella larvae showed significant difference in preference for different cotton genotypes. Studies on the relative preference indicated that third instar larvae had greater preference for bolls (7.29-7.50%) than for the squares (5.0-5.21%) and reverse was true for the first instar larvae which showed greater preference for squares (7.08-7.29%) than for the bolls (5.21-5.42%), in a multiple-choice test. It may be concluded that oviposition and larval preference of E. vittella did not differ significantly between Bt and isogenic non-Bt cotton genotypes. PMID- 26930871 TI - Isolation and identification of Trichoderma harzianum from groundwater: An effective biosorbent for defluoridation of groundwater. AB - The ability of non-viable form of Trichoderma harzianum, isolated from fluoride rich groundwater, was investigated as biosorbent for defluoridation of groundwater. Biosorption experiments were carried out at laboratory scale for removal of fluoride from groundwater. Significant effect of operational parameters on fluoride biosorption using Trichoderma harzianum as biosorbent was evaluated by varying operational parameters such as: initial fluoride concentration (2-8 mgl(-1)), biosorbent dose (0.4-1.6g/100ml), groundwater pH (6 10), temperature (30-50 degrees C) and biosorption time (30-120 min). The fluoride adsorption isotherms were modeled by Langmuir and Freundlich isotherms. Our result showed that fluoride biosorption, significantly increased with increase in groundwater pH, biosorbent dose, temperature and biosorption time, whereas increase in initial fluoride concentration reduced fluoride removal. The fluoride biosorption was rapid and maximum fluoride uptake was attained with 1.6g 100ml(-1) biosorbent within 60 min. Optimal pH 10 and temperature 50 degrees C gave maximum defluoridation efficiency. Freundlich isotherm fits well for defluoridation of groundwater using Trichoderma harzianum as biosorbent which indicated that biosorbent surface sites were heterogeneous in nature and fitted into heterogeneous site binding model. PMID- 26930870 TI - Studies on antimicrobial activity of Poncirus trifoliata ethyl extract fraction against methicillin-resistant Staphylococcus aureus and to elucidate its antibacterial mechanism. AB - Traditional medicinal plants contain a wide variety of chemicals that have potent antibacterial activity. To find an alternative agent of overcoming the problems of methicillin-resistant Staphylococcus aureus (MRSA), the antibacterial mechanism of Ponciruss trifoliata against MRSA was investigated. Ethyl acetate (EtOAc)-soluble extract of P. trifoliata methanolic extract was evaluated for antibacterial activity using minimum inhibitory concentration (MIC). An EtOAc sub fraction 08 (EA08) from silica-gel open column chromatography exhibited strong anti-MRSA activity. Apart from the study to isolate single compound from EA08, a synergistic antibacterial effect between the sub-fraction and beta-lactam antibiotics against MRSA was determined. In order to elucidate the antibacterial restoring mechanism of EA08 on MRSA, mRNA expression of mecA gene and production penicillin-binding protein 2a (PBP2a) encoded by mecA gene were monitored. EA 08 showed the strongest antibacterial activity with MIC value of 256 MUg ml(-1). MIC of oxacillin against MRSA was dramatically reduced from 512 to 16 MUg ml(-1) in combination with 256 MUg ml(-1) of EA08. The fractional inhibitory concentration index of oxacillin was measured at 0.53 in combination with EA08 against MRSA, suggesting that EA08-oxacillin combinations exert synergetic effect against MRSA. The analysis of RT-PCR and Western blotting profiles revealed that EA08 inhibited mRNA expression of mecA gene and production PBP2a, which is a key determinant for beta-lactam antibiotic resistance, in a dose-dependent manner. These results indicated that EA08 eventually led to the reduction or inhibition of PBP2a production through translational inhibition in MRSA. PMID- 26930872 TI - Evaluation of pollen germination of some palm males and pollination impact on bunch weight and fruit quality in Kadary date palm cultivar (Phoenix dactylifera L.). AB - The present study was carried out during two successive seasons (2013-2014) at the Research and Agriculture Experiment Station, Dirab, College of Food and Agricultural Sciences, King Saud University, Riyadh. Pollen grains, used in this trial, were collected from eleven male, namely Succary, Menify, Sallag, Dikhiny, Nabout Zamel, Serry, Khalas, Shagra, Safry, Maktumi and Kadary in order to pollinate female Kadary date palm cultivar. Results indicated that pollens of Safry male followed by Succary, Menify and Serry males increased the physical and biochemical characteristics of fruits during both seasons. Also, all the studied characters were significantly affected with different pollen males used in this trial. Pollens of Safry male gave highest fruit retention and bunch weight and best fruit quality like fruit and flesh weight, fruit size and fruit length and fruit biochemical properties as compared with other male. In vitro pollen germination of eleven males was studied using various concentration of sucrose (4, 6, 8 and 10%). The results showed that best germination was achieved with 8% sucrose concentration; however, 10% sucrose resulted in reduced percentage of pollen germination. In addition, pollen tube growth of five males (Succary, Sallag, Nabout-Zamel, Khalas and Safry) at 8% sucrose was alsostudied at 2, 4, 6 and 24 hr time interval. Elongation rate of pollen tube increased significantly after 24 hrs and it was found that pollens of Safry male gave highest pollen tube growth after 24 hrs than pollens of other male. PMID- 26930873 TI - Effect of organic manure and inorganic fertilizer on the growth and proximate composition of common carp, Cyprinus carpio. AB - The experiment was conducted to evaluate the effect of chicken manure and inorganic fertilizer (single super phosphate and urea) on growth performance viz. increase in wet body weight, length, specific growth rate (SGR), condition factor (CF), survival rate and proximate composition of Cyprinus carpio. Experimental water in tubs was treated in duplicates with low (PT) @8000 kgha , medium (PT2) @10,000 kgha(-1) and high (PT) @12,000 kg/ha doses of chicken manure and also with low, medium and high dose of inorganic fertilizer(urea + SSP) @ 104 kgha(-1) + 155 kgha(-1) (IT(1)), @218 kgha(-1) + 310 kg/ha (IT2) and 322 kgha(-1) +470 kgha(-1)(IT3) respectively, along with control. At the end of the experiment, C. carpio showed maximum growth in PT, with significant higher SGR and CF. Survival rate ranged beween 93.3 to 100 % in all the treatments. Level of crude protein and total fat were a2so highest in PT, Moisture and carbohydrate showed no significant changes while ash content changed significantly in all the treatments and control. These observations indicate that chicken manure alone was effective to stimulate productivity and growth of fish without affecting proximate composition of fish meat. PMID- 26930874 TI - The development of ecological environment in China based on the system dynamics method from the society, economy and environment perspective. AB - The harmonious development in society, economy and environment are crucial to regional sustained boom. However, the society, economy and environment are not respectively independent, but both mutually promotes one which, or restrict mutually complex to have the long-enduring overall process. The present study is an attempt to investigate the relationship and interaction of society, economy and environment in China based on the data from 2004 to 2013. The principal component analysis (PCA) model was employed to identify the main factors effecting the society, economy and environment subsystems, and SD (system dynamics) method used to carry out dynamic assessment for future state of sustainability from society, economy and environment perspective with future indicator values. Sustainable development in China was divided in the study into three phase from 2004 to 2013 based competitive values of these three subsystems. According to the results of PCA model, China is in third phase, and the economy growth is faster than the environment development, while the social development still maintained a steady and rapid growth, implying that the next step for sustainable development in China should focus on society development, especially the environment development. PMID- 26930875 TI - Effect of calcium carbonate on cadmium and nutrients uptake in tobacco (Nicotiana tabacum L.) planted on contaminated soil. AB - In the present study, calcium carbonate (CaCO3) was applied to Cd-contaminated soil at rates of 0, 0.5 and 1.0 g kg(-1). The effect of CaCO3 on soil pH, organic matter, available Cd, exchangeable Cd and level of major nutrients in a tobacco field and on accumulation of various elements in tobacco plants was determined. The results showed that CaCO3 application significantly increased the pH level, available P and exchangeable Ca but decreased organic matter, available Cd, exchangeable Cd, available heavy metals (Fe, Mn, Zn and Cu) and available K in soil. Additionally, CaCO3 application substantially reduced Cd accumulation in tobacco roots, stems, upper leaves, middle leaves and lower leaves, with maximum decrease of 22.3%, 32.1%, 24.5%, 22.0% and 18.2%, respectively. There were large increase in total Ca and slight increases in total N and K but decrease to varying degrees in total Fe, Cu and Zn due to CaCO3 application. CaCO3 had little effect on total P and Mn levels in tobacco leaves. PMID- 26930876 TI - Editorial. PMID- 26930877 TI - The origins and nature of acupuncture in dentistry. AB - A description is given of the origins and different types of acupuncture. The historical origins and their application in dentistry are discussed. PMID- 26930878 TI - Memories of being a dental student in Liverpool Dental Hospital and School 1962 1966. AB - Recollections of being an undergraduate dental student in Liverpool during the 1960s. PMID- 26930879 TI - The bicentenary of the birth of Sir John Tomes. AB - John Tomes was initially destined for a career in medicine but after being introduced to dental histology, changed careers and gave the first series of lectures on dentistry in Middlesex Hospital. His early academic career resulted in four major papers on the structure of teeth and bone that were read before the Royal Society, establishing his reputation as a leading histologist. He was awarded an FRS at the age of 35. The last 40 years of his life were devoted to establishing dentistry as a regulated profession with the founding of a dental hospital, examinations undertaken by the Royal College of Surgeons, a dental register and regulation by the British Dental Association. He was knighted in 1886. The bicentenary of his birth was recognised with the restoration of his grave. PMID- 26930880 TI - Discussing a Forensic Dental Examination of 1861--A Scientific and Historic Overview. AB - This work is a discussion on a report of dental examination and exclusion made by a British dentist Francis Robertus Lloyd on 30th April 1861. The report entitled: 'Dentistry as a means of Identification' was published in the 'British Journal of Dental Science' under the section 'Miscellanea' in 1861; Mr. Lloyd was contacted by the Indian authorities in order to identify a skull. He may well be the first British dentist to officially report a dental examination in an academic journal. The aims of this discussion are to briefly analyze the difficulties of access to scientific techniques in that century and to provide Mr. Lloyd recognition of his report in the history of Forensic Dentistry. PMID- 26930881 TI - Sair teeth-the hell o'a' diseases. AB - A discussion of a poem about toothache, written in Scots and published in 1917 and a comparing it to Robert Burns' Address to the Toothache. PMID- 26930882 TI - A short account of forensic dentistry in France. AB - The earliest records and more recent cases where forensic dentistry has been used to identify bodies in France are described. The establishment of the French Society of Forensic Odontology is detailed. PMID- 26930883 TI - How visible light curing came into dentistry. AB - The present paper details the history of the introduction of visible light curing into dentistry. This history provides an excellent example of 'out of the box', lateral thinking translation of innovative scientific technology into dentistry. Visible light curing is an important UK contribution to the recent history and current practice of dentistry, with several million visible light curing procedures being carried out globally on a daily basis. PMID- 26930884 TI - Malaria in Papua New Guinea 2000-2013: back from the brink, but where to now? PMID- 26930885 TI - Evaluation of the Global Fund-supported National Malaria Control Program in Papua New Guinea, 2009-2014. AB - The Global Fund to Fight AIDS, Tuberculosis and Malaria is the major funaer Of the National Malaria Control Program in Papua New Guinea (PNG). One of the requirements of a Global Fund grant is the regular and accurate reporting of program outcomes and impact. Under-performance as well as failure to report can result in reduction or discontinuation of program funding. While national information systems should be in a position to provide accurate and comprehensive information for program evaluation, systems in developing countries are often insufficient. This paper describes the five-year plan for the evaluation of the Global Fund Round 8 malaria grant to PNG (2009-2014) developed by the Papua New Guinea Institute of Medical Research (PNGIMR). It builds on a complementary set of studies including national surveys and sentinel site surveillance for the assessment of program outcomes and impact. The PNGIMR evaluation plan is an integral part of the Global Fund grant. The evaluation program assesses intervention coverage (at individual, household and health facility levels), antimalarial drug efficacy, indicators of malaria transmission and morbidity (prevalence, incidence), and all-cause mortality. Operational research studies generate complementary information for improving the control program. Through the evaluation, PNGIMR provides scientific expertise to the PNG National Malaria Control Program and contributes to building local capacity in monitoring and evaluation. While a better integration of evaluation activities into routine systems would be desirable, it is unlikely that sufficient capacity for data analysis and reporting could be established at the National Department of Health (NDoH) within a short period of time. Long-term approaches should aim at strengthening the national health information system and building sufficient capacity at NDoH for routine analysis and reporting, while more complex scientific tasks can be supported by the PNGIMR as the de facto research arm of NDoH. PMID- 26930886 TI - A qualitative study of how affected individuals or their caregivers respond to suspected malaria infection in rural Papua New Guinea. AB - This paper presents findings from a qualitative study that sought to identify the ways in which affected individuals or their caregivers respond to a suspected malaria infection and to illuminate the rationale underlying the decision-making process. In-depth interviews (IDIs) were conducted with a sub-sample (n = 44) of participants in a country-wide household survey who reported experiencing, or caring for someone who experienced, a suspected malaria infection in the two weeks before the survey. All IDIs were completed between March and July 2011. Analysis was informed by a general inductive methodology. The most commonly reported response involved the use of antimalarial medication and some form of traditional remedy prepared in the home. Reported treatment responses were frequently consistent with a stepped-care approach to disease management, the first step of which was characterized by convenience and was often relatively generic in nature. Seeking assistance from a formal health care provider was the exception amongst study participants, with fewer than half attending a health facility during the target illness episode. A number of barriers to health service access were reported; however, a range of other factors contributed to the decision not to seek formal health care such as perceived severity of illness, positive past experiences using home-based treatments and the aforementioned preference for utilizing convenient 'treatment' options in the first instance. Traditional healers were rarely considered an appropriate treatment option for malaria. PMID- 26930887 TI - The proportion of fevers attributable to malaria varies significantly between sites in Papua New Guinea. AB - Malaria is endemic across lowland Papua New Guinea (PNG) and case management has been based on symptomatic diagnosis and presumptive treatment of fever cases with an antimalarial. This study aimed to investigate the prevalence of malaria infection among fever cases presenting to 5 purposely selected sentinel health facilities in order to estimate the proportion of patients requiring antimalarial drugs. A total of 1807 fever patients were screened. Overall, 45% of fever patients had a positive malaria blood slide; 35% were infected with Plasmodium falciparum, 9% with P. vivax and 2% with P. malariae. Slide positivity was highest in Dreikikir (75%) and lowest in Wipim (2%). Among patients aged 1-4 years, 22% had moderate to severe anaemia (Hb < 8 g/dI) and 21% of children 2-9 years of age showed signs of splenomegaly (Hackett score 1-5). Comorbidity differed significantly between study sites and was not closely correlated with malaria infection. Clinical diagnosis by health facility staff was malaria for 67% of all fever cases, including 89% of slide-positive and 48% of slide-negative patients. 70% of rapid diagnostic test-negative cases were treated with an antimalarial. It is estimated that due to the lack of parasitological diagnosis the selected health facilities reported an excess of 18% (Dreikikir) to 98% (Wipim) malaria patients on average each month. In consideration of the significant differences in malaria-attributable fevers between study sites, the implementation of parasitological diagnosis in health facilities and administration of antimalarials only to test-positive patients has the potential to significantly improve the management of fever cases and reporting of malaria. A better tailoring to different settings may increase the effectiveness of malaria control interventions. PMID- 26930888 TI - An investigation into febrile illnesses of unknown aetiology in Wipim, Papua New Guinea. AB - In Papua New Guinea the aetiology of febrile illnesses remains poorly characterized, mostly due to poor diagnostic facilities and the inaccessibility of much of the rural areas of the country. We investigated the aetiological agents of febrile illnesses for 136 people presenting to Wipim Health Centre in Western Province, Papua New Guinea. Arboviral and rickettsial real-time polymerase chain reaction (PCR) assays, malaria blood smears and a malaria PCR test were used to identify pathogens associated with a history of fever. In 13% (n = 18) of cases an aetiological agent was identified. Dengue virus type 1 was detected in 11% (n = 15) of the samples tested and malaria in 2% (n = 3). None of the other arboviral or rickettsial pathogens tested for were detected in any of the samples. Although dengue viruses have been identified in Papua New Guinea using serological methods, this study represents the first direct detection of dengue in the country. The detection of malaria, on the other hand, was surprisingly low considering the previous notion that this was a hyperendemic region of Papua New Guinea. PMID- 26930889 TI - Diagnostic capacity and antimalarial availability in Papua New Guinea before the introduction of a revised national malaria treatment protocol. AB - BACKGROUND: Papua New Guinea (PNG) introduced a revised national malaria treatment protocol (NMTP) in late 2011. Successful implementation of the revised protocol requires all health facilities in PNG to have reliable access to microscopy or malaria rapid diagnostic kits as well as a reliable supply of all recommended first-line medications. This paper presents findings from a study that sought to assess the availability of microscopy, malaria rapid diagnostic kits and recommended first-line antimalarial medication in Papua New Guinean health facilities across the country before the introduction of the revised treatment protocol. METHODS: A country-wide cross-sectional survey of 79 randomly selected health centres, health subcentres and aid posts. Data were collected via an interviewer-administered questionnaire completed with the officer in charge of participating health facilities. RESULTS: Overall, 15% of surveyed health facilities had unexpired rapid diagnostic test (RDT) in stock or working microscopy available. A recommended first-line antimalarial for uncomplicated malaria was available in 85% of health facilities. The preferred first-line antimalarial combination for treating severe malaria was present in 42% of health facilities, although 68% had the capacity to provide either the preferred or recommended substitute first-line medication for severe malaria. The total number of health workers employed in the 79 surveyed health facilities was 443, only 3 of whom were medical doctors. CONCLUSIONS: Our findings indicate that diagnostic capacity was low in Papua New Guinean health facilities before the introduction of the new NMTP and that access to recommended first-line antimalarial medication was variable. Substantial improvements in diagnostic capacity and antimalarial procurement and distribution will need to be made if the revised protocol is to be adhered to. PMID- 26930890 TI - Primaquine treatment for Plasmodium vivax--an essential tool for malaria control and elimination in Papua New Guinea. AB - Plasmodium vivax is a major cause of malarial infection and disease in young children in Papua New Guinea. Recent increase in funding for malaria control has improved accessibility to preventive measures, diagnosis and artemisinin combination therapies. Yet the current treatment and control measures are more effective against P. falciparum than against P. vivax and P. ovale due to the biological differences in the liver stage life-cycle of these parasites. P. vivax and P. ovale have a dormant liver stage called a hypnozoite. The artemisinin combination therapies, while highly effective against the blood stages of all plasmodium species causing human malarial illness, have no effect upon the hypnozoites in the liver and the stage V gametocytes of P. falciparum. Currently, primaquine is the only licensed drug shown to be effective against both the hypnozoites of P. vivax and P. ovale in the liver and the stage V gametocytes of P. falciparum. Primaquine has a high associated risk of life-threatening haemolytic anaemia when administered to glucose-6-phosphate dehydrogenase (G6PD) deficient persons. The lack of cheap, reliable point-of-care testing for the diagnosis of G6PD deficiency remains a major obstacle to the widespread use of primaquine in clinical and public health practice. Furthermore, there is a paucity of primaquine safety and tolerability data, especially in young children with the highest P. vivax disease burden. For malaria control and elimination efforts to be effective, interventions such as mass drug administration must include primaquine. This opinion paper highlights the need to eradicate hypnozoites in the liver of the human host with primaquine treatment for radical cure of malarial illness and discusses the challenges in the use of primaquine as a public health tool for malaria control and elimination programs in countries such as Papua New Guinea. PMID- 26930891 TI - How molecular epidemiology studies can support the National Malaria Control Program in Papua New Guinea. AB - Papua New Guinea (PNG) is undertaking intensified efforts to control malaria. The National Malaria Control Program aims to reduce the burden of disease by large scale distribution of insecticide-treated bednets, improved diagnosis and implementation of new treatments. A scientific program monitoring the effect of these interventions, including molecular epidemiology studies, closely accompanies the program. Laboratory assays have been developed in (or transferred to) PNG to measure prevalence of infection and intensity of transmission as well as potential resistance to currently used drugs. These assays help to assess the impact of the National Malaria Control Program, and they reveal a much clearer picture of malaria epidemiology in PNG. In addition, analysis of the geographical clustering of parasites aids in selecting areas where intensified control will be most successful. This paper gives an overview of current research and recently completed studies in the molecular epidemiology of malaria conducted in Papua New Guinea. PMID- 26930892 TI - Long-lasting insecticidal nets remain efficacious after five years of use in Papua New Guinea. AB - Long-lasting insecticide-treated nets (LLINs) have been distributed throughout Papua New Guinea since 2004 as part of the country's malaria control program. This study aimed to evaluate the efficacy of these used bednets over time and with respect to the various household factors related to their use in order to enable the National Department of Health to maximize on the benefits of LLINs. In 2008 and early 2009, used LLINs (0-9 years old) were collected in various villages in Papua New Guinea as part of the Global Fund to Fight AIDS, Tuberculosis and Malaria (GFATM)-supported National Malaria Control Program and data were collected on net usage. A subset of the nets were tested for residual insecticide content. Net efficacy was measured by the rate of knockdown of Anopheles farauti s.s. following exposure to LLINs using the World Health Organization cone bioassay. Optimal effectiveness (> 95% knockdown 1 hour post exposure) was observed in 92% of the LLINs. A slight reduction in efficacy was observed after two years of household use and there was a significant relationship between the number of years in use and percent knockdown (p < 0.001) as well as deltamethrin concentration (p < 0.001). Washing of nets was not associated with a reduction in deltamethrin concentration, but drying them in the sun was (p = 0.008). The physical conditions of these nets also degraded over time with a significant increase in the number of large holes after 5 years (p = 0.02). These findings are in support of the current recommendation to replace LLINs after five years of use, and demonstrate that proper net care can extend the length of efficacy. PMID- 26930893 TI - Missing in the line of duty. PMID- 26930894 TI - Dr Adolf Saweri MBE, MD (Hon, UPNG), Dip Med & Surg (PMC), DTM&H (Liverpool). PMID- 26930895 TI - Adolf Saweri (28 Jul 1941 - 11 Nov 2012). PMID- 26930896 TI - In celebration of Adolf Saweri. PMID- 26930897 TI - Adolf Saweri. PMID- 26930898 TI - Dr Adolf Saweri--an inspirational academic, researcher and mentor. PMID- 26930899 TI - A brief personal reflection on Adolf Saweri. PMID- 26930900 TI - Adolf Saweri: a tribute. PMID- 26930901 TI - Celebration of Adolf's life. PMID- 26930902 TI - [Related factors analysis of spontaneous cerebrospinal fluid leak recurrence after endoscope operation]. AB - OBJECTIVE: To Summarize and analyze the clinical characteristics and treatment of patients with spontaneous cerebrospinal fluid rhinorrhea, and to explore the related factors of recurrence. METHOD: Retrospective- ly analyze the clinical data of 58 patients of spontaneous cerebrospinal fluid rhinorrhea from July 2002 to July 2012, combined with its clinical characteristics, and statistically analyze the related recurrence factors. RESULT: Fifty-eight cases were accepted the nasal endoscopic repairment of cerebrospinal fluid rhinorrheak, follow-up 3 years, 20 cases (34.5%) recurred, 1 case recurred in half a year after operation. In the first year, there were 10 cases recurred. In the second year there were 9 cases recurred, and 1 case recurred in the third year. Through multiariable analysis it was found that higher BMI, empty sella and skull base bone defect were the independent risk factors influencing the recurrence of spontaneous cerebrospinal fluid rhinorrhea (P < 0.05). CONCLUSION: The recurrence rate of spontaneous cerebrospinal fluid rhinorrhea is high, needing long-term follow-up. Higher BMI, empty sella, skull base bone defect are independent risk factors of recurrence of the disease, and the treatment should be individualized. PMID- 26930903 TI - [Clinical analysis of patients with sphenoid sinus mucocele and literature review]. AB - OBJECTIVE: Aimed to analyse the clinical features of the patients with sphenoid sinus mucocele, achieve earlier diagnosis and more timely intervention and decrease the occurrence of misdiagnoses. METHOD: A retrospective study was first conducted in patients with sphenoid sinus mucoele treated in Xiangya hospital from Jan 2000 to Jan 2015. Then literature reports on this disease were collected and analyzed from China National Knowledge Infrastructure (CNKI) and Wan Fang database. RESULT: We collected 82 patients with sphenoid sinus mucocele treated in Xiangya hospital. There were 52 patients presented with headache, 31 patients presented with visual impairment, 10 patients presented with cranial nerve palsy, 2 patients presented with exophthalmos, 15 patients presented with nasal symptoms, and 5 patients with no obvious symptoms. There was no significant difference for symptoms distribution between male and female patients (P > 0.05). Among 45 patients with headache as first symptom and 10 patients with ethmoid sinus mucocele, there were 18 patients and 8 patients subsequently suffering from visual impairment, respectively. We also collected 161 patients in literature except for enrolling, the 82 patients treated in Xiangya hospital, and found that headache was the most common symptom, followed by visual impairment, in the two independent cohorts. CONCLUSION: To the best of our knowledge, this is the study of maximum sample for sphenoid sinus mucocele in China. Headache and visual impairment are the most common symptoms for sphenoid sinus mucocele. Surgical treatment should be early performed when the desease accompanied with headache or ethmoid sinus mucocele, to avoid other complications such as visual impairment and even blindness. PMID- 26930904 TI - [The analysis of correlation between tongue body MRI and upper airway pressure measurements of blocked lingual region in patients with moderate and severe OSAHS]. AB - OBJECTIVE: To investigate the correlation between tongue body MRI measurements and the lingual region obstruction in patients with obstructive sleep apnea hypopnea syndrome (obstructive sleep apnea hypopnea syndrome, OSAHS), and the relationship of two diagnosis methods in positioning obstructive level, in order to improve the preoperative diagnostic accuracy of obstructive level in OSAHS patients . METHOD: Fifty-nine patients with OSAHS definited by the AG200 sleep apnea monitoring and obstruction plane positioning system was included. They all underwent tongue MRI scan, after three-dimensional reconstruction, the tongue body length to diameter, relative thickness, basal diameter, wide around central about wide diameter and tongue body volume were measured. The lower blocking (mainly composed of lingual region) constituent ratio P established by AG200 was correlated with tongue parameters measured by MRI. At the same time, To analysis of differences of P in patients with different degree of OSAHS. RESULT: Among these patients with OSAHS in different degree, the coefficient correlation between tongue parameters(tongue length, relative thickness, basal diameter, wide middle diameter, tongue body volume) and lower blocking constitute ratio P werer LP = 0.051,rHP = 0.069, r1 = 0.215, r2 = 0.147, rVP = 0.259, respectively. lower obstruction of form than the differences had statistical significance. The measured tongue parameters and value P(the lower blocking constituent ratio) were negatively correlated, which demonstrated that exclusing of the larynx and hypopharynx airway obstruction, the lower airway obstruction detected by AG200 was related with tongue parameters measured by MRI, and was strongestly related with the tongue body volume. CONCLUSION: The volume of tongue and AG had correlation in judgement of lower blocking. In OSAHS patients the lower blocking constituent ratio varies between the defferent severity groups of the disease, the combina tion of the two method can be used to predict the obstructive plane in OSAHS patients with upper airway obstruction, and provide the basis for the individual treatment of patients with OSAHS. PMID- 26930905 TI - [Short-term efficacy and factors of specific immunotherapy on patients with allergic rhinitis]. AB - OBJECTIVE: To evaluate the short-term efficacy and investigate the factors of specific immunotherapy (SIT) efficacy of allergic rhinitis. METHOD: Fifty-seven patients with allergic rhinitis to dermatophagoides pteronysinus were included to receive SIT. Pair t-test was used to compare the symptom scores, visual analogue scores (VAS) and medication scores in patients before SIT and into maintain treatment statement to evaluate the clinical efficacy. T-test and Spearman correlation analysis were used to analyze the correlation between gender, age,reaction condition of skin prick test (SPT) and serum sIgE and the efficacy of SIT. RESULT: SIT was able to significantly reduce the symptom scores, VAS and medication scores. But the correlation between gender, age, SPT, and sIgE and theefficacy of SIT were not significant. CONCLUSION: SIT is effective in the short-term treatment of AR. Further research is needed to investigate the factors that impact the efficacy of SIT. PMID- 26930906 TI - [Clinical study on efficacy of nasal surgical expansion as a basic operation in treatment of patients with OSAHS]. AB - OBJECTIVE: To observe the clinical effect of nasal surgical expansion as basical surgical treatment of patients with OSAHS. METHOD: A total of 320 patients with OSAHS were retrospectively analyzed. The patient was diagnosed by PSG. The electronic nasopharyngolarygnoscope exam airway CT, and MRI were applied to determining the nasal plane block. According to the concrete reasons, the nasal endoscopic nasal septum corrective surgery and open surgery were carried out, respectively. Nasal sinus neoplasm resection of off shoring, inferior turbinate fracture surgery or inferior turbinate back-end 1/3 line expansion and low temperature plasma ablation of nasal surgery, respectively. Pittsburgh sleep quality index (PSQI), snore outcome survey (SOS), epworth sleepiness score (ESS), the lowest arterial oxygen saturation (LSaO2) and AHI, time and ratio of slow wave sleep (SWS) stage and rapid eye movement (REM) stage were applied to comparing the curative effect between pre-operation and post-operation periods. RESULT: Snoring, sleep apnea, subjective mental symptoms of all patients with OSAHS were improved after operation; PSQI, SOS and ESS score were improved compared to pretreatment (P < 0.05); according to the 2009 OSAHS diagnosis and curative effect evaluation standard, 38 cases cured, 189 cases had obvious effect, 93 cases effective, and the total effective rate was 100%; there was statistical difference between the pre-operative period and 6 months post operative in PSQI, SOS and ESS, LSaO2, AHI and proportion of REM (P < 0.05); sleep structure was improved, time and proportion of SWS were increased after the operation (P < 0.05). CONCLUSION: Solving the problem of nasal airway obstruction is the first step in surgical treatment of patients with OSAHS. PMID- 26930907 TI - [Changes in small airway function in rhinitis without asthma]. AB - OBJECTIVE: Observe the changes of small airway function in patients with rhinitis but without asthma and/or lower airway symptoms. METHOD: Between June 2008 and December 2012, we recruited 903 subjects, including 377 with allergic rhinitis (AR), 262 with non-allergic rhinitis (NAR) and 264 healthy subjects. All subjects underwent meticulous history taking, nasal examination, allergen skin prick test, blood routine test, serum total immunoglobin E assay, pulmonary ventilation function test and bronchial challenge test. RESULT: The indices of FEV1/FVC%, MEF25pred% and MMEFpred% were lower in AR group than in the control group (P < 0.05). The indices of FEV1/FVC, MMEFpred%, MEF25pred% and MEF50pred% were also lower in NAR group than in the control group (P < 0.05). According to the FVCpred% and FEV1pred%, there were no differences between rhinitis group and the control group (P > 0.05). The positive rate of airway hyperresponsiveness(AHR) in AR group and in NAR group was 12.2%, 6.1% respectively. Indices of small airway function were all lower in the AHR group than NAHR group in rhinitis. CONCLUSION: Compared with healthy controls, small airway function in patients with rhinitis has apparent changes, part of rhinitis patients has AHR, and is associated with small airway function changes. PMID- 26930908 TI - [Meta-analysis of The olfaction effectiveness of glucocorticoid in the management of chronic rhinosinusitis with nasal polyposis]. AB - OBJECTIVE: To evaluate the effectiveness of glucocorticoid in the management of olfaction in patients with chronic rhinosinusitis accompanied with nasal polyposis. METHOD: The published studies of the effectiveness of glucocorticoid in the management of chronic rhinosinusitis with nasal polyposis were searched in the Medline, Cochrane, EMBASE, Springer and CNKI databases(from the date of establishment of the databases to December 2014). The trails selection based on inclusion criteria and the quality of the included studies was assessed and meta analysis was performed with RevMan 5. 3 software. RESULT: A total of 5 trials involving 325 patients were included. The Meta-analysis showed that oral glucocorticoid showed more significant improvement in subjective olfaction scores compared to placebo [SMD = -2.22, 95% CI (-3.94 - -0. 49), P < 0.05], oral glucocorticoid also showed significant improvement in objective olfaction scores compared to placebo [SMD = 0.65, 95% CI (0.28-1.01), P < 0.05]. But subsequent use of nasal glucocorticoid had no impact on subjective and objective olfaction scores [SMD = -2.15, 95% CI (-5.67-1.38), P > 0.05], [SMD = 0.28, 95% CI (-0.08 0.64) P > 0.05]. CONCLUSION: According to current evidence, oral glucocorticoid can significantly improve subjective and objective olfaction among patients with CRSwNP, but nasal glucocorticoid cannot improve subjective or objective olfaction dysfunction. PMID- 26930909 TI - [Treatment of recurrent laryngeal papilloma by submucosal resection and the effect on prognosis]. AB - OBJECTIVE: To investigate the efficacy of submucosal resection by CO2 laser in the treatment of recurrent laryngeal papilloma and the effect on prognosis. METHOD: A total of 11 patients diagnosed as recurrent laryngeal papilloma were included in this review. Papilloma was marked before operation and checked under fibro-laryngoscope. Papilloma was resected completely including the submucosal tissure with CO2 laser or microequipment. In widespread papilloma, false membrane in raw surface were cleared 7-10 days after operation. Surgical specimens (including membrane) were detected by routine pathology, HPV typing and immunohistochemical pathologic examination. The patients were checked once a month in the first 3 months after operation, and then once for every 3 months. Once the hoarseness and other symptoms aggravated or the disease was recurrent, the patients were treated immediately. RESULT: HPV viral DNA was found in 10/11 cases, with HPV11 (7/11 cases) and HPV6 (3/11 cases). Cases with regards to follow-up, from 6 months to 1 year, 3 cases were followed up 1 year after operation, without recurrence. Five patients including 2 children were followed up 6 to 12 months after operation, without recurrence. Two children underwent 2 or 3 operations, were followed-up more than 6 months withouting recurrence. CONCLUSION: Papilloma submucosal resection could decrease postoperative recurrence and is worth to be further investigated. PMID- 26930910 TI - [Coblation treatment for laryngopharynx hemangioma]. AB - OBJECTIVE: To evaluate the effect and feasibility of coblation treatment for laryngopharynx hemangioma. METHOD: Retrospectively analyzed 24 cases with coblation treatment for laryngopharynx hemangioma in recent years. RESULT: Twenty four patients were treated with coblation, follow-ups range 6 months to 24 months after surgry. Recurrence occurred in 2 months after surgry in one patient who was cured with coblation for second time. There was incomplete vocal cord paralysis in another patient because of wide range angeioma. CONCLUSION: Coblation treatment for laryngopharynx hemangioma was an ideal way to less bleeding, less damage and more clearfield of vision. PMID- 26930911 TI - [Analysis of risk factors for emergence agitation in adults undergoing general anesthesia for nasal surgery]. AB - OBJECTIVE: To identify the incidence and the risk factors for emergence agitation (EA) in adults undergoing general anesthesia for nasal surgery. METHOD: We examined 674 patients aged >= 18 years who underwent general anesthesia for nasal surgery between February 2013 and February 2015. The patients were divided into control group (518 cases) and EA group (156 cases) by Sedation-agitation scale (SAS) method. Demographic and clinical variables were assessed and the data were analyzed by multiple logistic regression analysis. RESULT: The overall incidence of emergence agitation was 23. 15%. Significant difference was observed between EA and the control group in many aspects, such as sex, age, ASA classify, smoking history, history of cerebrovascular disease, preoperative anxiety, the use of midazolam, anesthesia means, postoperative pain, postoperative analgesia, presence of a tracheal tube, and presence of a urinary catheter. The results of multiple logistic regression analysis indicated that the occurring of EA was significantly correlated with younger age, male, preoperative anxiety, inhalation anesthesia, postoperative pain, presence of a tracheal tube, and presence of a urinary catheter, while seniors, with the use of midazolam, total intravenous anesthesia, analgesia and natural awakening were protective factors. CONCLUSION: EA following general anesthesia is a common complication in patients with adult nasal surgery. To reduce the occurrence and consequences of agitation episodes, elimination of the associated risk factors is necessary, especially in patients with risk factors. PMID- 26930912 TI - [The inhibiting role of recombinant plasmid PGCsi-AQP1 on laryngeal carcinoma in vivo]. AB - OBJECTIVE: To construct a kind of recombinant plasmid PGCsi-AQP1 delivery with DOPC and explore the inhibit effect of laryngeal carcinoma by RNAi targeting AQP1 in vivo. METHOD: Male BALB/c mice, 6 weeks of age transplanted with laryngeal carcinoma cell line Hep-2, four groups were divided randomly: Tail vein injection group (TVIG), Carcinoma around injection group (CAIG), negative control group (NCG) and blank control group (BCG). The recombinant plasmid PGCsi-AQP1 delivery with DOPC were inject into tail vein or surrounding tumor. HE pathological slides and tumor size were observed and inhibitory rate was figured up. The level of AQP1 protein expression and high microvessel density were detected by Immunohistochemical staining (IHC). RESULT: We constructed BALB/c mice models of laryngeal carcinoma successfully (1) HE staining: cell putrescence, nuclear pyknosis and apoptotic bodies were more in the tumor tissues of experimental groups than two control groups. (2) The total volumes of tumor in experimental group were both smaller than in two control groups (P < 0.01). The inhibition rate of TVIG and CAIG were 52.4% and 53.5% respectively and there was no significant difference (P > 0.05). (3) IHC: the AQP1 positive cells and microvessel density in TVIG and CAIG were both less than in two control groups (P < 0.01). CONCLUSION: Neutral lipsomes DOPC could help carriaging the recombinant plasmid PGCsi-AQP1 to tumor and then play an inhibit role in laryngeal carcinoma tissue by RNAi targeting AQP1 in vivo. PMID- 26930913 TI - [Reconstruction of maxillary sinus superior wall fractures with calcium phosphate cement/recombinant human bonemorphogenetic protein 7 compound implanted material in rabbit]. AB - OBJECTIVE: To evaluate the osteogenetic character and repairing maxillary sinus superior wall fractures capability of calcium phosphate cement (CPC) before and after combined with recombinant human bone morphogenetie protein-7(rhBMP-7). METHOD: A 10 mmX5 mm bone defect in the maxillary sinus superior wall was induced by surgery in all 24 New Zealand white rabbits. These 24 rabbits were randomly divided into two groups. The defects were repaired with CPC group (n = 12) and CPC/rhBMP-7 group (n = 12). The osteogenesis of bone defect was monitored by gro'ss observation, histological examination, observation under scanning electron microscope and measurement of ALP activity at 6 and 12 weeks after the implantation. RESULT: In group CPC,new bone was found to form slowly and little by little. In group CPC/rhBMP-7, however, new bone was observed to form early and massively. The ALP activity in group CPC showed significant statistical difference with that of group CPC/rhBMP-7 (P < 0.05). CONCLUSION: The CPC/rhBMP-7 composite has osteoconductibility and osteoinductibility, comparing the use of CPC/rhBMP-7 with CPC for the repair of orbital fracture, the former show obvious advantage repairing ability in maxillary sinus superior wall defect. PMID- 26930914 TI - [Multiple reoperation of recurrent maxillofacial huge dermatofibrosarcoma protuberans]. AB - OBJECTIVE: To Summary the experience of surgical treatment for many times in 1 case of maxillofacial huge dermatofibrosarcoma protuberans. METHOD: The patient was diagnosed with dermatofibrosarcoma protuberans according to the pathological examination. From 2004 to 2011, the patient underwent extensive surgical resection, Mohs micrographic surgery(MMS) and free flap grafting method as surgical treatment for many times, and was closely followed-up after operation. RESULT: The tumor was completely removed in each operation, with wound skin graft survived. But relapse occured repeatedly, recurrence interval was from 7 months up to five years and eight months,recurrence interval gradually extended, all of the recurrence occurred at Mohs microsurgery cut edge. CONCLUSION: Eexpanded resection is the preferred treatment for the early stage maxillofacial huge dermatofibrosarcoma protuberans. For advanced stage tumor, expanded resection should be combined with Mohs microsurgery. Free flap grafting was suggested in primary repair insteading of myocutaneous flap. At the same time, postoperative assistant radiotherapy, strengthen follow-up and early intervention were suggested. PMID- 26930915 TI - [Langerhans cell histiocytosis of the temporal bone in children: 7 cases analysis]. AB - OBJECTIVE: To analyze the clinical manifestations, diagnosis, therapy and prognosis of Langerhans cell histiocytosis (LCH) of the temporal bone in children. METHOD: Seven children with LCH of the temporal bone n our hospital were retrospectively summed up from April 2009 to April 2014. The patients were followed up 1-5 years, their clinical manifestations, imaging findings, diagnosis, therapy and prognosis were studied. Correlation between clinical classifications and prognosis was also analyzed. RESULT: Among the 7 patients, 4 were boys and 3 were girls. 5 cases belonged to the single system group and 2 cases belonged to the multisystem group. The most common clinical characters were temporal tumor, otorrhea, otalgia, hearing loss and granulation of external auditory canal. CT of the temporal bones showed extensive osteolytic destructions with diffuse soft tissure density, without border sclerotization. The cases were. received different therapies. Followed up for 1-5 years, 4 cases were regressive, 1 case kept stable, while 2 cases showed progressive. The two boys then received standard treatment combined steroids with vinblastine. The prognosis in the multisystem group was significantly different from the single system group (P < 0.05). CONCLUSION: The clinical manifestations of LCH vary a lot. The diagnosis is based on histological and immunophenotypic examination of lesion tissue. The main therapy includs surgery, chemotherapy and radiotherapy. The prognosis of the single system group is much better than the multisystem group. PMID- 26930916 TI - [Surgical treatment experience of different approaches in eight cases with parapharyngeal space foreign bodies]. AB - OBJECTIVE: To analyze the surgical treatment of parapharyngeal space foreign body and to discuss feasibility of Endoscopic transoral approach. METHOD: Reviewing surgical treatment in eight cases of parapharyngeal space foreign body, nature and location of foreign body. surgical methods, and treatment results were analyzed. RESULT: Eight patients' foreign bodies were all removed by surgical treatment, there were no postoperative infection. Three cases of foreign body were removed through laterocervical approaches, one removed through submandibular approach. In four cases the foreign body were removed through Endoscopy, two of them were transoral approach and the other two were taken out after antiotomy. CONCLUSION: Different approaches should be taken in the surgery treatment of parapharyngeal space foreign body according to imaging positioning. PMID- 26930917 TI - [Different views on budesonide suspension for inhalation conventional treatment of acute laryngitis in children]. PMID- 26930918 TI - [Children acute sinusitis conservative treatment of orbital cellulitis]. PMID- 26930919 TI - [Kartagener syndrome and papillary thyroid carcinoma: an unusual combination]. AB - A case of a papillary thyroid carcinoma in a patient with situs inversus with associated bronchiectasis and chronic sinusitis (Kartagener's syndrome) is reported. A 61-year-old male patient has the symptoms of nasal obstruction. nasal purulent discharge and headache for 2 years. Physical examination: right nasal purulent in right nasal cavity and multiple lychee-like opaque mass in right middle meatus. A nodule, one centimeter in diameter, locates in the upper pole of right thyroid. Evidence of full situs inversus viscerum can be confirmmed by chest radiographs and ultrasound doppler. Pathology: right nasal polyps, the right small papillary thyroid cancer. TEM Tip primary ciliary dyskinesia. Clinical diagnosis: Kartagener syndrome, papillary thyroid carcinoma (T1a N0 M0, I period), chronic sinusitis-nasal polyps. PMID- 26930920 TI - [Laryngeal polypus at the ventricular band symptomized firstly by hemoptysis: a case report]. AB - Published reports about polyps of larynx at the ventricular bands are extremely rare. The first symptom of this case presents recurrent hemoptysis. The video laryngoscope demonstrated that a smooth-faced and hyperemic polypoid lesion was found in the anterior part of the right false vocal cord, close to laryngeal surface of epiglottis. Postoperative pathological report revealed that the mass was a vascular polyp. PMID- 26930921 TI - [Treatment of postherpetic neuralgia on the right side of nose: a case report]. AB - Postherpetic neuralgia (PHN) is a difficult medical issue and symptomatic treatment with medication is common. One case of PHN was cured by nerve avulsion and microtherm plasma nerve block. The male patient was 48-year-old with PHN on the right side of the nose, suffering recurrent pains within one year. The symptoms occurred irregularly and lasted for several minutes to hours every time. Electroacupuncture and Chinese medicine treatments in other hospitals made little efficacy. Physical examination showed skin of right side of the nose and nasal mucosa was normal and all laboratory reports confirmed negative. After microtherm plasma treatment in nasal cavity and corresponding area of nasal septum, the pain disappeared. PMID- 26930922 TI - [Rhinoscleroma disease accompanied with laryngotracheal stenosis: a case report]. AB - Rhinoscleroma disease accompanied with laryngotracheal stenosis as a main clinical manifestation is seldom. Here one case is reported. At the beginning, the patient had pharyngalgia and his swallowing was not smooth. After that, he had difficulty in breathing. Surgical therapy, antibiotics treatment and nutritional support were performed. The patient was cured. PMID- 26930923 TI - [Benign symmetric lipomatosis (Madelung's disease): four cases report]. AB - Benign symmetrical lipomatosis (BSL), or Madelung's disease, is a rare disease characterized by he progressive growth of diffuse, painless, non-enveloped symmetric lipomas at typical sites in the body. The etiology of this disease remains unknown. A disturbance of lipid metabolism is involved, and there is a proven connection with chronic alcoholism. Problems with the differential diagnosis of the characteristic clinical picture arise from the fact that this disease is not widely recognized. Surgical lipectomy in several sessions can relieve pressure and provide satisfactory patient functional recovery as well as cosmetic disfiguration. PMID- 26930924 TI - [The development of multi-level diagnosis of obstructive sleep apnea hypopnea syndrome]. AB - The obstruction of OSAHS patient is not limited to a single level. These blockages of multiple sites trend to influence each other and participate in a complex process. To date, the determination of obstruction is often depends on empirical judgment of clinician. However, it is a key issue to find out which level of obstruction is most significant. The article will focus on the commonly used values in laboratory examinations and their relationship with AHI. Based on the existing work, we decide to make a comprehensive analysis of their predictive value. PMID- 26930925 TI - [The anatomical research progress of extended endoscopic endonasal approach to the clivus]. AB - The clival region refers to the skull base between dorsum sellae and anterior border of foramen magnum. It is located in central area of skull base and is in close proximity to pons, medulla oblongata, basilar artery and other crucial intracranial structures. Although there are various microsurgical approaches using craniotomy to reach this region, there are still a lot of difficulty in exposure of clivus. With the increasing development in extended endoscopic endonasal approach, a new route to clivus, as well as meticulous endoscopic anatomy studies is emerging. This article reviewed related researches progress of the detailed anatomical studies from endoscopic perspective. PMID- 26930926 TI - [Diagnosis and treatment of schistosomiasis japonica-concensuses among ex- perts in Hunan, Hubei and Jiangxi provinces]. AB - In order to further standardize the diagnosis and treatment of schistosomiasis japonica in China, on the basis of evidence-based medicine, the experts on schistosomiasis control from Hunan, Hubei and Jiangxi provinces summarized their consensuses on the disease after the discussion on the current situation and progress of clinical diagnosis and treatment of schistosomiasis in China, with the reference to the Diagnostic Criteria for Schistosomiasis (WS261-2006), which aimed to establish the therapeutic standards or guideline of schistosomiasis in China. PMID- 26930927 TI - [Effect of mid- and long-term schistosomiasis control plan and discussion of consolidation strategy in marshland endemic regions]. AB - OBJECTIVE: To evaluate the effectiveness of mid- and long-term schistosomiasis control plan and explore the consolidation strategy in marshland endemic regions, so as to provide an effective approach for interrupting and eliminating schistosomiasis in the regions. METHODS: A prospective field study was designed. Dantu District of Zhenjiang City, a marshland schistosomiasis endemic region, was selected, and the "key village, key environment, and key water regions" comprehensive control strategy was implemented according to the endemic level of schistosomiasis. The morbidity due to schistosomiasis in humans and domestic animals, and Oncomelania hupensis snails were surveyed, and the data of the implementation of control measures were collected. The schistosomiasis morbidity and snail status were compared before and after the implementation of the mid- and long-term plan for schistosomiasis prevention and control, and the changing trends of human, domestic animal and snail infections were plotted. RESULTS: During the implementation of the plan from 2005 to 2014, 16.84 km concrete and bank protection and 9 snail sinks were built, 10 culverts re-built, 3.85 hm2 fences were constructed, 29.5 thousand domestic animals were examined and treated, 170 cattle were eliminated, 4930 hm2 fishing farms were built for snail control, 1 560.00 hM2 land were improved, and 376.00 hm2 forests were built for snail control. In addition, 19,364.80 hm2 snail areas were surveyed, 4694.6 hm2 area received molluscicide, 207.9 thousand of people (person-times) received the examination and treatment, 69.1 thousand of harmless toilets were built, 282.2 thousand health education materials and protection materials were allocated, 958 warning signs were established, and 5435 slogans were pasted or hung. After the implementation of the mid- and long-term plan, the percentages of human, bovine and snail infections appeared decline tendencies year by year, and reduced from 0.08%, 1.28% and 0.13% in 2005 to 0 in 2014, respectively, while the areas with snails and infected snails reduced from 284.34 hm2 and 55.10 hm2 in 2005 to 73.60 hm2 and 0 hm2 in 2014, with reduction rates of 74.12% and 100%, respectively. The infection rate of sheep appeared a fluctuation between 2005 and 2014, with the rate of 1.13% in 2005, 0 in 2007 and 2008, rising in 2009 and then between 0.25% and 0.95% from 2009 to 2012, and reducing to 0 in 2013 and 2014. During the 10 year period, the number of cattle reduced year by year from 2005 to 2010, and slightly increased after 2011, showing an overall stable level, while the number of sheep increased year by year after 2006, peaked in 2010, and appeared a decline tendency since 2011, which was almost consistent with the fluctuation of schistosome infection rate in sheep. CONCLUSIONS: The sustainable comprehensive control strategy with the "key village, key environments, and key water regions" is an effective approach for schistosomiasis control in marshland endemic regions. However, the endemic situation of schistosomiasis is extremely easy to repeat. The prevention and control of the impact of sheep and wild animals on schistosomiasis transmission should be strengthened in order to consolidate the schistosomiasis control achievements gained. PMID- 26930928 TI - [Analysis of schistosomiasis endemic status of national surveillance sites in Yunnan Province, 2014]. AB - OBJECTIVE: To master the dynamic endemic status and influencing factors of schistosomiasis in Yunnan Province, so as to provide the evidence for making the control and prevention measures. METHODS: Four villages of four schistosomiasis heavy endemic counties were selected as survey sites. Then, the serological screening and etiological tests were carried out in the residents, and the basic situations of the survey sites were investigated. The infection status of the livestock and relevant information of Oncomelania hupensis snails were surveyed. All the results were analyzed statistically. RESULTS: Totally 4310 residents were surveyed by the indirect hemagglutination assay with the examination rate of 79.68% and serum positive rate of 8.40%. The positive rate reached upwards 12.53% in Qiandian Village of Eryuan County. The serum positive rate of the female was higher than that of the male, and the positive rates of the 30 years and older age groups were higher than those of the other age groups. The serum positive rates of the peasants, migrant labourers and residents with the junior high school education level were higher. No positive feces were found. A total of 24 advanced cases were reported. No positive livestock and snails were found, and the average density of living snails was 0.023 3-0.056 6/0.1 m2. CONCLUSION: Right now, the schistosomiasis is at a low prevalence status in Yunnan Province, and the endemic situation has been effectively controlled. PMID- 26930929 TI - [Preliminary study of toxicity of niclosamide ethanolamine salt on wetland creatures along lower reaches of Yangtze River in Nanjing City]. AB - OBJECTIVE: To understand the impact of niclosamide ethanolamine salt on the Yangtze River wetland creatures, so as to provide an evidence for the environmental impact assessment of the Oncomelania hupensis control measures. METHODS: Eriocheir sinensis, Procambarus clarkii, freshwater mysis and Bellamya aeruginosa were chosen as the test organisms from the lower reaches of the Yangtze River in Nanjing City, and they were immersed in the different concentrations of niclosamide ethanolamine salt solution for 24-96 h. The mortality rates and LC50 values were calculated. RESULTS: There was only 1 death (with a mortality rate of 8.33%) of P. clarkia immersed in niclosamide ethanolamine salt with the concentration of 400 mg/L for 96 h. There was no death of the E. sinensis immersed in niclosamide ethanolamine salt with the concentration of 640 mg/L for 96 h. The LC50 values were 2.170 4, 1.303 6, 1.013 1 mg/L and 0.720 5 mg/L respectively when the freshwater mysis were immersed in the solution for 24, 48, 72 h and 96 h. The LC50 values were 1.173 5, 0.642 1, 0.477 3 mg/L respectively when the B. aeruginosa were immersed in the solution for 24, 48, 72, 96 h. CONCLUSIONS: The impacts of niclosamide ethanolamine salt on the different wetland creatures are different. E. sinensis and P. clarkii have high resistance to niclosamide ethanolamine salt. However, niclosamide ethanolamine salt shows heavy toxicity on the freshwater mysis and Bellamya aeruginosa. PMID- 26930930 TI - [Expression of Tim-3 on peripheral blood CD4+ T cells and its correlation with liver function damage parameters in advanced schistosomiasis patients]. AB - OBJECTIVE: To explore the expression levels of T cell immunoglobulin and mucin domain protein 3 (Tim-3) on peripheral blood CD4+ T cells and its correlation with liver function damage parameters in advanced schistosomiasis patients. METHOD: Totally 28 advanced schistosomiasis patients were selected as study subjects, and 20 chronic schistosomiasis patients and 30 healthy persons were selected as controls. The expression levels of Tim-3 on CD4+ T cell were detected by flow cytometry, and the serum IFN-gamma and IL-4 levels were detected by ELISA. Hitachi 7600 biochemical analyzer was used to analyze the liver function parameters (ALT, gamma-GT and TBIL). RESULTS: There was a significant difference in Tim-3 expression among the three groups (F = 4.578,P < 0.05). Tim-3 expression level in advanced schistosomiasis patients was (8.33 +/- 2.28)%, which was significantly higher than that of the healthy control group (6.57 +/- 1.99)% (t = 3.015, P < 0.01). The Spearman nonparametric correlation analysis showed that the Tim-3 expression level on CD4+ T cells in advanced schistosomiasis patients was positively correlated with the serum ALT(r, = 0.746, P < 0.01), gamma-GT(r, = 0.656, P < 0.01) and IL-4(r, = 0.672, P < 0.01) levels, but negatively correlated with the serum IFN-gamma levels (r(s) = -0.404, P < 0.05). CONCLUSION: The expression of Tim-3 on peripheral CD4' T cells is increased in advanced schistosomiasis patients, which may regulate the function of CD4' T cells and then be involved in the liver damage process of advanced schistosomiasis. PMID- 26930931 TI - [Development of colloidal gold immunochromatography assay strip for schistosomiasis diagnosis in domestic animals]. AB - OBJECTIVE: To develop a quick and easy colloidal gold immunochromatography assay (GICA) strip for schistosomiasis diagnosis in domestic animals. METHODS: The reconstruction of Streptococcal Protein G (SPG) was designed and its gene was subcloned into plasmid pET-28a(+) to express in Escherichia coli. The recombinant SPG was purified and labeled with colloidal gold. The Schistosoma japonicum soluble egg antigen (SEA) and rSPG were blotted on the nitrocellulose membrane for the test line and control line respectively. The specificity, sensitivity and cross-reaction of the strip method were detected. RESULTS: The rSPG was successfully expressed and purified to label with colloidal gold. The colloidal gold immunochromatography assay strips were assembled and they could detect the sera of S. japonicum infected BALB/c mice, New Zealand white rabbits, buffalo and sheep successfully. Besides, the sensitivity of GICA strip was 100% in the sera of mice and the serum of rabbits with S. japonicum infection. The specificity was 100% in the serum of mice and the sera of rabbits with free of infection. The sensitivity was 100% in the sera of sheep with miracidia of S. japonicum hatching from the stool and the specificity was 88.46% in the sera of sheep without that. The sensitivity was 94.44% in the sera of buffalo with miracidia hatching from the stool and the specificity was 100% in the sera of buffalo without that. The cross-reaction rate was 5.88% in Paramphistomum. CONCLUSION: The GICA strip can successfully detect a variety of S. japonicum infected domestic animals and may be a useful tool for screening on a large scale in the endemic areas. PMID- 26930932 TI - [Analysis of sensitization effect of chimeric allergen TAT-IhC-R8 derived from major allergen group 1 genes of dust mites]. AB - OBJECTIVE: To explore the sensitization effect of allergen TAT-IhC-R8, derived from major allergen group 1 genes of dust mites. METHODS: Forty BALB/c mice were randomly divided into 4 groups, namely PBS group, ovalbumin (OVA) group, R8 group and TAT-IhC-R8 (TIR8) group, 10 mice each group. All the mice in OVA, R8 and TIR8 groups were treated with corresponding allergens (10 ug/ml) on the 0, 7th and 14th day by intraperitoneal injection and nebulized inhalation on day 21 with the concentration of 30 min/d for 7 days. The mice in PBS group were treated with PBS. Twenty-four hours after the last challenge, all the mice were sacrificed, their bronchoalveolar lavage fluids (BALFs) and sera were collected and their spleen cells were cultured. ELISA was performed to detect the levels of IFN-gamma and IL-13 in BALFs and supernatants of cultured splenocytes (SCSs) of the mice, as well as the levels of allergen-specific IgE (sIgE), IgG, and IgG2 in their sera. The number of white blood cells and eosinophils in BALF were calculated. In addition, the airway inflammation and mucus secretion were analyzed by haematoxylin and eosin (H&E) staining. RESULTS: Compared with the PBS group, the lung inflammations of mice in the OVA, R8 and TIR8 groups were observed obviously, including inflammatory infiltration, bronchial epithelial cell breakage and falling off, as well as vasculitis. The numbers of the total white blood cells and eosinophils in BALF of mice in the TIR8 group were significantly more than those in the OVA and R8 groups (all P < 0.01). The IL-13 levels in BALFs and SCSs of mice in the TIR8 group were significantly higher than those in the OVA group and R8 group (all P < 0.01). However, the level of IFN-gamma of mice in the TIR8 group was lower than those in the latter 2 groups (all P < 0.01). In addition, the levels of sera sIgE and IgG of mice from the TIR8 group were significantly higher than those in the OVA group and R8 group (all P < 0.01), but the level of IgG2a of the former was significantly lower than those of the latter groups (all P < 0.01). CONCLUSIONS: TAT-IhC-R8 can effectively stimulate lung inflammations of mice, and its sensitization effect is better than R8's. PMID- 26930933 TI - [Immunotherapy effect of ploypeptide vaccine of allergen group 1 from Dermatophagoides farinae on asthma mice]. AB - OBJECTIVE: To investigate the enzymatic hydrolysates of ProDer f land their hydrolytic products for specific immunotherapy. METHODS: The asthma models of mice made by ProDer f 1 allergen were treated by using two kinds of hydrolysates as vaccine for analyzing their effects of immunotherapy. Fifty female BALB/c mice were randomly divided into 5 groups (n = 10 for each), i.e., a PBS group, an asthma group, an immunotherapy group by ProDer f 1 protein, an immunotherapy groups by papain hydrolysates and trypsin hydrolysates. On day 0, 7 and 14, the mice were intraperitoneally injected with 10 ug of ProDer f 1 allergen, which was dissolved in 100 ul PBS containing 2% (W/V) Al (OH)3 suspension. At day 21, the animals were caged in the airway challenge apparatus, and challenged by nebulized inhalation of allergen suspension (0.5 ug/ml) for 30 min for 7 successive days. The mice were undergone allergen specific immunotherapy (ASIT) by intraperitoneal injection and of the immunotherapy group by ProDer f 1 protein, immunotherapy groups by papain hydrolysates and trypsin hydrolysates (100 ug/ml) in a dose of 200 ul of reactive allergens, 30 min prior to the inhalation treatment at day 25, 26 and 27, respectively. The PBS group was managed with both intraperitoneal injection and aerosol of PBS. Twenty-four hours after the last challenge, all the mice were sacrificed. The bronchoalveolar lavage fluid (BALF) and sera were collected, and the splenocytes were cultured. The levels of IL-4, IL-10, IL-17 and IFN-gamma in BALF and supernatant of splenocytes cultured (SSCC) were detected by ELISA, and the serum levels of specific IgE and IgG2a antibodies were also detected by ELISA. RESULTS: Compared with the asthma group, the histo- logic examination of the lungs taken from the mice in the immunotherapy group by ProDer f 1 protein, immunotherapy groups by papain hydrolysates and trypsin hydrolysates showed alleviated peribronchial and perivascular inflammatory infiltration, absently of eosinophils. The normal lung architectures were also exhibited, particularly, the epithelium was of normal size and morphology, similar to that of the PBS-challenged group. The levels of IL-4 in BLAF of the ASIT groups and asthma group were (231.61 +/- 11.73), (206.20 +/- 14.33), (200.44 +/- 9.34), (299.68 +/- 12.46) pg/ml; the levels of IL-10 in BLAF were (361.87 +/- 13.62), (376.27 +/- 20.57), (413.57 +/- 12.98), (171.28 +/- 19.79) pg/ml; the levels of IL-17 in BLAF were (142.12 +/- 5.01), (128.27 +/- 5.34), (130.79 +/- 6.30), (273.59 +/- 11.56) pg/ml; the levels of IFN-gamma in BLAF were (229.60 +/- 11.32), (269.13 +/- 11.98), (282.25 +/- 19.65), (147.76 +/- 11.36) pg/ml. The levels of IL-4 in SCCS of the ASIT groups and asthma group were (218.54 +/- 12.62), (220.21 +/- 10.73), (201.59 +/- 18.54), (256.86 +/- 15.53) pg/ml; the levels of IL-10 were (360.45 +/- 13.10), (383.41 +/- 19.81), (413.51+/-13.14), (173.50 +/- 20.25) pg/ml; the levels of IL-17 were (154.23 +/- 5.18), (137.72 +/- 6.66), (141.01 +/- 7.35), (297.55 +/- 8.97) pg/ml, the levels of IFN-gamma were (243.22 +/- 25.01), (275.20 +/- 14.65), (284.67 +/- 25.87), (154.54 +/- 17.45) pg/ml. The levels of antigen-specific IgE antibody of the ASIT groups and asthma group were (309.66 +/- 13.56), (256.61 +/- 40.64), (248.83 +/- 10.51), (359.60 +/ 29.48) ug/ml, and the antigen-specific IgG2a antibody levels were (8.87 +/- 0.82), (9.15 +/- 0.83), (10.56 +/- 1.68), (7.04 +/- 0.42) ug/ml. The resulting serum antigen-specific IgE antibody levels suggested that the IgE levels in the immunotherapy group by ProDer f 1 protein, immunotherapy groups by papain hydrolysates and trypsin hydrolysates were significantly lower than that in the asthma group. Conversely, the level of antigen-specific IgG2a in sera was significantly higher in the immunotherapy group by ProDer f 1 protein, immunotherapy groups by papain hydrolysates and trypsin hydrolysates than that in the asthmatic group. The levels of IL-4, IL- 17 in BALF and SCCS in the immunotherapy group by ProDer f 1 protein, immunotherapy groups by papain hydrolysates and trypsin hydrolysates significantly decreased, compared with that in the asthma group. However, the levels of IL-10 and IFN-gamma in BALF and SCCS in the immunotherapy group by ProDer f 1 protein, immunotherapy groups by papain hydrolysates and trypsin hydrolysates were increased dramatically in the immunotherapy group by ProDer f 1 protein, immunotherapy groups by papain hydrolysates and trypsin hydrolysates than that in the asthma group. CONCLUSION: The hydrolytic products above-mentioned can alleviate asthmatic symptoms effectively after the antigen-specific immunotherapy in murine asthma models. PMID- 26930934 TI - [Surveillance of schistosomiasis in Xixi National Wetland Park, 2012-2014]. AB - OBJECTIVE: To understand the endemic dynamic and situation of schistosomiasis in the Xixi National Wetland Park. METHODS: The surveillances of Oncomelania hupensis snail situation and the schistosome infection status of the permanent residents and floating population in the Xixi National Wetland were conducted annually from 2012 to 2014 according to the Surveillance Programs of Schistosomiasis in Surveillance Sites of Zhejiang Province. RESULTS: From 2012 to 2014, accumulatively 12.31 hm2 of area, 4965 m2 of vegetation and 75,379 alien plants were surveyed in the Xixi National Wetland Park, and no Oncomelania snails were found. The seropositive rates in the permanent residents and floating population were 0.71% (5/706) and 1.36% (25/1 834), respectively, and 1 imported chronic schistosomiasis case was found in 2014. Totally 3 006 floating personnel were involved in the investigation of infection status and awareness on knowledge of schistosomiasis control in 2013, the sero-positive rate was 0.63% (19/3 006), and the rates of those from endemic and non-endemic areas were 1.00% (15/1 503) and 0.27% (4/1 503), respectively, and the difference was statistically significant ( chi2 = 6.41, P < 0.05). The results of the fecal examinations among the seropositive cases were all negative. The awareness rates on the Regulation of Schistosomiasis Control and Prevention as well as related knowledge about Oncomelania snails were low. The indoor survival experiment of Oncomelania snails showed the survival rates of Oncomelania snails were 58.33% and 1.25% after observing for 3 and 6 months respectively. CONCLUSIONS: The Xixi National Wetland Park is suitable for Oncomelania snails to inhabit and breed. The imported cases in floating population pose a serious threat to the endemic situation of schistosomiasis in local. In the future, the surveillance on snails and floating population as well as the health education should be strengthened. PMID- 26930935 TI - [Effect of schistosomiasis control in towns reached criteria of infection controlled in Nanchang City]. AB - OBJECTIVE: To evaluate the effect of schistosomiasis control in towns that had reached the criteria of infection controlled in Nanchang City. METHODS: The residents and livestock of 14 towns that had reached the criteria of infection controlled in Nanchang, Xinjian and Jinxian counties of Nanchang City were sampled to investigate the schistosomiasis endemic situation, Oncomelania hupensis snail status, and data of schistosomiasis control work. RESULTS: The positive rate of serum tests of the residents was 2.58%, and no positive stool samples were found. No cattle or sheep were positive in stool tests. Totally 1 635 snails were caught, and 1278 were alive with an average density of living snails of 0.051/0.1 M2, while no schistosome infected snails were found. All the surveyed administrative villages had the completed files of schistosomiasis control. Conclusion All the 14 towns that had reached the criteria of infection controlled of schistosomiasis have already reached the criteria of transmission controlled in Nanchang City. PMID- 26930936 TI - [Effect of integrated measures on schistosomiasis transmission--interruption in hilly areas]. AB - OBJECTIVE: To evaluate the effect of control integrative measures which persist in snail eradication and chemotherapy on schistosomiasis transmission interruption in hilly areas. METHODS: The data of integrated control and endemic situation of schistosomiasis from 2004 to 2014 were collected, and the control effect of integrated measures was evaluated. RESULTS: From 2004 to 2014, both the Oncomelania hupensis snail area and density of living snails of Jurong City were reduced from 43.13 hm2 and 1.48 snails/0.1 m2 to 0; the residents' seropositive rate declined continuously; the residents' and students' awareness rates on schistosomiasis control were increased from 88.43% and 82.04% to 92.56% and 95.74% respectively; the snail area was significantly negatively correlated with the coverage rate of snail control (r = -0.864, P < 0.05). CONCLUSIONS: In the hilly areas, the schistosomiasis control integrated measures which persist in snail eradication and chemotherapy could control the endemic situation rapidly and steadily, accelerating to achieve the goal of schistosomiasis transmission interruption. PMID- 26930937 TI - [Application of clinical nursing pathway in fast-track program of splenomegaly advanced schistosomiasis patients]. AB - OBJECTIVE: To evaluate the effect of clinical nursing pathway in fast-track program (FTS-CNP) in splenomegaly advanced schistosomiasis patients during the perioperative period. METHODS: A total of 80 patients with splenomegaly advanced schistosomiasis who were treated with selective operation in the Affiliated Xiangyue Hospital of Hunan Institute of Parasitic Diseases from January, 2012 to December, 2014 were divided into an observation group (n = 40) and a control group (n = 40). FTS-CNP was implemented in the observation group, while the routine nursing was used in the control group. Then the physical rehabilitation and psychological health levels of the patients in the two groups post-operation were observed and compared. RESULTS: After the operation, the duration of first taking food [(14.67 +/- 2.90) h], first anus exhausting [(25.30 +/- 3.46) h], first off-bed activity [ (29.40 +/- 5.57) h], as well as the duration of hospital stays [(19.00 +/- 2.82) d] of patients in the observation group were all shorter than those of the patients in the control group [(44.50 +/- 6.71) h, (52.80 +/- 6.95) h, (35.05 +/- 10.37) h, (25.08 +/- 2.39) d, respectively] , and the incidence rate of postoperative complications (7.50%) of the former was lower than that of the latter (25.00%), and all the differences were statistically significant (all P < 0.05). Both the scores of SAS (41.22 +/- 5.60) and SDS (40.28 +/- 6.67) of the patients in the observation group were lower than those of the patients in the control group (46.89 8.92, 47.06 +/- 10.29), both differences were statistically significant (both P < 0.01). CONCLUSION: FTS-CNP can promote the physical and psychological recovery of the splenomegaly advanced schistosomiasis patients post-operation, and also can shorten the hospitals stays and reduce the complications. PMID- 26930938 TI - [Effect of soil-transmitted helminthes control through mass deworming and latrine improvement]. AB - OBJECTIVE: To evaluate the effect of soil-transmitted helminthes control through mass deworming and latrine improvement in rural areas. METHODS: The data including mass deworming (1998-2000) and latrine improvement (2001-2010) were collected, summarized and analyzed in Danyang City. The infection rate of the soil-transmitted helminthes was monitored annually by using Kato-Katz method from 2001 to 2010. In addition, 2 villages with the improved latrines strategy and one village without the strategy were selected for hygienic evaluation. RESULTS: Totally 1 130 000 person-times of mass deworming were carried out in Danyang City from 1998 to 2000, and the infection rate of soil transmitted helminthes of human was decreased from 40.82% to 1.10%. The infection rate (2.49%-4.81%) was bounced in the first five years (from 2001 to 2005) after mass deworming, while it gradually declined in the following five years (from 2006 to 2010) and maintained at a low level (0.07%-0.52%), and there was a significant difference between the average infection rates during the above two stages (chi2 = 353.83, P < 0.01). There was a negative correlation between the coverage rate of harmless latrine and the infection rate (r = -0.83, P < 0.01). CONCLUSION: The mass deworming and latrine improvement are effective measures for the control of soil-trans-mitted helminthes infection in rural areas. PMID- 26930939 TI - [Imaging characteristics of different types of cerebral cysticercosis]. AB - OBJECTIVE: To study the imaging characteristics of different types of cerebral cysticercosis. METHODS: The CT and MRI findings of 166 patients with clinical diagnostic cerebral cysticercosis were reviewed retrospectively. RESULTS: Among the 166 cerebral cysticercosis patients, there were 108 cerebral parenchyma type cases, 15 ventricles type cases, 3 meningeal type cases, and 40 mixed type cases according to the cysticerci being in the parts of the brain. The CT and MRI imaging characteristics of various types were as the following. (1) Brain parenchyma type included the cystoid subtype, encephalitis subtype, nodular or multiple ring enhancement subtype, and chronic calcification subtype. The cystoid subtype: CT showed single or multiple cystic shadow (s) with clear boundary, and the sac with a high density of scolex; MRI showed round long T1 and long T2 signals, eccentric punctate shadows inside the sac, cystic wall and scolex signals, but no significant enhancement. The encephalitis subtype: CT showed scattered low density lesions and MRI showed patchy slightly long T1 and long T2 signals, but no enhancement or irregular enhancement in the majority. The nodular or multiple ring enhancement subtype: CT scan showed low density lesions in multiple nodules, or CT enhancement scan showed multiple nodules or ring enhancement. The chronic calcification subtype: CT showed single or multiple dot like high density single (s), and MRI showed equal or long T I and short T2 signals. (2) Ventricular type: The lesions were often in the third and fourth ventricles complicated with obstructive hydrocephalus. (3) Meningeal type: there were expand and asymmetric cerebrospinal space limitations, communicating hydrocephalus, and the enhanced scan showed leptomeningeal enhancement. (4) Mixed type: The performance was mixed as two or more types above mentioned, and there existed mixed acute and chronic phases. CONCLUSIONS: The imaging findings of the different types of cerebral cysticercosis are differ from one another. The analysis of the imaging characteristics of the different types of cerebral cysticercosis has a significance for the clinical diagnosis, treatment and prognostic judgment of cerebral cysticercosis patients. PMID- 26930940 TI - [Clinical application of diagnostic therapy of praziquantel for suspected cere- bral cysticercosis]. AB - OBJECTIVE: To explore the clinical application value of diagnostic therapy of praziquantel for suspected cerebral cysticercosis. METHODS: The suspected cerebral cysticercosis patients were collected and treated with the diagnostic therapy [praziquantel, 50 mg/(kg . d)], and followed up for 1-2 years. RESULTS: Totally 94 suspected cerebral cysticercosis patients were collected. After the diagnostic therapy, 78 (82.98%) cases were confirmed as cerebral cysticercosis, 13 (13.83%) were diagnosed as other diseases, and 3 (3.19%) were not definitely diagnosed. CONCLUSION: The diagnostic therapy for suspected cerebral cysticercosis can reduce or avoid the missed diagnosis and misdiagnosis in some atypical cerebral cysticercosis patients. PMID- 26930941 TI - [Malaria surveillance in Tengchong County of Yunnan Province in 2013]. AB - OBJECTIVE: To analyze the surveillance data of malaria in Tengchong County of Yunnan Province in 2013, so as to provide the evidence for carrying out the malaria elimination in the future. METHODS: The data of epidemic situation and surveillance of malaria in Tengchong County in 2013 were collected and analyzed for the prevalence state as well as and the monitoring indicators including the blood examination of fever patients of unknown origin, initiative detection of cases, under-reporting survey, sentinel surveillance and species and density investigation of Anopheles mosquitoes. RESULTS: Totally 138 malaria cases were reported in Tengchong County in 2013, among which 118 cases were infected with Plasmodium vivax and 20 cases with P. falciparum, and all the reported cases were imported. The completion rates of blood examinations, case reports and case investigations all reached 100%. A total of 57 cases were involved in initiative detection, but no positive cases were found. The twice under-reporting of malaria case surveys were conducted and 1 case had been under-reported. The sentinel surveillance was carried out both in the domestic and overseas sites at the same time to detect the suspected malaria cases, 172 cases were screened totally, and 15 ones were detected as positives. Totally 528 returnees were screened, and there were no positive case found. A. sinensis and A. liangshanensis were the dominant species, followed by A. minimus, A. maculatus and others. CONCLUSIONS: The malaria epidemic situation is stable in Tengchong County in 2013, and all the work in surveillance has been conducted successfully, but there still exist some difficulties in the process of malaria elimination. The local health departments should further strengthen the surveillance on imported cases and the management on migrant population as well as the capability building for health workers in malaria control in the future. PMID- 26930942 TI - [Preservation of live eggs of Schistosoma japonicum]. AB - OBJECTIVE: To observe the preservation time and activity of miracidium hatching from schistosome eggs preserved in different solutions, so as to obtain the optimal preservation conditions and then provide quality control products for field application. METHODS: The rectum stool of rabbits infected with Schistosoma japonicum was collected and the coarse fecal residue was removed with a series of sample sieves of 80, 100, 160 and 200 meshes respectively, and then the schistosome eggs were concentrated with the sample sieve of 260 meshes. The concentrated eggs were preserved in 0.9% sodium chloride solution, 1.2% sodium chloride solution, phosphate buffered saline solution (PBS, PH 7.2), 1.0% sucrose solution, and Mili-Q water, respectively, and then were conserved in a 4 degrees C refrigerator and 15 degrees C constant temperature incubator, respectively. The preserved eggs were hatched in different time (7-day interval) , the vitality and quantity of the miracidia were observed, and the hatching rates were calculated. RESULTS: Under the condition of 4 degrees C, the hatching rates of eggs dropped to 0 in 1.0% sucrose solution and 1.2% sodium chloride solution at the 49th and 126th day, respectively, and the hatching rates of eggs in the 0.9% sodium chloride solution and PBS solution dropped to 10% at the 112th day, and the activity of miracidium was weakened since 140th. In the Mili-Q water, the hatching rate dropped less than 10% at the 196th day and the activity of miracidia was weakened since the 280th day. Under the condition of 15 degrees C, the hatching rate of eggs in different solutions gradually dropped to 0 from the 49th day to 105th day. CONCLUSION: The eggs preserved in Mili-Q water at the temperature of 4 degrees C can be used as the positive reference for hatching tests within 196 days. PMID- 26930943 TI - [Investigation of natural foci of Metorchis taiwanensis in Wuhu area]. AB - OBJECTIVE: To explore the existence of natural foci of Metorchis taiwanensis in Wuhu area. METHODS: The ecological environment and daily living habits of residents were investigated; the eggs of M. taiwanensis in the dung of ducks in local region were collected by the sedimentation method; the Parafossarulus striatulus were disposed by the tabletting method and examined with a microscope to isolate the rediae and cercariae; the metacercariae in Pseudorasbora parve were isolated by using the homogenation. The duckling were fed directively by metacercaria of M. taiwanensis or by P. parve infected with metacercaria of M. taiwanensis for artificial infection, and M. taiwanensis were separated from ducks by dissecting the gallbladder and bile ducts. RESULTS: The survey revealed that there were staggered lake river, rich vegetation, overgrown shrubs, aquatic plants, rich variety of freshwater snails and fish resources in Wuhu area, and it was home to a variety of waterfowl and duck. The average detection rate of eggs of M. tanwanensis in stool of ducks was 33.33% (10/30); that of rediae and cercarriae in P. striatulus was 1.17%(7/600); and that of encysted metacercaria in P. parve was 13.33% (8/60); the number of M. taiwanensis detected in the infected ducklings in 3 groups were 31, 8 and 0, respectively, the natural M. tanwanensis infection rate of ducks was 23.33% (7/30). CONCLUSION: We have confirmed the existence of natural foci of M. tanwanensis in Wuhu area. PMID- 26930944 TI - [Analysis of capability of examining helminthes: National technique competition of parasitic disease diagnosis in 2013]. AB - OBJECTIVES: To understand the ability of worm detection of staff of centers for disease control and prevention (CDC) in China, so as to promote the ability construction. METHODS: In each province, four competitors were selected from the institutions of parasitic diseases control to attend the National Technique Competition for Parasitic Disease Diagnosis and the results of competition were collected and analyzed. RESULTS: The average scores of microscopic identification and slide preparation of all the 124 competitors were 27.3 and 7.6 respectively and the scores were increased significantly (t = 3.169, 5.009, both P < 0.05) compared to those in 2012. The average detection rate of helminthes was 62.7%, and it was increased significantly (chi2 = 28.630, P < 0.05) compared to that in 2012. The scores of competitors of different genders, ages, and profession titles were significantly different (t = 1.400, 2.080, F = 2.366-3.864, all P < 0.05). The scores of competitors of provinces with the control task of parasites were higher than those without any control task (t = 6.650, 4.630, both P < 0.01). CONCLUSIONS: The competition has enhanced the ability of staff of CDCs, especially for the young staff. However, the ability of detection for soil transmitted helminth eggs should be intensified. Monitoring sites should be established in low endemic areas of parasites and provinces without the prevention and control task and the training for the professional staff should be strengthened. PMID- 26930945 TI - [Risk assessment of schistosomiasis transmission on rescue workers involved in "Oriental Star shipwreck event"]. AB - OBJECTIVE: To assess the impact of the "Oriental Star shipwreck event" on the risk of schistosomiasis transmission in Jianli County, Hubei Province, so as to provide the evidence for formulating appropriate measures of schistosomiasis prevention and control. METHODS: Based on the field observation and investigation, the data of the on-the-spot rescue and the historical endemic situation of schistosomiasis in Jianli County were collected and analyzed. Meanwhile, the focus group discussion and risk matrix were conducted to assess the risk of schistosome infection of the rescuers. RESULTS: Over 10 000 rescuers participated in the search operation, including the armed police forces, local people, reservists and so on. The armed police forces were the major components, which accounted for 39%. Jianli country was schistosomiasis endemic area with a high infection level in history, but the endemic situation had been mitigated significantly after years of positive prevention and treatment; the schistosome infection rate of population was 0.44% in 2014 and the Oncomelania hupensis snail area was only 6.6 hm2 around the rescue areas in the upstream and downstream. In addition, the snail density was not high, and no infected snails had been found for 11 years. The risk of schistosome infection was in the medium level. CONCLUSIONS: Though there exists the schistosome infection risk in the water area where the accident happened, the probability of occurrence is not high. In order to prevent the outbreak and endemic of schistosomiasis, the protection measures and health education to the rescuers as well as snail control and monitoring, and early-warning should be strengthened. PMID- 26930946 TI - [Endemic situation of schistosomiasis in Tongling County of Anhui Province from 2009 to 2014]. AB - OBJECTIVE: To understand the endemic situation of schistosomiasis in Tongling County of Anhui Province, so as to provide the evidence for summarizing the "Twelfth Five-Year Plan" and formulating the "Thirteenth Five-Year Plan". METHODS: The data of schistosomiasis control reports and other information about Oncomelania hupensis status and schistosomiasis situation of population and livestock were collected and analyzed statistically in Tongling County from 2009 to 2014. RESULTS: From 2009 to 2014, the schistosome infection rate and blood positive rate of the population decreased significantly, and only one case of acute schistosome infection was found in 2009. The schistosome infection rate of livestock decreased significantly, and the decreasing rate was 91.10% from 2009 to 2010. From 2009 to 2014, the snail area and average density of living snails presented decreasing trends but the densities of living snails increased in 2011 and 2012. After 2011, no schistosome infected snails were found. CONCLUSIONS: The schistosome infection rate of population has been controlled at a low level in Tongling County, but the snail area is still large in the marshland and lake regions, and the density of living snails is relatively high in the inland. Therefore, the schistosomiasis control work, especially snail control, still should be strengthened. PMID- 26930947 TI - [Analysis of schistosomiasis situation at a surveillance site in Kailhua County, Zhejiang Province from 2008 to 2014]. AB - OBJECTIVE: To master the dynamics of schistosomiasis situation in Kaihua County, so as to provide the evidence for formulating the prevention and control scheme. METHODS: According to the "Schistosomiasis Monitoring Work Program in Zhejiang Province", the Oncomelania hupensis snail status, schistosome infections of residents and livestock, and the influencing factors were investigated. RESULTS: Totally 62 snail sites were discovered, the area with snails was 2.30 hm2, the snail density was 0.023 snail/0.1 m2, and the snail status declined with time. No schistosome infected snails, local residents, mobile people or livestock were found. CONCLUSION: The endemic situation of schistosomiasis is stable in Kaihua County, but the surveillance of snail situation and mobile population is still needed. PMID- 26930948 TI - [Schistosomiasis surveillance in mobile population of Xiuzhou District, Jiaxing City, 2013-2014]. AB - OBJECTIVE: To understand the schistosome infection situation of mobile population in Xiuzhou District. METHODS: The data about the distribution of mobile population from the counties not reaching schistosomiasis transmission controlled in Xiuzhou District were collected, then the questionnaire survey combined with laboratory detection were used to investigate the situation of imported schistosomiasis in this district. In addition, the average infection rate and the estimated number of schistosomiasis patients were calculated. RESULTS: From 2013 to 2014, there were 15 940 people from the counties not reaching schistosomiasis transmission controlled in Xiuzhou District, among which, 4405 were investigated, and 124 of them had schistosomiasis and treatment history. Thirty-eight people were positive in serological tests, and 3 cases were positive in the etiological detection. The average infection rate of schistosome of the mobile population in Xiuzhou District was 0.068%, the calculated number of schistosomiasis patients was 11. CONCLUSIONS: The imported sources of infection are the main risk for the consolidation of the results of schistosomiasis control, which may result to the rebound of the endemic situation. So the management and surveillance of mobile population should be strengthened. PMID- 26930949 TI - [Effect of health education intervention on schistosomiasis control in Mianyang City]. AB - OBJECTIVE: To evaluate the effect of health education on schistosomiasis control in Mianyang City. METHODS: The population aged 6-65 years in 12 moderately and heavy schistosomiasis endemic villages of 6 endemic counties in Mianyang City were selected as the investigation objects, among which, the health education on schistosomiasis control were implemented. The questionnaire surveys were carried out to understand the knowledge, attitude and behavior on schistosomiasis control of the target population, and the scores before and after the intervention were compared to evaluate the effect. RESULTS: Totally 600 people were investigated, including 298 villagers and 302 students. After the health education intervention, the average scores of knowledge, attitude and behavior on schistosomiasis control of the villagers improved from (77.17 +/- 5.04) , (77.83 +/- 5.74), (72.17 +/- 2.48) to (89.12 +/- 3.18), 100, 100, respectively, while those of the students improved from (79.50 +/- 5.82), (84.33 +/- 2.66), (82.17 +/ 4.71) to (87.00 +/- 3.59), 100, 100, respectively, all the differences were statistically significant (all P < 0.01). CONCLUSIONS: The health education of schistosomiasis control in Mianyang City achieves a good effect. How to consolidate the results and enhance the consciousness of the mass to participate in schistosomiasis control is still the primary mission at present. PMID- 26930950 TI - [Analysis of malaria situation and discussion of control strategies in Huai'an City, 2014]. AB - OBJECTIVE: To understand the malaria epidemic situation in Huai'an City in 2014, so as to provide the evidence for formulating and adjusting effective strategies and measures to eliminate malaria. METHODS: The reported malaria cases from the Internet Reporting System and the epidemiological data of malaria of Huai'an City in 2014 were collected and analyzed statistically. RESULTS: A total of 56 malaria cases were reported in Huai'an City in 2014 with the incidence of 0.12/10,000, and 43.59% of increasing rate compared with the previous year (39 cases). All these cases were imported from African countries. There were 50 cases of falciparum malaria, 4 cases of ovale malaria, 1 case of quartan malaria and 1 case of mixed infections. All the patients were male and aged 24-59 years. Totally 96.43% of the patients (54 cases) were peasants and 69.64% of them (39 cases) only received junior high school education. The malaria cases were mainly distributed in Huai'an District (32 cases), Xuyi County (8 cases) and Huaiyin District (6 cases), totally accounting for 82.14%. There was no significant seasonal variation in the reporting time of the cases. The median time from onset to seeing a doctor was 2 days and the median time from seeing a doctor to being diagnosed was 1 day. Totally 16.67% of the patients (8 cases) were misdiagnosed when they first visited a doctor. All the patients were laboratory confirmed and all of them received the standard treatment after diagnosis. CONCLUSIONS: There have been no local malaria cases reported from Huai'an City in the last three years. However, the situation of imported malaria is more serious and the species of infected Plasmodium are more diverse. Therefore, to accomplish the aim of malaria elimination in the whole city, it is necessary to further strengthen the multi-sectoral cooperation, health education, malaria screening and professional training to control the imported malaria. PMID- 26930951 TI - [Quality analysis of malaria blood smear preparations of febrile patients in Chenzhou Prefecture, 2014]. AB - OBJECTIVE: To standardize the malaria smear preparations of febrile patients in Chenzhou Prefecture, Hunan Province, so as to provide the technical support for malaria elimination. METHODS: According to the Technical Solutions to Eliminate Malaria (2011 edition) , the blood smear preparations of febrile patients from each county, included more than 3% negatives and all positives, were reviewed monthly in 2014. The quality of blood smear manufacture, dyeing, cleanliness and results was reviewed by malaria microscopic examination experts. The data were analyzed with the descriptive epidemiological methods. RESULTS: Totally 231 blood smears were reviewed in 2014 with a reviewed rate of 6.91%. The blood smear production qualified rate was 80.52%, the dyeing pass rate was 84.42%, the cleanliness pass rate was 86.58%, and there were no false detections and no leak detections. The highest blood smear production qualified rate, dyeing pass rate and cleanliness pass rate were found in Guiyang County and Linwu County, with all the rates of 100% respectively. The lowest blood smear production qualified rate and cleanliness pass rate were found in Yizhang County, with the rates of 52.94 % and 70.59% respectively. The lowest blood smear dyeing pass rate was found in Yongxing County with the rate of 63.64%. There were statistically significant differences between Guiyang County and Yizhang County in the production qualified rates and cleanliness pass rates (chi2 = 18.60, 9.73, both P < 0.01). There was a statistically significant difference between Guiyang County and Yongxing County in the dyeing pass rates (chi2 = 11.43, P < 0.01). CONCLUSION: Through the review of blood smears, the problems will be timely discovered. Therefore, the blood smear quality should improve, which is helpful for achieving the goal of malaria elimination. PMID- 26930952 TI - [Application of high resolution remote sensing technology in research of schistosomiasis surveillance]. AB - Schistosomiasis is closely related to environmental factors, the changes of environmental factors, such as vegetation, temperature, hydrology and soil, could impact the transmission of the disease. The environmental factors associated with schistosomiasis could be extracted by remote sensing technology quickly and precisely, and be applied to monitor the schistosomiasis transmission. The studies on high resolution remote sensing technology applied in the research of schistosomiasis are reviewed in this paper. PMID- 26930953 TI - [Advances in researches on mechanism of anti-Toxoplasma Chinese herbal medicine]. AB - Toxoplasma gondii is an opportunity cellular parasite, related to the infection of various animals and human beings and severely impairing agriculture and human health. Because of the complexity of T. gondii life cycle, its different biological characteristics, and multifarious pathogenesis, there are no specific treatment and preventive medicines at present. Chinese herbal medicine can balance "yin-yang" and regulate the immunity and its side-effect is slight. Now, it has been a hot topic of the research on effective and secure medicines in anti toxoplasmosis. This paper summarizes and analyzes the curative effect and mechanism of anti-Toxoplasma Chinese herbal medicine, such as Scutellaria baicalensis, Inontus obliquus polysaccharide, Radix glycyrrhizae, pumpkin seeds, and Semen arecae. PMID- 26930954 TI - [Upper gastrointestinal bleeding induced by hookworm infection: one case report]. AB - This paper reports a case of upper gastrointestinal bleeding induced by hookworm infection, which was misdiagnosed at the beginning, and analyzes the causes of misdiagnosis. PMID- 26930955 TI - [First report of one imported case of schistosomiasis haematobia in Guangxi Zhuang Autonomous Region]. AB - The first case of imported schistosomiasis haematobia in Guangxi Zhuang Autonomous Region is reported in this paper, so as to improve the doctors' understanding of the common tropic diseases abroad. PMID- 26930956 TI - [State of art of liquid chromatography]. PMID- 26930957 TI - [Determination of six amide pesticide residues in vegetables and fruits by solid phase extraction-ultra high performance liquid chromatography-tandem mass spectrometry]. AB - A solid phase extraction coupled with ultra high performance liquid chromatography-tandem mass spectrometry (SPE-UPLC-MS/MS) method was developed for simultaneous determination of six amide pesticides, cyantraniliprole, mandipropamid, boscalid, fluopicolide, thifluzamide and flubendiamide, in vegetables and fruits. After extraction with acetonitrile, purification with Florisil SPE cartridges and dissolution with methanol, the targets in the sample solutions were analyzed by UPLC-MS/MS on an Agilent Proshell 120 EC-C18 column with a mixture of 0.1% formic acid solution and methanol as the mobile phases under gradient elution conditions. The mass spectrometer operated in multiple reaction monitoring (MRM) mode with the negative and positive modes. Good linearity was obtained for the six amide pesticides at the mass concentrations of 0.000 5 - 1.00 mg/L with the correlation coefficients more than 0.999. The fortified recoveries were in the range of 72.4% - 119.4% with the concentration levels at 0.01, 0.1 and 1.0 mg/kg for cyantraniliprole, mandipropamid, boscalid, fluopicolide, thifluzamide, and 0.001, 0.01 and 0.1 mg/kg for flubendiamide. The relative standard deviations (RSDs) were less than 15% and the limits of quantification were 0.01 mg/kg for cyantraniliprole, mandipropamid, boscalid, fluopicolide, thifluzamide, and 0.001 mg/kg for flubendiamide. All the above observations indicate that the established analytical method is simple, efficient and sensitive, and suitable for the determination of the six amide pesticides in vegetables and fruits. PMID- 26930958 TI - [Determination of twelve chemical drugs illegally added in herbal tea by ultra high performance liquid chromatography-tandem mass spectrometry coupled with modified QuEChERS]. AB - An ultra high performance liquid chromatography-tandem mass spectrometry method with modified QuEChERS procedure for sample preparation was developed for the simultaneous determination of 12 chemical drugs (chlorpheniramine, piroxicam, alpha-asarone etc) illegally added in herbal tea. The samples were extracted with acetonitrile, purified with QuEChERS procedure and filtrated by 0.22 MUm microporous filters. The separation was carried on an XBridge BEH C18 column (100 mm x 2.1 mm, 3.5 MUm) by a gradient elution using acetonitrile/0.1% (v/v) formic acid aqueous solution as mobile phases. The analytes were detected by tandem mass spectrometry with positive electrospray ionization (ESI+) in multiple reaction monitoring (MRM) mode, and quantified by external standard calibration method. The correlation coefficients of the standard calibration curves for the 12 analytes were all above 0.997. The limits of detection ranged from 0.1 MUg/L to 2.1 MUg/L, and the limits of quantification ranged from 0.4 g/L to 8.0 MUg/L. The average recoveries of the 12 analytes spiked at three levels in blank samples ranged from 62.7% to 95.2% with the RSDs from 1.3% to 10.8%. The samples bought from markets were screened, and some of the samples showed positive for these analytes. The method developed is easy to operate, sensitive, and with good purification effect. It can be applied to the rapid determination of the 12 chemical drugs illegally added in herbal tea. PMID- 26930959 TI - [Simultaneous determination of 16 flavonoids in the ginkgo dietary supplement tea by high performance liquid chromatography-tandem mass spectrometry]. AB - A method for the determination of 16 functional components of ginkgo dietary supplement tea such as catechin, vitexin, puerarin, isoflavoues aglycone, silymarin, quercetin, luteolin, apigenin, naringenin, hesperitin dihydrochalcone, kaempferol, hesperitin, isorhamnetin, baicalein, nobiletin and tangeretin by high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) was proposed. The conditions of chromatography and mass spectrometry were optimized. The 16 flavonoids were separated on a C18 chromatographic column with acetonitrile and water (additional 0.1% formic acid) as mobile phases under gradient elution at a flow rate of 0.25 mL/min. The determination was conducted by tandem mass spectrometry in positive ESI mode under multiple reaction monitoring (MRM) mode. Good linearities for all the compounds, with correlation coefficients over 0.996, were acquired. The recoveries were in the range of 70.9% to 100.0% (n = 6), while the relative standard deviations (RSDs) were less than 10%. The results showed that the nine flavonoids, which were kaempferol, quercetin, hesperitin, vitexin, luteolin, catechin, apigenin, naringenin and isorhamnetin, were higher in contents among the 16 flavonoids in real samples, and they constituted up to 99.6% of the total flavonoids. The contents of these nine flavonoids can be considered as the quality control index of the ginkgo dietary supplement tea. The method proved to be rapid, selective, sensitive and stable, and it can be applied to control the quality of the ginkgo dietary supplement tea. PMID- 26930960 TI - [Determination of fructo-oligosaccharides in milk powder by high performance liquid chromatography-quadrupole/electrostatic field orbitrap high resolution mass spectrometry]. AB - A method of high performance liquid chromatography-quadrupole/electrostatic field Orbitrap high resolution mass spectrometry (HPLC-Q/Orbitrap MS) was developed to determine fructo-oligosaccharides in milk powder. The milk powder samples were dissolved in deionized water. Subsequently, an aqueous solution of zinc acetate was used to precipitate protein. After centrifugation, the final aqueous solution was filtered by a polytetrafluoroethylene (PTFE) membrane with pore size of 0.22 MUm. The analytes were separated on a Carbohydrate column (100 mm x 2.1 mm, 2.6 MUm) through gradient elution with the combination of acetonitrile and 0.1% formic acid aqueous solution. The target-MS/MS templates were performed at isolation window of m/z 4.0 and collision energy of 30 eV in positive mode to extract the accurate product ion mass of analytes. Under the optimal condition, 1 kestose (GF2), nystose (GF3) and 1-F-beta-fructofuranosyl nystose (GF4) were well separated and the accuracy of extracted mass routinely detected was below 5 x 10( 6) (5 ppm). The whole analysis time is only ten minutes. The detection limits for GF2 and GF3 were 100 MUg/kg, and the detection limit for GF4 was 55 MUg/kg. Good linearities were obtained in their respective linear ranges with correlation coefficients higher than 0.998. The average recoveries at three spiked levels (5, 10 and 20 mg/kg) were in the range of 75.8%-107.3% and the relative standard deviations (RSDs) were in the range of 1.6% - 8.3%. The proposed method is simple, sensitive, fast and only in need of precipitation of proteins. The interference of matrix can be eliminated through the selection of product ion. The results were convenient and reliable and thus can be used in the large batch determination of any milk powder. PMID- 26930961 TI - [Identification of ustiloxins in false smut balls of rice based on high performance liquid chromatography-high resolution mass spectrometry]. AB - A sensitive method was developed for the simultaneous identification of five ustiloxins in the false smut balls of rice by high performance liquid chromatography-linear ion trap/orbitrap high resolution mass spectrometry (HPLC LTQ/Orbitrap MS). The samples were extracted with deionized water under ultrasonic condition for 10 min, then purified by a strong cation exchange column (PCX). The ustiloxins were separated on an Xselect HSS T3 column (150 mm x 2.1 mm, 3.5 MUm) by using 0.1% (v/v) formic acid water solution and methanol as mobile phases with gradient elution at a flow rate of 0.3 mL/min. The full scan range was m/z 200-1 000. The confirmatory analysis of the target compounds was carried out by the accurate mass of quasi-molecular ion, isotope abundance ratio and qualitative fragments. The results showed that the five ustiloxins (A, B, C, D and F) were identified from the false smut balls with mass accuracy less than 1 x 10(-6) (1 ppm) and the absolute values of the deviation of isotope abundance ratio were not more than 3.3%. The product ions were consistent with the theoretical fragment mode. The recoveries were 90% to 105%. This method is accurate and sensitive for the simultaneous identification of the five ustiloxins, which can provide technical means for the research of the ability in toxin producing by Ustilaginodea virens. PMID- 26930962 TI - Development and validation of a stability-indicating reverse phase ultra performance liquid chromatographic method for the estimation of nebivolol impurities in active pharmaceutical ingredients and pharmaceutical formulation. AB - A sensitive, stability-indicating gradient reverse phase ultra performance liquid chromatographic method has been developed for the quantitative estimation of nebivolol impurities in active pharmaceutical ingredient (API) and pharmaceutical formulation. Efficient chromatographic separation was achieved on an Acquity BEH C18 column (100 mm x 2.1 mm, 1.7 MUm) with mobile phase of a gradient mixture. The flow rate of the mobile phase was 0.18 mL/min with column temperature of 30 degrees C and detection wavelength of 281 nm. The relative response factor values of (R*)-2-( benzylamino)-1-((S*)-6-fluorochroman-2-yl) ethanol ((R x S*) NBV-), (R)-1-((R)-6-fluorochroman-2-yl)-2-((S)-2-((S)-6-fluoro-chroman-2-yl)-2 hydroxyethyl-amino) ethanol ((RRSS) NBV-3), 1-(chroman-2-yl)-2-(2-(6 fluorochroman-2-yl)-2-hydroxyethyl amino) ethanol (monodesfluoro impurity), (S)-1 ((R)-6-fluorochroman-2-yl)-2-((R)-2 (S*)-6-fluoro-chroman-2-yl)-2 hydroxyethylamino) ethanol hydrochloride ((RSRS) NBV-3) and (R*)-1-((S*)-6 fluorochroman-2-yl)-2-((S*)-2-((S*)-6-fluoro-chroman-2-yl)-2-hydroxyethylamino) ethanol ((R* S* S* S*) NBV-2) were 0.65, 0.91, 0.68, 0.92 and 0.91 respectively. Nebivolol formulation sample was subjected to the stress conditions of acid, base, oxidative, hydrolytic, thermal, humidity and photolytic degradation. Nebivolol was found to degrade significantly under peroxide stress condition. The degradation products were well resolved from nebivolol and its impurities. The peak purity test results confirmed that the nebivolol peak was homogenous and pure in all stress samples and the mass balance was found to be more than 98%, thus proving the stability-indicating power of the method. The developed method was validated according to International Conference on Hormonization (ICH) guidelines with respect to specificity, linearity, limits of detection and quantification, accuracy, precision and robustness. PMID- 26930963 TI - [Determination of 18 polycyclic aromatic hydrocarbons in plastic products by ultra performance convergence chromatography]. AB - A method for rapid determination of naphthalene, acenaphthylene, acenaphthene, fluorene, phenanthrene, anthracene, fluoranthene, pyrene, benzo (a) anthracene, chrysene, benzo(b) fluoranthene, benzo(k) fluoranthene, benzo(j) fluoranthene, benzo (e) pyrene, benzo (a) pyrene, indeno (1, 2, 3-cd) pyrene, dibenzo (a, h) anthracene, benzo (g, h, i) perylene in plastic products by ultra performance convergence chromatography (UPC2) coupled photodiode array detector (PAD) was developed. The 18 polycyclic aromatic hydrocarbons (PAHs) were successfully separated in less than 8.5 min on a Daicel IB-3 chiral column with a mobile phase of CO2, the mobile-phase additive of methanol/acetonitrile (25 :75, v/v) at column temperature of 40 degrees C, and a back pressure of 15.17 MPa. There was a linear correlation between peak area and PAH concentration in the range of 0.05 50 mg/L (r >= 0.999 5) for each PAH. The limits of quantification (LOQs)(S/N > 10) were 0.05 mg/L. After ultrasonic-assisted extraction in toluene, the sample was analyzed by UPC2-PDA. The recoveries of PAHs spiked in plastic samples were from 78.3% to 117.6%, and the repeatabilities of peak areas for the 18 PAHs were less than 5% (RSD, n = 5). The present UPC2-PDA method has the advantages of rapid speed, high resolution, and low organic reagent consumption. PMID- 26930964 TI - [Determination of alkyl-phenols in textiles by in-tube capillary solid-phase extraction-gas chromatography]. AB - An in-tube capillary solid-phase extraction (SPE) -gas chromatography (GC) method was developed for confirmation and quantitative determination of octylphenol (OP) and nonylphenol (NP) in textiles. To make the in-tube capillary SPE column, the best SPE cartridge was chosen from four kinds of SPE cartridges. The adsorbent in the cartridge was used as the filling material to make the in-tube capillary SPE column. The nature, volume used, flow rate and adsorption capacity of the eluent were compared. Finally, the in-tube capillary solid-phase extraction was combined with gas chromatography to detect the alkyl phenols (APs). Abselut NEXUS extraction cartridge was chosen as the best solid phase extractant. The optimal in-tube capillary SPE extraction conditions were as follows: 1.2 MUL methanol and 1.2 MUL ultra-pure water for activating the extraction column, 1.2 MUL methanol for eluting, 0.4 MUL/min for solution loading. The method showed a good linear relationship in the low concentration range, and the enrichment ratios for the APs were about 100 times. The detection limits of octylphenol and nonylphenol were 3.7 MUg/L and 4.5 MUg/L, respectively. The recoveries of octylphenol were 85.6%-98.2%, and those of nonylphenol were 83.8%-95.7%. The experimental results demonstrated that the method is simple, rapid, and useful for detecting APs in textiles. PMID- 26930965 TI - [Determination of atmospheric polybrominated diphenyl ethers and polybrominated biphenyl 153 using isotope dilution-high resolution gas chromatography/high resolution mass spectrometry]. AB - Considering the features and demands of the environmental monitoring, an isotope dilution-high resolution gas chromatography/high resolution mass spectrometry method was developed for the determination of polybrominated diphenyl ethers (PBDEs) and polybrominated biphenyls 153 (BB153) in the ambient air. PBDEs and BB153 were extracted using an accelerated solvent extraction apparatus with a mixture of hexane-dichloromethane (v/v, 1:1) and hexane, respectively. The concentrated extracts were loaded on the composite silica gel column for cleanup. The mean recoveries of native compounds at 10% and 90% of the highest levels of calibration curves were 100% and 104% with 5% and 6% of the mean relative standard deviations (n = 7), respectively. The recoveries of 13C labeled surrogates for di- to deca-brominated diphenyl ethers and BB153 were in the range of 36.5%-133%. However, the recoveries of 13C-monobrominated diphenyl ethers were relatively low, maybe due to the different physicochemical properties compared with the other homologues. No breakthrough of pollutants was estimated under real sampling volume of 300 m3. The limits of detection were lower than 2 x 10(-4) ng/Nm3. The recoveries of 13C labeled surrogates were between 56% and 126%, except monoBDEs. The results demonstrated that the method is suitable for the analysis of di- to decabrominated diphenyl ethers and BB153 in the ambient air with precise quantification. PMID- 26930966 TI - [Rapid screening and confirmation of 205 pesticide residues in rice by QuEChERS and liquid chromatography-mass spectrometry]. AB - A method for rapid screening and confirmation of 205 pesticide residues in rice was developed by combining QuEChERS and high performance liquid chromatography triple quadrupole-linear ion trap mass spectrometry (LC-Q-TRAP/MS). The rice samples were extracted with acetonitrile, and then cleaned up with primary secondary amine (PSA), anhydrous magnesium sulfate (MgSO4) and C18 adsorbent. Finally, the samples were detected by LC-Q-TRAP/MS in multiple reaction monitoring with information-dependent acquisition of enhanced product ion (MRM IDA-EPI) mode followed with database searching. A total of 205 pesticide residues were confirmed by retention times, ion pairs and the database searching using EPI library, and quantified by external standard method. All the pesticides showed good linearities with linear correlation coefficients all above 0.995. The limits of quantification (LOQs) for the 205 pesticides were 0.5-10.0 MUg/kg. The average recoveries of the 205 pesticides ranged from 62.4% to 127.1% with the relative standard deviations (RSDs) of 1.0% - 20.0% at spiked levels of 10 MUg/kg and 50 MUg/kg, and only 20 min were needed for the analysis of an actual rice sample. In brief, the method is fast, accurate and highly sensitive, and is suitable for the screening and confirmation of pesticide residues in rice. PMID- 26930967 TI - [Simultaneous determination of glyphosate and glufosinate-ammonium residues in tea by ultra performance liquid chromatography-tandem mass spectrometry coupled with pre-column derivatization]. AB - A method was developed for the determination of glyphosate (GLY) and glufosinate ammonium (GLUF) in tea using ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The sample was extracted with ultrapure water and dichloromethane for 30 min under ultrasonication, followed by a simple cleanup with a C18 solid phase extraction (SPE) cartridge, and then GLY and GLUF were derivatized using 9-fluorenylmethoxycarbonyl (FMOC-Cl) in borate buffer for 2 h. The derivatives of GLY and GLUF were separated on a Waters C18 column (50 mm x 2.1 mm, 1.7 MUm) in a gradient elution mode, and finally detected with positive electrospray ionization-mass spectrometry (ESI-MS/MS ) in multiple reaction monitoring (MRM) mode. The quantification analysis was performed by external standard method. The method showed a good linearity (r > 0. 990) in the range of 0.003 125-0.1 mg/L. The limits of detection (LODs) of GLY and GLUF were 0.03 mg/kg. At the spiked levels of 0.375, 1.5 and 4.5 mg/kg, the recoveries of GLY and GLUF were 87.37%-99.11% and 81.44% -86.17% respectively, and the relative standard deviations (RSDs) (n = 6) of GLY and GLUF were 0.68%-1.35% and 1.01% 2.33%, respectively. This method is simple, rapid and characterized with acceptable sensitivity and accuracy to meet the requirements for the analysis of GLY and GLUF simultaneously in tea. PMID- 26930968 TI - [Rapid screen of 15 basic artificial dyes in fishery products by ultra performance liquid chromatography coupled with quadrupole-time of flight mass spectrometry]. AB - A new method was established for the simultaneous determination of 15 basic artificial dyes in fishery products by ultra performance liquid chromatography coupled with quadrupole-time of flight mass spectrometry (UPLC-Q-TOF MS). The analytes in fishery products were extracted with acetonitrile containing 10% (v/v) acetic acid, then purified by dispersive solid phase extraction with C18 silicone adsorbent. The compounds were separated by a C18 column with acetonitrile and 0.1% (v/v) formic acid-5 mmol/L ammonium acetate solution as the mobile phases, and measured by UPLC-Q-TOF MS with electrospray ionization in positive mode. As a result, the limits of quantification (LOQs, S/N = 10) of the 15 target compounds were 0.1-100 MUg/kg in fishery products. The 15 analytes behaved linearly in their respective ranges with the correlation coefficients no less than 0.993. The average recoveries of the 15 analytes spiked at three levels were ranged from 80.60% to 107.37% with the RSDs of 3.33%-6. 69% (n = 6). This method is suitable for routine qualitative and quantitative analyses of the 15 basic artificial dyes in fishery products due to its fastness, simplicity and relatively high sensitivity. PMID- 26930969 TI - [Rapid screening and identification of 22 allergenic disperse dyes in ecological textiles by high performance liquid chromatography-linear ion trap/orbitrap mass spectrometry]. AB - A rapid screening method based on high performance liquid chromatography-linear ion trap/orbitrap high-resolution mass spectrometry (HPLC-LTQ/Orbitrap MS) for 22 disperse dyes in ecological textiles has been established. The target compounds were extracted by pyridine/water (1:1, v/v) by shaking extraction in 90 degrees C water bath. The extracts were then separated by a CAPCELL PAK C18 column (100 mm x 2.0 mm, 5 MUm) using gradient elution with acetonitrile-5 mmol/L ammonium acetate containing 0.01% (v/v) formic acid as mobile phases, and finally analyzed by HPLC-LTQ/Orbitrap in positive and negative ESI modes. The retention time and accurate mass of parent ion were used for fast screening of 22 disperse dyes, while the confirmatory analysis was obtained by fragments generated by collision induced dissociation (CID) MS/MS. Target analysis exhibited high mass accuracy (< 5 x 10(-6)). Each target showed a good linearity in its own concentration range and the correlation coefficient was higher than 0.99. The LOQs were 0.125-2.5 mg/kg. Except for Disperse Yellow 49, the average recoveries of most disperse dyes at three spiked levels were 65%-120%, and the relative standard deviations (n = 6) were less than 15%. The method was applied for screening 40 different kinds of textiles, and Disperse Orange 37/76 was detected in one of them. With high selectivity and strong anti-jamming ability, this method is simple, rapid, accurate, and it can be used for the inspection of disperse dyes in textiles. PMID- 26930970 TI - [Determination of trace and ultra-trace level bromate in water by large volume sample injection with enrichment column for on-line preconcentration coupled with ion chromatography]. AB - A method for the determination of trace and ultra-trace level bromate in water by ion chromatography with large volume sample injection for on-line preconcentration was established. A high capacity Dionex IonPac AG23 guard column was simply used as the enrichment column instead of the loop for the preconcentration of bromate. High purity KOH solution used as eluent for gradient elution was on-line produced by an eluent generator automatically. The results showed that a good linear relationship of bromate was exhibited in the range of 0.05-51.2 MUg/L (r >= 0.999 5), and the method detection limit was 0.01 MUg/L. Compared with conventional sample injection, the injection volume was up to 5 mL, and the enrichment factor of this method was about 240 times. This method was successfully applied for several real samples of pure water which were purchased in the supermarket, and the recoveries of bromate were between 90%-100% with the RSDs (n = 6) of 2.1%-6.4% at two spiked levels. This method without pretreatment is simple, and of high accuracy and precision. The preconcentration can be achieved by large volume sample injection. It is suitable for the analysis of trace and ultra-trace level bromate. PMID- 26930971 TI - [Research on Breeding of Dioscorea opposita cv. Tiegun]. AB - OBJECTIVE: To breeding the new varieties Dioscorea opposita cv. Tiegun with the best comprehensive properties. METHODS: Seven new Dioscorea opposita. cv. Tiegun cultivars were screened by space mutation breeding of Dioscorea opposita cv. Tiegun bulbils. Yield,allantoin content,water soluble extractive and the resistance of these seven cultivars were compared with the main cultivar Dioscorea opposita cv. Tiegun( CK). Meanwhile, the nutrition quality of new cultivars No. 6 and No. 10 were compared with the main cultivar. RESULTS: (1) The fresh weight per plant ranked in the order as follows: No. 6 > No. 10 > No. 4 > No. 9 > No. 1 > CK > No. 2 > No. 8. The drying rate ranked in the order as follows: No. 2 > No. 10 > No. 9 > No. 6 > No. 8 > CK > No. 1 > No. 4. Dry weight per plant ranked in the order as follows: No. 10 > No. 9 > No. 6 > No. 2 > No. 1 > CK > No. 4 > No. 8. The fresh weight per plant, drying rate and dry weight per plant of No. 6 and No. 10 were higher than the main cultivar. (2) The allantoin content ranked in the order as follows: No. 6 > No. 4 > No. 10 > CK > No. 9 > No. 8 > No. 2 > No. 1. (3) The water soluble extractive contents ranked in the order as follows: No. 6 > No. 2 > No. 4 > No. 10 > No. 1 > CK > No. 9 > No. 8. The water soluble extractive content of No. 6 was higher than No. 10 and the main cultivar. (4) No. 10 had the best taste of dry, soft, sweet and fragrant, No. 6 had the taste of dry, floury and hard, and No. 9 had the taste of dry and crisp. (5) No. 6 had the strongest resistance to Gloeosporium pestis and Cykindrosporium dioscoreae; No. 10 had a middle resistance to Gloeosporium pestis and a strong resistance to Cykindrosporium dioscoreae; and the main cultivar had a middle degree of being prone to Gloeosporium pestis and a middle resistance to Cykindrosporium dioscoreae. (6) The content of starch, reducing sugar, protein and ash in No. 6 and No. 10 were higher than that of the main cultivar,while the content of water in No. 6 and No. 10 were lower,which indicated that the nutrition quality of No. 6 and No. 10 is better than the main cultivar. CONCLUSION: The new cultivar No. 10 is suitable for popularizing as a new variety of edible Dioscorea opposita cv. Tiegun. The new cultivar No. 6 is suitable for popularizing as a new variety of medicinal Dioscorea opposita cv. Tiegun. PMID- 26930972 TI - [Effects of Different Altitudes and Sowing Dates on Direct Sowing Angelica sinensis Yield and Quality]. AB - OBJECTIVE: To study the effects of different altitudes and sowing dates on direct sowing Angelica sinensis biomass, yield and quality, and to provide a theoretical basis for Angelica sinensis direct sowing cultivation techniques. METHODS: Two factors trials were used to research the influence of altitude and sowing dates on yield and quality of direct sowing Angelica sinensis. The altitudes were located at 2500, 2000 and 1500 m, and the sowing dates were set up at autumn August 29, and Spring April 3 and April 24. The experiments were designed with split plot. RESULTS: Under the same altitude, roots and aboveground biomass of direct sowing Angelica sinensis were higher when sowing earlier. In the same sowing date, the root and aboveground biomass was the maximum at 2 000 m altitude, followed by elevation of 1 500 m. At 2 500 m altitude, Angelica sinensis root and aboveground biomass was the minimum. Sowing at 2 000 m altitude at August 29 direct sowing Angelica sinensis showed the highest biomass and yield, reaching 13 840.95 kg/hm2, significantly higher than the other treatments. Compared with transplanting Angelica sinensis in this region, the production of direct sowing Angelica sinensis was also 15. 3% higher. Angelica sinensis medicinal grade was significantly higher than the rest of the process. Angelica sinensis extract, volatile oil and ferulic acid content had reached the standard of Chinese Pharmacopoeia. CONCLUSION: Angelica sinensis sowed in late August at 2000 m altitude has the best yield and quality on root length, root diameter, plant height, leaf number, dry and fresh matter accumulation, followed by 1500 m altitude, and 2500 m worst. Therefore, altitude range of Angelica sinensis direct sowing cultivation area can be reduced to 1500-2000 m. CONCLUSION: Angelica sinensis sowed in late August, at 2000 m altitude, the indicators like root length,root diameter,plant height,leaf number,and dry and fresh matter accumulation showed the best, followed by 1500 m altitude, 2500 m worst. Therefore, altitude range of Angelica sinensis direct sowing cultivation area can be reduced to 1500~2000 m. PMID- 26930973 TI - [Fertilizer Effect on Yield and Quality of Gentiana crassicaulis]. AB - OBJECTIVE: To find the best fertilizer formula of yield-quality-fertilizer effect, and to establish a new comprehensive evaluation-fertilizer effect method. METHODS: Grey related degree analysis and DTOPSIS method were combined to comprehensive evaluate the 11 indexes of 14 fertilizer formulas of nitrogen, phosphorus and potassium, in order to explore the best dosage and ratio. RESULTS: The fertilizer requirements of the factors which contribute to the yield and quality of Gentiana crassicaulis were different and the most appropriate rates of nitrogen, phosphorus and potassium fertilizer were 21.49~42.03 kg/667 m2, 49.53~65.75 kg/667 m2 and 26.34~ 42.97 kg/667 m2, respectively. CONCLUSION: The fertilizer formula in this study can be widely used in the standardized plantation of Gentiana crassicaulis. PMID- 26930974 TI - [Study on Dormant Culture and Plant Regeneration via Cluster Buds of Gentiana straminea]. AB - OBJECTIVE: In order to provide scientific basis for micropropagation and cryopreservation of Gentiana straminea,plantlets were regenerated from dormant buds by cluster buds. METHODS: Based on MS medium, dormant buds were inoculated in mediums containing different type and concentration of cytokinin and auxin for inducing cluster buds. 1/2MS medium with different concentration of auxin were used for inducing root. RESULTS: The medium of MS with 2.0 mg/L 6-BA, 0.01 mg/L NAA,30 g/L sucrose and 7 g/L agar was suitable for cluster buds' primary culture and subculture. The cluster buds inducing rate was 93. 3%. Multiple shoot clumps multiplication factor was 5.6. The medium of 1/2MS with 2.0 mg/L IAA, 0.5 mg/L IBA, 15 g/L sucrose and 7 g/L agar was suitable for root induction, its inducing rate was 93.5% with plantlets growing well. CONCLUSION: Plantlets regenerated from dormant buds of Gentiana straminea via cluster buds are established in this study. PMID- 26930975 TI - [UPLC/Q-TOF MS-Based Metabolomics Analysis of Chemical uiterences in Different Polygala tenuifolia Varieties]. AB - OBJECTIVE: The chemical differences of Polygala tenuifolia varieties-JinYuan 1 (JY1), FenYuan 2 (FY2) and traditional FenYang (FY) were studied, in order to provide reference for the breeding of Polygala tenuifolia. METHODS: The samples of JY1, FY2 and FY were subjected to ultra-high performance liquid chromatography (UPLC) quadrupole time-of-flight mass spectrometry (Q-TOF MS) analysis. The obtained data were analyzed using Principal Component Analysis (PCA) and other statistical analysis methods, and differential metabolites were further figured out. RESULTS: Compared with FY,sucrose esters (such as sibiricoses A5 and tenuifoliside B) and oligosaccharides (such as tenuifoliose K) in JY1 and FY2 contributed more to the separation of Polygala tenuifolia varieties in the PCA score plot. Compared with JYl, The sugar esters (such as tenuifoliside B and tenuifoliside A) and oligosaccharides( such as tenuifoliose A) in the FY2 also contributed more to the separation of Polygala tenuifolia varieties in the PCA score plot. In addition, the relative contents of sibiricaxanthone A,3,6' disinapoly sucrose and senegin III showed significant differences among FY, JY1 and FY2. CONCLUSION: As new Polygala tenuifolia varieties, JY1 and FY2 had certain differences and respective advantages on the chemical composition compared with FY,which could provide data support for the directional breeding of Polygala tenuifolia based on the contents of some active compounds. PMID- 26930977 TI - [Effects of Processing on Phellodendri Chinensis Cortex Based on Material and Energy Metabolism]. AB - OBJECTIVE: To compare the pharmacodynamic indicators of Phellodendri Chinensis Cortex with its processed products, in order to study the processing mechanism. METHODS: The effects of raw Phellodendri Chinensis Cortex and its processed products on 17 kinds of indicators in rats were compared, such as the biological characteristics (weight and rectal temperature), material metabolism (lactic acid, acetone acid and triglyceride), energy metabolism (Na+ - K+ -ATPase, Ca2+ Mg2+ -ATPase, LDH, SDH and liver glyco- gen), thyroid function axis (T3, T4, TSH and TRH), cyclic nucleotide ( cAMP, cGMP and cAMP/cGMP value). RESULTS: Phellodendri Chinensis Cortex and its salt processing product changed the indicators including weight, rectal temperature, material metabolism, energy metabolism, thyroid function shaft and cyclic nucleotide in rats. The effect of salt processing product was better than that of the raw one, but wine processing product had little effects. CONCLUSION: The "cold" influence of Philodendri Chinensis Cortex is enhanced after pro- cessing with salt,but induced after processing with wine. PMID- 26930976 TI - [Distribution and Community Characteristics or Epimedium myrianthum in Chongqing]. AB - OBJECTIVE: To make clear the distribution area in Chongqing and community characteristics of Epimedium myrianthum, in order to provide evidence for sustainable utilization of resources. METHODS: Based on field investigation, recorded the GPS, and used the quadrat method to observe and analyze the abundance, frequentness and importance value of Epimedium myrianthum in the seven well-concentrated sample plots of different habitats. RESULTS: Epimedium myrianthum distributed in Changshou County, Dianjiang County, Zhongxian County and Fengdu County of Chongqing at present. The altitude of its distribution areas ranged from 351~663 m. The types of its habitats included coniferous forest, broad-leaved forest and bamboo forest. The plants in these communities were composed of 56 species belonging to 48 genera,33 families. Among associated plants, the dominant species of tree layer were Bambusa distegia, Quercus variabilis , Cupressusfunebris etc. The dominant species of shrub layer were Pittosporum illicioides, Loropetalum chinense, Myrsine africana, Ardisia japonica, Smilax china etc. The dominant species of field layer were Iris japonica, Miscanthus floridulus, Veronicastrum longispicatum, Carex lancifolia, Epimedium myrianthum etc. Species abundance index of D was between 1.1143 to 3.7781 in seven populations,the species in these communities were relatively less,and the numbers of individuals were relatively more. Compared with others, the population of the 3rd and 6th had relatively low index of H' (Shannon-wiener index) and E (Pielou index). The distribution of these species in the community was obviously uneven. The D value,H' value and E value of tree layer species richness were lower than those of shrub layer and field layer, the species diversity was worse. CONCLUSION: It is suggested to incorporate Epimedium myrianthum in the new edition of Chinese Pharmacopeia. PMID- 26930978 TI - [Comparative Study on Morphological Characteristics of Root of Six Species in Sect. Cruciata]. AB - OBJECTIVE: To provide evidences for the identification of Gentianae Macrophyllae Radix by comparing the morphological characteristics of six species of Sect. Cruciata (Gentiana macrophylla, G. crassicaulis, G. straminea, G. dahurica, G. officinalis and G. siphonantha). METHODS: By microscope, the tissue characteristics with freehand section of the upper, middle and lower of root and the powder characteristics with chloral hydrate were studied. RESULTS: The vascular cylinder of G. crassicaulis was not split. The vascular cylinder of G. macrophylla, G. dahurica and G. officinalis, were only split in the upper part. The root of G. straminea and G. siphonantha wre completely divided into several smaller roots twisting together. There were a lot of thick walled cells in the powder of G. dahurica, G. straminea and G. siphonantha, but their shapes were different. No thick walled cells were found in the other three species. CONCLUSION: There are obviously differences among the microscopic morphological characteristics of root of six species of Sect. Cruciata, which can provide the basis for identification of Gentianae macrophyllae Radix. PMID- 26930979 TI - [DNA Molecular Identification of Datura Medicinal Plants Using ITS2 Barcode Sequence]. AB - OBJECTIVE: To identify Datura medicinal plants in Solanaceae using DNA barcode technique and ITS2 sequence. METHODS: The second internal transcribed spacer (ITS2) of Datura and Nicotiana medicinal plant samples was amplified by PCR and sequenced. To expand scope of the research topic, ITS2 sequences of related species were downloaded from GenBank. Sequence assembly and consensus sequence generation were performed by CodonCode Aligner. All the ITS2 sequences in the study were compared and analyzed using software DNAMAN. The related data analysis and processing were performed using software MEGA 5. 10 and the NJ tree was constructed. The ITS2 secondary structure was predicted using ITS2 web server, and distinguishing differences of the ITS2 secondary structures of the samples. RESULTS: In the cluster dendrogram, all of samples were clustered into three branches. The plants of Nicotiana were clustered into a single branch, and the same as Datura (Brugmansia) arborea, which is similar to the results of previous studies. These proved that Brugmansia and Datura belonged to two different genera. Other species of Datura were clustered into a branch where all the intra species samples were clustered to one branch respectively and obviously distinguished, which showed monophyletic. Bootstrap support rates between each two branches were more than 95%. CONCLUSION: ITS2 sequences have great potential in terms of systematics study and variety identification. PMID- 26930981 TI - [Chemical Composition of n-Butanol Fraction from Polygonum amplexicaule var. sinense]. AB - OBJECTIVE: To study chemical composition of n-butanol fraction from Polygonoum amplexicaule var. sinense. METHODS: TLC,normal-phase silica gel, reveres-phase silica gel, Sephadex-LH and semi-preparative HPLC were used to isolate chemical compositions of n-butanol fraction from Polygonoum amplexicaule var. sinense. RESULTS: Nine compounds were identified as: caffeic acid n-butly ester (1), p methoxy benzoic acid propyl ester (2),p-E-coumarin quinic acid methyl ester (3),p Z-coumarin quinic acid methyl ester (4), ethyl ferulate (5), cinchonain I a (6), cinchonain Ib (7), methyl chlorogenate(8), and 6-O-beta-D-caffeoylglucose (9). CONCLUSION: All compounds are isolated from this genus for the first time. PMID- 26930980 TI - [Chemical Constituents from Dalbergia cochinchinensis]. AB - OBJECTIVE: To investigate the chemical constituents from the heartwood of Dalbergia cochinchinensis. METHODS: Isolate and purify compounds by various column chromatographic methods. Spectral analysis were taken to identify the structures. RESULTS: Elev- en compounds were isolated and identified as dibutyl terephthalate (1), medicarpin (2), pterostilbene (3), 6-hydroxy-2-(2-hydroxy-4- methoxyphenyl)-benzofuran (4), pterocarpol (5), butyl isobutyl phthalate (6), pterolinus B (7), methyl 4-hydroxybenzoate (8), ethyl 4- hydroxybenzoate (9),2 (2'-methoxy-4'-hydroxy)-aryl-3-methyl-6-hydroxy-benzofuran (10) and 6alpha hydroxycyclonerolidol (11). CONCLUSION: Compounds 1 and 6~10 are isolated from Dalbergia genus for the first time, and compounds 2, 4 and 11 are isolated from this plant for the first time. PMID- 26930982 TI - [Chemical Constituents of Paris polyphylla var. chinensis Aerial Parts]. AB - OBJECTIVE: To study the chemical constituents of aerial parts of Paris polyphylla var. chinensis . METHODS: Aerial parts of Paris polyphylla var. chinensis was extracted with 95% EtOH, and separated and purified by silica gel, RP 18 and Sephadex LH-20 col- umn chromatography. The structures were identified by spectroscopic analysis. RESULTS: A total of ten compounds were isolated and iden- tified as beta-sitosterol (1) ergosta-7, 22-dien-3-one (2), beta-ecdysone (3), kaempferol (4), daucosterol (5) luteolin (6) calonysterone (7), luteolin-7-O glucoside (8), quercetin (9), and 3beta, 5alpha, 9alpha-trihydroxyergosta-7, 22 dien-6-one (10). CONCLUSION: Compounds 2,6 and 10 are isolated from Paris polyphylla var. chinensis for the first time. PMID- 26930983 TI - [Chemical Constituents from Young Fruits of Citrus maxima cv. Shatian]. AB - OBJECTIVE: To investigate the chemical constituents from the young fruits of Citrus maxima cv. Shatian. METHODS: The chemical constituents were isolated and purified by silica gel column chromatography and recrystallization, and their structures were identified on the basis of physicochemical properties and spectral analysis. RESULTS: Seven compounds were isolated and identified as naringenin (I), marmin (II), naringin (III), beta-sitosterol (IV) 5,7 dihydroxylcoumarin (V) 1, 3,5-trihydroxyhenzene (VI) and xanthotoxol (VII). CONCLUSION: Except compound III, all compounds are isolated from the young fruits of Citrus maxima cv. Shatian for the first time. PMID- 26930984 TI - [Therapeutic Material Basis of Chemical Subdivisions of Anemarrhenae Rhizoma on Anti-inflammatory and Immunomudulatory Effects]. AB - OBJECTIVE: To study the relationship between chemical subdivision and immune suppressive activity in order to find out the anti-inflammatory and immunomudulatory pharmacological activity material basic of Anemarrhenae Rhizoma. METHOD: C57 mice was induced by 2,4-Dinitrofluorobenzene to build immune inflammation which was also called contact allergic dermatitis. The influence of Anemarrhenae Rhizoma decoction and chemical subdivisions on immune organ, ear edema and the Th1/Th2 immune balance was measured by analytical balance and Elisa method. The inflammatory factor TNF-alpha and NO level excreted by macrophage RAW264. 7 induced by LPS were also investigated. RESULT: AA decoction, timosaponin and polysaccharides significantly reduced the immune organ index and ear edema degree (P < 0.05), protein expression of IFN-gamma was inhibited by AA timosaponin fraction and polysaccharides fraction. In vitro experiments showed that the proliferation of spleen cells was inhibited by timosaponin and polysaccharides after induced by ConA (P < 0.05). The release of NO and TNF-alpha induced by LPS significantly decreased by Anemarrhenae Rhizoma decoction and timosaponin (P < 0.05). CONCLUSION: The significant anti-inflammatory and immunomudu latory effects of AA are related to timosaponin and polysaccharides. PMID- 26930985 TI - [In vivo Pharmacokinetics of Notoginsenoside R1 in Ischemia Rats After Acute Myocardial Infarction]. AB - OBJECTIVE: To establish an HPLC-UV method for determining pharmacokinetic difference of notoginsenoside R1 between normal rats and ischemic rats. METHODS: 48 male SD rats were randomly divided into normal group and acute myocardial ischemia( AMI) model group induced by pituitrin and each group was classified into high,middle and low-dose of groups with notoginsenoside R1 (200, 100 and 50 mg/kg) respectively. Blood samples were collected at different points in time after they were administered once by gavage and separated by Waters symmetry C18 column (250 mm x 4.6 mm, 5 um) under the detective wavelength 203 nm, the mobile phase was acetonitrile-water with icariin as the internal standard and the pharmacokinetic parameters were calculated by DAS 2. 0. RESULTS: Notoginsenoside R1 had good linearity in the ranges of 0.2~125 ug/mL (R2 = 0.9997) with SNR 1:3 and the lowest detection limit was 0.053 ug/mL, the extraction rate, RSDs of within-day and between-day, specificity, accuracy and precision accorded with the require-ment of bio-sample pretreatment. Compared to the normal group, AUC0-t, and AUC0-infinity was significantly increased (P < 0.01) and the terminal half life was prolonged markedly (P < 0.01) in AMI group. CONCLUSIONS: The method is simple, accurate and had high specificity and sensitivity, that could be applied in quantitative determination of notoginsenoside R1 and research of pharmacokinetics; the relative bioavailability of notoginsenoside R1 is increased significantly in AMI group,which indicates that notoginsenoside R1 has better effect in model rat. PMID- 26930986 TI - [Spectrum-Effect Relationship of GualouXiebai Dropping Pills on Myocardial Ischemia]. AB - OBJECTIVE: To study the relationship between HPLC characteristic spectrum and pharmacodynamics on anti-myocardial ischemia of GualouXiebai dropping pills. METHODS: HPLC characteristic spectrum of GualouXiebai dropping pills was established, dropping pills were divided into five dose groups (3.75, 11.25, 22.5, 33.75 and 45 g/kg, equivalent to the crude herb g/kg), the mice were orally administered dropping pills once daily for 7 d, 90 min after the mice were given by intraperitoneal injection of isoprenaline to establish myocardial ischemia models, the level of CK in blood plasma were detected; Then, the correlation between characteristic spectrum and biochemical index CK was studied by grey relational analysis method. RESULTS: The correlation between each common peak and CK had gradually increased with the dose increased from 3.73 g/kg to 33.75 g/kg, but when the dose reached to 45 g/kg, the correlation between each common peak and CK had decreased. The variation trends of correlation of spectrum-effect relationship for different dose were similar,but the correlation variation trend of the efficacy on the No. 8 peak in 33.75 g/kg group with the other four groups in the opposite, the change trends of the No. 11 peak in 22.5 g/kg group, the No. 24 peak in 33. 75 g/kg group and the No. 37 peak in 45 g/ kg group with 3.75 g/kg group and 11.25 g/kg group on the contrary. The relational orders of spectrum effect relationship were not consistent, respectively( the first 15 peaks) :11 > 37 > 24 > 30 > 8 > 21 > 2 > 16 > 1 > 3 > 20 > 15 > 12 > 19 > 7;11 > 37 > 30 > 8 > 21 > 24 > 2 > 1 > 16 > 3 > 27 > 12 > 22 > 20 >10; 8 > 30 > 1 > 2 > 21 > 27 > 31 > 22 > 16 > 12 > 3 > 10 > 9 > 20 > 4; 1 > 2 > 27 > 21 > 31 > 22 > 12 > 16 > 9 > 3 > 10 > 4 > 17 > 30 > 20; 8 > 30 > 1 > 2 > 2 > 2 > 7 > 31 > 22 > 16 > 12 > 3 > 9 > 10 > 20 > 17. CONCLUSION: Anti-myocardial ischemia effect of GualouXiebai dropping pills comes from the synergistic or antagonistic effect among various active ingredients related to the dose. With the difference of the dosage, the relational orders of chemical components to play the role is not the same, but the main components to play a pharmacodynamic of five dose groups are consistent,the existence of the component groups lay a foundation for further study of GualouXiebai dropping pills. PMID- 26930987 TI - [Effects and HPA Axis Related Mechanism of Kaixin-San and Danggui-Shaoyao-San on Glucose and Lipid Metabolism in Chronic Stress Rats with High-fat Diet]. AB - OBJECTIVE: To study the effects and potential mechanism of Kaixin-San and Danggui Shaoyao-San on glucose and lipid metabolism in chronic stress rats fed with high fat diet. METHODS: 50 male Wistar rats were randomly divided into normal control group (distilled water), high-fat diet with chronic stress group (distilled water), melatonin group(20 mg/kg), Kaixin-San group (445 mg/kg) and Danggui Shaoyao-San group (3360 mg/kg). All drugs were orally administered. In addition to the normal control group, each group of rats were fed with high-fat, diet. Simultaneously, stress were carried out after drugs administration 1 h daily. The duration was lasted for six weeks. The rat body weight daily was recorded, and the 24 h period urine was collected to detect the level of urine corticosterone (CORT) after three weeks. The level of plasma intraperitoneal glucose tolerance (IVGTT) was detected after six weeks. Finally, rats were executed, and serum fasting blood glucose (FBG), triglyceride (TG), total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), insulin (INS), adrenocorticotropic hormone releasing hormone (CRH), adrenocorticotropic hormone (ACTH), CORT and melatonin ( MLT) were determined. The weight of adrenal gland, liver glycogen and muscle glycogen levels were detected. The adrenal gland index, Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) and insulin sensitivity index( ISI) were calculated. RESULTS: Compared with normal group, model rats body weight, IVGTT (120 min), plasm CORT were decreased significantly. Serum TG, TC, LDL-C and urine CORT after three weeks were increased significantly. Kaixin-San and Danggui- Shaoyao-San could regulate the above indexes. CONCLUSION: Kaixin-San and Danggui-Shaoyao-San may regulate the activity of HPA axis, and improve glucose and lipid metabolism disorder in model rats by increasing melatonin secretion. PMID- 26930988 TI - [Chromatographic Fingerprinting Study of Zhenyuan Granules Dry Extract by HPLC DAD and HPLC-MS/MS]. AB - OBJECTIVE: To establish a novel, accurate and valid fingerprint method of Zhenyuan granules dry extract by using HPLC-DAD method, to study herbs belonging of fingerprint peaks and to identify some of the chromatographic peaks by HPLC MS/MS analysis, for providing the basis for scientific evaluation of the quality. METHODS: The sample solutions were analyzed by an Agilent SB C18 (250 mm x 4.6 mm, 5 um) column, and gradiently eluted with acetonitrile (containing 0.1% formic acid) and aqueous phase (containing 0.1% formic acid) as the mobile phase. The flow rates were 1.2 mL/min (0~70 min) and 0.8 mL/min (70~150 min); the column temperature was 30 degrees C; and the detection wavelength was 254 nm. RESULTS: 40 peaks were selected as fingerprint peaks under the optimal chromatographic condition, and the similarity coefficients of 10 batches of Zhenyuan granules dry extract were all greater than 0.98. 27 peaks were tentatively identified with reference to literature data based on their mass spectrometry. CONCLUSION: The chromatographic fingerprint of Zhenyuan granules is proved to be a reliable method for comprehensive quality control and assessment. PMID- 26930989 TI - [Simultaneous Determination of Seven Chemical Markers and Preliminary Identification of Chemical Constituents in Daodi Psoraleae Fructus-Myristicae Semen Chinese Drug Pair]. AB - OBJECTIVE: To study the simultaneous determination method of daodi Psoraleae Fructus-Myristicae Semen Chinese drug pair for the seven ingredients, and Psoraleae Fructus-Myristicae Semen Chinese drug pair on the chemical composition of initial ownership and identification. METHODS: UPLC BEH C18 column (2.1 mm x 100 mm, 1.7 um) was used in the determination. The flow rate was kept at 0.25 mL/min, and 2 uL of standard and sample solution were injected in each run. The mobile phase was consisted of acetonitrile and water using a gradient elution. The UPLC/Q-TOF MS condition: Waters HSS T3 (100 mm x 2.1 mm,1.7 um); capillary voltage 3.0 kV (positive ion mode) and 2.5 kV (negative ion mode); Mass spectrometric detection was carried out on a Waters Xevo G2 Q/ TOF mass spectrometer equipped with an ESI source operating in both positive and negative ion modes. The parameters of the mass spectrometer under the ESI mode were as follows: ion source temperature 110 degrees C, cone gas flow 50 L/h, desolvation gas temperature 450 degrees C, desolvation gas flow 800 L/h. RESULTS: The seven chemical markers in the selected linear range had good linearity. The recoveries were in the range of 95.07%-98.16% and RSDs were between 1.23%-1.97%. CONCLUSION: It is suitable for the quality control and further studies of the herb in vivo of daodi Psoraleae Fructus-Myristicae Semen Chinese drug pair. PMID- 26930990 TI - [Study on HPLC-DAD Fingerprint of Xiaoying Jiedu Decoction]. AB - OBJECTIVE: Based on backtracking method, identification and quality evaluation of Xiaoying Jiedu Decoction (XYJDD) by HPLC fingerprint analysis were carried out. METHODS: HPLC-DAD fingerprint of XYJDD was conducted with Dikma Platisil ODS C18 column (250 mm x 4.6 mm, 5 um) and gradient elution with the mobile phase consisting of acetonitrile-(0.1% phosphoric acid-0.1% triethylamine solution) at column temperature of 30 degrees C. On the basis of the established chromatographic pattern of XYJDD tracking backward to the corresponding crude herbal drugs in the formula and the attribution of most peaks in the XYJDD fingerprint can be figured out. RESULTS: 16 peaks of XYJDD HPLC fingerprint were assigned by parallel comparison with the fingerprint of the five corresponding crude drugs in the formula of Scutellariae Radix, Glycyrrhizae Radix et Rhizoma, Houttuyniae Herba, Aurantii Fructus, Arnebiae Radix. Four peaks can be identified with the chemical reference substances. CONCLUSION: The entirety of XYJDD HPLC fingerprint enhances the specialty for control and assessment of the product quality, and the backtracking experimental method can be expected to be applied in chromatographic fingerprinting analysis of complex Chinese patent medicine. PMID- 26930991 TI - [Formulation Optimization of Zuojin Floating-Bioadhesive Pellets by Central Composite Design-Response Surface Methodology]. AB - OBJECTIVE: To optimize the formulation of Zuojin floating-bioadhesive pellets by the central composite design-response surface methodology (CCD-RSM). METHODS: In the formulation design using CCD-RSM, independent variables were the amounts of sodium bicarbonate (X1), HPMC (X2) and MCC (X3) as factors. Small pills roundness, 12 h floating rate and the percentages of in vitro cumulative releases at 2,6 and 12 h were dependent variables. Multilinear and quadratic model were used to estimate the relationship between the dependent and the independent variables. According to best model, the contour plots and RSM were drawn, and the optional formulation was selected. According to the optional formulation,the pellets were prepared and validated. RESULTS: The quadratic was the best fitting mode. Small pills roundness was 15.04 degrees . 12 h floating rate was 75.07%. Percentages of in vitro cumulation release at 2,6 and 12 h of the option formulation pellets was 27.01%, 70.00% and 84.61%, respectively. The actual value was close to the predicted value. Deviation was less than 5%. CONCLUSION: Quadratic model was preferred in the optimization of formulation due to the statistical confidence. The multi-objective simultaneous optimization of Zuojin floating pellet formulation can be achieved by the central composite design response surface methodology. PMID- 26930992 TI - It's Nurses' Job to Help Patients and Families Make Informed Decisions. PMID- 26930993 TI - Maximize Your ONS Experience by Making Your Membership Work for You. PMID- 26930994 TI - Making Treatment Decisions Together. PMID- 26930995 TI - What Is the Shared Decision-Making Process for Lung Cancer Screening? PMID- 26930996 TI - Research Helps Guide Shared Decision Making in Cancer Clinical Trials. PMID- 26930997 TI - What Nurses Need to Know About Private Patient Advocates. PMID- 26930998 TI - How Targeted Therapies Are Changing Treatment for Non-Small Cell Lung Cancer. PMID- 26930999 TI - President Obama Challenges Nation With Moon Shot Cancer Cure. PMID- 26931000 TI - The Case of the Cancer Treatment Confusion. PMID- 26931001 TI - Death With Dignity Provides Options for Patients at the End of Life. PMID- 26931002 TI - Lidocaine Reduces Pain During Sexual Intercourse for Breast Cancer Survivors. PMID- 26931003 TI - [REAL-TIME PCR IN THE COMPLEX DIAGNOSTICS OF COMBINED PATHOLOGY OF THE PERIODONTIUM AND GASTRO-DUODENAL ZONE]. AB - Biological material of 92 patients (18-85 years old) with different severity chronic periodontitis were analyzed for bacterial pathogen colonization by using Dentofol kit (DNA-technology, Moscow). The cohort included 70 individuals with chronic gastritis, 2 patients with gastric and duodenal ulceration and 20 individuals with no gastric/duodenal pathology. The tight- est association with severity of the chronic periodontitis in the analyzed sub-cohort with the chronic gastritis was found with the prevalence of a complex T. for sythensis/T. denticola. Key contribution of this complex to progression of periodon- titis in males of the eldest group (above 55) was hypothesized. This data essentially differ from published results of other research groups where T. forsythensis and T. denticola were never reported as the principal causative agents of the chronic periodonitis in the gender/age/combined pathology normalized cohorts. PMID- 26931004 TI - [THE FEATURES OF SECRETION AND STOMACH MOTOR PROCESSES IN PATIENTS WITH DUODENAL ULCERS AS A CAUSE FOR REDUCING BIOAVAILABILITY OF PROTON PUMP INHIBITORS]. AB - The article contains the modern data about the role of duodenal reflux in the development of acid-dependent diseases of stomach and duodenum. There are the results of studies in which the known quantitative parameters of duodenal reflux in the duodenal ulcer patients were simulated to identify their influence on the disintegration of enterosoluble dosage forms and the bioavailability of proton pump inhibitors (in healthy volunteers, patients with gasritis, exacerbation and remission of peptic ulcer disease the pharmacokinetics of lansoprazole, intragastric pH-metry with floating capsule for teleradio-pH-metry were investigated, and in an in vitro study the dissolution tests of proton pump inhibitors with pH 3 and pH = 4 were made). CONCLUSION: The high-amplitude oscillations of intragastric pH, observed during exacerbation of duodenal ulcer, can lead to an early disintegration of enteric-coated dosage form of proton pump inhibitors in the stomach, its destruction and decreased bioavailability. PMID- 26931005 TI - [ENDOSCOPIC ANATOMY AND MORPHOLOGICAL CHANGES OF THE GASTRODUODENAL JUNCTION IN ULCER OF THE DUODENUM]. AB - OBJECTIVE: To Improve the diagnosis of duodenal ulcer and preneoplastic changes of gastroduodenal transition. MATERIALS AND METHODS: 112 patients with duodenal ulcer, 208 healthy pearsons of three age periods: second period of mature age, elderly and senile age were examined. Video endoscopy equipment company "OLYMPUS" (Japan), morphological methods and the determination of Helicobacter pylori (Hp) were used. RESULTS: The connecting line of gastric and duodenal mucous membrane can be located on the gastric side of the pylorus (13% in normal cases and 22.3% in cases of ulcer disease), on pylorus and go into the bulbus of duodenum (87% and 77.7 %, respectively), in cases of duodenal ulcer the connecting line more often has jagged and tongue-shaped form. Mucous membrane forms folds in prepyloric part of the stomach most often on the front wall in healthy pearsons in 14.4% of cases, in patients with duodenal ulcer--in 75.9%. The number of folds decreases with age. HP, atrophy, intestinal metaplasia of the mucous membrane is more often found in duodenal ulcer disease--76.8%, 69.7% and 62.5% comparing with healthy persons: 51.4%, 5.3% and 47.7% respectively. Frequency of preneoplastic changes increases with age. The individual differences of the mucous membrane of the gastroduodenal transition are identified. They are expressed in the particular location and shape of the connecting line of gastric and duodenal mucous membranes in normal cases and in cases of ulcer disease in different age groups. Some endoscopic changes requiring biopsy and morphological studies are revealed. PMID- 26931006 TI - [THE GEPATOPANCREATOBILIARY SYSTEM AFTER CHOLECYSTECTOMY]. AB - The article presents the results of a survey of 72 patients who underwent cholecystectomy in 2008-2010. 5 years after cholecystectomy were revealed the changes in the organs of the gastrointestinal tract caused by loss of the physiological function of the gallbladder: half of patients--had increasing fasting blood sugar and duodenal reflux, in 46% of patients--were reduction of pancreatic elastase-1 in stools. According to the fractional duodenal intubation prevails hypersecretory type of bile, 35%--hypotonia, in 45%-- hypertonicity of the sphincter of Oddi. Definition "postcholecystectomical syndrome" should not be limited only to the sphincter of Oddi dysfunction. PMID- 26931007 TI - [THE CONTENT OF BILE ACIDS IN THE SERUM OF PATIENTS WITH NONALCOHOLIC FATTY LIVER DISEASE]. AB - AIM: Rate content of primary, secondary, tertiary and unconjugated bile acids in the blood of patients with NAFLD. METHODS: The study involved 74 patients with NAFLD (male--30, female--44) And 51 healthy individuals (male--14, female--37). All patients underwent anthropometry and they had a complete clinical, biochemical and instrumental examination (determination of the amount of fat in the subcutaneous fat layer). Patients with hepatic steatosis were--64 people, with steatohepatitis--10 people. The content of bile acids (primary: cholic, chenodeoxycholic; secondary: lithocholic, deoxycholic and tertiary: ursodeoxycholic) in serum were determined by gas-liquid chromatography, chromatography "Chromos GC-1000" (Russia). RESULTS: In the blood of healthy individuals and patients with NAFLD are determined unconjugated primary, secondary and tertiary LCD. In healthy individuals there are no gender differences in the content of the LCD. NAFLD patients LCD level higher than that of healthy individuals. There is a significant difference in the concentration of secondary and tertiary LCD in patients with hepatic steatosis and steatohepatitis. CONCLUSIONS: 1. The content of the bile acids in the blood of patients with NAFLD significantly higher than in healthy individuals. 2. When steatohepatitis compared with hepatic steatosis, there are more significant fluctuations in the blood content of the LCD according to gender and type of LCD. So, cholic, chenodeoxycholic and deoxycholic higher than that of men, while, lithocholic and UDCA below. 3. Significant difference in the content of fatty acids in the blood between patients with hepatic steatosis and steatohepatitis exists only in relation to the secondary and tertiary LCD. Thus, when steatohepatitis compared with hepatic steatosis litoheolevaya acid and UDCA more in men and deoxycholic below. Conversely, women and lithocholic UDCA below and above deoxycholic acid. PMID- 26931008 TI - [ANXIETY AND DEPRESSIVE DISORDERS IN FUNCTIONAL DYSPEPSIA: CAUSE OR CONSEQUENCE?]. AB - The aim of this study was to evaluate the frequency and importance of anxiety and depression in patients with functional dyspepsia (FD), the relationship between these psychological characteristics, symptom severity and the quality of life. METHODS: We performed a cross-sectional study. 125 patients with FD according to the Rome criteria ill, as well as a control group of 30 healthy volunteers were investigated. All study participants filled out a scale to identify HADS anxiety depressive disorder, an overall assessment of the quality of life, using a questionnaire SF-8 (standard 4-week form). FD patients were asked to rate the severity of epigastric pain (burning) or abdominal discomfort (early satiation or postprandial fullness) with LPDS scale (Leuven postprandial distress scale). All statistical analyzes were performed in the Medstat program. The results obtained with p < 0.05 and 95% CI were considered statistically significant. RESULTS: Anxiety and depression were observed in 50.4% and 42.4% of FD patients, respectively, and in 13.3% and 6.66% of healthy subjects, respectively (p < 0.001 for both). The mean HADS scores for anxiety and depression in lBS patients were 7.93 +/- 3.75 and 6.94 +/- 3.78, respectively. Both anxiety and depression were associated with self-reported symptom severity (LPDS) (p < 0.05). As determined by correlation analysis, symptom severity was the most important factor in the prediction of anxiety and depression. Self-reported symptom severity, anxiety and depression were clearly and independently associated with the overall health related quality of life (HRQOL). CONCLUSIONS: Biopsychosocial model of FD explained the difficulties of the pathogenesis of this disease. Anxiety and de- pression were frequently observed in FD patients and were related to the severity of their symptoms and the impairment of the patient's HRQOL. Our data suggest that assessing anxiety and depression is important when evaluating FD patients. PMID- 26931009 TI - [CLINICAL FEATURE OF NONALCOHOLIC STEATOHEPATITIS, ASSOCIATED WITH CHRONIC CONSTIPATION]. AB - THE AIM OF THE STUDY: to conduct a comprehensive assessment of features of combined course NASH and functional constipation using laboratory parameters, the data of instrumental methods, indicators of quality of life in comparison with patients with Nash without proven pathology of the intestine. MATERIALS AND METHODS: In the cross-sectional comparative study involving 102 patients with NASH, among which identified patients with functional constipation, there were formed two groups: study group (patients with NASH and functional constipation) and comparison group (patients with NASH without pathology of the intestine). All patients underwent a comprehensive assessment of laboratory data (markers of cytolysis, cholestasis, lipid and carbohydrate metabolism), results of instrumental methods (hydrogen breath test), quality of life (questionnaire SF 36). RESULTS: All patients with NASH, regardless of the presence of functional bowel pathology was characterized by hyperlipidemia with a tendency to lower HDL and raise LDL with normal levels of triglycerides, fasting hyperglycemia, increased postprandial glucose, glycated hemoglobin and HOMA--IR higher than normal values and the availability of the SIBO. NASH is often associated with functional constipation (68.6%). Patients with functional constipation and NASH have a significantly higher average level of ALT (127.3 +/- 58.4 U/I in the control group and to 103.5 +/- 74.6 U/I in the comparison group, p = 0.02), more frequent association with the SIBO (65.7% in the main group opposed to 43.7% in the comparison group, p = 0.014) and a lower quality of life compared with patients without pathology of the intestine. CONCLUSION: NASH has frequent association with functional constipation, worsens its course, resulting in a significant increase in the level of the marker of cytolysis (ALT), the more expressed SIBO and a palpable decline in the quality of life of patients, therefore the impaired intestinal function in these patients requires close attention. PMID- 26931010 TI - [SOME ASPECTS OF DIAGNOSIS AND COMPREHENSIVE TREATMENT OF BARRETT'S ESOPHAGUS]. AB - OBJECTIVE: Assess the value of routine endoscopy in the diagnosis of Barrett's esophagus (BE) in patients with gastroesophageal reflux disease (GERD) and to show the feasibility of a comprehensive treatment algorithm that includes antireflux surgery as an essential component. MATERIALS AND METHODS: The study was conducted on a sample of 171 patients with Barrett's esophagus who underwent antireflux surgery. In evaluating the operating characteristics of endoscopy were recruited another 675 patients with GERD without BE. On the diagnostic phase was used endoscopy with double chromoscopy and biopsy followed by histological examination. At the stage of treatment, patients received conservative therapy by PPl after which underwent antireflux surgery and argon-plasma coagulation (in some cases). RESULTS: Endoscopy of the esophagus with a double chromoscopy in identification BE in patients with GERD, has a moderate sensitivity (71.9%, 95% Cl 64.6%-78.5%) and high specificity (100%, 95% Cl 99.5%-100%). A comprehensive treatment approach that includes antireflux surgery as an essential component has allowed to achieve excellent and satisfactory immediate results of treatment in 88.9% of patients (95% Cl 83.2%-93.2%). Excellent and satisfactory long-term results were achieved in 89.5 % of patients (95% Cl 83.9%-93.6 %). CONCLUSION: The results indicate the need for biopsy and histological examination in all patients with GERD, who has no suspicion of BE according to endoscopy, and prove high efficiency of complex treatment algorithm that includes antireflux surgery as an essential component. PMID- 26931011 TI - [CLINICO-ANATOMICAL EVALUATION OF MIRIZZI SYNDROME]. AB - Presentation of diagnostic capabilities of Mirizzi syndrome in a surgical hospital given its pathological anatomy. Were analyzed 70 case-records of patients with different types of Mirizzi syndrome who were sorted out to groups, relying on extended classification, comprising 6 types. The advantages and disadvantages of diagnostic methods used in Mirizzi syndrome were examined. The evaluation of output data of a number of diagnostic studies promotes concretization of diagnosis. When uninformative results of ultrasound is received the performance of additional diagnostic procedures is necessary. Differential diagnosis between inflammation and cancer of the extrahepatic biliary tract is a complex task. Choosing a less traumatic and dangerous reconstructive surgery depends on the results of preoperative diagnosis. PMID- 26931012 TI - [CLINICAL, ENDOSCOPIC AND MORPHOLOGICAL FEATURES OF GASTROESOPHAGEAL REFLUX DISEASE IN PATIENTS WITH CERTAIN SURGICAL DISEASES OF THE UPPER GASTROINTESTINAL TRACT]. AB - OBJECTIVE: To reveal the peculiarities of manifestations and treatment of gastroesophageal reflux disease (GERD) in patients with peptic ulcer disease of the stomach and duodenum, hiatal hernia (HH) and after stomach resection. MATERIALS AND METHODS: 387 patients with GERD, peptic ulcer disease of the stomach and duodenum (200 patients), after resection of the stomach Billroth II (150 patients), 37 patients with HH. Videoendoscopic equipment company OLYMPUS (Japan) was used. Biopsies of the mucous membranes of the pylorus, body, angle of the stomach and esophagus were studied to identify preneoplastic changes. HP was determined histologically, cytologically, urease tests. RESULTS: The patients with GERD and peptic ulcer disease of the stomach and duodenum were complained on the heartburn, the patients after resection of the stomach--on feeling bitterness in the mouth, with HH--on the pain behind the breastbone. More severe degree of GERD (C and D) was endoscopic feature in patients with HH and A degree or endoscopic negative form--after resection of the stomach. Preneoplastic changes of the esophageal mucosa with columnar epithelium were found in cases of less severe degrees of inflammation. The degree of esophagitis, presence of preneoplastic changes were determined depending on the presence of Helicobacter pylori. Antireflux surgery was performed under strict indications. CONCLUSION: Clinical features, endoscopic, morphological manifestations of GERD in patients with pectic ulcer disease of the stomach and duodenum, with resection of the stomach and patients with HH were determined. This is dictated the individual differentiated approach to the choice of the treatment. PMID- 26931014 TI - [EOSINOPHILIC DISORDERS OF GASTROINTESTINAL TRACT]. AB - Pathological eosinophilic infiltration of the various parts of the gastrointestinal tract (GIT) is a marker of a wide range of diseases, combined into three groups: eosinophil-associated gastrointestinal diseases (primary gastrointestinal eosinophilia), gastrointestinal disorders within the hypereosinophilic syndrome, gastrointestinal eosinophilia, developing, for obvious reasons. The article provides an overview of foreing and domestic literature about ethiopathogenesis, diagnosis and treatment methods of these three groups of gastrointestinal eosinophilia. PMID- 26931013 TI - [THE INFLUENCE OF LEU-ENKEPHALIN AND MEDICAL PLANTS ON MOTOR ACTIVITY OF STOMACH IN DOGS]. AB - The aim of the real research was a study influence of leu-enkephalin and extracts from the leaves of goose-grass large, of burdock of felted and root of chicory on the motor function of stomach for dogs. The study was carried out on 6 outbred dogs-males, by mass 14-17 kg, with the fistula of stomach by Basov. A leu enkephalin ("Vector", Russia) was entered intravenously in a dose 7 mcg/kg. The corresponding plant-based preparations entered perorally during 10-14 days to beginning of experiments, on an empty stomach, in a volume a no more than 20 ml. Experiments put in a morning clock, in 16-18 hours after eating, after the careful washing of stomach. For 30 mines to the record of motive activity of stomach an animal was enter a peptide or gave a corresponding extract as water or spirit infusion. At the choice of doses of vegetable preparations came from the before obtained data about the antiulcerous action of the used plants. The conduct of peptide rendered considerable stimulant influence on motor activity of stomach, that was expressed in the increase of period of work and increase of force of reductions especially tonic. All used plants preparations rendered modulating influence on motive activity of stomach. Changes consisted in strengthening of tonic and oppressing of phase component. The most considerable decline of amount of phase reductions caused application of extract of goose grass. Not only an amount but also force of phase reductions diminished thus. An extract from the root of chicory less considerably reduced the arnount of Phase reJuctions, but here substantially increased their force. All used herbal medicines stimulated tonic activity. Thus, peptide and all studied herbal medicines stimulated motion activity of the stomach that could cause acceleration of evacuation of food to duodenum. Such effect should be considered while choosing the medicine for correction of stomach functional activity. PMID- 26931015 TI - [BILIARY PAIN: CHARACTERISTICS, CAUSES, MEDICAL TREATMENT]. AB - The majority of the diseases of biliary tract circuit is accompanied by different degree of manifestation by pains. The paper gives different treatments of the determination of the pain, including of abdominal, the classification of abdominal pain, are determined the special features of biliary pain depending on kinds, levels of the defeat of the biliary circuit presence of primary and second functional disorders of the biliary tract. Accordingly, the presence of biliary pain is signal for taking of diagnostic measures for the purpose of the refinement of the nature of the defeat of biliary circuit and finalizing of the tactics of treatment. The analysis of effectiveness in the application of different spasmolitics preparations is carried out. Are shown the advantages of the use of preparation of hymecromone during the treatment of patients by the biliary pathology, that does not require surgical treatment, or as the means of the rehabilitation of patients after surgery treatment. PMID- 26931016 TI - [NON-ALCOHOLIC FATTY PANCREATIC DISEASE (NAFPD) AND THE METABOLIC SYNDROME: INITIATING FACTOR OR ADDITIONAL COMPONENT?]. AB - Nonalcoholic fatty pancreatic disease (NAFPD) integrates the spectrum of chronic clinical and morphological pancreatic changes: steatosis and nonalcoholic steatopancreatitis. NAFPD prevalence in USA was 27.8%, in China--12.9-16%. According to our data, 51.8% of patients with chronic pancreatitis was diagnosed MS. Association NAFPD with MS has been confirmed in most studies, the presence of any components of MS increases the prevalence NAFPD by 37 %. In the NAFPD pathogenesis is important not only excessive intake of free fatty acids (FFA), which leads to the pancreatic parenchyma inflammation and fibrosis, but also "glucolipotoxicity" (i.e., the combined toxicity of hyperglycemia and increased FFA level) for beta-cells. It is shown that NAFPD is an initial index ofectopic fat deposition, and the earlier manifestation of MS than NAFLD. Most likely, a stage (or degree) of the MS is usefully to determine as the pancreatic status- its exo- and endocrine functions, and fat deposition. This approach will allow us to develop new therapeutic approaches not only to treatment but also to the primary prevention of metabolic syndrome. PMID- 26931017 TI - [RARE COMPLICATION OF PANCREATITIS PANKREATOPLEVRALNY FISTULA BOTH PLEURAL CAVITY]. AB - This article presents a case of a rare complication--pankreatopleural fistula in a patient with chronic pancreatitis. The features of clinical manifestations and complications of this diagnostic search. PMID- 26931018 TI - [Effects of single heat stress treatment on spermatogenic cells in mice]. AB - OBJECTIVE: To investigate the effects of single heat stress treatment on spermatogenic cells in mice. METHODS: We randomly divided 36 C57 male mice into a control and a heat stress treatment group and submerged the lower part of the torso in water at 25 degrees C and 43 degrees C, respectively, both for 15 minutes. At 1, 7, and 14 days after treatment, we obtained the testicular organ indexes, observed the changes in testicular morphology by HE staining, and determined the location and expression levels of the promyelocytic leukemia zinc finger (PLZF) and synaptonemal comlex protein-3 (SCP-3) in the testis tissue by immunohistochemistry and Western blot. RESULTS: The testicular organ index was significantly lower in the heat stress treatment than in the control group (P < 0.05). Compared with the controls, the heat shock-treated mice showed loosely arranged spermatogenic cells scattered in the seminiferous tubules at 1 day after heat stress treatment, atrophied, loosely arranged and obviously reduced number of spermatogenic cells at 7 days, and relatively closely arranged seminiferous tubules and increased number and layers of spermatogenic cells at 14 days. The number of SCP-3 labelled spermatocytes obviously decreased in the heat stress treated animals at 1 and 7 days and began to increase at 14 days. The PLZF protein expression was significantly reduced in the heat stress treatment group at 1 day as compared with that in the control (0.19 +/- 0.12 vs 0.64 +/- 0.03, P < 0.01), but elevated to 0.77 +/- 0.02 at 7 and 14 days, even remarkably higher than in the control animals (P < 0.01). CONCLUSION: Heat stress treatment can induce short-term dyszoospermia in mice, which can be recovered with the prolonged time after treatment. PMID- 26931019 TI - [Expression characteristics of the Ccdc70 gene in the mouse testis during spermatogenesis]. AB - OBJECTIVE: To investigate the expression characteristics of the gene of coiled coil domain-containing protein 70 (Ccdc70) in the mouse testis and its potential role in spermatogenesis. METHODS: Using expression profile microarray, we screened the mouse testis-specific gene Ccdc70, studied its expression characteristics in the mouse testis by RT-PCR, real-time PCR, Western blot and immunohistochemistry, followed by bioinformatic analysis of the Ccdc70 protein. RESULTS: The Ccdc70 gene was expressed highly in the testis but lowly in the epididymis of the mice. The Ccdc70 protein was expressed mainly in the spermatocytes and round spermatids of the testis and in the epithelial cells of the epididymis. Bioinformatic analysis showed a structural domain in the Ccdc70 protein, which was highly conserved in mammalian evolution. CONCLUSION: The Ccdc70 gene is highly expressed in the mouse testis and mainly in the spermatocytes, round spermatids, and epididymal epithelial cells, which indicates that it is involved in the regulation of spermatogenesis and epididymal sperm maturation. PMID- 26931020 TI - [Association of the deleted DAZ gene copy related to gr/gr and b2/b3 deletions with spermatogenic impairment]. AB - OBJECTIVE: To investigate the correlation of the deleted azoospermia (DAZ) gene copy related to gr/gr and b2/b3 deletions in the AZFc region with male spermatogenic impairment. METHODS: This study included 121 infertile men with different de- grees of spermatogenic impairment and 95 healthy donors from the sperm bank. Using PCR, PCR-RFLP, and Y chromosome specific sequence tagged sites (STS) , we analyzed the association of DAZ gene copy deletions related to gr/gr and b2/b3 deletions in the AZFc region with spermatogenic impairment. RESULTS: There were 15 cases of gr/gr deletion (12. 40% ) and 6 cases of b2/b3 deletion (4.96%) in the infertility group as compared with 13 cases of gr/gr deletion (13.68%) and 1 case of b2/b3 deletion (1.05%) in the control. Analysis of the DAZ specific single nucleotide variant (SNV) loci revealed 11 gr/gr-DAZI/DAZ2 deletions (9.09%), 4 gr/gr-DAZ3/DAZ4 deletions (3.31%), and 6 b2/b3-DAZ1/DAZ2 deletions (4.96%) in the infertile men in comparison with 3 gr/ gr-DAZ1/DAZ2 deletions (3.16%), 10 gr/gr-DAZ3/DAZ4 deletions (10.53%), and 1 b2/b3- DAZ3/DAZ4 deletion (1.05%) in the control. CONCLUSION: Partial deletions of gr/gr and b2/b3 exist in both healthy men and male patients with different degrees of spermatogenic impairment and cannot be considered as a risk factor for spermatogenesis impairment. However, deletions of different DAZ duplicons in gr/gr and b2/b3 deletions have different effects on spermatogenesis. DAZ1/DAZ2 instead of DAZ3/DAZ4 deletions might be associated with spermatogenesis impairment. PMID- 26931021 TI - [Clinical assessment of chronic prostatitis based on infrared imaging technology]. AB - OBJECTIVE: To investigate the characteristic changes in the infrared thermogram of chronic prostatitis (CP) patients and find some evidence for the auxiliary diagnosis and therapeutic evaluation of the disease. METHODS: Fifty CP patients and 20 healthy male volunteers were included in this clinical trial. The infrared thermograms of the subjects were compared between the two groups for characteristic changes. The values obtained were used for the auxiliary diagnosis and therapeutic evaluation of the disease. RESULTS: Compared with the healthy males in the same age group, the CP patients showed extremely significant abnormal changes in the average temperature value in the hypogastrium (H), pubis (P), scrotum (S), and groin (G) (P < 0.01). The average H temperature value of the CP patients was correlated negatively with the CP symptom index (CPSI) (P < 0.01, Pearsons correlation coefficient = -0.519), while the S temperature positively with CPSI (P < 0.01, Pearsons correlation coefficient = 0.446). In addition to the H value, the P, S, and G values were all correlated in different degrees with CPSI (P < 0.01), which the S value exhibited the most significantly negative correlation (Pearson's correlation coefficient = -0.898). CONCLUSION: There are some characteristic changes in the hypogastrium temperature of CP patients in the infrared thermogram, which has a potential application value for the auxiliary diagnosis, symptom assessment, and therapeutic evaluation of CP. PMID- 26931022 TI - [Partial resection, inner thigh skin graft, and glans reconstruction for early stage penile cancer: A report of 6 cases]. AB - OBJECTIVE: To explore the optimal methods for the reconstruction and preservation of the glans after partial penis resection in the treatment of early-stage penile cancer. METHODS: Between January 2012 and June 2015, we treated 6 cases of early- stage penile cancer by partial penis resection, inner thigh skin graft, and glans reconstruction and followed them up for 0.5-3 years. RESULTS: The length of the penis before and after operation was ([6.5 +/- 1.2] vs [4.5 +/- 1.8] cm) in the flaccid state and ([12.8 +/- 2.3] vs [9.1 +/- 2.1] cm) in the erectile state. The sense of the reconstructed glans was completely recovered at 3 months after surgery. The glans skin was pale red and soft, nearly normal at 12 months, with no obvious graft contracture or scar formation. All the patients achieved normal erection and their partners were satisfied with their intercourse. No recurrence or metastasis was observed. CONCLUSION: The strategy of partial penis resection, inner thigh skin graft and glans reconstruction, simple, effective, and with few complications, is one of the best treatments of early-stage penile cancer, which not only ensures radical removal of the tumor but also maximally reserves the function of the organ. PMID- 26931023 TI - [Normal sperm morphology and the outcomes of routine in vitro fertilization]. AB - OBJECTIVE: To explore the application value of morphology assessment of sperm from fresh semen in routine in vitro fertilization (IVF). METHODS: We analyzed the morphology of the sperm from fresh or optimized semen samples and, based on the sperm morphology of the raw semen, allocated 908 IVF cycles due to the pure tubal factor to different groups: morphologically normal sperm (MNS) <= 4%, > 4% <= 15%, and > 15% in Trial 1 and MNS <= 1%, > 1% - <= 2%, > 2% - <= 3%, and > 3% - <= 4% in Trial 2. We compared the rates of fertilization, cleavage, high quality embryo, -blastocyst formation, and pregnancy among different groups. RESULTS: The total fertilization rate was significantly lower in the MNS <= 4% than in the MNS > 4% - <= 15% and >15% groups (74.40% vs 78.61% and 80.03%, P < 0.01). Compared with the MNS <= 1%, > 1% - <= 2%, and > 2% - <= 3% groups, the MNS > 3% - <= 4% group showed remarkably increased rates of 2PN normal fertilization (77.23%, 78.97% and 78.99% vs 85.47%, P < 0.01), cleavage (95.71%, 96.01% and 97.27% vs 98.73%, P < 0.05), and blastocyst formation (53.85%, 49.01% and 49.55% vs 63.41%, P < 0.01). No statistically significant differences were observed in the rates of clinical pregnancy, implantation, early abortion, live birth, or malformation at birth among different groups (P > 0.05). CONCLUSION: MNS <= 4% affected the total rate of fertilization while MNS <= 3% reduced the rate of normal fertilization in IVF. However, even MNS <= 1% did not result in fertilization disorder or failure. Therefore, teratozoospermia alone was not an indicator of ICSI and sperm mor- phology assessment had no obvious value for predicting the rates of embryo quality, clinical pregnancy, and live birth in IVF. PMID- 26931024 TI - [Reproducibility of Gleason scores in prostate cancer]. AB - OBJECTIVE: To investigate the reproducibility of Gleason scores for prostate cancer. METHODS: Based on the revised Gleason Scoring System of the International Society of Urological Pathology ( ISUP) , we analyzed the reproducibility and difference of Gleason scores in 49 cases of prostate cancer using the methods of combination and grouping. RESULTS: The total reproducibility of Gleason scores among 15 pathologists was good (kappa = 0.642), 62.2% by the combination method, the highest in Gleason 5 + 5 (81.2%) and 5 +4 (73.3%), then in Gleason 4 + 4 (67.5%), 3 + 3 (64.0%), 4 +3 (61.3%), and 3 + 4 (44.0%), and the lowest in Gleason 4 + 5 (38.9%) and 3 + 5 (33.3%). The total reproducibility of Gleason scores by the grouping method was 71.4%, the highest in Gleason 9-10 (84.9%) , then in Gleason 7 (76.7%) and 6 (64.0%), and the lowest in Gleason 8 (60.7%). CONCLUSION: The reproducibility of Gleason scores remains to be further improved in prostate cancer, mainly concerning the understanding of Gleason 3 and 4 carcinoma. PMID- 26931025 TI - [Combination of the ureteral dilation catheter and balloon catheter under the ureteroscope in the treatment of male urethral stricture]. AB - OBJECTIVE: To investigate the clinical application of the ureteral dilation catheter combined with the balloon catheter under the ureteroscope in the treatment of urethral stricture in men. METHODS: Under the ureteroscope, 45 male patients with urethral stricture received placement of a zebra guide wire through the strictured urethra into the bladder and then a ureteral dilation catheter along the guide wire, followed by dilation of the urethra from F8 initially to F14 and F16. Again, the ureteroscope was used to determine the length of the strictured urethra, its distance to the external urethral orifice, and whether it was normally located. An F24 balloon catheter and then a metal urethral calibrator was used for the dilation of the strictured urethra. After removal of the F18-F22 urethral catheter at 8 weeks, the urinary flow rate was measured immediately and again at 3 months. RESULTS: All the operations were successfully performed without serious complications. The maximum urinary flow rate was (13.3 29.9) ml/s (mean [17.7 +/- 3.2] ml/s) at the removal of the catheter and (15.2 30.8) ml/s (mean [19.8 +/- 3.9] ml/s) at 3 months after it. Smooth urination was found in all the patients during the 6-24 months follow-up. CONCLUSION: The application of the ureteral dilation catheter combined with, the balloon catheter under the ureteroscope is a good option for the treatment of male urethral stricture for its advantages of uncomplicatedness, safety, effectiveness, few complications, less pain, high success rate, and repeatable operation. PMID- 26931026 TI - [Brucella orchitis: A retrospective study of 69 cases]. AB - OBJECTIVE: To investigate the epidemiological characteristics, clinical manifestations, diagnosis, and treatment of Brucella orchitis, so as to provide reliable evidence for the prevention and treatment of the disease. METHODS: We conducted retrospective statistical analyses on the medical records of 48 outpatients and 21 inpatients with Brucella orchitis. RESULTS: Brucella orchitis was diagnosed in 6.67% of the male patients with brucellosis (69/1 034). The disease exhibited typical epidemiological features, with a higher incidence rate among those in frequent contact with sheep and elderly people, in the period from April to July, and in the areas with sheep husbandry. All the Brucella orchitis patients had such local symptoms as testicular pain and swelling, more frequently involving both testes, and other most common symptoms included fever, chills, sweating, and painful joints. Based on IIEF-5, 45 of the patients suffered from severe erectile dysfunction, with their reproductive function temporarily affected in the course of the disease. Misdiagnosis easily occurred in the early stage of the disease. Therapeutic options mainly included doxycycline hydrochloride and rifampicin, administered orally or intravenously, which could effect a cure, though relapse might occur in some cases. CONCLUSION: Bru- cella orchitis has distinct epidemiological characteristics, with clinical manifestations of testicular pain and swelling. Though a transient disease, it affects the reproductive function of the patient before cured. It can be treated by combined oral and intravenous medication, with painkillers or ice bags for testicular pain and swelling. PMID- 26931027 TI - [Longjintonglin Capsules for type IIIA prostatitis accompanied by abnormal semen liquefaction: A clinical observation]. AB - OBJECTIVE: To evaluate the therapeutic effect of Longjintonglin Capsules on type IIIA prostatitis accompanied by abnormal semen liquefaction. METHODS: We selected 140 patients with type IIIA prostatitis accompanied by abnormal semen liquefaction according to the diagnostic standards of the American Institutes of Health (NIH) and treated them with Longjintonglin Capsules orally 3 capsules once tid for 12 weeks. We obtained the NIH Chronic Prostatitis Symptom Indexes (NIH CPSI), traditional Chinese medicine (TCM) syndrome scores, leukocyte count in the expressed prostatic secretion (EPS), semen liquefaction time, and the results of semen analysis and compared these indicators before and after the treatment. RESULTS: Of the 140 cases, 132 were included in this study, excluding 8 due to their incomplete case histories. Before and after 4, 8 and 12 weeks of medication, the total NIH-CPSI scores were 24.52 +/- 5.43, 21.28 +/- 4.85, 18.01 +/- 4.28, and 14.49 +/- 3.65 (P < 0.01), the TCM syndrome scores were 35.63 +/- 6.07, 26.66 +/- 5.03, 17.37 +/- 4.18, and 11.11 +/- 3.96 (P < 0.01), and the leukocyte counts (/HP) were 27.50 +/- 7.01, 22.38 +/- 5.22, 16:76 +/- 4.10, and 11.40 +/- 4.74 (P < 0.01), respectively. After 12 weeks of treatment, 31 of the patients with type IIIA prostatitis were cured and another 72 well responded, with an overall response rate of 78.0%. Of those with abnormal semen liquefaction, 61 were cured, 39 well responded, and 32 failed to respond, with an overall effectiveness rate of 75.8%. Semen analysis showed significantly increased percentage of progressively motile sperm after 4, 8 and 12 weeks of medication as compared with the baseline (P < 0.01). No abnormal liver or renal function or other adverse reactions were observed during the treatment. CONCLUSION: Longjintonglin Capsules, with its advantages of safety, effectiveness and no obvious adverse effects, deserve to be recommended for the treatment of type IIIA prostatitis accompanied by abnormal semen liquefaction. PMID- 26931028 TI - [Biofeedback therapy for chronic prostatitis: Application and consideration]. AB - Studies of biological feedback (BF) for the treatment of chronic prostatitis (CP) are occasionally reported have exhibited some related problems. This article presents an evaluation of the published literature on the BF treatment of CP at home and abroad in the aspects of instrument, method, application, effect, function, and mechanism. UROSTYMTM and MyoTrac are often employed and their operating paths are basically the same. NIH prostate symptom scores, urinary function, pain, sexual function, immune function, prostate fluid, and other indicators are generally used for the analysis of the effects of BF alone or in combination with other therapies on CP and its related symptoms. Either BF alone or BF combined with other therapies can promote urination, reduce pain, improve the quality of life, attenuate inflammation, improve sexual function, adjust immunity, and lessen physical and chemical stimulation. However, the relevant literature is of low quantity and quality, the reported studies are not standardized, and exploration of the action mechanisms is neglected. PMID- 26931029 TI - [Immune mechanisms of the active ingredients of Chinese medicinal herbs for chronic prostatitis]. AB - Chronic prostatitis is a common male disease, and its pathogenesis is not yet clear. Most scholars believe that oxidative stress and immune imbalance are the keys to the occurrence and progression of chronic prostatitis. Currently immunotherapy of chronic prostatitis remains in the exploratory stage. This article relates the active ingredients of 5 Chinese medicinal herbs (total glucosides of paeony, tripterigium wilfordii polglycosidium, curcumin, geniposide, and quercetin) for the treatment of chronic prostatitis and their possible action mechanisms as follows: 1) inhibiting the immune response and activation and proliferation of T-cells, and adjusting the proportion of Th1/Th2 cells; 2) upregulating the expression of Treg and enhancing the patient's tolerability; 3) suppressing the activation of the NF-kB factor, reducing the release of iNOS, and further decreasing the release of NO, IL-2 and other inflammatory cytokines, which contribute to the suppression of the immune response; 4) inhibiting the production of such chemokines as MCP-1 and MIP-1alpha in order to reduce their induction of inflammatory response. Studies on the immune mechanisms of Chinese medicinal herbs in the treatment of chronic prostatitis are clinically valuable for the development of new drugs for this disease. PMID- 26931030 TI - [Ultrastructural observation of morphologically abnormal sperm: Advances in studies and application]. AB - Sperm ultrastructural abnormalities are often associated with sperm motility, the integrity of genetic material, and the fertilization potential. The investigation of sperm ultrastructural abnormalities is based on the evolution of microscopy techniques. In his paper, we review the improvement of the microscopy techniques and the ultrastructure of several specific morphological defects and he apoptotic spermatogenic cells in order to expound the significance of sperm ultrastructural observation in clinical practice. We deem it necessary to analyze the sperm ultrastructure before exploring the pathology and adopting assisted reproductive technology for some special patients with teratozoospermia. PMID- 26931031 TI - [Sperm acrosome formation-associated genes in mice: Advances in studies]. AB - Spermiogenesis is a complex process of differentiation and morphologic alteration, in which sperm acrosome formation is an important stage. Acrosome is an essential component of the sperm head, which develops in four distinct phases: Golgi, cap, acro- somal, and maturation, each supported by precise and orderly regulation of various genes. The regulatory genes which act on Golgi ap- paratus include GOPC, Hrb, SPATA16, PICK1, and CK2alpha', those involved in the cap phase are Fads2, syntaxin 2, Kdm3a, and UBR7, and participating in acrosomal and maturation phases are KIFC1, Rnf19a, and DPY19L2. The abnormalities of these genes may affect male fertility by influencing the connection of the nuclear dense lamina and acroplaxome with the nuclear membrane and then the fusion and transportation of vesicles. This review focuses on the genes involved in different phases of acrosome formation. PMID- 26931032 TI - [Sperm DNA fragmentation index and the success rate of IVF/ICSI]. AB - Sperm DNA fragmentation index (DFI) refers to the percentage of DNA strand breaks in the total sperm. Many studies suggest that elevated DFI can lead to male infertility and early spontaneous abortion. High-DFI patients are more likely to fail in assisted reproduction and preliminary treatment or prevention methods have been developed for this population. This review focuses on the impact of DFI on clinical pregnancy outcomes and progress in the studies of its treatment. PMID- 26931033 TI - [Malaria Situation in the People' s Republic of China in 2014]. AB - The 2014 malaria epidemiological data reported through the annual malaria statistics reporting system were collected and analyzed. A total of 3 078 malaria cases were reported in 680 counties of 30 Provinces/ Municipalities/Autonomous Regions (P/M/A)(except Inner Mongolia) in 2014, decreased by 25.4% compared with the 4 128 cases in 2013. The incidence rate was 0.022 6/10 000. More cases distributed in Yunnan (17.3%, 533/3 078), Jiangsu (11.5%, 355/3 078), Sichuan (8.6%, 266/3 078), Henan (7.0%, 216/3 078) and Zhejiang (7.0%, 215/3 078) Provinces. Of all the cases, 56 (1.8%) were indigenous cases, mainly from the border area of Yunnan (comprising 9 counties) and the Tibet Autonomous Region (one county). Locally-infected falciparum malaria was only found in Yingjiang County (4 cases) and Cangyuan County (2 cases) of Yunnan. Indigenous malaria prevalence was of over 1/10 000 in Motuo County and Yingjiang County. There were 3 021 abroad-imported cases of malaria (98.1% ), which widely distributed in the 30 P/M/As. In addition, one case of quartan malaria with long latency was reported' in Guangdong Province. Of all the reported cases, 3 057 (99.3%) were further confirmed by plasmodium species, comprising 846 cases of vivax malaria (27.7%), 1 882 cases of falciparum malaria (61.6%), 3 cases of quartan malaria (1.7%), 231 cases of ovale malaria (7.6%), 44 cases of mixed infections, and one case of P. knowlesi malaria. Furthermore, 170 cases (5.5%) with severe conditions were reported in 16 P/M/As, and 25 deaths were reported in 15 P/M/As. In summary, remarkable achievements have been made in eliminating malaria in China, despite increases in imported cases. The border areas of Yunnan and Motuo County of Tibet Autonomous Region remain the key regions for malaria elimination. Efforts are needed to reinforce the management of imported cases and the treatment of complicated malaria. PMID- 26931034 TI - [Oral cavity infestation by larvae of Psychoda sp., Psychodidae]. PMID- 26931035 TI - [Spatial Effect of the Dams and Sluices on the Risk of Schistosomiasis in Dongting Lake Region of Hunan Province]. AB - OBJECTIVE: To determine the spatial effect of the dams and the sluices on the risk of schistosomiasis in Dongting Lake Region, and its mechanism, type and degree. METHODS: The positions, levels and types of the dams and the sluices in Dongting Lake Region of Hunan Province were marked on the base map. Epidemiological data of schistosomiasis among populations in 334 Townships in the Region were collected during March and July in each year of 2010-2014, and the 5 year average infection rate was calculated. A grid system composed of 1 220 hexagons was built to spatially quantify the effect of the dams and the sluices on the risk of schistosomiasis and the infection rates among populations. A two step clustering was used to analyze the grid system, and the areas of infection peak were identified. The centrifugal model was used to simulate the degree and scope of the influence of these infection peak areas on the surrounding regions. The correlation coefficient model was used to determine the correlation coefficients between the dams and sluices and the spatial distribution of schistosomiasis. The correlation coefficients were then weighted, the integrated weighted risk of all grid cells calculated, and the weighted distribution figure for schistosomiasis risk produced. RESULTS: The results of two-step clustering revealed 15 areas of infection peak in the Region. The results of centrifugal model showed that the areas of infection peak significantly promoted the effect of the surrounding regions on the risk of infection. The correlation coefficients of the dams and the sluices with the infection rate among populations were 0.82 and 0.86, with the weights being 0.488 1 and 0.511 9, respectively. The areas with high and relatively high risks of infection had a Crescent-shaped distribution along the Lishui River, West Dongting Lake, South Dongting Lake, East Dongting Lake and Chenglingji. The results were further verified by MAE testing. CONCLUSION: The dams and sluices correlated strongly and positively with the risk of schistosomiasis. Fifteen areas of infection peak are identified to be determinant for schistosomiasis infection and spread, and have significant gradient spatial effect on schistosomiasis risk in surrounding areas. PMID- 26931036 TI - [The Effect of Lipopolysaccharide-Induced Mouse B Cell Activation on Schistosoma japonicum Development]. AB - OBJECTIVE: To investigate the effect of lipopolysaccharide (LPS)-induced B cell activation on the development of Schistosoma japonicum. METHODS: Eighteen BALB/c nude mice deficient in T cells and 23 BALB/c SCID mice deficient in T and B cells were used in this study. Each was infected with 30 +/- 1 S. japonicum cercariae. The nude (n=9, NL group) and SCID (n=12, SL group) mice then received 2-3 (every two weeks) intraperitoneal injections with LPS (100 MUg/mL, 0.2 mL for each mouse). The remaining nude(n=9, N group) and SCID (n=11, S group) mice received PBS injection as control. The mice were sacrificed on days 28 and 36 after infection (n=4/5, 4/5, 5/6, 6/6 for N, NL, S and SL groups, respectively), and adult worms were collected by hepatic portal vein perfusion. The collecting rate of the adult worms was calculated, the body-length measured, and pairs of worms recorded. The liver tissue was collected and digested with 5% KOH, and the number of eggs per gram of liver tissue was calculated. The levels of TGF-beta, IFN gamma and IL-10 in peripheral blood were evaluated. Spleen cell suspension was prepared for detecting the proportion of regulatory B cells (Bregs) in splenic lymphocytes. RESULTS: On day 28 after infection, the body-lengths of male worms in NL and N groups were (7.65+/-2.85) mm and (5.28+/-1.64) mm (P<0.01), and those of female worms were (9.64+/-1.99) mm and (7.49+/-1.63) mm (P<0.01), respectively. On day 36 after infection, the number of eggs per gram of liver tissue was significantly higher in the NL group than in the N group (1 088+/-297 vs 715+/-404, P<0.05), and significantly lower in the SL group than in the S group (217+/-33 vs 573+/-160, P<0.01). The proportions of CD(hi)CD5(+)CD19(+) Bregs in N group on days 28 and 36 after infection were (12.73+/-0.96)% and (37.15+/-3.04)% (P<0.05), respectively, with no significant difference with that of NL group. The serum levels of TGF-beta and IFN-y on day 28 after infection were significantly different between N and NL groups (TGF-beta, 101.75+/-46.72 vs 260.90+/-45.34 pg/mL; IFN-y, 7.91+/-1.62 vs 14.11+/-3.72 pg/mL, both P<0.01). Similarly, significant difference was found for the plasma level of IL-10 on day 36 after infection between the S and N groups (41.85+/-3.14 vs 66.25+/-4.16 pg/mL, P<0.01), and between the SL and NL groups (44.48+/-3.87 vs 72.22+/-17.76 pg/mL, P<0.01), but not between the LPS groups and the control groups. CONCLUSION: LPS can induce the release of cytokines (e.g. TGF-beta) from B cells of mice infected with S. japonium, to facilitate the early development of adult female and male worms. PMID- 26931037 TI - [A child case of visceral leishmaniasis misdiagnosed as blood disorder]. PMID- 26931038 TI - [Expression of Tim-3 on Peripheral CD56(+) NK Cells and ItsCorrelation with Liver Fibrosis in Patients withAdvanced Schistosomiasis]. AB - OBJECTIVE: To explore the expression of T cell immunoglobulin and mucin domain protein 3 (Tim-3) on CD56(+) NK cells in peripheral blood and its correlation with liver fibrosis indicators in patients with advanced schistosomiasis. METHODS: Tim-3 expression on CD6(+) NK cells from 28 patients with advanced schistosomiasis and 30 healthy controls was determined by flow cytometry. The serum levels of IFN-y and IL-4 were detected by enzyme-linked immunosorbent assay (ELISA). Fibroscan analyzer was used for liver stiffness measurement (LSM) to determine the extent of liver fibrosis. Four serological indicators of liver fibrosis, collagen type III N-peptide (PIIP N-P), Laminin (LN), collagen IV (CIV) and hyaluronic acid (HA) were measured by the Automated Chemiluminescence Immunoassay Analyzer. RESULTS: Flow cytometry analysis showed that Tim-3 expression on CD56(+) NK cells in advanced schistosomiasis patients was (62.3+/ 11.4)%, significantly higher than that (52.1+/-6.5)% (P< 0.01). In patients with advanced schistosomiasis and the healthy controls, the levels of PIIIP N-P were (86.5+/-29.5) ng/mL and (22.0+/-7.8) ng/mL, LN (49.3+/-21.5) ng/mL and (20.4+/ 6.3) ng/mL, CIV (67.5+/-22.3) ng/mL and (22.0+/-3.9) ng/mL, HA (645.9+/-483.1) ng/mL and (54.7+/-27.7) ng/mL, respectively. There were significant differences in all these indicators between the two groups (P<0.05). The levels of IFN-y were (93.9?20.1) ng/L and (107.7?24.6) ng/L, and those of IL-4 were (46.6+/-11.8) ng/L and (28.9+/-8.9) ng/L respectively in patients with advanced schistosomiasis and the healthy controls, both with significant differences (P<0.05). Spearman nonparametric correlation analysis showed that Tim-3 expression on CD56(+) NK cells in patients was positively correlated with the levels of LSM, PIIIP N-P, LN, CIV and IL-4 (r=0.528-0.834, P<0.01), but negatively with serum IFN-y (r= 0.501, P<0.01). No correlation was found with the HA level (r=0.352, P>0.05). CONCLUSION: The expression of Tim-3 on peripheral CD56(+) NK cells increases in patients with advanced schistosomiasis compared with the healthy controls, and it positively correlates with the levels of LSM, PIIIP N-P, LN, CIV and IL-4, four indicators of liver fibrosis. PMID- 26931039 TI - [The Anatomical Method of Isolating Central Ganglia from Oncomelania hupensis]. AB - In this experiment the soft tissue of Oncomelania hupensis was obtained by breaking the shell with a hemostat. The central ganglia of 0. hupensis were then collected from the fresh soft tissue under a dissecting microscope. This method lays a base for studying the effects of molluscicides or various biological and physicochemical factors on the central ganglia of 0. hupensis. PMID- 26931040 TI - [Endemic Situation of Echinococcosis in Gannan Tibetan Autonomous Prefecture]. AB - OBJECTIVE: To understand the endemic status of echinococcosis in Gannan Tibetan Autonomous Prefecture. METHODS: The 2007-2013 survey data on hydatid disease prevention and control were collected from 8 counties/cities in Gannan Tibetan Autonomous Prefecture and analyzed. Ultrasound scanning was used to detect echinococcosis infection, ELISA was performed to detect anti-Echinococcus IgG in serum of children under 12 years, and double-antibody sandwich ELISA method was used to detect Echinococcus antigen in dog's feces. Visceral dissection was performed to examine hydatid infection in domestic ruminants. RESULTS: The prevalence of echinococcosis in residents was 225/100 000 (810/360 440), comprising 224/10 0000 (807/360 440) for cystic echinococcosis and 1/100 000(3/360 440) for alveolar echinococcosis. The prevalence was 2.3/100 000(340/151 280) in males and 2.3/100 000(470/209 160) in females, with no significant difference(chi(2)=6.41 ,P>0.05). Among different age populations, the 30-40 age group had the highest proportion (44.2%, 358/810) to all detected infections. Besides, the prevalence was the highest in herdsmen, followed by farmers. Echinococcosis was detected in 372 administrative villages in the Prefecture. The positive rate for serum anti-Echinococcus IgG was 4.0%(1 921/47 841) in children under 12 years. The positive rate for Echinococcus antigen in dog's feces was 5.5% (3 523/64 521). The rate of hydatid infection in domestic ruminants was 3.3% (1 148/35 134). After seven years' comprehensive control, the prevalence of echinococcosis in residents dropped from 440/100 000(97/21 938) in 2007 to 290/100 000 (160/55 954) in 2013 (chi(2)=11.69,P<0.05). The positive rate for serum anti-Echinococcus IgG in children also dropped from 7.9% (150/1 902) in 2007 to 2.1% (151/7 100) in 2013. Consistently, the positive rate for Echinococcus antigen in dog's feces dropped from 11.9% (335/2 819) in 2007 to 3.3%(466/13 608) in 2013 (X(2)= 338.52,P<0.05); and the rate of hydatid infection in domestic ruminants dropped from 8.8%(235/2 658) in 2007 to 1.5%(107/7 271) in 2013(chi(2)=317.86, P<0.05). CONCLUSION: The control activities during 2007-2013 has shown significant achievements in reducing echinococcosis in Gannan Tibetan Autonomous Prefecture. PMID- 26931041 TI - [Investigation on the Outbreak of Visceral Leishmaniasis in 2014 in Jiashi County of Xinjiang]. AB - OBJECTIVE: To understand the epidemiological characteristics of visceral leishmaniasis (VL) outbreak in Jiashi County of Xinjiang Uygur Autonomous Region in 2014, and provide basis for VL prevention and control strategies. METHODS: Data on VL epidemic situation in Xinjiang from July 1, 2009 to June 30, 2015 were collected from Chinese CDC Infectious Disease Reporting Information Management System (reporting system). On-site epidemiological investigation was conducted in October, 2014, among children under 3 years in 23 villages in Gholtoghrak Township and Koxawat Township in Jiashi County, regions that had dramatically increased reports of VL cases from July 1. For suspected cases who showed symptoms such as fever and hepato-splenomegaly, blood (20 MUl) was collected through fingerstick (with parental guardian consent) for rk39 immunochromatographic strip testing. Chil- dren with positive results were given sodium stibogluconate treatment (6x200 mg/kg, intravenously). RESULTS: A total of 637 VL cases were reported in Xinjiang from July 1, 2009 to June 30, 2015. Among the 192 cases reported from July 1, 2014 to June 30, 2015 in Xinjiang, cases from Jiashi County occupied 86.46% (166/192) of the cases. The number of VL cases in Jiashi County showed a trend of increase since the first report in August, with a total number of 114 in October, November and December. The 166 cases in Jiashi County had an age range of 23 days-8 years, with those under one year accounting for 95.18%(158/166). The 113 cases in Gholtoghrak Township of the County had an age range of 23 days-3 years, with those under one year accounting for 96.46% (109/113). The age--distribution of VL casess in the County accorded with the characteristic of the desert type. On-site investigation of 833 children in the 23 villiages revealed 11 children with positive results of rk39 immunochromatographic strip testing out of 14 suspected cases, all recovered after one course of sodium stibogluconate treatment. CONCLUSION: In 2014, VL outbreak occurs in Jiashi County with 95% of the cases being children under one year old. This outbreak was identified to be the desert type. PMID- 26931042 TI - [Molecular Detection of Giardia lamblia and Cryptosporidium Species in Pet Dogs]. AB - OBJECTIVE: To determine the prevalence of Giardia lamblia and Cryptosporidium species infection in pet dogs, and identify the G. lamblia assemblages and Cryptosporidium species. METHODS: A total of 315 fresh fecal samples were collected from pet clinics in five counties of Anhui Province and in Hangzhou of Zhejiang Province. Hemi-nested-PCR targeting the GDH gene of G. lamblia and nested-PCR targeting the SSU rRNA gene of Cryptosporidium were performed in all the fecal samples. The PCR products were sequenced and analyzed using bioinformatics methods to identify the G. lamblia assemblages and Cryptosporidium species. RESULTS: The positive rates of G. lamblia and Cryptosporidium spp. infections in the 315 fecal samples were 3.2% (10/315) and 1.6% (5/315), respectively. Specifically, the two indicators were both significantly higher in dogs <=12 months (17.8% and 11.1%, respectively) than in adult dogs (0.7% and 0.0%)(P<0.05). However, there was no significant difference in the two indicators between male and female dogs. In addition, two G. lamblia assemblages were identified, assemblages B (n=6) and D (n=4). Sequence analysis of PCR products of the SSU rRNA gene showed that the five Cryptosporidium isolates were C. canis (n =5). CONCLUSION: The prevalences of G. lamblia and Cryptosporidium infection in pet dogs in Anhui and Zhejiang Provinces were 3.2 % and 1.6 %, respectively. The assemblages of G. lamblia in this study are of types B and D. PMID- 26931043 TI - [Expression of Cocktail DNA Vaccine Comprising Toxoplasma gondii SAGI, MIC3 and ROP2 Using Fluorescent Protein-Reporting Vectors and Evaluation of Its Immunogenicity]. AB - OBJECTIVE: To construct a cocktail DNA vaccine that expresses multiple genes of Toxoplasma gondii and investigate its immunogenicity in mice. METHODS: Genes for surface antigens (SAG), microneme(MIC), and rhoptry protein(ROP) were amplified from genomic DNA of T. gondii and then cloned separately into eukaryotic fluorescent protein expression vectors pShuttle-CMV-MCS-EFlalpha-AmCyan, pLVX IRES-Zsgreen and pLVX-IRES-rfp, to construct expression plasmids pShuttle-SAG1, pLVX-Zsgreen-MIC3 and pLVX-rfp-ROP2. 293F cells were transfected with a combination of the three plasmids using the polyethylenimine (PEI) method. Forty eight hours later, the expression of the three genes was observed under a fluorescence microscope. In addition, 30 C57BL/6 mice were randomized to receive intramuscular injection of saline (50 pA, group A), pShuttle+pLVX-Zsgreen+pLVX rfp empty plasmids(2 MUg/MUL, 17 MUL of each, group B) and pShuttle-SAG1+pLVX Zsgreen-MIC3+ pLVX-rfp-ROP2 recombinant plasmid (2 MUg/MUL, 17 MUL of each, group C). After 28 days, anti-T. gondii antibody in mouse serum was detected by ELISA, to evaluate the immunogenicity of the vaccine. RESULTS: The SAG1, MIC3 and ROP2 genes were amplified from the genomic DNA, with product sizes of 1, 1.1 and 1.7 kb. The eukaryotic expression plasmids pShuttle-SAG1, pLVX-Zsgreen-MIC3 and pLVX rfp-ROP2 were constructed, and the corresponding fluorescences (blue, green and red) were observed after transfection. On day 28 after mouse vaccination, ELISA showed that the mean A(450) values for serum IgG in groups A, B and C were (0.620+/-0.029), (0.741+/-0.040) and (1.561+/-0.131), respectively, with the group C value being significantly higher than the others (P<0.01). CONCLUSION: The cocktail DNA vaccine comprising T. gondii SAG1, MIC3 and ROP2 shows promising immunogenicity in mice, and the fluorescent protein expression vectors are reliable tools for expression of the target genes. PMID- 26931044 TI - [Extraction Method of Malaria Parasite DNA from Preserved Positive Blood Smears]. AB - OBJECTIVE: To develop a method for DNA extraction from malaria parasites on preserved blood smears, to provide basis for research on malaria genetic traceability. METHODS: The improved DNA extraction kit (QIAamp DNA Mini Kit) was used to extract plasmodium DNA from 41 giemsa-stained blood smears, and the extraction was compared with that using the Chelex-100 and Na(2)HPO(4) methods. Nested PCR was used to amplify small subunit ribosomal RNA to identify Plasmodium parasite. The PCR products underwent sequencing and sequence alignment, to analyze the difference in PCR positive rates between blood smears prepared in the 1980s and in recent 10 years, between blood smears with and without deoil/decoloration, and between blood smears with different qualities. RESULTS: The total PCR positive rate for the improved kit method was 70.7% (29/41). The PCR positive rate for blood smears prepared in the 1980s and in recent 10 years was 78.6% (11/14) and 66.7% (18/27) respectively, with no significant difference (W=0.63, P>0.05). The PCR positive rate for blood smears with and with- out deoil/decoloration was 62.5% (15/24) and 82.4% (14/17) respectively, also with no significant difference (chi(2)= 1.89, P>0.05). However, the PCR positive rate was significantly higher in blood smears with high quality [93.3% (28/30)] than those with low quality [9.1%(1/1l)](=27.59, P<0.01). Sequence alignment showed that the PCR products were consistent with the target DNA fragments. However, DNA extracted using the Chelex-100 and Na(2)HPO(4) methods showed negative PCR results. CONCLUSIONS: DNA extracted from blood smears prepared in the 1980s using the improved Kit (QIAamp DNA Mini Kit) shows a high PCR positive rate. Besides, blood smear staining and use of oil for microscopic examination do not affect DNA extraction. PMID- 26931045 TI - [SWOT Analysis of the National Survey on Current Status of Major Human Parasitic Diseases in China]. AB - The National Survey on Current Status of Major Human Parasitic Diseases in China has been carried out since 2014 under the organization of the National Health and Family Planning Commission of the People's Republic of China. The National Institute of Parasitic Diseases, Chinese Center for Disease Control and Prevention (NIPD, China CDC) provided technical support and was responsible for quality control in this survey. This study used SWOT method to analyze the strengths, weaknesses, opportunities and threats that were encountered by he NIPD, China CDC during the completion of the survey. Accordingly, working strategies were proposed to facilitate the future field work. PMID- 26931046 TI - [Recombinase Polymerase Amplification and its Applications in Parasite Detection]. AB - Recombinase polymerase amplification (RPA) is a recently -developed isothermal nucleic-acid-amplification technology that is based on the nucleic acid replication mechanism in T4 bacteriophage. With this technique, nucleic-acid templates can be amplified to measurable levels within 20 min at 37-42 degrees C. The. RPA process has high sensitivity and specificity, and is simple to operate, thus nucleic acids can be detected rapidly in non-laboratory conditions. Since its development in 2006, the RPA technique has been applied in agriculture, food safety, medicine, transgene detection, etc. In this review, we will give an overview on the research progress of RPA and its application in parasite detection. PMID- 26931047 TI - [Research Progress on Genetic Diversity in Animal Parasitic Nematodes]. AB - The development of molecular genetic markers for parasitic nematodes has significant implications in fundamental and applied research in Veterinary Parasitology. Knowledge on genetic diversity of nematodes would not only provide a theoretical basis for understanding the spread of drug-resistance alleles, but also have implications in the development of nematode control strategies. This review discusses the applications of molecular genetic markers (RFLP, RAPD, PCR SSCP, AFLP, SSR and mitochondrial DNA) in research on the genetic diversity of parasitic nematodes. PMID- 26931048 TI - [Malaria Epidemic Situation in Rudong County of Jiangsu Province during 1999 2014]. AB - From 1999 to 2014 a total of 23 cases of malaria were reported in Rudong County, Jiangsu Province, comprising one indigenous case of vivax malaria, 9 imported cases of vivax malaria, and 13 imported cases of falciparum malaria. The imported cases accounted for 95.7%(22/23) of all cases. The first diagnosis was mainly made in town hospitals and village clinics, accounting for 60.9%. There was no obvious seasonal variation in disease onset, and all cases reported in 2004 were imported. PMID- 26931049 TI - [Investigation of Soil-Transmitted Nematode Infections in Xuchang City of Henan Province in 2012]. AB - The Weidu District, Yanling County and Yuzhou City were selected in Xuchang City for investigation of the status of soil-transmitted nematode infections in 2012, in accordance with the National Monitoring Program for Soil-Transmitted Nematodiasis (2011 Revised Edition). Kato-Katz technique was used to detect soil- transmitted nematodes in feces of residents over 3 years old, and the cellophane tape peri-anal swab method was used to detect pinworm eggs in children between 3 12 years. A total of 2 991 fecal samples were examined. The total infection rate of soil-transmitted nematodiasis was 4.3%(128/2 991), decreased by 63.0% and 55.1% when compared with that in 2010 (11.6%) and that in Henan Province in 2004 (9.5%) respectively. The infection rates of roundworms, whipworms, hookworms and pinworms were 3.7%(110/2 991), 0.3%(9/2 991) , 0.1%(3/2 991) , and 0.2% ( 6/2 991) , respectively, all showing mild intensity of infection. The infection rate of soil-transmitted nematodiasis was highest in farmers (5.5%, 113/2 059), followed by children (3.1%, 3/98). PMID- 26931050 TI - [A case of vivax malaria complicated by severe thrombocytopenia]. PMID- 26931051 TI - Intervention Now to Eliminate Repeat Unintended Pregnancy in Teenagers (INTERUPT): a systematic review of intervention effectiveness and cost effectiveness, and qualitative and realist synthesis of implementation factors and user engagement. AB - BACKGROUND: The UK has one of the highest rates of teenage pregnancies in Western Europe. One-fifth of these are repeat pregnancies. Unintended conceptions can cause substantial emotional, psychological and educational harm to teenagers, often with enduring implications for life chances. Babies of teenage mothers have increased mortality and are at a significantly increased risk of poverty, educational underachievement and unemployment later in life, with associated costs to society. It is important to identify effective, cost-effective and acceptable interventions. OBJECTIVES: To identify who is at the greatest risk of repeat unintended pregnancies; which interventions are effective and cost effective; and what the barriers to and facilitators of the uptake of these interventions are. DATA SOURCES: We conducted a multistreamed, mixed-methods systematic review informed by service user and provider consultation to examine worldwide peer-reviewed evidence and UK-generated grey literature to find and evaluate interventions to reduce repeat unintended teenage pregnancies. We searched the following electronic databases: MEDLINE and MEDLINE In-Process & Other Non-Indexed Citations, PsycINFO, Cumulative Index to Nursing and Allied Health Literature, The Cochrane Library (Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects and the Health Technology Assessment Database), EMBASE (Excerpta Medica database), British Nursing Index, Educational Resources Information Center, Sociological Abstracts, Applied Social Sciences Index and Abstracts, BiblioMap (the Evidence for Policy and Practice Information and Co-ordinating Centre register of health promotion and public health research), Social Sciences Citation Index (supported by Web of Knowledge), Research Papers in Economics, EconLit (American Economic Association's electronic bibliography), OpenGrey, Scopus, Scirus, Social Care Online, National Research Register, National Institute for Health Research Clinical Research Network Portfolio and Index to THESES. Searches were conducted in May 2013 and updated in June 2014. In addition, we conducted a systematic search of Google (Google Inc., Mountain View, CA, USA) in January 2014. Database searches were guided by an advisory group of stakeholders. REVIEW METHODS: To address the topic's complexities, we used a structured, innovative and iterative approach combining methods tailored to each evidence stream. Quantitative data (effectiveness, cost effectiveness, risk factors and effect modifiers) were synthesised with reference to Cochrane guidelines for evaluating evidence on public health interventions. Qualitative evidence addressing facilitators of and barriers to the uptake of interventions, experience and acceptability of interventions was synthesised thematically. We applied the principles of realist synthesis to uncover theories and mechanisms underpinning interventions (what works, for whom and in what context). Finally, we conducted an overarching narrative of synthesis of evidence and gathered service user feedback. RESULTS: We identified 8664 documents initially, and 816 in repeat searches. We filtered these to 12 randomised controlled trials (RCTs), four quasi-RCTs, 10 qualitative studies and 53 other quantitative studies published between 1996 and 2012. None of the RCTs was based in the UK. The RCTs evaluated an emergency contraception programme and psychosocial interventions. We found no evidence for effectiveness with regard to condom use, contraceptive use or rates of unprotected sex or use of birth control. Our primary outcome was repeat conception rate: the event rate was 132 of 308 (43%) in the intervention group versus 140 of 289 (48%) for the control goup, with a non-significant risk ratio (RR) of 0.92 [95% confidence interval (CI) 0.78 to 1.08]. Four studies reported subsequent birth rates: 29 of 237 (12%) events for the intervention arm versus 46 out of 224 (21%) for the control arm, with a RR of 0.60 (95% CI 0.39 to 0.93). Many repeat conceptions occurred in the context of poverty, low expectations and aspirations, and negligible opportunities. Service user feedback suggested that there were specific motivations for many repeat conceptions, for example to replace loss or to please a partner. Realist synthesis highlighted that context, motivation, planning for the future and letting young women take control with connectedness and tailoring provide a conceptual framework for future research. LIMITATIONS: Included studies rarely characterised adolescent pregnancy as intended or unintended, that is interventions to reduce repeat conceptions rarely addressed whether or not pregnancies were intended. Furthermore, interventions were often not clearly defined, had multiple aims and did not indicate which elements were intended to address which aims. Nearly all of the studies were conducted in the USA and focused largely on African American or Hispanic and Latina American populations. CONCLUSIONS: We found no evidence to indicate that existing interventions to reduce repeat teenage pregnancy were effective; however, subsequent births were reduced by home-based interventions. Qualitative and realist evidence helped to explain gaps in intervention design that should be addressed. More theory-based, rigorously evaluated programmes need to be developed to reduce repeat teenage pregnancy in the UK. STUDY REGISTRATION: This study is registered as PROSPERO CRD42012003168. Cochrane registration number: i=fertility/0068. FUNDING: The National Institute for Health Research Health Technology Assessment programme. PMID- 26931052 TI - A comparison of cervical length measurement techniques for the prediction of spontaneous preterm birth. AB - OBJECTIVE: To evaluate the clinical utility of a novel means of assessing the cervix by measuring the angle of the curvature and to evaluate the performance of this technique as well as two other commonly used techniques of cervical length assessment in predicting spontaneous preterm birth (SPTB). METHODS: This was a retrospective cohort analysis of singleton gestations with a history of SPTB. Transvaginal ultrasound images of cervical length obtained between 20 and 23 6/7 weeks were re-measured using three techniques: (1) straight linear distance between the internal and external os, (2) sum of two contiguous linear segments tracing the internal to the external os, and (3) measurement of the angle of the curve within the cervix using an electronic protractor. A short cervical length was defined as <=25 mm. RESULTS: A total of 181 women were included. The relative risk (RR) for SPTB by cervical angle <=160 degrees was 1.2 (95% CI 0.7-2.0) and the ROC curve revealed an area under the curve of 0.54 (95% CI 0.44-0.63). The RR for SPTB by short cervical length measured by the straight technique was 2.3 (95% CI 1.3-4.0) and by the segmental technique 2.1 (95% CI 1.2-3.8). There was a 99.4% agreement between the two techniques with an intraclass Kappa coefficient of 0.96. CONCLUSIONS: In women with a history of SPTB, cervical angle measurement does not correlate with the risk of SPTB. Cervical length measured via straight and segmental techniques had excellent agreement in identifying short cervix, and both identified a short cervix predictive of SPTB. PMID- 26931053 TI - The Role of Religiosity in Satisfaction With Life: A Sample of Turkish Gay Men. AB - In this study, we investigated the role of religiosity in satisfaction with life in a sample of Turkish gay men. A one-way analysis of covariance (ANCOVA) revealed that the religiosity had a significant effect on life satisfaction of gay men. Extrinsically religious gay men displayed significantly higher life satisfaction scores than both intrinsically religious and nonreligious gay men. Moreover, intrinsically religious and nonreligious gay men did not significantly differ in terms of life satisfaction. Based on the findings of the study, we concluded that the role of a committed religiosity in enhancing satisfaction with life as documented by the overwhelming majority of previous research was reversed in the case of Turkish Muslim gay men. PMID- 26931054 TI - The incidence of congenital syphilis in the United Kingdom: February 2010 to January 2015. AB - OBJECTIVE: To estimate the incidence of congenital syphilis in the UK. DESIGN: Prospective study. SETTING AND POPULATION: United Kingdom. METHODS: Children born between February 2010 and January 2015 with a suspected diagnosis of congenital syphilis were reported through an active surveillance system. MAIN OUTCOME MEASURES: Number of congenital syphilis cases and incidence. RESULTS: For all years, reported incidence was below the WHO threshold for elimination (<0.5/1000 live births). Seventeen cases (12 male, five female) were identified. About 50% of infants (8/17) were born preterm (<37 weeks' gestation): median birthweight 2000 g (865-3170 g). Clinical presentation varied from asymptomatic to acute disease, including severe anaemia, hepatosplenomegaly, rhinitis, thrombocytopaenia, skeletal damage, and neurosyphilis. One infant was deaf and blind. Median maternal age was 20 years (17-31) at delivery. Where maternal stage of infection was recorded, 6/10 had primary, 3/10 secondary and 1/10 early latent syphilis. Most mothers were white (13/16). Country of birth was recorded for 12 mothers: UK (n = 6), Eastern Europe (n = 3), Middle East (n = 1), and South East Asia (n = 2). The social circumstances of mothers varied and included drug use and sex work. Some experienced difficulty accessing health care. CONCLUSION: The incidence of congenital syphilis is controlled and monitored by healthcare services and related surveillance systems, and is now below the WHO elimination threshold. However, reducing the public health impact of this preventable disease in the UK is highly dependent on the successful implementation of WHO elimination standards across Europe. TWEETABLE ABSTRACT: Congenital syphilis incidence in the UK is at a very low level and well below the WHO elimination threshold. PMID- 26931055 TI - N-acetylcysteine augmentation therapy for moderate-to-severe obsessive-compulsive disorder: randomized, double-blind, placebo-controlled trial. AB - WHAT IS KNOWN AND OBJECTIVE: N-acetylcysteine (NAC) has been proposed as a potential therapy for obsessive-compulsive disorder (OCD) as it may regulate the exchange of glutamate and prevent its pre-oxidant effects. The aim of the present double-blind, placebo-controlled trial was to assess the efficacy and tolerability of NAC augmentation in moderate-to-severe (OCD) treatment. METHODS: In this randomized, double-blind, two-centre, placebo-controlled, 10-week trial, patients with moderate-to-severe OCD were enrolled. Patients were randomized into two parallel groups to receive fluvoxamine (200 mg daily) plus placebo or fluvoxamine (200 mg daily) plus NAC (2000 mg daily). A total of 44 patients (22 in each group) were visited to evaluate response to therapy using the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) at baseline, and at weeks 4, 8 and 10. Side effects were recorded using predesigned checklists upon each visit. RESULTS AND DISCUSSION: Repeated-measures ANOVA showed a significant effect for time * treatment interaction (Greenhouse-Geisser corrected: F = 5.14, d.f. = 1.64, P = 0.012) in the Y-BOCS total score and a significant effect for time * treatment interaction (Greenhouse-Geisser corrected: F = 5.44, d.f. = 1.54, P = 0.011) in the Y-BOCS obsession subscale between the two groups. WHAT IS NEW AND CONCLUSION: Our results showed that NAC might be effective as an augmentative agent in the treatment of moderate-to-severe OCD. TRIAL REGISTRATION: Iranian Registry of Clinical Trials (www.irct.ir): IRCT201405271556N60. PMID- 26931056 TI - Pulp regeneration in a full-length human tooth root using a hierarchical nanofibrous microsphere system. AB - While pulp regeneration using tissue engineering strategy has been explored for over a decade, successful regeneration of pulp tissues in a full-length human root with a one-end seal that truly simulates clinical endodontic treatment has not been achieved. To address this challenge, we designed and synthesized a unique hierarchical growth factor-loaded nanofibrous microsphere scaffolding system. In this system, vascular endothelial growth factor (VEGF) binds with heparin and is encapsulated in heparin-conjugated gelatin nanospheres, which are further immobilized in the nanofibers of an injectable poly(l-lactic acid) (PLLA) microsphere. This hierarchical microsphere system not only protects the VEGF from denaturation and degradation, but also provides excellent control of its sustained release. In addition, the nanofibrous PLLA microsphere integrates the extracellular matrix-mimicking architecture with a highly porous injectable form, efficiently accommodating dental pulp stem cells (DPSCs) and supporting their proliferation and pulp tissue formation. Our in vivo study showed the successful regeneration of pulp-like tissues that fulfilled the entire apical and middle thirds and reached the coronal third of the full-length root canal. In addition, a large number of blood vessels were regenerated throughout the canal. For the first time, our work demonstrates the success of pulp tissue regeneration in a full-length root canal, making it a significant step toward regenerative endodontics. STATEMENT OF SIGNIFICANCE: The regeneration of pulp tissues in a full-length tooth root canal has been one of the greatest challenges in the field of regenerative endodontics, and one of the biggest barriers for its clinical application. In this study, we developed a unique approach to tackle this challenge, and for the first time, we successfully regenerated living pulp tissues in a full-length root canal, making it a significant step toward regenerative endodontics. This study will make positive scientific impact and interest the broad and multidisciplinary readership in the dental biomaterials and craniofacial tissue engineering community. PMID- 26931057 TI - Y-shaped ZnO Nanobelts Driven from Twinned Dislocations. AB - Y-shaped ZnO nanobelts are fabricated by a simple thermal evaporation method. Transmission Electron Microscopy (TEM) investigation shows that these ZnO nanobelts are crystals with twinned planes {11-21}. Convergent Beam Electron Diffraction studies show that the two sides of twinned nanobelts are O-terminated towards the twinned boundary and Zn-terminated outwards. The two branches of twinned ZnO nanobelts grow along [11-26] from the trunk and then turn to the polarization direction [0001]. The featured Y-shape morphology and TEM characterizations indicate that the growth of these novel nanostructures is driven by an unusual twinned dislocation growth mechanism. PMID- 26931058 TI - Dynamics of the frustrated spin in the low dimensional magnet Co3(OH)2(C4O4)2. AB - We describe powder inelastic neutron scattering experiments on a porous coordination polymer Co3(OH)2(C4O4)2, which has two different ordered magnetic phases known to display spin frustrated behaviour, resulting in an idle-spin phase. The moment on each ion is represented by an effective total angular moment J(eff ) = 1/2. A non-dispersive magnetic mode was observed in the idle-spin phase which is described by a simple dimer model that assumes DeltaJ = 0. The excitation was found to persist well above the long range ordering temperature into the paramagnetic region. A combination of frustration, the J(eff) = 1/2 and low dimensionality may induce these quantum phenomena. PMID- 26931060 TI - Exploring the coordinative adaptation and molecular shapes of trinuclear CuM(II) (M = Zn/Cd) complexes derived from salen type Schiff bases: structural and theoretical studies. AB - Three new trinuclear hetero-metallic complexes [(CuL)2Zn(NCS)2] (1), [(CuL(R))2Zn(NCS)(MU1,1-NCS)] (2) and [(CuL(R))2Cd(MU1,3-NCS)2] (4) have been synthesized using [CuL] and [CuL(R)] as "metalloligands" (where H2L = N,N' bis(salicylidene)-1,3-propanediamine and H2L(R) = N,N'-bis(2-hydroxybenzyl)-1,3 propanediamine). All three complexes are characterized by elemental analysis, spectroscopic methods and single crystal XRD. Complex 1 is an angular trinuclear species, in which two terminal four-coordinate square planar "metalloligands" [CuL] are coordinated to a central Zn(ii) through double phenoxido bridges along with two mutually cis nitrogen atoms of terminal isothiocyanate ions as is usually found in such complexes. In contrast, in complex 2, the two terminal "metalloligands" [CuL(R)] are square pyramidal, as one of the SCN(-) ions makes an unusual MU1,1-NCS bridge between copper centers while the other one coordinates to Zn(ii) through a N atom in a usual fashion making its geometry also square pyramidal. For 4 which possesses an angular trinuclear structure, in addition to double phenoxido bridges from two terminal [CuL(R)], both the SCN(-) ions are S-bonded to Cd(ii) and form a bridge (cis-MU1,3-SCN) between Cd(ii) and each of the terminal Cu(ii) ions. This structure is different from its unreduced analogue in which NCS(-) was N-terminal coordinated to Cd(ii) (3/3'). All the structures have been optimized using density functional theory (DFT) calculations. It has been found that for H2L, optimized structures like 1 and 2 differ only by 0.4 kcal mol(-1) but the H2L(R) structure 2 is more stable by 5.5 kcal mol(-1) than the structure resembling 1. For Cd(ii) complexes also, H2L optimized structures such as 3 and 4 do not differ significantly in energy (1.0 kcal mol(-1)) but the H2L(R) structure 4 is more stable than that of 3 by 4.6 kcal mol(-1). In fact, structure 4 has been found to be the most stable one among the other possible isomers of H2L(R). PMID- 26931059 TI - N-terminal domain of Bothrops asper Myotoxin II Enhances the Activity of Endothelin Converting Enzyme-1 and Neprilysin. AB - Neprilysin (NEP) and endothelin converting enzyme-1 (ECE-1) are two enzymes that degrade amyloid beta in the brain. Currently there are no molecules to stimulate the activity of these enzymes. Here we report, the discovery and characterisation of a peptide referred to as K49-P1-20, from the venom of Bothrops asper which directly enhances the activity of both ECE-1 and NEP. This is evidenced by a 2- and 5-fold increase in the Vmax of ECE-1 and NEP respectively. The K49-P1-20 concentration required to achieve 50% of maximal stimulation (AC50) of ECE-1 and NEP was 1.92 +/- 0.07 and 1.33 +/- 0.12 MUM respectively. Using BLITZ biolayer interferometry we have shown that K49-P1-20 interacts directly with each enzyme. Intrinsic fluorescence of the enzymes change in the presence of K49-P1-20 suggesting a change in conformation. ECE-1 mediated reduction in the level of endogenous soluble amyloid beta 42 in cerebrospinal fluid is significantly higher in the presence of K49-P1-20 (31 +/- 4% of initial) compared with enzyme alone (11 +/- 5% of initial; N = 8, P = 0.005, unpaired t-test). K49-P1-20 could be an excellent research tool to study mechanism(s) of enzyme stimulation, and a potential novel drug lead in the fight against Alzheimer's disease. PMID- 26931061 TI - Acceptance and Adherence of Endocrine Therapy in Women with Metastatic Breast Cancer: Is Parenteral Treatment Effective? PMID- 26931063 TI - Evaluation of Hepatic Tumors Using Intravoxel Incoherent Motion Diffusion Weighted MRI. AB - BACKGROUND This study aimed to evaluate the diagnostic value of the D value, D* value, and f magnitude for identifying benign and malignant hepatic tumors using intravoxel incoherent motion (IVIM) diffusion-weighted imaging (DWI). MATERIAL AND METHODS Data of 89 cases (123 lesions) with hepatic tumor confirmed by surgical pathology and postoperative follow-up were retrospectively collected. Among these cases, 40 cases were benign hepatic tumors (57 lesions) and 49 cases were malignant hepatic tumors (66 lesions). All subjects underwent conventional MRI with T1WI, T2WI, multi-b-value DWI, and dynamic enhanced LAVA scan. Diffusion weighted images with 11 b values (0, 10, 20, 30, 50, 80, 100, 200, 400, 800, and 1000 s/mm2) were obtained to calculate true molecular diffusion (D), perfusion related diffusion coefficient (D*), and perfusion fraction (f). The diagnostic performance in differentiating between malignant and benign hepatic lesions was analyzed. RESULTS Malignant lesions had a significantly lower D value ([1.04+/ 0.34]*10-3 mm2/s) and D* value ([16.5+/-7.7]*10-3 mm2/s) compared to benign lesions (D value: [1.70+/-0.55]*10-3 mm2/s, P<0.01; D* value: [21.7+/-9.9]*10-3 mm2/s, P<0.01). There was no statistically significant difference in f values between malignant (23.3+/-9.5) and benign lesions (33.5+/-14.9, P=0.13). In addition, D exhibited a better diagnostic performance than D* in terms of the area under the curve, sensitivity, and specificity when identifying malignancies from benign lesions. CONCLUSIONS D and D* are significant parameters for diagnosing hepatic tumors. Moreover, the D value is a more reliable parameter in distinguishing benign and malignant hepatic tumors. PMID- 26931064 TI - An exploratory investigation of teachers' intervention planning and perceived implementation barriers. AB - Increasingly teachers are the primary implementer responsible for providing evidence-based interventions to students. However, there is little knowledge regarding the extent to which teachers plan for intervention implementation, receive implementation support, or identify and address implementation barriers. This study explores survey data from over 1200 preschool through grade 12 teachers from 46 public school districts in a Northeastern state. Results indicate that teachers spend significant time engaging in intervention-related behavior and may be a primary source responsible for selecting student interventions. However, the current extent to which they plan for implementation and present levels of implementation support are inadequate to produce high levels of sustained intervention implementation. In addition, almost 60% of implementation barriers reported related to aspects of the intervention itself. Findings from this study provide guidance for future research and preliminary recommendations for ameliorating implementation barriers and proactively supporting treatment integrity in schools. PMID- 26931066 TI - Inter- and intra-individual differences in teachers' self-efficacy: A multilevel factor exploration. AB - This study explored inter- and intra-individual differences in teachers' self efficacy (TSE) by adapting Tschannen-Moran and Woolfolk Hoy's (2001) Teachers' Sense of Efficacy Scale (TSES) to the domain- and student-specific level. Multilevel structural equation modeling was used to evaluate the factor structure underlying this adapted instrument, and to test for violations of measurement invariance over clusters. Results from 841 third- to sixth-grade students and their 107 teachers supported the existence of one higher-order factor (Overall TSE) and four lower-order factors (Instructional Strategies, Behavior Management, Student Engagement, and Emotional Support) at both the between- and within teacher level. In this factor model, intra-individual differences in TSE were generally larger than inter-individual differences. Additionally, the presence of cluster bias in 18 of 24 items suggested that the unique domains of student specific TSE at the between-teacher level cannot merely be perceived as the within-teacher level factors' aggregates. These findings underscore the importance of further investigating TSE in relation to teacher, student, and classroom characteristics. PMID- 26931065 TI - Longitudinal evaluation of the importance of homework assignment completion for the academic performance of middle school students with ADHD. AB - The primary goal of this study was to longitudinally evaluate the homework assignment completion patterns of middle school age adolescents with ADHD, their associations with academic performance, and malleable predictors of homework assignment completion. Analyses were conducted on a sample of 104 middle school students comprehensively diagnosed with ADHD and followed for 18 months. Multiple teachers for each student provided information about the percentage of homework assignments turned in at five separate time points and school grades were collected quarterly. Results showed that agreement between teachers with respect to students assignment completion was high, with an intraclass correlation of .879 at baseline. Students with ADHD were turning in an average of 12% fewer assignments each academic quarter in comparison to teacher-reported classroom averages. Regression analyses revealed a robust association between the percentage of assignments turned in at baseline and school grades 18 months later, even after controlling for baseline grades, achievement (reading and math), intelligence, family income, and race. Cross-lag analyses demonstrated that the association between assignment completion and grades was reciprocal, with assignment completion negatively impacting grades and low grades in turn being associated with decreased future homework completion. Parent ratings of homework materials management abilities at baseline significantly predicted the percentage of assignments turned in as reported by teachers 18 months later. These findings demonstrate that homework assignment completion problems are persistent across time and an important intervention target for adolescents with ADHD. PMID- 26931067 TI - Maximizing measurement efficiency of behavior rating scales using Item Response Theory: An example with the Social Skills Improvement System - Teacher Rating Scale. AB - Measurement efficiency is an important consideration when developing behavior rating scales for use in research and practice. Although most published scales have been developed within a Classical Test Theory (CTT) framework, Item Response Theory (IRT) offers several advantages for developing scales that maximize measurement efficiency. The current study provides an example of using IRT to maximize rating scale efficiency with the Social Skills Improvement System - Teacher Rating Scale (SSIS - TRS), a measure of student social skills frequently used in practice and research. Based on IRT analyses, 27 items from the Social Skills subscales and 14 items from the Problem Behavior subscales of the SSIS - TRS were identified as maximally efficient. In addition to maintaining similar content coverage to the published version, these sets of maximally efficient items demonstrated similar psychometric properties to the published SSIS - TRS. PMID- 26931068 TI - Comparison of opportunities to respond and generation effect as potential causal mechanisms for incremental rehearsal with multiplication combinations. AB - Incremental rehearsal (IR) is an intervention with demonstrated effectiveness in increasing retention of information, yet little is known about how specific intervention components contribute to the intervention's effectiveness. The purpose of this study was to further the theoretical understanding of the intervention by comparing the effects of opportunities to respond (OTR) and generation demand on retention of multiplication combinations. Using a between subject 2 * 2 factorial design, 103 4th and 5th grade students were taught seven multiplication combinations using one of four versions of IR that orthogonally varied OTR (high versus low) and generation demands (high versus low). A two-way ANOVA revealed main effects for OTR, generation demands, and an interaction of the two factors. The effect of generation demands was large (d=1.31), whereas the overall effect of OTR was moderate (d=0.66). Critically, the two factors interacted, with the largest learning gains observed when OTR and generation demands were both high. The results of this study suggest that generation demand is an important factor in the effectiveness of rehearsal interventions. PMID- 26931069 TI - Tracking the migration of the Indian continent using the carbonate clumped isotope technique on Phanerozoic soil carbonates. AB - Approximately 140 million years ago, the Indian plate separated from Gondwana and migrated by almost 90 degrees latitude to its current location, forming the Himalayan-Tibetan system. Large discrepancies exist in the rate of migration of Indian plate during Phanerozoic. Here we describe a new approach to paleo latitudinal reconstruction based on simultaneous determination of carbonate formation temperature and delta(18)O of soil carbonates, constrained by the abundances of (13)C-(18)O bonds in palaeosol carbonates. Assuming that the palaeosol carbonates have a strong relationship with the composition of the meteoric water, delta(18)O carbonate of palaeosol can constrain paleo-latitudinal position. Weighted mean annual rainfall delta(18)O water values measured at several stations across the southern latitudes are used to derive a polynomial equation: delta(18)Ow = -0.006 * (LAT)(2) - 0.294 * (LAT) - 5.29 which is used for latitudinal reconstruction. We use this approach to show the northward migration of the Indian plate from 46.8 +/- 5.8 degrees S during the Permian (269 M.y.) to 30 +/- 11 degrees S during the Triassic (248 M.y.), 14.7 +/- 8.7 degrees S during the early Cretaceous (135 M.y.), and 28 +/- 8.8 degrees S during the late Cretaceous (68 M.y.). Soil carbonate delta(18)O provides an alternative method for tracing the latitudinal position of Indian plate in the past and the estimates are consistent with the paleo-magnetic records which document the position of Indian plate prior to 135 +/- 3 M.y. PMID- 26931062 TI - Gut mucosal DAMPs in IBD: from mechanisms to therapeutic implications. AB - Endogenous damage-associated molecular patterns (DAMPs) are released during tissue damage and have increasingly recognized roles in the etiology of many human diseases. The inflammatory bowel diseases (IBD), ulcerative colitis (UC) and Crohn's disease (CD), are immune-mediated conditions where high levels of DAMPs are observed. DAMPs such as calprotectin (S100A8/9) have an established clinical role as a biomarker in IBD. In this review, we use IBD as an archetypal common chronic inflammatory disease to focus on the conceptual and evidential importance of DAMPs in pathogenesis and why DAMPs represent an entirely new class of targets for clinical translation. PMID- 26931071 TI - Pun processing from a psycholinguistic perspective: Introducing the Model of Psycholinguistic Hemispheric Incongruity Laughter (M.PHIL). AB - Ambiguity processing was examined using a stimulus set consisting of homograph puns in which semantic salience, as measured by semantic co-occurrence, was manipulated. Two lexical decision tasks using puns as primes for ambiguous targets revealed that high co-occurrence meanings were processed faster than low co-occurrence meanings. A divided visual field protocol revealed involvement of both hemispheres, but with the pattern of priming from the right visual field more similar to that of the centrally presented condition than the left visual field pattern. In contrast to the lexical decision data that favoured high co occurrence targets, data from a forced-choice relatedness task showed an advantage for the low co-occurrence associates. Results from this series of experiments are consistent with Bryden's [(1982). Laterality: Functional asymmetry in the intact brain. New York, NY: Academic Press] proposal that there are several different laterality effects when processing language and emotionally valent stimuli. The results are used to frame a working model of pun processing based on the Graded Salience Hypothesis [Giora, R. (1997). Understanding figurative and literal language: The graded salience hypothesis. Cognitive Linguistics, 8(3), 183-206]. PMID- 26931070 TI - Specific LED-based red light photo-stimulation procedures improve overall sperm function and reproductive performance of boar ejaculates. AB - The present study evaluated the effects of exposing liquid-stored boar semen to different red light LED regimens on sperm quality and reproductive performance. Of all of the tested photo-stimulation procedures, the best pattern consisted of 10 min light, 10 min rest and 10 min of further light (10-10-10 pattern). This pattern induced an intense and transient increase in the majority of motility parameters, without modifying sperm viability and acrosome integrity. While incubating non-photo-stimulated sperm at 37 degrees C for 90 min decreased all sperm quality parameters, this reduction was prevented when the previously described light procedure was applied. This effect was concomitant with an increase in the percentage of sperm with high mitochondrial membrane potential. When sperm were subjected to 'in vitro' capacitation, photo-stimulation also increased the percentage of sperm with capacitation-like changes in membrane structure. On the other hand, treating commercial semen doses intended for artificial insemination with the 10-10-10 photo-stimulation pattern significantly increased farrowing rates and the number of both total and live-born piglets for parturition. Therefore, our results indicate that a precise photo-stimulation procedure is able to increase the fertilising ability of boar sperm via a mechanism that could be related to mitochondrial function. PMID- 26931072 TI - Silencing MicroRNA-155 Attenuates Cardiac Injury and Dysfunction in Viral Myocarditis via Promotion of M2 Phenotype Polarization of Macrophages. AB - Macrophage infiltration is a hallmark feature of viral myocarditis. As studies have shown that microRNA-155 regulates the differentiation of macrophages, we aimed to investigate the role of microRNA-155 in VM. We report that silencing microRNA-155 protects mice from coxsackievirus B3 induced myocarditis. We found that microRNA-155 expression was upregulated and localized primarily in heart infiltrating macrophages and CD4(+) T lymphocytes during acute myocarditis. In contrast with wildtype (WT) mice, microRNA-155(-/-) mice developed attenuated viral myocarditis, which was characterized by decreased cardiac inflammation and decreased intracardiac CD45(+) leukocytes. Hearts of microRNA-155(-/-) mice expressed decreased levels of the IFN-gamma and increased levels of the cytokines IL-4 and IL-13. Although total CD4(+) and regulatory T cells were unchanged in miR-155(-/-) spleen proportionally, the activation of T cells and CD4(+) T cell proliferation in miR-155(-/-) mice were significantly decreased. Beyond the acute phase, microRNA-15(5-/-) mice had reduced mortality and improved cardiac function during 5 weeks of follow-up. Moreover, silencing microRNA-155 led to increased levels of alternatively-activated macrophages (M2) and decreased levels of classically-activated macrophages (M1) in the heart. Combined, our studies suggest that microRNA-155 confers susceptibility to viral myocarditis by affecting macrophage polarization, and thus may be a potential therapeutic target for viral myocarditis. PMID- 26931073 TI - Mast cell degranulation is negatively regulated by the Munc13-4-binding small guanosine triphosphatase Rab37. AB - Mast cell degranulation is regulated by the small guanosine triphosphatases (GTPases) Rab27a and Rab27b, which have distinct and opposing roles: Rab27b acts as a positive regulator through its effector protein Munc13-4, a non-neuronal isoform of the vesicle-priming Munc13 family of proteins, whereas Rab27a acts as a negative regulator through its effector protein melanophilin, by maintaining integrity of cortical filamentous actin (F-actin), a barrier to degranulation. Here we investigated the role of Rab37, one of the Rab GTPases assumed to be implicated in regulated secretion during mast cell degranulation. Using the RBL 2H3 mast cell line, we detected Rab37 on the secretory granules and found that antigen-induced degranulation was extensively increased by either knockdown of Rab37 or overexpression of a dominant-active Rab37 mutant. This hypersecretion phenotype in the Rab37-knockdown cells was suppressed by simultaneous knockdown of Rab27a and Rab27b or of Munc13-4, but not by disruption of cortical F-actin. We further found that Rab37 interacted with Munc13-4 in a GTP-independent manner and formed a Rab27-Munc13-4-Rab37 complex. These results suggest that Rab37 is a Munc13-4-binding protein that inhibits mast cell degranulation through its effector protein, by counteracting the vesicle-priming activity of the Rab27 Munc13-4 system. PMID- 26931074 TI - Health conditions in people with spinal cord injury: Contemporary evidence from a population-based community survey in Switzerland. AB - BACKGROUND: Health conditions in people with spinal cord injury are major determinants for disability, reduced well-being, and mortality. However, population-based evidence on the prevalence and treatment of health conditions in people with spinal cord injury is scarce. OBJECTIVE: To investigate health conditions in Swiss residents with spinal cord injury, specifically to analyse their prevalence, severity, co-occurrence, and treatment. METHODS: Cross sectional data (n = 1,549) from the community survey of the Swiss Spinal Cord Injury (SwiSCI) cohort study, including Swiss residents with spinal cord injury aged over 16 years, were analysed. Nineteen health conditions and their self reported treatment were assessed with the spinal cord injury Secondary Conditions Scale and the Self-Administered Comorbidity Questionnaire. Prevalence and severity were compared across demographics and spinal cord injury characteristics. Co-occurrence of health conditions was examined using a binary non-metric dissimilarity measure and multi-dimensional scaling. Treatment rates were also examined. RESULTS: Number of concurrent health conditions was high (median 7; interquartile range 4-9; most frequent: spasticity, chronic pain, sexual dysfunction). Prevalence of health conditions increased with age and was higher in non-traumatic compared with traumatic spinal cord injury. Spinal cord injury specific conditions co-occurred. Relative frequencies of treatment were low (median 44%, interquartile range 25-64%), even for significant or chronic problems. DISCUSSION: A high prevalence of multimorbidity was found in community dwelling persons with spinal cord injury. Treatment for some highly prevalent health conditions was infrequent. PMID- 26931076 TI - Zoonotic cutaneous leishmaniasis in northeastern Iran: a GIS-based spatio temporal multi-criteria decision-making approach. AB - Zoonotic cutaneous leishmaniasis (ZCL) constitutes a serious public health problem in many parts of the world including Iran. This study was carried out to assess the risk of the disease in an endemic province by developing spatial environmentally based models in yearly intervals. To fill the gap of underestimated true burden of ZCL and short study period, analytical hierarchy process (AHP) and fuzzy AHP decision-making methods were used to determine the ZCL risk zones in a Geographic Information System platform. Generated risk maps showed that high-risk areas were predominantly located at the northern and northeastern parts in each of the three study years. Comparison of the generated risk maps with geocoded ZCL cases at the village level demonstrated that in both methods more than 90%, 70% and 80% of the cases occurred in high and very high risk areas for the years 2010, 2011, and 2012, respectively. Moreover, comparison of the risk categories with spatially averaged normalized difference vegetation index (NDVI) images and a digital elevation model of the study region indicated persistent strong negative relationships between these environmental variables and ZCL risk degrees. These findings identified more susceptible areas of ZCL and will help the monitoring of this zoonosis to be more targeted. PMID- 26931075 TI - Different in vitro proliferation and cytokine-production inhibition of memory T cell subsets after calcineurin and mammalian target of rapamycin inhibitors treatment. AB - Calcineurin inhibitors (CNI) and mammalian target of rapamycin inhibitors (mTORi) are the main immunosuppressants used for long-term maintenance therapy in transplant recipients to avoid acute rejection episodes. Both groups of immunosuppressants have wide effects and are focused against the T cells, although different impacts on specific T-cell subsets, such as regulatory T cells, have been demonstrated. A greater knowledge of the impact of immunosuppression on the cellular components involved in allograft rejection could facilitate decisions for individualized immunosuppression when an acute rejection event is suspected. Memory T cells have recently gained focus because they might induce a more potent response compared with naive cells. The impact of immunosuppressants on different memory T-cell subsets remains unclear. In the present study, we have studied the specific impact of CNI (tacrolimus) and mTORi (rapamycin and everolimus) over memory and naive CD4(+) T cells. To do so, we have analysed the proliferation, phenotypic changes and cytokine synthesis in vitro in the presence of these immunosuppressants. The present work shows a more potent effect of CNI on proliferation and cytokine production in naive and memory T cells. However, the mTORi permit the differentiation of naive T cells to the memory phenotype and allow the production of interleukin-2. Taken together, our data show evidence to support the combined use of CNI and mTORi in transplant immunosuppression. PMID- 26931077 TI - Polymeric near-infrared absorbing dendritic nanogels for efficient in vivo photothermal cancer therapy. AB - In recent years, several near-infrared light absorbing inorganic nanomaterials have been developed for photothermal therapy. However, their biological fate after injection limits their clinical utilization. In this work, we developed a novel polymeric near-infrared light absorbing material based on a biocompatible thermoresponsive nanogel that is semi-interpenetrated with polyaniline, a conjugated polymer with strong near-infrared absorbance. This polymeric nanocomposite generates heat after being irradiated by NIR light, thereby inducing a local hyperthermia that is used for photothermal cancer therapy in vitro and in vivo. PMID- 26931078 TI - Selection against abdominal fat percentage may increase intramuscular fat content in broilers. AB - Excessive abdominal fat content (AFC) has negative impacts on feed efficiency and carcass quality. Unlike AFC, intramuscular fat content (IMFC) could be a favourable trait, which has a positive impact on meat quality. To meet consumers' needs, a long-term goal of broiler breeders is to decrease AFC and improve the IMFC simultaneously. The current study was designed to investigate the relationship between AFC and IMFC and to compare IMFC, including the pectoral major muscle fat content (PIMFC) and intramuscular fat content of leg muscle (LIMFC), between two broiler lines divergently selected for abdominal fat percentage over 17 generations. The results showed that there was a significant difference in PIMFC and LIMFC between the two lines in all five generation populations used. The birds in the lean line had significantly lower AFC but higher PIMFC and LIMFC than the birds in the fat line. We also detected differences in the liver fat content (LFC) between the two lines and the results showed that birds in the fat line had significant higher LFC than birds in the lean line. Our results indicated that a desirable broiler line with higher IMFC but lower AFC could be obtained by genetic selection. PMID- 26931079 TI - Acute generalized exanthematous pustulosis mimicking toxic epidermal necrolysis in patients with psoriasis. PMID- 26931080 TI - Pioneering apoptosis-targeted cancer drug poised for FDA approval. PMID- 26931081 TI - Food allergy drugs step up to Phase III. PMID- 26931086 TI - Deal watch: MSD buys in to emerging epigenetic cancer target. PMID- 26931087 TI - Cancer: CARs: new models abound. PMID- 26931085 TI - Regulatory Watch: Impact of breakthrough therapy designation on cancer drug development. PMID- 26931088 TI - Biomaterials: Modified alginates provide a long-term disguise against the foreign body response. PMID- 26931089 TI - Anticancer drugs: Putting the brakes on KRAS-G12C nucleotide cycling. PMID- 26931090 TI - Facile access to thermoresponsive filomicelles with tuneable cores. AB - We report a novel library of filomicelles in water comprising either polystyrene or various polymethacrylate cores prepared via temperature-induced morphological transformation (TIMT). The nanoworms demonstrate reproducibly uniform morphology while exhibiting a broad range of glass transition temperatures, high stability in buffer, and the ability to form smart reversible thermoresponsive gels. PMID- 26931091 TI - Comparative morphometric and chemical analyses of phenotypes of two invasive ambrosia beetles (Euwallacea spp.) in the United States. AB - The polyphagous shot hole borer (PSHB), Euwallacea sp., was first detected in 2003 in Los Angeles County, California, USA. Recently, this invasive species has become a major pest of many hardwood trees in urban and wildland forests throughout southern California. PSHB is nearly identical in morphology and life history to the tea shot hole borer (TSHB), Euwallacea fornicatus, an invasive pest of hardwoods in Florida, USA and many other parts of the world. However, molecular studies have suggested that the taxa are different species. We conducted morphometric and chemical analyses of the phenotypes of Euwallacea sp. collected in southern California (Los Angeles County) and E. fornicatus collected in Florida (Miami-Dade County). Our analyses indicated that PSHB has 3 larval instars. The third larval instar was separated from the first 2 instars by head capsule width with 0 probability of misclassification. The body length, head width, and pronotal width of PSHB adult males were significantly less than those of females. Head width and pronotal width of female PSHB were significantly less than those of female TSHB. In contrast, body length, and ratio of body length to pronotal width of female PSHB were significantly greater than those of female TSHB. However, females of these 2 species could not be separated completely by these 4 measurements because of the overlapping ranges. Cuticular hydrocarbons detected in both species were exclusively alkanes (i.e., n-alkanes, monomethylalkanes, dimethylalkanes, and trimethylalkanes). Cuticular hydrocarbon profiles of PSHB males and females were similar, but they both differed from that of TSHB females. Cuticular hydrocarbons of PSHB were predominantly internally branched dimethylalkanes with backbones of 31 and 33 carbons, whereas cuticular hydrocarbons of TSHB females were dominated by internally branched monomethylalkanes and dimethylalkanes with backbones of 28 and 29 carbons. Multiple compounds within these classes appear to be diagnostic for PSHB and TSHB, respectively. PMID- 26931092 TI - Portal response related to shunt occlusion by balloon-occluded retrograde transvenous obliteration may determine the prognosis of cirrhosis. AB - AIM: To determine the prognostic effect of portal hemodynamic responses after balloon-occluded retrograde transvenous obliteration (B-RTO) for gastric varices (GV) in cirrhosis patients. METHODS: This retrospective study consisted of 37 cirrhosis patients (aged 62.5 +/- 9.7 years) with medium- or large-grade GV treated with B-RTO. Portal hemodynamic response was assessed by the changes in flow volume in the portal trunk (PFV, mL/min) before and after the treatment. Group I showed increased PFV and group II showed no increase in PFV. The median observation period was 49.8 months (range, 4.7-150.3 months). RESULTS: All patients showed complete embolization of GV without any recurrence. There were 30 patients in group I and 7 patients in group II (decreased PFV in 6 and unchanged PFV in 1). The PFV at baseline was significantly lower in the former (583.5 +/- 232.0 mL/min) than in the latter (880.7 +/- 345.9 mL/min; P = 0.009). The survival rate was significantly lower in group II (83.3% at 1 year and 66.7% at 3 years) than in group I (96.7% at 1 year, 81.5% at 3 years, and 61.8% at 5 years; P = 0.012). The incidence of deterioration of the esophageal varices was 18/30 (60%) in group I and 5/7 (71.4%; P = 0.687) in group II. Multivariate analysis identified only no increase in portal response (hazard ratio, 8.086; P = 0.005) as an independent factor for poor prognosis. CONCLUSION: Balloon-occluded retrograde transvenous obliteration for GV may result in a poor prognosis when portal hemodynamics shows no increase in portal response. PMID- 26931094 TI - Cobalt(III)-catalyzed C-H halogenation of 6-arylpurines: facile entry into arylated, sulfenylated and alkoxylated 6-arylpurines. AB - Cobalt-catalyzed C-H halogenation of biologically important 6-arylpurines has been reported under mild conditions with good functional group tolerance. The regioselective halogenation of thiophenes, as well as the synthetic applicability of the present protocol for the synthesis of arylated, sulfenylated and alkoxylated purine analogues was also demonstrated. PMID- 26931097 TI - Abstracts of the Diabetes UK Professional Conference 2016, Scottish Exhibition and Conference Centre, Glasgow, 2-4 March 2016. PMID- 26931093 TI - The incretin hormone glucagon-like peptide 1 increases mitral cell excitability by decreasing conductance of a voltage-dependent potassium channel. AB - KEY POINTS: The gut hormone called glucagon-like peptide 1 (GLP-1) is a strong moderator of energy homeostasis and communication between the peripheral organs and the brain. GLP-1 signalling occurs in the brain; using a newly developed genetic reporter line of mice, we have discovered GLP-synthesizing cells in the olfactory bulb. GLP-1 increases the firing frequency of neurons (mitral cells) that encode olfactory information by decreasing activity of voltage-dependent K channels (Kv1.3). Modifying GLP-1 levels, either therapeutically or following the ingestion of food, could alter the excitability of neurons in the olfactory bulb in a nutrition or energy state-dependent manner to influence olfactory detection or metabolic sensing. The results of the present study uncover a new function for an olfactory bulb neuron (deep short axon cells, Cajal cells) that could be capable of modifying mitral cell activity through the release of GLP-1. This might be of relevance for the action of GLP-1 mimetics now widely used in the treatment of diabetes. ABSTRACT: The olfactory system is intricately linked with the endocrine system where it may serve as a detector of the internal metabolic state or energy homeostasis in addition to its classical function as a sensor of external olfactory information. The recent development of transgenic mGLU-yellow fluorescent protein mice that express a genetic reporter under the control of the preproglucagon reporter suggested the presence of the gut hormone, glucagon-like peptide (GLP-1), in deep short axon cells (Cajal cells) of the olfactory bulb and its neuromodulatory effect on mitral cell (MC) first-order neurons. A MC target for the peptide was determined using GLP-1 receptor binding assays, immunocytochemistry for the receptor and injection of fluorescence-labelled GLP-1 analogue exendin-4. Using patch clamp recording of olfactory bulb slices in the whole-cell configuration, we report that GLP-1 and its stable analogue exendin-4 increase the action potential firing frequency of MCs by decreasing the interburst interval rather than modifying the action potential shape, train length or interspike interval. GLP-1 decreases Kv1.3 channel contribution to outward currents in voltage clamp recordings as determined by pharmacological blockade of Kv1.3 or utilizing mice with Kv1.3 gene-targeted deletion as a negative control. Because fluctuations in GLP-1 concentrations monitored by the olfactory bulb can modify the firing frequency of MCs, olfactory coding could change depending upon nutritional or physiological state. As a regulator of neuronal activity, GLP-1 or its analogue may comprise a new metabolic factor with a potential therapeutic target in the olfactory bulb (i.e. via intranasal delivery) for controlling an imbalance in energy homeostasis. PMID- 26931095 TI - Cooperation between the chloroplast psbA 5'-untranslated region and coding region is important for translational initiation: the chloroplast translation machinery cannot read a human viral gene coding region. AB - Chloroplast mRNA translation is regulated by the 5'-untranslated region (5'-UTR). Chloroplast 5'-UTRs also support translation of the coding regions of heterologous genes. Using an in vitro translation system from tobacco chloroplasts, we detected no translation from a human immunodeficiency virus tat coding region fused directly to the tobacco chloroplast psbA 5'-UTR. This lack of apparent translation could have been due to rapid degradation of mRNA templates or synthesized protein products. Replacing the psbA 5'-UTR with the E. coli phage T7 gene 10 5'-UTR, a highly active 5'-UTR, and substituting synonymous codons led to some translation of the tat coding region. The Tat protein thus synthesized was stable during translation reactions. No significant degradation of the added tat mRNAs was observed after translation reactions. These results excluded the above two possibilities and confirmed that the tat coding region prevented its own translation. The tat coding region was then fused to the psbA 5'-UTR with a cognate 5'-coding segment. Significant translation was detected from the tat coding region when fused after 10 or more codons. That is, translation could be initiated from the tat coding region once translation had started, indicating that the tat coding region inhibits translational initiation but not elongation. Hence, cooperation/compatibility between the 5'-UTR and its coding region is important for translational initiation. PMID- 26931098 TI - Reassessing Risk Factors for High Defibrillation Threshold: The EF-SAGA Risk Score and Implications for Device Testing. AB - OBJECTIVES: To reevaluate risk factors for high defibrillation threshold (DFT) and propose a risk assessment tool. BACKGROUND: Controversy exists over routine DFT testing during implantable cardioverter defibrillator (ICD) placement. METHODS: We retrospectively analyzed 1,642 consecutive patients who received an ICD and underwent DFT testing. RESULTS: The incidence of high DFT requiring addition of a subcutaneous array was 2.3%. Five significant independent variables predictive of high DFT were identified, including younger age, male gender (hazard ratio 1.99), left ventricular (LV) dysfunction, secondary prevention (hazard ratio 2.33), and amiodarone use (hazard ratio 2.39). Each 10-year increase in age was indicative of a 0.35-times lower chance of high DFT. Each 10% increase of LV ejection fraction (EF) was indicative of a 0.52-times lower chance of high DFT. These five variables form the EF-SAGA risk score (LVEF < 20%, Secondary prevention ICD indication, Age < 60 years, male Gender, Amiodarone use). Cumulative risk of high DFT increased incrementally; patients with four or more variables had an 8.9% likelihood of high DFT. Importantly, primary prevention patients with LVEF > 20% had a negative predictive value for high DFT of 99.3%. CONCLUSION: We identified five independent predictors of high DFT. We propose the EF-SAGA risk score to help decision making. Primary prevention patients with an LVEF > 20% had an exceedingly low incidence of high DFT suggesting that testing could be avoided in these patients. Careful assessment of the risk-benefit ratio of testing is important in high-risk patients. PMID- 26931099 TI - Confined blood chimerism in a monochorionic dizygotic sex discordant twin pregnancy conceived after induced ovulation. AB - BACKGROUND: Monochorionic twins are generally considered as a monozygotic twin pregnancy. However, several cases of monochorial dizygotic twin pregnancies have been reported. CASE REPORT: We report on a rare case of monochorionic dizygotic twin pregnancy conceived after induced ovulation in a 32-year-old woman. The diagnosis was made on morphological ultrasound examination at 18+4 weeks of gestation, showing two fetuses with discordant sex. The amniocentesis was declined by the patient. RESULTS: The monochorionic status was confirmed after a histopathalogical study of the placenta. At delivery, both a phenotypically normal boy and a phenotypically normal girl without sexual abnormality were observed. This analysis also revealed the presence of vascular anastomoses between both fetal circulations. Postnatal cytogenetic analyses indicated the presence of a chimerism in peripheral blood lymphocytes. This chimerism was not observed in cells obtained from a buccal swab. Molecular determination of zygosity confirmed the existence of the confined peripheral blood chimerism with the presence of four parental alleles. CONCLUSION: We report on a case of monochorionic dizygotic twin pregnancy. This observation underlies the need to carefully assess twin pregnancies, especially when obtained after assisted reproductive technology. PMID- 26931100 TI - Solution-Grown Monocrystalline Hybrid Perovskite Films for Hole-Transporter-Free Solar Cells. AB - High-quality perovskite monocrystalline films are successfully grown through cavitation-triggered asymmetric crystallization. These films enable a simple cell structure, ITO/CH3 NH3 PbBr3 /Au, with near 100% internal quantum efficiency, promising power conversion efficiencies (PCEs) >5%, and superior stability for prototype cells. Furthermore, the monocrystalline devices using a hole transporter-free structure yield PCEs ~6.5%, the highest among other similar structured CH3 NH3 PbBr3 solar cells to date. PMID- 26931102 TI - Outpatient thromboprophylaxis with low-molecular-weight heparin in solid tumors: Where do we stand today? PMID- 26931101 TI - Estimation of minimal clinically important change of the Japanese version of EQ 5D in patients with chronic noncancer pain: a retrospective research using real world data. AB - BACKGROUND: Quality of life (QoL) is routinely assessed and evaluated in medical research. However, in Japan, there is a lack of solid cutoff criteria for evaluating QoL improvement in chronic noncancer pain management. The present study was conducted to identify the minimal clinically important change (MCIC) of the Japanese version of EuroQol-5D 3L(EQ-5D) utility score and numeric rating scale (NRS) with an emphasis on chronic noncancer pain. METHODS: The data source for this post hoc research was the post-marketing surveillance (PMS) data for a tramadol/acetaminophen combination tablet, which was previously conducted in real world settings. The parameters extracted from the PMS data were sociodemographic characteristics, NRS, EQ-5D, and dichotomous physician's global impression of treatment effectiveness (PGI). The optimal cutoff points of MCIC for EQ-5D utility and NRS scores were evaluated using receiver operating characteristics (ROC) analysis. An anchor-based approach using PGI was applied. RESULTS: Data of 710 patients with chronic noncancer pain were extracted from the PMS database. The NRS score decreased by 2.7 (standard deviation, 2.3) points, whereas the EQ 5D score increased by 0.16 (0.20) points at 4 weeks from baseline. The changes from baseline in NRS and EQ-5D were significantly correlated (r = 0.53, p < 0.001). The estimated optimal cutoff points of MCIC for EQ-5D and NRS were 0.10 and -2.0 points, respectively. The area under the curve of ROC was > 0.80 in both analyses. CONCLUSION: These results demonstrated novel cutoff criteria for the Japanese version of EQ-5D, focusing on patients with chronic noncancer pain. The obtained criteria were fairly consistent and can be confidently utilized as an evaluation tool in medical research on chronic noncancer pain in Japan, with additional functionality and usability for QoL assessment in pain management practice. TRIAL REGISTRATION: The data source of this post hoc research was a PMS study with the identifier number UMIN000015901 at umin.ac.jp, UMIN clinical trial registry (UMIN-CTR). PMID- 26931104 TI - Visual and quantitative comparison of (18)F-fluorodeoxyglucose PET/CT findings in the detection of pelvic tumor recurrence in colorectal cancer. AB - OBJECTIVE: This study aimed to visually and quantitatively compare (18)F fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) imaging in determining postoperative pelvic recurrence in colorectal cancer (CRC). MATERIALS AND METHODS: This retrospective analysis focused on 96 patients (age: mean 62.6 +/- 10.5) with surgically resected CRC (time interval after surgery: 19.2 +/- 20.4 months). The standard of reference was histopathologic confirmation (n = 27) or imaging follow-up (n = 69). For visual analysis, three independent nuclear physicians interpreted the PET/CT findings. For the quantitative analysis, the normalized standardized uptake values (nSUVs: nSUVmax, nSUVpeak, nSUVmean) were calculated by applying the mean SUV of a normal liver. We evaluated the areas under the receiver operating characteristic curves (AUCs) for all the quantitative parameters. RESULTS: Of the 96 patients, 49 showed pelvic recurrence and 47 revealed no tumor recurrence. Sensitivity and specificity were 85.7 and 80.9 %, respectively, for visual analysis, and 65.3 and 83.0 %, respectively, for quantitative analysis. The AUC (0.766, CI: 0.668-0.846) of nSUVmax was largest comparing nSUVpeak and nSUVmean values, without significant difference (p value >0.316). Sensitivity of lesion detection was superior in visual analysis (p value = 0.02), but specificity was not significantly different (p = 0.80). After inclusive and exclusive combinations, sensitivity and specificity were slightly increased to 89.8 % (p = 0.54) and 91.5 % (p = 0.14), respectively. CONCLUSIONS: Visual interpretation was superior to quantitative analysis in pelvic tumor recurrence in CRC. Though it was possible to improve diagnostic performance through combinatory analysis, the effect was not statistically significant. PMID- 26931103 TI - Individual-level predictors of inpatient childhood burn injuries: a case-control study. AB - BACKGROUND: Burn injuries are considered one of the most preventable public health issue among children; however, are a cause of significant morbidity and mortality in Iran. The aim of this study was to assess individual-level predictors of severe burn injuries among children leading to hospitalization, in East Azerbaijan Province, in North-West of Iran. METHODS: The study was conducted through a hospital based case-control design involving 281 burn victims and 273 hospital-based controls who were frequency matched on age, gender and urbanity. Both bivariate and multivariate methods were used to analyze the data. RESULTS: Mean age of the participants was 40.5 months (95 % CI: 37-44) with the majority of burns occurring at ages between 2 months-13.9 years. It was demonstrated that with increase in the caregiver's age there was a decrease in the odds of burn injuries (OR = 0.94, 95 % CI: 0.92-0.97). According to the multivariate logistic regression there were independent factors associated with burn injuries including childhood ADHD (OR = 2.82, 95 % CI: 1.68 - 4.76), child's age (OR = 0.73, 95%CI: 0.67 - 0.80), flammability of clothing (OR = 1.60, 95 % CI: 1.12 - 2.28), daily length of watching television (OR = 1.31, 95 % CI: 1.06 - 1.61), playing outdoors (OR = 1.32, 95 % CI: 1.16 - 1.50) and increment in the economic status (OR = 1.37, 95 % CI: 1.18 - 1.60). CONCLUSION: Major risk predictors of burn injuries among the Iranian population included childhood ADHD, child's age, watching television, playing outdoors, high economic status and flammable clothing. PMID- 26931105 TI - Evidence for contribution of common genetic variants within chromosome 8p21.2 8p21.1 to restricted and repetitive behaviors in autism spectrum disorders. AB - BACKGROUND: Restricted and Repetitive Behaviors (RRB), one of the core symptom categories for Autism Spectrum Disorders (ASD), comprises heterogeneous groups of behaviors. Previous research indicates that there are two or more factors (subcategories) within the RRB domain. In an effort to identify common variants associated with RRB, we have carried out a genome-wide association study (GWAS) using the Autism Genetic Resource Exchange (AGRE) dataset (n = 1,335, all ASD probands of European ancestry) for each identified RRB subcategory, while allowing for comparisons of associated single nucleotide polymorphisms (SNPs) with associated SNPs in the same set of probands analyzed using all the RRB subcategories as phenotypes in a multivariate linear mixed model. The top ranked SNPs were then explored in an independent dataset. RESULTS: Using principal component analysis of item scores obtained from Autism Diagnostic Interview Revised (ADI-R), two distinct subcategories within Restricted and Repetitive Behaviors were identified: Repetitive Sensory Motor (RSM) and Insistence on Sameness (IS). Quantitative RSM and IS scores were subsequently used as phenotypes in a GWAS using the AGRE ASD cohort. Although no associated SNPs with genome-wide significance (P < 5.0E-08) were detected when RSM or IS were analyzed independently, three SNPs approached genome-wide significance when RSM and IS were considered together using multivariate association analysis. These included the top IS-associated SNP, rs62503729 (P-value = 6.48E-08), which is located within chromosome 8p21.2-8p21.1, a locus previously linked to schizophrenia. Notably, all of the most significantly associated SNPs are located in close proximity to STMN4 and PTK2B, genes previously shown to function in neuron development. In addition, several of the top-ranked SNPs showed correlations with STMN4 mRNA expression in adult CEU (Caucasian and European descent) human prefrontal cortex. However, the association signals within chromosome 8p21.2 8p21.1 failed to replicate in an independent sample of 2,588 ASD probands; the insufficient sample size and between-study heterogeneity are possible explanations for the non-replication. CONCLUSIONS: Our analysis indicates that RRB in ASD can be represented by two distinct subcategories: RSM and IS. Subsequent univariate and multivariate genome-wide association studies of these RRB subcategories enabled the detection of associated SNPs at 8p21.2-8p21.1. Although these results did not replicate in an independent ASD dataset, genomic features of this region and pathway analysis suggest that common variants in 8p21.2-8p21.1 may contribute to RRB, particularly IS. Together, these observations warrant future studies to elucidate the possible contributions of common variants in 8p21.2-8p21.1 to the etiology of RSM and IS in ASD. PMID- 26931106 TI - Health service provider education and/or training in infant male circumcision to improve short- and long-term morbidity outcomes: protocol for systematic review. AB - BACKGROUND: There has been an expansion of circumcision services in Africa as part of a long-term HIV prevention strategy. However, the effect of infant male circumcision on morbidity and mortality still remains unclear. Acute morbidities associated with circumcision include pain, bleeding, swelling, infection, tetanus or inadequate skin removal. Scale-up of circumcision services could lead to a rise in these associated morbidities that could have significant impact on health service delivery and the safety of infants. Multidisciplinary training programmes have been developed to improve skills of health service providers, but very little is known about the effectiveness of health service provider education and/or training for infant male circumcision on short- and long-term morbidity outcomes. This review aims to evaluate the effectiveness of health service provider education and/or training for infant male circumcision on short- and long-term morbidity outcomes. METHODS/DESIGN: The review will include studies comparing health service providers who have received education and/or training to improve their skills for infant male circumcision with those who have not received education and/or training. Randomised controlled trials (RCTs) and cluster RCTs will be included. The outcomes of interest are short-term morbidities of the male infant including pain, infection, tetanus, bleeding, excess skin removal, glans amputation and fistula. Long-term morbidities include urinary tract infection (UTI), HIV infection and abnormalities of urination. Databases such as MEDLINE (OVID), PsycINFO (OVID), EMBASE (OVID), CINAHL, Cochrane Library (including CENTRAL and DARE), WHO databases and reference list of papers will be searched for relevant articles. Study selection, data extraction and synthesis and risk of bias assessment using the Cochrane risk of bias assessment tool will be conducted. We will calculate the pooled estimates of the difference in means and risk ratios using random effects models. If insufficient data are available, we will present results descriptively. DISCUSSION: This review appears to be the first to be conducted in this area. The findings will have important implications for infant male circumcision programmes and policy. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42015029345. PMID- 26931108 TI - Simple construct evaluation with latent class analysis: An investigation of Facebook addiction and the development of a short form of the Facebook Addiction Test (F-AT). AB - In psychological research, there is a growing interest in using latent class analysis (LCA) for the investigation of quantitative constructs. The aim of this study is to illustrate how LCA can be applied to gain insights on a construct and to select items during test development. We show the added benefits of LCA beyond factor-analytic methods, namely being able (1) to describe groups of participants that differ in their response patterns, (2) to determine appropriate cutoff values, (3) to evaluate items, and (4) to evaluate the relative importance of correlated factors. As an example, we investigated the construct of Facebook addiction using the Facebook Addiction Test (F-AT), an adapted version of the Internet Addiction Test (I-AT). Applying LCA facilitates the development of new tests and short forms of established tests. We present a short form of the F-AT based on the LCA results and validate the LCA approach and the short F-AT with several external criteria, such as chatting, reading newsfeeds, and posting status updates. Finally, we discuss the benefits of LCA for evaluating quantitative constructs in psychological research. PMID- 26931107 TI - Gingival Crevicular Fluid and Salivary Periostin Levels in Non-Smoker Subjects With Chronic and Aggressive Periodontitis : Periostin Levels in Chronic and Aggressive Periodontitis. AB - Periostin, an extracellular matrix protein functioning as an important structural mediator and adhesion molecule, has been shown to be an important regulator of connective tissue integrity. This study aimed to evaluate the levels of periostin in chronic periodontitis (CP) and aggressive periodontitis (AgP) compared to non periodontitis (NP). Individuals were submitted to gingival crevicular fluid (GCF) and saliva sampling. Periodontal examination consisted of plaque index (PI), gingival index (GI), probing depth (PD), bleeding on probing (BOP), and clinical attachment level (CAL) measurements. Assays for periostin were performed by an enzyme-linked immunosorbent assay. Periodontitis patients presented more severe clinical indices compared to the NP group (p < 0.001). The mean GCF level of periostin was lowest in the AgP group as compared to the other groups and was lower in the CP group as compared to the NP group (p < 0.001). Increased levels of periostin were observed in the saliva of patients with AgP as compared to the CP and NP groups (p < 0.05). There was a negative relationship between GCF periostin levels and clinical parameters (p < 0.01), whereas a positive correlation was observed between salivary periostin levels and full-mouth GI and CAL scores (p < 0.01). To our knowledge, this is the first report investigating periostin levels in GCF and saliva in aggressive periodontitis. The results suggest that subjects with CP and AgP exhibit a different periostin profile. Periostin in GCF may have a protective role against periodontal disease. Furthermore, salivary periostin concentrations may have a promising diagnostic potential for the aggressive forms of periodontal disease. PMID- 26931109 TI - Validation of the MG-DIS: a disability assessment for myasthenia gravis. AB - This paper is aimed to present the validation of the myasthenia gravis disability assessment (MG-DIS), a MG-specific patient-reported disability outcome measure. Consecutive MG patients were enrolled, followed-up for 12 months and administered the SF-36, the WHO disability assessment schedule (WHODAS 2.0) and the preliminary 31-item MG-DIS addressing impairments and activity limitations. Factor structure and metric properties were assessed. In total, 109 patients were enrolled: 76 were females, mean age 50, mean MG duration 10.4 years, 86 were AChR positive. The MG-DIS was reduced to 20 items, explaining 70.6 % of the original questionnaire variance, four subscales (generalized impairment-related problems; bulbar function-related problems; mental health and fatigue-related problems; vision-related problems) and an overall disability index. The MG-DIS has good metric properties (Cronbach's alpha ranging between .808 and .930), is stable, showed to be more sensitive than the WHODAS 2.0 and SF-36 to detect group differences and longitudinal changes and was well correlated with the MG composite (.642). The MG-DIS includes items representing ocular, generalized, bulbar and respiratory symptoms, and is therefore well-built around MG-specific features. MG-DIS can be used in clinical trials as well as in observational or epidemiological studies to characterize patients' disability level and address the amount of improvement in disability. Further studies are needed to explore the possibility of a shorter disability scale. PMID- 26931110 TI - Patient-controlled oral analgesia versus nurse-controlled parenteral analgesia after caesarean section: a randomised controlled trial. AB - We assessed the effectiveness of early patient-controlled oral analgesia compared with parenteral analgesia in a randomised controlled non-inferiority trial of women undergoing elective caesarean section under regional anaesthesia. Seventy seven women received multimodal paracetamol, ketoprofen and morphine analgesia. The woman having patient-controlled oral analgesia were administered four pillboxes on the postnatal ward containing tablets and instructions for self medication, the first at 7 h after the spinal injection and then three more at 12 hourly intervals. Pain at rest and on movement was evaluated using an 11-point verbal rating scale at 2 h and then at 6-hourly intervals for 48 h. The pre defined non-inferiority limit for the difference in mean pain scores (patient controlled oral analgesia minus parenteral) was one. The one-sided 95% CI of the difference in mean pain scores was significantly lower than one at all time points at rest and on movement, demonstrating non-inferiority of patient controlled oral analgesia. More women used morphine in the patient-controlled oral analgesia group (22 (58%)) than in the parenteral group (9 (23%); p = 0.002). The median (IQR [range]) number of morphine doses in the patient controlled oral analgesia group was 2 (1-3 [1-7]) compared with 1 (1-1 [1-2]); p = 0.006) in the parenteral group. Minor drug errors or omissions were identified in five (13%) women receiving patient-controlled oral analgesia. Pruritus was more frequent in the patient-controlled oral analgesia group (14 (37%) vs 6 (15%) respectively; p = 0.03), but no differences were noted for other adverse events and maternal satisfaction. After elective caesarean section, early patient controlled oral analgesia is non-inferior to standard parenteral analgesia for pain management, and can be one of the steps of an enhanced recovery process. PMID- 26931112 TI - Fabrication of microscale materials with programmable composition gradients. AB - We present an original microfluidic technique coupling pervaporation and the use of Quake valves to fabricate microscale materials (~10 * 100 MUm(2) * 1 cm) with composition gradients along their longest dimension. Our device exploits pervaporation of water through a thin poly(dimethylsiloxane) (PDMS) membrane to continuously pump solutions (or dispersions) contained in different reservoirs connected to a microfluidic channel. This pervaporation-induced flow concentrates solutes (or particles) at the tip of the channel up to the formation of a dense material. The latter invades the channel as it is constantly enriched by an incoming flux of solutes/particles. Upstream Quake valves are used to select which reservoir is connected to the pervaporation channel and thus which solution (or dispersion) enriches the material during its growth. The microfluidic configuration of the pervaporation process is used to impose controlled growth along the channel thus enabling one to program spatial composition gradients using appropriate actuations of the valves. We demonstrate the possibilities offered by our technique through the fabrication of dense assemblies of nanoparticles and polymer composites with programmed gradients of fluorescent dyes. We also address the key issue of the spatial resolution of our gradients and we show that well-defined spatial modulations down to ~50 MUm can be obtained within colloidal materials, whereas gradients within polymer materials are resolved on length scales down to ~1 mm due to molecular diffusion. PMID- 26931111 TI - Multi-year optimization of malaria intervention: a mathematical model. AB - BACKGROUND: Malaria is a mosquito-borne, lethal disease that affects millions and kills hundreds of thousands of people each year, mostly children. There is an increasing need for models of malaria control. In this paper, a model is developed for allocating malaria interventions across geographic regions and time, subject to budget constraints, with the aim of minimizing the number of person-days of malaria infection. METHODS: The model considers a range of several conditions: climatic characteristics, treatment efficacy, distribution costs, and treatment coverage. An expanded susceptible-infected-recovered compartment model for the disease dynamics is coupled with an integer linear programming model for selecting the disease interventions. The model produces an intervention plan for all regions, identifying which combination of interventions, with which level of coverage, to use in each region and year in a 5-year planning horizon. RESULTS: Simulations using the model yield high-level, qualitative insights on optimal intervention policies: The optimal intervention policy is different when considering a 5-year time horizon than when considering only a single year, due to the effects that interventions have on the disease transmission dynamics. The vaccine intervention is rarely selected, except if its assumed cost is significantly lower than that predicted in the literature. Increasing the available budget causes the number of person-days of malaria infection to decrease linearly up to a point, after which the benefit of increased budget starts to taper. The optimal policy is highly dependent on assumptions about mosquito density, selecting different interventions for wet climates with high density than for dry climates with low density, and the interventions are found to be less effective at controlling malaria in the wet climates when attainable intervention coverage is 60 % or lower. However, when intervention coverage of 80 % is attainable, then malaria prevalence drops quickly in all geographic regions, even when factoring in the greater expense of the higher coverage against a constant budget. CONCLUSIONS: The model provides a qualitative decision-making tool to weigh alternatives and guide malaria eradication efforts. A one-size-fits all campaign is found not to be cost-effective; it is better to consider geographic variations and changes in malaria transmission over time when determining intervention strategies. PMID- 26931113 TI - Sensitive and accurate quantification of JAK2 V617F mutation in chronic myeloproliferative neoplasms by droplet digital PCR. AB - The JAK2 V617F mutation can be detected with a high frequency in patients with myeloproliferative neoplasms (MPN). MPN treatment efficiency can be assessed by JAK2 V617F quantification. Real-time quantitative PCR (qPCR) is widely used for JAK2 V617F quantification. Emerging alternative technologies like digital droplet PCR (ddPCR) have been described to overcome inherent qPCR limitations. The purpose of this study was to evaluate the utility of ddPCR for JAK2 V617F quantification in patient samples with MPN. Sensitivity and specificity were established by using DNA artificial mixtures. In addition, 101 samples from 59 patients were evaluated for JAK2 V617F mutation. Limit of detection was 0.01 % for both qPCR and ddPCR. The JAK2 V617F mutation was detected in 43 out of 59 patients by both PCR platforms. However, in 14 % of the samples, JAK2 V617F mutation was detected only with ddPCR. This 14 % of discrepant samples were from patients shortly after allogeneic stem cell transplantation. Percentage of JAK2 V617F mutation measured by qPCR and ddPCR in clinical samples showed a high degree of correlation (Spearman r: 0.9637 p < 0.001) and an excellent agreement assessed by Bland-Altman analysis. In conclusion, ddPCR is a suitable, precise, and sensitive method for quantification of the JAK 2 V617F mutation. PMID- 26931114 TI - Complete remission of refractory disseminated NK/T cell lymphoma with brentuximab vedotin and bendamustine. PMID- 26931115 TI - Prognostic value of pretransplant FDG-PET in refractory/relapsed Hodgkin lymphoma treated with autologous stem cell transplantation: systematic review and meta analysis. AB - This study aimed to systematically review the prognostic value of pretransplant (18)F-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) in refractory/relapsed Hodgkin lymphoma treated with autologous stem cell transplantation (SCT). MEDLINE was systematically searched for appropriate studies. Included studies were methodologically appraised. Results of individual studies were meta-analyzed, if possible. Eleven studies, comprising a total of 745 refractory/relapsed Hodgkin lymphoma patients who underwent FDG-PET before autologous SCT, were included. The overall methodological quality of these studies was moderate. The proportion of pretransplant FDG-PET positive patients ranged between 25 and 65.2 %. Progression-free survival ranged between 0 and 52 % in pretransplant FDG-PET positive patients, and between 55 and 85 % in pretransplant FDG-PET negative patients. Overall survival ranged between 17 and 77 % in pretransplant FDG-PET positive patients, and between 78 and 100 % in FDG PET negative patients. Based on five studies that provided sufficient data for meta-analysis, pooled sensitivity and specificity of pretransplant FDG-PET in predicting treatment failure (i.e., either progressive, residual, or relapsed disease) were 67.2 % (95 % confidence interval [CI] 58.2-75.3 %) and 70.7 % (95 % CI 64.2-76.5 %), respectively. Based on two studies that provided sufficient data for meta-analysis, pooled sensitivity and specificity of pretransplant FDG-PET in predicting death during follow-up were 74.4 % (95 % CI 58.8-86.5 %) and 58.0 % (95 % CI 49.3-66.3 %), respectively. In conclusion, the moderate quality evidence suggests pretransplant FDG-PET to have value in predicting outcome in refractory/relapsed Hodgkin lymphoma patients treated with autologous SCT. Nevertheless, a considerable proportion of pretransplant FDG-PET positive patients remains disease free and a considerable proportion of pretransplant FDG PET negative patients develops disease relapse after autologous SCT. PMID- 26931116 TI - Serum zinc levels in patients with iron deficiency anemia and its association with symptoms of iron deficiency anemia. AB - Iron deficiency anemia (IDA) is a major public health problem especially in underdeveloped and developing countries. Zinc is the co-factor of several enzymes and plays a role in iron metabolism, so zinc deficiency is associated with IDA. In this study, it was aimed to investigate the relationship of symptoms of IDA and zinc deficiency in adult IDA patients. The study included 43 IDA patients and 43 healthy control subjects. All patients were asked to provide a detailed history and were subjected to a physical examination. The hematological parameters evaluated included hemoglobin (Hb); hematocrit (Ht); red blood cell (erythrocyte) count (RBC); and red cell indices mean corpuscular volume (MCV), mean corpuscular hemoglobin (MSN), mean corpuscular hemoglobin concentration (MSNS), and red cell distribution width (RDW). Anemia was defined according to the criteria defined by the World Health Organization (WHO). Serum zinc levels were measured in the flame unit of atomic absorption spectrophotometer. Symptoms attributed to iron deficiency or depletion, defined as fatigue, cardiopulmonary symptoms, mental manifestations, epithelial manifestations, and neuromuscular symptoms, were also recorded and categorized. Serum zinc levels were lower in anemic patients (103.51 +/- 34.64 MU/dL) than in the control subjects (256.92 +/- 88.54 MU/dL; <0.001). Patients with zinc level <99 MU/dL had significantly more frequent mental manifestations (p < 0.001), cardiopulmonary symptoms (p = 0.004), restless leg syndrome (p = 0.016), and epithelial manifestations (p < 0.001) than patients with zinc level > 100 MU/dL. When the serum zinc level was compared with pica, no statistically significant correlation was found (p = 0.742). Zinc is a trace element that functions in several processes in the body, and zinc deficiency aggravates IDA symptoms. Measurement of zinc levels and supplementation if necessary should be considered for IDA patients. PMID- 26931117 TI - Safety and effectiveness of sorafenib in Japanese patients with hepatocellular carcinoma in daily medical practice: interim analysis of a prospective postmarketing all-patient surveillance study. AB - BACKGROUND: Sorafenib was approved for treatment of unresectable hepatocellular carcinoma (HCC) in Japan in 2009. A prospective postmarketing all-patient surveillance (PMS) study was requested by Japanese authorities to confirm safety and effectiveness of sorafenib in Japanese HCC population. METHODS: Patients with unresectable HCC treated with sorafenib were followed up for 12 months. Data on patient demographic characteristics, treatment status, clinical outcome, and adverse events (AEs) were collected. RESULTS: This interim analysis included 1109 and 1065 patients evaluable for safety and effectiveness, respectively. Most patients (83.4 %) received the recommended initial dose of 400 mg twice daily. After a follow-up of 12-months, 89.8 % had discontinued treatment, most because of AEs (44.5 %) or progression (33.8 %). The most common drug-related adverse events (DRAE) were hand-foot skin reaction (51.4 %), liver dysfunction (26.4 %), diarrhea (25.1 %), and hypertension (21.6 %). The median overall survival (OS) was 348 days [95 % confidence interval (CI) 299-389 days], and the median duration of treatment was 87 days (95 % CI 78-98 days). Multivariate analyses identified baseline prognostic factors for longer OS, including female sex, low Child-Pugh score, Eastern Cooperative Oncology Group performance status 0, tumor stage I/II/III, low aspartate aminotransferase level, high hemoglobin level, hepatitis C and history of surgical resection. CONCLUSIONS: In general, the safety and effectiveness findings in this PMS were consistent with findings from previous clinical studies. Sorafenib was well tolerated and clinically useful for Japanese patients. CLINICAL TRIAL REGISTRATION NUMBER: NCT01411436. PMID- 26931118 TI - Does distracting pain justify performing brain computed tomography in multiple traumas with mild head injury? AB - Traumatic brain injury (TBI) is a significant health concern classified as mild, moderate, and severe. Although the indications to perform brain computed tomography (CT) are clear in moderate and severe cases, there still exists controversy in mild TBI (mTBI). We designed the study to evaluate the significance of distracting pain in patients with mTBI. The study population included patients with mild traumatic brain injury (GCS >=13). Moderate and high risk factors including age <18 months or >=60 years, moderate to severe or progressive headache, >=2 episodes of vomiting, loss of consciousness (LOC), post traumatic amnesia, seizure or prior antiepileptic use, alcohol intoxication, previous neurosurgical procedures, uncontrolled hypertension, anticoagulant use, presence of focal neurologic deficits, deformities in craniofacial region, and penetrating injuries were excluded. The patients were then grouped based on presence (DP+) or absence (DP-) of another organ fracture with severe pain (based on VAS). The primary outcome was any abnormal findings on brain CT scans; 330 patients were enrolled (184 DP+ and 146 DP-). Overall, two DP+ and one DP- patients had mild cerebral edema in brain CT (p > 0.99). No patients had any neurologic symptoms or signs in follow-up. Our results show that in the absence of any other risk factors, distracting pain from other organs (limbs, pelvis, and non-cervical spine) cannot be regarded as a brain CT indication in patients with mild TBI, as it is never associated with significant intracranial lesions. PMID- 26931119 TI - Anti-tumor effects of Atractylenolide I on bladder cancer cells. AB - BACKGROUND: Atractylenolide I (ATR-1), an active component of Rhizoma Atractylodis Macrocephalae, possesses cytotoxicity against various carcinomas. However, little is known about the effects of ATR-1on bladder cancer. In the present study, the anti-tumor activity of ATR-1 was examined on bladder cancer cells both in vivo and in vitro. METHODS: MTT assay was used to assess the cytotoxic effect of ATR-1. Cell cycle distribution and apoptosis levels were evaluated using flow cytometry. Western blotting assay was applied to measure the levels of proteins associated with the apoptotic pathway, cell cycle progression and PI3K/Akt/mTOR signaling pathway. Tumor models in nude mice were induced by injection of T-24 and 253J human bladder cancer cells. RESULTS: ATR-1 inhibited bladder cancer cell proliferation, arrested cell cycle in G2/M phase through up regulation of p21 and down-regulation of cyclin B1, CDK1 and Cdc25c. Meanwhile, ATR-1 also triggered cellular apoptosis depending on the activation of mitochondrial apoptotic pathway. Mechanism investigation indicated that ATR-1 exerts its anti-tumor effect also relies on the inhibition of PI3K/Akt/mTOR signaling pathway. Finally, mice studies showed that ATR-1 blocked the T-24 or 253J-induced xenograft tumor growth without noticeable toxicity. CONCLUSIONS: ATR 1 may be served as a potential therapeutic agent for the treatment of bladder cancer. PMID- 26931121 TI - Molecular ion index assisted comprehensive profiling of B-type oligomeric proanthocyanidins in rhubarb by high performance liquid chromatography-tandem mass spectrometry. AB - Proanthocyanidins (PAs) are major anti-diarrhea constituents in rhubarb, one of the frequently used traditional medicines. However, the phytochemical investigation of PAs in rhubarb was hampered by their strenuous purification and identification. In the present study, aiming to clarify the distribution of PAs in different rhubarb species, a molecular ion index was priorly established according to the structural features of B-type PAs, which led to a series of targeted discovery of oligomeric PAs in rhubarb by the HPLC-ESI-MS/MS method. Totally, 66 oligomeric PAs including 27 dimers, 29 trimers, and 10 tetramers were tentatively identified on the basis of their MS/MS spectra from 28 rhubarb samples derived from 5 Rheum species as R. palmatum, R. tanguticum, R. officinale, R. coreanum, and R. laciniatum. It is noteworthy that 6 propelargonidins, 14 prodelphinidins, and 10 procyanidin-tetramers were identified from rhubarb for the first time. The profiling comparison of these oligomeric PAs in different rhubarb samples was achieved by visualizing their abundance in a heat map, which indicated the dominant PAs in rhubarb were procyanidin-dimer and its galloylated derivatives. PMID- 26931120 TI - Increased first and second pulse harmonics in Tai Chi Chuan practitioners. AB - BACKGROUND: Tai Chi Chuan (TCC) is known to be a good calisthenics for people. This study examined the relationship between pulse harmonics and autonomic nervous modulation in TCC practitioners. METHODS: Power spectral measures of right pulse wave and heart rate variability (HRV) measures were compared between TCC practitioners and control subjects. Correlation analyses between pulse harmonics and HRV measures were performed using linear regression analysis. RESULTS: At baseline, the total power of pulse (TPp), powers of all individual pulse harmonics, normalized power of the 1(st) harmonics (nPh1) of TCC practitioners were greater, while the normalized power of the 4(th) pulse harmonics (nPh4) of TCC practitioners was smaller, than those of the controls. Similarly, the baseline standard deviation (SD(RR)), coefficient of variation (CV(RR)), and normalized high-frequency power (nHFP) of RR intervals were smaller, while the normalized very low-frequency power (nVLFP) and low-/high- frequency power ratio (LHR) were larger in the TCC practitioners. The TCC age correlated significantly and negatively with nPh1, and nearly significantly and negatively with nPh2 in the TCC practitioners. Thirty min after TCC exercise, the percentage changes in mRRI, SDRR, TP, VLFP were decreased, while the percentage changes in HR, ULFP, nLFP, and Ph2 were increased, relative to the controls. Correlation analysis shows that the %Ph2 correlates significantly and negatively with %mRRI and significantly and positively with %HR. CONCLUSION: The TCC practitioners had increased baseline total power of pulse and the 1(st) and 2(nd) pulse harmonics, and decreased power of the 4(th) pulse harmonics, along with decreased vagal modulation and increased sympathetic modulation. After TCC exercise, the power of the 2(nd) harmonics of TCC practitioners was increased which might be related to the increase in HR due to decreased vascular resistance after TCC exercise. PMID- 26931122 TI - Postmortem interval estimation: a novel approach utilizing gas chromatography/mass spectrometry-based biochemical profiling. AB - While the molecular mechanisms underlying postmortem change have been exhaustively investigated, the establishment of an objective and reliable means for estimating postmortem interval (PMI) remains an elusive feat. In the present study, we exploit low molecular weight metabolites to estimate postmortem interval in mice. After sacrifice, serum and muscle samples were procured from C57BL/6J mice (n = 52) at seven predetermined postmortem intervals (0, 1, 3, 6, 12, 24, and 48 h). After extraction and isolation, low molecular weight metabolites were measured via gas chromatography/mass spectrometry (GC/MS) and examined via semi-quantification studies. Then, PMI prediction models were generated for each of the 175 and 163 metabolites identified in muscle and serum, respectively, using a non-linear least squares curve fitting program. A PMI estimation panel for muscle and serum was then erected which consisted of 17 (9.7%) and 14 (8.5%) of the best PMI biomarkers identified in muscle and serum profiles demonstrating statistically significant correlations between metabolite quantity and PMI. Using a single-blinded assessment, we carried out validation studies on the PMI estimation panels. Mean +/- standard deviation for accuracy of muscle and serum PMI prediction panels was -0.27 +/- 2.88 and -0.89 +/- 2.31 h, respectively. Ultimately, these studies elucidate the utility of metabolomic profiling in PMI estimation and pave the path toward biochemical profiling studies involving human samples. PMID- 26931123 TI - The Patient-Centered Medical Home: How Is It Related to Quality and Equity Among the General Adult Population? AB - This study investigates whether patient-reported characteristics of the medical home are associated with improved quality and equity of preventive care, advice on health habits, and emergency department use. We used adjusted risk ratios to examine the association between medical home characteristics and care measures based on the 2010 Medical Expenditure Panel Survey. Medical home characteristics are associated with 6 of the 11 outcome measures, including flu shots, smoking advice, exercise advice, nutrition advice, all advice, and emergency department visits. Educational and income groups benefit relatively equally from medical home characteristics. However, compared with insurance and access to a provider, medical home characteristics have little influence on overall disparities in care. In sum, our findings support that medical home characteristics can improve quality and reduce emergency visits but we find no evidence that medical home characteristics alleviate disparities in care. PMID- 26931124 TI - Rigorous determination of the ground-state phases and thermodynamics in an Ising type multiferroic chain. AB - To understand the ferroelectricity driven by collinear magnetism in a multiferroic spin-chain system, we have adopted an elastic diatomic Ising spin chain model with axial next-nearest-neighbor interaction to describe its magnetoelectric properties. By employing magneto-phonon decoupling and the transfer-matrix method, the possible ground-state configurations and thermodynamic behaviors of the system have been determined exactly. The parameter relation for the appearance of electric polarization has been discussed from the perspective of the ground-state configuration. In the case of nearest-neighbor antiferromagnetic coupling, a novel series of zero-temperature transitions induced by magnetic field have been observed, from the ???? spin configuration associated with ferroelectric order to the ??? state with a peculiar 1/3 magnetization plateau, then to the ???? state, and finally saturation in the ???? state. PMID- 26931125 TI - Correction to: "Psychedelics". PMID- 26931126 TI - Seven day NHS services: what trusts are doing. PMID- 26931127 TI - Exploring strategies to improve the health promotion orientation of Flemish sports clubs. AB - Sports clubs are increasingly recognized as an innovative setting for health promotion, as exemplified by the health promoting sports club concept. This study aims to assess the health promotion orientation of both youth sports clubs (YSC) and adult sports clubs (ASC) in Flanders and to identify the motives and barriers as reported by their representatives as a basis for proposing intervention strategies to improve the health promotion orientation in sports clubs. A total of 253 Flemish sports clubs, consisting of 156 YSC and of 97 ASC, completed the online questionnaire, covering club characteristics (e.g. finances, human resources), perceived motives and barriers for health promotion and the health promoting sports club index. Even though YSC were more health promoting than ASC, the results indicated that all sports clubs could improve their health promotion orientation. The most consistent predictors of health promotion orientation are perceived motives index for YSC and perceived lack of resources for ASC. Based on these results, interventions to enhance the health promoting orientation need to tackle the lack of resources such as lack of expertise regarding health promotion. Interventions aimed specifically at YSC should emphasize the direct benefits, for example by demonstrating how health promotion helps clubs to improve the provision of high quality sports participation and by awarding a health promotion quality label. PMID- 26931130 TI - An unfortunate injection. AB - Intramuscular injection has been used to administer medications for more than a hundred years. However, despite our profession's long experience with intramuscular administration, preventable complications such as injection nerve palsies are still prevalent in developing countries. Injections account for one fifth of all traumatic nerve injuries. These injuries largely occur due to indiscriminate use of intramuscular injections for treating common illnesses, frequently by unlicensed or undertrained practitioners administering unnecessary treatment to impoverished patients. The sciatic nerve is the most commonly injured, and frequently the resulting muscle weakness and associated disability are irreversible. This case report includes a video of a patient with foot drop 6 weeks after gluteal intramuscular injection. Such injuries can be prevented by proper awareness and training, the implementation of safer injection techniques, and quality assurance methods. PMID- 26931128 TI - Heightened TWEAK-NF-kappaB signaling and inflammation-associated fibrosis in paralyzed muscles of men with chronic spinal cord injury. AB - Individuals with long-standing spinal cord injury (SCI) often present with extreme muscle atrophy and impaired glucose metabolism at both the skeletal muscle and whole body level. Persistent inflammation and increased levels of proinflammatory cytokines in the skeletal muscle are potential contributors to dysregulation of glucose metabolism and atrophy; however, to date no study has assessed the effects of long-standing SCI on their expression or intracellular signaling in the paralyzed muscle. In the present study, we assessed the expression of genes (TNFalphaR, TNFalpha, IL-6R, IL-6, TWEAK, TWEAK R, atrogin-1, and MuRF1) and abundance of intracellular signaling proteins (TWEAK, TWEAK R, NF kappaB, and p-p65/p-50/105) that are known to mediate inflammation and atrophy in skeletal muscle. In addition, based on the effects of muscle inflammation on promotion of skeletal muscle fibrosis, we assessed the degree of fibrosis between myofibers and fascicles in both groups. For further insight into the distribution and variability of muscle fiber size, we also analyzed the frequency distribution of SCI fiber size. Resting vastus lateralis (VL) muscle biopsy samples were taken from 11 men with long-standing SCI (~22 yr) and compared with VL samples from 11 able-bodied men of similar age. Our results demonstrated that chronic SCI muscle has heightened TNFalphaR and TWEAK R gene expression and NF-kappaB signaling (higher TWEAK R and phospho-NF-kappaB p65) and fibrosis, along with substantial myofiber size heterogeneity, compared with able-bodied individuals. Our data suggest that the TWEAK/TWEAK R/NF-kappaB signaling pathway may be an important mediator of chronic inflammation and fibrotic adaptation in SCI muscle. PMID- 26931131 TI - Interface Induced Growth and Transformation of Polymer-Conjugated Proto Crystalline Phases in Aluminosilicate Hybrids: A Multiple-Quantum (23)Na-(23)Na MAS NMR Correlation Spectroscopy Study. AB - Nanostructured materials typically offer enhanced physicochemical properties because of their large interfacial area. In this contribution, we present a comprehensive structural characterization of aluminosilicate hybrids with polymer conjugated nanosized zeolites specifically grown at the organic-inorganic interface. The inorganic amorphous Al-O-Si framework is formed by alkali activated low-temperature transformation of metakaoline, whereas simultaneous copolymerization of organic comonomers creates a secondary epoxide network covalently bound to the aluminosilicate matrix. This secondary epoxide phase not only enhances the mechanical integrity of the resulting hybrids but also introduces additional binding sites accessible for compensating negative charge on the aluminosilicate framework. This way, the polymer network initiates growth and subsequent transformation of protocrystalline short-range ordered zeolite domains that are located at the organic-inorganic interface. By applying an experimental approach based on 2D (23)Na-(23)Na double-quantum (DQ) MAS NMR spectroscopy, we discovered multiple sodium binding sites in these protocrystalline domains, in which immobilized Na(+) ions form pairs or small clusters. It is further demonstrated that these sites, the local geometry of which allows for the pairing of sodium ions, are preferentially occupied by Pb(2+) ions during the ion exchange. The proposed synthesis protocol thus allows for the preparation of a novel type of geopolymer hybrids with polymer-conjugated zeolite phases suitable for capturing and storage of metal cations. The demonstrated (23)Na-(23)Na DQ MAS NMR combined with DFT calculations represents a suitable approach for understanding the role of Na(+) ions in aluminositicate solids and related inorganic-organic hybrids, particularly their specific arrangement and clustering at interfacial areas. PMID- 26931132 TI - Community and provider perceptions of traditional and skilled birth attendants providing maternal health care for pastoralist communities in Kenya: a qualitative study. AB - BACKGROUND: Kenya has a high burden of maternal and newborn mortality. Consequently, the Government of Kenya introduced health system reforms to promote the availability of skilled birth attendants (SBAs) and proscribed deliveries by traditional birth attendants (TBAs). Despite these changes, only 10% of women from pastoralist communities are delivered by an SBA in a health facility, and the majority are delivered by TBAs at home. The aim of this study is to better understand the practices and perceptions of TBAs and SBAs serving the remotely located, semi-nomadic, pastoralist communities of Laikipia and Samburu counties in Kenya, to inform the development of an SBA/TBA collaborative care model. METHODS: This descriptive qualitative study was undertaken in 2013-14. We conducted four focus group discussions (FGDs) with TBAs, three with community health workers, ten with community women, and three with community men. In-depth interviews were conducted with seven SBAs and eight key informants. Topic areas covered were: practices and perceptions of SBAs and TBAs; rewards and challenges; managing obstetric complications; and options for SBA/TBA collaboration. All data were translated, transcribed and thematically analysed. RESULTS: TBAs are valued and accessible members of their communities who adhere to traditional practices and provide practical and emotional support to women during pregnancy, delivery and post-partum. Some TBA practices are potentially harmful to women e.g., restricting food intake during pregnancy, and participants recognised that TBAs are unable to manage obstetric complications. SBAs are acknowledged as having valuable technical skills and resources that contribute to safe and clean deliveries, especially in the event of complications, but there is also a perception that SBAs mistreat women. Both TBAs and SBAs identified a range of challenges related to their work, and instances of mutual respect and informal collaborations between SBAs and TBAs were described. CONCLUSIONS: These findings clearly indicate that an SBA/TBA collaborative model of care consistent with Kenyan Government policy is a viable proposition. The transition from traditional birth to skilled birth attendance among the pastoralist communities of Laikipia and Samburu is going to be a gradual one, and an interim collaborative model is likely to increase the proportion of SBA assisted deliveries, improve obstetric outcomes, and facilitate the transition. PMID- 26931134 TI - [Venous saturation : Between oxygen delivery and consumption]. AB - Venous saturation is an important parameter to assess the ratio between oxygen delivery and oxygen consumption for both intensive care medicine and during perioperative care. Mixed venous saturation (SvO2) is the most reliable parameter in this setting. Due to the high invasiveness of measuring mixed venous saturation, the less invasive central venous saturation (ScvO2) has been entrenched for determining the balance of oxygen delivery and consumption. However, central venous saturation is inferior compared to mixed venous saturation as it does not cover the lower part of the body, including splanchnic perfusion. Nevertheless, studies have shown that central venous saturation is a reliable marker for goal-directed therapy in intensive care medicine, especially in patients with septic or hemorrhagic shock. Furthermore, central venous saturation has deep impact as a prognostic factor concerning morbidity and mortality. It has to be mentioned that not only decreased venous saturations but also elevated venous saturations are associated with poor outcome. Besides mixed venous and central venous saturation, intensivists and anesthesiologists focus on the central venous-arterial pCO2 difference (dCO2). An elevated dCO2 is associated with poor outcome in patients after cardiac surgery or patients with sepsis. Yet, further investigations have to be performed to implement the dCO2 as a reliable marker in daily routine. PMID- 26931135 TI - Insulin resistance and sarcopenia: mechanistic links between common co morbidities. AB - Insulin resistance (IR) in skeletal muscle is a key defect mediating the link between obesity and type 2 diabetes, a disease that typically affects people in later life. Sarcopenia (age-related loss of muscle mass and quality) is a risk factor for a number of frailty-related conditions that occur in the elderly. In addition, a syndrome of 'sarcopenic obesity' (SO) is now increasingly recognised, which is common in older people and is applied to individuals that simultaneously show obesity, IR and sarcopenia. Such individuals are at an increased risk of adverse health events compared with those who are obese or sarcopenic alone. However, there are no licenced treatments for sarcopenia or SO, the syndrome is poorly defined clinically and the mechanisms that might explain a common aetiology are not yet well characterised. In this review, we detail the nature and extent of the clinical syndrome, highlight some of the key physiological processes that are dysregulated and discuss some candidate molecular pathways that could be implicated in both metabolic and anabolic defects in skeletal muscle, with an eye towards future therapeutic options. In particular, the potential roles of Akt/mammalian target of rapamycin signalling, AMP-activated protein kinase, myostatin, urocortins and vitamin D are discussed. PMID- 26931133 TI - [Prevalence and severity of pulmonary embolism are dependent on clinical and paraclinical parameters : Analysis of 1,943 consecutive patients with CT pulmonary angiography]. AB - BACKGROUND: Patients with pulmonary embolism (PE) have heterogeneous symptoms. Clinical scores and age-adjusted D-dimer should help clinicians to establish the correct diagnosis. METHODS: A cohort of 1,943 consecutive patients with positive D-dimer levels who were referred for CT pulmonary angiography (CTPA) over a period of 5 years to rule PE in or out were retrospectively analyzed. RESULTS: On CTPA n = 362 (19 %) had PE. The prevalence of PE increased stepwise with increasing D-dimer levels (prevalence of PE with 10 percentiles of D-dimers was: 3 %, 4 %, 7 %, 8 %, 8 %, 21 %, 20 %, 27 %, 37 %, 52 %; p < 0.001). D-dimers > 2.0 were significantly associated with PE (OR 7.17 95 % CI 5.27-9.76, p < 0.001). Chest discomfort and tachypnea showed no association with PE. Dyspnoea, pleuritic pain, and general fatigue showed significant associations with age: pleuritic chest pain was more frequent in patients aged < 76 years than in patients aged > 76 years (15 % vs 3 %; p < 0.001) and was highly significantly associated with PE (OR 4.99 95 % CI 2.83-8.81; p < 0.001). General fatigue was more prevalent in patients aged > 76 years (44 % vs 24 %; p < 0.001). PE patients with D-dimers > 6.0 mg/l were hemodynamically more compromised than patients with D-dimers < 6.0 mg/l: tachycardia 32 % vs 20 %, p = 0.015; right ventricular strain on echocardiography: 38 % vs 23 %, p = 0.003; right ventricular strain on ECG: 27 % vs 13 %; p = 0.001; resuscitation 4 % vs 0 %, p = 0.003; lytic therapy 6 % vs 1 %, p = 0.014. CONCLUSION: The symptoms of PE patients are often vague. Particularly in older patients, fatigue may be the only symptom. The absolute level of D-dimers, particularly > 2.0 mg/l, is a strong predictor of PE. A D dimer level > 6.0 mg/l is associated with more severe hemodynamic impairment in patients with PE. PMID- 26931136 TI - Voluntary exercise improves hypothalamic and metabolic function in obese mice. AB - Exercise plays a critical role in regulating glucose homeostasis and body weight. However, the mechanism of exercise on metabolic functions associated with the CNS has not been fully understood. C57BL6 male mice (n=45) were divided into three groups: normal chow diet, high-fat diet (HFD) treatment, and HFD along with voluntary running wheel exercise training for 12 weeks. Metabolic function was examined by the Comprehensive Lab Animal Monitoring System and magnetic resonance imaging; phenotypic analysis included measurements of body weight, food intake, glucose and insulin tolerance tests, as well as insulin and leptin sensitivity studies. By immunohistochemistry, the amount changes in the phosphorylation of signal transducer and activator of transcription 3, neuronal proliferative maker Ki67, apoptosis positive cells as well as pro-opiomelanocortin (POMC)-expressing neurons in the arcuate area of the hypothalamus was identified. We found that 12 weeks of voluntary exercise training partially reduced body weight gain and adiposity induced by an HFD. Insulin and leptin sensitivity were enhanced in the exercise training group verses the HFD group. Furthermore, the HFD-impaired POMC expressing neuron is remarkably restored in the exercise training group. The restoration of POMC neuron number may be due to neuroprotective effects of exercise on POMC neurons, as evidenced by altered proliferation and apoptosis. In conclusion, our data suggest that voluntary exercise training improves metabolic symptoms induced by HFD, in part through protected POMC-expressing neuron from HFD and enhanced leptin signaling in the hypothalamus that regulates whole-body energy homeostasis. PMID- 26931137 TI - Asymmetrical distribution of delta and PP cells in human pancreatic islets. AB - The aim of this study was to evaluate the location of PP and delta cells in relation to the vascularization within human pancreatic islets. To this end, pancreas sections were analysed by immunofluorescence using antibodies against endocrine islet and endothelial cells. Staining in different islet areas corresponding to islet cells adjacent or not to peripheral or central vascular channels was quantified by computerized morphometry. As results, alpha, PP and delta cells were preferentially found adjacent to vessels. In contrast to alpha cells, which were evenly distributed between islet periphery and intraislet vascular channels, PP and delta cells had asymmetric and opposite distributions: PP staining was higher and somatostatin staining was lower in the islet periphery than in the area around intraislet vascular channels. Additionally, frequencies of PP and delta cells were negatively correlated in the islets. No difference was observed between islets from the head and the tail of the pancreas, and from type 2 diabetic and non-diabetic donors. In conclusion, the distribution of delta cells differs from that of PP cells in human islets, suggesting that vessels at the periphery and at the centre of islets drain different hormonal cocktails. PMID- 26931138 TI - Constructions and Negotiations of Sexuality in Canadian Federal Men's Prisons. AB - Nuances lacing the organization of sexuality across cultures and contexts shape sexual behavior and identity. In this article, the culture and understandings of sexual identity and behavior in Canadian men's federal prisons are examined to reveal how prisoners construct and interpret their own sexuality, as well as that of others, within the heteronormative prison space. Drawing from interviews with formerly incarcerated men, we explore how sexuality constitutes a product of dominant cultural discourses that differentiates between sexual behavior and identity. We frame how sexuality is constructed and regulated in prison within the theoretical context of shame and stigmatization, finding definitions of heterosexuality that do not preclude same-sex sexual activity. PMID- 26931139 TI - Do the Big Five personality traits predict individual differences in the left cheek bias for emotion perception? AB - Like language, emotion is a lateralized function. Because the right hemisphere typically dominates emotion processing, people express stronger emotion on the left side of their face. This prompts a left cheek bias: we offer the left cheek to express emotion and rate left cheek portraits more emotionally expressive than right cheek portraits. Though the majority of the population show this left cheek bias (60-70%), individual differences exist but remain largely unexplained. Given that people with higher self-rated emotional expressivity show a stronger left cheek bias, personality variables associated with increased emotional expressivity and emotional intelligence, such as extraversion and openness, may help account for individual differences. The present study thus examined whether the Big Five traits predict left cheek preferences. Participants (M = 58, F = 116) completed the NEO-Five Factor Personality Inventory (NEO-FFI) [Costa, P. T. J., & McCrae, R. R. (1992). NEO PI-R professional manual. Odessa, FL: Psychological Assessment Resources] and viewed pairs of left and right cheek images (half mirror-reversed); participants made forced-choice decisions, indicating which image in each pair looked happier. Hierarchical regression indicated that neither trait extraversion nor openness predicted left cheek selections, with NEO-FFI personality subscales accounting for negligible variance in preferences. As the Big Five traits have been discounted, exploration of other potential contributors to individual differences in the left cheek bias is clearly needed. PMID- 26931140 TI - The Impact of Selection, Gene Conversion, and Biased Sampling on the Assessment of Microbial Demography. AB - Recent studies have linked demographic changes and epidemiological patterns in bacterial populations using coalescent-based approaches. We identified 26 studies using skyline plots and found that 21 inferred overall population expansion. This surprising result led us to analyze the impact of natural selection, recombination (gene conversion), and sampling biases on demographic inference using skyline plots and site frequency spectra (SFS). Forward simulations based on biologically relevant parameters from Escherichia coli populations showed that theoretical arguments on the detrimental impact of recombination and especially natural selection on the reconstructed genealogies cannot be ignored in practice. In fact, both processes systematically lead to spurious interpretations of population expansion in skyline plots (and in SFS for selection). Weak purifying selection, and especially positive selection, had important effects on skyline plots, showing patterns akin to those of population expansions. State-of-the-art techniques to remove recombination further amplified these biases. We simulated three common sampling biases in microbiological research: uniform, clustered, and mixed sampling. Alone, or together with recombination and selection, they further mislead demographic inferences producing almost any possible skyline shape or SFS. Interestingly, sampling sub-populations also affected skyline plots and SFS, because the coalescent rates of populations and their sub-populations had different distributions. This study suggests that extreme caution is needed to infer demographic changes solely based on reconstructed genealogies. We suggest that the development of novel sampling strategies and the joint analyzes of diverse population genetic methods are strictly necessary to estimate demographic changes in populations where selection, recombination, and biased sampling are present. PMID- 26931141 TI - Common Structural Core of Three-Dozen Residues Reveals Intersuperfamily Relationships. AB - Identification of relationships among protein families or superfamilies is a challenge. However, functionally essential protein regions typically retain structural integrity, even when the corresponding protein sequences evolve. Consequently, comparison of protein structures enables deeper phylogenetic analyses than achievable through the use of sequence information only. Here, we focus on a group of distantly related viral and cellular enzymes involved in nucleic acid or nucleotide processing and synthesis. All these enzymes share an apparently similar protein fold at their active site, which resembles the palm subdomain of the right-hand-shaped polymerases. Using a structure-based hierarchical clustering method, we identified a common structural core of 36 equivalent residues for this functionally diverse group of enzymes, representing five protein superfamilies. Based on the properties of these 36 residues, we deduced a structural distance-based tree in which the proteins were accurately clustered according to the established family classification. Within this tree, the enzymes catalyzing genomic nucleic acid replication or transcription were separated from those performing supplementary nucleic acid or nucleotide processing functions. In addition, we found that the family Y DNA polymerases are structurally more closely related to the nucleotide cyclase superfamily members than to the other members of the DNA/RNA polymerase superfamily, and these enzymes share 88 equivalent residues comprising a Beta: 1- Alpha: 1- Alpha: 2- Beta: 2- Beta: 3- Alpha: 3- Beta: 4- Alpha: 4- Beta: 5 fold. The results highlight the power of structure-based hierarchical clustering in identifying remote evolutionary relationships. Furthermore, our study implies that a protein substructure of only three-dozen residues can contain a substantial amount of information on the evolutionary history of proteins. PMID- 26931142 TI - Should we reframe how we think about physical activity and sedentary behaviour measurement? Validity and reliability reconsidered. AB - BACKGROUND: The measurement of physical activity (PA) and sedentary behaviour (SB) is fundamental to health related research, policy, and practice but there are well known challenges to these measurements. Within the academic literature, the terms "validity" and "reliability" are frequently used when discussing PA and SB measurement to reassure the reader that they can trust the evidence. DISCUSSION: In this paper we argue that a lack of consensus about the best way to define, assess, or utilize the concepts of validity and reliability has led to inconsistencies and confusion within the PA and SB evidence base. Where possible we propose theoretical examples and solutions. Moreover we present an overarching framework (The Edinburgh Framework) which we believe will provide a process or pathway to help researchers and practitioners consider validity and reliability in a standardized way. CONCLUSION: Further work is required to identify all necessary and available solutions and generate consensus in our field to develop the Edinburgh Framework into a useful practical resource. We envisage that ultimately the proposed framework will benefit research, practice, policy, and teaching. We welcome critique, rebuttal, comment, and discussion on all ideas presented. PMID- 26931143 TI - Maternal, fetal and perinatal alterations associated with obesity, overweight and gestational diabetes: an observational cohort study (PREOBE). AB - BACKGROUND: Maternal overweight, obesity, and gestational diabetes (GD) have been negatively associated with offspring development. Further knowledge regarding metabolic and nutritional alterations in these mother and their offspring are warranted. METHODS: In an observational cohort study we included 331 pregnant women from Granada, Spain. The mothers were categorized into four groups according to BMI and their GD status; overweight (n:56), obese (n:64), GD (n:79), and healthy normal weight controls (n:132). We assessed maternal growth and nutritional biomarkers at 24 weeks (n = 269), 34 weeks (n = 310) and at delivery (n = 310) and the perinatal characteristics including cord blood biomarkers. RESULTS: Obese and GD mothers had significantly lower weight gain during pregnancy and infant birth weight, waist circumference, and placental weight were higher in the obese group, including a significantly increased prevalence of macrosomia. Except for differences in markers of glucose metabolism (glucose, HbA1c, insulin and uric acid) we found at some measures that overweight and/or obese mothers had lower levels of transferrin saturation, hemoglobin, Vitamin B12 and folate and higher levels of C-reactive protein, erythrocyte sedimentation rate, ferritin, and cortisol. GD mothers had similar differences in hemoglobin and C-reactive protein but higher levels of folate. The latter was seen also in cord blood. CONCLUSIONS: We identified several metabolic alterations in overweight, obese and GD mothers compared to controls. Together with the observed differences in infant anthropometrics, these may be important biomarkers in future research regarding the programming of health and disease in children. TRIAL REGISTRATION: The trial was registered at clinicaltrials.gov, identifier ( NCT01634464 ). PMID- 26931144 TI - The major histocompatibility complex in Old World camelids and low polymorphism of its class II genes. AB - BACKGROUND: The Major Histocompatibility Complex (MHC) is a genomic region containing genes with crucial roles in immune responses. MHC class I and class II genes encode antigen-presenting molecules expressed on the cell surface. To counteract the high variability of pathogens, the MHC evolved into a region of considerable heterogeneity in its organization, number and extent of polymorphism. Studies of MHCs in different model species contribute to our understanding of mechanisms of immunity, diseases and their evolution. Camels are economically important domestic animals and interesting biomodels. Three species of Old World camels have been recognized: the dromedary (Camelus dromedarius), Bactrian camel (Camelus bactrianus) and the wild camel (Camelus ferus). Despite their importance, little is known about the MHC genomic region, its organization and diversity in camels. The objectives of this study were to identify, map and characterize the MHC region of Old World camelids, with special attention to genetic variation at selected class MHC II loci. RESULTS: Physical mapping located the MHC region to the chromosome 20 in Camelus dromedarius. Cytogenetic and comparative analyses of whole genome sequences showed that the order of the three major sub-regions is "Centromere - Class II - Class III - Class I". DRA, DRB, DQA and DQB exon 2 sequences encoding the antigen binding site of the corresponding class II antigen presenting molecules showed high degree of sequence similarity and extensive allele sharing across the three species. Unexpectedly low extent of polymorphism with low numbers of alleles and haplotypes was observed in all species, despite different geographic origins of the camels analyzed. The DRA locus was found to be polymorphic, with three alleles shared by all three species. DRA and DQA sequences retrieved from ancient DNA samples of Camelus dromedarius suggested that additional polymorphism might exist. CONCLUSIONS: This study provided evidence that camels possess an MHC comparable to other mammalian species in terms of its genomic localization, organization and sequence similarity. We described ancient variation at the DRA locus, monomorphic in most species. The extent of molecular diversity of MHC class II genes seems to be substantially lower in Old World camels than in other mammalian species. PMID- 26931145 TI - Total hip arthroplasty-related osteogenic osteosarcoma: case report and review of the literature. AB - BACKGROUND: Orthopedic implant-related sarcoma is an exceedingly rare, but a known complication of total hip arthroplasty (THA). CASE PRESENTATION: The authors describe clinical and radiologic features, histologic appearance, and treatment of osteogenic osteosarcoma located in the proximal femoral diaphysis associated with an unstable femoral prosthesis following THA in a 65-year-old male patient. The patient with HLA-B27 positive ankylosing spondylitis underwent arthroplasty 15 years ago. CONCLUSIONS: The neoplastic process may be considered as an extraordinary complication of THA and might just be coincidental or the result of some derangement of the healing process in host tissue with no definitely proven hypothesis that the implants or their by-products are carcinogenic. The soluble chemical substances from the implanted prosthetic material are, at least in animals, suspected to play a vital role in the pathogenesis of the neoplastic transformation of the bone tissue. The presented case shall alert orthopedic surgeons to clinical, radiologic, and macroscopic similarities between a malignant tumor and benign lesions caused by wear debris at THA sites. At the examination of plane X-rays of patients with THA loosening, the differential diagnosis should always include osteogenic sarcoma, as well. To our knowledge, there have been only nine cases of THA-related osteogenic osteosarcomas described in the English-language literature. PMID- 26931147 TI - A theoretical study of the electronic structure and charge transport properties of thieno[2,3-b]benzothiophene based derivatives. AB - The electronic structure and charge transport properties of thieno[2,3 b]benzothiophene (TBT) and its eight derivatives are investigated via density functional theory (DFT). The impact of different pi-bridge spacers (1, the dimer of TBT; 2, vinyl; 3, phenyl; and 4, tetrafluorophenyl) and substituents (5, phenyl; 6, biphenyl; 7, naphthalenyl; and 8, benzothiophenyl) on the geometric structures, reorganization energy, absorption spectra, frontier orbitals, ionization potentials (IPs) and electron affinities (EAs) of all the compounds is explored to establish the relationship between the structure and properties. All the compounds show wide band gaps and low-lying HOMOs, and the IPs of all the TBT derivatives are higher than that of pentacene. The crystal packing interactions, transfer integrals and charge carrier mobilities of compounds 1, 2, 4 and 6 are also calculated. The calculated results demonstrated that these kinds of materials may exhibit good environmental stability and high charge mobility due to their large conjugated planar structure, close pi-stacking arrangement, and multiple intermolecular interactions. For compounds 1 and 4, the predicted hole mobility is as high as 0.28 and 0.17 cm(2) V(-1) s(-1), respectively, indicating that both of them benefit hole transport, while compounds 2 and 6 exhibit balanced charge transport properties with the hole and electron mobilities of 0.012 and 0.013 cm(2) V(-1) s(-1), respectively, for compound 2. Compound 6 shows a relatively lower charge mobilities of 10(-3) order of magnitude for both holes and electrons due to the larger reorganization energy and lower transfer integrals. PMID- 26931146 TI - Development of insulated isothermal PCR for rapid on-site malaria detection. AB - BACKGROUND: Detection of Plasmodium spp. is sometimes inconvenient especially in rural areas that are distant from a laboratory. In this study a portable diagnostic test of Plasmodium spp. was developed using insulated isothermal polymerase chain reaction (iiPCR) as an alternative approach to improve this situation. METHODS: A pair of universal primers and probe were designed to amplify and detect gene encoding 18S small sub-unit rRNA of Plasmodium spp using iiPCR method in a portable device, POCKITTM. The efficiency and detection limit of the assay were evaluated using quantitative real-time polymerase chain reaction (qPCR) approach before being subjected to testing in POCKITTM. Detection results of POCKITTM were displayed as '+', '-' or '?' based on the fluorescence ratio after/before reaction. A total of 55 and 35 samples from malaria patients and healthy subjects, respectively, were screened to evaluate the feasibility of this newly designed iiPCR assay. RESULTS: The iiPCR assay allowed the detection of various species of Plasmodium, including those infecting humans (Plasmodium falciparum, P. vivax, P. knowlesi, P. malariae, P. ovale), monkeys, birds, and rodents. Efficiency of the assay achieved 96.9 % while the lower detection limit was >=100 copies of plasmodial DNA. Specificity of the assay was assured as it could not detect human, bacterial and other parasitic DNA. Among the 55 clinical samples tested, 47 (85.4 %) of them were detected as positive by POCKITTM. Four (7.3 %) samples with fluorescence ratio after/before reaction of <1.2 were reported as negative while another four (7.3 %) were ambiguously detected as they had fluorescence ratios between 1.2 and 1.3. The fluorescence ratio was not found to be associated with the copy number of plasmodial DNA. This approach can only be considered as a qualitative method. CONCLUSIONS: The portable iiPCR system may serve as an alternative approach for preliminary screening of malaria in endemic rural areas. The system may also be useful for detecting animal malaria in the field. Although it is not as quantitative as qPCR method, it is comparatively fast and easy to handle. It is believed that the POCKIT-iiPCR assay is able to achieve 100 % sensitivity if increased amount of DNA from each sample is used. The iiPCR assay can also be upgraded in future to detect multiple Plasmodium spp. at the same time by designing the specific primers and probes. PMID- 26931148 TI - Bilaterian-like promoters in the highly compact Amphimedon queenslandica genome. AB - The regulatory systems underlying animal development must have evolved prior to the emergence of eumetazoans (cnidarians and bilaterians). Although representatives of earlier-branching animals - sponges ctenophores and placozoans - possess most of the developmental transcription factor families present in eumetazoans, the DNA regulatory elements that these transcription factors target remain uncharted. Here we characterise the core promoter sequences, U1 snRNP binding sites (5' splice sites; 5'SSs) and polyadenylation sites (PASs) in the sponge Amphimedon queenslandica. Similar to unicellular opisthokonts, Amphimedon's genes are tightly packed in the genome and have small introns. In contrast, its genes possess metazoan-like core promoters populated with binding motifs previously deemed to be specific to vertebrates, including Nrf-1 and Kruppel-like elements. Also as in vertebrates, Amphimedon's PASs and 5'SSs are depleted downstream and upstream of transcription start sites, respectively, consistent with non-elongating transcripts being short-lived; PASs and 5'SSs are more evenly distributed in bidirectional promoters in Amphimedon. The presence of bilaterian-like regulatory DNAs in sponges is consistent with these being early and essential innovations of the metazoan gene regulatory repertoire. PMID- 26931150 TI - Preface to the special section on nano- and mesoscale friction. PMID- 26931149 TI - Low-Power Light Guiding and Localization in Optoplasmonic Chains Obtained by Directed Self-Assembly. AB - Optoplasmonic structures contain plasmonic components embedded in a defined photonic environment to create synergistic interactions between photonic and plasmonic components. Here, we show that chains of optical microspheres containing gold nanoparticles in their evanescent field combine the light guiding properties of a microsphere chain with the light localizing properties of a plasmonic nanoantenna. We implement these materials through template guided self assembly and investigate their fundamental electromagnetic working principles through combination of electromagnetic simulations and experimental characterization. We demonstrate that optoplasmonic chains implemented by directed self-assembly achieve a significant reduction in guiding losses when compared with conventional plasmonic waveguides and, at the same time, retain the light localizing properties of plasmonic antennas at pre-defined locations. The results reinforce the potential of optoplasmonic structures for realizing low loss optical interconnects with high bandwidth. PMID- 26931151 TI - Enantioselective total synthesis and structural reassignment of (+) alsmaphorazine E via a traceless chirality transfer strategy. AB - The first enantioselective total synthesis of (+)-alsmaphorazine E has been achieved through a traceless chirality transfer strategy, which also enabled structural reassignment of the natural product. Key features of this efficient approach entail a catalytic intramolecular oxidative cyclization, a diastereoselective oxidative cyclic aminal formation and a radical cyclization/transannular aza-Michael addition cascade. PMID- 26931152 TI - Sol-gel preparation of low oxygen content, high surface area silicon nitride and imidonitride materials. AB - Reactions of Si(NHMe)4 with ammonia are effectively catalysed by small ammonium triflate concentrations, and can be used to produce free-standing silicon imide gels. Firing at various temperatures produces amorphous or partially crystallised silicon imidonitride/nitride samples with high surface areas and low oxygen contents. The crystalline phase is entirely alpha-Si3N4 and structural similarities are observed between the amorphous and crystallised materials. PMID- 26931153 TI - Novel small molecules targeting ciliary transport of Smoothened and oncogenic Hedgehog pathway activation. AB - Trafficking of the G protein-coupled receptor (GPCR) Smoothened (Smo) to the primary cilium (PC) is a potential target to inhibit oncogenic Hh pathway activation in a large number of tumors. One drawback is the appearance of Smo mutations that resist drug treatment, which is a common reason for cancer treatment failure. Here, we undertook a high content screen with compounds in preclinical or clinical development and identified ten small molecules that prevent constitutive active mutant SmoM2 transport into PC for subsequent Hh pathway activation. Eight of the ten small molecules act through direct interference with the G protein-coupled receptor associated sorting protein 2 (Gprasp2)-SmoM2 ciliary targeting complex, whereas one antagonist of ionotropic receptors prevents intracellular trafficking of Smo to the PC. Together, these findings identify several compounds with the potential to treat drug-resistant SmoM2-driven cancer forms, but also reveal off-target effects of established drugs in the clinics. PMID- 26931154 TI - Interleukin-1 in Stroke: From Bench to Bedside. PMID- 26931155 TI - Leakage Sign for Primary Intracerebral Hemorrhage: A Novel Predictor of Hematoma Growth. AB - BACKGROUND AND PURPOSE: Recent studies of intracerebral hemorrhage treatments have highlighted the need to identify reliable predictors of hematoma expansion. Several studies have suggested that the spot sign on computed tomographic angiography (CTA) is a sensitive radiological predictor of hematoma expansion in the acute phase. However, the spot sign has low sensitivity for hematoma expansion. In this study, we evaluated the usefulness of a novel predictive method, called the leakage sign. METHODS: We performed CTA for 80 consecutive patients presenting with spontaneous intracerebral hemorrhage. Two scans were completed: CTA phase and delayed phase (5 minutes after the CTA phase). By comparing the CTA phase images, we set a region of interest with a 10-mm diameter and calculated the Hounsfield units. We defined a positive leakage sign as a >10% increase in Hounsfield units in the region of interest. Additionally, hematoma expansion was determined on plain computed tomography at 24 hours in patients who did not undergo emergent surgery. RESULTS: Positive spot signs and leakage signs were present in 18 (22%) patients and 35 (43%) patients, respectively. The leakage sign had higher sensitivity (93.3%) and specificity (88.9%) for hematoma expansion than the spot sign. The leakage sign, but not the spot sign, was significantly related with poor outcomes (severely disabled, vegetative state, and death) in all of the patients (P=0.03) and in patients with a hemorrhage in the putamen (P=0.0016). CONCLUSIONS: The results indicate that the leakage sign is a useful and sensitive method to predict hematoma expansion. PMID- 26931156 TI - Safety of Endovascular Thrombectomy in Patients Receiving Non-Vitamin K Antagonist Oral Anticoagulants. AB - BACKGROUND AND PURPOSE: Prospective data on the safety of endovascular thrombectomy in acute stroke patients on non-vitamin K antagonist oral anticoagulants are lacking. METHODS: Prospective multicenter observational study. Patients with ischemic stroke undergoing thrombectomy with or without preceding thrombolysis were enrolled into the Registry of Acute Ischemic Stroke Under New Oral Anticoagulants. Baseline characteristics and functional outcome at 3 months were assessed. Hemorrhagic transformation and symptomatic intracranial hemorrhage were analyzed. Reperfusion was graded using the modified Thrombolysis in Cerebral Infarction score. RESULTS: Of 28 patients treated with thrombectomy, 5 had received also systemic thrombolysis (18%). Intracranial hemorrhage was observed in 46%, but symptomatic intracranial hemorrhage occurred only in 1 patient. Successful reperfusion (Thrombolysis in Cerebral Infarction score, 2b-3) was achieved in 59%. At 3 months, 19% had a modified Rankin Scale score of 0 to 2, and mortality was 26%. CONCLUSIONS: Thrombectomy in non-vitamin K antagonist oral anticoagulant patients seems safe although a comparatively high rate of asymptomatic hemorrhagic transformation was noted. Confirmation in larger prospective controlled cohorts is necessary. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01850797. PMID- 26931157 TI - Stroke, Physical Function, and Death Over a 15-Year Period in Older Australian Women. AB - BACKGROUND AND PURPOSE: As populations age, an increasing number of older women are living with stroke. This study looks at long-term outcomes for women with stroke, comparing mortality rates for women with poor physical function (PF) and those with higher levels of function. The purpose is to understand not only how long women might live after a stroke, but also how long they live with physical disability. METHODS: The study uses 15 years of data on women from the Australian Longitudinal Study on Women's Health 1921 to 1926 cohort. The risk of stroke and the risk of stroke and poor PF were estimated using Cox proportional hazard model. Among women who reported a stroke during the study period, mortality risk was compared according to their physical functioning level after that stroke. RESULTS: Almost half of the women who had a stroke and poor PF survived past 10 years. The 10-year mortality rate was 37% for women with stroke and adequate PF and 51% for women with stroke and poor PF at the time of the stroke (hazard rate ratio, 1.52; 95% CI, 1.18-1.95; P=0.0015 adjusting for demographic and health covariates). CONCLUSIONS: This study provides evidence of the long-term outcomes of stroke among older women, with women living for many years with poor PF. This outcome has important implications for the women's quality of life during their later years and in understanding the burden of disability associated with stroke. PMID- 26931158 TI - Marital Transition and Risk of Stroke: How Living Arrangement and Employment Status Modify Associations. AB - BACKGROUND AND PURPOSE: There have been consistent findings reported that marital transition (ie, change in marital status during a given time period) is associated with risk of cardiovascular disease; however, few studies have been conducted on stroke risk, particularly stroke subtypes. Moreover, no studies have examined the moderating effect of living arrangement and employment status on the association between marital transition and stroke risk. METHODS: We examined sex specific associations between marital transition and stroke risk using data from Japan Public Health Center-based Prospective Study. We included 24 162 men and 25 626 women who were married at prebaseline (5 years before baseline). Marital transition was determined by marital status at baseline. Weighted hazard ratios of stroke risk were estimated by Cox proportional regression analysis with inverse probability of weighting using a propensity score. RESULTS: An increased risk of stroke, particularly hemorrhagic stroke, was observed among men and women with marital transition (ie, married to unmarried); weighted hazard ratios (95% confidence interval [CI]) for men and women were 1.26 (1.13-1.41) and 1.26 (1.09 1.45), respectively. Participants with marital transition and lived with children had increased stroke risk. Living with parents buffered the increased stroke risk owing to marital transition among men; however, no such effect was identified among women. Elevated stroke risk owing to marital transition was magnified among women if they were unemployed; weighted hazard ratio=2.98 (95% CI, 1.66-5.33). CONCLUSIONS: Living arrangement and employment status modified the positive associations between marital transition and stroke risk, which differed by sex. PMID- 26931159 TI - Circular RNA Related to the Chondrocyte ECM Regulates MMP13 Expression by Functioning as a MiR-136 'Sponge' in Human Cartilage Degradation. AB - Circular RNAs (circRNAs) are involved in the development of various diseases, but there is little knowledge of circRNAs in osteoarthritis (OA). The aim of study was to identify circRNA expression in articular cartilage and to explore the function of chondrocyte extracellular matrix (ECM)-related circRNAs (circRNA-CER) in cartilage. To identify circRNAs that are specifically expressed in cartilage, we compared the expression of circRNAs in OA cartilage with that in normal cartilage. Bioinformatics was employed to predict the interaction of circRNAs and mRNAs in cartilage. Loss-of-function and rescue experiments for circRNA-CER were performed in vitro. A total of 71 circRNAs were differentially expressed in OA and normal cartilage. CircRNA-CER expression increased with interleukin-1 and tumor necrosis factor levels in chondrocytes. Silencing of circRNA-CER using small interfering RNA suppressed MMP13 expression and increased ECM formation. CircRNA-CER could compete for miR-136 with MMP13. Our results demonstrated that circRNA-CER regulated MMP13 expression by functioning as a competing endogenous RNA (ceRNA) and participated in the process of chondrocyte ECM degradation. We propose that circRNA-CER could be used as a potential target in OA therapy. PMID- 26931160 TI - Facile construction of a highly sensitive DNA biosensor by in-situ assembly of electro-active tags on hairpin-structured probe fragment. AB - An ultrasensitive DNA biosensor has been developed through in-situ labeling of electroactive melamine-Cu(2+) complex (Mel-Cu(2+)) on the end of hairpin-like probe using gold nanoparticles (AuNPs) as the signal amplification platform. The 3'-thiolated hairpin-like probe was first immobilized to the gold electrode surface by the Au-S bond. The AuNPs were then tethered on the free 5'-end of the immobilized probe via the special affinity between Au and the modified -NH2. Followed by, the Mel and Cu(2+) were assembled on the AuNPs surface through Au-N bond and Cu(2+)-N bond, respectively. Due to the surface area and electrocatalytic effects of the AuNPs, the loading amount and electron transfer kinetic of the Mel-Cu(2+) were enhanced greatly, resulting in significantly enhanced electrochemical response of the developed biosensor. Compared with the synthesis process of conventional electroactive probe DNA accomplished by homogeneous method, the method presented in this work is more reagent- and time saving. The proposed biosensor showed high selectivity, wide linear range and low detection limit. This novel strategy could also be extended to the other bioanalysis platforms such as immunosensors and aptasensors. PMID- 26931161 TI - Titanium trisulfide (TiS3): a 2D semiconductor with quasi-1D optical and electronic properties. AB - We present characterizations of few-layer titanium trisulfide (TiS3) flakes which, due to their reduced in-plane structural symmetry, display strong anisotropy in their electrical and optical properties. Exfoliated few-layer flakes show marked anisotropy of their in-plane mobilities reaching ratios as high as 7.6 at low temperatures. Based on the preferential growth axis of TiS3 nanoribbons, we develop a simple method to identify the in-plane crystalline axes of exfoliated few-layer flakes through angle resolved polarization Raman spectroscopy. Optical transmission measurements show that TiS3 flakes display strong linear dichroism with a magnitude (transmission ratios up to 30) much greater than that observed for other anisotropic two-dimensional (2D) materials. Finally, we calculate the absorption and transmittance spectra of TiS3 in the random-phase-approximation (RPA) and find that the calculations are in qualitative agreement with the observed experimental optical transmittance. PMID- 26931162 TI - A simple and sensitive flow injection method based on the catalytic activity of CdS quantum dots in an acidic permanganate chemiluminescence system for determination of formaldehyde in water and wastewater. AB - A simple and sensitive flow injection chemiluminescence (CL) method in which CdS quantum dots (QDs) enhanced the CL intensity of a KMnO4-formaldehyde (HCHO) reaction was offered for the determination of HCHO. This CL system was based on the catalytic activity of CdS QDs and their participation in the CL resonance energy transfer (CRET) phenomenon. A possible mechanism for the supplied CL system was proposed using the kinetic curves of the CL systems and the spectra of CL, photoluminescence (PL) and ultraviolet-visible (UV-Vis). The emanated CL intensity of the KMnO4-CdS QDs system was amplified in the presence of a trace level of HCHO. Based on this enhancement effect, a simple and sensitive flow injection CL method was suggested for the determination of HCHO concentration in environmental water and wastewater samples. Under selected optimized experimental conditions, the increased CL intensity was proportional to the HCHO concentration in the range of 0.03-4.5 MUg L(-1) and 4.5-10.0 MUg L(-1). The detection limits (3sigma) were 0.0003 MUg L(-1) and 1.2 MUg L(-1). The relative standard deviations (RSD%) for eleven replicate determinations of 4.0 MUg L(-1) HCHO were 2.2%. Furthermore, the feasibility of the developed method was investigated via the determination of HCHO concentration in environmental water and wastewater samples. PMID- 26931163 TI - Therapy: Positioning of dilation in eosinophilic oesophagitis. PMID- 26931167 TI - Ultrathin Cu2O as an efficient inorganic hole transporting material for perovskite solar cells. AB - We demonstrate that ultrathin P-type Cu2O thin films fabricated by a facile thermal oxidation method can serve as a promising hole-transporting material in perovskite solar cells. Following a two-step method, inorganic-organic hybrid perovskite solar cells were fabricated and a power conversion efficiency of 11.0% was achieved. We found that the thickness and properties of Cu2O layers must be precisely tuned in order to achieve the optimal solar cell performance. The good performance of such perovskite solar cells can be attributed to the unique properties of ultrathin Cu2O, including high hole mobility, good energy level alignment with CH3NH3PbI3, and longer lifetime of photo-excited carriers. Combining the merits of low cost, facile synthesis, and high device performance, ultrathin Cu2O films fabricated via thermal oxidation hold promise for facilitating the developments of industrial-scale perovskite solar cells. PMID- 26931168 TI - Evolution of photorespiration from cyanobacteria to land plants, considering protein phylogenies and acquisition of carbon concentrating mechanisms. AB - Photorespiration and oxygenic photosynthesis are intimately linked processes. It has been shown that under the present day atmospheric conditions cyanobacteria and all eukaryotic phototrophs need functional photorespiration to grow autotrophically. The question arises as to when this essential partnership evolved, i.e. can we assume a coevolution of both processes from the beginning or did photorespiration evolve later to compensate for the generation of 2 phosphoglycolate (2PG) due to Rubisco's oxygenase reaction? This question is mainly discussed here using phylogenetic analysis of proteins involved in the 2PG metabolism and the acquisition of different carbon concentrating mechanisms (CCMs). The phylogenies revealed that the enzymes involved in the photorespiration of vascular plants have diverse origins, with some proteins acquired from cyanobacteria as ancestors of the chloroplasts and others from heterotrophic bacteria as ancestors of mitochondria in the plant cell. Only phosphoglycolate phosphatase was found to originate from Archaea. Notably glaucophyte algae, the earliest branching lineage of Archaeplastida, contain more photorespiratory enzymes of cyanobacterial origin than other algal lineages or land plants indicating a larger initial contribution of cyanobacterial-derived proteins to eukaryotic photorespiration. The acquisition of CCMs is discussed as a proxy for assessing the timing of periods when photorespiratory activity may have been enhanced. The existence of CCMs also had marked influence on the structure and function of photorespiration. Here, we discuss evidence for an early and continuous coevolution of photorespiration, CCMs and photosynthesis starting from cyanobacteria via algae, to land plants. PMID- 26931170 TI - Transporters involved in mineral nutrient uptake in rice. AB - One of the most important roles of plant roots is to take up essential mineral nutrients from the soil for use in plant growth and development. The uptake of mineral elements is mediated by various transporters belonging to different transporter families. Here we reviewed transporters for the uptake of macronutrients and micronutrients identified in rice, an important staple food for half of the world's population. Rice roots are characterized by having two Casparian strips on the exodermis and endodermis and by the formation of aerenchyma in the mature root zone. This distinct anatomical structure dictates that a pair of influx and efflux transporters at both the exodermis and endodermis is required for the radial transport of a mineral element from the soil solution to the stele. Some transporters showing polar localization at the distal and proximal sides of the exodermis and endodermis have been identified for silicon and manganese, forming an efficient uptake system. However, transporters for the uptake of most mineral elements remain to be identified. PMID- 26931171 TI - Root phenology in a changing climate. AB - Plant phenology is one of the strongest indicators of ecological responses to climate change, and altered phenology can have pronounced effects on net primary production, species composition in local communities, greenhouse gas fluxes, and ecosystem processes. Although many studies have shown that aboveground plant phenology advances with warmer temperatures, demonstration of a comparable association for belowground phenology has been lacking because the factors that influence root phenology are poorly understood. Because roots can constitute a large fraction of plant biomass, and root phenology may not respond to warming in the same way as shoots, this represents an important knowledge gap in our understanding of how climate change will influence phenology and plant performance. We review studies of root phenology and provide suggestions to direct future research. Only 29% of examined studies approached root phenology quantitatively, strongly limiting interpretation of results across studies. Therefore, we suggest that researchers emphasize quantitative analyses in future phenological studies. We suggest that root initiation, peak growth, and root cessation may be under different controls. Root initiation and cessation may be more constrained by soil temperature and the timing of carbon availability, whereas the timing of peak root growth may represent trade-offs among competing plant sinks. Roots probably do not experience winter dormancy in the same way as shoots: 89% of the studies that examined winter phenology found evidence of growth during winter months. More research is needed to observe root phenology, and future studies should be careful to capture winter and early season phenology. This should be done quantitatively, with direct observations of root growth utilizing rhizotrons or minirhizotrons. PMID- 26931169 TI - Allantoin, a stress-related purine metabolite, can activate jasmonate signaling in a MYC2-regulated and abscisic acid-dependent manner. AB - Allantoin is a metabolic intermediate of purine catabolism that often accumulates in stressed plants. Recently, we used Arabidopsis knockout mutants (aln) of ALLANTOINASE to show that this purine metabolite activates abscisic acid (ABA) production, thereby stimulating stress-related gene expression and enhancing seedling tolerance to abiotic stress. A detailed re-examination of the microarray data of an aln mutant (aln-1) confirmed the increased expression of ABA-related genes and also revealed altered expression of genes involved in jasmonic acid (JA) responses, probably under the control of MYC2, a master switch in the JA signaling pathway. Consistent with the transcriptome profiles, the aln-1 mutant displayed increased JA levels and enhanced responses to mechanical wounding and exogenous JA. Moreover, aln mutants demonstrated modestly increased susceptibility to Pseudomonas syringae and Pectobacterium carotovorum, probably reflecting the antagonistic action of MYC2 on the defense against these bacterial phytopathogens. Exogenously administered allantoin elicited the expression of JA responsive genes, including MYC2, in wild-type plants, supporting the idea that allantoin might be responsible for the observed JA-related phenotypes of aln mutants. However, mutants deficient in bioactive JA (jar1-1), insensitive to JA (myc2-3), or deficient in ABA (aba2-1 and bglu18) suppressed the effect of exogenous allantoin. The suppression was further confirmed in aln-1 jar1-1 and aln-1 bglu18 double mutants. These results indicate that allantoin can activate the MYC2-regulated JA signaling pathway through ABA production. Overall, this study suggests a possible connection of purine catabolism with stress hormone homeostasis and signaling, and highlights the potential importance of allantoin in these interactions. PMID- 26931172 TI - The type 3 effector NopL of Sinorhizobium sp. strain NGR234 is a mitogen activated protein kinase substrate. AB - Pathogenic bacteria utilize type 3 secretion systems to inject type 3 effectors (T3Es) into host cells, thereby subverting host defense reactions. Similarly, T3Es of symbiotic nitrogen-fixing rhizobia can affect nodule formation on roots of legumes. Previous work showed that NopL (nodulation outer protein L) of Sinorhizobium(Ensifer) sp. strain NGR234 is multiply phosphorylated in eukaryotic cells and that this T3E suppresses responses mediated by mitogen-activated protein (MAP) kinase signaling in yeast (mating pheromone signaling) and plant cells (expression of pathogenesis-related defense proteins). Here, we show that NopL is a MAP kinase substrate. Microscopic observations of fluorescent fusion proteins and bimolecular fluorescence complementation analysis in onion cells indicated that NopL is targeted to the nucleus and forms a complex with SIPK (salicylic acid-induced protein kinase), a MAP kinase of tobacco. In vitro experiments demonstrated that NopL is phosphorylatyed by SIPK. At least nine distinct spots were observed after two-dimensional gel electrophoresis, indicating that NopL can be hyperphosphorylated by MAP kinases. Senescence symptoms in nodules of beans (Phaseolus vulgaris cv. Tendergreen) were analyzed to determine the symbiotic effector activity of different NopL variants with serine to alanine substitutions at identified and predicted phosphorylation sites (serine-proline motif). NopL variants with six or eight serine to alanine substitutions were partially active, whereas NopL forms with 10 or 12 substituted serine residues were inactive. In conclusion, our findings provide evidence that NopL interacts with MAP kinases and reveals the importance of serine-proline motifs for effector activity during symbiosis. PMID- 26931173 TI - Doubly thermo-responsive copolymers in ionic liquid. AB - We report the behaviour of thermoresponsive block copolymers of n-butyl acrylate and N-alkyl acrylamides in [C2mim][NTf2]. Poly(N-isopropylacrylamide) exhibits an upper critical solution temperature in [C2mim][NTf2] whereas poly(n-butyl acrylate) has a lower critical solution temperature. Consequently, these polymers exhibit double thermo-responsiveness correlated with the macromolecular structure. Moreover, a switching from micellar to reverse micellar structures was induced by a change in temperature. This property enables the development of reversible shuttles between ionic liquids and water. PMID- 26931175 TI - Flagellate erythema induced by cisplatin. PMID- 26931176 TI - The origin and future of oxidative stress pathology: From the recognition of carcinogenesis as an iron addiction with ferroptosis-resistance to non-thermal plasma therapy. AB - Helmut Sies established the concept of oxidative stress in 1985. However, it took some time to introduce this concept into pathology, where investigators count on formalin-fixed paraffin-embedded tissue sections. I sought out antigens for this purpose based on an oxidative stress-induced rat renal carcinogenesis model, which revealed that 8-hydroxy-2'-deoxyguanosine and 4-hydroxy-2-nonenal-modified proteins are ideal. These two monoclonal antibodies successfully revealed the involvement of oxidative stress in numerous human diseases, including carcinogenesis and atherosclerosis. Shigeru Okada established the aforementioned ferric nitrilotriacetate (Fe-NTA)-induced rat renal carcinogenesis model, which thus far has answered many questions regarding the presence of target genes in oxidative stress-induced carcinogenesis and the sites that are susceptible to oxidative stress in the genome. Particularly, the similarity of genomic alterations between Fe-NTA-induced renal cancer and human cancers suggests that excess iron plays a role also in human carcinogenesis. Furthermore, excess iron is a major pathology in asbestos-induced mesothelioma, including chrysotile. Despite an analogy to asbestos, multi-wall carbon nanotubes were distinct in that diameter is another responsible factor for mesothelial carcinogenesis. Recently, non-thermal plasma emerged as a candidate for medical intervention for wounds and cancers via manipulating oxidative stress. Counteracting excess iron is a promising preventive strategy for major diseases. PMID- 26931179 TI - Uterine transplantation: past, present and future. PMID- 26931178 TI - Exercise training improves obesity-related lymphatic dysfunction. AB - KEY POINTS: Obesity results in perilymphatic inflammation and lymphatic dysfunction. Lymphatic dysfunction in obesity is characterized by decreased lymphatic vessel density, decreased collecting lymphatic vessel pumping frequency, decreased lymphatic trafficking of immune cells, increased lymphatic vessel leakiness and changes in the gene expression patterns of lymphatic endothelial cells. Aerobic exercise, independent of weight loss, decreases perilymphatic inflammatory cell accumulation, improves lymphatic function and reverses pathological changes in gene expression in lymphatic endothelial cells. ABSTRACT: Although previous studies have shown that obesity markedly decreases lymphatic function, the cellular mechanisms that regulate this response remain unknown. In addition, it is unclear whether the pathological effects of obesity on the lymphatic system are reversible with behavioural modifications. The purpose of this study, therefore, was to analyse lymphatic vascular changes in obese mice and to determine whether these pathological effects are reversible with aerobic exercise. We randomized obese mice to either aerobic exercise (treadmill running for 30 min per day, 5 days a week, for 6 weeks) or a sedentary group that was not exercised and analysed lymphatic function using a variety of outcomes. We found that sedentary obese mice had markedly decreased collecting lymphatic vessel pumping capacity, decreased lymphatic vessel density, decreased lymphatic migration of immune cells, increased lymphatic vessel leakiness and decreased expression of lymphatic specific markers compared with lean mice (all P < 0.01). Aerobic exercise did not cause weight loss but markedly improved lymphatic function compared with sedentary obese mice. Exercise had a significant anti-inflammatory effect, resulting in decreased perilymphatic accumulation of inflammatory cells and inducible nitric oxide synthase expression. In addition, exercise normalized isolated lymphatic endothelial cell gene expression of lymphatic specific genes, including VEGFR-3 and Prox1. Taken together, our findings suggest that obesity impairs lymphatic function via multiple mechanisms and that these pathological changes can be reversed, in part, with aerobic exercise, independent of weight loss. In addition, our study shows that obesity induced lymphatic endothelial cell gene expression changes are reversible with behavioural modifications. PMID- 26931177 TI - SHARPIN controls the development of regulatory T cells. AB - SHARPIN is an essential component of the linear ubiquitin chain assembly complex (LUBAC) complex that controls signalling pathways of various receptors, including the tumour necrosis factor receptor (TNFR), Toll-like receptor (TLR) and antigen receptor, in part by synthesis of linear, non-degrading ubiquitin chains. Consistent with SHARPIN's function in different receptor pathways, the phenotype of SHARPIN-deficient mice is complex, including the development of inflammatory systemic and skin diseases, the latter of which depend on TNFR signal transduction. Given the established function of SHARPIN in primary and malignant B cells, we hypothesized that SHARPIN might also regulate T-cell receptor (TCR) signalling and thereby control T-cell biology. Here, we focus primarily on the role of SHARPIN in T cells, specifically regulatory T (Treg) cells. We found that SHARPIN-deficient (Sharpin(cpdm/cpdm) ) mice have significantly reduced numbers of FOXP3(+) Treg cells in lymphoid organs and the peripheral blood. Competitive reconstitution of irradiated mice with mixed bone marrow from wild-type and SHARPIN-deficient mice revealed an overall reduced thymus population with SHARPIN deficient cells with almost complete loss of thymic Treg development. Consistent with this cell-intrinsic function of SHARPIN in Treg development, TCR stimulation of SHARPIN-deficient thymocytes revealed reduced activation of nuclear factor kappaB and c-Jun N-terminal kinase, establishing a function of SHARPIN in TCR signalling, which may explain the defective Treg development. In turn, in vitro generation and suppressive activity of mature SHARPIN-deficient Treg cells were comparable to wild-type cells, suggesting that maturation, but not function, of SHARPIN-deficient Treg cells is impaired. Taken together, these findings show that SHARPIN controls TCR signalling and is required for efficient generation of Treg cells in vivo, whereas the inhibitory function of mature Treg cells appears to be independent of SHARPIN. PMID- 26931180 TI - Evidence-based and unlicensed indications for proton pump inhibitors and patients' preferences for discontinuation: a pilot study in a sample of Italian community pharmacies. AB - WHAT IS KNOWN AND OBJECTIVE: Despite the widespread use of proton pump inhibitors (PPIs), little is known about the appropriateness of treatment according to the indications reported by patients and their involvement in the process of treatment discontinuation. In patients who are unlikely to benefit, the medication should be stopped and dose tapering is recommended to reduce the risk of rebound symptoms. The aims of this pilot study were to evaluate the appropriateness of treatment according to the reported indications by PPI users, patients' preferences for drug withdrawal, and the modalities of previous attempts to discontinue the medications. METHODS: This observational study was conducted in nine community pharmacies. Each pharmacist was asked to interview a sample of patients with prescriptions for PPIs and to collect a minimum set of information about socio-demographic characteristics, drug indication, duration of drug treatment, number of drugs used for acid-related disorders, preference about drug withdrawal, previous attempts at drug discontinuation and the method of drug tapering when this was performed. RESULTS AND DISCUSSION: The study included 260 patients, 126 (48.5%) females; 81 patients received more than one drug for acid related problems and the second medication was more frequently prescribed by a general practitioner, community pharmacist or specialist. Unlicensed indication was reported by 125 patients, and 77 patients did not receive any information about the duration of treatment. Fifty-one patients were in favour of drug discontinuation. PPI withdrawal was attempted but was unsuccessful in 12 cases. Nine patients discussed the method of drug withdrawal with their physician, and abrupt discontinuation was the most frequent suggestion. Many patients were treated with PPIs for unlicensed indications such as gastroprotection because of the number of concomitant drugs used or unspecified gastroprotection. Recommendations about the main indications and the duration of treatment are essential to avoid unnecessary prescriptions and undefined prolongation of drug use. Correct information about the method of drug discontinuation is essential for success. WHAT IS NEW AND CONCLUSION: Many patients using PPIs are treated for unlicensed indications such as non-specific gastroprotection. The use of more than one drug for acid-related disorders is frequent among PPI users although this is not supported by evidence. Patients should be given clear and appropriate information about the duration of treatment and method of drug discontinuation. PMID- 26931181 TI - Detection of dermatophytes in human nail and skin dust produced during podiatric treatments in people without typical clinical signs of mycoses. AB - Pedicures are the most common cosmetic foot treatment. Many pedicurists and podiatrists suffer from respiratory infections and diseases such as asthma, sinusitis, chronic cough and bronchitis. Skin and nail dust may play an important role in the development of occupational diseases and the transmission of mycosis to other clients. To examine the presence of dermatophytes in nail and skin dust produced during podiatric treatments of people without typical symptoms of mycosis and to assess the epidemiological hazards of tinea pedis for podiatrists as well as other clients. Seventy-seven samples underwent direct microscopy and culture. The results of direct microscopy were positive in 28/77 samples (36.36%) and doubtful in 3/77 (3.9%). Fungi were cultured from 36/77 samples (46.75%), including 8/77 (10.3%) positive for dermatophytes (Trichophyton rubrum-6 isolates and Trichophyton mentagrophytes-2). Material collected during podiatric treatments is potentially infected by pathogenic fungi; thus, there is a need to protect both workers who perform such treatments, as well as other clients, to prevent the transmission of pathogens in the Salon environment. Exposure to this occupational hazard may increase not only the risk of respiratory infections but also increase asthmatic or allergic reactions to Trichophyton. PMID- 26931182 TI - Strengthening health services to deliver nutrition education to promote complementary feeding and healthy growth of infants and young children: formative research for a successful intervention in peri-urban Trujillo, Peru. AB - Formative research is critical for developing effective nutrition-specific interventions to improve infant and young child (IYC) feeding practices and promote healthy growth. Health workers interact with caregivers during health facility visits, yet there is limited research about how to optimize delivery of such interventions during these visits. The extensive reach of IYC health services globally calls for research to address this gap. In Trujillo, Peru, formative research was conducted to explore complementary feeding practices with caregivers as well as health worker routines and interactions with caregivers related to feeding and healthy growth; results informed the development and delivery of an educational intervention. Multiple qualitative methods were used to collect data on a purposive sample of health workers and caregivers from three health facilities and communities: household trials followed. Complementary feeding messages with doable behaviours were developed, and three were selected as key to promote based on their nutritional impact and cultural acceptability. In the health facilities, medical consultation, well-child visits and nutrition consultation all dealt with aspects of IYC nutrition/growth during their interactions with caregivers but were independent and inconsistent in approach. A nutrition education strategy was developed based on consistency, quality and coverage in the IYC health services. We conclude that formative research undertaken in the community and IYC health services was critical to developing a successful and culturally relevant intervention to promote optimal complementary feeding practices and healthy growth during interactions between health workers and caregivers at routine health facility visits. (c) 2016 John Wiley & Sons Ltd. PMID- 26931183 TI - HGVS Recommendations for the Description of Sequence Variants: 2016 Update. AB - The consistent and unambiguous description of sequence variants is essential to report and exchange information on the analysis of a genome. In particular, DNA diagnostics critically depends on accurate and standardized description and sharing of the variants detected. The sequence variant nomenclature system proposed in 2000 by the Human Genome Variation Society has been widely adopted and has developed into an internationally accepted standard. The recommendations are currently commissioned through a Sequence Variant Description Working Group (SVD-WG) operating under the auspices of three international organizations: the Human Genome Variation Society (HGVS), the Human Variome Project (HVP), and the Human Genome Organization (HUGO). Requests for modifications and extensions go through the SVD-WG following a standard procedure including a community consultation step. Version numbers are assigned to the nomenclature system to allow users to specify the version used in their variant descriptions. Here, we present the current recommendations, HGVS version 15.11, and briefly summarize the changes that were made since the 2000 publication. Most focus has been on removing inconsistencies and tightening definitions allowing automatic data processing. An extensive version of the recommendations is available online, at http://www.HGVS.org/varnomen. PMID- 26931184 TI - Circulating melanoma cells as a potential biomarker to detect metastasis and evaluate prognosis. AB - TNM staging is mainly used to evaluate the prognosis of melanoma patients. Serum biomarkers such as 5-S-cysteinyldopa (5-S-CD) have occasionally been used but most do not respond until the tumour burden becomes high. Recently, circulating melanoma cells (CMC) have been reported as a possible new biomarker to detect metastasis, monitor treatment response and predict prognosis. The object of this exploratory study was to evaluate the efficacy of CMC to detect metastasis and predict prognosis by cross-sectional and prospective observational analyses, respectively. Altogether 15 patients with stages II-IV melanoma were enrolled and CMC were enumerated by CellSearch system with cut-off values of two cells/7.5 mL. Serum 5-S-CD and lactate dehydrogenase (LDH) were also measured. The sensitivity of CMC and 5-S-CD for the detection of metastasis was 33 and 50%, respectively. The combination of CMC and 5-S-CD showed a sensitivity of 67%, the best performance among CMC, 5-S-CD, LDH and any combination of two of the markers. Additionally, a 30-month prospective observation showed that CMC could segregate patients with poorer prognosis. The median survival time for the patients with <2 CMC and those with >=2 CMC was 19.5 and 4.5 months, respectively. The limitation of this study is the small sample size. These preliminary results indicate CMC may complement the efficacy of 5-S-CD to detect metastasis and can be a prognostic marker. Although there is still room for improvement to maximise the sensitivity, the CellSearch system is reproducible, standardised and suitable for multi-centre studies. PMID- 26931185 TI - Hepatitis B virus vaccination-related seroprevalence among health-care personnel in a Japanese tertiary medical center. AB - AIM: Few studies concerning the protective management of hepatitis B virus (HBV) infection among health-care personnel (HCP), excluding occult HBV or carriers, have been reported. Therefore, we undertook a cross-sectional study of the updated status of HBV vaccine management by measuring the antibody to hepatitis B surface antigen (anti-HBs) along with the antibody to hepatitis B core antigen (anti-HBc). METHODS: Both anti-HBs and anti-HBc were assessed in 1085 HCP employed by our institute. Hepatitis B virus vaccination-related histories were recorded using self-administered questionnaires. RESULTS: Of 1085 HCP, 27 (2.5%) were positive for anti-HBc, and its positive rate increased with age. Of the 1058 subjects with negative anti-HBc, 879 (83.1%) were positive for anti-HBs. The median titer of anti-HBs was 71.1 mIU/mL, which was higher in female subjects (P = 0.037). By age group, the positive rate of anti-HBs were 77.5%, 89.3%, 90.8%, and 81.6% in the groups aged <=29, 30-39, 40-49, and >=50 years, respectively (P < 0.001). Of the 908 subjects who reported receiving HBV vaccination, 6 (0.7%) were positive for anti-HBc. Among them, one subject was suspected to have a possible subclinical HBV infection after the HBV vaccination. CONCLUSION: We report the current HBV vaccination-related seroprevalence of anti-HBs along with anti-HBc in a Japanese tertiary medical institution consisting of more than 1000 HCP, which was an level comparable to similar sized hospitals in developed countries. Anti-HBc would be important for understanding HBV status, but not necessary for general HBV vaccine management for HCP. PMID- 26931186 TI - Measuring self-reported quality of life in 8- to 11-year-old children born with gastroschisis: Is the KIDSCREEN questionnaire acceptable? AB - BACKGROUND: Children born with gastroschisis have a good prognosis but require surgical correction and long-term follow up. There has been little research on the impact of gastroschisis on the child's health-related quality of life (QoL). The aim was to assess face and content validity of the KIDSCREEN-52 questionnaire as a measurement of self- and proxy-reported QoL in children born with gastroschisis and to evaluate self-reported QoL in these children compared with the reference population. METHODS: In this cross-sectional exploratory study, we used the validated KIDSCREEN-52 questionnaire and individual interview with 8- to 11-year-old children born with gastroschisis who were identified from the Northern Congenital Abnormality Survey. Self-reported QoL scores were compared with age-matched UK norms by using the two-sample t test. RESULTS: Ten children (median age 9.6 years, interquartile range 8.3-11.0) and their parents participated. Children found KIDSCREEN a helpful tool to explore their feelings and that it covered life aspects important to them. Parents believed that all priority areas were represented and that it was straightforward for their children to complete. In nine KIDSCREEN domains, children with gastroschisis had similar QoL scores to those in the reference population, and in one (psychological well-being) the mean score was significantly better (p = 0.03). All children described their health as good/very good or excellent; eight said they would not like to change anything about their body. CONCLUSION: The KIDSCREEN questionnaire has adequate face and content validity as a measure of QoL in children with gastroschisis and is acceptable to both children and parents. PMID- 26931187 TI - Murine mesothelin: characterization, expression, and inhibition of tumor growth in a murine model of pancreatic cancer. AB - BACKGROUND: Mesothelin has attracted much interest as a tumor specific antigen; it has been reported to promote tumor development and to be a good target for cancer treatment. Most studies to date have used human mesothelin in immunocompromised mice. Since these models do not allow for study of the natural immune response to mesothelin expressing tumors, we have undertaken the characterization of mouse mesothelin so the effects of this protein can be assessed in immunocompetent mouse strains. METHODS: We analyzed mouse mesothelin expression, tissue distribution, shedding and biochemistry. In addition we constructed stable mesothelin overexpressing lines of the pancreatic cancer line Panc02 by two methods and tested them for growth and tumorigencity in vitro and in vivo. RESULTS: We show here that mouse mesothelin is similar to human mesothelin in biochemical characteristics, tumor expression and tissue distribution, suggesting the mouse may be a suitable model for study of mesothelin. Stable overexpression of mesothelin in a pancreatic cancer cell line did not increase cell proliferation or anchorage-independent growth in vitro, suggesting that mesothelin is not necessarily a tumor progression factor. Surprisingly overexpression of mesothelin inhibited tumor formation in vivo in immunocompetent mice. CONCLUSION: The mouse may be a good model for studying mesothelin in the context of an intact immune response. Mesothelin is not necessarily a tumor progression factor, and indeed mesothelin overexpression inhibited tumor growth in immunocompetent mice. PMID- 26931188 TI - Current utilization and influencing factors of complementary and alternative medicine among children with neuropsychiatric disease: a cross-sectional survey in Korea. AB - BACKGROUND: Complementary and alternative medicine (CAM) is widespread but has various utilization rates according to country and the condition of patients. Generally, CAM is more frequently used in diseases that have no clear treatment method in conventional medicine. Therefore, a high utilization rate of CAM can be assumed in pediatric neurological diseases, but few studies have investigated the utilization of CAM in children with neuropsychiatric diseases. In particular, studies regarding the current use of CAM are scarce. METHODS: We conducted a survey of the parents or caregivers of patients who visited the pediatric rehabilitation clinic, pediatric neurology clinic, or pediatric psychiatry clinic at one university hospital from April to July 2011. We analyzed the factors that affect the utilization of CAM and other rehabilitation therapies. RESULTS: Among the 578 patients recruited, 258 patients have ever received CAM (51.5%), and the current CAM utilization rate was 19.0% (110 patients). Two hundred patients (34.6%) were currently receiving only other rehabilitation therapies, and 268 patients (46.4%) were currently receiving no type of therapy. The rate of current CAM usage was significantly high in epilepsy patients. The ORs of 1-6-year-old and 7-12-year-old children compared with 13-19-year-old children were 3.14 (95 % CI 1.31-7.53) and 3.34 (95% CI 1.64-6.79), respectively, and the OR of the group with longer disease duration (>=48 months) compared with the group with shorter disease duration was 3.36 (95% CI 1.71-6.59). Only the age and disease duration showed statistically significant differences between the patients who were administered CAM and those who received other rehabilitation therapies (p < 0.0001). CONCLUSIONS: CAM is preferred by patients under 13 years of age compared with patients aged 13-19 years, whereas other rehabilitation therapies are preferred by patients aged 1-6 years, followed by those aged 6-12 years and then by those aged 13-19 years. The patient's age and disease duration are the major factors influencing CAM use. Future studies should specify particular diseases, rather than combining all types of neuropsychiatric diseases, and include the socio-economic status of the parents. PMID- 26931189 TI - Performance of the OP correlation functional in relation to its formulation: Influence of the exchange component and the effect of incorporating same-spin correlations. AB - In the present study, we have investigated two significant features of the OP correlation functional, namely the incorporation of the exchange functional into itself, and the inclusion of only opposite-spin (OS) effects. To explore the latter feature, we have compared OP with B95 and a new functional introduced in the present study - the OPB method that combines OP with the same-spin (SS) component of B95. In general, we find that B95 and OPB perform comparably. Our comparisons of the various DFT procedures suggest that the incorporation of a meta-GGA (e.g., TPSS) into OP and OPB does not necessarily lead to a chemically more accurate procedure than the use of a related GGA (e.g., PBE). An important finding is the more notable (and somewhat more consistent) improvement in performance with the incorporation of SS correlation, particularly for longer range chemical properties. Nonetheless, on average across our test sets of over 800 systems, the difference between the performances of OP versus B95 or OPB is not exceedingly large. By drawing a parallel between these DFT methods and the wavefunction scaled-MP2-type methods, we reason that one can further develop the OP functional, and perhaps a wider range of correlation functionals by combining it with the technique of range separation. PMID- 26931190 TI - Regular control at the general practitioner is positively correlated with patient satisfaction with chronic care management. AB - INTRODUCTION: The aim of the study is to identify how disease management programmes for patients with a chronic disease work. This issue is explored from the patients' perspective. Specifically, we study how transition and coordination are related to the patient's perception of quality of care, with a particular focus on the general practitioner's (GP) role. METHODS: The study is based on a survey conducted among patients with Type 2 diabetes, chronic obstructive pulmonary disease (COPD) or acute coronary syndrome (ACS) in the Central Denmark Region in 2011 and 2012. Data are analysed using logistic regression models. RESULTS: A total of 4,174 patients answered the questionnaire. The response rate was 43%. Whether the patient attends regular visits with the GP or not has a significant influence on both the patient's overall perception of the healthcare sector and on the patient's perception of the organisation of care. Variation among patient groups was identified and COPD patients had the least positive overall perception of the care received. CONCLUSIONS: Patients who visit their GP for regular control both have a better overall perception of the healthcare sector and are more likely to think that their treatment is well organised. Patients with COPD have a less positive score than patients with ACS and diabetes. FUNDING: none. TRIAL REGISTRATION: not relevant. PMID- 26931191 TI - Higher rate of serious perinatal events in non-Western women in Denmark. AB - INTRODUCTION: To elucidate possible mechanisms behind the increased risk of stillbirth and infant mortality among migrants in Denmark, this study aimed to analyse characteristics of perinatal deaths at Hvidovre Hospital 2006-2010 - according to maternal country of origin. METHODS: We identified children born at Hvidovre Hospital who died perinatally and included the patient files in a series of case studies. Our data were linked to data from population-covering registries in Statistics Denmark. Timing, causes of death as well as social, medical and obstetric characteristics of the parents were described according to maternal country of origin. RESULTS: This study included 125 perinatal deaths. The data indicated that intrapartum death, death caused by maternal disease, lethal malformation and preterm birth may be more frequent among non-Western than among Danish-born women. Obesity and disposition to diabetes may also be more prevalent among the non-Western women. CONCLUSIONS: The role of obesity, gestational diabetes, preeclampsia and severe congenital anomalies should be a main focus in improving our understanding the increased risk of perinatal death among non Western migrant women in Denmark. Six of 28 perinatal deaths in the non-Western group were intrapartum deaths and warrants further concern. FUNDING: This project was funded by the Danish Council for Strategic Research as part of the SULIM project. TRIAL REGISTRATION: The linkage of data from patient files to data from Statistics Denmark was approved by the Danish Data Protection Agency. Only anonymised data were used. PMID- 26931192 TI - Probiotics to prevent necrotising enterocolitis in very preterm infants. AB - INTRODUCTION: Meta-analyses of randomised trials have shown that probiotics reduce the risk of necrotising enterocolitis (NEC) in preterm infants. However, the generalisability of these results, particularly for the most preterm infants, remains unresolved. Hence, we wanted to evaluate the benefit of implementing prophylactic use of probiotics as standard care in infants younger than 30 weeks of gestation. METHODS: Two three-year periods were compared. The first period was prior to a policy change. In this period no probiotics were used. The second period featured routine administration of probiotics (bifidobacillus and lactobacillus) once daily by nasogastric tube from the third day of life. The main outcome: NEC grades 2 and 3 were assessed in a blinded fashion from a clinical abstract and available X-rays. RESULTS: A total of 381 infants treated before the change of policy were compared with 333 infants treated after the policy change had been introduced. There was no statistically significant change in NEC (odds ratio (OR) = 0.75, p = 0.34, 95% confidence interval (CI): 0.43 1.30). The OR for death was 0.92 (p = 0.55, 95% CI: 0.62-1.40). Unexpectedly, symptoms of NEC appeared earlier in the latter period (median six versus 14 days, p = 0.004). No side effects and no blood cultures with lactobacillus or bifidobacterium were observed. CONCLUSIONS: This historically controlled study did not indicate that probiotics had a significant effect on NEC. We continue our practice, but larger cohort studies or meta-analyses of such studies are needed to confirm previous beneficial findings in randomised trials. FUNDING: none. TRIAL REGISTRATION: Clinicaltrials.gov NCT01670916. PMID- 26931193 TI - Psychiatric disorders are overlooked in patients with drug abuse. AB - INTRODUCTION: Psychiatric disease is overlooked in drug users. Patients with both drug abuse and a psychiatric disease - dual diagnosis - suffer decreased compliance to treatment and decreased life expectancy compared with single diagnosis patients. Identifying the patients among either drug addicts or mentally ill patients is difficult. METHODS: All drug addicts autopsied at the Department of Forensic Medicine, University of Copenhagen, Denmark, in the years 1992, 2002 and 2012 were included. The group was divided into two subpopulations of possible dual diagnosis patients either according to police reports stating mental illness or to psychotropics found in the toxicology screening after autopsy. RESULTS: We found a rise in possible mental illness in both subpopulations in the study period. Drug addicts with psychotropics in the blood at the time of death increased from 3.1% in 1992 to 48.1% in 2012, and this group was significantly younger at the time of death than those without psychotropics in the blood. CONCLUSIONS: Suspected dual diagnosis patients have increased in number. They die earlier than their drug addict counterparts. Methadone remains the leading cause of death in all subpopulations. Possible causes are misuse of treatment and/or illegally bought methadone, wrongly assigned cause of death due to unknown tolerance and/or polydrug toxicity in combination with psychotropic medicine. FUNDING: none. TRIAL REGISTRATION: not relevant. PMID- 26931194 TI - Alternative pre-mRNA splicing leads to potential biomarkers in diffuse large B cell lymphoma - a systematic review. AB - INTRODUCTION: The study of potential biomarkers in haematological malignancies has gained momentum in past decades. We compiled a systematic review to outline potential biomarkers based on alternative pre-mRNA splicing that were suggested to be clinically useful for the diagnosis, prognosis and response to therapeutics in diffuse large B-cell lymphoma (DLBCL). METHODS: A comprehensive search of the literature in PubMed, Embase and Scopus was performed and supplemented with screening of reference lists. Only articles concerning potential biomarkers originating from reports on alternative pre-mRNA splicing were included. The contributions of these studies will help develop personalised medicine. Therefore, the clinical utility of the potential biomarkers was evaluated. RESULTS: A total of 16 studies were included of which eight described seven different potential diagnostic biomarkers. Eight studies reported two potential prognostic biomarkers for CD44, its spliced mRNA variants and the resulting proteins that were the most frequently reported. Furthermore, two studies reported two proteins originating from alternative pre-mRNA splicing as potentially predictive biomarkers. CONCLUSIONS: Alternative pre-mRNA splicing is a promising potential diagnostic, prognostic and predictive biomarker for the identification of pathogenic impacts in DLBCL. The use of these potential biomarkers in the clinical management of DLBCL awaits prospective clinical validation supporting its potential to contribute to the shift towards more personalised medicine. PMID- 26931195 TI - Admission of elderly medical patients to fast track or standard hospitalisation: protocol for a randomised trial. AB - INTRODUCTION: Emergency department-based short stay units (SSUs) are increasingly being introduced to provide accelerated care. The effects of treatment in SSUs for elderly medical patients are not well-studied. METHODS: The ELDER trial is a single-blinded, randomised parallel trial with 1:1 allocation between hospitalisation in an SSU (intervention) and the Department of Internal Medicine (standard care). The study is conducted at Holbaek Hospital, Denmark. Elderly patients are screened for inclusion if an emergency physician assesses that treatment in an SSU is possible. Eligible participants are patients aged >= 75 years needing in-hospital treatment of an acute medical problem and who are stable upon admission. The primary outcome is 90-day all-cause mortality. Secondary outcomes include: length of stay in hospital, incidence of complications during hospitalisation, rate of unplanned readmissions and change in instrumental activities of daily living. We aim at recruiting 430 patients based on an estimated effects size of reducing mortality by 10%. All outcome measures will be assessed in an intention-to-treat analysis. Recruitment started on 5 January 2015. By 16 October 2015, we have enrolled 203 patients. An interim safety analysis is scheduled. CONCLUSION: In the ELDER trial, we explore benefits and harms related to treatment in an SSU for elderly medical patients compared with standard hospitalisation. FUNDING: Region Zealand's Forskningsfond, the Tryg Foundation and University of Copenhagen. TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT02395718. PMID- 26931196 TI - Gender differences in multiple sclerosis epidemiology and treatment response. AB - There is an increasing incidence of multiple sclerosis (MS) in women in Denmark and Danish women's risk of developing MS has more than doubled in 25 years, while it has remained virtually unchanged for men. The explanation for these epidemiological changes should be sought in the environment, as genetics only explain a small part of the MS risk as the changes are too rapid to be explained by gene alterations. The rapid increase of MS incidence likely reflects unidentified changes in the environment and probably gene-environmental interactions. My PhD thesis work was conceived and designed to investigate the relevant exposures in different periods of life that may have contributed to the increasing female to male ratio of cases of multiple sclerosis in Denmark. To study this, we investigated the effect of numerous biological, social, physical and chemical environmental factors available from population-based registries in a case-control approach. Pregnancy may have a biological protective effect against developing MS in women, lasting for about five years. The protective effect is probably due to the modulation of the immune system by pregnancy. Our data on social behaviour changes regarding educational level, income, and relationship stability did not indicate reversed causality as a significant contributor to the lower number of childbirths in the five years before onset. Fewer pregnancies are one possible explanation we found for the increasing incidence of MS in women in our study. The trend towards fewer childbirths in the female population over decades may contribute to the increasing sex ratio and female incidence of MS. Socio-economic status and lifestyle expressed in educational level and the sanitary conditions in youth are not associated with the risk of MS, and cannot contribute to the increasing epidemiological disparity between the genders over the last decades. A greater likelihood to be exposed to common infections did not show any effect on the MS risk neither in puberty nor in adulthood. The apparent protective effect of childbirth does not appear to reflect postnatal child exposure. The only factor that may show association with a higher MS risk in women is working in agriculture but it was based on very small numbers and cannot contribute quantitatively to the incidence of MS in women. Women are generally more prone to autoimmune diseases than men, but significant increased occurrence of some other autoimmune diseases was only found in male MS cases in the period before clinical onset. None of the investigated autoimmune diseases occurred less frequently in MS patients than in control persons. Treatment response to interferon-beta, expressed in relapse rate was independently influenced by gender and the presence of NAbs, but it seems that the presence of NAbs does not affect the treatment effect differently in women and men. The results indicate that men's and women's treatment response to interferon-beta is similar. Females had a higher frequency of relapses than males. Our study did not reveal only one reason for the incidence increase, but as MS is multifactorial it is presumed that the incidence increase is caused by more than one factor, because women's lifestyle has undergone tremendous changes in the last half century. Our study contributes to clarification of this issue, with the role of pregnancies on the risk of MS. It is accepted that sex hormones have a clear immunologic involvement in the female predominance in MS, but there is no knowledge yet to explain the changes over time. PMID- 26931197 TI - Radiation-induced hypothyroidism after treatment of head and neck cancer. AB - Head and neck cancer is the sixth most common cancer in the world. In Denmark the incidence was 1,287 in 2013 (thyroid cancer excluded). Head and neck cancer is predominantly a loco-regional disease, and radiotherapy (RT) and surgery are major treatment options. Approximately 70% of Danish patients receive definitive RT, and the rest are treated with surgery with or without post-operative RT. Radiation to the normal tissues is inevitable during RT. The current advanced treatment modalities allow precise calculation of radiation doses to normal tissues and there is a potential to distribute the dose to avoid adverse effects from radiation. However, this requires knowledge about the radiation tolerance levels of individual organs. Radiation-induced hypothyroidism (RIHT) is a well known late effect of radiation to the thyroid gland, which can develop months to years after RT. The reported incidence of RIHT varies considerably, however, and the tolerance level of the thyroid gland is poorly defined. The aim of this PhD project was thus to elucidate these issues. The first study included a cohort of 203 patients with head and neck cancer who were treated with definitive RT and no surgery at Odense University Hospital, Denmark, in 2002-2010. Analysis of patient characteristics, precise radiation doses to the thyroid gland and follow-up assessments of thyroid function after radiotherapy gave an estimated five-year incidence of RIHT of 26%. Significant risk factors for the development of RIHT were a small thyroid volume and a high mean radiation dose to the gland. Two models were developed for predicting the risk of RIHT, taking both the thyroid volume and the mean radiation dose into account. One model was based on the collected data alone, while the other model included an estimated time distribution for the development of RIHT (i.e. latency). Using the model that considered latency, dose constraints for the thyroid gland were proposed for keeping the risk of RIHT after radiotherapy below 25%. This model emerged as the preferred model, and its robustness was tested in the following two studies. The second study aimed at assessing the impact of variation of estimated risk of RIHT due to intra- and inter-observer variability in delineated thyroid gland volume. Fifty treatment plans were randomly chosen for either repeat delineation by the author (intra-observer) or delineation by another radiation oncologist (inter observer). The variations in delineated thyroid gland volume and mean radiation dose, and the subsequent variation in estimated risk of RIHT were assessed. For the entire study population, the variation in predicted risk of RIHT was small and the model was robust towards observer variations in delineation of the thyroid gland. However, for some patients there were pronounced differences in the estimated risk due to variation in organ delineation, and thus precise delineation is of utmost importance for the individual patient. The third study aimed at studying the robustness of the model in a cohort of head and neck cancer patients treated with definitive RT at the Department of Oncology, Aarhus University Hospital. A total of 198 patients were included after one assessment of thyroid function (blood sample of thyrotropin, TSH) during routine follow-up after radiotherapy. A small thyroid volume and a high mean radiation dose were also found to be significant risk factors for RIHT in this cohort. These factors were included in a new risk model. Direct comparison of the two models was not possible, however, due to a different number of TSH assessments in the two cohorts. It was also not possible to estimate latency on the basis of a single measurement of thyroid function. Nevertheless, when the number of TSH assessments was taken into account, the estimated risk of RIHT was very similar in the two cohorts. CONCLUSION: Hypothyroidism is a frequent late effect after definitive radiotherapy. As the condition has been linked to increased risk of cardiac disease and mortality, and decreased quality of life, it is important to consider the risk of RIHT when planning radiation treatment. The size of the thyroid gland and the radiation dose to the gland are key factors in the development of RIHT, and both these factors should be considered when determining dose constraints for the thyroid gland. A risk of RIHT below 25% is recommended. Furthermore, routine assessment of thyroid gland function should be offered after radiotherapy in the neck area. Finally, the robustness of the risk model should be studied in a longitudinal follow-up of a cohort of patients with repeated thyroid function assessment. PMID- 26931198 TI - Applications of markerless motion capture in gait recognition. AB - This thesis is based on four manuscripts where two of them were accepted and two were submitted to peer-reviewed journals. The experimental work behind the thesis was conducted at the Institute of Neuroscience and Pharmacology, University of Copenhagen. The purpose of the studies was to explore the variability of human gait and to conduct new methods for precise estimation of the kinematic parameters applied in forensic gait analysis. The gait studies were conducted in a custom built gait laboratory designed to obtain optimal conditions for markerless motion analysis. The set-up consisted of eight synchronised cameras located in the corners of the laboratory, which were connected to a single computer. The captured images were processed with stereovision-based algorithms to provide accurate 3D reconstructions of the participants. The 3D reconstructions of the participants were obtained during normal walking and the kinematics were extracted with manual and automatic methods. The kinematic results from the automatic approach were compared to marker-based motion capture to validate the precision. The results showed that the proposed markerless motion capture method had a precision comparable to marker-based methods in the frontal plane and the sagittal plane. Similar markerless motion capture methods could therefore provide the basis for reliable gait recognition based on kinematic parameters. The manual annotations were compared to the actual anthropometric measurements obtained from MRI scans and the intra- and inter-observer variability was also quantified to observe the associated effect on recognition. The results showed not only that the kinematics in the lower extremities were important but also that the kinematics in the shoulders had a high discriminatory power. Likewise, the shank length was also highly discriminatory, which has not been previously reported. However, it is important that the same expert performs all annotations, as the inter-observer variability was high compared to the variability between the participants. The MRI scans were also applied to estimate the errors of existing marker-based regression equations to predict the joint centres. The errors in the HJC and the AJC were surprisingly high, which may affect the computations of the joint kinetics and thus the understanding of gait dynamics. On the other hand, the effect on the kinematics would be limited and thus the existing regression equations provide a reliable basis to validate markerless motion capture methods as long as the limitations regarding STA and the placement of the markers are considered in the data interpretation. New regression equations corrected the estimated bias and they also accounted for the significant sex differences in pelvis. PMID- 26931199 TI - Follicle Diameter and Systemic Hormone Interrelationships during Induction of Follicle Collapse with Intrafollicular Prostaglandin E2 and F2alpha in Mares. AB - The objectives were to determine: (i) whether intrafollicular administration of PGE2 and PGF2alpha to mares would hasten follicle collapse and (ii) the differences in reproductive hormone characteristics in mares with spontaneous and prostaglandin-induced follicle collapses. Six mares were followed for two oestrous cycles each: when the mares reached a follicle diameter of 30-35 mm and showed mild-to-moderate endometrial oedema, mares were administered a single 0.5 ml dose containing 500 MUg PGE2 and 125 MUg PGF2alpha (treatment cycle) or a placebo (0.5 ml of water for injection; control cycle) into the preovulatory follicle (Hour 0). Blood samples were collected, and serial ultrasound examinations were performed until follicle collapse. Treated mares showed follicle collapse significantly earlier (20.0 +/- 5.9 h) than the control mares (72.0 +/- 10.7 h). The LH, progesterone, total oestrogens and oestradiol concentrations did not differ between groups; however, the progesterone concentration increased more between 48 and 72 h after follicle injection in the treatment compared to the control cycles (P < 0.05). In conclusion, intrafollicular treatment with PGE2 and PGF2alpha hastened follicle collapse in mares without the simultaneous use of an inductor of ovulation; despite the early induction of follicle collapse, the profiles of LH and oestradiol were not altered. This study provides information on the role of prostaglandins (PGs) in the process of follicle wall rupture and collapse and suggests that this may happen even before the beginning of the sharp rise in circulating LH at the final stage of the ovulatory surge. PMID- 26931200 TI - Fascicular corneal vascularisation responds rapidly to removal of retained corneal foreign body. PMID- 26931201 TI - Encapsulation of Polymer Colloids in a Sol-Gel Matrix. Direct-Writing of Coassembling Organic-Inorganic Hybrid Photonic Crystals. AB - The spontaneous self-assembly of polymer colloids into ordered arrangements provides a facile strategy for the creation of photonic crystals. However, these structures often suffer from defects and insufficient cohesion, which result in flaking and delamination from the substrate. A coassembly process has been developed for convective assembly, resulting in large-area encapsulated colloidal crystals. However, to generate patterns or discrete deposits in designated places, convective assembly is not suitable. Here we experimentally develop conditions for direct-writing of coassembling monodisperse dye-doped polystyrene particles with a sol-gel precursor to form solid encapsulated photonic crystals. In a simple procedure the colloids are formulated in a sol-gel precursor solution, drop-cast on a flat substrate, and dried. We here establish the optimal parameters to form reproducible highly ordered photonic crystals with good optical performance. The obtained photonic crystals interact with light in the visible spectrum with a narrow optical stop-gap. PMID- 26931202 TI - Four Dibutylamino Substituents Are Better Than Eight in Modulating the Electronic Structure and Third-Order Nonlinear-Optical Properties of Phthalocyanines. AB - 2(3),9(10),16(17),23(24)-Tetrakis(dibutylamino)phthalocyanine compounds M{Pc[N(C4H9)2]4} (1-5; M = 2H, Mg, Ni, Cu, Zn) were prepared and characterized by a range of spectroscopic methods in addition to elemental analysis. Electrochemical and electronic absorption spectroscopic studies revealed the more effective conjugation of the nitrogen lone pair of electrons in the dibutylamino side chains with the central phthalocyanine pi system in M{Pc[N(C4H9)2]4} than in M{Pc[N(C4H9)2]8}, which, in turn, results in superior third-order nonlinear optical (NLO) properties of H2{Pc[N(C4H9)2]4} (1) over H2{Pc[N(C4H9)2]8}, as revealed by the obviously larger effective imaginary third-order molecular hyperpolarizability (Im{chi((3))}) of 6.5 * 10(-11) esu for the former species than for the latter one with a value of 3.4 * 10(-11) esu. This is well rationalized on the basis of both structural and theoretical calculation results. The present result seems to represent the first effort toward directly connecting the peripheral functional substituents, electronic structures, and NLO functionality together for phthalocyanine molecular materials, which will be helpful for the development of functional phthalocyanine materials via molecular design and synthesis even through only tuning of the peripheral functional groups. PMID- 26931203 TI - Erratum. PMID- 26931204 TI - Self-regulation in older Thai women with self-reported knee osteoarthritis: A path analysis. AB - This study aimed at testing factors influencing coping behavior and health status among older women with knee osteoarthritis. A total of 274 participants completed questionnaires. Model testing revealed that self-efficacy was the most powerful predictor of coping behavior. Illness representation had a significant direct and indirect effect on health status and was a better predictor of health status than were the other variables. Understanding the complex relationships among study variables should help to tailor future interventions to better address the symptoms of osteoarthritis and to promote optimal health in older Thai women who report knee osteoarthritis. PMID- 26931205 TI - Qualitative exploration of facilitating factors and barriers to use of antenatal care services by pregnant women in urban and rural settings in Pakistan. AB - BACKGROUND: World Health Organisation recommends that pregnant women with no complications should visit a healthcare provider at least four times to receive sufficient antenatal care services. In Pakistan only 37% of women reported to have had four or more antenatal care visits during their last pregnancy. This study aimed to explore facilitators and barriers to use of antenatal care services in rural and urban communities of two selected districts in Pakistan. METHODS: Qualitative explorative study using in-depth interviews with currently pregnant women, lady health workers and doctors providing antenatal care services, and focus group discussion with women who had a child aged 5 years or younger, was conducted in a rural community in the district Swabi and in a tertiary care hospital in urban Islamabad in Pakistan. The audio-recorded interviews and discussions were transcribed verbatim in Urdu (the language spoken by the respondents). A list of topical codes for all topics related to the research questions was developed. Subsequently the text pertaining to each topical code was discussed and summarised in a document that presented the findings for each topic using quotes and tables. RESULTS: We conducted in-depth interviews with six lady health workers, four doctors, and ten currently pregnant women, and facilitated ten focus group discussions with women who had a child aged 5 years or younger. Currently pregnant women, and women who had a child aged 5 years or younger, were not aware of the recommended minimum number of antenatal care visits to be made during pregnancy. Facilitating factors to visit a particular health care facility were: availability of qualified healthcare providers (private facility); trust in healthcare providers; recommendation from a family member, friend or lady health worker (in rural areas); availability of good quality services including medical equipment and laboratory facilities; low cost (public facility); and easy access to the health facility (private facility). Common barriers to visiting a health facility for antenatal care services were: financial limitations; perceived absence of any major health problems during pregnancy; difficulties in reaching the health facility; restriction from husband or mother-in-law; busy performing household chores; no previous experience of antenatal care visits; and perceived unavailability of healthcare providers and/or services. CONCLUSIONS: The current study identified several policy-relevant facilitating factors and barriers to visiting a health facility for antenatal care services as reported by urban and rural women, and healthcare providers. There is a need to formulate and implement intervention packages based on these findings to increase the coverage of the recommended four antenatal care visits in Pakistan. PMID- 26931206 TI - Dietary patterns of obese and normal-weight women of reproductive age in urban slum areas in Central Jakarta. AB - Developing countries including Indonesia imperatively require an understanding of factors leading to the emerging problem of obesity, especially within low socio economic groups, whose dietary pattern may contribute to obesity. In this cross sectional study, we compared the dietary patterns and food consumption of 103 obese and 104 normal-weight women of reproductive age (19-49 years) in urban slum areas in Central Jakarta. A single 24-h food recall was used to assess energy and macronutrient intakes (carbohydrate, protein and fat) and calculate energy density. A principal component analysis was used to define the dietary patterns from the FFQ. Obese women had significantly higher intakes of energy (8436.6 (sd 2358.1) v. 7504.4 (sd 1887.8) kJ (2016.4 (sd 563.6) v. 1793.6 (sd 451.2) kcal)), carbohydrate (263.9 (sd 77.0) v. 237.6 (sd 63.0) g) and fat (83.11 (sd 31.3) v. 70.2 (sd 26.1) g) compared with normal-weight women; however, their protein intake (59.4 (sd 19.1) v. 55.9 (sd 18.5) g) and energy density (8.911 (sd 2.30) v. 8.58 (sd 1.88) kJ/g (2.13 (sd 0.55) v. 2.05 (sd 0.45) kcal/g)) did not differ significantly. Two dietary patterns were revealed and subjectively named 'more healthy' and 'less healthy'. The 'less healthy' pattern was characterised by the consumption of fried foods (snacks, soyabean and roots and tubers) and meat and poultry products, whereas the more healthy pattern was characterised by the consumption of seafood, vegetables, eggs, milk and milk products and non-fried snacks. Subjects with a high score for the more healthy pattern had a lower obesity risk compared with those with a low score. Thus, obesity is associated with high energy intake and unhealthy dietary patterns characterised by consumption of oils and fats through fried foods and snacks. PMID- 26931207 TI - Association of Streptococcus pneumoniae nasopharyngeal colonization and other risk factors with acute otitis media in an unvaccinated Indian birth cohort. AB - In order to study the epidemiology of acute otitis media (AOM) and Streptococcus pneumoniae nasopharyngeal colonization in the first 2 years of life, we followed up an unvaccinated birth cohort monthly and at visits when sick, with otoscopy to detect AOM and performed nasopharyngeal swabbing to detect S. pneumoniae. Serotyping of positive cultures was also performed. Of 210 babies who were enrolled at birth, 61 (29.05%) experienced 128 episodes of AOM [relative risk 2.63, 95% confidence interval (CI) 1.21-5.75] with maximum incidence in the second half of the first year of life. Episodes ranged from 1 to 7 (mean 2.1 episodes). Most (86.9%) babies with AOM had a positive culture swab giving an odds ratio (OR) of 1.93 (95% CI 1.03-3.62, P = 0.041) for this association. Other risk factors identified for AOM were winter season (OR 3.46, 95% CI 1.56-7.30, P = 0.001), upper respiratory infection (OR 2.43, 95% CI 1.43-4.51, P = 0.005); residents of small households were less likely to develop AOM (OR 0.32, 95% CI 0.17-0.57, P < 0.01). Common S. pneumoniae serotypes isolated during episodes were 19, 6, 15, 35, 7, 23, 9 and 10 which indicated a theoretical coverage for pneumococcal vaccines PCV10 and PCV13 constituent serotypes of 62.8%. We conclude that AOM in Indian infants is often associated with S. pneumoniae colonization of the nasopharynx as well as other risk factors. PMID- 26931211 TI - This special issue is dedicated to French faculty members. Introduction. PMID- 26931209 TI - Selective regulation of YB-1 mRNA translation by the mTOR signaling pathway is not mediated by 4E-binding protein. AB - The Y-box binding protein 1 (YB-1) is a key regulator of gene expression at the level of both translation and transcription. The mode of its action on cellular events depends on its subcellular distribution and the amount in the cell. So far, the regulatory mechanisms of YB-1 synthesis have not been adequately studied. Our previous finding was that selective inhibition of YB-1 mRNA translation was caused by suppression of activity of the mTOR signaling pathway. It was suggested that this event may be mediated by phosphorylation of the 4E binding protein (4E-BP). Here, we report that 4E-BP alone can only slightly inhibit YB-1 synthesis both in the cell and in vitro, although it essentially decreases binding of the 4F-group translation initiation factors to mRNA. With inhibited mTOR kinase, the level of mRNA binding to the eIF4F-group factors was decreased, while that to 4E-BP1 was increased, as was observed for both mTOR kinase-sensitive mRNAs and those showing low sensitivity. This suggests that selective inhibition of translation of YB-1 mRNA, and probably some other mRNAs as well, by mTOR kinase inhibitors is not mediated by the action of the 4E binding protein upon functions of the 4F-group translation initiation factors. PMID- 26931208 TI - Regulation of fibroblast growth factor 15/19 and 21 on metabolism: in the fed or fasted state. AB - Fibroblast growth factor (FGF) 15/19 and FGF21 are two atypical members of FGF19 subfamily that function as hormones. Exogenous FGF15/19 and FGF21 have pharmacological effects, and endogenous FGF15/19 and FGF21 play vital roles in the maintenance of energy homeostasis. Recent reports have expanded the effects of FGF15/19 and FGF21 on carbohydrate and lipid metabolism. However, the regulations of FGF15/19 and FGF21 on metabolism are different. FGF15/19 is mainly secreted from the small intestine in response to feeding, and FGF21 is secreted from the liver in response to extended fasting and from the liver and adipose tissue in response to feeding. In this work, we reviewed the regulatory effects of FGF15/19 and FGF21 on metabolism in the fast and fed states. This information may provide some insight into the metabolic regulation of FGF15/19 and FGF21 in different physiological condition. PMID- 26931212 TI - Advances in Homogeneous Catalysis Using Secondary Phosphine Oxides (SPOs): Pre ligands for Metal Complexes. AB - The secondary phosphine oxides are known to exist in equilibrium between the pentavalent phosphine oxides (SPO) and the trivalent phosphinous acids (PA). This equilibrium can be displaced in favour of the trivalent tautomeric form upon coordination to late transition metals. This tutorial review provides the state of the art of the use of secondary phosphine oxides as pre-ligands in transition metal-catalysed reactions. Using a combination of SPOs and several metals such as Pd, Pt, Ru, Rh and Au, a series of effective and original transformations have been obtained and will be discussed here. PMID- 26931213 TI - New Insights into the Synthesis and Biological Activity of the Pamamycin Macrodiolides. AB - After a brief account of the biological properties of pamamycins, this review highlights the latest developments on the total synthesis and the biosynthesis of these macrodiolides. PMID- 26931214 TI - Polymer-containing Organo-Polyoxometalate: Towards New Catalytic Object. AB - Polyoxometalates (POMs) are early transition metal oxide clusters, which form a diverse family of compounds with highly tunable shapes, sizes, charges, etc. Generating hybrid structures is an attractive path to increase the structural diversity of POMs. The present article is a personal account that retraces how we inserted polyoxometallic platforms onto polymeric chains. We focused on two main families of functionalized organo-POMs: the organotin-substituted Dawson polyoxotunstates alpha1 and alpha2-[P(2)W(17)O(61)(SnR)](7-) and the Dawson vanadotungstates [P(2)V(3)W(15)O(59){(OCH(2))(2)-C(Et)NHC(=O)R}](5-). Herein we discuss how the connection of POMs to polymers affects the self-assembly of the polymers and the catalytic properties of the polyoxometalates. PMID- 26931215 TI - Free-radical Carbo-functionalization of Olefins Using Sulfonyl Derivatives. AB - This review provides an overview of the recent progress made in the area of free radical additions across the pi-system of olefins, with a focus on the role of sulfonyl derivatives as one of the reaction partners in multicomponent processes. The mechanism and utility in organic synthesis of carbo-alkenylation, alkynylation, oximation and azidation of olefins are thus discussed and illustrated with some applications in total synthesis of natural products. PMID- 26931216 TI - Lithium/Element Exchange as an Efficient Tool for Accessing Atropo-enriched Biaryls via Arynes. AB - This account documents the development of transition metal-free, aryne-mediated aryl-aryl coupling, the 'ARYNE coupling', which began in 2001 in Lausanne. ortho,ortho'-Di-, tri- and even tetrasubstituted biphenyls have now become accessible on a multi-gram scale. The reaction is perfectly regioselective and the obtained polybromobiphenyls can be submitted to regioselective bromine/lithium interconversions. The access to enantiopure biphenyls is now possible using enantiopure sulfoxides as chiral auxiliaries, which allow for subsequent chemoselective sulfoxide/metal exchange on each atropo-diastereoisomer with configurational stability of the intermediate biaryllithiums. Direct atropo diastereoselective ARYNE coupling has been reported more recently. PMID- 26931217 TI - Long-range Effect of Bromine in the Deprotonative Metalation of Aromatic Compounds. AB - Deprotonative metalation has been largely used to functionalize aromatic compounds. The efficiency of such reactions, as well as their regioselectivity, depends on the substituents connected to the rings. In contrast with other groups such as fluorine and methoxy, bromine exhibits a long-range acidifying effect. Here we try to depict this particular effect of bromine through different examples in which deprotometalation takes place at a remote position. PMID- 26931218 TI - From Ruthenium to Copper: A la carte Tools for the Synthesis of Molecules of Interest. AB - Well-defined ruthenium complexes and simple copper-ligand systems proved to be powerful catalysts for the construction of complex molecules from simple and abundant organic sources. In this account, chosen examples of reactions involving C-C bond formation catalyzed by [Ru(eta(5)-C(5)H(5))-(CH(3)CN)(3)][PF(6)] will be presented. A practical synthesis of the versatile catalyst [Ru(eta(5)-C(5)H(5)) (CH(3)CN)(3)][PF(6)] is also described via a simple and easy-handled procedure discovered in Geneva ten years ago. The second part of this review is focused on methodologies catalyzed by an association of a copper salt and a simple ligand for the formation of C-N, C-O and C-C bonds developed in our group in Montpellier. A brief overview of applications in life sciences and materials will conclude this article. PMID- 26931219 TI - From Pillar[n]arene Scaffolds for the Preparation of Nanomaterials to Pillar[5]arene-containing Rotaxanes. AB - Pillar[n]arenes are a new class of macrocycles that are efficiently prepared from readily available building blocks. In this particular field, our research teams became interested in the use of a pillar[5]arene core as a compact scaffold for the synthesis of nanomaterials with a controlled distribution of functional groups on both rims of the macrocyclic framework. Such compounds have found applications in biology as multivalent ligands for specific lectines or as polycationic compounds for gene delivery. Liquid-crystalline derivatives have been prepared by grafting mesogenic subunits on the pillar[5]arene core. On the other hand, we also became interested in the preparation of pillar[5]arene containing [2]rotaxanes. In particular, we have shown that pillar[5] arene-based [2]rotaxanes can be obtained from the reaction of amine stoppers with pseudo rotaxanes resulting from the association of a pillar[5]arene derivative with a diacyl chloride reagent. Finally, amphiphilic [2]rotaxanes have been prepared and incorporated in thin ordered films at the air-water interface. PMID- 26931220 TI - Tin-free Alternatives to the Barton-McCombie Deoxygenation of Alcohols to Alkanes Involving Reductive Electron Transfer. AB - Echoing the recent celebration of the fortieth anniversary of the Barton-McCombie reaction, this review aims to explore another facet of radical processes for deoxygenation of alcohols by considering SET (single electron transfer) reduction of carboxylic ester, thiocarbonate and thiocarbamate derivatives. Various protocols have been developed relying on the use of organic and organometallic SET reagents, electrochemical conditions, photoinduced electron transfer processes and visible-light photoredox catalysis. Applications to the synthesis of molecules of interest provide a glimpse into the scope of these different approaches. PMID- 26931221 TI - Nitrogen-functionalized Isohexides in Asymmetric Induction. AB - Biosourced isohexides have attracted the considerable attention of both the academic and industrial chemistry communities over the last 50 years. This highlight focuses on the synthesis of nitrogen-containing isohexides and their applications in asymmetric catalysis. PMID- 26931222 TI - tert-Butanesulfinamides as Nitrogen Nucleophiles in Carbon-Nitrogen Bond Forming Reactions. AB - The use of tert-butanesulfinamides as nitrogen nucleophiles in carbon-nitrogen bond forming reactions is reviewed. This field has grown in the shadow of the general interest in N-tert-butanesulfinyl imines for asymmetric synthesis and occupies now an important place in its own right in the chemistry of the chiral amine reagent tert-butanesulfinamide. This article provides an overview of the area and emphasizes recent contributions wherein the tert-butanesulfinamides act as chiral auxiliaries or perform as nitrogen donors in metal-catalyzed amination reactions. PMID- 26931223 TI - Ynol Ethers: Synthesis and Reactivity. AB - Ynol ethers are highly valuable substrates offering a wide range of reactivity. These highly electron-rich heterosubstitued alkynes can be of great synthetic potential. In this mini-review, the different methods for the synthesis of ynol ethers are first presented, divided in three main approaches involving a beta elimination, a carbene rearrangement and a direct oxidation of an alkyne. Their reactivity is then summarized underlying their synthetic utility. This non exhaustive review aims at presenting the intrinsic reactivity of these compounds, still underexploited in synthesis. PMID- 26931224 TI - Recent Achievements in Enantioselective Borrowing Hydrogen by the Combination of Iron- and Organocatalysis. AB - This article summarizes our recent developments in allylic alcohol functionalization by the interconnection of two catalytic cycles. By combining an iron-catalyzed borrowing hydrogen with an organocatalytic enantioselective nucleophilic addition, allylic alcohols can be converted to enantioenriched chiral aliphatic alcohols in up to 92% ee. This eco-compatible one-operation multi-catalytic process allows the classical oxidation-addition-reduction steps usually required for this transformation to be bypassed. Synthetic applications in the synthesis of different fragments of some important natural products have highlighted the great potential of this transformation. PMID- 26931229 TI - 15th EuCheMS International Conference on Chemistry and the Environment - ICCE 2015. PMID- 26931225 TI - Smart Contrast Agents for Magnetic Resonance Imaging. AB - By visualizing bioactive molecules or biological parameters in vivo, molecular imaging is searching for information at the molecular level in living organisms. In addition to contributing to earlier and more personalized diagnosis in medicine, it also helps understand and rationalize the molecular factors underlying physiological and pathological processes. In magnetic resonance imaging (MRI), complexes of paramagnetic metal ions, mostly lanthanides, are commonly used to enhance the intrinsic image contrast. They rely either on the relaxation effect of these metal chelates (T(1) agents), or on the phenomenon of paramagnetic chemical exchange saturation transfer (PARACEST agents). In both cases, responsive molecular magnetic resonance imaging probes can be designed to report on various biomarkers of biological interest. In this context, we review recent work in the literature and from our group on responsive T(1) and PARACEST MRI agents for the detection of biogenic metal ions (such as calcium or zinc), enzymatic activities, or neurotransmitter release. These examples illustrate the general strategies that can be applied to create molecular imaging agents with an MRI detectable response to biologically relevant parameters. PMID- 26931230 TI - High Added Value - but Many Stumbling Blocks along the Way NTN Biotech Identifies where the Shoe Pinches. AB - The year 1958, when DNA was first made in a test tube, marked the birth of modern biotechnology. DNA has now developed into an important technology that makes a key contribution in various sectors such as agriculture, environment and cleansing, and it has triggered a veritable boom in medicine. Today, biologics account for more than 60% of newly approved drugs. They are efficient, save time and money and have few or minimal side effects, fuelling the appetite of big pharma to take over biotech companies. Where will the journey lead? PMID- 26931231 TI - NTN Swiss Biotech - A Look at Support Measures for Dynamic Start-ups. AB - The Swiss biotech landscape seems to be on a healthy footing: There are many imaginative start-ups, we have first-class hospitals, highly advanced clinical research and the availability of a great deal of capital. But we have no reason to rest on our laurels as countries like the USA lead the field. We must lay down the tracks today to remain an attractive country and maintain our ranking among the 10 best locations. PMID- 26931232 TI - Three Bronze Medals for Switzerland at the 47th International Chemistry Olympiad in Baku, Azerbaijan. PMID- 26931235 TI - Characterization of an extensive rainbow trout miRNA transcriptome by next generation sequencing. AB - BACKGROUND: MicroRNAs (miRNAs) have emerged as important post-transcriptional regulators of gene expression in a wide variety of physiological processes. They can control both temporal and spatial gene expression and are believed to regulate 30 to 70% of the genes. Data are however limited for fish species, with only 9 out of the 30,000 fish species present in miRBase. The aim of the current study was to discover and characterize rainbow trout (Oncorhynchus mykiss) miRNAs in a large number of tissues using next-generation sequencing in order to provide an extensive repertoire of rainbow trout miRNAs. RESULTS: A total of 38 different samples corresponding to 16 different tissues or organs were individually sequenced and analyzed independently in order to identify a large number of miRNAs with high confidence. This led to the identification of 2946 miRNA loci in the rainbow trout genome, including 445 already known miRNAs. Differential expression analysis was performed in order to identify miRNAs exhibiting specific or preferential expression among the 16 analyzed tissues. In most cases, miRNAs exhibit a specific pattern of expression in only a few tissues. The expression data from sRNA sequencing were confirmed by RT-qPCR. In addition, novel miRNAs are described in rainbow trout that had not been previously reported in other species. CONCLUSION: This study represents the first characterization of rainbow trout miRNA transcriptome from a wide variety of tissue and sets an extensive repertoire of rainbow trout miRNAs. It provides a starting point for future studies aimed at understanding the roles of miRNAs in major physiological process such as growth, reproduction or adaptation to stress. These rainbow trout miRNAs repertoire provide a novel resource to advance genomic research in salmonid species. PMID- 26931237 TI - Operational challenges to continuous LLIN distribution: a qualitative rapid assessment in four countries. AB - BACKGROUND: The World Health Organization recommends that long-lasting insecticidal nets (LLINs) for malaria prevention should be distributed continuously through antenatal care (ANC) and the expanded programme on immunization (EPI) in addition to mass campaigns. Despite these recommendations, the continuous distribution (CD) of LLIN distribution through ANC and EPI is not policy in many countries, and where there is a policy, implementation is incomplete. This study aims to identify the operational strengths and weaknesses of LLINs CD in four country programmes in sub-Saharan Africa. METHODS: A qualitative rapid assessment process was conducted using semi-structured individual and group interviews at the national, sub-national, and facility level in four countries. Seventy participants were included (23 in Kenya, 13 in Malawi, 18 in Mali and 16 in Rwanda), drawn from malaria programmes, ANC and EPI programmes, government logistics units, and partner organizations. Interviews were structured to identify themes within a health systems approach. Policy and guideline documents and data collection tools were reviewed as a means of triangulation. Data analysis focused on pre-determined and emergent themes. RESULTS: The four countries used a wide variety of management systems for the supply of LLINs to routine services. Issues related to quantification, supply logistics and data collection all contributed to stock-outs at facility level. None of the four countries had guidelines for responding to stock-outs or system enabling local staff to request additional supplies of LLINs. In all four countries, data collection of LLIN distribution was incomplete or absent at facility level, and such data were not used for planning. Training of staff at the facility level was implemented less frequently than national and sub-national staff would have preferred. Logistics systems, independent of other commodities, and in-country partner support strengthened the continuous distribution of LLINs. CONCLUSIONS: In these countries, stock-outs were the most important single obstacle to the smooth operations of continuous LLIN distribution. Stock-outs can be avoided if facilities have the capacity to place orders for LLIN resupply as needed. Revised data collection and management systems for LLIN distribution have the potential to increase coverage of the target populations by improving LLIN stock-out response, and strengthening monitoring and evaluation of distribution. PMID- 26931236 TI - The impact of long-term school-based physical activity interventions on body mass index of primary school children - a meta-analysis of randomized controlled trials. AB - BACKGROUND: Physical activity (PA) intervention is a commonly recommended strategy to combat childhood obesity. However, its effectiveness has long been controversial. This paper aims to examine the effectiveness of long-term (>=12 months) school-based PA interventions on body mass index (BMI) in primary school children, who are gaining BMI. METHODS: Original papers were retrieved from PubMed, Google Scholar, the Cochrane Library and Web of Science, published between 1990 and 2015. The inclusion criteria were those research studies that were: randomized controlled trials (RCTs), conducted in primary school settings, had valid data on BMI at baseline and at the final follow up (or on BMI changes), and involved PA intervention that lasted for at least 12 months. RESULTS: Out of 11,158 potentially eligible articles, 18 papers were included in the analysis, involving 22,381 primary school children with intervention durations ranging from 12 to 72 months. Compared to the control groups, the BMI increment was 2.23 kg/m(2) less in the intervention groups (p < 0.05). The heterogeneity was high across the studies (99.8 %), but declined after sub-group analyses. The intervention type, intervention duration, and weekly PA intervention time were among the factors leading to the heterogeneity. CONCLUSION: Long-term school based interventions containing PA as a core component appear to be effective in achieving healthier BMI. However, the results should be interpreted with caution due to the high heterogeneity among the studies. More high quality school-based RCTs among diverse populations are needed to improve the homogeneity and to yield a more robust conclusion. PMID- 26931238 TI - Complexes of adamantane-based group 13 Lewis acids and superacids: Bonding analysis and thermodynamics of hydrogen splitting. AB - The electronic structure and chemical bonding in donor-acceptor complexes formed by group 13 element adamantane and perfluorinated adamantane derivatives EC9 R'15 (E = B, Al; R' = H, F) with Lewis bases XR3 and XC9 H15 (X = N, P; R= H, CH3 ) have been studied using energy decomposition analysis at the BP86/TZ2P level of theory. Larger stability of complexes with perfluorinated adamantane derivatives is mainly due to better electrostatic and orbital interactions. Deformation energies of the fragments and Pauli repulsion are of less importance, with exception for the boron-phosphorus complexes. The MO analysis reveals that LUMO energies of EC9 R'15 significantly decrease upon fluorination (by 4.7 and 3.6 eV for E = B and Al, respectively) which results in an increase of orbital interaction energies by 27-38 (B) and 15-26 (Al) kcal mol(-1) . HOMO energies of XR3 increase in order PH3 < NH3 < PMe3 < PC9 H15 < NMe3 < NC9 H15 . For the studied complexes, there is a linear correlation between the dissociation energy of the complex and the energy difference between HOMO of the donor and LUMO of the acceptor. The fluorination of the Lewis acid significantly reduces standard enthalpies of the heterolytic hydrogen splitting H2 + D + A = [HD](+) + [HA](-) . Analysis of several types of the [HD](+) ...[HA](-) ion pair formation in the gas phase reveals that structures with additional H...F interactions are energetically favorable. Taking into account the ion pair formation, hydrogen splitting is predicted to be highly exothermic in case of the perfluorinated derivatives both in the gas phase and in solution. Thus, fluorinated adamantane based Lewis superacids are attractive synthetic targets for the construction of the donor-acceptor cryptands. (c) 2016 Wiley Periodicals, Inc. PMID- 26931240 TI - Acute Kidney Injury is More Common in Acute Haemorrhagic Stroke in Mymensingh Medical College Hospital. AB - Acute kidney injury (AKI) is a common complication after acute stroke and is an independent predictor of both early and long-term mortality after acute stroke. Acute kidney injury is associated with increased mortality in haemorrhagic stroke patients. This cross sectional observational study was conducted in Nephrology, Neuromedicine and Medicine department of Mymensingh Medical College & Hospital, Mymensingh from July 2012 to June 2014. A total of 240 patients with newly detected acute stroke confirmed by CT scan of brain were included in this study. According to this study, 15.42% of acute stroke patients developed AKI. Among the patients with haemorrhagic stroke 21.87% developed AKI while only 13.07% patients with ischaemic stroke developed AKI. So, early diagnosis and management of AKI in patients with acute stroke especially in haemorrhagic stroke is very important to reduce the morbidity and mortality of these patients. PMID- 26931241 TI - Variations of Thickness of Splenic Capsule of Different Age and Sex in Bangladeshi Cadaver. AB - The spleen is the most frequently injured organ in the abdomen. Splenic rupture is usually precipitated by a crushing injury or severe blow. If ruptured the spleen will bleed profusely because its capsule is thin and its parenchyma is soft and pulpy. Such "spontaneous ruptures" never occur in truly normal spleen but rather than from some minor physical insult to a spleen that has been rendered fragile by an underlying condition. The most common predisposing conditions are infectious mononucleosis, malaria, typhoid fever and lymphoid neoplasms. These diverse entities can all cause rapid splenic enlargement, producing a thin, tense splenic capsule that is susceptible to rupture. Understanding of splenic capsular structure may help explain mechanical properties of the normal and diseased spleen. Histological changes are evident in advancing age along with functional capability of the human spleen. This cross sectional descriptive study was done to measure the thickness of splenic capsule to establish the difference between sexes of different age groups in Bangladeshi cadaver. The study was carried out in the department of Anatomy, Mymensingh Medical College, Mymensingh from June 2013 to July 2014. A total 30 human spleen were collected by purposive sampling technique from October 2013 to April 2014, among them 14 were male and 16 were female. The specimens were collected from Bangladeshi cadavers of age ranging from 6 months to 60 years, from autopsy laboratory of the Department of Forensic Medicine of Mymensingh Medical College. For convenience of differentiating the thickness of splenic capsule in relation to age and sex, the collected specimens were divided into three groups like Group A (upto 20 years), Group B (21 to 40 years) & Group C (41 to 60 years). Each group was again divided into male & female groups. In this study 10 slides from each age group were chosen for measuring the thickness of splenic capsule and examined under low power objective. In present study the mean capsular thickness of spleen was 107.71+/-8.70, 125.71+/-31.29 and 136.39+/-6.49 MUm in Group A, B and C respectively. The mean difference of capsular thickness of spleen between Group A & B, Group B & C was statistically non-significant but the difference between C & A was highly significant (p<0.001). From this study it was also observed that the mean+/-SD thickness of splenic capsule was higher in male than that of female among the age groups but there was no significant difference between sexes. In statistical analysis, differences between age groups and sexes were calculated by using one way ANOVA test and unpaired 't' test respectively. PMID- 26931242 TI - Awareness among Parents of beta-Thalassemia Major Patients Regarding Prenatal Diagnosis and Premarital Screening in Day Care Centre of Transfusion Medicine Department. AB - Thalassemia is one of the most common genetic diseases in the world. It is a major health problem, brings much morbidity, early mortality and a great deal of misery for a family both financially and emotionally. The patients suffering from beta thalassemia major do not survive for more than 5 years without blood transfusion. Blood transfusion is usually administered every two to five weeks to maintain the pre-transfusion hemoglobin level of 9-10 gm/dL. This study carried out in the department of Transfusion Medicine of Mymensingh Medical College Hospital from January 2014 to June 2014. A total of 200 parents were interviewed. There was a slight preponderance of females which accounted for 57.5% of the parents. Ninety seven (45.5%) had an income less than Rs. 5000 per month. Nearly 50% were illiterate with only 24.5% with a higher education. Consanguinity was positive in 72.5% of the parents with extended family history of thalassemia positive in 40.8%. Only 29.5% were immunized against Hepatitis B. Around 27.5% did not know whether they should be immunized. Fifty five percent of parents knew children should receive Dysferol. Twelve percent were aware of consanguinity to be a risk factor for thalassaemia with only 5% having undergone antenatal diagnosis. Parental knowledge about thalassemia and its preventive measures is inadequate; this requires intervention in the form of public health education programs concentrating on high risk/targeted population. PMID- 26931243 TI - Blood Pressure in Third Trimester of Pregnancy. AB - Pregnancy is a great stressful physiological condition in women during their reproductive period. During pregnancy several hemodynamic, biochemical and hematological modifications occur as a part of the physiological adaptation of the body. Changes in blood pressure occur in third trimester of pregnancy, which may be associated with increased maternal and infant mortality and morbidity. This cross-sectional study was carried out in the Department of Physiology, Mymensingh Medical College, Mymensingh, from July 2013 to June 2014. Study subjects were selected by following purposive sampling procedure and the protocol of this study was approved by Institutional Ethics Committee (IEC) of Mymensingh. This study enrolled 100 pregnant women of third trimester of pregnancy and 100 aged matched non-pregnant women from Mymensingh district. Mean systolic blood pressure in study group were 124.8+/-14.51 mm of Hg and in control group were 106.50+/-10.67 mm of Hg, which was statistically increased. Diastolic blood pressure in study group was 83.00+/-13.37 mm of Hg and in control group 71.05+/ 7.12 mm of Hg, which was also statistically significant. The changes in blood pressure in third trimester of pregnancy is the major concern of developing the risk of pre-eclampsia & eclampsia, and increased prevalence of IUGR, pre-maturity and perinatal mortality. This study reveals significant changes of blood pressure during third trimester of pregnancy. PMID- 26931245 TI - Status of Serum Zinc in Multidrug Resistant Tuberculosis. AB - Zinc plays a vital role in the immune status. Its deficiency affects host defense by reducing the number of circulating T cells and phagocytosis activity of other cells which ultimately impair cell mediated immunity. The cell-mediated immunity plays a major role in the causation of pulmonary tuberculosis. The present study was carried out to estimate serum zinc level in newly detected multidrug resistant tuberculosis (MDR-TB) in adult population. In this study total fifty (50) MDR-TB patients were enrolled conveniently from the in-patients departments of National Institute of Diseases of the Chest Hospital (NIDCH), Bangladesh. Serum zinc was estimated by atomic absorption spectrophotometry method from early morning fasting blood sample. Serum zinc level was assessed according to normal cut-off value 70-120 MUgm/dl and 76% studied population were found lower than this value. The mean+/-SD serum zinc level was observed 60.40+/-8.91 MUgm/dl. No associations were found between serum zinc level with age (p=0.11) and with sex (p=0.085) of the study population respectively. The low level of serum zinc in MDR-TB patients suggested impaired immune status of our study population. PMID- 26931244 TI - Anti-Bacterial effect of Aqueous Garlic Extract (AGE) determined by Disc Diffusion Method against Escherichia coli. AB - The study was performed to determine the antibacterial effect of aqueous extract of garlic (Allium sativum) against standard strain of Escherichia coli ATCC 25922. An interventional study was conducted in Department of Pharmacology and Therapeutics in collaboration with Department of Microbiology, Mymensingh Medical College, Mymensingh. Antibacterial effect of AGE was determined by disc diffusion method. Sensitivity of AGE determined in disc diffusion and the zone of inhibition (ZOI) was 4 mm, 10 mm and 20 mm at 25 MUg/10 MUl, 50 MUg/10 MUl and 100 MUg/10 MUl concentrations respectively. From the findings it is clearly determined the extract has definite antibacterial effect upon Escherichia coli. Further studies are required to detect and isolate the active ingredients present in the Garlic extract as well as detail steps of mechanism responsible for antibacterial effect. Then their effects against the studied organism should be studied in vivo separately and its toxicity profile should also be taken into account. PMID- 26931246 TI - Biomass Fuel Smoke and Tuberculosis: A Case-Control Study. AB - This case control study was done to ascertain the association between exposures to biomass cooking fuel smoke and pulmonary tuberculosis. Cases were all newly diagnosed pulmonary tuberculosis patients, randomly collected from the Hospital (DOTS centers) Registry from January 2012 to June 2012 from two Upazillas of Sirajganj district, Bangladesh. A home visitation program was done subsequently. Healthy controls were recruited from the neighbourhood of each case through a predefined procedure. Total 276 new pulmonary tuberculosis cases and 276 neighbourhood controls were enrolled. A semi-structured questionnaire containing demographic information, smoking habits, cooking place, kitchen condition, use of biomass fuel for cooking was used for interview. Crude (unadjusted) odd ratios and their corresponding 95% confidence limits for independent variables were determined by binary logistic regression. All significant variables were entered into a multivariate conditional logistic regression model and a final fitted model was determined by backward elimination methods. In univariate analysis, member of a nuclear family {Unadjusted odd ratio (Unadj. OR) 1.570, 95% CI 1.008 2.44)}, having non-formal education (Unadj. OR 2.739, 95% CI 1.219, 6.153) or primary (Unadj. OR 3.407, 95% CI 1.492, 7.782) to secondary level (Unadj. OR 2.392, 95% CI 1.032, 5.544) education, using cow dung (Unadj. OR 3.961, 95% CI 1.267, 12.376) and biomass fuel i.e. plant origin (Unadj. OR 3.382, 95% CI 1.087, 10.518) for cooking, past smoker (Unadj. OR 2.504, 95% CI 1.061, 5.910), using open oven (Unadj. OR 3.109, 95% CI 0.995, 9.716), having small kitchen area (Unadj. OR 0.99, 95% CI 0.989, 0.999) all were significantly associated with tuberculosis. When all significant variables were entered into a multivariate conditional logistic regression model nuclear family {Adjusted odd ratio (Adj OR) 1.808, 95% CI 1.127, 2.9)}, primary level education (Adj OR 2.86, 95% CI 1.23, 6.647) and non formal education (Adj OR 2.312, 95% CI 1.013, 5.276), biomass fuel (plant origin, Adj OR 3.497, 95% CI 1.059, 11.55), and cow dung (Adj OR 4.368, 95% CI 1.319, 14.464)) used in cooking and irregular smoker (who stop smoking at least 6 month back) (Adj OR 2.806, 95% CI 1.141, 6.901) were significantly associated with tuberculosis cases. From this study significant association have been found between exposure to combustion of biomass cooking fuel and tuberculosis. PMID- 26931247 TI - Malignancy in Solitary Thyroid Nodule. AB - This prospective study was done to find out the relative frequency of the malignancy in cold solitary thyroid nodules with other solitary thyroid nodules (hot and warm). This study was carried out in the Department of General Surgery and Otolaryngology-Head & Neck Surgery, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh from January 2011 to February 2012. One hundred (100) patients with clinically and ultrasonographically diagnosed as solitary thyroid nodules were included. Out of them, 52% of patients were in the third and fourth decades of life and 26% were in the second decade of life. In sex distribution, females were more affected than males and female: male ratio was 2.1:1. All patients presented with neck swelling, which moved with deglutition and 18% presented with palpitation. Solitary nodule was present in about 60% in the right lobe and 32% in the left lobe. In 72% patients, radioiodine uptake was low; in 25% patient's radioiodine uptake was normal. The thyroid scan revealed 72% cold nodule, in 25% patients radioiodine uptake was normal. On Ultrasonographic study, 60% were solid, 28% cystic and others mixed. Each and every patient of this series was treated surgically. Mostly (73%) lobectomy was done. Total thyroidectomy was done in 16% cases. On histopathology, 56% were colloid nodule, 28% were adenoma and 16% were carcinoma. Among the 16% malignant patients, majority of the patients had their age between 21-48 years. Histopathological types were mostly papillary (50%). Complications of surgery were mostly hoarseness of voice (5%), hematoma (4%), infection (2%) and hypoparathyroidism (3%). In this study, more malignant cases (20.83%) were found in cold solitary nodules. PMID- 26931248 TI - Morphometric Study of Nutrient Foramen in Adult Human Dry Left Humerus. AB - The major blood supply to long bones occurs through the nutrient arteries, which enter through the nutrient foramen. The supply of nutrient artery starts during the early phases of ossification. It is essential in operative procedures such as bone graft, tumour resection, trauma healing and bone transplant techniques both in orthopedics and micro vascular surgery. The present study is an observational analytic type of study which was performed on two hundred (n=200; male=117 & female=83) left sided dry humerus bones. In this present study the majority of the bones had a single nutrient foramen which may represent a single source of blood supply. The location of the nutrient foramen is predominant on the antero medial aspect of humerus. The position of the nutrient foramen is predominant on the middle 1/5th of the shaft humerus. There was no significant difference (p=0.319) in presence, absence, number, location and position of nutrient foramen in male and female left human humerus. This study and recorded data may help in surgical procedures in orthopedics and in micro vascular surgery. PMID- 26931249 TI - Comparison of Common Tonsillectomy Methods. AB - This prospective randomized study was done to compare operative time, intra operative blood loss, post operative pain, secondary haemorrhage in common tonsillectomy methods. Thirty two (32) paediatric population of age 7-12 years from each group randomly selected, operative techniques adopted consecutively and this study was conducted in Bangabandhu Sheikh Mujib Medical University, Dhaka, Islami Bank Hospital, Dhaka, and Desh Medical Services, Chittagong, from January 2011 to December 2013. Surgery was performed by single midlevel surgeon. Postoperatively one month was followed the entire patient. Total 96 pediatrics population (32 for each group) was studied. Mean operating time and mean intra operative blood loss was in cold dissection method 22 min and 15 ml, in bipolar dissection tonsillectomy 18 min and 10 ml & in laser tonsillectomy 17 min and 9 ml. Differences of operating time and variation of blood loss in various methods are not statistically significant. Laser and bipolar electro dissection tonsillectomy are popularized due to its relative less bleeding and quicker methods than that of cold dissection tonsillectomy; there is no significant difference among them. PMID- 26931250 TI - Mass Screening of Apolipoprotein B May Detect Young People at Risk of Acute Coronary Syndrome. AB - Incidence of acute coronary syndrome in young people is progressively increasing. Apolipoprotein B is now regarded as a nobel parameter over conventional lipid profile, predicting acute coronary syndrome. A case control study was carried out in Department of Cardiology of Mymensingh Medical College Hospital from June 2009 to May 2010. Total 50 cases of 18-45 years of age with first attack of acute coronary syndrome and 50 healthy controls of same age and sex distribution were studied. Of them 42(84.0%) of cases and 24(48%) of controls had hyper apoB condition. Mass screening of apolipoprotein B in apparently healthy young people may detect persons with hyper apoB status, who may develop acute coronary syndrome in future. PMID- 26931251 TI - Correlation of the Serum Level of Carcinoembryonic Antigen and Prolactin with Different Stages of Colorectal Carcinoma According to Dukes' Staging. AB - Carcinoembryonic antigen (CEA) is well established tumor marker for colorectal cancers worldwide. Recent studies show that serum prolactin level is also raised in colorectal cancers. The purpose of the study is to evaluate the correlation of serum CEA and Prolactin with Dukes' staging of colorectal carcinomas. Between January 2013 and June 2013, Serum CEA and Serum Prolactin were measured by radioimmunoassay from 103 patients who were histopathologically diagnosed as colorectal carcinomas. Evaluation of the stages of the colorectal cancers was done on the basis of preoperative investigations and postoperative histopathology and correlated with Preoperative Serum CEA and Serum Prolactin. Results were presented as median value, range and percentage. Male to female ratio was 1.4:1 with median age of 42.26 years (range 17-78 years). Most of the patients in this series presented with carcinoma rectum (42%). Most of the patients (52%) were found in Dukes' stage C and 27% and 15% cases were found as Dukes' stage B and Dukes' stage D respectively. Stage of the disease is directly proportionate to percentage of the patient with high serum prolactin except early stage (Dukes' A 50%, Dukes' B-28.6%, Dukes' C-33.3% & Dukes' D-46.7%). Similarly serum CEA level is directly proportionate to tumor stage (Dukes' A-0%, Dukes' B-32%, Dukes' C 40.7% & Dukes' D-74.7%). A preoperative high serum CEA value suggests advanced disease either locally or with distant metastasis. In contrast preoperative high serum prolactin (hyperprolactinaemia) did not suggest advanced disease as it can be elevated even in early stage of disease. Serum CEA and Serum Prolactin both are valuable tumor markers but serum CEA could not be replaced by serum Prolactin. Serum Prolactin may be a helpful marker in earlier stages of the colorectal cancer. PMID- 26931252 TI - Comparison of Success of Clomiphene citrate and Letrozole in Ovulation Induction. AB - The study was carried out to evaluate which drug is better in ovulation induction between clomiphene citrate and letrozole. The study was carried out in the infertility unit of Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka and Centre for Assisted Reproduction (CARE) at Bangladesh Institute of Research and Rehabilitation in Diabetes Endocrine and Metabolic Disorders (BIRDEM), Dhaka from January 2007 to December 2007. One hundred and sixty five cases were taken for the study. It was a prospective interventional comparative study of clomiphene citrate and letrozole in infertile cases. The patients were divided into three groups. Group I--newly detected cases of sub fertility studied with clomiphene citrate. Group II--clomiphene citrate resistant cases studied with letrozole, Group III--newly detected cases of sub fertility studied with letrozole. The cases were followed up for outcome; (ovulation). The TVS was done on 12th or 13th day of menstruation and level of serum progesterone on 21st day of menstrual cycle to see the evidence of ovulation. Endometrial thickness was also measured. The data was collected on a predesigned questionnaire. The variables that influenced the study were-age, occupation, socioeconomic status, menstrual cycle, marital age, parity, history of MR, history of abortion, past medical and surgical history. In the current study it was observed that the signs of ovulation were significantly (p<0.05) higher in Group I treated with clomiphene citrate in comparison to Group II clomiphene citrate resistant cases treated with letrozole. The rate of ovulation was higher in Group I than that of Group III treated with letrozole, but the difference was not statistically significant (p>0.05). The signs of ovulation were present in 45(81.8%) cases in Group I, 33(60.0%) cases in Group II and 37(67.3%) cases in Group III. This findings of the study suggested that clomiphene citrate is higher successful than letrozole though not statistically significant. Letrozole can be preferred in clomiphene citrate resistant cases before starting other expensive therapies. PMID- 26931253 TI - Prevalence and Symptom Correlation of Lactose Intolerance in the North East Part of Bangladesh. AB - This study was designed to see the prevalence of lactose intolerance and symptom correlation following oral lactose challenge in healthy volunteers in the north east part of Bangladesh. Symptoms of abdominal pain, nausea, borborygmi, flatulence, diarrhea and others were noted for 24 hours and blood glucose was estimated at 0 hour and 30 minutes after 50 gm oral lactose load to healthy volunteers. Failure to rise blood glucose level >=1.1 mmol/l at 30 minutes after lactose intake from fasting level was taken as lactose malabsorption (LM) i.e., lactose intolerance. Sensitivity and specificity of different symptoms were then found out. A total of 171 volunteers (male 123, female 48) with a mean age 34.08 years participated in this study. Lactose intolerance was found among 82.5% (n=141, M=100, F=41) subjects. Symptoms mostly experience by the lactose malabsorbers were diarrhea 93(66.0%), borborygmi 80(56.7%), abdominal pain 31(22.0%) and flatulence 32(22.7%). LM prevalence was found to increase with increasing number of symptoms up to 3 symptoms. A week positive correlation (r=0.205, P=0.007) was found between the number of symptoms and proportion of subjects having positive lactose tolerance test. Lactose intolerance among healthy adults of North East part of our country is as common as in other Asian countries including China and Malaysia. But LM is higher than that of Europeans and south Indians. Diarrhea and borborygmi were mostly associated with LM. PMID- 26931254 TI - The Aspect of NK2 Transcription Factor Related Locus-5 (NKX2.5) Gene Mutations in Bangladeshi Atrial Septal Defect (ASD) patients and 2D Relationship with their Age. AB - Atrial septal defect (ASD) is a developmental defect of the heart which arises from the congenital abnormality of interatrial septum that perturbs the normal blood flow. Development of the heart is a complex biological process regulated by numerous genetic and environmental factors. During this process DNA binding proteins Myocardin, NKX2.5 (NK2 Transcription Factor Related Locus-5) and GATA4 (GATA Binding Protein-4) function by binding to SRF (Serum Response Factor) which is also a key regulator of myogenic terminal differentiation and frequently results in mitogenesis. Several studies suggest that mutations in the homeodomain containing transcription factor, NKX2.5, is implicated with atrial septal defect. This cross sectional descriptive study was done to investigate the frequency of NKX2.5 gene mutations among the patient with ASD who were undergoing surgical repair at the National Institute of Cardiovascular Diseases (NICVD) and National Heart Foundation and Research Institute (NHF&RI), Dhaka from July 2010 to June 2011. Patients presented with ASD at any age of both sexes were selected as study population. We found six distinct polymorphic sites among Bangladeshi population. Among six polymorphic sites, two were located at position 487 and 495. These were present in around 80% of the affected individuals. However they were not present in control population. Our study also revealed that mutations present in the downstream sites or towards the end of the genes are restricted to older people, whereas mutations present towards the 5' site is common to population of all ages. This interesting relationship has encouraged us to raise two new hypotheses. PMID- 26931255 TI - Alanine Aminotransferase and Total Bilirubin Concentration in Preeclampsia and Eclampsia. AB - Eclampsia is an important cause of maternal mortality in developing countries. This cross-sectional comparative study was conducted in the Departments of Clinical Pathology, Bangabandhu Sheikh Mujib Medical University (BSMMU), and Obstetrics and Gynecology, BSMMU, and Dhaka Medical College Hospital, Dhaka, Bangladesh, from March 2012 to February 2013 and was designed to evaluate liver markers to predict preeclampsia. One hundred fifty (150) women with pregnancy of >=28 weeks, 50 for each normal, preeclampsia and eclampsia group, were enrolled purposively. The protocol was approved by IRB of BSMMU. Consent was taken from each patient. Serum total Bilirubin and ALT were assessed. Data was collected in a questionnaire and analyzed by SPSS-16. Quantitative data were compared by ANOVA or 't' test and qualitative data by chi-square test. P value <0.05 was considered significant. The patients of all groups were similar in age and gravida. The mean+/-SD serum total bilirubin and ALT were significantly higher in preeclampsia and eclampsia groups than normal pregnancy. However they were similar in preeclampsia and eclampsia group. PMID- 26931256 TI - Serum Prolactin Level of Subfertile Women. AB - Subfertility is a major reproductive health problem all over the world as well as Bangladesh, and the problem is increasing day by day. This study was done to estimate the serum prolactin concentration in primary and secondary subfertile women. Laboratory investigation included serum prolactin level, as well as LH, FSH, TSH blood glucose (2 hours after 75 gm glucose load) of 50 women who attended infertility unit, Department of Obstetrics and Gynaecology, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh from March 2009 and February 2010. In most cases, common age group 26-30 years (52%), primary subfertility (74%), duration of marriage >5 years (60%), trying to conceive duration <=5 years (54%), BMI >25 kg/m2 (60%), menstrual cycle regular (58%), history of abortion absent (90%), and history of menstrual regulation absent (94%). Common investigation findings was normal serum follicle stimulating hormone (FSH) 1.0-10.0 mIU/ml in 82%, normal serum luteinizing hormone (LH) 1.0 10.0 mIU/ml in 50%, normal serum prolactin 1.9-25.0 ng/ml in 36%, normal serum thyroid stimulating hormone (TSH) 0.4-4.0 MUIU/ml in 56%, and normal blood glucose level (2 hours after breakfast) (<7.8 mmol/) in 66% women. Ultrasonographic finding of lower abdomen was normal in 14% women. Common finding of semen analysis husbands of the study women was normozoospermia in 88% cases. Serum prolactin concentration may have role to play in subfertility of women. PMID- 26931257 TI - Clinical Profile of Early Childhood Epilepsy: A Cross Sectional Study in a Tertiary Care Hospital. AB - Epilepsy is one of the most common chronic neurological disorder in children. Incidence is highest in children less than 3 years of age. This cross sectional study was conducted at outpatient department of Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka from January 2010 to December 2010 to explore clinical profile of early childhood epilepsy. Total 50 Children with two or more unprovoked seizure after 28 days up to 36 months of age were included in this study. Majority cases were in the age group of 1 to 12 months (56%) with male predominance (78%). Onset of first seizures was found to be the highest at the age group 0-1 month (50%) with generalized seizures (66%) as the most common type of initial seizures. Highest 16(32%) patients presented with tonic clonic seizure followed by clonic seizure in 15(30%) and tonic in 11(22%) patients. Myoclonic seizure was found to be 4(8%). Only 4(8%) cases were presented with infantile spasm. Majority cases were associated with cerebral palsy (72%). Family history of epilepsy was present in 16%. EEG was done in all patients. Among them 62% were abnormal. Total 21 cases had done CT scan of brain. Among them 6(28.6%) were normal and 15(71.4%) were abnormal. The abnormal findings were cerebral atrophy 73.3%, ventricular dilatation 13.3%, encephalomalacia 6.7% and cerebral infractions were found in 26.7%. In this study majority of cases in 22(44%) were treated with Phenobarbitone (PHB) as a first line drug followed by Valproate (VPA) in 19(38%). Limited study has been conducted on early childhood epilepsy in Bangladesh. The result of this study might be helpful for further large scale study in the field of early childhood epilepsy. PMID- 26931258 TI - Celiac Disease in Patients Fulfilling the Rome III Criteria for Irritable Bowel Syndrome Attending Gastroenterology Department of A Tertiary Care Hospital in Bangladesh. AB - Irritable bowel syndrome (IBS) is a chronic gastrointestinal disorder that substantially affects patients' quality of life and is associated with a considerable drain of health-care resources and economic burden. But some IBS patients may have celiac disease that could be treated by gluten-free diet which will subsequently improve their quality of life. This study was done to see the prevalence of celiac disease among the IBS patients fulfilling Rome III criteria. The present cross-sectional study was conducted in the Department of Gastroenterology at BSMMU, Dhaka from July 2010 to September 2011. A total of 107 patients aged ranging between 16-60 years clinically labeled as IBS and fulfilled Rome III criteria were included as study sample. The test statistics used to analyze the data were descriptive statistics. The mean age of the patients was 31.5+/-10.3 years and male to female ratio was roughly 6:1. The mean duration of IBS was 32.0+/-2.1 months. All of the patients had abdominal discomfort or pain in the preceding 6 months and had a history of loose (mushy) or watery stool, 99.1% had pain or discomfort relieved with defaecation. The prevalence of diarrhoea was found in 78.5% and mixed 21.5% of the patients. About 5% of the patients had raised ESR and majority (86.9%) of the patients had normal level of hemoglobin. Ten (9%) of 107 patients were found positive for anti-t TG (IgA). These findings suggest that an around one-tenth of IBS especially diarrhoea predominant patients may have celiac disease who will respond to simple gluten free diet thus minimizing the morbidity and mortality. So, all clinically diagnosed IBS patients especially diarrhoea predominant cases should be suggested for the screening for celiac disease. PMID- 26931259 TI - Determination of Insulin Secretory Defect and Insulin Sensitivity in Type 2 Diabetic Subjects in Bangladesh. AB - Diabetes mellitus (DM) is defined as a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. This study was undertaken to explore the basic defect in type 2 diabetes patients in Bangladesh. This was an observational study with case control design, was conducted in the Biomedical Research Group, Research Division, Bangladesh Institute of Research and Rehabilitation in Diabetes, Endocrine Metabolic Disorders (BIRDEM), Dhaka, Bangladesh, during the period of July 2008 to June 2009. A total of 153 subjects were included in study of which 63 belonged to type 2 diabetes mellitus group and 90 were healthy controls. Fasting and 2 hours postprandial blood glucose, serum insulin, HOMA%B, HOMA%S, QuickI, Glucose /insulin ratio, TG were measured and age, BMI, WHR were recorded. Waist-hip ratio (WHR), was significantly higher in T2DM as compared to control subjects [WHR, mean+/-SD, 0.94+/-0.12 vs. 0.88+/-0.06, p<0.001]; Glucose and insulin ratio of T2DM was significantly higher as compared to control subject [Glu: Ins, Median (range) of 0.54 (0.17-2.33) vs. 0.37(0.06-1.52)]. Insulin secretion (HOMA%B) was significantly lower in diabetic as compared to control subjects [HOMA%B, median (range), 71(4.90-391) vs. 180(59-634) p<0.001]; The quantitative insulin sensitivity check Index (QUICKI) of diabetic subjects were significantly higher as compared to control [QUICKI median (range) 39.90(4.80-138.10) vs. 0.55(0.36 0.85), <0.001]. Triglyceride (TG) and cholesterol (Chol) were significantly higher [(mg/dl), (mean+/-SD), TG (142+/-80.14) vs. (142+/-80.14); Chol (189+/ 50.76) vs. (172+/-45), p=0.029] in T2DM as compared to control subjects. Those with diabetes showed significant association with insulin secretory defect (HOMA%B, p=0.006) and insulin resistance as assessed by GINR (p<0.001) and QuickI (p<0.001) but not by HOMA%S (p=0.127). The present data suggest that both insulin secretory defect and insulin sensitivity are present in T2 diabetic subjects of Bangladesh. PMID- 26931260 TI - Evaluation of Serum Ferritin Concentration in Mild and Severe Pre-Eclamptic Women. AB - Pre-eclampsia is one of the most important complications of pregnancy. About 16% of maternal death is associated with pre-eclampsia in Bangladesh. It is necessary to diagnose or to predict pre-eclampsia for minimizing maternal morbidity and mortality. This case control study was carried out in the department of Clinical Pathology, in collaboration with department of Obstetrics and Gynaecology, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, from March 2011 to February 2012 which included 20 mild pre-eclamptic and 20 severe pre-eclamptic patients and 30 gestation matched normotensive pregnant women within 28-40 weeks of gestation. Serum iron profile was measured and PBF was done to observe the association of higher concentration of serum ferritin, serum iron, percent saturation of total iron binding capacity, hemoglobin and lower level of total iron binding capacity, increased neutrophil count and decreased platelet count with pre-eclampsia. The mean serum ferritin concentration of mild pre-eclamptic group 99.91+/-7.84 ng/ml was 5 times and severe pre-eclamptic group 149.59+/ 13.75 ng/ml was 8 times higher than that of control group 18.47+/-2.03 ng/ml. The mean serum iron level of mild pre-eclamptic group was (114.45+/-8.72 MUg/dl) and in severe pre-eclamptic group was (174.35+/-13.59 MUg/dl) and control group was (72.64+/-4.72 MUg/dl) (p<0.05). The mean TIBC was higher and percent saturation was lower in control group than mild and severe pre-eclamptic group. The mean differences of iron parameters were statistically significant (p<0.05) among the three groups in ANOVA test. Both hemoglobin (gm/dl), total count of WBC and percentage of neutrophil were significantly higher (p<0.05) but platelet count was significantly lower in mild and severe pre-eclamptic group than normal control group. So higher concentration of serum ferritin, serum iron, percent saturation of total iron binding capacity and hemoglobin level increased and total iron binding capacity decreased in mild and severe pre-eclampsia than those of uncomplicated normal pregnancy. Pre-eclampsia is one of the most important complications of pregnancy. About 16% of maternal death is associated with pre eclampsia in Bangladesh. It is necessary to diagnose or to predict pre-eclampsia for minimizing maternal morbidity and mortality. This case control study was carried out in the department of Clinical Pathology, in collaboration with department of Obstetrics and Gynaecology, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, from March 2011 to February 2012 which included 20 mild pre-eclamptic and 20 severe pre-eclamptic patients and 30 gestation matched normotensive pregnant women within 28-40 weeks of gestation. Serum iron profile was measured and PBF was done to observe the association of higher concentration of serum ferritin, serum iron, percent saturation of total iron binding capacity, hemoglobin and lower level of total iron binding capacity, increased neutrophil count and decreased platelet count with pre-eclampsia. The mean serum ferritin concentration of mild pre-eclamptic group 99.91+/-7.84 ng/ml was 5 times and severe pre-eclamptic group 149.59+/-13.75 ng/ml was 8 times higher than that of control group 18.47+/-2.03 ng/ml. The mean serum iron level of mild pre-eclamptic group was (114.45+/-8.72 MUg/dl) and in severe pre-eclamptic group was (174.35+/ 13.59 MUg/dl) and control group was (72.64+/-4.72 MUg/dl) (p<0.05). The mean TIBC was higher and percent saturation was lower in control group than mild and severe pre-eclamptic group. The mean differences of iron parameters were statistically significant (p<0.05) among the three groups in ANOVA test. Both hemoglobin (gm/dl), total count of WBC and percentage of neutrophil were significantly higher (p<0.05) but platelet count was significantly lower in mild and severe pre eclamptic group than normal control group. So higher concentration of serum ferritin, serum iron, percent saturation of total iron binding capacity and hemoglobin level increased and total iron binding capacity decreased in mild and severe pre-eclampsia than those of uncomplicated normal pregnancy. PMID- 26931261 TI - Total Serum IgE Level Estimation in Asthma Patient and Healthy Volunteers in a Tertiary Care Hospital, Bangladesh. AB - A strong association between total serum Immunoglobulin E (IgE) levels, skin test reactivity to aeroallergens, and asthma phenotype was found in previous studies. The current study has been undertaken to observe the total serum IgE level in asthmatic patients compared with normal healthy volunteers (control) of Bangladeshi subjects and to see its prospect in diagnostic aid. This case-control study was carried out in the department of Respiratory Medicine of National Institute of Diseases of the Chest and Hospital (NIDCH), Dhaka during the period from July 2008 to June 2009. Four hundred & eight (408) cases (asthmatics matching age, sex and geographic location) and 478 controls (non-asthmatics matching age, sex and geographic location) were studied. The level of serum IgE was found more in asthma patients than control group which were 345.88 and 224.64 respectively (p<0.001). In both group, serum IgE level was more in male than female. There was wide variation in serum IgE level in both the asthma and control group (4.2 to 3471.0 iu/ml in asthma group and 1.2 to 1045.7 iu/ml in control). Considerable overlap has been observed between the IgE values of control and asthma group. Due to this overlap its diagnostic significance in allergic condition in Bangladeshi population seems to be limited. PMID- 26931263 TI - Correlation between Histopathological and Endoscopic Findings of Stomach Growth. AB - This study was carried out in the Department of Pathology of Islami Bank Hospital, Barisal to correlate between histopathological and endoscopic diagnosis of suspected malignant gastric lesions. A total of sixty six endoscopic biopsies were studied retrospectively, during the period from February 2011 to January 2014. The biopsies were retrieved using video-endoscope. These were transferred to a bottle containing 10% neutral formalin, processed and stained routinely with Haematoxylin and Eosin. Out of 66(100%) gastric endoscopic biopsies, 29(44%) were malignant. The correlation of endoscopic and histopathological diagnosis of these gastric lesions was 44%. Endoscopic examination and biopsy is a convenient procedure for accurate objective assessment of patients with symptoms of gastrointestinal tract. Endoscopy is incomplete without biopsy and histopathology is the gold standard for the diagnosis of endoscopically detected lesions. PMID- 26931262 TI - Pattern of Pulmonary Involvement and Outcome of Aspiration Pneumonia in Patients with Altered Consciousness Admitted in Dhaka Medical College Hospital. AB - Aspiration is well recognized as a cause of pulmonary disease and is not uncommon in patients with altered consciousness.The mortality rate of aspiration pneumonia is approximately 1% in outpatient setting and upto 25% in those requiring hospitalization. This study was done to see the pattern of pulmonary involvement and outcome of aspiration pneumonia in patients with altered consciousness admitted in medicine department of a tertiary care hospital in our country. This was a prospective observational study conducted among the 52 adult patients of aspiration pneumonia with altered consciousness admitted in the medicine department of Dhaka Medical College Hospital (DMCH), during June 2010 to December 2010. Aspiration pneumonia was confirmed by clinical examination and laboratory investigations. Hematologic measurements (TC of WBC, Hb%, ESR, platelet count), chest X-ray, blood gas analysis, blood urea, creatinine and random blood sugar, sputum for Gram staining, sputum for culture sensitivity and blood culture were done in all patients.Assessment of altered conscious patient was done by application of the Glasgow Coma Scale. Case record forms with appropriate questionnaire were filled for all patients. The mean+/-SD age was 57.42+/-13.63 years with ranged from 25 to 90 years. Out of 52 patients, 37(71.15%) patients were male and 15(28.85%) patients were female. Following aspiration 76.92% patients developed pneumonitis, 13.46% patients developed lung abscess and only 9.62% patients developed ARDS. Most (33) of the patients had opacity in right lower zone and 13 patients had opacity in the left lower zone, 6 patients had opacity in right mid zone. Only 10 patients had opacity in both lower zones. In this study overall mortality rate was 23%. If only one lobe was involved radiologically, mortality was 8.33%. If two or more lobes on one or both sides were involved, mortality was in the range of 25-91%. PMID- 26931264 TI - The Role of Selective Nerve Root Block in the Treatment of Lumbar Radicular Leg Pain. AB - The objective of this retrospective study was to investigate the clinical effectiveness of nerve root blocks (i.e., periradicular injection of Lidocaine and triamcinolone) for lumbar monoradiculopathy in patients with a mild neurological deficit in National Institute of Traumatology & Orthopaedic Rehabilitation (NITOR), Dhaka, Bangladesh from March 2014 to December 2014. We Included 24 patients (32-74 years) with a minor sensory/motor deficit and an unequivocal MRI finding (18 disc herniations, 6 foraminal stenosis) treated with a selective nerve root block. Based on the clinical and imaging findings, surgery (decompression of the nerve root) was justifiable in all cases. Seventeen patients (87%) had rapid (1-4 days) and substantial regression of pain, four required a repeat injection. Sixty percent (60%) of the patients with disc herniation or foraminal stenosis had permanent resolution of pain, so that an operation was avoided over an average of 6 months (2-9 months) follow-up. Nerve root blocks are very effective in the non-operative treatment of minor monoradiculopathy and should be recommended as the initial treatment of choice for this condition. PMID- 26931265 TI - Association of Oxidative Stress and Obesity with Insulin Resistance in Type 2 Diabetes Mellitus. AB - Oxidative stress occurs due to delicate imbalance between pro-oxidant and anti oxidant forces in our system. It has been found to be associated with many morbidities but its association with obesity and insulin resistance is still controversial. Here in our study we examined 167 patients of recent onset type 2 diabetes mellitus and 60 age sex matched non-diabetic control. Body Mass Index (BMI), abdominal circumference, fasting blood glucose, serum insulin and plasma Malondealdehyde (MDA, marker for oxidative stress) were measured in them. On the basis of BMI, subjects were divided into obese (BMI>=25) and non obese (BMI<25) groups. Insulin resistance scores were calculated by Homeostatic Model Assessment Insulin Resistance (HOMA-IR) method. Physical parameters (BMI, abdominal circumference) as well as levels of insulin and MDA were found to be significantly higher in subjects with diabetes than their non diabetic controls. The said parameters also showed significant difference in obese and non-obese sub groups. Insulin resistance score showed positive correlation with BMI, abdominal circumference, and plasma MDA, strength of association being highest with abdominal circumference. Plasma MDA was found to have positive correlation with physical parameters. Study concludes that, obesity mainly central type may predispose to insulin resistance and oxidative stress may be a crucial factor in its pathogenesis. Thus, oxidative stress may be the connecting link between obesity and type 2 diabetes mellitus, two on going global epidemics. PMID- 26931266 TI - Incomplete Pentalogy of Cantrell--A Case Report. AB - Cantrell's Pentalogy is a rare congenital malformation consists of supraumbilical abdominal wall defect, defect in the lower part of sternum, agenesis of anterior portion of diaphragm, an absence of the diaphragmatic part of the pericardium and intracardiac malformation. This case report presents a female neonate, who was born at 40 weeks of gestation weighing 2400 gm and was admitted 4 hours after delivery with the complaints of something coming out from chest. On physical examination her vital signs were within normal limit, she had a systolic murmur on heart at lower left sternal area and there was a vascular structure present on the upper part of abdomen which was pulsatile and pulsation was synchronized with cardiac pulsation. On investigation chest X-ray lateral view showed absence of lower part of sternum, echocardiography findings were different in different institutes. Echocardiography findings at Mymensingh medical college hospital (MMCH) were large VSD (Ventriculo septal defect), ASD (Atrial septal defect) and rotated heart. On colour Doppler ultrasonogram at MMCH showed there were VSD, ASD, and a small epigastric swelling which was vascular and appears to be attached to the apex of the heart. On the other hand echocardiography findings of LAB AID hospital in Dhaka were Dextrocardia, complete AV (atrio ventricular) canal defect, almost common atrium, almost single ventricle, common AV valve, double outlet right ventricle (DORV), Cortriatriatum, mild A-V valve regurgitation and severe pulmonary hypertension (PAH). Echocardiography was also done at national heart foundation hospital in Dhaka. Findings were situs solitus, mesocardia to dextrocardia, DORV, large VSD, mild mitral inflow, mild TR (triuspid regurgitation), good LV (left ventricle) and RV (right ventricle) systolic function. Cardiologists at Dhaka in Bangladesh were suggested for surgery. Then the patient was consulted at Naryan Institute of Cardiac Science, Chennai in India. Here echocardiography findings were dextroversion/dextrocardia, DILV (Double inlet left ventricle), large inlet VSD with bidirectional shunt, mild TR, severe PAH with good ventricular function. Cardiologists in India were given comment about this patient. This patient was highly risky for surgery. They advised medical treatment and requested to review after one year. By taking medical treatment patient condition is well except failure to thrive and cyanosis develops during feeding and crying according to the statement of guardian of the patient. This case has 3 criterias among the five criteria of Cantrell's Pentalogy. So, it is incomplete Pentalogy of Cantrell. PMID- 26931267 TI - A Rapid and Reliable End-To-End Anastomosis Technique for Emergency Vascular Surgery--A Case Report. AB - A 28 year old male presented to us with 8 hours old open fracture of distal shaft of left femur which was already stabilized with external fixator but had no palpable distal pulse both clinically and on doppler examination. He underwent a primary repair following limited segmental resection. Commonly end-to-end anastomosis techniques following transection of arteries include interrupted and continuous suturing with or without 'parachuting' of the vessel or graft. Here we offer a rapid and reliable technique with following advantages: i) operating system always towards the surgeon, ii) posterior row of suture placed as both ends are well visualized, iii) less chance of catching posterior wall, iv) flushing performed easily before completing anterior row suture. Upto 2nd post operative day anticoagulant used in the form of inj. Heparin 2500 IU subcutaneously 8 hourly and patient was discharged from hospital on 3rd post operative day with presence of good distal pulses both on clinical and Doppler examination. Fourteen days later, on follow up Duplex study showed normal arterial flow without any stenosis or occlusion. PMID- 26931268 TI - Neonatal Conjunctivitis Leading to Neonatal Sepsis--A Case Report. AB - Neonatal conjunctivitis is the most common occular disease in neonates. Most infections are acquired during vaginal delivery. In spite most of these cases are benign; some of them may progress to systemic complications like loss of vision if left untreated. The authors present a case of a newborn who developed late onset neonatal sepsis from E. coli positive conjunctivitis. The baby was treated with Injection Meropenem and Injection Amikacin for 10 days. The course was uneventful, after that baby responded well and discharged home on 24th day. PMID- 26931269 TI - Surgical Closure of Atrial Septal Defect with High Pulmonary Vascular Resistance- A Case Report. AB - We have reported a case of successful pericardial patch closure of atrial septal defect with high pulmonary vascular resistance in a 32 years aged male. Diagnosis was confirmed by Doppler Echocardiography, Cardiac catheterization and lung biopsy. Before starting (orally) bosentan pulmonary arterial pressure was 105 mm Hg and pulmonary vascular resistance was 8 wood's unit. Bosentan was started at a dosage of 125 mg per day (62.5 mg twice a day) for 4 months before operation in this case. Just day before operation pulmonary arterial pressure was 87 mm Hg. Bosentan lowered pulmonary arterial pressure and reversed remodeling of pulmonary arteries and allowed surgical correction. During the post operative course, partial pressure of oxygen was significantly decreased and bilateral radiolucent opacity was present in lower zone of both lungs. All these were managed successfully in postoperative period. This case report has demonstrated that surgical correction of an atrial septal defect is feasible but requires long time pre and post operative treatment with pulmonary vasodilators. PMID- 26931270 TI - The Castleman's Disease and Related Disorders--A Case Report. AB - Castleman's disease is a rare primary disease of the lymph nodes. Little is known about the management of the disease. Surgical treatment gives a very good result. What other modalities of treatment could be done is not yet established. The role of surgery gives good result and follow up evaluation is satisfactory. We found a solitary intra-abdominal mass of lymphoid hyperplasia with a histological diagnosis of Castlemans disease identified in the pathological data base. Unicentric disease was defined as it was a solitary mass. Clinical, Radiological and Laboratory data were analysed to evaluate treatment response. The patient also has related disorders as Acanthosis nigricans, Myoneuronal disorder as-MG and bronchiolitis. The patient diagnosed as angiofollicular hyperplasia (Castleman's disease). After evaluation patient under went surgical treatment, partial excision of tumor mass due to morbid adhesion with inferior vena cava. The patient becomes symptom free and lump disappears within 60 days of treatment. There was no recurrence of the disease after further evaluation. The author recommends that in Unicentric variant of Castlemans disease surgical resection of the tumor is curative. The unicentric tumour may be hyaline-vascular or hyaline vascular/ plasma cell type. Partial resection, Radiotherapy or observation alone may avoid excessive aggressive therapy. PMID- 26931271 TI - Methanol Induced Toxic Amblyopia--A Case Report. AB - A 28-year-old man, smoker having history of occasional alcohol intake--was admitted in the Department of Medicine, Bangabandhu Sheikh Mujib Medical University (BSMMU) with gradual diminution of vision in both eyes 10 days after consumption of homemade alcoholic beverage in a wedding ceremony. His initial acuity of vision was limited to no perception of light in right eye and hand movement in left eye. Fundus examination revealed pale optic discs in both eyes. The patient was treated with Injection Methylprednisolone 1000 mg intravenous slowly over 1 hour for 3 consecutive days. This was followed by oral prednisolone 60 mg daily for 14 days and then gradually tapered over 4 weeks. The patient also received Injection Hydroxycobalamine and Injection Folinic Acid for 2 weeks. On the 3rd day of treatment there was perception of light in the right eye and on the 10th day the visual acuity improved to hand movement. In the left eye, the visual acuity gradually improved to 6/60 on 3rd day and on 10th day improved to 6/24. Four weeks later, the visual acuity had recovered in both eyes to 6/18. Combination of intravenous and oral steroid along with vitamin B1 and folinic acid has been found effective in treating severe methanol induced optic neuropathy. PMID- 26931272 TI - Salt Losing Variety of Congenital Adrenal Hyperplasia--A Case Report. AB - Congenital adrenal hyperplasia is a genetic endocrinologic disorder. The severe classic form occurs in one in 15,000 births worldwide. Twenty-one-hydroxylase deficiency (21-OHD) is the most common cause in this autosomal recessive disease. It can cause virilization, ambiguous genitalia at birth and severe life threatening condition due to salt wasting. In this report we describe the clinical course of a male neonate presenting with lethargy, failure to thrive (FTT), genital pigmentation, electrolytes imbalance and high serum 17-hydroxy progesterone (17-OHP) level and subsequently diagnosed as Congenital Adrenal Hyperplasia. After the initial crises management, the child was continued on replacement therapy. During the follow up, he was found to grow appropriately and achieving normal milestones for age. PMID- 26931273 TI - Pericardial Tumor Presenting As Recurrent Pericardial Effusion--A Case Report. AB - Pericardial tumors are unusual and may be difficult to characterise with imaging. They manifest as large, non-contractile, solid masses within the pericardium. Presenting symptoms include heart failure, arrhythmias, sudden death, cyanosis and chest pain. But it can also present as recurrent pericardial effusion misdiagnosed as tuberculosis and other infectious causes. Accordingly a patient with pericardial mass (tumor) presented with recurrent pericardial effusion as a rare case. PMID- 26931274 TI - Hypogonadotropic Hypogonadism in a Boy with Myopathy. AB - Hypogonadism is seldom seen together with myopathy, although testosterone contributes to muscle strength. We present here a rare case of hypogonadotropic hypogonadism with myopathy in a 20 year old male. He had flaccid quadriparesis with raised creatinine phosphokinase. Hormone assays revealed low testosterone as well as low luteinising hormone and follicle stimulating hormone levels. Tests to exclude androgen deficiency should be carried out in male patients with myopathy. PMID- 26931275 TI - 'It's the little things that count': healthcare professionals' views on delivering dignified care: a qualitative study. AB - AIMS: To explore healthcare professionals' perspectives of dignified care and experiences of providing care. BACKGROUND: Although 'care' and dignity in care are seen as central to the delivery of good care by patients, families and professionals, we still lack a clear understanding of what these, often contested and elusive concepts, mean in the practice setting, particularly from the perspective of healthcare professionals. DESIGN: Interview based qualitative research design. METHODS: In-depth interviews were conducted with healthcare professionals working in four UK NHS trusts. Data were collected between June November 2012. Interviews were audio-recorded, transcribed and analysed using thematic analysis. FINDINGS: Forty-eight healthcare professionals took part in this interview based study. Two main themes that encapsulated how care and dignity in care is enacted by professionals were identified: focusing on the 'little' things that matter to both professionals and patients; and improving care by making poor care 'visible'. CONCLUSION: Our findings show that the 'little things' in care allow professionals to 'care for' but also 'care about' patients, suggesting that these two aspects of caring become intrinsically interlinked. Our findings also suggest that 'making poor care visible' challenges engrained and task rather than human focused care in a non-threatening way, which can be the catalyst for providing care that is caring and dignified. PMID- 26931278 TI - Porous inverse vulcanised polymers for mercury capture. AB - Supercritical carbon dioxide is used to generate macroporosity in an inverse vulcanised polymer, which shows excellent promise for enhanced mercury capture and filtration from water. PMID- 26931280 TI - Atomistic Simulation of Stacked Nucleosome Core Particles: Tail Bridging, the H4 Tail, and Effect of Hydrophobic Forces. AB - We report the first atomistic simulation of two stacked nucleosome core particles (NCPs), with an aim to understand, in molecular detail, how they interact, the effect of salt concentration, and how different histone tails contribute to their interaction, with a special emphasis on the H4 tail, known to have the largest stabilizing effect on the NCP-NCP interaction. We do not observe specific K16 mediated interaction between the H4 tail and the H2A-H2B acidic patch, in contrast with the findings from crystallographic studies, but find that the stacking was stable even in the absence of this interaction. We perform simulations with the H4 tail (partially/completely) removed and find that the region between LYS-16 and LYS-20 of the H4 tail holds special importance in mediating the inter-NCP interaction. Performing similar tail-clipped simulations with the H3 tail removed, we compare the roles of the H3 and H4 tails in maintaining the stacking. We discuss the relevance of our simulation results to the bilayer and other liquid-crystalline phases exhibited by NCPs in vitro and, through an analysis of the histone-histone interface, identify the interactions that could possibly stabilize the inter-NCP interaction in these columnar mesophases. Through the mechanical disruption of the stacked nucleosome system using steered molecular dynamics, we quantify the strength of inter-NCP stacking in the presence and absence of salt. We disrupt the stacking at some specific sites of internucleosomal tail-DNA contact and perform a comparative quantification of the binding strengths of various tails in stabilizing the stacking. We also examine how hydrophobic interactions may contribute to the overall stability of the stacking and find a marked difference in the role of hydrophobic forces as compared with electrostatic forces in determining the stability of the stacked nucleosome system. PMID- 26931279 TI - Differential Effects of Teriparatide and Zoledronic Acid on Bone Mineralization Density Distribution at 6 and 24 Months in the SHOTZ Study. AB - The Skeletal Histomorphometry in Patients on Teriparatide or Zoledronic Acid Therapy (SHOTZ) study assessed the progressive effects of teriparatide (TPTD) and zoledronic acid (ZOL) on bone remodeling and material properties in postmenopausal women with osteoporosis. Previously, we reported that biochemical and histomorphometric bone formation indices were significantly higher in patients receiving TPTD versus ZOL. Here we report bone mineralization density distribution (BMDD) results based on quantitative backscattered electron imaging (qBEI). The 12-month primary study was randomized and double blind until the month 6 biopsy, then open label. Patients (TPTD, n = 28; ZOL, n = 31) were then eligible to enter a 12-month open-label extension with their original treatment: TPTD 20 MUg/d (subcutaneous injection) or ZOL 5 mg/yr (intravenous infusion). A second biopsy was collected from the contralateral side at month 24 (TPTD, n = 10; ZOL, n = 10). In cancellous bone, ZOL treatment was associated at 6 and 24 months with significantly higher average degree of mineralization (CaMEAN, +2.2%, p = 0.018; +3.9%, p = 0.009, respectively) and with lower percentage of low mineralized areas (CaLOW , -34.6%, p = 0.029; -33.7%, p = 0.025, respectively) and heterogeneity of mineralization CaWIDTH (-12.3%, p = 0.003; -9.9%, p = 0.012, respectively), indicating higher mineralization density and more homogeneous mineral content versus TPTD. Within the ZOL group, significant changes were found in all parameters from month 6 to 24, indicating a progressive increase in mineralization density. In sharp contrast, mineralization density did not increase over time with TPTD, reflecting ongoing deposition of new bone. Similar results were observed in cortical bone. In this study, TPTD stimulated new bone formation, producing a mineralized bone matrix that remained relatively heterogeneous with a stable mean mineral content. ZOL slowed bone turnover and prolonged secondary mineralization, producing a progressively more homogeneous and highly mineralized bone matrix. Although both TPTD and ZOL increase clinical measures of bone mineral density (BMD), this study shows that the underlying mechanisms of the BMD increases are fundamentally different. (c) 2016 American Society for Bone and Mineral Research. PMID- 26931281 TI - Effect of intermittent feedback control on robustness of human-like postural control system. AB - Humans have to acquire postural robustness to maintain stability against internal and external perturbations. Human standing has been recently modelled using an intermittent feedback control. However, the causality inside of the closed-loop postural control system associated with the neural control strategy is still unknown. Here, we examined the effect of intermittent feedback control on postural robustness and of changes in active/passive components on joint coordinative structure. We implemented computer simulation of a quadruple inverted pendulum that is mechanically close to human tiptoe standing. We simulated three pairs of joint viscoelasticity and three choices of neural control strategies for each joint: intermittent, continuous, or passive control. We examined postural robustness for each parameter set by analysing the region of active feedback gain. We found intermittent control at the hip joint was necessary for model stabilisation and model parameters affected the robustness of the pendulum. Joint sways of the pendulum model were partially smaller than or similar to those of experimental data. In conclusion, intermittent feedback control was necessary for the stabilisation of the quadruple inverted pendulum. Also, postural robustness of human-like multi-link standing would be achieved by both passive joint viscoelasticity and neural joint control strategies. PMID- 26931282 TI - Dual-Color Fluorescence Imaging of Magnetic Nanoparticles in Live Cancer Cells Using Conjugated Polymer Probes. AB - Rapid growth in biological applications of nanomaterials brings about pressing needs for exploring nanomaterial-cell interactions. Cationic blue-emissive and anionic green-emissive conjugated polymers are applied as dual-color fluorescence probes to the surface of negatively charged magnetic nanoparticles through sequentially electrostatic adsorption. These conjugated polymers have large extinction coefficients and high fluorescence quantum yield (82% for PFN and 62% for ThPFS). Thereby, one can visualize trace amount (2.7 MUg/mL) of fluorescence labeled nanoparticles within cancer cells by confocal laser scanning microscopy. Fluorescence labeling by the conjugated polymers is also validated for quantitative determination of the internalized nanoparticles in each individual cell by flow cytometry analysis. Extensive overlap of blue and green fluorescence signals in the cytoplasm indicates that both conjugated polymer probes tightly bind to the surface of the nanoparticles during cellular internalization. The highly charged and fluorescence-labeled nanoparticles non-specifically bind to the cell membranes, followed by cellular uptake through endocytosis. The nanoparticles form aggregates inside endosomes, which yields a punctuated staining pattern. Cellular internalization of the nanoparticles is dependent on the dosage and time. Uptake efficiency can be enhanced three-fold by application of an external magnetic field. The nanoparticles are low cytotoxicity and suitable for simultaneously noninvasive fluorescence and magnetic resonance imaging application. PMID- 26931283 TI - Gene Variant Databases and Sharing: Creating a Global Genomic Variant Database for Personalized Medicine. AB - Revolutionary changes in sequencing technology and the desire to develop therapeutics for rare diseases have led to the generation of an enormous amount of genomic data in the last 5 years. Large-scale sequencing done in both research and diagnostic laboratories has linked many new genes to rare diseases, but has also generated a number of variants that we cannot interpret today. It is clear that we remain a long way from a complete understanding of the genomic variation in the human genome and its association with human health and disease. Recent studies identified susceptibility markers to infectious diseases and also the contribution of rare variants to complex diseases in different populations. The sequencing revolution has also led to the creation of a large number of databases that act as "keepers" of data, and in many cases give an interpretation of the effect of the variant. This interpretation is based on reports in the literature, prediction models, and in some cases is accompanied by functional evidence. As we move toward the practice of genomic medicine, and consider its place in "personalized medicine," it is time to ask ourselves how we can aggregate this wealth of data into a single database for multiple users with different goals. PMID- 26931284 TI - Low- and middle-income countries face many common barriers to implementation of maternal health evidence products. AB - OBJECTIVES: To explore similarities and differences in challenges to maternal health and evidence implementation in general across several low- and middle income countries (LMICs) and to identify common and unique themes representing barriers to and facilitators of evidence implementation in LMIC health care settings. STUDY DESIGN: Secondary analysis of qualitative data. SETTING: Meeting reports and articles describing projects undertaken by the authors in five LMICs on three continents were analyzed. Projects focused on identifying barriers to and facilitators of implementation of evidence products: five World Health Organization maternal health guidelines, and a knowledge translation strategy to improve adherence to tuberculosis treatment. Data were analyzed using thematic content analysis. RESULTS: Among identified barriers to evidence implementation, a high degree of commonality was found across countries and clinical areas, with lack of financial, material, and human resources most prominent. In contrast, few facilitators were identified varied substantially across countries and evidence implementation products. CONCLUSION: By identifying common barriers and areas requiring additional attention to ensure capture of unique barriers and facilitators, these findings provide a starting point for development of a framework to guide the assessment of barriers to and facilitators of maternal health and potentially to evidence implementation more generally in LMICs. PMID- 26931286 TI - Dave and Barbara Sackett in Oxford. PMID- 26931285 TI - GRADE Guidelines: 16. GRADE evidence to decision frameworks for tests in clinical practice and public health. AB - OBJECTIVES: To describe the grading of recommendations assessment, development and evaluation (GRADE) interactive evidence to decision (EtD) frameworks for tests and test strategies for clinical, public health, or coverage decisions. STUDY DESIGN AND SETTING: As part of the GRADE Working Group's DECIDE project, we conducted workshops, user testing with systematic review authors, guideline developers and other decision makers, and piloted versions of the EtD framework. RESULTS: EtD frameworks for tests share the structure, explicitness, and transparency of other EtD frameworks. They require specifying the purpose of the test, linked or related management, and the key outcomes of concern for different test results and subsequent management. The EtD criteria address test accuracy and assessments of the certainty of the additional evidence necessary for decision making. When there is no direct evidence of test effects on patient important outcomes, formal or informal modeling is needed to estimate effects. We describe the EtD criteria based on examples developed with GRADEpro (www.gradepro.org), GRADE's software that also allows development and dissemination of interactive summary of findings tables. CONCLUSION: EtD frameworks for developing recommendations and making decisions about tests lay out the sequential steps in reviewing and assessing the different types of evidence that need to be linked. PMID- 26931287 TI - David Sackett was one of a kind. PMID- 26931288 TI - The PROMIS satisfaction with social participation measures demonstrated responsiveness in diverse clinical populations. AB - OBJECTIVES: To conduct a longitudinal evaluation of Patient-Reported Outcomes Measurement Information System (PROMIS) social function measures (satisfaction with participation in social roles and satisfaction with participation in discretionary social activities) in English-speaking people with chronic health conditions. STUDY DESIGN AND SETTING: Adults receiving treatment for chronic heart failure (CHF), chronic obstructive pulmonary disease (COPD), chronic back pain, or depression completed PROMIS computer-based measures of social health at two time points approximately 3 months apart and global ratings of change. Linear mixed effects models and standardized response means were estimated for the two social function measures. RESULTS: A total of 599 people participated: 79 with stable COPD, 46 COPD exacerbation, 60 with CHF, 196 with depression, and 218 with back pain. Four groups experienced improvement over time, one (COPD stable) changed very little. Those who reported better global ratings of change in overall health experienced larger changes in social function than those who reported the same or worse global health. CONCLUSION: This study provided support for responsiveness to change for two PROMIS social function measures. These results provide further evidence of the PROMIS goal to enable comparable measurement of universally relevant symptoms and experiences that apply to people with a variety of diseases. PMID- 26931290 TI - David Sackett's legacy includes evidence-based mentorship. PMID- 26931289 TI - Clinical validity of PROMIS Depression, Anxiety, and Anger across diverse clinical samples. AB - OBJECTIVES: The purpose of this study was to evaluate the responsiveness to change of the PROMIS negative affect measures (depression, anxiety, and anger) using longitudinal data collected in six chronic health conditions. STUDY DESIGN AND SETTING: Individuals with major depressive disorder (MDD), back pain, chronic obstructive pulmonary disease (COPD), chronic heart failure (CHF), and cancer completed PROMIS negative affect instruments as computerized adaptive test or as fixed-length short form at baseline and a clinically relevant follow-up interval. Participants also completed global ratings of health. Linear mixed effects models and standardized response means (SRM) were estimated at baseline and follow-up. RESULTS: A total of 903 individuals participated (back pain, n = 218; cancer, n = 304; CHF, n = 60; COPD, n = 125; MDD, n = 196). All three negative affect instruments improved significantly for treatments of depression and pain. Depression improved for CHF patients (anxiety and anger not administered), whereas anxiety improved significantly in COPD groups (stable and exacerbation). Response to treatment was not assessed in cancer. Subgroups of patients reporting better or worse health showed a corresponding positive or negative average SRM for negative affect across samples. CONCLUSION: This study provides evidence that the PROMIS negative affect scores are sensitive to change in intervention studies in which negative affect is expected to change. These results inform the estimation of meaningful change and enable comparative effectiveness research. PMID- 26931291 TI - Content validity across methods of malnutrition assessment in patients with cancer is limited. AB - OBJECTIVE: To identify malnutrition assessment methods in cancer patients and assess their content validity based on internationally accepted definitions for malnutrition. STUDY DESIGN AND SETTING: Systematic review of studies in cancer patients that operationalized malnutrition as a variable, published since 1998. Eleven key concepts, within the three domains reflected by the malnutrition definitions acknowledged by European Society for Clinical Nutrition and Metabolism (ESPEN) and the American Society for Parenteral and Enteral Nutrition (ASPEN): A: nutrient balance; B: changes in body shape, body area and body composition; and C: function, were used to classify content validity of methods to assess malnutrition. Content validity indices (M-CVIA-C) were calculated per assessment method. Acceptable content validity was defined as M-CVIA-C >= 0.80. RESULTS: Thirty-seven assessment methods were identified in the 160 included articles. Mini Nutritional Assessment (M-CVIA-C = 0.72), Scored Patient-Generated Subjective Global Assessment (M-CVIA-C = 0.61), and Subjective Global Assessment (M-CVIA-C = 0.53) scored highest M-CVIA-C. CONCLUSION: A large number of malnutrition assessment methods are used in cancer research. Content validity of these methods varies widely. None of these assessment methods has acceptable content validity, when compared against a construct based on ESPEN and ASPEN definitions of malnutrition. PMID- 26931292 TI - Comparison of high-dimensional confounder summary scores in comparative studies of newly marketed medications. AB - OBJECTIVE: To compare confounding adjustment by high-dimensional propensity scores (hdPSs) and historically developed high-dimensional disease risk scores (hdDRSs) in three comparative study examples of newly marketed medications: (1) dabigatran vs. warfarin on major hemorrhage; (2) on death; and (3) cyclooxygenase 2 inhibitors vs. nonselective nonsteroidal anti-inflammatory drugs on gastrointestinal bleeds. STUDY DESIGN AND SETTING: In each example, we constructed a concurrent cohort of new and old drug initiators using US claims databases. In historical cohorts of old drug initiators, we developed hdDRS models including investigator-specified plus empirically identified variables and using principal component analysis and lasso regression for dimension reduction. We applied the models to the concurrent cohorts to obtain predicted outcome probabilities, which we used for confounding adjustment. We compared the resulting estimates to those from hdPS. RESULTS: The crude odds ratio (OR) comparing dabigatran to warfarin was 0.52 (95% confidence interval: 0.37-0.72) for hemorrhage and 0.38 (0.26-0.55) for death. Decile stratification yielded an OR of 0.64 (0.46-0.90) for hemorrhage using hdDRS vs. 0.70 (0.49-1.02) for hdPS. ORs for death were 0.69 (0.45-1.06) and 0.73 (0.48-1.10), respectively. The relative performance of hdDRS in the cyclooxygenase-2 inhibitors example was similar. CONCLUSION: hdDRS achieved similar or better confounding adjustment compared to conventional regression approach but worked slightly less well than hdPS. PMID- 26931293 TI - Change score or follow-up score? Choice of mean difference estimates could impact meta-analysis conclusions. AB - OBJECTIVES: In randomized controlled clinical trials, continuous outcomes are typically measured at both baseline and follow-up, and mean difference could be estimated using the change scores from baseline or the follow-up scores. This study assesses the impact of using change score vs. follow-up score on the conclusions of meta-analyses. STUDY DESIGN AND SETTING: A total of 63 meta analyses from six comparative effectiveness reviews were included. The combined mean difference was estimated using a random-effects model, and we also evaluated whether the impact qualitatively varied by alternative random-effects estimates. RESULTS: Based on the Dersimonian-Laird (DL) method, using the change vs. the follow-up score led to five meta-analyses (7.9%) showing discrepancy in conclusions. Based on the profile likelihood (PL) method, nine (14.3%) showed discrepancy in conclusions. Using change score was more likely to show a significant difference in effects between interventions (DL method: 4 of 5; PL method: 7 of 9). A significant difference in baseline scores did not necessarily lead to discrepancies in conclusions. CONCLUSIONS: Using the change vs. the follow-up score could lead to important discrepancies in conclusions. Sensitivity analyses should be conducted to check the robustness of results to the choice of mean difference estimates. PMID- 26931294 TI - Introduction: PROMIS a first look across diseases. PMID- 26931295 TI - Revering the irreverent. PMID- 26931297 TI - An observational case series on dermatoscopic patterns of fading melanocytic naevi. AB - BACKGROUND/OBJECTIVES: The prevalence of melanocytic naevi falls with age. It has been postulated that this could be due to spontaneous involution (fading). Our objective was to provide dermatoscopic evidence of fading naevi and to describe the patterns of fading observed. METHODS: Serial dermatoscopic images of naevi demonstrating fading were collected from a set of 25 000 images. Any naevi that showed significant fading, as compared to previous imaging of the same lesion, were included in the analysis. RESULTS: A total of 47 naevi in 21 patients were found to have significantly faded over a span of 2-11 years. The dermatoscopic fading was observed to occur in two patterns. The most common pattern observed was generalised fading (n = 45), where fading was present over all the naevus. There were two cases of focal fading (n = 2) where fading was present only over one area of the naevus. CONCLUSIONS: Fading melanocytic naevi are uncommon. Melanocytic naevi fade in recognisable patterns, with generalised fading most commonly observed in our series. PMID- 26931296 TI - Evidence from diverse clinical populations supported clinical validity of PROMIS pain interference and pain behavior. AB - OBJECTIVE: To evaluate clinical validity, including responsiveness, of Patient Reported Outcomes Measurement Information System (PROMIS) pain interference (PROMIS-PI) and pain behavior (PROMIS-PB) T-scores. STUDY DESIGN AND SETTING: Data were aggregated from longitudinal studies of cancer, chronic low back pain (cLBP), rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), and major depressive disorder (MDD). Linear mixed-effects models were used to compare baseline score differences and score changes over time. We calculated standardized response means (SRMs) for subgroups defined by self-reported change in general health and pain. RESULTS: A total of 1,357 individuals participated at baseline and 1,225 at follow-up. Hypotheses of significant change in PROMIS-PI and PROMIS-PB scores were supported in the intervention groups (cLBP and MDD). Differences in baseline scores for COPD exacerbators compared to stable COPD patients were in the hypothesized direction but were not statistically significant. Subgroups reporting better health showed corresponding negative SRM values supporting responsiveness of T-scores to improvement. Responsiveness to decrements was supported in some but not all clinical groups and varied by anchor. More congruent values were obtained when using a pain-specific anchor. CONCLUSION: This study provides evidence that PROMIS-PI and PROMIS-PB scores are sensitive to changes in pain in studies of interventions expected to impact pain. The results inform estimation of meaningful change and support power analyses for comparative effectiveness research. PMID- 26931298 TI - Preparation and Characterization of a Polymer-Based "Molecular Accordion". AB - A urethane-based polymer material, denoted HDI-1, was obtained from the addition reaction of beta-cyclodextrin (beta-CD) with 1,6-hexamethylene diisocyanate (HDI) at the 1:1 mole ratio. In aqueous solution and ambient temperature conditions, HDI-1 adopts a compact (coiled) morphology where the cross-linker units become coiled and are partially self-included in the annular hydroxyl (interstitial) region of beta-CD. As the temperature is raised or as p-nitrophenol (PNP) was included within the beta-CD cavity and the noninclusion sites of the polymer, an extended (uncoiled) morphology was adopted. The equilibrium distribution between the extended and the compact forms of HDI-1 is thermally and chemically switchable, in accordance with the hydration properties and host-guest chemistry of this responsive polymer system. The molecular structure of this water-soluble urethane polymer and its host-guest complexes with PNP were investigated using spectroscopic (Raman, (1)H NMR, induced circular dichroism), dynamic light scattering (DLS), and calorimetric (DSC) methods in aqueous solution at ambient pH, and compared with native beta-CD. This study reports on the unique supramolecular properties of a polymer that resembles a thermally and chemically responsive "molecular accordion". PMID- 26931299 TI - The fetal ovary exhibits temporal sensitivity to a 'real-life' mixture of environmental chemicals. AB - The development of fetal ovarian follicles is a critical determinant of adult female reproductive competence. Prolonged exposure to environmental chemicals (ECs) can perturb this process with detrimental consequences for offspring. Here we report on the exposure of pregnant ewes to an environmental mixture of ECs derived from pastures fertilized with sewage sludge (biosolids): a common global agricultural practice. Exposure of pregnant ewes to ECs over 80 day periods during early, mid or late gestation reduced the proportion of healthy early stage fetal follicles comprising the ovarian reserve. Mid and late gestation EC exposures had the most marked effects, disturbing maternal and fetal liver chemical profiles, masculinising fetal anogenital distance and greatly increasing the number of altered fetal ovarian genes and proteins. In conclusion, differential temporal sensitivity of the fetus and its ovaries to EC mixtures has implications for adult ovarian function following adverse exposures during pregnancy. PMID- 26931300 TI - Allergens of Arachis hypogaea and the effect of processing on their detection by ELISA. AB - Food allergies are an emerging public health problem in industrialized areas of the world. They represent a considerable health problem in these areas because of the relatively high number of reported cases. Usually, food allergens are proteins or glycoproteins with a molecular mass ranging from 10 to 70 kDa. Among the food allergies, peanut is accounted to be responsible for more than 50% of the food allergy fatalities. Threshold doses for peanut allergenic reactions have been found to range from as low as 100 ug to 1 g of peanut protein, which equal to 400 ug to 4 g peanut meal. Allergens from peanut are mainly seed storage proteins that are composed of conglutin, vicilin, and glycinin families. Several peanut proteins have been identified to induce allergic reactions, particularly Ara h 1-11. This review is mainly focused on different classes of peanut allergens, the effect of thermal and chemical treatment of peanut allergens on the IgY binding and detectability of these allergens by enzyme linked immunosorbent assay (ELISA) to provide knowledge for food industry. PMID- 26931301 TI - Autonomy dimensions and care seeking for delivery in Zambia; the prevailing importance of cluster-level measurement. AB - It is widely held that decisions whether or when to attend health facilities for childbirth are not only influenced by risk awareness and household wealth, but also by factors such as autonomy or a woman's ability to act upon her own preferences. How autonomy should be constructed and measured - namely, as an individual or cluster-level variable - has been less examined. We drew on household survey data from Zambia to study the effect of several autonomy dimensions (financial, relationship, freedom of movement, health care seeking and violence) on place of delivery for 3200 births across 203 rural clusters (villages). In multilevel logistic regression, two autonomy dimensions (relationship and health care seeking) were strongly associated with facility delivery when measured at the cluster level (OR 1.27 and 1.57, respectively), though not at the individual level. This suggests that power relations and gender norms at the community level may override an individual woman's autonomy, and cluster-level measurement may prove critical to understanding the interplay between autonomy and care seeking in this and similar contexts. PMID- 26931302 TI - A randomized trial of high-dairy-protein, variable-carbohydrate diets and exercise on body composition in adults with obesity. AB - OBJECTIVE: This study determined the effects of 16-week high-dairy-protein, variable-carbohydrate (CHO) diets and exercise training (EXT) on body composition in men and women with overweight/obesity. METHODS: One hundred and eleven participants (age 47 +/- 6 years, body mass 90.9 +/- 11.7 kg, BMI 33 +/- 4 kg/m(2) , values mean +/- SD) were randomly stratified to diets with either: high dairy protein, moderate CHO (40% CHO: 30% protein: 30% fat; ~4 dairy servings); high dairy protein, high CHO (55%: 30%: 15%; ~4 dairy servings); or control (55%: 15%: 30%; ~1 dairy serving). Energy restriction (500 kcal/day) was achieved through diet (~250 kcal/day) and EXT (~250 kcal/day). Body composition was measured using dual-energy X-ray absorptiometry before, midway, and upon completion of the intervention. RESULTS: Eighty-nine (25 M/64 F) of 115 participants completed the 16-week intervention, losing 7.7 +/- 3.2 kg fat mass (P < 0.001) and gaining 0.50 +/- 1.75 kg lean mass (P < 0.01). There was no difference in the changes in body composition (fat mass or lean mass) between groups. CONCLUSIONS: Compared to a healthy control diet, energy-restricted high protein diets containing different proportions of fat and CHO confer no advantage to weight loss or change in body composition in the presence of an appropriate exercise stimulus. PMID- 26931303 TI - Celiac crisis in children in Serbia. AB - BACKGROUND: To assess the prevalence and risk factors of celiac crisis (CC) in children with classical celiac disease (CD). METHODS: This retrospective study comprised 367 children with classical CD diagnosed from 1994 to 2015. The diagnosis of CD was based on the revised ESPGHAN criteria and CC on acute worsening and rapid progression of chronic diarrhea and vomiting followed by severe dehydration, multiple metabolic derangements and a marked decrease of body weight. RESULTS: Celiac crisis was confirmed in six (1.63 %) children, five in the first and one in the second year of life. In three patients CC was precipitated by rotavirus and in one by Salmonella enteritidis infection, while in the remaining two, except for a too long-standing disease and severe malnutrition, no additional causes of CC were found. CONCLUSION: Celiac crisis in Serbia is still-present in children exclusively below the second year of life as a spontaneous or intestinal infection precipitated complication of previously unrecognized CD. PMID- 26931304 TI - The Facial Appearance Inventory: Development and Preliminary Evidence for Reliability and Validity in People with HIV and Lipoatrophy. AB - BACKGROUND: Facial lipoatrophy is common in people on antiretroviral (ARV) regimens for HIV/AIDS and can impair health-related quality of life. OBJECTIVES: We developed the Facial Appearance Inventory (FAI) to measure the impact of ARV associated facial lipoatrophy. METHODS: Qualitative methods were used to identify key concerns of people with facial lipoatrophy. The major concerns were used to identify 24 items for the FAI. The FAI was administered to a cross-sectional sample of 96 people with HIV and facial lipoatrophy and compared to the established Assessment of Body Change Distress (ABCD) and MOS-HIV questionnaires. RESULTS: Mean age was 48.8 years, 87.5% were men, 69.8% were Caucasian, and 60% had some college education. Mean CD4 count was 435 cells/mm(3). There were few missing data, and the summary score showed no floor or ceiling effects, with a mean (SD) of 25.6 (17.9). Cronbach's alpha for the scale was 0.98. FAI items satisfied criteria for convergent and discriminant construct validity. FAI items were more strongly correlated with mental health domains (R = 0.33) than with physical health domains (R = 0.26) on the MOS-HIV. Patients with greater severity of lipoatrophy had significantly worse scores than those with less severity (James 3-4, vs. James 0-2). There were no significant differences for FAI scores by age group, income group, CD4 cell count, or HIV viral load group. Those with less education and those with darker skin types reported less impairment (P < .05). CONCLUSIONS: The 24-item FAI shows evidence for reliability, validity, and usefulness as a measure of the impact of facial lipoatrophy. PMID- 26931305 TI - Commentary on: SMAS Fusion Zones Determine the Subfacial and Subcutaneous Anatomy of the Human Face: Fascial Spaces, Fat Compartments, and Models of Facial Aging. PMID- 26931306 TI - Total Composite Flap Facelift and the Deep-Plane Transition Zone: A Critical Consideration in SMAS-Release Midface Lifting. AB - BACKGROUND: Recent anatomic studies suggest the superficial musculoaponeurotic system (SMAS) layer attenuates in the midface. This led the author to switch from a bilamellar high SMAS dissection to a "total composite flap" technique, preserving skin and SMAS/platysma as one layer in a critical "deep-plane transition zone" (DTZ) lateral to the zygomaticus major muscle. This allows traction on the SMAS to translate to the malar fat pad via a "cantilever bridge" effect, which is lost when skin is undermined in the DTZ. OBJECTIVES: This paper attempts to answer the question of whether the composite flap or bilamellar technique better lifts the midface, comparing groups where the DTZ was undermined: (1) only at a sub-SMAS level; or (2) at both subcutaneous and sub SMAS levels. METHODS: Thirty-five patients underwent bilamellar facelifts with skin and SMAS separated in the DTZ. Midfacial elevation was measured using size matched preoperative and 18-month (average) postoperative photographs for the 70 hemi-midfaces. The same analysis was done for 35 patients undergoing total composite flap facelift, maintaining skin and SMAS as one layer in the DTZ. The two groups were compared. RESULTS: In the bilamellar group, the mean percentage of midfacial elevation at 18 months postoperative was 5.5% (range, 0.0%-17.8%). In the composite flap group, the percentage was 11.7% (range, 0.1%-32.3%). The difference was statistically significant. CONCLUSIONS: Maintaining skin-SMAS attachments in the DTZ improves midface elevation during SMAS facelifting, exploiting a "cantilever bridge" effect of the skin transferring traction on the SMAS to the malar fat pad. PMID- 26931307 TI - Commentary on: Improvements in Vertebral-Column Angles and Psychological Metrics After Abdominoplasty with Rectus Plication. PMID- 26931308 TI - Am I Too Old To Do This Anymore? PMID- 26931309 TI - Alloplastic Augmentation of the Asian Face: A Review of 215 Patients. AB - BACKGROUND: Asian aesthetic surgery has become increasingly popular over the last decade, especially augmentation of characteristically flattened facial features. Alloplastic implants are an option for facial augmentation, however many avoid their use due to concerns for morbidity associated with their use. OBJECTIVES: To validate our hypothesis that when used properly, alloplastic implants have a low complication profile and provides excellent aesthetic results. METHODS: A retrospective review was performed of all Asian patients undergoing alloplastic facial augmentation between 2009 and 2013 by a single surgeon. Procedures included augmentation of the forehead, nasal dorsum, midface, and chin. Charts were reviewed for outcomes including infection, extrusion, malposition, and operative revision. RESULTS: Two hundred and fifteen patients had 243 implants placed. Of 141 nasal augmentations, there were 2 infections (1.4%), 1 extrusion (0.7%), 7 malpositions (4.9%), and 16 revisions (11.3%), 5 for malposition, 2 for contour irregularity, and 9 for aesthetic change. Augmentation genioplasty was performed in 40 patients with 1 malposition (2.5%) and 6 revisions (15%), 4 for under-correction and 2 for aesthetic change. Thirty-one midface and 31 forehead augmentations were performed without complications. One patient (3.2%) had forehead implant removal for aesthetic change. Overall infection and extrusion rates were 0.8% and 0.4%, respectively. CONCLUSIONS: By utilizing surgical techniques such as creation of a precise sub-periosteal pocket, placing the implant away from the incision site, and leaving well-vascularized soft tissue coverage under minimal tension, alloplastic implants can safely be used as a first-line option for Asian facial augmentation. LEVEL OF EVIDENCE: 4 Therapeutic. PMID- 26931310 TI - Commentary on: Total Composite Flap Facelift and the Deep-Plane Transition Zone: A Critical Consideration in SMAS-Release Midface Lifting. PMID- 26931311 TI - Responsiveness of beef cattle (Bos taurus) to human approach, novelty, social isolation, restraint and trade-offs between feeding and social companionship. AB - This study investigated responsiveness of beef cattle to various environmental stimuli by subjecting 15-16 Japanese Black cows to five tests repeated twice. Within individual behavioral measures, cows were moderately (repeatability = 0.54 0.70) or highly (repeatability = 0.74-0.89) consistent in flight distance during grazing and resting in the human approach tests, maximum distance from the group pen and the number of total and different feed tub visits in the feeding sociability trade-off test, and unwillingness to enter the restraint, movement under restraint and flight speed after release from restraint in the social isolation and restraint test. By contrast, cows were not consistent in the latency to make the first contact and the number of contacts with novel object(s) in the novelty test (repeatability = 0.24-0.39). Across behavioral measures in different tests, cows showed no consistency (P >= 0.05) in any combinations of measures from the two human approach tests, the trade-off test and the social isolation and restraint test. In conclusion, human approach (particularly during resting), feeding-sociability trade-off and social isolation and restraint situations can be used for evaluating personality in Japanese Black cows, while the value of the novelty test needs to be reexamined. PMID- 26931312 TI - Mixed-Valent Mn16-Containing Heteropolyanions: Tuning of Oxidation State and Associated Physicochemical Properties. AB - The two 16-manganese-containing, Keggin-based 36-tungsto-4-silicates [Mn(III)10Mn(II)6O6(OH)6(PO4)4(A-alpha-SiW9O34)4](28-) (1) and [Mn(III)4Mn(II)12(OH)12(PO4)4(A-alpha-SiW9O34)4](28-) (2) have been prepared by reaction of the trilacunary Keggin precursor [A-alpha-SiW9O34](10-) with either Mn(OOCCH3)3.2H2O (for 1) or MnCl2.4H2O (for 2), in aqueous phosphate solution at pH 9. Polyanions 1 and 2 comprise mixed-valent, cationic {Mn(III)10Mn(II)6O6(OH)6}(24+) and {Mn(III)4Mn(II)12(OH)12}(24+) cores, respectively, encapsulated by four phosphate groups and four {SiW9} units in a tetrahedral fashion. Both polyanions were structurally and compositionally characterized by single-crystal XRD, IR, thermogravimetric analysis, and X-ray absorption spectroscopy. Furthermore, studies were performed probing the magnetic, electrochemical, oxidation catalytic, and Li-ion battery performance of 1 and 2. PMID- 26931314 TI - Focusing on the Medicine in Dental Medicine. PMID- 26931313 TI - A cross-sectional internet-based patient survey of the management strategies for gout. AB - BACKGROUND: Almost half of the patients with gout are not prescribed urate lowering therapy (ULT) by their health care provider and >50 % use complementary and alternative therapies. Diet modification is popular among gout patients due to known associations of certain foods with gout flares. The interplay of the use of dietary supplements, diet modification, and ULT adherence in gout patients is not known. Despite the recent interest in diet and supplements, there are limited data on their use. Our objective was to assess ULT use and adherence and patient preference for non-pharmacological interventions by patients with gout, using a cross-sectional survey. METHODS: People who self-reported physician-diagnosed gout during their visit to a gout website ( http://gouteducation.org ) were invited to participate in a brief anonymous cross-sectional Internet survey between 08/11/2014 to 04/14/2015 about the management of their gout. The survey queried ULT prescription, ULT adherence, the use of non-pharmacological interventions (cherry extract, diet modification) and the likelihood of making a lifelong diet modification for gout management. RESULTS: A total of 499 respondents with a mean age 56.3 years were included; 74% were males and 74% were White. Of these, 57% (285/499) participants were prescribed a ULT for gout, of whom 88% (251/285) were currently taking ULT. Of those using ULT, 78% (97/251) reported ULT adherence >80%. Gender, race, and age were not significantly associated with the likelihood of receiving a ULT prescription or ULT adherence >80%. Fifty-six percent of patients with gout preferred ULT as a lifelong treatment for gout, 24% preferred cherry extract and 16% preferred diet modification (4% preferred none). Men had significantly lower odds of preferring ULT as the lifelong treatment choice for gout vs. other choices (p = 0.03). We found that 38.3% participants were highly motivated to make a lifelong dietary modification to improve their gout (score of 9-10 on a 0-10 likelihood scale). Older age was significantly associated with high level of willingness to modify diet (p = 0.02). CONCLUSION: We found that only 57% of gout patients reported being prescribed ULT. 40% of gout patients preferred non- pharmacological interventions such as cherry extract and diet modification for gout management. The latter finding requires further investigation. PMID- 26931315 TI - Evolution of procalcitonin, C-reactive protein and fibrinogen levels in neutropenic leukaemia patients with invasive pulmonary aspergillosis or mucormycosis. AB - Unlike bacterial infections, the value of procalcitonin (PCT) in detecting fungal infections in leukaemia patients is not clear. To determine whether the monitoring of PCT coupled with C-reactive protein (CRP) and fibrinogen (Fib) could be helpful in the management of pulmonary aspergillosis (IPA) or mucormycosis (PM), we retrospectively analysed the evolution of PCT, CRP and Fib levels in 94 leukaemia patients with proven/probable IPA (n = 77) or PM (n = 17) from D-12 to D12 relative to IFI onset defined as D0. Overall, 2140 assays were performed. From D-12 to D0, 12%, 5% and 1.4% of patients had PCT >0.5, 1 and 1.5 MUg l(-1) , respectively, while CRP was >50, 75 and 100 mg l(-1) in 84%, 70% and 57% and Fib was >4, 5 and 6 g l(-1) in 96%, 80% and 61% of cases respectively (P < 10(-7) ). The same trends were observed from D1 to D12. Overall, between D-12 and D12, only 6.4% of patients had PCT >1.5 MUg l(-1) , while CRP >100 mg l(-1) and Fib >6 g l(-1) were observed in 80% and 75% of cases respectively (P < 10(-7) ). In leukaemia patients, IPA or PM was accompanied by a significant increase in CRP and Fib while PCT remained low. PMID- 26931317 TI - Metabolism: Restoring brown fat commitment. PMID- 26931316 TI - Acid-sensing ion channels are tuned to follow high-frequency stimuli. AB - KEY POINTS: Acid-sensing ion channels (ASICs) act as neurotransmitter receptors by responding to synaptic cleft acidification. We investigated how ASIC1a homomers and ASIC1a/2a heteromers respond to brief stimuli, jumping from pH 8.0 to 5.0, approximating the time course of neurotransmitter in the cleft. We find that ASICs deactivate surprisingly fast in response to such brief stimuli from pH 8.0 to 5.0, whereas they desensitize comparatively slowly to prolonged activation. The combination of unusually fast deactivation with slow desensitzation enables recombinant ASIC1a homomers and ASIC1a/2a heteromers, as well as native ASICs of sensory neurons, to follow trains of such brief pH 8.0 to 5.0 stimuli at high frequencies. This capacity for high-frequency signalling persists under a physiological pH of 7.4 with ASIC1a/2a heteromers, suggesting that they may sustain postsynaptic responses when other receptors desensitize. ABSTRACT: The neurotransmitter-gated ion channels that underlie rapid synaptic transmission are often subjected to bursts of very brief neurotransmitter release at high frequencies. When challenged with such short duration high-frequency stimuli, neurotransmitter-gated ion channels generally exhibit the common response of desensitization. Recently, acid-sensing ion channels (ASICs) were shown to act as neurotransmitter-gated ion channels because postsynaptic ASICs can be activated by the transient acidification of the synaptic cleft accompanying neurotransmission. In the present study, we examined the responses of recombinant ASIC1a homomers, ASIC1a/2a heteromers and native ASICs from sensory neurons to 1 ms acidification stimuli, switching from pH 8.0 to 5.0, as either single pulses or trains of pulses at physiologically relevant frequencies. We found that ASIC deactivation is extremely fast and, in contrast to most other neurotransmitter-gated ion channels, ASICs show no desensitization during high frequency stimulus trains under these conditions. We also found that accelerating ASIC desensitization by anion substitution can induce depression during high frequency trains. When using a baseline physiological pH of 7.4, the ASIC1a responses were too small to reliably measure, presumably as a result of steady state desensitization. However, ASIC1a/2 heteromers gave robust responses when using a baseline pH of 7.4 and were also able to sustain these responses during high-frequency stimulus trains. In conclusion, we report that the slow desensitization and fast deactivation of ASIC1a/2a heteromers enables them to sustain postsynaptic responses to bursts at high frequencies at a physiological pH that may desensitize other receptors. PMID- 26931318 TI - Cancer biology: TGFbeta and EMT as double agents. PMID- 26931320 TI - Metabolic engineering of astaxanthin biosynthesis in maize endosperm and characterization of a prototype high oil hybrid. AB - Maize was genetically engineered for the biosynthesis of the high value carotenoid astaxanthin in the kernel endosperm. Introduction of a beta-carotene hydroxylase and a beta-carotene ketolase into a white maize genetic background extended the carotenoid pathway to astaxanthin. Simultaneously, phytoene synthase, the controlling enzyme of carotenogenesis, was over-expressed for enhanced carotenoid production and lycopene epsilon-cyclase was knocked-down to direct more precursors into the beta-branch of the extended ketocarotenoid pathway which ends with astaxanthin. This astaxanthin-accumulating transgenic line was crossed into a high oil- maize genotype in order to increase the storage capacity for lipophilic astaxanthin. The high oil astaxanthin hybrid was compared to its astaxanthin producing parent. We report an in depth metabolomic and proteomic analysis which revealed major up- or down- regulation of genes involved in primary metabolism. Specifically, amino acid biosynthesis and the citric acid cycle which compete with the synthesis or utilization of pyruvate and glyceraldehyde 3-phosphate, the precursors for carotenogenesis, were down regulated. Nevertheless, principal component analysis demonstrated that this compositional change is within the range of the two wild type parents used to generate the high oil producing astaxanthin hybrid. PMID- 26931322 TI - Finite cohesion due to chain entanglement in polymer melts. AB - Three different types of experiments, quiescent stress relaxation, delayed rate switching during stress relaxation, and elastic recovery after step strain, are carried out in this work to elucidate the existence of a finite cohesion barrier against free chain retraction in entangled polymers. Our experiments show that there is little hastened stress relaxation from step-wise shear up to gamma = 0.7 and step-wise extension up to the stretching ratio lambda = 1.5 at any time before or after the Rouse time. In contrast, a noticeable stress drop stemming from the built-in barrier-free chain retraction is predicted using the GLaMM model. In other words, the experiment reveals a threshold magnitude of step-wise deformation below which the stress relaxation follows identical dynamics whereas the GLaMM or Doi-Edwards model indicates a monotonic acceleration of the stress relaxation dynamics as a function of the magnitude of the step-wise deformation. Furthermore, a sudden application of startup extension during different stages of stress relaxation after a step-wise extension, i.e. the delayed rate-switching experiment, shows that the geometric condensation of entanglement strands in the cross-sectional area survives beyond the reptation time taud that is over 100 times the Rouse time tauR. Our results point to the existence of a cohesion barrier that can prevent free chain retraction upon moderate deformation in well entangled polymer melts. PMID- 26931319 TI - DEGRO practical guidelines for radiotherapy of breast cancer VI: therapy of locoregional breast cancer recurrences. AB - OBJECTIVE: To update the practical guidelines for radiotherapy of patients with locoregional breast cancer recurrences based on the current German interdisciplinary S3 guidelines 2012. METHODS: A comprehensive survey of the literature using the search phrases "locoregional breast cancer recurrence", "chest wall recurrence", "local recurrence", "regional recurrence", and "breast cancer" was performed, using the limits "clinical trials", "randomized trials", "meta-analysis", "systematic review", and "guidelines". CONCLUSIONS: Patients with isolated in-breast or regional breast cancer recurrences should be treated with curative intent. Mastectomy is the standard of care for patients with ipsilateral breast tumor recurrence. In a subset of patients, a second breast conservation followed by partial breast irradiation (PBI) is an appropriate alternative to mastectomy. If a second breast conservation is performed, additional irradiation should be mandatory. The largest reirradiation experience base exists for multicatheter brachytherapy; however, prospective clinical trials are needed to clearly define selection criteria, long-term local control, and toxicity. Following primary mastectomy, patients with resectable locoregional breast cancer recurrences should receive multimodality therapy including systemic therapy, surgery, and radiation +/- hyperthermia. This approach results in high local control rates and long-term survival is achieved in a subset of patients. In radiation-naive patients with unresectable locoregional recurrences, radiation therapy is mandatory. In previously irradiated patients with a high risk of a second local recurrence after surgical resection or in patients with unresectable recurrences, reirradiation should be strongly considered. Indication and dose concepts depend on the time interval to first radiotherapy, presence of late radiation effects, and concurrent or sequential systemic treatment. Combination with hyperthermia can further improve tumor control. In patients with isolated axillary or supraclavicular recurrence, durable disease control is best achieved with multimodality therapy including surgery and radiotherapy. Radiation therapy significantly improves local control and should be applied whenever feasible. PMID- 26931321 TI - Hypomorphic phenotype of Foxn1 gene-modified rats by CRISPR/Cas9 system. AB - The Foxn1 gene is known as a critical factor for the differentiation of thymic and skin epithelial cells. This study was designed to examine the phenotype of Foxn1-modified rats generated by the CRISPR/Cas9 system. Guide-RNA designed for first exon of the Foxn1 and mRNA of Cas9 were co-injected into the pronucleus of Crlj:WI zygotes. Transfer of 158 injected zygotes resulted in the birth of 50 offspring (32 %), and PCR identified five (10 %) as Foxn1-edited. Genomic sequencing revealed the deletion of 44 or 60 bp from and/or insertion of 4 bp into the Foxn1 gene in a single allele. The number of T-cells in the peripheral blood lymphocytes of mutant rats decreased markedly. While homozygous deleted mutant rats had no thymus, the mutant rats were not completely hairless and showed normal performance in delivery and nursing. Splicing variants of the indel mutation in the Foxn1 gene may cause hypomorphic allele, resulting in the phenotype of thymus deficiency and incomplete hairless. In conclusion, the mutant rats in Foxn1 gene edited by the CRISPR/Cas9 system showed the phenotype of thymus deficiency and incomplete hairless which was characterized by splicing variants. PMID- 26931323 TI - Visual acuity measured with a smartphone app is more accurate than Snellen testing by emergency department providers. AB - PURPOSE: To assess the accuracy of best-corrected visual acuity (BCVA) measured by non-ophthalmic emergency department (ED) staff with a standard Snellen chart versus an automated application (app) on a handheld smartphone (Paxos Checkup, San Francisco, CA, USA). METHODS: The study included 128 subjects who presented to the Stanford Hospital ED for whom the ED requested an ophthalmology consultation. We conducted the study in two phases. During phase 1 of the study, ED staff tested patient BCVA using a standard Snellen test at 20 feet. During phase 2 of the study, ED staff tested patient near BCVA using the app. During both phases, ophthalmologists measured BCVA with a Rosenbaum near chart, which was treated as the gold standard. ED BCVA measurements were benchmarked prospectively against ophthalmologists' measurements and converted to logMAR. RESULTS: ED logMAR BCVA was 0.21 +/- 0.35 (approximately 2 Snellen lines difference +/- 3 Snellen lines) higher than that of ophthalmologists when ED staff used a Snellen chart (p = .0.00003). ED BCVA was 0.06 +/- 0.40 (less than 1 Snellen line +/- 4 Snellen lines) higher when ED staff used the app (p = 0.246). Inter-observer difference was therefore smaller by more than 1 line (0.15 logMAR) with the app (p = 0.046). CONCLUSIONS: BCVA measured by non-ophthalmic ED staff with an app was more accurate than with a Snellen chart. Automated apps may provide a means to standardize and improve the efficiency of ED ophthalmologic care. PMID- 26931324 TI - Son Preference, Fertility Decline, and the Nonmissing Girls of Turkey. AB - Couples in Turkey exhibit son preference through son-biased differential stopping behavior that does not cause a sex ratio imbalance in the population. Demand for sons leads to lower ratios of boys to girls in larger families but higher ratios in smaller families. Girls are born earlier than their male siblings, and son biased fertility behavior is persistent in response to decline in fertility over time and across households with parents from different backgrounds. Parents use contraceptive methods to halt fertility following a male birth. The sibling sex composition is associated with gender disparities in health. Among third- or later-born children, female infant mortality is 1.5 percentage points lower if the previous sibling is male. The female survival advantage, however, disappears if the previous sibling is female. Having an older female sibling shifts the gender gap in infant mortality rate by 2 percentage points in favor of males. The improvement in infant mortality is strongest in favor of males who have no older male siblings. PMID- 26931325 TI - Emergency department visits in older people: pattern of use, contributing factors, geographical differences and outcomes. AB - AIMS: To assess the pattern of use of Emergency Departments (EDs), factors contributing to the visits, geographical distribution and outcomes in people aged 65 years or more living in the Italian Lombardy Region in 2012. METHODS: Based on an administrative database the study population was divided into groups according to the number of ED visits. A multinomial logistic regression model was performed to compare the characteristics of each group. The Getis-Ord's G statistic was used to evaluate the clusters of high and low visit prevalence odd ratios (OR) at district level. To estimate the severity of the disease leading to ED attendance, visits were stratified based on the level of emergency and outcome. RESULTS: About 2 million older people were included in the analyses: 78 % had no ED visit, 15 % only 1, 7 % 2 or more. Male sex, age 85 years or more, high number of drugs, ED visits and hospital admissions in the previous year and the location of an ED within 10 km from the patient's place were all factors associated with a higher risk to have more ED visits. Clusters of high and low prevalence of visits were found for occasional users. Overall, 83 % of ED visit with a low emergency triage code at admission had as visit outcome discharge at home. CONCLUSIONS: In older people several variables were associated with an increased risk to have a high number of ED visits. Most of the visits were done for non-urgent problems and significant geographic differences were observed for occasional users. PMID- 26931328 TI - Microscopic bilateral decompression by unilateral approach in spinal stenosis. PMID- 26931329 TI - TPLIF (decompression and TLIF) in degenerative spondylolisthesis L4/5. PMID- 26931327 TI - Detection and Phenotypic Characterization of Adult Neurogenesis. AB - Studies of adult neurogenesis have greatly expanded in the last decade, largely as a result of improved tools for detecting and quantifying neurogenesis. In this review, we summarize and critically evaluate detection methods for neurogenesis in mammalian and human brain tissue. Besides thymidine analog labeling, cell cycle markers are discussed, as well as cell stage and lineage commitment markers. Use of these histological tools is critically evaluated in terms of their strengths and limitations, as well as possible artifacts. Finally, we discuss the method of radiocarbon dating for determining cell and tissue turnover in humans. PMID- 26931330 TI - Minimally invasive thoracoscopic partial corpectomy of T12, followed by anterior stabilization and fusion through cage implantation with an anterior plate fixation. PMID- 26931331 TI - An RCT study on the feasibility of anterior transpedicular screw fixation in the cervicothoracic junction. AB - STUDY DESIGN: We evaluated the trajectory and the entry points of anterior transpedicular screws (ATPS) in the cervicothoracic junction (CTJ). OBJECTIVE: This study aimed at investigating the feasibility of ATPS fixation in the CTJ. Application of an ATPS in the lower cervical spine has been reported; however, there were no reports exploring the feasibility of anterior transpedicular screw fixation in the CTJ. METHODS: CT scans were performed in 50 cases and multiplanar reformation was used to measure the related parameters on pedicle axis view at C6 T2. Transverse pedicle angle, outer pedicle width, pedicle axis length, distance transverse intersection point (DtIP), sagittal pedicle angle, anterior vertebral body height, outer pedicle height, and distance sagittal intersection point (DsIP) were measured. The prozone of CTJ was divided into three different regions, which were named as the "manubrium region", the region "above" and "below" the manubrium. The distribution of the trajectory of sagittal pedicle axes was recorded in the three regions and the related data were statistically analyzed. RESULTS: There was no statistical difference in gender (P > 0.05). The transverse pedicle angle decreased from C6 (46.77 degrees +/- 2.72 degrees ) to T2 (20.62 degrees +/- 5.04 degrees ). DtIP increased from C6 to T2. DsIP was an average of 7.17 mm. The sagittal pedicle axis lines of the C6 and C7 were located in the region above the manubrium. T1 was mainly in the manubrium region followed by the region above the manubrium. T2 was mainly located in the manubrium region followed by the region below the manubrium. CONCLUSION: Implantation of ATPS at C6, C7, and some T1 is feasible through the low anterior cervical approach, while it is almost impossible to approach T2 that way. PMID- 26931326 TI - A Structural Perspective on Readout of Epigenetic Histone and DNA Methylation Marks. AB - This article outlines the protein modules that target methylated lysine histone marks and 5mC DNA marks, and the molecular principles underlying recognition. The article focuses on the structural basis underlying readout of isolated marks by single reader molecules, as well as multivalent readout of multiple marks by linked reader cassettes at the histone tail and nucleosome level. Additional topics addressed include the role of histone mimics, cross talk between histone marks, technological developments at the genome-wide level, advances using chemical biology approaches, the linkage between histone and DNA methylation, the role for regulatory lncRNAs, and the promise of chromatin-based therapeutic modalities. PMID- 26931332 TI - Prognosis of posterior osteophyte after anterior cervical decompression and fusion in patients with cervical spondylotic myelopathy using three-dimensional computed tomography study. AB - BACKGROUND: Inadequacy of posterior osteophyte resection in anterior cervical decompression and fusion (ACDF) surgery has long been a clinical concern as it may influence surgical outcome. There has been no agreement on the prognosis in the presence of remnant posterior osteophytes. METHODS: This study retrospectively investigated 26 cervical spondylotic myelopathy patients after ACDF in whom a remnant posterior osteophyte was identified by long-term follow-up CT scans (minimum of 2 years). Remnant posterior osteophytes and osseous spinal canal were measured and compared between pre-operation CT and long-term post operation CT. The post-operative clinical outcomes were also studied. RESULTS: The remnant osteophytes did not obviously decrease in size in any patient and significantly enlarged in 10 patients, with a new posterior osteophyte developing in one patient. In patients whose remnant osteophyte is enlarged, the incidence of pseudoarthrosis, as well as clinical deterioration during follow-up was significantly higher than patients with stable osteophytes. CONCLUSION: Contrary to previous reports, none of the remnant posterior osteophytes decreased obviously in size during follow up. Despite the persistence of posterior osteophytes, ACDF is still effective in CSM treatment. Posterior osteophyte enlargement at fused segment appears to be associated with symptomatic pseudoarthrosis and clinical deterioration after surgery. PMID- 26931333 TI - Surgical planning, manufacturing and implantation of an individualized cervical fusion titanium cage using patient-specific data. AB - BACKGROUND: Most cervical fusion cages imperfectly mimic the anatomy of the intervertebral disc space. The production of individualized cages might be the next step to further improve spinal implants due to their enhanced load-bearing surface. OBJECTIVE: To evaluate the planning, manufacturing, and implantation of an individualized cervical cage in co-operation with EIT and 3D Systems. METHODS: A digital 3D model of the patient's cervical spine was rendered from the patients CT data. It was then possible to correct degenerative deformities by digitally repositioning the vertebrae and virtually resecting the osteophytes. The implantation of the cage can be simulated to check the accuracy of the fit. The cage is made of trabecular titanium and manufactured by Direct Metal Printing. RESULTS: The pilot project for the implantation of the first individualized cervical cage ever, resulted in a highly accurate fit. During surgery, the cage self-located into the correct position after suspending distraction due to the implants unique end plate design. Furthermore, it was impossible to move the cage in any direction with the inserting instrument after suspending distraction for the same reason. Thus, it can be assumed that an individualized cervical implant provides excellent primary stability. CONCLUSION: Preconditions for the manufacturing of individualized cervical fusion cages using specific patient data are given. The implantation is uncomplicated. The improved load-bearing surface will lower the rate of implant dislocation and subsidence. The production of individualized cages at a reasonable price has to be evaluated by spine surgeons and the industry. PMID- 26931334 TI - Pretend Play and Social Engagement in Toddlers at High and Low Genetic Risk for Autism Spectrum Disorder. AB - Toddlers with an older sibling with autism spectrum disorder (ASD) and low risk (LR) toddlers with typically-developing older siblings were observed during free play with a parent and elicited pretend with an examiner at 22-months. Functional and pretend play, children's social engagement, and parent sensitivity were assessed during free play. Complexity of play was assessed during the elicited pretend task. Toddlers with an ASD diagnosis showed less pretend play across contexts and less social engagement with parents or the examiner than either LR toddlers or high risk toddlers without a diagnosis (HR-noASD). Lower levels of pretend play and social engagement were associated with symptom severity within the high risk group, reflecting emerging ASD in toddlerhood. PMID- 26931335 TI - Magnetic response of hybrid ferromagnetic and antiferromagnetic core-shell nanostructures. AB - The synthesis of FeTiO3-Ni(Ni80Fe20) core-shell nanostructures by a two-step method (sol-gel and DC electrodeposition) has been demonstrated. XRD analysis confirms the rhombohedral crystal structure of FeTiO3(FTO) with space group R3[combining macron]. Transmission electron microscopy clearly depicts better morphology of nanostructures with shell thicknesses of ~25 nm. Room temperature magnetic measurements showed significant enhancement of magnetic anisotropy for the permalloy (Ni80Fe20)-FTO over Ni-FTO core-shell nanostructures. Low temperature magnetic measurements of permalloy-FeTiO3 core-shell structure indicated a strong exchange bias mechanism with magnetic coercivity below the antiferromagnetic Neel temperature (TN = 59 K). The exchange bias is attributed to the alignment of magnetic moments in the antiferromagnetic material at low temperature. Our scheme opens a path towards optimum automotive systems and wireless communications wherein broader bandwidths and smaller sizes are required. PMID- 26931336 TI - Lipid accumulation by oleaginous and non-oleaginous yeast strains in nitrogen and phosphate limitation. AB - We investigated the possibility of utilizing both oleaginous yeast species accumulating large amounts of lipids (Yarrowia lipolytica, Rhodotorula glutinis, Trichosporon cutaneum, Candida sp.) and traditional biotechnological non oleaginous ones characterized by high biomass yield (Kluyveromyces polysporus, Torulaspora delbrueckii, Saccharomyces cerevisiae) as potential producers of biofuel-utilizable and nutritionally valuable lipids. The main objective was to increase lipid accumulation by increasing C/P ratio together with higher C/N ratio, while maintaining high biomass yield. The C/N ratio of 30 was found to lead to higher biomass content and the total lipid content increased significantly with higher C/P ratio. With higher ratios of both C/N and C/P, the content of monounsaturated fatty acids (FAs) in cell lipids increased while polyunsaturated FAs decreased. Oleaginous yeast species had a lower proportion of unsaturated FAs (approx. 80 %) than non-oleaginous strains (approx. 90 %). At a C/N ratio of 30 and C/P ratio 1043, T. cutaneum produced a high amount of omega-6 unsaturated linoleic acid, the precursor of some prostaglandins, leukotrienes, and thromboxanes, while Candida sp. and K. polysporus accumulated a high content of palmitoleic acid. PMID- 26931337 TI - Complex interfaces in "phase-change" contrast agents. AB - In this paper we report on the study of the interface of hybrid shell droplets encapsulating decafluoropentane (DFP), which exhibit interesting potentialities for ultrasound (US) imaging. The fabrication of the droplets is based on the deposition of a dextran methacrylate layer onto the surface of surfactants. The droplets have been stabilized against coalescence by UV curing, introducing crosslinks in the polymer layer and transforming the shell into an elastomeric membrane with a thickness of about 300 nm with viscoelastic behaviour. US irradiation induces the evaporation of the DFP core of the droplets transforming the particles into microbubbles (MBs). The presence of a robust crosslinked polymer shell introduces an unusual stability of the droplets also during the core phase transition and allows the recovery of the initial droplet state after a few minutes from switching off US. The interfacial tension of the droplets has been investigated by two approaches, the pendant drop method and an indirect method, based on the determination of the liquid <-> gas transition point of DFP confined in the droplet core. The re-condensation process has been followed by capturing images of single MBs by confocal microscopy. The time evolution of MB relaxation to droplets was analysed in terms of a modified Church model to account for the structural complexity of the MB shell, i.e. a crosslinked polymer layer over a layer of surfactants. In this way the microrheology parameters of the shell were determined. In a previous paper (Chem. Commun., 2013, 49, 5763 5765) we showed that these systems could be used as ultrasound contrast agents (UCAs). In this work we substantiate this view assessing some key features offered by the viscoelastic nature of the droplet shell. PMID- 26931338 TI - Incidental appendectomy? Microscopy tells another story: A retrospective cohort study in patients presenting acute right lower quadrant abdominal pain. AB - BACKGROUND: Optimal management of macroscopically normal appendix encountered during laparoscopy for acute abdominal pain is still unclear. METHODS: 164 acute abdominal pain cases in which laparoscopy showed a normal appendix were reviewed. No other intra-peritoneal acute disease was present in 50 patients (Group 1) whereas a miscellanea of intra-peritoneal conditions was identified in the other 114 (Group 2). All the patients underwent appendectomy with specimen examination. RESULTS: Following incidental appendectomy significant microscopical changes were seen in 125 specimens (76%). Among these, inflammation was found in 122 and neuroendocrine tumors in 3. Appendices harbored pathological changes in n = 45 patients (90%) of Group 1 and in n = 34 patients (70%) of Group 2 patients (p < 0.05). Morbidity for incidental appendectomy was 2%. CONCLUSION: This study supports an appendectomy in patients who are undergoing laparoscopy for acute right lower quadrant abdominal pain even when the appendix appears normal on visual inspection. PMID- 26931339 TI - Anemia after gastrectomy in long-term survivors of gastric cancer: A retrospective cohort study. AB - INTRODUCTION: The prevalence of gastric cancer in Korea is increasing, and anemia is one of the most common complications of a gastrectomy. The purpose of this study was to estimate the incidence of anemia and assess its associated factors in long-term gastric cancer survivors. METHODS: This study was a retrospective cohort study of gastric cancer patients who visited a single medical center from January 2009 to December 2014 in Korea. We included 385 patients who survived for at least five years after gastrectomy with no recurrence or metastasis. Anemia was defined by World Health Organization criteria (Hb < 12 g/dL in women and <13 g/dL in men). RESULTS: Hemoglobin levels decreased from 14.24 +/- 1.23 mg/dL before surgery to 13.60 +/- 1.57 mg/dL one year after surgery (P < 0.001). The cumulative incidence rate of anemia after surgery increased linearly from 18.7% in the first year to 39.5% in the fifth year. The risk of anemia was higher in females (RR, 2.00; 95% CI, 1.26-3.18), patients that received total gastrectomy (RR, 3.00; 95% CI, 2.09-4.30) and patient with diabetes (RR, 1.87; 95% CI, 1.05 3.22). A higher postoperative BMI decreased the risk of anemia (RR, 0.38; 95% CI, 0.22-0.67). CONCLUSIONS: During five years of follow-up after gastrectomy, the incidence of anemia steadily increased, and the risk of anemia was higher in females, total gastrectomy patients, patients with diabetes, low BMI patients. PMID- 26931340 TI - The COGs (context, object, and goals) in multisensory processing. AB - Our understanding of how perception operates in real-world environments has been substantially advanced by studying both multisensory processes and "top-down" control processes influencing sensory processing via activity from higher-order brain areas, such as attention, memory, and expectations. As the two topics have been traditionally studied separately, the mechanisms orchestrating real-world multisensory processing remain unclear. Past work has revealed that the observer's goals gate the influence of many multisensory processes on brain and behavioural responses, whereas some other multisensory processes might occur independently of these goals. Consequently, other forms of top-down control beyond goal dependence are necessary to explain the full range of multisensory effects currently reported at the brain and the cognitive level. These forms of control include sensitivity to stimulus context as well as the detection of matches (or lack thereof) between a multisensory stimulus and categorical attributes of naturalistic objects (e.g. tools, animals). In this review we discuss and integrate the existing findings that demonstrate the importance of such goal-, object- and context-based top-down control over multisensory processing. We then put forward a few principles emerging from this literature review with respect to the mechanisms underlying multisensory processing and discuss their possible broader implications. PMID- 26931341 TI - Retention of titanium dioxide nanoparticles in biological activated carbon filters for drinking water and the impact on ammonia reduction. AB - Given the increasing discoveries related to the eco-toxicity of titanium dioxide (TiO2) nanoparticles (NPs) in different ecosystems and with respect to public health, it is important to understand their potential effects in drinking water treatment (DWT). The effects of TiO2 NPs on ammonia reduction, ammonia-oxidizing archaea (AOA) and ammonia-oxidizing bacteria (AOB) in biological activated carbon (BAC) filters for drinking water were investigated in static and dynamic states. In the static state, both the nitrification potential and AOB were significantly inhibited by 100 MUg L(-1) TiO2 NPs after 12 h (p < 0.05), and the threshold decreased to 10 MUg L(-1) with prolonged exposure (36 h, p < 0.05). However, AOA were not considerably affected in any of the tested conditions (p > 0.05). In the dynamic state, different amounts of TiO2 NP pulses were injected into three pilot scale BAC filters. The decay of TiO2 NPs in the BAC filters was very slow. Both titanium quantification and scanning electron microscope analysis confirmed the retention of TiO2 NPs in the BAC filters after 134 days of operation. Furthermore, the TiO2 NP pulses considerably reduced the performance of ammonia reduction. This study identified the retention of TiO2 NPs in BAC filters and the negative effect on the ammonia reduction, suggesting a potential threat to DWT by TiO2 NPs. PMID- 26931342 TI - Elevated Acoustic Startle Responses in Humans: Relationship to Reduced Loudness Discomfort Level, but not Self-Report of Hyperacusis. AB - Increases in the acoustic startle response (ASR) of animals have been reported following experimental manipulations to induce tinnitus, an auditory disorder defined by phantom perception of sound. The increases in ASR have been proposed to signify the development of hyperacusis, a clinical condition defined by intolerance of normally tolerable sound levels. To test this proposal, the present study compared ASR amplitude to measures of sound-level tolerance (SLT) in humans, the only species in which SLT can be directly assessed. Participants had clinically normal/near-normal hearing thresholds, were free of psychotropic medications, and comprised people with tinnitus and without. ASR was measured as eyeblink-related electromyographic activity in response to a noise pulse presented at a range of levels and in two background conditions (noise and quiet). SLT was measured as loudness discomfort level (LDL), the lowest level of sound deemed uncomfortable, and via a questionnaire on the loudness of sounds in everyday life. Regardless of tinnitus status, ASR amplitude at a given stimulus level increased with decreasing LDL, but showed no relationship to SLT self reported via the questionnaire. These relationships (or lack thereof) could not be attributed to hearing threshold, age, anxiety, or depression. The results imply that increases in ASR in the animal work signify decreases in LDL specifically and may not correspond to the development of hyperacusis as would be self-reported by a clinic patient. PMID- 26931343 TI - Safety and tolerability of AZD5363 in Japanese patients with advanced solid tumors. AB - PURPOSE: Investigate the safety and tolerability of AZD5363 and define a recommended dose for evaluation in Japanese patients with advanced solid malignancies. METHODS: AZD5363 was administered orally as a single dose, and then the dose was escalated to twice daily (bid) in separate continuous (every day) and intermittent (4 days on, 3 days off [4/3] or 2 days on, 5 days off [2/5]) dosing schedules to reach recommended doses defined by dose-limiting toxicity (DLT). Doses for continuous, 4/3, and 2/5 intermittent dosing schedules were 80 400, 360-480, and 640 mg, respectively, and were informed by results from an equivalent study in Caucasian patients. RESULTS: Forty-one patients received AZD5363. DLTs were only experienced with continuous dosing. 97.6 % of patients reported at least one adverse event (AE); most common were diarrhea (78.0 %), hyperglycemia (68.3 %), nausea (56.1 %), and maculopapular rash (56.1 %). Grade >=3 AEs were reported by 63.4 % of patients. Exposure of AZD5363 was generally dose proportional for both single and multiple doses. Single-dose pharmacokinetics of AZD5363 was generally predictive of multiple-dose pharmacokinetics. Confirmed partial responses were reported by two patients, both of whom were Akt1 (E17K) mutation positive. One patient in the 480 mg bid 4/3 dosing cohort maintained partial response for >2 years. CONCLUSIONS: Intermittent dosing of AZD5363 was more tolerable than continuous dosing. 480 mg bid intermittent 4/3 dosing for AZD5363 monotherapy was selected for further investigation. Preliminary evidence of antitumor activity was observed. Akt1 (E17K) is a potent driver mutation that may predict clinical response to AZD5363. PMID- 26931344 TI - Celecoxib induces apoptosis but up-regulates VEGF via endoplasmic reticulum stress in human colorectal cancer in vitro and in vivo. AB - PURPOSE: In our previous study, we found that celecoxib, a kind of COX-2 inhibitor, led to cell apoptosis while up-regulating the expression of vascular endothelial growth factor (VEGF) in colorectal cancer HCT116 cells (COX-2 deficient), and endoplasmic reticulum (ER) stress was involved in the mechanism. Thus, we would like to explore whether these results are universal for other colorectal cancer cells, especially for COX-2-expressing ones, and whether the results in vitro and in vivo are matched. METHODS: HT29 cells (COX-2 expressing) were treated with celecoxib under different conditions to evaluate cell apoptosis, VEGF expression and the activation of ER stress. HT29 and HCT116 xenograft tumor models were established to evaluate anti-tumor effects and verify the experiment results we obtained in vitro. RESULTS: Celecoxib (>=60 uM) up regulated the expression of ER stress markers (GRP78 and CHOP) and induced cell apoptosis accompanying with a correlated increased expression of VEGF in HT29 cells. Celecoxib-induced gene expression and cell apoptosis were inhibited by an ER stress inhibitor, PBA. In xenograft models, celecoxib treatment inhibited tumor growth with increased GRP78 and VEGF, which was consistent with the results in vitro. CONCLUSIONS: Celecoxib, both in vitro and in vivo, induced apoptosis of colorectal cancer cells but increased the VEGF levels at the same time in a COX-2 independent manner, namely by activating ER stress. The increased VEGF would impair the effect of celecoxib and bring drug resistant; hence, the optimal schedule of the combination of celecoxib with anti-VEGF drugs needs to be explored. PMID- 26931345 TI - Obituary. PMID- 26931347 TI - alpha-Tocopherol in breast milk of women with preterm delivery after a single postpartum oral dose of vitamin E. AB - We evaluated the effect of maternal vitamin E supplementation on the alpha tocopherol concentrations of colostrum, transitional milk and mature milk of women who had given birth prematurely. This longitudinal randomised-controlled trial divided eighty-nine women into two groups: a control group and a supplemented group. Blood and breast milk were collected from all the participants after delivery. Next, each woman in the supplemented group received 400 IU of RRR-alpha-tocopheryl acetate. Further breast milk samples were collected 24 h after the first collection, as well as 7 and 30 d after delivery. alpha-Tocopherol concentrations were determined by HPLC. The baseline alpha tocopherol concentrations in the maternal serum of the two groups were similar: 1159.8 (sd 292.4) MUg/dl (27.0 (SD 6.8) MUmol/l) for the control group and 1128.3 (sd 407.2) MUg/dl (26.2 (SD 9.5) MUmol/l) for the supplemented group. None of the women was vitamin E deficient. Breast milk alpha-tocopherol concentrations increased by 60 % 24 h after supplementation in the intervention group and did not increase at all in the control group. alpha-Tocopherol concentration of the transitional milk in the supplemented group was 35 % higher compared with the control group. alpha-Tocopherol concentrations of the mature milk in both groups were similar. Maternal supplementation with 400 IU of RRR-alpha-tocopherol increased the vitamin E concentrations of the colostrum and transitional milk, but not of the mature milk. This study presents relevant information for the design of strategies to prevent and combat vitamin E deficiency in the risk group of preterm infants. PMID- 26931349 TI - Effect of earthworm active protein on fibroblast proliferation and its mechanism. AB - CONTEXT: Earthworms have been used as a traditional medicine in China from thousands of years. In recent years, research has demonstrated that earthworm extracts might promote wound healing; however, its mechanism is still unknown. OBJECTIVE: The study investigates the mechanism and effects of earthworm active protein (EAP), on mouse embryonic fibroblast (NIH/3T3) proliferation. MATERIALS AND METHODS: The effects of earthworm active protein (EAP) in different concentrations (0, 25, 50, 100, 150, and 200 MUg/mL) on NIH3T3 cell were detected by the MTT and Brdu incorporation assay (50, 100, and 150 MUg/mL). The effects of EAP (37.5, 75, and 150 MUg/mL) on the cell cycle were detected by flow cytometry. The cell signaling pathways of EAP-promoting NIH3T3 cell proliferation were studied by the MTT and Western blot by using different signaling pathway inhibitors. RESULTS: The results showed that EAP (50, 100, and 150 MUg/mL) could promote NIH3T3 fibroblasts proliferation (36.4 +/- 4.4%, 59.1 +/- 4.9%, and 71.5 +/- 5.7%). The mechanism of EAP promoting NIH3T3 cell proliferation should be as follows: EAP elevated cyclin D1 expression by activating MEK/ERK signaling pathway, and then promoted cell cycle from G1 to S phase, finally caused the proliferation of NIH3T3 cell. PI3K signaling pathway may be the upstream of MEK/ERK signaling pathway. DISCUSSION AND CONCLUSION: The study demonstrates that EAP is effective in promoting effects on proliferation and migration activity of NIH3T3 cell, and the proliferation activity of EAP on NIH3T3 cell may be achieved through the PI3K->Rac->PAK->MEK signaling pathway. PMID- 26931348 TI - Effect of Musca domestic maggot polypeptide extract on HUVEC dysfunction induced by early-activated macrophages. AB - CONTEXT: Musca domestica Linn. maggot is a traditional Chinese medicine. In our previous studies, Musca domestica maggot protein-enriched fraction and polypeptide extract (molecular weight <30 kD) were found to reverse endothelial cell dysfunction in atherosclerotic lesions. OBJECTIVE: This study determines whether and how M. domestica maggot polypeptide extract affects the dysfunction of human umbilical vein endothelial cells (HUVEC) induced by macrophages (Mphi). MATERIALS AND METHODS: HUVEC and early-activated THP-1 Mphi (incubated with LPS of 1 MUg/ml for 2 h) were co-cultured in a Transwell system. The effects of Musca domestica maggot polypeptide extract (with increasing concentrations, i.e., 1.0, 2.5, 5.0, 10.0, 20.0, and 40.0 ug/ml) on the proliferation and migration HUVEC and their secretion of vascular endothelial growth factor (VEGF) were determined by flow cytometry, modified Boyden chamber assay, and enzyme-linked immunosorbent assay (ELISA) after incubation for 24 h. RESULTS: Musca domestica maggot polypeptide extract decreased the proliferation of HUVEC in a concentration dependent manner, with a 50% effective concentration (EC50) of 22.16 +/- 1.48 ug/ml, and effectively inhibited HUVEC migration (EC50 = 35.15 +/- 2.03 ug/ml) and VEGF secretion (EC50 = 28.64 +/- 1.29 ug/ml). DISCUSSION AND CONCLUSION: Musca domestica maggot polypeptide extract can inhibit the dysfunction of HUVEC induced by early-activated THP-1 Mphi. PMID- 26931350 TI - Linkage Between Hourly Precipitation Events and Atmospheric Temperature Changes over China during the Warm Season. AB - We investigated changes in the temporospatial features of hourly precipitation during the warm season over mainland China. The frequency and amount of hourly precipitation displayed latitudinal zonation, especially for light and moderate precipitation, which showed successive downward change over time in northeastern and southern China. Changes in the precipitation amount resulted mainly from changes in frequency rather than changes in intensity. We also evaluated the linkage between hourly precipitation and temperature variations and found that hourly precipitation extreme was more sensitive to temperature than other categories of precipitation. A strong dependency of hourly precipitation on temperature occurred at temperatures colder than the median daily temperature; in such cases, regression slopes were greater than the Clausius-Clapeyron (C-C) relation of 7% per degree Celsius. Regression slopes for 31.6%, 59.8%, 96.9%, and 99.1% of all stations were greater than 7% per degree Celsius for the 75th, 90th, 99th, and 99.9th percentiles for precipitation, respectively. The mean regression slopes within the 99.9th percentile of precipitation were three times the C-C rate. Hourly precipitation showed a strong negative relationship with daily maximum temperature and the diurnal temperature range at most stations, whereas the equivalent correlation for daily minimum temperature was weak. PMID- 26931351 TI - Incidence and viral aetiologies of acute respiratory illnesses (ARIs) in the United States: a population-based study. AB - We conducted prospective, community-wide surveillance for acute respiratory illnesses (ARIs) in Rochester, NY and Marshfield, WI during a 3-month period in winter 2011. We estimated the incidence of ARIs in each community, tested for viruses, and determined the proportion of ARIs associated with healthcare visits. We used a rolling cross-sectional design to sample participants, conducted telephone interviews to assess ARI symptoms (defined as a current illness with feverishness or cough within the past 7 days), collected nasal/throat swabs to identify viruses, and extracted healthcare utilization from outpatient/inpatient records. Of 6492 individuals, 321 reported an ARI within 7 days (4.9% total, 5.7% in Rochester, 4.4% in Marshfield); swabs were collected from 208 subjects. The cumulative ARI incidence for the entire 3-month period was 52% in Rochester [95% confidence interval (CI) 42-63] and 35% in Marshfield (95% CI 28-42). A specific virus was identified in 39% of specimens: human coronavirus (13% of samples), rhinovirus (12%), RSV (7%), influenza virus (4%), human metapneumovirus (4%), and adenovirus (1%). Only 39/200 (20%) had a healthcare visit (2/9 individuals with influenza). ARI incidence was ~5% per week during winter. PMID- 26931352 TI - Macroscopic electric field inside water-filled biological nanopores. AB - Multi-drug resistance bacteria are a challenging problem of contemporary medicine. This is particularly critical for Gram-negative bacteria, where antibiotics are hindered by the outer membrane to reach internal targets. Here more polar antibiotics make use of nanometric water-filled channels to permeate inside. We present in this work a computational all-atom approach, using water as a probe, for the calculation of the macroscopic electric field inside water filled channels. The method allows one to compare not only different systems but also the same system under different conditions, such as pH and ion concentration. This provides a detailed picture of electrostatics in biological nanopores shedding more light on how the charged residues of proteins determine the electric field inside, and also how medium can tune it. These details are central to unveil the filtering mechanism behind the permeation of small polar molecules through nanometric water-filled channels. PMID- 26931353 TI - Ultrafast Microwave Nano-manufacturing of Fullerene-Like Metal Chalcogenides. AB - Metal Chalcogenides (MCs) have emerged as an extremely important class of nanomaterials with applications ranging from lubrication to energy storage devices. Here we report our discovery of a universal, ultrafast (60 seconds), energy-efficient, and facile technique of synthesizing MC nanoparticles and nanostructures, using microwave-assisted heating. A suitable combination of chemicals was selected for reactions on Polypyrrole nanofibers (PPy-NF) in presence of microwave irradiation. The PPy-NF serves as the conducting medium to absorb microwave energy to heat the chemicals that provide the metal and the chalcogenide constituents separately. The MCs are formed as nanoparticles that eventually undergo a size-dependent, multi-stage aggregation process to yield different kinds of MC nanostructures. Most importantly, this is a single-step metal chalcogenide formation process that is much faster and much more energy efficient than all the other existing methods and can be universally employed to produce different kinds of MCs (e.g., MoS2, and WS2). PMID- 26931355 TI - First example of the correlated calculation of the one-bond tellurium-carbon spin spin coupling constants: Relativistic effects, vibrational corrections, and solvent effects. AB - This work reports on the comprehensive calculation of the NMR one-bond spin-spin coupling constants (SSCCs) involving carbon and tellurium, (1) J((125) Te,(13) C), in four representative compounds: Te(CH3 )2 , Te(CF3 )2 , Te(C?CH)2 , and tellurophene. A high-level computational treatment of (1) J((125) Te,(13) C) included calculations at the SOPPA level taking into account relativistic effects evaluated at the 4-component RPA and DFT levels of theory, vibrational corrections, and solvent effects. The consistency of different computational approaches including the level of theory of the geometry optimization of tellurium-containing compounds, basis sets, and methods used for obtainig spin spin coupling values have also been discussed in view of reproducing the experimental values of the tellurium-carbon SSCCs. Relativistic corrections were found to play a major role in the calculation of (1) J((125) Te,(13) C) reaching as much as almost 50% of the total value of (1) J((125) Te,(13) C) while relativistic geometrical effects are of minor importance. The vibrational and solvent corrections account for accordingly about 3-6% and 0-4% of the total value. It is shown that taking into account relativistic corrections, vibrational corrections and solvent effects at the DFT level essentially improves the agreement of the non-relativistic theoretical SOPPA results with experiment. (c) 2016 Wiley Periodicals, Inc. PMID- 26931354 TI - POU5F1/Oct-4 expression in breast cancer tissue is significantly associated with non-sentinel lymph node metastasis. AB - BACKGROUND: At present, few studies have explored the significance of POU5F1 (also known as octamer-bingding factor, Oct-4 or Oct-3) expression in breast cancer tissues. METHODS: A total of 121 patients were retrospectively selected between May 2010 and March 2013 to investigate the relationship between POU5F1/Oct-4 expression in breast cancer tissues and non-sentinel lymph node (non SLN) metastases and to validate the Memorial Sloan-Kettering Cancer Center (MSKCC) nomogram. All patients had early-stage breast cancer, which was histologically confirmed by the Department of Surgical Oncology, The First Affiliated Hospital of China Medical University. Histological type and grade of tumors were determined from tissue samples by hematoxylin and eosin staining, while the presence of POU5F1/Oct-4 protein was determined by immunohistochemistry. POU5F1/Oct-4 expression levels in tissues obtained from patients with sentinel lymph node (SLN) and non-SLN metastasis and in tissues obtained from patients without lymph node metastases were compared. RESULTS: POU5F1/Oct-4 expression levels in breast cancer tissues were significantly higher in both the SLN metastasis and non-SLN metastasis groups (P = 0.003 and P = 0.030, respectively). Furthermore, POU5F1/Oct-4 expression was found to be associated to both histological (P = 0.01) and molecular type (P = 0.03). Thus, our data once again confirms the validity of the MSKCC nomogram. The area under curve (AUC) was 0.919 (95 % CI: 0.869-0.969, P < 0.001). The probability of non SLN metastasis generated from the MSKCC nomgram was significantly higher in the POU5F1/Oct-4 positive group than in the POU5F1/Oct-4 negative group. Both univariate and multivariate analysis revealed that Oct-4 expression levels were significantly associated with non-SLN metastases (P = 0.030 and P = 0.034, respectively). CONCLUSIONS: POU5F1/Oct-4 expression levels are significantly associated with non-SLN metastases. Patients with higher probabilities of metastasis generated from the MSKCC nomogram may also have higher POU5F1/Oct-4 expression levels. PMID- 26931356 TI - Skeletal variation in Tennessee Walking Horses maps to the LCORL/NCAPG gene region. AB - Conformation has long been a driving force in horse selection and breed creation as a predictor for performance. The Tennessee Walking Horse (TWH) ranges in size from 1.5 to 1.7 m and is often used as a trail, show, and pleasure horse. To investigate the contribution of genetics to body conformation in the TWH, we collected DNA samples, body measurements, and gait/training information from 282 individuals. We analyzed the 32 body measures with a principal component analysis. Principal component (PC)1 captured 28.5% of the trait variance, while PC2 comprised just 9.5% and PC3 6.4% of trait variance. All 32 measures correlated positively with PC1, indicating that PC1 describes overall body size. We genotyped 109 horses using the EquineSNP70 bead chip and marker association assessed the data using PC1 scores as a phenotype. Mixed-model linear analysis (EMMAX) revealed a well-documented candidate locus on ECA3 (raw P = 3.86 * 10( 9)) near the LCORL gene. A custom genotyping panel enabled fine-mapping of the PC1 body-size trait to the 3'-end of the LCORL gene (P = 7.09 * 10(-10)). This position differs from other reports suggesting single nucleotide polymorphisms (SNPs) upstream of the LCORL coding sequence regulate expression of the gene and, therefore, body size in horses. Fluorescent in situ hybridization analysis defined the position of a highly homologous 5 kb retrogene copy of LCORL (assigned to unplaced contigs of the EquCab 2.0 assembly) at ECA9 q12-q13. This is the first study to identify putative causative SNPs within the LCORL transcript itself, which are associated with skeletal size variation in horses. PMID- 26931357 TI - Natural and Unnatural Compounds Rescue Folding Defects of Human Alanine: Glyoxylate Aminotransferase Leading to Primary Hyperoxaluria Type I. AB - The functional deficit of alanine:glyoxylate aminotransferase (AGT) in human hepatocytes leads to a rare recessive disorder named primary hyperoxaluria type I (PH1). PH1 is characterized by the progressive accumulation and deposition of calcium oxalate stones in the kidneys and urinary tract, leading to a life threatening and potentially fatal condition. In the last decades, substantial progress in the clarification of the molecular pathogenesis of the disease have been made. They resulted in the understanding that many mutations cause AGT deficiency by affecting the folding pathway of the protein leading to a reduced expression level, an increased aggregation propensity, and/or an aberrant mitochondrial localization. Thus, PH1 can be considered a misfolding disease and possibly treated by approaches aimed at counteracting the conformational defects of the variants. In this review, we summarize recent advances in the development of new strategies to identify molecules able to rescue AGT folding and trafficking either by acting as pharmacological chaperones or by preventing the mistargeting of the protein. PMID- 26931358 TI - Targeting Cystathionine Beta-Synthase Misfolding in Homocystinuria by Small Ligands: State of the Art and Future Directions. AB - Classical homocystinuria (HCU) is the most common loss-of-function inborn error of sulfur amino acids metabolism. HCU is caused by a deficiency in enzymatic degradation of homocysteine, a toxic intermediate of methionine transformation to cysteine, chiefly due to missense mutations in the cystathionine betasynthase (CBS) gene. As with many other inherited disorders, the pathogenic mutations do not target key catalytic residues, but rather introduce structural perturbations leading to an enhanced tendency of the mutant CBS to misfold and either to form non-functional aggregates or to undergo proteasome-dependent degradation. Thus correction of CBS misfolding represents an alternative therapeutic approach for HCU. In this review, we summarize the complex nature of CBS, its multidomain architecture, the interplay between the three cofactors required for CBS function (heme, pyridoxal-5'-phosphate (PLP) and S-adenosyl-L-methionine) as well as the intricate allosteric regulatory mechanism only recently explained thanks to advances in CBS crystallography. While roughly half of the patients responds to treatment with a PLP precursor pyridoxine, many studies suggested usefulness of small chemicals, such as chemical and pharmacological chaperones or proteasome inhibitors, rescuing mutant CBS activity in cellular and animal models of HCU. Non-specific chemical chaperones and proteasome inhibitors assist in mutant CBS folding process and/or prevent its rapid degradation, thus resulting in increased steady state levels of the enzyme and CBS activity. Recent increased interest in the field and available structural information will hopefully yield CBS-specific compounds by using high-throughput screening and computational modeling of novel ligands improving folding, stability and activity of CBS. PMID- 26931359 TI - Could Physician Use of Realistic Previews Increase Treatment Adherence and Patient Satisfaction? PMID- 26931360 TI - Brazil struggles to cope with Zika epidemic. PMID- 26931361 TI - Procyanidins alleviates morphine tolerance by inhibiting activation of NLRP3 inflammasome in microglia. AB - BACKGROUND: The development of antinociceptive tolerance following repetitive administration of opioid analgesics significantly hinders their clinical use. Evidence has accumulated indicating that microglia within the spinal cord plays a critical role in morphine tolerance. The inhibitor of microglia is effective to attenuate the tolerance; however, the mechanism is not fully understood. Our present study investigated the effects and possible mechanism of a natural product procyanidins in improving morphine tolerance via its specific inhibition on NOD-like receptor protein3 (NLRP3) inflammasome in microglia. METHODS: CD-1 mice were used for tail-flick test to evaluate the degree of pain. The microglial cell line BV-2 was used to investigate the effects and the mechanism of procyanidins. Reactive oxygen species (ROS) produced from BV-2 cells was evaluated by flow cytometry. Cell signaling was measured by western blot assay and immunofluorescence assay. RESULTS: Co-administration of procyanidins with morphine potentiated its antinociception effect and attenuated the development of acute and chronic morphine tolerance. Procyanidins also inhibited morphine induced increase of interleukin-1beta and activation of NOD-like receptor protein3 (NLRP3) inflammasome. Furthermore, procyanidins decreased the phosphorylation of p38 mitogen-activated protein kinase, inhibited the translocation of nuclear factor-kappaB (NF-kappaB), and suppressed the level of reactive oxygen species in microglia. CONCLUSIONS: Procyanidins suppresses morphine-induced activation of NLRP3 inflammasome and inflammatory responses in microglia, and thus resulting in significant attenuation of morphine antinociceptive tolerance. PMID- 26931362 TI - Proactive tobacco treatment offering free nicotine replacement therapy and telephone counselling for socioeconomically disadvantaged smokers: a randomised clinical trial. AB - BACKGROUND: Evidenced-based tobacco cessation treatments are underused, especially by socioeconomically disadvantaged smokers. This contributes to widening socioeconomic disparities in tobacco-related morbidity and mortality. METHODS: The Offering Proactive Treatment Intervention trial tested the effects of a proactive outreach tobacco treatment intervention on population-level smoking abstinence and tobacco treatment use among a population-based sample of socioeconomically disadvantaged smokers. Current smokers (n=2406), regardless of interest in quitting, who were enrolled in the Minnesota Health Care Programs, the state's publicly funded healthcare programmes for low-income populations, were randomly assigned to proactive outreach or usual care. The intervention comprised proactive outreach (tailored mailings and telephone calls) and free cessation treatment (nicotine replacement therapy and intensive, telephone counselling). Usual care comprised access to a primary care physician, insurance coverage of Food and Drug Administration-approved smoking cessation medications, and the state's telephone quitline. The primary outcome was self-reported 6-month prolonged smoking abstinence at 1 year and was assessed by follow-up survey. FINDINGS: The proactive intervention group had a higher prolonged abstinence rate at 1 year than usual care (16.5% vs 12.1%, OR 1.47, 95% CI 1.12 to 1.93). The effect of the proactive intervention on prolonged abstinence persisted in selection models accounting for non-response. In analysis of secondary outcomes, use of evidence-based tobacco cessation treatments were significantly greater among proactive outreach participants compared with usual care, particularly combination counselling and medications (17.4% vs 3.6%, OR 5.69, 95% CI 3.85 to 8.40). INTERPRETATION: Population-based proactive tobacco treatment increases engagement in evidence-based treatment and is effective in long-term smoking cessation among socioeconomically disadvantaged smokers. Findings suggest that dissemination of population-based proactive treatment approaches is an effective strategy to reduce the prevalence of smoking and socioeconomic disparities in tobacco use. TRIAL REGISTRATION NUMBER: NCT01123967. PMID- 26931363 TI - Association between FTO gene polymorphism (rs9939609 T/A) and cancer risk: a meta analysis. AB - Obesity is a risk factor of cancer. Several genes have been found to play an important role in aetiology of obesity and tumourigenesis. Recently, some studies suggested that rs9939609 polymorphism might be significantly associated with cancer risk, while the results of some other studies were controversial. Databases with time limitation from January 1984 to April 2015 were searched. The pooled odds ratio (OR) with 95% confidence interval was calculated to assess the associations, and subgroup meta-analyses were performed according to the type of cancer and ethnicity of the study populations. Overall, the significant association between rs9939609 polymorphism and cancer risk was found in homozygote model and recessive model. As to subgroup classified by cancer type, there was significant association in endometrial cancer and pancreatic cancer, while no statistical significance was detected in other kind of cancers. Besides, in the subgroup analysis of ethnicity, our results indicated that rs9939609 polymorphism was significantly associated with cancer risk in Asians. The rs9939609 polymorphism may be involved the susceptibility of endometrial cancer and pancreatic cancer, especially in Asian populations. Thus, rs9939609 may be a potential biomarker in early diagnosis or gene therapy target of endometrial cancer and pancreatic cancer. PMID- 26931364 TI - Cluster-randomized trials: A closer look. AB - BACKGROUND: The cluster-randomized trial is the methodology of choice for evaluating interventions administered at the group level such as public health and healthcare quality improvement interventions. Because of unique features of this design, it can be difficult to apply standard research ethics guidelines to cluster-randomized trials. The Ottawa Statement on the Ethical Design and Conduct of Cluster-Randomized Trials provides researchers and research ethics committees with comprehensive guidance on the ethical design, conduct and review of cluster randomized trials. The Ottawa Statement supplements current national and international research ethics guidelines with guidance that is specific to cluster-randomized trials. In a recently published commentary, three examples drawn from the ClinicalTrials.gov registry were used to illustrate challenges associated with the cluster-randomized trial design. The commentary argued that the Ottawa Statement fails to provide comprehensive ethical guidance. In this article, we illustrate the application of the Ottawa Statement to the three trials. We challenge the conclusions reached in the commentary by demonstrating that an ethical analysis requires complete information. We correct some misperceptions about the cluster-randomized trial design. METHODS: We collected essential additional information by contacting the authors of trials and by referring to published trial articles. We used the Ottawa Statement to conduct an ethical analysis of each trial and to address a number of substantive concerns raised regarding the identification of study participants, informed consent and harm benefit analysis. RESULTS: In the two cases in which we were able to obtain detailed study information, we were able to complete the ethical analysis prescribed by the Ottawa Statement. CONCLUSION: The Ottawa Statement does provide a useful framework for the ethical design, review and conduct of cluster randomized trials. PMID- 26931365 TI - Prevalence, characteristics, and survival of children with esophageal atresia: A 32-year population-based study including 1,417,724 consecutive newborns. AB - BACKGROUND: Esophageal atresia (EA) is a congenital malformation of the upper gastrointestinal tract with an estimated prevalence varying from 1 in 2500 to 1 in 4500 births. The aim of this study was to describe the epidemiology of EA between 1981 and 2012 and evaluate patients' survival. METHODS: This study used data from a population-based Italian Congenital Malformation Registry. The survival status was ascertained by linking the registry records, vital records and the regional registries of patients. Kaplan-Meier methods were used to estimate survival probabilities up to 25 years and Cox proportional hazards regression was used to evaluate factors that affected survival. RESULTS: A total of 407 cases of EA were identified among 1,417,724 total births. After the exclusion of cases with chromosomal anomalies, 49.9% of the patients presented with at least one associated congenital anomaly. The 25-year survival probability was 85.1% (95% confidence interval [CI], 80.8-89.4), with most deaths occurring during the first months of life. Patients' characteristics associated with decreased survival probability were low birth weight (hazard ratio, 3.7; 95% CI, 1.7-8.3) and presence of additional major defects (hazard ratio, 2.8; 95% CI, 1.3 6.0). A significant improvement in survival over the decades was observed for patients with nonisolated EA. CONCLUSION: This study detected a significant improvement in survival of individuals with EA over the past decades and identified the strongest predictors of mortality. These results will be important for the planning of the clinical management and formulation of prognosis when EA is diagnosed in a newborn. Birth Defects Research (Part A) 106:542-548, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26931366 TI - Mental health support for healthcare workers after the Great East Japan Earthquake: Five years on. PMID- 26931367 TI - A conversation with Max van Manen on phenomenology in its original sense. PMID- 26931368 TI - RhCl(PPh3)3-mediated C-H oxyfunctionalization of pyrrolido-functionalized bisazoaromatic pincers: a combined experimental and theoretical scrutiny of redox active and spectroscopic properties. AB - A potentially symmetrical NNN pyrrolido-functionalized pincer ligand, HL = 2,5 bis(phenylazo)-1H-pyrrole, reacts with [Rh(I)Cl(PPh3)3] in toluene in the presence of air, affording an emerald crystalline solid of the composition [Rh(III)(L(O))Cl(PPh3)2]. A spontaneous C-H oxyfunctionalization of the aromatic ring with atmospheric oxygen leads to phenoxido functionalized organic transformation at room temperature. X-ray diffraction and MASS spectral analyses authenticate the unsymmetrical NNO coordination of the title ligand with a dangling phenylazo moiety. Cyclic voltammetry of redox innocent Rh(iii) complexes exhibits a reversible oxidative response at E1/2~ 0.9 V vs. Ag/AgCl along with a quasi-reversible reductive response near -1.0 V. The electronic structures of the electro-active species are scrutinized by DFT calculations at the B3LYP-level of theory and both the responses are found to be ligand-centered (LC) in nature. Furthermore, an EPR study of the one-electron oxidized radical cation [Rh(III)(L(O))Cl(PPh3)2](+) validates that the oxidation process is confined exclusively on the ligand framework (spin density: rhoPhenoxido~-0.50 and rhoPyrrolido~-0.40). Moreover, an appreciable involvement of the pyrrolido function apart from the phenoxido group of the redox-active ligand (L(O)) is apparent in the oxidation process from the nature of HOMO and thus, this type of ligand system provides two oxidizable domains within the single ligand backbone. A comparison of the relative oxidizability power between the two potential oxidizable centers viz. pyrrolido and phenoxido rings reveals that the former is somewhat less efficient for oxidation. In contrast, reductive response is mainly associated with both the coordinated and free azo chromophores. Time-dependent DFT and natural transition orbital (NTO) analyses on the complexes elucidate the origin of UV-vis absorptions. PMID- 26931369 TI - Immunobiological effects of gemcitabine and capecitabine combination chemotherapy in advanced pancreatic ductal adenocarcinoma. AB - BACKGROUND: Preclinical studies suggest that chemotherapy may enhance the immune response against pancreatic cancer. METHODS: The levels of granulocyte macrophage colony-stimulating factor (GM-CSF) and interleukin-6 (IL-6) and the associated inflammatory marker C-reactive protein (CRP) were assessed in 38 patients receiving gemcitabine and capecitabine combination chemotherapy for advanced pancreatic cancer within the TeloVac trial. Apoptosis (M30) and total immune response (delayed-type hypersensitivity and/or T-cell response) were also assessed and levels of apoptosis induction correlated with immune response. The telomerase GV1001 vaccine was given either sequentially (n=18) or concomitantly (n=24) with the combination chemotherapy. RESULTS: There were no differences between baseline and post-treatment levels of CRP (P=0.19), IL-6 (P=0.19) and GM CSF (P=0.71). There was a positive correlation between post-chemotherapy CRP and IL-6 levels (r=0.45, P=0.005) and between CRP with carbohydrate antigen-19-9 (CA19-9) levels at baseline (r=0.45, P=0.015) and post treatment (r=0.40, P=0.015). The change in CRP and IL-6 levels was positively correlated (r=0.40, P=0.012). Hazard ratios (95% CI) for baseline CA19-9 (1.30 (1.07-1.59), P=0.009) and CRP (1.55 (1.00-2.39), P=0.049) levels were each independently predictive of survival. The M30 mean matched differences between pre- and post-chemotherapy showed evidence of apoptosis in both the sequential (P=0.058) and concurrent (P=0.0018) chemoimmunotherapy arms. Respectively, 5 of 10 and 9 of 20 patients had a positive immune response but there was no association with apoptosis. CONCLUSIONS: Combination gemcitabine and capecitabine chemotherapy did not affect circulating levels of GM-CSF, IL-6 and CRP. Chemotherapy-induced apoptosis was not associated with the immunogenicity induced by the GV1001 vaccine in advanced pancreatic cancer. PMID- 26931370 TI - HPV immunisation and cervical screening--confirmation of changed performance of cytology as a screening test in immunised women: a retrospective population-based cohort study. AB - BACKGROUND: To document the effect of bivalent HPV immunisation on cervical cytology as a screening test and assess the implications of any change, using a retrospective analysis of routinely collected data from the Scottish Cervical Screening Programme (SCSP). METHODS: Data were extracted from the Scottish Cervical Call Recall System (SCCRS), the Scottish Population Register and the Scottish Index of Multiple Deprivation. A total of 95 876 cytology records with 2226 linked histology records from women born between 1 January 1988 and 30 September 1993 were assessed. Women born in or after 1990 were eligible for the national catch-up programme of HPV immunisation. The performance of cervical cytology as a screening test was evaluated using the key performance indicators used routinely in the English and Scottish Cervical Screening Programmes (NHSCSP and SCSP), and related to vaccination status. RESULTS: Significant reductions in positive predictive value (16%) and abnormal predictive value (63%) for CIN2+ and the mean colposcopy score (18%) were observed. A significant increase (38%) in the number of women who had to be referred to colposcopy to detect one case of CIN2+ was shown. The negative predictive value of negative- or low-grade cytology for CIN2+ increased significantly (12%). Sensitivity and specificity, as used by the UK cervical screening programmes, were maintained. CONCLUSIONS: The lower incidence of disease in vaccinated women alters the key performance indicators of cervical cytology used to monitor the quality of the screening programme. These findings have implications for screening, colposcopy referral criteria, colposcopy practice and histology reporting. PMID- 26931371 TI - A transcriptomic insight into the infective juvenile stage of the insect parasitic nematode, Heterorhabditis indica. AB - BACKGROUND: Nematodes are the most numerous animals in the soil. Insect parasitic nematodes of the genus Heterorhabditis are capable of selectively seeking, infecting and killing their insect-hosts in the soil. The infective juvenile (IJ) stage of the Heterorhabditis nematodes is analogous to Caenorhabditis elegans dauer juvenile stage, which remains in 'arrested development' till it finds and infects a new insect-host in the soil. H. indica is the most prevalent species of Heterorhabditis in India. To understand the genes and molecular processes that govern the biology of the IJ stage, and to create a resource to facilitate functional genomics and genetic exploration, we sequenced the transcriptome of H. indica IJs. RESULTS: The de-novo sequence assembly using Velvet-Oases pipeline resulted in 13,593 unique transcripts at N50 of 1,371 bp, of which 53 % were annotated by blastx. H. indica transcripts showed higher orthology with parasitic nematodes as compared to free living nematodes. In-silico expression analysis showed 30 % of transcripts expressing with >=100 FPKM value. All the four canonical dauer formation pathways like cGMP-PKG, insulin, dafachronic acid and TGF-beta were active in the IJ stage. Several other signaling pathways were highly represented in the transcriptome. Twenty-four orthologs of C. elegans RNAi pathway effector genes were discovered in H. indica, including nrde-3 that is reported for the first time in any of the parasitic nematodes. An ortholog of C. elegans tol-1 was also identified. Further, 272 kinases belonging to 137 groups, and several previously unidentified members of important gene classes were identified. CONCLUSIONS: We generated high-quality transcriptome sequence data from H. indica IJs for the first time. The transcripts showed high similarity with the parasitic nematodes, M. hapla, and A. suum as opposed to C. elegans, a species to which H. indica is more closely related. The high representation of transcripts from several signaling pathways in the IJs indicates that despite being a developmentally arrested stage; IJs are a hotbed of signaling and are actively interacting with their environment. PMID- 26931372 TI - Spatially aggregated clusters and scattered smaller loci of elevated malaria vector density and human infection prevalence in urban Dar es Salaam, Tanzania. AB - BACKGROUND: Malaria transmission, primarily mediated by Anopheles gambiae, persists in Dar es Salaam (DSM) despite high coverage with bed nets, mosquito proofed housing and larviciding. New or improved vector control strategies are required to eliminate malaria from DSM, but these will only succeed if they are delivered to the minority of locations where residual transmission actually persists. Hotspots of spatially clustered locations with elevated malaria infection prevalence or vector densities were, therefore, mapped across the city in an attempt to provide a basis for targeting supplementary interventions. METHODS: Two phases of a city-wide population-weighted random sample of cross sectional household surveys of malaria infections were complemented by two matching phases of geographically overlapping, high-resolution, longitudinal vector density surveys; spanning 2010-2013. Spatial autocorrelations were explored using Moran's I and hotspots were detected using flexible spatial scan statistics. RESULTS: Seven hotspots of spatially clustered elevated vector density and eight of malaria infection prevalence were detected over both phases. Only a third of vectors were collected in hotspots in phase 1 (30 %) and phase 2 (33 %). Malaria prevalence hotspots accounted for only half of malaria infections detected in phase 1 (55 %) and phase 2 (47 %). Three quarters (76 % in phase 1 and 74 % in phase 2) of survey locations with detectable vector populations were outside of hotspots. Similarly, more than half of locations with higher infection prevalence (>10 %) occurred outside of hotspots (51 % in phase 1 and 54 % in phase 2). Vector proliferation hazard (exposure to An. gambiae) and malaria infection risk were only very loosely associated with each other (Odds ratio (OR) [95 % Confidence Interval (CI)] = 1.56 [0.89, 1.78], P = 0.52)). CONCLUSION: Many small, scattered loci of local malaria transmission were haphazardly scattered across the city, so interventions targeting only currently identifiable spatially aggregated hotspots will have limited impact. Routine, spatially comprehensive, longitudinal entomological and parasitological surveillance systems, with sufficient sensitivity and spatial resolution to detect these scattered loci, are required to eliminate transmission from this typical African city. Intervention packages targeted to both loci and hotspots of transmission will need to suppress local vector proliferation, treat infected residents and provide vulnerable residents with supplementary protective measures against exposure. PMID- 26931373 TI - Experimental febrile seizures impair interastrocytic gap junction coupling in juvenile mice. AB - Prolonged and focal febrile seizures (FSs) have been associated with the development of temporal lobe epilepsy (TLE), although the underlying mechanism and the contribution of predisposing risk factors are still poorly understood. Using a kainate model of TLE, we previously provided strong evidence that interruption of astrocyte gap junction-mediated intercellular communication represents a crucial event in epileptogenesis. To elucidate this aspect further, we induced seizures in immature mice by hyperthermia (HT) to study the consequences of FSs on the hippocampal astrocytic network. Changes in interastrocytic coupling were assessed by tracer diffusion studies in acute slices from mice 5 days after experimental FS induction. The results reveal that HT-induced FSs cause a pronounced reduction of astrocyte gap junctional coupling in the hippocampus by more than 50%. Western blot analysis indicated that reduced connexin43 protein expression and/or changes in the phosphorylation status account for this astrocyte dysfunction. Remarkably, uncoupling occurred in the absence of neuronal death and reactive gliosis. These data provide a mechanistic link between FSs and the subsequent development of TLE and further strengthen the emerging view that astrocytes have a central role in the pathogenesis of this disorder. (c) 2016 Wiley Periodicals, Inc. PMID- 26931374 TI - Creating symbolic cultures of consumption: an analysis of the content of sports wagering advertisements in Australia. AB - BACKGROUND: Since 2008, Australia has seen the rapid emergence of marketing for online and mobile sports wagering. Previous research from other areas of public health, such as tobacco and alcohol, has identified the range of appeal strategies these industries used to align their products with culturally valued symbols. However, there is very limited research that has investigated the tactics the sports wagering industry uses within marketing to influence the consumption of its products and services. METHOD: This study consisted of a mixed method interpretive content analysis of 85 sports wagering advertisements from 11 Australian and multinational wagering companies. Advertisements were identified via internet searches and industry websites. A coding framework was applied to investigate the extent and nature of symbolic appeal strategies within advertisements. RESULTS: Ten major appeal strategies emerged from this analysis. These included sports fan rituals and behaviours; mateship; gender stereotypes; winning; social status; adventure, thrill and risk; happiness; sexualised imagery; power and control; and patriotism. Symbols relating to sports fan rituals and behaviours, and mateship, were the most common strategies used within the advertisements. DISCUSSION/CONCLUSIONS: This research suggests that the appeal strategies used by the sports wagering industry are similar to those strategies adopted by other unhealthy commodity industries. With respect to gambling, analysis revealed that strategies are clearly targeted to young male sports fans. Researchers and public health practitioners should seek to better understand the impact of marketing on the normalisation of sports wagering for this audience segment, and implement strategies to prevent gambling harm. PMID- 26931375 TI - Shisa6 traps AMPA receptors at postsynaptic sites and prevents their desensitization during synaptic activity. AB - Trafficking and biophysical properties of AMPA receptors (AMPARs) in the brain depend on interactions with associated proteins. We identify Shisa6, a single transmembrane protein, as a stable and directly interacting bona fide AMPAR auxiliary subunit. Shisa6 is enriched at hippocampal postsynaptic membranes and co-localizes with AMPARs. The Shisa6 C-terminus harbours a PDZ domain ligand that binds to PSD-95, constraining mobility of AMPARs in the plasma membrane and confining them to postsynaptic densities. Shisa6 expressed in HEK293 cells alters GluA1- and GluA2-mediated currents by prolonging decay times and decreasing the extent of AMPAR desensitization, while slowing the rate of recovery from desensitization. Using gene deletion, we show that Shisa6 increases rise and decay times of hippocampal CA1 miniature excitatory postsynaptic currents (mEPSCs). Shisa6-containing AMPARs show prominent sustained currents, indicating protection from full desensitization. Accordingly, Shisa6 prevents synaptically trapped AMPARs from depression at high-frequency synaptic transmission. PMID- 26931376 TI - Metabolism of aceclofenac in cattle to vulture-killing diclofenac. AB - The nonsteroidal anti-inflammatory drug (NSAID) diclofenac is highly toxic to Gyps vultures, and its recent widespread use in South Asia caused catastrophic declines in at least 3 scavenging raptors. The manufacture of veterinary formulations of diclofenac has since been banned across the region with mixed success. However, at least 12 other NSAIDs are available for veterinary use in South Asia. Aceclofenac is one of these compounds, and it is known to metabolize into diclofenac in some mammal species. The metabolic pathway of aceclofenac in cattle, the primary food of vultures in South Asia, is unknown. We gave 6 cattle the recommended dose of aceclofenac (2 mg/kg), collected blood thereafter at intervals for up to 12 h, and used liquid chromatography with mass spectrometry in a pharmacokinetic analysis of aceclofenac and diclofenac in the plasma. Nearly all the aceclofenac administered to the cattle was very rapidly metabolized into diclofenac. At 2 h, half the aceclofenac had been converted into diclofenac, and at 12 h four-fifths of the aceclofenac had been converted into diclofenac. Therefore, administering aceclofenac to livestock poses the same risk to vultures as administering diclofenac to livestock. This, coupled with the risk that aceclofenac may replace diclofenac in the veterinary market, points to the need for an immediate ban on all aceclofenac formulations that can be used to treat livestock. Without such a ban, the recovery of vultures across South Asia will not be successful. PMID- 26931377 TI - Comment on "Proton Transfer of Guanine Radical Cations Studied by Time-Resolved Resonance Raman Spectroscopy Combined with Pulse Radiolysis". PMID- 26931379 TI - Increasing 'ease of sliding' also increases friction: when is a lubricant effective? AB - We investigate experimentally the effective Coulomb friction exerted by a granular medium on a shearing plate, varying the medium depth. The plate is driven by a spring connected to a motor turning at a constant speed and, depending on the system configuration, performs continuous sliding or stick and slip in different proportions. We introduce an order parameter which discriminates between the different regimes expressing the fraction of time spent in slipping. At low driving speed, starting from zero layers of interstitial granular material, the average friction coefficient decreases when a few layers are added, while the order parameter stays close to zero. By further increasing the granular depth, the friction undergoes a sudden increase but the order parameter does not change notably. At an intermediate driving speed, however, both the friction and the order parameter undergo a sudden increase, which for the order parameter amounts to several orders of magnitude, indicating that the plate is more braked but nevertheless keeps sliding more easily. For medium-high driving speeds, full sliding is obtained for only one layer of interstitial matter, where friction has a minimum, and is maintained for all increasing depths while friction increases. These observations show that the ease of slipping is not determined by friction alone, rather by the highly complex interplay between driving velocity, friction, and the depth of the medium. PMID- 26931378 TI - Adding constraints to predation through allometric relation of scats to consumption. AB - A thorough understanding of mechanisms of prey consumption by carnivores and the constraints on predation help us in evaluating the role of carnivores in an ecosystem. This is crucial in developing appropriate management strategies for their conservation and mitigating human-carnivore conflict. Current models on optimal foraging suggest that mammalian carnivores would profit most from killing the largest prey that they can subdue with minimal risk of injury to themselves. Wild carnivore diets are primarily estimated through analysis of their scats. Using extensive feeding experiments (n = 68) on a wide size range (4.5-130 kg) of obligate carnivores - lion, leopard, jungle cat and domestic cat, we parameterize biomass models that best relate consumption to scat production. We evaluate additional constraints of gut fill, prey digestibility and carcass utilization on carnivory that were hereto not considered in optimal foraging studies. Our results show that patterns of consumption to scat production against prey size are similar and asymptotic, contrary to established linear models, across these carnivores after accounting for the effect of carnivore size. This asymptotic, allometric relationship allowed us to develop a generalized model: biomass consumed per collectable scat/predator weight = 0.033-0.025exp(-4.284(prey weight/predator weight)) , which is applicable to all obligate carnivores to compute prey biomass consumed from scats. Our results also depict a relationship for prey digestibility which saturates at about 90% for prey larger than predator size. Carcass utilization declines exponentially with prey size. These mechanisms result in digestible biomass saturating at prey weights approximately equal to predator weight. Published literature on consumption by tropical carnivores that has relied on linear biomass models is substantially biased. We demonstrate the nature of these biases by correcting diets of tiger, lion and leopard in recent publications. Our analysis suggests that consumption of medium-sized prey was significantly underestimated, while large prey consumption was grossly overestimated in large carnivore diets to date. We highlight that additional constraints of prey digestibility and utilization combined with escalating handling time and risks of killing large prey make prey larger than the predator size unprofitable for obligate carnivores. PMID- 26931380 TI - A new approach to chemotherapy: drug-induced differentiation kills African trypanosomes. AB - Human African trypanosomiasis (sleeping sickness) is a neglected tropical disease caused by Trypanosoma brucei spp. The parasites are transmitted by tsetse flies and adapt to their different hosts and environments by undergoing a series of developmental changes. During differentiation, the trypanosome alters its protein coat. Bloodstream form trypanosomes in humans have a coat of variant surface glycoprotein (VSG) that shields them from the immune system. The procyclic form, the first life-cycle stage to develop in the tsetse fly, replaces the VSG coat by procyclins; these proteins do not protect the parasite from lysis by serum components. Our study exploits the parasite-specific process of differentiation from bloodstream to procyclic forms to screen for potential drug candidates. Using transgenic trypanosomes with a reporter gene in a procyclin locus, we established a whole-cell assay for differentiation in a medium-throughput format. We screened 7,495 drug-like compounds and identified 28 hits that induced expression of the reporter and loss of VSG at concentrations in the low micromolar range. Small molecules that induce differentiation to procyclic forms could facilitate studies on the regulation of differentiation as well as serving as scaffolds for medicinal chemistry for new treatments for sleeping sickness. PMID- 26931381 TI - The viral G protein-coupled receptor ORF74 unmasks phospholipase C signaling of the receptor tyrosine kinase IGF-1R. AB - Kaposi's sarcoma-associated herpesvirus (KSHV) encodes the constitutively active G protein-coupled receptor ORF74, which is expressed on the surface of infected host cells and has been linked to the development of the angioproliferative tumor Kaposi's sarcoma. Furthermore, the insulin-like growth factor (IGF)-1 receptor, a receptor tyrosine kinase, also plays an essential role in Kaposi's sarcoma growth and survival. In this study we examined the effect of the constitutively active viral receptor ORF74 on human IGF-1R signaling. Constitutive and CXCL1-induced ORF74 signaling did not transactivate IGF-1R. In contrast, IGF-1 stimulated phospholipase C (PLC) activation in an ORF74-dependent manner without affecting chemokine binding to ORF74. Inhibition of constitutive ORF74 activity by mutagenesis or the inverse agonist CXCL10, or neutralizing IGF-1R with an antibody or silencing IGF-1R expression using siRNA inhibited PLC activation by IGF-1. Transactivation of ORF74 in response to IGF-1 occurred independently of Src, PI3K, and secreted ORF74 ligands. Furthermore, tyrosine residues in the carboxyl-terminus and intracellular loop 2 of ORF74 are not essential for IGF-1 induced PLC activation. Interestingly, PLC activation in response to IGF-1 is specific for ORF74 as IGF-1 was unable to activate PLC in cells expressing the constitutively active human cytomegalovirus (HCMV)-encoded GPCR US28. Interestingly, IGF-1 does not induce beta-arrestin recruitment to ORF74. The proximity ligation assay revealed close proximity between ORF74 and IGF-1R on the cell surface, but a physical interaction was not confirmed by co immunoprecipitation. Unmasking IGF-1R signaling to PLC in response to IGF-1 is a previously unrecognized action of ORF74. PMID- 26931383 TI - Cytoprotective Effect of Hydroalcoholic Extract of Pinus eldarica Bark against H2O2-Induced Oxidative Stress in Human Endothelial Cells. AB - BACKGROUND: Pinus eldarica is a widely growing pine in Iran consisting of biologically active constituents with antioxidant properties. This study investigates the effect of hydroalcoholic extract of P. eldarica bark against oxidative damage induced by hydrogen peroxide (H2O2) in human umbilical vein endothelial cells (HUVECs). METHODS: The total phenolic content of P. eldarica extract was determined using Folin-Ciocalteu method. The cytotoxicity of P. eldarica extract (25-1000 ug/ml) on HUVECs was assessed using 3-(4,5- Dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) method. Cytoprotective effect of P. eldarica extract (25-500 ug/ml) on H2O2-induced oxidative stress was also evaluated by MTT assay. The intra- and extra-cellular hydroperoxides concentration and ferric reducing antioxidant power (FRAP) were measured in pretreated cells. RESULTS: The total phenolic content of P. eldarica extract was estimated as 37.04+/-1.8% gallic acid equivalent. P. eldarica extract (25-1000 ug/ml) had no cytotoxic effect on HUVECs viability. The pretreatment of HUVECs with P. eldarica extract at the concentrations of 50-500 ug/ml significantly reduced the cytotoxicity of H2O2. P. eldarica extract decreased hydroperoxides concentration and increased FRAP value in intra-cellular fluid at the concentration range of 100-500 ug/ml and in extra-cellular fluid at the concentration range of 25-500 ug/ml. CONCLUSIONS: This study revealed the antioxidant and cytoprotective effects of P. eldarica extract against H2O2 induced oxidative stress in HUVECs. Concerning the high content of phenolic compounds in P. eldarica, more research is needed to evaluate its clinical value in endothelial dysfunction and in other oxidative conditions. PMID- 26931384 TI - Existence of two groups of Staphylococcus aureus strains isolated from bovine mastitis based on biofilm formation, intracellular survival, capsular profile and agr-typing. AB - Staphylococcus (S.) aureus is recognised worldwide as an important pathogen causing contagious acute and chronic bovine mastitis. Chronic mastitis account for a significant part of all bovine cases and represent an important economic problem for dairy producers. Several properties (biofilm formation, intracellular survival, capsular expression and group agr) are thought to be associated with this chronic status. In a previous study, we found the existence of two groups of strains based on the association of these features. The aim of the present work was to confirm on a large international and non-related collection of strains the existence of these clusters and to associate them with case history records. In addition, the genomes of eight strains were sequenced to study the genomic differences between strains of each cluster. The results confirmed the existence of both groups based on capsular typing, intracellular survival and agr-typing: strains cap8-positive, belonging to agr group II, showing a low invasion rate and strains cap5-positive, belonging to agr group I, showing a high invasion rate. None of the two clusters were associated with the chronic status of the cow. When comparing the genomes of strains belonging to both clusters, the genes specific to the group "cap5-agrI" would suggest that these strains are better adapted to live in hostile environment. The existence of these two groups is highly important as they may represent two clusters that are adapted differently to the host and/or the surrounding environment. PMID- 26931382 TI - ALG1-CDG: Clinical and Molecular Characterization of 39 Unreported Patients. AB - Congenital disorders of glycosylation (CDG) arise from pathogenic mutations in over 100 genes leading to impaired protein or lipid glycosylation. ALG1 encodes a beta1,4 mannosyltransferase that catalyzes the addition of the first of nine mannose moieties to form a dolichol-lipid linked oligosaccharide intermediate required for proper N-linked glycosylation. ALG1 mutations cause a rare autosomal recessive disorder termed ALG1-CDG. To date 13 mutations in 18 patients from 14 families have been described with varying degrees of clinical severity. We identified and characterized 39 previously unreported cases of ALG1-CDG from 32 families and add 26 new mutations. Pathogenicity of each mutation was confirmed based on its inability to rescue impaired growth or hypoglycosylation of a standard biomarker in an alg1-deficient yeast strain. Using this approach we could not establish a rank order comparison of biomarker glycosylation and patient phenotype, but we identified mutations with a lethal outcome in the first two years of life. The recently identified protein-linked xeno-tetrasaccharide biomarker, NeuAc-Gal-GlcNAc2 , was seen in all 27 patients tested. Our study triples the number of known patients and expands the molecular and clinical correlates of this disorder. PMID- 26931385 TI - Co-colonization and clonal diversity of methicillin-sensitive and methicillin resistant Staphylococcus aureus in sows. AB - Methicillin-susceptible Staphylococcus (S.) aureus (MSSA) and methicillin resistant S. aureus (MRSA) are colonizers of skin and mucosa. In humans, MSSA and MRSA compete for colonization space in the anterior nares of pig farmers; however, it was also shown that MSSA/MRSA co-colonization is common and one clone can be found rather than differing types of MSSA and MRSA. We investigated the colonization and clonality of both, MSSA and MRSA in pigs over a longer time. Eighteen sows were nasally sampled three times every ten weeks. Additionally, environmental samples were taken. Samples were investigated for MSSA and MRSA, respectively. The spa type was defined from up to five MRSA and MSSA isolates found per sample and sampling time; selected isolates were further investigated by microarray. Three sows (16.7%) were completely negative for MSSA and MRSA. Twelve pigs (66.7%) were irregularly positive for both, MSSA and MRSA over the time, whereas seven out of them (38.9%) were simultaneously colonized. CC398 (t034, t011) MRSA and CC9 (t337, t1430, and t13816) MSSA associated spa types were exclusively found. In 44.4% (n=8) of sows up to two different types of MSSA were present at the same time and sample. Strains of the same clonal lineage showed a high genetic identity despite their origin. Highly identic clones were present in sows and their environment. As conclusion, MSSA/MRSA may not exclude each other in the anterior nares of pigs. Pigs may also carry different clones at the same time. PMID- 26931386 TI - African swine fever virus: current state and future perspectives in vaccine and antiviral research. AB - African swine fever (ASF) is among the most significant of swine diseases for which no effective vaccines and antivirals are available. The disease, which is endemic in Africa, was introduced to Trans-Caucasian countries and the Russian Federation in 2007, where it remains prevalent today among domestic pigs and wild boars. Although some measures were implemented, ASF continues to pose a global risk for all countries, and thereby highlighting the importance of vaccine and antiviral research. In this review, an overview of research efforts toward the development of effective vaccines during the past decades is presented. As an alternative to vaccine development, the current state in antiviral research against ASFV is also presented. Finally, future perspectives in vaccine and antiviral research giving emphasis on some strategies that may allow researchers to develop effective countermeasures against ASF are discussed. PMID- 26931387 TI - Innate and adaptive immune responses to tick-borne flavivirus infection in sheep. AB - The flaviviruses tick-borne encephalitis virus (TBEV) and louping ill virus (LIV) are closely-related genetically and antigenically, have broadly similar host ranges that include rodents and other mammals (including sheep), and are both transmitted by the same tick species, Ixodes ricinus. Although human infection with TBEV results in a febrile illness followed in some cases by encephalitis, humans appear to be much less susceptible to infection with LIV. However, these viruses demonstrate different susceptibilities in sheep; LIV infection causes encephalitic disease, whereas TBEV infection generally does not. To investigate the role of the immune response in this mixed outcome, groups of sheep were inoculated with either virus, or with a primary inoculation with one virus and secondary inoculation with the other. Markers of both adaptive and innate immune responses were measured. In each group studied, infection resulted in seroconversion, demonstrated by the detection of virus specific neutralising antibodies. This appeared to control infection with TBEV but not LIV, which progressed to a febrile infection, with transient viraemia and elevated levels of serum interferon. This was followed by neuroinvasion, leading to up-regulation of innate immune transcripts in discrete areas of the brain, including interferon inducible genes and chemokines. Prior inoculation with TBEV did not prevent infection with LIV, but did appear to reduce disease severity and viraemia. We postulate that LIV has adapted to replicate efficiently in sheep cells, and disseminate rapidly following infection. By contrast, TBEV fails to disseminate in sheep and is controlled by the immune response. PMID- 26931388 TI - Impact of the administration of a third-generation cephalosporin (3GC) to one-day old chicks on the persistence of 3GC-resistant Escherichia coli in intestinal flora: An in vivo experiment. AB - The aim of the experiment was to evaluate under controlled conditions the impact on the excretion of 3GC-resistant Escherichia coli of the injection of one-day old chicks with ceftiofur, a third-generation cephalosporin (3GC). Three isolators containing specific-pathogen-free chicks were used. In the first one, 20 birds were injected with ceftiofur then ten of them were orally inoculated with a weak inoculum of a 3GC-resistant E. coli field isolate containing an IncI1/ST3 plasmid encoding a blaCTX-M-1 beta-lactamase. The other chicks were kept as contact birds. None of the 20 birds in the second isolator were injected with ceftiofur, but ten of them were similarly inoculated with the 3GC-resistant strain and the others kept as contact birds. A third isolator contained ten non injected, non-inoculated chicks. Fecal samples were collected regularly over one month and the E. coli isolated on non-supplemented media were characterized by antimicrobial agar dilution, detection of selected resistance genes and determination of phylogenetic group by PCR. The titers of 3GC-resistant E. coli in individual fecal samples were evaluated by culturing on 3GC-supplemented media. Results showed that the inoculated strain rapidly and abundantly colonized the inoculated and contact birds. The ceftiofur injection resulted in significantly higher percentages of 3GC-resistant E. coli isolates among the analyzed E. coli. No transfer of the 3GC-encoding plasmid to other isolates could be evidenced. In conclusion, these results highlight the dramatic capacity of 3GC resistant E. coli to colonize and persist in chicks, and the selecting pressure imposed by the off-label use of ceftiofur. PMID- 26931389 TI - Comparative genomics of toxigenic and non-toxigenic Staphylococcus hyicus. AB - The most common causative agent of exudative epidermitis (EE) in pigs is Staphylococcus hyicus. S. hyicus can be grouped into toxigenic and non-toxigenic strains based on their ability to cause EE in pigs and specific virulence genes have been identified. A genome wide comparison between non-toxigenic and toxigenic strains has never been performed. In this study, we sequenced eleven toxigenic and six non-toxigenic S. hyicus strains and performed comparative genomic and phylogenetic analysis. Our analyses revealed two genomic regions encoding genes that were predominantly found in toxigenic strains and are predicted to encode for virulence determinants for EE. All toxigenic strains encoded for one of the exfoliative toxins ExhA, ExhB, ExhC, or ExhD. In addition, one of these regions encoded for an ADP-ribosyltransferase (EDIN, epidermal cell differentiation inhibitor) and a novel putative RNase toxin (polymorphic toxin) and was associated with the gene encoding ExhA. A clear differentiation between toxigenic and non-toxigenic strains based on genomic and phylogenetic analyses was not apparent. The results of this study support the observation that exfoliative toxins of S. hyicus and S. aureus are located on genetic elements such as pathogenicity islands, phages, prophages and plasmids. PMID- 26931390 TI - Vibrio lentus protects gnotobiotic sea bass (Dicentrarchus labrax L.) larvae against challenge with Vibrio harveyi. AB - Due to the mounting awareness of the risks associated with the use of antibiotics in aquaculture, treatment with probiotics has recently emerged as the preferred environmental-friendly prophylactic approach in marine larviculture. However, the presence of unknown and variable microbiota in fish larvae makes it impossible to disentangle the efficacy of treatment with probiotics. In this respect, the recent development of a germ-free culture model for European sea bass (Dicentrarchus labrax L.) larvae opened the door for more controlled studies on the use of probiotics. In the present study, 206 bacterial isolates, retrieved from sea bass larvae and adults, were screened in vitro for haemolytic activity, bile tolerance and antagonistic activity against six sea bass pathogens. Subsequently, the harmlessness and the protective effect of the putative probiotic candidates against the sea bass pathogen Vibrio harveyi were evaluated in vivo adopting the previously developed germ-free sea bass larval model. An equivalence trial clearly showed that no harmful effect on larval survival was elicited by all three selected probiotic candidates: Bacillus sp. LT3, Vibrio lentus and Vibrio proteolyticus. Survival of Vibrio harveyi challenged larvae treated with V. lentus was superior in comparison with the untreated challenged group, whereas this was not the case for the larvae supplemented with Bacillus sp. LT3 and V. proteolyticus. In this respect, our results unmistakably revealed the protective effect of V. lentus against vibriosis caused by V. harveyi in gnotobiotic sea bass larvae, rendering this study the first in its kind. PMID- 26931391 TI - Lack of association between polymorphic copies of endogenous Jaagsiekte sheep retrovirus (enJSRVs) and Ovine Pulmonary Adenocarcinoma. AB - Ovine Pulmonary Adenocarcinoma (OPA) is a retrovirus-induced lung tumor of sheep, goat and mouflon, and its etiologic agent, Jaagsiekte sheep retrovirus (JSRV) is the only virus known to cause a naturally occurred lung adenocarcinoma. The oncogenic JSRV has several endogenous counterparts termed enJSRVs, some of which have been shown to interfere with JSRV replication at early and late stages of the retroviral cycle inhibiting JSRV exit from the cell, and thus, protecting sheep against the infection. In this work, Latxa sheep breed animals were classified depending on the presence/absence of OPA-characteristic clinical lesions in the lung. Using a PCR genotyping method and a logistic regression based association study, five polymorphic enJSRV copies were analyzed in 49 OPA positive sheep and 124 control individuals. Our results showed that the frequency of the provirus enJSRV-16 is much higher in Latxa sheep breed than in other breeds, suggesting a recent proliferation of this provirus in the studied breed. However, no polymorphic enJSRV was found to be statistically associated with the susceptibility/resistance to OPA development. PMID- 26931392 TI - Bacterial and viral pathogens detected in sea turtles stranded along the coast of Tuscany, Italy. AB - During 2014, six loggerhead turtles, Caretta caretta and one green turtle, Chelonia mydas, found stranded on the Tuscany coast of Italy, were examined for the presence of specific bacterial and viral agents, along with their role as carriers of fish and human pathogens. Thirteen different species of bacteria, 10 Gram negative and 3 Gram positive, were identified. Among them, two strains of Vibrio parahaemolyticus and one strain of Lactococcus garviae were recovered and confirmed by specific PCR protocols. No trh and tdh genes were detected in V. parahaemolyticus. The first isolation of L. garviae and the first detection of Betanodavirus in sea turtles indicate the possibility for sea turtles to act as carriers of fish pathogens. Furthermore, the isolation of two strains of V. parahaemolyticus highlights the possible role of these animals in human pathogens' diffusion. PMID- 26931393 TI - Nonstructural protein p39 of feline calicivirus suppresses host innate immune response by preventing IRF-3 activation. AB - Feline calicivirus (FCV) is an important veterinary pathogen that causes acute upper respiratory tract diseases and, occasionally, highly contagious febrile hemorrhagic syndrome in cats. Many viruses have adopted mechanisms for evading IFN-alpha/beta signaling, particularly by directly or indirectly suppressing activation of IRF-3. In this study, we investigated whether nonstructural proteins of FCV possess these mechanisms. When p39, a nonstructural protein of FCV, was transiently expressed in 293T cells, it suppressed IFN-beta and ISG15 mRNA production induced by dsRNA. Expression of p39 also suppressed phosphorylation and dimerization of IRF-3 induced by dsRNA. These results suggest that p39 suppresses type 1 IFN production by preventing IRF-3 activation. This may become an important factor in understanding the pathogenesis and virulence of FCV. PMID- 26931394 TI - TOX expression in cutaneous T-cell lymphomas: an adjunctive diagnostic marker that is not tumour specific and not restricted to the CD4(+) CD8(-) phenotype. AB - BACKGROUND: TOX (thymocyte selection-associated high-mobility group box) was shown to be aberrantly expressed in mycosis fungoides (MF) and Sezary syndrome (SS) and is suggested to have additional diagnostic value. However, data on expression in other types of cutaneous T-cell lymphoma (CTCL) are scarce and it is unknown whether TOX is expressed only by MF with a CD4(+) CD8(-) phenotype. OBJECTIVES: To investigate TOX expression in various types of CTCL with different T-cell phenotypes. METHODS: Immunohistochemical expression of TOX was evaluated on 153 skin biopsies of 132 patients with CTCL and 60 patients with benign inflammatory dermatoses (BIDs). RESULTS: TOX was expressed by > 50% of the neoplastic T cells in 49 of 59 patients (83%) with MF and in 19 of 22 patients (86%) with SS. The TOX(+) cases of MF included 34 of 35 cases (97%) with a CD4(+) CD8(-) phenotype, but also five of eight cases (63%) with a CD4(-) CD8(+) phenotype and 10 of 16 cases (63%) with a CD4(-) CD8(-) phenotype. TOX expression in other types of CTCL was common but showed variable intensity. Although only one of 60 patients (2%) with a BID expressed TOX in > 50% of the skin-infiltrating T cells, some caution is warranted, as the majority of BIDs had TOX(+) T cells varying between 11% and 50%. CONCLUSIONS: TOX expression is not tumour specific, is not restricted to CTCL with a CD4(+) CD8(-) phenotype, and, on its own, is insufficient for diagnosis of CTCL. However, it may have an adjunctive diagnostic role in conjunction with other clinical and histological data. PMID- 26931395 TI - The Synthesis of 1,3,5-triazine Derivatives and JNJ7777120 Analogues with Histamine H4 Receptor Affinity and Their Interaction with PTEN Promoter. AB - The involvement of histamine and H4 receptor (H4 R) in cancer has been investigated recently using the H4 R agonists and antagonists. The scope of the research project was synthesis and exploration of the consequences of a group of compounds with histamine H4 receptor (H4 R) affinity on the promoter of PTEN gene encoding the antitumor PTEN protein. The series of novel compounds based either on H4 R antagonists JNJ7777120 structure or 1,3,5-triazine scaffold were synthesized, evaluated for histamine H4 R affinity and used in this study. Compounds 5 and 7 belonging to the group of JNJ7777120 analogues showed the highest interaction with the promoter of PTEN gene and weak affinity against H4 R with Ki value >100 MUm. These compounds showed no significant effect on neuroblastoma IMR-32 cells viability indicating no correlation between PTEN gene promoter affinity and antitumor activity. Compound 6, another JNJ7777120 analogue, showed the highest effect on IMR-32 viability with calculated IC50 = 23.27 MUm. The 1,3,5-triazine derivatives exhibited generally low or medium interaction with PTEN gene promoter. However, the 1,3,5-triazine derivative 11 with the para-bromo substituent showed the highest affinity against H4 R with Ki value of 520 nm and may be considered as a new lead structure. PMID- 26931396 TI - Structure-based Inhibitor Design for the Intrinsically Disordered Protein c-Myc. AB - Intrinsically disordered proteins (IDPs) are associated with various diseases and have been proposed as promising drug targets. However, conventional structure based approaches cannot be applied directly to IDPs, due to their lack of ordered structures. Here, we describe a novel computational approach to virtually screen for compounds that can simultaneously bind to different IDP conformations. The test system used c-Myc, an oncoprotein containing a disordered basic helix-loop helix-leucine zipper (bHLH-LZ) domain that adopts a helical conformation upon binding to Myc-associated factor X (Max). For the virtual screen, we used three binding pockets in representative conformations of c-Myc370-409, which is part of the disordered bHLH-LZ domain. Seven compounds were found to directly bind c Myc370-409 in vitro, and four inhibited the growth of the c-Myc-overexpressing cells by affecting cell cycle progression. Our approach of IDP conformation sampling, binding site identification, and virtual screening for compounds that can bind to multiple conformations provides a useful strategy for structure-based drug discovery targeting IDPs. PMID- 26931397 TI - A Campus-Wide Investigation of Clicker Implementation: The Status of Peer Discussion in STEM Classes. AB - At the University of Maine, middle and high school teachers observed more than 250 university science, technology, engineering, and mathematics classes and collected information on the nature of instruction, including how clickers were being used. Comparisons of classes taught with (n = 80) and without (n = 184) clickers show that, while instructional behaviors differ, the use of clickers alone does not significantly impact the time instructors spend lecturing. One possible explanation stems from the observation of three distinct modes of clicker use: peer discussion, in which students had the opportunity to talk with one another during clicker questions; individual thinking, in which no peer discussion was observed; and alternative collaboration, in which students had time for discussion, but it was not paired with clicker questions. Investigation of these modes revealed differences in the range of behaviors, the amount of time instructors lecture, and how challenging the clicker questions were to answer. Because instructors can vary their instructional style from one clicker question to the next, we also explored differences in how individual instructors incorporated peer discussion during clicker questions. These findings provide new insights into the range of clicker implementation at a campus-wide level and how such findings can be used to inform targeted professional development for faculty. PMID- 26931398 TI - Features of Knowledge Building in Biology: Understanding Undergraduate Students' Ideas about Molecular Mechanisms. AB - Research has suggested that teaching and learning in molecular and cellular biology (MCB) is difficult. We used a new lens to understand undergraduate reasoning about molecular mechanisms: the knowledge-integration approach to conceptual change. Knowledge integration is the dynamic process by which learners acquire new ideas, develop connections between ideas, and reorganize and restructure prior knowledge. Semistructured, clinical think-aloud interviews were conducted with introductory and upper-division MCB students. Interviews included a written conceptual assessment, a concept-mapping activity, and an opportunity to explain the biomechanisms of DNA replication, transcription, and translation. Student reasoning patterns were explored through mixed-method analyses. Results suggested that students must sort mechanistic entities into appropriate mental categories that reflect the nature of MCB mechanisms and that conflation between these categories is common. We also showed how connections between molecular mechanisms and their biological roles are part of building an integrated knowledge network as students develop expertise. We observed differences in the nature of connections between ideas related to different forms of reasoning. Finally, we provide a tentative model for MCB knowledge integration and suggest its implications for undergraduate learning. PMID- 26931399 TI - Testing CREATE at Community Colleges: An Examination of Faculty Perspectives and Diverse Student Gains. AB - CREATE (Consider, Read, Elucidate the hypotheses, Analyze and interpret the data, and Think of the next Experiment) is an innovative pedagogy for teaching science through the intensive analysis of scientific literature. Initiated at the City College of New York, a minority-serving institution, and regionally expanded in the New York/New Jersey/Pennsylvania area, this methodology has had multiple positive impacts on faculty and students in science, technology, engineering, and mathematics courses. To determine whether the CREATE strategy is effective at the community college (2-yr) level, we prepared 2-yr faculty to use CREATE methodologies and investigated CREATE implementation at community colleges in seven regions of the United States. We used outside evaluation combined with pre/postcourse assessments of students to test related hypotheses: 1) workshop trained 2-yr faculty teach effectively with the CREATE strategy in their first attempt, and 2) 2-yr students in CREATE courses make cognitive and affective gains during their CREATE quarter or semester. Community college students demonstrated positive shifts in experimental design and critical-thinking ability concurrent with gains in attitudes/self-rated learning and maturation of epistemological beliefs about science. PMID- 26931400 TI - Adjuvant Endocrine Therapy for Women With Hormone Receptor-Positive Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update on Ovarian Suppression Summary. PMID- 26931401 TI - Cancer Screening Patterns and Concerns in Caregivers of Patients Undergoing Radiation Therapy. AB - PURPOSE: Evolving cancer screening guidelines can confuse the public. Caregivers of patients undergoing radiation oncology may represent a promising outreach target for disseminating and clarifying screening information. We aimed to: (1) determine the incidence of cancer screening in this cohort, and (2) identify barriers to and deficiencies in screening. METHODS: We distributed a 21-item survey on cancer screening history and related concerns to caregivers >= 18 years old at one urban and two suburban radiation oncology centers. Reported screening habits were compared with American Cancer Society/American Urological Association guidelines for breast, cervical, colon, and prostate cancer. Statistical analysis included Pearson chi(2) tests. RESULTS: A total of 209 caregivers (median age, 55.5 years; 146 women) were surveyed. Although 92% had primary care physicians (PCPs), only 58% reported being informed about recommended screening intervals. Participants <= 49 years old were less likely to report PCP discussion of cancer screening than older participants (41% and 66%, respectively; P = .006). Ninety eight respondents (47%) had one or more screening concern(s). Among screening eligible caregivers, 23 (18%) reported not undergoing regular colonoscopies. Fourteen women (13%) did not have Papanicolaou smears at recommended intervals, and 21 (18%) did not have annual mammograms. Six men (21%) did not undergo annual prostate screening. Decreased recommended screening with colonoscopy and mammography correlated with younger age. CONCLUSION: This survey of relatively unexplored caregivers identified cancer screening deficiencies and concerns that might be addressed by targeted interventions. With approximately 60% of patients with cancer receiving radiation therapy, advice in the radiation oncology setting could positively affect cancer screening behaviors in caregivers. PMID- 26931402 TI - Assessing the Quality of a Radiation Oncology Case-Based, Peer-Review Program in an Integrated Academic and Community Cancer Center Network. AB - PURPOSE: Academic centers increasingly find a need to define a comprehensive peer review program that can translate high-quality radiation therapy (RT) to community network sites. In this study, we describe the initial results of a quarterly quality audit program that aims to improve RT peer-review and provider educational processes across community sites. MATERIALS AND METHODS: An electronic tool was used by community-based certified member (CM) sites to enter clinical treatment information about patients undergoing peer review. At least 10% of the patient load for each CM physician was selected for audit on a quarterly basis by expert academic faculty. Quality metrics included the review of the management plan, technical plan, and other indicators. RT was scored as being concordant or nonconcordant with institutional guidelines, national standards, or expert judgment. RESULTS: A total of 719 patients were entered into the peer-review database by the first four CM sites. Of 14% of patients audited, 17% (18 of 104) were deemed nonconcordant. Nonconcordance rates were lowest in prevalent disease sites, such as breast (16%), colorectal (14%), and lung (12%), whereas rates were highest in lymphoma (50%), brain (44%), and gynecology (27%). Deficiencies included incomplete staging work-up, incorrect target and normal tissue delineation, and nonadherence to accepted dose-volume constraints. CONCLUSION: Given the high rate of nonconcordance, we recommend prospective, pre RT peer review of all patients, and, in particular, expert review of patients that are from low-volume or complex disease sites. An integrated approach to peer review holds a promise of improving the quality, safety, and value of cancer therapy in the community setting. PMID- 26931403 TI - Interaction dynamics of two diffusing particles: contact times and influence of nearby surfaces. AB - Interactions of diffusing particles are governed by hydrodynamics on different length and timescales. The local hydrodynamics can be influenced substantially by simple interfaces. Here, we investigate the interaction dynamics of two micron sized spheres close to plane interfaces to mimic more complex biological systems or microfluidic environments. Using scanned line optical tweezers and fast 3D interferometric particle tracking, we are able to track the motion of each bead with precisions of a few nanometers and at a rate of 10 kilohertz. From the recorded trajectories, all spatial and temporal information is accessible. This way, we measure diffusion coefficients for two coupling particles at varying distances h to one or two glass interfaces. We analyze their coupling strength and length by cross-correlation analysis relative to h and find a significant decrease in the coupling length when a second particle diffuses nearby. By analysing the times the particles are in close contact, we find that the influence of nearby surfaces and interaction potentials reduce the diffusivity strongly, although we found that the diffusivity hardly affects the contact times and the binding probability between the particles. All experimental results are compared to a theoretical model, which is based on the number of possible diffusion paths following the Catalan numbers and a diffusion probability, which is biased by the spheres' surface potential. The theoretical and experimental results agree very well and therefore enable a better understanding of hydrodynamically coupled interaction processes. PMID- 26931404 TI - Tumor-induced remote ECM network orientation steers angiogenesis. AB - Tumor angiogenesis promotes tumor growth and metastasis. Here, we use automated sequential microprinting of tumor and endothelial cells in extracellular matrix (ECM) scaffolds to study its mechanical aspects. Quantitative reflection microscopy shows that tumor spheroids induce radial orientation of the surrounding collagen fiber network up to a distance of five times their radius. Across a panel of ~20 different human tumor cell lines, remote collagen orientation is correlated with local tumor cell migration behavior. Tumor induced collagen orientation requires contractility but is remarkably resistant to depletion of collagen-binding integrins. Microvascular endothelial cells undergo directional migration towards tumor spheroids once they are within the tumor oriented collagen fiber network. Laser ablation experiments indicate that an intact physical connection of the oriented network with the tumor spheroid is required for mechanical sensing by the endothelial cells. Together our findings indicate that, in conjunction with described activities of soluble angiogenic factors, remote physical manipulation of the ECM network by the tumor can help to steer angiogenesis. PMID- 26931405 TI - Finnish experiences of health monitoring: local, regional, and national data sources for policy evaluation. AB - BACKGROUND: Finland has a long tradition of gathering information about the health and welfare of the adult population. DESIGN: Surveys and administrative registers form the basis for national and local health monitoring in Finland. RESULTS: Different data sources are used in Finland to develop key indicators, which can be used to evaluate how the national health policy targets have been met in different parts of the country and in different population subgroups. Progress has been shown in chronic disease risk factors, such as smoking reduction. However, some health policy targets have not been met. Socioeconomic health differences, for example, have remained large compared with other European countries. CONCLUSION: Although data availability for key health indicators is good in Finland, there is a need for wider and more comprehensive use of this information by political decision-makers and healthcare professionals. PMID- 26931407 TI - Noninnocence of Indigo: Dehydroindigo Anions as Bridging Electron-Donor Ligands in Diruthenium Complexes. AB - Complexes of singly or doubly deprotonated indigo (H2Ind) with one or two [Ru(pap)2](2+) fragments (pap = 2-phenylazopyridine) have been characterized experimentally [molecular structure, voltammetry, electron paramagnetic resonance (EPR), and UV-vis-near-IR spectroelectrochemistry] and by time-dependent density functional theory calculations. The compound [Ru(pap)2(HInd(-))]ClO4 ([1]ClO4) was found to contain an intramolecular NH---O hydrogen bond, whereas [{Ru(pap)2}2(MU-Ind(2-))](ClO4)2 ([2](ClO4)2), isolated as the meso diastereoisomer with near-IR absorptions at 1162 and 991 nm, contains two metals bridged at 6.354 A distance by the bischelating indigo dianion. The spectroelectrochemical study of multiple reversible reduction and oxidation processes of 2(n) (n = 4+, 3+, 2+, 1+, 0, 1-, 2-, 3-, 4-) reveals the stepwise addition of electrons to the terminal pi-accepting pap ligands, whereas the oxidations occur predominantly at the anionic indigo ligand, producing an EPR identified indigo radical intermediate and revealing the suitability of deprotonated indigo as a sigma- and pi-donating bischelating bridge. PMID- 26931406 TI - Live imaging of transforming growth factor-beta activated kinase 1 activation in Lewis lung carcinoma 3LL cells implanted into syngeneic mice and treated with polyinosinic:polycytidylic acid. AB - Transforming growth factor-beta activated kinase 1 (TAK1) has been shown to play a crucial role in cell death, differentiation, and inflammation. Here, we live imaged robust TAK1 activation in Lewis lung carcinoma 3LL cells implanted into the s.c. tissue of syngeneic C57BL/6 mice and treated with polyinosinic:polycytidylic acid (PolyI:C). First, we developed and characterized a Forster resonance energy transfer-based biosensor for TAK1 activity. The TAK1 biosensor, named Eevee-TAK1, responded to stress-inducing reagents such as anisomycin, tumor necrosis factor-alpha, and interleukin1-beta. The anisomycin induced increase in Forster resonance energy transfer was abolished by the TAK1 inhibitor (5z)-7-oxozeaenol. Activity of TAK1 in 3LL cells was markedly increased by PolyI:C in the presence of macrophages. 3LL cells expressing Eevee-TAK1 were implanted into mice and observed through imaging window by two-photon excitation microscopy. During the growth of tumor, the 3LL cells at the periphery of the tumor showed higher TAK1 activity than the 3LL cells located at the center of the tumor, suggesting that cells at the periphery of the tumor mass were under stronger stress. Injection of PolyI:C, which is known to induce regression of the implanted tumors, induced marked and homogenous TAK1 activation within the tumor tissues. The effect of PolyI:C faded within 4 days. These observations suggest that Eevee-TAK1 is a versatile tool to monitor cellular stress in cancer tissues. PMID- 26931408 TI - Nasopharyngeal fiberendoscopy in children: a survey of current Italian pediatric otolaryngological practices. AB - BACKGROUND: Nasopharyngeal fiberendoscopy (NFE) is the gold standard diagnostic procedure for adenoidal disease, but there is no consensus concerning the optimal technical approach. The aim of this study was to investigate the attitudes of Italian otolaryngologists towards diagnostic NFE in children, and the most widely used methods. METHODS: Nine hundred randomly selected members of the two largest Italian otolaryngological scientific societies were e-mailed an anonymous web based questionnaire containing 29 multiple-choice items regarding their opinions about, and use of NFE in children. RESULTS: Questionnaires were returned by 764 clinicians (84.9 %). About 75 % declared they used NFE, but 35 % said they preferred alternative diagnostic methods. Most of the respondents considered NFE safe, but more than 80 % judged it to be poorly or only fairly well tolerated. Almost all declared that they generally use flexible, small-diameter instruments, with the patient seated on a chair or a parent's lap; 65 % use gentle restraining methods. Fewer than 50 % reported using a standardised hypertrophy grading system. CONCLUSION: Italian otolaryngologists have a generally positive attitude towards using NFE in children. However, some have reservations, and there was no unanimous agreement concerning how it should be done. Given the medical advantages of NFE, it is essential to clarify the many still controversial aspects of the procedure by means of comparative studies and educational programmes. PMID- 26931409 TI - Ultrathin Hf0.5Zr0.5O2 Ferroelectric Films on Si. AB - Because of their immense scalability and manufacturability potential, the HfO2 based ferroelectric films attract significant attention as strong candidates for application in ferroelectric memories and related electronic devices. Here, we report the ferroelectric behavior of ultrathin Hf0.5Zr0.5O2 films, with the thickness of just 2.5 nm, which makes them suitable for use in ferroelectric tunnel junctions, thereby further expanding the area of their practical application. Transmission electron microscopy and electron diffraction analysis of the films grown on highly doped Si substrates confirms formation of the fully crystalline non-centrosymmetric orthorhombic phase responsible for ferroelectricity in Hf0.5Zr0.5O2. Piezoresponse force microscopy and pulsed switching testing performed on the deposited top TiN electrodes provide further evidence of the ferroelectric behavior of the Hf0.5Zr0.5O2 films. The electronic band lineup at the top TiN/Hf0.5Zr0.5O2 interface and band bending at the adjacent n(+)-Si bottom layer attributed to the polarization charges in Hf0.5Zr0.5O2 have been determined using in situ X-ray photoelectron spectroscopy analysis. The obtained results represent a significant step toward the experimental implementation of Si-based ferroelectric tunnel junctions. PMID- 26931410 TI - Diurnal variation of anterior scleral and conjunctival thickness. AB - PURPOSE: To examine whether anterior scleral and conjunctival thickness undergoes significant diurnal variation over a 24-h period. METHODS: Nineteen healthy young adults (mean age 22 +/- 2 years) with minimal refractive error (mean spherical equivalent refraction -0.08 +/- 0.39 D), had measures of anterior scleral and conjunctival thickness collected using anterior segment optical coherence tomography (AS-OCT) at seven measurement sessions over a 24-h period. The thickness of the temporal anterior sclera and conjunctiva were determined at six locations (each separated by 0.5 mm) at varying distances from the scleral spur (SS) for each subject at each measurement session. RESULTS: Both the anterior sclera and conjunctiva were found to undergo significant diurnal variations in thickness over a 24-h period (both p < 0.01). The sclera and conjunctiva exhibited a similar pattern of diurnal change, with a small magnitude thinning observed close to midday, and a larger magnitude thickening observed in the early morning immediately after waking. The amplitude of diurnal thickness change was larger in the conjunctiva (mean amplitude 69 +/- 29 MUm) compared to the sclera (21 +/- 8 MUm). The conjunctiva exhibited its smallest magnitude of change at the SS location (mean amplitude 56 +/- 17 MUm) whereas the sclera exhibited its largest magnitude of change at this location (52 +/- 21 MUm). CONCLUSIONS: This study provides the first evidence of diurnal variations occurring in the thickness of the anterior sclera and conjunctiva. Studies requiring precise measures of these anatomical layers should therefore take time of day into consideration. The majority of the observed changes occurred in the early morning immediately after waking and were of larger magnitude in the conjunctiva compared to the sclera. Thickness changes at other times of the day were of smaller magnitude and generally not statistically significant. PMID- 26931412 TI - The effect of Community Based Education and Service (COBES) on medical graduates' choice of specialty and willingness to work in rural communities in Ghana. AB - BACKGROUND: Career choices and placements of healthcare professionals in rural areas are a major problem worldwide, and their recruitment and retention to these areas have become a challenge to the health sector. The purpose of this study was to investigate the effect of Community Based Education and Service (COBES) on medical graduates' choice of specialty and willingness to work in a rural area. METHOD: This cross sectional survey was conducted among 56 pioneering graduates that followed a Problem Based Learning/Community Based Education and Service (PBL/COBES) curriculum. Using a mixed methods approach, open-and closed-ended questionnaire was administered to 56 graduates. Cross tabulation using Chi-square test were used to compare findings of the quantitative data. All qualitative data analysis was performed using the principles of primary, secondary and tertiary coding. RESULTS: All 56 graduates answered and returned the questionnaire giving a 100 % response rate. 57.1 % (32) of them were male. Majority of them lived in towns (41.1 %) and cities (50 %) prior to medical school. A significant number of graduates (53.6 %,) from the cities, without any female or male predominance said COBES had influenced their choice of specialty. Again, a significant proportion of graduates from the towns (60.9 %,) and cities (67.8 %,), indicated that COBES had influenced them to work in the rural area. However, there was no significant difference between males and females from the towns and cities regarding the influence of COBES to work in the rural area. Qualitative data supported the finding that COBES will influence graduates willingness to work in the rural area CONCLUSION: The majority of graduates from the towns and cities in Ghana, with a male predominance, indicated that COBES may have influenced their choice of specialty and willingness to practice in the rural areas despite their town or city based upbringing. PMID- 26931411 TI - Genetic alteration of the metal/redox modulation of Cav3.2 T-type calcium channel reveals its role in neuronal excitability. AB - KEY POINTS: In this study, we describe a new knock-in (KI) mouse model that allows the study of the H191-dependent regulation of T-type Cav3.2 channels. Sensitivity to zinc, nickel and ascorbate of native Cav3.2 channels is significantly impeded in the dorsal root ganglion (DRG) neurons of this KI mouse. Importantly, we describe that this H191-dependent regulation has discrete but significant effects on the excitability properties of D-hair (down-hair) cells, a sub-population of DRG neurons in which Cav3.2 currents prominently regulate excitability. Overall, this study reveals that the native H191-dependent regulation of Cav3.2 channels plays a role in the excitability of Cav3.2 expressing neurons. This animal model will be valuable in addressing the potential in vivo roles of the trace metal and redox modulation of Cav3.2 T-type channels in a wide range of physiological and pathological conditions. ABSTRACT: Cav3.2 channels are T-type voltage-gated calcium channels that play important roles in controlling neuronal excitability, particularly in dorsal root ganglion (DRG) neurons where they are involved in touch and pain signalling. Cav3.2 channels are modulated by low concentrations of metal ions (nickel, zinc) and redox agents, which involves the histidine 191 (H191) in the channel's extracellular IS3-IS4 loop. It is hypothesized that this metal/redox modulation would contribute to the tuning of the excitability properties of DRG neurons. However, the precise role of this H191-dependent modulation of Cav3.2 channel remains unresolved. Towards this goal, we have generated a knock-in (KI) mouse carrying the mutation H191Q in the Cav3.2 protein. Electrophysiological studies were performed on a subpopulation of DRG neurons, the D-hair cells, which express large Cav3.2 currents. We describe an impaired sensitivity to zinc, nickel and ascorbate of the T-type current in D-hair neurons from KI mice. Analysis of the action potential and low-threshold calcium spike (LTCS) properties revealed that, contrary to that observed in WT D-hair neurons, a low concentration of zinc and nickel is unable to modulate (1) the rheobase threshold current, (2) the afterdepolarization amplitude, (3) the threshold potential necessary to trigger an LTCS or (4) the LTCS amplitude in D-hair neurons from KI mice. Together, our data demonstrate that this H191-dependent metal/redox regulation of Cav3.2 channels can tune neuronal excitability. This study validates the use of this Cav3.2-H191Q mouse model for further investigations of the physiological roles thought to rely on this Cav3.2 modulation. PMID- 26931413 TI - Increased choroidal mast cells and their degranulation in age-related macular degeneration. AB - BACKGROUND/AIMS: Inflammation has been implicated in age-related macular degeneration (AMD). This study investigates the association of mast cells (MCs), a resident choroidal inflammatory cell, with pathological changes in AMD. METHODS: Human donor eyes included aged controls (n=10), clinically diagnosed with early AMD (n=8), geographic atrophy (GA, n=4) and exudative AMD (n=11). The choroids were excised and incubated for alkaline phosphatase (APase; blood vessels) and non-specific esterase activities (MCs). Degranulated (DG) and non degranulated MCs in four areas of posterior choroid (nasal, non-macular, paramacular and submacular) were counted in flat mounts (4-6 fields/area). Choroids were subsequently embedded in JB-4 and sectioned for histological analyses. RESULTS: The number of MCs was significantly increased in all choroidal areas in early AMD (p=0.0006) and in paramacular area in exudative AMD (139.44+/ 55.3 cells/mm(2); p=0.0091) and GA (199.08+/-82.0 cells/mm(2); p=0.0019) compared with the aged controls. DG MCs were also increased in paramacular (p=0.001) and submacular choroid (p=0.02) in all forms of AMD. Areas with the greatest numbers of DG MCs had loss of choriocapillaris (CC). Sections revealed that the MCs were widely distributed in Sattler's and Haller's layer in the choroidal stroma in aged controls, whereas MCs were frequently found in close proximity with CC in GA and exudative AMD and in choroidal neovascularisation (CNV). CONCLUSION: Increased MC numbers and degranulation were observed in all AMD choroids. These results suggest that MC degranulation may contribute to the pathogenesis of AMD: death of CC and retinal pigment epithelial and CNV formation. The proteolytic enzymes released from MC granules may result in thinning of AMD choroid. PMID- 26931414 TI - Candidemia in major burns patients. AB - Major burn patients have characteristics that make them especially susceptible to candidemia, but few studies focused on this have been published. The objectives were to evaluate the epidemiological, microbiological and clinical aspects of candidemia in major burn patients, determining factors associated with a poorer prognosis and mortality. We conducted a retrospective observational study of candidemia between 1996 and 2012 in major burn patients admitted to the La Fe University Hospital, Valencia, Spain. The study included 36 episodes of candidemia in the same number of patients, 55.6% men, mean age 37.33 years and low associated comorbidity. The incidence of candidemia varied between 0.26 and 6.09 episodes/1000 days stay in the different years studied. Candida albicans was the most common species (61.1%) followed by Candida parapsilosis (27.8%). Candidemia by C. krusei, C. glabrata or C. tropicalis were all identified after 2004. Central vascular catheter (CVC) was established as a potential source of candidemia in 36.1%, followed by skin and soft tissues of thermal injury (22.2%) and urinary tract (8.3%). Fluconazole was used in 19 patients (52.7%) and its in vitro resistance rate was 13.9%. The overall mortality was 47.2%, and mortality related to candidemia was 30.6%. Factors associated with increased mortality were those related to severe infection and shock. CVC was the most usual focus of candidemia. Fluconazole was the most common antifungal drug administered. The management of candidemia in major burn patients is still a challenge. PMID- 26931415 TI - Elevating the alternating-access model. PMID- 26931416 TI - A new communication hub in the RNA world. PMID- 26931417 TI - Using T cells to detect noncanonical translation. PMID- 26931418 TI - Competitive adsorption of amylopectin and amylose on cationic nanoparticles: a study on the aggregation mechanism. AB - In this study we investigate the interactions between cationic nanoparticles and anionic starch, where the starch was composed of 20 wt% of amylose, a linear polymer, and 80 wt% of amylopectin, a branched polymer. The mechanism of aggregation was investigated by scattering techniques. It was found that the cationic particles formed large aggregates with the starch as a result of selective adsorption of the amylopectin. Amylose did not participate significantly in the aggregate formation even when the charge ratio of starch to particles was <1. For starch to particle ratio >1 stabilization was recovered mostly due to the large hindrance brought about by the highly branched amylopectin. This results in a shift of the stabilization mechanism from electrostatic to electrosteric. The internal structure of the aggregates was composed of primary particles with starch coils adsorbed on the surface. This information supports the proposed aggregation mechanism, which is based on adsorption of the negatively charged starch in patches on the positively charged nanoparticles causing attractive interaction between the particles. PMID- 26931419 TI - [Wholeheartedly, we wish "all the best" to others : But does "the best" actually come from the heart?]. PMID- 26931420 TI - [Carbon monoxide poisoning: Hyperbaric O2therapy (HBOT) recommended]. PMID- 26931421 TI - Updates of underactive bladder: a review of the recent literature. AB - Underactive bladder (UAB) is a major component of lower urinary tract symptoms. The physiopathology mechanisms underlying UAB include detrusor underactivity, acontractile detrusor, and reduced or absent bladder sensation. UAB can influence lower and upper urinary tract function and lead to serious consequences; however, the symptom syndrome is poorly understood and incompletely researched at present. Moreover, there is no agreement among authorities regarding the terminology, definition, epidemiology, classification, risk factors, animal model, pathogenesis, diagnosis, and treatment of UAB. In this review, we discuss the current terminology, epidemiology, physiopathology, evaluation, and management of UAB. PMID- 26931424 TI - Magnetic micro-solid-phase-extraction of polycyclic aromatic hydrocarbons in water. AB - A novel sorbent, magnetic chitosan functionalized graphene oxide (MCFG) was synthesized and used in the micro-solid-phase-extraction (MU-SPE) and gas chromatography-mass spectrometric (GC-MS) analysis of polycyclic aromatic hydrocarbons (PAHs) from water. Through the use of the magnetic sorbent, the MU SPE device also functioned as a stir bar during extraction. Three types of MCFG were prepared using glutaraldehyde cross-linked chitosan and graphene oxide with different amounts of magnetic nanoparticles (Fe3O4) (0.05g, 0.07g and 0.1g). The material was characterized using Fourier transform infrared spectroscopy and field emission scanning electron microscopy. Parameters affecting the extraction such as the type of sorbent, extraction and desorption times, volume of sample solution and type of desorption solvent were optimized. Under the most favourable conditions, the highest extraction was obtained by using the composite prepared with 0.1g of Fe3O4. For the latter material as sorbent, the linearity of the analytes was in the range of 0.01 and 100MUgL(-1) for naphthalene, fluoranthene and pyrene while acenaphthylene and phenanthrene exhibited linearity in the range of 0.05 and 100MUgL(-1). For fluorene and anthracene, the linearity range was from 0.01 to 50MUgL(-1). The coefficients of determination (r(2)) associated with the above linear ranges were higher than 0.987. The limits of detection from GC MS analysis of the seven PAHs were in the range 0.2-1.8ngL(-1); limits of quantification were between 0.8 and 5.9ngL(-1) while the relative standard deviations (RSDs) varied from 2.1 to 8.2%. The recoveries of the method for the compounds at spiking levels of 1 and 5MUgL(-1) were in the range 67.5-106.9% with RSDs below 15%. The enrichment factors were found to be in between 67 and 302. The developed method afforded an interesting and innovative approach using MCFG as an efficient and promising sorbent. PMID- 26931423 TI - 17beta-estradiol ameliorates age-associated loss of fibroblast function by attenuating IFN-gamma/STAT1-dependent miR-7 upregulation. AB - Age-related defects in fibroblast differentiation and functionality were previously shown to be associated with impaired hyaluronan (HA) synthase 2 (HAS2) and epidermal growth factor receptor (EGFR) function, as a result of upregulated microRNA-7 (miR-7) expression. In aging fibroblasts, inhibiting miR-7 prevented the dysregulation of the HA-mediated CD44/EGFR signaling pathway. Here, we investigated transcriptional upregulation of miR-7 and implicated the age associated over-activation of JAK/STAT1 as a primary candidate. STAT1 binding sites were identified on the putative miR-7 promoter and stimulation of fibroblasts with the inflammatory cytokine, interferon-gamma (IFN-gamma), significantly increased miR-7 transcriptional activity and resulted in upregulated miR-7 and loss of EGFR. Additionally, we demonstrated a role for the anti-inflammatory steroid, 17beta-estradiol (E2), in the attenuation of miR-7 expression. E2 stimulation promoted estrogen receptor (ER) interactions with the miR-7 putative promoter and suppressed miR-7 expression. E2 also attenuated STAT1 expression and activity. Furthermore, treatments with E2 restored fibroblast functionality, including proliferation, migration and differentiation, key events in effective wound healing. In light of our findings, we propose that the regulation of miR-7 by pro- and anti-inflammatory mediators plays a wider role than previously thought. The modulation of fibroblast functions and ultimately wound healing by miR-7 activators or inhibitors could provide realistic targets for the restoration of chronic wound healing capabilities in the elderly. PMID- 26931425 TI - Chiral stationary phases based on chitosan bis(methylphenylcarbamate) (isobutyrylamide) for high-performance liquid chromatography. AB - A series of chitosan bis(methylphenylcarbamate)-(isobutyrylamide) derivatives were synthesized by carbamylating chitosan isobutyrylamide with different methylphenyl isocyanates. Then the prepared chitosan derivatives were coated onto 3-aminopropyl silica particles, resulting in a series of new chiral stationary phases (CSPs) for high-performance liquid chromatography. It was observed that the chiral recognition abilities of these coated-type CSPs depended very much on the substituents on the phenyl moieties of the chitosan derivatives, the eluent composition, as well as the structure of racemates. As a typical example, the eluent tolerance of the prepared CSP with the best enantioseparation ability was investigated in detail, and the results revealed that the CSP exhibited extraordinary solvent tolerance and could still work without significant loss in enantioseparation capability after being flushed with chloroform (100%), ethyl acetate (100%) and even THF/n-hexane (70/30, v/v), while the traditional coated type CSPs based on the cellulose and amylose derivatives, such as cellulose tris(3,5-dimethylphenylcarbamate) (CDMPC) and amylose tris(3,5 dimethylphenylcarbamate) (ADMPC), might be dissolved or highly swollen in these eluents. Therefore, the application of the resultant CSPs could address the problem of the dissolution and high swelling of traditional coated-type CSPs in some unusual eluents, broadening the possibility of eluent choice. In addition, a comparison of the prepared CSPs with the well known CDMPC- and ADMPC- based CSPs concerning the chiral recognition ability was also made. Separation performances achieved on the as-prepared CSPs in different eluents were found to be even superior to CDMPC- and ADMPC-based CSPs for the tested chiral compounds. In summary, we could safely draw the conclusion that the CSPs derived from chitosan isobutyrylamide derivatives were capable of excellent chiral recognition ability, and meanwhile possessed satisfactory eluent tolerance in a wider range of solvents. PMID- 26931422 TI - Effects of elastic band resistance training and nutritional supplementation on muscle quality and circulating muscle growth and degradation factors of institutionalized elderly women: the Vienna Active Ageing Study (VAAS). AB - PURPOSE: Regular resistance exercise training and a balanced diet may counteract the age-related muscular decline on a molecular level. The aim of this study was to investigate the influence of elastic band resistance training and nutritional supplementation on circulating muscle growth and degradation factors, physical performance and muscle quality (MQ) of institutionalized elderly. METHODS: Within the Vienna Active Ageing Study, 91 women aged 83.6 (65.0-92.2) years were randomly assigned to one of the three intervention groups (RT, resistance training; RTS, resistance training plus nutritional supplementation; CT, cognitive training). Circulating levels of myostatin, activin A, follistatin, IGF 1 and GDF-15, as well as MQ and functional parameters were tested at baseline as well as after 3 and 6 months of intervention. RESULTS: MQ of lower extremities significantly increased in the RT group (+14 %) and RTS group (+12 %) after 6 months. Performance improved in the RT and RTS groups for chair stand test (RT: +18 %; RTS: +15 %). Follistatin increased only in the RT group (+18 %) in the latter phase of the intervention, accompanied by a decrease in the activin A-to follistatin ratio (-7 %). IGF-1, myostatin and GDF-15 levels were not affected by the intervention. CONCLUSION: Our data confirm that strength training improves physical performance and MQ even in very old institutionalized women. This amelioration appears to be mediated by blocking muscle degradation pathways via follistatin rather than inducing muscle growth through the IGF-1 pathway. As plasma levels of biomarkers reflect an overall status of various organ systems, future studies of tissue levels are suggested. PMID- 26931426 TI - Inverse supercritical fluid extraction as a sample preparation method for the analysis of the nanoparticle content in sunscreen agents. AB - We demonstrate the use of inverse supercritical carbon dioxide (scCO2) extraction as a novel method of sample preparation for the analysis of complex nanoparticle containing samples, in our case a model sunscreen agent with titanium dioxide nanoparticles. The sample was prepared for analysis in a simplified process using a lab scale supercritical fluid extraction system. The residual material was easily dispersed in an aqueous solution and analyzed by Asymmetrical Flow Field Flow Fractionation (AF4) hyphenated with UV- and Multi-Angle Light Scattering detection. The obtained results allowed an unambiguous determination of the presence of nanoparticles within the sample, with almost no background from the matrix itself, and showed that the size distribution of the nanoparticles is essentially maintained. These results are especially relevant in view of recently introduced regulatory requirements concerning the labeling of nanoparticle containing products. The novel sample preparation method is potentially applicable to commercial sunscreens or other emulsion-based cosmetic products and has important ecological advantages over currently used sample preparation techniques involving organic solvents. PMID- 26931427 TI - Rapid separation of phosphopeptides by microchip electrophoresis-electrospray ionization mass spectrometry. AB - Protein phosphorylation is a significant biological process, but separation of phosphorylated peptide isomers is often challenging for many analytical techniques. We developed a microchip electrophoresis (MCE) method for rapid separation of phosphopeptides with on-chip electrospray ionization (ESI) facilitating online sample introduction to the mass spectrometer (MS). With the method, two monophosphorylated positional isomers of insulin receptor peptide (IR1A and IR1B) and a triply phosphorylated insulin receptor peptide (IR3), all with the same amino acid sequence, were separated from the nonphosphorylated peptide (IR0) in less than one minute. For efficient separation of the positional peptide isomers from each other derivatization with 9-fluorenylmethyl reagents (either chloroformate, Fmoc-Cl, or N-succinimidyl carbonate, Fmoc-OSu) was required before the analysis. The derivatization improved not only the separation of the monophosphorylated positional peptide isomers in MCE, but also identification of the phosphorylation site based on MS/MS. PMID- 26931428 TI - A rapid method for the separation of vitamin D and its metabolites by ultra-high performance supercritical fluid chromatography-mass spectrometry. AB - In this study, a new supercritical fluid chromatography-mass spectrometry (SFC MS) method has been developed for the separation of nine vitamin D metabolites within less than eight minutes. This is the first study of analysis of vitamin D and its metabolites carried out by SFC-MS. Six columns of orthogonal selectivity were examined, and the best separation was obtained by using a 1-aminoanthracene (1-AA) column. The number and the position of hydroxyl groups in the structure of the studied compounds as well as the number of unsaturated bonds determine the physiochemical properties and, thus the separation of vitamin D metabolites that is achieved on this column. All D2 and the D3 forms were baseline separated with resolution values>1.5. The effects of pressure, temperature, flow rate and different gradient modes were studied. Electrospray ionization (ESI) and atmospheric pressure chemical ionization (APCI) were compared in positive mode, both by direct infusion and after SFC separation. The results showed that the sensitivity in APCI(+) was higher than in ESI(+) using direct infusion. In contrast, the sensitivity in APCI(+) was 6-fold lower than in ESI(+) after SFC separation. The SFC-MS method was validated between 10 and 500ng/mL for all analytes with coefficient of determination (R(2))>=0.999 for all calibration curves. The limits of detection (LOD) were found to range between 0.39 and 5.98ng/mL for 24,25-dihydroxyvitamin D3 (24,25(OH)2D3) and 1-hydroxyvitamin D2 (1OHD2), respectively. To show its potential, the method was applied to human plasma samples from healthy individuals. Vitamin D3 (D3), 25-hydroxyvitamin D3 (25OHD3) and 24,25(OH)2D3 were determined in plasma samples and the concentrations were 6.6+/-3.0ng/mL, 23.8+/-9.2ng/mL and 5.4+/-2.7ng/mL, respectively. PMID- 26931429 TI - Tracing gadolinium-based contrast agents from surface water to drinking water by means of speciation analysis. AB - In recent decades, a significant amount of anthropogenic gadolinium has been released into the environment as a result of the broad application of contrast agents for magnetic resonance imaging (MRI). Since this anthropogenic gadolinium anomaly has also been detected in drinking water, it has become necessary to investigate the possible effect of drinking water purification on these highly polar microcontaminats. Therefore, a novel highly sensitive method for speciation analysis of gadolinium is presented. For that purpose, the hyphenation of hydrophilic interaction liquid chromatography (HILIC) and inductively coupled plasma-mass spectrometry (ICP-MS) was employed. In order to enhance the detection power, sample introduction was carried out by ultrasonic nebulization. In combination with a novel HILIC method using a diol-based stationary phase, it was possible to achieve superior limits of detection for frequently applied gadolinium-based contrast agents below 20pmol/L. With this method, the contrast agents Gd-DTPA, Gd-DOTA and Gd-BT-DO3A were determined in concentrations up to 159pmol/L in samples from several waterworks in a densely populated region of Germany alongside the river Ruhr as well as from a waterworks near a catchment lake. Thereby, the direct impact of anthropogenic gadolinium species being present in the surface water on the amount of anthropogenic gadolinium in drinking water was shown. There was no evidence for the degradation of contrast agents, the release of Gd(3+) or the presence of further Gd species. PMID- 26931430 TI - Cellulolytic and proteolytic ability of bacteria isolated from gastrointestinal tract and composting of a hippopotamus. AB - The bioprospection for cellulase and protease producers is a promise strategy for the discovery of potential biocatalysts for use in hydrolysis of lignocellulosic materials as well as proteic residues. These enzymes can increment and turn viable the production of second generation ethanol from different and alternative sources. In this context, the goal of this study was the investigation of cellulolytic and proteolytic abilities of bacteria isolated from the gastrointestinal tract of a hippopotamus as well as from its composting process. It is important to highlight that hippopotamus gastrointestinal samples were a non-typical sources of efficient hydrolytic bacteria with potential for application in biotechnological industries, like biofuel production. Looking for this, a total of 159 bacteria were isolated, which were submitted to qualitative and quantitative enzymatic assays. Proteolytic analyzes were conducted through the evaluation of fluorescent probes. Qualitative assays for cellulolytic abilities revealed 70 positive hits. After quantitative analyzes, 44 % of these positive hits were selected, but five (5) strains showed cellulolytic activity up to 11,8 FPU/mL. Regarding to proteolytic activities, six (6) strains showed activity above 10 %, which overpassed results described in the literature. Molecular analyzes based on the identification of 16S rDNA, revealed that all the selected bacterial isolates were affiliated to Bacillus genus. In summary, these results strongly indicate that the isolated bacteria from a hippopotamus can be a potential source of interesting biocatalysts with cellulolytic and proteolytic activities, with relevance for industrial applications. PMID- 26931431 TI - Inhibition of Migration and Invasion by Tet-1 Overexpression in Human Lung Carcinoma H460 Cells. AB - In the present study, we found that lung cancer cell line (H460 cells) expressing Tet1 showed higher levels of adhesion, and Tet1 inhibited H460 cell proliferation. In addition, these cells showed a significantly reduced ability of collagen degradation and Smad2/3 phosphorylation compared to controls. Furthermore, vimentin was found to be highly expressed in larger metastatic cancer area. Tet1 overexpression was reduced in the epithelial marker E-cadherin. Moreover, Tet1 repressed cancer cell metastasis in nude mice. Collectively, these findings suggest that Tet1 expression plays a critical role in metastasis of lung cancer cells by suppression of invasion and epithelial-mesenchymal transition (EMT). PMID- 26931432 TI - Long Noncoding RNA H19-Derived miR-675 Enhances Proliferation and Invasion via RUNX1 in Gastric Cancer Cells. AB - The lncRNA H19 and its mature product miR-675 have recently been shown to be upregulated and promote the progression of gastric cancer. However, the detailed function and underlying molecular mechanism of H19/miR-675 in the carcinogenesis of gastric cancer remains unclear. In this study, we found that H19 depended on miR-675 to enhance the proliferation and invasion of gastric cancer AGS cells, and the expression of miR-675 was positively correlated with H19 in patients with gastric cancer. Subsequently, the tumor-suppressor runt domain transcription factor 1 (RUNX1) was confirmed to be a downstream molecule of H19/miR-675 axis, since overexpression of H19 or miR-675 significantly decreased RUNX1 expression in AGS cells, and knockdown of H19 or miR-675 enhanced RUNX1 expression. More importantly, a series of assays further demonstrated that introduction of RUNX1 abrogated H19/miR-675-induced Akt/mTOR pathway activation and the following cellular proliferation and invasion of AGS cells. To our knowledge, this is the time to demonstrate that RUNX1 serves as a link between H19/miR-675 axis and Akt/mTOR signaling and is a pivotal mediator in gastric cancer progression induced by H19/miR-675. Thus, our study provides important clues for understanding the key roles of lncRNA-miRNA functional network and identifying new therapeutic targets for gastric cancer. PMID- 26931433 TI - ERK Signaling Pathway Is Involved in HPV-16 E6 but not E7 Oncoprotein-Induced HIF 1alpha Protein Accumulation in NSCLC Cells. AB - Extracellular signal-regulated kinase (ERK)1/2 signaling pathway plays a critical role in regulating tumor angiogenesis. Our previous studies have demonstrated that HPV-16 oncoproteins enhanced hypoxia-inducible factor-1alpha (HIF-1alpha) protein accumulation and vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8) expression in non-small cell lung cancer (NSCLC) cells, thus contributing to angiogenesis. In this study, we further investigated the role of ERK1/2 signaling pathway in HPV-16 oncoprotein-induced HIF-1alpha, VEGF, and IL-8 expression and in vitro angiogenesis in NSCLC cells. Our results showed that HPV 16 E6 and HPV-16 E7 oncoproteins promoted the activation of ERK1/2 signaling pathway in A549 and NCI-H460 cells. Moreover, PD98059, a specific inhibitor of ERK1/2, blocked in vitro angiogenesis stimulated by HPV-16 E6 but not E7 oncoprotein. Additionally, HIF-1alpha protein accumulation and VEGF and IL-8 expression in NSCLC cells induced by HPV-16 E6 but not E7 oncoprotein were significantly inhibited by PD98059. Taken together, our results suggest that ERK1/2 signaling pathway is involved in HPV-16 E6 but not E7 oncoprotein-induced HIF-1alpha, VEGF, and IL-8 expression in NSCLC cells, leading to the enhanced angiogenesis in vitro. PMID- 26931434 TI - HSP27 Knockdown Increases Cytoplasmic p21 and Cisplatin Sensitivity in Ovarian Carcinoma Cells. AB - Drug resistance is the leading cause of chemotherapy failure in the treatment of ovarian cancer. So far, little is known about the mechanism of chemoresistance in ovarian cancer. In this study, we explored the mechanism that HSP27 was involved in cisplatin resistance of ovarian cancer both in vitro and clinically. HSP27 protein was found to be upregulated and expressed in cisplatin-resistant ovarian cancer cell line C13*, and HSP27 siRNA transfection reversed the chemoresistance of C13*. We found that HSP27 exerted its chemoresistant role by inhibiting p21 transferring from the nucleus to the plasma through the activation of phosphorylated-Akt pathway. These findings have implications for clinical trials aimed at a potential therapeutic target for ovarian tumors that are refractory to conventional treatment. PMID- 26931435 TI - Enhancement of Drug Sensitivity by Knockdown of HIF-1alpha in Gastric Carcinoma Cells. AB - In this study, the effects of hypoxia-inducible factor-1alpha (HIF-1alpha) on gastric carcinoma (GC) drug resistance through apoptosis-related genes are investigated. First, HIF-1alpha-specific siRNA was synthetized and transfected into drug-resistant GC cell line OCUM-2MD3/L-OHP. Then MTT assay was applied to test the inhibition rate of GC cells by 5-fluorouracil (5-FU) and oxaliplatin (L OHP). After that, flow cytometry (FCM) was applied to measure apoptosis rate. qPCR and Western blot assay were employed to detect HIF-1alpha and apoptosis related genes. Results showed that HIF-1alpha in OCUM-2MD3/L-OHP cells was higher than that in OCUM-2MD3 and gastric epithelial cells. After HIF-1alpha-siRNA transfection, inhibition rates of 5-FU and L-OHP to tumor cells increased significantly. FCM results showed that apoptosis rate of OCUM-2MD3/L-OHP cells increased significantly. After HIF-1alpha-siRNA transfection, survivin and Bcl-2 decreased, whereas Bax, caspase 3, and caspase 8 increased significantly. Results from this study seem to confirm that HIF-1alpha getting involved in GC drug resistance is possibly due to its regulation of some apoptosis-related genes. HIF 1alpha may be a potential target to reverse drug resistance of GC. PMID- 26931436 TI - Flow Cytometric Evaluation of Double/Triple Hit Lymphoma. AB - "Double" or "triple" hit lymphomas (D/THL) with recurrent translocations involving MYC/8q24 and BCL2/18q21 and/or BCL6/3q27 are characterized by a poor prognosis, but their identification is hampered by the clinicopathologic overlap with other disease categories. Cases with circulating blastic-appearing cells may initially cause concern for lymphoblastic leukemia a diagnostic dilemma, which has not been well studied. There is only limited literature regarding the flow cytometric (FC) D/THL phenotype and its clinical correlates. The FC features of 20 D/THL (11 BCL2(+)/MYC(+), 5 BCL6(+)/MYC(+), 4 BCL2(+)/BCL6(+)/MYC(+)) were evaluated, compared to 20 B-lymphoblastic leukemias (B-LBL), and correlated with overall survival. Most (89%, 17/19) D/THL were CD10(+), 47% (9/19) lacked surface light chain, and a significant subset underexpressed CD45 (47%, 9/19), CD20 (42% 8/19), and/or CD19 (39%, 7/18), which did not vary by genetic subgroup. Compared to B-LBL, D/THL less frequently underexpressed CD45 (p = 0.0001) and CD20 (p = 0.0004). Lower levels of BCL2 expression were noted in the BCL6(+)/MYC(+) and BCL2(+)/BCL6(+)/MYC(+) subgroups versus BCL2(+)/MYC(+) cases (p = 0.0014). Of the flow cytometric parameters assessed, dim CD45 expression correlated with inferior survival (p = 0.01). Although there is some overlap with B-LBL, D/THL demonstrates a characteristic immunophenotype which may have prognostic significance and warrants further investigation. PMID- 26931437 TI - Large-area, uniform and low-cost dual-mode plasmonic naked-eye colorimetry and SERS sensor with handheld Raman spectrometer. AB - We demonstrated a highly-sensitive, wafer-scale, highly-uniform plasmonic nano mushroom substrate based on plastic for naked-eye plasmonic colorimetry and surface-enhanced Raman spectroscopy (SERS). We gave it the name FlexBrite. The dual-mode functionality of FlexBrite allows for label-free qualitative analysis by SERS with an enhancement factor (EF) of 10(8) and label-free quantitative analysis by naked-eye colorimetry with a sensitivity of 611 nm RIU(-1). The SERS EF of FlexBrite in the wet state was found to be 4.81 * 10(8), 7 times stronger than in the dry state, making FlexBrite suitable for aqueous environments such as microfluid systems. The label-free detection of biotin-streptavidin interaction by both SERS and colorimetry was demonstrated with FlexBrite. The detection of trace amounts of the narcotic drug methamphetamine in drinking water by SERS was implemented with a handheld Raman spectrometer and FlexBrite. This plastic-based dual-mode nano-mushroom substrate has the potential to be used as a sensing platform for easy and fast analysis in chemical and biological assays. PMID- 26931438 TI - Research on Climate and Dengue in Malaysia: A Systematic Review. AB - BACKGROUND & OBJECTIVES: Dengue is a climate-sensitive infectious disease. Climate-based dengue early warning may be a simple, low-cost, and effective tool for enhancing surveillance and control. Scientific studies on climate and dengue in local context form the basis for advancing the development of a climate-based early warning system. This study aims to review the current status of scientific studies in climate and dengue and the prospect or challenges of such research on a climate-based dengue early warning system in a dengue-endemic country, taking Malaysia as a case study. METHOD: We reviewed the relationship between climate and dengue derived from statistical modeling, laboratory tests, and field studies. We searched electronic databases including PubMed, Scopus, EBSCO (MEDLINE), Web of Science, and the World Health Organization publications, and assessed climate factors and their influence on dengue cases, mosquitoes, and virus and recent development in the field of climate and dengue. RESULTS & DISCUSSION: Few studies in Malaysia have emphasized the relationship between climate and dengue. Climatic factors such as temperature, rainfall, and humidity are associated with dengue; however, these relationships were not consistent. Climate change projections for Malaysia show a mounting risk for dengue in the future. Scientific studies on climate and dengue enhance dengue surveillance in the long run. CONCLUSION: It is essential for institutions in Malaysia to promote research on climate and vector-borne diseases to advance the development of climate-based early warning systems. Together, effective strategies that improve existing research capacity, maximize the use of limited resources, and promote local-international partnership are crucial for sustaining research on climate and health. PMID- 26931439 TI - The novel isotopically coded short-range photo-reactive crosslinker 2,4,6 triazido-1,3,5-triazine (TATA) for studying protein structures. AB - : Short-distance molecular-modeling constraints are advantageous for elucidating the structures of individual proteins and protein conformational changes. Commonly used amine-reactive crosslinks are relatively long (14A), partly due to the length of the lysine side-chain, and are sparsely distributed throughout a protein. Short-distance non-specific crosslinkers can provide a larger number of tighter molecular-modeling constraints. Here we describe the use of a short-range homo-trifunctional isotopically-coded non-specific photo-reactive crosslinking reagent, 2,4,6-triazido-1,3,5-triazine (TATA)-12C3/13C3, for MS-based protein crosslinking studies. Upon activation by 254nm UV light, TATA-12C3/13C3 generates up to three nitrene radicals capable of non-selective crosslinking at ~5A. This reagent was validated using cyclohexane, several test peptides, and myoglobin, and was found to react with a large number of amino acids, forming multiple crosslinked products. The myoglobin crosslinks detected by MS agreed with the known structure of myoglobin; arranging the protein's secondary-structure motifs into their correct fold was possible based solely on the constraints imposed by the crosslinks. Finally, TATA was used to crosslink the alpha-synuclein monomer. The 10 short-distance constraints provided by TATA crosslinking led to an initial model of the molten-globule form of the native alpha-synuclein monomer; this provides a suggested structure for the precursor of the misfolded alpha-synuclein proteoforms involved in synucleopathies. BIOLOGICAL SIGNIFICANCE: The isotopically labeled short-range non-specific crosslinker TATA-12C3/13C3 was characterized for use in crosslinking-based protein structural studies. The crosslinking products of TATA can provide a distance constraint of merely 5A between crosslinked residues. TATA-12C3/13C3 had broad reactivity, crosslinking a wide variety of amino acids, including lysine, glutamic and aspartic acid, asparagine, glutamine, glycine, alanine, valine, proline, methionine, serine, cysteine, tyrosine, and the N-terminus. The short-distance crosslinking constraints provided by TATA allowed us to predict the fold of myoglobin using a combination of these distance constraints with a prediction of myoglobin's secondary structure motifs. TATA was also used to crosslink alpha-synuclein in its native, molten globule form, which has not been characterized using other structural biology techniques. The distance constraints provided by the crosslinks allowed for the manual modeling of a rudimentary structure for the alpha-synuclein monomer. PMID- 26931440 TI - Time-lapse variables and embryo gender: a retrospective analysis of 81 live births obtained following minimal stimulation and single embryo transfer. AB - PURPOSE: The purpose of this study was to determine which morphokinetic variables are related to embryo gender in a cohort of consecutive live births obtained through single blastocyst transfer following mild ovarian stimulation. METHODS: Eighty-one live births (49 % of them females) from successfully treated, consecutive infertile patients (maternal age 36.9 +/- 3.8 years, range 28-46) who underwent minimal ovarian stimulation, prolonged embryo culture in a time-lapse monitoring (TLM) incubator and elective single blastocyst transfers during 2012 2014. Early (PNf, t2-t9, cc2a, b, s2, s3) and late (tM, tSB, tfullB, texpB1, and texpB2) morphokinetic variables were scored according to published consensus criteria and were normalized to the time of pronuclear fading. For each variable, the ranges with the highest proportion of female embryos (optimal range) were determined by detailed examination of histograms. RESULTS: Female embryo gender was associated both with late cleavage (t8), morula (tM), and blastocyst stage morphokinetic variables. The strongest associations (adjusted ORs, 7.0-7.8) were found for late, expanded stage blastocyst parameters; tfullB, texpB1, and texpB2. The proportion of female embryos was 69-71 and 25-26 % inside and outside of the optimal ranges, respectively. This allowed to predict 74-78 % of them, increasing their proportion by 57 % compared to the average. CONCLUSIONS: Although the sample size of our cohort was limited, our findings suggest that several expanded blastocyst stage morphokinetic parameters are associated with female embryo gender. If confirmed on a larger sample these could be potentially used to increase the proportion of female embryos among non-invasively selected blastocysts following single embryo transfer. PMID- 26931441 TI - Anterior shoulder stabilization by Bristow-Latarjet procedure in athletes: return to-sport and functional outcomes at minimum 2-year follow-up. AB - PURPOSE: The aim of this study was to assess return-to-sport outcomes following the Latarjet-Bristow procedure. METHODS: This retrospective study included all athletes <50 years old, who underwent a Latarjet-Bristow procedure for anterior shoulder instability in 2009-2012. Main criteria assessments were the number of athletes returning to any sport and the number returning to the same sport at their preinjury level. The main follow-up was 46.8 +/- 9.7 months. RESULTS: Forty seven patients were analyzed, 46 men/1 women, mean age 27.9 +/- 7.9 years. Eighteen patients practiced competitive sports and 29 recreational sports. None of them were professional athletes. One hundred percent returned to sports after a mean 6.3 +/- 4.3 months. Thirty/47 (63.8 %) patients returned to the same sport at the same level at least and 10/47 (21.3 %) patients changed sport because of their shoulder. Compared to patients who returned to the same sport at the same level, patients who changed sports or returned to a lower level had practiced overhead or forced overhead sports [OR = 4.7 (1.3-16.9), p = 0.02] before surgery, experienced avoidance behavior at the final follow-up (p = 0.002), apprehension (p = 0.00001) and had a worse Western Ontario Shoulder Instability Index score and sub-items (p = 0.003) except for daily activities (p = 0.21). At the final follow-up, 45/47 (95.7 %) patients were still practicing a sport. CONCLUSION: All the patients returned to sports, most to their preinjury sport at the same level. Patients who practiced an overhead sport were more likely to play at a lower level or to change sport postoperatively. LEVEL OF EVIDENCE: IV, retrospective study-Case series with no comparison group. PMID- 26931443 TI - Effect of Lipophilicity and Drug Ionization on Permeation Across Porcine Sublingual Mucosa. AB - Sublingual route is one of the oldest alternative routes studied for the administration of drugs. However, the effect of physical-chemical properties on drug permeation via this route has not been systemically investigated. The objective of this study was to determine the effect of two key physicochemical properties, lipophilicity and ionization, on the transport of drugs across porcine sublingual mucosa. A series of beta-blockers were used to study the effect of lipophilicity on drug permeation across the sublingual mucosa, while nimesulide (pKa 6.5) was used as a model drug to study the effect of degree of ionization on sublingual mucosa permeation of ionized and unionized species. Permeation of beta-blockers increased linearly with an increase in the lipophilicity for the range of compounds studied. The permeability of nimesulide across sublingual mucosa decreased with an increase of pH. The flux of ionized and unionized forms of nimesulide was determined to delineate the contribution of ionized and unionized species to the total flux. At low pH, the apparent flux was primarily contributed by unionized species; however, when the pH is increased beyond its pKa, the primary contributor to the apparent flux, nimesulide, is ionized species. The contribution of each species to the apparent flux was shown to be determined by the thermodynamic activity of ionized or unionized species. This study identified the roles of lipophilicity and thermodynamic activity in drug permeation across the sublingual mucosa. The findings can help guide the design of sublingual drug delivery systems with optimal pH and solubility. PMID- 26931444 TI - Ab initio study of the influence of resonance stabilization on intramolecular ring closure reactions of hydrocarbon radicals. AB - The intramolecular ring closure reactions of unsaturated hydrocarbon radicals potentially play an important role for the formation of molecular weight growth species, especially during the pyrolysis and oxidation of alkenes under low to intermediate temperatures. In this work we investigated a series of intramolecular cycloaddition reactions of both allylic- and alkyl-type dienyl radicals. In the first set of reactions, a resonant linear radical is converted into a non-resonant cyclic radical. In the second set, a non-resonant linear alkenyl radical isomerizes to either a resonant cyclic radical or a cyclic carbinyl radical. In both cases, three different reaction schemes are examined based on the location of the partially-formed resonance structure in the cyclic transition state. For each reaction scheme, both the endo- and exo-pathways were investigated. High pressure rate parameters are obtained from the results of CBS QB3 electronic structure calculations combined with canonical transition state theory calculations. The results are discussed in the context of a Benson-type model to examine the impact of the partially-formed resonance stabilization on both the activation energies and pre-exponential factors. The results are compared to previously reported rate parameters for cycloaddition reactions of alkenyl radicals. The differences in the activation energies are primarily due to the bimolecular component of the activation energy. However, in some cases, the presence of the partial resonance structure significantly increases the strain energy for the ring that is formed in the transition state. The pre-exponential factors are also impacted by the formation of a partial resonance structure in the transition state. Lastly, the C6H9 potential energy surface is examined to show how the trends that are outlined here can be used to estimate rate parameters, which are needed to analyze pressure-dependent reaction systems. PMID- 26931442 TI - Design and Concept of Polyzwitterionic Copolymer Microgel Drug Delivery Systems In Situ Loaded with Non-steroidal Anti-inflammatory Ibuprofen. AB - Nowadays, the modern pharmaceutical investigations are directed toward obtaining of new polymer micro- and nano-sized drug delivery carriers. In this respect, the use of hydrogel carriers based on polyzwitterions (PZIs) is an opportunity in the preparation of polymer drug delivery systems with desired characteristics. This paper describes the synthesis and characterization of micro-structured p(VA-co DMAPS) systems with different compositions in situ loaded with Ibuprofen by emulsifier-free emulsion copolymerization (EEC) in water. The mean size of the prepared microparticles was measured by SEM and particles have been visualized by AFM. The inclusion of Ibuprofen in the polyzwitterionic copolymer microgel systems was established by using DSC. In vitro drug release experiments were carried out in order to estimate the ability of the obtained microgels to modify the release of water-insoluble Ibuprofen. PMID- 26931445 TI - Human Papillomavirus (HPV) L1 Serum Antibodies and the Risk of Subsequent Oral HPV Acquisition in Men: The HIM Study. AB - The role of antibody-mediated immunity in preventing newly acquired oral human papillomavirus (HPV) is not well understood. Among 1618 men participating in the HPV Infection in Men (HIM) Study, we evaluated oral rinses for HPV DNA and baseline sera for HPV-6, -11, -16, and -18 L1 antibodies. Thirty percent of men (486) were seropositive for >=1 HPV type, and 25 men developed incident oral HPV infection (HPV-6 was detected in 7, HPV-11 in 0, HPV-16 in 17, and HPV-18 in 1). Cox models revealed that men with circulating antibodies to HPV-6, -11, -16, or 18 were not less likely to acquire type-specific oral HPV than men without antibodies (hazard ratio for the risk of acquiring HPV-6, -11, -16, or -18, 1.63; 95% confidence interval, .56-4.76). PMID- 26931446 TI - Climatic Drivers of Diarrheagenic Escherichia coli Incidence: A Systematic Review and Meta-analysis. AB - BACKGROUND: Positive associations have been noted between temperature and diarrhea incidence, but considerable uncertainty surrounds quantitative estimates of this relationship because of pathogen-specific factors and a scarcity of data on the influence of meteorological factors on the risk of disease. Quantifying these relationships is important for disease prevention and climate change adaptation. METHODS: To address these issues, we performed a systematic literature review of studies in which at least 1 full year of data on the monthly incidence of diarrheagenic Escherichia coli were reported. We characterized seasonal patterns of disease incidence from 28 studies. In addition, using monthly time- and location-specific weather data for 18 studies, we performed univariate Poisson models on individual studies and a meta-analysis, using a generalized estimating equation, on the entire data set. RESULTS: We found an 8% increase in the incidence of diarrheagenic E. coli (95% confidence interval, 5% 11%; P < .0001) for each 1 degrees C increase in mean monthly temperature. We found a modest positive association between 1-month-lagged mean rainfall and incidence of diarrheagenic E. coli, which was not statistically significant when we controlled for temperature. CONCLUSIONS: These results suggest that increases in ambient temperature correspond to an elevated incidence of diarrheagenic E. coli and underscore the need to redouble efforts to prevent the transmission of these pathogens in the face of increasing global temperatures. PMID- 26931449 TI - Erratum to: Generation of MCF-7 cells with aggressive metastatic potential in vitro and in vivo. PMID- 26931447 TI - Mannose Receptor Is Required for Optimal Induction of Vaccine-Induced T-Helper Type 17 Cells and Resistance to Blastomyces dermatitidis Infection. AB - We investigated how innate sensing by the mannose receptor (MR) influences the development of antifungal immunity. We demonstrate that MR senses mannan on the surface of attenuated Blastomyces dermatitidis vaccine yeast and that MR(-/-) mice demonstrate impaired vaccine immunity against lethal experimental blastomycosis, compared with wild-type control mice. Using naive Blastomyces specific transgenic CD4(+) T cells, we found that MR regulates differentiation of naive T cells into T-helper type 17 (Th17) effector cells, which are essential in vaccine immunity against systemic dimorphic fungi. Thus, MR regulates differentiation of Th17 cells and is required to induce vaccine immunity against lethal pulmonary blastomycosis. PMID- 26931450 TI - Breast cancer screening using tomosynthesis in combination with digital mammography compared to digital mammography alone: a cohort study within the PROSPR consortium. AB - Digital breast tomosynthesis (DBT) is emerging as the new standard of care for breast cancer screening based on improved cancer detection coupled with reductions in recall compared to screening with digital mammography (DM) alone. However, many prior studies lack follow-up data to assess false negatives examinations. The purpose of this study is to assess if DBT is associated with improved screening outcomes based on follow-up data from tumor registries or pathology. Retrospective analysis of prospective cohort data from three research centers performing DBT screening in the PROSPR consortium from 2011 to 2014 was performed. Recall and biopsy rates were assessed from 198,881 women age 40-74 years undergoing screening (142,883 DM and 55,998 DBT examinations). Cancer, cancer detection, and false negative rates and positive predictive values were assessed on examinations with one year of follow-up. Logistic regression was used to compare DBT to DM adjusting for research center, age, prior breast imaging, and breast density. There was a reduction in recall with DBT compared to DM (8.7 vs. 10.4 %, p < 0.0001), with adjusted OR = 0.68 (95 % CI = 0.65-0.71). DBT demonstrated a statistically significant increase in cancer detection over DM (5.9 vs. 4.4/1000 screened, adjusted OR = 1.45, 95 % CI = 1.12-1.88), an improvement in PPV1 (6.4 % for DBT vs. 4.1 % for DM, adjusted OR = 2.02, 95 % CI = 1.54-2.65), and no significant difference in false negative rates for DBT compared to DM (0.46 vs. 0.60/1000 screened, p = 0.347). Our data support implementation of DBT screening based on increased cancer detection, reduced recall, and no difference in false negative screening examinations. PMID- 26931451 TI - Greater flavonoid intake is associated with improved CVD risk factors in US adults. AB - Epidemiological studies have reported that diets high in flavonoids are associated with a reduced risk of CVD. However, evidence on the association of dietary flavonoid intake with CVD risk factors is still scarce. The present study aimed to investigate the association of dietary flavonoid intake with CVD risk factors among US adults in the National Health and Nutrition Examination Survey (NHANES) 2007-2012. A total of 4042 US adults aged 19 years and older from the NHANES 2007-2012 participated in this cross-sectional, population-based study. Intakes of total and individual flavonoids were estimated from 2-d 24-h diet recall data by matching with the expanded US Department of Agriculture flavonoid, isoflavone and proanthocyanidin databases. After adjusting for covariates, increased HDL-cholesterol was associated with higher total flavonoid intake (0.54 % change). TAG and TAG:HDL-cholesterol ratio were inversely associated with anthocyanidin (-1.25 % change for TAG; -1.60 % change for TAG:HDL-cholesterol ratio) and total flavonoid intakes (-1.31 % change for TAG; -1.83 % change for TAG:HDL-cholesterol ratio), respectively. Insulin and homoeostasis model assessment for insulin resistance (HOMA-IR) were inversely associated with flavone (for insulin, -3.18 % change; 95 % CI -5.85, -0.44; for HOMA-IR, -3.10 % change; 95 % CI -5.93, -0.19) and isoflavone intakes (for insulin, -3.11 % change; 95 % CI -5.46, -0.70; for HOMA-IR, -4.01 % change; 95 % CI -6.67, -1.27). BMI was negatively associated with anthocyanidin intake (-0.60 % change). This study showed that higher flavonoid intake was associated with improved CVD risk factors. Further research is warranted to confirm the findings from this study as these associations were moderate in strength. PMID- 26931452 TI - Methylprednisolone blocks interleukin 1 beta induced calcitonin gene related peptide release in trigeminal ganglia cells. AB - BACKGROUND: Methylprednisolone (MPD) is a rapid acting highly effective cluster headache preventive and also suppresses the recurrence of migraine attacks. Previously, we could demonstrate that elevated CGRP plasma levels in a cluster headache bout are normalized after a course of high dose corticosteroids. Here we assess whether MPD suppresses interleukin-1beta (IL-1beta)- and prostaglandin E2 (PGE2)-induced CGRP release in a cell culture model of trigeminal ganglia cells, which could account for the preventive effect in migraine and cluster headache. Metoprolol (MTP), a migraine preventive with a slow onset of action, was used for comparison. METHODS: Primary cultures of rat trigeminal ganglia were stimulated for 24 h with 10 ng/ml IL-1beta or for 4 h with 10 MUM PGE2 following the exposure to 10 or 100 MUM MPD or 100 nM or 10 uM MTP for 45 min or 24 h. CGRP was determined by using a commercial enzyme immunoassay. RESULTS: MPD but not MTP blocked IL-1beta-induced CGRP release from cultured trigeminal cells. PGE2 stimulated CGRP release from trigeminal ganglia cell culture was not affected by pre-stimulation whether with MPD or MTP. CONCLUSION: MPD but not MTP suppresses cytokine (IL-1beta)-induced CGRP release from trigeminal ganglia cells. We propose that blockade of cytokine mediated trigeminal activation may represent a potential mechanism of action that mediates the preventive effect of MTP on cluster headache and recurrent migraine attacks. PMID- 26931453 TI - Progress in the use of microemulsions for transdermal and dermal drug delivery. AB - Transdermal drug delivery continues to attract considerable interest in the scientific community. However, due to the hindrance provided by the stratum corneum, it is not possible to deliver most medications in therapeutically significant amounts. One of the ways of increasing the penetration of drugs across the skin is through the use of microemulsions (MEs). This review focuses on the role of MEs in enhancing topical and transdermal drug delivery. PMID- 26931455 TI - Extensive multiplex PCR diagnostics reveal new insights into the epidemiology of viral respiratory infections. AB - Viral respiratory infections continue to pose a major global healthcare burden. At the community level, the co-circulation of respiratory viruses is common and yet studies generally focus on single aetiologies. We conducted the first comprehensive epidemiological analysis to encompass all major respiratory viruses in a single population. Using extensive multiplex PCR diagnostic data generated by the largest NHS board in Scotland, we analysed 44230 patient episodes of respiratory illness that were simultaneously tested for 11 virus groups between 2005 and 2013, spanning the 2009 influenza A pandemic. We measured viral infection prevalence, described co-infections, and identified factors independently associated with viral infection using multivariable logistic regression. Our study provides baseline measures and reveals new insights that will direct future research into the epidemiological consequences of virus co circulation. In particular, our study shows that (i) human coronavirus infections are more common during influenza seasons and in co-infections than previously recognized, (ii) factors associated with co-infection differ from those associated with viral infection overall, (iii) virus prevalence has increased over time especially in infants aged <1 year, and (iv) viral infection risk is greater in the post-2009 pandemic era, likely reflecting a widespread change in the viral population that warrants further investigation. PMID- 26931454 TI - Root proteomics reveals cucumber 24-epibrassinolide responses under Ca(NO3)2 stress. AB - KEY MESSAGE: The application of exogenous 24-epibrassinolide promotes Brassinosteroids intracellular signalling in cucumber, which leads to differentially expressed proteins that participate in different life process to relieve Ca(NO 3 ) 2 damage. NO3 (-) and Ca(2+) are the main anion and cation of soil secondary salinization during greenhouse cultivation. Brassinosteroids (BRs), steroidal phytohormones, regulate various important physiological and developmental processes and are used against abiotic stress. A two-dimensional electrophoresis gel coupled with MALDI-TOF/TOF MS was performed to investigate the effects of exogenous 24-epibrassinolide (EBL) on proteomic changes in cucumber seedling roots under Ca(NO3)2 stress. A total of 80 differentially accumulated protein spots in response to stress and/or exogenous EBL were identified and grouped into different categories of biological processes according to Gene Ontology. Under Ca(NO3)2 stress, proteins related to nitrogen metabolism and lignin biosynthesis were induced, while those related to cytoskeleton organization and cell-wall neutral sugar metabolism were inhibited. However, the accumulation of abundant proteins involved in protein modification and degradation, defence mechanisms against antioxidation and detoxification and lignin biosynthesis by exogenous EBL might play important roles in salt tolerance. Real-time quantitative PCR was performed to investigate BR signalling. BR signalling was induced intracellularly under Ca(NO3)2 stress. Exogenous EBL can alleviate the root indices, effectively reduce the Ca(2+) content and increase the K(+) content in cucumber roots under Ca(NO3)2 stress. This study revealed the differentially expressed proteins and BR signalling-associated mRNAs induced by EBL in cucumber seedling roots under Ca(NO3)2 stress, providing a better understanding of EBL-induced salt resistance in cucumber seedlings. The mechanism for alleviation provides valuable insight into improving Ca(NO3)2 stress tolerance of other horticultural plants. PMID- 26931456 TI - Microglial activation induces neuronal death in Chandipura virus infection. AB - Neurotropic viruses induce neurodegeneration either directly by activating host death domains or indirectly through host immune response pathways. Chandipura Virus (CHPV) belonging to family Rhabdoviridae is ranked among the emerging pathogens of the Indian subcontinent. Previously we have reported that CHPV induces neurodegeneration albeit the root cause of this degeneration is still an open question. In this study we explored the role of microglia following CHPV infection. Phenotypic analysis of microglia through lectin and Iba-1 staining indicated cells were in an activated state post CHPV infection in cortical region of the infected mouse brain. Cytokine Bead Array (CBA) analysis revealed comparatively higher cytokine and chemokine levels in the same region. Increased level of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), Nitric Oxide (NO) and Reactive Oxygen species (ROS) in CHPV infected mouse brain indicated a strong inflammatory response to CHPV infection. Hence it was hypothesized through our analyses that this inflammatory response may stimulate the neuronal death following CHPV infection. In order to validate our hypothesis supernatant from CHPV infected microglial culture was used to infect neuronal cell line and primary neurons. This study confirmed the bystander killing of neurons due to activation of microglia post CHPV infection. PMID- 26931457 TI - Drosophila Fed ARA and EPA Yields Eicosanoids, 15S-Hydroxy-5Z,8Z, 11Z, 13E Eicosatetraenoic Acid, and 15S-Hydroxy-5Z,8Z,11Z,13E,17Z-Eicosapentaenoic Acid. AB - Drosophila melanogaster has been a widely used as a model system for its powerful genetic tools. However, it remains to be illustrated if Drosophila can be used to examine the biochemical and physiological metabolism of eicosanoids. Thus, the analysis on the metabolism of C20 polyunsaturated fatty acids (PUFA) in Drosophila was implemented with high performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). Fatty acid (FA) analysis of the whole body, head, and thorax-abdomen in Drosophila showed C20 PUFA could only be found in Drosophila fed diets supplemented with eicosapentaenoic acid (EPA) and arachidonic acid (ARA), but not in Drosophila fed base diets. The C20 PUFA were found in abundance in the head. Drosophila fed ARA- and EPA-supplemented diets yielded 15S-hydroxy-5Z,8Z,11Z,13E-eicosatetraenoic acid [15(S)-HETE] and 15S hydroxy-5Z,8Z,11Z,13E,17Z-eicosapentaenoic acid [15(S)-HEPE], respectively, while other sampled eicosanoids could not be detected. Similar results were obtained by incubating fly tissue supplemented with ARA or EPA. Furthermore, a genome sequence scan indicated that no gene encoding the key enzymes synthesizing eicosanoids were found in Drosophila. These findings demonstrate that Drosophila may possess a special lipid metabolic system, which is different from mammals. PMID- 26931458 TI - Frog Virus 3 dissemination in the brain of tadpoles, but not in adult Xenopus, involves blood brain barrier dysfunction. AB - While increasing evidence points to a key role of monocytes in amphibian host defenses, monocytes are also thought to be important in the dissemination and persistent infection caused by ranavirus. However, little is known about the fate of infected macrophages or if ranavirus exploits immune privileged organs, such as the brain, in order to establish a reservoir. The amphibian Xenopus laevis and Frog Virus 3 (FV3) were established as an experimental platform for investigating in vivo whether ranavirus could disseminate to the brain. Our data show that the FV3 infection alters the BBB integrity, possibly mediated by an inflammatory response, which leads to viral dissemination into the central nervous system in X. laevis tadpole but not adult. Furthermore, our data suggest that the macrophages play a major role in viral dissemination by carrying the virus into the neural tissues. PMID- 26931460 TI - The Emergence of Geroscience as an Interdisciplinary Approach to the Enhancement of Health Span and Life Span. AB - Research on the biology of aging has accelerated rapidly in the last two decades. It is now at the point where translation of the findings into useful approaches to improve the health of the elderly population seems possible. In trying to fill that gap, a new field termed geroscience will be articulated here that attempts to identify the biological underpinnings for the age-dependency of most chronic diseases. Herein, I will review the major conceptual issues leading to the formulation of geroscience as a field, as well as give examples of current areas of inquiry in which basic aging biology research could lead to therapeutic approaches to address age-related chronic diseases, not one at a time, but most of them in unison. PMID- 26931459 TI - How Research on Human Progeroid and Antigeroid Syndromes Can Contribute to the Longevity Dividend Initiative. AB - Although translational applications derived from research on basic mechanisms of aging are likely to enhance health spans and life spans for most of us (the longevity dividend), there will remain subsets of individuals with special vulnerabilities. Medical genetics is a discipline that describes such "private" patterns of aging and can reveal underlying mechanisms, many of which support genomic instability as a major mechanism of aging. We review examples of three classes of informative disorders: "segmental progeroid syndromes" (those that appear to accelerate multiple features of aging), "unimodal progeroid syndromes" (those that impact on a single disorder of aging), and "unimodal antigeroid syndromes," variants that provide enhanced protection against specific disorders of aging; we urge our colleagues to expand our meager research efforts on the latter, including ancillary somatic cell genetic approaches. PMID- 26931461 TI - Cathepsin K induces platelet dysfunction and affects cell signaling in breast cancer - molecularly distinct behavior of cathepsin K in breast cancer. AB - BACKGROUND: Breast cancer comprises clinically and molecularly distinct tumor subgroups that differ in cell histology and biology and show divergent clinical phenotypes that impede phase III trials, such as those utilizing cathepsin K inhibitors. Here we correlate the epithelial-mesenchymal-like transition breast cancer cells and cathepsin K secretion with activation and aggregation of platelets. Cathepsin K is up-regulated in cancer cells that proteolyze extracellular matrix and contributes to invasiveness. Although proteolytically activated receptors (PARs) are activated by proteases, the direct interaction of cysteine cathepsins with PARs is poorly understood. In human platelets, PAR-1 and -4 are highly expressed, but PAR-3 shows low expression and unclear functions. METHODS: Platelet aggregation was monitored by measuring changes in turbidity. Platelets were immunoblotted with anti-phospho and total p38, Src-Tyr-416, FAK Tyr-397, and TGFbeta monoclonal antibody. Activation was measured in a flow cytometer and calcium mobilization in a confocal microscope. Mammary epithelial cells were prepared from the primary breast cancer samples of 15 women with Luminal-B subtype to produce primary cells. RESULTS: We demonstrate that platelets are aggregated by cathepsin K in a dose-dependent manner, but not by other cysteine cathepsins. PARs-3 and -4 were confirmed as the cathepsin K target by immunodetection and specific antagonists using a fibroblast cell line derived from PARs deficient mice. Moreover, through co-culture experiments, we show that platelets activated by cathepsin K mediated the up-regulation of SHH, PTHrP, OPN, and TGFbeta in epithelial-mesenchymal-like cells from patients with Luminal B breast cancer. CONCLUSIONS: Cathepsin K induces platelet dysfunction and affects signaling in breast cancer cells. PMID- 26931462 TI - Integrated analyses of gene expression and genetic association studies in a founder population. AB - Genome-wide association studies (GWASs) have become a standard tool for dissecting genetic contributions to disease risk. However, these studies typically require extraordinarily large sample sizes to be adequately powered. Strategies that incorporate functional information alongside genetic associations have proved successful in increasing GWAS power. Following this paradigm, we present the results of 20 different genetic association studies for quantitative traits related to complex diseases, conducted in the Hutterites of South Dakota. To boost the power of these association studies, we collected RNA-sequencing data from lymphoblastoid cell lines for 431 Hutterite individuals. We then used Sherlock, a tool that integrates GWAS and expression quantitative trait locus (eQTL) data, to identify weak GWAS signals that are also supported by eQTL data. Using this approach, we found novel associations with quantitative phenotypes related to cardiovascular disease, including carotid intima-media thickness, left atrial volume index, monocyte count and serum YKL-40 levels. PMID- 26931464 TI - Lovastatin protects neurite degeneration in LRRK2-G2019S parkinsonism through activating the Akt/Nrf pathway and inhibiting GSK3beta activity. AB - Parkinson's disease (PD) is a progressive neurodegenerative disorder that lacks a disease-modifying therapy. Leucine-rich repeat kinase 2 (LRRK2) was implicated as the most common genetic cause of PD. We previously established a LRRK2-G2019S Drosophila model that displayed the crucial phenotypes of LRRK2 parkinsonism. Here, we used a two-step approach to identify compounds from the FDA-approved licensed drug library that could suppress neurite degeneration in LRRK2-G2019S parkinsonism. Of 640 compounds, 29 rescued neurite degeneration phenotypes and 3 restored motor disability and dopaminergic neuron loss in aged LRRK2-G2019S flies. Of these three drugs, lovastatin had the highest lipophilicity, which facilitated crossing the blood-brain barrier. In LRRK2-G2019S knock-in mice and stably transfected human dopaminergic cells, lovastatin significantly rescued neurite degeneration in a dose-dependent manner, within a range of 0.05-0.1 MUm The beneficial effect of lovastatin was exerted by activating anti-apoptotic Akt/Nrf signaling and decreasing caspase 3 levels. We also observed that lovastatin inhibited GSK3beta activity, a kinase downstream of Akt, by up regulating GSK3beta (Ser9) phosphorylation. This inhibition subsequently decreased tau phosphorylation, which was linked to neuronal cytoskeleton instability. Conversely, pre-treatment with the Akt inhibitor, A6730, blocked the lovastatin-induced neuroprotective effect. The rescuing effects of lovastatin in dendritic arborization of LRRK2-G2019S neurons were abolished by co-expressing either a mutant allele of Akt (Akt104226) or a constitutively active form of GSK3beta (sggS9A). Our findings demonstrated that lovastatin restored LRRK2 G2019S neurite degeneration by augmenting Akt/NRF2 pathway and inhibiting downstream GSK3beta activity, which decreased phospho-tau levels. We suggested that lovastatin is a potential disease-modifying agent for LRRK2-G2019S parkinsonism. PMID- 26931463 TI - Drosophila clueless is involved in Parkin-dependent mitophagy by promoting VCP mediated Marf degradation. AB - PINK1/Parkin-mediated mitochondrial quality control (MQC) requires valosin containing protein (VCP)-dependent Mitofusin/Marf degradation to prevent damaged organelles from fusing with the healthy mitochondrial pool, facilitating mitochondrial clearance by autophagy. Drosophila clueless (clu) was found to interact genetically with PINK1 and parkin to regulate mitochondrial clustering in germ cells. However, whether Clu acts in MQC has not been investigated. Here, we show that overexpression of Drosophila Clu complements PINK1, but not parkin, mutant muscles. Loss of clu leads to the recruitment of Parkin, VCP/p97, p62/Ref(2)P and Atg8a to depolarized swollen mitochondria. However, clearance of damaged mitochondria is impeded. This paradox is resolved by the findings that excessive mitochondrial fission or inhibition of fusion alleviates mitochondrial defects and impaired mitophagy caused by clu depletion. Furthermore, Clu is upstream of and binds to VCP in vivo and promotes VCP-dependent Marf degradation in vitro Marf accumulates in whole muscle lysates of clu-deficient flies and is destabilized upon Clu overexpression. Thus, Clu is essential for mitochondrial homeostasis and functions in concert with Parkin and VCP for Marf degradation to promote damaged mitochondrial clearance. PMID- 26931465 TI - Poly-dipeptides encoded by the C9ORF72 repeats block global protein translation. AB - The expansion of the GGGGCC hexanucleotide repeat in the non-coding region of the Chromosome 9 open-reading frame 72 (C9orf72) gene is the most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). This genetic alteration leads to the accumulation of five types of poly dipeptides translated from the GGGGCC hexanucleotide repeat. Among these, poly proline-arginine (poly-PR) and poly-glycine-arginine (poly-GR) peptides are known to be neurotoxic. However, the mechanisms of neurotoxicity associated with these poly-dipeptides are not clear. A proteomics approach identified a number of interacting proteins with poly-PR peptide, including mRNA-binding proteins, ribosomal proteins, translation initiation factors and translation elongation factors. Immunostaining of brain sections from patients with C9orf72 ALS showed that poly-GR was colocalized with a mRNA-binding protein, hnRNPA1. In vitro translation assays showed that poly-PR and poly-GR peptides made insoluble complexes with mRNA, restrained the access of translation factors to mRNA, and blocked protein translation. Our results demonstrate that impaired protein translation mediated by poly-PR and poly-GR peptides plays a role in neurotoxicity and reveal that the pathways altered by the poly-dipeptides-mRNA complexes are potential therapeutic targets for treatment of C9orf72 FTD/ALS. PMID- 26931466 TI - Pharmacokinetics, pharmacodynamics, and efficacy of a small-molecule SMN2 splicing modifier in mouse models of spinal muscular atrophy. AB - Spinal muscular atrophy (SMA) is caused by the loss or mutation of both copies of the survival motor neuron 1 (SMN1) gene. The related SMN2 gene is retained, but due to alternative splicing of exon 7, produces insufficient levels of the SMN protein. Here, we systematically characterize the pharmacokinetic and pharmacodynamics properties of the SMN splicing modifier SMN-C1. SMN-C1 is a low molecular weight compound that promotes the inclusion of exon 7 and increases production of SMN protein in human cells and in two transgenic mouse models of SMA. Furthermore, increases in SMN protein levels in peripheral blood mononuclear cells and skin correlate with those in the central nervous system (CNS), indicating that a change of these levels in blood or skin can be used as a non invasive surrogate to monitor increases of SMN protein levels in the CNS. Consistent with restored SMN function, SMN-C1 treatment increases the levels of spliceosomal and U7 small-nuclear RNAs and corrects RNA processing defects induced by SMN deficiency in the spinal cord of SMNDelta7 SMA mice. A 100% or greater increase in SMN protein in the CNS of SMNDelta7 SMA mice robustly improves the phenotype. Importantly, a ~50% increase in SMN leads to long-term survival, but the SMA phenotype is only partially corrected, indicating that certain SMA disease manifestations may respond to treatment at lower doses. Overall, we provide important insights for the translation of pre-clinical data to the clinic and further therapeutic development of this series of molecules for SMA treatment. PMID- 26931467 TI - Dominant-negative kinase domain mutations in FGFR1 can explain the clinical severity of Hartsfield syndrome. AB - Mutations in FGFR1 have recently been associated with Hartsfield syndrome, a clinically distinct syndromic form of holoprosencephaly (HPE) with ectrodactly, which frequently includes combinations of craniofacial, limb and brain abnormalities not typical for classical HPE. Unrelated clinical conditions generally without craniofacial or multi-system malformations include Kallmann syndrome and idiopathic hypogonadotropic hypogonadism. FGFR1 is a principal cause for these less severe diseases as well. Here we demonstrate that of the nine FGFR1 mutations recently detected in our screen of over 200 HPE probands by next generation sequencing, only five distinct mutations in the kinase domain behave as dominant-negative mutations in zebrafish over-expression assays. Three FGFR1 mutations seen in HPE probands behave identical to wild-type FGFR1 in rescue assays, including one apparent de novo variation. Interestingly, in one HPE family, a deleterious FGFR1 allele was transmitted from one parent and a loss-of function allele in FGF8 from the other parent to both affected daughters. This family is one of the clearest examples to date of gene:gene synergistic interactions causing HPE in humans. PMID- 26931469 TI - Oncologists' and oncology nurses' attitudes and practices towards family involvement in cancer consultations. AB - Family members (FMs) regularly attend cancer consultations with patients, may assume an array of roles (e.g. emotional, informational) and their involvement may result in benefits and/or challenges. Little is currently known about how oncology health professionals (HPs) view FMs who accompany a patient in consultations. This study aimed to explore the attitudes and practices of Australian oncologists and oncology nurses regarding family involvement in consultations. Eleven oncologists and 10 nurses from a range of subspecialties and tumour streams participated in semi-structured interviews. Interviews were transcribed and qualitatively analysed using framework analysis methods. Five relevant themes were identified: (1) the varied and dynamic nature of family roles during consultations; (2) positivity towards FMs; (3) the benefits of family involvement to the FM themselves; (4) current HP practices to facilitate positive family involvement; and (5) the challenges of family involvement in consultations and HP practices to manage them. Overall, participants held mostly positive attitudes towards family involvement. Although they identified a number of challenges which can arise when family are involved, many noted these situations are the exception, that there are strategies which can help to overcome the challenges, and that the benefits of family involvement typically outweigh the costs. PMID- 26931470 TI - Impact of Introducing Catheter-based Renal Denervation into Japan for Hypertension Management: Estimation of Number of Target Patients and Clinical Relevance of Ambulatory Blood Pressure Reduction. AB - BACKGROUND: New medical approaches to the autonomic nervous system, such as catheterbased renal denervation, have been introduced into clinical practice in the recent years for patients who have resistant hypertension. OBJECTIVES AND METHODS: We estimate the number of subjects in Japan who would benefit from renal denervation when this treatment is introduced into Japan, based on data from the Jichi Medical University clinical trials. We also discuss the logical basis of changing the formerly used primary endpoint, i.e., office BP, to 24-hr ambulatory BP in future clinical trials. RESULTS: Among JAMP registry data, the total number of hypertensives was 5,858 and the patients who were prescribed >= 3 drugs including diuretics were 749. The poorly controlled hypertension rate was 32% in the group prescribed >= 3 drugs including diuretics and it constitutes 4.1% of the total hypertensive patients. We also analyzed the data of JMS ABPM cohort study wave 1 (811 patients). The hazard ratios (HRs) for each 10-mmHg increase in BP was 1.38 (95%CI 1.17-1.63, p<0.001) for 24-hr BP and 1.18 (95%CI 1.05-1.33, p=0.006) for office BP. However, the significance for office BP was lost once the 24-hr, daytime and nighttime ambulatory BP data were added to the covariates. CONCLUSION: The prevalence of resistant hypertensive patients among all of the hypertensive patients is 4.1%. Based on this prevalence, the number of resistant hypertensive individuals in Japan would be 1,870,000 patients. In future renal denervation clinical studies in Japan, we should set the primary endpoint as a 24 hr systolic BP reduction measured by ABPM. PMID- 26931468 TI - Missense variants in the middle domain of DNM1L in cases of infantile encephalopathy alter peroxisomes and mitochondria when assayed in Drosophila. AB - Defects in organelle dynamics underlie a number of human degenerative disorders, and whole exome sequencing (WES) is a powerful tool for studying genetic changes that affect the cellular machinery. WES may uncover variants of unknown significance (VUS) that require functional validation. Previously, a pathogenic de novo variant in the middle domain of DNM1L (p.A395D) was identified in a single patient with a lethal defect of mitochondrial and peroxisomal fission. We identified two additional patients with infantile encephalopathy and partially overlapping clinical features, each with a novel VUS in the middle domain of DNM1L (p.G350R and p.E379K). To evaluate pathogenicity, we generated transgenic Drosophila expressing wild-type or variant DNM1L. We find that human wild-type DNM1L rescues the lethality as well as specific phenotypes associated with the loss of Drp1 in Drosophila. Neither the p.A395D variant nor the novel variant p.G350R rescue lethality or other phenotypes. Moreover, overexpression of p.A395D and p.G350R in Drosophila neurons, salivary gland and muscle strikingly altered peroxisomal and mitochondrial morphology. In contrast, the other novel variant (p.E379K) rescued lethality and did not affect organelle morphology, although it was associated with a subtle mitochondrial trafficking defect in an in vivo assay. Interestingly, the patient with the p.E379K variant also has a de novo VUS in pyruvate dehydrogenase 1 (PDHA1) affecting the same amino acid (G150) as another case of PDHA1 deficiency suggesting the PDHA1 variant may be pathogenic. In summary, detailed clinical evaluation and WES with functional studies in Drosophila can distinguish different functional consequences of newly-described DNM1L alleles. PMID- 26931471 TI - Blood Pressure Management in Acute Stroke. AB - Raised blood pressure is common in ischaemic stroke and intracerebral haemorrhage and is an independent risk factor for unfavourable outcome. Yet, the approach to blood pressure management represents an unresolved issue in acute stroke treatment. The aim of this review is to present the current knowledge regarding the management of raised blood pressure in patients with acute ischaemic stroke or intracerebral haemorrhage. In ischaemic stroke, several large clinical trials have tested the efficacy of several strategies that lower blood pressure. Overall, blood pressure lowering in the acute phase has no beneficial effect and should not be included in routine clinical practice apart from when treating patients with very raised blood pressure or those who are eligible for thrombolytic treatment. These findings in patients with acute ischaemic stroke are in contrast with those in intracerebral haemorrhage. A recent clinical trial has strongly suggested a clinical benefit of blood pressure lowering during the first few hours in intracerebral haemorrhage, which have led to changes in international guidelines. An important unanswered question in blood pressure management in the acute phase of ischaemic stroke involves the first few hours, when there is still penumbral tissue at risk. Forthcoming trials may help to answer this remaining issue. PMID- 26931472 TI - Epigenetic Regulation Through SIRT1 in Podocytes. AB - SIRT1 is an NAD-dependent deacetylase. One important role of SIRT1 is its deacetylation activity in the modulation of cell stress signals via epigenetics. In podocytes, SIRT1 regulates the expression of important genes such as PGC 1alpha, Foxo4, p65 and STAT3, which act to maintain podocyte function by modulating the levels of histone acetylation. Here, we confirmed that SIRT1 protects podocytes by maintaining PGC-1alpha via its deacetylase-activated transcriptional activity in mitochondria and podocytes. We then showed that the alteration of Foxo4 (forkhead box O4) acetylation and decrease in SIRT1 promote podocyte apoptosis in diabetic nephropathy, resulting in the gradual development of diabetic nephropathy. Next, we showed that advanced glycation end products (AGEs) induced p65 and STAT3 acetylation in human podocytes. Decreased Sirt1 activity in podocytes results in the development of proteinuria and kidney injury via the acetylation of p65 and STAT3. These findings suggest that the beneficial effects of SIRT1 in diabetic nephropathy act via the deacetylation of transcription factors. In addition to its essential role in regulating the epigenetics of podocytes, we recently showed that SIRT1 is necessary to maintaining the function of slit membranes and podocytes. The actin cytoskeleton becomes vulnerable to various stresses, including oxidative stress, which in turn leads to the derangement and effacement of foot processes, slit membrane dysfunction, and proteinuria. SIRT1 protects podocytes and prevents glomerular injury by deacetylating cortactin and changing cortactin localization, thereby maintaining the integrity of the actin cytoskeleton. We expect that SIRT1 will be shown to sufficiently suppress the development of kidney dysfunction and will be proven useful in the near future. The clinical application of SIRT1-activated chemical agents has just started, and results are eagerly anticipated. PMID- 26931473 TI - DNA Damage and Epigenetic Changes in Kidney Diseases - Focused on Transcription Factors in Podocytes. AB - Recently it has been shown that epigenetic mechanisms are involved in initiation and progression of caridiovascular and metabolic diseases, including diabetes, obesity, atherosclerosis, heart failure, hypertension and kidney diseases. In these chronic diseases, various exogenous and endogenous stresses cause DNA damage, followed by DNA repair process. Accumulation of DNA damages and impaired repair process can lead to epigenetic changes, which may contribute to onset and progression of diseases. Recently we have shown that therapeutic effect of transcription factor KLF4 (Kruppel-like factor 4) in kidney glomerular epithelial cells (podocytes) on proteinuric kidney diseases through epigenetic mechanisms. Our result suggests the possibility of transcription factors as a target of selective epigenetic therapy. Moreover, we have reported that renin-angiotensin system (RAS) blockers, which are widely prescribed for the treatment of cardiovascular diseases, can restore epigenetic changes through KLF4 in part. These results suggest that activation of RAS causes epigenetic changes in disease states, and elucidation of the precise mechanism may lead to establishment of novel therapeutic target of kidney diseases. In this review we focus on DNA damage repair system and epigenetic modulators in disease states, and speculate a candidate for epigenetic therapy of kidney diseases. PMID- 26931474 TI - Communication from Tubular Epithelial Cells to Podocytes through Sirt1 and Nicotinic Acid Metabolism. AB - We have recently published that tubular epithelial cells affect the podocyte epigenome though nicotinic acid metabolism in diabetic nephropathy (DN), and we have named this relationship "proximal tubule-podocyte communication". In this review, we describe this novel mechanism in the early stage of DN, focusing on the function of renal tubular Sirt1 and Sirt1-related nicotinic acid metabolism. Mainly, we discuss the following three findings. First, we described the details of proximal tubule-podocyte communication. Second, we explained how Sirt1 regulates albuminuria via epigenetic mechanisms. This means that repeated high glucose stress triggers the initial changes in proximal tubules, which lead to the epigenetically irreversible glomerular damages. However, proximal tubular Sirt1 overexpression can rescue these changes. Our previous data indicated that the decrease in Sirt1 expression in proximal tubules caused the reduction in glomerular Sirt1 and the subsequent increase in glomerular Claudin-1. It seemed plausible that some humoral mediator is released from proximal tubules, migrates to podocytes and glomeruli, and affects Sirt1 expression in podocytes. Third, we mentioned a mediator connecting this communication, nicotinamide mononucleotide (NMN). We suggest the potential of Sirt1 or NMN as not only a therapeutic target but also as a prognostic marker of very early stage DN. PMID- 26931475 TI - Angiotensins and Their Receptors in Cardiac and Vascular Injury. AB - The renin-angiotensin system is involved in hypertension and, thus, in cardiac and vascular injury. In general, angiotensin II is considered as the main mediator of this system but angiotensin IIderived peptides were also shown to exert effects in such diseases. Moreover, it became obvious that different cell and corresponding tissue types are characterized by their own renin-angiotensin system. This system is composed of various peptidic derivatives of the precursor angiotensinogen. Those angiotensinogen-derived peptides can be processed further by peptidases and can bind corresponding receptors. Various clinical trials were initiated considering inhibition of the renin-angiotensin system at different stages in cardiac injuries. Recently, a phase 3 trial using infused angiotensin II (LJPC-501) as treatment option in catecholamine-resistent hypotension was established (ClinicalTrials.gov identifier NCT02338843) although it might be that an influence of AngII-derived peptides is not considered. In general, more intense research on AngII-derived peptides should result in novel strategies and therapeutic options in treatment of cardiac and vascular injuries since these peptides exert actions by themselves, some may interfere with AngII-mediated effects, and some can bind different receptors as well. Consequently, they may also become new promising therapeutics in clinical settings in the future. This short review introduces all currently known angiotensins at once, their production and role related to cardiac and vascular injury, which immune cells show renin-angiotensin system components, and how immune cells containing such components might be involved in such diseases as well. PMID- 26931476 TI - Update of Targeted Therapy-Induced Hypertension: Basics for Non-Oncology Providers. AB - Over the past several years, cancer treatments have expanded from usual chemotherapy standards with introduction of newer targeted therapies. As with chemotherapy, the targeted therapies also have unique side effects affecting various organ systems producing toxicities, such as cardiac and renal. This manuscript focuses on hypertension induced by vascular endothelial growth factor (VEGF) inhibitors and tyrosine kinase inhibitors (TKI). Hypertension due to these cancer therapies is important because these agents are now frequently used in common cancers. In addition, patients with cancer may not be treated in a comprehensive cancer center with experts available to manage the cancer and other side effects either from the malignancy or treatment of the malignancy. Especially in rural areas, patients are often managed or co-managed by a primary care provider with input from an oncologist that may not be nearby. Our aim is to provide an overview of the latest Federal Drug Administration (FDA) approved VEGF inhibitors and TKI's causing hypertension so that others managing patients on these treatments may easily recognize hypertension attributable to these agents and feel comfortable and confident in providing appropriate management and treatment of this side effect. This update includes characteristics, such as mechanism of action, metabolism and route of administration, and management and treatment of hypertension with aspects such as the timing, duration and monitoring of these agents. In addition, an algorithm for monitoring and treating hypertension before, during and after treatment with these therapies is included. It is imperative for patients to have hypertension promptly treated to prevent complications so they may continue with these agents with the least interruption or discontinuation of treatment, ensuring the best benefit available in their cancer trajectory. PMID- 26931477 TI - Plasma levels of endothelial and B-cell-derived microparticles are restored by fingolimod treatment in multiple sclerosis patients. AB - BACKGROUND: No molecular marker can monitor disease progression and treatment efficacy in multiple sclerosis (MS). Circulating microparticles represent a potential snapshot of disease activity at the blood brain barrier. OBJECTIVES AND METHODS: To profile plasma microparticles by flow cytometry in MS and determine how fingolimod could impact endothelial microparticles production. RESULTS: In non-treated MS patients compared to healthy and fingolimod-treated patients, endothelial microparticles were higher, while B-cell-microparticle numbers were lower. Fingolimod dramatically reduced tumour necrosis factor (TNF)-induced endothelial microparticle release in vitro. CONCLUSION: Fingolimod restored dysregulated endothelial and B-cell-microparticle numbers, which could serve as a biomarker in MS. PMID- 26931478 TI - Adverse obstetric symptoms and rural-urban difference in cesarean delivery in Rupandehi district, Western Nepal: a cohort study. AB - BACKGROUND: The burden of maternal morbidity is high in developing countries including Nepal. This study investigated obstetric complications and rural-urban difference in cesarean delivery rate in Western Nepal. METHODS: A community-based cohort study was conducted in the Rupandehi district of Western Nepal during January-October, 2014, by interviewing 735 mothers within one month postpartum. The prevalence of obstetric complications was reported via frequency distribution, while factors associated with cesarean delivery were assessed using logistic regression analysis. RESULTS: The prevalence of adverse obstetric symptoms during antenatal, intranatal and postnatal periods were 19.7%, 27.8% and 21.6%, respectively. In total, 81 (11.0%) mothers reported having stillbirths. The cesarean delivery rate was 14.1% overall but was four times higher in the urban (23.0%) than in the rural areas (5.8%). Prolonged labor (19.0%) and heavy bleeding (16.7%) were common among rural women. Logistic regression analysis confirmed that cesarean section was more likely for mothers residing in urban areas than in rural areas (adjusted odds ratio 3.41; 95 % confidence interval 2.01 to 5.78). CONCLUSIONS: About one in five mothers reported some adverse obstetric symptoms. Obstetric problems were more common in the rural areas, whereas cesarean delivery rate was much higher in the urban areas. Further investigations are required to determine whether these cesarean sections are medically warranted or provider induced. PMID- 26931479 TI - Seven day services: how are trusts doing against Keogh's clinical standards? PMID- 26931480 TI - Tobacco industry responsibility for butts: a Model Tobacco Waste Act. AB - Cigarette butts and other postconsumer products from tobacco use are the most common waste elements picked up worldwide each year during environmental cleanups. Under the environmental principle of Extended Producer Responsibility, tobacco product manufacturers may be held responsible for collection, transport, processing and safe disposal of tobacco product waste (TPW). Legislation has been applied to other toxic and hazardous postconsumer waste products such as paints, pesticide containers and unused pharmaceuticals, to reduce, prevent and mitigate their environmental impacts. Additional product stewardship (PS) requirements may be necessary for other stakeholders and beneficiaries of tobacco product sales and use, especially suppliers, retailers and consumers, in order to ensure effective TPW reduction. This report describes how a Model Tobacco Waste Act may be adopted by national and subnational jurisdictions to address the environmental impacts of TPW. Such a law will also reduce tobacco use and its health consequences by raising attention to the environmental hazards of TPW, increasing the price of tobacco products, and reducing the number of tobacco product retailers. PMID- 26931481 TI - Oriented bone regenerative capacity of octacalcium phosphate/gelatin composites obtained through two-step crystal preparation method. AB - The present study was designed to investigate whether composite of coprecipitating octacalcium phosphate and gelatin (C-OCP/Gel) has an effect in repairing critical-sized defect of rat calvaria with oriented regenerative bone if implanted. The materials were prepared through two steps to disperse homogenous and well-elongated OCP toward long axis of the crystals in gelatin (Gel) matrix with the distinct concentration 17-44 wt %: OCP precipitates recovered from the coprecipitated with Gel molecules in aqueous solution (referred to as C-OCP hereafter) were mixed again in fresh aqueous Gel solution with various mixing ratio to form C-OCP/Gel for implantation. C-OCP/Gel disks with 9 mm diameter and 1 mm thickness after the dehydrothermal treatment was implanted in 9 mm diameter rat calvaria critical-sized defect. The histology, the histomorphometry in the regenerated bone and the quantitative analysis of the orientation of collagen with picrosirius red staining were carried out. It was found that C-OCP/Gel is capable of not only inducing sufficiently regenerative bone over 80% of the defect coupled with practically complete material biodegradation but also forming oriented bone significantly in relation to the amount of C-OCP in Gel matrix until 12 weeks after the implantation. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 1029 1039, 2017. PMID- 26931482 TI - Pyruvate dehydrogenase kinase 2 and 4 gene deficiency attenuates nociceptive behaviors in a mouse model of acute inflammatory pain. AB - Pyruvate dehydrogenase (PDH) kinases (PDKs) 1-4, expressed in peripheral and central tissues, regulate the activity of the PDH complex (PDC). The PDC is an important mitochondrial gatekeeping enzyme that controls cellular metabolism. The role of PDKs in diverse neurological disorders, including neurometabolic aberrations and neurodegeneration, has been described. Implications for a role of PDKs in inflammation and neurometabolic coupling led us to investigate the effect of genetic ablation of PDK2/4 on nociception in a mouse model of acute inflammatory pain. Deficiency in Pdk2 and/or Pdk4 in mice led to attenuation of formalin-induced nociceptive behaviors (flinching, licking, biting, or lifting of the injected paw). Likewise, the pharmacological inhibition of PDKs substantially diminished the nociceptive responses in the second phase of the formalin test. Furthermore, formalin-provoked paw edema formation and mechanical and thermal hypersensitivities were significantly reduced in Pdk2/4-deficient mice. Formalin driven neutrophil recruitment at the site of inflammation, spinal glial activation, and neuronal sensitization were substantially lessened in the second or late phase of the formalin test in Pdk2/4-deficient animals. Overall, our results suggest that PDK2/4 can be a potential target for the development of pharmacotherapy for the treatment of acute inflammatory pain. (c) 2016 Wiley Periodicals, Inc. PMID- 26931484 TI - David C Seldin, MD, PhD: scientist, clinician, teacher, gentleman, 1957-2015. PMID- 26931485 TI - Tacrolimus compared with cyclosporine A after haploidentical T-cell replete transplantation with post-infusion cyclophosphamide. PMID- 26931486 TI - Antioxidant activity and nutrient release from polyphenol-enriched cheese in a simulated gastrointestinal environment. AB - Green tea polyphenols are recognized for their antioxidant properties and their effects on lipid digestion kinetics. Polyphenols are sensitive to degradation in the intestinal environment. Interactions with dairy proteins could modulate the stability and biological activity of polyphenols during digestion. The objective of this study was to evaluate the release of nutrients (polyphenols, fatty acids and peptides) and the antioxidant activity in polyphenol-enriched cheese containing different levels of calcium in a simulated gastrointestinal environment. The relationship between cheese matrix texture, matrix degradation and nutrient release during digestion was also studied. Green tea extract was added to milk at 0% or 0.1%, and cheeses were produced on a laboratory scale. The level of available calcium was adjusted to low (Ca(low)), regular (Ca(reg)) or high (Ca(high)) during the salting step of the cheese-making process. Cheeses were subjected to simulated digestion. The rate and extent of fatty acid release were 21% lower for Ca(low) cheese than for Ca(reg) and Ca(high) cheeses. The greater adhesiveness of Ca(low) cheese, which resulted in lower rates of matrix degradation and proteolysis, contributed to the reduced rate of lipolysis. The presence of green tea extract in cheese reduced the release of free fatty acids at the end of digestion by 7%. The addition of green tea extract increased cheese hardness but did not influence matrix degradation or proteolysis profiles. The formation of complexes between tea polyphenols and proteins within the cheese matrix resulted in a more than twofold increase in polyphenol recovery in the intestinal phase compared with the control (tea polyphenol extract incubated with polyphenol-free cheese). Antioxidant activity was 14% higher in the digest from polyphenol-enriched cheese than in the control. These results suggest that cheese is an effective matrix for the controlled release of nutrients and for the protection of green tea polyphenol integrity and biological activity in the gastrointestinal environment. PMID- 26931487 TI - Sub-nanometer resolution of an organic semiconductor crystal surface using friction force microscopy in water. AB - Organic semiconductors (OSC) are attracting much interest for (opto)electronic applications, such as photovoltaics, LEDs, sensors or solid state lasers. In particular, crystals formed by small pi-conjugated molecules have shown to be suitable for constructing OSC devices. However, the (opto)electronic properties are complex since they depend strongly on both the mutual orientation of molecules as well as the perfection of bulk crystal surfaces. Hence, there is an urgent need to control nano-topographic OSC features in real space. Here we show that friction force microscopy in water is a very suitable technique to image the free surface morphology of an OSC single crystal (TDDCS) with sub-nanometer resolution. We demonstrate the power of the method by direct correlation to the structural information extracted from combined single crystal (SC-) and specular (s-) XRD studies, which allows us to identify the pinning centers encountered in the stick-slip motion of the probing tip with the topmost methyl groups on the TDDCS surface. PMID- 26931489 TI - Patient-Centered Quality of Care in Dialysis: An Introduction. PMID- 26931488 TI - Reactive case-detection of malaria in Pailin Province, Western Cambodia: lessons from a year-long evaluation in a pre-elimination setting. AB - BACKGROUND: As momentum towards malaria elimination grows, strategies are being developed for scale-up in elimination settings. One prominent strategy, reactive case detection (RACD), involves screening and treating individuals living in close proximity to passively detected, or "index" cases. This study aims to use RACD to quantify Plasmodium parasitaemia in households of index cases, and identify risk factors for infection; these data could inform reactive screening approaches and identify target risk groups. METHODS: This study was conducted in the Western Cambodian province of Pailin between May 2013 and March 2014 among 440 households. Index participants/index cases (n = 270) and surrounding households (n = 110) were screened for Plasmodium infection with rapid diagnostic tests (RDT), microscopy and real-time polymerase chain reaction (PCR). Participants were interviewed to identify risk factors. A comparison group of 60 randomly-selected households was also screened, to compare infection levels of RACD and non-RACD households. In order to identify potential risk factors that would inform screening approaches and identify risk groups, multivariate logistic regression models were applied. RESULTS: Nine infections were identified in households of index cases (RACD approach) through RDT screening of 1898 individuals (seven Plasmodium vivax, two Plasmodium falciparum); seven were afebrile. Seventeen infections were identified through PCR screening of 1596 individuals (15 P. vivax, and 22 % P. falciparum/P. vivax mixed infections). In the control group, 25 P. falciparum infections were identified through PCR screening of 237 individuals, and no P. vivax was found. Plasmodium falciparum infection was associated with fever (p = 0.013), being a member of a control household (p <= 0.001), having a history of malaria infection (p = 0.041), and sleeping without a mosquito net (p = 0.011). Significant predictors of P. vivax infection, as diagnosed by PCR, were fever (p = 0.058, borderline significant) and history of malaria infection (p <= 0.001). CONCLUSION: This study found that RACD identified very few secondary infections when targeting index and neighbouring households for screening. The results suggest RACD is not appropriate, where exposure to malaria occurs away from the community, and there is a high level of treatment-seeking from the private sector. Piloting RACD in a range of transmission settings would help to identify the ideal environment for feasible and effective reactive screening methods. PMID- 26931492 TI - Pd(II)/CuBr2 catalysed keto alpha-C(sp3)-H benzoxylation of N,N-dialkylamides directed by o-hydroxy groups. AB - A hydroxy group directed keto alpha-C(sp3)-H benzoxylation of amides, including N,N-dialkylamides and cyclic amides, has been accomplished involving ortho hydroxy substrates possessing either an aldehydic or a keto methyl (-COCH3) group with a Pd(II)/CuBr2 catalytic combination. The carboxy group obtained via the in situ oxidation of -CHO or -COCH3 groups of ortho-hydroxy substrates then undergoes a cross-dehydrogenative coupling (CDC) with amides to furnish an alpha benzoxylation product with concurrent aromatic ring bromination. PMID- 26931493 TI - Stigma: Content analysis of the representation of people with personality disorder in the UK popular press, 2001-2012. AB - There is evidence that people with personality disorder are stigmatized within healthcare settings; however, little is known about the role that the media has played in the wider processes of stigmatization. This research examines the degree to which the popular press in the UK have established a link between personality disorder and homicide, and the impact this may have had on the processes of stigmatization. Using a content analysis approach, it was identified that there were 552 articles in the popular press, between 2001 and 2012, that made reference to personality disorder and 42% of those articles established a link with homicide. Comparison between two time periods, 2001-2006 and 2007-2012, identified that there was a significant reduction in the proportion of homicide articles (Pearson chi2 (5, n = 552) = 5.64, P > .05), however, the effect size of this change was only small. These findings suggest that the press may have contributed to the processes of stigmatization, and may have encouraged the general public to hold prejudicial attitudes towards people with a diagnosis of personality disorder. PMID- 26931491 TI - The HAPPY (Healthy and Active Parenting Programmme for early Years) feasibility randomised control trial: acceptability and feasibility of an intervention to reduce infant obesity. AB - BACKGROUND: The prevalence of infant obesity is increasing, but there is a lack of evidence-based approaches to prevent obesity at this age. This study tested the acceptability and feasibility of evaluating a theory-based intervention aimed at reducing risk of obesity in infants of overweight/obese women during and after pregnancy: the Healthy and Active Parenting Programme for Early Years (HAPPY). METHODS: A feasibility randomised controlled trial was conducted in Bradford, England. One hundred twenty overweight/obese pregnant women (Body Mass Index [BMI] >=25 kg/m(2)) were recruited between 10-26 weeks gestation. Consenting women were randomly allocated to HAPPY (6 antenatal, 6 postnatal sessions: N = 59) or usual care (N = 61). Appropriate outcome measures for a full trial were explored, including: infant's length and weight, woman's BMI, physical activity and dietary intake of the women and infants. Health economic data were collected. Measurement occurred before randomisation and when the infant was aged 6 months and 12 months. Feasibility outcomes were: recruitment/attrition rates, and acceptability of: randomisation, measurement, and intervention. Intra-class correlations for infant weight were calculated. Fidelity was assessed through observations and facilitator feedback. Focus groups and semi-structured interviews explored acceptability of methods, implementation, and intervention content. RESULTS: Recruitment targets were met (~20 women/month) with a recruitment rate of 30 % of eligible women (120/396). There was 30 % attrition at 12 months; 66 % of recruited women failed to attend intervention sessions, but those who attended the first session were likely to continue to attend (mean 9.4/12 sessions, range 1-12). Reaction to intervention content was positive, and fidelity was high. Group clustering was minimal; an adjusted effect size of -0.25 standard deviation scores for infant weight at 12 months (95 % CI: -0.16-0.65) favouring the intervention was observed using intention to treat analyses. No adverse events were reported. CONCLUSIONS: The HAPPY intervention appeared feasible and acceptable to participants who attended and those delivering it, however attendance was low; adaptations to increase initial attendance are recommended. Whilst the study was not powered to detect a definitive effect, our results suggest a potential to reduce risk of infant obesity. The evidence reported provides valuable lessons to inform progression to a definitive trial. TRIAL REGISTRATION: Current Controlled Trials ISRCTN56735429. PMID- 26931495 TI - Beyond neutral and forbidden links: morphological matches and the assembly of mutualistic hawkmoth-plant networks. AB - A major challenge in evolutionary ecology is to understand how co-evolutionary processes shape patterns of interactions between species at community level. Pollination of flowers with long corolla tubes by long-tongued hawkmoths has been invoked as a showcase model of co-evolution. Recently, optimal foraging models have predicted that there might be a close association between mouthparts' length and the corolla depth of the visited flowers, thus favouring trait convergence and specialization at community level. Here, we assessed whether hawkmoths more frequently pollinate plants with floral tube lengths similar to their proboscis lengths (morphological match hypothesis) against abundance-based processes (neutral hypothesis) and ecological trait mismatches constraints (forbidden links hypothesis), and how these processes structure hawkmoth-plant mutualistic networks from five communities in four biogeographical regions of South America. We found convergence in morphological traits across the five communities and that the distribution of morphological differences between hawkmoths and plants is consistent with expectations under the morphological match hypothesis in three of the five communities. In the two remaining communities, which are ecotones between two distinct biogeographical areas, interactions are better predicted by the neutral hypothesis. Our findings are consistent with the idea that diffuse co evolution drives the evolution of extremely long proboscises and flower tubes, and highlight the importance of morphological traits, beyond the forbidden links hypothesis, in structuring interactions between mutualistic partners, revealing that the role of niche-based processes can be much more complex than previously known. PMID- 26931494 TI - A Helitron transposon reconstructed from bats reveals a novel mechanism of genome shuffling in eukaryotes. AB - Helitron transposons capture and mobilize gene fragments in eukaryotes, but experimental evidence for their transposition is lacking in the absence of an isolated active element. Here we reconstruct Helraiser, an ancient element from the bat genome, and use this transposon as an experimental tool to unravel the mechanism of Helitron transposition. A hairpin close to the 3'-end of the transposon functions as a transposition terminator. However, the 3'-end can be bypassed by the transposase, resulting in transduction of flanking sequences to new genomic locations. Helraiser transposition generates covalently closed circular intermediates, suggestive of a replicative transposition mechanism, which provides a powerful means to disseminate captured transcriptional regulatory signals across the genome. Indeed, we document the generation of novel transcripts by Helitron promoter capture both experimentally and by transcriptome analysis in bats. Our results provide mechanistic insight into Helitron transposition, and its impact on diversification of gene function by genome shuffling. PMID- 26931496 TI - Cell death and neurodegeneration in the postnatal development of cerebellar vermis in normal and Reeler mice. AB - Programmed cell death (PCD) was demonstrated in neurons and glia in normal brain development, plasticity, and aging, but also in neurodegeneration. (Macro)autophagy, characterized by cytoplasmic vacuolization and activation of lysosomal hydrolases, and apoptosis, typically entailing cell shrinkage, chromatin and nuclear condensation, are the two more common forms of PCD. Their underlying intracellular pathways are partly shared and neurons can die following both modalities, according to the type of death-triggering stimulus. Reelin is an extracellular protein necessary for proper neuronal migration and brain lamination. In the mutant Reeler mouse, its absence causes neuronal mispositioning, with a notable degree of cerebellar hypoplasia that was tentatively related to an increase in PCD. We have carried out an ultrastructural analysis on the occurrence and type of postnatal PCD affecting the cerebellar neurons in normal and Reeler mice. In the forming cerebellar cortex, PCD took the form of apoptosis or autophagy and mainly affected the cerebellar granule cells (CGCs). Densities of apoptotic CGCs were comparable in both mouse strains at P0 P10, while, in mutants, they increased to become significantly higher at P15. In WT mice the density of autophagic neurons did not display statistically significant differences in the time interval examined in this study, whereas it was reduced in Reeler in the P0-P10 interval, but increased at P15. Besides CGCs, the Purkinje neurons also displayed autophagic features in both WT and Reeler mice. Therefore, cerebellar neurons undergo different types of PCD and a Reelin deficiency affects the type and degree of neuronal death during postnatal development of the cerebellum. PMID- 26931497 TI - Caveolin interaction governs Kv1.3 lipid raft targeting. AB - The spatial localization of ion channels at the cell surface is crucial for their functional role. Many channels localize in lipid raft microdomains, which are enriched in cholesterol and sphingolipids. Caveolae, specific lipid rafts which concentrate caveolins, harbor signaling molecules and their targets becoming signaling platforms crucial in cell physiology. However, the molecular mechanisms involved in such spatial localization are under debate. Kv1.3 localizes in lipid rafts and participates in the immunological response. We sought to elucidate the mechanisms of Kv1.3 surface targeting, which govern leukocyte physiology. Kv1 channels share a putative caveolin-binding domain located at the intracellular N terminal of the channel. This motif, lying close to the S1 transmembrane segment, is situated near the T1 tetramerization domain and the determinants involved in the Kvbeta subunit association. The highly hydrophobic domain (FQRQVWLLF) interacts with caveolin 1 targeting Kv1.3 to caveolar rafts. However, subtle variations of this cluster, putative ancillary associations and different structural conformations can impair the caveolin recognition, thereby altering channel's spatial localization. Our results identify a caveolin-binding domain in Kv1 channels and highlight the mechanisms that govern the regulation of channel surface localization during cellular processes. PMID- 26931499 TI - Canine versus human epilepsy: are we up to date? AB - In this paper we analyse and compare features of canine and human epilepsy and we suggest new tools for better future understanding of canine epilepsy. The prevalence of epileptic seizures in dogs ranges between 0.5% and 5.7% and between 1% and 3% in the human population. Studies on human epilepsy provide a ready-made format for classification, diagnosis and treatment in veterinary epilepsy. Human studies highlight the value of a thorough seizure classification. Nevertheless, a matter of concern in canine epilepsy is the limited information regarding seizure description and classification because of the lack of EEG-video recording. Establishment of a consensus protocol for ambulatory home video-recording in dogs who suffer from epilepsy, mainly considering indications, duration of monitoring, the sufficient essential training for an optimal interpretation of ictal semiology and the methodology of recordings is needed. The ultimate goal is that the information gathered by these videos will be analysed to describe the epileptic seizures thoroughly, recognize patterns and move towards a better understanding and therefore classification of canine epileptic seizures. PMID- 26931498 TI - The Risk of Glioblastoma with TNF Inhibitors. AB - PURPOSE: To quantify the risk of glioblastoma (GBM) and its most aggressive form, glioblastoma multiforme (GBM-M), in patients treated with tumor necrosis factor (TNF) inhibitors. METHODS: Data from the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) and the World Health Organization (WHO) Collaborating Centre for International Drug Monitoring were used to perform a disproportionality analysis. We computed reporting odds ratios (RORs) and corresponding 95% confidence intervals for the association between use of TNF inhibitors (infliximab, adalimumab, etanercept, certolizumab, and golimumab) and GBM or GBM-M compared to all other drugs with adverse events reported in the databases. A harmful signal was deemed for a lower limit of the 95% confidence interval above 1. RESULTS: We identified 81 cases of GBM or GBM-M with adalimumab in the U.S. FDA FAERS and 49 cases in the WHO drug monitoring database. For infliximab, 40 and 32 cases were identified in the FAERS and WHO databases, respectfully. Infliximab had the highest association with GBM (WHO: ROR = 7.41 (5.19-10.57), FAERS: ROR = 2.80 [1.89-4.15]). Adalimumab was also highly associated with GBM (WHO: ROR = 3.54 [2.58-4.89], FAERS: ROR = 1.99 [1.41-2.80]). CONCLUSION: Several TNF inhibitors appear to be more strongly associated with GBM compared to other drugs in both the FAERS and WHO databases. Large epidemiologic studies are needed to confirm these findings. Although these results do not demonstrate a cause-and-effect relationship, they warrant further investigation by well-designed epidemiologic studies. PMID- 26931500 TI - Evaluation of capsule endoscopy to detect mucosal lesions associated with gastrointestinal bleeding in dogs. AB - OBJECTIVE: The objective of this study was to examine the utility of capsule endoscopy to detect mucosal abnormalities in dogs with gastrointestinal haemorrhage. METHODS: Capsules were administered to 2 healthy controls and 8 patients with gastrointestinal haemorrhage. Images were evaluated for quality, gastric emptying time, small intestinal transit time and presence of lesions. RESULTS: There were no adverse effects of capsule endoscopy in dogs weighing from 7.7 to 58 kg. The capsule traversed the entire gastrointestinal tract in 5 of 8 patients, with high quality images obtained in the stomach and small intestine. Gastric emptying time and small intestinal transit time ranged from 1 to 270 and 15 to 180 minutes, respectively. In 3 of 8 patients, the capsule remained in the stomach despite pro-kinetics. Gastric lesions included mild haemorrhage and pinpoint erosion (4 of 8), a mass (1) and thickened bleeding pyloric mucosa (2). Two of 3 dogs with capsule retention had gastric lesions. Intestinal lesions included a healing duodenal ulcer, abnormal villi, ileal ulceration and colonic bleeding. Lesions identified by capsule endoscopy were considered a significant source of haemorrhage in 4 of 7 dogs with active bleeding. The relevance of pinpoint gastric mucosal erosions to blood loss is unclear. CLINICAL SIGNIFICANCE: Capsule endoscopy can enable the non-invasive detection of gastric and small intestinal mucosal lesions in dogs presenting for evaluation of gastrointestinal bleeding. PMID- 26931501 TI - Survival in practice. PMID- 26931502 TI - Reply. PMID- 26931503 TI - Temperature-dependent impact of thermal aminolaevulinic acid photodynamic therapy on apoptosis and reactive oxygen species generation in human dermal fibroblasts. AB - BACKGROUND: Actinic keratoses (AKs) are generally accepted as common precursor lesions to invasive squamous cell carcinoma. Photodynamic therapy (PDT) is a common, in-office, field therapy modality used in the treatment of AKs. Clinical and laboratory observations have demonstrated that temperature modulation can affect PDT efficacy. OBJECTIVES: To demonstrate thermal PDT increases apoptotic cell death, and to investigate the mechanistic role of reactive oxygen species (ROS) free radicals in an in vitro human skin fibroblast model. METHODS: This study was completed using commercially available primary human skin fibroblasts treated with aminolaevulinic acid (ALA) at specific concentrations and controlled temperatures. Cell death, apoptosis and superoxide ROS levels were quantified. RESULTS: We found that thermal PDT with 0.5 mmol L(-1) ALA resulted in significant temperature-dependent increases in total apoptosis and superoxide ROS generation between 33 degrees C and 42 degrees C. CONCLUSIONS: Our results indicate that thermal PDT significantly increases apoptotic cell death through increased generation of superoxide ROS in a temperature-dependent manner. PMID- 26931504 TI - A prospective observational study of vulvovagintis in pregnant women in Argentina, with special reference to candidiasis. AB - To evaluate the frequency of yeast, bacteria or protozoa in pregnant women and to correlate the possible associations of these microorganisms and their relationships with vulvovaginitis (VV) and cervicitis. Vaginal specimens were collected and prepared for smears in microscope slides for the evaluation of yeast, Trichomonas vaginalis and bacteria. Samples were cultured in specific culture medium. Cervical specimens were used to investigate the presence of Neisseria gonorrhoeae, Chlamydia trachomatis, Ureaplasma spp. and Mycoplasma hominis. We enrolled 210 pregnant women, aged 10-42 years old. Of them, 38.1% were symptomatic. Symptoms were most prevalent in the second and third trimesters of pregnancy coincident with a major prevalence of microorganisms. In this study, 39.5% of pregnant women had normal microbial biota and symptoms of VV due to non infectious causes were observed (6.2%). The occurrence of vulvovaginal candidiasis was 25% and Candida albicans with a prevalence of 80.7% was the dominant species (P = 0.005) while non-albicans Candida species and other yeast were more common in asymptomatic ones (P = 0.0038). The frequency of bacterial vaginosis, T. vaginalis, C. trachomatis and N. gonorrhoeae were 18.1%, 1.4, 1.4% and 0.5% respectively. PMID- 26931505 TI - Severe bone marrow edema on sacroiliac joint MRI increases the risk of low BMD in patients with axial spondyloarthritis. AB - To determine the association between inflammatory and structural lesions on sacroiliac joint (SIJ) MRI and BMD and to identify risk factors for low BMD in patients with axial spondyloarthritis (axSpA). Seventy-six patients who fulfilled the ASAS axSpA criteria were enrolled. All underwent SIJ MRI and BMD measurement at the lumbar spine, femoral neck, and total hip. Inflammatory and structural lesions on SIJ MRI were scored. Laboratory tests and assessment of radiographic and disease activity were performed at the time of MRI. The association between SIJ MRI findings and BMD was evaluated. Among the 76 patients, 14 (18%) had low BMD. Patients with low BMD showed significantly higher bone marrow edema (BME) and deep BME scores on MRI than those with normal BMD (p < 0.047 and 0.007, respectively). Inflammatory lesions on SIJ MRI correlated with BMD at the femoral neck and total hip. Multivariate analysis identified the presence of deep BME on SIJ MRI, increased CRP, and sacroiliitis on X-ray as risk factors for low BMD (OR = 5.6, 14.6, and 2.5, respectively). The presence of deep BME on SIJ MRI, increased CRP levels, and severity of sacroiliitis on X-ray were independent risk factors for low BMD. PMID- 26931507 TI - Integrated health service delivery networks and tuberculosis avoidable hospitalizations: is there a relation between them in Brazil? AB - BACKGROUND: The early identification of the Breathing Symptoms within the scope of Primary Health Care is recommended, and is also one of the strategies of national sanitary authorities for reaching the elimination of tuberculosis. The purpose of this study is to consider which attributes and which territories have shown the most significant progress in Primary Health Care, in terms of coordination of Health Care Networks, and also check if those areas of Primary Health Care that are most critical regarding coordination, there were more or less cases of avoidable hospitalizations for tuberculosis. METHODS: This is an ecological study that uses primary and secondary data. For analysis, coropletic maps were developed through the ArcGIS software, version 10.2. There was also the calculation of gross annual and Bayesian rates for hospitalizations for tuberculosis, for each Primary Health Care territory. RESULTS: There were satisfactory results for attributes such as Population (n = 37; 80.4 %), Primary Health Care (n = 43; 93.5 %), Support System (n = 45; 97.8 %); the exceptions were Logistics System (n = 32; 76.0 %) and Governance System, with fewer units in good condition (n = 31; 67.3 %). There is no evidence of any connection between networks' coordination by Primary Health Care and tuberculosis avoidable admissions. CONCLUSION: The results show that progress has been made regarding the coordination of the Health Care Networks, and a positive trend has been shown, even though the levels are not excellent. It was found no relationship between the critical areas of Primary Health Care and tuberculosis avoidable hospitalizations, possibly because other variables necessary to comprehend the phenomena. PMID- 26931508 TI - DNAzyme-Controlled Cleavage of Dimer and Trimer Origami Tiles. AB - Dimers of origami tiles are bridged by the Pb(2+)-dependent DNAzyme sequence and its substrate or by the histidine-dependent DNAzyme sequence and its substrate to yield the dimers T1-T2 and T3-T4, respectively. The dimers are cleaved to monomer tiles in the presence of Pb(2+)-ions or histidine as triggers. Similarly, trimers of origami tiles are constructed by bridging the tiles with the Pb(2+)-ion dependent DNAzyme sequence and the histidine-dependent DNAzyme sequence and their substrates yielding the trimer T1-T5-T4. In the presence of Pb(2+)-ions and/or histidine as triggers, the programmed cleavage of trimer proceeds. Using Pb(2+) or histidine as trigger cleaves the trimer to yield T5-T4 and T1 or the dimer T1 T5 and T4, respectively. In the presence of Pb(2+)-ions and histidine as triggers, the cleavage products are the monomer tiles T1, T5, and T4. The different cleavage products are identified by labeling the tiles with 0, 1, or 2 streptavidin labels and AFM imaging. PMID- 26931510 TI - Echocardiographic and Surgical Correlation of Coronary Artery Patterns in Transposition of the Great Arteries. AB - OBJECTIVE: Determine the accuracy of echocardiography to diagnose coronary anatomy in transposition of the great arteries and to evaluate the effect of accuracy on surgical outcomes and changes in accuracy over time. DESIGN: Retrospective chart review of neonates admitted February 1999 to March 2013 with transposition. Coronary pattern from the preoperative echocardiogram and operative reports were collected and compared with determine diagnostic accuracy. Coronary patterns were further confirmed by intraoperative images taken during surgery. SETTING: Tertiary care children's hospital. PATIENTS: Neonates with transposition of the great arteries and planned arterial switch operation with an echo and operative report or image describing the coronaries. INTERVENTIONS: Not applicable. OUTCOME MEASURES: Accuracy of echocardiography to diagnose coronary anatomy in transposition, and to identify factors related to correct diagnosis. RESULTS: One hundred forty-two patients met inclusion criteria with 122 correctly diagnosed, 16 incorrect, and 4 inconclusive. Accuracy was 86%, with 95% accuracy in patients with typical coronary patterns, 85% with the most common variant (left coronary from the leftward sinus and right and circumflex from the rightward sinus), and 61% with less common patterns. Typical and common variants were more likely to be correct than atypical patterns (P < .001). Cases with ventricular septal defect were more likely to have correctly diagnosed coronaries than with an intact ventricular septum (94% vs. 79%, P = .01). There was no change in accuracy over time (P > .05). There was no difference in duration of cardiopulmonary bypass, cross-clamp times, length of stay, or postoperative stay between the correct and incorrectly diagnosed groups (P > .05). CONCLUSIONS: In our center, accuracy of echocardiographic imaging of the coronary arteries in transposition was 86% without improvement over time, and perioperative outcomes were not affected by diagnostic accuracy. Further invasive imaging may not be necessary to determine the coronary pattern in this lesion. PMID- 26931509 TI - Heart rate, blood pressure and repolarization effects of an energy drink as compared to coffee. AB - The goal of this study was to investigate the impact of energy drinks on haemodynamic and cardiac physiology. Comparisons were made to coffee as well as water consumption. In Protocol #1 the caffeine content was normalized to body weight to represent a controlled environment. Heart rate, blood pressure and cardiac QTc interval were assessed in 15 participants, on 4 days, prior to and for 6.5 h postconsumption of (i) energy drink (2 mg caffeine per kg body weight; low dose), (ii) energy drink (3 mg caffeine per kg body weight; medium dose), (iii) coffee (2 mg caffeine per kg body weight) and (iv) 250 ml water. In Protocol #2, the beverages were consumed in volumes that they are purchased to represent real-life conditions. The aforementioned measurements were repeated in 15 participants following (i) 1 16 oz can of energy drink (16 oz Monster), (ii) 1 24 oz can of energy drink (24 oz Monster), (iii) 1 packet of Keurig K-Cup Starbucks coffee (coffee) and (iv) 250 ml water. The order of the beverages was performed in a randomized double-blinded fashion. For both protocols, QTc interval, heart rate and systolic blood pressure were unchanged in any condition (P>0.05). Diastolic blood pressure and mean blood pressure were slightly elevated in Protocol #1 (P<0.05, main effect of time) with no difference between beverages (P<0.05, interaction of beverage * time); however, they were unaffected in Protocol #2 (P>0.05). These findings suggest that acute consumption of these commonly consumed beverages has no negative effect on cardiac QTc interval. PMID- 26931511 TI - Intracranial EEG potentials estimated from MEG sources: A new approach to correlate MEG and iEEG data in epilepsy. AB - Detection of epileptic spikes in MagnetoEncephaloGraphy (MEG) requires synchronized neuronal activity over a minimum of 4cm2. We previously validated the Maximum Entropy on the Mean (MEM) as a source localization able to recover the spatial extent of the epileptic spike generators. The purpose of this study was to evaluate quantitatively, using intracranial EEG (iEEG), the spatial extent recovered from MEG sources by estimating iEEG potentials generated by these MEG sources. We evaluated five patients with focal epilepsy who had a pre-operative MEG acquisition and iEEG with MRI-compatible electrodes. Individual MEG epileptic spikes were localized along the cortical surface segmented from a pre-operative MRI, which was co-registered with the MRI obtained with iEEG electrodes in place for identification of iEEG contacts. An iEEG forward model estimated the influence of every dipolar source of the cortical surface on each iEEG contact. This iEEG forward model was applied to MEG sources to estimate iEEG potentials that would have been generated by these sources. MEG-estimated iEEG potentials were compared with measured iEEG potentials using four source localization methods: two variants of MEM and two standard methods equivalent to minimum norm and LORETA estimates. Our results demonstrated an excellent MEG/iEEG correspondence in the presumed focus for four out of five patients. In one patient, the deep generator identified in iEEG could not be localized in MEG. MEG estimated iEEG potentials is a promising method to evaluate which MEG sources could be retrieved and validated with iEEG data, providing accurate results especially when applied to MEM localizations. Hum Brain Mapp 37:1661-1683, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26931512 TI - A cluster of 3' coterminal transcripts from US12-US17 locus of human cytomegalovirus. AB - Among all the human cytomegalovirus (HCMV) gene families, US12 family is relatively undefined in their transcriptional profile and biological functions. In this study, the transcription pattern and characteristics of HCMV US12-US17 gene region were studied extensively. Twenty-three clones harboring US12 cDNA sequence were screened out from a late cDNA library of an HCMV clinical isolate, Han. Using a set of US12-US17 gene-specific probes, six transcripts from US12 US17 locus were detected by northern blot at late kinetics of the clinical isolate. One additional transcript was found in late RNA of HCMV strain AD169. No evidence showing these transcripts contain introns by reverse transcription PCR. 3' and 5' termini of these transcripts were confirmed by Rapid Amplification of cDNA Ends. A novel protein-coding region was predicted in the shorter US14 transcript with an alternative in-frame 5' translation initiation site compared to that of the previously predicted US14 ORF. Our findings demonstrate the existence of a cluster of 3' coterminal unspliced transcripts with distinct 5' transcriptional initiation sites originated from US12-US17 gene region in the late infection phase of an HCMV clinical strain. PMID- 26931514 TI - Sequence evidence for common ancestry of eukaryotic endomembrane coatomers. AB - Eukaryotic cells are defined by compartments through which the trafficking of macromolecules is mediated by large complexes, such as the nuclear pore, transport vesicles and intraflagellar transport. The assembly and maintenance of these complexes is facilitated by endomembrane coatomers, long suspected to be divergently related on the basis of structural and more recently phylogenomic analysis. By performing supervised walks in sequence space across coatomer superfamilies, we uncover subtle sequence patterns that have remained elusive to date, ultimately unifying eukaryotic coatomers by divergent evolution. The conserved residues shared by 3,502 endomembrane coatomer components are mapped onto the solenoid superhelix of nucleoporin and COPII protein structures, thus determining the invariant elements of coatomer architecture. This ancient structural motif can be considered as a universal signature connecting eukaryotic coatomers involved in multiple cellular processes across cell physiology and human disease. PMID- 26931515 TI - A 12-lead ECG-method for quantifying ischemia-induced QRS prolongation to estimate the severity of the acute myocardial event. AB - INTRODUCTION: Studies have shown terminal QRS distortion and resultant QRS prolongation during ischemia to be a sign of low cardiac protection and thus a faster rate of myocardial cell death. A recent study introduced a single lead method to quantify the severity of ischemia by estimating QRS prolongation. This paper introduces a 12-lead method that, in contrast to the previous method, does not require access to a prior ECG. METHODS: QRS duration was estimated in the lead that showed the maximal ST deviation according to a novel method. The degree of prolongation was determined by subtracting the measured QRS duration in the lead that showed the least ST deviation. RESULTS: The method is demonstrated in examples of acute occlusion in two of the major coronary arteries. CONCLUSION: This paper presents a 12-lead method to quantify the severity of ischemia, by measuring QRS prolongation, without requiring comparison with a previous ECG. PMID- 26931516 TI - Left ventricular regional contraction abnormalities by echocardiographic speckle tracking in combined right bundle branch with left anterior fascicular block compared to left bundle branch block. AB - BACKGROUND: In contrast to LBBB patients less is known about patients with RBBB+LAFB regarding LV contractile abnormalities and the potential role of CRT. This study investigated whether patients with RBBB+LAFB morphology have echocardiographic mechanical strain abnormalities between the inferior and anterior LV walls, similar to abnormalities between septal and lateral walls in LBBB. METHODS AND RESULTS: Ten healthy volunteers with no-BBB, 28 LBBB and 28 RBBB+LAFB heart failure patients were included in this retrospective study. Two dimensional regional-strains were obtained by speckle-tracking. Scar was assessed by CMR. Response on echo was defined as normal, classical, borderline or other pattern. The number of classical patterns in LBBB was significantly higher than in RBBB+LAFB and no-BBB groups (p<0.001 for both). Contrary, the RBBB+LAFB group showed a significantly higher number of borderline patterns compared to other groups (LBBB: p=0.042, no-block: p=0.012). In addition, RBBB+LAFB patients had more scar than LBBB patients (9.9% vs 3.4%, p=0.041), and the average amount of scar in each wall was also higher in RBBB+LAFB (<5% in LBBB and <16% in RBBB+LAFB). CONCLUSIONS: Patients with RBBB+LAFB on ECG and clinical HF demonstrate echocardiographic wall motion abnormalities between inferior and anterior LV walls, similar to abnormalities found between septal and lateral LV walls in patients with LBBB and HF. Fewer patients with RBBB+LAFB showed a classical pattern of opposing wall motion compared to LBBB. Factors that might alter strain patterns in RBBB+LAFB, including the detailed presence or absence of LV scar and coexisting block of the central fascicle, should be assessed in future studies. PMID- 26931513 TI - Therapy-induced microenvironmental changes in cancer. AB - In the past decade, the focus of tumor biology research has been switching from the functional dissection of oncogenes and tumor suppressor genes to investigation of the cross-talk between tumor cells and their microenvironment. Tumorigenesis requires the organized assembly of cancer cells with non-malignant cells and non-cellular stroma, resembling an abnormal organogenesis. This process can be modulated by local cellular stress responses, such as senescence, ER stress and autophagy, and inflammatory and immunosuppressive cells and effector molecules within the tumor microenvironment (TME). Various cellular stress responses and cell death modalities are triggered in response to chemotherapies, radiotherapies, and targeted therapies (including immunotherapies). The exposure of immunostimulatory factors could (re)awaken anti-tumor immunity. Unexpectedly, the gut microbial flora is becoming recognized as an important external modulator of the TME. We will discuss in detail the TME changes that take place after certain cancer therapies, highlighting the importance of cellular stress responses, tumor-infiltrating immune cells, and microbiota-derived factors. PMID- 26931517 TI - Education in thyroid surgery: a matched-pair analysis comparing residents and board-certified surgeons. AB - PURPOSE: Resident participation in operative procedures is mandatory in educational residency programs but remains controversial, especially in the context of patient safety. This study compared the surgical quality and outcomes of thyroidectomies performed by surgical residents (RESs) and board-certified surgeons (BCSs). METHODS: This retrospective matched-pair study included patients undergoing thyroidectomies for multinodular goiter, Grave's disease and early stage thyroid cancer that were performed by a RES with BCS supervision between 2006 and 2014. The intraoperative and postoperative course, complication rates and handling of the recurrent laryngeal nerve (RLN) and parathyroid glands were analyzed. RESULTS: In total, 112 thyroidectomies that were performed by a RES fulfilled the inclusion criteria and were matched 1:1 with BCS patients. We included 88 hemithyroidectomies, 80 subtotal thyroidectomies and 56 total thyroidectomies. No significant differences in the handling of the RLN or parathyroid glands, the rates of postoperative RLN palsies or the rates of hypocalcaemia were found. No intraoperative complications led to the replacement of the RES as the surgeon-in-charge. Three RES and two BCS patients experienced postoperative haemorrhages (p = 0.205), and three surgical site infections (p = 1.000) occurred in each group. The mean operative time and the length of stay did not differ significantly between the two groups. CONCLUSIONS: Major aspects of patient safety in thyroid surgery are not affected by resident participation. Thyroidectomies performed by RES are not significantly longer and reveal no differences in length of stay or complication rates. The economic burden of resident involvement is modest. PMID- 26931519 TI - Synthesis of highly uniform Cu2O spheres by a two-step approach and their assembly to form photonic crystals with a brilliant color. AB - Monodisperse semiconductor colloidal spheres with a high refractive index hold great potential for building photonic crystals with a strong band gap, but the difficulty in separating the nucleation and growth processes makes it challenging to prepare highly uniform semiconductor colloidal spheres. Herein, real monodisperse Cu2O spheres were prepared via a hot-injection & heating-up two-step method using diethylene glycol as a milder reducing agent. The diameter of the as prepared Cu2O spheres can be tuned from 90 nm to 190 nm precisely. The SEM images reveal that the obtained Cu2O spheres have a narrow size distribution, which permits their self-assembly to form photonic crystals. The effects of precursor concentration and heating rates on the size and morphology of the Cu2O spheres were investigated in detail. The results indicate that the key points of the method include the burst nucleation to form seeds at a high temperature followed by rapid cooling to prevent agglomeration, and appropriate precursor concentration as well as a moderate growth rate during the further growth process. Importantly, photonic crystal films exhibiting a brilliant structural color were fabricated with the obtained monodisperse Cu2O spheres as building blocks, proving the possibility of making photonic crystals with a strong band gap. The developed method was also successfully applied to prepare monodisperse CdS spheres with diameters in the range from 110 nm to 210 nm. PMID- 26931518 TI - Perioperative quality assessment of varicose vein surgery : Commission for quality assessment of the German Society for Vascular Surgery. AB - PURPOSE: An estimated 350,000 varicose vein (VV) surgical procedures are performed in Germany each year, with annual treatment costs amounting to about 800 million Euro. To evaluate the outcome quality of this treatment, we examined the intraoperative and postoperative complication rates on record in the VV surgery quality assessment (QA) registry of the German Society for Vascular Surgery (GSVS). METHODS: Data on 89,647 patients (27,463 men, 62,184 women; average age 52.8 years, range 15-96 years) collected in the GSVS varicose surgery QA registry between 2001 and 2009 were analyzed. In these patients, 95,214 surgical procedures were performed on 105,296 limbs. Complication rates were correlated with the type of VV surgical procedure, with whether surgery was performed on an inpatient or outpatient basis, and with the CEAP classification (C stage) and American Society of Anaesthesiologists' (ASA) stage at the time of surgery. Statistical analyses were performed using a chi-square test, a Cochrane Armitage test, and an odds ratio calculation. RESULTS: Intraoperative and postoperative complication was low (0.18 and 0.43 %, respectively), being the lowest for radiofrequency ablation (0.25 %) but not differing significantly from those for endovenous laser therapy and high ligation and stripping. General complications occurred in 0.67 % of outpatients and in 0.25 % of inpatients, a highly significant statistical difference (p < 0.0001, chi-square test). With regard to C stage, the higher the stage, the higher the local complication rate. A clear correlation was also found between preoperative ASA stage and postoperative complication rates: for ASA stages I and II, the complication rates were 0.2 and 0.5 %, respectively, increasing for ASA stage III to 1.2 % and for ASA IV to 2.2 %. The differences between the ASA classes were highly statistically significant (p < 0.0001, Cochrane-Armitage test) CONCLUSIONS: Outcome quality as reflected in the intraoperative and postoperative complication rates was very good for all patients undergoing inpatient or outpatient VV surgery. Data from the GSVS QA registry shows that VV surgery is performed with very good perioperative results in specialized centers in Germany. PMID- 26931520 TI - Unmasking Cleckley's psychopath: assessing historical case studies. AB - The current study investigated original case descriptions of psychopathy (Cleckley, 1941) in relation to current conceptualizations and general personality traits. Attorneys, forensic psychologists and clinical faculty members completed ratings of psychopathy and personality after reading vignettes based on Cleckley's descriptions of a psychopath. The results suggest that professionals' ratings are consistent with current conceptualizations of psychopathy. Furthermore, the five-factor model (FFM) personality traits of the vignettes aligned with the current literature on the FFM and psychopathy (i.e. low neuroticism, conscientiousness and agreeableness). The results further supported that a general trait model, like the FFM, may be well suited to describe the underlying personality traits of psychopathy. Gender differences were also examined. PMID- 26931521 TI - Transcriptional regulation of miR-15b by c-Rel and CREB in Japanese encephalitis virus infection. AB - MicroRNAs (miRNAs) have been well known to play diverse roles in viral infection at the level of posttranscriptional repression. However, much less is understood about the mechanism by which miRNAs are regulated during viral infection. It is likely that both host and virus contain factors to modulate miRNA expression. Here we report the up-regulation of microRNA-15b (miR-15b) in vitro upon infection with Japanese encephalitis virus (JEV). Analysis of miR-15b precursor, pri-miR-15b and pre-miR-15b, suggest that the regulation occurs transcriptionally. Further, we identified the transcriptional regulatory region of miR-15b that contains consensus binding motif for NF-kappaB subunit c-Rel and cAMP-response element binding protein (CREB), which are known as transcription factor to regulate gene expression. By promoter fusion and mutational analyses, we demonstrated that c-Rel and CREB bind directly to the promoter elements of miR 15b, which are responsible for miR-15b transcription in response to JEV infection. Finally, we showed that pharmacological inhibition of ERK and NF kappaB signaling pathway blocked induction of miR-15b in JEV infection, suggesting important roles of ERK and NF-kappaB pathway in the regulation of miR 15b gene. Therefore, our observations indicate that induced expression of miR-15b is modulated by c-Rel and CREB in response to JEV infection. PMID- 26931523 TI - Epidemiological Data are Lacking. PMID- 26931522 TI - Tonsillectomy with Uvulopalatopharyngoplasty in Obstructive Sleep Apnea. AB - BACKGROUND: Obstructive sleep apnea (OSA) is a very common disorder (prevalence 2 7% in women, 7-14% in men). It impairs the quality of life and increases mortality. Conservative treatment with continuous positive airway pressure is highly effective, but patient compliance is variable. Surgical treatments are controversial, as only a few are supported by evidence from controlled clinical trials. METHODS: Adult patients with OSA, CPAP intolerance, and oropharyngeal obstruction were included in the trial. All underwent polysomnography (PSG) and were randomly allotted to one of two groups. Patients in the treatment group underwent tonsillectomy with uvulopalatopharyngoplasty (TE-UPPP) within one month. All patients had a follow-up PSG at three months, and all PSGs were evaluated in blinded fashion. The primary outcome variable was the apneahypopnea index (AHI) as determined by PSG. Other outcome variables were subjective symptoms (daytime sleepiness, quality of life), complications, and patient satisfaction. RESULTS: 42 patents were included in the trial (23 in the treatment group, 19 in the control group). The baseline AHI was 35.7 +/- 19.4/hr in the control group and 33.7 +/- 14.6/hr in the treatment group. The corresponding figures at 3 months were 28.6 +/- 19.4/hr in the control group and 15.4 +/- 14.1/hr in the treatment group (p = 0.036). The intervention also led to significant improvement in daytime sleepiness and in snoring, according to the patients' and their bed partners' assessment. 97% of the patients who underwent surgery were satisfied with the outcome. 65% of them needed no further treatment for OSA. CONCLUSION: TE-UPPP significantly improved apnea/hypopnea, daytime sleepiness, and snoring compared to control (i.e., no) treatment. It is a safe and effective treatment for OSA.. PMID- 26931524 TI - Largest Epidemiological Study not Mentioned. PMID- 26931525 TI - In Reply. PMID- 26931527 TI - Fluorine-Terminated Diamond Surfaces as Dense Dipole Lattices: The Electrostatic Origin of Polar Hydrophobicity. AB - Despite the pronounced polarity of C-F bonds, many fluorinated carbon compounds are hydrophobic: a controversial phenomenon known as "polar hydrophobicity". Here, its underlying microscopic mechanisms are explored by ab initio calculations of fluorinated and hydrogenated diamond (111) surfaces interacting with single water molecules. Gradient- and van der Waals-corrected density functional theory simulations reveal that "polar hydrophobicity" of the fully fluorinated surfaces is caused by a negligible surface/water electrostatic interaction. The densely packed C-F surface dipoles generate a short-range electric field that decays within the core repulsion zone of the surface and hence vanishes in regions accessible by adsorbates. As a result, water physisorption on fully F-terminated surfaces is weak (adsorption energies Ead < 0.1 eV) and dominated by van der Waals interactions. Conversely, the near-surface electric field generated by loosely packed dipoles on mixed F/H-terminated surfaces has a considerably longer range, resulting in a stronger water physisorption (Ead > 0.2 eV) that is dominated by electrostatic interactions. The suppression of electrostatic interactions also holds for perfluorinated molecular carbon compounds, thus explaining the prevalent hydrophobicity of fluorocarbons. In general, densely packed polar terminations do not always lead to short-range electric fields. For example, surfaces with substantial electron density spill out give rise to electric fields with a much slower decay. However, electronic spill-out is limited in F/H-terminated carbon materials. Therefore, our ab initio results can be reproduced and rationalized by a simple classical point-charge model. Consequently, classical force fields can be used to study the wetting of F/H-terminated diamond, revealing a pronounced correlation between adsorption energies of single H2O molecules and water contact angles. PMID- 26931526 TI - The Presentation, Diagnosis, and Treatment of Sexually Transmitted Infections. AB - BACKGROUND: The reported incidence of sexually transmitted infections (STIs) in Germany is rising. For example, the number of new reported cases of syphilis rose from 3034 in 2010 to 4410 in 2012. METHODS: This review is based on pertinent articles retrieved by a selective search in MEDLINE, and on guidelines and systematic reviews from Germany and abroad. RESULTS: We discuss sexually transmitted infections presenting with genital, anal, perianal, or oral ulcers, urethritis, cervicitis, urethral or vaginal discharge, or genital warts. We also discuss sexually transmitted infection with HIV and the hepatitis C virus (HCV). Acquired sexually transmitted infections elevate the risk of transmission of other sexually transmitted infections; thus, patients presenting for the diagnosis or treatment of any kind of sexually transmitted infection should be evaluated for others as well. For most of these diseases, treatment of the patient's sexual partner(s) is indicated. Diagnostic nucleic acid amplification techniques are over 90% sensitive and specific and are generally the best way to detect the responsible pathogen. Factors impeding effective treatment include antibiotic resistance (an increasing problem) and the late diagnosis of HIV and HCV infections. CONCLUSION: Sexually transmitted infections are common around the world, and any such infection increases the patient's risk of contracting other types of sexually transmitted infection. Molecular genetic diagnostic techniques should be made widely available. PMID- 26931528 TI - Neurology of the cryopyrin-associated periodic fever syndrome. AB - BACKGROUND AND PURPOSE: The cryopyrin-associated periodic fever syndrome (CAPS) is an autosomal dominant autoinflammatory disorder caused by mutations in the NLRP3 gene and is typified by recurrent episodes of systemic inflammation resulting in fever, urticarial rash and arthralgia. In addition to these systemic aspects, CAPS has multiple neurological manifestations. The largest case series to date is presented focusing on the neurological features of this disorder. METHODS: The case histories of a cohort of 38 UK patients with genetically proven CAPS who were treated with interleukin 1beta (IL-1beta) inhibition as part of a national treatment programme and underwent detailed neurological assessment were reviewed. RESULTS: Across the entire disease course neurological manifestations were present in 95% of patients; 84% had some form of headache; 66% sensorineural hearing loss; 60% myalgia; 34% papilloedema and 26% optic atrophy. Patients with the T348M mutation tended to have a more severe neurological phenotype with an earlier age of onset. Four patients had cerebrospinal fluid examination, three of whom had evidence of aseptic meningitis. There was a marked response to IL-1beta inhibition, which has revolutionized management of these patients (29/32 patients with headache responding). CONCLUSION: Neurological symptoms are extremely common in CAPS and these results highlight the importance of increasing awareness amongst neurologists, particularly as highly effective therapies are available. PMID- 26931530 TI - Multivoxel Pattern Analysis Does Not Provide Evidence to Support the Existence of Basic Emotions. AB - Saarimaki et al. (2015) published a paper claiming to find the neural "fingerprints" for anger, fear, disgust, happiness, sadness, and surprise using multivariate pattern analysis. There are 2 ways in which Saarimaki et al.'s interpretation mischaracterizes their actual findings. The first is statistical: a pattern that successfully distinguishes the members of one category from the members of another (with an accuracy greater than that which might be expected by chance) is not a "fingerprint" (i.e., an essence); it is an abstract, statistical summary of a variable population of instances. The second way in which Saarimaki et al.'s interpretation mischaracterizes their results is conceptual: their findings do not actually meet the specific criteria for basic emotion theory. Instead, their findings are more consistent with a theory of constructed emotion. In our view, Saarimaki et al. is elegant in method and important in that it demonstrates empirical support for a theory of emotion that relies on population thinking; it is also an example of how essentialism-the belief that all instances of a category possesses necessary features that define what is, and what is not, a category member-contributes to a fundamental misunderstanding of the neural basis of emotion. PMID- 26931531 TI - Improved COD Measurements for Organic Content in Flowback Water with High Chloride Concentrations. AB - An improved method was used to determine chemical oxygen demand (COD) as a measure of organic content in water samples containing high chloride content. A contour plot of COD percent error in the Cl(-)-Cl(-):COD domain showed that COD errors increased with Cl(-):COD. Substantial errors (>10%) could occur in low Cl( ):COD regions (<300) for samples with low (<10 g/L) and high chloride concentrations (>25 g/L). Applying the method to flowback water samples resulted in COD concentrations ranging in 130 to 1060 mg/L, which were substantially lower than the previously reported values for flowback water samples from Marcellus Shale (228 to 21 900 mg/L). It is likely that overestimations of COD in the previous studies occurred as result of chloride interferences. Pretreatment with mercuric sulfate, and use of a low-strength digestion solution, and the contour plot to correct COD measurements are feasible steps to significantly improve the accuracy of COD measurements. PMID- 26931532 TI - Cytokine Responses in Gills of Capoeta umbla as Biomarkers of Environmental Pollution. AB - Immunological biomarkers reflect the effects of exposure to environmental contaminants. In this study, the suitability and sensitivity of cytokine responses, interleukin1beta (IL-1beta), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha) in gill tissues of Capoeta umbla (Heckel, 1843), collected from different regions, as early warning indices of environmental pollution and ecosystem health was evaluated. Fish and water samples were taken from ten stations in March and September 2011 and 2012. Tumor necrosis factor alpha, IL-1beta and IL-6 levels were determined in samples of the gill tissues by using an ELISA kit. Significant variations of TNF-alpha, IL-1beta and IL-6 levels observed between stations and seasons. The results of this study show that seasonal variations of cytokine responses in gills of Capoeta umbla are sensitive to the contaminants present in Uzuncayir Dam Lake (Tunceli, Turkey) water and are valuable biomarkers for environmental pollution and ecosystem health. PMID- 26931529 TI - The Chemistry and Biological Activities of Natural Products from Northern African Plant Families: From Taccaceae to Zygophyllaceae. AB - Traditional medicinal practices have a profound influence on the daily lives of people living in developing countries, particularly in Africa, since the populations cannot generally afford the cost of Western medicines. We have undertaken to investigate the correlation between the uses of plants in Traditional African medicine and the biological activities of the derived natural products, with the aim to validate the use of traditional medicine in Northern African communities. The literature is covered for the period 1959-2015 and part III of this review series focuses on plant families with names beginning with letters T to Z. The authors have focused on curating data from journals in natural products and phytomedicine. Within each journal home page, a query search based on country name was conducted. All articles "hits" were then verified, one at a time, that the species was harvested within the Northern African geographical regions. The current data partly constitutes the bases for the development of the Northern African natural compounds database. The review discusses 284 plant-based natural compounds from 34 species and 11 families. It was observed that the ethnobotanical uses of less than 40 % of the plant species surveyed correlated with the bioactivities of compounds identified. PMID- 26931533 TI - Nitrogen Removal from Water Resource Recovery Facility Secondary Effluent Using a Bioreactor. AB - Solid-phase denitrification technology can potentially be used to remove nitrogen compounds, such as total nitrogen and nitrate nitrogen (NO3(-)-N), from wastewater. In this study, the authors made use of an internal-circulation baffled biofilm reactor in which filamentous bamboo acted as a biocarrier for the removal of nitrogen (N) from water resource recovery facility (WRRF) secondary effluent. A laboratory-scale experiment was conducted to assess the efficacy and mechanisms of N removal from the WRRF secondary effluent operated in continuous flow mode. Results indicated that total nitrogen and NO3(-)-N removal rates reached 66.58 to 75.23% and 75.6 to 85.6%, respectively. Infrared spectrum analysis indicated biodegradation in the filamentous bamboo. A comparison of this method with the use of filamentous plastics as biocarriers indicated that higher NO3(-)-N removal (as volumetric loading) and lower nitrite nitrogen accumulation rates were obtained when filamentous bamboo was used as a biocarrier. A NO3(-)-N removal volumetric loading of 2.09 mg/L.h was reached when using bamboo as a single solid carbon source. These results confirm that filamentous bamboo can be used as an alternative to inert biocarriers in WRRF secondary effluent treatment systems. PMID- 26931535 TI - Airflow in Gravity Sewers - Determination of Wastewater Drag Coefficient. AB - Several experiments have been conducted in order to improve the understanding of the wastewater drag and the wall frictional force acting on the headspace air in gravity sewers. The aim of the study is to improve the data basis for a numerical model of natural sewer ventilation. The results of the study shows that by integrating the top/side wall shear stresses the log-law models for the air velocity distribution along the unwetted perimeter resulted in a good agreement with the friction forces calculated by use of the Colebrook-White formula for hydraulic smooth pipes. Secondly, the water surface drags were found by log-law models of the velocity distribution in turbulent flows to fit velocity profiles measured from the water surface and by integrating the water surface drags along the wetted perimeter, mean water surface drags were found and a measure of the water surface drag coefficient was found. PMID- 26931534 TI - Adsorption of 2,4-Dichlorophenoxyacetic Acid from an Aqueous Solution on Fly Ash. AB - The adsorption of 2,4-dichlorophenoxyacetic acid (2,4-D) on fly ash was studied. The effects of adsorbent dose, contact time, pH, ionic strength, and temperature on the adsorption were investigated. Adsorption kinetic data were analyzed using pseudo-first and pseudo-second order models, and results showed that adsorption kinetics were better represented by the pseudo-second order model. Adsorption isotherms of 2,4-D on fly ash were analyzed using the Freundlich and Langmuir models. Thermodynamic parameters (DeltaG degrees , DeltaH degrees , and DeltaS degrees ) indicated that the adsorption process was spontaneous and endothermic. The negative values of DeltaG degrees and the positive value of DeltaH degrees indicate the spontaneous nature of 2,4-D adsorption on fly ash, and that the adsorption process was endothermic. Results showed that fly ash is an efficient, low-cost adsorbent for removal of 2,4-D from water. PMID- 26931536 TI - Treatment of Pulp Mill D-Stage Bleaching Effluent Using a Pilot-Scale Electrocoagulation System. AB - A pilot-scale study was conducted using electrocoagulation technology to treat chlorine dioxide bleaching-stage effluent of a local pulp mill, with the purpose of evaluating the treatment performance. The operating variables were the current density (0 ~ 133.3 A/m(2)) and hydraulic retention time (HRT, 6.5 ~ 16.25 minutes). Water quality indicators investigated were the conductivity, suspended solids (SS), chemical oxygen demand (COD), true color, and hardness. The results showed that electrocoagulation technology can be used to treat D-stage bleaching effluent for water reuse. Under the operating conditions studied, the removal of conductivity and COD always increased with increases in either the current density or HRT. The highest removals obtained at 133.3 A/m(2) and an HRT of 16.25 minutes for conductivity, SS, COD, true color, and hardness were respectively 44.2, 98.5, 75.0, 85.9, and 36.9% with aluminum electrodes. Iron electrodes were not applicable to the D-stage effluent due to formation of dark-colored ferric complexes. PMID- 26931537 TI - Mangrove Ecosystems: An Adopted Habitat for Pathogenic Salmonella spp. AB - Mangroves are affected by industrial and anthropogenic factors. Although mangroves have been widely studied, investigations of pathogens that may affect public health significance are largely lacking even while incidences of diseases linked with the consumption of mangrove-associated food have increased. A total of 150 samples of water, sediment, and biota were collected from ten mangrove ecosystems in Goa, India. Total viable counts of pathogens such as E. coli, Listeria, Salmonella, and Vibrio spp. ranged from 1.25 to 3.9 * 10(3) cfu/ mL, which were above the relevant standards. Salmonella counts were the highest at 3.1 to 3.9 * 10(3)cfu/mL, with a prevalence of 40%. Considering its high prevalence, the virulence of Salmonella spp. was studied. The invA gene was detected in 35% of the Salmonella isolates by polymerase chain reaction (PCR). The findings suggested that pathogens adapt to this habitat, resulting in contamination of the indigenous fauna. PMID- 26931538 TI - Experimental Assessment of the Degradation of "Unbiodegradable" Organic Solids in Activated Sludge. AB - In current process models activated sludge consists of biodegradable and unbiodegradable organic fractions. Recent evidence suggests that this approach may not be accurate because some of this "unbiodegradable" material may indeed be degradable. To improve sludge production predictions, it is important to know to what extent the "unbiodegradable" organic fraction is degradable. Assuming that volatile suspended solids (VSS) is a measure of the sum of biodegradable and unbiodegradable organic solids and the integral of the oxygen uptake rate (OUR) is representative of the biodegradable organics, the combination of these measurements can be used to predict the change of unbiodegradable organic solids within an aerobic digestion batch experiment. This procedure was used to estimate degradation rates of "unbiodegradable" VSS between 0.006 to 0.029 d(-1). The advantage of the proposed method is that the degradation rate can be determined directly based on measurements and relies on a limited number of assumptions. PMID- 26931539 TI - Performance Evaluation of Integrated Constructed Wetland for Domestic Wastewater Treatment. AB - Simple, budget friendly, laboratory-scale integrated constructed wetland (ICW) was designed to assess domestic wastewater treatment performance at a loading rate of 75 mm/d, planted with native plant species: Veronica-angallis aquatica and compared with non-vegetative control system at various residence times of 4, 8, 12, 16, 20, 24, and 28 days. Results revealed that the vegetated ICW demonstrated superior performance over non-vegetated control: 69.12 vs 17.12%, 67.77 vs 16.04%, 68 vs 16.48%, 71.19 vs 6.56%, 71.54 vs 14.80%, and 72.04 vs 11.41% for total dissolved solids, total suspended solids, phosphates (PO4(-)), sulfate (SO4(-)), nitrate (NO3(-)), and nitrite (NO2(-)), respectively, at 20 days residence times. Reduction in bacterial counts (2.79 * 10(4) CFU/mL) and fecal pathogens (345.5 MPN index/100 mL) was observed in V. aquatica at 20 days residence time. Therefore, the present study highlights not only the presence of vegetation but also appropriate residence time in constructed wetlands for better performances. PMID- 26931540 TI - Aqueous-Processed Insulating Polymer/Nanocrystal Hybrid Solar Cells. AB - A novel kind of hybrid solar cell (HSC) was developed by introducing water soluble insulating polymer poly(vinyl alcohol) (PVA) into nanocrystals (NCs), which revealed that the most frequently used conjugated polymer could be replaced by an insulating one. It was realized by strategically taking advantage of the characteristic of decomposition for the polymer at annealing temperature, and it was interesting to discover that partial decomposition of PVA left behind plenty of pits on the surfaces of CdTe NC films, enlarging surface contact area between CdTe NCs and subsequently evaporated MoO3. Moreover, the residual annealed PVA filled in the voids among spherical CdTe NCs, which led to the decrease of leakage current. An improved shunt resistance (increased by ~80%) was achieved, indicating the charge-carrier recombination was effectively overcome. As a result, the new HSCs were endowed with increased Voc, fill factor, and power conversion efficiency compared with the pure NC device. This approach can be applied to other insulating polymers (e.g., PVP) with advantages in synthesis, type, economy, stability, and so on, providing a novel universal cost-effective way to achieve higher photovoltaic performance. PMID- 26931541 TI - Transforaminal Endoscopic Foraminoplasty and Discectomy for the Treatment of a Thoracic Disc Herniation. AB - Transforaminal endoscopic spine surgery has emerged internationally as a minimally invasive technique that can be performed in an awake patient in the outpatient setting. Advances in high-definition endoscopic camera technologies as well as the availability of specialty graspers, reamers, drills, and other instruments that can be used down a working channel endoscope have made a myriad of spine diseases accessible to the minimally invasive spine surgeon. The major challenge inherent in the surgical treatment of thoracic disc disease is that the disc herniation is often ventral to the spinal cord. The transforaminal approach and the angled endoscopic camera are an ideal combination for creating a technical advantage to accessing thoracic disc disease. PMID- 26931543 TI - Evaluation of the Efficacy of Titanium Mesh Cages with Posterior C1 Lateral Mass and C2 Pedicle Screw Fixation in Patients with Atlantoaxial Instability. AB - BACKGROUND: Atlantoaxial fusion is a surgical technique that is performed for the treatment of atlantoaxial instability. The standard surgical procedure is fixation of the atlantoaxial complex via a C1 lateral mass and C2 pedicle screw with posterior wiring. Bone grafting material may still be biomechanically suboptimal, such as autologous bone obtained from osteoporotic patients, and may result in collapse and loosening of posterior wiring. METHODS: Fourteen patients with C1 lateral mass and C2 pedicle fixation as a result of atlantoaxial instability were included in this study. All patients were treated by a single surgeon using a titanium mesh cage with demineralized bone matrix packing. Patient clinical history, imaging data, and medical records were reviewed. To evaluate bony fusion, measurement of the atlantodental interval and computed tomography were performed in the preoperative period, immediate postoperative period, and at 1, 3, 6, and 12 months postoperatively. The Wilcoxon signed-rank test was used to compare differences in the radiologic evaluation at 1 and 12 months postoperatively. RESULTS: Bone fusion was achieved in all patients (100%). Of the 14 patients, 11 had rheumatoid arthritis and 3 had trauma. The mean atlantodental interval of patients with rheumatoid arthritis was 1.85 mm in the immediate postoperative period, 1.96 mm at 1 month postoperatively, 1.98 mm at 3 months postoperatively, 1.96 mm at 6 months, and 1.93 mm at 12 months. Hardware failure and other complications were not observed. CONCLUSIONS: The titanium mesh cage has several advantages compared with bone autografts, including reduced donor-site morbidity, immediate rigid fixation, and successful bone fusion. PMID- 26931542 TI - Microvascular Decompression for Hemimasticatory Spasm: A Case Report and Review of the Literature. AB - BACKGROUND: Hemimasticatory spasm is a rare clinical entity characterized by involuntary and paroxysmal contractions of the jaw-closing muscles on 1 side of the face. Although its cause is not fully known, vascular compression of the trigeminal nerve has been speculated. CASE DESCRIPTION: Here, we report 1 case of hemimasticatory spasm that was cured by microvascular decompression of the motor branch of the trigeminal nerve; a relevant literature review was also performed. CONCLUSIONS: Hemimasticatory spasm is a rare disease that may be recalcitrant to conservative medical therapy, and vascular decompression of the trigeminal nerve may be required to relieve the spasm. PMID- 26931544 TI - New-Onset Stutter After Electrode Insertion in the Ventrocaudalis Nucleus for Face Pain. AB - BACKGROUND: Deep brain stimulation (DBS) of the ventrocaudalis nucleus of the thalamus is a last resort treatment for chronic refractory pain. DBS is generally a safe procedure, although it can result in functional disturbances depending on the site of stimulation. There has been 1 previous report of stuttering induced by microlesioning of the thalamus, as well as several reports of stuttering induced by stimulation of the thalamus and other related structures in the brain. CASE DESCRIPTION: We describe the case of a patient with trigeminal deafferentation face pain who was treated with DBS of the ventrocaudalis nucleus thalamus and developed a reversible stutter immediately on insertion of the electrode. The stutter improved significantly over 12 days after implant; however, the device was not effective in relieving the patient's pain and was removed. CONCLUSIONS: Stuttering is a rare complication of deep brain exploration of the sensory thalamus. Our coordinates are near to but in a distinct anatomic region compared with cases previously described as having similar effects on speech. PMID- 26931546 TI - Status of Tenure Among Black and Latino Faculty in Academic Medicine. AB - Tenure has been used for years to recruit, promote, and retain faculty in higher education and has been associated with job security and academic freedom. Absence of tenure and not being in tenure-earning tracks is grouped with the challenges faced by underrepresented minorities in academic medicine. Those challenges include being found at the assistant professor rank more often, having more clinical responsibilities, and not being in leadership positions as often as compared to non-minority faculty. The role of tenure and tenure tracks is unclear as it relates to the presence of minority faculty. This article presents a look at the status of tenure among black and Latino faculty in academic medicine at US medical schools. PMID- 26931547 TI - Loss of Complex I activity in the Escherichia coli enzyme results from truncating the C-terminus of subunit K, but not from cross-linking it to subunits N or L. AB - Complex I is a multi-subunit enzyme of the respiratory chain with seven core subunits in its membrane arm (A, H, J, K, L, M, and N). In the enzyme from Escherichia coli the C-terminal ten amino acids of subunit K lie along the lateral helix of subunit L, and contribute to a junction of subunits K, L and N on the cytoplasmic surface. Using double cysteine mutagenesis, the cross-linking of subunit K (R99C) to either subunit L (K581C) or subunit N (T292C) was attempted. A partial yield of cross-linked product had no effect on the activity of the enzyme, or on proton translocation, suggesting that the C-terminus of subunit K has no dynamic role in function. To further elucidate the role of subunit K genetic deletions were constructed at the C-terminus. Upon the serial deletion of the last 4 residues of the C-terminus of subunit K, various results were obtained. Deletion of one amino acid had little effect on the activity of Complex I, but deletions of 2 or more amino acids led to total loss of enzyme activity and diminished levels of subunits L, M, and N in preparations of membrane vesicles. Together these results suggest that while the C-terminus of subunit K has no dynamic role in energy transduction by Complex I, it is vital for the correct assembly of the enzyme. PMID- 26931545 TI - Genomic approaches for understanding dengue: insights from the virus, vector, and host. AB - The incidence and geographic range of dengue have increased dramatically in recent decades. Climate change, rapid urbanization and increased global travel have facilitated the spread of both efficient mosquito vectors and the four dengue virus serotypes between population centers. At the same time, significant advances in genomics approaches have provided insights into host-pathogen interactions, immunogenetics, and viral evolution in both humans and mosquitoes. Here, we review these advances and the innovative treatment and control strategies that they are inspiring. PMID- 26931548 TI - No-touch isolation techniques for pancreatic cancer. AB - The rate of recurrence, including liver metastasis is high in pancreatic cancer, even when complete surgical resection is performed as a curative treatment. In patients with pancreatic cancer, the handling and grasping of the pancreas during surgery may increase the risk of liver metastasis, as squeezing may spread cancer cells via the portal vein. A no-touch isolation technique might prevent the spread of cancer cells via the hematogenous metastatic route in patients with pancreatic cancer. However, while no-touch isolation techniques are simple, feasible and, in theory, ideal procedures for the surgical treatment of pancreatic cancer, there have been no randomized controlled prospective studies to validate their advantages and their efficacy remains controversial. It is, therefore, worth investigating the use of no-touch isolation techniques in pancreatic cancer. PMID- 26931550 TI - Relationship between general nutrition knowledge and diet quality in Australian military personnel. AB - A balanced diet informed by sound nutrition knowledge is key for operational readiness and the health of military personnel. Unfortunately, research suggests that military personnel have inadequate dietary intakes. This study assessed general nutrition knowledge, diet quality and their association in Australian military personnel. A convenience sample of male military personnel (n 211) including Army soldiers and officers completed a validated general nutrition knowledge questionnaire (GNKQ) and FFQ. The GNKQ assessed knowledge of dietary guidelines (Section A), sources of nutrients (Section B), choosing everyday foods (Section C) and diet-disease relationships (Section D). The Australian Recommended Food Score (ARFS) was used to assess diet quality from FFQ data. Statistical analyses included the chi 2 test, Spearman's correlation test, t test, median test, ANCOVA and ordinal logistic regression. The mean total GNKQ score was 52.7 %. Participants performed best on Section A (58.5 %) followed by Sections B (57.3 %) and C (57.0 %) and worst on Section D (31.0 %). Overall, officers scored significantly higher than soldiers (58.7 v. 51.9 %, P=0.001). Age was weakly but positively correlated with GNKQ total scores (r 0.307; P<0.0005), with no significant effects seen for level of education (P=0.463) or living arrangement (P=0.167). Overall ARFS was 37.6 (sd 7.7) (50.8 %) with officers scoring significantly higher than soldiers (54.7 v. 50.3 %, P=0.040). No demographic variables influenced total ARFS. The total GNKQ score had a significant, positive but weak relationship with total ARFS (r 0.179; P=0.009). Given the importance of nutrition to personnel health and operational readiness, initiatives to improve nutrition knowledge and diet quality are recommended in this population, especially in soldiers. PMID- 26931551 TI - A short-term zinc-deficient diet decreases bone formation through down-regulated BMP2 in rat bone. AB - We investigated the effects of a short-term dietary zinc deficiency on bone metabolism. Zinc deficiency increased the mRNA expression of zinc uptake transporters such as Zip1, Zip13, and Zip14 in bone. However, zinc deficiency might not maintain zinc storage in bone, resulting in a decrease in bone formation through downregulation of the expression levels of osteoblastogenesis related genes. PMID- 26931552 TI - 3,4-Dihydroxyphenylacetic acid, a microbiota-derived metabolite of quercetin, attenuates acetaminophen (APAP)-induced liver injury through activation of Nrf-2. AB - 1. Acetaminophen (APAP) overdose leads to severe hepatotoxicity. 3,4 dihydroxyphenylacetic acid (DOPAC) is a scarcely studied microbiota-derived metabolite of quercetin. The aim of this study was to determine the protective effect of DOPAC against APAP-induced liver injury. 2. Mice were treated intragastrically with DOPAC (10, 20 or 50 mg/kg) for 3 days before APAP (300 mg/kg) injection. APAP alone caused increase in serum aminotransferase levels and changes in hepatic histopathology. APAP also promoted oxidative stress by increasing lipid peroxidation and decreasing anti-oxidant enzyme activities. These events led to hepatocellular necrosis and reduced liver function. DOPAC increased nuclear factor erythroid 2-related factor 2 (Nrf-2) translocation to the nucleus and enhanced the expression of phase II enzymes and anti-oxidant enzymes, and thereby reduced APAP hepatotoxicity and enhanced anti-oxidant ability. 3. Our data provide evidence that DOPAC protected the liver against APAP induced injury, which is involved in Nrf-2 activation, implying that DOPAC can be considered as a potential natural hepatoprotective agent. PMID- 26931553 TI - Determination of the complete genome and functional analysis of HPV6 isolate VBD19/10 from a patient with aggressive recurrent respiratory papillomatosis. AB - Human papillomavirus (HPV) types 6 and 11 are the aetiological agent of recurrent respiratory papillomatosis (RRP). The complete genome of an HPV6 isolate with a 170 base pair (bp) duplication identified within the long control region (LCR) from a patient with aggressive recurrent respiratory papillomatosis was determined. The promoter sequence from the HPV LCR including the 170 bp duplication was placed upstream of a heterologous reporter gene and the activity of the reporter gene product determined using transfected cells. In total, mutations were observed at 157 nucleotide positions of the complete genome and included nucleotide substitutions, deletions and insertions, resulting in amino acid changes at 43 residue positions. Reporter gene activity using an HPV-derived LCR region with a 170 bp duplication was significantly higher than that using an HPV-derived LCR region with no duplication within this region. The results suggest that novel HPV variants warrant further investigation for potential biomarkers of aggressive disease. PMID- 26931554 TI - Efficient upconversion luminescence from Ba5Gd8Zn4O21:Yb(3+), Er(3+) based on a demonstrated cross-relaxation process. AB - Under 971 nm excitation, bright green and red emissions from Yb(3+)/Er(3+) co doped Ba5Gd8Zn4O21 phosphor can be observed, especially the intense red emission in highly doped samples. The experimental results indicate that Ba5Gd8Zn4O21:Yb(3+), Er(3+) emits stronger upconversion luminescence than NaYF4:Yb(3+), Er(3+) under a low excitation power, and a maximum upconversion power efficiency of 2.7% for Ba5Gd8Zn4O21:Yb(3+), Er(3+) was achieved. More significantly, to explain the red emission enhanced with the dopant concentration, this paper presents a possible cross-relaxation process and demonstrates it based on the rate equation description and temporal evolution. In view of the strong upconversion luminescence, colour tunable ability and stable chemical nature, Yb(3+)/Er(3+) co-doped Ba5Gd8Zn4O21 phosphor could be an excellent candidate for efficient upconversion luminescence generation. PMID- 26931555 TI - Response: Limited sampling strategies for once daily tacrolimus exposure monitoring. PMID- 26931556 TI - Intralymphatic mRNA vaccine induces CD8 T-cell responses that inhibit the growth of mucosally located tumours. AB - The lack of appropriate mouse models is likely one of the reasons of a limited translational success rate of therapeutic vaccines against cervical cancer, as rapidly growing ectopic tumours are commonly used for preclinical studies. In this work, we demonstrate that the tumour microenvironment of TC-1 tumours differs significantly depending on the anatomical location of tumour lesions (i.e. subcutaneously, in the lungs and in the genital tract). Our data demonstrate that E7-TriMix mRNA vaccine-induced CD8(+) T lymphocytes migrate into the tumour nest and control tumour growth, although they do not express mucosa associated markers such as CD103 or CD49a. We additionally show that despite the presence of the antigen-specific T cells in the tumour lesions, the therapeutic outcomes in the genital tract model remain limited. Here, we report that such a hostile tumour microenvironment can be reversed by cisplatin treatment, leading to a complete regression of clinically relevant tumours when combined with mRNA immunization. We thereby demonstrate the necessity of utilizing clinically relevant models for preclinical evaluation of anticancer therapies and the importance of a simultaneous combination of anticancer immune response induction with targeting of tumour environment. PMID- 26931557 TI - Assessing asthma severity based on claims data: a systematic review. AB - INTRODUCTION: Asthma is one of the most common chronic diseases in Germany. Substantial economic evaluation of asthma cost requires knowledge of asthma severity, which is in general not part of claims data. Algorithms need to be defined to use this data source. AIMS AND OBJECTIVES: The aim of this study was to systematically review the international literature to identify algorithms for the stratification of asthma patients according to disease severity based on available information in claims data. METHODS: A systematic literature review was conducted in September 2015 using the DIMDI SmartSearch, a meta search engine including several databases with a national and international scope, e.g. BIOSIS, MEDLINE, and EMBASE. Claims data based studies that categorize asthma patients according to their disease severity were identified. RESULTS: The systematic research yielded 54 publications assessing asthma severity based on claims data. Thirty-nine studies used a standardized algorithm such as HEDIS, Leidy, the GINA based approach or CACQ. Sixteen publications applied a variety of different criteria for the severity categorisation such as asthma diagnoses, asthma-related drug prescriptions, emergency department visits, and hospitalisations. CONCLUSION: There is no best practice method for the categorisation of asthma severity with claims data. Rather, a combination of algorithms seems to be a pragmatic approach. A transfer to the German context is not entirely possible without considering particular conditions associated with German claims data. PMID- 26931558 TI - Prognostic value of right ventricular free wall strain in pulmonary hypertension patients with pseudo-normalized tricuspid annular plane systolic excursion values. AB - Pulmonary hypertension (PH) is a progressively fatal disease having a significant impact on right ventricular (RV) function, a major determinant of long-term outcome in PH patients. In our clinic we frequently noticed the combination of PH and reduced RV function, but with discordant Tricuspid Annular Plane Systolic Excursion (TAPSE) values. The present study focuses on whether RV free wall strain measured using 2-dimensional speckle-tracking echocardiography is able to predict mortality in this subgroup of PH patients. 57 patients with PH and RV dysfunction (visual echocardiographic assessment of >=2) and pseudo-normalized TAPSE values (defined as >=16 mm) were retrospectively evaluated. Patients were divided by RV free -20 % as cut-off value. Follow-up data on all-cause mortality were registered after a median follow-up time of 27.9 +/- 1.7 months. RV free of >=-20 % was predictive of all-cause mortality after a median follow-up time of 27.9 +/- 1.7 months (HR 3.76, 95 % CI 1.02-13.92, p = 0.05). RV free >=-20 % remained a significant predictor of all-cause mortality (HR 4.30, 95 % CI 1.11 16.61, p = 0.04) after adjusting for PH-specific treatment. On the contrary, TAPSE was not a significant predictor of all-cause mortality. RV free wall strain provides prognostic information in patients with PH and RV dysfunction, but with normal TAPSE values. Future studies with larger cohorts, longer follow-up periods and inclusion of more echocardiographic parameters measuring LV and RV function could confirm the strength of RV free >=-20 % as a predictor of mortality for this subgroup of patients with PH. PMID- 26931559 TI - Impact of parenchymal loss on renal function after laparoscopic partial nephrectomy under warm ischemia. AB - PURPOSE: To elucidate the impact of renal parenchymal loss and the ischemic reperfusion injury (RI) on the renal function after laparoscopic partial nephrectomy (LPN) under warm ischemia (WI). METHODS: Thirty-five patients with a single polar renal mass <=4 cm and normal contralateral kidney underwent LPN. Transperitoneal LPN with WI using en bloc hilar occlusion was performed. The total differential renal function (T-DRF) using 99mTc-dimercaptosuccinic acid was evaluated preoperatively and postoperatively over a period of 1 year. A special region of interest (ROI) was selected on the non-tumorous pole of the involved kidney, and was compared with the same ROI in the contralateral kidney. The latter comparison was defined as partial differential renal function (P-DRF). Any postoperative decline in the P-DRF of the operated kidney was attributed to the RI. Subtraction of the P-DRF decline from the T-DRF decline was attributed to the parenchymal loss caused by the resection of the tumor and suturing of the normal parenchyma. RESULTS: The mean WI time was 22 min, and the mean weight of resected specimen was 18 g. The mean postoperative eGFR declined to 87 ml/min/1.73 m2 from its baseline mean value of 97 ml/min/1.73 m2 (p value = 0.075). Mean postoperative T-DRF and P-DRF of the operated kidney declined by 7 and 3 %, respectively. CONCLUSIONS: After LPN of small renal mass, decline in renal function is primarily attributed to parenchymal loss caused by tumor resection and suturing of the normal parenchyma rather than the RI. PMID- 26931560 TI - Clinical impact of prostate biopsy undergrading in an academic and community setting. AB - PURPOSE: To evaluate whether the rate of Gleason score (GS) upgrade on final pathology, the rate of positive surgical margins (PSM) and the rate of biochemical recurrence (BCR) after radical prostatectomy (RP) were different if prostate biopsy (PB) was graded by community pathologists (CP) as compared to specialized uro-pathologists (UP). METHODS: A consecutive series of patients undergoing RP in our institution between 2005 and 2013 were retrospectively reviewed. Any GS higher or lower in RP specimen as compared to PB GS was defined as GS upgrade or downgrade, respectively. Additionally, stratification for the new ISUP 2014 grading system was performed. Predictors of GS upgrade and PSMs and prognostic parameters for BCR were assessed by stepwise logistic regression models and by multivariable Cox regression analyses, respectively. RESULTS: A total of 786 patients were available for analysis, and median follow-up was 36 months (1-101 months). A GS upgrade was found in 345 patients (43.9 %) and a GS downgrade in 91 patients (11.6 %). Discordance between PB GS and RP GS was significantly more frequent when grading had been performed by a CP (50.5 % upgrade, 9.0 % downgrade) than by a UP (33.1 % upgrade, 15.7 % downgrade, p < 0.001). CP evaluation was an independent predictor for GS upgrade (odds ratio [OR] 1.91, p < 0.001) and for PSMs (OR 1.69, p = 0.003), as well as an independent predictor of BCR (hazard ratio [HR] 1.65, p = 0.028). CONCLUSIONS: Pathologic evaluation of PBs by a dedicated UP should be recommended to reduce the rate of biopsy undergrading, PSM and BCR after RP. PMID- 26931561 TI - Histology-Specific Uses of Tyrosine Kinase Inhibitors in Non-gastrointestinal Stromal Tumor Sarcomas. AB - OPINION STATEMENT: Adult sarcomas, especially those with metastatic or unresectable disease, have limited treatment options. Traditional chemotherapeutic options have been limited by poor response rates in patients with advanced sarcomas. The important clinical question is whether the success of targeted therapy in GIST can be extended to other sarcomas and also if preclinical data describing targets across this heterogeneous group of cancers can be translated to clinical efficacy of known and upcoming target specific agents. Multi-targeted tyrosine kinase inhibitors (TKI) such as pazopanib, sorafenib, sunutinib, cediranib have shown benefits across various histologies of soft tissue sarcoma as well as bone sarcomas. The efficacy of imatinib in Dermatofibrosarcoma Protruberans; sunitinib and cediranib in alveolar soft part sarcoma; and sorafenib and imatinib in chordomas have provided a treatment option of these rare tumors where no effective options existed. TKIs are being tested in combination with chemotherapy as well as radiation to improve response. Although traditional RECIST criteria may not adequately reflect response to these targeted agents, the studies have shown promise for the efficacy of TKIs across the spectrum of sarcomas. The integration of biomarker studies with clinical trials may help further identify responders beyond that defined by histology. With the current data, TKIs are being used both as first-line treatment and beyond in non GIST sarcomas. PMID- 26931563 TI - Characteristics of Children Reported to Child Protective Services for Medical Neglect. AB - OBJECTIVES: Medical neglect can have serious consequences. There is little evidence base to guide medical neglect management and research. Our objective was to describe a group of children reported to child protective services (CPS) for medical neglect to define this population as well as identify prevention and intervention approaches. METHODS: This was a retrospective descriptive study of all patients at a pediatric hospital reported to CPS for medical neglect over a 6 year period. Data about health, health care, CPS involvement, and social history were obtained through medical record review. RESULTS: Of the 154 patients reported for medical neglect, 140 (91%) had chronic illness. The most common diagnoses were type 1 diabetes, organ transplantation, and prematurity-related conditions. Most patients (83%) were black or Hispanic and 90% were publically insured. More than half of patients (54%) had >1 CPS report during the study period. Almost all patients (88%) returned to the hospital for care subsequent to the medical neglect report. Risk factors for child maltreatment, family stressors in the year preceding the report, and practical barriers to care were documented in more than two-thirds of patients. CONCLUSIONS: Overall, children reported for medical neglect have serious chronic medical conditions. There is need and opportunity for improved interventions. Avenues for future study include interventions tailored to the underlying diagnosis, racial/ethnic disparities, effectiveness of CPS interventions, and targeted prevention for at-risk families with medically complex children. PMID- 26931562 TI - Clinical significance of AGE-RAGE axis in colorectal cancer: associations with glyoxalase-I, adiponectin receptor expression and prognosis. AB - BACKGROUND: Advanced glycation end products (AGEs) and their receptor RAGE emerge as important pathogenic contributors in colorectal carcinogenesis. However, their relationship to the detoxification enzyme Glyoxalase (GLO)-I and Adiponectin receptors (AdipoR1, AdipoR2) in colorectal carcinoma (CRC) is currently understudied. In the present study, we investigated the expression levels of the above molecules in CRC compared to adjacent non-tumoral tissue and their potential correlation with clinicopathological characteristics and patients' survival. METHODS: We analyzed the immunohistochemical expression of AGE, RAGE, GLO-1, AdipoR1 and AdipoR2 in 133 primary CRC cases, focusing on GLO-I. The tumour MSI status was further assessed in mucinous carcinomas. Western immunoblotting was employed for validation of immunohistochemical data in normal and tumoral tissues as well in three CRC cell lines. An independent set of 55 patients was also used to validate the results of univariate survival analysis regarding GLO-I. RESULTS: CRC tissue showed higher intensity of both AGE and RAGE expression compared with normal colonic mucosa which was negative for GLO-I in most cases (78 %). Western immunoblotting confirmed AGE, RAGE and GLO-I overexpression in tumoral tissue. GLO-I expression was directly related to RAGE and inversely related to AGE immunolabeling. There was a trend towards higher expression of all markers (except for RAGE) in the subgroup of mucinous carcinomas which, although of borderline significance, seemed to be more prominent for AdipoR1 and AGE. Additionally, AGE, AdipoR1 and Adipo R2 expression was related to tumor grade, whereas GLO-1 and AdipoR1 to T-category. In survival analysis, AdipoR2 and GLO-I overexpression predicted shortened survival in the entire cohort and in early stage cases, an effect which for GLO-I was reproduced in the validation cohort. Moreover, GLO-I emerged as an independent prognosticator of adverse significance in the patients' cohort. CONCLUSIONS: We herein provide novel evidence regarding the possible interactions between the components of AGE-RAGE axis, GLO-I and adiponectin receptors in CRC. AGE and AdipoR1 are possibly involved in colorectal carcinogenesis, whereas AdipoR2 and GLO-I emerged as novel independent prognostic biomarkers of adverse significance for patients with early disease stage. Further studies are warranted to extend our observations and investigate their potential therapeutic significance. PMID- 26931564 TI - Development of behavioural regulation in Do and Don't contexts among behaviourally inhibited Chinese children. AB - Behavioural inhibition influences the development of behavioural regulation in early childhood. Previous studies have mainly focused on the relationship between inhibition and regulation in the Don't context (e.g., inhibitory control), while few have investigated this relationship in the Do context (e.g., task persistence). This longitudinal study examined the effect of temperamental inhibition on behavioural regulation during both the Do and Don't contexts in 112 Chinese preschoolers. At 3.5 years of age, children's behavioural inhibition was assessed by behavioural observation and parental report, and then at 4.5 years of age, their regulatory behaviours were measured in the following two challenging contexts: Do [locked box (LB)] and Don't [toy inhibition (TI)]. In each task, children were randomly assigned to either a high- or a low-incentive condition designed to vary the value of a given goal. Results suggested that higher inhibition was associated with poorer regulation (lower task persistence) in both conditions of the Do context (LB), whereas in the Don't context (TI) highly inhibited children showed better regulation (less violation behaviours) in the low-incentive condition than they did in the high-incentive condition. The results highlight the context characteristics and goal incentive as important factors for behavioural regulation development in inhibited children in China. PMID- 26931565 TI - Inhibition of protein kinase C promotes dengue virus replication. AB - BACKGROUND: Dengue virus (DENV) is a member of the Flaviviridae family, transmitted to human via mosquito. DENV infection is common in tropical areas and occasionally causes life-threatening symptoms. DENV contains a relatively short positive-stranded RNA genome, which encodes ten viral proteins. Thus, the viral life cycle is necessarily rely on or regulated by host factors. METHODS: In silico analyses in conjunction with in vitro kinase assay were used to study kinases that potentially phosphorylate DENV NS5. Potential kinase was inhibited or activated by a specific inhibitor (or siRNA), or an activator. Results of the inhibition and activation on viral entry/replication and host cell survival were examined. RESULTS: Our in silico analyses indicated that the non-structural protein 5 (NS5), especially the RNA-dependent RNA polymerase (RdRp) domain, contains conserved phosphorylation sites for protein kinase C (PKC). Phosphorylation of NS5 RdRp was further verified by PKC in vitro kinase assay. Inhibitions of PKC by a PKC-specific chemical inhibitor or siRNA suppressed NS5 phosphorylation in vivo, increased viral replication and reduced viability of the DENV-infected cells. In contrary, activation of PKC effectively suppressed intracellular viral number. CONCLUSIONS: These results indicated that PKC may act as a restricting mechanism that modulates the DENV replication and represses the viral outburst in the host cells. PMID- 26931568 TI - Tousled-like kinase 2 regulates recovery from a DNA damage-induced G2 arrest. AB - In order to maintain a stable genome, cells need to detect and repair DNA damage before they complete the division cycle. To this end, cell cycle checkpoints prevent entry into the next cell cycle phase until the damage is fully repaired. Proper reentry into the cell cycle, known as checkpoint recovery, requires that a cell retains its original cell cycle state during the arrest. Here, we have identified Tousled-like kinase 2 (Tlk2) as an important regulator of recovery after DNA damage in G2. We show that Tlk2 regulates the Asf1A histone chaperone in response to DNA damage and that depletion of Asf1A also produces a recovery defect. Both Tlk2 and Asf1A are required to restore histone H3 incorporation into damaged chromatin. Failure to do so affects expression of pro-mitotic genes and compromises the cellular competence to recover from damage-induced cell cycle arrests. Our results demonstrate that Tlk2 promotes Asf1A function during the DNA damage response in G2 to allow for proper restoration of chromatin structure at the break site and subsequent recovery from the arrest. PMID- 26931567 TI - Expression of A152T human tau causes age-dependent neuronal dysfunction and loss in transgenic mice. AB - A152T-variant human tau (hTau-A152T) increases risk for tauopathies, including Alzheimer's disease. Comparing mice with regulatable expression of hTau-A152T or wild-type hTau (hTau-WT), we find age-dependent neuronal loss, cognitive impairments, and spontaneous nonconvulsive epileptiform activity primarily in hTau-A152T mice. However, overexpression of either hTau species enhances neuronal responses to electrical stimulation of synaptic inputs and to an epileptogenic chemical. hTau-A152T mice have higher hTau protein/mRNA ratios in brain, suggesting that A152T increases production or decreases clearance of hTau protein. Despite their functional abnormalities, aging hTau-A152T mice show no evidence for accumulation of insoluble tau aggregates, suggesting that their dysfunctions are caused by soluble tau. In human amyloid precursor protein (hAPP) transgenic mice, co-expression of hTau-A152T enhances risk of early death and epileptic activity, suggesting copathogenic interactions between hTau-A152T and amyloid-beta peptides or other hAPP metabolites. Thus, the A152T substitution may augment risk for neurodegenerative diseases by increasing hTau protein levels, promoting network hyperexcitability, and synergizing with the adverse effects of other pathogenic factors. PMID- 26931570 TI - Genome-wide transcriptome profiling of nitrogen fixation in Paenibacillus sp. WLY78. AB - BACKGROUND: Diazotrophic (nitrogen-fixing) Gram-positive and endospore-formed Paenibacillus spp. have potential uses as a bacterial fertilizer in agriculture. The transcriptional analysis of nitrogen fixation in Paenibacillus is lacking, although regulation mechanisms of nitrogen fixation have been well studied in Gram-negative diazotrophs. RESULTS: Here we report a global transcriptional profiling analysis of nitrogen fixation in Paenibacillus sp. WLY78 cultured under N2-fixing condition (without O2 and NH4(+)) and non-N2-fixing condition (air and 100 mM NH4(+)). The nif (nitrogen fixation) gene operon composed of 9 genes (nifBHDKENXhesAnifV) in this bacterium was significantly up-regulated in N2 fixing condition compared to non-N2-fixing condition, indicating that nif gene transcription is strictly controlled by NH4(+) and O2. qRT-PCR confirmed that these nif genes were differently expressed. Non-nif genes specifically required in nitrogen fixation, such as mod, feoAB and cys encoding transporters of Mo, Fe and S atoms, were coordinately transcribed with nif genes in N2-fixing condition. The transcript abundance of suf operon specific for synthesis of Fe-S cluster was up-regulated in N2-fixing condition, suggesting that Sul system, which takes place of nifS and nifU, plays important role in the synthesis of nitrogenase. We discover potential specific electron transporters which might provide electron from Fe protein to MoFe protein of nitrogenase. The glnR whose predicted protein might mediate nif transcription regulation by NH4(+) is significantly up regulated in N2-fixing condition. The transcription levels of nitrogen metabolism and anaerobic respiration were also analyzed. CONCLUSIONS: The nif gene operon (nifBHDKENXhesAnifV) in Paenibacillus sp. WLY78 is significantly up-regulated in N2-fixing condition compared to non-N2-fixing condition. Non-nif genes specifically required in nitrogen fixation were also significantly up-regulated in N2-fixing condition. Fur and Fnr which are involved in anaerobic regulation and GlnR which might mediate nif gene transcription regulation by NH4(+) were significantly up-regulated in N2-fixing condition. This study provides valuable insights into nitrogen fixation process and regulation in Gram-positive firmicutes. PMID- 26931569 TI - The Tau/A152T mutation, a risk factor for frontotemporal-spectrum disorders, leads to NR2B receptor-mediated excitotoxicity. AB - We report on a novel transgenic mouse model expressing human full-length Tau with the Tau mutation A152T (hTau(AT)), a risk factor for FTD-spectrum disorders including PSP and CBD Brain neurons reveal pathological Tau conformation, hyperphosphorylation, mis-sorting, aggregation, neuronal degeneration, and progressive loss, most prominently in area CA3 of the hippocampus. The mossy fiber pathway shows enhanced basal synaptic transmission without changes in short or long-term plasticity. In organotypic hippocampal slices, extracellular glutamate increases early above control levels, followed by a rise in neurotoxicity. These changes are normalized by inhibiting neurotransmitter release or by blocking voltage-gated sodium channels. CA3 neurons show elevated intracellular calcium during rest and after activity induction which is sensitive to NR2B antagonizing drugs, demonstrating a pivotal role of extrasynaptic NMDA receptors. Slices show pronounced epileptiform activity and axonal sprouting of mossy fibers. Excitotoxic neuronal death is ameliorated by ceftriaxone, which stimulates astrocytic glutamate uptake via the transporter EAAT2/GLT1. In summary, hTau(AT) causes excitotoxicity mediated by NR2B-containing NMDA receptors due to enhanced extracellular glutamate. PMID- 26931572 TI - The Adolescent Girls Initiative-Kenya (AGI-K): study protocol. AB - BACKGROUND: Many adolescent girls in Kenya and elsewhere face considerable risks and vulnerabilities that affect their well-being and hinder a safe, healthy, and productive transition into early adulthood. Early adolescence provides a critical window of opportunity to intervene at a time when girls are experiencing many challenges, but before those challenges have resulted in deleterious outcomes that may be irreversible. The Adolescent Girls Initiative-Kenya (AGI-K) is built on these insights and designed to address these risks for young adolescent girls. The long-term goal of AGI-K is to delay childbearing for adolescent girls by improving their well-being. INTERVENTION: AGI-K comprises nested combinations of different single-sector interventions (violence prevention, education, health, and wealth creation). It will deliver interventions to over 6000 girls between the ages of 11 and 14 years in two marginalized areas of Kenya: 1) Kibera in Nairobi and 2) Wajir County in Northeastern Kenya. The program will use a combination of girl-, household- and community-level interventions. The violence prevention intervention will use community conversations and planning focused on enhancing the value of girls in the community. The educational intervention includes a cash transfer to the household conditioned on school enrollment and attendance. The health intervention is culturally relevant, age-appropriate sexual and reproductive health education delivered in a group setting once a week over the course of 2 years. Lastly, the wealth creation intervention provides savings and financial education, as well as start-up savings. METHODS/DESIGN: A randomized trial will be used to compare the impact of four different packages of interventions, in order to assess if and how intervening in early adolescence improves girls' lives after four years. The project will be evaluated using data from behavioural surveys conducted before the start of the program (baseline in 2015), at the end of the 2-year intervention (endline in 2017), and 2 years post intervention (follow-up in 2019). Monitoring data will also be collected to track program attendance and participation. Primary analyses will be on an intent-to treat basis. Qualitative research including semi-structured interviews of beneficiaries and key adult stakeholders in 2016 and 2018 will supplement and complement the quantitative survey results. In addition, the cost-effectiveness of the interventions will be assessed. DISCUSSION: AGI-K will provide critical evidence for policy-makers, donors and other stakeholders on the most effective ways to combine interventions for marginalized adolescent girls across sectors, and which packages of interventions are most cost-effective. TRIAL REGISTRATION: ISRCTN77455458 , December 24, 2015. PMID- 26931573 TI - Characteristics of good quality pharmaceutical services common to community pharmacies and dispensing general practices. AB - BACKGROUND: In the United Kingdom, pharmaceutical services can be delivered by both community pharmacies (CPs) and dispensing doctor practices (DPs). Both must adhere to minimum standards set out in NHS regulations; however, no common framework exists to guide quality improvement. Previous phases of this research had developed a set of characteristics indicative of good pharmaceutical service provision. OBJECTIVE: To ask key stakeholders to confirm, and rank the importance of, a set of characteristics of good pharmaceutical service provision. METHODS: A two-round Delphi-type survey was conducted in south-west England and was sent to participants representing three stakeholder groups: DPs, CPs and patients/lay members. Participants were asked to confirm, and rank, the importance of these characteristics as representing good quality pharmaceutical services. KEY FINDINGS: Thirty people were sent the first round survey; 22 participants completed both rounds. Median ratings for the 23 characteristics showed that all were seen to represent important aspects of pharmaceutical service provision. Participants' comments highlighted potential problems with the practicality of the characteristics. Characteristics relating to patient safety were deemed to be the most important and those relating to public health the least important. CONCLUSIONS: A set of 23 characteristics for providing good pharmaceutical services in CPs and DPs was developed and attained approval from a sample of stakeholders. With further testing and wider discussion, it is hoped that the characteristics will form the basis of a quality improvement tool for CPs and DPs. PMID- 26931571 TI - Serum magnesium is inversely associated with coronary artery calcification in the Genetics of Atherosclerotic Disease (GEA) study. AB - BACKGROUND: Serum magnesium is inversely associated to coronary artery calcification (CAC) in patients with chronic kidney disease. There is little information on this association in a general healthy population. OBJECTIVE: The aim of this study was to examine the cross-sectional association of serum magnesium levels with CAC. METHODS: We included 1276 Mexican-mestizo subjects (50 % women), aged 30-75 years, free of symptomatic cardiovascular disease. CAC was quantified by multidetector computed tomography using the method described by Agatston. Cross-sectional associations of serum magnesium with cardiometabolic factors and subclinical atherosclerosis defined as a CAC score > 0, were examined in logistic regression models adjusted for age, sex, education, smoking status, body mass index, systolic blood pressure, physical activity, elevated abdominal visceral tissue, fasting insulin and glucose, alcohol consumption, menopausal status (women only), low (LDL-C) and high density lipoprotein cholesterol (HDL C), triglycerides, diuretic use, type 2 diabetes mellitus (DM2), and family history of DM2. RESULTS: After full adjustment, subjects in the highest quartile of serum magnesium had 48 % lower odds of hypertension (p = 0.028), 69 % lower odds of DM2 (p = 0.003), and 42 % lower odds of CAC score > 0 (p = 0.016) compared to those with the lowest serum magnesium. The analyses also showed that a 0.17 mg/dL (1SD) increment in serum magnesium was independently associated with 16 % lower CAC (OR 0.84, 95 % CI 0.724-0.986). CONCLUSIONS: In a sample of Mexican-mestizo subjects, low serum magnesium was independently associated to higher prevalence not only of hypertension and DM2, but also to coronary artery calcification, which is a marker of atherosclerosis and a predictor of cardiovascular morbidity and mortality. PMID- 26931574 TI - Syntheses and preliminary evaluation of [(18) F]AlF-NOTA-G-TMTP1 for PET imaging of high aggressive hepatocellular carcinoma. AB - The goal of this study is to evaluate a new (18) F-labeled imaging agent for diagnosing high metastatic (aggressive) hepatocellular carcinoma using positron emission tomography (PET). The new (18) F-labeled imaging agent [(18) F]AlF-NOTA G-TMTP1 was synthesized and radiolabeled with (18) F using NOTA-AlF chelation method. The tumor-targeting characteristics of [(18) F]AlF-NOTA-G-TMTP1 was assessed in HepG2, SMCC-7721, HCC97L and HCCLM3 xenografts. The total synthesis time was about 20 min with radiochemical yield of 25 +/- 6%. The specific activity was about 11.1-14.8 GBq/umol at the end of synthesis based on the amount of peptide used and the amount of radioactivity trapped on the C18 column. The log P value of [(18) F]AlF-NOTA-G-TMTP1 was -3.166 +/- 0.022. [(18) F]AlF-NOTA-G TMTP1 accumulated in SMCC-7721 and HCCLM3 tumors (high metastatic potential) in vivo and result in tumor/muscle (T/M) ratios of 4.5 +/- 0.3 and 4.7 +/- 0.2 (n = 4) as measured by PET at 40 min post-injection (p.i.). Meanwhile, the tumor/muscle (T/M) ratios of HepG2 and HCC97L tumors (low metastatic potential) were1.6 +/- 0.3 and 1.8 +/- 0.4. The tumor uptake of [(18) F]AlF-NOTA-G-TMTP1 could be inhibited 61.9% and 57.6% by unlabeled G-TMTP1 in SMCC-7721 and HCCLM3 xenografts at 40 min p.i., respectively. Furthermore, [(18) F]AlF-NOTA-G-TMTP1 showed pretty low activity in the liver and intestines in all tumor bearing mice, such in vivo distribution pattern would be advantageous for the detection of hepatic carcinoma. Overall, [(18) F]AlF-NOTA-G-TMTP1 may specifically target high metastatic or/and aggressive hepatocellular carcinoma with low background activity and, therefore, holds the potential to be used as an imaging agent for detecting tumor lesions within the liver area. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26931575 TI - Looking Beyond "Fistula First" in the Elderly on Hemodialysis. AB - Vascular access preparation, a pervasive challenge in hemodialysis (HD), is emerging as a multidimensional subject in geriatric nephrology. Previously published guidelines declared arteriovenous fistulas (AVF) as the preferred vascular access for all patients on HD. In this article, the benefit-risk evidence for using AVF versus an alternative access (arteriovenous graft [AVG] or tunneled central venous catheter [TCVC]) in the elderly is pondered. Compared to their younger counterparts, the elderly have significantly lower survival rates independent of the vascular access used for HD. Recent studies point to comparable dialysis survival rates between AVF and AVG or TCVC in subgroups of elderly patients, as well as lower rates of access-related infections, and lower catheter dependence after AVG compared to AVF construction in these patients. Comprehensive and longitudinal assessments that integrate comorbidities, physical function, cognitive status, and quality of life to estimate prognosis and assist with vascular access selection ought to be employed. In circumstances where patient survival is limited by comorbidities and functional status, AVF is unlikely to confer meaningful benefits compared to AVG or even TCVC in the ill elderly. PMID- 26931576 TI - PGE2-treated macrophages inhibit development of allergic lung inflammation in mice. AB - In healthy lungs, many macrophages are characterized by IL-10 production, and few are characterized by expression of IFN regulatory factor 5 (formerly M1) or YM1 and/or CD206 (formerly M2), whereas in asthma, this balance shifts toward few producing IL-10 and many expressing IFN regulatory factor 5 or YM1/CD206. In this study, we tested whether redressing the balance by reinstating IL-10 production could prevent house dust mite-induced allergic lung inflammation. PGE2 was found to be the best inducer of IL-10 in macrophages in vitro. Mice were then sensitized and challenged to house dust mites during a 2 wk protocol while treated with PGE2 in different ways. Lung inflammation was assessed 3 d after the last house dust mite challenge. House dust mite-exposed mice treated with free PGE2 had fewer infiltrating eosinophils in lungs and lower YM1 serum levels than vehicle-treated mice. Macrophage-specific delivery of PGE2 did not affect lung inflammation. Adoptive transfer of PGE2-treated macrophages led to fewer infiltrating eosinophils, macrophages, (activated) CD4(+), and regulatory T lymphocytes in lungs. Our study shows that the redirection of macrophage polarization by using PGE2 inhibits development of allergic lung inflammation. This beneficial effect of macrophage repolarization is a novel avenue to explore for therapeutic purposes. PMID- 26931577 TI - Role of CXCR4-mediated bone marrow colonization in CNS infiltration by T cell acute lymphoblastic leukemia. AB - Infiltration of the central nervous system is a severe trait of T cell acute lymphoblastic leukemia. Inhibition of CXC chemokine receptor 4 significantly ameliorates T cell acute lymphoblastic leukemia in murine models of the disease; however, signaling by CXC chemokine receptor 4 is important in limiting the divagation of peripheral blood mononuclear cells out of the perivascular space into the central nervous system parenchyma. Therefore, Inhibition of CXC chemokine receptor 4 potentially may untangle T cell acute lymphoblastic leukemia cells from retention outside the brain. Here, we show that leukemic lymphoblasts massively infiltrate cranial bone marrow, with diffusion to the meninges without invasion of the brain parenchyma, in mice that underwent xenotransplantation with human T cell acute lymphoblastic leukemia cells or that developed leukemia from transformed hematopoietic progenitors. We tested the hypothesis that T cell acute lymphoblastic leukemia neuropathology results from meningeal infiltration through CXC chemokine receptor 4-mediated bone marrow colonization. Inhibition of leukemia engraftment in the bone marrow by pharmacologic CXC chemokine receptor 4 antagonism significantly ameliorated neuropathologic aspects of the disease. Genetic deletion of CXCR4 in murine hematopoietic progenitors abrogated leukemogenesis induced by constitutively active Notch1, whereas lack of CCR6 and CCR7, which have been shown to be involved in T cell and leukemia extravasation into the central nervous system, respectively, did not influence T cell acute lymphoblastic leukemia development. We hypothesize that lymphoblastic meningeal infiltration as a result of bone marrow colonization is responsible for the degenerative alterations of the neuroparenchyma as well as the alteration of cerebrospinal fluid drainage in T cell acute lymphoblastic leukemia xenografts. Therefore, CXC chemokine receptor 4 may constitute a pharmacologic target for T cell acute lymphoblastic leukemia neuropathology. PMID- 26931579 TI - Establishment of a confluent monolayer model with human primary trophoblast cells: novel insights into placental glucose transport. AB - STUDY HYPOTHESIS: Using optimized conditions, primary trophoblast cells isolated from human term placenta can develop a confluent monolayer in vitro, which morphologically and functionally resembles the microvilli structure found in vivo. STUDY FINDING: We report the successful establishment of a confluent human primary trophoblast monolayer using pre-coated polycarbonate inserts, where the integrity and functionality was validated by cell morphology, biophysical features, cellular marker expression and secretion, and asymmetric glucose transport. WHAT IS KNOWN ALREADY: Human trophoblast cells form the initial barrier between maternal and fetal blood to regulate materno-fetal exchange processes. Although the method for isolating pure human cytotrophoblast cells was developed almost 30 years ago, a functional in vitro model with primary trophoblasts forming a confluent monolayer is still lacking. STUDY DESIGN, SAMPLES/MATERIALS, METHODS: Human term cytotrophoblasts were isolated by enzymatic digestion and density gradient separation. The purity of the primary cells was evaluated by flow cytometry using the trophoblast-specific marker cytokeratin 7, and vimentin as an indicator for potentially contaminating cells. We screened different coating matrices for high cell viability to optimize the growth conditions for primary trophoblasts on polycarbonate inserts. During culture, cell confluency and polarity were monitored daily by determining transepithelial electrical resistance (TEER) and permeability properties of florescent dyes. The time course of syncytia-related gene expression and hCG secretion during syncytialization were assessed by quantitative RT-PCR and enzyme linked immunosorbent assay, respectively. The morphology of cultured trophoblasts after 5 days was determined by light microscopy, scanning electron microscopy (SEM) and transmission electron microscopy (TEM). Membrane makers were visualized using confocal microscopy. Additionally, glucose transport studies were performed on the polarized trophoblasts in the same system. MAIN RESULTS AND THE ROLE OF CHANCE: During 5-day culture, the highly pure trophoblasts were cultured on inserts coated with reconstituted basement membrane matrix . They exhibited a confluent polarized monolayer, with a modest TEER and a size-dependent apparent permeability coefficient (Papp) to fluorescently labeled compounds (MW ~400-70 000 Da). The syncytialization progress was characterized by gradually increasing mRNA levels of fusogen genes and elevating hCG secretion. SEM analyses confirmed a confluent trophoblast layer with numerous microvilli, and TEM revealed a monolayer with tight junctions. Immunocytochemistry on the confluent trophoblasts showed positivity for the cell-cell adhesion molecule E-cadherin, the tight junction protein 1 (ZO-1) and the membrane proteins ATP-binding cassette transporter A1 (ABCA1) and glucose transporter 1 (GLUT1). Applying this model to study the bidirectional transport of a non-metabolizable glucose derivative indicated a carrier-mediated placental glucose transport mechanism with asymmetric kinetics. LIMITATIONS, REASONS FOR CAUTION: The current study is only focused on primary trophoblast cells isolated from healthy placentas delivered at term. It remains to be evaluated whether this system can be extended to pathological trophoblasts isolated from diverse gestational diseases. WIDER IMPLICATIONS OF THE FINDINGS: These findings confirmed the physiological properties of the newly developed human trophoblast barrier, which can be applied to study the exchange of endobiotics and xenobiotics between the maternal and fetal compartment, as well as intracellular metabolism, paracellular contributions and regulatory mechanisms influencing the vectorial transport of molecules. LARGE-SCALE DATA: Not applicable. STUDY FUNDING AND COMPETING INTERESTS: This study was supported by the Swiss National Center of Competence in Research, NCCR TransCure, University of Bern, Switzerland, and the Swiss National Science Foundation (grant no. 310030_149958, C.A.). All authors declare that their participation in the study did not involve factual or potential conflicts of interests. PMID- 26931578 TI - Linked in: immunologic membrane nanotube networks. AB - Membrane nanotubes, also termed tunneling nanotubes, are F-actin-based structures that can form direct cytoplasmic connections and support rapid communication between distant cells. These nanoscale conduits have been observed in diverse cell types, including immune, neuronal, stromal, cancer, and stem cells. Until recently, little was known about the mechanisms involved in membrane nanotube development in myeloid origin APCs or how membrane nanotube networks support their ability to bridge innate and adaptive immunity. New research has provided insight into the modes of induction and regulation of the immune process of "reticulation" or the development of multicellular membrane nanotube networks in dendritic cells. Preprogramming by acute type 1 inflammatory mediators at their immature stage licenses mature type 1-polarized dendritic cells to reticulate upon subsequent interaction with CD40 ligand-expressing CD4(+) Th cells. Dendritic cell reticulation can support direct antigen transfer for amplification of specific T cell responses and can be positively or negatively regulated by signals from distinct Th cell subsets. Membrane nanotubes not only enhance the ability of immature dendritic cells to sense pathogens and rapidly mobilize nearby antigen-presenting cells in the peripheral tissues but also likely support communication of pathogen-related information from mature migratory dendritic cells to resident dendritic cells in lymph nodes. Therefore, the reticulation process facilitates a coordinated multicellular response for the efficient initiation of cell-mediated adaptive immune responses. Herein, we discuss studies focused on the molecular mechanisms of membrane nanotube formation, structure, and function in the context of immunity and how pathogens, such as HIV-1, may use dendritic cell reticulation to circumvent host defenses. PMID- 26931581 TI - A reactive nitrone-based organogel that self-assembles from its constituents in chloroform. AB - The reversible reaction of an aldehyde with a hydroxylamine affords a nitrone which is capable of forming a stiff gel with chloroform at concentrations as low as 0.20 wt% (6 mM). The gelator forms dynamically from its constituents and the gel assembly can be degraded in a controlled manner through a recognition mediated reaction that targets the nitrone component of the gel network. PMID- 26931580 TI - Service user and caregiver involvement in mental health system strengthening in low- and middle-income countries: systematic review. AB - BACKGROUND: The involvement of mental health service users and their caregivers in health system policy and planning, service monitoring and research can contribute to mental health system strengthening, but as yet there have been very few efforts to do so in low- and middle-income countries (LMICs). METHODS: This systematic review examined the evidence and experience of service user and caregiver involvement in mental health system strengthening, as well as models of best practice for evaluation of capacity-building activities that facilitate their greater participation. Both the peer-reviewed and the grey literature were included in the review, which were identified through database searches (MEDLINE, Embase, PsycINFO, Web of Knowledge, Web of Science, Scopus, CINAHL, LILACS, SciELO, Google Scholar and Cochrane), as well as hand-searching of reference lists and the internet, and a snowballing process of contacting experts active in the area. This review included any kind of study design that described or evaluated service user, family or caregiver (though not community) involvement in LMICs (including service users with intellectual disabilities, dementia, or child and adolescent mental health problems) and that were relevant to mental health system strengthening across five categories. Data were extracted and summarised as a narrative review. RESULTS: Twenty papers matched the inclusion criteria. Overall, the review found that although there were examples of service user and caregiver involvement in mental health system strengthening in numerous countries, there was a lack of high-quality research and a weak evidence base for the work that was being conducted across countries. However, there was some emerging research on the development of policies and strategies, including advocacy work, and to a lesser extent the development of services, service monitoring and evaluation, with most service user involvement having taken place within advocacy and service delivery. Research was scarce within the other health system strengthening areas. CONCLUSIONS: Further research on service user and caregiver involvement in mental health system strengthening in LMICs is recommended, in particular research that includes more rigorous evaluation. A series of specific recommendations are provided based on the review. PMID- 26931582 TI - Modeling heart rate variability including the effect of sleep stages. AB - We propose a model for heart rate variability (HRV) of a healthy individual during sleep with the assumption that the heart rate variability is predominantly a random process. Autonomic nervous system activity has different properties during different sleep stages, and this affects many physiological systems including the cardiovascular system. Different properties of HRV can be observed during each particular sleep stage. We believe that taking into account the sleep architecture is crucial for modeling the human nighttime HRV. The stochastic model of HRV introduced by Kantelhardt et al. was used as the initial starting point. We studied the statistical properties of sleep in healthy adults, analyzing 30 polysomnographic recordings, which provided realistic information about sleep architecture. Next, we generated synthetic hypnograms and included them in the modeling of nighttime RR interval series. The results of standard HRV linear analysis and of nonlinear analysis (Shannon entropy, Poincare plots, and multiscale multifractal analysis) show that-in comparison with real data-the HRV signals obtained from our model have very similar properties, in particular including the multifractal characteristics at different time scales. The model described in this paper is discussed in the context of normal sleep. However, its construction is such that it should allow to model heart rate variability in sleep disorders. This possibility is briefly discussed. PMID- 26931583 TI - The role of asymmetrical and repulsive coupling in the dynamics of two coupled van der Pol oscillators. AB - A system of two asymmetrically coupled van der Pol oscillators has been studied. We show that the introduction of a small asymmetry in coupling leads to the appearance of a "wideband synchronization channel" in the bifurcational structure of the parameter space. An increase of asymmetry and transition to repulsive interaction leads to the formation of multistability. As the result, the tip of the Arnold's tongue widens due to the formation of folds defined by saddle-node bifurcation curves for the limit cycles on the torus. PMID- 26931584 TI - Evaluating gambles using dynamics. AB - Gambles are random variables that model possible changes in wealth. Classic decision theory transforms money into utility through a utility function and defines the value of a gamble as the expectation value of utility changes. Utility functions aim to capture individual psychological characteristics, but their generality limits predictive power. Expectation value maximizers are defined as rational in economics, but expectation values are only meaningful in the presence of ensembles or in systems with ergodic properties, whereas decision makers have no access to ensembles, and the variables representing wealth in the usual growth models do not have the relevant ergodic properties. Simultaneously addressing the shortcomings of utility and those of expectations, we propose to evaluate gambles by averaging wealth growth over time. No utility function is needed, but a dynamic must be specified to compute time averages. Linear and logarithmic "utility functions" appear as transformations that generate ergodic observables for purely additive and purely multiplicative dynamics, respectively. We highlight inconsistencies throughout the development of decision theory, whose correction clarifies that our perspective is legitimate. These invalidate a commonly cited argument for bounded utility functions. PMID- 26931585 TI - Analytically solvable chaotic oscillator based on a first-order filter. AB - A chaotic hybrid dynamical system is introduced and its analytic solution is derived. The system is described as an unstable first order filter subject to occasional switching of a set point according to a feedback rule. The system qualitatively differs from other recently studied solvable chaotic hybrid systems in that the timing of the switching is regulated by an external clock. The chaotic analytic solution is an optimal waveform for communications in noise when a resistor-capacitor-integrate-and-dump filter is used as a receiver. As such, these results provide evidence in support of a recent conjecture that the optimal communication waveform for any stable infinite-impulse response filter is chaotic. PMID- 26931586 TI - Critical density of a soliton gas. AB - We quantify the notion of a dense soliton gas by establishing an upper bound for the integrated density of states of the quantum-mechanical Schrodinger operator associated with the Korteweg-de Vries soliton gas dynamics. As a by-product of our derivation, we find the speed of sound in the soliton gas with Gaussian spectral distribution function. PMID- 26931587 TI - Velocity synchronization of multi-agent systems with mismatched parameters via sampled position data. AB - Power systems are special multi-agent systems with nonlinear coupling function and symmetric structures. This paper extends these systems to a class of multi agent systems with mismatched parameters, linear coupling function, and asymmetric structures and investigates their velocity synchronization via sampled position data. The dynamics of the agents is adopted as that of generators with mismatched parameters, while the system structures are supposed to be complex. Two distributed linear consensus protocols are designed, respectively, for multi agent systems without or with communication delay. Necessary and sufficient conditions based on the sampling period, the mismatched parameters, the delay, and the nonzero eigenvalues of the Laplacian matrix are established. It is shown that velocity synchronization of multi-agent systems with mismatched parameters can be achieved if the sampled period is chosen appropriately. Simulations are given to illustrate the effectiveness of the theoretical results. PMID- 26931588 TI - Using forbidden ordinal patterns to detect determinism in irregularly sampled time series. AB - It is known that when symbolizing a time series into ordinal patterns using the Bandt-Pompe (BP) methodology, there will be ordinal patterns called forbidden patterns that do not occur in a deterministic series. The existence of forbidden patterns can be used to identify deterministic dynamics. In this paper, the ability to use forbidden patterns to detect determinism in irregularly sampled time series is tested on data generated from a continuous model system. The study is done in three parts. First, the effects of sampling time on the number of forbidden patterns are studied on regularly sampled time series. The next two parts focus on two types of irregular-sampling, missing data and timing jitter. It is shown that forbidden patterns can be used to detect determinism in irregularly sampled time series for low degrees of sampling irregularity (as defined in the paper). In addition, comments are made about the appropriateness of using the BP methodology to symbolize irregularly sampled time series. PMID- 26931589 TI - Local immunization program for susceptible-infected-recovered network epidemic model. AB - The immunization strategies through contact tracing on the susceptible-infected recovered framework in social networks are modelled to evaluate the cost effectiveness of information-based vaccination programs with particular focus on the scenario where individuals belonging to a specific set can get vaccinated due to the vaccine shortages and other economic or humanity constraints. By using the block heterogeneous mean-field approach, a series of discrete-time dynamical models is formulated and the condition for epidemic outbreaks can be established which is shown to be not only dependent on the network structure but also closely related to the immunization control parameters. Results show that increasing the immunization strength can effectively raise the epidemic threshold, which is different from the predictions obtained through the susceptible-infected susceptible network framework, where epidemic threshold is independent of the vaccination strength. Furthermore, a significant decrease of vaccine use to control the infectious disease is observed for the local vaccination strategy, which shows the promising applications of the local immunization programs to disease control while calls for accurate local information during the process of disease outbreak. PMID- 26931590 TI - Novel application of multi dynamic trend analysis as a sensitive tool for detecting the effects of aging and congestive heart failure on heart rate variability. AB - The complex fluctuations in heart rate variability (HRV) reflect cardiac autonomic modulation and are an indicator of congestive heart failure (CHF). This paper proposes a novel nonlinear approach to HRV investigation, the multi dynamic trend analysis (MDTA) method, based on the empirical mode decomposition algorithm of the Hilbert-Huang transform combined with a variable-sized sliding-window method. Electrocardiographic signal data obtained from the PhysioNet database were used. These data were from subjects with CHF (mean age = 59.4 +/- 8.4), an age-matched elderly healthy control group (59.3 +/- 10.6), and a healthy young group (30.3 +/- 4.8); the HRVs of these subjects were processed using the MDTA method, time domain analysis, and frequency domain analysis. Among all HRV parameters, the MDTA absolute value slope (MDTS) and MDTA deviation (MDTD) exhibited the greatest area under the curve (AUC) of the receiver operating characteristics in distinguishing between the CHF group and the healthy controls (AUC = 1.000) and between the healthy elderly subject group and the young subject group (AUC = 0.834 +/- 0.067 for MDTS; 0.837 +/- 0.066 for MDTD). The CHF subjects presented with lower MDTA indices than those of the healthy elderly subject group. Furthermore, the healthy elderly subjects exhibited lower MDTA indices than those of the young controls. The MDTA method can adaptively and automatically identify the intrinsic fluctuation on variable temporal and spatial scales when investigating complex fluctuations in the cardiac autonomic regulation effects of aging and CHF. PMID- 26931591 TI - Correlation between weighted spectral distribution and average path length in evolving networks. AB - The weighted spectral distribution (WSD) is a metric defined on the normalized Laplacian spectrum. In this study, synchronic random graphs are first used to rigorously analyze the metric's scaling feature, which indicates that the metric grows sublinearly as the network size increases, and the metric's scaling feature is demonstrated to be common in networks with Gaussian, exponential, and power law degree distributions. Furthermore, a deterministic model of diachronic graphs is developed to illustrate the correlation between the slope coefficient of the metric's asymptotic line and the average path length, and the similarities and differences between synchronic and diachronic random graphs are investigated to better understand the correlation. Finally, numerical analysis is presented based on simulated and real-world data of evolving networks, which shows that the ratio of the WSD to the network size is a good indicator of the average path length. PMID- 26931592 TI - Controllability of Boolean networks via input controls under Harvey's update scheme. AB - In this article, the controllability of Boolean networks via input controls under Harvey's update scheme is investigated. First, the model of Boolean control networks under Harvey's stochastic update is proposed, by means of semi-tensor product approach, which is converted into discrete-time linear representation. And, a general formula of control-depending network transition matrix is provided. Second, based on discrete-time dynamics, controllability of the proposed model is analytically discussed by revealing the necessary and sufficient conditions of the reachable sets, respectively, for three kinds of controls, i.e., free Boolean control sequence, input control networks, and close loop control. Examples are showed to demonstrate the effectiveness and feasibility of the proposed scheme. PMID- 26931593 TI - Stretching and folding in finite time. AB - Complex flows mix efficiently, and this process can be understood by considering the stretching and folding of material volumes. Although many metrics have been devised to characterize stretching, fewer are able to capture folding in a quantitative way in spatiotemporally variable flows. Here, we extend our previous methods based on the finite-time curving of fluid-element trajectories to nonzero scales and show that this finite-scale finite-time curvature contains information about both stretching and folding. We compare this metric to the more commonly used finite-time Lyapunov exponent and illustrate our methods using experimental flow-field data from a quasi-two-dimensional laboratory flow. Our new analysis tools add to the growing set of Lagrangian methods for characterizing mixing in complex, aperiodic fluid flows. PMID- 26931594 TI - Mixing of discontinuously deforming media. AB - Mixing of materials is fundamental to many natural phenomena and engineering applications. The presence of discontinuous deformations-such as shear banding or wall slip-creates new mechanisms for mixing and transport beyond those predicted by classical dynamical systems theory. Here, we show how a novel mixing mechanism combining stretching with cutting and shuffling yields exponential mixing rates, quantified by a positive Lyapunov exponent, an impossibility for systems with cutting and shuffling alone or bounded systems with stretching alone, and demonstrate it in a fluid flow. While dynamical systems theory provides a framework for understanding mixing in smoothly deforming media, a theory of discontinuous mixing is yet to be fully developed. New methods are needed to systematize, explain, and extrapolate measurements on systems with discontinuous deformations. Here, we investigate "webs" of Lagrangian discontinuities and show that they provide a template for the overall transport dynamics. Considering slip deformations as the asymptotic limit of increasingly localised smooth shear, we also demonstrate exactly how some of the new structures introduced by discontinuous deformations are analogous to structures in smoothly deforming systems. PMID- 26931595 TI - Chaotifying delayed recurrent neural networks via impulsive effects. AB - In this paper, chaotification of delayed recurrent neural networks via chaotically changing moments of impulsive actions is considered. Sufficient conditions for the presence of Li-Yorke chaos with its ingredients proximality, frequent separation, and existence of infinitely many periodic solutions are theoretically proved. Finally, effectiveness of our theoretical results is illustrated by an example with numerical simulations. PMID- 26931596 TI - Entropy-based complexity measures for gait data of patients with Parkinson's disease. AB - Shannon, Kullback-Leibler, and Klimontovich's renormalized entropies are applied as three different complexity measures on gait data of patients with Parkinson's disease (PD) and healthy control group. We show that the renormalized entropy of variability of total reaction force of gait is a very efficient tool to compare patients with respect to disease severity. Moreover, it is a good risk predictor such that the sensitivity, i.e., the percentage of patients with PD who are correctly identified as having PD, increases from 25% to 67% while the Hoehn-Yahr stage increases from 2.5 to 3.0 (this stage goes from 0 to 5 as the disease severity increases). The renormalized entropy method for stride time variability of gait is found to correctly identify patients with a sensitivity of 80%, while the Shannon entropy and the Kullback-Leibler relative entropy can do this with a sensitivity of only 26.7% and 13.3%, respectively. PMID- 26931597 TI - Coarse-graining time series data: Recurrence plot of recurrence plots and its application for music. AB - We propose a nonlinear time series method for characterizing two layers of regularity simultaneously. The key of the method is using the recurrence plots hierarchically, which allows us to preserve the underlying regularities behind the original time series. We demonstrate the proposed method with musical data. The proposed method enables us to visualize both the local and the global musical regularities or two different features at the same time. Furthermore, the determinism scores imply that the proposed method may be useful for analyzing emotional response to the music. PMID- 26931598 TI - Inverse period-doubling bifurcations determine complex structure of bursting in a one-dimensional non-autonomous map. AB - We propose a simple one-dimensional non-autonomous map, in which some novel bursting patterns (e.g., "fold/double inverse flip" bursting, "fold/multiple inverse flip" bursting, and "fold/a cascade of inverse flip" bursting) can be observed. Typically, these bursting patterns exhibit complex structures containing a chain of inverse period-doubling bifurcations. The active states related to these bursting can be period-2(n) (n = 1, 2, 3,...) attractors or chaotic attractors, which may evolve to quiescence by a chain of inverse period doubling bifurcations when the slow excitation decreases through period-doubling bifurcation points of the map. This accounts for the complex inverse period doubling bifurcation structures observed in bursting patterns. Our findings enrich the possible routes to bursting as well as the underlying mechanisms of bursting. PMID- 26931599 TI - Multifractal analysis of visibility graph-based Ito-related connectivity time series. AB - In this study, we investigate multifractal properties of connectivity time series resulting from the visibility graph applied to normally distributed time series generated by the Ito equations with multiplicative power-law noise. We show that multifractality of the connectivity time series (i.e., the series of numbers of links outgoing any node) increases with the exponent of the power-law noise. The multifractality of the connectivity time series could be due to the width of connectivity degree distribution that can be related to the exit time of the associated Ito time series. Furthermore, the connectivity time series are characterized by persistence, although the original Ito time series are random; this is due to the procedure of visibility graph that, connecting the values of the time series, generates persistence but destroys most of the nonlinear correlations. Moreover, the visibility graph is sensitive for detecting wide "depressions" in input time series. PMID- 26931600 TI - Effective low-order models for atmospheric dynamics and time series analysis. AB - The paper focuses on two interrelated problems: developing physically sound low order models (LOMs) for atmospheric dynamics and employing them as novel time series models to overcome deficiencies in current atmospheric time series analysis. The first problem is warranted since arbitrary truncations in the Galerkin method (commonly used to derive LOMs) may result in LOMs that violate fundamental conservation properties of the original equations, causing unphysical behaviors such as unbounded solutions. In contrast, the LOMs we offer (G-models) are energy conserving, and some retain the Hamiltonian structure of the original equations. This work examines LOMs from recent publications to show that all of them that are physically sound can be converted to G-models, while those that cannot lack energy conservation. Further, motivated by recent progress in statistical properties of dynamical systems, we explore G-models for a new role of atmospheric time series models as their data generating mechanisms are well in line with atmospheric dynamics. Currently used time series models, however, do not specifically utilize the physics of the governing equations and involve strong statistical assumptions rarely met in real data. PMID- 26931601 TI - Disentangling regular and chaotic motion in the standard map using complex network analysis of recurrences in phase space. AB - Recurrence in the phase space of complex systems is a well-studied phenomenon, which has provided deep insights into the nonlinear dynamics of such systems. For dissipative systems, characteristics based on recurrence plots have recently attracted much interest for discriminating qualitatively different types of dynamics in terms of measures of complexity, dynamical invariants, or even structural characteristics of the underlying attractor's geometry in phase space. Here, we demonstrate that the latter approach also provides a corresponding distinction between different co-existing dynamical regimes of the standard map, a paradigmatic example of a low-dimensional conservative system. Specifically, we show that the recently developed approach of recurrence network analysis provides potentially useful geometric characteristics distinguishing between regular and chaotic orbits. We find that chaotic orbits in an intermittent laminar phase (commonly referred to as sticky orbits) have a distinct geometric structure possibly differing in a subtle way from those of regular orbits, which is highlighted by different recurrence network properties obtained from relatively short time series. Thus, this approach can help discriminating regular orbits from laminar phases of chaotic ones, which presents a persistent challenge to many existing chaos detection techniques. PMID- 26931603 TI - Enhanced versatility of fluid control in centrifugal microfluidic platforms using two degrees of freedom. AB - Centrifugal microfluidic platforms have significant potential in commercial applications because of their operational flexibility and minimal external infrastructure requirements. However, the dynamic and real-time control of fluid flow within traditional centrifugal microfluidic platforms is problematic. To address this significant limitation, we propose a two degrees of freedom platform, in which a digital servo is located at each end of an arm driven by a motor. This allows for reversible inward pumping between multiple chambers with perfect efficiency. Furthermore, the addition of a second degree of freedom allows position-based pressure controlled burst valves to be accessed and operated in an independent fashion. To demonstrate the efficacy of this technical innovation, we show rapid and configurable flow switching between three target chambers within a centrifugal microfluidic device. PMID- 26931602 TI - Sequential detection of learning in cognitive diagnosis. AB - In order to look more closely at the many particular skills examinees utilize to answer items, cognitive diagnosis models have received much attention, and perhaps are preferable to item response models that ordinarily involve just one or a few broadly defined skills, when the objective is to hasten learning. If these fine-grained skills can be identified, a sharpened focus on learning and remediation can be achieved. The focus here is on how to detect when learning has taken place for a particular attribute and efficiently guide a student through a sequence of items to ultimately attain mastery of all attributes while administering as few items as possible. This can be seen as a problem in sequential change-point detection for which there is a long history and a well developed literature. Though some ad hoc rules for determining learning may be used, such as stopping after M consecutive items have been successfully answered, more efficient methods that are optimal under various conditions are available. The CUSUM, Shiryaev-Roberts and Shiryaev procedures can dramatically reduce the time required to detect learning while maintaining rigorous Type I error control, and they are studied in this context through simulation. Future directions for modelling and detection of learning are discussed. PMID- 26931604 TI - Microalgae from the Selenastraceae as emerging candidates for biodiesel production: a mini review. AB - Over the years, microalgae have been identified to be a potential source of commercially important products such as pigments, polysaccharides, polyunsaturated fatty acids and in particular, biofuels. Current demands for sustainable fuel sources and bioproducts has led to an extensive search for promising strains of microalgae for large scale cultivation. Prospective strains identified for these purposes were among others, mainly from the genera Hematococcus, Dunaliella, Botryococcus, Chlorella, Scenedesmus and Nannochloropsis. Recently, microalgae from the Selenastraceae emerged as potential candidates for biodiesel production. Strains from the Selenastraceae such as Monoraphidium sp. FXY-10, M. contortum SAG 47.80, Ankistrodesmus sp. SP2 15 and M. minutum were high biomass and lipid producers when cultivated under optimal conditions. A number of Selenastraceae strains were also reported to be suitable for cultivation in wastewater. This review highlights recent reports on potential strains from the Selenastraceae for biodiesel production and contrasts their biomass productivity, lipid productivity as well as fatty acid profile. Cultivation strategies employed to enhance their biomass and lipid productivity as well as to reduce feedstock cost are also discussed in this paper. PMID- 26931605 TI - The price of independence: cell separation in fission yeast. AB - The ultimate goal of cell division is to give rise to two viable independent daughter cells. A tight spatial and temporal regulation between chromosome segregation and cytokinesis ensures the viability of the daughter cells. Schizosaccharomyces pombe, commonly known as fission yeast, has become a leading model organism for studying essential and conserved mechanisms of the eukaryotic cell division process. Like many other eukaryotic cells it divides by binary fission and the cleavage furrow undergoes ingression due to the contraction of an actomyosin ring. In contrast to mammalian cells, yeasts as cell-walled organisms, also need to form a division septum made of cell wall material to complete the process of cytokinesis. The division septum is deposited behind the constricting ring and it will constitute the new ends of the daughter cells. Cell separation also involves cell wall degradation and this process should be precisely regulated to avoid cell lysis. In this review, we will give a brief overview of the whole cytokinesis process in fission yeast, from the positioning and assembly of the contractile ring to the final step of cell separation, and the problems generated when these processes are not precise. PMID- 26931606 TI - Bacterial communities in full-scale wastewater treatment systems. AB - Bacterial metabolism determines the effectiveness of biological treatment of wastewater. Therefore, it is important to define the relations between the species structure and the performance of full-scale installations. Although there is much laboratory data on microbial consortia, our understanding of dependencies between the microbial structure and operational parameters of full-scale wastewater treatment plants (WWTP) is limited. This mini-review presents the types of microbial consortia in WWTP. Information is given on extracellular polymeric substances production as factor that is key for formation of spatial structures of microorganisms. Additionally, we discuss data on microbial groups including nitrifiers, denitrifiers, Anammox bacteria, and phosphate- and glycogen accumulating bacteria in full-scale aerobic systems that was obtained with the use of molecular techniques, including high-throughput sequencing, to shed light on dependencies between the microbial ecology of biomass and the overall efficiency and functional stability of wastewater treatment systems. Sludge bulking in WWTPs is addressed, as well as the microbial composition of consortia involved in antibiotic and micropollutant removal. PMID- 26931607 TI - Biofilm control with natural and genetically-modified phages. AB - Bacteriophages, as the most dominant and diverse entities in the universe, have the potential to be one of the most promising therapeutic agents. The emergence of multidrug-resistant bacteria and the antibiotic crisis in the last few decades have resulted in a renewed interest in phage therapy. Furthermore, bacteriophages, with the capacity to rapidly infect and overcome bacterial resistance, have demonstrated a sustainable approach against bacterial pathogens particularly in biofilm. Biofilm, as complex microbial communities located at interphases embedded in a matrix of bacterial extracellular polysaccharide substances (EPS), is involved in health issues such as infections associated with the use of biomaterials and chronic infections by multidrug resistant bacteria, as well as industrial issues such as biofilm formation on stainless steel surfaces in food industry and membrane biofouling in water and wastewater treatment processes. In this paper, the most recent studies on the potential of phage therapy using natural and genetically-modified lytic phages and their associated enzymes in fighting biofilm development in various fields including engineering, industry, and medical applications are reviewed. Phage-mediated prevention approaches as an indirect phage therapy strategy are also explored in this review. In addition, the limitations of these approaches and suggestions to overcome these constraints are discussed to enhance the efficiency of phage therapy process. Finally, future perspectives and directions for further research towards a better understanding of phage therapy to control biofilm are recommended. PMID- 26931608 TI - Nutrient scavenging activity and antagonistic factors of non-photobiont lichen associated bacteria: a review. AB - Lichens are defined as the specific symbiotic structure comprising a fungus and a green alga and/or cyanobacterium. Up until recently, non-photobiont endothallic bacteria, while known to be present in large numbers, have generally been dismissed as functionally irrelevant cohabitants of the lichen thallus, or even environmental contaminants. Recent analyses of lichen metagenomes and innovative co-culture experiments have uncovered a functionally complex community that appears to contribute to a healthy lichen thallus in several ways. Lichen associated bacteriomes are typically dominated by several lineages of Proteobacteria, some of which may be specific for lichen species. Recent work has implicated members of these lineages in several important ecophysiological roles. These include nutrient scavenging, including mobilization of iron and phosphate, nitrogen fixation, cellulase, xylanase and amylase activities, and oxidation of recalcitrant compounds, e.g. aromatics and aliphatics. Production of volatile organic compounds, conferring antibacterial and antifungal activity, has also been demonstrated for several lichen-associated isolates. In the present paper we review the nature of non-phototrophic endolichenic bacteria associated with lichens, and give insight into the current state of knowledge on their importance the lichen symbiotic association. PMID- 26931610 TI - Shell bone histology of the long-necked chelid Yaminuechelys (Testudines: Pleurodira) from the late Cretaceous-early Palaeocene of Patagonia with comments on the histogenesis of bone ornamentation. AB - Yaminuechelys is a long-necked chelid turtle whose remains have been recovered from outcrops of the Santonian-Maastrichtian and Danian of South America. With the purpose of providing data about shell sculpturing origin and palaeoecology, the bone histology of several shell elements (including neural, costal, peripheral and plastral plates) of Yaminuechelys is described herein. Histological analysis reveals that Yaminuechelys shares with Chelidae the presence of interwoven structural fibre bundles in the external cortex, and parallel-fibred bone of the internal cortex. The presence of resorption lines in several samples indicates that the particular ornamentation of the external surfaces originated, at least in part, by focalized resorption and new bone deposition. This mechanism for ornamentation origin and maintenance is here described for the first time in a turtle. Compactness of the shell bones is consistent with an aquatic habitat, which supports previous hypothesis based on palaeoenvironmental and morphological data. PMID- 26931609 TI - Elimination of viruses from domestic wastewater: requirements and technologies. AB - Domestic wastewater contains various pathogens, which, if not sufficiently eliminated, may enter the receiving water bodies and cause water-transmitted diseases. Among the waterborne pathogens, viruses may occur, survive and/or decay much differently from bacteria in water. In many cases, the diseases caused by viruses are more severe. Therefore, research efforts are mainly directed at the behavior of viruses in water environments, as well as the elimination of viruses from wastewater. In this paper, an overview of the occurrence of viruses in wastewater is presented, together with their categories, methods of detection and potential to cause waterborne diseases. As wastewater treatment plants are critical nodes for the influx and termination of virus transmission, the behavior of viruses at each stage of treatment is reviewed. Particular attention is paid to the unit operations, which play crucial roles in virus removals, such as coagulation and membrane filtration, and that for virus inactivation, such as chemical disinfection and UV irradiation. Future needs for the development of new technologies for virus elimination, source control, and finding more suitable indicators of viral pathogens are also highlighted. PMID- 26931611 TI - Crisis averted: How consumers experienced a police and clinical early response (PACER) unit responding to a mental health crisis. AB - When mental health crisis situations in the community are poorly handled, it can result in physical and emotional injuries. The purpose of this study was to ascertain the experiences and opinions of consumers about the way police and mental health services worked together, specifically via the Alfred Police and Clinical Early Response (A-PACER) model, to assist people experiencing a mental health crisis. Semi-structured in-depth interviews were conducted with 12 mental health consumers who had direct contact with the A-PACER team between June 2013 and March 2015. The study highlighted that people who encountered the A-PACER team generally valued and saw the benefit of a joint police-mental health clinician team response to a mental health crisis situation in the community. In understanding what worked well in how the A-PACER team operated, consumers perspectives can be summarized into five themes: communication and de-escalation, persistence of the A-PACER team, providing a quick response and working well under pressure, handover of information, and A-PACER helped consumers achieve a preferred outcome. All consumers acknowledged the complementary roles of the police officer and mental health clinician, and described the A-PACER team's supportive approach as critical in gaining their trust, engagement and in de escalating the crises. Further education and training for police officers on how to respond to people with a mental illness, increased provision of follow-up support to promote rehabilitation and prevent future crises, and measures to reduce public scrutiny for the consumer when police responded, were proposed opportunities for improvement. PMID- 26931613 TI - Postmortem Attraction of Sarcosaprophagous Diptera to Tramadol-Treated Rats and Morphometric Aspects of the Developed Larvae. AB - The presence of some specific drugs in animal tissues may affect the time of minimal postmortem intervals estimated during forensic entomological investigations. To test the effects of a specific drug on decomposition, a field study was conducted at Fayoum University campus, Egypt, from March to May 2013, using tramadol, a synthetic analgesic opioid used to treat moderate to severe pain in humans. Albino rats were used as the animal model during this study. The duration of the fresh stage of tramadol treated rat (Ttr) carcasses was significantly shorter (2.4 +/- 0.27 days) compared to tramadol free rat (Tfr) carcasses (6.4 +/- 0.49 days). The dry carcass stage of Ttr lasted longer (10.3 +/- 0.99 days) as compared to (7.4 +/- 0.18 days) the Tfr carcass. The decomposition process of the (Ttr) carcass was not significantly faster (24.9 +/- 1.58 days) as compared to (Tfr) carcasses (29.5 +/- 1.69). Lucilia cuprina (Wiedemann), Chrysomya albiceps (Wiedemann), and Musca domestica L. were less attracted to Ttr carcass-baited traps than traps with Tfr carcasses. However, females of Sarcophaga spp. showed a greater attraction to Ttr carcasses. Females of another sarcophagid fly, Wohlfahrtia spp. exhibited similar attraction tendencies to both types of trap baits. Larvae of S. argyrostoma (Robineau Desvoidy) collected from Ttr carcasses developed to a significantly longer total body length (10.4 +/- 0.04 mm) as compared to the average length of the larvae collected from Tfr carcasses (8.9 +/- 0.34 mm). During days 9-13 after rat death, the relative lengths of larvae from Ttr carcasses were not significantly different from Tfr carcasses. Larvae fed on Ttr carcasses pupated 2 days later than the control larvae. PMID- 26931614 TI - Codonopsis lanceolata: A Review of Its Therapeutic Potentials. AB - Codonopsis lanceolata (Campanulaceae) is dicotyledonous herbaceous perennial plant, predominantly found in Central, East, and South Asia. This plant has been widely used in traditional medicine and is considered to have medicinal properties to treat diseases and symptoms such as bronchitis, coughs, spasm, psychoneurosis, cancer, obesity, hyperlipidemia, edema, hepatitis, colitis, and lung injury. C. lanceolata contains many biologically active compounds, including polyphenols, saponins, tannins, triterpene, alkaloids, and steroids, which contribute to its numerous pharmacological activities. Through systematic studies, the pharmacological actions of these compounds have been revealed. Therapeutic potentialities of C. lanceolata and its previously reported molecular mechanisms are described in this review. PMID- 26931615 TI - Listerine(r) Products: An Update on the Efficacy and Safety. AB - In the 19th century, the mouthwash Listerine(r) was formulated from four essential oils. Later, the oils were replaced by their marker substances. To keep them in solution, 24-27% ethanol was added as a vehicle. This is an update of our previous review on the efficacy and safety of Listerine(r). METHOD: PubMed was searched for clinical studies on the therapeutic benefits and safety of Listerine(r) from the end of 2011 to the end of October 2015. RESULTS: Sixteen studies were found and extracted. Three of the four 6-month studies were of sound confirmatory design. Two of these investigated Listerine(r) and one Listerine Zero(r). The evidence of effectiveness for Listerine(r), based on the bulk of three confirmatory studies and numerous exploratory studies carried out so far, is strong, but only moderate for Listerine(r) Zero and poor for Listerine(r) Cool Blue. In the three safety studies identified, we found methodological flaws that biased the results. CONCLUSIONS: Evidence is accumulating that Listerine(r) is effective in improving oral health, but the absence of systematic toxicological studies means that an accurate safety assessment cannot be made. PMID- 26931616 TI - Plant Phenols as Antibiotic Boosters: In Vitro Interaction of Olive Leaf Phenols with Ampicillin. AB - The antimicrobial properties of olive leaf extract (OLE) have been well recognized in the Mediterranean traditional medicine. Few studies have investigated the antimicrobial properties of OLE. In this preliminary study, commercial OLE and its major phenolic secondary metabolites were evaluated in vitro for their antimicrobial activities against Escherichia coli and Staphylococcus aureus, both individually and in combination with ampicillin. Besides luteolin 7-O-glucoside, OLE and its major phenolic secondary metabolites were effective against both bacteria, with more activity on S. aureus. In combination with ampicillin, OLE, caffeic acid, verbascoside and oleuropein showed additive effects. Synergistic interaction was observed between ampicillin and hydroxytyrosol. The phenolic composition of OLE and the stability of olive phenols in assay medium were also investigated. While OLE and its phenolic secondary metabolites may not be potent enough as stand-alone antimicrobials, their abilities to boost the activity of co-administered antibiotics constitute an imperative future research area. PMID- 26931618 TI - Sniping the scout: Targeting the key molecules in dendritic cell functions for treatment of autoimmune diseases. AB - Dendritic cells (DCs) are a power tool for manipulating immune system. They play important roles in the induction of immunity as well as inducing intrathymic and peripheral tolerance. After generated from stem cells in the bone marrow, DCs traffic to the peripheral tissues, where they capture and process antigens, express lymphocyte co-stimulators, migrate to the secondary lymph organs and present the processed antigen to naive T cells to either activate or tolerize them. These processes are modulated subtly and influenced by various factors. Aberrant regulation of the processes may cause autoimmunity. Investigation into the biology of DCs and the molecules and mechanisms that regulate them helps us understanding the pathogenesis of autoimmune diseases and reveals numerous steps for pharmacological manipulation. In this review, we made a sketch line of the critical events of DC biology that are potential pharmacologic targets for the treatment of autoimmune diseases. PMID- 26931617 TI - Influence of plasma-activated compounds on melanogenesis and tyrosinase activity. AB - Many organic chemists around the world synthesize medicinal compounds or extract multiple compounds from plants in order to increase the activity and quality of medicines. In this work, we synthesized new eugenol derivatives (ED) and then treated them with an N2 feeding gas atmospheric pressure plasma jet (APPJ) to increase their utility. We studied the tyrosinase-inhibition activity (activity test) and structural changes (circular dichroism) of tyrosinase with ED and plasma activated eugenol derivatives (PAED) in a cell-free environment. Later, we used docking studies to determine the possible interaction sites of ED and PAED compounds with tyrosinase enzyme. Moreover, we studied the possible effect of ED and PAED on melanin synthesis and its mechanism in melanoma (B16F10) cells. Additionally, we investigated the structural changes that occurred in activated ED after plasma treatment using nuclear magnetic resonance (NMR). Hence, this study provides a new perspective on PAED for the field of plasma medicine. PMID- 26931620 TI - Topological phase transitions and chiral inelastic transport induced by the squeezing of light. AB - There is enormous interest in engineering topological photonic systems. Despite intense activity, most works on topological photonic states (and more generally bosonic states) amount in the end to replicating a well-known fermionic single particle Hamiltonian. Here we show how the squeezing of light can lead to the formation of qualitatively new kinds of topological states. Such states are characterized by non-trivial Chern numbers, and exhibit protected edge modes, which give rise to chiral elastic and inelastic photon transport. These topological bosonic states are not equivalent to their fermionic (topological superconductor) counterparts and, in addition, cannot be mapped by a local transformation onto topological states found in particle-conserving models. They thus represent a new type of topological system. We study this physics in detail in the case of a kagome lattice model, and discuss possible realizations using nonlinear photonic crystals or superconducting circuits. PMID- 26931619 TI - Oral steroids for the resolution of otitis media with effusion (OME) in children (OSTRICH): study protocol for a randomised controlled trial. AB - BACKGROUND: Otitis media with effusion (OME) is an accumulation of fluid in the middle ear affecting about 80 % of children by the age of 4 years. While OME usually resolves spontaneously, it can affect speech, behaviour and development. Children with persistent hearing loss associated with OME are usually offered hearing aids or insertion of ventilation tubes through the tympanic membrane. Oral steroids may be a safe and effective treatment for OME, which could be delivered in primary care. Treatment with oral steroids has the potential to benefit large numbers of children and reduce the burden of care on them and on health services. However, previous trials have either been too small with too short a follow-up period, or of too poor quality to give a definite answer. The aim of the Oral Steroids for the Resolution of Otitis Media with Effusion in Children (OSTRICH) trial is to determine if a short course of oral steroids improves the hearing of children with OME in the short and longer term. METHODS/DESIGN: A total of 380 participants (children of 2 to 8 years of age) are recruited from Hospital Ear, Nose and Throat departments in Wales and England. A trained clinician seeks informed consent from parents of children with symptoms for at least 3 months that are attributable to OME and with confirmed bilateral hearing loss at study entry. Participants are randomised to a course of oral steroid or a matched placebo for 1 week. Outcomes include audiometry, tympanometry and otoscopy assessments; symptoms; adverse effects; functional health status; quality of life; resource use; and cost effectiveness. Participants are followed up at 5 weeks, and at 6 and 12 months after the day of randomisation. The primary outcome is audiometry-confirmed satisfactory hearing at 5 weeks. DISCUSSION: An important evidence gap exists regarding the clinical and cost effectiveness of short courses of oral steroid treatment for OME. Identifying an effective, safe, nonsurgical intervention for OME in children for use in primary care would be of great benefit to children, their families and the NHS. TRIAL REGISTRATION: ISRCTN: ISRCTN49798431 (Registered 7 December 2012). PMID- 26931621 TI - Territoriality in the tompot blenny Parablennius gattorugine from photographic records. AB - The behaviour of the tompot blenny Parablennius gattorugine was studied from a long-term underwater photographic record from two sites on the south-west coast of the U.K. Repeated observations of individually identifiable P. gattorugine during 112 dives revealed that male P. gattorugine may guard eggs in a particular crevice over subsequent breeding seasons, reside in the same location for up to 4 years and recover from injuries received in disputes over territory. Further observations included resident males wiping eggs with greatly expanded anal glands, adult-type fighting between juveniles and unusual behaviour where a large male manipulated an empty mollusc shell for the attention of two smaller conspecifics. PMID- 26931623 TI - Chronic Kidney Disease (Not) on the Agenda. PMID- 26931622 TI - Rasagiline prevents cyclosporine A-sensitive superoxide flashes induced by PK11195, the initial signal of mitochondrial membrane permeabilization and apoptosis. AB - Rasagiline, a neuroprotective inhibitor of type B monoamine oxidase, prevented PK111195-induced apoptosis in SH-SY5Y cells through inhibition of mitochondrial apoptosis signaling (J Neural Transm 120:1539-1551, 2013, J Neural Transm 122:1399-1407, 2015). This paper presents that PK11195 induced superoxide flashes, the transit production burst, mediated by cyclosporine A-sensitive membrane permeability transition. Rasagiline prevented superoxide flashes, calcium efflux, and cell death by PK11195. Regulation of the initial pore formation at the inner mitochondrial membrane was confirmed as the decisive mechanism of neuroprotection by rasagiline. PMID- 26931624 TI - The Prevalence of Renal Failure. Results from the German Health Interview and Examination Survey for Adults, 2008-2011 (DEGS1). AB - BACKGROUND: The prevalence of non-end stage renal failure among adults in Germany is unknown. Accurate figures would enable us to estimate the overall need for kidney replacement therapies and the unexploited potential for disease prevention. Renal failure is also an important cardiovascular risk factor. Until now, American prevalence figures have often been applied to Germany despite dissimilarities between the two populations. METHODS: We analyzed data on renal function from the nationwide German Health Interview and Examination Survey for Adults, 2008-2011 (DEGS1), which was carried out by the Robert Koch Institute. The glomerular filtration rate was estimated (eGFR) from the serum creatinine and cystatin C levels (CKD-EPI formula) and a semiquantitative measure of albuminuria. Relationships between renal failure and its possible determinants were quantified with adjusted prevalence ratios (PR) and 95% confidence intervals (95% CI). RESULTS: Roughly 2.3% (95% CI: [1.9; 2.6 ]) of persons aged 18-79 had an eGFR below 60 mL/min/1.73 m2. The prevalence rose with age. We extrapolated these figures conservatively to persons aged 80 and above, who were not included in the DEGS1, and arrived at a figure of at least 2 million persons in Germany with renal failure. 11.5% of the population have albuminuria of at least 30 mg/L. Diabetes mellitus (PR = 2.25, 95% CI: [1.59; 3.16]) and arterial hypertension (PR = 3.46, 95% CI: [1.95; 6.12]) are important determinants. CONCLUSION: This study provides the first representative estimate of the prevalence of renal failure in Germany. The condition is highly dependent on age but less prevalent than previously assumed on the basis of American prevalence figures. PMID- 26931626 TI - Account for Increased Fat Mass. PMID- 26931625 TI - Renal Insufficiency and Medication in Nursing Home Residents. A Cross-Sectional Study (IMREN). AB - BACKGROUND: Nursing home residents often suffer from a multiplicity of medical conditions and take many different drugs. Many drugs are eliminated via the kidneys and thus require dose adjustment in patients with renal insufficiency. This is the first study to address the prevalence of renal insufficiency among nursing home residents in Germany, and the extent to which such persons take drugs that are contraindicated or incorrectly dosed because of renal insufficiency. METHODS: We carried out a cross-sectional study in nursing homes in the German regions of Bremen and Lower Saxony. Data were collected by nursing staff and given to us anonymously. Whenever the nursing home data did not include a current creatinine value, the patient's general practitioner was asked to supply this value. The estimated creatinine clearance (eCCr) was calculated with the Cockcroft-Gault formula. RESULTS: 852 residents of 21 nursing homes were included in the study; eCCr values were obtainable for 685 (80.4%) of them (average age, 83.3 years; 75.2% female). 48.2% of these patients (95% confidence interval [CI] 41.8-54.5) had moderate renal insufficiency (eCCr 59-30 mL/min), and 15.5% (95% CI 12.4-18.6) had severe renal insufficiency (eCCr <30 mL/min). 19.7% were regularly taking at least one medication that was contraindicated or incorrectly dosed in the light of renal insufficiency. Predictors for such inappropriate drug use were advanced age, female sex, arterial hypertension, and polypharmacy. The drugs that were most often inappropriately used were metformin, ramipril, and potassium chloride. CONCLUSION: Nursing home residents often suffer from renal insufficiency and should therefore have their creatinine levels measured regularly. A knowledge of the creatinine level is a prerequisite for the proper adjustment of drug doses (if necessary). A practical and compact summary of dose-adjustment recommendations for patients with renal insufficiency would be desirable but is not yet available. PMID- 26931627 TI - Slightly Distorted Impression. PMID- 26931628 TI - In Reply. PMID- 26931630 TI - Nanoscale triboactivity of functionalized c-Si surfaces by Fe+ ion implantation. AB - In the present work, we present a study of the effect of Fe(+) ion implantation on the tribological response at nanoscale contact lengths of crystalline silicon (c-Si) surfaces. (1 0 0) silicon wafers were implanted with Fe(+) at a fluence of 2 * 10(17) cm(-2), followed by annealing treatments at temperatures of 800 degrees C and 1000 degrees C. After microstructural characterization, nanoabrasive wear tests were performed with an atomic force microscope (AFM) using an AFM diamond tip with a stiff steel cantilever that enables the application of loads between 1 MUN and 8 MUN. After the nanowear tests, the same AFM was used to visualize and measure the worn craters. It was observed that the as-implanted samples present the poorest nanowear response, i.e. the highest wear rate, even higher than that of the unimplanted Si wafers used as a reference. Nevertheless, annealing treatments result in a measurable increase in the nanowear resistance. In this way we show that Fe(+) ion implantation of c-Si, followed by the proper post-heat treatment, results in the formation of FeSi2 nanoprecipitates finely dispersed in a recrystallized matrix. This can be a valuable way of optimizing the nanotribological behavior of silicon. PMID- 26931629 TI - Age-related changes in amygdala-frontal connectivity during emotional face processing from childhood into young adulthood. AB - The ability to process and respond to emotional facial expressions is a critical skill for healthy social and emotional development. There has been growing interest in understanding the neural circuitry underlying development of emotional processing, with previous research implicating functional connectivity between amygdala and frontal regions. However, existing work has focused on threatening emotional faces, raising questions regarding the extent to which these developmental patterns are specific to threat or to emotional face processing more broadly. In the current study, we examined age-related changes in brain activity and amygdala functional connectivity during an fMRI emotional face matching task (including angry, fearful, and happy faces) in 61 healthy subjects aged 7-25 years. We found age-related decreases in ventral medial prefrontal cortex activity in response to happy faces but not to angry or fearful faces, and an age-related change (shifting from positive to negative correlation) in amygdala-anterior cingulate cortex/medial prefrontal cortex (ACC/mPFC) functional connectivity to all emotional faces. Specifically, positive correlations between amygdala and ACC/mPFC in children changed to negative correlations in adults, which may suggest early emergence of bottom-up amygdala excitatory signaling to ACC/mPFC in children and later development of top-down inhibitory control of ACC/mPFC over amygdala in adults. Age-related changes in amygdala-ACC/mPFC connectivity did not vary for processing of different facial emotions, suggesting changes in amygdala-ACC/mPFC connectivity may underlie development of broad emotional processing, rather than threat-specific processing. Hum Brain Mapp 37:1684-1695, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26931631 TI - Safety and efficacy of BAY 81-8973 for surgery in previously treated patients with haemophilia A: results of the LEOPOLD clinical trial programme. AB - INTRODUCTION: BAY 81-8973 is a recombinant factor VIII (rFVIII) with the same amino acid sequence as Bayer's sucrose-formulated rFVIII (rFVIII-FS) but manufactured with certain more advanced technologies. AIM: To describe surgery outcomes with BAY 81-8973 in the LEOPOLD trials. METHODS: Male patients with severe haemophilia A and no inhibitors aged 12-65 years with >=150 exposure days (EDs) to FVIII (LEOPOLD I and II), or aged <=12 years with >=50 EDs to FVIII (LEOPOLD Kids), received BAY 81-8973 based on dosing recommendations for rFVIII FS according to surgical requirements. Haemostasis-related complications, investigator/surgeon assessment of haemostasis, blood loss, need for transfusion and use of BAY 81-8973 were determined. RESULTS: In LEOPOLD I and II, 11 patients (mean age, 35.3 years) underwent 13 major surgeries. In LEOPOLD Kids, one patient (aged 6 years) underwent one major surgery. Thirty-two adult and paediatric patients underwent 46 minor surgeries. Haemostasis was rated good or excellent in all major and minor surgeries. Blood loss during surgery did not exceed expected amounts; blood transfusions were required in three of the 14 major surgeries. For major surgeries in LEOPOLD I and II, patients received a presurgical 50-IU kg(-1) dose of BAY 81-8973; median nominal dose on day of surgery was 7000 IU (107.5 IU kg(-1) ). Total BAY 81-8973 dose was 2500 IU (108.7 IU kg(-1) ) on the day of the only major surgery in LEOPOLD Kids. No haemostasis-related complications were reported. CONCLUSIONS: Haemostatic control with BAY 81-8973 during all surgeries in the LEOPOLD trials was good or excellent, with no haemostasis-related complications. PMID- 26931633 TI - Myocardial perfusion of infarcted and normal myocardium in propofol-anesthetized minipigs using (82)Rubidium PET. AB - Cardiac Rubidium-82 ((82)Rb) positron-emission-tomography (PET) is a good method for quantification of myocardial blood flow in man. Quantification of myocardial blood flow in animals to evaluate new treatment strategies or to understand underlying disease is also of great interest but raises some challenges. Animals, which have been anesthetized during PET acquisition, might react differently to used stress medications, and therefore difficulties might exist while evaluating the resulting PET images using standard software packages from commercial vendors optimized for human hearts. Furthermore propofol, used for anesthesia, can influence myocardial perfusion and coronary flow reserve due to its vasorelaxant effect, and interactions might exist between propofol and used stress agents, potentially affecting the result of the examination. We present cardiac (82)Rb PET studies performed in propofol-anesthetized minipigs with normal and infarcted myocardium stressed with both adenosine and dipyridamole. Despite the mentioned challenges, we were able to trace the small minipig heart with software designed for human cardiac PET and to achieve blood flow measurements comparable with results in humans with both adenosine and dipyridamole. We found dipyridamole to be a superior stress agent for this experimental setup. Finally, we were able to clearly identify the myocardial perfusion defect after an induced myocardial infarction. PMID- 26931632 TI - FgSsn3 kinase, a component of the mediator complex, is important for sexual reproduction and pathogenesis in Fusarium graminearum. AB - Fusarium graminearum is an important pathogen of wheat and barley. In addition to severe yield losses, infested grains are often contaminated with harmful mycotoxins. In this study, we characterized the functions of FgSSN3 kinase gene in different developmental and infection processes and gene regulation in F. graminearum. The FgSSN3 deletion mutant had a nutrient-dependent growth defects and abnormal conidium morphology. It was significantly reduced in DON production, TRI gene expression, and virulence. Deletion of FgSSN3 also resulted in up regulation of HTF1 and PCS1 expression in juvenile cultures, and repression of TRI genes in DON-producing cultures. In addition, Fgssn3 was female sterile and defective in hypopodium formation and infectious growth. RNA-seq analysis showed that FgSsn3 is involved in the transcriptional regulation of a wide variety genes acting as either a repressor or activator. FgSsn3 physically interacted with C type cyclin Cid1 and the cid1 mutant had similar phenotypes with Fgssn3, indicating that FgSsn3 and Cid1 form the CDK-cyclin pair as a component of the mediator complex in F. graminearum. Taken together, our results indicate that FgSSN3 is important for secondary metabolism, sexual reproduction, and plant infection, as a subunit of mediator complex contributing to transcriptional regulation of diverse genes. PMID- 26931634 TI - Deciphering Halogen Competition in Organometallic Halide Perovskite Growth. AB - Organometallic halide perovskites (OHPs) hold great promise for next-generation, low-cost optoelectronic devices. During the chemical synthesis and crystallization of OHP thin films, a major unresolved question is the competition between multiple halide species (e.g., I(-), Cl(-), Br(-)) in the formation of the mixed-halide perovskite crystals. Whether Cl(-) ions are successfully incorporated into the perovskite crystal structure or, alternatively, where they are located is not yet fully understood. Here, in situ X-ray diffraction measurements of crystallization dynamics are combined with ex situ TOF-SIMS chemical analysis to reveal that Br(-) or Cl(-) ions can promote crystal growth, yet reactive I(-) ions prevent them from incorporating into the lattice of the final perovskite crystal structure. The Cl(-) ions are located in the grain boundaries of the perovskite films. These findings significantly advance our understanding of the role of halogens during synthesis of hybrid perovskites and provide an insightful guidance to the engineering of high-quality perovskite films, essential for exploring superior-performing and cost-effective optoelectronic devices. PMID- 26931635 TI - Emotional eating is associated with weight loss success among adults enrolled in a weight loss program. AB - To examine associations between decreased emotional eating and weight loss success; and whether participation in a behavioral weight loss intervention was associated with a greater reduction in emotional eating over time compared to usual care. Secondary data analysis of a randomized controlled trial conducted at two university medical centers with 227 overweight adults with diabetes. Logistic and standard regression analyses examined associations between emotional eating change and weight loss success (i.e., weight loss of >=7 % of body weight and decrease in BMI). After 6 months of intervention, decreased emotional eating was associated with greater odds of weight loss success (p = .05). The odds of weight loss success for subjects with decreased emotional eating at 12 months were 1.70 times higher than for subjects with increased emotional eating. No differences in change in emotional eating were found between subjects in the behavioral weight loss intervention and usual care. Strategies to reduce emotional eating may be useful to promote greater weight loss among overweight adults with diabetes. PMID- 26931636 TI - Multidrug resistance protein 4 is a critical protein associated with the antiviral efficacy of nucleos(t)ide analogues. AB - BACKGROUND & AIMS: Multidrug resistance protein 4 (MRP4) has been associated with nucleos(t)ide analogue (NA) antiretroviral therapy failure, though is unclear if MRP4 is also correlated with the failure of anti-hepatitis B virus (HBV) therapy. METHODS: Multidrug resistance protein 4 expression in human peripheral blood mononuclear cells (PBMCs), liver tissues and human hepatoma cell lines was detected by real-time polymerase chain reaction (PCR), western blotting and immunohistochemistry assays. Supernatant and intracellular HBV DNA levels of MRP4 overexpressing or silenced HepG2.4D14 (wild-type) and HepG2.A64 (entecavir resistant mutant) cells were measured by quantitative PCR. NA concentrations and HBV mutational analysis were assessed by liquid chromatography/mass spectrometry assays and DNA sequencing. Multivariate analysis was used to assess predictive factors for treatment failure. RESULTS: High expression of MRP4 was found in hepatoma cell lines and PBMCs, and up- or down-regulation of MRP4 expression altered the susceptibility of cells to NAs. MRP inhibitors increased NA intracellular accumulation and decreased extracellular levels. Moreover, MRP4 expression in PBMCs was correlated with that in paired liver tissues. Furthermore, multivariate analysis showed MRP4 mRNA expression to be an independent predictor of NA treatment failure. CONCLUSIONS: Multidrug resistance protein 4 is a critical protein associated with the antiviral efficacy of NAs, and combination therapy of NA and MRP inhibitors could reduce the dosage for long term NA use. This is the first report to demonstrate that MRP4 expression is an important factor predicting treatment failure in chronic hepatitis B patients and will provide a potential therapeutic target against HBV. PMID- 26931637 TI - Separation of Nadolol Stereoisomers Using Chiralpak IA Chiral Stationary Phase. AB - Chiralpak IA adsorbent is used for both analytical and preparative chromatographic separation of nadolol stereoisomers. The results include a complete screening of the mobile phase composition for both the baseline resolution of all four nadolol stereoisomers (analytical separation) and the simulated moving bed (SMB) pseudo-binary separation of the most retained stereoisomer. The experimental results show that analytical baseline resolution of nadolol stereoisomers can be achieved using alcohol/hydrocarbon and alcohol/acetonitrile solvent mixtures. The 10%ethanol/90%acetonitrile mixture is presented as the one that presents baseline resolution with lower retention. For the preparative pseudo-binary separation, pure ethanol, pure methanol, alcohol/acetonitrile, and alcohol/tetrahydrofuran mixtures proved to allow good separation results. The 100%methanol/0.1%diethylamine solvent composition was selected to perform the experimental SMB separation. Using a 10 g/L total feed concentration, the more retained stereoisomer was recovered at the extract outlet stream with 99.5% purity, obtaining a system productivity of 1.98 gL(-1) h(-1) and requiring a solvent consumption of 3.13 L/g of product. Comparing these results with the ones recently presented by Ribeiro et al. (2013), this work shows that the Chiralpak IA chiral adsorbent is an interesting alternative to Chiralpak AD for the separation of nadolol stereoisomers at both analytical and preparative scales. Chirality 28:399-408, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26931638 TI - Examining associations between dietary patterns and metabolic CVD risk factors: a novel use of structural equation modelling. AB - The association between dietary patterns and metabolic cardiovascular risk factors has long been addressed but there is a lack of evidence towards the effects of the overall diet on the complex net of biological inter-relationships between risk factors. This study aimed to derive dietary patterns and examine their associations with metabolic cardiovascular risk factors following a theoretic model for the relationship between them. Participants included 417 adults of both sexes, enrolled to the cross-sectional population-based study performed in Brazil. Body weight, waist circumference, high-sensitivity C reactive protein, blood pressure, total cholesterol:HDL-cholesterol ratio, TAG:HDL-cholesterol ratio, fasting plasma glucose and serum leptin were evaluated. Food consumption was assessed by two non-consecutive 24-h dietary recalls adjusted for the within-person variation of intake. A total of three dietary patterns were derived by exploratory structural equation modelling: 'Traditional', 'Prudent' and 'Modern'. The 'Traditional' pattern had a negative and direct effect on obesity indicators (serum LEP, body weight and waist circumference) and negative indirect effects on total cholesterol:HDL-cholesterol ratio, TAG:HDL-cholesterol ratio and fasting plasma glucose. The 'Prudent' pattern had a negative and direct effect on systolic blood pressure. No association was observed for the 'Modern' pattern and metabolic risk factors. In conclusion, the 'Traditional' and 'Prudent' dietary patterns were negatively associated with metabolic cardiovascular risk factors among Brazilian adults. Their apparent protective effects against obesity and high blood pressure may be important non-pharmacological strategies for the prevention and control of obesity-related metabolic disorders and CVD. PMID- 26931639 TI - LabDisk for SAXS: a centrifugal microfluidic sample preparation platform for small-angle X-ray scattering. AB - We present a centrifugal microfluidic LabDisk for protein structure analysis via small-angle X-ray scattering (SAXS) on synchrotron beamlines. One LabDisk prepares 120 different measurement conditions, grouped into six dilution matrices. Each dilution matrix: (1) features automatic generation of 20 different measurement conditions from three input liquids and (2) requires only 2.5 MUl of protein solution, which corresponds to a tenfold reduction in sample volume in comparison to the state of the art. Total hands on time for preparation of 120 different measurement conditions is less than 5 min. Read-out is performed on disk within the synchrotron beamline P12 at EMBL Hamburg (PETRA III, DESY). We demonstrate: (1) aliquoting of 40 nl aliquots for five different liquids typically used in SAXS and (2) confirm fluidic performance of aliquoting, merging, mixing and read-out from SAXS experiments (2.7-4.4% CV of protein concentration). We apply the LabDisk for SAXS for basic analysis methods, such as measurement of the radius of gyration, and advanced analysis methods, such as the ab initio calculation of 3D models. The suitability of the LabDisk for SAXS for protein structure analysis under different environmental conditions is demonstrated for glucose isomerase under varying protein and NaCl concentrations. We show that the apparent radius of gyration of the negatively charged glucose isomerase decreases with increasing protein concentration at low salt concentration. At high salt concentration the radius of gyration (Rg) does not change with protein concentrations. Such experiments can be performed by a non expert, since the LabDisk for SAXS does not require attachment of tubings or pumps and can be filled with regular pipettes. The new platform has the potential to introduce routine high-throughput SAXS screening of protein structures with minimal input volumes to the regular operation of synchrotron beamlines. PMID- 26931640 TI - Fasciola hepatica tegumental antigens induce anergic-like T cells via dendritic cells in a mannose receptor-dependent manner. AB - FoxP3(+) Treg cells and anergic T cells are the two regulatory phenotypes of T cell responses associated with helminth infection. Here, we examine the T-cell responses in mice during Fasciola hepatica infection, and to its tegumental coat antigens (FhTeg) that are shed from the fluke every 2-3 h. FhTeg comprises a rich source of glycoproteins, mainly oligomannose N-glycans that bind to mannose receptor. This study demonstrated a novel mechanism for the T-cell unresponsiveness observed during F. hepatica infection and after injection with FhTeg. Markers of T-cell anergy, such as GRAIL, EGR2, ICOS, and ITCH, are enhanced amongst CD4(+) T-cell populations during infection and following FhTeg injection. This is characterized by a lack of cytokine responses and reduced proliferative activity, which can be reversed with the addition of IL-2. FhTeg activated dendritic cells (DCs) suppress T cells in vitro as measured by enhanced GRAIL and CTLA4 by RNA and suppressed cytokine expression in anti-CD3 stimulated CD4(+) T cells. FhTeg-treated DCs have enhanced MR expression, which is critical for DC-CD4(+) T-cell communication. Taken together, this study presents markers of anergy in a mouse model of F. hepatica infection, and improves our understanding of host-pathogen interactions and how helminths modulate host immunity. PMID- 26931641 TI - Nipple-sparing mastectomy: A contemporary perspective. AB - Increasing numbers of women are undergoing nipple-sparing mastectomy, and evidence to support its use for cancer treatment and prophylaxis is expanding. An understanding of technical aspects and pitfalls of the procedure is paramount to ensure that the best results are attained. J. Surg. Oncol. 2016;113:883-890. (c) 2016 Wiley Periodicals, Inc. PMID- 26931642 TI - Low-cost microarray thin-film electrodes with ionic liquid gel-polymer electrolytes for miniaturised oxygen sensing. AB - A robust, miniaturised electrochemical gas sensor for oxygen (O2) has been constructed using a commercially available Pt microarray thin-film electrode (MATFE) with a gellified electrolyte containing the room temperature ionic liquid (RTIL) 1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide ([C2mim][NTf2]) and poly(methyl methacrylate) (PMMA) in a 50 : 50 mass ratio. Diffusion coefficients and solubilities for oxygen in mixtures of PMMA/RTIL at different PMMA doping concentrations (0-50% mass) were derived from potential step chronoamperometry (PSCA) on a Pt microdisk electrode. The MATFE was then used with both the neat RTIL and 50% (by mass) PMMA/RTIL gel, to study the analytical behavior over a wide concentration range (0.1 to 100 vol% O2). Cyclic voltammetry (CV) and long-term chronoamperometry (LTCA) techniques were employed and it was determined that the gentler CV technique is better at higher O2 concentrations (above 60 vol%), but LTCA is more reliable and accurate at lower concentrations (especially below 0.5% O2). In particular, there was much less potential shifting (from the unstable Pt quasi-reference electrode) evident in the 50% PMMA/RTIL gel than in the neat RTIL, making this a much more suitable electrolyte for long-term continuous oxygen monitoring. The mass production and low-cost of the electrode array, along with the minimal amounts of RTIL/PMMA required, make this a viable sensing device for oxygen detection on a bulk scale in a wide range of environmental conditions. PMID- 26931644 TI - Ionothermal Synthesis of High-Voltage Alluaudite Na2+2xFe2-x(SO4)3 Sodium Insertion Compound: Structural, Electronic, and Magnetic Insights. AB - Exploring future cathode materials for sodium-ion batteries, alluaudite class of Na2Fe(II)2(SO4)3 has been recently unveiled as a 3.8 V positive insertion candidate (Barpanda et al. Nat. Commun. 2014, 5, 4358). It forms an Fe-based polyanionic compound delivering the highest Fe-redox potential along with excellent rate kinetics and reversibility. However, like all known SO4-based insertion materials, its synthesis is cumbersome that warrants careful processing avoiding any aqueous exposure. Here, an alternate low temperature ionothermal synthesis has been described to produce the alluaudite Na2+2xFe(II)2-x(SO4)3. It marks the first demonstration of solvothermal synthesis of alluaudite Na2+2xM(II)2-x(SO4)3 (M = 3d metals) family of cathodes. Unlike classical solid state route, this solvothermal route favors sustainable synthesis of homogeneous nanostructured alluaudite products at only 300 degrees C, the lowest temperature value until date. The current work reports the synthetic aspects of pristine and modified ionothermal synthesis of Na2+2xFe(II)2-x(SO4)3 having tunable size (300 nm ~5 MUm) and morphology. It shows antiferromagnetic ordering below 12 K. A reversible capacity in excess of 80 mAh/g was obtained with good rate kinetics and cycling stability over 50 cycles. Using a synergistic approach combining experimental and ab initio DFT analysis, the structural, magnetic, electronic, and electrochemical properties and the structural limitation to extract full capacity have been described. PMID- 26931643 TI - Rare Helicobacter pylori Virulence Genotypes in Bhutan. AB - Both the prevalence of Helicobacter pylori infection and the incidence of gastric cancer are high in Bhutan. The high incidence of atrophic gastritis and gastric cancer suggest the phylogeographic origin of an infection with a more virulent strain of H. pylori. More than 90% of Bhutanese strains possessed the highly virulent East Asian-type CagA and all strains had the most virulent type of vacA (s1 type). More than half also had multiple repeats in East Asian-type CagA, which are rare in other countries and are reported characteristictly found in assciation with atrophic gastritis and gastric cancer consistent with Bhutanese strains having multiple H. pylori virulence factors associated with an increase in gastric cancer risk. Phylogeographic analyses showed that most Bhutanese strains belonged to the East Asian population type with some strains (17.5%) sharing East Asian and Amerindian components. Only 9.5% belonged to the European type consistant with H. pylori in Bhutan representing an intermediate evolutionary stage between H. pylori from European and East Asian countries. PMID- 26931645 TI - Dermatophytosis: fluorostaining enhances speed and sensitivity in direct microscopy of skin, nail and hair specimens from dermatology outpatients. AB - Direct microscopy of keratinised specimens is a standard screening procedure that assists clinicians to differentiate true superficial mycoses from non-fungal disorders of the skin, nail and hair. Most clinical dermatologists use bright field microscopy when searching for dermatophyte fungi in clinical samples while laboratory-based mycologists increasingly favour fluorescence microscopy in order to optimise visualisation of fungal elements. This study compared the validity and speediness of fluorescence microscopy vs. conventional light microscopy when screening for fungi in 206 dermatological samples from dermatology outpatients. Both senior dermatologist and a less experienced investigator (medical student) attained high and comparable levels of specificity (91.7-93.8%), positive predictive value (77.1-81.4%) and negative predictive value (83.7-89.9%) using either method. Fluorostaining with Blankophor prior to fluorescence microscopy increased the sensitivity by 22 +/- 1% as compared to light microscopy of unstained samples. For both investigators, the time required to identify fungal elements by the fluorescence-based technique was reduced by at least 50%, thus improving the performance of direct microscopy in the clinical setting. PMID- 26931646 TI - Comparison of descriptors for predicting selectivity of protein-imprinted polymers. AB - Molecular imprinting is a technique that is used to create artificial receptors by the formation of a polymer network around a template molecule, creating a molecularly imprinted polymer. These artificial receptors may be used in applications that require molecular recognition, such as enantioseparations, biosensors, artificial catalysis, drug delivery and others. Small molecules, such as drugs, have been imprinted with high efficiency and, combined with the low cost of preparation, molecularly imprinted polymers have acquired commercial usage. While attempts at imprinting proteins have been significantly less successful, the great potential of protein-imprinted polymers (PIPs) in medicine and industry attracted much research. Multifunctionality, conformational flexibility, large size of the proteins, and aqueous polymerization environment are some of the obstacles faced by protein imprinting. We explore the relation between PIP selectivity and the properties of the template and competitor proteins. A comprehensive statistical analysis of published studies reveals a statistically significant correlation between four protein descriptors and the corresponding selectivity of PIPs. Namely, a PIP will generally be more selective against large competitor proteins with a smooth surface, whose isoelectric point and aspect ratio are significantly different than those of the template protein. The size of the protein, as measured by its molecular weight, appears to be independent of the template protein characteristics. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26931647 TI - Emergence and accumulation of novel pathogens suppress an invasive species. AB - Emerging pathogens are a growing threat to human health, agriculture and the diversity of ecological communities but may also help control problematic species. Here we investigated the diversity, distribution and consequences of emerging fungal pathogens infecting an aggressive invasive grass that is rapidly colonising habitats throughout the eastern USA. We document the recent emergence and accumulation over time of diverse pathogens that are members of a single fungal genus and represent multiple, recently described or undescribed species. We also show that experimental suppression of these pathogens increased host performance in the field, demonstrating the negative effects of emerging pathogens on invasive plants. Our results suggest that invasive species can facilitate pathogen emergence and amplification, raising concerns about movement of pathogens among agricultural, horticultural, and wild grasses. However, one possible benefit of pathogen accumulation is suppression of aggressive invaders over the long term, potentially abating their negative impacts on native communities. PMID- 26931649 TI - Periscope: quantitative prediction of soluble protein expression in the periplasm of Escherichia coli. AB - Periplasmic expression of soluble proteins in Escherichia coli not only offers a much-simplified downstream purification process, but also enhances the probability of obtaining correctly folded and biologically active proteins. Different combinations of signal peptides and target proteins lead to different soluble protein expression levels, ranging from negligible to several grams per litre. Accurate algorithms for rational selection of promising candidates can serve as a powerful tool to complement with current trial-and-error approaches. Accordingly, proteomics studies can be conducted with greater efficiency and cost effectiveness. Here, we developed a predictor with a two-stage architecture, to predict the real-valued expression level of target protein in the periplasm. The output of the first-stage support vector machine (SVM) classifier determines which second-stage support vector regression (SVR) classifier to be used. When tested on an independent test dataset, the predictor achieved an overall prediction accuracy of 78% and a Pearson's correlation coefficient (PCC) of 0.77. We further illustrate the relative importance of various features with respect to different models. The results indicate that the occurrence of dipeptide glutamine and aspartic acid is the most important feature for the classification model. Finally, we provide access to the implemented predictor through the Periscope webserver, freely accessible at http://lightning.med.monash.edu/periscope/. PMID- 26931650 TI - High resolution single particle refinement in EMAN2.1. AB - EMAN2.1 is a complete image processing suite for quantitative analysis of grayscale images, with a primary focus on transmission electron microscopy, with complete workflows for performing high resolution single particle reconstruction, 2-D and 3-D heterogeneity analysis, random conical tilt reconstruction and subtomogram averaging, among other tasks. In this manuscript we provide the first detailed description of the high resolution single particle analysis pipeline and the philosophy behind its approach to the reconstruction problem. High resolution refinement is a fully automated process, and involves an advanced set of heuristics to select optimal algorithms for each specific refinement task. A gold standard FSC is produced automatically as part of refinement, providing a robust resolution estimate for the final map, and this is used to optimally filter the final CTF phase and amplitude corrected structure. Additional methods are in place to reduce model bias during refinement, and to permit cross-validation using other computational methods. PMID- 26931651 TI - Nonresonant, femtosecond laser vaporization and electrospray post-ionization mass spectrometry as a tool for biological tissue imaging. AB - An ambient mass spectrometry imaging (MSI) source is demonstrated with both high spatial and mass resolution that enables measurement of the compositional heterogeneity within a biological tissue sample. The source is based on nonresonant, femtosecond laser electrospray mass spectrometry (LEMS) coupled to a quadrupole time-of-flight (QTOF) mass analyzer. No matrix deposition and minimal sample preparation is necessary for the source. The laser, translation stage, and mass spectrometer are synchronized and controlled using a customized user interface. Single or multiple laser shots may be applied to each pixel. A scanning rate of 2.0s per pixel is achieved. Measurement of a patterned ink film indicates the potential of LEMS for ambient imaging with a lateral resolution of ~60MUm. Metabolites including sugar, anthocyanins and other small metabolites were successfully mapped from plant samples without oversampling using a spot size of 60*70MUm(2). Molecular identification of the detected analytes from the tissue was enabled by accurate mass measurement in conjunction with tandem mass spectrometry. Statistical analysis, non-negative matrix factorization and principle component analysis, were applied to the imaging data to extract regions with distinct and/or correlated spectral profiles. PMID- 26931653 TI - Genetic traits for hematogeneous tumor cell dissemination in cancer patients. AB - Metastatic relapse in patients with solid tumors is the consequence of cancer cells that disseminated to distant sites, adapted to the new microenvironment, and escaped systemic adjuvant therapy. There is increasing evidence that hematogeneous dissemination starts at an early stage of cancer progression with single tumor cells or cell clusters leaving the primary site and entering the blood circulation. These circulating tumor cells (CTCs) can extravasate into secondary tissues where they become disseminated tumor cells (DTCs). Patients might relapse years after initial resection of the primary tumor when DTCs become overt metastases. Current diagnostic strategies for stratification of therapies against metastatic cells focus on the primary tumor tissue. This approach is based on the availability of stored primary tumors obtained at primary surgery, but it ignores that the DTCs might have evolved over years, which can affect the antimetastatic drug response. However, taking biopsies from metastatic tissues is an invasive procedure, and multiple metastases located at different sites in an individual patient show marked genomic heterogeneity. Thus, capturing CTCs from the peripheral blood as a "liquid biopsy" has obvious advantages in particular when repeated sampling is required for monitoring therapies in cancer patients. However, the biology behind tumor cell dissemination and its contribution to metastatic progression in cancer patients is still subject to controversial discussions. This manuscript reviews current theories on the genetic traits behind the spread of CTCs and progression of DTCs into overt metastases. PMID- 26931654 TI - Molecular pathology in real time. AB - With the development of sophisticated individualized therapeutic approaches, the role of pathology in classification of tumors is enormously increasing. The solely morphological characterization of neoplastic process is no more sufficient for qualified decision on optimal therapeutic approach. Thus, morphologic diagnosis must be supplemented by molecular analysis of the lesion with emphasis on the detection of status of certain markers used as predictive factors for targeted therapy. Both intrinsic and acquired types of intratumor heterogeneity have an impact at various moments of cancer diagnostics and therapy. The primary heterogeneity of neoplastic tissue represents a significant problem in patients, where only limited biopsy samples from the primary tumor are available for diagnosis, such as core needle biopsy specimens in breast cancer, transthoracic or endobronchial biopsies in lung cancer, or endoscopic biopsies in gastric cancer. Detection of predictive markers may be influenced by this heterogeneity, and the marker detection may be falsely negative or (less probably) falsely positive. In addition, as these markers are often detected in the tissue samples from primary tumor, the differences between molecular features of the primary lesion and its metastases may be responsible for failure of systemic therapy in patients with discordant phenotype between primary and metastatic disease. The fact of tumor heterogeneity must be taken into consideration already in establishing pathological diagnosis. One has to be aware that limited biopsy specimen must not always be fully representative of the entire tumor volume. To overcome these limitations, there does not exist one single simple solution. Examination of more tissue (preference of surgical resection specimens over biopsies, whenever possible), use of ultra-sensitive methods able to identify the minute subclones as a source of possible resistance to treatment, and detection of secondary molecular events from the circulating tumor cells or circulating cell-free DNA are potential solutions how to handle this issue. PMID- 26931652 TI - An introduction to sample preparation and imaging by cryo-electron microscopy for structural biology. AB - Transmission electron microscopy (EM) is a versatile technique that can be used to image biological specimens ranging from intact eukaryotic cells to individual proteins >150kDa. There are several strategies for preparing samples for imaging by EM, including negative staining and cryogenic freezing. In the last few years, cryo-EM has undergone a 'resolution revolution', owing to both advances in imaging hardware, image processing software, and improvements in sample preparation, leading to growing number of researchers using cryo-EM as a research tool. However, cryo-EM is still a rapidly growing field, with unique challenges. Here, we summarise considerations for imaging of a range of specimens from macromolecular complexes to cells using EM. PMID- 26931655 TI - Genetic variants and expression study of FOXP3 gene in acute coronary syndrome in Iranian patients. AB - Acute coronary syndrome (ACS) is the most serious form of coronary artery disease. Inflammatory processes participate in different stages of this disorder. FOXP3 gene plays an important role for the development and function of regulatory T cells. Consequently, the expression level and polymorphisms of this gene have been studied in many immune related diseases. In the present study, we analysed the expression of FOXP3 as well as the association between two variants in this gene (rs3761548A/C and rs5902434del/ATT) and occurrence of ACS in Iranian patients. FOXP3 expression analysis showed a significant decrease in patients with ACS compared with controls (P = 0.029). In addition, a significant decrease has been detected in female patients compared with normal female subjects (P = 0.020). No significant change has been observed in FOXP3 expression in male patients compared with normal male subjects. In addition, no difference has been detected between ACS and normal subjects in combined genotype frequencies of both polymorphisms and the allele frequencies of rs5902434. However, rs3761548 C allele was more prevalent in controls compared with patients with ACS (P = 0.024). Consequently, our data demonstrated that FOXP3 expression is markedly decreased in female patients with ACS, which highlight the role of immune responses in plaque destabilization in such patients. Copyright (c) 2016 John Wiley & Sons, Ltd. SIGNIFICANCE PARAGRAPH: Considering the role of immune system in different stages of acute coronary syndrome (ACS), we evaluated the expression of FOXP3 gene as a master regulator of immune response in these patients compared with normal subjects. We detected a significant down-regulation of this gene in patients with ACS. Such decreased expression was more prominent in female patients, which implies the role of immune responses in plaque destabilization in such patients. PMID- 26931657 TI - Poultry feed based on protein hydrolysate derived from chrome-tanned leather solid waste: creating value from waste. AB - Leather industry generates huge amount of chrome-containing leather solid waste which creates major environment problems to tanners worldwide. Chrome-tanned leather solid waste is primarily chromium complex of collagen protein. The presence of chromium limits its protein application in animal feed industry. The purified protein hydrolysate with zero chromium could be used in poultry feed. In this study, an attempt has been made to assess performance of poultry with purified protein hydrolysate as a feed derived from chrome-tanned leather waste as partial replacement of soyabean meal as a sole source of protein for growing broiler chickens. Growth study was conducted to evaluate the effect of feeding protein hydrolysate on performance and physiochemical characteristics of meat of broiler chickens. Two experimental diets containing various levels of protein hydrolysate (EI-20 % and EII-30 %) were evaluated. The comparative study was performed as control with soyabean meal. Daily feed intake, body weight gain and feed conversion ratio were measured from day 8 to day 35. At the end of the study, birds were randomly selected and slaughtered to evaluate for physiochemical characteristics of meat. Diet had significant effects on feed intake and body weight gain. Birds fed with 20 and 30 % protein hydrolysate consumed 9.5 and 17.5 % higher amount of feed and gained 6.5 and 16.6 % higher than soyabean meal-fed birds. The current study produced evidence that protein hydrolysate can replace up to 75 % of soyabean meal in broiler diets without affecting either growth performance or meat characteristics. PMID- 26931658 TI - Plant tolerance to mercury in a contaminated soil is enhanced by the combined effects of humic matter addition and inoculation with arbuscular mycorrhizal fungi. AB - In a greenhouse pot experiment, lettuce plants (Lactuca sativa L.) were grown in a Hg-contaminated sandy soil with and without inoculation with arbuscular mycorrhizal fungi (AMF) (a commercial inoculum containing infective propagules of Rhizophagus irregularis and Funneliformis mosseae) amended with different rates of a humic acid (0, 1, and 2 g kg(-1) of soil), with the objective of verifying the synergistic effects of the two soil treatments on the Hg tolerance of lettuce plants. Our results indicated that the plant biomass was significantly increased by the combined effect of AMF and humic acid treatments. Addition of humic matter to soil boosted the AMF effect on improving the nutritional plant status, enhancing the pigment content in plant leaves, and inhibiting both Hg uptake and Hg translocation from the roots to the shoots. This was attributed not only to the Hg immobilization by stable complexes with HA and with extraradical mycorrhizal mycelium in soil and root surfaces but also to an improved mineral nutrition promoted by AMF. This work indicates that the combined use of AMF and humic acids may become a useful practice in Hg-contaminated soils to reduce Hg toxicity to crops. PMID- 26931656 TI - Energetic costs and implications of the intake of plant secondary metabolites on digestive and renal morphology in two austral passerines. AB - Seed-eating birds have a diet of high nutritional value; however, they must cope with plant secondary metabolites (PSM). We postulated that the detoxification capacity of birds is associated with a metabolic cost, given that the organs responsible for detoxification significantly contribute to energetic metabolism. We used an experimental approach to assess the effects of phenol-enriched diets on two passerines with different feeding habits: the omnivorous rufous-collared sparrow (Zonotrichia capensis) and the granivorous common diuca-finch (Diuca diuca). The birds were fed with one of three diets: control diet, supplemented with tannic acid, or supplemented with Opuntia ficus-indica phenolic extract (a common food of the sparrow but not the finch). After 5 weeks of exposure to the diets, we measured basal metabolic rates (BMR), energy intake, glucuronic acid output and digestive and kidney structure. In both species, detoxification capacity expressed as glucuronic acid output was higher in individuals consuming phenol-enriched diets compared to the control diet. However, whereas sparrows increase energy intake and intestinal mass when feeding on phenol-enriched diets, finches had lower intestinal mass and energy intake remains stable. Furthermore, sparrows had higher BMR on phenol-enriched diets compared to the control group, whereas in the finches BMR remains unchanged. Interspecific differences in response to phenols intake may be determined by the dietary habits of these species. While both species can feed on moderate phenolic diets for 5 weeks, energy costs may differ due to different responses in food intake and organ structure to counteract the effects of PSM intake. PMID- 26931659 TI - Air-sea exchange of gaseous mercury in the tropical coast (Luhuitou fringing reef) of the South China Sea, the Hainan Island, China. AB - The air-sea exchange of gaseous mercury (mainly Hg(0)) in the tropical ocean is an important part of the global Hg biogeochemical cycle, but the related investigations are limited. In this study, we simultaneously measured Hg(0) concentrations in surface waters and overlaying air in the tropical coast (Luhuitou fringing reef) of the South China Sea (SCS), Hainan Island, China, for 13 days on January-February 2015. The purpose of this study was to explore the temporal variation of Hg(0) concentrations in air and surface waters, estimate the air-sea Hg(0) flux, and reveal their influencing factors in the tropical coastal environment. The mean concentrations (+/-SD) of Hg(0) in air and total Hg (THg) in waters were 2.34 +/- 0.26 ng m(-3) and 1.40 +/- 0.48 ng L(-1), respectively. Both Hg(0) concentrations in waters (53.7 +/- 18.8 pg L(-1)) and Hg(0)/THg ratios (3.8 %) in this study were significantly higher than those of the open water of the SCS in winter. Hg(0) in waters usually exhibited a clear diurnal variation with increased concentrations in daytime and decreased concentrations in nighttime, especially in cloudless days with low wind speed. Linear regression analysis suggested that Hg(0) concentrations in waters were positively and significantly correlated to the photosynthetically active radiation (PAR) (R (2) = 0.42, p < 0.001). Surface waters were always supersaturated with Hg(0) compared to air (the degree of saturation, 2.46 to 13.87), indicating that the surface water was one of the atmospheric Hg(0) sources. The air-sea Hg(0) fluxes were estimated to be 1.73 +/- 1.25 ng m(-2) h( 1) with a large range between 0.01 and 6.06 ng m(-2) h(-1). The high variation of Hg(0) fluxes was mainly attributed to the greatly temporal variation of wind speed. PMID- 26931660 TI - Anomalous abundance and redistribution patterns of rare earth elements in soils of a mining area in Inner Mongolia, China. AB - The Bayan Obo Mine, the largest rare earth element (REE) deposit ever found in the world, has been mined for nearly 60 years for iron and rare earth elements. To assess the influences of mining activities on geochemical behavior of REEs in soils, 27 surface soil samples and three soil profile samples were collected from different directions in the vicinity of the mine area. The total concentrations of REEs in surface soils varied from 149.75 to 18,891.81 mg kg(-1) with an average value of 1906.12 mg kg(-1), which was apparently higher than the average values in China (181 mg kg(-1)). The order of the average concentrations of individual REEs in surface soils was similar to that in Bayan Obo ores, which confirmed that the concentration and distribution of REEs in the soils was influenced by the mining activities. The concentrations of single REE in the soil profiles showed a similar trend with depth with an increase at 0-25 cm section, then decreased and remained relatively stable in the deep part. The normalized curves inclined to the right side, showing the conspicuous fractionation between the light and heavy REEs, which supported by the North American Shale Composite (NASC) and Post-Archean Australian Shale (PAAS) normalized concentration ratios calculated for selected elements (La N /Yb N , La N /Sm N , Gd N /Yb N ). Slight positive Ce anomaly and negative Eu anomaly were also observed. PMID- 26931661 TI - Efficient degradation of rhodamine B using modified graphite felt gas diffusion electrode by electro-Fenton process. AB - The electro-Fenton (EF) process treatment of 0.1-M (rhodamine B) RhB solution was studied with different graphite cathode materials, and graphite felt (GF) was selected as a promising material in further investigation. Then, the degradation performances of gas diffusion electrode (GDE) and graphite felt (GF) were compared, and GDE was confirmed to be more efficient in RhB removal. The operational parameters such as Fe(2+) dosage and current density were optimized, and comparison among different modified methods-polytetrafluoroethylene-carbon black (PTFE-CB), polytetrafluoroethylene-carbon nanotube (PTFE-CNT), electrodeposition-CB, and electrodeposition-CNT-showed 98.49 % RhB removal by PTFE-CB-modified cathode in 0.05 M Na2SO4 at a current density of 50 A/m(2) and an air flow rate of 1 L/min after 20 min. Meanwhile, after cathode modified by PTFE-CB, the mineralization efficiency and mineralization current efficiency performed absolutely better than the pristine one. Cyclic voltammograms, SEM images, contact angles, and BET surface area were carried out to demonstrate stronger current responses and higher hydrophilicity of GF after modified. The value of biochemical oxygen demand/chemical oxygen demand (BOD5/COD) increased from 0.049 to 0.331 after 90-min treatment, suggesting the solution was biodegradable, and the modified cathode was confirmed to be stable after ten circle runs. Finally, a proposed degradation pathway of RhB was put forward. PMID- 26931662 TI - Assessment of trace metal contamination in the sea cucumber (Holothuria tubulosa) and sediments from the Dardanelles Strait (Turkey). AB - This study was performed to determine the concentrations of some trace metals (Cd, Cu, Pb, Ni, Zn, and Fe) in Holothuria tubuosa (Gmelin, 1788) belonging to Echinoderm species and in sediments that they live at three different stations (Gelibolu, Umur Bey/Lapseki, and Dardanos) on Dardanelles Strait between April 2013 and March 2014. The mean trace metal concentrations determined in H. tubulosa and sediment were as follows: Cd 0.18 mg/kg, Cu 2.43 mg/kg, Pb 2.09 mg/kg, Ni 14.58 mg/kg, Zn 16.86 mg/kg, and Fe 73.46 mg/kg and Cd 0.70 mg/kg, Cu 5.03 mg/kg, Pb 14.57 mg/kg, Ni 27.15 mg/kg, Zn 54.52 mg/kg, and Fe 3779.9 mg/kg, respectively. It was detected that the statistical difference between trace metals determined seasonally in muscle tissue of H. tubulosa was significant (p > 0.05). As a result of the study, it was detected that H. tubulosa is a bioindicator species in determining Ni trace metal in sediment. The results were compared to the limit values of National and International Food Safety, and it was detected that Cd and Ni concentrations measured in sediment were above LEL of Ni and Cd concentrations according to Sediment Quality Guidelines. PMID- 26931663 TI - Reconstruction of the pollution history of alkylphenols (4-tert-octylphenol, 4 nonylphenol) in the Baltic Sea. AB - This paper reports the reconstruction of the pollution history of 4-tert octylphenol (OP) and 4-nonylphenol (NP) in the Baltic Sea. Alkylphenols are endocrine-disrupting compound and therefore toxic to aquatic organisms. Sediment cores were collected from regions with relatively stable sedimentation conditions. The cores were dated by the (210)Pb method. The OP and NP were determined using HPLC-FL. The highest inventory of these compounds was observed in the Gotland Deep (610 MUg m(2) of NP and 47 MUg m(2) of OP) and the lowest-on the slope of the Gdansk Deep (24 MUg m(2) of NP and 16 MUg m(2) of OP). Such spatial distribution was probably, among other factors, the result of the uplift of the sea floor. The pollution trends of OP and NP in sediments coincided with the following: (1) the beginnings of eutrophication (1960s/1970s of the twentieth century) and (2) strong increase in the areal extent and volume of hypoxia and anoxia in the Baltic (present century). PMID- 26931665 TI - Performance of fully private and concessionary water and sewerage companies: a metafrontier approach. AB - As many countries have privatized their water industries, there is increasing interest in comparing the efficiency of public and private water and sewerage companies (WaSCs). However, previous studies have not considered that privatization can be carried out following two main approaches: fully private WaSCs, which involve the sale of utilities to the private sector, and concessionary WaSCs, in which only the operation of the services is privatized. This paper investigates, for the first time, the impact of both privatization approaches on the efficiency of WaSCs. In doing so, data envelopment analysis (DEA) was applied. However, unlike traditional models, the metafrontier concept was used in this research as it cannot be assumed that fully private and concessionary WaSCs share the same production frontier. The empirical application focused on the Chilean water industry as it was privatized from 1998 to 2004 following the two approaches described. The results suggest that the performance of fully private WaSCs is better than that of concessionary WaSCs. The conclusions of this study will be of great interest to water authorities worldwide facing the challenge of water industry privatization. PMID- 26931664 TI - Effect of alginate on the aggregation kinetics of copper oxide nanoparticles (CuO NPs): bridging interaction and hetero-aggregation induced by Ca(2.). AB - The stability of CuO nanoparticles (NPs) is expected to play a key role in the environmental risk assessment of nanotoxicity in aquatic systems. In this study, the effect of alginate (model polysaccharides) on the stability of CuO NPs in various environmentally relevant ionic strength conditions was investigated by using time-resolved dynamic light scattering. Significant aggregation of CuO NPs was observed in the presence of both monovalent and divalent cations. The critical coagulation concentrations (CCC) were 54.5 and 2.9 mM for NaNO3 and Ca(NO3)2, respectively. The presence of alginate slowed nano-CuO aggregation rates over the entire NaNO3 concentration range due to the combined electrostatic and steric effect. High concentrations of Ca(2+) (>6 mM) resulted in stronger adsorption of alginate onto CuO NPs; however, enhanced aggregation of CuO NPs occurred simultaneously under the same conditions. Spectroscopic analysis revealed that the bridging interaction of alginate with Ca(2+) might be an important mechanism for the enhanced aggregation. Furthermore, significant coagulation of the alginate molecules was observed in solutions of high Ca(2+) concentrations, indicating a hetero-aggregation mechanism between the alginate covered CuO NPs and the unabsorbed alginate. These results suggested a different aggregation mechanism of NPs might co-exist in aqueous systems enriched with natural organic matter, which should be taken into consideration in future studies. Graphical abstract Hetero-aggregation mechanism of CuO nanoparticles and alginate under high concentration of Ca(2.) PMID- 26931666 TI - How does nutritional state change during a subacute admission? Findings and implications for practice. AB - BACKGROUND/OBJECTIVES: Nutritional status influences patients' clinical and functional outcomes. The aims were to identify changes in nutritional state during subacute care and associated participant characteristics. SUBJECTS/METHODS: A longitudinal study was undertaken with consecutive patients admitted to subacute care wards during a 3-month period. Participants were recruited under a waiver of consent to reflect the usual demographic. Change in classification (malnourished, at risk of malnutrition, well nourished) of the full Mini Nutritional Assessment (full MNA) between admission and discharge was the primary outcome. Weight (kg), mid-arm and calf circumference (cm) change were secondary outcomes. Hand grip strength (kg) and fat-free mass (kg) (assessed using bioelectrical impedance analysis) were measured for a consenting subgroup. RESULTS: Participants (n=248, 36.7% male) had a median age of 80 years and a length of stay of 17 days. On admission, 29.1% were classified as malnourished. By discharge, nutritional classification remained stable for 62.0% of participants (n=132), declined for 10.3% (n=22) and improved for 27.7% (n=59, including 52.5% malnourished on admission). Impaired cognition (odds ratio (OR)=0.169, P=0.002) and higher full MNA score at admission (OR=0.870, P=0.001) reduced odds of improvement in full MNA. There was no change in hand grip strength (n=46), but there was a decline in mean fat-free mass (-1.1 kg, 95% confidence interval: -0.1 to -2.2 kg, P=0.043, n=24). CONCLUSIONS: Multidisciplinary care supports the nutritional state of most patients admitted to subacute care. Those with cognitive impairments or at risk of malnutrition were less likely to demonstrate improvement and may benefit from more intensive or tailored nutritional care. PMID- 26931667 TI - Glycaemic and insulin index of four common German breads. AB - BACKGROUND/OBJECTIVES: German-style breads are recommended as a lower glycaemic index (GI) alternative, yet little data is available. Our aim was to test the GI and insulin index (II) of four breads and rolls commonly consumed in Germany. SUBJECTS/METHODS: Four German bread products were tested for their GI and II in 12 healthy subjects according to the International Standard Organization guidelines. RESULTS: Only the wholemeal rye bread with visible intact grains and sunflower seeds was identified as low GI (GI=55). Both the wholemeal spelt wheat (GI=63) and the rye wheat sourdough bread (GI=62) were classified as medium GI, whereas soft pretzel was high GI (GI=80, P<0.05 compared with other products). The II of soft pretzels (II=102) was also highest and differed significantly from wholemeal rye (II=70) and rye sourdough bread (II=72) but not from wholemeal spelt wheat (II=77). CONCLUSIONS: Contrary to popular belief, these German-style breads are medium to high GI, with the exception of the rye bread with intact grains and seeds. The results highlight the need to test, rather than 'guestimate', the GI of local products, and develop a broader range of low-GI breads. PMID- 26931668 TI - Vegetarianism, low meat consumption and the risk of lung, postmenopausal breast and prostate cancer in a population-based cohort study. AB - BACKGROUND/OBJECTIVES: The few prospective studies that examined lung, female breast and prostate cancer risk in vegetarians have yielded mixed results, whereas none have studied the effects of low meat diets. Moreover, little is known about the explanatory role of (non-) dietary factors associated with these diets. SUBJECTS/METHODS: The Netherlands Cohort Study-Meat Investigation Cohort (NLCS-MIC)- is an analytical cohort of 11 082 individuals including 1133 self reported vegetarians (aged 55-69 years at baseline). At baseline (1986), subjects completed a questionnaire on dietary habits and other risk factors for cancer and were classified into vegetarians (n=691), pescetarians (n=389), 1 day per week (n=1388), 2-5 days per week (n=2965) and 6-7 days per week meat consumers (n=5649). RESULTS: After 20.3 years of follow-up, 279 lung, 312 postmenopausal breast and 399 prostate cancer cases (including 136 advanced) were available for analyses. After adjustment for confounding variables, we found no statistically significant association between meat consumption groups and the risk of lung cancer. As well, no significant associations were observed for postmenopausal breast and overall prostate cancer. After adjustment for confounders, individuals consuming meat 1 day per week were at a 75% increased risk of advanced prostate cancer compared with 6-7 days per week meat consumers (95%CI 1.03-2.97). CONCLUSIONS: Vegetarians, pescetarians and 1 day per week meat consumers did not have a reduced risk of lung, postmenopausal breast and overall prostate cancer compared with individuals consuming meat on a daily basis after taking confounders into account. PMID- 26931672 TI - Perspective: 4D ultrafast electron microscopy--Evolutions and revolutions. AB - In this Perspective, the evolutionary and revolutionary developments of ultrafast electron imaging are overviewed with focus on the "single-electron concept" for probing methodology. From the first electron microscope of Knoll and Ruska [Z. Phys. 78, 318 (1932)], constructed in the 1930s, to aberration-corrected instruments and on, to four-dimensional ultrafast electron microscopy (4D UEM), the developments over eight decades have transformed humans' scope of visualization. The changes in the length and time scales involved are unimaginable, beginning with the micrometer and second domains, and now reaching the space and time dimensions of atoms in matter. With these advances, it has become possible to follow the elementary structural dynamics as it unfolds in real time and to provide the means for visualizing materials behavior and biological functions. The aim is to understand emergent phenomena in complex systems, and 4D UEM is now central for the visualization of elementary processes involved, as illustrated here with examples from past achievements and future outlook. PMID- 26931670 TI - Food groups associated with a reduced risk of 15-year all-cause death. AB - BACKGROUND/OBJECTIVES: Long-term observational cohorts provide the opportunity to investigate the potential impact of dietary patterns on death. We aimed to investigate all-cause death according to the consumption of selected food groups, and then to identify those independently associated with reduced mortality. SUBJECTS/METHODS: Population survey of middle-aged men randomly selected in the period 1995-1997 from the general population of three French areas and followed over a median of 14.8 years. Dietary data were collected through a 3-day food record. Cox modeling was used to assess the risk of death according to selected foods groups after extensive adjustment for confounders, including a diet quality index. RESULTS: The study population comprised 960 men (mean age 55.5 +/-6.2 years). After a median follow-up of 14.8 (interquartile range 14.3-15.2) years, 150 (15.6%) subjects had died. Food groups that remained independently predictive of a lower risk of death after extensive adjustment were an above-median consumption of milk (adjusted relative risk: 0.61, 95% confidence interval (CI): 0.43-0.86, P-value=0.005), fruits and vegetables (0.68, 0.46-0.98, P-value=0.041) and a moderate consumption of yogurts and cottage cheese (0.50, 95% CI: 0.31 0.81, P-value=0.005), other cheeses (0.62, 0.39-0.97, P-value=0.036) and bread (0.57, 0.37-0.89, P-value=0.014). Besides, there was a nonsignificant trend for a higher risk of death associated with highest sodium intakes. CONCLUSIONS: Consumption of food groups that largely match recommendations is associated with a reduced risk of all-cause death in men. A diet providing moderate amounts of diverse food groups appears associated with the highest life expectancy. PMID- 26931669 TI - Plasma levels of marine n-3 fatty acids and cardiovascular risk markers in renal transplant recipients. AB - BACKGROUND/OBJECTIVES: Cardiovascular (CV) disease is the leading cause of death after renal transplantation. Marine n-3 polyunsaturated fatty acids (PUFAs) exert potential cardio-protective metabolic effects and might reduce CV morbidity and mortality in renal transplant recipients (RTRs). SUBJECTS/METHODS: In this cross sectional study of 1990 Norwegian RTRs, transplanted between 1999 and 2011, associations between plasma phospholipid marine n-3 PUFA levels and various CV risk markers at 10 weeks after transplant were evaluated. RESULTS: Higher plasma marine n-3 PUFA levels were associated with lower resting heart rate (rHR), lower fasting plasma glucose (fPG) levels, lower plasma triglyceride levels and higher plasma high-density lipoprotein (HDL) cholesterol levels. Plasma levels of eicosapentaenoic acid, but not docosahexaenoic acid, showed a positive association with plasma HDL cholesterol levels. Plasma marine n-3 PUFA levels were not associated with plasma low-density lipoprotein cholesterol levels, pulse wave velocity or systolic and diastolic blood pressure. A negative association between plasma marine n-3 PUFA levels and CV mortality was weakened by additional adjustment for plasma triglyceride levels and rHR. The ratio of n-6 to n-3 PUFAs showed similar associations with CV risk markers as absolute plasma marine n-3 PUFA levels. CONCLUSIONS: This is the first study in RTRs showing that marine n-3 PUFAs are negatively associated with rHR and fPG in addition to beneficial effects on plasma HDL cholesterol and triglyceride levels. Especially, effects on autonomic nervous function and triglyceride metabolism might contribute to explain the lower CV mortality risk with higher plasma marine n-3 PUFA levels previously shown in this cohort. PMID- 26931673 TI - Communication: Role of short chain branching in polymer structure and dynamics. AB - A comprehensive understanding of chain-branching effects, essential for establishing general knowledge of the structure-property-phenomenon relationship in polymer science, has not yet been found, due to a critical lack of knowledge on the role of short-chain branches, the effects of which have mostly been neglected in favor of the standard entropic-based concepts of long polymers. Here, we show a significant effect of short-chain branching on the structural and dynamical properties of polymeric materials, and reveal the molecular origins behind the fundamental role of short branches, via atomistic nonequilibrium molecular dynamics and mesoscopic Brownian dynamics by systematically varying the strength of the mobility of short branches. We demonstrate that the fast random Brownian kinetics inherent to short branches plays a key role in governing the overall structure and dynamics of polymers, leading to a compact molecular structure and, under external fields, to a lesser degree of structural deformation of polymer, to a reduced shear-thinning behavior, and to a smaller elastic stress, compared with their linear analogues. Their fast dynamical nature being unaffected by practical flow fields owing to their very short characteristic time scale, short branches would substantially influence (i.e., facilitate) the overall relaxation behavior of polymeric materials under various flowing conditions. PMID- 26931671 TI - Hypovitaminosis D in pregnancy in the Mediterranean region: a systematic review. AB - Despite high levels of sunshine, maternal hypovitaminosis D during pregnancy is prevalent in the Mediterranean region. The aim of this study is to systematically review trials that investigated vitamin D concentrations during pregnancy in this region, in order to determine predictors of hypovitaminosis D and explain this phenomenon. After applying inclusion/exclusion criteria, 15 studies were entered into the systematic review involving 2649 pregnant women and 820 neonates. The main outcome was maternal vitamin D status, assessed by serum 25-hydroxy-vitamin D (25(OH)D) concentrations. Possible predictors of the outcome included maternal age, body mass index (BMI), race, socioeconomic status, skin type, gestational age, sun exposure, calcium and vitamin D intake and supplementation, smoking status, parity and season of delivery. Studies differed widely in vitamin D deficiency criteria, method of measurement and outcomes. The prevalence of vitamin D insufficiency ranges from 9.3 to 41.4%, whereas that of vitamin D deficiency from 22.7 to 90.3%. A positive association with 25(OH)D concentrations exists for light skin color, white race, uncovered dressing pattern, maternal vitamin D supplementation and season of gestation (spring/summer). An inverse association exists for BMI and gestational age, whereas data for smoking and socioeconomic status are controversial. We concluded that vitamin D deficiency in pregnancy seems to be quite common, even in the Mediterranean region. Racial, social and cultural habits, as well as the absence of preventive supplementation/dietary strategies, seem to negate the benefits of sun exposure. PMID- 26931674 TI - Communication: Resonance reaction in diffusion-influenced bimolecular reactions. AB - We investigate the influence of a stochastically fluctuating step-barrier potential on bimolecular reaction rates by exact analytical theory and stochastic simulations. We demonstrate that the system exhibits a new "resonant reaction" behavior with rate enhancement if an appropriately defined fluctuation decay length is of the order of the system size. Importantly, we find that in the proximity of resonance, the standard reciprocal additivity law for diffusion and surface reaction rates is violated due to the dynamical coupling of multiple kinetic processes. Together, these findings may have important repercussions on the correct interpretation of various kinetic reaction problems in complex systems, as, e.g., in biomolecular association or catalysis. PMID- 26931675 TI - Molecular finite-size effects in stochastic models of equilibrium chemical systems. AB - The reaction-diffusion master equation (RDME) is a standard modelling approach for understanding stochastic and spatial chemical kinetics. An inherent assumption is that molecules are point-like. Here, we introduce the excluded volume reaction-diffusion master equation (vRDME) which takes into account volume exclusion effects on stochastic kinetics due to a finite molecular radius. We obtain an exact closed form solution of the RDME and of the vRDME for a general chemical system in equilibrium conditions. The difference between the two solutions increases with the ratio of molecular diameter to the compartment length scale. We show that an increase in the fraction of excluded space can (i) lead to deviations from the classical inverse square root law for the noise strength, (ii) flip the skewness of the probability distribution from right to left-skewed, (iii) shift the equilibrium of bimolecular reactions so that more product molecules are formed, and (iv) strongly modulate the Fano factors and coefficients of variation. These volume exclusion effects are found to be particularly pronounced for chemical species not involved in chemical conservation laws. Finally, we show that statistics obtained using the vRDME are in good agreement with those obtained from Brownian dynamics with excluded volume interactions. PMID- 26931676 TI - On the connection between dissipative particle dynamics and the Ito-Stratonovich dilemma. AB - Dissipative Particle Dynamics (DPD) is a popular simulation model for investigating hydrodynamic behavior of systems with non-negligible equilibrium thermal fluctuations. DPD employs soft core repulsive interactions between the system particles, thus allowing them to overlap. This supposedly permits relatively large integration time steps, which is an important feature for simulations on large temporal scales. In practice, however, an increase in the integration time step leads to increasingly larger systematic errors in the sampling statistics. Here, we demonstrate that the prime origin of these systematic errors is the multiplicative nature of the thermal noise term in Langevin's equation, i.e., the fact that it depends on the instantaneous coordinates of the particles. This lead to an ambiguity in the interpretation of the stochastic differential Langevin equation, known as the Ito-Stratonovich dilemma. Based on insights from previous studies of the dilemma, we propose a novel algorithm for DPD simulations exhibiting almost an order of magnitude improvement in accuracy, and nearly twice the efficiency of commonly used DPD Langevin thermostats. PMID- 26931677 TI - Hilbert space renormalization for the many-electron problem. AB - Renormalization is a powerful concept in the many-body problem. Inspired by the highly successful density matrix renormalization group (DMRG) algorithm, and the quantum chemical graphical representation of configuration space, we introduce a new theoretical tool: Hilbert space renormalization, to describe many-electron correlations. While in DMRG, the many-body states in nested Fock subspaces are successively renormalized, in Hilbert space renormalization, many-body states in nested Hilbert subspaces undergo renormalization. This provides a new way to classify and combine configurations. The underlying wavefunction Ansatz, namely, the Hilbert space matrix product state (HS-MPS), has a very rich and flexible mathematical structure. It provides low-rank tensor approximations to any configuration interaction (CI) space through restricting either the "physical indices" or the coupling rules in the HS-MPS. Alternatively, simply truncating the "virtual dimension" of the HS-MPS leads to a family of size-extensive wave function Ansatze that can be used efficiently in variational calculations. We make formal and numerical comparisons between the HS-MPS, the traditional Fock space MPS used in DMRG, and traditional CI approximations. The analysis and results shed light on fundamental aspects of the efficient representation of many electron wavefunctions through the renormalization of many-body states. PMID- 26931678 TI - Asymptotic behavior and interpretation of virtual states: The effects of confinement and of basis sets. AB - A real-space high order finite difference method is used to analyze the effect of spherical domain size on the Hartree-Fock (and density functional theory) virtual eigenstates. We show the domain size dependence of both positive and negative virtual eigenvalues of the Hartree-Fock equations for small molecules. We demonstrate that positive states behave like a particle in spherical well and show how they approach zero. For the negative eigenstates, we show that large domains are needed to get the correct eigenvalues. We compare our results to those of Gaussian basis sets and draw some conclusions for real-space, basis sets, and plane-waves calculations. PMID- 26931679 TI - Optimisation of simulations of stochastic processes by removal of opposing reactions. AB - Models invoking the chemical master equation are used in many areas of science, and, hence, their simulation is of interest to many researchers. The complexity of the problems at hand often requires considerable computational power, so a large number of algorithms have been developed to speed up simulations. However, a drawback of many of these algorithms is that their implementation is more complicated than, for instance, the Gillespie algorithm, which is widely used to simulate the chemical master equation, and can be implemented with a few lines of code. Here, we present an algorithm which does not modify the way in which the master equation is solved, but instead modifies the transition rates. It works for all models in which reversible reactions occur by replacing such reversible reactions with effective net reactions. Examples of such systems include reaction diffusion systems, in which diffusion is modelled by a random walk. The random movement of particles between neighbouring sites is then replaced with a net random flux. Furthermore, as we modify the transition rates of the model, rather than its implementation on a computer, our method can be combined with existing algorithms that were designed to speed up simulations of the stochastic master equation. By focusing on some specific models, we show how our algorithm can significantly speed up model simulations while maintaining essential features of the original model. PMID- 26931680 TI - Unbiased diffusion in two-dimensional channels with corrugated walls. AB - This paper deals with diffusion of point particles in linearly corrugated two dimensional channels. Such geometry allows one to obtain an approximate analytical expression that gives the particle effective diffusivity as a function of the geometric parameters of the channel. To establish its accuracy and the range of applicability, the expression is tested against Brownian dynamics simulation results. The test shows that the expression works very well for long channel periods, but fails when the period is not long enough compared to the minimum width of the channel. To fix this deficiency, we propose a simple empirical correction to the analytical expression. The resulting corrected expression for the effective diffusivity is in excellent agreement with the simulation results for all values of the channel period. PMID- 26931681 TI - Visualization and analysis of the Kohn-Sham kinetic energy density and its orbital-free description in molecules. AB - We visualize the Kohn-Sham kinetic energy density (KED) and the ingredients--the electron density, its gradient, and Laplacian--used to construct orbital-free models of it, for the AE6 test set of molecules. These are compared to related quantities used in metaGGA's, to characterize two important limits--the gradient expansion and the localized-electron limit typified by the covalent bond. We find the second-order gradient expansion of the KED to be a surprisingly successful predictor of the exact KED, particularly at low densities where this approximation fails for exchange. This contradicts the conjointness conjecture that the optimal enhancement factors for orbital-free kinetic and exchange energy functionals are closely similar in form. In addition we find significant problems with a recent metaGGA-level orbital-free KED, especially for regions of strong electron localization. We define an orbital-free description of electron localization and a revised metaGGA that improves upon atomization energies significantly. PMID- 26931682 TI - Developments in stochastic coupled cluster theory: The initiator approximation and application to the uniform electron gas. AB - We describe further details of the stochastic coupled cluster method and a diagnostic of such calculations, the shoulder height, akin to the plateau found in full configuration interaction quantum Monte Carlo. We describe an initiator modification to stochastic coupled cluster theory and show that initiator calculations can at times be extrapolated to the unbiased limit. We apply this method to the 3D 14-electron uniform electron gas and present complete basis set limit values of the coupled cluster singles and doubles (CCSD) and previously unattainable coupled cluster singles and doubles with perturbative triples (CCSDT) correlation energies for up to r(s) = 2, showing a requirement to include triple excitations to accurately calculate energies at high densities. PMID- 26931683 TI - Molecular energies from an incremental fragmentation method. AB - The systematic molecular fragmentation method by Collins and Deev [J. Chem. Phys. 125, 104104 (2006)] has been used to calculate total energies and relative conformational energies for a number of small and extended molecular systems. In contrast to the original approach by Collins, we have tested the accuracy of the fragmentation method by utilising an incremental scheme in which the energies at the lowest level of the fragmentation are calculated on an accurate quantum chemistry level while lower-cost methods are used to correct the low-level energies through a high-level fragmentation. In this work, the fragment energies at the lowest level of fragmentation were calculated using the random-phase approximation (RPA) and two recently developed extensions to the RPA while the incremental corrections at higher levels of the fragmentation were calculated using standard density functional theory (DFT) methods. The complete incremental fragmentation method has been shown to reproduce the supermolecule results with a very good accuracy, almost independent on the molecular type, size, or type of decomposition. The fragmentation method has also been used in conjunction with the DFT-SAPT (symmetry-adapted perturbation theory) method which enables a breakdown of the total nonbonding energy contributions into individual interaction energy terms. Finally, the potential problems of the method connected with the use of capping hydrogen atoms are analysed and two possible solutions are supplied. PMID- 26931684 TI - Can quantum transition state theory be defined as an exact t = 0+ limit? AB - The definition of the classical transition state theory (TST) as a t -> 0+ limit of the flux-side time correlation function relies on the assumption that simultaneous measurement of population and flux is a well defined physical process. However, the noncommutativity of the two measurements in quantum mechanics makes the extension of such a concept to the quantum regime impossible. For this reason, quantum TST (QTST) has been generally accepted as any kind of quantum rate theory reproducing the TST in the classical limit, and there has been a broad consensus that no unique QTST retaining all the properties of TST can be defined. Contrary to this widely held view, Hele and Althorpe (HA) [J. Chem. Phys. 138, 084108 (2013)] recently suggested that a true QTST can be defined as the exact t -> 0+ limit of a certain kind of quantum flux-side time correlation function and that it is equivalent to the ring polymer molecular dynamics (RPMD) TST. This work seeks to question and clarify certain assumptions underlying these suggestions and their implications. First, the time correlation function used by HA as a starting expression is not related to the kinetic rate constant by virtue of linear response theory, which is the first important step in relating a t = 0+ limit to a physically measurable rate. Second, a theoretical analysis calls into question a key step in HA's proof which appears not to rely on an exact quantum mechanical identity. The correction of this makes the true t = 0+ limit of HA's QTST different from the RPMD-TST rate expression, but rather equal to the well-known path integral quantum transition state theory rate expression for the case of centroid dividing surface. An alternative quantum rate expression is then formulated starting from the linear response theory and by applying a recently developed formalism of real time dynamics of imaginary time path integrals [S. Jang, A. V. Sinitskiy, and G. A. Voth, J. Chem. Phys. 140, 154103 (2014)]. It is shown that the t -> 0+ limit of the new rate expression vanishes in the exact quantum limit. PMID- 26931685 TI - Interatomic Coulombic decay widths of helium trimer: A diatomics-in-molecules approach. AB - We report a new method to compute the Interatomic Coulombic Decay (ICD) widths for large clusters which relies on the combination of the projection-operator formalism of scattering theory and the diatomics-in-molecules approach. The total and partial ICD widths of a cluster are computed from the energies and coupling matrix elements of the atomic and diatomic fragments of the system. The method is applied to the helium trimer and the results are compared to fully ab initio widths. A good agreement between the two sets of data is shown. Limitations of the present method are also discussed. PMID- 26931686 TI - Solvent activity in electrolyte solutions from molecular simulation of the osmotic pressure. AB - A method for determining the activity of the solvent in electrolyte solutions by molecular dynamics simulations is presented. The electrolyte solution is simulated in contact with the pure solvent. Between the two phases, there is a virtual membrane, which is permeable only for the solvent. In the simulation, this is realized by an external field which acts only on the solutes and confines them to a part of the simulation volume. The osmotic pressure, i.e., the pressure difference between both phases, is obtained with high accuracy from the force on the membrane, so that reliable data on the solvent activity can be determined. The acronym of the new method is therefore OPAS (osmotic pressure for activity of solvents). The OPAS method is verified using tests of varying complexity. This includes a comparison of results from the OPAS method for aqueous NaCl solutions to results from the literature which were obtained with other molecular simulation methods. Favorable agreement is observed not only for the solvent activity but also for the activity coefficient of NaCl, which is obtained by application of the Gibbs-Duhem equation. PMID- 26931687 TI - An investigation of one- versus two-dimensional semiclassical transition state theory for H atom abstraction and exchange reactions. AB - We investigate which terms in Reduced-Dimensionality Semiclassical Transition State Theory (RD SCTST) contribute most significantly in rate constant calculations of hydrogen extraction and exchange reactions of hydrocarbons. We also investigate the importance of deep tunneling corrections to the theory. In addition, we introduce a novel formulation of the theory in Jacobi coordinates. For the reactions of H atoms with methane, ethane, and cyclopropane, we find that a one-dimensional (1-D) version of the theory without deep tunneling corrections compares well with 2-D SCTST results and accurate quantum scattering results. For the "heavy-light-heavy" H atom exchange reaction between CH3 and CH4, deep tunneling corrections are needed to yield 1-D results that compare well with 2-D results. The finding that accurate rate constants can be obtained from derivatives of the potential along only one dimension further validates RD SCTST as a computationally efficient yet accurate rate constant theory. PMID- 26931688 TI - General formulation of vibronic spectroscopy in internal coordinates. AB - Our general platform integrating time-independent and time-dependent evaluations of vibronic effects at the harmonic level for different kinds of absorption and emission one-photon, conventional and chiral spectroscopies has been extended to support various sets of internal coordinates. Thanks to the implementation of analytical first and second derivatives of different internal coordinates with respect to cartesian ones, both vertical and adiabatic models are available, with the inclusion of mode mixing and, possibly, Herzberg-Teller contributions. Furthermore, all supported non-redundant sets of coordinates are built from a fully automatized algorithm using only a primitive redundant set derived from a bond order-based molecular topology. Together with conventional stretching, bending, and torsion coordinates, the availability of additional coordinates (including linear and out-of-plane bendings) allows a proper treatment of specific systems, including, for instance, inter-molecular hydrogen bridges. A number of case studies are analysed, showing that cartesian and internal coordinates are nearly equivalent for semi-rigid systems not experiencing significant geometry distortions between initial and final electronic states. At variance, delocalized (possibly weighted) internal coordinates become much more effective than their cartesian counterparts for flexible systems and/or in the presence of significant geometry distortions accompanying electronic transitions. PMID- 26931689 TI - Multiscale simulation of ideal mixtures using smoothed dissipative particle dynamics. AB - Smoothed dissipative particle dynamics (SDPD) [P. Espanol and M. Revenga, Phys. Rev. E 67, 026705 (2003)] is a thermodynamically consistent particle-based continuum hydrodynamics solver that features scale-dependent thermal fluctuations. We obtain a new formulation of this stochastic method for ideal two component mixtures through a discretization of the advection-diffusion equation with thermal noise in the concentration field. The resulting multicomponent approach is consistent with the interpretation of the SDPD particles as moving volumes of fluid and reproduces the correct fluctuations and diffusion dynamics. Subsequently, we provide a general multiscale multicomponent SDPD framework for simulations of molecularly miscible systems spanning length scales from nanometers to the non-fluctuating continuum limit. This approach reproduces appropriate equilibrium properties and is validated with simulation of simple one dimensional diffusion across multiple length scales. PMID- 26931690 TI - Numerical and exact kinetic energy operator using Eckart conditions with one or several reference geometries: Application to HONO. AB - For the computation of rovibrational levels and their spectroscopic intensities, the Eckart conditions are essential to achieve the optimal separation between rotation and vibration. Dymarsky and Kudin [J. Chem. Phys. 122, 124103 (2005)] proposed a procedure for a simplified calculation of the Eckart rotation matrix. In the present work, we have adapted their approach to obtain a kinetic energy operator in curvilinear coordinates using a numerical but exact procedure without resorting to finite differences. Furthermore, we have modified this approach for the study of molecular systems with several minima, for which several Eckart reference geometries are required. The HONO molecular system has been used to show the efficiency of our implementation. Using the Eckart conditions with multi reference geometries allows for a calculation of the rotational levels as well as frequencies and intensities of the infrared spectra of both HONO isomers with a single calculation. PMID- 26931691 TI - A hierarchy of local coupled cluster singles and doubles response methods for ionization potentials. AB - We present a hierarchy of local coupled cluster (CC) linear response (LR) methods to calculate ionization potentials (IPs), i.e., excited states with one electron annihilated relative to a ground state reference. The time-dependent perturbation operator V(t), as well as the operators related to the first-order (with respect to V(t)) amplitudes and multipliers, thus are not number conserving and have half integer particle rank m. Apart from calculating IPs of neutral molecules, the method offers also the possibility to study ground and excited states of neutral radicals as ionized states of closed-shell anions. It turns out that for comparable accuracy IPs require a higher-order treatment than excitation energies; an IP-CC LR method corresponding to CC2 LR or the algebraic diagrammatic construction scheme through second order performs rather poorly. We therefore systematically extended the order with respect to the fluctuation potential of the IP-CC2 LR Jacobian up to IP-CCSD LR, keeping the excitation space of the first-order (with respect to V(t)) cluster operator restricted to the m=1/2?3/2 subspace and the accuracy of the zero-order (ground-state) amplitudes at the level of CC2 or MP2. For the more expensive diagrams beyond the IP-CC2 LR Jacobian, we employ local approximations. The implemented methods are capable of treating large molecular systems with hundred atoms or more. PMID- 26931692 TI - Alternative definitions of the frozen energy in energy decomposition analysis of density functional theory calculations. AB - In energy decomposition analysis (EDA) of intermolecular interactions calculated via density functional theory, the initial supersystem wavefunction defines the so-called "frozen energy" including contributions such as permanent electrostatics, steric repulsions, and dispersion. This work explores the consequences of the choices that must be made to define the frozen energy. The critical choice is whether the energy should be minimized subject to the constraint of fixed density. Numerical results for Ne2, (H2O)2, BH3-NH3, and ethane dissociation show that there can be a large energy lowering associated with constant density orbital relaxation. By far the most important contribution is constant density inter-fragment relaxation, corresponding to charge transfer (CT). This is unwanted in an EDA that attempts to separate CT effects, but it may be useful in other contexts such as force field development. An algorithm is presented for minimizing single determinant energies at constant density both with and without CT by employing a penalty function that approximately enforces the density constraint. PMID- 26931693 TI - Impact of the intermixed phase and the channel network on the carrier mobility of nanostructured solar cells. AB - We analyzed the impact of the complex channel network of donor and acceptor domains in nanostructured solar cells on the mobility of the charge carriers moving by thermally activated hopping. Particular attention was given to the so called intermixed phase, or interface roughness, that has recently been shown to promote an increase in the cell efficiency. The domains were obtained from a Monte Carlo simulation of a two-species lattice gas. We generated domain morphologies with controllable channel size and interface roughness. The field and density dependence of the carrier hopping mobility in different morphologies was obtained by solving a master equation. Our results show that the mobility decreases with roughness and increases with typical channel sizes. The deleterious effect of the roughness on the mobility is quite dramatic at low carrier densities and high fields. The complex channel network is shown to be directly responsible for two potentially harmful effects to the cell performance: a remarkable decrease of the mobility with increasing field and the accumulation of charge at the domains interface, which leads to recombination losses. PMID- 26931694 TI - Visualizing competing intersystem crossing and internal conversion with a complementary measurement. AB - A complementary measurement method based on a home-built double-sided velocity map imaging setup is introduced. This method can simultaneously obtain time resolved photoelectron imaging and fragment ion imaging. It has been successfully applied to investigate the ultrafast dynamics of the second singlet electronically excited state (S2) in m-xylene. Time-resolved photoelectron and ion signals derived from the initial populated S2 state are tracked following two photon absorption of a pump pulse. Time-of-flight mass spectra (TOFMS) show that there are dominant parent ions and one fragment ions with methyl loss during such a process. According to the measured photoelectron images and fragment ions images, transient kinetic energy distributions and angular distributions of the generated photoelectrons and fragments are obtained and analyzed. Compared to stand-alone photoelectron imaging, the obtained fragment ion imaging is powerful for further understanding the mechanisms especially when the dissociation occurs during the pump-probe ionization. Two competing channels intersystem crossing T3< S2 and internal conversion S1<-S2 are attributed to the deactivation of the S2 state. A lifetime of ~50 fs for the initially excited S2 state, of ~276 fs for the secondary populated S1 state, and of 5.76 ps for the T3 state is inferred. PMID- 26931695 TI - Nuclear magnetic relaxation by the dipolar EMOR mechanism: General theory with applications to two-spin systems. AB - In aqueous systems with immobilized macromolecules, including biological tissue, the longitudinal spin relaxation of water protons is primarily induced by exchange-mediated orientational randomization (EMOR) of intra- and intermolecular magnetic dipole-dipole couplings. We have embarked on a systematic program to develop, from the stochastic Liouville equation, a general and rigorous theory that can describe relaxation by the dipolar EMOR mechanism over the full range of exchange rates, dipole coupling strengths, and Larmor frequencies. Here, we present a general theoretical framework applicable to spin systems of arbitrary size with symmetric or asymmetric exchange. So far, the dipolar EMOR theory is only available for a two-spin system with symmetric exchange. Asymmetric exchange, when the spin system is fragmented by the exchange, introduces new and unexpected phenomena. Notably, the anisotropic dipole couplings of non-exchanging spins break the axial symmetry in spin Liouville space, thereby opening up new relaxation channels in the locally anisotropic sites, including longitudinal transverse cross relaxation. Such cross-mode relaxation operates only at low fields; at higher fields it becomes nonsecular, leading to an unusual inverted relaxation dispersion that splits the extreme-narrowing regime into two sub regimes. The general dipolar EMOR theory is illustrated here by a detailed analysis of the asymmetric two-spin case, for which we present relaxation dispersion profiles over a wide range of conditions as well as analytical results for integral relaxation rates and time-dependent spin modes in the zero-field and motional-narrowing regimes. The general theoretical framework presented here will enable a quantitative analysis of frequency-dependent water-proton longitudinal relaxation in model systems with immobilized macromolecules and, ultimately, will provide a rigorous link between relaxation-based magnetic resonance image contrast and molecular parameters. PMID- 26931696 TI - Experimental and theoretical cross sections for positron scattering from the pentane isomers. AB - Isomerism is ubiquitous in chemistry, physics, and biology. In atomic and molecular physics, in particular, isomer effects are well known in electron impact phenomena; however, very little is known for positron collisions. Here we report on a set of experimental and theoretical cross sections for low-energy positron scattering from the three structural isomers of pentane: normal-pentane, isopentane, and neopentane. Total cross sections for positron scattering from normal-pentane and isopentane were measured at the University of Trento at incident energies between 0.1 and 50 eV. Calculations of the total cross sections, integral cross sections for elastic scattering, positronium formation, and electronic excitations plus direct ionization, as well as elastic differential cross sections were computed for all three isomers between 1 and 1000 eV using the independent atom model with screening corrected additivity rule. No definitive evidence of a significant isomer effect in positron scattering from the pentane isomers appears to be present. PMID- 26931697 TI - Electron impact ionization and multiphoton ionization of doped superfluid helium droplets: A comparison. AB - We compare characteristics of electron impact ionization (EI) and multiphoton ionization (MPI) of doped superfluid helium droplets using the same droplet source. Selected dopant ion fragments from the two ionization schemes demonstrate different dependence on the doping pressure, which could be attributed to the different ionization mechanisms. While EI directly ionizes helium atoms in a droplet therefore has higher yields for bigger droplets (within a limited size range), MPI is insensitive to the helium in a droplet and is only dependent on the number of dopant molecules. The optimal timing of the ionization pulse also varies with the doping pressure, implying a velocity slip among different sized droplets. Calculations of the doping statistics and ionization probabilities qualitatively agree with the experimental data. Our results offer a word of caution in interpreting the pressure and timing dependence of superfluid helium droplets, and we also devise a scheme in achieving a high degree of doping while limiting the contribution of dopant clusters. PMID- 26931698 TI - Absorption, autoionization, and predissociation in molecular hydrogen: High resolution spectroscopy and multichannel quantum defect theory. AB - Absorption and photoionization spectra of H2 have been recorded at a resolution of 0.09 and 0.04 cm(-1), respectively, between 125,600 cm(-1) and 126,000 cm(-1). The observed Rydberg states belong to series (n = 10 - 14) converging on the first vibrationally excited level of the X (2)Sigma(g)(+) state of H2(+), and of lower members of series converging on higher vibrational levels. The observed resonances are characterized by the competition between autoionization, predissociation, and fluorescence. The unprecedented resolution of the present experimental data leads to a full characterization of the predissociation/autoionization profiles of many resonances that had not been resolved previously. Multichannel quantum defect theory is used to predict the line positions, widths, shapes, and intensities of the observed spectra and is found to yield quantitative agreement using previously determined quantum defect functions as the unique set of input parameters. PMID- 26931699 TI - Electronic spectra of 2- and 3-tolunitrile in the gas phase. II. Geometry changes from Franck-Condon fits of fluorescence emission spectra. AB - We determined the changes of the geometries of 2- and 3-tolunitrile upon excitation to the lowest excited singlet states from Franck-Condon fits of the vibronic intensities in several fluorescence emission spectra and of the rotational constant changes upon excitation. These structural changes can be connected to the altered electron distribution in the molecules and are compared to the results of ab initio calculations. We show how the torsional barriers of the methyl groups in both components are used as probe of the molecular changes upon electronic excitation. PMID- 26931700 TI - High resolution spectroscopy of six SOCl2 isotopologues from the microwave to the far-infrared. AB - Despite its potential role as an atmospheric pollutant, thionyl chloride, SOCl2, remains poorly characterized in the gas phase. In this study, the pure rotational and ro-vibrational spectra of six isotopologues of this molecule, all detected in natural abundance, have been extensively studied from the cm-wave band to the far infrared region by means of three complementary techniques: chirped-pulse Fourier transform microwave spectroscopy, sub-millimeter-wave spectroscopy using frequency multiplier chain, and synchrotron-based far-infrared spectroscopy. Owing to the complex line pattern which results from two nuclei with non-zero spins, new, high-level quantum-chemical calculations of the hyperfine structure played a crucial role in the spectroscopic analysis. From the combined experimental and theoretical work, an accurate semi-experimental equilibrium structure (r(e)(SE)) of SOCl2 has been derived. With the present data, spectroscopy-based methods can now be applied with confidence to detect and monitor this species, either by remote sensing or in situ. PMID- 26931701 TI - Structure and spectroscopic properties of low-lying states of the HOC(O)O radical. AB - The HOC(O)O radical is a product of the reaction of HOCO radicals with oxygen atoms. The present study provides theoretical prediction of critical spectroscopic features of this radical that should aid in its experimental characterization. Energies, structures, rotational constants, and harmonic frequencies are presented for the ground and two low-lying excited electronic states of HOC(O)O. The energies for the A(2)A"<-X(2)A' and B(2)A'<-X(2)A' electronic transitions are reported. The band origin of the B<-X transition of HOC(O)O is predicted to occur in the near infrared region of the spectrum at around 1.5 eV and it is suggested to be the most promising one for observing this radical spectroscopically. The structural and spectroscopic similarities between HOC(O)O and the isoelectronic radical FC(O)O are discussed. The abundance of experimental data on the FC(O)O radical should guide the spectroscopic characterization of HOC(O)O and serve as a benchmark for the structural and spectroscopic parameters obtained from theory. PMID- 26931702 TI - Photoionization of furan from the ground and excited electronic states. AB - Here we present a comparative computational study of the photoionization of furan from the ground and the two lowest-lying excited electronic states. The study aims to assess the quality of the computational methods currently employed for treating bound and continuum states in photoionization. For the ionization from the ground electronic state, we show that the Dyson orbital approach combined with an accurate solution of the continuum one particle wave functions in a multicenter B-spline basis, at the density functional theory (DFT) level, provides cross sections and asymmetry parameters in excellent agreement with experimental data. On the contrary, when the Dyson orbitals approach is combined with the Coulomb and orthogonalized Coulomb treatments of the continuum, the results are qualitatively different. In excited electronic states, three electronic structure methods, TDDFT, ADC(2), and CASSCF, have been used for the computation of the Dyson orbitals, while the continuum was treated at the B spline/DFT level. We show that photoionization observables are sensitive probes of the nature of the excited states as well as of the quality of excited state wave functions. This paves the way for applications in more complex situations such as time resolved photoionization spectroscopy. PMID- 26931703 TI - Acetic acid-water complex: The first observation of structures containing the higher-energy acetic acid conformer. AB - Non-covalent interaction of acetic acid (AA) and water is studied experimentally by IR spectroscopy in a nitrogen matrix and theoretically at the MP2 and coupled cluster with single and double and perturbative triple excitations [CCSD(T)]/6 311++G(2d,2p) levels of theory. This work is focused on the first preparation and characterization of complexes of higher-energy (cis) conformer of AA with water. The calculations show three 1:1 structures for the trans-AA?H2O complexes and three 1:1 structures for the cis-AA?H2O complexes. Two trans-AA?H2O and two cis AA?H2O complexes are found and structurally assigned in the experiments. The two cis-AA? ? H2O complexes are obtained by annealing of a matrix containing water and cis-AA molecules prepared by selective vibrational excitation of the ground state trans form. The less stable trans-AA?H2O complex is obtained by vibrational excitation of the less stable cis-AA?H2O complex. In addition, the 1:2 complexes of trans-AA and cis-AA with water molecules are studied computationally and the most stable forms of the 1:2 complexes are experimentally identified. PMID- 26931704 TI - A combined photoelectron spectroscopy and relativistic ab initio studies of the electronic structures of UFO and UFO(-). AB - The observation of the gaseous UFO(-) anion is reported, which is investigated using photoelectron spectroscopy and relativisitic ab initio calculations. Two strong photoelectron bands are observed at low binding energies due to electron detachment from the U-7ssigma orbital. Numerous weak detachment bands are also observed due to the strongly correlated U-5f electrons. The electron affinity of UFO is measured to be 1.27(3) eV. High-level relativistic quantum chemical calculations have been carried out on the ground state and many low-lying excited states of UFO to help interpret the photoelectron spectra and understand the electronic structure of UFO. The ground state of UFO(-) is linear with an O-U-F structure and a (3)H4 spectral term derived from a U 7ssigma(2)5fphi(1)5fdelta(1) electron configuration, whereas the ground state of neutral UFO has a (4)H(7/2) spectral term with a U 7ssigma(1)5fphi(1)5fdelta(1) electron configuration. Strong electron correlation effects are found in both the anionic and neutral electronic configurations. In the UFO neutral, a high density of electronic states with strong configuration mixing is observed in most of the scalar relativistic and spin-orbit coupled states. The strong electron correlation, state mixing, and spin-orbit coupling of the electronic states make the excited states of UFO very challenging for accurate quantum chemical calculations. PMID- 26931705 TI - Electronic excitations in solution-processed oligothiophene small-molecules for organic solar cells. AB - First principles calculations based on density functional theory and many body perturbation theory have been employed to study the optical absorption properties of a newly synthesized oligo-thiophene molecule, with a quaterthiophene central unit, that has been designed for solution-processed bulk-heterojunction solar cells. To this aim we have employed the GW approach to obtain quasiparticle energies as a pre-requisite to solve the Bethe-Salpeter equation for the excitonic Hamiltonian. We show that the experimental absorption spectrum can be explained only by taking into account the inter-molecular transitions among the pi-stacked poly-conjugated molecules that are typically obtained in solid-state organic samples. PMID- 26931707 TI - Breadth versus depth: Interactions that stabilize particle assemblies to changes in density or temperature. AB - We use inverse methods of statistical mechanics to explore trade-offs associated with designing interactions to stabilize self-assembled structures against changes in density or temperature. Specifically, we find isotropic, convex repulsive pair potentials that maximize the density range for which a two dimensional square lattice is the stable ground state subject to a constraint on the chemical potential advantage it exhibits over competing structures (i.e., "depth" of the associated minimum on the chemical potential hypersurface). We formulate the design problem as a nonlinear program, which we solve numerically. This allows us to efficiently find optimized interactions for a wide range of possible chemical potential constraints. We find that assemblies designed to exhibit a large chemical potential advantage at a specified density have a smaller overall range of densities for which they are stable. This trend can be understood by considering the separation-dependent features of the pair potential and its gradient required to enhance the stability of the target structure relative to competitors. Using molecular dynamics simulations, we further show that potentials designed with larger chemical potential advantages exhibit higher melting temperatures. PMID- 26931706 TI - Understanding the large solubility of lidocaine in 1-n-butyl-3-methylimidazolium based ionic liquids using molecular simulation. AB - Room temperature ionic liquids have been proposed as replacement solvents in a wide range of industrial separation processes. Here, we focus on the use of ionic liquids as solvents for the pharmaceutical compound lidocaine. We show that the solubility of lidocaine in seven common 1-n-butyl-3-methylimidazolium based ionic liquids is greatly enhanced relative to water. The predicted solubility is greatest in [BMIM](+)[CH3CO2](-), which we find results from favorable hydrogen bonding between the lidocaine amine hydrogen and the [CH3CO2](-) oxygen, favorable electrostatic interactions between the lidocaine amide oxygen with the [BMIM](+) aromatic ring hydrogens, while lidocaine does not interfere with the association of [BMIM](+) with [CH3CO2](-). Additionally, by removing functional groups from the lidocaine scaffold while maintaining the important amide group, we found that as the van der Waals volume increases, solubility in [BMIM](+)[CH3CO2](-) relative to water increases. PMID- 26931708 TI - Equation of state and critical point behavior of hard-core double-Yukawa fluids. AB - A theoretical study on the equation of state and the critical point behavior of hard-core double-Yukawa fluids is presented. Thermodynamic perturbation theory, restricted to first order in the inverse temperature and having the hard-sphere fluid as the reference system, is used to derive a relatively simple analytical equation of state of hard-core multi-Yukawa fluids. Using such an equation of state, the compressibility factor and phase behavior of six representative hard core double-Yukawa fluids are examined and compared with available simulation results. The effect of varying the parameters of the hard-core double-Yukawa intermolecular potential on the location of the critical point is also analyzed using different perspectives. The relevance of this analysis for fluids whose molecules interact with realistic potentials is also pointed out. PMID- 26931709 TI - Dynamics of water confined in lyotropic liquid crystals: Molecular dynamics simulations of the dynamic structure factor. AB - The properties of water under confinement are of practical and fundamental interest. In this work, we study the properties of water in the self-assembled lyotropic phases of Gemini surfactants with a focus on testing the standard analysis of quasi-elastic neutron scattering (QENS) experiments. In QENS experiments, the dynamic structure factor is measured and fit to models to extract the translational diffusion constant, D(T), and rotational relaxation time, tau(R). We test this procedure by using simulation results for the dynamic structure factor, extracting the dynamic parameters from the fit as is typically done in experiments, and comparing the values to those directly measured in the simulations. We find that the de-coupling approximation, where the intermediate scattering function is assumed to be a product of translational and rotational contributions, is quite accurate. The jump-diffusion and isotropic rotation models, however, are not accurate when the degree of confinement is high. In particular, the exponential approximations for the intermediate scattering function fail for highly confined water and the values of D(T) and tau(R) can differ from the measured value by as much as a factor of two. Other models have more fit parameters, however, and with the range of energies and wave-vectors accessible to QENS, the typical analysis appears to be the best choice. In the most confined lamellar phase, the dynamics are sufficiently slow that QENS does not access a large enough time scale. PMID- 26931710 TI - Search for anisotropy in the Debye-Waller factor of HCP solid (4)He. AB - The properties of hexagonal close packed (hcp) solid (4)He are dominated by large atomic zero point motions. An accurate description of these motions is therefore necessary in order to accurately calculate the properties of the system, such as the Debye-Waller (DW) factors. A recent neutron scattering experiment reported significant anisotropy in the in-plane and out-of-plane DW factors for hcp solid (4)He at low temperatures, where thermal effects are negligible and only zero point motions are expected to contribute. By contrast, no such anisotropy was observed either in earlier experiments or in path integral Monte Carlo (PIMC) simulations of solid hcp (4)He. However, the earlier experiments and the PIMC simulations were both carried out at higher temperatures where thermal effects could be substantial. We seek to understand the cause of this discrepancy through variational quantum Monte Carlo simulations utilizing an accurate pair potential and a modified trial wavefunction which allows for anisotropy. Near the melting density, we find no anisotropy in an ideal hcp (4)He crystal. A theoretical equation of state is derived from the calculated energies of the ideal crystal over a range of molar volumes from 7.88 to 21.3 cm(3), and is found to be in good qualitative agreement with experimental data. PMID- 26931711 TI - Thermal conductivity of molten salt mixtures: Theoretical model supported by equilibrium molecular dynamics simulations. AB - A theoretical model for the description of thermal conductivity of molten salt mixtures as a function of composition and temperature is presented. The model is derived by considering the classical kinetic theory and requires, for its parametrization, only information on thermal conductivity of pure compounds. In this sense, the model is predictive. For most molten salt mixtures, no experimental data on thermal conductivity are available in the literature. This is a hindrance for many industrial applications (in particular for thermal energy storage technologies) as well as an obvious barrier for the validation of the theoretical model. To alleviate this lack of data, a series of equilibrium molecular dynamics (EMD) simulations has been performed on several molten chloride systems in order to determine their thermal conductivity in the entire range of composition at two different temperatures: 1200 K and 1300 K. The EMD simulations are first principles type, as the potentials used to describe the interactions have been parametrized on the basis of first principle electronic structure calculations. In addition to the molten chlorides system, the model predictions are also compared to a recent similar EMD study on molten fluorides and with the few reliable experimental data available in the literature. The accuracy of the proposed model is within the reported numerical and/or experimental errors. PMID- 26931712 TI - Interstitial diffusion of O, N, and C in alpha-Ti from first-principles: Analytical model and kinetic Monte Carlo simulations. AB - The high affinity of O, N, and C with alpha-Ti has a serious detrimental influence on the high-temperature properties of these alloys, promoting the formation of alpha-case. These elements dissolve in interstitial sites and diffuse very fast in alpha-Ti (10(3)-10(8) times higher than the self-diffusivity of Ti) at high temperature accelerating the growth of alpha phase surface layer. Understanding the diffusion mechanisms of these elements is crucial to the design of high-temperature Ti alloys. This work aims to determine the stable interstitial sites and migration paths of O, N, and C in alpha-Ti. Diffusion coefficients were evaluated applying an analytical model, the multi-state diffusion method, and kinetic Monte Carlo simulations informed by first principles calculations. The results show the reliability of these two methods with respect to the experimental data. In addition to octahedral sites, less traditional interstitial sites are shown to be stable configurations for these elements instead of tetrahedral sites. This requires to update the transition pathway networks through which these elements have been thought to migrate in alpha-Ti. PMID- 26931713 TI - Application of van der Waals functionals to the calculation of dissociative adsorption of N2 on W(110) for static and dynamic systems. AB - The fundamental understanding of molecule-surface reactions is of great importance to heterogeneous catalysis, motivating many theoretical and experimental studies. Even though much attention has been dedicated to the dissociative chemisorption of N2 on tungsten surfaces, none of the existing theoretical models has been able to quantitatively reproduce experimental reaction probabilities for the sticking of N2 to W(110). In this work, the dissociative chemisorption of N2 on W(110) has been studied with both static electronic structure and ab initio molecular dynamics (AIMD) calculations including the surface temperature effects through surface atom motion. Calculations have been performed using density functional theory, testing functionals that account for the long range van der Waals (vdW) interactions, which were previously only considered in dynamical calculations within the static surface approximation. The vdW-DF2 functional improves the description of the potential energy surface for N2 on W(110), returning less deep molecular adsorption wells and a better ratio between the barriers for the indirect dissociation and the desorption, as suggested by previous theoretical work and experimental evidence. Using the vdW-DF2 functional less trapping-mediated dissociation is obtained compared to results obtained with standard semi-local functionals such as PBE and RPBE, improving agreement with experimental data at E(i) = 0.9 eV. However, at E(i) = 2.287 and off-normal incidence, the vdW-DF2 AIMD underestimates the experimental reaction probabilities, showing that also with the vdW-DF2 functional the N2 on W(110) interaction is not yet described with quantitative accuracy. PMID- 26931714 TI - Si-rich W silicide films composed of W-atom-encapsulated Si clusters deposited using gas-phase reactions of WF6 with SiH4. AB - We formed Si-rich W silicide films composed of Sin clusters, each of which encapsulates a W atom (WSi(n) clusters with 8 < n <= ~ 12), by using a gas-phase reaction between WF6 and SiH4 in a hot-wall reactor. The hydrogenated WSi(n)H(x) clusters with reduced F concentration were synthesized in a heated gas phase and subsequently deposited on a substrate heated to 350-420 degrees C, where they dehydrogenated and coalesced into the film. Under a gas pressure of SiH4 high enough for the WSi(n)H(x) reactant to collide a sufficient number of times with SiH4 molecules before reaching the substrate, the resulting film was composed of WSi(n) clusters with a uniform n, which was determined by the gas temperature. The formed films were amorphous semiconductors with an optical gap of ~0.8-1.5 eV and an electrical mobility gap of ~0.05-0.12 eV, both of which increased as n increased from 8 to 12. We attribute this dependence to the reduction of randomness in the Si network as n increased, which decreased the densities of band tail states and localized states. PMID- 26931715 TI - Density-functional theory molecular dynamics simulations of a-HfO2/Ge(100)(2 * 1) and a-ZrO2/Ge(100)(2 * 1) interface passivation. AB - The structural properties of a-HfO2/Ge(2 * 1)-(001) and a-ZrO2/Ge(2 * 1)-(001) interfaces were investigated with and without a GeOx interface interlayer using density-functional theory (DFT) molecular dynamics (MD) simulations. Realistic a HfO2 and a-ZrO2 samples were generated using a hybrid classical-DFT MD "melt-and quench" approach and tested against experimental properties. The oxide/Ge stacks were annealed at 700 K, cooled to 0 K, and relaxed providing the system with enough freedom to form realistic interfaces. For each high-K/Ge stack type, two systems with single and double interfaces were investigated. All stacks were free of midgap states; however, stacks with a GeO(x) interlayer had band-edge states which decreased the band gaps by 0%-30%. These band-edge states were mainly produced by under-coordinated Ge atoms in GeO(x) layer or its vicinity due to deformation, intermixing, and bond-breaking. The DFT-MD simulations show that electronically passive interfaces can be formed either directly between high-K dielectrics and Ge or with a monolayer of GeO2 if the processing does not create or properly passivate under-coordinated Ge atoms and Ge's with significantly distorted bonding angles. Comparison to the charge states of the interfacial atoms from DFT to experimental x-ray photoelectron spectroscopy results shows that while most studies of gate oxide on Ge(001) have a GeO(x) interfacial layer, it is possible to form an oxide/Ge interface without a GeO(x) interfacial layer. Comparison to experiments is consistent with the dangling bonds in the suboxide being responsible for midgap state formation. PMID- 26931716 TI - Analytical model for thermal boundary conductance and equilibrium thermal accommodation coefficient at solid/gas interfaces. AB - We develop an analytical model for the thermal boundary conductance between a solid and a gas. By considering the thermal fluxes in the solid and the gas, we describe the transmission of energy across the solid/gas interface with diffuse mismatch theory. From the predicted thermal boundary conductances across solid/gas interfaces, the equilibrium thermal accommodation coefficient is determined and compared to predictions from molecular dynamics simulations on the model solid-gas systems. We show that our model is applicable for modeling the thermal accommodation of gases on solid surfaces at non-cryogenic temperatures and relatively strong solid-gas interactions (epsilon(sf) ? k(B)T). PMID- 26931717 TI - Impact of MoO3 interlayer on the energy level alignment of pentacene-C60 heterostructure. AB - Using in situ ultraviolet photoelectron spectroscopy, the electronic structure evolutions at the interface between pentacene and fullerene (C60), a classical organic donor-acceptor heterostructure in organic electronic devices, on indium tin oxide (ITO) and MoO3 modified ITO substrates have been investigated. The insertion of a thin layer MoO3 has a significant impact on the interfacial energy level alignment of pentacene-C60 heterostructure. For the deposition of C60 on pentacene, the energy difference between the highest occupied molecular orbital of donor and the lowest unoccupied molecular orbital of acceptor (HOMO(D) LUMO(A)) offset of C60/pentacene heterostructure increased from 0.86 eV to 1.54 eV after the insertion of a thin layer MoO3 on ITO. In the inverted heterostructrure where pentacene was deposited on C60, the HOMO(D)-LUMO(A) offset of pentacene/C60 heterostructure increased from 1.32 to 2.20 eV after MoO3 modification on ITO. The significant difference of HOMO(D)-LUMO(A) offset shows the feasibility to optimize organic electronic device performance through interfacial engineering approaches, such as the insertion of a thin layer high work function MoO3 films. PMID- 26931718 TI - The electron and spin polarized transport in wide-voltage-ranges through colbaltporphyrin-based molecular junctions. AB - The electron and spin polarized transport properties of Co benzene-porphyrin benzene (BPB) molecule coupled to gold (Au) nanowires in a wide voltage range (0 3.0 V) are investigated. By successively removing the front-end Au atoms, we construct Au nanowires with different molecule-electrode contact symmetries. Multiple negative differential resistance (NDR) peaks emerge at different bias voltage regions. It is found that the low-voltage NDR effect at 0.4 V can only be found in the junctions with S-Au top bindings. High-bias NDR effects intrinsic to central molecule at 2.8 V are observed in all the six structures. In particular, both the electron and spin polarized current-voltage (I-V) curves depend strongly on the contact configurations between Co-BPB molecule and the Au electrodes. And the top-binding may result in spin dependent transport properties and will be the priority selection in the design of molecular devices. PMID- 26931719 TI - Structure and role of metal clusters in a metal-organic coordination network determined by density functional theory. AB - We present a comprehensive theoretical investigation of the structures formed by self-assembly of tetrahydroxybenzene (THB)-derivatives on Cu(111). The THB molecule is known to dehydrogenate completely during annealing, forming a reactive radical which assembles into a close-packed structure or a porous metal coordinated network depending on the coverage of the system. Here, we present details on how the structures are determined by density functional theory calculations, using scanning tunneling microscopy-derived information on the periodicity. The porous network is based on adatom trimers. By analysing the charge distribution of the structure, it is found that this unusual coordination motif is preferred because it simultaneously provides a good coordination of all oxygen atoms and allows for the formation of a two-dimensional network on the surface. PMID- 26931720 TI - Loop statistics in polymers in crowded environment. AB - We analyze the probability to find a single loop in a long flexible polymer chain in disordered environment in d dimensions. The structural defects are considered to be correlated on large distances r according to a power law ~r(-a). Working within the frames of continuous chain model and applying the direct polymer renormalization scheme, we obtain the values of critical exponents governing the scaling of probabilities to find the loops of various positions along the chain as function of loops' length. Our results quantitatively reveal that the presence of structural defects in environment decreases the probability of loop formation in polymer macromolecules. PMID- 26931721 TI - Electrostatic energy barriers from dielectric membranes upon approach of translocating DNA molecules. AB - We probe the electrostatic cost associated with the approach phase of DNA translocation events. Within an analytical theory at the Debye-Huckel level, we calculate the electrostatic energy of a rigid DNA molecule interacting with a dielectric membrane. For carbon or silicon based low permittivity neutral membranes, the DNA molecule experiences a repulsive energy barrier between 10 k(B)T and 100 k(B)T. In the case of engineered membranes with high dielectric permittivities, the membrane surface attracts the DNA with an energy of the same magnitude. Both the repulsive and attractive interactions result from image charge effects and their magnitude survive even for the thinnest graphene-based membranes of size d ~ 6 A. For weakly charged membranes, the electrostatic energy is always attractive at large separation distances but switches to repulsive close to the membrane surface. We also characterise the polymer length dependence of the interaction energy. For specific values of the membrane charge density, low permittivity membranes repel short polymers but attract long polymers. Our results can be used to control the strong electrostatic energy of DNA-membrane interactions prior to translocation events by chemical engineering of the relevant system parameters. PMID- 26931722 TI - Colloidal crystallite suspensions studied by high pressure small angle x-ray scattering. AB - We report on high pressure small angle x-ray scattering on suspensions of colloidal crystallites in water. The crystallites made out of charge-stabilized poly-acrylate particles exhibit a complex pressure dependence which is based on the specific pressure properties of the suspending medium water. The dominant effect is a compression of the crystallites caused by the compression of the water. In addition, we find indications that also the electrostatic properties of the system, i.e. the particle charge and the dissociation of ions, might play a role for the pressure dependence of the samples. The data further suggest that crystallites in a metastable state induced by shear-induced melting can relax to a similar structural state upon the application of pressure and dilution with water. X-ray cross correlation analysis of the two-dimensional scattering patterns indicates a pressure-dependent increase of the orientational order of the crystallites correlated with growth of these in the suspension. This study underlines the potential of pressure as a very relevant parameter to understand colloidal crystallite systems in aqueous suspension. PMID- 26931723 TI - Screening out the non-Arrhenius behaviour of nematic-isotropic transition by room temperature ionic liquid. AB - Differential Scanning Calorimetry (DSC) and optical polarization microscopy of a mixture of the liquid crystalline material (N-(4-methoxybenzylidene)-4 butylaniline, MBBA) and a Fe-based room temperature ionic liquid 1-ethyl-3 methylimidazolium tetrachloroferrate ([Emim](+) [FeCl4](-), EMIF) indicate a decrease in the nematic-isotropic (N-I) phase transition temperature (T(NI)) with an increase in EMIF concentration, explained by a proposed model of Coulomb "screening" of MBBA quadrupoles by the EMIF ions along with ionic "self screening." DSC studies of EMIF-MBBA and pure EMIF and comparison with pure MBBA results show that the major transitions in pure EMIF have Arrhenius behaviour, but more importantly the previously found convex Arrhenius behaviour of the pristine MBBA [K. Dan et al., Europhys. Lett. 108, 36007 (2014)] becomes Arrhenius in the mixture, indicating a conversion of the entropic N-I activation barrier to an enthalpic one. In presence of EMIF, a drastic decrease in the intensity of out-of-plane distortions of benzene rings in MBBA is found from Fourier transform infrared spectroscopy, consistent with significant reduction in the conformational states of MBBA. This suppression of large amplitude motion is again consistent with a Coulomb screening and gives a molecular basis for the entropic-to-enthalpic conversion of the N-I activation barrier. PMID- 26931724 TI - Lattice Boltzmann simulation of asymmetric flow in nematic liquid crystals with finite anchoring. AB - Liquid crystals (LCs) display many of the flow characteristics of liquids but exhibit long range orientational order. In the nematic phase, the coupling of structure and flow leads to complex hydrodynamic effects that remain to be fully elucidated. Here, we consider the hydrodynamics of a nematic LC in a hybrid cell, where opposite walls have conflicting anchoring boundary conditions, and we employ a 3D lattice Boltzmann method to simulate the time-dependent flow patterns that can arise. Due to the symmetry breaking of the director field within the hybrid cell, we observe that at low to moderate shear rates, the volumetric flow rate under Couette and Poiseuille flows is different for opposite flow directions. At high shear rates, the director field may undergo a topological transition which leads to symmetric flows. By applying an oscillatory pressure gradient to the channel, a net volumetric flow rate is found to depend on the magnitude and frequency of the oscillation, as well as the anchoring strength. Taken together, our findings suggest several intriguing new applications for LCs in microfluidic devices. PMID- 26931726 TI - Interaction-component analysis of the hydration and urea effects on cytochrome c. AB - Energetics was analyzed for cytochrome c in pure-water solvent and in a urea water mixed solvent to elucidate the solvation effect in the structural variation of the protein. The solvation free energy was computed through all-atom molecular dynamics simulation combined with the solution theory in the energy representation, and its correlations were examined over sets of protein structures against the electrostatic and van der Waals components in the average interaction energy of the protein with the solvent and the excluded-volume component in the solvation free energy. It was observed in pure-water solvent that the solvation free energy varies in parallel to the electrostatic component with minor roles played by the van der Waals and excluded-volume components. The effect of urea on protein structure was then investigated in terms of the free energy change upon transfer of the protein solute from pure-water solvent to the urea-water mixed solvent. The decomposition of the transfer free energy into the contributions from urea and water showed that the urea contribution is partially canceled by the water contribution and governs the total free energy of transfer. When correlated against the change in the solute-solvent interaction energy upon transfer and the corresponding changes in the electrostatic, van der Waals, and excluded-volume components, the transfer free energy exhibited strong correlations with the total change in the solute-solvent energy and its van der Waals component. The solute-solvent energy was decomposed into the contributions from the protein backbone and side chain, furthermore, and neither of the contributions was seen to be decisive in the correlation to the transfer free energy. PMID- 26931725 TI - Electromagnetic-field effects on structure and dynamics of amyloidogenic peptides. AB - Electromagnetic fields (EMFs) are ever-present, and so is the need to better understand their influence on human health and biological matter in general. The interaction between a molecular system and external EMF can alter the structure, and dynamical behaviour, and, hence, biological function of proteins with uncertain health consequences. This urges a detailed investigation of EMF-induced effects on basic protein biophysics. Here, we used all-atom non-equilibrium molecular dynamics simulations to understand and quantify the response mechanisms of the amyloidogenic apoC-II(60-70) peptides to non-ionising radiation by modelling their behaviour under external electromagnetic and electric fields of different strengths. Our simulations show high strength fields (>0.04 V/nm) cause structural changes in apoC-II(60-70) due to the peptide dipole alignment along the applied field direction, which disrupts the inherent beta-hairpin conformation known to be the intermediate state for fibril formation. The intermediate field-strength range (0.04-0.004 V/nm) causes a significant acceleration in peptide dynamics, which leads to the increased population of structures with fibril-inhibiting characteristics, such as the separated N- and C termini and colocation of the aromatic residues at the same peptide face. In contrast, lower field strengths (<0.004 V/nm) promote the formation of the amyloid-prone hairpin structures relative to the ambient conditions. These findings suggest that intermediate-strength electromagnetic fields could be considered for designing alternative treatments of amyloid diseases, while the very high and low field strengths could be employed for engineering well-ordered fibrillar aggregates for non-medicinal applications. PMID- 26931727 TI - A coarse grained protein model with internal degrees of freedom. Application to alpha-synuclein aggregation. AB - Particles in simulations are traditionally endowed with fixed interactions. While this is appropriate for particles representing atoms or molecules, objects with significant internal dynamics--like sequences of amino acids or even an entire protein--are poorly modelled by invariable particles. We develop a highly coarse grained polymorph patchy particle with the ultimate aim of simulating proteins as chains of particles at the secondary structure level. Conformational changes, e.g., a transition between disordered and beta-sheet states, are accommodated by internal coordinates that determine the shape and interaction characteristics of the particles. The internal coordinates, as well as the particle positions and orientations, are propagated by Brownian Dynamics in response to their local environment. As an example of the potential offered by polymorph particles, we model the amyloidogenic intrinsically disordered protein alpha-synuclein, involved in Parkinson's disease, as a single particle with two internal states. The simulations yield oligomers of particles in the disordered state and fibrils of particles in the "misfolded" cross-beta-sheet state. The aggregation dynamics is complex, as aggregates can form by a direct nucleation-and-growth mechanism and by two-step-nucleation through conversions between the two cluster types. The aggregation dynamics is complex, with fibrils formed by direct nucleation-and growth, by two-step-nucleation through the conversion of an oligomer and by auto catalysis of this conversion. PMID- 26931729 TI - Comment on "Nonlinear dielectric response of polar liquids" [J. Chem. Phys. 142, 244502 (2015)]. PMID- 26931728 TI - Molecular dynamics study of lipid bilayers modeling the plasma membranes of mouse hepatocytes and hepatomas. AB - Molecular dynamics (MD) calculations of lipid bilayers modeling the plasma membranes of normal mouse hepatocytes and hepatomas in water have been performed under physiological isothermal-isobaric conditions (310.15 K and 1 atm). The changes in the membrane properties induced by hepatic canceration were investigated and were compared with previous MD calculations included in our previous study of the changes in membrane properties induced by murine thymic canceration. The calculated model membranes for normal hepatocytes and hepatomas comprised 23 and 24 kinds of lipids, respectively. These included phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, sphingomyelin, lysophospholipids, and cholesterol. We referred to previously published experimental values for the mole fraction of the lipids adopted in the present calculations. The calculated structural and dynamic properties of the membranes such as lateral structure, order parameters, lateral self-diffusion constants, and rotational correlation times all showed that hepatic canceration causes plasma membranes to become more ordered laterally and less fluid. Interestingly, this finding contrasts with the less ordered structure and increased fluidity of plasma membranes induced by thymic canceration observed in our previous MD study. PMID- 26931730 TI - Response to "Comment on 'Nonlinear dielectric response of polar liquids"' [J. Chem. Phys. 144, 087101 (2016)]. PMID- 26931731 TI - Publisher's Note: "H-bonding of an NH3 gas molecule to H2O/Pt(111)--A barrier free path" [J. Chem. Phys. 144, 054701 (2016)]. PMID- 26931732 TI - alpha-Solanine Isolated From Solanum Tuberosum L. cv Jayoung Abrogates LPS Induced Inflammatory Responses Via NF-kappaB Inactivation in RAW 264.7 Macrophages and Endotoxin-Induced Shock Model in Mice. AB - alpha-Solanine, a trisaccharide glycoalkaloid, has been reported to possess anti cancer effects. In this study, we investigated the anti-inflammatory effects of alpha-solanine isolated from "Jayoung" a dark purple-fleshed potato by examining its in vitro inhibitory effects on inducible nitric-oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and pro-inflammatory cytokines in LPS-induced RAW 264.7 macrophages and its in vivo effects on LPS-induced septic shock in a mouse model. alpha-Solanine suppressed the expression of iNOS and COX-2 both at protein and mRNA levels and consequently inhibited nitric oxide (NO) and prostaglandin E2 (PGE2 ) production in LPS-induced RAW 264.7 macrophages. alpha-Solanine also reduced the production and mRNA expression of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and interleukin-1beta (IL-1beta) induced by LPS. Furthermore, molecular mechanism studies indicated that alpha-solanine inhibited LPS-induced activation of nuclear factor-kappaB (NF-kappaB) by reducing nuclear translocation of p65, degradation of inhibitory kappaBalpha (IkappaBalpha), and phosphorylation of IkappaB kinasealpha/beta (IKKalpha/beta). In an in vivo experiment of LPS-induced endotoxemia, treatment with alpha solanine suppressed mRNA expressions of iNOS, COX-2, IL-6, TNF-alpha, and IL 1beta, and the activation of NF-kappaB in liver. Importantly, alpha-solanine increased the survival rate of mice in LPS-induced endotoxemia and polymicrobial sepsis models. Taken together, our data suggest that the alpha-solanine may be a promising therapeutic against inflammatory diseases by inhibiting the NF-kappaB signaling pathway. J. Cell. Biochem. 117: 2327-2339, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26931733 TI - TLC Fingerprinting and Pattern Recognition Methods in the Assessment of Authenticity of Poplar-Type Propolis. AB - Propolis is a "natural" remedy with prominent biological activity, which is used as dietary supplement. In the absence of clinical studies that would substantiate these claims, information on the biological activity of propolis is valuable. This study comprises chromatographic, image processing and chemometric approach for phenolic profiling of Serbian, Croatian and Slovenian propolis test solutions. Modern thin-layer chromatography equipment in combination with software for image processing was applied for fingerprinting and data acquisition, whereas the principal component analysis was used as pattern recognition method. Characterization of phenolic profile was performed along with the determination of the botanical and geographical origin of propolis. High performance thin-layer chromatograms reveal that Central and Southeastern European propolis samples are rich in flavonoids. In addition, phenolic compounds proved to be suitable markers for the determination of European propolis authenticity. PMID- 26931734 TI - Development and Validation of a Rapid and Simple UPLC-ESI-MS Method for Pharmacokinetics and Tissue Distribution of Astragaloside III in Rats. AB - A rapid and simple ultra-performance liquid chromatography-electrospray ionization-mass spectrometry (UPLC-ESI-MS) method for the determination of astragaloside III was developed and used in a pharmacokinetic and tissue distribution study in rats following the oral administration 95% ethanol extraction of Zhenqi Fuzheng capsules. Although astragaloside III and astragaloside IV have the same molecular weight and very similar structures, they were successfully separated using this method. Quantification was performed using low-energy collision tandem mass spectrometry (CID-MS-MS) with the multiple reaction monitoring scan mode of the following precursor ion -> product ion atm/z807.61->335.22 for astragaloside III and atm/z633.18->331.18 for the internal standard (hesperidin). Both astragaloside III and astragaloside IV in rat plasma were best fit to a two-compartment model. The tissue distribution study showed the overall trend of disposition of astragaloside III were C thymus > C spleen > C stomach > C liver > C heart > C kidney > C lung > C testicle The high levels of astragaloside III in thymus and spleen indicated an accumulation in organs involved in immune responses and showed that these organs are major target sites in vivo The results in the article will provide valuable information for use in clinical applications of astragaloside III. PMID- 26931735 TI - mTORC1-mediated inhibition of polycystin-1 expression drives renal cyst formation in tuberous sclerosis complex. AB - Previous studies report a cross-talk between the polycystic kidney disease (PKD) and tuberous sclerosis complex (TSC) genes. mTOR signalling is upregulated in PKD and rapamycin slows cyst expansion, whereas renal inactivation of the Tsc genes causes cysts. Here we identify a new interplay between the PKD and TSC genes, with important implications for the pathophysiology of both diseases. Kidney specific inactivation of either Pkd1 or Tsc1 using an identical Cre (KspCre) results in aggressive or very mild PKD, respectively. Unexpectedly, we find that mTORC1 negatively regulates the biogenesis of polycystin-1 (PC-1) and trafficking of the PC-1/2 complex to cilia. Genetic interaction studies reveal an important role for PC-1 downregulation by mTORC1 in the cystogenesis of Tsc1 mutants. Our data potentially explain the severe renal manifestations of the TSC/PKD contiguous gene syndrome and open new perspectives for the use of mTOR inhibitors in autosomal dominant PKD caused by hypomorphic or missense PKD1 mutations. PMID- 26931736 TI - The current use and attitudes towards tumor genome sequencing in breast cancer. AB - There is increasing availability of technologies that can interrogate the genomic landscape of an individual tumor; however, their impact on daily practice remains uncertain. We conducted a 28-item survey to investigate the current attitudes towards the integration of tumor genome sequencing in breast cancer management. A link to the survey was communicated via newsletters of several oncological societies, and dedicated mailing by academic research groups. Multivariable logistic regression modeling was carried out to determine the relationship between predictors and outcomes. 215 physicians participated to the survey. The majority were medical oncologists (88%), practicing in Europe (70%) and working in academic institutions (66%). Tumor genome sequencing was requested by 82 participants (38%), of whom 21% reported low confidence in their genomic knowledge, and 56% considered tumor genome sequencing to be poorly accessible. In multivariable analysis, having time allocated to research (OR 3.37, 95% CI 1.84 6.15, p < 0.0001), working in Asia (OR 5.76, 95% CI 1.57 - 21.15, p = 0.01) and having institutional guidelines for molecular sequencing (OR 2.09, 95% 0.99-4.42, p = 0.05) were associated with a higher probability of use. In conclusion, our survey indicates that tumor genome sequencing is sometimes used, albeit not widely, in guiding management of breast cancer patients. PMID- 26931737 TI - Reproductive parameters of the Pacific angel shark Squatina californica (Selachii: Squatinidae). AB - Reproductive characteristics of the Pacific angel shark, Squatina californica, were evaluated from 420 specimens obtained from the artisanal fishery in La Paz Bay, Gulf of California, Mexico. Females (99 cm, 6000 g) were larger than males (95 cm, 5000 g) in terms of both total length (L(T)) and body mass (M(T)). The overall sex ratio was significantly different from the expected 1:1, suggesting sexual segregation of mature individuals in La Paz Bay. Males had developed reproductive organs and calcified claspers from 72 cm L(T); the median size at maturity (LT50 ) was 75.6 cm. In females, only the left ovary was functional and mature ovarian follicles were present from 77 cm L(T); the estimated LT50 was 77.7 cm. For the 10 gravid females sampled, uterine fecundity was between two and 10 embryos. Mature, non-gravid females with small and large ovarian follicles appeared simultaneously with gravid females with follicles that did not exceed 1.9 cm diameter. PMID- 26931738 TI - Primary Care Physician-Pharmacist Collaborative Care Model: Strategies for Implementation. AB - The Collaboration Among Pharmacists and Physicians To Improve Outcomes Now (CAPTION) trial recently found that a pharmacist intervention for hypertension could be implemented in diverse medical offices. In this issue of Pharmacotherapy, the article by Brian Isetts and colleagues discusses the complexity of the patient population, the specific functions the pharmacists performed, and the time estimates from billing records used to quantify time spent during face-to-face patient encounters. This invited commentary will discuss findings from the CAPTION trial and provide recommendations for strategies to implement similar interventions for patients with other chronic medical conditions seen in primary care practices. PMID- 26931739 TI - Existence of nontrivial topologically protected states at grain boundaries in bilayer graphene: signatures and electrical switching. AB - Recent experiments [L. Ju, et al., Nature, 2015, 520, 650] confirm the existence of gapless states at domain walls created in gated bilayer graphene, when the sublattice stacking is changed from AB to BA. These states are significant because they are topologically protected, valley-polarized and give rise to conductance along the domain wall. Current theoretical models predict the appearance of such states only at domain walls, which preserve the sublattice order. Here we show that the appearance of the topologically protected states in stacking domain walls can be much more common in bilayer graphene, since they can also emerge in unexpected geometries, e.g., at grain boundaries with atomic-scale topological defects. We focus on a bilayer system in which one of the layers contains a line of octagon-double pentagon defects that mix graphene sublattices. We demonstrate that gap states are preserved even with pentagonal defects. Remarkably, unlike previous predictions, the number of gap states changes by inverting the gate polarization, yielding an asymmetric conductance along the grain boundary under gate reversal. This effect, linked to defect states, should be detectable in transport measurements and could be exploited in electrical switches. PMID- 26931740 TI - Update on the effect of estradiol in postmenopause women with Alzheimer's disease: a systematic review. AB - Estradiol (E2) has been used in the treatment of Alzheimer's disease (AD) for many years but with various responses. Evidence from clinical studies, randomized clinical trials (RCTs), and observational studies further underscores the importance of E2 in postmenopause women diagnosed with AD. The purpose of this article is to review all clinical trials to date focusing on the E2 in AD patients to explore the evidence regarding use of E2 in AD treatments. To achieve this objective, clinical studies regarding E2 levels in AD patients and RCTs assessing AD treatment in postmenopause women were identified through searches of MEDLINE, The Cochrane Library, EMBASE, Web of Science, Ovid, and Google Scholar. E2 has demonstrated good therapeutic effectiveness in AD patients, however, further larger scale, double-blind RCTs are required before a definitive conclusion can be reached and the results need to be compared with other drugs. This update reviews the newest clinical information regarding the role of E2 in postmenopause women with AD. To our knowledge, this is the only systematic review of this area. PMID- 26931742 TI - Is extracorporeal treatment useful for managing severe baclofen poisoning even on patients with normal renal function? Indeed a very open debate! PMID- 26931741 TI - HOXB13 protein expression in metastatic lesions is a promising marker for prostate origin. AB - The HOXB13 gene is a member of the homeobox gene family, and prostate development depends on HOXB13 function. HOXB13 is a very sensitive and specific marker of prostate tissue and prostate cancer. When the origin of a tumor in a resection specimen or in biopsy material is unclear, it allows determining the prostate as the primary. Our aim was to determine whether HOXB13 has similar sensitivity for determining prostate origin of lymph node and bone metastases. We retrieved cases of lymph node and bone metastases of histologically confirmed prostate cancer (PCa) and selected lymph node metastases of urothelial carcinoma (UCa). A panel of antibodies against HOXB13, PSA, ERG, Androgen receptors, p504S, p63, GATA-3, CK7, and Uroplakin 2 and 3 was tested on these tissue samples. Two pathologists analysed and scored staining as either 0 (negative) or + (positive). The selected cohort consisted of 74 cases of lymph node and 15 of bone metastases of PCa and 15 of lymph node metastases of UCa. HOXB13 was expressed in 93 % of lymph node and in 33 % of bone metastases of PCa. All lymph node metastases of UCa were negative. Sensitivity of HOXB13 as a marker for prostate origin in lymph node metastases was 93 % and for bone metastases 33 %. Inter-observer variability in assessment of staining was good, as only two (1.9 %) of lymph node metastasis of PCa were discordant. HOXB13 is a useful marker for prostate origin when doubt exists regarding the site of the primary of a metastatic lesion. On bone metastases, HOXB13 immunohistochemistry performed less well, probably due to the use of tissue decalcification. PMID- 26931743 TI - Dynamic shear force microscopy of viscosity in nanometer-confined hexadecane layers. AB - Hexadecane exhibits pronounced molecular layering upon confinement to gaps of a few nanometer width which is discussed for its role in boundary lubrication. We have probed the mechanical properties of the confined layers with the help of an atomic force microscope, by quasi-static normal force measurements and by analyzing the lateral tip motion of a magnetically actuated torsional cantilever oscillation. The molecular layering is modeled by a oscillatory force curve and the tip approach is simulated assuming thermal equilibrium correlations in the liquid. The shear response of the confined layers reveals gradually increasing stiffness and viscous dissipation for a decreasing number of confined layers. PMID- 26931744 TI - Outcome of liver transplantation in patients with hereditary bleeding disorders: a single centre UK experience. AB - INTRODUCTION: Patients with hereditary bleeding disorders who have developed end stage liver disease as a consequence of hepatitis C infection (HCV) acquired from factor concentrates prior to the introduction of viral inactivation continue to be referred for liver transplantation. METHODS: A retrospective review of case notes and electronic records was performed on all patients with bleeding disorders who have undergone liver transplantation at the University Hospital Birmingham (UHB). RESULTS: Between 1990 and 2014, 35 liver transplants have been performed in 33 patients with hereditary bleeding disorders. The indication for transplantation was mainly end-stage liver disease secondary to HCV. Five patients had human immunodeficiency virus (HIV) co-infection. No excess mortality due to bleeding occurred in the peri or postoperative period. Median overall survival post transplant is 9.7 years. Overall survival rates at 1, 3 and 5 years are 90%, 72% and 64% respectively. The predominant cause of mortality was liver failure secondary to either recurrent HCV or recurrent hepatocellular carcinoma (HCC). The median overall survival in patients with HIV co-infection is shorter than in those with mono-infection but this is not statistically significant. Patients with a pre-existing HCC had a statistically significant shorter survival (2.4 years vs. 13.6 years, P = 0.007). CONCLUSION: Liver transplantation has become an accepted treatment option for patients with hereditary bleeding disorders and HCV associated end-stage liver disease with survival rates similar to non-bleeding disorder patients. PMID- 26931746 TI - A survey and multilevel analysis of nursing unit tenure diversity and medication errors. AB - AIM: This empirical research aimed to identify relationships between nurses' unit tenure, nursing unit tenure diversity and medication errors. BACKGROUND: Research examining medication errors has paid little attention to the effects of multilevel precursors. METHOD: In total, 567 registered nurses (from 36 nursing units) completed a survey questionnaire at a university hospital during September 2012. Of these, 334 (completed by nurses from 22 nursing units) were eligible for multilevel analysis. RESULTS: The average frequency of self-reported medication errors per registered nurse in the preceding 6 months was 0.98. Multilevel analysis showed that medication errors were significantly negatively associated with nurses' unit tenure at individual level (B = -0.64, P = 0.002) and nursing unit tenure diversity at unit level (B = -0.69, P < 0.001). Furthermore, nursing unit tenure diversity moderated the relationship between nurses' unit tenure and medication errors (B = 0.48, P = 0.012). CONCLUSION: This study provided evidence indicating that novice nurses made a higher number of medication errors relative to experienced nurses, and that including a mixture of novice and experienced nurses in a nursing unit attenuated novice nurses' medication errors. IMPLICATIONS FOR NURSING MANAGEMENT: The development of staffing strategies that enhance nursing unit tenure diversity is required. PMID- 26931745 TI - Atopic dermatitis induces the expansion of thymus-derived regulatory T cells exhibiting a Th2-like phenotype in mice. AB - Atopic dermatitis (AD) is a widespread inflammatory skin disease with an early onset, characterized by pruritus, eczematous lesions and skin dryness. This chronic relapsing disease is believed to be primarily a result of a defective epidermal barrier function associated with genetic susceptibility, immune hyper responsiveness of the skin and environmental factors. Although the important role of abnormal immune reactivity in the pathogenesis of AD is widely accepted, the role of regulatory T cells (Tregs) remains elusive. We found that the Treg population is expanded in a mouse model of AD, i.e. mice topically treated with vitamin D3 (VitD). Moreover, mice with AD-like symptoms exhibit increased inducible T-cell costimulator (ICOS)-, cytotoxic T-lymphocyte antigen-4 (CTLA-4)- and Glycoprotein-A repetitions predominant receptor (GARP)-expressing Tregs in skin-draining lymph nodes. Importantly, the differentiation of Tregs into thymus derived Tregs is favoured in our mouse model of AD. Emigrated skin-derived dendritic cells are required for Treg induction and Langerhans cells are responsible for the biased expansion of thymus-derived Tregs . Intriguingly, thymus-derived Tregs isolated from mice with AD-like symptoms exhibit a Th2 cytokine profile. Thus, AD might favour the expansion of pathogenic Tregs able to produce Th2 cytokines and to promote the disease instead of alleviating symptoms. PMID- 26931747 TI - Transplantation of bone marrow-derived mesenchymal stem cells (BMSCs) improves brain ischemia-induced pulmonary injury in rats associated to TNF-alpha expression. AB - BACKGROUND: Bone marrow mesenchymal stem cell (BMSCs)-based therapy seems to be a promising treatment for acute lung injury, but the therapeutic effects of BMSCs transplantation on acute lung injury induced by brain ischemia and the mechanisms have not been totally elucidated. This study explores the effects of transplantation of BMSCs on acute lung injury induced by focal cerebral ischemia and investigates the underlying mechanism. METHODS: Acute lung injury model was induced by middle cerebral artery occlusion (MCAO). BMSCs (with concentration of 1 * 10(6)/ml) were transplanted into host through tail vein 1 day after MCAO. Then, the survival, proliferation and migration of BMSCs in lung were observed at 4 days after transplantation, and histology observation and lung function were assessed for 7 days. Meanwhile, in situ hybridization (ISH), qRT-PCR and western blotting were employed to detect the expression of TNF-alpha in lung. RESULTS: Neurobehavioral deficits and acute lung injury could be seen in brain ischemia rats. Implanted BMSCs could survive in the lung, and relieve pulmonary edema, improve lung function, as well as down regulate TNF-alpha expression. CONCLUSIONS: The grafted BMSCs can survive and migrate widespread in lung and ameliorate lung injury induced by focal cerebral ischemia in the MCAO rat models. The underlying molecular mechanism, at least partially, is related to the suppression of TNF-alpha. PMID- 26931749 TI - Extreme Sport/Adventure Activity Correlates in Gynecologic Cancer Survivors. AB - OBJECTIVE: We examined the demographic, medical and behavioral correlates of participation and interest in extreme sport/adventure activities (ESAA) in gynecologic cancer survivors. METHODS: A random sample of 621 gynecologic cancer survivors in Alberta, Canada, completed a mailed self-report questionnaire assessing medical, demographic, and behavioral variables and participation and interest in ESAA. RESULTS: Multivariate analyses revealed that gynecologic cancer survivors were more likely to participate in ESAA if they met aerobic exercise guidelines (OR=1.75 [95%CI:1.02-2.99]), had better general health (OR=1.71 [95%CI: 1.01-2.90]), had cervical or ovarian cancer (OR=1.95 [95%CI:0.97-3.93]), were employed (OR=1.71 [95%CI:0.95-3.08]), and were of healthy weight (OR=1.58 [95%CI:0.93-2.68]). Moreover, gynecologic cancer survivors were more likely to be interested in trying an ESAA if they had cervical or ovarian cancer (OR=1.76 [95%CI:0.94-3.27]) and were meeting the strength exercise guidelines (OR=1.68 [95%CI:0.95-2.98]). CONCLUSIONS: Medical, demographic, and behavioral variables correlate with participation and interest in ESAA in gynecologic cancer survivors. The pattern of correlates suggests that gynecologic cancer survivors are more likely to participate in ESSA if they have the physical capability and financial resources. Interventions to promote ESAA in gynecologic cancer survivors need to address these 2 key barriers. PMID- 26931748 TI - Meta-analyses of Theory Use in Medication Adherence Intervention Research. AB - OBJECTIVE: This systematic review applied meta-analytic procedures to integrate primary research that examined theory- or model-linked medication adherence interventions. METHODS: Extensive literature searching strategies were used to locate trials testing interventions with medication adherence behavior outcomes measured by electronic event monitoring, pharmacy refills, pill counts, and self reports. Random-effects model analysis was used to calculate standardized mean difference effect sizes for medication adherence outcomes. RESULTS: Codable data were extracted from 146 comparisons with 19,348 participants. The most common theories and models were social cognitive theory and motivational interviewing. The overall weighted effect size for all interventions comparing treatment and control participants was 0.294. The effect size for interventions based on single theories was 0.323 and for multiple-theory interventions was 0.214. Effect sizes for individual theories and models ranged from 0.041 to 0.447. The largest effect sizes were for interventions based on the health belief model (0.477) and adult learning theory (0.443). The smallest effect sizes were for interventions based on PRECEDE (0.041) and self-regulation (0.118). CONCLUSION: These findings suggest that theory- and model-linked interventions have a significant but modest effect on medication adherence outcomes. PMID- 26931750 TI - Association between Daytime Napping and Chronic Diseases in China. AB - OBJECTIVES: To explore the relationship between daytime napping and incidence of chronic diseases over the past 6 months among adults in China. METHODS: Based on data collected from 13,469 respondents over age 40 in the Chinese Family Panel Studies in 2010, logistic regression models were estimated to examine the association between daytime napping and the incidence of any chronic diseases and 3 specific chronic diseases (hypertension, diabetes, and heart disease) after adjusting for confounders. Differences of risks by sex and age were also investigated. RESULTS: In the sample, 50.8% were women and 32.2% were over 60 years old. Adjusted estimates show respondents with daytime napping had elevated odds of developing any chronic diseases, hypertension, and diabetes compared to those who did not nap; having over 60 minutes of daytime napping had weaker association compared with shorter duration of daytime napping. The association between daytime napping and hypertension was found in women but not in men. CONCLUSIONS: Daytime napping appears to be associated with elevated risk of incidence of any chronic diseases, hypertension, and diabetes. PMID- 26931753 TI - Development and Impact of a Worksite Wellness Champions Program. AB - OBJECTIVES: Wellness champions have potential to be a high-reach, low-cost intervention for improving employee health, but research is needed to support this premise. Therefore, this project assessed the impact of a worksite wellness champions program at a large integrated healthcare organization. METHODS: A total of 2315 employees responded (56% response rate) to a survey. RESULTS: Program participants (N = 666) were more likely to agree that the organization provides a supportive environment to live a healthy lifestyle (82.7% vs 69.4%, p < .001), more likely to agree co-workers support one another in practicing a healthy lifestyle (76.8% vs 53.7%, p < .001), and to rate their overall health and wellness higher (p < .005) compared to those not familiar with the wellness champions program (N = 675). CONCLUSIONS: Employees participating in wellness champion activities have increased their awareness of wellness opportunities, feel supported for having a healthy lifestyle, and rate their perceived health and wellness higher. PMID- 26931752 TI - Medical Marijuana Legalization and Co-use in Adult Cigarette Smokers. AB - OBJECTIVES: We examined effects of long-term medical marijuana legalization on cigarette co-use in a sample of adults. METHODS: We conducted secondary analysis using data from the 2014 US Tobacco Attitudes and Beliefs Survey, which consisted of cigarette smokers, aged >= 45 years (N = 506). Participants were categorized by their state residence, where medical marijuana was (1) illegal, (2) legalized < 10 years, and (3) legalized >= 10 years. The Web-based survey assessed participants' marijuana use, beliefs and attitudes on marijuana, and nicotine dependence using Fagerstrom Tolerance for Nicotine Dependence (FTND) and Hooked on Nicotine Checklist (HONC) scores. RESULTS: In cigarette smokers aged >= 45 years, long-term legalization of medical marijuana was associated with stable positive increases in marijuana use prevalence (ever in a lifetime) (p = .005) and frequency (number of days in past 30 days) (unadjusted p = .005; adjusted p = .08). Those who reported marijuana co-use had greater FTND and HONC scores after adjusting for covariates (p = .05). CONCLUSIONS: These preliminary findings warrant further examination of the potential impact of long-term legalization of medical marijuana on greater cigarette and marijuana co-use in adults and higher nicotine dependence among co-users at the population level. PMID- 26931751 TI - Barriers to Self-management of Serious Mental Illness and Diabetes. AB - OBJECTIVES: Individuals with serious mental illness (SMI) (major depressive disorder, bipolar disorder, schizophrenia), and diabetes (DM), face significant challenges in managing their physical and mental health. The objective of this study was to assess perceived barriers to self-management among patients with both SMI and DM in order to inform healthcare delivery practices. METHODS: We conducted 20 in-depth interviews with persons who had diagnoses of both SMI and DM. All interviews were audiotaped, transcribed verbatim, and analyzed using content analysis with an emphasis on dominant themes. RESULTS: Transcript-based analysis generated 3 major domains of barriers to disease self-management among patients with both DM and SMI: (1) personal level barriers (stress, isolation, stigma); (2) family and community level barriers (lack of support from family and friends); and (3) provider and health care system level barriers (poor relationships and communication with providers, fragmentation of care). CONCLUSIONS: Care approaches that provide social support, help in managing stress, optimize communication with providers, and reduce compartmentalization of medical and psychiatric care are needed to help these vulnerable individuals avoid health complications and premature mortality. PMID- 26931755 TI - The Association between Deliberate Self-harm and College Student Subjective Quality of Life. AB - OBJECTIVES: The association between deliberate self-harm (DSH) and domain-based life satisfaction reports and health-related quality of life (HRQOL) was explored simultaneously among college students. METHODS: Randomly selected participants (N = 723) completed an online survey. Relationships among DSH, 7 life satisfaction domains, and HRQOL (as assessed by mean good physical and mental health days, GHDs) were examined through correlational and general linear modeling procedures with post hoc analyses. RESULTS: DSH was a significant predictor for all life satisfaction domains, overall life satisfaction, and mean GHDs, even after controlling for covariates (p < .0001), with greatest dissatisfaction with friendships and selves. Effect sizes ranged from .42 (living environment) to 1.18 (overall). Students who engaged in DSH reported 15.2 mean GHDs during the past 30 days compared to 20.4 for the referent group (Cohen's d = .63). CONCLUSIONS: Those engaging in DSH report greatest dissatisfaction with friendships and selves compared to those not engaging in DSH. Surprisingly, DSH was only weakly associated with satisfaction with family, and behind that of satisfaction with physical appearance, school, and romantic relationships. Lastly, those engaging in DSH experience on average 60 fewer GHDs each year than those not engaging in DSH. PMID- 26931756 TI - The Impact of Spirituality and Religiosity on Unprotected Sex for Adult Women. AB - OBJECTIVES: To explore the relationship of spirituality and religiosity with sexual behavioral self-efficacy in predicting recent unprotected sex in a sample of adult women, predominantly comprised of African Americans. METHODS: Data were collected from a sample of 171 adult women via a paper-and-pencil questionnaire. We conducted a path analysis to test the proposed relationships. RESULTS: An increase in both religiosity and spirituality predicted a decrease in number of types of recent unprotected sex, indirectly through sexual behavior self efficacy. All indirect effects were similar in magnitude. CONCLUSIONS: The results suggest that religiosity and spirituality are both associated with unprotected sex through sexual self-efficacy among African-American women. Faith based strategies warrant further examination as components of sexual risk reduction efforts for this population. PMID- 26931754 TI - Father Involvement in Feeding Interactions with Their Young Children. AB - OBJECTIVE: To examine the associations of father-child feeding and physical interactions with dietary practices and weight status in children. METHODS: A nationally representative sample of children, mothers, and fathers who participated in the Early Childhood Longitudinal Study Birth cohort study (N = 2441) was used to explore the relationship of father-child feeding and physical activity interactions with child dietary practices and weight status. Logistic multivariable regression analyses were adjusted for child, father, mother, and socio-demographic characteristics. RESULTS: Approximately 40% of fathers reported having a great deal of influence on their preschool child's nutrition and about 50% reported daily involvement in preparing food for their child and assisting their child with eating. Children had over 2 times the odds of consuming fast food at least once a week if fathers reported eating out with their child a few times a week compared to fathers who reported rarely or never eating out with their child (OR, 2.89; 95% CI, 1.94-4.29), adjusting for all covariates. Whether fathers reported eating out with their children was also significantly associated with children's sweetened beverage intake. CONCLUSIONS: Potentially modifiable behaviors that support healthy dietary practices in children may be supported by targeting fathers. PMID- 26931757 TI - Health Beliefs of Marshallese Regarding Type 2 Diabetes. AB - OBJECTIVES: The Marshallese population suffers from disproportionate rates of type 2 diabetes. This study identifies the underlying beliefs and perceptions that affect diabetes self-management behavior in the US Marshallese population living in Arkansas. METHODS: The study employs focus groups with a semi structured interview guide developed using a community-based participatory research (CBPR) approach and the Health Belief Model. Data were collected from 41 participants; bilingual community co-investigators provided translation as needed. RESULTS: The results show high-perceived threat, with most participants describing diabetes as inevitable and a death sentence. Participants are generally unaware of the benefits of diabetes self-management behaviors, and the Marshallese population faces significant policy, environmental, and systems barriers to diabetes self-management. The primary cue to action is a diagnosis of diabetes, and there are varying levels of self-efficacy. CONCLUSIONS: The research grounded in the Health Belief Model provides important contributions that can help advance diabetes self-management efforts within Pacific Islander communities. PMID- 26931759 TI - Electronic Cigarette Use in Straight-to-Work Young Adults. AB - OBJECTIVE: We explored beliefs about electronic cigarettes (e-cigarettes) as well as social influences on e-cigarette use in straight-to-work (STW) young adults. METHODS: Thirty interviews were conducted with STW young adults ages 19-31 years old. We asked participants about smoking and e-cigarette use, beliefs about e cigarettes, and influences on decisions to use e-cigarettes. We conducted interviews in community locations and transcribed and coded them using NVivo. RESULTS: We identified 4 themes: benefits of e-cigarette use; dual use/continued smoking; social influences; and quitting smoking and e-cigarettes. STW young adults initiated e-cigarette use to quit smoking but most became dual users or reported cycles of smoking and e-cigarette use. Flavors were a primary attraction for e-cigarette users. Family and friends supported e-cigarette use and often provided participants with their first e-cigarette. Most participants who no longer identified as smokers still smoked occasionally. Users felt they were more positively perceived by others when they used e-cigarettes but were still seen as smokers or former smokers. CONCLUSIONS: E-cigarette use may bring STW young adults closer to their aspirational identity of non-smoker but many may be vulnerable to smoking relapse or increased dependence on nicotine through dual use. PMID- 26931758 TI - Associations of Mindfulness with Glucose Regulation and Diabetes. AB - OBJECTIVE: To evaluate whether dispositional mindfulness is associated with glucose regulation and type 2 diabetes. METHODS: Study participants (N = 399) were from the New England Family Study, a prospective birth cohort, with median age 47 years. Dispositional mindfulness was assessed using the Mindful Attention Awareness Scale (MAAS). Type 2 diabetes and "normal plasma glucose" were defined using American Diabetes Association criteria. RESULTS: Multivariable-adjusted regression analyses demonstrated that participants with high versus low MAAS scores were significantly more likely to have normal plasma glucose levels (prevalence ratio = 1.35 (95% confidence interval (CI): 1.08,1.87)), and were not significantly associated with type 2 diabetes (prevalence ratio = 0.83, 95% CI: 0.38,1.79), adjusted for age, sex, race/ethnicity, family history of diabetes and childhood socioeconomic status. Mediation analyses provided evidence of mediation via obesity and sense of control, where indirect effects were prevalence ratios (95% CI) of 1.03 (1.00,1.10) and 1.08 (1.00,1.21), respectively. CONCLUSIONS: Dispositional mindfulness may be associated with better glucose regulation, in part because of a lower likelihood of obesity and greater sense of control among participants with higher levels of mindfulness. These findings need to be replicated by prospective studies to establish causality and to evaluate potential implications for mindfulness-based interventions to reduce risk of type 2 diabetes. PMID- 26931760 TI - Physical Activity and Transitioning to College: The Importance of Intentions and Habits. AB - OBJECTIVES: First generation students transitioning to college experience specific challenges that impact on their engagement in physical activity. Furthermore, this population experiences a context disruption that provides a unique opportunity to examine whether intention and habit predict physical activity. The aim of the current research was to determine the efficacy of the theory of planned behavior in the prediction of intention and behavior within this population, and to determine whether habit contributes to the prediction of physical activity. METHODS: In this observational study, a convenience sample of first generation college students (N = 101) completed measures of theory of planned behavior variables and habit strength at Time 1, and one week later reported physical activity. RESULTS: The theory of planned behavior was partially supported in this context, as intention was the only significant predictor of behavior. Habit strength accounted for additional variance in physical activity but did not moderate the relationship between intention and behavior. The hypothesized model accounted for 46.9% of the variance in physical activity, and intention (beta = .455) and habit (beta = .364) were significant predictors. CONCLUSIONS: Intention and habit exert independent effects on physical activity within this population, and are both suitable targets for intervention. PMID- 26931762 TI - The energy-level crossing behavior and quantum Fisher information in a quantum well with spin-orbit coupling. AB - We study the energy-level crossing behavior in a two-dimensional quantum well with the Rashba and Dresselhaus spin-orbit couplings (SOCs). By mapping the SOC Hamiltonian onto an anisotropic Rabi model, we obtain the approximate ground state and its quantum Fisher information (QFI) via performing a unitary transformation. We find that the energy-level crossing can occur in the quantum well system within the available parameters rather than in cavity and circuit quantum eletrodynamics systems. Furthermore, the influence of two kinds of SOCs on the QFI is investigated and an intuitive explanation from the viewpoint of the stationary perturbation theory is given. PMID- 26931761 TI - Impact of Trypanosoma cruzi on antimicrobial peptide gene expression and activity in the fat body and midgut of Rhodnius prolixus. AB - BACKGROUND: Rhodnius prolixus is a major vector of Trypanosoma cruzi, the causative agent of Chagas disease in Latin America. In natural habitats, these insects are in contact with a variety of bacteria, fungi, virus and parasites that they acquire from both their environments and the blood of their hosts. Microorganism ingestion may trigger the synthesis of humoral immune factors, including antimicrobial peptides (AMPs). The objective of this study was to compare the expression levels of AMPs (defensins and prolixicin) in the different midgut compartments and the fat body of R. prolixus infected with different T. cruzi strains. The T. cruzi Dm 28c clone (TcI) successfully develops whereas Y strain (TcII) does not complete its life- cycle in R. prolixus. The relative AMP gene expressions were evaluated in the insect midgut and fat body infected on different days with the T. cruzi Dm 28c clone and the Y strain. The influence of the antibacterial activity on the intestinal microbiota was taken into account. METHODS: The presence of T. cruzi in the midgut of R. prolixus was analysed by optical microscope. The relative expression of the antimicrobial peptides encoding genes defensin (defA, defB, defC) and prolixicin (prol) was quantified by RT-qPCR. The antimicrobial activity of the AMPs against Staphylococcus aureus, Escherichia coli and Serratia marcescens were evaluated in vitro using turbidimetric tests with haemolymph, anterior and posterior midgut samples. Midgut bacteria were quantified using colony forming unit (CFU) assays and real time quantitative polymerase chain reaction (RT-qPCR). RESULTS: Our results showed that the infection of R. prolixus by the two different T. cruzi strains exhibited different temporal AMP induction profiles in the anterior and posterior midgut. Insects infected with T. cruzi Dm 28c exhibited an increase in defC and prol transcripts and a simultaneous reduction in the midgut cultivable bacteria population, Serratia marcescens and Rhodococcus rhodnii. In contrast, the T. cruzi Y strain neither induced AMP gene expression in the gut nor reduced the number of colony formation units in the anterior midgut. Beside the induction of a local immune response in the midgut after feeding R. prolixus with T. cruzi, a simultaneous systemic response was also detected in the fat body. CONCLUSIONS: R. prolixus AMP gene expressions and the cultivable midgut bacterial microbiota were modulated in distinct patterns, which depend on the T. cruzi genotype used for infection. PMID- 26931763 TI - Study protocol of the ESUB-MG cluster randomized trial: a pragmatic trial assessing the implementation of urine drug screening in general practice for buprenorphine maintained patients. AB - BACKGROUND: In addiction care, urine drug screening tests are recommended to assess psychoactive substances use. While intrinsic diagnostic value of these tests is demonstrated, the consequences of carrying out these tests on opiate maintenance treatment (OMT) have not been established. The main objective will be to assess the impact of on-site urine drug screening tests (OS-UDS) in general practice compared to routine medical care on OMT retention at 6 months in opioid dependent patients initiating buprenorphine. METHODS/DESIGN: The ESUB-MG study uses a pragmatic, cluster randomized controlled trial design. General Practitioners (GPs) regularly managing patients treated with buprenorphine and consenting for participating will be invited to participate. GPs will be randomly assigned to one of two groups for 6 to 24 months: (a) control group (usual care: standard medical strategy for assessing drug use); (b) interventional group (including 1/ a training session on practice and interpretation of OS-UDS; 2/ the supply of OS-UDS at GPs' medical offices; 3/ performing an OS-UDS before the first prescription of buprenorphine). GPs will have to include 1 to 10 patients aged 18 years-old or more, consulting for starting treatment by buprenorphine, not opposed to participate. The primary outcome will be OMT retention at 6 months. DISCUSSION: This randomized interventional trial should bring sufficient level of evidence to assess effectiveness of performing OS-UDS in general practice for patients treated by buprenorphine. Training GPs to drug tests and supplying them in their office should lead to an improvement of opioid-addicted patients' care through helping decision. TRIALS REGISTRATION: NCT02345655 (first registration May 14, 2014). PMID- 26931764 TI - Diagnostic Value of CRP, Procalcitonin, and Ferritin Levels in Cerebrospinal Fluid of Children with Meningitis. AB - BACKGROUND AND OBJECTIVE: Bacterial meningitis is a serious disease with high rate of mortality and morbidity in children. Invasion of pathogens causes brain and meningeal inflammation, which leads to the release of biomarkers into cerebrospinal fluid (CSF). Identification of these biomarkers can help the physicians to differentiate between bacterial and aseptic meningitis. In the current study, some of these biomarkers such as Procalcitonin, C reactive protein (CRP), and Ferritin, were compared in cerebrospinal fluid (CSF) of patients with bacterial and aseptic meningitis. METHODS: In a prospective cross sectional study in a referral children hospital in Tehran during 2011- 2013, the CSF levels of Procalcitonin, Ferritin, and CRP were measured in 57 children with clinically suspected meningitis. The Mann-Whitney u test and the chi-square test were used to compare two groups, children with bacterial and aseptic meningitis. The cut offs of biomarker levels for differentiation between the 2 groups were constructed by receiver-operating - characteristic curve (ROC). RESULTS: 57 subjects (30 bacterial and 27 aseptic meningitis), were enrolled in this survey. In comparing the two groups, the CSF levels of Ferritin, CRP, and procalcitonin in bacterial meningitis were significantly higher than in aseptic meningitis (P values=?0.001, 0.001, ?0.001respectively), with sensitivity/ specificity being 92.9% / 68%, 92.9% / 84%, and 96.4% / 80%, respectively. Positive Predictive Values (PPV) were, correspondingly, 96.4%, 92.8%, and 92.8% for procalcitonin, Ferritin, and CRP. Corresponding Negative Predictive Values (NPV) were, respectively equal to 95.4%, 70%, and 88%. CONCLUSION: CSF of children with bacterial meningitis contains higher levels of inflammatory mediators including Procalcitonin, Ferritin, and CRP, compared to aseptic meningitis The biomarkers provided high sensitivity (especially PCT) and specificity (especially CRP). Using these complementary biomarkers would be useful for early diagnosis of bacterial meningitis and selection of appropriate treatment. PMID- 26931765 TI - Analgesic Effects Mediated by Muscarinic Receptors: Mechanisms and Pharmacological Approaches. AB - Chronic pain represents a research field on great clinical relevance and social impactful. It is associated to a variety of pathological events causing un altered excitability of peripheral nerves derived by tissue damage depending on physical, biological and chemical injury. In the last years much attention has been paid in the identification of novel molecules involved in mediating pain sensation useful as therapeutic tools for the development of new analgesic drugs. Muscarinic receptors are widely distributed both in the central and peripheral nervous system. It is known that muscarinic agonists cause analgesic effects via spinal and supraspinal mechanisms. Considering that the analgesia induced by cholinergic agonists is comparable to that observed with morphine, the identification of receptor subtypes involved and the identification of the muscarinic ligands capable of selectively activate these receptors, is of considerable interest for potential therapeutic application. In the present review we describe the role of muscarinic receptors in mediating central and peripheral pain and the mechanisms downstream these receptors responsible of the modulation of nociceptive stimuli. Moreover the therapeutic perspectives and the identification of potential drugs binding muscarinic receptors involved in pain modulation will also be discussed. PMID- 26931767 TI - Ethical challenges when using coercion in mental healthcare: A systematic literature review. AB - BACKGROUND: To better understand the kinds of ethical challenges that emerge when using coercion in mental healthcare, and the importance of these ethical challenges, this article presents a systematic review of scientific literature. METHODS: A systematic search in the databases MEDLINE, PsychInfo, Cinahl, Sociological Abstracts and Web of Knowledge was carried out. The search terms derived from the population, intervention, comparison/setting and outcome. A total of 22 studies were included. Ethical considerations: The review is conducted according to the Vancouver Protocol. RESULTS: There are few studies that study ethical challenges when using coercion in an explicit way. However, promoting the patient's best interest is the most important justification for coercion. Patient autonomy is a fundamental challenge facing any use of coercion, and some kind of autonomy infringement is a key aspect of the concept of coercion. The concepts of coercion and autonomy and the relations between them are very complex. When coercion is used, a primary ethical challenge is to assess the balance between promoting good (beneficence) and inflicting harm (maleficence). In the included studies, findings explicitly related to justice are few. Some studies focus on moral distress experienced by the healthcare professionals using coercion. CONCLUSION: There is a lack of literature explicitly addressing ethical challenges related to the use of coercion in mental healthcare. It is essential for healthcare personnel to develop a strong awareness of which ethical challenges they face in connection with the use of coercion, as well as challenges related to justice. How to address ethical challenges in ways that prevent illegitimate paternalism and strengthen beneficent treatment and care and trust in connection with the use of coercion is a 'clinical must'. By developing a more refined and rich language describing ethical challenges, clinicians may be better equipped to prevent coercion and the accompanying moral distress. PMID- 26931766 TI - Lifestyle Modification for the Prevention of Morbidity and Mortality in Adult Congenital Heart Disease. AB - Patients with adult congenital heart disease are now living longer due to the advancements in medicine. As such, these patients are now experiencing morbidities that are commonly seen in the general population such as myocardial infarction, heart failure, and arrhythmias. Often times these problems can be attributed to the underlying adult congenital heart disease; however, a patient making poor lifestyle choices only compounds their risk for these life threatening comorbidities. The aim of this article is to propose recommendations for health care providers to follow with this specific patient population. These recommendations encompass the importance of proper caloric intake, methods of weight loss (including behavioral therapy, drugs, and surgeries), practical recommendations for physical activity, and the implications of substance abuse. Being proactive and addressing important lifestyle choices in this population can reduce comorbidities and, therefore, medical cost. PMID- 26931768 TI - Looking beyond the veil of the European crisis--the need to uncover the structural causes of health inequalities. PMID- 26931769 TI - Microbiology and risk factors associated with war-related wound infections in the Middle East. AB - The Middle East region is plagued with repeated armed conflicts that affect both civilians and soldiers. Injuries sustained during war are common and frequently associated with multiple life-threatening complications. Wound infections are major consequences of these war injuries. The microbiology of war-related wound infections is variable with predominance of Gram-negative bacteria in later stages. The emergence of antimicrobial resistance among isolates affecting war related wound injuries is a serious problem with major regional and global implications. Factors responsible for the increase in multidrug-resistant pathogens include timing and type of surgical management, wide use of antimicrobial drugs, and the presence of metallic or organic fragments in the wound. Nosocomial transmission is the most important factor in the spread of multidrug-resistant pathogens. Wound management of war-related injuries merits a multidisciplinary approach. This review aims to describe the microbiology of war related wound infections and factors affecting their incidence from conflict areas in Iraq, Syria, Israel, and Lebanon. PMID- 26931770 TI - Self-spinning nanoparticle laden microdroplets for sensing and energy harvesting. AB - Exposure of a volatile organic vapour could set in powerful rotational motion a microdroplet composed of an aqueous salt solution loaded with metal nanoparticles. The solutal Marangoni motion on the surface originating from the sharp difference in the surface tension of water and organic vapour stimulated the strong vortices inside the droplet. The vapour sources of methanol, ethanol, diethyl ether, toluene, and chloroform stimulated motions of different magnitudes could easily be correlated to the surface tension gradient on the drop surface. Interestingly, when the nanoparticle laden droplet of aqueous salt solution was connected to an external electric circuit through a pair of electrodes, an ~85 95% reduction in the electrical resistance was observed across the spinning droplet. The extent of reduction in the resistance was found to have a correlation with the difference in the surface tension of the vapour source and the water droplet, which could be employed to distinguish the vapour sources. Remarkably, the power density of the same prototype was estimated to be around 7 MUW cm(-2), which indicated the potential of the phenomenon in converting surface energy into electrical in a non-destructive manner and under ambient conditions. Theoretical analysis uncovered that the difference in the zeta-potential near the electrodes was the major reason for the voltage generation. The prototype could also detect the repeated exposure and withdrawal of vapour sources, which helped in the development of a proof-of-concept detector to sense alcohol issuing out of the human breathing system. PMID- 26931772 TI - Differences in crestal bone-to-implant contact following an under-drilling compared to an over-drilling protocol. A study in the rabbit tibia. AB - OBJECTIVES: The objective of this study is to compare bone-to-implant contact (BIC) between implants inserted at high torque due to under-drilling of the crestal bone to those inserted at low torque due to over-drilling of the crestal bone. MATERIALS AND METHODS: Forty implants with diameters of 3.75 mm (group A) or 3.55 mm (group B) were inserted in the proximal tibiae of NZW rabbits in two separate surgeries on day 0 or 21. Osteotomy of the crestal bone was finalized with a 3.65-mm drill. In group A, implants were inserted at torque >=35 Ncm (under-drilling) and in group B with torque <10 Ncm (over-drilling). Implants and their surrounding bone were retrieved on day 42, thus creating 3- and 6-week observation periods, processed for non-decalcified histology and stained with toluidine blue. Crestal BIC (c-BIC) and total BIC (t-BIC) were measured. Wilcoxon test was used to evaluate differences between groups. RESULTS: Three weeks post surgery, the mean c-BIC in group A was 16.3 +/- 3.3 vs 31.5 +/- 3.4 % in group B (P < 0.05). At 6 weeks, a similar trend was observed (group A: 28.7 +/- 3.6 %; group B: 38.4 +/- 4.9 %) (P > 0.05). No differences in t-BIC were noted at 3 weeks and at 6 weeks between the groups. CONCLUSIONS: Insertion of implants with an over-drilling protocol of the crestal aspect of the osteotomy resulted in increased short-term crestal bone-to-implant contact. CLINICAL RELEVANCE: Insertion of implants with a high torque following an under-drilling protocol, commonly used for immediate loading, may reduce crestal bone-to-implant contact at early healing stages. PMID- 26931771 TI - Innate myeloid cell TNFR1 mediates first line defence against primary Mycobacterium tuberculosis infection. AB - TNF is crucial for controlling Mycobacterium tuberculosis infection and understanding how will help immunomodulating the host response. Here we assessed the contribution of TNFR1 pathway from innate myeloid versus T cells. We first established the prominent role of TNFR1 in haematopoietic cells for controlling M. tuberculosis in TNFR1 KO chimera mice. Further, absence of TNFR1 specifically on myeloid cells (M-TNFR1 KO) recapitulated the uncontrolled M. tuberculosis infection seen in fully TNFR1 deficient mice, with increased bacterial burden, exacerbated lung inflammation, and rapid death. Pulmonary IL-12p40 over expression was attributed to a prominent CD11b(+) Gr1(high) cell population in infected M-TNFR1 KO mice. By contrast, absence of TNFR1 on T-cells did not compromise the control of M. tuberculosis infection over 6-months. Thus, the protective TNF/TNFR1 pathway essential for controlling primary M. tuberculosis infection depends on innate macrophage and neutrophil myeloid cells, while TNFR1 pathway in T cells is dispensable. PMID- 26931774 TI - Molecular characterization and expression of metallothionein from freshwater pearl mussel, Hyriopsis schlegelii. AB - Two metallothionein genes (HsMT1 and HsMT2) were first identified and described from Hyriopsis schlegelii. The open reading frame of HsMT1 and HsMT2 were 216 and 222 bp, encoding a protein of 71 and 73 amino acid residues. The deduced amino acid sequences showed they contained parts of typical MT characteristics, apart from HsMT2 lacked Cys-Cys motifs. The phylogenetic tree showed HsMT1 shared a high similarity with that of other molluscs, but HsMT2 was split into a distinct group separated from known molluscan MTs. HsMT1 exhibited constitutive expression in all examined tissues and the highest expression occurred in hepatopancreas, however, nearly all HsMT2 was just detected in gonad. After Cd exposure, their mRNA levels presented similar expression patterns. The transgenic bacteria of HsMT1 showed higher tolerance than HsMT2 in Cd environment. It was implied that HsMT1 and HsMT2 were involved in metal response but HsMT2 might have other physiological functions. PMID- 26931775 TI - Magnetic ordering temperature of nanocrystalline Gd: enhancement of magnetic interactions via hydrogenation-induced "negative" pressure. AB - Gadolinium is a nearly ideal soft-magnetic material. However, one cannot take advantage of its properties at temperatures higher than the room temperature where Gd loses the ferromagnetic ordering. By using high-purity bulk samples with grains ~200 nm in size, we present proof-of-concept measurements of an increased Curie point (TC) and spontaneous magnetization in Gd due to hydrogenation. From first-principles we explain increase of TC in pure Gd due to the addition of hydrogen. We show that the interplay of the characteristic features in the electronic structure of the conduction band at the Fermi level in the high temperature paramagnetic phase of Gd and "negative" pressure exerted by hydrogen are responsible for the observed effect. PMID- 26931773 TI - A bacterial-biofilm-induced oral osteolytic infection can be successfully treated by immuno-targeting an extracellular nucleoid-associated protein. AB - Periodontal disease exemplifies a chronic and recurrent infection with a necessary biofilm component. Mucosal inflammation is a hallmark response of the host seen in chronic diseases, such as colitis, gingivitis, and periodontitis (and the related disorder peri-implantitis). We have taken advantage of our recently developed rat model of human peri-implantitis that recapitulates osteolysis, the requirement of biofilm formation, and the perpetuation of the bona fide disease state, to test a new therapeutic modality with two novel components. First we used hyperimmune antiserum directed against the DNABII family of proteins, now known to be a critical component of the extracellular matrix of bacterial biofilms. Second we delivered the antiserum as cargo in biodegradable microspheres to the site of the biofilm infection. We demonstrated that delivery of a single dose of anti-DNABII in poly(lactic-co-glycolic acid) (PLGA) microspheres induced significant resolution of experimental peri implantitis, including marked reduction of inflammation. These data support the continued development of a DNABII protein-targeted therapeutic for peri implantitis and other chronic inflammatory pathologies of the oral cavity in animals and humans. PMID- 26931778 TI - Extending our confidence in sustained virological response. PMID- 26931776 TI - Applicability of visceral adiposity index in predicting metabolic syndrome in adults with obstructive sleep apnea: a cross-sectional study. AB - BACKGROUND: Obstructive sleep apnea (OSA) is severely affected by visceral adiposity (VA) that correlates to another disorder-metabolic syndrome (MetS). However, little is known concerning the relation of visceral adiposity index (VAI)-a novel and simple indicator of VA, with OSA and MetS. The objective of the study was to analyze the association of VAI with both disorders and applicability to identify OSA patients at risk of MetS. METHODS: Consecutive individuals undergoing polysomnography and biochemical tests were enrolled, and differences in all subjects grouped by apnea-hypopnea index (AHI) were analyzed. Spearman correlation was performed for assessing the relationship between VAI, OSA-related indices and metabolic score-total number of the positive diagnostic criteria of MetS. Receiver operating characteristic (ROC) curve was conducted to obtain a cut off value of VAI for predicting incident MetS by sex. Then, the risk of MetS in OSA patients according to the cut-offs was attained by logistic regression. RESULTS: A total of 411 individuals were enrolled. Of whom, 361 subjects were diagnosed OSA (mild in 67 patients, moderate in 89 and severe in 205, respectively). A significant increasing trend based on AHI was observed in the variables of blood pressure, triglycerides, fasting glucose, incident MetS, metabolic score and VAI (all p < 0.05). Irrespective of gender, VAI was all significantly correlated with PSG characteristics as AHI, mean nocturnal oxygen saturation, the lowest oxygen saturation, metabolic score(all p < 0.05). A VAI of 2.282, 2.105, 2.511 (for all subjects, males and females, separately) were calculated to determine the occurrence of MetS. According to the cut-offs, OSA patients tended to suffer from greater risk in MetS (odds ratio [OR] = 10.237, p = 0.000; OR = 13.556, p = 0.000; OR = 21.458, p = 0.000). CONCLUSIONS: The present study suggested that VAI was significantly associated with MetS and OSA. As a simple and alternative approach obtained in everyday practice, it may offer a powerful tool to identify patients with OSA at risk of MetS. PMID- 26931777 TI - Disposition and metabolism of [(14)C] Sacubitril/Valsartan (formerly LCZ696) an angiotensin receptor neprilysin inhibitor, in healthy subjects. AB - 1. Sacubitril/valsartan (LCZ696) is an angiotensin receptor neprilysin inhibitor (ARNI) providing simultaneous inhibition of neprilysin (neutral endopeptidase 24.11; NEP) and blockade of the angiotensin II type-1 (AT1) receptor. 2. Following oral administration, [(14)C]LCZ696 delivers systemic exposure to valsartan and AHU377 (sacubitril), which is rapidly metabolized to LBQ657 (M1), the biologically active neprilysin inhibitor. Peak sacubitril plasma concentrations were reached within 0.5-1 h. The mean terminal half-lives of sacubitril, LBQ657 and valsartan were ~1.3, ~12 and ~21 h, respectively. 3. Renal excretion was the dominant route of elimination of radioactivity in human. Urine accounted for 51.7-67.8% and feces for 36.9 to 48.3 % of the total radioactivity. The majority of the drug was excreted as the active metabolite LBQ657 in urine and feces, total accounting for ~85.5% of the total dose. 4. Based upon in vitro studies, the potential for LCZ696 to inhibit or induce cytochrome P450 (CYP) enzymes and cause CYP-mediated drug interactions clinically was found to be low. PMID- 26931779 TI - Development of high efficiency 100% aqueous cobalt electrolyte dye-sensitised solar cells. AB - In this study we report the application of three cobalt redox shuttles in 100% aqueous electrolyte dye-sensitised solar cells (DSCs). By using chloride as a counter-ion for cobalt bipyridine, cobalt phenanthroline and cobalt bipyridine pyrazole, the redox shuttles were made water soluble; no surfactant or further treatment was necessary. A simple system of merely the redox shuttles and 1 methylbenzimidazole (MBI) in water as an electrolyte in combination with an organic dye and a mesoporous PEDOT counter electrode was optimised. The optimisation resulted in an average efficiency of 5.5% (record efficiency of 5.7%) at 1 sun. The results of this study present promising routes for further improvements of aqueous cobalt electrolyte DSCs. PMID- 26931780 TI - The Cyberchondria Severity Scale (CSS): German Validation and Development of a Short Form. AB - PURPOSE: 'Cyberchondria' describes a pattern of researching health information online motivated by distress or anxiety about health, which becomes excessive and in turn increases distress. The Cyberchondria Severity Scale (CSS) assesses this construct. The aims of the present study were to validate a German version of the CSS and to propose a short form. METHOD: The CSS was translated and posted online. Inclusion criteria were fulfilled by n = 500 participants (age 29.1 +/- 10.4 years, 73.6 % women). Item analyses, an exploratory factor analysis and correlations with health anxiety, somatic symptoms, health-care utilization and depression were calculated. A brief version with 15 items was developed (CSS-15) and validated in a second sample (n = 292; age 24.2 +/- 4.1 years, 76.4 % women). RESULTS: The internal consistency of the CSS was alpha = .93 and its split-half reliability alpha = .95. The mean item-total correlation was r itc = .51, the mean inter-item correlation r = .29 and the mean item difficulty p i = .36. The principal component analysis extracted five factors. The CSS score correlated highly with health anxiety and moderately with somatic symptoms and health-care utilization. The CSS-15 still had an internal consistency of alpha = .82 and the confirmatory factor analysis confirmed the five factors. The correlation coefficients with health-related measures were unaffected. CONCLUSION: The German version of the CSS possesses very good psychometric characteristics, which were preserved in a short version. The factorial structure was replicated. The correlations with health anxiety and depression for both scales underscore their validity and clinical relevance. PMID- 26931782 TI - Biosynthesis of two quercetin O-diglycosides in Escherichia coli. AB - Various flavonoid glycosides are found in nature, and their biological activities are as variable as their number. In some cases, the sugar moiety attached to the flavonoid modulates its biological activities. Flavonoid glycones are not easily synthesized chemically. Therefore, in this study, we attempted to synthesize quercetin 3-O-glucosyl (1->2) xyloside and quercetin 3-O-glucosyl (1->6) rhamnoside (also called rutin) using two uridine diphosphate-dependent glycosyltransferases (UGTs) in Escherichia coli. To synthesize quercetin 3-O glucosyl (1->2) xyloside, sequential glycosylation was carried out by regulating the expression time of the two UGTs. AtUGT78D2 was subcloned into a vector controlled by a Tac promoter without a lacI operator, while AtUGT79B1 was subcloned into a vector controlled by a T7 promoter. UDP-xyloside was supplied by concomitantly expressing UDP-glucose dehydrogenase (ugd) and UDP-xyloside synthase (UXS) in the E. coli. Using these strategies, 65.0 mg/L of quercetin 3-O glucosyl (1->2) xyloside was produced. For the synthesis of rutin, one UGT (BcGT1) was integrated into the E. coli chromosome and the other UGT (Fg2) was expressed in a plasmid along with RHM2 (rhamnose synthase gene 2). After optimization of the initial cell concentration and incubation temperature, 119.8 mg/L of rutin was produced. The strategies used in this study thus show promise for the synthesis of flavonoid diglucosides in E. coli. PMID- 26931783 TI - Longitudinal study on diffusion tensor imaging and diffusion tensor tractography following spinal cord contusion injury in rats. AB - INTRODUCTION: Diffusion tensor imaging (DTI) as a potential technology has been used in spinal cord injury (SCI) studies, but the longitudinal evaluation of DTI parameters after SCI, and the correlation between DTI parameters and locomotor outcomes need to be defined. METHODS: Adult Wistar rats (n = 6) underwent traumatic thoracic cord contusion by an NYU impactor. DTI and Basso-Beattie Bresnahan datasets were collected pre-SCI and 1, 3, 7, 14, and 84 days post-SCI. Diffusion tensor tractography (DTT) of the spinal cord was also generated. Fractional anisotropy (FA) and connection rate of fibers at the injury epicenter and at 5 mm rostral/caudal to the epicenter were calculated. The variations of these parameters after SCI were observed by one-way analysis of variance and the correlations between these parameters and motor function were explored by Pearson's correlation. RESULTS: FA at the epicenter decreased most remarkably on day 1 post-SCI (from 0.780 +/- 0.012 to 0.330 +/- 0.015), and continued to decrease slightly by day 3 post-SCI (0.313 +/- 0.015), while other parameters decreased significantly over the first 3 days after SCI. DTT showed residual fibers concentrated on ventral and ventrolateral sides of the cord. Moreover, FA at the epicenter exhibited the strongest correlation (r = 0.887, p = 0.000) with the locomotion performance. CONCLUSION: FA was sensitive to degeneration in white matter and DTT could directly reflect the distribution of the residual white matter. Moreover, days 1 to 3 post-SCI may be the optimal time window for SCI examination and therapy. PMID- 26931784 TI - Deletion of the entire interferon-gamma receptor 1 gene causing complete deficiency in three related patients. AB - PURPOSE: Complete interferon-gamma receptor 1 (IFN-gammaR1) deficiency is a primary immunodeficiency causing predisposition to severe infection due to intracellular pathogens. Only 36 cases have been reported worldwide. The purpose of this article is to describe a large novel deletion found in 3 related cases, which resulted in the complete removal of the IFNGR1 gene. METHODS: Whole blood from three patients was stimulated with lipopolysaccharide (LPS) and IFN-gamma to determine production of tumor necrosis factor (TNF), interleukin-12 p40 (IL 12p40) and IL-10. Expression of IFN-gammaR1 on the cell membrane of patients' monocytes was assessed using flow cytometry. IFNGR1 transcript was analyzed in RNA and the gene and adjacent regions were analyzed in DNA. Finally, IL22RA2 transcript levels were analyzed in whole blood cells and dendritic cells. RESULTS: There was no expression of the IFN-gammaR1 on the monocytes. Consistent with this finding, there was no IFN-gamma response in the whole blood assay as measured by effect on LPS-induced IL-12p40, TNF and IL-10 production. A 119.227 nt homozygous deletion on chromosome 6q23.3 was identified, removing the IFNGR1 gene completely and ending 117 nt upstream of the transcription start of the IL22RA2 gene. Transcript levels of IL22RA2 were similar in patient and control. CONCLUSIONS: We identified the first large genomic deletion of IFNGR1 causing complete IFN-gammaR1 deficiency. Despite the deletion ending very close to the IL22RA2 gene, it does not appear to affect IL22RA2 transcription and, therefore, may not have any additional clinical consequence. PMID- 26931787 TI - Clinical Importance of Echogenic Swirling Pleural Effusions. AB - Thoracic sonography is an important tool in diagnosis and assessment of pleural effusions and can provide valuable information about the characteristics of accumulated pleural fluid, in addition to improving the safety of thoracentesis. In addition to the 4 classic sonographic pleural effusion patterns (anechoic, complex nonseptate, complex septate, and homogeneously echogenic), an echogenic swirling pattern has been previously described, which was originally thought to be associated with malignant effusion. Two cases of pleural effusion with an echogenic swirling pattern are described below, illustrating that this sonographic finding can be seen in both exudative and transudative effusions. PMID- 26931786 TI - Routine Screening for Callosal Dysgenesis in the Second Trimester Is Achievable With Intensive Training. AB - OBJECTIVES: The purpose of this study was to determine whether routine direct visualization of the corpus callosum is achievable during second-trimester sonography when performed by a large group of sonographers in a general second trimester sonographic screening program. The secondary aim was to determine the time taken to obtain a sagittal corpus callosum image. METHODS: We conducted a retrospective cohort study of visualization of the corpus callosum before and after intensive training. Images from 150 consecutive second-trimester scans were reviewed before and after training to evaluate the image quality of the corpus callosum. RESULTS: A total of 300 cases were evaluated before and after training. There was a significant increase in the rate of complete visualization of the corpus callosum after intensive training (P < .0001). Before training 35 of 150 cases (23%) had complete visualization of the corpus callosum versus 107 of 150 (71%) after training. The mean time to perform the corpus callosum views was 53.4 seconds before training compared to 56.2 seconds after training. CONCLUSIONS: Assessing the corpus callosum in the sagittal view is difficult and requires appropriate training and patience; however, this view is feasible without adding substantial time to the examination and provides additional information during a routine second-trimester morphologic scan. PMID- 26931785 TI - X-Linked Agammagobulinemia in a Large Series of North African Patients: Frequency, Clinical Features and Novel BTK Mutations. AB - PURPOSE: X-linked agammagobulinemia (XLA) is a primary immunodeficiency caused by Bruton's tyrosine kinase (BTK) gene defect. XLA patients have absent or reduced number of peripheral B cells and a profound deficiency in all immunoglobulin isotypes. This multicenter study reports the clinical, immunological and molecular features of Bruton's disease in 40 North African male patients. METHODS: Fifty male out of 63 (male and female) patients diagnosed with serum agammaglobulinemia and non detectable to less than 2% peripheral B cells were enrolled. The search for BTK gene mutations was performed for all of them by genomic DNA amplification and Sanger sequencing. RESULTS: We identified 33 different mutations in the BTK gene in 40 patients including 12 missense mutations, 6 nonsense mutations, 6 splice-site mutations, 5 frameshift, 2 large deletions, one complex mutation and one in-frame deletion. Seventeen of these mutations are novel. This large series shows a lower frequency of XLA among male patients from North Africa with agammaglobulinemia and absent to low B cells compared with other international studies (63.5% vs. 85%). No strong evidence for genotype-phenotype correlation was observed. CONCLUSIONS: This study adds to other reports from highly consanguineous North African populations, showing lower frequency of X-linked forms as compared to AR forms of the same primary immunodeficiency. Furthermore, a large number of novel BTK mutations were identified and could further help identify carriers for genetic counseling. PMID- 26931788 TI - Relationship Between Third-Trimester Sonographic Estimate of Fetal Weight and Mode of Delivery. AB - OBJECTIVES: Some have suggested, based on limited data, that knowledge of an estimated fetal weight from a sonogram in a low-risk population, particularly in the setting of a larger fetus, is associated with increased risk of cesarean delivery. We aimed to investigate, among women delivering neonates weighing greater than 3500 g, whether having had a sonographically estimated fetal weight in temporal proximity to delivery was associated with the risk of cesarean delivery. METHODS: We conducted a retrospective cohort study of term nulliparous women delivering live-born, cephalic, singleton, nonanomalous fetuses with birth weights of greater than 3500 g. The study was powered to detect a 30% change in cesarean delivery frequency with the presence of a sonographic examination after 36 weeks' gestation. RESULTS: Of the 2099 women meeting inclusion criteria, 419 (20%) had a sonographic examination after 36 weeks' gestation. Women were similar with respect to demographic and obstetric characteristics regardless of whether they underwent sonography. There were no differences in rates of cesarean delivery regardless of whether women had or did not undergo sonography after 36 weeks (33.2% versus 29.4%, respectively; P = .13). There also were no differences in rates of chorioamnionitis, postpartum hemorrhage, episiotomy, third- or fourth degree perineal laceration, or neonatal adverse outcomes based on sonographic status. Findings were similar in a multivariable analysis, as well as when the study population was restricted to those with birth weights of greater than 4000 and 4500 g. CONCLUSIONS: In this population of neonates weighing greater than 3500 g, the presence of a sonographic examination was not associated with the frequency of cesarean delivery. PMID- 26931789 TI - Ultrasound-Guided Nerve Blocks in Emergency Medicine Practice. AB - OBJECTIVES: The purpose of this study was to investigate the current practice of ultrasound (US)-guided regional anesthesia at academic emergency departments, including education, protocols, policies, and quality assessment. METHODS: We conducted a cross-sectional study. A questionnaire on US-guided nerve blocks was electronically sent to all emergency US directors and emergency US fellowship directors. RESULTS: A total of 121 of 171 academic institutions with an emergency medicine residency program participated in this study, representing a 71% response rate. Eighty-four percent (95% confidence interval [CI], 77%-91%) of programs perform US-guided nerve blocks at their institutions. The most common type of nerve block performed is a forearm nerve block (ulnar, median, or radial). The most common indication for US-guided nerve blocks is fracture pain management. Only 7% (95% CI, 2%-12%) of programs have a separate credentialing pathway for US-guided nerve blocks. Regarding quality assessment review of US guided nerve blocks, none of the programs have a separate program in place. In 57% (95% CI, 48%-66%) of programs, it is a component of the emergency US quality assessment program. Eighty-four percent (95% CI, 77%-90%) of programs do not have specific agreements with other specialty services with regard to performing US guided nerve blocks in the emergency department. The most common educational methods used to teach US-guided nerve blocks are didactic sessions, at 67% (95% CI, 59%-75%); online resources, at 54% (95% CI, 45%-63%); and supervised training with real patients, at 48% (95% CI, 39%-57%). CONCLUSIONS: Ultrasound-guided nerve blocks are performed at most academic emergency departments. However, there is a substantial variation in the practices and policies within these institutions. PMID- 26931790 TI - Sonography of Common Peripheral Nerve Disorders With Clinical Correlation. AB - Sonography is now considered an effective method to evaluate peripheral nerves. Low cost, high resolution, the ability to image an entire limb in a short time, and dynamic assessment are several of the positive attributes of sonography. This article will review the normal appearance of peripheral nerves as shown with sonography. In addition, the most common applications for sonography of the peripheral nerves will be reviewed, which include entrapment neuropathies, intraneural ganglion cyst, nerve trauma, and peripheral nerve sheath tumors. Clinical information related to nerve disorders is also included, as it provides valuable information that can be obtained during sonographic examinations, increasing diagnostic accuracy. PMID- 26931791 TI - Three-Dimensional Sonography of Biliary Tract Disorders. AB - In this pictorial essay, we review the 3-dimensional sonographic appearance of the normal gallbladder and biliary tree, as well as the appearance of congenital and acquired biliary tract disorders. Using examples, we demonstrate the advantage of 3-dimensional scanning compared with 2-dimensional sonography and, even in certain cases, magnetic resonance cholangiopancreatography. PMID- 26931793 TI - Using portable particle sizing instrumentation to rapidly measure the penetration of fine and ultrafine particles in unoccupied residences. AB - Much of human exposure to particulate matter of outdoor origin occurs inside buildings, particularly in residences. The particle penetration factor through leaks in a building's exterior enclosure assembly is a key parameter that governs the infiltration of outdoor particles. However, experimental data for size resolved particle penetration factors in real buildings, as well as penetration factors for fine particles less than 2.5 MUm (PM2.5 ) and ultrafine particles less than 100 nm (UFPs), remain limited, in part because of previous limitations in instrumentation and experimental methods. Here, we report on the development and application of a modified test method that utilizes portable particle sizing instrumentation to measure size-resolved infiltration factors and envelope penetration factors for 0.01-2.5 MUm particles, which are then used to estimate penetration factors for integral measures of UFPs and PM2.5 . Eleven replicate measurements were made in an unoccupied apartment unit in Chicago, IL to evaluate the accuracy and repeatability of the test procedure and solution methods. Mean estimates of size-resolved penetration factors ranged from 0.41 +/- 0.14 to 0.73 +/- 0.05 across the range of measured particle sizes, while mean estimates of penetration factors for integral measures of UFPs and PM2.5 were 0.67 +/- 0.05 and 0.73 +/- 0.05, respectively. Average relative uncertainties for all particle sizes/classes were less than 20%. PMID- 26931792 TI - Grisel's syndrome, a rare cause of anomalous head posture in children: a case report. AB - BACKGROUND: Anomalous head posture (AHP) or torticollis is a relatively common condition in children. Torticollis is not a diagnosis, but it is a sign of underlying disease. Grisel's syndrome (GS) is a rare condition of uncertain etiology characterized by a nontraumatic atlanto-axial subluxation (AAS), secondary to an infection in the head and neck region. It has not been considered, in ophthalmological papers, as a possible cause of AHP. CASE PRESENTATION: A case of AAS secondary to an otitis media is studied. The children showed neck pain, head tilt, and reduction in neck mobility. The patient had complete remission with antibiotic and anti-inflammatory therapy and muscle relaxants. Signs of GS should always be taken into account during ophthalmological examination (recent history of upper airway infections and/or head and neck surgeries associated to a new onset of sudden, painful AHP with normal ocular exam). In such cases it is necessary to require quick execution of radiological examinations (computer tomography and/or nuclear magnetic resonance), which are essential to confirm the diagnosis. CONCLUSION: GS is a multidisciplinary disease. We underline the importance of an accurate orthoptic and ophthalmological examination. Indeed, early detection and diagnosis are fundamental to achieve proper management, avoid neurological complications and lead to a good prognosis. PMID- 26931794 TI - Olfactory event-related potentials: a new approach for the evaluation of olfaction in nasopharyngeal carcinoma patients treated with chemo-radiotherapy. AB - OBJECTIVE: Olfactory dysfunction is a possible side effect of chemo-radiotherapy performed in patients affected by nasopharyngeal carcinoma. Self-rating measurements and olfactory event-related potentials were used and compared in order to evaluate the impact of this treatment on the olfactory system. METHODS: Nine patients underwent subjective evaluation of olfactory function (using visual analogue scales for olfactory symptoms and quality of life, and a six-item Hyposmia Rating Scale), and a quantitative and objective measurement (olfactory event-related potentials). RESULTS: Spearman's rank correlation analyses highlighted significant relationships between the clinical scales and olfactory event-related potentials. Inter-group analyses showed significant differences in the latency and in the amplitude of olfactory event-related potentials between patients and controls. CONCLUSION: Taking into account the small sample size and the lack of pre-treatment assessment, olfactory event-related potentials seemed to allow a more objective diagnosis of unilateral and bilateral olfactory loss. Moreover, olfactory event-related potentials and subjective scales results were concordant. PMID- 26931796 TI - Proteomics and the search for welfare and stress biomarkers in animal production in the one-health context. AB - Stress and welfare are important factors in animal production in the context of growing production optimization and scrutiny by the general public. In a context in which animal and human health are intertwined aspects of the one-health concept it is of utmost importance to define the markers of stress and welfare. These are important tools for producers, retailers, regulatory agents and ultimately consumers to effectively monitor and assess the welfare state of production animals. Proteomics is the science that studies the proteins existing in a given tissue or fluid. In this review we address this topic by showing clear examples where proteomics has been used to study stress-induced changes at various levels. We adopt a multi-species (cattle, swine, small ruminants, poultry, fish and shellfish) approach under the effect of various stress inducers (handling, transport, management, nutritional, thermal and exposure to pollutants) clearly demonstrating how proteomics and systems biology are key elements to the study of stress and welfare in farm animals and powerful tools for animal welfare, health and productivity. PMID- 26931795 TI - New Targeted Agents in Gynecologic Cancers: Synthetic Lethality, Homologous Recombination Deficiency, and PARP Inhibitors. AB - OPINION STATEMENT: Inhibitors of poly (ADP-ribose) polymerase (PARP) have emerged as a new class of anti-cancer drugs, specifically for malignancies bearing aberrations of the homologous recombination pathway, like those with mutations in the BRCA 1 and BRCA 2 genes. Olaparib, a potent PARP1 and PARP2 inhibitor, has been shown to significantly increase progression-free survival (PFS) in women with recurrent ovarian cancer related to a germline BRCA mutation and is currently approved fourth-line treatment in these patients. PARP inhibitors (PARPi) target the genetic phenomenon known as synthetic lethality to exploit faulty DNA repair mechanisms. While ovarian cancer is enriched with a population of tumors with known homologous recombination defects, investigations are underway to help identify pathways in other gynecologic cancers that may demonstrate susceptibility to PARPi through synthetically lethal mechanisms. The ARIEL2 trial prospectively determined a predictive assay to identify patients with HRD. The future of cancer therapeutics will likely incorporate these HRD assays to determine the best treatment plan for patients. While the role of PARPi is less clear in non-ovarian gynecologic cancers, the discovery of a predictive assay for HRD may open the door for clinical trials in these other gynecologic cancers enriched with patients with HRD. Identification of patients with tumors deficient in homologous repair or have HRD-like behavior moves cancer treatment towards individualized therapies in order to maximize treatment effect and quality of life for women living with gynecologic cancers. PMID- 26931797 TI - Fine-scale spatial ecology drives kin selection relatedness among cooperating amoebae. AB - Cooperation among microbes is important for traits as diverse as antibiotic resistance, pathogen virulence, and sporulation. The evolutionary stability of cooperation against "cheater" mutants depends critically on the extent to which microbes interact with genetically similar individuals. The causes of this genetic social structure in natural microbial systems, however, are unknown. Here, we show that social structure among cooperative Dictyostelium amoebae is driven by the population ecology of colonization, growth, and dispersal acting at spatial scales as small as fruiting bodies themselves. Despite the fact that amoebae disperse while grazing, all it takes to create substantial genetic clonality within multicellular fruiting bodies is a few millimeters distance between the cells colonizing a feeding site. Even adjacent fruiting bodies can consist of different genotypes. Soil populations of amoebae are sparse and patchily distributed at millimeter scales. The fine-scale spatial structure of cells and genotypes can thus account for the otherwise unexplained high genetic uniformity of spores in fruiting bodies from natural substrates. These results show how a full understanding of microbial cooperation requires understanding ecology and social structure at the small spatial scales microbes themselves experience. PMID- 26931798 TI - Self-assembly of a redox active water soluble Pd6L8 'molecular dice'. AB - A water soluble 'molecular dice' was synthesised via coordination driven self assembly of a Pd(II) ion with a flexible cationic tritopic donor and was fully characterised using NMR, ESI-MS and single crystal X-ray diffraction analysis. The donor-inherited redox active nature of the 'molecular dice' was studied using cyclic voltammetry. PMID- 26931799 TI - Amylose content decreases during tuber development in potato. AB - BACKGROUND: Potato starch is composed primarily of amylopectin and amylose in an approximately 3:1 ratio. Amylose is considered to be nutritionally desirable in North American and European markets, so there is interest in finding strategies to increase the amylose content of potato starch. There is also interest in marketing 'baby' potatoes, which are harvested when they are physiologically immature. This study was carried out to determine weekly changes in amylose content in potato tubers of 11 North American cultivars during the growing season. The trial was repeated across 3 years. RESULTS: We determined that amylose content is highest early and it decreases in a linear fashion as the growing season progresses. Mean amylose content across cultivars and years declined from 30.0% in late June to 26.8% in late August. The rate of decrease varied across years, with slopes of linear regression plots ranging from -0.17 in 2012 to -0.74 in 2011. Amylose content in tuber starch varied among cultivars, with the highest levels observed in Ranger Russet (30.7%) and White Pearl (31.6%); it was lowest in Kennebec (25.7%) and Langlade (25.6%). CONCLUSIONS: This study adds to a growing body of literature on the nutritional value of immature potato tubers. In addition to having higher levels of some phytonutrients, as reported in other studies, immature tubers have a higher proportion of amylose in the starch. This is nutritionally desirable in affluent regions where high fiber content is more important than calories from carbohydrates. Published 2016. This article is a U.S. Government work and is in the public domain in the USA. PMID- 26931801 TI - A High-Performance Rechargeable Mg(2+)/Li(+) Hybrid Battery Using One-Dimensional Mesoporous TiO2(B) Nanoflakes as the Cathode. AB - Mg(2+)/Li(+) hybrid batteries have recently been constructed combining a Mg anode, a Li(+)-intercalation electrode, and an electrolyte containing both Mg(2+) and Li(+). These batteries have been reported to outperform all the previously reported magnesium batteries in terms of specific capacity, cycling stability, and rate capability. Herein, we report the outstanding electrochemical performance of Mg(2+)/Li(+) hybrid batteries consisting of a one-dimensional mesoporous TiO2(B) cathode, a Mg anode, and an electrolyte consisting of 0.5 mol L(-1) Mg(BH4)2 + 1.5 mol L(-1) LiBH4 in tetraglyme. A highly synergetic interaction between Li(+) and Mg(2+) ions toward the pseudo-capacitive reaction is proposed. The hybrid batteries show superior rate performance with 130 mAh g( 1) at 1 C and 115 mAh g(-1) at 2 C, together with excellent cyclability up to 6000 cycles. PMID- 26931800 TI - Ingestion of genetically modified yeast symbiont reduces fitness of an insect pest via RNA interference. AB - RNA interference has had major advances as a developing tool for pest management. In laboratory experiments, double-stranded RNA (dsRNA) is often administered to the insect by genetic modification of the crop, or synthesized in vitro and topically applied to the crop. Here, we engineered genetically modified yeast that express dsRNA targeting y-Tubulin in Drosophila suzukii. Our design takes advantage of the symbiotic interactions between Drosophila, yeast, and fruit crops. Yeast is naturally found growing on the surface of fruit crops, constitutes a major component of the Drosophila microbiome, and is highly attractive to Drosophila. Thus, this naturally attractive yeast biopesticide can deliver dsRNA to an insect pest without the need for genetic crop modification. We demonstrate that this biopesticide decreases larval survivorship, and reduces locomotor activity and reproductive fitness in adults, which are indicative of general health decline. To our knowledge, this is the first study to show that yeast can be used to deliver dsRNA to an insect pest. PMID- 26931802 TI - Diversity and origins of Indian multi-triazole resistant strains of Aspergillus fumigatus. AB - Aspergillus fumigatus is a widespread opportunistic fungal pathogen causing an alarmingly high mortality rate in immunocompromised patients. Nosocomial infections by drug-resistant A. fumigatus strains are of particular concern, and there is a pressing need to understand the origin, dispersal and long-term evolution of drug resistance in this organism. The objective of this study was to investigate the diversity and putative origins of triazole resistance of A. fumigatus from India. Eighty-nine isolates, including 51 multiple triazole resistant (MTR) isolates and 38 azole-susceptible isolates, were genotyped using multilocus sequence typing (MLST), mating typing and PCR fingerprinting. MLST resolved the 51 MTR isolates into three genotypes, two of which have susceptible counterparts, suggesting that MTR isolates originated multiple times in India. The multiple-origin hypothesis was further supported by the diversity of sequences at the triazole target gene CYP51A among the MTR isolates, and by PCR fingerprints. Interestingly, there is abundant evidence for mating and recombination in natural population of A. fumigatus in India, suggesting that sexual spread of TR34 /L98H, the dominant MTR allele, is possible. Our results call for greater attention to MTR in A. fumigatus and for better management of antifungal drug use. PMID- 26931803 TI - Increased expression of bitter taste receptors in human allergic nasal mucosa and their contribution to the shrinkage of human nasal mucosa. AB - OBJECTIVE: Bitter taste receptors (TAS2Rs) are expressed in the extraoral tissues, where they possess various physiological functions. This study is to characterize TAS2Rs expression in normal and allergic nasal mucosa and analyse nasal symptom after challenge with bitter tastes to evaluate their pathophysiological function in normal and allergic nasal mucosa. METHODS: The expression levels of TAS2Rs (TAS2R4, 5, 7, 10, 14, 39, and 43) in nasal mucosa were investigated by real-time PCR, Western blot, and immunohistochemistry. The expression levels of TAS2Rs and Ca(2+) imaging in cultured epithelial cells were measured after stimulation with type 2 cytokines (IL-4, IL-5, and IL-13) or bitter tastes. Nasal symptoms in control subjects and allergic rhinitis patients using visual analogue score and acoustic rhinometry were evaluated before and after stimulation with bitter tastes. Vascular diameter of rat nasal septum was measured before and after treatment with bitter tastes. RESULTS: TAS2Rs tested here were expressed in nasal mucosa where they were commonly distributed in superficial epithelium, submucosal glands, and endothelium. Their expression levels are increased in allergic nasal mucosa and up-regulated in cultured epithelial cells simulated with type 2 cytokines. After treatment with bitter tastes, intracellular Ca(2+) signalling was increased in cultured epithelial cells, and vascular constriction was found in rat nasal septum. Increased nasal patency was observed in human nasal mucosa without pain or sneezing. CONCLUSION AND CLINICAL RELEVANCE: TAS2Rs are constitutively expressed in human nasal mucosa and their expression levels are increased in allergic nasal mucosa, where they could potentially contribute to shrinkage of normal and allergic nasal mucosa. PMID- 26931804 TI - Phenological response of a key ecosystem function to biological invasion. AB - Although climate warming has been widely demonstrated to induce shifts in the timing of many biological events, the phenological consequences of other prominent global change drivers remain largely unknown. Here, we investigated the effects of biological invasions on the seasonality of leaf litter decomposition, a crucial freshwater ecosystem function. Decomposition rates were quantified in 18 temperate shallow lakes distributed along a gradient of crayfish invasion and a temperature-based model was constructed to predict yearly patterns of decomposition. We found that, through direct detritus consumption, omnivorous invasive crayfish accelerated decomposition rates up to fivefold in spring, enhancing temperature dependence of the process and shortening the period of major detritus availability in the ecosystem by up to 39 days (95% CI: 15-61). The fact that our estimates are an order of magnitude higher than any previously reported climate-driven phenological shifts indicates that some powerful drivers of phenological change have been largely overlooked. PMID- 26931806 TI - Hyperpolarization-Activated Cyclic Nucleotide-Gated (HCN) Channels in Epilepsy. AB - Epilepsy is a common brain disorder characterized by the occurrence of spontaneous seizures. These bursts of synchronous firing arise from abnormalities of neuronal networks. Excitability of individual neurons and neuronal networks is largely governed by ion channels and, indeed, abnormalities of a number of ion channels resulting from mutations or aberrant expression and trafficking underlie several types of epilepsy. Here, we focus on the hyperpolarization-activated cyclic nucleotide-gated ion (HCN) channels that conduct Ih current. This conductance plays complex and diverse roles in the regulation of neuronal and network excitability. We describe the normal function of HCN channels and discuss how aberrant expression, assembly, trafficking, and posttranslational modifications contribute to experimental and human epilepsy. PMID- 26931807 TI - Status Epilepticus. AB - Although the majority of seizures are brief and cause no long-term consequences, a subset is sufficiently prolonged that long-term consequences can result. These very prolonged seizures are termed "status epilepticus" (SE) and are considered a neurological emergency. The clinical presentation of SE can be diverse. SE can occur at any age but most commonly occurs in the very young and the very old. There are numerous studies on SE in animals in which the pathophysiology, medication responses, and pathology can be rigorously studied in a controlled fashion. Human data are consistent with the animal data. In particular, febrile status epilepticus (FSE), a form of SE common in young children, is associated with injury to the hippocampus and subsequent temporal lobe epilepsy (TLE) in both animals and humans. PMID- 26931808 TI - Translating the Science of Aging into Therapeutic Interventions. AB - Life and health span have been extended in experimental animals using drugs that are potentially translatable into humans. Considerable effort is needed beyond the usual steps in drug development to devise the models, and realistic preclinical and clinical trial strategies are required to advance these agents into clinical application. It will be important to focus on subjects who already have symptoms or are at imminent risk of developing disorders related to fundamental aging processes, to use short-term, clinically relevant outcomes, as opposed to long-term outcomes, such as health span or life span, and to validate endpoint measures so they are acceptable to regulatory agencies. Funding is a roadblock, as is shortage of investigators with combined expertise in the basic biology of aging, clinical geriatrics, and investigational new drug clinical trials. Strategies for developing a path from the bench to the bedside are reviewed for interventions that target fundamental aging mechanisms. PMID- 26931809 TI - Metformin: A Hopeful Promise in Aging Research. AB - Even though the inevitable process of aging by itself cannot be considered a disease, it is directly linked to life span and is the driving force behind all age-related diseases. It is an undisputable fact that age-associated diseases are among the leading causes of death in the world, primarily in industrialized countries. During the last several years, an intensive search of antiaging treatments has led to the discovery of a variety of drugs that promote health span and/or life extension. The biguanide compound metformin is widely used for treating people with type 2 diabetes and appears to show protection against cancer, inflammation, and age-related pathologies. Here, we summarize the recent developments about metformin use in translational aging research and discuss its role as a potential geroprotector. PMID- 26931812 TI - Fast generation of three-atom singlet state by transitionless quantum driving. AB - Motivated by "transitionless quantum driving", we construct shortcuts to adiabatic passage in a three-atom system to create a singlet state with the help of quantum zeno dynamics and non-resonant lasers. The influence of various decoherence processes is discussed by numerical simulation and the results reveal that the scheme is fast and robust against decoherence and operational imperfection. We also investigate how to select the experimental parameters to control the cavity dissipation and atomic spontaneous emission which will have an application value in experiment. PMID- 26931810 TI - The Cell-Cycle Arrest and Apoptotic Functions of p53 in Tumor Initiation and Progression. AB - P53 is a transcription factor highly inducible by many stress signals such as DNA damage, oncogene activation, and nutrient deprivation. Cell-cycle arrest and apoptosis are the most prominent outcomes of p53 activation. Many studies showed that p53 cell-cycle and apoptosis functions are important for preventing tumor development. p53 also regulates many cellular processes including metabolism, antioxidant response, and DNA repair. Emerging evidence suggests that these noncanonical p53 activities may also have potent antitumor effects within certain context. This review focuses on the cell-cycle arrest and apoptosis functions of p53, their roles in tumor suppression, and the regulation of cell fate decision after p53 activation. PMID- 26931811 TI - Resistance Mechanisms and the Future of Bacterial Enoyl-Acyl Carrier Protein Reductase (FabI) Antibiotics. AB - Missense mutations leading to clinical antibiotic resistance are a liability of single-target inhibitors. The enoyl-acyl carrier protein reductase (FabI) inhibitors have one intracellular protein target and drug resistance is increased by the acquisition of single-base-pair mutations that alter drug binding. The spectrum of resistance mechanisms to FabI inhibitors suggests criteria that should be considered during the development of single-target antibiotics that would minimize the impact of missense mutations on their clinical usefulness. These criteria include high-affinity, fast on/off kinetics, few drug contacts with residue side chains, and no toxicity. These stringent criteria are achievable by structure-guided design, but this approach will only yield pathogen specific drugs. Single-step acquisition of resistance may limit the clinical application of broad-spectrum, single-target antibiotics, but appropriately designed pathogen-specific antibiotics have the potential to overcome this liability. PMID- 26931813 TI - Delta, theta, beta, and gamma brain oscillations index levels of auditory sentence processing. AB - A growing number of studies indicate that multiple ranges of brain oscillations, especially the delta (delta, <4Hz), theta (theta, 4-8Hz), beta (beta, 13-30Hz), and gamma (gamma, 30-50Hz) bands, are engaged in speech and language processing. It is not clear, however, how these oscillations relate to functional processing at different linguistic hierarchical levels. Using scalp electroencephalography (EEG), the current study tested the hypothesis that phonological and the higher level linguistic (semantic/syntactic) organizations during auditory sentence processing are indexed by distinct EEG signatures derived from the delta, theta, beta, and gamma oscillations. We analyzed specific EEG signatures while subjects listened to Mandarin speech stimuli in three different conditions in order to dissociate phonological and semantic/syntactic processing: (1) sentences comprising valid disyllabic words assembled in a valid syntactic structure (real word condition); (2) utterances with morphologically valid syllables, but not constituting valid disyllabic words (pseudo-word condition); and (3) backward versions of the real-word and pseudo-word conditions. We tested four signatures: band power, EEG-acoustic entrainment (EAE), cross-frequency coupling (CFC), and inter-electrode renormalized partial directed coherence (rPDC). The results show significant effects of band power and EAE of delta and theta oscillations for phonological, rather than semantic/syntactic processing, indicating the importance of tracking delta- and theta-rate phonetic patterns during phonological analysis. We also found significant beta-related effects, suggesting tracking of EEG to the acoustic stimulus (high-beta EAE), memory processing (theta-low-beta CFC), and auditory-motor interactions (20-Hz rPDC) during phonological analysis. For semantic/syntactic processing, we obtained a significant effect of gamma power, suggesting lexical memory retrieval or processing grammatical word categories. Based on these findings, we confirm that scalp EEG signatures relevant to delta, theta, beta, and gamma oscillations can index phonological and semantic/syntactic organizations separately in auditory sentence processing, compatible with the view that phonological and higher-level linguistic processing engage distinct neural networks. PMID- 26931814 TI - Neural basis of phonological awareness in beginning readers with familial risk of dyslexia-Results from shallow orthography. AB - Phonological processing ability is a key factor in reading acquisition, predicting its later success or causing reading problems when it is weakened. Our aim here was to establish the neural correlates of auditory word rhyming (a standard phonological measure) in 102 young children with (FHD+) and without familial history of dyslexia (FHD-) in a shallow orthography (i.e. Polish). Secondly, in order to gain a deeper understanding on how schooling shapes brain activity to phonological awareness, a comparison was made of children who had had formal literacy instruction for several months (in first grade) and those who had not yet had any formal instruction in literacy (in kindergarten). FHD+ children compared to FHD- children in the first grade scored lower in an early print task and showed longer reaction times in the in-scanner rhyme task. No behavioral differences between FHD+ and FHD- were found in the kindergarten group. On the neuronal level, overall familial risk was associated with reduced activation in the bilateral temporal, tempo-parietal and inferior temporal-occipital regions, as well as the bilateral inferior and middle frontal gyri. Subcortically, hypoactivation was found in the bilateral thalami, caudate, and right putamen in FHD+. A main effect of the children's grade was present only in the left inferior frontal gyrus, where reduced activation for rhyming was shown in first-graders. Several regions in the ventral occipital cortex, including the fusiform gyrus, and in the right middle frontal and postcentral gyri, displayed an interaction between familial risk and grade. The present results show strong influence of familial risk that may actually increase with formal literacy instruction. PMID- 26931815 TI - The occipital place area represents the local elements of scenes. AB - Neuroimaging studies have identified three scene-selective regions in human cortex: parahippocampal place area (PPA), retrosplenial complex (RSC), and occipital place area (OPA). However, precisely what scene information each region represents is not clear, especially for the least studied, more posterior OPA. Here we hypothesized that OPA represents local elements of scenes within two independent, yet complementary scene descriptors: spatial boundary (i.e., the layout of external surfaces) and scene content (e.g., internal objects). If OPA processes the local elements of spatial boundary information, then it should respond to these local elements (e.g., walls) themselves, regardless of their spatial arrangement. Indeed, we found that OPA, but not PPA or RSC, responded similarly to images of intact rooms and these same rooms in which the surfaces were fractured and rearranged, disrupting the spatial boundary. Next, if OPA represents the local elements of scene content information, then it should respond more when more such local elements (e.g., furniture) are present. Indeed, we found that OPA, but not PPA or RSC, responded more to multiple than single pieces of furniture. Taken together, these findings reveal that OPA analyzes local scene elements - both in spatial boundary and scene content representation while PPA and RSC represent global scene properties. PMID- 26931816 TI - Medial temporal lobe viscoelasticity and relational memory performance. AB - Structural and functional imaging studies have been among converging lines of evidence demonstrating the importance of the hippocampus in successful memory performance. The advent of a novel neuroimaging technique - magnetic resonance elastography (MRE) - now makes it possible for us to investigate the relationship between the microstructural integrity of hippocampal tissue and successful memory processing. Mechanical properties of brain tissue estimated with MRE provide a measure of the integrity of the underlying tissue microstructure and have proven to be sensitive measures of tissue health in neurodegeneration. However, until recently, MRE methods lacked sufficient resolution necessary to accurately examine specific neuroanatomical structures in the brain, and thus could not contribute to examination of specific structure-function relationships. In this study, we took advantage of recent developments in MRE spatial resolution and mechanical inversion techniques to measure the viscoelastic properties of the human hippocampus in vivo, and investigated how these properties reflect hippocampal function. Our data reveal a strong relationship between relative elastic/viscous behavior of the hippocampus and relational memory performance (N=20). This is the first report linking the mechanical properties of brain tissue with functional performance. PMID- 26931818 TI - Transcriptional profiling of subcutaneous adipose tissue in Italian Large White pigs divergent for backfat thickness. AB - Fat deposition is a widely studied trait in pigs because of its implications with animal growth efficiency, technological and nutritional characteristics of meat products, but the global framework of the biological and molecular processes regulating fat deposition in pigs is still incomplete. This study describes the backfat tissue transcription profile in Italian Large White pigs and reports genes differentially expressed between fat and lean animals according to RNA-seq data. The backfat transcription profile was characterised by the expression of 23 483 genes, of which 54.1% were represented by known genes. Of 63 418 expressed transcripts, about 80% were non-previously annotated isoforms. By comparing the expression level of fat vs. lean pigs, we detected 86 robust differentially expressed transcripts, 72 more highly expressed (e.g. ACP5, BCL2A1, CCR1, CD163, CD1A, EGR2, ENPP1, GPNMB, INHBB, LYZ, MSR1, OLR1, PIK3AP1, PLIN2, SPP1, SLC11A1, STC1) and 14 lower expressed (e.g. ADSSL1, CDO1, DNAJB1, HSPA1A, HSPA1B, HSPA2, HSPB8, IGFBP5, OLFML3) in fat pigs. The main functional categories enriched in differentially expressed genes were immune system process, response to stimulus, cell activation and skeletal system development, for the overexpressed genes, and unfolded protein binding and stress response, for the underexpressed genes, which included five heat shock proteins. Adipose tissue alterations and impaired stress response are linked to inflammation and, in turn, to adipose tissue secretory activity, similar to what is observed in human obesity. Our results provide the opportunity to identify biomarkers of carcass fat traits to improve the pig production chain and to identify genetic factors that regulate the observed differential expression. PMID- 26931817 TI - DR-TAMAS: Diffeomorphic Registration for Tensor Accurate Alignment of Anatomical Structures. AB - In this work, we propose DR-TAMAS (Diffeomorphic Registration for Tensor Accurate alignMent of Anatomical Structures), a novel framework for intersubject registration of Diffusion Tensor Imaging (DTI) data sets. This framework is optimized for brain data and its main goal is to achieve an accurate alignment of all brain structures, including white matter (WM), gray matter (GM), and spaces containing cerebrospinal fluid (CSF). Currently most DTI-based spatial normalization algorithms emphasize alignment of anisotropic structures. While some diffusion-derived metrics, such as diffusion anisotropy and tensor eigenvector orientation, are highly informative for proper alignment of WM, other tensor metrics such as the trace or mean diffusivity (MD) are fundamental for a proper alignment of GM and CSF boundaries. Moreover, it is desirable to include information from structural MRI data, e.g., T1-weighted or T2-weighted images, which are usually available together with the diffusion data. The fundamental property of DR-TAMAS is to achieve global anatomical accuracy by incorporating in its cost function the most informative metrics locally. Another important feature of DR-TAMAS is a symmetric time-varying velocity-based transformation model, which enables it to account for potentially large anatomical variability in healthy subjects and patients. The performance of DR-TAMAS is evaluated with several data sets and compared with other widely-used diffeomorphic image registration techniques employing both full tensor information and/or DTI-derived scalar maps. Our results show that the proposed method has excellent overall performance in the entire brain, while being equivalent to the best existing methods in WM. PMID- 26931819 TI - Identifying new Risk Markers and Potential Targets: The Value of the Proteome. AB - Several protein biomarkers, including cardiac troponin T, cardiac troponin I, B type natriuretic peptide, C-reactive protein and apolipoprotein A-I, are widely employed in the evaluation of cardiovascular disease. Several of such potential biomarkers, or their multiscores, have been assessed over the last years for the prediction of cardiovascular risk but only a few of them have been validated for clinical use. Substantial improvement in the cardiovascular risk prediction and reclassification relative to traditional models therefore remains a difficult task presently unresolved. Hence, a potential importance of alternative approaches which may rely on novel proteomic biomarkers among others. Plasma or serum concentrations of numerous proteins were measured using proteomic approaches to establish their relationships with cardiovascular disease; none of them was however evaluated for cardiovascular risk prediction and subject stratification in rigorous large-scale studies. Thus, further research is needed to identify novel candidates that can improve cardiovascular risk prediction, subject stratification and standard care. Proteomics will undoubtedly remain a key approach to address this major clinical and scientific challenge. PMID- 26931820 TI - Erratum to: Posterior reversible encephalopathy syndrome (PRES): a rare condition after resection of posterior fossa tumors: two new cases and review of the literature. PMID- 26931821 TI - Tissue explant coculture model of the hypothalamic-pituitary-gonadal-liver axis of the fathead minnow (Pimephales promelas) as a predictive tool for endocrine disruption. AB - Endocrine-disrupting compounds (EDCs) can impact the reproductive system by interfering with the hypothalamic-pituitary-gonadal (HPG) axis. Although in vitro testing methods have been developed to screen chemicals for endocrine disruption, extrapolation of in vitro responses to in vivo action shows inconsistent accuracy. The authors describe a tissue coculture of the fathead minnow (Pimephales promelas) HPG axis and liver (HPG-L) as a tissue explant model that mimics in vivo results. Brain (hypothalamus), pituitary, gonad, and liver tissue explants from adult fish were examined for function both individually and in coculture to determine combinations and conditions that could replicate in vivo behavior. Only cocultures had the ability to respond to an EDC, trenbolone, similarly to in vivo studies, based on estradiol, testosterone, and vitellogenin production trends, where lower exposure doses suppressed hormone production but higher doses increased production, resulting in distinctive U-shaped curves. These data suggest that a coculture system with all components of the HPG-L axis can be used as a link between in vitro and in vivo studies to predict endocrine system disruption in whole organisms. This tissue-based HPG-L system acts as a flexible deconstructed version of the in vivo system for better control and examination of the minute changes in system operation and response on EDC exposure with options to isolate, interrogate, and recombine desired components. Environ Toxicol Chem 2016;35:2530-2541. Published 2016 Wiley Periodicals Inc. on behalf of SETAC. This article is a US Government work and, as such, is in the public domain in the United States of America. PMID- 26931823 TI - Yeast-based systems for tropical disease drug discovery. PMID- 26931822 TI - Lower extremity muscular strength, sedentary behavior, and mortality. AB - To examine whether lower extremity strength (LES) is predictive of all-cause mortality, independent of physical activity and among those with vary levels of sedentary behavior. Data from the 1999-2002 National Health and Nutrition Examination Survey was used (N = 2768; 50-85 years). Peak isokinetic knee extensor strength was objectively measured, sedentary behavior and physical activity were self-reported, and mortality was assessed via the National Death Index, with follow-up through 2011. Participants were followed for up to 12.6 years with the weighted average follow-up period lasting 9.9 years (standard error, 1.13). In the sample, 321,996 person-months occurred with a mortality rate of 2.1 deaths per 1000 person-months. After adjustments (including physical activity), for every 15 N increase in LES, participants had a 7 % reduced risk of all-cause mortality (HR = 0.93; 95 % CI 0.91-0.95; P < 0.001). When adding a three-level sedentary behavior variable (< 2, 2-4, 5+ h/day) as a covariate in this model, results were unchanged (HR = 0.93; 95 % CI 0.92-0.96; P < 0.001). Similarly, when sedentary behavior was included as a continuous covariate in the model, results regarding the relationship between LES and mortality were unchanged (HR = 0.94; 95 % CI 0.91-0.96; P < 0.001). There was no evidence of statistical interaction between LES and sedentary behavior on all-cause mortality (HRinteraction = 1.01; 95 % CI 0.92-1.10; P = 0.88). LES was inversely associated with all-cause mortality, and this association was unchanged when considering the participant's sedentary behavior. PMID- 26931824 TI - Volcanic ash melting under conditions relevant to ash turbine interactions. AB - The ingestion of volcanic ash by jet engines is widely recognized as a potentially fatal hazard for aircraft operation. The high temperatures (1,200 2,000 degrees C) typical of jet engines exacerbate the impact of ash by provoking its melting and sticking to turbine parts. Estimation of this potential hazard is complicated by the fact that chemical composition, which affects the temperature at which volcanic ash becomes liquid, can vary widely amongst volcanoes. Here, based on experiments, we parameterize ash behaviour and develop a model to predict melting and sticking conditions for its global compositional range. The results of our experiments confirm that the common use of sand or dust proxy is wholly inadequate for the prediction of the behaviour of volcanic ash, leading to overestimates of sticking temperature and thus severe underestimates of the thermal hazard. Our model can be used to assess the deposition probability of volcanic ash in jet engines. PMID- 26931826 TI - Invited Article: miniTimeCube. AB - We present the development of the miniTimeCube (mTC), a novel compact neutrino detector. The mTC is a multipurpose detector, aiming to detect not only neutrinos but also fast/thermal neutrons. Potential applications include the counterproliferation of nuclear materials and the investigation of antineutrino short-baseline effects. The mTC is a plastic 0.2% (10)B-doped scintillator (13 cm)(3) cube surrounded by 24 Micro-Channel Plate (MCP) photon detectors, each with an 8 * 8 anode totaling 1536 individual channels/pixels viewing the scintillator. It uses custom-made electronics modules which mount on top of the MCPs, making our detector compact and able to both distinguish different types of events and reject noise in real time. The detector is currently deployed and being tested at the National Institute of Standards and Technology Center for Neutron Research nuclear reactor (20 MWth) in Gaithersburg MD. A shield for further tests is being constructed, and calibration and upgrades are ongoing. The mTC's improved spatiotemporal resolution will allow for determination of incident particle directions beyond previous capabilities. PMID- 26931827 TI - Contributed Review: Recent developments in acoustic energy harvesting for autonomous wireless sensor nodes applications. AB - Rapid developments in micro electronics, micro fabrication, ultra-large scale of integration, ultra-low power sensors, and wireless technology have greatly reduced the power consumption requirements of wireless sensor nodes (WSNs) and make it possible to operate these devices with energy harvesters. Likewise, other energy harvesters, acoustic energy harvesters (AEHs), have been developed and are gaining swift interest in last few years. This paper presents a review of AEHs reported in the literature for the applications of WSNs. Based on transduction mechanism, there are two types of AEHs: piezoelectric acoustic energy harvesters (PEAEHs) and electromagnetic acoustic energy harvesters (EMAEHs). The reported AEHs are mostly characterized under the sound pressure level (SPL) that ranges from 45 to 161 dB. The range for resonant frequency of the produced AEHs is from 146 Hz to 24 kHz and these produced 0.68 * 10(-6) MUW to 30 mW power. The maximum power (30 mW) is produced by a PEAEH, when the harvester is subjected to a SPL of 161 dB and 2.64 kHz frequency. However, for EMAEHs, the maximum power reported is about 1.96 mW (at 125 dB and 143 Hz). Under the comparable SPLs, the power production by the reported EMAEHs is relatively better than that of PEAEHs, moreover, due to lower resonant frequency, the EMAEHs are more feasible for the low frequency band acoustical environment. PMID- 26931828 TI - Application of photon Doppler velocimetry to direct impact Hopkinson pressure bars. AB - Direct impact Hopkinson pressure bar systems offer many potential advantages over split Hopkinson pressure bars, including access to higher strain rates, higher strains for equivalent striker velocity and system length, lower dispersion, and faster achievement of force equilibrium. Currently, these advantages are gained at the expense of all information about the striker impacted specimen face, preventing the experimental determination of force equilibrium, and requiring approximations to be made on the sample deformation history. In this paper, we discuss an experimental method and complementary data analysis for using photon Doppler velocimetry to measure surface velocities of the striker and output bars in a direct impact bar experiment, allowing similar data to be recorded as in a split bar system. We discuss extracting velocity and force measurements, and the precision of measurements. Results obtained using the technique are compared to equivalent split bar tests, showing improved stress measurements for the lowest and highest strains in fully dense metals, and improvement for all strains in slow and non-equilibrating materials. PMID- 26931829 TI - A modified time-of-flight method for precise determination of high speed ratios in molecular beams. AB - Time-of-flight (TOF) is a standard experimental technique for determining, among others, the speed ratio S (velocity spread) of a molecular beam. The speed ratio is a measure for the monochromaticity of the beam and an accurate determination of S is crucial for various applications, for example, for characterising chromatic aberrations in focussing experiments related to helium microscopy or for precise measurements of surface phonons and surface structures in molecular beam scattering experiments. For both of these applications, it is desirable to have as high a speed ratio as possible. Molecular beam TOF measurements are typically performed by chopping the beam using a rotating chopper with one or more slit openings. The TOF spectra are evaluated using a standard deconvolution method. However, for higher speed ratios, this method is very sensitive to errors related to the determination of the slit width and the beam diameter. The exact sensitivity depends on the beam diameter, the number of slits, the chopper radius, and the chopper rotation frequency. We present a modified method suitable for the evaluation of TOF measurements of high speed ratio beams. The modified method is based on a systematic variation of the chopper convolution parameters so that a set of independent measurements that can be fitted with an appropriate function are obtained. We show that with this modified method, it is possible to reduce the error by typically one order of magnitude compared to the standard method. PMID- 26931825 TI - Cells release subpopulations of exosomes with distinct molecular and biological properties. AB - Cells release nano-sized membrane vesicles that are involved in intercellular communication by transferring biological information between cells. It is generally accepted that cells release at least three types of extracellular vesicles (EVs): apoptotic bodies, microvesicles and exosomes. While a wide range of putative biological functions have been attributed to exosomes, they are assumed to represent a homogenous population of EVs. We hypothesized the existence of subpopulations of exosomes with defined molecular compositions and biological properties. Density gradient centrifugation of isolated exosomes revealed the presence of two distinct subpopulations, differing in biophysical properties and their proteomic and RNA repertoires. Interestingly, the subpopulations mediated differential effects on the gene expression programmes in recipient cells. In conclusion, we demonstrate that cells release distinct exosome subpopulations with unique compositions that elicit differential effects on recipient cells. Further dissection of exosome heterogeneity will advance our understanding of exosomal biology in health and disease and accelerate the development of exosome-based diagnostics and therapeutics. PMID- 26931830 TI - Research on calibration method of relative infrared radiometer. AB - The Relative Infrared Radiometer (RIR) is commonly used to measure the irradiance of the Infrared Target Simulator (ITS), and the calibration of the RIR is central for the measurement accuracy. RIR calibration is conventionally performed using the Radiance Based (RB) calibration method or Irradiance Based (IB) calibration method, and the relationship between the radiation of standard source and the response of RIR is determined by curve fitting. One limitation existing in the calibration of RIR is the undesirable calibration voltage fluctuation in single measurement or in the reproducibility measurement, which reduces the calibration reproducibility and irradiance measurement accuracy. To address this limitation, the Equivalent Blackbody Temperature Based (EBTB) calibration method is proposed for the calibration of RIR. The purpose of this study is to compare the proposed EBTB calibration method with conventional RB and IB calibration methods. The comparison and experiment results have shown that the EBTB calibration method is not only able to provide comparable correlation between radiation and response to other calibration methods (IB and RB) in the irradiance measurement but also reduces the influence of calibration voltage fluctuation on the irradiance measurement result, which improves the calibration reproducibility and irradiance measurement accuracy. PMID- 26931831 TI - Design verification of large time constant thermal shields for optical reference cavities. AB - In order to achieve high frequency stability in ultra-stable lasers, the Fabry Perot reference cavities shall be put inside vacuum chambers with large thermal time constants to reduce the sensitivity to external temperature fluctuations. Currently, the determination of thermal time constants of vacuum chambers is based either on theoretical calculation or time-consuming experiments. The first method can only apply to simple system, while the second method will take a lot of time to try out different designs. To overcome these limitations, we present thermal time constant simulation using finite element analysis (FEA) based on complete vacuum chamber models and verify the results with measured time constants. We measure the thermal time constants using ultrastable laser systems and a frequency comb. The thermal expansion coefficients of optical reference cavities are precisely measured to reduce the measurement error of time constants. The simulation results and the experimental results agree very well. With this knowledge, we simulate several simplified design models using FEA to obtain larger vacuum thermal time constants at room temperature, taking into account vacuum pressure, shielding layers, and support structure. We adopt the Taguchi method for shielding layer optimization and demonstrate that layer material and layer number dominate the contributions to the thermal time constant, compared with layer thickness and layer spacing. PMID- 26931832 TI - Production and characterization of a dual species magneto-optical trap of cesium and ytterbium. AB - We describe an apparatus designed to trap and cool a Yb and Cs mixture. The apparatus consists of a dual species effusive oven source, dual species Zeeman slower, magneto-optical traps in a single ultra-high vacuum science chamber, and the associated laser systems. The dual species Zeeman slower is used to load sequentially the two species into their respective traps. Its design is flexible and may be adapted for other experiments with different mixtures of atomic species. The apparatus provides excellent optical access and can apply large magnetic bias fields to the trapped atoms. The apparatus regularly produces 10(8) Cs atoms at 13.3 MUK in an optical molasses, and 10(9) (174)Y b atoms cooled to 22 MUK in a narrowband magneto-optical trap. PMID- 26931833 TI - Design and test of a broadband split-and-delay unit for attosecond XUV-XUV pump probe experiments. AB - We present the design of a split-and-delay unit for the production of two delayed replicas of an incident extreme ultraviolet (XUV) pulse. The device features a single grazing incidence reflection in combination with attenuation of remaining infrared light co-propagating with the XUV beam, offering a high throughput without the need of introducing additional optics that would further decrease the XUV flux. To achieve the required spatial and temporal stabilities, the device is controlled by two PID-controllers monitoring the delay and the beam pointing using an optical reference laser beam, making collimation of the beam by additional optics unnecessary. Finally, we demonstrate the stability of the split and-delay unit by performing all-reflective autocorrelation measurements on broadband few-cycle laser pulses. PMID- 26931834 TI - Double-arm three-dimensional ion imaging apparatus for the study of ion pair channels in resonance enhanced multiphoton ionization. AB - We present a novel experimental configuration for the full quantitative characterization of the multichannel resonance enhanced multiphoton ionization (REMPI) of small molecules in cases when the ion-pair dissociation channel is important. For this purpose, a double-arm time-of-flight mass spectrometer with three-dimensional (3D) ion imaging detectors at both arms is constructed. The REMPI of HCl molecules is used to examine the constructed setup. The apparatus allows us to perform simultaneous measurements of the 3D velocity vector distributions of positive (H(+), HCl(+), and Cl(+)) and negative (Cl(-)) photoions. The characterization consists of the determination of "two-photon absorption cross sections" for the process HCl(X)+2hnu -> HCl*, one-photon absorption cross sections for subsequent processes HCl* + hnu -> HCl*, and the probability of the subsequent non-adiabatic transition HCl* -> HCl(B) -> H(+) + Cl(-), which leads to ionic pairs. All these data should be obtained from the analysis of the dependencies of the number of ions on the laser energy. The full characterization of the laser beam and the knowledge of the ion detection probability are necessary parts of the analysis. Detailed knowledge of losses of produced ions in the mass spectrometer before detection requires understanding and characterization of such processes like electron emission from metallic grids under ion bombardment or charge transfer between positive ions and the metal surface of the grids, like Cl(+) + (grid) -> Cl(-). These important phenomena from surface science are rarely discussed in the imaging literature, and here, we try to compensate for this shortcoming. PMID- 26931835 TI - Fast resonant target vibrating wire scanner for photon beam. AB - We propose a new type of wire scanner for beam profile measurements, based on the use of a vibrating wire as a scattering target. Synchronous measurements with the wire oscillation allow to detect only the signal coming from the scattering of the beam on the wire. This resonant method enables fast beam profiling in the presence of a high level of background. The developed wire scanner, called resonant target vibrating wire scanner, is applied to photon beam profiling, in which the photons reflected on the wire are measured by a fast photodiode. In addition, the proposed measurement principle is expected to monitor other types of beams as well, such as neutrons, protons, electrons, and ions. PMID- 26931836 TI - Study of matrix crack-tilted fiber bundle interaction using caustics and finite element method. AB - In this work, the interaction between the matrix crack and a tilted fiber bundle was investigated via caustics and the finite element method (FEM). First, the caustic patterns at the crack tip with different distances from the tilted fiber were obtained and the stress intensity factors were extracted from the geometry of the caustic patterns. Subsequently, the shielding effect of the fiber bundle in front of the crack tip was analyzed. Furthermore, the interaction between the matrix crack and the broken fiber bundle was discussed. Finally, a finite element simulation was carried out using ABAQUS to verify the experimental results. The results demonstrate that the stress intensity factors extracted from caustic experiments are in excellent agreement with the data calculated by FEM. PMID- 26931837 TI - Simple laser stabilization to the strontium 88Sr transition at 707 nm. AB - We describe frequency stabilization of a laser at 707 nm wavelength using FM spectroscopy in a hollow cathode lamp. The laser is stabilized to the (88)Sr metastable (3)P2 to (3)S1 optical transition. The stabilized laser is utilized for laser-cooling and trapping of strontium atoms. We also briefly describe how the same hollow cathode lamp is used to simultaneously derive a polarization spectroscopy signal for stabilizing the blue-MOT laser at 461 nm. PMID- 26931838 TI - Direct single-mode fibre-coupled miniature White cell for laser absorption spectroscopy. AB - We present the design, setup, and characterization of a new lens-free fibre coupled miniature White cell for extractive gas analysis using direct tunable diode laser absorption spectroscopy (dTDLAS). The construction of this cell is based on a modified White cell design and allows for an easy variation of the absorption length in the range from 29 cm to 146 cm. The design avoids parasitic absorption paths outside the cell by using direct, lensless fibre coupling and allows small physical cell dimensions and cell volumes. To characterize the cell performance, different H2O and CH4 concentration levels were measured using dTDLAS. Detection limits of 2.5 ppm ? m for CH4 (at 1.65 MUm) and 1.3 ppm ? m for H2O (at 1.37 MUm) were achieved. In addition, the gas exchange time and its flow rate dependence were determined for both species and found to be less than 15 s for CH4 and up to a factor of thirteen longer for H2O. PMID- 26931839 TI - Online beam energy measurement of Beijing electron positron collider II linear accelerator. AB - This paper describes online beam energy measurement of Beijing Electron Positron Collider upgraded version II linear accelerator (linac) adequately. It presents the calculation formula, gives the error analysis in detail, discusses the realization in practice, and makes some verification. The method mentioned here measures the beam energy by acquiring the horizontal beam position with three beam position monitors (BPMs), which eliminates the effect of orbit fluctuation, and is much better than the one using the single BPM. The error analysis indicates that this online measurement has further potential usage such as a part of beam energy feedback system. The reliability of this method is also discussed and demonstrated in this paper. PMID- 26931840 TI - Mechanical design and fabrication of the VHF-gun, the Berkeley normal-conducting continuous-wave high-brightness electron source. AB - A high repetition rate, MHz-class, high-brightness electron source is a key element in future high-repetition-rate x-ray free electron laser-based light sources. The VHF-gun, a novel low frequency radio-frequency gun, is the Lawrence Berkeley National Laboratory (LBNL) response to that need. The gun design is based on a normal conducting, single cell cavity resonating at 186 MHz in the VHF band and capable of continuous wave operation while still delivering the high accelerating fields at the cathode required for the high brightness performance. The VHF-gun was fabricated and successfully commissioned in the framework of the Advanced Photo-injector EXperiment, an injector built at LBNL to demonstrate the capability of the gun to deliver the required beam quality. The basis for the selection of the VHF-gun technology, novel design features, and fabrication techniques are described. PMID- 26931841 TI - Commissioning of the PRIOR proton microscope. AB - Recently, a new high energy proton microscopy facility PRIOR (Proton Microscope for FAIR Facility for Anti-proton and Ion Research) has been designed, constructed, and successfully commissioned at GSI Helmholtzzentrum fur Schwerionenforschung (Darmstadt, Germany). As a result of the experiments with 3.5-4.5 GeV proton beams delivered by the heavy ion synchrotron SIS-18 of GSI, 30 MUm spatial and 10 ns temporal resolutions of the proton microscope have been demonstrated. A new pulsed power setup for studying properties of matter under extremes has been developed for the dynamic commissioning of the PRIOR facility. This paper describes the PRIOR setup as well as the results of the first static and dynamic proton radiography experiments performed at GSI. PMID- 26931842 TI - Development of particle characteristics diagnosis system for nanoparticle analysis in vacuum. AB - A particle characteristics diagnosis system (PCDS) was developed to measure nano sized particle properties by a combination of particle beam mass spectrometry, scanning electron microscopy (SEM), and energy dispersive x-ray spectroscopy (EDS). It allows us to measure the size distributions of nano-sized particles in real time, and the shape and composition can be determined by in situ SEM imaging and EDS scanning. PCDS was calibrated by measuring the size-classified nano-sized NaCl particles generated using an aqueous solution of NaCl by an atomizer. After the calibration, the characteristics of nano-sized particles sampled from the exhaust line of the plasma-enhanced chemical vapor deposition process were determined using PCDS. PMID- 26931843 TI - Bayesian modelling of the emission spectrum of the Joint European Torus Lithium Beam Emission Spectroscopy system. AB - A Bayesian model of the emission spectrum of the JET lithium beam has been developed to infer the intensity of the Li I (2p-2s) line radiation and associated uncertainties. The detected spectrum for each channel of the lithium beam emission spectroscopy system is here modelled by a single Li line modified by an instrumental function, Bremsstrahlung background, instrumental offset, and interference filter curve. Both the instrumental function and the interference filter curve are modelled with non-parametric Gaussian processes. All free parameters of the model, the intensities of the Li line, Bremsstrahlung background, and instrumental offset, are inferred using Bayesian probability theory with a Gaussian likelihood for photon statistics and electronic background noise. The prior distributions of the free parameters are chosen as Gaussians. Given these assumptions, the intensity of the Li line and corresponding uncertainties are analytically available using a Bayesian linear inversion technique. The proposed approach makes it possible to extract the intensity of Li line without doing a separate background subtraction through modulation of the Li beam. PMID- 26931844 TI - Comparison of velocimetry techniques for turbulent structures in gas-puff imaging data. AB - Recent analysis of Gas Puff Imaging (GPI) data from Alcator C-Mod found blob velocities with a modified tracking time delay estimation (TDE). These results disagree with velocity analysis performed using direct Fourier methods. In this paper, the two analysis methods are compared. The implementations of these methods are explained, and direct comparisons using the same GPI data sets are presented to highlight the discrepancies in measured velocities. In order to understand the discrepancies, we present a code that generates synthetic sequences of images that mimic features of the experimental GPI images, with user specified input values for structure (blob) size and velocity. This allows quantitative comparison of the TDE and Fourier analysis methods, which reveals their strengths and weaknesses. We found that the methods agree for structures of any size as long as all structures move at the same velocity and disagree when there is significant nonlinear dispersion or when structures appear to move in opposite directions. Direct Fourier methods used to extract poloidal velocities give incorrect results when there is a significant radial velocity component and are subject to the barber pole effect. Tracking TDE techniques give incorrect velocity measurements when there are features moving at significantly different speeds or in different directions within the same field of view. Finally, we discuss the limitations and appropriate use of each of methods and applications to the relationship between blob size and velocity. PMID- 26931846 TI - Feedback system for divertor impurity seeding based on real-time measurements of surface heat flux in the Alcator C-Mod tokamak. AB - Mitigation of the intense heat flux to the divertor is one of the outstanding problems in fusion energy. One technique that has shown promise is impurity seeding, i.e., the injection of low-Z gaseous impurities (typically N2 or Ne) to radiate and dissipate the power before it arrives to the divertor target plate. To this end, the Alcator C-Mod team has created a first-of-its-kind feedback system to control the injection of seed gas based on real-time surface heat flux measurements. Surface thermocouples provide real-time measurements of the surface temperature response to the plasma heat flux. The surface temperature measurements are inputted into an analog computer that "solves" the 1-D heat transport equation to deliver accurate, real-time signals of the surface heat flux. The surface heat flux signals are sent to the C-Mod digital plasma control system, which uses a proportional-integral-derivative (PID) algorithm to control the duty cycle demand to a pulse width modulated piezo valve, which in turn controls the injection of gas into the private flux region of the C-Mod divertor. This paper presents the design and implementation of this new feedback system as well as initial results using it to control divertor heat flux. PMID- 26931845 TI - A diamond 14 MeV neutron energy spectrometer with high energy resolution. AB - A self-standing single-crystal chemical vapor deposited diamond was obtained using lift-off method. It was fabricated into a radiation detector and response function measurements for 14 MeV neutrons were taken at the fusion neutronics source. 1.5% of high energy resolution was obtained by using the (12)C(n, alpha)(9)Be reaction at an angle of 100 degrees with the deuteron beam line. The intrinsic energy resolution, excluding energy spreading caused by neutron scattering, slowing in the target and circuit noises was 0.79%, which was also the best resolution of the diamond detector ever reported. PMID- 26931847 TI - An x-ray backlit Talbot-Lau deflectometer for high-energy-density electron density diagnostics. AB - X-ray phase-contrast techniques can measure electron density gradients in high energy-density plasmas through refraction induced phase shifts. An 8 keV Talbot Lau interferometer consisting of free standing ultrathin gratings was deployed at an ultra-short, high-intensity laser system using K-shell emission from a 1-30 J, 8 ps laser pulse focused on thin Cu foil targets. Grating survival was demonstrated for 30 J, 8 ps laser pulses. The first x-ray deflectometry images obtained under laser backlighting showed up to 25% image contrast and thus enabled detection of electron areal density gradients with a maximum value of 8.1 +/- 0.5 * 10(23) cm(-3) in a low-Z millimeter sized sample. An electron density profile was obtained from refraction measurements with an error of <8%. The 50 +/ 15 MUm spatial resolution achieved across the full field of view was found to be limited by the x-ray source-size, similar to conventional radiography. PMID- 26931848 TI - Detecting divertor damage during steady state operation of Wendelstein 7-X from thermographic measurements. AB - Wendelstein 7-X (W7-X) aims to demonstrate the reactor capability of the stellarator concept, by creating plasmas with pulse lengths of up to 30 min at a heating power of up to 10 MW. The divertor plasma facing components will see convective steady state heat flux densities of up to 10 MW/m(2). These high heat flux target elements are actively cooled and are covered with carbon fibre reinforced carbon (CFC) as plasma facing material. The CFC is bonded to the CuCrZr cooling structure. Over the life time of the experiment this interface may weaken and cracks can occur, greatly reducing the heat conduction between the CFC tile and the cooling structure. Therefore, there is not only the need to monitor the divertor to prevent damage by overheating but also the need to detect these fatigue failures of the interface. A method is presented for an early detection of fatigue failures of the interface layer, solely by using the information delivered by the IR-cameras monitoring the divertor. This was developed and validated through experiments made with high heat flux target elements prior to installation in W7-X. PMID- 26931849 TI - Development of a low-drift integrator system on the HL-2A tokamak. AB - In this work, we developed a new integrator system with low-drift and small integration time constant less than 1 ms, which applies to the weak signals from magnetic measurements. This integrator system is designed on the basis of the analog drift compensation and the real-time digital correction of residual drift. The analog drift compensation is achieved by the subtraction between two integrators and the digital correction method is available due to the stability of integral drift in short time scale. The algorithm of the residual drift calculation and correction is implemented by the field programmable gate array. The integral drift can be well compensated within 10 mV/10 s at RC = 0.5 ms and meet the requirements of magnetic diagnostic on HL-2A. PMID- 26931850 TI - A compact lithium pellet injector for tokamak pedestal studies in ASDEX Upgrade. AB - Experiments have been performed at ASDEX Upgrade, aiming to investigate the impact of lithium in an all-metal-wall tokamak and attempting to enhance the pedestal operational space. For this purpose, a lithium pellet injector has been developed, capable of injecting pellets carrying a particle content ranging from 1.82 * 10(19) atoms (0.21 mg) to 1.64 * 10(20) atoms (1.89 mg). The maximum repetition rate is about 2 Hz. Free flight launch from the torus outboard side without a guiding tube was realized. In such a configuration, angular dispersion and speed scatter are low, and a transfer efficiency exceeding 90% was achieved in the test bed. Pellets are accelerated in a gas gun; hence special care was taken to avoid deleterious effects by the propellant gas pulse. Therefore, the main plasma gas species was applied as propellant gas, leading to speeds ranging from 420 m/s to 700 m/s. In order to minimize the residual amount of gas to be introduced into the plasma vessel, a large expansion volume equipped with a cryopump was added into the flight path. In view of the experiments, an optimal propellant gas pressure of 50 bars was chosen for operation, since at this pressure maximum efficiency and low propellant gas flux coincide. This led to pellet speeds of 585 m/s +/- 32 m/s. Lithium injection has been achieved at ASDEX Upgrade, showing deep pellet penetration into the plasma, though pedestal broadening has not been observed yet. PMID- 26931851 TI - A megawatt solid-state modulator for high repetition rate pulse generation. AB - A novel solid-state modulator capable of generating rapid consecutive power pulses is constructed to facilitate experiments on plasma interaction with high power microwave pulses. The modulator is designed to output a 100 kHz tone burst, which consists of up to 10 pulses, each with 1 MUs duration and 1 MW peak power. The pulses are formed by discharging a total of 480 MUF capacitors through 24 synchronized MOSFETs and 6 step-up transformers. The highly modular design, as a replacement of an old single-pulse version used in earlier experiments which employs a pulse forming network, brings great flexibility and wide potential to its application. A systematic cost-effectiveness analysis is also presented. PMID- 26931852 TI - Implementation of a new iterative learning control algorithm on real data. AB - In this paper, a newly presented approach is proposed for closed-loop automatic tuning of a proportional integral derivative (PID) controller based on iterative learning control (ILC) algorithm. A modified ILC scheme iteratively changes the control signal by adjusting it. Once a satisfactory performance is achieved, a linear compensator is identified in the ILC behavior using casual relationship between the closed loop signals. This compensator is approximated by a PD controller which is used to tune the original PID controller. Results of implementing this approach presented on the experimental data of Damavand tokamak and are consistent with simulation outcome. PMID- 26931853 TI - Advances in x-ray framing cameras at the National Ignition Facility to improve quantitative precision in x-ray imaging. AB - We describe an experimental method to measure the gate profile of an x-ray framing camera and to determine several important functional parameters: relative gain (between strips), relative gain droop (within each strip), gate propagation velocity, gate width, and actual inter-strip timing. Several of these parameters cannot be measured accurately by any other technique. This method is then used to document cross talk-induced gain variations and artifacts created by radiation that arrives before the framing camera is actively amplifying x-rays. Electromagnetic cross talk can cause relative gains to vary significantly as inter-strip timing is varied. This imposes a stringent requirement for gain calibration. If radiation arrives before a framing camera is triggered, it can cause an artifact that manifests as a high-intensity, spatially varying background signal. We have developed a device that can be added to the framing camera head to prevent these artifacts. PMID- 26931854 TI - X-ray topography using the forward transmitted beam under multiple-beam diffraction conditions. AB - X-ray topographs are taken for a sapphire wafer with the [0001] surface normal, as an example, by forward transmitted synchrotron x-ray beams combined with two dimensional electronic arrays in the x-ray detector having a spatial resolution of 1 MUm. They exhibit no shape deformation and no position shift of the dislocation lines on the topographs. Since the topography is performed under multiple-beam diffraction conditions, the topographic images of a single diffraction (two-wave approximation condition) or plural diffractions (six-wave approximation condition) can be recorded without large specimen position changes. As usual Lang topographs, it is possible to determine the Burgers vector of each dislocation line. Because of high parallelism of the incoming x-rays and linear sensitivity of the electronic arrays to the incident x-rays, the present technique can be used to visualize individual dislocations in single crystals of the dislocation density as high as 1 * 10(5) cm(-2). PMID- 26931855 TI - Evaluation and optimization of quartz resonant-frequency retuned fork force sensors with high Q factors, and the associated electric circuits, for non contact atomic force microscopy. AB - High-Q factor retuned fork (RTF) force sensors made from quartz tuning forks, and the electric circuits for the sensors, were evaluated and optimized to improve the performance of non-contact atomic force microscopy (nc-AFM) performed under ultrahigh vacuum (UHV) conditions. To exploit the high Q factor of the RTF sensor, the oscillation of the RTF sensor was excited at its resonant frequency, using a stray capacitance compensation circuit to cancel the excitation signal leaked through the stray capacitor of the sensor. To improve the signal-to-noise (S/N) ratio in the detected signal, a small capacitor was inserted before the input of an operational (OP) amplifier placed in an UHV chamber, which reduced the output noise from the amplifier. A low-noise, wideband OP amplifier produced a superior S/N ratio, compared with a precision OP amplifier. The thermal vibrational density spectra of the RTF sensors were evaluated using the circuit. The RTF sensor with an effective spring constant value as low as 1000 N/m provided a lower minimum detection limit for force differentiation. A nc-AFM image of a Si(111)-7 * 7 surface was produced with atomic resolution using the RTF sensor in a constant frequency shift mode; tunneling current and energy dissipation images with atomic resolution were also simultaneously produced. The high-Q factor RTF sensor showed potential for the high sensitivity of energy dissipation as small as 1 meV/cycle and the high-resolution analysis of non conservative force interactions. PMID- 26931856 TI - Scanning magnetoresistive microscopy: An advanced characterization tool for magnetic nanosystems. AB - An advanced scanning magnetoresistive microscopy (SMRM) - a robust magnetic imaging and probing technique - will be presented, which utilizes state-of-the art recording heads of a hard disk drive as sensors. The spatial resolution of modern tunneling magnetoresistive sensors is nowadays comparable to the more commonly used magnetic force microscopes. Important advantages of SMRM are the ability to detect pure magnetic signals directly proportional to the out-of-plane magnetic stray field, negligible sensor stray fields, and the ability to apply local bipolar magnetic field pulses up to 10 kOe with bandwidths from DC up to 1 GHz. Moreover, the SMRM can be further equipped with a heating stage and external magnetic field units. The performance of this method and corresponding best practices are demonstrated by presenting various examples, including a temperature dependent recording study on hard magnetic L1(0) FeCuPt thin films, imaging of magnetic vortex states in an in-plane magnetic field, and their controlled manipulation by applying local field pulses. PMID- 26931857 TI - Construction of a 3He magnetic force microscope with a vector magnet. AB - We constructed a (3)He magnetic force microscope operating at the base temperature of 300 mK under a vector magnetic field of 2-2-9 T in the x-y-z direction. Fiber optic interferometry as a detection scheme is employed in which two home-built fiber walkers are used for the alignment between the cantilever and the optical fiber. The noise level of the laser interferometer is close to its thermodynamic limit. The capabilities of the sub-Kelvin and vector field are demonstrated by imaging the coexistence of magnetism and superconductivity in a ferromagnetic superconductor (ErNi2B2C) at T = 500 mK and by probing a dipole shape of a single Abrikosov vortex with an in-plane tip magnetization. PMID- 26931858 TI - Developing of an environmental cell TEM holder for dynamic in situ observation. AB - This paper deals with the subject of "in situ" development of environmental transmission electron microscope (E-TEM) holder assemblies. In E-TEM, the sample is continuously subjected to gases as opposed to conventional TEM where the sample is under high vacuum. E-TEM offers the possibility of achieving a new level of material analysis. E-TEM allows obtaining information about chemical information during the reaction at atomic level. Rarefied gas dynamics analysis is used to assess the proposed design. The analysis is focused on determining the molecular distribution inside the vacuum chamber and calculating the impingement rate on the target surface of the specimen. Simulations are performed to predict the molecular interaction with the specimen at given pressures to determine the proper position of a specimen within a vacuum chamber to optimize and predict reaction characteristics. Results of direct simulation Monte Carlo show that the two sides of the sample operate at different temperatures due to the gas flow and experience different molecular distributions. PMID- 26931859 TI - Optical transparency of paper as a function of moisture content with applications to moisture measurement. AB - Accurate measurement of the moisture content of paper is essential in papermaking and is also important in some paper-based microfluidic devices. Traditional measurement techniques provide very limited spatiotemporal resolution and working range. This article presents a novel method for moisture content measurement whose operating principle is the strong correlation between the optical transparency of paper and its moisture content. Spectrographic and microscopic measurement techniques were employed to characterize the relation of moisture content and relative transparency of four types of paper: hardwood chemi thermomechanical pulp paper, Northern bleached softwood kraft paper, unbleached softwood kraft paper, and General Electric((r)) WhatmanTM grade 1 chromatography paper. It was found that for all paper types, the paper transparency increased monotonically with the moisture content (as the ratio of the mass-of-water to the mass-of-dry-paper increased from 0% to 120%). This significant increase in relative transparency occurred due to the refractive index matching role of water in wet paper. It is further shown that mechanical loading of the paper has little impact on the relative transparency, for loadings that would be typical on a paper machine. The results of two transient water absorption experiments are presented that show the utility and accuracy of the technique. PMID- 26931860 TI - Qualification of a sublimation tool applied to the case of metalorganic chemical vapor deposition of In2O3 from In(tmhd)3 as a solid precursor. AB - A solid delivery system consisting of a source canister, a gas management, and temperature controlled enclosure designed and manufactured by Air Liquide Electronics Systems was tested in the context of gas-phase delivery of the In(tmhd)3 solid precursor. The precursor stream was delivered to a thermal metalorganic chemical vapor deposition reactor to quantify deposition yield under various conditions of carrier gas flow and sublimation temperature. The data collected allowed the determination of characteristic parameters such as the maximum precursor flow rate (18.2 mg min(-1) in specified conditions) and the critical mass (defined as the minimum amount of precursor able to attain the maximum flow rate) found to be about 2.4 g, as well as an understanding of the influence of powder distribution inside the canister. Furthermore, this qualification enabled the determination of optimal delivery conditions which allowed for stable and reproducible precursor flow rates over long deposition times (equivalent to more than 47 h of experiment). The resulting In2O3 layers was compared with those elaborated via pulsed liquid injection obtained in the same chemical vapor deposition chamber and under the same deposition conditions. PMID- 26931862 TI - Mapping the process dependent conductivity of carbon nanotube thin-films using a non-invasive contact probing system. AB - We report on a non-invasive contact probing (NICP) system for measuring the distribution of local surface conductivity of macroscopic thin-films of carbon nanotubes. Using the NICP system, we were able to obtain the local sheet resistance of the conducting thin-films continuously at ~10 MUm resolution over few centimeters which would not have been possible using conventional contact probing methods. Measurements performed on carbon nanotube thin-films with various nanotube densities, physical, and chemical treatments revealed that the local variation in electrical characteristics was not reflected in global conductance measurements. This demonstrated the usefulness of the NICP system for evaluating the effect of processing on the electrical uniformity of conducting thin-films made using nanomaterials. PMID- 26931861 TI - A load-lock compatible system for in situ electrical resistivity measurements during thin film growth. AB - An experimental setup designed for in situ electrical resistance measurement during thin film growth is described. The custom-built sample holder with a four point probe arrangement can be loaded into a high-vacuum magnetron sputter deposition chamber through a load-lock transfer system, allowing measurements on series of samples without venting the main chamber. Electrical contact is ensured with circular copper tracks inserted in a Teflon plate on a mounting holder station inside the deposition chamber. This configuration creates the possibility to measure thickness-dependent electrical resistance changes with sub-monolayer resolution and is compatible with use of sample rotation during growth. Examples are presented for metallic films with high adatom mobility growing in a Volmer Weber mode (Ag and Pd) as well as for refractory metal (Mo) with low adatom mobility. Evidence for an amorphous-to-crystalline phase transition at a film thickness of 2.6 nm is reported during growth of Mo on an amorphous Si underlayer, supporting previous findings based on in situ wafer curvature measurements. PMID- 26931863 TI - Photothermal method for absorption measurements in anisotropic crystals. AB - A measurement system for quantitative determination of both surface and bulk contributions to the photo-thermal absorption has been extended to anisotropic optical media. It bases upon a highly sensitive Hartmann-Shack wavefront sensor, accomplishing precise on-line monitoring of wavefront deformations of a collimated test beam transmitted perpendicularly through the laser-irradiated side of a cuboid sample. Caused by the temperature dependence of the refractive index as well as thermal expansion, the initially plane wavefront of the test beam is distorted. Sign and magnitude depend on index change and expansion. By comparison with thermal theory, a calibration of the measurement is possible, yielding a quantitative absolute measure of bulk and surface absorption losses from the transient wavefront distortion. Results for KTP and BBO single crystals are presented. PMID- 26931864 TI - Time-resolved local strain tracking microscopy for cell mechanics. AB - A uniaxial cell stretching technique to measure time-resolved local substrate strain while simultaneously imaging adherent cells is presented. The experimental setup comprises a uniaxial stretcher platform compatible with inverted microscopy and transparent elastomer samples with embedded fluorescent beads. This integration enables the acquisition of real-time spatiotemporal data, which is then processed using a single-particle tracking algorithm to track the positions of fluorescent beads for the subsequent computation of local strain. The present local strain tracking method is demonstrated using polydimethylsiloxane (PDMS) samples of rectangular and dogbone geometries. The comparison of experimental results and finite element simulations for the two sample geometries illustrates the capability of the present system to accurately quantify local deformation even when the strain distribution is non-uniform over the sample. For a regular dogbone sample, the experimentally obtained value of local strain at the center of the sample is 77%, while the average strain calculated using the applied cross head displacement is 48%. This observation indicates that considerable errors may arise when cross-head measurement is utilized to estimate strain in the case of non-uniform sample geometry. Finally, the compatibility of the proposed platform with biological samples is tested using a unibody PDMS sample with a well to contain cells and culture media. HeLa S3 cells are plated on collagen-coated samples and cell adhesion and proliferation are observed. Samples with adherent cells are then stretched to demonstrate simultaneous cell imaging and tracking of embedded fluorescent beads. PMID- 26931865 TI - Development of a spin polarized low energy electron diffraction system. AB - We have designed and constructed a spin polarized low energy electron diffraction system working in the reflected electron pulse counting mode. This system is capable of measuring asymmetries due to spin-orbit and exchange interactions. Photoemission from a strained GaAs/GaAsP super lattice is used as the source of spin polarized electrons. Spin-orbit asymmetry is evaluated for Ir(100) single crystal at various energies. Subsequently, exchange asymmetry has been evaluated on 40 monolayer Fe deposited on Ir(100). This instrument proves to be useful in understanding structure and magnetism at surfaces. PMID- 26931866 TI - Pressure cell for transport measurements under high pressure and low temperature in pulsed magnetic fields. AB - We present a new specially designed pressure cell and technique adapted for resistivity measurements in pulsed magnetic fields up to 60 T at pressures up to at least 4 GPa, and temperatures down to 1.5 K. We show that heating effects during the pulse are acceptable (less than 1 K) and can be corrected allowing reliable temperature dependences of the magnetoresistance to be obtained. We illustrate the performance with a study of the phase diagram of the heavy fermion antiferromagnet CeRh2Si2. PMID- 26931867 TI - Towards microfluidic reactors for in situ synchrotron infrared studies. AB - Anodically bonded etched silicon microfluidic devices that allow infrared spectroscopic measurement of solutions are reported. These extend spatially well resolved in situ infrared measurement to higher temperatures and pressures than previously reported, making them useful for effectively time-resolved measurement of realistic catalytic processes. A data processing technique necessary for the mitigation of interference fringes caused by multiple reflections of the probe beam is also described. PMID- 26931868 TI - All-solid-state deep ultraviolet laser for single-photon ionization mass spectrometry. AB - We report here the development of a reflectron time-of-flight mass spectrometer utilizing single-photon ionization based on an all-solid-state deep ultraviolet (DUV) laser system. The DUV laser was achieved from the second harmonic generation using a novel nonlinear optical crystal KBe2BO3F2 under the condition of high-purity N2 purging. The unique property of this laser system (177.3-nm wavelength, 15.5-ps pulse duration, and small pulse energy at ~15 MUJ) bears a transient low power density but a high single-photon energy up to 7 eV, allowing for ionization of chemicals, especially organic compounds free of fragmentation. Taking this advantage, we have designed both pulsed nanospray and thermal evaporation sources to form supersonic expansion molecular beams for DUV single photon ionization mass spectrometry (DUV-SPI-MS). Several aromatic amine compounds have been tested revealing the fragmentation-free performance of the DUV-SPI-MS instrument, enabling applications to identify chemicals from an unknown mixture. PMID- 26931869 TI - Simple non-invasive analysis of embryonic stem cell-derived cardiomyocytes beating in vitro. AB - The analysis of digital video output enables the non-invasive screening of various active biological processes. For the monitoring and computing of the beating parameters of cardiomyocytes in vitro, CB Analyser (cardiomyocyte beating analyser) software was developed. This software is based on image analysis of the video recording of beating cardiomyocytes. CB Analyser was tested using cardiomyocytes derived from mouse embryonic stem cells at different stages of cardiomyogenesis. We observed that during differentiation (from day 18), the beat peak width decreased, which corresponded to the increased speed of an individual pulse. However, the beating frequency did not change. Further, the effects of epinephrine modulating mature cardiomyocyte functions were tested to validate the CB Analyser analysis. In conclusion, data show that CB Analyser is a useful tool for evaluating the functions of both developing and mature cardiomyocytes under various conditions in vitro. PMID- 26931871 TI - Generation of pressures over 40 GPa using Kawai-type multi-anvil press with tungsten carbide anvils. AB - We have generated over 40 GPa pressures, namely, 43 and 44 GPa, at ambient temperature and 2000 K, respectively, using Kawai-type multi-anvil presses (KMAP) with tungsten carbide anvils for the first time. These high-pressure generations were achieved by combining the following pressure-generation techniques: (1) precisely aligned guide block systems, (2) high hardness of tungsten carbide, (3) tapering of second-stage anvil faces, (4) materials with high bulk modulus in a high-pressure cell, and (5) high heating efficiency. PMID- 26931870 TI - Broadband optical mammography instrument for depth-resolved imaging and local dynamic measurements. AB - We present a continuous-wave instrument for non-invasive diffuse optical imaging of the breast in a parallel-plate transmission geometry. The instrument measures continuous spectra in the wavelength range 650-1000 nm, with an intensity noise level <1.5% and a spatial sampling rate of 5 points/cm in the x- and y directions. We collect the optical transmission at four locations, one collinear and three offset with respect to the illumination optical fiber, to recover the depth of optical inhomogeneities in the tissue. We imaged a tissue-like, breast shaped, silicone phantom (6 cm thick) with two embedded absorbing structures: a black circle (1.7 cm in diameter) and a black stripe (3 mm wide), designed to mimic a tumor and a blood vessel, respectively. The use of a spatially multiplexed detection scheme allows for the generation of on-axis and off-axis projection images simultaneously, as opposed to requiring multiple scans, thus decreasing scan-time and motion artifacts. This technique localizes detected inhomogeneities in 3D and accurately assigns their depth to within 1 mm in the ideal conditions of otherwise homogeneous tissue-like phantoms. We also measured induced hemodynamic changes in the breast of a healthy human subject at a selected location (no scanning). We applied a cyclic, arterial blood pressure perturbation by alternating inflation (to a pressure of 200 mmHg) and deflation of a pneumatic cuff around the subject's thigh at a frequency of 0.05 Hz, and measured oscillations with amplitudes up to 1 MUM and 0.2 MUM in the tissue concentrations of oxyhemoglobin and deoxyhemoglobin, respectively. These hemodynamic oscillations provide information about the vascular structure and functional integrity in tissue, and may be used to assess healthy or abnormal perfusion in a clinical setting. PMID- 26931873 TI - Design and characterization of a novel toroidal split-ring resonator. AB - The design and characterization of a novel toroidal split-ring resonator (SRR) are described in detail. In conventional cylindrical SRRs, there is a large magnetic flux within the bore of the resonator. However, there also exists a non negligible magnetic flux in the free space surrounding the resonator. The energy losses associated with this radiated power diminish the resonator's quality factor. In the toroidal SRR, on the other hand, the magnetic field lines are strongly confined within the bore of the resonator resulting in high intrinsic quality factors and stable resonance frequencies without requiring additional electromagnetic shielding. This paper describes the design and construction of a toroidal SRR as well as an experimental investigation of its cw response in the frequency-domain and its time-domain response to a rf pulse. Additionally, the dependence of the toroidal SRR's resonant frequency and quality factor on the strength of inductive coupling to external circuits is investigated both theoretically and experimentally. PMID- 26931872 TI - New experimental capability to investigate the hypervelocity micrometeoroid bombardment of cryogenic surfaces. AB - Ice is prevalent throughout the solar system and beyond. Though the evolution of many of these icy surfaces is highly dependent on associated micrometeoroid impact phenomena, experimental investigation of these impacts has been extremely limited, especially at the impactor speeds encountered in space. The dust accelerator facility at the Institute for Modeling Plasmas, Atmospheres, and Cosmic Dust (IMPACT) of NASA's Solar System Exploration Research Virtual Institute has developed a novel cryogenic system that will facilitate future study of hypervelocity impacts into ice and icy regolith. The target consists of a copper block, cooled by liquid nitrogen, upon which layers of vapor-deposited ice, pre-frozen ice, or icy regolith can be built in a controlled and quantifiable environment. This ice can be grown from a variety of materials, including H2O, CH3OH, NH3, and slurries containing nanophase iron. Ice temperatures can be varied between 96 K and 150 K and ice thickness greater than 150 nm can be accurately measured. Importantly, the composition of ion plumes created during micrometeoroid impacts onto these icy layers can be measured even in trace amounts by in situ time-of-flight mass spectroscopy. In this paper, we present the fundamental design components of the cryogenic target chamber at IMPACT and proof-of-concept results from target development and from first impacts into thick layers of water ice. PMID- 26931874 TI - Compact high-power microwave divider and combiner. AB - A novel, compact, TM01-TE10 mode power divider and a novel, compact, four-way TE10-TM01 mode power combiner were theoretically designed and experimentally tested as a proof of principle. The theoretical and experimental S parameters are consistent with each other. High-power experiments show that their power capacities are no less than 1.5 GW and 3 GW, respectively. The devices have the merits of high power capacities and low insertion losses. PMID- 26931875 TI - Development of a novel voltage divider for measurement of sub-nanosecond rise time high voltage pulses. AB - This paper is about the development of a copper sulphate based aqueous electrolytic voltage divider for the measurement of high voltage pulses, 100 kV, with pulse widths of 1-2 ns and rise time <1 ns. Novel features are incorporated in the design of the divider, to meet the performance requirements for the application. Analytical calculations to justify design are described. Structural simulation of the divider is carried out using field wave simulation software to verify the effectiveness. A calibration procedure has been developed to calibrate the divider. Results obtained during calibration are subjected to statistical analysis to determine the confidence of measurement. Details of design, analysis, and simulation are described in this paper. PMID- 26931876 TI - Digital synthetic impedance for application in vibration damping. AB - In this work we present construction details of a precision, standalone, and compact digital synthetic impedance for application in the field of vibration damping. The presented device is based on an embedded ARM microcontroller with external AD and DA converters and a special analog front-end. The performance of the device is tested by comparing the actually synthesized impedance with several prescribed impedances and shows very good match. Fine-tuning ability of the device, which is crucial for the considered application, is also demonstrated and reaches as small step as 0.1% for the most complicated impedance structure and drops below the level of direct measurability with less complex structures. The real application in vibration damping is demonstrated on a simple and well understood case of a one-dimensional vibrating spring-mass system with piezoelectric actuator embedded as the interface between source of vibrations and vibrating mass. PMID- 26931877 TI - High performance electronic device for the measurement of the inverse spin Hall effect. AB - We have developed a high performance analog electronic device that can be used for the measurement of the inverse spin Hall effect (ISHE) as a function of the applied magnetic field. The electronic circuit is based on the synchronous detection technique with a careful selection of the active components in order to optimize the response in this application. The electronic accessory was adapted for the simultaneous measurement of the ISHE signal and the microwave absorption in an electron spin resonance spectrometer and tested with a bilayer sample of 5 nm of permalloy (Ni80Fe20) and 5 nm of tantalum. The response of the electronic device was characterized as a function of the microwave power, the amplitude and frequency of the modulation signal, and the relative phase between signal and reference. This last characterization reveals a simple method to put in phase the signal with the reference. The maximum signal to noise ratio was achieved for a modulation frequency between 6 and 12 kHz, for the largest possible values of field modulation amplitude and microwave power. PMID- 26931878 TI - A comparison between finite element modeling and various thermographic non destructive testing techniques for the quantification of the thermal integrity of macro-brush plasma facing components used in a tokamak. AB - The plasma facing components (PFCs) inside a tokamak are typically exposed to extremely high heat flux of the order of MW/m(2). The brazing quality between the plasma facing materials (PFMs) and the heat sink will determine the structural integrity and hence the effective service life of these PFCs. Suitable non destructive testing (NDT) techniques for the pre-qualification of these components are thus essential to evaluate their structural integrity at various stages of their service life. Macro-brush type mockups of prototype PFCs with graphite as PFM have been inspected for their brazing quality using different active Infrared (IR)-thermographic NDT techniques. The results obtained from these techniques are compared and discussed. The brazing quality was quantified by establishing a comparison between the experimental results and the results from Finite Element Analysis (FEA). The percentage of contact between the PFM and the substrate was varied in FEA. FEA results when compared with experiments shows that tiles have different amounts of contact with the substrate ranging between 10% and 80%. PMID- 26931879 TI - Temperature measurements during high flux ion beam irradiations. AB - A systematic study of the ion beam heating effect was performed in a temperature range of -170 to 900 degrees C using a 10 MeV Au(3+) ion beam and a Yttria stabilized Zirconia (YSZ) sample at a flux of 5.5 * 10(12) cm(-2) s(-1). Different geometric configurations of beam, sample, thermocouple positioning, and sample holder were compared to understand the heat/charge transport mechanisms responsible for the observed temperature increase. The beam heating exhibited a strong dependence on the background (initial) sample temperature with the largest temperature increases occurring at cryogenic temperatures and decreasing with increasing temperature. Comparison with numerical calculations suggests that the observed heating effect is, in reality, a predominantly electronic effect and the true temperature rise is small. A simple model was developed to explain this electronic effect in terms of an electrostatic potential that forms during ion irradiation. Such an artificial beam heating effect is potentially problematic in thermostated ion irradiation and ion beam analysis apparatus, as the operation of temperature feedback systems can be significantly distorted by this effect. PMID- 26931880 TI - An examination of the elastic properties of tissue-mimicking phantoms using vibro acoustography and a muscle motor system. AB - Tissue hardness, often quantified in terms of elasticity, is an important differentiating criterion for pathological identity and is extensively used by surgeons for tumor localization. Delineation of malignant regions from benign regions is typically performed by visual inspection and palpation. Although practical, this method is highly subjective and does not provide quantitative metrics. We have previously reported on Vibro-Acoustography (VA) for tumor delineation. VA is unique in that it uses the specific, non-linear properties of tumor tissue in response to an amplitude modulated ultrasound beam to generate spatially resolved, high contrast maps of tissue. Although the lateral and axial resolutions (sub-millimeter and sub-centimeter, respectively) of VA have been extensively characterized, the relationship between static stiffness assessment (palpation) and dynamic stiffness characterization (VA) has not been explicitly established. Here we perform a correlative exploration of the static and dynamic properties of tissue-mimicking phantoms, specifically elasticity, using VA and a muscle motor system. Muscle motor systems, commonly used to probe the mechanical properties of materials, provide absolute, quantitative point measurements of the elastic modulus, analogous to Young's modulus, of a target. For phantoms of varying percent-by-weight concentrations, parallel VA and muscle motor studies conducted on 18 phantoms reveal a negative correlation (p < - 0.85) between mean signal amplitude levels observed with VA and calculated elastic modulus values from force vs. indentation depth curves. Comparison of these elasticity measurements may provide additional information to improve tissue modeling, system characterization, as well as offer valuable insights for in vivo applications, specifically surgical extirpation of tumors. PMID- 26931881 TI - Thermometry of a high temperature high speed micro heater. AB - A high temperature high-speed tungsten micro heater was fabricated and tested for application in phase change switches to indirectly heat and transform phase change material. Time domain transmissometry was used to measure heater temperature transients for given electrical inputs. Finite element modeling results on heater temperature transients show a good consistency between experiments and simulations with 0.2% mismatch in the best case and 13.1% in the worst case. The heater described in this work can reliably reach 1664 K at a rate of 1.67 * 10(10) K/s and quench to room temperature with a thermal RC time constant (time for T to fall by a factor of e) of less than 40 ns. PMID- 26931882 TI - An integrated temperature-compensated flexible shear-stress sensor microarray with concentrated leading-wire. AB - Flexible shear stress sensor is quite important for characterizing curved surface flows. In this work, a novel integrated shear stress sensor microarray is designed with twenty parallel channels, which share the concentrated leading-wire to transmit the ground signal. Electrical pads in rows are easily connected to the circuits with two separate Wheatstone bridges and constant-temperature difference mode operation is provided for the hot-wires. Temperature crosstalk between adjacent hot-wires is prevented well and the effectiveness of the temperature compensated circuits is verified. Relatively large output response is obtained as the shear stress varies and the sensitivity of the sensors is measured about 0.086 V(2)/Pa(1/3) with nonlinearity lower than 1%, revealing high performance characteristic of the sensors. PMID- 26931884 TI - Hybrid acoustic energy harvesting using combined electromagnetic and piezoelectric conversion. AB - This paper reports a novel hybrid acoustic energy harvester. The harvester utilizes both the electromagnetic and piezoelectric conversion mechanisms simultaneously to convert the ambient acoustical noise into electrical power for self-powered wireless sensor nodes. The proposed harvester is comprised of a Helmholtz resonator, two magnets mounted on a piezoelectric plate, and a wound coil located under the magnets. The harvester is characterized both under harmonic and real random acoustical excitations. In-lab, under harmonic acoustical excitation at a sound pressure level of 130 dB and frequency of 2.1 kHz, an optimum power of 2.86 MUW (at 114 Omega optimum load) is obtained from electromagnetic conversion and 50 MUW (at 1000 Omega optimum load) is generated by the piezoelectric harvester's part. Moreover, in real acoustical environment of a domestic electric generator the peak voltages of 40 and 123 mV are produced by the electromagnetic and piezoelectric portions of the acoustic energy harvester. PMID- 26931883 TI - A biomimetic tactile sensing system based on polyvinylidene fluoride film. AB - Polyvinylidene fluoride (PVDF) film has been widely investigated as a sensing material due to its outstanding properties such as biocompatibility, high thermal stability, good chemical resistance, high piezo-, pyro- and ferro-electric properties. This paper reports on the design, test, and analysis of a biomimetic tactile sensor based on PVDF film. This sensor consists of a PVDF film with aluminum electrodes, a pair of insulating layers, and a "handprint" friction layer with a copper foil. It is designed for easy fabrication and high reliability in outputting signals. In bionics, the fingerprint of the glabrous skin plays an important role during object handling. Therefore, in order to enhance friction and to provide better manipulation, the ridges of the fingertips were introduced into the design of the proposed tactile sensor. And, a basic experimental study on the selection of the high sensitivity fingerprint type for the biomimetic sensor was performed. In addition, we proposed a texture distinguish experiment to verify the sensor sensitivity. The experiment's results show that the novel biomimetic sensor is effective in discriminating object surface characteristics. Furthermore, an efficient visual application program (LabVIEW) and a quantitative evaluation method were proposed for the verification of the biomimetic sensor. The proposed tactile sensor shows great potential for contact force and slip measurements. PMID- 26931885 TI - Development of a new direct liquid injection system for nanoparticle deposition by chemical vapor deposition using nanoparticle solutions. AB - Nanoparticles of different materials are already in use for many applications. In some applications, these nanoparticles need to be deposited on a substrate in a fast and reproducible way. We have developed a new direct liquid injection system for nanoparticle deposition by chemical vapor deposition using a liquid nanoparticle precursor. The system was designed to deposit nanoparticles in a controlled and reproducible way by using two direct liquid injectors to deliver nanoparticles to the system. The nanoparticle solution is first evaporated and then the nanoparticles flow onto a substrate inside the vacuum chamber. To allow injection and evaporation of the liquid, a direct liquid injection and vaporization system are mounted on top of the process chamber. The deposition of the nanoparticles is controlled by parameters such as deposition temperature, partial pressure of the gases, and flow rate of the nanoparticle suspension. The concentration of the deposited nanoparticles can be varied simply by changing the flow rate and deposition time. We demonstrate the capabilities of this system using gold nanoparticles. The selected suspension flow rates were varied between 0.25 and 1 g/min. AFM analysis of the deposited samples showed that the aggregation of gold nanoparticles is well controlled by the flow and deposition parameters. PMID- 26931886 TI - Multilayer based soft-x-ray polarimeter at MAX IV Laboratory. AB - A high precision five rotation-axes polarimeter using transmission multilayers as polarizers and reflection multilayers as analyzers has been designed and manufactured. To cover the extreme ultraviolet regime, Mo/Si, Cr/C, Sc/Cr, and W/B4C multilayers for transmission and reflection have also been designed and produced. The polarimeter mechanics is supported on a hexapod to simplify the alignment relative to photon beam. The instrument is designed so that it can be easily transferred between different beamlines. PMID- 26931888 TI - A one-piece 3D printed flexure translation stage for open-source microscopy. AB - Open source hardware has the potential to revolutionise the way we build scientific instruments; with the advent of readily available 3D printers, mechanical designs can now be shared, improved, and replicated faster and more easily than ever before. However, printed parts are typically plastic and often perform poorly compared to traditionally machined mechanisms. We have overcome many of the limitations of 3D printed mechanisms by exploiting the compliance of the plastic to produce a monolithic 3D printed flexure translation stage, capable of sub-micron-scale motion over a range of 8 * 8 * 4 mm. This requires minimal post-print clean-up and can be automated with readily available stepper motors. The resulting plastic composite structure is very stiff and exhibits remarkably low drift, moving less than 20 MUm over the course of a week, without temperature stabilisation. This enables us to construct a miniature microscope with excellent mechanical stability, perfect for time-lapse measurements in situ in an incubator or fume hood. The ease of manufacture lends itself to use in containment facilities where disposability is advantageous and to experiments requiring many microscopes in parallel. High performance mechanisms based on printed flexures need not be limited to microscopy, and we anticipate their use in other devices both within the laboratory and beyond. PMID- 26931887 TI - A Mo-anode-based in-house source for small-angle X-ray scattering measurements of biological macromolecules. AB - We demonstrate the use of a molybdenum-anode-based in-house small-angle X-ray scattering (SAXS) setup to study biological macromolecules in solution. Our system consists of a microfocus X-ray tube delivering a highly collimated flux of 2.5 * 10(6) photons/s at a beam size of 1.2 * 1.2 mm(2) at the collimation path exit and a maximum beam divergence of 0.16 mrad. The resulting observable scattering vectors q are in the range of 0.38 A(-1) down to 0.009 A(-1) in SAXS configuration and of 0.26 A(-1) up to 5.7 A(-1) in wide-angle X-ray scattering (WAXS) mode. To determine the capabilities of the instrument, we collected SAXS data on weakly scattering biological macromolecules including proteins and a nucleic acid sample with molecular weights varying from ~12 to 69 kDa and concentrations of 1.5-24 mg/ml. The measured scattering data display a high signal-to-noise ratio up to q-values of ~0.2 A(-1) allowing for an accurate structural characterization of the samples. Moreover, the in-house source data are of sufficient quality to perform ab initio 3D structure reconstructions that are in excellent agreement with the available crystallographic structures. In addition, measurements for the detergent decyl-maltoside show that the setup can be used to determine the size, shape, and interactions (as characterized by the second virial coefficient) of detergent micelles. This demonstrates that the use of a Mo-anode based in-house source is sufficient to determine basic geometric parameters and 3D shapes of biomolecules and presents a viable alternative to valuable beam time at third generation synchrotron sources. PMID- 26931889 TI - The upgraded Large Plasma Device, a machine for studying frontier basic plasma physics. AB - In 1991 a manuscript describing an instrument for studying magnetized plasmas was published in this journal. The Large Plasma Device (LAPD) was upgraded in 2001 and has become a national user facility for the study of basic plasma physics. The upgrade as well as diagnostics introduced since then has significantly changed the capabilities of the device. All references to the machine still quote the original RSI paper, which at this time is not appropriate. In this work, the properties of the updated LAPD are presented. The strategy of the machine construction, the available diagnostics, the parameters available for experiments, as well as illustrations of several experiments are presented here. PMID- 26931890 TI - Sub-micron solid air tracers for quantum vortices and liquid helium flows. AB - The dynamics of quantized vortices in superfluids has received increased attention recently because of novel techniques developed to visualize them directly. One of these techniques [G. P. Bewley et al., Nature 441, 588 (2006)] visualized quantized vortices and their reconnections in superfluid flows of (4)He by using solid hydrogen tracers of micron-size or larger. The present work improves upon the previous technique by using substantially smaller particles created by injecting atmospheric air diluted in helium gas. These smaller particles are detectable thanks to the higher index of refraction of nitrogen compared to hydrogen and thanks to an improved visualization setup. The optical counting estimate, which agrees with terminal velocity estimates, suggests that the tracer diameter is typically 400 +/- 200 nm and could be as small as 200 nm; being smaller, but not so small as to be influenced by thermal motion, the particles get trapped on the vortices faster, perturb the vortices less, possess smaller Stokes drag, and stay trapped on fast-moving vortices, as also on vortices generated closer to the superfluid transition temperature. Unlike the past, the ability to create particles in the superfluid state directly (instead of creating them above the lambda-point and cooling the fluid subsequently), ensures greater temperature stability for longer periods, and enables the tracking of long and isolated vortices. These advantages have also led to the direct visualization of Kelvin waves. The use of other seed gases could lead to the visualization of even smaller tracers for quantized vortices. We discuss the visualization setup and provide suggestions for further improvement. PMID- 26931891 TI - An innovative spraying setup to obtain uniform salt(s) mixture deposition to investigate hot corrosion. AB - A hot corrosion study via molten salt deposition and its interaction with creep/fatigue play a critical role in predicting the life of gas turbine engine components. To do systematic hot corrosion studies, deposition of molten salts on specimens should be uniform with good adherence. Thus, the present study describes an in-house developed spraying setup that produces uniform and reliable molten salt deposition in a repeatable fashion. The efficacy of the present method was illustrated by depositing 90 wt. % Na2SO4 + 5 wt. % NaCl + 5 wt. % NaVO3 salt mixture on hot corrosion coupons and on creep specimens, and also by comparing with other deposition methods. PMID- 26931892 TI - A 500 A device characterizer utilizing a pulsed-linear amplifier. AB - With the advent of modern power semiconductor switching elements, the envelope defining "high power" is an ever increasing quantity. Characterization of these semiconductor power devices generally falls into two categories: switching, or transient characteristics, and static, or DC characteristics. With the increasing native voltage and current levels that modern power devices are capable of handling, characterization equipment meant to extract quasi-static IV curves has not kept pace, often leaving researchers with no other option than to construct ad hoc curve tracers from disparate pieces of equipment. In this paper, a dedicated 10 V, 500 A curve tracer was designed and constructed for use with state of the art high power semiconductor switching and control elements. The characterizer is a physically small, pulsed power system at the heart of which is a relatively high power linear amplifier operating in a switched manner in order to deliver well defined square voltage pulses. These actively shaped pulses are used to obtain device's quasi-static DC characteristics accurately without causing any damage to the device tested. Voltage and current waveforms from each pulse are recorded simultaneously by two separate high-speed analog to digital converters and averaged over a specified interval to obtain points in the reconstructed IV graph. PMID- 26931893 TI - An online debris sensor system with vibration resistance for lubrication analysis. AB - The health condition of the lubricated systems can be directly indicated by the concentration and material type of the abrasive particles, which may provide very early warnings of faults/failures and benefit the condition based maintenance. Oil debris particle detecting techniques are thus important for machinery condition monitoring and fault diagnosis. This work proposes a new structure of online debris sensor (ODS), which applies the radial magnetic field, different from the traditional axial magnetic field. The designed ODS can effectively reduce the interferences of the background noise and the vibration of the machine in operation. Moreover, in order to optimally determine the number of turns of an inductive coil and the current of the drive coils, two methods are developed respectively in this work which can ensure sensitivity and anti-vibration features of the ODS. The instrumentation circuit system for detecting debris particles and sensing signals has been also designed to extract and to record the signatures of particles. The designed ODS device is then applied to analyze micro debris particles in the lubricating system on a test rig. Experimental results have demonstrated that ODS can successfully detect the 120 MUm(H) ferrous particles and 500 MUm(H) non-ferrous particles under vibration conditions. PMID- 26931894 TI - Design of roundness measurement model with multi-systematic error for cylindrical components with large radius. AB - The paper designs a roundness measurement model with multi-systematic error, which takes eccentricity, probe offset, radius of tip head of probe, and tilt error into account for roundness measurement of cylindrical components. The effects of the systematic errors and radius of components are analysed in the roundness measurement. The proposed method is built on the instrument with a high precision rotating spindle. The effectiveness of the proposed method is verified by experiment with the standard cylindrical component, which is measured on a roundness measuring machine. Compared to the traditional limacon measurement model, the accuracy of roundness measurement can be increased by about 2.2 MUm using the proposed roundness measurement model for the object with a large radius of around 37 mm. The proposed method can improve the accuracy of roundness measurement and can be used for error separation, calibration, and comparison, especially for cylindrical components with a large radius. PMID- 26931895 TI - A novel technique towards deployment of hydrostatic pressure based level sensor in nuclear fuel reprocessing facility. AB - A novel approach towards deployment of a hydrostatic pressure based level monitoring device is presented for continuous monitoring of liquid level in a reservoir with high resolution and precision. Some of the major drawbacks such as spurious information of measured level due to change in ambient temperature, requirement of high resolution pressure sensor, and bubbling effect by passing air or any gaseous fluid into the liquid are overcome by using such a newly designed hydrostatic pressure based level monitoring device. The technique involves precise measurement of hydrostatic pressure exerted by the process liquid using a high sensitive pulsating-type differential pressure sensor (capacitive type differential pressure sensor using a specially designed oil manometer) and correlating it to the liquid level. In order to avoid strong influence of temperature on liquid level, a temperature compensation methodology is derived and used in the system. A wireless data acquisition feature has also been provided in the level monitoring device in order to work in a remote area such as a radioactive environment. At the outset, a prototype level measurement system for a 1 m tank is constructed and its test performance has been well studied. The precision, accuracy, resolution, uncertainty, sensitivity, and response time of the prototype level measurement system are found to be less than 1.1 mm in the entire range, 1%, 3 mm, <1%, 10 Hz/mm, and ~4 s, respectively. PMID- 26931896 TI - Geometrical and total efficiencies of CdZnTe rectangular parallelepiped detector using arbitrary positioned point, plane, and volumetric sources. AB - Gamma-ray detectors are widely used in many fields like environmental measurements, medicine, space science, and industry, where the detector geometrical, total, photopeak efficiencies and peak-to-total ratio could be required. The calculation of the detector efficiency depends mainly on the value of the geometrical efficiency, which depends on the solid angle subtended by the source-detector system. The present work introduces a direct analytical method to calculate the geometrical and total efficiencies of CdZnTe gamma-ray detector using off-axis isotropic radiating gamma-ray [point, disk, and cylindrical] sources. To test the validity of the present work, the results are compared with some published data and also to prove how much it is important to determine the efficiency of difficult gamma-ray detection arrangement. PMID- 26931897 TI - A noninvasive high frequency oscillation ventilator: Achieved by utilizing a blower and a valve. AB - After the High Frequency Oscillatory Ventilation (HFOV) has been applied in the invasive ventilator, the new technique of noninvasive High Frequency Oscillatory Ventilation (nHFOV) which does not require opening the patient's airway has attracted much attention from the field. This paper proposes the design of an experimental positive pressure-controlled nHFOV ventilator which utilizes a blower and a special valve and has three ventilation modes: spontaneous controlled ventilation combining HFOV, time-cycled ventilation combining HFOV (T HFOV), and continuous positive airway pressure ventilation combining HFOV. Experiments on respiratory model are conducted and demonstrated the feasibility of using nHFOV through the control of fan and valve. The experimental ventilator is able to produce an air flow with small tidal volume (VT) and a large minute ventilation volume (MV) using regular breath tubes and nasal mask (e.g., under T HFOV mode, with a maximum tidal volume of 100 ml, the minute ventilation volume reached 14,400 ml). In the process of transmission, there is only a minor loss of oscillation pressure. (Under experimental condition and with an oscillation frequency of 2-10 Hz, peak pressure loss was around 0%-50% when it reaches the mask.). PMID- 26931898 TI - Design and development of a prototype 25 kV, 10 A long pulse Marx modulator for high power klystron. AB - Research, design, and development of high average power modulators for the proposed Indian Spallation Neutron Source are in progress at Raja Ramanna Centre for Advanced Technology. With this objective, a prototype of 25 kV, 10 A, 1 ms Marx modulator at repetition rate of 1 Hz has been designed and developed which serves as a proof of principle and technology assessment stage for further development of high repetition rate high voltage high average power modulators. Insulated Gate Bipolar Transistor (IGBT) based modules of 2.8 kV switching capability have been used as main modules. The modulator had 8.2% droop in output voltage pulse without any droop compensation circuit. A droop compensation involving 15 corrector modules has been used to reduce the droop up to 1%. We have used IGBT based 250 V switches to realize the corrector module. A microcontroller based control unit was designed and developed for triggering the main and corrector modules. With this control unit, programmable output pulse has been achieved. Electrical isolation between high voltage circuits and control circuit has been achieved by the use of fiber optic based control signal transmission. Output pulses of 1 ms pulse width, 800 ns rise time, and 5 MUs fall time have been achieved. The modulator has advantages of modular design, adjustable pulse width, adjustable rise time, and fall time. PMID- 26931899 TI - Multi-mode sliding mode control for precision linear stage based on fixed or floating stator. AB - This paper presents the control performance of a linear motion stage driven by Voice Coil Motor (VCM). Unlike the conventional VCM, the stator of this VCM is regulated, which means it can be adjusted as a floating-stator or fixed-stator. A Multi-Mode Sliding Mode Control (MMSMC), including a conventional Sliding Mode Control (SMC) and an Integral Sliding Mode Control (ISMC), is designed to control the linear motion stage. The control is switched between SMC and IMSC based on the error threshold. To eliminate the chattering, a smooth function is adopted instead of a signum function. The experimental results with the floating stator show that the positioning accuracy and tracking performance of the linear motion stage are improved with the MMSMC approach. PMID- 26931900 TI - Note: Optimal choice of the reflector by phase analysis for heterodyne interferometric roll angle measurement. AB - The choice of an actual reflector instead of an ideal or perfect reflector has to be dealt with for heterodyne-interferometric roll angle measurement methods. The candidates of regular reflectors such as corner cube prism and right angle prism are analyzed by the homogeneous coordinate transformation method, which provides a theoretical basis for the determination of the actual reflector. Furthermore, the influences of the phase loss of the determined reflector are strictly argued due to non-perfect or natural characteristics itself. Several tactics are considered to solve this problem by phase analysis. By contrast, it is an optimal choice that mirrors-based right angle prism can improve evidently the phase loss by experiment. PMID- 26931901 TI - Note: Differential configurations for the mitigation of slow fluctuations limiting the resolution of digital lock-in amplifiers. AB - The resolution of digital lock-in amplifiers working with a narrow bandwidth (<100 Hz) is limited by slow fluctuations, which can be two orders of magnitude larger (MUV range) than the noise of the input amplifier (tens of nV). In order to tackle this issue, affecting state-of-the-art laboratory instrumentation and here systematically quantified, three differential sensing configurations are presented. They adapt to different setup conditions and are based on manual and automatic tuning of dummy references, allowing a 25-fold resolution improvement for enhanced long-term tracking of impedance sensors. PMID- 26931902 TI - Note: A top-view optical approach for observing the coalescence of liquid drops. AB - We developed a new device that is capable of top-view optical examination of the coalescence of liquid drops. The device exhibits great potential for visualization, particularly for the early stage of liquid bridge expansion, owing to the use of a high-speed shadowgraph technique. The fluid densities of the two approaching drops and that of the ambient fluid are carefully selected to be negligibly different, which allows the size of the generated drops to be unlimitedly large in principle. The unique system design allows the point of coalescence between two drops to serve as an undisturbed optical pathway through which to image the coalescence process. The proposed technique extended the dimensionless initial finite radius of the liquid bridge to 0.001, in contrast to 0.01 obtained for conventional optical measurements. An examination of the growth of the bridge radius for a water and oil-tetrachloroethylene system provided results similar to Paulsen's power laws of the inertially limited viscous and inertial regimes. Furthermore, a miniscule shift in the center of the liquid bridge was detected at the point of crossover between the two regimes, which can be scarcely distinguished with conventional side-view techniques. PMID- 26931903 TI - Note: Durability analysis of optical fiber hydrogen sensor based on Pd-Y alloy film. AB - The Pd-Y alloy sensing film has an excellent property for hydrogen detection, but just for one month, the sensing film's property decreases seriously. To study the failure of the sensing film, the XPS spectra analysis was used to explore the chemical content of the Pd-Y alloy film, and analysis results demonstrate that the yttrium was oxidized. The paper presented that such an oxidized process was the potential reason of the failure of the sensing film. By understanding the reason of the failure of the sensing film better, we could improve the manufacturing process to enhance the property of hydrogen sensor. PMID- 26931904 TI - Note: Photopyroelectric measurement of thermal effusivity of transparent liquids by a method free of fitting procedures. AB - In a recent paper published in this journal [R. Ivanov et al., Rev. Sci. Instrum. 86, 064902 (2015)], a methodology free of fitting procedures for determining the thermal effusivity of liquids using the electropyroelectric technique was reported. Here the same measurement principle is extended to the well-known photopyroelectric technique. The theoretical basis and experimental basis of the method are presented and its usefulness is demonstrated with measurements on test samples. PMID- 26931905 TI - Note: Photoluminescence excitation measurements in the 1.1-1.6 MUm spectral range. AB - Pressure-tuned laser diodes are used for photoluminescence excitation in quantum well samples grown on InP. With two bent-waveguide, external cavity lasers, the spectral range from 1.1 to 1.6 MUm can be covered. This range is important for telecommunication devices, for quantum-dot emitters etc. while it is inaccessible to solid-state tunable lasers or dye lasers. PMID- 26931908 TI - Brightness Award. PMID- 26931907 TI - Preface: Proceedings of the 16th International Conference on Ion Sources, New York City, USA 2015. PMID- 26931909 TI - Novel modification of Hall-type ion source (study and the first results). AB - We present the original approach to use plasma accelerators with closed electron drift (Hall-type ion sources), which, unlike traditional accelerators with metal and dielectric walls, have open walls and can be applied for creation cost effective low maintenance plasma devices based on plasma lens configuration for production of converging towards axis accelerated ion beams. The paper describes pilot sample of Hall-type plasma accelerator, the first experimental results, one dimensional theoretical model, and exact analytical solutions following from it. PMID- 26931910 TI - Simulation of diatomic gas-wall interaction and accommodation coefficients for negative ion sources and accelerators. AB - Particle-wall interactions determine in different ways the operating conditions of plasma sources, ion accelerators, and beams operating in vacuum. For instance, a contribution to gas heating is given by ion neutralization at walls; beam losses and stray particle production-detrimental for high current negative ion systems such as beam sources for fusion-are caused by collisional processes with residual gas, with the gas density profile that is determined by the scattering of neutral particles at the walls. This paper shows that Molecular Dynamics (MD) studies at the nano-scale can provide accommodation parameters for gas-wall interactions, such as the momentum accommodation coefficient and energy accommodation coefficient: in non-isothermal flows (such as the neutral gas in the accelerator, coming from the plasma source), these affect the gas density gradients and influence efficiency and losses in particular of negative ion accelerators. For ideal surfaces, the computation also provides the angular distribution of scattered particles. Classical MD method has been applied to the case of diatomic hydrogen molecules. Single collision events, against a frozen wall or a fully thermal lattice, have been simulated by using probe molecules. Different modelling approximations are compared. PMID- 26931911 TI - Neutral resonant ionization in a H- plasma source: Potential of doubly excited **H-. AB - Hydrogen plasmas are optically dense to Lyman-alpha radiation, maintaining *H(n = 2) neutral atoms that may undergo neutral resonant ionization to **H(-). One state, **H(-)(2p(2) (3)P(e)), is thought bound at 9.7 meV with a several nanosecond lifetime while all others are unbound resonances. Collision dynamics of two *H(2s) shows that an ionic pair of (p, **H(-)) resolves at least three long-standing collision experiments. The doubly excited anion also has a path to the unexcited ion pair whose only physical distinction is that both (p, H(-)) have energy of 3.7 eV. PMID- 26931912 TI - Anion formation in sputter ion sources by neutral resonant ionization. AB - Focused Cs(+) beams in sputter ion sources create mm-diameter pits supporting small plasmas that control anionization efficiencies. Sputtering produces overwhelmingly neutral products that the plasma can ionize as in a charge-change vapor. Electron capture between neutral atoms rises as the inverse square of the difference between the ionization potential of the Cs state and the electron affinity of the sputtered atom, allowing resonant ionization at very low energies. A plasma collision-radiation model followed electronic excitation up to Cs(7d). High modeled Cs(7d) in a 0.5 mm recess explains the 80 MUA/mm(2) C(-) current density compared to the 20 MUA/mm(2) from a 1 mm recess. PMID- 26931913 TI - Recent progress in plasma modelling at INFN-LNS. AB - At Istituto Nazionale di Fisica Nucleare - Laboratori Nazionali del Sud (INFN LNS), the development of intense ion and proton sources has been supported by a great deal of work on the modelling of microwave generated plasmas for many years. First, a stationary version of the particle-in-cell code was developed for plasma modelling starting from an iterative strategy adopted for the space charge dominated beam transport simulations. Electromagnetic properties of the plasma and full-waves simulations are now affordable for non-homogenous and non isotropic magnetized plasma via "cold" approximation. The effects of Coulomb collisions on plasma particles dynamics was implemented with the Langevin formalism, instead of simply applying the Spitzer 90 degrees collisions through a Monte Carlo technique. A wide database of different cross sections related to reactions occurring in a hydrogen plasma was implemented. The next step consists of merging such a variety of approaches for retrieving an "as-a-whole" picture of plasma dynamics in ion sources. The preliminary results will be summarized in the paper for a microwave discharge ion source designed for intense and high quality proton beams production, proton source for European Spallation Source project. Even if the realization of a predictive software including the complete processes involved in plasma formation is still rather far, a better comprehension of the source behavior is possible and so the simulations may support the optimization phase. PMID- 26931914 TI - Photoelectron emission from metal surfaces induced by radiation emitted by a 14 GHz electron cyclotron resonance ion source. AB - Photoelectron emission measurements have been performed using a room-temperature 14 GHz ECR ion source. It is shown that the photoelectron emission from Al, Cu, and stainless steel (SAE 304) surfaces, which are common plasma chamber materials, is predominantly caused by radiation emitted from plasma with energies between 8 eV and 1 keV. Characteristic X-ray emission and bremsstrahlung from plasma have a negligible contribution to the photoelectron emission. It is estimated from the measured data that the maximum conceivable photoelectron flux from plasma chamber walls is on the order of 10% of the estimated total electron losses from the plasma. PMID- 26931915 TI - Experimental investigation of non-linear wave to plasma interaction in a quasi flat magnetostatic field. AB - A characterization of wave-to-plasma interaction in a quasi-flat magnetostatic field at 3.75 GHz has been carried out by using a small-wire movable RF antenna, connected to a spectrum analyzer. The coupling between electromagnetic and electrostatic waves leads to a characteristic spectral emission in low frequency range and around the pumping wave frequency. The most relevant results consist in the broadening of the pumping wave spectrum above critical RF power thresholds and in the generation of sidebands of the pumping frequency, with corresponding components in low frequency domain. The non-linearities are accompanied by the generation of overdense plasmas and intense fluxes of X-rays. PMID- 26931916 TI - Oscillatory instability development in extraction system of a negative ion source. AB - Conditions of oscillatory instability development in the extraction system of a negative hydrogen ion source based on a volume-produced plasma are studied. Such an ion source is characterized by the presence of the parent gas in the extraction system due to the leakage from the gas-discharge chamber. The secondary electrons in the area of the ion-optical system become the reason of oscillation appearance and possible beam current modulation. Analytically the range of the stable beam propagation is found. The instability increment is shown to be rather small. Maximum increment of the oscillations corresponds to the beam velocity equal to the thermal velocity of plasma electrons. The group velocity of the oscillations is close to the beam velocity so the oscillations are convective. Simulation of the low energy beam propagation is performed in COMSOL Multiphysics, the beam current modulation being observed. PMID- 26931917 TI - Mixed Pierce-two-stream instability development in an extraction system of a negative ion source. AB - Mixed Pierce-two-stream instability may occur in an extraction system of a negative ion source based on a volume-produced plasma. The reasons for instability development are discussed. Analytically the conditions of unstable beam propagation are determined. The instability threshold is shown to be increased compared with the pure Pierce instability. The influence of inclined perturbations on the instability behavior is investigated. The numerical calculations are performed in COMSOL Multiphysics. The simulation results confirm the existence of such a mixed instability appearance that develops due to both the electrons of the external circuit and the background positive ions. PMID- 26931918 TI - Electron cyclotron resonance ion source plasma characterization by X-ray spectroscopy and X-ray imaging. AB - An experimental campaign aiming to investigate electron cyclotron resonance (ECR) plasma X-ray emission has been recently carried out at the ECRISs-Electron Cyclotron Resonance Ion Sources laboratory of Atomki based on a collaboration between the Debrecen and Catania ECR teams. In a first series, the X-ray spectroscopy was performed through silicon drift detectors and high purity germanium detectors, characterizing the volumetric plasma emission. The on purpose developed collimation system was suitable for direct plasma density evaluation, performed "on-line" during beam extraction and charge state distribution characterization. A campaign for correlating the plasma density and temperature with the output charge states and the beam intensity for different pumping wave frequencies, different magnetic field profiles, and single-gas/gas mixing configurations was carried out. The results reveal a surprisingly very good agreement between warm-electron density fluctuations, output beam currents, and the calculated electromagnetic modal density of the plasma chamber. A charge coupled device camera coupled to a small pin-hole allowing X-ray imaging was installed and numerous X-ray photos were taken in order to study the peculiarities of the ECRIS plasma structure. PMID- 26931919 TI - Kinetic instabilities in pulsed operation mode of a 14 GHz electron cyclotron resonance ion source. AB - The occurrence of kinetic plasma instabilities is studied in pulsed operation mode of a 14 GHz A-electron cyclotron resonance type electron cyclotron resonance ion source. It is shown that the temporal delay between the plasma breakdown and the appearance of the instabilities is on the order of 10-100 ms. The most important parameters affecting the delay are magnetic field strength and neutral gas pressure. It is demonstrated that kinetic instabilities limit the high charge state ion beam production in the unstable operating regime. PMID- 26931920 TI - Development status of a next generation ECRIS: MARS-D at LBNL. AB - To demonstrate a Mixed Axial and Radial field System (MARS) as the best magnet scheme for future ECRISs, MARS-D, a demonstrative ECRIS using a NbTi MARS magnet is progressing at Lawrence Berkeley National Laboratory. An optimized MARS design can use either NbTi or Nb3Sn coils with reduced engineering complexities to construct the needed high-field magnets. The optimized magnet design could enhance MARS-D to a next generation ECRIS by producing minimum-B field maxima of 5.6 T axially and 3.2 T radially for operating frequencies up to 45 GHz. In progress test winding has achieved a milestone demonstrating the fabrication feasibility of a MARS closed-loop coil. PMID- 26931921 TI - Limitation of the ECRIS performance by kinetic plasma instabilities (invited). AB - Electron cyclotron resonance ion source (ECRIS) plasmas are prone to kinetic instabilities due to anisotropic electron velocity distribution. The instabilities are associated with strong microwave emission and periodic bursts of energetic electrons escaping the magnetic confinement. The instabilities explain the periodic ms-scale oscillation of the extracted beam current observed with several high performance ECRISs and restrict the parameter space available for the optimization of extracted beam currents of highly charged ions. Experiments with the JYFL 14 GHz ECRIS have demonstrated that due to the instabilities the optimum Bmin-field is less than 0.8BECR, which is the value suggested by the semiempirical scaling laws guiding the design of ECRISs. PMID- 26931922 TI - Correlations between density distributions, optical spectra, and ion species in a hydrogen plasma (invited). AB - An experimental study of plasma distributions in a 2.45 GHz hydrogen discharge operated at 100 Hz repetition rate is presented. Ultrafast photography, time integrated visible light emission spectra, time resolved Balmer-alpha emission, time resolved Fulcher Band emission, ion species mass spectra, and time resolved ion species fraction measurements have been implemented as diagnostic tools in a broad range of plasma conditions. Results of plasma distributions and optical emissions correlated with H(+), H2(+), and H3(+) ion currents by using a Wien filter system with optical observation capability are reported. The magnetic field distribution and strength is found as the most critical factor for transitions between different plasma patterns and ion populations. PMID- 26931923 TI - High intensity proton injector for facility of antiproton and ion research. AB - The high current ion source with the low energy beam transport (LEBT) will serve as injector into the proton LINAC to provide primary proton beam for the production of antiprotons. The pulsed ion source developed and built in CEA/Saclay operates with a frequency of 2.45 GHz based on ECR plasma production with two coils with 87.5 mT magnetic field necessary for the electron cyclotron resonance. The compact LEBT consists of two solenoids with a maximum magnetic field of 500 mT including two integrated magnetic steerers to adjust the horizontal and vertical beam positions. The total length of the compact LEBT is 2.3 m and was made as short as possible to reduced emittance growth along the beam line. To measure ion beam intensity behind the pentode extraction system, between solenoids and at the end of the beam line, two current transformers and a Faraday cup are installed. To get information about the beam quality and position, the diagnostic chamber with different equipment will be installed between the two solenoids. This article reports the current status of the proton injector for the facility of antiproton and ion research. PMID- 26931924 TI - Improvements of PKU PMECRIS for continuous hundred hours CW proton beam operation. AB - In order to improve the source stability, a long term continuous wave (CW) proton beam experiment has been carried out with Peking University compact permanent magnet 2.45 GHz ECR ion source (PKU PMECRIS). Before such an experiment a lot of improvements and modifications were completed on the source body, the Faraday cup and the PKU ion source test bench. At the beginning of 2015, a continuous operation of PKU PMECRIS for 306 h with more than 50 mA CW beam was carried out after success of many short term tests. No plasma generator failure or high voltage breakdown was observed during that running period and the proton source reliability is near 100%. Total beam availability, which is defined as 35-keV beam-on time divided by elapsed time, was higher than 99% [S. X. Peng et al., Chin. Phys. B 24(7), 075203 (2015)]. A re-inspection was performed after another additional 100 h operation (counting time) and no obvious sign of component failure was observed. Counting the previous source testing time together, this PMECRs longevity is now demonstrated to be greater than 460 h. This paper is mainly concentrated on the improvements for this long term experiment. PMID- 26931925 TI - Advancement of highly charged ion beam production by superconducting ECR ion source SECRAL (invited). AB - At Institute of Modern Physics (IMP), Chinese Academy of Sciences (CAS), the superconducting Electron Cyclotron Resonance (ECR) ion source SECRAL (Superconducting ECR ion source with Advanced design in Lanzhou) has been put into operation for about 10 years now. It has been the main working horse to deliver intense highly charged heavy ion beams for the accelerators. Since its first plasma at 18 GHz, R&D work towards more intense highly charged ion beam production as well as the beam quality investigation has never been stopped. When SECRAL was upgraded to its typical operation frequency 24 GHz, it had already showed its promising capacity of very intense highly charged ion beam production. And it has also provided the strong experimental support for the so called scaling laws of microwave frequency effect. However, compared to the microwave power heating efficiency at 18 GHz, 24 GHz microwave heating does not show the omega(2) scale at the same power level, which indicates that microwave power coupling at gyrotron frequency needs better understanding. In this paper, after a review of the operation status of SECRAL with regard to the beam availability and stability, the recent study of the extracted ion beam transverse coupling issues will be discussed, and the test results of the both TE01 and HE11 modes will be presented. A general comparison of the performance working with the two injection modes will be given, and a preliminary analysis will be introduced. The latest results of the production of very intense highly charged ion beams, such as 1.42 emA Ar(12+), 0.92 emA Xe(27+), and so on, will be presented. PMID- 26931926 TI - 24 GHz microwave mode converter optimized for superconducting ECR ion source SECRAL. AB - Over-sized round waveguide with a diameter about O33.0 mm excited in the TE01 mode has been widely adopted for microwave transmission and coupling to the ECR (Electron Cyclotron Resonance) plasma with the superconducting ECR ion sources operating at 24 or 28 GHz, such as SECRAL and VENUS. In order to study the impact of different microwave modes on ECRH (Electron Cyclotron Resonance Heating) efficiency and especially the production of highly charged ions, a set of compact and efficient TE01-HE11 mode conversion and coupling system applicable to 24 GHz SECRAL whose overall length is 330 mm has been designed, fabricated and tested. Good agreements between off-line tests and calculation results have been achieved, which indicates the TE01-HE11 converter meets the application design. The detailed results of the optimized coupling system will be presented in the paper. PMID- 26931927 TI - Progress in high-temperature oven development for 28 GHz electron cyclotron resonance ion source. AB - We have been developing a high-temperature oven using UO2 in the 28 GHz superconducting electron cyclotron resonance ion source at RIKEN since 2013. A total of eleven on-line tests were performed. The longest operation time in a single test was 411 h, and the consumption rate of UO2 was approximately 2.4 mg/h. In these tests, we experienced several problems: the ejection hole of a crucible was blocked with UO2 and a crucible was damaged because of the reduction of tungsten strength at high temperature. In order to solve these problems, improvements to the crucible shape were made by simulations using ANSYS. PMID- 26931929 TI - First operation and effect of a new tandem-type ion source based on electron cyclotron resonance. AB - A new tandem type source has been constructed on the basis of electron cyclotron resonance plasma for producing synthesized ion beams in Osaka University. Magnetic field in the first stage consists of all permanent magnets, i.e., cylindrically comb shaped one, and that of the second stage consists of a pair of mirror coil, a supplemental coil and the octupole magnets. Both stage plasmas can be individually operated, and produced ions in which is energy controlled by large bore extractor also can be transported from the first to the second stage. We investigate the basic operation and effects of the tandem type electron cyclotron resonance ion source (ECRIS). Analysis of ion beams and investigation of plasma parameters are conducted on produced plasmas in dual plasmas operation as well as each single operation. We describe construction and initial experimental results of the new tandem type ion source based on ECRIS with wide operation window for aiming at producing synthesized ion beams as this new source can be a universal source in future. PMID- 26931928 TI - Accessibility condition of wave propagation and multicharged ion production in electron cyclotron resonance ion source plasma. AB - A new tandem type source of electron cyclotron resonance (ECR) plasmas has been constructing for producing synthesized ion beams in Osaka University. Magnetic mirror field configuration with octupole magnets can be controlled to various shape of ECR zones, namely, in the 2nd stage plasma to be available by a pair mirror and a supplemental coil. Noteworthy correlations between these magnetic configurations and production of multicharged ions are investigated in detail, as well as their optimum conditions. We have been considering accessibility condition of electromagnetic and electrostatic waves propagating in ECR ion source plasma, and then investigated their correspondence relationships with production of multicharged ions. It has been clarified that there exits efficient configuration of ECR zones for producing multicharged ion beams experimentally, and then has been suggested from detail accessibility conditions on the ECR plasma that new resonance, i.e., upper hybrid resonance, must have occurred. PMID- 26931930 TI - Investigation of pulsed mode operation with the frequency tuned CAPRICE ECRIS. AB - In order to increase the intensity of the highly charged ions produced by the Electron Cyclotron Resonance Ion Sources (ECRISs), techniques like the frequency tuning and the afterglow mode have been developed and in this paper the effect on the ion production is shown for the first time when combining both techniques. Recent experimental results proved that the tuning of the operating frequency of the ECRIS is a promising technique to achieve higher ion currents of higher charge states. On the other hand, it is well known that the afterglow mode of the ECRIS operation can provide more intense pulsed ion beams in comparison with the continuous wave (cw) operation. These two techniques can be combined by pulsing the variable frequency signal driving the traveling wave tube amplifier which provides the high microwave power to the ECRIS. In order to analyze the effect of these two combined techniques on the ion source performance, several experiments were carried out on the pulsed frequency tuned CAPRICE (Compacte source A Plusiers Resonances Ionisantes Cyclotron Electroniques)-type ECRIS. Different waveforms and pulse lengths have been investigated under different settings of the ion source. The results of the pulsed mode have been compared with those of cw operation. PMID- 26931931 TI - Nitrogen ion implantation into various materials using 28 GHz electron cyclotron resonance ion source. AB - The installation of the 28 GHz electron cyclotron resonance ion source (ECRIS) ion implantation beamline was recently completed at the Korea Basic Science Institute. The apparatus contains a beam monitoring system and a sample holder for the ion implantation process. The new implantation system can function as a multipurpose tool since it can implant a variety of ions, ranging hydrogen to uranium, into different materials with precise control and with implantation areas as large as 1-10 mm(2). The implantation chamber was designed to measure the beam properties with a diagnostic system as well as to perform ion implantation with an in situ system including a mass spectrometer. This advanced implantation system can be employed in novel applications, including the production of a variety of new materials such as metals, polymers, and ceramics and the irradiation testing and fabrication of structural and functional materials to be used in future nuclear fusion reactors. In this investigation, the first nitrogen ion implantation experiments were conducted using the new system. The 28 GHz ECRIS implanted low-energy, multi-charged nitrogen ions into copper, zinc, and cobalt substrates, and the ion implantation depth profiles were obtained. SRIM 2013 code was used to calculate the profiles under identical conditions, and the experimental and simulation results are presented and compared in this report. The depths and ranges of the ion distributions in the experimental and simulation results agree closely and demonstrate that the new system will enable the treatment of various substrates for advanced materials research. PMID- 26931932 TI - Experimental results of superimposing 9.9 GHz extraordinary mode microwaves on 2.45 GHz ECRIS plasma. AB - Efficient production of multicharged ions has been investigated on the tandem type ECRIS in Osaka University. According to the consideration of the accessibility conditions of microwaves to resonance and cutoff regions, it was suggested that the upper hybrid resonance (UHR) heating contributed to enhancement of ion beam intensity. In order to enhance multicharged ion beams efficiently, injecting higher frequency microwave with extraordinary (X-mode) toward UHR region has been tried. In this study, 2.45 GHz frequency microwaves are used for conventional ECR discharge, and 9.9 GHz frequency microwaves with X mode are superimposed for UHR heating. The effects of additive microwave injection are investigated experimentally in terms of plasma parameters and electron energy distribution function (EEDF) measured by Langmuir probe and ion beam current. As the results show, it is confirmed that the electrons in the high energy region are affected by 9.9 GHz X-mode microwave injection from the detailed analysis of EEDF. PMID- 26931933 TI - First experiments with gasdynamic ion source in CW mode. AB - A new type of ECR ion source-a gasdynamic ECR ion source-has been recently developed at the Institute of Applied Physics. The main advantages of such device are extremely high ion beam current with a current density up to 600-700 emA/cm(2) in combination with low emittance, i.e., normalized RMS emittance below 0.1 pi mm mrad. Previous investigations were carried out in pulsed operation with 37.5 or 75 GHz gyrotron radiation with power up to 100 kW at SMIS 37 experimental facility. The present work demonstrates the first experience of operating the gasdynamic ECR ion source in CW mode. A test bench of SMIS 24 facility has been developed at IAP RAS. 24 GHz radiation of CW gyrotron was used for plasma heating in a magnetic trap with simple mirror configuration. Initial studies of plasma parameters were performed. Ion beams with pulsed and CW high voltage were successfully extracted from the CW discharge. Obtained experimental results demonstrate that all advantages of the gasdynamic source can be realized also in CW operation. PMID- 26931934 TI - New progress of high current gasdynamic ion source (invited). AB - The experimental and theoretical research carried out at the Institute of Applied Physics resulted in development of a new type of electron cyclotron resonance ion sources (ECRISs)-the gasdynamic ECRIS. The gasdynamic ECRIS features a confinement mechanism in a magnetic trap that is different from Geller's ECRIS confinement, i.e., the quasi-gasdynamic one similar to that in fusion mirror traps. Experimental studies of gasdynamic ECRIS were performed at Simple Mirror Ion Source (SMIS) 37 facility. The plasma was created by 37.5 and 75 GHz gyrotron radiation with power up to 100 kW. High frequency microwaves allowed to create and sustain plasma with significant density (up to 8 * 10(13) cm(-3)) and to maintain the main advantages of conventional ECRIS such as high ionization degree and low ion energy. Reaching such high plasma density relies on the fact that the critical density grows with the microwave frequency squared. High microwave power provided the average electron energy on a level of 50-300 eV enough for efficient ionization even at neutral gas pressure range of 10(-4)-10(-3) mbar. Gasdynamic ECRIS has demonstrated a good performance producing high current (100-300 mA) multi-charged ion beams with moderate average charge (Z = 4-5 for argon). Gasdynamic ECRIS has appeared to be especially effective in low emittance hydrogen and deuterium beams formation. Proton beams with current up to 500 emA and RMS emittance below 0.07 pi ? mm ? mrad have been demonstrated in recent experiments. PMID- 26931936 TI - Compact permanent magnet H+ ECR ion source with pulse gas valve. AB - Compact H(+) ECR ion source using permanent magnets is under development. Switching the hydrogen gas flow in pulse operations can reduce the gas loads to vacuum evacuation systems. A specially designed piezo gas valve chops the gas flow quickly. A 6 GHz ECR ion source equipped with the piezo gas valve is tested. The gas flow was measured by a fast ion gauge and a few ms response time is obtained. PMID- 26931935 TI - First results of 28 GHz superconducting electron cyclotron resonance ion source for KBSI accelerator. AB - The 28 GHz superconducting electron cyclotron resonance (ECR) ion source has been developed to produce a high current heavy ion for the linear accelerator at KBSI (Korea Basic Science Institute). The objective of this study is to generate fast neutrons with a proton target via a p(Li,n)Be reaction. The design and fabrication of the essential components of the ECR ion source, which include a superconducting magnet with a liquid helium re-condensed cryostat and a 10 kW high-power microwave, were completed. The waveguide components were connected with a plasma chamber including a gas supply system. The plasma chamber was inserted into the warm bore of the superconducting magnet. A high voltage system was also installed for the ion beam extraction. After the installation of the ECR ion source, we reported the results for ECR plasma ignition at ECRIS 2014 in Russia. Following plasma ignition, we successfully extracted multi-charged ions and obtained the first results in terms of ion beam spectra from various species. This was verified by a beam diagnostic system for a low energy beam transport system. In this article, we present the first results and report on the current status of the KBSI accelerator project. PMID- 26931937 TI - The characteristic of evaporative cooling magnet for ECRIS. AB - Compared with traditional de-ionized pressurized-water cooled magnet of ECRIS, evaporative cooling magnet has some special characteristics, such as high cooling efficiency, simple maintenance, and operation. The analysis is carried out according to the design and operation of LECR4 (Lanzhou Electron Cyclotron Resonance ion source No. 4, since July 2013), whose magnet is cooled by evaporative cooling technology. The insulation coolant replaces the de-ionized pressurized-water to absorb the heat of coils, and the physical and chemical properties of coolant remain stable for a long time with no need for purification or filtration. The coils of magnet are immersed in the liquid coolant. For the higher cooling efficiency of coolant, the current density of coils can be greatly improved. The heat transfer process executes under atmospheric pressure, and the temperature of coils is lower than 70 degrees C when the current density of coils is 12 A/mm(2). On the other hand, the heat transfer temperature of coolant is about 50 degrees C, and the heat can be transferred to fresh air which can save cost of water cooling system. Two years of LECR4 stable operation show that evaporative cooling technology can be used on magnet of ECRIS, and the application advantages are very obvious. PMID- 26931938 TI - Two-chamber configuration of Bio-Nano electron cyclotron resonance ion source for fullerene modification. AB - We report on the modification of fullerenes with iron and chlorine using two individually controllable plasmas in the Bio-Nano electron cyclotron resonance ion source (ECRIS). One of the plasmas is composed of fullerene and the other one is composed of iron and chlorine. The online ion beam analysis allows one to investigate the rate of the vapor-phase collisional modification process in the ECRIS, while the offline analyses (e.g., liquid chromatography-mass spectrometry) of the materials deposited on the plasma chamber can give information on the surface-type process. Both analytical methods show the presence of modified fullerenes such as fullerene-chlorine, fullerene-iron, and fullerene-chlorine iron. PMID- 26931939 TI - Production of multicharged metal ion beams on the first stage of tandem-type ECRIS. AB - Multicharged metal ion beams are required to be applied in a wide range of fields. We aim at synthesizing iron-endohedral fullerene by transporting iron ion beams from the first stage into the fullerene plasma in the second stage of the tandem-type electron cyclotron resonance ion source (ECRIS). We developed new evaporators by using a direct ohmic heating method and a radiation heating method from solid state pure metal materials. We investigate their properties in the test chamber and produce iron ions on the first stage of the tandem-type ECRIS. As a result, we were successful in extracting Fe(+) ion beams from the first stage and introducing Fe(+) ion beams to the second stage. We will try synthesizing iron-endohedral fullerene on the tandem-type ECRIS by using these evaporators. PMID- 26931940 TI - Control system renewal for efficient operation in RIKEN 18 GHz electron cyclotron resonance ion source. AB - A RIKEN 18 GHz electron cyclotron resonance ion source (18 GHz ECRIS) is used as an external ion source at the Radioactive Ion Beam Factory (RIBF) accelerator complex to produce an intense beam of medium-mass heavy ions (e.g., Ca and Ar). In most components that comprise the RIBF, the control systems (CSs) are integrated by the Experimental Physics and Industrial Control System (EPICS). On the other hand, a non-EPICS-based system has hardwired controllers, and it is used in the 18 GHz ECRIS CS as an independent system. In terms of efficient and effective operation, the 18 GHz ECRIS CS as well as the RIBF CS should be renewed using EPICS. Therefore, we constructed an 18 GHz ECRIS CS by using programmable logic controllers with embedded EPICS technology. In the renewed system, an operational log system was developed as a new feature, for supporting of the 18 GHz ECRIS operation. PMID- 26931941 TI - Producing multicharged fullerene ion beam extracted from the second stage of tandem-type ECRIS. AB - We have been constructing the tandem-type electron cyclotron resonance ion source (ECRIS). Two ion sources of the tandem-type ECRIS are possible to generate plasma individually, and they also confined individual ion species by each different plasma parameter. Hence, it is considered to be suitable for new materials production. As the first step, we try to produce and extract multicharged C60 ions by supplying pure C60 vapor in the second stage plasma because our main target is producing the endohedral fullerenes. We developed a new evaporator to supply fullerene vapor, and we succeeded in observation about multicharged C60 ion beam in tandem-type ECRIS for the first time. PMID- 26931942 TI - Ion beam emittance from an ECRIS. AB - Simulation of ion beam extraction from an Electron Cyclotron Resonance Ion Source (ECRIS) is a fully 3 dimensional problem, even if the extraction geometry has cylindrical symmetry. Because of the strong magnetic flux density, not only the electrons are magnetized but also the Larmor radius of ions is much smaller than the geometrical dimension of the plasma chamber (O 64 * 179 mm). If we assume that the influence of collisions is small on the path of particles, we can do particle tracking through the plasma if the initial coordinates of particles are known. We generated starting coordinates of plasma ions by simulation of the plasma electrons, accelerated stochastically by the 14.5 GHz radio frequency power fed to the plasma. With that we were able to investigate the influence of different electron energies on the extracted beam. Using these assumptions, we can reproduce the experimental results obtained 10 years ago, where we monitored the beam profile with the help of viewing targets. Additionally, methods have been developed to investigate arbitrary 2D cuts of the 6D phase space. To this date, we are able to discuss full 4D information. Currently, we extend our analysis tool towards 5D and 6D, respectively. PMID- 26931943 TI - Ion source research and development at University of Jyvaskyla: Studies of different plasma processes and towards the higher beam intensities. AB - Several ion source related research and development projects are in progress at the Department of Physics, University of Jyvaskyla (JYFL). The work can be divided into investigation of the ion source plasma and development of ion sources, ion beams, and diagnostics. The investigation covers the Electron Cyclotron Resonance Ion Source (ECRIS) plasma instabilities, vacuum ultraviolet (VUV) and visible light emission, photon induced electron emission, and the development of plasma diagnostics. The ion source development covers the work performed for radiofrequency-driven negative ion source, RADIS, beam line upgrade of the JYFL 14 GHz ECRIS, and the development of a new room-temperature-magnet 18 GHz ECRIS, HIISI. PMID- 26931944 TI - Installation and first operation of the International Fusion Materials Irradiation Facility injector at the Rokkasho site. AB - The International Fusion Materials Irradiation Facility (IFMIF) linear IFMIF prototype accelerator injector dedicated to high intensity deuteron beam production has been designed, built, and tested at CEA/Saclay between 2008 and 2012. After the completion of the acceptance tests at Saclay, the injector has been fully sent to Japan. The re-assembly of the injector has been performed between March and May 2014. Then after the check-out phase, the production of the first proton beam occurred in November 2014. Hydrogen and deuteron beam commissioning is now in progress after having proceeded with the final tests on the entire injector equipment including high power diagnostics. This article reports the different phases of the injector installation pointing out the safety and security needs, as well as the first beam production results in Japan and chopper tests. Detailed operation and commissioning results (with H(+) and D(+) 100 keV beams) are reported in a second article. PMID- 26931945 TI - Measurement of ion species in high current ECR H+/D+ ion source for IFMIF (International Fusion Materials Irradiation Facility). AB - Ion species ratio of high current positive hydrogen/deuterium ion beams extracted from an electron-cyclotron-resonance ion source for International Fusion Materials Irradiation Facility accelerator was measured by the Doppler shift Balmer-alpha line spectroscopy. The proton (H(+)) ratio at the middle of the low energy beam transport reached 80% at the hydrogen ion beam extraction of 100 keV/160 mA and the deuteron (D(+)) ratio reached 75% at the deuterium ion beam extraction of 100 keV/113 mA. It is found that the H(+) ratio measured by the spectroscopy gives lower than that derived from the phase-space diagram measured by an Allison scanner type emittance monitor. The H(+)/D(+) ratio estimated by the emittance monitor was more than 90% at those extraction currents. PMID- 26931946 TI - Heavy-ion injector based on an electron cyclotron ion source for the superconducting linear accelerator of the Rare Isotope Science Project. AB - The injector for the main driver linear accelerator of the Rare Isotope Science Project in Korea, has been developed to allow heavy ions up to uranium to be delivered to the inflight fragmentation system. The critical components of the injector are the superconducting electron cyclotron resonance (ECR) ion sources, the radio frequency quadrupole (RFQ), and matching systems for low and medium energy beams. We have built superconducting magnets for the ECR ion source, and a prototype with one segment of the RFQ structure, with the aim of developing a design that can satisfy our specifications, demonstrate stable operation, and prove results to compare the design simulation. PMID- 26931947 TI - Cyclotron instability in the afterglow mode of minimum-B ECRIS. AB - It was shown recently that cyclotron instability in non-equilibrium plasma of a minimum-B electron cyclotron resonance ion source (ECRIS) causes perturbation of the extracted ion current and generation of strong bursts of bremsstrahlung emission, which limit the performance of the ion source. The present work is devoted to the dynamic regimes of plasma instability in ECRIS operated in pulsed mode. Instability develops in decaying plasma shortly after heating microwaves are switched off and manifests itself in the form of powerful pulses of electromagnetic emission associated with precipitation of high energy electrons. Time-resolved measurements of microwave emission bursts are presented. It was found that even in various gases (helium and oxygen were studied) and at different values of magnetic field and heating power, the dynamic spectra demonstrate common features: decreasing frequency within a single burst as well as from one burst to another. PMID- 26931948 TI - First results of the 2.45 GHz Oshima electron cyclotron resonance ion source. AB - A new electron cyclotron resonance ion source has been constructed at Oshima College with a 2.45 GHz magnetron microwave source and permanent magnets employed as the main components. In addition, a solid-state power amplifier with a frequency range of 2.5-6.0 GHz was installed to study two-frequency plasma heating. Three solenoid coils were set up for adjusting the axial magnetic fields. Argon plasma generation and ion beam production have been conducted during the first year of operation. Ion current densities in the ECR plasma were measured using a biased disk. For 2.45 and 4.65 GHz two-frequency plasma heating, the ion density was approximately 1.5 times higher than that of 2.45 GHz single frequency heating. PMID- 26931949 TI - Beam experiments with the Grenoble test electron cyclotron resonance ion source at iThemba LABS. AB - At iThemba Laboratory for Accelerator Based Sciences (iThemba LABS) an electron cyclotron ion source was installed and commissioned. This source is a copy of the Grenoble Test Source (GTS) for the production of highly charged ions. The source is similar to the GTS-LHC at CERN and named GTS2. A collaboration between the Accelerators and Beam Physics Group of CERN and the Accelerator and Engineering Department of iThemba LABS was proposed in which the development of high intensity argon and xenon beams is envisaged. In this paper, we present beam experiments with the GTS2 at iThemba LABS, in which the results of continuous wave and afterglow operation of xenon ion beams with oxygen as supporting gases are presented. PMID- 26931950 TI - Ion beam production with sub-milligram samples of material from an ECR source for AMS. AB - Current accelerator mass spectrometry experiments at the Argonne Tandem Linac Accelerator System facility at Argonne National Laboratory push us to improve the ion source performance with a large number of samples and a need to minimize cross contamination. These experiments can require the creation of ion beams from as little as a few micrograms of material. These low concentration samples push the limit of our current efficiency and stability capabilities of the electron cyclotron resonance ion source. A combination of laser ablation and sputtering techniques coupled with a newly modified multi-sample changer has been used to meet this demand. We will discuss performance, stability, and consumption rates as well as planned improvements. PMID- 26931951 TI - Status of the SPIRAL2 injector commissioning. AB - The SPIRAL2 injector, installed in its tunnel, is currently under commissioning at GANIL, Caen, France. The injector is composed of two low energy beam transport lines: one is dedicated to the light ion beam production, the other to the heavy ions. The first light ion beam, created by a 2.45 GHz electron cyclotron resonance ion source, has been successfully produced in December 2014. The first beam of the PHOENIX V2 18 GHz heavy ion source was analyzed on 10 July 2015. A status of the SPIRAL2 injector commissioning is given. An upgrade of the heavy ion source, named PHOENIX V3 aimed to replace the V2, is presented. The new version features a doubled plasma chamber volume and the high charge state beam intensity is expected to increase by a factor of 1.5 to 2 up to the mass ~50. A status of its assembly is proposed. PMID- 26931952 TI - Development of superconducting magnets for RAON 28 GHz ECR ion source. AB - RAON, a 28 GHz electron cyclotron resonance ion source (ECR IS), was designed and tested as a Rare Isotope Science Project. It is expected that RAON would provide not only rare-isotope beams but also stable heavy ions ranging from protons to uranium. In order to obtain the steady heavy-ion beam required for ECR IS, we must use a 28 GHz microwave source as well as a high magnetic field. A superconducting magnet using a NbTi wire was designed and manufactured for producing the ECR IS and a test was conducted. In this paper, the design and fabrication of the superconducting magnet for the ECR IS are presented. Experimental results show that the quench current increases whenever quenching occurs, but it has not yet reached the designed current. The experiment is expected to reveal the ideal conditions required to reach the designed current. PMID- 26931953 TI - Emittance study of a 28 GHz electron cyclotron resonance ion source for the Rare Isotope Science Project superconducting linear accelerator. AB - A 28 GHz electron cyclotron resonance (ECR) ion source is being developed for use as an injector for the superconducting linear accelerator of the Rare Isotope Science Project. Beam extraction from the ECR ion source has been simulated using the KOBRA3-INP software. The simulation software can calculate charged particle trajectories in three dimensional complex magnetic field structures, which in this case are formed by the arrangement of five superconducting magnets. In this study, the beam emittance is simulated to understand the effects of plasma potential, mass-to-charge ratio, and spatial distribution. The results of these simulations and their comparison to experimental results are presented in this paper. PMID- 26931954 TI - Investigation on the electron flux to the wall in the VENUS ion source. AB - The long-term operation of high charge state electron cyclotron resonance ion sources fed with high microwave power has caused damage to the plasma chamber wall in several laboratories. Porosity, or a small hole, can be progressively created in the chamber wall which can destroy the plasma chamber over a few year time scale. A burnout of the VENUS plasma chamber is investigated in which the hole formation in relation to the local hot electron power density is studied. First, the results of a simple model assuming that hot electrons are fully magnetized and strictly following magnetic field lines are presented. The model qualitatively reproduces the experimental traces left by the plasma on the wall. However, it is too crude to reproduce the localized electron power density for creating a hole in the chamber wall. Second, the results of a Monte Carlo simulation, following a population of scattering hot electrons, indicate a localized high power deposited to the chamber wall consistent with the hole formation process. Finally, a hypervapotron cooling scheme is proposed to mitigate the hole formation in electron cyclotron resonance plasma chamber wall. PMID- 26931955 TI - Effect of axial magnetic field on a 2.45 GHz permanent magnet ECR ion source. AB - Herein, we conduct a fundamental study to improve the generation efficiency of a multi-charged ion source using argon. A magnetic field of our electron cyclotron resonance ion source is composed of a permanent magnet and a solenoid coil. Thereby, the axial magnetic field in the chamber can be tuned. Using the solenoid coil, we varied the magnetic field strength in the plasma chamber and measured the ion beam current extracted at the electrode. We observed an approximately three times increase in the Ar(4+) ion beam current when the magnetic field on the extractor-electrode side of the chamber was weakened. From our results, we can confirm that the multi-charged ion beam current changes depending on magnetic field intensity in the plasma chamber. PMID- 26931956 TI - High intensity high charge state ion beam production with an evaporative cooling magnet ECRIS. AB - LECR4 (Lanzhou ECR ion source No. 4) is a room temperature electron cyclotron resonance ion source, designed to produce high current, high charge state ion beams for the SSC-LINAC injector (a new injector for sector separated cyclotron) at the Institute of Modern Physics. LECR4 also serves as a PoP machine for the application of evaporative cooling technology in accelerator field. To achieve those goals, LECR4 ECR ion source has been optimized for the operation at 18 GHz. During 2014, LECR4 ion source was commissioned at 18 GHz microwave of 1.6 kW. To further study the influence of injection stage to the production of medium and high charge state ion beams, in March 2015, the injection stage with pumping system was installed, and some optimum results were produced, such as 560 eMUA of O(7+), 620 eMUA of Ar(11+), 430 eMUA of Ar(12+), 430 eMUA of Xe(20+), and so on. The comparison will be discussed in the paper. PMID- 26931958 TI - Injection of auxiliary electrons for increasing the plasma density in highly charged and high intensity ion sources. AB - Different electron guns based on cold- or hot-cathode technologies have been developed since 2009 at INFN for operating within ECR plasma chambers as sources of auxiliary electrons, with the aim of boosting the source performances by means of a higher plasma lifetime and density. Their application to microwave discharge ion sources, where plasma is not confined, has required an improvement of the gun design, in order to "screen" the cathode from the plasma particles. Experimental tests carried out on a plasma reactor show a boost of the plasma density, ranging from 10% to 90% when the electron guns are used, as explained by plasma diffusion models. PMID- 26931957 TI - Operation and commissioning of IFMIF (International Fusion Materials Irradiation Facility) LIPAc injector. AB - The objective of linear IFMIF prototype accelerator is to demonstrate 125 mA/CW deuterium ion beam acceleration up to 9 MeV. The injector has been developed in CEA Saclay and already demonstrated 140 mA/100 keV deuterium beam [R. Gobin et al., Rev. Sci. Instrum. 85, 02A918 (2014)]. The injector was disassembled and delivered to the International Fusion Energy Research Center in Rokkasho, Japan. After reassembling the injector, commissioning has started in 2014. Up to now, 100 keV/120 mA/CW hydrogen and 100 keV/90 mA/CW deuterium ion beams have been produced stably from a 10 mm diameter extraction aperture with a low beam emittance of 0.21 pi mm mrad (rms, normalized). Neutron production by D-D reaction up to 2.4 * 10(9) n/s has been observed in the deuterium operation. PMID- 26931960 TI - High density plasmas and new diagnostics: An overview (invited). AB - One of the limiting factors for the full understanding of Electron Cyclotron Resonance Ion Sources (ECRISs) fundamental mechanisms consists of few types of diagnostic tools so far available for such compact machines. Microwave-to-plasma coupling optimisation, new methods of density overboost provided by plasma wave generation, and magnetostatic field tailoring for generating a proper electron energy distribution function, suitable for optimal ion beams formation, require diagnostic tools spanning across the entire electromagnetic spectrum from microwave interferometry to X-ray spectroscopy; these methods are going to be implemented including high resolution and spatially resolved X-ray spectroscopy made by quasi-optical methods (pin-hole cameras). The ion confinement optimisation also requires a complete control of cold electrons displacement, which can be performed by optical emission spectroscopy. Several diagnostic tools have been recently developed at INFN-LNS, including "volume-integrated" X-ray spectroscopy in low energy domain (2-30 keV, by using silicon drift detectors) or high energy regime (>30 keV, by using high purity germanium detectors). For the direct detection of the spatially resolved spectral distribution of X-rays produced by the electronic motion, a "pin-hole camera" has been developed also taking profit from previous experiences in the ECRIS field. The paper will give an overview of INFN-LNS strategy in terms of new microwave-to-plasma coupling schemes and advanced diagnostics supporting the design of new ion sources and for optimizing the performances of the existing ones, with the goal of a microwave absorption oriented design of future machines. PMID- 26931959 TI - X-ray pinhole camera setups used in the Atomki ECR Laboratory for plasma diagnostics. AB - Imaging of the electron cyclotron resonance (ECR) plasmas by using CCD camera in combination with a pinhole is a non-destructive diagnostics method to record the strongly inhomogeneous spatial density distribution of the X-ray emitted by the plasma and by the chamber walls. This method can provide information on the location of the collisions between warm electrons and multiple charged ions/atoms, opening the possibility to investigate the direct effect of the ion source tuning parameters to the plasma structure. The first successful experiment with a pinhole X-ray camera was carried out in the Atomki ECR Laboratory more than 10 years ago. The goal of that experiment was to make the first ECR X-ray photos and to carry out simple studies on the effect of some setting parameters (magnetic field, extraction, disc voltage, gas mixing, etc.). Recently, intensive efforts were taken to investigate now the effect of different RF resonant modes to the plasma structure. Comparing to the 2002 experiment, this campaign used wider instrumental stock: CCD camera with a lead pinhole was placed at the injection side allowing X-ray imaging and beam extraction simultaneously. Additionally, Silicon Drift Detector (SDD) and High Purity Germanium (HPGe) detectors were installed to characterize the volumetric X-ray emission rate caused by the warm and hot electron domains. In this paper, detailed comparison study on the two X-ray camera and detector setups and also on the technical and scientific goals of the experiments is presented. PMID- 26931961 TI - Status of ECR ion sources for the Facility for Rare Isotope Beams (FRIB) (invited). AB - Ahead of the commissioning schedule, installation of the first Electron Cyclotron Resonance (ECR) ion source in the front end area of the Facility for Rare Isotope Beam (FRIB) is planned for the end of 2015. Operating at 14 GHz, this first ECR will be used for the commissioning and initial operation of the facility. In parallel, a superconducting magnet structure compatible with operation at 28 GHz for a new ECR ion source is in development at Lawrence Berkeley National Laboratory. The paper reviews the overall work in progress and development done with ECR ion sources for FRIB. PMID- 26931962 TI - Calcium and lithium ion production for laser ion source. AB - Calcium and lithium ion beams are required by NASA Space Radiation Laboratory at Brookhaven National Laboratory to simulate the effects of cosmic radiation. To identify the difficulties in providing such highly reactive materials as laser targets, both species were experimentally tested. Plate shaped lithium and calcium targets were fabricated to create ablation plasmas with a 6 ns 1064 nm neodymium-doped yttrium aluminum garnet laser. We found significant oxygen contamination in both the Ca and Li high charge state beams due to the rapid oxidation of the surfaces. A large spot size, low power density laser was used to create low charge state beams without scanning the targets. The low charge state Ca beam did not have any apparent oxygen contamination, showing the potential to clean the target entirely of oxide with a low power beam once in the chamber. The Li target was clearly still oxidizing in the chamber after each low power shot. To measure the rate of oxidation, we shot the low power laser at the target repeatedly at 10 s, 30 s, 60 s, and 120 s interval lengths, showing a linear relation between the interval time and the amount of oxygen in the beam. PMID- 26931963 TI - Boron ion beam generation utilizing lanthanum hexaboride cathodes: Comparison of vacuum arc and planar magnetron glow. AB - Boron ion beams are widely used for semiconductor ion implantation and for surface modification for improving the operating parameters and increasing the lifetime of machine parts and tools. For the latter application, the purity requirements of boron ion beams are not as stringent as for semiconductor technology, and a composite cathode of lanthanum hexaboride may be suitable for the production of boron ions. We have explored the use of two different approaches to boron plasma production: vacuum arc and planar high power impulse magnetron in self-sputtering mode. For the arc discharge, the boron plasma is generated at cathode spots, whereas for the magnetron discharge, the main process is sputtering of cathode material. We present here the results of comparative test experiments for both kinds of discharge, aimed at determining the optimal discharge parameters for maximum yield of boron ions. For both discharges, the extracted ion beam current reaches hundreds of milliamps and the fraction of boron ions in the total extracted ion beam is as high as 80%. PMID- 26931964 TI - Brightness measurement of an electron impact gas ion source for proton beam writing applications. AB - We are developing a high brightness nano-aperture electron impact gas ion source, which can create ion beams from a miniature ionization chamber with relatively small virtual source sizes, typically around 100 nm. A prototype source of this kind was designed and successively micro-fabricated using integrated circuit technology. Experiments to measure source brightness were performed inside a field emission scanning electron microscope. The total output current was measured to be between 200 and 300 pA. The highest estimated reduced brightness was found to be comparable to the injecting focused electron beam reduced brightness. This translates into an ion reduced brightness that is significantly better than that of conventional radio frequency ion sources, currently used in single-ended MeV accelerators. PMID- 26931965 TI - Lifetime of hydrogenated composite cathodes in a vacuum arc ion source. AB - The paper reports on a study of the mass-charge state of the plasma produced in a vacuum arc discharge with composite cathodes which were copper-disk coated with a hydrogenated Zr film of thicknesses 9, 22, and 35 MUm. The cathodes allow the generation of multicomponent gas and metal ion beams with a hydrogen ion content from several to several tens of percent. Also investigated is the dependence of the H ion fraction in a beam on the Zr film thickness during erosion to the point of disappearance of Zr peaks in mass-charge spectra. The ability of the vacuum arc system to produce H ions is analyzed by analyzing the cathode lifetime as a function of the film thickness and pulse repetition frequency. PMID- 26931966 TI - A vacuum spark ion source: High charge state metal ion beams. AB - High ion charge state is often important in ion beam physics, among other reasons for the very practical purpose that it leads to proportionately higher ion beam energy for fixed accelerating voltage. The ion charge state of metal ion beams can be increased by replacing a vacuum arc ion source by a vacuum spark ion source. Since the voltage between anode and cathode remains high in a spark discharge compared to the vacuum arc, higher metal ion charge states are generated which can then be extracted as an ion beam. The use of a spark of pulse duration less than 10 MUs and with current up to 10 kA allows the production of ion beams with current of several amperes at a pulse repetition rate of up to 5 pps. We have demonstrated the formation of high charge state heavy ions (bismuth) of up to 15 + and a mean ion charge state of more than 10 +. The physics and techniques of our vacuum spark ion source are described. PMID- 26931967 TI - Proton beam production by a laser ion source with hydride target. AB - We studied proton beam production from a laser ion source using hydrogen rich target materials. In general, gas based species are not suitable for laser ion sources since formation of a dense laser target is difficult. In order to achieve reliable operation, we tested hydride targets using a sub nanosecond Q-switched Nd-YAG laser, which may help suppress target material consumption. We detected enough yields of protons from a titanium hydride target without degradation of beam current during the experiment. The combination of a sub nanosecond laser and compressed hydride target may provide stable proton beam. PMID- 26931968 TI - Positive and negative singly charged ion production of a laser induced plasma using a capillary graphite target. AB - A new type of laser ion source is being developed aiming at the production of positive and negative singly charged ions using a capillary graphite target structure. The initial results of the laser plasma produced inside of the 10 mm diameter conduit indicated the formation of the secondary charged particle production inside the target. A high speed camera clearly recorded the plasma plume expansion inside the target. The time-of-flight spectrum of the laser produced plasma in vacuum showed that the signal of the positive ions formed two peaks as the laser power density exceeded 10 GW/cm(2). The addition of neutral gas to the system produced a signal corresponding to negative ions after the positive signal. PMID- 26931969 TI - Simulation of ion beam injection and extraction in an EBIS. AB - An example simulation of Au+ charge breeding using FAR-TECH's integrated EBIS (electron beam ion source) modeling toolset is presented with the emphasis on ion beam injection and extraction. The trajectories of injected ions are calculated with PBGUNS (particle beam gun simulation) self-consistently by including the space charges from both ions and electrons. The ion beam, starting with initial conditions within the 100% acceptance of the electron beam, is then tracked by EBIS-PIC (particle-in-cell EBIS simulation code). In the trap, the evolution of the ion charge state distribution is estimated by charge state estimator. The extraction of charge bred ions is simulated with PBGUNS. The simulations of the ion injections show significant ion space charge effects on beam capture efficiency and the ionization efficiency. PMID- 26931970 TI - Investigation on target normal sheath acceleration through measurements of ions energy distribution. AB - An experimental campaign aiming at investigating the ion acceleration mechanisms through laser-matter interaction in femtosecond domain has been carried out at the Intense Laser Irradiation Laboratory facility with a laser intensity of up to 2 * 10(19) W/cm(2). A Thomson parabola spectrometer was used to obtain the spectra of the ions of the different species accelerated. Here, we show the energy spectra of light-ions and we discuss their dependence on structural characteristics of the target and the role of surface and target bulk in the acceleration process. PMID- 26931971 TI - Recent charge-breeding developments with EBIS/T devices (invited). AB - Short breeding times, narrow charge state distributions, low background, high efficiency, and the flexible time structure of the ejected low-emittance ion pulses are among the most attractive features of electron beam ion source or trap (EBIS/T) based charge breeders. Significant progress has been made to further improve these properties: Several groups are working to increase current densities towards 10(3) or even 10(4) A/cm(2). These current densities will become necessary to deliver high charge states of heavy nuclei in a short time and/or provide sufficient space-charge capacity to handle high-current ion beams in next-generation rare-isotope beam (RIB) facilities. Efficient capture of continuous beams, attractive because of its potential of handling highest-current ion beams, has become possible with the development of high-density electron beams of >1 A. Requests for the time structure of the charge bred ion pulse range from ultra-short pulses to quasi-continuous beams. Progress is being made on both ends of this spectrum, by either dividing the extracted charge in many pulse lets, adjusting the extraction potential for a near-uniform long pulse, or adding dedicated devices to spread the ion bunches delivered from the EBIS/T in time. Advances in EBIS/T charge state breeding are summarized, including recent results with NSCL's ReA EBIS/T charge breeder. PMID- 26931972 TI - RF synchronized short pulse laser ion source. AB - A laser ion source that produces shortly bunched ion beam is proposed. In this ion source, ions are extracted immediately after the generation of laser plasma by an ultra-short pulse laser before its diffusion. The ions can be injected into radio frequency (RF) accelerating bucket of a subsequent accelerator. As a proof of-principle experiment of the ion source, a RF resonator is prepared and H2 gas was ionized by a short pulse laser in the RF electric field in the resonator. As a result, bunched ions with 1.2 mA peak current and 5 ns pulse length were observed at the exit of RF resonator by a probe. PMID- 26931973 TI - Behavior of moving plasma in solenoidal magnetic field in a laser ion source. AB - In a laser ion source, a solenoidal magnetic field is useful to guide the plasma and to control the extracted beam current. However, the behavior of the plasma drifting in the magnetic field has not been well understood. Therefore, to investigate the behavior, we measured the plasma ion current and the total charge within a single pulse in the solenoid by changing the distance from the entrance of the solenoid to a detector. We observed that the decrease of the total charge along the distance became smaller as the magnetic field became larger and then the charge became almost constant with a certain magnetic flux density. The results indicate that the transverse spreading speed of the plasma decreased with increasing the field and the plasma was confined transversely with the magnetic flux density. We found that the reason of the confinement was not magnetization of ions but an influence induced by electrons. PMID- 26931974 TI - Liquid metal ion source assembly for external ion injection into an electron string ion source (ESIS). AB - An assembly for a commercial Ga(+) liquid metal ion source in combination with an ion transportation and focusing system, a pulse high-voltage quadrupole deflector, and a beam diagnostics system has been constructed in the framework of the iThemba LABS (Cape Town, South Africa)-JINR (Dubna, Russia) collaboration. First, results on Ga(+) ion beam commissioning will be presented. Outlook of further experiments for measurements of charge breeding efficiency in the electron string ion source with the use of external injection of Ga(+) and Au(+) ion beams will be reported as well. PMID- 26931975 TI - Ion acceleration with a narrow energy spectrum by nanosecond laser-irradiation of solid target. AB - In laser-driven plasma, ion acceleration of aluminum with the production of a quasi-monoenergetic beam has occurred. A useful device to analyze the ions is the Thomson parabolas spectrometer, a well-known diagnostic that is able to obtain information on charge-to-mass ratio and energy distribution of the charged particles. At the LENS (Laser Energy for Nuclear Science) laboratory of INFN-LNS in Catania, experimental measures were carried out; the features of LENS are: Q switched Nd:YAG laser with 2 J laser energy, 1064 nm fundamental wavelengths, and 6 ns pulse duration. PMID- 26931976 TI - Effect of the solenoid in various conditions of the laser ion source at Brookhaven National Laboratory. AB - In the laser ion source (LIS) at the Brookhaven National Laboratory (BNL), a solenoid is used to guide the laser ablation plasma and modulate the extracted beam current. Many types of ion species are guided. In some cases, the plasma plume is injected into the solenoid away from the solenoidal axis. To investigate the effects of the solenoid on the beam extracted from the plasma that has different properties, the beam current was measured in the setup of the LIS at the BNL. The beam current of Li, Al, Si, Fe, and Au increased when the magnetic field was applied. For most of the species the peak current and the total charge within a single beam pulse increased around 10 times with a magnetic field less than 100 G. In addition, for some species the rate of increase of the peak currents became smaller when the magnetic flux densities were larger than certain values depending on the species. In this case, the current waveforms were distorted. At the same magnetic field value, the field was more effective on lighter species than on heavier ones. When plasma was injected offset from the axis of the solenoid, peak current and total charge became half of those without offset. The experimental data are useful for the operation of the LIS at the BNL. PMID- 26931977 TI - Low charge state heavy ion production with sub-nanosecond laser. AB - We have investigated laser ablation plasma of various species using nanosecond and sub-nanosecond lasers for both high and low charge state ion productions. We found that with sub-nanosecond laser, the generated plasma has a long tail which has low charge state ions determined by an electrostatic ion analyzer even under the laser irradiation condition for highly charged ion production. This can be caused by insufficient laser absorption in plasma plume. This property might be suitable for low charge state ion production. We used a nanosecond laser and a sub-nanosecond laser for low charge state ion production to investigate the difference of generated plasma using the Zirconium target. PMID- 26931978 TI - New development of laser ion source for highly charged ion beam production at Institute of Modern Physics (invited). AB - A laser ion source based on Nd:YAG laser has been being studied at the Institute of Modern Physics for the production of high intensity high charge state heavy ion beams in the past ten years, for possible applications both in a future accelerator complex and in heavy ion cancer therapy facilities. Based on the previous results for the production of multiple-charged ions from a wide range of heavy elements with a 3 J/8 ns Nd:YAG laser [Zhao et al., Rev. Sci. Instrum. 85, 02B910 (2014)], higher laser energy and intensity in the focal spot are necessary for the production of highly charged ions from the elements heavier than aluminum. Therefore, the laser ion source was upgraded with a new Nd:YAG laser, the maximum energy of which is 8 J and the pulse duration can be adjusted from 8 to 18 ns. Since then, the charge state distributions of ions from various elements generated by the 8 J Nd:YAG laser were investigated for different experimental conditions, such as laser energy, pulse duration, power density in the focal spot, and incidence angle. It was shown that the incidence angle is one of the most important parameters for the production of highly charged ions. The capability of producing highly charged ions from the elements lighter than silver was demonstrated with the incidence angle of 10 degrees and laser power density of 8 * 10(13) W cm(-2) in the focal spot, which makes a laser ion source complementary to the superconducting electron cyclotron resonance ion source for the future accelerator complex especially in terms of the ion beam production from some refractory elements. Nevertheless, great efforts with regard to the extraction of intense ion beams, modification of the ion beam pulse duration, and reliability of the ion source still need to be made for practical applications. PMID- 26931979 TI - Eliminating unwanted electrons in EBIS devices. AB - In electron beam ion sources, step-wise ionization to high charge states is accomplished by magnetically confined electron beam. Electron space charge and high voltage electrodes confine the ions. The relativistic heavy ion collider (RHIC) ion source Debye length meets requirements for instabilities with free source of energy to grow. Electrons stripped from ions provide energy for a variety of microinstabilities to grow. Possible solution is to remove these electrons from the trap to a drift tube biased to higher voltage than the other tubes between the gate and the collector. If needed, a split drift tube for bleeding these electrons to ground is added. PMID- 26931980 TI - Iron plasma generation using a Nd:YAG laser pulse of several hundred picoseconds. AB - We investigated the high intensity plasma generated by using a Nd:YAG laser to apply a laser-produced plasma to the direct plasma injection scheme. The capability of the source to generate high charge state ions strongly depends on the power density of the laser irradiation. Therefore, we focused on using a higher power laser with several hundred picoseconds of pulse width. The iron target was irradiated with the pulsed laser, and the ion current of the laser produced iron plasma was measured using a Faraday cup and the charge state distribution was investigated using an electrostatic ion analyzer. We found that higher charge state iron ions (up to Fe(21+)) were obtained using a laser pulse of several hundred picoseconds in comparison to those obtained using a laser pulse of several nanoseconds (up to Fe(19+)). We also found that when the laser irradiation area was relatively large, the laser power was absorbed mainly by the contamination on the target surface. PMID- 26931981 TI - Laser ion source for isobaric heavy ion collider experiment. AB - Heavy-ion collider experiment in isobaric system is under investigation at Relativistic Heavy Ion Collider. For this experiment, ion source is required to maximize the abundance of the intended isotope. The candidate of the experiment is (96)Ru + (96)Zr. Since the natural abundance of particular isotope is low and composition of isotope from ion source depends on the composites of the target, an isotope enriched material may be needed as a target. We studied the performance of the laser ion source required for the experiment for Zr ions. PMID- 26931982 TI - Contribution of material's surface layer on charge state distribution in laser ablation plasma. AB - To generate laser ablation plasma, a pulse laser is focused onto a solid target making a crater on the surface. However, not all the evaporated material is efficiently converted to hot plasma. Some portion of the evaporated material could be turned to low temperature plasma or just vapor. To investigate the mechanism, we prepared an aluminum target coated by thin carbon layers. Then, we measured the ablation plasma properties with different carbon thicknesses on the aluminum plate. The results showed that C(6+) ions were generated only from the surface layer. The deep layers (over 250 nm from the surface) did not provide high charge state ions. On the other hand, low charge state ions were mainly produced by the deeper layers of the target. Atoms deeper than 1000 nm did not contribute to the ablation plasma formation. PMID- 26931983 TI - Compact surface plasma H- ion source with geometrical focusing. AB - Factors limiting operating lifetime of a Compact Surface Plasma Sources (CSPS) are analyzed and possible treatments for lifetime enhancement are considered. Increased cooling permeate increased discharge power and increased beam intensity and duty factor. A design of an advanced CSPS with geometrical focusing of H(-) flux is presented. PMID- 26931984 TI - Power efficiency improvements with the radio frequency H- ion source. AB - CW 13.56 MHz radio frequency-driven H(-) ion source is under development at the University of Jyvaskyla for replacing an existing filament-driven ion source at the MCC30/15 cyclotron. Previously, production of 1 mA H(-) beam, which is the target intensity of the ion source, has been reported at 3 kW of RF power. The original ion source front plate with an adjustable electromagnet based filter field has been replaced with a new front plate with permanent magnet filter field. The new structure is more open and enables a higher flux of ro vibrationally excited molecules towards the plasma electrode and provides a better control of the potential near the extraction due to a stronger separation of the main plasma from the plasma electrode. While the original system provided better control over the e(-)/H(-) ratio, the new configuration has led to a higher production efficiency of 1 mA H(-) at 1.75 kW RF power. The latest results and upgrade plans are presented. PMID- 26931985 TI - Charged particle flows in the beam extraction region of a negative ion source for NBI. AB - Experiments by a four-pin probe and photodetachment technique were carried out to investigate the charged particle flows in the beam extraction region of a negative hydrogen ion source for neutral beam injector. Electron and positive ion flows were obtained from the polar distribution of the probe saturation current. Negative hydrogen ion flow velocity and temperature were obtained by comparing the recovery times of the photodetachment signals at opposite probe tips. Electron and positive ions flows are dominated by crossed field drift and ambipolar diffusion. Negative hydrogen ion temperature is evaluated to be 0.12 eV. PMID- 26931986 TI - Determination of discharge parameters via OES at the Linac4 H- ion source. AB - Optical emission spectroscopy (OES) measurements of the atomic Balmer series and the molecular Fulcher transition have been carried out at the Linac4 ion source in order to determine plasma parameters. As the spectroscopic system was only relatively calibrated, the data evaluation only yielded rough estimates of the plasma parameters (T(e) ~ 1.2 eV, n(e) ~ 1 * 10(19) m(-3), and n(H/)n(H2) ~ 0.5 at standard operational parameters). The analysis of the Fulcher transition revealed a non-thermal "hockey-stick" rotational population of the hydrogen molecules. At varying RF power, the measurements at the on-axis line of sight (LOS) showed a peak in the rotational temperatures between 25 and 40 kW of RF power, whereas a steady decrease with power was observed at a tilted LOS, indicating the presence of strong plasma parameter gradients. PMID- 26931987 TI - An overview of the new test stand for H- ion sources at FNAL. AB - A new test stand at Fermi National Accelerator Laboratory (FNAL) is being constructed to carry out experiments to develop and upgrade the present magnetron type sources of H(-) ions of up to 80 mA at 35 keV in the context of the Proton Improvement Plan. The aim of this plan is to provide high-power proton beams for the experiments at FNAL. The technical details of the construction and layout of this test stand are presented, along with a prospective set of diagnostics to monitor the sources. PMID- 26931988 TI - Saddle antenna radio frequency ion sources. AB - Existing RF ion sources for accelerators have specific efficiencies for H(+) and H(-) ion generation ~3-5 mA/cm(2) kW, where about 50 kW of RF power is typically needed for 50 mA beam current production. The Saddle Antenna (SA) surface plasma source (SPS) described here was developed to improve H(-) ion production efficiency, reliability, and availability. In SA RF ion source, the efficiency of positive ion generation in the plasma has been improved to 200 mA/cm(2) kW. After cesiation, the current of negative ions to the collector was increased from 1 mA to 10 mA with RF power ~1.5 kW in the plasma (6 mm diameter emission aperture) and up to 30 mA with ~4 kW RF. Continuous wave (CW) operation of the SA SPS has been tested on the test stand. The general design of the CW SA SPS is based on the pulsed version. Some modifications were made to improve the cooling and cesiation stability. CW operation with negative ion extraction was tested with RF power up to ~1.2 kW in the plasma with production up to Ic = 7 mA. A stable long time generation of H(-) beam without degradation was demonstrated in RF discharge with AlN discharge chamber. PMID- 26931989 TI - Balmer-alpha spectrum measurements of the LHD one-third ion source. AB - Wavelength spectra of Balmer-alpha light from plasmas in the extraction region of the Large Helical Device-R&D negative ion source, or the LHD one-third ion source have exhibited a blue shift as a negative bias voltage was applied to the plasma grid. The blue shift increased as the negative bias voltage with respect to the local plasma potential was increased. The measured spectra were compared with the velocity distributions of surface reflected hydrogen atoms calculated by atomic collisions in amorphous target code. The arc power and the source H2 pressure also affected the shift and broadening in the observed Balmer-alpha spectra. The possibility of identifying the negative hydrogen ions produced at the low work function plasma grid surface by high resolution spectroscopy is discussed. PMID- 26931990 TI - Analysis of electron energy distribution function in the Linac4 H- source. AB - To understand the Electron Energy Distribution Function (EEDF) in the Radio Frequency Inductively Coupled Plasmas (RF-ICPs) in hydrogen negative ion sources, the detailed analysis of the EEDFs using numerical simulation and the theoretical approach based on Boltzmann equation has been performed. It is shown that the EEDF of RF-ICPs consists of two parts, one is the low energy part which obeys Maxwellian distribution and the other is high energy part deviated from Maxwellian distribution. These simulation results have been confirmed to be reasonable by the analytical approach. The results suggest that it is possible to enhance the dissociation of molecules and the resultant H(-) negative ion production by reducing the gas pressure. PMID- 26931991 TI - A negative ion source test facility. AB - Progress is being made in the development of an Ion Source Test Facility (ISTF) by D-Pace Inc. in collaboration with Buckley Systems Ltd. in Auckland, NZ. The first phase of the ISTF is to be commissioned in October 2015 with the second phase being commissioned in March 2016. The facility will primarily be used for the development and the commercialization of ion sources. It will also be used to characterize and further develop various D-Pace Inc. beam diagnostic devices. PMID- 26931992 TI - A collisional radiative model of hydrogen plasmas developed for diagnostic purposes of negative ion sources. AB - A collisional radiative model of low-pressure hydrogen plasmas is elaborated and applied in optical emission spectroscopy diagnostics of a single element of a matrix source of negative hydrogen ions. The model accounts for the main processes determining both the population densities of the first ten states of the hydrogen atom and the densities of the positive hydrogen ions H(+), H2 (+), and H3 (+). In the calculations, the electron density and electron temperature are varied whereas the atomic and molecular temperatures are included as experimentally obtained external parameters. The ratio of the Halpha to Hbeta line intensities is calculated from the numerical results for the excited state population densities, obtained as a solution of the set of the steady-state rate balance equations. The comparison of measured and theoretically obtained ratios of line intensities yields the values of the electron density and temperature as well as of the degree of dissociation, i.e., of the parameters which have a crucial role for the volume production of the negative ions. PMID- 26931993 TI - Electron stripping processes of H- ion beam in the 80 kV high voltage extraction column and low energy beam transport line at LANSCE. AB - Basic vacuum calculations were performed for various operating conditions of the Los Alamos National Neutron Science H(-) Cockcroft-Walton (CW) injector and the Ion Source Test Stand (ISTS). The vacuum pressure was estimated for both the CW and ISTS at five different points: (1) inside the H(-) ion source, (2) in front of the Pierce electrode, (3) at the extraction electrode, (4) at the column electrode, and (5) at the ground electrode. A static vacuum analysis of residual gases and the working hydrogen gas was completed for the normal ion source working regime. Gas density and partial pressure were estimated for the injected hydrogen gas. The attenuation of H(-) beam current and generation of electron current in the high voltage acceleration columns and low energy beam transport lines were calculated. The interaction of H(-) ions on molecular hydrogen (H2) is discussed as a dominant collision process in describing electron stripping rates. These results are used to estimate the observed increase in the ratio of electrons to H(-) ion beam in the ISTS beam transport line. PMID- 26931994 TI - Different approaches to modeling the LANSCE H- ion source filament performance. AB - An overview of different approaches to modeling of hot tungsten filament performance in the Los Alamos Neutron Science Center (LANSCE) H(-) surface converter ion source is presented. The most critical components in this negative ion source are two specially shaped wire filaments heated up to the working temperature range of 2600 K-2700 K during normal beam production. In order to prevent catastrophic filament failures (creation of hot spots, wire breaking, excessive filament deflection towards source body, etc.) and to improve understanding of the material erosion processes, we have simulated the filament performance using three different models: a semi-empirical model, a thermal finite-element analysis model, and an analytical model. Results of all three models were compared with data taken during LANSCE beam production. The models were used to support the recent successful transition from the beam pulse repetition rate of 60 Hz-120 Hz. PMID- 26931995 TI - Installation of spectrally selective imaging system in RF negative ion source. AB - A spectrally selective imaging system has been installed in the RF negative ion source in the International Thermonuclear Experimental Reactor-relevant negative ion beam test facility ELISE (Extraction from a Large Ion Source Experiment) to investigate distribution of hydrogen Balmer-alpha emission (Halpha) close to the production surface of hydrogen negative ion. We selected a GigE vision camera coupled with an optical band-path filter, which can be controlled remotely using high speed network connection. A distribution of Halpha emission near the bias plate has been clearly observed. The same time trend on Halpha intensities measured by the imaging diagnostic and the optical emission spectroscopy is confirmed. PMID- 26931996 TI - An advanced negative hydrogen ion source. AB - The results of investigation of emission productivity of negative particles source with cesiated combined discharge are presented. A cylindrical beam of negative hydrogen ions with density about 2 A/cm(2) in low noise mode on source emission aperture is obtained. The total beam current values are up to 200 mA for negative hydrogen ions and up to 1.5 A for all negative particles with high divergence after source. The source has simple design and can produce stable discharge with low level of oscillation. PMID- 26931997 TI - Motivation of concepts for the negative ion extraction from a single element of the matrix source. AB - A single element of a matrix source of negative hydrogen ions (a planar-coil inductively driven small-radius discharge equipped with an extraction system) is studied regarding the ion extraction. Since the spatial distribution of the negative ions obeys that of the dc potential, the latter is controlled by applying a high bias to the plasma electrode of the extraction system. This leads to discharge maintenance by both rf and dc power deposition and, respectively, to similarities with the axial profile of the dc potential in the glow discharges. The discharge length, the applied rf power, and the bias to the plasma electrode and its radius are the parameters varied in determination of proper conditions for the ion extraction. PMID- 26931998 TI - Single element of the matrix source of negative hydrogen ions: Measurements of the extracted currents combined with diagnostics. AB - Combining measurements of the extracted currents with probe and laser photodetachment diagnostics, the study is an extension of recent tests of factors and gas-discharge conditions stimulating the extraction of volume produced negative ions. The experiment is in a single element of a rf source with the design of a matrix of small-radius inductively driven discharges. The results are for the electron and negative-ion densities, for the plasma potential and for the electronegativity in the vicinity of the plasma electrode as well as for the currents of the extracted negative ions and electrons. The plasma-electrode bias and the rf power have been varied. Necessity of a high bias to the plasma electrode and stable linear increase of the extracted currents with the rf power are the main conclusions. PMID- 26931999 TI - Electron cyclotron resonance heating by magnetic filter field in a negative hydrogen ion source. AB - The influence of magnetic filter field on plasma properties in the heating region has been investigated in a planar-type inductively coupled radio-frequency (RF) H(-) ion source. Besides filtering high energy electrons near the extraction region, the magnetic filter field is clearly observed to increase the electron temperature in the heating region at low pressure discharge. With increasing the operating pressure, enhancement of electron temperature in the heating region is reduced. The possibility of electron cyclotron resonance (ECR) heating in the heating region due to stray magnetic field generated by a filter magnet located at the extraction region is examined. It is found that ECR heating by RF wave field in the discharge region, where the strength of an axial magnetic field is approximately ~4.8 G, can effectively heat low energy electrons. Depletion of low energy electrons in the electron energy distribution function measured at the heating region supports the occurrence of ECR heating. The present study suggests that addition of axial magnetic field as small as several G by an external electromagnet or permanent magnets can greatly increase the generation of highly ro-vibrationally excited hydrogen molecules in the heating region, thus improving the performance of H(-) ion generation in volume-produced negative hydrogen ion sources. PMID- 26932000 TI - Background gas density and beam losses in NIO1 beam source. AB - NIO1 (Negative Ion Optimization 1) is a versatile ion source designed to study the physics of production and acceleration of H- beams up to 60 keV. In ion sources, the gas is steadily injected in the plasma source to sustain the discharge, while high vacuum is maintained by a dedicated pumping system located in the vessel. In this paper, the three dimensional gas flow in NIO1 is studied in the molecular flow regime by the Avocado code. The analysis of the gas density profile along the accelerator considers the influence of effective gas temperature in the source, of the gas temperature accommodation by collisions at walls, and of the gas particle mass. The calculated source and vessel pressures are compared with experimental measurements in NIO1 during steady gas injection. PMID- 26932001 TI - Effect of plasma grid bias on extracted currents in the RF driven surface-plasma negative ion source. AB - Extraction of negative ions from the large inductively driven surface-plasma negative ion source was studied. The dependencies of the extracted currents vs plasma grid (PG) bias potential were measured for two modifications of radio frequency driver with and without Faraday screen, for different hydrogen feeds and for different levels of cesium conditioning. The maximal PG current was independent of driver modification and it was lower in the case of inhibited cesium. The maximal extracted negative ion current depends on the potential difference between the near-PG plasma and the PG bias potentials, while the absolute value of plasma potential in the driver and in the PG area is less important for the negative ion production. The last conclusion confirms the main mechanism of negative ion production through the surface conversion of fast atoms. PMID- 26932002 TI - High voltage holding in the negative ion sources with cesium deposition. AB - High voltage holding of the large surface-plasma negative ion source with cesium deposition was studied. It was found that heating of ion-optical system electrodes to temperature >100 degrees C facilitates the source conditioning by high voltage pulses in vacuum and by beam shots. The procedure of electrode conditioning and the data on high-voltage holding in the negative ion source with small cesium seed are described. The mechanism of high voltage holding improvement by depletion of cesium coverage is discussed. PMID- 26932003 TI - The ISIS pre-injector reconfiguration. AB - With the introduction of a new "low energy beams" group at ISIS, the decision was taken to expand the ion source area. This paper will explain what actions were taken, how this has improved the present working environment and how the space will be used to accommodate a medium energy beam transport (MEBT) section after the existing radio-frequency quadrupole. The MEBT will incorporate three 202.5 MHz re-bunching cavities and will achieve a transmission of 96% with minimal emittance growth. PMID- 26932004 TI - Detailed beam and plasma measurements on the vessel for extraction and source plasma analyses (VESPA) Penning H- ion source. AB - A vessel for extraction and source plasma analyses (VESPA) is operational at the Rutherford Appleton Laboratory (RAL). This project supports and guides the overall ion source R&D effort for the ISIS spallation neutron and muon facility at RAL. The VESPA produces 100 mA of pulsed H(-) beam, but perveance scans indicate that the source is production-limited at extraction voltages above 12 kV unless the arc current is increased. A high resolution optical monochromator is used to measure plasma properties using argon as a diagnostic gas. The atomic hydrogen temperature increases linearly with arc current, up to 2.8 eV for 50 A; whereas the electron temperature has a slight linear decrease toward 2.2 eV. The gas density is 10(21) m(-3), whilst the electron density is two orders of magnitude lower. Densities follow square root relationships with arc current, with gas density decreasing whilst electron (and hence ion) density increases. Stopping and range of ions in matter calculations prove that operating a high current arc with an argon admixture is extremely difficult because cathode-coated cesium is heavily sputtered by argon. PMID- 26932005 TI - 3D self-consistent modeling of a matrix source of negative hydrogen ions. AB - The paper is in the scope of studies on the rf driving of a matrix source of negative hydrogen ions: a matrix of small radius discharges with planar-coil inductive driving and single aperture extraction from each discharge. The results from a three-dimensional model, in which plasma description is coupled to electrodynamics, confirm former conclusion that a single coil driving of the whole matrix by a zigzag coil with an omega-shaped conductor on the bottom of each discharge tube ensures efficient rf power deposition to the plasma. The latter is due to similarities with the rf driving of a single discharge by a single planar coil, shown by the obtained induced current and spatial distribution of the plasma parameters. Distinctions associated with the coil configuration as a single coil for the whole matrix are also discussed. PMID- 26932006 TI - Analysis of the beam halo in negative ion sources by using 3D3V PIC code. AB - The physical mechanism of the formation of the negative ion beam halo and the heat loads of the multi-stage acceleration grids are investigated with the 3D PIC (particle in cell) simulation. The following physical mechanism of the beam halo formation is verified: The beam core and the halo consist of the negative ions extracted from the center and the periphery of the meniscus, respectively. This difference of negative ion extraction location results in a geometrical aberration. Furthermore, it is shown that the heat loads on the first acceleration grid and the second acceleration grid are quantitatively improved compared with those for the 2D PIC simulation result. PMID- 26932007 TI - Duty factor variation possibility from 1% to 100% with PKU microwave driven Cs free volume H- sources. AB - Microwave driven cesium-free volume H(-) sources, that have the ability to deliver tens of mA H(-) at 35 keV both in CW and 10% duty factor (100 Hz/1 ms), were developed at Peking University (PKU) [S. X. Peng et al., in Proceeding of IPAC 2015, WEPWA027, Richmond, Virginia, USA, 3-8 May 2015]. Recently, special efforts were paid on the investigation of duty factor variation possibility from 1% to 100% with them. Most of the experiments were carried out with a pulsed length (tau) of 1 ms and different intervals of 99 ms, 49 ms, 39 ms, 29 ms, 19 ms, 9 ms, 4 ms, 2 ms, 1 ms, 0.5 ms, and 0 ms, respectively. Other experiments were focused on CW operation and fixed duty factor of 1%. Experimental results prove that PKU H(-) sources can deliver tens of mA H(-) at duty factor from 1% to 100%. The RF power efficiency increases steadily with the increasing of duty factor from 1% to CW at a fixed pulsed length. Under a given duty factor and pulsed length, RF power efficiency keeps constant and the H(-) current increases with RF power linearly. Details will be presented in the paper. PMID- 26932008 TI - Development and tests of molybdenum armored copper components for MITICA ion source. AB - In order to prevent detrimental material erosion of components impinged by back streaming positive D or H ions in the megavolt ITER injector and concept advancement beam source, a solution based on explosion bonding technique has been identified for producing a 1 mm thick molybdenum armour layer on copper substrate, compatible with ITER requirements. Prototypes have been recently manufactured and tested in the high heat flux test facility Garching Large Divertor Sample Test Facility (GLADIS) to check the capability of the molybdenum copper interface to withstand several thermal shock cycles at high power density. This paper presents both the numerical fluid-dynamic analyses of the prototypes simulating the test conditions in GLADIS as well as the experimental results. PMID- 26932009 TI - Effect of high energy electrons on H- production and destruction in a high current DC negative ion source for cyclotron. AB - Recently, a filament driven multi-cusp negative ion source has been developed for proton cyclotrons in medical applications. In this study, numerical modeling of the filament arc-discharge source plasma has been done with kinetic modeling of electrons in the ion source plasmas by the multi-cusp arc-discharge code and zero dimensional rate equations for hydrogen molecules and negative ions. In this paper, main focus is placed on the effects of the arc-discharge power on the electron energy distribution function and the resultant H(-) production. The modelling results reasonably explains the dependence of the H(-) extraction current on the arc-discharge power in the experiments. PMID- 26932010 TI - Numerical study of plasma generation process and internal antenna heat loadings in J-PARC RF negative ion source. AB - A numerical model of plasma transport and electromagnetic field in the J-PARC (Japan Proton Accelerator Research Complex) radio frequency ion source has been developed to understand the relation between antenna coil heat loadings and plasma production/transport processes. From the calculation, the local plasma density increase is observed in the region close to the antenna coil. Electrons are magnetized by the magnetic field line with absolute magnetic flux density 30 120 Gauss which leads to high local ionization rate. The results suggest that modification of magnetic configuration can be made to reduce plasma heat flux onto the antenna. PMID- 26932012 TI - Fine-tuning to minimize emittances of J-PARC RF-driven H- ion source. AB - The Japan Proton Accelerator Research Complex (J-PARC) cesiated RF-driven H(-) ion source has been successfully operated for about one year. By the world's brightest level beam, the J-PARC design beam power of 1 MW was successfully demonstrated. In order to minimize the transverse emittances, the rod-filter field (RFF) was optimized by changing the triple-gap-lengths of each of pairing five piece rod-filter-magnets. The larger emittance degradation seems to be caused by impurity-gases than the RFF. The smaller beam-hole-diameter of the extraction electrode caused the more than expected improvements on not only the emittances but also the peak beam intensity. PMID- 26932011 TI - Pre-conditioning procedure suitable for internal-RF-antenna of J-PARC RF-driven H ion source. AB - The Japan Proton Accelerator Research Complex (J-PARC) cesiated RF-driven H(-) ion source has been successfully operated for about 1 yr. By the world brightest level beam, the J-PARC design beam power of 1 MW was successfully demonstrated. Although no internal-RF-antenna failure, except for the once caused by an excess cesium due to a misoperation, occurred in the operation, many antennas failed in pre-conditionings for the first hundred days. The antenna failure rate was drastically decreased by using an antenna with coating thicker than a standard value and the pre-conditioning procedure repeating 15 min 25 kW RF-power operation and impurity-gas evacuation a few times, before the full power (50 kW) operation. PMID- 26932013 TI - The mechanical design and simulation of a scaled H- Penning ion source. AB - The existing ISIS Penning H(-) source is unable to produce the beam parameters required for the front end test stand and so a new, high duty factor, high brightness scaled source is being developed. This paper details first the development of an electrically biased aperture plate for the existing ISIS source and second, the design, simulation, and development of a prototype scaled source. PMID- 26932014 TI - Optimum plasma grid bias for a negative hydrogen ion source operation with Cs. AB - The functions of a biased plasma grid of a negative hydrogen (H(-)) ion source for both pure volume and Cs seeded operations are reexamined. Proper control of the plasma grid bias in pure volume sources yields: enhancement of the extracted negative ion current, reduction of the co-extracted electron current, flattening of the spatial distribution of plasma potential across the filter magnetic field, change in recycling from hydrogen atomic/molecular ions to atomic/molecular neutrals, and enhanced concentration of H(-) ions near the plasma grid. These functions are maintained in the sources seeded with Cs with additional direct emission of negative ions under positive ion and neutral hydrogen bombardment onto the plasma electrode. PMID- 26932015 TI - Efficient cesiation in RF driven surface plasma negative ion source. AB - Experiments on hydrogen negative ions production in the large radio-frequency negative ion source with cesium seed are described. The system of directed cesium deposition to the plasma grid periphery was used. The small cesium seed (~0.5 G) provides an enhanced H(-) production during a 2 month long experimental cycle. The gradual increase of negative ion yield during the long-term source runs was observed after cesium addition to the source. The degraded H(-) production was recorded after air filling to the source or after the cesium washing away from the driver and plasma chamber walls. The following source conditioning by beam shots produces the gradual recovery of H(-) yield to the high value. The effect of H(-) yield recovery after cesium coverage passivation by air fill was studied. The concept of cesium coverage replenishment and of H(-) yield recovery due to sputtering of cesium from the deteriorated layers is discussed. PMID- 26932016 TI - New source of MeV negative ion and neutral atom beams. AB - The scenario of "electron-capture and -loss" was recently proposed for the formation of negative ion and neutral atom beams with MeV kinetic energies. However, it does not explain why the formation of negative ions in a liquid spray is much more efficient than with an isolated atom. The role of atomic excited states in the charge-exchange processes is considered, and it is shown that it cannot account for the observed phenomena. The processes are more complex than the single electron-capture and -loss approach. It is suggested that the shell effects in the electronic structure of the projectile ion and/or target atoms may influence the capture/loss probabilities. PMID- 26932017 TI - High current DC negative ion source for cyclotron. AB - A filament driven multi-cusp negative ion source has been developed for proton cyclotrons in medical applications. In Cs-free operation, continuous H(-) beam of 10 mA and D(-) beam of 3.3 mA were obtained stably at an arc-discharge power of 3 kW and 2.4 kW, respectively. In Cs-seeded operation, H(-) beam current reached 22 mA at a lower arc power of 2.6 kW with less co-extracted electron current. The optimum gas flow rate, which gives the highest H(-) current, was 15 sccm in the Cs-free operation, while it decreased to 4 sccm in the Cs-seeded operation. The relationship between H(-) production and the design/operating parameters has been also investigated by a numerical study with KEIO-MARC code, which gives a reasonable explanation to the experimental results of the H(-) current dependence on the arc power. PMID- 26932018 TI - Optimization of plasma parameters with magnetic filter field and pressure to maximize H- ion density in a negative hydrogen ion source. AB - Transverse magnetic filter field as well as operating pressure is considered to be an important control knob to enhance negative hydrogen ion production via plasma parameter optimization in volume-produced negative hydrogen ion sources. Stronger filter field to reduce electron temperature sufficiently in the extraction region is favorable, but generally known to be limited by electron density drop near the extraction region. In this study, unexpected electron density increase instead of density drop is observed in front of the extraction region when the applied transverse filter field increases monotonically toward the extraction aperture. Measurements of plasma parameters with a movable Langmuir probe indicate that the increased electron density may be caused by low energy electron accumulation in the filter region decreasing perpendicular diffusion coefficients across the increasing filter field. Negative hydrogen ion populations are estimated from the measured profiles of electron temperatures and densities and confirmed to be consistent with laser photo-detachment measurements of the H(-) populations for various filter field strengths and pressures. Enhanced H(-) population near the extraction region due to the increased low energy electrons in the filter region may be utilized to increase negative hydrogen beam currents by moving the extraction position accordingly. This new finding can be used to design efficient H(-) sources with an optimal filtering system by maximizing high energy electron filtering while keeping low energy electrons available in the extraction region. PMID- 26932019 TI - Measurement of heat load density profile on acceleration grid in MeV-class negative ion accelerator. AB - To understand the physics of the negative ion extraction/acceleration, the heat load density profile on the acceleration grid has been firstly measured in the ITER prototype accelerator where the negative ions are accelerated to 1 MeV with five acceleration stages. In order to clarify the profile, the peripheries around the apertures on the acceleration grid were separated into thermally insulated 34 blocks with thermocouples. The spatial resolution is as low as 3 mm and small enough to measure the tail of the beam profile with a beam diameter of ~16 mm. It was found that there were two peaks of heat load density around the aperture. These two peaks were also clarified to be caused by the intercepted negative ions and secondary electrons from detailed investigation by changing the beam optics and gas density profile. This is the first experimental result, which is useful to understand the trajectories of these particles. PMID- 26932020 TI - Status of the RF-driven H- ion source for J-PARC linac. AB - For the upgrade of the Japan Proton Accelerator Research Complex linac beam current, a cesiated RF-driven negative hydrogen ion source was installed during the 2014 summer shutdown period, with subsequent operations commencing on September 29, 2014. The ion source has been successfully operating with a beam current and duty factor of 33 mA and 1.25% (500 MUs and 25 Hz), respectively. The result of recent beam operation has demonstrated that the ion source is capable of continuous operation for approximately 1100 h. The spark rate at the beam extractor was observed to be at a frequency of less than once a day, which is an acceptable level for user operation. Although an antenna failure occurred during operation on October 26, 2014, no subsequent serious issues have occurred since then. PMID- 26932022 TI - Recent performance of and plasma outage studies with the SNS H- source. AB - Spallation Neutron Source ramps to higher power levels that can be sustained with high availability. The goal is 1.4 MW despite a compromised radio frequency quadrupole (RFQ), which requires higher radio frequency power than design levels to approach the nominal beam transmission. Unfortunately at higher power the RFQ often loses its thermal stability, a problem apparently enhanced by beam losses and high influxes of hydrogen. Delivering as much H(-) beam as possible with the least amount of hydrogen led to plasma outages. The root cause is the dense 1-ms long ~55-kW 2-MHz plasma pulses reflecting ~90% of the continuous ~300 W, 13-MHz power, which was mitigated with a 4-ms filter for the reflected power signal and an outage resistant, slightly detuned 13-MHz match. Lowering the H2 gas also increased the H(-) beam current to ~55 mA and increased the RFQ transmission by ~7% (relative). PMID- 26932021 TI - Linac4 H- ion sources. AB - CERN's 160 MeV H(-) linear accelerator (Linac4) is a key constituent of the injector chain upgrade of the Large Hadron Collider that is being installed and commissioned. A cesiated surface ion source prototype is being tested and has delivered a beam intensity of 45 mA within an emittance of 0.3 pi ? mm ? mrad. The optimum ratio of the co-extracted electron- to ion-current is below 1 and the best production efficiency, defined as the ratio of the beam current to the 2 MHz RF-power transmitted to the plasma, reached 1.1 mA/kW. The H(-) source prototype and the first tests of the new ion source optics, electron-dump, and front end developed to minimize the beam emittance are presented. A temperature regulated magnetron H(-) source developed by the Brookhaven National Laboratory was built at CERN. The first tests of the magnetron operated at 0.8 Hz repetition rate are described. PMID- 26932023 TI - Multi-beamlet investigation of the deflection compensation methods of SPIDER beamlets. AB - SPIDER (Source for Production of Ions of Deuterium Extracted from a Rf plasma) is an ion source test bed designed to extract and accelerate a negative ion current up to 40 A and 100 kV whose first beam is expected by the end of 2016. Two main effects perturb beamlet optics during the acceleration stage: space charge repulsion and the deflection induced by the permanent magnets (called co extracted electron suppression magnets) embedded in the EG. The purpose of this work is to evaluate and compare benefits, collateral effects, and limitations of electrical and magnetic compensation methods for beamlet deflection. The study of these methods has been carried out by means of numerical modeling tools: multi beamlet simulations have been performed for the first time. PMID- 26932024 TI - Alternative modeling methods for plasma-based Rf ion sources. AB - Rf-driven ion sources for accelerators and many industrial applications benefit from detailed numerical modeling and simulation of plasma characteristics. For instance, modeling of the Spallation Neutron Source (SNS) internal antenna H(-) source has indicated that a large plasma velocity is induced near bends in the antenna where structural failures are often observed. This could lead to improved designs and ion source performance based on simulation and modeling. However, there are significant separations of time and spatial scales inherent to Rf driven plasma ion sources, which makes it difficult to model ion sources with explicit, kinetic Particle-In-Cell (PIC) simulation codes. In particular, if both electron and ion motions are to be explicitly modeled, then the simulation time step must be very small, and total simulation times must be large enough to capture the evolution of the plasma ions, as well as extending over many Rf periods. Additional physics processes such as plasma chemistry and surface effects such as secondary electron emission increase the computational requirements in such a way that even fully parallel explicit PIC models cannot be used. One alternative method is to develop fluid-based codes coupled with electromagnetics in order to model ion sources. Time-domain fluid models can simulate plasma evolution, plasma chemistry, and surface physics models with reasonable computational resources by not explicitly resolving electron motions, which thereby leads to an increase in the time step. This is achieved by solving fluid motions coupled with electromagnetics using reduced-physics models, such as single-temperature magnetohydrodynamics (MHD), extended, gas dynamic, and Hall MHD, and two-fluid MHD models. We show recent results on modeling the internal antenna H(-) ion source for the SNS at Oak Ridge National Laboratory using the fluid plasma modeling code USim. We compare demonstrate plasma temperature equilibration in two-temperature MHD models for the SNS source and present simulation results demonstrating plasma evolution over many Rf periods for different plasma temperatures. We perform the calculations in parallel, on unstructured meshes, using finite-volume solvers in order to obtain results in reasonable time. PMID- 26932025 TI - Characterization of the CW starter plasma RF matching network for operating the SNS H- ion source with lower H2 flows. AB - The Spallation Neutron Source H(-) ion source is operated with a pulsed 2-MHz RF (50-60 kW) to produce the 1-ms long, ~50 mA H(-) beams at 60 Hz. A continuous low power (~300 W) 13.56-MHz RF plasma, which is initially ignited with a H2 pressure bump, serves as starter plasma for the pulsed high power 2-MHz RF discharges. To reduce the risk of plasma outages at lower H2 flow rates which is desired for improved performance of the following radio frequency quadrupole, the 13.56-MHz RF matching network was characterized over a broad range of its two tuning capacitors. The H-alpha line intensity of the 13.56-MHz RF plasma and the reflected power of the 13.56-MHz RF were mapped against the capacitor settings. Optimal tunes for the maximum H-alpha intensity are consistent with the optimal tunes for minimum reflected power. Low limits of the H2 flow rate not causing plasma outages were explored within the range of the map. A tune region that allows lower H2 flow rate has been identified, which differs from the optimal tune for global minimum reflected power that was mostly used in the past. PMID- 26932026 TI - Time evolution of negative ion profile in a large cesiated negative ion source applicable to fusion reactors. AB - To understand the physics of the cesium (Cs) recycling in the large Cs-seeded negative ion sources relevant to ITER and JT-60SA with ion extraction area of 45 60 cm * 110-120 cm, the time evolution of the negative ion profile was precisely measured in JT-60SA where the ion extraction area is longitudinally segmented into 5. The Cs was seeded from the oven at 180 degrees C to the ion source. After 1 g of Cs input, surface production of the negative ions appeared only in the central segment where a Cs nozzle was located. Up to 2 g of Cs, the negative ion profile was longitudinally expanded over full ion extraction area. The measured time evolution of the negative ion profile has the similar tendency of distribution of the Cs atoms that is calculated. From the results, it is suggested that Cs atom distribution is correlated with the formation of the negative ion profile. PMID- 26932027 TI - The characterization and optimization of NIO1 ion source extraction aperture using a 3D particle-in-cell code. AB - The geometry of a single aperture in the extraction grid plays a relevant role for the optimization of negative ion transport and extraction probability in a hybrid negative ion source. For this reason, a three-dimensional particle-in cell/Monte Carlo collision model of the extraction region around the single aperture including part of the source and part of the acceleration (up to the extraction grid (EG) middle) regions has been developed for the new aperture design prepared for negative ion optimization 1 source. Results have shown that the dimension of the flat and chamfered parts and the slope of the latter in front of the source region maximize the product of production rate and extraction probability (allowing the best EG field penetration) of surface-produced negative ions. The negative ion density in the plane yz has been reported. PMID- 26932028 TI - The status of the SNS external antenna ion source and spare RFQ test facility. AB - The Oak Ridge National Laboratory operates the Spallation Neutron Source, consisting of a H(-) ion source, a 1 GeV linac and an accumulator ring. The accumulated <1 MUs-long, ~35 A beam pulses are extracted from the ring at 60 Hz and directed onto a liquid Hg target. Spalled neutrons are directed to ~20 world class instruments. Currently, the facility operates routinely with ~1.2 MW of average beam power, which soon will be raised to 1.4 MW. A future upgrade with a second target station calls for raising the power to 2.8 MW. This paper describes the status of two accelerator components expected to play important roles in achieving these goals: a recently acquired RFQ accelerator and the external antenna ion source. Currently, the RFQ is being conditioned in a newly constructed 2.5 MeV Integrated Test Facility (ITF) and the external antenna source is also being tested on a separate test stand. This paper presents the results of experiments and the testing of these systems. PMID- 26932029 TI - Performance of positive ion based high power ion source of EAST neutral beam injector. AB - The positive ion based source with a hot cathode based arc chamber and a tetrode accelerator was employed for a neutral beam injector on the experimental advanced superconducting tokamak (EAST). Four ion sources were developed and each ion source has produced 4 MW @ 80 keV hydrogen beam on the test bed. 100 s long pulse operation with modulated beam has also been tested on the test bed. The accelerator was upgraded from circular shaped to diamond shaped in the latest two ion sources. In the latest campaign of EAST experiment, four ion sources injected more than 4 MW deuterium beam with beam energy of 60 keV into EAST. PMID- 26932030 TI - Development and preliminary results of radio frequency ion source. AB - A radio frequency (RF) ion source was designed and developed for neutral beam injector. A RF driver test bed was used with a RF generator with maximum power of 25 kW with 1 MHz frequency and a matching box. In order to study the characteristic of RF plasma generation, the capacitance in the matching box was adjusted with different cases. The results show that lower capacitance will better the stability of the plasma with higher RF power. In the future, new RF coils and matching box will be developed for plasma generators with higher RF power of 50 kW. PMID- 26932031 TI - Multi-slit triode ion optical system with ballistic beam focusing. AB - Multi-slit triode ion-optical systems with spherical electrodes are of interest for formation of intense focused neutral beams for plasma heating. At present, two versions of focusing multi-slit triode ion optical system are developed. The first ion optical system forms the proton beam with 15 keV energy, 140 A current, and 30 ms duration. The second ion optical system is intended for heating neutral beam injector of Tokamak Configuration Variable (TCV). The injector produces focused deuterium neutral beam with 35 keV energy, 1 MW power, and 2 s duration. In the later case, the angular beam divergence of the neutral beam is 20-22 mrad in the direction across the slits of the ion optical system and 12 mrad in the direction along the slits. PMID- 26932032 TI - Development of design technique for vacuum insulation in large size multi aperture multi-grid accelerator for nuclear fusion. AB - Design techniques for the vacuum insulation have been developed in order to realize a reliable voltage holding capability of multi-aperture multi-grid (MAMuG) accelerators for fusion application. In this method, the nested multi stage configuration of the MAMuG accelerator can be uniquely designed to satisfy the target voltage within given boundary conditions. The evaluation of the voltage holding capabilities of each acceleration stages was based on the previous experimental results about the area effect and the multi-aperture effect. Since the multi-grid effect was found to be the extension of the area effect by the total facing area this time, the total voltage holding capability of the multi-stage can be estimated from that per single stage by assuming the stage with the highest electric field, the total facing area, and the total apertures. By applying these consideration, the analysis on the 3-stage MAMuG accelerator for JT-60SA agreed well with the past gap-scan experiments with an accuracy of less than 10% variation, which demonstrated the high reliability to design MAMuG accelerators and also multi-stage high voltage bushings. PMID- 26932033 TI - Ion collector design for an energy recovery test proposal with the negative ion source NIO1. AB - Commercial viability of thermonuclear fusion power plants depends also on minimizing the recirculation power used to operate the reactor. The neutral beam injector (NBI) remains one of the most important method for plasma heating and control. For the future fusion power plant project DEMO, a NBI wall plug efficiency at least of 0.45 is required, while efficiency of present NBI project is about 0.25. The D(-) beam from a negative ion source is partially neutralized by a gas cell, which leaves more than 40% of energy in residual beams (D(-) and D(+)), so that an ion beam energy recovery system can significantly contribute to optimize efficiency. Recently, the test negative ion source NIO1 (60 keV, 9 beamlets with 15 mA H(-) each) has been designed and built at RFX (Padua) for negative ion production efficiency and the beam quality optimization. In this paper, a study proposal to use the NIO1 source also for a beam energy recovery test experiment is presented and a preliminary design of a negative ion beam collector with simulations of beam energy recovery is discussed. PMID- 26932034 TI - Particle model of full-size ITER-relevant negative ion source. AB - This work represents the first attempt to model the full-size ITER-relevant negative ion source including the expansion, extraction, and part of the acceleration regions keeping the mesh size fine enough to resolve every single aperture. The model consists of a 2.5D particle-in-cell Monte Carlo collision representation of the plane perpendicular to the filter field lines. Magnetic filter and electron deflection field have been included and a negative ion current density of j(H(-)) = 660 A/m(2) from the plasma grid (PG) is used as parameter for the neutral conversion. The driver is not yet included and a fixed ambipolar flux is emitted from the driver exit plane. Results show the strong asymmetry along the PG driven by the electron Hall (E * B and diamagnetic) drift perpendicular to the filter field. Such asymmetry creates an important dis homogeneity in the electron current extracted from the different apertures. A steady state is not yet reached after 15 MUs. PMID- 26932035 TI - Towards 20 A negative hydrogen ion beams for up to 1 h: Achievements of the ELISE test facility (invited). AB - The large-scale RF-driven ion source of the test facility extraction from a large ion source experiment is aimed to deliver an accelerated ion current of 20 A D(-) (23 A H(-)) with an extracted electron-to-ion ratio below one for up to 1 h. Since the first plasma pulses for 20 s in volume operation in early 2013, followed by caesiation of the ion source, substantial progress has been achieved in extending the pulse length and the RF power. The record pulses in hydrogen are stable 400 s pulses with an extracted ion current of 18.3 A at 180 kW total RF power and 9.3 A at 80 kW stable for 1 h. For deuterium pulse, length and RF power are limited by the amount of co-extracted electrons. PMID- 26932036 TI - Self-induced steady-state magnetic field in the negative ion sources with localized rf power deposition. AB - The study is in the scope of a recent activity on modeling of SPIDER (Source for Production of Ions of Deuterium Extracted from RF plasma) which is under development regarding the neutral beam injection heating system of ITER. The regime of non-ambipolarity in the source, established before, is completed here by introducing in the model the steady state magnetic field, self-induced in the discharge due to the dc current flowing in it. Strong changes in the discharge structure are reported. PMID- 26932038 TI - Investigation of the boundary layer during the transition from volume to surface dominated H- production at the BATMAN test facility. AB - BATMAN (Bavarian Test Machine for Negative ions) is a test facility equipped with a 18 scale H(-) source for the ITER heating neutral beam injection. Several diagnostics in the boundary layer close to the plasma grid (first grid of the accelerator system) followed the transition from volume to surface dominated H(-) production starting with a Cs-free, cleaned source and subsequent evaporation of caesium, while the source has been operated at ITER relevant pressure of 0.3 Pa: Langmuir probes are used to determine the plasma potential, optical emission spectroscopy is used to follow the caesiation process, and cavity ring-down spectroscopy allows for the measurement of the H(-) density. The influence on the plasma during the transition from an electron-ion plasma towards an ion-ion plasma, in which negative hydrogen ions become the dominant negatively charged particle species, is seen in a strong increase of the H(-) density combined with a reduction of the plasma potential. A clear correlation of the extracted current densities (j(H(-)), j(e)) exists with the Cs emission. PMID- 26932039 TI - Off-normal and failure condition analysis of the MITICA negative-ion accelerator. AB - The negative-ion accelerator for the MITICA neutral beam injector has been designed and optimized in order to reduce the thermo-mechanical stresses in all components below limits compatible with the required fatigue life. However, deviation from the expected beam performances can be caused by "off-normal" operating conditions of the accelerator. The purpose of the present work is to identify and analyse all the "off-normal" operating conditions, which could possibly become critical in terms of thermo-mechanical stresses or of degradation of the optical performances of the beam. PMID- 26932037 TI - Final design of the beam source for the MITICA injector. AB - The megavolt ITER injector and concept advancement experiment is the prototype and the test bed of the ITER heating and current drive neutral beam injectors, currently in the final design phase, in view of the installation in Padova Research on Injector Megavolt Accelerated facility in Padova, Italy. The beam source is the key component of the system, as its goal is the generation of the 1 MeV accelerated beam of deuterium or hydrogen negative ions. This paper presents the highlights of the latest developments for the finalization of the MITICA beam source design, together with a description of the most recent analyses and R&D activities carried out in support of the design. PMID- 26932040 TI - Physics-electrical hybrid model for real time impedance matching and remote plasma characterization in RF plasma sources. AB - Plasma characterization and impedance matching are an integral part of any radio frequency (RF) based plasma source. In long pulse operation, particularly in high power operation where plasma load may vary due to different reasons (e.g. pressure and power), online tuning of impedance matching circuit and remote plasma density estimation are very useful. In some cases, due to remote interfaces, radio activation and, due to maintenance issues, power probes are not allowed to be incorporated in the ion source design for plasma characterization. Therefore, for characterization and impedance matching, more remote schemes are envisaged. Two such schemes by the same authors are suggested in these regards, which are based on air core transformer model of inductive coupled plasma (ICP) [M. Bandyopadhyay et al., Nucl. Fusion 55, 033017 (2015); D. Sudhir et al., Rev. Sci. Instrum. 85, 013510 (2014)]. However, the influence of the RF field interaction with the plasma to determine its impedance, a physics code HELIC [D. Arnush, Phys. Plasmas 7, 3042 (2000)] is coupled with the transformer model. This model can be useful for both types of RF sources, i.e., ICP and helicon sources. PMID- 26932041 TI - Transmission of electrons inside the cryogenic pumps of ITER injector. AB - Large cryogenic pumps are installed in the vessel of large neutral beam injectors (NBIs) used to heat the plasma in nuclear fusion experiments. The operation of such pumps can be compromised by the presence of stray secondary electrons that are generated along the beam path. In this paper, we present a numerical model to analyze the propagation of the electrons inside the pump. The aim of the study is to quantify the power load on the active pump elements, via evaluation of the transmission probabilities across the domain of the pump. These are obtained starting from large datasets of particle trajectories, obtained by numerical means. The transmission probability of the electrons across the domain is calculated for the NBI of the ITER and for its prototype Megavolt ITer Injector and Concept Advancement (MITICA) and the results are discussed. PMID- 26932042 TI - Design optimization of RF lines in vacuum environment for the MITICA experiment. AB - This contribution regards the Radio Frequency (RF) transmission line of the Megavolt ITER Injector and Concept Advancement (MITICA) experiment. The original design considered copper coaxial lines of 1" 5/8, but thermal simulations under operating conditions showed maximum temperatures of the lines at regime not compatible with the prescription of the component manufacturer. Hence, an optimization of the design was necessary. Enhancing thermal radiation and increasing the conductor size were considered for design optimization: thermal analyses were carried out to calculate the temperature of MITICA RF lines during operation, as a function of the emissivity value and of other geometrical parameters. Five coating products to increase the conductor surface emissivity were tested, measuring the outgassing behavior of the selected products and the obtained emissivity values. PMID- 26932043 TI - Concepts of magnetic filter fields in powerful negative ion sources for fusion. AB - The performance of large negative ion sources used in neutral beam injection systems is in long pulses mainly determined by the increase of the currents of co extracted electrons. This is in particular a problem in deuterium and limits the ion currents which are for long pulses below the requirements for the ITER source. In the source of the ELISE test facility, the magnetic field in front of the first grid, which is essential to reduce the electron current, is generated by a current of several kA flowing through the plasma facing grid. Weakening of this field by the addition of permanent magnets placed close to the lateral walls has led to a reduction of the electron current by a factor three without loss of ion current when source was operated in volume production. If this effect can be validated for the cesiated source, it would be a large step towards achieving the ITER parameter in long pulses. PMID- 26932044 TI - Inductively driven surface-plasma negative ion source for N-NBI use (invited). AB - The long-pulse surface-plasma source prototype is developed at Budker Institute of Nuclear Physics for negative-ion based neutral beam injector use. The essential source features are (1) an active temperature control of the ion optical system electrodes by circulation of hot thermal fluid through the channels, drilled in the electrode bodies, (2) the concaved transverse magnetic field in the extraction and acceleration gaps, preventing the electrons trapping and avalanching, and (3) the directed cesium deposition via distribution tubes adjacent to the plasma grid periphery. The long term effect of cesium was obtained just with the single cesium deposition. The high voltage strength of ion optical system electrodes was improved with actively heated electrodes. A stable H(-) beam with a current ~1 A and energy 90 keV was routinely extracted and accelerated. PMID- 26932045 TI - Modification to the accelerator of the NBI-1B ion source for improving the injection efficiency. AB - Minimizing power loss of a neutral beam imposes modification of the accelerator of the ion source for further improvement of the beam optics. The beam optics can be improved by focusing beamlets. The injection efficiencies by the steering of ion beamlets are investigated numerically to find the optimum modification of the accelerator design of the NBI-1B ion source. The beam power loss was reduced by aperture displacement of three edge beamlets arrays considering power loadings on the beamline components. Successful testing and operation of the ion source at 60 keV/84% of injection efficiency led to the possibility of enhancing the system capability to a 2.4 MW power level at 100 keV/1.9 MUP. PMID- 26932046 TI - A feasibility study of a NBI photoneutralizer based on nonlinear gating laser recirculation. AB - The neutralization efficiency of negative ion neutral beam injectors is a major issue for future fusion reactors. Photon neutralization might be a valid alternative to present gas neutralizers, but still with several challenges for a valid implementation. Some concepts have been presented so far but none has been validated yet. A novel photoneutralization concept is discussed here, based on an annular cavity and a duplicated frequency laser beam (recirculation injection by nonlinear gating). The choice of lithium triborate as the material for the second harmonic extractor is discussed and a possible cooling method via crystal slicing is presented; laser intensity enhancement within the cavity is evaluated in order to quantify the achievable neutralization rate. Mockups of the critical components are proposed as intermediate steps toward system realization. PMID- 26932047 TI - First hydrogen operation of NIO1: Characterization of the source plasma by means of an optical emission spectroscopy diagnostic. AB - NIO1 (Negative Ion Optimization 1) is a compact and flexible radio frequency H(-) ion source, developed by Consorzio RFX and INFN-LNL. The aim of the experimentation on NIO1 is the optimization of both the production of negative ions and their extraction and beam optics. In the initial phase of its commissioning, NIO1 was operated with nitrogen, but now the source is regularly operated also with hydrogen. To evaluate the source performances, an optical emission spectroscopy diagnostic was installed. The system includes a low resolution spectrometer in the spectral range of 300-850 nm and a high resolution (50 pm) one, to study, respectively, the atomic and the molecular emissions in the visible range. The spectroscopic data have been interpreted also by means of a collisional-radiative model developed at IPP Garching. Besides the diagnostic hardware and the data analysis methods, the paper presents the first plasma measurements across a transition to the full H mode, in a hydrogen discharge. The characteristic signatures of this transition in the plasma parameters are described, in particular, the sudden increase of the light emitted from the plasma above a certain power threshold. PMID- 26932048 TI - First experiments with the negative ion source NIO1. AB - Neutral Beam Injectors (NBIs), which need to be strongly optimized in the perspective of DEMO reactor, request a thorough understanding of the negative ion source used and of the multi-beamlet optics. A relatively compact radio frequency (rf) ion source, named NIO1 (Negative Ion Optimization 1), with 9 beam apertures for a total H(-) current of 130 mA, 60 kV acceleration voltage, was installed at Consorzio RFX, including a high voltage deck and an X-ray shield, to provide a test bench for source optimizations for activities in support to the ITER NBI test facility. NIO1 status and plasma experiments both with air and with hydrogen as filling gas are described. Transition from a weak plasma to an inductively coupled plasma is clearly evident for the former gas and may be triggered by rising the rf power (over 0.5 kW) at low pressure (equal or below 2 Pa). Transition in hydrogen plasma requires more rf power (over 1.5 kW). PMID- 26932049 TI - Improvement of accelerator of negative ion source on the Large Helical Device. AB - To improve the performance of negative-ion based neutral beam injection on the Large Helical Device, the accelerator was modified on the basis of numerical investigations. A field limiting ring was installed on the upper side of a grounded grid (GG) support and a multi-slot GG was adopted instead of a multi aperture GG. As a result, the voltage holding capability is improved and the heat load on the GG decreases by 40%. In addition, the arc efficiency is improved significantly only by replacing the GG. PMID- 26932050 TI - Development of the negative ion beams relevant to ITER and JT-60SA at Japan Atomic Energy Agency. AB - In order to realize negative ion sources and accelerators to be applicable to International Thermonuclear Experimental Reactor and JT-60 Super Advanced, a large cesium (Cs)-seeded negative ion source and a multi-aperture and multi-stage electric acceleration have been developed at Japan Atomic Energy Agency (JAEA). Long pulse production and acceleration of the negative ion beams have been independently carried out. The long pulse production of the high current beams has achieved 100 s at the beam current of 15 A by modifying the JT-60 negative ion source. The pulse duration time is increased three times longer than that before the modification. As for the acceleration, a pulse duration time has been also extended two orders of magnitudes from 0.4 s to 60 s. The developments of the negative ion source and acceleration at JAEA are well in progress towards the realization of the negative ion sources and accelerators for fusion applications. PMID- 26932051 TI - Steady state thermal-hydraulic analyses of the MITICA cooling circuits. AB - Megavolt ITER Injector Concept Advancement is the full scale prototype of the heating and current drive neutral beam injectors for ITER, to be built at Consorzio RFX (Padova). The engineering design of its components is challenging: the total heat loads they will be subjected to (expected between 2 and 19 MW), the high heat fluxes (up to 20 MW/m(2)), and the beam pulse duration up to 1 h, set demanding requirements for reliable active cooling circuits. In support of the design, the thermo-hydraulic behavior of each cooling circuit under steady state condition has been investigated by using one-dimensional models. The final results, obtained considering a number of optimizations for the cooling circuits, show that all the requirements in terms of flow rate, temperature, and pressure drop are properly fulfilled. PMID- 26932052 TI - Effect of advanced nanowire-based targets in nanosecond laser-matter interaction (invited). AB - An experimental campaign aiming to investigate the effects of innovative nanostructured targets based on Ag nanowires on laser energy absorption in the ns time domain has been carried out at the Laser Energy for Nuclear Science laboratory of INFN-LNS in Catania. The tested targets were realized at INFN Bologna by anodizing aluminium sheets in order to obtain layers of porous Al2O3 of different thicknesses, on which nanowires of various metals are grown by electro-deposition with different heights. Targets were then irradiated by using a Nd:YAG laser at different pumping energies. Advanced diagnostic tools were used for characterizing the plasma plume and ion production. As compared with targets of pure Al, a huge enhancement (of almost two order of magnitude) of the X-ray flux emitted by the plasma has been observed when using the nanostructured targets, with a corresponding decrease of the "optical range" signal, pointing out that the energetic content of the laser produced plasma was remarkably increased. This analysis was furthermore confirmed from time-of-flight spectra. PMID- 26932053 TI - A new deflection technique applied to an existing scheme of electrostatic accelerator for high energy neutral beam injection in fusion reactor devices. AB - A scheme of a neutral beam injector (NBI), based on electrostatic acceleration and magneto-static deflection of negative ions, is proposed and analyzed in terms of feasibility and performance. The scheme is based on the deflection of a high energy (2 MeV) and high current (some tens of amperes) negative ion beam by a large magnetic deflector placed between the Beam Source (BS) and the neutralizer. This scheme has the potential of solving two key issues, which at present limit the applicability of a NBI to a fusion reactor: the maximum achievable acceleration voltage and the direct exposure of the BS to the flux of neutrons and radiation coming from the fusion reactor. In order to solve these two issues, a magnetic deflector is proposed to screen the BS from direct exposure to radiation and neutrons so that the voltage insulation between the electrostatic accelerator and the grounded vessel can be enhanced by using compressed SF6 instead of vacuum so that the negative ions can be accelerated at energies higher than 1 MeV. By solving the beam transport with different magnetic deflector properties, an optimum scheme has been found which is shown to be effective to guarantee both the steering effect and the beam aiming. PMID- 26932054 TI - Charge state breeding experiences and plans at TRIUMF. AB - At the Isotope Separation and ACceleration (ISAC) facility at TRIUMF, an electron cyclotron resonance ion source (ECRIS) has been set up for the charge state breeding of radioactive ions. In order to reduce background from stable ions generated in the ECRIS, several measures, including changing materials for the plasma chamber and the surrounding components, have been implemented. Further reduction has been achieved by using the post-accelerator chain as a mass filter. Since the implementation of those measures in 2013, physics experiments with accelerated radioactive isotopes of Rb, Sr, K, and Mg have been performed. In most cases, a charge breeding efficiency of several percent has been achieved. With the planned expansion of the isotope production capabilities at TRIUMF within the Advanced Rare IsotopE Laboratory project, two new target stations, one using photo-fission induced by a high-power electron beam at 50 MeV and the other one using 480 MeV protons as at ISAC, will be put into operation within the next 5 yr. Additionally, a new electron beam ion source (EBIS) based charge state breeding system will be installed. Background from such a source is expected to be much lower. The drawback is that for the efficient operation of such a system, pulsed beam operation is required, which makes the installation of an additional ion buncher in front of the EBIS necessary. PMID- 26932055 TI - Thermal-electric coupled-field finite element modeling and experimental testing of high-temperature ion sources for the production of radioactive ion beams. AB - In isotope separation on line facilities the target system and the related ion source are two of the most critical components. In the context of the selective production of exotic species (SPES) project, a 40 MeV 200 MUA proton beam directly impinges a uranium carbide target, generating approximately 10(13) fissions per second. The radioactive isotopes produced in this way are then directed to the ion source, where they can be ionized and finally accelerated to the subsequent areas of the facility. In this work both the surface ion source and the plasma ion source adopted for the SPES facility are presented and studied by means of numerical thermal-electric models. Then, numerical results are compared with temperature and electric potential difference measurements, and finally the main advantages of the proposed simulation approach are discussed. PMID- 26932056 TI - The new ECR charge breeder for the Selective Production of Exotic Species project at INFN--Laboratori Nazionali di Legnaro. AB - The Selective Production of Exotic Species (SPES) project is an ISOL facility under construction at Istituto Nazionale di Fisica Nucleare-Laboratori Nationali di Legnaro (INFN-LNL). 1+ radioactive ions, produced and extracted from the target-ion-source system, will be charge bred to high charge states by an ECR charge breeder (SPES-CB): the project will adopt an upgraded version of the PHOENIX charge breeder, developed since about twenty years by the Laboratoire de Physique Subatomique et de Cosmologie (LPSC). The collaboration between LNL and LPSC started in 2010 with charge breeding experiments performed on the LPSC test bench and led, in June 2014, to the signature of a Research Collaboration Agreement for the delivery of a complete charge breeder and ancillaries, satisfying the SPES requirements. Important technological aspects were tackled during the construction phase, as, for example, beam purity issues, electrodes alignment, and vacuum sealing. This phase was completed in spring 2015, after which the qualification tests were carried out at LPSC on the 1+/q+ test stand. This paper describes the characteristics of the SPES-CB, with particular emphasis on the results obtained during the qualification tests: charge breeding of Ar, Xe, Rb, and Cs satisfied the SPES requirements for different intensities of the injected 1+ beam, showing very good performances, some of which are "best ever" for this device. PMID- 26932057 TI - Integration of RFQ beam coolers and solenoidal magnetic fields. AB - Electromagnetic traps are a flexible and powerful method of controlling particle beams, possibly of exotic nuclei, with cooling (of energy spread and transverse oscillations) provided by collisions with light gases as in the Radio Frequency Quadrupole Cooler (RFQC). A RFQC prototype can be placed inside the existing Eltrap solenoid, capable of providing a magnetic flux density component B(z) up to 0.2 T, where z is the solenoid axis. Confinement in the transverse plane is provided both by B(z) and the rf voltage V(rf) (up to 1 kV at few MHz). Transport is provided by a static electric field E(z) (order of 100 V/m), while gas collisions (say He at 1 Pa, to be maintained by differential pumping) provide cooling or heating depending on V(rf). The beamline design and the major parameters V(rf), B(z) (which affect the beam transmission optimization) are here reported, with a brief description of the experimental setup. PMID- 26932058 TI - Electromagnetic analysis of the plasma chamber of an ECR-based charge breeder. AB - The optimization of the efficiency of an ECR-based charge breeder is a twofold task: efforts must be paid to maximize the capture of the injected 1+ ions by the confined plasma and to produce high charge states to allow post-acceleration at high energies. Both tasks must be faced by studying in detail the electrons heating dynamics, influenced by the microwave-to-plasma coupling mechanism. Numerical simulations are a powerful tools for obtaining quantitative information about the wave-to-plasma interaction process: this paper presents a numerical study of the microwaves propagation and absorption inside the plasma chamber of the PHOENIX charge breeder, which the selective production of exotic species project, under construction at Legnaro National Laboratories, will adopt as charge breeder. Calculations were carried out with a commercial 3D FEM solver: first, all the resonant frequencies were determined by considering a simplified plasma chamber; then, the realistic geometry was taken into account, including a cold plasma model of increasing complexity. The results gave important information about the power absorption and losses and will allow the improvement of the plasma model to be used in a refined step of calculation reproducing the breeding process itself. PMID- 26932059 TI - Off-line commissioning of EBIS and plans for its integration into ATLAS and CARIBU. AB - An Electron Beam Ion Source Charge Breeder (EBIS-CB) has been developed at Argonne to breed radioactive beams from the CAlifornium Rare Isotope Breeder Upgrade (CARIBU) facility at Argonne Tandem Linac Accelerator System (ATLAS). The EBIS-CB will replace the existing ECR charge breeder to increase the intensity and significantly improve the purity of reaccelerated radioactive ion beams. The CARIBU EBIS-CB has been successfully commissioned offline with an external singly charged cesium ion source. The performance of the EBIS fully meets the specifications to breed rare isotope beams delivered from CARIBU. The EBIS is being relocated and integrated into ATLAS and CARIBU. A long electrostatic beam transport system including two 180 degrees bends in the vertical plane has been designed. The commissioning of the EBIS and the beam transport system in their permanent location will start at the end of this year. PMID- 26932060 TI - A three-dimensional numerical modelling of the PHOENIX-SPES charge breeder based on the Langevin formalism. AB - A Charge Breeder (CB) is a crucial device of an ISOL facility, allowing post acceleration of radioactive ions: it accepts an incoming 1+ beam, then multiplying its charge with a highly charged q+ beam as an output. The overall performances of the facility (intensity and attainable final energy) critically depend on the charge breeder optimization. Experimental results collected along the years confirm that the breeding process is still not fully understood and room for improvements still exists: a new numerical approach has been therefore developed and applied to the description of a (85)Rb(1+) beam capture by the plasma of the 14.5 GHz PHOENIX ECR-based CB, installed at the Laboratoire de Physique Subatomique et de Cosmologie (LPSC), and adopted for the Selective Production of Exotic Species project under construction at Laboratori Nazionali di Legnaro. The results of the numerical simulations, obtained implementing a plasma-target model of increasing accuracy and different values for the plasma potential, will be described along the paper: results very well agree with the theoretical predictions and with the experimental results obtained on the LPSC test bench. PMID- 26932061 TI - Charge breeder for the SPIRAL1 upgrade: Preliminary results. AB - In the framework of the SPIRAL1 upgrade under progress at the GANIL lab, the charge breeder based on a LPSC Phoenix ECRIS, first tested at ISOLDE has been modified to benefit of the last enhancements of this device from the 1+/n+ community. The modifications mainly concern the 1 + optics, vacuum techniques, and the RF-buffer gas injection into the charge breeder. Prior to its installation in the midst of the low energy beam line of the SPIRAL1 facility, it has been decided to qualify its performances and several operation modes at the test bench of LPSC lab. This contribution shall present preliminary results of experiments conducted at LPSC concerning the 1 + to n+ conversion efficiencies for noble gases as well as for alkali elements and the corresponding transformation times. PMID- 26932062 TI - A singly charged ion source for radioactive 11C ion acceleration. AB - A new singly charged ion source using electron impact ionization has been developed to realize an isotope separation on-line system for simultaneous positron emission tomography imaging and heavy-ion cancer therapy using radioactive (11)C ion beams. Low-energy electron beams are used in the electron impact ion source to produce singly charged ions. Ionization efficiency was calculated in order to decide the geometric parameters of the ion source and to determine the required electron emission current for obtaining high ionization efficiency. Based on these considerations, the singly charged ion source was designed and fabricated. In testing, the fabricated ion source was found to have favorable performance as a singly charged ion source. PMID- 26932063 TI - Optimizing charge breeding techniques for ISOL facilities in Europe: Conclusions from the EMILIE project. AB - The present paper summarizes the results obtained from the past few years in the framework of the Enhanced Multi-Ionization of short-Lived Isotopes for Eurisol (EMILIE) project. The EMILIE project aims at improving the charge breeding techniques with both Electron Cyclotron Resonance Ion Sources (ECRIS) and Electron Beam Ion Sources (EBISs) for European Radioactive Ion Beam (RIB) facilities. Within EMILIE, an original technique for debunching the beam from EBIS charge breeders is being developed, for making an optimal use of the capabilities of CW post-accelerators of the future facilities. Such a debunching technique should eventually resolve duty cycle and time structure issues which presently complicate the data-acquisition of experiments. The results of the first tests of this technique are reported here. In comparison with charge breeding with an EBIS, the ECRIS technique had lower performance in efficiency and attainable charge state for metallic ion beams and also suffered from issues related to beam contamination. In recent years, improvements have been made which significantly reduce the differences between the two techniques, making ECRIS charge breeding more attractive especially for CW machines producing intense beams. Upgraded versions of the Phoenix charge breeder, originally developed by LPSC, will be used at SPES and GANIL/SPIRAL. These two charge breeders have benefited from studies undertaken within EMILIE, which are also briefly summarized here. PMID- 26932064 TI - Optimization of a hot-cavity type resonant ionization laser ion source. AB - Resonant Ionization Laser Ion Source (RILIS) is nowadays an important technique in many Radioactive Ion Beam (RIB) facilities for its reliability and ability to ionize efficiently and element selectively. Grand Accelerateur National d'Ions Lourds (GANIL) Ion Source using Electron Laser Excitation (GISELE) is an off-line test bench for RILIS developed to study a fully operational resonant laser ion source at GANIL facility. The ion source body has been designed as a modular system to investigate different experimental approaches by varying the design parameters, to develop the future on-line laser ion source. The aim of this project is to determine the best technical solution which combines high selectivity and ionization efficiency with small ion beam emittance and stable long term operation. Latest results concerning emittance and time profile development as a function of the temperature for different ion source versions will be presented. PMID- 26932066 TI - Operating modes of a hydrogen ion source based on a hollow-cathode pulsed Penning discharge. AB - An ion source based on a hollow-cathode Penning discharge was switched to a high current pulsed mode (tens of amperes and tens of microseconds) to produce an intense hydrogen ion beam. With molecular hydrogen (H2), the ion beam contained three species: H(+), H2(+), and H3(+). For all experimental conditions, the fraction of H2 (+) ions in the beam was about 10 / 15% of the total ion beam current and varied little with ion source parameters. At the same time, the ratio of H(+) and H3(+) depended strongly on the discharge current, particularly on its distribution in the gap between the hollow and planar cathodes. Increasing the discharge current increased the H(+) fraction in ion beam. The maximum fraction of H(+) reached 80% of the total ion beam current. Forced redistribution of the discharge current in the cathode gap for increasing the hollow cathode current could greatly increase the H3(+) fraction in the beam. At optimum parameters, the fraction of H3(+) ions reached 60% of the total ion beam current. PMID- 26932065 TI - Molecular ion sources for low energy semiconductor ion implantation (invited). AB - Smaller semiconductors require shallow, low energy ion implantation, resulting space charge effects, which reduced beam currents and production rates. To increase production rates, molecular ions are used. Boron and phosphorous (or arsenic) implantation is needed for P-type and N-type semiconductors, respectively. Carborane, which is the most stable molecular boron ion leaves unacceptable carbon residue on extraction grids. A self-cleaning carborane acid compound (C4H12B10O4) was synthesized and utilized in the ITEP Bernas ion source resulting in large carborane ion output, without carbon residue. Pure gaseous processes are desired to enable rapid switch among ion species. Molecular phosphorous was generated by introducing phosphine in dissociators via 4PH3 = P4 + 6H2; generated molecular phosphorous in a pure gaseous process was then injected into the HCEI Calutron-Bernas ion source, from which P4(+) ion beams were extracted. Results from devices and some additional concepts are described. PMID- 26932067 TI - A high intensity H2+ multicusp ion source for the isotope decay-at-rest experiment, IsoDAR. AB - The Isotope Decay-At-Rest (IsoDAR) experimental program aims to decisively test the sterile neutrino hypothesis. In essence, it is a novel cyclotron based neutrino factory that will improve the frontiers in both high-intensity cyclotrons and electron flavor anti-neutrino sources. By using a source in which the usual H(-) ions are replaced with the more tightly bound H2(+) ions, we can negate the effects of Lorentz stripping in a cyclotron, reduce the overall perveance due to the space-charge effect, and deliver twice the number of protons per nuclei on target. To produce the H2(+), we are currently developing a dedicated multicusp ion source, MIST-1 (generation-1 Multicusp Ion Source Technologies at MIT), and a low-energy beam transport system for the IsoDAR cyclotron. This will increase the overall H2(+) current leading up to the cyclotron and improve the emittance of the beam injected into the cyclotron. PMID- 26932068 TI - The RHIC polarized H- ion source. AB - A novel polarization technique had been successfully implemented for the Relativistic Heavy Ion Collider (RHIC) polarized H(-) ion source upgrade to higher intensity and polarization. In this technique, a proton beam inside the high magnetic field solenoid is produced by ionization of the atomic hydrogen beam (from external source) in the He-gaseous ionizer cell. Further proton polarization is produced in the process of polarized electron capture from the optically pumped Rb vapor. The use of high-brightness primary beam and large cross sections of charge-exchange cross sections resulted in production of high intensity H(-) ion beam of 85% polarization. The source very reliably delivered polarized beam in the RHIC Run-2013 and Run-2015. High beam current, brightness, and polarization resulted in 75% polarization at 23 GeV out of Alternating Gradient Synchrotron (AGS) and 60%-65% beam polarization at 100-250 GeV colliding beams in RHIC. PMID- 26932069 TI - Development of Wien filter for small ion gun of surface analysis. AB - The gas cluster ion beam (GCIB) and liquid metal ion beam have been studied in the context of ion beam usage for analytical equipment in applications such as X ray photoelectron spectroscopy and secondary ion mass spectroscopy (SIMS). In particular, small ion sources are used for the secondary ion generation and ion etching. To set the context to this study, the SIMS project has been launched to develop ion-gun based analytical equipment for the Korea Basic Science Institute. The objective of the first stage of the project is the generation of argon beams with a GCIB system [A. Kirkpatrick, Nucl. Instrum. Methods Phys. Res., Sect. B 206, 830-837 (2003)] that consists of a nozzle, skimmer, ionizer, acceleration tube, separation system, transport system, and target. The Wien filter directs the selected cluster beam to the target system by exploiting the velocity difference of the generated particles from GCIB. In this paper, we present the theoretical modeling and three-dimensional electromagnetic analysis of the Wien filter, which can separate Ar(+) 2500 clusters from Ar(+) 2400 to Ar(+) 2600 clusters with a 1-mm collimator. PMID- 26932071 TI - First results on Ge resonant laser photoionization in hollow cathode lamp. AB - In the framework of the research and development activities of the SPES project regarding the optimization of the radioactive beam production, a dedicated experimental study has been recently started in order to investigate the possibility of in-source ionization of germanium using a set of tunable dye lasers. Germanium is one of the beams to be accelerated by the SPES ISOL facility, which is under construction at Legnaro INFN Laboratories. The three step, two color ionization schemes have been tested using a Ge hollow cathode lamp. The slow and the fast optogalvanic signals were detected and averaged by an oscilloscope as a proof of the laser ionization inside the lamp. As a result, several wavelength scans across the resonances of ionization schemes were collected with the fast optogalvanic signal. Some comparisons of ionization efficiency for different ionization schemes were made. Furthermore, saturation curves of the first excitation transitions have been obtained. This investigation method and the setup built in the laser laboratory of the SPES project can be applied for the photo-ionization scheme studies also for the other possible radioactive elements. PMID- 26932070 TI - Development and testing of a pulsed helium ion source for probing materials and warm dense matter studies. AB - The neutralized drift compression experiment was designed and commissioned as a pulsed, linear induction accelerator to drive thin targets to warm dense matter (WDM) states with peak temperatures of ~1 eV using intense, short pulses (~1 ns) of 1.2 MeV lithium ions. At that kinetic energy, heating a thin target foil near the Bragg peak energy using He(+) ions leads to more uniform energy deposition of the target material than Li(+) ions. Experiments show that a higher current density of helium ions can be delivered from a plasma source compared to Li(+) ions from a hot plate type ion source. He(+) beam pulses as high as 200 mA at the peak and 4 MUs long were measured from a multi-aperture 7-cm-diameter emission area. Within +/-5% variation, the uniform beam area is approximately 6 cm across. The accelerated and compressed pulsed ion beams can be used for materials studies and isochoric heating of target materials for high energy density physics experiments and WDM studies. PMID- 26932072 TI - Production of high current proton beams using complex H-rich molecules at GSI. AB - In this contribution, the concept of production of intense proton beams using molecular heavy ion beams from an ion source is described, as well as the indisputable advantages of this technique for operation of the GSI linear accelerator. The results of experimental investigations, including mass-spectra analysis and beam emittance measurements, with different ion beams (CH3(+),C2H4(+),C3H7(+)) using various gaseous and liquid substances (methane, ethane, propane, isobutane, and iodoethane) at the ion source are summarized. Further steps to improve the ion source and injector performance with molecular beams are depicted. PMID- 26932073 TI - Recent development of plasma optical systems (invited). AB - The article devotes a brief description of the recent development and current status of an ongoing research of plasma optical systems based on the fundamental plasma optical idea magnetic electron isolation, equipotentialization magnetic field lines, and the axi-symmetric cylindrical electrostatic plasma lens (PL) configuration. The experimental, theoretical, and simulation investigations have been carried out over recent years collaboratively between IP NASU (Kiev), LBNL (Berkeley, USA), and HCEI RAS (Tomsk). The crossed electric and magnetic fields inherent the PL configuration that provides the attractive method for establishing a stable plasma discharge at low pressure. Using PL configuration, several high reliability plasma devices were developed. These devices are attractive for many high-tech applications. PMID- 26932074 TI - A new solid state extractor pulser for the FNAL magnetron ion source. AB - A new solid state extractor pulser has been installed on the Fermi National Accelerator Laboratory (FNAL) magnetron ion source, replacing a vacuum tube style pulser that was used for over 40 years. The required ion source extraction voltage is 35 kV for injection into the radio frequency quadrupole. At this voltage, the old pulser had a rise time of over 150 MUs due to the current limit of the vacuum tube. The new solid state pulsers are capable of 50 kV, 100 A peak current pulses and have a rise time of 9 MUs when installed in the operational system. This paper will discuss the pulser design and operational experience to date. PMID- 26932075 TI - Status of intense permanent magnet proton source for China-accelerator driven sub critical system Linac. AB - Two compact intense 2.45 GHz permanent magnet proton sources and their corresponding low energy beam transport (LEBT) system were developed successfully for China accelerator driven sub-critical system in 2014. Both the proton sources operate at 35 kV potential. The beams extracted from the ion source are transported by the LEBT, which is composed of two identical solenoids, to the 2.1 MeV Radio-Frequency Quadrupole (RFQ). In order to ensure the safety of the superconducting cavities during commissioning, an electrostatic-chopper has been designed and installed in the LEBT line that can chop the continuous wave beam into a pulsed one. The minimum width of the pulse is less than 10 MUs and the fall/rise time of the chopper is about 20 ns. The performance of the proton source and the LEBT, such as beam current, beam profile, emittance and the impact to RFQ injection will be presented. PMID- 26932076 TI - Beam imaging in the injection line of the INFN-LNS superconducting cyclotron. AB - A cheap and efficient diagnostic system for beam monitoring has been recently developed at INFN-LNS in Catania. It consists of a high sensitivity CCD camera detecting the light produced by an ion beam hitting the surface of a scintillating screen and a frame grabber for image acquisition. A scintillating screen, developed at INFN-LNS and consisting of a 2 MUm BaF2 layer evaporated on an aluminium plate, has been tested by using (20)Ne and (40)Ar beams in the keV energy range. The CAESAR ECR ion source has been used for investigating the influence of the frequency and magnetic field tuning effects, the impact of the microwave injected power, and of the focusing solenoids along the low energy beam transport on the beam shape and current. These tests will allow to better understand the interplay between the plasma and beam dynamics and, moreover, to improve the transport efficiency along the low energy beam line and the matching with the superconducting cyclotron, particularly relevant in view of the expected upgrade of the machine. PMID- 26932077 TI - Particle transport and heat loads in NIO1. AB - NIO1 is a compact radio frequency ion source designed to generate a 60 kV-135 mA hydrogen negative ion beam and it aims at continuous operation, which implies a detailed thermo-mechanical analysis of the beam-facing components, in particular, the accelerator grids. A 3D analysis of the entire NIO1 beam has been performed for the first time with a fully 3D version of EAMCC, a relativistic particle tracking code for the calculation of the grid power deposition induced by particle impacts. According to the results presented in this paper, secondary and co-extracted electrons cause a non-negligible heat load on the grids, where different high-power density regions, within reasonable sustainable standard limits, are calculated. PMID- 26932078 TI - Overview of ion source characterization diagnostics in INTF. AB - INdian Test Facility (INTF) is envisaged to characterize ITER diagnostic neutral beam system and to establish the functionality of its eight inductively coupled RF plasma driver based negative hydrogen ion source and its beamline components. The beam quality mainly depends on the ion source performance and therefore, its diagnostics plays an important role for its safe and optimized operation. A number of diagnostics are planned in INTF to characterize the ion source performance. Negative ions and its cesium contents in the source will be monitored by optical emission spectroscopy (OES) and cavity ring down spectroscopy. Plasma near the extraction region will be studied using standard electrostatic probes. The beam divergence and negative ion stripping losses are planned to be measured using Doppler shift spectroscopy. During initial phase of ion beam characterization, carbon fiber composite based infrared imaging diagnostics will be used. Safe operation of the beam will be ensured by using standard thermocouples and electrical voltage-current measurement sensors. A novel concept, based on plasma density dependent plasma impedance measurement using RF electrical impedance matching parameters to characterize the RF driver plasma, will be tested in INTF and will be validated with OES data. The paper will discuss about the overview of the complete INTF diagnostics including its present status of procurement, experimentation, interface with mechanical systems in INTF, and integration with INTF data acquisition and control systems. PMID- 26932079 TI - Design and fabrication of a duoplasmatron extraction geometry and LEBT for the LANSCE H+ RFQ project. AB - The 750-keV H(+) Cockcroft-Walton at LANSCE will be replaced with a recently fabricated 4-rod Radio Frequency Quadrupole (RFQ) with injection energy of 35 keV. The existing duoplasmatron source extraction optics need to be modified to produce up to 35 mA of H(+) current with an emittance <0.02 pi-cm-mrad (rms, norm) for injection into the RFQ. Parts for the new source have been fabricated and assembly is in process. We will use the existing duoplasmatron source with a newly designed extraction system and low energy beam transport (LEBT) for beam injection into the RFQ. In addition to source modifications, we need a new LEBT for transport and matching into the RFQ. The LEBT uses two magnetic solenoids with enough drift space between them to accommodate diagnostics and a beam deflector. The LEBT is designed to work over a range of space-charge neutralized currents and emittances. The LEBT is optimized in the sense that it minimizes the beam size in both solenoids for a point design of a given neutralized current and emittance. Special attention has been given to estimating emittance growth due to source extraction optics and solenoid aberrations. Examples of source-to-RFQ matching and emittance growth (due to both non-linear space charge and solenoid aberrations) are presented over a range of currents and emittances about the design point. A mechanical layout drawing will be presented along with the status of the source and LEBT, design, and fabrication. PMID- 26932080 TI - Optics of the NIFS negative ion source test stand by infrared calorimetry and numerical modelling. AB - At National Institute for Fusion Science (NIFS), a multi-ampere negative ion source is used to support the R&D on H(-) production, extraction, and acceleration. In this contribution, we study the characteristics of the acceleration system of this source, in order to characterize the beam optics at different operational conditions. A dedicated experimental campaign was carried out at NIFS, using as main diagnostic the infra-red imaging of the beam profiles. The experimental measurements are also compared with 3D numerical simulations, in order to validate the codes and to assess their degree of reliability. The simulations show a satisfactory agreement with the experimental results. PMID- 26932081 TI - Microwave frequency sweep interferometer for plasma density measurements in ECR ion sources: Design and preliminary results. AB - The Electron Cyclotron Resonance Ion Sources (ECRISs) development is strictly related to the availability of new diagnostic tools, as the existing ones are not adequate to such compact machines and to their plasma characteristics. Microwave interferometry is a non-invasive method for plasma diagnostics and represents the best candidate for plasma density measurement in hostile environment. Interferometry in ECRISs is a challenging task mainly due to their compact size. The typical density of ECR plasmas is in the range 10(11)-10(13) cm(-3) and it needs a probing beam wavelength of the order of few centimetres, comparable to the chamber radius. The paper describes the design of a microwave interferometer developed at the LNS-INFN laboratories based on the so-called "frequency sweep" method to filter out the multipath contribution in the detected signals. The measurement technique and the preliminary results (calibration) obtained during the experimental tests will be presented. PMID- 26932082 TI - Simulation study of LEBT for transversely coupled beam from an ECR ion source. AB - A Low-Energy intense-highly charged ion Accelerator Facility (LEAF) program has been launched at Institute of Modern Physics. This accelerator facility consists of a superconducting Electron Cyclotron Resonance (ECR) ion source, a Low Energy Beam Transport (LEBT) system, and a Radio Frequency Quadrupole (RFQ). It is especially of interest for the extracted ion beam from the ECR ion source, which is transversely coupled, and this property will significantly affect the beam transmission in the LEBT line and the matching with the downstream RFQ. In the beam transport design of LEAF, beam decoupling in the LEBT is considered to lower down the projection emittances and the feasibility of the design has been verified by beam simulation with a transversely coupled beam from the ECR ion source. PMID- 26932083 TI - Beam dynamics simulations of post low energy beam transport section in RAON heavy ion accelerator. AB - RAON (Rare isotope Accelerator Of Newness) heavy ion accelerator of the rare isotope science project in Daejeon, Korea, has been designed to accelerate multiple-charge-state beams to be used for various science programs. In the RAON accelerator, the rare isotope beams which are generated by an isotope separation on-line system with a wide range of nuclei and charges will be transported through the post Low Energy Beam Transport (LEBT) section to the Radio Frequency Quadrupole (RFQ). In order to transport many kinds of rare isotope beams stably to the RFQ, the post LEBT should be devised to satisfy the requirement of the RFQ at the end of post LEBT, simultaneously with the twiss parameters small. We will present the recent lattice design of the post LEBT in the RAON accelerator and the results of the beam dynamics simulations from it. In addition, the error analysis and correction in the post LEBT will be also described. PMID- 26932084 TI - Upgrade of the beam extraction system of the GTS-LHC electron cyclotron resonance ion source at CERN. AB - Linac3 is the first accelerator in the heavy ion injector chain of the Large Hadron Collider (LHC), providing multiply charged heavy ion beams for the CERN experimental program. The ion beams are produced with GTS-LHC, a 14.5 GHz electron cyclotron resonance ion source, operated in afterglow mode. Improvement of the GTS-LHC beam formation and beam transport along Linac3 is part of the upgrade program of the injector chain in preparation for the future high luminosity LHC. A mismatch between the ion beam properties in the ion source extraction region and the acceptance of the following Low Energy Beam Transport (LEBT) section has been identified as one of the factors limiting the Linac3 performance. The installation of a new focusing element, an einzel lens, into the GTS-LHC extraction region is foreseen as a part of the Linac3 upgrade, as well as a redesign of the first section of the LEBT. Details of the upgrade and results of a beam dynamics study of the extraction region and LEBT modifications will be presented. PMID- 26932085 TI - Preliminary results concerning the simulation of beam profiles from extracted ion current distributions for mini-STRIKE. AB - The Radio Frequency (RF) negative hydrogen ion source prototype has been chosen for the ITER neutral beam injectors due to its optimal performances and easier maintenance demonstrated at Max-Planck-Institut fur Plasmaphysik, Garching in hydrogen and deuterium. One of the key information to better understand the operating behavior of the RF ion sources is the extracted negative ion current density distribution. This distribution-influenced by several factors like source geometry, particle drifts inside the source, cesium distribution, and layout of cesium ovens-is not straightforward to be evaluated. The main outcome of the present contribution is the development of a minimization method to estimate the extracted current distribution using the footprint of the beam recorded with mini STRIKE (Short-Time Retractable Instrumented Kalorimeter). To accomplish this, a series of four computational models have been set up, where the output of a model is the input of the following one. These models compute the optics of the ion beam, evaluate the distribution of the heat deposited on the mini-STRIKE diagnostic calorimeter, and finally give an estimate of the temperature distribution on the back of mini-STRIKE. Several iterations with different extracted current profiles are necessary to give an estimate of the profile most compatible with the experimental data. A first test of the application of the method to the BAvarian Test Machine for Negative ions beam is given. PMID- 26932086 TI - Modeling of the charge-state separation at ITEP experimental facility for material science based on a Bernas ion source. AB - The experiment automation system is supposed to be developed for experimental facility for material science at ITEP, based on a Bernas ion source. The program CAMFT is assumed to be involved into the program of the experiment automation. CAMFT is developed to simulate the intense charged particle bunch motion in the external magnetic fields with arbitrary geometry by means of the accurate solution of the particle motion equation. Program allows the consideration of the bunch intensity up to 10(10) ppb. Preliminary calculations are performed at ITEP supercomputer. The results of the simulation of the beam pre-acceleration and following turn in magnetic field are presented for different initial conditions. PMID- 26932087 TI - Study on space charge compensation in negative hydrogen ion beam. AB - Negative hydrogen ion beam can be compensated by the trapping of ions into the beam potential. When the beam propagates through a neutral gas, these ions arise due to gas ionization by the beam ions. However, the high neutral gas pressure may cause serious negative hydrogen ion beam loss, while low neutral gas pressure may lead to ion-ion instability and decompensation. To better understand the space charge compensation processes within a negative hydrogen beam, experimental study and numerical simulation were carried out at Peking University (PKU). The simulation code for negative hydrogen ion beam is improved from a 2D particle-in cell-Monte Carlo collision code which has been successfully applied to H(+) beam compensated with Ar gas. Impacts among ions, electrons, and neutral gases in negative hydrogen beam compensation processes are carefully treated. The results of the beam simulations were compared with current and emittance measurements of an H(-) beam from a 2.45 GHz microwave driven H(-) ion source in PKU. Compensation gas was injected directly into the beam transport region to modify the space charge compensation degree. The experimental results were in good agreement with the simulation results. PMID- 26932088 TI - Prototyping of beam position monitor for medium energy beam transport section of RAON heavy ion accelerator. AB - A heavy ion accelerator, RAON is going to be built by Rare Isotope Science Project in Korea. Its target is to accelerate various stable ions such as uranium, proton, and xenon from electron cyclotron resonance ion source and some rare isotopes from isotope separation on-line. The beam shaping, charge selection, and modulation should be applied to the ions from these ion sources because RAON adopts a superconducting linear accelerator structure for beam acceleration. For such treatment, low energy beam transport, radio frequency quadrupole, and medium energy beam transport (MEBT) will be installed in injector part of RAON accelerator. Recently, development of a prototype of stripline beam position monitor (BPM) to measure the position of ion beams in MEBT section is under way. In this presentation, design of stripline, electromagnetic (EM) simulation results, and RF measurement test results obtained from the prototyped BPM will be described. PMID- 26932089 TI - Simulation of space charge compensation in a multibeamlet negative ion beam. AB - Ion beam space charge compensation occurs by cumulating in the beam potential well charges having opposite polarity, usually generated by collisional processes. In this paper we investigate the case of a H(-) ion beam drift, in a bi-dimensional approximation of the NIO1 (Negative Ion Optimization phase 1) negative ion source. H(-) beam ion transport and plasma formation are studied via particle-in-cell simulations. Differential cross sections are sampled to determine the velocity distribution of secondary particles generated by ionization of the residual gas (electrons and slow H2 (+) ions) or by stripping of the beam ions (electrons, H, and H(+)). The simulations include three beamlets of a horizontal section, so that multibeamlet space charge and secondary particle diffusion between separate generation regions are considered, and include a repeller grid biased at various potentials. Results show that after the beam space charge is effectively screened by the secondary plasma in about 3 MUs (in agreement with theoretical expectations), a plasma grows across the beamlets with a characteristic time three times longer, and a slight overcompensation of the electric potential is verified as expected in the case of negative ions. PMID- 26932090 TI - Effect of Coulomb collision on the negative ion extraction mechanism in negative ion sources. AB - To improve the H(-) ion beam optics, it is necessary to understand the energy relaxation process of surface produced H(-) ions in the extraction region of Cs seeded H(-) ion sources. Coulomb collisions of charged particles have been introduced to the 2D3V-PIC (two dimension in real space and three dimension in velocity space particle-in-cell) model for the H(-) extraction by using the binary collision model. Due to Coulomb collision, the lower energy part of the ion energy distribution function of H(-) ions has been greatly increased. The mean kinetic energy of the surface produced H(-) ions has been reduced to 0.65 eV from 1.5 eV. It has been suggested that the beam optics of the extracted H(-) ion beam is strongly affected by the energy relaxation process due to Coulomb collision. PMID- 26932091 TI - Beam simulation studies of ECR beam extraction and low energy beam transport for FRIB. AB - To meet the beam power requirements of 400 kW at the fragmentation target for facility for Rare Isotope Beams (FRIB), simultaneous acceleration of two-charge states should be used for heavier ions. These intense multi-charged ion beams will be produced by a 28 GHz electron cyclotron resonance (ECR) ion source at a high voltage of 35 kV. After extraction, the ion beam will be pre-accelerated to 12 keV/u with a 50 kV platform, transported down to an achromatic charge state selection (CSS) system followed by a vertical transport line, and then injected into a radio frequency quadrupole accelerator. The TRACK code developed at ANL is used to perform the simulations of the ECR beam extraction and low energy beam transport for FRIB. In this study, we include the magnetic field of ECR ion source into simulations. Different initial beam conditions as well as different space charge neutralization levels are tested for the ECR beamline. The beam loss in CSS system and the corresponding protective measures are discussed. The detailed results about the beam dynamic simulation and beam loss in CSS system will be presented in this paper. PMID- 26932092 TI - Development of a pepper-pot emittance meter for diagnostics of low-energy multiply charged heavy ion beams extracted from an ECR ion source. AB - Several fluorescent materials were tested for use in the imaging screen of a pepper-pot emittance meter that is suitable for investigating the beam dynamics of multiply charged heavy ions extracted from an ECR ion source. SiO2 (quartz), KBr, Eu-doped CaF2, and Tl-doped CsI crystals were first irradiated with 6.52-keV protons to determine the effects of radiation damage on their fluorescence emission properties. For such a low-energy proton beam, only the quartz was found to be a suitable fluorescent material, since the other materials suffered a decay in fluorescence intensity with irradiation time. Subsequently, quartz was irradiated with heavy (12)C(4+), (16)O(4+), and (40)Ar(11+) ions, but it was found that the fluorescence intensity decreased too rapidly to measure the emittance of these heavy-ion beams. These results suggest that a different energy loss mechanism occurs for heavier ions and for protons. PMID- 26932093 TI - Transportation of a radioactive ion beam for precise laser-trapping experiments. AB - Francium is the heaviest species among the alkali elements. Due to its properties, francium is said to be of advantage in measurements of tiny observations, such as atomic parity violation and electric dipole moment. Before executing experiments with francium, it must be produced artificially because it is one of the most unstable elements. We produced francium with the nuclear fusion reaction of an oxygen beam and gold target, ionized the produced francium through a thermal ionization process, and extracted the ion with electrostatic fields. However, the thermal ionization process is known to ionize not only an objective atom but also other atomic species. Therefore, a Wien filter was installed to analyze the composition of the ion beam and purify the beam. This allowed us to improve the beam purity from ~10(-6) to ~10(-3). PMID- 26932094 TI - Study of electron current extraction from a radio frequency plasma cathode designed as a neutralizer for ion source applications. AB - Plasma cathodes are insert free devices that are developed to be employed as electron sources in electric propulsion and ion source applications as practical alternatives to more commonly used hollow cathodes. Inductively coupled plasma cathodes, or Radio Frequency (RF) plasma cathodes, are introduced in recent years. Because of its compact geometry, and simple and efficient plasma generation, RF plasma source is considered to be suitable for plasma cathode applications. In this study, numerous RF plasma cathodes have been designed and manufactured. Experimental measurements have been conducted to study the effects of geometric and operational parameters. Experimental results of this study show that the plasma generation and electron extraction characteristics of the RF plasma cathode device strongly depend on the geometric parameters such as chamber diameter, chamber length, orifice diameter, orifice length, as well as the operational parameters such as RF power and gas mass flow rate. PMID- 26932095 TI - Studies of the beam extraction system of the GTS-LHC electron cyclotron resonance ion source at CERN. AB - The 14.5 GHz GTS-LHC Electron Cyclotron Resonance Ion Source (ECRIS) provides multiply charged heavy ion beams for the CERN experimental program. The GTS-LHC beam formation has been studied extensively with lead, argon, and xenon beams with varied beam extraction conditions using the ion optical code IBSimu. The simulation model predicts self-consistently the formation of triangular and hollow beam structures which are often associated with ECRIS ion beams, as well as beam loss patterns which match the observed beam induced markings in the extraction region. These studies provide a better understanding of the properties of the extracted beams and a way to diagnose the extraction system performance and limitations, which is otherwise challenging due to the lack of direct diagnostics in this region and the limited availability of the ion source for development work. PMID- 26932096 TI - Extraction characteristics of a low-energy ion beam system with a remote plasma chamber. AB - Low-energy argon beams were extracted from a dual-chamber ion source system. The first chamber is a quartz cylinder where dense inductively coupled plasmas were produced using 13.56 MHz radio frequency (rf) power. The discharge was driven into an adjacent chamber which acts as a reservoir for ion beam extraction using a dual-electrode extractor configuration. Extraction of ions from the second chamber with energies in the 100 eV range was achieved while minimizing fluctuations induced by the rf signal. A custom-built retarding potential analyzer was used to analyze the effectiveness of ion beam transport using the remote plasma chamber. Well-defined beams were extracted between 60 and 100 V extraction potentials at 50-100 W rf powers. An increase in rf power resulted in an increase in average ion energy, increase in ion current density while the energy spread remains constant. PMID- 26932097 TI - Castellated tiles as the beam-facing components for the diagnostic calorimeter of the negative ion source SPIDER. AB - This paper presents the results of numerical simulations and experimental tests carried out to assess the feasibility and suitability of graphite castellated tiles as beam-facing component in the diagnostic calorimeter of the negative ion source SPIDER (Source for Production of Ions of Deuterium Extracted from Radio frequency plasma). The results indicate that this concept could be a reliable, although less performing, alternative for the present design based on carbon fiber composite tiles, as it provides thermal measurements on the required spatial scale. PMID- 26932098 TI - Integral electrical characteristics and local plasma parameters of a RF ion thruster. AB - Comprehensive diagnostics has been carried out for a RF ion thruster based on inductively coupled plasma (ICP) source with an external flat antenna coil enhanced by ferrite core. The ICP was confined within a cylindrical chamber with low aspect ratio to minimize plasma loss to the chamber wall. Integral diagnostics of the ICP electrical parameters (RF power balance and coil current) allowed for evaluation of the antenna coils, matching networks, and eddy current loss and the true RF power deposited to plasma. Spatially resolved electron energy distribution functions, plasma density, electron temperatures, and plasma potentials were measured with movable Langmuir probes. PMID- 26932099 TI - Numerical simulations of the first operational conditions of the negative ion test facility SPIDER. AB - In view of the realization of the negative ion beam injectors for ITER, a test facility, named SPIDER, is under construction in Padova (Italy) to study and optimize production and extraction of negative ions. The present paper is devoted to the analysis of the expected first operations of SPIDER in terms of single beamlet and multiple-beamlet simulations of the hydrogen beam optics in various operational conditions. The effectiveness of the methods adopted to compensate for the magnetic deflection of the particles is also assessed. Indications for a sequence of the experimental activities are obtained. PMID- 26932100 TI - Developments of fast emittance monitors for ion sources at RCNP. AB - Recently, several developments of low energy beam transport line and its beam diagnostic systems have been performed to improve the injection efficiency of ion beam to azimuthally varying field cyclotron at Research Center for Nuclear Physics, Osaka University. One of those is the fast emittance monitor which can measure within several seconds for the efficient beam development and a Pepper Pot Emittance Monitor (PPEM) has been developed. The PPEM consists of pepper-pot mask, multichannel plate, fluorescent screen, mirror, and CCD camera. The CCD image is taken via IEEE1394b to a personal computer and analyzed immediately and frequently, and then real time measurement with about 2 Hz has been achieved. PMID- 26932101 TI - Preliminary design of a RFQ direct injection scheme for the IsoDAR high intensity H2+ cyclotron. AB - IsoDAR (Isotope Decay-At-Rest) is a novel experiment designed to measure neutrino oscillations through nu(e) disappearance, thus providing a definitive search for sterile neutrinos. In order to generate the necessary anti-neutrino flux, a high intensity primary proton beam is needed. In IsoDAR, H2(+) is accelerated and is stripped into protons just before the target, to overcome space charge issues at injection. As part of the design, we have refined an old proposal to use a RFQ to axially inject bunched H2(+) ions into the driver cyclotron. This method has several advantages over a classical low energy beam transport (LEBT) design: (1) The bunching efficiency is higher than for the previously considered two-gap buncher and thus the overall injection efficiency is higher. This relaxes the constraints on the H2(+) current required from the ion source. (2) The overall length of the LEBT can be reduced. (3) The RFQ can also accelerate the ions. This enables the ion source platform high voltage to be reduced from 70 kV to 15 kV, making underground installation easier. We are presenting the preliminary RFQ design parameters and first beam dynamics simulations from the ion source to the spiral inflector entrance. PMID- 26932102 TI - Effects of a dielectric material in an ion source on the ion beam current density and ion beam energy. AB - To understand a strong focusing phenomenon that occurs in a low-energy hydrogen ion beam, the electron temperature, the electron density, and the space potential in an ion source with cusped magnetic fields are measured before and after the transition to the focusing state using an electrostatic probe. The experimental results show that no significant changes are observed before or after the transition. However, we found unique phenomena that are characterized by the position of the electrostatic probe in the ion source chamber. Specifically, the extracted ion beam current density and energy are obviously enhanced in the case where the electrostatic probe, which is covered by a dielectric material, is placed close to an acceleration electrode. PMID- 26932103 TI - Preliminary design of electrostatic sensors for MITICA beam line components. AB - Megavolt ITER Injector and Concept Advancement, the full-scale prototype of ITER neutral beam injector, is under construction in Italy. The device will generate deuterium negative ions, then accelerated and neutralized. The emerging beam, after removal of residual ions, will be dumped onto a calorimeter. The presence of plasma and its parameters will be monitored in the components of the beam line, by means of specific electrostatic probes. Double probes, with the possibility to be configured as Langmuir probes and provide local ion density and electron temperature measurements, will be employed in the neutralizer and in the residual ion dump. Biased electrodes collecting secondary emission electrons will be installed in the calorimeter with the aim to provide a horizontal profile of the beam. PMID- 26932104 TI - Analysis of diagnostic calorimeter data by the transfer function technique. AB - This paper describes the analysis procedure applied to the thermal measurements on the rear side of a carbon fibre composite calorimeter with the purpose of reconstructing the energy flux due to an ion beam colliding on the front side. The method is based on the transfer function technique and allows a fast analysis by means of the fast Fourier transform algorithm. Its efficacy has been tested both on simulated and measured temperature profiles: in all cases, the energy flux features are well reproduced and beamlets are well resolved. Limits and restrictions of the method are also discussed, providing strategies to handle issues related to signal noise and digital processing. PMID- 26932105 TI - Development of an ion beam analyzing system for the KBSI heavy-ion accelerator. AB - The Korea Basic Science Institute (KBSI) has been developing a heavy ion accelerator system to accelerate high current, multi-charge state ions produced by a 28 GHz superconducting electron cyclotron ion source. A beam analyzing system as a part of the low energy beam transport apparatus was developed to select charged particles with desirable charge states from the ion beams. The desired species of ion, which is generated and extracted from the ECR ion source including various ion particles, can be selected by 90 degrees dipole electromagnet. Due to the non-symmetrical structure in the coil as well as the non-linear permeability of the yoke material coil, a three dimensional analysis was carried out to confirm the design parameters. In this paper, we present the experimental results obtained as result of an analysis of KBSI accelerator. The effectiveness of beam selection was confirmed during the test of the analyzing system by injecting an ion beam from an ECR ion source. PMID- 26932106 TI - Progress of beam diagnosis system for EAST neutral beam injector. AB - Neutral beam injection has been recognized as one of the most effective means for plasma heating. According to the research plan of the EAST physics experiment, two sets of neutral beam injector (NBI) were built and operational in 2014. The paper presents the development of beam diagnosis system for EAST NBI and the latest experiment results obtained on the test-stand and EAST-NBI-1 and 2. The results show that the optimal divergence angle is (0.62 degrees , 1.57 degrees ) and the full energy particle is up to 77%. They indicate that EAST NBI work properly and all targets reach or almost reach the design targets. All these lay a solid foundation for the achievement of high quality plasma heating for EAST. PMID- 26932107 TI - Charge neutralized low energy beam transport at Brookhaven 200 MeV linac. AB - The H(-) magnetron source provides about 100 mA H(-) beam to be match into the radio-frequency quadrupole accelerator. As H(-) beam traverses through low energy transport, it ionizes the residual gas and electrons are repelled and positive ions are trapped in the beam, due to negative potential of the beam, providing charge neutralization for the H(-) beam. The neutralization time for the critical density depends upon the background gas and its pressure. Critical density for xenon gas at 35 keV is about 43 times smaller than that of hydrogen and stripping cross section is only 5 times than that of hydrogen gas. We are using xenon gas to reduce neutralization time and to improve transmission through the 200 MeV linac. We are also using pulse nitrogen gas to improve transmission and stability of polarized H(-) beam from optically pumped polarized ion source. PMID- 26932108 TI - Negative ion production and beam extraction processes in a large ion source (invited). AB - Recent research results on negative-ion-rich plasmas in a large negative ion source have been reviewed. Spatial density and flow distributions of negative hydrogen ions (H(-)) and positive hydrogen ions together with those of electrons are investigated with a 4-pin probe and a photodetachment (PD) signal of a Langmuir probe. The PD signal is converted to local H(-) density from signal calibration to a scanning cavity ring down PD measurement. Introduction of Cs changes the slope of plasma potential local distribution depending upon the plasma grid bias. A higher electron density H2 plasma locally shields the bias potential and behaves like a metallic free electron gas. On the other hand, the bias and extraction electric fields penetrate in a Cs-seeded electronegative plasma even when the electron density is similar. Electrons are transported by the penetrated electric fields from the driver region along and across the filter and electron deflection magnetic fields. Plasma ions exhibited a completely different response against the penetration of electric fields. PMID- 26932109 TI - Beam transport and space charge compensation strategies (invited). AB - The transport of intense ion beams is affected by the collective behavior of this kind of multi-particle and multi-species system. The space charge expressed by the generalized perveance dominates the dynamical process of thermalisation, which leads to emittance growth. To prevent changes of intrinsic beam properties and to reduce the intensity dependent focusing forces, space charge compensation seems to be an adequate solution. In the case of positively charged ion beams, electrons produced by residual gas ionization and secondary electrons provide the space charge compensation. The influence of the compensation particles on the beam transport and the local degree of space charge compensation is given by different beam properties as well as the ion beam optics. Especially for highly charged ion beams, space charge compensation in combination with poor vacuum conditions leads to recombination processes and therefore increased beam losses. Strategies for providing a compensation-electron reservoir at very low residual gas pressures will be discussed. PMID- 26932110 TI - Investigation of ion beam space charge compensation with a 4-grid analyzer. AB - Experiments to investigate the space charge compensation of pulsed high-current heavy ion beams are performed at the GSI ion source text benches with a 4-grid analyzer provided by CEA/Saclay. The technical design of the 4-grid analyzer is revised to verify its functionality for measurements at pulsed high-current heavy ion beams. The experimental investigation of space charge compensation processes is needed to increase the performance and quality of current and future accelerator facilities. Measurements are performed directly downstream a triode extraction system mounted to a multi-cusp ion source at a high-current test bench as well as downstream the post-acceleration system of the high-current test injector (HOSTI) with ion energies up to 120 keV/u for helium and argon. At HOSTI, a cold or hot reflex discharge ion source is used to change the conditions for the measurements. The measurements were performed with helium, argon, and xenon and are presented. Results from measurements with single aperture extraction systems are shown. PMID- 26932111 TI - Overview of the negative ion based neutral beam injectors for ITER. AB - The ITER baseline foresees 2 Heating Neutral Beams (HNB's) based on 1 MeV 40 A D( ) negative ion accelerators, each capable of delivering 16.7 MW of deuterium atoms to the DT plasma, with an optional 3rd HNB injector foreseen as a possible upgrade. In addition, a dedicated diagnostic neutral beam will be injecting ~22 A of H(0) at 100 keV as the probe beam for charge exchange recombination spectroscopy. The integration of the injectors into the ITER plant is nearly finished necessitating only refinements. A large number of components have passed the final design stage, manufacturing has started, and the essential test beds for the prototype route chosen-will soon be ready to start. PMID- 26932112 TI - Surface modification of ferritic steels using MEVVA and duoplasmatron ion sources. AB - Metal Vapor Vacuum Arc (MEVVA) ion source (IS) is a unique tool for production of high intensity metal ion beam that can be used for material surface modification. From the other hand, the duoplasmatron ion source provides the high intensity gas ion beams. The MEVVA and duoplasmatron IS developed in Institute for Theoretical and Experimental Physics were used for the reactor steel surface modification experiments. Response of ferritic-martensitic steel specimens on titanium and nitrogen ions implantation and consequent vacuum annealing was investigated. Increase in microhardness of near surface region of irradiated specimens was observed. Local chemical analysis shows atom mixing and redistribution in the implanted layer followed with formation of ultrafine precipitates after annealing. PMID- 26932113 TI - Low-energy ion beam-based deposition of gallium nitride. AB - An ion source with a remote plasma chamber excited by a 13.56 MHz radio frequency power was used for low-energy broad ion beam extraction. Optical emission spectral analyses showed the sputtering and postionization of a liquid gallium (Ga) target placed in a chamber separated from the source bombarded by argon (Ar) plasma guided by a bent magnetic field. In addition, an E * B probe successfully showed the extraction of low-energy Ga and Ar ion beams using a dual-electrode extractor configuration. By introducing dilute amounts of nitrogen gas into the system, formation of thin Ga-based films on a silicon substrate was demonstrated as determined from X-ray diffraction and X-ray reflectivity studies. PMID- 26932114 TI - Development of a long-slot microwave plasma source. AB - A 20 cm long 10 cm wide microwave plasma source was realized by inserting two 20 cm long 1.5 mm diameter rod antennas into the plasma. Plasma luminous distributions around the antennas were changed by magnetic field arrangement created by permanent magnets attached to the source. The distributions appeared homogeneous in one direction along the antenna when the spacing between the antenna and the source wall was 7.5 mm for the input microwave frequency of 2.45 GHz. Plasma density and temperature at a plane 20 cm downstream from the microwave shield were measured by a Langmuir probe array at 150 W microwave power input. The measured electron density and temperature varied over space from 3.0 * 10(9) cm(-3) to 5.8 * 10(9) cm(-3), and from 1.1 eV to 2.1 eV, respectively. PMID- 26932115 TI - Compact RF ion source for industrial electrostatic ion accelerator. AB - Korea Multi-purpose Accelerator Complex is developing a single-ended electrostatic ion accelerator to irradiate gaseous ions, such as hydrogen and nitrogen, on materials for industrial applications. ELV type high voltage power supply has been selected. Because of the limited space, electrical power, and robust operation, a 200 MHz RF ion source has been developed. In this paper, the accelerator system, test stand of the ion source, and its test results are described. PMID- 26932116 TI - Dust particle diffusion in ion beam transport region. AB - Dust particles of MUm size produced by a monoplasmatron ion source are observed by a laser light scattering. The scattered light signal from an incident laser at 532 nm wavelength indicates when and where a particle passes through the ion beam transport region. As the result, dusts with the size more than 10 MUm are found to be distributed in the center of the ion beam, while dusts with the size less than 10 MUm size are distributed along the edge of the ion beam. Floating potential and electron temperature at beam transport region are measured by an electrostatic probe. This observation can be explained by a charge up model of the dust in the plasma boundary region. PMID- 26932117 TI - Recent developments of ion sources for life-science studies at the Heavy Ion Medical Accelerator in Chiba (invited). AB - With about 1000-h of relativistic high-energy ion beams provided by Heavy Ion Medical Accelerator in Chiba, about 70 users are performing various biology experiments every year. A rich variety of ion species from hydrogen to xenon ions with a dose rate of several Gy/min is available. Carbon, iron, silicon, helium, neon, argon, hydrogen, and oxygen ions were utilized between 2012 and 2014. Presently, three electron cyclotron resonance ion sources (ECRISs) and one Penning ion source are available. Especially, the two frequency heating techniques have improved the performance of an 18 GHz ECRIS. The results have satisfied most requirements for life-science studies. In addition, this improved performance has realized a feasible solution for similar biology experiments with a hospital-specified accelerator complex. PMID- 26932118 TI - Development of a microwave ion source for ion implantations. AB - A microwave ion source is expected to have a long lifetime, as it has fewer consumables. Thus, we are in the process of developing a microwave ion source for ion implantation applications. In this paper, we report on a newly developed plasma chamber and the extracted P(+) beam currents. The volume of the plasma chamber is optimized by varying the length of a boron nitride block installed within the chamber. The extracted P(+) beam current is more than 30 mA, at a 25 kV acceleration voltage, using PH3 gas. PMID- 26932119 TI - Development of C6+ laser ion source and RFQ linac for carbon ion radiotherapy. AB - A prototype C(6+) injector using a laser ion source has been developed for a compact synchrotron dedicated to carbon ion radiotherapy. The injector consists of a laser ion source and a 4-vane radio-frequency quadrupole (RFQ) linac. Ion beams are extracted from plasma and directly injected into the RFQ. A solenoid guides the low-energy beams into the RFQ. The RFQ is designed to accelerate high intensity pulsed beams. A structure of monolithic vanes and cavities is adopted to reduce its power consumption. In beam acceleration tests, a solenoidal magnetic field set between the laser ion source and the RFQ helped increase both the peak currents before and after the RFQ by a factor of 4. PMID- 26932120 TI - Development of a compact ECR ion source for various ion production. AB - There is a desire that a carbon-ion radiotherapy facility will produce various ion species for fundamental research. Although the present Kei2-type ion sources are dedicated for the carbon-ion production, a future ion source is expected that could provide: (1) carbon-ion production for medical use, (2) various ions with a charge-to-mass ratio of 1/3 for the existing Linac injector, and (3) low cost for modification. A prototype compact electron cyclotron resonance (ECR) ion source, named Kei3, based on the Kei series has been developed to correspond to the Kei2 type and to produce these various ions at the National Institute of Radiological Sciences (NIRS). The Kei3 has an outer diameter of 280 mm and a length of 1120 mm. The magnetic field is formed by the same permanent magnet as Kei2. The movable extraction electrode has been installed in order to optimize the beam extraction with various current densities. The gas-injection side of the vacuum chamber has enough space for an oven system. We measured dependence of microwave frequency, extraction voltage, and puller position. Charge state distributions of helium, carbon, nitrogen, oxygen, and neon were also measured. PMID- 26932122 TI - Promising electron mobility and high thermal conductivity in Sc2CT2 (T = F, OH) MXenes. AB - MXenes, the new 2D transition metal carbides and nitrides, have recently attracted extensive attention due to their diverse applications and excellent performances. However, the thermal and electrical properties of most MXene materials are yet to be studied. In this work, we investigate the electrical and thermal properties of semiconducting Sc2CT2 (T = F, OH) MXenes using first principles calculations. Both of the Sc2CT2 (T = F, OH) MXenes are determined to show excellent carrier mobilities. The electron mobility in the Sc2CF2 MXene is found to be strongly anisotropic at room temperature, with values of 5.03 * 10(3) and 1.07 * 10(3) cm(2) V(-1) s(-1) in the zigzag and armchair directions, respectively. The predicted electron mobility in the zigzag direction of the Sc2CF2 is nearly four-fold that in the armchair direction of the promising semiconductor phosphorene. In contrast to Sc2CF2, Sc2C(OH)2 presents approximately isotropic electron mobility. The values at room temperature in the zigzag and armchair directions are calculated as 2.06 * 10(3) cm(2) V(-1) s(-1) and 2.19 * 10(3) cm(2) V(-1) s(-1), respectively. In regard to the thermal properties, the thermal conductivities of the Sc2CT2 (T = F, OH) MXenes have been determined. The predicted values are higher than those of most metals and semiconducting low-dimensional materials, such as monolayer MoS2 and phosphorene. In particular, the room-temperature thermal conductivity along the Sc2CF2 armchair direction has been determined to be as high as 472 W m(-1) K(-1) based on a flake length of 5 MUm, which is even higher than that of the best traditional conductor silver. The corresponding value in the zigzag direction of Sc2CF2 is calculated to be 178 W m(-1) K(-1). The thermal conductivity in Sc2C(OH)2 is less anisotropic and lower compared to that in Sc2CF2. The room temperature value in the armchair (zigzag) direction is determined to be 173 W m( 1) K(-1) (107 W m(-1) K(-1)). Based on their excellent electron mobilities and high thermal conductivities, both of the Sc2CT2 (T = F, OH) MXenes could be promising candidate materials for the next generation of electronic devices. PMID- 26932123 TI - Preface. PMID- 26932121 TI - Envirotyping for deciphering environmental impacts on crop plants. AB - Global climate change imposes increasing impacts on our environments and crop production. To decipher environmental impacts on crop plants, the concept "envirotyping" is proposed, as a third "typing" technology, complementing with genotyping and phenotyping. Environmental factors can be collected through multiple environmental trials, geographic and soil information systems, measurement of soil and canopy properties, and evaluation of companion organisms. Envirotyping contributes to crop modeling and phenotype prediction through its functional components, including genotype-by-environment interaction (GEI), genes responsive to environmental signals, biotic and abiotic stresses, and integrative phenotyping. Envirotyping, driven by information and support systems, has a wide range of applications, including environmental characterization, GEI analysis, phenotype prediction, near-iso-environment construction, agronomic genomics, precision agriculture and breeding, and development of a four-dimensional profile of crop science involving genotype (G), phenotype (P), envirotype (E) and time (T) (developmental stage). In the future, envirotyping needs to zoom into specific experimental plots and individual plants, along with the development of high-throughput and precision envirotyping platforms, to integrate genotypic, phenotypic and envirotypic information for establishing a high-efficient precision breeding and sustainable crop production system based on deciphered environmental impacts. PMID- 26932124 TI - The missing cause approach to unmeasured confounding in pharmacoepidemiology. AB - Unmeasured confounding is a major threat to the validity of pharmacoepidemiological studies of medication safety and effectiveness. We propose a new method for detecting and reducing the impact of unobserved confounding in large observational database studies. The method uses assumptions similar to the prescribing preference-based instrumental variable (IV) approach. Our method relies on the new 'missing cause' principle, according to which the impact of unmeasured confounding by (contra-)indication may be detected by assessing discrepancies between the following: (i) treatment actually received by individual patients and (ii) treatment that they would be expected to receive based on the observed data. Specifically, we use the treatment-by-discrepancy interaction to test for the presence of unmeasured confounding and correct the treatment effect estimate for the resulting bias. Under standard IV assumptions, we first proved that unmeasured confounding induces a spurious treatment-by discrepancy interaction in risk difference models for binary outcomes and then simulated large pharmacoepidemiological studies with unmeasured confounding. In simulations, our estimates had four to six times smaller bias than conventional treatment effect estimates, adjusted only for measured confounders, and much smaller variance inflation than unbiased but very unstable IV estimates, resulting in uniformly lowest root mean square errors. The much lower variance of our estimates, relative to IV estimates, was also observed in an application comparing gastrointestinal safety of two classes of anti-inflammatory drugs. In conclusion, our missing cause-based method may complement other methods and enhance accuracy of analyses of large pharmacoepidemiological studies. PMID- 26932125 TI - Real-time PCR identification of lake whitefish Coregonus clupeaformis in the Laurentian Great Lakes. AB - The purpose of this study was to develop a real-time PCR assay to specifically identify lake whitefish Coregonus clupeaformis in larval fish assemblages based on a 122 bp amplicon from the mitochondrial genome. The efficiency of the reaction, as calculated from the standard curve, was 90.77% with the standard curve having an r(2) value of 0.998. Specificity of the assay provided single melt peak in a melt-curve analysis and amplification of only the target species. The assay successfully identified target DNA in as low as 0.1% proportion of a DNA mixture. This assay was designed on the portable Smart Cycler II platform and can be used in both field and laboratory settings to successfully identify C. clupeaformis. PMID- 26932126 TI - Effect of counseling by paraprofessionals on depression, anxiety, somatization, and functioning in Indonesian torture survivors. AB - The Indonesian population has faced political violence, victimization, and torture throughout the last 70 years. Due to the scarcity of mental health professionals in many low and middle-income countries, counseling programs are increasingly utilizing paraprofessionals to provide support to the affected population as a strategy of task shifting. In this article, we would like to examine the effectiveness of counseling services provided by such trained paraprofessionals. This study was part of program evaluation to determine whether the participants (torture survivors) improved after counseling services provided by trained paraprofessionals in Indonesia. Local communities were invited to join the psychosocial program created and implemented by an NGO in 2005. The 178 participants were recruited from Jakarta, Papua, and Aceh, Indonesia for the program, which aimed to help survivors of violence suffering from "heavy hearts." The intervention lasted three months, and the follow-up intake was conducted after four months. The results indicated the participants' anxiety symptoms, depressive symptoms, somatic symptoms, and functioning improved from the intake to the follow-up. The program appeared to have been effective in reducing the participants' symptoms and impairment in functioning. This indicates that in countries where there is a scarcity of mental health professionals, working with paraprofessionals has the potential to help survivors of torture and violence. PMID- 26932127 TI - Geographical distribution of torture: An epidemiological study of torture reported by asylum applicants examined at the Department of Forensic Medicine, University of Copenhagen. AB - Using reports from 154 examinations of alleged torture victims among asylum applicants to Denmark conducted by the Department of Forensic Medicine, University of Copenhagen, between 2001 and 2013, we have categorized the victims into four geographical regions, as well as according to the conflict that caused them to flee. The torture incidents described by the victims were divided into 12 different categories defined by the Istanbul Protocol. These data were cross referenced in order to identify any differences in the prevalence of the 12 forms of torture. The study showed that crush injuries were only reported by refugees from Asia, including Afghanistan and Pakistan, and that incidents of electrical torture were reported twice as frequently by torture victims from Middle Eastern and North African countries, though it was lower among Iraqis, Iranians and ethnic Kurds. Sexual torture was reported by 78% of females and 25% of males. PMID- 26932128 TI - Testimonial Therapy: Impact on social participation and emotional wellbeing among Indian survivors of torture and organized violence. AB - INTRODUCTION: Traumatizing events, such as torture, cause considerable impairments in psycho-social functioning. In developing countries, where torture is often perpetrated, few resources exist for the provision of therapeutic or rehabilitating interventions. The current study investigated the effectiveness of Testimonial Therapy (TT) as a brief psycho-social intervention to ameliorate the distress of Indian survivors of torture and related violence. METHOD: Three outcome measures (the WHO-5 Well-Being Scale, Social Participation-Scale and Pain and Anger Analogue) were compared before and after receiving TT, and semi structured interviews were conducted with survivors who had previously received TT. FINDINGS: Participants showed significant improvements in emotional well being, social participation, and self-perceived pain and anger. Furthermore, three qualitative interviews with survivors indicated that TT had a positive impact at the community level. DISCUSSION: Although the study was conducted without a control group for comparison, TT appeared to be an effective method for improving well-being and ameliorating distress among survivors of torture. Furthermore, TT can potentially promote community empowerment. However, more research on this aspect is needed. PMID- 26932129 TI - Descriptive, inferential, functional outcome data on 9,025 torture survivors over six years in the United States. AB - BACKGROUND: The National Consortium of Torture Treatment Programs conducted a large voluntary research project among torture rehabilitation centers in the United States (US). Its goal is to fill the void in the literature on demographic and diagnostic data of torture survivors across a large country. METHODS: Twenty three centers across the US collaborated over six years, utilizing training and making decisions via conference calls and webinars. A data use agreement signed by all the participating centers governed plans and the use of the data. FINDINGS: This study reports on torture survivors from 125 countries, 109 of which signed the United Nations Convention against Torture (UNCAT). Of the 9,025 torture survivors represented, most came from Africa and Asia and reported an average of 3.5 types of torture. Asylum seekers have different immigration experiences and show significantly higher rates of major depressive disorder (MDD) and posttraumatic stress disorder (PTSD) than refugees. Torture survivors at high risk of PTSD and MDD in this sample reported three or more types of torture, reported rape, and had the immigration status of asylum seeker. At one and two years after beginning treatment, both asylum seekers and refugees reported increased rates of employment and improvements in their immigration status. INTERPRETATION: This longitudinal project provides basic data on a large number of torture survivors who accessed services in the US, and provides a foundation for long-term follow up on immigration status, employment status, diagnostic status, medical diagnoses, and eventually, the effectiveness of treatment for torture survivors in the US. This article shares demographic and diagnostic findings useful for informing programmatic and policy decisions. However, these findings on refugees and asylum seekers in the US may not reflect the experience in other receiving countries. Collaboration with other researchers across continents is required to provide a much needed, more complete picture of torture survivors seeking rehabilitation across the world. PMID- 26932130 TI - Elusive retributive justice in post-Khmer Rouge Cambodia: Challenges of using ECCC Victim Information Forms as a victim participatory rights mechanism. AB - This paper focuses on the procedural challenges of using the Victim Information Forms (VIFs) to analyze survivors' experiences with the Extraordinary Chambers in the Courts of Cambodia (ECCC), commonly known as the Khmer Rouge Tribunal. The paper takes a systematic public/medical sociology approach to examining the VIF as a participatory rights mechanism for victims wishing to pursue justice for themselves and their loved ones who experienced the Khmer Rouge atrocities, torture, forced relocation, starvation, forced labor, rape, robbery, and other physical and psychological torment, firsthand. It provides the first comparative, critical analysis of both the original VIF and the revised form issued midway through the submission period; both forms appear as appendices to the paper. Conclusions are drawn and suggestions made by the researcher based on the firsthand collection and submission of the largest group of VIFs from any single source around the world (outside of Cambodia itself), as well as on support work with victims/survivors during the ECCC proceedings in Phnom Penh, Cambodia in 2013. PMID- 26932131 TI - Transmissibility and Pathogenicity of Ebola Virus: A Systematic Review and Meta analysis of Household Secondary Attack Rate and Asymptomatic Infection. AB - Factors affecting our ability to control an Ebola outbreak include transmissibility of the virus and the proportion of transmissions occurring asymptomatically. We performed a meta-analysis of Ebola household secondary attack rate (SAR), disaggregating by type of exposure (direct contact, no direct contact, nursing care, direct contact but no nursing care). The estimated overall household SAR is 12.5% (95% confidence interval [CI], 8.6%-16.3%). Transmission was driven by direct contact, with little transmission occurring in its absence (SAR, 0.8% [95% CI, 0%-2.3%]). The greatest risk factor was the provision of nursing care (SAR, 47.9% [95% CI, 23.3%-72.6%]). There was evidence of a decline in household SAR for direct contact between 1976 and 2014 (P = .018). We estimate that 27.1% (95% CI, 14.5%-39.6%) of Ebola infections are asymptomatic. Our findings suggest that surveillance and containment measures should be effective for controlling Ebola. PMID- 26932132 TI - Mental Fitness for patients with acute coronary syndrome: A randomized clinical trial. AB - OBJECTIVES: The aim of this study was to verify the efficacy of a manualized, cognitively oriented psychological intervention, called Mental Fitness, in improving the mental and physical health of patients with acute coronary syndrome (ACS). Mental Fitness is a small-group four-session treatment aimed at increasing awareness of one's own bodily perceptions, emotions, and thoughts and is overall tailored on participants' perception of control over their health. DESIGN: Prospective randomized controlled single-blind trial. METHODS: Patients with ACS were recruited within a week from their acute cardiac event. Patients in the intervention group underwent one of two variants of Mental Fitness, depending on their perceived (internal or external) control over their health. Patients in the control group underwent standard treatment. All the patients were submitted to a clinical and psychological follow-up for 8 months. RESULTS: The patients who underwent the Mental Fitness intervention (N = 31) showed, compared to the control patients (N = 34), increased quality of life in its physical, psychological, social and environmental domains, more functional emotional and problem-centred coping strategies, and higher emotional awareness. They also showed improved high-density lipoprotein cholesterol, triglycerides, heart rate, and left ventricular ejection fraction compared to the controls. In addition, they were more successful in maintaining physical exercise. CONCLUSIONS: This study demonstrates the efficacy of Mental Fitness in modifying specific psychological and physical variables conditioning cardiological patients' prognosis. It also confirms the importance of differentiating psychological interventions based on the psychological characteristics of the patients. Statement of contribution What is already known on this subject? Traditional symptom-based interventions in heart disease are aimed at diagnosing and reducing psychological symptomatology (e.g., depression), but recent work has shown the usefulness of orienting psychological interventions to patients' representations of themselves and of the world and to how such representations influence their thoughts, feelings, and behaviours (e.g., Chiavarino et al., ). What does this study add? Mental Fitness, by working on awareness of bodily perceptions, emotions, and thoughts, leads to positive changes in physical and psychological health. Mental Fitness is a cost-effective psychological intervention that adds significantly to the effectiveness of standard medical care. PMID- 26932133 TI - Developmental and Ultrastructural Characterization and Phylogenetic Analysis of Trypanosoma herthameyeri n. sp. of Brazilian Leptodactilydae Frogs. AB - We described the phylogenetic affiliation, development in cultures and ultrastructural features of a trypanosome of Leptodacylus chaquensis from the Pantanal biome of Brazil. In the inferred phylogeny, this trypanosome nested into the Anura clade of the basal Aquatic clade of Trypanosoma, but was separate from all known species within this clade. This finding enabled us to describe it as Trypanosoma herthameyeri n. sp., which also infects other Leptodacylus species from the Pantanal and Caatinga biomes. Trypanosoma herthameyeri multiplies as small rounded forms clumped together and evolving into multiple-fission forms and rosettes of epimastigotes released as long forms with long flagella; scarce trypomastigotes and glove-like forms are common in stationary-phase cultures. For the first time, a trypanosome from an amphibian was observed by field emission scanning electron microscopy, revealing a cytostome opening, well-developed flagellar lamella, and many grooves in pumpkin-like forms. Transmission electron microscopy showed highly developed Golgi complexes, relaxed catenation of KDNA, and a rich set of spongiome tubules in a regular parallel arrangement to the flagellar pocket as confirmed by electron tomography. Considering the basal position in the phylogenetic tree, developmental and ultrastructural data of T. herthameyeri are valuable for evolutionary studies of trypanosome architecture and cell biology. PMID- 26932134 TI - ABO-Nonidentical Liver Transplantation in the United States. AB - Under the United Network for Organ Sharing (UNOS) policy, deceased donor livers may be offered to ABO-nonidentical candidates at each given Model for End-Stage Liver Disease (MELD) score and to blood type B candidates at MELD >=30. To evaluate ABO-nonidentical liver transplantation (LT) in the United States, we examined all adult LT non-status 1 candidates, recipients and deceased liver donors from 2013 to 2015. There were 34 920 LT candidates (47% type O, 38% type A, 12% type B, 3% type AB) and 10 479 deceased liver donors (47% type O, 38% type A, 12% type B, 3% type AB). ABO-nonidentical LT occurred in 2%, 3%, 20% and 36% of types O, A, B and AB recipients, respectively, which led to a net liver loss of 6% for type O and 2% for type A recipients but a net liver gain of 14% for type B and 55% for type AB recipients. The LT MELD scores of ABO-identical versus -nonidentical recipients were 29 versus 34 for type O, 29 versus 19 for type A, 25 versus 38 for type B, and 22 versus 28 for type AB (p < 0.01). ABO nonidentical LT increased liver supply for candidates with blood types B and AB but decreased supply for type O and A candidates. We urge refinement of UNOS policy surrounding ABO-nonidentical LT. PMID- 26932135 TI - Effect of early goal-directed therapy on mortality in patients with severe sepsis or septic shock: a meta-analysis of randomised controlled trials. AB - OBJECTIVE: To determine whether patients with severe sepsis or septic shock could benefit from a strict and early goal-directed therapy (EGDT) protocol recommended by Surviving Sepsis Campaign (SSC) Guidelines. METHODS: MEDLINE/PubMed, EMBASE/OVID and Cochrane Central Register of Controlled Trials (CENTRAL) were searched between March 1983 and March 2015. Eligible studies evaluated the outcomes of EGDT versus usual care or standard therapy in patients with severe sepsis or septic shock. The primary outcomes were mortality within 28 days, 60 days and 90 days. Included studies must report at least one metric of mortality. RESULTS: 5 studies that enrolled 4303 patients with 2144 in the EGDT group and 2159 in the control group were included in this meta-analysis. Overall, there were slight decreases of mortality within 28 days, 60 days and 90 days in the random-effect model in patients with severe sepsis or septic shock receiving EGDT resuscitation. However, none of the differences reached statistical significance (RR=0.86; 95% CI 0.69 to 1.06; p=0.16; p for heterogeneity=0.008, I(2)=71%; RR=0.94; 95% CI 0.81 to 1.10; p=0.46; p for heterogeneity=0.16, I(2)=43%; RR=0.98; 95% CI 0.88 to 1.10; p=0.75; p for heterogeneity=0.87, I(2)=0%, respectively). CONCLUSIONS: The current meta-analysis pooled data from five RCTs and found no survival benefit of EGDT in patients with sepsis. However, the included trials are not sufficiently homogeneous and potential confounding factors in the negative trials (ProCESS, ARISE and ProMISe) might bias the results and diminish the treatment effect of EGDT. Further well-designed studies should eliminate all potential source of bias to determine if EGDT has a mortality benefit. PMID- 26932136 TI - Association between employment status change and depression in Korean adults. AB - OBJECTIVES: This study investigated the association between employment status and depression. METHODS: Data from the Korea Welfare Panel Study (KOWEPS) collected from 2008 to 2011 were used. A total of 7368 subjects were included in this study after exclusion of subjects with missing data and those who were self-employed or could not work. Depression was assessed using the Center for Epidemiologic Studies Depression Scale (CES-D). Employment status, age, sex, region, education, marital status, income, head of household, self-rated health, smoking status, drinking habits, and the current year's and the previous year's CES-D scores were included in the model as independent variables. A generalised linear mixed effects model for longitudinal binary data was used. RESULTS: Compared with those who were permanently employed, individuals who moved from permanent to precarious employment (OR 1.45, 95% CI 1.23 to 1.70) or to unemployment (OR 1.78, 95% CI 1.30 to 2.43) and from precarious employment to unemployment (OR 1.65, 95% CI 1.32 to 2.06) showed a significantly increased the odds of having depression. Continuing precarious employment (OR 1.54, 95% CI 1.30 to 1.83) or unemployment (OR 1.45, 95% CI 1.23 to 1.70) also significantly increased the odds of having depression. These results were particularly identified in men and head of household women. The effects were not significant among non-head of household women. CONCLUSIONS: Precarious employment and unemployment were clearly associated with having depression. In addition, in view of our findings, policy makers should consider sex and head of household status when developing welfare policies. The inequity between precarious jobs and permanent jobs should be tackled. PMID- 26932137 TI - Effectiveness of a multicentre nasopharyngeal carcinoma awareness programme in Indonesia. AB - OBJECTIVE: To evaluate the effectiveness of a nasopharyngeal carcinoma (NPC) awareness programme on the short-term and long-term improvement of knowledge and referral of patients with NPC by primary healthcare centres (PHCCs) staff in Indonesia. DESIGN: The NPC awareness programme consisted of 12 symposia including a Train-The-Trainer component, containing lectures about early symptoms and risk factors of NPC, practical examination and the referral system for NPC suspects. Before and after training participants completed a questionnaire. The Indonesian Doctors Association accredited all activities. PARTICIPANTS: 1 representative general practitioner (GP) from each PHCC attended an NPC awareness symposium. On the basis of the Train-The-Trainer principle, GPs received training material and were obligated to train their colleagues in the PHCC. RESULTS: 703 GPs attended the symposia and trained 1349 staff members: 314 other GPs, 685 nurses and 350 midwives. After the training, respondents' average score regarding the knowledge of NPC symptoms increased from 47 points (of the 100) to 74 points (p<0.001); this increase was similar between symposium and Train-The-Trainer component (p=0.88). At 11/2 years after the training, this knowledge remained significantly increased at 59 points (p<0.001). CONCLUSIONS: The initial results of this NPC awareness programme indicate that the programme effectively increases NPC knowledge in the short and long term and therefore should be continued. Effects of the improved knowledge on the stage at diagnoses of the patients with NPC will still need to be scrutinised. This awareness programme can serve as a blueprint for other cancer types in Indonesia and for other developing countries. PMID- 26932138 TI - Cohort profile of the South London and Maudsley NHS Foundation Trust Biomedical Research Centre (SLaM BRC) Case Register: current status and recent enhancement of an Electronic Mental Health Record-derived data resource. AB - PURPOSE: The South London and Maudsley National Health Service (NHS) Foundation Trust Biomedical Research Centre (SLaM BRC) Case Register and its Clinical Record Interactive Search (CRIS) application were developed in 2008, generating a research repository of real-time, anonymised, structured and open-text data derived from the electronic health record system used by SLaM, a large mental healthcare provider in southeast London. In this paper, we update this register's descriptive data, and describe the substantial expansion and extension of the data resource since its original development. PARTICIPANTS: Descriptive data were generated from the SLaM BRC Case Register on 31 December 2014. Currently, there are over 250,000 patient records accessed through CRIS. FINDINGS TO DATE: Since 2008, the most significant developments in the SLaM BRC Case Register have been the introduction of natural language processing to extract structured data from open-text fields, linkages to external sources of data, and the addition of a parallel relational database (Structured Query Language) output. Natural language processing applications to date have brought in new and hitherto inaccessible data on cognitive function, education, social care receipt, smoking, diagnostic statements and pharmacotherapy. In addition, through external data linkages, large volumes of supplementary information have been accessed on mortality, hospital attendances and cancer registrations. FUTURE PLANS: Coupled with robust data security and governance structures, electronic health records provide potentially transformative information on mental disorders and outcomes in routine clinical care. The SLaM BRC Case Register continues to grow as a database, with approximately 20,000 new cases added each year, in addition to extension of follow-up for existing cases. Data linkages and natural language processing present important opportunities to enhance this type of research resource further, achieving both volume and depth of data. However, research projects still need to be carefully tailored, so that they take into account the nature and quality of the source information. PMID- 26932140 TI - Costs, effects and implementation of routine data emergency admission risk prediction models in primary care for patients with, or at risk of, chronic conditions: a systematic review protocol. AB - INTRODUCTION: Emergency admission risk prediction models are increasingly used to identify patients, typically with one or more chronic conditions, for proactive management in primary care to avoid admissions, save costs and improve patient experience. AIM: To identify and review the published evidence on the costs, effects and implementation of emergency admission risk prediction models in primary care for patients with, or at risk of, chronic conditions. METHODS: We shall search for studies of healthcare interventions using routine data-generated emergency admission risk models. We shall report: the effects on emergency admissions and health costs; clinician and patient views; and implementation findings. We shall search ASSIA, CINAHL, the Cochrane Library, HMIC, ISI Web of Science, MEDLINE and Scopus from 2005, review references in and citations of included articles, search key journals and contact experts. Study selection, data extraction and quality assessment will be performed by two independent reviewers. ETHICS AND DISSEMINATION: No ethical permissions are required for this study using published data. Findings will be disseminated widely, including publication in a peer-reviewed journal and through conferences in primary and emergency care and chronic conditions. We judge our results will help a wide audience including primary care practitioners and commissioners, and policymakers. TRIAL REGISTRATION NUMBER: CRD42015016874; Pre-results. PMID- 26932141 TI - How adolescents experience and cope with pain in daily life: a qualitative study on ways to cope and the use of over-the-counter analgesics. AB - OBJECTIVE: The aim of this study was to describe how different adolescents experience and manage pain in their daily life, with a focus on their use of over the-counter analgesics. More specifically, the aim was to explore different patterns among the adolescents in pain descriptions, in the management of pain, in relationships with others, and in their daily life. DESIGN: Qualitative semistructured interviews on experiences with pain, pain management and involvement of family and friends during pain. Pain and stress management strategies and attachment theory will be in focus for interpretations. PARTICIPANTS AND SETTING: 25 participants aged 15-16-years from six different junior high schools, both genders, with and without immigrant background were interviewed at their local schools in Norway. RESULTS: We identified 4 groups of adolescents with similarities in attitudes and management strategies to pain: 'pain is manageable', 'pain is communicable', 'pain is inevitable' and 'pain is all over'. The participants within each group differed in how they engaged their parents in pain; how they perceived, communicated and managed pain; and how they involved emotions and used over-the-counter analgesics. CONCLUSIONS: The adolescents' different involvement with the family during pain related to their pain perception and management. Knowledge of the different ways of approaching pain is important when supporting adolescents and may be a subject for further research on the use of over-the-counter analgesics in the family. PMID- 26932139 TI - Vulnerability for new episodes in recurrent major depressive disorder: protocol for the longitudinal DELTA-neuroimaging cohort study. AB - INTRODUCTION: Major depressive disorder (MDD) is widely prevalent and severely disabling, mainly due to its recurrent nature. A better understanding of the mechanisms underlying MDD-recurrence may help to identify high-risk patients and to improve the preventive treatment they need. MDD-recurrence has been considered from various levels of perspective including symptomatology, affective neuropsychology, brain circuitry and endocrinology/metabolism. However, MDD recurrence understanding is limited, because these perspectives have been studied mainly in isolation, cross-sectionally in depressed patients. Therefore, we aim at improving MDD-recurrence understanding by studying these four selected perspectives in combination and prospectively during remission. METHODS AND ANALYSIS: In a cohort design, we will include 60 remitted, unipolar, unmedicated, recurrent MDD-participants (35-65 years) with >= 2 MDD-episodes. At baseline, we will compare the MDD-participants with 40 matched controls. Subsequently, we will follow-up the MDD-participants for 2.5 years while monitoring recurrences. We will invite participants with a recurrence to repeat baseline measurements, together with matched remitted MDD-participants. Measurements include questionnaires, sad mood-induction, lifestyle/diet, 3 T structural (T1-weighted and diffusion tensor imaging) and blood-oxygen-level-dependent functional MRI (fMRI) and MR-spectroscopy. fMRI focusses on resting state, reward/aversive related learning and emotion regulation. With affective neuropsychological tasks we will test emotional processing. Moreover, we will assess endocrinology (salivary hypothalamic-pituitary-adrenal-axis cortisol and dehydroepiandrosterone sulfate) and metabolism (metabolomics including polyunsaturated fatty acids), and store blood for, for example, inflammation analyses, genomics and proteomics. Finally, we will perform repeated momentary daily assessments using experience sampling methods at baseline. We will integrate measures to test: (1) differences between MDD-participants and controls; (2) associations of baseline measures with retro/prospective recurrence-rates; and (3) repeated measures changes during follow-up recurrence. This data set will allow us to study different predictors of recurrence in combination. ETHICS AND DISSEMINATION: The local ethics committee approved this study (AMC-METC-Nr.:11/050). We will submit results for publication in peer-reviewed journals and presentation at (inter)national scientific meetings. TRIAL REGISTRATION NUMBER: NTR3768. PMID- 26932143 TI - Managing the screen-viewing behaviours of children aged 5-6 years: a qualitative analysis of parental strategies. AB - OBJECTIVES: The present study used qualitative methods to: (1) examine the strategies that were used by parents of children aged 5-6 years to manage screen viewing; (2) identify key factors that affect the implementation of the strategies and (3) develop suggestions for future intervention content. DESIGN: Telephone interviews were conducted with parents of children aged 5-6 years participating in a larger study. Interviews were transcribed verbatim and analysed using an inductive and deductive content analysis. Coding and theme generation was iterative and refined throughout. SETTING: Parents were recruited through 57 primary schools located in the greater Bristol area (UK). PARTICIPANTS: 53 parents of children aged 5-6 years. RESULTS: Parents reported that for many children, screen viewing was a highly desirable behaviour that was difficult to manage, and that parents used the provision of screen viewing as a tool for reward and/or punishment. Parents managed screen viewing by setting limits in relation to daily events such as meals, before and after school, and bedtime. Screen-viewing rules were often altered depending on parental preferences and tasks. Inconsistent messaging within and between parents represented a source of conflict at times. Potential strategies to facilitate reducing screen viewing were identified, including setting screen-viewing limits in relation to specific events, collaborative rule setting, monitoring that involves mothers, fathers and the child, developing a family-specific set of alternative activities to screen viewing and developing a child's ability to self monitor their own screen viewing. CONCLUSIONS: Managing screen viewing is a challenge for many parents and can often cause tension in the home. The data presented in this paper provide key suggestions of new approaches that could be incorporated into behaviour change programmes to reduce child screen viewing. PMID- 26932142 TI - Duloxetine in OsteoArthritis (DOA) study: study protocol of a pragmatic open label randomised controlled trial assessing the effect of preoperative pain treatment on postoperative outcome after total hip or knee arthroplasty. AB - INTRODUCTION: Residual pain is a major factor in patient dissatisfaction following total hip arthroplasty or total knee arthroplasty (THA/TKA). The proportion of patients with unfavourable long-term residual pain is high, ranging from 7% to 34%. There are studies indicating that a preoperative degree of central sensitisation (CS) is associated with poorer postoperative outcomes and residual pain. It is thus hypothesised that preoperative treatment of CS could enhance postoperative outcomes. Duloxetine has been shown to be effective for several chronic pain syndromes, including knee osteoarthritis (OA), in which CS is most likely one of the underlying pain mechanisms. This study aims to evaluate the postoperative effects of preoperative screening and targeted duloxetine treatment of CS on residual pain compared with care-as-usual. METHODS AND ANALYSIS: This multicentre, pragmatic, prospective, open-label, randomised controlled trial includes patients with idiopathic hip/knee OA who are on a waiting list for primary THA/TKA. Patients at risk for CS will be randomly allocated to the preoperative duloxetine treatment programme group or the care-as usual control group. The primary end point is the degree of postoperative pain 6 months after THA/TKA. Secondary end points at multiple time points up to 12 months postoperatively are: pain, neuropathic pain-like symptoms, (pain) sensitisation, pain catastrophising, joint-associated problems, physical activity, health-related quality of life, depressive and anxiety symptoms, and perceived improvement. Data will be analysed on an intention-to-treat basis. ETHICS AND DISSEMINATION: The study is approved by the local Medical Ethics Committee (METc 2014/087) and will be conducted according to the principles of the Declaration of Helsinki (64th, 2013) and the Good Clinical Practice standard (GCP), and in compliance with the Medical Research Involving Human Subjects Act (WMO). TRIAL REGISTRATION NUMBER: 2013-004313-41; Pre-results. PMID- 26932145 TI - New nurses' perceptions of professional practice behaviours, quality of care, job satisfaction and career retention. AB - AIM: To test a model examining the effects of structural empowerment and support for professional practice on new graduate nurses' perceived professional practice behaviours, perceptions of care quality and subsequent job satisfaction and career turnover intentions. BACKGROUND: The nursing worklife model describes relationships between supportive nursing work environments and nurse and patient outcomes. The influence of support for professional practice on new nurses' perceptions of professional nursing behaviours within this model has not been tested. METHODS: Structural equation modelling in Mplus was used to analyse data from a national survey of new nurses across Canada (n = 393). FINDINGS: The hypothesised model was supported: chi2(122) = 346.726, P = 0.000; CFI = 0.917; TLI = 0.896; RMSEA = 0.069. Professional practice behaviour was an important mechanism through which empowerment and supportive professional practice environments influenced nurse-assessed quality of care, which was related to job satisfaction and lower intentions to leave nursing. CONCLUSION: Job satisfaction and career retention of new nurses are related to perceptions of work environment factors that support their professional practice behaviours and high-quality patient care. IMPLICATIONS: Nurse managers can support new graduate nurses' professional practice behaviour by providing empowering supportive professional practice environments. PMID- 26932144 TI - Treatment of optic neuritis with erythropoietin (TONE): a randomised, double blind, placebo-controlled trial-study protocol. AB - INTRODUCTION: Optic neuritis leads to degeneration of retinal ganglion cells whose axons form the optic nerve. The standard treatment is a methylprednisolone pulse therapy. This treatment slightly shortens the time of recovery but does not prevent neurodegeneration and persistent visual impairment. In a phase II trial performed in preparation of this study, we have shown that erythropoietin protects global retinal nerve fibre layer thickness (RNFLT-G) in acute optic neuritis; however, the preparatory trial was not powered to show effects on visual function. METHODS AND ANALYSIS: Treatment of Optic Neuritis with Erythropoietin (TONE) is a national, randomised, double-blind, placebo controlled, multicentre trial with two parallel arms. The primary objective is to determine the efficacy of erythropoietin compared to placebo given add-on to methylprednisolone as assessed by measurements of RNFLT-G and low-contrast visual acuity in the affected eye 6 months after randomisation. Inclusion criteria are a first episode of optic neuritis with decreased visual acuity to <= 0.5 (decimal system) and an onset of symptoms within 10 days prior to inclusion. The most important exclusion criteria are history of optic neuritis or multiple sclerosis or any ocular disease (affected or non-affected eye), significant hyperopia, myopia or astigmatism, elevated blood pressure, thrombotic events or malignancy. After randomisation, patients either receive 33,000 international units human recombinant erythropoietin intravenously for 3 consecutive days or placebo (0.9% saline) administered intravenously. With an estimated power of 80%, the calculated sample size is 100 patients. The trial started in September 2014 with a planned recruitment period of 30 months. ETHICS AND DISSEMINATION: TONE has been approved by the Central Ethics Commission in Freiburg (194/14) and the German Federal Institute for Drugs and Medical Devices (61-3910-4039831). It complies with the Declaration of Helsinki, local laws and ICH-GCP. TRIAL REGISTRATION NUMBER: NCT01962571. PMID- 26932146 TI - Sustained Effect of Delayed-Release Dimethyl Fumarate in Newly Diagnosed Patients with Relapsing-Remitting Multiple Sclerosis: 6-Year Interim Results From an Extension of the DEFINE and CONFIRM Studies. AB - INTRODUCTION: Delayed-release dimethyl fumarate (DMF; also known as gastro resistant DMF) demonstrated clinical and neuroradiologic efficacy and safety in the Phase 3 DEFINE and CONFIRM trials, and in the extension study (ENDORSE), in patients with relapsing-remitting multiple sclerosis (RRMS). This post hoc analysis assessed DMF efficacy in newly diagnosed patients with RRMS with 6-year minimum follow-up. METHODS: Patients randomized in DEFINE/CONFIRM to DMF 240 mg twice (BID) or thrice daily (TID) continued on same dosage in ENDORSE. Patients randomized to placebo (PBO) or glatiramer acetate (CONFIRM only) were re randomized to DMF BID or TID. Results for DMF BID (approved dosage) are reported. Newly diagnosed patients were diagnosed within 1 year prior to DEFINE/CONFIRM entry and either treatment-naive or previously treated with corticosteroids alone. RESULTS: The newly diagnosed population included 144 patients continuously treated with DMF BID in DEFINE/CONFIRM and ENDORSE (DMF/DMF) and 85 treated with PBO for 2 years in DEFINE/CONFIRM followed by 4 years of DMF BID in ENDORSE (PBO/DMF). At 6 years (ENDORSE Year 4), the annualized relapse rates [ARR; 95% confidence interval (CI)] were 0.137 (0.101, 0.186) and 0.168 (0.113, 0.252) for DMF/DMF and PBO/DMF, respectively; representing 19% risk reduction (P = 0.3988). PBO/DMF patients demonstrated improvements in ARR after switching to DMF in ENDORSE: 0.260 (0.182, 0.372) for Years 0-2 (DEFINE/CONFIRM) and 0.102 (0.064, 0.163) for Years 3-6 (ENDORSE), representing 61% risk reduction for Years 3-6 versus Years 1-2 (P < 0.0001). The proportion of patients with 24-week confirmed disability progression (95% CI) at 6 years was 15.7% (10.3%, 23.7%) in DMF/DMF and 24.3% (15.9%, 36.2%) in PBO/DMF, representing 49% risk reduction versus PBO/DMF (P = 0.0397). CONCLUSION: Long-term DMF treatment demonstrated strong and sustained efficacy in newly diagnosed patients. Results suggest greater clinical benefits with earlier initiation of treatment in this patient population. FUNDING: Biogen. TRIAL REGISTRATION: ClinicalTrials.gov identifiers, NCT00835770 (ENDORSE); NCT00420212 (DEFINE); NCT00451451 (CONFIRM). PMID- 26932148 TI - Congenital atrophic dermatofibrosarcoma protuberans detected by COL1A1-PDGFB rearrangement. AB - BACKGROUND: Atrophic variant of dermatofibrosarcoma protuberans (DFSP) is a distinct form of DFSP. CASE PRESENTATION: Here, we report the case of a 19-year old woman with a small congenital atrophic plaque on the right precordium. The lesion remained atrophic for more than 10 years. Several years earlier, a portion of the plaque became tuberous and enlarged. Physical examination revealed a 25 * 30 mm erythematous atrophic plaque surrounded by three hard, smooth, and orange colored nodules of varying sizes on the right precordium, along with visible subcutaneous adipose tissue and cutaneous veins. Biopsy of the nodule and atrophic plaque revealed dense proliferation of spindle-shaped tumor cells from the dermis to the subcutaneous adipose tissue, and positive immunostaining for CD34 and vimentin in addition to negative staining for factor XIIIa and alpha smooth muscle actin. Reverse transcription polymerase chain reaction (RT-PCR) of the tumor tissue revealed the presence of a COL1A1-PDGFB fusion gene. Thus, congenital atrophic dermatofibrosarcoma protuberans was diagnosed. No metastasis to the lungs or regional lymph nodes was found on magnetic resonance imaging. Wide local excision and split-thickness skin grafting was performed and neither recurrence nor metastasis has been observed for 5 years and 8 months since the surgery. CONCLUSION: This case indicates that a congenital atrophic lesion could represent a quiescent phase of DFSP. Awareness of this rare condition can aid with early diagnosis and thereby improve the prognosis of DFSP. PMID- 26932149 TI - Bayesian latent class estimation of the incidence of chest radiograph-confirmed pneumonia in rural Thailand. AB - Pneumonia is a leading cause of mortality and morbidity worldwide with radiographically confirmed pneumonia a key disease burden indicator. This is usually determined by a radiology panel which is assumed to be the best available standard; however, this assumption may introduce bias into pneumonia incidence estimates. To improve estimates of radiographic pneumonia incidence, we applied Bayesian latent class modelling (BLCM) to a large database of hospitalized patients with acute lower respiratory tract illness in Sa Kaeo and Nakhon Phanom provinces, Thailand from 2005 to 2010 with chest radiographs read by both a radiology panel and a clinician. We compared these estimates to those from conventional analysis. For children aged <5 years, estimated radiographically confirmed pneumonia incidence by BLCM was 2394/100 000 person-years (95% credible interval 2185-2574) vs. 1736/100 000 person-years (95% confidence interval 1706 1766) from conventional analysis. For persons aged ?5 years, estimated radiographically confirmed pneumonia incidence was similar between BLCM and conventional analysis (235 vs. 215/100 000 person-years). BLCM suggests the incidence of radiographically confirmed pneumonia in young children is substantially larger than estimated from the conventional approach using radiology panels as the reference standard. PMID- 26932147 TI - The Aurora kinase inhibitors in cancer research and therapy. AB - Compounds that affect enzymatic function of kinases are valuable for the understanding of the complex biochemical processes in cells. Aurora kinases (AURKs) play a key role in the control of the mitosis. These kinases are frequently deregulated in different human cancers: overexpression, amplifications, translocations and deletions were reported in many cancer cell lines as well as patient tissues. These findings steered a rigorous hunt for small-molecule AURK inhibitors not only for research purposes as well as for therapeutic uses. In this review, we describe a number of AURK inhibitors and their use in cancer research and/or therapy. We hope to assist researchers and clinicians in deciding which inhibitor is most appropriate for their specific purpose. The review will also provide a broad overview of the clinical studies performed with some of these inhibitors (if such studies have been performed). PMID- 26932150 TI - The Solar Spectrum in the Atacama Desert. AB - The Atacama Desert has been pointed out as one of the places on earth where the highest surface irradiance may occur. This area is characterized by its high altitude, prevalent cloudless conditions and relatively low columns of ozone and water vapor. Aimed at the characterization of the solar spectrum in the Atacama Desert, we carried out in February-March 2015 ground-based measurements of the spectral irradiance (from the ultraviolet to the near infrared) at seven locations that ranged from the city of Antofagasta (on the southern pacific coastline) to the Chajnantor Plateau (5,100 m altitude). Our spectral measurements allowed us to retrieve the total ozone column, the precipitable water, and the aerosol properties at each location. We found that changes in these parameters, as well as the shorter optical path length at high-altitude locations, lead to significant increases in the surface irradiance with the altitude. Our measurements show that, in the range 0-5100 m altitude, surface irradiance increases with the altitude by about 27% in the infrared range, 6% in the visible range, and 20% in the ultraviolet range. Spectral measurements carried out at the Izana Observatory (Tenerife, Spain), in Hannover (Germany) and in Santiago (Chile), were used for further comparisons. PMID- 26932151 TI - Catheter-measured Hemodynamics of Adult Fontan Circulation: Associations with Adverse Event and End-organ Dysfunctions. AB - BACKGROUND: In heart failure, a high systemic vascular resistance index (SVRI), high central venous pressure (CVP), and low cardiac index (CI) predict poor outcomes. Conversely, late hemodynamic manifestations of failing Fontan circulation and associations with end-organ dysfunction are not well understood. METHODS: A retrospective review of right-heart catheterization data of adult Fontan patients between 2002 and 2014 was conducted. Relationships between hemodynamic variables and serious adverse events (death or heart transplant) were examined using the Cox proportional hazard analysis. Correlations between the hemodynamic measurements and signs of end-organ dysfunction (MELD-XI, Child-Pugh, VAST score, estimated glomerular filtration rate [eGFR]) were analyzed. RESULTS: Sixty post-Fontan patients (85% systemic left ventricle, 40% atriopulmonary Fontan, mean age of 28 years, and mean time since Fontan operation of 21.9 years) were included. At baseline, those with an event were statistically younger, had lower transcutaneous oxygen saturations, were more likely to have an atriopulmonary Fontan, and were more likely to have a pacemaker. Eighteen experienced a cardiovascularly significant event. Using univariate analysis to compare the event and nonevent groups, mean CI was 2.8 +/- 0.9 vs. 2.4 +/- 0.5 L/min/m2 (P = .004), and CVP was 18.6 +/- 6.5 vs. 16.1 +/- 4.3 mmHg (P = .03). However, the statistical significances did not persist in the multivariate model. Higher CVP and pulmonary capillary wedge pressure (PCWP) were associated with higher MELD-XI and Child-Pugh scores, and the VAST score was only associated with PCWP. CONCLUSIONS: Symptomatic adult Fontan patients who experienced an event manifested with a higher CI and CVP, although the multivariate Cox proportional hazard analysis did not yield any significant associations. The presences of hepatic dysfunction and portal venous outflow obstruction were associated with a higher CVP and PCWP. Renal dysfunction was prevalent but no statistically significant association between the hemodynamic measurements was identified, although trends toward a higher CVP and transpulmonary gradient were identified. PMID- 26932153 TI - Metastatic ductal carcinoma of the breast to the thyroid gland diagnosed with fine needle aspiration: A case report with emphasis on morphologic and immunophenotypic features. AB - Metastases to the thyroid are uncommon [<0.2% of thyroid fine needle aspirations (FNA)]. Of metastases to the thyroid, breast carcinoma is relatively common. The diagnosis of metastasis to the thyroid has important therapeutic and prognostic implications. To our knowledge, a morphologic and immunophenotypic comparison of metastatic ductal carcinoma of the breast and primary thyroid carcinomas has not been reported. Here, we report the case of a 37-year-old female with a history of metastatic ductal carcinoma of the breast (modified Bloom-Richardson grade 2; ER+, PgR+, HER2+) diagnosed 6 years prior. She developed hoarseness, prompting a CT scan. Multiple thyroid nodules were found, including a 1.5 cm hypoechoic, solid, irregularly-shaped nodule. On FNA, cells were arranged singly and in crowded groups, varied in size and degree of pleomorphism, and exhibited rare nuclear grooves, inconspicuous nucleoli, and rare intracytoplasmic lumina with no nuclear pseudoinclusions or colloid (Figs. 1A and B). These findings raised the differential of papillary thyroid carcinoma (Fig. 1C), follicular neoplasm (Fig. 1D), medullary carcinoma (Fig. 1E), parathyroid (Fig. 1F), and metastatic breast carcinoma. Immunostaining for GATA-3 (+), ER (+), PAX-8 (-), and TTF-1 (-) was consistent with metastatic breast carcinoma (Fig. 2). We conclude that metastatic breast carcinoma to the thyroid may morphologically mimic primary thyroid carcinoma on FNA; a panel of immunomarkers, such as GATA-3, hormonal marker(s), PAX-8, and TTF-1, may be useful in some cases. GATA-3 immunostaining for metastatic breast carcinoma was helpful in our case and has not been previously reported in a thyroid metastasis sampled by FNA. Diagn. Cytopathol. 2016;44:530 534. (c) 2016 Wiley Periodicals, Inc. PMID- 26932152 TI - Time budget, oxygen consumption and body mass responses to parasites in juvenile and adult wild rodents. AB - BACKGROUND: The study of changes in a host's energy allocation in response to parasites is crucial for understanding parasite impact on both individual- and population-level processes. Experimental studies have explored such responses mainly in a single subsample of hosts per study, primarily adult males, and have only assessed either the overall energy acquisition or expenditure, rather than their different components simultaneously, or the behavioral responses. Accordingly, two fundamental questions arise: why have multiple host strategies evolved to cope with increased energy expenditure? and, which factors determine this variation (e.g. host species, identity, age)? This study provides an important step towards addressing both questions by experimentally disentangling the short-term physiological and behavioral responses of juvenile and non reproductive adult rodents to natural levels of flea infestation. These two cohorts represent extreme cases of the energy demand continuum, as the former, in contrast to the latter, is involved in growth--a highly energy-demanding process- and may not be able to operate far below its upper limit of energy expenditure, and thus should reduce its energy expenses upon the occurrence of extra demands (e.g. due to parasitic pressure). Accordingly, we hypothesized that the response to fleas is age-dependent and varies according to the age-specific energy requirements and constraints. METHODS: We monitored the behavior and physiology of juvenile and non-reproductive adult rodents before and after experimental flea infestation. First, we used a model selection approach to search for the factors that best explained the variability in the time budget, oxygen consumption, and body mass change in response to fleas. Then, using a path analysis approach, we quantified the different pathways connecting the important associations revealed at stage 1. RESULTS: Compared to their flea-free counterparts, flea-infested adults groomed longer and had a higher oxygen consumption rate, but did not lose body mass. Infested juveniles also groomed longer but grew slower and had a similar rate of oxygen consumption. CONCLUSIONS: Results suggest that both juvenile and adult rodents suffer from natural flea infestation levels. However, the comparison between the responses of juveniles and adults to experimental infestation, also suggests that juveniles may reallocate their energy expenditure from growth to maintenance, while non-reproductive adults increase their energy acquisition. Such age-dependent responses suggest that juveniles may be constrained by their higher need to rest for full functioning or by an upper limit in energy expenditure. Taken together, our study provides experimental evidence that hosts can compensate for the costs incurred by parasitism through physiological and behavioral plasticity, depending on their age, which probably determines their requirements and constraints. These compensatory responses may have important implications for the population dynamics of hosts and their parasites. PMID- 26932154 TI - Effect and potential mechanism of action of sea cucumber saponins on postprandial blood glucose in mice. AB - Postprandial blood glucose control is the major goal in the treatment of diabetes. Here, we investigated the effect of sea cucumber saponins (SCSs) on postprandial blood glucose levels. SCS inhibited yeast as well as rat intestinal alpha-glucosidase activity in a dose-dependent manner and showed better inhibition of yeast alpha-glucosidases compared to the positive control. Further studies were performed using ICR mice treated with SCS and starch or SCS alone by oral gavage. Unexpectedly, SCS increased postprandial blood glucose levels a short time (1 h) after oral gavage. The serum corticosterone (CORT) level showed a consistent correlation with glucose levels. In vitro experiments confirmed that SCS treatment increased the secretion of CORT in the Y1 adrenal cell line. Overall, these studies demonstrated that SCS gavage could inhibit alpha glucosidase activity but cannot attenuate postprandial blood glucose level within short time periods. The underlying mechanisms are probably related to increased serum CORT levels. PMID- 26932155 TI - Using a geographic information system to enhance patient access to point-of-care diagnostics in a limited-resource setting. AB - BACKGROUND: Rapid and accurate diagnosis drives evidence-based care in health. Point-of-care testing (POCT) aids diagnosis by bringing advanced technologies closer to patients. Health small-world networks are constrained by natural connectivity in the interactions between geography of resources and social forces. Using a geographic information system (GIS) we can understand how populations utilize their health networks, visualize their inefficiencies, and compare alternatives. METHODS: This project focuses on cardiac care resource in rural Isaan, Thailand. A health care access analysis was created using ArcGIS Network Analyst 10.1 from data representing aggregated population, roads, health resource facilities, and diagnostic technologies. The analysis quantified cardiac health care access and identified ways to improve it using both widespread and resource-limited strategies. RESULTS: Results indicated that having diagnostic technologies closer to populations streamlines critical care paths. GIS allowed us to compare the effectiveness of the implementation strategies and put into perspective the benefits of adopting rapid POCT within health networks. CONCLUSIONS: Geospatial analyses derive high impact by improving alternative diagnostic placement strategies in limited-resource settings and by revealing deficiencies in health care access pathways. Additionally, the GIS provides a platform for comparing relative costs, assessing benefits, and improving outcomes. This approach can be implemented effectively by health ministries seeking to enhance cardiac care despite limited resources. PMID- 26932156 TI - Parental death in childhood and self-inflicted injuries in young adults-a national cohort study from Sweden. AB - Previous studies have shown that parental death influences health and mortality in bereaved offspring. To date, few studies have examined whether exposure to parental bereavement in childhood is associated with suicidality later in life. The aim of the present research was to investigate whether parental death during childhood influences self-inflicted injuries/poisoning in young adulthood. A national cohort born during 1973-1982 (N = 871,402) was followed prospectively in the National Patient Discharge Register from age 18 to 31-40 years. Cox regression analyses of proportional hazards, with adjustment for socio demographic confounders and parental psychosocial covariates, were used to test hypotheses regarding parental loss and hospital admission due to self-inflicted injuries/poisoning. Parental deaths were divided into deaths caused by (1) external causes/substance abuse and (2) natural causes. Persons who had lost a parent to an external cause/substance abuse-related death had the highest risk of being admitted to a hospital for a self-inflicted injury/poisoning; HRs 2.03 (1.67-2.46) for maternal death and 2.03 (1.84-2.25) for paternal death, after adjustment for socio-demographic confounders and risk factors among surviving parents. Risks were also increased for parental death due to natural causes, but at a lower level: 1.19 (1.01-1.39) and 1.28 (1.15-1.43), respectively. Losing a father before school age was associated with a higher risk of hospital admission for a self-inflicted injury/poisoning than was loss at an older age for both genders. Maternal loss before school age was associated with a higher risk only for men, particularly maternal death by natural causes (p < 0.01). PMID- 26932157 TI - Immunomodulatory functions of mesenchymal stem cells and possible mechanisms. AB - In addition to their well-studied self-renewal capabilities and multipotent differentiation properties, mesenchymal stem cells (MSCs) have been reported to possess profound immunomodulatory functions both in vitro and in vivo. More and more studies have shown that MSCs are capable of interacting closely with almost all subsets of immune cells, such as T cells, B cells, dendritic cells, natural killer cells, macrophages, and neutrophils etc. The immunomodulatory property of MSCs may shed light on the treatment of a variety of autoimmune and inflammation related diseases. In this article, we will review the studies on the immunomodulatory and anti-inflammatory functions of MSCs and the mechanisms responsible for the interaction between immune cells and MSCs, which could improve the development of promising approaches for cell-mediated immune therapies. PMID- 26932158 TI - Robust ultrasensitive tunneling-FET biosensor for point-of-care diagnostics. AB - For point-of-care (POC) applications, robust, ultrasensitive, small, rapid, low power, and low-cost sensors are highly desirable. Here, we present a novel biosensor based on a complementary metal oxide semiconductor (CMOS)-compatible silicon nanowire tunneling field-effect transistor (SiNW-TFET). They were fabricated "top-down" with a low-cost anisotropic self-stop etching technique. Notably, the SiNW-TFET device provided strong anti-interference capacity by applying the inherent ambipolarity via both pH and CYFRA21-1 sensing. This offered a more robust and portable general protocol. The specific label-free detection of CYFRA21-1 down to 0.5 fgml(-1) or ~12.5 aM was achieved using a highly responsive SiNW-TFET device with a minimum sub-threshold slope (SS) of 37 mVdec(-1). Furthermore, real-time measurements highlighted the ability to use clinically relevant samples such as serum. The developed high performance diagnostic system is expected to provide a generic platform for numerous POC applications. PMID- 26932159 TI - ABC Transporters in the Development of Multidrug Resistance in Cancer Therapy. AB - Cancer is one of the leading causes of mortality in the developed countries. The search for novel drug candidates is a priority goal for cancer therapy. However, the emergence of drug resistance reduces the effectiveness of new medications. The ATP binding cassette (ABC) family of proteins are efflux pumps that transport various structurally unrelated and potentially dangerous substances out of the cells. These transporters have evolved as a complex cellular defense system, for the recognition and removal of toxic agents entering the cells from their environment. Several of the ABC transporters are related to chemoresistance in cancer therapy, as the rapidly dividing malignant cells use them to protect themselves from medical interventions. Here we review the members of the ABC transporter families responsible for the multidrug resistance in anticancer therapy. PMID- 26932160 TI - Ligand-Based Virtual Screening Using Tailored Ensembles: A Prioritization Tool for Dual A2AAdenosine Receptor Antagonists / Monoamine Oxidase B Inhibitors. AB - BACKGROUND: Virtual Screening methodologies have emerged as efficient alternatives for the discovery of new drug candidates. At the same time, ensemble methods are nowadays frequently used to overcome the limitations of employing a single model in ligand-based drug design. However, many applications of ensemble methods to this area do not consider important aspects related to both virtual screening and the modeling process. During the application of ensemble methods to virtual screening the proper validation of the models in virtual screening conditions is often neglected. No analysis of the diversity of the ensemble members is performed frequently or no considerations regarding the applicability domain of the base models are being made. METHODS: In this research, we review basic concepts and definitions related to virtual screening. We comment recent applications of ensemble methods to ligand-based virtual screening and highlight their advantages and limitations. RESULTS: Next, we propose a method based on genetic algorithms optimization for the generation of virtual screening tailored ensembles which address the previously identified problems in the current applications of ensemble methods to virtual screening. CONCLUSION: Finally, the proposed methodology is successfully applied to the generation of ensemble models for the ligand-based virtual screening of dual target A2A adenosine receptor antagonists and MAO-B inhibitors as potential Parkinson's disease therapeutics. PMID- 26932161 TI - Sodium tanshinone IIA sulfonate and its interactions with human CYP450s. AB - 1.Sodium tanshinone IIA sulfonate (STS) is a water-soluble derivative of tanshinone IIA, a famous Chinese medicine used for many years to treat cardiovascular disorders. However, the role of cytochrome P450 (CYP) enzymes in the metabolism of STS was unclear. In this study, we screened the main CYPs for the metabolism of STS and studied their interactions in vitro. 2.Seven CYPs were screened for the metabolism of STS by human liver microsomes (HLMs) or recombinant CYP isoforms. To determine the potential of STS to affect CYP mediated phase I metabolism in humans, phenacetin (CYP1A2), coumarin (CYP2A6), tolbutamide (CYP2C9), metoprolol (CYP2D6), chlorzoxazone (CYP2E1), S-Mephenytoin (CYP2C19), and midazolam (CYP3A4) were used as the respective probe substrates. Enzyme kinetic studies were performed to investigate the mode of inhibition of the enzyme-substrate interactions. 3.STS inhibited the activity of CYP3A4 in a dose-dependent manner in the HLMs and CYP3A4 isoform. Other CYP isoforms, including CYP1A2, CYP2A6, CYP2C9, CYP2D6, CYP2E1, and CYP2C19, showed minimal or no effect on the metabolism of STS. 4.The results suggested that STS primarily inhibits the activities of CYP3A4 in vitro, and STS has the potential to perpetrate drug-drug interactions with other CYP3A4 substrates. PMID- 26932162 TI - Both pelvic radiography and lateral abdominal radiography correlate well with coronary artery calcification measured by computed tomography in hemodialysis patients: A cross-sectional study. AB - Introduction Lateral abdominal radiograph is suggested as an alternative to coronary artery computed tomography (CT) in evaluating vascular calcification. Simple scoring systems including pelvic radiograph scoring and abdominal scoring system were utilized to study their correlation with coronary artery calcification. Methods In 106 MHD patients, coronary artery CT, lateral abdominal, and pelvic radiograph were taken. The Agatston scoring system was applied to evaluate the degree of coronary artery calcification which was categorized according to Agatston coronary artery calcification score (CACS) >= 30, >=100, >=400, and >=1000. Abdominal aortic calcification was scored by 4 scored and 24-scored systems. Pelvic artery calcification was scored by a 4 scored system. Sensitivities and specificities of abdominal aortic calcification scores and pelvic artery calcification scores to predict different categories of coronary artery calcification were analyzed. We studied the diagnostic capability of abdominal aorta calcification and pelvic artery calcification to predict different CACS categories by calculating likelihood ratios. Receiver operator characteristic curves were used to determine the area under the curve for each of these testing procedures. Findings The prevalence was 48(45.3%), 15 (14.2%), 11 (10.4%), 11 (10.4%), and 11 (10.4%) for CACs > 0, >=30, >=100, >=400, and >=1000, respectively. The degree of CACs was positively correlated with patient age, prevalence of diabetes, abdominal aorta scores, and pelvic calcification scores. The areas under the curves for different CACS by all X-ray scoring systems were above 0.70 except pelvic 4-scored system for diagnosing CACS >=30, without significant difference (P > 0.05). Discussion Both lateral abdominal and pelvic plain radiographs were demonstrated as acceptable alternatives to CT in evaluating vascular calcification. PMID- 26932164 TI - Antiferromagnetic proximity effect in epitaxial CoO/NiO/MgO(001) systems. AB - Magnetic proximity effect between two magnetic layers is an important focus of research for discovering new physical properties of magnetic systems. Antiferromagnets (AFMs) are fundamental systems with magnetic ordering and promising candidate materials in the emerging field of antiferromagnetic spintronics. However, the magnetic proximity effect between antiferromagnetic bilayers is rarely studied because detecting the spin orientation of AFMs is challenging. Using X-ray linear dichroism and magneto-optical Kerr effect measurements, we investigated antiferromagnetic proximity effects in epitaxial CoO/NiO/MgO(001) systems. We found the antiferromagnetic spin of the NiO underwent a spin reorientation transition from in-plane to out-of-plane with increasing NiO thickness, with the existence of vertical exchange spring spin alignment in thick NiO. More interestingly, the Neel temperature of the CoO layer was greatly enhanced by the adjacent NiO layer, with the extent of the enhancement closely dependent on the spin orientation of NiO layer. This phenomenon was attributed to different exchange coupling strengths at the AFM/AFM interface depending on the relative spin directions. Our results indicate a new route for modifying the spin configuration and ordering temperature of AFMs through the magnetic proximity effect near room temperature, which should further benefit the design of AFM spintronic devices. PMID- 26932166 TI - The morbidity and cost of vocal cord dysfunction misdiagnosed as asthma. AB - BACKGROUND: Vocal cord dysfunction (VCD) is frequently misdiagnosed and mistreated as asthma, which leads to morbidity secondary to unnecessary medication use and increased health care utilization. OBJECTIVE: We identified discriminating symptoms and triggers, and analyzed the costs, morbidity, and health care burden associated with misdiagnosis of VCD as asthma. We sought to determine if current measures of asthma control contributed to these findings. We evaluated if a simple set of breathing exercises would be an effective low-cost treatment option for those with VCD. METHODS: We compared the demographics, comorbidities, clinical symptoms, and symptom triggers of subjects with VCD misdiagnosed as asthma compared with those not misdiagnosed as asthma. Costs secondary to asthma misdiagnosis were quantified, and the effectiveness of breathing exercises as a treatment option was evaluated. RESULTS: We identified symptoms of shortness of breath, wheezing, chest tightness, and a trigger of exercise as being more common in the subjects with VCD misdiagnosed as asthma. Asthma medication use and health care utilization and costs were also higher in this group. The subjects with VCD had Asthma Control Questionnaire scores that labelled them as having uncontrolled asthma. Breathing exercises appeared to offer an inexpensive and effective treatment option for subjects with VCD. CONCLUSION: Misdiagnosis of VCD as asthma leads to significant morbidity and increased costs, and misuse of measures of asthma control may be contributing to these findings. Timely and accurate diagnosis of VCD and the use of breathing exercises have the potential to eliminate or minimize the burdens on the patient and the health care system. PMID- 26932163 TI - Clinical and radiological outcome after mechanical thrombectomy in acute ischemic stroke: What matters? AB - OBJECTIVE: Recent studies have shown the efficacy of mechanical thrombectomy in acute ischemic stroke. We sought to identify prognostic parameters for clinical and radiological outcome after mechanical thrombectomy. METHODS: In 34 patients (age 72 +/- 13 years, 64.7% women) with acute occlusion of the distal ICA and/or M1 segment who were treated with mechanical thrombectomy, the Spearman correlation was performed to assess potential prognostic outcome parameters (age, NIHSS, ASPECT, thrombus length (TL), clot burden score (CBS), relative filling time delay (rFTD), time to recanalization (TTR) and TICI score). The modified Rankin scale (mRS) and the Alberta Stroke Program Early CT (ASPECT) score were used for clinical and radiological outcome, respectively. Receiver operating characteristic (ROC) analysis was performed to assess parameters predicting favorable clinical (DeltamRS <= 2) and radiological outcome (DeltaASPECT <= 2). RESULTS: Variables associated with favorable clinical outcome included NIHSS, TL, TTR and TICI score (p <= 0.01) with NIHSS <= 15 (p = 0.001, area under the curve (AUC) 0.87), TL <= 2 cm (p = 0.017, AUC 0.75), TTR <= 231 min (p = 0.001 AUC 0.88) and TICI >= 2b (p = 0.050, AUC 0.70). Shorter TTR and higher TICI scores were associated with favorable radiological outcome (p < 0.001) with TTR <= 224 min (p = 0.023, AUC 0.77) and TICI >= 2b (p = 0.000, AUC 0.86). CONCLUSION: Fast and complete recanalization is essential to achieve a favorable radiological and functional outcome after mechanical thrombectomy in acute ischemic stroke. Age, CBS and collateral supply play a subordinate role. PMID- 26932165 TI - Protective effects of elafin against adult asthma. AB - BACKGROUND: Elafin inhibits serine proteases, such as human neutrophil elastase and proteinase 3, to prevent excessive damage during inflammation. However, the relationship between elafin and asthma is still unclear. Microarray technology was used to evaluate smoking- and asthma-related biomarkers in a discovery-driven manner. We identified candidate genes, e.g., proteinase inhibitor 3 (PI3), related to asthma and smoking from gene expression microarray data sets and evaluated their potential as biomarkers for asthma. METHODS: We used human genome microarray data sets from smoking- and asthma-related gene expression data sets and performed real-time quantitative polymerase chain reaction to measure and validate differences in gene expression. We also recruited adult patients with asthma and age- and sex-matched control patients who were administered a structured questionnaire and evaluated for lung function and plasma elafin levels, which are encoded by the PI3 gene. RESULTS: Six significantly altered candidate genes, PI3, protein kinase C iota, phosphoserine phosphatase, IQ motif containing GTPase activating protein 1, interleukin 13 receptor alpha 1, and signal transducing adaptor molecule SH3 domain and ITAM motif 2, were identified from comparisons across the four asthma- and four smoking-related data sets included in this study. An in vitro study of human airway epithelial cells (A549) and a human monocytic cell line (THP-1) demonstrated that PI3 messenger RNA levels were significantly altered by nicotine exposure. Elafin concentration was significantly higher in control patients than in patients with asthma (p < 0.001). The plasma elafin concentration in the highest quartile (>=12.69 ng/mL) was inversely associated with asthma (adjusted odds ratio 0.122 [95% confidence interval, 0.053-0.278]) compared with the lowest quartile (<5.82 ng/mL) after adjusting for age, sex, smoking status, waist-to-hip ratio, percentage predicted forced expiratory volume in 1 second, cockroaches in the home, incense burning, and family history. CONCLUSION: Our study revealed that high elafin levels identified in smoking- and asthma-related microarray data sets and an epidemiologic study significantly reduced the risk of asthma. Further studies of elafin as a potential therapy for asthma are warranted. PMID- 26932167 TI - Editorial: All that wheezes is not asthma, and all that itches is not allergy. PMID- 26932168 TI - Approach to evaluation and management of a patient with multiple food allergies. AB - BACKGROUND: Diagnosing food allergy is often challenging, and validated testing modalities are mostly limited to immunoglobulin E (IgE)-mediated reactions to foods. Use of food-specific IgE tests and skin prick tests in individuals without a history that supports an IgE-mediated reaction to the specific food being tested diminishes the predictive capabilities of the test. OBJECTIVE: To review the literature regarding evaluation of patients with a concern for multiple food allergies and to demonstrate an evidence-based approach to diagnosis and management. METHODS: A literature search was performed and articles identified as relevant based on the search terms "food allergy," "food allergy diagnosis," "skin prick test," "serum IgE test," "oral food challenge", and "food allergy management." RESULTS: Patients at risk of food allergy are often misdiagnosed and appropriate evaluation of patients with concern for food allergy includes taking a thorough diet history and reaction history, performing specific tests intentionally and when indicated, and conducting an oral food challenge in a safe environment by an experienced provider when test results are inconclusive. CONCLUSION: An evidence-based approach to diagnosing and managing a patient at risk of having a life-threatening food allergy is reviewed. PMID- 26932169 TI - The clinical effect of vitamin D supplementation combined with grass-specific sublingual immunotherapy in children with allergic rhinitis. AB - BACKGROUND: An important issue in sublingual immunotherapy (SLIT) is how to improve efficacy. OBJECTIVE: To compare the clinical efficacy of SLIT with vitamin D supplementation with placebo in children with allergic rhinitis. Secondary end points included lung function, exhaled nitric oxide concentration, methacholine bronchial provocation test, and serum level of calcifediol (25[OH]D). METHODS: Fifty children, ages 5-12 years, sensitive to grass pollen, with allergic rhinitis (eight patients had concomitant asthma) participated in a 5-month prospective, randomized, double-blind, placebo-controlled trial. Children received a 5-grass pollen sublingual 300 IR tablet with either vitamin D 1000 IU daily supplementation or placebo. RESULTS: When compared with the placebo group, SLIT plus vitamin D group therapy was more effective in the reduction of nasal symptoms (p = 0.04), asthma symptoms (p = 0.001), and the combined symptom medication score (p = 0.001); there was no significant difference between the groups in medication and ocular scores. We observed a significant improvement of forced expiratory volume in 1 second (vitamin D group, p = 0.014; placebo group, p = 0.015) and the proportion of a person's vital capacity expired in the first second of forced expiration levels (vitamin D group, p = 0.004; placebo group, p < 0.001), within both groups, between visits. Fractional exhaled nitric oxide and provocative dose producing a 20% fall in forced expiratory volume in 1 second results did not statistically significantly differentiate the study participants in terms of receiving SLIT along with vitamin D or placebo. We showed a significant increase in calcifediol in the SLIT plus vitamin D group as well as in SLIT plus placebo group. CONCLUSIONS: Vitamin D supplementation combined with grass-specific SLIT was more effective in the reduction of nasal and asthma symptoms. Vitamin D supplementation combined with SLIT provides an effective and well-tolerated new immunotherapy modality for treating children with allergic rhinitis. A 5-grass pollen sublingual 300 IR tablet was effective in both studied groups and also in children with comorbid mild asthma. PMID- 26932170 TI - Increased specific immunoglobulin G4 antibodies induced by natural exposure to ambrosia pollen in patients with allergy. AB - BACKGROUND: Induction of specific immunoglobulin G4 (sIgG4) response (so-called blocking antibodies) in patients who receive specific immunotherapy (SIT) has been observed for many years. Although many other mechanisms have been identified as key regulators of immunologic processes in peripheral tolerance to allergens, the rise of sIgG4 during immunotherapy, together with the clinical improvement, is still believed to be one of the most important mechanisms through which SIT reaches its clinical efficacy. OBJECTIVE: The aim of this prospective study was to measure levels of IgG4 and sIgE in subjects allergic to Ambrosia elatior pollen (common ragweed), before and during natural exposure to A. elatior pollen. Healthy controls were also included. METHODS: Twenty-four patients with allergic diseases of the respiratory tract and 24 healthy controls entered the study. The sIgG4 and sIgE levels were measured by using the enzyme-linked immunosorbent assay method before and during A. elatior pollination season. RESULTS: A significant increase of the sIgG4 level in subjects with allergy during natural exposure to an allergen (0.676 increased to 0.937; p < 0.05) was shown. An increase in sIgE levels was also observed. Healthy subjects had comparable levels of sIgG4 as in subjects with allergy before the pollination season and no change in sIgG4 and sIgE levels during the pollination season. CONCLUSION: Increases of sIgG4 and sIgE levels were induced by natural allergen exposure in subjects with allergy but not in healthy individuals. This result support further reevaluation of the "blocking" antibodies concept as one concept responsible for allergen tolerance in patients who receive SIT. PMID- 26932171 TI - Evaluation of allergic sensitivity to Acanthamoeba allergen in patients with chronic cough. AB - BACKGROUND: Acanthamoeba and their proteins can elicit severe allergic airway inflammation in experimental mice. OBJECTIVE: Although Acanthamoeba can induce severe allergic airway inflammation in mice, there is no allergenicity data for humans. METHODS: We performed a skin-prick test on 65 patients with chronic cough by using 54 previously known allergens and Acanthamoeba excretory-secretory proteins and enzyme-linked immunosorbent assay on 34 patients to evaluate Acanthamoeba-specific serum immunoglobulin (Ig) levels. To detect a novel Acanthamoeba allergen, Western blot analysis was performed on serum from patients who reacted positively to Acanthamoeba or some pollen allergens. RESULTS: After skin-prick testing, 29 patients (44.6%) showed positive reactions to one or more common aeroallergens. Acanthamoeba allergenicity was evaluated in 4 of 65 subjects (6.1%). An Acanthamoeba-positive reaction was closely related to several pollen allergens, especially willow tree, poplar, elm, oak, velvet grass, and cockroach. Average levels of Acanthamoeba-specific IgG subtypes in patient serum did not differ compared with healthy subjects; however, Acanthamoeba-specific IgE titers of patients were significantly higher than in healthy subjects. IgE antibodies of patients who tested positive in the skin-prick test reacted strongly to the 15 kDa excretory-secretory protein. Moreover, these antigens also reacted with those who tested positive in the skin-prick test to pollens. CONCLUSION: Taken together, our results indicated that some patients with allergy showed a positive response to the skin-prick test and that they also have high IgE serum levels. However, further experimental investigation is warranted because our preliminary findings indicated that Acanthamoeba might be a new allergen in humans. PMID- 26932172 TI - Th1/Th2/Th17 cells imbalance in patients with asthma with and without psychological symptoms. AB - BACKGROUND: The prevalence of psychological symptoms such as anxiety and depression among patients with asthma is high. Both asthma and psychological symptoms are characterized by immune inflammation in which CD4+ T cells play a role. OBJECTIVE: To investigate whether T-helper (Th) 1, Th2, and Th17 cells imbalance exists in patients with asthma and with and in patients without psychological symptoms. METHODS: The messenger RNA (mRNA) expression of T-box 21 (T-bet), GATA binding protein 3 (GATA-3), and RAR-related orphan receptor C (RORC) in peripheral CD4+ T cells of 20 patients with asthma and with psychological symptoms, 30 patients with asthma and without psychological symptoms, and 30 healthy subjects were detected by real-time polymerase chain reaction. A Luminex-based approach quantified the levels of interferon gamma (IFN gamma), tumor necrosis factor alpha (TNF-alpha), interleukin (IL) 4, and IL-17A cytokines in serum. RESULTS: The mRNA expressions of T-bet, GATA-3 and RORC were significantly different among the three groups. Significant elevations of the expressions of T-bet, GATA-3, and RORC mRNA were found in patients with asthma and with psychological symptoms than in healthy subjects, along with the higher levels of IFN-gamma, TNF-alpha, and IL-17A. Increased expressions of T-bet mRNA were found in patients with asthma and with psychological symptoms but not in those without psychological symptoms. However, the ratio of T-bet to GATA-3 was in balance in patients with asthma and with psychological symptoms. CONCLUSION: Analysis of our data revealed Th1 and Th2 cells activated in balance in the peripheral blood of patients with asthma and with psychological symptoms, along with activated Th17 cells. This finding provided an improved understanding of the immune-inflammation responses in patients with asthma and with psychological symptoms, and offered information for new targeted therapy to patients with asthma and with psychological symptoms. PMID- 26932173 TI - Parental perception of efficacy of antihistamines for pruritus in pediatric atopic dermatitis. AB - BACKGROUND: Clinicians have previously prescribed antihistamines for relief of atopic dermatitis (AD) associated pruritus. The use of antihistamines in AD has recently received less emphasis from newly published practice parameters that currently only recommend short-term, intermittent use of first-generation antihistamines to induce sleep in patients with AD. OBJECTIVE: Our study aimed to determine parents' perception of the usefulness of antihistamines in reducing their child's itch due to AD. METHODS: A 12-question survey was mailed to parents of patients who were attending a pediatric allergy clinic. Patients with physician-diagnosed AD who had a clinic visit in the past 3 years were included. Questions included the following: time since AD diagnosis, itching frequency, impact on sleep, frequency and relief provided from using antihistamines, and comparison of antihistamines to other antipruritus treatments. RESULTS: Sixty three percent of parents surveyed responded that antihistamines were helpful in the management of their child's AD, and only 5% did not find any itch relief. The majority of the responders were parents of younger patients (ages, 2-10 years) with immunoglobulin E sensitization and AD for more than a year. Eighty-five parents (68.5%) reported no interruption of sleep due to itching, and, among them, an almost equal number were currently solely using either a first- or second-generation antihistamine. The more antihistamines were perceived as relieving itching, the more they were used (rho = 0.209, p = 0.025) and provided more relief than other products (rho = -0.336, p < 0.001). When compared, parents ranked antihistamines to be as helpful as topical corticosteroids. CONCLUSION: Parents of pediatric patients with AD found that antihistamines were an important part of AD management. PMID- 26932175 TI - For the Patient. Are antihistamines useful in treating childhood eczema? PMID- 26932174 TI - Chronic pruritic dermatitis and peripheral eosinophilia in a 42-year-old man. AB - Chronic pruritic dermatitis with or without accompanying peripheral eosinophilia can be caused by a vast array of underlying disorders broadly classified as allergic/immunologic, infectious, or neoplastic. An organized and thorough work up is crucial in order to arrive at a definitive diagnosis enabling appropriate treatment. We present the case of a 42-year-old man with a history of chronic pruritic dermatitis and peripheral eosinophilia in a patient-oriented, problem solving format including the clinical presentation, physical findings, results of pertinent lab/radiologic studies, differential diagnosis, and final diagnosis with discussion. PMID- 26932176 TI - External orthogonality in subsystem time-dependent density functional theory. AB - Subsystem density functional theory (subsystem DFT) is a DFT partitioning method that is exact in principle, but depends on approximations to the kinetic energy density functional (KEDF). One may avoid the use of approximate KEDFs by ensuring that the inter-subsystem molecular orbitals are orthogonal, termed external orthogonality (EO). We present a method that extends a subsystem DFT method, that includes EO, into the time-dependent DFT (TDDFT) regime. This method therefore removes the need for approximations to the kinetic energy potential and kernel, and we show that it can accurately reproduce the supermolecular TDDFT results for weakly and strongly coupled subsystems, and for systems with strongly overlapping densities (where KEDF approximations traditionally fail). PMID- 26932177 TI - Exploring the electrochemical properties of hole transport materials with spiro cores for efficient perovskite solar cells from first-principles. AB - Perovskite solar cells (PSCs) with organic small molecules as hole transport materials (HTMs) have attracted considerable attention due to their power conversion efficiencies as high as 20%. In the present work, three new spiro-type hole transport materials with spiro-cores, i.e. Spiro-F1, Spiro-F2 and Spiro-F3, are investigated by using density functional theory combined with the Marcus theory and Einstein relation. Based on the calculated and experimental highest occupied molecular orbital (HOMO) levels of 30 reference molecules, an empirical equation, which can predict the HOMO levels of hole transport materials accurately, is proposed. Moreover, a simplified method, in which the hole transport pathways are simplified to be one-dimensional, is presented and adopted to qualitatively compare the molecular hole mobilities. The calculated results show that the perovskite solar cells with the new hole transport materials can have higher open-circuit voltages due to the lower HOMO levels of Spiro-F1 (-5.31 eV), Spiro-F2 (-5.42 eV) and Spiro-F3 (-5.10 eV) compared with that of Spiro OMeTAD (-5.09 eV). Furthermore, the hole mobilities of Spiro-F1 (1.75 * 10(-2) cm(2) V(-1) s(-1)) and Spiro-F3 (7.59 * 10(-3) cm(2) V(-1) s(-1)) are 3.1 and 1.4 times that of Spiro-OMeTAD (5.65 * 10(-3) cm(2) V(-1) s(-1)) respectively, due to small reorganization energies and large transfer integrals. Interestingly, the stability properties of Spiro-F1 and Spiro-F2 are shown to be comparable to that of Spiro-OMeTAD, and the dimers of Spiro-F2 and Spiro-F3 possess better stability than that of Spiro-OMeTAD. Taking into consideration the appropriate HOMO level, improved hole mobility and enhanced stability, Spiro-F1 and Spiro-F3 may become the most promising alternatives to Spiro-OMeTAD. The present work offers a new design strategy and reliable calculation methods towards the development of excellent organic small molecules as HTMs for highly efficient and stable PSCs. PMID- 26932178 TI - Early conversion from cyclosporine to everolimus following living-donor kidney transplantation: outcomes at 5 years posttransplant in the randomized ZEUS trial. AB - AIMS: To assess 5-year efficacy, renal, and safety outcomes following early conversion from cyclosporine to everolimus vs. a standard cyclosporine-based regimen in living-donor kidney transplant (LDKT) recipients. MATERIALS AND METHODS: The ZEUS study was a randomized, open-label, 1-year, multicenter study in which 300 de novo kidney transplant recipients continued to receive cyclosporine or converted to everolimus at 4.5 months post-transplant, with annual follow-up visits to 5 years post-transplant. RESULTS: Of the 80 LDKT patients who were randomized, 75 completed the 1-year core study and 60 attended the 5-year follow-up visit. At year 5, 15/31 (48.4%) everolimus patients and 20/29 (69.0%) cyclosporine patients remained on the study drug. Mean adjusted estimated glomerular filtration rate (GFR) at year 5 in LDKT recipients was 67.2 vs. 60.8 mL/min/1.73m2 for everolimus vs. cyclosporine (mean difference 6.4 mL/min/1.73m2; p = 0.031). For patients who remained on study drug, the mean difference was 13.2 mL/min/1.73m2 (p = 0.003), but no significant difference was seen in patients who switched from study drug (mean -2.6 mL/min/1.73m2, p = 0.701). Patient and graft survival rates were similar with everolimus and cyclosporine. Biopsy-proven acute rejection occurred in 22.0% vs. 7.5% of LDKT patients randomized to everolimus vs. cyclosporine (p = 0.116). Only 1 LDKT patient discontinued everolimus due to adverse events during years 1 - 5. CONCLUSIONS: Early initiation of everolimus with calcineurin-inhibitor (CNI) withdrawal after LDKT improved graft function to 5 years post-transplant compared to standard CNI-based therapy. The renal benefit was concentrated in patients who remained on everolimus. An increase in mild acute rejection was not associated with long-term graft loss. PMID- 26932179 TI - An unexpected cause of acute kidney injury in a patient with ANCA associated vasculitis. AB - Diagnostic kidney biopsies sometimes yield clinically unsuspected diagnoses. We present a case of a 69-year-old woman with established ANCA-associated vasculitis (AAV) of 4 years duration who was in clinical remission following cytotoxic therapy and was on maintenance immunosuppression. She presented to the hospital with acute kidney injury (AKI), symptoms suggestive of a systemic vasculitis, and in addition had hypercalcemia, metabolic alkalosis. A relapse in the AAV was suspected but a diagnostic kidney biopsy showed acute tubular necrosis, patchy interstitial inflammation, and calcium phosphate deposits. It was found that the patient recently started consuming large doses of over-the-counter calcium containing antacids and vitamin Dcontaining multivitamin supplements. Cessation of these drugs led to improvement of renal function to baseline. This case highlights several teaching points: (1) the kidney biopsy can prove to be critically important even in cases where there appears to be a more obvious clinical diagnosis, (2) AK due to calcium-alkali syndrome has characteristic histopathological changes, and (3) that the triad of hypercalcemia, metabolic alkalosis, and AKI is exclusively associated with the ingestion of excessive quantities of calcium-containing antacids. The physician should keep this in mind, and pro-actively seek pertinent medication history from the patient. A brief review of calcium-alkali syndrome is given. PMID- 26932181 TI - Lethal multiple pterygium syndrome, the extreme end of the RYR1 spectrum. AB - BACKGROUND: Lethal multiple pterygium syndrome (LMPS, OMIM 253290), is a fatal disorder associated with anomalies of the skin, muscles and skeleton. It is characterised by prenatal growth failure with pterygium present in multiple areas and akinesia, leading to muscle weakness and severe arthrogryposis. Foetal hydrops with cystic hygroma develops in affected foetuses with LMPS. This study aimed to uncover the aetiology of LMPS in a family with two affected foetuses. METHODS AND RESULTS: Whole exome sequencing studies have identified novel compound heterozygous mutations in RYR1 in two affected foetuses with pterygium, severe arthrogryposis and foetal hydrops with cystic hygroma, characteristic features compatible with LMPS. The result was confirmed by Sanger sequencing and restriction fragment length polymorphism analysis. CONCLUSIONS: RYR1 encodes the skeletal muscle isoform ryanodine receptor 1, an intracellular calcium channel with a central role in muscle contraction. Mutations in RYR1 have been associated with congenital myopathies, which form a continuous spectrum of pathological features including a severe variant with onset in utero with fetal akinesia and arthrogryposis. Here, the results indicate that LMPS can be considered as the extreme end of the RYR1-related neonatal myopathy spectrum. This further supports the concept that LMPS is a severe disorder associated with defects in the process known as excitation-contraction coupling. PMID- 26932183 TI - Galactosaminogalactan of Aspergillus fumigatus, a bioactive fungal polymer. AB - Galactosaminogalactan (GAG) is an extracellular polysaccharide produced by the mycelium of the opportunistic human fungal pathogen Aspergillus fumigatus GAG is the first polysaccharide described as a virulence factor in medical mycology. This review presents our current knowledge of the structural organization and biosynthesis of this polymer. The function of this molecule as an adhesin that also masks Aspergillus PAMPs and the impact of GAG on the modulation of the host immune response by inducing neutropenia and blocking the IL-1 signaling pathway also will be emphasised. PMID- 26932180 TI - Baicalin Attenuates Ketamine-Induced Neurotoxicity in the Developing Rats: Involvement of PI3K/Akt and CREB/BDNF/Bcl-2 Pathways. AB - Ketamine is widely used as an anesthetic in pediatric clinical practice. However, numerous studies have reported that exposure to ketamine during the developmental period induces neurotoxicity. Here we investigate the neuroprotective effects of baicalin, a natural flavonoid compound, against ketamine-induced apoptotic neurotoxicity in the cortex and hippocampus of the Sprague-Dawley postnatal day 7 (PND7) rat pups. Our results revealed that five continuous injections of ketamine (20 mg/kg) at 90-min intervals over 6 h induced obvious morphological damages of neuron by Nissl staining and apoptosis by TUNEL assays in the prefrontal cortex and hippocampus of PND7 rat pups. Baicalin (100 mg/kg) pretreatment alleviated ketamine-induced morphological change and apoptosis. Caspase-3 activity and caspase-3 mRNA expression increase induced by ketamine were also inhibited by baicalin treatment. LY294002, an inhibitor of PI3K, abrogated the effect of baicalin against ketamine-induced caspase-3 activity and caspase-3 mRNA expression increase. In addition, Western blot studies indicated that baicalin not only inhibited ketamine-induced p-Akt and p-GSK-3beta decrease, but also relieved ketamine-induced p-CREB and BDNF expression decrease. Baicalin also attenuated ketamine-induced Bcl-2/Bax decrease and caspase-3 expression increase. Further in vitro experiments proved that baicalin mitigated ketamine-induced cell viability decrease in the MTT assay, morphological change by Rosenfeld's staining, and caspase-3 expression increase by Western blot in the primary neuron glia mixed cultures. LY294002 abrogated the protective effect of baicalin. These data demonstrate that baicalin exerts neuroprotective effect against ketamine induced neuronal apoptosis by activating the PI3K/Akt and its downstream CREB/BDNF/Bcl-2 signaling pathways. Therefore, baicalin appears to be a promising agent in preventing or reversing ketamine's apoptotic neurotoxicity at an early developmental stage. PMID- 26932182 TI - Cyclophilin A (CypA) Plays Dual Roles in Regulation of Bone Anabolism and Resorption. AB - CypA (Cyclophilin A) is a peptidyl-prolyl isomerase previously shown to be required for chondrogenic differentiation and endochondral ossification. However, the effects of CypA on osteoclast activity and bone maintenance are entirely unknown. Here, we show that Ppia(-/-) mice demonstrate low bone mineral density, reduced osteoblast numbers, and increased osteoclast numbers. When isolated from the calvaria, Ppia(-/-) osteoblasts demonstrate decreased osteogenic differentiation, whereas Ppia(-/-) osteoclasts derived from the long bones showed increased osteoclastic activity. Overexpression and gene silencing of CypA verified osteogenic and anti-osteoclastic effects. In osteoblasts, CypA is necessary for BMP-2 (Bone Morphogenetic Protein-2)-induced Smad phosphorylation. In osteoclasts, loss of CypA activates BtK (Bruton's tyrosine kinase) and subsequently integrates with TRAF6 (TNF receptor-associated factor 6) and/or c fos signaling to induce NFATc1 (nuclear factors of activated T cells, cytoplasmic 1). Collectively, CypA dually exerts pro-osteogenic and anti-osteoclastic effects. Thus, modulation of CypA may be useful in future efforts targeting osteoporosis. PMID- 26932184 TI - Roles of Aspergillus nidulans Cdc42/Rho GTPase regulators in hyphal morphogenesis and development. AB - The Rho-related family of GTPases are pivotal regulators of morphogenetic processes in diverse eukaryotic organisms. In the filamentous fungi two related members of this family, Cdc42 and Rac1, perform particularly important roles in the establishment and maintenance of hyphal polarity. The activity of these GTPases is tightly controlled by two sets of regulators: guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). Despite the importance of Cdc42 and Rac1 in polarized hyphal growth, the morphogenetic functions of their cognate GEFs and GAPs have not been widely characterized in filamentous fungi outside the Saccharomycotina. Here we present a functional analysis of the Aspergillus nidulans homologs of the yeast GEF Cdc24 and the yeast GAP Rga1. We show that Cdc24 is required for the establishment of hyphal polarity and localizes to hyphal tips. We also show that Rga1 is necessary for the suppression of branching in developing conidiophores. During asexual development Rga1 appears to act primarily via Cdc42 and in doing so serves as a critical determinant of conidiophore architecture. Our results provide new insight into the roles of Cdc42 during development in A nidulans. PMID- 26932185 TI - The Golgi apparatus: insights from filamentous fungi. AB - Cargo passage through the Golgi, albeit an undoubtedly essential cellular function, is a mechanistically unresolved and much debated process. Although the main molecular players are conserved, diversification of the Golgi among different eukaryotic lineages is providing us with tools to resolve standing controversies. During the past decade the Golgi apparatus of model filamentous fungi, mainly Aspergillus nidulans, has been intensively studied. Here an overview of the most important findings in the field is provided. Golgi architecture and dynamics, as well as the novel cell biology tools that were developed in filamentous fungi in these studies, are addressed. An emphasis is placed on the central role the Golgi has as a crossroads in the endocytic and secretory-traffic pathways in hyphae. Finally the major advances that the A. nidulans Golgi biology has yielded so far regarding our understanding of key Golgi regulators, such as the Rab GTPases RabC(Rab6) and RabE(Rab11), the oligomeric transport protein particle, TRAPPII, and the Golgi guanine nucleotide exchange factors of Arf1, GeaA(GBF1/Gea1) and HypB(BIG/Sec7), are highlighted. PMID- 26932186 TI - The interaction of fungi with the environment orchestrated by RNAi. AB - The fungal kingdom has been key in the investigation of the biogenesis and function of small RNAs (sRNAs). The discovery of phenomena such as quelling in Neurospora crassa represents pioneering work in the identification of the main elements of the RNA interference (RNAi) machinery. Recent discoveries in the regulatory mechanisms in some yeast and filamentous fungi are helping us reach a deeper understanding of the transcriptional and post-transcriptional gene silencing mechanisms involved in genome protection against viral infections, DNA damage and transposon activity. Although most of these mechanisms are reasonably well understood, their role in the physiology, response to the environment and interaction of fungi with other organisms had remained elusive. Nevertheless, studies in fungi such as Mucor circinelloides, Magnaporthe oryzae, Cryptococcus neoformans, Trichoderma atroviride, Botrytis cinerea and others have started to shed light on the relevance of the RNAi pathway. In these fungi gene regulation by RNAi is important for growth, reproduction, control of viral infections and transposon activity, as well as in the development of antibiotic resistance and interactions with their hosts. Moreover, the increasing number of reports of the discovery of microRNA-like RNAs in fungi under different conditions highlights the importance of fungi as models for understanding adaptation to the environment using regulation by sRNAs. The goal of this review is to provide the reader with an up-to-date overview of the importance of RNAi in the interaction of fungi with their environment. PMID- 26932188 TI - Evaluation of the genetic diversity of microsatellite markers among four strains of Oreochromis niloticus. AB - Different strains of Nile tilapia can be found worldwide. To successfully use them in breeding programs, they must be genetically characterized. In this study, four strains of Nile tilapia - UFLA, GIFT, Chitralada and Red-Stirling - were genetically characterized using 10 noncoding microsatellite loci and two microsatellites located in the promoter and first intron of the growth hormone gene (GH). The two microsatellites in the GH gene were identified at positions 693 to -679 in the promoter [motif (ATTCT)8 ] and in intron 1 at positions +140 to +168 [motif (CTGT)7 ]. Genetic diversity was measured as mean numbers of alleles and expected heterozygosity, which were 4 and 0.60 (GIFT), 3.5 and 0.71 (UFLA), 4.5 and 0.57 (Chitralada) and 2.5 and 0.42 (Red-Stirling) respectively. Genetic differentiation was estimated both separately and in combination for noncoding and GH microsatellites markers using Jost's DEST index. The UFLA and GIFT strains were the least genetically divergent (DEST = 0.10), and Chitralada and Red-Stirling were the most (DEST = 0.58). The UFLA strain was genetically characterized for the first time and, because of its unique origin and genetic distinctness, may prove to be an important resource for genetic improvement of Nile tilapia. This study shows that polymorphisms found in coding gene regions might be useful for assessing genetic differentiation among strains. PMID- 26932187 TI - Colonization of maritime glacier ice by bdelloid Rotifera. AB - Very few animal taxa are known to reside permanently in glacier ice/snow. Here we report the widespread colonization of Icelandic glaciers and ice fields by species of bdelloid Rotifera. Specimens were collected within the accumulation zones of Langjokull and Vatnajokull ice caps, among the largest European ice masses. Rotifers reached densities up to ~100 individuals per liter-equivalent of glacier ice/snow, and were freeze-tolerant. Phylogenetic analyses indicate that glacier rotifers are polyphyletic, with independent ancestries occurring within the Pleistocene. Collectively, these data identify a previously undescribed environmental niche for bdelloid rotifers and suggest their presence in comparable habitats worldwide. PMID- 26932189 TI - A polymorphic Alu insertion that mediates distinct disease-associated deletions. AB - Large deletions that are associated with insertions of Alu-derived sequence represent a rare, but potentially unique class of alterations. Whether they form by a one-step mechanism or by a primary insertion step followed by an independent secondary deletion step is not clear. We resolved two disease-associated SPAST deletions, which involve distinct exons by long range PCR. Alu-derived sequence was observed between the breakpoints in both cases. The intronic regions that represent the targets of potentially involved Alu retrotransposition events overlapped. Microsatellite- and SNP-based haplotyping indicated that both deletions originated on one and the same founder allele. Our data suggest that the deletions are best explained by two-step insertion-deletion scenarios for which a single Alu retrotransposition event represents the shared primary step. This Alu then mediated one of the deletions by non-homologous end joining and the other by non-allelic homologous recombination. Our findings thus strongly argue for temporal separation of insertion and deletion in Alu insertion-associated deletions. They also suggest that certain Alu integrations confer a general increase in local genomic instability, and that this explains why they are usually not detected during the probably short time that precedes the rearrangements they mediate. PMID- 26932190 TI - Genome-wide linkage analysis and whole-genome sequencing identify a recurrent SMARCAD1 variant in a unique Chinese family with Basan syndrome. AB - Basan syndrome is a rare autosomal dominant genodermatosis, characterized by rapidly healing congenital acral bullae, congenital milia and lack of fingerprints. A mutation in the SMARCAD1 gene was recently reported to cause Basan syndrome in one family. Here, we present a large Chinese family with Basan syndrome; some patients presented with hyperpigmentation and knuckle pads in addition to previously reported clinical manifestations. We used genome-wide linkage analysis and whole-genome sequencing (WGS) to identify the pathogenic gene in this unique pedigree. Genome-wide linkage analysis successfully mapped the candidate gene to 4p15.31-4p14 and 4q13.2-4q23. The maximal LOD score was 3.01. WGS in one patient identified a splice variant (c.378+1G>T) in the SMARCAD1 gene (NG_031945.1) that was confirmed by Sanger sequencing. Co-segregation of the variant was confirmed in this pedigree. The same variant was recently found to be associated with isolated adermatoglyphia (ADG) in another family, suggesting that this variant is causative for both Basan syndrome and autosomal dominant ADG (OMIM 136 000). This indicates that ADG and Basan syndrome may be the phenotypic variants of the same disease. Further studies should be performed to elucidate the pathogenic mechanisms induced by this variant. This report increases the phenotypic spectrum of Basan syndrome and furthers our understanding of the genetic basis of this disease. Our results also highlight the power of combining WGS and genome-wide linkage analysis in identifying causative genes in pedigrees with a genetic disorder. PMID- 26932192 TI - Comparative transcriptome analysis of muscular dystrophy models Large(myd), Dmd(mdx)/Large(myd) and Dmd(mdx): what makes them different? AB - Muscular dystrophies (MD) are a clinically and genetically heterogeneous group of Mendelian diseases. The underlying pathophysiology and phenotypic variability in each form are much more complex, suggesting the involvement of many other genes. Thus, here we studied the whole genome expression profile in muscles from three mice models for MD, at different time points: Dmd(mdx) (mutation in dystrophin gene), Large(myd-/-) (mutation in Large) and Dmd(mdx)/Large(myd-/-) (both mutations). The identification of altered biological functions can contribute to understand diseases and to find prognostic biomarkers and points for therapeutic intervention. We identified a substantial number of differentially expressed genes (DEGs) in each model, reflecting diseases' complexity. The main biological process affected in the three strains was immune system, accounting for the majority of enriched functional categories, followed by degeneration/regeneration and extracellular matrix remodeling processes. The most notable differences were in 21-day-old Dmd(mdx), with a high proportion of DEGs related to its regenerative capacity. A higher number of positive embryonic myosin heavy chain (eMyHC) fibers confirmed this. The new Dmd(mdx)/Large(myd-/-) model did not show a highly different transcriptome from the parental lineages, with a profile closer to Large(myd-/-), but not bearing the same regenerative potential as Dmd(mdx). This is the first report about transcriptome profile of a mouse model for congenital MD and Dmd(mdx)/Large(myd). By comparing the studied profiles, we conclude that alterations in biological functions due to the dystrophic process are very similar, and that the intense regeneration in Dmd(mdx) involves a large number of activated genes, not differentially expressed in the other two strains. PMID- 26932191 TI - Clinical, neuroradiological and molecular characterization of cerebellar dysplasia with cysts (Poretti-Boltshauser syndrome). AB - Cerebellar dysplasia with cysts and abnormal shape of the fourth ventricle, in the absence of significant supratentorial anomalies and of muscular involvement, defines recessively inherited Poretti-Boltshauser syndrome (PBS). Clinical features comprise non-progressive cerebellar ataxia, intellectual disability of variable degree, language impairment, ocular motor apraxia and frequent occurrence of myopia or retinopathy. Recently, loss-of-function variants in the LAMA1 gene were identified in six probands with PBS. Here we report the detailed clinical, neuroimaging and genetic characterization of 18 PBS patients from 15 unrelated families. Biallelic LAMA1 variants were identified in 14 families (93%). The only non-mutated proband presented atypical clinical and neuroimaging features, challenging the diagnosis of PBS. Sixteen distinct variants were identified, which were all novel. In particular, the frameshift variant c.[2935delA] recurred in six unrelated families on a shared haplotype, suggesting a founder effect. No LAMA1 variants could be detected in 27 probands with different cerebellar dysplasias or non-progressive cerebellar ataxia, confirming the strong correlate between LAMA1 variants and PBS. PMID- 26932193 TI - Halogenated carbazoles induce cardiotoxicity in developing zebrafish (Danio rerio) embryos. AB - Halogenated carbazoles are increasingly identified as a novel class of environmental contaminants. However, no in vivo acute toxicity information on those compounds was available. In the present study, an in vivo zebrafish embryonic model (Danio rerio) was used to investigate the developmental toxicity of those halogenated carbazoles. The results suggested that acute toxicity was structure-dependent. Two of the 6 tested carbazoles, 2,7-dibromocarbazole (27 DBCZ) and 2,3,6,7-tetrachlorocarbazole, showed obvious developmental toxicity at nanomolar levels. The typical phenotypes were similar to dioxin-induced cardiotoxicity, including swollen yolk sac, pericardial sac edema, elongated and unlooped heart, and lower jaw shortening. During embryonic development 27-DBCZ also induced a unique pigmentation decrease. Gene expression and protein staining of cytochrome P4501A (CYP1A) showed that both halogenated carbazoles could induce CYP1A expression at the micromolar level and primarily in the heart area, which was similar to dioxin activity. Further, aryl hydrocarbon receptor-(AhR)2 gene knockdown with morpholino confirmed that the acute cardiotoxicity is AhR dependent. In conclusion, the results demonstrate that halogenated carbazoles represent yet another class of persistent organic pollutants with dioxin-like activity in an in vivo animal model. Environ Toxicol Chem 2016;35:2523-2529. (c) 2016 SETAC. PMID- 26932194 TI - MicroCT assessment of bone microarchitecture in implant sites reconstructed with autogenous and xenogenous grafts: a pilot study. AB - PURPOSE: To assess bone microarchitecture in maxillary sites grafted with autogenous or xenogenous grafts as well as to demonstrate the usefulness of microCT in dental implant research. MATERIALS AND METHODS: Samples (n = 12) consisting of titanium fixation screws covered by at least 0.5-1 mm of human bone were obtained from 17 sites grafted with autogenous or xenogenous materials and prepared for microCT scanning and conventional histology. Bone histomorphometric parameters were evaluated in three distinct regions (graft region, transitional region, and native bone region). Three-dimensional (3D) bone-to-implant contact (BIC) calculation was performed using microCT data. Histological sections were used to calculate two-dimensional (2D) BIC percentages, which were compared with values obtained from 2D microCT images. RESULTS: Histomorphometric parameters varied according to the type of graft used, but sites reconstructed with autogenous bone showed higher mean values in general. In autograft samples, indices for parameters such as Tb.Th and Tb.Sp were significantly different when the native bone region was compared to the graft region. While a higher mean 3D BIC was found in the native bone region for both graft materials, significant BIC differences were absent when graft types were compared. The 2D BIC percentages obtained from histological and microCT images were similar. CONCLUSIONS: Autografts outperformed the xenogenous material used in this study concerning the histomorphometric parameters assessed. While graft type did not seem to influence 3D BIC, the native bone region showed the highest BIC percentages when compared to the other regions in both graft groups. In addition, 2D BIC ratios were similar regardless of graft material or image source (histological sections x microCT slices). Taken together, our findings suggest that microCT is an effective tool for 2D and 3D histomorphometric and BIC assessments in dental implant research. PMID- 26932195 TI - Presence of an isoform of H+-pyrophosphatase located in the alveolar sacs of a scuticociliate parasite of turbot: physiological consequences. AB - H+-pyrophosphatases (H+-PPases) are integral membrane proteins that couple pyrophosphate energy to an electrochemical gradient across biological membranes and promote the acidification of cellular compartments. Eukaryotic organisms, essentially plants and protozoan parasites, contain various types of H+-PPases associated with vacuoles, plasma membrane and acidic Ca+2 storage organelles called acidocalcisomes. We used Lysotracker Red DND-99 staining to identify two acidic cellular compartments in trophozoites of the marine scuticociliate parasite Philasterides dicentrarchi: the phagocytic vacuoles and the alveolar sacs. The membranes of these compartments also contain H+-PPase, which may promote acidification of these cell structures. We also demonstrated for the first time that the P. dicentrarchi H+-PPase has two isoforms: H+-PPase 1 and 2. Isoform 2, which is probably generated by splicing, is located in the membranes of the alveolar sacs and has an amino acid motif recognized by the H+-PPase specific antibody PABHK. The amino acid sequences of different isolates of this ciliate are highly conserved. Gene and protein expression in this isoform are significantly regulated by variations in salinity, indicating a possible physiological role of this enzyme and the alveolar sacs in osmoregulation and salt tolerance in P. dicentrarchi. PMID- 26932196 TI - Biochemical reconstitution of TET1-TDG-BER-dependent active DNA demethylation reveals a highly coordinated mechanism. AB - Cytosine methylation in CpG dinucleotides is an epigenetic DNA modification dynamically established and maintained by DNA methyltransferases and demethylases. Molecular mechanisms of active DNA demethylation began to surface only recently with the discovery of the 5-methylcytosine (5mC)-directed hydroxylase and base excision activities of ten-eleven translocation (TET) proteins and thymine DNA glycosylase (TDG). This implicated a pathway operating through oxidation of 5mC by TET proteins, which generates substrates for TDG dependent base excision repair (BER) that then replaces 5mC with C. Yet, direct evidence for a productive coupling of TET with BER has never been presented. Here we show that TET1 and TDG physically interact to oxidize and excise 5mC, and proof by biochemical reconstitution that the TET-TDG-BER system is capable of productive DNA demethylation. We show that the mechanism assures a sequential demethylation of symmetrically methylated CpGs, thereby avoiding DNA double strand break formation but contributing to the mutability of methylated CpGs. PMID- 26932198 TI - Advances in plant-based inhibitors of P-glycoprotein. AB - Multidrug resistance (MDR) has emerged as the main problem in anti-cancer therapy. Although MDR involves complex factors and processes, the main pivot is the expression of multidrug efflux pumps. P-glycoprotein (P-gp) belongs to the family of adenosine triphosphate (ATP)-binding cassette (ABC) transporters. It functions in cellular detoxification, pumping a wide range of xenobiotic compounds out of the cell. An attractive therapeutic strategy for overcoming MDR is to inhibit the transport function of P-gp and thus, increase intracellular concentration of drugs. Recently, various types of P-gp inhibitors have been found and used in experiments. However, none of them has passed clinical trials due to their high side-effects. Hence, the search for alternatives, such as plant based P-gp inhibitors have gained attention recently. Therefore, we give an overview of the source, function, structure and mechanism of plant-based P-gp inhibitors and give more attention to cancer-related studies. These products could be the future potential drug candidates for further research as P-gp inhibitors. PMID- 26932197 TI - Integrated metabolomics and metagenomics analysis of plasma and urine identified microbial metabolites associated with coronary heart disease. AB - Coronary heart disease (CHD) is top risk factor for health in modern society, causing high mortality rate each year. However, there is no reliable way for early diagnosis and prevention of CHD so far. So study the mechanism of CHD and development of novel biomarkers is urgently needed. In this study, metabolomics and metagenomics technology are applied to discover new biomarkers from plasma and urine of 59 CHD patients and 43 healthy controls and trace their origin. We identify GlcNAc-6-P which has good diagnostic capability and can be used as potential biomarkers for CHD, together with mannitol and 15 plasma cholines. These identified metabolites show significant correlations with clinical biochemical indexes. Meanwhile, GlcNAc-6-P and mannitol are potential metabolites originated from intestinal microbiota. Association analysis on species and function levels between intestinal microbes and metabolites suggest a close correlation between Clostridium sp. HGF2 and GlcNAc-6-P, Clostridium sp. HGF2, Streptococcus sp. M143, Streptococcus sp. M334 and mannitol. These suggest the metabolic abnormality is significant and gut microbiota dysbiosis happens in CHD patients. PMID- 26932200 TI - Nano-scale polar-nonpolar oxide heterostructures for photocatalysis. AB - We proposed based on first principles density functional theory calculations that a nano-scale thin film based on a polar-nonpolar transition-metal oxide heterostructure can be used as a highly-efficient photocatalyst. This is demonstrated using a SrTiO3/LaAlO3/SrTiO3 sandwich-like heterostructure with photocatalytic activity in the near-infrared region. The effect of the polar nature of LaAlO3 is two-fold. First, the induced electrostatic field accelerates the photo-generated electrons and holes into opposite directions and minimizes their recombination rates. Hence, the reduction and oxidation reactions can be instigated at the SrTiO3 surfaces located on the opposite sides of the heterostructure. Second, the electric field reduces the band gap of the system making it photoactive in the infrared region. We also show that charge separation can be enhanced by using compressive strain engineering that creates ferroelectric instability in STO. The proposed setup is ideal for tandem oxide photocatalysts especially when combined with photoactive polar materials. PMID- 26932199 TI - Repositioning "old" drugs for new causes: identifying new inhibitors of prostate cancer cell migration and invasion. AB - The majority of prostate cancer (PCa) deaths occur due to the metastatic spread of tumor cells to distant organs. Currently, there is a lack of effective therapies once tumor cells have spread outside the prostate. It is therefore imperative to rapidly develop therapeutics to inhibit the metastatic spread of tumor cells. Gain of cell motility and invasive properties is the first step of metastasis and by inhibiting motility one can potentially inhibit metastasis. Using the drug repositioning strategy, we developed a cell-based multi-parameter primary screening assay to identify drugs that inhibit the migratory and invasive properties of metastatic PC-3 PCa cells. Following the completion of the primary screening assay, 33 drugs were identified from an FDA approved drug library that either inhibited migration or were cytotoxic to the PC-3 cells. Based on the data obtained from the subsequent validation studies, mitoxantrone hydrochloride, simvastatin, fluvastatin and vandetanib were identified as strong candidates that can inhibit both the migration and invasion of PC-3 cells without significantly affecting cell viability. By employing the drug repositioning strategy instead of a de novo drug discovery and development strategy, the identified drug candidates have the potential to be rapidly translated into the clinic for the management of men with aggressive forms of PCa. PMID- 26932201 TI - Metabolomics reveals the physiological response of Pseudomonas putida KT2440 (UWC1) after pharmaceutical exposure. AB - Human pharmaceuticals have been detected in wastewater treatment plants, rivers, and estuaries throughout Europe and the United States. It is widely acknowledged that there is insufficient information available to determine whether prolonged exposure to low levels of these substances is having an impact on the microbial ecology in such environments. In this study we attempt to measure the effects of exposing cultures of Pseudomonas putida KT2440 (UWC1) to six pharmaceuticals by looking at differences in metabolite levels. Initially, we used Fourier transform infrared (FT-IR) spectroscopy coupled with multivariate analysis to discriminate between cell cultures exposed to different pharmaceuticals. This suggested that on exposure to propranolol there were significant changes in the lipid complement of P. putida. Metabolic profiling with gas chromatography-mass spectrometry (GC MS), coupled with univariate statistical analyses, was used to identify endogenous metabolites contributing to discrimination between cells exposed to the six drugs. This approach suggested that the energy reserves of exposed cells were being expended and was particularly evident on exposure to propranolol. Adenosine triphosphate (ATP) concentrations were raised in P. putida exposed to propranolol. Increased energy requirements may be due to energy dependent efflux pumps being used to remove propranolol from the cell. PMID- 26932202 TI - Cyproterone acetate vs leuprolide acetate in combination with transdermal oestradiol in transwomen: a comparison of safety and effectiveness. AB - OBJECTIVE: To retrospectively compare the effectiveness and safety of 1-year administration of transdermal oestradiol (TE) with cyproterone acetate (CPA) or leuprolide acetate (Leu) in transwomen. DESIGN, PATIENTS AND MEASUREMENTS: Forty transwomen received 50 mg of CPA daily orally (n = 20; CPA+E group) or Leu at a dose of 3.75 mg i.m. monthly (n = 20; Leu+E group) in combination with TE at a dose of 1 or 2 mg daily for 1 year. Reproductive hormones, biochemical parameters, body composition and bone mineral density were assessed. RESULTS: LH, FSH and total testosterone levels were significantly decreased by month three of hormone administration in both groups and continued to decrease until month 12; the decrease in LH levels in the first 12 months was significantly faster in the Leu+E group. Prolactin was significantly increased at month 12 in the CPA+E group only. Bone metabolism parameters and bone mineral density as detected at DEXA did not significantly change in either group, apart from a statistically significant increase in parathyroid hormone after 52 weeks of Leu administration. Total cholesterol and HDL-cholesterol were significantly increased in the Leu+E group and reduced in the CPA+E group. No major adverse effects were registered in either group. Psychological well-being parameters did not differ between the two groups. CONCLUSIONS: Preliminary results from this retrospective observational pilot study suggest that CPA and Leu in combination with TE are equally effective in the suppression of gonadotrophins and testosterone levels over 1 year. Whether the different effects on HDL-cholesterol may lead to long-term different cardiovascular safety profiles remains to be defined. PMID- 26932204 TI - Multicomponent self-assembly of a pentanuclear Ir-Zn heterometal-organic polyhedron for carbon dioxide fixation and sulfite sequestration. AB - By incorporating a fac-tris(4-(2-pyridinyl)phenylamine)iridium as the backbone of the tripodal ligand to constrain the coordination geometry of Zn(II) ions, a pentanuclear Ir-Zn heterometal-organic luminescent polyhedron was obtained via a subcomponent self-assembly for carbon dioxide fixation and sulfite sequestration. PMID- 26932205 TI - Use of streambed substrate as refuge by steelhead or rainbow trout Oncorhynchus mykiss during simulated freshets. AB - A flume was used to estimate the carrying capacity of streambed substrates for juvenile steelhead or rainbow trout Oncorhynchus mykiss seeking refuge from simulated freshets. The simulated freshets had mean water column velocities of c. 1.1 m s(-1). The number of O. mykiss finding cover within the interstices of the substrate was documented for different substrate sizes and levels of embeddedness. The availability of suitable refuges determined the carrying capacity of the substrate for O. mykiss. For the size of the O. mykiss tested [mean +/- s.d. fork length (L(F)) = 122 +/- 12.6 mm], the number of interstices with depths >=200 mm measured with a 14.0 mm diameter flexible plastic tube was the best predictor of the number of O. mykiss able to find cover (r(2) = 0.75). Oncorhynchus mykiss seeking refuge from freshets may need deeper interstices than those seeking concealment at autumn or winter base flows. The availability of interstices suitable as refuge from high flows may determine autumn and winter carrying capacity. PMID- 26932203 TI - Dexmedetomidine Postconditioning Reduces Brain Injury after Brain Hypoxia Ischemia in Neonatal Rats. AB - Perinatal asphyxia can lead to death and severe disability. Brain hypoxia ischemia (HI) injury is the major pathophysiology contributing to death and severe disability after perinatal asphyxia. Here, seven-day old Sprague-Dawley rats were subjected to left brain HI. Dexmedetomidine was given intraperitoneally after the brain HI. Yohimbine or atipamezole, two alpha2 adrenergic receptor antagonists, were given 10 min before the dexmedetomidine injection. Neurological outcome was evaluated 7 or 28 days after the brain HI. Frontal cerebral cortex was harvested 6 h after the brain HI. Left brain HI reduced the left cerebral hemisphere weight assessed 7 days after the brain HI. This brain tissue loss was dose-dependently attenuated by dexmedetomidine. Dexmedetomidine applied within 1 h after the brain HI produced this effect. Dexmedetomidine attenuated the brain HI-induced brain tissue and cell loss as well as neurological and cognitive dysfunction assessed from 28 days after the brain HI. Dexmedetomidine postconditioning-induced neuroprotection was abolished by yohimbine or atipamezole. Brain HI increased tumor necrosis factor alpha and interleukin 1beta in the brain tissues. This increase was attenuated by dexmedetomidine. Atipamezole inhibited this dexmedetomidine effect. Our results suggest that dexmedetomidine postconditioning reduces HI-induced brain injury in the neonatal rats. This effect may be mediated by alpha2 adrenergic receptor activation that inhibits inflammation in the ischemic brain tissues. PMID- 26932206 TI - Rhodococcus equi hyperimmune plasma decreases pneumonia severity after a randomised experimental challenge of neonatal foals. AB - Since a vaccine is not available against Rhodococcus equi, R equi-specific hyperimmune plasma (HIP) is commonly used, although its efficacy remains controversial. The objective of this study was to evaluate the ability of a commercially available HIP to prevent clinical rhodococcal pneumonia in neonatal foals after experimental challenge. PMID- 26932208 TI - [PTEN and NBS1 gene mutations in familial breast cancer and early-onset breast cancer from Hunan Province in China]. AB - OBJECTIVE: To investigate the profile and potential significance of PTEN and NBS1 mutations among patients with familial or at early onset breast cancer in Hunan province.? METHODS: A total of 131 breast cancer patients with familial history or suffered from breast cancer at the age of less than 35 years old were included in this study. A comprehensive phosphatase and tensin homolog (PTEN) and nibrin (NBS1) mutation analysis was performed through denaturing high performance liquid chromatography (DHPLC) and subsequent DNA direct sequencing.? RESULTS: Among 131 patients, a reported mutation IVS4+109insTCTTA in PTEN gene were identified in two patients. The mutation frequency of IVS4+109insTCTTA was 1.15%. Two mutations in PTEN gene, 225 A>C (Thr 160 Pro) and IVS5+13T>C, was firstly discovered. Another reported missense mutation was rs121909229 G>A (Arg 130 Gln). Three mutations were detected in NBS1 gene, of which IVS6+43A>G and IVS6+127A>G were firstly discovered and another reported synonymous mutations was rs1805794 G>C (Glu 185 Gln).? CONCLUSION: The novel mutations in PTEN and NBS1 might be specific to the familial and early-onset breast cancer of Chinese Hunan population. PMID- 26932207 TI - A study on the transfection of antisense oligonucletide into kidney mediated by lipid microbubbles. AB - OBJECTIVE: To study the safety and efficiency of the transfection of antisense oligonucletide into kidney mediated by lipid microbubbles, and to evaluate its potential clinical application. METHODS: The potential and conditions regarding the transfection self-made lipid microbubbles (CY5)-labeled-oligonucleotide (ODN) or CY5-labeled-ODN connective tissue growth factor (CTGF) into the rat kidney were evaluated. Th e safety was evaluated by HE staining, liver and renal function tests. The transfection efficiency was evaluated by fluorescence microscopy. Th e expression of CTGF was detected by RT-PCR and Western blot. RESULTS: Self-made lipid microbubble and/or ultrasound significantly enhanced the efficiency of gene transfer and expression in the kidney. Especially, 85%-90% of total glomerular could be transfected. CY5-labeled-ODN expression could be observed in glomerular, tubular and interstitial area. Th ere was no significant change in blood tests aft er gene transfer. Levels of LDH in 7 days were decreased compared with that at the fi rst day aft er the transfection (P<0.05). CTGF expression was successfully suppressed by transfection of CTGF-antisense-ODN into kidney. CONCLUSION: The ultrasound-mediated gene transfer by self-made lipid microbubble could enhance the efficiency of ODN and expression in the rat kidney. Th is self-made lipid microbubbles supplement may be use for transfection of target genes. PMID- 26932209 TI - [Expression of LXR-beta in human gastric cancer tissue and the effect of GW3965 on the proliferation of gastric cancer cell line SGC-7901]. AB - OBJECTIVE: To examine the expression of liver X receptor-beta (LXR-beta) in human gastric cancer tissue, and to explore the effect of GW3965, an agonist of LXRs, on proliferation of gastric cancer cell line SGC-7901.? METHODS: The immunohistochemical assay was used to detect the expression of LXR-beta, activating transcription factor 4 (ATF4) in gastric cancer tissues and the corresponding pericarcinoma tissues in 114 patients. Real-time quantitative PCR and Western blot were used to determine mRNA and protein levels of ATF4 and ATP binding cassette 1 (ABCA1), one of the downstream target genes of LXRs, in SGC 7901 cells with or without GW3965 treatment. Cell counting kit-8 (CCK-8) assay was performed to detect cell proliferation. The expression of ATF4 was silenced by short hairpin RNA (shRNA).? RESULTS: The expressions of LXR-beta and ATF-4 were obviously down-regulated in the gastric cancer tissues than that in the corresponding pericarcinoma tissues (both P<0.05). Compared with the control cells, GW3965 treatment inhibited proliferation of SGC-7901 cells and up regulated ATF4 and ABCA1 expressions (both P<0.05). Knockdown of ATF4 can reverse the antiproliferative effect of GW3965 on SGC-7901 cells.? CONCLUSION: The expression of LXR-beta is decreased in human gastric cancer tissues, and activation of LXRs by GW3965 could inhibit the proliferation of SGC-7901 cells via ATF4. PMID- 26932210 TI - [Effects of compound malt pills on expressions of ERalpha and ERbeta in ovaries of rats with letrozole-induced polycystic ovarian syndrome]. AB - OBJECTIVE: To explore the effect of compound malt pills (CMP) on polycystic ovarian syndrome (PCOS) rat model induced by letrozole and the underlying mechanisms.? METHODS: To establish a PCOS rat model, 48 female SD rats aged 6 weeks were randomly divided into 6 groups (n=8): A normal group, a model control group, a positive control group, a low-dose CMP group, a middle-dose CMP group, and a high-dose CMP group. Rats were treated for 21 days after the PCOS model was successfully established. Ovarian morphology changes were observed, and the expressions of ERalpha and ERbeta was examined by immunohistochemistry, Western blot and RT-PCR, respectively.? RESULTS: Compared with the normal group, the number of follicular cystic dilatation in the model control group was increased and the granulosa cells were decreased. After the treatment, the number of follicular cystic dilatation was reduced compared with the model control group, but the primordial follicles, corpus luteum and granulosa cells were increased. The expressions of ERalpha and ERbeta in the model control group were significantly decreased (P<0.01), which were increased in the intervention groups (P<0.05 or P<0.01).? CONCLUSION: CMP may play a role in the treatment of PCOS by regulating the expressions of ERalpha and ERbeta. PMID- 26932211 TI - [Correlation between cognitive impairment and diabetic nephropathy in patients with Type 2 diabetes mellitus]. AB - OBJECTIVE: To explore the correlation between diabetic nephropathy (DN) and cognitive impairment through examining the cognitive function and the metabolism of the cerebrum in Type 2 diabetes mellitus patients at different stages of renal function.? METHODS: Eighty six patients with Type 2 diabetes mellitus (T2DM) were enrolled for this study. According to the urinary albumin excretion rate (UAER), the patients were divided into a T2DM without DN group (DM group, n=33), an early DN group (DN-III group, n=26) and a clinical stage group (DN-IV group, n=27). Thirty healthy adults were selected as a control group (NC group). Biochemical indexes and UAER were measured, and glomerular filtration rate (GFR) was detected by single-photon emission computed tomography (SPECT). The cognitive function was measured by Montreal Cognitive Assessment (MoCA, Beijing version) and mini-mental state examination (MMSE). The peak areas of N-acetylasparte (NAA), creatine (Cr), choline-containing compounds (Cho) were detected by proton magnetic resonance spectroscopy (1H-MRS).? RESULTS: 1) There was no statistical difference in MMSE scores between the DM group and the control group. The scores of MoCA in the DN III group or in the DN-IV group were significant less than that in the NC group (F=3.66, P<0.05); 2) There was significant difference in left N-acetylaspartate (LNAA), left choline (LCho) among the diabetes groups. Compared with the DM group, the level of LNAA was decreased significantly (t=3.826, P<0.05) while the LCho was increased significantly (t=4.373, P<0.05) in the DN groups, with statistic difference between the 2 groups (t=3.693, P<0.05); 3) The MoCA scores of T2DM patients were negatively correlated with UAER (r=-0.285, P<0.05), while positively correlated with GFR (r=0.379, P<0.05); 4) Logistic regression analysis indicated that UAER and GFR were the major risky factors for diabetic cognitive impairment.? CONCLUSION: Diabetic cognitive impairment is closely correlated with the nephropathy in patients with Type 2 diabetes. With the decline in glomerular filtration function, the cognitive disorder tends to be aggravated. The hippocampal brain metabolism may have some changes in left side of Cho/Cr in patients with diabetic nephropathy. PMID- 26932212 TI - [Clinical study on surgical method and prognosis in diffuse-type advanced gastric cancer]. AB - OBJECTIVE: To explore the prognosis and surgical method for diffuse-type advanced gastric cancer (AGC).? METHODS: The clinicopathological data of patient, who underwent curative gastrectomy in the Second Hospital Affiliated to Lanzhou University from 2005 to 2010, were analyzed retrospectively. The prognostic factors of diffuse-type AGC were analyzed by Cox regression models. The patients were divided into a total gastrectomy group (n=120) and a subtotal gastrectomy group (n=167) according to the surgical approach. Survival rates were established by the Kaplan-Meier method and compared by the Log-rank test between the total gastrectomy group and the subtotal gastrectomy group.? RESULTS: A total of 287 patients with diffuse-type AGC were enrolled in this study, including 120 patients in the total gastrectomy group and 167 patients in the subtotal gastrectomy group. Univariate analysis showed that the prognosis of diffuse-type AGC was associated with body mass index, number of retrieved lymph nodes, Borrmann type, tumor size, T stage, N stage, tumor-node-metastasis (TNM) stage, extent of resection, surgical margin, postoperative complication, perineural and vascular invasion (all P<0.01). Multivariate analysis showed that normal body mass index, tumor size, T stage, N stage, total gastrectomy, surgical margin, postoperative complication were the independent predictors for diffuse-type AGC (all P<0.05). The 5-year overall survival rate and progression-free survival rate for diffuse-type AGC after curative gastrectomy were 17.8% and 13.6%, respectively. The median survival time and progression-free survival of them were 22 and 18 months, respectively. The overall survival rate and progression-free survival rate in the total gastrectomy group was significantly higher than that in the subtotal gastrectomy (P<0.01); the extended extent of lymph node dissection, the lower rate of positive surgical margin and postoperative complications were present in the total gastrectomy group (all P<0.05 or P<0.01).? CONCLUSION: The patients with diffuse-type AGC have a poor prognosis. The great tumor diameter, advanced T stage, advanced N stage, subtotal gastrectomy, high rate of positive surgical margin and postoperative complication are independent risky factors for the diffuse-type AGC. However, the total gastrectomy may be beneficial to patients. PMID- 26932213 TI - [Efficacy and safety of peroral endoscopic myotomy in the treatment of achalasia cardia]. AB - OBJECTIVE: To evaluate the efficacy and safety of peroral endoscopic myotomy (POEM) for achalasia cardia (AC).? METHODS: A total of 62 patients with AC were enrolled and treated with POEM in the Third Xiangya Hospital, Central South University from April 2012 to October 2014. The symptoms and complications were retrospectively analyzed.? RESULTS: The ages of patients, including 32 males and 30 females, were 14-68 (43.2+/-5.6) years old. Eckardt scores were 4-6 or >=7 for 25 patients or 37 patients (including 20 patients were at a score of 12). Thirteen patients suffered balloon expansion for 2-3 times. Sixty-one patients had completed POEM treatment, 1 patient were given Heller surgery instead of POEM because of extensive submucosal adhesion during POEM. The operative time for POEM was (60.8+/-15.1) min. Fourteen patients had mild subcutaneous emphysema. Among them, 5 suffered pneumoperitoneum and felt better after abdominal puncture exhaust; 2 patients suffered bronchospasm hypoxemia and were relieved after treatment by positive pressure oxygen for 1 h. The hospital stay was (4.3+/-1.2) d. The postoperative follow-up period was (11.4+/-5.4) months. Swallowing obstruction, vomiting and chest pain in patients was relieved at different degrees. The treatment effective rate was 100%. ? CONCLUSION: POEM is a safe, effective and minimally invasive approach for AC. PMID- 26932215 TI - [Effects of orthokeratology lenses on the magnitude of accommodative lag and accommodativeconvergence/accommodation]. AB - OBJECTIVE: To evaluate the change in accommodative lag and accommodation convergence/accommodation (AC/A) after patients with myopia wear orthokeratology lenses. ? METHODS: A total of 48 myopic subjects (a test group), who wore orthokeratology lenses regularly, and 48 myopic subjects (a control group), who wore spectacles regularly, were enrolled for this study from January 2011 to January 2013 in Optometric Center, the Forth Hospital of Changsha. Accommodative lag was measured by fused cross cylinder method, where the patients should gaze at the front optotypes 40 cm away. Gradient of the AC/A ratio was measured by Von Grafe method to check closer distance heterophoria. Accommodative lag and AC/A ratio were analyzed by statistics.? RESULTS: After 1-year follow-up, accommodative lag and AC/A rate in patients with low or moderate myopia in the test group was decreased in 1, 3, 6 months or 1 year compared with that in the control group (P<0.05). ? CONCLUSION: Compared with spectacles, orthokeratology lenses are able to decrease accommodative lag and high AC/A rate in patients with low or moderate myopia. The relationship between accommodation and convergence is improved by orthokeratology lenses. Orthokeratology is an effective way to control myopia. PMID- 26932214 TI - [Compliance of extramural hospital treatment and long-term survival status in patients with acute myocardial infarction]. AB - OBJECTIVE: To explore the compliance of extramural hospital treatment and the long-term survival status in patients with acute myocardial infarction (AMI) in Chongqing.? METHODS: A total of 636 patients with AMI, from grade 3 and first class hospitals in Chongqing during Jan 2005 and Jan 2009, were enrolled for this study. The patients were followed-up for 5 years to investigate the extramural hospital treatment and influential factors.? RESULTS: A total of 574 patients finished a five-year follow-up, and 180 cases died from cardiac death. The mortality was 31.4%. The poor compliance was a major feature in the pass away patients.? CONCLUSION: The low treatment compliance is the independent risky factor for 5-year prognosis. PMID- 26932216 TI - [Accuracy of three common optometry methods in examination of refraction in juveniles]. AB - OBJECTIVE: To compare the results of the three methods of Suresight handheld autorefractor, table-mounted autorefractor and retinoscopy in examination of juveniles patients with or without cycloplegia.? METHODS: Firstly, 156 eyes of 78 juveniles (5 to 17 years old) were examined by using WelchAllyn Suresight handheld autorefractor and NIDEK ARK-510A table-mounted autorefractor with or without cycloplegia; secondly, retinoscopy was performed with cycloplegia.? RESULTS: The spherical power measured by methods without cycloplegia were significantly greater than those measured with cycloplegia (P<0.05); without cycloplegia, there was no significant difference in spherical power, cylindrical power and cylindrical axis between Suresight handheld autorefractor and retinoscopy (P>0.05). These results were highly consistent, suggesting a tendency towards a short sight. However, the spherical power and cylindrical power measured by table-mounted autorefractor was significantly different (P<0.05); with cycloplegia, there was significant difference in spherical power between Suresight handheld autorefractor and retinoscopy (P<0.05).? CONCLUSION: Cycloplegic retinoscopy is necessary for juvenile refraction examination. Under natural pupil situation, Suresight handheld autorefractor is better than table mounted autorefractor, though both show a myopia tendency. Nevertheless, table mounted autorefractor can be taken as a recommendation for the prescription of lens trial. As a strong reference for subjective optometry, retinoscopy should be the gold standard for measuring refractive errors. PMID- 26932217 TI - [Comprehensive evaluation on the prescription behavior for outpatients in primary health care institutions of Yiyang]. AB - OBJECTIVE: To evaluate the prescription behavior for outpatients in primary health care institutions of Yiyang and to provide scientific basis for promoting the rational use of drugs.? METHODS: A multi-stage random sampling method was conducted in 21 primary health care institutions from Yiyang. Fifteen prescriptions were randomly selected in every month from each institution and a total of 3780 prescriptions were eventually collected in a year.? RESULTS: Both the number of drugs and percentage of injection in a prescription were greater than the international standards. Children were more likely to be prescribed by multiple prescriptions, antibiotics prescriptions, hormones and injections prescriptions. The utilization of essential drug was more frequent in female. Antibiotics and hormones were more frequently used in summer and autumn season. Polypharmacy, antibiotics, injections and essential drugs were more frequently used in hospitals of small town. The skin and subcutaneous tissue diseases were often treated with multiple prescriptions, while the respiratory diseases were often treated with antibiotics, hormones and injections. Most primary health care institutions were at the upper limit of rational drug use.? CONCLUSION: The usage of prescription drug in most primary health care is rational, but some still surpass international standards. Thus, primary health care physicians should strictly control their prescriptions behavior. PMID- 26932218 TI - [Study on the risk of HIV transmission by heterosexual contact and the correlation factors]. AB - OBJECTIVE: To understand the associated factors on human immunodeficiency virus (HIV) transmission via heterosexual contact and to provide evidence for decision maker for prevention of HIV.? METHODS: Questionnaire survey was conducted in 250 HIV-positive persons to understand their socio-demographic characteristics and sexual behavior. Meanwhile, 431 persons who had heterosexual contact with the HIV carriers were traced to their HIV infection status. The factors associated with continued HIV transmission were reviewed by case-control analysis.? RESULTS: Among the 432 persons, 59 were HIV-positive because of heterosexual contact. The secondary attack rate and the growth rate was 13.7% (59/431) and 0.236 (59/250), respectively. The factors associated with the spread of HIV included: the degree of knowledge on HIV/AIDS, psychological reflection after infection, the condition for condom usage among spouses, and regular sexual partners or non regular sexual partners.? CONCLUSION: The secondary attack rate and the growth rate of HIV transmission by heterosexual contact are high. Improvement of the knowledge about HIV/AIDS prevention and control, enhancement of psychological education and promotion of condom usage can reduce the risk for continued HIV transmission. PMID- 26932219 TI - Application of next generation sequencing technology in Mendelian movement disorders. AB - Next generation sequencing (NGS) has developed very rapidly in the last decade. Compared with Sanger sequencing, NGS has the advantages of high sensitivity and high throughput. Movement disorders are a common type of neurological disease. Although traditional linkage analysis has become a standard method to identify the pathogenic genes in diseases, it is getting difficult to find new pathogenic genes in rare Mendelian disorders, such as movement disorders, due to a lack of appropriate families with high penetrance or enough affected individuals. Thus, NGS is an ideal approach to identify the causal alleles for inherited disorders. NGS is used to identify genes in several diseases and new mutant sites in Mendelian movement disorders. This article reviewed the recent progress in NGS and the use of NGS in Mendelian movement disorders from genome sequencing and transcriptome sequencing. A perspective on how NGS could be employed in rare Mendelian disorders is also provided. PMID- 26932220 TI - [Progress in studies on the role of beta-catenin in regulating the self-renewal and pluripotency of embryonic stem cells]. AB - Embryonic stem cells (ESCs) is one of the best cell types for regenerative medicine. It is derived from inner cell mass of the blastocyst stage and characterized by self-renewal and pluripotency, which are regulated by kinds of signal molecules, such as the Wnt/beta-catenin signaling pathway. beta-catenin is a multifunctional protein and plays a key role in Wnt/beta-catenin signaling pathway. beta-catenin involves self-renewal of ESCs and promotes the differentiation of ESCs into three primary germ layers in space and time. Elucidating the mechanisms of beta-catenin in regulating the self-renewal and pluripotency of ESCs will pave the way to use it in research and application. PMID- 26932221 TI - [Progress in research on obstructive sleep apnea syndrome with hypertension]. AB - Obstructive sleep apnea syndrome (OSAS) is a complicated chronic disease caused by certain reasons, characterized by obstruction of the upper airway and apnea or hypopnea during sleep, which can be followed by anoxia, snoring and daytime sleepiness. Recent studies have shown that hypertension is closely connected to OSAS. OSAS can lead to hypertension by several possible mechanisms. The diagnosis of OSAS mainly depends on the medical history, sign, polysomnogram (PSG) result and the frequency of apnea and hypopnea. OSAS can be relieved by continuous positive airway pressure (CPAP), oral orthodontic treatment, medicine, change of lifestyles and others. This brief review focuses on the mechanism of hypertension due to OSAS and the diagnosis criteria and treatment of OSAS. PMID- 26932222 TI - [Strategies for measuring medication adherence in patients with schizophrenia]. AB - Long-term therapy should be administrated for patients with schizophrenia and the medication adherence is very important for the prognosis and outcome in these patients. In this study, we screened the literatures from various databases in accordance with our search criteria. A total of 11 literatures with the results of reliability and validity regarding the measurement of schizophrenia medication adherence were enrolled in our analysis. Based on the measurements, they were classified into subjective methods and objective ones. The objective methods include blood plasma and urine concentrations, pharmacy records, pill counts and Medication Event Monitoring System. The subjective methods include Drug Attitude Inventory, Rating of Medication Influences Scale, Brief Evaluation of Medication Influences and Beliefs, the Brief Adherence Rating Scale, Medication Adherence Rating Scale, and Morisky scales. In general, single method for measuring medication adherence in patients with schizophrenia is limited. We recommend researchers to use 2 or more methods when measuring the medication adherence in patients with schizophrenia. PMID- 26932223 TI - Assessment of yeast Saccharomyces cerevisiae component binding to Mycobacterium avium subspecies paratuberculosis using bovine epithelial cells. AB - BACKGROUND: Since yeast Saccharomyces cerevisiae and its components are being used for the prevention and treatment of enteric diseases in different species, they may also be useful for preventing Johne's disease, a chronic inflammatory bowel disease of ruminants caused by Mycobacterium avium spp. paratuberculosis (MAP). This study aimed to identify potential yeast derivatives that may be used to help prevent MAP infection. The adherence of mCherry-labeled MAP to bovine mammary epithelial cell line (MAC-T cells) and bovine primary epithelial cells (BECs) co-cultured with yeast cell wall components (CWCs) from four different yeast strains (A, B, C and D) and two forms of dead yeast from strain A was investigated. RESULTS: The CWCs from all four yeast strains and the other two forms of dead yeast from strain A reduced MAP adhesion to MAC-T cells and BECs in a concentration-dependent manner after 6-h of exposure, with the dead yeast having the greatest effect. CONCLUSIONS: The following in vitro binding studies suggest that dead yeast and its' CWCs may be useful for reducing risk of MAP infection. PMID- 26932224 TI - Niacin Alternatives for Dyslipidemia: Fool's Gold or Gold Mine? Part II: Novel Niacin Mimetics. AB - Two cardiovascular outcome trials established niacin 3 g daily prevents hard cardiac events. However, as detailed in part I of this series, an extended release (ER) alternative at only 2 g nightly demonstrated no comparable benefits in two outcome trials, implying the alternative is not equivalent to the established cardioprotective regimen. Since statins leave a significant treatment gap, this presents a major opportunity for developers. Importantly, the established regimen is cardioprotective, so the pathway is likely beneficial. Moreover, though effective, the established cardioprotective regimen is cumbersome, limiting clinical use. At the same time, the ER alternative has been thoroughly discredited as a viable substitute for the established cardioprotective regimen. Therefore, by exploiting the pathway and skillfully avoiding the problems with the established cardioprotective regimen and the ER alternative, developers could validate cardioprotective variations facing little meaningful competition from their predecessors. Thus, shrewd developers could effectively tap into a gold mine at the grave of the ER alternative. The GPR109A receptor was discovered a decade ago, leading to a large body of evidence commending the niacin pathway to a lower cardiovascular risk beyond statins. While mediating niacin's most prominent adverse effects, GPR109A also seems to mediate anti-lipolytic, anti-inflammatory, and anti-atherogenic effects of niacin. Several developers are investing heavily in novel strategies to exploit niacin's therapeutic pathways. These include selective GPR109A receptor agonists, niacin prodrugs, and a niacin metabolite, with encouraging early phase human data. In part II of this review, we summarize the accumulated results of these early phase studies of emerging niacin mimetics. PMID- 26932227 TI - SIMS of transfer ribonucleic acid molecules encapsulated between free-standing graphene sheets. AB - In this study, the authors used cluster-secondary ion mass spectrometry method to investigate the preserved transfer ribonucleic acid (tRNA) encapsulated between two free-standing graphene sheets. Single impacts of 50 keV C60 (2+) projectiles generated the emission of tRNA fragment ions in the transmission direction for mass selection and detection in a time-of-flight mass spectrometer. Ribonucleic acid (RNA) is extremely unstable and prone to rapid enzymatic degradation by ribonucleases. Employing graphene to isolate RNA from the environment, the authors prevent the aforementioned process. Encapsulation was achieved by drop casting a solution of tRNA, prepared using deuterated water, onto one graphene sheet and covering it with another. The event-by-event bombardment/detection mode allowed us to use colocalization analysis method to characterize the tRNA and its immediate environment. The authors found that upon drying, tRNA agglomerated into nanostructures ~60 nm in diameter via formation and subsequent drying of aqua cells. The tRNA nanoagglomerates had a density of ~42 structures per MUm(2) with coverage of ~12% of the surface area. In addition, trace amounts of water remained mostly around the tRNA nanoagglomerates, probably in the form of hydration. PMID- 26932225 TI - Gemfibrozil in Combination with Statins-Is It Really Contraindicated? AB - Gemfibrozil is a lipid-modifying agent that belongs to the fibric acid derivative class. Fibric acid derivatives activate peroxisome proliferator activated receptor alpha (PPAR-alpha). The primary role of these agents in clinical practice is for the management of hypertriglyceridemia. Triglycerides may be reduced by as much as 74 % in some patients. In addition to lowering triglycerides, these agents can also decrease very low-density lipoprotein cholesterol (VLDL-C) and low-density lipoprotein cholesterol (LDL-C) as well as raise high-density lipoprotein cholesterol (HDL-C). Based on the 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults and the National Lipid Association, pharmacologic therapy to reduce triglycerides should be considered when triglyceride levels are >=500 mg/dL. While the use of gemfibrozil has decreased over the years for a variety of reasons, muscle-associated adverse effects is the predominant reason and the one that is most clinically relevant. However, despite these concerns, there are situations in which the use of gemfibrozil in combination with a statin may be necessary. Understanding the metabolism of gemfibrozil and the degree of interaction with the various statins will assist health-care providers to optimize safety when this combination is clinically indicated. PMID- 26932226 TI - Testosterone Replacement Therapy and the Cardiovascular System. AB - As testosterone replacement therapy (TRT) has emerged as a commonly prescribed therapy for symptomatic low testosterone, conflicting data have been reported in terms of both its efficacy and potential adverse outcomes. One of the most controversial associations has been that of TRT and cardiovascular morbidity and mortality. This review briefly provides background on the history of TRT, the indications for TRT, and the data behind TRT for symptomatic low testosterone. It then specifically delves into the rather limited data for cardiovascular outcomes of those with low endogenous testosterone and those who receive TRT. The available body of literature strongly suggests that more work, by way of clinical trials, needs to be done to better understand the impact of testosterone and TRT on the cardiovascular system. PMID- 26932228 TI - Biological Impacts in Fathead Minnow Larvae Following a 7-Day Exposure to Agricultural Runoff: A Microcosm Study. AB - The objective of this study was to investigate the impact of agricultural runoff on growth and development in fathead minnow larvae. Identifying these impacts in the field is difficult due to the complexity of pulsatile events and the challenge of maintaining larval fish under environmental conditions. This paper presents evidence of sublethal impacts on minnow larvae, maintained in microcosms, following a 7-day exposure to agricultural runoff. Fathead minnow larvae (5-12 dph) were exposed to agricultural runoff in the Elkhorn River, NE, USA. At 28 dph, 16 days after the field exposure, river exposed larvae showed reductions in body mass and length compared to controls. Female larvae exposed to river water also showed a reduction in the expression of cyp19a compared to controls. Further research will be necessary to separate the impact of agrichemicals from that of other stressors, such as suspended sediment and daily oscillation in water temperature. PMID- 26932229 TI - Personalized Telehealth in the Future: A Global Research Agenda. AB - As telehealth plays an even greater role in global health care delivery, it will be increasingly important to develop a strong evidence base of successful, innovative telehealth solutions that can lead to scalable and sustainable telehealth programs. This paper has two aims: (1) to describe the challenges of promoting telehealth implementation to advance adoption and (2) to present a global research agenda for personalized telehealth within chronic disease management. Using evidence from the United States and the European Union, this paper provides a global overview of the current state of telehealth services and benefits, presents fundamental principles that must be addressed to advance the status quo, and provides a framework for current and future research initiatives within telehealth for personalized care, treatment, and prevention. A broad, multinational research agenda can provide a uniform framework for identifying and rapidly replicating best practices, while concurrently fostering global collaboration in the development and rigorous testing of new and emerging telehealth technologies. In this paper, the members of the Transatlantic Telehealth Research Network offer a 12-point research agenda for future telehealth applications within chronic disease management. PMID- 26932230 TI - Reasons for Frequent Emergency Department Use by Medicaid Enrollees: A Qualitative Study. AB - BACKGROUND: The Affordable Care Act initiated several care coordination programs tailored to reduce emergency department (ED) use for Medicaid-enrolled frequent ED users. It is important to clarify from the patient's perspective why Medicaid enrollees who want to receive care coordination services to improve primary care utilization frequently use the ED. METHODS: We conducted a qualitative data analysis of patient summary reports obtained from Medicaid enrolled frequent ED users who agreed to participate in a randomized control trial (RCT) evaluating the impact of patient navigation intervention compared with standard of care on ED use and hospital admissions. We defined frequent ED users as those who used the ED four to 18 times in the past year. The study was conducted at an urban, teaching hospital ED with approximately 90,000 visits per year. The research staff conducted interviews (~30-40 minutes), regarding the patient's medical history, reasons for ED visits, health care access issues, and social distresses. The aforementioned findings were summarized in a 1- to 2-page report and presented to the RCT's project team (social worker, emergency medicine physician, primary care physician, and patient navigators) on a weekly basis to further understand the needs of this patient population. A diverse team of researchers (program staff and physicians) coded all reports and reached consensus using reflexive team analysis. We reconciled differences in code interpretations and generated themes. RESULTS: One-hundred patients enrolled in the RCT from March 2013 to February 2014, and all 100 patient summary reports were evaluated. We identified three key themes associated with Medicaid enrollee frequent ED use: 1) negative personal experiences with the healthcare system, 2) challenges associated with having low socioeconomic status, and 3) significant chronic mental and physical disease burden. CONCLUSIONS: Medicaid frequent ED users engaged in receiving patient navigation services with the goal to reduce ED use and hospital admissions describe barriers that go beyond timely primary care access issues. These include sociodeterminants of health, lack of trust in primary care providers, and healthcare system. PMID- 26932232 TI - Dosimetric comparison of 3-dimensional conformal radiation therapy and intensity modulated radiation therapy and impact of setup errors in lower limb sarcoma radiation therapy. AB - PURPOSE: This study compared dosimetric data between 3-dimensional conformal radiation therapy (3DCRT) and intensity modulated radiation therapy (IMRT) plans in a population of patients with lower limb sarcoma immobilized with an in-house device and quantified the impact of systematic and random errors on these techniques. The dosimetric effects of displacements on target coverage and organs at risk (OARs) were considered. METHODS AND MATERIALS: Plans were created for 11 postoperative patients using both 3DCRT and IMRT. The techniques were compared dosimetrically. Population-based systematic and random errors were applied and the results compared with the initial plans. RESULTS: Higher target D95, D2, D98, and D50 and the best homogeneity index resulted with IMRT compared with 3DCRT. Systematic errors increased target D2 in IMRT. Random errors decreased target homogeneity in IMRT. Maximum bone dose was higher in IMRT than in 3DCRT. Neither error type increased OAR dose for either technique. CONCLUSIONS: IMRT could become the favored lower limb sarcoma radiation therapy technique because of superior target coverage and homogeneity. Offline imaging can adequately correct for systematic errors in these patients when an in-house immobilization device is used. PMID- 26932231 TI - Basophils Trigger Fibroblast Activation in Cardiac Allograft Fibrosis Development. AB - Fibrosis is a major component of chronic cardiac allograft rejection. Although several cell types are able to produce collagen, resident (donor-derived) fibroblasts are mainly responsible for excessive production of extracellular matrix proteins. It is currently unclear which cells regulate production of connective tissue elements in allograft fibrosis and how basophils, as potential producers of profibrotic cytokines, are involved this process. We studied this question in a fully MHC-mismatched model of heart transplantation with transient depletion of CD4(+) T cells to largely prevent acute rejection. The model is characterized by myocardial infiltration of leukocytes and development of interstitial fibrosis and allograft vasculopathy. Using depletion of basophils, IL-4-deficient recipients and IL-4 receptor-deficient grafts, we showed that basophils and IL-4 play crucial roles in activation of fibroblasts and development of fibrotic organ remodeling. In the absence of CD4(+) T cells, basophils are the predominant source of IL-4 in the graft and contribute to expansion of myofibroblasts, interstitial deposition of collagen and development of allograft vasculopathy. Our results indicated that basophils trigger the production of various connective tissue elements by myofibroblasts. Basophil derived IL-4 may be an attractive target for treatment of chronic allograft rejection. PMID- 26932233 TI - Adsorption according to the Langmuir-Freundlich model is the detection mechanism of the antigen p53 for early diagnosis of cancer. AB - Biosensors for early detection of cancer biomarkers normally depend on specific interactions between such biomarkers and immobilized biomolecules in the sensing units. Though these interactions are expected to yield specific, irreversible adsorption, the underlying mechanism appears not to have been studied in detail. In this paper, we show that adsorption explained with the Langmuir-Freundlich model is responsible for detection of the antigen p53 associated with various types of cancers. Irreversible adsorption was proven between anti-p53 antibodies immobilized on the biosensors and the antigen p53, with the adequacy of the Langmuir-Freundlich model being confirmed with three independent experimental methods, viz. polarization-modulated infrared reflection absorption spectroscopy (PM-IRRAS), nanogravimetry using a quartz crystal microbalance and electrochemical impedance spectroscopy. The method based on this irreversible adsorption was sufficiently sensitive (limit of detection of 1.4 pg mL(-1)) for early diagnosis of Hodgkin lymphoma, pancreatic and colon carcinomas, and bladder, ovarian and lung cancers, and could distinguish between MCF7 cells containing the antigen p53 from Saos-2 cells that do not contain it. PMID- 26932237 TI - The impact of forced migration on the mental health of the elderly: a scoping review. AB - BACKGROUND: The worldwide elderly population fraction is increasing, with the greatest rise in developing countries. Older adults affected by conflict and forced migration mainly taking place in developing countries may be particularly vulnerable to poor mental health due to other age-specific risk factors. This review aims to explore global evidence on the effect of conflict-induced forced migration on the mental health of older adults. METHODS: Seven bibliographic databases were searched. The title and abstract of 797 results were reviewed for qualitative and quantitative studies meeting inclusion and exclusion criteria. RESULTS: Six studies were selected for the in-depth review. Five papers assessed mental health in older adult populations displaced as refugees. One paper assessed mental health of older adults with varying immigration status. CONCLUSIONS: This review highlights the dearth of evidence about the impact of forced migration on the mental health of older adults. Further research is needed to explore the risk factors and processes that contribute to adverse mental health outcomes among older adult populations. This is essential to the development of interventions for this vulnerable and at-risk population, particularly in resource-poor settings. PMID- 26932238 TI - Obituary: Georges Salamon. PMID- 26932235 TI - NO-Mediated [Ca2+]cyt Increases Depend on ADP-Ribosyl Cyclase Activity in Arabidopsis. AB - Cyclic ADP ribose (cADPR) is a Ca(2+)-mobilizing intracellular second messenger synthesized from NAD by ADP-ribosyl cyclases (ADPR cyclases). In animals, cADPR targets the ryanodine receptor present in the sarcoplasmic/endoplasmic reticulum to promote Ca(2+) release from intracellular stores to increase the concentration of cytosolic free Ca(2+) in Arabidopsis (Arabidopsis thaliana), and cADPR has been proposed to play a central role in signal transduction pathways evoked by the drought and stress hormone, abscisic acid, and the circadian clock. Despite evidence for the action of cADPR in Arabidopsis, no predicted proteins with significant similarity to the known ADPR cyclases have been reported in any plant genome database, suggesting either that there is a unique route for cADPR synthesis or that a homolog of ADPR cyclase with low similarity might exist in plants. We sought to determine whether the low levels of ADPR cyclase activity reported in Arabidopsis are indicative of a bona fide activity that can be associated with the regulation of Ca(2+) signaling. We adapted two different fluorescence-based assays to measure ADPR cyclase activity in Arabidopsis and found that this activity has the characteristics of a nucleotide cyclase that is activated by nitric oxide to increase cADPR and mobilize Ca(2.) PMID- 26932234 TI - Chloroplasts Are Central Players in Sugar-Induced Leaf Growth. AB - Leaves are the plant's powerhouses, providing energy for all organs through sugar production during photosynthesis. However, sugars serve not only as a metabolic energy source for sink tissues but also as signaling molecules, affecting gene expression through conserved signaling pathways to regulate plant growth and development. Here, we describe an in vitro experimental assay, allowing one to alter the sucrose (Suc) availability during early Arabidopsis (Arabidopsis thaliana) leaf development, with the aim to identify the affected cellular and molecular processes. The transfer of seedlings to Suc-containing medium showed a profound effect on leaf growth by stimulating cell proliferation and postponing the transition to cell expansion. Furthermore, rapidly after transfer to Suc, mesophyll cells contained fewer and smaller plastids, which are irregular in shape and contain fewer starch granules compared with control mesophyll cells. Short-term transcriptional responses after transfer to Suc revealed the repression of well-known sugar-responsive genes and multiple genes encoded by the plastid, on the one hand, and up-regulation of a GLUCOSE-6-PHOSPHATE TRANSPORTER (GPT2), on the other hand. Mutant gpt2 seedlings showed no stimulation of cell proliferation and no repression of chloroplast-encoded transcripts when transferred to Suc, suggesting that GPT2 plays a critical role in the Suc mediated effects on early leaf growth. Our findings, therefore, suggest that induction of GPT2 expression by Suc increases the import of glucose-6-phosphate into the plastids that would repress chloroplast-encoded transcripts, restricting chloroplast differentiation. Retrograde signaling from the plastids would then delay the transition to cell expansion and stimulate cell proliferation. PMID- 26932242 TI - N-Arylazetidines: Preparation through Anionic Ring Closure. AB - We report herein an efficient synthesis of diversely substituted N-aryl-2 cyanoazetidines based on an anionic ring-closure reaction. These compounds can be prepared from beta-amino alcohols in enantiomerically pure form through a three step sequence involving (i) copper-catalyzed N-arylation, (ii) N-cyanomethylation of the secondary aniline, and (iii) one-pot mesylation followed by ring closure induced by a base. This high-yielding sequence gives access to azetidines with a predictable and adjustable substitution pattern and also with predictable diastereoselectivity. These compounds are susceptible to multiple further derivatizations through Suzuki coupling or nitrile transformation, thus appearing as valuable new scaffolds for medicinal chemistry. Their rigid shape, featuring an almost planar N-arylamine and a planar four-membered ring, was revealed by both AM1 calculations and X-ray crystallography. PMID- 26932240 TI - A novel dinuclear iridium(III) complex as a G-quadruplex-selective probe for the luminescent switch-on detection of transcription factor HIF-1alpha. AB - A novel dinuclear Ir(III) complex 5 was discovered to be specific to G-quadruplex DNA, and was utilized in a label-free G-quadruplex-based detection platform for transcription factor activity. The principle of this assay was demonstrated by using HIF-1alpha as a model protein. Moreover, this HIF-1alpha detection assay exhibited potential use for biological sample analysis. PMID- 26932243 TI - No apparent cost of evolved immune response in Drosophila melanogaster. AB - Maintenance and deployment of the immune system are costly and are hence predicted to trade-off with other resource-demanding traits, such as reproduction. We subjected this longstanding idea to test using laboratory experimental evolution approach. In the present study, replicate populations of Drosophila melanogaster were subjected to three selection regimes-I (Infection with Pseudomonas entomophila), S (Sham-infection with MgSO4 ), and U (Unhandled Control). After 30 generations of selection flies from the I regime had evolved better survivorship upon infection with P. entomophila compared to flies from U and S regimes. However, contrary to expectations and previous reports, we did not find any evidence of trade-offs between immunity and other life history related traits, such as longevity, fecundity, egg hatchability, or development time. After 45 generations of selection, the selection was relaxed for a set of populations. Even after 15 generations, the postinfection survivorship of populations under relaxed selection regime did not decline. We speculate that either there is a negligible cost to the evolved immune response or that trade offs occur on traits such as reproductive behavior or other immune mechanisms that we have not investigated in this study. Our research suggests that at least under certain conditions, life-history trade-offs might play little role in maintaining variation in immunity. PMID- 26932245 TI - Revealing the dynamic heterogeneity of PMMA/PVDF blends: from microscopic dynamics to macroscopic properties. AB - An effort was made to demonstrate the dynamic heterogeneity of poly(methyl methacrylate) (PMMA)/poly(vinylidene fluoride) (PVDF) blends, where its composition dependence and the role of interphase were probed. Firstly, the composition dependence of thermorheological complexity of PMMA/PVDF blends in the melt was revealed. The molecular entanglement state involving intra- and interchain entanglements was found to govern the scenario of thermorheological complexity. Intriguingly, local heterogeneity was further demonstrated to exist in the melt-state blends with intermediate compositions, and its origin was depicted to be the interphase. The interphase, coupled with unfavourable interchain entanglements in those blends, could explain the reduced viscosity and speed-up relaxations, contributing to the overall thermorheological complexity. Besides, two experimental glass transition temperatures of blends were resolved in view of segment motions in the miscible phase and the crystal-amorphous interphase, and further assessed via the "self-concentration" concept. The presence of a crystal-amorphous interphase, likely leading to three distinct dynamics of segments in blends, was supposed to contribute to the dynamic heterogeneity in segment relaxations for PMMA/PVDF blends in the solid state. Lastly, effects of dynamic heterogeneity on dynamic mechanical properties were also evaluated. PMID- 26932244 TI - Induced maize salt tolerance by rhizosphere inoculation of Bacillus amyloliquefaciens SQR9. AB - Salt stress reduces plant growth and is now becoming one of the most important factors restricting agricultural productivity. Inoculation of plant growth promoting rhizobacteria (PGPR) has been shown to confer plant tolerance against abiotic stress, but the detailed mechanisms of how this occurs remain unclear. In this study, hydroponic experiments indicated that the PGPR strain Bacillus amyloliquefaciens SQR9 could help maize plants tolerate salt stress. After exposure to salt stress for 20 days, SQR9 significantly promoted the growth of maize seedlings and enhanced the chlorophyll content compared with the control. Additional analysis showed that the involved mechanisms could be the enhanced total soluble sugar content for decreasing cell destruction, improved peroxidase/catalase activity and glutathione content for scavenging reactive oxygen species, and reduced Na(+) levels in the plant to decrease Na(+) toxicity. These physiological appearances were further confirmed by the upregulation of RBCS, RBCL, H(+) -PPase, HKT1, NHX1, NHX2 and NHX3, as well as downregulation of NCED expression, as determined by quantitative reverse transcription-polymerase chain reaction. However, SQR9 counteracted the increase of abscisic acid in response to salt stress. In summary, these results show that SQR9 confers plant salt tolerance by protecting the plant cells and managing Na(+) homeostasis. Hence, it can be used in salt stress prone areas, thereby promoting agricultural production. PMID- 26932246 TI - Cytomorphology of ovarian clear cell carcinomas in peritoneal effusions. AB - OBJECTIVE: To investigate and describe the cytomorphology of malignant effusions from ovarian clear cell carcinomas (OCCC). METHODS: Five cases of malignant peritoneal effusions from OCCC histologically confirmed were analysed and compared. RESULTS: Among the malignant peritoneal effusions exhibiting clear cell features, a characteristic feature of OCCC was the presence of large deposits of a hyaline matrix. This matrix may be typically arranged either in 'raspberry bodies' or 'globule-like' structures. Other rare neoplasms composed of clear cells must be considered in the differential diagnosis such as yolk sac tumour of the ovary, clear cell subtype of endometrial carcinoma and, less frequently, malignant peritoneal mesothelioma as well as metastatic renal cell carcinoma. CONCLUSIONS: Ovarian clear cell carcinomas have distinct morphological features that are helpful in making a cytological diagnosis of this entity. The role of cytological examination in ovarian neoplasms is of paramount importance, as stated by The International Federation of Gynecology and Obstetrics (FIGO) recommendations. PMID- 26932247 TI - Weekday vs. weekend repair of esophageal atresia and tracheoesophageal fistula. AB - PURPOSE: We hypothesize that weekend esophageal atresia and tracheoesophageal fistula (EA/TEF) repair has worse outcomes compared to procedures performed on weekdays. METHODS: Kids' Inpatient Database (1997-2009) was searched for EA/TEF in infants admitted at <8days of life. Cases were limited to patients who underwent repair during their hospitalization. Risk-adjusted multivariate analysis (MVA) compared complications, mortality, and resource utilization (length of stay [LOS] total charges [TC]) between weekday and weekend procedures. RESULTS: Overall, 861 EA/TEF cases with known day of repair were identified. Cohort survival was 96%. On risk-adjusted MVA, complication rates were higher with EA/TEF repair on a weekend (OR: 2.2) compared to a weekday. Additionally, complications (OR: 6.5) and LOS (OR: 9.3) were found to be higher among African American children compared to Caucasians. LOS was higher in patients with Medicaid (OR: 2.4) and repairs performed at non-teaching hospitals (OR: 3.2). Weekend vs. weekday procedure had no significant effect on mortality or resource utilization. CONCLUSION: By risk-adjusted MVA, increased complication rates for EA/TEF are seen in patients undergoing repair on weekends compared to weekdays. Additionally, African American children experienced higher complication rates compared to Caucasians. LOS after repair varies according to race, payer status, and hospital characteristics. PMID- 26932248 TI - Cost of ambulatory care for the pediatric intestinal failure patient: One-year follow-up after primary discharge. AB - BACKGROUND: Survival of children with intestinal failure has improved over the last decade, resulting in increased health care expenditures. Our objective was to determine outpatient costs for the first year after primary discharge. METHODS: A retrospective analysis was performed in pediatric intestinal failure (PIF) patients between 2010 and 2012. Patients were stratified into 3 groups (1=enteral support with no devices [7 patients], 2=enteral support with devices (gastrostomy and/or ostomy) [19 patients], 3=home parenteral nutrition (HPN) [22 patients]). Data abstraction included clinical characteristics and costs related to medication, enteral/parenteral nutrition, and supplies were calculated. Data were analyzed using one way ANOVA. RESULTS: Forty-eight patients (mean age 7.6months; 31 males [65%]) were studied. See attached table for results. HPN patients had significantly more ambulatory visits (p<0.0001), number of admitted days (p=0.01), and productive days lost (p<0.0001). Total cost of care was significantly higher for HPN patients (mean=$320,368.50, p<0.0001) when compared to other groups. Costs covered by the health care system were significantly higher for patients on HPN (mean=$316,101.56, p<0.0001). CONCLUSION: The outpatient expenditures to care for PIF patients in the first year post primary discharge are significant. Our single payer health care system supports the majority of costs, but families are also incurring expenses related to travel and lost productivity. Children on HPN have more visits to hospital, but have access to more funding options. Children solely on gastrostomy or stoma therapy, however, have a significantly greater personal financial burden. PMID- 26932249 TI - Congenital diaphragmatic hernia: Observed/expected lung-to-head ratio as a predictor of long-term morbidity. AB - AIM: The aim of this study was to investigate the association of observed/expected (O/E) lung-to-head ratio (LHR) with long-term morbidity for isolated fetal congenital diaphragmatic hernia (CDH) patients in a single institution. METHODS: We performed a retrospective study of prenatally diagnosed CDH from 18 to 38weeks of gestation (01/2002-04/2010). Two cohorts of O/E LHR were defined (22.6-45%, 45.1-78.3%) based upon previous studies. Survivors with at least 1-year follow-up of prospectively collected long-term morbidity assessments were included. RESULTS: O/E LHR was available in 43 survivors (median 40%, range 22.8-78.3%). Follow-up data were available in 41 survivors (M:F=24:17, left CDH=39/41). Median follow-up was 6.5years (1-11years). Height/weight trajectories were similar between the two cohorts, with the majority below the 50th centile. There were no differences between the two cohorts by age 3years for Bayley scales (developmental domains) and/or REEL-3 (language development). In addition, V/Q scans in the two cohorts demonstrated similar degrees of mismatch (mean delta V/Q=35.4 versus 31.3). CONCLUSIONS: In fetuses with isolated CDH, a reduction in O/E LHR does not predict a worse outcome in long-term follow-up. There is no association between a lower O/E LHR and a reduction in REEL-3 or Bayley score nor V/Q mismatch. PMID- 26932250 TI - The impact of transfer on pediatric trauma outcomes. AB - BACKGROUND: Recently, concerns have been raised over delays that result from transferring patients to designated trauma centers. This study aimed to assess whether transfer status had an impact on pediatric trauma outcomes. METHODS: Using a local 1996-2014 pediatric trauma database containing 1541 patients, the following outcomes were tested: death, major complication, time to definitive treatment (TDT), hospital length of stay (LOS), and ICU length of stay (ICU LOS). Logistic, generalized linear, and Poisson regression models were used. RESULTS: Mortality and complication rates did not differ significantly between direct (mortality=52/1000, complications=54/1000) and transferred (mortality=59/1000; complications=67/1000) patients (mortality aRR: 1.17, 95% CI: 0.76-1.80, p=0.48; complication aRR: 1.13, 95% CI: 0.75-1.70, p=0.57). Transfer status was not a significant predictor of ICU LOS (p=0.72). Transfer status was a significant predictor of time to definitive treatment (transfer x-=17.4h vs. direct x-=2.6h, p=0.0035) and of LOS for severely injured patients (p=0.005). The significant predictors of pediatric trauma mortality were: ISS, transport mode, age, and TDT, and of major complication were ISS and TDT. CONCLUSIONS: Although transferred patients had longer time to specialized care, there were no significant differences in the mortality or complication rates between transferred and direct patients after adjusting for injury severity. PMID- 26932251 TI - Assessing quality of life in pediatric gastroschisis patients using the Pediatric Quality of Life Inventory survey: An institutional study. AB - BACKGROUND: The purpose of this study was to quantify quality of life (QOL) outcomes in gastroschisis children using a validated QOL inventory survey. METHODS: A chart review and prospective survey (2012 Pediatric Quality of Life InventoryTM (PedsQLTM)) were performed for gastroschisis patients from 2005 to 2011. Demographics and scores were compared between patents with simple versus complicated gastroschisis and patients with and without bowel resection. RESULTS: One hundred nineteen patients (>2years of age) were identified. Twenty-eight families participated in the prospective survey with an average patient age of 5.8+/-2.3years. There were 11 complicated and 17 simple cases. Children with simple gastroschisis had lower rates of reoperation (0.06% versus 90%, p<0.001) and bowel resection (12% and 64%, p=0.004) than complicated patients. Average QOL scores for children with simple and complicated gastroschisis were 81.69/100+/ 19.50 and 78.7/100+/-20.14 (p=0.70), respectively. Scores were also similar in children with and without bowel resection (74.72/100+/-19.94 and 83.29/100+/ 19.10, p=0.171). Cronbach's alpha correlation was 0.912 for the overall survey. DISCUSSION: Despite increased need for reoperation and bowel resection, at >2years of age, PedsQLTM scores were similar between patients with simple and complicated gastroschisis. This study provides preliminary data on QOL outcomes for antenatal counseling of gastroschisis families. PMID- 26932252 TI - The value of preoperative liver biopsy in the diagnosis of extrahepatic biliary atresia: A systematic review and meta-analysis. AB - BACKGROUND: In extrahepatic biliary atresia (EHBA) obstruction of the biliary tree causes severe cholestasis leading to cirrhosis and death if left untreated in a timely manner. Infants with cholestasis may undergo many tests before EHBA diagnosis is reached. The role and place of preoperative liver biopsy in the diagnostic paradigm for EHBA have not been established. METHODS: We conducted a systematic review of MEDLINE, Embase, and CENTRAL to obtain all publications describing the sensitivity/specificity/accuracy/positive predictive value (PPV)/negative predictive value (NPV) of preoperative liver biopsy in infants with cholestasis. Screening, data extraction, and quality assessment were done in duplicate. Extracted data are described narratively and analyzed using forest plots and receiver operating characteristic curves. RESULTS: A total of 22 articles were included. Overall, the pooled accuracy of preoperative liver biopsy was 91.7%, with a sensitivity of 91.2%, specificity of 93.0% (n=1231), PPV of 91.2%, NPV of 92.5% (n=1182), and accuracy of 91.6% (n=1106). In patients who were 60days or less at time of presentation or diagnosis, the pooled sensitivity, specificity, PPV, NPV, and accuracy were 96.4%, 96.3%, 95.8%, 96.3%, and 94.9%, respectively. CONCLUSION: Quantitative analysis demonstrated preoperative biopsy to be both highly specific and sensitive in diagnosing EHBA preoperatively. It is a highly reliable test that offers a means of arriving at an early definitive diagnosis of EHBA. PMID- 26932254 TI - Increased c-kit and stem cell factor expression in the pulmonary vasculature of nitrofen-induced congenital diaphragmatic hernia. AB - PURPOSE: Persistent pulmonary hypertension(PPH) in congenital diaphragmatic hernia (CDH) is caused by increased vascular cell proliferation and endothelial cell (EC) dysfunction, thus leading to obstructive changes in the pulmonary vasculature. C-Kit and its ligand, stem cell factor(SCF), are expressed by ECs in the developing lung mesenchyme, suggesting an important role during lung vascular formation. Conversely, absence of c-Kit expression has been demonstrated in ECs of dysplastic alveolar capillaries. We hypothesized that c-Kit and SCF expression is increased in the pulmonary vasculature of nitrofen-induced CDH. METHODS: Timed pregnant rats received nitrofen or vehicle on gestational day 9(D9). Fetuses were sacrificed on D15, D18, and D21, and divided into control and CDH group. Pulmonary gene expression levels of c-Kit and SCF were analyzed by qRT-PCR. Immunofluorescence double staining for c-Kit and SCF was combined with CD34 to evaluate protein expression in ECs of the pulmonary vasculature. RESULTS: Relative mRNA levels of c-Kit and SCF were significantly increased in lungs of CDH fetuses on D15, D18, and D21 compared to controls. Confocal laser scanning microscopy confirmed markedly increased vascular c-Kit and SCF expression in mesenchymal ECs of CDH lungs on D15, D18, and D21 compared to controls. CONCLUSION: Increased expression of c-Kit and SCF in the pulmonary vasculature of nitrofen-induced CDH lungs suggest that increased c-Kit signaling during lung vascular formation may contribute to vascular remodeling and thus to PPH. PMID- 26932253 TI - Effect of gestational age at birth on neonatal outcomes in gastroschisis. AB - INTRODUCTION: Induced birth of fetuses with gastroschisis from 34weeks gestational age (GA) has been proposed to reduce bowel damage. We aimed to determine the effect of birth timing on time to full enteral feeds (ENT), length of hospital stay (LOS), and sepsis. METHODS: A retrospective analysis (2000-2014) of gastroschisis born at >=34weeks GA was performed. Associations between birth timing and outcomes were analyzed by Mann-Whitney test, Cox regression, and Fisher's exact test. RESULTS: 217 patients were analyzed. Although there was no difference in ENT between those born at 34-36+6weeks GA (median 28 range [6-639] days) compared with >=37weeks GA (27 [8-349] days) when analyzed by Mann-Whitney test (p=0.5), Cox regression analysis revealed that lower birth GA significantly prolonged ENT (p=0.001). LOS was significantly longer in those born at 34 36+6weeks GA (42 [8-346] days) compared with >=37weeks GA 34 [11-349] days by both Mann-Whitney (p=0.02) and Cox regression analysis (p<0.0005). Incidence of sepsis was higher in infants born at 34-36+6weeks (32%) vs. infants born at >=37weeks (17%; p=0.02). CONCLUSIONS: Early birth of fetuses with gastroschisis was associated with delay in reaching full enteral feeds, prolonged hospitalization, and a higher incidence of sepsis. PMID- 26932255 TI - Accuracy of prenatal detection of tracheoesophageal fistula and oesophageal atresia. AB - AIMS: This study aims to determine the rate of prenatal detection of tracheoesophageal fistula and oesophageal atresia (TOF/OA), by identifying a small or absent stomach bubble with or without polyhydramnios, on the prenatal ultrasound scans (USS). METHODS: A retrospective study of prenatal ultrasound findings of babies with a prenatal and postnatal diagnosis of TOF/OA born between 1st January 2004 and 31st December 2013 was undertaken. RESULTS: A total of 58 babies were born with TOF/OA. 40% of mothers had their prenatal investigations performed within our tertiary centre, and the remaining 60% had their antenatal care at their local district general hospital (DGH). The overall sensitivity for prenatal USS was 26%, with a specificity of 99% and a positive predictive value (PPV) of 35%. However, the sensitivity of the prenatal USS within the tertiary centre was significantly higher at 57%, while only 2 cases were detected prenatally in the DGHs. Polyhydramnios was seen in 67% of mothers that had a prenatal diagnosis of TOF/OA and its presence did significantly increase the positive predictive value of prenatal USS (from 35% to 63%). Of those that were postnatally diagnosed, 21% had prenatal polyhydramnios. There was no significant difference in postnatal outcomes between those that were prenatally diagnosed and those that were postnatally diagnosed. CONCLUSION: Prenatal diagnosis of TOF/OA remains challenging. However within a specialist centre the accuracy of successful prenatal detection can be significantly improved. This is beneficial both for prenatal counselling of families and for planning appropriate perinatal and postnatal care for the baby. PMID- 26932256 TI - Adjuvant antifungal therapy using tissue tolerable plasma on oral mucosa and removable dentures in oral candidiasis patients: a randomised double-blinded split-mouth pilot study. AB - Extended use of antimycotics in oral candidiasis therapy gives rise to problems related to fungal drug resistance. The aim of this pilot study was to investigate the efficacy of tissue tolerable plasma (TTP) in denture stomatitis patients. It was hypothesised that (I): erythema and (IIa): complaint remission would be accelerated and (IIb): colony forming unit (CFU) reduction would be improved. The halves of the upper jaws of eight patients were randomly assigned to control (nystatin, chlorhexidine and placebo treatment) and test sides (nystatin, chlorhexidine and TTP administered six times each 7 days). The patients and the investigators, who were different from the therapists, were both blinded. Compared to the control sides, the erythema surface was reduced significantly more extensively on the test sides between 2 and 6 weeks of antifungal therapy (P <= 0.05). Visual analogue scale values and the frequency of moderate or heavy growth of Candida post-treatment did not differ significantly between both sides (P > 0.05). The primary hypothesis was confirmed, which may be interpreted as an accelerated remission. As drug therapy is usually limited to the time in which signs of infection are present, TTP might help reducing antifungal use. Even though the secondary hypotheses were not confirmed, persistence of Candida might be only colonisation. PMID- 26932257 TI - Dissociation of Structural and Functional Integrities of the Motor System in Amyotrophic Lateral Sclerosis and Behavioral-Variant Frontotemporal Dementia. AB - BACKGROUND AND PURPOSE: This study investigated the structural and functional changes in the motor system in amyotrophic lateral sclerosis (ALS; n=25) and behavioral-variant fronto-temporal dementia (bvFTD; n=17) relative to healthy controls (n=37). METHODS: Structural changes were examined using a region-of interest approach, applying voxel-based morphometry for gray-matter changes and diffusion tensor imaging for white-matter changes. Functional changes in the motor system were elucidated using threshold-tracking transcranial magnetic stimulation (TMS) measurements of upper motor-neuron excitability. RESULTS: The structural analyses showed that in ALS there were more white-matter changes in the corticospinal and motor-cortex regions and more gray-matter changes in the cerebellum in comparison to controls. bvFTD showed substantial gray- and white matter changes across virtually all motor-system regions compared to controls, although the brainstem was affected less than the other regions. Direct comparisons across patient groups showed that the gray- and white-matter motor system changes inclusive of the motor cortex were greater in bvFTD than in ALS. By contrast, the functional integrity of the motor system was more adversely affected in ALS than in bvFTD, with both patient groups showing increased excitability of upper motor neurons compared to controls. CONCLUSIONS: Cross correlation of structural and functional data further revealed a neural dissociation of different motor-system regions and tracts covarying with the TMS excitability across both patient groups. The structural and functional motor system integrities appear to be dissociated between ALS and bvFTD, which represents useful information for the diagnosis of motor-system changes in these two disorders. PMID- 26932258 TI - Association between Parkinson's Disease and Helicobacter Pylori. AB - Helicobacter pylori (HP) is a common infection of the gastrointestinal system that is usually related to peptic ulcers. However, recent studies have revealed relationships between HP and many other diseases. Although the exact mechanism is unknown, HP can prevent the absorption of certain drugs. A high prevalence of HP has been found in patients with Parkinson's disease, and this bacterium causes motor fluctuations by affecting the absorption of levodopa, which is the main drug used to treat Parkinson's disease. Eradicating HP from patients with Parkinson's disease by applying antibiotic treatment will increase the absorption of levodopa and decrease their motor fluctuations. PMID- 26932259 TI - Normal Caloric Responses during Acute Phase of Vestibular Neuritis. AB - BACKGROUND AND PURPOSE: We report a novel finding of caloric conversion from normal responses into unilateral paresis during the acute phase of vestibular neuritis (VN). METHODS: We recruited 893 patients with a diagnosis of VN at Dizziness Clinic of Seoul National University Bundang Hospital from 2003 to 2014 after excluding 28 patients with isolated inferior divisional VN (n=14) and those without follow-up tests despite normal caloric responses initially (n=14). We retrospectively analyzed the neurotological findings in four (0.5%) of the patients who showed a conversion from initially normal caloric responses into unilateral paresis during the acute phase. RESULTS: In those four patients, the initial caloric tests were performed within 2 days of symptom onset, and conversion into unilateral caloric paresis was documented 1-4 days later. The clinical and laboratory findings during the initial evaluation were consistent with VN in all four patients except for normal findings in bedside head impulse tests in one of them. CONCLUSIONS: Normal findings in caloric tests should be interpreted with caution during the acute phase of suspected VN. Follow-up evaluation should be considered when the findings of the initial caloric test are normal, but VN remains the most plausible diagnosis. PMID- 26932260 TI - Fish Reveal Origins of Melanoma. AB - A new study of zebrafish may explain why only certain skin cells grow into tumors. Besides melanoma-promoting mutations, these cells express key neural crest genes, such as crestin and sox10, that induce regression to an embryonic state. They also bear epigenetic changes that might amplify expression of these genes. PMID- 26932261 TI - Not poles apart: Antarctic soil fungal communities show similarities to those of the distant Arctic. AB - Antarctica's extreme environment and geographical isolation offers a useful platform for testing the relative roles of environmental selection and dispersal barriers influencing fungal communities. The former process should lead to convergence in community composition with other cold environments, such as those in the Arctic. Alternatively, dispersal limitations should minimise similarity between Antarctica and distant northern landmasses. Using high-throughput sequencing, we show that Antarctica shares significantly more fungi with the Arctic, and more fungi display a bipolar distribution, than would be expected in the absence of environmental filtering. In contrast to temperate and tropical regions, there is relatively little endemism, and a strongly bimodal distribution of range sizes. Increasing southerly latitude is associated with lower endemism and communities increasingly dominated by fungi with widespread ranges. These results suggest that micro-organisms with well-developed dispersal capabilities can inhabit opposite poles of the Earth, and dominate extreme environments over specialised local species. PMID- 26932262 TI - The Cost-Effectiveness of Pregabalin Versus Gabapentin for Peripheral Neuropathic Pain (pNeP) and Postherpetic Neuralgia (PHN) in China. AB - INTRODUCTION: Postherpetic neuralgia (PHN), a type of peripheral neuropathic pain (pNeP), is the most common complication of herpes zoster. The objective of this analysis was to determine the cost-effectiveness of pregabalin compared with gabapentin in pNeP and PHN in China. METHODS: We developed a China-localized 12 week simulation model to determine the cost-effectiveness of pregabalin compared to gabapentin in 1000 patients with pNeP and PHN. We utilized a questionnaire of Chinese key opinion leaders to estimate the pre-treatment distribution of pain scores for pNeP and PHN. Treatment outcomes for pregabalin and gabapentin were acquired from the published literature. RESULTS: Treatment with pregabalin lead to 12-week decreases in pain scores of 0.6 (pNeP) and 0.7 (PHN) when compared to patients receiving gabapentin, at an incremental cost per additional day of mild/no pain of $45. The difference in mean days of no or mild pain, moderate pain, and severe pain was 8.8, -5.7, and -3.1, when comparing pregabalin and gabapentin, respectively. Pregabalin had more mean days with a >30% (7.71 days), 40% (8.97 days), and 50% reduction (9.97 days) in pain when compared with gabapentin. In the pNeP scenario, pregabalin was associated with a lower average pain score compared with gabapentin (3.91 vs. 4.55). The difference in mean days of no or mild pain, moderate pain, and severe pain was 9.39, -5.56, and -3.82, when comparing pregabalin and gabapentin, respectively. Pregabalin had more mean days with a >30% (8.77 days), 40% (9.81 days), and 50% reduction (10.55 days) in pain when compared with gabapentin. CONCLUSION: Pregabalin is an effective treatment for PHN and even for pNeP extensively, but at increased cost. It leads to improved outcomes including lower pain scores and more days with no or mild pain. FUNDING: Pfizer, China. PMID- 26932264 TI - Rapid assessment of insect fauna based on local knowledge: comparing ecological and ethnobiological methods. AB - BACKGROUND: The rapid assessment of biodiversity making use of surveys of local knowledge has been successful for different biological taxa. However, there are no reports on the testing of such tools for sampling insect fauna. The present study aimed to evaluate the efficiency of different ethnobiological techniques for rapid sampling of insect fauna. METHODS: Field research for the conventional survey of insect fauna was conducted on a private farm (9 degrees 43'38.95 "S, 37 degrees 45'11.97" W) , where there was intensive cultivation of okra (Abelmoschus esculentus L. (Moench)). The survey of local entomological knowledge was conducted among all the producers of okra living in the rural villages Pereira, Santa Luzia, and Nassau de Souza, within the Jacare Curituba irrigated settlement scheme. The combined use of the techniques "free list" and projective interviews was analyzed, using two types of visual stimuli: stock photos and an entomological box. RESULTS: During the conventional survey of insect fauna, the species Bemisia tabaci biotype B, Aphis gossypii, Phenacoccus sp., Icerya purchasi and Lagria villosa were the primary pests found in the okra crop. Regarding the survey of insect pests, the results were convergent in both techniques (conventional sampling and free list). Comparing the interview with visual stimuli (pictures) and specimen witnesses (entomological box) revealed that the latter was more effective. CONCLUSION: Techniques based on the recording and analysis of local knowledge about insects are effective for quick sampling of pest insects, but ineffective in sampling predator insects. The utilization of collected insects, infested branches, or photos of the symptoms of damage caused by pests in projective interviews is recommended. PMID- 26932263 TI - Declining malaria, rising of dengue and Zika virus: insights for mosquito vector control. AB - The fight against mosquito-borne diseases is a challenge of huge public health importance. To our mind, 2015 was an extraordinary year for malaria control, due to three hot news: the Nobel Prize to Youyou Tu for the discovery of artemisinin, the development of the first vaccine against Plasmodium falciparum malaria [i.e. RTS,S/AS01 (RTS,S)], and the fall of malaria infection rates worldwide, with special reference to sub-Saharan Africa. However, there are major challenges that still deserve attention, in order to boost malaria prevention and control. Indeed, parasite strains resistant to artemisinin have been detected, and RTS,S vaccine does not offer protection against Plasmodium vivax malaria, which predominates in many countries outside of Africa. Furthermore, the recent outbreaks of Zika virus infections, occurring in South America, Central America and the Caribbean, represent the most recent of four arrivals of important arboviruses in the Western Hemisphere, over the last 20 years. Zika virus follows dengue (which slyly arrived in the hemisphere over decades and became more aggressive in the 1990s), West Nile virus (emerged in 1999) and chikungunya (emerged in 2013). Notably, there are no specific treatments for these arboviruses. The emerging scenario highlights that the effective and eco-friendly control of mosquito vectors, with special reference to highly invasive species such as Aedes aegypti and Aedes albopictus, is crucial. The concrete potential of screening plant species as sources of metabolites for parasitological purposes is worthy of attention, as elucidated by the Y. Tu's example. Notably, plant-borne molecules are often effective at few parts per million against Aedes, Ochlerotatus, Anopheles and Culex young instars, can be used for the rapid synthesis of mosquitocidal nanoformulations and even employed to prepare cheap repellents with low human toxicity. In addition, behaviour-based control tools relying to the employ of sound traps and the manipulation of swarming behaviour (i.e. "lure and kill" approach) are discussed. The importance of further research on the chemical cues routing mosquito swarming and mating dynamics is highlighted. Besides radiation, transgenic and symbiont-based mosquito control approaches, an effective option may be the employ of biological control agents of mosquito young instars, in the presence of ultra-low quantities of nanoformulated botanicals, which boost their predation rates. PMID- 26932266 TI - Transforming growth factor-beta1 induces cholesterol synthesis by increasing HMG CoA reductase mRNA expression in keratinocytes. AB - In this study, we investigated the effect of TGF-beta1 on cholesterol synthesis in human keratinocytes. TGF-beta1 increased the level of cholesterol and the mRNA level of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase in human keratinocytes. These results show that TGF-beta1 induces cholesterol synthesis by increasing HMG-CoA reductase mRNA expression in human keratinocytes. PMID- 26932265 TI - Population-based assessment of visual impairment among ethnic Dai adults in a rural community in China. AB - Dai ethnicity is one of the major Chinese ethnic minorities with a population of about 1.2 million. We aimed to determine the prevalence and potential causes of visual impairment (VI) among ethnic Dai adults aged 50 years or older in a rural community in China. A population-based survey including 2163 ethnic Dai people (80.5%) was undertaken using a random cluster sampling strategy. The detailed eye examination was performed after pupil dilation by trained study ophthalmologists and optometrists. Presenting visual acuity (PVA) and best-corrected visual acuity (BCVA) was measured using the Early Treatment Diabetic Retinopathy Study logMAR chart and VI was defined as a VA of less than 20/63 in the better-seeing eye. The overall prevalence of presenting blindness and low vision was 3.0% (95% CI, 2.3 3.7) and 13.3% (95% CI, 11.9-14.8), respectively. The prevalence estimates were reduced to 2.1% (95% CI, 1.5-2.8) and 6.7% (95% CI, 5.7-7.8) when BCVA was considered. Men were more likely to be affected by low vision but less likely to be blind compared with women. Cataract accounted for 62.7% of presenting low vision and 68.8% of presenting blindness, respectively. In conclusion, VI was a significant health concern in Dai Chinese in China. PMID- 26932269 TI - Erratum to: 'Expression of granzyme B sensitizes ALK+ ALCL tumour cells to apoptosis-inducing drugs'. PMID- 26932267 TI - Genotypes of Cryptosporidium spp., Enterocytozoon bieneusi and Giardia duodenalis in dogs and cats in Shanghai, China. AB - BACKGROUND: Controversies exist on the potential role of companion animals in the transmission of enteric pathogens in humans. This study was conducted to examine the genotype distribution of Cryptosporidium spp., Enterocytozoon bieneusi, and Giardia duodenalis in companion animals in Shanghai, China, and to assess their zoonotic potential. METHODS: Fecal specimens from 485 dogs and 160 cats were examined for the occurrence and genotype distribution of the three pathogens by PCR. PCR products were sequenced to determine the species and genotypes. The chi(2) test was used to compare differences in infection rates between living conditions or age groups. RESULTS: Cryptosporidium spp., E. bieneusi and G. duodenalis were found in 39 (8.0 %), 29 (6.0 %) and 127 (26.2 %) of dogs, and 6 (3.8 %), 9 (5.6 %) and 21 (13.1 %) of cats, respectively. Infection rates of the pathogens in dogs from pet shops and a clinic were higher than those in household dogs, and higher in cats from one animal shelter than from pet shops. No significant differences in infection rates were detected among age groups. Cryptosporidium canis and C. felis were the only Cryptosporidium species found in dogs and cats, respectively. Enterocytozoon bieneusi genotype PtEb IX was the dominant genotype in dogs, whereas Type IV and D were the most common ones in cats. Multi-locus sequence typing at the glutamate dehydrogenase, beta-giardin, and triosephosphate isomerase loci revealed the presence of G. duodenalis assemblages A (n = 23), B (n = 1), C (n = 26), and D (n = 58) in dogs (only A in household dogs) and assemblages A (n = 2), B (n = 6), C (n = 2), D (n = 1), and F (n = 7) in cats. Co-infection was detected in 24 dogs and 5 cats, especially those living in crowded conditions. CONCLUSIONS: Living condition is a major risk factor affecting the occurrence of enteric protists in companion animals in China, and although dogs and cats can be potential sources of human infections, the different distribution of pathogen species and genotypes between dogs and cats suggests that inter-species transmission of these pathogens is probably rare in the study area. PMID- 26932268 TI - Extraterritorial hunting expeditions to intense fire scars by feral cats. AB - Feral cats are normally territorial in Australia's tropical savannahs, and hunt intensively with home-ranges only two to three kilometres across. Here we report that they also undertake expeditions of up to 12.5 km from their home ranges to hunt for short periods over recently burned areas. Cats are especially likely to travel to areas burned at high intensity, probably in response to vulnerability of prey soon after such fires. The movements of journeying cats are highly directed to specific destinations. We argue that the effect of this behaviour is to increase the aggregate impact of cats on vulnerable prey. This has profound implications for conservation, considering the ubiquity of feral cats and global trends of intensified fire regimes. PMID- 26932270 TI - Conjugative plasmid transfer from Escherichia coli is a versatile approach for genetic transformation of thermophilic Bacillus and Geobacillus species. AB - We previously demonstrated efficient transformation of the thermophile Geobacillus kaustophilus HTA426 using conjugative plasmid transfer from Escherichia coli BR408. To evaluate the versatility of this approach to thermophile transformation, this study examined genetic transformation of various thermophilic Bacillus and Geobacillus spp. using conjugative plasmid transfer from E. coli strains. E. coli BR408 successfully transferred the E. coli Geobacillus shuttle plasmid pUCG18T to 16 of 18 thermophiles with transformation efficiencies between 4.1 * 10(-7) and 3.8 * 10(-2)/recipient. Other E. coli strains that are different from E. coli BR408 in intracellular DNA methylation also generated transformants from 9 to 15 of the 18 thermophiles, including one that E. coli BR408 could not transform, although the transformation efficiencies of these strains were generally lower than those of E. coli BR408. The conjugation was performed by simple incubation of an E. coli donor and a thermophile recipient without optimization of experimental conditions. Moreover, thermophile transformants were distinguished from abundant E. coli donor only by high temperature incubation. These observations suggest that conjugative plasmid transfer, particularly using E. coli BR408, is a facile and versatile approach for plasmid introduction into thermophilic Bacillus and Geobacillus spp., and potentially a variety of other thermophiles. PMID- 26932271 TI - ModFossa: A library for modeling ion channels using Python. AB - The creation and simulation of ion channel models using continuous-time Markov processes is a powerful and well-used tool in the field of electrophysiology and ion channel research. While several software packages exist for the purpose of ion channel modeling, most are GUI based, and none are available as a Python library. In an attempt to provide an easy-to-use, yet powerful Markov model-based ion channel simulator, we have developed ModFossa, a Python library supporting easy model creation and stimulus definition, complete with a fast numerical solver, and attractive vector graphics plotting. PMID- 26932272 TI - Normalization of transposon-mutant library sequencing datasets to improve identification of conditionally essential genes. AB - Sequencing of transposon-mutant libraries using next-generation sequencing (TnSeq) has become a popular method for determining which genes and non-coding regions are essential for growth under various conditions in bacteria. For methods that rely on quantitative comparison of counts of reads at transposon insertion sites, proper normalization of TnSeq datasets is vitally important. Real TnSeq datasets are often noisy and exhibit a significant skew that can be dominated by high counts at a small number of sites (often for non-biological reasons). If two datasets that are not appropriately normalized are compared, it might cause the artifactual appearance of Differentially Essential (DE) genes in a statistical test, constituting type I errors (false positives). In this paper, we propose a novel method for normalization of TnSeq datasets that corrects for the skew of read-count distributions by fitting them to a Beta-Geometric distribution. We show that this read-count correction procedure reduces the number of false positives when comparing replicate datasets grown under the same conditions (for which no genuine differences in essentiality are expected). We compare these results to results obtained with other normalization procedures, and show that it results in greater reduction in the number of false positives. In addition we investigate the effects of normalization on the detection of DE genes. PMID- 26932273 TI - An efficient algorithm for planar drawing of RNA structures with pseudoknots of any type. AB - An RNA pseudoknot is a tertiary structural element in which bases of a loop pair with complementary bases are outside the loop. A drawing of RNA secondary structures is a tree, but a drawing of RNA pseudoknots is a graph that has an inner cycle within a pseudoknot and possibly outer cycles formed between the pseudoknot and other structural elements. Visualizing a large-scale RNA structure with pseudoknots as a planar drawing is challenging because a planar drawing of an RNA structure requires both pseudoknots and an entire structure enclosing the pseudoknots to be embedded into a plane without overlapping or crossing. This paper presents an efficient heuristic algorithm for visualizing a pseudoknotted RNA structure as a planar drawing. The algorithm consists of several parts for finding crossing stems and page mapping the stems, for the layout of stem-loops and pseudoknots, and for overlap detection between structural elements and resolving it. Unlike previous algorithms, our algorithm generates a planar drawing for a large RNA structure with pseudoknots of any type and provides a bracket view of the structure. It generates a compact and aesthetic structure graph for a large pseudoknotted RNA structure in O([Formula: see text]) time, where n is the number of stems of the RNA structure. PMID- 26932274 TI - Reverse engineering of gene regulatory networks based on S-systems and Bat algorithm. AB - The correct inference of gene regulatory networks for the understanding of the intricacies of the complex biological regulations remains an intriguing task for researchers. With the availability of large dimensional microarray data, relationships among thousands of genes can be simultaneously extracted. Among the prevalent models of reverse engineering genetic networks, S-system is considered to be an efficient mathematical tool. In this paper, Bat algorithm, based on the echolocation of bats, has been used to optimize the S-system model parameters. A decoupled S-system has been implemented to reduce the complexity of the algorithm. Initially, the proposed method has been successfully tested on an artificial network with and without the presence of noise. Based on the fact that a real-life genetic network is sparsely connected, a novel Accumulative Cardinality based decoupled S-system has been proposed. The cardinality has been varied from zero up to a maximum value, and this model has been implemented for the reconstruction of the DNA SOS repair network of Escherichia coli. The obtained results have shown significant improvements in the detection of a greater number of true regulations, and in the minimization of false detections compared to other existing methods. PMID- 26932275 TI - Issues in performance evaluation for host-pathogen protein interaction prediction. AB - The study of interactions between host and pathogen proteins is important for understanding the underlying mechanisms of infectious diseases and for developing novel therapeutic solutions. Wet-lab techniques for detecting protein-protein interactions (PPIs) can benefit from computational predictions. Machine learning is one of the computational approaches that can assist biologists by predicting promising PPIs. A number of machine learning based methods for predicting host pathogen interactions (HPI) have been proposed in the literature. The techniques used for assessing the accuracy of such predictors are of critical importance in this domain. In this paper, we question the effectiveness of K-fold cross validation for estimating the generalization ability of HPI prediction for proteins with no known interactions. K-fold cross-validation does not model this scenario, and we demonstrate a sizable difference between its performance and the performance of an alternative evaluation scheme called leave one pathogen protein out (LOPO) cross-validation. LOPO is more effective in modeling the real world use of HPI predictors, specifically for cases in which no information about the interacting partners of a pathogen protein is available during training. We also point out that currently used metrics such as areas under the precision-recall or receiver operating characteristic curves are not intuitive to biologists and propose simpler and more directly interpretable metrics for this purpose. PMID- 26932276 TI - Low-dose aspirin for prevention of cardiovascular disease in patients on hemodialysis: A 5-y prospective cohort study. AB - Introduction Aspirin is an effective antiplatelet drug for preventing cardiovascular events in high-risk subjects. However, for patients with chronic kidney disease and undergoing hemodialysis (HD), its preventive efficacy remains controversial. The present study aimed to determine whether aspirin therapy reduces the risk of cardiovascular disease (CVD) and all-cause mortality in patients on HD. Methods We conducted a 5-y prospective cohort study involving patients on HD. Major exposure variables included prescription of aspirin (100 mg/d) and no aspirin (nonaspirin). The primary outcomes included all-cause death, cardiovascular events, hemorrhage, and ischemic stroke. The secondary outcome included bleeding events defined by the requirement of hospitalization. Findings In this study, 406 patients on regular HD were involved during a 5-y follow-up. Among these, 152 and 254 propensity-matched patients were enrolled in the aspirin and nonaspirin cohort, respectively. The cumulative survival rate was not significantly higher in the aspirin than in the nonaspirin users (log rank chi2 = 1.080, P = 0.299). Aspirin use was not significantly associated with reduced all-cause mortality, fatal and nonfatal congestive heart failure, as well as acute myocardial infarction and ischemic stroke. The risk of fatal cerebral hemorrhage was not significantly increased in the aspirin users (HR = 1.795, 95% CI 0.666-4.841, P = 0.174). After adjustment for other confounders, aspirin use was also not associated with decreased risk of all-cause mortality and CVD. Discussion The present prospective cohort study suggests that low-dose aspirin use is not associated with a significant decrease in the risks of all-cause mortality, CVD, and stroke in population undergoing HD (ClinicalTrials.gov number, NCT02261025). PMID- 26932278 TI - Impact of Rest Myocardial Perfusion Imaging on Clinical Management of Non-High Risk Chest Pain in the VA Caribbean Healthcare System Emergency Department: 2006 2008. AB - OBJECTIVE: To evaluate the appropriate clinical use of an acute rest myocardial perfusion imaging (R-MPI) in the initial emergency department (ED) evaluation of a patient presenting with chest pain (CP). METHODS: This is a retrospective study of patients evaluated with CP at the ED with an acute R-MPI. The data collected included medical history, clinical presentation, electrocardiogram, laboratory data, MPI results, confirmatory studies, disposition diagnosis and cost analysis. RESULTS: Three-hundred-sixty-six (366) patients were evaluated. The population studied had a mean Thrombolysis in Myocardial Infarction (TIMI) score of 2 and predominance of patients in the Virginia Commonwealth University (VCU) CP Category-Scale between level 3 and 4 (34% and 49% respectively). The risk of acute coronary syndrome (ACS) was significantly higher in patients with abnormal compared to normal studies (50% versus 0.4%; P < .0005; RR, 129.5; 95% CI, 18 to 924). There were a total of 14 and 19 major adverse cardiovascular events (MACE) events during the follow-up of 30-days and 1-year respectively. There were no cardiovascular fatalities. The risk of MACE at 30-days was significantly higher in patients with abnormal compared to normal studies (12% versus 0.4%; P < .001; RR, 32; 95% CI, 4.2 to 240), as well as with 1-year of follow-up (14% versus 1.6%; P < .001; RR, 9.1; 95% CI, 3.1 to 27). CONCLUSION: Using acute R-MPI in the evaluation of non-high risk patients presenting with CP is a safe, reliable and cost-effective strategy to be used in the ED to predict ACS and future MACE. PMID- 26932277 TI - Pathway Analysis using Gene-expression Profiles of HPV-positive and HPV-negative Oropharyngeal Cancer Patients in a Hispanic Population: Methodological Procedures. AB - OBJECTIVE: The incidence of oral cavity and pharyngeal cancer in Puerto Rican men is higher than it is in the men of any other ethnic/racial group in the United States of America (US). The information regarding the effect of the human papilloma virus (HPV) in the gene-expression profile among patients with this cancer is limited in Hispanic community. We aim to describe the methodology for future studies to identify the molecular networks for determining overrepresented signaling and metabolic canonical pathways, based on the differential gene expression profiles of HPV+ and HPV- samples from patients with oropharyngeal squamous cell carcinoma in Puerto Rico. METHODS: We analyzed the RNA expression of 5 tissue samples from subjects diagnosed with oropharyngeal squamous cell carcinoma, 2 HPV+ and 3 HPV-, using Affymetrix GeneChips. The relative difference between the average gene expressions of the HPV+ and HPV- samples was assessed, based on the fold change (log2-scale). RESULTS: Our analysis revealed 10 up regulated molecules (Mup1, LRP1, P14KA, ALYREF, and BHMT) and 5 down regulated ones (PSME4, KEAP1, ELK3, FAM186B, and PRELID1), at a cutoff of 1.5-fold change. Ingenuity Pathway Analysis showed the following biological functions to be affected in the HPV+ samples: cancer, hematological disease, and RNA post transcriptional modification. QRT-PCR analysis confirmed only the differential regulation of ALYREF, KEAP1, and FAM186B genes. CONCLUSION: The relevant methodological procedures described are sufficient to detect the most significant biological functions and pathways according to the HPV status in patients with oropharyngeal cancer in Puerto Rico. PMID- 26932279 TI - Diagnostic Yield of Pulmonary CT Angiography in the Evaluation of Pulmonary Embolisms Treated at the Puerto Rico Medical Center from 2008 to 2012. AB - OBJECTIVE: The objective of this study was to determine the diagnostic yield of pulmonary CT angiography (PCTA) in the evaluation of pulmonary embolisms treated at the Puerto Rico Medical Center from 2008 to 2012. METHODS: A total of 1,004 CT angiograms were reviewed in the evaluation of pulmonary embolisms. Patient records covering from 2008 to 2012 were obtained from the picture archiving and communication system (PACS) of the Puerto Rico Medical Center. Follow-up studies and those of pediatric patients were excluded from the study. The results were recorded as either positive or negative for pulmonary embolism, according to the final report rendered by board-certified radiologists. RESULTS: Of the 1,004 patient records reviewed, 964 were included in the study. Forty-six out of the total studies reviewed were positive, while a total of 918 studies were negative. A mean diagnostic yield of 4.8% (SD = 0.63) was obtained. CONCLUSION: At the Puerto Rico Medical Center, the mean diagnostic yield in the evaluation of pulmonary embolism using PCTA was 4.8%, which is in concordance with those of several previous studies, all of which had similar low yields. New diagnostic algorithms for efficiently employing PCTA for the evaluation of pulmonary embolisms are discussed herein. PMID- 26932280 TI - Is Waist-to-Height Ratio a Better Obesity Risk-Factor Indicator for Puerto Rican Children than is BMI or Waist Circumference? AB - OBJECTIVE: Puerto Rican children could have a higher prevalence of obesity, compared to US children or even to US Hispanic children. Obese youths are more likely to have risk factors for cardiovascular conditions, such as hypertension. Although BMI provides a simple, convenient measurement of obesity, it does not measure body fat distribution, associated with mortality and morbidity. Waist circumference (WC) and waist-to-height ratio (WHtR) have been suggested to estimate obesity health risks. This study aimed to explore the association of a single blood pressure reading with 3 different obesity indicators (WC, BMI, and WHtR). METHODS: A representative sample of students (first to sixth grade) from public and private schools in Puerto Rico was selected. The sample size consisted of 249 students, representing a 63% response rate. According to the sex-specific BMIs, approximately 38.1% of the children were obese or overweight. The prevalence of obesity was slightly higher when determined using WHtR but lower when using WC as the overweight indicator. The prevalence of high blood pressure among students was 12.5%; an additional 11.3% of the students were classified as possible prehypertensive. RESULTS: Regardless of the weight indicator used, overweight children were shown to have a higher risk of pre hypertension/hypertension (as defined by a single BP measure) than were non overweight children. The odds for high blood pressure were almost 3 times higher using WHtR. Logistic regression showed a stronger relationship between WHtR and the risk of pre-hypertension/hypertension than that between the former and either BMI or WC. CONCLUSION: This study suggests the possibility of higher prevalence of high blood pressure in obese Puerto Rican children. The waist-to height ratio could be the best indicator to measure obesity and potential hypertension in Puerto Rican children. PMID- 26932281 TI - Database of Surgical Procedures: A Summary of Selected Characteristics of the Surgical Population of the University of Puerto Rico-Affiliated Hospitals. AB - OBJECTIVE: To evaluate the age distribution and selected characteristics of the cases recorded in the University of Puerto Rico (UPR) Surgical Database. METHODS: All the surgical cases (from 1/1/2013 to 12/31/2013) in the Surgery Department's database were examined. This database collects patient and procedural information from the surgical services of the UPR-affiliated hospitals (University District Hospital; University Pediatric Hospital; UPR Carolina Hospital; Oncologic Hospital (Dr. I. Gonzalez Martinez), Pavia Hospital-colorectal service; and Auxilio Mutuo Hospital colorectal and oncologic services). The patients in the group were subdivided by age (less than 60 or equal or greater than 65 years). The difference between age groups was evaluated using a chi2, t-test, or ANOVA, whichever was appropriate, with a p-value less than 0.05 being considered significant. RESULTS: Information on 5,263 surgical patients was available for the study period. The mean age was 48 years (+/-23 years), with 28% of the patients being over 65 years of age. The age group with the highest rate of surgery was that of 61 to 70 years. The gender distribution was found to be similar to that of the general population: 55%, female, and 45%, male. The distribution by surgical service was as follows: general surgery, 32%; colorectal surgery, 21%; oncologic surgery, 22%; and others, 25%. The surgeries were elective in 87% of the cases and emergency procedures in 13% of them. Complications were reported in 3% of the cases; the mortality rate was 1%. CONCLUSION: Despite the fact that only 14% of our population was 65 years of age or older, 28% of the patients requiring surgery were in this age group. Older patients now represent a significant proportion of the surgical workload. Our study found that 75% of the surgical procedures performed were in the areas of general, oncologic, and colorectal surgery. PMID- 26932283 TI - Gender Distribution of General Surgery Residents at the University of Puerto Rico. AB - OBJECTIVE: To determine whether the number of women accepted to the University of Puerto Rico (UPR) general surgery residency program has increased in recent years. METHODS: We examined the gender distribution of residents accepted in their first postgraduate year (PGY-1) by the UPR Surgery Department from 1958 to 2014. This information was obtained from the database of graduate residents, which collects information on gender, medical school from which they graduated, the years in which they were in the residency program, and, their specialty. We evaluated all the residents admitted to PGY-1 positions in surgery (1958-2014) and of those admitted to PGY-1 categorical general surgery positions (1983-2014). The study was IRB approved. RESULTS: Since 1958 the number of female residents admitted as PGY-1s to the UPR Surgery Department has augmented, starting with 2% in the 1960s and rising to 36% in 2014. The percentage of categorical female residents was 11% in the 1983 to 1990 period, 14% in the 1991 to 2000 period, 18% in the 2001 to 2010 period, and 35% in the 2011 to 2014 period. CONCLUSION: We found an increase in the number of women admitted to the general surgery program over the last several years. However, despite this increase some degree of gender inequality remains in most surgery programs. Currently, 60% of undergraduate students and 50% of medical students are women, but only 36% of surgical residents are women. Future studies need to address the reasons for the small number of women in surgical programs. PMID- 26932282 TI - Chronic Hepatitis C: Treatment, Complications, and Long-term Outcomes in a Population of Latino Veterans. AB - OBJECTIVE: Chronic hepatitis C (CHC) is a major public health problem in Puerto Rico. It is the most common cause of chronic liver disease and the most frequent indication for liver transplantation in the United States. Our main objectives were to estimate the seroprevalence of CHC infection, to describe the demographic and histological parameters of the infection in our sample population, and to evaluate the treatment outcomes in Puerto Rican veterans. METHODS: To determine overall seroprevalence, we reviewed all the hepatitis C cases (encompassing from January 1, 2002, to December 31, 2009) of the VA Caribbean Healthcare System, Department of Veterans Affairs. The records of only those individuals who received treatment with pegylated interferon and ribavirin were reviewed to determine risks factors for infection, response rates, adverse events, and outcomes. RESULTS: During the study period, there were a total of 1,496 patients identified as being infected with HCV, for an estimated seroprevalence of 2.3%. Of these, approximately 10% (137) were treated with combination therapy and were included in this study. The mean age was 58 (+/-6.4); 96.4% were men. The most common genotype was type 1. The responses to treatment were generally poor, with only 48.4% of the patients achieving sustained virological response. DISCUSSION: Though the seroprevalence of chronic hepatitis C in the Latino veteran population of Puerto Rico is high, relatively few patients have received treatment, most probably because of the contraindications of the medications used. Combination therapy with pegylated interferon plus weight-based ribavirin was inefficient and plagued with side effects; as a whole, this therapy was not found to be overly beneficial to our patients. New emerging and approved therapies will change this paradigm, allowing the treatment of a larger population without the side effects of the studied therapy. PMID- 26932284 TI - Menstruation-Related Hypersomnia Treated with Hormonal Contraception: Case Report and Review of Literature. AB - Menstrual-related hypersomnia (MRH) is a rare disorder consisting of recurrent hypersomnia that is temporally linked with menses. An unusual case of an 18 yearold female with repeated episodes of hypersomnia was referred to a psychiatrist and a neurologist. A review of the literature was done so that an accurate diagnosis could be made, thereby enabling the development of an appropriate treatment plan. Making an effective diagnosis was a challenge because of the similarity of the symptoms of MRH with other psychiatric disorders. As additional clinical features were identified and treatments were ruled ineffective, further diagnoses were proposed. The patient's symptoms ceased with oral contraceptive treatment. Hormones play a role in the menstrual cycle and frequently affect behavior (such as sleep patterns). This case underlines the importance of multidisciplinary evaluation and treatment in unusual cases. The potential role of hormone fluctuation in patients with psychiatric conditions should be considered when diagnosing and treating those who are unresponsive to traditional pharmacological treatments. PMID- 26932285 TI - Rapid Resolution of Polyhydramnios Foretells Circulatory Collapse for the Donor Twin in Feto-Fetal Transfusion Syndrome. AB - Feto-fetal transfusion syndrome is a pathological process unique to diamniotic monochorionic pregnancies. It is the consequence of an unbalanced fetal blood flow through communicating vessels within a shared placenta. When it occurs, a polyuric, hypervolemic recipient twin co-exists with a hypovolemic oliguric donor. The presence of polyhydramnios or oligohydramnios is considered a poor prognostic indicator, whereas normal amniotic fluid volumes indicate a lack of clinically significant twintwin transfusion. In addition, the spontaneous normalization of amniotic fluid volume is usually seen as a favorable prognostic sign. Here, however, we present a case of feto-fetal transfusion in a 31 year-old primigravida at 19 week, in which the spontaneous normalization of amniotic fluid volume in the recipient twin preceded the death of the donor. PMID- 26932286 TI - Editorial: Vascular Damage In Systemic Sclerosis. PMID- 26932287 TI - Novel Aspects in the Pathophysiology of Peripheral Vasculopathy in Systemic Sclerosis. AB - Systemic sclerosis (SSc) is a multisystem connective tissue disease characterized by fibrosis, autoimmunity and vascular damage. Although fibrosis is often considered the main feature of the disease, there is evidence that the underlying vasculopathy plays an important role in the initiation and perpetuation of SSc. Vascular manifestations such as Raynaud's phenomenon and digital ulcers are prominent in early disease stages and might substantially contribute to the SSc related mortality in later disease stages when pulmonary arterial hypertension becomes clinically evident. Vascular damage is thought to start with endothelial cell injury and apoptosis resulting in tissue hypoxia. Hypoxia is considered a main stimulus for vascular regenerative processes. However, despite the significant deterioration in number and quality of microvessels, there is a lack of appropriate compensatory repair processes by angiogenesis and vasculogenesis. In this review, we will discuss recent data about the pathophysiology of peripheral (acral) microvascular damage in SSc, highlight novel aspects behind the defective repair mechanisms in the vascular system in SSc and focus on SSc animal models with peripheral vascular changes. PMID- 26932288 TI - From Raynaud's Phenomenon to Very Early Diagnosis of Systemic Sclerosis- The VEDOSS approach. AB - Systemic sclerosis (SSc) is a heterogeneous chronic autoimmune disease that is very difficult to diagnose in the early phase, because of the low sensitivity of the classification criteria currently used to identify patients without skin involvement, with an important delay on the therapy that is often started when internal organ involvement has already irreversible. The biggest challenge in the fight against SSc is to detect valid predictors of disease so as to treat patients since the earliest stages of disease. Raynaud's phenomenon (RP), antinuclear antibodies (ANA) positivity, and puffy fingers have been recently indicated as the"red flags", the main elements to suspect SSc and then to perform further tests to confirm the diagnosis in particular nailfold video capillaroscopy and evaluation of specific disease antibodies (anticentromere and anti-topoisomerase I). Particularly, RP is the earliest, even if aspecific sign of SSc, and more and more attention should be paid to its early identification in order to reduce the diagnostic delay. Besides, the time gap between the onset of RP and the diagnosis should be considered as a "window of opportunity" for SSc patients, through which the physician can act with effective drugs able to block or at least slow the progression of the disease. PMID- 26932289 TI - Early Diagnostic and Predictive Value of Capillaroscopy in Systemic Sclerosis. AB - Nailfold microvascular impairment represents an early feature of systemic sclerosis (SSc) and its progression through different patterns of capillary damage and their validated scoring, is evaluable by nailfold videocapillaroscopy (NVC) in a safe and reliable manner. The presence of specific morphological microvascular alterations at the NVC (i.e., presence of giant capillaries) is fundamental and mandatory for the early diagnosis of SSc, together with the presence of the Raynaud's phenomenon. Furthermore, a recent longitudinal study showed a dynamic transition of microvascular damage through different NVC patterns of microangiopathy in almost 50% of SSc patients and clinical symptoms progressed in accordance with the NVC morphologic changes in 60% of the SSc patients. A pilot study was the first demonstrating an association between baseline NVC patterns and future severe, peripheral vascular and lung involvement with stronger odds according to worsening scleroderma patterns. Prognostic indexes for digital trophic lesions, especially for daily use in SSc clinics and simply limited to the mean score of capillary loss are now validated. Very recently, it has been described that efficacious potentially disease modifying therapies in SSc may interfere with progression of nailfold microvascular damage, as assessed by NVC, over long term at least in presence of digital ulcers. NVC is a safe and reliable tool for the early diagnosis of SSc and the different NVC scleroderma patterns have a predictive value for the clinical complications of the disease. PMID- 26932290 TI - Nailfold Capillaroscopy - Its Role in Diagnosis and Differential Diagnosis of Microvascular Damage in Systemic Sclerosis. AB - In the nailfold area, specific diagnostic microvascular abnormalities are easily recognized via capillaroscopic examination in systemic sclerosis (SSc). They are termed "scleroderma" type capillaroscopic pattern, which includes presence of dilated, giant capillaries, haemorrhages, avascular areas, and neoangiogenic capillaries and are observed in the majority of SSc patients (in more than 90%). LeRoy and Medsger (2001) proposed criteria for early diagnosis of SSc with inclusion of the abnormal capillaroscopic changes and suggested to prediagnose SSc prior to the development of other manifestations of the disease. It is a new era in the diagnosis of SSc. At present, an international multicenter project is performed. It aims validation of criteria for very early diagnosis of SSc (project VEDOSS (Very Early Diagnosis of Systemic Sclerosis) and is organized by European League Against Rheumatism (EULAR) Scleroderma Trials and Reasearch. Very recently the first results of the VEDOSS project were processed and new EULAR/ACR (American College of Rheumatology) classification criteria have been validated and published (2013), in which the characteristic capillaroscopic changes have been included. Our observations confirm the high frequency of the specific capillaroscopic changes of the fingers in SSc, which have been found in 97.2% of the cases from the studied patient population. We have performed for the first time capillaroscopic examinations of the toes in SSc. Interestingly,"scleroderma type" capillaroscopic pattern was also found at the toes in a high proportion of patients - 66.7%, but it is significantly less frequent as compared with fingers (97.2%, p<0.05). In our opinion, the examination of the toes of SSc patients should be considered as it suggests an additional opportunity for evaluation of the microvascular changes in these patients although the observed changes are in a lower proportion of cases. Thus, capillaroscopic examination is a cornerstone for the very early diagnosis of SSc. Patients with clinical symptoms of peripheral vasospasm (Raynaud's phenomenon (RP)) in association with puffy fingers and/or sclerodactyly should be carefully examined. Hence, appearance of "scleroderma" type capillaroscopic changes in RP patients should be interpreted in the clinical context, because some of the components of this pattern may be observed in several other connective tissue diseases such as mixed connective tissue disease, undifferentiated connective tissue disease that are termed "scleroderma-like" capillaroscopic changes. Capillaroscopic examination is an obligatory screening method in these cases, but the pathologic capillaroscopic changes are not specific and their interpretation is in clinical context. PMID- 26932291 TI - Novel Ideas: The Increased Skin Viscoelasticity - A Possible New Fifth Sign for the Very Early Diagnosis of Systemic Sclerosis. AB - INTRODUCTION: Diagnosis of systemic sclerosis (SSc) at very early stage could allow starting an appropriate therapy and improving the patient outcome. Skin involvement is often the first non-Raynaud's phenomenon (RP) symptom. Its uncovering may play an important role for the initial diagnosis. OBJECTIVE: To introduce a simplified method for non-invasive evaluation of skin mechanical properties in patients with clinically evident or suspected SSc. MATERIAL AND METHODS: A total of 94 patients and 162 healthy subjects were studied. According to clinical and nailfold videocapillaroscopy findings the patients were divided into four groups: 20 with edematous phase of SSc (group 1), 28 with indurative phase of SSc (group 2), 26 with suspected secondary RP (group 3), and 20 with primary RP (group 4). Mechanical properties of the volar forearm skin were evaluated using a non-invasive suction device (Cutometer) equipped with 2-mm diameter probe. The skin mechanical parameters analyzed were distensibility (Uf), elasticity (Ua/Uf) and viscoelasticity (Uv/Ue). RESULTS: Skin distensibility was reduced and skin viscoelasticity increased in group 1-3 compared to age matched healthy controls. There were no significant changes in skin elasticity. Mechanical parameters in group 4 were normal. Comparison of individual patient's values with population 95% confidence intervals of the mean showed increased skin viscoelasticity in group 1 (100%), group 2 (93%), and group 3 (81%), whereas the incidence in group 4 was 10%. CONCLUSIONS: Noninvasive method applied is appropriate for objective and quantitative evaluation of sclerodermatous skin. In combination with nailfold videocapillaroscopy it could be predictive in pre scleroderma patients. The increased skin viscoelasticity parameter could be proposed as the possible new fifth sign for the very early diagnosis of SSc. PMID- 26932292 TI - Digital Ulcers in Systemic Sclerosis - Frequency, Subtype Distribution and Clinical Outcome. AB - Digital ulcers (DUs) are frequent and recurrent complication in systemic sclerosis (SSc) and are the main cause of pain, impaired function of the hand and disability in SSc. The current study is a retrospective analysis of 60 SSc patients (47 patients with limited cutaneous SSc, 8 patients with diffuse cutaneous SSc and 5 patients with overlap syndrome, mean age 54.5+/-14.2 years, 52 women and 8 men). The frequency and evolution of DUs as well as the applied therapeutic strategies were analyzed. During the follow-up for a period between 6 months and 6 years, DUs at the fingers were registered in 35% of patients (21/60), more often in patients with diffuse cutaneous SSc (75%, 6/8) as compared with patients with limited cutaneous SSc (29%, 14/47, p<0.05) and overlap syndrome (20%, 1/5). The most frequently observed DUs were ischemic lesions at the fingerpads (85.7%, 18/21) and ulcerations over bony prominences of the fingers (23%, 5/21), which may be found simultaneously. More rare types of DUs were necrotic lesions (14%, 3/21). Thirty-eight percents (8/21) of the patients with DUs showed signs of inflammation. In one patient (4.76%, 1/21) an osteomyelitis developed and an amputation of a finger's distal phalanx was performed. DUs at the toes were significantly less frequent as compared with DUs at the fingers (10%, 6/60, p<0.05). The period of healing of the DUs is prolonged and in the studied group was 3.39+/-2.39 months. The treatment regimen in SSc patients with DUs included vasodilators, local antiseptic treatment, antiplatelet drug; anticoagulant in cases with development of necrotic lesions, antibiotics in cases of infection or necrotic lesions, and other symptomatic therapies. In conclusion, DUs are a common complication in SSc and require complex therapeutic measures for achievement of a positive outcome. PMID- 26932293 TI - Digital Ulcers in Systemic Sclerosis - How to Manage in 2013? AB - Digital ulcers (DUs) are among the most frequent and disabling vascular complications in patients with systemic sclerosis (SSc). The etiology and pathogenesis of DUs differs depending on the lesion localization. For this reason the underlying etiologic and pathogenetic factors will guide the therapeutic decision. The main pathogenic mechanism that contributes to the development of fingertip DUs is ischemia owing to SSc-related vasculopathy. DUs over bony prominences are mainly a result of skin fibrosis, epidermal thinning and mechanical friction. At the areas of subcutaneous calcinosis DUs can develop as a result of mechanical friction and inflammation. Thus, in cases of DUs over bony prominences and calcinosis, avoidance of trauma and skin care are main measures of primary prophylaxis. In pure ischemic DUs, a combination of vasodilators (calcium channel blockers (CCBs), intravenous prostanoid, phosphodiesterase inhibitors) and antiplatelet drugs should be applied. Despite the lack of controlled trials addressing the administration of antiplatelet agents and anticoagulants in DUs in the context of SSc, the current knowledge about the platelet and coagulation dysfunction leads to their frequent administration from the leading experts in the field of SSc. In our opinion, as more powerful agents, anticoagulants should be considered in severe cases of development of digital gangrenes. Analgetics and antibiotics may be indicated and local treatment is a mandatory care. Currently, the EUSTAR recommendations for the treatment of RP and DUs in SSc include CCBs, intravenous prostanoids and endothelin receptor antagonists. Although for the inclusion of other options in the official recommendations, their efficacy should be confirmed by controlled clinical trials, they are routinely used in the leading scleroderma-centers based on the current knowledge about the pathogenesis of development of DUs in SSc. PMID- 26932294 TI - Systematic Review of the Role of Microparticles in Systemic Sclerosis. AB - Microparticles (MPs) are small, membrane-coated vesicles released in response to injury, cell activation or apoptosis. Growing evidence suggests associations between MPs and disease manifestations in systemic sclerosis (SSc). The aim of this study is to systematically review published articles and abstracts that discuss the role of MPs in SSc. The Web of Science((r)), PubMed((r)) and Google Scholar databases were searched for all articles and abstracts that discussed MPs in the context of SSc. The literature search was conducted on 18 July 2013 and restricted to English-language articles and abstracts. From a total of 150 distinct articles and 10 abstracts, only 14 articles and 4 abstracts met the criteria for an attempt of quantitative synthesis. Twenty articles were accepted for a review of reviews. Conference proceedings and journals not cataloged in either Web of Science((r)) or PubMed((r)) or searchable by Google Scholar would have been undetected. There is a risk of valid studies with negative results going unpublished. Few studies have been conducted on MPs in patients with SSc so it was possible to thoroughly consider each. While there is low quality evidence from studies that plasma concentrations of circulating endothelial and platelet MPs are elevated in SSc patients and that plasma concentrations of circulating endothelial MPs are higher in SSc cases with either pulmonary hypertension or interstitial lung disease than those SSc cases without, definitive conclusions are not possible due to heterogeneity of the studies with respect to inclusion criteria, populations studied, laboratory analysis methods, and choice of outcome statistics. PMID- 26932295 TI - Risk for Cervical Intraepithelial Neoplasia in Systemic Lupus Erythematosus is not Related to Disease Severity. AB - INTRODUCTION: Cervical intraepithelial neoplasia (CIN) is increased in women with systemic lupus erythematosus (SLE). Cervical neoplasia is caused by human papilloma virus (HPV) infection which persists and causes malignant transformation of infected cervical cells. Women with lupus have impaired immune systems which can facilitate HPV persistence. We hypothesized that women with SLE who developed CIN would be younger, have more severe disease and received more immunosuppressive treatment. To test this hypothesis, a case-control study was conducted focusing on two key variables, SLE disease severity and immunosuppressive treatment, which we believed would be the major determinants of CIN development in SLE. METHODS: A case control analysis was performed to compare the clinical characteristics of SLE women with cervical neoplasia (cases) to SLE women without cervical neoplasia (controls). Formalin fixed blocks of neoplastic cervical tissue were obtained from 113 women with SLE and tissue histology confirmed by 2 pathologists. Clinical data was obtained by retrospective chart reviews. Logistic regression was used to evaluate for any significant differences in clinical variables between the cases and the controls. Two sets of controls were used for comparison with a 2:1 match for each control group to cases group. RESULTS: Using matched controls adjusting for age and race, logistic regression analysis showed no significant difference between cases and controls for any of the clinical variables. In particular, there were no significant differences between cases vs. matched and vs. unmatched controls for factors related to SLE (disease severity, use of immunosuppressive drugs), chronic metabolic diseases (hypertension, diabetes) and HPV risk factors (marital status, smoking, gravidity parity). CONCLUSION: The key finding of this study is that SLE patients who develop CIN are not clinically different from SLE patients who do not develop CIN. Thus, lupus disease severity and immunosuppressive treatment were not susceptibility factors for CIN in our female lupus cohort. PMID- 26932296 TI - Observation of single-file diffusion in a MOF. AB - The translational and rotational dynamics of neopentane adsorbed in the one dimensional channels of MIL-47(V) has been studied by quasi-elastic neutron scattering. The rotational motion of neopentane is well-described by the rotational diffusion model, with a correlation time of 41 ps at 300 K. The translational motion of the molecule has been fitted by several models: isotropic diffusion, normal 1D and single-file diffusion. It is found that the observed line shapes can only be reproduced by the single-file diffusion model. The single file mobility factor, F, is (8 +/- 1) * 10(-14) m(2) s(-1/2) at 300 K. This is the first observation of this unusual diffusion behaviour in a MOF. PMID- 26932297 TI - Hydrogen Sulfide Recruits Macrophage Migration by Integrin beta1-Src-FAK/Pyk2-Rac Pathway in Myocardial Infarction. AB - Myocardial infarction (MI) triggers an inflammatory reaction, in which macrophages are of key importance for tissue repairing. Infiltration and/or migration of macrophages into the infarct area early after MI is critical for infarct healing, vascularization, and cardiac function. Hydrogen sulfide (H2S) has been demonstrated to possess cardioprotective effects post MI and during the progress of cardiac remodeling. However, the specific molecular and cellular mechanisms involved in macrophage recruitment by H2S remain to be identified. In this study, the NaHS (exogenous sources of H2S) treatment exerted an increased infiltration of macrophages into the infarcted myocardium at early stage of MI cardiac tissues in both wild type (WT) and cystathionine-gamma-lyase-knockout (CSE-KO) mice. And NaHS accelerated the migration of macrophage cells in vitro. While, the inhibitors not only significantly diminished the migratory ability in response to NaHS, but also blocked the activation of phospho-Src, -Pyk2, FAK(397), and -FAK(925). Furthermore, NaHS induced the internalization of integrin beta1 on macrophage surface, but, integrin beta1 silencing inhibited macrophage migration and Src signaling activation. These results indicate that H2S may have the potential as an anti-infarct of MI by governing macrophage migration, which was achieved by accelerating internalization of integrin beta1 and activating downstream Src-FAK/Pyk2-Rac pathway. PMID- 26932298 TI - Inorganic phosphate-triggered release of anti-cancer arsenic trioxide from a self delivery system: an in vitro and in vivo study. AB - On-demand drug delivery is becoming feasible via the design of either exogenous or endogenous stimulus-responsive drug delivery systems. Herein we report the development of gadolinium arsenite nanoparticles as a self-delivery platform to store, deliver and release arsenic trioxide (ATO, Trisenox), a clinical anti cancer drug. Specifically, unloading of the small molecule drug is triggered by an endogenous stimulus: inorganic phosphate (Pi) in the blood, fluid, and soft or hard tissue. Kinetics in vitro demonstrated that ATO is released with high ON/OFF specificity and no leakage was observed in the silent state. The nanoparticles induced tumor cell apoptosis, and reduced cancer cell migration and invasion. Plasma pharmacokinetics verified extended retention time, but no obvious disturbance of phosphate balance. Therapeutic efficacy on a liver cancer xenograft mouse model was dramatically potentiated with reduced toxicity compared to the free drug. These results suggest a new drug delivery strategy which might be applied for ATO therapy on solid tumors. PMID- 26932299 TI - Tunable nanoplasmonic sensor based on the asymmetric degree of Fano resonance in MDM waveguide. AB - We first report a simple nanoplasmonic sensor for both universal and slow-light sensing in a Fano resonance-based waveguide system. A theoretical model based on the coupling of resonant modes is provided for the inside physics mechanism, which is supported by the numerical FDTD results. The revealed evolution of the sensing property shows that the Fano asymmetric factor p plays an important role in adjusting the FOM of sensor, and a maximum of ~4800 is obtained when p = 1. Finally, the slow-light sensing in such nanoplasmonic sensor is also investigated. It is found that the contradiction between the sensing width with slow-light (SWS) and the relevant sensitivity can be resolved by tuning the Fano asymmetric factor p and the quality factor of the superradiant mode. The presented theoretical model and the pronounced features of this simple nanoplasmonic sensor, such as the tunable sensing and convenient integration, have significant applications in integrated plasmonic devices. PMID- 26932300 TI - LaSota fusion (F) cleavage motif-mediated fusion activity is affected by other regions of the F protein from different genotype Newcastle disease virus in a chimeric virus: implication for virulence attenuation. AB - The cleavage site sequence of the fusion (F) protein contributes to a wide range of virulence of Newcastle disease virus (NDV). In this study, we identified other important amino acid sequences of the F protein that affect cleavage and modulation of fusion. We generated chimeric Beaudette C (BC) viruses containing the cleavage site sequence of avirulent strain LaSota (Las-Fc) together with various regions of the F protein of another virulent strain AKO. We found that the F1 subunit is important for cleavage inhibition. Further dissection of the F1 subunit showed that replacement of four amino acids in the BC/Las-Fc protein with their AKO counterparts (T341S, M384I, T385A and I386L) resulted in an increase in fusion and replication in vitro. In contrast, the mutation N403D greatly reduced cleavage and viral replication, and affected protein conformation. These findings will be useful in developing improved live NDV vaccines and vaccine vectors. PMID- 26932301 TI - High-throughput FACS-based mutant screen identifies a gain-of-function allele of the Fusarium graminearum adenylyl cyclase causing deoxynivalenol over-production. AB - Fusarium head blight and crown rot, caused by the fungal plant pathogen Fusarium graminearum, impose a major threat to global wheat production. During the infection, plants are contaminated with mycotoxins such as deoxynivalenol (DON), which can be toxic for humans and animals. In addition, DON is a major virulence factor during wheat infection. However, it is not fully understood how DON production is regulated in F. graminearum. In order to identify regulators of DON production, a high-throughput mutant screen using Fluorescence Activated Cell Sorting (FACS) of a mutagenised TRI5-GFP reporter strain was established and a mutant over-producing DON under repressive conditions identified. A gain-of function mutation in the F. graminearum adenylyl cyclase (FAC1), which is a known positive regulator of DON production, was identified as the cause of this phenotype through genome sequencing and segregation analysis. Our results show that the high-throughput mutant screening procedure developed here can be applied for identification of fungal proteins involved in diverse processes. PMID- 26932302 TI - Pharmacokinetics of fixed-dose combinations of empagliflozin/metformin compared with individual tablets in healthy subjects. AB - OBJECTIVE: To compare the pharmacokinetics of fixed-dose combination (FDC) tablets of empagliflozin/metformin with individual tablets taken together. METHODS: In 3 randomized, open-label studies, healthy subjects received a single FDC tablet of empagliflozin/metformin in 1 of 6 dose combinations (empagliflozin 12.5 mg or 5 mg; metformin 500 mg, 850 mg, or 1,000 mg) in 1 period and the individual tablets taken together under fed conditions in another period. Empagliflozin 12.5 mg/metformin 1,000 mg FDC and individual tablets were also given under fasted conditions. RESULTS: Adjusted geometric mean ratios (GMRs) of empagliflozin area under the plasma concentration-time curve (AUC(0-infinity)) for the FDCs vs. individual tablets ranged from 97.92 to 106.00%, and 90% CIs ranged from 93.53 to 109.39%. Adjusted GMRs of empagliflozin maximum plasma concentrations (C(max)) for the FDCs vs. individual tablets ranged from 100.97 to 106.52%, and 90% CIs ranged from 95.86 to 118.35%. Adjusted GMRs of metformin AUC(0-infinity) for the FDCs vs. individual tablets ranged from 96.25 to 101.61%, and 90% CIs ranged from 88.54 to 106.62%. Adjusted GMRs of metformin C(max) for the FDCs vs. individual tablets ranged from 93.83 to 102.95%, and 90% CIs ranged from 88.01 to 109.08%. Bioequivalence was also established under fasted conditions for empagliflozin 12.5 mg/metformin 1,000 mg FDC vs. individual tablets taken together. All treatments were well tolerated. CONCLUSION: Empagliflozin/metformin FDC tablets were found to be bioequivalent to individual tablets taken together at all tested dose strengths. PMID- 26932303 TI - High prevalence of self-medication practices among medical and pharmacy students: a study from Jordan. AB - OBJECTIVE: To assess self-medication practices and to evaluate the impact of obtaining medical knowledge on self-medication among medical and pharmacy students at Jordan University of Science and Technology. METHODS: This was a cross-sectional study. A well-validated questionnaire that included 3 sections about self-medication was administered to the subjects after introducing the term "self-medication" verbally. RESULTS: 1,317 students had participated in the study and were subgrouped according to their academic level into seniors and juniors. Compared to the general population rate of 42.5%, self-medication practice was reported by (1,034, 78.5%) of the students and most common amongst pharmacy students (n = 369, 82.9%) compared to Pharm.D. (n = 357, 77.9%) and medical students (n = 308, 74.4%) (p = 0.009). There was no significant difference between juniors and seniors (557, 79.1% vs. 477, 77.8%, p = 0.59, respectively). Headache (71.2%) and common cold (56.5%) were frequent ailments that provoked self-medication. Analgesics (79.9%) and antibiotics (59.8%) were frequently used to self-treat these aliments. Reasons for self-medication included previous disease experience (55.7%); minor aliments (55.3%); and having enough medical knowledge (32.1%). Medicines were used according to instructions obtained mainly from the leaflet (28.8%); pharmacist (20.7%); and university courses (19.7%). Senior students were more aware of the risk of self-medication than junior students. The majority of students frequently advise other people about self medication (83.6%). CONCLUSIONS: Self-medication was common among students irrespective to their level of medical knowledge. Obtaining medical knowledge increased the students' awareness of the risk of self-medication which may result in practicing responsible self-medication. However, medical teaching institutions need to educate students about the proper use of medicines as a therapeutic tool. PMID- 26932304 TI - Treatment with everolimus for a patient with systemic metastatic breast cancer results in severe pulmonary injury: a case report. AB - Everolimus has been used in patients with hormone receptor-positive breast cancer. This study reports that treatment with everolimus alone induced severe pulmonary injury in a patient with systemic metastatic breast cancer. A 58 yearold woman with systemic metastatic breast cancer was treated with everolimus alone for 4 weeks and developed severe cough and dyspnea. Computed tomography (CT) scan of the chest showed a progressive lung tumor accompanied by bilateral pulmonary homogeneous ground-glass opacity, especially in the inferior lobe of the left lung. Laboratory examinations revealed a high frequency of monocytes, higher levels of serum alanine aminotransferase (ALT), lactate dehydrogenase (LDH), and C-reactive protein as well as mild hypoxemia and hypocarbia. However, she had no evidence of infection with mycoplasma pneumoniae, chlamydia, pneumocystis, tuberculosis, influenza A virus, and was negative for serum galactomannan (GM) antigen assay. She was suspected to have drug-induced interstitial pneumonia. Everolimus treatment was stopped, and treated with methylprednisolone and empiric antibiotic therapy for 7 days. She received further corticosteroid treatment and felt much better, accompanied by clearance of lung inflammation; she was discharged from hospital. Our experience suggests that treatment with everolimus alone may cause severe pulmonary injury and should be considered carefully in cases of patients with systemic metastatic breast cancer. PMID- 26932305 TI - Bioequivalence and food effect assessment for vildagliptin/metformin fixed-dose combination tablets relative to free combination of vildagliptin and metformin in Japanese healthy subjects. AB - OBJECTIVE: To assess the bioequivalence of vildagliptin/metformin fixeddose combination (FDC) tablets (50/250 mg and 50/500 mg) to free combinations of vildagliptin and metformin and the effect of food on the pharmacokinetics (PK) of vildagliptin and metformin following administration of 50/500 mg FDC tablets. METHODS: Two openlabel, randomized, single-center, singledose, 2-period crossover studies were conducted in Japanese healthy male volunteers. Participants were administered vildagliptin/ metformin FDC tablets (study I: 50/250 mg, study II: 50/500 mg) or their free combinations under fasted condition. Food effect (standard Japanese breakfast: fat, 20 - 30% with ~ 600 kcal in total) was assessed during an additional period in study II (50/500 mg). PK parameters (AUC, C(max), t(max), t(1/2)) were calculated for vildagliptin and metformin. RESULTS: In both studies, vildagliptin/metformin FDC tablets were bioequivalent to their respective free combinations. Administration of FDC tablets after meals had no effect on vildagliptin PK parameters. The rate of absorption of metformin decreased when administered under fed condition, as reflected by a prolonged t(max) (3 hours in fasted state vs. 4 hours in fed state) and decrease in C(max) by 26%, however, the extent of absorption (AUC(last)) was similar to that in the fasted state. CONCLUSIONS: Vildagliptin/metformin FDC tablets were bioequivalent to their free combinations. Food decreased the C(max) of metformin by 26%, while AUC(last) was unchanged, consistent with previous reports. No food effect was observed on the C(max) or AUC(last) of vildagliptin. Thus, food had no clinically relevant effects on the PK of metformin or vildagliptin. PMID- 26932306 TI - Pain leads the way: the development of evidence-based medicine for pain relief. AB - This paper describes the development of evidence based methods in pain medicine since the 1980s at the Pain Research Department of the Nuffield Department of Clinical Neurosciences, Oxford University. Pain medicine can be said to have led the way in terms of developing registers of randomized controlled trials (RCTs) and in developing appropriate methodology for assessing clinical trials and developing metanalytical techniques. This paper tells the story of that development which occurred in conjunction with the development of the Cochrane Collaboration. Pain has a larger body of evidence than many medical specialties with more than 30,000 RCTs and over 2,500 published systematic reviews. Our work continues to raise methodological challenges and a number of key ones are described: Size: We have added to the existing literature to show that small studies overestimate treatment effects. We consider studies with less than 50 participants per treatment group to be at high risk of bias. Mean pain scores: We have shown these to be unhelpful and misleading. We illustrate that response to analgesics is a U-shaped curve with a larger proportion of participants having either a poor response or a good response. Imputation: We discuss the problems of current methods. Tiers of evidence: We propose a way to assess evidence for pain studies. Duplicate publication of data can lead to inflated benefits in systematic reviews. In addition we touch on fraud, pharmaceutical company funding. The final sections cover developments in several areas of pain medicine, and suggest some developments going forward. PMID- 26932307 TI - Analysis of genomic copy number variation in equine recurrent airway obstruction (heaves). AB - We explored the involvement of genomic copy number variants (CNVs) in susceptibility to recurrent airway obstruction (RAO), or heaves-an asthmalike inflammatory disease in horses. Analysis of 16 RAO-susceptible (cases) and six RAO-resistant (control) horses on a custom-made whole-genome 400K equine tiling array identified 245 CNV regions (CNVRs), 197 previously known and 48 new, distributed on all horse autosomes and the X chromosome. Among the new CNVRs, 30 were exclusively found in RAO cases and were further analyzed by quantitative PCR, including additional cases and controls. Suggestive association (P = 0.03; corrected P = 0.06) was found between RAO and a loss on chromosome 5 involving NME7, a gene necessary for ciliary functions in lungs and involved in primary ciliary dyskinesia in humans. The CNVR could be a potential marker for RAO susceptibility but needs further study in additional RAO cohorts. Other CNVRs were not associated with RAO, although several involved genes of interest, such as SPI2/SERPINA1 from the serpin gene family, which are associated with chronic obstructive pulmonary disease and asthma in humans. The SPI2/SERPINA1 CNVR showed striking variation among horses, but it was not significantly different between RAO cases and controls. The findings provide baseline information on the relationship between CNVs and RAO susceptibility. Discovery of new CNVs and the use of a larger population of RAO-affected and control horses are needed to shed more light on their significance in modulating this complex and heterogeneous disease. PMID- 26932309 TI - The Use of a Brochure to Enable CAM-with-Chemotherapy Patient Education. AB - The majority of cancer patients receiving chemotherapy will consider taking complementary and alternative medicine (CAM) during their treatment. As biologically-active CAM may detrimentally interfere with chemotherapy treatment, cancer patients require evidence-based information on chemotherapy-CAM integration consequences. This study aimed to assess if the availability of a purpose-designed brochure within a cancer service aided doctors' discussions with their patients on CAM use and helped patients understand the effects of CAM during their chemotherapy treatment. Cancer care doctors consulting in an adult day unit completed a structured post-intervention feedback survey form (n = 17), and cancer patients receiving chemotherapy treatment were provided the brochure and completed the local health service consumer testing feedback form (n = 30). All cancer care doctors perceived a need for the brochure and recommended the brochure to their patients. All doctors thought the brochure made it easier for them to discuss CAM with their patients, and 59 % believed that it saved them time during patient consultations. Ninety percent of cancer patients reported the brochure had enough information to answer their CAM questions, and all patients thought the information was easy to read and understand. An evidence-based CAM with-chemotherapy patient brochure was perceived to have enabled cancer care doctors to discuss CAM with their patients and to have answered patients' CAM questions. PMID- 26932308 TI - The cacao pathogen Moniliophthora roreri (Marasmiaceae) possesses biallelic A and B mating loci but reproduces clonally. AB - The cacao pathogen Moniliophthora roreri belongs to the mushroom-forming family Marasmiaceae, but it has never been observed to produce a fruiting body, which calls to question its capacity for sexual reproduction. In this study, we identified potential A (HD1 and HD2) and B (pheromone precursors and pheromone receptors) mating genes in M. roreri. A PCR-based method was subsequently devised to determine the mating type for a set of 47 isolates from across the geographic range of the fungus. We developed and generated an 11-marker microsatellite set and conducted association and linkage disequilibrium (standardized index of association, IA(s)) analyses. We also performed an ancestral reconstruction analysis to show that the ancestor of M. roreri is predicted to be heterothallic and tetrapolar, which together with sliding window analyses support that the A and B mating loci are likely unlinked and follow a tetrapolar organization within the genome. The A locus is composed of a pair of HD1 and HD2 genes, whereas the B locus consists of a paired pheromone precursor, Mr_Ph4, and receptor, STE3_Mr4. Two A and B alleles but only two mating types were identified. Association analyses divided isolates into two well-defined genetically distinct groups that correlate with their mating type; IA(s) values show high linkage disequilibrium as is expected in clonal reproduction. Interestingly, both mating types were found in South American isolates but only one mating type was found in Central American isolates, supporting a prior hypothesis of clonal dissemination throughout Central America after a single or very few introductions of the fungus from South America. PMID- 26932310 TI - Evaluation of the Knowledge Levels of 50-Year-Old and Older Individuals Regarding Colorectal Cancer. AB - Our aim was to determine some risk factors for colorectal cancer and evaluate the knowledge levels about it among individuals aged 50 and over. A cross-sectional study was conducted among 1161 patients aged 50 and over in 2014. The data were collected by a questionnaire form consisting of 46 questions. The chi square test and the logistic regression analysis were performed in the data analysis. The mean age of the participants was 57.9 +/- 5.6, 60; 4 % were women, and 77.7 % were married. It was determined that 23.0 % of the elderly people were smokers, and 46.5 % did not do regular physical exercises. It was detected that 29.8 % had fatigue, 27.5 % had abdominal pain, 14.9 % had melena, and 10.3 % had constipation or diarrhea in the last 3 months. The mean colorectal cancer knowledge score was 6.84 +/- 2.46. It was determined that the socio-demographic variables and the risk factors that were based on self-report of the elderly influenced the knowledge scores on colorectal cancer and its early diagnosis (p < 0.05). Consequently, it has been determined that the elderly people have the risk factors of colorectal cancer; however, they do not have adequate knowledge about this disease. PMID- 26932311 TI - Hospital-based herpes zoster diagnoses in Denmark: rate, patient characteristics, and all-cause mortality. AB - BACKGROUND: Herpes zoster (HZ) may result in severe complications requiring hospital treatment, particularly in patients with comorbidity. Nevertheless, data on HZ from nationwide population-based hospital registries are sparse. METHODS: We conducted a cohort study describing first-time hospital-based (inpatient, outpatient, and emergency room) HZ diagnoses in the Danish National Patient Registry, 1994-2012. We computed the diagnosis rate; prevalence of demographic characteristics, comorbidities, and complications; length of hospital stay; and standardized mortality ratios (SMRs) using the Danish population as reference. We classified comorbidity using the Charlson Comorbidity Index (CCI) scoring system and categorized patients in groups of no (score 0), moderate (score 1), severe (score 2), and very severe comorbidity (score >=3). In addition, we computed the prevalence of certain conditions associated with immune dysregulation (stem cell or bone marrow transplantation, solid organ transplantation, HIV infection, primary immunodeficiency, any cancer, and autoimmune diseases). RESULTS: The diagnosis rate increased almost exponentially from 6 to 91.9 per 100,000 person years between age 50 and >=90 years. The age-standardized rate was stable throughout the study period. The median length of hospital stay was 4 days (interquartile range: 1-8 days) for inpatients with HZ as the main reason for admission. According to the CCI, 44.3 % of patients had no comorbidity, 17.3 % moderate comorbidity, 17.4 % severe comorbidity, and 21.0 % very severe comorbidity. Comorbidities involving immune dysregulation, such as malignant (21 %) and autoimmune diseases (17 %), were particularly prevalent. Thirty percent had neurological, ophthalmic, or other complications. HZ was associated with increased all-cause mortality overall (SMR 1.8, 95 % CI: 1.7-1.8), but not in analyses restricted to patients without comorbidity (SMR 1.0, 95 % CI: 0.9-1.0). CONCLUSIONS: This study provides estimates of the epidemiology of hospital-based (severe) HZ. The diagnosis rate increased substantially with age. Complications and comorbidities were prevalent, likely resulting in increased mortality. PMID- 26932312 TI - Prevalence of biologics monotherapy in a cohort of patients with Rheumatoid Arthritis in daily clinical practice. AB - BACKGROUND: Real-life registry data reveal approximately one-third of patients taking biologic agents use them as monotherapy, in spite that combination therapy with Disease Modifying Drugs is more efficacious than monotherapy. The aim of our study was to assess the prevalence of biologics monotherapy in a cohort of patients with RA followed at a single center, and to analyze the reasons for monotherapy, including patients with prescriptions that do not take the medication. METHODS: All patients with Rheumatoid Arthritis, with biologic therapy followed at our Rheumatology Unit were included. Prevalence and reasons for biologics monotherapy was calculated in general, for each biologic course and for each biologic. Prescription data was obtained from the Electronic Medical Record, and drugs acquisition was obtained from the Hospital Administrative database. Drug survival was also calculated and compared between monotherapy and combination therapy. RESULTS: Seventy nine patients with 115 courses of biologic treatments were included. In 40 (35 %, 95 % CI: 26-44 %) of all biologics courses, biologics were initiated as monotherapy. In 27 courses (23 %, 95 % CI: 16-32 %) biologic monotherapy was prescribed by the treating rheumatologists, and in the other 13 (11 %, 95 % CI: 6-18 %) it was initiated as such by decision of the patient regardless of the physician indication. Reasons for prescription of biologic monotherapy by the treating rheumatologists were adverse events with previous DMARDs in 55.5 %, and was not specified in the remaining courses. Only 25 % of biologics' courses were monotherapy from the beginning to the end of the biologic therapy. The overall survival on biologics was 45 % (95 % CI: 35-55 %) at 3 years. There were no statistically differences in biologics survival by modality (monotherapy vs combination) (p = 0.543), course (p = 0.4454), or by biologic drug (p = 0.9612). CONCLUSIONS: Almost 1/3 of patients on biologics use them as monotherapy. This is due to physician's preferences in 60 % of the cases, and to patients not compliance with the indication in around 40 % of the cases. Better communications is needed to assure that physicians and patients agree on the prescribed and used medication. PMID- 26932313 TI - Using an interlaboratory study to revise methods for conducting 10-d to 42-d water or sediment toxicity tests with Hyalella azteca. AB - Studies have been conducted to refine US Environmental Protection Agency, ASTM International, and Environment Canada standard methods for conducting 42-d reproduction tests with Hyalella azteca in water or in sediment. Modifications to the H. azteca method include better-defined ionic composition requirements for exposure water (i.e., >15 mg/L of chloride and >0.02 mg/L of bromide) and improved survival, growth, and reproduction with alternate diets provided as increased rations over time in water-only or whole-sediment toxicity tests. A total of 24 laboratories volunteered to participate in the present interlaboratory study evaluating the performance of H. azteca in 42-d studies in control sand or control sediment using the refined methods. Improved growth and reproduction of H. azteca was observed with 2 alternate diets of 1) ramped diatoms (Thalassiosira weissflogii) + ramped Tetramin or 2) yeast-cerophyll-trout chow (YCT) + ramped Tetramin, especially when compared with results from the traditional diet of 1.8 mg YCT/d. Laboratories were able to meet proposed test acceptability criteria and in most cases had lower variation in growth or reproduction compared with previous interlaboratory studies using the traditional YCT diet. Laboratory success in conducting 42-d H. azteca exposures benefited from adherence to several key requirements of the detailed testing, culturing, and handling methods. Results from the present interlaboratory study are being used to help revise standard methods for conducting 10-d to 42-d water or sediment toxicity exposures with H. azteca. Environ Toxicol Chem 2016;35:2439 2447. (c) 2016 SETAC. PMID- 26932314 TI - Protein dynamics from nuclear magnetic relaxation. AB - Nuclear magnetic resonance is a ubiquitous spectroscopic tool to explore molecules with atomic resolution. Nuclear magnetic relaxation is intimately connected to molecular motions. Many methods and models have been developed to measure and interpret the characteristic rates of nuclear magnetic relaxation in proteins. These approaches shed light on a rich and diverse range of motions covering timescales from picoseconds to seconds. Here, we introduce some of the basic concepts upon which these approaches are built and provide a series of illustrations. PMID- 26932315 TI - Adsorption behavior of methacryloyloxydecyl dihydrogen phosphate on an apatite surface at neutral pH. AB - This study aimed to quantify the adsorption affinity of neutralized 10 methacryloyloxydecyl dihydrogen phosphate (10-MDP-N) toward hydroxyapatite (HA) and dicalcium phosphate dihydrate (DCPD) at pH 7.0 by employing the Langmuir isotherm model. Furthermore, the effects of inorganic phosphate (Pi) and fluoride (F(-) ) ions on the adsorption of 10-MDP-N onto HA and DCPD were examined. Fixed amounts of HA and DCPD powders were suspended in different concentrations of 10 MDP-N solutions and were incubated for 18 h. Equilibrated concentrations of 10 MDP-N were measured by spectrophotometry and the adsorption affinity was estimated using the Langmuir model. Moreover, the adsorption was examined by zeta potential analysis. The results indicated that significant Langmuir correlation was noted in both substrates, along with an increasing negative zeta-potential; however, in DCPD the correlation was less strong. The addition of 1.0 mM Pi slightly delayed the adsorption of 10-MDP-N onto both substrates, whereas 3.0 mM Pi drastically delayed adsorption onto HA but completely inhibited adsorption onto DCPD. Up to 50 ppm, F(-) enhanced the adsorption onto HA, and the adsorption plateaued at higher concentrations of F(-) , whereas no obvious influence of F(-) on the adsorption onto DCPD was noted. PMID- 26932316 TI - Observation of magnon-mediated current drag in Pt/yttrium iron garnet/Pt(Ta) trilayers. AB - Pure spin current, a flow of spin angular momentum without flow of any accompanying net charge, is generated in two common ways. One makes use of the spin Hall effect in normal metals (NM) with strong spin-orbit coupling, such as Pt or Ta. The other utilizes the collective motion of magnetic moments or spin waves with the quasi-particle excitations called magnons. A popular material for the latter is yttrium iron garnet, a magnetic insulator (MI). Here we demonstrate in NM/MI/NM trilayers that these two types of spin currents are interconvertible across the interfaces, predicated as the magnon-mediated current drag phenomenon. The transmitted signal scales linearly with the driving current without a threshold and follows the power-law T(n) with n ranging from 1.5 to 2.5. Our results indicate that the NM/MI/NM trilayer structure can serve as a scalable pure spin current valve device which is an essential ingredient in spintronics. PMID- 26932317 TI - N-terminal fusion of a toll-like receptor 2-ligand to a Neospora caninum chimeric antigen efficiently modifies the properties of the specific immune response. AB - Immunoprophylactic products against neosporosis during pregnancy should induce an appropriately balanced immune response. In this respect, OprI, a bacterial lipoprotein targeting toll like receptor (TLR)2, provides promising adjuvant properties. We report on the manipulation of the innate and the T-cell immune response through the fusion of OprI with the Neospora caninum chimeric protein Mic3-1-R. In contrast to Mic3-1-R, OprI-MIC3-1-R significantly activated bone marrow dendritic cells from naive mice. Mice immunized with OprI-Mic3-1-R induced an immune response with mixed T helper (Th)1 and Th2 properties (high levels of both immunoglobulin (Ig)G1 and IgG2a and of interleukin (IL)-10, IL-12(p70) and interferon-gamma responses) whereas Mic3-1-R+saponin induced a clear Th2-biased response (low IgG2a and high IL-4 and IL-10). After mating and challenge with N. caninum, increased expression of interferon-gamma was only found in placentas from OprI-Mic3-1-R immunized dams. However, no protection against vertical transmission and neonatal mortality was observed in either of the two groups. These results indicated that more exhaustive studies must be done to elucidate the immune mechanisms associated with transplacental transmission. Antigen linkage to TLR2-ligands, such as OprI, is a useful tool to investigate this enigma by reorienting the innate and adaptive immune responses against other candidate antigens in future studies. PMID- 26932319 TI - The purpose and appropriateness of carbapenem use in a single university hospital, 2009-2013. AB - This is a retrospective review study to investigate changes in carbapenem consumption and to evaluate the proportion of inappropriate empirical use of carbapenem in the months of September and October of 2009, 2011, and 2013 in a single university-affiliated hospital. Total carbapenem use was classified into 3 categories: prophylactic, directed, and empirical. If an empirical prescription was continued without documentation of any eligible etiologic microorganism, we defined this as 'inappropriate' use. We also considered it 'inappropriate' when a patient's culture revealed no pathogen and the patient was initially not in severe sepsis or septic shock and did not have a history of admission to a health care facility or of colonization with a pathogen eligible for carbapenem within 3 months. The total amount was 48.1, 51.1, and 91.0 defined daily doses/1000 patient-days in 2009, 2011, and 2013, respectively. Empirical use accounted for 78.4% of all prescriptions. The proportion of inappropriate empirical use ranged from 15.0 to 38.9% of the empirical carbapenem prescriptions. PMID- 26932318 TI - Untargeted plasma and tissue metabolomics in rats with chronic kidney disease given AST-120. AB - Chronic kidney disease (CKD) results in the accumulation of metabolic waste products that are normally cleared by the kidney, known as uremia. Many of these waste products are from bacteria metabolites in the gut. Accumulation of uremic toxins in plasma and tissue, as well as the gut-plasma-tissue metabolic axis are important for understanding pathophysiological mechanisms of comorbidities in CKD. In this study, an untargeted metabolomics approach was used to determine uremic toxin accumulation in plasma, liver, heart and kidney tissue in rats with adenine-induced CKD. Rats with CKD were also given AST-120, a spherical carbon adsorbent, to assess metabolic changes in plasma and tissues with the removal of gut-derived uremic toxins. AST-120 decreased >55% of metabolites that were increased in plasma, liver and heart tissue of rats with CKD. CKD was primarily defined by 8 gut-derived uremic toxins, which were significantly increased in plasma and all tissues. These metabolites were derived from aromatic amino acids and soy protein including: indoxyl sulfate, p-cresyl sulfate, hippuric acid, phenyl sulfate, pyrocatechol sulfate, 4-ethylphenyl sulfate, p-cresol glucuronide and equol 7-glucuronide. Our results highlight the importance of diet and gut derived metabolites in the accumulation of uremic toxins and define the gut plasma-tissue metabolic axis in CKD. PMID- 26932320 TI - Co-immobilization of multiple enzymes by metal coordinated nucleotide hydrogel nanofibers: improved stability and an enzyme cascade for glucose detection. AB - Preserving enzyme activity and promoting synergistic activity via co-localization of multiple enzymes are key topics in bionanotechnology, materials science, and analytical chemistry. This study reports a facile method for co-immobilizing multiple enzymes in metal coordinated hydrogel nanofibers. Specifically, four types of protein enzymes, including glucose oxidase, Candida rugosa lipase, alpha amylase, and horseradish peroxidase, were respectively encapsulated in a gel nanofiber made of Zn(2+) and adenosine monophosphate (AMP) with a simple mixing step. Most enzymes achieved quantitative loading and retained full activity. At the same time, the entrapped enzymes were more stable against temperature variation (by 7.5 degrees C), protease attack, extreme pH (by 2-fold), and organic solvents. After storing for 15 days, the entrapped enzyme still retained 70% activity while the free enzyme nearly completely lost its activity. Compared to nanoparticles formed with AMP and lanthanide ions, the nanofiber gels allowed much higher enzyme activity. Finally, a highly sensitive and selective biosensor for glucose was prepared using the gel nanofiber to co-immobilize glucose oxidase and horseradish peroxidase for an enzyme cascade system. A detection limit of 0.3 MUM glucose with excellent selectivity was achieved. This work indicates that metal coordinated materials using nucleotides are highly useful for interfacing with biomolecules. PMID- 26932321 TI - Long-term regular dental attendance and periodontal disease in the 1998 adult dental health survey. AB - AIM: The aim of this study was to explore the association between long-term pattern of dental attendance and periodontal disease among British adults. METHODS: We used data from 3272 adults who participated in the 1998 Adult Dental Health Survey in the UK. Participants were classified into four trajectories (current, always, former and never regular attenders) based on their responses to three questions on lifetime dental attendance patterns. The numbers of teeth with pocket depth (PD) >=4 mm and loss of attachment (LOA) >=4 mm were the outcome measures. The association between dental attendance patterns and each periodontal measure was assessed in crude and adjusted models using negative binomial regression. RESULTS: Never and former regular attenders had more teeth with PD >=4 mm (Rate Ratios with 95% Confidence Interval: 1.58 [1.28-1.95] and 1.34 [1.12 1.60] respectively) and LOA >=4 mm (1.34 [1.04-1.72] and 1.37 [1.07-1.75] respectively) than always regular attenders, after adjustments for demographic (sex, age and country of residence) and socioeconomic factors (education and social class). However, no differences in periodontal measures were found between always and current regular attenders. CONCLUSION: This analysis of national cross sectional data shows that adults with different long-term patterns of dental attendance have different periodontal health status. PMID- 26932322 TI - Fibroblast VEGF-receptor 1 expression as molecular target in periodontitis. AB - AIM: Degradation of extracellular matrices is an integral part in periodontitis. For antagonizing this pathophysiological mechanism, we aimed at identifying gene expression profiles in disease progression contributing periodontitis-associated fibroblasts (PAFs) versus normal gingival fibroblasts to determine their molecular repertoire, and exploit it for therapeutic intervention. MATERIALS AND METHODS: Applying an exploratory analysis using a small number of microarrays in combination with a three dimensional (3D) in vitro culture model that incorporates some aspects of periodontitis, PAFs were initially characterized by gene-expression analyses, followed by targeted gene down-regulation and pharmacological intervention in vitro. Further, immunohistochemistry was applied for phosphorylation analyses in tissue specimens. RESULTS: PAFs were characterized by 42 genes being commonly up-regulated >1.5-fold, and by five genes that were concordantly down-regulated (<0.7-fold). Expression of vascular endothelial growth factor (VEGF)-receptor 1 (Flt-1) was highly enhanced, and was thus further explored in in vitro culture models of periodontal fibroblasts without accounting for the microbiome. Phosphorylation of the VEGF-receptor 1 was enhanced in PAFs. Receptor inhibition by a specific VEGF-receptor inhibitor or intrinsic down-regulation by RNAi of the VEGF-receptor kinase in 3D gel cultures resulted in significant reduction in collagen degradation associated with increased tissue inhibitor of metalloproteinase expression, suggesting that Flt-1 may contribute to periodontitis. CONCLUSION: Based on the finding that VEGF receptor kinase inhibition impaired collagen degradation pathways, Flt-1 may represent a candidate for therapeutic approaches in periodontitis. PMID- 26932323 TI - Tooth loss in molars with and without furcation involvement - a systematic review and meta-analysis. AB - BACKGROUND: The aim of this study was to investigate risk of tooth loss in molars with furcation involvement (FI) based on initial diagnosis. MATERIALS AND METHODS: A systematic search of the literature was conducted in Ovid Medline, Embase, LILACS and Cochrane Library for longitudinal studies with at least 3 years follow-up including measures of FI and data on tooth loss. RESULTS: A total of 21 studies were included in the review, from an initial search of 1207 titles. The relative risk of tooth loss during maintenance therapy attributable to FI was 1.46 (95% CI = 0.99-2.15, p = 0.06) for studies up to 10 years and 2.21 (95% CI = 1.79-2.74, p < 0.0001) for studies with a follow-up of 10-15 years. A gradual increase in the risk of tooth loss was observed for molars with degree II and III FI. CONCLUSIONS: The presence of FI approximately doubles the risk of tooth loss for molars maintained in supportive periodontal therapy for up to 10-15 years. However, most molars, even with grade III FI respond well to periodontal therapy, suggesting that every effort should be made to maintain these teeth when possible. Long-term studies reporting patient-reported outcomes are needed to substantiate this conclusion. PMID- 26932325 TI - One-pot synthesis of single-crystalline PtPb nanodendrites with enhanced activity for electrooxidation of formic acid. AB - Bimetallic PtPb nanodendrites with a single-crystalline structure were obtained by a facile one-pot strategy. The as-synthesized dendritic structure was well characterized and the growth mechanism was investigated. PtPb nanodendrites exhibited superior activity (5.1 times higher than commercial Pd black) and strong anti-poisoning ability for electrooxidation of formic acid. PMID- 26932324 TI - Abstinence and Use of Community-Based Cessation Treatment After a Motivational Intervention Among smokers with Severe Mental Illness. AB - Motivational interventions help people with mental illness try to quit smoking, but few studies have evaluated factors associated with this groups' cessation with community treatment. We examined predictors of abstinence after a brief motivational intervention among smokers with severe mental illness. Education, stage of change post intervention, and use of cessation treatment predicted any 1 week period of self-reported abstinence over 6 months (29%). Cessation treatment mediated the relationship between stage of change and abstinence. Because treatment was the key modifiable predictor of abstinence, future research should establish strategies that improve motivation for, access to, and retention in cessation treatment. Clinical Trials Identifier NCT01412866. PMID- 26932326 TI - Embedding telephone therapy in statutory mental health services: a qualitative, theory-driven analysis. AB - BACKGROUND: Telephone-administered cognitive behavioural therapy (T-CBT) has attracted international recognition as a potential means of providing effective psychological treatment whilst simultaneously lowering costs, maximizing service efficiency and improving patient access to care. A lack of rigorous exploration of therapist perspectives means that little is known about professional readiness to adopt such delivery models, or the work that may be involved in ensuring successful implementation. METHODS: This paper reports on a qualitative exploration of professional views of high intensity T-CBT. Semi-structured interviews with 18 UK accredited Cognitive Behavioural Therapists with nursing or allied health backgrounds were collected and analysed according to Normalisation Process Theory, a contemporary and empirically-derived theory of health technology implementation. RESULTS: Despite increasing research effort seeking to determine the effectiveness of T-CBT, the clinical rationale for its use remains insecure. Professional perceptions of T-CBT as a high risk delivery strategy emerge as a key factor delaying T-CBT routinisation in practice. T-CBT champions draw on experiential knowledge to demonstrate that remote services can add value, a key factor being the recognition that telephone-mediated services can provide viable access for hard to reach populations. T-CBT uptake will be facilitated by i) the modification of existing protocols to address new methods of exchanging information and data, and (ii) greater clarification of the reach and span of telephone therapies, including the most appropriate division of labour across different service levels and settings. CONCLUSIONS: The integration and normalisation of high intensity T-CBT into mental health services demands greater recognition and redress of the existing socio-technical matrices within which nursing and allied health practitioners work. The future spread of higher intensity T-CBT is contingent upon the willingness of service managers to support staff in the delivery and governance of non-face-to-face therapy models. Clear delineation of the role and scope of T-CBT and the extent to which it will extend or replace existing provision is required. PMID- 26932327 TI - SUMO-regulated mitochondrial function in Parkinson's disease. AB - Parkinson's disease (PD) is the second most common neurodegenerative disorder characterized by cardinal motor signs such as rigidity, bradykinesia or rest tremor that arise from a significant death of dopaminergic neurons. Non dopaminergic degeneration also occurs and it seems to induce the deficits in olfactory, emotional, and memory functions that precede the classical motor symptoms in PD. Despite the majority of PD cases being sporadic, several genes have previously been associated with the hereditary forms of the disease. The proteins encoded by some of these genes, including alpha-synuclein, DJ-1, and parkin, are modified by small ubiquitin-like modifier (SUMO), a post translational modification that regulates a variety of cellular processes. Among the several pathogenic mechanisms proposed for PD is mitochondrial dysfunction. Recent studies suggest that SUMOylation can interfere with mitochondrial dynamics, which is essential for neuronal function, and may play a pivotal role in PD pathogenesis. Here, we present an overview of recent studies on mitochondrial disturbance in PD and the potential SUMO-modified proteins and pathways involved in this process. SUMOylation, a post-translational modification, interferes with mitochondrial dynamics, and may play a pivotal role in Parkinson's disease (PD). SUMOylation maintains alpha-synuclein (alpha-syn) in a soluble form and activates DJ-1, decreasing mitochondrial oxidative stress. SUMOylation may reduce the amount of parkin available for mitochondrial recruitment and decreases mitochondrial biogenesis through suppression of peroxisomal proliferator-activated receptor-gamma co-activator 1 alpha (PGC 1alpha). Mitochondrial fission can be regulated by dynamin-related protein 1 SUMO 1- or SUMO-2/3-ylation. A fine balance for the SUMOylation/deSUMOylation of these proteins is required to ensure adequate mitochondrial function in PD. PMID- 26932328 TI - [Clinical Significance of Primary Tumor Resection in Patients with Metastatic Urothelial Carcinoma at Initial Presentation]. AB - We retrospectively reviewed 67 patients who presented with metastatic urothelial carcinoma to the Department of Urology, Asahikawa Medical University Hospital between 2000 and 2013. Furthermore, 13 patients with comparatively longer survival (2 years or longer after diagnosis) were analyzed to find any clinical characteristics among these patients. The primary site was the upper tract in 41 patients and bladder in 26. The most frequent metastatic site was regional lymph nodes (49 patients), followed by viscera (36 patients) and distant lymph nodes (17 patients). Primary tumor resections were performed on 83% of the patients with only regional lymph node metastasis, but on only 35% of the patients with distant metastasis. Median overall survival (OS) of patients was 8.5 months in this series. Median OS of patients with only regional lymph node metastasis was 15 months, which was significantly longer than that (8 months) of patients with distant metastasis. Multivariate analysis revealed only regional lymph node metastasis and the number of metastatic sites were significant prognostic factors for OS. We further investigated the clinical characteristics of 13 patients with comparatively longer survival. Other than a small number of metastatic sites (1 or 2) and no distant lymph node metastasis, we could not find any significant characteristics to predict longer prognosis. The present study showed that primary tumor resection did not have a significant benefit on survival in patients with metastatic urothelial carcinoma at initial presentation. However, primary tumor resection should be considered when there is only regional lymph node metastasis and few metastatic sites. PMID- 26932329 TI - [The Diagnostic Value of Pre-Biopsy Magnetic Resonance Imaging (MRI) for Detecting Prostate Cancer]. AB - We examined the value of pre-biopsy magnetic resonance imaging (MRI) for detecting prostate cancer. We analyzed 267 men with prostate-specific antigen (PSA) levels of 3-10 ng/ml who underwent systematic prostate needle biopsy. From April 2009 to March 2011, a total of 98 male patients underwent 16-core prostatic biopsies without pre-biopsy magnetic resonance imaging (MRI) (nonenforcement group). From April 2011 to March 2013, 169 men underwent pre-biopsy MRI [T2 weighted imaging (T2WI) and diffusion-weighted imaging (DWI)] (enforcement group). When MRI findings indicated cancer in the latter group, in addition to the systematic 16-core biopsy one or two targeted biopsies were performed. Patients without suspicious MRI findings underwent only systematic 16-core biopsy. Cancer detection rates in the nonenforcement and enforcement groups were 42.9% (48/92) and 46. 2% (78/169), respectively. The difference did not reach significance (p=0.612). Although the cancer detection rates were 39.4% (41/104) in the MRI-negative group and 56. 9% (37/65) in the MRI-positive group (p=0.039), the sensitivity and specificity for cancer detection by MRI were relatively low: 47.4% and 69.2%, respectively. By receiver-operating curve analysis, the area under the curve for cancer detection by MRI was only 0.583. There were two study limitations. First, the patient sample size was small. Second, it is unclear whether an adequate sample of the suspicious lesion was obtained by biopsy. We thus demonstrated that it might be improper to base a diagnosis solely on pre biopsy MRI (T2WI and DWI) findings in men with serum PSA levels of 3-10 ng/ml. PMID- 26932330 TI - [A Case of Adrenocortical Carcinoma Successfully Treated with Multimodal Therapy]. AB - Adrenocortical carcinoma is a rare cancer with poor prognosis. We report a case of metastatic adrenocortical carcinoma in a 61-year-old man successfully treated with multimodal therapy. A left adrenal tumor was detected incidentally in the patient and an adrenalectomy was performed. The pathological diagnosis was adrenocortical carcinoma, stage II. After 1 year, multiple local recurrences were detected in the retroperitoneum space. The patient underwent a metastasectomy and received three courses of adjuvant chemotherapy consisting of etoposide, doxorubicin, and cisplatin plus mitotane. No obvious recurrence has been observed in the 60 months since the treatment. PMID- 26932331 TI - [A Case of Renal Angiomyolipoma with Tumor Thrombus Invading the Inferior Vena Cava]. AB - A 64-year-old man with flank pain was diagnosed with right renal angiomyolipoma (AML) with tumor thrombus invading the inferior vena cava (IVC). Computed tomography showed a 55 mm IVC tumor thrombus with fat density. The patient underwent radical nephrectomy and IVC thrombcetomy with uneventful postoperative recovery. Pathological diagnosis was AML without malignancy. No recurrence has been observed for 18 months after surgery. We reviewed 60 case reports of AML with venous involvement. Furthermore, we discussed differential diagnosis between AML and other renal tumors mimicking AML with caval involvement. PMID- 26932333 TI - [A Case of Atazanavir Urolithiasis Diagnosed by Stone Analysis]. AB - A 70-year-old man was referred to our hospital for right back pain. His past history included human immunodeficiency virus infection, which had been treated with atazanavir for 7 years. Abdominal and pelvic computed tomographic scan showed right hydronephrosis due to a strongly suspected right ureteral radiolucent stone. He underwent indwelling of a right ureteral stent because of obstructive pyelonephritis due to the ureteral stone. After improvement of the pyelonephritis, he underwent transurethral ureterolithotripsy for the right ureteral stone. Stone analysis showed the atazanavir stone. He has been followed up for 8 months without evidence of recurrence. Herein, we report this rare case of an atazanavir stone in Japan, which was confirmed by calculus analysis, and present a review of the literature. PMID- 26932332 TI - [A Case Report of Suspected Tuberculous Granuloma in the Kidney after BCG Perfusion Therapy for Urothelial Carcinoma of the Renal Pelvis]. AB - A 66-year-old male patient was referred to our hospital for bilateral renal pelvic tumors. Ureteroscopic biopsy revealed urothelial carcinoma (UC) of low grade (G1) of the renal pelvis. Renal sparing treatment with systemic chemotherapy and percutaneous tumor resection was performed. However, during subsequent follow up, a recurrent tumor was found on the left ureter. After ureteroscopic laser ablation of the tumor, Bacillus Calmette-Guerin (BCG) perfusion therapy (once a week, total 6 weeks) was performed via a single J ureteral catheter with no adverse events. Later, another recurrent recurrence was found on the right ureter, and was managed by ureteroscopic laser ablation followed by BCG perfusion therapy via a single J ureteral catheter. However, the patient developed high fever with chill from the day after initial BCG perfusion therapy on the right side. Although we started antibiotics, high fever continued. Then antituberculous drugs were administered and his condition was improved. Computed tomographic scan revealed a right renal mass 57 mm in diameter, which was consistent with tuberculous granuloma. The tuberculous granuloma persisted despite the continuation of anti-tuberculous drugs. In exceptional cases of upper tract UC such as single kidney and bilateral tumor, BCG perfusion therapy has been used as adjunctive treatment to cure or prevent UC. However, dosages and administration methods of BCG perfusion therapy for upper tract UC still remain to be standardized. Serious adverse events after BCG perfusion therapy require prompt and proper management including the use of anti-tuberculous drugs. PMID- 26932334 TI - [Advanced Adenocarcinoma of the Bladder after Augmentation Gastrocystoplasty]. AB - A 29-year-old woman had undergone gastrocystoplasty with Mitrofanoff appendicovesicostomy for urethral trauma at 9 years of age. Since then, she was being followed up for performing clean intermittent self-catheterization at regular intervals. Twenty years after the surgery, she presented with gross hematuria. Ultrasonographic findings revealed bilateral hydronephrosis. Cystoscopy and computed tomography (CT) revealed invasive bladder cancer with pelvic lymph node metastases. A biopsy confirmed the diagnosis of adenocarcinoma with signet ring cell carcinoma. Subsequently, neo-adjuvant combination chemotherapy with TS-1 and cisplatin (CDDP) was initiated, which was followed by open radical cystectomy with extended pelvic lymphadenectomy. The tumor was found to infiltrate from the anastomotic site into the entire native bladder and histopathological diagnosis was muscle invasive adenocarcinoma with neuroendocrine differentiation and lymph node metastasis (ypT3bN2). TS-1 was continued as adjuvant chemotherapy and the patient did not have any evidence of recurrence for 12 months postoperatively. PMID- 26932335 TI - [A Case of Bisphosphonate-Related Osteonecrosis of the Jaw with Difficulty in Treatment]. AB - A 65-year-old man with urination difficulty visited our hospital. Because his prostate-specific antigen level was 1,619 ng/ml, we performed a prostate biopsy. The biopsy specimen yielded a diagnosis of adenocarcinoma with a Gleason score of 4+4. Computed tomography and bone scintigraphy showed lymph node, lung, and bone metastasis (cT3bN1M1). After 13 months of combined androgen blockade, he underwent treatment with a bisphosphonate. At 22 months of treatment, he developed bisphosphonate-related osteonecrosis of the jaw, and all necrotic bone and teeth were removed. He subsequently underwent repeated cleaning and fixation (splinting) for an oral fistula and mandibular fracture. Emergency transcatheter arterial embolization was then performed to treat a bleeding of the facial artery aneurysm. An oral infection and aspiration pneumonia repeatedly developed secondary to the oral fistula. The patient underwent a gastrostomy, after which his nutritional status improved and he was discharged. PMID- 26932336 TI - [A Case of Granulomatous Orchitis]. AB - A 54-year-old man presented with slight pain and swelling of the right scrotum. On performing scrotal ultrasonography, the right testis showed swelling and diffused hypoechogenicity compared with the left normal testis. T2-weighted magnetic resonance imaging (MRI) revealed swelling and low intensity areas in the right testis. Diffusion-weighted MRI revealed increased diffusion in the right testis. A testicular tumor was suspected and right high orchitectomy was performed. Histopathological diagnosis was granulomatous orchitis. To our knowledge, this is the 22nd case in Japan. PMID- 26932337 TI - Quantitative analysis of the patellofemoral motion pattern using semi-automatic processing of 4D CT data. AB - PURPOSE: To present a semi-automatic method with minimal user interaction for quantitative analysis of the patellofemoral motion pattern. METHODS: 4D CT data capturing the patellofemoral motion pattern of a continuous flexion and extension were collected for five patients prone to patellar luxation both pre- and post surgically. For the proposed method, an observer would place landmarks in a single 3D volume, which then are automatically propagated to the other volumes in a time sequence. From the landmarks in each volume, the measures patellar displacement, patellar tilt and angle between femur and tibia were computed. RESULTS: Evaluation of the observer variability showed the proposed semi automatic method to be favorable over a fully manual counterpart, with an observer variability of approximately 1.5[Formula: see text] for the angle between femur and tibia, 1.5 mm for the patellar displacement, and 4.0[Formula: see text]-5.0[Formula: see text] for the patellar tilt. The proposed method showed that surgery reduced the patellar displacement and tilt at maximum extension with approximately 10-15 mm and 15[Formula: see text]-20[Formula: see text] for three patients but with less evident differences for two of the patients. CONCLUSIONS: A semi-automatic method suitable for quantification of the patellofemoral motion pattern as captured by 4D CT data has been presented. Its observer variability is on par with that of other methods but with the distinct advantage to support continuous motions during the image acquisition. PMID- 26932339 TI - Why I Pray For My Patients. PMID- 26932338 TI - Control and management of congenital Chagas disease in Europe and other non endemic countries: current policies and practices. AB - OBJECTIVES: Identifying pregnant women infected with Trypanosoma cruzi is one of the major challenges for preventing and controlling Chagas disease (CD) in non endemic countries. The aim of this paper was to perform a policy evaluation of the current practices of congenital Chagas disease (CCD) control in non-endemic countries and to propose specific targets for enhanced interventions to tackle this emerging health problem outside the endemic areas of Latin America. METHODS: We conducted a mixed method review of CCD policy strategies by searching the literature in the PubMed, Google Scholar and the World Health Organization (WHO) databases using the key terms 'CCD', 'paediatric Chagas disease' and 'non-endemic countries'; as free text and combined as one phrase to increase the search sensitivity. Reviews, recommendations, guidelines and control/surveillance programme reports were included. RESULTS: Of 427 CCD papers identified in non endemic countries, 44 matched the inclusion. Although local programmes were launched in different countries with large numbers of Latin American immigrants, there were considerable disparities in terms of the programmes' distribution, delivery, integration and appropriated CCD control strategies. Moreover, Catalonia, Spain is the only region/country with an established systematic monitoring of CCD in pregnant women from Latin American countries. CONCLUSIONS: Given the worldwide dissemination of CD, the nature of its vertical transmission, and the gaps of the current strategies in non-endemic countries, there is an urgent need to standardise, expand and reinforce the control measures against CCD transmission. PMID- 26932340 TI - Effects of Rituximab and Infliximab Treatment on Carboxypeptidase B and Its Substrates in RA Synovium. AB - OBJECTIVE: We evaluated the synovial effects of 2 potent biologic rheumatoid arthritis (RA) therapies, focusing on their effect on the expression level of carboxypeptidase B (CPB) and its substrates. METHODS: Patients with RA receiving infliximab (IFX; n = 9) or rituximab (RTX; n = 5) had an arthroscopic synovial biopsy at baseline and 16 weeks posttherapy. Expression of CPB, C5a, osteopontin (OPN), CD3, CD20, CD55, and CD68 was assessed by immunohistochemistry and image analysis, and compared with OA synovium. RA disease activity score was assessed at multiple timepoints. Serial serum samples were analyzed for soluble CPB and C5a levels. RESULTS: The baseline clinical characteristics of patients receiving IFX and RTX were similar. At the time of the second biopsy, 50% of patients had achieved a European League Against Rheumatism good or moderate response. At baseline, expression of CPB, C5a, and OPN was markedly higher in RA compared with OA synovium and correlated with mononuclear cell infiltration. There was an overall reduction in synovial expression of CPB, C5a, and OPN paralleling a reduction in mononuclear cell infiltration, but these changes were not associated with clinical response. After an early reduction in serum C5a levels, these returned to baseline levels at later timepoints. CONCLUSION: In response to IFX and RTX treatment, RA synovial expression of CPB, C5a, and OPN decrease independently of the clinical response, reflecting the complex proinflammatory and antiinflammatory effects of this pathway. PMID- 26932341 TI - Patients with Psoriatic Arthritis Fulfilling the Minimal Disease Activity Criteria Do Not Have Swollen and Tender Joints, but Have Active Skin. AB - OBJECTIVE: To evaluate components of the minimal disease activity (MDA) criteria in psoriatic arthritis (PsA). METHODS: In patients achieving and not achieving MDA, fulfillment of each of the 7 criteria was evaluated. RESULTS: Among 41 patients with MDA, 7.4% did not fulfill the tender/swollen joint count whereas 49% did not fulfill the skin criteria. Of the 42 patients not fulfilling MDA, 100%, 76.5%, and 65% did not fulfill the patient pain score, the patient's global assessment, and the Psoriasis Area and Severity Index (PASI), respectively. CONCLUSION: A minority of patients with PsA fulfilling the MDA criteria presented active joints, but half had active skin. Visual analog scale scores and the PASI prevented patients from achieving MDA. PMID- 26932342 TI - A Multidisciplinary Evaluation Helps Identify the Antisynthetase Syndrome in Patients Presenting as Idiopathic Interstitial Pneumonia. AB - INTRODUCTION: Interstitial lung disease (ILD) is 1 possible manifestation of the idiopathic inflammatory myopathies (IIM). Occasionally, patients presenting with ILD are mistakenly diagnosed with idiopathic interstitial pneumonia (IIP), but after multidisciplinary evaluation, their ILD is determined to be because of antisynthetase syndrome (SynS) or myositis spectrum of disease. METHODS: We used retrospective analytic methods to identify patients with ILD evaluated at the National Jewish Health between February 2008 and August 2014 and believed initially to have IIP but ultimately diagnosed with SynS or myositis spectrum of disease. RESULTS: The cohort included 33 patients; most were white women with a mean age at presentation of 55 years. Their pulmonary physiologic impairment was moderate. In 31 cases, the ILD pattern by thoracic high-resolution computed tomography scan was nonspecific interstitial pneumonia (NSIP), organizing pneumonia (OP), or a combination of the 2. Surgical lung biopsy was performed in 21 patients; NSIP was the most common pattern. Less than one-third of the cohort had positive antinuclear antibodies. Two-thirds had positive SSA. All patients had either myositis-specific or myositis-associated autoantibody. Most had subtle extrathoracic symptoms or signs of SynS; 12 had an elevated serum creatine phosphokinase, but none had clinical evidence of myositis. None met the Peter and Bohan classification criteria for polymyositis/dermatomyositis. CONCLUSION: Among patients who present with presumed IIP, a multidisciplinary evaluation that includes the integration of clinical evaluations by rheumatologists and pulmonologists, morphologic (both histopathologic and radiographic) data, and serologic features is helpful in the detection of occult SynS or the myositis spectrum of disease. PMID- 26932343 TI - How to Attract Trainees, a Pan-Canadian Perspective: Phase 1 of the "Training the Rheumatologists of Tomorrow" Project. AB - OBJECTIVE: To identify what learners and professionals associated with rheumatology programs across Canada recommend as ways to attract future trainees. METHODS: Data from online surveys and individual interviews with participants from 9 rheumatology programs were analyzed using the thematic framework analysis to identify messages and methods to interest potential trainees in rheumatology. RESULTS: There were 103 participants (78 surveyed, 25 interviewed) who indicated that many practitioners were drawn to rheumatology because of the aspects of work life, and that educational events and hands-on experiences can interest students. Messages centered on working life, career opportunities, and the lifestyle of rheumatologists. Specific ways to increase awareness about rheumatology included information about practice type, intellectual and diagnostic challenges, diversity of diseases, and patient populations. Increased opportunity for early and continued exposure for both medical students and internal medicine residents was also important, as was highlighting job flexibility and availability and a good work-life balance. Although mentors were rarely mentioned, many participants indicated educational activities of role models. The relatively low pay scale of rheumatologists was rarely identified as a barrier to choosing a career in rheumatology. CONCLUSION: This is the first pan-Canadian initiative using local data to create a work plan for developing and evaluating tools to promote interest in rheumatology that could help increase the number of future practitioners. PMID- 26932344 TI - Two-year Efficacy and Safety of Etanercept in Pediatric Patients with Extended Oligoarthritis, Enthesitis-related Arthritis, or Psoriatic Arthritis. AB - OBJECTIVE: The main objective was to determine the 2-year clinical benefit and safety of etanercept (ETN) in children with the juvenile idiopathic arthritis (JIA) categories of extended oligoarthritis (eoJIA), enthesitis-related arthritis (ERA), or psoriatic arthritis (PsA). METHODS: CLIPPER was a 96-week, phase IIIb, open-label, multicenter study. Patients with eoJIA, ERA, or PsA received ETN 0.8 mg/kg once weekly (50 mg max) for up to 96 weeks. The proportions of patients reaching the JIA American College of Rheumatology (ACR) 30/50/70/90/100 and inactive disease responses at Week 96 were calculated. Adverse events (AE) were collected throughout the study (intention-to-treat sample). RESULTS: There were 127 patients (eoJIA n = 60, ERA n = 38, PsA n = 29) who received >= 1 dose of ETN. The mean disease duration was 31.6 (eoJIA), 23.0 (ERA), and 21.8 (PsA) months. At Week 96, JIA ACR 30/50/70/90/100/inactive disease responses (95% CI) were achieved by 84.3% (76.7, 90.1), 83.5% (75.8, 89.5), 78.7% (70.6, 85.5), 55.1% (46.0, 63.9), 45.7% (36.8, 54.7), and 27.6% (20.0, 36.2) of patients, respectively. The most common AE (no. events, events per 100 patient-yrs) overall were headache (23, 10.7), pyrexia (12, 5.6), and diarrhea (10, 4.6). The most common infections were upper respiratory tract infection (83, 38.6), pharyngitis (50, 23.2), gastroenteritis (22, 10.2), bronchitis (19, 8.8), and rhinitis (17, 7.9). No cases of malignancy, active tuberculosis, demyelinating disorders, or death were reported. CONCLUSION: Over 96 weeks of therapy, ETN demonstrated sustained efficacy at treating the clinical symptoms of all 3 JIA categories, with no major safety issues. PMID- 26932345 TI - Serum Vascular Endothelial Growth Factor Levels Lack Predictive Value in Patients with Active Ankylosing Spondylitis Treated with Golimumab. AB - OBJECTIVE: To assess vascular endothelial growth factor (VEGF) correlations with new bone formation and bone marrow edema in patients with ankylosing spondylitis (AS) treated with golimumab (GOL). METHODS: Following placebo control (through weeks 16 and 24), GO-RAISE (A Multicenter Randomized, Double-blind, Placebo controlled Trial of Golimumab, a Fully Human Anti-TNF-alpha Monoclonal Antibody, Administered Subcutaneously, in Subjects with Active Ankylosing Spondylitis; ClinicalTrials.gov: NCT00265083) all patients received GOL; sera/images were available at weeks 0, 104, and 208. Lateral spinal radiographs and magnetic resonance imaging (MRI) were scored using the modified Stokes Ankylosing Spondylitis Spine Score (mSASSS) and the Ankylosing Spondylitis Spinal MRI activity score, respectively. RESULTS: VEGF levels and the mSASSS did not significantly correlate. Logistic regression analyses showed no association between VEGF levels and an increased risk of syndesmophyte formation at weeks 104 and 208. Pretreatment/Week 14 VEGF did not predict MRI scores/changes at Week 104. CONCLUSION: Serum VEGF did not predict radiographic progression/spinal inflammation in patients receiving antitumor necrosis factor. PMID- 26932346 TI - Accelerated Phase CML: Outcomes in Newly Diagnosed vs. Progression From Chronic Phase. AB - The introduction of tyrosine kinase inhibitors (TKIs) has fundamentally changed the management of chronic myeloid leukemia (CML). Disease progression to advanced phase (accelerated or blast phase) has been reduced to 1 to 1.5 % per year from more than 20 % per year in the pre-TKI era. However, once the disease has progressed to accelerated or blast phase, there is no consensus regarding optimal therapy. The prognosis of these patients is dismal with median survival ranging from 7 to 11 months. TKIs along with allogeneic hematopoietic cell transplantation are conventional strategies in managing these patients but there are very few long-term survivors. Advanced phase CML represents the new frontier for CML treatment where research is critically needed to improve patient outcomes. PMID- 26932347 TI - What's new in ARDS: can we prevent it? PMID- 26932348 TI - Vasopressors in shock: are we meeting our target and do we really understand what we are aiming at? PMID- 26932349 TI - Systematic review of cardiac output measurements by echocardiography vs. thermodilution: the techniques are not interchangeable. AB - PURPOSE: Echocardiography is frequently used in the hemodynamic evaluation of critically ill patients, but inaccurate measurements may lead to wrong clinical decisions. The aim of our systematic review was to investigate the interchangeability of echocardiography with thermodilution technique in measuring cardiac output and its changes. METHODS: In August 2015 we systematically searched electronic databases and included studies investigating the echocardiographic measurement of cardiac output compared with thermodilution technique using the Bland-Altman method. Two authors independently reviewed the studies and extracted data on type of measurements, clinical setting and characteristics, and those of the Bland-Altman and trending ability analyses. RESULTS: We identified 13,834 citations and included 24 studies in the final analysis. The median number of participants was 32 (range 8-65). Most of the studies assessed left-sided heart structures and the majority had small bias, wide limits of agreement, and high percentage error between echocardiography and thermodilution. In only two of the 24 studies the precision of each technique (echocardiography and thermodilution) was assessed before comparing them. In the single study evaluating trending ability using valid methodology, agreement was observed between echocardiography and thermodilution in detecting the directional changes in cardiac output, but the magnitude of changes varied considerably. CONCLUSIONS: The majority of studies comparing echocardiography with thermodilution were difficult to interpret, but current evidence does not support interchangeability between these techniques in measuring cardiac output. The techniques may be interchangeable in tracking directional changes in cardiac output, but this has to be confirmed in large high-quality studies. PMID- 26932351 TI - Modelling the influence of dimerisation sequence dissimilarities on the auxin signalling network. AB - BACKGROUND: Auxin is a major phytohormone involved in many developmental processes by controlling gene expression through a network of transcriptional regulators. In Arabidopsis thaliana, the auxin signalling network is made of 52 potentially interacting transcriptional regulators, activating or repressing gene expression. All the possible interactions were tested in two-way yeast-2-hybrid experiments. Our objective was to characterise this auxin signalling network and to quantify the influence of the dimerisation sequence dissimilarities on the interaction between transcriptional regulators. RESULTS: We applied model-based graph clustering methods relying on connectivity profiles between transcriptional regulators. Incorporating dimerisation sequence dissimilarities as explanatory variables, we modelled their influence on the auxin network topology using mixture of linear models for random graphs. Our results provide evidence that the network can be simplified into four groups, three of them being closely related to biological groups. We found that these groups behave differently, depending on their dimerisation sequence dissimilarities, and that the two dimerisation sub domains might play different roles. CONCLUSIONS: We propose here the first pipeline of statistical methods combining yeast-2-hybrid data and protein sequence dissimilarities for analysing protein-protein interactions. We unveil using this pipeline of analysis the transcriptional regulator interaction modes. PMID- 26932350 TI - Mental Health Smartphone Apps: Review and Evidence-Based Recommendations for Future Developments. AB - BACKGROUND: The number of mental health apps (MHapps) developed and now available to smartphone users has increased in recent years. MHapps and other technology based solutions have the potential to play an important part in the future of mental health care; however, there is no single guide for the development of evidence-based MHapps. Many currently available MHapps lack features that would greatly improve their functionality, or include features that are not optimized. Furthermore, MHapp developers rarely conduct or publish trial-based experimental validation of their apps. Indeed, a previous systematic review revealed a complete lack of trial-based evidence for many of the hundreds of MHapps available. OBJECTIVE: To guide future MHapp development, a set of clear, practical, evidence-based recommendations is presented for MHapp developers to create better, more rigorous apps. METHODS: A literature review was conducted, scrutinizing research across diverse fields, including mental health interventions, preventative health, mobile health, and mobile app design. RESULTS: Sixteen recommendations were formulated. Evidence for each recommendation is discussed, and guidance on how these recommendations might be integrated into the overall design of an MHapp is offered. Each recommendation is rated on the basis of the strength of associated evidence. It is important to design an MHapp using a behavioral plan and interactive framework that encourages the user to engage with the app; thus, it may not be possible to incorporate all 16 recommendations into a single MHapp. CONCLUSIONS: Randomized controlled trials are required to validate future MHapps and the principles upon which they are designed, and to further investigate the recommendations presented in this review. Effective MHapps are required to help prevent mental health problems and to ease the burden on health systems. PMID- 26932353 TI - Added sugar intake and metabolic syndrome in US adolescents: cross-sectional analysis of the National Health and Nutrition Examination Survey 2005-2012. AB - OBJECTIVE: To examine the association between added sugar intake and metabolic syndrome among adolescents. DESIGN: Dietary, serum biomarker, anthropometric and physical activity data from the US National Health and Nutrition Examination Survey cycles between 2005 and 2012 were analysed using multivariate logistic regression models. Added sugar intake in grams per day was estimated from two 24 h standardized dietary recalls and then separated into quintiles from lowest to highest consumption. Multivariate logistic regression analyses were adjusted for physical activity, age, BMI Z-score and energy intake, and their interactions with race were included. SETTING: Nationally representative sample, USA. SUBJECTS: US adolescents aged 12-19 years (n 1623). RESULTS: Added sugar was significantly associated with metabolic syndrome. The adjusted prevalence odds ratios for having metabolic syndrome comparing adolescents in the third, fourth and fifth quintiles v. those in the lowest quintile of added sugar were 5.3 (95 % CI 1.4, 20.6), 9.9 (95 % CI 1.9, 50.9) and 8.7 (95 % CI 1.4, 54.9), respectively. CONCLUSIONS: Our findings suggest that higher added sugar intake, independent of total energy intake, physical activity or BMI Z-score, is associated with increased prevalence of metabolic syndrome in US adolescents. Further studies are needed to determine if reducing intake of added sugar may help US adolescents prevent or reverse metabolic syndrome. PMID- 26932354 TI - [Trend of the selenium supply of cattle in Germany, Austria, Switzerland, and Denmark. Retrospective analysis of serum samples of the years 2006-2015]. AB - OBJECTIVE: An optimal selenium supply of cattle is essential, because an insufficiency can lead to health disorders and reduced performance. The aim of the study was to retrospectively evaluate the selenium supply of cattle in Germany, Austria, Switzerland, and Denmark. MATERIAL AND METHODS: Serum samples from 45 068 cattle with unknown clinical status originating from countries all across Europe, which had been sent by veterinarians to the IDEXX Laboratory Ludwigsburg, Germany, between January 1st, 2006 and June 30th, 2015, were routinely analyzed for the selenium concentration by means of Inductively Coupled Plasma Mass Spectrometry. A total of 40 949 samples (30 462 from Germany, 4004 from Austria, 3232 from Switzerland, 3251 from Denmark) were included in the evaluation. Results were categorized as follows: 50-150 ug/l: sufficient supply, < 50 ug/l: supply too low, > 150 ug/l: supply too high. RESULTS: During the observation period, a generalized trend towards a decreasing selenium supply was clear. Denmark showed the best selenium supply (77.4% of samples indicating a sufficient supply); however, even in this country a tendency towards a deterioration was seen. A very poor situation with a strongly decreasing selenium supply was observed in Austria, followed by Germany (38% and 30% of samples, respectively, indicating an undersupply). For Switzerland, a constantly poor selenium supply was found (49% of samples indicating an undersupply). CONCLUSION AND CLINICAL RELEVANCE: Due to the ongoing trend of a selenium undersupply in cattle herds, it is recommended to control the serum selenium concentration annually and supplement this trace element via mineral food when necessary. PMID- 26932355 TI - Lineage analysis by microsatellite loci deep sequencing in mice. AB - Lineage analysis is the identification of all the progeny of a single progenitor cell, and has become particularly useful for studying developmental processes and cancer biology. Here, we propose a novel and effective method for lineage analysis that combines sequence capture and next-generation sequencing technology. Genome-wide mononucleotide and dinucleotide microsatellite loci in eight samples from two mice were identified and used to construct phylogenetic trees based on somatic indel mutations at these loci, which were unique enough to distinguish and parse samples from different mice into different groups along the lineage tree. For example, biopsies from the liver and stomach, which originate from the endoderm, were located in the same clade, while samples in kidney, which originate from the mesoderm, were located in another clade. Yet, tissue with a common developmental origin may still contain cells of a mixed ancestry. This genome-wide approach thus provides a non-invasive lineage analysis method based on mutations that accumulate in the genomes of opaque multicellular organism somatic cells. Mol. Reprod. Dev. 83: 387-391, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26932352 TI - Protecting the Kidney in Liver Transplant Recipients: Practice-Based Recommendations From the American Society of Transplantation Liver and Intestine Community of Practice. AB - Both acute and chronic kidney disease are common after liver transplantation and result in significant morbidity and mortality. The introduction of the Model for End-stage Liver Disease score has directly correlated with an increased prevalence of perioperative renal dysfunction and the number of simultaneous liver-kidney transplantations performed. Kidney dysfunction in this population is typically multifactorial and related to preexisting conditions, pretransplantation renal injury, perioperative events, and posttransplantation nephrotoxic immunosuppressive therapies. The management of kidney disease after liver transplantation is challenging, as by the time the serum creatinine level is significantly elevated, few interventions affect the course of progression. Also, immunological factors such as antibody-mediated kidney rejection have become of greater interest given the rising liver-kidney transplant population. Therefore, this review, assembled by experts in the field and endorsed by the American Society of Transplantation Liver and Intestine Community of Practice, provides a critical assessment of measures of renal function and interventions aimed at preserving renal function early and late after liver and simultaneous liver-kidney transplantation. Key points and practice-based recommendations for the prevention and management of kidney injury in this population are provided to offer guidance for clinicians and identify gaps in knowledge for future investigations. PMID- 26932356 TI - Relationship Education for Military Couples: Recommendations for Best Practice. AB - Military couples have a number of distinctive strengths and challenges that are likely to influence their relationship adjustment. Military couples' strengths include stable employment, financial security, and subsidized health and counseling services. At the same time, military couples often experience long periods of separation and associated difficulties with emotional disconnect, trauma symptoms, and reintegrating the family. This paper describes best practice recommendations for working with military couples, including: addressing the distinctive challenges of the military lifestyle, ensuring program delivery is seen as relevant by military couples, and providing relationship education in formats that enhance the accessibility of programs. PMID- 26932357 TI - Quantitatively probing the magnetic behavior of individual nanoparticles by an AC field-modulated magnetic force microscopy. AB - Despite decades of advances in magnetic imaging, obtaining direct, quantitative information with nanometer scale spatial resolution remains an outstanding challenge. Current approaches, for example, Hall micromagnetometer and nitrogen vacancy magnetometer, are limited by highly complex experimental apparatus and a dedicated sample preparation process. Here we present a new AC field-modulated magnetic force microscopy (MFM) and report the local and quantitative measurements of the magnetic information of individual magnetic nanoparticles (MNPs), which is one of the most iconic objects of nanomagnetism. This technique provides simultaneously a direct visualization of the magnetization process of the individual MNPs, with spatial resolution and magnetic sensitivity of about 4.8 nm and 1.85 * 10(-20) A m(2), respectively, enabling us to separately estimate the distributions of the dipolar fields and the local switching fields of individual MNPs. Moreover, we demonstrate that quantitative magnetization moment of individual MNPs can be routinely obtained using MFM signals. Therefore, it underscores the power of the AC field-modulated MFM for biological and biomedical applications of MNPs and opens up the possibility for directly and quantitatively probing the weak magnetic stray fields from nanoscale magnetic systems with superior spatial resolution. PMID- 26932358 TI - A Metal-Free Diverse Synthesis of Difluoromethylthioethers and Difluorobis(arylthio)methanes from RSX (X = SR, Cl, SO2Ph) and TMSCF2H. AB - Construction of difluoromethylthioethers (2) and difluorobis(arylthio)methanes (3) from RSX (X = SR, Cl, SO2Ph) and TMSCF2H in the absence of transition metals has been explored. The reaction is dramatically influenced by the nature of the base and the molar ratio of the reactants. Reactions between RSX and TMSCF2H in the presence of CsF provided 2 in good yields, whereas the reaction of RSX with TMSCF2H in the presence of t-BuOK afforded 3 in good yields. These protocols allow for convenient and efficient access to both difluoromethylthioethers and difluorobis(arylthio)methanes. PMID- 26932359 TI - Multiplex detection and identification of viral, bacterial, and protozoan pathogens in human blood and plasma using a high-density resequencing pathogen microarray platform. AB - BACKGROUND: The implementation of nucleic acid-based tests for blood donor screening has improved the safety of the blood supply; however, the increasing number of emerging pathogen tests is burdensome. Development of multiplex testing platforms that allow simultaneous screening for different pathogens is a potential solution. STUDY DESIGN AND METHODS: The TessArray resequencing microarray is a platform that allows multiplex detection and identification of 97 different blood-borne pathogens in one single test. The objective was to evaluate the lowest concentration detected in blood or plasma, species discrimination, and applicability of the TessArray microarray platform for testing blood donors. Human blood or plasma spiked with selected pathogens (10,000, 1000, or 100 cells or copies/mL), including three viral, four bacterial, and four protozoan pathogens were each tested on this platform. The nucleic acids were extracted, amplified using multiplexed sets of pooled specific primers, fragmented, labeled, and hybridized to a microarray. Finally, the detected sequences were identified using an automated genomic database alignment algorithm. RESULTS: The performance of this platform demonstrated detection for spiked bacterial and protozoan pathogens of 100 cells/mL and viral pathogens as low as 100 copies/mL. Coded specimens, including spiked and negative controls, were identified correctly for blood specimens (31/32, 97%) and for plasma specimens (20/22, 91%) demonstrating the effectiveness of the platform. CONCLUSION: These results indicated that the TessArray microarray platform could be employed for multiplex detection and identification, with a high level of discriminatory power for numerous blood borne pathogen targets with potential for use in blood safety. PMID- 26932360 TI - Triage of LSIL/ASC-US with p16/Ki-67 dual staining and human papillomavirus testing: a 2-year prospective study. AB - OBJECTIVE: To investigate human papillomavirus (HPV) DNA testing and p16/Ki-67 staining for detecting cervical intraepithelial grade 2 or worse (CIN2+) and CIN3 in women referred to colposcopy with minor abnormal cervical cytology low-grade squamous intraepithelial lesions (LSIL) and atypical squamous cells of undermined significance (ASC-US). The clinical performance of both tests was evaluated as stand-alone tests and combined, for detection CIN2+ and CIN3 over 2 years. METHODS: ThinPrep((r)) liquid-based cytology (LBC) specimens were collected from 1349 women with repeat LSIL or ASC-US. HPV DNA was performed using Hybrid Capture. Where adequate material remained (n = 471), p16/Ki-67 overexpression was assessed. Clinical performance for detection of histologically diagnosed CIN2+ and CIN3 was calculated. RESULTS: Approximately 62.2% of the population were positive for HPV DNA, and 30.4% were positive for p16/Ki-67. p16/Ki-67 showed no significant difference in positivity between LSIL and ASC-US referrals (34.3% versus 28.6%; P = 0.189). Women under 30 years had a higher rate of p16/Ki-67 compared to those over 30 years (36.0% versus 26.6%; P = 0.029). Overall HPV DNA testing produced a high sensitivity for detection of CIN3 of 95.8% compared to 79.2% for p16/Ki-67. In contrast, p16/Ki-67 expression offered a higher specificity, 75.2% versus 40.4% for detection of CIN3. Combining p16/Ki-67 with HPV DNA improved the accuracy in distinguishing between CIN3 and =2 (N = 39). Midterm survival (median 4 years) by group was: (1) 95 %, (2) 91 %, and (3) 15 %, (p = 0.001). In conclusion, hybrid palliation was associated with excellent midterm results for high-risk 2V and low-risk 1V patients with ductal-dependent systemic circulation. In contrast, high-risk 1V patients had significantly worse outcomes. PMID- 26932365 TI - The Benefit of a General, Systematic Use of Mapping Systems During Electrophysiological Procedures in Children and Teenagers: The Experience of an Adult EP Laboratory. AB - Standard imaging during electrophysiological procedures (EPs) uses fluoroscopy. The aim of this study was to evaluate the feasibility, efficacy, safety and effect of an extended use of non-fluoroscopic mapping systems (NMSs) for imaging during paediatric EPs in an adult EP laboratory focusing on the amount of X-ray exposure. This study is a retrospective analysis that includes consecutive young patients (83 pts, aged between 8 and 18) who underwent EPs from March 2005 to February 2015. We compare the fluoroscopy data of two groups of pts: Group I, pts who underwent EPs from 2005 to 2008 using only fluoroscopy and Group II, pts who underwent EPs from 2008 to 2015 performed also using NMSs. The use of an NMS resulted in reduced fluoroscopy time in Group II {median value 0.1 min (95 % CI [0.00-1.07])} compared to Group I {median value 3.55 min (95 % CI [1.93-7.83]) (MW test, P < 0.05)}. There was a complementary reduction in the total X-ray exposure from 2.53 Gy cm(2) (95 % CI [1.51-4.66]) in Group I to 0.05 Gy cm(2) in Group II (95 % CI [0.00-1.22]) (MW test, P < 0.05). Regarding ablation procedures, the median effective dose decreased from 3.04 mSv (95 % CI [1.22 6.89]) to 0.25 mSv (95 % CI [0.00-0.60]) (MW test, P < 0.05). The use of an NMS dramatically reduces fluoroscopy time and total X-ray exposure during EPs in children and teenagers in an adult EP laboratory. In our experience, this reduction is mainly related to the systematic day-to-day use of NMSs. PMID- 26932366 TI - Cryptococcus neoformans infection in malignancy. AB - Cryptococcosis is an opportunistic invasive fungal infection that is well described and easily recognised when it occurs as meningitis in HIV-infected persons. Malignancy and its treatment may also confer a higher risk of infection with Cryptococcus neoformans, but this association has not been as well described. A case of cryptococcosis in a cancer patient is presented, and all cases of coincident C. neoformans infection and malignancy in adults published in the literature in English between 1970 and 2014 are reviewed. Data from these cases were aggregated in order to describe the demographics, type of malignancy, site of infection, clinical manifestations, treatment and outcomes of cryptococcosis in patients with cancer. Haematologic malignancies accounted for 82% of cases, with lymphomas over-represented compared to US population data (66% vs. 53% respectively). Cryptococcosis was reported rarely in patients with solid tumours. Haematologic malignancy patients were more likely to have central nervous system (P < 0.001) or disseminated disease (P < 0.001), receive Amphotericin B as part of initial therapy (P = 0.023), and had higher reported mortality rates than those with solid tumours (P = 0.222). Providers should have heightened awareness of the possibility of cryptococcosis in patients with haematologic malignancy presenting with infection. PMID- 26932367 TI - Worldwide patterns of bird colouration on islands. AB - Island environments share distinctive characteristics that offer unique opportunities to investigate parallel evolution. Previous research has produced evidence of an island syndrome for morphological traits, life-history strategies and ecological niches, but little is known about the response to insularity of other important traits such as animal signals. Here, we tested whether birds' plumage colouration is part of the island syndrome. We analysed with spectrophotometry the colouration of 116 species endemic to islands and their 116 closest mainland relatives. We found a pattern of reduced brightness and colour intensity for both sexes on islands. In addition, we found a decrease in the number of colour patches on islands that, in males, was associated with a decrease in the number of same-family sympatric species. These results demonstrate a worldwide pattern of parallel colour changes on islands and suggest that a relaxation of selection on species recognition may be one of the mechanisms involved. PMID- 26932368 TI - Engineering Electronic Structure of a Two-Dimensional Topological Insulator Bi(111) Bilayer on Sb Nanofilms by Quantum Confinement Effect. AB - We report on the fabrication of a two-dimensional topological insulator Bi(111) bilayer on Sb nanofilms via a sequential molecular beam epitaxy growth technique. Our angle-resolved photoemission measurements demonstrate the evolution of the electronic band structure of the heterostructure as a function of the film thickness and reveal the existence of a two-dimensional spinful massless electron gas within the top Bi bilayer. Interestingly, our first-principles calculation extrapolating the observed band structure shows that, by tuning down the thickness of the supporting Sb films into the quantum dimension regime, a pair of isolated topological edge states emerges in a partial energy gap at 0.32 eV above the Fermi level as a consequence of quantum confinement effect. Our results and methodology of fabricating nanoscale heterostructures establish the Bi bilayer/Sb heterostructure as a platform of great potential for both ultra-low-energy-cost electronics and surface-based spintronics. PMID- 26932369 TI - Costs and trade-offs of grazer-induced defenses in Scenedesmus under deficient resource. AB - The green alga Scenedesmus obliquus can form inducible defensive morphs under grazing threat. Costs and trade-offs of inducible defense are expected to accompany the benefits of defensive morphs, but are hard to detect under nutrient sufficient experimental conditions. To test the existence of costs associated with inducible defense, we cultured S. obliquus along resource availability gradients in the presence or absence of infochemical cues from Daphnia, and measured the strength of defensive colony formation and fitness characters. Under the lowest phosphorous concentration, the expression of inducible defensive colony resulted in decreased growth rate, which provides direct evidence for physiological costs. Along the gradient reduction of phosphorous concentration or light intensity, inducible defense in S. obliquus showed a decreasing trend. However, the photosynthetic efficiency of S. obliquus was barely affected by its defense responses, suggesting that the negative correlations between resource availability and colony formation of this alga may be due to resource-based trade offs in the allocation of limited resources. Thus, our results indicated that expression of inducible defense of S. obliquus was impaired under insufficient phosphorus or light. Furthermore, under severe phosphate deficiency, obvious physiological costs of inducible defense could be detected even though defensive colony formation also decreased significantly. PMID- 26932370 TI - A Prognosis Tool Based on Fuzzy Anthropometric and Questionnaire Data for Obstructive Sleep Apnea Severity. AB - Obstructive sleep apnea (OSA) are linked to the augmented risk of morbidity and mortality. Although polysomnography is considered a well-established method for diagnosing OSA, it suffers the weakness of time consuming and labor intensive, and requires doctors and attending personnel to conduct an overnight evaluation in sleep laboratories with dedicated systems. This study aims at proposing an efficient diagnosis approach for OSA on the basis of anthropometric and questionnaire data. The proposed approach integrates fuzzy set theory and decision tree to predict OSA patterns. A total of 3343 subjects who were referred for clinical suspicion of OSA (eventually 2869 confirmed with OSA and 474 otherwise) were collected, and then classified by the degree of severity. According to an assessment of experiment results on g-means, our proposed method outperforms other methods such as linear regression, decision tree, back propagation neural network, support vector machine, and learning vector quantization. The proposed method is highly viable and capable of detecting the severity of OSA. It can assist doctors in pre-diagnosis of OSA before running the formal PSG test, thereby enabling the more effective use of medical resources. PMID- 26932371 TI - Community dynamics of denitrifying bacteria in full-scale wastewater treatment plants. AB - Effective and stable nitrogen removal from wastewater requires abundant and active denitrifying populations. In this study, a one-year investigation of the population dynamics of phylogenetic groups known to harbor nitrate reducers was conducted in three municipal wastewater treatment plants (WWTPs). The bacterial community composition was determined by amplicon sequencing of the 16S rRNA gene, and putative nitrate reducers were identified by sequencing narG and napA genes. Fluorescence in situ hybridization with oligonucleotide probes targeting known nitrate reducers in wastewater revealed that certain bacteria predominated in the WWTPs: Curvibacter-related bacteria, Comamonadaceae, Azoarcus, Thauera, Dechloromonas, and Candidatus Accumulibacter within Rhodocyclaceae. The data showed high diversity in the nitrate-reducing community and a large degree of redundancy, with a relatively stable core group of bacteria in each plant that ensured small yearly variation in nitrate reduction rates. PMID- 26932372 TI - SNP discovery in common bean by restriction-associated DNA (RAD) sequencing for genetic diversity and population structure analysis. AB - Researchers have made great advances into the development and application of genomic approaches for common beans, creating opportunities to driving more real and applicable strategies for sustainable management of the genetic resource towards plant breeding. This work provides useful polymorphic single-nucleotide polymorphisms (SNPs) for high-throughput common bean genotyping developed by RAD (restriction site-associated DNA) sequencing. The RAD tags were generated from DNA pooled from 12 common bean genotypes, including breeding lines of different gene pools and market classes. The aligned sequences identified 23,748 putative RAD-SNPs, of which 3357 were adequate for genotyping; 1032 RAD-SNPs with the highest ADT (assay design tool) score are presented in this article. The RAD-SNPs were structurally annotated in different coding (47.00 %) and non-coding (53.00 %) sequence components of genes. A subset of 384 RAD-SNPs with broad genome distribution was used to genotype a diverse panel of 95 common bean germplasms and revealed a successful amplification rate of 96.6 %, showing 73 % of polymorphic SNPs within the Andean group and 83 % in the Mesoamerican group. A slightly increased He (0.161, n = 21) value was estimated for the Andean gene pool, compared to the Mesoamerican group (0.156, n = 74). For the linkage disequilibrium (LD) analysis, from a group of 580 SNPs (289 RAD-SNPs and 291 BARC SNPs) genotyped for the same set of genotypes, 70.2 % were in LD, decreasing to 0.10 %in the Andean group and 0.77 % in the Mesoamerican group. Haplotype patterns spanning 310 Mb of the genome (60 %) were characterized in samples from different origins. However, the haplotype frameworks were under-represented for the Andean (7.85 %) and Mesoamerican (5.55 %) gene pools separately. In conclusion, RAD sequencing allowed the discovery of hundreds of useful SNPs for broad genetic analysis of common bean germplasm. From now, this approach provides an excellent panel of molecular tools for whole genome analysis, allowing integrating and better exploring the common bean breeding practices. PMID- 26932374 TI - Transcriptional factor snail controls tumor neovascularization, growth and metastasis in mouse model of human ovarian carcinoma. AB - BACKGROUND: Snail, a transcriptional factor and repressor of E-cadherin is well known for its role in cellular invasion. It can regulate epithelial to mesenchymal transition (EMT) during embryonic development and in epithelial cells. Snail also mediates tumor progression and metastases. Silencing of Snail and its associate member Slug in human A2780 ovarian epithelial carcinoma cell line was investigated to identify its role in tumor neovascularization. METHODS: Live cell sialidase, WST-1 cell viability and immunohistochemistry assays were used to evaluate sialidase activity, cell survival and the expression levels of tumor E-cadherin, N-cadherin, VE-cadherin, and host endothelial CD31+(PECAM-1) cells in archived paraffin-embedded ovarian A2780, A2780 Snail shRNA GIPZ lentiviral knockdown (KD) and A2780 Slug shRNA GIPZ lentiviral KD tumors grown in RAGxCgamma double mutant mice. RESULTS: Oseltamivir phosphate (OP), anti-Neu1 antibodies and MMP-9 specific inhibitor blocked Neu1 activity associated with epidermal growth factor (EGF) stimulated A2780 ovarian epithelial carcinoma cells. Silencing Snail in A2780 cells abrogated the Neu1 activity following EGF stimulation of the cells compared to A2780 and A2780 Slug KD cells. OP treatment of A2780 and cisplatin-resistant A2780cis cells reproducibly and dose-dependently abated the cell viability with a LD50 of 7 and 4 MUm, respectively, after 48 h of incubation. Heterotopic xenografts of A2780 and A2780 Slug KD tumors developed robust and bloody tumor vascularization in RAG2xCgamma double mutant mice. OP treatment at 50 mg/kg daily intraperitoneally did not significantly impede A2780 tumor growth rate but did cause a significant reduction of lung metastases compared with the untreated and OP 30mg/kg cohorts. Silencing Snail in A2780 tumor cells completely abrogated tumor vascularization, tumor growth and spread to the lungs in RAGxCgamma double mutant mice. A2780 and A2780 Slug KD tumors expressed high levels of human N- and VE-cadherins, and host CD31+ endothelial cells, while A2780 Snail KD tumors expressed E-cadherin and reduced host CD31+ cells. OP 50mg/kg cohort tumors had reduced numbers of host CD31+ cells compared to a higher expression levels of CD31+ cells in tumors from the untreated control and OP 30mg/kg cohorts. CONCLUSION: Snail transcriptional factor is an important intermediate player in human ovarian tumor neovascularization. PMID- 26932373 TI - The hippo signaling pathway: implications for heart regeneration and disease. AB - Control of cell number and organ size is critical for appropriate development and tissue homeostasis. Studies in both Drosophila and mammals have established the Hippo signaling pathway as an important modulator of organ size and tumorigenesis. Upon activation, this kinase cascade modulates gene expression through the phosphorylation and inhibition of transcription co-activators that are involved in cell proliferation, differentiation, growth and apoptosis. Hippo signaling serves to limit organ size and suppress malignancies, and has been implicated in tissue regeneration following injury. These outcomes highlight the important role that Hippo signaling plays in regulating both physiologic and pathologic processes. In this review, an overview of the signaling pathway will be discussed as well as recent work that has investigated its role in cardiac development, regeneration and disease. PMID- 26932375 TI - Targeting met mediated epithelial-mesenchymal transition in the treatment of breast cancer. AB - Mesenchymal epithelial transition factor receptor (Met) is a receptor tyrosine kinase that plays a critical role in promoting cancer cell malignant progression. Met is activated by its ligand hepatocyte growth factor (HGF). HGF-dependent Met activation plays an important role in stimulating epithelial-mesenchymal transition (EMT) in tumor cells, resulting in increased tumor cell proliferation, survival, motility, angiogenesis, invasion, and metastasis. The HGF/Met axis has thus attracted great interest as a potential target in the development of novel cancer therapies. In an effort to suppress tumor cell malignant progression, efforts have been made to develop agents capable of inhibiting inhibit Met induced EMT, including specific Met tyrosine kinase inhibitors, HGF antagonists that interfere with HGF binding to Met, and antibodies that prevent Met activation and/or dimerization. Tocotrienols, a subgroup within the vitamin E family of compounds, display potent anticancer activity that results, at least in part, from inhibition of HGF-dependent Met activation and signaling. The present review will provide a brief summary of the increasing importance of the HGF/Met axis as an attractive target for cancer chemotherapy and the role of tocotrienols in suppressing Met activation, signaling and HGF-induced EMT in breast cancer cells. Evidence provided suggests that gamma-tocotrienol therapy may afford significant benefit in the treatment of breast cancers characterized by Met dysregulation. PMID- 26932377 TI - Clinical significance of epithelial mesenchymal transition (EMT) in chronic obstructive pulmonary disease (COPD): potential target for prevention of airway fibrosis and lung cancer. AB - Unfortunately, the research effort directed into chronic obstructive pulmonary disease (COPD) has been disproportionately weak compared to its social importance, and indeed it is the least researched of all common chronic conditions. Tobacco smoking is the major etiological factor. Only 25% of smokers will develop "classic" COPD; in these vulnerable individuals the progression of airways disease to symptomatic COPD occurs over two or more decades. We know surprisingly little about the pathobiology of COPD airway disease, though small airway fibrosis and obliteration are likely to be the main contributors to physiological airway dysfunction and these features occur earlier than any subsequent development of emphysema. One potential mechanism contributing to small airway fibrosis/obliteration and change in extracellular matrix (ECM) is epithelial mesenchymal transition (EMT), so called Type-II EMT. When associated with angiogenesis (Type-III EMT) it may well also be a link with the development of lung (airway) cancer which is closely associated with COPD. Active EMT in COPD may help to explain why lung cancer is so common in smokers and also the core pathophysiology of small airway fibrosis. Better understanding may lead to new markers for incipient neoplasia, and better preventive management of patients. There is serious need to understand key components of airway EMT in smokers and COPD, and to demarcate novel drug targets for the prevention of lung cancer and airway fibrosis, as well as better secondary management of COPD. Since over 90% of human cancer arises in epithelia and the involvement of EMT in all of these may be a central paradigm, insights gained in COPD may have important generalizable value. PMID- 26932376 TI - Biological and clinical significance of cancer stem cell plasticity. AB - In the past decade, the traditional view of cancers as a homogeneous collection of malignant cells is being replaced by a model of ever increasing complexity suggesting that cancers are complex tissues composed of multiple cell types. This complex model of tumorigenesis has been well supported by a growing body of evidence indicating that most cancers including those derived from blood and solid tissues display a hierarchical organization of tumor cells with phenotypic and functional heterogeneity and at the apex of this hierarchy are cells capable of self-renewal. These "tumor imitating cells" or "cancer stem cells" drive tumorigenesis and contribute to metastasis, treatment resistance and tumor relapse. Although tumor stem cells themselves may display both genetic and phenotypic heterogeneity, recent studies have demonstrated that cancer stem cells maintain plasticity to transition between mesenchymal-like (EMT) and epithelial like (MET) states, which may be regulated by the tumor microenvironment. These stem cell state transitions may play a fundamental role in tumor progression and treatment resistance. In this review, we discuss the emerging knowledge regarding the plasticity of cancer stem cells with an emphasis on the signaling pathways and noncoding RNAs including microRNAs (miRNA) and long non-coding RNAs (lncRNAs) in regulation of this plasticity during tumor growth and metastasis. Lastly, we point out the importance of targeting both the EMT and MET states of CSCs in order to eliminate these lethal seeds of cancers. PMID- 26932378 TI - Application of clinical proteomics in acute respiratory distress syndrome. AB - Acute Respiratory Distress Syndrome (ARDS) is a devastating cause of hypoxic respiratory failure, which continues to have high mortality. It is expected that a comprehensive systems- level approach will identify global and complex changes that contribute to the development of ARDS and subsequent repair of the damaged lung. In the last decade, powerful genome-wide analytical and informatics tools have been developed, that have provided valuable insights into the mechanisms of complex diseases such as ARDS. These tools include the rapid and precise measure of gene expression at the proteomic level. This article reviews the contemporary proteomics platforms that are available for comprehensive studies in ARDS. The challenges of various biofluids that could be investigated and some of the studies performed are also discussed. PMID- 26932380 TI - The Effect of Pulmonary Function Testing on the Success of Smoking Cessation. AB - BACKGROUND: In several studies, low spirometric levels have been shown to increase the success rates of smoking cessation, whereas other studies have indicated that pulmonary function has no effects on quitting smoking. Given the fact that there are contradictory results on this subject, we aimed to investigate the effect of identifying airway obstruction via spirometry and its explanation to subjects on the success rate of smoking cessation in the short term. METHODS: Subjects who were admitted to the smoking cessation out-patient clinic, underwent pulmonary function tests (PFTs) and completed at least 3 months of the cessation program following their admittance were included in the study. At the first interview, all subjects were asked about their comorbid diseases and smoking habits. PFTs were performed. Subjects who had an obstruction on PFT were informed that their condition was smoking-related, and that further deterioration could be prevented following smoking cessation. Then the smoking cessation date was determined together with the subject, and one of the smoking cessation medicines was prescribed. All subjects were given control appointments twice for the first month and once per month for the following 2-month follow-up period. Subjects who had CO levels between 0 and 5 parts per million were considered as non-smokers. RESULTS: The mean age of the 563 subjects was 41.9 +/- 12.1 y 340 subjects (60.4%) were male. A total of 162 subjects (28.8%) came to the follow-up visits following the first interview. The success of smoking cessation for 3 months was 11.3% for all subjects and 39.5% for subjects who came to follow-up visits. Of the subjects with obstruction on PFT; 22.8% stopped smoking, whereas 8.4% of the subjects without obstruction did so (P < .001). The percentage of subjects with obstruction on PFT was significantly higher (P < .001) and the FEV1 % (P = .005), FEV1/FVC (P < .001), and forced expiratory flow 25-75% (P = .008) levels were significantly lower in the quitters compared with the non-quitters. Logistic regression analysis showed that age (P = .001) and the presence of obstruction on PFT (P = .029) were independent variables. CONCLUSIONS: Advanced age and the presence of obstruction on PFT increase the success of smoking cessation. Pulmonary function tests should be performed on all patients who apply to smoking cessation out-patient clinics, and patients should be informed about their condition. PMID- 26932379 TI - The significance of macrophage phenotype in cancer and biomaterials. AB - Macrophages have long been known to exhibit heterogeneous and plastic phenotypes. They show functional diversity with roles in homeostasis, tissue repair, immunity and disease. There exists a spectrum of macrophage phenotypes with varied effector functions, molecular determinants, cytokine and chemokine profiles, as well as receptor expression. In tumor microenvironments, the subset of macrophages known as tumor-associated macrophages generates byproducts that enhance tumor growth and angiogenesis, making them attractive targets for anti cancer therapeutics. With respect to wound healing and the foreign body response, there is a necessity for balance between pro-inflammatory, wound healing, and regulatory macrophages in order to achieve successful implantation of a scaffold for tissue engineering. In this review, we discuss the multitude of ways macrophages are known to be important in cancer therapies and implanted biomaterials. PMID- 26932381 TI - Using a Post-Intubation Checklist and Time Out to Expedite Mechanical Ventilation Monitoring: Observational Study of a Quality Improvement Intervention. AB - BACKGROUND: Delayed mechanical ventilation monitoring may impede recognition of life-threatening acidemia. Coordination of multidisciplinary processes can be improved by using a checklist and time-out procedure. The study objective was to evaluate process-related outcomes after implementation of a post-intubation checklist and time out. METHODS: An observational study of a 24-bed medical ICU in Philadelphia, Pennsylvania, was conducted from January to December 2011. A random sample of mechanically ventilated adults was selected from the pre intervention (n = 80) and post-intervention (n = 144) periods. The primary outcome was the proportion of subjects with an arterial blood gas (ABG) result within 60 min of mechanical ventilation initiation. Secondary outcomes included rates of respiratory acidosis, moderate-severe acidemia (pH <7.25), checklist initiation, and project sustainability. Chi-square analysis was used to evaluate differences in outcomes between time periods. RESULTS: After the intervention, the proportion of subjects with an ABG result within 60 min increased (56% vs 37%, P = .01), and time to ABG result improved (58 min vs 79 min, P = .004). Adjusting for illness severity, the proportion with an ABG result within 60 min remained significantly higher in the post-intervention period (odds ratio 2.42, 95% CI 1.25-4.68, P = .009). Checklist adherence was higher with ICU intubations than for intubations performed outside the ICU (71% vs 27% checklist initiation rate, P < .001). Transfer from referring institutions (23% checklist initiation rate, P = .006) negatively impacted checklist use. Implementation challenges included frequent stakeholder turnover, undefined process ownership, and lack of real-time performance feedback. CONCLUSIONS: A post-intubation checklist and time out improved the timeliness of mechanical ventilation monitoring through more rapid assessment of arterial blood gases. Implementing this peri-intubation procedure may reduce the risks associated with transitioning to full mechanical ventilatory support. Optimal implementation necessitates strategies to surmount organizational and behavioral barriers to change. PMID- 26932382 TI - Diagnostic Yield and Safety of Cryoprobe Transbronchial Lung Biopsy in Diffuse Parenchymal Lung Diseases: Systematic Review and Meta-Analysis. AB - BACKGROUND: Transbronchial lung biopsy with flexible forceps is the most commonly used technique in diagnosis of diseases diffusely involving the lung parenchyma. Recently, transbronchial lung biopsy using the flexible cryoprobe (cryo transbronchial lung biopsy) has also been reported. Herein, we perform a systematic review and meta-analysis describing the efficacy and safety of cryo transbronchial lung biopsy. METHODS: The PubMed and EMBASE databases were searched for studies reporting the outcomes of cryo-transbronchial lung biopsy in subjects with diffuse parenchymal lung involvement. The quality of individual studies was assessed using the QualSyst tool. The pooled diagnostic yield of cryo transbronchial lung biopsy was calculated using proportion meta-analysis (random effects model). Heterogeneity was evaluated using the I(2) test and Cochran Q test. Publication bias was determined using both statistical and graphical methods. RESULTS: Our search yielded 14 studies (1,183 subjects). The pooled diagnostic yield of cryo-transbronchial lung biopsy was 76.9% (95% CI 67.2-85.3) if only definitive diagnoses were considered and 85.9% (95% CI 78.2-92.2) if both definitive and probable diagnoses were considered. Four studies (321 subjects) the performance of flexible forceps biopsy and cryo-transbronchial lung biopsy. The diagnostic yield of cryo-transbronchial lung biopsy (86.3, 95% CI 80.2-90.8) was significantly higher than that of flexible forceps biopsy (56.5%, 95% CI 27.5 83.2) with an odds ratio of 6.7 (95% CI 3.6-12.4) and a number needed to treat of 4. Lung tissue was obtained in 98% of all samples with cryo-transbronchial lung biopsy and was free of compression artifacts. The size of samples obtained with cryo-transbronchial lung biopsy was significantly bigger compared with flexible forceps biopsy (20.4 vs 4.3 mm(2), P = .005). The complications of cryo transbronchial lung biopsy included pneumothorax (6.8%), severe bleeding (0.3%), and death (0.1%). Clinical and statistical heterogeneity was present, and there was evidence of publication bias. CONCLUSIONS: Cryo-transbronchial lung biopsy is a relatively safe procedure with good diagnostic yield in diseases diffusely involving the lung parenchyma. PMID- 26932383 TI - Characterization of Ribavirin Aerosol With Small Particle Aerosol Generator and Vibrating Mesh Micropump Aerosol Technologies. AB - BACKGROUND: Ribavirin is an antiviral drug that can be administered by inhalation. Despite advancements in the oral delivery of this medication, there has been a renewed interested in delivering ribavirin via the pulmonary system. Although data are not conclusive that inhaled ribavirin improves outcomes, we set out to determine whether delivery by a newer generation nebulizer, the vibrating mesh micropump, was as effective as the recommended small-particle aerosol generator system. METHODS: We compared the physicochemical makeup and concentrations of ribavirin before and after nebulization with 0.9% NaCl and sterile water. An Andersen cascade impactor was used to determine particle size distribution and mass median aerodynamic diameter, and an absolute filter was used to measure total aerosol emitted output and inhaled dose during mechanical ventilation and spontaneous breathing. Ribavirin was analyzed and quantified using high-performance liquid chromatography with tandem mass spectrometric detection. RESULTS: Ribavirin was found to be stable in both 0.9% aqueous NaCl and sterile water with an r(2) value of 0.96 and identical coefficients of variation with no difference in drug concentration before and after nebulization with the vibrating mesh micropump. The small-particle aerosol generator produced a smaller mass median aerodynamic diameter (1.84 MUm) than the vibrating mesh micropump (3.63 MUm, P = .02); however, there was no significant difference in the proportion of drug mass in the 0.7-4.7-MUm particle range. Total drug delivery was similar with the small-particle aerosol generator and vibrating mesh micropump in both spontaneously breathing (P = .77) and mechanical ventilation (P = .48) models. CONCLUSIONS: The vibrating mesh micropump nebulizer may provide an effective alternative to the small-particle aerosol generator in administration of ribavirin using NaCl or sterile water, both on and off the ventilator. Further clinical studies are needed to compare efficacy. PMID- 26932384 TI - Incapacity, Handicap, and Oxidative Stress Markers of Male Smokers With and Without COPD. AB - BACKGROUND: Mechanisms of incapacity and quality of life (QOL) of smokers with COPD and those free from COPD (non-COPD) are still unclear. The aims of this work were to compare the submaximal exercise, the QOL, and the blood and lung oxidative stress biomarker data of smokers without and with COPD. METHODS: Thirty two male-smokers 40-60 y old were included (16 with COPD). QOL (Saint George Respiratory Questionnaire) and physical activity (Voorrips questionnaire) scores were determined. Blood sample levels of malondialdehyde, protein sulfhydryl, and glutathione were measured. Fraction of exhaled nitric oxide, plethysmographic data, and 6-min walk distance (6MWD) were collected. All data are presented as mean +/- SD, except oxidative stress biomarkers expressed as mean +/- SE. Correlation coefficient (r) evaluated the association between oxidative stress biomarkers and 6MWD, QOL, and physical activity data. RESULTS: Two age- and amount of tobacco used-matched groups of smokers were included. Compared with the non-COPD group, the COPD group had significantly lower 6MWD (573 +/- 63 vs 476 +/ 53 m) and physical activity score (7.14 +/- 1.50 vs 2.86 +/- 1.50) and significantly worse QOL (19.47 +/- 15.33 vs 47.70 +/- 16.73) and lower glutathione level (39.44 +/- 6.28 vs 24.67 +/- 5.41 MUg/mL). The COPD group malondialdehyde level was significantly correlated with 6MWD, symptoms, and QOL scores (good r value between 0.50 and 0.70). The non-COPD group fraction of exhaled nitric oxide and glutathione levels were significantly correlated with leisure activity score and 6MWD, respectively (good r value between 0.50 and 0.70). CONCLUSIONS: Compared with the non-COPD group, the COPD group had a marked decrease in submaximal exercise data and in QOL score. Oxidative stress could be one explanation of incapacity and handicap observed in the COPD group. PMID- 26932386 TI - Editorial: Senescent angiogenic T cells: the use of CD28 makes the difference in endothelial homeostasis. PMID- 26932385 TI - Factors Influencing Cognitive Function in Subjects With COPD. AB - BACKGROUND: The aim of this study was to assess the association between cognitive function and age, pulmonary function, comorbidity index, and the 6-min walk distance in subjects with COPD as well as to compare the Mini Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) in terms of their ability to identify cognitive dysfunction in subjects with COPD. METHODS: A total of 52 individuals with stable COPD were included in this study. Cognitive function was assessed using MMSE and MoCA. Age, body mass index, the Modified Cumulative Illness Rating Scale, 6-min walk distance, arterial blood gases, and pulmonary function tests were assessed and recorded. RESULTS: The range and SD of scores in subjects with COPD were larger with MoCA than with MMSE. MMSE and MoCA scores are associated with 6-min walk distance and comorbidity index in subjects with COPD. General cognitive function measured by MoCA was negatively correlated with the comorbidity index but was positively associated with 6-min walk distance in subjects with COPD after controlling for possible confounding factors in the multivariate model. However, general cognitive function measured by MMSE was not correlated with the comorbidity index and 6-min walk distance in subjects with COPD, after controlling for possible confounding factors in the multivariate model. CONCLUSIONS: MoCA may be a more reliable screening test than MMSE in detecting cognitive impairment in subjects with COPD. The addition of cognitive tests on assessment of subjects with COPD can provide further benefit. PMID- 26932387 TI - Editorial: Flt3 ligand-friend or foe? PMID- 26932390 TI - High-symmetry hydrogen-bonded organic frameworks: air separation and crystal-to crystal structural transformation. AB - By changing the size of a substituent group, benzotrisimidazoles can self assembly to give a honeycomb-like (hcb) layer or a three-dimensional (10,3)-a (srs) network. While the former is highly stable and rigid with little porosity, the latter can undergo a water-induced reversible crystal-to-crystal transformation and selectively adsorb O2 over Ar and N2. PMID- 26932391 TI - Association between Gastroesophageal Reflux Disease and Appendicitis: A Population-Based Case-Control Study. AB - Appendicitis and gastroesophageal reflux disease (GERD) are both prevalent diseases and might share similar pathological mechanisms. The aim of this study was to investigate the association between GERD and appendicitis using a large population-based dataset. This study used administrative claims data from the Taiwan Longitudinal Health Insurance Database 2005. We identified 7113 patients with appendicitis as cases, and 28452 matched patients without appendicitis as controls. This study revealed that GERD was found in 359 (5.05%) cases and 728 (2.56%) controls (p < 0.001). Conditional logistic regression shows that the adjusted odds ratio (OR) of GERD for cases was 2.05 (95% confidence interval (CI): 1.08~2.33) compared to controls. The adjusted ORs of prior GERD for patients aged 18~39, 40~59, and >=60 years with appendicitis were 1.96 (95% CI: 1.56~2.47), 2.36 (95% CI: 1.94~2.88), and 1.71 (95% CI: 1.31~2.22) than controls, respectively. We concluded that patients with appendicitis had higher odds of prior GERD than those without appendicitis regardless of age group. PMID- 26932393 TI - From molecular germanates to microporous Ge@C via twin polymerization. AB - Four molecular germanates based on salicyl alcoholates, bis(dimethylammonium) tris[2-(oxidomethyl)phenolate(2-)]germanate (1), bis(dimethylammonium) tris[4 methyl-2-(oxidomethyl)phenolate(2-)]germanate (2), bis(dimethylammonium) tris[4 bromo-2-(oxidomethyl)phenolate(2-)]germanate (3) and dimethylammonium bis[2-tert butyl-4-methyl-6-(oxidomethyl)phenolate(2-)][2-tert-butyl-4-methyl-6 (hydroxymethyl)phenolate(1-)]germanate (4), were synthesized and characterized including single crystal X-ray diffraction analysis. In the solid state, compounds 1 and 2 exhibit one-dimensional hydrogen bonded networks, whereas compound 4 forms separate ion pairs, which are connected by hydrogen bonds between the dimethylammonium and the germanate moieties. The potential of these compounds for thermally induced twin polymerization (TP) was studied. Germanate 1 was converted by TP to give a hybrid material (HM-1) composed of phenolic resin and germanium dioxide. Subsequent reduction with hydrogen provided a microporous composite containing crystalline germanium and carbon (Ge@C -C-1, germanium content ~20%). Studies on C-1 as an anode material for Li-ion batteries revealed reversible capacities of ~370 mA h gGe@C(-1) at a current density up to 1384 mA g(-1) without apparent fading for 500 cycles. PMID- 26932392 TI - The effectiveness of low-level laser therapy as an adjunct to non-surgical periodontal treatment: a meta-analysis. AB - BACKGROUND AND OBJECTIVES: Although low-level laser therapy (LLLT) has been demonstrated to have a biomodulatory effect on periodontal tissue, no systematic review has exclusively addressed its effectiveness as an adjunct to non-surgical periodontal treatment. This study aimed to evaluate whether an additional benefit exists for the application of LLLT compared with scaling and root planing (SRP) alone. MATERIAL AND METHODS: An extensive search was conducted in the Cochrane Library (Issue 8, 2015), PubMed (1997) and EMBASE (1947) before August 2015 for randomized controlled trials (RCTs). The bias risk was assessed with the Cochrane tool for risk of bias evaluation. A meta-analysis was performed using REVMAN 5.3. RESULTS: After independent screening of 354 initial records, eight publications (seven RCTs) were included. However, six were rated as 'having a high risk of bias' as a result of major methodological weakness in 'allocation concealment' and 'blinding of key personnel'. Meta-analysis showed that LLLT-mediated SRP demonstrated significant short-term benefits over SRP monotherapy in the improvement of the probing pocket depth (p = 0.0009 at 1 mo; p = 0.03 at 2 mo) and the level of interleukin-1beta in the gingival crevicular fluid (p = 0.01 at 1 mo). Nevertheless, LLLT failed to show significant additional intermediate-term (3 and 6 mo) effects in terms of clinical parameters and alveolar bone density. CONCLUSION: These findings indicated that LLLT showed only short-term additional benefits after conventional SRP. Its long-term effects remain unclear due to substantial methodological weaknesses and an insufficient number of current studies. Future RCTs with better designs and longer follow-up periods are required to assess the effectiveness of LLLT as an adjunctive treatment strategy in patients with periodontal disease. PMID- 26932394 TI - Increased Identification of Emergency Department 72-hour Returns Using Multihospital Health Information Exchange. AB - OBJECTIVES: Emergency departments (EDs) commonly analyze cases of patients returning within 72 hours of initial ED discharge as potential opportunities for quality improvement. In this study, we tested the use of a health information exchange (HIE) to improve identification of 72-hour return visits compared to individual hospitals' site-specific data. METHODS: We collected deidentified patient data over a 5-year study period from Healthix, an HIE in the New York metropolitan area. We measured site-specific 72-hour ED returns and compared these data to those obtained from a regional 31-site HIE (Healthix) and to those from a smaller, antecedent 11-site HIE. Although only ED visits were counted as index visits, either ED or inpatient revisits within 72 hours of the index visit were considered as early returns. RESULTS: A total of 12,669,657 patient encounters were analyzed across the 31 HIE EDs, including 6,352,829 encounters from the antecedent 11-site HIE. Site-specific 72-hour return visit rates ranged from 1.1% to 15.2% (median = 5.8%) among the individual 31 sites. When the larger HIE was used to identify return visits to any site, individual EDs had a 72-hour return frequency of 1.8% to 15.5% (median = 6.8%). HIE increased the identification ability of 72-hour ED return analyses by a mean of 11.16% (95% confidence interval = 11.10% to 11.22%) compared with site-specific (no HIE) analyses. CONCLUSION: This analysis demonstrates incremental improvements in our ability to identify early ED returns using increasing levels of HIE data aggregation. Although intuitive, this has not been previously described using HIE. ED quality measurement and patient safety efforts may be aided by using HIE in 72-hour return analyses. PMID- 26932389 TI - Regulation of immunity during visceral Leishmania infection. AB - Unicellular eukaryotes of the genus Leishmania are collectively responsible for a heterogeneous group of diseases known as leishmaniasis. The visceral form of leishmaniasis, caused by L. donovani or L. infantum, is a devastating condition, claiming 20,000 to 40,000 lives annually, with particular incidence in some of the poorest regions of the world. Immunity to Leishmania depends on the development of protective type I immune responses capable of activating infected phagocytes to kill intracellular amastigotes. However, despite the induction of protective responses, disease progresses due to a multitude of factors that impede an optimal response. These include the action of suppressive cytokines, exhaustion of specific T cells, loss of lymphoid tissue architecture and a defective humoral response. We will review how these responses are orchestrated during the course of infection, including both early and chronic stages, focusing on the spleen and the liver, which are the main target organs of visceral Leishmania in the host. A comprehensive understanding of the immune events that occur during visceral Leishmania infection is crucial for the implementation of immunotherapeutic approaches that complement the current anti-Leishmania chemotherapy and the development of effective vaccines to prevent disease. PMID- 26932395 TI - Presence of diverse Candidatus Methylomirabilis oxyfera-like bacteria of NC10 phylum in agricultural soils. AB - AIMS: To better explore the distribution and diversity of Candidatus Methylomirabilis oxyfera (M. oxyfera)-like bacteria of NC10 phylum in soil environments. METHODS AND RESULTS: The vertical distribution and diversity of NC10 phylum bacteria were investigated in an agricultural field (surface layer, 0 10 cm; subsurface layer, 20-30 cm; deep layers, 50-60 and 90-100 cm) by using Illumina-based 16S rRNA (V3-V4 region) gene sequencing of soil DNA samples and quantitative PCR assays. It was found that the NC10-related reads accounted for 0.8-4.5% of the 16S rRNA pool in each examined core sample, with greater percentage being observed in deep soils than in surface soils and subsurface soils. The recovered NC10-related reads showed 85.1-96.9% identity to the 16S rRNA gene of M. oxyfera. A high diversity of NC10 phylum bacteria was observed in the examined soil cores. A total of 115 operational taxonomic units (OTU) were detected based on 3% sequence divergence in the recovered 16S rRNA genes. Phylogenetic analysis showed that four distinct groups of NC10 phylum bacteria (groups A, B, C and D) were present in the examined soil cores, with group B members being the dominant bacteria. The group A members, which are identified as the dominant bacteria responsible for anaerobic methane oxidation (AMO) coupled to nitrite reduction, can mainly be detected at 50-60 cm. Quantitative PCR further confirmed the presence of NC10 phylum bacteria, ranging from 3.8 * 10(6) to 9.3 * 10(6) copies g(-1) soil. CONCLUSIONS: The results showed the presence of diverse NC10 phylum bacteria in agricultural soils by using Illumina-based 16S rRNA gene sequencing and qPCR assays. SIGNIFICANCE AND IMPACT OF THE STUDY: The greatest level of diversity of NC10 phylum bacteria was reported to date in this study, which improved our understanding of the distribution of NC10 phylum bacterial communities in soil environments. PMID- 26932396 TI - Electronic cigarette use among adolescents: a cross-sectional study in Hong Kong. AB - BACKGROUND: Little is known about electronic cigarette (e-cigarette) use among Chinese adolescents. We examined the prevalence of current (past 30-day) e cigarette use and its associated factors in a large sample of adolescents in Hong Kong. METHODS: We analyzed data of the School-based Survey on Smoking among Students 2012/13 from a representative sample of 45,857 secondary school students (mean age: 14.8 +/- 1.9). We conducted chi-square tests and t-test to compare current e-cigarette use by covariates. We used multivariable logistic regression to examine the association between current e-cigarette use and demographic variables, parental smoking, peer smoking, knowledge about the harm of cigarette smoking, attitudes toward cigarette smoking, cigarette smoking status, use of other tobacco products, and alcohol consumption. RESULTS: Overall, 1.1% of students reported current e-cigarette use. Of e-cigarette users, 11.7% were never cigarette smokers, 15.8% were experimental cigarette smokers, 39.3% were former cigarette smokers, and 33.2% were current cigarette smokers. Current e-cigarette use was associated with male sex, poor knowledge about the harm of smoking, cigarette smoking, use of other tobacco products, and alcohol consumption. CONCLUSIONS: Surveillance and intervention efforts should address a wide range of tobacco products, including e-cigarettes. Tobacco cessation programs should also address alcohol use collectively. Policies prohibiting e-cigarette sales to minors may help prevent e-cigarette uptake among adolescents. PMID- 26932397 TI - Diagnosis and management of gastric dysplasia. AB - Gastric dysplasia is a neoplastic lesion and a precursor of gastric cancer. The Padova, Vienna, and World Health Organization classifications were developed to overcome the discrepancies between Western and Japanese pathologic diagnoses and to provide a universally accepted classification of gastric epithelial neoplasia. At present, the natural history of gastric dysplasia is unclear. Much evidence suggests that patients with high-grade dysplasia are at high risk of progression to carcinoma or synchronous carcinoma. Therefore, endoscopic resection is required. Although patients with low-grade dysplasia have been reported to be at low risk of progression to carcinoma, due to the marked histologic discrepancies between forceps biopsy and endoscopic specimens, endoscopic resection for this lesion is recommended, particularly in the presence of other risk factors (large size; depressed gross type; surface erythema, unevenness, ulcer, or erosion; and tubulovillous or villous histology). Helicobacter pylori eradication in patients with dysplasia after endoscopic resection appear to reduce the incidence of metachronous lesions. PMID- 26932398 TI - Current concepts in the management of rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by inflammation and joint destruction that causes significant morbidity and mortality. However, the combined use of methotrexate, a synthetic disease modifying antirheumatic drug (DMARD), and biologic DMARD has revolutionized treatment of RA. Clinical remission is now realistic targets, achieved by a large proportion of RA patients, and rapid and appropriate induction of remission by intensive treatment with biological DMARD and methotrexate is prerequisite to halt joint damage and functional disabilities. However, biological DMARD is limited to intravenous or subcutaneous uses and orally available small but strong molecules have been developed. Oral administration of tofacitinib targeting the Janus kinase (JAK) is significantly effective than placebo in active patients with methotrexatenaive, inadequately responsive to methotrexate or tumor necrosis factor (TNF)-inhibitors. The efficacy was rapid and as strong as adalimumab, a TNF-inhibitor. Meanwhile, association of tofacitinib on carcinogenicity and malignancy is under debate and further investigation on post-marketing survey would be warranted. On the other hand, discontinuation of a biological DMARD without disease flare is our next goal and desirable from the standpoint of risk reduction and cost effectiveness, especially for patients with clinical remission. Recent reports indicate that more than half of early RA patients could discontinue TNF-targeted biological DMARD without clinical flare and functional impairment after obtaining clinical remission. Contrarily, for established RA, fewer patients sustained remission after the discontinuation of biological DMARD and "deep remission" at the discontinuation was a key factor to keep the treatment holiday of biological DMARD. PMID- 26932400 TI - Angiotensin converting enzyme inhibitors remain the first treatment of choice. PMID- 26932399 TI - The specialist physician's approach to rheumatoid arthritis in South Africa. AB - Rheumatoid arthritis (RA) is expected to increase in Africa and South Africa. Due to the low numbers of rheumatologists in South Africa, specialist physicians also have to care for patients with RA. Furthermore several new developments have taken place in recent years which improved the management and outcome of RA. Classification criteria were updated, assessment follow-up tools were refined and above all, several new biological disease-modifying anti-rheumatic drugs were developed. Therefore it is imperative for specialist physicians to update themselves with the newest developments in the management of RA. This article provides an overview of the newest developments in the management of RA in the South African context. This approach may well apply to countries with similar specialist to patient ratios and disease profiles. PMID- 26932401 TI - Effects of bispectral index monitoring as an adjunct to nurse-administered propofol combined sedation during colonoscopy: a randomized clinical trial. AB - BACKGROUND/AIMS: The efficacy of bispectral index (BIS) monitoring during colonoscopic sedation is debated. We aimed to determine whether BIS monitoring was useful for propofol dose titration, and to evaluate differences in sedative administration between expert and inexperienced medical personnel during colonoscopy procedures that required moderate sedation. METHODS: Between February 2012 and August 2013, 280 consecutive patients scheduled to undergo a screening colonoscopy participated in this study and were randomly allocated to the expert or inexperienced endoscopist group. Each group was further divided into either a BIS or a modified Observer's Assessment of Alertness/Sedation Scale (MOAA/S) subgroup. Trained nurses administered combined propofol sedation and monitored sedation using either the BIS or MOAA/S scale. RESULTS: The mean BIS value throughout the procedure was 74.3 +/- 6.7 for all 141 patients in the BIS group. The mean total propofol dose administered in the BIS group was higher than that in the MOAA/S group, independently of the endoscopists' experience level (36.9 +/ 29.6 and 11.3 +/- 20.7, respectively; p < 0.001). The total dose of propofol administered was not significantly different between the inexperienced endoscopist group and the expert endoscopist group, both with and without the use of BIS (p = 0.430 and p = 0.640, respectively). CONCLUSIONS: Compared with monitoring using the MOAA/S score alone, BIS monitoring was not effective for titrating the dose of propofol during colonoscopy, irrespective of colonoscopist experience. PMID- 26932402 TI - Concomitant inhibition of renin angiotensin system and Toll-like receptor 2 attenuates renal injury in unilateral ureteral obstructed mice. AB - BACKGROUND/AIMS: There has been controversy about the role of Toll-like receptor 2 (TLR2) in renal injury following ureteric obstruction. Although inhibition of the renin angiotensin system (RAS) reduces TLR2 expression in mice, the exact relationship between TLR2 and RAS is not known. The aim of this study was to determine whether the RAS modulates TLR2. METHODS: We used 8-week-old male wild type (WT) and TLR2-knockout (KO) mice on a C57Bl/6 background. Unilateral ureteral obstruction (UUO) was induced by complete ligation of the left ureter. Angiotensin (Ang) II (1,000 ng/kg/min) and the direct renin inhibitor aliskiren (25 mg/kg/day) were administrated to mice using an osmotic minipump. Molecular and histologic evaluations were performed. RESULTS: Ang II infusion increased mRNA expression of TLR2 in WT mouse kidneys (p < 0.05). The expression of renin mRNA in TLR2-KO UUO kidneys was significantly higher than that in WT UUO kidneys (p < 0.05). There were no differences in tissue injury score or mRNA expression of monocyte chemotactic protein 1 (MCP-1), osteopontin (OPN), or transforming growth factor beta (TGF-beta) between TLR2-KO UUO and WT UUO kidneys. However, aliskiren decreased the tissue injury score and mRNA expression of TLR2, MCP-1, OPN, and TGF-beta in WT UUO kidneys (p < 0.05). Aliskiren-treated TLR2-KO UUO kidneys showed less kidney injury than aliskiren-treated WT UUO kidneys. CONCLUSIONS: TLR2 deletion induced activation of the RAS in UUO kidneys. Moreover, inhibition of both RAS and TLR2 had an additive ameliorative effect on UUO injury of the kidney. PMID- 26932403 TI - Painful immunoglobulin G4-related thyroiditis treated by total thyroidectomy. PMID- 26932405 TI - Many faces of Meckel's diverticulum and its complications. AB - Meckel's diverticulum is the most common congenital abnormality of the gastrointestinal tract. It is a true diverticulum containing all layers of the intestinal wall and identified as a saccular, blind-ending structure located on the antimesenteric border of the distal ileum. Most patients remain asymptomatic during their lifetime. Symptomatic cases are nonspecific and can present as small bowel obstruction, diverticulitis, perforation, gastrointestinal bleeding, and rarely, a neoplasm. Therefore, the radiological diagnosis is of paramount important for proper patient management. PMID- 26932406 TI - Long-range doublon transfer in a dimer chain induced by topology and ac fields. AB - The controlled transfer of particles from one site of a spatial lattice to another is essential for many tasks in quantum information processing and quantum communication. In this work we study how to induce long-range transfer between the two ends of a dimer chain, by coupling states that are localized just on the chain's end-points. This has the appealing feature that the transfer occurs only between the end-points - the particle does not pass through the intermediate sites-making the transfer less susceptible to decoherence. We first show how a repulsively bound-pair of fermions, known as a doublon, can be transferred from one end of the chain to the other via topological edge states. We then show how non-topological surface states of the familiar Shockley or Tamm type can be used to produce a similar form of transfer under the action of a periodic driving potential. Finally we show that combining these effects can produce transfer by means of more exotic topological effects, in which the driving field can be used to switch the topological character of the edge states, as measured by the Zak phase. Our results demonstrate how to induce long range transfer of strongly correlated particles by tuning both topology and driving. PMID- 26932404 TI - Contribution of metals to brain MR signal intensity: review articles. AB - Various metals are essential nutrients in humans, and metal shortages lead to a variety of deficiency diseases. Metal concentration abnormalities may cause metal deposition in the brain, and magnetic resonance imaging (MRI) is the most potent and sensitive technique now available for detecting metal deposition given the difficulties associated with performing brain tissue biopsy. However, the brain contains many kinds of metals that affect the signal intensity of MRI, which has led to numerous misunderstandings in the history of metal analysis. We reviewed the history of brain metal analysis with histologic findings. Typically, manganese overload causes high signal intensity on T1-weighted images (T1WI) in the globus pallidus, iron overload causes low signal intensity in the globus pallidus on T2-weighted images, and gadolinium deposition causes high signal intensity in the dentate nucleus, globus pallidus, and pulvinar of thalamus on T1WI. However, because nonparamagnetic materials and other coexisting metals also affect the signal intensity of brain MRI, the quantitative analysis of metal concentrations is difficult. Thus, when analyzing metal deposition using MRI, caution should be exercised when interpreting the validity and reliability of the obtained data. PMID- 26932407 TI - In vitro characterization and inhibition of the interaction between ciprofloxacin and berberine against multidrug-resistant Klebsiella pneumoniae. AB - Ciprofloxacin is a quinolone antibiotic used to treat Klebsiella pneumoniae infections in the clinic. Previous studies have demonstrated that berberine exhibits antibacterial activity and less acquired resistance related to efflux pumps. The multidrug efflux pump acrAB-tolC can be stimulated to expel as much toxic material as possible from the cells, but a detrimental effect can be produced owing to an overcrowded periplasm with excess expression products, which inhibits bacterial growth. In this study, the in vitro antibacterial activities of ciprofloxacin in combination with berberine were evaluated and compared with those of ciprofloxacin and berberine alone by evaluating the MIC, MBC and summation fractional IC against 20 clinical multidrug-resistant K. pneumoniae isolates, 1 quality control bacterium and 1 induced-resistance bacterium. Susceptibility tests showed that the MIC for the combination of berberine and ciprofloxacin was 1/2 that of the individual agents or less. Antimicrobial activities of 18.18% synergy and 77.27% additivity were found. Furthermore, synergism was verified through a time-kill assay, which suggested that the synergistic antibacterial effect of the two-drug combination may, to some extent, be related to the high expression of the acrAB-tolC and acrR multidrug efflux pumps. Indeed, the expression of these genes was increased >14-fold in the isolates affected by ciprofloxacin-berberine combination synergism. PMID- 26932408 TI - Organic synthesis in the Smith Group: a personal selection of a dozen lessons learned at the University of Pennsylvania. AB - The passionate study of the complex and ever-evolving discipline of organic synthesis over more than a four-decade span is certain to elucidate meaningful and significant lessons. Over this period, Amos B. Smith III, the Rhodes-Thompson Professor of Chemistry and Member of the Monell Chemical Senses Center at the University of Pennsylvania, has mentored well over 100 doctoral and masters students, more than 200 postdoctoral associates and numerous undergraduates, in addition to collaborating with a wide spectrum of internationally recognized scholars. His research interests, broadly stated, comprise complex molecule synthesis, the development of new, versatile and highly effective synthetic methods, bioorganic and medicinal chemistry, peptide mimicry chemistry and material science. Each area demands a high level of synthetic design and execution. United by a passion to unlock the secrets of organic synthesis, and perhaps of Nature itself, innumerable lessons have been, and continue to be, learned by the members of the Smith Group. This lead article in a Special Issue of the Journal of Antibiotics affords an opportunity to share some of those lessons learned, albeit a small selection of personal favorites. PMID- 26932410 TI - [Not Available]. PMID- 26932409 TI - Anti-obesity activities of the yoshinone A and the related marine gamma-pyrone compounds. PMID- 26932411 TI - Editorial: mongersen in Crohn's disease--a new contribution to the beginning of a long-awaited therapeutic revolution? PMID- 26932412 TI - Letter: new treatments for hepatitis C have implications for quality of life in people who inject drugs. PMID- 26932413 TI - Letter: new treatments for hepatitis C have implications for quality of life in people who inject drug--authors' reply. PMID- 26932414 TI - Letter: safety and efficacy of sofosbuvir plus daclatasvir with ribavirin for 12 weeks in Chinese treatment-experienced cirrhotic genotype 1b patients with HCV. PMID- 26932415 TI - Letter: could sequential therapy extended to 14 days replace prolonged triple regimens for Helicobacter pylori treatment? PMID- 26932416 TI - Letter: could sequential therapy extended to 14 days replace prolonged triple regimens for Helicobacter pylori treatment? Authors' reply. PMID- 26932417 TI - Letter: lessons from the 'real-world' entecavir therapy in chronic hepatitis B patients. PMID- 26932418 TI - Letter: lessons from the 'real-world' entecavir therapy in chronic hepatitis B patients--authors' reply. PMID- 26932419 TI - Letter: orlistat as a potential treatment for chronic idiopathic constipation. PMID- 26932420 TI - Attorney Questions Predict Jury-eligible Adult Assessments of Attorneys, Child Witnesses, and Defendant Guilt. AB - Children are often the primary source of evidence in maltreatment cases, particularly cases of child sexual abuse, and may be asked to testify in court. Although best-practice protocols for interviewing children suggest that interviewers ask open-ended questions to elicit detailed responses from children, during in-court testimony, attorneys tend to rely on closed-ended questions that elicit simple (often "yes" or "no") responses (e.g., Andrews, Lamb, & Lyon, ; Klemfuss, Quas, & Lyon, ). How then are jurors making decisions about children's credibility and ultimately the case outcome? The present study examined the effect of two attorney-specific factors (e.g., temporal structure and questioning phase) on mock jurors' perceptions of attorney performance, child witness credibility, storyline clarity, and defendant guilt. Participants were randomly assigned to read a trial excerpt from one of eight conditions and were then asked to evaluate the attorney, child witness, and the case. Selected excerpts were from criminal court case transcripts and contained either high attorney temporal structure (e.g., use of temporal markers) or low temporal structure (e.g., frequent topic switching), involved direct or cross-examination, and represented cases resulting in a conviction or acquittal. Child responses were kept consistent across all excerpts. Results showed that participants perceived the attorney's performance and child's credibility more favorably and thought the storyline was clearer when attorneys provided high rather than low temporal structure and when the excerpt contained direct rather than cross-examination. Participants who read a direct rather than cross-examination excerpt were also more likely to think the defendant was guilty. The study highlights the impact of attorney questioning style on mock jurors' perceptions. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26932422 TI - On Patients Who Purchase Organ Transplants Abroad. AB - The international transplant community portrays organ trade as a growing and serious crime involving large numbers of traveling patients who purchase organs. We present a systematic review about the published number of patients who purchased organs. With this information, we discuss whether the scientific literature reflects a substantial practice of organ purchase. Between 2000 and 2015, 86 studies were published. Seventy-six of these presented patients who traveled and 42 stated that the transplants were commercial. Only 11 studies reported that patients paid, and eight described to what or whom patients paid. In total, during a period of 42 years, 6002 patients have been reported to travel for transplantation. Of these, only 1238 were reported to have paid for their transplants. An additional unknown number of patients paid for their transplants in their native countries. We conclude that the scientific literature does not reflect a large number of patients buying organs. Organ purchases were more often assumed than determined. A reporting code for transplant professionals to report organ trafficking networks is a potential strategy to collect and quantify cases. PMID- 26932421 TI - Expression of the energy substrate transporters in uterine fibroids. AB - Proliferating cells exhibit accelerated rates of substrate utilization, favoring glucose over fatty acids (FA's) oxidation. Protein-mediated transport is thought to play a predominant role in facilitating either glucose or FA routing into the cells. In the present study, we examined the expression of glucose transporters (GLUT-1, GLUT-4) and fatty acids transporters (FAT/CD36, FATP-1, FATP-4) at transcript and protein levels as well as cytosolic fatty acid binding proteins (H FABP, ACBP) in human fibroids (n=74, size up to 3cm diameter) and compared with pair-matched healthy myometrium. Additionally lipid content (diacylglycerols, triacylglycerols and ceramide) was estimated by gas liquid chromatography (GLC). Uterine fibroids displayed decreased expression of both FAT/CD36 and FATP-1 proteins along with lower diacylglycerol (DAG) and triacylglycerol (TAG) content as compared to healthy pair-matched myometrium. The expression of glucose transport proteins (GLUT-4 and GLUT-1) remained relatively constant, although the higher expression of GLUT-1 in uterine fibroids did not reach the minimum significance threshold (p=0.056). However, no change in either cytochrome c oxidase (COX IV) or hydroxyacyl-CoA dehydrogenase (HADHSC) was observed and these data confirm a possible metabolic shift favoring glucose utilization over fatty acid oxidation in human uterine fibroids. PMID- 26932423 TI - Man-made molecular machines: membrane bound. AB - Nature's molecular machines are a constant source of inspiration to the chemist. Many of these molecular machines function within lipid membranes, allowing them to exploit potential gradients between spatially close, but chemically distinct environments to fuel their work cycle. Indeed, the realisation of such principles in synthetic transmembrane systems remains a tantalising goal. This tutorial review opens by highlighting seminal examples of synthetic molecular machines. We illustrate the importance of surfaces for facilitating the extraction of work from molecular switches and motors. We chart the development of man-made transmembrane systems; from passive to machine-like stimuli-responsive channels, to fully autonomous transmembrane molecular machines. Finally, we highlight higher-order compartmentalised systems that exhibit emergent properties. We suggest that such higher-order architectures could serve as platforms for sophisticated devices that co-ordinate the activity of numerous transmembrane molecular machines. PMID- 26932424 TI - Acute hypoxic-ischemia in cardiac arrest encephalopathy causes only minimal demyelination. AB - The underlying pathological process of "ischemic leukoencephalopathy" is not well studied in humans and "demyelination" is thought to represent a major component. We selected brains from autopsy cases with definite histories of recent cardiac arrest, in which the autopsy findings demonstrated gray matter ischemic changes consistent with the survival time. We excluded cases with clinical or pathological evidence of other diseases that may affect the white matter, specifically those with moderate-severe edema. The selected cases were then subjected to a review of the gross pathology (photographs) and microscopy. We used the normal white matter areas in the same brains as internal controls to exclude artefactual changes. Sixteen cases were selected. The pathological changes in acute ischemic leukoencephalopathy include: white matter pallor with separation of myelinated fibers and fine vacuoles, coarse vacuoles with or without attenuated axons, apoptotic nuclei, axonal abnormalities, focal scattered demyelinated axons and infarcts. The interpretation of these findings is controversial (i.e. ischemia, edema, artifact or combination) due to the postmortem nature of the specimens. However, these factors should not affect our interpretation of minimal demyelination in the pathological process. The major underlying pathological process in acute ischemic leukoencephalopathy is axonal degeneration, while demyelination represents only a minor component. PMID- 26932425 TI - Sonic hedgehog signaling pathway and gallbladder cancer: targeting with precision medicine approach. PMID- 26932426 TI - Targeting the hedgehog pathway for gallbladder cancer therapy? AB - Gallbladder carcinoma is a fatal malignancy of hepatobiliary tract that is generally diagnosed at advanced stages of cancer because of its asymptomatic nature. Advanced GBC tumors are unresectable with poor prognosis. Improvement in GBC patient care requires better understanding of the biological signaling pathways and application of newly discovered drugs for cancer therapy. Herein, we discuss the possibilities and challenges in targeting the hedgehog pathway in gallbladder cancer therapy based on recent developments in the area. PMID- 26932427 TI - The effects of illness beliefs and chemotherapy impact on quality of life in Japanese and Dutch patients with breast or lung cancer. AB - BACKGROUND: Responses to diagnosis and treatment of cancer are mediated by a patient's illness perceptions. Such perceptions, though different among individuals, may be culturally dependent, and act upon health related quality of life (HRQOL). Over time, individual patients show different types of response trajectories. Four issues were investigated: (I) country and disease differences in illness beliefs between Japanese and Dutch patients with lung or breast cancer; (II) country and disease differences in HRQOL in early chemotherapy; (III) individual, country, and disease differences among HRQOL trajectories; (IV) the impact of illness beliefs on HRQOL trajectories. METHODS: A total of 89 Japanese and Dutch patients with lung or breast cancer cooperated immediately before, one week after, and eight weeks after the start of chemotherapy. Data included the EORTC QLQ-C30 quality of life (QL) questionnaire and the Brief Illness Perception Questionnaire (B-IPQ). EORTC QLQ-C30 scales were summarized by two dimensions: generalized quality of life (GENQOL) and psychological well-being (PSYQOL). RESULTS: (I) Japanese patients had higher means on B-IPQ's concern and time line than Dutch patients. Japanese lung cancer patients had a higher mean on treatment control than all other patients; (II) no differences between country and cancer type occurred on the two HRQOL dimensions. First assessment HRQOL differed significantly from the second and third assessments without differences between the latter two. Between the first two assessments, a decrease in GENQOL occurred, together with an improvement in PSYQOL; (III) individual differences dominated the trajectories; (IV) negative beliefs usually coincided with lower scores on GENQOL and PSYQOL. Patients initially lower on PSYQOL generally showed larger improvement. CONCLUSIONS: Individual differences in HRQOL dominate differences between culture and cancer type, and illness beliefs influence HRQOL changes in individual patients. Clinical application is possible through influencing the patient's illness beliefs to create an optimal starting position for chemotherapy. PMID- 26932428 TI - Neuroendocrine tumors (NETs) of unknown primary: is early surgical exploration and aggressive debulking justifiable? AB - BACKGROUND: Neuroendocrine tumors (NETs) are rare tumors that often present with vague symptoms. Identification and localization of the primary NET can be challenging and the true incidence remains unclear. These patients have been thought to have a poor prognosis compared to those patients with a known primary. Therefore, traditionally the treatments for patients with unknown primaries have been passive and directed towards symptom control and/or cytoreduction of metastatic disease. We hypothesized that NET of unknown primary are predominantly low-grade and easily located surgically and therefore are amendable to surgical debulking and cytoreduction, which will likely increase survival in these patients. METHODS: The charts for all 342 surgical patients, seen in our clinic at Ochsner-Kenner between 1/2009 and 9/2012 were retrospectively reviewed to determine which patients had a pre-operative diagnosis of a "NET with unknown primary". Twenty-two patients (6.4%) were identified. For these patients, the rate of successful surgical exploration in which a primary site was identified was recorded. Survival for these "unknown primary" patients were compared to a large similar group of NET patients from a recent study collected from this same Ochsner clinic group. RESULTS: Twenty-two (22/342, 6.4%) NET patients with a pre operative diagnosis of an unknown primary were explored and cytoreduced. The primary tumor site was identified in all 22 patients (100%). The primary sites identified for these patients were 19 small intestines (86.4%) and 3 pancreatic (13.6%). All 22 patients had low-grade tumors and all were still alive as of 9/2012, not allowing for a survival curve to be generated. CONCLUSIONS: Unknown primary NETs are not associated with a poor prognosis as previously reported. Timely surgical exploration and debulking always results in the identification of the primary and a maximum cytoreduction. Early surgical exploration with aggressive debulking is indicated for the treatment of these patients, as for the known counterpart. PMID- 26932429 TI - Harnessing the innate immune system to treat cancer: enhancement of antibody dependent cellular cytotoxicity with anti-CD137 Ab. PMID- 26932430 TI - beta-catenin and SKP2 proteins as predictors of grade and stage of non-muscle invasive urothelial bladder carcinoma. AB - BACKGROUND: To evaluate the expression of beta-catenin (beta-catenin) and SKP2 proteins in superficial bladder cancer cases and their correlation with tumor grade and stage. METHODS: After institutional review board approval, we retrospectively evaluated the expression of beta-catenin and SKP2 proteins in tissue specimens from patients with non-muscle invasive bladder cancer (NMIBC) and compared their results with a cohort of chronic nonspecific cystitis's. Then we and explored these markers association with tumor grade and stage. RESULTS: A total of 40 patients were retrospectively identified, 50% was NMIBC and the rest were chronic nonspecific cystitis. beta-catenin was expressed in 18 (90%) patients of the NMIBC group in comparison to 14 (70%) of the control group with (P=0.1), while SKP2 protein was only expressed in NMIBC groups (P=0.03). A statistically significant correlation was identified between nucleocytoplasmic localization of beta-catenin and SKP2 with tumor grade, stage. CONCLUSIONS: beta catenin and SKP2 expression are providing promising results for differentiating higher grade and stage non muscle invasive bladder cancers. PMID- 26932431 TI - The supportive care needs for prostate cancer patients in Sarawak. AB - BACKGROUND: This cross-sectional study aimed to determine the prevalence of unmet supportive care needs among prostate cancer patients. METHODS: The cross sectional study was conducted among all prostate cancer patients at the Sarawak General Hospital. Interview was done using the Supportive Care Needs Survey-Short Form (SCNS-SF) and the Health Service Utilization Questionnaires (HSUQ). Data were analysed using Statistical Package for the Social Sciences (SPSS) 20. RESULTS: A total of ninety-five patients participated, with majority were aged 65 and above and of primary educational level. The two most frequently reported unmet supportive care needs were "informed about cancer which is under control or diminishing" and "informed about things you can do to help yourself to get well" under the domain Health System and Information. Respondents who were older (65 years and above) had significant lower unmet needs in psychology (P<0.01), and sexuality compared to the younger group below 65 years (P<0.01). Except for physical and daily living, respondents with primary school level had significant lower unmet needs in all domains compared to secondary school level. Respondents with known stages of cancer had higher unmet needs in all domains compared to those who did not know. CONCLUSIONS: Healthcare providers should provide more responsive, emotionally sensitive and client-centered care to patients with prostate cancer, particularly in the area of Health System and Information, and psychological support. PMID- 26932432 TI - Anticipatory extended cholecystectomy: the 'Lucknow' approach for thick walled gall bladder with low suspicion of cancer. AB - BACKGROUND: Gall stones (GS) cause inflammation of the gall bladder (GB) i.e., chronic cholecystitis (CC) and xantho-granulomatous cholecystitis (XGC) which can result in a thick walled GB (TWGB). Gall bladder cancer (GBC) may also present as TWGB. While CC and XGC can be treated with simple cholecystectomy (SC), GBC merits extended cholecystectomy (EC). We propose a new surgical approach, anticipatory extended cholecystectomy (AEC), for doubtful TWGB in the belief that AEC would not violate the sacrosanct cholecysto-hepatic plane in doubtful cases and thereby not ruin the chances of cure for a patient whose GB demonstrates malignancy on frozen section histopathology. The addition of lymphadenectomy in cases which turn out to be malignant completes the procedure for GB cancer, but spares all problems related to lymphadenectomy in an undeserving patient. METHODS: AEC involves removal of GB with a 2-cm wedge of liver, which is then subjected to frozen section histological examination. Lymphadenectomy is performed if GBC is confirmed. AEC was performed in 13 patients between January 2011 and June 2014. During the same period, 1,673 SC for CC/XGC and 116 EC for GBC were performed. RESULTS: All patients were symptomatic for GS (3 with acute cholecystitis). Ultrasonography (US) raised suspicion of GBC in 11 patients. CT raised suspicion of GBC in 9 patients. Preoperative FNAC was done in 2 patients; in 1 it was negative and in 1 it was suspicious for malignancy. Preoperative diagnosis was GBC in 8, TWGB in 2, XGC, porcelain GB and GB perforation in 1 each. AEC and frozen section was done in all 13 patients. It was reported as GBC in 2 patients and as suspicious of GBC in 1 patient; lymphadenectomy was performed in these 3 patients. Final histopathology revealed XGC in 9, CC in 2 and GBC in 2 patients. CONCLUSIONS: In patients with TWGB on US/ CT with low suspicion of cancer, AEC serves as a triage-if frozen section biopsy turns out to be positive for GBC, AEC can be completed to EC by performing lymphadenectomy. We wish to name this approach as the 'Lucknow' approach for TWGB. PMID- 26932433 TI - Surgical management of intrahepatic cholangiocarcinoma in the modern era: advances and challenges. AB - Intrahepatic cholangiocarcinoma (ICC) is one of the few gastrointestinal cancers with increasing incidence and mortality worldwide. Unlike hepatocellular carcinoma (HCC) which arises usually in a cirrhotic environment ICC frequently arises in the context of normal hepatic parenchyma. Surgical resection represents the mainstay of curative treatment, with minimally invasive approaches being increasingly utilized. Despite good surgical outcomes, most patients suffer from disease recurrence and eventually succumb to their disease. Effective adjuvant treatments are therefore needed. For unresectable disease hepatic artery utilization techniques are becoming more widely used. New treatments for non metastatic disease such as proton beam therapy (PBT) are also emerging. Systemic chemotherapy is also changing and targeted biologic agents are being added to conventional chemotherapeutic agents. PMID- 26932434 TI - Phase III design: principles. AB - Phase III clinical trials are the gold standard to demonstrate the effects of an experimental therapy compared to standard therapy for a disease of interest. The first step when planning a phase III trial is to specify the statistical hypothesis that the trial purports to test, which is usually that the experimental therapy provides some efficacy benefit over standard therapy, without adding significant harm. In a phase III trial, a pre-specified number of patients from the target population are randomized to receive experimental or standard therapy. The patients are treated and followed up according to a protocol that also defines the endpoints of interest, in particular the primary endpoint which is chosen to reflect a clinical benefit of experimental therapy over standard therapy. The trial data are typically monitored by an independent committee who may recommend stopping the trial early, if appropriate. The benefit of experimental therapy over standard therapy, if any, may be observed across all patients, or may be confined to a subset of patients. PMID- 26932435 TI - Statistical aspect of translational and correlative studies in clinical trials. AB - In this article, we describe statistical issues related to the conduct of translational and correlative studies in cancer clinical trials. In the era of personalized medicine, proper biomarker discovery and validation is crucial for producing groundbreaking research. In order to carry out the framework outlined in this article, a team effort between oncologists and statisticians is the key for success. PMID- 26932436 TI - Chinese guidelines on the management of renal cell carcinoma (2015 edition). PMID- 26932437 TI - CROSS and beyond: a clinical perspective on the results of the randomized ChemoRadiotherapy for Oesophageal cancer followed by Surgery Study. AB - Despite extensive research efforts oesophageal cancer remains a malignancy with a poor prognosis. Improvement of treatment is urgently needed. Although multimodality treatment for resectable oesophageal cancer has established it place in standard practice, there are still many differences worldwide in the preferred treatment. The Dutch ChemoRadiotherapy for Oesophageal cancer followed by Surgery Study (CROSS) trial has contributed significantly to the current use of neoadjuvant chemoradiation. This study compared neoadjuvant chemoradiotherapy (CRT) using a moderate radiation dose weekly combined with carboplatin and paclitaxel followed by surgery versus surgery alone. Median overall survival in the CRT group is 49.4 months compared to 24.0 months in the surgery alone group, resulting in an overall survival benefit of 13% in favor of the CRT group (HR, 0.81; 95% CI: 0.70-0.93; P=0.002). Recently the results after long-term follow-up (median 60 months) have been published and confirm the benefit of neoadjuvant CRT to surgery alone. Perioperative mortality rates are low and did not increase by adding CRT (4%) and the CROSS scheme has a favorable toxicity profile. Recurrence patterns in patients treated according to the CROSS protocol report significantly reduced loco regional recurrence in the CRT group (34% to 14%; P<0.001) and less peritoneal carcinomatosis (14% to 4%; P<0.001). With the contemporary focus of research on tumor tailored therapy, the effective and safe CROSS protocol serves as a backbone in many ongoing trials. PMID- 26932438 TI - Development and Initial Evaluation of the Web-Based Self-Management Program "Partner in Balance" for Family Caregivers of People With Early Stage Dementia: An Exploratory Mixed-Methods Study. AB - BACKGROUND: People with dementia increasingly depend on informal caregivers. Internet-based self-management interventions hold considerable promise for meeting the educational and support needs of early stage dementia caregivers (EDCs) at a reduced cost. OBJECTIVE: This study aimed to (1) develop an online self-management program for EDC to increase self-efficacy and goal attainment, and (2) evaluate the program's feasibility and report preliminary data on effectiveness. METHODS: Based on the Medical Research Council (MRC) framework for the development and evaluation of complex interventions, a stepwise approach was adopted to explore potential user needs and develop and validate the content by means of (1) focus group discussions with dementia caregivers (N=28), (2) interviews with dementia care professionals (N=11), and (3) individual think aloud usability tests with EDC (N=2) and experts (N=2). A pilot evaluation was conducted with EDC (N=17) to test the feasibility and establish preliminary effects. Self-report measures of feasibility were completed after the completion of intervention. Self-efficacy and goal attainment were evaluated before and after the intervention. RESULTS: The different steps provided useful information about the needs of potential users regarding the content and delivery of the program. This resulted in the newly developed "Partner in Balance" program. At the start, system failures resulted in a high noncompleter rate (7/17, 41%), but at the end, an acceptable feasibility score of 209 (range 54-234) was found. The convenience of completing the program at home, the tailored content, and the guidance (face-to-face and online) were appraised positively. Preliminary effects on caregiver self-efficacy (P<.05) and goal attainment (T>50) were promising. CONCLUSIONS: Adaptations were made to the program to limit the amount of system failures and prevent high noncompleter rates. As recommended by the MRC framework, confirming the feasibility and preliminary effectiveness is a valuable step toward examining the effectiveness of this newly developed intervention. TRIAL REGISTRATION: Dutch Trial Register (NTR): NTR4217; http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=4217 (Archived by WebCite at http://www.webcitation.org/6f6B8lvRP). PMID- 26932439 TI - GSG1L suppresses AMPA receptor-mediated synaptic transmission and uniquely modulates AMPA receptor kinetics in hippocampal neurons. AB - Regulation of AMPA receptor (AMPAR)-mediated synaptic transmission is a key mechanism for synaptic plasticity. In the brain, AMPARs assemble with a number of auxiliary subunits, including TARPs, CNIHs and CKAMP44, which are important for AMPAR forward trafficking to synapses. Here we report that the membrane protein GSG1L negatively regulates AMPAR-mediated synaptic transmission. Overexpression of GSG1L strongly suppresses, and GSG1L knockout (KO) enhances, AMPAR-mediated synaptic transmission. GSG1L-dependent regulation of AMPAR synaptic transmission relies on the first extracellular loop domain and its carboxyl-terminus. GSG1L also speeds up AMPAR deactivation and desensitization in hippocampal CA1 neurons, in contrast to the effects of TARPs and CNIHs. Furthermore, GSG1L association with AMPARs inhibits CNIH2-induced slowing of the receptors in heterologous cells. Finally, GSG1L KO rats have deficits in LTP and show behavioural abnormalities in object recognition tests. These data demonstrate that GSG1L represents a new class of auxiliary subunit with distinct functional properties for AMPARs. PMID- 26932441 TI - Aberrant Myeloid Differentiation Contributes to the Development of Osteoporosis in Neurofibromatosis Type 1. AB - Neurofibromatosis type 1 (NF1), also known as von Recklinghausen disease, is a common autosomal dominant genetic disorder affecting approximately 1 in 3000 individuals worldwide. NF1 results from heritable or spontaneous mutations of the NF1 tumor suppressor gene. NF1 encodes the protein neurofibromin, which functions to negatively regulate Ras-activity. Approximately 50 % of NF1 patients develop osteopenia or osteoporosis, resulting in significantly increased rates of long bone fracture and morbidity. While defective osteoblast bone anabolism has been implicated as a central factor in the pathogenesis of NF1 associated skeletal deficits, recent data suggest that NF1 (Nf1) haploinsufficiency within the hematopoietic compartment, particularly in osteoclasts and myeloid progenitors, plays a pivotal role in engendering NF1 osseous manifestations. In this chapter, we review the latest data from clinical studies and murine models delineating a critical role for hematopoietic compartment, myeloid progenitors of NF1 (Nf1) haploinsufficient and their progeny-osteoclasts, in the pathogenesis of NF1 associated osteopenia/osteoporosis and discuss putative targets for future therapeutics. PMID- 26932442 TI - Discovery of hantavirus circulating among Rattus rattus in French Mayotte island, Indian Ocean. AB - Hantaviruses are emerging zoonotic viruses that cause human diseases. In this study, sera from 642 mammals from La Reunion and Mayotte islands (Indian Ocean) were screened for the presence of hantaviruses by molecular analysis. None of the mammals from La Reunion island was positive, but hantavirus genomic RNA was discovered in 29/160 (18 %) Rattus rattus from Mayotte island. The nucleoprotein coding region was sequenced from the liver and spleen of all positive individuals allowing epidemiological and intra-strain variability analyses. Phylogenetic analysis based on complete coding genomic sequences showed that this Murinae associated hantavirus is a new variant of Thailand virus. Further studies are needed to investigate hantaviruses in rodent hosts and in Haemorrhagic Fever with Renal Syndrome (HFRS) human cases. PMID- 26932443 TI - Cancel the denosumab holiday. PMID- 26932444 TI - Sarcocystis masoni, n. sp. (Apicomplexa: Sarcocystidae), and redescription of Sarcocystis aucheniae from llama (Lama glama), guanaco (Lama guanicoe) and alpaca (Vicugna pacos). AB - There is considerable confusion concerning the species of Sarcocystis in South American camelids (SAC). Several species names have been used; however, proper descriptions are lacking. In the present paper, we redescribe the macroscopic sarcocyst forming Sarcocystis aucheniae and describe and propose a new name, Sarcocystis masoni for the microscopic sarcocyst forming species. Muscles samples were obtained from llamas (Lama glama) and guanacos (Lama guanicoe) from Argentina and from alpacas (Vicugna pacos) and llamas from Peru. Individual sarcocysts were processed by optical and electron microscopy, and molecular studies. Microscopic sarcocysts of S. masoni were up to 800 um long and 35-95 um wide, the sarcocyst wall was 2.5-3.5 um thick, and had conical to cylindrical villar protrusions (vp) with several microtubules. Each vp had 11 or more rows of knob-like projections. Seven 18S rRNA gene sequences obtained from sarcocysts revealed 95-96% identity with other Sarcocystis spp. sequences reported in the GenBank. Sarcocysts of S. aucheniae were macroscopic, up to 1.2 cm long and surrounded by a dense and laminar 50 um thick secondary cyst wall. The sarcocyst wall was up to 10 um thick, and had branched vp, appearing like cauliflower. Comparison of the 11 sequences obtained from individual macroscopic cysts evidenced a 98-99% of sequence homology with other S. aucheniae sequences. In conclusion, 2 morphologically and molecularly different Sarcocystis species, S. masoni (microscopic cysts) and S. aucheniae (macroscopic cysts), were identified affecting different SAC from Argentina and Peru. PMID- 26932445 TI - How to support patients who are crying in palliative home care: an interview study from the nurses' perspective. AB - Aim The aim of this study was to explore how nurses can support patients who are crying in a palliative home care context. BACKGROUND: In palliative care the nurse has a central role in the team whose duty it is to create a sense of security and trust, as well as to give comfort and support the patients. The nurse's responsibility is to identify different needs of the patients for support and develop a relationship with them. Patients may express their pain, anxiety, fear and suffering by crying. No studies have been found which focus on how nurses can support patients who are crying in different ways and crying for different reasons. METHODS: A qualitative explorative study was performed. Semi structured interviews were held with eight nurses aged 32-63 years (Median 40) working in Swedish palliative home care. The data were analysed using Qualitative Content analysis. Findings It was reported that the nurse should meet and confirm the patient during different types of crying episodes and should also be able to alternate between being close and physically touching the in such close contact with the patients, the nurse can provide emotional support by showing empathy, merely being present and letting the patients cry as much as they want. When the crying finally stops, the nurse can support the person by speaking with them, showing sensitivity, humility and respect for the patient's wishes. A few examples of the patients' need for information or practical support emerged. The nurse can emotionally support the person who is crying by just being present, confirming, showing empathy, offering a chance to talk and showing respect for their individual needs and the different ways they may cry. PMID- 26932447 TI - [Evaluation of sulfur status in dairy cows in Germany]. AB - OBJECTIVE: Sulfur deficiency and toxicity in livestock is associated with decreased performance and diseases. However, little is known about the diagnostics of sulfur status in dairy herds. The objectives of this study were to describe sulfur concentrations in feed rations in German dairy herds, to assess associations between feed sulfur concentrations and health and milk yield, to determine suitable laboratory diagnostic methods of sulfur status, and to propose reference values for the assessment of sulfur status in different sample media. MATERIALS AND METHODS: Between 2006 and 2014, a total of 569 dairy herds were visited. Blood, urine, and hair samples were obtained from 10 animals per group in the groups -3 to 0, 0 to 1, 3 to 5, and 15 to 18 weeks post partum (p. p.) (farms > 200 animals) or -3 to 0, 0 to 5, and 6 to 20 weeks p. p. (farms <= 200 animals). Pooled whole blood, serum, plasma, urine, and hair samples (n = 5663) were analyzed by ICP-OES. The sulfur content of the total mixed ration (TMR) of the group -3 to 0 weeks p. p. was determined in a certified feed laboratory (n = 625). Data analyses were performed using ANOVA, Chi-squared test and Spearman correlation. Reference values were determined using the 2.5% and 97.5% percentiles. RESULTS: Median sulfur concentration in the feed rations was 2.3 g/kg dry matter (DM). Deficiency (< 1.6 g/kg DM; 31% of farms) and oversupply (> 4.0 g/kg DM; 11% of farms) of sulfur in feed rations were regularly diagnosed. Sulfur deficiency was associated with reduced milk yield (p < 0.001), retained placenta (OR = 1.74; p = 0.037), milk fever (OR = 2.68; p < 0.001) and silent heat (OR = 2.56; p = 0.014). Positive correlations were found between sulfur concentration in feed rations and sulfur content in urine (r = 0.50), serum (r = 0.17), plasma (r = 0.18) and whole blood (r = 0.16). Reference values for sulfur diagnostics in dairy herds were proposed. CONCLUSION AND CLINICAL RELEVANCE: Diagnostics of sulfur status in dairy herds is relevant for veterinary practitioners and can be performed using TMR analysis and clinical laboratory parameters. Urine can be considered a short-term parameter, serum, plasma, and whole blood as intermediate parameters, and hair as a long-term parameter for the evaluation of the sulfur status. PMID- 26932446 TI - Type VI adenylyl cyclase negatively regulates GluN2B-mediated LTD and spatial reversal learning. AB - The calcium-sensitive type VI adenylyl cyclase (AC6) is a membrane-bound adenylyl cyclase (AC) that converts ATP to cAMP under stimulation. It is a calcium inhibited AC and integrates negative inputs from Ca(2+) and multiple other signals to regulate the intracellular cAMP level. In the present study, we demonstrate that AC6 functions upstream of CREB and negatively controls neuronal plasticity in the hippocampus. Genetic removal of AC6 leads to cyclase independent and N-terminus of AC6 (AC6N)-dependent elevation of CREB expression, and enhances the expression of GluN2B-containing NMDA receptors in hippocampal neurons. Consequently, GluN2B-dependent calcium signaling and excitatory postsynaptic current, long-term depression, and spatial reversal learning are enhanced in the hippocampus of AC6(-/-) mice without altering the gross anatomy of the brain. Together, our results suggest that AC6 negatively regulates neuronal plasticity by modulating the levels of CREB and GluN2B in the hippocampus. PMID- 26932448 TI - Spatiotemporal modeling of microbial metabolism. AB - BACKGROUND: Microbial systems in which the extracellular environment varies both spatially and temporally are very common in nature and in engineering applications. While the use of genome-scale metabolic reconstructions for steady state flux balance analysis (FBA) and extensions for dynamic FBA are common, the development of spatiotemporal metabolic models has received little attention. RESULTS: We present a general methodology for spatiotemporal metabolic modeling based on combining genome-scale reconstructions with fundamental transport equations that govern the relevant convective and/or diffusional processes in time and spatially varying environments. Our solution procedure involves spatial discretization of the partial differential equation model followed by numerical integration of the resulting system of ordinary differential equations with embedded linear programs using DFBAlab, a MATLAB code that performs reliable and efficient dynamic FBA simulations. We demonstrate our methodology by solving spatiotemporal metabolic models for two systems of considerable practical interest: (1) a bubble column reactor with the syngas fermenting bacterium Clostridium ljungdahlii; and (2) a chronic wound biofilm with the human pathogen Pseudomonas aeruginosa. Despite the complexity of the discretized models which consist of 900 ODEs/600 LPs and 250 ODEs/250 LPs, respectively, we show that the proposed computational framework allows efficient and robust model solution. CONCLUSIONS: Our study establishes a new paradigm for formulating and solving genome-scale metabolic models with both time and spatial variations and has wide applicability to natural and engineered microbial systems. PMID- 26932449 TI - Racial/Ethnic Pay Disparities among Registered Nurses (RNs) in U.S. Hospitals: An Econometric Regression Decomposition. AB - OBJECTIVE: To detect the presence of racial and ethnic pay disparities between minority and white hospital RNs using a national sample. DATA SOURCES/STUDY SETTING: The National Sample Survey of Registered Nurses, 2008, which is representative at both the state and national level. STUDY DESIGN: Cross sectional data were analyzed using multivariate regression and regression decomposition. Differences between groups were decomposed into differences in the possession of characteristics and differences in the value of the same characteristic between different groups, the latter being a commonly used measure of wage discrimination. DATA COLLECTION/EXTRACTION METHODS: As the majority of minority hospital RNs are employed within the most densely populated (central) counties of metropolitan statistical areas (MSAs), only hospital RNs employed in the central counties of MSAs were selected. PRINCIPAL FINDINGS: Regression decomposition found that black and Hispanic RNs earned less than whites and Asians, while Asian RNs earned more than white RNs. The majority of pay variation between white RNs, versus Asian, black, or Hispanic RNs was due to unexplained differences in the value of the same characteristic between groups. CONCLUSIONS: Differences in earnings between underrepresented and overrepresented hospital RNs is suggestive of discrimination. PMID- 26932450 TI - Premature termination codons in modern human genomes. AB - The considerable range of genetic variation in human populations may partly reflect distinctive processes of adaptation to variable environmental conditions. However, the adaptive genomic signatures remain to be completely elucidated. This research explores candidate loci under selection at the population level by characterizing recently arisen premature termination codons (PTCs), some of which indicate a human knockout. From a total of 7595 participants from two population exome projects, 246 PTCs were found where natural selection has resulted in new alleles with a high frequency (from 1% to 96%) of derived alleles and various levels of population differentiation (FST = 0.00139-0.626). The PTC genes formed protein and regulatory networks limited to 15 biological processes or gene families, of which seven categories were previously unreported. PTC mutations have a strong tendency to be introduced into members of the same gene family, even during modern human evolution, although the exact nature of the selection is not fully known. The findings here suggest the ongoing evolutionary plasticity of modern humans at the genetic level and also partly provide insights into common human knockouts. PMID- 26932451 TI - Clinical and epidemiological features of the 2014 large-scale dengue outbreak in Guangzhou city, China. AB - BACKGROUND: Dengue virus is transmitted by mosquito around the tropical and sub tropical regions. There was a large-scale dengue epidemic in Guangdong province, China during 2014 and around fifty thousands dengue fever cases, including six deaths, have been reported. In this study, we aimed to understand the clinical characteristics of hospitalized patients with laboratory-confirmed dengue virus (DENV) infection and determined the origin of the virus from the outbreak. METHODS: We have summarized the data from 138 hospitalized patients who were laboratory confirmed for dengue infection in Guangzhou city. Patients were classified as either non-severe dengue fever or severe dengue fever according to the guidelines from the WHO. Viral serotypes were determined by real time RT-PCR. Genetic sequences of the envelope and non-structural genes were amplified and analyzed from the serum samples of eleven patients. RESULTS: Co-circulation of dengue serotype 1 and 2 were identified from the outbreak. Patients infected by serotype 1 or 2 showed similar clinical features. Patients with severe dengue fever showed prolonged hospitalization and significant impairment of organ functions. Four samples from serotype 1 and five samples from serotype 2 were closely related respectively and clustered with Guangzhou isolates from previous years. The remaining isolates of serotype 1 were related to viruses found in Malaysia, India, Bangladesh and Singapore. CONCLUSION: The phylogenetic grouping of Guangdong isolates suggests that dengue is no longer an imported disease in China. Analysis of the isolates obtained in this study together with the size of the outbreak are suggestive of endemic circulation in Guangdong province. PMID- 26932452 TI - Population structure and genome characterization of local pig breeds in Russia, Belorussia, Kazakhstan and Ukraine. AB - BACKGROUND: It is generally accepted that domestication of pigs took place in multiple locations across Eurasia; the breeds that originated in Europe and Asia have been well studied. However, the genetic structure of pig breeds from Russia, Belorussia, Kazakhstan and Ukraine, which represent large geographical areas and diverse climatic zones in Eurasia, remains largely unknown. RESULTS: This study provides the first genomic survey of 170 pigs representing 13 breeds from Russia, Belorussia, Kazakhstan and Ukraine; 288 pigs from six Chinese and seven European breeds were also included for comparison. Our findings show that the 13 novel breeds tested derived mainly from European pigs through the complex admixture of Large White, Landrace, Duroc, Hampshire and other breeds, and that they display no geographic structure based on genetic distance. We also found a considerable Asian contribution to the miniature Siberian pigs (Minisib breed) from Russia. Apart from the Minisib, Urzhum, Ukrainian Spotted Steppe and Ukrainian White Steppe breeds, which may have undergone intensive inbreeding, the breeds included in this study showed relatively high genetic diversity and low levels of homozygosity compared to the Chinese indigenous pig breeds. CONCLUSIONS: This study provides the first genomic overview of the population structure and genetic diversity of 13 representative pig breeds from Russia, Belorussia, Kazakhstan and Ukraine; this information will be useful for the preservation and management of these breeds. PMID- 26932454 TI - Comparison of Thiyl, Alkoxyl, and Alkyl Radical Addition to Double Bonds: The Unusual Contrasting Behavior of Sulfur and Oxygen Radical Chemistry. AB - High-level ab initio calculations have been used to compare prototypical thiyl, alkoxyl, and alkyl radical addition reactions. Thiyl radical addition to the sulfur center of thioketones is exothermic and rapid, occurring with negative enthalpic barriers and only weakly positive Gibbs free energy barriers. In stark contrast, alkoxyl radical addition to the oxygen center of ketones is highly endothermic and occurs with very high reaction barriers, though these are also suppressed. On the basis of analysis of the corresponding alkyl radical additions to these substrates and the corresponding reactions of these heteroatom radicals with alkenes, it suggested that addition reactions involving thiyl radicals have low intrinsic barriers because their unpaired electrons are better able to undergo stabilizing resonance interactions with the pi* orbitals of the substrate in the transition state. PMID- 26932453 TI - Economic analysis of two-stage septic revision after total hip arthroplasty: What are the relevant costs for the hospital's orthopedic department? AB - BACKGROUND: The number of septic total hip arthroplasty (THA) revisions is increasing continuously, placing a growing financial burden on hospitals. Orthopedic departments performing septic THA revisions have no basis for decision making regarding resource allocation as the costs of this procedure for the departments are unknown. It is widely assumed that septic THA procedures can only be performed at a loss for the department. Therefore, the purpose of this study was to investigate whether this assumption is true by performing a detailed analysis of the costs and revenues for two-stage septic THA revision. METHODS: Patients who underwent revision THA for septic loosening in two sessions from January 2009 through March 2012 were included in this retrospective, consecutive cost study from the orthopedic department's point of view. We analyzed variable and case-fixed costs for septic revision THA with special regard to implantation and explantation stay. By using marginal costing approach we neglected hospital fixed costs. Outcome measures include reimbursement and daily contribution margins. RESULTS: The average direct costs (reimbursement) incurred for septic two-stage revision THA was ?10,828 (?24,201). The difference in cost and contribution margins per day was significant (p < .001 and p = 0.019) for ex- and implantation (?4147 vs. ?6680 and ?429 vs. ?306) while length of stay and reimbursement were comparable. CONCLUSIONS: This is the first detailed analysis of the hospital department's cost for septic revision THA performed in two sessions. Disregarding hospital-fixed costs the included variable and case fixed costs were covered by revenues. This study provides cost data, which will be guidance for health care decision makers. PMID- 26932455 TI - Few-layered MoS2 nanosheets wrapped ultrafine TiO2 nanobelts with enhanced photocatalytic property. AB - Photocatalytic materials comprised of semiconductor nanostructures have attracted tremendous scientific and technological interest over the last 30 years. This is due to the fact that these photocatalytic materials have unique properties that allow for an effective direct energy transfer from light to highly reactive chemical species which are applicable in the remediation of environmental pollutants and photocatalytic hydrogen generation. Heterostructured photocatalysts are a promising type of photocatalyst which can combine the properties of different components to generate a synergic effect, resulting in a high photocatalytic activity. In this work, a heterostructured photocatalyst comprised of few-layered MoS2 nanosheets coated on a TiO2 nanobelts surface was synthesized through a simple hydrothermal treatment. The hybrid heterostructures with enhanced broad spectrum photocatalytic properties can harness UV and visible light energy to decompose organic contaminants in aqueous solutions as well as split water to hydrogen and oxygen. The mechanism of the enhancement is that the MoS2/TiO2 nanobelts heterostructure can enhance the separation of the photo induced carriers, which results in a higher photocurrent due to the special electronic characteristics of the graphene-like layered MoS2 nanosheets. This methodology is potentially applicable to the synthesis of a range of hybrid nanostructures with promising applications in photocatalysis and other relevant areas. PMID- 26932458 TI - The In-Gap Electronic State Spectrum of Methylammonium Lead Iodide Single-Crystal Perovskites. AB - The density of trap states within the bandgap of methylammonium lead iodide single crystals is investigated. Defect states close to both the conduction and valence bands are probed. Additionally, a comprehensive electronic characterization of crystals is carried out, including measurements of the electron and hole mobility, and the energy landscape (band diagram) at the surface. PMID- 26932457 TI - Molecular and biochemical characterizations of the monoacylglycerol lipase gene family of Arabidopsis thaliana. AB - Monoacylglycerol lipase (MAGL) catalyzes the last step of triacylglycerol breakdown, which is the hydrolysis of monoacylglycerol (MAG) to fatty acid and glycerol. Arabidopsis harbors over 270 genes annotated as 'lipase', the largest class of acyl lipid metabolism genes that have not been characterized experimentally. In this study, computational modeling suggested that 16 Arabidopsis putative MAGLs (AtMAGLs) have a three-dimensional structure that is similar to a human MAGL. Heterologous expression and enzyme assays indicated that 11 of the 16 encoded proteins indeed possess MAG lipase activity. Additionally, AtMAGL4 displayed hydrolase activity with lysophosphatidylcholine and lysophosphatidylethanolamine (LPE) substrates and AtMAGL1 and 2 utilized LPE as a substrate. All recombinant AtMAGLs preferred MAG substrates with unsaturated fatty acids over saturated fatty acids and AtMAGL8 exhibited the highest hydrolase activities with MAG containing 20:1 fatty acids. Except for AtMAGL4, 14 and -16, all AtMAGLs showed similar activity with both sn-1 and sn-2 MAG isomers. Spatial, temporal and stress-induced expression of the 16 AtMAGL genes was analyzed by transcriptome analyses. AtMAGL:eYFP fusion proteins provided initial evidence that AtMAGL1, -3, -6, -7, -8, -11, -13, -14 and -16 are targeted to the endoplasmic reticulum and/or Golgi network, AtMAGL10, -12 and -15 to the cytosol and AtMAGL2, -4 and -5 to the chloroplasts. Furthermore, AtMAGL8 was associated with the surface of oil bodies in germinating seeds and leaves accumulating oil bodies. This study provides the broad characterization of one of the least well-understood groups of Arabidopsis lipid-related enzymes and will be useful for better understanding their roles in planta. PMID- 26932459 TI - The fossil record of the sixth extinction. AB - Comparing the magnitude of the current biodiversity crisis with those in the fossil record is difficult without an understanding of differential preservation. Integrating data from palaeontological databases with information on IUCN status, ecology and life history characteristics of contemporary mammals, we demonstrate that only a small and biased fraction of threatened species (< 9%) have a fossil record, compared with 20% of non-threatened species. We find strong taphonomic biases related to body size and geographic range. Modern species with a fossil record tend to be large and widespread and were described in the 19(th) century. The expected magnitude of the current extinction based only on species with a fossil record is about half of that of one based on all modern species; values for genera are similar. The record of ancient extinctions may be similarly biased, with many species having originated and gone extinct without leaving a tangible record. PMID- 26932456 TI - Specific pathogen free macaque colonies: a review of principles and recent advances for viral testing and colony management. AB - Specific pathogen free (SPF) macaques provide valuable animal models for biomedical research. In 1989, the National Center for Research Resources [now Office of Research Infrastructure Programs (ORIP)] of the National Institutes of Health initiated experimental research contracts to establish and maintain SPF colonies. The derivation and maintenance of SPF macaque colonies is a complex undertaking requiring knowledge of the biology of the agents for exclusion and normal physiology and behavior of macaques, application of the latest diagnostic technology, facilitiy management, and animal husbandry. This review provides information on the biology of the four viral agents targeted for exclusion in ORIP SPF macaque colonies, describes current state-of-the-art viral diagnostic algorithms, presents data from proficiency testing of diagnostic assays between laboratories at institutions participating in the ORIP SPF program, and outlines management strategies for maintaining the integrity of SPF colonies using results of diagnostic testing as a guide to decision making. PMID- 26932460 TI - Genome engineering through CRISPR/Cas9 technology in the human germline and pluripotent stem cells. AB - BACKGROUND: With the recent development of CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 genome editing technology, the possibility to genetically manipulate the human germline (gametes and embryos) has become a distinct technical possibility. Although many technical challenges still need to be overcome in order to achieve adequate efficiency and precision of the technology in human embryos, the path leading to genome editing has never been simpler, more affordable, and widespread. OBJECTIVE AND RATIONALE: In this narrative review we seek to understand the possible impact of CRISR/Cas9 technology on human reproduction from the technical and ethical point of view, and suggest a course of action for the scientific community. SEARCH METHODS: This non-systematic review was carried out using Medline articles in English, as well as technical documents from the Human Fertilisation and Embryology Authority and reports in the media. The technical possibilities of the CRISPR/Cas9 technology with regard to human reproduction are analysed based on results obtained in model systems such as large animals and laboratory rodents. Further, the possibility of CRISPR/Cas9 use in the context of human reproduction, to modify embryos, germline cells, and pluripotent stem cells is reviewed based on the authors' expert opinion. Finally, the possible uses and consequences of CRISPR/cas9 gene editing in reproduction are analysed from the ethical point of view. OUTCOMES: We identify critical technical and ethical issues that should deter from employing CRISPR/Cas9 based technologies in human reproduction until they are clarified. WIDER IMPLICATIONS: Overcoming the numerous technical limitations currently associated with CRISPR/Cas9 mediated editing of the human germline will depend on intensive research that needs to be transparent and widely disseminated. Rather than a call to a generalized moratorium, or banning, of this type of research, efforts should be placed on establishing an open, international, collaborative and regulated research framework. Equally important, a societal discussion on the risks, benefits, and preferred applications of the new technology, including all relevant stakeholders, is urgently needed and should be promoted, and ultimately guide research priorities in this area. PMID- 26932461 TI - Akt mediated phosphorylation of LARP6; critical step in biosynthesis of type I collagen. AB - La ribonucleoprotein domain family, member 6 (LARP6) is the RNA binding protein, which regulates translation of collagen mRNAs and synthesis of type I collagen. Posttranslational modifications of LARP6 and how they affect type I collagen synthesis have not been studied. We show that in lung fibroblasts LARP6 is phosphorylated at 8 serines, 6 of which are located within C-terminal domain. Phosphorylation of LARP6 follows a hierarchical order; S451 phosphorylation being a prerequisite for phosphorylations of other serines. Inhibition of PI3K/Akt pathway reduced the phosphorylation of LARP6, but had no effect on the S451A mutant, suggesting that PI3K/Akt pathway targets S451 and we have identified Akt as the responsible kinase. Overexpression of S451A mutant had dominant negative effect on collagen biosynthesis; drastically reduced secretion of collagen and induced hyper-modifications of collagen alpha2 (I) polypeptides. This indicates that LARP6 phosphorylation at S451 is critical for regulating translation and folding of collagen polypeptides. Akt inhibitor, GSK-2141795, which is in clinical trials for treatment of solid tumors, reduced collagen production by human lung fibroblasts with EC50 of 150 nM. This effect can be explained by inhibition of LARP6 phosphorylation and suggests that Akt inhibitors may be effective in treatment of various forms of fibrosis. PMID- 26932463 TI - Erratum. PMID- 26932462 TI - It's what's inside that counts: egg contaminant concentrations are influenced by estimates of egg density, egg volume, and fresh egg mass. AB - In egg contaminant studies, it is necessary to calculate egg contaminant concentrations on a fresh wet weight basis and this requires accurate estimates of egg density and egg volume. We show that the inclusion or exclusion of the eggshell can influence egg contaminant concentrations, and we provide estimates of egg density (both with and without the eggshell) and egg-shape coefficients (used to estimate egg volume from egg morphometrics) for American avocet (Recurvirostra americana), black-necked stilt (Himantopus mexicanus), and Forster's tern (Sterna forsteri). Egg densities (g/cm(3)) estimated for whole eggs (1.056 +/- 0.003) were higher than egg densities estimated for egg contents (1.024 +/- 0.001), and were 1.059 +/- 0.001 and 1.025 +/- 0.001 for avocets, 1.056 +/- 0.001 and 1.023 +/- 0.001 for stilts, and 1.053 +/- 0.002 and 1.025 +/- 0.002 for terns. The egg-shape coefficients for egg volume (K v ) and egg mass (K w ) also differed depending on whether the eggshell was included (K v = 0.491 +/ 0.001; K w = 0.518 +/- 0.001) or excluded (K v = 0.493 +/- 0.001; K w = 0.505 +/- 0.001), and varied among species. Although egg contaminant concentrations are rarely meant to include the eggshell, we show that the typical inclusion of the eggshell in egg density and egg volume estimates results in egg contaminant concentrations being underestimated by 6-13 %. Our results demonstrate that the inclusion of the eggshell significantly influences estimates of egg density, egg volume, and fresh egg mass, which leads to egg contaminant concentrations that are biased low. We suggest that egg contaminant concentrations be calculated on a fresh wet weight basis using only internal egg-content densities, volumes, and masses appropriate for the species. For the three waterbirds in our study, these corrected coefficients are 1.024 +/- 0.001 for egg density, 0.493 +/- 0.001 for K v , and 0.505 +/- 0.001 for K w . PMID- 26932464 TI - Antibiotic Resistance Genes in Freshwater Biofilms May Reflect Influences from High-Intensity Agriculture. AB - Antibiotic resistance is a major public health concern with growing evidence of environmental gene reservoirs, especially in freshwater. However, the presence of antibiotic resistance genes in freshwater, in addition to the wide spectrum of land use contaminants like nitrogen and phosphate, that waterways are subjected to is inconclusive. Using molecular analyses, freshwater benthic rock biofilms were screened for genes conferring resistance to antibiotics used in both humans and farmed animals (aacA-aphD to aminoglycosides; mecA to beta-lactams; ermA and ermB to macrolides; tetA, tetB, tetK, and tetM to tetracyclines; vanA and vanB to glycopeptides). We detected widespread low levels of antibiotic resistance genes from 20 waterways across southern New Zealand throughout the year (1.3 % overall detection rate; 480 samples from three rocks per site, 20 sites, eight occasions; July 2010-May 2011). Three of the ten genes, ermB, tetK, and tetM, were detected in 62 of the 4800 individual screens; representatives confirmed using Sanger sequencing. No distinction could be made between human and agricultural land use contamination sources based on gene presence distribution alone. However, land use pressures are suggested by moderate correlations between antibiotic resistance genes and high-intensity farming in winter. The detection of antibiotic resistance genes at several sites not subject to known agricultural pressures suggests human sources of resistance, like waterway contamination resulting from unsatisfactory toilet facilities at recreational sites. PMID- 26932465 TI - Changes in corneal aberrations after cataract surgery. AB - PURPOSE: To study the changes in corneal aberrations after cataract surgery. METHODS: This study comprised 36 eyes of 36 patients (mean age, 67.3 years) who underwent cataract surgery through a 2.2-mm superior sclerocorneal incision. The anterior, posterior, and total corneal wavefront aberrations for the 6.0-mm pupillary diameter were measured preoperatively and 1 month postoperatively. The postoperative changes in corneal aberrations were evaluated for individual Zernike terms (Z 2 (-2) , Z 2 (0) , Z 2 (2) , Z 3 (-1) , Z 3 (1) , and Z 4 (0) ) and the root mean squares of the third, fourth, and total higher-order aberrations (S3, S4, and THOA). RESULTS: No significant postoperative changes were observed in S3 and S4 of the total and anterior cornea, although significant changes were observed in S4 and THOA of the posterior cornea. Regarding the preoperative and postoperative Zernike terms of the total cornea, the oblique astigmatism (Z 2 (-2) ) changed significantly (P = 0.02). Significant positive correlations were observed in the Z 2 (-2) , Z 2 (0) , Z 2 (2) Z 3 (-1) , Z 3 (1) and Z 4 (0) between the changes in the total and the anterior cornea (P < 0.001 for all comparisons). However, no correlations were observed in the changes in the Zernike terms between the total and the posterior cornea, except for the Z 2 (0) . CONCLUSIONS: The oblique astigmatism (Z 2 (-2) ) of the total cornea significantly changed after 2.2-mm-incision cataract surgery. The changes in the lower- and higher-order aberrations of the anterior cornea mainly contributed to the changes in the total cornea. PMID- 26932466 TI - Input estimation for drug discovery using optimal control and Markov chain Monte Carlo approaches. AB - Input estimation is employed in cases where it is desirable to recover the form of an input function which cannot be directly observed and for which there is no model for the generating process. In pharmacokinetic and pharmacodynamic modelling, input estimation in linear systems (deconvolution) is well established, while the nonlinear case is largely unexplored. In this paper, a rigorous definition of the input-estimation problem is given, and the choices involved in terms of modelling assumptions and estimation algorithms are discussed. In particular, the paper covers Maximum a Posteriori estimates using techniques from optimal control theory, and full Bayesian estimation using Markov Chain Monte Carlo (MCMC) approaches. These techniques are implemented using the optimisation software CasADi, and applied to two example problems: one where the oral absorption rate and bioavailability of the drug eflornithine are estimated using pharmacokinetic data from rats, and one where energy intake is estimated from body-mass measurements of mice exposed to monoclonal antibodies targeting the fibroblast growth factor receptor (FGFR) 1c. The results from the analysis are used to highlight the strengths and weaknesses of the methods used when applied to sparsely sampled data. The presented methods for optimal control are fast and robust, and can be recommended for use in drug discovery. The MCMC-based methods can have long running times and require more expertise from the user. The rigorous definition together with the illustrative examples and suggestions for software serve as a highly promising starting point for application of input estimation methods to problems in drug discovery. PMID- 26932467 TI - Complementarity among four highly productive grassland species depends on resource availability. AB - Positive species richness-productivity relationships are common in biodiversity experiments, but how resource availability modifies biodiversity effects in grass legume mixtures composed of highly productive species is yet to be explicitly tested. We addressed this question by choosing two grasses (Arrhenatherum elatius and Dactylis glomerata) and two legumes (Medicago * varia and Onobrychis viciifolia) which are highly productive in monocultures and dominant in mixtures (the Jena Experiment). We established monocultures, all possible two- and three species mixtures, and the four-species mixture under three different resource supply conditions (control, fertilization, and shading). Compared to the control, community biomass production decreased under shading (-56 %) and increased under fertilization (+12 %). Net diversity effects (i.e., mixture minus mean monoculture biomass) were positive in the control and under shading (on average +15 and +72 %, respectively) and negative under fertilization (-10 %). Positive complementarity effects in the control suggested resource partitioning and facilitation of growth through symbiotic N2 fixation by legumes. Positive complementarity effects under shading indicated that resource partitioning is also possible when growth is carbon-limited. Negative complementarity effects under fertilization suggested that external nutrient supply depressed facilitative grass-legume interactions due to increased competition for light. Selection effects, which quantify the dominance of species with particularly high monoculture biomasses in the mixture, were generally small compared to complementarity effects, and indicated that these species had comparable competitive strengths in the mixture. Our study shows that resource availability has a strong impact on the occurrence of positive diversity effects among tall and highly productive grass and legume species. PMID- 26932468 TI - Recent range expansion of a terrestrial orchid corresponds with climate-driven variation in its population dynamics. AB - The population dynamics and distribution limits of plant species are predicted to change as the climate changes. However, it remains unclear to what extent climate variables affect population dynamics, which vital rates are most sensitive to climate change, and whether the same vital rates drive population dynamics in different populations. In this study, we used long-term demographic data from two populations of the terrestrial orchid Himantoglossum hircinum growing at the northern edge of their geographic range to quantify the influence of climate change on demographic vital rates. Integral projection models were constructed to study how climate conditions between 1991 and 2006 affected population dynamics and to assess how projected future climate change will affect the long-term viability of this species. Based on the parameterised vital rate functions and the observed climatic conditions, one of the studied populations had an average population growth rate above 1 (lambda = 1.04), while the other was declining at ca. 3 % year(-1) (lambda = 0.97). Variation in temperature and precipitation mainly affected population growth through their effect on survival and fecundity. Based on UK Climate Projection 2009 estimates of future climate conditions for three greenhouse gas emission scenarios, population growth rates are expected to increase in one of the studied populations. Overall, our results indicate that the observed changes in climatic conditions appeared to be beneficial to the long term survival of the species in the UK and suggest that they may have been the driving force behind the current range expansion of H. hircinum in England. PMID- 26932469 TI - Land colonisation by fish is associated with predictable changes in life history. AB - The colonisation of new environments is a central evolutionary process, yet why species make such transitions often remains unknown because of the difficulty in empirically investigating potential mechanisms. The most likely explanation for transitions to new environments is that doing so conveys survival benefits, either in the form of an ecological release or new ecological opportunity. Life history theory makes explicit predictions about how traits linked to survival and reproduction should change with shifts in age-specific mortality. We used these predictions to examine whether a current colonisation of land by fishes might convey survival benefits. We found that blenny species with more terrestrial lifestyles exhibited faster reproductive development and slower growth rates than species with more marine lifestyles; a life history trade off that is consistent with the hypothesis that mortality has become reduced in younger life stages on land. A plausible explanation for such a shift is that an ecological release or opportunity on land has conveyed survival benefits relative to the ancestral marine environment. More generally, our study illustrates how life history theory can be leveraged in novel ways to formulate testable predictions on why organisms might make transitions into novel environments. PMID- 26932470 TI - Phase Conjugated and Transparent Wavelength Conversions of Nyquist 16-QAM Signals Employing a Single-Layer Graphene Coated Fiber Device. AB - We fabricate a nonlinear optical device based on a fiber pigtail cross-section coated with a single-layer graphene grown by chemical vapor deposition (CVD) method. Using the fabricated graphene-assisted nonlinear optical device and employing Nyquist 16-ary quadrature amplitude modulation (16-QAM) signal, we experimentally demonstrate phase conjugated wavelength conversion by degenerate four-wave mixing (FWM) and transparent wavelength conversion by non-degenerate FWM in graphene. We study the conversion efficiency as functions of the pump power and pump wavelength and evaluate the bit-error rate (BER) performance. We also compare the time-varying symbol sequence for graphene-assisted phase conjugated and transparent wavelength conversions of Nyquist 16-QAM signal. PMID- 26932471 TI - Population physiologically-based pharmacokinetic model incorporating lymphatic uptake for a subcutaneously administered pegylated peptide. AB - PURPOSE: Physiologically-based pharmacokinetic (PBPK) models provide a rational mechanistic approach for predicting the time course of macromolecules in plasma. Population PBPK models for large molecules necessitate incorporation of lymphatic circulation to mechanistically account for biodistribution. Moreover, characterization of subcutaneous absorption requires consideration of the microvascular transit from the injection site to the systemic circulation. A PBPK model for a pegylated peptide conjugate, previously developed for primates, was modified to describe the lymphatic uptake in a population of humans by incorporation of interindividual variability in the lymphatic circulation and a unique lymphatic drainage compartment (LDC). The model was then used to simulate the time course of the drug in a population of humans and compared to the same drug administered to a group of human subjects participating in a first-in-human study. METHODS: Organ, blood and lymph masses for the population were sampled from either normal or log-normal distributions. Blood flows were calculated for each organ based on mean organ perfusion per gram of organ tissue and lymphatic flow was set as a fixed fraction of blood flow. Interindividual variability in lymphatic volume was assumed to be similar to that of blood volume. The volume of the LDC was parameterzed as a fraction of the injection volume. Sensitivity analysis was performed to study uncertain parameters and distribution assumptions. RESULTS: The population generator was capable of simulating a virtual population incorporating the lymphatic circulation. Incorporation of a LDC resulted in similar line shape relative to the observed data and incorporation of anthropometric variability accounted for individual differences in the absorption and elimination phases across all dose cohorts. Line shape was sensitive to the inclusion of LDC while peak and elimination portions of the time course were influenced by the magnitude of variance assumed for blood volume and renal clearance, respectively. CONCLUSION: Lymphatic circulation can be incorporated into a population PBPK model assuming similar interindividual variability as observed for blood volume. Incorporation of an LDC, where the volume of this transit compartment is proportional to the SC injection volume may be an important mechanistic means of predicting the transit from the SC depot to the systemic circulation. PMID- 26932473 TI - In Memoriam: Osamu Hayaishi (1920 - 2015). PMID- 26932472 TI - Gut microbiota-involved mechanisms in enhancing systemic exposure of ginsenosides by coexisting polysaccharides in ginseng decoction. AB - Oral decoctions of traditional Chinese medicines (TCMs) serve for therapeutic and prophylactic management of diseases for centuries. Small molecules and polysaccharides are the dominant chemicals co-occurred in the TCM decoction. Small molecules are well-studied by multidisciplinary elaborations, whereas the role of polysaccharides remains largely elusive. Here we explore a gut microbiota involved mechanism by which TCM polysaccharides restore the homeostasis of gut microbiota and consequently promote the systemic exposure of concomitant small molecules in the decoction. As a case study, ginseng polysaccharides and ginsenosides in Du-Shen-Tang, the decoction of ginseng, were investigated on an over-fatigue and acute cold stress model. The results indicated that ginseng polysaccharides improved intestinal metabolism and absorption of certain ginsenosides, meanwhile reinstated the perturbed holistic gut microbiota, and particularly enhanced the growth of Lactobacillus spp. and Bacteroides spp., two major metabolic bacteria of ginsenosides. By exploring the synergistic actions of polysaccharides with small molecules, these findings shed new light on scientization and rationalization of the classic TCM decoctions in human health care. PMID- 26932474 TI - Why does Togni's reagent I exist in the high-energy hypervalent iodine form? Re evaluation of benziodoxole based hypervalent iodine reagents. AB - Togni's reagents have become very popular trifluoromethylating reagents in organic synthesis. The existing form of Togni's reagent I is a hypervalent iodine compound which lies much higher in energy than its ether isomer. The high-energy hypervalent iodine form makes Togni's reagent I very effective and versatile. The energy differences between the two forms correlate with the trans influence of the substituents. The five-membered ring in the benziodoxole-based scaffold is an important reason for its existence in the higher-energy form. The relation to Buchwald's 2014 research is discussed. PMID- 26932477 TI - Molecular dynamics study of the isothermal crystallization mechanism of polyethylene chain: the combined effects of chain length and temperature. AB - A molecular level understanding of the polyethylene (PE) crystallization process was elucidated by molecular dynamics simulation of three states, with varying chain length and temperature. The process can be classified into the following three states: (1) nucleation controlled state, (2) competitive state of crystal growth process and new nuclei formation, and (3) crystal growth controlled state, which could be quantified by the evolution of nuclei number. With increasing chain length, two phenomena occur: the single crystallization mechanism changes from state (1) to (3), and the crystal size increases while the b/a axial ratio in the lateral surface decreases. These changes can be explained from a thermodynamic point of view, in that the van der Waals (vdW) interaction per CH2 unit is strengthened and more nucleation sites are generated for longer chain. Size effect (meaning different surface fractions when the chain collapses into a globule) was an important factor determining vdW energy per unit and the crystallization states of a single PE chain. On the other hand, the crystallization states were independent of chain length for short chains systems with the same size effect. In both conditions, a long chain generates multi crystal domains, and a short chain prefers a single crystal domain. Our results not only provide molecular level evidence for crystallization states but also clarify the influence of chain length on the crystallization process. PMID- 26932476 TI - Nudt3 is an mRNA decapping enzyme that modulates cell migration. AB - Removal of the 5'-end 7-methylguanosine cap structure is a critical step in the highly regulated process of mRNA decay. The Nudix hydrolase, Dcp2, was identified as a first decapping enzyme and subsequently shown to preferentially modulate stability of only a subset of mRNAs. This observation led to the hypothesis that mammalian cells possess multiple decapping enzymes that may function in distinct pathways. Here we report Nudt3 is a Nudix protein that possesses mRNA decapping activity in cells and is a modulator of MCF-7 breast cancer cell migration. Reduction of Nudt3 protein levels in MCF-7 cells promotes increased cell migration and corresponding enhanced filopodia extensions. Importantly, this phenotype was reversed by complementation with wild type, but not catalytically inactive Nudt3 protein indicating Nudt3 decapping activity normally functions to control cell migration. Genome-wide analysis of Nudt3 compromised cells identified elevated levels of transcripts involved in cell motility including integrin beta6, lipocalin-2, and fibronectin. The observed increase in mRNA abundance was dependent on Nudt3 decapping activity where integrin beta6 and lipocalin-2 were modulated directly through mRNA stability, while fibronectin was indirectly controlled. Moreover, increased cell migration observed in Nudt3 knockdown cells was mediated through the extracellular integrin beta6 and fibronectin protein nexus. We conclude that Nudt3 is an mRNA decapping enzyme that orchestrates expression of a subset of mRNAs to modulate cell migration and further substantiates the existence of multiple decapping enzymes functioning in distinct cellular pathways in mammals. PMID- 26932475 TI - Medical implications of technical accuracy in genome sequencing. AB - BACKGROUND: As whole exome sequencing (WES) and whole genome sequencing (WGS) transition from research tools to clinical diagnostic tests, it is increasingly critical for sequencing methods and analysis pipelines to be technically accurate. The Genome in a Bottle Consortium has recently published a set of benchmark SNV, indel, and homozygous reference genotypes for the pilot whole genome NIST Reference Material based on the NA12878 genome. METHODS: We examine the relationship between human genome complexity and genes/variants reported to be associated with human disease. Specifically, we map regions of medical relevance to benchmark regions of high or low confidence. We use benchmark data to assess the sensitivity and positive predictive value of two representative sequencing pipelines for specific classes of variation. RESULTS: We observe that the accuracy of a variant call depends on the genomic region, variant type, and read depth, and varies by analytical pipeline. We find that most false negative WGS calls result from filtering while most false negative WES variants relate to poor coverage. We find that only 74.6% of the exonic bases in ClinVar and OMIM genes and 82.1% of the exonic bases in ACMG-reportable genes are found in high confidence regions. Only 990 genes in the genome are found entirely within high confidence regions while 593 of 3,300 ClinVar/OMIM genes have less than 50% of their total exonic base pairs in high-confidence regions. We find greater than 77 % of the pathogenic or likely pathogenic SNVs currently in ClinVar fall within high-confidence regions. We identify sites that are prone to sequencing errors, including thousands present in publicly available variant databases. Finally, we examine the clinical impact of mandatory reporting of secondary findings, highlighting a false positive variant found in BRCA2. CONCLUSIONS: Together, these data illustrate the importance of appropriate use and continued improvement of technical benchmarks to ensure accurate and judicious interpretation of next generation DNA sequencing results in the clinical setting. PMID- 26932478 TI - Associations of components of PTEN/AKT/mTOR pathway with cancer stem cell markers and prognostic value of these biomarkers in hepatocellular carcinoma. AB - AIM: We aimed to investigate the associations between components of the phosphatase and tensin homolog deleted on chromosome 10/protein kinase B/mammalian target of rapamycin (PTEN/AKT/mTOR) pathway and liver cancer stem cell (LCSC) markers, including CD133, CD90, CD44, and epithelial cell adhesion molecule (EpCAM), and to further evaluate the predictive values of these biomarkers for recurrence and survival in hepatocellular carcinoma (HCC). METHOD: Protein expressions and mRNA levels of PTEN and LCSC markers were determined in 110 HCC tissues and 98 adjacent non-tumor tissues. Protein expressions of phosphorylated AKT (p-AKT) and phosphorylated mTOR (p-mTOR) were detected to evaluate the activation of the PTEN/AKT/mTOR pathway by using immunohistochemistry. Prognostic significance was analyzed by univariate and multivariate analysis. RESULTS: Loss of PTEN expression was negatively correlated with positive expression of CD133, CD90, and EpCAM (P < 0.05). Positive expression of p-AKT and p-mTOR were positively associated with positive expression for CD133, CD90, and EpCAM (P < 0.05). By univariate and multivariate analysis, a higher level of alpha-fetoprotein, loss of PTEN expression, and CD133 positive, p-AKT-positive, p-mTOR-positive, and EpCAM-positive signals were predictors for HCC recurrence, whereas advanced TNM stage, loss of PTEN expression, and positive expression of p-AKT, p-mTOR, and CD133 were predictors for survival. Patients with PTEN- /CD133+ or PTEN- /EpCAM+ HCC had shorter recurrence-free survival and overall survival times. CONCLUSION: The PTEN/AKT/mTOR pathway might play a crucial role in driving recurrence and influencing prognosis in HCC. There could be a potential repressive relationship between components of the PTEN/AKT/mTOR pathway and LCSCs. The combination of PTEN with CD133 or EpCAM expression may serve as a screening tool to monitor recurrence and predict prognosis. PMID- 26932479 TI - Interconnected or disconnected? Promotion of mental health and prevention of mental disorder in the digital age. AB - To date there have been few peer-reviewed studies on the feasibility, acceptability and effectiveness of digital technologies for mental health promotion and disorder prevention. Any evaluation of these evolving technologies is complicated by a lack of understanding about the specific risks and possible benefits of the many forms of internet use on mental health. To adequately meet the mental health needs of today's society, psychiatry must engage in rigorous assessment of the impact of digital technologies. PMID- 26932480 TI - Psychotherapies should be assessed for both benefit and harm. AB - The past four decades have witnessed a transformation in research on the benefits of psychological therapies. However, even though therapists highlight that negative and adverse effects are seen in day-to-day practice, research on the negative effects of psychotherapy is insufficient. Given the unrelenting popularity of therapies, the argument for examining the adverse effects of psychotherapy would seem to be compelling. Such a strategy would extend beyond supervision of individual therapists to the introduction of monitoring systems that allow for a more systematic examination of failed psychotherapy interventions (such as exist for medication prescribing). The starting point could be the development of a consensus on how to define, classify and assess psychotherapy side-effects, unwanted events, adverse reactions, etc. This would provide a conceptual framework for communication, monitoring and research. This approach should not be viewed as an attack on therapies: every branch of medicine learns from mistakes, the same must surely be true for psychological treatments. PMID- 26932481 TI - Iatrogenic harm from psychological therapies--time to move on. AB - The problem of adverse effects of psychotherapy has been recognised for decades, yet research on causes and prevention of harm has failed to progress. There is confusion between different definitions and a lack of systematic recording and reporting. A new framework for moving this field forward is proposed. PMID- 26932482 TI - The Babadook--psychiatry in the movies. PMID- 26932483 TI - Psychological interventions for adults with bipolar disorder: systematic review and meta-analysis. AB - BACKGROUND: Psychological interventions may be beneficial in bipolar disorder. AIMS: To evaluate the efficacy of psychological interventions for adults with bipolar disorder. METHOD: A systematic review of randomised controlled trials was conducted. Outcomes were meta-analysed using RevMan and confidence assessed using the GRADE method. RESULTS: We included 55 trials with 6010 participants. Moderate quality evidence associated individual psychological interventions with reduced relapses at post-treatment (risk ratio (RR) = 0.66, 95% CI 0.48-0.92) and follow up (RR = 0.74, 95% CI 0.63-0.87), and collaborative care with a reduction in hospital admissions (RR = 0.68, 95% CI 0.49-0.94). Low-quality evidence associated group interventions with fewer depression relapses at post-treatment and follow-up, and family psychoeducation with reduced symptoms of depression and mania. CONCLUSIONS: There is evidence that psychological interventions are effective for people with bipolar disorder. Much of the evidence was of low or very low quality thereby limiting our conclusions. Further research should identify the most effective (and cost-effective) interventions for each phase of this disorder. PMID- 26932485 TI - Anxiety and new onset of cardiovascular disease: critical review and meta analysis. AB - BACKGROUND: Anxiety has been associated with new-onset cardiovascular disease (CVD), but the quality of this relationship is unclear. Only if anxiety is a causal, independent cardiovascular risk factor might it be a target for CVD prevention. AIMS: To determine and examine the independent association and causality between anxiety and incident CVD. METHOD: PubMed, EMBASE and PsycINFO databases were searched up to October 2013. A review of Hill's criteria for causality and random effects meta-analysis were conducted of prospective, population-based studies examining anxiety and incident CVD in people free from CVD at baseline. RESULTS: The meta-analysis comprised 37 papers (n = 1 565 699). The follow-up ranged from 1 to 24 years. Anxiety was associated with a 52% increased incidence of CVD (hazard ratio = 1.52, 95% CI 1.36-1.71). The risk seemed independent of traditional risk factors and depression. The evaluation of Hill's criteria largely argued in favour of causality. CONCLUSIONS: Anxiety may be of interest for CVD prevention. Future research should examine biological and behavioural underpinnings of the association in order to identify targets for intervention. PMID- 26932486 TI - Patient experience of negative effects of psychological treatment: results of a national survey?. AB - BACKGROUND: To make informed choices, patients need information about negative as well as positive effects of treatments. There is little information about negative effects of psychological interventions. AIMS: To determine the prevalence of and risk factors for perceived negative effects of psychological treatment for common mental disorders. METHOD: Cross-sectional survey of people receiving psychological treatment from 184 services in England and Wales. Respondents were asked whether they had experienced lasting bad effects from the treatment they received. RESULTS: Of 14 587 respondents, 763 (5.2%) reported experiencing lasting bad effects. People aged over 65 were less likely to report such effects and sexual and ethnic minorities were more likely to report them. People who were unsure what type of therapy they received were more likely to report negative effects (odds ratio (OR) = 1.51, 95% CI 1.22-1.87), and those that stated that they were given enough information about therapy before it started were less likely to report them (OR = 0.65, 95% CI 0.54-0.79). CONCLUSIONS: One in 20 people responding to this survey reported lasting bad effects from psychological treatment. Clinicians should discuss the potential for both the positive and negative effects of therapy before it starts. PMID- 26932489 TI - Neuroimaging distinction between neurological and psychiatric disorders--was there really one? PMID- 26932490 TI - Authors' reply. PMID- 26932491 TI - Ten books. PMID- 26932493 TI - On Blackstar: deaths, dying and dominions of discovery. PMID- 26932495 TI - Beneficial changes in food consumption and nutrient intake after 10 years of follow-up in a Mediterranean cohort: the SUN project. AB - BACKGROUND: The assessment of changes in dietary habits provides interesting information on whether or not the observed trends are in line with accepted nutritional guidelines. The objective was to evaluate within-subject longitudinal changes in food consumption and nutrient intake and in a 10-year follow-up study. METHODS: The SUN (Seguimiento Universidad de Navarra) project is a prospective Spanish cohort study. Diet was assessed using a 136-item food-frequency questionnaire (FFQ), previously validated in Spain. The participants were 3036 university graduates (55.8 % women) of Spain and the main outcome measures the changes in dietary quality and in food consumption and nutrient intake. Paired t tests and conditional logistic regression models were used to evaluate within subject longitudinal dietary changes and the risk of inadequacy respectively, after 10 years of follow-up. RESULTS: During follow-up, participants showed a relevant and significant increase (p < 0.001) in the consumption of fruits (7.4 %), vegetables (8.6 %), low-fat dairy products (35.2 %), lean meat (12.4 %), fish (2.9 %), whole grains (53.2 %), nuts (52.4 %) and a significant decrease in legumes (-7.4 %), whole-fat dairy products (-44.2 %), red meat (-17.6 %), sugar sweetened beverages (-58.7 %) and wine (-11.9 %). With respect to nutrients, we found a higher proportion of carbohydrates (3.6 %) and fiber (7.4 %) and a decrease in total energy intake (2.7 %), total fat (-4.5 %), SFA (-9.4 %), MUFA ( 4.9 %), PUFA (-12.7 %), w-3 and w-6 fatty acids (-9.1 and -20.5 % respectively) and cholesterol (-9.6 %). CONCLUSIONS: In this Mediterranean cohort study, mainly beneficial changes in the consumption of most foods and macronutrients were observed after 10 years of follow-up. PMID- 26932496 TI - Professional and personal enhancement: a pragmatic approach in dental education. AB - PURPOSE: Students of health education are often offended by the transitions and challenges they face while encountering diverse people, ideas and academic workloads. They may be offended because of reasons not only related to their societal background but also to their basic competence in managing transitions. In the Asian scenario, students enter the first year of professional education in their late teen age along with the definition of self which was created by their parents. There are different issues that arise in this age group that may positively shape or negatively affect the personalities of students. They need to achieve a sense of balance between personal and professional traits on their own. Several students are often unable to cultivate the expected required qualities, which leads to an abject state of mind and hinder their progress. We identified the most common personal and professional hurdles in the lives of dental students and we provided experiential solutions to overcome the hurdles by using a sociable approach through an integrated, continuing education program. METHODS: Designing and implementing a cohesive, amalgamated and inspiring personal and professional enhancement action program for dental students. RESULTS: Feedback from students reflected that the needs and expectations of students vary with academic phase. In addition students expressed that this program series inculcated some positive skills, and overall, they are satisfied with the utility of the program. CONCLUSION: Personal and professional enhancement of students in accordance with individual needs as well as with expected requirements needs a committed administrative action plan. Our results in this context are encouraging and can be considered for application in dental institutions. PMID- 26932497 TI - Photographing Injuries in the Acute Care Setting: Development and Evaluation of a Standardized Protocol for Research, Forensics, and Clinical Practice. AB - BACKGROUND: Photographing injuries in the acute setting allows for improved documentation as well as assessment by clinicians and others who have not personally examined a patient. This tool is important, particularly for telemedicine, tracking of wound healing, the evaluation of potential abuse, and injury research. Despite this, protocols to ensure standardization of photography in clinical practice, forensics, or research have not been published. In preparation for a study of injury patterns in elder abuse and geriatric falls, our goal was to develop and evaluate a protocol for standardized photography of injuries that may be broadly applied. METHODS: We conducted a literature review for techniques and standards in medical, forensic, and legal photography. We developed a novel protocol describing types of photographs and body positioning for eight body regions, including instructional diagrams. We revised it iteratively in consultation with experts in medical photography; forensics; and elder, child, and domestic abuse. The resulting protocol requires a minimum of four photos of each injury at multiple distances with and without a ruler/color guide. To evaluate the protocol's efficacy, multiple research assistants without previous photography experience photographed injuries from a convenience sample of elderly patients presenting to a single large, urban, academic emergency department. A selection of these patients' images were then evaluated in a blinded fashion by four nontreating emergency medicine physicians and the inter rater reliability between these physicians was calculated. RESULTS: Among the 131 injuries, from 53 patients, photographed by 18 photographers using this protocol, photographs of 25 injuries (10 bruises, seven lacerations, and eight abrasions) were used to assess characterization of the injury. Physicians' characterizations of the injuries were reliable for the size of the injury (kappa = 0.91, 95% confidence interval [CI] = 0.77 to 1.00), side of the body (kappa = 0.97, 95% CI = 0.88 to 1.00), precise location of the injury (kappa = 0.74, 95% CI = 0.63 = 0.81), and type of abrasion (kappa = 0.76, 95% CI = 0.45 to 1.00). The exact shape of the injury (kappa = 0.44, 95% CI = 0.17 to 0.51), and the primary color of bruises (kappa = 0.37, 95% CI = 0.25 to 0.48) were not as reliably characterized. CONCLUSIONS: Standardizing the documentation of injuries with photographs for clinical and research assessment can be conducted by nonprofessional photographers. A photography protocol will ensure that this important mechanism for documentation is optimized. PMID- 26932498 TI - The sphingosine-1-phosphate receptor 1 binding molecule FTY720 inhibits osteoclast formation in rats with ligature-induced periodontitis. AB - BACKGROUND AND OBJECTIVE: Osteoclast precursors (OPs) re-migrate from the bone surface into blood vessels through sphingosine-1-phosphate receptor 1 (S1PR1) expression. T cells also express S1PR1, mediating their migration from the lymph nodes into blood vessels. OP and T-cell migration are one of the sequential steps related to osteoclast formation. To characterize the role of S1PR1 in osteoclast formation induced by periodontitis, we investigated the effect of S1PR1-binding molecule FTY720 (FTY) on the number of OPs and T cells in periodontal tissue and peripheral blood of rats with ligature-induced periodontitis. MATERIAL AND METHODS: Rats were divided into four groups; control (Con), FTY, periodontitis (Peri), and periodontitis+FTY (Peri+FTY) groups. Ligatures were placed around the first molars in the left and right mandibles. The rats were intraperitoneally injected with vehicle or 3 mg/kg FTY daily until they were killed. The number of osteoclasts and cluster of differentiation (CD)11b, CD3 and receptor activator of NF-kappaB ligand (RANKL)-positive cells in first molar furcation were counted by tartrate-resistant acid phosphatase or immunohistochemistry staining. The number of CD11b- and CD3-positive cells in peripheral blood was estimated by flow cytometry. RESULTS: The number of osteoclasts in the Peri group was higher than Con, Peri+FTY and FTY groups (p < 0.05) and CD11b, CD3 and RANKL-positive cells were also higher in the Peri group than other groups in furcation (p < 0.05). While CD11b-positive cells in furcation of the Peri+FTY group were lower than the Peri group (p < 0.05), they were higher in peripheral blood (p < 0.05). Dissimilar to CD11b-positive cells, CD3-positive cells in the Peri+FTY group were lower in peripheral blood as well as furcation than the Peri group (p < 0.05). RANKL-positive cells in furcation of the Peri+FTY group were also lower than Peri group (p < 0.05). CONCLUSION: These results indicate that FTY may facilitate re migration of OPs from the alveolar bone surface into blood vessels, blocking T cell migration from the lymph nodes into blood vessels and subsequently reducing osteoclast formation induced by periodontitis. This suggests that S1PR1-S1P binding may play a role in osteoclast formation of periodontitis by modulating OP and T-cell migration. PMID- 26932499 TI - Correction: Self-assembly of arene ruthenium acylpyrazolone fragments to tetranuclear metallacycles. Molecular structures and solid-state (15)N CPMAS NMR correlations. AB - Correction for 'Self-assembly of arene ruthenium acylpyrazolone fragments to tetranuclear metallacycles. Molecular structures and solid-state (15)N CPMAS NMR correlations' by Riccardo Pettinari et al., Dalton Trans., 2016, 45, 3974-3982. PMID- 26932500 TI - Mechanistic investigation of trimethylamine-N-oxide reduction catalysed by biomimetic molybdenum enzyme models. AB - In this paper, we report a theoretical investigation of the reduction reaction mechanism of Me3NO using molybdenum containing systems that are functional and structural analogues of trimethylamine N-oxide reductase mononuclear molybdenum enzyme. The reactivity of the monooxomolybdenum(IV) benzenedithiolato complex and its derivatives to carbamoyl (t-BuNHCO) and acylamino (t-BuCONH) substituents on the benzene rings in both cis and trans arrangements was explored. The calculated energy profiles describing the steps of two mechanisms of attack considered viable (named cis- and trans-attack) by the Me3NO substrate at cis and trans positions with respect to the oxo ligand show that the attack on cis is energetically more favourable than the attack on trans. Along the pathway for the cis-attack the first step of the reaction, that is rate-determining for all the studied compounds, is the approach of the substrate to the Mo centre in cis to the oxo ligand that causes a distortion of the initial square-pyramidal geometry of the complex. The reaction steps involved in the trans position attack were also explored. Calculations confirm that, as previously suggested, the introduction of ligands able to form intramolecular NH...S hydrogen bonds accelerates the reduction of the Me3NO substrate and contributes to the tuning of the reactivity of molybdoenzyme models. PMID- 26932501 TI - Gliosarcomas lack BRAFV600E mutation, but a subset exhibit beta-catenin nuclear localization. AB - Gliosarcoma (GS) is a rare subtype of glioblastoma (GBM) characterized by both glial and mesenchymal components. Unlike GBM, there are no specific prognostic markers, and optimized treatments for patients with GS do not exist. Recent reports describe BRAFV600E mutation in malignant peripheral nerve sheath tumors, and aberrant Wnt signaling and CTNNB1 (beta-catenin gene) mutations have been described in GBM. We sought to determine whether GS tumors harbor BRAFV600E mutations or aberrant Wnt signaling, as indicated by nuclear localization of beta catenin, by immunohistochemical detection. Forty-eight (48) cases of primary and secondary adult GS (including recurrent ones) were evaluated by immunohistochemical techniques for the presence of nuclear beta-catenin and the BRAFV600E mutation. A small subset (6/46, 13%) showed nuclear localization of beta-catenin. None of the cases harbored BRAFV600E mutations (0/48). These results are the first to describe the presence of Wnt signaling pathway abnormalities, manifested by nuclear beta-catenin, in a subset, as well as the lack of BRAFV600E mutation in GS. We propose a potential role for Wnt pathway alterations in the pathogenesis of a subset of GS. PMID- 26932502 TI - Deconstructing the "July Effect" in Operative Outcomes: A National Study. AB - This study analyzes the relationship between hospital teaching status, failure to rescue, and time of year in select gastrointestinal operations. Procedure codes for laparoscopic cholecystectomy, colectomy, and pancreatectomy were queried from the Nationwide Inpatient Sample (2004-2011). Failure to rescue was defined as inpatient mortality when >=1 complication. A total of 2,777,267 laparoscopic cholecystectomies, 2,519,903 colectomies, and 129,619 pancreatectomies were performed. Teaching hospitals had increased overall rates of failure to rescue compared to non-teaching hospitals, 10.0 vs. 9.5 % (p = 0.0187), particularly between May and August. There was greater inter-month variability in non-teaching hospitals amongst individual operations. On multivariable analysis, July was not predictive of increased odds of failure to rescue. Teaching status, hospital characteristics, and patient demographics were associated with increased odds of failure to rescue. Although teaching hospitals have a higher overall failure to rescue rate amongst the selected gastrointestinal operations, odds of failure to rescue are not increased in the month of July. Non-teaching hospitals tend to exhibit more monthly variation in failure to rescue rates, and hospital/patient demographics are predictive of failure to rescue. Further investigation targeted at identifying drivers of temporal variation is warranted to optimize patient outcomes. PMID- 26932505 TI - Fibrin sheath endocarditis: a new entity via echocardiography. PMID- 26932504 TI - Meta-analysis of genome-wide association studies identifies three novel loci for saturated fatty acids in East Asians. AB - PURPOSE: We aimed to characterize common genetic variants that influence saturated fatty acid concentrations in East Asians. METHODS: Meta-analysis of genome-wide association studies for circulating SFAs was conducted in two population-based cohorts comprising 3521 participants of Chinese ancestry. RESULTS: We identified two novel 14:0-associated loci at LMX1A (LIM homeobox transcription factor 1) and AMPD3 (AMP deaminase 3) (P = 5.08 * 10-9 and P = 4.33 * 10-8, respectively), and a novel 20:0-associated locus at CERS4 (ceramide synthase 4) (P = 1.76 * 10-10). We also confirmed the previously reported association of FADS1/2-rs102275 with 18:0 (P = 1.12 * 10-5). In addition, the A alleles of rs11042834 in AMPD3 and rs17159388 in CERS4 also exhibited evidence of associations with high-density lipoprotein cholesterol (P = 0.0162 and P = 0.0161, respectively). CONCLUSIONS: To our knowledge, this is the first GWAS analysis to examine SFA concentrations in East Asian populations. Our findings provide novel evidence that genetic variations of several genes from multiple pathways are associated with SFA concentrations in human body. PMID- 26932503 TI - Caffeine and cardiovascular diseases: critical review of current research. AB - Caffeine is a most widely consumed physiological stimulant worldwide, which is consumed via natural sources, such as coffee and tea, and now marketed sources such as energy drinks and other dietary supplements. This wide use has led to concerns regarding the safety of caffeine and its proposed beneficial role in alertness, performance and energy expenditure and side effects in the cardiovascular system. The question remains "Which dose is safe?", as the population does not appear to adhere to the strict guidelines listed on caffeine consumption. Studies in humans and animal models yield controversial results, which can be explained by population, type and dose of caffeine and low statistical power. This review will focus on comprehensive and critical review of the current literature and provide an avenue for further study. PMID- 26932507 TI - Muscle strength is associated with vitamin D receptor gene variants. AB - Vitamin D receptor (VDR) is an important candidate gene in muscle function. Scientific reports on the effect of its genetic variants on muscle strength are contradictory likely due to the inconsistent study designs. Hand grip strength (HGS) is a highly heritable phenotype of muscle strength but only limited studies are available on its genetic background. Association between VDR polymorphisms and HGS has been poorly investigated and previous reports are conflicting. We studied the effect of VDR gene variants on HGS in a sample of 706 schoolchildren. Genomic DNA was extracted from saliva samples and six candidate single nucleotide polymorphisms (SNPs) across the VDR gene were genotyped with Sequenom MassARRAY technique. HGS was measured with a digital dynamometer in both hands. Single marker and haplotype associations were adjusted for demographic parameters. Three SNPs, rs4516035 (A1012G; p = 0.009), rs1544410 (BsmI; p = 0.010), and rs731236 (TaqI; p = 0.038) and a 3' UTR haploblock constructed by three SNPs (Bsml-Taq1 rs10783215; p < 0.005) showed significantly associations with HGS of the dominant hand. In the non-dominant hand, the effects of the A1012G (p = 0.034) and the 3' UTR haploblock (p < 0.01) on HGS were also significant. Since the promoter SNP (A10112G) and the 3' UTR haplotype were proved to be associated with the expression and the stability of the VDR mRNA in earlier studies, VDR variants can be supposed to have a direct effect on muscle strength. The individual genetic patterns can also explain the inconsistency of the previously published clinical results on the association between vitamin D and muscle function. (c) 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:2031-2037, 2016. PMID- 26932506 TI - Quantitative and predictive model of kinetic regulation by E. coli TPP riboswitches. AB - Riboswitches are non-coding elements upstream or downstream of mRNAs that, upon binding of a specific ligand, regulate transcription and/or translation initiation in bacteria, or alternative splicing in plants and fungi. We have studied thiamine pyrophosphate (TPP) riboswitches regulating translation of thiM operon and transcription and translation of thiC operon in E. coli, and that of THIC in the plant A. thaliana. For all, we ascertained an induced-fit mechanism involving initial binding of the TPP followed by a conformational change leading to a higher-affinity complex. The experimental values obtained for all kinetic and thermodynamic parameters of TPP binding imply that the regulation by A. thaliana riboswitch is governed by mass-action law, whereas it is of kinetic nature for the two bacterial riboswitches. Kinetic regulation requires that the RNA polymerase pauses after synthesis of each riboswitch aptamer to leave time for TPP binding, but only when its concentration is sufficient. A quantitative model of regulation highlighted how the pausing time has to be linked to the kinetic rates of initial TPP binding to obtain an ON/OFF switch in the correct concentration range of TPP. We verified the existence of these pauses and the model prediction on their duration. Our analysis also led to quantitative estimates of the respective efficiency of kinetic and thermodynamic regulations, which shows that kinetically regulated riboswitches react more sharply to concentration variation of their ligand than thermodynamically regulated riboswitches. This rationalizes the interest of kinetic regulation and confirms empirical observations that were obtained by numerical simulations. PMID- 26932508 TI - In vivo imaging of advanced glycation end products (AGEs) of albumin: first observations of significantly reduced clearance and liver deposition properties in mice. AB - Advanced glycation end products (AGEs) are associated with various diseases, especially during aging and the development of diabetes and uremia. To better understand these biological processes, investigation of the in vivo kinetics of AGEs, i.e., analysis of trafficking and clearance properties, was carried out by molecular imaging. Following the preparation of Cy7.5-labeled AGE-albumin and intravenous injection in BALB/cA-nu/nu mice, noninvasive fluorescence kinetics analysis was performed. In vivo imaging and fluorescence microscopy analysis revealed that non-enzymatic AGEs were smoothly captured by scavenger cells in the liver, i.e., Kupffer and other sinusoidal cells, but were unable to be properly cleared from the body. Overall, these results highlight an important link between AGEs and various disorders associated with them, which may serve as a platform for future research to better understand the processes and mechanisms of these disorders. PMID- 26932509 TI - Towards an understanding of tensile deformation in Ti-based bulk metallic glass matrix composites with BCC dendrites. AB - The microstructure and tension ductility of a series of Ti-based bulk metallic glass matrix composite (BMGMC) is investigated by changing content of the beta stabilizing element vanadium while holding the volume fraction of dendritic phase constant. The ability to change only one variable in these novel composites has previously been difficult, leading to uninvestigated areas regarding how composition affects properties. It is shown that the tension ductility can range from near zero percent to over ten percent simply by changing the amount of vanadium in the dendritic phase. This approach may prove useful for the future development of these alloys, which have largely been developed experimentally using trial and error. PMID- 26932510 TI - Helicobacter pylori in children with asthmatic conditions at school age, and their mothers. AB - BACKGROUND: Helicobacter pylori prevalence in Western countries has been declining simultaneously with increases in childhood asthma and allergic diseases; prior studies have linked these phenomena. AIMS: To examine the association between H. pylori colonisation in children and risk of asthma and related conditions at school age. We secondly examined additional effects of maternal H. pylori status by pairing with children's status. METHODS: This study was embedded in a multi-ethnic population-based cohort in Rotterdam, The Netherlands. We measured anti-H. pylori and anti-CagA antibodies in serum of children obtained at age 6 years, and of their mothers obtained during midpregnancy. Asthma or related conditions were reported for children at age 6 years. We used multivariate logistic regression analyses among 3797 subjects. RESULTS: In children, the H. pylori positivity rate was 8.7%, and 29.2% of these were CagA-positive. A child's colonisation with a CagA-negative-H. pylori strain was associated with an increased risk of asthma (Odds ratio 2.11; 95% CI 1.23 3.60), but this differed for European (3.64; 1.97-6.73) and non-European (0.52; 0.14-1.89) children. When taking into account maternal H. pylori status, only H. pylori-positive children with an H. pylori-negative mother had increased risk of asthma (2.42; 1.11-5.27), accounting for 3.4% of the asthma risk. CONCLUSIONS: Colonisation of a European child with a CagA-negative-H. pylori strain at age 6 was associated with an increased prevalence of asthma, but there was no association for non-European children. The underlying mechanisms for the observed risk differences require further research. PMID- 26932511 TI - The influence of espresso coffee on neurocognitive function in HIV-infected patients. AB - The aim of our study was to evaluate the impact of coffee intake on cognitive function in persons living with HIV (PLWH). 130 PLWH with CD4 > 200 cells/mm(3), undetectable viral load, treated with HAART were included. A structured interview was applied and relevant clinical and laboratory data were assessed, including coffee intake. For neuropsychological assessment, the HIV Neurobehavioral Research Center Battery was chosen. Univariate nonparametric statistics and multivariate regression model were used. A significant association between espresso coffee use and a better cognitive function was verified in five of the eight psychometric measurements. In the multivariate analysis, after variable adjustment, linear regression analysis showed that coffee intake was a positive predictor for attention/working memory, executive functions and Global Deficit Score. Although the mechanisms behind the influence of caffeine on cognitive functioning are controversial, regular espresso coffee intake may have favourable effects on cognitive deterioration caused by HIV. PMID- 26932513 TI - Successful Treatment of Hepatitis C Virus Genotype 4 in Renal Transplant Recipients With Direct-Acting Antiviral Agents. PMID- 26932512 TI - Myocardial pathology induced by aldosterone is dependent on non-canonical activities of G protein-coupled receptor kinases. AB - Hyper-aldosteronism is associated with myocardial dysfunction including induction of cardiac fibrosis and maladaptive hypertrophy. Mechanisms of these cardiotoxicities are not fully understood. Here we show that mineralocorticoid receptor (MR) activation by aldosterone leads to pathological myocardial signalling mediated by mitochondrial G protein-coupled receptor kinase 2 (GRK2) pro-death activity and GRK5 pro-hypertrophic action. Moreover, these MR-dependent GRK2 and GRK5 non-canonical activities appear to involve cross-talk with the angiotensin II type-1 receptor (AT1R). Most importantly, we show that ventricular dysfunction caused by chronic hyper-aldosteronism in vivo is completely prevented in cardiac Grk2 knockout mice (KO) and to a lesser extent in Grk5 KO mice. However, aldosterone-induced cardiac hypertrophy is totally prevented in Grk5 KO mice. We also show human data consistent with MR activation status in heart failure influencing GRK2 levels. Therefore, our study uncovers GRKs as targets for ameliorating pathological cardiac effects associated with high-aldosterone levels. PMID- 26932514 TI - Phospholipid analysis in sera of horses with allergic dermatitis and in matched healthy controls. AB - BACKGROUND: Lipids have become an important target for searching new biomarkers typical of different autoimmune and allergic diseases. The most common allergic dermatitis of the horse is related to stings of insects and is known as insect bite hypersensitivity (IBH) or summer eczema, referring to its recurrence during the summer months. This intense pruritus has certain similarities with atopic dermatitis of humans. The treatment of IBH is difficult and therefore new strategies for therapy are needed. Autoserum therapy based on the use of serum phospholipids has recently been introduced for horses. So far, serum lipids relating to these allergic disorders have been poorly determined. The main aim of this study was to analyse phospholipid profiles in the sera of horses with allergic dermatitis and in their healthy controls and to further assess whether these lipid profiles change according to the clinical status after therapy. METHODS: Sera were collected from 10 horses with allergic dermatitis and from 10 matched healthy controls both before and 4 weeks after the therapy of the affected horses. Eczema horses were treated with an autogenous preparation made from a horse's own serum and used for oral medication. Samples were analysed for their phospholipid content by liquid chromatography coupled to a triple quadrupole mass spectrometer (LC-MS). Data of phospholipid concentrations between the groups and over the time were analysed by using the Friedman test. Correlations between the change of concentrations and the clinical status were assessed by Spearman's rank correlation test. RESULTS: The major phospholipid classes detected were phosphatidylcholine (PC), sphingomyelin (SM), phosphatidylinositol (PI) and phosphatidylethanolamine (PE). Eczema horses had significantly lower total concentrations of PC (p < 0.0001) and SM (p = 0.0115) than their healthy controls. After a 4-week therapy, no significant differences were found between the groups. Changes in SM concentrations correlated significantly with alterations in clinical signs (p = 0.0047). CONCLUSIONS: Horses with allergic dermatitis have an altered phospholipid profile in their sera as compared with healthy horses and these profiles seem to change according to their clinical status. Sphingomyelin seems to have an active role in the course of equine insect bite hypersensitivity. PMID- 26932515 TI - Characterization of Nipah virus infection in a model of human airway epithelial cells cultured at an air-liquid interface. AB - Nipah virus (NiV) is an emerging paramyxovirus that can cause lethal respiratory illness in humans. No vaccine/therapeutic is currently licensed for humans. Human to-human transmission was previously reported during outbreaks and NiV could be isolated from respiratory secretions, but the proportion of cases in Malaysia exhibiting respiratory symptoms was significantly lower than that in Bangladesh. Previously, we showed that primary human basal respiratory epithelial cells are susceptible to both NiV-Malaysia (M) and -Bangladesh (B) strains causing robust pro-inflammatory responses. However, the cells of the human respiratory epithelium that NiV targets are unknown and their role in NiV transmission and NiV-related lung pathogenesis is still poorly understood. Here, we characterized NiV infection of the human respiratory epithelium using a model of the human tracheal/bronchial (B-ALI) and small airway (S-ALI) epithelium cultured at an air liquid interface. We show that NiV-M and NiV-B infect ciliated and secretory cells in B/S-ALI, and that infection of S-ALI, but not B-ALI, results in disruption of the epithelium integrity and host responses recruiting human immune cells. Interestingly, NiV-B replicated more efficiently in B-ALI than did NiV-M. These results suggest that the human tracheal/bronchial epithelium is favourable to NiV replication and shedding, while inducing a limited host response. Our data suggest that the small airways epithelium is prone to inflammation and lesions as well as constituting a point of virus entry into the pulmonary vasculature. The use of relevant models of the human respiratory tract, such as B/S-ALI, is critical for understanding NiV-related lung pathogenesis and identifying the underlying mechanisms allowing human-to-human transmission. PMID- 26932516 TI - Child Psychiatric Emergencies: Updates on Trends, Clinical Care, and Practice Challenges. AB - Over the past 15 years, the number of pediatric patients presenting to the emergency room in psychiatric crisis has nearly doubled. Suicidality and aggression are among the most common presenting problems, making it important for providers to have up-to-date knowledge about the assessment and management of these frequently encountered clinical issues. Psychometrically sound suicide risk assessment tools are available for use in the emergency room setting, which can be administered efficiently with minimal provider training. Rates of off-label medication use in the pediatric population continue to increase and are often used in the management of acute agitation in the pediatric population. The current literature will be reviewed and summarized for application in emergent treatment settings. Overall, evidence to inform best practice is limited, leading to opportunities for innovation in health care delivery, the development of new research aims, and discussion of challenging clinical dilemmas. PMID- 26932517 TI - Reply to the Commentary "To Gorelenkova Miller and Mieyal (2015): Sulfhydryl mediated redox signaling in inflammation: role in neurodegenerative diseases" by M. Kato. PMID- 26932519 TI - Density-dependent regulation of fecundity in Syngamus trachea infrapopulations in semi-naturally occurring ring-necked pheasants (Phasianus colchicus) and wild Carrion Crows (Corvus corone). AB - Previous work has highlighted increased opportunities for the transmission of Syngamus trachea within pheasant release pens, due in part to high levels of environmental contamination around communal areas. Despite this, the distribution of adult worms within their definitive hosts is not significantly different from predicted distributions under Taylor's power law. Therefore, density-dependent processes are probably acting to regulate S. trachea population dynamics. Patterns of nematode fecundity were investigated in a semi-naturally occurring population of ring-necked pheasants (Phasianus colchicus) and a wild population of carrion crows (Corvus carone). Worm length was a reliable indicator of nematode fecundity, and a negative association between mean worm length and mean worm burden was identified within both the species. The stunting of worms at greater parasite densities was present in both immunologically naive and previously exposed pheasants, so is unlikely to be a function of age-dependent acquired immunity. Interestingly, the effect of parasite crowding in the crow population explained more of the variation in mean worm length, apparently driven by a greater mean worm burden when compared with pheasants. The findings of the present study suggest that fecundity is a function of parasite density, i.e. parasite-mediated competition and not host-mediated heterogeneities in immunocompetence. PMID- 26932520 TI - Cost-effectiveness thresholds: a comment on the commentaries. PMID- 26932518 TI - Single nucleotide polymorphism in IL1B is associated with infection risk in paediatric acute myeloid leukaemia. AB - We evaluated single nucleotide polymorphisms (SNPs) associated with infection risk in children with newly diagnosed acute myeloid leukaemia (AML). We conducted a multicentre, prospective cohort study that included children aged <=18 years with de novo AML. DNA was isolated from blood lymphocytes or buccal swabs, and candidate gene SNP analysis was conducted. Primary outcome was the occurrence of microbiologically documented sterile site infection during chemotherapy. Secondary outcomes were Gram-positive and -negative infections, viridans group streptococcal infection and proven/probable invasive fungal infection. Interpretation was guided by consistency in risk alleles and microbiologic agent with previous literature. Over the study period 254 children and adolescents with AML were enrolled. Overall, 190 (74.8%) had at least one sterile site microbiologically documented infection. Among the 172 with inferred European ancestry and DNA available, nine significant associations were observed; two were consistent with previous literature. Allele A at IL1B (rs16944) was associated with decreased microbiologically documented infection, and allele G at IL10 (rs1800896) was associated with increased risk of Gram-positive infection. We identified SNPs associated with infection risk in paediatric AML. Genotype may provide insight into mechanisms of infection risk that could be used for supportive-care novel treatments. PMID- 26932521 TI - Top-emitting quantum dots light-emitting devices employing microcontact printing with electricfield-independent emission. AB - Recent breakthroughs in quantum dot light-emitting devices (QD-LEDs) show their promise in the development of next-generation displays. However, the QD-LED with conventional ITO-based bottom emission structure is difficult to realize the high aperture ratio, electricfield-independent emission and flexible full-color displays. Hence, we demonstrate top-emitting QD-LEDs with dry microcontact printing quantum dot films. The top-emitting structure is proved to be able to accelerate the excitons radiative transition rate, then contributing to stable electroluminescent efficiency with a very low roll-off, and preventing spectra from shifting and broadening with the electric field increases. The results suggest potential routes towards creating high aperture ratio, wide color gamut, color-stable and flexible QD-LED displays. PMID- 26932522 TI - USPIO-Enhanced MRI Neuroimaging: A Review. AB - MRI is a powerful tool for the diagnosis and management for a variety of central nervous system (CNS) diseases. Ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles are a novel category of MRI contrast agents that seem to play a crucial role in the imaging of CNS. Due to their physical properties, USPIOs act as blood pool agents. USPIOs improve visualization of tumor vasculature and relative cerebral blood volume measurements, tumor-associated inflammation, inflammatory-immune mediated disorders, stroke and vascular malformations. Ferumoxytol, a new type of USPIO agent, appears to have ideal characteristics for the imaging of CNS. The last few years, ferumoxytol has been successfully used to image CNS neoplasms, CNS inflammations and cerebral malformations offering useful information on cellular and molecular level. In addition, ferumoxytol studies focused on the pathophysiology of other CNS disorders like multiple sclerosis and epilepsy are already in progress. Aim of this review article is to provide the potential role of USPIO-enhanced MRI and the latest clinical applications of ferumoxytol agent in CNS imaging. PMID- 26932523 TI - Differentiation resistance through altered retinoblastoma protein function in acute lymphoblastic leukemia: in silico modeling of the deregulations in the G1/S restriction point pathway. AB - BACKGROUND: As in many cancer types, the G1/S restriction point (RP) is deregulated in Acute Lymphoblastic Leukemia (ALL). Hyper-phosphorylated retinoblastoma protein (hyper-pRb) is found in high levels in ALL cells. Nevertheless, the ALL lymphocyte proliferation rate for the average patient is surprisingly low compared to its normal counterpart of the same maturation level. Additionally, as stated in literature, ALL cells possibly reside at or beyond the RP which is located in the late-G1 phase. This state may favor their differentiation resistant phenotype. A major phenomenon contributing to this fact is thought to be the observed limited redundancy in the phosphorylation of retinoblastoma protein (pRb) by the various Cyclin Dependent Kinases (Cdks). The latter may result in partial loss of pRb functions despite hyper-phosphorylation. RESULTS: To test this hypothesis, an in silico model aiming at simulating the biochemical regulation of the RP in ALL is introduced. By exploiting experimental findings derived from leukemic cells and following a semi-quantitative calibration procedure, the model has been shown to satisfactorily reproduce such a behavior for the RP pathway. At the same time, the calibrated model has been proved to be in agreement with the observed variation in the ALL cell cycle duration. CONCLUSIONS: The proposed model aims to contribute to a better understanding of the complex phenomena governing the leukemic cell cycle. At the same time it constitutes a significant first step in the creation of a personalized proliferation rate predictor that can be used in the context of multiscale cancer modeling. Such an approach is expected to play an important role in the refinement and the advancement of mechanistic modeling of ALL in the context of the emergent and promising scientific domains of In Silico Oncology and more generally In Silico Medicine. PMID- 26932524 TI - Inflammatory arthritis in HIV positive patients: A practical guide. AB - BACKGROUND: Musculoskeletal manifestations of the human immunodeficiency virus (HIV) have been described since the outset of the global HIV epidemic. Articular syndromes that have been described in association with HIV include HIV-associated arthropathy, seronegative spondyloarthropathies (SPA) (reactive arthritis, psoriatic arthritis (PsA) and undifferentiated SPA), rheumatoid arthritis (RA) and painful articular syndrome. METHODS: We carried out a computer-assisted search of PubMed for the medical literature from January 1981 to January 2015 using the keywords HIV, acquired immune-deficiency syndrome, rheumatic manifestations, arthritis, spondyloarthropathy, anti-TNF and disease modifying antirheumatic drugs. Only English language literature was included and only studies involving adult human subjects were assessed. RESULTS: There are challenges in the management of inflammatory arthritis in patients who are HIV positive, including difficulties in the assessment of disease activity and limited information on the safety of immunosuppressive drugs in these individuals. CONCLUSIONS: This review focuses on the clinical characteristics of the inflammatory articular syndromes that have been described in association with HIV infection and discusses the therapeutic options for these patients. PMID- 26932525 TI - [Canine peritoneal larval cestodosis caused by Mesocestoides spp. larval stages]. AB - In a female dog with unspecific clinical symptoms, sonography detected a hyperechoic mass in the middle abdomen and blood analysis a middle grade systemic inflammatory reaction. Laparotomy revealed a peritoneal larval cestodosis (PLC). The diagnosis of an infection with tetrathyridia of Mesocestoides spp. was confirmed by parasitological examination and molecularbiological analysis. Reduction of the intra-abdominal parasitic load as well as a high dose administration of fenbendazole over 3 months led to a successful treatment which could be documented sonographically and by decreased concentrations of C-reactive protein (CRP). Seven months after discontinuation of fenbendazole administration, PLC recurred, pre-empted by an elevation of serum CRP values. According to the literature a life-long fenbendazole treatment was initiated. In cases of unclear chronic granulomatous inflammations in the abdominal cavity in dogs, PLC should be considered. CRP concentration and sonographic examinations are suitable to control for treatment success and a possibly occurring relapse. PMID- 26932526 TI - Biological evaluation of the toxicity and the cell cycle interruption by some benzimidazole derivatives. AB - In this work, the in vitro tests of biological activity of benzimidazoles were conducted. This group of benzimidazole derivatives was evaluated as potential bioreductive agents and their characteristic pro-apoptosis activity and cell cycle interruption on the human lung adenocarcinoma A549 cells were discussed. Their toxicity on the healthy human erythrocytes and their influence on the healthy human erythrocytes acetylcholinesterase enzyme (AChE) were established. Their apoptosis activity on A549 cells line was determined by Annexin V-APC test, and it was visualized by Hoechst test. In the next stage, their influence on the cell cycle interruption was determined by using the ribonuclease reagent. The AChE inhibition test was defined by the Ellman method, and the red blood cell lysis was defined by erythrotoxicity test. The results proved the pro-apoptosis properties of all tested compounds in normoxia and hypoxia. The DNA content assay showed that the benzimidazoles possess the ability to interrupt S phase of tumor cell cycle. The best activity in this action was presented by compound 1, especially in hypoxia, and it proves that the N-oxide analogs are predispositioned to the hypoxic target. In this study, the benzimidazoles were found as potentially biocompatible and their inhibition of acetylcholinesterase was lower than tirapazamine and much lower than tacrine which constitutes their desired effect of potential biological activity. PMID- 26932527 TI - An Evaluation of Performance Thresholds in Nursing Home Pay-for-Performance. AB - OBJECTIVE: Performance thresholds are commonly used in pay-for-performance (P4P) incentives, where providers receive a bonus payment for achieving a prespecified target threshold but may produce discontinuous incentives, with providers just below the threshold having the strongest incentive to improve and providers either far below or above the threshold having little incentive. We investigate the effect of performance thresholds on provider response in the setting of nursing home P4P. DATA SOURCES: The Minimum Data Set (MDS) and Online Survey, Certification, and Reporting (OSCAR) datasets. STUDY SETTING AND DESIGN: Difference-in-differences design to test for changes in nursing home performance in three states that implemented threshold-based P4P (Colorado, Georgia, and Oklahoma) versus three comparator states (Arizona, Tennessee, and Arkansas) between 2006 and 2009. PRINCIPAL FINDINGS: We find that those farthest below the threshold (i.e., the worst-performing nursing homes) had the largest improvements under threshold-based P4P while those farthest above the threshold worsened. This effect did not vary with the percentage of Medicaid residents in a nursing home. CONCLUSIONS: Threshold-based P4P may provide perverse incentives for nursing homes above the performance threshold, but we do not find evidence to support concerns about the effects of performance thresholds on low-performing nursing homes. PMID- 26932528 TI - Organization and characteristics of the major histocompatibility complex class II region in the Yangtze finless porpoise (Neophocaena asiaeorientalis asiaeorientalis). AB - Little is known about the major histocompatibility complex (MHC) in the genome of Yangtze finless porpoise (Neophocaena asiaeorientalis asiaeorientalis) (YFP) or other cetaceans. In this study, a high-quality YFP bacterial artificial chromosome (BAC) library was constructed. We then determined the organization and characterization of YFP MHC class II region by screening the BAC library, followed by sequencing and assembly of positive BAC clones. The YFP MHC class II region consists of two segregated contigs (218,725 bp and 328,435 bp respectively) that include only eight expressed MHC class II genes, three pseudo MHC genes and twelve non-MHC genes. The YFP has fewer MHC class II genes than ruminants, showing locus reduction in DRB, DQA, DQB, and loss of DY. In addition, phylogenic and evolutionary analyses indicated that the DRB, DQA and DQB genes might have undergone birth-and-death evolution, whereas the DQB gene might have evolved under positive selection in cetaceans. These findings provide an essential foundation for future work, such as estimating MHC genetic variation in the YFP or other cetaceans. This work is the first report on the MHC class II region in cetaceans and offers valuable information for understanding the evolution of MHC genome in cetaceans. PMID- 26932529 TI - Enumeration method for tree-like chemical compounds with benzene rings and naphthalene rings by breadth-first search order. AB - BACKGROUND: Drug discovery and design are important research fields in bioinformatics. Enumeration of chemical compounds is essential not only for the purpose, but also for analysis of chemical space and structure elucidation. In our previous study, we developed enumeration methods BfsSimEnum and BfsMulEnum for tree-like chemical compounds using a tree-structure to represent a chemical compound, which is limited to acyclic chemical compounds only. RESULTS: In this paper, we extend the methods, and develop BfsBenNaphEnum that can enumerate tree like chemical compounds containing benzene rings and naphthalene rings, which include benzene isomers and naphthalene isomers such as ortho, meta, and para, by treating a benzene ring as an atom with valence six, instead of a ring of six carbon atoms, and treating a naphthalene ring as two benzene rings having a special bond. We compare our method with MOLGEN 5.0, which is a well-known general purpose structure generator, to enumerate chemical structures from a set of chemical formulas in terms of the number of enumerated structures and the computational time. The result suggests that our proposed method can reduce the computational time efficiently. CONCLUSIONS: We propose the enumeration method BfsBenNaphEnum for tree-like chemical compounds containing benzene rings and naphthalene rings as cyclic structures. BfsBenNaphEnum was from 50 times to 5,000,000 times faster than MOLGEN 5.0 for instances with 8 to 14 carbon atoms in our experiments. PMID- 26932530 TI - Bistable self-assembly in homogeneous colloidal systems for flexible modular architectures. AB - This paper presents a homogeneous system of magnetic colloidal particles that self-assembles via two structural patterns of different symmetry. Based on a qualitative comparison between a real magnetic particles system, analytical calculations and molecular dynamics simulations, it is shown that bistability can be achieved by a proper tailoring of an anisotropic magnetization distribution inside the particles. The presented bistability opens new possibilities to form two-dimensionally extended and flexible structures where the connectivity between the particles can be changed in vivo. PMID- 26932532 TI - Ego-depletion and aggressive behavior. AB - Multiple theoretical frameworks postulate that ego-depletion can influence aggressive behavior. Our experimental study assessed whether ego-depletion is related to aggressive behavioral change and whether provocation moderated this effect. Aggression was measured by asking participants to take raffle tickets from an ostensible partner. First, participants were randomly assigned to either high or low ego-depletion (by having them memorize a short or long number throughout the entire study) prior to engaging in the first ticket exchange. Participants were then either provoked (or not) by having their "partner" take more or fewer tickets than the partner originally requested. The ticket exchange occurred three times to assess behavioral change. Results showed that aggression was highest for ego depleted participants who were provoked. Implications are discussed in terms of the General Aggression Model and the Strength Model of Self Control. Aggr. Behav. 42:533-541, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26932531 TI - Establishment of a preclinical ovine screening model for the investigation of bone tissue engineering strategies in cancellous and cortical bone defects. AB - BACKGROUND: New tissue engineering strategies for bone regeneration need to be investigated in a relevant preclinical large animal model before making the translation into human patients. Therefore, our interdisciplinary group established a simplified large animal screening model for intramembranous bone defect regeneration in cancellous and cortical bone. METHODS: Related to a well established model of cancellous drill hole defect regeneration in sheep, both the proximal and distal epimetaphyseal regions of the femur and the humerus were used bilaterally for eight drill hole cancellous defects (O 6 mm, 15 mm depth). Several improvements of the surgical procedure and equipment for an easier harvest of samples were invented. For the inclusion of cortical defect regeneration, a total of eight unicortical diaphyseal drill holes (6 mm O) were placed in the proximal-lateral and distal-medial parts of the metacarpal (MC) and metatarsal (MT) diaphyseal bone bilaterally. Acting moments within a normal gait cycle in the musculoskeletal lower limb model were compared with the results of the biomechanical in vitro torsion test until failure to ensure a low accidental fracture risk of utilized bones (ANOVA, p < 0.05). The model was tested in vivo, using thirteen adult, female, black-face sheep (O 66 kg; +/- 5 kg; age >= 2.5 years). In a two-step surgical procedure 16 drill holes were performed for the investigation of two different time points within one animal. Defects were left empty, augmented with autologous cancellous bone or soft bone graft substitutes. RESULTS: The in vitro tests confirmed this model a high comparability between drilled MC and MT bones and a high safety margin until fracture. The exclusion of one animal from the in vivo study, due to a spiral fracture of the left MC bone led to a tolerable failure rate of 8 %. CONCLUSIONS: As a screening tool, promising biomaterials can be tested in this cancellous and cortical bone defect model prior to the application in a more complex treatment site. PMID- 26932533 TI - Medium-chain fatty acid reduces lipid accumulation by regulating expression of lipid-sensing genes in human liver cells with steatosis. AB - Accumulation of lipids in the liver can lead to cell dysfunction and steatosis, an important factor in pathogenesis causing non-alcoholic fatty liver disease. The mechanisms related to lipid deposition in the liver, however, remain poorly understood. This study was aimed to investigate the effects of medium-chain fatty acid (MCFA) on the lipolysis and expression of lipid-sensing genes in human liver cells with steatosis. A cellular steatosis model, which is suitable to experimentally investigate the impact of fat accumulation in the liver, was established in human normal liver cells (LO2 cells) with a mixture of free fatty acids (oleate/palmitate, 2:1) at 200 MUm for 24 h incubation. MCFA was found to down-regulate expression of liver X receptor-alpha, sterol regulatory element binding protein-1, acetyl-CoA carboxylase, fatty acid synthase, CD 36 and lipoprotein lipase in this cellular model, and have positive effects on adipose triglyceride lipase and hormone-sensitive lipase. These results suggest that MCFA may reduce lipid accumulation by regulating key lipid-sensing genes in human liver cells with steatosis. PMID- 26932534 TI - A perplexing case. PMID- 26932535 TI - Direct and indirect resource use, healthcare costs and work force absence in patients with non-infectious intermediate, posterior or panuveitis. AB - PURPOSE: To ascertain resource use, costs and risk of workforce absence in non infectious uveitis cases versus matched controls. METHODS: In a retrospective claims analysis of employees in the United States, prevalent (N = 705) and incident (N = 776) cases 18-64 years old with >=2 diagnoses of non-infectious intermediate, posterior or panuveitis were matched 1:1 to controls without uveitis. Persistent prevalent cases (treated for >=90 days, N = 112) also were analysed. Outcomes were annual direct resource use and costs associated with inpatient stays; emergency department, outpatient and ophthalmologist/optometrist visits; and prescription drugs. Indirect resource use and costs associated with work loss from disability and medically related absenteeism also were compared. Multivariate regression assessed cost differences between cases and controls. RESULTS: Cases had significantly (p < 0.05) more medical resource use versus controls including 0.4 versus 0.2 emergency visits and 16.5 versus 7.6 outpatient/other visits. Cases used more prescription drugs (7.8 versus 4.1) and had more disability days (10.3 versus 4.6), medically related absenteeism days (8.5 versus 3.8), and work loss days (18.7 versus 8.4) than controls (all p < 0.05). Total direct ($12 940 versus $3730) and indirect ($3144 versus $1378) costs were higher in cases than controls (all p < 0.05). Results for persistent cases suggested greater utilization and associated cost and work loss burden. Compared with controls, cases had significantly greater risks of workforce absence, leave of absence and long-term disability (all p < 0.05). CONCLUSION: Non-infectious intermediate, posterior or panuveitis, particularly persistent disease, is associated with substantial medical and work loss costs suggesting an unmet need for more effective treatments. PMID- 26932536 TI - Gene expression profiling of reproductive meristem types in early rice inflorescences by laser microdissection. AB - In rice, inflorescence architecture is established at early stages of reproductive development and contributes directly to grain yield potential. After induction of flowering, the complexity of branching, and therefore the number of seeds on the panicle, is determined by the activity of different meristem types and the timing of transitions between them. Although some of the genes involved in these transitions have been identified, an understanding of the network of transcriptional regulators controlling this process is lacking. To address this we used a precise laser microdissection and RNA-sequencing approach in Oryza sativa ssp. japonica cv. Nipponbare to produce quantitative data that describe the landscape of gene expression in four different meristem types: the rachis meristem, the primary branch meristem, the elongating primary branch meristem (including axillary meristems), and the spikelet meristem. A switch in expression profile between apical and axillary meristem types followed by more gradual changes during transitions in axillary meristem identity was observed, and several genes potentially involved in branching were identified. This resource will be vital for a mechanistic understanding of the link between inflorescence development and grain yield. PMID- 26932537 TI - Dynamic bio-adhesion of polymer nanoparticles on MDCK epithelial cells and its impact on bio-membranes, endocytosis and paracytosis. AB - Nowadays, concern about the use of nanotechnology for biomedical application is unprecedentedly increasing. In fact, nanosystems applied for various potential clinical uses always have to cross the primary biological barrier consisting of epithelial cells. However, little is really known currently in terms of the influence of the dynamic bio-adhesion of nanosystems on bio-membranes as well as on endocytosis and transcytosis. This was investigated here using polymer nanoparticles (PNs) and MDCK epithelial cells as the models. Firstly, the adhesion of PNs on cell membranes was found to be time-dependent with a shift of both location and dispersion pattern, from the lateral adhesion of mainly mono dispersed PNs initially to the apical coverage of the PN aggregate later. Then, it was interesting to observe in this study that the dynamic bio-adhesion of PNs only affected their endocytosis but not their transcytosis. It was important to find that the endocytosis of PNs was not a constant process. A GM1 dependent CDE (caveolae dependent endocytosis) pathway was dominant in the preliminary stage, followed by the co-existence of a CME (clathrin-mediated endocytosis) pathway for the PN aggregate at a later stage, in accordance with the adhesion features of PNs, suggesting the modification of PN adhesion patterns on the endocytosis pathways. Next, the PN adhesion was noticed to affect the structure of cell junctions, via altering the extra- and intra-cellular calcium levels, leading to the enhanced paracellular transport of small molecules, but not favorably enough for the obviously increased passing of PNs themselves. Finally, FRAP and other techniques all demonstrated the obvious impact of PN adhesion on the membrane confirmation, independent of the adhesion location and time, which might lower the threshold for the internalization of PNs, even their aggregates. Generally, these findings confirm that the transport pathway mechanism of PNs through epithelial cells is rather dynamic, and is remarkably affected by the adhesion patterns of PNs on the cell membrane. PMID- 26932538 TI - MiR-708 promotes steroid-induced osteonecrosis of femoral head, suppresses osteogenic differentiation by targeting SMAD3. AB - Steroid-induced osteonecrosis of femoral head (ONFH) is a serious complication of glucocorticoid (GC) use. We investigated the differential expression of miRs in the mesenchymal stem cells (MSCs) of patients with ONFH, and aimed to explain the relationship between GC use and the development of MSC dysfunction in ONFH. Cells were collected from bone marrow of patients with ONFH. Samples were assigned to either GCs Group or Control Group at 1:1 matched with control. We then used miRNA microarray analysis and real-time PCR to identify the differentially expressed miRs. We also induced normal MSCs with GCs to verify the differential expression above. Subsequently, we selected some of the miRs for further studies, including miRNA target and pathway prediction, and functional analysis. We discovered that miR-708 was upregulated in ONFH patients and GC-treated MSCs. SMAD3 was identified as a direct target gene of miR-708, and functional analysis demonstrated that miR-708 could markedly suppress osteogenic differentiation and adipogenesis differentiation of MSCs. Inhibition of miR-708 rescued the suppressive effect of GC on osteonecrosis. Therefore, we determined that GC use resulted in overexpression of miR-708 in MSCs, and thus, targeting miR-708 may serve as a novel therapeutic biomarker for the prevention and treatment of ONFH. PMID- 26932539 TI - Use of Dog Parks and the Contribution to Physical Activity for Their Owners. AB - PURPOSE: This study described the use of dog parks in several diverse locations and explored the contribution dog parks made to physical activity of the dog owners. METHOD: The Systematic Observation of Play and Recreation in Communities (SOPARC) tool was used to count the number and characteristics of people using parks. Observations were conducted 4 times per day, 4 days per week during for 1 week in 6 urban/suburban parks during different seasons. Collection sites included 3 dog parks in Chapel Hill/Durham, NC; 2 dog parks in Los Angeles, CA; and 1 dog park in Philadelphia, PA. Interviews at the NC and PA parks were conducted among 604 adults. RESULTS: We counted 2,124 people (11.9%) in the dog park area compared with 15,672 people in the remaining park areas. Based on observations, dog park visitors were more likely to be female and White or Other race/ethnicity compared with Hispanics, and were less likely to be children or engaged in walking or vigorous activity. Park interviews revealed that compared with other park activities, reporting walking/watching a dog at the park was more common among those who visited the park more frequently ( >= 1 time per week), stayed at the park for a shorter time ( <= 1 hr), or visited the park alone. CONCLUSION: Although dog parks may be an important destination for dog owners and contribute to physical activity, the contribution of dog parks to participants' moderate-to-vigorous physical activity was limited. PMID- 26932541 TI - Recent Developments in Mechanochemical Materials Synthesis by Extrusion. AB - Mechanochemical synthesis, i.e., reactions conducted by grinding solid reactants together with no or minimal solvent, has been demonstrated as an excellent technique for the formation of both organic and inorganic compounds. Mechanochemistry is viewed as an alternative approach to chemical synthesis and is not always considered when developing manufacturing processes of fine chemicals. Here, recent advances are highlighted regarding mechanochemical synthesis, by utilizing a well-developed continuous technique - extrusion, and the advantages it offers to further support its use in the manufacturing of these chemicals. To put this work into context, it is shown how extrusion plays a vital role for manufacturing in the food, polymer, and pharmaceutical industries, and how the research carried out by these respective industrialists provides great insight and understanding of the technique, with the results being applicable in the chemical industry. The synthesis of metal-organic frameworks (MOFs) is highlighted herein as an excellent example showcasing the advantages that extrusion provides to the manufacture of these materials, one advantage being the exceptional space time yields (STYs) reported for these processes, at three orders of magnitude greater than conventional (solvothermal) synthesis. PMID- 26932540 TI - Global patterns and substrate-based mechanisms of the terrestrial nitrogen cycle. AB - Nitrogen (N) deposition is impacting the services that ecosystems provide to humanity. However, the mechanisms determining impacts on the N cycle are not fully understood. To explore the mechanistic underpinnings of N impacts on N cycle processes, we reviewed and synthesised recent progress in ecosystem N research through empirical studies, conceptual analysis and model simulations. Experimental and observational studies have revealed that the stimulation of plant N uptake and soil retention generally diminishes as N loading increases, while dissolved and gaseous losses of N occur at low N availability but increase exponentially and become the dominant fate of N at high loading rates. The original N saturation hypothesis emphasises sequential N saturation from plant uptake to soil retention before N losses occur. However, biogeochemical models that simulate simultaneous competition for soil N substrates by multiple processes match the observed patterns of N losses better than models based on sequential competition. To enable better prediction of terrestrial N cycle responses to N loading, we recommend that future research identifies the response functions of different N processes to substrate availability using manipulative experiments, and incorporates the measured N saturation response functions into conceptual, theoretical and quantitative analyses. PMID- 26932542 TI - Flow Chronopotentiometry with Ion-Selective Membranes for Cation, Anion, and Polyion Detection. AB - We report here on the development of a chronopotentiometric readout for ion selective electrodes that allows one to record transition times in continuous flow conditions without the necessity to stop the flow. A sample plug of 150 MUL is injected into the carrier solution (0.5 mM NaCl) and subsequently transported to the detection cell (~20 MUL) at moderate flow rates (~0.5 mL min(-1)), where a short current pulse (5s) is applied between the ionophore-based working electrode and a biocompatible and nonpolarizable Donnan exclusion anion-exchanger membrane reference/counter electrode. Flow conditions bear an influence on the thickness of the aqueous diffusion layer and result in a shift of the chronopotentiometric transition time with respect to stopped flow. Two models based on rotating disk electrodes and flow chronopotentiometry at metal-based electrodes were used to corroborate the data. The method was successfully applied to the determination of calcium, chloride, alkalinity, acidity, and protamine with a range of ion selective membranes. Because of the limiting exposure time of ca. 20 s of the membranes with the sample, this approach is demonstrated to be useful for the detection of protamine in the therapeutic range of undiluted human blood. PMID- 26932543 TI - Quantifying Demyelination in NK venom treated nerve using its electric circuit model. AB - Reduction of myelin in peripheral nerve causes critical demyelinating diseases such as chronic inflammatory demyelinating polyneuropathy, Guillain-Barre syndrome, etc. Clinical monitoring of these diseases requires rapid and non invasive quantification of demyelination. Here we have developed formulation of nerve conduction velocity (NCV) in terms of demyelination considering electric circuit model of a nerve having bundle of axons for its quantification from NCV measurements. This approach has been validated and demonstrated with toad nerve model treated with crude Naja kaouthia (NK) venom and also shows the effect of Phospholipase A2 and three finger neurotoxin from NK-venom on peripheral nerve. This opens future scope for non-invasive clinical measurement of demyelination. PMID- 26932544 TI - Mononuclear phagocyte accumulates a stearic acid derivative during differentiation into macrophages. Effects of stearic acid on macrophage differentiation and Mycobacterium tuberculosis control. AB - The fatty acid composition of monocytes changes substantially during differentiation into macrophages, increasing the proportion of saturated fatty acids. These changes prompted us to investigate whether fatty acid accumulation in the extracellular milieu could affect the differentiation of bystander mononuclear phagocytes. An esterified fatty acid derivative, stearate, was the only fatty acid that significantly increased in macrophage supernatants, and there were higher levels when cells differentiated in the presence of Mycobacterium tuberculosis H37Rv or purified protein derivative (PPD). Exogenous stearic acid enhanced the expression of HLA-DR and CD64; there was also accumulation of IL-12, TNF-alpha, IL-6, MIP-1 alpha and beta and a reduction in MCP-1 and the bacterial load. These results suggested that during differentiation, a derivative of stearic acid, which promotes the process as well as the effector mechanisms of phagocytes against the mycobacterium, accumulates in the cell supernatants. PMID- 26932545 TI - Gender influence on clinical presentation and high-resolution ultrasound findings in primary carpal tunnel syndrome: do women only differ in incidence? AB - PURPOSE: High-resolution ultrasound is increasingly used in the diagnosis of carpal tunnel syndrome; yet little is known about gender differences in clinical presentation and ultrasound findings. MATERIALS AND METHODS: In this high resolution ultrasound-based retrospective study in 170 cases, we assessed gender influence in CTS in terms of the severity of neural alterations by wrist-to forearm ratio (WFR), epineural thickening, loss of fascicular anatomy, as well as classical signs and symptoms. The control group consisted of 42 wrists. RESULTS: Women present with a greater WFR at first admission are affected more often bilaterally, and report less subjective pain intensity, while men report fewer nightly pain episodes at higher WFR. Loss of fascicular anatomy is three times more frequent in women. An increase in epineural thickness, loss of fascicular anatomy, and involvement of more than 1.5 fingers correlate significantly with WFR regardless of sex. CONCLUSION: Women differ significantly from men in terms of clinical presentation and ultrasound findings upon first diagnosis of CTS, which should be included in further diagnostic considerations. PMID- 26932546 TI - Extensive hydrolysis of phosphonates as unexpected behaviour of the known His6 organophosphorus hydrolase. AB - The catalytic activity of hexahistidine-tagged organophosphorus hydrolase (His6 OPH) in hydrolytic reactions of methylphosphonic acid (MPA) and its monoesters and diesters being decomposition products of R-VX was demonstrated for the first time. The catalytic constants of enzyme in such reactions were determined. The mechanism of C-P bond cleavage in the MPA by His6-OPH was proposed. Such reaction was estimated to be carried out with the soluble and nanocapsulated forms of His6 OPH. His6-OPH was demonstrated to be capable of degrading the key organophosphorus components of reaction masses (RMs) that are produced by the chemical detoxification of R-VX and RMs are multi-substrate mixtures for this enzyme. The kinetic model describing the behaviour of His6-OPH in RMs was proposed and was shown to adequately fit experimental points during degradation of the real samples of RMs. PMID- 26932547 TI - Pediatric inguinal hernia repair with a single-incision approach using an Endo CloseTM suturing device. AB - BACKGROUND: Diverse techniques have been described for pediatric inguinal hernia repair, based on extraperitoneal [1-4] and intraperitoneal [5-8] methodologies. In this video, we describe a novel technique to repair pediatric inguinal hernia using an Endo CloseTM suturing device by percutaneous puncture with a single incision. METHODS: With a transumbilical approach, a 5-mm trocar is inserted for a 30 degrees laparoscope. A 3-mm incision is made, and the Endo CloseTM suturing device (Covidien, Minneapolis, MN, USA), with a 2-0 polypropylene suture retained by the stylet, is inserted perpendicularly to the skin. An extraperitoneal dissection is made on a side the inguinal ring and the needle of the device penetrates the peritoneum through the inferior border. Then, the stylet mechanism is pushed to free the lasso inside the cavity. At the same incision site, the needle of the Endo CloseTM is inserted again, but an extraperitoneal dissection is made on the other side of the ring, ensuring that the needle penetrates at the same exit orifice. Now, the suture lasso is recovered and retracted to close the ring. Finally, the suture is extracted and knots are tied extracorporeally at the level of the skin. RESULTS: A total of 34 patients (20 females and 14 males) underwent surgery with this procedure. Operative time for unilateral repair was 10-15 and 25-30 min for the bilateral repair (29 unilateral/5 bilateral). The patients experienced minimal postoperative pain. The follow-up period was 12 months with no complications, no recurrence and without cases of postoperative hydrocele. There were no injuries to the structures as vessels or vas deferens, and the esthetic outcome was excellent. CONCLUSIONS: The technique presents a simple, safe and reliable method to repair inguinal hernias in children. The long term results of this novel technique will be evaluated in future studies. PMID- 26932548 TI - Peroral endoscopic myotomy for esophageal achalasia: outcomes of the first over 100 patients with short-term follow-up. AB - BACKGROUND: POEM is a recently developed achalasia treatment method, which combines the efficacy of surgical myotomy with the benefits of endoscopic procedures. Very few studies have focussed on the efficacy and usefulness of POEM in over 100 cases. METHODS: The first 100 adult patients treated according to standard POEM technique in a single center and followed up for 3 months were identified and included in this study (men 42; women 58; mean age 48.2 +/- 18.8; range 9-91 years) The pre- and postoperative assessments included Eckardt scores, manometry, endoscopy, and monitoring pH. RESULTS: Mean operative time was 150.8 +/- 49.3 min (75-370 min). Adverse events over Grade IIIb by the Clavien-Dindo classification were not encountered. The mean preoperative and postoperative lower esophageal sphincter pressures were 43.6 +/- 26.2 and 20.9 +/- 12.7 mmHg, respectively, indicating a statistically significant decrease after POEM (P < 0.05). The mean preoperative and postoperative integrated relaxation pressure values were 33.5 +/- 15.2 and 15.3 +/- 6.5 mmHg (P < 0.05). Furthermore, the Eckardt score significantly decreased from 5.9 +/- 2.5 preoperatively to 0.8 +/- 0.9 postoperatively (P < 0.05). Clinical success was documented in 99 % of the patients. Short-term outcomes after POEM were extremely good and independent of the age, type of achalasia, and previous treatment method. The percent of monitoring time with a pH < 4 was 25.6 % (22/86) in patients not on proton-pump inhibitors. Nine patients were diagnosed with symptomatic gastroesophageal reflux disease (GERD); patients with reflux esophagitis and symptomatic GERD improved with PPI treatment. CONCLUSIONS: Our results confirm the efficacy of POEM in a large patient series and support POEM as one of the first-line achalasia therapies in the near future. PMID- 26932549 TI - Outcomes in laparoscopic cholecystectomy by single incision with SPIDER surgical system are comparable to conventional multiport technique: one surgeon's experience. AB - BACKGROUND: Single-incision laparoscopic cholecystectomy has emerged as an alternative to conventional multiport laparoscopic cholecystectomy (LC). Technical difficulty, prolonged surgical times and increased complication rates have been reported in single-incision laparoscopic surgery. One of the concerns is lack of triangulation of instruments. The SPIDER(r) surgical system is a single-incision laparoscopic device that utilizes flexible instruments with the purpose of achieving adequate triangulation. The purpose of this study is to compare the outcomes of SPIDER versus LC. METHODS: A retrospective chart review of patients who underwent LC and SPIDER cholecystectomy by a single surgeon during a concurrent 44-month period at Baptist Health South Florida hospitals was performed focusing on demographics, indication for surgery, complications and incisional hernia rates. Exclusion criteria were concomitant surgery and hernia repair at the time of surgery. RESULTS: A total of 612 patients underwent minimally invasive cholecystectomy: 279 cases for SPIDER cholecystectomy and 333 for multiport LC. Baseline differences in patient characteristics between the SPIDER and LC groups were statistically significant. The SPIDER group had younger and healthier patients (lower ASA classification scores) with predominant diagnosis of cholelithiasis (69 %) compared to the LC group which had more complex cases. Total complications rate for both SPIDER and LC were 0.4 % (n = 1) and 3 % (n = 10), respectively. Conversion to open cholecystectomy occurred in one patient from the LC group (0.3 %). Conversion rate from SPIDER to additional ports or LC was performed in 5 cases (1.8 %) with no conversions to open surgery. Hemoperitoneum was reported in 2 cases, one for each approach, requiring reoperation. CONCLUSION: Single-incision laparoscopic cholecystectomy with SPIDER is a safe and feasible technique with similar outcomes to multiport LC. However, statistical significant difference was reported in baseline characteristics of both groups. No incisional hernias were reported in this case series for either technique. PMID- 26932550 TI - Tips and tricks to avoid bile duct injury in SILC: an experience of 500 cases. AB - INTRODUCTION: Conventional laparoscopic cholecystectomy is the gold standard surgical treatment for symptomatic gallstones. Surgeons have attempted to minimize the number of incisions via single-incision laparoscopic cholecystectomy (SILC), which offers benefits including improved cosmesis, possibly less postoperative pain, and improved patient satisfaction. However, studies show that there is an increased risk of operative complications-in particular bile duct injuries. We report 500 consecutive cases of SILC performed without bile duct injury. METHODS: A retrospective study of 500 continuous cases of SILC performed by the same surgeon at a single institution was conducted. Data on patient demographics, operative details, and postoperative outcomes were collected and evaluated. Detailed analysis of surgical techniques specifically to reduce bile duct injury was performed and described in this study. RESULTS: In total, 500 patients underwent SILC during the study period. Eight patients needed additional ports to complete the surgery, while one was converted to an open surgery. No serious intraoperative complications, such as bile duct injury, were encountered. CONCLUSION: Our experience shows that with due care and caution during SILC, with particular attention towards achieving the critical view of safety and a standardized technique, bile duct injury in SILC can be avoided. PMID- 26932551 TI - The comparative costs of laparoscopic and open liver resection: a report for the 2nd International Consensus Conference on Laparoscopic Liver Resection. AB - BACKGROUND: The techniques of laparoscopic liver resection (LLR) have developed rapidly in selected centers, while global adoption of this approach has been cautious. The costs of LLR compared to open resection (OLR) are considered an important metric in evaluating this approach and may be a barrier to adoption in some centers. METHODS: To formulate a consensus statement using the Zurich-Danish consensus model to the question of "What are the comparative outcomes of cost for LLR and OLR, minor and major?" a systematic search of the literature was conducted. Results were presented to the jury in September 2014 and updated in August 30, 2015. Adjustments for currency conversions and inflation were not performed due to limitations in available data. RESULTS: Thirty-four studies were reviewed, and 11 relevant papers were selected for inclusion. No randomized control studies were found. Five studies were case-matched comparisons, while the remaining studies were retrospective reviews. The number of patients in each study ranged from 28 to 74, and the cumulative number of patients was 643 comparing 350 OLR to 293 LLR. Overall median hospital stay was lower for LLR at 4.6 versus 7.4 days. This remained valid when only the case-matched studies were analyzed, 4.6 (n = 178) versus 6.6 days (n = 266). The median overall total costs were 16.3 % lower (range 0 to -22 %) for LLR compared to OLR. This remained valid in the subgroup analysis of the case-matched studies, with a median 17.4 % lower costs for the LLR. Median OR costs were 3 % higher for LLR (range -9 to 40 %) but 32.9 % lower for hospital ward costs (range 0 to -60 %) when compared to OLR. CONCLUSIONS: Currently, the published literature indicates that overall hospital costs are less for LLR when compared to OLR (Level of evidence 3a and 3b). This evidence is strongest for minor hepatic resections. The decreased cost is based on savings in hospital ward costs and likely related to a significantly shorter hospital stay for LLR. PMID- 26932553 TI - Alcohol Use in College: The Relationship Between Religion, Spirituality, and Proscriptive Attitudes Toward Alcohol. AB - Developing interventions to address the problem of college drinking requires the identification of contributing factors to drinking behavior. It is believed that religion and spirituality (R/S) play a role, but the mechanism is unclear. Using a multi-dimensional R/S measure, an alcohol behavior inventory, and a religious affiliation proscription question, this study was designed to dive deeper into this connection. This study found that religious singing/chanting and reading sacred text were the best predictors of lower alcohol consumption. Furthermore, participants who perceive their religious tradition to be proscriptive reported less alcohol consumption and higher religious/spiritual profiles. PMID- 26932554 TI - Understanding the Relationship Between State Forgiveness and Psychological Wellbeing: A Qualitative Study. AB - Over the last 20 years, increasing attention has been given to associations between dispositional forgiveness and specific mental health problems. However, few studies have assessed whether forgiving real-life interpersonal hurts may be related to diverse psychological health outcomes. The present study addresses this gap by investigating, in depth, relationships between perceptions about state forgiveness and a variety of mental wellbeing outcomes as well as exploring perceptions about the factors that may modify such effects. Developing an understanding of a forgiveness wellbeing relationship is of relevance to healthcare workers, researchers and policy makers with an interest in improving public health. In-depth semi-structured interviews were conducted, and data were analysed using grounded theory methods. From England and Ireland, eleven adults who were affiliated with religious/spiritual and secular/atheist groups were recruited using purposive and convenience sampling methods. Key themes that appeared to be related to the effects of unforgiveness were: increases in negative affect; reduction in cognitive abilities and barriers to psychological and social growth. For the majority of participants, state forgiveness had strong ties to participants perceived sense of mental wellbeing, including reductions in negative affect, feeling positive emotions, positive relations with others, spiritual growth, a sense of meaning and purpose in life as well as a greater sense of empowerment. The data also revealed a number of factors that may positively or negatively influence a forgiveness-wellbeing link such as: viewing an offender as spiritually similar or different, responsibility/karma, blaming, wanting restitution/apology as well as practices such as meditation and prayer. The findings suggest that forgiving a range of real-life interpersonal offences may be an important determinant of psychological wellbeing, particularly among religious/spiritual populations. Further research is, however, needed. PMID- 26932552 TI - Targeting the Oxytocin System to Treat Addictive Disorders: Rationale and Progress to Date. AB - The neuropeptide oxytocin plays a role in reward, stress, social affiliation, learning, and memory processes. As such, there is increasing interest in oxytocin as a potential treatment for addictions. The endogenous oxytocin system is itself altered by short- or long-term exposure to drugs of abuse. A large number of preclinical studies in rodents have investigated the effect of oxytocin administration on various drug-induced behaviors to determine whether oxytocin can reverse the neuroadaptations occurring with repeated drug and alcohol use. In addition, the mechanisms by which oxytocin acts to modify the behavioral response to drugs of abuse are beginning to be understood. More recently, a few small clinical studies have been conducted in cocaine, cannabis, and alcohol dependence. This review summarizes the preclinical as well as clinical literature to date on the oxytocin system and its relevance to drug and alcohol addiction. PMID- 26932555 TI - Polycyclic aromatic hydrocarbons (PAHs) in water and sediment from a river basin: sediment-water partitioning, source identification and environmental health risk assessment. AB - The information on concentration levels, partitioning and sources of pollutants in aquatic environment is quite necessary for pollution treatment and quality criteria. In this work, sixteen priority polycyclic aromatic hydrocarbons (PAHs) recommended by U.S. Environmental Protection Agency in the water and sediment of Yinma River Basin were firstly investigated. Among 16 individual PAHs, naphthalene was the highest average concentration in water samples as well as in sediment samples, 67.2 ng/L and 825.06 ng/g, respectively, whereas benzo(g,h,i)perylene was undetected in water samples nor in sediment samples. For three PAH compositional patterns, concentrations of light (2-3 ring) PAHs were dominant in water and sediment, accounting for 71.69 and 86.98 % respectively. The PAH partitioning in the sediment-water system was studied, results showed that PAH partitioning was in an unsteady state and tended to accumulate in the sediment. The possible sources of PAHs in water and sediment were both identified as a mixed source of petroleum and combustion. The benzo(a)pyrene equivalents (EBaP) values for PAHs in the water and sediment in some sites were relatively higher, suggesting the existence of environmental health risk. PMID- 26932556 TI - Retraction Note to: Release, deposition and elimination of radiocesium (137Cs) in the terrestrial environment. PMID- 26932557 TI - Retraction Note to: Estimation of Anticipated Performance Index and Air Pollution Tolerance Index and of vegetation around the marble industrial areas of Potwar region: bioindicators of plant pollution response. PMID- 26932559 TI - Human health risks in an old gold mining area with circum-neutral drainage, central Portugal. AB - The former mine of Escadia Grande was active at the middle of 1900 and was exploited for Au and Ag. The mineralized quartz veins consist mainly of quartz, arsenopyrite, pyrite, rare chalcopyrite, galena, sphalerite, gold and argentite. The mine dumps and tailings were deposited close to a stream, and there is a river beach downstream used for recreational proposes. Two villages are also located close to the old mining area. Mine wastes contained up to 8090 mg/kg of As and 70.1 mg/kg of Sb. The waters of the stream that cross the mining area have circum-neutral pH values and contained elevated concentrations of As reaching up to 284 ug/L. However, geochemical speciation modeling (Phreeq C) revealed that As was mainly present as As (V). Arsenic concentrations in waters are attenuated throughout the stream, mainly by the iron-(hydro)-oxides adsorption upstream. However, at 2 km downstream of mine wastes in the river beach, the waters still exceeded 10 ug/L of As, the drinking water limit. The waters also have NO2-, Cu and Cd concentrations higher than drinking water limit. The stream sediments have As concentrations up to 45 times higher (3140 mg/kg) than the limit of the sediment guideline values of NWQMS (2000). The maximum arsenic concentrations in soils are also up to 27 times higher (5940 mg/kg) than the maximum concentrations in streams from FOREGS Geochemical Atlas of Europe. The use of river beach for recreational purposes causes cancer risk (4.48 * 10-6) higher than USEPA limit, mainly due to the arsenic exposure. Even for recreational purposes, stream sediments and soils in the old mining area have high non-carcinogenic effects (2.76 and 4.78, respectively) for children, also related to the arsenic exposure mainly by the ingestion pathway, and the risk is unacceptable according to the limits of USEPA. Moreover, the cancer risk resulting from exposure of adults to arsenic in soils also has unacceptable non-cancer risk (1.13). Arsenic is the main trace element that causes a human health concern in the Escadia Grande mining area. PMID- 26932558 TI - Risk mitigation by waste-based permeable reactive barriers for groundwater pollution control at e-waste recycling sites. AB - Permeable reactive barriers (PRBs) have proved to be a promising passive treatment to control groundwater contamination and associated human health risks. This study explored the potential use of low-cost adsorbents as PRBs media and assessed their longevity and risk mitigation against leaching of acidic rainfall through an e-waste recycling site, of which Cu, Zn, and Pb were the major contaminants. Batch adsorption experiments suggested a higher adsorption capacity of inorganic industrial by-products [acid mine drainage sludge (AMDS) and coal fly ash (CFA)] and carbonaceous recycled products [food waste compost (FWC) and wood-derived biochar] compared to natural inorganic minerals (limestone and apatite). Continuous leaching tests of sand columns with 10 wt% low-cost adsorbents were then conducted to mimic the field situation of acidic rainfall infiltration through e-waste-contaminated soils (collected from Qingyuan, China) by using synthetic precipitation leaching procedure (SPLP) solution. In general, Zn leached out first, followed by Cu, and finally delayed breakthrough of Pb. In the worst-case scenario (e.g., at initial concentrations equal to 50-fold of average SPLP result), the columns with limestone, apatite, AMDS, or biochar were effective for a relatively short period of about 20-40 pore volumes of leaching, after which Cu breakthrough caused non-cancer risk concern and later-stage Pb leaching considerably increased both non-cancer and lifetime cancer risk associated with portable use of contaminated water. In contrast, the columns with CFA or FWC successfully mitigated overall risks to an acceptable level for a prolonged period of 100-200 pore volumes. Therefore, with proper selection of low cost adsorbents (or their mixture), waste-based PRBs is a technically feasible and economically viable solution to mitigate human health risk due to contaminated groundwater at e-waste recycling sites. PMID- 26932560 TI - An unusual 32-membered copper(II) metallomacrocube based on a Cu4O3X cubic core: photocatalytic, electrocatalytic, and magnetic properties. AB - The first 32-membered Cu(II) cluster with a big cubic structure consisting of eight small cubic cores exhibited a high photocatalytic activity for the degradation of rhodamine B (~99%) dye within 15 min under UV light irradiation, effective electrocatalytic activity for nitrite reduction and strong antiferromagnetic interactions among the Cu(II) centers. PMID- 26932563 TI - Spin Circuit Model for 2D Channels with Spin-Orbit Coupling. AB - In this paper we present a general theory for an arbitrary 2D channel with "spin momentum locking" due to spin-orbit coupling. It is based on a semiclassical model that classifies all the channel electronic states into four groups based on the sign of the z-component of the spin (up (U), down (D)) and the sign of the x component of the velocity (+, -). This could be viewed as an extension of the standard spin diffusion model which uses two separate electrochemical potentials for U and D states. Our model uses four: U+, D+, U-, and D-. We use this formulation to develop an equivalent spin circuit that is also benchmarked against a full non-equilibrium Green's function (NEGF) model. The circuit representation can be used to interpret experiments and estimate important quantities of interest like the charge to spin conversion ratio or the maximum spin current that can be extracted. The model should be applicable to topological insulator surface states with parallel channels as well as to other layered structures with interfacial spin-orbit coupling. PMID- 26932562 TI - Anti-TNF certolizumab pegol induces antioxidant response in human monocytes via reverse signaling. AB - BACKGROUND: Anti TNF drugs have been widely used in rheumatoid arthritis (RA) but only 70 to 80 % of patients respond to this therapy. Exploring the mode of action of anti-TNF drugs remains important in order to improve the efficiency of the treatment and enhance our knowledge of inflammation. TNF-alpha exists as classical soluble cytokine as well as transmembrane protein (tmTNF-alpha). Evidence suggests that tmTNF-alpha can induce reverse signaling. In the present study, we have explored consequences of reverse signaling in human monocytes using certolizumab pegol (CZP). METHODS: Monocytes were purified from healthy blood donors and were incubated with CZP. Nuclear translocation of Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) was evaluated by wide-field microscopy and cell fractionation. Heme oxygenase 1 (HO-1) was assessed by RT-qPCR and western blot. Monocytes were stimulated with lipopolysaccharide (LPS). IL-1beta was quantitated by RT-qPCR. Reactive oxygen species (ROS) were evaluated by flow cytometry using the H2DCFDA fluorescent marker. RESULTS: CZP induced rapid minimal ROS production and Nrf2 nuclear translocation. This was followed by HO-1 mRNA and protein production. IL-1beta induction by LPS was inhibited at the mRNA and protein level. At a later time-point, CZP was able to counteract the strong production of ROS induced by LPS. Reverse signaling was suggested by short kinetics of Nrf2 translocation, extensive washing of CZP and the use of anti-TNF Rs antibodies. CONCLUSION: Our data suggest a novel mechanism of ROS modulation by CZP. This observation sheds new light on the function of reverse signaling and on potential mechanisms of action of anti-TNF drugs. PMID- 26932561 TI - Re-irradiating spinal column metastases using IMRT and VMAT with and without flattening filter - a treatment planning study. AB - BACKGROUND: The aim of this study was to investigate the potential of the flattening filter free (FFF) mode of a linear accelerator for intensity modulated radiation therapy (IMRT) and volumetric modulated arc therapy (VMAT) for patients with in-field recurrence of vertebral metastases. METHODS: An Elekta Synergy Linac with AgilityTM head is used to simulate the treatment of ten patients with locally recurrent spinal column metastases. Four plans were generated for each patient treating the vertebrae sparing the spinal cord: Dual arc VMAT and nine field step and shoot IMRT each with and without flattening filter. Plan quality was assessed considering target coverage and sparing of the spinal cord and normal tissue. All plans were verified by a 2D-ionisation-chamber-array, peripheral doses were measured and compared to calculations. Delivery times were measured and compared. The Wilcoxon test was used for statistical analysis with a significance level of 0.05. RESULTS: Target coverage, homogeneity index and conformity index were comparable for both flat and flattening filter free beams. The volume of the spinal cord receiving the allowed maximum dose to keep the risk of radiation myelopathy at 0 % was at the same time significantly reduced to below the clinically relevant 1 ccm using FFF mode. In addition the mean dose deposited in the surrounding healthy tissue was significantly reduced in the FFF mode. All four techniques showed equally good gamma scores for plan verification. FFF plans required considerably more MU per fraction dose. Regardless of the large number of MU, out-of-field point dose was significantly lower for FFF plans, with an average reduction of 33 % and mean delivery time was significantly reduced by 22 % using FFF beams. When compared to IMRT FF, VMAT FFF offered even a reduction of 71 % in delivery time and 45 % in peripheral dose. CONCLUSIONS: FFF plans showed a significant improvement in sparing of normal tissue and the spinal cord, keeping target coverage and homogeneity comparable. In addition, delivery times were significantly reduced for FFF treatments, minimizing intrafractional motion as well as strain for the patient. Shortest delivery times were achieved using VMAT FFF. For radiotherapy of spinal column metastases VMAT FFF may therefore be considered the preferable treatment option for the combination of Elekta Synergy Linacs and Oncentra(r) External Beam v4.5 treatment planning system. PMID- 26932564 TI - Atrial Fibrillation Identified During Echocardiography in a Patient with Recurrent Cardioembolic Events: A Case Report. AB - BACKGROUND: Stroke is the major cause of disability and the fifth leading cause of death in the United States. In 30-40% of strokes the etiology remains uncertain or unknown. Identifying the cause of a cerebrovascular event offers the opportunity for an intervention that may decrease the risk of future stroke and thus prevent the resultant impairment. CASE REPORT: We report the case of an 80 year-old African American woman with a prior right middle cerebral artery stroke, who presented to the hospital with new left-sided weakness and was found to have a new right-sided frontal lobe infarct. Twenty-four hour Holter monitoring performed during this hospitalization and prior 24-h electrocardiogram (ECG) recording did not reveal an arrhythmia. However, the patient was found to have an isolated episode of atrial fibrillation (AF) during an echocardiogram as part of the evaluation for stroke etiology. CONCLUSIONS: AF is an important and treatable cause of recurrent stroke and needs to be ruled out by thorough evaluation before the diagnosis of cryptogenic stroke is assigned. Despite meticulous diagnostic work-up, many strokes caused by paroxysmal AF remain undetected and longer ECG monitoring (>24 h) may be required. PMID- 26932565 TI - Two-dimensional-NGC-SENSE-GRAPPA for fast, ghosting-robust reconstruction of in plane and slice-accelerated blipped-CAIPI echo planar imaging. AB - PURPOSE: Ghosting-robust reconstruction of blipped-CAIPI echo planar imaging simultaneous multislice data with low computational load. METHODS: To date, Slice GRAPPA, with "odd-even" kernels that improve ghosting performance, has been the framework of choice for such reconstructions due to its predecessor SENSE-GRAPPA being deemed unsuitable for blipped-CAIPI data. Modifications to SENSE-GRAPPA are used to restore CAIPI compatibility and to make it robust against ghosting. Two implementations are tested, one where slices and in-plane unaliasing are dealt in the same serial manner as in Slice-GRAPPA [referred to as one-dimensional (1D) NGC-SENSE-GRAPPA, where NGC stands for Nyquist Ghost Corrected] and one where both are unaliased in a single step (2D-NGC-SENSE-GRAPPA), which is analytically and experimentally shown to be computationally cheaper. RESULTS: The 1D-NGC-SENSE GRAPPA and odd-even Slice-GRAPPA perform identically, whereas 2D-NGC-SENSE-GRAPPA shows reduced error propagation, less residual ghosting when reliable reference data were available. When the latter was not the case, error propagation was increased. CONCLUSION: Unlike Slice-GRAPPA, SENSE-GRAPPA operates fully within the GRAPPA framework, for which improved reconstructions (e.g., iterative, nonlinear) have been developed over the past decade. It could, therefore, bring benefit to the reconstruction of SMS data as an attractive alternative to Slice GRAPPA. Magn Reson Med 77:998-1009, 2017. (c) 2016 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. PMID- 26932566 TI - Modeling Demic and Cultural Diffusion: An Introduction. AB - Identifying the processes by which human cultures spread across different populations is one of the most topical objectives shared among different fields of study. Seminal works have analyzed a variety of data and attempted to determine whether empirically observed patterns are the result of demic and/or cultural diffusion. This special issue collects articles exploring several themes (from modes of cultural transmission to drivers of dispersal mechanisms) and contexts (from the Neolithic in Europe to the spread of computer programming languages), which offer new insights that will augment the theoretical and empirical basis for the study of demic and cultural diffusion. In this introduction we outline the state of art in the modeling of these processes, briefly discuss the pros and cons of two of the most commonly used frameworks (equation-based models and agent-based models), and summarize the significance of each article in this special issue. PMID- 26932567 TI - Cultural Incubators and Spread of Innovation. AB - Several forms of social learning rely on the direct or indirect evaluation of the fitness of cultural traits. Here we argue, via a simple agent-based model, that payoff uncertainty, that is, the correlation between a trait and the signal used to evaluate its fitness, plays a pivotal role in the spread of beneficial innovation. More specifically, we examine how this correlation affects the evolutionary dynamics of different forms of social learning and how each form can generate divergent historical trajectories depending on the size of the sample pool. In particular, we demonstrate that social learning by copying the best model is particularly susceptible to a sampling effect caused by the interaction of payoff uncertainty, the number of models sampled (the sample pool), and the frequency with which a trait is present in the population. As a result, we identify circumstances in which smaller sample pools can act as "cultural incubators" that promote the spread of innovations, while more widespread sampling of the population actually retards the rate of cultural evolution. PMID- 26932568 TI - So You Think You Can Model? A Guide to Building and Evaluating Archaeological Simulation Models of Dispersals. AB - With the current surge of simulation studies in archaeology, there is a growing concern for the lack of engagement and feedback between modelers and domain specialists. To facilitate this dialogue, I present a compact guide to the simulation modeling process applied to a common research topic and the focus of this special issue of Human Biology--human dispersals. The process of developing a simulation is divided into nine steps grouped in three phases. The conceptual phase consists of identifying research questions (step 1), finding the most suitable method (step 2), designing the general framework and the resolution of the simulation (step 3), and filling in that framework with the modeled entities and the rules of interactions (step 4). This is followed by the technical phase of coding and testing (step 5), parameterizing the simulation (step 6), and running it (step 7), and the results of the simulation are analyzed and recontextualized (step 8). In the dissemination phase, the findings of the model are disseminated in publications and code repositories (step 9). Each step is defined and characterized and then illustrated with examples of published human dispersal simulation studies. While not aiming to be a comprehensive textbook style guide to simulation, this overview of the process of modeling human dispersals should arm any nonmodeler with enough understanding to evaluate the quality, strengths, and weaknesses of any particular archaeological simulation and provide a starting point for further exploration of this common scientific tool. PMID- 26932569 TI - Inference of Cultural Transmission Modes Based on Incomplete Information. AB - In this article we explore the theoretical limits of the inference of cultural transmission modes based on sparse population-level data. We approach this problem by investigating whether different transmission modes produce different temporal dynamics of cultural change. In particular, we explore whether different transmission modes result in sufficiently different distributions of the average time a variant stays the most common variant in the population, tmax, so that their inference can be guaranteed on the basis of an estimate of tmax. We assume time series data detailing the frequencies of different variants of a cultural trait in a population at different points in time and investigate the temporal resolution (i.e., the length of the time series and the distance between consecutive time points) that is needed to ensure distinguishability between transmission modes. We find that under complete information most transmission modes can be distinguished on the basis of the statistic tmax; however, we should not expect the same results if only infrequent information about the most common cultural variant in the population is available. PMID- 26932570 TI - Does Environmental Knowledge Inhibit Hominin Dispersal? AB - We investigated the relationship between the dispersal potential of a hominin population, its local-scale foraging strategies, and the characteristics of the resource environment using an agent-based modeling approach. In previous work we demonstrated that natural selection can favor a relatively low capacity for assessing and predicting the quality of the resource environment, especially when the distribution of resources is highly clustered. That work also suggested that the more knowledge foraging populations had about their environment, the less likely they were to abandon the landscape they know and disperse into novel territory. The present study gives agents new individual and social strategies for learning about their environment. For both individual and social learning, natural selection favors decreased levels of environmental knowledge, particularly in low-heterogeneity environments. Social acquisition of detailed environmental knowledge results in crowding of agents, which reduces available reproductive space and relative fitness. Agents with less environmental knowledge move away from resource clusters and into areas with more space available for reproduction. These results suggest that, rather than being a requirement for successful dispersal, environmental knowledge strengthens the ties to particular locations and significantly reduces the dispersal potential as a result. The evolved level of environmental knowledge in a population depends on the characteristics of the resource environment and affects the dispersal capacity of the population. PMID- 26932571 TI - A Cultural Diffusion Model for the Rise and Fall of Programming Languages. AB - Our interaction with complex computing machines is mediated by programming languages (PLs), which constitute one of the major innovations in the evolution of technology. PLs allow flexible, scalable, and fast use of hardware and are largely responsible for shaping the history of information technology since the rise of computers in the 1950s. The rapid growth and impact of computers were followed closely by the development of PLs. As occurs with natural, human languages, PLs have emerged and gone extinct. There has been always a diversity of coexisting PLs that compete somewhat while occupying special niches. Here we show that the statistical patterns of language adoption, rise, and fall can be accounted for by a simple model in which a set of programmers can use several PLs, decide to use existing PLs used by other programmers, or decide not to use them. Our results highlight the influence of strong communities of practice in the diffusion of PL innovations. PMID- 26932572 TI - Productivity of Premodern Agriculture in the Cucuteni-Trypillia Area. AB - We present paleoeconomy reconstructions for premodern agriculture, selecting, wherever required, features and parameter values specific for the Cucuteni Trypillia cultural unity (CTU; 5,400-2,700 BC, mostly the territory of modern Ukraine, Moldova, and Romania). We verify the self-consistency and viability of the archaeological evidence related to all major elements of the agricultural production cycle within the constraints provided by environmental and technological considerations. The starting point of our analysis is the paleodiet structure suggested by archaeological data, stable isotope analyses of human remains, and palynology studies in the CTU area. We allow for the archeologically attested contributions of domesticated and wild animal products to the diet, develop plausible estimates of the yield of ancient cereal varieties cultivated with ancient techniques, and quantify the yield dependence on the time after initial planting and on rainfall (as a climate proxy). Our conclusions involve analysis of the labor costs of various seasonal parts of the agricultural cycle of both an individual and a family with a majority of members that do not engage in productive activities that require physical fitness, such as tillage. Finally, we put our results into the context of the exploitation territory and catchment analysis, to project various subsistence strategies into the exploitation territory of a farming settlement. The simplest economic complex based on cereals and domestic and wild animal products, with fallow cropping, appears to be capable of supporting an isolated, relatively small farming settlement of 50-300 people (2-10 ha in area) even without recourse to technological improvements such as the use of manure fertilizer. Our results strongly suggest that dairy products played a significant role in the dietary and labor balance. The smaller settlements are typical of the earliest Trypillia A stage but remain predominant at the later stages. A larger settlement of several hundred people could function in isolation, perhaps with a larger fraction of cereals in the diet, only with technological innovations, such as manure fertilizer and, most important, ard tillage. The ard radically relieves the extreme time pressure associated with soil preparation for sowing. It appears that very large settlements of a few hundred hectares in area, found in the CTU region, could function only if supported by satellite farming villages and stable exchange networks. In turn, this implies social division of labor and occupation, sufficiently complex social relations, stable exchange channels, and so on: altogether, a proto-urban character of such settlements. A model is proposed for the lifetime of a farming settlement, assuming that it is limited by the soil fertility (the depleted resources model), that provides a lifetime estimate consistent with the archaeological evidence available (100-150 years). The model shows that the lifetime strongly depends on the fraction of the arable land area kept fallow. We also discuss, quantify, and assess some strategies to mitigate the risks of arable agriculture associated with strong temporal fluctuations in the cereal yield, such as manure fertilization, and increased fraction of cereals in the diet combined with producing grain surplus for emergency storage. PMID- 26932573 TI - Winners of the 2015 AAAG Outstanding Postdoc Presentation in Anthropological Genetics Awards. PMID- 26932574 TI - Spin generation via bulk spin current in three-dimensional topological insulators. AB - To date, spin generation in three-dimensional topological insulators is primarily modelled as a single-surface phenomenon, attributed to the momentum-spin locking on each individual surface. In this article, we propose a mechanism of spin generation where the role of the insulating yet topologically non-trivial bulk becomes explicit: an external electric field creates a transverse pure spin current through the bulk of a three-dimensional topological insulator, which transports spins between the top and bottom surfaces. Under sufficiently high surface disorder, the spin relaxation time can be extended via the Dyakonov-Perel mechanism. Consequently, both the spin generation efficiency and surface conductivity are largely enhanced. Numerical simulation confirms that this spin generation mechanism originates from the unique topological connection of the top and bottom surfaces and is absent in other two-dimensional systems such as graphene, even though they possess a similar Dirac cone-type dispersion. PMID- 26932575 TI - Changes in Discard Rate After the Introduction of the Kidney Donor Profile Index (KDPI). AB - Since March 26, 2012, the Kidney Donor Profile Index (KDPI) has been provided with all deceased-donor kidney offers, with the goal of improving the expanded criteria donor (ECD) indicator. Although an improved risk index may facilitate identification and transplantation of marginal yet viable kidneys, a granular percentile system may reduce provider-patient communication flexibility, paradoxically leading to more discards ("labeling effect"). We studied the discard rates of the kidneys recovered for transplantation between March 26, 2010 and March 25, 2012 ("ECD era," N = 28 636) and March 26, 2012 and March 25, 2014 ("KDPI era," N = 29 021) using Scientific Registry of Transplant Recipients (SRTR) data. There was no significant change in discard rate from ECD era (18.1%) to KDPI era (18.3%) among the entire population (adjusted odds ratio [aOR] = 0.97 1.041.10 , p = 0.3), or in any KDPI stratum. However, among kidneys in which ECD and KDPI indicators were discordant, "high risk" standard criteria donor (SCD) kidneys (with KDPI > 85) were at increased risk of discard in the KDPI era (aOR = 1.07 1.421.89 , p = 0.02). Yet, recipients of these kidneys were at much lower risk of death (adjusted Risk Ratio [aRR] = 0.56 0.770.94 at 2 years posttransplant) compared to those remaining on dialysis waiting for low-KDPI kidneys. Our findings suggest that there might be an unexpected, harmful labeling effect of reporting a high KDPI for SCD kidneys, without the expected advantage of providing a more granular risk index. PMID- 26932577 TI - Bordetella pertussis epidemiology and evolution in the light of pertussis resurgence. AB - Whooping cough, or pertussis, is resurgent in many countries world-wide. This is linked to switching from the use of whole cell vaccines to acellular vaccines in developed countries. Current evidence suggests that this has resulted in the earlier waning of vaccine-induced immunity, an increase in asymptomatic infection with concomitant increases in transmission and increased selection pressure for Bordetellapertussis variants that are better able to evade vaccine-mediated immunity than older isolates. This review discusses recent findings in B. pertussis epidemiology and evolution in the light of pertussis resurgence, and highlights the important role for genomics-based studies in monitoring B. pertussis adaptation. PMID- 26932576 TI - PU.1 cooperates with IRF4 and IRF8 to suppress pre-B-cell leukemia. AB - The Ets family transcription factor PU.1 and the interferon regulatory factor (IRF)4 and IRF8 regulate gene expression by binding to composite DNA sequences known as Ets/interferon consensus elements. Although all three factors are expressed from the onset of B-cell development, single deficiency of these factors in B-cell progenitors only mildly impacts on bone marrow B lymphopoiesis. Here we tested whether PU.1 cooperates with IRF factors in regulating early B cell development. Lack of PU.1 and IRF4 resulted in a partial block in development the pre-B-cell stage. The combined deletion of PU.1 and IRF8 reduced recirculating B-cell numbers. Strikingly, all PU.1/IRF4 and ~50% of PU.1/IRF8 double deficient mice developed pre-B-cell acute lymphoblastic leukemia (B-ALL) associated with reduced expression of the established B-lineage tumor suppressor genes, Ikaros and Spi-B. These genes are directly regulated by PU.1/IRF4/IRF8, and restoration of Ikaros or Spi-B expression inhibited leukemic cell growth. In summary, we demonstrate that PU.1, IRF4 and IRF8 cooperate to regulate early B cell development and to prevent pre-B-ALL formation. PMID- 26932578 TI - Bluetongue virus surveillance in the Islamic Republic of Mauritania: Is serotype 26 circulating among cattle and dromedaries? AB - In March 2013, EDTA-blood and serum samples were collected from 119 cattle and 159 dromedaries at the slaughterhouse of Nouakchott, the capital city of the Islamic Republic of Mauritania. Serum samples were screened for the presence of Bluetongue (BT) antibodies by competitive ELISA (cELISA). Positive samples were then tested by serum-neutralization (SN) to determine BTV serotype. RNA from blood samples was first tested by a genus-specific quantitative RT-PCR assay which is able to detect all 27 existing BTV serotypes (RT-qPCR1-27). Positive samples were further screened by a RT-qPCR assay which, instead, is able to detect the classical 24 BTV serotypes only (RT-qPCR1-24). Of the 278 serum samples tested, 177 (mean=63.7%; 95% CI: 57.9%-69.1%) resulted positive by cELISA. Of these, 69 were from cattle (mean=58.0%; 95% CI: 49.0%-66.5%) and 108 from dromedaries (mean=67.9%; 95% CI: 60.3%-74.7%). BTV-26 neutralizing antibodies were by far the most frequently found as they were detected in 146 animals with titres ranging from 1:10 to 1:80. Out of 278 blood samples, 25 (mean=9.0%; 95% CI: 6.2%-12.9%) were found positive for BTV by RT-qPCR1-27, 20 (mean=16.8%; 95% CI: 11.2%-24.6%) were from cattle and 5 (mean=3.1%; 95% CI: 1.4% 7.1%) from dromedaries. When tested by RT-qPCR1-24 the 25 BTV positive samples were negative. Unfortunately, no genetic information by molecular typing or by next generation sequencing has been obtained as for the very low levels of RNA in the blood samples. PMID- 26932579 TI - Obesity and oxidative stress in patients with different periodontal status: a case-control study. AB - BACKGROUND AND OBJECTIVE: Obesity has become an important global health concern as obesity-associated adiposity is supposedly related to systemic immunologic and inflammatory alterations. The aim of this study was to evaluate the effects of obesity on periodontally healthy and diseased tissue according to the changes in malondialdehyde (MDA), protein carbonyl (PC) and total antioxidant capacity (TAOC) levels in gingival crevicular fluid as biomarkers of oxidative stress (OS). MATERIAL AND METHODS: The study sample comprised systemically healthy normal-weight (n = 45) and obese (n = 48) adults. Obesity was diagnosed according to body mass index, waist circumference and waist/hip ratio. Periodontal status was evaluated according to plaque index, gingival index, bleeding on probing, probing depth and clinical attachment level. Participants were distributed among six groups according to obesity and periodontal status, as follows: normal weight+periodontally healthy (NH); normal weight+gingivitis (NG); normal weight+generalized chronic periodontitis (NCP); obese+periodontally healthy (OH); obese+gingivitis (OG); and obese+generalized chronic periodontitis (OCP). MDA, PC and TAOC levels were measured using ELISA. RESULTS: The MDA and PC levels in gingival crevicular fluid varied among groups, as follows: NCP > NG > NH (p < 0.01) and OCP > OG > OH (p < 0.01). Conversely, the levels of TAOC in gingival crevicular fluid varied as follows: NCP < NG < NH (p < 0.01) and OCP < OG < OH (p < 0.01). Paired comparisons conducted according to periodontal status showed MDA and PC levels to be higher, and TAOC levels to be lower, in the OCP group than in the NCP group, in the OG group than in the NG group and in the OH group than in the NH group. However, only the differences between the OCP and NCP groups were significant (p < 0.01). In both obese and normal-weight individuals, clinical assessments showed significant, positive correlations with MDA and PC levels and negative correlations with TAOC levels (p < 0.01). CONCLUSION: Obesity may influence periodontal tissue destruction and disease severity by increasing the level of oxidative stress in the presence of periodontal disease. PMID- 26932580 TI - Alpha proteobacteria of genus Anaplasma (Rickettsiales: Anaplasmataceae): Epidemiology and characteristics of Anaplasma species related to veterinary and public health importance. AB - The Anaplasma species are important globally distributed tick-transmitted bacteria of veterinary and public health importance. These pathogens, cause anaplasmosis in domestic and wild animal species including humans. Rhipicephalus, Ixodes, Dermacentor and Amblyomma genera of ticks are the important vectors of Anaplasma. Acute anaplasmosis is usually diagnosed upon blood smear examination followed by antibodies and nucleic acid detection. All age groups are susceptible but prevalence increases with age. Serological cross-reactivity is one of the important issues among Anaplasma species. They co-exist and concurrent infections occur in animals and ticks in same geographic area. These are closely related bacteria and share various common attributes which should be considered while developing vaccines and diagnostic assays. Movement of susceptible animals from non-endemic to endemic regions is the major risk factor of bovine/ovine anaplasmosis and tick-borne fever. Tetracyclines are currently available drugs for clearance of infection and treatment in humans and animals. Worldwide vaccine is not yet available. Identification, elimination of reservoirs, vector control (chemical and biological), endemic stability, habitat modification, rearing of tick resistant breeds, chemotherapy and tick vaccination are major control measures of animal anaplasmosis. Identification of reservoirs and minimizing the high-risk tick exposure activities are important control strategies for human granulocytic anaplasmosis. PMID- 26932581 TI - The autophagy-related protein LC3 is processed in stallion spermatozoa during short-and long-term storage and the related stressful conditions. AB - Use of cooled and frozen semen is becoming increasingly prevalent in the equine industry. However, these procedures cause harmful effects in the sperm cell resulting in reduced cell lifespan and fertility rates. Apoptosis and necrosis related events are increased during semen cryopreservation. However, a third type of cell death, named autophagy, has not been studied during equine semen storage. Light chain (LC)3 protein is a key component of the autophagy pathway. Under autophagy activation, LC3-I is lipidated and converted to LC3-II. The ratio of LC3-II/LC3-I is widely used as a marker of autophagy activation. The main objective of this study was to investigate whether LC3 is processed during cooling, freezing and the stressful conditions associated with these technologies. A secondary objective was to determine if LC3 processing can be modulated and if that may improve the quality of cryopreserved semen. LC3 processing was studied by Western blot with a specific antibody that recognized both LC3-I and LC3-II. Viability was assessed by flow cytometry. Modulation of LC3-I to LC3-II was studied with known autophagy activators (STF-62247 and rapamycin) or inhibitors (chloroquine and 3-MA) used in somatic cells. The results showed that conversion of LC3-I to LC3-II increased significantly during cooling at 4 degrees C, freezing/thawing and each of the stressful conditions tested (UV radiation, oxidative stress, osmotic stress and changes in temperature). STF-62247 and rapamycin increased the LC3-II/LC3-I ratio and decreased the viability of equine sperm, whereas chloroquine and 3-MA inhibited LC3 processing and maintained the percentage of viable cells after 2 h of incubation at 37 degrees C. Finally, refrigeration at 4 degrees C for 96 h and freezing at -196 degrees C in the presence of chloroquine and 3-MA resulted in higher percentages of viable cells. In conclusion, results showed that an 'autophagy-like' mechanism may be involved in the regulation of sperm viability during equine semen cryopreservation. Modulation of autophagy during these reproductive technologies may result in an improvement of semen quality and therefore in higher fertility rates. PMID- 26932582 TI - The Milky Way Sign: A New Diagnostic Finding of Ductal Carcinoma in situ on Digital Breast Tomosynthesis. PMID- 26932584 TI - Inconsistencies in reporting of renal elimination among NOACs: the case of apixaban. PMID- 26932583 TI - Small Molecule Inhibited Parathyroid Hormone Mediated cAMP Response by N-Terminal Peptide Binding. AB - Ligand binding to certain classes of G protein coupled receptors (GPCRs) stimulates the rapid synthesis of cAMP through G protein. Human parathyroid hormone (PTH), a member of class B GPCRs, binds to its receptor via its N terminal domain, thereby activating the pathway to this secondary messenger inside cells. Presently, GPCRs are the target of many pharmaceuticals however, these drugs target only a small fraction of structurally known GPCRs (about 10%). Coordination complexes are gaining interest due to their wide applications in the medicinal field. In the present studies we explored the potential of a coordination complex of Zn(II) and anthracenyl-terpyridine as a modulator of the parathyroid hormone response. Preferential interactions at the N-terminal domain of the peptide hormone were manifested by suppressed cAMP generation inside the cells. These observations contribute a regulatory component to the current GPCR cAMP paradigm, where not the receptor itself, but the activating hormone is a target. To our knowledge, this is the first report about a coordination complex modulating GPCR activity at the level of deactivating its agonist. Developing such molecules might help in the control of pathogenic PTH function such as hyperparathyroidism, where control of excess hormonal activity is essentially required. PMID- 26932585 TI - Blood lipid levels, statin therapy and the risk of intracerebral hemorrhage. AB - Dyslipidemia has been proven to play an important role in the occurrence and development of the ischemic stroke and lipid-lowering therapy could significantly decrease the risk of the ischemic stroke. However, the association between lipid levels, lipid-lowering therapy and the risk of intracerebral hemorrhage (ICH) is not clear. Studies have shown that low serum levels of total cholesterol might be associated with increasing risk of ICH, whereas the SPARCL study, a large prospective, randomized, placebo-controlled trial, demonstrated an increased risk of hemorrhagic stroke during high-dose statin therapy among the patients with previous stroke. The relationship between lipid-lowering therapy and ICH has become a hot topic in the recent years. We searched PubMed for articles published in English to review the existing evidence on the association of lipid levels, statin therapy and risk of ICH as well as the underlying mechanisms in order to provide practical recommendations for clinical decision-making and a foundation for further researches. PMID- 26932586 TI - Salinomycin efficiency assessment in non-tumor (HB4a) and tumor (MCF-7) human breast cells. AB - The search for anticancer drugs has led researchers to study salinomycin, an ionophore antibiotic that selectively destroys cancer stem cells. In this study, salinomycin was assessed in two human cell lines, a breast adenocarcinoma (MCF-7) and a non-tumor breast cell line (HB4a), to verify its selective action against tumor cells. Real-time assessment of cell proliferation showed that HB4a cells are more resistant to salinomycin than MCF-7 tumor cell line, and these data were confirmed in a cytotoxicity assay. The half maximal inhibitory concentration (IC50) values show the increased sensitivity of MCF-7 cells to salinomycin. In the comet assay, only MCF-7 cells showed the induction of DNA damage. Flow cytometric analysis showed that cell death by apoptosis/necrosis was only induced in the MCF-7 cells. The increased expression of GADD45A and CDKN1A genes was observed in all cell lines. Decreased expression of CCNA2 and CCNB1 genes occurred only in tumor cells, suggesting G2/M cell cycle arrest. Consequently, cell death was activated in tumor cells through strong inhibition of the antiapoptotic genes BCL-2, BCL-XL, and BIRC5 genes in MCF-7 cells. These data demonstrate the selectivity of salinomycin in killing human mammary tumor cells. The cell death observed only in MCF-7 tumor cells was confirmed by gene expression analysis, where there was downregulation of antiapoptotic genes. These data contribute to clarifying the mechanism of action of salinomycin as a promising antitumor drug and, for the first time, we observed the higher resistance of HB4a non-tumor breast cells to salinomycin. PMID- 26932587 TI - The Evolution of Mechanical Thrombectomy for Acute Stroke. AB - OPINION STATEMENT: The natural history of an acute ischemic stroke from a large vessel occlusion (LVO) is poor and has long challenged stroke therapy. Recently, endovascular therapy has demonstrated superiority to medical management in appropriately selected patients. This advance has revolutionized acute care for LVO and mandates a reevaluation of the entire chain of stroke care delivery, including patient selection, intervention, and post-procedural care. Since endovascular therapy is a therapy specifically targeting LVO, its application should be restricted to those patients only. Clinical and radiologic parameters need to be considered in patient selection. Data supports that all patients over the age of 18 years presenting with a National Institutes of Health Stroke Scale (NIHSS) of 6 or greater within 6 hours of symptom onset should be considered for emergent endovascular therapy. Radiologically, those with a LVO of the internal carotid artery (ICA) or middle cerebral artery (MCA) M1 portion, intermediate or good collaterals and without large established infarct should be considered endovascular candidates. Selection beyond these parameters remains an open question and is being actively evaluated. In all cases, revascularization should be attempted with a new generation device (stentriever or direct aspiration), as these techniques are most likely to deliver adequate reperfusion. Post revascularization, patients are closely monitored in an intensive care setting followed by discharge to rehabilitation, if required, or directly home. Patients should be evaluated in delayed fashion to assess recovery (typically at 3 months post-treatment). Ultimately, the poor natural history of ischemic stroke from LVO and the potential significant benefit from endovascular therapy over medical management alone necessitate a national response to ensure we identify and treat all eligible patients as rapidly and effectively as possible. PMID- 26932589 TI - Skin cancer in patients with psoriasis. AB - BACKGROUND: Psoriasis is a chronic inflammatory skin disease that is commonly treated with ultraviolet phototherapy and systemic immunosuppressant drugs, which may confer a risk of skin cancer. Previous studies on the risk of skin cancer in patients with psoriasis have shown conflicting results. OBJECTIVES: We investigated the risk of new-onset melanoma and non-melanoma skin cancer (NMSC), respectively, in a large cohort of patients with psoriasis and psoriatic arthritis. METHODS: Data on all Danish individuals aged >=18 years between 1 January 1997 and 31 December 2012 were linked at individual-level in nationwide registers. Incidence rates per 10 000 person-years were calculated, and incidence rate ratios (IRRs) were estimated by Poisson regression models. RESULTS: The study comprised 5 559 420 individuals with a maximum follow-up time of 16 years. There were 75 410 patients with psoriasis, and 25 087 and 58 051 individuals developed melanoma and NMSC, respectively, during follow-up. Adjusted IRRs (95% CI) of melanoma were 1.19 (1.03-1.37), 1.09 (0.75-1.58) and 1.36 (0.94-1.99), in mild psoriasis, severe psoriasis and psoriatic arthritis, respectively, and the corresponding adjusted IRRs of NMSC were 1.67 (1.55-1.81), 1.32 (1.10-1.59) and 1.62 (1.27-2.05) respectively. CONCLUSIONS: We observed a modestly increased risk of melanoma and NMSC in patients with mild psoriasis, whereas patients with severe psoriasis and psoriatic arthritis had increased risk of NMSC but not melanoma. While the risk of skin cancer is only modestly increased in patients with psoriasis, clinicians should remain vigilant. PMID- 26932588 TI - Anti-VEGF-Induced Hypertension: a Review of Pathophysiology and Treatment Options. AB - OPINION STATEMENT: Abnormal intracellular signaling has been implicated in the development of many different types of cancer. Therapies targeting these abnormal pathways have revolutionized the treatment of many malignancies leading to significantly improved outcomes and survival. Despite these advances, cardiovascular toxicity is a frequently reported complication. Angiogenesis is the physiologic process of new blood vessel development and can be dysregulated in some forms of cancer. VEGF inhibitors are the pharmaceutical agents targeting this pathway; however hypertension is a commonly observed toxicity which can have significant adverse consequences including premature cessation of therapy if adequate blood pressure control cannot be achieved. This review will provide a comprehensive discussion about hypertension due to VEGF inhibition, focusing on pathophysiology, frequently used agents, and available treatment options for VEGF induced hypertension. PMID- 26932590 TI - Development of a multiplex PCR assay to detect the major clonal complexes of Streptococcus suis relevant to human infection. AB - Multilocus sequence typing (MLST) is considered a reliable method for providing insight into the Streptococcus suis population structure, clonal relationships and the potential of particular clones to cause disease. Indeed, MLST has revealed the presence of several clonal complexes (CCs) within the Streptococcus suis population. However, the method is costly, time-consuming and difficult to use for screening large numbers of isolates. In this study, a multiplex PCR assay was developed to identify Streptococcus suis CCs that are relevant to human infections. The multiplex PCR assay was capable of simultaneously distinguishing CC1, CC25, CC28, CC104, CC221/234 and CC233/379, which are related to human infections in Thailand, in a single reaction. The multiplex PCR assay is useful for low-cost screening of large numbers of isolates with rapid analytical capacity and could be utilized in most laboratories. PMID- 26932591 TI - Correction: Convenient C-alkylation of the [HCB11Cl11](-) carborane anion. AB - Correction for 'Convenient C-alkylation of the [HCB11Cl11](-) carborane anion' by Rodrigo Ramirez-Contreras and Oleg V. Ozerov, Dalton Trans., 2012, 41, 7842-7844. PMID- 26932592 TI - Cancer survival analysis using semi-supervised learning method based on Cox and AFT models with L1/2 regularization. AB - BACKGROUND: One of the most important objectives of the clinical cancer research is to diagnose cancer more accurately based on the patients' gene expression profiles. Both Cox proportional hazards model (Cox) and accelerated failure time model (AFT) have been widely adopted to the high risk and low risk classification or survival time prediction for the patients' clinical treatment. Nevertheless, two main dilemmas limit the accuracy of these prediction methods. One is that the small sample size and censored data remain a bottleneck for training robust and accurate Cox classification model. In addition to that, similar phenotype tumours and prognoses are actually completely different diseases at the genotype and molecular level. Thus, the utility of the AFT model for the survival time prediction is limited when such biological differences of the diseases have not been previously identified. METHODS: To try to overcome these two main dilemmas, we proposed a novel semi-supervised learning method based on the Cox and AFT models to accurately predict the treatment risk and the survival time of the patients. Moreover, we adopted the efficient L1/2 regularization approach in the semi-supervised learning method to select the relevant genes, which are significantly associated with the disease. RESULTS: The results of the simulation experiments show that the semi-supervised learning model can significant improve the predictive performance of Cox and AFT models in survival analysis. The proposed procedures have been successfully applied to four real microarray gene expression and artificial evaluation datasets. CONCLUSIONS: The advantages of our proposed semi-supervised learning method include: 1) significantly increase the available training samples from censored data; 2) high capability for identifying the survival risk classes of patient in Cox model; 3) high predictive accuracy for patients' survival time in AFT model; 4) strong capability of the relevant biomarker selection. Consequently, our proposed semi-supervised learning model is one more appropriate tool for survival analysis in clinical cancer research. PMID- 26932594 TI - Hypertension and non-alcoholic fatty liver disease proven by transient elastography. AB - AIM: The relationship between non-alcoholic fatty liver disease (NAFLD) and hypertension is poorly understood. In the present study, we aimed to assess the relationship between essential hypertension and NAFLD, by using a new diagnostic tool, transient elastography (TE). METHODS: We enrolled 836 subjects in this study. All subjects underwent a comprehensive questionnaire survey and blood test. Each patient had undergone TE to detect the controlled attenuation parameter, which was used to and quantify liver steatosis with the help of TE. RESULTS: Participants with hypertension showed a higher prevalence of NAFLD defined by TE (P < 0.05). After adjusting for body mass index (BMI), aspartate aminotransferase (AST), alanine aminotransferase, triglycerides, total cholesterol, and high-density lipoprotein cholesterol, the odds ratio for NAFLD, comparing the grade 3 group (systolic blood pressure level >= 180 mmHg and/or diastolic blood pressure level >= 110 mmHg) with the normal group, was 1.476 (95% confidence interval, 1.166-2.551). A stepwise multivariate linear regression analysis (R2 = 0.084, P = 0.043) retained NAFLD, BMI, and AST as significant predictors of the systolic blood pressure levels. Additionally, stepwise multivariate linear regression analysis (R2 = 0.199, P = 0.037) retained NAFLD, controlled attenuation parameter, BMI, triglycerides, and high-density lipoprotein cholesterol as significant predictors of diastolic blood pressure levels. In addition, BMI, AST, and alanine aminotransferase were associated with systolic blood pressure levels among individuals with NAFLD; BMI, AST, and total cholesterol were associated with diastolic blood pressure levels among individuals with NAFLD. CONCLUSION: The main finding of our study is that hypertensive patients have a higher prevalence of NAFLD defined by TE, and NAFLD is independently associated with hypertension and blood pressure category. PMID- 26932593 TI - Complications related to bone augmentation procedures of localized defects in the alveolar ridge. A retrospective clinical study. AB - PURPOSE: This retrospective clinical study aims to evaluate complications after augmentation of localized bone defects of the alveolar ridge. METHODS: From standardized registrations, the following complications related to bone augmentation procedures were recorded: soft tissue dehiscence, infection, sensory disturbance, additional augmentation procedures needed, and early implant failure. RESULTS: A total of 223 patients (132 women, 91 men; mean age 23.5 years; range 17-65 years) with 331 bone defects had bone augmentation performed into which 350 implants were placed. Soft tissue dehiscence occurred in 1.7 % after GBR procedures, 25.9 % after staged horizontal ridge augmentation, and 18.2 % after staged vertical ridge augmentation. Infections were diagnosed in 2 % after GBR procedures, 12.5 % after sinus floor elevation (SFE) (transcrestal technique), 5 % after staged SFE, 11 % after staged horizontal ridge augmentation, and 9 % after staged vertical ridge augmentation. Additional augmentation procedures were needed in 2 % after GBR procedures, 37 % after staged horizontal ridge augmentation, and 9 % after staged vertical ridge augmentation. A total of six early implant failures occurred (1.7 %), four after GBR procedures (1.6 %), and two (12 %) after staged vertical ridge augmentation. CONCLUSIONS: Predictable methods exist to augment localized defects in the alveolar ridge, as documented by low complication rates and high early implant survival rates. PMID- 26932595 TI - The Nursing Profession, Diversity, and Wages. PMID- 26932596 TI - Experimental constraints on light elements in the Earth's outer core. AB - Earth's outer core is liquid and dominantly composed of iron and nickel (~5-10 wt%). Its density, however, is ~8% lower than that of liquid iron, and requires the presence of a significant amount of light element(s). A good way to specify the light element(s) is a direct comparison of density and sound velocity measurements between seismological data and those of possible candidate compositions at the core conditions. We report the sound velocity measurements of a model core composition in the Fe-Ni-Si system at the outer core conditions by shock-wave experiments. Combining with the previous studies, we found that the best estimate for the outer core's light elements is ~6 wt% Si, ~2 wt% S, and possible ~1-2.5 wt% O. This composition satisfies the requirements imposed by seismology, geochemistry, and some models of the early core formation. This finding may help us to further constrain the thermal structure of the Earth and the models of Earth's core formation. PMID- 26932597 TI - Chiral phosphoric acid catalyzed asymmetric addition of naphthols to para-quinone methides. AB - An asymmetric addition of naphthols to in situ generated para-quinone methides catalyzed by a chiral phosphoric acid is described. A range of useful triarylmethanes can be generated from stable general para-hydroxybenzyl alcohols with good efficiency and enantioselectivity. PMID- 26932598 TI - Polymorphisms in the 5' upstream regulatory region of p21(WAF1/CIP1) and susceptibility to oesophageal squamous cell carcinoma. AB - This study aims to scan the 5'-upstream regulatory region of the p21 gene to identify all putative functional single nucleotide polymorphisms (SNPs) and to evaluate the contribution of p21 variants to oesophageal squamous cell carcinoma (ESCC) in the Chinese Han population. Common SNPs were identified, and both locus based and haplotype-based association tests were used to evaluate the potential risk of these p21 gene polymorphisms for ESCC. Immunohistochemistry assay was further performed to detect the P21 protein expression in ESCC specimens. Twenty three SNPs were identified and seven Tagging SNPs were chosen to represent all 23 SNPs. Univariate analysis indicated that the rs3829963 C and the rs2395655 G alleles increased susceptibility to ESCC (OR = 1.606 and OR = 1.572, respectively). The rs3829963 C and rs2395655 G alleles, combined with cigarette smoking, could further increase the risk for ESCC (OR = 2.657 and OR = 2.828, respectively). Additionally, the rs2395655 G allele appeared to elevate the positive rate of P21 expression in ESCC tissues, as compared to the A allele. This report demonstrates for the first time that rs3829963 and rs2395655, in the promoter of the p21 gene are potentially functional, modulating susceptibility to ESCC among the high-risk cigarette-smoking Chinese population. PMID- 26932600 TI - VORTEC technique in central venous recanalization for haemodialysis access salvage. PMID- 26932599 TI - Lack of clinical or haemodynamic rebound after abrupt interruption of beta blockers in patients with cirrhosis. AB - BACKGROUND: Beta-blockers may have to be interrupted in patients with cirrhosis. The concept of a rebound after interruption of beta-blockers is based on an animal study and on isolated case reports of variceal bleeding. AIM: To determine if a rebound occurs in patients with cirrhosis following abrupt interruption of beta-blockers. METHODS: We prospectively included all consecutive patients with cirrhosis undergoing right heart and hepatic vein catheterisation. Four groups were defined: 'no beta-blockers' including patients not receiving beta-blockers; '<=1 day', '2-3 days' and '>=4 days' classified according to the time patients had interrupted beta-blockers before catheterisation. Results were expressed as median (interquartile range). RESULTS: A total of 150 patients were included. Among the 25 patients in the groups '2-3 days' and '>=4 days', median duration of beta-blockers interruption was 4 (3-6) days. No gastrointestinal bleeding occurred during that period, nor during the following month. Hepatic venous pressure gradient was not different among patients in usually treated with beta blockers. After adjustment, beta-blockers interruption was not associated with hepatic venous pressure gradient. Cardiac index was higher in the '>=4 days' group [4.6 L/min/m(2) (3.5-5.1)] than in the '<=1 day' group [3.4 (2.6-4.0); P = 0.001] or in the '2-3 days' group [3.1 (2.7-3.7); P = 0.007], but not different from the 'no beta-blockers' group. CONCLUSIONS: Abrupt interruption of beta blockers is associated neither with an apparent increase in the risk of variceal bleeding nor with a haemodynamic rebound. Thus, interruption of beta-blockers in patients with cirrhosis may not require particular dosing or surveillance. PMID- 26932601 TI - Exendin-4 promotes proliferation of adipose-derived stem cells through ERK and JNK signaling pathways. AB - Adipose-derived stem cell (ADSC) transplantation has emerged as a potential tool for the treatment of cardiovascular disease. However, with a limited renewal capacity and the need for mass cells during the engraftment, strategies are needed to enhance ADSC proliferative capacity. In this study, we explored the effects of exendin-4 (Ex-4), a glucagon-like peptide-1 analog, on the growth of ADSCs, focusing in particular on c-Jun NH2-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) signaling pathways. Firstly, ADSCs were isolated and cultured in vitro. Then, flow cytometry demonstrated that ADSCs were positive for CD90 and CD29 but negative for CD31, CD34, and CD45. Ex-4 (0-50 nM) treatment increased ADSC proliferation in a dose-dependent manner but had no effects on stem cell markers of ADSCs. Moreover, we found that Ex-4 treatment elevated the phosphorylation levels of the JNK and ERK signaling pathways. Furthermore, utilization of Ex-4 also promoted cyclin D1 and cyclin E protein expression, which was accompanied by more Edu(+) cells and a higher percentage of cells in the S-phase of the cell cycle after Ex-4 treatment. In parallel, the application of inhibitors SP600125 and PD98059, inhibitors of the JNK and ERK signaling pathways, respectively, not only reversed such effects of Ex-4 on JNK and ERK but also resulted in lower percentages of S-phase cells and fewer numbers of Edu(+) cells. In summary, Ex-4 has no effects on stem cell markers in ADSCs but promotes ADSC growth via JNK and ERK signaling pathways. PMID- 26932602 TI - Sheep grazing in the North Atlantic region: A long-term perspective on environmental sustainability. AB - Sheep grazing is an important part of agriculture in the North Atlantic region, defined here as the Faroe Islands, Greenland, Iceland, Norway and Scotland. This process has played a key role in shaping the landscape and biodiversity of the region, sometimes with major environmental consequences, and has also been instrumental in the development of its rural economy and culture. In this review, we present results of the first interdisciplinary study taking a long-term perspective on sheep management, resource economy and the ecological impacts of sheep grazing, showing that sustainability boundaries are most likely to be exceeded in fragile environments where financial support is linked to the number of sheep produced. The sustainability of sheep grazing can be enhanced by a management regime that promotes grazing densities appropriate to the site and supported by area-based subsidy systems, thus minimizing environmental degradation, encouraging biodiversity and preserving the integrity of ecosystem processes. PMID- 26932605 TI - You can't argue with statistics - or can you? AB - The results of two major surveys were released last week and laid bare the extent to which nurses are overstretched and undervalued. Both the annual NHS staff survey and an investigation by the BBC provided further proof that there are not enough staff around to ensure that nurses can deliver safe and effective care. PMID- 26932606 TI - Charity raises a glass to brewery windfall. AB - Sales of more than 45,000 pints of beer named after heroic first world war nurse Edith Cavell have raised more than L2,000 for a nurses' charity. PMID- 26932603 TI - Angiopoietin-2-induced blood-brain barrier compromise and increased stroke size are rescued by VE-PTP-dependent restoration of Tie2 signaling. AB - The homeostasis of the central nervous system is maintained by the blood-brain barrier (BBB). Angiopoietins (Ang-1/Ang-2) act as antagonizing molecules to regulate angiogenesis, vascular stability, vascular permeability and lymphatic integrity. However, the precise role of angiopoietin/Tie2 signaling at the BBB remains unclear. We investigated the influence of Ang-2 on BBB permeability in wild-type and gain-of-function (GOF) mice and demonstrated an increase in permeability by Ang-2, both in vitro and in vivo. Expression analysis of brain endothelial cells from Ang-2 GOF mice showed a downregulation of tight/adherens junction molecules and increased caveolin-1, a vesicular permeability-related molecule. Immunohistochemistry revealed reduced pericyte coverage in Ang-2 GOF mice that was supported by electron microscopy analyses, which demonstrated defective intra-endothelial junctions with increased vesicles and decreased/disrupted glycocalyx. These results demonstrate that Ang-2 mediates permeability via paracellular and transcellular routes. In patients suffering from stroke, a cerebrovascular disorder associated with BBB disruption, Ang-2 levels were upregulated. In mice, Ang-2 GOF resulted in increased infarct sizes and vessel permeability upon experimental stroke, implicating a role of Ang-2 in stroke pathophysiology. Increased permeability and stroke size were rescued by activation of Tie2 signaling using a vascular endothelial protein tyrosine phosphatase inhibitor and were independent of VE-cadherin phosphorylation. We thus identified Ang-2 as an endothelial cell-derived regulator of BBB permeability. We postulate that novel therapeutics targeting Tie2 signaling could be of potential use for opening the BBB for increased CNS drug delivery or tighten it in neurological disorders associated with cerebrovascular leakage and brain edema. PMID- 26932604 TI - Identification of STOML2 as a putative novel asthma risk gene associated with IL6R. AB - BACKGROUND: Functional variants in the interleukin-6 receptor gene (IL6R) are associated with asthma risk. We hypothesized that genes co-expressed with IL6R might also be regulated by genetic polymorphisms that are associated with asthma risk. The aim of this study was to identify such genes. METHODS: To identify genes whose expression was correlated with that of IL6R, we analyzed gene expression levels generated for 373 human lymphoblastoid cell lines by the Geuvadis consortium and for 38 hematopoietic cell types by the Differentiation Map Portal (DMAP) project. Genes correlated with IL6R were then screened for nearby single nucleotide polymorphisms (SNPs) that were significantly associated with both variation in gene expression levels (eSNPs) and asthma risk. RESULTS: We identified 90 genes with expression levels correlated with those of IL6R and that also had a nearby eSNP associated with disease risk in a published asthma GWAS (N = 20 776). For 16 (18%) genes, the association between the eSNP and asthma risk replicated with the same direction of effect in a further independent published asthma GWAS (N = 27 378). Among the top replicated associations (FDR < 0.05) were eSNPs for four known (IL18R1, IL18RAP, BCL6, and STAT6) and one putative novel asthma risk gene, stomatin-like protein 2 (STOML2). The expression of STOML2 was negatively correlated with IL6R, while eSNPs that increased the expression of STOML2 were associated with an increased asthma risk. CONCLUSION: The expression of STOML2, a gene that plays a key role in mitochondrial function and T-cell activation, is associated with both IL-6 signaling and asthma risk. PMID- 26932607 TI - Students' age profile sparks fears about deterrent effect of loans. AB - Almost one in four nursing students is 30 or older - raising fresh concern about changes to their funding. PMID- 26932608 TI - Trust deal offers higher salaries in lieu of pension. AB - An NHS trust has been criticised for offering nurses higher starting salaries if they opt out of the NHS pension. PMID- 26932609 TI - Skipping meals 'typical' in NHS work day. AB - Most nurses and doctors skip meals and snack instead, with about one third of nurses eating only one meal a day at work, a study has found. PMID- 26932610 TI - 'Modest' boost in training places is not enough - RCN. AB - Poor workforce planning has been blamed for almost one in ten nursing posts in England, Wales and Northern Ireland remaining vacant. PMID- 26932611 TI - Careers clinic helps turn around trust's staff retention troubles. AB - Two nurse-led projects at a leading trust are having a positive effect on its staff retention and vacancy rates. PMID- 26932612 TI - 'Worrying picture' of violence and work-related stress in staff survey. AB - Almost two fifths of NHS nurses in England experienced work-related stress last year, while 60% felt pressured to work while sick, according to the latest NHS staff survey. PMID- 26932614 TI - Lincolnshire nurses trial phone assessment service. AB - A nurse-led telephone service is helping patients to have investigative tests on their bowels up to two weeks faster than usual. PMID- 26932615 TI - Training aid for mental care staff. AB - A training pack to help mental health professionals challenge discrimination in health services was launched last week. PMID- 26932616 TI - Call for 24/7 end of life community nursing. AB - The government must ensure dying people have access to 24/7 community nursing, according to the End of Life Care Coalition. PMID- 26932617 TI - Pressure ulcer scanners rolled out to more trusts after successful trial. AB - A hand-held scanner that has helped to eliminate pressure ulcers is to be rolled out across NHS community hospitals where Virgin Care operates. PMID- 26932618 TI - Collapse in overseas nurse recruits exposes UK's staffing shortfall. AB - A 'collapse' in the number of overseas nurses coming to work in the NHS is contributing to high vacancy levels, according to a new report on clinical staff shortages. PMID- 26932624 TI - Pneumonia. AB - Essential facts: An infection of the lung tissue, pneumonia is common and has a high mortality rate. According to the National Institute for Health and Care Excellence (NICE), between 0.5% and 1% of adults will develop community-acquired pneumonia (CAP) every year. It is diagnosed in 5-12% of those who present to GPs with lower respiratory tract infection, with 22% to 42% admitted to hospital, where the mortality rate is between 5% and 14%. Hospital-acquired pneumonia is estimated to increase hospital stay by about eight days, and has a reported mortality rate ranging from 30% to 70%. PMID- 26932625 TI - Where age is no bar to friendship. AB - In an award winning project in Dundee,secondary school pupils pay weekly visits to a care home and interact with the residents, who love their cheery company. The project improves understanding between generations and helps dispel myths about care home nursing. PMID- 26932626 TI - A lifeline for cancer patients in Africa. AB - In Rwanda, many people with cancer are diagnosed too late because of low awareness of the disease coupled with a lack of specialist facilities and staff. The opening of a specialist centre in the northern part of the country is extending and saving lives. PMID- 26932627 TI - Time to sweep aside the tyranny of paperwork. AB - A physiotherapist who has recently moved from outpatients to a ward-based role speaks out against the mountain of paperwork heaped on nurses. He argues that much of it is of little value to patient care - its real purpose is to provide a scapegoat when things go wrong. PMID- 26932640 TI - Could Italy's new primary care model be the way forward? AB - I was interested to hear of Italy's new model of care in managing chronic conditions. The country has the most rapidly ageing population in the world, and is confronted with an already overstretched healthcare system. Sound familiar? PMID- 26932641 TI - Nurse roles should not be at the 'whim of the political class'. AB - If assistant practitioners are doing the work proposed for nursing associates already then fine, but let us formalise who is responsible for what, right here and now. PMID- 26932642 TI - With such an NHS staff shortfall, who will work on the 'mothballed' wards? AB - I was interested to read your article about Lord Carter of Coles' report on saving the NHS L5 billion a year (analysis, February 17). However, the article and Lord Carter's report fail to mention the L4.5 billion wasted on the NHS internal market, which adds nothing to patient care according to independent and parliamentary reports into the NHS since 2010. PMID- 26932643 TI - From Facebook: on the NHS losing its role models and mentors, with cuts to senior nurse posts. PMID- 26932644 TI - Correction. AB - In the Careers article Life As An Independent Midwife in our February 24 issue, an interviewee suggested that insurance provided via Independent Midwives UK (IMUK) was insufficient to cover home births. IMUK has pointed out that the personal indemnity insurance product held by all IMUK members does cover home births and indeed the full scope of independent midwifery practice. We apologise for the error. PMID- 26932648 TI - How to apply vacuum-assisted closure therapy. AB - RATIONALE AND KEY POINTS: This article aims to provide an overview of the technique for applying vacuum-assisted closure therapy (V.A.C. therapy), using the example of one of the most basic dressing types: V.A.C. GranuFoam, a black polyurethane foam. Practitioners should refer to the manufacturer's instructions for application of other dressing types. ? V.A.C. therapy is used to apply negative pressure to the wound bed to promote wound healing. ? V.A.C therapy promotes perfusion, reduces oedema, draws the wound edges together and stimulates the formation of granulation tissue. ? The correct technique for applying V.A.C. therapy is essential to ensure patient safety and optimum wound healing outcomes. REFLECTIVE ACTIVITY: Clinical skills articles can help update your practice and ensure it remains evidence based. Apply this article to your practice. Reflect on and write a short account of: 1. How you think this article will change your practice. 2. How the use of V.A.C. therapy might affect the patient's experience. PMID- 26932649 TI - Best practice in wound assessment. AB - Accurate and considered wound assessment is essential to fulfil professional nursing requirements and ensure appropriate patient and wound management. This article describes the main aspects of holistic assessment of the patient and the wound, including identifying patient risk factors and comorbidities, and factors affecting wound healing to ensure optimal outcomes. PMID- 26932650 TI - Use of compression therapy in patients with lymphoedema. AB - Compression therapy is an effective and common approach to the management of lymphoedema, a chronic condition requiring long-term treatment. Lymphoedema is caused by the accumulation of fluid in soft tissue, resulting in swelling of the affected limb or area. Lymphoedema may be primary, as a result of a genetic abnormality, or secondary, as a result of injury, including non-accidental injury, or following treatments such as radiotherapy and/or surgery. The condition is characterised by a high protein oedema and secondary skin changes. This article outlines features of the various types of compression therapy used to treat patients with lymphoedema, including details of their application, effectiveness, indications and contraindications. PMID- 26932651 TI - Preventing CAUTIs. AB - I read the CPD article because of my role as a staff nurse on a new acute medical ward for older people. Many patients have a urinary catheter in place, often inserted in the community. The article identified the importance of clear documentation to prevent unnecessary catheter-associated urinary tract infections (CAUTIs), indicating the reason for catheterisation, any complications and when the catheter should be removed. PMID- 26932652 TI - How to land that job. AB - Job adverts for nursing positions in the NHS and elsewhere often include a name and number for potential applicants to contact for more information, and applicants are being encouraged to make good use of them. PMID- 26932654 TI - From acute to primary care. AB - Moving from secondary to primary care nursing may feel like a daunting prospect, but a new resource from the Queen's Nursing Institute (QNI) could help to make the transition smoother. PMID- 26932655 TI - Student life - Tips for placement success. AB - Placements are an inevitable part of a nursing degree which provide a platform for on-the-job learning and development, greatly enhancing a student nurse's understanding of their career choice. PMID- 26932657 TI - Oligohydramnios and growth restriction do not portend worse prognosis in gastroschisis pregnancies. AB - OBJECTIVES: Gastroschisis is a common abdominal wall defect. While most neonates have an excellent prognosis, complications do occur. Several risk factors for adverse neonatal outcomes have been identified, however, the impact of intrauterine growth restriction (IUGR) and oligohydramnios on neonatal morbidity and mortality has not been fully elucidated. METHODS: In this retrospective cohort study of pregnancies complicated by gastroschisis at two tertiary-care centers during an eight-year period, maternal, fetal and neonatal data were analyzed to estimate the impact of IUGR and oligohydramnios upon neonatal outcomes. Adverse outcomes were defined as five-minute Apgar score <7, umbilical cord pH <7.12, neonatal sepsis, prolonged ventilator support, prolonged total parenteral nutrition, extended NICU stay, death and a composite of the above. RESULTS: Among the 179 cases of gastroschisis, there were no differences in maternal demographics between cases with and without IUGR or oligohydramnios. Fetuses with oligohydramnios demonstrated a trend toward lower birthweight (p = 0.06). Small for gestational age infants showed a trend toward prolonged ventilator support (p = 0.06). Oligohydramnios and IUGR were otherwise not associated with adverse neonatal outcomes. CONCLUSIONS: While risk factors for adverse neonatal outcomes have been identified in pregnancies complicated by gastroschisis, IUGR and oligohydramnios do not appear to be among them. PMID- 26932656 TI - Hepatitis B infection is highly prevalent among patients presenting with jaundice in Kenya. AB - BACKGROUND: Viral hepatitis is a major concern worldwide, with hepatitis A (HAV) and E (HEV) viruses showing sporadic outbreaks while hepatitis B (HBV) and C (HCV) viruses are associated with chronic hepatitis, cirrhosis and hepatocellular carcinoma. The present study determined the proportion, geographic distribution and molecular characterization of hepatitis viruses among patients seeking medical services at hospitals throughout Kenya. METHODS: Patients presenting with jaundice at four selected hospitals were recruited (n = 389). Sera were tested for the presence of antibody to hepatitis viruses A through E, and HBV surface antigen (HBsAg). Nucleic acid from anti-HAV IgM antibody and HBsAg positive samples was extracted, amplified and sequenced. RESULTS: Chronic HBV infection was the leading cause of morbidity among patients with symptoms of liver disease seeking medical help. Incident HCV, HEV and HDV infection were not detected among the patients in this study, while the proportion of acute HAV was low; HAV IgM positivity was observed in 6.3 % of patients and sequencing revealed that all cases belonged to genotype 1B. HCV seropositivity upon initial screening was 3.9 % but none were confirmed positive by a supplementary immunoblot assay. There was no serological evidence of HDV and acute HEV infection (anti-HEV IgM). HBsAg was found in 50.6 % of the patients and 2.3 % were positive for IgM antibody to the core protein, indicating probable acute infection. HBV genotype A was predominant (90.3 %) followed by D (9.7 %) among HBV DNA positive specimens. Full genome analysis showed HBV/D isolates having similarity to both D4 and D6 subgenotypes and D/E recombinant reference sequences. Two recombinant sequences demonstrated > 4 % nucleotide divergence from other previously known D/E recombinants. CONCLUSIONS: HBV is highly prevalent among patients seeking care for symptoms consistent with hepatitis, compared to the general population. Molecular characterization of HBV isolates indicated recombinant strains that may give rise to new circulating variants. There is a need to document the prevalence, clinical manifestation and distribution of the variants observed. HAV genotype 1B, prevalent in Africa, was observed; however, the absence of HCV, HDV and acute HEV in this study does not rule out their presence in Kenya. PMID- 26932658 TI - Bone characteristics, anthropometry and lifestyle in late adolescents. AB - BACKGROUND: Physical activity and adequate calcium intake have favourable influences on the bone status, while body structure and function can be altered with lifestyle changes. The use of portable quantitative ultrasound measurements provides a non-invasive method of evaluating bone characteristics. AIM: To analyze relationships between physical activity, anthropometric variables, milk consumption and bone parameters in late adolescents. SUBJECTS AND METHODS: The subjects were 16-18-year-old athletic and non-athletic adolescents (N = 377). Calcaneal quantitative ultrasound parameters were registered with Sonost 3000 bone densitometer. The analysis included speed of sound (SOS, m s-1), broadband ultrasound attenuation (BUA, dB MHz-1), bone quantity index (BQI = alphaSOS + betaBUA). Anthropometry was measured according to the guidelines of International Biological Program (Weiner and Lourie 1969). Body composition was assessed by Parizkova's (1961), and Drinkwater & Ross (1980) method. The level of dairy consumption and habitual physical activity were estimated with the use of self reported questionnaires. Differences between subgroups were tested by Student's t test and by one-way ANOVA. Correlation patterns of the variables for total sample and subgroups were analyzed (p < 0.05). RESULTS: Athletic and non-athletic subgroups differed, with the athletes having better values: SOS (boys: 1507.00 +/ 12.25 vs. 1493.16 +/- 11.51; girls: 1501.40 +/- 13.87 vs. 1486.68 +/- 11.14), BUA (boys: 91.99 +/- 11.78 vs. 83.79 +/- 14.26; girls: 90.96 +/- 8.48 vs. 85.25 +/- 12.51), BQI (boys: 77.77 +/- 11.29 vs. 66.17 +/- 13.28; girls: 73.28 +/- 9.31 vs. 63.25 +/- 12.39). QUS parameters differed significantly by frequency of milk consumption: SOS (1502.25 +/- 16.7 vs. 1495.9 +/- 13.48); BUA (90.12 +/- 15.9 vs. 85.79 +/- 14.56); and BQI (73.29 +/- 17.15 vs. 67.24 +/- 14.3). CONCLUSIONS: Bone variables differed in athletic and non-athletic 16-18-year-old adolescents. Regular dairy consumption proved beneficial in all osteoid characteristics. Quantitative bone characteristics depend on gender, physical activity and nutrition. Findings have the potential to inform the development of more effective interventions. PMID- 26932659 TI - The structural influence of Ca(2+) counter-ions on uranyl(VI) tricarbonate in aqueous solution. AB - The presented study elucidates the influence of calcium(II) counter-ions on the structure of the environmentally relevant uranyl tricarbonates using hybrid quantum mechanical/molecular mechanical (QM/MM) MD simulations. Since experimental investigations may be subject to limitations in detecting the presence of counter-ions in solution, the present study is of importance to obtain a profound understanding of the effects counter-ions may have on coordination complexes. It can be concluded from the obtained simulation data that two calcium(II) ions are essential for stabilizing the experimentally observed uranyl tricarbonate complex in aqueous solution. Including only one calcium(II) ion in the coordination sphere was found to be insufficient to form a six-fold equatorial coordination of carbonates, but a five-fold coordination is adopted similar to the counter-ion free case in aqueous solution reported in a previous study. PMID- 26932660 TI - Tramadol-induced peripheral oedema. PMID- 26932661 TI - IL-27 inhibits the TGF-beta1-induced epithelial-mesenchymal transition in alveolar epithelial cells. AB - BACKGROUND: IL-27 is a multifunctional cytokine that has both pro-inflammatory and anti-inflammatory functions. Although IL-27 has been shown to potently inhibit lung fibrosis, the detailed mechanism of IL-27 in this process is poorly understood. Epithelial-mesenchymal transition (EMT) is one of the key mechanisms involved in pulmonary fibrosis. We assessed the effects of IL-27 on TGF-beta1 induced EMT in alveolar epithelial cells. METHODS: A549 cells (a human AEC cell line) were incubated with TGF-beta1, IL-27, or both TGF-beta1 and IL-27, and changes in E-cadherin, beta-catenin, vimentin and a-SMA levels were measured using real-time PCR, western blotting and fluorescence microscopy. The related proteins in the JAK/STAT and TGF-beta/Smad signalling pathways were examined by western blot. RESULTS: IL-27 increased the expression of epithelial phenotypic markers, including E-cadherin and beta-catenin, and inhibited mesenchymal phenotypic markers, including vimentin and a-SMA in A549 cells. Moreover, TGF beta1-induced EMT was attenuated by IL-27. Furthermore, we found that TGF-beta1 activated the phosphorylation of JAK1, STAT1, STAT3, STAT5, Smad1, Smad3 and Smad5, and IL-27 partially inhibited these changes in this process. When cells were treated with the STAT3 specific inhibitor wp1006 and the Smad3 specific inhibitor SIS3, the inhibition of EMT by IL-27 was significantly strengthened. CONCLUSION: Our results suggest that IL-27 attenuates epithelial-mesenchymal transition in alveolar epithelial cells in the absence or presence of TGF-beta1 through the JAK/STAT and TGF-beta/Smad signalling pathways. PMID- 26932662 TI - Vocal Development as a Guide to Modeling the Evolution of Language. AB - Modeling of evolution and development of language has principally utilized mature units of spoken language, phonemes and words, as both targets and inputs. This approach cannot address the earliest phases of development because young infants are unable to produce such language features. We argue that units of early vocal development-protophones and their primitive illocutionary/perlocutionary forces should be targeted in evolutionary modeling because they suggest likely units of hominin vocalization/communication shortly after the split from the chimpanzee/bonobo lineage, and because early development of spontaneous vocal capability is a logically necessary step toward vocal language, a root capability without which other crucial steps toward vocal language capability are impossible. Modeling of language evolution/development must account for dynamic change in early communicative units of form/function across time. We argue for interactive contributions of sender/infants and receiver/caregivers in a feedback loop involving both development and evolution and propose to begin computational modeling at the hominin break from the primate communicative background. PMID- 26932663 TI - CardioBengo study protocol: a population based cardiovascular longitudinal study in Bengo Province, Angola. AB - BACKGROUND: Cardiovascular diseases and other non-communicable diseases are major causes of morbidity and mortality, responsible for 38 million deaths in 2012, 75 % occurring in low- and middle-income countries. Most of these countries are facing a period of epidemiological transition, being confronted with an increased burden of non-communicable diseases, which challenge health systems mainly designed to deal with infectious diseases. With the adoption of the World Health Organization "Global Action Plan for the Prevention and Control of non communicable diseases, 2013-2020", the national dimension of risk factors for non communicable diseases must be reported on a regular basis. Angola has no national surveillance system for non-communicable diseases, and periodic population-based studies can help to overcome this lack of information. CardioBengo will collect information on risk factors, awareness rates and prevalence of symptoms relevant to cardiovascular diseases, to assist decision makers in the implementation of prevention and treatment policies and programs. METHODS: CardioBengo is designed as a research structure that comprises a cross-sectional component, providing baseline information and the assembling of a cohort to follow-up the dynamics of cardiovascular diseases risk factors in the catchment area of the Dande Health and Demographic Surveillance System of the Health Research Centre of Angola, in Bengo Province, Angola. The World Health Organization STEPwise approach to surveillance questionnaires and procedures will be used to collect information on a representative sex-age stratified sample, aged between 15 and 64 years old. DISCUSSION: CardioBengo will recruit the first population cohort in Angola designed to evaluate cardiovascular diseases risk factors. Using the structures in place of the Dande Health and Demographic Surveillance System and a reliable methodology that generates comparable results with other regions and countries, this study will constitute a useful tool for the surveillance of cardiovascular diseases. Like all longitudinal studies, a strong concern exists regarding dropouts, but strategies like regular visits to selected participants and a strong community involvement are in place to minimize these occurrences. PMID- 26932664 TI - Extended total arch replacement via the L-incision approach: single-stage repair for extensive aneurysms of the aortic arch. AB - OBJECTIVES: Total arch replacement via the L-incision approach (a combination of left anterior thoracotomy and upper median sternotomy) can be used to achieve more extensive replacement. METHODS: In the period between 2002 and 2014, 279 total arch replacement procedures were performed. After excluding cases of acute aortic dissection and cases involving concomitant, hybrid or frozen elephant trunk procedures, patients who underwent isolated total arch replacement via an L incision (n = 29) and via median sternotomy (n = 143) were identified and the data pertaining to their cases were analysed. RESULTS: Operative mortality was higher in the L-incision group than in the median sternotomy group (6.9 vs 2.1%); however, the difference was not statistically significant. The L-incision group displayed a higher rate of respiratory complications, including pneumonia (28 vs 7.0%, P = 0.0034), the need for tracheostomy (17 vs 2.1%, P = 0.0038) and pulmonary haemorrhage (6.9 vs 0%, P = 0.028). The rate of paraplegia was similar between the groups (0 vs 1.4%, P = 1.00), despite the wider range replaced via the L-incision approach (7.3 +/- 1.5 vs 4.7 +/- 0.8 anatomical zones, P < 0.001). The rates of other complications and functional recovery were similar. The long term survival (73 vs 84% at 5 years) and aortic event-free rates (94 vs 96% at 5 years) were similar in both groups. CONCLUSIONS: A combination of left anterior thoracotomy and upper median sternotomy can be applied to the single-stage repair of extended aneurysms with acceptable results in appropriately selected patients. PMID- 26932665 TI - Pulmonary atypical carcinoid in a patient with Cowden syndrome. AB - Cowden syndrome is a phosphatase and tensin homologue on chromosome ten (PTEN) hamartoma tumour syndrome. The loss of function of the PTEN protein is associated with the risk of development and progression of several types of tumours, such as pulmonary neuroendocrine tumours and carcinoids. We present a 65-year old male non-smoker, who was diagnosed with Cowden syndrome and had a pulmonary tumour. He underwent wedge resection via video-assisted thoracoscopic surgery and was histopathologically diagnosed with an atypical carcinoid. To our knowledge, this is the first report on a pulmonary atypical carcinoid in a patient with Cowden syndrome. The present findings suggest a potential link between phosphoinositide 3 kinase/protein kinase B signalling in Cowden syndrome and the development of pulmonary neuroendocrine tumours, such as carcinoids. PMID- 26932666 TI - Spike-dip transformation of Setaria viridis. AB - Traditional method of Agrobacterium-mediated transformation through the generation of tissue culture had limited success for Setaria viridis, an emerging C4 monocot model. Here we present an efficient in planta method for Agrobacterium mediated genetic transformation of S. viridis using spike dip. Pre-anthesis developing spikes were dipped into a solution of Agrobacterium tumefaciens strain AGL1 harboring the beta-glucuronidase (GUS) reporter gene driven by the cauliflower mosaic virus 35S (CaMV35S) promoter to standardize and optimize conditions for transient as well as stable transformations. A transformation efficiency of 0.8 +/- 0.1% was obtained after dipping of 5-day-old S3 spikes for 20 min in Agrobacterium cultures containing S. viridis spike-dip medium supplemented with 0.025% Silwet L-77 and 200 MUm acetosyringone. Reproducibility of this method was demonstrated by generating stable transgenic lines expressing beta-glucuronidase plus (GUSplus), green fluorescent protein (GFP) and Discosoma sp. red fluorescent protein (DsRed) reporter genes driven by either CaMV35S or intron-interrupted maize ubiquitin (Ubi) promoters from three S. viridis genotypes. Expression of these reporter genes in transient assays as well as in T1 stable transformed plants was monitored using histochemical, fluorometric GUS activity and fluorescence microscopy. Molecular analysis of transgenic lines revealed stable integration of transgenes into the genome, and inherited transgenes expressed in the subsequent generations. This approach provides opportunities for the high-throughput transformation and potentially facilitates translational research in a monocot model plant. PMID- 26932667 TI - Monitoring the efficacy of mutated Allium sativum leaf lectin in transgenic rice against Rhizoctonia solani. AB - BACKGROUND: Rice sheath blight, caused by Rhizoctonia solani is one of the most devastating diseases of rice. It is associated with significant reduction in rice productivity worldwide. A mutant variant of mannose binding Allium sativum leaf agglutinin (mASAL) was previously reported to exhibit strong antifungal activity against R. solani. In this study, the mASAL gene has been evaluated for its in planta antifungal activity in rice plants. RESULTS: mASAL was cloned into pCAMBIA1301 binary vector under the control of CaMV35S promoter. It was expressed in an elite indica rice cv. IR64 by employing Agrobacterium tumefaciens-mediated transformation. Molecular analyses of transgenic plants confirmed the presence and stable integration of mASAL gene. Immunohistofluorescence analysis of various tissue sections of plant parts clearly indicated the constitutive expression of mASAL. The segregation pattern of mASAL transgene was observed in T1 progenies in a 3:1 Mendelian ratio. The expression of mASAL was confirmed in T0 and T1 plants through western blot analysis followed by ELISA. In planta bioassay of transgenic lines against R. solani exhibited an average of 55 % reduction in sheath blight percentage disease index (PDI). CONCLUSIONS: The present study opens up the possibility of engineering rice plants with the antifungal gene mASAL, conferring resistance to sheath blight. PMID- 26932668 TI - Building and re-building the heart by cardiomyocyte proliferation. AB - The adult human heart does not regenerate significant amounts of lost tissue after injury. Rather than making new, functional muscle, human hearts are prone to scarring and hypertrophy, which can often lead to fatal arrhythmias and heart failure. The most-cited basis of this ineffective cardiac regeneration in mammals is the low proliferative capacity of adult cardiomyocytes. However, mammalian cardiomyocytes can avidly proliferate during fetal and neonatal development, and both adult zebrafish and neonatal mice can regenerate cardiac muscle after injury, suggesting that latent regenerative potential exists. Dissecting the cellular and molecular mechanisms that promote cardiomyocyte proliferation throughout life, deciphering why proliferative capacity normally dissipates in adult mammals, and deriving means to boost this capacity are primary goals in cardiovascular research. Here, we review our current understanding of how cardiomyocyte proliferation is regulated during heart development and regeneration. PMID- 26932670 TI - GATA4 and GATA6 regulate pancreatic endoderm identity through inhibition of hedgehog signaling. AB - GATA4 and GATA6 are zinc finger transcription factors that have important functions in several mesodermal and endodermal organs, including heart, liver and pancreas. In humans, heterozygous mutations of either factor are associated with pancreatic agenesis; however, homozygous deletion of both Gata4 and Gata6 is necessary to disrupt pancreas development in mice. In this study, we demonstrate that arrested pancreatic development in Gata4(fl/fl); Gata6(fl/fl); Pdx1:Cre (pDKO) embryos is accompanied by the transition of ventral and dorsal pancreatic fates into intestinal or stomach lineages, respectively. These results indicate that GATA4 and GATA6 play essential roles in maintaining pancreas identity by regulating foregut endodermal fates. Remarkably, pancreatic anlagen derived from pDKO embryos also display a dramatic upregulation of hedgehog pathway components, which are normally absent from the presumptive pancreatic endoderm. Consistent with the erroneous activation of hedgehog signaling, we demonstrate that GATA4 and GATA6 are able to repress transcription through the sonic hedgehog (Shh) endoderm-specific enhancer MACS1 and that GATA-binding sites within this enhancer are necessary for this repressive activity. These studies establish the importance of GATA4/6-mediated inhibition of hedgehog signaling as a major mechanism regulating pancreatic endoderm specification during patterning of the gut tube. PMID- 26932669 TI - A comparative view of regenerative neurogenesis in vertebrates. AB - In all vertebrate species studied thus far, the adult central nervous system harbors neural stem cells that sustain constitutive neurogenesis, as well as latent neural progenitors that can be awakened in lesional contexts. In spite of this common theme, many species differ dramatically in their ability to recruit constitutive progenitors, to awaken latent progenitors, or to enhance or bias neural progenitor fate to achieve successful neuronal repair. This Review summarizes the striking similarities in the essential molecular and cellular properties of adult neural stem cells between different vertebrate species, both under physiological and reparative conditions. It also emphasizes the differences in the reparative process across evolution and how the study of non-mammalian models can provide insights into both basic neural stem cell properties and stimulatory cues shared between vertebrates, and subsequent neurogenic events, which are abortive under reparative conditions in mammals. PMID- 26932671 TI - KMT2D regulates specific programs in heart development via histone H3 lysine 4 di methylation. AB - KMT2D, which encodes a histone H3K4 methyltransferase, has been implicated in human congenital heart disease in the context of Kabuki syndrome. However, its role in heart development is not understood. Here, we demonstrate a requirement for KMT2D in cardiac precursors and cardiomyocytes during cardiogenesis in mice. Gene expression analysis revealed downregulation of ion transport and cell cycle genes, leading to altered calcium handling and cell cycle defects. We further determined that myocardial Kmt2d deletion led to decreased H3K4me1 and H3K4me2 at enhancers and promoters. Finally, we identified KMT2D-bound regions in cardiomyocytes, of which a subset was associated with decreased gene expression and decreased H3K4me2 in mutant hearts. This subset included genes related to ion transport, hypoxia-reoxygenation and cell cycle regulation, suggesting that KMT2D is important for these processes. Our findings indicate that KMT2D is essential for regulating cardiac gene expression during heart development primarily via H3K4 di-methylation. PMID- 26932673 TI - Robust derivation of epicardium and its differentiated smooth muscle cell progeny from human pluripotent stem cells. PMID- 26932674 TI - Ultraporous superhydrophobic gas-permeable nano-layers by scalable solvent-free one-step self-assembly. AB - Superhydrophobic materials with excellent humidity tolerance, high porosity and light transmittance are being investigated for numerous applications including moisture-sensitive catalysts and perovskite solar cells. Here, we report the one step solvent-free synthesis of ultraporous superhydrophobic nano-layers by the on the-fly functionalization of nanoparticle aerosols. Short exposure of surfaces to hot Mn3O4, ZnO and TiO2 aerosols results in ultraporous nanoparticle networks with repulsive dewetting state approaching ideal Cassie-Baxter superhydrophobicity. In addition to showcasing sliding angles of ca. 0 degrees and very low contact angle hysteresis of 3 degrees +/- 2 degrees , these optimal nano-layers have up to 98% porosity and pore size of several micrometres, a key feature to enable efficient penetration of gases to the substrate surface. The stability of this ultraporous superhydrophobic morphology is demonstrated by rapidly applying Moses effect-functionality to substrates that parts water up to 5 mm high. This scalable synthesis method offers a flexible and rapid approach for the production of numerous moisture-resistant devices including gas sensors, catalysts and perovskite solar cells. PMID- 26932672 TI - Selection of cell fate in the organ of Corti involves the integration of Hes/Hey signaling at the Atoh1 promoter. AB - Determination of cell fate within the prosensory domain of the developing cochlear duct relies on the temporal and spatial regulation of the bHLH transcription factor Atoh1. Auditory hair cells and supporting cells arise in a wave of differentiation that patterns them into discrete rows mediated by Notch dependent lateral inhibition. However, the mechanism responsible for selecting sensory cells from within the prosensory competence domain remains poorly understood. We show in mice that rather than being upregulated in rows of cells, Atoh1 is subject to transcriptional activation in groups of prosensory cells, and that highly conserved sites for Hes/Hey repressor binding in the Atoh1 promoter are needed to select the hair cell and supporting cell fate. During perinatal supporting cell transdifferentiation, which is a model of hair cell regeneration, we show that derepression is sufficient to induce Atoh1 expression, suggesting a mechanism for priming the 3' Atoh1 autoregulatory enhancer needed for hair cell expression. PMID- 26932675 TI - Colour and pattern change against visually heterogeneous backgrounds in the tree frog Hyla japonica. AB - Colour change in animals can be adaptive phenotypic plasticity in heterogeneous environments. Camouflage through background colour matching has been considered a primary force that drives the evolution of colour changing ability. However, the mechanism to which animals change their colour and patterns under visually heterogeneous backgrounds (i.e. consisting of more than one colour) has only been identified in limited taxa. Here, we investigated the colour change process of the Japanese tree frog (Hyla japonica) against patterned backgrounds and elucidated how the expression of dorsal patterns changes against various achromatic/chromatic backgrounds with/without patterns. Our main findings are i) frogs primarily responded to the achromatic differences in background, ii) their contrasting dorsal patterns were conditionally expressed dependent on the brightness of backgrounds, iii) against mixed coloured background, frogs adopted intermediate forms between two colours. Using predator (avian and snake) vision models, we determined that colour differences against different backgrounds yielded perceptible changes in dorsal colours. We also found substantial individual variation in colour changing ability and the levels of dorsal pattern expression between individuals. We discuss the possibility of correlational selection on colour changing ability and resting behaviour that maintains the high variation in colour changing ability within population. PMID- 26932676 TI - Is the content and duration of the graduated return to play protocol after concussion demanding enough? A challenge for Berlin 2016. PMID- 26932677 TI - The Moderating Role of Physical Self-Perceptions in the Relationship Between Maturity Status and Physical Self-Worth. AB - PURPOSE: We tested the moderating role of physical self-perceptions in the relationship between physical maturity and physical self-worth (PSW). METHOD: Students in Grades 5 through 8 (N = 241; 57% females; Mage = 12.30 years) completed a questionnaire assessing physical self-perceptions (i.e., perceived sport competence, conditioning, strength, and body attractiveness), PSW, and maturity status. Hierarchical multiple regression was used to test interactions between maturity and physical self-perceptions predicting PSW separately for boys and girls. RESULTS: For girls, maturity level and physical self-perceptions explained significant variance, F(5, 131) = 73.44, p < .001, R(2) = .74, with interactions explaining a little extra variance, DeltaF = 3.42, p = .01, DeltaR(2) = .03. Perceived attractiveness interacted with maturity status to predict PSW (p = .01), indicating that maturity was positively related to PSW only for girls with higher body attractiveness. Maturity status and physical self perceptions also significantly predicted PSW in boys, F(5, 98) = 46.52, p < .001, R(2) = .70, with interactions explaining a little extra variance, DeltaF = 3.16, p = .02, DeltaR(2) = .04. A statistically significant interaction between perceived strength and maturity (p < .001) indicated that maturity related positively to PSW, but only for boys with higher perceived strength. CONCLUSIONS: The maturity-PSW relationship differs by gender and depends partly on physical self-perceptions. This finding reinforces previous findings that illustrate the relative importance of perceived attractiveness and strength for girls and boys, respectively. PSW is an important predictor of physical activity behavior; therefore, it is critical to understand the interplay between these key antecedents. PMID- 26932678 TI - Assessing variation in life-history tactics within a population using mixture regression models: a practical guide for evolutionary ecologists. AB - Mixed models are now well-established methods in ecology and evolution because they allow accounting for and quantifying within- and between-individual variation. However, the required normal distribution of the random effects can often be violated by the presence of clusters among subjects, which leads to multi-modal distributions. In such cases, using what is known as mixture regression models might offer a more appropriate approach. These models are widely used in psychology, sociology, and medicine to describe the diversity of trajectories occurring within a population over time (e.g. psychological development, growth). In ecology and evolution, however, these models are seldom used even though understanding changes in individual trajectories is an active area of research in life-history studies. Our aim is to demonstrate the value of using mixture models to describe variation in individual life-history tactics within a population, and hence to promote the use of these models by ecologists and evolutionary ecologists. We first ran a set of simulations to determine whether and when a mixture model allows teasing apart latent clustering, and to contrast the precision and accuracy of estimates obtained from mixture models versus mixed models under a wide range of ecological contexts. We then used empirical data from long-term studies of large mammals to illustrate the potential of using mixture models for assessing within-population variation in life-history tactics. Mixture models performed well in most cases, except for variables following a Bernoulli distribution and when sample size was small. The four selection criteria we evaluated [Akaike information criterion (AIC), Bayesian information criterion (BIC), and two bootstrap methods] performed similarly well, selecting the right number of clusters in most ecological situations. We then showed that the normality of random effects implicitly assumed by evolutionary ecologists when using mixed models was often violated in life-history data. Mixed models were quite robust to this violation in the sense that fixed effects were unbiased at the population level. However, fixed effects at the cluster level and random effects were better estimated using mixture models. Our empirical analyses demonstrated that using mixture models facilitates the identification of the diversity of growth and reproductive tactics occurring within a population. Therefore, using this modelling framework allows testing for the presence of clusters and, when clusters occur, provides reliable estimates of fixed and random effects for each cluster of the population. In the presence or expectation of clusters, using mixture models offers a suitable extension of mixed models, particularly when evolutionary ecologists aim at identifying how ecological and evolutionary processes change within a population. Mixture regression models therefore provide a valuable addition to the statistical toolbox of evolutionary ecologists. As these models are complex and have their own limitations, we provide recommendations to guide future users. PMID- 26932679 TI - A General and Extremely Simple Remote Approach toward Graphene Bulks with In Situ Multifunctionalization. AB - Functional graphene bulks are developed by a general and simple approach for largescale preparation. This method shows promise for energy-related applications. PMID- 26932680 TI - Salinized rivers: degraded systems or new habitats for salt-tolerant faunas? AB - Anthropogenic salinization of rivers is an emerging issue of global concern, with significant adverse effects on biodiversity and ecosystem functioning. Impacts of freshwater salinization on biota are strongly mediated by evolutionary history, as this is a major factor determining species physiological salinity tolerance. Freshwater insects dominate most flowing waters, and the common lotic insect orders Ephemeroptera (mayflies), Plecoptera (stoneflies) and Trichoptera (caddisflies) are particularly salt-sensitive. Tolerances of existing taxa, rapid adaption, colonization by novel taxa (from naturally saline environments) and interactions between species will be key drivers of assemblages in saline lotic systems. Here we outline a conceptual framework predicting how communities may change in salinizing rivers. We envision that a relatively small number of taxa will be saline-tolerant and able to colonize salinized rivers (e.g. most naturally saline habitats are lentic; thus potential colonizers would need to adapt to lotic environments), leading to depauperate communities in these environments. PMID- 26932681 TI - Lineage tracing of the bivalve shell field with special interest in the descendants of the 2d blastomere. AB - By evolving bilaterally separated shell plates, bivalves acquired a unique body plan in which their soft tissues are completely protected by hard shell plates. In this unique body plan, mobility between the separated shell plates is provided by novel structures such as a ligament and adductor muscles. As a first step towards understanding how the bivalve body plan was established, we investigated the development of the separated shell plates and ligament. Over 100 years ago, it was hypothesized that the development of separated shell plates is tightly linked with the unique cell cleavage (division) pattern of bivalves during development, wherein each bilateral daughter cell of the 2d descendant 2d(1121) develops into one of the bilateral shell fields. In this study, we tested this hypothesis by tracing the cell lineages of the Japanese purple mussel Septifer virgatus. Although the shell fields were found to be exclusively derived from the bilateral descendant cells of 2d: 2d(11211) and 2d(11212), the descendants of these cells were not restricted to shell fields alone, nor were they confined to the left or right side of the shell field based on their lineage. Our study demonstrated that ligament cells are also derived from 2d(11211) and 2d(11212), indicating that the ligament cells emerged as a subpopulation of shell field cells. This also suggests that the establishment of the novel developmental system for the ligament cells was critical for the evolution of the unique body plan of bivalves. PMID- 26932682 TI - Enhanced call effort in Japanese tree frogs infected by amphibian chytrid fungus. AB - Some amphibians have evolved resistance to the devastating disease chytridiomycosis, associated with global population declines, but immune defences can be costly. We recorded advertisement calls of male Japanese tree frogs (Hyla japonica) in the field. We then assessed whether individuals were infected by Batrachochytrium dendrobatidis (Bd), the causal agent of the disease. This allowed us to analyse call properties of males as a function of their infection status. Infected males called more rapidly and produced longer calls than uninfected males. This enhanced call effort may reflect pathogen manipulation of host behaviour to foster disease transmission. Alternatively, increased calling may have resulted from selection on infected males to reproduce earlier because of their shortened expected lifespan. Our results raise the possibility that sublethal effects of Bd alter amphibian life histories, which contributes to long term population declines. PMID- 26932684 TI - New low bandgap near-IR conjugated D-A copolymers for BHJ polymer solar cell applications. AB - We synthesized two novel ultra low bandgap donor-acceptor (D-A) copolymers (E(g) <= 1.2 eV), containing the thiadiazoloquinoxaline unit as the main electron accepting unit (A) and benzodithiophene (BDT) and dithienosilole (DTS) as different donor units (D), denoted as P1 and P2, respectively, using the cross coupling Stille reaction. The copolymers possess light absorption ranging from UV (350 nm) to near-IR (1300 nm) with optical bandgaps of 1.16 eV and 1.08 eV, respectively. Quantum-chemical calculations and experimental data were compared for proposing a more detailed concept for the optical and electronic properties of these copolymers which can be used as donors for polymer solar cells (PSCs). The PSCs based on optimized P1:PC71BM and P2:PC71BM showed overall power conversion efficiencies (PCEs) of 4.32% and 3.48%, respectively. Although P2 possesses a broad absorption coverage of up to 1300 nm, the lower PCE may be attributed to the low J(sc), due to the poor driving force for exciton dissociation, since the LUMO offset with PC71BM is less than 0.3 eV. The PCE has been significantly increased to 7.27% and 6.68% for solvent vapor annealing (SVA) treated P1:PC71BM and P2:PC71BM active layers, respectively. This improvement arises from the appropriate nanoscale morphology and an increase in hole mobility, induced by the SVA treatment of the active layers. PMID- 26932683 TI - Zinc levels in seminal plasma and their correlation with male infertility: A systematic review and meta-analysis. AB - Zinc is an essential trace mineral for the normal functioning of the male reproductive system. Current studies have investigated the relationship between seminal plasma zinc and male infertility but have shown inconsistent results. Hence, we systematically searched PubMed, EMBASE, Science Direct/Elsevier, CNKI and the Cochrane Library for studies that examined the relationship between seminal plasma zinc and male infertility, as well as the effects of zinc supplementation on sperm parameters. Twenty studies were identified, including 2,600 cases and 867 controls. Our meta-analysis results indicated that the seminal plasma zinc concentrations from infertile males were significantly lower than those from normal controls (SMD (standard mean differences) [95% CI] -0.64 [ 1.01, -0.28]). Zinc supplementation was found to significantly increase the semen volume, sperm motility and the percentage of normal sperm morphology (SMD [95% CI]: -0.99 [-1.60, -0.38], -1.82 [-2.63, -1.01], and -0.75 [-1.37, -0.14], respectively). The present study showed that the zinc level in the seminal plasma of infertile males was significantly lower than that of normal males. Zinc supplementation could significantly increase the sperm quality of infertile males. However, further studies are needed to better elucidate the correlation between seminal plasma zinc and male infertility. PMID- 26932685 TI - Urinary biomarkers to predict CKD: is the future in multi-marker panels? PMID- 26932687 TI - Immunogenicity and safety of quadrivalent human papillomavirus types 6/11/16/18 recombinant vaccine in chronic kidney disease stage IV, V and VD. AB - Background: Up to >80% of sexually active adults will become infected with human papillomavirus (HPV) during their lifetime. Persistent HPV infection can result in cervical, vulvovaginal, penile and anogenital cancer. Clinical studies have shown the efficacy of three doses of quadrivalent HPV-6/11/16/18 L1 virus-like particle (VLP) vaccination, at Day 0, Month 2 and Month 6, to lower the occurrence of HPV infection and its complications. However, immunogenicity and safety of the HPV vaccine have not been proven in the chronic kidney disease (CKD) population. Methods: Sixty CKD stage IV, V and VD patients were enrolled for quadrivalent HPV-6/11/16/18 vaccination. A dose of vaccine was given at Day 0, Month 2 and Month 6. Each dose contained 20 MUg HPV-6 L1 VLP, 40 MUg HPV-11 L1 VLP, 40 MUg HPV-16 L1 VLP and 20 MUg HPV-18 L1 VLP, along with 225 MUg of amorphous aluminum hydroxyphosphate sulfate adjuvant. HPV type-specific antibody response to neutralizing epitopes on HPV-6/11/16/18 was performed by multiplexed, competitive Luminex(r) immunoassays (cLIA) at Day 0 and Month 7. Results: At Day 0, anti-HPV seropositivity was 0-6.6% depending on HPV genotype. Patients who received three doses of vaccine had 98.2, 100, 100 and 98.2% seropositivity for genotypes 6/11/16/18, respectively. The average cLIA at Month 7 for genotypes 6/11/16/18 were 928.4 +/- 231.1, 1136.1 +/- 264.6, 6951.0 +/- 1872.3 and 2196.3 +/- 761.2 milliMerck units (mMu)/mL, respectively. No serious vaccine-related adverse events were observed. Conclusions: Quadrivalent HPV vaccine has been well tolerated, is safe and provides excellent immunogenicity in late-stage CKD. PMID- 26932688 TI - Urinary dedifferentiated podocytes as a non-invasive biomarker of lupus nephritis. AB - BACKGROUND: Currently, renal biopsy remains the gold standard for the diagnosis and prognosis of lupus nephritis (LN). However, it is an invasive method, and new non-invasive laboratory tests are needed to identify renal involvement without renal biopsy. Podocyte damage plays an important role in the pathogenesis and progression of systemic lupus erythematosus (SLE). We characterize whether the phenotype of urinary podocytes (viability, apoptosis, mRNA and protein levels of the podocyte-associated molecules) is a novel marker of clinical and histological features in SLE patients with or without LN. METHODS: We quantified in urinary sediments of 32 SLE patients and 20 controls, mRNA and protein levels of podocalyxin, synapotopodin, podocin, nephrin and WT-1 by quantitative real-time polymerase chain reaction and western blot analysis and correlated these with clinical and histological parameters. The viability of detached urine podocytes was analysed by flow cytometry with podocalyxin and annexin V/7-AAD double staining and immunofluorescence of urine podocyte cultures. RESULTS: The degree of a poptotic podocytes from urine samples was significantly decreased in patients with LN, especially in the active state (33% compared with 75% in controls, P < 0.001), and the majority of the detached podocytes in the urine of patients with active LN were viable (70% grew in culture). Furthermore, urinary mRNA of podocyte-associated molecules was significantly lower in patients with active LN (P < 0.05) compared with healthy controls, and protein levels of podocyte markers were significantly increased in SLE patients, especially with LN compared with SLE without LN (P < 0.05) and the healthy control group (P < 0.01). Finally, urinary protein levels of podocyte-related markers were associated with proteinuria and histological features (P < 0.05 and P < 0.01), and receiver operating characteristics curves of protein levels discriminate between LN and healthy controls with an area under the curve (AUC) between 0.91 and 0.77 (P < 0.001). CONCLUSIONS: Urinary dedifferentiated podocytes were shown in active LN, and their protein levels correlated with proteinuria and histological features in LN. These preliminary results suggest that it could be a potentially useful non invasive marker for evaluating the progression of glomerular disease in SLE. PMID- 26932690 TI - Prenatal diagnosis of fetal multicystic dysplastic kidney via high-resolution whole-genome array. AB - BACKGROUND: Women with fetal multicystic dysplastic kidneys (MCDK) are commonly referred for genetic counseling, for which identification of the correct etiology is a prerequisite. METHODS: A total of 72 women with fetal MCDK at Guangzhou Women and Children's Medical Center were examined via invasive prenatal diagnosis from May 2010 to June 2015. Standard karyotyping analysis was provided to all fetuses, and chromosomal microarray with Affymetrix CytoSan HD arrays was offered to cases whose DNA samples were available. RESULTS: Abnormal karyotypes were detected in 3 of 72 (4.17%) fetuses. Of the 69 (95.8%, 69/72) fetuses with normal karyotypes, 30 (42%, 30/69) underwent chromosome microarray analysis (CMA) testing. The CMA identified pathogenic copy number variations in five fetuses, leading to a pathogenic detection rate of 16.7% (5/30). Well-known microdeletion or microduplication syndromes including renal cysts and diabetes (RCAD) syndrome and Williams-Beuren syndrome (WBS) were identified in three cases. Moreover, four chromosomal imbalanced regions were also identified in our MCDK fetuses: 22q11.1 duplication, 4q35.2 deletion, 22q13.33 duplication and 1p33 duplication. Genes PEX26, ELN, HNF1B, ALG12, FRG1, FRG2 and CYP4A11 were possible candidates for fetal MCDK. The proportions of variants of unknown significance before and after parental analysis were 13.3% (4/30) and 3.3% (1/30), respectively. CONCLUSIONS: In the present study, the frequency of chromosomal abnormalities in MCDK fetuses was 4.17% and all rearrangements were imbalanced aberrations. CMA was able to increase the pathogenic detection rate to 16.7% in MCDK fetuses with normal karyotype. Critical regions for RCAD syndrome, WBS and copy number variants of 22q11.1 duplication, 4q35.2 deletion, 22q13.33 duplication and 1p33 duplication were associated with fetal MCDK. Genes PEX26, ELN, HNF1B, ALG12, FRG1, FRG2 and CYP4A11 were possible candidates for fetal MCDK. PMID- 26932689 TI - Effect of genotype on the severity and volume progression of polycystic liver disease in autosomal dominant polycystic kidney disease. AB - BACKGROUND: The autosomal dominant polycystic kidney disease (APDKD) genotype influences renal phenotype severity but its effect on polycystic liver disease (PLD) is unknown. Here we analyzed the influence of genotype on liver phenotype severity. METHODS: Clinical data were retrieved from electronic records of patients who were mutation screened with the available liver imaging (n = 434). Liver volumes were measured by stereology (axial or coronal images) and adjusted to height (HtLV). RESULTS: Among the patients included, 221 (50.9%) had truncating PKD1 (PKD1-T), 141 (32.5%) nontruncating PKD1 (PKD1-NT) and 72 (16.6%) PKD2 mutations. Compared with PKD1-NT and PKD2, patients with PKD1-T had greater height-adjusted total kidney volumes (799 versus 610 and 549 mL/m; P < 0.001). HtLV was not different (1042, 1095 and 1058 mL/m; P = 0.64) between the three groups, but females had greater HtLVs compared with males (1114 versus 1015 mL/m; P < 0.001). Annualized median liver growth rates were 1.68, 1.5 and 1.24% for PKD1-T, PKD1-NT and PKD2 mutations, respectively (P = 0.49), and remained unaffected by the ADPKD genotype when adjusted for age, gender and baseline HtLV. Females <48 years of age had higher annualized growth rates compared with those who were older (2.65 versus 0.09%; P < 0.001). After age 48 years, 58% of females with severe PLD had regression of HtLV, while HtLV continued to increase in males. CONCLUSIONS: In contrast to the renal phenotype, the ADPKD genotype was not associated with the severity or growth rate of PLD in ADKPD patients. This finding, along with gender influence, indicates that modifiers beyond the disease gene significantly influence the liver phenotype. PMID- 26932691 TI - Effect of assistance on peritonitis risk in diabetic patients treated by peritoneal dialysis: report from the French Language Peritoneal Dialysis Registry. AB - BACKGROUND: Diabetic patients treated by peritoneal dialysis (PD) have been reported to be at an increased risk of peritonitis. This has been attributed to impairment in host defense, visual impairment, disability and muscle wasting, which could compromise ability to safely perform catheter connections. This study aimed to evaluate whether assisted PD is associated with a lower risk of peritonitis in diabetic patients. METHODS: This was a retrospective study based on data from the French Language Peritoneal Dialysis Registry. We included diabetic patients starting PD between 1 January 2002 and 31 December 2012. The end of the observation period was 31 December 2013. Using complementary regression analysis (Fine and Gray, Hurdle models), we assessed the relationship between peritonitis occurrence, peritonitis number over time and the type of assisted PD. RESULTS: Of the 3598 diabetic patients, there were 2040 patients on nurse-assisted PD. These patients were older, more comorbid and more frequently on continuous ambulatory peritoneal dialysis (CAPD). In the multivariate analysis, nurse assistance was associated with a reduced risk of peritonitis in the Fine and Gray [subdistribution hazard ratio: 0.78 (95% confidence interval, CI, 0.68-0.89)] and in the first component of the Hurdle models [rate ratio: 0.82 (95% CI 0.71-0.93)], but not a lower incidence of peritonitis after an initial episode [rate ratio: 0.82 (95% CI 0.95-1.38)]. Transplant failure, glomerulonephritis and CAPD were associated with an increased risk. CONCLUSIONS: In France, nurse-assisted PD is associated with a lower risk of peritonitis in diabetic patients treated by PD but not a lower incidence of peritonitis. PMID- 26932692 TI - Highlights of the 2015 ERA-EDTA congress: chronic kidney disease, hypertension. AB - This paper reports the highlights in the field of chronic kidney disease (CKD) and hypertension of the last European Renal Association (ERA-EDTA) Congress (London, May 21-24, 2016). The items include an European survey on CKD epidemiology and a multicenter, open-label, randomized controlled trial on the effect of renal denervation for hypertension management. Furthermore, a polar view regarding ABPM for the diagnosis and the monitoring of hypertension in dialysis patients is presented. PMID- 26932694 TI - Enhanced External Counterpulsation in Chronic Heart Failure: Where Do We Stand? PMID- 26932695 TI - The Effect of Enhanced External Counterpulsation Therapy and Improvement of Functional Capacity in Chronic Heart Failure patients: a Randomized Clinical Trial. AB - AIM: to investigate the efficacy of enhanced external counterpulsation (EECP) therapy to improve functional capacity in patients with chronic heart failure (CHF). METHODS: a double-blind random clinical trial was performed in 99 patients with CHF who had received EECP therapy at Jade Cardiovascular Clinic, Manado, North Sulawesi, Indonesia between January 2014 and June 2015. Subjects were categorized into 2 groups, i.e. 49 subjects had sham EECP therapy and 50 subjects had EECP therapy. All subjects performed six-minute walking test (6MWT) before and after receiving EECP therapy. RESULTS: there was no significant difference between both groups regarding the basic characteristics of patients with CHF. The 6MWT result before EECP therapy showed that there were 30 patients (61.2%) with walk distance of <300 meter in the sham EECP group; while in the group receiving EECP therapy, we found 34 patients (68%); p=0.24. Post-EECP therapy, there were 33 patients (67.3%) with walk distance of <300 meters in EECP sham group; while in the group receiving EECP alone, there was only 1 patient (2%); p<0.01.The 6MWT walk distance in sham group before EECP therapy was 252.65 (SD 97.55) meters and it was 243.65 (SD 86.96) meters following the EECP therapy; p=0.18. In EECP group, the 6MWT walk distance before therapy was 256.88 (SD 85.56) meters and after EECP therapy the walk distance was 449.46 (SD 92.08) meters; p<0.01. CONCLUSION: EECP therapy is effective to improve functional capacity in patients with CHF. PMID- 26932693 TI - An estimated glomerular filtration rate equation for the full age spectrum. AB - BACKGROUND: Glomerular filtration rate (GFR) is accepted as the best indicator of kidney function and is commonly estimated from serum creatinine (SCr)-based equations. Separate equations have been developed for children (Schwartz equation), younger and middle-age adults [Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation] and older adults [Berlin Initiative Study 1 (BIS1) equation], and these equations lack continuity with ageing. We developed and validated an equation for estimating the glomerular filtration rate that can be used across the full age spectrum (FAS). METHODS: The new FAS equation is based on normalized serum creatinine (SCr/Q), where Q is the median SCr from healthy populations to account for age and sex. Coefficients for the equation are mathematically obtained by requiring continuity during the paediatric-adult and adult-elderly transition. Research studies containing a total of 6870 healthy and kidney-diseased white individuals, including 735 children, <18 years of age, 4371 adults, between 18 and 70 years of age, and 1764 older adults, >=70 years of age with measured GFR (inulin, iohexol and iothalamate clearance) and isotope dilution mass spectrometry-equivalent SCr, were used for the validation. Bias, precision and accuracy (P30) were evaluated. RESULTS: The FAS equation was less biased [-1.7 (95% CI -3.4, -0.2) versus 6.0 (4.5, 7.5)] and more accurate [87.5% (85.1, 89.9) versus 83.8% (81.1, 86.5)] than the Schwartz equation for children and adolescents; less biased [5.0 (4.5, 5.5) versus 6.3 (5.9, 6.8)] and as accurate [81.6% (80.4, 82.7) versus 81.9% (80.7, 83.0)] as the CKD-EPI equation for young and middle-age adults; and less biased [-1.1 (-1.6, -0.6) versus 5.6 (5.1, 6.2)] and more accurate [86.1% (84.4, 87.7) versus 81.8% (79.7, 84.0)] than CKD-EPI for older adults. CONCLUSIONS: The FAS equation has improved validity and continuity across the full age-spectrum and overcomes the problem of implausible eGFR changes in patients which would otherwise occur when switching between more age-specific equations. PMID- 26932697 TI - The Influence of Hyperglycemia at Admission on In-hospital Arrhythmia Patients with Acute Coronary Syndrome. AB - AIM: to determine the incidence of in-hospital arrhythmias in patients with acute coronary syndrome (ACS) and to determine the influence of hyperglycemia at admission (HA) on in-hospital arrhythmias complicating ACS. METHODS: a retrospective cohort study was conducted using secondary data from medical records of patients with ACS who were admitted to ICCU RSCM, between January 1st December 31st, 2014. Hyperglycemia at admission was defined when the blood glucose level at admission was >140 mg/dL. The in-hospital arrhythmias encompassed atrial arrhythmia, supraventricular tacchycardia (SVT), high grade AV block (HAVB), and ventricular arrhythmia, during the first seven days of hospitalization. RESULTS: there were 232 subjects in this study. The prevalence of HA was 50.43%. The incidence of in-hospital arrhythmia was 21.55% (95% CI 16.26-26.84). In bivariate analysis, there was significant association between HA and in-hospital arrhythmia (RR 1.75; 95% CI 1.04-2.93). There were no association between type of ACS, diabetes mellitus (DM), obesity, and hypertension, with the in-hospital arrhythmias. In multivariate analysis, the adjusted OR of HA was 2.85 (95% CI 1.35-6.02), and DM was the confounding variable. CONCLUSION: the incidence of in-hospital arrhythmias in patients with ACS was 21.55% (95% CI 16.26-26.84). Hyperglycemia at admission may increase the risk of in-hospital arrhythmia in patients with ACS. PMID- 26932696 TI - Association of Tumor Necrosis Factor Alpha and Lymphotoxin Alpha Gene Polymorphisms with the Presence of Chronic Obstructive Pulmonary Disease. AB - AIM: to analyze the occurrence of chronic obstructive pulmonary disease (COPD) and its association with the polymorphisms of -308G/A, -238G/A of TNF gene and +252A/G LT gene polymorphism in smokers. METHODS: cross-sectional study, comparing the genetic group of people who have COPD and who do not have COPD with the same smoking history. The study was conducted from January 2011 to March 2012 at several health centers; such as Adam Malik Hospital, Pirngadi Hospital, Tembakau Deli Hospital, Siti Hajar Hospital in Medan and several health centers in the city of Medan. Examination of lung function was done using spirometry and the existence of genetic polymorhisms in the TNF and LT gene was performed using polymerase chain reaction-restriction fragment length polymorphisms (PCR-RFLP). RESULTS: of the total of 227 samples that met inclusion criteria and after equalizing the age and history of smoking, 186 subjects were enrolled, of which, 93 people as COPD group and 93 people as non-COPD group. Analysis of the association between the -308G/A polymorphism with the COPD revealed the odds ratio (OR) 0.436 (95% CI 0.224-0.850, p=0.014). Polymorphism at -238G/A of the TNF gene showed the OR 2.094 (95% CI 0.608 - 7.211, p=0.241). Polymorphism at +252A/G LT gene showed OR 1.256 (95% CI 0.694 - 2.272; p=0.450). The findings indicated that polymorphism at -308G showed a protective factor whereas the 238G/A of the TNF and +252A/G of the LT genes did not show any significant association with the COPD. CONCLUSION: polymorphism -308 TNF gene shown to be a protective factor for the occurrence of COPD. Polymorphism -238 TNF gene and +252 LT gene did not show any significant association with COPD. PMID- 26932698 TI - Seroprevalence and Socio-demographic Factors of Helicobacter pylori Infection in Patients with Dyspepsia in Kalibaru Primary Health Care North Jakarta. AB - AIM: to identify the seroprevalence and its association with socio-demographic factors of Helicobacter pylori infection. METHODS: a cross-sectional study was performed in 111 patients with dyspepsia (according to ROME III) who got treatment at Kalibaru Primary Health Care, North Jakarta from January to February 2015. Patients aged over 18 years and no history of gastrectomy were interviewed and 3 cc venous blood was drawn. Bioramps Laboratories's Immunochromatography Diagnostic Test (Bio M Pylori) was used to diagnose patient with Helicobacter pylori infection. Chi Square were used to analyzed socio-demographic and T test were used to analyze age. Variables with p<0.25 were analyzed by logistic regression. RESULTS: seroprevalence of Helicobacter pylori of 111 dyspepsia patients who got treatment in Kalibaru Primary Health Care in this study was 22.5% (95% CI 14.8%-30.2%). There is no relation between age and Helicobacter pylori infection (p=0.270). Higher socio-economic class was related to lower risk Helicobacter pylori infection (OR 0.2; 95% CI 0.02-1.71). Higher crowding index was related to higher risk Helicobacter pylori infection (OR 1.2; 95% CI 0.37 4.49). Lower clean water index was related to higher risk Helicobacter pylori infection (OR 1.5; 95% CI 0.57-4.04). Lower sanitation status was related to higher risk Helicobacter pylori infection (OR 2.5; 95% CI 1.01-6.19). CONCLUSION: seroprevalence of Helicobacter pylori infection in patient with dyspepsia in Kalibaru village was 22.5%. There is an association between sanitation and Helicobacter pylori infection. PMID- 26932699 TI - ST2 Levels Before and After Treatment of NYHA III and IV Heart Failure. AB - AIM: to find whether ST2 can be used to determine clinical improvement in patients with NYHA III and IV heart failure. METHODS: this is a longitudinal, pre and post-test study without a control group. Study subjects are 23 NYHA III and IV heart failure patients. ST2 was tested at the start and end of hospital treatment. RESULTS: of 23 heart failure patients, 70% were classified as NYHA III while 30% were NYHA IV. There were more male subjects than females (51.4% vs. 48.6%). Median age for NYHA III heart failure patients was 52 years and mean age for NYHA IV heart failure patients was 58 years. Heart failure was mostly caused by coronary artery disease (52%). ST2 levels did not correlate with age, length of care, sex and cause of heart failure. ST2 levels in NYHA IV heart failure patients (58.82+/-37.36 ng/mL) tended to be higher than the one in NYHA III group (30.75 [14.4-84.5] ng/mL), but the difference was statistically not insignificant (p=0.89). ST2 levels at the start of treatment was significantly higher than at the end (31.4 [14-129.2] ng/mL vs. 18.4 [7.6-77.8] ng/mL), p=0.001. This shows that clinical improvement is associated with significant reduction of ST2 levels. CONCLUSION: ST2 can be used as a marker to determine clinical improvement in NYHA III and IV heart failure. PMID- 26932700 TI - Early Implementation of Universal Health Coverage Among Hypertension Subjects in Sleman District of Yogyakarta. AB - AIM: to evaluate the participant rate of the new universal health coverage (UHC) and its impact on the hypertensive subjects from the rural area in the Sleman District of Yogyakarta during the early implementation. METHODS: this epidemiological survey of the new UHC implementation was included as an analytical cross-sectional study done with cluster random sampling. The subject criteria were aged 30-85 year, not in pregnancy, and signed the informed-consent. Subjects were grouped based on the health coverage disparity and analyzed with chi-square statistics for the hypertension prevalence, awareness, therapy, and control. The additional variables of BMI, education, occupation, income, smoking, diet control, physical activity, and health facilities were grouped into binomial data and analyzed based-on the health coverage disparity. RESULTS: of 926 total subjects, 602 (65.0%) subjects had the health coverage including 9.2% of the new UHC. The groups of with and without health coverage were not significantly different in hypertension prevalence, the profile of age, blood pressure, and the proportion of the other variables (p>0.05) except for smoking and physical activities. In the high blood pressure sub-group (n=446), the subjects without health coverage had lower proportion of the hypertension awareness p<0.02; OR: 0.60 (CI95%:0.39-0.91) and therapy p<0.03; OR: 0.50 (CI95%:0.27-0.94), but not in the blood pressure control (p>0.05). CONCLUSION: the participant rate of new UHC was relatively low at 9.2%. Among the subgroup with 140/90mmHg blood pressure, the subjects without health coverage were more likely to have lower hypertension awareness and suboptimal therapy than those with the health coverage program. PMID- 26932701 TI - Hyperuricemia as a Risk Factors of Major Adverse Cardiac Events in Patients with Acute Coronary Syndrome: a Retrospective Cohort Study. AB - AIM: to investigate the MACE-free survivals difference between hyperuricemic and normouricemic patients and to determine its role as risk factor for MACE occurrence in hospitalized acute coronary syndrome patients. METHODS: retrospective cohort study with survival analysis approach was conducted in 251 patients with acute coronary syndrome who were treated in ICCU Cipto Mangunkusumo Hospital during period from January 2009 to December 2011. Clinical data, laboratory results, electrocardiography result, echocardiography result, and coronary angiography were collected. Patients were observed and followed on major adverse cardiac event during 7 days of hospitalization in ICCU. Major adverse Cardiac Event is an event as a complication occur after acute coronary syndrome such as cardiogenic syock, acute heart failure, stoke, reinfarct during early ward treatment, sudden cardiac death, repeat PCI during ward ulang and perform coronary artery bypass graft (CABG) surgery. Difference in survival is shown in Kaplan-meier curve and difference in survival between groups were tested with Log rank test, and multivariate analysis with Cox proportional hazard regression to calculate adjusted HR on major adverse cardiac event with confounding variables as covariates. RESULTS: there was a significant difference in survival between hyperuricemia group and non-hyperuricemia group (Log-rank test (p<0.001)) with crude HR 2.7 (CI 95% 1.6-4) and adjusted HR 2.67 (CI 95% 1.6-4.3).There was significant difference in survival between hyperuricemia group (mean survival 6.05 days with SE 0.2 (CI 95% 5.6-6.4) and non-hyperuricemia group (mean survival 7.33 days with SE 0.1 (CI 95% 7.0-7.6). CONCLUSION: survival of patients suffering from ACS with hyperuricemia is worse compared to those without hyperuricemia during ICCU hospitalization. PMID- 26932702 TI - Integrative Approach in Haemophillic Arthropathy of The Knee: a Case Report. AB - Haemophilic arthropathy is the most prevalent joint disorder in haemophilia. This disorder is characterized by chronic synovitis and progressive destruction of joint cartilage. We report a case of arthroscopic synovectomy to reduce bleeding frequency in haemophilic arthropathy of the knee. Patient was a 15 years old male with haemophilic arthropathy of the left knee. We performed an arthroscopic synovectomy under tightly regulated factor VIII replacement therapy. There were villous synovial hypertrophy at all part of the joint, multiple bone and cartilage defect, and also anterior cruciate ligament (ACL) and posterior cruciate ligament (PCL) deficiency found intraoperatively. After 6 month follow up, subjective complain and bleeding frequency decreased significantly. The visual analog scale improved from 5-6 to 1-2, and the International Knee Documentation Committee Score increased from 49 to 66. Bleeding frequency decreased from 4-8 times per month to less than 1 time per month. Arthroscopic synovectomy performed in this case could reduce the pain, decrease the frequency of bleeding, and improve patient's functional outcome. PMID- 26932703 TI - Supraclavicular Lymphnodes: Unusual Manifestation of Metastase Adenocarcinoma Colon. AB - We report a patient with supraclavicular lymph node metastasis from an undetectable adenocarcinoma of the transverse colon, who presented with cough and was diagnosed with typhoid fever, bronchitis as well as liver metastasis. There were an abdominal fullness, weight loss, constipation, pencil-like stool with mucous and blood, low-grade fever, bone ache, and tea-color urine. The first colonoscopy revealed lymphocytic ileitis and microscopic findings also showed lymphocytic ileitis. Abdominal USG and CT revealed liver metastasis of unknown origin. Based on the clinical sign and symptoms, we suspected that colorectal carcinoma was the primary site. Then, the second colonoscopy was performed and it revealed a small polyp, which was followed with a biopsy and the result supported a well-differentiated colon adenocarcinoma. Similar result was also revealed by the histopathological evaluation. This is an unusual case of liver and supraclavicular lymph node metastasis arising from a small polyp adenocacinoma of the transverse colon. PMID- 26932704 TI - The Role of Endothelial Progenitor Cell in Cardiovascular Disease Risk Factors. AB - Endothelial progenitor cells (EPCs) are cell derived from bone marrow and the cells circulate in peripheral blood. These cells have characteristics similar to stem cells, but their ability to proliferate and differentiate is more limited. EPC discovery has changed the old paradigm in the field of vascular biology and it brings huge implications in medicine as EPCs can mediate the processes of vasculogenesis and maintain the vascular integrity. Increasing amount of EPC in the circulation is important since it has positive correlation with reendothelialization and neovascularization and they are closely linked to cardiovascular health. Thus, EPC could potentially be used for treatment of disease caused by endothelial dysfunction. PMID- 26932705 TI - Recurrent Bilateral Staghorn Stones as a Manifestation of Primary Hyperparathyroidism due to Parathyroid Adenoma. AB - Primary hyperparathyroidism is a medical condition caused by overactive of parathyroid gland. It is most commonly caused by solitary adenoma of the parathyroid gland. Other causes of this condition are hyperplasia, multiple adenomas, and parathyroid cancer. Primary hyperparathyroidism has some metabolic consequences in the calcium metabolism. Hypercalcemia in patient with primary hyperparathyroidism will resulted to the most important comorbidity that is chronic deposition of calcium in the kidney forming nephrolithiasis or other urolithiasis. It is not uncommon, patient with parathyroid adenoma come to health care professionals with the chief complain of recurrence nephrolithiasis. PMID- 26932706 TI - The Role of Ursodeoxycholic Acid in Acute Viral Hepatitis: an Evidence-based Case Report. AB - AIM: to review the role of ursodeoxycholic acid in acute viral hepatitis. METHODS: following literature searching according to the clinical question on Pubmed and Cochrane Library. After filtered with our inclusion and exclusion criteria, one meta-analysis and two randomized clinical trials are obtained. Through critical appraisal, it was concluded that the articles meet the criteria for validity and relevance. RESULTS: the article found that there is a positive effect of ursodeoxycholic acid on the activity of serum transaminases and cholestasis indexes. However, there is insufficient evidence to support or to refute effects of ursodeoxycholic acid on disease's course as well as the viral load. CONCLUSION: better method of clinical trials are needed to obtain a valid and applicable result for daily practice. PMID- 26932707 TI - Snakebite in Indonesia. AB - Indonesia as one of the largest tropical and agricultural countries in the world shared the particularly high burden cases of snakebite. In the last decade, World Health Organization (WHO) has listed snakebite as one of the neglected tropical disease. The clinical manifestations of snakebite could vary according to the type of venoms ranging from mild to life threatening condition. Appropriate first aid treatment and comprehensive management of snakebite cases are warranted to reduce mortality and morbidity rates. PMID- 26932708 TI - Consensus Conference on North American Training in Hepatopancreaticobiliary Surgery: A Review of the Conference and Presentation of Consensus Statements. AB - The findings and recommendations of the North American Consensus Conference on Training in HPB Surgery held October 2014 are presented. The conference was hosted by the Society for Surgical Oncology (SSO), Americas Hepatopancreaticobiliary Association (AHPBA), and the American Society of Transplant Surgeons (ASTS). The current state of training in HPB surgery in North America was defined through three pathways-HPB, Surgical Oncology, and Solid Organ Transplant fellowships. Consensus regarding programmatic requirements included establishment of minimum case volumes and inclusion of quality metrics. Formative assessment, using milestones as a framework and inclusive of both operative and non-operative skills, must be present. Specific core HPB cases should be defined and used for evaluation of operative skills. The conference concluded with a focus on the optimal means to perform summative assessment to evaluate the individual fellow completing a fellowship in HPB surgery. Presentations from the hospital perspective and the American Board of Surgery led to consensus that summative assessment was desired by the public and the hospital systems, and should occur in a uniform but possibly modular manner for all HPB fellowship pathways. A task force comprised of representatives of the SSO, AHPBA, and ASTS are charged with implementation of the consensus statements emanating from this consensus conference.Copyright (c) 2016 The American Society of Transplantation, the American Society of Transplant Surgeons, and the Society of Surgical Oncology. All rights reserved. No part of this document may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without written permission by The American Society of Transplantation, the American Society of Transplant Surgeons, or the Society of Surgical Oncology. PMID- 26932709 TI - Activated Caspase 3 Expression in Remnant Disease After Neoadjuvant Chemotherapy May Predict Outcomes of Breast Cancer Patients. AB - BACKGROUND: A number of studies have indicated that patients obtaining a pathological complete response (pCR) from neoadjuvant chemotherapy (NAC) have a good prognosis; however, prognostic factors for non-pCR patients are not yet well established. By examining remnant cancer in non-pCR patients, the expression of cleaved Caspase 3 (Casp3), an activated apoptotic marker, was immunohistochemically investigated to determine whether this protein has the potential to serve as a novel marker for predicting patient outcomes. METHODS: We investigated 218 patients with invasive breast cancer who received NAC and underwent surgery during the 2006 through 2008 period at our institution. Following surgery, standard adjuvant endocrine therapy was administered if a tumor was hormone receptor-positive. Casp3 was evaluated in remnant cancer based on the number of positive cells in five high-power fields. RESULTS: pCR was obtained in 49 patients, and 50 of the 169 non-pCR patients developed recurrences during the median 82-month observation period. We found large tumor size, lymph node involvement, lymph vessel invasion, estrogen receptor-negative, progesterone receptor-negative, high Ki67 and high Casp3 expression to be factors related to tumor recurrence. A logistic regression model revealed that lymph node involvement, as well as high Ki67 and Casp3, to be factors independently predicting recurrence, while lymph vessel invasion and high Ki67 expression were found to be related to breast cancer mortality. CONCLUSIONS: Patients with remnant cancer showing high Casp3 expression had poor outcomes. Our results showed that Casp3 is a potential prognostic marker for non-pCR patients. PMID- 26932710 TI - Sentinel Lymph Node Biopsy in Thin Cutaneous Melanoma: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Most patients with melanoma have a thin (<=1.00 mm) lesion. There is uncertainty as to which patients with thin melanoma should undergo sentinel lymph node (SN) biopsy. We sought to quantify the proportion of SN metastases in patients with thin melanoma and to determine the pooled effect of high-risk features of the primary lesion on SN positivity. METHODS: Published literature between 1980 and 2015 was searched and critically appraised. Primary outcome was the proportion of SN metastases in patients with thin cutaneous melanoma. Secondary outcomes included the effect of high-risk pathological features of the primary lesion on the proportion of SN metastases. Summary measures were estimated by Mantel-Haenszel method using random effects meta-analyses. RESULTS: Sixty studies (10,928 patients) met the criteria for inclusion. Pooled SN positivity was 4.5 % [95 % confidence interval (CI) 3.8-5.2 %]. Predictors of a positive SN were: thickness >=0.75 mm [adjusted odds ratio (AOR) 1.90 (95 % CI 1.08-3.34); with a likelihood of SN metastases of 8.8 % (95 % CI 6.4-11.2 %)]; Clark level IV/V [AOR 2.24 (95 % CI 1.23-4.08); with a likelihood of 7.3 % (95 % CI 6.2-8.4 %)]; >=1 mitoses/mm2 [AOR 6.64 (95 % CI 2.77-15.88); pooled likelihood 8.8 % (95 % CI 6.2-11.4 %)]; and the presence of microsatellites [unadjusted OR 6.94 (95 % CI 2.13-22.60); likelihood 26.6 % (95 % CI 4.3-48.9 %)]. CONCLUSIONS: The pooled proportion of SN metastases in thin melanoma is 4.5 %. Thickness >=0.75 mm, Clark level IV/V, mitoses, and microsatellites significantly increased the odds of SN positivity and should prompt strong consideration of SN biopsy. PMID- 26932711 TI - Comparison of Definitive Chemoradiotherapy in Locally Advanced Esophageal Squamous Cell Carcinoma. AB - BACKGROUND: This retrospective study was designed to estimate the efficacy and toxicity of definitive radiotherapy with concurrent or sequential docetaxel/S-1 for patients with locally advanced esophageal squamous cell carcinoma (ESCC). METHODS: Of the 62 eligible patients enrolled in this study during January 1, 2010 to December 31, 2014 from Qilu Hospital, Shandong University, Shandong Province, 39 patients received 3 cycles of docetaxel/S-1 during and after radiotherapy (concurrent chemoradiotherapy, CCRT), and 23 patients had radiotherapy followed by 3 cycles of docetaxel and S-1 (sequential chemoradiotherapy, SCRT). RESULTS: The CR of CCRT and SCRT groups were 48.72 and 21.74 %, respectively (p = 0.035). The median progress-free survival (PFS) of CCRT group (23.5 months) was significantly higher than SCRT group (11.7 months; p = 0.004). The median overall survival (OS) of CCRT group (33.5 months) also was significantly higher than SCRT group (24.0 months; p = 0.004). At 2 years, in this patient population, the rate of PFS of CCRT group was (44.2 +/- 8.2 %), significantly higher than SCRT group (11.9 +/- 9.6 %; p = 0.002). The 2-year OS rate of CCRT (68.6 +/- 7.5 %) was significantly higher than SCRT group as well (42.0 +/- 14.0 %; p = 0.002). The incidence of adverse events was higher in CCRT than SCRT group. No grade 4 or grade 5 adverse events occurred in our study. CONCLUSIONS: Definitive radiotherapy with concurrent or sequential docetaxel and S-1 for inoperable locally advanced ESCC was very well tolerated and remarkably active. In both CCRT and SCRT groups, acute toxicities were manageable. This regimen holds promises for treatment of esophageal carcinoma and warrants further investigation. PMID- 26932712 TI - Copper(I)-catalyzed olefination of N-sulfonylhydrazones with sulfones. AB - The Cu(I)-catalyzed olefination of N-sulfonylhydrazones with sulfones via metal carbene intermediates is reported. This reaction uses readily available starting materials and is operationally simple, thus representing a practical method for the construction of carbon-carbon double bonds. Mechanistically, Cu(I) carbene formation and subsequent carbene migratory insertion are proposed as the key steps. PMID- 26932713 TI - Malignant phaeochromocytoma with cavoatrial extension imaged with (123)I-MIBG. PMID- 26932714 TI - Medication Safety Systems and the Important Role of Pharmacists. AB - Preventable medication-related adverse events continue to occur in the healthcare setting. While the Institute of Medicine's To Err is Human, published in 2000, highlighted the prevalence of medical and medication-related errors in patient morbidity and mortality, there has not been significant documented progress in addressing system contributors to medication errors. The lack of progress may be related to the myriad of pharmaceutical options now available and the nuances of optimizing drug therapy to achieve desired outcomes and prevent undesirable outcomes. However, on a broader scale, there may be opportunities to focus on the design and performance of the many processes that are part of the medication system. Errors may occur in the storage, prescribing, transcription, preparation and dispensing, or administration and monitoring of medications. Each of these nodes of the medication system, with its many components, is prone to failure, resulting in harm to patients. The pharmacist is uniquely trained to be able to impact medication safety at the individual patient level through medication management skills that are part of the clinical pharmacist's role, but also to analyze the performance of medication processes and to lead redesign efforts to mitigate drug-related outcomes that may cause harm. One population that can benefit from a focus on medication safety through clinical pharmacy services and medication safety programs is the elderly, who are at risk for adverse drug events due to their many co-morbidities and the number of medications often used. This article describes the medication safety systems and provides a blueprint for creating a foundation for medication safety programs within healthcare organizations. The specific role of pharmacists and clinical pharmacy services in medication safety is also discussed here and in other articles in this Theme Issue. PMID- 26932715 TI - Impact of meteorological changes on the incidence of scarlet fever in Hefei City, China. AB - Studies on scarlet fever with meteorological factors included were few. We aimed to illustrate meteorological factors' effects on monthly incidence of scarlet fever. Cases of scarlet fever were collected from the report of legal infectious disease in Hefei City from 1985 to 2006; the meteorological data were obtained from the weather bureau of Hefei City. Monthly incidence and corresponding meteorological data in these 22 years were used to develop the model. The model of auto regressive integrated moving average with covariates was used in statistical analyses. There was a highest peak from March to June and a small peak from November to January. The incidence of scarlet fever ranges from 0 to 0.71502 (per 105 population). SARIMAX (1,0,0)(1,0,0)12 model was fitted with monthly incidence and meteorological data optimally. It was shown that relative humidity (beta = -0.002, p = 0.020), mean temperature (beta = 0.006, p = 0.004), and 1 month lag minimum temperature (beta = -0.007, p < 0.001) had effect on the incidence of scarlet fever in Hefei. Besides, the incidence in a previous month (AR(beta) = 0.469, p < 0.001) and in 12 months before (SAR(beta) = 0.255, p < 0.001) was positively associated with the incidence. This study shows that scarlet fever incidence was negatively associated with monthly minimum temperature and relative humidity while was positively associated with mean temperature in Hefei City, China. Besides, the ARIMA model could be useful not only for prediction but also for the analysis of multiple correlations. PMID- 26932716 TI - Genetic and pharmacological inhibition of vanin-1 activity in animal models of type 2 diabetes. AB - Vanins are enzymes that convert pantetheine to pantothenic acid (vitamin B5). Insights into the function of vanins have evolved lately, indicating vanin-1 to play a role in inflammation, oxidative stress and cell migration. Moreover, vanin 1 has recently gained attention as a novel modulator of hepatic glucose and lipid metabolism. In the present study, we investigated the role of vanin-1 in the development of hepatic steatosis and insulin resistance in animal models of obesity and diabetes. In addition, we evaluated the potency of RR6, a novel pharmacological vanin-1 inhibitor, as an anti-diabetic drug. Increased vanin activity was observed in plasma and liver of high fat diet (HFD)-induced obese mice, as well as ZDF-diabetic rats. Ablation of vanin-1 (Vnn1(-/-) mice) mildly improved glucose tolerance and insulin sensitivity in HFD-fed mice, but had no effects on body weight, hepatic steatosis or circulating lipid levels. Oral administration of RR6 for 8 days completely inhibited plasma vanin activity, but did not affect hepatic glucose production, insulin sensitivity or hepatic steatosis in ZDF-diabetes rats. In conclusion, absence of vanin-1 activity improves insulin sensitivity in HFD-fed animals, yet short-term inhibition of vanin activity may have limited value as an anti-diabetic strategy. PMID- 26932717 TI - Anti-Inflammatory and Antioxidant Effects of Repeated Exposure to Cruciferous Allyl Nitrile in Sensitizer-Induced Ear Edema in Mice. AB - BACKGROUND: Skin sensitizers induce allergic reactions through the induction of reactive oxygen species. Allyl nitrile from cruciferous vegetables has been reported to induce antioxidants and phase II detoxification enzymes in various tissues. We assessed the effects of repeated exposure to allyl nitrile on sensitizer-induced allergic reactions. MATERIAL AND METHODS: Mice were dosed with allyl nitrile (0-200 umol/kg), and then received a dermal application of 1 of 3 sensitizers on the left ear or 1 of 2 vehicles on the right ear. Quantitative assessment of edema was carried out by measuring the difference in weight between the portions taken from the right and left ears. We tested enzymes (superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and thiobarbituric acid reactive substances (TBARS) in ears. RESULTS: Repeated exposure to allyl nitrile reduced edemas induced by glutaraldehyde and by 2, 4-dinitrochlorobenzene (DNCB), but not by formaldehyde. The repeated exposure decreased levels of TBARS, a marker of oxidative stress, induced by glutaraldehyde and by DNCB, but not by formaldehyde. Allyl nitrile elevated SOD levels for the 3 sensitizers, and CAT levels for formaldehyde and DNCB. Allyl nitrile also increased GPx levels for formaldehyde and DNCB, but not for glutaraldehyde. The reduced edemas were associated with changes in oxidative stress levels and antioxidant enzymes. CONCLUSIONS: Repeated exposure to allyl nitrile reduced allergic reactions induced by glutaraldehyde and by DNCB, but not by formaldehyde. This reduction was associated with changes in ROS levels and antioxidant enzyme activities. PMID- 26932718 TI - Monoamine Oxidase A (MAOA) and Catechol-O-Methyltransferase (COMT) Gene Polymorphisms Interact with Maternal Parenting in Association with Adolescent Reactive Aggression but not Proactive Aggression: Evidence of Differential Susceptibility. AB - To date, whether and how gene-environment (G * E) interactions operate differently across distinct subtypes of aggression remains untested. More recently, in contrast with the diathesis-stress hypothesis, an alternative hypothesis of differential susceptibility proposes that individuals could be differentially susceptible to environments depending on their genotypes in a "for better and for worse" manner. The current study examined interactions between monoamine oxidase A (MAOA) T941G and catechol-O-methyltransferase (COMT) Val158Met polymorphisms with maternal parenting on two types of aggression: reactive and proactive. Moreover, whether these potential G * E interactions would be consistent with the diathesis-stress versus the differential susceptibility hypothesis was tested. Within the sample of 1399 Chinese Han adolescents (47.2 % girls, M age = 12.32 years, SD = 0.50), MAOA and COMT genes both interacted with positive parenting in their associations with reactive but not proactive aggression. Adolescents with T alleles/TT homozygotes of MAOA gene or Met alleles of COMT gene exhibited more reactive aggression when exposed to low positive parenting, but less reactive aggression when exposed to high positive parenting. These findings provide the first evidence for distinct G * E interaction effects on reactive versus proactive aggression and lend further support for the differential susceptibility hypothesis. PMID- 26932719 TI - Time Out from Sex or Romance: Sexually Experienced Adolescents' Decisions to Purposefully Avoid Sexual Activity or Romantic Relationships. AB - Researchers have given significant attention to abstinence among adolescents, but far less is known about purposeful avoidance of sexual activity (and relationship involvement). Typically, it is assumed that, once adolescents have initiated sexual activity, they will thereafter engage in sexual activity if given the opportunity. However, it is unclear whether that is true as some research indicates that many adolescents engage in sexual activity intermittently. Sexually experienced adolescents may purposefully avoid engaging in sexual activity for a period of time and, if so, this has implications for understanding their sexual decision-making. We used a mixed methods approach to investigate sexually experienced adolescents' decisions to purposefully avoid further sexual activity and/or romantic relationships with a focus on how common these decisions are and factors influencing them. Participants were 411 (56 % female) adolescents (16-21 years old) who completed an on-line survey that assessed reasons for each type of avoidance, religiosity, sexual esteem, sexual distress, sexual coercion, and dysfunctional sexual beliefs. Overall, 27 % of participants had engaged in sexual avoidance and 47 % had engaged in romantic avoidance. Significantly more female than male adolescents reported sexual and romantic avoidance. Adolescents' reasons for sexual avoidance included: lack of sexual pleasure or enjoyment, relationship reasons, negative emotions, values, fear of negative outcomes, negative physical experience, and other priorities. Reasons for romantic avoidance included: effects of previous relationship, not interested in commitment, wrong time, other priorities, negative emotions, no one was good enough, and sexual concerns. Logistical regressions were used to assess associations between age, religiosity, sexual esteem, sexual distress, experience of sexual coercion, and dysfunctional sexual beliefs and having engaged in romantic and/or sexual avoidance. The female adolescents who had avoided sexual activity were more likely to have experienced sexual coercion. The male adolescents who had avoided sexual activity were more religious and likely to have experienced sexual coercion. The male adolescents who had avoided romantic relationships were more sexually distressed and likely to have experienced sexual coercion. No associations were found for romantic avoidance among female adolescents. These results reflect considerable agency in the decision-making of adolescents in intimate contexts. They are discussed in terms of their challenge to current discourses about rampant adolescent sexuality as well as their implications for education and prevention interventions that incorporate personal choice and decision-making into their protocols. PMID- 26932721 TI - Comparison of Hyperemic Impedance Echocardiography with Dobutamine Stress Echocardiography to Detect Inducible Myocardial Ischemia: A Pilot Study. AB - BACKGROUND: Stress echocardiography using exercise or pharmacological stressors is either contraindicated or associated with significant side effects in some patients. This pilot study was designed to evaluate a new technique, hyperemic impedance echocardiography (HIE). It is based on reactive coronary hyperemia when transient limb ischemia is induced by tourniquet inflation. We hypothesized that this physiologic coronary hyperemia can identify inducible myocardial ischemia by assessment of regional wall motion abnormalities on echocardiography when compared with dobutamine stress echocardiography (DSE). METHODS: Twenty consecutive outpatients with suspected stable coronary artery disease (CAD) who underwent clinically indicated DSE were recruited for performance of HIE after informed consent was obtained. Standard graded dobutamine infusion protocol from 5 to 40 MUg/kg per min was used for DSE. HIE was performed by inflating tourniquets at a pressure of 10 mmHg below the systolic blood pressure for 1 minute in three of four extremities at a time for total of four cycles. Echocardiography was performed immediately after the last rotating tourniquet deflation. DSE and HIE were classified as abnormal for development of new or worsening wall motion abnormality in at least one myocardial segment. Test characteristics were also determined for a subset of these patients (n = 12) who underwent clinically indicated coronary angiography. RESULTS: Hyperemic impedance echocardiography showed 86% sensitivity, 67% specificity, 86% positive predictive value, and 67% negative predictive value with a test accuracy of 80% to detect inducible myocardial wall motion abnormalities when compared with DSE. HIE also showed 83% sensitivity, 75% negative predictive value with a test accuracy of 66.7% for detection of significant (>=50% diameter stenosis) CAD on coronary angiography. CONCLUSION: In this pilot study, HIE was a feasible, safe, and promising method for detection of inducible myocardial ischemia by assessment of regional wall motion abnormalities when compared to DSE and coronary angiography. Larger studies are needed to confirm these findings. PMID- 26932725 TI - Follow-up of Patients Treated for pT1aN0M0 Breast Cancer: 10-year Survival and Prognostic Factors. PMID- 26932724 TI - Do Cochrane summaries help student midwives understand the findings of Cochrane systematic reviews: the BRIEF randomised trial. AB - BACKGROUND: Abstracts and plain language summaries (PLS) are often the first, and sometimes the only, point of contact between readers and systematic reviews. It is important to identify how these summaries are used and to know the impact of different elements, including the authors' conclusions. The trial aims to assess whether (a) the abstract or the PLS of a Cochrane Review is a better aid for midwifery students in assessing the evidence, (b) inclusion of authors' conclusions helps them and (c) there is an interaction between the type of summary and the presence or absence of the conclusions. METHODS: Eight hundred thirteen midwifery students from nine universities in the UK and Ireland were recruited to this 2 * 2 factorial trial (abstract versus PLS, conclusions versus no conclusions). They were randomly allocated to one of four groups and asked to recall knowledge after reading one of four summary formats of two Cochrane Reviews, one with clear findings and one with uncertain findings. The primary outcome was the proportion of students who identified the appropriate statement to describe the main findings of the two reviews as assessed by an expert panel. RESULTS: There was no statistically significant difference in correct response between the abstract and PLS groups in the clear finding example (abstract, 59.6 %; PLS, 64.2 %; risk difference 4.6 %; CI -0.2 to 11.3) or the uncertain finding example (42.7 %, 39.3 %, -3.4 %, -10.1 to 3.4). There was no significant difference between the conclusion and no conclusion groups in the example with clear findings (conclusions, 63.3 %; no conclusions, 60.5 %; 2.8 %; -3.9 to 9.5), but there was a significant difference in the example with uncertain findings (44.7 %; 37.3 %; 7.3 %; 0.6 to 14.1, p = 0.03). PLS without conclusions in the uncertain finding review had the lowest proportion of correct responses (32.5 %). Prior knowledge and belief predicted student response to the clear finding review, while years of midwifery education predicted response to the uncertain finding review. CONCLUSIONS: Abstracts with and without conclusions generated similar student responses. PLS with conclusions gave similar results to abstracts with and without conclusions. Removing the conclusions from a PLS with uncertain findings led to more problems with interpretation. PMID- 26932726 TI - Effects of thermal manipulations during embryogenesis of broiler chickens on developmental stability, hatchability and chick quality. AB - Stress based on high temperature and humidity reduces the production performance of fast-growing broilers and causes high mortality. Temperatures higher than optimum have been applied to broilers in the embryonic period in order to overcome thermal stress. This study was conducted to investigate the effects of exposure to two long-term high-thermal environments on the developmental stability of embryonic growth, hatchability and chick quality. For this purpose, 600 broiler eggs were incubated. Treatments consisted of eggs incubated at 37.8 degrees C at 55% relative humidity throughout (control), heated to 39.6 degrees C at 60% relative humidity for 6 h daily from 0 to 8th day, and heated to 39.6 degrees C at 60% relative humidity for 6 h daily from the 10 to 18th day. Embryo weights and lengths of face, wing, femur, tibia and metatarsus were measured daily between the 10th and 21st day of the experiment. Daily relative asymmetry values of bilateral traits were estimated. The hatchability, the weight of the 1 day-old chicks and chick quality were determined. In conclusion, no negative effects of the treatments of the long-term high-thermal environment in the early and late stages of incubation for epigenetic adaptation were determined on the embryo morphology, development stability and weight of the chick. Moreover, regressed hatchability of embryos that were exposed to a long-term high-thermal environment was detected. Especially between the 10 and 18th day, the thermal manipulation considerably reduced the quality of the chicks. Acclimation treatments of high temperature on the eggs from cross-breeding flocks should not be made long term; instead, short-term treatments should be made by determining the stage that generates epigenetic adaptation. PMID- 26932723 TI - Vitamin D interacts with Esr1 and Igf1 to regulate molecular pathways relevant to Alzheimer's disease. AB - BACKGROUND: Increasing evidence suggests a potential therapeutic benefit of vitamin D supplementation against Alzheimer's disease (AD). Although studies have shown improvements in cognitive performance and decreases in markers of the pathology after chronic treatment, the mechanisms by which vitamin D acts on brain cells are multiple and remain to be thoroughly studied. We analyzed the molecular changes observed after 5 months of vitamin D3 supplementation in the brains of transgenic 5xFAD (Tg) mice, a recognized mouse model of AD, and their wild type (Wt) littermates. We first performed a kinematic behavioural examination at 4, 6 and 8 months of age (M4, M6 and M8) followed by a histologic assessment of AD markers. We then performed a comparative transcriptomic analysis of mRNA regulation in the neocortex and hippocampus of 9 months old (M9) female mice. RESULTS: Transcriptomic analysis of the hippocampus and neocortex of both Wt and Tg mice at M9, following 5 months of vitamin D3 treatment, reveals a large panel of dysregulated pathways related to i) immune and inflammatory response, ii) neurotransmitter activity, iii) endothelial and vascular processes and iv) hormonal alterations. The differentially expressed genes are not all direct targets of the vitamin D-VDR pathway and it appears that vitamin D action engages in the crosstalk with estrogen and insulin signaling. The misexpression of the large number of genes observed in this study translates into improved learning and memory performance and a decrease in amyloid plaques and astrogliosis in Tg animals. CONCLUSIONS: This study underlies the multiplicity of action of this potent neurosteroid in an aging and AD-like brain. The classical and non classical actions of vitamin D3 can act in an additive and possibly synergistic manner to induce neuroprotective activities in a context-specific way. PMID- 26932727 TI - Prosodic disambiguation of noun/verb homophones in child-directed speech. AB - One strategy that children might use to sort words into grammatical categories such as noun and verb is distributional bootstrapping, in which local co occurrence information is used to distinguish between categories. Words that can be used in more than one grammatical category could be problematic for this approach. Using naturalistic corpus data, this study asks whether noun and verb uses of ambiguous words might differ prosodically as a function of their grammatical category in child-directed speech. The results show that noun and verb uses of ambiguous words in sentence-medial positions do differ from one another in terms of duration, vowel duration, pitch change, and vowel quality measures. However, sentence-final tokens are not different as a function of the category in which they were used. The availability of prosodic cues to category in natural child-directed speech could allow learners using a distributional bootstrapping approach to avoid conflating grammatical categories. PMID- 26932728 TI - Drug use among men with unfulfilled wish to father children: a retrospective analysis and discussion of specific drug classes. AB - PURPOSE: Male infertility is a multifactorial state. Among other risk factors, drugs can adversely affect male fertility and male sexual function. In a retrospective study we aimed to analyse how many involuntarily childless men seeking fertility evaluation consume drugs, which drugs and if these are potentially affecting male reproductive function. METHODS: We retrospectively identified involuntarily childless men presenting for fertility evaluation at an andrologic outpatient department from 2011 to 2014. Medical records were searched for current drug use, age, diseases affecting male fertility, and number and kind of drugs. Drugs were classified according to their Anatomical Therapeutic Chemical code. Adverse drug reactions on male sexual function and fertility were searched in two independent literature sources. RESULTS: Drug use was documented for 244 of 522 patients (46.7%). The patients' mean age was 37.7 +/- 8.7; the total number of drug intakes was 554 (mean 2.3 +/- 1.9), corresponding to 201 different drugs. The most often involved Anatomical Therapeutic Chemical groups were nervous system (N), alimentary tract/metabolism (A), cardiovascular (C), and respiratory system (R) (n = 277; 50.0%). Fertility impairment was reported for 15.9%, and adverse drug reactions on male sexual function were found for 51.2% of all identified drugs. Underreporting of consumed drugs was likely, especially for non-prescription drugs. CONCLUSIONS: A high percentage of involuntarily childless men is taking drugs that can potentially influence male reproductive function. As drug intake represents a modifiable risk factor, fertility evaluation requires a comprehensive medication review including prescription and non-prescription drugs. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26932730 TI - Renal Function Alters Antihypertensive Regimens in Type 2 Diabetic Patients. AB - To determine the prevalence of multidrug antihypertensive therapy (MDAT), records were evaluated for patients with both type 2 diabetes and hypertension during a 5 year period at Joslin Diabetes Center. Hypertension control was defined as requiring multiple drugs if three or more antihypertensive drugs were used, one of which must be a diuretic (unless patient is receiving dialysis), or use of four or more antihypertensive drugs, one of which a diuretic (unless patient is receiving dialysis) was established. The objective was to determine the prevalence of multidrug requirement for hypertensive therapy in relationship to four levels of renal function estimated by the Modification of Diet in Renal Disease formula for glomerular filtration rate (GFR). Among 10,151 patients, mean estimated GFR was 80 mL/min. Using standard (ASN) classification for renal function, we noted the following breakdown of MDAT use: Estimated GFR Drugs, Mean No. >=3 Drugs, No. (%) >=4 Drugs, No. (%) <30 3.1 379 (67) 214 (38) 30-60 2.7 1233 (55) 538 (24) 60-90 2.0 1279 (33) 458 (12) >90 1.5 600 (17) 185 (5) Prevalence of multidrug antihypertensive therapy is markedly increased in the presence of reduced renal function. PMID- 26932729 TI - Sestrin2 is induced by glucose starvation via the unfolded protein response and protects cells from non-canonical necroptotic cell death. AB - Sestrin2 is a member of a family of stress responsive proteins, which controls cell viability via antioxidant activity and regulation of the mammalian target of rapamycin protein kinase (mTOR). Sestrin2 is induced by different stress insults, which diminish ATP production and induce energetic stress in the cells. Glucose is a critical substrate for ATP production utilized via glycolysis and mitochondrial respiration as well as for glycosylation of newly synthesized proteins in the endoplasmic reticulum (ER) and Golgi. Thus, glucose starvation causes both energy deficiency and activation of ER stress followed by the unfolding protein response (UPR). Here, we show that UPR induces Sestrin2 via ATF4 and NRF2 transcription factors and demonstrate that Sestrin2 protects cells from glucose starvation-induced cell death. Sestrin2 inactivation sensitizes cells to necroptotic cell death that is associated with a decline in ATP levels and can be suppressed by Necrostatin 7. We propose that Sestrin2 protects cells from glucose starvation-induced cell death via regulation of mitochondrial homeostasis. PMID- 26932731 TI - Changes in Deceased Donor Kidney Transplantation One Year After KAS Implementation. AB - After over a decade of discussion, analysis, and consensus-building, a new kidney allocation system (KAS) was implemented on December 4, 2014. Key goals included improving longevity matching between donor kidneys and recipients and broadening access for historically disadvantaged subpopulations, in particular highly sensitized patients and those with an extended duration on dialysis but delayed referral for transplantation. To evaluate the early impact of KAS, we compared Organ Procurement and Transplantation Network data 1 year before versus after implementation. The distribution of transplants across many recipient characteristics has changed markedly and suggests that in many ways the new policy is achieving its goals. Transplants in which the donor and recipient age differed by more than 30 years declined by 23%. Initial, sharp increases in transplants were observed for Calculated Panel-Reactive Antibody 99-100% recipients and recipients with at least 10 years on dialysis, with a subsequent tapering of transplants to these groups suggesting bolus effects. Although KAS has arguably increased fairness in allocation, the potential costs of broadening access must be considered. Kidneys are more often being shipped over long distances, leading to increased cold ischemic times. Delayed graft function rates have increased, but 6-month graft survival rates have not changed significantly. PMID- 26932732 TI - Modified immunotherapy for alopecia areata. AB - Squaric acid dibutylester (SADBE) is a commonly used contact sensitizer in immunotherapy for alopecia areata (AA). Severe contact dermatitis is induced by the currently high recommended sensitization dose of 1%-2% SADBE, often decreasing patient compliance. We assessed a modified immunotherapy for AA using SADBE at a starting concentration of 0.01% without sensitization. After one or two weeks of initial 0.01% SADBE application, the concentration of SADBE was increased gradually to 0.025%, 0.05%, 0.1%, 0.25%, 0.5%, 1% and 2% until the patients felt itching or erythema at the AA lesion site. The modified immunotherapy showed a response rate of 69.4% (25/36), equivalent to conventional immunotherapy using SADBE starting at 1%-2% sensitization. Furthermore, we investigated the combination therapy of SADBE and multiple courses of steroid pulses for AA. The response rate for combination therapy was 73.7% (28/38); however, the group receiving combination therapy showed a significant prevalence of severe AA compared with the group receiving modified immunotherapy only. We reviewed the efficacy and safety of modified immunotherapy without initial sensitization and combination therapy with immunotherapy and multiple courses of pulses for AA. PMID- 26932733 TI - Influence of a triclosan toothpaste on periodontopathic bacteria and periodontitis progression in cardiovascular patients: a randomized controlled trial. AB - BACKGROUND AND OBJECTIVE: Triclosan/copolymer toothpaste is effective in controlling plaque and gingivitis and in slowing the progression of periodontitis. This study describes its influence on microbiological and clinical outcomes, over a 5-year period, in patients with established cardiovascular disease (CVD). MATERIAL AND METHODS: Four-hundred and thirty-eight patients were recruited from the Cardiovascular Unit at The Prince Charles Hospital, Brisbane, Australia, and randomized to triclosan or placebo groups. Six sites per tooth were examined annually for probing pocket depth and loss of attachment. These outcomes were analysed, using generalized linear modelling, in 381 patients who had measurements from consecutive examinations. Concurrent load of the periodontal pathogens Aggregatibacter actinomycetemcomitans, Fusobacterium nucleatum, Tannerella forsythia and Porphyromonas gingivalis was determined, using quantitative real-time PCR, in 437 patients with baseline plaque samples. Group comparisons were expressed as geometric means. The chi-square test was used to test for differences between the two groups of patients with regard to the proportion of patients with different numbers of bacterial species. RESULTS: There was no difference in general health or periodontal status between the groups at baseline. There was a significant reduction in the number of interproximal sites showing loss of attachment between examinations, by 21% on average (p < 0.01), in the triclosan group compared with the placebo group. The prevalence of patients with F. nucleatum and A. actinomycetemcomitans was high and remained relatively constant throughout the 5 years of the study. In contrast, the prevalence of T. forsythia and P. gingivalis showed more variability; however, there was no significant difference between the groups, at any time point, in the prevalence of any organism. A significant difference in the geometric means for P. gingivalis (p = 0.01) was seen at years 1 and 4, and for F. nucleatum (p = 0.01) and in the total bacterial load (p = 0.03) at year 2; however, these differences were not statistically significant following a Bonferroni correction for multiple comparisons. There was no difference between the groups in the geometric means for each organism at year 5. CONCLUSION: Within the limitations of the study, these data suggest that the use of triclosan/copolymer toothpaste significantly slowed the progression of periodontitis in patients with CVD but that it had little influence on key subgingival periodontopathic bacteria in these patients over the 5 years of the study. PMID- 26932734 TI - A case of chondroma cutis showing callus-like appearance. PMID- 26932736 TI - Correction: In vitro analysis of partially hydrolyzed guar gum fermentation differences between six individuals. AB - Correction for 'In vitro analysis of partially hydrolyzed guar gum fermentation differences between six individuals' by Justin Carlson, et al., Food Funct., 2016, DOI: 10.1039/c5fo01232e. PMID- 26932735 TI - Comparison of serological methods with PCR-based methods for the diagnosis of community-acquired pneumonia caused by atypical bacteria. AB - BACKGROUND: The diagnosis of community-acquired pneumonia (CAP) caused by Legionella pneumophila, Mycoplasma pneumoniae, and Chlamydophila pneumoniae is traditionally based on cultures and serology, which have special requirements, are time-consuming, and offer delayed results that limit their clinical usefulness of these techniques. We sought to develop a multiplex PCR (mPCR) method to diagnosis these bacterial infections in CAP patients and to compare the diagnostic yields obtained from mPCR of nasopharyngeal aspirates (NPAs), nasopharyngeal swabs (NPSs), and induced sputum (IS) with those obtained with specific PCR commercial kits, paired serology, and urinary antigen. RESULTS: A total of 225 persons were included. Of these, 10 patients showed serological evidence of L. pneumophila infection, 30 of M. pneumoniae, and 18 of C. pneumoniae; 20 individuals showed no CAP. The sensitivities were mPCR-NPS = 23.1%, mPCR-IS = 57.1%, Seeplex(r)-IS = 52.4%, and Speed-oligo(r)-NPA/NPS = 11.1%, and the specificities were mPCR-NPS = 97.1%, mPCR-IS = 77.8%, Seeplex(r) IS = 92.6%, and Speed-oligo(r)-NPA/NPS = 96.1%. The concordance between tests was poor (kappa <0.4), except for the concordance between mPCR and the commercial kit in IS (0.67). In individuals with no evidence of CAP, positive reactions were observed in paired serology and in all PCRs. CONCLUSIONS: All PCRs had good specificity but low sensitivity in nasopharyngeal samples. The sensitivity of mPCR and Seeplex(r) in IS was approximately 60%; thus, better diagnostic techniques for these three bacteria are required. PMID- 26932737 TI - Safety and tolerability of intranasal cocaine during phendimetrazine maintenance. AB - RATIONALE: Phendimetrazine appears to have limited abuse potential and reduces cocaine self-administration in preclinical studies. No human studies have evaluated the safety and tolerability of cocaine in combination with phendimetrazine, which is a necessary next step in evaluating the efficacy of phendimetrazine for treating cocaine use disorder. OBJECTIVES: This study determined the safety and tolerability of acute cocaine doses during chronic phendimetrazine treatment. METHODS: Ten subjects completed this within-subject, placebo-controlled, inpatient study. Subjects were maintained on ascending oral phendimetrazine doses (0, 70, 140, and 210 mg/day). After at least seven maintenance days at each dose, subjects received ascending doses of intranasal cocaine (0, 10, 20, 40, and 80 mg), separated by 90 min, within one session. RESULTS: Cocaine produced prototypical cardiovascular and subject-rated effects (e.g., increased blood pressure and ratings of like drug). The cardiovascular effects of cocaine alone were not clinically significant for an acute drug response (e.g., average heart rate did not approach tachycardia, 100 beats/min). Phendimetrazine enhanced peak heart rate following placebo and low cocaine doses, but these effects were also not clinically significant. Phendimetrazine was otherwise devoid of effects alone and did not alter the subject-rated effects of cocaine or hypothetical demand for cocaine on a purchase task. CONCLUSIONS: Cocaine was safe and well tolerated during maintenance on a threefold range of phendimetrazine doses. Given this safety profile, the reduced abuse potential of phendimetrazine and promising preclinical research, future human laboratory studies, and possibly clinical trials should evaluate the efficacy of phendimetrazine for reducing cocaine use. PMID- 26932738 TI - Does Teriparatide Improve Femoral Neck Fracture Healing: Results From A Randomized Placebo-controlled Trial. AB - BACKGROUND: There is a medical need for therapies that improve hip fracture healing. Teriparatide (Forteo((r))/ Forsteo((r)), recombinant human parathyroid hormone) is a bone anabolic drug that is approved for treatment of osteoporosis and glucocorticoid-induced osteoporosis in men and postmenopausal women at high fracture risk. Preclinical and preliminary clinical data also suggest that teriparatide may enhance bone healing. QUESTIONS/PURPOSES: We wished to test the hypotheses that treatment with teriparatide versus placebo would improve femoral neck fracture healing after internal fixation as measured by (1) frequency of revision surgery, (2) radiographic fracture healing, and (3) other outcomes including pain control, gait speed, and safety. METHODS: We initiated two separate, but identically designed, clinical trials to meet FDA requirements to provide substantial evidence to support approval of a new indication. The two prospective, randomized double-blind, placebo-controlled Phase III studies were designed to evaluate the effect of subcutaneous teriparatide (20 MUg/day) for 6 months versus placebo on fracture healing at 24 months. The trials were conducted concurrently with a planned enrollment of 1220 patients per trial. However, enrollment was stopped owing to very slow patient accrual, and an a priori decision was made to pool the results of those studies for statistical analyses before study completion; pooling was specified in both protocols. Randomization was stratified by fixation (sliding hip screw or multiple cancellous screws) and fracture type (displaced or nondisplaced). An independent Central Adjudication Committee reviewed revision surgical procedures and radiographs. A total of 159 patients were randomized in the two trials (81 placebo, 78 teriparatide). The combined program had very low power to detect the originally expected treatment effect but had approximately 80% power to detect a larger difference of 12% between treatment groups for risk of revision surgery. RESULTS: The proportion of patients undergoing revision surgery at 12 months was 14% (11 of 81) in the placebo group versus 17% (13 of 78) in the teriparatide group. Central Adjudication Committee review excluded two of these patients treated with placebo from the primary analysis. After exclusions, the proportion of patients who did not undergo revision surgery at 12 months (primary endpoint) was not different between the study and placebo groups, at 88% in the placebo group (90% CI, 0.79 0.93) versus 84% in the teriparatide group (90% CI, 0.75-0.90; p = 0.743). There also were no differences between groups in the proportion of patients achieving radiographic fracture healing at 12 months (75% [61 of 81] placebo versus 73% [57 of 78] teriparatide; odds ratio, 0.89; 90% CI, 0.46-1.72; p = 0.692) or in measures of pain control (such as pain during ambulation, 92% [55 of 62] placebo versus 91% [52 of 57] teriparatide; odds ratio, 0.91; 90% CI, 0.25-3.37; p = 0.681). The frequency of patients reporting adverse events was 49% [40 of 81] in the placebo group versus 45% [35 of 78] in the teriparatide group (p = 0.634) during the 6-month treatment period. CONCLUSIONS: The small sample size limited this study's power to detect potential differences, and the results are exploratory. With the patients available, teriparatide did not decrease the risk of revision surgery, improve radiographic signs of fracture healing, or decrease pain compared with the placebo. The adverse event data observed were consistent with the teriparatide safety profile. Functional and health outcome data from the studies may help improve our understanding of patients recovering from femoral neck fractures. Further large controlled studies are required to determine the effect of teriparatide on fracture healing. LEVEL OF EVIDENCE: Level II, prospective study. PMID- 26932739 TI - Supplemental Bone Grafting in Giant Cell Tumor of the Extremity Reduces Nononcologic Complications. AB - BACKGROUND: Giant cell tumors (GCTs) are treated with resection curettage and adjuvants followed by stabilization. Complications include recurrence, fracture, and joint degeneration. Studies have shown treatment with polymethylmethacrylate (PMMA) may increase the risk of joint degeneration and fracture. Other studies have suggested that subchondral bone grafting may reduce these risks. QUESTIONS/PURPOSES: Following standard intralesional resection-curettage and adjuvant treatment, is the use of bone graft, with or without supplemental PMMA, (1) associated with fewer nononcologic complications; (2) associated with differences in tumor recurrence between patients treated with versus those treated without bone grafting for GCT; and (3) associated with differences in Musculoskeletal Tumor Society (MSTS) scores? METHODS: Between 1996 and 2014, 49 patients presented with GCT in the epiphysis of a long bone. Six patients were excluded, four who were lost to followup before 12 months and two because they presented with displaced, comminuted, intraarticular pathologic fractures with a nonreconstructable joint surface. The remaining 43 patients were included in our study at a mean followup of 59 months (range, 12-234 months). After resection curettage, 21 patients were reconstructed using femoral head allograft with or without PMMA (JB) and 22 patients were reconstructed using PMMA alone (FRP, KSB); each surgeon used the same approach (that is, bone graft or no bone graft) throughout the period of study. The primary study comparison was between patients treated with bone graft (with or without PMMA) and those treated without bone graft. RESULTS: Nononcologic complications occurred less frequently in patients treated with bone graft than those treated without (10% [two of 21] versus 55% [12 of 22]; odds ratio, 0.088; 95% confidence interval [CI], 0.02-0.47; p = 0.002). Patients with bone graft had increased nononcologic complication-free survival (hazard ratio, 4.59; 95% CI, 1.39-15.12; p = 0.012). With the numbers available, there was no difference in tumor recurrence between patients treated with bone graft versus without (29% [six of 21] versus 32% [seven of 22]; odds ratio, 0.70; 95% CI, 0.1936-2.531; p = 0.586) or in recurrence-free survival among patients with bone graft versus without (hazard ratio, 0.94; 95% CI, 0.30 2.98; p = 0.920). With the numbers available, there was no difference in mean MSTS scores between patients treated with bone graft versus without (92% +/- 2% versus 93% +/- 1.4%; mean difference 1.0%; 95% CI, -3.9% to 6.0%; p = 0.675). CONCLUSIONS: Compared with PMMA alone, the use of periarticular bone graft constructs reduces postoperative complications apparently without increasing the likelihood of tumor recurrence. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 26932741 TI - Characterization of an rmtB-carrying IncI1 ST136 plasmid in avian Escherichia coli isolates from chickens. AB - The rmtB gene, one of the 16S rRNA methylase genes whose products confer high level resistance to aminoglycosides, is most prevalent among Enterobacteriaceae strains. In this study, eight non-duplicate rmtB-carrying avian Escherichia coli strains from a farm in China were isolated and characterized, and further examined by phylogenetic grouping, conjugation experiments and PCR-based replicon typing. In addition, the genetic environment of rmtB was investigated by cloning and sequencing. Six rmtB-carrying E. coli were identified as phylogroup A, sequence type (ST) 156 (A-ST156), with two assigned to D-ST117; however, all of them carried the same IncI1 ST136 plasmid. The genetic environment of the rmtB gene in these eight plasmids was the same, as shown by PCR mapping. A multidrug resistant region carrying blaTEM-1, rmtB, a class 1 integron cassette array (intI1-dfrA12-orfF-aadA2-qacEDelta1-sul1) and aacC2 was characterized on the conjugative IncI1 ST136 plasmid. Co-location of the rmtB gene with a class 1 integron cassette array and aacC2 on the conjugative plasmid will facilitate its maintenance and dissemination. PMID- 26932740 TI - Vascularized versus Nonvascularized Bone Grafts: What Is the Evidence? AB - BACKGROUND: There is a general perception in practice that a vascular supply should be used when large pieces of bone graft are used, particularly those greater than 6 cm in length for long-bone and large-joint reconstructions. However, the scientific source of this recommendation is not clear. QUESTIONS/PURPOSES: We wished to perform a systematic review to (1) investigate the origin of evidence for this 6-cm rule, and (2) to identify whether there is strong evidence to support the importance of vascularization for longer grafts and/or the lack of vascularization for shorter grafts. METHODS: Two systematic reviews were performed using SCOPUS and Medline, one for each research question. For the first research purpose, a review of studies from 1975 to 1983 matching article title ("bone" and "graft") revealed 725 articles, none of which compared graft length. To address the second purpose, a review of articles before 2014 that matched "bone graft" AND ("vascularised" OR "vascularized") AND ("non vascularised" OR "non-vascularized") revealed 633 articles, four met prespecified inclusion criteria and were evaluated qualitatively. MINORS ratings ranged from 16 to 18 of 24, and National Health and Medical Research Council [NHMRC] Evidence Hierarchy ratings ranged from III-2 (comparative studies without concurrent controls) to III-3 (comparative studies with concurrent controls). RESULTS: No evidence was found that clarified grafts longer than 6 cm should be vascularized. The first reference to the 6-cm rule cites articles that do not provide strong evidence for the rule. Of the four articles found in the second systematic review, none examined osseous union of vascularized and nonvascularized grafts with respect to length. One study (III-3, MINORS 18 of 24) of fibular grafts to various limb defects found that vascularization made no difference to union rate or time to union. Vascularized grafts were more likely to require surgical revision for wound breakdown, nonunion, graft fracture, or mechanical problems (hazard ratio [HR], 5.97, p = 0.008) and grafts smaller than 10 cm had fewer complications requiring revision (HR, 0.88; p = 0.03). Three studies (III-2 to III-3, MINORS 16 to 18 of 24) that examined fibular grafts to the femoral head found that vascularized grafts had superior Harris hip and pain scores. Two of the three articles showed that vascularization was associated with superior radiologic measures of collapse progression. CONCLUSIONS: No compelling evidence was found to illuminate the origin of the 6-cm rule for vascularized bone grafts, or that such a rule is based on published research. The evidence we found for grafts to long-bone defects suggested that vascularization might increase the risk of complications that require a surgical revision without increasing union rates or time to union. For large joints, vascularization may result in better functional scores and pain scores, while the evidence that they improve radiologic measures of progression is mixed. There were no studies of long-bone or large-joint reconstructions that examined the role of length with respect to osseous union. We suggest that future studies should present data for graft lengths quantitatively and with individual data points rather than categories of length ranges. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 26932744 TI - Aminoquinoline-assisted vinylic C-H arylation of unsubstituted acrylamide for the selective synthesis of Z olefins. AB - A method for Pd-catalyzed, aminoquinoline-directed arylation of vinylic C-H bonds with aryl iodides has been developed. This reaction represents a rare example of Pd-catalyzed vinylic C-H functionalization of unsubstituted acrylamide, allowing for the highly regio- and stereoselective preparation of Z-olefins. High tolerance to functional groups is observed with good yields and excellent selectivity. It offers a complementary synthetic method to traditional pathways for Z-olefins. PMID- 26932742 TI - Risks of cardiovascular diseases associated with dipeptidyl peptidase-4 inhibitors and other antidiabetic drugs in patients with type 2 diabetes: a nation-wide longitudinal study. AB - BACKGROUND: Several antidiabetic drugs (i.e., sulfonylureas; SU, rosiglitazone) have been reported to be associated with increased risks of cardiovascular diseases (CVD) in patients with type 2 diabetes mellitus (T2DM). Dipeptidyl peptidase-4 inhibitors (DPP4i) are newly available antidiabetic drugs. Most studies only compared DPP4i with a placebo or SU, or targeted a specific CVD event of interest (i.e., heart failure; HF). Comparative research of CVD risks of DPP4i with other antidiabetic drugs (i.e., metformin, thiazolidinediones, meglitinides, acarbose, and insulin) remains scarce. This study was aimed to assess comparative risks of CVD, including ischemic stroke, myocardial infarction (MI) and HF, and hypoglycemia of DPP4i with other antidiabetic drugs. METHODS: We utilized Taiwan's National Health Insurance Research Database. A total of 123,050 T2DM patients newly prescribed oral antidiabetic treatments were identified in 2009-2010 and followed until 2013. Outcome endpoints included a composite of CVD events: hospitalizations for ischemic stroke, MI and HF, and hypoglycemia. Time varying Cox proportional hazards regression was applied to assess the time to event hazards of various antidiabetic drugs, adjusted for patients' demographics, comorbidity, diabetic complications, and co-medications. Additional analyses were performed for the patients with and without CVD history, respectively. RESULTS: DPP4i users had significantly lower CVD risks as compared to that of non-DPP4i users (adjusted hazard ratio [aHR]: 0.83, 95 % confidence interval [CI]: 0.76 0.91). Compared to DPP4i users, meglitinides (aHR 1.3, 95 % CI 1.20-1.43) and insulin users (aHR 3.73, 95 % CI 3.35, 4.14) had significantly higher risks for composite CVD, as well as those for stroke, MI, HF, and hypoglycemia. Additionally, metformin users had significantly lower risks for composite CVD risk (aHR 0.87, 95 % CI 0.79-0.94), as well as those for MI, HF, and hypoglycemia, as compared to those of DPP4i users. Although there was a trend toward low CVD risks in pioglitazone users, the role of potential confounding by indication cannot be excluded. CONCLUSIONS: DPP4i-treated T2DM patients had lower risks for CVD as compared to those for non-DPP4i users, except metformin users. PMID- 26932745 TI - Randomized trial of combined triple therapy comprising two types of peginterferon with simeprevir in patients with hepatitis C virus genotype 1b. AB - : Simeprevir (SMV) is a potent, macrocyclic hepatitis C virus (HCV) non structural 3/4 A protease inhibitor. This prospective study compared the efficacy and safety of SMV in combination with peginterferon alpha2a + ribavirin (P2aR) and with peginterferon alpha2b + ribavirin (P2bR) in Japanese patients with HCV genotype 1b infection. METHODS: Hepatitis C virus genotype 1b patients were randomly assigned to receive SMV (100 mg QD) with P2aR for 12 weeks, then P2aR alone for 12 or 36 weeks; or SMV (100 mg QD) with P2bR for 12 weeks, then P2bR alone for 12 or 36 weeks. The primary endpoint was a sustained virologic response 24 weeks after completing treatment (SVR24). RESULTS: In total, 151 patients were randomly assigned to the P2aR (n = 76) or P2bR group (n = 75). Six patients dropped out. Sustained virologic response 24 weeks after completing treatment was achieved in 55 (75.3%) of 73 P2aR patients and 55 (76.4%) of 72 P2bR patients. There was no difference in the rate of SVR24 between the two groups (P = 0.88). No differences in the proportion of patients who became HCV RNA-negative were detected between the P2aR and P2bR groups. The two groups had comparable numbers of adverse events, which led to the discontinuation of treatment in 9.6% and 8.3% of participants in the P2aR and P2bR groups, respectively. CONCLUSION: Peginterferon alpha2a or alpha2b in combination with SMV + ribavirin therapy showed identical antiviral effects in patients with chronic hepatitis C. Also, the incidence of adverse events was identical for both regimens. PMID- 26932743 TI - The economic burden of incisional ventral hernia repair: a multicentric cost analysis. AB - PURPOSE: A systematic review of literature led us to take note that little was known about the costs of incisional ventral hernia repair (IVHR). METHODS: Therefore we wanted to assess the actual costs of IVHR. The total costs are the sum of direct (hospital costs) and indirect (sick leave) costs. The direct costs were retrieved from a multi-centric cost analysis done among a large panel of 51 French public hospitals, involving 3239 IVHR. One hundred and thirty-two unitary expenditure items were thoroughly evaluated by the accountants of a specialized public agency (ATIH) dedicated to investigate the costs of the French Health Care system. The indirect costs (costs of the post-operative inability to work and loss of profit due to the disruption in the ongoing work) were estimated from the data the Hernia Club registry, involving 790 patients, and over a large panel of different Collective Agreements. RESULTS: The mean total cost for an IVHR in France in 2011 was estimated to be 6451?, ranging from 4731? for unemployed patients to 10,107? for employed patients whose indirect costs (5376?) were slightly higher than the direct costs. CONCLUSION: Reducing the incidence of incisional hernia after abdominal surgery with 5 % for instance by implementation of the European Hernia Society Guidelines on closure of abdominal wall incisions, or maybe even by use of prophylactic mesh augmentation in high risk patients could result in a national cost savings of 4 million Euros. PMID- 26932747 TI - miR-8-3p regulates mitoferrin in the testes of Bactrocera dorsalis to ensure normal spermatogenesis. AB - Genetics-enhanced sterile insect techniques (SIT) are promising novel approaches to control Bactrocera dorsalis, the most destructive horticultural pest in East Asia and the Pacific region. To identify novel genetic agents to alter male fertility of B. dorsalis, previous studies investigated miRNA expression in testes of B. dorsalis. One miRNA, miR-8-3p was predicted to bind the 3'UTR of putative B. dorsalis mitoferrin (bmfrn). The ortholog of bmfrn in D. melanogaster is essential for male fertility. Here we show that bmfrn has all conserved amino acid residues of known mitoferrins and is most abundantly expressed in B. dorsalis testes, making miR-8-3p and mitoferrin candidates for genetics-enhanced SIT. Furthermore, using a dual-luciferase reporter system, we show in HeLa cells that miR-8-3p interacts with the 3'UTR of bmfrn. Dietary treatments of adult male flies with miR-8-3p mimic, antagomiR, or bmfrn dsRNA, altered mitoferrin expression in the testes and resulted in reduced male reproductive capacity due to reduced numbers and viability of spermatozoa. We show for the first time that a mitoferrin is regulated by a miRNA and we demonstrate miR-8-3p as well as bmfrn dsRNA to be promising novel agents that could be used for genetics-enhanced SIT. PMID- 26932746 TI - Plasmodium yoelii infection of BALB/c mice results in expansion rather than induction of CD4(+) Foxp3(+) regulatory T cells. AB - Recently, we demonstrated elevated numbers of CD4(+) Foxp3(+) regulatory T (Treg) cells in Plasmodium yoelii-infected mice contributing to the regulation of anti malarial immune response. However, it remains unclear whether this increase in Treg cells is due to thymus-derived Treg cell expansion or induction of Treg cells in the periphery. Here, we show that the frequency of Foxp3(+) Treg cells expressing neuropilin-1 (Nrp-1) decreased at early time-points during P. yoelii infection, whereas percentages of Helios(+) Foxp3(+) Treg cells remained unchanged. Both Foxp3(+) Nrp-1(+) and Foxp3(+) Nrp-1(-) Treg cells from P. yoelii infected mice exhibited a similar T-cell receptor Vbeta chain usage and methylation pattern in the Treg-specific demethylation region within the foxp3 locus. Strikingly, we did not observe induction of Foxp3 expression in Foxp3(-) T cells adoptively transferred to P. yoelii-infected mice. Hence, our results suggest that P. yoelii infection triggered expansion of naturally occurring Treg cells rather than de novo induction of Foxp3(+) Treg cells. PMID- 26932748 TI - Involvement of splenic iron accumulation in the development of nonalcoholic steatohepatitis in Tsumura Suzuki Obese Diabetes mice. AB - Nonalcoholic steatohepatitis (NASH) is a common hepatic manifestation of metabolic syndrome and can lead to hepatic cirrhosis and cancer. It is considered that NASH is caused by multiple parallel events, including abnormal lipid metabolism, gut-derived-endotoxin-induced inflammation, and adipocytokines derived from adipose tissue, suggesting that other tissues are involved in NASH development. Previous studies demonstrated that spleen enlargement is observed during the course of NASH pathogenesis. However, the involvement of splenic status in the progression of NASH remains unclear. In this study, we examined hepatic and splenic histopathological findings in the early stage of NASH using the Tsumura Suzuki Obese Diabetes (TSOD) mouse model established for assessing NASH. We found that 12-week-old TSOD mice clearly exhibited the histopathological features of NASH in the early stage. At this age, the spleen of TSOD mice showed markedly higher iron level than that of control Tsumura Suzuki Non Obesity (TSNO) mice. The level of accumulated iron was significantly decreased by feeding a diet with glucosyl hesperidin, a bioactive flavonoid, accompanied with alleviation of hepatic lesions. Furthermore, we found that splenic iron level was positively correlated with the severity of NASH manifestations, suggesting that abnormalities in the spleen are involved in the development of NASH. PMID- 26932749 TI - Genetic determinants of lipid-lowering response to atorvastatin therapy in an Indian population. AB - WHAT IS KNOWN AND OBJECTIVE: Statins form the backbone of lipid-lowering therapy for the prevention of cardiovascular disease. However, there is large interindividual variability in clinical response to statin treatment. Several gene variants that can be aligned to either the pharmacokinetics or pharmacodynamics of statin have been proposed as potentially important determinants of statin response. We aimed to study the association of known variations in SLCO1B1, CYP3A4, ABCB1, CYP3A5, ABCG5 and CYP7A1 genes with lipid levels in response to atorvastatin therapy. METHODS: Genotypes were determined using multiplex allele-specific polymerase chain reaction in 177 Indian patients, treated with 10 mg of atorvastatin for 8 weeks. Low-density lipoprotein cholesterol (LDL-C) levels were recorded at baseline and after 8 weeks of atorvastatin treatment. RESULTS AND DISCUSSION: A total of 177 hypercholesterolaemic patients were genotyped to study genetic determinants of atorvastatin response. The genotype distribution for all polymorphisms investigated was in Hardy-Weinberg equilibrium. In our study, patients with wild type genotypes of CYP7A1 (rs3808607), CYP3A4 (rs2740574), SLCO1B1 (rs2306283) and variant allele-carrying genotype of ABCB1 (rs2032582, rs1045642) showed significantly greater LDL-cholesterol reductions in response to atorvastatin therapy. WHAT IS NEW AND CONCLUSION: The variable response to atorvastatin therapy in terms of LDL-cholesterol lowering due to genetic variations in CYP7A1, CYP3A4, SLCO1B1 and ABCB1 is a promising finding. Further validation in large Indian cohorts is required before it can be assessed for clinical utility. PMID- 26932750 TI - Anti-vascular endothelial growth factor (VEGF) drugs for treatment of retinopathy of prematurity. AB - BACKGROUND: Vascular endothelial growth factor (VEGF) plays a key role in angiogenesis in fetal life. Recently, researchers have attempted to use anti-VEGF agents for the treatment of retinopathy of prematurity (ROP), a vasoproliferative disorder. There is currently uncertainty regarding the safety and efficacy of these agents in preterm infants with ROP. OBJECTIVES: To evaluate the efficacy and safety of anti-VEGF drugs when used either as monotherapy, i.e. without concomitant cryotherapy or laser therapy or in combination with planned cryo/laser therapy in preterm infants with type 1 ROP (defined as zone I any stage with plus disease, zone I stage 3 with or without plus disease or zone II stage 2 or 3 with plus disease). SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL 2016, Issue 1), MEDLINE (1966 to January 1, 2016), EMBASE (1980 to January 1, 2016), CINAHL (1982 to January 1, 2016), conference proceedings, and previous reviews. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials that evaluated the efficacy and safety of administration, or both, of anti-VEGF agents compared with conventional therapy in premature infants with ROP. DATA COLLECTION AND ANALYSIS: We used standard Cochrane and Cochrane Neonatal methods for data collection and analysis. MAIN RESULTS: Three trials, in which 239 infants participated, fulfilled the inclusion criteria. Two trials compared intravitreal bevacizumab with conventional laser therapy (monotherapy) while the third compared intravitreal pegaptanib plus laser treatment with laser and cryotherapy (combination therapy) in infants with type 1 ROP.Of the two studies that evaluated intravitreal bevacizumab, one randomized infants while the other randomized eyes of the infants to the intervention and control groups. The former did not report any difference in the incidence of complete or partial retinal detachment between the groups (143 infants; RR 1.04, 95% CI 0.21 to 5.13; RD 0.00, 95% CI -0.06 to 0.07; very low quality evidence) but reported a significant reduction in the risk of refractive errors - very high myopia - at 30 months of age (211 eyes; RR 0.06, 95% CI 0.02 to 0.20; RD -0.40, 95% CI -0.50 to -0.30; low quality evidence) and recurrence of ROP by 54 weeks' postmenstrual age (143 infants; RR 0.22, 95% CI 0.08 to 0.62; RD -0.20, 95% CI 0.31 to -0.09; moderate quality evidence) in the bevacizumab group. The study found no difference in the risk of mortality before discharge from the hospital (150 infants; RR 1.50; 95% CI 0.26 to 8.75; RD 0.01; 95% CI -0.04 to 0.07; low quality evidence), mortality at 30 months of age (150 infants; RR 0.86, 95% CI 0.30 to 2.45; RD -0.01; 95% CI -0.10 to 0.08; low quality evidence), corneal opacity requiring corneal transplant (286 eyes; RR 0.34, 95% CI 0.01 to 8.26; RD 0.01; 95% CI -0.03 to 0.02; very low quality evidence), or lens opacity requiring cataract removal (286 eyes; RR 0.15, 95% CI 0.01 to 2.79; RD -0.02; 95% CI -0.05 to 0.01; very low quality evidence). The second trial that randomized eyes of the infants did not find any difference in the risk of complete retinal detachment between the eyes randomized to bevacizumab and those that were randomized to laser therapy (13 eyes; RR 0.33, 95% CI 0.01 to 7.50; RD -0.08, 95% CI -0.27 to 0.11).When used in combination with laser therapy, intravitreal pegaptanib was found to reduce the risk of retinal detachment when compared to laser/cryotherapy alone (152 eyes; RR 0.26, 95% CI 0.12 to 0.55; RD -0.29, 95% CI -0.42 to -0.16; low quality evidence). The incidence of recurrence of ROP by 55 weeks' postmenstrual age was also lower in the pegaptanib + laser therapy group (76 infants; RR 0.29, 95% CI 0.12 to 0.7; RD -0.35, 95% CI -0.55 to -0.16; low quality evidence). There was no difference in the risk of perioperative retinal haemorrhages between the two groups (152 eyes; RR 0.62, 95% CI 0.24 to 1.56; RD 0.05, 95% CI -0.16 to 0.05; very low quality evidence). The risk of delayed systemic adverse effects with either of the drugs is, however, not known. AUTHORS' CONCLUSIONS: IMPLICATIONS FOR PRACTICE: Intravitreal bevacizumab reduces the risk of refractive errors during childhood when used as monotherapy while intravitreal pegaptanib reduces the risk of retinal detachment when used in conjunction with laser therapy in infants with type 1 ROP. Quality of evidence was, however, low for both the outcomes because of the risk of detection and other biases. Effect on other critical outcomes and, more importantly, the long term systemic adverse effects of the drugs are not known. The insufficient data precludes strong conclusions favouring routine use of intravitreal anti-VEGF agents in preterm infants with type 1 ROP. IMPLICATIONS FOR RESEARCH: Further studies are needed to evaluate the effect of anti-VEGF agents on structural and functional outcomes in childhood and delayed systemic adverse effects such as myocardial dysfunction and adverse neurodevelopmental outcomes. PMID- 26932753 TI - Ag-catalyzed azide alkyne cycloaddition: a DFT approach. AB - In this study, the mechanism of AgAAC reaction has been studied by quantum mechanical calculations to gain insights into this promising reaction and the first successful application of a Ag catalyst alone in AAC. Elucidating the reaction mechanism will enable more control over the synthesis and help to obtain tailor made products in good yields without copper. The feasibility of the experimentally proposed reaction mechanism was investigated by modelling the profound intermediates and the transition state structures connecting them. The DFT calculations with the wB97XD functional with MWB28 effective core potential and 6-31+G* basis set combination herein show that once the silver acetylide structure forms, triazole synthesis via the experimentally proposed cycloaddition is a facile reaction in terms of energetics. The number of metal atoms involved in a click reaction is one of the main questions considered in mechanistic studies. In AgAAC reaction, comparison of mononuclear and binuclear paths shows that the barrier for binuclear cases is lower than that of mononuclear cases. PMID- 26932752 TI - Repolarization variability - Friend or foe? PMID- 26932755 TI - Improving the ultrasound detection of isolated fetal limb abnormalities. AB - OBJECTIVE: The prenatal detection rate of isolated fetal limb abnormalities ranges from 4 to 29.5%. Our aim was to determine the accuracy of a detailed ultrasound protocol in detecting isolated fetal limb abnormalities Methods: This is a retrospective study of infants born at our institution with isolated limb defects from 2009 to 2014. Antepartum and postpartum records were reviewed for genetic testing results. We routinely image both upper and lower extremities, including all long bones, hands, feet, fingers and toes. Posturing, muscular tone and movement are also noted. RESULTS: During the study period, there were 52 neonates born with isolated fetal limb abnormalities who had received a fetal anatomic survey in our ultrasound unit and 15 930 sonograms performed with normal findings; 36 out of the 52 had been prenatally diagnosed (detection rate 69%). The specificity of the protocol was 100% as there were no false positive cases, the positive predictive value was 100% and negative predictive value 99.8%. Forty three of 52 neonates had normal genetic testing either prenatally or postnatally; 9 neonates did not undergo genetic testing. The average additional time required for this detailed protocol was <5 min for second trimester sonogram. CONCLUSION: A minimal investment in time for detailed evaluation of fetal limbs more than doubles the previously reported prenatal detection rate. PMID- 26932754 TI - Dysaesthetic penoscrotodynia may be a somatoform disorder: results from a two centre retrospective case series. AB - BACKGROUND: Dysaesthetic penoscrotodynia (DPSD) is a poorly understood disorder, in which men experience distressing symptoms such as burning pain in their genital skin. Drugs for neuropathic pain are often used, but with little success. AIM: To review a series of patients with DPSD to highlight common themes and response to treatment. METHODS: Ten consecutive patients with DPSD were identified from specialist male genital dermatology and psychodermatology clinics at two centres. Clinical details, including psychiatric history, were reviewed retrospectively. Patients with no previously diagnosed psychiatric illness completed either the Generalized Anxiety Disorder (GAD)-7 scale and the Patient Health Questionnaire (PHQ)-9 depression scale, or the Hospital Anxiety and Depression Scale (HADS) and the Dermatology Life Quality Index (DLQI). RESULTS: Of the 10 patients, 9 had known or newly diagnosed psychopathology. All patients were offered psychodermatological treatment, of which 7 of 10 accepted. All of those who accepted psychodermatological treatment experienced an improvement in their genital symptoms. When post-treatment scores were collected, improvement in psychiatric symptoms accompanied improvement in genital symptoms. CONCLUSIONS: Psychopathology is almost invariably present in individuals with DPSD, yet these patients rarely volunteer such information. DPSD is most likely to constitute a functional somatic symptom disorder, hence psychodermatological treatment is indicated for its management. This concept reflects a significant change in the approach to this condition. PMID- 26932756 TI - Assessment of VOR gain function and its test-retest reliability in normal hearing individuals. AB - Video head impulse test (vHIT) aids to assess all three pairs of semi-circular canals (SCCs) separately and can be utilized to find out the exact site of lesion in any three SCCs by measuring vestibulo ocular reflex (VOR) gain. VOR gain value of vHIT has been used to diagnose different vestibular pathologies. Hence, it is important to establish the test-retest reliability of the VOR gain parameters before it could be administered to the patients. Therefore, the aim of the present study was to obtain VOR gain data, correlate all planes in both sides of head (right and left) and assess the test-retest reliability of VOR gain measure using vHIT in 25 normal young adult participants. Video head impulse test tests were carried out with prototype ICS impulse video goggles with a camera speed of 250 frames/s, recording motion of the right eye in all three planes (lateral, right anterior left posterior, left anterior right posterior) for all the participants. vHIT testing was repeated for all the participants after 15 days. Statistical analysis revealed that mean VOR gain for right horizontal canal was higher than the left horizontal canal; right anterior canal was higher than left anterior canal and left anterior was higher than right posterior canal. Horizontal canals have more gain compared to anterior and posterior canals. There was no significant difference between the VOR gain of session 1 and session 2 for each SCC. PMID- 26932757 TI - Effects of the "Happy Together" integrated cognitive behavior program on elderly people with dementia being cared for at home in rural areas. AB - INTRODUCTION: The purpose of this research was to apply the "Happy Together" integrated cognitive behavior program for elderly people with dementia who are living at home. METHODS: This research applied the non-equivalent control group pretest-posttest design. Research participants included 46 pairs of elderly individuals and their caregivers. RESULTS: The program brought about positive changes in the instrumental activities of daily living of elderly people with dementia and alleviated the burden felt by family caregivers. CONCLUSIONS: Both elderly people with dementia and their family caregivers will be able to benefit from the "Happy Together" program. PMID- 26932758 TI - Detailed Study of the Influence of InGaAs Matrix on the Strain Reduction in the InAs Dot-In-Well Structure. AB - InAs/InGaAs dot-in-well (DWELL) structures have been investigated with the systematically varied InGaAs thickness. Both the strained buffer layer (SBL) below the dot layer and the strain-reducing layer (SRL) above the dot layer were found to be responsible for the redshift in photoluminescence (PL) emission of the InAs/InGaAs DWELL structure. A linear followed by a saturation behavior of the emission redshift was observed as a function of the SBL and SRL thickness, respectively. The PL intensity is greatly enhanced by applying both of the SRL and SBL. Finite element analysis simulation and transmission electron microscopy (TEM) measurement were carried out to analyze the strain distribution in the InAs QD and the InGaAs SBL. The results clearly indicate the strain reduction in the QD induced by the SBL, which are likely the main cause for the emission redshift. PMID- 26932759 TI - Electric Field-Controlled Crystallizing CaCO3 Nanostructures from Solution. AB - The role of electric field is investigated in determining the structure, morphology, and crystallographic characteristics of CaCO3 nanostructures crystallized from solution. It is found that the lattice structure and crystalline morphology of CaCO3 can be tailed by the electric field applied to the solution during its crystallization. The calcite structure with cubic-like morphology can be obtained generally without electric field, and the vaterite structure with the morphology of nanorod is formed under the high electric field. The vaterite nanorods can be piled up to the petaliform layers. Both the nanorod and the petaliform layer can have mesocrystal structures which are piled up by much fine units of the rods with the size of several nanometers. Beautiful rose like nanoflowers can be self-arranged by the petaliform layers. These structures can have potential application as carrier for medicine to involve into metabolism of living cell. PMID- 26932760 TI - One-Dimensional Perovskite Manganite Oxide Nanostructures: Recent Developments in Synthesis, Characterization, Transport Properties, and Applications. AB - One-dimensional nanostructures, including nanowires, nanorods, nanotubes, nanofibers, and nanobelts, have promising applications in mesoscopic physics and nanoscale devices. In contrast to other nanostructures, one-dimensional nanostructures can provide unique advantages in investigating the size and dimensionality dependence of the materials' physical properties, such as electrical, thermal, and mechanical performances, and in constructing nanoscale electronic and optoelectronic devices. Among the one-dimensional nanostructures, one-dimensional perovskite manganite nanostructures have been received much attention due to their unusual electron transport and magnetic properties, which are indispensable for the applications in microelectronic, magnetic, and spintronic devices. In the past two decades, much effort has been made to synthesize and characterize one-dimensional perovskite manganite nanostructures in the forms of nanorods, nanowires, nanotubes, and nanobelts. Various physical and chemical deposition techniques and growth mechanisms are explored and developed to control the morphology, identical shape, uniform size, crystalline structure, defects, and homogenous stoichiometry of the one-dimensional perovskite manganite nanostructures. This article provides a comprehensive review of the state-of-the-art research activities that focus on the rational synthesis, structural characterization, fundamental properties, and unique applications of one-dimensional perovskite manganite nanostructures in nanotechnology. It begins with the rational synthesis of one-dimensional perovskite manganite nanostructures and then summarizes their structural characterizations. Fundamental physical properties of one-dimensional perovskite manganite nanostructures are also highlighted, and a range of unique applications in information storages, field-effect transistors, and spintronic devices are discussed. Finally, we conclude this review with some perspectives/outlook and future researches in these fields. PMID- 26932761 TI - Peptide-Mediated Tumor Targeting by a Degradable Nano Gene Delivery Vector Based on Pluronic-Modified Polyethylenimine. AB - Polyethylenimine (PEI) is considered to be a promising non-viral gene delivery vector. To solve the toxicity versus efficacy and tumor-targeting challenges of PEI used as gene delivery vector, we constructed a novel non-viral vector DR5-TAT modified Pluronic-PEI (Pluronic-PEI-DR5-TAT), which was based on the attachment of low-molecular-weight polyethylenimine (LMW-PEI) to the amphiphilic polymer Pluronic to prepare Pluronic-modified LMW-PEI (Pluronic-PEI). This was then conjugated to a multifunctional peptide containing a cell-penetrating peptide (TAT) and a synthetic peptide that would bind to DR5-a receptor that is overexpressed in cancer cells. The vector showed controlled degradation, favorable DNA condensation and protection performance. The Pluronic-PEI-DR5 TAT/DNA complexes at an N/P ratio of 15:1 were spherical nanoparticles of 122 +/- 11.6 nm and a zeta potential of about 22 +/- 2.8 mV. In vitro biological characterization results indicated that Pluronic-PEI-DR5-TAT/DNA complexes had a higher specificity for the DR5 receptor and were taken up more efficiently by tumor cells than normal cells, compared to complexes formed with PEI 25 kDa or Pluronic-PEI. Thus, the novel complexes showed much lower cytotoxicity to normal cells and higher gene transfection efficiency in tumor cells than that exhibited by PEI 25 kDa and Pluronic-PEI. In summary, our novel, degradable non-viral tumor targeting vector is a promising candidate for use in gene therapy. PMID- 26932763 TI - Prostate cancer risk among French farmers in the AGRICAN cohort. AB - OBJECTIVES: Prostate cancer is one of the most frequent cancers among men worldwide. Its etiology is largely unknown, but an increased risk has been repeatedly observed among farmers. Our aim was to identify occupational risk factors for prostate cancer among farmers in the prospective cohort study AGRICAN. METHODS: Data on lifetime agricultural exposures (type of crops, livestock and tasks including pesticide use, re-entry and harvesting) were collected from the enrolment questionnaire. During the period from enrolment (2005-2007) to 31 December 2009, 1672 incident prostate cancers were identified. Hazard ratios (HR) were estimated using Cox regression analysis. RESULTS: We found an increased risk for cattle breeders using insecticides [HR 1.20, 95% confidence interval (95% CI) 1.01-1.42] with a significant dose-response relationship with number of cattle treated (P for trend 0.01). A dose-response relationship was also observed with the number of hogs (P for trend 0.06). We found an excess of prostate cancer risk among people involved in grassland activities, mainly in haymaking (HR 1.18, 95% CI 1.02-1.36). Pesticide use and harvesting among fruit growers were associated with an elevated prostate cancer risk, with a two-fold increased risk for the largest area. For potato and tobacco producers, an elevated prostate cancer risk was observed for almost all tasks, suggesting a link with pesticide exposure since all of them potentially involved pesticide exposure. CONCLUSIONS: Our analysis suggests that the risk of prostate cancer is increased in several farming activities (cattle and hog breeding, grassland and fruit-growing) and for some tasks including pesticide use. PMID- 26932762 TI - SaMpling Antibiotics in Renal Replacement Therapy (SMARRT): an observational pharmacokinetic study in critically ill patients. AB - BACKGROUND: Optimal antibiotic dosing is key to maximising patient survival, and minimising the emergence of bacterial resistance. Evidence-based antibiotic dosing guidelines for critically ill patients receiving RRT are currently not available, as RRT techniques and settings vary greatly between ICUs and even individual patients. We aim to develop a robust, evidence-based antibiotic dosing guideline for critically ill patients receiving various forms of RRT. We further aim to observe whether therapeutic antibiotic concentrations are associated with reduced 28-day mortality. METHODS/DESIGN: We designed a multi-national, observational pharmacokinetic study in critically ill patients requiring RRT. The study antibiotics will be vancomycin, linezolid, piperacillin/tazobactam and meropenem. Pharmacokinetic sampling of each patient's blood, RRT effluent and urine will take place during two separate dosing intervals. In addition, a comprehensive data set, which includes the patients' demographic and clinical parameters, as well as modality, technique and settings of RRT, will be collected. Pharmacokinetic data will be analysed using a population pharmacokinetic approach to identify covariates associated with changes in pharmacokinetic parameters in critically ill patients with AKI who are undergoing RRT for the five commonly prescribed antibiotics. DISCUSSION: Using the comprehensive data set collected, the pharmacokinetic profile of the five antibiotics will be constructed, including identification of RRT and other factors indicative of the need for altered antibiotic dosing requirements. This will enable us to develop a dosing guideline for each individual antibiotic that is likely to be relevant to any critically ill patient with acute kidney injury receiving any of the included forms of RRT. TRIAL REGISTRATION: Australian New Zealand Clinical Trial Registry ( ACTRN12613000241730 ) registered 28 February 2013. PMID- 26932764 TI - Elucidation of defense-related signaling responses to spot blotch infection in bread wheat (Triticum aestivum L.). AB - Spot blotch disease, caused by Bipolaris sorokiniana, is an important threat to wheat, causing an annual loss of ~17%. Under epidemic conditions, these losses may be 100%, yet the molecular responses of wheat to spot blotch remain almost uncharacterized. Moreover, defense-related phytohormone signaling genes have been poorly characterized in wheat. Here, we have identified 18 central components of salicylic acid (SA), jasmonic acid (JA), ethylene (ET), and enhanced disease susceptibility 1 (EDS1) signaling pathways as well as the genes of the phenylpropanoid pathway in wheat. In time-course experiments, we characterized the reprogramming of expression of these pathways in two contrasting genotypes: Yangmai #6 (resistant to spot blotch) and Sonalika (susceptible to spot blotch). We further evaluated the performance of a population of recombinant inbred lines (RILs) by crossing Yangmai#6 and Sonalika (parents) and subsequent selfing to F10 under field conditions in trials at multiple locations. We characterized the reprogramming of defense-related signaling in these RILs as a consequence of spot blotch attack. During resistance to spot blotch attack, wheat strongly elicits SA signaling (SA biogenesis as well as the NPR1-dependent signaling pathway), along with WRKY33 transcription factor, followed by an enhanced expression of phenylpropanoid pathway genes. These may lead to accumulation of phenolics-based defense metabolites that may render resistance against spot blotch. JA signaling may synergistically contribute to the resistance. Failure to elicit SA (and possibly JA) signaling may lead to susceptibility against spot blotch infection in wheat. PMID- 26932767 TI - Rapid and Checkable Electrical Post-Treatment Method for Organic Photovoltaic Devices. AB - Post-treatment processes improve the performance of organic photovoltaic devices by changing the microscopic morphology and configuration of the vertical phase separation in the active layer. Thermal annealing and solvent vapor (or chemical) treatment processes have been extensively used to improve the performance of bulk heterojunction (BHJ) organic photovoltaic (OPV) devices. In this work we introduce a new post-treatment process which we apply only electrical voltage to the BHJ-OPV devices. We used the commercially available P3HT [Poly(3 hexylthiophene)] and PC61BM (Phenyl-C61-Butyric acid Methyl ester) photovoltaic materials as donor and acceptor, respectively. We monitored the voltage and current applied to the device to check for when the post-treatment process had been completed. This electrical treatment process is simpler and faster than other post-treatment methods, and the performance of the electrically treated solar cell is comparable to that of a reference (thermally annealed) device. Our results indicate that the proposed treatment process can be used efficiently to fabricate high-performance BHJ-OPV devices. PMID- 26932766 TI - A descriptive analysis of the spatio-temporal distribution of enteric diseases in New Brunswick, Canada. AB - BACKGROUND: Enteric diseases affect thousands of Canadians annually and several large outbreaks have occurred due to infection with enteric pathogens. The objectives of this study were to describe the spatial and temporal distributions of reportable Campylobacter, Escherichia coli, Giardia, Salmonella and Shigella from 1994 to 2002 in New Brunswick, Canada. By examining the spatial and temporal distributions of disease incidence, hypotheses as to potential disease risk factors were formulated. METHODS: Time series plots of monthly disease incidence were examined for seasonal and secular trends. Seasonality of disease incidence was evaluated using the temporal scan statistic and seasonal-trend loess (STL) decomposition methods. Secular trends were evaluated using negative binomial regression modeling. The spatial distribution of disease incidence was examined using maps of empirical Bayes smoothed estimates of disease incidence. Spatial clustering was examined by multiple methods, which included Moran's I and the spatial scan statistic. RESULTS: The peak incidence of Giardia infections occurred in the spring months. Salmonella incidence exhibited two peaks, one small peak in the spring and a main peak in the summer. Campylobacter and Escherichia coli O157 disease incidence peaked in the summer months. Moran's I indicated that there was significant positive spatial autocorrelation for the incidence of Campylobacter, Giardia and Salmonella. The spatial scan statistic identified clusters of high disease incidence in the northern areas of the province for Campylobacter, Giardia and Salmonella infections. The incidence of Escherichia coli infections clustered in the south-east and north-east areas of the province, based on the spatial scan statistic results. Shigella infections had the lowest incidence rate and no discernable spatial or temporal patterns were observed. CONCLUSIONS: By using several different spatial and temporal methods a robust picture of the spatial and temporal distributions of enteric disease in New Brunswick was produced. Disease incidence for several reportable enteric pathogens displayed significant geographic clustering indicating that a spatially distributed risk factor may be contributing to disease incidence. Temporal analysis indicated peaks in disease incidence, including previously un reported peaks. PMID- 26932765 TI - ViromeScan: a new tool for metagenomic viral community profiling. AB - BACKGROUND: Bioinformatics tools available for metagenomic sequencing analysis are principally devoted to the identification of microorganisms populating an ecological niche, but they usually do not consider viruses. Only some software have been designed to profile the viral sequences, however they are not efficient in the characterization of viruses in the context of complex communities, like the intestinal microbiota, containing bacteria, archeabacteria, eukaryotic microorganisms and viruses. In any case, a comprehensive description of the host microbiota interactions can not ignore the profile of eukaryotic viruses within the virome, as viruses are definitely critical for the regulation of the host immunophenotype. RESULTS: ViromeScan is an innovative metagenomic analysis tool that characterizes the taxonomy of the virome directly from raw data of next generation sequencing. The tool uses hierarchical databases for eukaryotic viruses to unambiguously assign reads to viral species more accurately and >1000 fold faster than other existing approaches. We validated ViromeScan on synthetic microbial communities and applied it on metagenomic samples of the Human Microbiome Project, providing a sensitive eukaryotic virome profiling of different human body sites. CONCLUSIONS: ViromeScan allows the user to explore and taxonomically characterize the virome from metagenomic reads, efficiently denoising samples from reads of other microorganisms. This implies that users can fully characterize the microbiome, including bacteria and viruses, by shotgun metagenomic sequencing followed by different bioinformatic pipelines. PMID- 26932768 TI - Recombinant Lactococcus lactis expressing porcine insulin-like growth factor I ameliorates DSS-induced colitis in mice. AB - BACKGROUND: Insulin-like growth factor I (IGF-I) is one important family of growth factors, which plays key role in intestinal growth, regeneration, and damage repair. However, the low natural abundance of IGF-I limits its research opportunities and practical application in the fields of medicine and animal husbandry. In this study, a tandem repeat strategy was used to express three copies of the same pIGF-I3 protein in L. lactis. The activity of recombinant pIGF I3 (rpIGF-I3) was further examined by a mouse model of dextran sulfate sodium (DSS)-induced colitis. In addition, the potential of recombinant L. lactis expressing pIGF-I3 to reduce inflammatory disease was evaluated. RESULTS: pIGF-I3 could be expressed in L. lactis by the detection of SDS-PAGE and Western blot. Experimental colitis was induced in BALB/c mice by administration of 5 % DSS in drinking water, and the clinical symptoms were observed in DSS-treated mice. Oral administration of recombinant L. lactis expressing pIGF-I3 improved the colonic architecture, and significantly reduced the increase of colonic damage score (P < 0.05). Furthermore, recombinant L. lactis expressing pIGF-I3 treatment significantly reduced serum DAO activity and colonic MPO level, and elevated colonic occludin level compared to the DSS group (P < 0.05). CONCLUSIONS: The pIGF-I3 expressed in L. lactis has good biological activity, and oral administration of recombinant L. lactis expressing pIGF-I3 attenuated the symptoms and development of DSS-induced colitis in mice. These suggested that L. lactis could be a potential host bacterium for production and delivery of IGF-I against intestinal diseases. PMID- 26932769 TI - Skeletal Muscle Hypertrophy with Concurrent Exercise Training: Contrary Evidence for an Interference Effect. AB - Over the last 30+ years, it has become axiomatic that performing aerobic exercise within the same training program as resistance exercise (termed concurrent exercise training) interferes with the hypertrophic adaptations associated with resistance exercise training. However, a close examination of the literature reveals that the interference effect of concurrent exercise training on muscle growth in humans is not as compelling as previously thought. Moreover, recent studies show that, under certain conditions, concurrent exercise may augment resistance exercise-induced hypertrophy in healthy human skeletal muscle. The purpose of this article is to outline the contrary evidence for an acute and chronic interference effect of concurrent exercise on skeletal muscle growth in humans and provide practical literature-based recommendations for maximizing hypertrophy when training concurrently. PMID- 26932770 TI - Epidemiologic Investigation of Injuries Associated With the 2013 Fertilizer Plant Explosion in West, Texas. AB - OBJECTIVE: On April 17, 2013, a fire and subsequent explosion occurred at the West Fertilizer Company plant in West, Texas, and caused extensive damage to the adjacent neighborhood. This investigation described the fatal and nonfatal injuries caused by the explosion. METHODS: Persons injured by the fertilizer plant explosion were identified through death certificates, medical examination reports, medical records, and survivor interviews. Data on patient characteristics, type of injury, and location of injury were collected. RESULTS: Medical record review indicated that 252 individuals sought medical care for nonfatal injuries directly related to the explosion immediately after the explosion. Fifteen patients died of injuries sustained by the blast. Almost one quarter of patients were admitted for treatment of injuries. Injuries sustained in the explosion included abrasions/contusions, lacerations/penetrating trauma, traumatic brain injuries/concussions, tinnitus/hearing problems, eye injuries, and inhalational injuries. Patients located closer to the explosion were more likely to be admitted to the hospital for treatment of injuries than were those who were located further away. CONCLUSION: Explosions of this magnitude are rare, but can inflict severe damage to a community and its residents. This investigation could be a useful planning resource for other communities, public health agencies, first responders, and medical facilities. (Disaster Med Public Health Preparedness. 2016;10:583-590). PMID- 26932771 TI - An optimal stratified Simon two-stage design. AB - In Phase II oncology trials, therapies are increasingly being evaluated for their effectiveness in specific populations of interest. Such targeted trials require designs that allow for stratification based on the participants' molecular characterisation. A targeted design proposed by Jones and Holmgren (JH) Jones CL, Holmgren E: 'An adaptive Simon two-stage design for phase 2 studies of targeted therapies', Contemporary Clinical Trials 28 (2007) 654-661.determines whether a drug only has activity in a disease sub-population or in the wider disease population. Their adaptive design uses results from a single interim analysis to decide whether to enrich the study population with a subgroup or not; it is based on two parallel Simon two-stage designs. We study the JH design in detail and extend it by providing a few alternative ways to control the familywise error rate, in the weak sense as well as the strong sense. We also introduce a novel optimal design by minimising the expected sample size. Our extended design contributes to the much needed framework for conducting Phase II trials in stratified medicine. (c) 2016 The Authors Pharmaceutical Statistics Published by John Wiley & Sons Ltd. PMID- 26932772 TI - Effect of non-invasive ventilation on the measurement of ventilatory and metabolic variables. AB - The effect of non-invasive ventilation (NIV) on the accuracy of measurements of ventilation, oxygen consumption (VO2) and carbon dioxide production (VCO2) was examined using a simulator. Known gas volumes of oxygen and carbon dioxide were delivered to a metabolic system that measured tidal volume, respiratory rate, VO2 and VCO2, both with and without NIV. Bland-Altman analyses were used to compare between conditions. NIV at pressure support (PS) 20cm H2O compared to without NIV showed: VT, mean difference (MD) 0mL (limits of agreement (LOA) -21 to 21) mL; VO2 MD -413 (LOA -810 to 16) mL/min; and VCO2 MD 32 (LOA -32 to 97) mL/min. For VO2 measurements during NIV, a correction was applied to account for increased air density due to PS. After correction, VO2 measurement accuracy improved; MD 46 (LOA -108 to 17) mL/min. Tidal volume and metabolic variables can be measured with acceptable accuracy during NIV, providing VO2 is corrected for altered gas density. PMID- 26932773 TI - The provision of oral hygiene instructions and patient motivation in a dental care system without dental hygienists. AB - INTRODUCTION: Oral hygiene instructions (OHI) and patient motivation (PM), often provided by dental hygienists, are essential attributes to establishing good oral health in patients. The purpose of this study was to investigate the provision of OHI and PM by dental professionals in a dental care system without dental hygienists. METHODS AND MATERIALS: A questionnaire, including 22 items (demographics, OHI and PM), was presented to 1037 dental professionals (=21.6% Flemish population). Descriptive statistics were used to analyse the provision of OHI and PM. Additionally, the Fisher-Freeman-Halton exact test was used to investigate the influence of qualification (general practitioner/specialist), work experience (< or >= 25 years), workload (< or >= 30 h), location of practice (rural/urban) and chair-side assistance (with/without). RESULTS: Response rate was 75%. Participants reported a single strategy for preventive care and felt their efforts were not in harmony with the results. Lack of time, remuneration and patient interest were reported as complicating factors and participants agreed on allowing assistants to provide preventive care. Significant variance was found based on qualification (12/17 items), work experience (7/17 items), workload (1/17 items), location of practice (2/17 items) and chair-side assistance (15/17 items). CONCLUSION: In a context without dental hygienists, OHI and PM appeared non-compliant with current international guidelines. Although dental professionals were concerned with preventive dentistry, they reported barriers including lack of time, remuneration and patient compliance. Almost all participants expressed the need for delegation of in-mouth OHI, suggesting a need for dental hygienists. PMID- 26932774 TI - Implementation of a virtual learning from discrepancy meeting: a method to improve attendance and facilitate shared learning from radiological error. AB - AIM: To assess the effect on radiologist participation in learning from discrepancy meetings (LDMs) in a multisite radiology department by establishing virtual LDMs using OsiriX (Pixmeo). MATERIALS AND METHODS: Sets of anonymised discrepancy cases were added to an OsiriX database available for viewing on iMacs in all radiology reporting rooms. Radiologists were given a 3-week period to review the cases and send their feedback to the LDM convenor. Group learning points and consensus feedback were added to each case before it was moved to a permanent digital LDM library. Participation was recorded and compared with that from the previous 4 years of conventional LDMs. Radiologist feedback comparing the two types of LDM was collected using an anonymous online questionnaire. RESULTS: Numbers of radiologists attending increased significantly from a mean of 12+/-2.9 for the conventional LDM to 32.7+/-7 for the virtual LDM (p<0.0001) and the percentage of radiologists achieving the UK standard of participation in at least 50% of LDMs annually rose from an average of 18% to 68%. The number of cases submitted per meeting rose significantly from an average of 11.1+/-3 for conventional LDMs to 15.9+/-5.9 for virtual LDMs (p<0.0097). Analysis of 35 returned questionnaires showed that radiologists welcomed being able to review cases at a time and place of their choosing and at their own pace. CONCLUSION: Introduction of virtual LDMs in a multisite radiology department improved radiologist participation in shared learning from radiological discrepancy and increased the number of submitted cases. PMID- 26932775 TI - New horizons in cardiac CT. AB - Until recently, cardiovascular computed tomography angiography (CCTA) was associated with considerable radiation doses. The introduction of tube current modulation and automatic tube potential selection as well as high-pitch prospective ECG-triggering and iterative reconstruction offer the ability to decrease dose with approximately one order of magnitude, often to sub millisievert dose levels. In parallel, advancements in computational technology have enabled the measurement of fractional flow reserve (FFR) from CCTA data (FFRCT). This technique shows potential to replace invasively measured FFR to select patients in need of coronary intervention. Furthermore, developments in scanner hardware have led to the introduction of dual-energy and photon-counting CT, which offer the possibility of material decomposition imaging. Dual-energy CT reduces beam hardening, which enables CCTA in patients with a high calcium burden and more robust myocardial CT perfusion imaging. Future-generation CT systems will be capable of counting individual X-ray photons. Photon-counting CT is promising and may result in a substantial further radiation dose reduction, vastly increased spatial resolution, and the introduction of a whole new class of contrast agents. PMID- 26932776 TI - The effect of trauma backboards on computed tomography radiation dose. AB - AIM: To assess the effect of trauma backboards on the radiation dose at computed tomography (CT) when using automatic tube current modulation (ATCM). MATERIALS AND METHODS: An anthropomorphic phantom was scanned with two commercially available CT systems (GE LightSpeed16 Pro and Siemens Definition AS+) without and with backboards. Tube current-time product (mAs), and CTDIvol (mGy) were recorded for each examination. Thermoluminescent dosimeters were used to measure skin entrance dose in the pelvis and breast. Statistical significance was determined using a two-sample t-test. In addition, an institutional review board-approved retrospective image review was performed to quantify the frequency of backboard use during CT in the emergency department. RESULTS: There was a statistically significant increase in maximum tube current-time product (p<0.05) and CTDIvol (p<0.05) with the presence of a backboard; tube current-time product increased up to 31% and CTDIvol increased up to 27%. There was a significant increase in skin entrance dose in the anterior and posterior pelvis (p<0.05) with the presence of a backboard; skin entrance dose increased up to 25% in the anterior pelvis. Skin entrance dose to the breast increased with a backboard, although this was not statistically significant. The frequency of backboard use during CT markedly decreased (from 77% to 3%) after instituting a multidisciplinary policy to promptly remove patients from backboards upon arrival to the emergency department after a primary clinical survey. CONCLUSIONS: Using backboards during CT with ATCM can significantly increase the radiation dose. Although the decision to maintain patients on backboards is multifactorial, attempts should be made to minimise backboard use during CT when possible. PMID- 26932777 TI - A composite nanostructured electron-transport layer for stable hole-conductor free perovskite solar cells: design and characterization. AB - A novel composite nanostructured titanium dioxide (TiO2) based electron-transport layer (ETL) is designed by combining size blended nanoparticles (SBNP) and nanoarrays (NA) for efficient perovskite solar cell (PSC) applications. The composite nanostructured (SBNP + NA) ETL is successfully employed in hole conductor free PSCs, there by achieving a stable device with a maximum efficiency of 13.5%. The improvement in the performance is attributed to the better charge transport and lower recombination in the SBNP + NA ETL. Despite the stable high efficiency, SBNP + NA ETL based PSCs are advantageous owing to their low cost, ease of all-solution fabrication process in an open environment and good reproducibility. PMID- 26932778 TI - Triple Emulsion Drops with An Ultrathin Water Layer: High Encapsulation Efficiency and Enhanced Cargo Retention in Microcapsules. AB - Triple emulsion drops with an ultrathin water layer are developed to achieve high encapsulation efficiency of hydrophobic cargo in a hydrophobic polymeric shell, directly dispersed in water. Furthermore, enhanced retention of volatile hydrophobic cargo is achieved by forming a hydrogel network within this water layer that serves as a physical barrier. PMID- 26932779 TI - Differential toxicity of an organic PM2.5 extract to human lung cells cultured in three dimensions (3D) and monolayers. AB - Several epidemiological studies have associated PM2.5 (particulate matter, aerodynamic diameter 2.5 um) exposure with an increase in morbidity and mortality attributed to cardiopulmonary diseases. Based upon these observations and the growing effort to replace the use of animals in research, in vitro A549 cells cultured in three dimensions (3D), an alternative method to the use of animals, as well as monolayers were investigated to examine whether organic PM2.5 extract induced equivalent cytotoxic changes in vitro as compared to in vivo. PM2.5 was collected on Brazil Avenue, Rio de Janeiro, Brazil, from November 2010 to May 2011, except March, and analyzed for the ability to induce cytotoxicity in A549 cells using various established assays. Samples collected in all months significantly decreased viability of A549 cells using both types of cell death assays, and those collected in November showed lower cytotoxicity. It is worthwhile noting that for samples collected in all months except for April, PM2.5 induced greater toxicity in cells grown in monolayers than in 3D. Data demonstrated that cell behavior varied based upon type of culture system employed. Since the 3D cell culture mimics the architecture of in vivo tissue to a greater extent than monolayers, it is suggested that data from 3D studies resemble more closely human exposure conditions and thus may provide more reliable findings to be utilized in risk assessment following PM exposure than results obtained in traditional culture system. PMID- 26932780 TI - Post-operative retransfusion of unwashed filtered shed blood reduces allogenic blood demand in hip hemiarthroplasty in traumatic femoral neck fractures-a prospective randomized trial. AB - PURPOSE: Patients who undergo hip hemiarthroplasty (HHA) due to traumatic femoral neck fracture frequently require red blood cell (RBC) transfusion. Although post operative autologous blood transfusion (ABT) is well established in elective arthroplasty, its role in trauma patients remains unclear. METHODS: Two hundred twenty-nine patients with a traumatic femoral neck fracture that underwent HHA at our level-I trauma centre between 2005 and 2009 were prospectively randomized to a high-vacuum drainage or an ABT device. In this single-institution analysis, the number of RBC units as well as the amount of retransfused shed blood were recorded and compared according to study groups. Additionally, the significance of confounding factors for allogenic blood demand such as age, gender, pre operative Hb level, surgical approach, type of prosthesis and amount of intra operative RBC units were evaluated using multivariate analysis. RESULTS: One hundred thirty-five patients were randomized in the high-vacuum group while 94 patients received an ABT device. Intention to treat analysis revealed no significant difference in post-operative RBC demand (ABT: 0.87 RBC, high-vacuum drainage: 1.01 RBC; P = 0.374). However, patients that actually received retransfusion (N = 35) had a reduced post-operative RBC demand (0.49 RBC units, P = 0.014). CONCLUSION: While only one third of trauma patients treated with an ABT device during HHA actually receive retransfusion, retransfused patients seem to significantly benefit from this treatment as reflected by a reduced pos toperative RBC demand. PMID- 26932782 TI - Preclinical evaluation of the AR inhibitor enzalutamide in triple-negative breast cancer cells. AB - The androgen receptor (AR) is present in approximately 80% of invasive breast cancer patients and in up to 30% of patients with triple-negative breast cancer (TNBC). Therefore, our aim was to investigate the targeting of AR as a possible hormonal approach to the treatment of TNBC. Analysis of 2091 patients revealed an association between AR expression and poor overall survival, selectively in patients with the basal subtype of breast cancer, the vast majority of which are TNBC. IC50 values for the second-generation anti-androgen enzalutamide across 11 breast cancer cell lines varied from 4 uM to >50 uM. The activity of enzalutamide was similar in TN and non-TN cell lines but was dependent on the presence of AR. Enzalutamide reduced clonogenic potential and cell growth in a 3D matrix in AR positive cells. In addition, enzalutamide also inhibited cell migration and invasion in an AR-dependent manner. Enzalutamide appeared to mediate these processes through down-regulation of the transcription factors AP-1 and SP-1. The first-generation anti-androgen flutamide similarly blocked cell growth, migration and invasion. AR-positive TNBC cells clustered separately from AR-negative cells based on an androgen-related gene expression signature, independently of TNBC subtype. We conclude that targeting of the AR with drugs such as enzalutamide may provide an alternative treatment strategy for patients with AR-positive TNBC. PMID- 26932783 TI - High risk of myelodysplastic syndrome and acute myeloid leukemia after 177Lu octreotate PRRT in NET patients heavily pretreated with alkylating chemotherapy. PMID- 26932784 TI - A surface acoustic wave (SAW)-enhanced grating-coupling phase-interrogation surface plasmon resonance (SPR) microfluidic biosensor. AB - A surface acoustic wave (SAW)-enhanced, surface plasmon resonance (SPR) microfluidic biosensor in which SAW-induced mixing and phase-interrogation grating-coupling SPR are combined in a single lithium niobate lab-on-a-chip is demonstrated. Thiol-polyethylene glycol adsorption and avidin/biotin binding kinetics were monitored by exploiting the high sensitivity of grating-coupling SPR under azimuthal control. A time saturation binding kinetics reduction of 82% and 24% for polyethylene and avidin adsorption was obtained, respectively, due to the fluid mixing enhancement by means of the SAW-generated chaotic advection. These results represent the first implementation of a nanostructured SAW-SPR microfluidic biochip capable of significantly improving the molecule binding kinetics on a single, portable device. In addition, the biochip here proposed is suitable for a great variety of biosensing applications. PMID- 26932781 TI - Pharmacoproteomic analysis reveals that metapristone (RU486 metabolite) intervenes E-cadherin and vimentin to realize cancer metastasis chemoprevention. AB - Metapristone is the most predominant biological active metabolite of mifepristone, and being developed as a novel cancer metastasis chemopreventive agent by us. Despite its prominent metastasis chemopreventive effect, the underlying mechanism remains elusive. Our study, for the first time, demonstrated that metapristone had the ability to prevent breast cancer cells from migration, invasion, and interfere with their adhesion to endothelial cells. To explore the underlying mechanism of metapristone, we employed the iTRAQ technique to assess the effect of metapristone on MDA-MB-231 cells. In total, 5,145 proteins were identified, of which, 311 proteins showed significant differences in metapristone treated cells compared to the control group (P-value < 0.05). Bioinformatic analysis showed many differentially expressed proteins (DEPs) functionally associated with post-translational modification, chaperones, translation, transcription, replication, signal transduction, etc. Importantly, many of the DEPs, such as E-cadherin, vimentin, TGF-beta receptor I/II, smad2/3, beta catenin, caveolin, and dystroglycan were associated with TGF-beta and Wnt signaling pathways, which were also linked to epithelial-to-mesenchymal transition (EMT) process. Further validation of the epithelial marker "E-caderin" and mesenchymal marker "vimetin" were carried out using immunoblot and immunofluorescence. These results have revealed a novel mechanism that metapristone-mediated metastasis chemoprevention is through intervening the EMT related signaling pathways. PMID- 26932785 TI - Flowerlike WSe2 and WS2 microspheres: one-pot synthesis, formation mechanism and application in heavy metal ion sequestration. AB - Flowerlike WSe2 and WS2 microspheres were synthesized by a facile and scalable one-pot solvothermal method. Their formation mechanism followed the reaction between dissolved W(CO)6 and dissolved S or melted Se without complete decomposition of W(CO)6 into tungsten. As novel efficient sorbents, WSe2 and WS2 demonstrated outstanding uptake capacities for Pb(2+) and Hg(2+). PMID- 26932786 TI - Validity and reliability of short forms of parental-caregiver perception and family impact scale in a Telugu speaking population of India. AB - BACKGROUND: Parental-Caregiver Perception Questionnaire (P-CPQ) and Family Impact Scale (FIS) are commonly used measures to evaluate the parent's perception of the impact of children's oral health on quality of life and family respectively. Recently, shorter forms of P-CPQ and FIS have been developed. No study has sought to validate these short forms in other languages and cultures. This study aimed to evaluate the validity and reliability of FIS, 8 and 16-item P-CPQ in a Telugu speaking population of India. METHODS: For this cross-sectional study, a multi stage random sampling technique was used to recruit 11-13 year-old schoolchildren of Medak district, Telangana, India and their parents (n = 1342). Parents were approached with questionnaires through their children who underwent clinical examinations for dental caries, fluorosis and malocclusion. The translated versions underwent pilot testing (n = 40), test-retest reliability was also assessed (n = 161). RESULTS: The overall summary scale and subscales of the short forms of P-CPQ and FIS failed to discriminate between the categories of dental caries severity. Also, malocclusion status was not related to the domain or overall scores of both the short forms of P-CPQ. There were significant differences in subscale and overall scores of 16 and 8-item P-CPQ and FIS between the fluorosis categories. Both 16 and 8-item P-CPQ summary scales were significantly related to parent's global rating of oral health (16-item, r = 0.30, p < 0.01; 8-item, r = 0.28, p < 0.01) and overall wellbeing (16-item, r = 0.22, p < 0.01; 8-item, r = 0.22, p < 0.01), thereby exhibiting good construct validity. However, the correlation of emotional and social wellbeing scales of short forms of P-CPQ and FIS with global ratings was of low strength. Cronbach's alphas for FIS, 16-items and 8-items P-CPQ scales were 0.78, 0.83 and 0.71 respectively, while the Intra-Class Correlation coefficients were 0.752, 0.812 and 0.816 respectively. Cronbach's alphas for most of the subscales of short forms of P-CPQ were less than 0.7. CONCLUSIONS: The overall scales of 16 and 8 items P-CPQ scales demonstrated good construct validity while the construct validity of FIS was questionable. Discriminant validity of all the three instruments was good only in relation to fluorosis. Overall scales of all three short forms exhibited acceptable internal consistency and reliability on repeated administrations. PMID- 26932788 TI - A one-pot, three-step process for the diastereoselective synthesis of aminobicyclo[4.3.0]nonanes using consecutive palladium(II)- and ruthenium(II) catalysis. AB - A diastereoselective synthesis of highly substituted aminobicyclo[4.3.0]nonanes has been attained using a one-pot multi-bond forming process. A four-step synthetic route was developed for the efficient synthesis of a series of C-7 substituted hept-2-en-6-yn-1-ols. These compounds were then investigated as substrates for a one-pot, three-step tandem process involving a palladium(ii) catalysed Overman rearrangement, a ruthenium(ii)-catalysed ring closing enyne metathesis reaction followed by a hydrogen bond directed Diels-Alder reaction. The optimisation of the one-pot process has allowed the rapid preparation of a library of aminobicyclo[4.3.0]nonanes with significant molecular complexity and up to four stereogenic centres. PMID- 26932787 TI - Opposing presynaptic roles of BDNF and ProBDNF in the regulation of persistent activity in the entorhinal cortex. AB - BACKGROUND: Sustained, persistent firing (PF) of cortical pyramidal neurons following a short depolarization is a crucial cellular mechanism required for spatial and working memory. Pyramidal neurons in the superficial and deep layers of the medial and lateral entorhinal cortex (EC) display this property of prolonged firing activity. Here, we focused on the regulation of this activity in EC neurons by mature brain derived neurotrophic factor (BDNF) and its precursor proBDNF. RESULTS: Using patch clamp electrophysiology in acute mouse cortical slices, we observed that BDNF facilitates cholinergic PF in pyramidal neurons in layer V of the medial EC. Inhibition of TrkB with K252a blocks the potentiating effect of BDNF whereas inhibition of p75NTR with function-blocking antibodies does not. By recording spontaneous excitatory post-synaptic currents (sEPSC), we find that BDNF acts pre-synaptically via TrkB to increase glutamate release whereas proBDNF acting via p75NTR acts to reduce it. MPEP abolished the facilitating effect of BDNF on PF, demonstrating that the metabotropic glutamate receptor mGluR5 plays a critical role in the BDNF effect. In contrast, paired pulse ratio and EPSC measurements indicated that proBDNF, via presynaptic p75NTR, is a negative regulator of glutamate release in the EC. CONCLUSIONS: Taken together, our findings demonstrate that the BDNF/TrkB pathway facilitates persistent activity whereas the proBDNF/p75NTR pathway inhibits this mnemonic property of entorhinal pyramidal neurons. PMID- 26932789 TI - Comparing the coverage, recall, and precision of searches for 120 systematic reviews in Embase, MEDLINE, and Google Scholar: a prospective study. AB - BACKGROUND: Previously, we reported on the low recall of Google Scholar (GS) for systematic review (SR) searching. Here, we test our conclusions further in a prospective study by comparing the coverage, recall, and precision of SR search strategies previously performed in Embase, MEDLINE, and GS. METHODS: The original search results from Embase and MEDLINE and the first 1000 results of GS for librarian-mediated SR searches were recorded. Once the inclusion-exclusion process for the resulting SR was complete, search results from all three databases were screened for the SR's included references. All three databases were then searched post hoc for included references not found in the original search results. RESULTS: We checked 4795 included references from 120 SRs against the original search results. Coverage of GS was high (97.2 %) but marginally lower than Embase and MEDLINE combined (97.5 %). MEDLINE on its own achieved 92.3 % coverage. Total recall of Embase/MEDLINE combined was 81.6 % for all included references, compared to GS at 72.8 % and MEDLINE alone at 72.6 %. However, only 46.4 % of the included references were among the downloadable first 1000 references in GS. When examining data for each SR, the traditional databases' recall was better than GS, even when taking into account included references listed beyond the first 1000 search results. Finally, precision of the first 1000 references of GS is comparable to searches in Embase and MEDLINE combined. CONCLUSIONS: Although overall coverage and recall of GS are high for many searches, the database does not achieve full coverage as some researchers found in previous research. Further, being able to view only the first 1000 records in GS severely reduces its recall percentages. If GS would enable the browsing of records beyond the first 1000, its recall would increase but not sufficiently to be used alone in SR searching. Time needed to screen results would also increase considerably. These results support our assertion that neither GS nor one of the other databases investigated, is on its own, an acceptable database to support systematic review searching. PMID- 26932790 TI - Conduction Threshold in Accumulation-Mode InGaZnO Thin Film Transistors. AB - The onset of inversion in the metal-oxide-semiconductor field-effect transistor (MOSFET) takes place when the surface potential is approximately twice the bulk potential. In contrast, the conduction threshold in accumulation mode transistors, such as the oxide thin film transistor (TFT), has remained ambiguous in view of the complex density of states distribution in the mobility gap. This paper quantitatively describes the conduction threshold of accumulation-mode InGaZnO TFTs as the transition of the Fermi level from deep to tail states, which can be defined as the juxtaposition of linear and exponential dependencies of the accumulated carrier density on energy. Indeed, this permits direct extraction and visualization of the threshold voltage in terms of the second derivative of the drain current with respect to gate voltage. PMID- 26932791 TI - Ischemic postconditioning confers cardioprotection and prevents reduction of Trx 1 in young mice, but not in middle-aged and old mice. AB - Thioredoxin-1 (Trx-1) is part of an antioxidant system that maintains the cell redox homeostasis but their role on ischemic postconditioning (PostC) is unknown. The aim of this work was to determine whether Trx-1 participates in the cardioprotective mechanism of PostC in young, middle-aged, and old mice. Male FVB young (Y: 3 month-old), middle-aged (MA: 12 month-old), and old (O: 20 month-old) mice were used. Langendorff-perfused hearts were subjected to 30 min of ischemia and 120 min of reperfusion (I/R group). After ischemia, we performed 6 cycles of R/I (10 s each) followed by 120 min of reperfusion (PostC group). We measured the infarct size (triphenyltetrazolium); Trx-1, total and phosphorylated Akt, and GSK3beta expression (Western blot); and the GSH/GSSG ratio (HPLC). PostC reduced the infarct size in young mice (I/R-Y: 52.3 +/- 2.4 vs. PostC-Y: 40.0 +/- 1.9, p < 0.05), but this protection was abolished in the middle-aged and old mice groups. Trx-1 expression decreased after I/R, and the PostC prevented the protein degradation in young animals (I/R-Y: 1.05 +/- 0.1 vs. PostC-Y: 0.52 +/- .0.07, p < 0.05). These changes were accompanied by an improvement in the GSH/GSSG ratio (I/R-Y: 1.25 +/- 0.30 vs. PostC-Y: 7.10 +/- 2.10, p < 0.05). However, no changes were observed in the middle-aged and old groups. Cytosolic Akt and GSK3beta phosphorylation increased in the PostC compared with the I/R group only in young animals. Our results suggest that PostC prevents Trx-1 degradation, decreasing oxidative stress and allowing the activation of Akt and GSK3beta to exert its cardioprotective effect. This protection mechanism is not activated in middle aged and old animals. PMID- 26932792 TI - Identification of unusual Chlamydia pecorum genotypes in Victorian koalas (Phascolarctos cinereus) and clinical variables associated with infection. AB - Chlamydia pecorum infection is a threat to the health of free-ranging koalas (Phascolarctos cinereus) in Australia. Utilizing an extensive sample archive we determined the prevalence of C. pecorum in koalas within six regions of Victoria, Australia. The ompA genotypes of the detected C. pecorum were characterized to better understand the epidemiology of this pathogen in Victorian koalas. Despite many studies in northern Australia (i.e. Queensland and New South Wales), prior Chlamydia studies in Victorian koalas are limited. We detected C. pecorum in 125/820 (15 %) urogenital swabs, but in only one ocular swab. Nucleotide sequencing of the molecular marker C. pecorum ompA revealed that the majority (90/114) of C. pecorum samples typed were genotype B. This genotype has not been reported in northern koalas. In general, Chlamydia infection in Victorian koalas is associated with milder clinical signs compared with infection in koalas in northern populations. Although disease pathogenesis is likely to be multifactorial, the high prevalence of genotype B in Victoria may suggest it is less pathogenic. All but three koalas had C. pecorum genotypes unique to southern koala populations (i.e. Victoria and South Australia). These included a novel C. pecorum ompA genotype and two genotypes associated with livestock. Regression analysis determined that significant factors for the presence of C. pecorum infection were sex and geographical location. The presence of 'wet bottom' in males and the presence of reproductive tract pathology in females were significantly associated with C. pecorum infection, suggesting variation in clinical disease manifestations between sexes. PMID- 26932793 TI - Hydrochemical characteristics and quality assessment of deep groundwater from the coal-bearing aquifer of the Linhuan coal-mining district, Northern Anhui Province, China. AB - There is little information available about the hydrochemical characteristics of deep groundwater in the Linhuan coal-mining district, Northern Anhui Province, China. In this study, we report information about the physicochemical parameters, major ions, and heavy metals of 17 groundwater samples that were collected from the coal-bearing aquifer. The results show that the concentrations of total dissolved solids, electrical conductivity, and potassium and sodium (K(+) + Na(+)) in most of the groundwater samples exceeded the guidelines of the World Health Organization (WHO) and the Chinese National Standards for Drinking Water Quality (GB 5749-2006). The groundwater from the coal-bearing aquifer was dominated by the HCO3.Cl-K + Na and HCO3.SO4-K + Na types. Analysis with a Gibbs plot suggested that the major ion chemistry of the groundwater was primarily controlled by weathering of rocks and that the coal-bearing aquifer in the Linhuan coal-mining district was a relatively closed system. K(+) and Na(+) originated from halite and silicate weathering reactions, while Ca(2+) and Mg(2+) originated from the dissolution of calcite, dolomite, and gypsum or anhydrite. Ion exchange reactions also had an influence on the formation of major ions in groundwater. The concentrations of selected heavy metals decreased in the order Mn > Zn > Cr > Cu > Ni > Pb. In general, the heavy metal concentrations were low; however, the Cr, Mn, and Ni concentrations in some of the groundwater samples exceeded the standards outlined by the WHO, the GB 5749-2006, and the Chinese National Standards for Groundwater (GB/T 14848-93). Analysis by various indices (% Na, SAR, and EC), a USSL diagram, and a Wilcox diagram showed that both the salinity and alkalinity of the groundwater were high, such that the groundwater could not be used for irrigating agricultural land without treatment. These results will be significant for water resource exploiting and utilization in coal mine area. PMID- 26932796 TI - Quantification provides a conceptual basis for convergent evolution. AB - While much of evolutionary biology attempts to explain the processes of diversification, there is an important place for the study of phenotypic similarity across life forms. When similar phenotypes evolve independently in different lineages this is referred to as convergent evolution. Although long recognised, evolutionary convergence is receiving a resurgence of interest. This is in part because new genomic data sets allow detailed and tractable analysis of the genetic underpinnings of convergent phenotypes, and in part because of renewed recognition that convergence may reflect limitations in the diversification of life. In this review we propose that although convergent evolution itself does not require a new evolutionary framework, none the less there is room to generate a more systematic approach which will enable evaluation of the importance of convergent phenotypes in limiting the diversity of life's forms. We therefore propose that quantification of the frequency and strength of convergence, rather than simply identifying cases of convergence, should be considered central to its systematic comprehension. We provide a non-technical review of existing methods that could be used to measure evolutionary convergence, bringing together a wide range of methods. We then argue that quantification also requires clear specification of the level at which the phenotype is being considered, and argue that the most constrained examples of convergence show similarity both in function and in several layers of underlying form. Finally, we argue that the most important and impressive examples of convergence are those that pertain, in form and function, across a wide diversity of selective contexts as these persist in the likely presence of different selection pressures within the environment. PMID- 26932794 TI - Entomological aspects and the role of human behaviour in malaria transmission in a highland region of the Republic of Yemen. AB - BACKGROUND: The Republic of Yemen has the highest incidence of malaria in the Arabian Peninsula, yet little is known of its vectors or transmission dynamics. METHODS: A 24-month study of the vectors and related epidemiological aspects of malaria transmission was conducted in two villages in the Taiz region in 2004 2005. RESULTS: Cross-sectional blood film surveys recorded an overall malaria infection rate of 15.3 % (250/1638), with highest rates exceeding 30 % in one village in May and December 2005. With one exception, Plasmodium malariae, all infections were P. falciparum. Seven Anopheles species were identified among 3407 anophelines collected indoors using light traps (LT) and pyrethrum knockdown catches (PKD): Anopheles arabiensis (86.9 %), An. sergentii (9 %), An. azaniae, An. dthali, An. pretoriensis, An. coustani and An. algeriensis. Sequences for the standard barcode region of the mitochondrial COI gene confirmed the presence of two morphological forms of An. azaniae, the typical form and a previously unrecognized form not immediately identifiable as An. azaniae. ELISA detected Plasmodium sporozoites in 0.9 % of 2921 An. arabiensis (23 P. falciparum, two P. vivax) confirming this species as the primary malaria vector in Yemen. Plasmodium falciparum sporozoites were detected in An. sergentii (2/295) and a single female of An. algeriensis, incriminating both species as malaria vectors for the first time in Yemen. A vector in both wet and dry seasons, An. arabiensis was predominantly anthropophilic (human blood index = 0.86) with an entomological inoculation rate of 1.58 infective bites/person/year. Anopheles sergentii fed on cattle (67.3 %) and humans (48.3; 20.7 % mixed both species), but only 14.7 % were found in PKDs, indicating predominantly exophilic behaviour. A GIS analysis of geographic and socio-economic parameters revealed that An. arabiensis were significantly higher (P < 0.001) in houses with televisions, most likely due to the popular evening habit of viewing television collectively in houses with open doors and windows. CONCLUSIONS: The predominantly indoor human biting vectors recorded in this study could be targeted effectively with LLINs, indoor residual spraying and/or insecticide-treated window/door curtains reinforced by education to instil a perception that effective and affordable malaria prevention is achievable. PMID- 26932795 TI - No predictive effect of body mass index on clinical response in patients with rheumatoid arthritis after 24 weeks of biological disease-modifying antirheumatic drugs: a single-center study. AB - The aim of this study was to determine whether body mass index (BMI) is associated with clinical response to biologics in patients with rheumatoid arthritis (RA). We enrolled 68 patients with RA who were treated with biological disease-modifying antirheumatic drugs (bDMARDs). Biologics included abatacept, tocilizumab, and tumor necrosis factor-alpha (TNF-alpha) blockers (etanercept and adalimumab). Baseline BMI (kg/m(2)) was classified as normal (BMI < 23.0), overweight (23.0 <= BMI < 25.0), or obese (BMI >= 25.0). Improvement of disease activity score 28 (DAS28) and achievement of the European League Against Rheumatism (EULAR) remission and responses between baseline and 24 weeks were our measures of clinical improvement. Mean baseline BMI before treatment with bDMARDs in patients with RA was 22.2 (SD 3.6). DAS28-ESR and DAS28-CRP were significantly reduced from baseline after 24 weeks of treatment with bDMARDs (p < 0.001 of both). ?DAS28-ESR and ?DAS28-CRP were not found among patients with normal, overweight, or obese BMI (p = 0.133 and p = 0.255, respectively) nor were EULAR responses or EULAR remission (p = 0.540 and p = 0.957, respectively). Logistic regression analysis showed no relationship of BMI with EULAR clinical responses (p = 0.093 for good response and p = 0.878 for EULAR remission). This study reveals that BMI is not a predictive factor of clinical response to bDMARDs in patients with RA. PMID- 26932797 TI - The impact of Helicobacter pylori eradication on serum hepcidin-25 level and iron parameters in patients with iron deficiency anemia. AB - BACKGROUND AND AIM: The aim of this study was to evaluate the efficacy of bismuth based quadruple regiment as a first-line treatment for Helicobacter pylori (H. pylori) eradication in patients with unexplained iron deficiency anemia (IDA). The serum hepcidin-25, iron, ferritin levels and total iron-binding capacity were evaluated at baseline and after H. pylori eradication in order to assess whether H. pylori eradication plays a role in IDA related to H. pylori infection. METHODS: The study included 80 patients with unexplained IDA and H. pylori infection. All patients received pantoprazole (40 mg b.i.d.), bismuth subcitrate (120 mg q.i.d.), tetracycline (500 mg q.i.d.) and metronidazole (500 mg t.i.d.) over 14 days as H. pylori eradication regimen. In all patients, blood samples were drawn at baseline and 1 month after eradication therapy. In all patients, serum hepcidin-25 levels were determined by using commercially available enzyme linked immunosorbent assay kits. RESULTS: There was an improvement in hemoglobin, iron, total iron-binding capacity and ferritin values after H. pylori eradication in all subjects. Serum hepcidin-25 levels significantly decreased after H. pylori eradication (p < 0.001). CONCLUSION: Gastric H. pylori infection is a common cause of IDA of unknown origin in adult patients. Our results provide evidence indicating that hepcidin level decreases after successful H. pylori eradication with improvement in IDA. PMID- 26932798 TI - Use of mental techniques for competition and recovery in professional athletes. AB - BACKGROUND: The present study aims to describe knowledge about and usage of mental techniques to prepare before competitions and after sport-associated injuries (SAIs) by professional athletes (team sports) in Austria. METHODS: In this cross-sectional study, 191 professional athletes (basketball, football, hockey, ice hockey, and volleyball teams, m:f = 142:49, 24 +/- 5, 18-39 years) filled in a questionnaire assessing socio-demographic data, duration/frequency of sport practice, rate and severity of SAIs. Furthermore, the use of mental techniques and of spiritual practices before competitions and for recovery after SAI was assessed. The use of mental techniques before competitions and after SAI was correlated with socio-demographic data, duration and frequency of sport practice, and injury patterns of SAIs of the last 24 months. RESULTS: Approximately, 96 % reported knowledge about at least one mental technique. Only 13 participants used them for regeneration after SAI. Approximately, 31 % of males and 13 % of females reported the use before competitions (p = 0.017). 54 % of participants using spiritual practices used mental techniques before competitions, whereas only 13 % of participants not using spiritual practices used them (p < 0.001). 67 % of participants not using mental techniques before competitions and 88 % using them believed in the effectiveness of mental techniques in the regeneration after a SAI (p = 0.03). A significant increase of the probability of using mental techniques before competition with increasing age was found [Odds ratio (OR) = 1.101, confidence interval (CI) = (1.03, 1.18), p = 0.006]. CONCLUSION: Mental techniques seem to be well-accepted but rarely used among professional athletes. Further studies are needed to give new information about this relevant topic in professional sports. PMID- 26932799 TI - Three dimensional left atrial volume index is correlated with P wave dispersion in elderly patients with sinus rhythm. AB - BACKGROUND: P wave dispersion is a noninvasive electrocardiographic predictor for atrial fibrillation. The aim of the study was to explore relation between left atrial volume index assessed by 3-dimensional echocardiography and P wave dispersion in elderly patients. METHODS: Seventy-three consecutive patients over the age of 65 (mean age: 75 +/- 7 years, 17 men) were included. P wave dispersion is calculated as the difference between maximum and minimum P wave durations. Left atrial volume index was measured by both 2-dimensional and 3-dimensional echocardiography and categorized as normal (<= 34 mL/m(2)) or increased (mild, 35 41 mL/m(2); moderate, 42-48 mL/m(2); severe, >= 49 mL/m(2)). RESULTS: Thirty-one patients had normal left atrium while 24 patients had mildly enlarged, nine had moderately enlarged, and nine had severely enlarged left atrium. Prolongation of P wave dispersion was more prevalent in patients with dilated left atrium. P wave dispersion was significantly correlated with both 2-dimensional (r = 0.600, p < 0.001) and 3-dimensional left atrial volume index (r = 0.688, p < 0.001). Both left atrial volume indexes were associated with prolonged P wave dispersion when adjusted for age, sex, presence of hypertension, and left ventricular mass index. Receiver-operator characteristic (ROC) analysis revealed that a 3-dimensional left atrial volume index >= 25 mL/m(2) separated patients with prolonged P wave dispersion with a sensitivity of 82.2 %, specificity of 67.9 %, positive predictive value of 80.4 %, and negative predictive value of 70.4 %. CONCLUSION: In elderly patients, 3-dimensional left atrial volume index showed a better correlation with P wave dispersion and might be helpful in discriminating patients with prolonged P wave dispersion, who might be prone to atrial fibrillation. PMID- 26932800 TI - A novel approach to the management of carotid blowout syndrome: the use of thrombin in a case of failed covered stenting. AB - Acute hemorrhage relating to an expanding pseudoaneurysm of the carotid artery is referred to as carotid blowout syndrome (CBS). CBS is associated with a high morbidity and mortality. We describe the case of a patient who presented with dysphagia and a pulsatile mass in the neck. Imaging revealed a pseudoaneurysm originating from the bifurcation of the distal right common carotid artery. On neuroangiography the patient lacked sufficient collaterals to allow for vessel sacrifice. A decision was made to use covered stents to prevent flow into the pseudoaneurysm while maintaining vessel patency. Despite placement of multiple covered stents there was residual slow filling of the pseudoaneurysm. We augmented this therapy with direct percutaneous thrombin injection into the pseudoaneurysm. This resulted in complete thrombosis of the pseudoaneurysm. For recalcitrant lesions in which the usual methods of stopping blood flow to the pseudoaneurysmal sac fail, an adjuvant approach with thrombin should be considered. PMID- 26932801 TI - Implications of limiting mechanical thrombectomy to patients with emergent large vessel occlusion meeting top tier evidence criteria. AB - BACKGROUND: Recent guidelines for endovascular management of emergent large vessel occlusion (ELVO) award top tier evidence to the same selective criteria in recent trials. We aimed to understand how guideline adherence would have impacted treatment numbers and outcomes in a cohort of patients from a comprehensive stroke center. METHODS: A retrospective observational study was conducted using consecutive emergent endovascular patients. Mechanical thrombectomy (MT) was performed with stent retrievers or large bore clot aspiration catheters. Procedural outcomes were compared between patients meeting, and those failing to meet, top tier evidence criteria. RESULTS: 126 patients receiving MT from January 2012 to June 2015 were included (age 31-89 years, National Institutes of Health Stroke Scale (NIHSS) score 2-38); 62 (49%) patients would have been excluded if top tier criteria were upheld: pretreatment NIHSS score <6 (10%), Alberta Stroke Program Early CT score <6 (6.5%), premorbid modified Rankin Scale (mRS) score >=2 (27%), M2 occlusion (10%), posterior circulation (32%), symptom to groin puncture >360 min (58%). 26 (42%) subjects had more than one top tier exclusion. Symptomatic intracerebral hemorrhage (sICH) and systemic hemorrhage rates were similar between the groups. 3 month mortality was 45% in those lacking top tier evidence compared with 26% (p=0.044), and 3 month mRS score 0-2 was 33% versus 46%, respectively (NS). After adjusting for potential confounders, top tier treatment was not associated with neurological improvement during hospitalization (beta -8.2; 95% CI -24.6 to -8.2; p=0.321), 3 month mortality (OR=0.38; 95% CI 0.08 to 1.41), or 3 month favorable mRS (OR=0.97; 95% CI 0.28 to 3.35). CONCLUSIONS: Our study showed that with strict adherence to top tier evidence criteria, half of patients may not be considered for MT. Our data indicate no increased risk of sICH and a potentially higher mortality that is largely due to treatment of patients with basilar occlusions and those treated at an extended time window. Despite this, good functional recovery is possible, and consideration of MT in patients not meeting top tier evidence criteria may be warranted. PMID- 26932802 TI - Randomized multicenter phase 2 study of pomalidomide, cyclophosphamide, and dexamethasone in relapsed refractory myeloma. AB - Pomalidomide and low-dose dexamethasone (PomDex) is standard treatment of lenalidomide refractory myeloma patients who have received >2 prior therapies. We aimed to assess the safety and efficacy of the addition of oral weekly cyclophosphamide to standard PomDex. We first performed a dose escalation phase 1 study to determine the recommended phase 2 dose of cyclophosphamide in combination with PomDex (arm A). A randomized, multicenter phase 2 study followed, enrolling patients with lenalidomide refractory myeloma. Patients were randomized (1:1) to receive pomalidomide 4 mg on days 1 to 21 of a 28-day cycle in combination with weekly dexamethasone (arm B) or pomalidomide, dexamethasone, and cyclophosphamide (PomCyDex) 400 mg orally on days 1, 8, and 15 (arm C). The primary end point was overall response rate (ORR). Eighty patients were enrolled (10 in phase 1 and 70 randomized in phase 2: 36 to arm B and 34 to arm C). The ORR was 38.9% (95% confidence interval [CI], 23-54.8%) and 64.7% (95% CI, 48.6 80.8%) for arms B and C, respectively (P = .035). As of June 2015, 62 of the 70 randomized patients had progressed. The median progression-free survival (PFS) was 4.4 (95% CI, 2.3-5.7) and 9.5 months (95% CI, 4.6-14) for arms B and C, respectively (P = .106). Toxicity was predominantly hematologic in nature but was not statistically higher in arm C. The combination of PomCyDex results in a superior ORR and PFS compared with PomDex in patients with lenalidomide refractory multiple myeloma. The trial was registered at www.clinicaltrials.gov as #NCT01432600. PMID- 26932803 TI - p21-activated kinase 2 regulates HSPC cytoskeleton, migration, and homing via CDC42 activation and interaction with beta-Pix. AB - Cytoskeletal remodeling of hematopoietic stem and progenitor cells (HSPCs) is essential for homing to the bone marrow (BM). The Ras-related C3 botulinum toxin substrate (Rac)/cell division control protein 42 homolog (CDC42) effector p21 activated kinase (Pak2) has been implicated in HSPC homing and engraftment. However, the molecular pathways mediating Pak2 functions in HSPCs are unknown. Here, we demonstrate that both Pak2 kinase activity and its interaction with the PAK-interacting exchange factor-beta (beta-Pix) are required to reconstitute defective ITALIC! Pak2 (ITALIC! Delta/Delta)HSPC homing to the BM. Pak2 serine/threonine kinase activity is required for stromal-derived factor-1 (SDF1alpha) chemokine-induced HSPC directional migration, whereas Pak2 interaction with beta-Pix is required to regulate the velocity of HSPC migration and precise F-actin assembly. Lack of SDF1alpha-induced filopodia and associated abnormal cell protrusions seen in ITALIC! Pak2 (ITALIC! Delta/Delta)HSPCs were rescued by wild-type (WT) Pak2 but not by a Pak2-kinase dead mutant (KD). Expression of a beta-Pix interaction-defective mutant of Pak2 rescued filopodia formation but led to abnormal F-actin bundles. Although CDC42 has previously been considered an upstream regulator of Pak2, we found a paradoxical decrease in baseline activation of CDC42 in ITALIC! Pak2 (ITALIC! Delta/Delta)HSPCs, which was rescued by expression of Pak2-WT but not by Pak2-KD; defective homing of ITALIC! Pak2-deleted HSPCs was rescued by constitutive active CDC42. These data demonstrate that both Pak2 kinase activity and its interaction with beta-Pix are essential for HSPC filopodia formation, cytoskeletal integrity, and homing via activation of CDC42. Taken together, we provide mechanistic insights into the role of Pak2 in HSPC migration and homing. PMID- 26932805 TI - THE ESTABLISHMENT OF LOCAL DIAGNOSTIC REFERENCE LEVELS IN ENDOSCOPIC RETROGRADE CHOLANGIOPANCREATOGRAPHY: A PRACTICAL TOOL FOR THE OPTIMISATION AND FOR QUALITY ASSURANCE MANAGEMENT. AB - Fluoroscopic procedures are an area of special concern in relation to radiation protection. The aim of this study was to describe the current level of patient radiation doses in endoscopic retrograde cholangiopancreatography (ERCP) collected from a single centre, as well as to establish and review local diagnostic reference levels (DRLs) in ERCP. A total of 100 patients' radiation doses in ERCP were recorded, and the third-quartile method was adopted to establish local DRLs for ERCP. The mean dose area product (DAP) was 2.05 Gy cm2, fluoroscopy time (FT) 1.7 min and the number of images was 3. The proposed local DRLs for ERCP were 3.00 Gy cm2 and 3.0 min. Local DRLs were reviewed in a sample of 25 patients 5 y after they had been established. In reviewing data, the averages of DAP and FT were below the local DRLs. Local DRLs help in the optimisation process of fluoroscopic procedures and guides to a good clinical practice. PMID- 26932806 TI - Handedness, sexual orientation, and somatic markers for prenatal androgens: Are southpaws really that gay? AB - BACKGROUND: Some evidence suggests that prenatal androgens influence both handedness and sexual orientation. This study sought to clarify how androgens, handedness, and sexual orientation are interrelated. METHODS: Data were obtained from large samples of students enrolled at universities in Malaysia and the US, including self-reported information on handedness, sexual orientation, and five somatic markers of prenatal androgen exposure (2D:4D, height, strength, muscularity, and athletic ability). Factor analysis of these somatic markers yielded two factors: a muscular coordination and a bone growth factor. RESULTS: In women, but not in men, ambidextrousness was more prevalent among those with homosexual tendencies. Modest and often complex associations were found between the androgen factors and handedness. Clear links between the androgen factors and sexual orientation were found, especially for muscular coordination. For males and females, intermediate sex-typical androgen exposure was associated with heterosexual preferences. CONCLUSIONS: Ambidextrousness appears to be somewhat more common among females with homosexual tendencies, but left-handedness is nearly as strongly associated with heterosexual preferences, particularly in males, as is right-handedness. Factors indicative of prenatal androgen exposure are associated with sexual orientation in theoretically predictable ways, especially for muscular coordination, but associations between prenatal androgens and handedness are complex. PMID- 26932804 TI - Role of platelets, neutrophils, and factor XII in spontaneous venous thrombosis in mice. AB - Recently, platelets, neutrophils, and factor XII (FXII) have been implicated as important players in the pathophysiology of venous thrombosis. Their role became evident in mouse models in which surgical handling was used to provoke thrombosis. Inhibiting anticoagulation in mice by using small interfering RNA (siRNA) targeting Serpinc1 and Proc also results in a thrombotic phenotype, which is spontaneous (no additional triggers) and reproducibly results in clots in the large veins of the head and fibrin deposition in the liver. This thrombotic phenotype is fatal but can be fully rescued by thrombin inhibition. The mouse model was used in this study to investigate the role of platelets, neutrophils, and FXII. After administration of siRNAs targeting Serpinc1 and Proc, antibody mediated depletion of platelets fully abrogated the clinical features as well as microscopic aspects in the head. This was corroborated by strongly reduced fibrin deposition in the liver. Whereas neutrophils were abundant in siRNA-triggered thrombotic lesions, antibody-mediated depletion of circulating Ly6G-positive neutrophils did not affect onset, severity, or thrombus morphology. In addition, absence of circulating neutrophils did not affect quantitative liver fibrin deposition. Remarkably, siRNA-mediated depletion of plasma FXII accelerated the onset of the clinical phenotype; mice were affected with more severe thrombotic lesions. To summarize, in this study, onset and severity of the thrombotic phenotype are dependent on the presence of platelets but not circulating neutrophils. Unexpectedly, FXII has a protective effect. This study challenges the proposed roles of neutrophils and FXII in venous thrombosis pathophysiology. PMID- 26932808 TI - Restricted mobility of specific functional groups reduces anti-cancer drug activity in healthy cells. AB - The most common cancer treatments currently available are radio- and chemo therapy. These therapies have, however, drawbacks, such as, the reduction in quality of life and the low efficiency of radiotherapy in cases of multiple metastases. To lessen these effects, we have encapsulated an anti-cancer drug into a biocompatible matrix. In-vitro assays indicate that this bio-nanocomposite is able to interact and cause morphological changes in cancer cells. Meanwhile, no alterations were observed in monocytes and fibroblasts, indicating that this system might carry the drug in living organisms with reduced clearance rate and toxicity. X-rays and neutrons were used to investigate the carrier structure, as well as to assess the drug mobility within the bio-nanocomposite. From these unique data we show that partial mobility restriction of active groups of the drug molecule suggests why this carrier design is potentially safer to healthy cells. PMID- 26932811 TI - Stomach Intestinal Pylorus Sparing (SIPS) Surgery for Morbid Obesity: Retrospective Analyses of Our Preliminary Experience. AB - BACKGROUND: Although the duodenal switch (DS) has been the most effective weight loss surgical procedure, it is a small minority of the total bariatric surgical cases performed. Modifications that can make the operation technically simpler and reduce a long-term risk of short bowel syndrome would be of benefit. The aim of this study was to detail our initial experience with a modified DS called stomach intestinal pylorus sparing (SIPS) procedure. METHODS: Data from patients who underwent a primary SIPS procedure performed by two surgeons at two centers from January 2013 to August 2014 were retrospectively analyzed. All revisions of prior bariatric procedures were excluded. Regression analyses were performed for all follow-up weight loss data. RESULTS: One hundred twenty-three patients were available. One hundred two patients were beyond 1 year postoperative, with data available for 64 (62 % followed up). The mean body mass index (BMI) was 49.4 kg/m(2). Two patients had diarrhea (1.6 %), four had abdominal hematoma (3.2 %), and one had a stricture (0.8 %) in the gastric sleeve. Two patients (1.6 %) were readmitted within 30 days. One patient (0.8 %) was reoperated due to an early postoperative ulcer. At 1 year, patients had an average change in BMI of 19 units (kg/m(2)), which was compared to an average of 38 % of total weight loss or 72 % of excess weight loss. CONCLUSIONS: Modification of the classic DS to one with a single anastomosis and a longer common channel had effective weight loss results. Morbidity seems comparable to other stapling reconstructive procedures. Future analyses are needed to determine whether a SIPS procedure reduces the risk of future small bowel obstructions and micronutrient deficiencies. PMID- 26932809 TI - Factors Associated with Depression in COPD: A Multicenter Study. AB - INTRODUCTION: Depression is a prevalent comorbidity in COPD and has an impact on the prognosis of these patients, thereby making it important to study the factors associated with depression in patients with COPD. METHOD: A multicenter, observational and cross-sectional study was conducted to study the factors associated with depression in patients with COPD measured by the hospital anxiety and depression (HAD) questionnaire. We analyzed anthropometric variables and the number of exacerbations in the previous year and calculated the 6-min walking test and the body mass index, airflow obstruction, dyspnea, and exercise (BODE) index. All the patients completed the quality of life EQ-5D and the LCADL physical activity questionnaires. The relationship of these variables with depression was evaluated with two multiple logistic regression models. RESULTS: One hundred fifteen patients were evaluated (93 % male) with a mean age of 66.9 years (SD 8.8) and a mean FEV1 % of 44.4 % (SD 15.7 %). 24.3 % presented symptoms of depression (HAD-D > 8). These latter patients had worse lung function, greater dyspnea, reduced exercise capacity, a higher score in the BODE index, poorer quality of life, reduced physical activity, and more exacerbations. In the first logistic regression model, quality of life and the BODE index were associated with depression (AUC: 0.84; 0.74-0.94). In the second model including the variables in the BODE index, quality of life and dyspnea measured with the MRC scale (AUC: 0.87; 0.79-0.95) were associated with depression. CONCLUSIONS: Nearly one-quarter of the patients with COPD in this study presented clinically significant depression associated with worse quality of life, reduced exercise capacity, greater dyspnea, and a higher score in the BODE index. PMID- 26932812 TI - Erratum to: Preoperative Predictive Factors of Successful Weight Loss and Glycaemic Control 1 Year After Gastric Bypass for Morbid Obesity. PMID- 26932810 TI - Pre-transplant Panel Reactive Antibody and Survival in Adult Cystic Fibrosis Patients After Lung Transplantation. AB - BACKGROUND: Survival implications of pre-transplant antibodies to human leukocyte antigens prior to lung transplantation (LTx) in adult cystic fibrosis (CF) patients are unknown. METHODS: Data from the United Network for Organ Sharing Registry (1987-2013) were used to compare survival differences in adult CF patients with pre-transplant class I and II panel reactive antibody (PRA) levels <=10 versus >10 %. RESULTS: Of 3149 CF LTx recipients, 1526 and 1399 were included in univariate survival analyses of class I and II PRA, respectively, while 1106 and 1001 were included in multivariate Cox analyses for class I and class II, respectively. Kaplan-Meier survival functions failed to demonstrate significant differences in survival with PRA >10 % for class I (Log-rank test: chi (2) (df = 1): 1.11, p = 0.293) or class II (Log-rank test: chi (2) (df = 1): 0.99, p = 0.320). Adjusting for covariates, multivariate Cox models demonstrated that class II PRA >10 % was associated with a significant increase in mortality hazard (HR 1.918; 95 % CI 1.128, 3.261; p = 0.016), whereas class I PRA >10 % was uncorrelated with this outcome. CONCLUSIONS: Pre-transplant PRA class II >10 % in adult CF patients is associated with elevated mortality hazard after LTx. PMID- 26932813 TI - Preoperative Prediction of Type 2 Diabetes Remission After Gastric Bypass Surgery: a Comparison of DiaRem Scores and ABCD Scores. AB - BACKGROUND: Gastric bypass surgery has been well accepted as a novel treatment modality for type 2 diabetes mellitus (T2DM) in obese patients. Some scoring systems have been proposed for the selection of T2DM patients who are eligible for gastric bypass surgery. This study compares two scoring systems with regard to remission of T2DM after gastric bypass surgery. METHODS: This retrospective cohort study included 245 patients (150 females and 95 males) who had undergone gastric bypass surgery for the treatment of T2DM with 1 year follow-up. We examined the predictive power of complete remission of two scoring systems, the DiaRem score, and the ABCD score. The DiaRem score includes the factors of age, HbA1c, medication, and insulin usage. The ABCD score includes the factors of age, BMI, C-peptide level, and duration of T2DM. The rate of remission of T2DM after gastric bypass surgery was evaluated using both scoring systems. RESULTS: At 1 year after surgery, the percent weight loss was 26.5 % and the mean BMI decreased from 35.7 to 26.2 kg/m(2). The mean HbA1c decreased from 8.8 to 6.2 %. A significant number of patients showed improvement in glycemic control, including 130 (53.1 %) patients with complete remission (HbA1c < 6.0 %), 36 (14.7 %) patients with partial remission (HbA1c < 6.5 %), and 26 (10.6 %) patients with improvement (HbA1c < 7 %). Both the DiaRem score and the ABCD score predicted the success of the gastric bypass surgery, but the ABCD score was better at differentiating patients with poorer score (27.9 vs. 9.1 %, p < 0.001). CONCLUSIONS: Gastric bypass surgery is a treatment option for obese T2DM patients. The ABCD score is better at predicting T2DM remission at 1 year after gastric bypass surgery than the DiaRem score. PMID- 26932815 TI - Schisandra sphenanthera Extract Facilitates Liver Regeneration after Partial Hepatectomy in Mice. AB - Liver regeneration after surgical liver resection is crucial for the restoration of liver mass and the recovery of liver function.Schisandra sphenanthera extract (Wuzhi tablet, WZ) is a preparation of an extract from the dried ripe fruit of Schisandra sphenanthera Rehd. et Wils, a traditional hepatoprotective herb. Previously, we found that WZ could induce liver regeneration-related genes against acetaminophen-induced liver injury. However, whether WZ can directly facilitate liver regeneration after liver resection remains unknown. We investigated whether WZ has potential in promoting liver regeneration after a partial hepatectomy (PHX) in mice. Remnant livers were collected 1, 1.5, 2, 3, 5, 7, and 10 days after PHX. Hepatocyte proliferation was assessed using the Ki-67 labeling index. Western blot analysis was performed on proteins known to be involved in liver regeneration. The results demonstrated that WZ significantly increased the liver-to-body weight ratio of mice after PHX but had no effect on that of mice after a sham operation. Additionally, the peak hepatocyte proliferation was observed at 1.5 days in PHX/WZ-treated mice but at 2 days in PHX/saline-treated mice, as evidenced by the Ki-67 positive ratio. Furthermore, WZ significantly increased the protein expression of ligand-induced phosphorylation of epidermal growth factor receptor and up-regulated cyclin D1, cyclin D-dependent kinase 4, phosphorylated retinoblastoma, and proliferating cell nuclear antigen protein expression and down-regulated the expression of cell cycle inhibitors p21 and p27 in the regenerative process after PHX. These results demonstrate that WZ significantly facilitates hepatocyte proliferation and liver regeneration after PHX. PMID- 26932814 TI - Emphysematous cholecystitis presenting as gas-forming liver abscess and pneumoperitoneum in a dialysis patient: a case report and review of the literature. AB - BACKGROUND: Emphysematous cholecystitis is a rare variant of acute cholecystitis with a high mortality rate. The combination of emphysematous cholecystitis, liver abscess and pneumoperitoneum are even rarer. Herein we present a case of emphysematous cholecystitis in a senile diabetic lady who had worsening hemodynamics while undergoing hemodialysis. CASE PRESENTATION: A 64-year-old woman with history of type 2 diabetes mellitus and end stage renal disease with regular hemodialysis presented to the emergency department with a 1-day history of sudden onset of lassitude and hypotension during hemodialysis. The result of a computed tomography (CT)-scan revealed air encircling the gallbladder, liver parenchymal and minimal pneumoperitoneal and liver abscess with no cholelithiasis. The patient had received empirical antibiotics with piperacillin tazobactam 2.25 g intravenous route every 6 h for 14 days and cholecystectomy with surgical debridement and lead an uneventful postoperative hospital course. Escherichia coli was demonstrated as well as blood culture and peritoneal fluid culture. CONCLUSION: In a senile diabetic and dialysis patient, we should take emphysematous cholecystitis into consideration once vague abdominal pain occurrs. Empirical antibiotic therapy and adequate surgical intervention should take place as soon as possible. PMID- 26932816 TI - The Consequence of Drug-Drug Interactions Influencing the Interplay between P Glycoprotein and Cytochrome P450 3a: An Ex Vivo Study with Rat Precision-Cut Intestinal Slices. AB - P-glycoprotein (P-gp) and cytochrome P450 3A (CYP3A) are differentially expressed along the intestine and work coordinately to reduce the intracellular concentration of xenobiotics and the absorption of orally taken drugs. Drug-drug interactions (DDIs) based on P-gp/CYP3A interplay are of clinical importance and require preclinical investigation. We investigated the P-gp/Cyp3a interplay and related DDIs with different P-gp inhibitors in the various regions of the rat intestine ex vivo using precision-cut intestinal slices (PCIS) with quinidine (Qi), a dual substrate of P-gp and Cyp3a, as the probe. The results showed that P gp efflux was the main factor limiting the intracellular Qi content at concentrations below 5uM, whereas both efflux and metabolism were saturated at [Qi] > 50uM. The selective P-gp inhibitors CP100356 [N-(3,4-dimethoxyphenethyl)-4 (6,7-dimethoxy-3,4-dihydroisoquinolin-2[1H]-yl)-6,7-dimethoxyquinazolin-2-amine] and PSC833 [valspodar, 6-[(2S,4R,6E)-4-methyl-2-(methylamino)-3-oxo-6-octenoic acid]-7-l-valine-cyclosporin A] enhanced the Qi accumulation in slices in line with the different P-gp expression in the intestinal regions and, as a result, also enhanced metabolism in the jejunum and ileum. Dual inhibitors of both P-gp and Cyp3a (verapamil and ketoconazole) increased the concentration of Qi in the jejunum and ileum, but less 3-hydroxy-quinidine was produced due to inhibition of Cyp3a. The results indicate that the P-gp/Cyp3a interplay depends on the concentration of the drug and on the intestinal region under study. Furthermore, due to the P-gp/Cyp3a interplay, DDIs can lead to remarkable changes in the intracellular concentration of both the parent drug and the metabolite, which varies among the intestinal regions and depends on the selectivity of the inhibitors, with potentially important implications for disposition and toxicity of drugs and their metabolites. PMID- 26932817 TI - Reply to the Comment on: "Analysis of Silicones Released from Household Items and Baby Articles by Direct Analysis in Real Time-Mass Spectrometry" by Jurgen H. Gross. J. Am. Soc. Mass Spectrom. 26, 511-521 (2015). PMID- 26932818 TI - Interventions for helping people adhere to compression treatments for venous leg ulceration. AB - BACKGROUND: Chronic venous ulcer healing is a complex clinical problem that requires intervention from skilled, costly, multidisciplinary wound-care teams. Compression therapy has been shown to help heal venous ulcers and to reduce recurrence. It is not known which interventions help people adhere to compression treatments. This review is an update of a previous Cochrane review. OBJECTIVES: To assess the benefits and harms of interventions designed to help people adhere to venous leg ulcer compression therapy, to improve healing and prevent recurrence after healing. SEARCH METHODS: In June 2015, for this first update, we searched: The Cochrane Wounds Specialised Register; The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library); Ovid MEDLINE; Ovid MEDLINE (In-Process & Other Non-Indexed Citations); Ovid EMBASE and EBSCO CINAHL. We also searched trial registries, and reference lists of relevant publications for published and ongoing trials. There were no language or publication date restrictions. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of interventions that aim to help people with venous leg ulcers adhere to compression treatments compared with usual care, or no intervention, or another active intervention. Our main outcomes were ulcer healing, ulcer recurrence, quality of life, pain, adherence to compression therapy and number of people with adverse events. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies for inclusion, extracted data, assessed the risk of bias of each included trial, and assessed overall quality of evidence for the main outcomes in 'Summary of findings' tables. MAIN RESULTS: One randomised controlled trial was added to this update making a total of three. One ongoing study was also identified.One trial (67 participants) compared a community-based Leg Club(r) that provided mechanisms for peer-support, assistance with goal setting and social interaction with home-based care. There was no clear difference in healing rates at three months (12/28 people healed in Leg Club group versus 7/28 in home based care group; risk ratio (RR) 1.71, 95% confidence interval (CI) 0.79 to 3.71); or six months (15/33 healed in Leg Club group versus 10/34 in home-based care group; RR 1.55, 95% CI 0.81 to 2.93); or in quality of life outcomes at six months (MD 0.85 points, 95% CI -0.13 to 1.83; 0 to 10 point scale). The Leg Club may lead to a small reduction in pain at six months, that may not be clinically significant (MD -12.75 points, 95% CI -24.79, -0.71; 0 to 100 point scale, 15 point reduction is usually considered the minimal clinically important difference) (low quality evidence downgraded for risk of selection bias and imprecision).Another trial (184 participants) compared a community-based, nurse led self-management programme of six months' duration promoting physical activity (walking and leg exercises) and adherence to compression therapy via counselling and behaviour modification (Lively Legs(r)) with usual care in a wound clinic. At 18 months follow-up, there were no clear differences in healing rates (51/92 healed in Lively Legs group versus 41/92 in usual care group; RR 1.24 (95% CI 0.93 to 1.67)); rates of recurrence of venous leg ulcers (32/69 with recurrence in Lively Legs group versus 38/67 in usual care group; RR 0.82 (95% CI 0.59 to 1.14)); or adherence to compression therapy (42/92 people fully adherent in Lively Legs group versus 41/92 in usual care group; RR 1.02 (95% CI 0.74 to 1.41)). The evidence from this trial was also downgraded to low quality due to risk of selection bias and imprecision.A single study compared patient education delivered via video with education delivered by text (pamphlet). However, no outcomes relevant to this review were reported.We found no studies that investigated other interventions to promote adherence to compression therapy. AUTHORS' CONCLUSIONS: It is unclear whether interventions designed to help people adhere to compression therapy improve venous ulcer healing and reduce recurrence. There is a lack of trials of interventions that promote adherence to compression therapy for venous ulcers. PMID- 26932819 TI - Deep Brain Stimulation in Animal Models of Fear, Anxiety, and Posttraumatic Stress Disorder. AB - Although medications and psychotherapy are often effective for the treatment of posttraumatic stress disorder (PTSD), 20-30% of patients do not respond to these conventional therapies. In psychiatry, DBS has been either approved or is currently under investigation for different disorders. At present, whether DBS may be used to treat PTSD remains unknown. Preclinical research may provide the scientific rationale for helping conceive and further improve such trials. Some of the animal models commonly used to date are more suitable for investigating mechanisms of anxiety and fear than the long-lasting behavior that characterized PTSD. That said, mechanisms and neurocircuits involved in paradigms such as fear conditioning and extinction share several common features with those of PTSD. In this article, we review preclinical studies in which electrical stimulation has been delivered to animal models of PTSD-like behavior. In those studies, commonly targeted regions were the basolateral amygdala, ventral striatum, hippocampus, and prefrontal cortex. Overall, stimulation delivered at high frequencies to most of these targets improved fear extinction and anxiety-like behavior. Though further research is certainly needed, promising findings from DBS studies in animals are encouraging and suggest a positive future perspective for the field. PMID- 26932820 TI - SSRI Augmentation by 5-Hydroxytryptophan Slow Release: Mouse Pharmacodynamic Proof of Concept. AB - Drugs, notably SSRIs, that elevate brain extracellular 5-HT (5-HTExt) are antidepressants. Unfortunately, most patients fail to remit. Multipronged clinical evidence suggests that elevating 5-HTExt beyond the SSRI effect enhances antidepressant efficacy, but previous such drug strategies had prohibitive limitations. In humans, adjunct treatment with the 5-HT precursor 5 hydroxytryptophan (5-HTP) elevates 5-HTExt beyond the SSRI effect. Small pilot trials suggest that adjunct 5-HTP can confer antidepressant response in treatment resistant depression (TRD). However, sustained, stable 5-HTExt elevation is required for antidepressant effect; therefore, the rapid absorption and elimination of standard 5-HTP immediate release (IR) likely curtail 5-HTP IR's antidepressant potential. Slow-release (SR) drug delivery can crucially improve efficacy and safety of rapidly absorbed and eliminated compounds. Here we tested in mice the hypothesis that SR delivery will substantially improve 5-HTP's drug properties, by minimizing adverse effects and securing sustained 5-HTExt elevation beyond the SSRI effect. We modeled 5-HTP SR with minipumps, 5-HTP IR with injections, and chronic SSRI with dietary fluoxetine. We tested adjunct 5 HTP SR in wild-type mice and in mice with low brain 5-HT owing to expression of a mutant form of the brain 5-HT synthesis enzyme, tryptophan hydroxylase 2. In both lines of mice, adjunct 5-HTP SR synergized with SSRI to elevate 5-HTExt beyond the SSRI effect. We observed no adverse effect. Adjunct 5-HTP IR could not produce this therapy-like profile, producing transient 5-HTExt spikes and marked adverse effects. Integrated with a body of clinical data, our mouse data suggest that an adjunct 5-HTP SR drug could safely and effectively elevate 5-HTExt beyond the SSRI effect and represent a novel treatment for TRD. PMID- 26932822 TI - How is adults' screen time behaviour influencing their views on screen time restrictions for children? A cross-sectional study. AB - BACKGROUND: High screen time in children and its detrimental health effects is a major public health problem. How much screen time adults think is appropriate for children remains little explored, as well as whether adults' screen time behaviour would determine their views on screen time restrictions for children. This study aimed to investigate how adults' screen time behaviour influences their views on screen time restrictions for children, including differences by gender and parental status. METHODS: In 2013, 2034 Australian adults participated in an online survey conducted by the Population Research Laboratory at Central Queensland University, Rockhampton. Adult screen time behaviour was assessed using the Workforce Sitting Questionnaire. Adults reported the maximum time children aged between 5-12 years should be allowed to spend watching TV and using a computer. Ordinal logistic regression was used to compare adult screen time behaviour with views on screen time restrictions for children. RESULTS: Most adults (68%) held the view that children should be allowed no more than 2 h of TV viewing and computer use on school days, whilst fewer adults (44%) thought this screen time limit is needed on weekend days. Women would impose higher screen time restrictions for children than men (p < 0.01). Most adults themselves spent > 2 h on watching TV and using the computer at home on work days (66%) and non work days (88%). Adults spending <= 2 h/day in leisure-related screen time were less likely to permit children > 2 h/day of screen time. These associations did not differ by adult gender and parental status. CONCLUSIONS: Most adults think it is appropriate to limit children's screen time to the recommended <= 2 h/day but few adults themselves adhere to this screen time limit. Adults with lower screen use may be more inclined to limit children's screen time. Strategies to reduce screen time in children may also need to target adult screen use. PMID- 26932823 TI - Single-molecule imaging of DNA polymerase I (Klenow fragment) activity by atomic force microscopy. AB - We report a DNA origami-facilitated single-molecule platform that exploits atomic force microscopy to study DNA replication. We imaged several functional activities of the Klenow fragment of E. coli DNA polymerase I (KF) including binding, moving, and dissociation from the template DNA. Upon completion of these actions, a double-stranded DNA molecule was formed. Furthermore, the direction of KF activities was captured and then confirmed by shifting the KF binding sites on the template DNA. PMID- 26932821 TI - Nur77-deficiency in bone marrow-derived macrophages modulates inflammatory responses, extracellular matrix homeostasis, phagocytosis and tolerance. AB - BACKGROUND: The nuclear orphan receptor Nur77 (NR4A1, TR3, or NGFI-B) has been shown to modulate the inflammatory response of macrophages. To further elucidate the role of Nur77 in macrophage physiology, we compared the transcriptome of bone marrow-derived macrophages (BMM) from wild-type (WT) and Nur77-knockout (KO) mice. RESULTS: In line with previous observations, SDF-1alpha (CXCL12) was among the most upregulated genes in Nur77-deficient BMM and we demonstrated that Nur77 binds directly to the SDF-1alpha promoter, resulting in inhibition of SDF-1alpha expression. The cytokine receptor CX3CR1 was strongly downregulated in Nur77-KO BMM, implying involvement of Nur77 in macrophage tolerance. Ingenuity pathway analyses (IPA) to identify canonical pathways regulation and gene set enrichment analyses (GSEA) revealed a potential role for Nur77 in extracellular matrix homeostasis. Nur77-deficiency increased the collagen content of macrophage extracellular matrix through enhanced expression of several collagen subtypes and diminished matrix metalloproteinase (MMP)-9 activity. IPA upstream regulator analyses discerned the small GTPase Rac1 as a novel regulator of Nur77-mediated gene expression. We identified an inhibitory feedback loop with increased Rac1 activity in Nur77-KO BMM, which may explain the augmented phagocytic activity of these cells. Finally, we predict multiple chronic inflammatory diseases to be influenced by macrophage Nur77 expression. GSEA and IPA associated Nur77 to osteoarthritis, chronic obstructive pulmonary disease, rheumatoid arthritis, psoriasis, and allergic airway inflammatory diseases. CONCLUSIONS: Altogether these data identify Nur77 as a modulator of macrophage function and an interesting target to treat chronic inflammatory disease. PMID- 26932824 TI - Subcellular dissemination of prothymosin alpha at normal physiology: immunohistochemical vis-a-vis western blotting perspective. AB - BACKGROUND: The cell type, cell status and specific localization of Prothymosin alpha (PTMA) within cells seemingly determine its function. PTMA undergoes 2 types of protease proteolytic modifications that are useful in elucidating its interactions with other molecules; a factor that typifies its roles. Preferably a nuclear protein, PTMA has been shown to function in the cytoplasm and extracellularly with much evidence leaning on pathognomonic status. As such, determination of its cellular distribution under normal physiological context while utilizing varied techniques is key to illuminating prospective validation of its distinct functions in different tissues. Differential distribution insights at normal physiology would also portent better basis for further clarification of its interactions and proteolytic modifications under pathological conditions like numerous cancer, ischemic stroke and immunomodulation. We therefore raised an antibody against the C terminal of PTMA to use in tandem with available antibody against the N terminal in a murine model to explicate the differences in its distribution in brain cell types and major peripheral organs through western blotting and immunohistochemical approaches. RESULTS: The newly generated antibody was applied against the N-terminal antibody to distinguish truncated versions of PTMA or deduce possible masking of the protein by other interacting molecules. Western blot analysis indicated presence of a truncated form of the protein only in the thymus, while immunohistochemical analysis showed that in brain hippocampus the full-length PTMA was stained prominently in the nucleus whereas in the stomach full-length PTMA staining was not observed in the nucleus but in the cytoplasm. CONCLUSION: Truncated PTMA could not be detected by western blotting when both antibodies were applied in all tissues examined except the thymus. However, immunohistochemistry revealed differential staining by these antibodies suggesting possible masking of epitopes by interacting molecules. The differential localization patterns observed in the context of nucleic versus cytoplasmic presence as well as punctate versus diffuse pattern in tissues and cell types, warrant further investigations as to the forms of PTMA interacting partners. PMID- 26932825 TI - MiR-590-5p Inhibits Oxidized- LDL Induced Angiogenesis by Targeting LOX-1. AB - Oxidized low-density lipoprotein (ox-LDL) is, at least in part, responsible for angiogenesis in atherosclerotic regions. This effect of ox-LDL has been shown to be mediated through a specific receptor LOX-1. Here we describe the effect of miR 590-5p on ox-LDL-mediated angiogenesis in in vitro and in vivo settings. Human umbilical vein endothelial cells (HUVECs) were transfected with miR-590-5p mimic or inhibitor followed by treatment with ox-LDL. In other experiments, Marigel plugs were inserted in the mice subcutaneous space. Both in vitro and in vivo studies showed that miR-590-5p mimic (100 nM) inhibited the ox-LDL-mediated angiogenesis (capillary tube formation, cell proliferation and migration as well as pro-angiogenic signals- ROS, MAPKs, pro-inflammatory cytokines and adhesion related proteins). Of note, miR-590-5p inhibitor (200 nM) had the opposite effects. The inhibitory effect of miR-590-5p on angiogenesis was mediated by inhibition of LOX-1 at translational level. The inhibition of LOX-1 by miR-590-5p was confirmed by luciferase assay. In conclusion, we show that MiR-590-5p inhibits angiogenesis by targeting LOX-1 and suppressing redox-sensitive signals. PMID- 26932826 TI - Interpersonal-psychological theory and parental bonding predict suicidal ideation among soldiers in Taiwan. AB - INTRODUCTION: Suicide is an important issue among military personnel, who have higher suicide rates compared with the general population. The interpersonal psychological theory of suicide (IPTS) might provide an empirical explanation of this phenomenon, and parental bonding influences social adjustment and suicide. To investigate the relevance of IPTS and parental bonding for suicide among Taiwanese soldiers, a case-control study was conducted. METHODS: Using a suicide reporting system in a teaching general hospital in Southern Taiwan, 226 at-risk maladjusted soldiers and 229 well-adjusted controls were enrolled. We collected basic information, and participants answered four IPTS-based questions. Suicide risk was assessed using the Brief Symptom Rating Scale item 6. A four-factor model of the Parental Bonding Instrument assessed parental bonding. All participants were interviewed using the Mini International Neuropsychiatric Interview for primary screening and to recheck the accuracy of the Brief Symptom Rating Scale item 6 score. RESULTS: A parsimonious model obtained by regression analysis of risk factors indicated that poor academic performance, conduct related issues in childhood, and exposure to life-threatening situations are risk factors for suicide intention. Maladjusted suicidal soldiers showed a sense of thwarted belongingness (beta = 0.145; P < 0.001), higher perceived burdensomeness (beta = 0.311; P < 0.001), less fear of death (beta = 0.124; P < 0.05), lower paternal autonomy (beta = -0.122; P < 0.05), and higher maternal indifference (beta = 0.162; P < 0.0001). DISCUSSION: Interpersonal-psychological theory of suicide, accompanied by an assessment of parental bonding, could be used for assessing suicide risk and preventing suicide attempts. PMID- 26932827 TI - Recurrent corneal erosion syndrome associated with oral isotretinoin: a cautionary tale. PMID- 26932828 TI - A quality assessment of randomized controlled trial reports in endodontics. AB - AIM: To assess the quality of the randomized clinical trial (RCT) reports published in Endodontics between 1997 and 2012. METHODOLOGY: Retrieval of RCTs in Endodontics was based on a search of the Thomson Reuters Web of Science (WoS) database (March 2013). Quality evaluation was performed using a checklist based on the Jadad criteria, CONSORT (Consolidated Standards of Reporting Trials) statement and SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials). Descriptive statistics were used for frequency distribution of data. Student's t-test and Welch test were used to identify the influence of certain trial characteristics upon report quality (alpha = 0.05). RESULTS: A total of 89 RCTs were evaluated, and several methodological flaws were found: only 45% had random sequence generation at low risk of bias, 75% did not provide information on allocation concealment, and 19% were nonblinded designs. Regarding statistics, only 55% of the RCTs performed adequate sample size estimations, only 16% presented confidence intervals, and 25% did not provide the exact P-value. Also, 2% of the articles used no statistical tests, and in 87% of the RCTs, the information provided was insufficient to determine whether the statistical methodology applied was appropriate or not. Significantly higher scores were observed for multicentre trials (P = 0.023), RCTs signed by more than 5 authors (P = 0.03), articles belonging to journals ranked above the JCR median (P = 0.03), and articles complying with the CONSORT guidelines (P = 0.000). CONCLUSIONS: The quality of RCT reports in key areas for internal validity of the study was poor. Several measures, such as compliance with the CONSORT guidelines, are important in order to raise the quality of RCTs in Endodontics. PMID- 26932829 TI - The role of family meals in the treatment of eating disorders: a scoping review of the literature and implications. AB - Family meal research is a fast growing field that has significant implications for the prevention and treatment of eating disorders (ED). Using a scoping review procedure, this article overviewed major historical and clinical trends that have guided the use of family meals or lunch sessions in adolescent ED family therapy over the past 40 years, and synthesized essential findings from current therapeutic family meal research. The relevant body of literature is reported within the framework of three models of family therapy (Maudsley model, family based treatment, multi-family therapy), with a focus on their specific use of family lunch sessions and related empirical evidence. Although promising, current evidence remains contradictory, tentative and colored by therapists' convictions, resistance and fears. Future research priorities are discussed, including the need for a more direct examination of the impact of the family meal practice on therapeutic change, as well as a better understanding of its active ingredients and of the characteristics of patients/families that may benefit most from it. This review of the literature may help clinicians and family therapists (1) adhere more reliably and confidently to ED-focused treatment protocols that include a strong family meal component, and (2) make more informed decisions regarding the inclusion or exclusion of family meals in their practice. When feasibility or acceptability issues preclude their use, alternatives to family meals are also discussed, including family meal role-plays and drawings, coaching of home-based family meals and manual/DVD-based guidance. PMID- 26932830 TI - Nasoethmoidal meningocele in a child presenting bilateral congenital cystic adenomatoid malformation: Evidence for a new entity or consequence of gestational exposures? AB - BACKGROUND: Nasoethmoidal meningocele is considered an uncommon type of cephalocele, and congenital cystic adenomatoid malformation (CCAM) is a rare lung disorder characterized by overgrowth of the terminal bronchioles. CASE: We report the unusual association between a nasoethmoidal meningocele and CCAM type II in a fetus exposed to valproic acid and misoprostol. The mother was an 18-year-old woman on her first pregnancy. She had a history of absence seizures since she was 5 years old. She took valproic acid from the beginning of the gestation until the end of the third month. At the end of the third month, she attempted interruption of her pregnancy using misoprostol. The fetal nasoethmoidal meningocele and CCAM type II were identified through morphological ultrasound examination and magnetic resonance imaging. A genome-wide study detected one copy number variation classified as rare, entirely contained into the SPATA5 gene. However, it does not seem to be associated to the clinical findings of the patient. CONCLUSION: To our knowledge, there is only one case reported in the literature showing the same association between a nasoethmoidal meningocele and CCAM. Thus, the malformations observed in our patient may be related to the gestational exposures. Also, we cannot rule out that the patient may present the same condition characterized by a cephalocele and CCAM described by some authors, or even an undescribed entity, because some hallmark features, such as laryngeal atresia and limb defects, were not observed in our case. Further reports will be very important to better understand the associations described in our study. PMID- 26932831 TI - Synthesis of novel and potent vorapaxar analogues. AB - Vorapaxar is a first-in-class PAR-1 antagonistic drug based on the ent-himbacine scaffold. Detailed in this article are enantioselective and racemic routes to various novel vorapaxar analogues. Biological testing revealed these compounds to have moderate to excellent potencies against PAR-1 with the most potent analogue demonstrating an IC50 of 27 nM. PMID- 26932832 TI - 3D Interconnected Electrode Materials with Ultrahigh Areal Sulfur Loading for Li S Batteries. AB - Sulfur electrodes based on a 3D integrated hollow carbon fiber foam (HCFF) are synthesized with high sulfur loadings of 6.2-21.2 mg cm(-2) . Benefiting from the high electrolyte absorbability of the HCFF and the multiple conductive channels, the obtained electrode demonstrates excellent cycling stability and a high areal capacity of 23.32 mAh cm(-2) , showing great promise in commercially viable Li-S batteries. PMID- 26932833 TI - Collective modes in three-dimensional magnonic vortex crystals. AB - Collective modes in three-dimensional crystals of stacked permalloy disks with magnetic vortices are investigated by ferromagnetic resonance spectroscopy and scanning transmission X-ray microscopy. The size of the arrangements is increased step by step to identify the different contributions to the interaction between the vortices. These contributions are the key requirement to understand complex dynamics of three dimensional vortex crystals. Both vertical and horizontal coupling determine the collective modes. In-plane dipoles strongly influence the interaction between the disks in the stacks and lead to polarity-dependent resonance frequencies. Weaker contributions discern arrangements with different polarities and circularities that result from the lateral coupling of the stacks and the interaction of the core regions inside a stack. All three contributions are identified in the experiments and are explained in a rigid particle model. PMID- 26932834 TI - Modeling Sustainable Food Systems. AB - The processes underlying environmental, economic, and social unsustainability derive in part from the food system. Building sustainable food systems has become a predominating endeavor aiming to redirect our food systems and policies towards better-adjusted goals and improved societal welfare. Food systems are complex social-ecological systems involving multiple interactions between human and natural components. Policy needs to encourage public perception of humanity and nature as interdependent and interacting. The systemic nature of these interdependencies and interactions calls for systems approaches and integrated assessment tools. Identifying and modeling the intrinsic properties of the food system that will ensure its essential outcomes are maintained or enhanced over time and across generations, will help organizations and governmental institutions to track progress towards sustainability, and set policies that encourage positive transformations. This paper proposes a conceptual model that articulates crucial vulnerability and resilience factors to global environmental and socio-economic changes, postulating specific food and nutrition security issues as priority outcomes of food systems. By acknowledging the systemic nature of sustainability, this approach allows consideration of causal factor dynamics. In a stepwise approach, a logical application is schematized for three Mediterranean countries, namely Spain, France, and Italy. PMID- 26932835 TI - Development of an implementation plan for the 6-PACK falls prevention programme as part of a randomised controlled trial: protocol for a series of preimplementation studies. AB - BACKGROUND: Inhospital falls cause morbidity, staff burden and increased healthcare costs. It is unclear if the persistent problem of inhospital falls is due to the use of ineffective interventions or their suboptimal implementation. The 6-PACK programme appears to reduce fall injuries and a randomised controlled trial (RCT) was undertaken to confirm effects. This paper describes the protocol for the preimplementation studies that aimed to identify moderators of the effective use of the 6-PACK programme to inform the development of an implementation plan to be applied in the RCT. METHODS: The 6-PACK project included five preimplementation studies: (1) a profile of safety climate; (2) review of current falls prevention practice; (3) epidemiology of inhospital falls; (4) acceptability of the 6-PACK programme; and (5) barriers and enablers to implementation of the 6-PACK programme. The Theoretical Domain Framework that includes 12 behaviour change domains informed the design of these studies that involved 540 staff and 8877 patients from 24 wards from six Australian hospitals. Qualitative and quantitative methods were applied with data collected via: structured bedside observation; daily nurse unit manager verbal report of falls; audit of medical records, incident reporting and hospital administrative data; surveys of ward nurses; focus groups with ward nurses; and key informant interviews with senior staff. DISCUSSION: Information on contextual, system, intervention, patient and provider level factors is critical to the development of an implementation plan. Information gained from these studies was used to develop a plan applied in the RCT that addressed the barriers and harnessed enablers. TRIAL REGISTRATION NUMBER: The RCT is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12611000332921. PMID- 26932836 TI - Efficacy of Cranial Electrotherapy Stimulation Combined with Biofeedback Therapy in Patients with Functional Constipation. AB - BACKGROUND/AIMS: A large number of studies have shown that function constipation (FC) has an extremely high incidence of mental and psychological disorders. Cranial electrotherapy stimulation (CES) was applied to the treatment of psychological disorders such as anxiety and depression. We explored the effects of CES combined with biofeedback therapy (BFT) on the psychological state, clinical symptoms, and anorectal function in patients with FC. METHODS: A total of 74 patients with FC were randomly divided into 2 groups. The control group received BFT. CES combined with BFT was carried out in the experiment group. All patients were assessed using the self-rating anxiety scale (SAS), self-rating depression scale (SDS), and Wexner constipation score at baseline and the end of each course. Anorectal manometry and balloon expulsion tests were performed before and after treatment. RESULTS: After treatment, the participants in the experiment group had significantly lower score SAS, SDS, and Wexner constipation scores than the control group (all P < 0.05). The number of successful expulsion in the experiment group was larger than the control group (P = 0.016). CONCLUSIONS: CES combined with BFT was effective in improving the psychological status of anxiety, depression, and bowel symptoms in patients with FC. PMID- 26932838 TI - A convenient method for the synthesis of alpha-carboxylate ester bromolactones via bromolactonization of alkenoic diesters. AB - We developed a simple and efficient method to construct a variety of alpha-ester bromolactones in good to excellent yields with high diastereoselectivies. The protocol uses readily prepared malonate ester derivatives as substrates, water as an additive and inexpensive N-bromosuccinimide as the halogen source; no catalyst or toxic additive is required. The resulting substituted bromolactones are the fundamental units of many useful molecules. PMID- 26932837 TI - Artificial Sweeteners: A Systematic Review and Primer for Gastroenterologists. AB - Artificial sweeteners (AS) are ubiquitous in food and beverage products, yet little is known about their effects on the gastrointestinal (GI) tract, and whether they play a role in the development of GI symptoms, especially in patients with irritable bowel syndrome. Utilizing the PubMed and Embase databases, we conducted a search for articles on individual AS and each of these terms: fermentation, absorption, and GI tract. Standard protocols for a systematic review were followed. At the end of our search, we found a total of 617 eligible papers, 26 of which were included. Overall, there is limited medical literature available on this topic. The 2 main areas on which there is data to suggest that AS affect the GI tract include motility and the gut microbiome, though human data is lacking, and most of the currently available data is derived from in vivo studies. The effect on motility is mainly indirect via increased incretin secretion, though the clinical relevance of this finding is unknown as the downstream effect on motility was not studied. The specific effects of AS on the microbiome have been conflicting and the available studies have been heterogeneous in terms of the population studied and both the AS and doses evaluated. Further research is needed to assess whether AS could be a potential cause of GI symptoms. This is especially pertinent in patients with irritable bowel syndrome, a population in whom dietary interventions are routinely utilized as a management strategy. PMID- 26932839 TI - Comments on 'Inserting the etonogestrel contraceptive implant': author's response. PMID- 26932840 TI - Mitral Valve Regurgitation with a Rotary Left Ventricular Assist Device: The Haemodynamic Effect of Inlet Cannulation Site and Speed Modulation. AB - Mitral valve regurgitation (MVR) is common in patients receiving left ventricular assist device (LVAD) support, however the haemodynamic effect of MVR is not entirely clear. This study evaluated the haemodynamic effect of MVR with LVAD support and the influence of inflow cannulation site and LVAD speed modulation. Left atrial (LAC) and ventricular (LVC) cannulation was evaluated in a mock circulation loop with no, mild, moderate and severe MVR with constant speed and speed modulation (+/-600 RPM) modes. The use of an LVAD relieved pulmonary congestion during severe MVR, by reducing left atrial pressure from 20.5 to 10.8 (LAC) and 11.5 (LVC) mmHg. However, LAC resulted in decreased left ventricular stroke work (-0.08 J), ejection fraction (-7.9%) and higher MVR volume (+12.7 mL) and pump speed (+100 RPM) compared to LVC. This suggests that LVC, in addition to reducing MVR severity, also improves ventricular washout over LAC. LVAD speed modulation in synchrony with ventricular systole reduced MVR volume and increased ejection fraction with LAC and LVC, thus demonstrating the potential benefits of this mode, despite a reduction in cardiac output. PMID- 26932841 TI - Limitations of the Driver/Passenger Model in Cancer Prevention. AB - Mutations detected in cancers are often divided into "drivers" and "passengers." We suggest that this classification is potentially misleading for purposes of early detection and prevention. Specifically, some mutations are frequent in tumors and thus appear to be drivers, but are poor predictors of cancer; other mutations are individually rare and thus appear to be passengers, but may collectively explain a large proportion of risk. The assumptions bundled into the terms "driver" and "passenger" can lead to misunderstandings of neoplastic progression, with unintended consequences including overdiagnosis, overtreatment, and failure to identify the true sources of risk. We argue that samples from healthy, benign, or neoplastic tissues are critical for evaluating the risk of future cancer posed by mutations in a given gene. Cancer Prev Res; 9(5); 335-8. (c)2016 AACR. PMID- 26932843 TI - Effect of endoscopic variceal obliteration by band ligation on portal hypertensive gastro-duodenopathy: endoscopic and pathological study. AB - INTRODUCTION AND AIM: A few studies have shown that the degree of portal hypertensive gastropathy (PHG) and duodenopathy (PHD) has been worsening after the introduction of therapeutic endoscopic interventions. This study aimed to determine the impact of esophageal variceal eradication by endoscopic variceal ligation (EVL) on PHG and PHD using endoscopic and histopathologic assessment. METHODS: Fifty patients with esophageal varices for which EVL was indicated were included. EVL was carried out until complete variceal eradication was achieved. The degree of severity of PHG and PHD were recorded before and 4 weeks after variceal eradication. Biopsies were taken from various parts of the stomach and duodenum before and 4 weeks after variceal eradication. RESULTS: The whole Baveno score (4 vs. 2.5) increased significantly after variceal eradication when compared to those before eradication (p < 0.05). After obliteration, only 19 (38 %) patients had mild PHG versus 37 (74 %) before EVL, while severe PHG was found in 31 (62 %) patients versus 11 (22 %) before EVL and the difference was highly statistically significant. No significant changes were found regarding endoscopic PHD lesions before and after variceal eradication. Pathological changes as average blood vessel count, angiogenesis, ectasia and blood extravasation in stomach and duodenum significantly increased after EVL. Large esophageal varices (III-IV) and Baveno score (>1) at baseline endoscopy were independent risk factors for development of severe PHG after variceal obliteration (p < 0.05). CONCLUSION: PHG increased significantly, endoscopically and pathologically, after variceal obliteration by EVL. Although PHD did not significantly change as documented by endoscopy, pathological examination documented statistically significant changes in the duodenum after EVL. PMID- 26932842 TI - Biliary complications in right lobe living donor liver transplantation. AB - Living donor liver transplantation is an alternative to deceased donor liver transplantation in the face of insufficient deceased donor liver grafts. Unfortunately, the incidence of biliary complication after living donor liver transplantation is significantly higher than that after deceased donor liver transplantation using grafts from non-cardiac-death donations. The two most common biliary complications after living donor liver transplantation are bile leakage and biliary anastomotic stricture. Early treatment with endoscopic and interventional radiological approaches can achieve satisfactory outcomes. If treatment with these approaches fails, the salvage measure for prompt rectification will be surgical revision, which is now seldom performed. This paper also discusses risk factors in donor biliary anatomy that can affect recipients. PMID- 26932844 TI - The effects of starvation and re-feeding on growth and swimming performance of juvenile black carp (Mylopharyngodon piceus). AB - We investigated the effects of starvation and re-feeding on growth and swimming performance and their relationship in juvenile black carp (Mylopharyngodon piceus). We measured the specific growth rate (SGR), resting metabolic rate (RMR) and constant acceleration test speed (U CAT, the maximum swimming speed at exhaustion by constant acceleration test with 0.1667 cm s(-2) rate) in a treatment group (21 days of starvation then 21 days of re-feeding) and control group (routine feeding) (n = 20). Starvation resulted in a 17 % decrease in body mass of black carp (P < 0.05). After 21 days of re-feeding, body mass was greater than that of pre-starvation but still less than that of the control group at 42 days. During the re-feeding phase, the SGR of the treatment group was higher than that of the control group (P < 0.05). Starvation resulted in a significant decrease in the RMR and U CAT. After 21 days of re-feeding, both the RMR and U CAT recovered to the pre-starvation levels. In the control group, individual juvenile black carp displayed strong repeatability of the RMR and U CAT across the measurement periods (P <= 0.002). In the treatment group, RMR showed significant repeatability between pre-starvation and re-feeding (P = 0.007), but not between pre-starvation and starvation or between starvation and re-feeding. U CAT showed significant repeatability between pre-starvation and starvation (P = 0.006) and between pre-starvation and re-feeding (P = 0.001), but not between starvation and re-feeding. No correlation or only a weak correlation was found between any two variables of RMR, U CAT and SGR, whereas the increment of the U CAT (DeltaU CAT) was negatively correlated with that of SGR during the starvation phase (r = -0.581, n = 20, P = 0.007) and re-feeding phase (r = -0.568, n = 20, P = 0.009). This suggested that within individual black carp, there is a trade-off between growth and maintenance (or development) of swimming performance under food-limited conditions. PMID- 26932846 TI - Shock Wave Response of Iron-based In Situ Metallic Glass Matrix Composites. AB - The response of amorphous steels to shock wave compression has been explored for the first time. Further, the effect of partial devitrification on the shock response of bulk metallic glasses is examined by conducting experiments on two iron-based in situ metallic glass matrix composites, containing varying amounts of crystalline precipitates, both with initial composition Fe49.7Cr17.7Mn1.9Mo7.4W1.6B15.2C3.8Si2.4. The samples, designated SAM2X5-600 and SAM2X5-630, are X-ray amorphous and partially crystalline, respectively, due to differences in sintering parameters during sample preparation. Shock response is determined by making velocity measurements using interferometry techniques at the rear free surface of the samples, which have been subjected to impact from a high velocity projectile launched from a powder gun. Experiments have yielded results indicating a Hugoniot Elastic Limit (HEL) to be 8.58 +/- 0.53 GPa for SAM2X5-600 and 11.76 +/- 1.26 GPa for SAM2X5-630. The latter HEL result is higher than elastic limits for any BMG reported in the literature thus far. SAM2X5-600 catastrophically loses post-yield strength whereas SAM2X5-630, while showing some strain-softening, retains strength beyond the HEL. The presence of crystallinity within the amorphous matrix is thus seen to significantly aid in strengthening the material as well as preserving material strength beyond yielding. PMID- 26932845 TI - Gill denervation eliminates the barostatic reflex in a neotropical teleost, the tambaqui (Colossoma macropomum). AB - The baroreflex is one of the most important regulators of cardiovascular homeostasis in vertebrates. It begins with the monitoring of arterial pressure by baroreceptors, which constantly provide the central nervous system with afferent information about the status of this variable. Any change in arterial pressure relative to its normal state triggers autonomic responses, which are characterized by an inversely proportional change in heart rate and systemic vascular resistance and which tend to restore pressure normality. Although the baroreceptors have been located in mammals and other terrestrial vertebrates, their location in fish is still not completely clear and remains quite controversial. Thus, the objective of this study was to locate the baroreceptors in a teleost, the Colossoma macropomum. To do so, the occurrence and efficiency of the baroreflex were both analyzed when this mechanism was induced by pressure imbalancements in intact fish (IN), first-gill-denervated fish (G1), and total gill-denervated fish (G4). The pressure imbalances were initiated through the administration of the alpha1-adrenergic agonist phenylephrine (100 ug kg(-1)) and the alpha1-adrenergic antagonist prazosin (1 mg kg(-1)). The baroreflex responses were then analyzed using an electrocardiogram that allowed for the measurement of the heart rate, the relationship between pre- and post-pharmacological manipulation heart rates, the time required for maximum chronotropic baroreflex response, and total heart rate variability. The results revealed that the barostatic reflex was attenuated in the G1 group and nonexistent in G4 group, findings which indicate that baroreceptors are exclusively located in the gill arches of C. macropomum. PMID- 26932847 TI - When and where to practice: social influences on the development of nut-cracking in bearded capuchins (Sapajus libidinosus). AB - The habitual use of tools by wild capuchin monkeys presents a unique opportunity to study the maintenance and transmission of traditions. Young capuchins spend several years interacting with nuts before cracking them efficiently with stone tools. Using a two-observer method, we quantified the magnitude of the social influences that sustain this long period of practice. During five collection periods (over 26 months), one observer recorded the behavior of 16 immature monkeys, and another observer concurrently recorded behavior of group members in the focal monkey's vicinity. The two-observer method provides a means to quantify distinct social influences. Data show that immatures match the behavior of the adults in time and especially in space. The rate of manipulation of nuts by the immatures quadrupled when others in the group cracked and ate nuts, and immatures were ten times more likely to handle nuts and 40 times more likely to strike a nut with a stone when they themselves were near the anvils. Moreover, immature monkeys were three times more likely to be near an anvil when others were cracking. We suggest a model for social influence on nut-cracking development, based on two related processes: (1) social facilitation from observing group members engaged in nut-cracking, and (2) opportunity for practice provided by the anvils, hammer stones and nut shells available on and around the anvils. Nut cracking activities by others support learning by drawing immatures to the anvils, where extended practice can take place, and by providing materials for practice at these places. PMID- 26932849 TI - [Significance and research of biomarkers in obstructive sleep apnea hypopnea syndrome]. PMID- 26932848 TI - A qualitative evaluation of a group phone-based weight loss intervention for rural breast cancer survivors: Themes and mechanisms of success. AB - PURPOSE: Obesity is prevalent in breast cancer survivors and is a significant risk factor for recurrence and mortality. Weight management interventions for survivors have been diverse in design (in-person vs. phone-based, group vs. individual) and yielded varying weight loss results. Given these issues, participants themselves may provide insight into treatment-based factors that contributed to their weight loss outcomes. Here, we report qualitative results from interviews with survivors in a group phone-based weight loss intervention, with the objective of identifying mechanisms that facilitated or hindered adherence and weight loss. We explored interest in paying for continued treatment as an indicator of dissemination potential. METHODS: Individual interviews were conducted with 186 rural, obese breast cancer survivors upon completion of a 6 month weight loss intervention that produced clinically meaningful weight loss (>5 %) in 91 % of participants. A thematic analysis of the interview data was performed. RESULTS: Five themes were identified as impacting adherence and success: (1) accountability; (2) importance of the group, with varying levels of connectedness; (3) dietary convenience; (4) difficulty maintaining intervention components that required more effort; and (5) importance of internal motivation to attributions of physical activity success or failure. Most were interested in paying to continue the program if it were extended beyond the study. CONCLUSIONS: Key intervention components that participants attributed to their success included supportive group processes and convenience. Results highlight the group phone-based approach as a potential venue for disseminating an effective weight loss program for breast cancer survivors. TRIAL REGISTRATION: NCT01441011. PMID- 26932850 TI - [Effects of obstructive sleep apnea on occurrence and treatment of atrial fibrillation]. PMID- 26932851 TI - [Comparison of polysomnographic characteristics in preschool and school aged children with obstructive sleep apnea hypopnea syndrome]. AB - OBJECTIVE: To compare the characteristics of polysomnography in preschool and school aged children with obstructive sleep apnea hypopnea syndrome (OSAHS). METHODS: The clinical data were collected from October 2009 to October 2013 among children monitored in Sleep Medical Center of West China Hospital. Among them, 189 preschool aged (aged 3-5 years) and 211 school aged (aged 6-13 years) children with sleep breathing disorder, and 33 children complained with sleep talking as controls were enrolled and underwent polysomnography. According to apnea hyponea index (AHI), they were classified as primary snoring (AHI<1/h), mild OSAHS (1/h<=AHI<5/h), and moderate/severe OSAHS (AHI>=5/h) and then their sleep architecture was compared among groups. RESULTS: No significant difference was found in sleep latency, total sleep time, sleep efficiency, the percentage of rapid eye movement stage and N2 stage among groups (P>0.05). In preschool aged children, the percentage of N1 stage in the moderate/severe group was more than other three groups (moderate/severe group vs control group, primary snoring group, mild group: 24.7%+/-13.7% vs 17.0%+/-8.7%, 21.7%+/-12.4%, 20.9%+/-11.6%, all P<0.05). In school aged children, the percentage of N1 stage in the moderate/severe group was more than the control group (moderate/severe group vs control group: 18.0%+/-10.4% vs 12.0%+/-4.8%, P<0.05), the percentage of N3 stage in the moderate/severe group and the mild group were less than the control group (moderate/severe group, mild group vs control group: 28.3%+/-9.6%, 28.8%+/-8.8% vs 33.9%+/-13.0%, both P<0.05). In addition, in preschool and school aged children group, the arouse index in the moderate/severe group was higher than other three groups, the mean oxygen saturation and the lowest oxygen saturation in the moderate/severe group were lower than those of the other three groups, the differences were statistically significant (all P<0.05). Correlation analysis suggested that no significant correlation was found between AHI and body mass index (BMI) in preschool children (r=-0.02, P>0.05). However, there was significance in school aged children (r=0.26, P<0.01). In addition, the correlations were significant between AHI and arousal index in preschool and school aged (r=0.42, 0.55, both P<0.01). CONCLUSIONS: The sleep architecture is milder affected by OSAHS in preschool children than in school aged children. The severity is mainly related to enlarged tonsils and adenoids. School aged children with OSAHS may be more susceptible to sleep structure disorder and the severity is mainly related to BMI. PMID- 26932852 TI - [Analysis of clinical characteristics and risk factors of obstructive sleep apnea hypopnea syndrome with hypertension]. AB - OBJECTIVE: To study the risk factors contributing to the development of hypertension in patients with obstructive sleep apnoea hypopnea syndrome (OSAHS), and the clinical characteristics of OSAHS with hypertension. METHODS: A total of 2397 OSAHS patients aged above 30 years old and diagnosed by the sleep-disordered breathing center of Guangxi between July 2012 and August 2015 were recruited. OSAHS patients with new-onset hypertension (OSAHS with hypertension group) and those without hypertension (simple OSAHS group) were identified and their clinical data, including general status, family history of hypertension or snoring, Epworth Sleepiness Scale (ESS) score for daytime sleepiness, physical examination findings, and polysomnography monitoring data were collected. OSAHS patients with new-onset hypertension (n=101) and OSAHS patients without hypertension (n=202) matched by age and body mass index (BMI) (age difference, 2 years; BMI difference, 1.5 kg/m(2)) were recruited in the OSAHS with hypertension group and the simple OSAHS group. A case-control study was used to compare the clinical characteristics of these two groups, and univariate and multivariate Logistic regression were used to analyze all the factors contributing to hypertension development besides age and BMI. RESULTS: The average age and BMI of the OSAHS with hypertension group and the simple OSAHS group were respectively (46.2+/-9.3), (46.2+/-9.2) years old and (28.2+/-2.8), (28.2+/-2.8) kg/m(2). Patients in the two groups were well-matched with respect to age and BMI (P>0.05). The systolic blood pressure (SBP) and diastolic blood pressure (DBP) in the OSAHS with hypertension group were significantly higher than those in the simple OSAHS group at the first admission to the clinic and before and after the PSG examination. ESS values in the OSAHS with hypertension group and the simple OSAHS group were respectively 10.0+/-6.4 and 9.2+/-6.3 (P>0.05). There was no significant intergroup difference in neck circumference, waist circumference, duration of snoring, family history of snoring, and family history of hypertension (P>0.05) either. The apnea-hypopnea index (AHI) and apnea index (AI) in the OSAHS with hypertension group were higher than those in the simple OSAHS group (P<0.05); the longest apnea duration (LAD), mean apnea duration (MAD), and the total time spent with oxygen saturation below 90% (T90%) in the OSAHS with hypertension group were significantly longer than those in the simple OSAHS group (P<0.05). The minimal pulse oxygen saturation (MinSpO2) in the OSAHS with hypertension group was significantly lower than that in the simple OSAHS group (P<0.05). Six factors were identified to be associated with OSAHS with hypertension through univariate analysis: AHI (OR=0.985, P=0.001), AI (OR=0.983, P<0.001), LAD (OR=0.955, P=0.013), MAD (OR=0.874, P=0.015), MinSpO2 (OR=0.874, P=0.015), T90% (OR=0.997, P=0.036). Only MinSpO2 (P<0.001, OR=0.894) was closely related to OSAHS hypertension development in the multivariate Logistic regression model. CONCLUSIONS: OSAHS patients with hypertension may show lower MinSpO2, higher AHI and AI, and longer LAD, MAD, and T90% than OSAHS patients without hypertension. MinSpO2 is probably closely related to OSAHS hypertension development. PMID- 26932853 TI - [Modulation of hippocampal synaptic transmission in a mouse model of chronic intermittent hypoxia: implications for neurocognitive impairments]. AB - OBJECTIVE: To investigate the effects of chronic intermittent hypoxia (CIH) on neuronal excitatory synaptic transmission in mice and explore their role in CIH induced neurocognitive impairments. METHODS: Three-week old ICR male mice were randomly divided into three experimental groups, the unhandled control + vehicle group (UC+ VEH group), CIH exposure + vehicle group (CIH+ VEH group) and CIH exposure + memantine pretreatment group (CIH+ MEM group) (n=10 each), wherein 5 for electrophysiological recordings, 5 for Western blot. The CIH+ VEH and CIH+ MEM groups were exposed to intermittent hypoxia while UC+ VEH mice to room air for 8 hours per day for 2 weeks. Mice in the CIH+ MEM group were pretreated with intraperitoneal injection of memantine solution 5 ml/kg (concentration of 1 mg/ml) approximately 15 minutes prior to starting daily CIH exposure, and the other two groups were treated with equal saline as vehicle. Using the whole cell patch clamp technique to evaluate the amplitude and frequency of hippocampal neuronal spontaneous excitatory postsynaptic currents (sEPSC) and the electrophysiological characteristics, the western blotting method to measure the expression of N-methyl-D-aspartic acid receptor (NMDAR) subunit 2B (NR2B) and brain derived neurotrophic factor (BDNF) in hippocampus. RESULTS: The neuronal spike threshold in CIH+ VEH group was depolarized compared to the UC+ VEH and CIH+ MEM groups ((-40.4+/-3.5) vs (-43.3+/-3.7), (-44.7+/-5.4) mV, both P<0.05). Furthermore, the frequency and amplitude of sEPSC in hippocampal CA1 neurons in CIH+ VEH group were significantly greater than the UC+ VEH and CIH+ MEM groups ((6.7+/-4.6) vs (3.6+/-1.7), (3.2+/-1.4) Hz, and (18.4+/-11.6) vs (13.0+/-2.5), (12.4+/-2.7) pA, both P<0.05). The expressions of NR2B increased significantly in CIH+ VEH group compared to UC+ VEH and CIH+ MEM groups (1.46+/-0.14 vs 0.93+/ 0.07, 0.95+/-0.10, both P<0.01), whereas the expressions of BDNF decreased significantly in CIH+ VEH group versus UC+ VEH and CIH+ MEM groups (0.44+/-0.16 vs 0.86+/-0.08, 0.73+/-0.06, both P<0.05). There was no statistical difference between UC+ VEH group and CIH+ MEM group for these electrophysiological and biochemical assessments. CONCLUSION: Chronic intermittent hypoxia induces excitatory synaptic transmission abnormal, decreases neuronal excitability, and dysregulates NMDAR mediated signaling pathway, these changes may play an important role in CIH-induced neurocognitive impairments. PMID- 26932854 TI - [Clinical and biological characteristics multiple myeloma with 1q21 amplification]. AB - OBJECTIVE: To study the clinical features of multiple myeloma (MM) patients with 1q21 amplification and the detection and biological characteristics of 1q21 copy number variation among different stages of plasma cell dyscrasias. METHODS: We analyzed the amplification and copy number variation of 1q21 in a cohort of 397 MM patients (290 newly diagnosed patients and 107 relapsed/refractory patients) in Institute of Hematology and Blood Diseases Hospital in the period between January 2009 and December 2012, using fluorescence in situ hybridization (FISH). We compared the incidence and biological characteristics of 1q21 gains among different stages of MM. RESULTS: Among the newly diagnosed MM patients, the cases without 1q21 gains (148 cases) had difference prevalence of q13 deletion (38.3% (56/146) vs 57.7% (82/142), P=0.001), t(4; 14) translocation (17.4% (25/144) vs 30.7% (42/137), P=0.009), and high-risk cytogenetic abnormalities (28.3% (39/138) vs 41.9% (57/136), P=0.018), and International Staging System (ISS) stage (P=0.010) compared to those with 1q21 gains (142 cases); however, there were no significant differences in age(P=0.448), Durie-Salmon clinical stage (P=0.352) and beta2-microglobulin level (P=0.414). In the newly diagnosed patients, the incidence of this 1q21 aberration with the percentages of plasma cells involved being >=10%, >=20%, and >=30% was 52.4% (152/290), 49.0% (142/290), and 46.2% (134/290), respectively, lower than that in the relapsed/refractory patients (71.0% (76/107), P=0.001; 68.2% (73/107), P=0.001; 63.6% (68/107), P=0.002). Differences were found between the newly diagnosed MM patients and the relapsed/refractory ones in terms of the incidence of 1q21 copy number gains being 2 (52.2% (145/278) vs 33.3% (34/102), P=0.001), but not in the incidence of 1q21 copy number gains being 3, 4, and >5 (all P>0.05). CONCLUSIONS: Amplification of chromosome 1q21 is a common genetic abnormality in MM patients. The copy number varies in patients carrying 1q21 gains, mainly with two or more copies of 1q21. It may therefore be recommended to include testing for 1q21 gains in routine genetic testing of MM patients. PMID- 26932855 TI - [GDF11 level in patients with myelodysplastic syndrome and its clinical significance]. AB - OBJECTIVE: To detect the expression level of growth differentiation factor 11 (GDF11) in patients with myelodysplastic syndrome (MDS), and to evaluate the relationship between GDF11 level and erythropoiesis functions. METHODS: A total of 44 MDS patients (18 low-risk group patients and 26 high-risk group patients) in Department of Hematology in Tianjin Medical University General Hospital and 10 normal controls were selected from September 2014 to June 2015. The concentration of GDF11 in peripheral blood was detected using enzyme-linked immunosorbent assay (ELISA). GDF11 mRNA expression in bone marrow mononuclear cells (BMMNC) was detected using RT-PCR method. The percentage of erythroid cells (CD235a) in bone marrow was detected by flow cytometry. The correlation between these indexes and erythropoiesis functions (including red blood cell count (RBC), hemoglobin level (Hb), hematocrit (Hct), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), reticulocyte percentage (Ret%), and proportion of nucleated eryhrocyte in bone marrow) were evaluated. RESULTS: (1) The GDF11 level in peripheral blood was significantly higher in high-risk group ((128.67+/-47.62) MUg/L) than in low-risk group ((65.96+/-36.55) MUg/L, P<0.01) and in normal controls ((29.76+/-10.10) MUg/L, P<0.01), also significantly higher in low-risk group than in normal controls (P<0.05). The concentration of GDF11 in severe/moderate anemic MDS patients ((80.97+/-9.94) MUg/L) was higher than that in normal controls/ mild anemic MDS patients((66.82+/-19.52) MUg/L), but with no statistically significant (P>0.05). (2) The percentages of CD235a(+) cells in high-risk and low-risk groups were 38.49%+/-5.42% and 42.64%+/-7.36%, respectively, showing no statistically significant difference (P>0.05). (3) In high-risk group, the GDF11 level in peripheral blood was negatively correlated with Hb, RBC and Hct in peripheral blood (r=-0.437, -0.430, -0.306, all P<0.05), and positively correlated with nucleated eryhrocyte, Ret%, MCV and CD235a(+) cells in bone marrow (r=0.465, 0.392, 0.505, 0.387, all P<0.05), but not correlated with MCH and MCHC (both P>0.05). In low-risk group, the GDF11 level in peripheral blood was positively correlated with CD235a(+) cells in bone marrow (r=0.429, P<0.05), and not correlated with Hb, RBC, Ret%, MCHC, MCV, MCH, Hct and nucleated eryhrocyte (all P>0.05). (4) The mRNA expression of GDF11 in MDS patients (39.82+/-14.55) was higher than that in the controls (1.84+/-0.64, P<0.01). CONCLUSIONS: GDF11 level in peripheral blood is higher in patients with MDS and increases with the disease risk. The more severe the anemia, the higher the GDF11 level. It may be closely correlated with erythropoiesis indicators in MDS. PMID- 26932856 TI - [The effect of patterns of recurrence after radical resection of rectal cancer on long-term survival after recurrence]. AB - OBJECTIVE: To establish the classification of colorectal cancer recurrence patterns based on their relations to prognosis and recurrence. METHODS: A total of 463 patients with recurrent rectal cancer (Stage I-III) following curative resection in our hospital from June 2002 to June 2012 were included consecutively. Recurrence status, time, location, survival time after relapse, curability, symptoms and CEA level were recorded. The correlation between each recurrent pattern and recurrent survival (RS) rate were analyzed retrospectively. The survival curve was drawn by Kaplan-Meier method. The Log-rank test was used to test the significance. Univariate analysis was performed by using Cox proportional hazard model. RESULTS: Patients with recurrence within one year, multiple metastases, symptomatic disease, elevated CEA level and unresectable recurrence had significantly lower RS rate than patients with recurrence after one year, solitary metastasis, asymptomatic manifestation, normal CEA level and resectable recurrence respectively. The hazard ratio were 1.34 (95%CI 1.02-1.76, P= 0.033), 1.41 (95%CI 1.04-1.91, P= 0.026), 1.74 (95%CI 1.05-2.88, P= 0.032), 4.06 (95%CI 2.11-7.85, P<0.001) and 1.99 (95%CI 1.34-2.97, P= 0.001) respectively. CONCLUSION: Early recurrence (<12 months), multiple metastases, symptomatic, unresectable recurrence and elevated CEA indicate poor prognosis after relapse. This study provides a systematic basis for the classification of recurrence in colorectal cancer after radical resection. PMID- 26932857 TI - [Finite element analysis of the effects of two kinds of individual extralevator abdominalperineal excision on female pelvic floor]. AB - OBJECTIVE: To evaluate the effects of two kinds of individual extralevator abdominalperineal excision(ELAPE) on female pelvic floor biomechanics. METHODS: Four kinds of finite element model were developed: intact models, ELAPE models and two kinds of individual ELAPE models. The maximal stress and stress distributions of each model under the same pressure were analyzed and compared. RESULTS: In the individual ELAPE models of dissection plane close to rectum on one side, non-levator ani tissue's maximal stress on levator ani partly reserved side and totally removed side were (3.114+/-0.129) and (4.856 +/-0.128) MPa. The former were lower than the latter (P<0.01). They were both lower than those in ELAPE models which were (5.127+/-0.070) MPa (P<0.01), and were higher than those in intact model which were (1.963+/-0.061) MPa (P<0.01). In the individual ELAPE models of dissection plane close to pelvic on one side, non-levator ani tissue's maximal stress on both sides, which were (5.131+/-0.067) MPa, were similar to those in ELAPE models (P>0.05). CONCLUSION: ELAPE of dissection plane close to rectum on one side is able to reduce the stress of non-levator ani tissue on both sides, especially on levator ani partly reserved side; conversely, ELAPE of dissection plane close to pelvic on one side may not reduce the stress of non levator ani tissue on either side. PMID- 26932858 TI - [Clinical application of automated digital image analysis for morphology review of peripheral blood leukocyte]. AB - OBJECTIVE: To explore the clinical application of automated digital image analysis in leukocyte morphology examination when review criteria of hematology analyzer are triggered. METHODS: The reference range of leukocyte differentiation by automated digital image analysis was established by analyzing 304 healthy blood samples from Peking University First Hospital. Six hundred and ninty-seven blood samples from Peking University First Hospital were randomly collected from November 2013 to April 2014, complete blood cells were counted on hematology analyzer, blood smears were made and stained at the same time. Blood smears were detected by automated digital image analyzer and the results were checked (reclassification) by a staff with abundant morphology experience. The same smear was examined manually by microscope. The results by manual microscopic differentiation were used as"golden standard", and diagnostic efficiency of abnormal specimens by automated digital image analysis was calculated, including sensitivity, specificity and accuracy. The difference of abnormal leukocytes detected by two different methods was analyzed in 30 samples of hematological and infectious diseases. RESULTS: Specificity of identifying abnormalities of white blood cells by automated digital image analysis was more than 90% except monocyte. Sensitivity of neutrophil toxic abnormities (including Dohle body, toxic granulate and vacuolization) was 100%; sensitivity of blast cells, immature granulates and atypical lymphocytes were 91.7%, 60% to 81.5% and 61.5%, respectively. Sensitivity of leukocyte differential count was 91.8% for neutrophils, 88.5% for lymphocytes, 69.1% for monocytes, 78.9% for eosinophils and 36.3 for basophils. The positive rate of recognizing abnormal cells (blast, immature granulocyte and atypical lymphocyte) by manual microscopic method was 46.7%, 53.3% and 10%, respectively. The positive rate of automated digital image analysis was 43.3%, 60% and 10%, respectively. There was no statistic significance between two methods (chi(2) = 0.067, 0.271, 0.000, all P>0.05). Automated digital image analysis could be used to morphology examination with abnormal leukocytes and optimize review criteria of hematology analyzer. CONCLUSION: Sensitivity and specificity of recognizing abnormal blood leukocytes by automated digital image analysis are satisfactory, which can be used as a tool of leukocyte morphology review when review criteria of hematology analyzer are triggered. PMID- 26932859 TI - [Short-term efficacy and toxicity of Nimotuzumab combined with simultaneous integrated boost intensity-modulated radiotherapy for locally advanced esophageal cancer]. AB - OBJECTIVE: To evaluate the short-term efficacy and toxicity of Nimotuzumab combined with simultaneous integrated boost intensity-modulated radiotherapy (SIB IMRT) in the treatment of locally advanced esophageal carcinoma. METHODS: Twenty nine patients with esophageal carcinoma were treated with SIB-IMRT. Planning gross target volume (PGTV) was given at a dose of 60 Gy/2.4 Gy/25 F and planning target volume (PTV) was given at a dose of 50 Gy/2 Gy/25 F. Nimotuzumab was given by intravenous drip at the dose of 200 mg, once a week before radiotherapy. Short term efficacy and toxicity were evaluated in all patients. RESULTS: All patients completed the treatment successfully. Fourteen of them achieved a complete response (CR, 48.3%), 13 had a partial response (PR, 44.8%), 1 showed stable disease (SD, 3.6%), and 1 showed progressive disease (PD, 3.6%). The overall response rate (CR+ PR) was 93.1%. Most adverse reactions were radioactive esophagitis, radioactive dermatitis and bone marrow suppression (grade 1-2). Only 1 patient developed a slight skin rash. CONCLUSION: Nimotuzumab combined with SIB IMRT is a safe and effective modality for locally advanced esophageal cancer. The patient is well tolerated and worthy of further clinical study. PMID- 26932860 TI - [Analysis of the cause of missed diagnosis in transperineal prostate biopsy with 4 cases report]. AB - OBJECTIVE: To investigate the causes of missed diagnosis in transrectal ultrasound-guided transperineal prostate biopsy. METHODS: The biopsy results of total 278 patients who received transrectal ultrasound-guided transperineal prostate biopsy from January 2012 to December 2014 in Subei People's Hospital were retrospectively analyzed, using 11 systemic divisions. RESULTS: One hundred and twenty-nine patients were diagnosed with prostate cancer, and 149 patients were hyperplasia of prostate. Fifty-six patients with biopsy-negative and obvious symptoms of lower urinary tract obstruction were underwent transurethral resection of the prostate. Four of which were found to be prostate cancer. CONCLUSION: Early-stage prostate cancer, special prostate tumor location, inadequate biopsy tissue, special patients in limited position, and dissatisfied anesthesia may increase the risk of missed diagnosis. Targeted and individualized puncture may improve the effectiveness. PMID- 26932861 TI - [Serum IgG subtypes features and differential diagnosis of autoimmunepancreatitis patients]. AB - OBJECTIVE: To investigate clinical value of serum IgG subclass distribution in differential diagnosis of autoimmune pancreatitis. METHODS: Inpatients were enrolled as follow, autoimmune pancreatitis (AIP, n=28), acute and chronic pancreatitis (ACP, n=112), pancreatic cancer (PC, n=15), cholangiocarcinoma (CC, n=9), retroperitoneal fibrosis (RPF, n=37), together with healthy controls (n=52). IgG subtypes, amylase, lipase, glucose and CA19-9 were tested.For patients with autoimmune pancreatitis and pancreatic cancer, radiographic CT of abdomen and pathological staining were included for comparison. RESULTS: IgG4 subtype distributed in a wide range as 7.6(1.7-13.8) g/L in AIP, 0.4(0.2-0.7) g/L in ACP, 0.7(0.2-0.9) g/L in PC, 0.5(0.4-6.5) g/L in CC and 0.4(0.2-0.7) g/L in control group, the difference was significant (H=40.536, P<0.001). There were no significant differences of IgG1, IgG3 level in AIP, RPC and control group (all P>0.05). While IgG4 level was 7.6(1.7-13.8), 1.3(0.5-2.6), 0.4(0.2-0.7) g/L in AIP, RPC and control group, respectively. The difference was significant (H=36.833, P<0.001). IgG4 level in RPC group was lower than that in AIP group (P<0.05). And it was meaningful in the differential diagnosis. CONCLUSION: Serum IgG4 subtype plays an important role in differentiation of autoimmune pancreatitis from associated diseases. PMID- 26932863 TI - [Cheek blood sampling of mice]. AB - OBJECTIVE: To explore the method of cheek blood sampling in mice in continuous blood test. METHODS: Cheek blood sampling was carried out in 10 9-week-old mice once every 2-3 days. The volumes of blood samples were recorded. Reactions of the mice were observed. RESULTS: Cheek blood sampling collected 0.3-0.6 ml of blood every time, and did not affect the normal activities of the mice. The blood sampling could be repeated every 2-3 days. CONCLUSIONS: Cheek blood sampling has several advantages including being capable to draw adequate blood, simple and easy to operate, well tolerated, and ethical in treating laboratory animals. PMID- 26932862 TI - [Comparison and bias estimation of three methods in determination of glycated hemoglobin A1c]. AB - OBJECTIVE: To evaluate the bias of three different methods in determination of glycated hemoglobin A1c (HbA1c). METHODS: According to Clinical and Laboratory Standards Institute (CLSI)EP9-A3 document, 40 serum specimens among linear range were tested by immunoturbidimetry assay (Roche Tina-quant), capillary electrophoresis (Sebia Minicap FP), high performance liquid chromatography system (HPLC, Trinity Biotech Premier Hb 9210TM). RESULTS were analyzed by pairwise comparision. The difference plots and scatter plots were analyzed. The results of outliers were examined by extreme studentized deviate (ESD) method. The best regression model was chosen to fit the regression equation and the biases were calculated at the level of medical decision and judged the comparability according to the half of Tea acceptance standard. RESULTS: Scatter plots and ESD results showed good correlation among test results of 40 samples, no abnormal values were found. Based on proportional difference deviation plots, proportional difference rank order deviation plots, numerical deviation plots and ranked order difference plots, weighted least squares (WLS) (Roche(X) vs sebia(Y1)), ordinary linear regression (OLR) (Roche(X) vs Trinity (Y2)) and Deming (Sebia(Y1) vs Trinity(Y2)) were chosen to fit regression analysis model. The regression equations were Y1 =-0.420 3+ 1.052 7X, Y2 =-0.174 0+ 1.027 0X, Y2=0.423 1+ 0.959 0Y1, respectively. Assuming the HbA1c medical decision points of 10%, 16% to regression equation, the proportional biases were 1.06% and 2.61% at Roche(X) and sebia(Y1) system, 0.96% and 1.60% at Roche(X) and Trinity (Y2) system, 0.13% and 1.47% at Sebia(Y1) and Trinity(Y2) system respectively, which were all lower than the acceptable values. CONCLUSION: The measurement values of HbA1c by capillary electrophoresis (Sebia Minicap FP), HPLC (Trinity Biotech Premier Hb 9210TM) and immunoturbidimetry assay (Roche Tina-quant), are comparable. PMID- 26932864 TI - Lateralized courtship in a parasitic wasp. AB - Lateralization (i.e. left-right asymmetries in the brain and behaviour) of courtship displays has been examined in a growing number vertebrate species, while evidence for invertebrates is limited. In this study, we investigated lateralization of courtship and mating displays in the parasitic wasp Leptomastidea abnormis. Results showed a population-level lateralization of male courtship displays. Male antennal tapping on the female's head was right-biased. However, right-biased male courtship acts were not characterized by higher male antennal tapping frequencies, nor success in mating although antennal tapping frequency was higher in males with mating success with respect to unsuccessful males. Overall, our results add basic knowledge to the behavioural ecology of insect parasitoids. To the best of our knowledge, this is the first report of behavioural lateralization in parasitic Hymenoptera. PMID- 26932865 TI - Genetic structure and differentiation analysis of a Eurasian Uyghur population by use of 27 continental ancestry-informative SNPs. AB - Previously, we developed and validated a multiplex assay of 27 ancestry informative markers (AIMs) for analyzing African (AFR), European (EUR), and East Asian (EAS) ancestry components. In this study, we typed and collectively analyzed a large Uyghur sample of 979 individuals to estimate the genetic coefficients of the 27 AIMs and investigate differentiation parameters between Uyghur and Han. The Uyghur allele frequencies ranged from 0.243 to 0.952, and heterozygosities ranged from 0.091 to 0.500. Values of F st 3 and I n 3 for EUR, Uyghur, and EAS ranged from 0.028 to 0.550 and 0.0002 to 0.345, respectively. The Uyghur population displays a substantial ancestry contribution of 50.3:49.7 (EUR:EAS) and was efficiently discriminated from Han Chinese with an accuracy of 99.285 %. All populations were clustered into AFR, EUR, EAS, and admixture groups of these three ancestries. Central Asian was obviously stratified from the other admixture populations of South Asians, North Asians, and the Americans. The 27 SNPs yield a circle with an average distance of 0.936 from the center (0, 0) in PCA analysis. Using this set, Chinese Uyghur and Han populations achieved accurate differentiation, and our updated genotype database (by citing 1000 Genomes data) of 43 worldwide populations is a useful resource for forensic applications and disease association studies. PMID- 26932866 TI - Analysis of 27 Y-chromosomal STR haplotypes in a Han population of Henan province, Central China. AB - A total of 1225 unrelated Han males from Henan province were analyzed with the prototype Yfiler(r) Plus kit (Life Technologies, Thermo Fisher Scientific, Waltham, MA, USA). The calculated gene diversity (GD) values ranged from 0.3855 to 0.9673 for the DYS391 and DYS385a/b loci, respectively. The discriminatory capacity (DC) was 86.94 % with 1065 observed haplotypes using 17 Yfiler loci, by the addition of 10 Y-STRs to the Yfiler(r) Plus system, the DC was increased to 98.94 % while showing 1212 observed haplotypes. Among the new incorporated Y STRs, DYS576, DYF387S1, DYS518, DYS627, and DYS449 were major contributors to enhancing discrimination. In the analysis of molecular variance, the Henan Han population clustered with Asian origin populations and showed significant differences from other reference populations. In this study, the improvement of adding additional Y-STR markers with the Yfiler(r) Plus kit provided substantially stronger discriminatory power in the Henan Han population. PMID- 26932868 TI - Reconstruction of crimes by infrared photography. AB - Whenever blunt or sharp forces are used in a crime, analysis of bloodstain pattern distribution may provide important information for the reconstruction of happenings. Thereby, attention should be paid to both the crime scene and the clothes of everyone involved in the crime. On dark textiles, though, it is difficult or even impossible for the human eye to detect bloodstains because of the low contrast to the background. However, in the near infrared wavelength range, contrast is considerably higher. Many textiles reflect light beyond a wavelength of 830 nm and thus appear light-colored, whereas blood absorbs the light and appears dark. In our studies, a D7000 NIKON reflex camera modified for infrared photography produced high-resolution photographs visualizing even very small spatter stains on dark textiles. The equipment can be used at any crime scene or lab and provides immediately available and interpretable images. Thus, important findings can be obtained at an early stage of police investigations, as two examples (homicide and attempted homicide) illustrate. PMID- 26932867 TI - Systematic review of the toxicological and radiological features of body packing. AB - Body packing is the term used for the intracorporeal concealment of illicit drugs, mainly cocaine, heroin, methamphetamine, and cannabinoids. These drugs are produced in the form of packages and are swallowed or placed in various anatomical cavities and body orifices. Basing on these two ways of transportation a distinction between body stuffers and body pushers can be made, with the former described as drug users or street dealers who usually carry small amounts of drugs and the latter as professional drug couriers who carry greater amounts of drugs. A review of the literature regarding body packing is presented, with the aim to highlight the toxicological and radiological features related to this illegal practice. Raising awareness about the encountered mean body levels of the drugs and the typical imaging signs of the incorporated packages could be useful for clinicians and forensic pathologists to (a) identify possible unrecognized cases of body packing and (b) prevent the serious health consequences and deaths frequently occurring after the packages' leakage or rupture or the packages' mass obstructing the gastrointestinal lumen. PMID- 26932869 TI - A SNP panel for identity and kinship testing using massive parallel sequencing. AB - Within forensic genetics, there is still a need for supplementary DNA marker typing in order to increase the power to solve cases for both identity testing and complex kinship issues. One major disadvantage with current capillary electrophoresis (CE) methods is the limitation in DNA marker multiplex capability. By utilizing massive parallel sequencing (MPS) technology, this capability can, however, be increased. We have designed a customized GeneRead DNASeq SNP panel (Qiagen) of 140 previously published autosomal forensically relevant identity SNPs for analysis using MPS. One single amplification step was followed by library preparation using the GeneRead Library Prep workflow (Qiagen). The sequencing was performed on a MiSeq System (Illumina), and the bioinformatic analyses were done using the software Biomedical Genomics Workbench (CLC Bio, Qiagen). Forty-nine individuals from a Swedish population were genotyped in order to establish genotype frequencies and to evaluate the performance of the assay. The analyses showed to have a balanced coverage among the included loci, and the heterozygous balance showed to have less than 0.5 % outliers. Analyses of dilution series of the 2800M Control DNA gave reproducible results down to 0.2 ng DNA input. In addition, typing of FTA samples and bone samples was performed with promising results. Further studies and optimizations are, however, required for a more detailed evaluation of the performance of degraded and PCR-inhibited forensic samples. In summary, the assay offers a straightforward sample-to-genotype workflow and could be useful to gain information in forensic casework, for both identity testing and in order to solve complex kinship issues. PMID- 26932870 TI - Population data of 13 nonCODIS STR markers located inside the 6 nonsyndromic oculocutaneous albinism genes. AB - Allele frequencies and forensic statistics of 13 autosomal short tandem repeat loci were estimated in 56 unrelated Iranian individuals. Except for two loci which were monomorph, a total of 5-11 alleles at each locus were observed and altogether 94 alleles for all selected loci were found. Our results show that 11 out of 13 nonCODIS STR loci are polymorphic and can be useful for human identification and kinship analysis and relationship investigations in Iran. PMID- 26932871 TI - Population data of 17 short tandem repeat loci in 2923 individuals from the Han population of Nantong in East China. AB - Nantong is located in mid-eastern China, and the Han population in Nantong may be greatly affected by population admixture between northern and southern Han Chinese populations. In this study, we analyzed 17 autosomal short tandem repeat (STR) loci on 2923 unrelated individuals collected from the Han population of Nantong. No significant deviation from Hardy-Weinberg equilibrium was observed at all STR loci, and the expected heterozygosity ranged from 0.6184 to 0.9187. The combined match probability (CMP) was 3.87 * 10(-21), and the combined power of discrimination (CPD) was 99.999999999999999999613 %. No significant difference of allele frequencies was observed between Nantong and other Han populations at all STR loci, as well as Dai, Mongolian, and Tibetan. Significant differences were only observed between Nantong Han and Uyghur at TH01, as well as Nantong Han and Dong at CSF1PO and FGA. Nantong Han showed significant differences between She, Bouyei, and Miao at multiple STR loci. PMID- 26932873 TI - Type 1 diabetes is associated with increased risk of several cancers. PMID- 26932872 TI - Distractors associated with reward break through the focus of attention. AB - In the present study, we investigated the conditions in which rewarded distractors have the ability to capture attention, even when attention is directed toward the target location. Experiment 1 showed that when the probability of obtaining reward was high, all salient distractors captured attention, even when they were not associated with reward. This effect may have been caused by participants suboptimally using the 100%-valid endogenous location cue. Experiment 2 confirmed this result by showing that salient distractors did not capture attention in a block in which no reward was expected. In Experiment 3, the probability of the presence of a distractor was high, but it only signaled reward availability on a low number of trials. The results showed that those very infrequent distractors that signaled reward captured attention, whereas the distractors (both frequent and infrequent ones) not associated with reward were simply ignored. The latter experiment indicates that even when attention is directed to a location in space, stimuli associated with reward break through the focus of attention, but equally salient stimuli not associated with reward do not. PMID- 26932874 TI - Differences in Perceptions of the Food Environment Between African American Men Who Did and Did Not Consume Recommended Levels of Fruits and Vegetables. AB - African American men have high rates of chronic disease morbidity and mortality associated with their low rates of fruit and vegetable consumption. In an effort to inform tailored behavioral interventions for this demographic, we sought to assess if men with healthier eating practices viewed their environment differently than those who ate less healthy. We segmented participants into high/low healthy eating categories based on the daily fruit and vegetable serving recommendations from the U.S. Department of Agriculture to determine if differences among environmental and social barriers were associated with different healthy eating patterns. We found key differences between men who consumed the recommended amount of fruits and vegetables (five or more servings/day, high healthy eating) and men who did not (low healthy eating). Men who consumed recommended levels of fruits and vegetables found eating healthy to be easy, and they described how they were able to overcome barriers such as the cost of healthy food, their limited knowledge of nutrition guidelines, and their lack of willpower to make healthier food choices. Men with healthier eating practices also identified individuals, plans, and resources they used or could use to help them have healthier eating practices. Conversely, men who were not eating recommended levels of fruits and vegetables also found eating healthy to be easy; however, they identified barriers limiting their access and did not articulate strategies to overcome these perceived barriers. Many of these men also indicated that they did not have social support to help them engage in healthier eating practices. These findings highlight the need to understand how African American men's conceptualization of environmental resources and social supports relate to their eating practices. PMID- 26932875 TI - Association of dementia in patients with benign paroxysmal positional vertigo. AB - OBJECTIVE: We conducted a cohort study to investigate whether benign paroxysmal positional vertigo (BPPV) is correlated with an increased risk of dementia. METHODS: We established a case cohort comprising 7818 patients aged over 20 years who were diagnosed with BPPV from 2000 to 2010. In addition, we formed a control cohort by randomly selecting 31,272 people without BPPV and matched them with the BPPV patients according to gender, age, and index year. Cox proportional hazard regressions were performed to compute the hazard ratio (HR) of dementia after we adjusted for demographic characteristics and comorbidity. RESULTS: The prevalence of comorbidity was higher among patients with BPPV than among those without BPPV. In addition, patients with BPPV exhibited a 1.24-fold (95% confidence interval, CI 1.09-1.40; P < 0.001) higher risk of dementia than those without BPPV after we adjusted for age, gender, and comorbidity. An analysis stratified according to demographic factors revealed that women with BPPV exhibited a 1.36-fold (95% CI 1.16-1.59; P < 0.001) higher risk of dementia. Patients with BPPV aged over 65 years exhibited a significantly higher risk of dementia (adjusted HR: 1.26; 95% CI 1.10-1.43; P < 0.001) than those without BPPV. CONCLUSIONS: Patients with BPPV exhibited a higher risk of dementia than those without BPPV. PMID- 26932877 TI - Access to Cesarean Section Will Reduce Maternal Mortality in Low-Income Countries: A Mathematical Model. AB - BACKGROUND: Despite global efforts to reduce the maternal mortality ratio (MMR) through the World Health Organization's (WHO) Millennium Development Goal 5 (MDG5), MMR remains unacceptably high in low-income countries (LICs). Maternal death and disability from hemorrhage, infection, and obstructed labor may be averted by timely cesarean section (CS). Most LICs have CS rates less than that recommended by the WHO. Without access to timely CS, it is unlikely that MMR in LICs will be further reduced. Our purpose was to measure the MMR gap between the current MMR in LICs and the MMR if LICs were to raise their CS rates to the WHO recommended levels (10-15 %). METHODS: This model makes the assumption that increasing the CS rates to the recommended rates of 10-15 % will similarly decrease the MMR in these LICs. WHO health statistics were used to generate estimated MMRs for countries with CS rates between 10 and 15 % (N = 14). A weighted MMR average was determined for these countries. This MMR was subtracted from the MMR of each LIC to determine the MMR gap. The percent decrease in MMR due to increasing CS rate was calculated and averaged across the LICs. RESULTS: We found an average 62.75 %, 95 %CI [56.38, 69.11 %] reduction in MMR when LICs increase their CS rates to WHO recommended levels (10-15 %). CONCLUSIONS: Maternal mortality is unacceptably high in LICs. Increasing CS rates to WHO recommended rates will decrease the maternal mortality in these countries, significantly decreasing the mortality ratio toward the projected MDG5. PMID- 26932876 TI - Analysis of Risk Factors for Gunshot Wound Infection in a Nigerian Civilian Trauma Setting. AB - BACKGROUND: Survivors of firearm injury are at risk of wound infection. On average, civilian gunshot wound infection rates in developing countries are relatively high and almost on a par with infection rates in war trauma settings. Overall, there are limited data on civilian gunshot wound infection and its predisposing factors. The aim of this study was to determine the risk factors for gunshot wound infection in a civilian trauma setting of a developing nation. MATERIALS AND METHOD: This was a retrospective analysis of data on the entire patients who presented in Federal Teaching Hospital Abakaliki with firearm injury from January 2005 to December 2014. RESULTS: There were 196 patients, and wound infection was a complication in 58 (29.6 %) of them. The significant factors for high wound infection rate in univariate analysis were perforating wound (p < 0.001), high velocity injury (p < 0.001), haematocrit <30 % (p < 0.001), presence of fracture (p < 0.001), hollow viscus injury (p < 0.001) and injury to hospital arrival interval later than 6 h (p < 0.014). Anatomical site of injury correlated with infection rate (p < 0.001), highest rate (40.6 %) in lower extremity and least (9.1 %) in head and neck wounds. Multivariate logistic regression analysis identified haematocrit (p < 0.001), perforating wound (p < 0.021), presence of fracture (p < 0.043) and hollow viscus injury (p < 0.039) as independent predictors of gunshot wound infection. CONCLUSION: The independent predictors of infection identified in this study call for judicious replacement of blood loss and high priority accorded to perforating wound, fractures and hollow viscus injury in interventions aimed at reducing gunshot wound infection rate. PMID- 26932878 TI - Improving Minimally Invasive Adrenalectomy: Selection of Optimal Approach and Comparison of Outcomes. AB - INTRODUCTION: Minimally invasive adrenalectomy is commonly performed by either a transperitoneal laparoscopic (TLA) or posterior retroperitoneoscopic (PRA) approach. Our group described the technique for robot-assisted PRA (RAPRA) in 2010. Few studies are available that directly compare outcomes between the available operative approaches. We reviewed our results for minimally invasive adrenalectomy using the three different approaches over a 10-year period. METHODS: Between January 2005 and April 2015, 160 minimally invasive adrenalectomies were performed. Clinicopathologic data were prospectively collected and retrospectively analyzed. The primary endpoints evaluated were operative time, blood loss, length of stay (LOS), and morbidity. RESULTS: The study included 67 TLA, 76 PRA, and 17 RAPRA procedures. Tumor size for PRA/RAPRA was smaller than for patients undergoing TLA (2.38 vs 3.6 cm, p <= 0.0001). Procedure time was shorter for PRA versus TLA (133.3 vs 152.8 min, p = 0.0381), as was LOS (1.85 vs 2.82 days, p = 0.0145). Procedure time was longer in RAPRA versus TLA/PRA (177 vs 153/133 min, p = 0.008), but LOS was significantly decreased (1.53 vs 2.82/1.85 days, p = 0.004). CONCLUSIONS: Minimally invasive adrenalectomy is associated with expected excellent outcomes regardless of approach. In our series, the posterior approach is associated with decreased operative time and LOS. Robotic technology provides potential advantages for the surgeon at the expense of more complex setup requirements and costs. Further study is required to demonstrate clear benefit of one surgical approach. Utilization of the entire spectrum of available operative techniques can allow for selection of the optimal approach based on individual patient factors. PMID- 26932879 TI - Child with Jaundice and Pruritus: How to Evaluate? AB - Jaundice with pruritus is a manifestation of cholestasis. The defective biliary drainage causes accumulation of substances that are usually excreted in bile, which in turn causes pruritus. The exact nature of the pruritogen is under evaluation. However, lysophosphatidic acid is the current favourite. The causes of cholestasis can be broadly classified as intra or extrahepatic, with intrahepatic disorders being more often associated with pruritus. Cholestatic phase of acute viral hepatitis, progressive familial intrahepatic cholestasis, syndromic and non-syndromic paucity of intralobular bile ductules, drug induced cholestasis and sclerosing cholangitis (SC) are the common causes in children. An algorithmic approach facilitates early etiological diagnosis by careful clinical evaluation combined with investigations including gamma glutamyl transpeptidase, radiological imaging (ultrasonography, magnetic resonance cholangiopancreatography), liver biopsy and genetic analysis. Management is largely supportive and includes nutritional rehabilitation with supplement of fat soluble vitamins and calcium, stepwise therapy of pruritus with drugs (ursodeoxycholic acid, rifampicin, bile acid sequestrants and/or opioid antagonists) and biliary diversion surgery. Complications of advanced liver disease and portal hypertension need to be addressed. Liver transplantation is required in children with refractory pruritus affecting the quality of life or those with end stage liver disease. Relief of biliary obstruction by endoscopy or surgery and treatment of diseases associated with SC like histiocytosis may be rewarding. Long-term follow-up for development of complications of liver disease and hepatocellular/ cholangiocarcinoma is essential. Thus, an early diagnosis and stepwise treatment with an understanding of the pathogenesis of pruritus in cholestatic disorders may decrease morbidity and mortality. PMID- 26932881 TI - [From standard to precision treatment: the development of surgery for gastric cancer]. AB - Gastric cancer remains a significant health problem worldwide. The incidence of gastric cancer is the 5(th) of all the malignancies, and the mortality is the 3(rd). The type and resection area of gastric cancer surgery have changed a lot. D2 lymph node dissection is recommended for locally advanced gastric cancer. Prophylactic pancreatectomy or splenectomy is not necessary for radical resection. Indication of minimally invasive surgery is confined to early gastric cancer with distal gastrectomy. Less extensive approach of early stage cases is suitable, and application of sentinel lymph node is a potential method. Meanwhile, the development of chemotherapy, radiotherapy, targeted therapy and immunotherapy during the perioperative period also improved the prognosis of gastric cancer patients. Recently, the development of molecular biology, such as the maturity of the new generation sequencing approach, started a new era of precision treatment for gastric cancer. PMID- 26932880 TI - [Current status and prospect of perioperative thrombus management in gastrointestinal cancer]. AB - Thanks to the progress of surgical theory and skills, as well as the application of modern medical devices in general surgery, both the occurrence of perioperative complications and mortality of gastrointestinal surgery have significantly reduced recently. However, it is still far from optimal in terms of the perioperative venous thromboembolism (VTE) management in gastrointestinal cancer, and what is responsible for that? This paper aims at finding out the reasons contributing to the current status, giving suggestions for how to make improvement at both disease level and hospital management level. At the same time, while paying attention for the prophylaxis of VTE, there have been more and more patients receiving antithrombotic treatment require elective or emergent surgery in clinical practice, due to aging and increased incidence of cardiovascular disease year by year. How to balance the bleeding and thrombosis risk for these patients during perioperative periods is also a question we are going to discuss. In conclusion, as to the issue of the management of perioperative thrombosis, there will be a long way for Chinese doctors to go. Our peers should pay more attention to this problem and take more efforts, so that the thrombotic complications in surgical patients can be reduced. PMID- 26932882 TI - [The conversion therapy for unresectable gastric cancer]. AB - The unresectable gastric cancer refers to be unable to accept radical gastrectomy because of advanced stage, which is mainly treated with adjuvant chemotherapy, and obtains only poor prognosis in the past. In recent years, however, some scholars found that the unresectable gastric cancer cases which were treated with systematic chemotherapy, radiochemotherapy, interventional therapy, hyperthermic intraperitoneal peroperative chemotherapy and so on, could be converted into resectable (radical D2 gastrectomy) cases successfully, and their survival time and quality of life are promoted significantly. The conversion therapy for unresectable gastric cancer provides a novel surgical strategy for the comprehensive treatment of part of the advanced gastric cancer patients. PMID- 26932883 TI - [An introduction of surgical update in 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer]. AB - Both of the incidences of thyroid nodules and thyroid cancer have increased in recent years, which have attracted extensive attention. Surgical treatment plays an important role on the management of thyroid nodules and differentiated thyroid cancer (DTC). Usually patients will have an excellent prognosis after standard surgery, in the meantime, they will suffer from wrongly performed operation, which induces bad outcomes for the patients and their families both physically and psychologically, as well as economic burden. There are many guidelines concerning the suitable treatment for thyroid nodules and thyroid cancer all over the world, and the most famous one is American Thyroid Association (ATA) Management Guidelines for Patients with Thyroid Nodules and DTC in 1996 and the revised version in 2009. Over the past several years, there have been many advances in both the diagnosis and treatment of thyroid nodules and DTC. As a result, the ATA had updated the guidelines in 2015. In this article, we introduced the surgical update in 2015 ATA management guidelines for adult patients with thyroid nodules and DTC compared to the 2009 version, which consists of appropriate operation for thyroid nodules and DTC, operation for pregnant women with DTC, lymph node dissection, completion thyroidectomy, appropriate perioperative approach to voice and parathyroid, and surgery for advanced cancer. PMID- 26932884 TI - [Application of da Vinci robotic surgical system in radical resection of gastric and colorectal cancer: a report of 647 cases]. AB - OBJECTIVE: To investigate the feasibility and safety of robotic-assisted radical resection of gastric and colorectal cancer. METHODS: The clinical data of 305 patients who received radical resection of gastric cancer and 342 patients who received radical resection of colorectal cancer both accomplished by the da Vinci robotic surgical system at the Southwest Hospital, Third Military Medical University from March 2010 to December 2014 were retrospectively analyzed. In gastric cancer group, radical total gastrectomy were performed in 69 cases, proximal gastrectomy in 11 cases, distal gastrectomy in 213 cases and 12 cases of gastric stump cancer.In colorectal cancer group, radical resection of the right colon were performed in 6 cases, left colon in 4 cases, transverse colon in 1 case, sigmoid colon low anterior resection procedure in 24 cases, rectal low anterior resection procedure in 222 cases, abdominoperineal excision procedure in 79 cases and Hartmann procedure in 6 cases. RESULTS: All cases had robotic assisted radical resection successfully. In gastric cancer group, the mean operation time was (226+/-62) minutes, the mean blood loss was (125+/-77) ml, the mean number of harvested lymph nodes was 34+/-10; the mean time for patients taking normal activity was (3.2+/-1.5) days, the mean time for gastrointestinal function recovery was (3.1+/-1.3) days, the mean time for taking liquid food was (3.5+/-1.9) days. The mean hospitalization was (7.9+/-3.7) days postoperatively. In colorectal group, the mean operation time was (181+/-61) minutes, the mean blood loss was (110+/-93) ml, the mean number of harvested lymph nodes was 19+/ 6; the mean time for patients taking normal activity was (2.9+/-1.5) days, passage of first flatus was (2.7+/-1.7) days. The mean hospitalization was (7.1+/ 1.6) days postoperatively. Surgical complications occurred in 28 patients (9.2%) of gastric cancer group and 30 patients (8.8%) of colorectal cancer group, all the cases were recovery before leaving hospital with non-operation therapy. The short-term efficiency was obvious. CONCLUSION: Robotic-assisted radical resection for gastric and colorectal cancer is a feasible and safe surgical procedure combined the minimal trauma and fast recovery. PMID- 26932885 TI - [Retrospective clinical analysis of surgical treatment for gastric stump carcinoma]. AB - OBJECTIVES: To investigate the clinical feature and surgical procedures of gastric stump carcinoma (GSC) and to identify the prognostic factors which influence survival rate of GSC patients. METHODS: Clinical data of 167 patients who underwent R0 resection for gastric stump carcinoma at Chinese People's Liberation Army General Hospital between January 1990 and December 2012 was collected. There were 144 male and 23 female cases. The clinicopathological features of GSC patients were compared between those who underwent initial surgery for benign disease (GSC-B group, 78 cases) and for gastric cancer (GSC-M group, 89 cases). The analysis of therapeutic methods and survival time were also performed.t-test was used to compare the quantitative data between two groups. Pearson chi(2) test was used to compare the various clinicopathological characteristics between the two groups. Kaplan-Meier method was used to analyze the survival rate. Multivariate survival analysis was based on the Cox proportional hazard model. RESULTS: Compared with GSC-M group, the interval time between initial gastrectomy and surgery in GSC-B group was longer ( (28.2+/-10.2) years vs. (10.8+/-1.0) years, t=15.902, P=0.001). There were 56 patients (71.8%) who received BillrothI reconstruction in GSC-B group, and 49 patients (55.1%) who received BillrothII reconstruction in GSC-M group, the difference of anastomosis method between the two groups was statistically significant (chi(2)=25.770, P=0.001). Compared with GSC-M group, the tumor of GSC-B group was usually located at the anastomotic site (chi(2)=6.975, P=0.031). The overall 1-, 3-, and 5-year survival rates of the 167 patients were 87%, 60%, and 41%. The 5-year survival rates for TNM stagesI, II, and III were 65%, 43%, and 22%, respectively (P= 0.001). Multivariate analysis showed that small intestinal or esophageal infiltration (HR=1.957, 95%CI: 1.096 to 3.494, P=0.023), tumor location (HR=1.618, 95%CI: 1.104 to 2.372, P=0.014), and TNM stage (HR=2.307, 95%CI: 1.708 to 3.118, P=0.001) have independent effect on survival. The metastasis rates of perigastric lymph nodes, jejunum anastomosis and mesenteric lymph nodes were very high (56.3% and 65.2%, respectively). CONCLUSIONS: The GSC appears earlier in patients with gastrectomy for malignant disease than those with benign disease. Appropriate curative resection including residual lymph node dissection is very important to improve the prognosis. Small intestinal or esophageal infiltration, tumor location, and TNM stage have independent effect on survival. PMID- 26932886 TI - [The clinical characteristics and the diagnosis and treatment of tumors of duodenal papilla]. AB - OBJECTIVE: To assess the clinical features, diagnosis, treatment and prognosis of duodenal papilla tumors. METHODS: The clinical data of 76 patients diagnosed as tumor of duodenal papilla for endoscopic or surgical treatment, in the Second Affiliated Hospital of Zhejiang University, School of Medicine since April 2004 to April 2015 were collected and analyzed retrospectively. There were 50 male and 26 female patients aging from 38 to 83 years with a median age of 62 years. All patients were diagnosed by ultrasound, CT or endoscopic retrograde cholangiopancreatography. All the 76 patients accepted surgical treatment, among which 61 cases accepted pancreaticoduodenectomy, 6 cases accepted trans-duodenum papillae resection and reconstruction, 5 cases accepted endoscopic duodenal papilla tumor resection and 4 cases accepted palliative operations. Kaplan-Meier method was used to analyze the survival rate. RESULTS: Among the 76 cases of patients, the pathological diagnosis included 10 cases of benign tumors, 8 cases of precancerous lesions, 58 cases of malignant tumor. Death cases were not caused by postoperative complications. Coincidence rate of preoperative biopsy and postoperative pathological diagnosis was 77.6%. Postoperative follow-up was 2 to 120 months, the results showed that the 1, 3, 5 year survival rates were 73.2%, 51.8%, 32.1% for 53 patients with duodenal papillary carcinoma. CONCLUSIONS: Duodenal papilla tumors had varied clinical manifestations, ultrasound, CT and endoscopic examination and ERCP can improve the diagnostic rate of duodenal papilla tumors. For benign tumors and early stage malignant tumors, local excision or endoscopic resection was safe and effective. For advanced malignancies, radical pancreaticoduodenectomy was essential. PMID- 26932887 TI - [Analysis of intrahepatic Glisson's sheath vascular disconnection approach for anatomical hepatectomy by three-dimensional laparoscope]. AB - OBJECTIVE: To investigate the clinical value of the intrahepatic Glisson's sheath vascular disconnection approach for anatomical hepatectomy by three dimensional(3D) laparoscope. METHODS: Twenty-two patients(11 liver cancer and 11 benign diseases)underwent hepatectomy in Zhujiang Hospital, Southern Medical University from November 2013 to March 2015 were involved. All patients were performed anatomical hepatectomy by 3D laparoscope with the intrahepatic Glisson's sheath vascular disconnection approach.The anatomical time of first hepatic portal, operation time, intraoperative bleeding, postoperation hospitalization and the complication incidences were observed. RESULTS: All the 22 cases were performed successfully with the intrahepatic Glisson's sheath vascular disconnection and the anatomic hepatectomy. The anatomical time of first hepatic portal, operation time, intraoperative bleeding, the postoperation hospitalization duration and complication incidence rate were(43+/-14) minutes(22 74 minutes), (295+/-89) minutes(105-480 minutes), (546+/-390) ml (50-1 500 ml), (9.8+/-2.8) days(5-16 days) and 18.2%(4/22)in 22 patients, respectively. There was no death. CONCLUSIONS: With the help of 3D laparoscope, the anatomy of Glisson pedicle could perform precisely and the dissection of vessels would be easy and accuracy. The 3D laparoscope is feasible for performing the anatomical hepatectomy. PMID- 26932888 TI - [Analysis of 113 cases with mucinous cystic neoplasms in a single institutional study]. AB - OBJECTIVE: To describe the clinicopathological characteristics and prognostic factors of mucinous cystic neoplasm(MCN). METHODS: One hundred and thirteen patients with MCN comfirmed by histological examination admitted in People's Liberation Army General Hospital from January 1994 to June 2015 were analyzed, including 21 male and 92 female patients with mean age of (50.2+/-14.5) years. Forty-eight patients had incidental discovery of their cystic neoplasm for another reason, 65 patients were symptomatic, and abdominal pain or distension was main clinical symptom. Among 113 patients with MCN, 75 cases were MCN with dysplasia, and 38 cases were MCN with invasive carcinoma. Wilcoxon test and chi(2) test, et al were used to analyzed the data, respectively. RESULTS: MCN was mostly located in body and tail of pancreas.Sex, mean age, clinical symptom, tumor size, and CA19-9 showed significant difference between MCN with dysplasia and MCN with invasive carcinoma (all P<0.05). The presence of a solid component (chi(2)=32.460, P=0.000)and main pancreatic duct dilation(chi(2)= 5.729, P=0.022) were significantly associated with malignancy. Fifty-eight patients with dysplasia were followed up, only one patient occurred tumor recurrence. Thirty one patients with malignancy were followed up, among which there were 22 patients dead, 1-, 3-, 5-year survival of MCN with malignancy was 76.9%, 56.5%, 36.6%, respectively. Lymphatic metastasis and tumor recurrence were important prognostic factors of MCN with malignancy(both P<0.05). CONCLUSIONS: MCN is most affected by old female with no specific symptom, most tumors are located at the body and tail of the pancreas.MCN with dysplasia have excellent prognosis underwent surgery. Even with complete resection, the long-term survival of MCN with malignancy is not satisfied. PMID- 26932889 TI - [Viability of extended distal pancreatectomy for pancreatic adenocarcinoma of the body or tail]. AB - OBJECTIVE: To analyze the viability of extended distal pancreatectomy and the associated prognostic factors. METHODS: The data of 57 patients with pancreatic adenocarcinoma who underwent standard distal pancreatectomy(DP) or extended distal pancreatectomy(EDP) from January 2011 to December 2014 were reviewed retrospectively. Thirty-five patients were performed with DP and 22 with EDP. Operation safety and survival benefit between DP and EDP were compared by t-test or chi(2) test.Cox regression analysis was used to explore the prognostic indicators. RESULTS: Compared to DP group, operation time((255+/-91)min vs.(208+/ 80)min)(t=2.066, P=0.044) and ratio of blood transfusion (50.0% vs.17.1%)(chi(2)=12.836, P=0.008) were greater in EDP group, respectively.There were no significant differences in amount of intraoperative blood loss and postoperative duration of hospitalization. Delayed gastric emptying was greater in EDP(22.7% vs.2.9%)(Z=-2.251, P=0.027), while other complications had no differences. Mortality and ratio of relaparotomy also showed no differences. Median survival following DP was 13.1 months compared to 8.2 months following EDP. There was no difference in survival between DP and EDP. According to the results of multivariate analysis, tumor size(RR=1.275, P=0.03)and perioperative blood transfusions(RR=2.673, P=0.04) were independent prognostic factors. CONCLUSIONS: Though patients with pancreatic adenocarcinoma who undergo EDP have a worse pathologic staging, they will gain a comparable long-term survival to the patients undergo DP. Tumor size and perioperative blood transfusions are independent prognostic factors. PMID- 26932890 TI - [Risk factors of hypoparathyroidism following total or near total thyroidectomy]. AB - OBJECTIVE: To study the risk factors for postoperative hypoparathyroidism or hypocalcemia. METHODS: Totally 414 patients with thyroid diseases who underwent total or near total thyroidectomy at Department of Head and Neck Surgery, Peking University Cancer Hospital and Institute from June 2007 to June 2014 were studied retrospectively. There were 119 male and 295 female patients with a median age of 47 years. The clinical and pathological features that related to post-operative hypoparathyroidism were studied by chi(2) test and multivariate Logistic regression analysis. RESULTS: Of the 414 patients, 36.2% developed transient hypocalcemia, 36.5% developed transient hypoparathyroidism, 2.2% developed permanent hypoparathyroidism. In regression analysis, unilateral or bilateral center lymph node dissection were associated with mild transient hypocalcemia after surgery (OR=2.366, P=0.022; OR=5.216, P=0.000); unilateral or bilateral center lymph node dissection as well as surgical options were significant risk factors for severe transient hypocalcemia (OR=4.029, P=0.001; OR=8.384, P=0.000; OR=2.073, P=0.017) and hypoparathyroidism (OR=1.755, P=0.040; OR=4.144, P=0.000; OR=2.287, P=0.000). The parathyroid hormone concentration on postoperative day 1 was an independent risk factor for permanent hypoparathyroidism (OR=2.011, P=0.014). The concentration of parathyroid hormone threshold <5.28 ng/L was a predictor to permanent hypoparathyroidism with accuracy of 95.0%. CONCLUSIONS: Bilateral center lymph node dissection is a risk factor of permanent hypoparathyroidism in patients received total thyroidectomy should be taken thoughtfully. The parathyroid hormone concentration on postoperative day 1 provides better prediction for persistent hypoparathyroidism. PMID- 26932891 TI - [A biomechanical evaluation of odontoid screw plate fixation system]. AB - OBJECTIVE: To evaluate the biomechanical stability of anterior odontoid screw plate (AOSP). METHODS: Eight fresh-frozen cadaveric cervical spine specimens were subjected to stepwise destabilization of the C1-C3 complex, simulating a type I Hangman fracture, type II odontoid fracture, and the C2-3 disc injury. Intact specimens, fractured specimens, and fractured specimens with posterior, anterior fixation techniques were divided into six groups: control group (intact), injury group of type II odontoid fracture and type I Hangman fracture combined with C2-3 disk injury, after anterior cervical plate+ odontoid screw+ cage (ACP+ OS+ cage) group, after anterior odontoid screw plate (AOSP) fixation system group, after affixing rods from pedicle screws in C2 to lateral mass screws in C3+ odontoid screw (C2PS+ C3LMS+ OS) group, after affixing rods from pedicle screws in C1 to pedicle screws in C2 and lateral mass screws in C3 (C1PS+ C2PS+ C3LMS) group. The range of motion (ROM) and neutral zone of C1-C2 and C2-C3 segment was tested. RESULTS: There was statistically significant difference between the C1PS+ C2PS+ C3LMS fixation group and the AOSP fixation group of ROMC1-C2(P<0.05). During all loading modes, AOSP+ Bone graft fixation significantly outperformed the ACP+ OS+ cage fixation in limiting ROMC2-C3. During flexion and extension, AOSP fixation significantly outperformed the C1PS+ C2PS+ C3LMS fixation and C2PS+ C3LMS+ OS fixation in limiting ROMC2-C3. CONCLUSION: The AOSP fixation system has excellent biomechanical performance when dealing with type I Hangman fracture, type II odontoid fracture, and the C2-3 disc injury, and appear to be a safe and effective technique for dealing with the combined injury. PMID- 26932892 TI - [Value of perineural invasion in prostatectomy specimen in the assessment on tumor progression and prognosis]. AB - OBJECTIVE: To assess perineural invasion in prostatectomy specimen(PNIp)on tumor progression and prognosis after radical prostatectomy. METHODS: Retrospective analysis including 502 prostate cancer patients admitted in Renji Hospital, School of Medicine, Shanghai Jiaotong University from December 2002 to May 2014 was studied.Differences of serum prostate specific antigen(PSA), Gleason score of prostate biopsy, Gleason score of prostatectomy specimen, tumor stage, capsular invasion, positive surgical margin, seminal invasion, pelvic lymph node metastasis, nadir PSA were analyzed in patients with PNIp and without PNIp. Logistic regression analysis, Log-rank test and Cox regression analysis was used to analyzed the data, respectively. RESULTS: There were 91 patients with PNIp(18.1%) and 411 patients without PNIp(81.9%). Differences of serum PSA, Gleason score of prostate biopsy, Gleason score of prostatectomy specimen, tumor stage, capsular invasion, seminal invasion, nadir PSA between the two groups were found(all P<0.05). In the multivariable logistic regression analysis, PNIp was independent predictor of Gleason score of prostate biopsy, Gleason score of prostatectomy specimen, tumor stage, capsular invasion(OR=1.515, 1.955, 2.069, 1.859, all P<0.05). One hundred and twenty-one patients with biochemical serum recurrence(26.7%). Serum PSA, Gleason score of prostate biopsy, Gleason score of prostatectomy specimen, tumor stage, PNIp, seminal invasion were related to biochemical serum recurrence(P<0.05). In the multivariable cox regression analysis, serum PSA, Gleason score of prostate biopsy, PNIp, seminal invasion were independent predictors of biochemical serum recurrence(HR=1.021, 1.441, 1.663, 3.257, all P<0.05). CONCLUSION: PNIp is the important predictor of the tumor progression and prognosis of prostate cancer. PMID- 26932894 TI - [Advances on endoscopic treatment of intestinal fistulas]. AB - Intestinal fistulas are severe complications after abdominal surgical procedures. The endoscopic therapy makes it possible to close fistulas without surgical interventions. When patients achieved stabilization and had no signs of systemic sepsis or inflammation, these therapies could be conducted, which included endoscopic vacuum therapy, fibrin glue sealing, stents, fistula plug, suture, and Over The Scope Clip (OTSC). Various techniques may be combined. Endoscopy vacuum therapy could be applied to control systemic inflammation and prevent continuing septic contamination by active drainage. Endoscopic stent is placed over fistulas and gastrointestinal continuity is recovered. The glue sealing is applied for enterocutaneous fistulas, and endoscopy suture has the best results seen in fistulas <1 cm in diameter. Insertion of the fistula plug is used to facilitate fistula healing. The OTSC is effective to treat leaks with large defects. Endoscopic treatment could avoid reoperation and could be regarded as the first line treatment for specific patients. PMID- 26932893 TI - [Artemisinin inhibits proliferation of gallbladder cancer cell lines through triggering cell cycle arrest and apoptosis]. AB - OBJECTIVE: To evaluate the effects of artemisinin on proliferation, cell cycle and apoptosis of gallbladder cancer cells. METHODS: Gallbladder carcinoma cell lines(GBC-SD and NOZ)were cultured in vitro. The effects of artemisinin in different concentration on proliferation of the two cell lines in vitro were examined using MTT assay. The cell cycle distribution of GBC-SD and NOZ cells 24 h after treatments with artemisinin(20 MUmol/L) were examined using flow cytometry. The apoptosis of GBC-SD and NOZ cells 24 h after treatments with artemisinin (20 MUmol/L) were examined using Annexin V/PI staining.The expressions of p-ERK1/2, CDK4, cyclin D1, p16, cytochrome C and caspase-3 were examined by Western blot assay. t-test and one way ANOVA were used to evaluate the differences between two groups and more than two groups, respectively. RESULTS: The cell proliferation was significantly inhibited by artemisinin, the IC50 of artemisinin against GBC-SD and NOZ cells were 14.05 MUmol/L and 12.42 MUmol/L, respectively.Artemisinin induced cycle arrest, and G1 population of GBC SD and NOZ cells increased to 74.60% and 78.86%. Cell apoptosis and apoptotic population of GBC-SD and NOZ cells were increased to 15.67% and 16.51% after dealt with artemisinin, respectively. In addition, expression of p16 was increased, and expressions of p-ERK1/2, CDK4 and cyclin D1 were down-regulated by artemisinin(all P<0.05). Cytochrome C was released from mitochondria to cytoplasm leading to the activation of caspase-3 and PARP after dealt with artemisinin(P<0.05). CONCLUSION: The inhibition effect of artemisinin on the proliferation gallbladder cancer cells is accompanied by down-regulation of ERK1/2 signaling pathway, G1 phase arrest and triggering caspase-3-mediate apoptosis. PMID- 26932895 TI - [New progress of BRAF gene and thyroid cancer]. AB - It is noteworthy that the incidence of thyroid cancer around the world has increased significantly in recent decades, raising an imperative need to research its pathogenesis, diagnosis and treatment. Up to now, fine needle aspiration biopsy (FNAB) of thyroid has been acknowledged to discriminate benign from malignant thyroid nodules with the highest sensitivity and specificity. However, 10% to 40% thyroid nodules cannot be discriminated by FNAB. Therefore, it is vitally important to look for highly-correlated tumor makers in molecule level. BRAF mutation is a focus in thyroid cancer research, and some studies showed that this mutation is essential to the onset and development of thyroid cancer, especially papillary thyroid cancer. Joint detection of BRAF mutation could improve diagnostic sensitivity of thyroid cancer, which is crucial for thyroid cancer diagnosis and classification. As for treatment, the discovery of target gene enabled molecule therapy for thyroid cancer, raising hopes for patients with thyroid cancer that refractory to conventional treatments. Currently, many molecule therapeutics relating to BRAF has already undergone clinical trials. It is believed that further research on BRAF-thyroid cancer relationship could create a new field for diagnosis and treatment of thyroid cancer, and set a mode for discovering others molecule markers. PMID- 26932896 TI - Esophageal Submucosal Injection of Capsaicin but Not Acid Induces Symptoms in Normal Subjects. AB - BACKGROUND/AIMS: Transient receptor potential vanilloid-1 (TRPV1) is a candidate for mediating acid-induced symptoms in the esophagus. We conducted studies to determine if the presence of acid in the mucosa/submucosa and direct activation of TRPV1 by capsaicin elicited symptoms in normal healthy subjects. We also studied the presence of TRPV1 receptors in the esophagus. METHODS: Unsedated endoscopy was performed on healthy subjects with no symptoms. Using a sclerotherapy needle, normal saline (pH 2.0-7.5) was injected into the mucosa/submucosa, 5 cm above the Z line. In a separate group of healthy subjects, injection of capsaicin and vehicle was also studied. Quality of symptoms was reported using the McGill Pain Questionnaire, and symptom intensity using the visual analogue scale (VAS). Immunohistochemistry was performed on 8 surgical esophagus specimens using TRPV1 antibody. RESULTS: Acid injection either did not elicit or elicited mild symptoms in subjects at all pH solutions. Capsaicin but not the vehicle elicited severe heartburn/chest pain in all subjects. Mean VAS for capsaicin was 91 +/- 3 and symptoms lasted for 25 +/- 1 minutes. Immunohistochemistry revealed a linear TRPV1 staining pattern between the epithelial layer and the submucosa that extended into the papillae. Eighty-five percent of papillae stained positive for TRPV1 with a mean 1.1 positive papillae per high-powered field. CONCLUSIONS: The mechanism of acid-induced heartburn and chest pain is not the simple interaction of hydrogen ions with afferents located in the esophageal mucosa and submucosa. TRPV1 receptors are present in the lamina propria and their activation induces heartburn and chest pain. PMID- 26932897 TI - Protective Effect of Proton Pump Inhibitor for Survival in Patients with Gastroesophageal Reflux Disease and Idiopathic Pulmonary Fibrosis. AB - BACKGROUND/AIMS: The prevalence of gastroesophageal reflux disease (GERD) is high in patients with idiopathic pulmonary fibrosis (IPF). GERD may cause chronic microaspiration that leads to repeated subclinical lung injury, which leads to pulmonary fibrosis. Although some studies have suggested that proton pump inhibitors (PPI) were associated with a good prognosis in IPF, their effects remain unclear. METHODS: We retrospectively reviewed 786 consecutive adult patients with IPF at Seoul National University Bundang Hospital between April 2003 and March 2015. RESULTS: Mean duration of follow-up was 2.6 +/- 2.8 years. Of the 786 patients with IPF, 107 (13.6%) were given diagnoses of GERD, and 103 (13.1%) died due to IPF-related pneumonia or respiratory failure. The prevalence of GERD and the cumulative incidence of de novo GERD increased depending on the period of follow-up in patients with IPF. Patients administered PPI for more than four months had a lower IPF-related mortality rate than patients on PPI less than 4 months (Log-rank P -value = 0.024 in Kaplan-Meier curve). In a univariate and multivariate Cox regression hazard model, younger age (hazard ratio [HR], 1.06; 95% CI, 1.03-1.10; P = 0.001), higher initial forced vital capacity (HR, 0.98; 95% CI, 0.96-0.99; P = 0.004), and longer duration of PPI use (HR, 0.97; 95% CI, 0.95-1.00; P = 0.022), but not a diagnosis of GERD, were significantly associated with lower IPF-related mortality. CONCLUSIONS: In Korean patients with IPF, the prevalence of GERD was lower than in other countries. PPI use for at least 4 months may have a protective effect against IPF-related mortality. PMID- 26932898 TI - The Effect of DA-9701 in Opioid-induced Bowel Dysfunction of Guinea Pig. AB - BACKGROUND/AIMS: Opioid induced bowel dysfunction (OIBD) is associated with decreased gastrointestinal (GI) propulsive activity due to intake of opioid analgesics. DA-9701, a novel prokinetic agent formulated with Pharbitis Semen and Corydalis Tuber has promising effects on GI motor function. Therefore, we aim to evaluate the prokinetic effects of DA-9701 in an OIBD model of guinea pig. METHODS: The ileal and distal colon muscle contraction in presence of different doses of DA-9701, morphine, and combination (morphine + DA-9701) was measured by tissue bath study. The prokinetic effect of DA-9701 was assessed by charcoal transit and fecal pellet output assay in an OIBD model of guinea pig. RESULTS: DA 9701 significantly increased the amplitude and area under the curve of ileal muscle contraction, while there was insignificant effect on the distal colon compared to the control. The maximal amplitude of ileal muscle contraction was acquired at a concentration of 10 MUg/mL of DA-9701. In contrast, morphine significantly decreased the amplitude of ileal and distal colon muscle contraction compared to the control. Morphine delayed both upper (P < 0.01) and lower (P < 0.05) GI transit, and delayed GI transit was restored by the administration of DA-9701. Morphine induced reduction of contractility was significantly ameliorated by addition of DA-9701 in both ileal and distal colon muscles. CONCLUSIONS: DA-9701 significantly increased the amplitude of contraction of the ileal muscle, however the distal colon muscle contraction was insignificant. Additionally, it restored delayed upper and lower GI transit in an OIBD model of guinea pig, and it might prove to be a useful candidate drug in a clinical trial for OIBD. PMID- 26932899 TI - Post-stroke restless leg syndrome and periodic limb movements in sleep. AB - OBJECTIVES: Primary restless leg syndrome (RLS) and periodic limb movements in sleep (PLMS) frequently co-exist, obscuring the boundaries between the two conditions. In such instances, a study of secondary cases with focal lesions such as post-stroke RLS and PLMS (psRLS and psPLMS, respectively) can be helpful in identifying characteristics of the individual conditions. MATERIALS AND METHODS: Patients who had suffered strokes and who subsequently developed psRLS or psPLMS were recruited. To determine the overall features of psRLS/PLMS, historical cases were selected from the literature. All cases with either psRLS or psPLMS alone were further analyzed to elucidate the distinctive pathomechanisms of the two conditions. RESULTS: Six patients with either psRLS or psPLMS were recruited from our hospital; two patients had both conditions contemporaneously. The literature contains details on 30 cases of psRLS or psPLMS. The causative lesion was most frequently located in the pons. We found that psRLS was more often bilateral, and usually detected later in time. Lesions in both the pontine base and tegmentum (together) were associated with unilateral psPLMS, whereas lesions in the corona radiata and adjacent basal ganglia were associated with bilateral RLS. Lesions confined to the corona radiata resulted in either unilateral or bilateral RLS. CONCLUSIONS: The observed differences in the clinical and radiological features of psRLS and psPLMS suggest that the pathophysiologies of the two conditions are distinct. Further research is needed to understand the pathophysiologies of primary RLS and PLMS. PMID- 26932900 TI - Erratum to: Deletion of arcA increased the production of acetyl-CoA-derived chemicals in recombinant Escherichia coli. PMID- 26932901 TI - Erratum to: Research advances in expansins and expansin-like proteins involved in lignocellulose degradation. PMID- 26932902 TI - Strain improvement of Trichoderma viride for increased cellulase production by irradiation of electron and (12)C(6+)-ion beams. AB - OBJECTIVES: To improve cellulase production and activity, Trichoderma viride GSICC 62010 was subjected to mutation involving irradiation with an electron beam and subsequently with a (12)C(6+)-ion beam. RESULTS: Mutant CIT 626 was the most promising cellulase producer after preliminary and secondary screening. Soluble protein production and cellulase activities were increased mutifold. The optimum temperature, pH and culture time for the maximum cellulase production of the selected mutant were 35 degrees C, pH 5 and 6 days. The highest cellulase production was obtained using wheat bran. The prepared cellulases from T. viride CIT 626 had twice the hydrolytic performance with sawdust (83 %) than that from the parent strain (42.5 %). Furthermore, molecular studies demonstrated that there were some key mutation sites suggesting that some amino acid changes in the protein caused by base mutations had led to the enhanced cellulase production and activity. CONCLUSIONS: Mutagenesis with electron and (12)C(6+)-ion beams could be developed as an effective tool for improvement of cellulase producing strains. PMID- 26932903 TI - Improved production of carotenoid-free welan gum in a genetic-engineered Alcaligenes sp. ATCC31555. AB - OBJECTIVE: To improve the production of welan gum and obtain a carotenoid-free strain while reducing the fermentation and post-treatment costs. RESULTS: The vitreoscilla globin (vgb) gene combined with the beta-galactosidase (lacZ) promoter was inserted into the phytoene synthase (crtB) gene region of the chromosome in Alcaligenes sp. ATCC31555. When the recombinant strain was grown in a 5 l fermentor, welan gum was produced at 24 +/- 0.4 g l(-1) compared to 21 g +/ 0.4 g l(-1) in the wild type. Furthermore, the carotenoid-free welan gum produced using Alcaligenes sp. ATCC31555 VHb strain was less expensive with improved properties. CONCLUSIONS: Alcaligenes sp. ATCC31555 VHb strain was a better neutral welan-producing strain with a higher production than the wild-type strain. PMID- 26932904 TI - Hypoxia enhances the protective effects of placenta-derived mesenchymal stem cells against scar formation through hypoxia-inducible factor-1alpha. AB - OBJECTIVES: To explore the effect of placenta-derived mesenchymal stem cells on scar formation as well as the underlying mechanism. RESULTS: The isolated placenta-derived mesenchymal stem cells from mice were distributed in the wounded areas of scalded mouse models, attenuated inflammatory responses and decreased the deposition of collagens, thus performing a beneficial effect against scar formation. Hypoxia enhanced the protective effect of placenta-derived mesenchymal stem cells and hypoxia-inducible factor-1alpha was involved in the protective effect of placenta-derived mesenchymal stem cells in hypoxic condition. CONCLUSIONS: Hypoxia enhanced the protective effect of placenta-derived mesenchymal stem cells through hypoxia-inducible factor-1alpha and PMSCs may have a potential application in the treatment of wound. PMID- 26932905 TI - Benefits of female "libido" drug flibanserin are marginal, systematic review finds. PMID- 26932906 TI - Isotopic reconstructions of habitat change surrounding the extinction of Oreopithecus, the last European ape. AB - OBJECTIVE: Oreopithecus bambolii was the last hominoid to survive in Europe. The purpose of this investigation was to reconstruct, through stable isotope analyses, Oreopithecus' habitat, subsistence behavior, and changes in habitat that may have led to its extinction. METHODS: Carbon and oxygen stable isotopes from inorganic carbonate in tooth enamel from Oreopithecus and its contemporaneous faunas from localities in Tuscany and Sardinia were sampled. Also the fauna from localities in Tuscany shortly after Oreopithecus went extinct were sampled. RESULTS: Results indicated that Oreopithecus, compared with most modern hominoids, inhabited forests that probably had a more open canopy. At Tuscan localities, Oreopithecus yields some of the highest carbon isotope values but some of the lowest oxygen, suggesting a diet that may have included tubers or aquatic vegetation. Relatively higher oxygen values in Sardinia suggested that its diet included arboreal foods as well. Among modern and fossil hominoids, Oreopithecus only resembled chimpanzees living outside of rainforests. It also resembled Ardipithecus in carbon isotope values, suggesting possible similarities in feeding strategies concordant with shared skeletal features between Oreopithecus and early hominins. Isotope values from post-Oreopithecus faunas indicated a shift to more forested conditions, unlike other hominoid extinctions associated with loss of forest. CONCLUSIONS: Isotopic reconstructions of Oreopithecus' habitat and changes associated with its extinction indicated that its paleoecology was unique among hominoids. However, these reconstructions also suggested that like other hominoids, Oreopithecus was susceptible to changes in seasonality of precipitation, and it may have used wetlands as a buffer to seasonal regimes. Am J Phys Anthropol 160:254-271, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26932907 TI - Extracranial internal carotid artery: anatomical variations in asymptomatic patients. AB - The anatomical variations of internal carotid artery (ICA) are mostly asymptomatic, thus being disregarded and only incidentally diagnosed, with very few symptomatic patients. The awareness of these anomalies is crucial to solve the differential with other neck lesions, preventing accidental injuries during neck surgery. Therefore, the aim of our study is to estimate the prevalence of ICA anomalies, using magnetic resonance angiography (MRA) and computed tomography angiography (CTA). 253 patients underwent head and neck MRA and CTA examinations, with multiplanar and volumetric reformations. For each set of images, the following items were investigated: origin, development, course, persistence of embryonic vessels and anomalous origin of collateral branches. In our series, ICA arose from the bifurcation of the common carotid artery at the level of: C4 in 303 hemi-necks (59.9 %); C3 in 98 hemi-necks (19.3 %); C5 in 57 hemi-necks (11.3 %); C2 in 48 hemi-necks (9.5 %). ICA kinking and/or coiling was found in 105 hemi necks, and location variation of ICA (reversed-type) in two hemi-necks. In just one case the origin of the ascending pharyngeal artery was from ICA (0.2 %), while an anomalous persistence of the proatlantal artery was noticed in three cases (0.6 %). CTA and MRA showed similar accuracy in detecting ICA anomalies. PMID- 26932909 TI - Emotional Intelligence: For the Leader in Us All. PMID- 26932908 TI - Impaired Gallbladder Motility and Increased Gallbladder Wall Thickness in Patients with Nonalcoholic Fatty Liver Disease. AB - BACKGROUND/AIMS: Nonalcoholic fatty liver disease (NAFLD) is currently the most common chronic liver disease worldwide. Along with the increase in the incidence of NAFLD and associated obesity, an increase in gallbladder disease (GD) has been noted. This has led to the identification of a new disease entity called fatty GD. There is a gap in the literature on the dynamics of gallbladder function in patients with NAFLD. METHODS: An observational case-control study, a total of 50 patients with biopsy proven NAFLD without gallbladder stone/sludge and 38 healthy comparison subjects were enrolled. Fasting, postprandial gallbladder volumes (PGV), gallbladder ejection fraction (GEF), and fasting gallbladder wall thickness (FGWT) were measured by real-time 2-dimensional ultrasonography. RESULTS: Fasting gallbladder wall thickness, fasting gallbladder volumes and PGV were significantly higher in patients with NAFLD than control subjects (P < 0.001, P = 0.006, and P < 0.001, respectively). Gallbladder ejection fraction was significantly lower in the NAFLD group than the controls (P = 0.008). The presence of NAFLD was an independent predictor for GEF, PGV, and FGWT. Also, steatosis grade was an independent predictor for GEF, and GEF was significantly lower in the nonalcoholic steatohepatitis (NASH) subgroup than the controls. CONCLUSIONS: Gallbladder dysfunction and increase in gallbladder wall thickness exists in asymptomatic (without stone/sludge and related symptoms) patients with NAFLD and are useful in identifying fatty GD. Measurement of these variables in NAFLD patients may be useful in identifying those at higher risk for GD. PMID- 26932911 TI - Caring for Patients Who Are Unable to Speak. PMID- 26932912 TI - Bereavement Services Offered in Adult Intensive Care Units in the United States. AB - BACKGROUND: Losing a loved one in the intensive care unit (ICU) is stressful for family members. Providing bereavement support to them is recommended. However, little is known about the prevalence of bereavement services implemented in adult ICUs. OBJECTIVE: To describe current bereavement follow-up services in adult ICUs. METHOD: A cross-sectional prospective study design was used. ICU nurse leaders completed a 26-item online survey posted in the American Association of Critical-Care Nurses e-newsletter. The survey contained questions about current practices in bereavement care. Data were collected for 1 month and were analyzed by using descriptive statistics and binary logistic regression. RESULTS: A total of 237 ICU nurse leaders responded to the survey. Hospital and ICU types were diverse, with most being community (n = 81, 34.2%) and medical (n = 61, 25.7%). Most respondents reported that their ICUs (n = 148, 62.4%) did not offer bereavement follow-up services, and many barriers were noted. When bereavement follow-up care was offered, it was mainly informal (eg, condolence cards, brochures). Multiple logistic regression indicated that ICUs in hospitals with palliative care were almost 8 times (odds ratio, 7.66) more likely to provide bereavement support than were ICUs in hospitals without palliative care. CONCLUSIONS: The study findings provide insight into what type of bereavement evaluation methods are being used, what barriers are present that hinder use of bereavement follow-up services, and potential interventions to overcome those barriers in adult ICUs in the United States. PMID- 26932913 TI - Needs of Patients' Family Members in an Intensive Care Unit With Continuous Visitation. AB - BACKGROUND: Although many critical care experts and national organizations support open visitation in intensive care units (ICUs), most ICU visiting policies do not allow unrestricted presence of patients' family members. OBJECTIVE: To describe how well the needs of family members were met in an adult neuroscience ICU with a continuous visitation policy and an adjoining private suite for patients' family members. METHODS: An exploratory, descriptive study design was used to identify the effects of continuous family visitation in the neuroscience ICU on patients' family members and their needs and experiences during their time in the unit. A convenience sample of consenting family members completed a survey of family need items 72 hours after the patient was admitted to the unit. RESULTS: The most important needs identified by the 45 family members surveyed were items relating to information about the patient, visiting the patient, being given hope, talking with a doctor each day, and being assured that the best care is being given to the patient. Least important items were related to physical comforts for the family members. The vast majority of family members rated their needs as being met for all of the items in the survey and reported a high level of satisfaction with care. CONCLUSION: In a neuroscience ICU with an open visitation policy and a private suite for patients' family members, family members rated their needs as being met at a high level, unlike in prior studies in units with limitations on family visitation. The rank order of the importance of each need in the survey was similar to rankings in prior studies in a variety of critical care units. PMID- 26932914 TI - Measurement of Quality of Nursing Practice in Congenital Cardiac Care. AB - BACKGROUND: The impact of nursing care on patients' outcomes has been demonstrated in adult and pediatric settings. However, limited attention has been given to standardized measurement of pediatric nursing care. A collaborative group, the Consortium for Congenital Cardiac Care Measurement of Nursing Practice, was formed to address this gap. The purpose of this study was to assess the current state of measurement of the quality of pediatric cardiovascular nursing in freestanding children's hospitals across the United States. METHODS: A qualitative descriptive design was used to assess the state of measurement of nursing care from the perspective of experts in pediatric cardiovascular nursing. Nurse leaders from 20 sites participated in audiotaped phone interviews. The data were analyzed by using conventional content analysis. RESULTS: Each level of data coding was increasingly comprehensive. Guided by Donabedian's quality framework of structure, process, and outcome, 2 encompassing patterns emerged: (1) structure and process of health care delivery and (2) structure and process of evaluation of care. Similarities in the structure of health care delivery included program expansion and subsequent hiring of nurses with a bachelor of science in nursing and experienced nurses to provide safety and optimal outcomes for patients. Programs varied in how they evaluated care in terms of structure, measurement, collection and dissemination of data. CONCLUSION: External factors and response to internal processes of health care delivery were similar in different programs; evaluation was more varied. Seven opportunities for measurement that address both structure and process of nursing care were identified to be developed as benchmarks. PMID- 26932915 TI - Inadequacy of Headache Management After Subarachnoid Hemorrhage. AB - BACKGROUND: Headache profoundly affects management of spontaneous subarachnoid hemorrhage but is poorly characterized. OBJECTIVE: To characterize headache after spontaneous subarachnoid hemorrhage. METHODS: Medical records of patients with Hunt and Hess grades I-III subarachnoid hemorrhage admitted from 2011 to 2013 were reviewed. Demographics, clinical and radiographic features, medications, and pain scores were recorded through day 14 after hemorrhage. Headache pain was characterized on the basis of a numeric rating scale and analgesic use. Severe headache was defined as 2 or more days with maximum pain scores of 8 or greater or need for 3 or more different analgesics for 2 or more days. Univariate and multivariable models were used to analyze factors associated with severe headache. RESULTS: Of the 77 patients in the sample, 57% were women; median age was 57 years. Severe headache (73% overall) was associated nonlinearly with Hunt and Hess grade: grade I, 58%; grade II, 88%; and grade III, 56% (P = .01), and with Hijdra score: score 0-10, 56%; score 11-20, 86%; score 21-30, 76% (P = .03). By univariate analysis, patients with low Hijdra scores were less likely to have severe headache (27% vs 57%; P = .02). In a multivariable model, younger age and higher Hijdra score tended to be associated with severe headache. CONCLUSIONS: Headache after spontaneous subarachnoid hemorrhage was often severe, necessitating multiple opioid and nonopioid analgesics. Many patients reported persistent headache and inadequate pain control. PMID- 26932916 TI - Functional Status and Disability in Patients After Acute Stroke: A Longitudinal Study. AB - BACKGROUND: Stroke is a major public health problem. OBJECTIVE: To use the Barthel Index to evaluate basic activities of daily living in stroke survivors and detect any predictors of functional outcome at 6 months after stroke. METHODS: In an observational longitudinal study, data were gathered on consecutive patients admitted to the comprehensive stroke unit at Hospital San Pedro de Alcantara, Caceres, Spain. Sociodemographic and clinical data were obtained prospectively at hospital admission and during follow-up 6 months later. Information on type of stroke, score on the Barthel Index, findings from the neurological evaluation, and other relevant data were collected. RESULTS: Of 236 patients admitted, 175 participated in the study. Mean age was 69.60 (SD, 12.52) years, 64.6% were men, and mortality was 12.8%. Six months after experiencing a stroke, 84.8% of patients had returned to their own homes, 8.0% were institutionalized, and the others were residing at a family member's home. Scores on the Barthel Index 6 months after stroke correlated with baseline scores on the National Institute of Health Stroke Scale (r = -0.424; P < .001) and with depressive mood 6 months after stroke (r = -0.318; P < .001). Age was negatively associated with Barthel Index scores at the time of hospital discharge and 6 months after stroke. CONCLUSIONS: Functional status 6 months after stroke was influenced by age, sex, stroke severity, type of stroke, baseline status, mood, and social risk. Comorbid conditions, socioeconomic level, and area of residence did not affect patients' functional status. PMID- 26932917 TI - Use of a Comprehensive Program to Reduce the Incidence of Hospital-Acquired Pressure Ulcers in an Intensive Care Unit. AB - BACKGROUND: Hospital-acquired pressure ulcers (HAPUs) are a costly and largely preventable complication occurring in a variety of acute care settings. Because they are considered preventable, stage III and IV HAPUs are not reimbursed by Medicare. OBJECTIVES: To assess the effectiveness of a formal, year-long HAPU prevention program in an adult intensive care unit, with a goal of achieving at least a 50% reduction in 2013, compared with 2011. METHODS: Planning for the prevention program began in 2012, and the program was rolled out in the first quarter of 2013. Program components included use of Braden scores, a revised skin care protocol, fluidized repositioners, and silicone gel adhesive dressings. Efforts were made to educate and motivate staff and encourage them to be more proactive in detecting patients at risk of HAPUs. RESULTS: Incidence of HAPUs in the unit was reduced by 69% (n = 17; 3% of patients in 2013 vs n = 45, 10% of patients in 2011), despite a 22% increase in patient load. The potential cost saving as a result of this decrease was approximately $1 million. CONCLUSIONS: A comprehensive, proactive, collaborative ulcer prevention program based on staff education and a focus on adherence to protocols for patient care can be an effective way to reduce the incidence of HAPUs in intensive care units. PMID- 26932918 TI - A Model of Pressure, Oxygenation, and Perfusion Risk Factors for Pressure Ulcers in the Intensive Care Unit. AB - BACKGROUND: Although most intensive care patients are at risk for pressure ulcers, not all experience such ulcers. OBJECTIVE: To examine a model of variables related to extrinsic and intrinsic pressure on skin and underlying tissues, oxygenation, perfusion, and baseline comorbid conditions to identify risk factors associated with pressure ulcers in critically ill adults. METHOD: A retrospective chart review was conducted on patients identified by weekly rounds from January 2010 through October 2010 to determine the prevalence of pressure ulcers. Variables were analyzed via bivariate analysis and logistic regression for unit-acquired pressure ulcers. RESULTS: Data on 345 patients with 436 intensive care admissions were reviewed. Variables were significant in each model category at P < .05. In the regression analysis of first admission only (n = 306), the model was significant (P < .001) and yielded correct classification of 86.3% of patients. For all intensive care admissions (n = 391), the model was significant (P < .001) and yielded correct classification of 83.9% of patients. In both models, 4 of the same variables were significant: any transport off the unit, number of days to bed change, systolic blood pressure less than 90 mm Hg, and use of more than 1 vasopressor. History of pulmonary disease and presence of a feeding tube were also significant in regression analyses. CONCLUSIONS: Several variables within the model of pressure, oxygenation, and perfusion were significantly associated with development of pressure ulcers. PMID- 26932920 TI - Correction. PMID- 26932919 TI - Use of a Central Catheter Maintenance Bundle in Long-Term Acute Care Hospitals. AB - OBJECTIVE: Evidence-based guidelines have resulted in decreases in bloodstream infections associated with central catheters (CLABSIs) in hospital intensive care units. However, relatively little is known about CLABSI incidence and prevention in long-term acute care hospitals (LTACHs). METHODS: A central catheter maintenance bundle was implemented in 30 LTACHs, and compliance with the bundle was tracked for 6 months. CLABSI rates were monitored for 14 months before and 14 months after the bundle was implemented. RESULTS: The pooled mean CLABSI rate (No. of infections per 1000 days with a central catheter) was 1.28 before the bundle and 0.96 after the bundle (repeated measures general linear model; F1,58 = 6.973; P = .01; partial eta(2) = .11). From 14 months before to 14 months after the bundle was implemented, the mean number of CLABSIs per LTACH decreased by 4.5 (95% CI, 1.85-7.15). Time series modeling showed a significant decrease in the mean hospital CLABSI rate after the bundle was implemented (-0.511 CLABSI/1000 catheter days, SE = 0.050), indicating an immediate effect of the bundle. The mean hospital CLABSI rate was decreasing slightly before the bundle was implemented and continued to decrease at a reduced rate after the bundle was implemented. CONCLUSION: The bundle resulted in a significant and sustained reduction in CLABSI rates in 30 LTACHs for 14 months. These results encourage the development and implementation of similar bundles as effective strategies for infection reduction in LTACHs. PMID- 26932921 TI - No Decrease in Early Ventilator-Associated Pneumonia After Early Use of Chlorhexidine. AB - BACKGROUND: Oral chlorhexidine prophylaxis can decrease occurrence of ventilator associated pneumonia. However, the importance of timing has never been fully explored. OBJECTIVE: To see if early administration of oral chlorhexidine is associated with lower incidence of early ventilator-associated pneumonia (within 5 days of admission to intensive care unit) in intubated air ambulance patients. METHODS: A single-center, retrospective cohort study of intubated adults transported by a university-based air ambulance service and admitted to a surgical intensive care unit from July 2011 through April 2013. Primary exposure was time from helicopter retrieval to the first dose of oral chlorhexidine in the intensive care unit. Early chlorhexidine was defined as receipt of the drug within 6 hours of helicopter departure. The primary outcome was clinical diagnosis of early ventilator-associated pneumonia. Patients who were less than 18 years old, died within 72 hours of admission, or had pneumonia at admission were excluded. RESULTS: Among 134 patients, 49% were treated with chlorhexidine before 6 hours, 84% were treated before 12 hours, and 11% were treated for early pneumonia. Early chlorhexidine (before 6 hours; 15%) was not associated (P = .21) with early pneumonia (8%). Furthermore, median times to chlorhexidine did not differ significantly (P = .23) between patients in whom pneumonia developed (5.2 hours) and patients with no pneumonia (6.1 hours). CONCLUSIONS: Early administration of oral chlorhexidine in intubated patients was not associated with a reduction in the incidence of ventilator-associated pneumonia in a surgical intensive care unit with high rates of chlorhexidine administration before 12 hours. PMID- 26932922 TI - Enterovirus D68 Infection in an Adult. AB - The first confirmed US case of severe respiratory tract infection caused by enterovirus D68 in an adult occurred in a pregnant woman with no history of asthma in August 2014. Before she came to the hospital, she had a productive cough, headache, and increasing dyspnea. At the hospital, she was hypoxic and required admittance to the intensive care unit and management with noninvasive bilevel positive pressure assistance. Analysis of a nasopharyngeal swab sent to the Centers for Disease Control and Prevention for a viral respiratory panel of tests confirmed enterovirus D68 infection. She eventually had an uneventful vaginal delivery, was discharged without oxygen supplementation, and has resumed normal activities. This case suggests that pregnant women may be a sentinel group infected with this pathogen, similar to what has been described for influenza virus infection. PMID- 26932923 TI - Using Music to Promote Sleep for Hospitalized Adults. PMID- 26932924 TI - Symptomatic Bradycardia in a Healthy Older Adult. PMID- 26932925 TI - Improving Surveillance and Prevention of Surgical Site Infection in Pediatric Cardiac Surgery. AB - BACKGROUND: Postoperative cardiovascular surgical site infections are preventable events that may lead to increased morbidity, mortality, and health care costs. OBJECTIVE: To improve surgical wound surveillance and reduce the incidence of surgical site infections. METHODS: An institutional review of surgical site infections led to implementation of 8 surveillance and process measures: appropriate preparation the night before surgery and the day of surgery, use of appropriate preparation solution in the operating room, appropriate timing of preoperative antibiotic administration, placement of a photograph of the surgical site in the patient's chart at discharge, sending a photograph of the surgical site to the patient's primary care physician, 30-day follow-up of the surgical site by an advanced nurse practitioner, and placing a photograph of the surgical site obtained on postoperative day 30 in the patient's chart. RESULTS: Mean overall compliance with the 8 measures from March 2013 through February 2014 was 88%. Infections occurred in 10 of 417 total operative cases (2%) in 2012, in 8 of 437 total operative cases (2%) in 2013, and in 7 of 452 total operative cases (1.5%) in 2014. CONCLUSIONS: Institution of the surveillance process has resulted in improved identification of suspected surgical site infections via direct rather than indirect measures, accurate identification of all surgical site infections based on definitions of the National Healthcare Safety Network, collaboration with all persons involved, and enhanced communication with patients' family members and referring physicians. PMID- 26932926 TI - Communicating While Receiving Mechanical Ventilation: Texting With a Smartphone. AB - Two young adults with severe facial injuries were receiving care in the trauma/surgical intensive care unit at a tertiary care, level I trauma center in the southeastern United States. Both patients were able to communicate by texting on their cellphones to family members, friends, and caregivers in the intensive care unit. Patients who are awake and already have experience texting with a smartphone or other electronic handheld device may be able to communicate well while receiving mechanical ventilation. PMID- 26932928 TI - Bottled water for all, all the time? PMID- 26932927 TI - Pharmacological and Safety Profile of Dexlansoprazole: A New Proton Pump Inhibitor - Implications for Treatment of Gastroesophageal Reflux Disease in the Asia Pacific Region. AB - Although gastroesophageal reflux disease is not as common in Asia as in western countries, the prevalence has increased substantially during the past decade. Gastroesophageal reflux disease is associated with considerable reductions in subjective well-being and work productivity, as well as increased healthcare use. Proton pump inhibitors (PPIs) are currently the most effective treatment for gastroesophageal reflux disease. However, there are limitations associated with these drugs in terms of partial and non-response. Dexlansoprazole is the first PPI with a dual delayed release formulation designed to provide 2 separate releases of medication to extend the duration of effective plasma drug concentration. Dexlansoprazole has been shown to be effective for healing of erosive esophagitis, and to improve subjective well-being by controlling 24-hour symptoms. Dexlansoprazole has also been shown to achieve good plasma concentration regardless of administration with food, providing flexible dosing. Studies in healthy volunteers showed no clinically important effects on exposure to the active metabolite of clopidogrel or clopidogrel-induced platelet inhibition, with no dose adjustment of clopidogrel necessary when coprescribed. This review discusses the role of the new generation PPI, dexlansoprazole, in the treatment of gastroesophageal reflux disease in Asia. PMID- 26932930 TI - Importance of adipocyte cyclooxygenase-2 and prostaglandin E2-prostaglandin E receptor 3 signaling in the development of obesity-induced adipose tissue inflammation and insulin resistance. AB - We examined the involvement of adipocyte cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2)-prostaglandin E receptor (EP)3-mediated signaling during hypertrophy and hypoxia in the development of obesity-associated adipose tissue (AT) inflammation and insulin resistance. The experiments were conducted with high-fat diet (HFD)-induced obese rats, db/db mice, human subjects, and 3T3-L1 and the human Simpson-Golabi-Behmel syndrome (SGBS) adipocytes; the groups were treated with selective inhibitors of COX-2 [celecoxib 30 mg/kg, half maximal inhibitory concentration (IC50) ~ 0.04 uM] and EP3 (L-798106 100 ug/kg, IC50 ~ 0.5 uM) or a short interfering RNA. There were strong, positive correlations between adipocyte COX-2 and EP3 gene expressions and the AT TNF-alpha and monocyte chemotactic protein-1 contents and the homeostatic model assessment for insulin resistance in HFD-induced obese rats, as well as body mass index in human subjects. Treatment with COX-2 and EP3 inhibitors significantly reversed AT inflammatory gene and protein expressions (-50%) and impaired glucose and insulin tolerance in db/db mice. COX-2 inhibition diminished the chemotaxis of adipocytes isolated from HFD rats to macrophages and T cells. Targeting inhibition of adipocyte COX-2 and EP3 during hypertrophy and hypoxia reversed the release of the augmented proinflammatory adipokines and the diminished adiponectin and also suppressed NF-kappaB and hypoxia-inducible factor-1alpha transcription activation. These findings suggest that adipocyte COX-2 PGE2-EP3-mediated signaling is crucially involved in the development of obesity-associated AT inflammation and insulin resistance.-Chan, P.-C., Hsiao, F.-C., Chang, H.-M., Wabitsch, M., Hsieh, P. S. Importance of adipocyte cyclooxygenase-2 and prostaglandin E2-prostaglandin E receptor 3 signaling in the development of obesity-induced adipose tissue inflammation and insulin resistance. PMID- 26932929 TI - Divergence of mechanistic pathways mediating cardiovascular aging and developmental programming of cardiovascular disease. AB - Aging and developmental programming are both associated with oxidative stress and endothelial dysfunction, suggesting common mechanistic origins. However, their interrelationship has been little explored. In a rodent model of programmed cardiovascular dysfunction we determined endothelial function and vascular telomere length in young (4 mo) and aged (15 mo) adult offspring of normoxic or hypoxic pregnancy with or without maternal antioxidant treatment. We show loss of endothelial function [maximal arterial relaxation to acetylcholine (71 +/- 3 vs. 55 +/- 3%) and increased vascular short telomere abundance (4.2-1.3 kb) 43.0 +/- 1.5 vs. 55.1 +/- 3.8%) in aged vs. young offspring of normoxic pregnancy (P < 0.05). Hypoxic pregnancy in young offspring accelerated endothelial dysfunction (maximal arterial relaxation to acetylcholine: 42 +/- 1%, P < 0.05) but this was dissociated from increased vascular short telomere length abundance. Maternal allopurinol rescued maximal arterial relaxation to acetylcholine in aged offspring of normoxic or hypoxic pregnancy but not in young offspring of hypoxic pregnancy. Aged offspring of hypoxic allopurinol pregnancy compared with aged offspring of untreated hypoxic pregnancy had lower levels of short telomeres (vascular short telomere length abundance 35.1 +/- 2.5 vs. 48.2 +/- 2.6%) and of plasma proinflammatory chemokine (24.6 +/- 2.8 vs. 36.8 +/- 5.5 pg/ml, P < 0.05). These data provide evidence for divergence of mechanistic pathways mediating cardiovascular aging and developmental programming of cardiovascular disease, and aging being decelerated by antioxidants even prior to birth.-Allison, B. J., Kaandorp, J. J., Kane, A. D., Camm, E. J., Lusby, C., Cross, C. M., Nevin-Dolan, R., Thakor, A. S., Derks, J. B., Tarry-Adkins, J. L., Ozanne, S. E., Giussani, D. A. Divergence of mechanistic pathways mediating cardiovascular aging and developmental programming of cardiovascular disease. PMID- 26932933 TI - Editorial note. PMID- 26932931 TI - Inhibitors of pendrin anion exchange identified in a small molecule screen increase airway surface liquid volume in cystic fibrosis. AB - Pendrin (SLC26A4) is a Cl(-)/anion exchanger expressed in the epithelium of inflamed airways where it is thought to facilitate Cl(-) absorption and HCO3 (-) secretion. Studies using pendrin knockout mice and airway epithelial cells from hearing-impaired subjects with pendrin loss of function suggest involvement of pendrin in inflammatory lung diseases, including cystic fibrosis (CF), perhaps by regulation of airway surface liquid (ASL) volume. Here we identified small molecule pendrin inhibitors and demonstrated their efficacy in increasing ASL volume. A cell-based, functional high-throughput screen of ~36,000 synthetic small molecules produced 3 chemical classes of inhibitors of human pendrin. After structure-activity studies, tetrahydropyrazolopyridine and pyrazolothiophenesulfonamide compounds reversibly inhibited pendrin-facilitated Cl(-) exchange with SCN(-), I(-), NO3 (-), and HCO3 (-) with drug concentration causing 50% inhibition down to ~2.5 MUM. In well-differentiated primary cultures of human airway epithelial cells from non-CF and CF subjects, treatment with IL 13, which causes inflammation with strong pendrin up-regulation, strongly increased Cl(-)/HCO3 (-) exchange and the increase was blocked by pendrin inhibition. Pendrin inhibition significantly increased ASL depth (by ~8 MUm) in IL-13-treated non-CF and CF cells but not in untreated cells. These studies implicate the involvement of pendrin-facilitated Cl(-)/HCO3 (-) in the regulation of ASL volume and suggest the utility of pendrin inhibitors in inflammatory lung diseases, including CF.-Haggie, P. M., Phuan, P.-W., Tan, J.-A., Zlock, L., Finkbeiner, W. E., Verkman, A. S. Inhibitors of pendrin anion exchange identified in a small molecule screen increase airway surface liquid volume in cystic fibrosis. PMID- 26932932 TI - Overspending driven by oversized single dose vials of cancer drugs. PMID- 26932934 TI - Characterization of nineteen antimony(III) complexes as potent inhibitors of photosystem II, carbonic anhydrase, and glutathione reductase. AB - Nineteen antimony(III) complexes were obtained and examined as possible herbicides. Six of these were synthesized for the first time, and their structures were identified using elemental analyses, 1H-NMR, 13C-NMR, FTIR, LCMS, magnetic susceptibility, and conductivity measurement techniques. For the nineteen examined antimony(III) complexes their most-stable forms were determined by DFT/B3LYP/LanL2DZ calculation method. These compounds were examined for effects on photosynthetic electron transfer and carbonic anhydrase activity of photosystem II, and glutathione reductase from chloroplast as well were investigated. Our results indicated that all antimony(III) complexes inhibited glutathione reductase activity of chloroplast. A number of these also exhibited good inhibitory efficiency of the photosynthetic and carbonic anhydrase activity of Photosystem II. PMID- 26932935 TI - A 55-Year-Old French Man With Sudden Hemiparesis and Hemiplegia. PMID- 26932937 TI - Repetitive DNAs highlight the role of chromosomal fusions in the karyotype evolution of Dascyllus species (Pomacentridae, Perciformes). AB - The Dascyllus genus consists of 11 species spread over vast regions of the Indo Pacific, showing remarkable reductions in the diploid chromosome numbers (2n). The present study analyzed the karyotypes and other chromosomal characteristics of D. trimaculatus (2n = 48; 2st + 46a; NF = 50), D. carneus (2n = 48; 2st + 46a; NF = 50) and D. aruanus (2n = 30; 18m + 2st + 10a; NF = 50) from the Thailand Gulf (Pacific Ocean) and D. melanurus (2n = 48; 2st + 46a; NF = 50) from the Andaman Sea (Indian Ocean), employing conventional cytogenetic analyses and the chromosomal mapping of repetitive DNAs, using 18S and 5S rDNA, telomeric sequences and (CA)15, (GA)15, and (CAA)10 microsatellites as probes. The C positive heterochromatin was found in the centromeric regions of most chromosomal pairs and 18S rDNA phenotypes were single in all species. However, in D. aruanus (2n = 30), which harbors nine metacentric pairs; the 5S rDNA sites were located in the centromeric region of the shortest one. The mapping of the telomeric sequences in D. aruanus revealed the presence of interstitial telomeric sites (ITS) in the centromeric region of four metacentric pairs, with one of these pairs also displaying an additional ITS in the long arms. Distinct chromosomal markers confirmed the reduction of the 2n by chromosomal fusions, highlighting the precise characterization of these rearrangements by the cytogenetic mapping of the repetitive DNAs. PMID- 26932939 TI - Prediction of topological insulators in supercubane-like materials based on first principles calculations. AB - The lattice structures and topological properties of X8 (X = C, Si, Ge, Sn, Pb) under hydrostatic strain have been investigated based on first-principle calculations. Among the materials, 8, Si8, Ge8 and Sn8 are dynamically stable with negative formation energy and no imaginary phonon frequency. We find that the hydrostatic strain cannot induce a quantum phase transition between topological trivial and nontrivial state for both C8 and Si8, while for Ge8 and Sn8 the tensile strain can play a unique role in tuning the band topology, which will lead to a topological nontrivial state with Z2 invariants (1;111). Although the topological transition occurs above the Fermi level, the Fermi level can be tuned by applying electrostatic gating voltage. PMID- 26932938 TI - Evaluation of an Arabic version of the non-motor symptoms scale in Parkinson's disease. AB - Non-motor symptoms (NMS) of Parkinson Disease (PD) are common and can cause severe disability. They are often under-recognized and remain untreated. Tools to evaluate these symptoms in Arabic-speaking patients are still lacking. The objective of this study was to evaluate an Arabic version of the non-motor symptoms scale (NMSS) of PD as an instrument for measuring NMS in Arabic-speaking patients. Sixty-two PD patients clustered around Hoehn & Yahr Stages 2-3 were evaluated by the Arabic version of NMSS. They also underwent a battery of standard psychometric assessment measures that included the scales for outcomes of Parkinson's disease-autonomic (SCOPA-AUT), the Pittsburgh sleep quality index (PSQI), the Beck depression inventory, the geriatric depression scale (GDS), the mini-mental state examination (MMSE), the visual analogical scale for pain(VAS) and the neuro-psychiatric inventory (NPI). The metric properties of the NMSS were studied as well as its correlation with other standard tests evaluating NMS. The mean NMSS score was 82 +/- 56 (skewness 0.88). There were highly significant correlations between the NMSS and the SCOPA-AUT as well as the NMSS and PSQI scores. Significant positive correlations between NMSS and GDS, BECK and VAS were also observed. The sleep/fatigue domain significantly correlated with the PSQI, the cardiovascular/urinary/sexual function/gastrointestinal domains significantly correlated with the SCOPA-AUT, the mood/cognition domain significantly correlated with the GDS and BECK findings. The mean Cronbach's alpha coefficient was 0.87, showing a satisfactory internal consistency. The Arabic version of NMSS can be considered a comprehensive and reliable measure for non-motor symptoms in Arabic speaking PD patients. PMID- 26932940 TI - Ten towns that promote health to be built in England. PMID- 26932941 TI - E-cigarettes help up to 22,000 smokers in England quit each year. PMID- 26932942 TI - Thermal stability of mullite RMn2O5 (R = Bi, Y, Pr, Sm or Gd): combined density functional theory and experimental study. AB - Understanding and effectively predicting the thermal stability of ternary transition metal oxides with heavy elements using first principle simulations are vital for understanding performance of advanced materials. In this work, we have investigated the thermal stability of mullite RMn2O5 (R = Bi, Pr, Sm, or Gd) structures by constructing temperature phase diagrams using an efficient mixed generalized gradient approximation (GGA) and the GGA + U method. Simulation predicted stability regions without corrections on heavy elements show a 4-200 K underestimation compared to our experimental results. We have found the number of d/f electrons in the heavy elements shows a linear relationship with the prediction deviation. Further correction on the strongly correlated electrons in heavy elements could significantly reduce the prediction deviations. Our corrected simulation results demonstrate that further correction of R-site elements in RMn2O5 could effectively reduce the underestimation of the density functional theory-predicted decomposition temperature to within 30 K. Therefore, it could produce an accurate thermal stability prediction for complex ternary transition metal oxide compounds with heavy elements. PMID- 26932943 TI - Inhibition of Inflammation-Associated Olfactory Loss by Etanercept in an Inducible Olfactory Inflammation Mouse Model. AB - OBJECTIVE: To determine the effect of a soluble human tumor necrosis factor alpha (TNF-alpha) receptor blocker (etanercept) on an inducible olfactory inflammation (IOI) mouse model. STUDY DESIGN: An in vivo study using a transgenic mouse model. SETTING: Research laboratory. SUBJECTS AND METHODS: To study the impact of chronic inflammation on the olfactory system, a transgenic mouse model of chronic rhinosinusitis-associated olfactory loss was utilized (IOI mouse), expressing TNF alpha in a temporally controlled fashion within the olfactory epithelium. In one group of mice (n = 4), etanercept was injected intraperitoneally (100 MUg/dose, 3 times/week) concurrent with a 2-week period of TNF-alpha expression. A second group of mice (n = 2) underwent induction of TNF-alpha expression for 8 weeks, with etanercept treatment administered during the final 2 weeks of inflammation. Olfactory function was assayed by elecro-olfactogram (EOG), and olfactory tissue was processed for histology and immunohistochemical staining. Each group was compared with an equal-number control group. RESULTS: Compared with nontreated IOI mice, etanercept-treated IOI mice showed significantly improved EOG responses after 2 weeks (P < .001). After 8 weeks of induced inflammation, there was massive loss of olfactory epithelium and no EOG response in nontreated IOI mice. However, in etanercept-treated mice, regeneration of olfactory epithelium was observed. CONCLUSION: Concomitant administration of etanercept in IOI mice results in interruption of TNF-alpha-induced olfactory loss and induction of neuroepithelial regeneration. This demonstrates that etanercept has potential utility as a tool for elucidating the role of TNF-alpha in other olfactory inflammation models. PMID- 26932944 TI - "Rounded Insertion": A Useful Cochlear Implantation Technique for Patients with Cochlear Hypoplasia Type I. PMID- 26932945 TI - Postoperative Calcium Management in Same-Day Discharge Thyroid and Parathyroid Surgery. AB - OBJECTIVE: To describe a safe and effective postoperative prophylactic calcium regimen for same-day discharge thyroid and parathyroid surgery. STUDY DESIGN: Case series with chart review. SETTING: Tertiary referral academic institution. SUBJECTS AND METHODS: In total, 162 adult patients who underwent total thyroidectomy, completion thyroidectomy, unilateral parathyroidectomy, parathyroidectomy with bilateral neck exploration, or revision parathyroidectomy were identified preoperatively to be candidates for same-day discharge. All patients in this study were successfully discharged the same day on our standard prophylactic calcium regimen. RESULTS: Less than 1% (1/162) of patients re presented to the hospital within 30 days of surgery, and that patient was successfully discharged from the emergency department after negative workup for hypocalcemia. There was no significant difference between preoperative and postoperative calcium levels in the total/completion thyroidectomy groups (9.3 vs 9.2 mg/dL, respectively; P = .14). The average postoperative calcium level in the parathyroid group was well within normal limits (9.5 mg/dL), and the difference in postoperative calcium levels between revision and primary parathyroidectomy cases was not significantly different (P = .34). CONCLUSION: The reported calcium regimen demonstrates a safe, effective, and objective means of postoperative calcium management in outpatient thyroid and parathyroid surgery in appropriately selected patients. PMID- 26932946 TI - Nonvisualization of Sialoliths during Sialendoscopy. AB - OBJECTIVES: Analyze the characteristics of patients undergoing interventional sialendoscopy for sialolithiasis whose stones were not visualized intraoperatively. STUDY DESIGN: Case series with chart review. SETTING: Tertiary care hospital. SUBJECTS AND METHODS: Patients (n = 276) undergoing sialendoscopy between June 2008 and December 2014 were reviewed for patient characteristics, imaging characteristics, and outcomes. Nonvisualization was defined as a sialolith that was documented on imaging preoperatively but not visualized intraoperatively during sialendoscopy, despite successful ductal cannulation and evaluation. RESULTS: A total of 337 sialendoscopy procedures were preformed. Preoperative imaging documented a sialolith in 203 (60%) cases. Nonvisualization occurred in 31 (15%) cases with sialolith. The parotid gland was involved in 58% (18 of 31) of nonvisualization cases, as opposed to 21% (43 of 203) of all sialolith cases. The submandibular gland was involved in 42% (13 of 31) of nonvisualization cases, as compared with 79% (160 of 203) of all sialolith cases. Nonvisualization occurred in 42% (18 of 43) of parotid cases versus 8% (13 of 160) of submandibular cases, a statistically significant difference (P < .001). Parotid stones located posterior to the plane of insertion of the posterolateral edge of the masseter were significantly more likely to experience nonvisualization (73%) than those along and anterior to the masseter (25% and 0%, respectively; P = .009). CONCLUSIONS: Intraoperative nonvisualization of a sialolith is more likely to occur in the parotid gland. Proximal stone location may predict nonvisualization. These factors should be considered during treatment planning and counseling for patients with sialolithiasis. PMID- 26932947 TI - Endoscopic Radiofrequency Ablation-Assisted Resection of Juvenile Nasopharyngeal Angiofibroma: Comparison with Traditional Endoscopic Technique. AB - OBJECTIVES: To evaluate the feasibility of radiofrequency surgical instrumentation for endoscopic resection of juvenile nasopharyngeal angiofibroma (JNA) and to test the hypothesis that endoscopic radiofrequency ablation-assisted (RFA) resection will have superior intraoperative and/or postoperative outcomes as compared with traditional endoscopic (TE) resection techniques. STUDY DESIGN: Case series with chart review. SETTING: Two tertiary care pediatric hospitals. SUBJECTS AND METHODS: Twenty-nine pediatric patients who underwent endoscopic transnasal resection of JNA from January 2000 to December 2014. RESULTS: Twenty nine patients underwent RFA (n = 13) or TE (n = 16) JNA resection over the 15 year study period. Mean patient age was not statistically different between the 2 groups (P = .41); neither was their University of Pittsburgh Medical Center classification stage (P = .79). All patients underwent preoperative embolization. Mean operative times were not statistically different (P = .29). Mean intraoperative blood loss and the need for a transfusion were also not statistically different (P = .27 and .47, respectively). Length of hospital stay was not statistically different (P = .46). Recurrence rates did not differ between groups (P = .99) over a mean follow-up period of 2.3 years. CONCLUSION: There were no significant differences between RFA and TE resection in intraoperative or postoperative outcome parameters. PMID- 26932948 TI - A Systematic Review of Diuretics in the Medical Management of Meniere's Disease. AB - OBJECTIVE: (1) Review evidence for the use of oral diuretic medications in the management of Meniere's disease. (2) Analyze therapy-related hearing and vertigo outcomes. DATA SOURCES: Literature was obtained through directed searches of MEDLINE, EMBASE, Web of Science, EBSCO Host, Cochrane Reviews, and linked citations through seminal papers. We searched independent electronic databases for articles that reported the use of diuretics in patients with Meniere's disease. REVIEW METHODS: All articles of level 4 evidence or higher, per the Oxford Centre for Evidence-Based Medicine, were included with no limit for number of patients, duration of therapy, or follow-up period. Two independent investigators reviewed the articles for inclusion eligibility. Outcomes were tabulated, including subjective or quantitative measures of hearing, tinnitus, vertigo episode frequency, and medication adverse effects. RESULTS: Nineteen articles were included from 1962 to 2012 from 11 countries. Twelve retrospective case series, 4 randomized controlled trials, 2 case-control trials, and 1 prospective case series were identified. Six studies investigated isosorbide; 5, hydrochlorothiazide; 2, acetazolamide; 2, chlorthalidone; and 1 each of betahistine, hydrochlorothiazide, chlorthalidone, acetazolamide, hydrochlorothiazide-triamterene, and nimodipine. Eight (42.1%) studies reported hearing outcomes improvement. Fifteen (79.0%) studies reported vertigo outcomes improvement. Ten (52.6%) studies reported no side effects, and 4 studies (21.1%) reported abdominal discomfort. No significant morbidity or mortality was reported in any study. CONCLUSION: Multiple low evidence-level studies report that oral diuretic therapy may be beneficial in the medical management of Meniere's disease. Improvement in vertigo episode frequency was consistently reported, with less convincing evidence for improvement in hearing outcomes. PMID- 26932950 TI - Modeled Analysis of Entrance of Colloid Suspensions into the Middle Ear Cavity. AB - Otic suspensions have a positive effect on the duration of otorrhea in children with a tympanostomy tube. It is still questionable how eardrops reach the middle ear. We hypothesized that otic suspensions do not pass the tympanostomy tube if the middle ear is dry but pass by diffusion when wet. The median concentration of Evans blue (colorant) in the middle ear was <15.6 mg/mL (lower limit of quantification) when diffusion was impossible but 45.3 ug/mL when diffusion was possible (P = .01). When the outward flow was increased to 0.1 mL/h, the concentration of Evans blue in the middle ear increased significantly (P = .03). With further-increasing outward flows, the concentration of Evans blue decreased linearly (beta = -144, P < .001, R (2) = 0.44). We conclude that diffusion is the mechanism by which otic suspensions enter the middle ear in children with tympanostomy tubes and otorrhea. PMID- 26932949 TI - Orbital Decompression in the Endoscopic Age: The Modified Inferomedial Orbital Strut. AB - OBJECTIVE: Postoperative diplopia occurs in up to 45% of patients following orbital decompression for exophthalmos associated with Graves' orbitopathy. We sought to describe outcomes of our balanced orbital decompression strategy that includes the preservation of a modified inferomedial orbital strut (mIOS). STUDY DESIGN: Case series with chart review. SETTING: Academic medical center. SUBJECTS AND METHODS: A total of 115 consecutive orbital decompressions were performed on 73 patients (42 bilateral) with Graves' orbitopathy. All patients underwent (1) a balanced decompression technique incorporating an endoscopic medial and external lateral decompression and (2) a mIOS technique with preservation of the anterior half of the inferomedial orbital strut. A periorbital periosteal (orbital) sling was utilized in patients (n = 54) without threatened vision loss, proptosis >28 mm, or periorbital disruption to prevent prolapse of the medial rectus muscle. RESULTS: Utilization of the mIOS technique with or without a sling did not adversely affect the reduction in proptosis (5.1 mm with sling vs 5.0 mm without sling; P = .85).The incidence of new-onset postoperative diplopia was 17% (n = 6). The sling was not associated with postoperative diplopia (odds ratio = 0.54, 95% confidence interval: 0.08-3.40, P = .51), while it was associated with resolution of preexisting diplopia (odds ratio = 6.67, 95% confidence interval: 1.06-42.06, P = .04). No intraoperative complications occurred, and no patients suffered a decrement in visual acuity. CONCLUSION: Balanced orbital decompression utilizing a mIOS in patients with Graves' orbitopathy provides a safe and effective reduction in proptosis with a low rate of new-onset diplopia as compared with historical values. Utilization of an orbital sling may be beneficial in reducing postoperative diplopia in select patients. PMID- 26932951 TI - Endoscopic Transcanal Retrocochlear Approach to the Internal Auditory Canal with Cochlear Preservation: Pilot Cadaveric Study. AB - Contemporary operative approaches to the internal auditory canal (IAC) require the creation of large surgical portals for visualization with associated morbidity, including hearing loss, vestibular dysfunction, facial nerve injury, and skull base defects that increase the risk of cerebrospinal fluid leak. Transcanal approaches to the IAC have been possible only via a transcochlear technique. To preserve cochlear function, we describe a novel endoscopic transcanal infracochlear approach to the IAC in cadaveric temporal bones. Navigation fiducials were secured on fresh cadaveric heads, and real-time computed tomography imaging was used for surgical guidance. With a combination of curved instruments and rigid angled endoscopy, a transcanal hypotympanotomy and subcochlear tunnel were created with superior extension to access the IAC. Postprocedure imaging and temporal bone dissection confirmed access to the IAC without injury to the cochlea or neighboring neurovascular structures. PMID- 26932952 TI - Acute Rhinosinusitis: Prescription Patterns in a Real-World Setting. AB - OBJECTIVE: Understand real-world prescription patterns for patients presenting with a first diagnosis of ARS and evaluate adherence to published medical guidelines. STUDY DESIGN: Retrospective administrative database analysis. SETTING: US-based outpatient settings. METHODS: From a US claims database (MarketScan), 99,033 patients were identified with acute rhinosinusitis (ARS) in 2012 ("index"), with a complete medical and prescription history for 12 months preindex and 18 months postindex and no diagnoses of asthma or chronic rhinosinusitis. Of these, a random 10,000-patient sample was generated matched for age and sex to the initial cohort. Prescriptions and procedures at index, as well as complications up to 12 months postindex, were analyzed. RESULTS: Nearly 90% of all patients received a prescription at index. Antibiotics were prescribed for 84.8% patients, followed by antitussives (16.2% for adults, 6.2% for pediatrics), nasal corticosteroids (15.5% adults, 7.5% for pediatrics), and systemic corticosteroids (10.3% for adults, 5.5% for pediatrics), with 49% adults and 29% children receiving >1 medication at first visit. Macrolides were the most frequently prescribed antibiotics (35.6% adults, 28.6% pediatrics), followed by amoxicillin/clavulanate and amoxicillin. Within 12 months of index, 3 patients presented with meningitis and 3 with orbital cellulitis. CONCLUSION: Significant variability in ARS treatment was observed, highlighting the need for heightened awareness of existing guidelines. PMID- 26932953 TI - Biofilm's Role in Chronic Cholesteatomatous Otitis Media: A Pilot Study. AB - Cholesteatoma is a destructive lesion involving the temporal bone, which may induce severe complications due to its expansion and erosion of adjacent structures. Bacterial biofilm plays a crucial role in the pathogenesis of many otolaryngologic inflammatory/infectious chronic diseases. In this pilot study, we investigated, by means of cultural examination and with scanning electron microscope, the presence of bacterial biofilm in a series of samples from the epitympanic and mastoid region in patients affected by cholesteatoma and from the promontory region in patients with healthy mucosa who were undergoing to stapes surgery. The preliminary data support the association between biofilm and cholesteatoma (81.3% of the cases) and allow us to hypothesize that keratinized matrix of cholesteatoma may represent the ideal substrate for biofilm colonization and survival; this finding is consistent with the clinical course of aural cholesteatoma, characterized by recurrent exacerbations and recalcitrant course. PMID- 26932954 TI - Parathyroid 4D CT and Scintigraphy: What Factors Contribute to Missed Parathyroid Lesions? AB - OBJECTIVE: To determine the prevalence of missed lesions for parathyroid 4 dimensional computed tomography (4D CT) and scintigraphy and to describe the factors leading to missed lesions for both modalities. STUDY DESIGN: Case series with chart review. SETTING: Single center, hospital based. SUBJECTS AND METHODS: Forty patients undergoing 4D CT and scintigraphy before parathyroidectomy between July 2009 and October 2013 were included. Radiology reports and imaging were reviewed and correlated with operative notes to identify cases with missed lesions and the reasons for those misses. All lesions were then classified according to the following factors: multigland disease, lesion size, patient body weight, and multinodular goiter. RESULTS: Of the 40 patients, 6 had multigland disease, resulting in 51 lesions; 12 and 29 lesions were missed on 4D CT and scintigraphy, respectively. The sensitivity for detection of all lesions was 76% for 4D CT and 43% for scintigraphy. Sensitivities for single-gland disease were 88% for 4D CT and 50% for scintigraphy. Sensitivities for multigland disease were 53% for 4D CT and 24% for scintigraphy. Rates of multigland disease in patients with missed lesions were 75% on 4D CT and 48% on scintigraphy, as compared with patients with detected lesions, 23% and 18%, respectively (P <= .04). Mean weight of lesions missed on 4D CT was 0.3 and 0.6 g in detected lesions (P = .15). Mean weight of lesions missed on scintigraphy was 0.4 and 0.8 g in detected lesions (P = .03). CONCLUSION: 4D CT has higher sensitivity than scintigraphy. Missed lesions are more likely to occur with multigland disease for both modalities and in smaller lesions for scintigraphy. PMID- 26932955 TI - Lean Belt Certification: Pathway for Student, Resident, and Faculty Development and Scholarship. AB - Since July 2013, 20 trainee participants have completed the quality improvement curriculum within the Indiana University Department of Otolaryngology-Head & Neck Surgery, including 7 otolaryngology residents, 6 otolaryngology-bound medical students, and 7 psychiatry residents. Nine faculty and staff attended. Participants were highly satisfied with the quality and effectiveness of the program. Following program implementation, 2 otolaryngology residents and 2 medical students initiated their own quality improvement projects. Lean training directly resulted in oral and poster presentations at national conferences, journal publications, and institutional research and quality awards. Students completing the program established a local affiliate group of an international health care quality organization. Quality improvement training can be successfully incorporated into residency training with overwhelming program satisfaction and results in greater scholarly and professional development for motivated participants. The skillset acquired by participants leads to projects that improve patient care, increase value, and justify equipment and personnel retention and expansion. PMID- 26932957 TI - Antibiotic and Duration of Perioperative Prophylaxis Predicts Surgical Site Infection in Head and Neck Surgery. AB - OBJECTIVE: To examine the effect of giving antibiotics on the day of surgery (DOS) vs DOS and first postoperative day (DOS+1) for prophylaxis against surgical site infection (SSI) in clean-contaminated head and neck surgery (CCHNS). STUDY DESIGN: Retrospective multi-institution analysis using University HealthSystem Consortium data. METHODS: A multivariate logistic regression model of 8836 discharge records from patients undergoing CCHNS was used to determine the odds of SSI for antibiotic agent/duration combinations. SETTING: Ninety-two academic and affiliated medical centers from 2008 to 2011. RESULTS: Ampicillin/sulbactam, clindamycin, cefazolin + metronidazole, and cefazolin alone were the most common antibiotics. For patients receiving antibiotics only on DOS, there was no significant difference in odds of SSI based on antibiotic choice. When given on the DOS and DOS+1, patients receiving ampicillin/sulbactam had a reduction in odds of SSI by over two-thirds (odds ratio [OR], 0.28 [95% confidence interval, 0.13-0.61], P = .001, compared with ampicillin/sulbactam on DOS only), whereas this effect was not seen with clindamycin (1.82 [0.93-3.56], P = .078, compared with clindamycin on DOS only). Prolonging clindamycin beyond the DOS was associated with a higher odds of SSI compared with DOS-only ampicillin/sulbactam (OR, 2.66; 95% CI, 1.33-5.30; P = .006). These relationships held in a subset of physicians and hospitals that used multiple different regimens. DOS+1 regimens were not associated with an increased odds of antibiotic-induced complications. CONCLUSION: Prolonging ampicillin/sulbactam beyond the day of surgery may have a protective effect against SSI, and 1 or more days of ampicillin/sulbactam may be preferable to multiple days of clindamycin. New randomized trials are needed to define the ideal regimen for CCHNS. PMID- 26932956 TI - Anatomic Changes Caused by Endoscopic Endonasal Transsphenoidal Surgery and Their Effects on Nasal Functions. AB - OBJECTIVE: We evaluated postoperative changes in nasal cavity dimensions and their effects on nasal functions and symptoms. STUDY DESIGN: Case series with chart review. SETTING: Tertiary referral center. SUBJECTS AND METHODS: We studied patients who underwent binostril, 4-hand endoscopic endonasal transsphenoidal approach surgery with the bilateral modified nasoseptal rescue flap technique. Pre- and postoperative paranasal computed tomography scans were used to assess nasal cavity dimensional changes at 4 levels. We also performed several pre- and postoperative tests, including the Connecticut Chemosensory Clinical Research Center test and the Cross-Cultural Smell Identification Test (n = 119) to evaluate olfactory functions. Also, the Nasal Obstruction Symptoms Evaluation, the Sino-Nasal Outcome Test-20, and a visual analog scale were used (n = 157) to record subjective symptoms. We compared these data with the pre- and postoperative nasal cavity dimensions. RESULTS: Two-dimensional objective increases in nasal passage dimensions were evident postoperatively (all cross sectional areas, P < .001, except choana and left inferior turbinate). However, these did not correlate with subjectively assessed symptoms (Nasal Obstruction Symptoms Evaluation, all cross-sectional areas, P >= .05, except right middle turbinate; Sino-Nasal Outcome Test-20, all cross-sectional areas, P >= .05) or olfactory dysfunction evaluated with the Connecticut Chemosensory Clinical Research Center test (all cross-sectional areas, P >= .05) or the Cross-Cultural Smell Identification Test (all cross-sectional areas, P >= .05). CONCLUSION: Endoscopic endonasal transsphenoidal approach surgery altered the patients' nasal anatomy, but the changes in nasal cavity dimensions did not affect nasal functions and symptoms. These results will help surgeons to appropriately expose the surgical field during endoscopic endonasal transsphenoidal approach surgery. PMID- 26932958 TI - Quantitative Proteomics of Vestibular Schwannoma Cerebrospinal Fluid: A Pilot Study. AB - This pilot study aimed to identify candidate proteins for future study that are differentially expressed in vestibular schwannoma (VS) cerebrospinal fluid (CSF) and to compare such proteins with those previously identified in perilymph and specimen secretions. CSF was collected intraoperatively prior to removal of untreated sporadic VS (3 translabyrinthine, 3 middle cranial fossa approaches) and compared with reference CSF samples. After proteolytic digestion and iTRAQ labeling, tandem mass spectrometry with ProteinPilot was used to identify candidate proteins. Of the 237 proteins detected, 13 were dysregulated in >=3 of the 6 VS patients versus controls, and 13 were dysregulated (12 up, 1 down) in samples from patients with class D versus class B hearing. Four perilymph proteins of interest were dysregulated in >=1 VS CSF samples. Thus, 26 candidate VS CSF biomarkers were identified that should be considered in future VS biomarker and tumor pathophysiology investigations. PMID- 26932959 TI - Long-term Outcomes of Titanium Ossiculoplasty in Chronic Otitis Media. AB - OBJECTIVE: The primary objective is to report long-term hearing outcomes (>2 years) after titanium ossiculoplasty in patients with chronic otitis media. STUDY DESIGN: Case series with chart review. SETTING: Tertiary care hospital. SUBJECTS AND METHODS: In total, 156 patients with chronic otitis media undergoing titanium ossiculoplasty were included. The primary outcome measure was the long-term postoperative ABG. The stability of hearing over time was determined by comparing short-term and long-term postoperative air-bone gap (ABG). Secondary outcome measures included DeltaABG, postoperative speech reception thresholds, air conduction pure-tone average (AC PTA), word recognition scores, and percentage of patients achieving ABG <=20 dB. Revision and extrusion rates were examined. RESULTS: At short-term follow-up (<6 months), mean postoperative ABG was 18.4 +/- 10.6 dB and AC PTA was 31.7 +/- 15.2 dB; 67% of patients achieved ABG <=20 dB. At long-term follow-up (>2 years), mean ABG was 20.0 dB +/- 15.4 and AC PTA was 35.3 +/- 16.1 dB; 60% of patients achieved ABG <=20. At both short- and long-term follow-up, ABG and AC PTA were significantly improved compared with preoperative values. No difference in hearing outcomes was observed when comparing partial titanium ossicular prostheses (PORPs) to total titanium ossicular prostheses (TORPs) at either short- or long-term follow-ups. In patients with both short- and long-term follow-up (n = 50), deterioration in hearing was noted (3.4 dB, P = .04). When analyzed by type of prosthesis, PORPs demonstrated statistically significant deterioration in ABG over time (4.9 dB, P = .02), while TORPs did not (2.5 dB, P = .50). The long-term extrusion rate was 3.2%. CONCLUSION: With a minimum follow-up of 2 years, titanium ossiculoplasty provides good long-term hearing results. Modest deterioration in hearing is noted over time. PMID- 26932961 TI - Associations of Volume and Thyroidectomy Outcomes: A Nationwide Study with Systematic Review and Meta-Analysis. AB - OBJECTIVE: This study explored how different hospital volumes and surgeon volumes affect thyroidectomy outcomes in terms of length of stay (LOS), costs, and in hospital mortality. DATA SOURCES: MEDLINE and EMBASE databases. REVIEW METHODS: This study retrospectively analyzed a cohort of 125,037 thyroidectomy patients treated at Taiwan hospitals from 1996 to 2010. Relationships between hospital/surgeon volume and patient outcomes were retrospectively analyzed by propensity score matching. In conjunction with the retrospective study, a systematic review and meta-analysis of the relevant literature also were performed. RESULTS: The mean LOS for all thyroidectomies performed during the study period was 3.3 days, and the mean cost was $1193.5. Both high-volume hospitals and high-volume surgeons were associated with significantly shorter LOS and lower costs compared with their low-volume counterparts (P < .001). Different volume groups had similar in-hospital mortality rates. The meta-analysis results consistently showed that the benefits of high-volume hospitals/surgeons are reduced LOS and costs. However, low in-hospital mortality rates were associated with high-volume surgeons but not with high-volume hospitals. CONCLUSIONS: This meta-analysis showed that patients who received thyroidectomies performed by high volume hospitals and surgeons had shorter LOS and lower costs compared with those treated by low-volume hospitals and surgeons. In addition, in-hospital survival rates were better in patients treated by high-volume surgeons. Further research is needed to define the learning curve for thyroidectomy and to clarify how hospital volume and surgeon volume affect its success rate. PMID- 26932960 TI - A Charge Comparison of Audiometric Testing in the Pediatric Population. AB - OBJECTIVE: To determine the charges associated with performing combined tympanometry and otoacoustic emissions vs a comprehensive audiogram in the pediatric population and to analyze its implications for future practice. STUDY DESIGN: Retrospective charge analysis. SETTING: Tertiary care academic center. SUBJECTS AND METHODS: Analysis was performed on 538 pediatric patients who underwent audiometric hearing testing from May through October 2014. RESULTS: In total, 401 patients had combined tympanometry and otoacoustic emissions testing and 91 patients underwent a comprehensive audiogram, while 46 patients underwent all 3 tests. The technical and professional charges for combined tympanometry and otoacoustic emissions were $139 and $116, respectively, with an overall charge of $255. The technical and professional charges for an audiogram were $124 and $198, respectively, with an overall charge of $322. CONCLUSION: Objective testing with a combination of tympanometry and otoacoustic emissions charges insurers $67 less than an audiogram. Given the questionable reliability of behavioral audiometry in very young children, this is a factor to consider when choosing the appropriate test. With a large number of pediatric auditory hearing tests performed each year, the cost savings within the health care system could be substantial. PMID- 26932962 TI - Monothermal Caloric Screening Test Accuracy: A Systematic Review. AB - OBJECTIVE: To minimize discomfort, time, and costs, vestibular laboratories may perform monothermal caloric irrigations and discontinue testing if responses are symmetric. This systematic review aimed to determine the diagnostic accuracy of the monothermal caloric screening test (MCST) for unilateral vestibular dysfunction compared with bithermal caloric testing (BCT). DATA SOURCES: Ovid MEDLINE, EMBASE, Scopus, Cochrane CENTRAL, and manual bibliographic searches. REVIEW METHODS: Inclusion criteria specified concurrent MCST and BCT performance and reporting of test measures (monothermal caloric asymmetry, unilateral weakness). The primary outcomes were between-measure correlation, sensitivity, and specificity. Meta-analysis was performed with hierarchical bivariate and univariate random-effects models. Heterogeneity was assessed with the I(2) statistic. RESULTS: Fifteen studies (n = 5572 participants) met inclusion criteria. Thresholds varied between studies. Asymmetries calculated by MCST and BCT were strongly correlated, but a subgroup analysis showed no correlation for those with mild unilateral weakness. The sensitivity and specificity of the MCST ranged from 0.54 to 1.00 and 0.25 to 0.96, respectively. Predictably, higher sensitivity resulted from lower cutoff points for the MCST, higher thresholds for the BCT, and additional test positivity criteria. Warm irrigations yielded higher sensitivity than cool. Studies excluding participants with severe unilateral weakness yielded lower sensitivity estimates. After pooling by threshold, temperature, and risk of bias, most performance estimates remained substantially heterogeneous (I(2) > 60%). CONCLUSION: Accuracy of the MCST is lacking precisely where it is needed most-at the border of normal and abnormal vestibular function. To guide clinical practice, research should include analysis of subgroups with varying levels of function and employ standardized testing parameters. PMID- 26932963 TI - Reoperation following Adult Tonsillectomy: Review of the American College of Surgeons National Surgical Quality Improvement Program. AB - OBJECTIVE: Tonsillectomy remains a common procedure in adults; however, there are few population-level data evaluating risk factors for reoperation. STUDY DESIGN: Retrospective review of national database. SETTING: American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP), 2005-2013. SUBJECTS AND METHODS: The ACS-NSQIP was queried for patients undergoing tonsillectomy +/- adenoidectomy as their primary procedure (CPT 42821 or 42826). Demographic information and indications were reviewed along with complications and reoperation rates. RESULTS: In total, 12,542 cases met inclusion criteria. Patients were predominantly female (66.4%) and white (70.8%), with mean age of 30 +/- 12 years (range: 16-90+). Thirty-day mortality was 0.03%, and 4.8% of patients experienced at least 1 complication, including reoperation (3.6%). Risk of complications was associated with male sex (P < .0001; odds ratio [OR], 1.7), diabetes (P = .0002; OR, 2.1), and presence of a bleeding disorder (P = .002; OR, 3.2). Risk factors for reoperation were similar, in addition to older age (P = .002; OR, 0.986). Complications other than reoperation were correlated with older age (P = .001; OR, 1.02) and diabetes (P = .001; OR, 2.59). Procedures were done mostly for infectious/inflammatory (70.4%) versus hypertrophic (16.4%) indications. Indication had no significant effect on the rate of reoperation. Most reoperations occurred after postoperative day 1 (86%; mean, 6.4 +/- 4.2 days). CONCLUSION: This review of a large validated surgical database provides an overview of the rates of, and risk factors for, complications and reoperations following tonsillectomy in the adult population. PMID- 26932964 TI - Retrospective Review of Management and Outcomes of Pediatric Descending Mediastinitis. AB - OBJECTIVES: To review the management and outcomes of pediatric patients treated for descending mediastinitis at a single institution and contribute to an updated mortality rate. STUDY DESIGN: Case series with chart review. SETTING: Tertiary care pediatric hospital. SUBJECTS AND METHODS: This study is a 19-patient case series of all patients treated for descending mediastinitis at a tertiary pediatric hospital from 1997 to 2015, and it serves as an update to the case series published from this institution in 2008. Review of management included time to diagnosis, time to surgery, surgical procedures performed, and antibiotics administered. The primary outcomes measured were length of hospitalization and mortality. RESULTS: In addition to 8 previously reported patients, we identified 11 pediatric patients treated for descending mediastinitis in the period of review. All 19 patients were <18 months old, and all survived their hospitalization. Fourteen patients underwent surgical drainage at least twice. The median length of hospital stay was 15 days. Retropharyngeal abscess was the source of infection in 16 of 19 patients, and methicillin resistant Staphylococcus aureus (MRSA) was the isolated organism in 14 of 15 positive cultures. CONCLUSION: This review represents the largest reported series of pediatric patients with descending mediastinitis. With 100% survival, our results suggest that pediatric descending mediastinitis can be safely managed by prompt surgical drainage. Broad-spectrum antibiotics covering MRSA and a low threshold for repeat surgical intervention have been an important part of our successful approach and may decrease length of stay. PMID- 26932965 TI - Epidemiology of Wire-Bristle Grill Brush Injury in the United States, 2002-2014. AB - OBJECTIVES: The purpose of this study was to investigate the epidemiology of wire bristle grill brush injury. STUDY DESIGN AND SETTING: Cross-sectional analysis of national databases; literature review. SUBJECTS AND METHODS: The Consumer Product Safety Commission's National Electronic Injury Surveillance System (NEISS) was used to derive a national weighted estimate of emergency department visits for wire bristle injury from 2002 to 2014. Date, location of injury, demographics, and outcomes were analyzed. A literature search and a consumer-reported injury database (SaferProducts.gov) were interrogated to provide ancillary sources of data. RESULTS: A total of 43 cases were found within the NEISS database, which extrapolated to an estimated 1698 (95% confidence interval, 1468-1927) emergency department visits nationwide. In the NEISS database, the mean age was 30 years, and the sex distribution of the patients was similar (21 males vs 22 females). The most common location of injury was the oropharynx in both the NEISS database (23 of 43, 53.4%) and the literature review (11 of 36, 30.5%). However, the oral cavity was the most frequent site in the consumer-reported SaferProducts.gov database (9 of 24, 37.5%). The majority of patients in the NEISS were treated in the emergency department (31 of 43, 69.7%). Raw case counts were highest in June, July, and August, with the highest number of events in the month of July. CONCLUSION: Injury from wire-bristle grill brush is uncommon but prevalent during certain seasons. Otolaryngologists play an important in the diagnosis and treatment of these injuries. Awareness among consumers and product manufacturers is necessary to promote safety. PMID- 26932966 TI - Injection Laryngoplasty Using Micronized Acellular Dermis for Vocal Fold Paralysis: Long-term Voice Outcomes. AB - OBJECTIVES: Micronized acellular dermis has been used for nearly 15 years to correct glottic insufficiency. With previous demonstration of safety and efficacy, this study aims to evaluate intermediate and long-term voice outcomes in those who underwent injection laryngoplasty for unilateral vocal fold paralysis. Technique and timing of injection were also reviewed to assess their impact on outcomes. STUDY DESIGN: Case series with chart review. SETTING: Tertiary care center. SUBJECTS AND METHODS: Patients undergoing injection laryngoplasty from May 2007 to September 2012 were reviewed for possible inclusion. Pre- and postoperative Voice Handicap Index (VHI) scores, as well as senior speech-language pathologists' blinded assessment of voice, were collected for analysis. The final sample included patients who underwent injection laryngoplasty for unilateral vocal fold paralysis, 33 of whom had VHI results and 37 of whom had voice recordings. Additional data were obtained, including technique and timing of injection. RESULTS: Analysis was performed on those patients above with VHI and perceptual voice grades before and at least 6 months following injection. Mean VHI improved by 28.7 points at 6 to 12 months and 22.8 points at >12 months (P = .001). Mean perceptual voice grades improved by 17.6 points at 6 to 12 months and 16.3 points at >12 months (P < .001). No statistically significant difference was found with technique or time to injection. CONCLUSION: Micronized acellular dermis is a safe injectable that improved both patient-completed voice ratings and blinded reviewer voice gradings at intermediate and long-term follow-up. Further investigation may be warranted regarding technique and timing of injection. PMID- 26932967 TI - Transoral Robotic Surgery for Obstructive Sleep Apnea: A Systematic Review and Meta-Analysis. AB - OBJECTIVE: To perform a systematic review of the international biomedical literature evaluating the effectiveness, complications, and safety of transoral robotic surgery (TORS) for the treatment of obstructive sleep apnea (OSA). DATA SOURCES: PubMed/MEDLINE, Embase, and EMB Reviews databases were searched up to November 27, 2015. REVIEW METHODS: Two authors systematically and independently searched for articles on TORS for the treatment of OSA in adults that reported either outcomes for the apnea-hypopnea index (AHI), lowest oxygen saturation percentage (LSAT) or changes in the Epworth Sleepiness Scale (ESS), and/or rates and types of complications associated with the operation. RESULTS: In total, 181 records were identified and 16 articles met inclusion criteria. Transoral robotic surgery was almost always combined with other sleep surgery procedures. The summary estimate of the decrease in AHI using TORS as part of a multilevel surgical approach was 24.0 (95% confidence interval [CI], 22.1-25.8; P < .001, I(2) = 99%). The summary estimate of a decrease in ESS score was 7.2 (95% CI, 6.6 7.7; P < .001, I(2) = 99%) and of the overall surgical "success" (defined as AHI <20 and 50% reduction) was 48.2% (95% CI, 38.8%-57.7%; P < .001, I(2) = 99%). Three large studies reported on their total complication rates with an average of 22.3% (range, 20.5%-24.7%). CONCLUSIONS: The initial results for the use of TORS as part of a multilevel surgical approach for OSA are promising for select patients. However, the cost and morbidity may be greater than with other techniques offsetting its advantages in visualization and precision. More prospective studies are needed to determine the optimal role of this tool. PMID- 26932968 TI - Cholesterol Granuloma Development following Temporal Bone Surgery. AB - OBJECTIVE: To describe the clinical presentation and management of patients with cholesterol granulomas (CGs) that develop following temporal bone surgery. STUDY DESIGN: Case series with chart review. SETTING: Two independent tertiary academic referral centers. SUBJECTS AND METHODS: A multicenter retrospective review was performed to identify all patients between 2001 and 2014 who were diagnosed with a CG that developed following temporal bone surgery. Patients with a history of idiopathic petrous apex CGs were excluded, as were those with <6 months of follow up after diagnosis. Demographic and clinical data were recorded at presentation, and the main outcome measure was symptom evolution over time. RESULTS: A total of 20 patients met inclusion criteria (median age, 55.0 years; 70.0% female), and their cases were analyzed. Diagnosis was made, on average, 149.5 months (median, 94.5; range, 13.0-480.0) following a temporal bone operation, which was for chronic ear disease in 75.0% of cases. The most common presenting symptoms were otalgia (55.0%) and otorrhea (40.0%). In patients initially managed with observation, 71.4% required no surgical intervention through a mean of 56.8 months (median, 30; range, 12.0-178.0) of follow-up. For those who initially underwent surgical excision, durable symptom relief was achieved in 66.7% of cases. CONCLUSION: Postoperative CG formation in the temporal bone is a rare occurrence that can be encountered years following surgery. The present study suggests that conservative management can be appropriate for many cases in which patients are relatively asymptomatic. PMID- 26932969 TI - Sinus Computed Tomography Imaging in Pediatric Cystic Fibrosis: Added Value? AB - STUDY OBJECTIVE: To evaluate the prevalence of computed tomography (CT) sinus imaging in a pediatric cystic fibrosis (CF) population, determine changes in Lund Mackay (LM) scores over time, and estimate radiation exposure. STUDY DESIGN: Case series with chart review. SETTING: Tertiary care children's hospital. SUBJECTS AND METHODS: In total, 202 pediatric patients with CF who underwent endoscopic sinus surgery (ESS) were included. The total number of CT scans was calculated for each patient, with specific focus on the indications for and subsequent outcomes of the sinus CT scan subgroup. RESULTS: Patients underwent a total of 1718 CT scans, 832 of which were sinus CT scans (mean of 4.2 sinus scans per patient). Disease evaluation (54%) and preoperative planning (35%) were the most common indications. Otolaryngologists were more likely to order imaging for preoperative evaluation, and those scans were more likely to result in surgery compared with those requested by other physicians (P < .001). Ninety CT scans (10.8%) led to no change in management. There was no significant difference in LM scores between patients admitted to the hospital or prescribed antibiotics and those who were not. There was also no significant change in LM score following ESS after adjusting for age and sex (P = .23). CONCLUSION: Based on LM scores, all sinus CT scans in patients with CF reveal moderate to severe sinus disease. Effort should be made to minimize radiation exposure in patients with CF by limiting sinus CT scans to the preoperative context or for evaluation of potential sinusitis complications. PMID- 26932970 TI - Effects of a Fibrin Sealant on Skin Graft Tissue Adhesion in a Rodent Model. AB - OBJECTIVE: To establish a rodent model for skin grafting with fibrin glue and examine the effects of fibrin glue on the adhesive strength of skin grafts without bolsters. STUDY DESIGN: Animal cohort. SETTING: Academic hospital laboratory. SUBJECTS AND METHODS: Three skin grafts were created using a pneumatic microtome on the dorsum of 12 rats. Rats were evenly divided into experimental (n = 6) and control (n = 6) groups. The experimental group received a thin layer of fibrin glue between the graft and wound bed, and the control group was secured with standard bolsters. Adherence strength of the skin graft was tested by measurement of force required to sheer the graft from the recipient wound. Adhesion strength measurements were taken on postoperative days (PODs) 1, 2, and 3. RESULTS: The experimental group required an average force of 719 g on POD1, 895 g on POD2, and 676 g on POD3, while the average force in the control group was 161 g on POD1, 257 g on POD2, and 267 g on POD3. On each of the 3 PODs, there was a significant difference in adherence strength between the experimental and control groups (P = .036, P = .029, P = .024). CONCLUSION: There is a significant difference in the adhesion strength of skin grafts to the wound bed in the early postoperative period of the 2 groups. In areas of high mobility, using the fibrin sealant can keep the graft immobile during the critical phases of early healing. PMID- 26932971 TI - Ciprofloxacin Decreases Collagen in Mouse Tympanic Membrane Fibroblasts. AB - OBJECTIVES: To determine how collagen production by tympanic membrane fibroblasts is affected by ciprofloxacin at levels found in eardrops. STUDY DESIGN: Prospective, controlled, and blinded cell culture study. SETTING: Academic tertiary medical center. SUBJECTS: Cell culture of mouse fibroblasts. METHODS: A primary fibroblast culture was established from mouse tympanic membranes. Fibroblasts were cultured until they were 75% confluent, then treated with dilute hydrochloric acid (control) or ciprofloxacin (0.01% or 0.3%) for 24 or 72 hours for Western blotting and for 24 or 48 hours for cytotoxicity assay. Cells were observed with phase-contrast microscope. Western blotting was performed for collagen type 1 alpha1 (collagen 1A1) and alpha-tubulin. RESULTS: Fibroblasts treated with 0.01% and 0.3% ciprofloxacin for 24 hours had lower levels of collagen 1A1 (P = .0005 and P < .0001, respectively) and alpha-tubulin (both P < .0001) than control fibroblasts. Collagen 1A1 and alpha-tubulin levels were lower in fibroblasts treated with 0.3% than with 0.01% ciprofloxacin (P = .02 and P = .014). After 72 hours, 0.3% ciprofloxacin completely eliminated collagen 1A1 and alpha-tubulin (P < .001). Cells treated with 0.01% ciprofloxacin for 72 hours also had lower collagen 1A1 (P < .0001) and alpha-tubulin (P = .005) as compared with the control. Seventy-two-hour incubation in 0.01% or 0.3% ciprofloxacin resulted in lower levels of collagen 1A1 (P = .009 and P < .0001, respectively) and alpha-tubulin (P = .007 and P < .0001, respectively) than 24-hour incubation. Cytotoxicity assay and phase-contrast microscopy mirrored these findings. CONCLUSIONS: Treatment of tympanic membrane fibroblasts with 0.3% ciprofloxacin, as found in eardrops, reduces fibroblast viability and collagen and alpha-tubulin protein levels. These findings could explain tympanic membrane healing problems associated with quinolone eardrops. PMID- 26932972 TI - Trends in the Incidence of Oropharyngeal Cancers in the United States. AB - OBJECTIVE: The incidence of oropharyngeal squamous cell carcinoma (SCCa) has increased in the United States despite a decrease in tobacco usage, and it may be driven by an increase in oral human papilloma virus (HPV) infection. We studied the incidence of tongue base and tonsillar SCCa over time to understand the changing epidemiology of oropharyngeal SCCa. SETTING: Large national tumor registry. SUBJECTS AND METHODS: We studied patients diagnosed with oropharyngeal SCCa in SEER data (Surveillance, Epidemiology, and End Results) from 1973 to 2009. Age-adjusted incidence rates standardized to the 2000 US population were computed, with stratifications for age, sex, race, and stage. RESULTS: The sample included 10,061 tongue base and 11,515 tonsillar oropharyngeal cancers. When stratified by age, the incidence of oropharyngeal SCCa in patients <=55 years of age more than doubled over 30 years. While the incidence rate in females remained stable, the rate in males more than doubled, from 2 per 100,000 persons in 1973 to >4 per 100,000 persons in 2009. The age-adjusted incidence of oropharyngeal SCCa in patients of black race/ethnicity remained consistently elevated, but the incidence in patients of white race/ethnicity rose from 1.3 per 100,000 persons to >2.5 per 100,000 persons, surpassing the incidence in black patients starting in 2002. CONCLUSION: The observation that the incidence of oropharyngeal SCCa is increasing among younger white males, despite a reduction in tobacco usage in the United States, is consistent with HPV as the source. Primary and secondary prevention strategies may be warranted in this population. PMID- 26932973 TI - Oral Antibiotic Use for Otitis Media with Effusion: Ongoing Opportunities for Quality Improvement. AB - OBJECTIVES: (1) To evaluate the probability of antibiotic administration associated with ICD-9 diagnosis of otitis media with effusion (OME) in the absence of acute otitis media, (2) to determine whether usage varies according to visit setting, and (3) to ascertain if practice gaps are such that future practice changes might be measured. STUDY DESIGN: Cross-sectional analysis of an administrative database. SETTING: Ambulatory visits in the United States. SUBJECTS AND METHODS: National Ambulatory and Hospital Ambulatory Medical Care Surveys, 2005-2010; univariate, multivariate, and stratified analyses of antibiotic usage were performed. The study population was restricted to children without acute or unspecified otitis media. The primary outcome was the probability of oral antibiotic administration when OME was diagnosed. The impact of the location of service and subspecialty care was also analyzed. RESULTS: Data from 1,390,404,196 pediatric visits demonstrated that oral antibiotics were administered for 32% of visits with an OME diagnosis, even in the absence of acute otitis media (odds ratio, 4.31; 95% confidence interval: 2.88-6.44; P < .001). The highest antibiotic administration was seen in the emergency department (risk difference, 37.1%; number needed to harm, 3). No significant increased risk of antibiotic usage was seen during otolaryngology visits. Diagnoses of infections at nonotologic sites were associated with a 1.98 to 26.60 increase in odds of oral antibiotic administration. CONCLUSION: Oral antibiotics continue to be administered in children with OME in the absence of acute infection, with risk varying by location of service. There is a potential opportunity for quality improvement through reducing antibiotic administration for pediatric OME. PMID- 26932974 TI - Pediatric Endoscopic Cholesteatoma Surgery. AB - OBJECTIVES: (1) To describe and review a single center's pediatric endoscopic cholesteatoma experience, including surgical and audiologic outcomes. (2) To assess the most common locations of residual cholesteatoma following endoscopic removal. STUDY DESIGN: Case series with chart review. SETTING: Tertiary otologic referral center. SUBJECTS: Patients <19 years of age who underwent cholesteatoma removal with either endoscopic or microscopic visualization. METHODS: In a comparison of patients who underwent total endoscopic ear surgery (TEES), combined endoscopic-microscopic surgery, or microscopic surgery, analyzed outcomes included locations and incidence of recurrent and residual cholesteatoma, complications, and audiometric testing. RESULTS: Sixty-six patients (mean age, 10.9 years; range, 4-18 years; 43.4% female) with 76 ears met inclusion criteria. The average overall follow-up was 18.8 months (range, 6.7 48.3). Forty-seven (61.8%) ears underwent microscopic removal of cholesteatoma; 29 (38.1%) ears underwent combined endoscopic-microscopic removal; and 8 (10.5%) ears underwent TEES removal. Significantly more mastoidectomies were completed in microscopic cases as compared with endoscopic cases (P = .049). Though second look procedures occurred in 15 (51.7%) endoscopic cases and 10 (21.3%) microscopic cases (P = .006), the rate of residual disease was 20.0% and 40.0% in endoscopic and microscopic cases, respectively (P = .38). When controlling for preoperative hearing, only the air-bone gap for TEES demonstrated significant improvement (P = .009). No complications were noted. CONCLUSION: The present report describes our experience with pediatric endoscopic cholesteatoma surgery, demonstrating similar hearing outcomes, rates of recurrence and residual disease, and complication rates as compared with traditional microscopic techniques. PMID- 26932975 TI - Heterogeneous nucleation and growth dynamics in the light-induced phase transition in vanadium dioxide. AB - We report on ultrafast optical investigations of the light-induced insulator-to metal phase transition in vanadium dioxide with controlled disorder generated by substrate mismatch. These results reveal common dynamics of this optically induced phase transition that are independent of this disorder. Above the fluence threshold for completing the transition to the rutile crystalline phase, we find a common time scale, independent of sample morphology, of 40.5 +/- 2 ps that is consistent with nucleation and growth dynamics of the R phase from the parent M1 ground state. PMID- 26932976 TI - Study links Zika virus to Guillain-Barre syndrome. PMID- 26932977 TI - Single-patient multiple crossover studies to determine the effectiveness of paracetamol in relieving pain suffered by patients with advanced cancer taking regular opioids: A pilot study. PMID- 26932978 TI - Primary prevention and risk factor reduction in coronary heart disease mortality among working aged men and women in eastern Finland over 40 years: population based observational study. AB - OBJECTIVE: To estimate how much changes in the main risk factors of cardiovascular disease (smoking prevalence, serum cholesterol, and systolic blood pressure) can explain the reduction in coronary heart disease mortality observed among working aged men and women in eastern Finland. DESIGN: Population based observational study. SETTING: Eastern Finland. PARTICIPANTS: 34,525 men and women aged 30-59 years who participated in the national FINRISK studies between 1972 and 2012. INTERVENTIONS: Change in main cardiovascular risk factors through population based primary prevention. MAIN OUTCOME MEASURES: Predicted and observed age standardised mortality due to coronary heart disease. Predicted change was estimated with a logistic regression model using risk factor data collected in nine consecutive, population based, risk factor surveys conducted every five years since 1972. Data on observed mortality were obtained from the National Causes of Death Register. RESULTS: During the 40 year study period, levels of the three major cardiovascular risk factors decreased except for a small increase in serum cholesterol levels between 2007 and 2012. From years 1969 1972 to 2012, coronary heart disease mortality decreased by 82% (from 643 to 118 deaths per 100,000 people) and 84% (114 to 17) among men and women aged 35-64 years, respectively. During the first 10 years of the study, changes in these three target risk factors contributed to nearly all of the observed mortality reduction. Since the mid-1980s, the observed reduction in mortality has been larger than predicted. In the last 10 years of the study, about two thirds (69% in men and 66% in women) of the reduction could be explained by changes in the three main risk factors, and the remaining third by other factors. CONCLUSION: Reductions in disease burden and mortality due to coronary heart disease can be achieved through the use of population based primary prevention programmes. Secondary prevention among high risk individuals and treatment of acute events of coronary heart disease could confer additional benefit. PMID- 26932979 TI - Fever in an intravenous drug user. PMID- 26932981 TI - User experience of transtibial prosthetic liners: A systematic review. AB - BACKGROUND: The liner is an integral part of a transtibial prosthesis designed to protect the residual limb, enhance comfort and provide suspension. Literature is difficult to interpret and use given the variety of interventions, outcome measures and method designs. Critical appraisal and synthesis of the evidence is needed to help inform decisions about liner prescription based on the user experience. OBJECTIVES: To critically appraise and synthesise research describing the user experience of transtibial prosthetic liners. STUDY DESIGN: Systematic review. METHODS: A comprehensive suite of databases were searched using terms related to amputation level, liner type and user experience. Included studies were in English and measured the first-person experience of using a transtibial liner. Studies were appraised using the McMaster University Critical Review Forms. RESULTS: A total of 18 articles met the inclusion criteria. While the quality of the evidence has improved over time, a number of common issues (e.g. sampling bias, validity of outcome measures, incorrect inferential analysis) reduce our ability to differentiate between the user experience of different transtibial liners. CONCLUSION: There is insufficient research to differentiate between the user experience of different transtibial liners. High-quality research is needed to inform decisions about liner prescription based on the user experience. Clinical relevance The available evidence suggests that the user experience of commonly reported problems (e.g. sweating) may be very similar between different liners. Aspects of the user experience that differ most between liners (e.g. unwanted noises, rotation within the socket) can help focus attention on what matters most when discussing prescription. PMID- 26932980 TI - Movement quality of conventional prostheses and the DEKA Arm during everyday tasks. AB - BACKGROUND: Conventional prosthetic devices fail to restore the function and characteristic movement quality of the upper limb. The DEKA Arm is a new, advanced prosthesis featuring a compound, powered wrist and multiple grip configurations. OBJECTIVES: The purpose of this study was to determine if the DEKA Arm improved the movement quality of upper limb prosthesis users compared to conventional prostheses. STUDY DESIGN: Case series. METHODS: Three people with transradial amputation completed tasks of daily life with their conventional prosthesis and with the DEKA Arm. A total of 10 healthy controls completed the same tasks. The trajectory of the wrist joint center was analyzed to determine how different prostheses affected movement duration, speed, smoothness, and curvature compared to patients' own intact limbs and controls. RESULTS: Movement quality decreased with the DEKA Arm for two participants, and increased for the third. Prosthesis users made slower, less smooth, more curved movements with the prosthetic limb compared to the intact limb and controls, particularly when grasping and manipulating objects. CONCLUSION: The effects of one month of training with the DEKA Arm on movement quality varied with participants' skill and experience with conventional prostheses. Future studies should examine changes in movement quality after long-term use of advanced prostheses. Clinical relevance Movement quality with the DEKA Arm may depend on the user's previous experience with conventional prostheses. Quantitative analyses are needed to assess the efficacy of novel prosthetic devices and to better understand how to train people to use them effectively. PMID- 26932982 TI - Cutaneous sensory outcomes from three transhumeral targeted reinnervation cases. AB - BACKGROUND: Although targeted muscle reinnervation has been shown to be effective in enhancing prosthetic control for upper limb amputees, restored hand sensations have been variable. An understanding of possible sensory feedback channels is crucial in working toward more effective closed-loop prosthetic control. OBJECTIVES: To compare sensory outcomes of different targeted sensory reinnervation approaches. STUDY DESIGN: Case series, cross-sectional, and retrospective. METHODS: Three transhumeral amputees that had undergone different sensory reinnervation approaches were recruited. Skin pressure sensitivity thresholds and anatomic sensory mapping were performed using Semmes-Weinstein monofilaments. The clinical charts of the subjects were reviewed to compare the sensory maps performed during the earlier post-reinnervation period. RESULTS: While the first two subjects achieved return of hand sensations on the stump skin in early follow-up, the maps showed attenuation over time. The last subject developed discrete sensations of all digits in the recipient cutaneous nerve territories away from the reinnervated muscles. CONCLUSIONS: These findings confirm that it is feasible to restore hand sensation after transhumeral targeted reinnervation, but there is a significant intersubject variability. The intrafascicular approach may be particularly effective in restoring digit sensation and deserves further exploration, as do factors affecting stability of the hand maps over time. CLINICAL RELEVANCE: In addition to enabling intuitive motor control of myoelectric prosthesis, targeted reinnervation can also result in sensory restoration of the hand. Documentation of sensory mapping present after reinnervation may assist with exploring future techniques for sensory enhancement, with the goal of working toward closed-loop prosthetic control. PMID- 26932983 TI - Analytical workflow of double-digest restriction site-associated DNA sequencing based on empirical and in silico optimization in tomato. AB - Double-digest restriction site-associated DNA sequencing (ddRAD-Seq) enables high throughput genome-wide genotyping with next-generation sequencing technology. Consequently, this method has become popular in plant genetics and breeding. Although computational in silico prediction of restriction sites from the genome sequence is recognized as an effective approach for choosing the restriction enzymes to be used, few reports have evaluated the in silico predictions in actual experimental data. In this study, we designed and demonstrated a workflow for in silico and empirical ddRAD-Seq analysis in tomato, as follows: (i)in silico prediction of optimum restriction enzymes from the reference genome, (ii) verification of the prediction by actual ddRAD-Seq data of four restriction enzyme combinations, (iii) establishment of a computational data processing pipeline for high-confidence single nucleotide polymorphism (SNP) calling, and (iv) validation of SNP accuracy by construction of genetic linkage maps. The quality of SNPs based on de novo assembly reference of the ddRAD-Seq reads was comparable with that of SNPs obtained using the published reference genome of tomato. Comparisons of SNP calls in diverse tomato lines revealed that SNP density in the genome influenced the detectability of SNPs by ddRAD-Seq. In silico prediction prior to actual analysis contributed to optimization of the experimental conditions for ddRAD-Seq, e.g. choices of enzymes and plant materials. Following optimization, this ddRAD-Seq pipeline could help accelerate genetics, genomics, and molecular breeding in both model and non-model plants, including crops. PMID- 26932985 TI - Is There a Future for Interleukin 17 Blocking Agents in Rheumatoid Arthritis? PMID- 26932986 TI - Spondyloarthritis. Clinical Versus Imaging Assessment: And the Winner Is? PMID- 26932984 TI - Spatially coordinated replication and minimization of expression noise constrain three-dimensional organization of yeast genome. AB - Despite recent advances, the underlying functional constraints that shape the three-dimensional organization of eukaryotic genome are not entirely clear. Through comprehensive multivariate analyses of genome-wide datasets, we show that cis and trans interactions in yeast genome have significantly distinct functional associations. In particular, (i) the trans interactions are constrained by coordinated replication and co-varying mutation rates of early replicating domains through interactions among early origins, while cis interactions are constrained by coordination of late replication through interactions among late origins; (ii)cis and trans interactions exhibit differential preference for nucleosome occupancy; (iii)cis interactions are also constrained by the essentiality and co-fitness of interacting genes. Essential gene clusters associate with high average interaction frequency, relatively short-range interactions of low variance, and exhibit less fluctuations in chromatin conformation, marking a physically restrained state of engaged loci that, we suggest, is important to mitigate the epigenetic errors by restricting the spatial mobility of loci. Indeed, the genes with lower expression noise associate with relatively short-range interactions of lower variance and exhibit relatively higher average interaction frequency, a property that is conserved across Escherichia coli,yeast, and mESCs. Altogether, our observations highlight the coordination of replication and the minimization of expression noise, not necessarily co-expression of genes, as potent evolutionary constraints shaping the spatial organization of yeast genome. PMID- 26932987 TI - Do Biologic-treated Psoriatic Arthritis Patients with Spondylitis Respond Differently with or without Concomitant Methotrexate from Patients without Spondylitis? PMID- 26932988 TI - Sacroiliitis-like Changes in 2 Patients with Spina Bifida. PMID- 26932989 TI - Subcutaneous Sarcoidosis Mimicking Cellulitis. PMID- 26932990 TI - Systemic Sclerosis and Outcome in Intensive Care Unit: Do Not Close the Door, Open the Right Protocol. PMID- 26932991 TI - Dr. Pene, et al reply. PMID- 26932992 TI - Assessment of Serum Uric Acid in Young Male Patients with Ankylosing Spondylitis. PMID- 26932993 TI - Drs. Kang and Ju reply. PMID- 26932994 TI - Genetic Markers in a Medieval Case of Ankylosing Spondylitis. PMID- 26932995 TI - Specific Antinuclear Antibody Level Changes after B Cell Depletion Therapy in Systemic Sclerosis Are Associated with Improvement of Skin Thickening. PMID- 26932996 TI - Risk of Venous Thromboembolism after Total Knee Arthroplasty in Patients with Rheumatoid Arthritis. PMID- 26932997 TI - A Message from the Editor-in-Chief. PMID- 26932998 TI - [Le leadership en sante et l'ethique de la gestion des attentes des soignants et des patients]. AB - Les dispensateurs de soins et les patients sont souvent decus du niveau de soins que les hopitaux publics peuvent prodiguer. La solution consiste a reduire les attentes. Les dispensateurs devraient etre amenes a considerer que leur obligation consiste a prodiguer les meilleurs soins en fonction des ressources. Le public devrait etre bien informe des services que les hopitaux de soins actifs peuvent ou non lui offrir et participer aux prises de decision. Les leaders en sante peuvent jouer des roles novateurs a cet egard. PMID- 26932999 TI - Superior vena cava repair with left brachiocephalic vein flap. AB - Interposition with a vascular prosthesis or patch closure using autologous pericardium has been applied for superior vena cava (SVC) reconstruction during surgery for thoracic malignancies such as thymic epithelial tumors or lymphadenopathy that invade the SVC. We herein report a novel and simple method for repair of the SVC using a left brachiocephalic vein flap. This procedure is useful to repair the anterior wall of the distal portion of the SVC, which is a common site of invasion of thoracic malignancies. PMID- 26933000 TI - Pericecal hernia manifesting as a small bowel obstruction successfully treated with laparoscopic surgery. AB - A pericecal hernia is a type of internal hernia, which rarely causes small bowel obstruction (SBO). At our institution, a 92-year-old man presented with vomiting and abdominal pain. He was conservatively treated with a diagnosis of SBO. After 2 weeks of copious drainage output, he was taken to the operating room. Laparoscopy revealed a pericecal hernia that was successfully reduced. We conclude that laparoscopic surgery is an effective way to treat SBOs secondary to pericecal hernias. PMID- 26933001 TI - SVC obstruction and stridor relieved by nasogastric tube insertion. AB - Achalasia is an idiopathic motility disorder of the oesophagus of increasing incidence. It is characterized by aperistalsis of the lower oesophagus and failure of relaxation of the lower oesophageal sphincter. Patients classically present with chronic symptoms of dysphagia, chest pain, weight loss and regurgitation, and they commonly suffer pulmonary complications such as recurrent microaspiration of static, retained food contents of the upper oesophagus. However, it has also been described, uncommonly, to present with megaoesophagus and secondary tracheal compression. We present a case of megaoesophagus secondary to achalasia which presented with stridor and signs of acute superior vena caval obstruction. PMID- 26933002 TI - Letter to the Editor. PMID- 26933003 TI - Reply to Drs. Teppema and Berendsen. PMID- 26933004 TI - Corrigendum. PMID- 26933005 TI - Translating Knowledge: Promoting Health Through Intergenerational Community Arts Programming. AB - INTRODUCTION: Intergenerational programs have been touted to address the generation gaps and isolation of older adults. Mutual contact alone has produced mixed results, but attention to the intergenerational program content demonstrates well-being benefits. This practice-based article examines the benefits of creating and performing ensemble-created plays to older adults' and university students' well-being and the key processes that promote well-being. METHOD: This community participatory research project involved older adults as researchers as well as research subjects. Individual semistructured interviews were conducted by two trained interviewers with older adults (n = 15) and university students (n = 17). RESULTS: Professional dramaturgical processes of storytelling, reminiscence, and playfulness were key elements in participants' generative learning. They augmented older adults' and university students' ability to understand their situations and try innovative solutions. Skills such as openness, flexibility, and adaptation transferred into students' and older adults' daily lives. CONCLUSION: Participating in this intergenerational theatre group reduced ageism and improved intergenerational relationships. It increased older adults' and university students' well-being by building social networks, confidence, and self-esteem and developed a sense of social justice, empathy, and support for others. PMID- 26933006 TI - Evaluating Art Therapy to Heal the Effects of Trauma Among Refugee Youth: The Burma Art Therapy Program Evaluation. AB - BACKGROUND: Art therapy uses the creative process to encourage personal growth and alleviate symptoms of mental illness. The Art Therapy Institute provides programs for refugee adolescents from Burma to decrease their trauma-related symptoms. This article describes and discusses the methods and findings from an evaluation of this program. The challenges of assessing art therapy with this population and assessment tool gaps are explored and suggestions for future evaluations discussed. METHOD: Four validated clinical assessment tools were administered to 30 participants at baseline and follow-up to measure symptoms of anxiety, depression, and behavioral problems. Focus group discussions with clinicians were used to assess the evaluation. RESULTS: Nearly all participants had experienced one or more traumatic events. At baseline, results showed a higher prevalence of depression than national rates among adolescents. Follow-up results showed improvements in anxiety and self-concept. Qualitative findings suggest that specific benefits of art therapy were not adequately captured with the tools used. DISCUSSION: This evaluation showed some effects of art therapy; however, symptom-focused assessment tools are not adequate to capture clients' growth resulting from the traumatic experience and this unique intervention. Future evaluations will benefit by using an art-based assessment and measuring posttraumatic growth. PMID- 26933007 TI - Rethink Your Drink. AB - BACKGROUND: Sugar-sweetened beverages (SSBs) are linked to obesity; hospitals are a priority setting to reduce intake. This article describes the development, implementation, and results of a focused intervention to reduce SSB sales within a hospital setting. METHOD: After a formative research process, Rethink Your Drink was launched at a children's hospital in San Diego. The initiative consisted of an educational intervention using the stoplight system to categorize beverages as red, yellow, or green based on sugar content. Beverage sales data were collected for 3 months prior, during the 12-month intervention, and for 4 months after the intervention ended. RESULTS: Monthly red beverage sales decreased from an average of 56% during baseline to 32% at the end of the data collection period (p < .001). Monthly green beverage sales increased from an average of 12.2% during baseline to 38% at the end of the data collection period (p < .001). Sales revenue for all drinks remained constant. DISCUSSION: The intervention resulted in a decrease in SSB sales and an increase in sales of healthier beverage choices. Such interventions can play an important role in obesity prevention and may be more feasible for smaller hospitals with limited resources. PMID- 26933008 TI - RE: Weight Gain After Breast Cancer Diagnosis and All-Cause Mortality: Systematic Review and Meta-Analysis. PMID- 26933009 TI - Response. PMID- 26933010 TI - Impact of Early Breast Cancer Screening on Mortality Among Young Survivors of Childhood Hodgkin's Lymphoma. AB - BACKGROUND: Female survivors treated with thoracic radiation therapy (RT) for childhood cancer experience increased risks of breast cancer (BC). There are currently no data quantifying the potential mortality gains of early BC screening among such survivors. METHODS: A mathematical model of BC development was used to evaluate the marginal benefit of early-initiated screening of female survivors of adolescent Hodgkin's lymphoma (HL) starting at age 25 years on BC mortality compared with screening initiated at age 40 years. Sensitivity analyses were performed to evaluate the robustness of the estimates over a plausible range of conditions. RESULTS: For survivors treated at age 15 years, the absolute risk of BC mortality by age 75 years was predicted to decrease from 16.65% with no early screening to 16.28% (annual mammography), 15.40% (annual MRI), 15.38% (same-day annual mammography and MRI), and 15.37% (alternating mammography and MRI every six months). Approximately 80 patients would need to be invited to MRI-based screening to prevent one BC death. In sensitivity analyses, the number needed to invite to MRI-based screening to prevent one BC death ranged from 71 to 333. Combinations of MRI plus mammography were predicted to produce 99.52 false positives per 1000 screenings done between age 25 to 39 years. CONCLUSIONS: These findings are the first to indicate that early MRI-based screening should reduce BC mortality among women treated with RT for adolescent HL. The magnitude of this benefit is superior to that described for other accepted screening indications although MRI can produce a substantial rate of false-positive results. PMID- 26933011 TI - Winning in style: Longer styles receive more pollen, but style length does not affect pollen attrition in wild Clarkia populations. AB - PREMISE OF THE STUDY: One proposed function of long styles is to intensify selection among male gametophytes relative to short styles. If so, given sufficient competition, longer styles will have higher rates of pollen tube attrition (failure to reach the style base) within the style than shorter ones. Alternatively, style length may influence pollen receipt, which itself may affect attrition rates. METHODS: We tested these predictions by collecting senescing styles from wild populations of two insect-pollinated Clarkia species. We examined the number of pollen grains adhering to the stigma, length of styles, and rates of attrition from the stigma surface to the stigma-style junction (SSJ), from the SSJ to the style base, and from the stigma surface to the style base. Multivariate analyses estimated the independent effects of pollen grains per stigma, the number of pollen tubes at the SSJ, and style length on attrition. KEY RESULTS: Style length was generally positively correlated with pollen receipt, and the number of pollen grains per stigma was positively correlated with all three attrition rates. In neither species was any attrition rate affected by style length independent of the number of pollen grains per stigma. CONCLUSIONS: Pollen attrition was mediated by style length, but the function of style length was primarily to increase the number of germinating pollen grains, which affected attrition rates either through stigma clogging or pollen-pollen interactions. Style length may have a direct effect on pollen receipt due to the stigma's position relative to pollinator body parts, but traits correlated with style length may also directly affect pollen receipt. PMID- 26933012 TI - Diverse ecological relations of male gametophyte populations in stylar environments. AB - PREMISE OF STUDY: Pollen on a stigma represents a local population of male gametophytes vying for access to female gametophytes in the associated ovary. As in most populations, density-independent and density-dependent survival depend on intrinsic characteristics of male gametophytes and environmental (pistil) conditions. These characteristics and conditions could differ among flowers, plants, populations, and species, creating diverse male-gametophyte population dynamics, which can influence seed siring and production. METHODS: For nine species, we characterized the relations of both the mean and standard deviation of pollen-tube number at the style base to pollen receipt with nonlinear regression. Models represented asymptotic or peaked relations, providing information about the incidence and magnitude of facilitation and competition, the spatial and temporal characteristics of competition, and the intensity and relative timing of density-independent mortality. KEY RESULTS: We infer that pollen tubes of most species competed sequentially, their tips ceasing growth if earlier tubes had depleted stylar space/resources; although two species experienced simultaneous competition. Tube success of three species revealed positive density dependence (facilitation) at low density. For at least four species, density-independent mortality preceded competition. Tube success varied mostly within plants, rather than among plants or conspecific populations. Pollen quality influenced tube success for two of three species; affecting density independent survival in one and density-dependent performance in the other. CONCLUSIONS: The diverse relations of pollen-tube success to pollen receipt evident among just nine species indicate significant contributions of the processes governing pollen germination and tube growth to the reproductive diversity of angiosperms. PMID- 26933013 TI - Pollen limitation is not the rule in nival plants: A study from the European Central Alps. AB - PREMISE OF THE STUDY: Seed output of high-mountain plants in the uppermost life zones is highly variable. One possible reason might be pollen limitation due to inadequate pollinator services. METHODS: We tested this hypothesis for the insect pollinated species Cerastium uniflorum, Ranunculus glacialis, and Saxifraga bryoides, which have their distribution center in the subnival and nival zone of the European Central Alps. We recorded insect visitors and determined their impact as pollinators. By analyzing pollination success and seed set following natural and saturating hand pollination, the magnitude of quantitative and qualitative pollen limitation was assessed. KEY RESULTS: Anthomyiid and muscid flies had the highest pollination impact for R. glacialis and S. bryoides and syrphids for C. uniflorum. Natural stigma pollen load was highly variable in individual flowers of all species, but in most cases the number of conspecific pollen grains clearly exceeded the number of ovules to be fertilized. There was also a surplus in germinated pollen grains, whereas the pollen tube to ovule ratio was only sufficient in R. glacialis (2.6 on average) and S. bryoides (1.3), but not in C. uniflorum (0.6). Accordingly, seed to ovule ratio was around 0.8 in R. glacialis, 0.7 in S. bryoides but 0.4 in C. uniflorum. In C. uniflorum, saturating pollination slightly increased seed set. Regression analyses revealed that natural pollination success was more frequently limited by quality than by quantity. CONCLUSIONS: Our results do not support the idea of chronic, widespread pollen limitation in the subnival but rather fit into the concept of parental optimism by overinvesting in the number of ovules as an adaptation to variable resource availability. PMID- 26933014 TI - What Have We Learned From the Typhoid Fever Surveillance in Africa Program? AB - The Typhoid Fever Surveillance in Africa Program (TSAP) was established in 2009 to fill the data void concerning invasive Salmonella disease in sub-Saharan Africa, and to specifically estimate the burden of bloodstream infections caused by the key pathogen, Salmonella enterica serovar Typhi. TSAP has achieved this ambitious target, finding high incidences of typhoid fever in both rural and urban populations in several countries in sub-Saharan Africa. The results of TSAP will undoubtedly dictate the direction of future typhoid fever research in Africa, and at last provides a key piece of the disease burden jigsaw puzzle. With the dawn of new Vi conjugate vaccines against Salmonella Typhi, the next priority for the typhoid community must be providing the required data on these vaccines so they can be licensed and provided to those in high-risk groups and locations across sub-Saharan Africa. PMID- 26933015 TI - Variations of Invasive Salmonella Infections by Population Size in Asante Akim North Municipal, Ghana. AB - BACKGROUND: The Typhoid Fever Surveillance in Africa Program (TSAP) estimated adjusted incidence rates (IRs) for Salmonella enterica serovar Typhi and invasive nontyphoidal S. enterica serovars (iNTS) of >100 cases per 100 000 person-years of observation (PYO) for children aged <15 years in Asante Akim North Municipal (AAN), Ghana, between March 2010 and May 2012. We analyzed how much these rates differed between rural and urban settings. METHODS: Children recruited at the Agogo Presbyterian Hospital and meeting TSAP inclusion criteria were included in the analysis. Towns with >32 000 inhabitants were considered urban; towns with populations <5200 were considered rural. Adjusted IRs for Salmonella bloodstream infections were estimated for both settings. Setting-specific age-standardized incidence rates for children aged <15 years were derived and used to calculate age-standardized rate ratios (SRRs) to evaluate differences between settings. RESULTS: Eighty-eight percent (2651/3000) of recruited patients met inclusion criteria and were analyzed. IRs of Salmonella bloodstream infections in children <15 years old were >100 per 100 000 PYO in both settings. Among rural children, the Salmonella Typhi and iNTS rates were 2 times (SRR, 2.2; 95% confidence interval [CI], 1.3-3.5) and almost 3 times (SRR, 2.8; 95% CI, 1.9-4.3) higher, respectively, than rates in urban children. CONCLUSIONS: IRs of Salmonella bloodstream infections in children <15 years old in AAN, Ghana, differed by setting, with 2 to nearly 3 times higher rates in the less populated setting. Variations in the distribution of the disease should be considered to implement future studies and intervention strategies. PMID- 26933017 TI - The Emergence of Reduced Ciprofloxacin Susceptibility in Salmonella enterica Causing Bloodstream Infections in Rural Ghana. AB - BACKGROUND: Salmonella ranks among the leading causes of bloodstream infections in sub-Saharan Africa. Multidrug resistant typhoidal and nontyphoidal Salmonella (NTS) isolates have been previously identified in this region. However, resistance to ciprofloxacin has rarely been reported in West Africa. This study aims to assess susceptibility against ciprofloxacin in Salmonella causing invasive bloodstream infections among children in rural Ghana. METHODS: From May 2007 until May 2012, children attending a rural district hospital in central Ghana were eligible for recruitment. Salmonella enterica isolated from blood cultures were assessed for ciprofloxacin susceptibility by Etest (susceptible minimum inhibitory concentration [MIC] <= 0.06 ug/mL). The gyrA, gyrB, parC, and parE genes were sequenced to identify mutations associated with changes in susceptibility to fluoroquinolones. RESULTS: Two hundred eighty-five Salmonella enterica isolates from 5211 blood cultures were most commonly identified as Salmonella enterica serovar Typhimurium (n = 129 [45%]), Salmonella enterica serovar Typhi (n = 89 [31%]), Salmonella enterica serovar Dublin (n = 20 [7%]), and Salmonella enterica serovar Enteritidis (n = 19 [7%]). All S. Typhi and S. Dublin were susceptible to ciprofloxacin. Reduced susceptibility (MIC >0.06 ug/mL) was found in 53% (10/19) of S. Enteritidis and in 2% (3/129) of S. Typhimurium isolates. Sequencing detected a single gyrB mutation (Glu466Asp) and a single gyrA mutation (Ser83Tyr) in all 3 S. Typhimurium isolates, while 9 of 10 S. Enteritidis harbored single gyrA mutations (Asp87Gly, Asp87Asn, or Asp87Tyr). No mutations were found in the parC and parE genes. CONCLUSIONS: Ciprofloxacin susceptibility in invasive NTS in rural Ghana is highly dependent on serotype. Although reduced ciprofloxacin susceptibility is low in S. Typhimurium, more than half of all S. Enteritidis isolates are affected. Healthcare practitioners in Ghana should be aware of potential treatment failure in patients with invasive S. Enteritidis infections. PMID- 26933016 TI - The Relationship Between Invasive Nontyphoidal Salmonella Disease, Other Bacterial Bloodstream Infections, and Malaria in Sub-Saharan Africa. AB - BACKGROUND: Country-specific studies in Africa have indicated that Plasmodium falciparum is associated with invasive nontyphoidal Salmonella (iNTS) disease. We conducted a multicenter study in 13 sites in Burkina Faso, Ethiopia, Ghana, Guinea-Bissau, Kenya, Madagascar, Senegal, South Africa, Sudan, and Tanzania to investigate the relationship between the occurrence of iNTS disease, other systemic bacterial infections, and malaria. METHODS: Febrile patients received a blood culture and a malaria test. Isolated bacteria underwent antimicrobial susceptibility testing, and the association between iNTS disease and malaria was assessed. RESULTS: A positive correlation between frequency proportions of malaria and iNTS was observed (P = .01; r = 0.70). Areas with higher burden of malaria exhibited higher odds of iNTS disease compared to other bacterial infections (odds ratio [OR], 4.89; 95% CI, 1.61-14.90; P = .005) than areas with lower malaria burden. Malaria parasite positivity was associated with iNTS disease (OR, 2.44; P = .031) and gram-positive bacteremias, particularly Staphylococcus aureus, exhibited a high proportion of coinfection with Plasmodium malaria. Salmonella Typhimurium and Salmonella Enteritidis were the predominant NTS serovars (53/73; 73%). Both moderate (OR, 6.05; P = .0001) and severe (OR, 14.62; P < .0001) anemia were associated with iNTS disease. CONCLUSIONS: A positive correlation between iNTS disease and malaria endemicity, and the association between Plasmodium parasite positivity and iNTS disease across sub Saharan Africa, indicates the necessity to consider iNTS as a major cause of febrile illness in malaria-holoendemic areas. Prevention of iNTS disease through iNTS vaccines for areas of high malaria endemicity, targeting high-risk groups for Plasmodium parasitic infection, should be considered. PMID- 26933018 TI - Diagnosing Salmonella enterica Serovar Typhi Infections by Polymerase Chain Reaction Using EDTA Blood Samples of Febrile Patients From Burkina Faso. AB - BACKGROUND: Globally, there are an estimated 22 million cases of Salmonella enterica serovar Typhi infection each year. However, this figure is likely to be an underestimate due to the low sensitivity of blood culture in S. Typhi diagnosis. The aim of this study was to diagnose S. Typhi by conventional polymerase chain reaction (PCR) using patient's blood preserved with ethylenediamine tetraacetic acid (EDTA). METHODS: From April 2012 to September 2013, typhoid fever surveillance was conducted in Polesgo and Nioko, 2 dry slum areas in Ouagadougou, Burkina Faso. Blood culture was performed for febrile patients using an automated blood culture system. Additional blood was collected in EDTA tubes from those patients and preserved at -80 degrees C. DNA was extracted from EDTA blood and PCR was performed to identify presence of S. Typhi. Randomly selected PCR products were further sequenced to identify S. Typhi specific amplicons. RESULTS: Of 1674 patients, S. Typhi was isolated from 18 (1.1%) individuals by blood culture. EDTA blood was collected from 1578 patients, of which 298 EDTA samples were tested by PCR. Salmonella Typhi-specific DNA was identified in 44 (14.8%) samples. The sensitivity of S. Typhi-specific PCR from EDTA blood was 89% (74%-100%) among the blood culture-positive cases. Sixteen S. Typhi-positive PCR products were sequenced, and 13 retrieved the sequence of a S. Typhi-specific amplicon. CONCLUSIONS: These findings suggest that blood culture based diagnoses of S. Typhi underestimate the burden of typhoid fever in Burkina Faso. PCR could be considered as an alternative method for the identification and diagnosis of S. Typhi in blood samples. PMID- 26933019 TI - Challenges and Opportunities for Typhoid Fever Control: A Call for Coordinated Action. AB - The burden of enteric fever caused by Salmonella enterica serovars Typhi and Paratyphi is substantial and has high impact in toddlers and young children. This burden is relatively well documented in Asia, and this supplement provides new data on the substantial burden in several sub-Saharan African countries. Challenges in standardized surveillance and imperfect diagnostic tools have resulted in patchy local disease data, which are not well acknowledged or integrated into local country evidence and health awareness for decision making. There is a need to strengthen diagnostics for the generation of burden data in country. Furthermore, the guidelines and training for treatment of enteric fever cases in Africa are sorely needed to help mitigate the inappropriate use of antimicrobial treatment. Classic water safety and access to sanitation development remain powerful tools for the control of typhoid fever, yet the huge economic costs and long timelines are unlikely to provide a short- to middle-term solution. Emerging threats, including multidrug resistance and increasing urbanization in regions such as sub-Saharan Africa, warrant focused attention to shorter-term interventions including immunization, and must include vaccine strategies with the new typhoid conjugate vaccines. PMID- 26933021 TI - Detection of a Novel gyrB Mutation Associated With Fluoroquinolone-Nonsusceptible Salmonella enterica serovar Typhimurium Isolated From a Bloodstream Infection in Ghana. AB - A multidrug-resistant Salmonella enterica serovar Typhimurium with reduced susceptibility to ciprofloxacin was isolated from the blood of a hospitalized child in Ghana. DNA sequencing identified a novel gyrB mutation at codon 466 (Glu466Asp). An increase in fluoroquinolone susceptibility after the introduction of a wild-type gyrB(+) allele demonstrated that the gyrB466 mutation had a direct effect on fluoroquinolone susceptibility. PMID- 26933020 TI - A Multicountry Molecular Analysis of Salmonella enterica Serovar Typhi With Reduced Susceptibility to Ciprofloxacin in Sub-Saharan Africa. AB - BACKGROUND: Salmonella enterica serovar Typhi is a predominant cause of bloodstream infections in sub-Saharan Africa (SSA). Increasing numbers of S. Typhi with resistance to ciprofloxacin have been reported from different parts of the world. However, data from SSA are limited. In this study, we aimed to measure the ciprofloxacin susceptibility of S. Typhi isolated from patients with febrile illness in SSA. METHODS: Febrile patients from 9 sites within 6 countries in SSA with a body temperature of >=38.0 degrees C were enrolled in this study. Blood samples were obtained for bacterial culture, and Salmonella isolates were identified biochemically and confirmed by multiplex polymerase chain reaction (PCR). Antimicrobial susceptibility of all Salmonella isolates was performed by disk diffusion test, and minimum inhibitory concentrations (MICs) against ciprofloxacin were measured by Etest. All Salmonella isolates with reduced susceptibility to ciprofloxacin (MIC > 0.06 ug/mL) were screened for mutations in quinolone resistance-determining regions in target genes, and the presence of plasmid-mediated quinolone resistance (PMQR) genes was assessed by PCR. RESULTS: A total of 8161 blood cultures were performed, and 100 (1.2%) S. Typhi, 2 (<0.1%) Salmonella enterica serovar Paratyphi A, and 27 (0.3%) nontyphoid Salmonella (NTS) were isolated. Multidrug-resistant S. Typhi were isolated in Kenya (79% [n = 38]) and Tanzania (89% [n = 8]) only. Reduced ciprofloxacin-susceptible (22% [n = 11]) S. Typhi were isolated only in Kenya. Among those 11 isolates, all had a Glu133Gly mutation in the gyrA gene combined with either a gyrA (Ser83Phe) or gyrB mutation (Ser464Phe). One Salmonella Paratyphi A isolate with reduced susceptibility to ciprofloxacin was found in Senegal, with 1 mutation in gyrA (Ser83Phe) and a second mutation in parC (Ser57Phe). Mutations in the parE gene and PMQR genes were not detected in any isolate. CONCLUSIONS: Salmonella Typhi with reduced susceptibility to ciprofloxacin was not distributed homogenously throughout SSA. Its prevalence was very high in Kenya, and was not observed in other study countries. Continuous monitoring of antimicrobial susceptibility is required to follow the potential spread of antimicrobial-resistant isolates throughout SSA. PMID- 26933022 TI - Prevalence of Salmonella Excretion in Stool: A Community Survey in 2 Sites, Guinea-Bissau and Senegal. AB - BACKGROUND: Chronic and convalescent carriers play an important role in the transmission and endemicity of many communicable diseases. A high incidence of Salmonella enterica serovar Typhi and invasive nontyphoidal Salmonella (NTS) infection has been reported in parts of sub-Saharan Africa, yet the prevalence of Salmonella excretion in the general population is unknown. METHODS: Stool specimens were collected from a random sample of households in 2 populations in West Africa: Bissau, Guinea-Bissau, and Dakar, Senegal. Stool was cultured to detect presence of Salmonella, and antimicrobial susceptibility testing was performed on the isolated organisms. RESULTS: Stool was cultured from 1077 and 1359 individuals from Guinea-Bissau and Senegal, respectively. Salmonella Typhi was not isolated from stool samples at either site. Prevalence of NTS in stool samples was 24.1 (95% confidence interval [CI], 16.5-35.1; n = 26/1077) per 1000 population in Guinea-Bissau and 10.3 (95% CI, 6.1-17.2; n = 14/1359) per 1000 population in Senegal. CONCLUSIONS: Evidence of NTS excretion in stool in both study populations indicates a possible NTS transmission route in these settings. PMID- 26933023 TI - Utilization of Healthcare in the Typhoid Fever Surveillance in Africa Program. AB - BACKGROUND: Assessing healthcare utilization is important to identify weaknesses of healthcare systems, to outline action points for preventive measures and interventions, and to more accurately estimate the disease burden in a population. METHODS: A healthcare utilization survey was developed for the Typhoid Fever Surveillance in Africa Program (TSAP) to adjust incidences of salmonellosis determined through passive, healthcare facility-based surveillance. This cross-sectional survey was conducted at 11 sites in 9 sub-Saharan African countries. Demographic data and healthcare-seeking behavior were assessed at selected households. Overall and age-stratified percentages of each study population that sought healthcare at a TSAP healthcare facility and elsewhere were determined. RESULTS: Overall, 88% (1007/1145) and 81% (1811/2238) of the population in Polesgo and Nioko 2, Burkina Faso, respectively, and 63% (1636/2590) in Butajira, Ethiopia, sought healthcare for fever at any TSAP healthcare facility. A far smaller proportion-namely, 20%-45% of the population in Bissau, Guinea-Bissau (1743/3885), Pikine, Senegal (1473/4659), Wad-Medani, Sudan (861/3169), and Pietermaritzburg, South Africa (667/2819); 18% (483/2622) and 9% (197/2293) in Imerintsiatosika and Isotry, Madagascar, respectively; and 4% (127/3089) in Moshi, Tanzania-sought healthcare at a TSAP healthcare facility. Patients with fever preferred to visit pharmacies in Imerintsiatosika and Isotry, and favored self-management of fever in Moshi. Age-dependent differences in healthcare utilization were also observed within and across sites. CONCLUSIONS: Healthcare utilization for fever varied greatly across sites, and revealed that not all studied populations were under optimal surveillance. This demonstrates the importance of assessing healthcare utilization. Survey data were pivotal for the adjustment of the program's estimates of salmonellosis and other conditions associated with fever. PMID- 26933025 TI - A Way Forward for Healthcare in Madagascar? AB - A healthcare utilization survey was conducted as a component of the Typhoid Fever Surveillance in Africa Program (TSAP). The findings of this survey in Madagascar contrasted with those in other sites of the program; namely, only 30% of the population sought healthcare at the government-provided healthcare facilities for fever. These findings promoted us to determine the drivers and barriers in accessing and utilizing healthcare in Madagascar. Here we review the results of the TSAP healthcare utilization initiative and place them in the context of the current organization of the Madagascan healthcare system. Our work highlights the demands of the population for access to appropriate healthcare and the need for novel solutions that can quickly provide an affordable and sustainable basic healthcare infrastructure until a government-funded scheme is in place. PMID- 26933024 TI - A Qualitative Study Investigating Experiences, Perceptions, and Healthcare System Performance in Relation to the Surveillance of Typhoid Fever in Madagascar. AB - BACKGROUND: The burden of typhoid fever (TF) in sub-Saharan Africa is largely unknown but is increasingly thought to be high, given that water and sanitary conditions remain unimproved in many countries. To address this gap in information, the Typhoid Fever Surveillance in Africa Program (TSAP) founded a surveillance system for TF in 10 African countries. This study was a component of the TSAP surveillance project in Madagascar. METHODS: The study entailed a qualitative assessment of patients' experiences and perceptions of services for febrile symptoms at the studies' rural and urban sentinel public health clinics. The study examined influences on the use of these facilities, alternative sources of care, and providers' descriptions of medical consultations and challenges in providing services. Data were collected through semistructured and open-ended individual interviews and a focus group with patients, caregivers, and medical personnel. RESULTS: Thirty-three patients and 12 healthcare providers participated in the data collection across the 2 healthcare facilities. The quality of services, cost, and travel distance were key factors that enabled access to and use of these clinics. Divergent healthcare-seeking patterns were related to variability in the care utilized, socioeconomic status, and potential distance from the facilities : These factors influenced delivery of care, patient access, and the health facilities' capacity to identify cases of febrile illness such as TF. CONCLUSIONS: This approach provided an in-depth investigation and understanding of healthcare-seeking behavior at the study facilities, and factors that facilitated or acted as barriers to their use. Our findings demonstrate the relevance of these public health clinics as sites for the surveillance of TF in their role as central healthcare sources for families and communities within these rural and urban areas of Madagascar. PMID- 26933027 TI - Association Between Malaria and Invasive Nontyphoidal Salmonella Infection in a Hospital Study: Accounting for Berkson's Bias. AB - BACKGROUND: There is growing evidence for a positive association between malaria and invasive nontyphoidal Salmonella (iNTS) disease. However, case-control studies conducted within healthcare facilities also report inverse associations. This may be due to Berkson's bias, a selection bias that acts when both exposure and outcome are associated with hospital attendance and study participants are selected among attendees only. This study describes the effect of Berkson's bias on the malaria-iNTS association and provides a less biased effect estimate. METHODS: Data collected in 2 Ghanaian hospitals were analyzed using 2 case control approaches. In both approaches, cases were defined as iNTS-positive children, and concomitant malaria infection was the exposure of interest. In the first conventional sampling approach, children without any febrile bloodstream infection served as controls. In the second control-disease approach, children with non-iNTS bacteremia were used as controls. RESULTS: Data from 6746 children were suitable for the analyses. One hundred sixty children with iNTS infection were study cases. In the conventional case-control approach 6301 children were controls, and in the control-disease approach 285 children were controls. In the conventional case-control study, malaria was estimated to protect against iNTS disease (odds ratio [OR], 0.4; 95% confidence interval [CI], .3-.7), whereas in the control-disease approach, malaria was identified to be a risk factor for iNTS disease (OR, 1.9; 95% CI, 1.1-3.3). CONCLUSIONS: The study highlights how a selection bias may reverse results if an unsuitable control group is used and adds further evidence on the malaria-iNTS disease association. PMID- 26933026 TI - Validation and Identification of Invasive Salmonella Serotypes in Sub-Saharan Africa by Multiplex Polymerase Chain Reaction. AB - Salmonella enterica serovar Typhi and nontyphoidal Salmonella (NTS) cause the majority of bloodstream infections in sub-Saharan Africa; however, serotyping is rarely performed. We validated a multiplex polymerase chain reaction (PCR) assay with the White-Kauffmann-Le Minor (WKLM) scheme of serotyping using 110 Salmonella isolates from blood cultures of febrile children in Ghana and applied the method in other Typhoid Fever Surveillance in Africa Program study sites. In Ghana, 47 (43%) S. Typhi, 36 (33%) Salmonella enterica serovar Typhimurium, 14 (13%) Salmonella enterica serovar Dublin, and 13 (12%) Salmonella enterica serovar Enteritidis were identified by both multiplex PCR and the WKLM scheme separately. Using the validated multiplex PCR assay, we identified 42 (66%) S. Typhi, 14 (22%) S. Typhimurium, 2 (3%) S. Dublin, 2 (3%) S. Enteritidis, and 4 (6%) other Salmonella species from the febrile patients in Burkina Faso, Guinea Bissau, Madagascar, Senegal, and Tanzania. Application of this multiplex PCR assay in sub-Saharan Africa could advance the knowledge of serotype distribution of Salmonella. PMID- 26933029 TI - Influence of a Positive Family History on the Clinical Course of Inflammatory Bowel Disease. AB - BACKGROUND AND AIMS: Previous studies on the difference in phenotypes and disease course between familial and sporadic inflammatory bowel disease (IBD) have been controversial, although family history is considered to increase the risk of developing IBD. METHODS: The influence of family history on phenotype and disease course of IBD was analysed in 2805 Korean patients with Crohn's disease (CD) and 3266 with ulcerative colitis (UC). Familial IBD was defined as the existence of one or more first-, second- and/or third-degree relatives affected with CD or UC. RESULTS: A positive family history of IBD was noted in 191 patients with CD (6.8%) and 212 patients with UC (6.5%). In the patients with CD, the probability of anti-TNF use was higher in the familial cases than in the sporadic cases (56.3 vs 43.4%, respectively, at 10 years, p = 0.019). When analysed after excluding patients who had undergone intestinal resection within 1 year of diagnosis, the cumulative probability of intestinal resection was higher in the familial cases than in the sporadic cases (55.0 vs 32.2%, respectively, at 10 years; p = 0.007). In multivariate analysis, family history was an independent risk factor for the time to first intestinal resection in patients with CD (hazard ratio: 1.61, 95% confidence interval: 1.13-2.29; p = 0.009). In patients with UC, younger age at diagnosis and more females were observed in the familial cases (p < 0.001). CONCLUSIONS: The present study suggests the possibility of a more aggressive clinical course of CD in familial compared with sporadic cases. PMID- 26933030 TI - Long-lasting Remission Induced by Syngeneic Haematopoietic Stem Cell Transplantation in a Patient with Refractory Crohn's Disease. AB - BACKGROUND AND AIMS: Autologous haematopoietic stem cell transplantation (HSCT) is considered a salvage therapy for patients with refractory immune-mediated diseases. Syngeneic HSCT may be an alternative to autologous HSCT, with potential advantages in terms of safety and efficacy. METHODS: A patient with severe Crohn's disease refractory to available medical therapies underwent a syngeneic HSCT from her identical twin sister. Cyclophosphamide and rabbit anti-thymocyte globulin were administered for conditioning. RESULTS: After transplant, the patient presented successful engraftment, complete haematological and immunological reconstitution, and no severe complications. The patient achieved complete remission after transplant which is sustained 4 years after transplantation without any active treatment for Crohn's disease. CONCLUSIONS: Patients with refractory immune-mediated diseases who have an identical disease free twin may benefit from a syngeneic HSCT. PMID- 26933028 TI - The Typhoid Fever Surveillance in Africa Program (TSAP): Clinical, Diagnostic, and Epidemiological Methodologies. AB - BACKGROUND: New immunization programs are dependent on data from surveillance networks and disease burden estimates to prioritize target areas and risk groups. Data regarding invasive Salmonella disease in sub-Saharan Africa are currently limited, thus hindering the implementation of preventive measures. The Typhoid Fever Surveillance in Africa Program (TSAP) was established by the International Vaccine Institute to obtain comparable incidence data on typhoid fever and invasive nontyphoidal Salmonella (iNTS) disease in sub-Saharan Africa through standardized surveillance in multiple countries. METHODS: Standardized procedures were developed and deployed across sites for study site selection, patient enrolment, laboratory procedures, quality control and quality assurance, assessment of healthcare utilization and incidence calculations. RESULTS: Passive surveillance for bloodstream infections among febrile patients was initiated at thirteen sentinel sites in ten countries (Burkina Faso, Ethiopia, Ghana, Guinea Bissau, Kenya, Madagascar, Senegal, South Africa, Sudan, and Tanzania). Each TSAP site conducted case detection using these standardized methods to isolate and identify aerobic bacteria from the bloodstream of febrile patients. Healthcare utilization surveys were conducted to adjust population denominators in incidence calculations for differing healthcare utilization patterns and improve comparability of incidence rates across sites. CONCLUSIONS: By providing standardized data on the incidence of typhoid fever and iNTS disease in sub Saharan Africa, TSAP will provide vital input for targeted typhoid fever prevention programs. PMID- 26933031 TI - The Faroese IBD Study: Incidence of Inflammatory Bowel Diseases Across 54 Years of Population-based Data. AB - BACKGROUND AND AIMS: Inflammatory bowel diseases [IBDs] include Crohn's disease [CD], ulcerative colitis [UC], and IBD unclassified [IBDU]. In 2010 and 2011, the ECCO-EpiCom study found the worldwide highest incidence of inflammatory bowel disease [IBD] in the Faroe Islands: 83 per 100 000 [European Standard Population, ESP]. The present study assessed the long-term time trends in IBD incidence in the Faroese population. METHODS: In this population-based study, data were retrieved from the National Hospital of the Faroe Islands and included all incident cases of CD, UC, and IBDU diagnosed between July 1960 and July 2014. Patients of all ages were included and diagnoses were defined according to the Copenhagen Diagnostic Criteria. RESULTS: A total of 664 incident IBD patients were diagnosed: 113 with CD, 417 with UC, and 134 with IBDU. Of these, 51 [8%] were diagnosed with paediatric-onset IBD. Between 1960 and 1979, a total of 55 persons were diagnosed; 105 in 1980-89; 166 in 1990-99; 180 in 2000-09; and 158 in 2010-14. This represented an increase in the age-standardised IBD incidence rate from 7, 25, 40, and 42 to 74 per 100 000 [ESP]. For CD, the increase was from 1 to 10, for UC from 4 to 44, and for IBDU from 2 to 21 per 100 000 [ESP]. CONCLUSIONS: The high IBD incidence was found to be a relatively new phenomenon. The observed increase is unlikely to be an artefact resulting from, for instance, better registration. Our study indicated a real and increasing disease burden resulting from changing-so far unidentified-exposures. PMID- 26933032 TI - Inflammatory Bowel Disease Phenotype as Risk Factor for Cancer in a Prospective Multicentre Nested Case-Control IG-IBD Study. AB - BACKGROUND AND AIMS: Cancer risk in inflammatory bowel disease [IBD] is still debated. In a prospective, multicentre, nested case-control study, we aimed to characterise incident cases of cancer in IBD. The role of immunomodulators vs clinical characteristics of IBD as risk factors for cancer was also investigated. MATERIALS AND METHODS: From January 2012 to December 2014, each IBD patient with incident cancer was matched with two IBD patients without cancer for: IBD type, gender, and age. Risk factors were assessed by multivariate regression analysis. RESULTS: IBD patients considered numbered 44619: 21953 Crohn's disease [CD], 22666 ulcerative colitis [UC]. Cancer occurred in 174 patients: 99 CD [CD-K], 75 UC [UC-K]. Controls included 198 CD [CD-C], 150 UC [UC-C]. Cancer incidence in IBD was 3.9/1000, higher in CD (4.5/1000 [99/21,953]) than in UC (3.3/1000 [75/22,666]; p = 0.042). Cancers involved: digestive system [36.8%], skin [13.2%], urinary tract [12.1%], lung [8.6%], breast [8%], genital tract [6.9%], thyroid [4.6%], lymphoma [3.5%], others [6.3%]. In CD, penetrating behaviour and combined thiopurines and tumour necrosis factor alpha [TNFalpha] antagonists were risk factors for cancer overall: odds ratio [OR] (95% confidence interval [CI] 2.33 [1.01-5.47]); 1.97 [1.1-3.5]; and for extracolonic cancers 3.9 [1.56-10.1]; 2.15 [1.17-4.1], respectively. In UC, risk factors were pancolitis and disease related surgery for cancer overall (OR: 2.52 [1.26-5.1]; 5.09 [1.73-17.1]); disease-related surgery for colorectal cancer [CRC] (OR 3.6 [1.0-12]); and extensive and left-sided vs distal UC for extracolonic cancers (OR: 2.55 [1.15 5.9]; 2.6 [1.04-6.6]), respectively. CONCLUSIONS: In a multicentre study, penetrating CD and extensive UC were risk factors for cancer overall. Cancer incidence was higher in CD than in UC. PMID- 26933034 TI - Family-wide Characterization of Histone Binding Abilities of Human CW Domain containing Proteins. AB - Covalent modifications of histone N-terminal tails play a critical role in regulating chromatin structure and controlling gene expression. These modifications are controlled by histone-modifying enzymes and read out by histone binding proteins. Numerous proteins have been identified as histone modification readers. Here we report the family-wide characterization of histone binding abilities of human CW domain-containing proteins. We demonstrate that the CW domains in ZCWPW2 and MORC3/4 selectively recognize histone H3 trimethylated at Lys-4, similar to ZCWPW1 reported previously, while the MORC1/2 and LSD2 lack histone H3 Lys-4 binding ability. Our crystal structures of the CW domains of ZCWPW2 and MORC3 in complex with the histone H3 trimethylated at Lys-4 peptide reveal the molecular basis of this interaction. In each complex, two tryptophan residues in the CW domain form the "floor" and "right wall," respectively, of the methyllysine recognition cage. Our mutation results based on ZCWPW2 reveal that the right wall tryptophan residue is essential for binding, and the floor tryptophan residue enhances binding affinity. Our structural and mutational analysis highlights the conserved roles of the cage residues of CW domain across the histone methyllysine binders but also suggests why some CW domains lack histone binding ability. PMID- 26933033 TI - The Combining Sites of Anti-lipid A Antibodies Reveal a Widely Utilized Motif Specific for Negatively Charged Groups. AB - Lipopolysaccharide dispersed in the blood by Gram-negative bacteria can be a potent inducer of septic shock. One research focus has been based on antibody sequestration of lipid A (the endotoxic principle of LPS); however, none have been successfully developed into a clinical treatment. Comparison of a panel of anti-lipid A antibodies reveals highly specific antibodies produced through distinct germ line precursors. The structures of antigen-binding fragments for two homologous mAbs specific for lipid A, S55-3 and S55-5, have been determined both in complex with lipid A disaccharide backbone and unliganded. These high resolution structures reveal a conserved positively charged pocket formed within the complementarity determining region H2 loops that binds the terminal phosphates of lipid A. Significantly, this motif occurs in unrelated antibodies where it mediates binding to negatively charged moieties through a range of epitopes, including phosphorylated peptides used in diagnostics and therapeutics. S55-3 and S55-5 have combining sites distinct from anti-lipid A antibodies previously described (as a result of their separate germ line origin), which are nevertheless complementary both in shape and charge to the antigen. S55-3 and S55 5 display similar avidity toward lipid A despite possessing a number of different amino acid residues in their combining sites. Binding of lipid A occurs independent of the acyl chains, although the GlcN-O6 attachment point for the core oligosaccharide is buried in the combining site, which explains their inability to recognize LPS. Despite their lack of therapeutic potential, the observed motif may have significant immunological implications as a tool for engineering recombinant antibodies. PMID- 26933035 TI - Plasma Proteins Modified by Advanced Glycation End Products (AGEs) Reveal Site specific Susceptibilities to Glycemic Control in Patients with Type 2 Diabetes. AB - Protein glycation refers to the reversible reaction between aldoses (or ketoses) and amino groups yielding relatively stable Amadori (or Heyns) products. Consecutive oxidative cleavage reactions of these products or the reaction of amino groups with other reactive substances (e.g. alpha-dicarbonyls) yield advanced glycation end products (AGEs) that can alter the structures and functions of proteins. AGEs have been identified in all organisms, and their contents appear to rise with some diseases, such as diabetes and obesity. Here, we report a pilot study using highly sensitive and specific proteomics approach to identify and quantify AGE modification sites in plasma proteins by reversed phase HPLC mass spectrometry in tryptic plasma digests. In total, 19 AGE modification sites corresponding to 11 proteins were identified in patients with type 2 diabetes mellitus under poor glycemic control. The modification degrees of 15 modification sites did not differ among cohorts of normoglycemic lean or obese and type 2 diabetes mellitus patients under good and poor glycemic control. The contents of two amide-AGEs in human serum albumin and apolipoprotein A-II were significantly higher in patients with poor glycemic control, although the plasma levels of both proteins were similar among all plasma samples. These two modification sites might be useful to predict long term, AGE-related complications in diabetic patients, such as impaired vision, increased arterial stiffness, or decreased kidney function. PMID- 26933036 TI - Using a Genetically Encoded Sensor to Identify Inhibitors of Toxoplasma gondii Ca2+ Signaling. AB - The life cycles of apicomplexan parasites progress in accordance with fluxes in cytosolic Ca(2+) Such fluxes are necessary for events like motility and egress from host cells. We used genetically encoded Ca(2+) indicators (GCaMPs) to develop a cell-based phenotypic screen for compounds that modulate Ca(2+) signaling in the model apicomplexan Toxoplasma gondii In doing so, we took advantage of the phosphodiesterase inhibitor zaprinast, which we show acts in part through cGMP-dependent protein kinase (protein kinase G; PKG) to raise levels of cytosolic Ca(2+) We define the pool of Ca(2+) regulated by PKG to be a neutral store distinct from the endoplasmic reticulum. Screening a library of 823 ATP mimetics, we identify both inhibitors and enhancers of Ca(2+) signaling. Two such compounds constitute novel PKG inhibitors and prevent zaprinast from increasing cytosolic Ca(2+) The enhancers identified are capable of releasing intracellular Ca(2+) stores independently of zaprinast or PKG. One of these enhancers blocks parasite egress and invasion and shows strong antiparasitic activity against T. gondii The same compound inhibits invasion of the most lethal malaria parasite, Plasmodium falciparum Inhibition of Ca(2+)-related phenotypes in these two apicomplexan parasites suggests that depletion of intracellular Ca(2+) stores by the enhancer may be an effective antiparasitic strategy. These results establish a powerful new strategy for identifying compounds that modulate the essential parasite signaling pathways regulated by Ca(2+), underscoring the importance of these pathways and the therapeutic potential of their inhibition. PMID- 26933037 TI - Serum Albumin Stimulates Protein Kinase G-dependent Microneme Secretion in Toxoplasma gondii. AB - Microneme secretion is essential for motility, invasion, and egress in apicomplexan parasites. Although previous studies indicate that Ca(2+) and cGMP control microneme secretion, little is known about how these pathways are naturally activated. Here we have developed genetically encoded indicators for Ca(2+) and microneme secretion to better define the signaling pathways that regulate these processes in Toxoplasma gondii We found that microneme secretion was triggered in vitro by exposure to a single host protein, serum albumin. The natural agonist serum albumin induced microneme secretion in a protein kinase G dependent manner that correlated with increased cGMP levels. Surprisingly, serum albumin acted independently of elevated Ca(2+) and yet it was augmented by artificial agonists that raise Ca(2+), such as ethanol. Furthermore, although ethanol elevated intracellular Ca(2+), it alone was unable to trigger secretion without the presence of serum or serum albumin. This dichotomy was recapitulated by zaprinast, a phosphodiesterase inhibitor that elevated cGMP and separately increased Ca(2+) in a protein kinase G-independent manner leading to microneme secretion. Taken together, these findings reveal that microneme secretion is centrally controlled by protein kinase G and that this pathway is further augmented by elevation of intracellular Ca(2.) PMID- 26933038 TI - Exome Sequencing Identified a Splice Site Mutation in FHL1 that Causes Uruguay Syndrome, an X-Linked Disorder With Skeletal Muscle Hypertrophy and Premature Cardiac Death. AB - BACKGROUND: Previously, we reported a rare X-linked disorder, Uruguay syndrome in a single family. The main features are pugilistic facies, skeletal deformities, and muscular hypertrophy despite a lack of exercise and cardiac ventricular hypertrophy leading to premature death. METHODS AND RESULTS: An ~19 Mb critical region on X chromosome was identified through identity-by-descent analysis of 3 affected males. Exome sequencing was conducted on one affected male to identify the disease-causing gene and variant. A splice site variant (c.502-2A>G) in the FHL1 gene was highly suspicious among other candidate genes and variants. FHL1A is the predominant isoform of FHL1 in cardiac and skeletal muscle. Sequencing cDNA showed the splice site variant led to skipping of exons 6 of the FHL1A isoform, equivalent to the FHL1C isoform. Targeted analysis showed that this splice site variant cosegregated with disease in the family. Western blot and immunohistochemical analysis of muscle from the proband showed a significant decrease in protein expression of FHL1A. Real-time polymerase chain reaction analysis of different isoforms of FHL1 demonstrated that the FHL1C is markedly increased. CONCLUSIONS: Mutations in the FHL1 gene have been reported in disorders with skeletal and cardiac myopathy but none has the skeletal or facial phenotype seen in patients with Uruguay syndrome. Our data suggest that a novel FHL1 splice site variant results in the absence of FHL1A and the abundance of FHL1C, which may contribute to the complex and severe phenotype. Mutation screening of the FHL1 gene should be considered for patients with uncharacterized myopathies and cardiomyopathies. PMID- 26933039 TI - Robust Differentiation of mRNA-Reprogrammed Human Induced Pluripotent Stem Cells Toward a Retinal Lineage. AB - The derivation of human induced pluripotent stem cells (hiPSCs) from patient specific sources has allowed for the development of novel approaches to studies of human development and disease. However, traditional methods of generating hiPSCs involve the risks of genomic integration and potential constitutive expression of pluripotency factors and often exhibit low reprogramming efficiencies. The recent description of cellular reprogramming using synthetic mRNA molecules might eliminate these shortcomings; however, the ability of mRNA reprogrammed hiPSCs to effectively give rise to retinal cell lineages has yet to be demonstrated. Thus, efforts were undertaken to test the ability and efficiency of mRNA-reprogrammed hiPSCs to yield retinal cell types in a directed, stepwise manner. hiPSCs were generated from human fibroblasts via mRNA reprogramming, with parallel cultures of isogenic human fibroblasts reprogrammed via retroviral delivery of reprogramming factors. New lines of mRNA-reprogrammed hiPSCs were established and were subsequently differentiated into a retinal fate using established protocols in a directed, stepwise fashion. The efficiency of retinal differentiation from these lines was compared with retroviral-derived cell lines at various stages of development. On differentiation, mRNA-reprogrammed hiPSCs were capable of robust differentiation to a retinal fate, including the derivation of photoreceptors and retinal ganglion cells, at efficiencies often equal to or greater than their retroviral-derived hiPSC counterparts. Thus, given that hiPSCs derived through mRNA-based reprogramming strategies offer numerous advantages owing to the lack of genomic integration or constitutive expression of pluripotency genes, such methods likely represent a promising new approach for retinal stem cell research, in particular, those for translational applications. SIGNIFICANCE: In the current report, the ability to derive mRNA-reprogrammed human induced pluripotent stem cells (hiPSCs), followed by the differentiation of these cells toward a retinal lineage, including photoreceptors, retinal ganglion cells, and retinal pigment epithelium, has been demonstrated. The use of mRNA reprogramming to yield pluripotency represents a unique ability to derive pluripotent stem cells without the use of DNA vectors, ensuring the lack of genomic integration and constitutive expression. The studies reported in the present article serve to establish a more reproducible system with which to derive retinal cell types from hiPSCs through the prevention of genomic integration of delivered genes and should also eliminate the risk of constitutive expression of these genes. Such ability has important implications for the study of, and development of potential treatments for, retinal degenerative disorders and the development of novel therapeutic approaches to the treatment of these diseases. PMID- 26933040 TI - Adipose-Derived Stem Cells Induce Angiogenesis via Microvesicle Transport of miRNA-31. AB - Cell secretion is an important mechanism for stem cell-based therapeutic angiogenesis, along with cell differentiation to vascular endothelial cells or smooth muscle cells. Cell-released microvesicles (MVs) have been recently implicated to play an essential role in intercellular communication. The purpose of this study was to explore the potential effects of stem cell-released MVs in proangiogenic therapy. We observed for the first time that MVs were released from adipose-derived stem cells (ASCs) and were able to increase the migration and tube formation of human umbilical vein endothelial cells (HUVECs). Endothelial differentiation medium (EDM) preconditioning of ASCs upregulated the release of MVs and enhanced the angiogenic effect of the released MVs in vitro. RNA analysis revealed that microRNA was enriched in ASC-released MVs and that the level of microRNA-31 (miR-31) in MVs was notably elevated upon EDM-preconditioning of MV donor ASCs. Further studies exhibited that miR-31 in MVs contributed to the migration and tube formation of HUVECs, microvessel outgrowth of mouse aortic rings, and vascular formation of mouse Matrigel plugs. Moreover, factor inhibiting HIF-1, an antiangiogenic gene, was identified as the target of miR-31 in HUVECs. Our findings provide the first evidence that MVs from ASCs, particularly from EDM-preconditioned ASCs, promote angiogenesis and the delivery of miR-31 may contribute the proangiogenic effect. SIGNIFICANCE: This study provides the evidence that microvesicles (MVs) from adipose-derived stem cells (ASCs), particularly from endothelial differentiation medium (EDM)-preconditioned ASCs, promote angiogenesis. An underlying mechanism of the proangiogenesis may be the delivery of microRNA-31 via MVs from ASCs to vascular endothelial cells in which factor-inhibiting HIF-1 is targeted and suppressed. The study findings reveal the role of MVs in mediating ASC-induced angiogenesis and suggest a potential MV-based angiogenic therapy for ischemic diseases. PMID- 26933041 TI - CD11b+ and Sca-1+ Cells Exert the Main Beneficial Effects of Systemically Administered Bone Marrow-Derived Mononuclear Cells in a Murine Model of Mixed Th2/Th17 Allergic Airway Inflammation. AB - Systemic administration of bone marrow-derived mononuclear cells (BMDMCs) or bone marrow-derived mesenchymal stromal cells (MSCs) reduces inflammation and airway hyperresponsiveness (AHR) in a murine model of Th2-mediated eosinophilic allergic airway inflammation. However, since BMDMCs are a heterogeneous population that includes MSCs, it is unclear whether the MSCs alone are responsible for the BMDMC effects. To determine which BMDMC population(s) is responsible for ameliorating AHR and lung inflammation in a model of mixed Th2-eosinophilic and Th17 neutrophilic allergic airway inflammation, reminiscent of severe clinical asthma, BMDMCs obtained from normal C57Bl/6 mice were serially depleted of CD45, CD34, CD11b, CD3, CD19, CD31, or Sca-1 positive cells. The different resulting cell populations were then assessed for ability to reduce lung inflammation and AHR in mixed Th2/Th17 allergic airway inflammation induced by mucosal sensitization to and challenge with Aspergillus hyphal extract (AHE) in syngeneic C56Bl/6 mice. BMDMCs depleted of either CD11b-positive (CD11b+) or Sca-1-positive (Sca-1+) cells were unable to ameliorate AHR or lung inflammation in this model. Depletion of the other cell types did not diminish the ameliorating effects of BMDMC administration. In conclusion, in the current model of allergic inflammation, CD11b+ cells (monocytes, macrophages, dendritic cells) and Sca-1+ cells (MSCs) are responsible for the beneficial effects of BMDMCs. SIGNIFICANCE: This study shows that bone marrow-derived mononuclear cells (BMDMCs) are as effective as bone marrow-derived mesenchymal stromal cells (MSCs) in ameliorating experimental asthma. It also demonstrates that not only MSCs present in the pool of BMDMCs are responsible for BMDMCs' beneficial effects but also monocytes, which are the most important cell population to trigger these effects. All of this is in the setting of a clinically relevant model of severe allergic airways inflammation and thus provides further support for potential clinical use of cell therapy using MSCs, BMDMCs, and also adult cells such as monocytes in patients with severe asthma. PMID- 26933042 TI - Strategies and Challenges to Myocardial Replacement Therapy. AB - Cardiovascular diseases account for the majority of deaths globally and are a significant drain on economic resources. Although heart transplants and left ventricle assist devices are the solution for some, the best chance for many patients who suffer because of a myocardial infarction, heart failure, or a congenital heart disease may be cell-based regenerative therapies. Such therapies can be divided into two categories: the application of a cell suspension and the implantation of an in vitro engineered tissue construct to the damaged area of the heart. Both strategies have their advantages and challenges, and in this review, we discuss the current state of the art in myocardial regeneration, the challenges to success, and the future direction of the field. SIGNIFICANCE: This article outlines the advantages and limitations of the cell injection and patch approaches to cardiac regenerative therapy. If the field is to move forward, some fundamental questions require answers, including the limitations to the use of animal models for human cell-transplantation studies; the best way to measure success in terms of functional improvements, histological integration, electrical coupling, and arrhythmias; and where the cells should be applied for maximal benefit-the epicardium or the myocardium. PMID- 26933043 TI - Stem Cell-Derived Immature Human Dorsal Root Ganglia Neurons to Identify Peripheral Neurotoxicants. AB - Safety sciences and the identification of chemical hazards have been seen as one of the most immediate practical applications of human pluripotent stem cell technology. Protocols for the generation of many desirable human cell types have been developed, but optimization of neuronal models for toxicological use has been astonishingly slow, and the wide, clinically important field of peripheral neurotoxicity is still largely unexplored. A two-step protocol to generate large lots of identical peripheral human neuronal precursors was characterized and adapted to the measurement of peripheral neurotoxicity. High content imaging allowed an unbiased assessment of cell morphology and viability. The computational quantification of neurite growth as a functional parameter highly sensitive to disturbances by toxicants was used as an endpoint reflecting specific neurotoxicity. The differentiation of cells toward dorsal root ganglia neurons was tracked in relation to a large background data set based on gene expression microarrays. On this basis, a peripheral neurotoxicity (PeriTox) test was developed as a first toxicological assay that harnesses the potential of human pluripotent stem cells to generate cell types/tissues that are not otherwise available for the prediction of human systemic organ toxicity. Testing of more than 30 chemicals showed that human neurotoxicants and neurite growth enhancers were correctly identified. Various classes of chemotherapeutic agents causing human peripheral neuropathies were identified, and they were missed when tested on human central neurons. The PeriTox test we established shows the potential of human stem cells for clinically relevant safety testing of drugs in use and of new emerging candidates. SIGNIFICANCE: The generation of human cells from pluripotent stem cells has aroused great hopes in biomedical research and safety sciences. Neurotoxicity testing is a particularly important application for stem cell-derived somatic cells, as human neurons are hardly available otherwise. Also, peripheral neurotoxicity has become of major concern in drug development for chemotherapy. The first neurotoxicity test method was established based on human pluripotent stem cell-derived peripheral neurons. The strategies exemplified in the present study of reproducible cell generation, cell function based test system establishment, and assay validation provide the basis for a drug safety assessment on cells not available otherwise. PMID- 26933044 TI - L1-CAM is commonly expressed in testicular germ cell tumours. PMID- 26933045 TI - Fifteen-minute consultation: problems in the healthy child-toilet training. AB - Toilet training is a process that all healthy children go through. It is one of the developmental milestones for which parents most often seek medical help. Despite this, many paediatricians feel unconfident managing children presenting with a toilet training problem. We address some common questions arising when assessing and managing such a child, including identifying rare but important diagnoses not to miss. PMID- 26933046 TI - Heterogeneity of HIV incidence: a comparative analysis between fishing communities and in a neighbouring rural general population, Uganda, and implications for HIV control. AB - OBJECTIVES: To describe HIV heterogeneity in rural Uganda using incidence data collected between January 2012 and December 2014 among fishing cohort (FC) and in an adjacent rural general population cohort (GPC). METHODS: In the FC, eligible HIV high-risk adults aged 18+ years were enrolled, followed and HIV tested every 3 months. Demographic and sexual behaviour data were also collected. The GPC, approximately 47 km away from the FC, was followed through annual surveys, and sociodemographic and behavioural data collected. A subset of GPC with comparable risk profiles to the FC was selected. We presented sociodemographic and risk profiles and also computed stratified HIV incidence. Cox regression was used to assess factors associated with HIV incidence. RESULTS: Overall HIV incidence was higher in the FC than in the 'high-risk' GPC, 6.04 and 0.56 per 100 person years at risk, respectively, with a rate ratio (RR) of 10.83 (95% CI 6.11 to 19.76). This was higher among those aged 18-24 years, unmarried and those with more than two sex partners in the past year, RR of 15.44, 22.99 and 19.29, respectively. In the FC, factors associated with high incidence in multivariate analysis were duration in the community and unprotected sex. The factors in the GPC were ethnicity, marital status and duration in the community. CONCLUSIONS: We have observed a substantial heterogeneity in HIV incidence. The high incidence in fishing communities is contributing greatly to the overall HIV burden in Uganda, and thus urgent combination prevention efforts are needed towards national goal to reduce HIV epidemic. PMID- 26933048 TI - Improved Prediction by Dynamic Modeling: An Exploratory Study in the Adult Cardiac Surgery Database of the Netherlands Association for Cardio-Thoracic Surgery. AB - BACKGROUND: The predictive performance of static risk prediction models such as EuroSCORE deteriorates over time. We aimed to explore different methods for continuous updating of EuroSCORE (dynamic modeling) to improve risk prediction. METHODS AND RESULTS: Data on adult cardiac surgery from 2007 to 2012 (n=95 240) were extracted from the Netherlands Association for Cardio-Thoracic Surgery database. The logistic EuroSCORE predicting in-hospital death was updated using 6 methods: recalibrating the intercept of the logistic regression model; recalibrating the intercept and joint effects of the prognostic factors; re estimating all prognostic factor effects, re-estimating all prognostic factor effects, and applying shrinkage of the estimates; applying a test procedure to select either of these; and a Bayesian learning strategy. Models were updated with 1 or 3 years of data, in all cardiac surgery or within operation subgroups. Performance was tested in the subsequent year according to discrimination (area under the receiver operating curve, area under the curve) and calibration (calibration slope and calibration-in-the-large). Compared with the original EuroSCORE, all updating methods resulted in improved calibration-in-the-large (range -0.17 to 0.04 versus -1.13 to -0.97, ideally 0.0). Calibration slope (range 0.92-1.15) and discrimination (area under the curve range 0.83-0.87) were similar across methods. In small subgroups, such as aortic valve replacement and aortic valve replacement+coronary artery bypass grafting, extensive updating using 1 year of data led to poorer performance than using the original EuroSCORE. The choice of updating method had little effect on benchmarking results of all cardiac surgery. CONCLUSIONS: Several methods for dynamic modeling may result in good discrimination and superior calibration compared with the original EuroSCORE. For large populations, all methods are appropriate. For smaller subgroups, it is recommended to use data from multiple years or a Bayesian approach. PMID- 26933047 TI - Reimagining Anticoagulation Clinics in the Era of Direct Oral Anticoagulants. AB - Anticoagulation clinics were initially developed to provide safe and effective care for warfarin-treated patients with atrial fibrillation, venous thromboembolism, and mechanical valve replacement. Traditionally, these patients required ongoing laboratory monitoring and warfarin dose adjustment by expert providers. With the introduction of direct oral anticoagulants (dabigatran, rivaroxaban, apixaban, and edoxaban), many have questioned the need for anticoagulation clinic. However, we think that the growing number of oral anticoagulant choices creates an urgent need for expanding the traditional role of the anticoagulation clinic. We outline 3 key purposes that a reimagined anticoagulation clinic would serve: (1) to assist patients and clinicians with selecting the most appropriate drug and dose from a growing list of anticoagulant options (including warfarin), (2) to help patients minimize the risk of serious bleeding complications with careful long-term monitoring and peri-procedural management, and (3) to encourage ongoing adherence to these life-saving medications. We also describe how repurposing anticoagulation clinics as broader medication safety clinics would promote safe and effective care across a range of cardiovascular conditions for high-risk medications (eg, spironolactone, amiodarone). Finally, we highlight a few existing health systems that are overcoming key challenges to implementing a reimagined anticoagulation or medication safety clinic structure. PMID- 26933049 TI - Emergency Cardiovascular Hospitalization Risk Attributable to Cold Temperatures in Hong Kong. AB - BACKGROUND: Associations between ambient temperature and cardiovascular morbidity have been well studied worldwide; however, few studies determined the cardiovascular disease burden attributable to temperature. We aimed to assess the risk attributed to temperature based on the exposure-lag-response relationship between temperature and circulatory diseases. METHODS AND RESULTS: We collected daily time series data of emergency hospital admissions, mean temperature, and air pollution concentrations from January 2005 to December 2012 in Hong Kong. The association with temperature was modeled using a distributed lag nonlinear model integrated in quasi-Poisson regression. The cumulated effects of cold/hot temperature were abstracted. Attributable risk measures because of below optimal temperature (OT) were calculated to summarize the disease burden, and further separated into contributions from moderate and extreme cold temperatures. We observed significant nonlinear and delayed cold effect but no apparent hot effect lasting for 3 weeks on emergency circulatory hospitalizations. Compared with the identified OT at 23.0 degrees C, the cumulative relative risk during 0 to 21 lag days was 1.69 (95% confidence interval, 1.56-1.82) for extreme cold (first percentile) and 1.22 (95% confidence interval, 1.15-1.29) for moderate cold temperature (10th percentile). Cold temperatures were responsible for temperature related circulatory emergency hospitalizations, with attributable fraction of 6.33% for moderate cold and 0.82% for extreme cold while inducing 33 030 and 4257 cases, respectively. Several specific causes of cardiovascular diseases showed higher vulnerability. CONCLUSIONS: Moderate cold weather was responsible for a considerable attributable risk for cardiovascular diseases. The temperature related hospitalizations risk found in this study may provide evidence for guiding the public health policies and preventions for cardiovascular diseases. PMID- 26933050 TI - Spread of Mutant Middle East Respiratory Syndrome Coronavirus with Reduced Affinity to Human CD26 during the South Korean Outbreak. AB - The newly emerging Middle East respiratory syndrome coronavirus (MERS-CoV) causes a severe respiratory infection with a high mortality rate (~35%). MERS-CoV has been a global threat due to continuous outbreaks in the Arabian peninsula and international spread by infected travelers since 2012. From May to July 2015, a large outbreak initiated by an infected traveler from the Arabian peninsula swept South Korea and resulted in 186 confirmed cases with 38 deaths (case fatality rate, 20.4%). Here, we show the rapid emergence and spread of a mutant MERS-CoV with reduced affinity to the human CD26 receptor during the South Korean outbreak. We isolated 13 new viral genomes from 14 infected patients treated at a hospital and found that 12 of these genomes possess a point mutation in the receptor-binding domain (RBD) of viral spike (S) protein. Specifically, 11 of these genomes have an I529T mutation in RBD, and 1 has a D510G mutation. Strikingly, both mutations result in reduced affinity of RBD to human CD26 compared to wild-type RBD, as measured by surface plasmon resonance analysis and cellular binding assay. Additionally, pseudotyped virus bearing an I529T mutation in S protein showed reduced entry into host cells compared to virus with wild type S protein. These unexpected findings suggest that MERS-CoV adaptation during human-to-human spread may be driven by host immunological pressure such as neutralizing antibodies, resulting in reduced affinity to host receptor, and thereby impairs viral fitness and virulence, rather than positive selection for a better affinity to CD26. IMPORTANCE: Recently, a large outbreak initiated by an MERS-CoV-infected traveler from the Middle East swept South Korea and resulted in 186 confirmed cases with 38 deaths. This is the largest outbreak outside the Middle East, and it raised strong concerns about the possible emergence of MERS CoV mutations. Here, we isolated 13 new viral genomes and found that 12 of them possess a point mutation in the receptor-binding domain of viral spike protein, resulting in reduced affinity to the human cognate receptor, CD26, compared to the wild-type virus. These unexpected findings suggest that MERS-CoV adaptation in humans may be driven by host immunological pressure. PMID- 26933051 TI - Valpromide Inhibits Lytic Cycle Reactivation of Epstein-Barr Virus. AB - Reactivation of Epstein-Barr virus (EBV) from latency into the lytic phase of its life cycle allows the virus to spread among cells and between hosts. Valproic acid (VPA) inhibits initiation of the lytic cycle in EBV-infected B lymphoma cells. While VPA blocks viral lytic gene expression, it induces expression of many cellular genes, because it is a histone deacetylase (HDAC) inhibitor. Here we show, using derivatives of VPA, that blockade of EBV reactivation is separable from HDAC inhibition. Valpromide (VPM), an amide derivative of valproic acid that is not an HDAC inhibitor, prevented expression of two EBV genes, BZLF1 and BRLF1, that mediate lytic reactivation. VPM also inhibited expression of a viral late gene, but not early genes, when BZLF1 was exogenously expressed. Unlike VPA, VPM did not activate lytic expression of Kaposi's sarcoma-associated herpesvirus. Expression of cellular immediate-early genes, such as FOS and EGR1, is kinetically upstream of the EBV lytic cycle. VPM did not activate expression of these cellular immediate-early genes but decreased their level of expression when induced by butyrate, an HDAC inhibitor. VPM did not alter expression of several other cellular immediate-early genes, including STAT3, which were induced by the HDAC inhibitors in cells refractory to lytic induction. Therefore, VPM selectively inhibits both viral and cellular gene expression. VPA and VPM represent a new class of antiviral agents. The mechanism by which VPA and VPM block EBV reactivation may be related to their anticonvulsant activity. IMPORTANCE: Epstein-Barr virus, (EBV), a human tumor virus, establishes a life long latent infection. Reactivation of EBV into the lytic phase of its life cycle allows the virus to spread. Previously, we showed that EBV reactivation was blocked by valproic acid (VPA), an inhibitor of cellular histone deacetylases (HDACs). VPA alters the expression of thousands of cellular genes. In this study, we demonstrate that valpromide (VPM), an amide derivative of valproic acid that is not an HDAC inhibitor, prevented initiation of the EBV lytic cycle. VPA induced lytic reactivation of Kaposi's sarcoma-associated herpesvirus (KSHV), but VPM did not. Unlike VPA, VPM did not activate cellular immediate-early gene expression. VPM is a new type of antiviral agent. VPM will be useful in probing the mechanism of EBV lytic reactivation and may have therapeutic application. PMID- 26933052 TI - Revolutionary Science. AB - On rare occasions in the history of science, remarkable discoveries transform human society and forever alter mankind's view of the world. Examples of such discoveries include the heliocentric theory, Newtonian physics, the germ theory of disease, quantum theory, plate tectonics and the discovery that DNA carries genetic information. The science philosopher Thomas Kuhn famously described science as long periods of normality punctuated by times of crisis, when anomalous observations culminate in revolutionary changes that replace one paradigm with another. This essay examines several transformative discoveries in the light of Kuhn's formulation. We find that each scientific revolution is unique, with disparate origins that may include puzzle solving, serendipity, inspiration, or a convergence of disparate observations. The causes of revolutionary science are varied and lack an obvious common structure. Moreover, it can be difficult to draw a clear distinction between so-called normal and revolutionary science. Revolutionary discoveries often emerge from basic science and are critically dependent on nonrevolutionary research. Revolutionary discoveries may be conceptual or technological in nature, lead to the creation of new fields, and have a lasting impact on many fields in addition to the field from which they emerge. In contrast to political revolutions, scientific revolutions do not necessarily require the destruction of the previous order. For humanity to continue to benefit from revolutionary discoveries, a broad palette of scientific inquiry with a particular emphasis on basic science should be supported. PMID- 26933053 TI - Erratum for Monk et al., Complete Bypass of Restriction Systems for Major Staphylococcus aureus Lineages. PMID- 26933056 TI - Balance between Coiled-Coil Stability and Dynamics Regulates Activity of BvgS Sensor Kinase in Bordetella. AB - The two-component system BvgAS controls the expression of the virulence regulon of Bordetella pertussis. BvgS is a prototype of bacterial sensor kinases with extracytoplasmic Venus flytrap perception domains. Following its transmembrane segment, BvgS harbors a cytoplasmic Per-Arnt-Sim (PAS) domain and then a predicted 2-helix coiled coil that precede the dimerization-histidine phosphotransfer domain of the kinase. BvgS homologs have a similar domain organization, or they harbor only a predicted coiled coil between the transmembrane and the dimerization-histidine-phosphotransfer domains. Here, we show that the 2-helix coiled coil of BvgS regulates the enzymatic activity in a mechanical manner. Its marginally stable hydrophobic interface enables a switch between a state of great rotational dynamics in the kinase mode and a more rigid conformation in the phosphatase mode in response to signal perception by the periplasmic domains. We further show that the activity of BvgS is controlled in the same manner if its PAS domain is replaced with the natural alpha-helical sequences of PAS-less homologs. Clamshell motions of the Venus flytrap domains trigger the shift of the coiled coil's dynamics. Thus, we have uncovered a general mechanism of regulation for the BvgS family of Venus flytrap-containing two-component sensor kinases. IMPORTANCE: The two-component system BvgAS of the whooping cough agent Bordetella pertussis regulates the virulence factors necessary for infection in a coordinated manner. BvgS is the prototype of a family of sensor kinase proteins found in major bacterial pathogens. When BvgS functions as a kinase, B. pertussis is virulent, and the bacterium shifts to an avirulent phase after BvgS senses chemicals that make it switch to phosphatase. Our goal is to decipher the signaling mechanisms of BvgS in order to understand virulence regulation in Bordetella, which may lead to new antimicrobial treatments targeting those two-component systems. We discovered that the activity of BvgS is regulated in a mechanical manner. A short region of the protein that precedes the enzymatic domain switches between two states in response to signal perception by other BvgS domains. This switch region is conserved among BvgS homologs, and thus, the regulation uncovered here will likely be relevant for the family. PMID- 26933055 TI - Complex Interplay of the UL136 Isoforms Balances Cytomegalovirus Replication and Latency. AB - Human cytomegalovirus (HCMV), a betaherpesvirus, persists indefinitely in the human host through poorly understood mechanisms. The UL136 gene is carried within a genetic locus important to HCMV latency termed the UL133/8 locus, which also carries UL133, UL135, and UL138. Previously, we demonstrated that UL136 is expressed as five protein isoforms ranging from 33-kDa to 19-kDa, arising from alternative transcription and, likely, translation initiation mechanisms. We previously showed that the UL136 isoforms are largely dispensable for virus infection in fibroblasts, a model for productive virus replication. In our current work, UL136 has emerged as a complex regulator of HCMV infection in multiple contexts of infection relevant to HCMV persistence: in an endothelial cell (EC) model of chronic infection, in a CD34(+) hematopoietic progenitor cell (HPC) model of latency, and in an in vivo NOD-scid IL2Rgammac (null) humanized (huNSG) mouse model for latency. The 33- and 26-kDa isoforms promote replication, while the 23- and 19-kDa isoforms suppress replication in ECs, in CD34(+) HPCs, and in huNSG mice. The role of the 25-kDa isoform is context dependent and influences the activity of the other isoforms. These isoforms localize throughout the secretory pathway, and loss of the 33- and 26-kDa UL136 isoforms results in virus maturation defects in ECs. This work reveals an intriguing functional interplay between protein isoforms that impacts virus replication, latency, and dissemination, contributing to the overall role of the UL133/8 locus in HCMV infection. IMPORTANCE: The persistence of DNA viruses, and particularly of herpesviruses, remains an enigma because we have not completely defined the viral and host factors important to persistence. Human cytomegalovirus, a herpesvirus, persists in the absence of disease in immunocompetent individuals but poses a serious disease threat to transplant patients and the developing fetus. There is no vaccine, and current therapies do not target latent reservoirs. In an effort to define the viral factors important to persistence, we have studied viral genes with no known viral replication function in contexts important to HCMV persistence. Using models relevant to viral persistence, we demonstrate opposing roles of protein isoforms encoded by the UL136 gene in regulating latent and replicative states of infection. Our findings reveal an intriguing interplay between UL136 protein isoforms and define UL136 as an important regulator of HCMV persistence. PMID- 26933059 TI - Erratum for Juanola-Falgarona et al. Dietary intake of vitamin K is inversely associated with mortality risk. J Nutr 2014;144:743-50. PMID- 26933057 TI - Interaction of Mycobacterium tuberculosis Virulence Factor RipA with Chaperone MoxR1 Is Required for Transport through the TAT Secretion System. AB - Mycobacterium tuberculosis is a leading cause of death worldwide. The M. tuberculosis TAT (twin-arginine translocation) protein secretion system is present at the cytoplasmic membrane of mycobacteria and is known to transport folded proteins. The TAT secretion system is reported to be essential for many important bacterial processes that include cell wall biosynthesis. The M. tuberculosis secretion and invasion protein RipA has endopeptidase activity and interacts with one of the resuscitation antigens (RpfB) that are expressed during pathogen reactivation. MoxR1, a member of the ATPase family that is associated with various cellular activities, was predicted to interact with RipA based on in silico analyses. A bimolecular fluorescence complementation (BiFC) assay confirmed the interaction of these two proteins in HEK293T cells. The overexpression of RipA in Mycobacterium smegmatis and copurification with MoxR1 further validated their interaction in vivo. Recombinant MoxR1 protein, expressed in Escherichia coli, displays ATP-enhanced chaperone activity. Secretion of recombinant RipA (rRipA) protein into the E. coli culture filtrate was not observed in the absence of RipA-MoxR interaction. Inhibition of this export system in M. tuberculosis, including the key players, will prevent localization of peptidoglycan hydrolase and result in sensitivity to existing beta-lactam antibiotics, opening up new candidates for drug repurposing. IMPORTANCE: The virulence mechanism of mycobacteria is very complex. Broadly, the virulence factors can be classified as secretion factors, cell surface components, enzymes involved in cellular metabolism, and transcriptional regulators. The mycobacteria have evolved several mechanisms to secrete its proteins. Here, we have identified one of the virulence proteins of Mycobacterium tuberculosis, RipA, possessing peptidoglycan hydrolase activities secreted by the TAT secretion pathway. We also identified MoxR1 as a protein-protein interaction partner of RipA and demonstrated chaperone activity of this protein. We show that MoxR1-mediated folding is critical for the secretion of RipA within the TAT system. Inhibition of this export system in M. tuberculosis will prevent localization of peptidoglycan hydrolase and result in sensitivity to existing beta-lactam antibiotics, opening up new candidates for drug repurposing. PMID- 26933054 TI - What a Dinner Party! Mechanisms and Functions of Interkingdom Signaling in Host Pathogen Associations. AB - Chemical signaling between cells is an effective way to coordinate behavior within a community. Although cell-to-cell signaling has mostly been studied in single species, it is now appreciated that the sensing of chemical signals across kingdoms can be an important regulator of nutrient acquisition, virulence, and host defense. In this review, we focus on the role of interkingdom signaling in the interactions that occur between bacterial pathogens and their mammalian hosts. We discuss the quorum-sensing (QS) systems and other mechanisms used by these bacteria to sense, respond to, and modulate host signals that include hormones, immune factors, and nutrients. We also describe cross talk between these signaling pathways and strategies used by the host to interfere with bacterial signaling, highlighting the complex bidirectional signaling networks that are established across kingdoms. PMID- 26933061 TI - Properly dividing with YAP. AB - The Hippo pathway prevents organ overgrowth and maintains tissue architecture by inhibiting the transcriptional coactivator YAP. In this issue of Science Signaling, Bui et al. find a role for YAP during cytokinesis that is independent of its transcriptional activity. This function of YAP may be important for maintaining genomic stability in dividing cells. PMID- 26933058 TI - Loss of Multicellular Behavior in Epidemic African Nontyphoidal Salmonella enterica Serovar Typhimurium ST313 Strain D23580. AB - Nontyphoidal Salmonella enterica serovar Typhimurium is a frequent cause of bloodstream infections in children and HIV-infected adults in sub-Saharan Africa. Most isolates from African patients with bacteremia belong to a single sequence type, ST313, which is genetically distinct from gastroenteritis-associated ST19 strains, such as 14028s and SL1344. Some studies suggest that the rapid spread of ST313 across sub-Saharan Africa has been facilitated by anthroponotic (person-to person) transmission, eliminating the need for Salmonella survival outside the host. While these studies have not ruled out zoonotic or other means of transmission, the anthroponotic hypothesis is supported by evidence of extensive genomic decay, a hallmark of host adaptation, in the sequenced ST313 strain D23580. We have identified and demonstrated 2 loss-of-function mutations in D23580, not present in the ST19 strain 14028s, that impair multicellular stress resistance associated with survival outside the host. These mutations result in inactivation of the KatE stationary-phase catalase that protects high-density bacterial communities from oxidative stress and the BcsG cellulose biosynthetic enzyme required for the RDAR (red, dry, and rough) colonial phenotype. However, we found that like 14028s, D23580 is able to elicit an acute inflammatory response and cause enteritis in mice and rhesus macaque monkeys. Collectively, these observations suggest that African S. Typhimurium ST313 strain D23580 is becoming adapted to an anthroponotic mode of transmission while retaining the ability to infect and cause enteritis in multiple host species. IMPORTANCE: The last 3 decades have witnessed an epidemic of invasive nontyphoidal Salmonella infections in sub-Saharan Africa. Genomic analysis and clinical observations suggest that the Salmonella strains responsible for these infections are evolving to become more typhoid-like with regard to patterns of transmission and virulence. This study shows that a prototypical African nontyphoidal Salmonella strain has lost traits required for environmental stress resistance, consistent with an adaptation to a human-to-human mode of transmission. However, in contrast to predictions, the strain remains capable of causing acute inflammation in the mammalian intestine. This suggests that the systemic clinical presentation of invasive nontyphoidal Salmonella infections in Africa reflects the immune status of infected hosts rather than intrinsic differences in the virulence of African Salmonella strains. Our study provides important new insights into the evolution of host adaptation in bacterial pathogens. PMID- 26933064 TI - Occurrence, structure, and evolution of nitric oxide synthase-like proteins in the plant kingdom. AB - Nitric oxide (NO) signaling regulates various physiological processes in both animals and plants. In animals, NO synthesis is mainly catalyzed by NO synthase (NOS) enzymes. Although NOS-like activities that are sensitive to mammalian NOS inhibitors have been detected in plant extracts, few bona fide plant NOS enzymes have been identified. We searched the data set produced by the 1000 Plants (1KP) international consortium for the presence of transcripts encoding NOS-like proteins in over 1000 species of land plants and algae. We also searched for genes encoding NOS-like enzymes in 24 publicly available algal genomes. We identified no typical NOS sequences in 1087 sequenced transcriptomes of land plants. In contrast, we identified NOS-like sequences in 15 of the 265 algal species analyzed. Even if the presence of NOS enzymes assembled from multipolypeptides in plants cannot be conclusively discarded, the emerging data suggest that, instead of generating NO with evolutionarily conserved NOS enzymes, land plants have evolved finely regulated nitrate assimilation and reduction processes to synthesize NO through a mechanism different than that in animals. PMID- 26933066 TI - Innovation in health and care. PMID- 26933062 TI - Cytokinesis involves a nontranscriptional function of the Hippo pathway effector YAP. AB - YAP is a transcriptional coactivator that controls organ expansion and differentiation and is inhibited by the Hippo pathway in cells in interphase. Here, we demonstrated that, during mitosis, YAP localized to the midbody and spindle, subcellular structures that are involved in cytokinesis, the process by which contraction of the cytoskeleton produces two daughter cells. Furthermore, YAP was phosphorylated by CDK1, a kinase that promotes cell cycle progression. Knockdown of YAP by shRNA or expression of a nonphosphorylatable form of YAP delayed the separation of daughter cells (called abscission) and induced a cytokinesis phenotype associated with increased contractile force, membrane blebbing and bulges, and abnormal spindle orientation. Consequently, these defects led to an increased frequency of multinucleation, micronuclei, and aneuploidy. YAP was required for proper localization of proteins that regulate contraction during cytokinesis, including ECT2, MgcRacGap, Anillin, and RHOA. In addition, depletion of YAP increased the phosphorylation of myosin light chain, which would be expected to activate the contractile activity of myosin II, the molecular motor involved in cytokinesis. The polarity scaffold protein PATJ coprecipitated with YAP and colocalized with YAP at the cytokinesis midbody, and knockdown of PATJ phenocopied the cytokinetic defects and spindle orientation alterations induced by either YAP depletion or expression of a nonphosphorylatable YAP mutant. Together, these results reveal an unanticipated role for YAP in the proper organization of the cytokinesis machinery during mitosis through interaction with the polarity protein PATJ. PMID- 26933069 TI - Letter to the editor. PMID- 26933065 TI - Validity and test-retest reliability of an at-work production loss instrument. AB - BACKGROUND: Besides causing ill health, a poor work environment may contribute to production loss. Production loss assessment instruments emphasize health-related consequences but there is no instrument to measure reduced work performance related to the work environment. AIMS: To examine convergent validity and test retest reliability of health-related production loss (HRPL) and work environment related production loss (WRPL) against a valid comparable instrument, the Health and Work Performance Questionnaire (HPQ). METHODS: Cross-sectional study of employees, not on sick leave, who were asked to self-rate their work performance and production losses. Using the Pearson correlation and Bland and Altman's Test of Agreement, convergent validity was examined. Subgroup analyses were performed for employees recording problem-specific reduced work performance. Consistency of pairs of HRPL and WRPL for samples responding to both assessments was expressed using Intraclass Correlation Coefficient (ICC) and tests of repeatability. RESULTS: A total of 88 employees participated and 44 responded to both assessments. Test of agreement between measurements estimates a mean difference of 0.34 for HRPL and -0.03 for WRPL compared with work performance. This indicates that the production loss questions are valid and moderately associated with work performance for the total sample and subgroups. ICC for paired HRPL assessments was 0.90 and 0.91 for WRPL, i.e. the test-retest reliability was good and suggests stability in the instrument. CONCLUSIONS: HRPL and WRPL can be used to measure production loss due to health-related and work environment-related problems. These results may have implications for advancing methods of assessing production loss, which represents an important cost to employers. PMID- 26933070 TI - Policy. PMID- 26933063 TI - Structure of Saccharomyces cerevisiae Rtr1 reveals an active site for an atypical phosphatase. AB - Changes in the phosphorylation status of the carboxyl-terminal domain (CTD) of RNA polymerase II (RNAPII) correlate with the process of eukaryotic transcription. The yeast protein regulator of transcription 1 (Rtr1) and the human homolog RNAPII-associated protein 2 (RPAP2) may function as CTD phosphatases; however, crystal structures of Kluyveromyces lactis Rtr1 lack a consensus active site. We identified a phosphoryl transfer domain in Saccharomyces cerevisiae Rtr1 by obtaining and characterizing a 2.6 A resolution crystal structure. We identified a putative substrate-binding pocket in a deep groove between the zinc finger domain and a pair of helices that contained a trapped sulfate ion. Because sulfate mimics the chemistry of a phosphate group, this structural data suggested that this groove represents the phosphoryl transfer active site. Mutagenesis of the residues lining this groove disrupted catalytic activity of the enzyme assayed in vitro with a fluorescent chemical substrate, and expression of the mutated Rtr1 failed to rescue growth of yeast lacking Rtr1. Characterization of the phosphatase activity of RPAP2 and a mutant of the conserved putative catalytic site in the same chemical assay indicated a conserved reaction mechanism. Our data indicated that the structure of the phosphoryl transfer domain and reaction mechanism for the phosphoryl transfer activity of Rtr1 is distinct from those of other phosphatase families. PMID- 26933071 TI - How proper training is key to battling stigma surrounding dementia. PMID- 26933072 TI - ESCAPE-into the community--a community-based rehabilitation programme for elderly people with chronic joint pain. PMID- 26933073 TI - A brief introduction to ... Assistive robotics for independent living. PMID- 26933074 TI - Innovate UK: the long-term care revolution. PMID- 26933075 TI - Innovate UK: dallas. PMID- 26933076 TI - Precision medicine and improving future health care to an ageing population. PMID- 26933077 TI - Dementia risk reduction: it's never too early, it's never too late. PMID- 26933078 TI - 2020 vision for Welsh 'public health'? Proposing 'public sector' footprints. PMID- 26933079 TI - Meaningful activities for improving the wellbeing of people with dementia: beyond mere pleasure to meeting fundamental psychological needs. AB - AIMS: Dementia is being increasingly recognised as a major public health issue for our ageing populations. A critical aspect of supporting people with dementia is facilitating their participation in meaningful activities. However, research to date has not drawn on theories of ageing from developmental psychology that would help undergird the importance of such meaningful activity. For the first time, we connect existing activity provision for people with dementia with developmental psychology theories of ageing. METHOD: We reviewed the literature in two stages: first, we narratively searched the literature to demonstrate the relevance of psychological theories of ageing for provision of meaningful activities for people with dementia, and in particular focused on stage-based theories of adult development (Carl Jung and Erik Erikson), gerotranscendence (Tornstam), selective optimisation with compensation (Baltes and Baltes), and optimisation in primary and secondary control (Heckhausen and Schulz). Second, we systematically searched PubMed and PsycINFO for studies with people with dementia that made use of the aforementioned theories. RESULTS: The narrative review highlights that activity provision for people with dementia goes beyond mere pleasure to meeting fundamental psychological needs. More specifically, that life review therapy and life story work address the need for life review; spiritual/religious activities address the need for death preparation; intergenerational activities address the need for intergenerational relationships; re-acquaintance with previously conducted leisure activities addresses the need for a sense of control and to achieve life goals; and pursuit of new leisure activities addresses the need to be creative. The systematic searches identified two studies that demonstrated the utility of applying Erikson's theory of psychosocial development to dementia care. CONCLUSION: We argue for the importance of activity provision for people with dementia to help promote wellbeing among an increasing proportion of older people. PMID- 26933081 TI - Current Training in Quality and Safety: The Current Landscape in the Department of Veterans Affairs. PMID- 26933082 TI - Coronary Angiographic Findings in Acute Ischemic Stroke Patients With Elevated Cardiac Troponin: The Troponin Elevation in Acute Ischemic Stroke (TRELAS) Study. AB - BACKGROUND: A relevant proportion of patients with acute ischemic stroke (AIS) have elevated levels of cardiac troponins (cTn). However, the frequency of coronary ischemia as the cause of elevated cTn is unknown. The aim of our study was to analyze coronary vessel status in AIS patients with elevated cTn compared with patients presenting with non-ST-segment-elevation acute coronary syndrome (NSTE-ACS). METHODS AND RESULTS: Among 2123 consecutive patients with AIS prospectively screened at 2 tertiary hospitals, 13.7% had cTn elevation (>50 ng/L). According to a prespecified sample size estimation, 29 patients with AIS (median age, 76 years [first-third quartiles, 70-82 years]; 52% male) underwent conventional coronary angiography and were compared with age- and sex-matched patients with NSTE-ACS. The primary end point was presence of coronary culprit lesions on coronary angiograms as analyzed by independent interventional cardiologists blinded for clinical data. Median cTn on presentation did not differ between patients with AIS or NSTE-ACS (95 versus 94 ng/L; P=0.70). Compared with patients with NSTE-ACS, patients with AIS were less likely to have coronary culprit lesions (7 of 29 versus 23 of 29; P<0.001) or any obstructive coronary artery disease (15 of 29 versus 25 of 29; P=0.02; median number of vessels with >50% stenosis, 1 [first-third quartiles, 0-2] versus 2 [first-third quartiles, 1-3]; P<0.01). CONCLUSIONS: Coronary culprit lesions are significantly less frequent in AIS patients compared with age- and sex-matched patients with NSTE-ACS despite similar baseline cTn levels. Half of all AIS patients had no angiographic evidence of coronary artery disease. Further studies are needed to clinically identify the minority of patients with AIS and angiographic evidence of a culprit lesion. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01263964. PMID- 26933083 TI - Selective Stimulation of Cardiac Lymphangiogenesis Reduces Myocardial Edema and Fibrosis Leading to Improved Cardiac Function Following Myocardial Infarction. AB - BACKGROUND: The lymphatic system regulates interstitial tissue fluid balance, and lymphatic malfunction causes edema. The heart has an extensive lymphatic network displaying a dynamic range of lymph flow in physiology. Myocardial edema occurs in many cardiovascular diseases, eg, myocardial infarction (MI) and chronic heart failure, suggesting that cardiac lymphatic transport may be insufficient in pathology. Here, we investigate in rats the impact of MI and subsequent chronic heart failure on the cardiac lymphatic network. Further, we evaluate for the first time the functional effects of selective therapeutic stimulation of cardiac lymphangiogenesis post-MI. METHODS AND RESULTS: We investigated cardiac lymphatic structure and function in rats with MI induced by either temporary occlusion (n=160) or permanent ligation (n=100) of the left coronary artery. Although MI induced robust, intramyocardial capillary lymphangiogenesis, adverse remodeling of epicardial precollector and collector lymphatics occurred, leading to reduced cardiac lymphatic transport capacity. Consequently, myocardial edema persisted for several months post-MI, extending from the infarct to noninfarcted myocardium. Intramyocardial-targeted delivery of the vascular endothelial growth factor receptor 3-selective designer protein VEGF-CC152S, using albumin-alginate microparticles, accelerated cardiac lymphangiogenesis in a dose-dependent manner and limited precollector remodeling post-MI. As a result, myocardial fluid balance was improved, and cardiac inflammation, fibrosis, and dysfunction were attenuated. CONCLUSIONS: We show that, despite the endogenous cardiac lymphangiogenic response post-MI, the remodeling and dysfunction of collecting ducts contribute to the development of chronic myocardial edema and inflammation aggravating cardiac fibrosis and dysfunction. Moreover, our data reveal that therapeutic lymphangiogenesis may be a promising new approach for the treatment of cardiovascular diseases. PMID- 26933084 TI - Relative Lack of Culprit and Obstructive Coronary Lesions in Patients With Acute Ischemic Stroke and Elevated Cardiac Troponin. PMID- 26933085 TI - Investigating the Metabolic Syndrome: Contributions of Swine Models. AB - The metabolic syndrome (MetS), a cluster of dyslipidemia, hypertension, and diabetes and an important contributor to cardiovascular morbidity and mortality, occurs in nearly 35% of adults and 50% of the aging population in the United States. However, the underlying mechanisms by which MetS orchestrates and amplifies cardiovascular events remain elusive. Furthermore, traditional therapeutic strategies addressing lifestyle modifications and individual components of MetS are often unsuccessful in decreasing morbidity due to MetS. The availability of an adequate experimental platform that mimics the complexity of MetS may allow development of novel management techniques. Swine models, including domestic pigs and minipigs, have made important contributions to our understanding of many aspects of MetS. Given their similarity to human anatomy and physiology, those models may have significant predictive power for elucidating the pathophysiology of MetS in a manner applicable to humans. Moreover, experimental maneuvers and drugs can be tested in these preclinical models before application in patients with MetS. This review highlights the utility of the pig as an animal model for metabolic disorders, which may play a crucial role in novel drug development to optimize management of MetS. PMID- 26933087 TI - Identification of RNA-Binding Protein LARP4B as a Tumor Suppressor in Glioma. AB - Transposon-based insertional mutagenesis is a valuable method for conducting unbiased forward genetic screens to identify cancer genes in mice. We used this system to elucidate factors involved in the malignant transformation of neural stem cells into glioma-initiating cells. We identified an RNA-binding protein, La related protein 4b (LARP4B), as a candidate tumor-suppressor gene in glioma. LARP4B expression was consistently decreased in human glioma stem cells and cell lines compared with normal neural stem cells. Moreover, heterozygous deletion of LARP4B was detected in nearly 80% of glioblastomas in The Cancer Genome Atlas database. LARP4B loss was also associated with low expression and poor patient survival. Overexpression of LARP4B in glioma cell lines strongly inhibited proliferation by inducing mitotic arrest and apoptosis in four of six lines as well as in two patient-derived glioma stem cell populations. The expression levels of CDKN1A and BAX were also upregulated upon LARP4B overexpression, and the growth-inhibitory effects were partially dependent on p53 (TP53) activity in cells expressing wild-type, but not mutant, p53. We further found that the La module, which is responsible for the RNA chaperone activity of LARP4B, was important for the growth-suppressive effect and was associated with BAX mRNA. Finally, LARP4B depletion in p53 and Nf1-deficient mouse primary astrocytes promoted cell proliferation and led to increased tumor size and invasiveness in xenograft and orthotopic models. These data provide strong evidence that LARP4B serves as a tumor-suppressor gene in glioma, encouraging further exploration of the RNA targets potentially involved in LARP4B-mediatd growth inhibition. Cancer Res; 76(8); 2254-64. (c)2016 AACR. PMID- 26933086 TI - Rab11-FIP1C Is a Critical Negative Regulator in ErbB2-Mediated Mammary Tumor Progression. AB - Rab coupling protein (FIP1C), an effector of the Rab11 GTPases, including Rab25, is amplified and overexpressed in 10% to 25% of primary breast cancers and correlates with poor clinical outcome. Rab25 is also frequently silenced in triple-negative breast cancer, suggesting its ability to function as either an oncogene or a tumor suppressor, depending on the breast cancer subtype. However, the pathobiologic role of FIP family members, such as FIP1C, in a tumor-specific setting remains elusive. In this study, we used ErbB2 mouse models of human breast cancer to investigate FIP1C function in tumorigenesis. Doxycycline-induced expression of FIP1C in the MMTV-ErbB2 mouse model resulted in delayed mammary tumor progression. Conversely, targeted deletion of FIP1C in the mammary epithelium of an ErbB2 model coexpressing Cre recombinase led to accelerated tumor onset. Genetic and biochemical characterization of these FIP1C-proficient and -deficient tumor models revealed that FIP1C regulated E-cadherin (CDH1) trafficking and ZONAB (YBX3) function in Cdk4-mediated cell-cycle progression. Furthermore, we demonstrate that FIP1C promoted lysosomal degradation of ErbB2. Consistent with our findings in the mouse, the expression of FIP1C was inversely correlated with ErbB2 levels in breast cancer patients. Taken together, our findings indicate that FIP1C acts as a tumor suppressor in the context of ErbB2 positive breast cancer and may be therapeutically exploited as an alternative strategy for targeting aberrant ErbB2 expression. Cancer Res; 76(9); 2662-74. (c)2016 AACR. PMID- 26933089 TI - Advance: A Report on the University HealthSystem Consortium Annual Conference 2015. PMID- 26933090 TI - Risk and Protective Factors for Suicidal Ideation in African American Women With a History of Sexual Violence as a Minor. AB - Compared with other ethnic groups, African Americans have the highest rate of childhood victimization. The literature is sparse with regard to suicidal ideation among African American women with a history of sexual violence as a minor. Using survey data, this study utilized logistic regression to investigate the roles of a risk factor, criminal justice involvement, and protective factors, ethnic identity, and spiritual well-being, in experiencing suicidal ideation. Findings suggest that criminal justice involvement and the interaction of ethnic identity and spiritual well-being are important factors in understanding which African American women may be at a greater risk of experiencing suicidal ideation. PMID- 26933088 TI - Mathematical Modeling Reveals That Changes to Local Cell Density Dynamically Modulate Baseline Variations in Cell Growth and Drug Response. AB - Cell-to-cell variations contribute to drug resistance with consequent therapy failure in cancer. Experimental techniques have been developed to monitor tumor heterogeneity, but estimates of cell-to-cell variation typically fail to account for the expected spatiotemporal variations during the cell growth process. To fully capture the extent of such dynamic variations, we developed a mechanistic mathematical model supported by in vitro experiments with an ovarian cancer cell line. We introduce the notion of dynamic baseline cell-to-cell variation, showing how the emerging spatiotemporal heterogeneity of one cell population can be attributed to differences in local cell density and cell cycle. Manipulation of the geometric arrangement and spatial density of cancer cells revealed that given a fixed global cell density, significant differences in growth, proliferation, and paclitaxel-induced apoptosis rates were observed based solely on cell movement and local conditions. We conclude that any statistical estimate of changes in the level of heterogeneity should be integrated with the dynamics and spatial effects of the baseline system. This approach incorporates experimental and theoretical methods to systematically analyze biologic phenomena and merits consideration as an underlying reference model for cell biology studies that investigate dynamic processes affecting cancer cell behavior. Cancer Res; 76(10); 2882-90. (c)2016 AACR. PMID- 26933091 TI - When Is Science 'Ultimately Unreliable'? PMID- 26933092 TI - Trichome Formation: Gibberellins on the Move. PMID- 26933093 TI - A Talisman of Pathology. PMID- 26933095 TI - Cutaneous Lymphoma at Injection Sites: Pathological, Immunophenotypical, and Molecular Characterization in 17 Cats. AB - Feline primary cutaneous lymphomas (FPCLs) account for 0.2% to 3% of all lymphomas in cats and are more frequently dermal nonepitheliotropic small T-cell tumors. Emergence of FPCL seems unrelated to feline leukemia virus (FeLV) serological positivity or to skin inflammation. A total of 17 cutaneous lymphomas with a history of vaccine injection at the site of tumor development were selected from 47 FPCLs. Clinical presentation, histology, immunophenotype, FeLV p27 and gp70 expression, and clonality were assessed. A majority of male (12/17), domestic short-haired (13/17) cats with a mean age of 11.3 years was reported. Postinjection time of development ranged from 15 days to approximately 9 years in 5 cats. At diagnosis, 11 of 17 cats had no evidence of internal disease. Lymphomas developed in interscapular (8/17), thoracic (8/17), and flank (1/17) cutaneous regions; lacked epitheliotropism; and were characterized by necrosis (16/17), angiocentricity (13/17), angioinvasion (9/17), angiodestruction (8/17), and peripheral inflammation composed of lymphoid aggregates (14/17). FeLV gp70 and/or p27 proteins were expressed in 10 of 17 tumors. By means of World Health Organization classification, immunophenotype, and clonality, the lesions were categorized as large B-cell lymphoma (11/17), anaplastic large T-cell lymphoma (3/17), natural killer cell-like (1/17) lymphoma, or peripheral T-cell lymphoma (1/17). Lineage remained uncertain in 1 case. Cutaneous lymphomas at injection sites (CLIS) shared some clinical and pathological features with feline injection site sarcomas and with lymphomas developing in the setting of subacute to chronic inflammation reported in human beings. Persistent inflammation induced by the injection and by reactivation of FeLV expression may have contributed to emergence of CLIS. PMID- 26933094 TI - Changes in Pain Sensitivity and Pain Modulation During Oral Opioid Treatment: The Impact of Negative Affect. AB - OBJECTIVE: Opioids are frequently prescribed for chronic low back pain (CLBP), but there are broad individual differences in the benefits and risks of opioid therapy, including the development opioid-induced hyperalgesia. This study examined quantitative sensory testing (QST) data among a group of CLBP patients undergoing sustained oral opioid treatment. We investigated whether individual differences in psychological characteristics were related to opioid-induced changes in pain perception and pain modulation. DESIGN: The six-month, open-label trial evaluated patients with low to high levels of negative affect (e.g., symptoms of distress, depression and anxiety); participants underwent QST at baseline (prior to initiating treatment) and during oral opioid treatment. SETTING: A chronic pain management center. PATIENTS: The 31 study participants had chronic discogenic back pain, with a pain intensity rating >3/10. Participants were divided into groups with high vs. low levels of Negative Affect (NA). RESULTS: In the previously-published manuscript describing the clinical outcomes of the trial, high NA patients achieved only about half of the analgesic effect observed in the low NA group (Wasan AD, Michna E, Edwards RR, et al. Psychiatric comorbidity is associated prospectively with diminished opioid analgesia and increased opioid misuse in patients with chronic low back pain. Anesthesiology 2015;123:861-72). The QST findings reported here suggested that tolerance to experimental (cold pressor) pain and conditioned pain modulation tended to decrease in the high NA group over the course of opioid treatment, while temporal summation of mechanical pain declined in the low NA group. CONCLUSIONS: These results reveal that while the low NA group seemed to exhibit a generally adaptive, analgesic pattern of changes during opioid management, the high NA group showed a pattern more consistent with opioid-induced hyperalgesic processes. A greater susceptibility to hyperalgesia-promoting changes in pain modulation among patients with high levels of distress may contribute to a lower degree of benefit from opioid treatment in high NA patients. PMID- 26933096 TI - Clonality Testing in Veterinary Medicine: A Review With Diagnostic Guidelines. AB - The accurate distinction of reactive and neoplastic lymphoid proliferations can present challenges. Given the different prognoses and treatment strategies, a correct diagnosis is crucial. Molecular clonality assays assess rearranged lymphocyte antigen receptor gene diversity and can help differentiate reactive from neoplastic lymphoid proliferations. Molecular clonality assays are commonly used to assess atypical, mixed, or mature lymphoid proliferations; small tissue fragments that lack architecture; and fluid samples. In addition, clonality testing can be utilized to track neoplastic clones over time or across anatomic sites. Molecular clonality assays are not stand-alone tests but useful adjuncts that follow clinical, morphologic, and immunophenotypic assessment. Even though clonality testing provides valuable information in a variety of situations, the complexities and pitfalls of this method, as well as its dependency on the experience of the interpreter, are often understated. In addition, a lack of standardized terminology, laboratory practices, and interpretational guidelines hinders the reproducibility of clonality testing across laboratories in veterinary medicine. The objectives of this review are twofold. First, the review is intended to familiarize the diagnostic pathologist or interested clinician with the concepts, potential pitfalls, and limitations of clonality testing. Second, the review strives to provide a basis for future harmonization of clonality testing in veterinary medicine by providing diagnostic guidelines. PMID- 26933097 TI - Francisella Tularensis Clades B.FTN002-00 and B.13 Are Associated With Distinct Pathology in the European Brown Hare (Lepus europaeus). AB - Tularemia is a severe disease caused by Francisella tularensis This bacterium has a major pathogenic potential in countless animal species as well as in humans. Despite the relatively significant body of literature available on this microorganism, many questions are still open concerning its biological cycle in the environment, the pathology and pathogenesis of the disease, the possible routes of infection in animals, and the pathologic and ecological relevance of the distinct phylogenetic clusters of F. tularensis In order to address these questions, we have thoroughly characterized the pathology and microbiology of terminally ill European brown hares (Lepus europaeus) infected with F. tularensis subsp. holarctica, collected in Switzerland from 2012 to 2014. F tularensis isolates were typed by defining their phylogenetic clusters. We showed that the pathology associated with F. tularensis subsp. holarctica belonging to the clade B.FTNF002-00 is different from that previously reported to be associated with the clade B.13. In particular, strains of the clade B.FTNF002-00 were almost invariably associated with splenitis and hepatitis and not with the polyserositis affecting pleura, pericardium, and kidney reported in the literature for infections caused by the clade B.13. We describe findings suggesting that the ports of entry for the bacteria might be the respiratory and digestive routes. PMID- 26933098 TI - SIESTA trial: Is GA a drug you get from the hospital pharmacy? PMID- 26933099 TI - Recovery process of corticospinal tract injured by intracerebral hemorrhage from onset to chronic stage. PMID- 26933100 TI - Setting the Stage for a Great Performance As an Academic Department Chair. PMID- 26933101 TI - An Exploration of Dental Students' Assumptions About Community-Based Clinical Experiences. AB - The aim of this study was to ascertain which assumptions dental students recalled feeling prior to beginning community-based clinical experiences and whether those assumptions were fulfilled or challenged. All fourth-year students at the University of Iowa College of Dentistry & Dental Clinics participate in community based clinical experiences. At the completion of their rotations, they write a guided reflection paper detailing the assumptions they had prior to beginning their rotations and assessing the accuracy of their assumptions. For this qualitative descriptive study, the 218 papers from three classes (2011-13) were analyzed for common themes. The results showed that the students had a variety of assumptions about their rotations. They were apprehensive about working with challenging patients, performing procedures for which they had minimal experience, and working too slowly. In contrast, they looked forward to improving their clinical and patient management skills and knowledge. Other assumptions involved the site (e.g., the equipment/facility would be outdated; protocols/procedures would be similar to the dental school's). Upon reflection, students reported experiences that both fulfilled and challenged their assumptions. Some continued to feel apprehensive about treating certain patient populations, while others found it easier than anticipated. Students were able to treat multiple patients per day, which led to increased speed and patient management skills. However, some reported challenges with time management. Similarly, students were surprised to discover some clinics were new/updated although some had limited instruments and materials. Based on this study's findings about students' recalled assumptions and reflective experiences, educators should consider assessing and addressing their students' assumptions prior to beginning community-based dental education experiences. PMID- 26933102 TI - Characteristics Identified for Success by Restorative Dental Science Department Chairpersons. AB - The primary aim of this study was to determine the characteristics that current chairpersons in restorative dentistry, general dentistry, prosthodontics, and operative dentistry departments in U.S. dental schools feel are most relevant in contributing to their success. The secondary aim was to determine these individuals' rankings of the importance of a listed set of characteristics for them to be successful in their position. All 82 current chairs of the specified departments were invited to respond to an electronic survey. The survey first asked respondents to list the five most essential characteristics to serve as chair of a department and to rank those characteristics based on importance. Participants were next given a list of ten characteristics in the categories of management and leadership and, without being aware of the category of each individual item, asked to rank them in terms of importance for their success. A total of 39 chairpersons completed the survey (47.6% response rate; 83.3% male and 16.2% female). In section one, the respondents reported that leadership, vision, work ethic, integrity, communication, and organization were the most essential characteristics for their success. In section two, the respondents ranked the leadership characteristics as statistically more important than the management characteristics (p<0.0001) for being successful in their positions. PMID- 26933103 TI - Integration of Basic-Clinical Sciences, PBL, CBL, and IPE in U.S. Dental Schools' Curricula and a Proposed Integrated Curriculum Model for the Future. AB - The integration of basic and clinical sciences in dental curricula enhances the application of basic science principles to clinical decision making and improves students' critical thinking. The aim of this study was to define the characteristics of U.S. dental schools' curricula with regard to level of course integration and degree of incorporation of problem-based and case-based learning. A second aim was to propose a dental curriculum that supports effective integration of courses and addresses some of the concerns facing academic dentistry. A survey was sent to 58 academic deans in U.S. dental schools. The survey included questions about integrating courses in the schools' curricula and major changes in curricular structure or teaching pedagogy that respondents anticipated in the immediate future. A total of 31 schools responded to the survey, for a 53.4% response rate. The results showed that three-quarters of the responding schools still teach basic and clinical sciences separately, although 61.3% reported having an integrated curriculum. Among the responding schools, 16 had a PBL component integrated into their curricula (two had integrated PBL in all courses and 14 used a hybrid PBL approach). Two schools had CBL integrated in all courses, and ten had CBL integrated in >75% of courses. Only slightly more than half agreed that their curricula foster students' thinking "outside the box." Faculty shortages and lack of protected time and resources were the most frequent reasons given for a lack of integrated courses. The integrated model proposed in this article has the potential to provide a low stress environment for students and to address important issues like faculty shortages. PMID- 26933104 TI - Stakeholders' Perceptions About a Newly Established Dental School with a Problem Based, Student-Led, Patient-Centered Curriculum: A Qualitative Study. AB - The aim of this study was to explore the perceptions of stakeholders regarding a newly established dental school with a problem-based, student-led, patient centered curriculum in a community setting. Qualitative methods using 16 semistructured interviews and two focus groups were used to engage a range of stakeholders from students to faculty members to practitioners. Purposive sampling was employed with participants contacted through professional channels. Interview and focus group transcripts were transcribed verbatim. The data were analyzed thematically using an inductive approach. Themes related to preparedness of dental graduates were identified during data analyses. Early clinical exposure with patients in the first year of the course, holistic care using a patient centered approach, and the acquisition of communication skills, professionalism, team-working skills, reflective practice, and evidence-informed clinical practice were perceived to be key strengths of the curriculum. The participants also expressed the need to strengthen teaching of life sciences and provide additional clinical experience in simulated general dental practice clinics. This study provides insight into the perceptions of a wide range of stakeholders and provides a deeper understanding of the merits and challenges of an innovative undergraduate dental curriculum. PMID- 26933105 TI - Dental Students' Clinical Expectations and Experiences Treating Persons with Disabilities. AB - Persons with disabilities (PWDs) have a disproportionate level of dental disease relative to the general population. Access to care is a cause along with dentists' willingness to treat PWDs. The aim of this study was to investigate the expectations and experiences of dental students in providing treatment to these patients in a hospital-based dental clinic for PWDs. Senior dental students at the Faculty of Dentistry, University of Toronto (n=92) were surveyed prior to (Phase I) and at the end of (Phase II) mandatory clinical rotations at the Mount Sinai Hospital's Dentistry Clinic for Persons with Special Needs. Response rates were 88% for Phase I and 58% for Phase II. Before the rotations, 70% of the respondents reported little or no experience with PWDs, and 46% said they did not feel comfortable providing basic dental treatment to PWDs. However, in Phase II, significantly more students reported being comfortable than in Phase I (p=0.001). Overall, the majority of respondents (Phase I 95%; Phase II 98%) indicated they would at least attempt to provide basic dental care to PWDs after graduation. The majority also identified the opportunity to provide care and interact with PWDs as the most enjoyable aspect of their experience at the clinic. They reported that the experience helped reduce their concerns about treating PWDs including being more realistic about the time required and ideal quality of the treatment they could provide. These results suggest that their experience in the clinic significantly increased students' comfort in treating PWDs. The respondents expressed a willingness to treat PWDs once graduated and generally identified their experience as being more positive than their expectations. PMID- 26933106 TI - Dental Students' Perceived Value of Peer-Mentoring Clinical Leadership Experiences. AB - This pilot study compared second- and fourth-year dental students' perceived values of newly implemented clinical leadership experiences (CLEs) at one U.S. dental school during the 2012-13 academic year. In the CLEs, fourth-year (D4) students mentored second-year (D2) dental students during faculty-supervised patient treatment. The two cohorts' perceived value of the experiences was measured with questionnaires consisting of five-point Likert scale questions and open text responses. Out of a total of 114 D2 and 109 D4 students, 46 D2 students and 35 D4 students participated (response rates of 40.4% and 32.1%, respectively). While responses from both cohorts showed they highly valued the CLEs, the D2s perceived greater value: 4.07 (0.53) v. 3.51 (0.95), p<0.003. Both cohorts reported feeling that D4s were prepared to mentor D2s, that the CLEs had educational benefits, and that the CLEs increased their comfort with peer communication. Theme analysis of open text questions revealed that the respondents perceived the D4s were more accessible than faculty and provided guidance and individual attention; the CLEs increased student comfort; the CLEs reinforced D4 skills, knowledge, and confidence; and the CLEs provided management, leadership, and collaborative work experience. Theme analysis also highlighted student concerns about a lack of program structure. Overall, the majority of both groups valued CLEs in their dental education. Particular advantages they perceived were increased comfort, guidance, and attention. Further program development should address student concerns. These results suggest that similar programs should be considered and/or expanded in other dental schools' curricula. PMID- 26933107 TI - Comparing Integrated and Disciplinary Clinical Training Patterns for Dental Interns: Advantages, Disadvantages, and Effect on Students' Self-Confidence. AB - In China, the five-year program of undergraduate education for stomatology consists of four years of lecture courses and one year of internship focused on clinical training. Dental schools provide this clinical training either in their own clinics (referred to as the one-stage pattern because all forms of practice are completed together) or by placing students in external clinics usually at non affiliated hospitals (referred to as the three-stage program because the three primary areas are taught separately). The aims of this study were to investigate differences in teaching effect between the one-stage and the three-stage patterns and to evaluate advantages and disadvantages of the two patterns. A three section, 31-item questionnaire was designed to assess basic and clinic information about the interns' training and their self-confidence in performing clinical procedures. The survey was administered to graduates who finished the fifth-year internship in 2012-14. Of the 356 individuals invited to participate, 303 graduates who spent their intern years in 43 academic dental institutions returned completed surveys (response rate of 85%). The one-stage group (n=121) reported longer independent operation time than the three-stage group (n=182) (p<0.01). No significant difference was found between the groups for assessment of clinic infrastructure (p=0.121). The interns were most confident in oral hygiene instruction and scale and polish (overall median=5), but showed low confidence in rubber dam placement and four other procedures (overall median=2). The one-stage group rated their confidence level higher than the three-stage group on comprehensive skills such as arranging appointments and managing patients and procedures needing long treatment periods such as molar endodontics. The three-stage group showed higher confidence on more specialized procedures such as surgical extractions and suturing. This study found that both of the two intern patterns had advantages and shortcomings in clinical training in various procedures. Combining the two could be a way to improve clinical education in China. PMID- 26933108 TI - Expansion of a Predoctoral Surgical Implant Selective for Dental Students. AB - Historically, predoctoral dental education programs have focused on the restoration of implants in the clinical environment; however, given the increase in dental implant therapy being performed by general dentists, the need to incorporate surgical implant training is becoming evident. This article describes a predoctoral surgical implant selective at the University of Texas Health Science Center at San Antonio and its evolution across five years to include emerging techniques and technology to enhance students' understanding of dental implant therapy, both surgical and restorative. From virtual implant planning and guided surgery to intra-oral scanning of implants for custom abutments and restorations, students obtained first-hand experiences with a wide spectrum of aspects of implant therapy. The results of anonymous surveys completed by 2014-15 students before and after the year-long selective regarding their impression of the program are also discussed. PMID- 26933109 TI - OSCE and Case Presentations As Active Assessments of Dental Student Performance. AB - The aim of this study was to evaluate whether the objective structured clinical examination (OSCE) and case presentation (CP) as forms of active assessment were effective measures of overall didactic knowledge and clinical performance in a predoctoral dental curriculum. This evaluation was conducted by statistical analysis of quality points (QP) awarded for didactic and clinical performance, CP grades, and OSCE scores for 185 students at Harvard School of Dental Medicine who graduated during the period 2010-14. As part of the requirements for graduation, each student takes three OSCEs and presents two patient cases. Data for the study were obtained from the Office of the Registrar. The results showed no direct correlation between QP and CP grades and no correlation between CP grades and OSCE scores. However, there was a correlation between OSCE scores and QP. Students with honors-level scores on any of the three OSCEs received significantly more QP than students who did not receive honors. In addition, students with passing scores on OSCEs 2 and 3 received significantly more QP than students with failing or marginal OSCE scores. Innovative formats of active assessment such as OSCEs and CPs can promote a student-centered learning environment. These data indicated that, within this study population, there was a positive association between OSCE scores and clinical and didactic performance, supporting the value of OSCEs as a means of assessment. PMID- 26933110 TI - Three Modeling Applications to Promote Automatic Item Generation for Examinations in Dentistry. AB - Test items created for dentistry examinations are often individually written by content experts. This approach to item development is expensive because it requires the time and effort of many content experts but yields relatively few items. The aim of this study was to describe and illustrate how items can be generated using a systematic approach. Automatic item generation (AIG) is an alternative method that allows a small number of content experts to produce large numbers of items by integrating their domain expertise with computer technology. This article describes and illustrates how three modeling approaches to item content-item cloning, cognitive modeling, and image-anchored modeling-can be used to generate large numbers of multiple-choice test items for examinations in dentistry. Test items can be generated by combining the expertise of two content specialists with technology supported by AIG. A total of 5,467 new items were created during this study. From substitution of item content, to modeling appropriate responses based upon a cognitive model of correct responses, to generating items linked to specific graphical findings, AIG has the potential for meeting increasing demands for test items. Further, the methods described in this study can be generalized and applied to many other item types. Future research applications for AIG in dental education are discussed. PMID- 26933111 TI - Test-Enhanced Learning in Competence-Based Predoctoral Orthodontics: A Four-Year Study. AB - Dental educators intend to promote integration of knowledge, skills, and values toward professional competence. Studies report that retrieval, in the form of testing, results in better learning with retention than traditional studying. The aim of this study was to evaluate test-enhanced experiences on demonstrations of competence in diagnosis and management of malocclusion and skeletal problems. The study participants were all third-year dental students (2011 N=88, 2012 N=74, 2013 N=91, 2014 N=85) at New York University College of Dentistry. The 2013 and 2014 groups received the test-enhanced method emphasizing formative assessments with written and dialogic delayed feedback, while the 2011 and 2012 groups received the traditional approach emphasizing lectures and classroom exercises. The students received six two-hour sessions, spaced one week apart. At the final session, a summative assessment consisting of the same four cases was administered. Students constructed a problem list, treatment objectives, and a treatment plan for each case, scored according to the same criteria. Grades were based on the number of cases without critical errors: A=0 critical errors on four cases, A-=0 critical errors on three cases, B+=0 critical errors on two cases, B=0 critical errors on one case, F=critical errors on four cases. Performance grades were categorized as high quality (B+, A-, A) and low quality (F, B). The results showed that the test-enhanced groups demonstrated statistically significant benefits at 95% confidence intervals compared to the traditional groups when comparing low- and high-quality grades. These performance trends support the continued use of the test-enhanced approach. PMID- 26933112 TI - Relationships Among the Knowledge, Efficacy, and Practices Instrument, Color Blind Racial Attitudes Scale, Deamonte Driver Survey, and Defining Issues Test 2. AB - Concordance studies indicate the degree to which instruments measure the same or similar constructs or something different. The aims of this study were to identify the factor structure of the Deamonte Driver Survey and determine the relationship between the Deamonte Driver (a measure of social class stereotyping), the Defining Issues Test 2 (DIT2; a measure of ethical sensitivity), the Color-Blind Racial Attitudes Scale (CoBRAS; a measure of racial stereotyping), and the Knowledge, Efficacy, and Practices Instrument (KEPI; a measure of cultural competence). The results showed a three-factor solution for the Deamonte Driver Survey and significant relationships between CoBRAS and DIT2 subscales and between CoBRAS and Deamonte Driver subscales. Significant relationships between the measures and exploratory variables, underrepresented minority status, age, citizenship, marital status, political stance, English as a first language, and gender were found. The lack of a significant relationship between the KEPI and Deamonte Driver, DIT2, or CoBRAS subscales suggests that the KEPI is measuring a unique construct. These findings showed how these scales contributed to the assessment of cultural competence among dental students and faculty. PMID- 26933113 TI - Is There a Need for Change in Managing Mixed Arteriovenous Leg Ulcers? PMID- 26933114 TI - The Point Prevalence of Malignancy in a Wound Clinic. AB - The aim of this study was to determine the prevalence of malignant leg ulcers and to identify the most frequent characteristics of such wounds. This study was a retrospective investigation of patients with chronic leg ulcers in a North American tertiary wound clinic. Between January 2011 and September 2013, a total of 1189 patients with lower extremity wounds, including 726 patients with leg wounds, were identified. A total of 124 of the 726 had undergone a biopsy of their atypical wound, 16.1% (20/124) of which were malignant. Patients with malignant wounds were older than patients with nonmalignant leg wounds (P < .0001), and the common location of the malignant wound was the anterior shin (odds ratio = 3.5). The limitation of this analysis is the lack of distinction between malignant transformation of wounds and de novo presentation of malignancies as chronic nonhealing wounds. Three distinguishing morphological features in malignant wounds were irregular borders (P = .0002), presence of hypergranulation tissue (P < .0001), and friable/bleeding wound surface (P < .0001). The frequency of malignant wounds in patients with chronic leg ulcers highlights the need for a systematic approach, which would involve biopsy of wounds to identify malignancy in this patient population early on. PMID- 26933115 TI - Efficacy of a New Heparan Sulfate Mimetic Dressing in the Healing of Foot and Lower Extremity Ulcerations in Type 2 Diabetes: A Case Series. AB - A novel heparan sulfate glycosaminoglycan mimetic product for local application to promote wound healing (CACIPLIQ) has recently become available. It is a biophysical therapeutic product comprising a polysaccharide as an innovative biomaterial to accomplish mechanical tissue engineering and skin regeneration in the site of ulceration. We present a series of 12 patients with type 2 diabetes (4 men and 8 women; age 53-87 years; diabetes duration 8-25 years) having chronic resistance to therapy for foot and lower extremity ulcerations. CACIPLIQ was locally applied twice per week after careful debridement. Complete ulcer healing was accomplished in all patients after a mean treatment duration of 4.92 months (range = 2-12 months). The product was very well tolerated. In conclusion, these results, although preliminary, are encouraging and suggest adequate efficacy and safety of the new product in difficult-to-heal foot and lower extremity ulcerations in type 2 diabetes. PMID- 26933116 TI - Complicated Skin and Skin Structure Infection After Erysipelas: Urgent Need for Antibiosis and Surgery. AB - Erysipelas are common soft tissue infections responding to first-line antibiosis. Because of factors of related to responsible bacteria and host, complications can occur that need extensive surgery in addition to intensified drug therapy. We report on a 65-year-old woman with leg ulcer who developed an absceding and necrotizing panniculitis of the affected leg complicating erysipelas. Escherichia coli and Pseudomonas aeruginosa were identified. Debridement and surgical removal of inflamed subcutaneous adipose tissue was decisive to interrupt the process. Wound bed preparation was realized by vacuum-assisted closure. Final wound closure was done by split-skin mesh graft. Complicated skin and skin structure infections need a combined approach of intensified antibiosis and surgery to save life. PMID- 26933117 TI - Topical Negative Pressure Therapy for Diabetic Foot Ulcers: Where is the Evidence? PMID- 26933118 TI - Ethical Issues--the challenge to keep up with a changing environment. PMID- 26933119 TI - CardioPulse: Ethical issues for the European Society of Cardiology. PMID- 26933120 TI - Academic-industrial collaboration in the development of the first angiotensin receptor blocker: neprilysin inhibitor in the treatment of heart failure. PMID- 26933121 TI - Frailty as a predictor of hospitalisation among community-dwelling older people: a systematic review and meta-analysis. AB - BACKGROUND: Owing to detrimental hazards and substantial healthcare burden and costs, hospitalisation of older people has become a major focus. Frailty has increasingly been recognised as an important predictor of hospitalisation. This study aims to identify studies on physical frailty as a predictor of hospitalisation risks and to pool the risk estimates among community-dwelling older people. METHODS: A systematic literature search was performed in August 2015 using five databases: EMBASE, MEDLINE, CINAHL, PsycINFO and the Cochrane Library for prospective studies examining physical frailty as a predictor of hospitalisation published in 2000 or later. OR and HR were combined to synthesise pooled effect measures using fixed-effects models. The included studies were assessed for heterogeneity, methodological quality and publication bias. Subgroup analysis and meta-regression analysis were conducted to examine study characteristics in relation to the hospitalisation risks. RESULTS: Of the 4620 studies identified by the systematic review, 13 studies with average follow-up period of 3.1 years were selected. Frailty and prefrailty were significantly associated with higher hospitalisation risks among 10 studies with OR (pooled OR=1.90, 95% CI 1.74-2.07, p<0.00001; pooled OR=1.26, 95% CI 1.18-1.33, p<0.00001, respectively) and 3 studies with HR (pooled HR=1.30, 95% CI 1.12-1.52, p=0.0007; pooled HR=1.13, 95% CI 1.04-1.24, p=0.005, respectively). Heterogeneity was low to moderate. No publication bias was detected. The studies with older populations and unadjusted outcome measures were associated with higher hospitalisation risks in the subgroup analysis. CONCLUSIONS: This systematic review and meta-analysis demonstrated physical frailty is a significant predictor of hospitalisation among community-dwelling older people. Hospitalisation can potentially be reduced by treating or preventing frailty. PMID- 26933122 TI - Visualising variation in mortality rates across the life course and by sex, USA and comparator states, 1933-2010. AB - BACKGROUND: Previous research showed that younger adult males in the USA have, since the 1950s, died at a faster rate than females of the same age. In this paper, we quantify this difference, and explore possible explanations for the differences at different ages and in different years. METHODS: Using data from the Human Mortality Database (HMD), the number of additional male deaths per 10 000 female deaths was calculated for each year from 1933 to 2010, and for each year of age from 0 to 60 years, for the USA, and a number of other countries for comparison. The data were explored visually using shaded contour plots. RESULTS: Gender differences in excess mortality have increased. Coming of age (between the ages of 15 and 25 years of age) is especially perilous for men relative to women now compared with the past in the USA; the visualisations highlight this change as important. CONCLUSIONS: Sex differences in mortality risks at various ages are not static. While women may today have an advantage when it comes to life expectancy, in the USA, this has greatly increased since the 1930s. Just as young adulthood for women has been made safer through safer antenatal and childbirth practices, changes in public policy can make the social environment safer for men. PMID- 26933124 TI - Comprehensive Genomic Profiling Identifies Frequent Drug-Sensitive EGFR Exon 19 Deletions in NSCLC not Identified by Prior Molecular Testing. AB - PURPOSE: Reliable detection of drug-sensitive activating EGFR mutations is critical in the care of advanced non-small cell lung cancer (NSCLC), but such testing is commonly performed using a wide variety of platforms, many of which lack rigorous analytic validation. EXPERIMENTAL DESIGN: A large pool of NSCLC cases was assayed with well-validated, hybrid capture-based comprehensive genomic profiling (CGP) at the request of the individual treating physicians in the course of clinical care for the purpose of making therapy decisions. From these, 400 cases harboring EGFR exon 19 deletions (Deltaex19) were identified, and available clinical history was reviewed. RESULTS: Pathology reports were available for 250 consecutive cases with classical EGFR Deltaex19 (amino acids 743-754) and were reviewed to assess previous non-hybrid capture-based EGFR testing. Twelve of 71 (17%) cases with EGFR testing results available were negative by previous testing, including 8 of 46 (17%) cases for which the same biopsy was analyzed. Independently, five of six (83%) cases harboring C-helical EGFR Deltaex19 were previously negative. In a subset of these patients with available clinical outcome information, robust benefit from treatment with EGFR inhibitors was observed. CONCLUSIONS: CGP identifies drug-sensitive EGFR Deltaex19 in NSCLC cases that have undergone prior EGFR testing and returned negative results. Given the proven benefit in progression-free survival conferred by EGFR tyrosine kinase inhibitors in patients with these alterations, CGP should be considered in the initial presentation of advanced NSCLC and when previous testing for EGFR mutations or other driver alterations is negative. Clin Cancer Res; 22(13); 3281-5. (c)2016 AACR. PMID- 26933123 TI - GEMC1 is a critical regulator of multiciliated cell differentiation. AB - The generation of multiciliated cells (MCCs) is required for the proper function of many tissues, including the respiratory tract, brain, and germline. Defects in MCC development have been demonstrated to cause a subclass of mucociliary clearance disorders termed reduced generation of multiple motile cilia (RGMC). To date, only two genes, Multicilin (MCIDAS) and cyclin O (CCNO) have been identified in this disorder in humans. Here, we describe mice lacking GEMC1 (GMNC), a protein with a similar domain organization as Multicilin that has been implicated in DNA replication control. We have found that GEMC1-deficient mice are growth impaired, develop hydrocephaly with a high penetrance, and are infertile, due to defects in the formation of MCCs in the brain, respiratory tract, and germline. Our data demonstrate that GEMC1 is a critical regulator of MCC differentiation and a candidate gene for human RGMC or related disorders. PMID- 26933125 TI - Oncogenic ALK Fusion in Rare and Aggressive Subtype of Colorectal Adenocarcinoma as a Potential Therapeutic Target. AB - PURPOSE: Chromosomal translocations in the anaplastic lymphoma kinase (ALK) gene have been identified as oncogenic drivers in lung adenocarcinomas and other tumors, recently including rare cases of colorectal carcinoma. We identified a patient with refractory metastatic colorectal carcinoma harboring a STRN-ALK gene fusion who achieved an exceptional clinical benefit to the ALK inhibitor ceritinib. Our goal was to further define the clinicopathologic features of ALK rearranged colorectal carcinoma in a large cohort. EXPERIMENTAL DESIGN: Clinical cases of colorectal carcinoma evaluated by comprehensive genomic profiling (CGP) or by ALK immunohistochemistry (IHC) were reviewed retrospectively. FISH and microsatellite instability (MSI) analyses were performed. RESULTS: Nine colorectal carcinoma cases harbored ALK gene fusions. Six cases were identified by CGP of 3,157 colorectal carcinoma (0.2%) and three by IHC of 2,980 colorectal carcinoma (0.1%). The ALK fusions involved known ALK partners EML4, C2orf44, CAD, and the novel STRN, PPP1R21, SENPF, MAPRE3, and PRKAP1B partners. These advanced stage colorectal carcinomas lacked mutations in other oncogenic drivers, predominantly involved the proximal colon, and often exhibited MSI and mucinous phenotype. The index patient was treated with the ALK inhibitor ceritinib, resulting in a marked decrease in size of a skin metastasis, and resolution by computerized tomography of all contrast enhancing tumor. After 9 months of treatment, biopsy of progressive disease demonstrated a KRAS mutation, consistent with acquired resistance to ceritinib. CONCLUSIONS: Colorectal carcinoma harboring ALK fusions represent a rare aggressive subtype of colorectal carcinoma with distinct clinicopathologic features. This report provides the first clinical evidence that such patients may benefit from targeted monotherapy with ALK inhibitors. Clin Cancer Res; 22(15); 3831-40. (c)2016 AACR. PMID- 26933126 TI - Aplasia cutis congenita of the scalp with sagittal venous sinus exposure. PMID- 26933127 TI - Discovery of Novel Inhibitors of the Tautomerase Activity of Macrophage Migration Inhibitory Factor (MIF). AB - Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine associated with multiple diseases, including neurodegenerative disorders. With the ultimate goal of providing novel chemotypes as starting points for development of disease-modifying therapeutics for neurodegeneration, we endeavored to screen the GSK compound collection for MIF inhibitors using a miniaturized, activity-based kinetic assay. The assay monitors the increase in absorbance at 320 nm resulting from keto-to-enol tautomerization of 4 hydroxyphenylpyruvate, a reaction catalyzed by MIF. We ran a full-diversity screen evaluating the inhibitory activity of 1.6 million compounds. Primary hits were confirmed and retested in an orthogonal assay measuring tautomerization of l dopachrome methyl ester by the decrease in absorbance at 475 nm in kinetic mode. Selected compounds were progressed to medium-throughput mode-of-inhibition studies, which included time dependence, enzyme concentration dependence, and reversibility of their inhibitory effect. With these results and after inspection of the physicochemical properties of compounds, 17 chemotypes were prioritized and progressed to further stages of validation and characterization to better assess their therapeutic potential. PMID- 26933128 TI - Methodologic considerations in the evaluation of adaptive thermogenesis. PMID- 26933129 TI - Reply to MG Browning. PMID- 26933132 TI - Idelalisib for treatment of B-cell malignancies. AB - PURPOSE: The pharmacology, pharmacokinetics, clinical efficacy, safety and tolerability, dosing and administration, and place in therapy of idelalisib, a targeted therapy for certain types of non-Hodgkin's lymphoma (NHL), are reviewed. SUMMARY: Historically, conventional cancer chemotherapy agents were recommended for the management of progressive lymphomas requiring systemic treatment; in recent years, however, emerging targeted therapies have altered the landscape of lymphoma treatment. Idelalisib, a novel oral phosphatidylinositol 3-kinase (PI3K) inhibitor, disrupts downstream signaling pathways involved in cancer cell growth and survival. Inhibition of PI3K has been demonstrated to produce durable treatment responses and improved survival outcomes in clinical trials involving patients with indolent forms of NHL. Idelalisib is indicated for use in combination with rituximab for treatment of relapsed chronic lymphocytic leukemia (CLL) and as monotherapy for relapsed small lymphocytic leukemia and follicular lymphoma after the failure of at least two systemic treatments. The recommended dosage of idelalisib is 150 mg orally twice daily; the medication can be taken without regard to mealtimes. The most common adverse effects of idelalisib include diarrhea, nausea, fatigue, cough, and pyrexia. Severe hepatotoxicity and gastrointestinal toxicities, including colitis and intestinal perforation, have also been reported in association with idelalisib use. Ongoing clinical studies are exploring the potential for expanded use of idelalisib in the management of other B-cell malignancies. CONCLUSION: Idelalisib is a well-tolerated and effective treatment for patients with relapsed or refractory CLL or indolent NHL, providing a novel targeted therapeutic option for the management of these hematologic malignancies. PMID- 26933134 TI - Prevalence of Knee Osteoarthritis in 100 Athletically Active Veteran Soccer Players Compared With a Matched Group of 100 Military Personnel. AB - BACKGROUND: Although knee injuries in professional soccer (football) have been extensively studied, the prevalence of knee osteoarthritis (OA) in veteran players is not well documented. PURPOSE: To investigate the prevalence of knee OA in retired professional soccer players in comparison with a group of athletically active military personnel. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: A group of 100 veteran Greek soccer players aged 35 to 55 years (mean [+/-SD] age, 46.90 +/- 5.9 years) were examined for knee OA and were administered the Knee injury and Osteoarthritis Outcome Score (KOOS) questionnaire. A matched group of 100 athletically active military personnel served as a comparison group. RESULTS: The sonographic prevalence of OA was significantly higher in the veteran soccer group (52%) than in the military group (33%) (n = 200; P = .010). This difference remained significant even after excluding participants with a history of knee surgery (44.1% vs 25.3%, respectively) (n = 151; P = .010). Femoral cartilage thickness was similar between the 2 groups (P = .473), while altered knee alignment had no effect on the prevalence of OA (P = .740). With the exception of perceived pain being more prevalent in the military group, there were no other statistically significant differences between the 2 groups in KOOS values. CONCLUSION: Veteran soccer players had a higher sonographic prevalence of knee OA but better pain scores than a matched group of athletically active military personnel. PMID- 26933136 TI - From Artisanal to CAD-CAM Blocks: State of the Art of Indirect Composites. AB - Indirect composites have been undergoing an impressive evolution over the last few years. Specifically, recent developments in computer-aided design-computer aided manufacturing (CAD-CAM) blocks have been associated with new polymerization modes, innovative microstructures, and different compositions. All these recent breakthroughs have introduced important gaps among the properties of the different materials. This critical state-of-the-art review analyzes the strengths and weaknesses of the different varieties of CAD-CAM composite materials, especially as compared with direct and artisanal indirect composites. Indeed, new polymerization modes used for CAD-CAM blocks-especially high temperature (HT) and, most of all, high temperature-high pressure (HT-HP)-are shown to significantly increase the degree of conversion in comparison with light-cured composites. Industrial processes also allow for the augmentation of the filler content and for the realization of more homogeneous structures with fewer flaws. In addition, due to their increased degree of conversion and their different monomer composition, some CAD-CAM blocks are more advantageous in terms of toxicity and monomer release. Finally, materials with a polymer-infiltrated ceramic network (PICN) microstructure exhibit higher flexural strength and a more favorable elasticity modulus than materials with a dispersed filler microstructure. Consequently, some high-performance composite CAD-CAM blocks particularly experimental PICNs-can now rival glass-ceramics, such as lithium disilicate glass-ceramics, for use as bonded partial restorations and crowns on natural teeth and implants. Being able to be manufactured in very low thicknesses, they offer the possibility of developing innovative minimally invasive treatment strategies, such as "no prep" treatment of worn dentition. Current issues are related to the study of bonding and wear properties of the different varieties of CAD-CAM composites. There is also a crucial need to conduct clinical studies. Last, manufacturers should provide more complete information regarding their product polymerization process, microstructure, and composition, which significantly influence CAD-CAM material properties. PMID- 26933133 TI - Integrity of normal-appearing white matter: Influence of age, visible lesion burden and hypertension in patients with small-vessel disease. AB - White matter hyperintensities accumulate with age and occur in patients with stroke, but their pathogenesis is poorly understood. We measured multiple magnetic resonance imaging biomarkers of tissue integrity in normal-appearing white matter and white matter hyperintensities in patients with mild stroke, to improve understanding of white matter hyperintensities origins. We classified white matter into white matter hyperintensities and normal-appearing white matter and measured fractional anisotropy, mean diffusivity, water content (T1 relaxation time) and blood-brain barrier leakage (signal enhancement slope from dynamic contrast-enhanced magnetic resonance imaging). We studied the effects of age, white matter hyperintensities burden (Fazekas score) and vascular risk factors on each biomarker, in normal-appearing white matter and white matter hyperintensities, and performed receiver-operator characteristic curve analysis. Amongst 204 patients (34.3-90.9 years), all biomarkers differed between normal appearing white matter and white matter hyperintensities ( P < 0.001). In normal appearing white matter and white matter hyperintensities, mean diffusivity and T1 increased with age ( P < 0.001), all biomarkers varied with white matter hyperintensities burden ( P < 0.001; P = 0.02 signal enhancement slope), but only signal enhancement slope increased with hypertension ( P = 0.028). Fractional anisotropy showed complex age-white matter hyperintensities-tissue interactions; enhancement slope showed white matter hyperintensities-tissue interactions. Mean diffusivity distinguished white matter hyperintensities from normal-appearing white matter best at all ages. Blood-brain barrier leakage increases with hypertension and white matter hyperintensities burden at all ages in normal appearing white matter and white matter hyperintensities, whereas water mobility and content increase as tissue damage accrues, suggesting that blood-brain barrier leakage mediates small vessel disease-related brain damage. PMID- 26933137 TI - Mast Cells Contribute to Porphyromonas gingivalis-induced Bone Loss. AB - Periodontitis is a chronic inflammatory and bone-destructive disease. Development of periodontitis is associated with dysbiosis of the microbial community, which may be caused by periodontal bacteria, such as Porphyromonas gingivalis Mast cells are sentinels at mucosal surfaces and are a potent source of inflammatory mediators, including tumor necrosis factors (TNF), although their role in the pathogenesis of periodontitis remains to be elucidated. This study sought to determine the contribution of mast cells to local bone destruction following oral infection with P. gingivalis Mast cell-deficient mice (Kit(W-sh/W-sh)) were protected from P. gingivalis-induced alveolar bone loss, with a reduction in anti P. gingivalis serum antibody titers compared with wild-type infected controls. Furthermore, mast cell-deficient mice had reduced expression of Tnf, Il6, and Il1b mRNA in gingival tissues compared with wild-type mice. Mast cell-engrafted Kit(W-sh/W-sh) mice infected with P. gingivalis demonstrated alveolar bone loss and serum anti-P. gingivalis antibody titers equivalent to wild-type infected mice. The expression of Tnf mRNA in gingival tissues of Kit(W-sh/W-sh) mice was elevated following the engraftment of mast cells, indicating that mast cells contributed to the Tnf transcript in gingival tissues. In vitro, mast cells degranulated and released significant TNF in response to oral bacteria, and neutralizing TNF in vivo abrogated alveolar bone loss following P. gingivalis infection. These data indicate that mast cells and TNF contribute to the immunopathogenesis of periodontitis and may offer therapeutic targets. PMID- 26933138 TI - Interleukin-17 Impairs Salivary Tight Junction Integrity in Sjogren's Syndrome. AB - Sjogren's syndrome (SS) is an inflammatory autoimmune disease that causes secretory dysfunction of the salivary glands. It has been reported that proinflammatory cytokine interleukin-17 (IL-17) was elevated and tight junction (TJ) integrity disrupted in minor salivary glands from SS patients. However, whether the elevated IL-17 in SS affects TJ integrity and thereby alters the function of salivary gland is unknown. Here, by using nonobese diabetic (NOD) mice as SS model, we found that the stimulated salivary flow rate was significantly decreased in NOD mice. Lymphocyte infiltration was mainly observed in submandibular glands (SMGs), but not parotid glands (PGs), of NOD mice. IL-17 was significantly increased and mainly located in lymphocytic-infiltrating regions in SMGs but not detectable in PGs of NOD mice. Meanwhile, the epithelial barrier function was disrupted, as evidenced by an increased paracellular tracer clearance and an enlarged acinar TJ width in SMGs of NOD mice. Furthermore, claudin-1 and -3 were elevated especially at the basolateral membranes, whereas claudin-4, occludin, and zonula occludens-1 (ZO-1) were reduced in SMGs of NOD mice. Moreover, occludin and ZO-1 were dispersed into cytoplasm in SMGs of NOD mice. However, no change in the expression and distribution of TJ proteins was found in PGs. In vitro, IL-17 significantly decreased the levels and apical staining of claudin-4 and ZO-1 proteins in the cultured SMG tissues, as well as claudin-1, occludin, and ZO-1 in PG tissues. Moreover, IL-17 activated the phosphorylation of IkappaBalpha and p65 in SMG cells, whereas pretreatment with NF-kappaB inhibitor pyrrolidine dithiocarbamate suppressed the IL-17-induced downregulation of claudin-4 and ZO-1 in SMG tissues. Taken together, these findings indicate that IL-17 derived from infiltrating lymphocyte impairs the integrity of TJ barrier through NF-kappaB signaling pathway, and thus might contribute to salivary gland dysfunction in SS. PMID- 26933139 TI - A Primer on Observational Measurement. AB - Observational measurement plays an integral role in a variety of scientific endeavors within biology, psychology, sociology, education, medicine, and marketing. The current article provides an interdisciplinary primer on observational measurement; in particular, it highlights recent advances in observational methodology and the challenges that accompany such growth. First, we detail the various types of instrument that can be used to standardize measurements across observers. Second, we argue for the importance of validity in observational measurement and provide several approaches to validation based on contemporary validity theory. Third, we outline the challenges currently faced by observational researchers pertaining to measurement drift, observer reactivity, reliability analysis, and time/expense. Fourth, we describe recent advances in computer-assisted measurement, fully automated measurement, and statistical data analysis. Finally, we identify several key directions for future observational research to explore. PMID- 26933141 TI - The Reliability of Clock Drawing Test Scoring Systems Modeled on the Normative Data in Healthy Aging and Nonamnestic Mild Cognitive Impairment. AB - The Clock Drawing Test (CDT) is a commonly used tool in clinical practice and research for cognitive screening among older adults. The main goal of the present study was to analyze the interrater reliability of three different CDT scoring systems (by Shulman et al., Babins et al., and Cohen et al.). We used a clock with a predrawn circle. The CDT was evaluated by three independent raters based on the normative data set of healthy older and very old adults and patients with nonamnestic mild cognitive impairment (naMCI; N = 438; aged 61-94). We confirmed a high interrater reliability measured by the intraclass correlation coefficients (ICCs): Shulman ICC = .809, Babins ICC = .894, and Cohen ICC = .862, all p < .001. We found that age and education levels have a significant effect on CDT performance, yet there was no influence of gender. Finally, the scoring systems differentiated between naMCI and age- and education-matched controls: Shulman's area under the receiver operating characteristic curve (AUC) = .84, Cohen AUC = .71, all p < .001; and a slightly lower discriminative ability was shown by Babins: AUC = .65, p = .012. PMID- 26933140 TI - Characterizing Information Processing With a Mobile Device: Measurement of Simple and Choice Reaction Time. AB - Information processing is typically evaluated using simple reaction time (SRT) and choice reaction time (CRT) paradigms in which a specific response is initiated following a given stimulus. The measurement of reaction time (RT) has evolved from monitoring the timing of mechanical switches to computerized paradigms. The proliferation of mobile devices with touch screens makes them a natural next technological approach to assess information processing. The aims of this study were to determine the validity and reliability of using of a mobile device (Apple iPad or iTouch) to accurately measure RT. Sixty healthy young adults completed SRT and CRT tasks using a traditional test platform and mobile platforms on two occasions. The SRT was similar across test modality: 300, 287, and 280 milliseconds (ms) for the traditional, iPad, and iTouch, respectively. The CRT was similar within mobile devices, though slightly faster on the traditional: 359, 408, and 384 ms for traditional, iPad, and iTouch, respectively. Intraclass correlation coefficients ranged from 0.79 to 0.85 for SRT and from 0.75 to 0.83 for CRT. The similarity and reliability of SRT across platforms and consistency of SRT and CRT across test conditions indicate that mobile devices provide the next generation of assessment platforms for information processing. PMID- 26933142 TI - 2015 SNMMI Highlights Lecture: General Nuclear Medicine. PMID- 26933146 TI - Defining conditions where long-term glucocorticoid treatment has an acceptably low level of harm to facilitate implementation of existing recommendations: viewpoints from an EULAR task force. AB - There is convincing evidence for the known and unambiguously accepted beneficial effects of glucocorticoids at low dosages. However, the implementation of existing recommendations and guidelines on the management of glucocorticoid therapy in rheumatic diseases is lagging behind. As a first step to improve implementation, we aimed at defining conditions under which long-term glucocorticoid therapy may have an acceptably low level of harm. A multidisciplinary European League Against Rheumatism task force group of experts including patients with rheumatic diseases was assembled. After a systematic literature search, breakout groups critically reviewed the evidence on the four most worrisome adverse effects of glucocorticoid therapy (osteoporosis, hyperglycaemia/diabetes mellitus, cardiovascular diseases and infections) and presented their results to the other group members following a structured questionnaire for final discussion and consensus finding. Robust evidence on the risk of harm of long-term glucocorticoid therapy was often lacking since relevant study results were often either missing, contradictory or carried a high risk of bias. The group agreed that the risk of harm is low for the majority of patients at long-term dosages of <=5 mg prednisone equivalent per day, whereas at dosages of >10 mg/day the risk of harm is elevated. At dosages between >5 and <=10 mg/day, patient-specific characteristics (protective and risk factors) determine the risk of harm. The level of harm of glucocorticoids depends on both dose and patient-specific parameters. General and glucocorticoid-associated risk factors and protective factors such as a healthy lifestyle should be taken into account when evaluating the actual and future risk. PMID- 26933147 TI - The Effects of Body Composition, Dietary Intake, and Physical Activity on Calcaneus Quantitative Ultrasound in Spanish Young Adults. AB - Identifying modifiable factors that influence bone gain during early adulthood in order to maximize peak bone mass (PBM) is a potential primary strategy in the prevention of osteoporosis in later life. The present study examined the relationships between body composition, dietary intake and physical activity (PA), and bone health measured by quantitative ultrasound (QUS) at the right calcaneus. The study population consisted of 781 Spanish men and women (age 19.1 +/- 3.6). Body composition, dietary intake, PA, and bone strength were assessed. Calcaneus QUS was significantly correlated with age, height, weight, body mass index, lean mass, fat mass, protein intake, and moderate and high PA. No significant correlation between calcium intake and broadband ultrasound attenuation (BUA, dB/MHz) was detected. Linear regression analyses revealed that independent variables accounted for 18.8% of the total variance of calcaneus BUA (p = .000). Lean mass and high PA were significant predictors of BUA variance in young adults (p = .000 and p = .045, respectively). Results indicate that lifestyle choices and their consequences during early adulthood could influence bone mass, particularly PA and lean mass. Furthermore, this study provides novel data about bone mass as indicated by the QUS measurements at the time of PBM acquisition. PMID- 26933148 TI - Comparison of Methods for Determining Aerobic Exercise Intensity Using Heart Rate in Acute Leukemia Patients Prior to Induction Chemotherapy. AB - INTRODUCTION: Cardiopulmonary exercise testing (CPET), the gold standard of cardiopulmonary evaluation, is used to determine VO2 levels at different aerobic exercise training intensities; however, it may not be feasible to conduct CPET in all clinical settings. AIMS: To compare the heart rate reserve (HRR) and percent of 220-age methods for prescribing cycle ergometry exercise intensity using heart rate (HR) against the HRs obtained during a CPET in adults undergoing treatment for acute leukemia (AL). METHODS: In this exploratory study, part of a larger randomized controlled trial, 14 adults with AL completed CPET on a cycle ergometer with indirect calorimetry within 96 hr of admission to a cancer hospital to determine VO2peak and HR corresponding to low (40% VO2peak), moderate (60% VO2peak), and high (75% VO2peak) exercise intensities. Analyses of variance were used to compare estimated HR for each intensity level using the HRR and percent of 220-age methods with HR determined via VO2peak. RESULTS: HR corresponding to low-intensity exercise differed significantly across all three methods (p <= .05). No significant differences were observed between HR estimated via the percent of 220-age method and determined via VO2peak at moderate (100 +/- 8 and 113 +/- 24 bpm, p = .122) or high intensities (125 +/- 10 and 123 +/- 25 bpm, p = .994). CONCLUSION: In adults with AL, HR-based methods for defining aerobic exercise intensities should be used with caution. At low intensity, neither should be used, while at moderate and high intensities, the percent of 220-age equation might serve as an adequate substitute for CPET. PMID- 26933149 TI - Insight into infrageneric circumscription through complete chloroplast genome sequences of two Trillium species. AB - Genomic events including gene loss, duplication, pseudogenization and rearrangement in plant genomes are valuable sources for exploring and understanding the process of evolution in angiosperms. The family Melanthiaceae is distributed in temperate regions of the Northern Hemisphere and divided into five tribes (Heloniadeae, Chionographideae, Xerophylleae, Melanthieae and Parideae) based on the molecular phylogenetic analyses. At present, complete chloroplast genomes of the Melanthiaceae have been reported from three species. In the previous genomic study of Liliales, atrnI-CAU gene duplication event was reported fromParis verticillata, a member of Parideae. To clarify the significant genomic events of the tribe Parideae, we analysed the complete chloroplast genome sequences of twoTrilliumspecies representing two subgenera:TrilliumandPhyllantherum InTrillium tschonoskii(subgenusTrillium), the circular double-stranded cpDNA sequence of 156 852 bp consists of two inverted repeat (IR) regions of 26 501 bp each, a large single-copy (LSC) region of 83 981 bp and a small single-copy (SSC) region of 19 869 bp. The chloroplast genome sequence ofT. maculatum(subgenusPhyllantherum) is 157 359 bp in length, consisting of two IRs (25 535 bp), one SSC (19 949 bp) and one LSC (86 340 bp), and is longer than that ofT. tschonoskii The results showed that the cpDNAs of Parideae are highly conserved across genome structure, gene order and contents. However, the chloroplast genome ofT. maculatumcontained a 3.4-kb inverted sequence betweenndhCandrbcLin the LSC region, and it was a unique feature for subgeneraPhyllantherum In addition, we found three different types of gene duplication in the intergenic spacer betweenrpl23andycf2containingtrnI-CAU, which were in agreement with the circumscription of subgenera and sections in Parideae excludingT. govanianum These genomic features provide informative molecular markers for identifying the infrageneric taxa ofTrilliumand improve our understanding of the evolution patterns of Parideae in Melanthiaceae. PMID- 26933150 TI - How to make a red flower: the combinatorial effect of pigments. AB - Red flowers have evolved repeatedly across angiosperms and are frequently examined in an ecological context. However, less is known about the biochemical basis of red colouration in different taxa. In this study, we examine the spectral properties, anthocyanin composition and carotenoid expression of red flowers in the tomato family, Solanaceae, which have evolved independently multiple times across the group. Our study demonstrates that Solanaceae typically make red flowers either by the sole production of red anthocyanins or, more commonly, by the dual production of purple or blue anthocyanins and orange carotenoids. In using carotenoids to modify the effect of purple and/or blue anthocyanins, these Solanaceae species have converged on the same floral hue as those solely producing red anthocyanins, even when considering the visual system of pollinators. The use of blue anthocyanins in red flowers appears to differ from other groups, and suggests that the genetic changes underlying evolutionary shifts to red flowers may not be as predictable as previously suggested. PMID- 26933151 TI - New insights into environmental enteric dysfunction. AB - Environmental enteric dysfunction (EED) has been recognised as an important contributing factor to physical and cognitive stunting, poor response to oral vaccines, limited resilience to acute infections and ultimately global childhood mortality. The aetiology of EED remains poorly defined but the epidemiology suggests a multifactorial combination of prenatal and early-life undernutrition and repeated infectious and/or toxic environmental insults due to unsanitary and unhygienic environments. Previous attempts at medical interventions to ameliorate EED have been unsatisfying. However, a new generation of imaging and '-omics' technologies hold promise for developing a new understanding of the pathophysiology of EED. A series of trials designed to decrease EED and stunting are taking novel approaches, including improvements in sanitation, hygiene and nutritional interventions. Although many challenges remain in defeating EED, the global child health community must redouble their efforts to reduce EED in order to make substantive improvements in morbidity and mortality worldwide. PMID- 26933152 TI - Fortification of flour with folic acid is an overdue public health measure in the UK. PMID- 26933153 TI - Placebo caffeine reduces withdrawal in abstinent coffee drinkers. AB - BACKGROUND: Expectancies have been shown to play a role in the withdrawal syndrome of many drugs of addiction; however, no studies have examined the effects of expectancies across a broad range of caffeine withdrawal symptoms, including craving. AIMS: The purpose of the current study was to use caffeine as a model to test the effect of expectancy on withdrawal symptoms, specifically whether the belief that one has ingested caffeine is sufficient to reduce caffeine withdrawal symptoms and cravings in abstinent coffee drinkers. METHODS: We had 24-h abstinent regular coffee drinkers complete the Caffeine Withdrawal Symptom Questionnaire (CWSQ) before and after receiving decaffeinated coffee. One half of the participants were led to believe the coffee was regular caffeinated coffee (the 'Told Caffeine' condition) and one-half were told that it was decaffeinated (the 'Told Decaf' condition). RESULTS: Participants in the Told Caffeine condition reported a significantly greater reduction in the factors of cravings, fatigue, lack of alertness and flu-like feelings of the CWSQ, than those in the Told Decaf condition. CONCLUSIONS: Our results indicated that the belief that one has consumed caffeine can affect caffeine withdrawal symptoms, especially cravings, even when no caffeine was consumed. PMID- 26933154 TI - Evidence-based care for people with opioid use disorder: a clinician's international perspective. PMID- 26933155 TI - Personalised cancer care: promises and challenges of targeted therapy. PMID- 26933156 TI - Increasing the impact of health services research on service improvement: the researcher-in-residence model. PMID- 26933157 TI - Quality of Quality Accounts: transparency of public reporting of Never Events in England. A semi-quantitative and qualitative review. AB - OBJECTIVES: To describe the quality of reporting and investigation into surgical Never Events in public reports. DESIGN: Semi-quantitative and qualitative review of published Quality Accounts for three years (2011/2-2013/14). Data on Never Events were compared with previously collated Never Events rates. Quality of reported investigations was assessed using the London Protocol. SETTING: English National Health Service. PARTICIPANTS: All English acute hospital trusts. MAIN OUTCOME MEASURES: Quality of Never Event reporting. RESULTS: Quality Accounts were available for all Trusts for all three years, of which 342 referred to years when a surgical Never Event had occurred. A total of 125 of 342 (37%) accounts failed to report any or all Never Events that had occurred; 13/342 (4%) provided full disclosure; 197 (58%) reported that some investigation had taken place. Of these 197, 61 (31%) were limited in scope; 61 (31%) were categorised as detailed reports. Task and Technology factors were the commonest factor (103/211 (49%)) Identified in investigations, followed by Individual factors (48/211 (23%)). Team and Work environment factors were identified in 29/211 (14%) and 23/211 (11%), respectively. Organisational and Management 5/211 (2%) factors were rarely identified, and the Institutional context was never discussed. CONCLUSIONS: Reporting of Never Events and their investigations by English NHS Trusts in their Quality Accounts is neither consistently transparent nor adequate. As with clinical error, the true root causes are likely to be organisational rather than individual. PMID- 26933158 TI - Retraction. PMID- 26933159 TI - Multiple Chronic Condition Combinations and Depression in Community-Dwelling Older Adults. AB - BACKGROUND: The U.S. Department of Health and Human Services recently called for a paradigm shift from the study of individual chronic conditions to multiple chronic conditions (MCCs). We identify the most common combinations of chronic diseases experienced by a sample of community-dwelling older people and assess whether depression is differentially associated with combinations of illnesses. METHODS: Self-reports of diagnosed chronic conditions and depressive symptoms were provided by 5,688 people participating in the ORANJ BOWL(SM) research panel. Each respondent was categorized as belonging to one of 32 groups. ANOVA examined the association between depressive symptoms and combinations of illnesses. RESULTS: People with more health conditions experienced higher levels of depression than people with fewer health conditions. People with some illness combinations had higher levels of depressive symptoms than people with other illness combinations. CONCLUSIONS: Findings confirm extensive variability in the combinations of illnesses experienced by older adults and demonstrate the complex associations of specific illness combinations with depressive symptoms. Results highlight the need to expand our conceptualization of research and treatment around MCCs and call for a person-centered approach that addresses the unique needs of individuals with MCCs. PMID- 26933160 TI - Glucose Levels and Risk of Frailty. AB - BACKGROUND: The association between glucose levels and incident frailty in older persons remains unclear. We examined the extent to which higher glucose levels in older adults with and without diabetes are related to risk of frailty. METHODS: The data are from the Adult Changes in Thought study. We identified 1,848 individuals aged 65+ without dementia for whom glucose levels from laboratory measurements of glucose and glycated hemoglobin were available. Physical frailty using modified Fried's criteria was determined from biennial assessments. Frailty hazard was modeled as a function of time-varying measures of diabetes and average glucose levels using Cox regression. RESULTS: A total of 578 incident frailty cases (94 with diabetes, 484 without) occurred during a median follow-up of 4.8 years. The adjusted hazard ratio for frailty comparing those with and without diabetes was 1.52 (95% confidence interval = 1.19-1.94). In participants without diabetes, modeling suggested elevated frailty risk with greater average glucose levels (p = .019); for example, a glucose level of 110mg/dL compared with 100mg/dL yielded a hazard ratio of 1.32 (95% confidence interval = 1.09-1.59). In participants with diabetes, glucose levels less than 160mg/dL and greater than 180mg/dL were related to increased risk of frailty (p = .001). CONCLUSION: Higher glucose levels may be a risk factor for frailty in older adults without diabetes. The apparent U-shape association between glucose levels and frailty in people with diabetes is consistent with the literature on glycemia and mortality and deserves further examination. PMID- 26933161 TI - Melatonin Secretion and Muscle Strength in Elderly Individuals: A Cross-Sectional Study of the HEIJO-KYO Cohort. AB - BACKGROUND: Decreased muscle strength is associated with functional limitation and disability and is a predictor of cardiovascular and all-cause mortality. Recently, oxidative stress and inflammation have been shown to contribute to the loss of muscle strength, and although melatonin has antioxidative and anti inflammatory properties, the association between melatonin secretion and muscle strength remains unclear. METHODS: In this cross-sectional study of 760 community based elderly individuals (mean age, 71.0 years), we measured overnight urinary 6 sulfatoxymelatonin excretion (UME) and grip strength and quadriceps strength. RESULTS: Median UME was 7.0 MUg (interquartile range, 4.2-11.1), and mean grip and quadriceps strength were 27.5+/-8.4kg and 162.6+/-80.1 Nm, respectively. On dividing participants into quartiles by their UME level (lowest-highest UME, Q1 Q4), higher quartiles were significantly associated with increased grip strength and quadriceps strength (p for trend < .001, both). Multivariable analyses adjusted for potential confounders (age, gender, body mass index, smoking and drinking statuses, renal function, hypertension, diabetes, physical activity, depressed mood, cognitive impairment, bedtime, sleep duration, and day length) revealed that both grip and quadriceps strength were significantly increased in Q4 compared with that in Q1 (adjusted mean difference, Q4 - Q1: grip strength, 1.5kg; 95% confidence interval [CI], 0.4-2.6kg; p = .006; quadriceps strength, 14.2 Nm; 95% CI, 1.3-27.1 Nm; p = .031). CONCLUSIONS: Melatonin secretion was significantly associated with muscle strength in this elderly population. Further longitudinal studies are needed to ascertain the effect of melatonin levels on muscle strength. PMID- 26933162 TI - Prospective Study of Trajectories of Physical Performance and Mortality Among Community-Dwelling Older Japanese. AB - OBJECTIVE: Physical performance measures (PPMs) are good predictors of adverse health outcomes in later life. This prospective study used repeated measures analysis to examine sex-specific age trends in PPMs, identify potential PPM trajectory patterns, and determine whether PPM trajectory patterns were associated with all-cause mortality among older Japanese. METHODS: Among 1,524 adults aged 65 years or older who participated in a baseline survey, 1,048 adults (mean [SD] age, 71.6 [5.4] years; women, 57.0%) were followed up at least once. The total number of observations was 4,747, and the average number of follow-up assessments was 4.5 during the period from 2002 through 2011. The PPMs studied were handgrip strength, usual gait speed, and one-leg standing time. We checked local registries to identify deaths from any cause; 89 (8.5%) participants died during follow-up. RESULTS: All PPMs significantly decreased with advancing age, and handgrip strength and usual gait speed showed sex-specific age trends. We identified three distinct trajectory patterns (high, middle, and low trajectory groups) for each PPM in adults aged 65-90 years, and the trajectories for handgrip strength and usual gait speed showed parallel declines in men and women, respectively. After adjusting for important confounders, the trajectory groups for handgrip strength and one-leg standing time were independent predictors of all-cause mortality. CONCLUSIONS: Regardless of baseline level, the PPMs tended to show similar age-related changes in later life. However, individuals in low PPM trajectory groups had a higher mortality risk, which highlights the importance of interventions that maintain or improve physical performance, even among older adults with low physical performance. PMID- 26933164 TI - Commentary on Eagle and Foley: "Cytotoxicity in Human Cell Cultures". PMID- 26933165 TI - Commentary on Sandberg et al., "The In Vivo Chromosome Constitution of Marrow". PMID- 26933166 TI - Correction: Multiplex H. pylori Serology and Risk of Gastric Cardia and Noncardia Adenocarcinomas. PMID- 26933169 TI - Fulfilling Koch's postulates in glycoscience: HCELL, GPS and translational glycobiology. AB - Glycoscience-based research that is performed expressly to address medical necessity and improve patient outcomes is called "translational glycobiology". In the 19th century, Robert Koch proposed a set of postulates to rigorously establish causality in microbial pathogenesis, and these postulates can be reshaped to guide knowledge into how naturally-expressed glycoconjugates direct molecular processes critical to human well-being. Studies in the 1990s indicated that E-selectin, an endothelial lectin that binds sialofucosylated carbohydrate determinants, is constitutively expressed on marrow microvessels, and investigations in my laboratory indicated that human hematopoietic stem cells (HSCs) uniquely express high levels of a specialized glycoform of CD44 called "hematopoietic cell E-/L-selectin ligand" (HCELL) that functions as a highly potent E-selectin ligand. To assess the role of HCELL in directing HSC migration to marrow, a method called "glycosyltransferase-programmed stereosubstitution" (GPS) was developed to custom-modify CD44 glycans to enforce HCELL expression on viable cell surfaces. Human mesenchymal stem cells (MSCs) are devoid of E selectin ligands, but GPS-based glycoengineering of CD44 on MSCs licenses homing of these cells to marrow in vivo, providing direct evidence that HCELL serves as a "bone marrow homing receptor". This review will discuss the molecular basis of cell migration in historical context, will describe the discovery of HCELL and its function as the bone marrow homing receptor, and will inform on how glycoengineering of CD44 serves as a model for adapting Koch's postulates to elucidate the key roles that glycoconjugates play in human biology and for realizing the immense impact of translational glycobiology in clinical medicine. PMID- 26933170 TI - Grainyhead-like 2 regulates epithelial plasticity and stemness in oral cancer cells. AB - Grainyhead-like 2 (GRHL2) is one of the three mammalian homologues of Drosophila Grainyhead involved in epithelial morphogenesis. We recently showed that GRHL2 also controls normal epithelial cell proliferation and differentiation. In this study, we investigated the role of GRHL2 in oral carcinogenesis and the underlying mechanism. GRHL2 expression was elevated in cells and tissues of oral squamous cell carcinomas (OSCCs) compared with normal counterparts. Knockdown of GRHL2 resulted in the loss of in vivo tumorigenicity, cancer stemness and epithelial phenotype of oral cancer cells. GRHL2 loss also inhibited oral cancer cell proliferation and colony formation. GRHL2 regulated the expression of miR 200 family and Octamer-binding transcription factor 4 (Oct-4) genes through direct promoter DNA binding. Overexpression of miR-200 genes in the oral cancer cells depleted of GRHL2 partially restored the epithelial phenotype, proliferative rate and cancer stemness, indicating that miR-200 genes in part mediate the functional effects of GRHL2. Taken together, this study demonstrates a novel connection between GRHL2 and miR-200, and supports protumorigenic effect of GRHL2 on OSCCs. PMID- 26933172 TI - Lack of consensus for usage of beta-blockers in end-stage liver disease. PMID- 26933171 TI - Notch1 and Notch2 receptors regulate mouse and human gastric antral epithelial cell homoeostasis. AB - OBJECTIVE: We tested the ability of Notch pathway receptors Notch1 and Notch2 to regulate stem and epithelial cell homoeostasis in mouse and human gastric antral tissue. DESIGN: Mice were treated with the pan-Notch inhibitor dibenzazepine (DBZ) or inhibitory antibodies targeting Notch1 and/or Notch2. Epithelial proliferation, apoptosis and cellular differentiation were measured by histological and molecular approaches. Organoids were established from mouse and human antral glands; growth and differentiation were measured after treatment with Notch inhibitors. RESULTS: Notch1 and Notch2 are the predominant Notch receptors expressed in mouse and human antral tissue and organoid cultures. Combined inhibition of Notch1 and Notch2 in adult mice led to decreased epithelial cell proliferation, including reduced proliferation of LGR5 stem cells, and increased apoptosis, similar to the response to global Notch inhibition with DBZ. Less pronounced effects were observed after inhibition of individual receptors. Notch pathway inhibition with DBZ or combined inhibition of Notch1 and Notch2 led to increased differentiation of all gastric antral lineages, with remodelling of cells to express secretory products normally associated with other regions of the GI tract, including intestine. Analysis of mouse and human organoids showed that Notch signalling through Notch1 and Notch2 is intrinsic to the epithelium and required for organoid growth. CONCLUSIONS: Notch signalling is required to maintain gastric antral stem cells. Notch1 and Notch2 are the primary Notch receptors regulating epithelial cell homoeostasis in mouse and human stomach. PMID- 26933174 TI - New Strategies in Myeloproliferative Neoplasms: The Evolving Genetic and Therapeutic Landscape. AB - The classical BCR-ABL1-negative myeloproliferative neoplasms (MPN) include essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF). Although these clonal disorders share certain clinical and genetic features, MF in particular is distinct for its complex mutational landscape, severe disease phenotype, and poor prognosis. The genetic complexity inherent to MF has made this disease extremely challenging to treat. Pharmacologic JAK inhibition has proven to be a transformative therapy in MPNs, alleviating symptom burden and improving survival, but has been hampered by off-target toxicities and, as monotherapy, has shown limited effects on mutant allele burden. In this review, we discuss the genetic heterogeneity contributing to the pathogenesis of MPNs, focusing on novel driver and epigenetic mutations and how they relate to combination therapeutic strategies. We discuss results from ongoing studies of new JAK inhibitors and report on new drugs and drug combinations that have demonstrated success in early preclinical and clinical trials, including type II JAK inhibitors, antifibrotic agents, and telomerase inhibitors. PMID- 26933176 TI - PRAME as an Independent Biomarker for Metastasis in Uveal Melanoma. AB - PURPOSE: Uveal melanoma (UM) can be classified by gene expression profiling (GEP) into Class 1 (low metastatic risk) and Class 2 (high metastatic risk), the latter being strongly associated with mutational inactivation of the tumor suppressor BAP1. Nevertheless, a small percentage of Class 1 tumors give rise to metastatic disease. The purpose of this study was to identify biomarkers of metastasis in Class 1 tumors. EXPERIMENTAL DESIGN: A total of 389 consecutive patients with UM were assigned to Class 1 or Class 2 using a prospectively validated 12-gene prognostic classifier. Selected tumors were further analyzed using global GEP and single nucleotide polymorphism microarrays. PRAME (preferentially expressed antigen in melanoma) mRNA expression was analyzed in 64 Class 1 tumors by qPCR. RESULTS: Among Class 1 UMs, the most significant predictor of metastasis was PRAME mRNA expression (P = 0.0006). The 5-year actuarial rate of metastasis was 0% for Class1(PRAME-), 38% for Class1(PRAME+), and 71% for Class 2 tumors. Median metastasis-free survival for Class1(PRAME+) patients was 88 months, compared to 32 months for Class 2 patients. Findings were validated using three independent datasets, including one using disomy 3 to identify low-risk UM. Chromosome copy number changes associated with Class1(PRAME+) tumors included gain of 1q, 6p, 8q, and 9q and loss of 6q and 11q. PRAME expression was associated with larger tumor diameter (P = 0.05) and SF3B1 mutations (P = 0.003). CONCLUSIONS: PRAME is an independent prognostic biomarker in UM, which identifies increased metastatic risk in patients with Class 1 or disomy 3 tumors. This finding may further enhance the accuracy of prognostic testing and precision medicine for UM. PMID- 26933177 TI - VEGF and VTE Risk in Cancer Patients--Letter. PMID- 26933175 TI - PD-1 Blockade Boosts Radiofrequency Ablation-Elicited Adaptive Immune Responses against Tumor. AB - PURPOSE: Radiofrequency ablation (RFA) has been shown to elicit tumor-specific T cell immune responses, but is not sufficient to prevent cancer progression. Here, we investigated immune-suppressive mechanisms limiting the efficacy of RFA. EXPERIMENTAL DESIGN: We performed a retrospective case-controlled study on patients with synchronous colorectal cancer liver metastases who had received primary tumor resection with or without preoperative RFA for liver metastases. Tumor-infiltrating T cells and tumoral PD-L1 expression in human colorectal cancer tissues were analyzed by immunohistochemistry. T-cell immune responses and PD-1/PD-L1 expression were also characterized in an RFA mouse model. In addition, the combined effect of RAF and PD-1 blockade was evaluated in the mouse RFA model. RESULTS: We found that RFA treatment of liver metastases increased not only T-cell infiltration, but also PD-L1 expression in primary human colorectal tumors. Using mouse tumor models, we demonstrated that RFA treatment of one tumor initially enhanced a strong T-cell-mediated immune response in tumor. Nevertheless, tumor quickly overcame the immune responses by inhibiting the function of CD8(+) and CD4(+) T cells, driving a shift to higher regulatory T cell to Teff ratio, and upregulating PD-L1/PD-1 expression. Furthermore, we established that the combined therapy of RFA and anti-PD-1 antibodies significantly enhanced T-cell immune responses, resulting in stronger antitumor immunity and prolonged survival. CONCLUSIONS: The PD-L1-PD-1 axis plays a critical role in dampening RFA-induced antitumor immune responses, and this study provides a strong rationale for combining RFA and the PD-L1/PD-1 blockade in the clinical setting. PMID- 26933179 TI - Correction: p73 Expression Is Associated with the Cellular Radiosensitivity in Cervical Cancer after Radiotherapy. PMID- 26933178 TI - Correction: Differential Functions of Growth Factor Receptor-Bound Protein 7 (GRB7) and Its Variant GRB7v in Ovarian Carcinogenesis. PMID- 26933182 TI - Correction. PMID- 26933180 TI - Rlm1 mediates positive autoregulatory transcriptional feedback that is essential for Slt2-dependent gene expression. AB - Activation of the yeast cell wall integrity (CWI) pathway induces an adaptive transcriptional programme that is largely dependent on the transcription factor Rlm1 and the mitogen-activated protein kinase (MAPK) Slt2. Upon cell wall stress, the transcription factor Rlm1 is recruited to the promoters of RLM1 and SLT2, and exerts positive-feedback mechanisms on the expression of both genes. Activation of the MAPK Slt2 by cell wall stress is not impaired in strains with individual blockade of any of the two feedback pathways. Abrogation of the autoregulatory feedback mechanism on RLM1 severely affects the transcriptional response elicited by activation of the CWI pathway. In contrast, a positive trans-acting feedback mechanism exerted by Rlm1 on SLT2 also regulates CWI output responses but to a lesser extent. Therefore, a complete CWI transcriptional response requires not only phosphorylation of Rlm1 by Slt2 but also concurrent SLT2- and RLM1-mediated positive-feedback mechanisms; sustained patterns of gene expression are mainly achieved by positive autoregulatory circuits based on the transcriptional activation of Rlm1. PMID- 26933181 TI - Docking-complex-independent alignment of Chlamydomonas outer dynein arms with 24 nm periodicity in vitro. AB - The docking complex is a molecular complex necessary for assembly of outer dynein arms (ODAs) on the axonemal doublet microtubules (DMTs) in cilia and flagella. The docking complex is hypothesized to be a 24-nm molecular ruler because ODAs align along the DMTs with 24-nm periodicity. In this study, we rigorously tested this hypothesis using structural and genetic methods. We found that the ODAs can bind to DMTs and porcine microtubules with 24-nm periodicities even in the absence of the docking complexin vitro Using cryo-electron tomography and structural labeling, we observed that the docking complex took an unexpectedly flexible conformation and did not lie along the length of DMTs. In the absence of docking complex, ODAs were released from the DMT at relatively low ionic strength conditions, suggesting that the docking complex strengthens the electrostatic interactions between the ODA and DMT. Based on these results, we conclude that the docking complex serves as a flexible stabilizer of the ODA rather than as a molecular ruler. PMID- 26933183 TI - Hepatic abscess caused by Fusobacterium necrophorum after a trip to the dentist. AB - A 57-year-old man with no significant medical history was admitted to the hospital, with high-grade fever and right upper quadrant pain. He was found, on abdominal ultrasound, to have a right lobe hepatic cystic lesion. MRI of the abdomen confirmed a hepatic abscess. Cultures obtained under CT guidance showed the abscess to be caused by Fusobacterium necrophorum. This is a rare bacterium that can cause potentially fatal liver abscesses. Following drainage and intravenous antibiotic treatment, the patient improved and was discharged on a 4 week antibiotic course. An abdominal CT, performed 6 weeks after discharge, showed total resolution of the abscess. The patient had, 2 weeks prior to the development of the liver abscess, undergone routine dental cleaning. Neither upper respiratory symptoms nor sore throat had been identified prior to the presentation. PMID- 26933184 TI - Lethal acute liver failure in a patient treated with sunitinib. AB - Sunitinib is a tyrosine kinase inhibitor that is used as an anticancer drug in renal cell carcinoma (RCC), pancreatic neuroendocrine tumours (PNETs) and gastrointestinal stromal tumour. Elevated liver enzymes are frequently observed during treatment but acute liver failure is uncommon. We describe a case of fulminant acute liver failure and acute kidney injury during treatment with sunitinib for metastatic RCC. PMID- 26933185 TI - A young male runner with a posterior knee mass--not just your typical Baker's cyst. AB - We present the case of a 28-year-old man with a growing mass in his right popliteal fossa causing pain on exertion. The differential diagnosis included Baker's cyst, entrapment syndrome of the popliteal artery, as well as a benign or malignant neoplasm. An ultrasound was non-specific. Follow-up MRI of the knee demonstrated cystic adventitial disease (CAD). With only about 500 cases reported in the literature since its discovery in 1947, CAD is a rare entity. The disease is characterised by mucinous or gelatinous cysts in the arterial or venous adventitia. The disease is predominantly seen in the popliteal artery and typically affects otherwise healthy males in the fourth to fifth decade of life. It presents clinically as intermittent exertional claudication. Examination of our case and a review of the literature will highlight the importance of considering CAD in patients who report of a popliteal mass and intermittent claudication. PMID- 26933186 TI - A rare benign ovarian tumour. AB - Sclerosing stromal tumour (SST) of the ovary is an extremely rare and benign ovarian neoplasm, accounting for 6% of the sex cord stromal ovarian tumours subtype. Usually, it is found during the second and third decades of life. Patients commonly present with pelvic pain, a palpable pelvic mass or menstrual irregularity. We report a case of a 20-year-old woman reporting of mild pelvic pain, with normal laboratory data. On imaging examinations, a large right adnexal tumour was found, with features suggesting an ovarian sex cord tumour. The patient underwent right salpingo-oophorectomy, diagnosing a SST of the ovary. This paper also reviews the literature, and emphasises the typical pathological and imaging characteristics of these rare benign ovarian lesions, and their impact, in a conservative surgery. PMID- 26933187 TI - Orbital granuloma: a rare manifestation of extrapulmonary tuberculosis. PMID- 26933188 TI - Association of Plasminuria with Overhydration in Patients with CKD. AB - BACKGROUND AND OBJECTIVES: Hypervolemia is a common feature of patients with CKD and associated with hypertension. Recent work has shown stimulation of sodium retention by urinary plasmin during nephrotic syndrome. However, it is unclear whether plasminuria plays a role in patients with stable CKD and non-nephrotic proteinuria. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In this cross sectional study, we analyzed the fluid status of 171 patients with CKD consecutively presenting to our outpatient clinic from 2012 to 2013 using bioimpedance spectroscopy (Body Composition Monitor [BCM]; Fresenius Medical Care, Germany) and its associations to the urinary excretion of plasminogen and plasmin from a spot urine sample. Two-electrode voltage clamp measurements were performed in Xenopus laevis oocytes expressing human epithelial sodium channel to investigate whether plasmin in concentrations found in urine can activate the channel. RESULTS: Overhydration >5% and overhydration >10% of the extracellular volume were found in 29% and 17% of the patients, respectively, and overhydration was associated with edema, hypertension, higher stages of CKD, and proteinuria. Proteinuria was the strongest independent predictor for overhydration (+0.58 L/1.73 m(2) per 10-fold increase; P<0.001). Urinary excretion of plasmin(ogen) quantified by ELISA correlated strongly with proteinuria (r=0.87) and overhydration (r=0.47). Using a chromogenic substrate, active plasmin was found in 44% of patients and correlated with proteinuria and overhydration. Estimated urinary plasmin concentrations were in a range sufficient to activate epithelial sodium channel currents in vitro. In multivariable analysis, urinary excretion of plasmin(ogen) was associated with overhydration similar to proteinuria. CONCLUSIONS: Hypervolemia in patients with CKD is strongly associated with proteinuria, even in the non-nephrotic range. Protein-rich urine contains high amounts of plasminogen and active plasmin, rendering plasminuria as a possible link between proteinuria and hypervolemia. PMID- 26933189 TI - Height at First RRT and Mortality in Children. AB - BACKGROUND AND OBJECTIVES: Poor linear growth is common in children with CKD and has been associated with higher mortality. However, recent data in adult dialysis patients have suggested a higher risk of death in persons of tall stature. In this study, we aimed to examine the risk of all-cause and cause-specific mortality in children at both extremes of height at the time of first RRT. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Using the US Renal Data System, we performed a retrospective analysis of 13,218 children aged 2-19 years, who received their first RRT (dialysis or transplant) during 1995-2011. We used adjusted Cox models to examine the association between short (<3rd percentile) and tall (>3rd percentile) stature and risk of death, compared with less extreme heights. RESULTS: Over a median follow-up of 7.1 years, there were 1721 deaths. Risk of death was higher in children with short (hazard ratio, 1.49; 95% confidence interval, 1.33 to 1.66) and tall stature (hazard ratio, 1.32; 95% confidence interval, 1.03 to 1.69) in adjusted analysis. In secondary analyses, there was a statistically significant interaction between height and body mass index categories (P=0.04), such that the association of tall stature with higher mortality was limited to children with elevated body mass index (defined as >=95th percentile for age and sex). Children with short stature had a higher risk of cardiac- and infection-related death, whereas children with tall stature had a higher risk of cancer-related death. CONCLUSIONS: Children with short and tall stature are at higher mortality risk, although this association was modified by body mass index at time of first RRT. Studies to further explore the reasons behind the higher risk of mortality in children with extremes of height at the time of first RRT are warranted. PMID- 26933190 TI - Realizing Microbial Evolution. AB - Genome sequences have become the new phenotype for microbial evolutionists. The patterns of diversity revealed in the first 100 bacterial genomes fostered development of a comprehensive framework that can explain their contents, organization, and evolution. PMID- 26933191 TI - Computational Modeling of Adult Neurogenesis. AB - The restriction of adult neurogenesis to only a handful of regions of the brain is suggestive of some shared requirement for this dramatic form of structural plasticity. However, a common driver across neurogenic regions has not yet been identified. Computational studies have been invaluable in providing insight into the functional role of new neurons; however, researchers have typically focused on specific scales ranging from abstract neural networks to specific neural systems, most commonly the dentate gyrus area of the hippocampus. These studies have yielded a number of diverse potential functions for new neurons, ranging from an impact on pattern separation to the incorporation of time into episodic memories to enabling the forgetting of old information. This review will summarize these past computational efforts and discuss whether these proposed theoretical functions can be unified into a common rationale for why neurogenesis is required in these unique neural circuits. PMID- 26933194 TI - Correction. PMID- 26933192 TI - An Inducible Retroviral Expression System for Tandem Affinity Purification Mass Spectrometry-Based Proteomics Identifies Mixed Lineage Kinase Domain-like Protein (MLKL) as an Heat Shock Protein 90 (HSP90) Client. AB - Tandem affinity purification-mass spectrometry (TAP-MS) is a popular strategy for the identification of protein-protein interactions, characterization of protein complexes, and entire networks. Its employment in cellular settings best fitting the relevant physiology is limited by convenient expression vector systems. We developed an easy-to-handle, inducible, dually selectable retroviral expression vector allowing dose- and time-dependent control of bait proteins bearing the efficient streptavidin-hemagglutinin (SH)-tag at their N- or C termini. Concomitant expression of a reporter fluorophore allows to monitor bait expressing cells by flow cytometry or microscopy and enables high-throughput phenotypic assays. We used the system to successfully characterize the interactome of the neuroblastoma RAS viral oncogene homolog (NRAS) Gly12Asp (G12D) mutant and exploited the advantage of reporter fluorophore expression by tracking cytokine-independent cell growth using flow cytometry. Moreover, we tested the feasibility of studying cytotoxicity-mediating proteins with the vector system on the cell death-inducing mixed lineage kinase domain-like protein (MLKL) Ser358Asp (S358D) mutant. Interaction proteomics analysis of MLKL Ser358Asp (S358D) identified heat shock protein 90 (HSP90) as a high-confidence interacting protein. Further phenotypic characterization established MLKL as a novel HSP90 client. In summary, this novel inducible expression system enables SH tag-based interaction studies in the cell line proficient for the respective phenotypic or signaling context and constitutes a valuable tool for experimental approaches requiring inducible or traceable protein expression. PMID- 26933195 TI - Knowing-how to care. AB - This paper advances a new moral epistemology and explores some of its normative and practical, especially bioethical, implications. In the first part, it shows that there is moral knowledge and that it is best understood in terms of knowing how. Thus, moral knowledge cannot be analysed purely in the traditional terms of knowing-that. The fundamental idea is that one knows-how to act morally only if she is capable of following the right normative standards. In the second part, the paper discusses ways of integrating two expressions of moral knowing-how, namely caring and respecting into a coherent normative theory. It builds up the concept of respectful care as the central ingredient of such a normative theory. Finally, it illustrates how respectful care may transform some of our current clinical bioethical practices. PMID- 26933196 TI - Correction. A Moorean argument for the full moral status of those with profound intellectual disability. PMID- 26933193 TI - Adjuvant-induced Human Monocyte Secretome Profiles Reveal Adjuvant- and Age specific Protein Signatures. AB - Adjuvants boost vaccine responses, enhancing protective immunity against infections that are most common among the very young. Many adjuvants activate innate immunity, some via Toll-Like Receptors (TLRs), whose activities varies with age. Accordingly, characterization of age-specific adjuvant-induced immune responses may inform rational adjuvant design targeting vulnerable populations. In this study, we employed proteomics to characterize the adjuvant-induced changes of secretomes from human newborn and adult monocytes in response to Alum, the most commonly used adjuvant in licensed vaccines; Monophosphoryl Lipid A (MPLA), a TLR4-activating adjuvant component of a licensed Human Papilloma Virus vaccine; and R848 an imidazoquinoline TLR7/8 agonist that is a candidate adjuvant for early life vaccines. Monocytes were incubated in vitro for 24 h with vehicle, Alum, MPLA, or R848 and supernatants collected for proteomic analysis employing liquid chromatography-mass spectrometry (LC-MS) (data available via ProteomeXchange, ID PXD003534). 1894 non-redundant proteins were identified, of which ~30 - 40% were common to all treatment conditions and ~5% were treatment specific. Adjuvant-stimulated secretome profiles, as identified by cluster analyses of over-represented proteins, varied with age and adjuvant type. Adjuvants, especially Alum, activated multiple innate immune pathways as assessed by functional enrichment analyses. Release of lactoferrin, pentraxin 3, and matrix metalloproteinase-9 was confirmed in newborn and adult whole blood and blood monocytes stimulated with adjuvants alone or adjuvanted licensed vaccines with distinct clinical reactogenicity profiles. MPLA-induced adult monocyte secretome profiles correlated in silico with transcriptome profiles induced in adults immunized with the MPLA-adjuvanted RTS,S malaria vaccine (MosquirixTM). Overall, adjuvants such as Alum, MPLA and R848 give rise to distinct and age specific monocyte secretome profiles, paralleling responses to adjuvant containing vaccines in vivo Age-specific in vitro modeling coupled with proteomics may provide fresh insight into the ontogeny of adjuvant action thereby informing targeted adjuvanted vaccine development for distinct age groups. PMID- 26933197 TI - Opinion: Climate policy needs more than muddling. PMID- 26933199 TI - On being 'good' in the medical humanities. PMID- 26933202 TI - Repair of tracheo-oesophageal fistula. AB - Acquired non-malignant tracheo-oesophageal fistula (TOF) most commonly develops after prolonged intubation or tracheostomy. It may also develop after trauma, oesophagectomy, laryngectomy and other disparate conditions. TOF leads to respiratory compromise secondary to chronic aspiration and pulmonary sepsis. Difficulty with oral intake usually leads to nutritional compromise. After diagnosis, the goals are to eliminate or reduce ongoing pulmonary contamination and to restore proper nutrition. Operative repair of benign TOF is generally performed through a cervical approach. The majority of patients require tracheal resection and reconstruction to address concomitant tracheal or laryngotracheal stenosis. Muscle flap interposition between tracheal and oesophageal repairs reduces the risk of fistula recurrence. Operative repair of the fistula is associated with generally good outcomes with a minimal risk of mortality. PMID- 26933203 TI - Health Care Use During Transfer to Adult Care Among Youth With Chronic Conditions. AB - OBJECTIVE: To compare health care use and costs for youth with chronic health conditions before and after transfer from pediatric to adult health care services. METHODS: Youth born in Ontario, Canada, between April 1, 1989, and April 1, 1993, were assigned to 11 mutually exclusive, hierarchically arranged clinical groupings, including "complex" chronic conditions (CCCs), non-complex chronic conditions (N-CCCs), and chronic mental health conditions (CMHCs). Outcomes were compared between 2-year periods before and after transfer of pediatric services, the subjects' 18th birthday. RESULTS: Among 104,497 youth, mortality was highest in those with CCCs, but did not increase after transfer (1.3% vs 1.5%, P = .55). Costs were highest among youth with CCCs and decreased after transfer (before and after median [interquartile range]: $4626 [1253 21,435] vs $3733 [950-16,841], P < .001);Costs increased slightly for N-CCCs ($569 [263-1246] vs $589 [262-1333], P < .001), and decreased for CMHCs ($1774 [659-5977] vs $1545 [529-5128], P < .001). Emergency department visits increased only among youth with N-CCCs (P < .001). High-acuity emergency department visits increased CCCs (P = .04) and N-CCCs (P < .001), but not for CMHC (P = .59), who had the highest visit rate. Among the 11 individual conditions, costs only increased in youth with asthma (P < .001), and decreased (P < .05) in those with neurologic impairment, lupus, inflammatory bowel disease, and mood/affective disorders. CONCLUSIONS: Pediatric transfer to adult care is characterized by relatively stable short-term patterns of health service use and costs among youth with chronic conditions. PMID- 26933204 TI - Autoimmunity Including Intestinal Behcet Disease Bearing the KRAS Mutation in Lymphocytes: A Case Report. AB - We experienced the case of a 3-year-old male with a very rare combination of autoimmunity, including immune thrombocytopenia, recurrent Henoch-Schonlein purpura and intestinal Behcet disease. Exome sequencing of the patient's peripheral blood mononuclear cells identified a KRAS G13C mutation. Interestingly, the KRAS G13C mutation was observed in T and B lymphocytes, as well as natural killer cells, but not granulocytes. Our case was completely phenotypically different from RASopathies and did not meet the criteria for Ras associated lymphoproliferative disease or juvenile myelomonocytic leukemia. This is the first reported case in which the KRAS mutation existed only in the lymphoid lineage. Based on the findings of our case and the current literature, it is clear that the RAS mutation in lymphoid cells is tightly linked with various autoimmune symptoms. The presence of the RAS mutation in lymphocytes should be reconsidered as a pathogenesis in cases of autoimmunity. PMID- 26933205 TI - Determinants of Health and Pediatric Primary Care Practices. AB - More than 20% of children nationally live in poverty. Pediatric primary care practices are critical points-of-contact for these patients and their families. Practices must consider risks that are rooted in poverty as they determine how to best deliver family-centered care and move toward action on the social determinants of health. The Practice-Level Care Delivery Subgroup of the Academic Pediatric Association's Task Force on Poverty has developed a roadmap for pediatric providers and practices to use as they adopt clinical practice redesign strategies aimed at mitigating poverty's negative impact on child health and well being. The present article describes how care structures and processes can be altered in ways that align with the needs of families living in poverty. Attention is paid to both facilitators of and barriers to successful redesign strategies. We also illustrate how such a roadmap can be adapted by practices depending on the degree of patient need and the availability of practice resources devoted to intervening on the social determinants of health. In addition, ways in which practices can advocate for families in their communities and nationally are identified. Finally, given the relative dearth of evidence for many poverty-focused interventions in primary care, areas that would benefit from more in-depth study are considered. Such a focus is especially relevant as practices consider how they can best help families mitigate the impact of poverty related risks in ways that promote long-term health and well-being for children. PMID- 26933206 TI - Getting Physical: The Hypothesis Driven Physical Exam. PMID- 26933207 TI - Sporothrix schenckii complex in Iran: Molecular identification and antifungal susceptibility. AB - Sporotrichosis is a global subcutaneous fungal infection caused by the Sporothrix schenckii complex. Sporotrichosis is an uncommon infection in Iran, and there have been no phenotypic, molecular typing or antifungal susceptibility studies of Sporothrix species. This study aimed to identify nine Iranian isolates of the S. schenckii complex to the species level using colony morphology, carbohydrate assimilation tests, and PCR-sequencing of the calmodulin gene. The antifungal susceptibilities of these Sporothrix isolates to five antifungal agents (amphotericin B (AMB), voriconazole (VRC), itraconazole (ITC), fluconazole (FLC), and terbinafine (TRB)) were also evaluated according to the M27-A3 and M38-A2 protocols of the Clinical and Laboratory Standards Institute for yeast and mycelial phases, respectively. Five of seven clinical isolates were identified as S. schenckii, and two clinical and two environmental isolates were identified as S. globosa. This is the first report of S. globosa in Iran. There was significant agreement (73%) between the results of the phenotypic and genotypic identification methods. TRB and ITC were the most effective antifungals against the Sporothrix isolates. The minimum inhibitory concentration (MIC) values of TRB for the yeast and mycelial phases of S. schenckii differed significantly. There was also a significant difference in the minimum fungicidal concentration (MFC) values of AMB and TRB for the two phases. Considering the low efficacy of VRC and FLC and the wide MIC ranges of AMB (1-16 MUg/ml and 1-8 MUg/ml for yeast and mycelial forms, respectively) observed in the present study, in vitro antifungal susceptibility testing should be performed to determine appropriate therapeutic regimens. PMID- 26933208 TI - First isolation of Schizophyllum commune in a harbor seal (Phoca vitulina). AB - To date, Schizophyllum commune infection has been identified in only humans and dogs. A 7-year-old female harbor seal (Phoca vitulina) died after exhibiting corneal opacity, anorexia, and labored respiration. At necropsy, phthisis of the left eyeball was detected, and multiple nodular lesions were observed in the thoracic and abdominal regions, especially in the lung, heart, and lymph nodes. Histopathologically, numerous hyphae were seen in granulomatous lesions in the eyes, lung, heart, and lymph nodules. An isolate on potato dextrose agar from the eyes, lung, and sputum yielded a rapidly growing white woolly mycelia with basidiocarps (fruiting bodies) at 37 degrees C. A suitable temperature for mycelial growth was obtained at 25 degrees C, although sustained growth also occurred at 37 degrees C. The fungal isolate, KH-JPN15-011, had distinctive features including hyphae bearing spicules and clamp connections, which were consistent with the characteristics of basidiomycete fungus. The sequence of the internal transcribed spacer region of nuclear ribosomal DNA showed 99.67% (617 bp) similarity with those of S. commune Phylogenetic analysis showed that the present isolate is most closely related to the samples from the Old World. This is the first report of a fatal disease caused by S. commune in exotic animals. Previously reported human and canine infections have not included granulomatous endophthalmitis and myocarditis. After considering these and previous findings, there is a possibility that S. commune from the Old World may include numerous highly pathogenic strains. PMID- 26933210 TI - Staphylococcus aureus Infections in Children: The Implications of Changing Trends. PMID- 26933209 TI - Identification of Aspergillus fumigatus multidrug transporter genes and their potential involvement in antifungal resistance. AB - Aspergillus fumigatus can cause severe fatal invasive aspergillosis in immunocompromised patients but is also found in the environment. A. fumigatus infections can be treated with antifungals agents among which azole and echinocandins. Resistance to the class of azoles has been reported not only from patient samples but also from environmental samples. Azole resistance mechanisms involve for most isolates alterations at the site of the azole target (cyp51A); however, a substantial number of isolates can also exhibit non-cyp51A-mediated mechanisms.We aimed here to identify novel A. fumigatus genes involved in azole resistance. For this purpose, we designed a functional complementation system of A. fumigatus cDNAs expressed in a Saccharomyces cerevisiae isolate lacking the ATP Binding Cassette (ABC) transporter PDR5 and that was therefore more azole susceptible than the parent wild type. Several genes were recovered including two distinct ABC transporters (atrF, atrI) and a Major Facilitator transporter (mdrA), from which atrI (Afu3g07300) and mdrA (Afu1g13800) were not yet described. atrI mediated resistance to itraconazole and voriconazole, while atrF only to voriconazole in S. cerevisiae Gene inactivation of each transporter in A. fumigatus indicated that the transporters were involved in the basal level of azole susceptibility. The expression of the transporters was addressed in clinical and environmental isolates with several azole resistance profiles. Our results show that atrI and mdrA tended to be expressed at higher levels than atrF in normal growth conditions. atrF was upregulated in 2/4 of azole-resistant environmental isolates and was the only gene with a significant association between transporter expression and azole resistance. In conclusion, this work showed the potential of complementation to identify functional transporters. The identified transporters were suggested to participate in azole resistance of A. fumigatus; however, this hypothesis will need further approaches to be verified. PMID- 26933212 TI - Infant Deaths Due To Herpes Simplex Virus, Congenital Syphilis, and HIV in New York City. AB - BACKGROUND: Neonatal infection with herpes simplex virus (HSV) is not a nationally reportable disease; there have been few population-based measures of HSV-related infant mortality. We describe infant death rates due to neonatal HSV as compared with congenital syphilis (CS) and HIV, 2 reportable, perinatally transmitted diseases, in New York City from 1981 to 2013. METHODS: We identified neonatal HSV-, CS-, and HIV-related deaths using International Classification of Diseases (ICD) codes listed on certificates of death or stillbirth issued in New York City. Deaths were classified as HSV-related if certificates listed (1) any HSV ICD-9/ICD-10 codes for deaths <=42 days of age, (2) any HSV ICD-9/ICD-10 codes and an ICD code for perinatal infection for deaths at 43 to 365 days of age, or (3) an ICD-10 code for congenital HSV. CS- and HIV-related deaths were those listing any ICD code for syphilis or HIV. RESULTS: There were 34 deaths due to neonatal HSV (0.82 deaths per 100 000 live births), 38 from CS (0.92 per 100 000), and 262 from HIV (6.33 per 100 000). There were no CS-related deaths after 1996, and only 1 HIV-related infant death after 2004. The neonatal HSV-related death rate during the most recent decade (2004-2013) was significantly higher than in previous years. CONCLUSIONS: The increasing neonatal HSV-related death rate may reflect increases in neonatal herpes incidence; an increasing number of pregnant women have never had HSV type 1 and are therefore at risk of acquiring infection during pregnancy and transmitting to their infant. PMID- 26933211 TI - Changing Susceptibility of Staphylococcus aureus in a US Pediatric Population. AB - BACKGROUND: Staphylococcus aureus is a major cause of infection in both adult and pediatric populations. After several decades of increasing prevalence, the proportion of S aureus infections due to methicillin-resistant S aureus has been reported to be in decline in adults. Data for similar changes in pediatric populations are limited. METHODS: Evaluation of S aureus susceptibility data for pediatric patients receiving care in the US Military Health System was performed. Microbiology and demographic data were collected for years 2005 through 2014. Trends in antibiotic susceptibility results were evaluated. Clinical and demographic characteristics were explored to assess for association with antibiotic susceptibilities. RESULTS: In this study, 41 745 S aureus isolates from 39 207 pediatric patients were included. An overall increase in susceptibility of isolates to oxacillin was noted over this 10-year period; with over 60% of isolates oxacillin-susceptible in 2014. S aureus susceptibility to clindamycin declined over the study period; notably methicillin-susceptible S aureus susceptibility to clindamycin declined from 90% to 83% (P < .0001). Differences in oxacillin susceptibility between US regions decreased over time. CONCLUSIONS: Similar to recent trends seen in adults, the proportion of pediatric S aureus infections secondary to methicillin-resistant S aureus appear to be decreasing, as is variability in US geographical resistance rates. Increasing clindamycin resistance among methicillin-susceptible S aureus should raise caution in the use of empirical clindamycin in presumed S aureus infection. Clinicians should be aware of regional susceptibility patterns when choosing empirical regimens. PMID- 26933213 TI - Self-assembly of alkynylplatinum(II) terpyridine amphiphiles into nanostructures via steric control and metal-metal interactions. AB - A series of mono- and dinuclear alkynylplatinum(II) terpyridine complexes containing the hydrophilic oligo(para-phenylene ethynylene) with two 3,6,9 trioxadec-1-yloxy chains was designed and synthesized. The mononuclear alkynylplatinum(II) terpyridine complex was found to display a very strong tendency toward the formation of supramolecular structures. Interestingly, additional end-capping with another platinum(II) terpyridine moiety of various steric bulk at the terminal alkyne would lead to the formation of nanotubes or helical ribbons. These desirable nanostructures were found to be governed by the steric bulk on the platinum(II) terpyridine moieties, which modulates the directional metal-metal interactions and controls the formation of nanotubes or helical ribbons. Detailed analysis of temperature-dependent UV-visible absorption spectra of the nanostructured tubular aggregates also provided insights into the assembly mechanism and showed the role of metal-metal interactions in the cooperative supramolecular polymerization of the amphiphilic platinum(II) complexes. PMID- 26933215 TI - Mixotrophy stirs up our understanding of marine food webs. PMID- 26933214 TI - Architectural transitions in Vibrio cholerae biofilms at single-cell resolution. AB - Many bacterial species colonize surfaces and form dense 3D structures, known as biofilms, which are highly tolerant to antibiotics and constitute one of the major forms of bacterial biomass on Earth. Bacterial biofilms display remarkable changes during their development from initial attachment to maturity, yet the cellular architecture that gives rise to collective biofilm morphology during growth is largely unknown. Here, we use high-resolution optical microscopy to image all individual cells in Vibrio cholerae biofilms at different stages of development, including colonies that range in size from 2 to 4,500 cells. From these data, we extracted the precise 3D cellular arrangements, cell shapes, sizes, and global morphological features during biofilm growth on submerged glass substrates under flow. We discovered several critical transitions of the internal and external biofilm architectures that separate the major phases of V. cholerae biofilm growth. Optical imaging of biofilms with single-cell resolution provides a new window into biofilm formation that will prove invaluable to understanding the mechanics underlying biofilm development. PMID- 26933216 TI - Revealing the TCR bias for MHC molecules. PMID- 26933217 TI - PNAS at 101: Heading into the next century. PMID- 26933218 TI - Fuxianhuiid ventral nerve cord and early nervous system evolution in Panarthropoda. AB - Panarthropods are typified by disparate grades of neurological organization reflecting a complex evolutionary history. The fossil record offers a unique opportunity to reconstruct early character evolution of the nervous system via exceptional preservation in extinct representatives. Here we describe the neurological architecture of the ventral nerve cord (VNC) in the upper-stem group euarthropod Chengjiangocaris kunmingensis from the early Cambrian Xiaoshiba Lagerstatte (South China). The VNC of C. kunmingensis comprises a homonymous series of condensed ganglia that extend throughout the body, each associated with a pair of biramous limbs. Submillimetric preservation reveals numerous segmental and intersegmental nerve roots emerging from both sides of the VNC, which correspond topologically to the peripheral nerves of extant Priapulida and Onychophora. The fuxianhuiid VNC indicates that ancestral neurological features of Ecdysozoa persisted into derived members of stem-group Euarthropoda but were later lost in crown-group representatives. These findings illuminate the VNC ground pattern in Panarthropoda and suggest the independent secondary loss of cycloneuralian-like neurological characters in Tardigrada and Euarthropoda. PMID- 26933219 TI - Reply to Liu and Jiang: Maintenance of postreproductive cognitive capacity by inclusive fitness. PMID- 26933220 TI - Reply to Prince et al.: Ability of chemical dispersants to reduce oil spill impacts remains unclear. PMID- 26933221 TI - Oil dispersants do facilitate biodegradation of spilled oil. PMID- 26933222 TI - Alzheimer's disease CD33 rs3865444 variant does not contribute to cognitive performance. PMID- 26933224 TI - Trans Teen Shares Her Story. PMID- 26933223 TI - Approach to Children and Adolescents with Gender Dysphoria. PMID- 26933225 TI - Evaluation and Management of Chronic Pancytopenia. PMID- 26933226 TI - Knee Pain in Children, Part III: Stress Injuries, Benign Bone Tumors, Growing Pains. PMID- 26933227 TI - Case 1: Oral Mucosal Bleeding in a 2-day-old Boy. PMID- 26933228 TI - Case 2: Persistent Stridor After Upper Respiratory Tract Infection in a 2-month old Boy. PMID- 26933229 TI - Case 3: Bilateral Facial Edema with Gingival Swelling in a 6-year-old Boy. PMID- 26933230 TI - Pediatric Pulmonary Hypertension. PMID- 26933231 TI - Periorbital Edema in a 7-year-old Girl. PMID- 26933232 TI - Brain imaging in dementia. AB - The introduction of MRI and positron emission tomography (PET) brain imaging has contributed significantly to the understanding of different dementia syndromes. Over the past 20 years these imaging techniques have been increasingly used for clinical characterisation and differential diagnosis, and to provide insight into the effects on functional capacity of the brain, patterns of spatial distribution of different dementia syndromes and their natural history and evolution over time. Brain imaging is also increasingly used in clinical trials, as part of inclusion criteria and/or as a surrogate outcome measure. Here we review all the relatively specific findings that can be identified with different MRI and PET techniques in each of the most frequent dementing disorders. PMID- 26933233 TI - Culture and spirituality: essential components of palliative care. AB - Palliative care advocates a holistic, multiprofessional approach to the care of people with life-threatening disease. In addition to the control of physical symptoms attention should also be paid to psychosocial, cultural and spiritual aspects of the patient's experience of illness. Guidance documents and research evidence reflect the complexity of the patient's journey and the need to regularly assess these areas of need over time. Cultural background can shape how patients respond to life-threatening illness, as can the beliefs held by the patients, whether religious or more broadly spiritual. Research evidence shows the importance of identifying and addressing cultural and spiritual aspects of care held by patients, families and staff. These are often neglected in clinical practice due to the focus on biomedical concerns and staff discomfort in engaging with beliefs and culture. Recent studies have highlighted gaps in the research, and some methodological difficulties and indicate many patients welcome healthcare staff enquiring about the importance of their beliefs and culture. Identifying research priorities is necessary to guide future research and strengthen the evidence base. PMID- 26933234 TI - Effects of Eimeria acervulina infection severity on growth performance, apparent ileal amino acid digestibility, and plasma concentrations of amino acids, carotenoids, and alpha1-acid glycoprotein in broilers. AB - An experiment was conducted to evaluate growth performance, apparent ileal digestibility (AID) of amino acids, and plasma concentrations of amino acids, carotenoids, and alpha1-acid glycoprotein, an acute-phase protein, in broilers inoculated with graded doses of E. acervulina oocysts. Ross 308 male broilers (400 total) were housed in battery cages from 1 to 21 d post-hatch and received common corn-soybean meal-based diets throughout the experiment. At 9 d post hatch, birds were individually weighed and allotted to 4 treatment groups with 10 replicate cages of 10 birds per cage. At 15 d post-hatch, all birds were inoculated with 1 mL of distilled water that contained 0, 2.5 * 10(5), 5.0 * 10(5), or 1.0 * 10(6) sporulated E. acervulina oocysts. At 21 d, birds were euthanized for collection of blood and ileal digesta. Body weight gain and feed efficiency decreased linearly (P < 0.05) with increasing E. acervulina dose. With the exception of Trp and Gly, AID values decreased (P < 0.05) linearly or quadratically for all amino acids by an average of 2.6 percentage units for birds inoculated with 1.0 * 10(6) oocysts compared with uninfected birds. Infection with E. acervulina caused a quadratic decrease (P < 0.05) in plasma carotenoid concentrations. Plasma concentrations of Arg and Tyr decreased linearly (P < 0.05) with increasing E. acervulina inoculation dose and plasma Gln and Asn decreased quadratically (P < 0.01). Linear increases (P < 0.05) were observed for plasma Lys, Leu, Ile, Val, Pro, and Orn as E. acervulina inoculation dose increased. Plasma alpha1-acid glycoprotein of broilers was not influenced (P > 0.05) by E. acervulina infection. In conclusion, E. acervulina challenge adversely impacted growth performance, plasma carotenoids, and AID of amino acids in a dose-dependent manner. However, plasma amino acid responses to graded E. acervulina inoculation doses varied considerably among amino acids. Thus, these results indicated that alterations in amino acid metabolism caused by E. acervulina infection extended beyond reduced amino acid digestibility. PMID- 26933235 TI - Experimental infection of SPF and Korean native chickens with highly pathogenic avian influenza virus (H5N8). AB - In 2014, an H5N8 outbreak of highly pathogenic avian influenza (HPAI) occurred in South Korea. The H5N8 strain produced mild to moderate clinical signs and mortality rates in commercial chicken farms, especially Korean native chicken farms. To understand the differences between their pathogenicity in SPF chicken and Korean native chicken., we evaluated the mean bird lethal doses (BLD50) of the Korean representative H5N8 virus (A/broiler duck/Korea/Buan2/2014) The BLD50values of the H5N8 virus were 10(5.3)EID50 and 10(6.7)EID50 in SPF and Korean native chickens, respectively. In addition, the mean death time was much longer, and the viral titers in tissues of H5N8-infected chickens were significantly lower, in the Korean group than in the SPF group. These features of the H5N8 virus likely account for its mild-to-moderate pathogenicity in commercial chicken farms, especially Korean native chicken flocks, despite the fact that it is a highly pathogenic virus according to the OIE criteria. To improve current understanding and management of HPAI, pathogenic characterization of novel emerging viruses should be performed by natural route in major poultry species in each country. PMID- 26933236 TI - Chromium propionate in broilers: effect on insulin sensitivity. AB - The objective of this study was to evaluate the effects of dietary chromium (Cr), as chromium propionate, on measures of insulin sensitivity. Liver and muscle glycogen, and plasma glucose and non-esterified fatty acid (NEFA) concentrations were used as indicators of insulin sensitivity. In total, 288 newly hatched male Ross broilers were divided into 4 dietary treatments consisting of 0 (control diet analyzed 0.43 to 0.45 mg Cr/kg), 0.2, 0.4, or 0.6 mg supplemental Cr/kg diet, resulting in 4 treatments with 9 replicate pens per treatment containing eight birds per pen. At d 21, 2 birds per cage were removed based on the greatest deviation from pen mean BW, resulting in each pen containing 6 birds for the final analyses. Final BW were taken on d 40, and on d 42 two birds from each pen were sampled for plasma NEFA, glucose, and muscle and liver glycogen determination at the initiation and termination of a 22 h fast. The remaining 2 fasted birds were sampled after a 30 min refeeding period. No differences were observed in feed intake, BW gain, or feed efficiency on d 21 or d 40. Liver glycogen tended (P=0.10) to be greater in Cr-supplemented chicks in the fed state, and muscle glycogen concentrations tended (P=0.07) to be greater in Cr supplemented chicks compared with controls following fasting and refeeding. Plasma glucose concentrations were not affected by dietary Cr in the fed, fasted, or refed state. Plasma NEFA levels were not affected by treatment in fed or fasted birds. However, plasma NEFA concentrations were lower (P<0.01) in chicks supplemented with Cr than in controls following fasting and refeeding, suggesting that Cr increased insulin sensitivity. No differences were detected among birds supplemented with 0.2 or 0.4 mg Cr/kg, and among those receiving 0.4 or 0.6 mg Cr/kg. Results of this study indicate that Cr propionate supplementation of a control diet containing 0.43 to 0.45 mg Cr/kg enhanced insulin sensitivity. PMID- 26933237 TI - Human C-reactive protein impedes entry of leptin into the CNS and attenuates its physiological actions in the CNS. AB - Defective central leptin signalling and impaired leptin entry into the CNS (central nervous system) represent two important aspects of leptin resistance in obesity. In the present study, we tested whether circulating human CRP (C reactive protein) not only diminishes signalling of leptin within the CNS, but also impedes this adipokine's access to the CNS. Peripheral infusion of human CRP together with co-infused human leptin was associated with significantly decreased leptin content in the CSF of ob/ob mice. Furthermore, following peripheral infusion of human leptin, the CSF (cerebrospinal fluid) concentration of leptin in transgenic mice overexpressing human CRP was sharply lower than that achieved in similarly infused wild-type mice. Administration of LPS (lipopolysaccharide) to human CRP-transgenic mice dramatically elevated the concentrations of human CRP in the CSF. The i.c.v. (intracerebroventricular) delivery of human CRP into the lateral ventricles of ob/ob mice blocked the satiety and weight-reducing actions of human leptin, but not those of mouse leptin. I.c.v. injection of human CRP abolished hypothalamic signalling by human leptin, and ameliorated the effects of leptin on the expression of NPY (neuropeptide Y), AgRP (Agouti-related protein), POMC (pro-opiomelanocortin) and SOCS-3 (suppressor of cytokine signalling 3). Human CRP can impede the access of leptin to the CNS, and elevation of human CRP within the CNS can have a negative impact on the physiological actions of leptin. PMID- 26933239 TI - Stress and epilepsy: fact or fiction, and what can we do about it? AB - People with epilepsy report that stress is their most common trigger for seizures and some believe it caused their epilepsy in the first place. The extensive preclinical, epidemiological and clinical studies examining the link between stress and epilepsy have given confusing results; the clinical studies in particular are fraught with confounders. However stress is clearly bad for health, and we now have substantial preclinical evidence suggesting that chronic stress worsens epilepsy; in selected cases it may even be a causal factor for epilepsy. Healthcare professionals working with people with epilepsy should pay more attention to stress in clinical practice. This review includes some practical advice and guidance for stress screening and management. PMID- 26933238 TI - Uncommon functional properties of the first piscine 26S proteasome from the Antarctic notothenioid Trematomus bernacchii. AB - Protein homoeostasis is a fundamental process allowing the preservation of functional proteins and it has a great impact on the life of the Antarctic organisms. However, the effect of low temperatures on protein turnover is poorly understood and the cold-adaptation of the degradation machinery remains an unresolved issue. As the 26S proteasome represents the main proteolytic system devoted to the controlled degradation of intracellular proteins, the purpose of the present study was to investigate the functions of this complex in the notothenioid Trematomus bernacchii, in order to better understand its role in the physiology of Antarctic fish. To this aim, we purified and characterized the 26S proteasome from T. bernacchii and isolated the cDNAs codifying seven of the 14 subunits belonging to the proteasome 20S core particle. Results provided evidences of the high resistance of the piscine 26S proteasome to oxidative agents and of its 'uncommon' ability to efficiently hydrolyse oxidized bovine serum albumin (BSA), suggesting that this enzymatic complex could play a key role in the antioxidant defense systems in fish inhabiting permanently cold marine environments. These unique properties were also reflected by the 3D model analysis, which revealed a higher structural stability of the piscine complex respect to the murine template. Finally, a comparative analysis, performed in a variety of tissues collected from T. bernacchii and the temperate fish Dicentrarchus labrax, showed a lower protein retention in the cold-adapted fish, possibly due to a better efficiency of its degradation machinery. PMID- 26933240 TI - Erratum: Cellular Bioluminescence Imaging. PMID- 26933241 TI - Controlling Genetic Background in Crosses of Mouse Models of Cancer. AB - The design of a mouse cross can affect the distribution of variation in the control and experimental groups. Often, the goal of a study involving mouse cancer models is to determine the effect of a gene or intervention of interest in different mouse groups without the confounding effects of strain background differences. The appropriate procedure for controlling genetic background will depend on the mouse model employed; two examples are provided here. The first example describes a simple model in which a single-mutant allele is followed in crosses on an inbred strain background. The second example describes a more complex cross in which the model is homozygous for a floxed allele of the gene of interest and carries a tissue-specific Cre transgene. PMID- 26933242 TI - Using the Collaborative Cross to Study the Role of Genetic Diversity in Cancer Related Phenotypes. AB - Human populations are genetically diverse and often a single mouse model can only represent a small subset of the human population. Studying genetic diversity directly can improve the predictive value of mouse models of cancer biology and research on the effects of carcinogens and therapeutics in humans. The collaborative cross is a panel of inbred mouse lines that captures 90% of the genetic diversity of the Mus musculus strain and can help identify regions of the genome that are responsible for variation in cancer phenotypes across the population. The appropriate procedure will depend on the mouse model used; here, three mouse cross designs are described as examples. PMID- 26933243 TI - Preparation of a Total Membrane Fraction from 3T3-L1 Adipocytes. AB - The dynamic nature of insulin-sensitive glucose transporter isoform 4 (GLUT4) storage vesicles (GSVs) makes their characterization challenging. Fractionation techniques can facilitate isolation of GSVs from insulin-sensitive cells. In this protocol, we describe preparation of a total membrane fraction from 3T3-L1 adipocytes. The resulting pellet contains all membranes and allows for easier identification of membrane proteins, including the insulin-sensitive pool of GLUT4. A method for concentration of the soluble fraction is also included. PMID- 26933244 TI - 16K Fractionation of 3T3-L1 Adipocytes to Produce a Crude GLUT4-Containing Vesicle Fraction. AB - The insulin-sensitive pool of glucose transporter isoform 4 (GLUT4) can be isolated from total cell membranes using the 16K fractionation protocol, described here. This method produces a light membrane-containing supernatant that includes the insulin-sensitive pool of GLUT4 in GLUT4 storage vesicles. The 16K pellet fraction contains the heavy membranes (including the plasma membrane, mitochondria, nuclei, Golgi apparatus, and endoplasmic reticulum). The distribution of proteins between the two fractions is determined via immunoblotting. By subjecting insulin-stimulated versus unstimulated cells to this protocol, the mobilization of proteins out of the insulin-sensitive GLUT4 pool can be assessed. PMID- 26933245 TI - Time-Lapse Imaging of Cell Death. AB - The best approach to distinguish between necrosis and apoptosis is time-lapse video microscopy. This technique enables a biological process to be photographed at regular intervals over a period, which may last from a few hours to several days, and can be applied to cells in culture or in vivo. We have established two time-lapse microscopy methods based on different ways of calculating cell death: semiautomated and automated. In the semiautomated approach, cell death can be visualized by staining with combinations of Alexa Fluor 647-conjugated Annexin V and Sytox Green (SG), or Annexin V(FITC) and Propidium iodide (PI). The automated method is similar except that all cells are labeled with dyes. This allows faster quantification of data. To this end Cell Tracker Green is used to label all cells at time zero in combination with PI and Alexa Fluor 647-conjugated Annexin V. Necrotic cell death is accompanied by either simultaneous labeling with Annexin V and PI or SG (double-positive), or direct PI or SG staining. Additionally, necrotic cells display characteristic morphology, such as cytoplasmic swelling. In contrast to necrosis where membrane permeabilization is an early event, cells that die by apoptosis lose their membrane permeability relatively late. Therefore, the time between Annexin V staining and PI or SG uptake (double positive) can be used to distinguish necrosis from apoptosis. This protocol describes the analysis of cell death by time-lapse imaging of HT1080 and L929 cells stained with these dyes, but it can be readily adapted to other cell types of interest. PMID- 26933246 TI - Ripoptosome Analysis by Caspase-8 Coimmunoprecipitation. AB - The biochemical signaling of cell death pathways is executed at a number of different intracellular and/or membrane-bound high-molecular mass complexes. It is crucial to be able to detect the formation, differences in assembly, and differential composition of such complexes to understand their contribution to the execution phase of apoptotic or necroptotic cell death. We describe here the use of caspase-8 coimmunoprecipitation in the spontaneously transformed keratinocyte cell line, HaCaT, to study the formation and composition of the Ripoptosome, a complex that is based on the serine-threonine kinase receptor interacting protein 1 (RIPK1). However, the method can be adapted for use with other antibodies and cell lines. This protocol determines whether cells form the Ripoptosome complex, which is important for both apoptosis and necroptosis execution. Caspase-8 is an indispensible Ripoptosome component; therefore, caspase-8 antibodies are used to pull down the respective complex. However, the method cannot discriminate whether this complex triggers apoptosis (through the RIPK1 -> FADD -> caspase-8 activation pathway), necroptosis (through the RIPK1 -> RIPK3 -> MLKL activation pathway) or nondeath signaling. The actual signaling output (death or nondeath signaling) depends on the stoichiometry of the respective molecules as well as on the activity of FLIP, caspase-8, or other factors. PMID- 26933247 TI - Enrichment of Phosphopeptides via Immobilized Metal Affinity Chromatography. AB - Immobilized metal affinity chromatography (IMAC) is a frequently used method for the enrichment of phosphorylated peptides from complex, cellular lysate-derived peptide mixtures. Here we outline an IMAC protocol that uses iron-chelated magnetic beads to selectively isolate phosphorylated peptides for mass spectrometry-based proteomic analysis. Under acidic conditions, negatively charged phosphoryl modifications preferentially bind to positively charged metal ions (e.g., Fe(3+), Ga(3+)) on the beads. After washing away nonphosphorylated peptides, a pH shift to basic conditions causes the elution of bound phosphopeptides from the metal ion. Under optimal conditions, very high specificity for phosphopeptides can be achieved. PMID- 26933248 TI - Enrichment of Modified Peptides via Immunoaffinity Precipitation with Modification-Specific Antibodies. AB - Immunoaffinity precipitation is an effective method of purifying select protein posttranslational modifications (PTMs) for proteomic analysis via mass spectrometry. Peptides containing a modification of interest are isolated directly from protease-digested cellular protein extracts using an antibody with specificity against the modification, and the modified peptides are analyzed by tandem mass spectrometry. Antibodies now exist with specificity for a variety of individual PTMs, such as phosphotyrosine, acetyl-lysine, methyl-arginine, ubiquitylation (i.e., diglycyl-lysine affinity), etc. Here we outline a generalized protocol for the purification of modified peptides by immunoaffinity precipitation. The main restriction for using this protocol is the availability of an antibody against the modification of interest. To purify modified peptides, antibodies are first conjugated to a solid support, such as agarose beads. The beads are then incubated with a complex peptide mixture, derived from a cellular lysate, under neutral pH to facilitate binding of modified peptides. The incubation time can vary from 30 min to overnight, depending upon the antibody used and the complexity of the peptide sample. Finally, acidic buffer conditions are used to elute the PTM-enriched bound peptides for mass spectrometry analysis. PMID- 26933249 TI - Single Guide RNA Library Design and Construction. AB - This protocol describes how to generate a single guide RNA (sgRNA) library for use in genetic screens. There are many online tools available for predicting sgRNA sequences with high target specificity and/or cleavage activity. Here, we refer the user to genome-wide sgRNA sequence predictions that we have developed for both the human and mouse and that are available from the Broad Institute website. Once a set of target genes and corresponding sgRNA sequences has been identified, customized oligonucleotide pools can be rapidly synthesized by a number of commercial vendors. Thereafter, as described here, the oligonucleotides can be efficiently cloned into an appropriate lentiviral expression vector backbone. The resulting plasmid pool can then be packaged into lentiviral particles and used to generate knockouts in any cell line of choice. PMID- 26933250 TI - Viral Packaging and Cell Culture for CRISPR-Based Screens. AB - This protocol describes how to perform the tissue culture and high-throughput sequencing library preparation for a CRISPR-based screen. First, pantropic lentivirus is prepared from a single guide RNA (sgRNA) plasmid pool and applied to the target cells. Following antibiotic selection and a harvest of the initial population, cells are then cultured under the desired screening condition(s) for 14 population doublings. The sgRNA barcode sequences integrated in the genomic DNA of each cell population are amplified and subject to high-throughput sequencing. Guidelines for downstream analysis of the sequencing data are also provided. PMID- 26933251 TI - The Effects of Genetic Background of Mouse Models of Cancer: Friend or Foe? AB - Over the past century, mice have been selectively bred to give rise to the strains used in biomedical research today. Mouse models of cancer allow researchers to control variables of diet, environment, and genetic heterogeneity to better dissect the role of these factors in cancer in humans. Because of the important role of genetic background in cancer, the strain of the mouse can introduce confounding results in studies of mouse models if not properly controlled. Conversely, genetic variation between strains can also provide important new insights into cancer mechanisms. Here, the sources of genetic heterogeneity in mouse models are reviewed, with an explanation of how heterogeneity modifies cancer phenotypes. PMID- 26933252 TI - Proteomic Analysis of Protein Posttranslational Modifications by Mass Spectrometry. AB - The addition of posttranslational modifications (PTMs) to proteins is an influential mechanism to temporally control protein function and ultimately regulate entire cellular processes. Most PTMs are present at low stoichiometry and abundance, which limits their detection when analyzing whole cell lysates. PTM purification methods are thus required to comprehensively characterize the presence and dynamics of PTMs using mass spectrometry-based proteomics approaches. Here we describe several of the most influential PTMs and discuss the fundamentals of proteomics experiments and PTM purification methods. PMID- 26933254 TI - Large-Scale Single Guide RNA Library Construction and Use for CRISPR-Cas9-Based Genetic Screens. AB - The ability to systematically disrupt genes serves as a powerful tool for understanding their function. The programmable CRISPR-Cas9 system enables efficient targeting of large numbers of genes through the use of single guide RNA (sgRNA) libraries. In cultured mammalian cells, collections of knockout mutants can be readily generated by means of transduction of Cas9-sgRNA lentiviral pools, screened for a phenotype of interest, and counted using high-throughput DNA sequencing. This technique represents the first general method for undertaking systematic loss-of-function genetic screens in mammalian cells. Here, we introduce the methodology and rationale for conducting CRISPR-based screens, focusing on distinguishing positive and negative selection strategies. PMID- 26933255 TI - Imaging the Neocortex Functional Architecture Using Multiple Intrinsic Signals: Implications for Hemodynamic-Based Functional Imaging. AB - Optical imaging based on intrinsic signals has provided a new level of understanding of the principles underlying cortical development, organization, and function, providing a spatial resolution of up to 20 um for mapping cortical columns in vivo. This introduction briefly reviews the development of this technique, the types of applications that have been pursued, and the general implications of some findings for other neuroimaging techniques based on hemodynamic responses (e.g., functional magnetic resonance imaging). PMID- 26933253 TI - Growth and the Environment of Schizosaccharomyces pombe. AB - Here, we summarize the composition and uses of Schizosaccharomyces pombe media and discuss key issues for consideration in the generation of S. pombe cultures. We discuss the concept of "culture memory," in which the growth state and stress experienced by a strain during storage, propagation, and starter culture preparation can alter experimental outcomes at later stages. We also describe the triggers that are widely used to manipulate signaling through the environment sensing pathways. PMID- 26933256 TI - Between the guidelines: SQUIRE 2.0 and advances in healthcare improvement practice and reporting. PMID- 26933258 TI - Why veterinary school accreditation matters. PMID- 26933257 TI - Position of conflict and scripting an antibiotic - A comment. PMID- 26933259 TI - An ethicist's commentary on options for hurt animals. PMID- 26933260 TI - A problem with herd health policy applied to shelter animals. PMID- 26933261 TI - Behavioral response and cost comparison of manual versus pharmacologic restraint protocols in healthy dogs. AB - Although sedatives are routinely administered to dogs for diagnostic and minimally invasive procedures, manual restraint is often used. The study compared intra-procedural behavioral response, scored on a 100-point, visual analog scale, and cost of restraint in healthy dogs given 1 of 5 treatments: manual restraint, dexmedetomidine at 125 MUg/m(2) (Dex 125) or 375 MUg/m(2) (Dex 375), Dex 125 plus butorphanol at 0.4 mg/kg (Dex 125 + Bu), or Dex 375 plus butorphanol at 0.4 mg/kg (Dex 375 + Bu). Mean behavioral response scores in dogs declined from baseline in the manual restraint group and improved in a linear fashion in the group order Dex 125, Dex 375, Dex 125 + Bu, and Dex 375 + Bu. Dexmedetomidine at 375 MUg/m(2) or at 125 MUg/m(2) or at 375 MUg/m(2) in combination with butorphanol produced the best intra-procedural behavioral response. The cost of sedative drugs was offset by the opportunity cost of diverting personnel from revenue-generating activity to manual restraint. PMID- 26933263 TI - Comparison of efficacy and toxicity of doxorubicin and mitoxantrone in combination chemotherapy for canine lymphoma. AB - Forty-four dogs with multicentric lymphoma were treated using a cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) induction protocol or treated using a cyclophosphamide, mitoxantrone, vincristine, and prednisolone (CMOP) induction protocol. There was no statistical difference in signalment and the presence of historical negative prognostic factors between the groups. The median progression-free survival (PFS) in the CHOP and CMOP groups were 222 d and 162 d, respectively (P = 0.75). The median survival time (MST) of dogs in CHOP and CMOP groups were 318 d and 242 d, respectively (P = 0.63). Anorexia and diarrhea episodes were significantly higher in the CHOP group than in the CMOP group (P = 0.02 and P = 0.01, respectively). These results suggest that the CMOP protocol provides similar PFS, MST and causes fewer side effects compared to the CHOP protocol. Therefore, the CMOP protocol may be another treatment choice for canine multicentric lymphoma. PMID- 26933262 TI - A cross-sectional study of Tritrichomonas foetus infection in feral and shelter cats in Prince Edward Island, Canada. AB - A cross-sectional study examined the occurrence of Tritrichomonas foetus, and other intestinal parasites, in feral and shelter cats in Prince Edward Island (PEI). Fecal samples were collected from 100 feral cats, 100 cats from the PEI Humane Society, and 5 cats from a private residence. The occurrence of T. foetus, based on fecal culture, was 0% in feral and shelter cats. A single positive sample was obtained from an owned Abyssinian cat that was imported to PEI. Intestinal parasites were identified via fecal flotation in 76% of feral cats and 39% of cats from the humane society. Feral cats had a higher incidence of Toxocara cati than cats from the humane society (P < 0.001), conversely, shelter cats had a higher incidence of Cystoisospora spp. (P < 0.001). These results suggest that while T. foetus is not of importance in feral and shelter cats in PEI, imported cats could serve as reservoirs. PMID- 26933264 TI - Canine cystine urolithiasis: A review of 1760 submissions over 35 years (1979 2013). AB - This study reports a retrospective evaluation of epidemiological data from cystine stones of dogs submitted to the Urinary Stone Analysis Center Bonn, Germany, over a period of 35 years. Of the 20 316 uroliths submitted from 1979 to 2013, 1760 were cystine stones. In total, 109 breeds were affected with 16 breeds having an odds ratio > 1.0. Most of the cystine uroliths were retrieved from male dogs, with only 19 female dogs (1.1%) being affected. Percentage of submitted cystine stones amongst all stones decreased significantly over 35 years from 38.9% to 4.4%. PMID- 26933265 TI - Self-reported hand hygiene perceptions and barriers among companion animal veterinary clinic personnel in Ontario, Canada. AB - The objective of this study was to describe the perceived importance of and barriers to hand hygiene among companion animal clinic staff. An anonymous, voluntary written questionnaire was completed by 356 of approximately 578 individuals (62%) from 49/51 clinics. On a scale of 1 (not important) to 7 (very important), the percentage of respondents who rated hand hygiene as a 5 or higher was at least 82% in all clinical scenarios queried. The most frequently reported reason for not performing hand hygiene was forgetting to do so (40%, 141/353). Specific discussion of hand hygiene practices at work was recalled by 32% (114/354) of respondents. Although veterinary staff seem to recognize the importance of hand hygiene, it should be emphasized more during staff training. Other barriers including time constraints and skin irritation should also be addressed, possibly through increased access to and use of alcohol-based hand sanitizers. PMID- 26933266 TI - Heart rate variability in relation to stress in the Asian elephant (Elephas maximus). AB - This study describes a safe, reliable, and accessible means to measure heart rate (HR) and HR variability (HRV) and evaluates the use of HRV as a physiological correlate of stress in the Asian elephant. A probabilistic model indicates that HRV measurements may adequately distinguish between stressed and non-stressed elephants. PMID- 26933267 TI - Detection of Neorickettsia risticii, the agent of Potomac horse fever, in a Gypsy Vanner stallion from Manitoba. AB - A horse with colitis from Manitoba referred to the Veterinary Medical Centre, Western College of Veterinary Medicine, was diagnosed with Potomac horse fever (PHF). Polymerase chain reaction analysis of the feces confirmed Neorickettsia risticii infection. This is the first reported case of PHF in Manitoba. PMID- 26933268 TI - Survival of 4 dogs with persistent atrial standstill treated by pacemaker implantation. AB - Pacemakers were implanted in 4 client-owned female dogs which had persistent atrial standstill. Three dogs were alive after 14 to 39 months and 1 dog was euthanized after 10.5 years. This report demonstrates that some dogs with persistent atrial standstill can survive for extended time periods. PMID- 26933270 TI - Dorsal skin necrosis secondary to a solar-induced thermal burn in a brown-coated dachshund. AB - A 5-year-old neutered male brown dachshund dog was presented for a large dorsal cutaneous burn that occurred following direct sunlight exposure outdoors in high ambient temperatures. Although burns are quite common in dogs, full-thickness solar-induced radiation burns are less common and have not been previously reported in animals without a black hair coat. PMID- 26933271 TI - Ventriculoperitoneal shunt for treatment of hydrocephalus in a French bulldog puppy. AB - A 6.5-week-old bulldog was presented with lethargy, anorexia, and stunted growth. A domed skull, ventrolateral strabismus, hypermetria, and delayed hopping were observed. Congenital hydrocephalus was diagnosed and a ventriculoperitoneal shunt was placed. After surgery, a shunt obstruction occurred but resolved with treatment. The puppy responded well and neurological deficits continued to improve after surgery. PMID- 26933272 TI - Highs and lows across Canada: Average veterinary fees in 2015. PMID- 26933269 TI - Management of an invasive and metastatic Sertoli cell tumor with associated myelotoxicosis in a dog. AB - We describe the surgical and post-operative management of a large, invasive, and metastatic functional Sertoli cell tumor in a 9-year-old cryptorchid male Labrador retriever dog. Despite residual disease after surgery, bone marrow recovery occurred without administration of bone marrow stimulants and serum estradiol accurately predicted tumor recurrence. PMID- 26933273 TI - Diagnostic Ophthalmology. PMID- 26933274 TI - Solitary pulmonary nodule and (18)F-FDG PET/CT. Part 1: epidemiology, morphological evaluation and cancer probability. AB - Solitary pulmonary nodule corresponds to a common radiographic finding, which is frequently detected incidentally. The investigation of this entity remains complex, since characteristics of benign and malignant processes overlap in the differential diagnosis. Currently, many strategies are available to evaluate solitary pulmonary nodules with the main objective of characterizing benign lesions as best as possible, while avoiding to expose patients to the risks inherent to invasive methods, besides correctly detecting cases of lung cancer so as the potential curative treatment is not delayed. This first part of the study focuses on the epidemiology, the morfological evaluation and the methods to determine the likelihood of cancer in cases of indeterminate solitary pulmonary nodule. PMID- 26933275 TI - From the desk of the editor. PMID- 26933276 TI - Icon of this issue: Sir Archibald McIndoe. PMID- 26933277 TI - Fibrous dysplasia and cherubism. AB - Fibrous dysplasia (FD) is a non-malignant fibro-osseous bony lesion in which the involved bone/bones gradually get converted into expanding cystic and fibrous tissue. The underlying defect in FD is post-natal mutation of GNAS1 gene, which leads to the proliferation and activation of undifferentiated mesenchymal cells arresting the bone development in woven phase and ultimately converting them into fibro-osseous cystic tissue. Cherubism is a hereditary form of fibrous dysplasia in which the causative factor is transmission of autosomal dominant SH3BP2 gene mutation. The disease may present in two distinct forms, a less severe and limited monostotic form, and a more aggressive and more widespread polyostotic form. Polyostotic form may be associated with various endocrine abnormalities, which require active management apart from the management of FD. Management of FD is not free from controversies. While total surgical excision of the involved area and reconstruction using newer micro-vascular technique is the only definitive treatment available from the curative point of view, but this can be only offered to monostotic and very few polyostotic lesions. In polyostotic varieties on many occasions these radical surgeries are very deforming in these slow growing lesions and so their indication is highly debated. The treatment of cranio-facial fibrous dysplasia should be highly individualized, depending on the fact that the clinical behavior of lesion is variable at various ages and in individual patients. A more conservative approach in the form of aesthetic recontouring of deformed bone, orthodontic occlusal correction, and watchful expectancy may be the more accepted form of treatment in young patients. Newer generation real-time imaging guidance during recontouring surgery adds to accuracy and safety of these procedures. Regular clinical and radiological follow up is required to watch for quiescence, regression or reactivation of the disease process. Patients must be warned and watched for any sign of nerve compression, especially visual impairment due to optic nerve compression. Rather than going for prophylactic optic canal decompression (which does more harm than good), optic nerve decompression should be done in symptomatic patients only, and preferably be done via minimal invasive endoscopic neuro-surgical approach than the conventional more morbid open craniotomy approach. There is growing research and possibilities that newer generation bisphosphonate medication may change the management scenario, as these medications show encouraging response in not only reducing the osteoclastic activity, but simultaneously also stimulating the osteoblastic and osteocytic activities. The explosion of genetic research and stem cell therapy may lead to better understanding and subsequently better treatment of FD in future. PMID- 26933278 TI - Current trends of liposuction in India: Survey and Analysis. AB - BACKGROUND: Liposuction is the commonest aesthetic procedure performed by Indian plastic surgeons. However, there exists substantial disparity amongst Indian surgeons about guidelines concerning liposuction. To address this disparity, a nationwide email survey (Association of Plastic Surgeons of India [APSI] database) was started in December 2013 and continued for 5 months. MATERIAL AND METHODS: The survey was developed with software from www.fluidsurveys.com. The study was designed to cover most aspects of patient selection, perioperative management, technical considerations, postoperative management and complications. This is the first survey to be conducted in India for an extremely popular procedure. It is also one of the most exhaustive surveys that have been conducted in terms of the topics covered. RESULTS AND CONCLUSIONS: One hundred and eighteen surgeons (including a majority of the cosmetic surgery stalwarts in the country) completed the survey. As expected, the results show a disparity in most parameters but also consolidation on some issues. Liposuction is considered extremely safe (86.1%). The majority of surgeons (70.3%) aspirated >5 L at onetime. The majority (80.2%) felt that the limits for liposuction should be relative and not absolute. The survey highlights lack of standardization with respect to infiltration solutions. The commonest complications observed were contour irregularities, followed by seroma and inadequate skin redrape. The amount of aspirate is the only factor, which achieves statistical significance with respect to major complications. A review of the current evidence and recommendations has been incorporated, along with an in depth analysis of the survey. PMID- 26933279 TI - A novel 3D template for mandible and maxilla reconstruction: Rapid prototyping using stereolithography. AB - INTRODUCTION: Replication of the exact three-dimensional (3D) structure of the maxilla and mandible is now a priority whilst attempting reconstruction of these bones to attain a complete functional and aesthetic rehabilitation. We hereby present the process of rapid prototyping using stereolithography to produce templates for modelling bone grafts and implants for maxilla/mandible reconstructions, its applications in tumour/trauma, and outcomes for primary and secondary reconstruction. MATERIALS AND METHODS: Stereolithographic template assisted reconstruction was used on 11 patients for the reconstruction of the mandible/maxilla primarily following tumour excision and secondarily for the realignment of post-traumatic malunited fractures or deformity corrections. Data obtained from the computed tomography (CT) scans with 1-mm resolution were converted into a computer-aided design (CAD) using the CT Digital Imaging and Communications in Medicine (DICOM) data. Once a CAD model was constructed, it was converted into a stereolithographic format and then processed by the rapid prototyping technology to produce the physical anatomical model using a resin. This resin model replicates the native mandible, which can be thus used off table as a guide for modelling the bone grafts. DISCUSSION: This conversion of two dimensional (2D) data from CT scan into 3D models is a very precise guide to shaping the bone grafts. Further, this CAD can reconstruct the defective half of the mandible using the mirror image principle, and the normal anatomical model can be created to aid secondary reconstructions. CONCLUSION: This novel approach allows a precise translation of the treatment plan directly to the surgical field. It is also an important teaching tool for implant moulding and fixation, and helps in patient counselling. PMID- 26933280 TI - Pedicle streaking: A novel and simple aid in pedicle positioning in free tissue transfer. AB - INTRODUCTION: The pedicle positioning in free tissue transfer is critical to its success. Long thin pedicles are especially prone to this complication where even a slight twist in the perforator can result in flap loss. Pedicles passing through the long tunnels are similarly at risk. Streaking the pedicle with methylene blue is a simple and safe method which increases the safety of free tissue transfer. MATERIALS AND METHODS: Once the flap is islanded on the pedicle and the vascularity of the flap is confirmed, the pedicle is streaked with methylene blue dye at a distance of 6-7 mm. The streaking starts from the origin of the vessels and continued distally on to the under surface of flap to mark the complete course of the pedicle in alignment. The presence of streaking in some parts and not in rest indicates twist in the pedicle. OBSERVATION AND RESULTS: Four hundred and sixty five free flaps have been done at our centre in the last 5 years. The overall success rate of free flaps is 95.3% (22 free flap failures). There has not been a single case of pedicle twist leading to flap congestion and failure. CONCLUSION: This simple and novel method is very reliable for pedicle positioning avoiding any twist necessary for successful free tissue transfer. PMID- 26933281 TI - Tracheoesophageal puncture site closure with sternocleidomastoid musculocutaneous transposition flap. AB - INTRODUCTION: Tracheoesophageal voice prosthesis is highly effective in providing speech after total laryngectomy. Although it is a safe method, in certain cases dilatation or leakage occurs around the prosthesis that needs closure of tracheoesophageal fistula. Both non-surgical and surgical methods for closure have been described. Surgical methods are used when non-surgical methods fail. We present the use of the sternocleidomastoid musculocutaneous (SCMMC) transposition flap for the closure of tracheoesophageal fistula. MATERIALS AND METHODS: An incision is made at the mucocutaneous junction circumferentially around the tracheostoma. Tracheoesophageal space is dissected down to and beyond the fistula. The tracheoesophageal tract is divided. The oesophageal mucosa is closed with simple sutures. Then SCMMC transposition flap is raised and transposed to cover sutured oesophagus and the defect between the oesophagus and the trachea. RESULTS: This study was done prospectively over a period of 1 year from June 2012 to May 2013. This technique was used in patients with pliable neck skin. In nine patients, this procedure was done (inferior based flap in nine cases) and it was successful in eight patients. In one case, there was dehiscence at the leading edge of flap with oesophageal dehiscence, which required a second procedure. In two cases, there was marginal necrosis of flap, which healed without any intervention. Nine patients in this series were post-radiation. CONCLUSION: This method of closure is simple and effective for patients with pliable neck skin, who require permanent closure of the tracheoesophageal fistula. PMID- 26933282 TI - Axillary breast: Navigating uncharted terrain. AB - INTRODUCTION: Axillary breast is a common condition that leads to discomfort and cosmetic problems. Liposuction alone and open excision are two techniques used for treatment. MATERIALS AND METHODS: This study assesses the results of treatment in 24 consecutive patients, operated between 2005 and 2015. All patients had Kajava class IV masses. Three were treated by liposuction alone, while 21 were treated by open axillaplasty with limited liposuction. RESULTS: One patient treated by liposuction alone had to be re-operated for a residual lump, while with axillaplasty, no major complications were observed and the results were uniformly good. DISCUSSION: Certain points of technique emerged as major determinants in obtaining the best results. In brief, these are: a) limited skin excision; b) placing elliptical incisions within the most lax, apical axillary skin, irrespective of the location of the lump; c) raising skin flaps at the level of superficial fascia; d)meticulous dissection and preservation of the nerves, especially the second intercostobrachial; f) judicious liposuction for eliminating dog ears and axillary sculpting only; g) avoiding drains. CONCLUSION: Open axillaplasty with limited liposuction is the best way to minimise complications and produce good results. PMID- 26933283 TI - Hypothenar island flap: A safe and excellent choice for little finger defects. AB - Soft-tissue defects of the little finger are challenging especially when bone, tendon or vascular pedicle is exposed because of trauma. The hypothenar island flap is easy to harvest and has a good colour and texture match to the little finger pulp. We present nine clinical cases of soft tissue defects of the little finger covered using the reversed hypothenar fasciocutaneous island flap. This article intends to highlight the ease of elevation and good clinical results of the hypothenar flap which is rarely used. PMID- 26933284 TI - Simple device to determine the pressure applied by pressure clips for the treatment of earlobe keloids. AB - BACKGROUND: Keloids of the ear are common problems. Various treatment modalities are available for the treatment of ear keloids. Surgical excision with intralesional steroid injection along with compression therapy has the least recurrence rate. Various types of devices are available for pressure therapy. Pressure applied by these devices is uncontrolled and is associated with the risk of pressure necrosis. We describe here a simple and easy to use device to measure pressure applied by these clips for better outcome. OBJECTIVES: To devise a simple method to measure the pressure applied by various pressure clips used in ear keloid pressure therapy. MATERIALS AND METHODS: By using a force sensitive resistor (FSR), the pressure applied gets converted into voltage using electrical wires, resistors, capacitors, converter, amplifier, diode, nine-volt (9V) cadmium battery and the voltage is measured using a multimeter. The measured voltage is then converted into pressure using pressure voltage graph that depicts the actual pressure applied by the pressure clip. RESULTS: The pressure applied by different clips was variable. The spring clips were adjustable by slight variation in the design whereas the pressure applied by binder clips and magnet discs was not adjustable. CONCLUSION: The uncontrolled/suboptimal pressure applied by certain pressure clips can be monitored to provide optimal pressure therapy in ear keloid for better outcome. PMID- 26933285 TI - A report of 2 patients with transient blindness following Le Fort I osteotomy and a review of past reported cases. AB - Blindness following a LeFort I osteotomy is a rare but extremely serious complication. Ten cases have been reported to date. None of these patients recovered vision. Optic neuropathy is believed to be the cause but the exact mechanism has not been settled. We report the first, and the only two, documented cases of complete loss of vision that recovered subsequently. The first patient was a 19-year-old male with repaired bilateral cleft lip and palate. He developed loss of vision in the right eye on the second postoperative day. The second patient was a 22-year-old male with repaired unilateral cleft lip and palate. He developed complete loss of vision in the left eye on the day of surgery. Both these patients underwent ongoing studies, which did not show any abnormalities. Both were treated with methylprednisolone. Both the patients gradually showed improvement in their vision. The first patient recovered normal vision several months postoperatively. The second patient's vision improved to 4/60 by 4 months postoperatively. We discuss the probable mechanisms of optic nerve injury and also the possible reasons why sight was restored in these patients. This is a rare but serious complication following a fairly common procedure. Through this article we wish to create an awareness of this complication and also a possible way of avoiding such a disaster. PMID- 26933286 TI - Pentafid tongue: A new entity. AB - Tongue plays a pivotal role in both physiological and functional life of human beings. Structural and developmental abnormalities of the tongue in various forms have been reported in isolation or in combination with various syndromes. Though cases of bifid tongues have been mentioned in literature, no reports of pentafid tongue have been reported till date. Here we describe a unique case of congenital pentafid tongue along with bilateral polydactyly and its surgical management. PMID- 26933287 TI - Severe iatrogenic nostril stenosis. AB - Nostril stenosis (narrowing of the nasal inlet) is an uncommon deformity which results in aesthetic and breathing discomfort in patients. The literature review shows that trauma, infection, iatrogenic insults and congenital lesions are major causes of stenosis. Nowadays, rhinoplasty is one of most popular aesthetic surgeries which may have complications such as bleeding, swelling, bruising, asymmetry, obstruction of nasal airways. We present a 30-year-old female patient, who complained about breathing and aesthetic difficulties due to external nasal valve obstruction and nasal deformity. Past medical history showed that the patient had undergone three unsuccessful rhinoplasty surgeries with aesthetic goals. PMID- 26933288 TI - A simple external tissue expansion technique based on viscoelastic properties of skin to attain direct closure of a large scalp defect: A case report. AB - BACKGROUND: Direct closure of large scalp defects is not an easy task. Complicated flap designs or staged surgeries over a period of 6 months are often required. A case of a large scalp defect that was closed directly in 3 months by applying a simple external tissue expansion technique is presented in this report. PATIENT PROFILE: A 28-year-old male patient presented with a painful swelling of about 13 cm * 14 cm, on frontoparietal scalp. A biopsy done elsewhere reported it to be a neurofibroma. He sought tumour excision and scalp defect coverage by hair-bearing scalp in a period of less than 5 months. MATERIALS AND METHODS: The tumour was excised and the adjacent scalp was gradually expanded with the help of an external fixator. The patient had immediate pain relief after excision. The goal of repairing scalp defect and replacing it with hairy scalp was achieved in 3 months. CONCLUSION: The mechanical device required for this technique is relatively easily accessible. It is not difficult to achieve desirable outcomes, and the same can be applied to large wounds on other areas. PMID- 26933289 TI - A simplified modification of a reconstruction plate into a mandibular transport distraction device: A technical note. AB - Transport distraction is nowadays gaining enormous popularity and is becoming a promising option for reconstruction of mandibular defects. However, the vast number of distraction device designs create huge confusion in the clinician's mind to choose the right one. Considering these complex and costly designs, the authors decided to find a simplified way of combining a modified conventional reconstruction plate and monofocal distraction device that can act as a transport distraction device for bridging of bony defects. A case performed by this technique and device has been presented along with the description of device design. PMID- 26933290 TI - Management of asymptomatic silicone-injected breast with reduction mammoplasty. AB - Even though Silicone injection for breast augmentation has been related to disastrous long-term effects and complications, some patients do not develop significant symptoms at all (asymptomatic). Unfortunately, the management of asymptomatic Silicone-injected breast is still unclear and has never been reported exclusively. We present two cases of asymptomatic patients with a history of liquid Silicone injections who refused to have a mastectomy. They were concerned with the breast ptosis and chose to undergo reduction mammoplasty to improve the appearance of the breasts. Magnetic resonance imaging may be useful as an additional screening tool to confirm the diagnosis and exclude the presence of malignancy in breasts with injected Silicone. We believe that breast reduction may be the alternative option for women with a history of liquid Silicone injection who have no symptoms but desire to preserve their breasts and improve their aesthetics. PMID- 26933291 TI - A simple technique of marking the perforator of a free flap for postoperative monitoring. PMID- 26933292 TI - The pivotal role of pedicled perforator flaps amidst irradiation. PMID- 26933294 TI - Authors' Reply. PMID- 26933293 TI - Surgical revirgination: Four vaginal mucosal flaps for reconstruction of a hymen. PMID- 26933295 TI - Anticoagulation therapy and hand surgery: Do we worry too much? PMID- 26933296 TI - Ossified costal cartilage during rhinoplasty: A surgical dilemma. PMID- 26933297 TI - A simple method to facilitate oral surgery in patients with orthodontic appliances. PMID- 26933298 TI - Remodeling in asthma and COPD-recent concepts. PMID- 26933299 TI - Long-term outcomes of the bronchial artery embolization are diagnosis dependent. AB - BACKGROUND: Bronchial artery embolization (BAE) is an established, safe, and effective procedure for the treatment of hemoptysis but long-term outcomes of the BAE have never been investigated before. OBJECTIVES: To retrospectively analyze long-term outcomes of the BAE. MATERIALS AND METHODS: A retrospective chart analysis was done from the hospital central database for all patients undergoing the BAE over a consecutive 14-year period (January 2000-February 2014). A total of 58 patients were identified from the database. Eight patients were excluded due to the lack of follow-up. Data such as patient demographics, reason for hemoptysis, medical imaging results, bronchoscopy findings, recurrence rates, and morbidity/mortality rates after the BAE were collected. RESULTS: Eighty three embolizations were performed in 50 patients. The median follow-up was of 2.2 years. Cystic fibrosis (CF) bronchiectasis was the most common etiology (21/50), followed by non-CF bronchiectasis (9/50). Cavitary lung disease occurred in 12/50 patients, an additional 4/50 had cancer (primary lung and metastatic), and one patient had antineutrophil cytoplasmic antibody (ANCA) vasculitis. In three patients the etiology was unknown. Postprocedural complications occurred in 5/83 (6%) patients, two patients with two major complications - stroke (one) and paraplegia (one) - and three patients with minor complications - chest pain (two) and bronchial artery dissection (one). A total of 15/50 patients died during the follow-up. Three patients died of hemoptysis, and the remaining deaths were unrelated to the procedure or hemoptysis. Twenty four patients had recurrent hemoptysis. A Kaplan-Meier analysis revealed an excellent long-term survival that was 85% at 10 years. CONCLUSIONS: The BAE is a safe and effective procedure with excellent overall long-term survival. PMID- 26933300 TI - Surgical treatment of pulmonary aspergillosis: A single center experience. AB - BACKGROUND: Aspergillus fumigatus is a saprophytic fungus which colonizes in the cavitary lesions in the lungs. In our part of the world, where tuberculosis is endemic, the healed tubercular cavities form a good nidus for this fungus. The fungus forms a fungal ball or aspergilloma within the cavity, which erodes the walls of the cavity and causes hemoptysis by erosion of the bronchial vessels. Hemoptysis is the main symptom. Antifungal agents are not useful against the fungal ball. Surgery in the form of lobectomy is the primary treatment. Surgery for aspergilloma is known to be risky because of intra-pleural adhesions, obliteration of the interlobar fissures, massive hemorrhage during dissection and poor pulmonary reserve of the patient due to the underlying disease. MATERIALS AND METHODS: Clinical presentation, radiological investigations, operative techniques, postoperative outcome, and follow-up of 24 cases of pulmonary aspergilloma treated surgically were studied prospectively between August 2010 and July 2013 at IPGMER and SSKM Hospital, Kolkata. RESULTS: There were 15 male (62.5%) and 9 female (37.5%) patients. Mean age of the study population was 34.54 years. All the patients had complex aspergilloma. Tuberculosis was the underlying disease in 22 patients (91%). Hemoptysis was the main symptom in 79.16% cases. Chest X-ray was the first investigation, which gave a clue to the diagnosis. Computed tomography scan was diagnostic in all cases. Lobectomy was done in 16 patients (66.67%). There was one mortality and the overall complication was 33.33%. The average follow-up period was 21.65 months, during which there was no mortality and no recurrence of hemoptysis in these patients. CONCLUSIONS: Though surgery for aspergilloma is considered to be risky, excision of the cavity along with the involved lobe can be done with acceptable morbidity and mortality to provide the patient complete cure and symptom-free survival. PMID- 26933301 TI - A new approach for the assessment of sleepiness and predictivity of obstructive sleep apnea in drivers: A pilot study. AB - BACKGROUND: Falling asleep behind the wheel is one of the most relevant consequences of obstructive sleep apnea (OSA). We created a new screening questionnaire, named the Driver Sleepiness Score (DSS), aiming to assess sleepiness in drivers with suspected OSA. The primary aim of our study was to evaluate sleepiness in drivers with a suspicion of OSA by the DSS in order to assess its correlation with the apnea-hypopnea index (AHI), oxygen desaturation index (ODI), and total sleep time with oxyhemoglobin saturation below 90% (TST90). We also aimed to assess the diagnostic accuracy of DSS for three different cutoffs of AHI (AHI = 5, AHI = 15, AHI = 30), which allow stratification of the severity of OSA. MATERIALS AND METHODS: Seventy-three driving patients at risk for OSA participated in the study. DSS and the Epworth Sleepiness Scale (ESS) were both administered in operator-dependent modality and in randomized sequence. RESULTS: The DSS showed higher accuracy in screening patients with mild OSA [area under curve (AUC): 0.88 vs 0.74] and moderate OSA (AUC: 0.88 vs 0.79), whereas ESS showed higher accuracy in screening patients with severe OSA (AUC: 0.91 vs 0.78). A DSS score >= 7 is the optimal cutoff for distinguishing true positives from false positives for the presence of OSA and for its different severity levels. The administration of both questionnaires increases the accuracy for the detection of all OSA severity levels. CONCLUSIONS: If validated, DSS may qualify as a new screening tool specifically for drivers with the suspicion of having OSA, in combination with the ESS. PMID- 26933302 TI - Antisynthetase syndrome: An under-recognized cause of interstitial lung disease. AB - BACKGROUND: Antisynthetase syndrome (AS) is an uncommon and under-recognised connective tissue disease characterized by the presence of antibodies to anti aminoacyl t-RNA synthetase along with features of interstitial lung disease (ILD), myositis and arthritis. The aim of the current study is to describe our experience with management of AS. MATERIALS AND METHODS: This was a 2-year (2013 2014) retrospective analysis of patients diagnosed with anti-Jo-1-related AS. The presence of anti-Jo-1 antibody was tested by the immunoblot assay. All patients underwent high-resolution computed tomography of the chest, transthoracic echocardiography and evaluation for inflammatory myositis. Transbronchial lung biopsies and muscle biopsies were obtained when clinically indicated. RESULTS: Nine patients (mean age: 43.8 years) were diagnosed with anti-Jo-1-related AS. The median duration of symptoms before diagnosis of AS was 6 months. All patients were negative for antinuclear antibodies by indirect immunofluorescence. The prevalence of ILD, myositis and arthritis at presentation was 100%, 77.8% and 55.6%, respectively. The most common ILD pattern was non-specific interstitial pneumonia (n = 6) followed by organizing pneumonia (n = 2) and usual interstitial pneumonia (n = 1). ILD was the sole manifestation in two patients and was subclinical in two patients. Six patients had pleuropericardial effusions, three patients had pulmonary artery hypertension and two patients had venous thromboembolism. Eight of the nine patients improved after treatment with steroids and other immunosuppressants. CONCLUSION: Antisynthetase syndrome is an important and a treatable cause of ILD. Strong clinical suspicion is needed to achieve an early diagnosis. PMID- 26933303 TI - Drug resistance pattern of mycobacterial isolates in HIV and non-HIV population in South India. AB - BACKGROUND: Emergence of drug resistance has complicated the treatment of tuberculosis (TB). WHO reports India to be one among 27 "high burden" multidrug resistant (MDR) TB countries. OBJECTIVE: To diagnose TB and detect drug resistance of mycobacterial isolates in acid-fast bacilli (AFB) smear negative HIV reactive patients (Group A) and compare them with HIV seropositive AFB smear positive (Group B) and HIV-seronegative AFB positive cases (Group C). MATERIALS AND METHODS: Clinical specimens collected in all groups were processed as per the standard protocol except blood, which was processed by lysis centrifugation technique. They were then inoculated with Lowenstein-Jensen media and the isolates obtained were subjected to drug susceptibility test (DST) by proportion method and genotype MTBDR plus assay. RESULTS: In Group A, 162 patients were included. Of the 443 clinical samples collected, 76 mycobacterial strains were obtained from 67 (41%) patients. Of these, 50 (65.8%) were sensitive to all drugs and 26 (34.2%) resistant to one or more anti-tubercular drugs. Antibiogram of Group A when compared with Group B and C showed that the MDR rate 6.6%, 6.7% and 8% respectively) did not differ much; but resistance to at least single drug was (26 [34.2%], 3 [10%], and 8 [16%]), respectively. CONCLUSION: Our study suggests that HIV has no influence on the anti-tubercular resistance pattern, but increased MDR rate along with HIV in high TB burden setting stresses the need for early diagnosis and DST in providing proper regimens and improve prognosis. PMID- 26933304 TI - Resurvey of symptomatics of the Jaipur district population and suggestion for alternative diagnostic criteria of asthma for epidemiological surveys. AB - INTRODUCTION: The prevalence of asthma in Jaipur district of Rajasthan was reported as 0.96% in an earlier survey. It was far below the national average of 2.38%. It was reasoned then that this could be due to under diagnosis of asthma in the Jaipur population. MATERIAL AND METHODS: A resurvey of the symptomatics, not diagnosed as asthma at time of the original survey was, therefore, undertaken. The resurvey data were analysed and those who now fulfilled the twin criteria for diagnosis of asthma, as used in the original survey, were diagnosed as having asthma. The original data of these newly diagnosed asthma patients were reanalyzed in search for an alternative diagnostic criterion. RESULTS: Of the 382 symptomatics, 344 (90%) could be resurveyed and of them, 85 now fulfilled the twin diagnostic criteria for asthma. The reanalysis of the original survey data of these patients revealed that presence of shortness of breath (SOB) had the highest sensitivity, the presence of allergic symptoms in self or the family had the highest specificity and the presence of wheezing had the highest odds ratio (OR) for diagnosing asthma. Further, the OR for diagnosing asthma increased further and was highest with the presence of SOB and 2 additional symptoms. With the use of the "symptom criteria" for diagnosis of asthma i.e. the presence of SOB with 2 additional symptoms, it would have been possible to diagnose majority of the missed cases at the time of the original survey itself. CONCLUSIONS: Based on this study data it can be concluded that (a) the twin criteria for diagnosing asthma as used in earlier surveys led to under diagnosis of asthma and (b) the use of symptom criteria alone effectively checks the problem of under diagnosis of asthma. The symptom criteria are being suggested as an alternative method for use in future epidemiological surveys on asthma. PMID- 26933305 TI - Incremental shuttle walk test: Reference values and predictive equation for healthy Indian adults. AB - PURPOSE: Physical inactivity in Indians is leading to an increase in noncommunicable disorders at an early age in life. Early identification and quantification of the lack of physical activity using simple and reliable exercise testing is the need of the hour. The incremental shuttle walk test (ISWT) is an externally paced walk test widely used for the evaluation of exercise capacity. Currently the normative values available for clinical reference are generated from Western populations. Hence, the study was conducted to find normative values for the ISWT in healthy Indian adults (17-75 years). MATERIALS AND METHODS: A convenience sample of 862 subjects was recruited after ethical approval was obtained. All subjects were divided into groups as per age and gender. For age, the grouping was as follows: Group 1: Young adulthood (17-40 years), group 2: Middle adulthood (40-65 years), and group 3: Old adulthood (>65 years). The ISWT was performed as per standard protocol by Sally Singh. RESULTS: The average distance walked were 709.2m,556.4m and 441.3m in females and 807.9 m, 639.6 m and 478.2 m in males in the three respective age groups. Stepwise regression analysis revealed age and gender as key variables correlating with incremental shuttle walk distance (ISWD). The derived predictive equations for males and females may be given as follows: 740.351 - (5.676 * age) + (99.007 * gender). CONCLUSION: Reference values were generated for healthy Indian adults. Physiological response to the ISWT was shown to be affected by gender and increasing age. Easily measurable variables explained 68% of the variance seen in the test, making the reference equation a relevant part of the evaluation of the ISWT. PMID- 26933306 TI - Correlation between clinical characteristics, spirometric indices and high resolution computed tomography findings in patients of chronic obstructive pulmonary disease. AB - INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disease affecting the airways, leading to significant morbidity and mortality throughout the world. There is a need to have a holistic evaluation of COPD patients, other than just measuring the level of obstruction as performed by spirometry. High resolution computed tomography (HRCT) scan of thorax partly fulfills this requirement. MATERIALS AND METHODS: Fifty patients of COPD (confirmed on spirometry as per the GOLD guidelines 2014 guidelines) were enrolled, out of which 35 patients got a HRCT done. Complete clinical evaluation was done. The Philips computer program for lung densitometry was used with these limits (-800/-1, 024 Hounsfield unit [HU]) to calculate densities, after validating densitometry values with phantoms. We established the area with a free hand drawing of the region of interest, then we established limits (in HUs) and the computer program calculated the attenuation as mean lung density (MLD) of the lower and upper lobes. RESULTS: There was a significant correlation between smoking index and anteroposterior tracheal diameter (P = 0.036). Tracheal index was found to be decreasing with increasing disease severity which was statistically significant (P = 0.037). Mean upper lobe MLD was -839.27 HU, mean lower lobe MLD was -834.91 HU and the mean MLD was -837.08 HU. The lower lobes MLD were found to be decreasing with increasing disease severity. A mild linear correlation of pre forced expiratory volume in the first second (FEV1) was observed with lower lobe and total average MLD while a mild linear correlation of Post-FEV1 was observed with both coronal (P = 0.042) and sagittal (P = 0.001) lower lobes MLD. In addition, there was a linear correlation between both pre (P = 0.050) and post (P = 0.024) FEV1/forced vital capacity with sagittal lower lobe MLD. A predictive model can be derived to quantify obstruction severity (FEV1). CONCLUSION: HRCT may be an important additional tool in the holistic evaluation of COPD. HRCT can well be correlated with the spirometric and clinical features and the level of obstruction can be indirectly derived from it by measuring the MLD. PMID- 26933307 TI - Pulmonary involvement in rheumatoid arthritis: A cross-sectional study in Iran. AB - BACKGROUND: Interstitial lung disease (ILD) is a type of pulmonary manifestation in patients with rheumatoid arthritis (RA). Mostly RA-ILD has no symptoms and is only diagnosed by clinical examination, pulmonary function test (PFT), and high resolution computed tomography (HRCT); hence it seems that the diagnosis of pulmonary involvement in early stages of RA is of great importance. Therefore, we decided to answer this question whether the evaluation of RA patients without pulmonary symptoms using methods such as PFT and HRCT are justifiable and reasonable or not. METHODS: We conducted a cross-sectional study in a referral rheumatology clinic in Razi hospital of Rasht, Iran. Forty-four consecutive patients, diagnosed with RA, were enrolled. Physical examination of the joints was performed by an rheumatologist. The activity of RA was evaluated in all patients by Disease Activity Score 28. An expert pulmonologist performed the respiratory examination in all participants. Then, all subjects were referred for chest X-ray, PFT, and HRCT of lungs. RESULTS: Patients included in this study, 9 (20.45%) males and 35 (79.55%) females, were 21-73 years old and their mean age was 49 +/- 13 years. Significant relation between PFT and respiratory complaints was observed (P = 0.016). PFT had significant relation with respiratory examinations (P = 0.009). Our results indicated a significant relation between disease activity rate and PFT (P = 0.038). While HRCT had any significant relation with above items. CONCLUSION: We concluded, using PFT in the respiratory assessment of RA patients can be limited to persons with high disease activity, respiratory complaints, and positive findings in the clinical respiratory examination. PMID- 26933308 TI - Prognostic value of cardiac troponin I during acute exacerbation of chronic obstructive pulmonary disease: A prospective study. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a major cause of mortality and morbidity. It is the fourth leading cause of death worldwide. Acute exacerbations of COPD are common and are associated with worsening lung function and mortality. OBJECTIVES: To evaluate the prevalence of elevation of cTnI in patients admitted with acute exacerbation of COPD and to study its association with the need for ventilator support, duration of hospital stay, and in-hospital mortality. METHODS: In a prospective design, 50 patients admitted to our hospital with acute exacerbation of COPD were included. cTnI was assayed in a blood sample obtained at admission and 24 h later. Levels above 0.017 ug/L were taken as positive. The following data were also recorded-demographic data, pattern of tobacco use, clinical symptoms and signs, comorbidities, Glasgow Coma Scale, arterial blood gas, electrocardiogram/two-dimensional echocardiography, chest X ray, and peak expiratory flow rate. RESULTS: Among the 50 patients, 4 were females, and 46 were males. cTnI was positive in 32% of patients with a mean value of 0.272. Patients with cTnI positive were taken as Group I and those with negative were included in Group II. Prevalence of comorbidities was higher in cTnI positive group, so was the duration of COPD. cTnI elevation correlated significantly with the need for ICU admission and ventilator support. No significant difference was found in the duration of ventilator support, hospital stay, and in-hospital mortality. CONCLUSION: cTnI is elevated in a significant subset of patients with acute exacerbation of COPD. Duration of their illness was longer, higher incidence of ischemic heart disease was also found in these patients. Patients with cTnI elevation are more likely to require ICU care and ventilator support. However, it did not predict in-hospital mortality. Thus, it can be used as a marker to identify high-risk patients during acute exacerbation of COPD. PMID- 26933310 TI - Transbronchial lung biopsy with a flexible cryoprobe: First case report from India. AB - Sarcoidosis and tuberculosis are granulomatous disorders that mimic each other both clinically and radiologically. Both can present with fever and pulmonary nodules and often require the performance of transbronchial lung biopsy (TBLB) for diagnosis. In recent studies, the flexible cryoprobe for carrying out TBLB has been found to be useful in the diagnosis of disorders diffusely involving the lung parenchyma. Here, we present the case of a 29-year-old man who presented with fever and cough and was found to have multiple small nodules in both lungs. TBLB with a flexible cryoprobe helped in differentiating between sarcoidosis and tuberculosis. PMID- 26933309 TI - Depression in pulmonary arterial hypertension: An undertreated comorbidity. AB - Pulmonary arterial hypertension (PAH) is a debilitating condition leading to progressive decline in functional capacity. As a result, PAH can lead to psychological impairment that can impact the overall disease status. The medical community has developed several screening questionnaires in order to assess depression in their patients allowing physicians to be at the forefront of recognizing clinical depression. There is a suggestion that depression symptomatology is more prevalent in the PAH population. The aim of this article is to review the current thought process about diagnosis and management of depression in PAH patients. PMID- 26933311 TI - Pulmonary cryptosporidiosis in an immunocompetent host treated successfully with nitazoxanide. AB - Cryptosporidium parvum is an intracellular spore-forming protozoa which predominantly causes intestinal diseases. It causes severe and life-threatening diarrheal diseases in immunocompromised hosts and usually self-limiting disease in immunocompetent hosts. Extra-intestinal manifestations of cryptosporidium infection are very rare. Herein, we report a case of pulmonary cryptosporidiosis in a 35-yrs-old immunocompetent host, who presented with fever, cough and breathlessness which was soon followed by diarrhea and vomiting, had lung consolidation, and treated successfully with nitazoxanide. PMID- 26933312 TI - Different clinical and radiological features of solitary fibrous tumor of the pleura: Report of two cases. AB - We report two cases of solitary fibrous tumor of the pleura (SFTP). The first appeared in a young, new mother as a large mass in the upper lobe of the left lung that caused compression of lung parenchyma without significant respiratory symptoms but with polyarticular paraneoplastic syndrome; the other was documented by an occasional chest x-ray in a man affected by chronic obstructive pulmonary disease (COPD) as a small peripheral mass 4 years before and no longer controlled. Both patients underwent surgical resection with quick and full recovery. SFTP is a benign, slow growing neoplasm that is mostly localized. It appears in adult or elderly patients often with few symptoms. The computed tomography (CT) of the chest with contrast medium is important in order to see the shape of the mass and relationships with adjacent structures but only histology can provide the diagnosis. Surgery is the best treatment. PMID- 26933313 TI - Sarcoidosis and multiple myeloma: Concurrent presentation of an unusual association. AB - Literature on concurrent association of sarcoidosis with lymphoproliferative malignancies other than lymphoma e.g. multiple myeloma is meager. The rarity of the situation prompted us to report this patient who was a 51-year-old woman with a 2-years history of breathlessness, cough with expectoration, chest pain and backache. Initial evaluation revealed mild anemia, increased alkaline phosphatase with chest skiagram showing both lower zone non homogenous opacities with calcified hilar lymph nodes. CECT chest showed mediastinal with bilateral hilar lymphadenopathy, parenchymal fibrosis, traction bronchiectasis, ground glass opacities, septal and peribronchovascular thickening affecting mid and lower lung zones bilaterally. MRI Dorsolumbar spine was suggestive of marrow infiltrative disorder. EBUS FNA of intrathoracic nodes, EBB and TBLB confirmed sarcoidosis. PET CT revealed hyper metabolic activity in lung, multiple lymph nodes and lytic bone lesions. Serum protein electrophoresis and immunofixation revealed a monoclonal paraprotein, immunoglobulin IgG kappa type. Bone marrow biopsy revealed an increase in plasma cells (15%), but no granulomas. Diagnosis of Indolent or multiple myeloma with sarcoidosis was established. 12 cases of sarcoidosis and multiple myeloma have been reported in literature, and mostly preceding the onset of multiple myeloma by many years, in our case both were diagnosed concurrently. PMID- 26933314 TI - Pyopneumothorax of rare cause. AB - Rupture of pyriform sinus due to forced effort with closed glottis has been reported but is extremely rare. We report a case of rupture of pyriform sinus following multiple episodes of vomiting with subsequent development of pyopneumothorax. PMID- 26933315 TI - Inflammatory myofibroblastic tumor of the lung in pregnancy mimicking carcinoid tumor. AB - Inflammatory myofibroblastic tumors (IMT) are uncommon neoplasms of the lung in adults. They constitute less than 1% of all lung neoplasms and usually present as parenchymal masses. Diagnosis requires a high index of suspicion. They are characterized by spindle-shaped tumor cells (fibroblasts/myofibroblasts) in a background of lymphoplasmacytic infiltrate. About 50% of the tumors harbor an ALK gene rearrangement. They have to be differentiated from inflammatory pseudotumors (IPT), which show increased number of IgG4 plasma cells on immunostaining and are negative for anaplastic lymphoma kinase (ALK) protein. Herein, we present a case of a 28-year old female who presented with hemoptysis and was diagnosed with an IMT of lung in the first trimester of pregnancy. We have not only reviewed the occurrence of IMT during pregnancy but also discuss the management options for IMT during pregnancy. PMID- 26933316 TI - Diaphragmatic rupture precipitated by intercostal chest tube drainage in a patient of blunt thoraco-abdominal trauma. AB - Blunt thoraco-abdominal trauma in collision injuries in road traffic accident (RTA) occasionally results in diaphragmatic injury and rupture besides other serious multisystem injuries. These diaphragmatic injuries (DI) frequently go undetected specially when occur on the right side. DI associated with hemothorax need insertion of intercostal tube drainage (ICTD). ICTD has never been reported to precipitate diaphragmatic rupture and hernia. We are reporting such a rare case for the first time in medical literature. PMID- 26933317 TI - Pulmonary toxoplasmosis in human immunodeficiency virus-infected patients in the era of antiretroviral therapy. AB - Toxoplasmosis is a severe opportunistic infection in patients infected with the human immunodeficiency virus (HIV). The lung is a major site of infection after the central nervous system. In this report we described two cases of pneumonia due to Toxoplasma gondii infection in HIV patients with antiretroviral therapy. Clinical and radiological abnormalities are not specific. Pulmonary toxoplasmosis should be considered in HIV-infected patients with late stage of HIV, CD4 count less than 100 cells/ul and a poor adherence to HAART. PMID- 26933318 TI - Classic spectrum of interstitial lung diseases on HRCT. PMID- 26933319 TI - Mediastinal widening: An interesting quiz. PMID- 26933320 TI - Acral gangrene in sepsis. PMID- 26933321 TI - Noninvasive lung recruitment maneuver prevents reintubation and reduces ICU stay. PMID- 26933322 TI - Mucinous cyst adenocarcinoma of lung presented with recurrent pneumothorax. PMID- 26933323 TI - "Undulation on ventilator wave" may indicate serious lung pathology. PMID- 26933324 TI - Immune thrombocytopenic purpura in a case of tubercular pleural effusion: A rare presentation. PMID- 26933325 TI - Lung lysed: A case of Gaucher disease with pulmonary involvement. PMID- 26933326 TI - Acute changes in physiological cardiopulmonary parameters during and after flexible fiberoptic bronchoscopy. PMID- 26933327 TI - Pipe-cleaner sign. PMID- 26933328 TI - Phagocytic activity of neutrophils in chronic obstructive pulmonary disease. PMID- 26933329 TI - Response to "Miliary tuberculosis disease complicated by Pott's abscess in an infant: Seven-year follow-up". PMID- 26933330 TI - (18)F FDG-PET/CT of malignant thymoma with pleural and diaphragmatic metastases. PMID- 26933331 TI - Transbronchial lung biopsy in diffuse parenchymal lung disease - Question still remains whether to go for surgical lung biopsy or not? PMID- 26933332 TI - Unilateral hyperlucent lung. PMID- 26933333 TI - Erratum: Fluro-deoxygenase-positron emission tomography/computed tomography in hard metal lung disease. AB - [This corrects the article on p. 480 in vol. 32, PMID: 26628763.]. PMID- 26933334 TI - Intravenous thrombolysis: Still an important tool in the management of severe ischemic stroke patients. PMID- 26933335 TI - Neurologic complications and good outcomes from dengue virus infections. PMID- 26933336 TI - The role of imaging in Hirayama disease. PMID- 26933337 TI - Results of early cranial decompression as an initial approach for damage control therapy in severe traumatic brain injury in a hospital with limited resources. AB - INTRODUCTION: Severe traumatic brain injury (sTBI) is a disease that generates significant mortality and disability in Latin America, and specifically in Colombia. The purpose of this study was to evaluate the 12-month clinical outcome in patients with sTBI managed with an early cranial decompression (ECD) as the main procedure for damage control (DC) therapy, performed in a University Hospital in Colombia over a 4-year period. MATERIALS AND METHODS: A database of 106 patients who received the ECD procedure, and were managed according to the strategy for DC in neurotrauma, was analyzed. Variables were evaluated, and the patient outcome was determined according to the Glasgow Outcome Score (GOS) at 12 months postinjury. This was used to generate a dichotomous variable with "favorable" (GOS of 4 or 5) or "unfavorable" (GOS of 1-3) outcomes; analysis of variance was performed with the Chi-square, Wilcoxon-Mann-Whitney and Fisher tests. RESULTS: An overall survival rate of 74.6% was observed for the procedure, At 12 months postsurgery, a favorable clinical outcome (GOS 4-5) was found in 70 patients (66.1%), Unfavorable outcomes in patients were associated with the following factors: Closed trauma, an Injury Severity Score >16, obliterated basal cisterns, subdural hematoma as the main injury seen on the admission computed tomography, and nonreactive pupils observed in the emergency department. CONCLUSION: Twelve months outcome of patients with sTBI managed with ECD in a neuromonitoring limited resource University Hospital in Colombia shows an important survival rate with favorable clinical outcome measure with GOS. PMID- 26933338 TI - Hindi translation and evaluation of psychometric properties of Craig Hospital Inventory of Environmental Factors instrument in spinal cord injury subjects. AB - INTRODUCTION: The Craig Hospital Inventory of Environmental Factors instrument (CHIEF) is one of the few tools to assess the environmental barriers. The purpose of this study was to translate long and short CHIEF into Hindi language, and to determine its validity and reliability. DESIGN AND SETTING: The study design was observational case series with repeated measures. It was carried out at Indian Spinal Injuries Centre New Delhi, a specialized center for rehabilitation for spinal cord injury. METHODS: The CHIEF instrument was translated from English to Hindi based on the Beaton guidelines for the cross-cultural adaptation of health status measures. The Hindi version of the CHIEF instrument was then administered on a convenience sample of 30 spinal cord injured subjects. Its content validity, internal consistency, test-rest reliability (intraclass correlation coefficient [ICC] 2,1), standard error of measurement (SEM), and minimum detectable change (MDC) were determined for both the longer and shorter version. RESULTS: The mean +/- SD of total of Hindi-CHIEF instrument, longer version was 1.44 +/- 0.82 and total score of the shorter version was 1.07 +/- 0.66. The content validity determined by the content validity ratio was found to be 1 for all the items except item number 5, 11, and 12. The content validity index was 0.97 for the longer version and for the shorter version it was 0.98. Internal consistency, Cronbach's alpha value was found to be 0.92 and test-retest value (ICC 2,1) was 0.80 (P < 0.001). The MDC was found to be 0.99 and SEM was 0.36 for the longer version. The Cronbach's alpha was 0.731, ICC 2,1 was 0.63 (P < 0.001), SEM was 0.24, and MDC was 0.66 for the shorter version. CONCLUSION: The Hindi translated version of the CHIEF scale has acceptable content validity and reliability. It can be used to assess environmental barriers perceived by spinal cord injury patients. PMID- 26933339 TI - Stereotactic radiosurgery in hemangioblastoma: Experience over 14 years. AB - BACKGROUND: Although gamma knife has been advocated for hemangioblastomas, it is not used widely by neurosurgeons. OBJECTIVE: We review our experience over 14 years in an attempt to define the role of stereotactic radiosurgery (SRS) in the management of hemangioblastomas. PATIENTS AND METHODS: A retrospective study was conducted on all patients of hemangioblastoma who underwent SRS at our institute over a period of 14 years (1998-2011). Gamma knife plans, clinical history, and radiology were reviewed for all patients. RESULTS: A total of 2767 patients underwent gamma knife during the study period. Of these, 10 (0.36%) patients were treated for 24 hemangioblastomas. Eight patients (80%) had von Hippel-Lindau disease while two had sporadic hemangioblastomas. The median peripheral dose (50% isodose) delivered to the tumors was 29.9 Gy. Clinical and radiological follow-up data were available for eight patients. Of these, two were re-operated for persisting cerebellar symptoms. The remaining six patients were recurrence-free at a mean follow-up of 48 months (range 19-108 months). One patient had an increase in cyst volume along with a decrease in the size of the mural nodule. CONCLUSIONS: SRS should be the first option for asymptomatic hemangioblastomas. Despite the obvious advantages, gamma knife is not widely used as an option for hemangioblastomas. PMID- 26933340 TI - Impact on cognitive functions following gamma knife radiosurgery for cerebral arteriovenous malformations. AB - BACKGROUND: Radiosurgery is an alternative to surgical resection of arteriovenous malformation (AVM). Very few studies have addressed the concern of radiation injury to the brain and its attendant adverse effects on cognitive function. MATERIALS AND METHODS: This prospective study included all patients who underwent gamma knife radiosurgery (GKRS) at our institute for cerebral AVM between 2006 and December 2008 (n = 34). All patients underwent neuropsychological evaluation before the procedure. Neuropsychological evaluation was repeated in eighteen patients 2 years following GKRS. Clinical outcome, AVM obliteration, and factors influencing outcome were analyzed in these eighteen patients. RESULTS: Before GKRS, more than 50% had significant impairment of neuropsychological functions compared to normal population norms. 66.6% achieved the excellent radiosurgical outcome. At 2 years follow-up, patients showed varied improvement in neuropsychological function in various categories. Pretherapeutic median value for percentage perseverative responses was 26.5 and at follow-up, it reduced to 18.2 (P = 0.039). Set shifting improved in 11 patients (61.1%), remained same in 5 patients (27.7%), and deteriorated in two patients (11.1%). Patients with a higher Spetzler-Martin grade AVM demonstrated a significantly more favorable shift in follow-up test values for set shifting function (P = 0.021). Patients with postradiation imaging changes had lesser tendency to improve in neuropsychological performance at follow-up. CONCLUSIONS: GKRS has no clinically harmful effect on cognitive and neuropsychological functioning in patients with brain AVM. On the contrary, there is an improvement in majority of patients at 2 years following radiosurgery when nidus is obliterated. PMID- 26933341 TI - Outcomes of patients with large middle cerebral artery infarct treated with and without intravenous thrombolysis. AB - BACKGROUND: Many thrombolytic studies showed that severe stroke was associated with death and having symptomatic intracerebral hemorrhage and inversely related to a favorable outcome. AIMS: The purpose of this study is to compare the outcomes of patients with acute large middle cerebral artery (MCA) infarction with and without intravenous recombinant-tissue-plasminogen activator (rtPA) treatment. METHODS: Patients with acute, large MCA infarction (National Institute of Health Stroke Scale [NIHSS] >15) who were treated during 2011-2014 were studied. The demographic data and the outcomes were compared between patients with and without intravenous rtPA treatment. RESULTS: Two hundred and forty patients were included. Mean NIHSS score was 20. One hundred and twenty patients were treated with intravenous rtPA treatment. The patients with rtPA treatment had higher rates of favorable outcomes (39% vs. 17%, P < 0.001) and lower mortality rate (16% vs. 51%, P < 0.001). There was no significant difference in the occurrence of symptomatic intracerebral hemorrhage (6% vs. 4%, P = 0.715). CONCLUSIONS: The study showed the benefit and safety of intravenous rtPA treatment in patients with acute large MCA infarct. PMID- 26933342 TI - Down syndrome in tribal population in India: A field observation. AB - CONTEXT: Down syndrome (DS) is a prevalent genetic disorder in intellectual disability (ID) in India. Its prevalence in tribal population is not known. AIMS: The study aimed to understand the profile of DS in a tribal population with an objective of finding the prevalence of DS among those with ID. SETTINGS AND DESIGN: This is a community-based study with a survey design. SUBJECTS AND METHODS: A door-to-door survey was conducted by trained, community-based rehabilitation workers under close supervision of multidisciplinary team to identify people with ID. A standardized screening instrument National Institute for Mentally Handicapped-Developmental Screening Schedule was used in the survey. All identified ID cases were evaluated by therapists in IDs for diagnosis of ID on developmental screening test and Vineland social maturity scale. Clinical examination was performed by medical doctors for DS on people identified as ID. Only two parents brought their children for further lab investigations at Ashagram Trust, Barwani. STATISTICAL ANALYSIS USED: Descriptive statistics was applied manually to treat the data. RESULTS: The frequency of DS population in tribal population closely matches with DS prevalence in the USA. Mothers of DS children in the tribal community are relatively younger. CONCLUSION: Prevalence of DS in tribal population of India may greatly vary with that of the US data, but it is markedly associated with younger maternal age. Further studies are needed for prevalence and identification of potential correlates of this condition. PMID- 26933343 TI - Post-hoc principal component analysis on a largely illiterate elderly population from North-west India to identify important elements of mini-mental state examination. AB - BACKGROUND: Mini-mental state examination (MMSE) scale measures cognition using specific elements that can be isolated, defined, and subsequently measured. This study was conducted with the aim to analyze the factorial structure of MMSE in a largely, illiterate, elderly population in India and to reduce the number of variables to a few meaningful and interpretable combinations. METHODOLOGY: Principal component analysis (PCA) was performed post-hoc on the data generated by a research project conducted to estimate the prevalence of dementia in four geographically defined habitations in Himachal Pradesh state of India. RESULTS: Questions on orientation and registration account for high percentage of cumulative variance in comparison to other questions. DISCUSSION: The PCA conducted on the data derived from a largely, illiterate population reveals that the most important components to consider for the estimation of cognitive impairment in illiterate Indian population are temporal orientation, spatial orientation, and immediate memory. PMID- 26933344 TI - The dilemma of complicated shunt valves: How to identify patients with posthemorrhagic hydrocephalus after aneurysmatic subarachnoid hemorrhage who will benefit from a simple valve? AB - BACKGROUND: Sophisticated shunt valves provide the possibility of pressure adjustment and antisiphon control but have a higher probability of valve dysfunction especially in a posthemorrhagic setting. The aim of the present study is to analyze the clinical outcome of patients with shunt dependent posthemorrhagic hydrocephalus after aneurysmatic subarachnoid hemorrhage (SAH) in order to identify patients who would benefit from a simple differential pressure valve. METHODS: From 2000 to 2013, 547 patients with aneurysmatic SAH were treated at our institution, 114 underwent ventricular shunt placement (21.1%). 47 patients with available pre- and post-operative computed tomography scans, and an available follow-up of minimum 6 months were included. In order to measure the survival time which a nonprogrammable differential pressure valve would have had in an individual patient we defined the initial equalized shunt survival time (IESS). IESS is the time until surgical revisions of fixed differential pressure or flow-regulated valves for the treatment of over- or under-drainage as well as re-programming of adjustable valves due to over- or under-drainage. RESULTS: Twenty patients were treated with fixed differential pressure valves, 15 patients were treated with flow-regulated valves, and 12 underwent ventriculoperitoneal (VP) shunt placement with differential pressure valves assisted by a gravitational unit. Patients who reacted with remarkable changes of the ventricular width after the insertion of external ventricular drainage (EVD), before shunt placement, showed a significantly longer IESS. CONCLUSIONS: Decline of the ventricular width after EVD placement was a predictor for successful VP shunt therapy in the later course of disease. Possibly, this could allow identifying patients who benefit from a simple differential pressure valve or a flow-regulated valve, and thus could possibly avoid valve-associated complications of a programmable valve in the later course of disease. PMID- 26933345 TI - Feasibility and efficacy of thrombolysis in acute ischemic stroke: A study from National Institute of Neurological and Allied Sciences, Kathmandu, Nepal. AB - BACKGROUND: Stroke is the major cause of morbidity and mortality worldwide. The number of stroke patients receiving recombinant tissue plasminogen activator (rt PA), also known as Alteplase, in the developing world is extremely low. We aim to study the feasibility and efficacy of thrombolysis for the 1(st) time in our country. MATERIALS AND METHODS: In this retrospective study (July 2012-August 2015), acute ischemic stroke patients who were thrombolyzed within 3 h of stroke onset were included. Their demographic profiles, clinical profiles, risk factors, type of thrombolytic used, and outcomes were systematically recorded and analyzed. RESULTS: A total of 9 patients were thrombolyzed. The mean time from the onset of stroke symptoms to first dose of rt-PA (onset to treatment) was 1.2 h. Six patients had good neurological outcome as measured by modified Rankin Scale (mRS). The median mRS at discharge was 3. Thrombolysis-related post treatment complication was noted in 44.4%, of which nonfatal intracranial bleed occurred only in 2 patients (22.2%). None of the patients receiving intravenous tenecteplase had thrombolysis-related complications, and none of the patients had fatal intracranial bleed. CONCLUSION: This study clearly demonstrates the beginning of a feasible and effective thrombolysis in the treatment of acute ischemic stroke in Nepal. PMID- 26933346 TI - The QT dispersion and QTc dispersion in patients presenting with acute neurological events and its impact on early prognosis. AB - AIMS: To find out and investigate whether the QT dispersion and QTc dispersion is related to type and prognosis of the acute stroke in patients presenting within 24 h of the onset of stroke. SETTINGS AND DESIGN: This was a observational study conducted at Mahatma Gandhi Hospital, Dr. SN. Medical College, Jodhpur, during January 2014 to January 2015. SUBJECTS AND METHODS: The patients presented within 24 h of onset of acute stroke (hemorrhagic, infarction, or transient ischemic event) were included in the study. The stroke was confirmed by computed tomography scan and magnetic resonance imaging. Patients with (i) altered sensorium because of metabolic, infective, seizures, trauma, or tumor; (ii) prior history of cardiovascular disease, electrocardiographic abnormalities' because of dyselectrolytemia; and (iii) and patients who were on drugs (antiarrhythmic drugs, antipsychotic drugs, erythromycin, theophylline, etc.,) which known to cause electrocardiogram changes, were excluded from the study. National Institute of Health Stroke Score (NIHSS) was calculated at the time of admission and Modified Rankin Scale (MRS) at the time of discharge. Fifty age- and sex-matched healthy controls included. STATISTICAL ANALYSIS USED: Student's t-test, ANOVA, and area under curve for sensitivity and specificity for the test. RESULTS: We included 52 patients (male/female: 27/25) and 50 controls (26/24). The mean age of patients was 63.17 +/- 08.90 years. Of total patients, infarct was found in 32 (61.53%), hemorrhage in 18 (34.61%), transient ischemic attack (TIA) in 1 (1.9%), and subarachnoid hemorrhage in 1 (1.9%) patient. The QT dispersion and QTc dispersion were significantly higher in cases as compare to controls. (87.30 +/- 24.42 vs. 49.60 +/- 08.79 ms; P < 0.001) and (97.53 +/- 27.36 vs. 56.28 +/- 09.86 ms; P < 0.001). Among various types of stroke, the mean QT dispersion and QTc dispersion were maximum and significantly higher in hemorrhagic stroke as compared to infarct and TIA (P < 0.001). The mean QT dispersion and QTc dispersion was found significantly high in nonsurvivors (n = 16) as compared to survivors group (n = 36) (P < 0.05). The mean QT dispersion was directly correlated with the NIHSS and functional outcome score MRS. Patients with greater QT and QTc dispersion having high NIHSS had poor prognosis. CONCLUSION: We concluded that patients presenting with acute neurological events having increased QT dispersion and QTc dispersion is related to high mortality and poor functional outcomes on hospital discharge and if the values of dispersion score are very high we can predict for hemorrhagic stroke. PMID- 26933348 TI - Commentary. PMID- 26933347 TI - DOPA-sparing strategy in the treatment of young onset Parkinson's disease. AB - CONTEXT: Late onset Parkinson's disease (LOPD) is a neurodegenerative disorder afflicting individuals of ages 60 and older. However, 5-10% of cases can begin earlier between the ages 20 to 40, and are classified as young onset Parkinson disease (YOPD). AIM: In turn, this study aims to observe the trend in the choice of drug administered to patients with both YOPD and LOPD, with particular emphasis on this trend in its relation to the practice background of the neurologist. SETTINGS AND DESIGN: A cross-sectional study was conducted in a community based Parkinson's disease and movement disorder clinic. STATISTICAL ANALYSIS USED: Using a retrospective chart review data was obtained and analysed. RESULTS: The results showed that 83% of general neurologists prescribed levodopa to their patients with YOPD, whereas movement-disorder specialists took a different approach altogether. They opted not to use levodopa and, in its stead, prescribed a mixture of alternate drugs. PMID- 26933349 TI - Infratentorial posterior circulation stroke in a Nigerian population: Clinical characteristics, risk factors, and predictors of outcome. AB - BACKGROUND: Posterior circulation stroke (PCS), though less common, differs from stroke in anterior circulation in many aspects. Relatively, it portends a poorer prognosis. However, there is a paucity of data from African countries, in particular, where stroke is a menace. OBJECTIVE: The study aimed to evaluate the etiology, clinical characteristics, outcome, and predictors of outcome in a cohort of patients with IPCS in Northwestern Nigeria. MATERIALS AND METHODS: Out of 595 patients with stroke, we prospectively analyzed 57 patients with PCS in a Tertiary Care Center in Kano, Northwestern Nigeria. Patients were analyzed for demographic data, risk factors, clinical characteristics, stroke subtypes, mortality, and predictors of mortality. RESULTS: Posterior circulation ischemic stroke accounted for 57 (9.6%) of 595 of all strokes seen in the study period. They comprised 44 males (mean age 47.8 +/- 17.7) and 13 females (mean age 46.3 +/ 13.7). Overall, their age ranged between 24 and 90 (mean age 47.4 +/- 16.7). However, 52.7% of the patients were < 45 years of age. The most common site affected was the cerebellum seen in 33 (57.9%) patients. Hypertension was the most common risk factor (86%). Headache and vertigo were the most common features accounting for 83.6% and 86.3%, respectively. Thirty-eight (66.7%) patients had an ischemic stroke. Twenty-one (36.8%) of the patients died during the 1-month period of follow-up. Independent predictors of death in the study were hyperglycemia on admission and hemorrhagic stroke. CONCLUSIONS: IPCS occurred in a relatively younger age group. Headache and vertigo were the most common symptoms. The independent predictors of death in the study were hyperglycemia at presentation and hemorrhagic stroke. PMID- 26933350 TI - Reliability and sensitivity to change of the timed standing balance test in children with down syndrome. AB - OBJECTIVE: To estimate the reliability and sensitivity to change of the timed standing balance test in children with Down syndrome (DS). METHODS: It was a nonblinded, comparison study with a convenience sample of subjects consisting of children with DS (n = 9) aged 8-17 years. The main outcome measure was standing balance which was assessed using timed standing balance test, the time required to maintain in four conditions, eyes open static, eyes closed static, eyes open dynamic, and eyes closed dynamic. RESULTS: Relative reliability was excellent for all four conditions with an Interclass Correlation Coefficient (ICC) ranging from 0.91 to 0.93. The variation between repeated measurements for each condition was minimal with standard error of measurement (SEM) of 0.21-0.59 s, suggestive of excellent absolute reliability. The sensitivity to change as measured by smallest real change (SRC) was 1.27 s for eyes open static, 1.63 s for eyes closed static, 0.58 s for eyes open dynamic, and 0.61 s for eyes closed static. CONCLUSIONS: Timed standing balance test is an easy to administer test and sensitive to change with strong absolute and relative reliabilities, an important first step in establishing its utility as a clinical balance measure in children with DS. PMID- 26933351 TI - Can we evaluate cranial aneurysms on conventional brain magnetic resonance imaging? AB - PURPOSE: To evaluate the contribution of conventional brain magnetic resonance imaging (MRI) for the determination of intracranial aneurysms. MATERIALS AND METHODS: Brain MRI and computed tomography angiography (CTA) of 45 patients (29 women and 16 men; age range, 32-80 years) with aneurysm were analyzed. A comparison was made between brain MRI and CTA based on size and presence of aneurysm. The comparisons between MRI and CTA were investigated through Bland Altman graphics, receiver operating characteristic curve, and Kappa statistics. RESULTS: Fifty-seven aneurysms were evaluated. Forty-five percent of 57 aneurysms on CTA were detected on conventional brain MRI. A significant correlation was found between CTA and brain MRI in the diagnosis of aneurysm (P < 0.05). In an analysis of the size measurement, a significant correlation was observed between CTA and brain MRI. Seventy-seven percent of aneurysms <4 mm was not detected and the efficiency of MRI in the detection of aneurysms <4 mm was found to be low. CONCLUSION: Aneurysms can also be appreciated on conventional brain MRI, and vascular structures should be reviewed carefully while analyzing brain MRI. PMID- 26933352 TI - Surgical management of recurrent disc herniations with microdiscectomy and long term results on life quality: Detailed analysis of 70 cases. AB - BACKGROUND: Aim of this paper is to recall the surgical technique used in the recurrent lumbar disc herniations (LDHs) and to share our experiences. MATERIALS AND METHODS: Out of series of 1115 patients who underwent operations for LDH between 2006 and 2013, 70 patients underwent re-operations, which were included in this study. During surgery, lateral decompression performed over the medial facet joint to the superior facet joint border was seen after widening the laminectomy defect, and microdiscectomy was performed. The demographic findings of the patients, their complaints in admission to hospital, the level of operation, the condition of dural injury, the first admission in the prospective analysis, and their quality of life were evaluated through the Oswestry scoring during their postoperative 1(st), 3(rd), 6(th)-month and 1(st), 3(rd), 5(th) and 7(th)-year follow-up. In the statical analysis, Friedman test was performed for the comparison of the Oswestry scores and Siegel Castellan test was used for the paired nonparametrical data. A P < 0.05 was considered statistically significant. RESULTS: Considering the Oswestry Index during the follow-ups, the values in the postoperative early period and follow-ups were seen to be significantly lower than those at the time of admission to hospital (P < 0.05). None of the patients, who re-operated by microdiscectomy, presented with iatrogenic instability in 7 years follow-up period. CONCLUSION: Microdiscectomy performed through a proper technique in the re-operation of recurrent disc herniations eases complaints and improves the quality of life. Long-term follow-ups are required for more accurate results. PMID- 26933353 TI - How do repeat suicide attempters differ from first timers? An exploratory record based analysis. AB - BACKGROUND: Evidence indicates that repeat suicide attempters, as a group, may differ from 1(st) time attempters. The identification of repeat attempters is a powerful but underutilized clinical variable. AIMS: In this research, we aimed to compare individuals with lifetime histories of multiple attempts with 1(st) time attempters to identify factors predictive of repeat attempts. SETTING AND DESIGN: This was a retrospective record based study carried out at a teaching cum Tertiary Care Hospital in South India. METHODS: Relevant data was extracted from the clinical records of 1(st) time attempters (n = 362) and repeat attempters (n = 61) presenting to a single Tertiary Care Center over a 41/2 year period. They were compared on various sociodemographic and clinical parameters. The clinical measures included Presumptive Stressful Life Events Scale, Beck Hopelessness Scale, Coping Strategies Inventory - Short Form, and the Global Assessment of Functioning Scale. STATISTICAL ANALYSIS USED: First time attempters and repeaters were compared using appropriate inferential statistics. Logistic regression was used to identify independent predictors of repeat attempts. RESULTS: The two groups did not significantly differ on sociodemographic characteristics. Repeat attempters were more likely to have given prior hints about their act (chi(2) = 4.500, P = 0.034). In the final regression model, beck hopelessness score emerged as a significant predictor of repeat suicide attempts (odds ratio = 1.064, P = 0.020). CONCLUSION: Among suicide attempters presenting to the hospital, the presence of hopelessness is a predictor of repeat suicide attempts, independent of clinical depression. This highlights the importance of considering hopelessness in the assessment of suicidality with a view to minimize the risk of future attempts. PMID- 26933354 TI - Early management of traumatic brain injury in a Tertiary hospital in Central Kenya: A clinical audit. AB - BACKGROUND: Traumatic brain injury (TBI) is a major cause of death and disability worldwide and is mostly attributed to road traffic accidents in resource-poor areas. However, access to neurosurgical care is poor in these settings and patients in need of neurosurgical procedures are often managed by general practitioners or surgeons. MATERIALS AND METHODS: A retrospective clinical audit of the initial management of patients with TBI in Thika Level 5 Hospital (TL5H), a Tertiary Hospital in Central Kenya. Seventeen audit criteria divided into five clinical domains were identified and patient case notes reviewed for compliance with each criterion. Data were analyzed separately for those below 13 years owing to differences in response to brain trauma in those below this age. RESULTS: Overall, there was poor compliance with audit criteria in both groups. Among those below 13 years of age, only 3 out of 17 criteria achieved compliance and 4 out of 17 criteria achieved compliance for those above 13 years of age. Assessment for the need for a cervical radiograph (7.1% and 8.8% compliance) and administration of oxygen (21.4% and 20.6% compliance) had the worst performance in both groups. CONCLUSION: Poor compliance to audit criteria indicates the low quality of care for patients with TBI in TL5H. Quality improvement strategies with follow-up audits are needed to improve care. There is a need to develop and enforce evidence-based protocols and guidelines for use in the management of patients with TBI in sub-Saharan Africa. PMID- 26933355 TI - Advanced magnetic resonance neuroimaging in bulbar and limb onset early amyotrophic lateral sclerosis. AB - INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a fatal and most common motor neuron disease, caused by progressive loss of motor neurons. Diffusion tensor imaging (DTI) and magnetic resonance spectroscopic (MRS) studies detect pathological changes in neuronal fibers in vivo. We evaluated the role of DTI and MRS in early course of the disease, which may prove beneficial in the early diagnosis and better management. MATERIALS AND METHODS: Twenty-one patients with ALS and 13 age-matched controls received 1.5T DTI and three-dimensional multi voxel MRS. Fractional anisotropy (FA), apparent diffusion coefficient, N-acetyl aspartate (NAA)/Creatine (Cr), and NAA/Choline (Ch) ratios were analyzed in various regions of the brain and compared with healthy controls. ALS patients were classified as definite, possible, and probable category, and patients were also studied in limb versus bulbar onset. RESULTS: Decreased FA and increase mean diffusivity values in regions of corticospinal tract (CST) and corpus callosum (CC) was consistent finding in definite and probable disease category (P < 0.05). In possible disease, CC involvement was not significant. NAA/Cr and NAA/Ch ratios were lower in CC and regions of CST. However, in possible disease, CC involvement was not significant, while regions of CST were showing significant reduction in NAA/Cr and NAA/Ch ratios (P < 0.05). CONCLUSION: DTI and MRS detect changes associated with ALS even in the early phase of the disease. Bulbar onset and limb onset ALS patients show different pattern of involvement. Extramotor involvement suggested by CC involvement is a feature seen in bulbar onset patient and can suggest poor outcome in such patients. The present findings may be helpful for designing further studies in the direction of more early diagnosis of disease and its management. PMID- 26933356 TI - Influence of hydrotherapy on clinical and cardiac autonomic function in migraine patients. AB - BACKGROUND: Migraine is associated with autonomic symptoms. The growing body of literature suggests that the dysfunctional autonomic nervous system might play a pivotal role in the pathogenesis of migraine. Thermal therapies have been hypothesized to modulate these changes and alleviate pain. However, data regarding the efficacy of hydrotherapy in migraine remain scant. We evaluated the effect of add on hydrotherapy procedure (a hot arm and foot bath with ice massage to head) in migraine patients. METHODS: Forty chronic migraine patients fulfilling the International Classification of Headache Disorders II criteria were recruited from the neurology outpatient clinic. Patients were randomized to receive either hydrotherapy plus conventional pharmacological care (n = 20) or conventional medication only (n = 20). Hydrotherapy group received treatment with hot arm and foot bath (103 degrees F to 110 degrees F) and ice massage to head daily for 20 min for 45 days. Patients were assessed using headache impact test (HIT), visual analog scale for pain and cardiac autonomic function by heart rate variability (HRV) before and after intervention period. RESULTS: There was a significant decrease in HIT score, frequency, and intensity of headaches following treatment in both the groups. However, it was more evident in add on hydrotherapy group compared to pharmacological treatment alone group. There was also significant improvement in the HRV parameters. In particular, there was a significant decrease in heart rate (P = 0.017), increase in high frequency (HF) (P = 0.014) and decrease in low frequency/HF ratio (P = 0.004) in add on hydrotherapy group. CONCLUSION: Our study shows that add on hydrotherapy enhanced the vagal tone in addition to reducing the frequency and intensity of headaches in migraine patients. PMID- 26933357 TI - Clinico-radiological profile and outcome of dengue patients with central nervous system manifestations: A case series in an Eastern India tertiary care hospital. AB - BACKGROUND AND OBJECTIVE: Dengue, an acute viral disease, transmitted by Aedes mosquitoes, has a variable clinical spectrum ranging from asymptomatic infection to life-threatening dengue hemorrhagic fever and dengue shock syndrome. However, neurological complications, in general, are unusual but have been observed more frequently in the recent past, and some studies highlighted varied neurological complications during the course of illness. Although dengue is classically considered a nonneurotropic virus, there is increasing evidence for dengue viral neurotropism. In this study, we have evaluated clinico-radiological profile and outcome of nine serologically confirmed dengue patients having varied manifestations of central nervous system (CNS) involvement. MATERIALS AND METHODS: All the consecutive patients presented with neurological complications with positive serology for dengue infection (IgM positivity) in Department of Medicine, in a tertiary care hospital in Eastern India from August 2013 to October 2014 were included in the study. These patients were subjected to a detailed clinical evaluation, laboratory assessment including complete hemogram, coagulation profile, liver function test, serum electrolytes, and routine CSF (Cerebrospinal Fluid) study with the exclusion of other common neuroinvasive pathogens. RESULTS: Out of 9 patients with neurological complications associated with confirmed dengue infection, 2 (22%) patients had dengue encephalopathy, 5 (56%) patients have dengue encephalitis, 1 (11%) patient had dengue meningitis, and 1 (11%) patient had postdengue immune-mediated CNS involvement. CONCLUSION: This case series reaffirms the occurrence of varied CNS manifestations in dengue virus infection and underlines the importance of inclusion of dengue in the differential diagnosis of acute encephalitis syndrome. PMID- 26933358 TI - Dorsal spinal epidural psammomatous meningioma in an adult male. AB - Meningiomas are benign in nature and arise from the arachnoid cells. They are mostly situated in the intracranial compartment, whereas spinal meningiomas are rare. Approximately, in 10% of cases, an extradural component is seen but an exclusively extradural meningioma is quite uncommon. However, WHO Grade II (atypical) and Grade III (anaplastic) tumors can behave aggressively. We reported a case of purely extradural psammomatous meningioma in an adult male affecting the dorsal spine although uncommon meningiomas should be included in the differential diagnosis of extradural intraspinal masses. PMID- 26933359 TI - Neuroendoscopic treatment of idiopathic occlusion of unilateral foramen of Monro presenting as chronic headache. AB - Asymmetric ventriculomegly due to idiopathic occlusion of the foramen of Monro is rare. Such patients present with clinical features of raised intracranial pressure (ICP). Presentation as chronic headache has not been previously described. In the absence of raised ICP, pursuing surgical treatment raises a clinical dilemma as the headache may be a primary headache with no improvement after surgery. A 21-year-old woman presented with chronic headache. She was found to have asymmetric ventriculomegaly due to the occlusion of the foramen of Monro. She underwent endoscopic septostomy and widening of the foramen of Monro. Her headache subsided after surgery. At 15 months of follow-up, she was free from headache without medications. Unilateral occlusion of the foramen of Monro can present with asymmetric ventriculomegaly resulting in chronic headache. Though the symptoms of raised ICP may not be present, still endoscopic relief of ventriculomegaly leads to cure of headache. PMID- 26933360 TI - Commentary. PMID- 26933362 TI - Commentary. PMID- 26933361 TI - Cervical facet dislocation adjacent to the fused motion segment. AB - This study reports on a case that forces re-examination of merits and demerits of anterior cervical fusion. A 79-year-old male was brought to the emergency room (ER) of our hospital after he fell and struck the occipital region of his head following excessive alcohol consumption. Four years prior, he had undergone anterior cervical discectomy and fusion of C5/6 and a magnetic resonance imaging (MRI) performed 3 years after this surgery indicated that he was suffering from degeneration of C6/7 intervertebral discs. After arriving at the ER, he presented motor impairment at level C7 and lower of manual muscle testing grade 1 as well as moderate loss of physical sensation from the trunk and peripheries of both upper limbs to the peripheries of both lower limbs (Frankel B). Cervical computed tomography (CT) indicated anterior dislocation of C6/7, and MRI indicated severe spinal cord edema. We performed manipulative reduction of C6/7 with the patient under general anesthesia. Next, we performed laminectomy on C5-T1 and posterior fusion on C6/7. Postoperative CT indicated that cervical alignment had improved, and MRI indicated that the spinal cord edema observed prior to surgery had been mitigated. Three months after surgery, motor function and sensory impairment of the lower limbs had improved, and the patient was ambulatory upon discharge from the hospital (Frankel D). In the present case, although C5 and 6 were rigidly fused, degeneration of the C6/7 intervertebral disc occurred and stability was compromised. As a result, even slight trauma placed a severe dynamic burden on the facet joint of C6/7, which led to dislocation. PMID- 26933363 TI - En bloc resection of a thoracic chordoma is possible using minimally invasive anterior access: An 8-year follow-up. AB - Thoracic spine chordomas are a rare clinical entity and present several diagnostic and management challenges. Posterior debulking techniques are the traditional approach for the resection of thoracic tumors involving the vertebral body. Anterior approaches to the thoracic spine enable complete tumor resection and interbody fusion. However, this approach has previously required a thoracotomy incision, which is associated with significant perioperative morbidity, pain, and the potential for compromised ventilation and subsequent respiratory sequelae. The extreme lateral approach to the anterior spine has been used to treat degenerative disorders of the lower thoracic and lumbar spine, and reduces the potential complications compared with the anterior transperitoneal/transpleural approach. However, such an approach has not been utilized in the treatment of thoracic chordomas. We describe the first case of an en bloc resection of a thoracic chordoma via a minimally invasive eXtreme lateral interbody fusion approach. PMID- 26933364 TI - Extrapyramidal side-effects of low-dose aripiprazole in an 11-year-old child. AB - Partial agonism of D2 and 5-HT1A receptors accounts for the low incidence of extrapyramidal side-effects of aripiprazole. Extrapyramidal symptoms (EPS) during treatment with therapeutical doses of aripiprazole have been reported in adults and children. To the best of our knowledge, no cases of EPS with low doses (5 mg) have been reported until now. In this article, we present an 11-year-old child who developed EPS on low doses (5 mg) aripiprazole. This case emphasizes the need for careful surveillance for the development of EPS in patients treated even with low doses of aripiprazole. PMID- 26933365 TI - Spinal cord compression secondary to vertebral echinococcosis. AB - We describe a patient with progressive lower limb weakness and paresthesia 3 days after falling from a considerable height. Magnetic resonance imaging and computed tomography revealed collapsed Th2 and Th3 vertebrae. A tuberculous (TB) spondylitis was suspected, and anti-TB medication was started however with no clinical improvement. She was referred to our center and operated. A 3 level discectomy and 2 level corpectomy were performed with iliac bone grafting and anterior plating via an anterior cervical approach. The patient developed an esophagocutaneous fistula that was repaired and cured. The biopsy specimen showed a hydatid cyst of the vertebra as the cause of the lesion. After the result, she was started on oral albendazole. At follow-up nearly 4 months after surgery, the patient had regained significant power in her lower limbs with a muscular strength of 5/5 in both legs, thus making it possible to walk without support. PMID- 26933366 TI - Pediatric stiff-person syndrome with renal failure. AB - Stiff-person syndrome (SPS) is an autoimmune neuronitis with progressive myoclonus and stiffness. It is a rare but treatable disorder with few case reports in children. SPS is due to autoantibodies against the enzyme glutamic acid decarboxylase which is present in neuronal and nonneuronal tissues. This is the case report of an 8-year-old boy with clinical and investigational features suggestive of SPS with associated myoglobin-induced renal failure, who completely recovered with treatment. PMID- 26933367 TI - A toe that pointed the wrong way: An unusual presentation of tetanus. AB - We report the case of a 15-year-old girl who was initially diagnosed to have a striatal toe. Her condition progressed and she later developed clinical features consistent with tetanus. History of blunt trauma to nose was elicited retrospectively. Antimicrobial therapy with metronidazole and both active and passive immunization was started immediately. The patient went on to make a complete recovery. PMID- 26933368 TI - Neurological manifestations of Graves' disease: A case report and review of the literature. AB - Graves' disease (GD) is characterized by a hyperfunctioning thyroid gland due to stimulation of the thyroid-stimulating hormone receptor by autoantibodies directed against it. Apart from thyrotoxicosis, other clinical manifestations include ophthalmopathy, dermopathy, and rarely acropachy. GD is an organ-specific autoimmune disorder, and hence is associated with various other autoimmune disorders. Myasthenia gravis (MG) is one such disease, which is seen with patients of GD and vice versa. Though the association of GD and myasthenia is known, subtle manifestations of latter can be frequently missed in routine clinical practice. The coexistence of GD and ocular MG poses a significant diagnostic dilemma to treating physicians. The ocular manifestations of myasthenia can be easily missed in case of GD and falsely attributed to thyroid associated ophthalmopathy due to closely mimicking presentations of both. Hence, a high degree of the clinical vigil is necessary in such cases to appreciate their presence. We present a similar case which exemplifies the above said that the clinical challenge in diagnosing coexistent GD and ocular myasthenia. PMID- 26933369 TI - Kikuchi-Fujimoto disease presenting as brainstem encephalitis with secondary blepharospasm. AB - Central nervous system involvement in Kikuchi-Fujimoto disease is a very rare clinical manifestation. We report a 15-year-old girl who presented to us with fever, drowsiness, neck swellings, and involuntary closure of both eyelids of 2 days duration. Magnetic resonance imaging brain showed T2-weighted and fluid attenuated inversion recovery hyperintensities in dorsal midbrain and pons. Cervical lymph node fine-needle aspiration cytology was suggestive of Kikuchi Fujimoto disease. Blepharospasm secondary to infectious etiology is rare. Positron emission computed tomography brain showed increased focal uptake in anterior cingulate gyrus which can be the site of origin of blepharospasm. The patient was managed with steroids and trihexyphenidyl with significant recovery. Kikuchi-Fujimoto disease is a rare disease which has to be considered as one of the differential diagnosis in a case of acute encephalopathy with cervical lymphadenopathy. PMID- 26933370 TI - Isolated intermittent vertigo: A presenting feature of persistent trigeminal artery. AB - Embryonic carotid - basilar anastomosis when persistent in adult life can present with a variety of neurological symptoms. We present a patient with isolated intermittent vertigo attributable to the embryonic anastomosis and describe the different types of persistent trigeminal artery. A 76-year-old Caucasian man presented with isolated intermittent vertigo and symptoms suggestive of anterior and posterior circulation strokes. Impaired vasomotor reactivity was demonstrated on insonation of the anterior and posterior cerebral arteries in this patient with a persistent left trigeminal artery and 75% stenosis of the left internal carotid artery (ICA). The symptom of intermittent vertigo resolved with carotid endarterectomy. Decreased flow across the stenotic segment of the ICA which subserved the posterior circulation resulted in basilar insufficiency. Hypoperfusion to the flocculonodular lobe supplied by the anterior inferior cerebellar artery is a likely cause for the intermittent vertigo. PMID- 26933371 TI - Imaging in Hirayama disease. AB - Hirayama disease, also known as Sobue disease is a rare nonprogressive spinal muscular atrophy. Here, we report a case series of three young males presenting with atrophy of distal upper limb and Hirayama disease as their clinico radiological diagnosis. Magnetic resonance imaging (MRI) revealed loss of cervical lordosis with focal areas of lower cervical cord atrophy in a neutral position. MRI in flexion position revealed, anterior displacement of the detached posterior dura from the underlying lamina compressing the thecal sac and widened posterior epidural space with flow voids seen better on 3D-CISS images. All the three patients were managed conservatively. PMID- 26933372 TI - To evaluate the utility of 10 warning signs questionnaire in assessment of cognitive function among elderly people. AB - INTRODUCTION: Routine screening of high-risk elderly people for early cognitive impairment using mini-mental state examination (MMSE) and its modifications may be constrained by demographic and other variables. Warning signs (as reported by family/caregivers) may be a useful alternative. The present data analysis was carried out with the aim to identify the role of 10 warning signs screen as an alternative tool for screening for cognitive impairment among elderly. MATERIALS AND METHODS: For the purpose of this analysis (correlation), data available with us from a study conducted on the elderly population (60 years and above) from selected geographical areas (Migrant, Urban, Rural, and Tribal) of Himachal Pradesh was used. RESULTS: A high statistically significant was found between scores on 10 warning signs screen and Hindi mental state examination/Bharmouri mental state examination (modifications of MMSE). CONCLUSIONS: Ten warning signs screen can be an important screening total for assessment of cognitive impairment in the elderly Indians. PMID- 26933374 TI - Mercedes Benz craniosynostosis. PMID- 26933375 TI - Cerebral aneurysm with valvular heart disease: Anaesthetic management and challenges. PMID- 26933373 TI - Establishing a psychosomatic clinic in a low resource setting: Process, challenges, and opportunities. AB - BACKGROUND: Specialty psychosomatic clinics are a felt need in low- and middle income countries, but its benefits and challenges have not been reported so far. AIMS: To describe the process, challenges, and opportunities that we encountered in setting up a specialty psychosomatic clinic at a government medical college in South India. METHODS: The biweekly psychosomatic clinic was located in the Department of Psychiatry and manned by a multimodal team. Structured questionnaires were used to evaluate all patients. All psychiatric diagnoses were made as per International Classification of Diseases-10, clinical descriptions and diagnostic guidelines. Management comprised both pharmacotherapy and psychotherapeutic interventions. RESULTS: A total of 72 patients registered for services in the 1(st) year of the clinic. The mean age of the sample was 36.6 years (range 14-60 years). A median of 2 years and 19 visits to various care providers had elapsed before their visit to the clinic. The index contact was a general practitioner in the majority of cases though an overwhelming majority (95.6%) had also sought specialist care. The most common diagnostic cluster was the somatoform group of disorders (50.0%). Antidepressants were the most commonly prescribed medications (70.6%). CONCLUSION: The specialty psychosomatic clinic provided better opportunities for a more comprehensive evaluation of people with medically unexplained symptoms and better resident training and focused inter disciplinary research. It describes a scalable model that can be replicated in similar resource constrained settings. PMID- 26933376 TI - Subdural hematoma presenting as trigeminal neuralgia: A case report. PMID- 26933377 TI - A burning candle in the dark night-incidental intradiploic epidermoid cyst of occipital bone. PMID- 26933378 TI - Stroke in three patients due to spontaneous intra tumoral hemorrhage in meningiomas: Lessons learnt. PMID- 26933379 TI - Photo atlas of inner skull base using digital single lens reflex camera. PMID- 26933380 TI - Blunt orbital injury causing traumatic intracranial aneurysm in a child. PMID- 26933381 TI - A case of anterior cerebral artery A1 segment hypoplasia syndrome presenting with right lower limb monoplegia, abulia, and urinary incontinence. PMID- 26933382 TI - Introducing Phon: A Software Solution for the Study of Phonological Acquisition. PMID- 26933383 TI - Bone metastasis from malignant phyllodes breast tumor: report of two cases. AB - BACKGROUND: Phyllodes tumors are rare fibroepithelial tumors accounting for less than 1 % of all breast neoplasms. They are malignant in 20 % of cases. Only a few cases of malignant phyllodes tumors metastatic to bone have been reported. CASE PRESENTATION: Case 1: A 40 year-old white woman presented with three-week history of pain and functional impairment of the left lower limb. Her clinical past was remarkable for previous left mastectomy and radiotherapy for malignant phyllodes tumor performed one year ago. Computed tomography revealed a moth-eaten appearance of the left femoral head. The patient underwent computed guided femoral head biopsy. Pathological findings were consistent with metastatic malignant phyllodes tumor. The patient received ifosfamide and adriamycin chemotherapy. She is doing well without any evidence of progression on her imaging follow- up after 8 months. Case 2: A 48 year-old white woman, with history of bilateral mastectomy and radiotherapy for malignant phyllodes tumor performed one and two year ago, presented with four-week left lower quadrant abdominal pain. Computed tomography and magnetic resonance imaging revealed a solid aggressive osteolytic mass of the left iliac bone with extensive soft tissue invasion. Biopsy of the tumor was performed and showed a sarcomatous proliferation consistent with metastatic malignant phyllodes tumor. The patient received the same chemotherapy regimen as in the first case but without any response on her imaging follow up after 6 months. CONCLUSION: Malignant phyllodes tumor is a rare and aggressive fibroepithelial neoplasm. An accurate diagnosis of metastases should be based on clinicopathological correlation allowing exclusion of differential diagnoses. The goal of successful managing this tumor is early detection and complete resection prior to dissemination. PMID- 26933384 TI - Thai Nurses' experiences of post-operative pain assessment and its' influence on pain management decisions. AB - BACKGROUND: While many studies have addressed various issues with regards to pain management, there is limited knowledge about how nurses assess pain in surgical wards. This study aimed to describe Thai nurses' experiences of pain assessment in a surgical ward. METHODS: A cross-sectional explorative study was conducted. Participants were selected through theoretical sampling. Data was collected through interviews with twelve registered nurses working in surgical wards. Qualitative content analysis guided the analysis of the data. RESULTS: Nurses use a double/triple check system, communicated to the healthcare team via records and protocols, and they used their skills and experiences in pain assessment. The results showed that nurses missed the opportunity to include the patients' self reported pain in their accounts. Though much evidence of pain was collected, this did not seem to benefit the patients. Furthermore, the nurses were not using instruments to measure pain, which illustrates the potential unreliability of professionals who have differing opinions concerning the patients' pain. CONCLUSIONS: Thai nurses worked based on a 'patient-evidence' paradigm when assessing patients in pain; this should be shifted to an evidence-based paradigm. Furthermore, by including the patients' self-reported pain in their assessment, nurses would both improve the quality of the pain assessment and empower patients in their pain management. Pain management practices in Thailand should be improved through education, training, supportive innovation, and collegial competence development in order to improve the quality of care in the post operative field. PMID- 26933385 TI - Assessing time use in long-term institutional care: development, validity and inter-rater reliability of the Groningen Observational instrument for Long-Term Institutional Care (GO-LTIC). AB - BACKGROUND: Limited research has examined what is actually done in the process of care by nursing staff in long-term institutional care. The applied instruments employed different terminologies, and psychometric properties were inadequately described. This study aimed to develop and test an observational instrument to identify and examine the amount of time spent on nursing interventions in long term institutional care using a standardized language. METHODS: The Groningen Observational instrument for Long-Term Institutional Care (GO-LTIC) is based on the conceptual framework of the Nursing Interventions Classification. Developmental, validation, and reliability stages of the GO-LTIC included: 1) item generation to identify potential setting-specific interventions; 2) examining content validity with a Delphi panel resulting in relevant interventions by calculating the item content validity index; 3) testing feasibility with trained observers observing nursing assistants; and 4) calculating inter-rater reliability using (non) agreement and Cohen's kappa for the identification of interventions and an intraclass correlation coefficient for the amount of time spent on interventions. Bland-Altman plots were applied to visualize the agreement between observers. A one-sample student T-test verified if the difference between observers differed significantly from zero. RESULTS: The final version of the GO-LTIC comprised 116 nursing interventions categorized into six domains. Substantial to almost perfect kappa's were found for interventions in the domains basic (0.67-0.92) and complex (0.70-0.94) physiological care. For the domains of behavioral, family, and health system interventions, the kappa's ranged from fair to almost perfect (0.30-1.00). Intraclass correlation coefficients for the amount of time spent on interventions ranged from fair to excellent for the physiological domains (0.48-0.99) and poor to excellent for the other domains (0.00-1.00). Bland Altman plots indicated that the clinical magnitude of differences in minutes was small. No statistical significant differences between observers (p > 0.05) were found. CONCLUSIONS: The GO-LTIC shows good content validity and acceptable inter-rater reliability to examine the amount of time spent on nursing interventions by nursing staff. This may provide managers with valuable information to make decisions about resource allocation, task allocation of nursing staff, and the examination of the costs of nursing services. PMID- 26933386 TI - Decreased expression of Sushi Domain Containing 2 correlates to progressive features in patients with hepatocellular carcinoma. AB - BACKGROUND: Sushi Domain Containing 2 (SUSD2) has been identified as a regulator of colon and breast cancer. Increasing evidence suggests that SUSD2 plays a key role in tumorigenesis. However, the SUSD2 expression status and its functions in hepatocellular carcinoma (HCC) are still unrevealed. In the present study, we intended to investigate SUSD2 expression status and its correlation with the clinicopathological features in HCC patients. Furthermore,we examined the influence of SUSD2 on the proliferation, apoptosis, invasion and migration of the HCC cell lines HepG2 and SMMC7721. METHODS: We evaluated the SUSD2 expression in HCC tissues and paired normal liver tissues by quantitative real-time PCR and western blotting analysis. The clinicopathological significance of SUSD2 was investigated by immunohistochemistry (IHC) on a HCC tissue microarray. Receiver operating characteristic (ROC) analysis was applied to determine the optimal cut off score for positive expression of SUSD2. The correlation between SUSD2 protein expression and clinicopathological features of HCC was analyzed by Chi square test. The cell proliferation, apoptosis, invasion and migration potential were observed to detect the functions of SUSD2 in HCC cells. RESULTS: Decreased expression of SUSD2 mRNA and protein were observed in the majority of HCC tissues, compared with paired normal liver tissues. When SUSD2 high expression percentage was determined to be above 52.5 % (area under ROC curve = 0.769, P = 0.000), low expression of SUSD2 was observed in 62.2 % (112/180) of HCC tissues and high expression of SUSD2 was observed in all normal liver tissues (16/16) by IHC. Decreased expression of SUSD2 in patients was correlated with high histological grade (chi(2) = 5.198, P = 0.023), advanced clinical stage (chi(2) = 30.244, P = 0.000), pT status (chi(2) = 33.175, P = 0.000), pN status (chi(2) = 4.785, P = 0.029), pM status (chi(2) = 4.620, P = 0.032). Down-regulation of SUSD2 promoted cell proliferation,invasion and migration,reduced the cell apoptosis. CONCLUSIONS: Our findings suggest that SUSD2 may play as a tumor suppressor in HCC cells and could be served as an additional potential marker for diagnosis. PMID- 26933387 TI - Mortality and life expectancy in Kiribati based on analysis of reported deaths. AB - BACKGROUND: Kiribati is an atoll country of 103,058 (2010 Census) situated in the central Pacific. Previous mortality estimates have been derived from demographic analyses of census data. This is the first mortality analysis based on reported deaths. METHODS: Recorded deaths were from the Ministry of Health and the Civil Registration Office for 2000-2009; populations were from the 2000, 2005, and 2010 censuses. Duplicate death records were removed by matching deaths within and between data sources using a combination of names, date of death, age, sex, island of residence, and cause of death. Probability of dying <5 years (5q0) and 15-59 years (45q15), and life expectancy (LE) at birth, were computed with 95 % confidence intervals. These data were compared with previous census analyses. RESULTS: There were 8,681 unique deaths reported over the decade 2000-2009 in Kiribati. The reconciled mortality data indicate 5q0 for both sexes of 64 per 1,000 live births in 2000-2004, and 51 for 2005-2009 (assuming no under enumeration), compared with 69 and 59 for comparable periods from the 2005 and 2010 census analyses (children ever-born/children surviving method). Based on reconciled deaths, LE at birth (e0) for males was 54 years for 2000-2004 and 55 years in 2005-2009, five years lower than the 2005 and 2010 census estimates for comparable periods of 59 and 58 years. Female LE was 62 years for 2000-2004 and 63 years for 2005-2009, two-three years less than estimates for comparable periods of 63 and 66 years from the 2005 and 2010 census analyses. Adult mortality (45q15) was 47-48 % in males and 27-28 % in females from reconciled mortality over 2000-2009, higher than census estimates of 34-38 % in males and 21 26 % in females for the same periods. The reconciled data are very likely to be incomplete and actual mortality higher and life expectancy lower than reported here. CONCLUSION: This analysis indicates higher mortality than indirect demographic methods from the 2005 and 2010 Censuses. Reported deaths are most likely under-reported; especially 5q0, as many early neonatal deaths are probably classified as stillbirths. These analyses suggest that the health situation in Kiribati is more serious and urgent than previously appreciated. PMID- 26933389 TI - Editorial. PMID- 26933388 TI - Estimation of country-specific and global prevalence of male circumcision. AB - BACKGROUND: Male circumcision (MC) status and genital infection risk are interlinked and MC is now part of HIV prevention programs worldwide. Current MC prevalence is not known for all countries globally. Our aim was to provide estimates for country-specific and global MC prevalence. METHODS: MC prevalence data were obtained by searches in PubMed, Demographic and Health Surveys, AIDS Indicator Surveys, and Behavioural Surveillance Surveys. Male age was >=15 years in most surveys. Where no data were available, the population proportion whose religious faith or culture requires MC was used. The total number of circumcised males in each country and territory was calculated using figures for total males from (i) 2015 US Central Intelligence Agency (CIA) data for sex ratio and total population in all 237 countries and territories globally and (ii) 2015 United Nations (UN) figures for males aged 15-64 years. RESULTS: The estimated percentage of circumcised males in each country and territory varies considerably. Based on (i) and (ii) above, global MC prevalence was 38.7 % (95 % confidence interval [CI]: 33.4, 43.9) and 36.7 % (95 % CI: 31.4, 42.0). Approximately half of circumcisions were for religious and cultural reasons. For countries lacking data we assumed 99.9 % of Muslims and Jews were circumcised. If actual prevalence in religious groups was lower, then MC prevalence in those countries would be lower. On the other hand, we assumed a minimum prevalence of 0.1 % related to MC for medical reasons. This may be too low, thereby underestimating MC prevalence in some countries. CONCLUSIONS: The present study provides the most accurate estimate to date of MC prevalence in each country and territory in the world. We estimate that 37-39 % of men globally are circumcised. Considering the health benefits of MC, these data may help guide efforts aimed at the use of voluntary, safe medical MC in disease prevention programs in various countries. PMID- 26933390 TI - Present status of Accelerator-Based BNCT. AB - AIM: This work aims at giving an updated report of the worldwide status of Accelerator-Based BNCT (AB-BNCT). BACKGROUND: There is a generalized perception that the availability of accelerators installed in hospitals, as neutron sources, may be crucial for the advancement of BNCT. Accordingly, in recent years a significant effort has started to develop such machines. MATERIALS AND METHODS: A variety of possible charged-particle induced nuclear reactions and the characteristics of the resulting neutron spectra are discussed along with the worldwide activity in suitable accelerator development. RESULTS: Endothermic (7)Li(p,n)(7)Be and (9)Be(p,n)(9)B and exothermic (9)Be(d,n)(10)B are compared. In addition to having much better thermo-mechanical properties than Li, Be as a target leads to stable products. This is a significant advantage for a hospital based facility. (9)Be(p,n)(9)B needs at least 4-5 MeV bombarding energy to have a sufficient yield, while (9)Be(d,n)(10)B can be utilized at about 1.4 MeV, implying the smallest possible accelerator. This reaction operating with a thin target can produce a sufficiently soft spectrum to be viable for AB-BNCT. The machines considered are electrostatic single ended or tandem accelerators or radiofrequency quadrupoles plus drift tube Linacs. CONCLUSIONS: (7)Li(p,n)(7)Be provides one of the best solutions for the production of epithermal neutron beams for deep-seated tumors. However, a Li-based target poses significant technological challenges. Hence, Be has been considered as an alternative target, both in combination with (p,n) and (d,n) reactions. (9)Be(d,n)(10)B at 1.4 MeV, with a thin target has been shown to be a realistic option for the treatment of deep-seated lesions. PMID- 26933391 TI - Study on measuring device arrangement of array-type CdTe detector for BNCT-SPECT. AB - AIM: To design the measuring device arrangement of array-type CdTe detector for BNCT-SPECT. BACKGROUND: In a boron neutron capture therapy, a very serious unsolved problem exists, namely that the treatment effect for BNCT cannot be known during irradiation in real time. Therefore, we have been developing a so called BNCT-SPECT with a CdTe detector, which can obtain a three-dimensional image for the BNCT treatment effect by measuring 478 keV gamma-rays emitted from the excited state of (7)Li nucleus created by the (10)B(n,alpha) reaction. However, no practical uses were realized at present, because BNCT-SPECT requires very severe conditions for spatial resolution, measuring time, statistical accuracy and energy resolution. MATERIALS AND METHODS: The design study was performed with numerical simulations carried out by a 3-dimenaional transport code, MCNP5 considering the detector assembly, irradiation room and even arrangement of arrayed CdTe crystals. RESULTS: The estimated count rate of 478 keV gamma-rays was sufficiently large being more than the target value of over 1000 counts/h. However, the S/N ratio did not meet the target of S/N > 1. We confirmed that deterioration of the S/N ratio was caused by the influence of Compton scattering especially due to capture gamma-rays of hydrogen. Theoretical calculations were thereafter carried out to find out whether anti-Compton measurement in an array-type CdTe detector could decrease the noise due to Compton scatterings. CONCLUSIONS: The calculation result showed that the anti coincidence would possibly increase the S/N ratio. In the next phase, an arrayed detector with two CdTe crystals will be produced to test removal possibility of the anti-coincident event. PMID- 26933393 TI - Measurement of the (33)S(n,alpha) cross-section at n_TOF(CERN): Applications to BNCT. AB - AIM: The main purpose of this work is to present a new (n,alpha) cross-section measurement for a stable isotope of sulfur, (33)S, in order to solve existing discrepancies. BACKGROUND: (33)S has been studied as a cooperating target for Boron Neutron Capture Therapy (BNCT) because of its large (n,alpha) cross-section in the epithermal neutron energy range, the most suitable one for BNCT. Although the most important evaluated databases, such as ENDF, do not show any resonances in the cross-section, experimental measurements which provided data from 10 keV to 1 MeV showed that the lowest-lying and strongest resonance of (33)S(n,alpha) cross-section occurs at 13.5 keV. Nevertheless, the set of resonance parameters that describe such resonance shows important discrepancies (more than a factor of 2) between them. MATERIALS AND METHODS: A new measurement of the (33)S(n,alpha)(30)Si reaction cross-section was proposed to the ISOLDE and Neutron Time-of-Flight Experiments Committee of CERN. It was performed at n_TOF(CERN) in 2012 using MicroMegas detectors. RESULTS: In this work, we will present a brief overview of the experiment as well as preliminary results of the data analysis in the neutron energy range from thermal to 100 keV. These results will be taken into account to calculate the kerma-fluence factors corresponding to (33)S in addition to (10)B and those of a standard four-component ICRU tissue. CONCLUSIONS: MCNP simulations of the deposited dose, including our experimental data, shows an important kerma rate enhancement at the surface of the tissue, mainly due to the presence of (33)S. PMID- 26933392 TI - Detection of gammaH2AX foci in mouse normal brain and brain tumor after boron neutron capture therapy. AB - AIM: In this study, we investigated gammaH2AX foci as markers of DSBs in normal brain and brain tumor tissue in mouse after BNCT. BACKGROUND: Boron neutron capture therapy (BNCT) is a particle radiation therapy in combination of thermal neutron irradiation and boron compound that specifically accumulates in the tumor. (10)B captures neutrons and produces an alpha ((4)He) particle and a recoiled lithium nucleus ((7)Li). These particles have the characteristics of extremely high linear energy transfer (LET) radiation and therefore have marked biological effects. High LET radiation causes severe DNA damage, DNA DSBs. As the high LET radiation induces complex DNA double strand breaks (DSBs), large proportions of DSBs are considered to remain unrepaired in comparison with exposure to sparsely ionizing radiation. MATERIALS AND METHODS: We analyzed the number of gammaH2AX foci by immunohistochemistry 30 min or 24 h after neutron irradiation. RESULTS: In both normal brain and brain tumor, gammaH2AX foci induced by (10)B(n,alpha)(7)Li reaction remained 24 h after neutron beam irradiation. In contrast, gammaH2AX foci produced by gamma-ray irradiation at contaminated dose in BNCT disappeared 24 h after irradiation in these tissues. CONCLUSION: DSBs produced by (10)B(n,alpha)(7)Li reaction are supposed to be too complex to repair for cells in normal brain and brain tumor tissue within 24 h. These DSBs would be more difficult to repair than those by gamma-ray. Excellent anti-tumor effect of BNCT may result from these unrepaired DSBs induced by (10)B(n,alpha)(7)Li reaction. PMID- 26933395 TI - An improved neutron autoradiography set-up for (10)B concentration measurements in biological samples. AB - AIM: Boron Neutron Capture Therapy (BNCT) is a binary hadrontherapy which exploits the neutron capture reaction in boron, together with a selective uptake of boronated substances by the neoplastic tissue. There is increasing evidence that future improvements in clinical BNCT will be triggered by the discovery of new boronated compounds, with higher selectivity for the tumor with respect to clinically used sodium borocaptate (BSH) and boronophenylalanine (BPA). BACKGROUND: Therefore, a (10)B quantification technique for biological samples is needed in order to evaluate the performance of new boronated formulations. MATERIALS AND METHODS: This article describes an improved neutron autoradiography set-up employing radiation sensitive films where the latent tracks are made visible by proper etching conditions. RESULTS: Calibration curves for both liquid and tissue samples were obtained. CONCLUSIONS: The obtained calibration curves were adopted to set-up a mechanism to point out boron concentration in the whole sample. PMID- 26933394 TI - Radiotherapy dose enhancement using BNCT in conventional LINACs high-energy treatment: Simulation and experiment. AB - AIM: To employ the thermal neutron background that affects the patient during a traditional high-energy radiotherapy treatment for BNCT (Boron Neutron Capture Therapy) in order to enhance radiotherapy effectiveness. BACKGROUND: Conventional high-energy (15-25 MV) linear accelerators (LINACs) for radiotherapy produce fast secondary neutrons in the gantry with a mean energy of about 1 MeV due to (gamma, n) reaction. This neutron flux, isotropically distributed, is considered as an unavoidable undesired dose during the treatment. Considering the moderating effect of human body, a thermal neutron fluence is localized in the tumour area: this neutron background could be employed for BNCT by previously administering (10)B-Phenyl-Alanine ((10)BPA) to the patient. MATERIALS AND METHODS: Monte Carlo simulations (MCNP4B-GN code) were performed to estimate the total amount of neutrons outside and inside human body during a traditional X-ray radiotherapy treatment. Moreover, a simplified tissue equivalent anthropomorphic phantom was used together with bubble detectors for thermal and fast neutron to evaluate the moderation effect of human body. RESULTS: Simulation and experimental results confirm the thermal neutron background during radiotherapy of 1.55E07 cm(-2) Gy( 1). The BNCT equivalent dose delivered at 4 cm depth in phantom is 1.5 mGy-eq/Gy, that is about 3 Gy-eq (4% of X-rays dose) for a 70 Gy IMRT treatment. CONCLUSIONS: The thermal neutron component during a traditional high-energy radiotherapy treatment could produce a localized BNCT effect, with a localized therapeutic dose enhancement, corresponding to 4% or more of photon dose, following tumour characteristics. This BNCT additional dose could thus improve radiotherapy, acting as a localized radio-sensitizer. PMID- 26933396 TI - Experimental set up for the irradiation of biological samples and nuclear track detectors with UV C. AB - AIM: In this work we present a methodology to produce an "imprint" of cells cultivated on a polycarbonate detector by exposure of the detector to UV C radiation. BACKGROUND: The distribution and concentration of (10)B atoms in tissue samples coming from BNCT (Boron Neutron Capture Therapy) protocols can be determined through the quantification and analysis of the tracks forming its autoradiography image on a nuclear track detector. The location of boron atoms in the cell structure could be known more accurately by the simultaneous observation of the nuclear tracks and the sample image on the detector. MATERIALS AND METHODS: A UV C irradiator was constructed. The irradiance was measured along the lamp direction and at different distances. Melanoma cells were cultured on polycarbonate foils, incubated with borophenylalanine, irradiated with thermal neutrons and exposed to UV C radiation. The samples were chemically attacked with a KOH solution. RESULTS: A uniform irradiation field was established to expose the detector foils to UV C light. Cells could be seeded on the polycarbonate surface. Both imprints from cells and nuclear tracks were obtained after chemical etching. CONCLUSIONS: It is possible to yield cellular imprints in polycarbonate. The nuclear tracks were mostly present inside the cells, indicating a preferential boron uptake. PMID- 26933397 TI - Microdosimetry: Principles and applications. AB - AIM: to present the most important aspects of Microdosimetry, a research field in radiation biophysics. BACKGROUND: microdosimetry is the branch of radiation biophysics that systematically studies the spatial, temporal and spectral aspects of the stochastic nature of the energy deposition processes in microscopic structures. MATERIALS AND METHODS: we briefly review its history, the people, the formalism and the theories and devices that allowed researchers to begin to understand the true nature of radiation action on living matter. RESULTS AND CONCLUSIONS: we outline some of its applications, especially to Boron Neutron Capture Therapy, attempting to explain the biological effectiveness of the boron thermal neutron capture reaction. PMID- 26933398 TI - Effects of combined beta-hydroxy-beta-methylbutyrate (HMB) and whey protein ingestion on symptoms of eccentric exercise-induced muscle damage. AB - BACKGROUND: The purpose of this study was to examine the effects of combined beta hydroxy-beta-methylbutyrate (HMB) and whey protein ingestion on muscle strength and damage following a single bout of eccentric exercise. METHODS: Eighteen untrained male subjects were assigned to HMB and Whey protein (HMB + Whey; 3 g/day HMB and 36.6 g/day whey protein, n = 6), HMB (3 g/day, n = 6), or whey protein (36.6 g/day, n = 6) groups. Ingestion commenced 7 days before non dominant elbow flexor eccentric exercise (30 deg/sec, 6 reps * 7 sets) and continued until 4 days post-exercise. The maximal isometric strength, muscle soreness, plasma creatine kinase (CK), lactate dehydrogenase (LDH) were assessed pre-exercise, and at 1, 2, 3, and 5 days after exercise. RESULTS: The change scores of maximal isometric strength significantly decreased at day 1, 2, and 5 in the whey protein group compared to pre value and that in HMB + Whey protein and HMB groups decreased at day 1 and 5. The muscle soreness significantly increased in the whey and HMB + Whey protein groups at day 3 compared to pre value (p < 0.05). CK and LDH significantly increased (time effect: p < 0.05) after exercise. However, all data were not significant difference among the groups. CONCLUSIONS: These results suggest that ingestion of combined HMB and whey protein does not have a role to inhibit muscle strength loss and soreness, and decrease in muscle damage markers after eccentric exercise in comparison with HMB and whey protein alone. PMID- 26933399 TI - The proteomics of lung injury in childhood: challenges and opportunities. AB - Proteomics, the large-scale study of the structure and function of proteins of a cell or organism, is a rapidly developing area of biomedical research which is perfectly suited to the study of pediatric lung injury, where a variety of samples are easily, and repeatedly, accessible including plasma (reflecting a whole body response) and broncheoalveolar lung fluid (reflecting the lungs response). When applied to pediatric lung injury, proteomics could be used to develop much needed early biomarkers of lung injury, elucidate pathological pathways and determine protein alterations associated with specific disease processes. However despite the obvious benefits and need, proteomics is rarely utilized in studies of pediatric injury. This review primarily reports on the last decade of pediatric research into proteomes associated with specific respiratory diseases including bronchopulmonary dysplasia, respiratory infection, cystic fibrosis and asthma whilst also reflecting on the challenges unique to proteomic studies of the pediatric respiratory disease population. We conclude that the number of key pathological differences between the pediatric and adult study populations inhibit inference of results from adult studies onto a pediatric population and necessitate studies of the pediatric proteome. Furthermore the disparity amongst pediatric lung disease in terms of age at onset and underlying pathological mechanism (genetic, immunological, intervention based, developmental arrest, inhaled toxin) will require proteomic studies which are well designed, with large disease specific patient sets to ensure adequate power as well as matched controls. Regardless of causative agent, pulmonary biomarkers are needed to predict the clinical course of pediatric lung disease, status, progression and response to treatment. Identification of early biomarkers is particularly pertinent in order to understand the natural history of disease and monitor progression so prevention of ongoing lung injury and impact on childhood can targeted. PMID- 26933400 TI - Serum Vitamin D levels in patients with chronic kidney disease. AB - INTRODUCTION: Hypovitaminosis D is reported to be associated with several medical complications. Recent studies have reported a high worldwide prevalence of Vitamin D deficiency in the general population (up to 80 %). This is even higher in patients with chronic kidney disease (CKD) and increases with advancing stages of CKD. OBJECTIVES: To determine the difference in serum Vitamin D [25 hydroxyvitamin D, 25(OH) D] levels between CKD patients and normal healthy population. MATERIALS AND METHODS: A prospective cross-sectional study involving 50 normal volunteers (control) and 50 patients with CKD stages 2-4. Their demographic profiles were recorded and blood samples taken for serum 25(OH) D, intact parathyroid hormone (iPTH) and other routine blood tests. RESULTS: All subjects regardless of renal status had hypovitaminosis D (< 30ng/mL). The mean serum 25(OH) D were comparable in the control and CKD groups (15.3 +/- 4.2 ng/mL vs 16.1 +/- 6.2 ng/mL, p = NS). However, within the Vitamin D deficient group, the CKD group had lower levels of serum 25(OH) D [12.6(3.7) ng/mL vs 11.2(6.5) ng/mL, p = 0.039]. Female gender [OR 22.553; CI 95 % (2.16-235.48); p = 0.009] and diabetic status [OR 6.456; CI 95 % (1.144-36.433); p = 0.035] were independent predictors for 25(OH) D deficiency. CONCLUSIONS: Vitamin D insufficiency and vitamin D deficiency are indeed prevalent and under-recognized. Although the vitamin D levels among the study subjects and their control are equally low, the CKD group had severe degree of vitamin D deficiency. Diabetic status and female gender were independent predictors of low serum 25(OH)D. PMID- 26933401 TI - Inverse RNA folding solution based on multi-objective genetic algorithm and Gibbs sampling method. AB - In living systems, RNAs play important biological functions. The functional form of an RNA frequently requires a specific tertiary structure. The scaffold for this structure is provided by secondary structural elements that are hydrogen bonds within the molecule. Here, we concentrate on the inverse RNA folding problem. In this problem, an RNA secondary structure is given as a target structure and the goal is to design an RNA sequence that its structure is the same (or very similar) to the given target structure. Different heuristic search methods have been proposed for this problem. One common feature among these methods is to use a folding algorithm to evaluate the accuracy of the designed RNA sequence during the generation process. The well known folding algorithms take O(n(3)) times where n is the length of the RNA sequence. In this paper, we introduce a new algorithm called GGI-Fold based on multi-objective genetic algorithm and Gibbs sampling method for the inverse RNA folding problem. Our algorithm generates a sequence where its structure is the same or very similar to the given target structure. The key feature of our method is that it never uses any folding algorithm to improve the quality of the generated sequences. We compare our algorithm with RNA-SSD for some biological test samples. In all test samples, our algorithm outperforms the RNA-SSD method for generating a sequence where its structure is more stable. PMID- 26933402 TI - Resveratrol inhibits proteinase-activated receptor-2-induced release of soluble vascular endothelial growth factor receptor-1 from human endothelial cells. AB - We recently reported that (i) activation of the proinflammatory receptor, proteinase-activated receptor-2 (PAR-2) caused the release of an important biomarker in preeclampsia, soluble vascular endothelial growth factor receptor-1 (sVEGFR-1, also known as sFlt-1) from human umbilical vein endothelial cells (HUVECs), and (ii) that the anti-oxidant and anti-inflammatory agent, resveratrol, is capable of inhibiting the proinflammatory cytokine-induced sVEGFR 1 release from human placenta. Based on these findings and because PAR-2 is upregulated by proinflammatory cytokines, we sought to determine whether resveratrol can inhibit PAR-2-induced sVEGFR-1 release. PAR-2 expressing cells, HUVECs and human embryonic kidney cells (HEK-293) transfected with a human VEGFR 1 promoter-luciferase reporter construct were incubated with PAR-2-activating peptide and/or resveratrol. Cell supernatants were assayed for sVEGFR-1 by enzyme linked immunosorbent assay (ELISA), and VEGFR-1 promoter-luciferase assay was performed on the harvested cell lysates. Preincubation of HEK-293 cells with resveratrol significantly inhibited PAR-2-induced VEGFR-1 promoter activity without affecting cell viability as assessed by MTT assay. The addition of resveratrol also blocked PAR-2-mediated sVEGFR-1 release from HUVECs. The present study demonstrates that resveratrol suppressed both VEGFR-1 promoter activity and sVEGFR-1 protein release induced by PAR-2 activation, which further endorses our recent findings of a potential therapeutic role for resveratrol in preeclampsia. PMID- 26933403 TI - Chemical profile and antioxidant capacity verification of Psidium guajava (Myrtaceae) fruits at different stages of maturation. AB - Psidium guajava (Myrtaceae), a common plant in Cariri region, Ceara, Brazil, as well as in various parts of the world, contains high concentrations of bioactive compounds and in many communities its parts are used for therapeutic purposes. Studies describe antioxidant, antimicrobial and anti-diarrheal actions from extracts obtained from leaves, but information about the activities of the fruits and comparison of these at different maturity stages (immature, partially mature and mature) are scarce. This study aims to evaluate the antioxidant properties by quantifying the levels of phenolic and flavonoid compounds, carotenoids and vitamin C of P. guajava fruits at different stages of maturation. The content of phenolic compounds for the immature fruit, partially mature and mature were: 22.41; 34.61 and 32.92 mg of AG/g fraction. The flavonoid content for immature fruits, intermediate and mature were: 2.83; 5.10 and 5.65 mg RUT/g fraction, respectively. Following the same standards of maturation stages, the ascorbic acid content was determined with values of 0.48; 0.38 and 0.21 mg AA/g fraction, respectively. HPLC analysis identified and quantified the presence of gallic acid, catechin, chlorogenic acid, caffeic acid, epicatechin, rutin, quercitrin, isoquercitrin, quercetin, kaempferol, glycosylated campeferol, tocopherol, beta carotene and lycopene. The antioxidant activity carried out by DPPH method showed the mature fruits bearing the best results, whereas chelation of Fe2+ ions showed higher percentage for the immature fruit. The results obtained by lipidic peroxidation were not satisfactory. PMID- 26933404 TI - In vitro production of functional immune cells derived from human hematopoietic stem cells. AB - Hematopoietic stem cells (HSC) from cord blood are potentially high sources for transplantation due to their low immunogenicity and the presence of the multipotent cells. These cells are capable of differentiating to produce various lineages of blood cells under specific conditions. We have enriched highly purified CD34(+) cells from cord blood, determined in vitro growth of the cells in culture systems in the absence (condition A) or presence of GM-CSF and G-CSF (condition B), and determined the profile of immune cells during the period of cultivation by using flow cytometry. PhytohemagglutininA (PHA) was used as a mitogen to stimulate T lymphocytes derived from hematopoietic stem cells. GM-CSF and G-CSF prolonged the survival of the growing cells and also maintained expansion of cells in blastic stage. By day 12 of cultivation, when cell numbers peaked, various types of immune cells had appeared (CD14(+) cells, CD40(+)HLA DR(+) cells, CD3(+)CD56(+) cells, CD19(+) cells, CD3(+)CD4(+) cells, CD3(+)CD8(+)cells and CD3-CD56(+)). A significantly higher percentage of monocytes (p = 0.002) were observed under culture with GM-CSF, G-CSF when compared with culture without GM-CSF, G-CSF. In addition, T lymphocytes derived from HSC responded to 50 ug/ml of PHA. This is the first report showing the complete differentiation and proliferation of immune cells derived from CD34(+) HSC under in vitro culture conditions. Lymphocytes, monocytes, dendritic cells and polymorph nuclear cells derived from HSC in vitro are unique, and thus may benefit various studies such as innate immunity and pathophysiology of immune disorders. PMID- 26933405 TI - Biochemical and immunological parameters as indicators of osteoarthritis subjects: role of OH-collagen in auto-antibodies generation. AB - Osteoarthritis (OA) is characterized by inflammation of the knee joint, which is caused by accumulation of cytokines and C-reactive protein (CRP) in the extracellular matrix as an early immune response to infection. The articular cartilage destruction is discernible by elevated tumour necrosis factor-alpha (TNF-alpha). In this study, blood samples of knee osteoarthritis patients were analyzed for biochemical and physiological parameters based on the lipid profile, uric acid, total leukocyte count (TLC), hemoglobin percentage (Hb%) and absolute lymphocyte count (ALC). Furthermore, immunological parameters including TNF-alpha , interleukin-6 (IL-6) and CRP were analyzed. The presence of antibodies against hydroxyl radical modified collagen-II ((*)OH-collagen-II) was also investigated in arthritis patients using direct binding ELISA. The uric acid and lipid profiles changed extensively. Specifically, increased uric acid levels were associated with OA in both genders, as were enhanced immunological parameters. The TNF-alpha level also increased in both genders suffering from OA. Finally, auto-antibodies against OH-collagen II antigen were found in the sera of arthritis patients. These results indicated that immunological parameters are better predictors or indexes for diagnosis of OA than biochemical parameters. PMID- 26933406 TI - Hypophosphatemic effect of niacin extended release in ischemic kidney disease. AB - Ischemic nephropathy is an emerging cause of end stage renal disease, associated with many co-morbidities especially cardiovascular disease risk and derangement in calcium-phosphorus homeostasis resulting in hyperphosphatemia, influencing bones, a characteristic of advancing chronic kidney disease. The management of elevated serum phosphorus has been a challenge in this patient population with compromised kidney performance, as available phosphorus lowering agents possess many undesirable hazardous secondary effects and/or are very expensive. While niacin in different formulation is known to not only correct dyslipidemia but also reduce phosphorus level, but its clinical use restricted owing to side effects. The objective of present study is to evaluate such effect of niacin extended release (NER) in ischemic nephropathy. The chronic kidney disease patients fulfilling the pre-defined criteria were randomly categorized into two groups of equal size (n=60) and prescribed either atorvastatin 20 mg/day or NER 500 mg/day with the same dose of statin for four months. A control of 50 healthy characters matched was also incorporated for local reference range. Baseline and follow up phosphorus concentration was measured and means were compared using t test at SPSS version 17 with 0.05 chosen alpha. There was no difference in the baseline levels in both groups while significant (p<0.001) hyperphosphatemia was observed in both units as compared with healthy controls. The administration of atorvastatin alone for four weeks showed an insignificant decrease in phosphorus, whereas, NER significantly reduced phosphorus (p<0.001). The mean percent change from baseline to follow up further endorsed the finding as statin alone brought 13.8 % reduction in phosphorus and NER -47 % from baseline. NER, at its lowest prescribed dose once a day was well tolerated by most of the patients and demonstrated significant goal achievement of phosphorus reduction. It is concluded that NER even at low doses in renal compromised dyslipidemic patients may be a promising approach to prevent the harmful vascular, valvular effects caused by hyperphosphatemia in addition to its principal target of HDL-C elevation. PMID- 26933407 TI - A Case of Infantile Kyrle-Flegel Disease in a 6-Year-Old Yemeni Girl. AB - Kyrle disease (KD) and Flegel disease (FD) are rare variants of primary perforating dermatoses, characterized by transepidermal elimination of abnormal endogenous materials. We describe a 6-year-old Yemeni girl with a 2-year history of generalized asymptomatic, small, reddish-brown keratotic papules with a lenticular central keratotic plug. Although these features are synonymous with FD, the histology of a punch biopsy was consistent with KD. The patient was otherwise healthy, and no family members had a history of similar diseases. The patient was diagnosed with KD-FD, owing to the manifestation of features associated with both diseases. PMID- 26933408 TI - Allergy to Red Meat: A Diagnosis Made by the Patient and Confirmed by an Assay for IgE Antibodies Specific for Alpha-1,3-Galactose. AB - We report the first case of allergy to red meat observed in Ivory Coast. A 49 year-old male presented with pruritus. The diagnosis of allergy to red meat was confirmed by an assay for IgE antibodies specific for alpha-1,3 galactose. Interestingly, the disease was considered a spell to the patient who was suspected of being a sorcerer by the community. PMID- 26933409 TI - Fixed Drug Eruption due to Achiote Dye. AB - Fixed drug eruption (FDE) is a localized type IV sensitivity reaction to a systemically introduced allergen. It usually occurs as a result of new medication, making identification and avoidance of the trigger medication straightforward; however, in a rare subset of cases no pharmacological source is identified. In such cases, the causative agent is often a food or food additive. In this report we describe a case of a FDE in a 12-year-old girl recently immigrated to the United States from Ecuador who had no medication exposure over the course of her illness. Through an exhaustive patient history and literature review, we were able to hypothesize that her presentation was caused by a dietary change of the natural achiote dye used in the preparation of yellow rice to a locally available commercial dye mix containing tartrazine, or Yellow 5, which has previously been implicated in both systemic hypersensitivity reactions and specifically in FDE. This report adds to the small body of available literature on non-pharmacological fixed hypersensitivity eruptions and illustrates an effective approach to the management of such a presentation when history is not immediately revealing. PMID- 26933410 TI - Erythrodermia Congenitalis Ichthyosiformis Bullosa of Brocq. AB - A 50-year-old man presented with congenital scaling and hyperkeratosis on his palms, the soles of his feet and the extensor areas of his joints. The flexural areas were unaffected. His maternal grandmother, questionably his maternal uncle, his mother, all three brothers, one of his two sisters as well as two nephews and three nieces have or had similar skin changes. A punch biopsy was taken from the left palm. Clinical and histological signs led to the diagnosis of erythrodermia congenitalis ichthyosiformis bullosa of Brocq. We confirmed this genetically and found a heterozygous duplication (c.1752dupT) in the keratin 1 gene (KRT-1). To our knowledge, this is the first case of this skin condition reported in the literature with a heterozygous duplication (c.1752dupT) in KRT-1. PMID- 26933411 TI - Extranodal Natural Killer/T-Cell Lymphoma of the Nasal Type with Skin Metastases. AB - Extranodal natural killer/T-cell lymphoma (ENKL) of the nasal type is a rare, clinically aggressive disease. ENKL of the nasal type is often localized in the upper aerodigestive tract, including the nasal cavity, nasopharynx, paranasal sinuses, tonsils, hypopharynx and larynx, and usually presents as stage I/II. Extranasal involvement can occur, and a common site of extranasal involvement or metastatic disease includes the skin. Identifying skin metastases is important for the appropriate staging and treatment. We report a case of ENKL of the nasal type that presented with localized disease and subsequent skin lesions that were consistent with skin metastases. PMID- 26933412 TI - A Case of Advanced Extramammary Paget's Disease Successfully Controlled by Monthly but Not Weekly Docetaxel Chemotherapy. AB - Extramammary Paget's disease (EMPD) is an uncommon cutaneous adenocarcinoma arising from the apocrine glands within the epidermis or underlying skin appendages in the anogenital and axillary regions. Surgical excision is basically performed as a treatment for EMPD. However, therapeutic options for EMPD in an advanced stage are limited. Herein, we report the case of a Japanese woman with advanced EMPD successfully controlled by monthly but not weekly docetaxel therapy. We also demonstrate the possibility that a monthly regimen of docetaxel is a more effective and optimal schedule than a weekly one through this case report. PMID- 26933413 TI - Chondrosarcoma of the Rib Mimicking Malignant Pleural Mesothelioma. AB - A 62-year-old man with a history of long-term asbestos exposure was found to have a chest wall tumor invading the sixth rib on chest computed tomography. The computed tomography also revealed multiple plaques in the pleura. Malignant pleural mesothelioma was suspected, and thoracoscopic surgery was performed. Thoracoscopy revealed that the tumor location was extrapleural. Thus, excisional biopsy was performed. The tumor was histologically diagnosed as chondrosarcoma. Additional wide resection of the chest wall, including the fifth, sixth, and seventh ribs, was performed. Chest wall reconstruction was performed with a polypropylene mesh. PMID- 26933414 TI - Exceptional Response to Nanoparticle Albumin-Bound Paclitaxel and Gemcitabine in a Patient with a Refractory Adenocarcinoma of the Ampulla of Vater. AB - Ampullary carcinoma is a rare tumor and evidence on the treatment of recurrent metastatic disease is scarce. We report the case of a 60-year-old patient with an R0-resected node-positive adenocarcinoma of the papilla of Vater of an initially diagnosed intestinal subtype who developed pulmonary metastases 2 months after adjuvant gemcitabine chemotherapy and, subsequently, liver metastases. Palliative combination chemotherapy with standard regimens for intestinal-type adenocarcinoma (FOLFOX and FOLFIRI) failed. However, subsequent combination chemotherapy with nanoparticle albumin-bound paclitaxel and gemcitabine, a regimen with proven efficacy in metastatic adenocarcinoma of the pancreas, resulted in a durable, very good partial remission. Treatment was manageable and well tolerated. Primary tumor and metastatic tissue were reassessed by immunohistochemistry and had to be reclassified to a mixed phenotype containing predominant elements of the pancreatobiliary subtype. Our case suggests that combination chemotherapy with nanoparticle albumin-bound paclitaxel and gemcitabine could represent a promising option for the treatment of this rare disease and warrants further investigation within controlled clinical trials. Moreover, thorough characterization of ampullary carcinomas by histomorphology and additional immunohistochemistry should become mandatory in order to start a chemotherapeutic regimen tailored for the definitive subtype. PMID- 26933415 TI - Metastatic Mantle Cell Lymphoma to the Pituitary Gland: Case Report and Literature Review. AB - We present an unusual case of a metastatic mantle cell lymphoma (MCL) to the pituitary gland. The patient had a known history of MCL for which she previously received chemotherapy. She presented with new-onset diplopia and confusion, and reported a history of progressive vision blurriness associated with headache, nausea, and vomiting. MRI of the brain showed an enhancing lesion within the sella turcica involving the cavernous sinuses bilaterally, extending into Meckel's cave on the left, and abutting the optic nerves bilaterally. Following surgical excision, histopathology revealed the tumor to be a MCL. Metastatic pituitary tumors are rare and have been estimated to make up 1% of tumors discovered in the sellar region. The two most common secondary metastatic lesions to the sella are breast and lung carcinoma followed by prostate, renal cell, and gastrointestinal carcinoma. Metastatic lymphoma to the pituitary gland is especially rare and is estimated to constitute 0.5% of all metastatic tumors to the sella turcica. To our knowledge, this is the first reported case of MCL metastasizing to the pituitary gland. PMID- 26933416 TI - Unilateral Arm Urticaria Presenting as a Paraneoplastic Manifestation of Metachronous Bilateral Breast Cancer. AB - Various paraneoplastic syndromes (PNS) are reported to be associated with breast cancer and can range from mild dermatological symptoms to severe neurological complications. Neurological and dermatological manifestations tend to be the more commonly seen paraneoplastic manifestations, albeit both are relatively rare. Diagnosis of the underlying malignancy is often delayed since the presence and severity of paraneoplastic manifestations are not dependent on the tumor size or stage. Herein, we describe a unique case of unilateral arm urticaria presenting as a paraneoplastic manifestation of metachronous bilateral breast cancer. Similar reports and other PNS associated with breast cancer are described. Recognition of PNS associated with underlying malignancies and age-appropriate screening can facilitate diagnosis of the underlying occult malignancy. Resection of the underlying malignancy can lead to resolution and/or improvement of the PNS for some patients. PMID- 26933417 TI - A Case of Myxofibrosarcoma in an Unusual Thoracic Location. AB - Myxofibrosarcoma is a soft tissue neoplasm composed of malignant fibroblasts with a myxoid matrix. It is commonly found in patients during their 6th through 8th decades of life with a slight male predominance. Myxofibrosarcomas are classified as low- to high-grade tumors that are differentiated by hypercellularity, variation of mitotic activity and degree of necrosis. The most common sites are the extremities (77%) and trunk (12%), with the retroperitoneum and mediastinum being very rare. In this case report, we describe a patient presenting with myxofibrosarcoma of the mediastinum, a rare site for the development of myxofibrosarcoma. This case of primary mediastinal myxofibrosarcoma appears to be only the second described in the English-language literature. PMID- 26933418 TI - RRx-001-Induced Tumor Necrosis and Immune Cell Infiltration in an EGFR Mutation Positive NSCLC with Resistance to EGFR Tyrosine Kinase Inhibitors: A Case Report. AB - We present the case of a 49-year-old male with metastatic epidermal growth factor receptor (EGFR) mutation-positive adenocarcinoma of the lung that continues to outlive stage IV diagnosis of non-small cell lung cancer after treatment with RRx 001, an experimental anticancer agent with epigenetic and immunologic activity, in the context of a phase II clinical trial called TRIPLE THREAT. Currently, no adequate treatment options exist for patients with EGFR mutation-positive tumors who have failed a 1st-generation tyrosine kinase inhibitor (erlotinib or gefitinib) treatment and do not develop a resistant mutation. Biopsy of a large pancreatic metastasis after RRx-001 demonstrated extensive necrosis with CD3+ and CD8+ immune cell infiltration that appears to correlate with prolonged survival despite end-stage disease. These results suggest that the mode of action of RRx 001 is related to immune stimulation in addition to epigenetic inhibition. PMID- 26933420 TI - Pseudomyxoma Peritonei: Symptom Control and Objective Radiological Response after Treatment with Lanreotide Autogel. AB - Peritoneal mucinous carcinomatosis is an aggressive subtype of pseudomyxoma peritonei, which often leads to inoperable bowel obstruction and, ultimately, death. Due to the poor prognosis, treatment is often symptomatic and aimed at alleviating the symptoms - pain, nausea, and vomiting - associated with gastrointestinal obstruction. Due to their antisecretory activity, somatostatin analogues are commonly prescribed in such cases. In the case presented here, a patient diagnosed with disseminated peritoneal mucinous carcinomatosis of appendiceal origin responded well to symptomatic treatment with lanreotide Autogel((r)) at a dose of 120 mg/28 days. More importantly, radiological evidence of a reduction in peritoneal ascites, indicative of antiproliferative activity, was observed. These findings are important, particularly given the negative impact of this disease on both quality of life and survival. This case adds to the growing body of evidence supporting the antiproliferative and antisecretory activity of lanreotide Autogel. PMID- 26933419 TI - Successful Management of Crizotinib-Induced Neutropenia in a Patient with Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer: A Case Report. AB - Crizotinib, the first clinically available inhibitor of anaplastic lymphoma kinase (ALK) gene rearrangement, is generally well tolerated. In contrast, neutropenia induced by crizotinib is a commonly reported grade 3 or 4 adverse event. In such cases, interruption and dose reduction of crizotinib might be necessary for some patients with severe neutropenia. However, information concerning clinical experience and management of severe neutropenia is currently limited. In this report, the successful management of crizotinib-induced neutropenia by dose reduction of crizotinib in a patient with ALK-positive non small cell lung cancer is described. PMID- 26933421 TI - Partial Response to Platinum Doublets in Refractory EGFR-Positive Non-Small Cell Lung Cancer Patients after RRx-001: Evidence of Episensitization. AB - RRx-001, an experimental systemically non-toxic epi-immunotherapeutic agent, which potentiates the resensitization of resistant cancer cells to formerly effective therapies, is under active investigation in several clinical trials that are based on sequential or concomitant rechallenge to resistant first- or second-line regimens. One of these trials is designated TRIPLE THREAT (NCT02489903), because it explores the conditioning or priming effect of RRx-001 on three tumor types - non-small cell lung cancer (NSCLC), small cell lung cancer and high-grade neuroendocrine tumors - prior to re-administration of platinum doublets. In follow-up to a recent case study, which describes early monotherapeutic benefit with RRx-001 in a refractory EGFR-mutated NSCLC tumor, we present subsequent evidence of a radiological partial response to reintroduced platinum doublets after RRx-001. For the 50% of patients with EGFR-mutated NSCLC who progress on EGFR-tyrosine kinase inhibitors (without evidence of a T790M mutations) as well as platinum doublets and pemetrexed/taxane, no other clinically established treatment options exist. A retrial of these therapies in EGFR-positive NSCLC patients via priming with epigenetic agents such as RRx-001 constitutes a strategy to 'episensitize' tumors (i.e. reverse resistance by epigenetic means) and to extend overall survival. PMID- 26933422 TI - The Case of a Zebra That Was Misdiagnosed as a Horse: Pulmonary Tumor Thrombotic Microangiopathy, a New Paraneoplastic Syndrome, Mimicking PD-1-Induced Pneumonitis. AB - A case report of a 47-year-old woman with triple-negative breast cancer on a clinical trial called PRIMETIME (NCT02518958) who received the anti-PD-1 inhibitor nivolumab and the experimental anticancer agent RRx-001 is presented. Although initially diagnosed and treated for anti-PD-1-induced pneumonitis, clinical and radiological abnormalities triggered further investigation, leading to the diagnosis of pulmonary tumor thrombotic microangiopathy (PTTM). This example highlights the importance of exercising due diligence in determining immune-related adverse events and suggests that PD-1-induced pneumonitis should be a diagnosis of exclusion rather than a diagnosis by default. A case history and review of the literature are presented for PTTM, which we propose to define as a paraneoplastic syndrome. PMID- 26933423 TI - Case Report of Cirrhosis following Yttrium-90 Radioembolization for Pancreatic Neuroendocrine Liver Metastases. AB - BACKGROUND: Management options for pancreatic neuroendocrine tumors (pNETs) metastatic to the liver include surgical, ablative, cytotoxic, and radioisotope approaches. One potential local treatment option includes selective internal radiotherapy utilizing yttrium-90 ((90)Y) microspheres. (90)Y has also been used in the treatment of hepatocellular carcinoma and tumors metastatic to the liver. It appears to be well tolerated; however, there is no randomized controlled trial reporting long-term toxicities. Previous retrospective reports have described biliary damage as a potential complication of therapy with (90)Y and chemoembolization; however, the long-term sequelae of (90)Y treatment are poorly understood. CASE PRESENTATION: We present the case of a 65-year-old Caucasian woman who suffered biliary damage following (90)Y administration for metastatic pNETs and subsequently developed cirrhosis. Given the timeline of her various treatments and the lack of any other identifiable etiology for her cirrhosis, we believe this to be a potential long-term complication of (90)Y therapy. CONCLUSION: This case provides pathologic confirmation of cirrhosis as a potential long-term sequela of (90)Y treatment. This long-term risk needs to be considered when sequencing therapy for patients with neuroendocrine tumors who have a good prognosis. There are now several other systemic and ablative treatment options available to these patients, and long-term complications must be considered during treatment. PMID- 26933424 TI - Langerhans Cell Histiocytosis of the Rib in an Adult: A Case Report. AB - Single-site, single-system Langerhans cell histiocytosis (LCH) of the rib is one of the rarest causes of bone tumor in adults. Herein, we report a case of a healthy 35-year-old male who presented with upper back pain that was attributed to a solitary osteolytic lesion at the posterolateral aspect of his sixth rib. For diagnostic confirmation and treatment, partial resection of the sixth rib was performed and pathologic finding was consistent with LCH. At the final follow-up after 2 years, no local recurrence or metastasis was observed. PMID- 26933425 TI - Tonic-Clonic Seizure following Cytoreductive Surgery with Intraperitoneal Oxaliplatin: A Case Report and Review of the Literature. AB - Cytoreductive surgery (CRS) with hyperthermic intraperitoneal (IP) chemotherapy (HIPEC) is believed to improve outcomes in well-selected patients with peritoneal carcinomatosis. However, morbidity and mortality rates associated with this procedure are substantial. Here, we describe the case of a previously healthy young man who underwent CRS with hyperthermic IP oxaliplatin and developed one episode of tonic-clonic seizure on the second postoperative day. PMID- 26933426 TI - Muir-Torre Syndrome Presenting as Sebaceous Adenocarcinoma and Invasive MSH6 Positive Colorectal Adenocarcinoma. AB - Muir-Torre syndrome (MTS) is a rare genodermatosis, diagnosed by the presence of sebaceous neoplasms along with an internal malignancy, most commonly colorectal carcinomas. MTS is most commonly caused by microsatellite instabilities of the hMLH1 and hMSH2 mismatch repair genes, and is rarely caused by mutations of the hMSH6 gene. We describe the case of a 56-year-old male who presented with an enlarging mass on his back as well as hematochezia. The back mass was excised, and pathology confirmed microsatellite instability in MSH2 and MSH6. Abdominal CT and colonoscopy confirmed the presence of synchronous masses in the cecum, ascending colon, and the transverse colon. He refused any further workup or treatment, only to return 8 months later complaining of hematochezia and discomfort due to an enlarging mass protruding from the rectum. After consenting to surgical intervention, he agreed to outpatient chemotherapy treatment. The presence of sebaceous neoplasms should raise suspicion for the possibility of an associated internal malignancy. PMID- 26933427 TI - Adult Presentation of Dyke-Davidoff-Masson Syndrome: A Case Report. AB - Dyke-Davidoff-Masson syndrome (DDMS) is a rare disease which is clinically characterized by hemiparesis, seizures, facial asymmetry, and mental retardation. The classical radiological findings are cerebral hemiatrophy, calvarial thickening, and hyperpneumatization of the frontal sinuses. This disease is a rare entity, and it mainly presents in childhood. Adult presentation of DDMS is unusual and has been rarely reported in the medical literature. KEY MESSAGES: DDMS is a rare disease of childhood. However, it should be kept in mind as a diagnostic possibility in an adult who presents with a long duration of progressive hemiparesis with seizures and mental retardation. Cerebral hemiatrophy, calvarial thickening, and hyperpneumatization of the frontal sinuses are diagnostic for this illness on brain imaging. PMID- 26933428 TI - Peripheral (Seventh) Nerve Palsy and Multiple Sclerosis: A Diagnostic Dilemma - A Case Report. AB - During the last decades, only a few cases on the association between peripheral demyelinating diseases and multiple sclerosis (MS) have been reported. We describe the case of a young man who was initially diagnosed with Bell's palsy, and only after performing a brain MRI was the diagnosis of MS made. We review the literature and discuss some pitfalls which may lead to missing the diagnosis of MS. PMID- 26933429 TI - Congenital Bimelic Hypertrophy of the Hands. AB - Congenital hypertrophy of the hand is a rare phenomenon. The condition is characterized by hypertrophy of muscles, varies in severity and has been reported under different names. Some patients also have aberrant muscles. Electromyography is unremarkable, and the signal intensity on MRI and ultrasound is normal. The etiology is unknown and does not seem to be confined to a peripheral nerve, part of the plexus or nerve root. The condition is assumed to be congenital. We report a 28-year-old male with asymmetric hypertrophy of both hands and give a review of the 4 other cases known so far. PMID- 26933430 TI - What's in a Gene? Pseudoexfoliation Syndrome and Pigment Dispersion Syndrome in the Same Patient. AB - Pseudoexfoliation syndrome (PXS) and pigment dispersion syndrome (PDS) are two of the commonest disorders to produce secondary open-angle glaucoma through trabecular meshwork blockage. Each is a defined clinical entity, and while genetics likely play a significant role in the pathogenesis of both, the specific genes involved appear to be distinct. There is surprisingly little published in the literature regarding the coexistence of PDS and PXS in the same patient. We present the intriguing case of a patient who developed PDS in one eye and PXS in the other. This unusual case acts as a platform for an interesting discussion of the genomics of PXS and PDS. PMID- 26933431 TI - Cyclosporine-Associated Leukoencephalopathy in a Case of Sympathetic Ophthalmitis. AB - PURPOSE: Cyclosporine (CsA) is currently widely used as a primary immunosuppressive agent in ocular disease, particularly in severe uveitis. Posterior reversible encephalopathy syndrome (PRES) is a significant complication of CsA therapy. However, there are no reports of the occurrence of PRES in response to the treatment of uveitis in the ophthalmological area. CASE PRESENTATION: We report a case with CsA-associated PRES. A 70-year-old woman with sympathetic ophthalmitis was treated with 50 mg/day of CsA for 1 week. However, the trough level in her blood was too low; thus, we increased the dose to 100 mg/day of CsA with prednisolone. She had headaches, hypertension (systolic blood pressure 180-200 mm Hg), loss of consciousness for several hours, and reduced limb movement, and her MRI showed a high signal intensity in both posterior lobes, consistent with PRES. Examination of the cerebrospinal fluid indicated that it was within normal limits. Her CsA trough level in the blood was within normal ranges on the day of the attack. Her symptoms gradually improved over the next several days; however, she presented with cortical blindness, which lasted for several weeks. Finally, she returned to her baseline values from before the attack. Her MRI findings showed that PRES had essentially disappeared. CONCLUSION: PRES is not directly associated with the dosage of CsA administered; however, in general, it is well known that PRES can affect strongly immunosuppressed cases undergoing organ and bone marrow transplantation. Nevertheless, our CsA dose was only 100 mg (1.8 mg/kg). In this study, we report on the occurrence of PRES after the administration of CsA to treat sympathetic ophthalmia. To our knowledge, PRES can also occur after the administration of a small dose of CsA; thus, ophthalmologists using CsA should carefully observe the systemic conditions of CsA-treated patients. PMID- 26933432 TI - Vitrectomy for Proliferative Diabetic Retinopathy in a Patient with Heparin Induced Thrombocytopenia. AB - INTRODUCTION: In this study, we report a case of proliferative diabetic retinopathy in a patient with heparin-induced thrombocytopenia (HIT) in whom vitrectomy was performed with good results. CASE: A 57-year-old man presented with a chief complaint of decreased visual acuity (VA) in the left eye. Corrected VA of the left eye was 0.03, and ophthalmic examination showed fibrovascular membranes along the vascular arcade and a combined rhegmatogenous-traction retinal detachment with a macular hole. The patient began hemodialysis for diabetic nephropathy in March 2014; thrombocytopenia developed after dialysis was started, and HIT was diagnosed after further evaluation. Argatroban hydrate was being used during dialysis. Treatment was switched from warfarin to argatroban hydrate 6 days prior to vitrectomy being performed on the patient's left eye. Although there was bleeding with somewhat difficult hemostasis during the intraoperative treatment of the fibrovascular membranes, surgery was completed without complications and the postoperative course was good. DISCUSSION: Vitrectomy was performed with good results in this patient with HIT. Treatment with argatroban hydrate during surgery enabled surgery without the danger of intraoperative clotting. PMID- 26933433 TI - Anterior Uveitis Caused by Ocular Side Effects of Afatinib: A Case Report. AB - Afatinib is a second-generation epidermal growth factor receptor (EGFR) inhibitor that has been shown to be effective against EGFR-mutated non-small cell lung cancer (NSCLC) resistant to conventional EGFR inhibitors such as gefitinib and erlotinib. Although ocular side effects of gefitinib and erlotinib have been reported, those for afatinib have yet to be definitively established. This report presents details on the first case of unilateral iridocyclitis associated with the side effects of afatinib therapy. A 75-year-old Japanese male ex-smoker with EGFR-mutated NSCLC underwent afatinib therapy for multiple metastases. At 2 weeks, bilateral conjunctivitis developed. Topical medication and a 1-week afatinib washout period resulted in the improvement of the conjunctivitis. However, 3 days after the resumption of afatinib, the patient developed unilateral granulomatous anterior uveitis in his right eye. Best-corrected visual acuity (BCVA) measurement indicated a decimal visual acuity of 0.2, while the slit-lamp findings were characterized by granulomatous inflammation, keratic precipitates, Koeppe nodules and posterior synechiae. There was no evidence suggesting other intraocular inflammatory disease or metastatic tumor. The left eye was intact. The use of topical medication including steroids and a washout of afatinib resulted in a gradual subsiding of the anterior uveitis. After resolution of the anterior uveitis, oral afatinib was resumed. BCVA of the right eye finally recovered to a decimal acuity of 1.0. Ophthalmologists should be aware of the possibility that side effects associated with afatinib could cause granulomatous anterior uveitis. PMID- 26933434 TI - Minimally Invasive Pterygium Surgery: Sutureless Excision with Amniotic Membrane and Hydrogel Sealant. AB - PURPOSE: To describe a novel technique for sutureless pterygium surgery using ReSure((r)) tissue sealant. METHODS: In this retrospective observational case series, we describe a modified procedure for pterygium excision followed by amniotic membrane transplant (AMT) adhered to the corneal and conjunctival defects using ReSure tissue sealant. RESULTS: Nine eyes of seven patients (age range: 28-80 years, 4 females and 3 males) underwent pterygium removal with AMT followed by adherence of tissue to the conjunctival edges with ReSure. No issues with transplant dislocation or failure and no intra- or postoperative complications were noted. No recurrences were noted during the follow-up period. CONCLUSION: ReSure may be considered as a potential sealant to adhere AMT to defective corneal and conjunctival tissues in sutureless pterygium surgery. PMID- 26933435 TI - Obtaining Information from Family Caregivers Is Important to Detect Behavioral and Psychological Symptoms and Caregiver Burden in Subjects with Mild Cognitive Impairment. AB - BACKGROUND: The objectives of this study are to clarify the differences between the difficulties in daily life experienced by patients with both mild cognitive impairment (MCI) and chronic disease and those experienced by healthy elderly individuals. METHODS: We assessed (a) cognitive function; (b) gait ability; (c) behavioral and psychological symptoms (observed at home); (d) activities of daily living (observed at home); (e) family caregiver burden, and (f) intention to continue family caregiving of 255 cognitively normal and 103 MCI subjects attending adult day care services covered by long-term care insurance, and compared the two groups. RESULTS: Subjects with MCI display more behavioral and psychological symptoms than cognitively normal subjects, posing a heavy caregiver burden (p < 0.01). Behavioral and psychological symptoms most commonly observed in subjects with MCI are apathy, hallucinations, delusions, agitation, and aberrant motor behavior. CONCLUSION: Information regarding the behavioral and psychological symptoms displayed at home by patients with MCI can only be obtained from family caregivers living with the patients. To provide early-stage support for elderly patients with MCI, adult day care workers should collect information from family caregivers regarding behavioral and psychological symptoms observed at home. PMID- 26933437 TI - Memory Test Performance on Analogous Verbal and Nonverbal Memory Tests in Patients with Frontotemporal Dementia and Alzheimer's Disease. AB - BACKGROUND: Patients with frontotemporal dementia (FTD) typically have initial deficits in language or changes in personality, while the defining characteristic of Alzheimer's disease (AD) is memory impairment. Neuropsychological findings in the two diseases tend to differ, but can be confounded by verbal impairment in FTD impacting performance on memory tests in these patients. METHODS: Twenty seven patients with FTD and 102 patients with AD underwent a neuropsychological assessment before diagnosis. By utilizing analogous versions of a verbal and nonverbal memory test, we demonstrated differences in these two modalities between AD and FTD. DISCUSSION: Better differentiation between AD and FTD is found in a nonverbal memory test, possibly because it eliminates the confounding variable of language deficits found in patients with FTD. These results highlight the importance of nonverbal learning tests with multiple learning trials in diagnostic testing. PMID- 26933436 TI - Elevated C-Reactive Protein Is Associated with Cognitive Decline in Outpatients of a General Hospital: The Project in Sado for Total Health (PROST). AB - BACKGROUND/AIMS: We aimed to determine whether the concentration of serum C reactive protein (CRP) is associated with cognitive function in an adult Japanese population. METHODS: Participants of this cross-sectional study were from a subgroup of the Project in Sado for Total Health (PROST; n = 454; mean age, 70.5 years). The cognitive state was evaluated using the Mini-Mental State Examination (MMSE), and those with an MMSE score <24 were considered 'cognitively declined'. Concentrations of serum high-sensitivity CRP were measured. Multiple logistic regression analysis was used to calculate odds ratios (ORs) for cognitive decline, adjusting for the covariates of age, sex, BMI, disease history, and APOE allele. RESULTS: Of the 454 participants, 94 (20.7%) were cognitively declined. Relative to the lowest (first) quartile of CRP concentration, adjusted ORs were 1.29 (95% CI 0.61-2.75) for the second, 1.78 (95% CI 0.82-3.86) for the third, and 3.05 (95% CI 1.45-6.42) for the highest (fourth) quartiles (p for trend = 0.018). When data were stratified by sex, the association between CRP concentration and cognitive decline was observed only in women. CONCLUSION: Our findings suggest an association between higher CRP concentration and lower cognitive function. Chronic inflammation may affect cognitive function in adults, in particular women. PMID- 26933438 TI - Severity of Neuropsychiatric Symptoms in Nursing Home Residents. AB - We aimed at assessing time shift in the severity of neuropsychiatric symptoms (NPS) in nursing home residents between 2004/2005 and 2010/2011 and associations between NPS and socio-demographic variables, physical health status, dementia severity, and the use of psychotropic drugs. The Neuropsychiatric Inventory Nursing Home Version was used in 2004/2005 (n = 1,163) and 2010/2011 (n = 1,858). Linear mixed model analysis was applied. There was no time shift in the severity of apathy, psychosis, and affective symptoms, but agitation did exhibit a time shift. Agitation was less severe in 2010/2011 than in 2004/2005 in residents with a Clinical Dementia Rating (CDR) sum of boxes score <=4, and more severe in residents with a CDR sum of boxes score >16. Higher CDR sum of boxes scores and use of psychotropic medication were associated with more severe apathy, agitation, psychosis, and affective symptoms. Poor physical health was associated with more severe apathy, psychosis, and affective symptoms. Women had more severe agitation and less severe affective symptoms than men. A longer stay in a nursing home was associated with more severe agitation and less severe affective symptoms. In conclusion, agitation was less severe in 2010/2011 than in 2004/2005 among nursing home residents with a milder degree of dementia, and more severe in residents with severe dementia. PMID- 26933439 TI - Clinical Applicability of Various Treatment Approaches for Upper Gastrointestinal Submucosal Tumors. AB - Submucosal tumor (SMT) is a disease that is commonly discovered during endoscopic examination. With advances in endoscopic ultrasonography (EUS) technology, this technique has become the primary screening method for the diagnosis of upper gastrointestinal SMTs. The present study summarized the clinical data of patients who were examined and diagnosed with upper gastrointestinal SMTs by EUS, underwent endoscopic therapy or surgical treatment, and received final pathological results in our hospital between January 2011 and September 2014. Our results show that endoscopic therapy has become the main approach for the treatment of upper gastrointestinal SMTs with the development and maturation of endoscopic technology in recent years. Our conclusion suggests that the selection of endoscopic methods, such as endoscopic mucosal resection (EMR), endoscopic submucosal dissection (ESD), and peroral submucosal tunneling endoscopic resection (STER), under the guidance of EUS is safe and effective for the treatment of upper gastrointestinal SMTs. PMID- 26933440 TI - Adipose-Derived Mesenchymal Stem Cells in the Regeneration of Vocal Folds: A Study on a Chronic Vocal Fold Scar. AB - Background. The aim of the study was to assess the histological effects of autologous infusion of adipose-derived stem cells (ADSC) on a chronic vocal fold scar in a rabbit model as compared to an untreated scar as well as in injection of hyaluronic acid. Study Design. Animal experiment. Method. We used 74 New Zealand rabbits. Sixteen of them were used as control/normal group. We created a bilateral vocal fold wound in the remaining 58 rabbits. After 18 months we separated our population into three groups. The first group served as control/scarred group. The second one was injected with hyaluronic acid in the vocal folds, and the third received an autologous adipose-derived stem cell infusion in the scarred vocal folds (ADSC group). We measured the variation of thickness of the lamina propria of the vocal folds and analyzed histopathologic changes in each group after three months. Results. The thickness of the lamina propria was significantly reduced in the group that received the ADSC injection, as compared to the normal/scarred group. The collagen deposition, the hyaluronic acid, the elastin levels, and the organization of elastic fibers tend to return to normal after the injection of ADSC. Conclusions. Autologous injection of adipose-derived stem cells on a vocal fold chronic scar enhanced the healing of the vocal folds and the reduction of the scar tissue, even when compared to other treatments. PMID- 26933441 TI - Comment on "Comparison of Electroacupuncture in Restrained and Unrestrained Rat Models". PMID- 26933442 TI - Quantification of Phytochemicals from Commercial Spirulina Products and Their Antioxidant Activities. AB - The present study aimed to profile the polyunsaturated fatty acids, sugars, free amino acids, and polyphenols in 37 varieties of Spirulina commonly available in the market using gas chromatography and high performance liquid chromatography. In addition, the biological potentials of the Spirulina samples were evaluated by analysing the in vitro antioxidant activities using various analytical techniques. The analyses revealed the presence of 13 polyunsaturated fatty acids, 18 amino acids, 7 sugars, and polyphenols. The polyunsaturated fatty acids contents were varied between Spirulina samples. The total polyunsaturated fatty acids amount was 4.25 mg/100 g, and the average among of sapienic acid detected was 2.25 mg/100 g, which was followed by linoleic acid (16.7%) and gamma linolenic acid (14%). Among the 7 sugars, the hexose levels were the highest (73.85%). The total amino acids contents ranged from 11.49 to 56.14 mg/100 g, and the individual essential amino acids accounted for 17% to 39.18%. The "natural" tablets exhibited the highest polyphenols levels (24 mg/g). All of the Spirulina samples expressed dose-dependent antioxidant activities. The polyunsaturated fatty acids, sugars, free amino acids, and polyphenols contents varied widely, and the variations in these compounds between the Spirulina samples were significant. PMID- 26933444 TI - Donor/Recipient Delta Age: A Possible Risk for Arterial Stenosis in Renal Transplantation. AB - Different arterial wall properties can significantly increase the risk of blood turbulent fluxes leading to complications such as atherosclerosis. Since the mechanical properties of arterial vessels are influenced by age, we investigated, in a retrospective study, the effects on renal artery stenosis of an age difference >15 years between donor and recipient in a cohort of 164 patients undergoing renal transplantation between 1981 and 1991. The age difference between donor and recipient was <=15 years in 87 patients (53.0%) (Group A) and >15 years in 77 patients (47.0%) (Group B, p = ns). None of the Group A patients developed an anastomotic arterial stenosis, whereas 8/77 Group B patients (10.4%) had an anastomotic arterial stenosis (p < 0.001). This study shows that an age difference >15 years is significantly linked to the risk of developing arterial stenosis after renal transplantation. Indeed, different wall properties can significantly increase the risk of generation of blood turbulent fluxes and involve, in the arterial vessels, the development of complications such as atherosclerosis. PMID- 26933443 TI - Short chain acyl-CoA dehydrogenase deficiency and short-term high-fat diet perturb mitochondrial energy metabolism and transcriptional control of lipid handling in liver. AB - BACKGROUND: The liver is an important site of fat oxidation, which participates in the metabolic regulation of food intake. We showed previously that mice with genetically inactivated Acads, encoding short-chain acyl-CoA dehydrogenase (SCAD), shift food consumption away from fat and toward carbohydrate when tested in a macronutrient choice paradigm. This phenotypic eating behavior suggests a link between fat oxidation and nutrient choice which may involve an energy sensing mechanism. To identify hepatic processes that could trigger energy related signals, we have now performed transcriptional, metabolite and physiological analyses in Acads-/- mice following short-term (2 days) exposure to either high- or low-fat diet. METHODS AND RESULTS: Metabolite analysis revealed 25 acylcarnitine species that were altered by diet and/or genotype. Compared to wild-type mice, phosphorylated AMP-activated protein kinase was 40 % higher in Acads-/- mice after short-term high-fat diet, indicating a low ATP/AMP ratio. Metabolite analyses in isolated liver mitochondria from Acads-/- mice during ADP linked respiration on butyrate demonstrated a reduced oxygen consumption rate (OCR) compared to wild-type, an effect that was not observed with succinate or palmitoylcarnitine substrates. Liver transcriptomic responses in Acads-/- mice fed high- vs. lowfat diet revealed increased RXR/PPARA signaling, up-regulation of lipid handling pathways (including beta and omega oxidation), and increased mRNA expression of Nfe2l2 target genes. CONCLUSIONS: Together, these results point to an oxidative shortage in this genetic model and support the hypothesis of a lower hepatic energy state associated with SCAD deficiency and high-fat diet. PMID- 26933445 TI - Freeze-drying: an alternative method for the analysis of volatile organic compounds in the headspace of urine samples using solid phase micro-extraction coupled to gas chromatography - mass spectrometry. AB - BACKGROUND: Volatile organic compounds (VOCs) can be intermediates of metabolic pathways and their levels in biological samples may provide a better understanding about diseases in addition to potential methods for diagnosis. Headspace analysis of VOCs in urine samples using solid phase micro extraction (SPME) coupled to gas chromatography - mass spectrometry (GC-MS) is one of the most used techniques. However, it generally produces a limited profile of VOCs if applied to fresh urine. Sample preparation methods, such as addition of salt, base or acid, have been developed to improve the headspace-SPME-GC-MS analysis of VOCs in urine samples. These methods result in a richer profile of VOCs, however, they may also add potential contaminants to the urine samples, result in increased variability introduced by manually processing the samples and promote degradation of metabolites due to extreme pH levels. Here, we evaluated if freeze drying can be considered an alternative sample preparation method for headspace SPME-GC-MS analysis of urine samples. RESULTS: We collected urine from three volunteers and compared the performances of freeze-drying, addition of acid (HCl), addition of base (NaOH), addition of salt (NaCl), fresh urine and frozen urine when identifying and quantifying metabolites in 4 ml samples. Freeze-drying and addition of acid produced a significantly higher number of VOCs identified than any other method, with freeze-drying covering a slightly higher number of chemical classes, showing an improved repeatability and reducing siloxane impurities. CONCLUSION: In this work we compared the performance of sample preparation methods for the SPME-GC-MS analysis of urine samples. To the best of our knowledge, this is the first study evaluating the potential of freeze-dry as an alternative sample preparation method. Our results indicate that freeze-drying has potential to be used as an alternative method for the SPME-GC-MS analysis of urine samples. Additional studies using internal standard, synthetic urine and calibration curves will allow a more precise quantification of metabolites and additional comparisons between methods.Graphical abstractEnhancing VOC profiling from urine samples. PMID- 26933446 TI - Hospitalization of high and low inpatient service users before and after enrollment into Assertive Community Treatment teams: a naturalistic observational study. AB - BACKGROUND: Assertive Community Treatment (ACT) is more successful in reducing hospitalization when baseline use is high. However, with a growing recovery focus, ACT may be useful for people with severe mental illness who are difficult to engage but not high users of inpatient services. This study investigated hospitalization 2 years before and 2 years after ACT enrollment amongst patients both with and without high inpatient services use before enrollment into ACT. METHODS: This naturalistic observational study included 142 patients from 12 different ACT teams throughout Norway. Of these, 74 (52 %) were high users of inpatient services before ACT. The teams assessed the patients upon enrollment using clinician-rated and self-reported questionnaires. Hospitalization data from 2 years before and 2 years after enrollment into ACT were obtained from the Norwegian Patient Registry. Linear mixed models were used to assess changes in hospitalization and to explore associations between these changes and patient characteristics. RESULTS: When the participants enrolled into the ACT teams, high users of inpatient care were younger, more often living alone and more often subject to involuntary outpatient treatment than low users. The participants spent significantly fewer days in hospital during the 2 years of ACT follow-up compared to the 2 years before enrollment. The reduction was more evident amongst high users, whereas low users had an initial increase in inpatient days in the first year of ACT and a subsequent decrease in the second year. More severe negative symptoms and previous high use of inpatient care were associated with a reduction in both total and involuntary inpatient days. Additionally, a reduction in involuntary inpatient days was associated with being subject to involuntary outpatient treatment upon enrollment into ACT. CONCLUSION: The findings in this study may suggest that ACT contributes to more appropriate use of inpatient care, possibly by reducing the presumably avoidable hospitalization of high users and increasing the presumably needed inpatient care of low users. PMID- 26933447 TI - Utilization of a mental health collaborative care model among patients who require interpreter services. AB - BACKGROUND: Immigrants and refugees to the United States have a higher prevalence of depression compared to the general population and are less likely to receive adequate mental health services and treatment. Those with limited English proficiency (LEP) are at an even higher risk of inadequate mental health care. Collaborative care management (CCM) models for depression are effective in achieving treatment goals among a wide range of patient populations, including patients with LEP. The purpose of this study was to assess the utilization of a statewide initiative that uses CCM for depression management, among patients with LEP in a large primary care practice. METHODS: This was a retrospective cohort study of patients with depression in a large primary care practice in Minnesota. Patients who met criteria for enrollment into the CCM [with a provider-generated diagnosis of depression or dysthymia in the electronic medical records, and a Patient Health Questionnaire-9 (PHQ-9) score >=10]. Patient-identified need for interpreter services was used as a proxy for LEP. Rates of enrollment into the DIAMOND (Depression Improvement Across Minnesota, Offering A New Direction) program, a statewide initiative that uses CCM for depression management were measured. These rates were compared between eligible patients who require interpreter services versus patients who do not. RESULTS: Of the 7561 patients who met criteria for enrollment into the DIAMOND program during the study interval, 3511 were enrolled. Only 18.2 % of the eligible patients with LEP were enrolled into DIAMOND compared with the 47.2 % of the eligible English proficient patients. This finding persisted after adjustment for differences in age, gender and depression severity scores (adjusted OR [95 % confidence interval] = 0.43 [0.23, 0.81]). CONCLUSIONS: Within primary care practices, tailored interventions are needed, including those that address cultural competence and language navigation, to improve the utilization of this effective model among patients with LEP. PMID- 26933448 TI - Using a theory driven approach to develop and evaluate a complex mental health intervention: the friendship bench project in Zimbabwe. AB - BACKGROUND: There is a paucity of data on how to deliver complex interventions that seek to reduce the treatment gap for mental disorders, particularly in sub Saharan Africa. The need for well-documented protocols which clearly describe the development and the scale-up of programs and interventions is necessary if such interventions are to be replicated elsewhere. This article describes the use of a theory of change (ToC) model to develop a brief psychological intervention for common mental disorders and its' evaluation through a cluster randomized controlled trial in Zimbabwe. METHODS: A total of eight ToC workshops were held with a range of stakeholders over a 6-month period with a focus on four key components of the program: formative work, piloting, evaluation and scale-up. A ToC map was developed as part of the process with defined causal pathways leading to the desired impact. Interventions, indicators, assumptions and rationale for each point along the causal pathway were considered. RESULTS: Political buy-in from stakeholders together with key resources, which included human, facility/infrastructure, communication and supervision were identified as critical needs using the ToC approach. Ten (10) key interventions with specific indicators, assumptions and rationale formed part of the final ToC map, which graphically illustrated the causal pathway leading to the development of a psychological intervention and the successful implementation of a cluster randomized controlled trial. CONCLUSION: ToC workshops can enhance stakeholder engagement through an iterative process leading to a shared vision that can improve outcomes of complex mental health interventions particularly where scaling up of the intervention is desired. PMID- 26933450 TI - Exploiting HIV-1 protease and reverse transcriptase cross-resistance information for improved drug resistance prediction by means of multi-label classification. AB - BACKGROUND: Antiretroviral therapy is essential for human immunodeficiency virus (HIV) infected patients to inhibit viral replication and therewith to slow progression of disease and prolong a patient's life. However, the high mutation rate of HIV can lead to a fast adaptation of the virus under drug pressure and thereby to the evolution of resistant variants. In turn, these variants will lead to the failure of antiretroviral treatment. Moreover, these mutations cannot only lead to resistance against single drugs, but also to cross-resistance, i.e., resistance against drugs that have not yet been applied. METHODS: 662 protease sequences and 715 reverse transcriptase sequences with complete resistance profiles were analyzed using machine learning techniques, namely binary relevance classifiers, classifier chains, and ensembles of classifier chains. RESULTS: In our study, we applied multi-label classification models incorporating cross resistance information to predict drug resistance for two of the major drug classes used in antiretroviral therapy for HIV-1, namely protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). By means of multi-label learning, namely classifier chains (CCs) and ensembles of classifier chains (ECCs), we were able to improve overall prediction accuracy for all drugs compared to hitherto applied binary classification models. CONCLUSIONS: The development of fast and precise models to predict drug resistance in HIV-1 is highly important to enable a highly effective personalized therapy. Cross resistance information can be exploited to improve prediction accuracy of computational drug resistance models. PMID- 26933449 TI - A secretomic view of woody and nonwoody lignocellulose degradation by Pleurotus ostreatus. AB - BACKGROUND: Pleurotus ostreatus is the second edible mushroom worldwide, and a model fungus for delignification applications, with the advantage of growing on woody and nonwoody feedstocks. Its sequenced genome is available, and this gave us the opportunity to perform proteomic studies to identify the enzymes overproduced in lignocellulose cultures. RESULTS: Monokaryotic P. ostreatus (PC9) was grown with poplar wood or wheat straw as the sole C/N source and the extracellular proteins were analyzed, together with those from glucose medium. Using nano-liquid chromatography coupled to tandem mass spectrometry of whole protein hydrolyzate, over five-hundred proteins were identified. Thirty-four percent were unique of the straw cultures, while only 15 and 6 % were unique of the glucose and poplar cultures, respectively (20 % were produced under the three conditions, and additional 19 % were shared by the two lignocellulose cultures). Semi-quantitative analysis showed oxidoreductases as the main protein type both in the poplar (39 % total abundance) and straw (31 %) secretomes, while carbohydrate-active enzymes (CAZys) were only slightly overproduced (14-16 %). Laccase 10 (LACC10) was the main protein in the two lignocellulose secretomes (10 14 %) and, together with LACC2, LACC9, LACC6, versatile peroxidase 1 (VP1), and manganese peroxidase 3 (MnP3), were strongly overproduced in the lignocellulose cultures. Seven CAZys were also among the top-50 proteins, but only CE16 acetylesterase was overproduced on lignocellulose. When the woody and nonwoody secretomes were compared, GH1 and GH3 beta-glycosidases were more abundant on poplar and straw, respectively and, among less abundant proteins, VP2 was overproduced on straw, while VP3 was only found on poplar. The treated lignocellulosic substrates were analyzed by two-dimensional nuclear magnetic resonance (2D NMR), and a decrease of lignin relative to carbohydrate signals was observed, together with the disappearance of some minor lignin substructures, and an increase of sugar reducing ends. CONCLUSIONS: Oxidoreductases are strongly induced when P. ostreatus grows on woody and nonwoody lignocellulosic substrates. One laccase occupied the first position in both secretomes, and three more were overproduced together with one VP and one MnP, suggesting an important role in lignocellulose degradation. Preferential removal of lignin vs carbohydrates was shown by 2D NMR, in agreement with the above secretomic results. PMID- 26933451 TI - Mutations that prevent or mimic persistent post-translational modifications of the histone H3 globular domain cause lethality and growth defects in Drosophila. AB - BACKGROUND: Understanding the function of histone post-translational modifications is the key to deciphering how genomic activities are regulated. Among the least well-understood histone modifications in vivo are those that occur on the surface of the globular domain of histones, despite their causing the most profound structural alterations of the nucleosome in vitro. We utilized a Drosophila system to replace the canonical histone genes with mutated histone transgenes. RESULTS: Mutations predicted to mimic or prevent acetylation on histone H3 lysine (K) 56, K115, K122, and both K115/K122, or to prevent or mimic phosphorylation on H3 threonine (T) 118 and T80, all caused lethality, with the exception of K122R mutants. T118 mutations caused profound growth defects within wing discs, while K115R, K115Q, K56Q, and the K115/K122 mutations caused more subtle growth defects. The H3 K56R and H3 K122R mutations caused no defects in growth, differentiation, or transcription within imaginal discs, indicating that H3 K56 acetylation and K122 acetylation are dispensable for these functions. In agreement, we found the antibody to H3 K122Ac, which was previously used to imply a role for H3 K122Ac in transcription in metazoans, to be non-specific in vivo. CONCLUSIONS: Our data suggest that chromatin structural perturbations caused by acetylation of K56, K115, or K122 and phosphorylation of T80 or T118 are important for key developmental processes. PMID- 26933452 TI - libChEBI: an API for accessing the ChEBI database. AB - BACKGROUND: ChEBI is a database and ontology of chemical entities of biological interest. It is widely used as a source of identifiers to facilitate unambiguous reference to chemical entities within biological models, databases, ontologies and literature. ChEBI contains a wealth of chemical data, covering over 46,500 distinct chemical entities, and related data such as chemical formula, charge, molecular mass, structure, synonyms and links to external databases. Furthermore, ChEBI is an ontology, and thus provides meaningful links between chemical entities. Unlike many other resources, ChEBI is fully human-curated, providing a reliable, non-redundant collection of chemical entities and related data. While ChEBI is supported by a web service for programmatic access and a number of download files, it does not have an API library to facilitate the use of ChEBI and its data in cheminformatics software. RESULTS: To provide this missing functionality, libChEBI, a comprehensive API library for accessing ChEBI data, is introduced. libChEBI is available in Java, Python and MATLAB versions from http://github.com/libChEBI, and provides full programmatic access to all data held within the ChEBI database through a simple and documented API. libChEBI is reliant upon the (automated) download and regular update of flat files that are held locally. As such, libChEBI can be embedded in both on- and off-line software applications. CONCLUSIONS: libChEBI allows better support of ChEBI and its data in the development of new cheminformatics software. Covering three key programming languages, it allows for the entirety of the ChEBI database to be accessed easily and quickly through a simple API. All code is open access and freely available. PMID- 26933453 TI - GPURFSCREEN: a GPU based virtual screening tool using random forest classifier. AB - BACKGROUND: In-silico methods are an integral part of modern drug discovery paradigm. Virtual screening, an in-silico method, is used to refine data models and reduce the chemical space on which wet lab experiments need to be performed. Virtual screening of a ligand data model requires large scale computations, making it a highly time consuming task. This process can be speeded up by implementing parallelized algorithms on a Graphical Processing Unit (GPU). RESULTS: Random Forest is a robust classification algorithm that can be employed in the virtual screening. A ligand based virtual screening tool (GPURFSCREEN) that uses random forests on GPU systems has been proposed and evaluated in this paper. This tool produces optimized results at a lower execution time for large bioassay data sets. The quality of results produced by our tool on GPU is same as that on a regular serial environment. CONCLUSION: Considering the magnitude of data to be screened, the parallelized virtual screening has a significantly lower running time at high throughput. The proposed parallel tool outperforms its serial counterpart by successfully screening billions of molecules in training and prediction phases. PMID- 26933454 TI - Achieving asthma control: Providing a framework for clinicians. PMID- 26933456 TI - The effect of Ramadan intermittent fasting on lipid peroxidation in healthy young men while controlling for diet and sleep: A pilot study. AB - AIMS: We hypothesized that if we control for lifestyle changes during Ramadan, Ramadan Islamic intermittent fasting (IF) reduces oxidative stress. This study was conducted to examine the effect of Islamic IF during and outside of Ramadan on the circadian changes in lipid peroxidation marker malondialdehyde (MDA) during and outside while controlling for potential confounders. METHODS: Serum MDA concentration was measured in eight healthy male volunteers at baseline (BL), after fasting for 1 week before Ramadan (BL fasting), and during Ramadan. Blood samples were drawn at 22:00, 02:00, 04:00, 06:00, and 11:00. The participants were admitted to the sleep laboratory and monitored for 24 h on the day of the measurements. In the laboratory, each participant received meals of fixed compositions and caloric contents based on their ideal body weights. Light exposure, physical activity, and total sleep duration were uniformly maintained during the three study periods. RESULTS: The participants had a mean age of 26.6 +/- 4.9 years and a mean body mass index of 23.7 +/- 3.5 kg/m(2). No significant changes were observed in MDA levels and blood glucose during BL, BL fasting, or Ramadan. CONCLUSION: In this pilot study, under conditions of fixed sleep-wake schedules and caloric intake, Ramadan IF does not alter serum MDA levels in healthy subjects. Larger studies are needed to confirm these findings. PMID- 26933458 TI - Bacterial colonization and associated factors in patients with bronchiectasis. AB - OBJECTIVES: To evaluate the bacterial colonization and associated risk factors in patients with bronchiectasis. METHODS: A total of 121 patients followed at the Bronchiectasis Unit, between 1996 and 2013 and diagnosed as having noncystic fibrosis bronchiectasis with high resolution computed tomography or multi-slice computed tomography were included in this retrospective study. The following definition of colonization was used for study purposes: Detection of at least two isolates of an organism separated by at least 3 months in a year. RESULTS: Of these 121 patients, 65 (54%) were female and 56 (46%) were male. Mean age was 50.6 +/- 16.1 years. Mean duration of illness was 20.3 +/- 15.5 years. 43 (35.5%) cases had colonization. The major pathogens responsible for colonization were Pseudomonas aeruginosa (n = 25; 20.6%) and Haemophilus influenzae (n = 14, 11.5%). The stepwise logistic regression analysis showed a significant association between colonization and a low percentage of forced vital capacity (FVC%) and the presence of cystic bronchiectasis (P < 0.05). CONCLUSION: The following factors have been found to be associated with colonization in patients with bronchiectasis: Low FVC% and the presence of cystic bronchiectasis. PMID- 26933457 TI - Are there radiographic, metabolic, and prognostic differences between cavitary and noncavitary nonsmall cell lung carcinoma? A retrospective fluorodeoxyglucose positron emission tomography/computed tomography study. AB - AIMS: The prognosis of nonsmall cell lung cancer with cavitation (NSCLC-c) is not well-known. We compared the positron emission tomography/computed tomography (PET/CT) findings and survival data of patients with NSCLC-c patients with those without cavitation (NSCLC-nc). METHODS: Between 7/2004 and 6/2007, cavitary lung lesions were identified in 46/248 patients undergoing fluorodeoxyglucose (FDG) PET/CT for lung nodule characterization or lung cancer staging. Within the same period, 40 of 202 patients with NSCLC-nc were randomly selected for comparison. The primary was assessed by location, size, cell type, and standardized uptake value (SUV). Disease stage was determined according to American Joint Committee on Cancer guidelines for lung cancer. Kaplan-Meier method was used for survival analysis and Cox regression to assess the effect of clinical and imaging variables on survival. RESULTS: NSCLC-c was found in 87% of patients that had a cavitary lung lesion at PET/CT. Squamous cell carcinoma, primary size and primary to-liver SUV ratio differed significantly between NSCLC-c and NSCLC-nc, whereas age, gender, primary location, primary SUV, type of treatment, and disease stage did not. Median survival and overall 5-year survival were 19 months and 24% for NSCLC-c, and 31 months and 31% for NSCLC-nc, P = 0.23. Disease stage was the only predictor of survival. CONCLUSION: Cavitary lung lesions in patients undergoing FDG PET/CT harbor a significant risk for cancer. NSCLC-c is associated with squamous cell carcinoma, larger size, and greater FDG metabolism compared with NSCLC-nc, although these variables may not be predictive of survival. Nonetheless, PET/CT contributes to accurate staging and has an indirect impact on prognosis. PMID- 26933459 TI - Awareness regarding childhood asthma in Saudi Arabia. AB - OBJECTIVE: Assessing the knowledge and awareness of the Saudi society about bronchial asthma in children. METHODS: Structured questionnaires were randomly distributed to 1039 Saudi Arabians in May 2014 at Jeddah, Riyadh, and Dammam. RESULTS: The awareness of bronchial asthma questions showed that 67% of total sample thought that it could be a fatal disease, and only 13.2% thought that there is a difference between bronchial asthma and chest allergies in children. 86.1% thought that the symptoms of bronchial asthma include dyspnea and nocturnal cough, and 45.7% thought that fever, a runny nose and throat inflammation are not symptoms. 60.2% thought that infectious respiratory diseases may increase bronchial asthma progression. In addition, 40% thought that the use of antibiotics doesn't help in diminishing bronchial asthma complications, and some thought that the patient can stop medication after an acute asthma attack. 34.1% thought that inhaled medication for asthma doesn't cause addiction. Very highly significant results are shown between bronchial asthma knowledge and age, the level of education, marital status, and if the individual knows a person who suffers from bronchial asthma (P < 0.001). There are positive correlations between bronchial asthma knowledge and age, marital status, and level of education (r = 0.152, 0.150, 0.197), respectively. CONCLUSION: The study demonstrated that bronchial asthma knowledge in the Saudi Arabian population is insufficient, and efforts should be carried out to spread bronchial asthma management. PMID- 26933460 TI - Increased ischemia-modified albumin and malondialdehyde levels in videothoracoscopic surgery. AB - BACKGROUND: Videothoracoscopic surgery leads to general organ hypoperfusion by reducing mean arterial pressure, systemic vascular resistance, and end-diastolic volume index. Oxidative stress occurs as a result of hypoperfusion. Evaluation of the short-term effects of videothoracoscopic sympathectomy on serum ischemia modified albumin (IMA), malondialdehyde (MDA), and nitric oxide (NO) levels in patients with primary hyperhidrosis was aimed. METHODS: Twenty-six patients who underwent videothoracoscopic surgery were contributed in this study. Venous blood samples were obtained from these patients 1 h before and after the surgery. IMA, MDA, and NO levels were measured in serum samples by colorimetric methods. Albumin concentrations were also measured for each sample, and albumin-adjusted IMA levels were calculated. RESULTS: Postoperative IMA, albumin-adjusted IMA, and MDA values were significantly higher compared to the preoperative values (P = 0.003, 0.027, 0.018, respectively). However, postoperative NO levels were lower than the preoperative values (P = 0.002). There was no significant difference between pre- and postoperative albumin concentrations, and there was no significant correlation between the parameters tested. CONCLUSIONS: We can conclude that elevation in MDA and IMA levels after videothoracoscopic surgery was caused by increased oxidative stress due to minimal ischemia-reperfusion injury after the infusion of CO2 during the surgical process. Videothoracoscopic sympathectomy operation causes a decrease in NO production, and this should be taken in consideration when evaluating nitrosative stress in videothoracoscopic surgery. PMID- 26933461 TI - Video-assisted thoracoscopic decortication for the management of late stage pleural empyema, is it feasible? AB - BACKGROUND: Video-assisted thoracoscopic surgical decortication (VATSD) is widely applicable in fibrinopurulent Stage II empyema. While, more chronic thick walled Stage III empyema (organizing stage) needs conversion to open thoracotomy, and existing reports reveal a lacuna in the realm of late stage empyema patient's management through VATS utilization, particularly Stage III empyema. We prospectively evaluated the application of VATSD regardless of the stage of pleural empyema for the effective management of late stage empyema in comparison to open decortications (ODs) to minimize the adverse effects of the disease. METHODS: All patients with pyogenic pleural empyema (Stage II and Stage III) in King Khalid University Hospital (KKUH) (admitted from January 2009 to December 2013) who did not respond to chest tube/pigtail drainage and/or antibiotic therapy were treated with VATSD and/or open thoracotomy. Prospective evaluation was carried out, and the effect of this technique on perioperative outcomes was appraised to evaluate our technical learning with the passage of time and experience with VATS for late stage empyema management. RESULTS: Out of total 63 patients, 26 had Stage II empyema and 37 had Stage III empyema. VATSD was employed on all empyema patients admitted in the KKUH. VATSD was successful in all patients with Stage II empyema. Twenty-five patients (67.6%) with Stage III empyema completed VATSD successfully. However, only 12 cases (32.4%) required conversions to open (thoracotomy) drainage (OD). The median hospital stay for Stage III VATSD required 9.65 +/- 4.1 days. Whereas, patients who underwent open thoracotomy took longer time (21.82 +/- 16.35 days). Similarly, Stage III VATSD and Stage III open surgery cases showed significance difference among chest tube duration (7.84 +/- 3.33 days for VATS and 15.92 +/- 8.2 days for open thoracotomy). Significantly, lower postoperative complications were detected in patients treated with VATSD in terms of atelectasis, prolonged air leak, wound infection, etc. CONCLUSION: VATSD facilitates the management of fibrinopurulent, organized pyogenic pleural empyema with less postoperative discomfort, reduced hospitalization, and have fewer postoperative complications. VATSD can be an effective, safe first option for patients with Stage II pleural empyema, and feasible in most patients with Stage III pleural empyema. PMID- 26933462 TI - Pulmonary sarcoidosis presenting with acute respiratory distress syndrome. AB - Sarcoidosis is a common disease that involve almost constantly the lung. Usually the onset is insidious, and symptoms are slowly ingravescent. Very rarely, as in the case here reported, sarcoidosis can cause an acute respiratory failure with acute respiratory distress syndrome (ARDS). A 20-year-old girl from Pakistan presented for acute fatigue, fever, and cough with a chest X-ray displayed the micronodular interstitial disease. Despite of anti-tuberculosis therapy, ARDS developed in a few days requiring continuous positive airway pressure treatment. Examinations on transbronchial specimens obtained by bronchoscopy permitted to reach the diagnosis of sarcoidosis and steroid therapy improved rapidly clinical conditions. This is the first case report reported in Europe that confirms the rare onset of sarcoidosis as ARDS. Steroid therapy allows to cure rapidly this severe complication. PMID- 26933463 TI - Adenoid cystic carcinoma of the submandibular gland with rare metastasis to the sternum in a 52-year-old male. AB - Adenoid cystic carcinoma (ACC) is a rare tumor, described as being one of the most biologically destructive tumors of the head and neck. It is the most common malignancy that affects the minor salivary glands. Lung and bones are the most common regions of ACC distant metastasis. To the best of our knowledge, herein, we report the first ever case of latent isolated sternal metastasis from ACC in a 52-year-old gentleman, who was diagnosed to have ACC of the submandibular gland, excised 10 years ago. PMID- 26933464 TI - Pulmonary rehabilitation: Recommended but not implemented. PMID- 26933467 TI - Healing Rates in a Multicenter Assessment of a Sterile, Room Temperature, Acellular Dermal Matrix Versus Conventional Care Wound Management and an Active Comparator in the Treatment of Full-Thickness Diabetic Foot Ulcers. AB - OBJECTIVE: The purpose of this 16-week, multicenter, randomized, controlled trial was to assess the healed ulcer rate of a human acellular dermal matrix, DermACELL, compared with conventional care and a second acellular dermal matrix, Graftjacket, in the treatment of full-thickness diabetic foot ulcers. METHODS: One hundred sixty-eight patients were randomized into DermACELL, conventional care, and Graftjacket treatment arms in a 2:2:1 ratio. Patients in the acellular dermal matrix groups received either 1 or 2 applications of the graft at the discretion of the investigator. Weekly follow-up visits were conducted until the ulcer healed or the endpoint was reached. RESULTS: At 16 weeks, the DermACELL arm had a significantly higher proportion of completely healed ulcers than the conventional care arm (67.9% vs 48.1%; P = .0385) and a nonsignificantly higher proportion than the Graftjacket arm (67.9% vs 47.8%; P = .1149). The DermACELL arm also exhibited a greater average percent reduction in wound area than the conventional care arm (91.4% vs 80.3%; P = .0791) and the Graftjacket arm (91.4% vs 73.5%; P = .0762). The proportion of severe adverse events and the proportion of overall early withdrawals were similar among the 3 groups based on relative population size (P >= .05). CONCLUSIONS: The results presented here indicate that DermACELL is an appropriate clinical option in the treatment of diabetic foot ulcers, with significant increases in healing rates and rate of percentage wound closure as compared with conventional care options. PMID- 26933468 TI - Using a Vibration Device to Ease Pain During Facial Needling and Injection. AB - OBJECTIVE: In general, needling and injection are painful procedures, especially when the face is the target. Although local anesthetics (cream or tape) can be used to reduce the pain, they are not sufficiently effective. It has been suggested that vibration can reduce pain. The aim of this case study was to determine whether application of a vibration device to an area adjacent to the facial target area to be injected/needled would relieve pain. METHODS: Consecutive women scheduled to undergo facial injection with hyaluronic acid or botulinum toxin were recruited. Half of the face was injected with concomitant vibration, whereas the other half was injected without vibration. The pain experienced by the women during both procedures was assessed using the Numeric Rating Scale. The safety of injection with vibration was also assessed. RESULTS: Of the 32 patients, 28 indicated that vibration relieved the pain, 3 stated that it had no effect, and 1 (who received deep botulinum toxin injections to the masseter muscle) complained that it made the pain worse. Vibration did not affect the safety of the injections. The average Numeric Rating Scale scores for the no vibration and vibration injections were 4.5 +/- 1.5 and 2.3 +/- 0.9, respectively (P < .001). CONCLUSIONS: The Gate Control Theory of Pain explains why vibration reduces pain. PMID- 26933469 TI - Ring Avulsion Injuries. PMID- 26933470 TI - Collar Button Abscess. PMID- 26933465 TI - A multi-method approach to the molecular diagnosis of overt and borderline 11p15.5 defects underlying Silver-Russell and Beckwith-Wiedemann syndromes. AB - BACKGROUND: Multiple (epi)genetic defects affecting the expression of the imprinted genes within the 11p15.5 chromosomal region underlie Silver-Russell (SRS) and Beckwith-Wiedemann (BWS) syndromes. The molecular diagnosis of these opposite growth disorders requires a multi-approach flowchart to disclose known primary and secondary (epi)genetic alterations; however, up to 20 and 30 % of clinically diagnosed BWS and SRS cases remain without molecular diagnosis. The complex structure of the 11p15 region with variable CpG methylation and low-rate mosaicism may account for missed diagnoses. Here, we demonstrate the relevance of complementary techniques for the assessment of different CpGs and the importance of testing multiple tissues to increase the SRS and BWS detection rate. RESULTS: Molecular testing of 147 and 450 clinically diagnosed SRS and BWS cases provided diagnosis in 34 SRS and 185 BWS patients, with 9 SRS and 21 BWS cases remaining undiagnosed and herein referred to as "borderline." A flowchart including complementary techniques and, when applicable, the analysis of buccal swabs, allowed confirmation of the molecular diagnosis in all borderline cases. Comparison of methylation levels by methylation-specific multiplex ligation dependent probe amplification (MS-MLPA) in borderline and control cases defined an interval of H19/IGF2:IG-DMR loss of methylation that was distinct between "easy to diagnose" and "borderline" cases, which were characterized by values <=mean -3 standard deviations (SDs) compared to controls. Values >=mean +1 SD at H19/IGF2: IG-DMR were assigned to borderline hypermethylated BWS cases and those <=mean -2 SD at KCNQ1OT1: TSS-DMR to hypomethylated BWS cases; these were supported by quantitative pyrosequencing or Southern blot analysis. Six BWS cases suspected to carry mosaic paternal uniparental disomy of chromosome 11 were confirmed by SNP array, which detected mosaicism till 10 %. Regarding the clinical presentation, borderline SRS were representative of the syndromic phenotype, with exception of one patient, whereas BWS cases showed low frequency of the most common features except hemihyperplasia. CONCLUSIONS: A conclusive molecular diagnosis was reached in borderline methylation cases, increasing the detection rate by 6 % for SRS and 5 % for BWS cases. The introduction of complementary techniques and additional tissue analyses into routine diagnostic work-up should facilitate the identification of cases undiagnosed because of mosaicism, a distinctive feature of epigenetic disorders. PMID- 26933471 TI - Pyogenic (Suppurative) Flexor Tenosynovitis: Assessment and Management. PMID- 26933472 TI - Congenital Epulis. PMID- 26933455 TI - The Saudi Initiative for Asthma - 2016 update: Guidelines for the diagnosis and management of asthma in adults and children. AB - This is an updated guideline for the diagnosis and management of asthma, developed by the Saudi Initiative for Asthma (SINA) group, a subsidiary of the Saudi Thoracic Society. The main objective of SINA is to have guidelines that are up to date, simple to understand and easy to use by nonasthma specialists, including primary care and general practice physicians. SINA approach is mainly based on symptom control and assessment of risk as it is the ultimate goal of treatment. The new SINA guidelines include updates of acute and chronic asthma management, with more emphasis on the use of asthma control in the management of asthma in adults and children, inclusion of a new medication appendix, and keeping consistency on the management at different age groups. The section on asthma in children is rewritten and expanded where the approach is stratified based on the age. The guidelines are constructed based on the available evidence, local literature, and the current situation in Saudi Arabia. There is also an emphasis on patient-doctor partnership in the management that also includes a self-management plan. PMID- 26933473 TI - Hippophae rhamnoides L. Fruits Reduce the Oxidative Stress in Human Blood Platelets and Plasma. AB - Effects of the phenolic fraction from Hippophae rhamnoides fruits on the production of thiobarbituric acid reactive substances (TBARS, a marker of lipid peroxidation) and the generation of superoxide anion (O2 (-?)) in human blood platelets (resting platelets and platelets stimulated by a strong physiological agonist, thrombin) were studied in vitro. We also examined antioxidant properties of this fraction against human plasma lipid peroxidation and protein carbonylation induced by a strong biological oxidant, hydrogen peroxide (H2O2) or H2O2/Fe (a donor of hydroxyl radicals). The tested fraction of H. rhamnoides (0.5 50 ug/mL; the incubation time: 15 and 60 min) inhibited lipid peroxidation induced by H2O2 or H2O2/Fe. The H. rhamnoides phenolic fraction inhibited not only plasma lipid peroxidation, but also plasma protein carbonylation stimulated by H2O2 or H2O2/Fe. Moreover, the level of O2 (-?) in platelets significantly decreased. In comparative experiments, the H. rhamnoides fraction was a more effective antioxidant than aronia extract or grape seed extract (at the highest tested concentration, 50 ug/mL). The obtained results suggest that H. rhamnoides fruits may be a new, promising source of natural compounds with antioxidant and antiplatelet activity beneficial not only for healthy people, but also for those with oxidative stress-associated diseases. PMID- 26933474 TI - A Mechanistic Study on the Amiodarone-Induced Pulmonary Toxicity. AB - Amiodarone- (AM-) induced pulmonary toxicity (AIPT) is still a matter of research and is poorly understood. In attempting to resolve this issue, we treated Sprague Dawley rats with AM doses of 80 mg/kg/day/i.p. for one, two, three, and four weeks. The rats were weighed at days 7, 14, 21, and 28 and bronchoalveolar lavages (BAL) were obtained to determine total leukocyte count (TLC). For each group, lung weighing, histopathology, and homogenization were performed. Fresh homogenates were used for determination of ATP content, lipid peroxides, GSH, catalase, SOD, GPx, GR activities, NO, and hydroxyproline levels. The results showed a significant decrease in body weight and GSH depletion together with an increase in both lung weight and lung/body weight coefficient in the first week. Considerable increases in lung hydroxyproline level with some histopathological alterations were apparent. Treatment for two weeks produced a significant increase in BAL fluid, TLC, GR activity, and NO level in lung homogenate. The loss of cellular ATP and inhibition of most antioxidative protective enzymatic system appeared along with alteration in SOD activity following daily treatment for three weeks, while, in rats treated with AM for four weeks, more severe toxicity was apparent. Histopathological diagnosis was mostly granulomatous inflammation and interstitial pneumonitis in rats treated for three and four weeks, respectively. As shown, it is obvious that slow oedema formation is the only initiating factor of AIPT; all other mechanisms may occur as a consequence. PMID- 26933475 TI - Genome sequences of Knoxdaviesia capensis and K. proteae (Fungi: Ascomycota) from Protea trees in South Africa. AB - Two closely related ophiostomatoid fungi, Knoxdaviesia capensis and K. proteae, inhabit the fruiting structures of certain Protea species indigenous to southern Africa. Although K. capensis occurs in several Protea hosts, K. proteae is confined to P. repens. In this study, the genomes of K. capensis CBS139037 and K. proteae CBS140089 are determined. The genome of K. capensis consists of 35,537,816 bp assembled into 29 scaffolds and 7940 predicted protein-coding genes of which 6192 (77.98 %) could be functionally classified. K. proteae has a similar genome size of 35,489,142 bp that is comprised of 133 scaffolds. A total of 8173 protein-coding genes were predicted for K. proteae and 6093 (74.55 %) of these have functional annotations. The GC-content of both genomes is 52.8 %. PMID- 26933476 TI - Epidemiological Profile of Hepatitis B Virus Infection in Iran in the Past 25 years; A Systematic Review and Meta-analysis of General Population Studies. AB - BACKGROUND Chronic hepatitis B virus (HBV) infection is one of the most important health problems worldwide with a high rate of morbidity and mortality. It is a major risk factor for cirrhosis and liver cancer. Currently, Iran is located in the intermediate HBV zone; however, recent studies have provided some evidence indicating an epidemiological change in the country. The aim of this study was to estimate the prevalence of HBV in Iran. METHODS A systematic review was conducted to evaluate the studies performed in the past 25 years that have reported the prevalence of HBV infection and its associated factors in the Iranian general population (1990-2014). Any study assessing and reporting serum Hbs Ag levels was included in this review. RESULTS After excluding all impertinent studies, 19 eligible studies were included in the analysis. The overall prevalence of HBV was 3% (95% CI 2% to 3%). Its distribution showed that the prevalence of HBV varies in different provinces from 0.87% to 8.86%. The HBV rate was highest in the Golestan (8.86%) and lowest in the Kurdistan (0.87%) provinces. CONCLUSION This study provides some evidence about the prevalence of HBV in Iran. However, the collected data was very heterogenic, even within a single province, which made it hard to estimate a single-point prevalence. High quality studies are needed to find reliable information about HBV prevalence and to decrease the heterogeneity of results in the country. PMID- 26933477 TI - The Nail as a Biomonitor of Trace Element Status in Golestan Cohort Study. AB - BACKGROUND In the Golestan Cohort Study that was launched to investigate the causes of esophageal cancer, a complete biospecimen bank was established for storage of collected blood, urine, hair, and nail samples. The objective of this study was to evaluate the feasibility of nail samples as a biomarker of selected trace elements status. METHODS Thirty toenail samples were selected randomly from the participants of Golestan Cohort Study (GCS). The samples were cleaned and analyzed for selenium, mercury, chromium, iron, zinc, and scandium by instrumental neutron activation analysis at the University of Missouri Research Reactor Center. Pearson correlation coefficients were computed for selected trace elements concentration versus scandium concentration to assess terrestrial contamination. RESULTS The selenium, zinc, and mercury were not correlated with scandium, suggesting they were free from substantial contamination. The high correlations of scandium with iron and chromium suggest that the iron and chromium levels may be compromised by terrestrial contamination. The coefficients of variation for duplicate samples for selenium and zinc were 2.6% and 7.2%, respectively. CONCLUSION The nail samples from Golestan Cohort Study appears to be useable as a biomarker of selenium, zinc, and mercury and could be considered for use in future studies. PMID- 26933478 TI - Human Epidermal Growth Factor Receptor Expression in Colorectal Cancer and Its Relationship with Clinicopathological Characteristics. AB - BACKGROUND Some recent studies reported human epidermal growth factor receptor (HER-2/neu) as a marker that can be used in immunological studies of colorectal carcinoma for predicting the prognosis and the treatment. Therefore, we aimed to investigate the frequency of HER-2 expression in patients with colorectal cancer, and explore the relationship between clinicopathological prognostic factors and its expression based on immunohistochemical analysis. METHODS This study included 50 patients with a histologically proven diagnosis of colorectal carcinoma who received surgery at Imam Khomeini Hospital affiliated to Mazandaran University of Medical Sciences. First, HER-2/neu protein expressions were detected by immunohistochemistry and then the data extracted from recorded files. RESULTS The median age of the patients was 60.2+/-13.9 years (range: 25-93 years). There was no significant relationship between size of tumor, age, sex, lymph node metastases, distant metastasis, differentiation, and stage of the disease with positive expression of HER-2 in this study. CONCLUSION No significant relationship between expression of HER-2 and clinicopathological prognostic factors was found in our study. Further comprehensive and prospective trial with standard method to evaluate the role of HER-2 expression among patients with colorectal cancer is needed. PMID- 26933479 TI - Iron Status and Metabolic Syndrome in Patients with Non-Alcoholic Fatty Liver Disease. AB - BACKGROUND A hypothesis has been presented about the role of serum iron, ferritin and transferrin saturation among patients with non-alcoholic fatty liver disease (NAFLD) and resistance to insulin (metabolic syndrome [MetS]), but there is much controversy. This study aimed at investigating the level of serum iron and demographic characteristics in patients with NAFLD with or without MetS. METHODS A case-control study was conducted on patients with elevated liver enzymes referring to Baqiyatallah clinic, Tehran, Iran during 2010-2011. After ruling out other causes of increased aminotransferases and approving the diagnosis of NAFLD, the patients were divided into two groups of with or without MetS. Then, the individuals' demographic, sonographic, and laboratory characteristics were recorded. RESULTS This research included 299 patients suffering from NAFLD who were divided into MetS (n=143; 47.8%) and non-MetS (n=156; 52.2%) groups. The age, systolic and diastolic blood pressure, body mass index, waist/hip ratio, glucose tolerance test, serum insulin, C. peptide, triglyceride, and HB A1c were different between MetS and non-MetS groups (p<0.05). There was no significant difference in serum iron and ferritin levels between the two groups, however, a significant correlation was found between serum ferritin and alanine transaminase (p=0.005) and also aspartate aminotransferase (p=0.032). CONCLUSION Our findings did not show a significant relationship between iron, in free or storage form, and the presence of MetS among patients with NAFLD, but serum ferritin can correlate with hepatocytes injuries indicated by raised aminotransferases. Nevertheless, to clarify this relationship further molecular, genomic, and histopathological studies are required. PMID- 26933481 TI - Expression of P33(ING1b) Protein in Colorectal Cancer. AB - BACKGROUND Colorectal cancer (CRC) is the second most common malignancy in the world. However, its mortality rate can be reduced if diagnosed early. P33ING1b is a tumor suppressor protein, which plays a role in growth control and apoptosis. Suppression of p33(ING1b) is associated with the loss of cellular growth control. However, p33 (ING1b) expression in CRC and its correlations with clinicopathological factors have been less studied. The aim of this study was to examine p33(ING1b) expression in patients with CRC and evaluate its potential correlations with clinicopathological factors. METHODS P33(ING1b) protein expression was examined in 70 cases of CRC tissue samples and their corresponding neighboring normal tissues by immunhistochemistry. Moreover, p33(ING1b) expression in CRC and its correlations with clinicopathological variables including patients' sex and age, tumor type, location, stage, and differentiation grade were examined. RESULTS P33(ING1b) expression was significantly lower in tumor samples compared with the normal adjacent samples (p<0.002). CONCLUSION Low expression of P33(ING1b) in patients with colorectal cancer, may be an important molecular event in the pathogenesis of colorectal cancer. Our data suggest that reduced expression of p33(ING1b) may be contribute to tumor genesis and accompanied by the loss of cellular growth control. In fact cell growth is out of control in lower expression of P33 and dysfunctional program cell death. P33 expression might explain the etiology of CRC for reducing the expression of tumor suppressor proteins. PMID- 26933480 TI - A Comparison between Hybrid Therapy and Standard Triple Therapy for Helicobacter pylori Eradication in Patients with Uremia: A Randomized Clinical Trial. AB - BACKGROUND The prevalence of peptic ulcer disease in hemodialysis patients is more than the general population. They are also more prone to complications including upper gastrointestinal bleeding. The aim of this study was to compare the efficacy of 14 days hybrid regimen with 14 days triple therapy for Helicobacter pylori (H. pylori ) eradication in hemodialysis patients. METHODS Forty hemodialysis patients with naive H.pylori infection were randomized to receive either hybrid regimen (pantoprazole 40 mg + amoxicillin 500 mg, both twice a day during the first 7 days, followed by pantoprazole 40 mg + amoxicillin 500 mg + clarithromycin 500 mg + tinidazole 500 mg, all twice a day, for the second 7 days, or standard triple therapy including pantoprazole 40 mg, clarithromycin 500 mg, and amoxicillin 500 mg, all twice a day for 14 days. H.pylori eradication was assessed by fecal H.pylori antigen test 8 weeks after the treatment. RESULTS All the patients completed the study. According to both intention to treat and per-protocol analyses, H.pylori eradication rates were 100% (95% confidence interval (CI): 100) in those who received hybrid therapy and 70% (95% CI: 69.4 - 70.8) in those who were treated by standard triple therapy (p=0.02). Severe adverse effects were not reported by any patient; however, mild adverse effects were more frequent in those who received standard triple therapy (p<0.05). CONCLUSION Hybrid regimen could achieve ideal H.pylori eradication rates with low rates of adverse effects. PMID- 26933482 TI - Effects of Clarithromycin-Containing Quadruple Therapy on Helicobacter Pylori Eradication after Nitroimidazole-Containing Quadruple Therapy Failure. AB - BACKGROUND Several large clinical trials and meta-analyses have shown about 20% failure to eradicate Helicobacter pylori (H.pylori), necessitating investigations for second-line treatments. The aim of this study was to evaluate the effects of clarithromycin-containing quadruple regimen after nitroimidazole-containing quadruple therapy failure. METHODS Thirty two patients who had failed 10-day H.pylori treatment with omeprazole, amoxicillin, bismuth subcitrate, and metronidazole (OABM) regimen and 31 patients who had failed 10-day treatment with omeprazole, amoxicillin, bismuth subcitrate, and furazolidone (OAMF) regimen entered the study. They all received omeprazole (20 mg), amoxicillin (1 gr), bismuth subcitrate (240 mg) and clarithromycin (500 mg) twice a day for 10 days. Eight weeks after treatment, H. pylori eradication was assessed by (14)C-urea breath test. RESULTS Totally 61 patients completed the study. According to intention to treat (ITT) analysis, eradication rates by second-line OABC regimen were 84.37% (95% CI= 71.7-96.9%) in OABM group and 77.41% (95% CI= 62.71-92.11%) in OABF group (p=0.756). Per-protocol (pp) eradication rates were 87.09% (95% CI= 75.2-98.8%) and 82.75% (95% CI= 79.4-96%), respectively (p=0.638). Also the cumulative eradication rates by OABC regimen were 80.9% (95% CI= 71.2-90.6%) and 85% (95% CI= 75.9-94%) according to ITT and PP analyses, respectively. Severe side effects were reported in 3.1% of the patients. CONCLUSION Regarding ideal eradication rate (>80%) and very low adverse effects, it seems that clarithromycin-containing quadruple therapy can be an encouraging regimen after nitroimidazole-containing regimen failure. PMID- 26933483 TI - Assessment of Pneumatic Balloon Dilation in Patients with Symptomatic Relapse after Failed Heller Myotomy: A Single Center Experience. AB - BACKGROUND Although Heller myotomy is one of the most effective treatments for achalasia, it may be associated with early or late symptom relapse in some patients. Therefore, additional treatment is required to achieve better control of symptoms. AIM: To evaluate the safety and efficacy of pneumatic balloon dilation (PBD) in patients with symptom relapse after Heller myotomy. METHODS Thirty six post-myotomy patients were evaluated from 1993 to 2013. Six patients were excluded from the analysis because of comorbid diseases or epiphrenic diverticula. Thirty patients were treated with PBD. Primary outcome was defined as a decrease in symptom score to 4 or less and a reduction greater than 80% from the baseline in the volume of barium in timed barium esophagogram in 6 weeks. Achalasia symptom score (ASS) was assessed at 1.5, 3, 6, and 12 months after treatment and then every six months in all patients and PBD was repeated in case of symptom relapse (ASS>4). RESULTS The mean age of the patients was 45.5+/-13.9 years (range: 21-73). Primary outcome was observed in 25 patients (83%). The mean ASS of the patients dropped from 7.8 before treatment to 1.3+/-2.0 at 1.5 months after treatment (p=0.0001). The mean volume and height of barium decreased from 43.1+/-33.4 and 7.1+/-4.7 to 6.0+/-17.1 and 1.1+/-2.2, respectively (p=0.003, p=0.003). The mean duration of follow-up was 11.8+/-6.3 years. At the end of the study, 21 patients (70%) reported sustained good response. No major complications such as perforation or gross bleeding were seen. CONCLUSION PBD is an effective and safe treatment option for achalasia in patients with symptom relapse after Heller myotomy. PMID- 26933484 TI - Leech Induced Pyoderma Gangrenosum in an Ulcerative Colitis Patient: A Case Report. AB - Pyoderma gangrenosum (PG) is a painful skin lesion that results from excessive inflammatory response to a host of traumatic, inflammatory, or neoplastic processes in susceptible individuals. A clear pathogenetic mechanism as well as an exhaustive list of potential triggers for PG is yet to be fully characterized. This case documents the occurrence of pyoderma gangrenosum following leech therapy in a patient who is a known case of ulcerative colitis and it deserves attention because leeches have been part of medical armamentarium since ancient times and have re-emerged in the last century relying on their ancient charm and modern research revealing potential benefits of several bioactive substances in their saliva. PMID- 26933485 TI - Severe Abdominal Pain Caused by Lead Toxicity without Response to Oral Chelators: A Case Report. AB - A 19-year-old woman was referred to the Emergency Surgery Department with severe abdominal pain, icterus, and anemia. The patient's clinical and paraclinical findings in addition to her occupational and social history, convinced us to assay blood lead level (BLL), which was 41/5 MUg/dL. Therefore toxicology consult was performed to treat lead toxicity. Recheck of the BLL showed the level as 53/7 MUg/dL. So oral chelator with succimer was started. Despite consumption of oral chelator, there was no response and the pain continued. Because our repeated evaluations were negative, we decided to re-treat lead poisoning by intravenous and intramuscular chelators. Dimercaprol (BAL) + calcium EDTA was started, and after 5 days, the pain relieved dramatically and the patient was discharged. We recommend more liberal lead poisoning therapy in symptomatic patients, and also suggest parenteral chelator therapy, which is more potent, instead of oral chelators in patients with severe symptoms. PMID- 26933486 TI - Rectal Bleeding in a Young Patient with Cavernous Hemangioma and Bone Hypertrophy. PMID- 26933487 TI - Synaptic vesicle dynamic changes in a model of fragile X. AB - BACKGROUND: Fragile X syndrome (FXS) is a single-gene disorder that is the most common heritable cause of intellectual disability and the most frequent monogenic cause of autism spectrum disorders (ASD). FXS is caused by an expansion of trinucleotide repeats in the promoter region of the fragile X mental retardation gene (Fmr1). This leads to a lack of fragile X mental retardation protein (FMRP), which regulates translation of a wide range of messenger RNAs (mRNAs). The extent of expression level alterations of synaptic proteins affected by FMRP loss and their consequences on synaptic dynamics in FXS has not been fully investigated. METHODS: Here, we used an Fmr1 knockout (KO) mouse model to investigate the molecular mechanisms underlying FXS by monitoring protein expression changes using shotgun label-free liquid-chromatography mass spectrometry (LC-MS(E)) in brain tissue and synaptosome fractions. FXS-associated candidate proteins were validated using selected reaction monitoring (SRM) in synaptosome fractions for targeted protein quantification. Furthermore, functional alterations in synaptic release and dynamics were evaluated using live-cell imaging, and interpretation of synaptic dynamics differences was investigated using electron microscopy. RESULTS: Key findings relate to altered levels of proteins involved in GABA signalling, especially in the cerebellum. Further exploration using microscopy studies found reduced synaptic vesicle unloading of hippocampal neurons and increased vesicle unloading in cerebellar neurons, which suggests a general decrease of synaptic transmission. CONCLUSIONS: Our findings suggest that FMRP is a regulator of synaptic vesicle dynamics, which supports the role of FMRP in presynaptic functions. Taken together, these studies provide novel insights into the molecular changes associated with FXS. PMID- 26933488 TI - Cerebral collateral circulation in experimental ischemic stroke. AB - Cerebral collateral circulation is a subsidiary vascular network, which is dynamically recruited after arterial occlusion, and represents a powerful determinant of ischemic stroke outcome. Although several methods may be used for assessing cerebral collaterals in the acute phase of ischemic stroke in humans and rodents, they are generally underutilized. Experimental stroke models may play a unique role in understanding the adaptive response of cerebral collaterals during ischemia and their potential for therapeutic modulation. The systematic assessment of collateral perfusion in experimental stroke models may be used as a "stratification factor" in multiple regression analysis of neuroprotection studies, in order to control the within-group variability. Exploring the modulatory mechanisms of cerebral collaterals in stroke models may promote the translational development of therapeutic strategies for increasing collateral flow and directly compare them in term of efficacy, safety and feasibility. Collateral therapeutics may have a role in the hyperacute (even pre-hospital) phase of ischemic stroke, prior to recanalization therapies. PMID- 26933489 TI - Population structure and phylogeography of the Gentoo Penguin (Pygoscelis papua) across the Scotia Arc. AB - Climate change, fisheries' pressure on penguin prey, and direct human disturbance of wildlife have all been implicated in causing large shifts in the abundance and distribution of penguins in the Southern Ocean. Without mark-recapture studies, understanding how colonies form and, by extension, how ranges shift is challenging. Genetic studies, particularly focused on newly established colonies, provide a snapshot of colonization and can reveal the extent to which shifts in abundance and occupancy result from changes in demographic rates (e.g., reproduction and survival) or migration among suitable patches of habitat. Here, we describe the population structure of a colonial seabird breeding across a large latitudinal range in the Southern Ocean. Using multilocus microsatellite genotype data from 510 Gentoo penguin (Pygoscelis papua) individuals from 14 colonies along the Scotia Arc and Antarctic Peninsula, together with mitochondrial DNA data, we find strong genetic differentiation between colonies north and south of the Polar Front, that coincides geographically with the taxonomic boundary separating the subspecies P. p. papua and P. p. ellsworthii. Using a discrete Bayesian phylogeographic approach, we show that southern Gentoos expanded from a possible glacial refuge in the center of their current range, colonizing regions to the north and south through rare, long-distance dispersal. Our findings show that this dispersal is important for new colony foundation and range expansion in a seabird species that ordinarily exhibits high levels of natal philopatry, though persistent oceanographic features serve as barriers to movement. PMID- 26933490 TI - Mitogenomics reveals high synteny and long evolutionary histories of sympatric cryptic nematode species. AB - Species with seemingly identical morphology but with distinct genetic differences are abundant in the marine environment and frequently co-occur in the same habitat. Such cryptic species are typically delineated using a limited number of mitochondrial and/or nuclear marker genes, which do not yield information on gene order and gene content of the genomes under consideration. We used next generation sequencing to study the composition of the mitochondrial genomes of four sympatrically distributed cryptic species of the Litoditis marina species complex (PmI, PmII, PmIII, and PmIV). The ecology, biology, and natural occurrence of these four species are well known, but the evolutionary processes behind this cryptic speciation remain largely unknown. The gene order of the mitochondrial genomes of the four species was conserved, but differences in genome length, gene length, and codon usage were observed. The atp8 gene was lacking in all four species. Phylogenetic analyses confirm that PmI and PmIV are sister species and that PmIII diverged earliest. The most recent common ancestor of the four cryptic species was estimated to have diverged 16 MYA. Synonymous mutations outnumbered nonsynonymous changes in all protein-encoding genes, with the Complex IV genes (coxI-III) experiencing the strongest purifying selection. Our mitogenomic results show that morphologically similar species can have long evolutionary histories and that PmIII has several differences in genetic makeup compared to the three other species, which may explain why it is better adapted to higher temperatures than the other species. PMID- 26933491 TI - Responses of plant biomass, photosynthesis and lipid peroxidation to warming and precipitation change in two dominant species (Stipa grandis and Leymus chinensis) from North China Grasslands. AB - Influential factors of global change affect plant carbon uptake and biomass simultaneously. Although the effects from warming and precipitation change have been extensive studied separately, the responses of plant biomass, photosynthesis, and lipid peroxidation to the interaction of these factors are still not fully understood. In this study, we examined the physiological responses of two dominant plant species from grasslands of northern China with different functional traits to combinations of five simulated warming patterns and five simulated precipitation patterns in environment-controlled chambers. Our results showed that the biomass, net CO 2 assimilation rate (P n), maximal efficiency of photosystem II photochemistry (F v/F m), and chlorophyll content (Chl) of Stipa grandis and Leymus chinensis were enhanced by moderate warming and plus precipitation, but they declined drastically with high temperature and drought. High temperature and drought also led to significant malondialdehyde (MDA) accumulation, which had a negative correlation with leaf biomass. The lower level of lipid peroxidation in leaves of S. grandis suggests that this species is better protected from oxidative damage under heat stress, drought stress and their interactive conditions than L. chinensis. Using the subordinate function values method, we found S. grandis to be more sensitive to climate change than L. chinensis and the gross biomass and root biomass of S. grandis and the leaf biomass of L. chinensis were most sensitive to climate change. Furthermore, the P n of both S. grandis and L. chinensis had a significant linear relationship with F v/F m and Chl, indicating that carbon assimilation may be caused by nonstomatal limitations. PMID- 26933492 TI - Superior growth performance in broiler chicks fed chelated compared to inorganic zinc in presence of elevated dietary copper. AB - BACKGROUND: The goal of this study was to compare the antagonism of elevated dietary Cu (250 mg/kg) from CuSO4 on three different Zn sources (ZnSO4 . H2O; [Zn bis(-2-hydroxy-4-(methylthio)butanoic acid)], Zn(HMTBa)2, a chelated Zn methionine hydroxy analogue; and Zn-Methionine), as measured using multiple indices of animal performance in ROSS 308 broilers. METHODS: Three experiments were conducted in broiler chicks fed a semi-purified diet. All birds were fed a Zn-deficient diet (8.5 mg/kg diet) for 1 wk, and then provided with the experimental diets for 2 wks. RESULTS: Experiment 1 was a 2 * 2 factorial design with two levels of Cu (8 vs. 250 mg/kg diet from CuSO4) and two Zn sources at 30 mg/kg [ZnSO4 . H2O vs. Zn(HMTBa)2]. Elevated Cu impaired growth performance only in birds fed ZnSO4. Compared to ZnSO4 . H2O, Zn(HMTBa)2 improved feed intake (12 %; P < 0.001) and weight gain (12 %, P < 0.001) and the benefits were more pronounced in the presence of 250 mg/kg diet Cu. Experiment 2 was a dose titration of ZnSO4 . H2O and Zn(HMTBa)2 at 30, 45, 60, and 75 mg/kg diet in the presence of 250 mg/kg CuSO4. Feed:gain was decreased and tibia Zn was increased with increasing Zn levels from 30 to 75 mg/kg. Birds fed Zn(HMTBa)2 consumed more food and gained more weight compared to birds fed ZnSO4, especially at lower supplementation levels (30 and 45 mg/kg; interaction P < 0,05). Experiment 3 compared two organic Zn sources (Zn(HMTBa)2 vs. Zn-Methionine) at 30 mg/kg with or without 250 mg/kg CuSO4. No interactions were observed between Zn sources and Cu levels on performance or tissue mineral concentrations. High dietary Cu decreased weight gain (P < 0.01). Tibia Cu and liver Cu were significantly increased with 250 mg/kg dietary Cu supplementation (P < 0.01). No difference was observed between the two Zn sources. CONCLUSIONS: Dietary 250 mg/kg Cu significantly impaired feed intake and weight gain in birds fed ZnSO4 . H2O, but had less impact in birds fed Zn(HMTBa)2. No difference was observed between the two organic zinc sources. These results are consistent with the hypothesis that chelated organic Zn is better utilized than inorganic zinc in the presence of elevated Cu. PMID- 26933493 TI - Modified halloysite nanotubes reduce the toxic effects of zearalenone in gestating sows on growth and muscle development of their offsprings. AB - BACKGROUND: Zearalenone (ZEN) is an estrogenic mycotoxin that is primarily produced by Fusarium fungi and has been proven to affect the reproductive capacity of many species to varying degrees. The present experiment was designed to study the maternal persistent effects of zearalenone toxicity in gestating sows on growth and muscle development of their offsprings, and the alleviation of zearalenone toxicity by modified halloysite nanotubes (MHNTs). METHODS: Eighteen sows were fed with one of three dietary treatments that included the following: (1) a control diet, (2) a contaminated grain diet (with 50 % moldy corn, 2.77 mg/kg ZEN), and (3) a contaminated grain diet (with 50 % moldy corn, 2.76 mg/kg ZEN) + 1 % MHNTs. Each sow was exclusively fed its experimental diets from 35 to 70 d of gestation at a total of 2 kg daily. Muscle samples were collected from six piglets per treatment at birth, weaning and finishing. RESULTS: The results showed that feeding the sows with the ZEN-contaminated diets from 35 to 70 d of gestation decreased the ADG, ADFI and G:F of their offsprings (P < 0.05). The muscle fiber numbers in the newborn, weaning and growing-finishing pigs and the muscle fiber diameters at birth and weaning were also decreased by maternal ZEN exposure (P < 0.05). The expressions of IGF-I, IGF-II, Myf-5 and Mstn at birth and IGF-II, Pax7, Myf-5 and MyoD1 at weaning were altered by feeding gestating sows with ZEN-contaminated diets (P < 0.05). The MHNTs reduced most of the ZEN induced toxic effects: the ADG and ADFI on growth performance, the muscle fiber numbers at weaning and finishing and the muscle fiber diameters at weaning (P < 0.05). The expression levels of IGF-II and Mstn in newborn piglets and IGF-II and Myf-5 in weaning piglets were also prevented by adding 1 % MHNTs (P < 0.05). CONCLUSIONS: The present study demonstrated that the offsprings of sows fed with ZEN-contaminated diets from 35 to 70 day of gestation exhibited weakening on growth performance, physiological changes in their muscle fibers and alterations of mRNA expression in their muscle tissues, and also indicated that MHNTs prevented most of the ZEN-induced weakening in the muscle tissues. PMID- 26933494 TI - Latrine access and utilization among people with limited mobility: A cross sectional study. AB - BACKGROUND: Latrine access is one of the challenges faced by people with physical disabilities that limit their mobility (PPDs) in their home and working environments. Latrines should be designed, built and located such that they are easily accessible and utilizable by PPDs. Therefore, the aim of this study was to determine latrine access and utilization, and explore the challenges in latrine use among PPDs in Bahir Dar city, northwest Ethiopia. METHODS: A cross-sectional study design was conducted from July 15 to August 15, 2014. Data were collected using a structured and pre-tested questionnaire, and focus group discussions. Four hundred nineteen participants were included using a systematic random sampling technique. SPSS version 20 was used for data entry and analysis. Binary logistic regression was used to identify factors associated with latrine utilization. Qualitative data were analyzed using themes. RESULTS: Of 419 participants, 142 (33.9 %) had access to latrines and 173 (41.3 %) had satisfactory latrine utilization. Family support while using latrine (AOR = 4.7, 95 % CI (2.7, 8.3), latrine accessibility (AOR = 2.1, 95 % CI (1.2, 3.7) and past latrine modification (AOR = 3.1, 95 % CI (1.8, 5.4) were factors associated with latrine utilization. Presence of steps at the latrine entrance, privacy while using latrine, absence of handrails, unavailability of family support, narrower latrine door, distant latrine, unclean floor of the latrine and elevated foot rests were challenges mentioned by PPDs. CONCLUSIONS: Latrine access and utilization were low among PPDs. Family members should encourage and support PPDs when they need to use latrine, designing accessible latrines, modifying existing latrines to accommodate PPDs are the areas of interventions to increase latrine accessibility and utilization among PPDs. PMID- 26933495 TI - Differentiation of respiratory epithelium in a 3-dimensional co-culture with fibroblasts embedded in fibrin gel. AB - BACKGROUND: Tracheal tissue engineering is a promising option for the treatment of tracheal defects. In a previous study we proved the suitability of fibrin gel as a scaffold for tracheal tissue engineering. This study investigates whether the differentiation of respiratory epithelium can be increased by culturing epithelial cells in a three dimensional system containing fibroblasts embedded into fibrin gel. METHODS: Respiratory epithelial cells were isolated from porcine trachea, seeded onto a fibrin gel and kept in air-liquid-interface culture for 33 days. Morphology as well as pan-cytokeratin, MUC5AC and claudin-1 expression of cells cultured on pure fibrin gel were compared to culture on gels containing fibroblasts. RESULTS: After two weeks, cells seeded on pure fibrin gel were multilayered, showed hyperproliferation and dedifferentiation. Co-cultured cells built up a pseudostratified epithelium. The differentiation and organization of epithelial structure improved with respect to time. After four weeks, morphology of the co-cultured respiratory epithelium resembled native tracheal epithelium. Immunohistochemistry showed that respiratory epithelium co-cultured with fibroblasts had an increasing similarity of pan-cytokeratin expression compared to native trachea. Cells cultured without fibroblasts differed in pan-cytokeratin expression from native trachea and did not show any improvement of differentiation. Immunohistochemical staining of MUC5AC and claudin-1 proved seeded cells being respiratory epithelial cells. CONCLUSIONS: This study indicates that adding fibroblasts to fibrin gel positively influences the differentiation of respiratory epithelium. PMID- 26933496 TI - Chronic respiratory symptoms and associated factors among cement factory workers in Dejen town, Amhara regional state, Ethiopia, 2015. AB - BACKGROUND: Chronic respiratory diseases represent a public health challenge in both industrialized and developing countries. Chronic respiratory symptoms are more prevalent in cement factories of developing countries, where occupational health and safety issues are less emphasized. This study was conducted to determine the prevalence and factors affecting chronic respiratory symptoms among workers in Dejen cement factory, 2015. METHODS: Institution based cross sectional study was conducted among 404 randomly selected study participants. Data were collected through interviewer administered structured questions derived from British Medical Research Council (BMRC) adult respiratory symptom assessment questions and observational check lists for the assessment of dust exposure, hygienic practices and use of personal protective equipments. Multivariable logistic regression model was used to identify predictor variables which have association with chronic respiratory symptoms and finally the variables which had significant association were identified on the basis of Adjusted Odds Ratio (AOR) with 95 % Confidence Interval (CI) and p < 0.05. RESULTS: The prevalence of chronic respiratory symptoms among Dejen cement factory workers was 62.9 %, with prevalence of chronic cough 24.5 %, chronic wheezing 36.9 %, chronic phlegm 24.5 %, chronic shortness of breath 38.6 %, and chest pain 21.0 %. Chronic respiratory symptoms were associated with sex (AOR = 2.07, 95 % CI = 1.18, 3.63), age (AOR = 4.20, 95 % CI = 1.94, 9.12), education level (AOR = 4.07,95 % CI = 1.86, 8.92), cement mill (AOR = 3.72, 95 % CI = 1.92, 7.21), burner and clinker (AOR = 2.28, 95 % CI = 1.18, 4.43), work experience (AOR = 5.44, 95 % CI = 3.09, 9.59), training on occupational safety and health (AOR = 2.73, 95 % CI = 1.41, 5.29), smoking (AOR = 5.38, 95 % CI = 1.42, 20.39) and chronic respiratory diseases (AOR = 7.79, 95 % CI = 2.02, 30.04). CONCLUSION: Chronic respiratory symptoms were highly prevalent among Dejen cement factory workers. Age, sex, education level, working department, smoking, work experience, and training were identified factors. Pre employment and on service training, smoking cessation programs, improving hygienic practices are important tasks in order to maintain the health and safety of workers. PMID- 26933498 TI - To develop a regional ICU mortality prediction model during the first 24 h of ICU admission utilizing MODS and NEMS with six other independent variables from the Critical Care Information System (CCIS) Ontario, Canada. AB - BACKGROUND: Intensive care unit (ICU) scoring systems or prediction models evolved to meet the desire of clinical and administrative leaders to assess the quality of care provided by their ICUs. The Critical Care Information System (CCIS) is province-wide data information for all Ontario, Canada level 3 and level 2 ICUs collected for this purpose. With the dataset, we developed a multivariable logistic regression ICU mortality prediction model during the first 24 h of ICU admission utilizing the explanatory variables including the two validated scores, Multiple Organs Dysfunctional Score (MODS) and Nine Equivalents Nursing Manpower Use Score (NEMS) followed by the variables age, sex, readmission to the ICU during the same hospital stay, admission diagnosis, source of admission, and the modified Charlson Co-morbidity Index (CCI) collected through the hospital health records. METHODS: This study is a single-center retrospective cohort review of 8822 records from the Critical Care Trauma Centre (CCTC) and Medical-Surgical Intensive Care Unit (MSICU) of London Health Sciences Centre (LHSC), Ontario, Canada between 1 Jan 2009 to 30 Nov 2012. Multivariable logistic regression on training dataset (n = 4321) was used to develop the model and validate by bootstrapping method on the testing dataset (n = 4501). Discrimination, calibration, and overall model performance were also assessed. RESULTS: The predictors significantly associated with ICU mortality included: age (p < 0.001), source of admission (p < 0.0001), ICU admitting diagnosis (p < 0.0001), MODS (p < 0.0001), and NEMS (p < 0.0001). The variables sex and modified CCI were not significantly associated with ICU mortality. The training dataset for the developed model has good discriminating ability between patients with high risk and those with low risk of mortality (c-statistic 0.787). The Hosmer and Lemeshow goodness-of-fit test has a strong correlation between the observed and expected ICU mortality (chi (2) = 5.48; p > 0.31). The overall optimism of the estimation between the training and testing data set DeltaAUC = 0.003, indicating a stable prediction model. CONCLUSIONS: This study demonstrates that CCIS data available after the first 24 h of ICU admission at LHSC can be used to create a robust mortality prediction model with acceptable fit statistic and internal validity for valid benchmarking and monitoring ICU performance. PMID- 26933497 TI - The role of red blood cells and cell-free hemoglobin in the pathogenesis of ARDS. AB - The primary focus of research into the pathophysiology of the acute respiratory distress syndrome (ARDS) has been on the interaction between the lung, underlying causes of ARDS, and the role of white blood cells and platelets in contributing to lung injury. Given a lack of specific therapies for this common complication of critical illness, further insight into the pathophysiology of this syndrome is greatly needed to develop targeted interventions. The red blood cell (RBC) has been reported to undergo deleterious changes in critical illness and be present in the alveoli of patients with ARDS. Release of RBC contents is known to be injurious in other conditions but has only recently been studied in critical illness and ARDS. The contribution of the RBC to ARDS represents a new avenue of research that may produce new, targeted therapies for this deadly syndrome. PMID- 26933499 TI - Rates of gastrointestinal tract colonization of carbapenem-resistant Enterobacteriaceae and Pseudomonas aeruginosa in hospitals in Saudi Arabia. AB - Carbapenem-resistant Enterobacteriaceae (CRE) and carbapenem-resistant Pseudomonas aeruginosa (CRPAE) are globally a major medical issue, especially in intensive care units. The digestive tract is the main reservoir for these isolates; therefore, rectal swab surveillance is highly recommended. The purpose of this study was to detect the prevalence of gastrointestinal tract colonization of CRE and CRPAE in patients admitted to intensive care units in Saudi Arabia. This project also aimed to characterize carbapenem-hydrolyzing enzyme production in these isolates. From February to May 2015, 200 rectal swab specimens were screened by CHROMagar KPC. Organism identification and susceptibility testing were performed using the Vitek 2 system. One CRE and 13 CRPAE strains were identified, for a prevalence of 0.5% (1/200) and 6.5% (13/200) respectively. Strains showed high genetic diversity using enterobacterial repetitive intergenic consensus sequence-based PCR. NDM type and VIM type were detected by PCR in four and one CRPAE isolates respectively. ampC overexpression was detected in eight CRPAE isolates using Mueller-Hinton agar containing 1000 MUg/mL cloxacillin. CTX M-15 type was detected in 1 CRE by PCR. The prevalence of CRE strain colonization was lower than that of CRPAE isolates. The detection of NDM and VIM in the colonizing CRPAE strains is a major infection control concern. To our knowledge, this is the first study in Saudi Arabia and the gulf region focusing on digestive tract colonization of CRE and CRPAE organisms and characterizing the mechanisms of carbapenem resistance. PMID- 26933500 TI - Intraperitoneal meropenem for peritoneal dialysis peritonitis with Serratia marcescens immediately on commencing dialysis. AB - A 67-year-old man developed Serratia marcescens peritonitis within a week of commencing peritoneal dialysis. Dialysate cultures isolated multidrug-resistant S. marcescens, which was treated with intraperitoneal meropenem. This unusual case highlights the problem of multidrug-resistant peritoneal dialysis infections and the potential viability of intraperitoneal meropenem as ambulatory peritonitis therapy. PMID- 26933501 TI - Genome analysis of Listeria ivanovii strain G770 that caused a deadly aortic prosthesis infection. AB - We sequenced the genome of Listeria ivanovii strain G770, which caused a deadly infection of the thoracic aortic prosthesis of a 78-year-old man. The 2.9 Mb genome exhibited 21 specific genes among L. ivanovii strains, including five genes encoding a type I restriction modification system and one glycopeptide resistance gene. PMID- 26933502 TI - High-quality genome sequence and description of Chryseobacterium senegalense sp. nov. AB - Strain FF12(T) was isolated from the mouth of a West African lungfish (Protopterus annectens) in Senegal. MALDI-TOF-MS did not provide any identification. This strain exhibited a 97.97% 16S rRNA sequence identity with Kaistella flava. Using a polyphasic study including phenotypic and genomic analyses, strain FF12(T) is Gram-negative, aero-anaerobic, oxidase-positive, non motile, non-spore-forming, and exhibited a genome of 4,397,629 bp with a G+C content of 35.1% that coded 4,001 protein-coding and 55 RNA genes. On the basis of these data, we propose the creation of Chryseobacterium senegalense strain FF12(T). PMID- 26933503 TI - Massilibacterium senegalense gen. nov., sp. nov., a new bacterial genus isolated from the human gut. AB - Massilibacterium senegalense gen. nov., sp. nov., strain mt8(T), is the type strain of Massilibacterium gen. nov., a new genus within the Bacillaceae family. This Gram-negative facultative anaerobic rod was isolated from the gut microbiota of a severely malnourished boy. Its phenotypic description is hereby presented with a complete annotation of its genome sequence. This genome is 5 697 950 bp long and contains 5615 protein-coding genes and 178 RNA genes, among which are 40 rRNA genes. PMID- 26933504 TI - Panniculitis caused by Mycobacterium monacense mimicking erythema induratum: a case in Ecuador. AB - We report the first case of recently characterized species M. monacense associated with chronic nodular vasculitis, infecting a young woman. This case represents the first isolation of M. monacense from Ecuador. The isolate was identified by conventional and molecular techniques. PMID- 26933505 TI - Phenotypic, molecular characterization, antimicrobial susceptibility and draft genome sequence of Corynebacterium argentoratense strains isolated from clinical samples. AB - During a 12-year period we isolated five Corynebacterium argentoratense strains identified by phenotypic methods, including the use of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF) and 16S rRNA gene sequencing. In addition, antimicrobial susceptibility was determined, and genome sequencing for the detection of antibiotic resistance genes was performed. The organisms were isolated from blood and throat cultures and could be identified by all methods used. All strains were resistant to cotrimoxazole, and resistance to beta-lactams was partly present. Two strains were resistant to erythromycin and clindamycin. The draft genome sequences of theses isolates revealed the presence of the erm(X) resistance gene that is embedded in the genetic structure of the transposable element Tn5423. Although rarely reported as a human pathogen, C. argentoratense can be involved in bacteraemia and probably in other infections. Our results also show that horizontal transfer of genes responsible for antibiotic resistance is occurring in this species. PMID- 26933506 TI - Combined pulmonary fibrosis and emphysema: effect of pulmonary rehabilitation in comparison with chronic obstructive pulmonary disease. AB - OBJECTIVE: To evaluate the effectiveness of short-term comprehensive inpatient pulmonary rehabilitation for patients with combined pulmonary fibrosis and emphysema (CPFE), and to compare responses with those of patients with chronic obstructive pulmonary disease (COPD) who underwent an identical programme. DESIGN: Retrospective analysis of several outcome measures. SETTING: Pulmonary ward at a 358-bed community teaching hospital. METHODS: 3-week inpatient pulmonary rehabilitation programme assessed by pulmonary function tests, 6 min walk test and health-related quality of life (HRQL) using the Short Form-36 (SF 36). RESULTS: 17 patients with CPFE and 49 patients with COPD were referred to and completed the programme between March 2007 and February 2015. Age, sex, smoking status, body mass index and the Medical Research Council dyspnoea grade were comparable between groups. In the CPFE group, improvement from the start of the programme to the programme end was observed in forced expiratory volume in 1 s (FEV1) (from 1.7+/-0.4 to 1.8+/-0.4, p=0.034); however, there was no significant improvement in the 6 min walk test (distance, SpO2 nadir and Borg scale on exercise). With regard to HRQL, improvement was observed in physical function (p=0.015) whereas deterioration was observed in social functioning (p=0.044). In the COPD group, significant improvement was observed after the programme in the FEV1, 6 min walk test and 4 of the 8 SF-36 subscales. There was a significant difference in changes in the 6 min walk distance: -16.6+/-58.4 in CPFE versus 30.2+/-55.6 in COPD (p=0.009). In 2 domains, there was a significant difference in SF-36 scores between groups: Deltavitality, -6.3+/-22.4 in CPFE versus 11.3+/-21.1 in COPD, p=0.009; and Deltasocial functioning, -18.8+/-34.2 in CPFE versus 5.3+/-35.9 in COPD, p=0.027. CONCLUSION: Patients with COPD derived greater benefits than those with CPFE, from the relatively short periods of inpatient pulmonary rehabilitation. PMID- 26933507 TI - Tolerability in man following inhalation dosing of the selective TLR7 agonist, AZD8848. AB - BACKGROUND: Many patients with asthma have a T-helper type 2 (Th2) driven inflammation of the lung, whereas toll-like receptor 7 (TLR7) agonists, by inducing type I interferons, inhibit Th2 responses. In man, oral or parenteral TLR7 agonists can induce influenza-like symptoms through systemic induction of type I interferons. Design of a TLR7 agonist that is only active in the lung could reduce the risk of side effects and offer a new means for treating asthma. We developed a TLR7 agonist antedrug, AZD8848, to determine its local and systemic effects in preclinical models and man. METHODS: In vitro cellular potencies for the TLR7 antedrug agonist, AZD8848, were determined along with pharmacokinetics and efficacy in a rat allergy model. Sputum and blood biomarkers were measured in single ascending and multiple ascending dose clinical studies following inhalation delivery of AZD8848 and tolerability assessed. RESULTS: AZD8848 was potent in cellular assays and pharmacokinetics confirmed lack of systemic exposure to AZD8848. Weekly lung dosing in an animal model showed efficacy 26 days beyond the final dose. In healthy volunteers, AZD8848 was initially well tolerated with target engagement being demonstrated by induction of CXCL10 in sputum. A second inhaled dose, given 1 week later, amplified the systemic interferon signal in more than half the participants and resulted in significant influenza-like symptoms. CONCLUSIONS: The antedrug design restricted the direct actions of AZD8848 to the lung. However, the type I interferon induced locally by TLR7 spilled over systemically, limiting the utility of this inhaled antedrug approach. TRIAL REGISTRATION NUMBER: NCT01560234, NCT01818869. PMID- 26933508 TI - Effects of culture media conditions on production of eggs fertilized in vitro of embryos derived from ovary of high grade Hanwoo. AB - BACKGROUND: This study was investigated the effects of culture media conditions on production of eggs fertilized in vitro of embryos from ovaries of high grade Korean native cow, Hanwoo. METHODS: The IVMD 101 and IVF 100 were used for in vitro maturation of selected Hanwoo oocytes and In vitro embryo culture after in vitro fertilization, respectively. The IVMD 101 and IVD 101 were used for in vitro culture and completely free of serum. RESULTS: The cleavage rates of 2-cell embryos in reference to Hanwoo oocytes were 86.7, 92.9 , and 90.1 % in the control group, IVDM101 medium and IVD101 medium, respectively which indicates that the IVDM101 medium and IVD101 medium may result favorable outcomes. The in vitro development rates of blastocysts were 12.4, 38.4 and 32.4 % in the control group, serum free IVMD101 medium and IVD101 medium, respectively. For hatched blastocysts, it was 5.3, 33.9, and 28.6 % in the control group, serum free IVMD101 medium and IVD101 medium, respectively. Hence, more favorable results were expected for the hatched blastocysts in which the IVMD101 medium and IVD101 medium were used than the control group. Average cell numbers of blastocysts were 128.3, 165.7, and 163.6 in the groups of TCM-199 + 10 % FBS medium, IVMD 101 medium, and IVD 101 medium, respectively which clearly show that the IVMD 101 and IVD 101 medium consequence significantly higher cell numbers compared to the control group (i.e., TCM-199 + 10 % FBS medium). Pregnancy rate after embryo transfer was 39.6 % when the serum free medium was used which is higher than that of the medium supplemented with serum (32.8 %). In addition, stillbirth rates were 4.9 % in the group of serum free medium whereas it was 13.6 % in the serum supplemented medium (13.6 %). CONCLUSIONS: Taken altogether, serum free media, the IVMD 101 and IVD 101 represented more favorable results in the embryo development rate of embryos, cell numbers of blastocyst, and pregnancy rate. Of note, the IVMD 101 medium showed better outcomes hence, it might be a better option for future applications for in vitro culture of bovine embryos. PMID- 26933509 TI - Erratum to: Prevalence of resistant hypertension and associated factors for blood pressure control status using Korean ambulatory blood pressure monitoring registry data. AB - [This corrects the article DOI: 10.1186/s40885-016-0045-x.]. PMID- 26933510 TI - Nasal Septal Deviations: A Systematic Review of Classification Systems. AB - Objective. To systematically review the international literature for internal nasal septal deviation classification systems and summarize them for clinical and research purposes. Data Sources. Four databases (including PubMed/MEDLINE) were systematically searched through December 16, 2015. Methods. Systematic review, adhering to PRISMA. Results. After removal of duplicates, this study screened 952 articles for relevance. A final comprehensive review of 50 articles identified that 15 of these articles met the eligibility criteria. The classification systems defined in these articles included C-shaped, S-shaped, reverse C-shaped, and reverse S-shaped descriptions of the septal deviation in both the cephalocaudal and anteroposterior dimensions. Additional studies reported use of computed tomography and categorized deviation based on predefined locations. Three studies graded the severity of septal deviations based on the amount of deflection. The systems defined in the literature also included an evaluation of nasal septal spurs and perforations. Conclusion. This systematic review ascertained that the majority of the currently published classification systems for internal nasal septal deviations can be summarized by C-shaped or reverse C shaped, as well as S-shaped or reverse S-shaped deviations in the anteroposterior and cephalocaudal dimensions. For imaging studies, predefined points have been defined along the septum. Common terminology can facilitate future research. PMID- 26933511 TI - Ex Vivo Antioxidant Activity of Selected Medicinal Plants against Fenton Reaction Mediated Oxidation of Biological Lipid Substrates. AB - Free radical-mediated oxidation is often linked to various degenerative diseases. Biological substrates with lipids as major components are susceptible to oxygen derived lipid peroxidation due to their composition. Lipid peroxide products act as biomarkers in evaluating the antioxidant potential of various plants and functional foods. The study focused on evaluation of the antioxidant potential of two extracts (methanol and 80% methanol) of four medicinal plants, Andrographis paniculata, Costus speciosus, Canthium parviflorum, and Abrus precatorius, against Fenton reaction-mediated oxidation of three biological lipid substrates; cholesterol, low-density lipoprotein, and brain homogenate. The antioxidant activity of the extracts was measured by thiobarbituric acid reactive substances method. Also, the correlation between the polyphenol, flavonoid content, and the antioxidant activity in biological substrates was analyzed. Results indicated highest antioxidant potential by 80% methanol extract of Canthium parviflorum (97.55%), methanol extract of Andrographis paniculata (72.15%), and methanol extract of Canthium parviflorum (49.55%) in cholesterol, low-density lipoprotein, and brain, respectively. The polyphenol and flavonoid contents of methanol extract of Andrographis paniculata in cholesterol (r = 0.816) and low-density lipoprotein (r = 0.948) and Costus speciosus in brain (r = 0.977, polyphenols, and r = 0.949, flavonoids) correlated well with the antioxidant activity. The findings prove the antioxidant potential of the selected medicinal plants against Fenton reaction in biological lipid substrates. PMID- 26933512 TI - Examining Implementation of Tobacco Control Policy at the District Level: A Case Study Analysis from a High Burden State in India. AB - Introduction. While extensive scientific evidence exists on the tobacco epidemic, a lack of understanding of both policies and their appropriate way of implementation continues to hinder effective tobacco control. This is especially so in the developing countries such as India. The present study aims to understand current implementation practices and the challenges faced in mainstreaming tobacco control policy and program. Methods. We chose a qualitative study design to conduct the case analysis. A total of 42 in-depth interviews were undertaken with seven district officials in six districts of Andhra Pradesh. A conceptual framework was developed by applying grounded theory for analysis. Analysis was undertaken using case analysis approach. Results and Discussion. Our study revealed that most program managers were unfamiliar with the comprehensive tobacco control policy. Respondents have an ambiguous opinion regarding integration of tobacco control program into existing health and development programs. Respondents perceive lack of resources, low prioritization of tobacco control, and lack of monitoring and evaluation of smoke-free laws as limiting factors affecting implementation of tobacco control policy. Conclusion. The findings of this study highlighted the need for a systematic, organized action plan for effective implementation of tobacco control policy and program. PMID- 26933514 TI - Comment on "Retained Placenta Accreta Mimicking Choriocarcinoma". PMID- 26933513 TI - Structural, Synaptic, and Epigenetic Dynamics of Enduring Memories. AB - Our memories are the records of the experiences we gain in our everyday life. Over time, they slowly transform from an initially unstable state into a long lasting form. Many studies have been investigating from different aspects how a memory could persist for sometimes up to decades. In this review, we highlight three of the greatly addressed mechanisms that play a central role for a given memory to endure: the allocation of the memory to a given neuronal population and what brain areas are recruited for its storage; the structural changes that underlie memory persistence; and finally the epigenetic control of gene expression that might regulate and support memory perseverance. Examining such key properties of a memory is essential towards a finer understanding of its capacity to last. PMID- 26933515 TI - A model qualification method for mechanistic physiological QSP models to support model-informed drug development. AB - Mechanistic physiological modeling is a scientific method that combines available data with scientific knowledge and engineering approaches to facilitate better understanding of biological systems, improve decision-making, reduce risk, and increase efficiency in drug discovery and development. It is a type of quantitative systems pharmacology (QSP) approach that places drug-specific properties in the context of disease biology. This tutorial provides a broadly applicable model qualification method (MQM) to ensure that mechanistic physiological models are fit for their intended purposes. PMID- 26933516 TI - The Many Flavors of Model-Based Meta-Analysis: Part I-Introduction and Landmark Data. AB - Meta-analysis is an increasingly important aspect of drug development as companies look to benchmark their own compounds with the competition. There is scope to carry out a wide range of analyses addressing key research questions from preclinical through to postregistration. This set of tutorials will take the reader through key model-based meta-analysis (MBMA) methods with this first installment providing a general introduction before concentrating on classical and Bayesian methods for landmark data. PMID- 26933517 TI - Modeling Ribavirin-Induced Anemia in Patients with Chronic Hepatitis C Virus. AB - Ribavirin remains an important component of hepatitis C treatment in certain clinical scenarios, but it causes hemolytic anemia. A quantitative understanding of the ribavirin exposure-anemia relationship is important in dose individualization/optimization. We developed a model relating ribavirin triphosphate (RTP) exposure in red blood cells (RBCs), RBC lifespan, feedback regulation of RBC production when anemia occurs, and the resulting hemoglobin decline. Inosine triphosphatase (ITPA) and interleukin 28B (IL28B) genetics were found to be significant covariates. Clinical trial simulations predicted that anemia is least severe in IL28B non-CC (rs12979860, CT or TT), ITPA variant subjects, followed by IL28B non-CC, ITPA wild-type, IL28B CC, ITPA variant, and IL28B CC, ITPA wild-type subjects (most severe). Reducing the ribavirin dose from 1,200/1,000 mg to 800/600 mg could reduce the proportions of grade 2 anemia by about half. The resulting model framework will aid the development of dosing strategies that minimize the incidence of anemia in treatment regimens that include ribavirin. PMID- 26933518 TI - Application of a Physiologically Based Pharmacokinetic Model to Study Theophylline Metabolism and Its Interactions With Ciprofloxacin and Caffeine. AB - Theophylline is a commonly used bronchodilator. However, due to its narrow therapeutic range, moderate elevation of serum concentration can result in adverse drug reactions (ADRs). ADRs occur because of interhuman pharmacokinetic variability and interactions with coprescribed medicines. We developed a physiologically based pharmacokinetic (PBPK) model of theophylline, caffeine, and ciprofloxacin metabolisms to: examine theophylline pharmacokinetic variability, and predict population-level outcomes of drug-drug interactions (DDIs). A simulation-based equation for personalized dosing of theophylline was derived. Simulations of DDI show that calculated personalized doses are safe even after cotreatment with large doses of strong inhibitors. Simulations of adult populations indicate that the elderly are most susceptible to ADRs stemming from theophylline-ciprofloxacin and theophylline-caffeine interactions. Females, especially Asians, due to their smaller average size, are more susceptible to DDI induced ADRs following typical dosing practices. Our simulations also show that the higher adipose and lower muscle fractions in females significantly alter the pharmacokinetics of theophylline or ciprofloxacin. PMID- 26933520 TI - Porcine Vitreous Flow Behavior During High-Speed Vitrectomy up to 7500 Cuts per Minute. AB - PURPOSE: To evaluate the impact of high-speed cut rates (up to 7500 cuts per minute [cpm]) on vitreous flow through various gauge probes. METHODS: An open-sky vitrectomy technique was performed on porcine eyes using the CONSTELLATION Vision System with three different gauges of dual-pneumatic probes (27+-, 25+-, and 23 gauge UltraVit probes; n = 5 for each gauge). Flow rate was calculated by LabVIEW software that converted real-time mass measurements from an electronic scale into flow rate. RESULTS: Average vitreous flow rate increased slightly with increased cut rate in all probes with 50/50 duty cycle; more dramatic flow rate increases were observed for all probes with biased closed duty cycle. Under both conditions, maximum flow rate was observed at 7500 cpm for all gauges. Under the biased open duty cycle, average flow rate was inversely associated with cut rate. CONCLUSION: High-speed cut rate improved efficiency of vitreous aspiration. TRANSLATIONAL RELEVANCE: Increased vitreous aspiration of dual-pneumatic, high speed vitrectomy probes may improve the efficiency of current vitrectomy techniques, allowing surgeons to take advantage of the benefits of high cut rates without sacrificing flow rate. PMID- 26933519 TI - Mechanistic Models Predict Efficacy of CCR5-Deficient Stem Cell Transplants in HIV Patient Populations. AB - Combination antiretroviral therapy (cART) effectively suppresses viral load in HIV-infected individuals, but it is not a cure. Bone marrow transplants using HIV resistant stem cells have renewed hope that cure is achievable but key questions remain e.g., what percentage of stem cells must be HIV-resistant to achieve cure?. As few patients have undergone transplants, we built a mechanistic model of HIV/AIDS to approach this problem. The model includes major players of infection, reproduces the complete course of the disease, and simulates crucial components of clinical treatments, such as cART, irradiation, host recovery, gene augmentation, and donor chimerism. Using clinical data from 172 cART-naive HIV infected individuals, we created virtual populations to predict performance of CCR5-deficient stem-cell therapies and explore interpatient variability. We validated our model against a published clinical study of CCR5-modified T-cell therapy. Our model predicted that donor chimerism must exceed 75% to achieve 90% probability of cure across patient populations. PMID- 26933521 TI - Two Bioactive Molecular Weight Fractions of a Conditioned Medium Enhance RPE Cell Survival on Age-Related Macular Degeneration and Aged Bruch's Membrane. AB - PURPOSE: To characterize molecular weight fractions of bovine corneal endothelial cell conditioned medium (CM) supporting retinal pigment epithelium (RPE) cell survival on aged and age-related macular degeneration (AMD) Bruch's membrane. METHODS: CM was subject to size separation using centrifugal filters. Retentate and filtrate fractions were tested for bioactivity by analyzing RPE survival on submacular Bruch's membrane of aged and AMD donor eyes and behavior on collagen I coated tissue culture wells. Protein and peptide composition of active fractions was determined by mass spectrometry. RESULTS: Two bioactive fractions, 3-kDa filtrate and a 10-50-kDa fraction, were necessary for RPE survival on aged and AMD Bruch's membrane. The 3-kDa filtrate, but not the 10-50-kDa fraction, supported RPE growth on collagen 1-coated tissue culture plates. Mass spectrometry of the 10-50-kDa fraction identified 175 extracellular proteins, including growth factors and extracellular matrix molecules. Transforming growth factor (TGF)beta-2 was identified as unique to active CM. Peptides representing 29 unique proteins were identified in the 3-KDa filtrate. CONCLUSIONS: These results indicate there is a minimum of two bioactive molecules in CM, one found in the 3-kDa filtrate and one in the 10-50-kDa fraction, and that bioactive molecules in both fractions must be present to ensure RPE survival on Bruch's membrane. Mass spectrometry analysis suggested proteins to test in future studies to identify proteins that may contribute to CM bioactivity. TRANSLATIONAL RELEVANCE: Results of this study are the first steps in development of an adjunct to cell-based therapy to ensure cell transplant survival and functionality in AMD patients. PMID- 26933523 TI - Effects of Intraframe Distortion on Measures of Cone Mosaic Geometry from Adaptive Optics Scanning Light Ophthalmoscopy. AB - PURPOSE: To characterize the effects of intraframe distortion due to involuntary eye motion on measures of cone mosaic geometry derived from adaptive optics scanning light ophthalmoscope (AOSLO) images. METHODS: We acquired AOSLO image sequences from 20 subjects at 1.0, 2.0, and 5.0 degrees temporal from fixation. An expert grader manually selected 10 minimally distorted reference frames from each 150-frame sequence for subsequent registration. Cone mosaic geometry was measured in all registered images (n = 600) using multiple metrics, and the repeatability of these metrics was used to assess the impact of the distortions from each reference frame. In nine additional subjects, we compared AOSLO-derived measurements to those from adaptive optics (AO)-fundus images, which do not contain system-imposed intraframe distortions. RESULTS: We observed substantial variation across subjects in the repeatability of density (1.2%-8.7%), inter-cell distance (0.8%-4.6%), percentage of six-sided Voronoi cells (0.8%-10.6%), and Voronoi cell area regularity (VCAR) (1.2%-13.2%). The average of all metrics extracted from AOSLO images (with the exception of VCAR) was not significantly different than those derived from AO-fundus images, though there was variability between individual images. CONCLUSIONS: Our data demonstrate that the intraframe distortion found in AOSLO images can affect the accuracy and repeatability of cone mosaic metrics. It may be possible to use multiple images from the same retinal area to approximate a "distortionless" image, though more work is needed to evaluate the feasibility of this approach. TRANSLATIONAL RELEVANCE: Even in subjects with good fixation, images from AOSLOs contain intraframe distortions due to eye motion during scanning. The existence of these artifacts emphasizes the need for caution when interpreting results derived from scanning instruments. PMID- 26933522 TI - A Pilot Study of Perceptual-Motor Training for Peripheral Prisms. AB - PURPOSE: Peripheral prisms (p-prisms) shift peripheral portions of the visual field of one eye, providing visual field expansion for patients with hemianopia. However, patients rarely show adaption to the shift, incorrectly localizing objects viewed within the p-prisms. A pilot evaluation of a novel computerized perceptual-motor training program aiming to promote p-prism adaption was conducted. METHODS: Thirteen patients with hemianopia fitted with 57Delta oblique p-prisms completed the training protocol. They attended six 1-hour visits reaching and touching peripheral checkerboard stimuli presented over videos of driving scenes while fixating a central target. Performance was measured at each visit and after 3 months. RESULTS: There was a significant reduction in touch error (P = 0.01) for p-prism zone stimuli from pretraining median of 16.6 degrees (IQR 12.1 degrees -19.6 degrees ) to 2.7 degrees ( IQR 1.0 degrees -8.5 degrees ) at the end of training. P-prism zone reaction times did not change significantly with training (P > 0.05). P-prism zone detection improved significantly (P = 0.01) from a pretraining median 70% (IQR 50%-88%) to 95% at the end of training (IQR 73%-98%). Three months after training improvements had regressed but performance was still better than pretraining. CONCLUSIONS: Improved pointing accuracy for stimuli detected in prism-expanded vision of patients with hemianopia wearing 57Delta oblique p-prisms is possible and training appears to further improve detection. TRANSLATIONAL RELEVANCE: This is the first use of this novel software to train adaptation of visual direction in patients with hemianopia wearing peripheral prisms. PMID- 26933524 TI - Lookup Tables Versus Stacked Rasch Analysis in Comparing Pre- and Postintervention Adult Strabismus-20 Data. AB - PURPOSE: We compare two methods of analysis for Rasch scoring pre- to postintervention data: Rasch lookup table versus de novo stacked Rasch analysis using the Adult Strabismus-20 (AS-20). METHODS: One hundred forty-seven subjects completed the AS-20 questionnaire prior to surgery and 6 weeks postoperatively. Subjects were classified 6 weeks postoperatively as "success," "partial success," or "failure" based on angle and diplopia status. Postoperative change in AS-20 scores was compared for all four AS-20 domains (self-perception, interactions, reading function, and general function) overall and by success status using two methods: (1) applying historical Rasch threshold measures from lookup tables and (2) performing a stacked de novo Rasch analysis. Change was assessed by analyzing effect size, improvement exceeding 95% limits of agreement (LOA), and score distributions. RESULTS: Effect sizes were similar for all AS-20 domains whether obtained from lookup tables or stacked analysis. Similar proportions exceeded 95% LOAs using lookup tables versus stacked analysis. Improvement in median score was observed for all AS-20 domains using lookup tables and stacked analysis (P < 0.0001 for all comparisons). CONCLUSIONS: The Rasch-scored AS-20 is a responsive and valid instrument designed to measure strabismus-specific health-related quality of life. When analyzing pre- to postoperative change in AS-20 scores, Rasch lookup tables and de novo stacked Rasch analysis yield essentially the same results. TRANSLATIONAL RELEVANCE: We describe a practical application of lookup tables, allowing the clinician or researcher to score the Rasch-calibrated AS-20 questionnaire without specialized software. PMID- 26933525 TI - 2015 Relaunch as Open Access Pediatric Neurology Briefs. AB - Pediatric Neurology Briefs (PNB) has been published monthly since 1987 as a continuing education service designed to expedite and facilitate review of current medical literature concerning pediatric neurology. In 2015, PNB is relaunched as an open access, peer-reviewed, journal with an expanded editorial board. PNB has a new website and content management system capable of organizing peer-review and providing improved indexing, DOI assignment, and online full-text article view. Digitization of back issues, archiving, and inclusion in PubMed are future goals. The new online open access PNB aims to reach more physicians, researchers, and other healthcare providers with highlights of the latest advances in pediatric neurology and commentaries by specialists in the field. PMID- 26933526 TI - Ketogenic Diet as Preferred Treatment of FIRES. AB - Investigators from the University of Alabama, Birmingham, AL, and University of Michigan, Ann Arbor, MI, report 2 children who presented with FIRES and prolonged AED-resistant status epilepticus. PMID- 26933527 TI - Remission of Childhood-onset Epilepsy. AB - Investigators from the Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago IL and the Yale School of Medicine, New Haven, CT have conducted a prospective cohort study of 613 children with newly diagnosed epilepsy to evaluate the occurrence of complete remission and predictive factors. Of the 613 patients recruited, 516 were followed for greater than 10 years and of those, 328 (63.5%) attained complete remission. PMID- 26933528 TI - Delay in Diagnosis of Duchenne Muscular Dystrophy. AB - Investigators from Johns Hopkins Hospital, Baltimore, MD, retrospectively reviewed 179 records of patients with Duchenne muscular dystrophy (DMD) evaluated between 1989 and 2012. Diagnosis was confirmed by genetic testing or muscle biopsy, and clinical data were complete in 107 patients. PMID- 26933529 TI - Fatty Acyl-CoA Reductase 1 Deficiency. AB - Investigators from Erlangen, Germany; Calgary, CA; and Kafranbel, Syria, identified mutations in the gene, fatty acyl-CoA reductase 1 (FAR1) deficiency, adding to three other genes involved in plasmalogen biosynthesis, in two families affected by severe intellectual disability, early-onset epilepsy, microcephaly, congenital cataracts, growth retardation, and spasticity. PMID- 26933530 TI - Cyclic AMP Accumulation in Migraine Induction. AB - Investigators from Danish Headache Centre, Glostrup Hospital, and the University of Copenhagen investigated whether intracellular cyclic AMP accumulation induced migraine attacks among 14 migraine patients without aura. PMID- 26933532 TI - Impact of Seizure Burden in Hypoxic Ischemic Encephalopathy. AB - Investigators from Washington University St. Louis studied the impact of electroencephalographic monitoring of neonates with Hypoxic Ischemic Encephalopathy (HIE) and their degree of MRI injury and neurodevelopmental outcomes when increasing seizure burden was present. PMID- 26933531 TI - MRI Features Predictive of Aicardi-Goutieres Syndrome. AB - Investigators from Children's National Health System Washington, DC, USA: Harvard University, Boston, USA; Leeds Teaching Hospitals, UK; and other international centers review a series of patients with MRIs selected from IRB-approved leukodystrophy biorepositories to identify MRI patterns for recognition of early onset Aicardi-Goutieres (A-G) syndrome and scored for a panel of radiologic predictors. PMID- 26933533 TI - Autoregulation in Infants with Neonatal Encephalopathy. AB - Researchers from Johns Hopkins School of Medicine report a pilot observational study investigating the influence of hemodynamic management in 28 neonates with hypoxic ischemic injury (HIE). PMID- 26933534 TI - Preventable Pediatric Stroke via Vaccination? AB - Investigators from the Vascular Effects of Infection in Pediatric Stroke (VIPS) group studied the risk of arterial ischemic stroke (AIS) associated with minor infection and routine childhood vaccinations. PMID- 26933535 TI - Cerebrovascular Pressure Reactivity in Children with TBI. AB - Investigators from University of Melbourne, Australia, studied Pressure Reactivity Index (PRx) and optimal Cerebral Perfusion Pressure (CPP) in 36 children aged between 6 months and 16 years treated for traumatic brain injury (TBI) at the Royal Children's Hospital, Melbourne, from 2007 to 2013. PMID- 26933536 TI - Relationship between Age at Diagnosis of ADHD and ASD. AB - Investigators from the Division of Developmental Medicine and Clinical Research Center, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, studied the relationship between the timing of Attention Deficit Hyperactivity Disorder (ADHD) diagnosis in children with Autism Spectrum Disorder (ASD) and the age at ASD diagnosis. PMID- 26933537 TI - CSF Amino Acids, Pterins and Mechanism of the Ketogenic Diet. AB - Investigators from Hospital Sant Joan de Deu, Barcelona, Spain, studied the relationship between the etiology of refractory childhood epilepsy, CSF neurotransmitters, pterins, and amino acids, and response to a ketogenic diet in 60 patients with refractory epilepsy, 83% focal and 52% idiopathic. PMID- 26933538 TI - Visual Evoked Potentials in Rett Syndrome. AB - Investigators from the Boston Children's Hospital recorded pattern-reversal visual evoked potentials (VEPs) in Mecp2 heterozygous female mice and in 34 girls with Rett syndrome (RTT). PMID- 26933539 TI - Diagnostic NGS for Severe Neuromuscular Disorders. AB - Investigators from the University of Western Australia report the diagnostic yield of performing next generation sequencing (NGS; whole exome and targeted capture of 277 neuromuscular genes) in a heterogenous cohort of patients with neuromuscular disorders (NMD) presenting at or before birth. PMID- 26933540 TI - Hereditary Neuropathy with Liability to Pressure Palsies. AB - Investigators from 4 pediatric hospitals in Canada analyzed the clinical presentation and electrophysiological data of 12 children with hereditary neuropathy with liability to pressure palsies (HNPP), caused by PMP22 gene deletion. PMID- 26933541 TI - A Timely Review of the Genetics of Epileptic Encephalopathies. AB - Investigators from UCL Institute of Child Health, London and The University of Melbourne reviewed current knowledge of the genetics of epileptic encephalopathies of infancy and childhood. PMID- 26933543 TI - Histopathology of Polymicrogyria. AB - Investigators from Sainte Justine Hospital (Montreal), Montreal Neurological Hospital and Institute, King's College Hospital (London), and John Radcliffe Hospital (Oxford) retrospectively reviewed medical records, autopsy reports, and genetic studies containing "Polymicrogyria." PMID- 26933542 TI - Vaccinations and Dravet Syndrome. AB - Investigators from various university hospitals, reference medical institutions and epilepsy centers, and the national institute for public health and environment in the Netherlands, studied the effect of vaccinations on seizure risk and disease course in patients with Dravet syndrome (DS). PMID- 26933544 TI - Language Impairment in Adolescents with Sydenham Chorea. AB - Investigators from hospitals in Brazil tested verbal fluency in 20 adolescent patients, ages ranged from 11 to 16 years (mean 13.8 years), with Sydenham chorea compared with 20 patients with rheumatic fever without chorea and 20 healthy controls, matched for age and gender. PMID- 26933545 TI - Epstein-Barr Virus Neurologic Complications. AB - Investigators at the Karol Marcinkowski University of Medical Sciences, Poznan, Poland, analyzed the records of 194 children diagnosed with Epstein-Barr virus infection and having the viral capsid antigen IgM antibody. PMID- 26933546 TI - The Genetics of Febrile Seizures. AB - Investigators from Virginia Commonwealth University, Norwegian Center for Epilepsy and University of Southern Denmark carried out twin studies to analyse the genetic influence of developing epilepsy after febrile seizures. PMID- 26933547 TI - Incidental Findings: The Importance of Pretest Counseling. AB - Researchers at the University of Bourgogne in Dijon, France surveyed French geneticists who were members of the "Association Francais des Geneticiens" on incidental findings (IF) found on array-based comparative genomic hybridization (aCGH) technology retrospectively over a seven-year period. PMID- 26933548 TI - Incidence of Dravet Syndrome in a US Population. AB - Investigators from the University of California, San Francisco and Kaiser Permanente report the incidence of Dravet Syndrome in a population based cohort. PMID- 26933549 TI - Prediction of Infantile Spasms Recurrence after ACTH Therapy. AB - Investigators from Okayama University Hospital, Japan, studied the predictive value of serial EEG findings (every 2 to 4 weeks) in relapse of epileptic spasms after synthetic ACTH therapy in patients with West syndrome (WS). PMID- 26933550 TI - Complementary/Alternative versus Prescription Medications. AB - Investigators from the Mayo Clinic, Rochester MN, determined the use of complementary and alternative medicine (CAM) in an outpatient pediatric neurology clinic, and assessed family attitudes toward the efficacy of CAM versus prescription medications. PMID- 26933551 TI - Risk of Tics with Psychostimulants for ADHD. AB - Investigators at Yale University, New Haven, CT, conducted a meta-analysis to examine the risk of new onset or worsening of tics caused by psychostimulants used in the treatment of children with ADHD. PMID- 26933552 TI - Acute Flaccid Myelitis Outbreak. AB - Investigators from the University School of Medicine, Salt Lake City, Utah, report an outbreak of acute flaccid myelitis (AFM) occurring in 2014-2015 in several States and reported to the CDC. PMID- 26933553 TI - Atomoxetine/Methylphenidate Effects on Social Play Behavior. AB - Researchers at Utrecht University, The Netherlands, and University "Roma Tre," Rome, Italy, studied the neural substrates of the previously identified social play-suppressant effects of methylphenidate (MPH) and atomoxetine, drugs widely used for the treatment of attention-deficit hyperactivity disorder (ADHD). PMID- 26933554 TI - MRI Predicts Outcome After HIE Treated with Hypothermia. AB - Investigators from Children's National Medical Center and George Washington University School of Medicine, Washington, DC, studied the correlation between white matter tract changes and developmental outcomes in a series of infants with hypoxic ischemic encephalopathy (HIE) treated with whole body cooling. PMID- 26933555 TI - Outcome of Cerebellar Injury with Intraventricular Hemorrhage. AB - Investigators from the Department of Pediatric Neurology, Morinomiya Hospital, Osaka, Japan performed a retrospective IRB approved study of the prevalence of cerebellar injury (CI) and effect on functional outcomes among preterm children with intraventricular hemorrhage (IVH) and cerebral palsy (CP), comparing them to infants with post-hemorrhagic hydrocephalus (PH). PMID- 26933556 TI - MRI to Discriminate Pediatric MS from ADEM. AB - Investigators from Washington University School of Medicine and University of Florida College of Medicine, report that susceptibility-weight imaging (SWI) may be useful in differentiating initial presentation of pediatric multiple sclerosis (MS) from acute disseminated encephalomyelitis (ADEM). PMID- 26933557 TI - Clinical Variability of GLUT1DS. AB - Investigators from Pavia, Rho, Brescia and Milan, Italy, studied 22 patients diagnosed with GLUT1 deficiency syndrome (GLUT1DS) to document clinical or genetic differences between patients with familial SLC2A1 gene mutations (n=11) and those with sporadic mutations (n=11). PMID- 26933558 TI - Academic Underachievement in Children with Active Epilepsy. AB - Investigators from Lingfield, Surrey, UK; University of Gothenburg, Sweden; Great Ormond Street Hospital, London, UK, and other centers, conducted psychological assessment including measures of IQ, working memory and processing speed in 85 (74%) of 115 school aged children with active epilepsy (a seizure in the past year and/or on AEDs) from a population-based sample, without exclusion for intellectual deficiency. PMID- 26933559 TI - Spectrum of SCN8A-Related Epilepsy. AB - Investigators from the EuroEPINOMICS European research consortium studied 17 patients with epileptic encephalopathy due to SCN8A mutations and reported the specific genetic and phenotypic features. PMID- 26933560 TI - Childhood Stroke and Congenital Heart Disease. AB - Investigators from the University of California performed a case-control study of the association of stroke with congenital heart disease (CHD) within a population of 2.5 million children in Northern California. PMID- 26933561 TI - Prognosis with Incidental Rolandic Spikes. AB - Investigators from Johns Hopkins University reported a cohort of 27 patients with incidentally-noted rolandic spikes (RS) on EEG. PMID- 26933562 TI - Continuous EEG in Critically Ill Children. AB - Investigators from the Critical Care Continuous EEG Task Force of the American Clinical Neurophysiology Society reported a consensus statement on indications for the use of critical care continuous electroencephalographic monitoring (ccEEG) in adults and children. PMID- 26933563 TI - Neuropsychological-EEG Activation in Genetic Generalized Epilepsy. AB - Investigators from Lithuanian University of Health Sciences, Kaunas, evaluated the effects of neuropsychological activation (NPA) tasks on epileptiform discharges (ED) in adolescents with idiopathic generalized epilepsy (IGE) and in comparison with hyperventilation and photic stimulation. PMID- 26933564 TI - Gait Training and Ankle Dorsiflexors in Cerebral Palsy. AB - Investigators at University of Copenhagen, Denmark, evaluated whether 4 weeks of 30 min daily treadmill training with an incline may facilitate corticospinal transmission and improve control of the ankle joint in 16 children, aged 5-14 years, with cerebral palsy. PMID- 26933565 TI - Acute Treatment Regimens for Migraine in the ED. AB - Researchers at Children's Hospital, Boston, studied the comparative effectiveness of acute medication regimens for the prevention of ED visits with migraine. PMID- 26933566 TI - Differential Diagnosis of Kleine-Levin Syndrome. AB - Investigators at Pitie-Salpetriere and Robert Debre Hospitals, and other centers in France, evaluated consecutive patients referred for suspected Kleine-Levin (KLS) syndrome, detailed differential diagnoses, and examined characteristics of patients with prolonged (>30 days) episodes. PMID- 26933567 TI - Structural Connectivity in Gilles de la Tourette Syndrome. AB - Investigators from Centre de Reference National Maladie Rare 'Syndrome Gilles de la Tourette' and Sorbonne University report white matter abnormalities in the pathways connecting the cerebral cortex, basal ganglia, and thalamus in a group of 49 adults with Tourette syndrome (TS). PMID- 26933568 TI - KCNA2-Related Epileptic Encephalopathy. AB - Investigators from the University Leipzig and University of Tubingen report mutations of KCNA2 as a novel cause of epileptic encephalopathy. PMID- 26933569 TI - [Not Quite] The Ketogenic Diet in a Pill. AB - Researchers at Okayama University, Japan showed lactate dehydrogenase (LDH) inhibition suppresses neuronal excitation in vitro, reduces EEG discharges and seizures in rodent models, and may provide a novel mechanism for anticonvulsant medications in human patients. PMID- 26933570 TI - Diurnal and Seasonal Occurrence of Febrile Seizures. AB - Investigators from University of Oulu, Finland, evaluated the diurnal and seasonal occurrence of the first febrile seizures (FS) in 461 children in a population-based study of 1522 children. PMID- 26933571 TI - Blunt Head Trauma and Headache. AB - Investigators from New York Presbyterian Morgan Stanley Children's Hospital examined whether having an isolated headache following minor blunt head trauma was suggestive of traumatic brain injury (TBI) among a large cohort of children 2 18 years of age. PMID- 26933572 TI - Congenital Insensitivity to Pain (HSNA type IV). AB - Investigators from New York University, NY, studied 14 patients with congenital insensitivity to pain with anhidrosis (CIPA), compared to 10 patients with chronically deficient sympathetic activity (pure autonomic failure), and 15 normal age-matched controls. PMID- 26933574 TI - Axonal Damage in Pediatric Multiple Sclerosis. AB - Investigators from Georg August University, Gottingen, Germany, analyzed axonal pathology in brain biopsy and autopsy samples from 19 children with early multiple sclerosis (MS). PMID- 26933573 TI - Clinical Features of Infectious and Autoantibody Encephalitis. AB - Investigators from University of Sydney, Australia; John Radcliffe Hospital, Oxford, UK; Imperial College, London, UK; and other centers, studied infectious, immune-mediated/autoantibody associated and unknown forms of encephalitis, including frequencies, clinical and radiological phenotypes, and long-term outcome. PMID- 26933575 TI - Vestibular Deficits Following Concussion. AB - Investigators from the Division of Emergency Medicine, Sports Medicine, and Department of Pediatrics, Children's Hospital of Philadelphia, PA, and Sports Medicine, Somerset, NJ, performed a retrospective cohort study of 247 patients ages 5-18 years with concussion referred from July 2010 to Dec 2011; 81% of patients showed a vestibular abnormality on initial clinical examination. PMID- 26933576 TI - Prognosis of Neonatal Arterial Ischemic Stroke. AB - Investigators from University Children's Hospitals in Bern, Zurich, Aarau, and multiple other centers in Switzerland evaluated prospectively the epidemiology, manifestations, and treatment of all full-term neonates with neonatal arterial ischemic stroke (NAIS) and born 2000-2010. PMID- 26933577 TI - Long-term Outcome of Arterial Stroke in Children. AB - Investigators at University Children's Hospital, Inselspital, and Universities of Bern, Geneva, Basel, and Zurich, Switzerland compared long-term outcome of children (1 month-16 years) and young adults (16.1-45 years) with arterial ischemic stroke (AIS) using prospective data from the Swiss Neuropediatric Stroke Registry and the Adult Bernese stroke registry, between Jan 2000 and Dec 2008. PMID- 26933578 TI - Risk Factors for Late Diagnosis of Rett Syndrome. AB - Investigators at Emory University, Atlanta, GA; Stony Brook, New York; University of California, San Diego; and other centers determined the type of physician who makes the Rett syndrome (RTT) diagnosis and identified risk factors for delayed diagnosis. PMID- 26933579 TI - Indications for an EEG in a Child with ADHD. AB - Investigators at Departments of Child Neurology, Neuroscience, Biostatistics, Marmara University, Istanbul, Turkey studied the parameters for prediction of epileptiform abnormalities in the EEG of 148 children diagnosed with ADHD, according to DSM-IV criteria, aged between 6 and 13 years (mean 8.76 +/- 1.26; 25.7% female). Wake and sleep EEGs lasting about one hour were obtained in 89.2% patients and a WISC-R in 100%. PMID- 26933580 TI - Role of HHV-6B Infection in Mesial Temporal Lobe Epilepsy. AB - Investigators from Fujita Health University, Toyoake, and National Epilepsy Center, Shizuoka, Japan, studied the pathogenic role of HHV-6B in patients with mesial temporal lobe epilepsy (MTLE). PMID- 26933581 TI - Investigations in West Syndrome: Which, When and Why. AB - Investigators from the National Infantile Spasms Consortium (NISC) in the USA studied the etiology of new-onset infantile spasms (IS) in 251 infants (mean age at onset, 7.1, range, 0.1-22.7 months). PMID- 26933582 TI - Timing of Anticonvulsant Administration in Status Epilepticus. AB - Investigators from the Pediatric Status Epilepticus Research Group studied the time elapsed from onset of pediatric convulsive status epilepticus (SE) to administration of antiepileptic drugs (AED). PMID- 26933583 TI - GRIN1 Mutations in Early-Onset Epileptic Encephalopathy. AB - Investigators from Yokohama City University and other medical centers in Israel and Japan reported mutations on N-methyl-D-aspartate (NMDA) receptors subunit GRIN1 (GluN1) identified in patients with nonsyndromic intellectual disability and early-onset epileptic encephalopathy. PMID- 26933584 TI - Epilepsy Following Neonatal Seizures Symptomatic Of Stroke. AB - Investigators from Child Neurology and Clinical Neurophysiology, Pediatric University Hospital, Padua, Italy studied the long term risk of developing epilepsy in patients with EEG confirmed neonatal seizures and arterial ischemic stroke. PMID- 26933585 TI - Prognostic Factors of MS Conversion in Optic Neuritis. AB - Investigators from Children's Hospital Aschaffenburg, Germany; University of Manchester, Manchester, United Kingdom; University Children's Hospital Tubingen, Tubingen, Germany; and other international centers studied prognostic factors in optic neuritis. PMID- 26933586 TI - Cognitive Development of Children with Craniosynostosis. AB - Investigators from University of Washington, Seattle, WA; Harvard U, MA; St Louis, MO; Atlanta, GA; Northwestern U, and Shriner's Hospital, Chicago, compared the development of school-aged children with single-suture craniosynostosis (sagittal, metopic, unicoronal, lambdoid) and unaffected children. PMID- 26933587 TI - Clinical Features of NMDAR Ab-mediated Encephalitis. AB - Investigators from University of Oxford, Birmingham Children's Hospital, Guy's and St Thomas', London, UK, performed a prospective surveillance study in children with NMDAR-Ab-mediated neurological disease reported from Nov 2010 to Dec 2011. PMID- 26933588 TI - Todd Paralysis in Rolandic Epilepsy. AB - Investigators from University of Gaziantep, Turkey described the clinical and EEG findings of patients with benign epilepsy of childhood with centrotemporal spikes (BECTS) experiencing postictal Todd paralysis. PMID- 26933589 TI - Neuropsychological Effects of Anticonvulsants. AB - Investigators from 7 centers in Korea conducted a prospective, multicenter study with patients randomized into two open-label, parallel groups and treated with either levetiracetam (LVT) or carbamazepine (CBZ) monotherapy for newly diagnosed focal epilepsy. PMID- 26933590 TI - PI3K/AKT Pathway and Brain Malformations. AB - Investigators from Seattle Children's Research Institute, University of Washington, and collaborating institutions sought to evaluate 10 genes in the PI3K/AKT pathway as it relates epileptogenic brain malformations in patients with megalencephaly, hemimegalencephaly, and focal cortical dysplasia. PMID- 26933591 TI - Relation of Posterior Cerebellar Volume to Cognition in MS. AB - Investigators from the Montreal Neurological Institute, York University, Universities of Toronto and McGill, Canada, and University of Pennsylvania, studied the relationship between cerebellar pathology and cognitive function in adolescent and pediatric-onset multiple sclerosis (MS). PMID- 26933592 TI - Head Circumference and Neurocognitive Outcomes. AB - Investigators from Universities of Glasgow and Bristol, UK, determined the value of head circumference (HC) as a screening measure, the incidence of head centile shifting, and the relationship between extremes of head size and later neurodevelopmental problems. PMID- 26933593 TI - Risk of Neuropathy with Celiac Disease. AB - Investigators from Columbia University College of Physicians and Surgeons, New York, Karolinska Institutet, Stockholm, and Orebro University, Sweden, examined the risk of developing neuropathy in a nationwide population-based sample of 28,232 patients with biopsy-verified celiac disease (CD). PMID- 26933594 TI - Posterior Reversible Encephalopathy Syndrome in ALL. AB - Investigators from Soochow University, Suzhou, China, studied the possible pathogenetic mechanisms and treatment of posterior reversible encephalopathy syndrome (PRES) observed in 11 cases of pediatric acute lymphoblastic leukemia (ALL) after induction chemotherapy. PMID- 26933595 TI - Seizure Action Plans and Health Care Utilization. AB - Investigators from University of Utah School of Medicine studied the impact of a seizure action plan (SAP) on pediatric patients with epilepsy by measuring health care utilization as an outcome measure. PMID- 26933596 TI - Does Listening to Mozart benefit Children with Severe Epilepsy? AB - Investigators from the Universities of Salerno and Perugio, Italy, studied the effect of listening to a set of Mozart's compositions on sleep quality, behavior, and seizure recurrence in 11 outpatients (7 males and 4 females), between 1.5 and 21 years of age (mean age, 11.9 years), with drug-resistant epilepsy. PMID- 26933597 TI - MRI and Motor Outcomes in Children with Cerebral Palsy. AB - Investigators from University of Melbourne, Monash Children's Hospital, Royal Children's Hospital & Murdoch Children's Research Institute sought to identify correlation between magnetic resonance imaging (MRI) characteristics including white matter injury (WMI) in children with cerebral palsy (CP) and severity in motor outcomes later in life, irrespective of CP subtype. PMID- 26933598 TI - Intracranial Hypertension in Children without Papilledema. AB - Researchers at Nationwide Children's Hospital studied the frequency of intracranial hypertension without papilledema in children followed in a multispecialty pediatric intracranial hypertension clinic. PMID- 26933599 TI - De Novo Mutations in Patients with Ataxic CP. AB - As a part of a large study investigating childhood ataxias in the UK and Switzerland, Schnekenberg et al. analyzed the genetic associations with congenital cerebellar ataxia in 10 patients using either a targeted next generation sequencing panel of 118 genes or trio-based exome sequencing. PMID- 26933600 TI - Diagnostic Yield of Continuous Video EEG for Neonatal Seizures. AB - Investigators from the University of California, San Francisco studied the yield of continuous video EEG (vEEG) in diagnosing electrographic seizures in their neonatal intensive care unit. PMID- 26933601 TI - Hypsarhythmia or Hypsarrhythmia? AB - Hypsarhythmia was originally spelled with one 'r' by Drs Frederick and Erna Gibbs when they coined the term in 1952. PMID- 26933602 TI - Photosensitivity and CHD2 Variants. AB - Investigators from multinational institutions hypothesized that disruption of CHD2, which encodes chromodomain helicase DNA-binding protein 2, would be associated with common forms of photosensitive epilepsy or photosensitivity manifesting as a photoparoxysmal response alone. PMID- 26933603 TI - Ketone Bodies Mediate Antiseizure Effects. AB - Investigators from The Barrow Neurological Institute, Creighton University, University of Kentucky and the University of Calgary Faculty of Medicine investigated the effect of ketone bodies and the ketogenic diet on epileptic Kcna1-null mice. PMID- 26933604 TI - Orofacial EMG in Congenital Multiple Cranial Neuropathies. AB - Investigators from Armand-Trousseau hospital and University of Paris studied 90 infants aged birth to 6 months with multiple cranial nerve involvement. PMID- 26933605 TI - Focal MRI and Learning Disability with Reduced Automaticity. AB - Investigators from the Boston Children's Hospital, Harvard Medical School, MA, performed a retrospective analysis of 1,587 children referred for a learning disability, and 127 had a focal deficit demonstrated on either a neurologic or neuropsychological evaluation. PMID- 26933606 TI - ADCY5 Mutations and Benign Hereditary Chorea. AB - Investigators from the Institute of Neurology, London, UK, and centers in Italy, Germany, and Greece, studied 18 unrelated cases of benign hereditary chorea BHC (7 familial, 11 sporadic) who were negative for NKX2-1 mutations. PMID- 26933607 TI - Alternating Hemiplegia and Cardiac Dysrhythmia. AB - Investigators at the National Hospital for Neurology and Neurosurgery, Queen Square, London, and multiple centers in the UK, Europe, US, Melbourne, Australia, and Canada, analyzed ECG recordings of 52 patients with alternating hemiplegia from 9 countries; all had whole-exome, whole-genome, or direct Sanger sequencing of ATP1A3; 47 had a confirmed missense mutation in ATP1A3. PMID- 26933608 TI - MRI Screening for Optic Gliomas in Neurofibromatosis Type 1. AB - Investigators from Cincinnati Children's Hospital, OH, analysed retrospectively the utility of screening brain/orbital MRIs in 826 children with NF1 (ages 1-9 years; 402 female, 424 male) seen over a 20-year period between 1990 and 2010. PMID- 26933609 TI - Technology: Allowing for Journals on the Go. PMID- 26933610 TI - Improvement in Health State Utility after Sacroiliac Joint Fusion: Comparison to Normal Populations. AB - Study Design Prospective cohort study. Objective The sacroiliac joint (SIJ) is an important cause of lower back pain. The degree to which minimally invasive surgical fusion of the SIJ improves health state utility has not been previously documented. Methods Health state utility values were calculated using the EuroQOL 5D (EQ-5D) and Short Form-36 (SF-36) at baseline and 6 and 12 months after SIJ fusion surgery in subjects participating in a prospective, multicenter clinical trial (n = 172). Values were compared with individuals who participated in a nationally representative cross-sectional survey (National Health Measurement Study [NHMS], n = 3,844). Health utility values in the SIJ cohort were compared with those of the NMHS participants using both weighted linear regression and calculation of "health quantile" (i.e., percentile of health normalized to the NHMS cohort adjusted for age and gender). Results Baseline health state utility was significantly depressed in SIJ patients compared with normal subjects (SF-6D 0.509 versus 0.789, SF-36 physical component summary 31.7 versus 49.2, SF-36 mental component summary 8.5 versus 53.8, EQ-5D 0.433 versus 0.868; all p < 0.0001 after adjustment for age and gender). In the SIJ cohort, all the measures improved by 6 months postoperatively, and improvements were sustained at 12 months. Baseline health quantile was low (fifth percentile) in the SIJ cohort and improved significantly at follow-up. Conclusions Quality of life is markedly impaired in patients with SIJ pain compared with age- and gender-matched cohorts. SIJ fusion in this cohort resulted in a substantial improvement in health state utility, bringing the population back toward the expected levels of overall health. The quantile approach helps to explain the degree to which health is improved compared with age- and gender-matched cohorts. PMID- 26933611 TI - Elevated Patient Body Mass Index Does Not Negatively Affect Self-Reported Outcomes of Thoracolumbar Surgery: Results of a Comparative Observational Study with Minimum 1-Year Follow-Up. AB - Study Design Retrospective study. Objective Quantify the effect of obesity on elective thoracolumbar spine surgery patients. Methods Five hundred consecutive adult patients undergoing thoracolumbar spine surgery to treat degenerative pathologies with minimum follow-up of at least 1 year were included. Primary outcome measures included Numerical Rating Scales for back and leg pain, the Short Form 36 Physical Component Summary and Mental Component Summary, the modified Oswestry Disability Index, and patient satisfaction scores collected preoperatively and at 3, 6, 12, and 24 months postoperatively. Secondary outcome measures included perioperative and postoperative adverse events, postoperative emergency department presentation, hospital readmission, and revision surgeries. Patients were grouped according to World Health Organization body mass index (BMI) guidelines to isolate the effect of obesity on primary and secondary outcome measures. Results Mean BMI was 30 kg/m(2), reflecting a significantly overweight population. Each BMI group reported statistically significant improvement on all self-reported outcome measures. Contrary to our hypothesis, however, there was no association between BMI group and primary outcome measures. Patients with BMI of 35 to 39.99 visited the emergency department with complaints of pain significantly more often than the other groups. Otherwise, we did not detect any differences in the secondary outcome measures between BMI groups. Conclusions Patients of all levels of obesity experienced significant improvement following elective thoracolumbar spine surgery. These outcomes were achieved without increased risk of postoperative complications such as infection and reoperation. A risk-benefit algorithm to assist with surgical decision making for obese patients would be valuable to surgeons and patients alike. PMID- 26933612 TI - Radiographic Comparison between Cervical Spine Lateral and Whole-Spine Lateral Standing Radiographs. AB - Study Design Retrospective radiologic study. Objective The sagittal alignment of the cervical spine can be evaluated using either a lateral cervical radiograph or a whole-spine lateral view on which the cervical spine is included. To our knowledge, however, no report has compared the two. The purpose of this work is to identify the difference in radiographic parameters between the cervical spine lateral view and the whole-spine lateral view. Methods We retrospectively analyzed 59 adult patients suffering from neck pain with cervical spine lateral radiographs and whole-spine lateral radiographs from November 2007 to December 2011. The radiographs were measured using standard techniques to obtain the following parameters from the two different radiographs: occipital-C2 angle, C2 C7 angle, C7-sternal angle, sternal slope, T1 slope, C2 central offset distance, the distance between C2 and C7 plumb lines, C4 anteroposterior (AP) diameter, the ratio of C2 central off distance to C4 AP diameter, the ratio of plumb lines' distance to C4 AP diameter. Results We found that the occipital-C2 angle, sternal slope, and C4 AP diameter were similar, but the C2-C7 angle, C7-sternal angle, T1 slope, C2 central offset distance, distance between C2 and C7 plumb lines, ratio of C2 central off distance to C4 AP diameter, and ratio of plumb lines' distance to C4 AP diameter were different. However, the error of measurement was greater than the small angular and linear differences between the two views. Conclusions Most numerical values of the measured radiographic parameters appear to be different between the two views. However, the two views are comparable because the numerical differences were smaller than the errors of measurement. PMID- 26933613 TI - Union Rate and Complications in Spine Fusion with Recombinant Human Bone Morphogenetic Protein-7: Systematic Review and Meta-Analysis. AB - Study Design Systematic review and meta-analysis. Objective The objective of this meta-analysis was to evaluate the current best evidence to assess effectiveness and safety of recombinant human bone morphogenetic protein-7 (rhBMP-7) as a biological stimulant in spine fusion. Methods Studies were included if they reported on outcomes after spine fusion with rhBMP-7. The data was synthesized using Mantel-Haenszel pooled risk ratios (RRs) with 95% confidence intervals (CIs). Main end points were union rate, overall complications, postoperative back and leg pain, revision rates, and new-onset cancer. Results Our search produced 796 studies, 6 of which were eligible for inclusion. These studies report on a total of 442 patients (328 experimental, 114 controls) with a mean age of 59 +/- 11 years. Our analysis showed no statistically significant differences in union rates (RR 0.97, 95% CI 0.84 to 1.11, p = 0.247), overall complications (RR 0.92, 95% CI 0.71 to 1.20, p = 0.545), postoperative back and leg pain (RR 1.03, 95% CI 0.48 to 2.19, p = 0.941), or revision rate (RR 0.81, 95% CI 0.47 to 1.40, p = 0.449). There was a mathematical indicator of increased tumor rates, but with only one case, the clinical meaningfulness of this finding is questionable. Conclusion We were not able to find data in support of the use of rhBMP-7 for spine fusion. We found no evidence for increased complication or revision rates with rhBMP-7. On the other hand, we also found no evidence in support of improved union rates. PMID- 26933614 TI - The Quality and Readability of Information Available on the Internet Regarding Lumbar Fusion. AB - Study Design An Internet-based evaluation of Web sites regarding lumbar fusion. Objective The Internet has become a major resource for patients; however, the quality and readability of Internet information regarding lumbar fusion is unclear. The objective of this study is to evaluate the quality and readability of Internet information regarding lumbar fusion and to determine whether these measures changed with Web site modality, complexity of the search term, or Health on the Net Code of Conduct certification. Methods Using five search engines and three different search terms of varying complexity ("low back fusion," "lumbar fusion," and "lumbar arthrodesis"), we identified and reviewed 153 unique Web site hits for information quality and readability. Web sites were specifically analyzed by search term and Web site modality. Information quality was evaluated on a 5-point scale. Information readability was assessed using the Flesch-Kincaid score for reading grade level. Results The average quality score was low. The average reading grade level was nearly six grade levels above that recommended by National Work Group on Literacy and Health. The quality and readability of Internet information was significantly dependent on Web site modality. The use of more complex search terms yielded information of higher reading grade level but not higher quality. Conclusions Higher-quality information about lumbar fusion conveyed using language that is more readable by the general public is needed on the Internet. It is important for health care providers to be aware of the information accessible to patients, as it likely influences their decision making regarding care. PMID- 26933615 TI - Membrane-Stabilizing Agents Improve Quality-of-Life Outcomes for Patients with Lumbar Stenosis. AB - Study Design Retrospective cohort controlled study. Objective To determine quality-of-life (QOL) outcomes for patients with lumbar spinal stenosis (LSS) treated with membrane-stabilizing agents (MSAs). Methods Patients with LSS and concordant neurogenic claudication treated with MSAs (n = 701) or conservatively without MSAs (n = 2104) at a single tertiary care hospital were identified. Patient QOL measures (Patient Health Questionnaire-9 [PHQ9], EuroQOL-5 Dimensions [EQ-5D], Pain Disability Questionnaire [PDQ]) were recorded pretreatment and then 4 months following treatment. Propensity score matching was used to account for baseline demographic differences between the two groups. The primary outcome measure was posttreatment improvement in these QOL measures. Results Patients in both groups had statistically significant improvements in the EQ-5D. However, the EQ-5D improvement in the MSA group was significantly greater than the improvement in the control group (0.11 versus 0.06; p = 0.0494). The EQ-5D change in the MSA group also exceeded the minimum clinically important difference, thereby suggesting a clinical significance. Both groups had significant pre- to posttreatment improvements in PDQ and PHQ-9, but these changes were not significantly different between the groups. Conclusion The results of this study suggest that patients with LSS and neurogenic claudication can have greater QOL improvements when treated with MSAs compared with other forms of conservative management without MSAs. PMID- 26933617 TI - The Evaluation and Observation of "Hidden" Hypertrophy of Cervical Ligamentum Flavum, Cervical Canal, and Related Factors Using Kinetic Magnetic Resonance Imaging. AB - Study Design Retrospective cohort study. Objective The objective was to measure the change of flavum ligament diameter during positional changes of the cervical spine using kinetic magnetic resonance imaging (MRI) and to examine the correlational diameter changes of the flavum ligament, disk bulging, and the spinal canal from extension to flexion positions. Methods One hundred eight-nine patients underwent kinetic MRI in neutral, extension, and flexion positions. The diameters of cervical ligamentum flavum, disk bulging, and cervical spinal canal and the disk degeneration grade and Cobb angles were measured from C2-C3 to C7 T1. Results In all, 1,134 cervical spinal segments from 189 patients were included. There was a 0.26 +/- 0.85-mm average increase in the diameter of the ligamentum flavum from flexion to extension, and 62.70% of the segments had increased ligamentum flavum diameter from flexion to extension. For all segments of the 189 patients, the cervical spinal canal diameters had an average decrease at the disk level of 0.56 +/- 1.21 mm from flexion to extension. For all segments with cervical spinal canal narrowing >=1 mm from flexion to extension view, the ligamentum flavum diameters at C3-C4 to C5-C6 had significant increases compared with patients with spinal canal narrowing < 1 mm (p < 0.05). For patients with ligamentum flavum hypertrophy of >=1 mm from the flexion to extension view, the cervical spinal canal diameters at C2-C3, C4-C5, and C5-C6 had significant decreases compared with patients with ligamentum flavum hypertrophy of <1 mm (p < 0.05). Conclusion The "hidden" hypertrophy of ligamentum flavum was significant at C4-C5 and C5-C6 and significantly contributes to the stenosis of cervical spinal canal in the extension position. PMID- 26933616 TI - Approach-Related Complications of Anterior Lumbar Interbody Fusion: Results of a Combined Spine and Vascular Surgical Team. AB - Study Design Retrospective analysis of prospectively collected cohort data. Objective Anterior lumbar interbody fusion (ALIF) is a commonly performed procedure for the treatment of degenerative diseases of the lumbar spine. Detailed and comprehensive descriptions of intra- and postoperative complications of ALIF are surprisingly limited in the literature. In this report, we describe our experience with a team model for ALIF and report all complications occurring in our patient series. Methods Patients were prospectively enrolled between January 2009 and January 2013 by a combined spine surgeon and vascular surgeon team. All patients underwent an open ALIF using an anterior approach to the lumbosacral spine. Results From the 227 ALIF cases, mean operative blood loss was 103 mL, ranging from 30 to 900 mL. Mean operative time was 78 minutes. The average length of stay was 5.2 days. Intraoperative vascular injury requiring primary repair with suturing occurred in 15 patients (6.6%). There were 2 cases of postoperative retroperitoneal hematoma. Three patients (1.3%) had incisional hernia requiring revision surgery; 7 (3.1%) patients had prolonged ileus (>7 days) managed conservatively. Four patients described retrograde ejaculation. Sympathetic dysfunction occurred in 15 (6.6%) patients. There were 5 (2.2%) cases of superficial wound infection treated with oral antibiotics, with no deep wound infections requiring reoperation or intravenous therapy. There were no mortalities in this series. Conclusions ALIF is a safe procedure when performed by a combined vascular surgeon and spine surgeon team with acceptably low complication rates. Our series confirms that the team approach results in short operative times and length of stay, with rapid control of intraoperative vessel injury and low overall blood loss. PMID- 26933618 TI - Reliability Analysis of the Distal Radius and Ulna Classification for Assessing Skeletal Maturity for Patients with Adolescent Idiopathic Scoliosis. AB - Study Design Prospective radiographic study. Objective To test the reliability of the Distal Radius and Ulna Classification (DRU). Methods This single-center study included prospectively recruited subjects with adolescent idiopathic scoliosis managed with bracing. The left-hand radiographs were measured using the DRU classification by two examiners. Intra- and interobserver reliability analysis were performed using intraclass correlation (ICC) analysis. Results From these clinics, 161 patients (124 females and 37 males) with left-hand radiographs were included in the study. The mean age was 13.3 years (standard deviation: 1.5). There was excellent intra- (ICC: 0.93 to 0.95) and interobserver (ICC: 0.97) reliability. Conclusions The DRU classification scheme has been shown to be accurate in determining the peak growth phase and growth cessation. It has now been confirmed to be a reliable tool. Future prospective studies should be performed to investigate its application in deciding when to apply bracing or operative treatment. PMID- 26933619 TI - Radiographic Analysis of the Sacropelvic Parameters of the Spine and Their Correlation in Normal Asymptomatic Subjects. AB - Study Design Cross-sectional study. Objective Sacropelvic parameters in various spine and hip disorders have been published in various studies. We aimed to study the normal sacropelvic parameters and curvatures of the spine and their correlation in asymptomatic Indian adults in relation to variations in sex and age. Methods The study included 101 asymptomatic adults (50 men and 51 women with an average age of 47.16 and 48.59 years, respectively). For each subject, the thoracic kyphosis (TK), lumbar lordosis (LL), pelvic incidence (PI), pelvic tilt (PT), and sacral slope (SS) were measured from standing lateral radiographs. After stratification of the group by sex and age with a cutoff of 50 years, descriptive, correlation, and regression analysis were performed using SPSS software. Results The average PI, SS, PT, LL, and TK values were 55.48 (+/-5.31), 35.99 (+/-7.53), 17.97 (+/-7.16), 48.84 (+/-9.82), and 32.55 (+/-10.92), respectively. No statistically significant difference was observed in these values with regards to sex and age < 50 years and > 50 years but the pelvic incidence was found to be higher in women. A positive correlation between the PI and SS and a negative correlation between the SS and PT was observed. A positive correlation between the TK and LL was found in subjects > 50 years. Simple and multiple regression analyses were also performed for different groups. Conclusion The current study is the first of asymptomatic Indian adults and provides invaluable information to the clinicians about the normal range of sacropelvic and spinopelvic parameters, which is useful to plan spinal deformity corrections and to evaluate pathologic conditions associated with abnormal angular values. PMID- 26933621 TI - Open Versus Minimally Invasive Fixation Techniques for Thoracolumbar Trauma: A Meta-Analysis. AB - Study Design Systematic literature review and meta-analysis of studies published in English. Objective This study evaluated differences in outcome variables between percutaneous and open pedicle screws for traumatic thoracolumbar fractures. Methods A systematic review of PubMed, Cochrane, and Embase was performed. The variables of interest included postoperative visual analog scale (VAS) pain score, kyphosis angle, and vertebral body height, as well as intraoperative blood loss and operative time. The results were pooled by calculating the effect size based on the standardized difference in means. The studies were weighted by the inverse of the variance, which included both within- and between-study error. Confidence intervals were reported at 95%. Heterogeneity was assessed using the Q statistic and I (2). Results After two-reviewer assessment, 38 studies were eliminated. Six studies were found to meet inclusion criteria and were included in the meta-analysis. The combined effect size was found to be in favor of percutaneous fixation for blood loss and operative time (p < 0.05); however, there were no differences in vertebral body height (VBH), kyphosis angle, or VAS scores between open and percutaneous fixation. All of the studies demonstrated relative homogeneity, with I (2) < 25. Conclusions Patients with thoracolumbar fractures can be effectively managed with percutaneous or open pedicle screw placement. There are no differences in VBH, kyphosis angle, or VAS between the two groups. Blood loss and operative time were decreased in the percutaneous group, which may represent a potential benefit, particularly in the polytraumatized patient. All variables in this study demonstrated near-perfect homogeneity, and the effect is likely close to the true effect. PMID- 26933620 TI - Intramedullary Spinal Cord Tumors: Part II-Management Options and Outcomes. AB - Study Design Broad narrative review. Objectives Intramedullary spinal cord tumors (IMSCT) are uncommon lesions that can affect any age group or sex. However, numerous IMSCT exist and the clinical course of each tumor varies. The following article addresses the various management options and outcomes in patients with IMSCT. Methods An extensive review of the peer-reviewed literature was performed, addressing management options and clinical outcomes of patients with IMSCT. Results Early diagnosis and intervention are essential to obtain optimal functional outcome. Each IMSCT have specific imaging characteristics, which help in the clinical decision-making and prognostication. A comprehension of the tumor pathology and the clinical course associated with each tumor can allow for the proper surgical and nonsurgical management of these tumors, and reduce any associated morbidity and mortality. Recent advances in the operative management of such lesions have increased the success rate of tumor removal while minimizing iatrogenic-related trauma to the patient and, in tandem, improving patient outcomes. Conclusions Awareness and understanding of IMSCT is imperative to design proper management and obtain optimal patient outcomes. Meticulous operative technique and the use of surgical adjuncts are essential to accomplish proper tumor removal, diminish the risk of recurrence, and preserve neurologic function. Operative management of IMSCT should be individualized and based on tumor type, location, and dimensional extensions. To assist with preoperative and intraoperative decision-making, a general algorithm is provided. PMID- 26933623 TI - Development and validation of an HPLC method for the determination of vancomycin in human plasma and its comparison with an immunoassay (PETINIA). AB - Vancomycin (VAN) is among those antibiotics for which therapeutic drug monitoring is highly recommended. For this purpose a reliable method with small sample volume was required for quantification of VAN in human plasma. Therefore, a selective and sensitive method of high performance liquid chromatography was developed and validated. The separation was carried out isocratically by using a mobile phase NH4H2PO4 (50 mM, pH 2.2)-acetonitrile (88:12, v/v) at a flow rate of 0.36 mL/min on a nucleodur C18 column (125 mm * 4.6 mm, 5 um) with UV detection at 205 nm. Sample preparation was done by deproteination of plasma with 70 % perchloric acid and a liquid/liquid extraction. Validation was performed according to the European Medicines Agency guideline. The method showed linearity over the range of 0.25-60 mg/L with a coefficient of determination r(2) >= 0.999 and a lower limit of quantification of 0.25 mg/L. No interference was observed in blank plasma samples at the retention time of VAN. The percentage relative recovery and coefficient of variation (CV%) values for accuracy and precision were within the acceptable limits. Stability was proved at room temperature for 24 h, after repeated freeze and thaw cycles and storage at -20 degrees C for 3 months. A good correlation was observed (r = 0.947) by comparing with the results of an immunoassay (PETINIA, Siemens) in 289 samples. In conclusion the method proved simple, sensitive and cost effective for quantification of VAN in human plasma. PMID- 26933624 TI - Prognostic factors in patients with vulvar cancer treated with primary surgery: a single-center experience. AB - Vulvar cancer is a relatively rare disease. The aim of this study was to investigate prognostic factors in vulvar squamous cell carcinoma patients treated with primary surgery. Forty cases of vulvar squamous cell carcinoma treated with primary surgery were retrospectively analyzed. Overall survival (OS) and disease specific survival (DSS) were calculated using the Kaplan-Meier method and prognostic factors were analyzed by multivariate analyses. The median age was 68 years. The FIGO stage distribution was as follows: 18 cases (45.0 %) in stage I, four cases (10.0 %) in stage II, 15 cases (37.5 %) in stage III, and three cases (7.5 %) in stage IV. A radical local excision was performed in 15 patients, and radical vulvectomy in 25 patients, and seven of these patients were treated with postoperative RT. The 5-year DSS rate was 72.6 %, and the 5-year OS rate was 70.3 %. Age and surgical margin <=5 mm were independent prognostic factors for OS, and positive inguinal LN metastasis and surgical margin <=5 mm were identified as independent prognostic factors for DSS. Complete radical excision is important regardless of operation mode. Adjuvant treatment should be considered for inguinal LN positive patients. PMID- 26933622 TI - Ossification of the Posterior Longitudinal Ligament: Etiology, Diagnosis, and Outcomes of Nonoperative and Operative Management. AB - Study Design Narrative review. Objective To provide an overview on the diagnosis, natural history, and nonoperative and operative management of ossification of the posterior longitudinal ligament (OPLL). OPLL is a multifactorial condition caused by ectopic hyperostosis and calcification of the posterior longitudinal ligament. Familial inheritance and genetic factors have been implicated in the etiology of OPLL. The cervical spine is most commonly affected followed by the thoracic spine. The clinical manifestations range from asymptomatic to myelopathy or myeloradiculopathy. Methods Using PubMed, studies published prior to October 2014 with the keywords "OPLL, etiology"; "OPLL, genetics"; "OPLL, spinal cord injury"; "OPLL, natural history"; "OPLL, non-surgical management"; OPLL, surgical management"; "OPLL, surgical complications" were evaluated. Results The review addresses the etiology, epidemiology, classification, clinical presentation, imaging findings, and nonoperative and operative management of OPLL. Complications associated with surgical management of OPLL are also discussed. Conclusions OPLL commonly presents with myelopathy and radiculopathy. Spine providers should consider OPLL in their differential diagnosis and when reviewing images. If surgical intervention is pursued, imaging-based measurements and findings can help in choosing an anterior versus posterior surgical approach. PMID- 26933625 TI - Neimark-Sacker bifurcation of a two-dimensional discrete-time predator-prey model. AB - In this paper, we study the dynamics and bifurcation of a two-dimensional discrete-time predator-prey model in the closed first quadrant [Formula: see text]. The existence and local stability of the unique positive equilibrium of the model are analyzed algebraically. It is shown that the model can undergo a Neimark-Sacker bifurcation in a small neighborhood of the unique positive equilibrium and an invariant circle will appear. Some numerical simulations are presented to illustrate our theocratical results and numerically it is shown that the unique positive equilibrium of the system is globally asymptotically stable. PMID- 26933626 TI - Cognitive impairment and pragmatics. AB - BACKGROUND: One of the most important ingredients of felicitous conversation exchanges is the adequate expression of illocutionary force and the achievement of perlocutionary effects, which can be considered essential to the functioning of pragmatic competence. FINDINGS: The breakdown of illocutionary and perlocutionary functions is one of the most prominent external features of cognitive impairment in Alzheimer's Disease, with devastating psychological and social consequences for patients, their family and caregivers. CONCLUSIONS: The study of pragmatic functions is essential for a proper understanding of the linguistic and communicative aspects of Alzheimer's disease. PMID- 26933627 TI - The safety and efficacy of ERCP in the pediatric population with standard scopes: Does size really matter? AB - Experience with endoscopic retrograde cholangiopancreatography in the pediatric population is limited. The aim of this study was to evaluate the outcomes of ERCP in the pediatric population performed by adult gastroenterologists with standard duodenoscopes. This study is a structured retrospective review of endoscopic reports, computerized and paper medical records, and radiographic images of patients under the age of 18 who underwent ERCP for any indication at a tertiary referral centre. Data regarding demographic characteristics and medical history of patients, indications, technical success rate, final clinical diagnosis, and complications were analyzed. Forty-eight children with a mean age of 13 years (range 2-17) underwent a total of 65 ERCPs. The indications of ERCP were as follows; suspected choledocholithiasis (55 %), post-liver transplantation anastomotic biliary strictures (21 %), post-surgical bile duct injury (10 %), choledochal cyst (2 %), recurrent or chronic pancreatitis (10 %), and trauma (2 %). The cannulation success rate in the overall procedure was 93.8 %. Therapeutic interventions were performed in 70.7 % of patients. Post ERCP pancreatitis was the most common complication occurring in 9.2 % of patients, and no procedure related mortality occurred. When performed by well-trained adult gastroenterologists, the use of endoscopic retrograde cholangiopancreatography with standard duodenoscopes is safe in pediatric population. PMID- 26933628 TI - A modified Tessari method for producing more foam. AB - This study aimed to develop a modified Tessari method for producing more sclerosing foam in treatment of extensive venous malformations. Sclerosing foam was produced by using Tessari method and the modified Tessari method. The procedure of the later was as follows: prepared foam in a sclerosant-air ratio of 1:4; connected three disposable 10 ml syringes to two medical three-way taps; drawn 4 ml of liquid sclerosant into one syringe and 16 ml averagely of air into the other two; then moved the plungers of all syringes back and forth for 20 times to produce sclerosing foam. The volume and foam half time (FHT) of foam produced by the two methods were compared. The average volume of sclerosing foam produced by Tessari method and the modified Tessari method were 9.8 and 19.7 ml, and assessed to have statistical difference. The FHT of foam produced by the two methods were 120 and 150 s, and assessed to have statistical difference. In conclusion, the modified Tessari method could produce more fresh and stable sclerosing foam. PMID- 26933629 TI - Cryptogenic ischemic stroke and silent atrial fibrillation: What is the relationship? AB - Atrial fibrillation (AF) is responsible for up to one-third of ischemic strokes and associated with silent cerebral infarctions and transient ischemic attacks. Any method that predicts the stroke or unmasks the silent PAF would contribute to the treatment of ischemic stroke. Intraatrial conduction time (ICT) has been shown to be associated with intermittent AF. In this study, we evaluated the value of ICT detected by transthoracic echocardiography in normal population and in patients with cryptogenic stroke (CS) as a risk factor for stroke. The patients with CS and with normal left ventricular function without valvular disease are included in group 1. Patients with atypical symptoms admitted to cardiology clinics without any risk factor for cardiac disease and found to be normal constituted group 2. Age, gender, weight, height, echocardiographic parameters and ICT were compared between groups. 63 and 64 subjects were included in group 1 and 2, respectively. Two groups were similar according to age and gender. Among the parameters studied, left atrial diameter and height of the patients were significantly higher in group 1 (40 +/- 2 vs 37 +/- 4 mm, p < 0.001 and 167 +/- 9 vs 163 +/- 9 cm p = 0.027, respectively). ICT was significantly higher in group 1 (131 +/- 15 vs 118 +/- 13 ms, respectively, p < 0.000). According to ROC analysis, a cut point of 124 ms for ICT with a sensitivity of 74 % and specificity of 73 % in patients with CS (p < 0.001). This study show us, the measurements the ICT determined by means of echocardiography is longer in patients with CS. This simple and noninvasive technique can be applied widely and lead the clinicians to adopt the use of diagnostic and the treatment procedures. PMID- 26933630 TI - High efficient key-insulated attribute based encryption scheme without bilinear pairing operations. AB - Attribute based encryption (ABE) has been widely applied for secure data protection in various data sharing systems. However, the efficiency of existing ABE schemes is not high enough since running encrypt and decrypt algorithms need frequent bilinear pairing operations, which may occupy too much computing resources on terminal devices. What's more, since different users may share the same attributes in the system, a single user's private key exposure will threaten the security and confidentiality of the whole system. Therefore, to further decrease the computation cost in attribute based cryptosystem as well as provide secure protection when key exposure happens, in this paper, we firstly propose a high efficient key-insulated ABE algorithm without pairings. The key-insulated mechanism guarantees both forward security and backward security when key exposure or user revocation happens. Besides, during the running of algorithms in our scheme, users and attribute authority needn't run any bilinear pairing operations, which will increase the efficiency to a large extent. The high efficiency and security analysis indicate that our scheme is more appropriate for secure protection in data sharing systems. PMID- 26933631 TI - Surgical technique for the treatment of renal cell carcinoma with inferior vena cava tumor thrombus: tips, tricks and oncological results. AB - Renal cell carcinoma represents 3 % of all cancers. Around 4-10 % of cases present with inferior vena cava involvement, generally with tumor thrombus. Clinical and preoperative stage will be classified depending of the thrombus extension. A high quality preoperative workup is essential to properly plan surgical approach. Complete surgical resection of the tumor is potentially the only curative treatment, although it supposes a real challenge due to operative difficulty, potential for massive bleeding or tumor pulmonary thromboembolism. Surgery includes techniques derived from transplantation surgery and, in some cases, cardiovascular intervention with cardiopulmonary bypass. Long-term oncological outcomes after complete removal of the entire tumor burden are acceptable. In this report we describe step-by-step surgical maneuvers depending on the thrombus lever, and focusing in complete abdominal approach for the complete excision of the tumor. Moreover, a recent literature review about oncological results is reported. PMID- 26933633 TI - Risk factors of postoperative complications after radical cystectomy with continent or conduit urinary diversion in Armenia. AB - To estimate the surgical volume and the incidence of in-hospital complications of RC in Armenia from 2005 to 2012, and to investigate potential risk factors of complications. The study utilized a retrospective chart review in a cohort of patients who had RC followed by either continent or conduit urinary diversion in all hospitals of Armenia from 2005 to 2012. A detailed chart review was conducted abstracting information on baseline demographic and clinical characteristics, surgical procedural details, postoperative management and in-hospital complications. Multivariable logistic regression analysis was applied to estimate the independent risk factors for developing 'any postoperative complication'. The total study sample included 273 patients (mean age = 58.5 years, 93.4 % men). Overall, 28.9 % (n = 79) of patients had at least one in-hospital complication. The hospital mortality rate was 4.8 % (n = 13). The most frequent types of complications were wound-related (10.3 %), gastrointestinal (9.2 %) and infectious (7.0 %). The ischemic heart disease (OR = 3.3, 95 % CI 1.5-7.4), perioperative transfusion (OR = 2.0, 1.1-3.6), glucose level [OR = 0.71 (0.63 0.95)], and hospital type (OR = 2.3, 95 % CI 1.1-4.7) were independent predictors of postoperative complications. The rate of RC complications in Armenia was similar to those observed in other countries. Future prospective studies should evaluate the effect of RC complications on long-term outcomes and costs in Armenia. Policy recommendations should address the issues regarding surgeon training and hospital volume to decrease the risk of RC complications. PMID- 26933632 TI - Profiling postgraduate workplace-based assessment implementation in Ireland: a retrospective cohort study. AB - In 2010, workplace-based assessment (WBA) was formally integrated as a method of formative trainee assessment into 29 basic and higher specialist medical training (BST/HST) programmes in six postgraduate training bodies in Ireland. The aim of this study is to explore how WBA is being implemented and to examine if WBA is being used formatively as originally intended. A retrospective cohort study was conducted and approved by the institution's Research Ethics Committee. A profile of WBA requirements was obtained from 29 training programme curricula. A data extraction tool was developed to extract anonymous data, including written feedback and timing of assessments, from Year 1 and 2 trainee ePortfolios in 2012 2013. Data were independently quality assessed and compared to the reference standard number of assessments mandated annually where relevant. All 29 training programmes mandated the inclusion of at least one case-based discussion (max = 5; range 1-5). All except two non-clinical programmes (93 %) required at least two mini-Clinical Evaluation Exercise assessments per year and Direct Observation of Procedural Skills assessments were mandated in 27 training programmes over the course of the programme. WBA data were extracted from 50 % of randomly selected BST ePortfolios in four programmes (n = 142) and 70 % of HST ePortfolios (n = 115) in 21 programmes registered for 2012-2013. Four programmes did not have an eligible trainee for that academic year. In total, 1142 WBAs were analysed. A total of 164 trainees (63.8 %) had completed at least one WBA. The average number of WBAs completed by HST trainees was 7.75 (SD 5.8; 95 % CI 6.5-8.9; range 1-34). BST trainees completed an average of 6.1 assessments (SD 9.3; 95 % CI 4.01-8.19; range 1-76). Feedback-of varied length and quality-was provided on 44.9 % of assessments. The majority of WBAs were completed in the second half of the year. There is significant heterogeneity with respect to the frequency and quality of feedback provided during WBAs. The completion of WBAs later in the year may limit available time for feedback, performance improvement and re-evaluation. This study sets the scene for further work to explore the value of formative assessment in postgraduate medical education. PMID- 26933634 TI - The energy intake through regular nontherapeutic meals provision in long-term care: impact on nutritional status and related Geriatric Nutritional Risk Index. AB - To investigate how the energy intake of institutionalized long-term-care patients through the regular nontherapeutic meals provision is associated with the nutritional status and the Geriatric Nutritional Risk Index (GNRI). A 9 month longitudinal, observational study. Long-term-care Hospital. 66 long-term-care patients with multiple medical conditions and solely oral food-intake. 47 (71 %) patients, predominantly women (n = 39/47), with a mean age of 83.04 (+/-9.58) years completed study time and 19 (29 %) deceased. At week 1 and week 36 of observation time energy intake was measured by means of three-days-weighing records. Body composition was assessed with bioelectrical impedance analysis. Serum albumin, body weight and body height were taken from the medical report. Albumin content, body weight and height were used to calculate the Geriatric Nutritional Risk Index: GNRI = [1.489 * albumin (g/L)] + [41.7 * (weight/ideal body weight)]. Energy intake was significantly below 24 kcal/kg body weight per day. The GNRI of the deceased patients was significantly (p = 0.002) lower than the GNRI of the completers. During observation time energy-intake p < 0.001, body fat (p = 0.001) and phase angle (PA) of bio impedance measurement (p = 0.018) and likewise the GNRI (p = 0.021) of the completers decreased significantly. At the beginning and at the end of observation time energy intake correlated significantly with PA (p = 0.028/p < 0.001) and GNRI (p = 0.436/p = 0.004). Also GNRI and PA correlated significantly at the beginning (p = 0.001) and at the end (p < 0.001) of observation time. The energy intake through non therapeutic meals provision was too low for sustaining the nutritional status and likewise the GNRI. The malnourishment and the nutrition related clinical risk of the geriatric patients aggrevated during observation time. PMID- 26933635 TI - Response of soil respiration to experimental warming in a highland barley of the Tibet. AB - Highland barley is an important dominant crop in the Tibet and the croplands of the Tibet are experiencing obvious climatic warming. However, information about how soil respiration will respond to climatic warming in the highland barley system is still lacking. A field warming experiment using infrared heaters with two warming magnitudes was conducted in a highland barley system of the Tibet in May 2014. Five daily cycles of soil respiration was measured using a CO2 flux system (Li-8100, Li-COR Biosciences, Lincoln, NE, USA) during the period from early June to early September in 2014. The high and low experimental warming significantly increased soil temperature by 1.98 and 1.52 degrees C over the whole study period, respectively. The high experimental warming significantly decreased soil moisture. Soil respiration and its temperature sensitivity did not significantly change under both the high and low experimental warming. The response of soil respiration to experimental warming did not linearly correlate with warming magnitudes because a greater experimental warming resulted in a higher soil drying. Our findings suggested that clarifying the response of soil CO2 production and its temperature sensitivity to climatic warming need consider water availability in the highland barley system of the Tibet. PMID- 26933636 TI - Nanofat grafting under a split-thickness skin graft for problematic wound management. AB - INTRODUCTION: Obesity and certain medical disorders make the reconstruction of skin defects challenging. Different kind of procedure can be used for these defect, besides, skin grafting is one of the most common and simplest procedure. Fat grafting and stem cells which are located in the adipose tissue have been commonly used in plastic surgery for regeneration and rejuvenation purposes. To decrease graft failure rate we performed nanofat grafting under an autologous split-thickness skin graft in our patient who had a problematic wound. CASE DESCRIPTION: The case of a 35-year-old female patient with a traumatic skin defect on her left anterior crural region is described herein. After subsequent flap reconstruction, the result was disappointing and the defect size was widened. The defect was treated with combined grafting (nanofat grafting under an autologous split-thickness skin graft). At the 6 months follow-up assessment after combined grafting, the integrity of the skin graft was good with excellent pliability. CONCLUSIONS: Combined grafting for problematic wounds seems to be a useful technique for cases requiring reconstruction. The potential existence of stem cells may be responsible for the successful result in our patient. PMID- 26933637 TI - Ion uptake of marigold under saline growth conditions. AB - Salinity is one of most significant environmental stresses. Marigold is moderately tolerant to salinity stress. Therefore, in this study, the fresh weights of roots and shoots, rootFW/shootFW ratio, moisture content of shoots, micronutrient and macronutrient concentrations and ratios of K(+)/Na(+) and Ca(2+)/Na(+) in the roots and shoots of marigold were determined under salinity stress. Five salinity treatments (0, 50, 100, 150, and 200 mM NaCl) were maintained. In the current study, salinity affected the biomass of marigold. An increase of more than 100 mM in salt concentrations significantly reduced the shoot fresh weight. Increasing salinity stress increased the ratios of rootFW/shootFW, which were more significant under high salt levels (150 and 200 mM NaCl). Wet basis moisture contents of the shoots were reduced when salinity stress increased above 100 mM. In this study, salinity stress affected micronutrient and macronutrient uptake. Increases in the salt concentration and decreases in the concentration of Cu(2+) and Zn(2+) in the roots and Mn(2+) and Fe(2+) in the shoots were significant. Based on an increase in salinity stress, while the Ca(2+), Mg(2+), and Na(+) concentrations increased, the K(+) concentration decreased in the roots and shoots. Moreover, the K(+)/Na(+) and Ca(2+)/Na(+) ratios of the roots and shoots were significantly lower than those of the control in all of the salinity treatments. As a result, under increasing salinity stress, the Ca(2+), Mg(2+), K(+), and Na(+) uptakes in marigold were significant, revealing the effects of stress. PMID- 26933638 TI - Murine mammary stem/progenitor cell isolation: Different method matters? AB - Murine mammary stem/progenitor cell isolation has been routinely used in many laboratories, yet direct comparison among different methods is lacking. In this study, we compared two frequently used digestion methods and three sets of frequently used surface markers for their efficiency in enriching mammary stem and progenitor cells in two commonly used mouse strains, C57BL/6J and FVB. Our findings revealed that the slow overnight digestion method using gentle collagenase/hyaluronidase could be easily adopted and yielded reliable and consistent results in different batches of animals. In contrast, the different fast digestion protocols, as described in published studies, yielded high percent of non-epithelial cells with very few basal epithelial cells liberated in our hands. The three sets of markers tested in our hands reveal rather equally efficiency in separating luminal and basal cells if same fluorochrome conjugations were used. However, the tendency of non-epithelial cell inclusion in the basal cell gate was highest in samples profiled by CD24/CD29 and lowest in samples profiled by CD49f/EpCAM, this is especially true in mammary cells isolated from C57BL/6J mice. This finding will have significant implication when sorted basal cells are used for subsequent gene expression analysis. PMID- 26933639 TI - Sacral orientation and Scheuermann's kyphosis. AB - To examine whether the association between spinal alignment and sacral anatomical orientation (SAO) can be detected in skeletal populations, by comparing SAO values in individuals with a typical SD to individuals with normal spinal alignment. 2025 skeletons were screened for Scheuermann's disease. Scheuermann's kyphosis was established by the presence of apophyseal abnormalities associated with more than 5 degrees of anterior wedging in each of three adjacent vertebrae. SAO was measured as the angle created between the intersection of a line running parallel to the superior surface of the sacrum and a line running between the anterior superior iliac spine and the anterior-superior edge of the symphysis pubis (PUBIS). SAO was measured on 185 individuals with normal spines and 183 individuals with Scheuermann's kyphosis. Out of 2025 skeletons, 183 (9 %) were diagnosed with Scheuermann's kyphosis. The sacrum was significantly more horizontally oriented in individuals with Scheuermann's kyphosis compared with the control (SAO: 44.44 +/- 9.7 degrees vs. 50 +/- 9.9 degrees , p < 0.001). Alteration in spinal biomechanics due to a horizontally orientated sacrum may be an important contributing factor for the development of Scheuermann's kyphosis. PMID- 26933640 TI - Patient-Assessed Chronic Illness Care (PACIC) scenario in an Indian homeopathic hospital. AB - Homeopathy research has focused on chronic conditions; however, the extent to which current homeopathic care is compliant with the Chronic Care Model (CCM) has been sparsely shown. As the Bengali Patient-Assessed Chronic Illness Care (PACIC) 20 was not available, the English questionnaire was translated and evaluated in a government homeopathic hospital in West Bengal, India. The translation was done in six steps, and approved by an expert committee. Face validity was tested by 15 people for comprehension. Test/retest reliability (reproducibility) was tested on 30 patients with chronic conditions. Internal consistency was tested in 377 patients suffering from various chronic conditions. The questionnaire showed acceptable test/retest reliability [intraclass correlation coefficient (ICC) 0.57 0.75; positive to strong positive correlations; p < 0.0001] for all domains and the total score, strong internal consistency (Cronbach's alpha = 0.86 overall and 0.65-0.82 for individual subscales), and large responsiveness (1.11). The overall mean score percentage seemed to be moderate at 69.5 +/- 8.8%. Gender and presence of chronic conditions did not seem to vary significantly with PACIC-20 subscale scores (p > 0.05); however, monthly household income had a significant influence (p < 0.05) on the subscales except for "delivery system or practice design." Overall, chronic illness care appeared to be quite promising and CCM-compliant. The psychometric properties of the Bengali PACIC-20 were satisfactory, rendering it a valid and reliable instrument for assessing chronic illness care among the patients attending a homeopathic hospital. PMID- 26933641 TI - Publishing scientifically sound papers in Traditional and Complementary Medicine. AB - Non-conventional medical practices that make use of dietary supplements, herbal extracts, physical manipulations, and other practices typically associated with folk and Traditional Medicine are increasingly becoming popular in Western Countries. These practices are commonly referred to by the generic, all-inclusive term "Complementary and Alternative Medicine." Scientists, practitioners, and medical institutions bear the responsibility of testing and proving the effectiveness of these non-conventional medical practices in the interest of patients. In this context, the number of peer-reviewed journals and published articles on this topic has greatly increased in the recent decades. In this editorial article, we illustrate the policy of the Journal of Traditional and Complementary Medicine for publishing solid and scientifically sound papers in the field of Traditional and Complementary Medicine. PMID- 26933643 TI - Smoke-Free Universities Help Students Avoid Establishing Smoking by Means of Facilitating Quitting. AB - BACKGROUND: This study aimed to clarify whether smoke-free policies affect the initiation or the quitting of smoking among young adults. METHODS: In this natural quasi-experiment study, three universities with different enforcement of smoke-free policies were considered in Kazan City, Russian Federation. Exposure data were collected in 2008-2009 through measurement of particulate matter concentrations in typical sets of premises in each university to distinguish smoke-free universities (SFU) and those not smoke-free (NSFU). All present third year students were surveyed in class in April-June 2011. Number of valid questionnaires equaled 635. The questionnaire was adapted from the Health Professions Students Survey and contained questions on smoking initiation, current tobacco use, willingness to quit, quit attempts, percep-tion of smoke free policies enforcement, and the demographic data. RESULTS: Among students of SFU, the percentage of current smokers was smaller than in NSFU: 42% vs. 64% in men and 32% vs. 43% in women. Prevalence of daily smoking was 11-12% in SFU, 26% in NSFU overall and 42% among male students. No advantage of SFU in limiting smoking initiation was found. Percentage of former smokers in SFU was 33% vs. 10% in NSFU. Among current smokers, 57% expressed willingness to quit in SFU and only 28% in NSFU. About 60% of current smokers in SFU attempted to quit within a year and only 36% did so in NSFU with 23% vs. 3% having done three or more attempts. CONCLUSION: Smoke-free universities help young adults to avoid establishing regular smoking by means of facilitating quitting smoking. PMID- 26933642 TI - Fast Food Pattern and Cardiometabolic Disorders: A Review of Current Studies. AB - BACKGROUND: There are growing concern globally regarding the alarming trend of fast food consumption and its related cardiometabolic outcomes including overweight and obesity. This study aimed to review the current evidences available in relation to adverse effects of fast food pattern on cardiometa-bolic risk factors. METHODS: Relevant articles including epidemiological and clinical studies with appropriate design and good quality were obtained through searches of the Medline, PubMed, Scopus databases and Google scholar with related key words including "fast foods", "processed foods", "obesity", "overweight", "insulin resistance", "diabetes", "cardiovascular disease", "metabolic syndrome", "dyslipidemia" and "hypertension". RESULTS: Fast food consumption and out-of-home eating behavior is a main risk factor for lower diet quality, higher calorie and fat intake and lower micronutrients density of diet. Frequent consumption of fast foods was accompanied with overweight and abdominal fat gain, impaired insulin and glucose homeostasis, lipid and lipoprotein disorders, induction of systemic inflammation and oxidative stress. Higher fast food consumption also increases the risk of developmental diabetes, metabolic syndrome and cardiovascular disease. CONCLUSION: This review provides further evidence warning us against the irreparable effects of fast food consumption on public health especially the increasing global burden of obesity and cardiovascu-lar diseases. PMID- 26933644 TI - Development and Psychometric Evaluation of a Socioeconomic Status Questionnaire for Urban Households (SESIran): The Preliminary Version. AB - BACKGROUND: The aim of present study was to develop and validate an appropriate socioeconomic status (SES) assessment questionnaire to be used through health studies in Iranian urban households. METHODS: The study was conducted through a mixed method study design in Tabriz, northwest of Iran in 2014. It was conducted in several stages including: development of initial version, qualitative study, feasibility evaluation, and assessment of the validity as well as the reliability. The internal consistency, test-retest reliability, content validity, concurrent validity and construct validity were assessed. RESULTS: With respect to the assessment of construct validity, 5 domains (factors) were extracted includ-ing: main factor (alpha=0.84), self-evaluation of expenditure capacity (alpha=0.96), wealth (alpha=0.70), home and furniture (alpha=0.66) and costs related to health (alpha=0.55). Intraclass correlation coefficient was above 0.6 for all factors except for wealth domain. CONCLUSION: The questionnaire developed appeared to be a valid and reliable SES assessment tool. It may be of value to be used not only as a complementary questionnaire in most health surveys or clini cal studies, but also as a main questionnaire in health equity and health economics research. PMID- 26933645 TI - An Advertisement and Article Analysis of Skin Products and Topics in Popular Women's Magazines: Implications for Skin Cancer Prevention. AB - BACKGROUND: In the United States, skin cancer is the most commonly diagnosed cancer, with an estimated 5 million people treated per year and annual medical treatment expenditures that exceed 8 billion dollars. The purpose of this study was two-fold: 1) to enumerate the number of advertisements for skin products with and without Sun Protection Factor (SPF) and to further analyze the specific advertisements for sunblock to determine if models, when present, depict sun safe behaviors and 2) to enumerate the number of articles related to the skin for content. Both aims include an assessment for differences in age and in magazines targeting a Black or Latina population. METHODS: The sample for this cross sectional study was comprised of 99 issues of 14 popular United States magazines marketed to women, four of which market to a Black or Latina audience. RESULTS: There were 6,142 advertisements, of which 1,215 (19.8%, 95% CI: 18.8-20.8%) were related to skin products. Among the skin product advertisements, 1,145 (93.8%, 95% CI: 93.9-96.3%) depicted skin products without SPF. The majority of skin articles (91.2%, 95% CI: 91.7-100.0%), skin product advertisements (89.9%, 95% CI: 88.2-91.6%), and sunblock advertisements featuring models (were found in magazines aimed at the older (>24 yr) audience. CONCLUSION: Future research on this topic could focus on the extent to which images in these magazines translate into risky health behaviors, such as sun seeking, or excessive other harmful effects of UV radiation. PMID- 26933646 TI - Optimal Design of Air Quality Monitoring Network and its Application in an Oil Refinery Plant: An Approach to Keep Health Status of Workers. AB - BACKGROUND: Industrial air pollution is a growing challenge to humane health, especially in developing countries, where there is no systematic monitoring of air pollution. Given the importance of the availability of valid information on population exposure to air pollutants, it is important to design an optimal Air Quality Monitoring Network (AQMN) for assessing population exposure to air pollution and predicting the magnitude of the health risks to the population. METHODS: A multi-pollutant method (implemented as a MATLAB program) was explored for configur-ing an AQMN to detect the highest level of pollution around an oil refinery plant. The method ranks potential monitoring sites (grids) according to their ability to represent the ambient concentration. The term of cluster of contiguous grids that exceed a threshold value was used to calculate the Station Dosage. Selection of the best configuration of AQMN was done based on the ratio of a sta-tion's dosage to the total dosage in the network. RESULTS: Six monitoring stations were needed to detect the pollutants concentrations around the study area for estimating the level and distribution of exposure in the population with total network efficiency of about 99%. An analysis of the design procedure showed that wind regimes have greatest effect on the location of monitoring stations. CONCLUSION: The optimal AQMN enables authorities to implement an effective program of air quality management for protecting human health. PMID- 26933647 TI - Evaluation of Mental Workload among ICU Ward's Nurses. AB - BACKGROUND: High level of workload has been identified among stressors of nurses in intensive care units (ICUs). The present study investigated nursing workload and identified its influencing perfor-mance obstacles in ICUs. METHODS: This cross-sectional study was conducted, in 2013, on 81 nurses working in ICUs in Imam Khomeini Hospital in Tehran, Iran. NASA-TLX was applied for assessment of workload. Moreover, ICUs Performance Obstacles Questionnaire was used to identify performance obstacles associated with ICU nursing. RESULTS: Physical demand (mean=84.17) was perceived as the most important dimensions of workload by nurses. The most critical performance obstacles affecting workload included: difficulty in finding a place to sit down, hectic workplace, disorganized workplace, poor-conditioned equipment, waiting for using a piece of equipment, spending much time seeking for supplies in the central stock, poor quality of medical materials, delay in getting medications, unpredicted problems, disorganized central stock, outpatient surgery, spending much time dealing with family needs, late, inadequate, and useless help from nurse assistants, and ineffective morning rounds (P-value<0.05). CONCLUSION: Various performance obstacles are correlated with nurses' workload, affirms the significance of nursing work system characteristics. Interventions are recommended based on the results of this study in the work settings of nurses in ICUs. PMID- 26933648 TI - Older People's Perspectives on Health, Physical Activity and Nutritional Behaviors. AB - BACKGROUND: Approaches for investigating health-promoting lifestyle generally focus on physical activity and regular diet. To explore the perspectives of Iranian elders regarding health, healthy eating and physical activity (PA) this study was conducted in 2012. METHODS: Participants in this qualitative study were selected through purposeful sampling. Ten focus groups were conducted with 60 older adults in 3 elderly centers in Tehran. A moderator's guideline that consisted of general and specific questions was used. Focus groups were audio recorded, transcribed verbatim and analysis was performed using conventional content analysis. RESULTS: Participants explained their perspectives regarding health, healthy eating and PA in the following 5 categories: meaning of health was represented based on issues such as absence of pain and disorder, complete body wellbeing, staying away from hazards, complete individual satisfaction, experiencing positive events, effective communication, faithfulness and trust in God. The healthy eating category was featured by adequate eating, age balanced diet, refraining from under or over nutrition and sensible consumption of fruits and vegetables. The PA was described - according to the level of performing outdoor activities or household tasks. Expressions about the perceived benefits and barriers of healthy eating and PA were aligned the two remaining categories. CONCLUSIONS: Participants have referred to the association between both PA and dietary practices and health. Understanding how older people define physical activity and nutritional behavior and recognition of the most important perceived benefits and barriers that might contribute to have a healthy eating or adequate PA profile could procure insight into the type of interventions that are required to promote healthy lifestyle among Iranian older adults. PMID- 26933649 TI - Occupational Exposure and Health Impairments of Formaldehyde on Employees of a Wood Industry. AB - BACKGROUND: Occupational exposure to formaldehyde may decrease white blood cell counts and change blood concentration. In this study, the influences of occupational exposure to formaldehyde on the number of white blood cells and blood concentrations were studied. METHODS: This case-control study was conducted in June of 2012 at North Wood Factory, Golestan Province, Iran. The US-NIOSH method No. 2541 was used to determine the occupational exposure of 30 workers of the production line (case group) and 30 administrative staffs (control group) to formalde-hyde. The number of white blood cells and blood concentration were determined using the normal blood count method and related indices. Demographic features as well as the symptoms of being exposed to formaldehyde were collected using a standard questionnaire. RESULTS: The occupational exposure of case group ranged from 0.50 ppm to 1.52 ppm. The prevalence of all studied symptoms from formaldehyde exposure in workers (2=36 hr in between them. Heart rate peak (HRpeak), plasma lactate concentrations (Lac) and rating of perceived exertion (RPE) were measured during the test. A significant effect of sleep restriction was observed on the total distance covered in YYIRT (P<0.0005) and Lac (P<0.01) in comparison with the RN. In addition, performance more decreased after PSDEN (P<0.0005) than PSDBN (P<0.05). Also, Lac decreased significantly only after PS-DEN (P<0.05) compared with RN. However, there were no significant changes in HRpeak and RPE after the two types of partial sleep deprivation compared to RN. The present study indicates that short-term sleep restriction affect the intermittent performance, as well as the Lac levels of the Taekwondo players in the evening of the following day, without alteration of HRpeak and RPE. PMID- 26933662 TI - Motor ability of forelimb both on- and off-riding during walk and trot cadence of horse. AB - The aim of this study was to investigate the motor ability of forelimb according to on- or off-riding during cadences (walk and trot) of horse. Horses and rider selected as subject consisted of total 37 heads of Jeju native horse and 1 female rider. The variables analyzed composed of 1 stride length, 1 step length, elapsed time of stance, elapsed time of swing, elapsed time of 1 step, and forward velocity (x-axis). Two-way analysis of variance of variables was employed for the statistical analysis with the level of significance set at 5% (P<0.05). Trot cadence showed significant difference with the faster and shorter during trot than that of walk in velocity and elapsed time. When analyzed interaction effect in stance and swing phase, the locomotion showed the shorter elapsed time in trot than that of walk, but more delayed in case of on-riding during stance phase, whereas the case of on-riding showed with the shorter during swing phase than that of the case of off-riding These result of horse's analysis meant that there was very close relation among variables of rider's weight-velocity-stride length stride elapsed time. Next study will be necessary to analyze cadence variables added both stride length and rider's weight for riding activity and rehabilitation during horse riding using Jeju native horse. PMID- 26933663 TI - Extraction of Oleic Acid from Moroccan Olive Mill Wastewater. AB - The production of olive oil in Morocco has recently grown considerably for its economic and nutritional importance favored by the country's climate. After the extraction of olive oil by pressing or centrifuging, the obtained liquid contains oil and vegetation water which is subsequently separated by decanting or centrifugation. Despite its treatment throughout the extraction process, this olive mill wastewater, OMW, still contains a very important oily residue, always regarded as a rejection. The separated oil from OMW can not be intended for food because of its high acidity of 3.397% which exceeds the international standard for human consumption defined by the standard of the Codex Alimentarius, proving its poor quality. This work gives value addition to what would normally be regarded as waste by the extraction of oleic acid as a high value product, using the technique of inclusion with urea for the elimination of saturated and unsaturated fatty acids through four successive crystallizations at 4 degrees C and 20 degrees C to have a final phase with oleic acid purity of 95.49%, as a biodegradable soap and a high quality glycerin will be produced by the reaction of saponification and transesterification. PMID- 26933664 TI - Gender-Specific Association of ATP2B1 Variants with Susceptibility to Essential Hypertension in the Han Chinese Population. AB - Previous genome-wide association studies (GWASs) found that several ATP2B1 variants are associated with essential hypertension (EHT). But the "genome-wide significant" ATP2B1 SNPs (rs2681472, rs2681492, rs17249754, and rs1105378) are in strong linkage disequilibrium (LD) and are located in the same LD block in Chinese populations. We asked whether there are other SNPs within the ATP2B1 gene associated with susceptibility to EHT in the Han Chinese population. Therefore, we performed a case-control study to investigate the association of seven tagSNPs within the ATP2B1 gene and EHT in the Han Chinese population, and we then analyzed the interaction among different SNPs and nongenetic risk factors for EHT. A total of 902 essential hypertensive cases and 902 normotensive controls were involved in the study. All 7 tagSNPs within the ATP2B1 gene were retrieved from HapMap, and genotyping was performed using the Tm-shift genotyping method. Chi-squared test, logistic regression, and propensity score analysis showed that rs17249754 was associated with EHT, particularly in females. The MDR analysis demonstrated that the interaction of rs2070759, rs17249754, TC, TG, and BMI increased the susceptibility to hypertension. Crossover analysis and stratified analysis indicated that BMI has a major effect on the development of hypertension, while ATP2B1 variants have a minor effect. PMID- 26933665 TI - Characteristics and Treatment Outcomes of Propionibacterium acnes Prosthetic Shoulder Infections in Adults. AB - Background. Prosthetic joint infections (PJIs) significantly complicate joint arthroplasties. Propionibacterium acnes is an increasingly recognized PJI pathogen, yet limited clinical and therapeutic data exist. We sought to examine characteristics of P. acnes shoulder PJIs and compare surgical and nonsurgical management outcomes. Methods. A retrospective analysis of P. acnes shoulder PJIs was conducted at an academic center in Baltimore, Maryland from 2000 to 2013. Results. Of 24 cases of P. acnes shoulder PJIs, 92% were diagnosed after extended culture implementation; 42% in the delayed and 46% in the late postsurgical period. Joint pain and diminished function were the predominant presenting clinical signs. Erythrocyte sedimentation rate and C-reactive protein elevations occurred in 47% and 44%, respectively. All tested isolates were susceptible to beta-lactams, moxifloxacin, vancomycin, and rifampin. Clindamycin resistance was identified in 6%. Of the antibiotic-only treated cases, 67% had a favorable clinical outcome compared with 71% (P = 1.0) of cases with a combined antibiotic-surgical approach. Favorable outcome with and without rifampin therapy was 73% and 60% (P = .61), respectively. Conclusions. Propionibacterium acnes PJI diagnoses increased with extended culture. Inflammatory markers were elevated in a minority of cases. Isolates maintained broad antimicrobial susceptibility. Compared to combined antibiotic-surgical approaches, antibiotic-only approaches were similarly successful in selected cases. PMID- 26933666 TI - A Genomic Signature of Influenza Infection Shows Potential for Presymptomatic Detection, Guiding Early Therapy, and Monitoring Clinical Responses. AB - Early, presymptomatic intervention with oseltamivir (corresponding to the onset of a published host-based genomic signature of influenza infection) resulted in decreased overall influenza symptoms (aggregate symptom scores of 23.5 vs 46.3), more rapid resolution of clinical disease (20 hours earlier), reduced viral shedding (total median tissue culture infectious dose [TCID50] 7.4 vs 9.7), and significantly reduced expression of several inflammatory cytokines (interferon gamma, tumor necrosis factor-alpha, interleukin-6, and others). The host genomic response to influenza infection is robust and may provide the means for early detection, more timely therapeutic interventions, a meaningful reduction in clinical disease, and an effective molecular means to track response to therapy. PMID- 26933668 TI - Data of microstructure and mechanical properties of carbon foams derived from sucrose/polyacrylamide hydrogel. AB - An easy method that combined gel casting and physical foaming was used to fabricate modified carbon foams. The design of carbon foams from sucrose/polyacrylamide hydrogel is a new concept for controlling the microstructure and improving the compressive properties of carbon foams. This article provides the micrographs obtained from optical and scanning electron microscope for foaming solution and carbon foams. Weight loss data used to construct the thermo-gravimetric curves are included. Load-displacement data constructing the stress-strain curves and the derived compressive properties are also included. PMID- 26933667 TI - Data of multiple regressions analysis between selected biomarkers related to glutamate excitotoxicity and oxidative stress in Saudi autistic patients. AB - This work demonstrates data of multiple regression analysis between nine biomarkers related to glutamate excitotoxicity and impaired detoxification as two mechanisms recently recorded as autism phenotypes. The presented data was obtained by measuring a panel of markers in 20 autistic patients aged 3-15 years and 20 age and gender matching healthy controls. Levels of GSH, glutathione status (GSH/GSSG), glutathione reductase (GR), glutathione-s-transferase (GST), thioredoxin (Trx), thioredoxin reductase (TrxR) and peroxidoxins (Prxs I and III), glutamate, glutamine, glutamate/glutamine ratio glutamate dehydrogenase (GDH) in plasma and mercury (Hg) in red blood cells were determined in both groups. In Multiple regression analysis, R (2) values which describe the proportion or percentage of variance in the dependent variable attributed to the variance in the independent variables together were calculated. Moreover, beta coefficients values which show the direction either positive or negative and the contribution of the independent variable relative to the other independent variables in explaining the variation of the dependent variable were determined. A panel of inter-related markers was recorded. This paper contains data related to and supporting research articles currently published entitled "Mechanism of nitrogen metabolism-related parameters and enzyme activities in the pathophysiology of autism" [1], "Novel metabolic biomarkers related to sulfur dependent detoxification pathways in autistic patients of Saudi Arabia [2], and "A key role for an impaired detoxification mechanism in the etiology and severity of autism spectrum disorders" [3]. PMID- 26933669 TI - (1)H NMR and FT-IR dataset based structural investigation of poly(amic acid)s and polyimides from 4,4'-diaminostilbene. AB - Structural investigation of polymers by various available analytical methods is important in order to correlate the structure with polymer properties for which understanding of polymer structure is very important factor. The data presented here in this article shows the (1)H NMR spectra used for the characterization of prepared poly(amic acid)s (PAAs). It is often difficult to assigns the peak in NMR of polymers due to its complexity. Data presented here helps in assigning the proton peak in complex NMR of PAAs prepared from aromatic diamines. Further functionality in polymer chains can be confirmed by FT-IR spectra. Change in functionality during some reaction or process can be monitored by disappearance or appearance of peaks in FT-IR. The complete imidization of PAAs to Polyimides (PIs) is difficult to analyze because of the chemical stability i.e. insolubility of PIs in most of the solvent therefore the completion of imidization process was confirmed using FTIR. PMID- 26933670 TI - Determination and quantification of PCBs, POCs and PAHs in Thunnus thynnus from the Straits of Messina (Italy). AB - This data set is composed to assess the accumulation of persistent organic pollutants (POPs) such as polychlorinated biphenyls (PCBs) dioxin like (DL) and not dioxin like (NDL), organochlorine pesticides (POCs) and polycyclic aromatic hydrocarbons (PAHs) in Thunnus thynnus and to elucidate the suitability of this species as a bioindicator for monitoring contaminations of these compounds in the marine ecosystems of the Straits of Messina. This investigation was conducted on liver samples of 14 T. thynnus collected during April 2015. Quantitative determination of PCBs (DL and NDL), POCs and PAHs in the examined samples has been carried out by HRGC-MS/MS. Among the PCBs, high prevalence of DL was found while, generally, the values detected for PCBs-NDL were lower than the legal limits. Tuna samples analyzed for PAHs residues revealed that all the samples were contaminated with acenaphthalene, fluorene, phenanthrene and anthracene. Moreover, generally the residual levels of DDT and DDT metabolites were low. The total content of PCB-DL, in almost all the samples, showed higher concentration than the legal limit. PMID- 26933671 TI - Building a panel data set on fuel stations located in the Spanish regional areas of Madrid and Barcelona. AB - The data described in this article were collected daily over the period June 10, 2010, to November 25, 2012, from the website of the Spanish Ministry of Industry, Energy and Tourism. The database includes information about fuel stations regarding to their prices (both gross and net of taxes), brand, location (latitude and longitude), and postal code in the Spanish provinces of Madrid and Barcelona. Moreover, obtaining the postal codes has allowed us to select those stations that are operating within the metropolitan areas of Madrid and Barcelona. By considering those fuel stations that uninterruptedly provided prices during the entire period, the data can be especially useful to explore the dynamics of prices in fuel markets. This is the case of Balaguer and Ripolles (2016), "Asymmetric fuel price responses under heterogeneity" [1], who, taking into account the presence of the potential heterogeneity of the behaviour of fuel stations, used this statistical information to perform an analysis on asymmetric fuel price responses. PMID- 26933672 TI - Supporting Data for Multifunctional all-in-one drug delivery systems for tumor targeting and sequential release of three different anti-tumor drugs. AB - Although nanoparticulate drug delivery systems (NDDSs) can preferentially accumulate in tumors, active targeting by targeting ligands (e.g. monoclonal antibody) is necessary for increasing its targeting efficacy in vivo. We conjugated mAb198.3 on the SiO2@AuNP system surface to make it obtain active targeting efficacy. The FAT1 targeting capability of SiO2@AuNP system is the first issue to be solved. Thus, flow cytometry analysis was attempted to demonstrate that the SiO2@AuNP system could bind to native FAT1 molecules on the surface of Colo205 cells. Also, together with the drug release behavior study of self-decomposable SiO2 NPs, the continuous morphological evolution needed to be clarified. Therefore, to characterize the morphological evolution in vitro, we analyzed the morphology of inner self-decomposable NPs in different time intervals using transmission electron microscopy (TEM). A more comprehensive analysis of this data may be obtained from the article "Multifunctional all-in one drug delivery systems for tumor targeting and sequential release of three different anti-tumor drugs" in Biomaterials. PMID- 26933673 TI - Semantic Clustering of Search Engine Results. AB - This paper presents a novel approach for search engine results clustering that relies on the semantics of the retrieved documents rather than the terms in those documents. The proposed approach takes into consideration both lexical and semantics similarities among documents and applies activation spreading technique in order to generate semantically meaningful clusters. This approach allows documents that are semantically similar to be clustered together rather than clustering documents based on similar terms. A prototype is implemented and several experiments are conducted to test the prospered solution. The result of the experiment confirmed that the proposed solution achieves remarkable results in terms of precision. PMID- 26933674 TI - Comment on "Epidemiological Survey on Porcine Cysticercosis in Nay Pyi Taw Area, Myanmar". PMID- 26933675 TI - Comment on "Panniculectomy Combined with Bariatric Surgery by Laparotomy: An Analysis of 325 Cases". PMID- 26933676 TI - Four billion people facing severe water scarcity. AB - Freshwater scarcity is increasingly perceived as a global systemic risk. Previous global water scarcity assessments, measuring water scarcity annually, have underestimated experienced water scarcity by failing to capture the seasonal fluctuations in water consumption and availability. We assess blue water scarcity globally at a high spatial resolution on a monthly basis. We find that two-thirds of the global population (4.0 billion people) live under conditions of severe water scarcity at least 1 month of the year. Nearly half of those people live in India and China. Half a billion people in the world face severe water scarcity all year round. Putting caps to water consumption by river basin, increasing water-use efficiencies, and better sharing of the limited freshwater resources will be key in reducing the threat posed by water scarcity on biodiversity and human welfare. PMID- 26933677 TI - 3.5-Ga hydrothermal fields and diamictites in the Barberton Greenstone Belt Paleoarchean crust in cold environments. AB - Estimates of ocean temperatures on Earth 3.5 billion years ago (Ga) range between 26 degrees and 85 degrees C. We present new data from 3.47- to 3.43-Ga volcanic rocks and cherts in South Africa suggesting that these temperatures reflect mixing of hot hydrothermal fluids with cold marine and terrestrial waters. We describe fossil hydrothermal pipes that formed at ~200 degrees C on the sea floor >2 km below sea level. This ocean floor was uplifted tectonically to sea level where a subaerial hydrothermal system was active at 30 degrees to 270 degrees C. We also describe shallow-water glacial diamictites and diagenetic sulfate mineral growth in abyssal muds. These new observations reveal that both hydrothermal systems operated in relatively cold environments and that Earth's surface temperatures in the early Archean were similar to those in more recent times. PMID- 26933678 TI - Constraints on Earth's inner core composition inferred from measurements of the sound velocity of hcp-iron in extreme conditions. AB - Hexagonal close-packed iron (hcp-Fe) is a main component of Earth's inner core. The difference in density between hcp-Fe and the inner core in the Preliminary Reference Earth Model (PREM) shows a density deficit, which implies an existence of light elements in the core. Sound velocities then provide an important constraint on the amount and kind of light elements in the core. Although seismological observations provide density-sound velocity data of Earth's core, there are few measurements in controlled laboratory conditions for comparison. We report the compressional sound velocity (V P) of hcp-Fe up to 163 GPa and 3000 K using inelastic x-ray scattering from a laser-heated sample in a diamond anvil cell. We propose a new high-temperature Birch's law for hcp-Fe, which gives us the V P of pure hcp-Fe up to core conditions. We find that Earth's inner core has a 4 to 5% smaller density and a 4 to 10% smaller V P than hcp-Fe. Our results demonstrate that components other than Fe in Earth's core are required to explain Earth's core density and velocity deficits compared to hcp-Fe. Assuming that the temperature effects on iron alloys are the same as those on hcp-Fe, we narrow down light elements in the inner core in terms of the velocity deficit. Hydrogen is a good candidate; thus, Earth's core may be a hidden hydrogen reservoir. Silicon and sulfur are also possible candidates and could show good agreement with PREM if we consider the presence of some melt in the inner core, anelasticity, and/or a premelting effect. PMID- 26933679 TI - Spontaneous structural transition and crystal formation in minimal supramolecular polymer model. AB - The association of building blocks into supramolecular polymers allows the fabrication of diverse functional architectures at the nanoscale. The use of minimal assembly units to explore polymer dynamics and phase transitions significantly contributes to the application of polymer physicochemical paradigms in the field of supramolecular polymers. We present a minimal model that displays spontaneous coordinated structural transitions between micro- and nanostructures, hydrogels with nanoscale order, and single crystals. The simple amphiphilic 9 fluorenylmethoxycarbonyl-3,4-dihydroxyphenylalanine (Fmoc-DOPA) modified amino acid undergoes a noninduced transition from spherical assemblies into nanofibrils followed by sol-gel transition, nanotube formation via intermediate assembly, and crystallization within the gel. Notably, the transition kinetics is slow enough to allow both multistage and multiscale characterization of the supramolecular arrangement using electron microscopy, vibrational and circular dichroism spectroscopies, nuclear magnetic resonance, and x-ray crystallography. This minimalistic system is the first comprehensive model for a complete spontaneous structural transition between diverse states governed by distinct molecular interactions. PMID- 26933681 TI - A new phase diagram of water under negative pressure: The rise of the lowest density clathrate s-III. AB - Ice and ice clathrate are not only omnipresent across polar regions of Earth or under terrestrial oceans but also ubiquitous in the solar system such as on comets, asteroids, or icy moons of the giant planets. Depending on the surrounding environment (temperature and pressure), ice alone exhibits an exceptionally rich and complicated phase diagram with 17 known crystalline polymorphs. Water molecules also form clathrate compounds with inclusion of guest molecules, such as cubic structure I (s-I), cubic structure II (s-II), hexagonal structure H (s-H), tetragonal structure T (s-T), and tetragonal structure K (s K). Recently, guest-free clathrate structure II (s-II), also known as ice XVI located in the negative-pressure region of the phase diagram of water, is synthesized in the laboratory and motivates scientists to reexamine other ice clathrates with low density. Using extensive Monte Carlo packing algorithm and dispersion-corrected density functional theory optimization, we predict a crystalline clathrate of cubic structure III (s-III) composed of two large icosihexahedral cavities (8(6)6(8)4(12)) and six small decahedral cavities (8(2)4(8)) per unit cell, which is dynamically stable by itself and can be fully stabilized by encapsulating an appropriate guest molecule in the large cavity. A new phase diagram of water ice with TIP4P/2005 (four-point transferable intermolecular potential/2005) model potential is constructed by considering a variety of candidate phases. The guest-free s-III clathrate with ultralow density overtakes s-II and s-H phases and emerges as the most stable ice polymorph in the pressure region below -5834 bar at 0 K and below -3411 bar at 300 K. PMID- 26933680 TI - Darwinian sex roles confirmed across the animal kingdom. AB - Since Darwin's conception of sexual selection theory, scientists have struggled to identify the evolutionary forces underlying the pervasive differences between male and female behavior, morphology, and physiology. The Darwin-Bateman paradigm predicts that anisogamy imposes stronger sexual selection on males, which, in turn, drives the evolution of conventional sex roles in terms of female-biased parental care and male-biased sexual dimorphism. Although this paradigm forms the cornerstone of modern sexual selection theory, it still remains untested across the animal tree of life. This lack of evidence has promoted the rise of alternative hypotheses arguing that sex differences are entirely driven by environmental factors or chance. We demonstrate that, across the animal kingdom, sexual selection, as captured by standard Bateman metrics, is indeed stronger in males than in females and that it is evolutionarily tied to sex biases in parental care and sexual dimorphism. Our findings provide the first comprehensive evidence that Darwin's concept of conventional sex roles is accurate and refute recent criticism of sexual selection theory. PMID- 26933682 TI - MyShake: A smartphone seismic network for earthquake early warning and beyond. AB - Large magnitude earthquakes in urban environments continue to kill and injure tens to hundreds of thousands of people, inflicting lasting societal and economic disasters. Earthquake early warning (EEW) provides seconds to minutes of warning, allowing people to move to safe zones and automated slowdown and shutdown of transit and other machinery. The handful of EEW systems operating around the world use traditional seismic and geodetic networks that exist only in a few nations. Smartphones are much more prevalent than traditional networks and contain accelerometers that can also be used to detect earthquakes. We report on the development of a new type of seismic system, MyShake, that harnesses personal/private smartphone sensors to collect data and analyze earthquakes. We show that smartphones can record magnitude 5 earthquakes at distances of 10 km or less and develop an on-phone detection capability to separate earthquakes from other everyday shakes. Our proof-of-concept system then collects earthquake data at a central site where a network detection algorithm confirms that an earthquake is under way and estimates the location and magnitude in real time. This information can then be used to issue an alert of forthcoming ground shaking. MyShake could be used to enhance EEW in regions with traditional networks and could provide the only EEW capability in regions without. In addition, the seismic waveforms recorded could be used to deliver rapid microseism maps, study impacts on buildings, and possibly image shallow earth structure and earthquake rupture kinematics. PMID- 26933683 TI - Walls talk: Microbial biogeography of homes spanning urbanization. AB - Westernization has propelled changes in urbanization and architecture, altering our exposure to the outdoor environment from that experienced during most of human evolution. These changes might affect the developmental exposure of infants to bacteria, immune development, and human microbiome diversity. Contemporary urban humans spend most of their time indoors, and little is known about the microbes associated with different designs of the built environment and their interaction with the human immune system. This study addresses the associations between architectural design and the microbial biogeography of households across a gradient of urbanization in South America. Urbanization was associated with households' increased isolation from outdoor environments, with additional indoor space isolation by walls. Microbes from house walls and floors segregate by location, and urban indoor walls contain human bacterial markers of space use. Urbanized spaces uniquely increase the content of human-associated microbes-which could increase transmission of potential pathogens-and decrease exposure to the environmental microbes with which humans have coevolved. PMID- 26933684 TI - Miniature high-throughput chemosensing of yield, ee, and absolute configuration from crude reaction mixtures. AB - High-throughput experimentation (HTE) has emerged as a widely used technology that accelerates discovery and optimization processes with parallel small-scale reaction setups. A high-throughput screening (HTS) method capable of comprehensive analysis of crude asymmetric reaction mixtures (eliminating product derivatization or isolation) would provide transformative impact by matching the pace of HTE. We report how spontaneous in situ construction of stereodynamic metal probes from readily available, inexpensive starting materials can be applied to chiroptical chemosensing of the total amount, enantiomeric excess (ee), and absolute configuration of a wide variety of amines, diamines, amino alcohols, amino acids, carboxylic acids, alpha-hydroxy acids, and diols. This advance and HTS potential are highlighted with the analysis of 1 mg of crude reaction mixtures of a catalytic asymmetric reaction. This operationally simple assay uses a robust mix-and-measure protocol, is amenable to microscale platforms and automation, and provides critical time efficiency and sustainability advantages over traditional serial methods. PMID- 26933685 TI - Engineering two-photon high-dimensional states through quantum interference. AB - Many protocols in quantum science, for example, linear optical quantum computing, require access to large-scale entangled quantum states. Such systems can be realized through many-particle qubits, but this approach often suffers from scalability problems. An alternative strategy is to consider a lesser number of particles that exist in high-dimensional states. The spatial modes of light are one such candidate that provides access to high-dimensional quantum states, and thus they increase the storage and processing potential of quantum information systems. We demonstrate the controlled engineering of two-photon high-dimensional states entangled in their orbital angular momentum through Hong-Ou-Mandel interference. We prepare a large range of high-dimensional entangled states and implement precise quantum state filtering. We characterize the full quantum state before and after the filter, and are thus able to determine that only the antisymmetric component of the initial state remains. This work paves the way for high-dimensional processing and communication of multiphoton quantum states, for example, in teleportation beyond qubits. PMID- 26933686 TI - Ultra-broadband light trapping using nanotextured decoupled graphene multilayers. AB - The ability to engineer a thin two-dimensional surface for light trapping across an ultra-broad spectral range is central for an increasing number of applications including energy, optoelectronics, and spectroscopy. Although broadband light trapping has been obtained in tall structures of carbon nanotubes with millimeter tall dimensions, obtaining such broadband light-trapping behavior from nanometer scale absorbers remains elusive. We report a method for trapping the optical field coincident with few-layer decoupled graphene using field localization within a disordered distribution of subwavelength-sized nanotexturing metal particles. We show that the combination of the broadband light-coupling effect from the disordered nanotexture combined with the natural thinness and remarkably high and wavelength-independent absorption of graphene results in an ultrathin (15 nm thin) yet ultra-broadband blackbody absorber, featuring 99% absorption spanning from the mid-infrared to the ultraviolet. We demonstrate the utility of our approach to produce the blackbody absorber on delicate opto microelectromechanical infrared emitters, using a low-temperature, noncontact fabrication method, which is also large-area compatible. This development may pave a way to new fabrication methodologies for optical devices requiring light management at the nanoscale. PMID- 26933688 TI - Resolving thermoelectric "paradox" in superconductors. AB - For almost a century, thermoelectricity in superconductors has been one of the most intriguing topics in physics. During its early stages in the 1920s, the mere existence of thermoelectric effects in superconductors was questioned. In 1944, it was demonstrated that the effects may occur in inhomogeneous superconductors. Theoretical breakthrough followed in the 1970s, when the generation of a measurable thermoelectric magnetic flux in superconducting loops was predicted; however, a major crisis developed when experiments showed puzzling discrepancies with the theory. Moreover, different experiments were inconsistent with each other. This led to a stalemate in bringing theory and experiment into agreement. With this work, we resolve this stalemate, thus solving this long-standing "paradox," and open prospects for exploration of novel thermoelectric phenomena predicted recently. PMID- 26933687 TI - An anticancer drug suppresses the primary nucleation reaction that initiates the production of the toxic Abeta42 aggregates linked with Alzheimer's disease. AB - The conversion of the beta-amyloid (Abeta) peptide into pathogenic aggregates is linked to the onset and progression of Alzheimer's disease. Although this observation has prompted an extensive search for therapeutic agents to modulate the concentration of Abeta or inhibit its aggregation, all clinical trials with these objectives have so far failed, at least in part because of a lack of understanding of the molecular mechanisms underlying the process of aggregation and its inhibition. To address this problem, we describe a chemical kinetics approach for rational drug discovery, in which the effects of small molecules on the rates of specific microscopic steps in the self-assembly of Abeta42, the most aggregation-prone variant of Abeta, are analyzed quantitatively. By applying this approach, we report that bexarotene, an anticancer drug approved by the U.S. Food and Drug Administration, selectively targets the primary nucleation step in Abeta42 aggregation, delays the formation of toxic species in neuroblastoma cells, and completely suppresses Abeta42 deposition and its consequences in a Caenorhabditis elegans model of Abeta42-mediated toxicity. These results suggest that the prevention of the primary nucleation of Abeta42 by compounds such as bexarotene could potentially reduce the risk of onset of Alzheimer's disease and, more generally, that our strategy provides a general framework for the rational identification of a range of candidate drugs directed against neurodegenerative disorders. PMID- 26933690 TI - Direct observation of Sigma7 domain boundary core structure in magnetic skyrmion lattice. AB - Skyrmions are topologically protected nanoscale magnetic spin entities in helical magnets. They behave like particles and tend to form hexagonal close-packed lattices, like atoms, as their stable structure. Domain boundaries in skyrmion lattices are considered to be important as they affect the dynamic properties of magnetic skyrmions. However, little is known about the fine structure of such skyrmion domain boundaries. We use differential phase contrast scanning transmission electron microscopy to directly visualize skyrmion domain boundaries in FeGe1-x Si x induced by the influence of an "edge" of a crystal grain. Similar to hexagonal close-packed atomic lattices, we find the formation of skyrmion "Sigma7" domain boundary, whose orientation relationship is predicted by the coincidence site lattice theory to be geometrically stable. On the contrary, the skyrmion domain boundary core structure shows a very different structure relaxation mode. Individual skyrmions can flexibly change their size and shape to accommodate local coordination changes and free volumes formed at the domain boundary cores. Although atomic rearrangement is a common structural relaxation mode in crystalline grain boundaries, skyrmions show very unique and thus different responses to such local lattice disorders. PMID- 26933689 TI - Ion transport in complex layered graphene-based membranes with tuneable interlayer spacing. AB - Investigation of the transport properties of ions confined in nanoporous carbon is generally difficult because of the stochastic nature and distribution of multiscale complex and imperfect pore structures within the bulk material. We demonstrate a combined approach of experiment and simulation to describe the structure of complex layered graphene-based membranes, which allows their use as a unique porous platform to gain unprecedented insights into nanoconfined transport phenomena across the entire sub-10-nm scales. By correlation of experimental results with simulation of concentration-driven ion diffusion through the cascading layered graphene structure with sub-10-nm tuneable interlayer spacing, we are able to construct a robust, representative structural model that allows the establishment of a quantitative relationship among the nanoconfined ion transport properties in relation to the complex nanoporous structure of the layered membrane. This correlation reveals the remarkable effect of the structural imperfections of the membranes on ion transport and particularly the scaling behaviors of both diffusive and electrokinetic ion transport in graphene-based cascading nanochannels as a function of channel size from 10 nm down to subnanometer. Our analysis shows that the range of ion transport effects previously observed in simple one-dimensional nanofluidic systems will translate themselves into bulk, complex nanoslit porous systems in a very different manner, and the complex cascading porous circuities can enable new transport phenomena that are unattainable in simple fluidic systems. PMID- 26933691 TI - Long-range coupling of electron-hole pairs in spatially separated organic donor acceptor layers. AB - Understanding exciton behavior in organic semiconductor molecules is crucial for the development of organic semiconductor-based excitonic devices such as organic light-emitting diodes and organic solar cells, and the tightly bound electron hole pair forming an exciton is normally assumed to be localized on an organic semiconducting molecule. We report the observation of long-range coupling of electron-hole pairs in spatially separated electron-donating and electron accepting molecules across a 10-nanometers-thick spacer layer. We found that the exciton energy can be tuned over 100 megaelectron volts and the fraction of delayed fluorescence can be increased by adjusting the spacer-layer thickness. Furthermore, increasing the spacer-layer thickness produced an organic light emitting diode with an electroluminescence efficiency nearly eight times higher than that of a device without a spacer layer. Our results demonstrate the first example of a long-range coupled charge-transfer state between electron-donating and electron-accepting molecules in a working device. PMID- 26933694 TI - Study of the biochemical effects induced by X-ray irradiations in combination with gadolinium nanoparticles in F98 glioma cells: first FTIR studies at the Emira laboratory of the SESAME synchrotron. AB - One strategy to improve the clinical outcome of radiotherapy is to use nanoparticles as radiosensitizers. Along this line, numerous studies have shown the enhanced effectiveness of tumour cell killing when nanoparticles are exposed to irradiation. However, the mechanisms of action are not clear yet. In addition to the damage due to a possible local radiation dose enhancement, the interaction of nanoparticles with essential biological macromolecules could lead to changes in the cells, such as cell arrest at radiosensitive phases. Within this framework, vibrational spectroscopy was used to investigate the biochemical changes in F98 glioma cells induced by X-ray irradiations combined with gadolinium nanoparticles. Fourier transform infrared (FTIR) microspectroscopy experiments were performed at the Emira laboratory of the SESAME synchrotron (Jordan), allowing the characterisation of spectral signatures of nanoparticle induced effects in glioma cells. Multivariate analysis of the spectra recorded using principal component analysis reveals clear differences in the DNA, protein and lipid regions in the presence of nanoparticles. Prior to irradiation, results show that nanoparticles induce biochemical modifications in the cells, probably due to changes in the cellular function. Biochemical alterations are amplified in the presence of radiation. In particular, variations in the intensity and in the position of the PO2(-) symmetric and asymmetric modes are observed due to radiation damage to the DNA, which is increased in nanoparticle-treated cells. At 24 hours post-irradiation, biochemical changes related to the hallmark characteristics of cell death are detected. This includes a shift towards low wavenumbers in the amide I and II bands, relative amplitude changes in the CH2 and CH3 stretching modes, along with DNA chromatin condensation indications. Results were confirmed by two complementary cell viability assays. PMID- 26933693 TI - Bidirectional radial Ca(2+) activity regulates neurogenesis and migration during early cortical column formation. AB - Cortical columns are basic cellular and functional units of the cerebral cortex that are malformed in many brain disorders, but how they initially develop is not well understood. Using an optogenetic sensor in the mouse embryonic forebrain, we demonstrate that Ca(2+) fluxes propagate bidirectionally within the elongated fibers of radial glial cells (RGCs), providing a novel communication mechanism linking the proliferative and postmitotic zones before the onset of synaptogenesis. Our results indicate that Ca(2+) activity along RGC fibers provides feedback information along the radial migratory pathway, influencing neurogenesis and migration during early column development. Furthermore, we find that this columnar Ca(2+) propagation is induced by Notch and fibroblast growth factor activities classically implicated in cortical expansion and patterning. Thus, cortical morphogens and growth factors may influence cortical column assembly in part by regulating long-distance Ca(2+) communication along the radial axis of cortical development. PMID- 26933692 TI - Acoustic metamaterials: From local resonances to broad horizons. AB - Within a time span of 15 years, acoustic metamaterials have emerged from academic curiosity to become an active field driven by scientific discoveries and diverse application potentials. This review traces the development of acoustic metamaterials from the initial findings of mass density and bulk modulus frequency dispersions in locally resonant structures to the diverse functionalities afforded by the perspective of negative constitutive parameter values, and their implications for acoustic wave behaviors. We survey the more recent developments, which include compact phase manipulation structures, superabsorption, and actively controllable metamaterials as well as the new directions on acoustic wave transport in moving fluid, elastic, and mechanical metamaterials, graphene-inspired metamaterials, and structures whose characteristics are best delineated by non-Hermitian Hamiltonians. Many of the novel acoustic metamaterial structures have transcended the original definition of metamaterials as arising from the collective manifestations of constituent resonating units, but they continue to extend wave manipulation functionalities beyond those found in nature. PMID- 26933695 TI - Structural anisotropy of cyanido-bridged {CoII9WV6} single-molecule magnets induced by bidentate ligands: towards the rational enhancement of an energy barrier. AB - Pentadecanuclear {CII9[W(V)(CN)8]6} clusters were combined with bidentate 2,2' bipyridine N,N'-dioxide (2,2'-bpdo) ligands resulting in two distinct molecules, {Co9W6(2,2'-bpdo)7} (cluster A) and {Co9W6(2,2'-bpdo)6} (cluster B), capped by seven and six 2,2'-bpdo ligands, respectively. They crystallize within a single {Co9W6(2,2'-bpdo)7}.{Co9W6(2,2'-bpdo)6}.solvent (1) supramolecular network, and reveal single-molecule magnet behaviour with an enhanced energy barrier, a DeltaE/kB of 30.0(8) K, which was tentatively ascribed to seven-capped axially deformed cluster A. PMID- 26933697 TI - Preface. Regulatory signal networks of the B cell antigen receptor. PMID- 26933696 TI - Aryl-triazole foldamers incorporating a pyridinium motif for halide anion binding in aqueous media. AB - Aryl-triazole oligomers incorporating a pyridinium motif have been synthesized from their pyridine precursors. Anion binding studies show that methylation of the pyridine units can significantly enhance the halide anion affinities of the folded oligomers so that the foldamers are capable of binding halide anions in aqueous solutions. PMID- 26933698 TI - Status, challenges, goals. PMID- 26933699 TI - Preface. PMID- 26933701 TI - Author's response. PMID- 26933700 TI - Foreword. PMID- 26933702 TI - Long-awaited autonomy in sight for SA's doctors. PMID- 26933703 TI - High-risk specialties threatened by runaway legal costs. PMID- 26933704 TI - Basson's private ECG tutoring sets pulses racing. PMID- 26933705 TI - Cardiovascular medicine in primary healthcare in sub-Saharan Africa: minimum standards for practice (part 1). PMID- 26933706 TI - Heart failure in sub-Saharan Africa: A clinical approach. AB - Despite medical advances, heart failure (HF) remains a global health problem and sub-Saharan Africa (SSA) is no exception, with decompensated HF being the most common primary diagnosis for patients admitted to hospital with heart disease. In SSA the in-hospital mortality rate of decompensated HF is up to 8.3%. HF is a clinical syndrome that is caused by a diverse group of aetiologies, each requiring unique management strategies, highlighting the need for diagnostic certainty and a broad understanding of the complex pathophysiology of this condition. While there are a number of advanced medical, device and surgical interventions being tailored for HF internationally, the fundamental basic principles of HF management, such as patient education, effective management of congestion and initiation of disease-modifying medical therapies, remain a challenge on our continent. This review addresses both the epidemiology of HF in SSA and principles of management that focus specifically on symptom relief, prevention of hospitalisation and improving survival in this population. PMID- 26933707 TI - Dyspnoea: Pathophysiology and a clinical approach. AB - Dyspnoea, also known as shortness of breath or breathlessness, is a subjective awareness of the sensation of uncomfortable breathing. It may be of physiological, pathological or social origin. The pathophysiology of dyspnoea is complex, and involves the activation of several pathways that lead to increased work of breathing, stimulation of the receptors of the upper or lower airway, lung parenchyma, or chest wall, and excessive stimulation of the respiratory centre by central and peripheral chemoreceptors. Activation of these pathways is relayed to the central nervous system via respiratory muscle and vagal afferents, which are consequently interpreted by the individual in the context of the affective state, attention, and prior experience, resulting in the awareness of breathing. The clinical evaluation and approach to the management of dyspnoea are directed by the clinical presentation and underlying cause. The causes of dyspnoea are manifold, and include a spectrum of disorders, from benign to serious and life-threatening entities. The pathophysiology, aetiology, clinical presentation and management of dyspnoea are reviewed. PMID- 26933708 TI - An approach to the young hypertensive patient. AB - Hypertension is the leading cause of death worldwide. Globally and locally there has been an increase in hypertension in children, adolescents and young adults<40 years of age. In South Africa, the first decade of the millennium saw a doubling of the prevalence rate among adolescents and young adults aged 15-24 years. This increase suggests that an explosion of cerebrovascular disease, cardiovascular disease and chronic kidney disease can be expected in the forthcoming decades. A large part of the increased prevalence can be attributed to lifestyle factors such as diet and physical inactivity, which lead to overweight and obesity. The majority (>90%) of young patients will have essential or primary hypertension, while only a minority (<10%) will have secondary hypertension. We do not recommend an extensive workup for all newly diagnosed young hypertensives, as has been the practice in the past. We propose a rational approach that comprises a history to identify risk factors, an examination that establishes the presence of target-organ damage and identifies clues suggesting secondary hypertension, and a limited set of basic investigations. More specialised tests should be performed only where there is a clinical suspicion that a secondary cause for hypertension exists. There have been no randomised clinical trials on the treatment of hypertension in young patients. Expert opinion advises an initial emphasis on lifestyle modification. This can comprise a diet with reduced salt and refined carbohydrate intake, an exercise programme and management of substance abuse issues. Failure of lifestyle measures or the presence of target-organ damage should prompt the clinician to initiate pharmacotherapy. We recommend referral to a specialist practitioner in cases of resistant hypertension, where there is severe target-organ damage and when a secondary cause is suspected. PMID- 26933709 TI - An approach to the diagnosis and management of valvular heart disease. AB - Valvular heart disease poses a common yet difficult problem in everyday clinical practice. A thorough clinical evaluation with basic common investigations such as an electrocardiogram (ECG) and a chest radiograph (CXR) remains the cornerstone of diagnosis. Echocardiography and more invasive testing, if needed, are usually performed at specialist level to confirm the diagnosis, assess severity and assist in definitive decision-making.The causes and clinical, ECG and CXR features of the common valve lesions are described. Patients with symptomatic valve lesions should be referred for specialist assessment. In most cases, medical therapy serves as a bridge to definitive mechanical or surgical therapy. PMID- 26933710 TI - [Frank Bernard Cockett (1917-2014)]. PMID- 26933711 TI - Trans-Atlantic Debate: Are Branched/Fenestrated EVAR Procedures Better than Snorkels, Chimneys, or Periscopes in the Treatment of Most Thoracoabdominal and Juxtarenal Aneurysms? PMID- 26933712 TI - A matter of context--time to clinically validate 9-month infant HIV testing in South Africa? PMID- 26933713 TI - A matter of context--time to clinically validate 9-month infant HIV testing in South Africa? PMID- 26933714 TI - Rural district hospitals: ambulance services, staff attitudes, and other impediments to healthcare delivery. PMID- 26933715 TI - Gonadal pathology in a girl with 45,X/46,XY mosaicism. PMID- 26933716 TI - SAMA president, medicopolitical veteran, psychiatrist and treatment pioneer. PMID- 26933717 TI - Attacking 'prejudice' against generics could save SA billions. PMID- 26933718 TI - Musculoskeletal disorders--disease burden and challenges in the developing world. PMID- 26933719 TI - Lupus nephritis: An approach to diagnosis and treatment in South Africa. AB - Lupus nephritis (LN) is a significant cause of morbidity and mortality in patients with systemic lupus erythematosus. Delayed recognition and diagnosis of LN may be a common cause of chronic kidney disease among South Africans. Renal biopsy is the gold standard of diagnosing LN; however, this service is not available in many centres and the use of urinalysis, urine microscopic examination and other serological tests can be useful in identifying patients with proliferative LN. Proliferative types of LN (class III, class IV and mixed class V)comprise the larger proportion of patients with this condition. Patients receiving immunosuppressive therapy need to be monitored closely for side-effects and drug-related toxicities. LN patients with end-stage renal disease (class VI) need to be prepared for renal replacement therapy (dialysis and renal transplantation). In all patients, treatment should include adjunctive therapies such as renin angiotensin aldosterone system blockade, bone protection (with calcium supplements and vitamin D), blood pressure control and chloroquine-all of which help to retard the progression of kidney disease. PMID- 26933720 TI - Evidence-based treatment of systemic lupus erythematosus and its complications. AB - Outcomes for patients with systemic lupus erythematosus (SLE) have improved during the last two decades as our understanding of the disease expands. In particular, the importance of antimalarial therapy for addressing and preventing a host of complications in SLE has emerged. Furthermore, evidence is mounting that corticosteroids, while offering excellent control of disease activity, are responsible for many of the late complications of SLE and need to be prescribed in modest doses for the shortest time possible. To achieve this, an understanding of the available 'steroid-sparing' immunosuppressants is useful. Specific attention needs to be paid to the two most important complications of SLE, i.e. infections and atherosclerotic cardiovascular events. Awareness of, screening for and aggressive management of risk factors for these comorbidities are paramount. PMID- 26933721 TI - A clinical update on paediatric lupus. AB - Systemic lupus erythematosus in children is a life-threatening chronic disease that is being increasingly recognised. More black African children are being diagnosed and the proportion of males affected is much higher than in adult-onset lupus. The presenting manifestations of childhood-onset lupus are variable and many systems are involved. Children with lupus often present late with severe disease, and in South African (SA) children severe lupus nephritis occurs commonly at presentation. The investigations for lupus should be performed in a three-step process - initial essential investigations, antibody and serological tests, and supplementary investigations. The most important factor in the management is to involve a multidisciplinary team as soon as possible. All cases of lupus in SA should be discussed with a paediatric specialist so that a tailored management plan can be made, depending on the presenting features and course of the disease. PMID- 26933722 TI - Infections in the management of rheumatic diseases: An update. AB - Patients with inflammatory rheumatic conditions have an increased risk of infection. While this could be the result of the underlying disease, it may also be caused by the use of immunosuppressive therapies, which are needed to treat these disorders. An increasing number of patients with rheumatoid arthritis or other rheumatic diseases are using biologic therapies (biologics) in addition to the synthetic disease-modifying anti-rheumatic drugs. The side-effects and complications of these relatively new agents are unknown to many specialists (outside of rheumatology) and general practitioners. This article highlights updates on the most important infections encountered in the daily management of patients with rheumatic diseases and discusses how these may be prevented. PMID- 26933723 TI - Meeting the challenges in the diagnosis of inflammatory myopathies. AB - Inflammatory myopathy (IM) is a rubric term to describe a heterogeneous group of muscle diseases typified by dermatomyositis and polymyositis. The current classifications are unsatisfactory, but IM associated with other connective tissue diseases (CTDs), such as systemic lupus erythematosus, underlying malignancy and HIV, should also be included. Although uncommon, IM should always be considered in a patient who presents with proximal weakness of gradual onset and has raised serum muscle enzymes. The diagnosis may be obvious if the patient has diagnostic skin signs such as heliotropic rash (peri-orbital discoloration) and Gottron's lesions (typically on the extensor surfaces of the fingers). In the absence of obvious skin manifestations, other features of a CTD such as Raynaud's phenomenon, abnormal capilloroscopy and the presence of serum antinuclear factor antibody should be searched for. Conditions that mimic IM include other causes of myopathy such as endocrine disorders, adverse effects of medication, metabolic myopathies and muscle dystrophies. Atypical features suggesting an alternative diagnosis are acute onset, severe pain, asymmetrical involvement, distal weakness and wasting. Appropriate investigations include a chest radiograph indicating interstitial lung disease or malignancy. Electromyography and muscle biopsy are useful in cases where other diagnoses are suspected. PMID- 26933724 TI - Juvenile idiopathic arthritis-an update on its diagnosis and management. AB - Juvenile idiopathic arthritis (JIA) is the most common form of chronic arthritis in children and the most common cause of musculoskeletal disability in children. Early diagnosis may be challenging, but it is essential to ensure good outcomes. This review proposes an approach to the investigation and diagnosis of JIA. It also gives a summary of the latest available evidence-based treatment for this disease. PMID- 26933725 TI - Approach to lower back pain. AB - Lower back pain is one of the most common symptoms-and the most common musculoskeletal problem-seen by general practitioners. Iti s also a common cause of disability and an expensive condition in terms of economic impact because of absenteeism. This article discusses an approach to this common symptom and how to distinguish the benign, mechanical type of back pain from the more sinister, but less frequently encountered, inflammatory back pain. PMID- 26933726 TI - Gout and hyperuricaemia. AB - Gout is the most common crystal arthritis and its prevalence is rising. It is associated with the metabolic syndrome, and hyperuricaemia may be an independent risk factor for cardiovascular disease. The acute presentation of gout is easily managed, but the underlying cause is seldom addressed.Indications for initiating uric acid therapy have been clearly established. The classification criteria for gout have been reviewed and are presented here.Lifestyle modification is key to the management of gout. The clinician must screen for diabetes, hypertension and hypercholesterolaemia when the diagnosis of gout is made. The management of asymptomatic hyperuricaemia is still being researched. As yet, there is no indication to start urate-lowering therapy in such patients. Allopurinol remains the first line of treatment, but there are newer drugs being researched in various clinical trials. Probenecid is the alternative in patients with preserved renal function, who do not have a history of renal calculi. PMID- 26933727 TI - Trans-Atlantic Debate: Are Branched/Fenestrated EVAR Procedures Better than Snorkels, Chinmneys, or Periscopes in the Treatment of Most Thoracoabdominal and Juxtarenal Aneurysms? PMID- 26933728 TI - A Tribute to Dr. Hattie M. Bessent, EdD, MSN, RN, FAAN. PMID- 26933729 TI - [Establishment of malaria early warning system in Jiangsu Province VI Regular surveillance of eliminating malaria and its effect]. AB - OBJECTIVE: To analyze the regular surveillance and evaluate its effect during the elimination stage of malaria in Jiangsu Province from 2012 to 2014 and discuss the best way for surveillance and management, so as to provide the evidence for formulating and adjusting the strategy and methods for malaria elimination. METHOD: The data of network malaria reports, blood tests of feverish patients, epidemiology investigation forms of case study of malaria patients in the report system, and investigation and disposition forms of epidemic regions were collected and analyzed statistically. RESULTS: From 2012 to 2014, there were 894 malaria cases in total. Totally 1 625 034 feverish patients had blood tests, and 892 of them showed positive and the positive rate was 0.05%. The epidemiological case study showed that all the patients were foreign infection import patients except one was foreign import cases by blood transfusion. These cases were mainly distributed in Nantong City (125 cases), Yangzhou City (123 cases), Huai'an City (112 cases), Lianyungang City (111 cases) and Taizhou City (88 cases), and the total cases of the five cities accounted for 62.53% (559/894) of total cases of entire province. These cases were mainly diagnosed in country level CDC and medical organizations, and city level medical organizations. These units accounted for 87.02% of all the diagnostic organizations (778/894). CONCLUSIONS: From 2012 to 2014, there are no reports of local malaria infection cases in Jiangsu Province, meaning the preliminary realization of eliminating malaria. However, we still should strengthen the regular surveillance and treatment of import malaria cases. PMID- 26933730 TI - Cell Chemical Biology: Home of Exciting Chemical Biology. PMID- 26933731 TI - The Power of Sophisticated Phenotypic Screening and Modern Mechanism-of-Action Methods. AB - The enthusiasm for phenotypic screening as an approach for small-molecule discovery has increased dramatically over the last several years. The recent increase in phenotype-based discoveries is in part due to advancements in phenotypic readouts in improved disease models that recapitulate clinically relevant biology in cell culture. Of course, a major historical barrier to using phenotypic assays in chemical biology has been the challenge in determining the mechanism of action (MoA) for compounds of interest. With the combination of medically inspired phenotypic screening and the development of modern MoA methods, we can now start implementing this approach in chemical probe and drug discovery. In this Perspective, we highlight recent advances in phenotypic readouts and MoA determination by discussing several case studies in which both activities were required for understanding the chemical biology involved and, in some cases, advancing toward clinical development. PMID- 26933732 TI - The Impact of Chemical Probes in Drug Discovery: A Pharmaceutical Industry Perspective. AB - Chemical probes represent an important component of both academic and pharmaceutical drug discovery research. As a complement to prior reviews that have defined this scientific field, we aim to provide an industry perspective on the value of having high-quality chemical probes throughout the course of preclinical research. By studying examples from the internal Merck pipeline, we recognize that these probes require significant collaborative investment to realize their potential impact in clarifying the tractability and translation of a given therapeutic target. This perspective concludes with recommendations for chemical probe discovery aimed toward maximizing their potential to identify targets that result in the successful delivery of novel therapeutics. PMID- 26933733 TI - Exploring and Understanding the Biochemical Diversity of the Human Microbiota. AB - Recent studies have illuminated a remarkable diversity and abundance of microbes living on and within the human body. While we are beginning to appreciate associations of certain bacteria and genes with particular host physiological states, considerable information is lacking about the relevant functional activities of the human microbiota. The human gut microbiome encodes tremendous potential for the biosynthesis and transformation of compounds that are important for both microbial and host physiology. Implementation of chemical knowledge and techniques will be required to improve our understanding of the biochemical diversity of the human microbiota. Such efforts include the characterization of novel microbial enzymes and pathways, isolation of microbial natural products, and development of tools to modulate biochemical functions of the gut microbiota. Ultimately, a molecular understanding of gut microbial activities will be critical for elucidating and manipulating these organisms' contributions to human health and disease. PMID- 26933735 TI - Engineered Protein Machines: Emergent Tools for Synthetic Biology. AB - Nature has evolved an array of intricate protein assemblies that work together to perform the chemistry that maintains life. These protein machines function with exquisite specificity and coordination to accomplish their tasks, from DNA and RNA synthesis to protein folding and post-translational modifications. Despite their complexity, synthetic biologists have succeeded in redesigning many aspects of these molecular machines. For example, natural DNA polymerases have now been engineered to catalyze the synthesis of alternative genetic polymers called XNAs, orthogonal RNA polymerases and ribosomes have been engineered to enable the construction of genetic logic gates, and protein biogenesis machinery such as chaperonins and protein translocons have been repurposed to improve folding and expression of recombinant proteins. In this Review, we highlight the progress made in understanding, engineering, and repurposing bacterial protein machines for use in synthetic biology and biotechnology. PMID- 26933736 TI - Chemical Biology Approaches to Genome Editing: Understanding, Controlling, and Delivering Programmable Nucleases. AB - Programmable DNA nucleases have provided scientists with the unprecedented ability to probe, regulate, and manipulate the human genome. Zinc-finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and the clustered regularly interspaced short palindromic repeat-Cas9 system (CRISPR Cas9) represent a powerful array of tools that can bind to and cleave a specified DNA sequence. In their canonical forms, these nucleases induce double-strand breaks at a DNA locus of interest that can trigger cellular DNA repair processes that disrupt or replace genes. The fusion of these programmable nucleases with a variety of other protein domains has led to a rapidly growing suite of tools for activating, repressing, visualizing, and modifying loci of interest. Maximizing the usefulness and therapeutic relevance of these tools, however, requires precisely controlling their activity and specificity to minimize potentially toxic side effects arising from off-target activities. This need has motivated the application of chemical biology principles and methods to genome-editing proteins, including the engineering of variants of these proteins with improved or altered specificities, and the development of genetic, chemical, optical, and protein delivery methods that control the activity of these agents in cells. Advancing the capabilities, safety, effectiveness, and therapeutic relevance of genome-engineering proteins will continue to rely on chemical biology strategies that manipulate their activity, specificity, and localization. PMID- 26933734 TI - New Insights into the Biosynthetic Logic of Ribosomally Synthesized and Post translationally Modified Peptide Natural Products. AB - Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a large group of structurally diverse natural products. Their biological activities and unique biosynthetic pathways have sparked a growing interest in RiPPs. Furthermore, the relatively low genetic complexity associated with RiPP biosynthesis makes them excellent candidates for synthetic biology applications. This Review highlights recent developments in the understanding of the biosynthesis of several bacterial RiPP family members, the use of the RiPP biosynthetic machinery for generating novel macrocyclic peptides, and the implementation of tools designed to guide the discovery and characterization of novel RiPPs. PMID- 26933737 TI - Nucleic Acid Modifications in Regulation of Gene Expression. AB - Nucleic acids carry a wide range of different chemical modifications. In contrast to previous views that these modifications are static and only play fine-tuning functions, recent research advances paint a much more dynamic picture. Nucleic acids carry diverse modifications and employ these chemical marks to exert essential or critical influences in a variety of cellular processes in eukaryotic organisms. This review covers several nucleic acid modifications that play important regulatory roles in biological systems, especially in regulation of gene expression: 5-methylcytosine (5mC) and its oxidative derivatives, and N(6) methyladenine (6mA) in DNA; N(6)-methyladenosine (m(6)A), pseudouridine (Psi), and 5-methylcytidine (m(5)C) in mRNA and long non-coding RNA. Modifications in other non-coding RNAs, such as tRNA, miRNA, and snRNA, are also briefly summarized. We provide brief historical perspective of the field, and highlight recent progress in identifying diverse nucleic acid modifications and exploring their functions in different organisms. Overall, we believe that work in this field will yield additional layers of both chemical and biological complexity as we continue to uncover functional consequences of known nucleic acid modifications and discover new ones. PMID- 26933741 TI - Whole-body and Whole-Organ Clearing and Imaging Techniques with Single-Cell Resolution: Toward Organism-Level Systems Biology in Mammals. AB - Organism-level systems biology aims to identify, analyze, control and design cellular circuits in organisms. Many experimental and computational approaches have been developed over the years to allow us to conduct these studies. Some of the most powerful methods are based on using optical imaging in combination with fluorescent labeling, and for those one of the long-standing stumbling blocks has been tissue opacity. Recently, the solutions to this problem have started to emerge based on whole-body and whole-organ clearing techniques that employ innovative tissue-clearing chemistry. Here, we review these advancements and discuss how combining new clearing techniques with high-performing fluorescent proteins or small molecule tags, rapid volume imaging and efficient image informatics is resulting in comprehensive and quantitative organ-wide, single cell resolution experimental data. These technologies are starting to yield information on connectivity and dynamics in cellular circuits at unprecedented resolution, and bring us closer to system-level understanding of physiology and diseases of complex mammalian systems. PMID- 26933739 TI - Glycan Engineering for Cell and Developmental Biology. AB - Cell-surface glycans are a diverse class of macromolecules that participate in many key biological processes, including cell-cell communication, development, and disease progression. Thus, the ability to modulate the structures of glycans on cell surfaces provides a powerful means not only to understand fundamental processes but also to direct activity and elicit desired cellular responses. Here, we describe methods to sculpt glycans on cell surfaces and highlight recent successes in which artificially engineered glycans have been employed to control biological outcomes such as the immune response and stem cell fate. PMID- 26933738 TI - Chemical Methods for Encoding and Decoding of Posttranslational Modifications. AB - A large array of posttranslational modifications can dramatically change the properties of proteins and influence different aspects of their biological function such as enzymatic activity, binding interactions, and proteostasis. Despite the significant knowledge that has been gained about the function of posttranslational modifications using traditional biological techniques, the analysis of the site-specific effects of a particular modification, the identification of the full complement of modified proteins in the proteome, and the detection of new types of modifications remains challenging. Over the years, chemical methods have contributed significantly in both of these areas of research. This review highlights several posttranslational modifications where chemistry-based approaches have made significant contributions to our ability to both prepare homogeneously modified proteins and identify and characterize particular modifications in complex biological settings. As the number and chemical diversity of documented posttranslational modifications continues to rise, we believe that chemical strategies will be essential to advance the field in years to come. PMID- 26933740 TI - A Bright Future for Precision Medicine: Advances in Fluorescent Chemical Probe Design and Their Clinical Application. AB - The Precision Medicine Initiative aims to use advances in basic and clinical research to develop therapeutics that selectively target and kill cancer cells. Under the same doctrine of precision medicine, there is an equally important need to visualize these diseased cells to enable diagnosis, facilitate surgical resection, and monitor therapeutic response. Therefore, there is a great opportunity for chemists to develop chemically tractable probes that can image cancer in vivo. This review focuses on recent advances in the development of optical probes, as well as their current and future applications in the clinical management of cancer. The progress in probe development described here suggests that optical imaging is an important and rapidly developing field of study that encourages continued collaboration among chemists, biologists, and clinicians to further refine these tools for interventional surgical imaging, as well as for diagnostic and therapeutic applications. PMID- 26933743 TI - The Intersection of Structural and Chemical Biology - An Essential Synergy. AB - The continual improvement in our ability to generate high resolution structural models of biological molecules has stimulated and supported innovative chemical biology projects that target increasingly challenging ligand interaction sites. In this review we outline some of the recent developments in chemical biology and rational ligand design and show selected examples that illustrate the synergy between these research areas. PMID- 26933742 TI - Chemical Tools to Investigate Mechanisms Associated with HSP90 and HSP70 in Disease. AB - The chaperome is a large and diverse protein machinery composed of chaperone proteins and a variety of helpers, such as the co-chaperones, folding enzymes, and scaffolding and adapter proteins. Heat shock protein 90s and 70s (HSP90s and HSP70s), the most abundant chaperome members in human cells, are also the most complex. As we have learned to appreciate, their functions are context dependent and manifested through a variety of conformations that each recruit a subset of co-chaperone, scaffolding, and folding proteins and which are further diversified by the posttranslational modifications each carry, making their study through classic genetic and biochemical techniques quite a challenge. Chemical biology tools and techniques have been developed over the years to help decipher the complexities of the HSPs and this review provides an overview of such efforts with focus on HSP90 and HSP70. PMID- 26933746 TI - The development and psychometric properties of the Turkish death anxiety scale (TDAS). AB - The purpose of the present study was to develop the Turkish Death Anxiety Scale (TDAS) and test its initial psychometric properties. Four independent samples participated in the study: 943 college students in item generation, 388 college students in validation, 171 college students in reliability investigation, and 338 adults in cross-validation. Principal component analysis with a varimax rotation revealed that 20 items of the scale contained three factors (i.e., Ambiguity of Death, Exposure to Death, and Agony of Death), which explained over 67% of the total variability. Confirmatory factor analyses indicated acceptable fit. Significant correlations were found between the scale and death anxiety, state anxiety, trait anxiety, depression, and hopelessness in the student sample. In the adult sample, death anxiety significantly correlated with trait anxiety. Reliability coefficients were also found acceptable. The authors conclude that the TDAS is a promising instrument in assessing the death anxiety levels in Turkey. PMID- 26933747 TI - Development and Validation of the Short Crohn's Disease Work Disability Questionnaire. AB - BACKGROUND: The aim was to develop and validate a self-reported short Crohn's disease work disability questionnaire (sCDWDQ). METHODS: (1) Development of a shortened questionnaire-Patients' responses to the validation process (n = 108) of a previously developed, 16-item Spanish Crohn's disease work disability questionnaire (CDWDQ) were analyzed using the Rasch model for multiple response items. After this process, a 9-item sCDWDQ was obtained. (2) Validation phase-The validation assessed the questionnaire's convergent validity, discriminant validity, test-retest reproducibility, and internal consistency. Spearman rank correlation, t test, intra-class correlation and Cronbach's alpha were used for the analysis. RESULTS: One hundred fifty-one patients were included in the validation phase. (1) Convergent validity was confirmed by correlations between the sCDWDQ and clinical activity (r = 0.66, P < 0.01), the short inflammatory bowel disease questionnaire IBDQ-9 (r = 0.74, P < 0.001), Euroqol-5D (r = 0.63, P < 0.01), the EuroQol-5D visual analog scale (r = 0.54, P < 0.01), and overall work impairment (r = 0.66, P < 0.01); (2) Discriminant validity-sCDWDQ scores were higher in patients with active disease (20.1 +/- 6.3 versus 13.0 +/- 3.8 inactive, P < 0.001), in those requiring previous sick leave (19.6 +/- 6.9 versus no sick leave 14.2 +/- 4.8, P < 0.01) and in those requiring hospitalization (20.0 +/- 7.3 [n = 29] versus no hospitalization 14.1 +/- 7.3 [n = 90], P < 0.01); (3) Internal consistency was also good (Cronbach's alpha = 0.92); and (4) Reproducibility-sCDWDQ measures obtained 2 weeks apart showed an excellent intraclass correlation coefficient of 0.92 (95% confidence interval, 0.90-0.94). CONCLUSIONS: The self-reported sCDWDQ appears to be a simple, valid, and reliable tool for measuring work disability in Crohn's disease. PMID- 26933748 TI - Rates and Reasons for Nonuse of Prescription Medication for Inflammatory Bowel Disease in a Referral Clinic. AB - BACKGROUND: We aimed to determine the rates and reasons for nonuse of inflammatory bowel disease (IBD)-specific medication in a referral clinic. METHODS: Consecutive persons with Crohn's disease (CD) (n = 423) and ulcerative colitis (UC) (n = 342) were followed in a single clinic over 2 years. At each patient visit, it was determined whether and what type of IBD-specific medications were used at that visit. If medications were not used, the reason for nonuse was recorded. Disease remission, further stratified by "clinical remission" and "deep remission" (clinical remission plus imaging evidence of remission), was considered a reason for nonuse if the attending physician believed the person was in remission and agreed for them to be off medications. RESULTS: Nonuse of IBD-specific medication was seen in 121 persons with CD (29%) and 65 persons with UC (18%). In CD, increased age and disease duration were associated with nonuse; disease phenotype did not predict nonuse. In UC, disease duration was associated with nonuse but age was not. In CD, the most common reason for medication nonuse was deep remission (22.5%), followed by clinical remission (21.4%), not having seen a gastroenterologist for a lengthy period (21.4%) and nonadherence (16%). In UC, nonuse was attributed to deep remission (27.7%), followed by nonadherence (26.3%) and clinical remission (23%). CONCLUSIONS: Approximately a quarter of persons with IBD attending at a tertiary care practice do not use IBD-specific medications with a higher rate in CD than UC. The decision not to use medications was deemed appropriate in approximately one-half of all nonusers. PMID- 26933744 TI - DNA Charge Transport: from Chemical Principles to the Cell. AB - The DNA double helix has captured the imagination of many, bringing it to the forefront of biological research. DNA has unique features that extend our interest into areas of chemistry, physics, material science, and engineering. Our laboratory has focused on studies of DNA charge transport (CT), wherein charges can efficiently travel long molecular distances through the DNA helix while maintaining an exquisite sensitivity to base pair pi-stacking. Because DNA CT chemistry reports on the integrity of the DNA duplex, this property may be exploited to develop electrochemical devices to detect DNA lesions and DNA binding proteins. Furthermore, studies now indicate that DNA CT may also be used in the cell by, for example, DNA repair proteins, as a cellular diagnostic, in order to scan the genome to localize efficiently to damage sites. In this review, we describe this evolution of DNA CT chemistry from the discovery of fundamental chemical principles to applications in diagnostic strategies and possible roles in biology. PMID- 26933749 TI - Biosimilars in Crohn's Disease and Ulcerative Colitis. PMID- 26933751 TI - Comparative Effectiveness of Infliximab and Adalimumab in Crohn's Disease and Ulcerative Colitis. AB - BACKGROUND: The availability of monoclonal antibodies to tumor necrosis factor alpha has revolutionized management of Crohn's disease (CD) and ulcerative colitis. However, limited data exist regarding comparative effectiveness of these agents to inform clinical practice. METHODS: This study consisted of patients with CD or ulcerative colitis initiation either infliximab (IFX) or adalimumab (ADA) between 1998 and 2010. A validated likelihood of nonresponse classification score using frequency of narrative mentions of relevant symptoms in the electronic health record was applied to assess comparative effectiveness at 1 year. Inflammatory bowel disease-related surgery, hospitalization, and use of steroids were determined during this period. RESULTS: Our final cohort included 1060 new initiations of IFX (68% for CD) and 391 of ADA (79% for CD). In CD, the likelihood of nonresponse was higher in ADA than IFX (odds ratio, 1.62 and 95% CI, 1.21-2.17). Similar differences favoring efficacy of IFX were observed for the individual symptoms of diarrhea, pain, bleeding, and fatigue. However, there was no difference in inflammatory bowel disease-related surgery, hospitalizations, or prednisone use within 1 year after initiation of IFX or ADA in CD. There was no difference in narrative or codified outcomes between the 2 agents in ulcerative colitis. CONCLUSIONS: We identified a modestly higher likelihood of symptomatic nonresponse at 1 year for ADA compared with IFX in patients with CD. However, there were no differences in inflammatory bowel disease-related surgery or hospitalizations, suggesting these treatments are broadly comparable in effectiveness in routine clinical practice. PMID- 26933750 TI - Incidence, Clinical Characteristics, and Management of Psoriasis Induced by Anti TNF Therapy in Patients with Inflammatory Bowel Disease: A Nationwide Cohort Study. AB - BACKGROUND: Psoriasis induced by anti-tumor necrosis factor-alpha (TNF) therapy has been described as a paradoxical side effect. AIM: To determine the incidence, clinical characteristics, and management of psoriasis induced by anti-TNF therapy in a large nationwide cohort of inflammatory bowel disease patients. METHODS: Patients with inflammatory bowel disease were identified from the Spanish prospectively maintained Estudio Nacional en Enfermedad Inflamatoria Intestinal sobre Determinantes geneticos y Ambientales registry of Grupo Espanol de Trabajo en Enfermedad de Croh y Colitis Ulcerosa. Patients who developed psoriasis by anti-TNF drugs were the cases, whereas patients treated with anti-TNFs without psoriasis were controls. Cox regression analysis was performed to identify predictive factors. RESULTS: Anti-TNF-induced psoriasis was reported in 125 of 7415 patients treated with anti-TNFs (1.7%; 95% CI, 1.4-2). The incidence rate of psoriasis is 0.5% (95% CI, 0.4-0.6) per patient-year. In the multivariate analysis, the female sex (HR 1.9; 95% CI, 1.3-2.9) and being a smoker/former smoker (HR 2.1; 95% CI, 1.4-3.3) were associated with an increased risk of psoriasis. The age at start of anti-TNF therapy, type of inflammatory bowel disease, Montreal Classification, and first anti-TNF drug used were not associated with the risk of psoriasis. Topical steroids were the most frequent treatment (70%), achieving clinical response in 78% of patients. Patients switching to another anti-TNF agent resulted in 60% presenting recurrence of psoriasis. In 45 patients (37%), the anti-TNF therapy had to be definitely withdrawn. CONCLUSIONS: The incidence rate of psoriasis induced by anti-TNF therapy is higher in women and in smokers/former smokers. In most patients, skin lesions were controlled with topical steroids. More than half of patients switching to another anti-TNF agent had recurrence of psoriasis. In most patients, the anti-TNF therapy could be maintained. PMID- 26933752 TI - Epidemiology and Long-term Outcome of Inflammatory Bowel Disease Diagnosed at Elderly Age-An Increasing Distinct Entity? AB - BACKGROUND: Elderly onset (EO) inflammatory bowel disease (IBD) may become a more common entity as a result of population aging and the rising IBD incidence. Its management is challenging, because of multimorbidity, polypharmacy, and frailty. Insight into the long-term outcome is essential for optimal patient counseling and treatment. We studied the incidence and disease outcome of elderly-onset IBD in direct comparison to adult-onset (AO) IBD. METHODS: All 2823 cases with IBD from the Dutch population-based IBD South Limburg cohort, diagnosed between 1991 and 2011, were included. Long-term outcome (hospitalization, surgery, and disease phenotype) was compared between AO (<60 years at diagnosis) and EO (>=60 years at diagnosis) disease, for Crohn's disease (CD) and ulcerative colitis (UC) separately. RESULTS: In total, 1162 patients with CD (136 EO/1026 AO) and 1661 patients with UC (373 EO/1288 AO) were included. The EO IBD incidence increased from 11.71 per 100,000 persons in 1991 to 23.66 per 100,000 persons in 2010, P < 0.01. Immunomodulators were less often used in EO CD (61.8% versus 77.1%, P = 0.03) and EO UC (22.8% versus 35.4%, P < 0.01), even as biologicals (25.1% versus 55.1%, P = 0.03 and 7.8% versus 18.0%, P < 0.01, respectively). No differences were observed in surgery risk (CD: hazard ratio [HR] 1.19; 95% confidence interval [CI], 0.85-1.67 and UC: HR, 0.88; 95% CI, 0.53-1.46), or in CD phenotype progression (HR, 0.81; 95% CI, 0.52-1.25), but more patients with EO UC required hospitalization (HR, 1.29; 95% CI, 1.01-1.63). CONCLUSIONS: EO IBD is rising, warranting physicians' alertness for IBD in elderly patients. The long-term outcome was not different from AO disease, despite a less frequent use of immunomodulators and biologicals. PMID- 26933754 TI - Disentangling recoding processes and evaluative associations in a gender attitude implicit association test among adult males. AB - The course of male development of implicit gender attitudes between young age (N = 30, age 17-26 years) and old age (N = 34, age 56-78 years) was investigated. The findings demonstrated that younger males had a stronger implicit preference for females relative to males than did older participants, shedding light on the nature of age differences in gender attitudes in regard to implicit measures. Although younger and older participants demonstrated different levels of gender bias on an implicit association test (IAT), the application of the ReAL model [Meissner, F., & Rothermund, K. (2013). Estimating the contributions of associations and recoding in the implicit association test: The ReAL model for the IAT. Journal of Personality and Social Psychology, 104(1), 45-69.] showed that evaluative associations of both female and male were activated at equivalent levels among both the young and old age groups, but younger males were more able to recode the female gender and a positive evaluation into common categories. Thus, the differences in attitudinal responses between younger and older males exaggerated the differences in the underlying evaluative associations with respect to gender and concealed the differences in recoding processes. These findings have important implications for the measurement and interpretation of implicit gender attitudes. PMID- 26933755 TI - Leveraging the attributes of biologics and small molecules, and releasing the bottlenecks: a new wave of revolution in drug development. PMID- 26933753 TI - Inactivating Variants in ANGPTL4 and Risk of Coronary Artery Disease. AB - BACKGROUND: Higher-than-normal levels of circulating triglycerides are a risk factor for ischemic cardiovascular disease. Activation of lipoprotein lipase, an enzyme that is inhibited by angiopoietin-like 4 (ANGPTL4), has been shown to reduce levels of circulating triglycerides. METHODS: We sequenced the exons of ANGPTL4 in samples obtain from 42,930 participants of predominantly European ancestry in the DiscovEHR human genetics study. We performed tests of association between lipid levels and the missense E40K variant (which has been associated with reduced plasma triglyceride levels) and other inactivating mutations. We then tested for associations between coronary artery disease and the E40K variant and other inactivating mutations in 10,552 participants with coronary artery disease and 29,223 controls. We also tested the effect of a human monoclonal antibody against ANGPTL4 on lipid levels in mice and monkeys. RESULTS: We identified 1661 heterozygotes and 17 homozygotes for the E40K variant and 75 participants who had 13 other monoallelic inactivating mutations in ANGPTL4. The levels of triglycerides were 13% lower and the levels of high-density lipoprotein (HDL) cholesterol were 7% higher among carriers of the E40K variant than among noncarriers. Carriers of the E40K variant were also significantly less likely than noncarriers to have coronary artery disease (odds ratio, 0.81; 95% confidence interval, 0.70 to 0.92; P=0.002). K40 homozygotes had markedly lower levels of triglycerides and higher levels of HDL cholesterol than did heterozygotes. Carriers of other inactivating mutations also had lower triglyceride levels and higher HDL cholesterol levels and were less likely to have coronary artery disease than were noncarriers. Monoclonal antibody inhibition of Angptl4 in mice and monkeys reduced triglyceride levels. CONCLUSIONS: Carriers of E40K and other inactivating mutations in ANGPTL4 had lower levels of triglycerides and a lower risk of coronary artery disease than did noncarriers. The inhibition of Angptl4 in mice and monkeys also resulted in corresponding reductions in these values. (Funded by Regeneron Pharmaceuticals.). PMID- 26933756 TI - Bafilomycins and Odoriferous Sesquiterpenoids from Streptomyces albolongus Isolated from Elephas maximus Feces. AB - From a fermentation broth of Streptomyces albolongus obtained from Elephas maximus feces, nine bafilomycins (1-9) and seven odoriferous sesquiterpenoids (10 16) were isolated. The structures of the new compounds, including three bafilomycins, 19-methoxybafilomycin C1 amide (1), 21-deoxybafilomycin A1 (2), and 21-deoxybafilomycin A2 (3), and two sesquiterpenoid degradation products, (1beta,4beta,4abeta,8aalpha)-4,8a-dimethyloctahydronaphthalene-1,4a(2H)-diol (10) and (1beta,4beta,4abeta,7alpha,8aalpha)-4,8a-dimethyloctahydronaphthalene 1,4a,7(2H)-triol (11), were elucidated by comprehensive spectroscopic data analysis. The cytotoxicity activity against four human cancer cell lines and antimicrobial activities against a panel of bacteria and fungi of all compounds isolated were evaluated. Compounds 1, 7, and 8 were cytotoxic, with IC50 values ranging from 0.54 to 5.02 MUM. Compounds 2, 7, 8, and 10 showed strong antifungal activity against Candida parapsilosis, with MIC values of 3.13, 1.56, 1.56, and 3.13 MUg/mL respectively. PMID- 26933757 TI - Synthesis, Isolation and Structure of Trifluoromethylated Fullerene D3-C78, C78(1)(CF3)10-18. AB - High-temperature trifluoromethylation of fullerene C78 followed by HPLC separation of C78 (CF3)n derivatives resulted in the isolation and X-ray structural characterization of 15 compounds, that is, two C78(1)(CF3)10, three C78 (1)(CF3)12, four C78 (1)(CF3)14, and five C78 (1)(CF3)16 isomers as well as one isomer of C78(1)(CF3)18. The addition patterns of the C78(1)(CF3)n molecules are discussed in terms of trifluoromethylation pathways and relative formation energies. PMID- 26933759 TI - Further evidence for heredity of pterygium. AB - Epidemiological reports strongly indicate that pterygium is an ophthalmoheliosis: a sun-related eye disease. Familial occurrence of pterygium is rare but supports the concept that heredity may predispose the conjunctiva to react abnormally to atmospheric-environmental stimuli. We describe a two generation Caucasian family of five members from the United Kingdom, four of whom developed pterygia in early adulthood with autosomal dominant inheritance. The present report confirms the significance of heredity in the pathogenesis of pterygium. Understanding the genetic basis of pterygium pathogenesis is clinically relevant, particularly in the management of patients who develop recurrent and aggressive pterygia at younger ages. PMID- 26933758 TI - Photodynamic inactivation of Candida albicans by hematoporphyrin monomethyl ether. AB - AIM: To evaluate the capacity of hematoporphyrin monomethyl ether (HMME) in the presence of light to cause photodynamic inactivation (PDI) of Candida albicans. MATERIALS & METHODS: HMME photoactivity was evaluated against azole-susceptible and -resistant C. albicans. The mechanisms by which PDI of C. albicans occurred were also investigated. RESULTS: HMME-mediated PACT caused a dose-dependent inactivation of azole-susceptible and -resistant C. albicans. Incubation with 10 MUM HMME and irradiation with 72 J cm(-2) light decreased the viability of C. albicans by 7 log10, induced damage of genomic DNA, led to loss of cellular proteins and damaged the cell wall, membrane and intracellular targets. CONCLUSION: Candida albicans can be effectively inactivated by HMME in the presence of light, and HMME-mediated PACT shows its potential as an antifungal treatment. PMID- 26933760 TI - Advice from working women with retired partners. AB - in the 21st century, as more women are employed full-time and couples increasingly share egalitarian values, more women continue employment after their partners have voluntarily retired. However, we know very little about the experiences of this growing population of women. We asked working women with retired partners to share their advice for other women who may face this developmental transition. Open-ended responses from 97 women were analyzed to identify pertinent issues and themes. Four primary content areas were identified: time management, division of household labor, financial planning, and communication. Communication between partners was both a topic of concern as well as the solution suggested to resolve conflicts or differences that may arise when women live with a retired partner. It is expected that future changes in the workforce and improvements in the gender balance within relationships will continue to impact experiences for working women with retired partners. PMID- 26933762 TI - Exploring athletes' perceptions of coach stress in elite sport environments. AB - The present study aimed to extend research that has focused on the identification of stressors associated with coaching practice by systematically evaluating how such stressors effect athletes, and more broadly, the coach-athlete relationship. A total of 13 professional- and national-level athletes were interviewed to address the three study aims: how they detect when a coach is encountering stressors, how coach experiences of stress effects them as an athlete, and how effective the coach is when experiencing stress. Following content analysis, the data suggested athletes were able to detect when a coach was experiencing stress and this was typically via a variety of verbal and behavioural cues. Despite some positive effects of the coach experiencing stress, the majority were negative and varied across a range of personal influences on the athlete, and effects on the general coaching environment. It was also the broad view of the athletes that coaches were less effective when stressed, and this was reflected in performance expectations, perceptions of competence, and lack of awareness. The findings are discussed in relation to the existing theory and with reference to their implications for applied practice, future research, and development of the coach athlete relationship. PMID- 26933763 TI - Catalytic and Enantioselective Synthesis of Chiral Multisubstituted Tribenzothiepins by Intermolecular Cycloadditions. AB - The first catalytic and highly enantioselective synthesis of tribenzothiepin derivatives was achieved. Two types of intermolecular cycloadditions using either diphenyl-sulfide-tethered diynes or 2-phenyl sulfanylbenzene-tethered diynes with a monoalkyne successfully gave chiral multisubstituted tribenzothiepins in good to excellent ee values under mild conditions. The inversion energy of this saddle shaped molecule was calculated by measurement of the racemization rate of chiral tribenzothiepins using the Eyring kinetic equation under heating conditions. The present protocol could also be used to prepare a chiral tribenzoselenepin. PMID- 26933761 TI - Hyperthermia adds to trabectedin effectiveness and thermal enhancement is associated with BRCA2 degradation and impairment of DNA homologous recombination repair. AB - The tetrahydroisoquinoline trabectedin is a marine compound with approved activity against human soft-tissue sarcoma. It exerts antiproliferative activity mainly by specific binding to the DNA and inducing DNA double-strand breaks (DSB). As homologous recombination repair (HRR)-deficient tumors are more susceptible to trabectedin, hyperthermia-mediated on-demand induction of HRR deficiency represents a novel and promising strategy to boost trabectedin treatment. For the first time, we demonstrate enhancement of trabectedin effectiveness in human sarcoma cell lines by heat and characterize cellular events and molecular mechanisms related to heat-induced effects. Hyperthermic temperatures (41.8 or 43 degrees C) enhanced significantly trabectedin-related clonogenic cell death and G2/M cell cycle arrest followed by cell type-dependent induction of apoptosis or senescence. Heat combination increased accumulation of gammaH2AX foci as key marker of DSBs. Expression of BRCA2 protein, an integral protein of the HRR machinery, was significantly decreased by heat. Consequently, recruitment of downstream RAD51 to gammaH2AX-positive repair foci was almost abolished indicating relevant impairment of HRR by heat. Accordingly, enhancement of trabectedin effectiveness was significantly augmented in BRCA2-proficient cells by hyperthermia and alleviated in BRCA2 knockout or siRNA-transfected BRCA2 knockdown cells. In peripheral blood mononuclear cells isolated from sarcoma patients, increased numbers of nuclear gammaH2AX foci were detected after systemic treatment with trabectedin and hyperthermia of the tumor region. The findings establish BRCA2 degradation by heat as a key factor for a novel treatment strategy that allows targeted chemosensitization to trabectedin and other DNA damaging antitumor drugs by on-demand induction of HRR deficiency. PMID- 26933764 TI - Cancer survivorship care-planning: Practice, research, and policy implications for social work. AB - Increasing numbers of cancer survivors are living longer than 5 years from their diagnosis date. This has resulted in a growing population of cancer survivors, expected to reach 19 million by 2024. Survivors frequently experience late effects caused by cancer and its treatment, reducing survivors' quality of life in multiple domains. Survivorship care-plans may aid the many physical, psychosocial, and financial needs that emerge posttreatment. However, the lack of reimbursement mechanisms, the limited amount of effectiveness research, and minimal guidelines for content and delivery are barriers to the widespread provision of survivorship care-plans. Challenges and opportunities for social work practice, research, and policy are identified and discussed. PMID- 26933765 TI - Efficacy of trebananib (AMG 386) in treating epithelial ovarian cancer. AB - INTRODUCTION: Epithelial ovarian cancer (EOC) is the leading cause of death among gynecologic cancers. The majority of women are diagnosed with advanced stage disease. It is considered a chemosensitive cancer with a high initial response rate to first-line platinum and taxane-based chemotherapy. However, most patients with advanced EOC will relapse with subsequent resistance to conventional chemotherapy and ultimately succumb to their disease. Therefore, new therapeutic agents and strategies are desperately needed to improve the outcomes in patients with advanced EOC. AREAS COVERED: This review focuses on the use of Trebananib (a non-VEGF-dependent angiogenesis pathway inhibitor) in EOC. Angiogenesis has been recognized as an important process promoting EOC growth and metastasis. Targeting angiogenesis in EOC have been developed and studied with demonstrated clinical efficacy. Bevacizumab, a humanized monoclonal antibody, that targets vascular endothelial growth factor A (VEGF-A), has been the most well evaluated molecular targeted therapy in the treatment of advanced and recurrent EOC with proven clinical efficacy. However, VEGF-dependent angiogenesis pathway inhibitors are often associated with serious toxicities and drug resistance ultimately develops. Hence, new therapeutic approach targeting the angiopoietin-Tie-2 complex pathway (a non-VEGF-dependent angiogenesis pathway) has gained interest over the past few years as an alternative strategy to overcome VEGF-dependent anti-angiogenesis related toxicity and resistance. EXPERT OPINION: Targeting angiopoietin-Tie-2 pathway represents a promising alternative approach to tumor anti-angiogenesis with a distinct toxicity profile from the VEGF-dependent pathway inhibitors. However, there are still many questions to be answered regarding the optimal treatment schedules, maintenance regimens, duration of maintenance therapy, and the best combination strategy. Currently there is no reliable surrogate molecular, cellular, or genetic marker that would definitively predict response to anti-angiogenic therapy. Identification of certain relevant and predictive biomarkers in the future may optimize treatment's efficacy by distinguishing the subset group of patients with EOC that would derive the most benefit from existing antiangiogenic treatment regimens. PMID- 26933766 TI - Extracellular matrix couples the convergence movements of mesoderm and neural plate during the early stages of neurulation. AB - BACKGROUND: During the initial stages zebrafish neurulation, neural plate cells undergo highly coordinated movements before they assemble into a multicellular solid neural rod. We have previously identified that the underlying mesoderm is critical to ensure such coordination and generate correct neural tube organization. However, how intertissue coordination is achieved in vivo during zebrafish neural tube morphogenesis is unknown. RESULTS: In this work, we use quantitative live imaging to study the coordinated movements of neural ectoderm and mesoderm during dorsal tissue convergence. We show the extracellular matrix components laminin and fibronectin that lie between mesoderm and neural plate act to couple the movements of neural plate and mesoderm during early stages of neurulation and to maintain the close apposition of these two tissues. CONCLUSIONS: Our study highlights the importance of the extracellular matrix proteins laminin and libronectin in coupling the movements and spatial proximity of mesoderm and neuroectoderm during the morphogenetic movements of neurulation. Developmental Dynamics 245:580-589, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26933768 TI - Factors Associated with Insulin Resistance in Patients with Chronic HCV Genotype 1 Infection without Obesity or Type 2 Diabetes. AB - OBJECTIVE: To investigate the prevalence of insulin resistance (IR) and its association with clinical parameters in patients with hepatitis C virus (HCV) genotype 1 without obesity or type 2 diabetes. METHODS: One hundred and twenty seven HCV-infected patients admitted to the Nutrition and Hepatology Clinic were included. Statistical analysis was performed using the Mann-Whitney test, Fisher's exact test, and Poisson regression analysis. RESULTS: The prevalence of IR (homeostasis model assessment [HOMA]-IR >= 3.0) was 37.0%. The independent predictors for IR included the following: aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 1.5 times the upper normal limit (odds ratio [PR] = 2.06, 95% CI, 1.16-3.66; PR = 2.32, 95% CI, 1.26-4.49, respectively); gamma glutamyl transferase (gammaGT) >= 85 U/L (PR = 2.09, 95% CI, 1.12-4.12); increased waist circumference (PR = 2.24, 95% CI, 1.25-4.17); increased waist : hip ratio (PR = 2.24, 95% CI, 1.11-5.17); increased body fat percentage (PR = 2.21, 95% CI, 1.01-5.79); overweight (PR = 2.54, 95% CI, 1.40-4.82); and metabolic syndrome (PR = 3.05, 95% CI, 1.69-5.44). High ALT levels and anthropometric parameters remained in the model of multivariate regression analysis. CONCLUSIONS: Our findings showed a significantly high prevalence of insulin resistance in nondiabetic, nonobese patients with hepatitis C genotype 1. High ALT levels and anthropometric parameters were significantly associated with IR after multivariate regression analysis. Our data show the importance of monitoring IR, weight, and body composition in patients with chronic hepatitis C. Nutritional management seems to be important in the control of comorbidities related to excess weight and the enhancement of therapeutic responses. PMID- 26933767 TI - Comparative preclinical evaluation of AS01 versus other Adjuvant Systems in a candidate herpes zoster glycoprotein E subunit vaccine. AB - The candidate vaccine HZ/su is being developed to prevent herpes-zoster disease (HZ). HZ occurrence is attributed to declines in varicella-zoster virus (VZV) specific T-cell immunity. HZ/su contains VZV antigen, gE, and Adjuvant System AS01B (liposome-based formulation of MPL and QS-21). In clinical trials, AS01B enhances CD4+ T-cell responses to gE. In clinical trials of other vaccines, Adjuvant Systems AS03 and AS04 also enhance antigen-specific CD4+ T-cell responses. Hence the purpose of this study was to evaluate gE formulated with AS01B, AS01E (50% less MPL and QS-21 than AS01B), AS03 or AS04 in C57BL6 mice primed with live-attenuated VZV. Four-weeks post-vaccination, the gE-specific CD4+ T-cell response to gE/AS01B was 5.4, 2.8 and 2.2-fold greater than those to gE/AS03, gE/AS04 and gE/AS03, respectively (p<0.001). Therefore in the VZV-primed mouse model, CD4+ T-cell responses to gE appeared most enhanced by AS01B, and adds further support for the use of AS01B in the HZ/su formulation. PMID- 26933769 TI - MRI Detection of Extramural Venous Invasion in Rectal Cancer: Correlation With Histopathology Using Elastin Stain. AB - OBJECTIVE: The purpose of this article is to evaluate the diagnostic performance of MRI for detection of extramural venous invasion (EMVI) compared with histopathologic analysis using elastin stain. MATERIALS AND METHODS: Forty-nine patients with rectal cancer who had undergone surgical resection with preoperative MRI were identified. Thirty-seven patients had received preoperative chemoradiation therapy (CRT). Sixty-nine MRI studies were independently reviewed by two blinded radiologists for EMVI using a score of 0-4. Comparison was made with histopathologic results obtained by two pathologists reviewing the elastin stained slides in consensus. EMVI status was also correlated with other tumoral and prognostic features on imaging and pathologic analysis. Statistical analysis was performed using Fisher exact and McNemar tests. RESULTS: EMVI was present in 31% of the pathology specimens. An MRI EMVI score of 3-4 was 54% sensitive and 96% specific in detecting EMVI in veins 3 mm in diameter or larger. Inclusion of a score of 2 as positive for EMVI increased the sensitivity to 79% but decreased the specificity to 74%, with poor positive predictive value. Preoperative CRT had no significant effect on the diagnostic performance of MRI. Contrast-enhanced MRI increased reader confidence for diagnosis or exclusion of EMVI compared with T2 weighted imaging. EMVI status correlated with depth of extramural invasion and proximity to mesorectal fascia. CONCLUSION: Despite an anticipated increase in sensitivity for EMVI detection by histopathologic analysis using elastin compared with H and E staining, MRI maintains a high specificity and moderate sensitivity for the detection of EMVI. PMID- 26933770 TI - Domain wall conductivity in semiconducting hexagonal ferroelectric TbMnO3 thin films. AB - Although enhanced conductivity of ferroelectric domain boundaries has been found in BiFeO3 and Pb(Zr,Ti)O3 films as well as hexagonal rare-earth manganite single crystals, the mechanism of the domain wall conductivity is still under debate. Using conductive atomic force microscopy, we observe enhanced conductance at the electrically-neutral domain walls in semiconducting hexagonal ferroelectric TbMnO3 thin films where the structure and polarization direction are strongly constrained along the c-axis. This result indicates that domain wall conductivity in ferroelectric rare-earth manganites is not limited to charged domain walls. We show that the observed conductivity in the TbMnO3 films is governed by a single conduction mechanism, namely, the back-to-back Schottky diodes tuned by the segregation of defects. PMID- 26933771 TI - Improved sensitivity of ochratoxin A analysis in coffee using high-performance liquid chromatography with hybrid triple quadrupole-linear ion trap mass spectrometry (LC-QqQLIT-MS/MS). AB - A novel and sensitive method utilising high-performance liquid chromatography coupled to triple quadrupole-linear ion trap mass spectrometry (LC-QqQLIT-MS/MS) was developed in order to analyse the content of ochratoxin A (OTA) in coffee samples. The introduction of the triple-stage MS scanning mode (MS(3)) has been shown to increase greatly sensitivity and selectivity by eliminating the high chromatographic baseline caused by interference of complex coffee matrices. The analysis included the sample preparation procedure involving extraction of OTA using a methanol-water mixture and clean-up by immunoaffinity columns and detection using the MS(3) scanning mode of LC-QqQLIT-MS/MS. The proposed method offered a good linear correlation (r(2) > 0.998), excellent precision (RSD < 2.9%) and recovery (94%). The limit of quantification (LOQ) for coffee beans and espresso beverages was 0.010 and 0.003 ug kg(-1), respectively. The developed procedure was compared with traditional methods employing liquid chromatography coupled to fluorescent and tandem quadrupole detectors in conjunction with QuEChERS and solid-phase extraction. The proposed method was successfully applied to the determination of OTA in 15 samples of coffee beans and in 15 samples of espresso coffee beverages obtained from the Latvian market. OTA was found in 10 samples of coffee beans and in two samples of espresso in the ranges of 0.018 1.80 ug kg(-1) and 0.020-0.440 ug l(-1), respectively. No samples exceeded the maximum permitted level of OTA in the European Union (5.0 ug kg(-1)). PMID- 26933773 TI - Graphene-based half-metal and spin-semiconductor for spintronic applications. AB - In this letter we propose a strategy to make graphene become a half-metal or spin semiconductor by combining the magnetic proximity effects and sublattice symmetry breaking in graphone/graphene and graphone/graphene/BN heterostructures. Exchange interactions lift the spin degeneracy and sublattice symmetry breaking opens a band gap in graphene. More interestingly, the gap opening depends on the spin direction and the competition between the sublattice asymmetry and exchange field determines the system is a half-metal or a spin-semiconductor. By first principles calculations and a low-energy effective model analysis, we elucidate the underlying physical mechanism of spin-dependent gap opening and spin degeneracy splitting. This offers an alternative practical platform for graphene based spintronics. PMID- 26933772 TI - Spontaneous resolution of retinal vascular abnormalities and macular oedema in facioscapulohumeral muscular dystrophy. PMID- 26933774 TI - A Small Molecule for Controlled Generation of Peroxynitrite. AB - 2-Methyl-3-[1-(N,N-dimethylamino)diazen-1-ium-1,2-diol-2-ato-methyl]-naphthalene 1,4-dione 1 (HyPR-1), a small molecule containing a superoxide generator strategically linked to a diazeniumdiolate-based nitric oxide donor, is reported. Evidence for HyPR-1's ability to generate peroxynitrite in the presence of an enzyme as well as enhance peroxynitrite within cells is provided. The utility of this tool in generating peroxynitrite for cellular studies is demonstrated. PMID- 26933777 TI - Monoclonal Antibody Drugs for Systemic Lupus Erythematosus. AB - Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease which engages most of the immune cells in its development. Various studies concerning the application of antibodies against TNF-alpha, BlyS, CD20, CD22, IL-6R and complement factors in treatment of SLE have been recently conducted and in spite of the good results reported by some of them, no definite conclusion on their risk-benefit profile can be drawn. The current review summarizes the results obtained in the field and reveals the perspectives for the development of new and more effective strategies for SLE treatment in combination with other immunomodulating drugs. PMID- 26933778 TI - T-Lymphocyte Subset Absolute Counts in the Peripheral Blood of Mediterranean Spotted Fever Patients: Relations to Disease Severity. AB - INTRODUCTION: Mediterranean spotted fever (MSF) in Bulgaria is caused by Rickettsia conorii conorii. AIM: This study aims at investigating the absolute counts of T-lymphocyte subsets in the peripheral blood of patients with MSF in order to establish relationships with disease severity. MATERIALS AND METHODS: The absolute counts of T-lymphocyte subsets were tested in the blood of 62 patients in the acute stage of MSF. They were assigned into three age and sex matched groups, based on the severity of disease - with mild, moderate or severe forms. Controls were 32 age and sex matched healthy individuals. The diagnosis was confirmed by an immunofluorescence assay. Immunophenotyping was performed using Epics XL-MCL Coulter, USA flow-cytometer. RESULTS: The absolute counts of immune competent (CD3+) cells, as well as the counts of helper/inducer (CD3+ CD4+) and suppressor/ cytotoxic (CD3+ CD8+) T-cell subsets decreased in parallel with disease severity. Naive (CD4+ CD45RA+) and activated memory (CD4+ CD45RO+) T cell subsets were reduced, particularly in severe MSF. Taken as a whole, the counts of activated (CD3+ HLA-DR+) and that of presenting accessory (CD28+) or stimulatory (CD38+) molecules T-cell subsets was increased, but in the first two subsets the trend from mild to severe forms of the disease was descending. CONCLUSION: Reduced T-lymphocyte subset counts are likely related to trans migration into perivascular inflammatory foci. The increased number of T lymphocytes bearing activation molecules reflects a mobilization of the cell mediated immune response. An important issue of this study is the possible prognostic value of T-cell subsets counting, predicting the evolution of a clinical condition to clinical forms, according to the disease severity. PMID- 26933779 TI - Comparison of Directigen Flu A+B with Real Time PCR in the Diagnosis of Influenza. AB - Early diagnosis and treatment of patients with influenza is the reason why physicians need rapid high-sensitivity influenza diagnostic tests that require no complex lab equipment and can be performed and interpreted within 15 min. The Aim of this study was to compare the rapid Directigen Flu A+B test with real time PCR for detection of influenza viruses in the Republic of Macedonia. MATERIALS AND METHODS: One-hundred-eight respiratory samples (combined nose and throat swabs) were routinely collected for detection of influenza virus during influenza seasons. Forty-one patients were pediatric cases and 59 were adult. Their mean age was 23 years. The patients were allocated into 6 age groups: 0-4 yrs, 5-9 yrs, 10-14 yrs, 15-19 yrs, 20-64 yrs and > 65 yrs. Each sample was tested with Directigen Flu A+B and CDC real time PCR kit for detection and typisation/subtypisation of influenza according to the lab diagnostic protocol. RESULTS: Directigen Flu A+B identified influenza A virus in 20 (18.5%) samples and influenza B virus in two 2 (1.9%) samples. The high specificity (100%) and PPV of Directigen Flu A+B we found in our study shows that the positive results do not need to be confirmed. The overall sensitivity of Directigen Flu A+B is 35.1% for influenza A virus and 33.0% for influenza B virus. The sensitivity for influenza A is higher among children hospitalized (45.0%) and outpatients (40.0%) versus adults. CONCLUSION: Directigen Flu A+B has relatively low sensitivity for detection of influenza viruses in combined nose and throat swabs. Negative results must be confirmed. PMID- 26933781 TI - Impact Of Dental Anxiety On The Decision To Have Implant Treatment. AB - INTRODUCTION: Dental implants are increasingly used in modern dentistry as anchors for prosthetic restorations. Anxiety is a complex phenomenon which can become a risk factor for suppression of many functions of the body. AIM: The aim of this study was to investigate the effect dental anxiety exerts on the choice of method of treatment by patients wanting to have dental implants. MATERIALS AND METHODS: The study included 174 patients that were referred to us for dental implants placement because of partial or total loss of teeth. Their dental anxiety was measured using the Dental Anxiety Scale (DAS) proposed by Norman Corah. The patients decided to have or refused to have treatment with dental implants either because they had dental anxiety or gave other reasons. RESULTS: Distribution of patients by level of anxiety was as follows: 33% were anxiety free, in 34% the dental anxiety was moderate, 25% had severe anxiety, and 8% experienced an extremely severe anxiety. Dental fear was given as a reason for refusal of treatment by 24.1% of the patients wanting to have dental implants. Of the patients wanting to have dental implants, 40.8% decided to proceed with the treatment; these patients exhibited low dental anxiety. CONCLUSION: The decision to have dental treatment with implants is affected by the patient's level of dental anxiety. Only those with low level of dental anxiety decide to proceed with such a treatment. The mild anxiety some patients experience is beneficial as it eliminates a risk factor that may hinder the process of osseointegration. PMID- 26933780 TI - Neurotrophic Factor Receptors trkB and trkC in Experimental Model of Lesion in Rat Brain Structures in Schizophrenia. AB - INTRODUCTION: The maldevelopmental model of schizophrenia postulates pathological alterations in embryonal neurogenesis as the etiopathogenetic basis of schizophrenic psychoses. The neurotrophic factor hypothesis explains these neuropathological abnormalities as the result of alterations of the neurotrophin system caused by different mechanisms such as a genetic, infectious and traumatic factors. The tyrosine-kinase containing receptors trkB and trkC mediate growth promoting effects of neurotrophins and respond to changes in neurotrophic factors availability. AIM: The aim of the present study was to establish the expression pattern of trkB and trkC in rat brain structures by a developmental model of schizophrenia. MATERIALS AND METHODS: On cryostat coronal brain sections of control and lesioned rats (after infusion of ibotenic acid solution bilaterally into the hippocampal formation), immunoreactions for trkB and trkC were performed. RESULTS: We found diminished expression of trkB and trkC in the hippocampal formation of lesioned animals compared to the controls. Quantitative measurements of immunohistochemical reactions intensity and statistical analysis confi rmed the reduced immunoreactivity for antigens under study (trkB and trkC) in the positive hippocampal neurons of 56-day-old lesioned rats compared to the control animals. CONCLUSION: The observed downregulation of neurotrophic factor receptors expression may compromise the function and plasticity of hippocampal formation in schizophrenic brains. PMID- 26933782 TI - Acute Poisoning with Dapsone and Olanzapine: Severe Methemoglobinemia and Coma with a Favourable Outcome. AB - Dapsone is a drug commonly used in the treatment of leprosy. In Europe it is rarely prescribed, mostly for the treatment of skin diseases such as dermatitis herpetiformis. Poisoning with dapsone is rare and reports of such cases are of interest for toxicological practice. We describe the only acute dapsone poisoning in a caseload series of 21,000 intoxications treated in the Clinical Toxicology Clinic at St George University Hospital in Plovdiv, Bulgaria between 1999 and 2013. We report on a 36-year-old woman who attempted deliberate self-poisoning with an ingestion of approximately 4.5 g of dapsone and 0.3 g of olanzapine. On admission, the patient was in a state of severe intoxication and comatose. On admission to hospital 9 hours after the ingestion, the methemoglobin level was 51.7%. The patient recovered 8 days later. She received complex treatment including intubation, ventilation, repeated gastric lavage, hemodialysis, blood exchange transfusion and antidote treatment with methylene blue. She was discharged in good clinical condition with minimal organ damage such as mild toxic hepatitis. PMID- 26933783 TI - Cross-Cultural Validation of the Definition of Multimorbidity in the Bulgarian Language. AB - INTRODUCTION: Multimorbidity is a health issue with growing importance. During the last few decades the populations of most countries in the world have been ageing rapidly. Bulgaria is affected by the issue because of the high prevalence of ageing population in the country with multiple chronic conditions. The AIM of the present study was to validate the translated definition of multimorbidity from English into the Bulgarian language. MATERIALS AND METHODS: The present study is part of an international project involving 8 national groups. We performed a forward and backward translation of the original English definition of multimorbidity using a Delphi consensus procedure. RESULTS: The physicians involved accepted the definition with a high percentage of agreement in the first round. The backward translation was accepted by the scientific committee using the Nominal group technique. DISCUSSION: Some of the GPs provided comments on the linguistic expressions which arose in order to improve understanding in Bulgarian. The remarks were not relevant to the content. The conclusion of the discussion, using a meta-ethnographic approach, was that the differences were acceptable and no further changes were required. CONCLUSIONS: A native version of the published English multimorbidity definition has been finalized. This definition is a prerequisite for better management of multimorbidity by clinicians, researchers and policy makers. PMID- 26933784 TI - Dysfunctional Effects of a Conflict in a Healthcare Organization. AB - Conflicts in healthcare settings are quite common events because of the continuous changes and transformations today's healthcare organizations are undergoing and the vigorous interaction between the medical professionals working in them. AIM: To survey the opinions of medical professionals about the possible destructive effects of conflicts on them in the workplace. MATERIALS AND METHODS: We conducted a direct individual survey of 279 medical employees at four general hospitals. We used a set of questions that reflect the negative effects and consequences of conflict on healthcare professionals as direct or indirect participants. All data were analysed using the descriptive statistics and non parametric analysis at a significance level for the null hypothesis of p < 0.05. RESULTS: Workplace conflicts contribute a lot to the stress, psychological tension and emotional exhaustion medical professionals are exposed to. The confrontation the conflict brings the participants into acts as a catalyst of the conflict and enhances the manifestation of hostile actions. A conflict generates a situation which has an impact on the behaviour of all participants involved in it giving rise to emotional states such as anger, aggression and reproaches. The destructive consequences resulting from a conflict are seen in the reduced work satisfaction and demotivation to perform the work activity. The contradictions that arise as a result affect negatively the team cooperation and obstruct the collaborative efforts in solving the problems in the healthcare setting. CONCLUSION: A conflict in a healthcare setting exerts a considerable destructive effect on an employee, therefore it requires prompt identification and effective intervention to minimise its unfavourable outcomes. PMID- 26933785 TI - Risk Factors for Injuries in Professional Football Players. AB - AIM: The aim of this study was to identify risk factors related to the occurrence of injuries in football players. MATERIALS AND METHODS: The study included 216 football players from 12 teams in the elite football league. Football-related injury data were collected prospectively during the 2012/2013 competitive season. At baseline the following information was collected for the players: anthropometric measurements (weight, height, BMI, subcutaneous skinfolds), playing experience, injury history, physical fitness performance test (agility run), peak oxygen uptake. The incidence, type and severity of injuries and training and game exposure times were prospectively documented for each player. RESULTS: Most of the players (n = 155, 71.7%) sustained the injures during the study period. The overall injury incidence during the regular season was 6.3 injuries per 1000 athlete-exposures (95% confidence interval, 4.31-9.67). Multivariate logistic regression analysis showed that playing experience (odds ratio [OR] = 0.44; 95% CI = 0.32-0.61, p < 0.01), age (OR = 2.05; 95% CI = 1.49 2.81, p < 0.01) and a previous injury (OR = 4.4; 95% CI = 2.14-9.07, p < 0.01) were significantly correlated to increased risk of injuries. Body mass index was not associated with risk of injury. Strains (34.19%) and sprains (25.81%) were the major injury types. Twenty-seven percent of injured players were absent from football for more than 1 month, with knee injuries (25.42%) being the most severe type. CONCLUSION: The risk factors that increase injury rates in football players were previous injury, higher age and years of playing. Future research should include adequate rehabilitation program to reduce the risk of injuries. PMID- 26933786 TI - Sexual Fears and Avoidant Sexual Behavior in Medical Students. AB - Sexual fears, sometimes in the form of phobias, lead to aversive or sexually avoidant behavior blocking sexual closeness and resulting in deep personal and interpersonal distress. OBJECTIVE: To determine the types of sexual fears and aversive behavior in young people of reproductive age (students) and their degree of markedness as to encourage a further implementation of prevention programs and interventions. MATERIALS AND METHODS: The study included 116 fifth-year medical students in Plovdiv Medical University. Of these, 55 men and 61 women were assessed with the Sexual Aversion Scale, a 30-item self-rating questionnaire. The Diagnostic and Statistical Manual of Mental Disorders criteria of sexual aversion were used. The statistical analyses used were descriptive statistics and independent samples t-test. RESULTS: Sexual fears and aversive or blocking behavior are mild to moderate, mean score of 1.54 +/- 0.04, without statistically significant gender differences. Both sexes have established fear-related sexual aversive motives of sexual behavior related to the risk of unwanted pregnancy and HIV infection. Women have significantly higher average scores for the following statements: fear of sexual intercourse (1.61 vs 1.25), avoidance of situations in which they may be involved sexually (1.95 vs 1.51), avoidance of genital sexual contact (1.44 vs 1.16), fear of catching a sexually transmitted disease (2.46 vs 2.09 ), fear of pregnancy (2.61 vs 2.15) and concerns what other people think of them (2.34 vs 1.93 ). CONCLUSIONS: Sexual fears and aversive or blocking behavior were mild to moderate. In both sexes similar fears--aversive or blocking patterns of sexual behavior were found, mainly associated with the fear of unwanted pregnancy and the risk of HIV infection, more expressed in women. PMID- 26933788 TI - Editorial Comment to Pharmacotherapies for renal cell carcinoma in Japan. PMID- 26933789 TI - Serum biotin in Japanese children: Enzyme-linked immunosorbent assay measurement. AB - BACKGROUND: Biotin deficiency has been reported in Japanese infants fed special formulas for medical reasons, including those with milk allergy and congenital metabolic diseases, because these formulas contain little biotin. Serum biotin measurement is useful for diagnosing biotin deficiency. We applied a simple and rapid method to analyze serum biotin, and established normal ranges for children and adults. METHODS: Serum biotin in 188 healthy Japanese children aged 0-4 years and in 25 healthy adults was analyzed using a Biotin ELISA Kit (immundiagnostik). The effects of various conditions on the measurement of serum biotin were also examined. RESULTS: Median biotin in children aged 0-4 years was 10.4 ng/dL (IQR, 7.9-13.4 ng/dL), and that in adults was 12.9 ng/dL (IQR, 10.8-15.8 ng/dL). Normal range was 4.7-22.0 ng/dL in children and 8.4-20.5 ng/dL in adults (calculated using two-sided 95%CI). Measurements obtained with this method were not affected by frozen storage, freeze-thaw, or hemolysis, indicating that serum biotin can be analyzed accurately under these conditions, with a possible application to plasma samples. CONCLUSIONS: Serum biotin was significantly lower in children than in adults, with the normal range being 4.7-22.0 ng/dL in children and 8.4-20.5 ng/dL in adults. This simple and accurate enzyme-linked immunosorbent assay method is useful for diagnosing biotin deficiency. PMID- 26933790 TI - Nucleosome dynamics during chromatin remodeling in vivo. AB - Precise positioning of nucleosomes around regulatory sites is achieved by the action of chromatin remodelers, which use the energy of ATP to slide, evict or change the composition of nucleosomes. Chromatin remodelers act to bind nucleosomes, disrupt histone-DNA interactions and translocate the DNA around the histone core to reposition nucleosomes. Hence, remodeling is expected to involve nucleosomal intermediates with a structural organization that is distinct from intact nucleosomes. We describe the identification of a partially unwrapped nucleosome structure using methods that map histone-DNA contacts genome-wide. This alternative nucleosome structure is likely formed as an intermediate or by product during nucleosome remodeling by the RSC complex. Identification of the loss of histone-DNA contacts during chromatin remodeling by RSC in vivo has implications for the regulation of transcriptional initiation. PMID- 26933791 TI - Media Use, Cognitive Performance, and Life Satisfaction of the Chinese Elderly. AB - Media use and aging is an important interdisciplinary topic pertaining to communication, gerontology, and psychology, among others. Integrating research on media-induced recovery and life satisfaction, the present study examined media uses and effects in the context of health and aging. Specifically, data from a large random sample were analyzed to investigate the relationships between media use, cognitive performance, and life satisfaction among the Chinese elderly. Results, in general, lent support to the slightly modified structural model. Specifically, media-induced recovery outcomes can be categorized into proximate (e.g., cognitive performance), intermediate (e.g., health satisfaction), and distal levels (e.g., life satisfaction). Also, situational factors (e.g., disease history) had statistically significant effects on media-induced recovery outcomes. Theoretical and practical implications of the research findings were discussed, and future research directions were suggested. PMID- 26933793 TI - Infusion System Architecture Impacts the Ability of Intensive Care Nurses to Maintain Hemodynamic Stability in a Living Swine Simulator. AB - BACKGROUND: The authors have previously shown that drug infusion systems with large common volumes exhibit long delays in reaching steady-state drug delivery and pharmacodynamic effects compared with smaller common-volume systems. The authors hypothesized that such delays can impede the pharmacologic restoration of hemodynamic stability. METHODS: The authors created a living swine simulator of hemodynamic instability in which occlusion balloons in the aorta and inferior vena cava (IVC) were used to manipulate blood pressure. Experienced intensive care unit nurses blinded to the use of small or large common-volume infusion systems were instructed to maintain mean arterial blood pressure between 70 and 90 mmHg using only sodium nitroprusside and norepinephrine infusions. Four conditions (IVC or aortic occlusions and small or large common volume) were tested 12 times in eight animals. RESULTS: After aortic occlusion, the time to restore mean arterial pressure to range (t1: 2.4 +/- 1.4 vs. 5.0 +/- 2.3 min, P = 0.003, average +/- SD), time-out-of-range (tOR: 6.2 +/- 3.5 vs. 9.5 +/- 3.4 min, P = 0.028), and area-out-of-range (pressure-time integral: 84 +/- 47 vs. 170 +/- 100 mmHg . min, P = 0.018) were all lower with smaller common volumes. After IVC occlusion, t1 (3.7 +/- 2.2 vs. 7.1 +/- 2.6 min, P = 0.002), tOR (6.3 +/- 3.5 vs. 11 +/- 3.0 min, P = 0.007), and area-out-of-range (110 +/- 93 vs. 270 +/- 140 mmHg . min, P = 0.003) were all lower with smaller common volumes. Common-volume size did not impact the total amount infused of either drug. CONCLUSIONS: Nurses did not respond as effectively to hemodynamic instability when drugs flowed through large common-volume infusion systems. These findings suggest that drug infusion system common volume may have clinical impact, should be minimized to the greatest extent possible, and warrants clinical investigations. PMID- 26933792 TI - Impact of multimodal therapy in locally recurrent rectal cancer. AB - BACKGROUND: The practice of salvaging recurrent rectal cancer has evolved. The aim of this study was to define the evolving salvage potential over time among patients with locally recurrent disease, and to identify durable determinants of long-term success. METHODS: The study included consecutive patients with recurrent rectal cancer undergoing multimodal salvage with curative intent between 1988 and 2012. Predictors of long-term survival were defined by Cox regression analysis and compared over time. Re-recurrence and subsequent treatments were evaluated. RESULTS: After multidisciplinary evaluation of 229 patients, salvage therapy with curative intent included preoperative chemotherapy and/or radiotherapy (73.4 per cent; with 41.3 per cent undergoing repeat pelvic irradiation), surgical salvage resection with or without intraoperative irradiation (36.2 per cent), followed by postoperative adjuvant chemotherapy (38.0 per cent). Multivisceral resection was undertaken in 47.2 per cent and bone resection in 29.7 per cent. The R0 resection rate was 80.3 per cent. After a median follow-up of 56.5 months, the 5-year overall survival rate was 50 per cent in 2005-2012, markedly increased from 32 per cent in 1988-1996 (P = 0.044). Long term success was associated with R0 resection (P = 0.017) and lack of secondary failure (P = 0.003). Some 125 patients (54.6 per cent) developed further recurrence at a median of 19.4 months after salvage surgery. Repeat operative rescue was feasible in 21 of 48 patients with local re-recurrence alone and in 17 of 77 with distant re-recurrence, with a median survival of 19.8 months after further recurrence. CONCLUSION: The long-term salvage potential for recurrent rectal cancer improved significantly over time, with the introduction of an individualized treatment algorithm of multimodal treatments and surgical salvage. Durable predictors of long-term success were R0 resection at salvage operation, avoidance of secondary failure, and feasibility of repeat rescue after re recurrence. PMID- 26933796 TI - Reporting of Observational Research in ANESTHESIOLOGY: The Importance of the Analysis Plan. PMID- 26933797 TI - Maternal attitude towards first trimester screening for fetal abnormalities. AB - OBJECTIVE: To explore the maternal attitude towards the screening for structural abnormalities at the 11-13-week scan, according to the severity of the abnormality. A secondary aim was to analyse which maternal characteristics influence in the maternal response. METHODS: This is a descriptive study based on the responses to 300 self-administrated questionnaires completed immediately before routine ultrasounds scan. RESULTS: A totally of 296 (98.7%) women participated in the study. If the baby had any abnormality 93.9% would prefer to know at 12 weeks, 96.6% if the abnormality was lethal, 95.3% if the abnormality involves severe handicap, 91.2% if the abnormality can only be suspected, but not confirmed until the pregnancy is more advanced (16 or 20 weeks), 77.0% if the abnormality was minor and 79.4% women would like to know at 12 weeks if the baby appeared normal. Maternal age, gestational age at the time of the questionnaire and maternal attitude towards termination of pregnancy were the only factors affecting maternal responses. CONCLUSION: Pregnant women prefer to be informed in the first trimester about any abnormality in their fetuses, even in cases of minor or only suspected abnormalities. (c) 2016 John Wiley & Sons, Ltd. PMID- 26933798 TI - The prevalence of functional gastrointestinal disorders in children in Panama: a school-based study. AB - AIM: Functional gastrointestinal disorders (FGIDs) are common in children, but the epidemiology of FGIDs is incompletely understood. Our aim was to perform a population-based study using Rome III criteria to describe the prevalence of FGIDs in children in Panama. METHODS: We performed a cross-sectional study of children attending three schools in Panama City, Panama. Children with organic medical diseases were excluded. Subjects provided demographic information and completed the Questionnaire on Pediatric Gastrointestinal Symptoms - Rome III Spanish version. RESULTS: A total of 321 subjects (61.1% female, median age 10 years, range 8-14 years) completed our study. A total of 92 subjects (28.7%) met criteria for an FGID. Gender, age and school type did not differ significantly between subjects with and without FGIDs. The most common FGIDs included functional constipation (15.9%), irritable bowel syndrome (5.6%), and functional abdominal pain or functional abdominal pain syndrome (4.0%). Abdominal pain related FGIDs were present in 12.1%. CONCLUSION: FGIDs are common in school-aged children in Panama. The prevalence of abdominal pain-related FGIDs in children in Panama is similar to that described in other parts of the world. Further population-based studies utilising Rome III criteria to measure FGID prevalence in children are needed to advance our understanding of the pathogenesis of FGIDs. PMID- 26933799 TI - Role of Procalcitonin and C-Reactive Protein As Biomarkers of Infection in Children With Liver Disease. AB - OBJECTIVES: Early and accurate identification of infection in patients with liver disease is challenging. The present study evaluated the role of procalcitonin (PCT) and C-reactive protein (CRP) as biomarkers of bacterial infection in children with liver disease. METHODS: Demographic and clinical data of consecutive children admitted with acute liver failure (ALF) or decompensated chronic liver disease (DCLD) were collected. PCT and CRP were measured within 24 hours of admission. Blood and urine culture, chest x-ray, and ascitic fluid analysis were done. RESULTS: One hundred sixty-four children (113 boys, age 76 [0.5-204] months, ALF 69, DCLD 95) were enrolled. Seventy-seven (47%) had infection. Most common site was ascitic fluid (n = 35), followed by urinary tract (n = 26), pneumonia (n = 22), and blood stream infection (n = 16). Twenty-one children had multiple-site infections, 18 had severe sepsis, and 36 had systemic inflammatory response syndrome. PCT and CRP correlated with infection severity, higher in severe sepsis (8.3 [3.5-38] ng/mL and 4.1 [0.3-13.8] mg/dL) than only infection (0.89 [0.1-8] ng/mL and 1.7 [0.32-24] mg/dL) and no infection (0.3 [0.1 6.75] ng/mL and 0.3 [0.1-4.16 mg/dL]). Systemic inflammatory response syndrome was more common in patients with infection (31/77 vs 5/87, P = 0.00). PCT (>0.5 ng/mL) and CRP (>0.6 mg/dL) performed better in DCLD (AUC of 0.90 and 0.83) compared with patients with ALF (AUC of 0.73 and 0.69). CONCLUSIONS: PCT and CRP are reliable markers of infection and correlate with infection severity in children with liver disease. Their diagnostic accuracy is better in DCLD than ALF cases. PMID- 26933800 TI - Dietary Supplements in Infants and Children: Only Beneficial? PMID- 26933801 TI - Increased Epithelial Gap Density in the Noninflamed Duodenum of Children With Inflammatory Bowel Diseases. AB - OBJECTIVES: Inflammatory bowel diseases (IBD) present commonly in childhood, with unknown etiology, but an important role for the epithelial lining is suggested. Epithelial cell extrusion, measured by counting gaps between epithelial cells, is higher in adult patients with Crohn disease (CD) than in controls. Our objectives were to compare epithelial gaps in the duodenum of IBD and non-IBD pediatric patients, to study the correlation between epithelial gaps, inflammation, and disease activity, and identify potential mechanisms. METHODS: Epithelial gap density of the duodenum was evaluated using probe-based confocal laser endomicroscopy in 26 pediatric patients with IBD (16 CD, 10 ulcerative colitis [UC]) and 17 non-IBD controls during endoscopy. Epithelial gaps were correlated with serum inflammatory markers, disease activity indices, and intraepithelial lymphocytes. A panel of 10 inflammatory cytokines and expression of TNFAIP3 (A20; inhibits NF-kappabeta-induced inflammation) were analyzed in duodenal and ileal biopsies. RESULTS: Confocal imaging showed significantly higher epithelial gap density in patients with IBD, including UC. Interleukin (IL)-2 and IL-8 were higher in duodenal but not ileal biopsies of patients with UC. No significant correlation was present between C-reactive protein, erythrocyte sedimentation rate, disease activity indices, and epithelial gaps in patients with UC. In patients with CD, C-reactive protein positively correlated with epithelial gaps. A20 expression in the duodenum was unchanged among non-IBD and IBD cases. CONCLUSIONS: Duodenal epithelial gaps are increased in pediatric patients with IBD (including UC) but are unrelated to inflammation. This suggests that altered epithelial barrier is an important systemic feature of pediatric IBD and is not only secondary to inflammation. PMID- 26933802 TI - Advanced malignancies treated with a combination of the VEGF inhibitor bevacizumab, anti-EGFR antibody cetuximab, and the mTOR inhibitor temsirolimus. AB - BACKGROUND: Bevacizumab and temsirolimus are active agents in advanced solid tumors. Temsirolimus inhibits mTOR in the PI3 kinase/AKT/mTOR pathway as well as CYP2A, which may be a resistance mechanism for cetuximab. In addition, temsirolimus attenuates upregulation of HIF-1alpha levels, which may be a resistance mechanism for bevacizumab. PATIENTS AND METHODS: We analyzed safety and responses in 21 patients with advanced solid tumors treated with bevacizumab, cetuximab, and temsirolimus. RESULTS: The median age of patients was 60 years (range, 23-80 years). The median number of prior systemic therapies was 3 (range, 1-6). The maximum tolerated dose (MTD) was determined to be bevacizumab 10 mg/kg biweekly, temsirolimus 5 mg weekly and cetuximab 100/75 mg/m2 weekly. Grade 3 or 4 toxicities were seen in 52% of patients with the highest prevalence being hyperglycemia (14%) and hypophosphatemia (14%). Eighteen of the 21 patients were evaluable for response. Three patients were taken off the study before restaging for toxicities. Partial response (PR) was observed in 2/18 patients (11%) and stable disease (SD) lasting >= 6 months was observed in 4/18 patients (22%) (total = 6/18 (33%)). In 8 evaluable patients with squamous cell carcinoma of the head and neck (HNSCC) there were partial responses in 2/8 (25%) patients and SD >= 6 months in 1/8 (13%) patients (total = 3/8, (38%)). CONCLUSION: The combination of bevacizumab, cetuximab, and temsirolimus showed activity in HNSCC; however, there were numerous toxicities reported, which will require careful management for future clinical development. PMID- 26933803 TI - The effect of D-serine administration on cognition and mood in older adults. AB - BACKGROUND: D-serine is an endogenous co-agonist of the N-Methyl D-Aspartate Receptor (NMDAR) that plays a crucial role in cognition including learning processes and memory. Decreased D-serine levels have been associated with age related decline in mechanisms of learning and memory in animal studies. Here, we asked whether D-serine administration in older adults improves cognition. RESULTS: D-serine administration improved performance in the Groton Maze learning test of spatial memory and learning and problem solving (F(3, 38)= 4.74, p = 0.03). Subjects that achieved higher increases in plasma D-serine levels after administration improved more in test performance (r2=-0.19 p = 0.009). D-serine administration was not associated with any significant changes in the other cognitive tests or in the mood of older adults (p > 0.05). METHODS: Fifty healthy older adults received D-serine and placebo in a randomized, double blind, placebo controlled, crossover design study. We studied the effect of D-serine administration on the performance of cognitive tests and an analogue mood scale. We also collected blood samples to measure D-serine, L-serine, glutamate and glutamine levels. CONCLUSIONS: D-serine administration may be a strategy to improve spatial memory, learning and problem solving in healthy older adults. Future studies should evaluate the impact of long-term D-serine administration on cognition in older adults. PMID- 26933804 TI - PLA2G16 promotes osteosarcoma metastasis and drug resistance via the MAPK pathway. AB - The prognosis of metastatic osteosarcoma is dismal and a better understanding of the mechanisms underlying disease progression is essential to improve treatment options and patient outcomes. We previously demonstrated Pla2g16 overexpression in mouse osteosarcoma contributes to metastasis phenotypes and increased expression of PLA2G16 is associated with metastasis and poor prognosis in human tumors. To further examine the mechanisms through which PLA2G16 contributes to human osteosarcoma metastasis and explore the potential of PLA2G16 as a therapeutic target in osteosarcoma, we generated a panel of human osteosarcoma cell lines expressing different levels of PLA2G16. The functional analyses of these cell lines demonstrated high levels of PLA2G16 expression increased osteosarcoma cell migration, invasion, clonogenic survival, and anchorage independent colony formation. Importantly, this activity was dependent on the phospholipase activity of PLA2G16. Additionally, PLA2G16 overexpression decreased the sensitivity of cells to a panel of chemotherapeutic agents. Analysis of downstream pathways revealed the pro-metastasis functions of PLA2G16 were mediated through the MAPK pathway, as knockdown of PLA2G16 decreased ERK1/2 phosphorylation and pharmacological inhibition of MEK significantly repressed PLA2G16 mediated cell migration and clonogenic survival. Furthermore, PLA2G16 overexpression promoted xenograft tumor growth in vivo, and these tumors exhibit increased ERK1/2 phosphorylation. Lastly, the expression of PLA2G16 is strongly correlated with the increased ERK1/2 phosphorylation in human osteosarcoma samples, and the combined lesions are associated with reduced overall and metastasis-free survival. Collectively, these results demonstrate increased PLA2G16 expression activates the MAPK pathway to enhance osteosarcoma metastasis and may be a novel therapeutic target for these cancers. PMID- 26933805 TI - MicroRNA deregulation in triple negative breast cancer reveals a role of miR-498 in regulating BRCA1 expression. AB - Emerging evidence suggests that BRCA1 pathway contributes to the behavior of sporadic triple negative breast cancer (TNBC), but little is known about the mechanisms underlying this association. Considering the central role that microRNAs (miRNAs) play in gene expression regulation, the aim of this study was to identify miRNAs specifically deregulated in TNBC and investigate their involvement in BRCA1 regulation. Using locked nucleic acid (LNA)-based microarrays, expression levels of 1919 miRNAs were measured in paraffin-embedded tissues from 122 breast tumors and 11 healthy breast tissue samples. Differential miRNA expression was explored among the main subtypes of breast cancer, and 105 miRNAs were identified as specific for triple negative tumors. In silico prediction revealed that miR-498 and miR-187-5p target BRCA1, and these results were confirmed by luciferase reporter assay. While miR-187-5p was found overexpressed in a luminal B cell line, miR-498 was highly expressed in a triple negative cell line, Hs578T, and its expression was negatively correlated with the levels of BRCA1. We functionally demonstrated that miR-498 inhibits BRCA1 in breast cancer cell lines, and showed that inhibition of miR-498 led to reduced proliferation in the triple negative cell line Hs578T. Our results indicate that miR-498 regulates BRCA1 expression in breast cancer and its overexpression could contribute to the pathogenesis of sporadic TNBC via BRCA1 downregulation. PMID- 26933806 TI - CtBP1 associates metabolic syndrome and breast carcinogenesis targeting multiple miRNAs. AB - Metabolic syndrome (MeS) has been identified as a risk factor for breast cancer. C-terminal binding protein 1 (CtBP1) is a co-repressor of tumor suppressor genes that is activated by low NAD+/NADH ratio. High fat diet (HFD) increases intracellular NADH. We investigated the effect of CtBP1 hyperactivation by HFD intake on mouse breast carcinogenesis. We generated a MeS-like disease in female mice by chronically feeding animals with HFD. MeS increased postnatal mammary gland development and generated prominent duct patterns with markedly increased CtBP1 and Cyclin D1 expression. CtBP1 induced breast cancer cells proliferation. Serum from animals with MeS enriched the stem-like/progenitor cell population from breast cancer cells. CtBP1 increased breast tumor growth in MeS mice modulating multiple genes and miRNA expression implicated in cell proliferation, progenitor cells phenotype, epithelial to mesenchymal transition, mammary development and cell communication in the xenografts. These results define a novel function for CtBP1 in breast carcinogenesis. PMID- 26933807 TI - Optimized selection of three major EGFR-TKIs in advanced EGFR-positive non-small cell lung cancer: a network meta-analysis. AB - BACKGROUND: To answer which epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) is the best choice for advanced non-small cell lung cancer (NSCLC) EGFR mutants. RESULTS: 16 phase III randomized trials involving 2962 advanced NSCLC EGFR mutants were enrolled. Multiple treatment comparisons showed different EGFR-TKIs shared equivalent curative effect in terms of all outcome measures among the overall, chemo-naive and previously treated patients. Rank probabilities showed that erlotinib and afatinib had potentially better efficacy compared with gefitinib in both of the overall and chemo-naive patients. Potentially survival benefit of erlotinib was also observed in previously treated patients compared with gefitinib. Additionally, EGFR-TKI showed numerically greater survival benefit in 19 Del compared with chemotherapy, while it was opposite in 21 L858R. Furthermore, afatinib, erlotinib and gefitinib had high, moderate and low risk of rash & diarrhea, respectively, while the occurrence of elevated liver transaminase was more common in gefitinib. METHODS: Data of objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and adverse events were extracted from included studies. Efficacy and toxicity of all included treatments were integrated by network meta-analyses. CONCLUSION: Our study indicated a high efficacy-high toxicity pattern of afatinib, a high efficacy-moderate toxicity pattern of erlotinib and a medium efficacy-moderate toxicity pattern of gefitinib. Recommended EGFR-TKI should be suggested according to patients' tolerability and therapeutic efficacy in clinical practice. Moreover, the treatment for advanced EGFR-positive NSCLC might be different between 19 Del and 21 L858R. PMID- 26933810 TI - Acquired-resistance of bevacizumab treatment for radiation brain necrosis: a case report. AB - The case study reported on acquired bevacizumab resistance in one patient receiving re-treatment with bevacizumab following radiation brain necrosis progression after bevacizumab was discontinued. This case offers novel and additional insight for bevacizumab treatment. Low-dose bevacizumab is effective for radiation brain necrosis, and radiation brain necrosis may progress after bevacizumab discontinuation, whereas too many cycles of bevacizumab treatment may induce drug-resistance and re-treatment failure following the progression. Therefore, more rational administration for radiation brain necrosis with bevacizumab may include three aspects: short-course treatment, timely discontinuation upon obtaining satisfactory effects (to prevent long-term medication associated resistance) and re-treatment after brain necrosis progression. PMID- 26933808 TI - Multi-platform molecular profiling of a large cohort of glioblastomas reveals potential therapeutic strategies. AB - Glioblastomas (GBM) are the most aggressive and prevalent form of gliomas with abysmal prognosis and limited treatment options. We analyzed clinically relevant molecular aberrations suggestive of response to therapies in 1035 GBM tumors. Our analysis revealed mutations in 39 genes of 48 tested. IHC revealed expression of PD-L1 in 19% and PD-1 in 46%. MGMT-methylation was seen in 43%, EGFRvIII in 19% and 1p19q co-deletion in 2%. TP53 mutation was associated with concurrent mutations, while IDH1 mutation was associated with MGMT-methylation and TP53 mutation and was mutually exclusive of EGFRvIII mutation. Distinct biomarker profiles were seen in GBM compared with WHO grade III astrocytoma, suggesting different biology and potentially different treatment approaches. Analysis of 17 metachronous paired tumors showed frequent biomarker changes, including MGMT methylation and EGFR aberrations, indicating the need for a re-biopsy for tumor profiling to direct subsequent therapy. MGMT-methylation, PR and TOPO1 appeared as significant prognostic markers in sub-cohorts of GBM defined by age. The current study represents the largest biomarker study on clinical GBM tumors using multiple technologies to detect gene mutation, amplification, protein expression and promoter methylation. These data will inform planning for future personalized biomarker-based clinical trials and identifying effective treatments based on tumor biomarkers. PMID- 26933809 TI - The epidermal growth factor receptor regulates cofilin activity and promotes transmissible gastroenteritis virus entry into intestinal epithelial cells. AB - Transmissible gastroenteritis virus (TGEV), a coronavirus, causes severe diarrhea and high mortality in newborn piglets. The porcine intestinal epithelium is the target of TGEV infection, but the mechanisms that TGEV disrupts the actin cytoskeleton and invades the host epithelium remain largely unknown. We not only found that TGEV infection stimulates F-actin to gather at the cell membrane but the disruption of F-actin inhibits TGEV entry as well. Cofilin is involved in F actin reorganization and TGEV entry. The TGEV spike protein is capable of binding with EGFR, activating the downstream phosphoinositide-3 kinase (PI3K), then causing the phosphorylation of cofilin and F-actin polymerization via Rac1/Cdc42 GTPases. Inhibition of EGFR and PI3K decreases the entry of TGEV. EGFR is also the upstream activator of mitogen-activated protein kinase (MAPK) signaling pathways that is involved in F-actin reorganization. Additionally, lipid rafts act as signal platforms for the EGFR-associated signaling cascade and correlate with the adhesion of TGEV. In conlusion, these results provide valuable data of the mechanisms which are responsible for the TGEV pathogenesis and may lead to the development of new methods about controlling TGEV. PMID- 26933811 TI - Low-dose tacrolimus combined with donor-derived mesenchymal stem cells after renal transplantation: a prospective, non-randomized study. AB - Calcineurin inhibitors, including tacrolimus, are largely responsible for advances in allotransplantation. However, the nephrotoxicity associated with these immunosuppressants impairs patients' long-term survival after renal allograft. Therefore, novel regimens that minimize or even eliminate calcineurin inhibitors could improve transplantation outcomes. In this pilot study, we investigated the use of low-dose tacrolimus in combination with mesenchymal stem cells (MSCs), which are immunosuppressive and prolong allograft survival in experimental organ transplant models. Donor-derived, bone marrow MSCs combined with a sparing dose of tacrolimus (0.04-0.05 mg/kg/day) were administered to 16 de novo living-related kidney transplant recipients; 16 other patients received a standard dose of tacrolimus (0.07-0.08 mg/kg/day). The safety of MSC infusion, acute rejection, graft function, graft survival, and patient survival were evaluated over >=24 months following kidney transplantation. All patients survived and had stable renal function at the 24 month follow-up. The combination of low-dose tacrolimus and MSCs was as effective as standard dose tacrolimus in maintaining graft survival at least 2 years after transplantation. In addition, both groups had similar urea, urine protein, urinary RBC, urinary WBC, 24-h urine protein, and creatinine clearance rates from 7 days to 24 months after transplantation. Furthermore, no differences in the proportion of lymphocytes, CD19, CD3, CD34, CD38, and natural killer cells were detected between the control and experimental groups. None of the MSC recipients experienced immediate or long term toxicity from the treatment. This preliminary data suggests that the addition of MSCs permits the use of lower dosages of nephrotoxic calcineurin inhibitors following renal transplantation. PMID- 26933812 TI - Loss of myocardial protection against myocardial infarction in middle-aged transgenic mice overexpressing cardiac thioredoxin-1. AB - Thioredoxin-1 (Trx1) protects the heart from ischemia/reperfusion (I/R) injury. Given that the age at which the first episode of coronary disease takes place has considerably decreased, life at middle-aged (MA) emerges as a new field of study. The aim was determine whether infarct size, Trx1 expression and activity, Akt and GSK-3beta were altered in young (Y) and MA mice overexpressing cardiac Trx1, and in a dominant negative (DN-Trx1) mutant of Trx1. Langendorff-perfused hearts were subjected to 30 minutes of ischemia and 120 minutes of reperfusion (R). We used 3 and 12 month-old male of wild type (WT), Trx1, and DN-Trx1. Trx1 overexpression reduced infarct size in young mice (WT-Y: 46.8+/-4.1% vs. Trx1-Y: 27.6+/-3.5%, p < 0.05). Trx1 activity was reduced by 52.3+/-3.2% (p < 0.05) in Trx1-MA, accompanied by an increase in nitration by 17.5+/-0.9%, although Trx1 expression in transgenic mice was similar between young and middle-aged. The expression of p Akt and p-GSK-3beta increased during reperfusion in Trx1-Y. DN-Trx1 mice showed neither reduction in infarct size nor Akt and GSK-3beta phosphorylation. Our data suggest that the lack of protection in Trx1 middle-aged mice even with normal Trx1 expression may be associated to decreased Trx1 activity, increased nitration and inhibition of p-Akt and p-GSK-3beta. PMID- 26933813 TI - Rationale and design of the allogeneiC human mesenchymal stem cells (hMSC) in patients with aging fRAilTy via intravenoUS delivery (CRATUS) study: A phase I/II, randomized, blinded and placebo controlled trial to evaluate the safety and potential efficacy of allogeneic human mesenchymal stem cell infusion in patients with aging frailty. AB - Frailty is a syndrome associated with reduced physiological reserves that increases an individual's vulnerability for developing increased morbidity and/or mortality. While most clinical trials have focused on exercise, nutrition, pharmacologic agents, or a multifactorial approach for the prevention and attenuation of frailty, none have studied the use of cell-based therapies. We hypothesize that the application of allogeneic human mesenchymal stem cells (allo hMSCs) as a therapeutic agent for individuals with frailty is safe and efficacious. The CRATUS trial comprises an initial non-blinded phase I study, followed by a blinded, randomized phase I/II study (with an optional follow-up phase) that will address the safety and pre-specified beneficial effects in patients with the aging frailty syndrome. In the initial phase I protocol, allo hMSCs will be administered in escalating doses via peripheral intravenous infusion (n=15) to patients allocated to three treatment groups: Group 1 (n=5, 20 million allo-hMSCs), Group 2 (n=5, 100 million allo-hMSCs), and Group 3 (n=5, 200 million allo-hMSCs). Subsequently, in the randomized phase, allo-hMSCs or matched placebo will be administered to patients (n=30) randomly allocated in a 1:1:1 ratio to one of two doses of MSCs versus placebo: Group A (n=10, 100 million allo hMSCs), Group B (n=10, 200 million allo-hMSCs), and Group C (n=10, placebo). Primary and secondary objectives are, respectively, to demonstrate the safety and efficacy of allo-hMSCs administered in frail older individuals. This study will determine the safety of intravenous infusion of stem cells and compare phenotypic outcomes in patients with aging frailty. PMID- 26933814 TI - Biological outcome and mapping of total factor cascades in response to HIF induction during regenerative angiogenesis. AB - Hypoxia Inducible Factor (HIF) is the main transcription factor that mediates cell response to hypoxia. Howeverthe complex factor cascades induced by HIF during regenerative angiogenesis are currently incompletely mapped and the biological outcome mediated by chronic HIF induction during vessel regeneration are not well known. Here, we investigated the biological impact of HIF induction on vascular regeneration and identified the differentially regulated genes during regeneration, HIF induction and hypoxic regeneration. The use of the fin zebrafish regeneration model revealed that exposure to HIF inducer (cobalt chloride) prevents vessel differentiation by maintaining their vascular plexuses in an immature state. The regenerated fins are easily breakable, lacking completely endochondral ossification. Gene expression arrays combined to gene functional enrichment analysis revealed that regenerative process and HIF induction shared the regulation of common genes mainly involved in DNA replication and proteasome complex. HIF induction during regeneration affected the expression of exclusive genes involved in cell differentiation and communication, consistent with the observed immature vascular plexuses of the regenerated fins during HIF induction. The use of morpholino (MO) knockdown strategy revealed that the expression of some of these genes such as tubulin and col10a1 are required for fin regeneration. Taken together, this study revealed the impact of HIF induction on regenerative angiogenesis and provided a framework to develop a gene network leading to regenerative process during HIF expression. PMID- 26933815 TI - The expression of plakoglobin is a potential prognostic biomarker for patients with surgically resected lung adenocarcinoma. AB - PURPOSE: This study aimed to explore the relationship between plakoglobin expression and clinical data in the patients with surgically resected lung adenocarcinoma. RESULTS: With follow-up of median 50.14 months, the average PFS and OS were 16.82 and 57.92 months, respectively. In 147 patients, recurrence or death was observed in 131 patients. According to the log-rank test, low plakoglobin expression was a significant predictor for favorable DFS (P=0.006) and OS (P=0.043). For the analyses within subgroups, high plakoglobin expression was an independent factor for reducing DFS in non-metastatic patients with resected lung adenocarcinoma (P < 0.05). Moreover, high plakoglobin expression was associated with poor DFS even receiving adjuvant chemotherapy (P =0.028) and with a shorter DFS (HR, 2.01, 95%CIs, 1.35 to 2.97, P=0.001) and OS (HR, 1.94, 95%CIs, 1.12 to 3.37, P=0.019). PATIENTS AND METHODS: The expression of plakoglobin in 147 primary tumor tissues was examined by using immunohistochemistry and clinical data were collected. The optimal cutoff value of immunoreactivity score (IRS) was calculated and used to divide all the patients into two groups: low-level group (IRS: 0-3, n=59) and high-level group (IRS: 4-12, n=88). Kaplan-Meier curves were applied to assess the plakoglobin expression and clinical variables. The univariate and multivariate Cox model analyses were performed to evaluate the effects of clinical factors and plakoglobin expression on disease-free survival (DFS) and overall survival (OS). CONCLUSIONS: High plakoglobin expression is an independent negative prognostic factor for patients with surgically resected lung adenocarcinoma. PMID- 26933817 TI - The mitochondrial and death receptor pathways involved in the thymocytes apoptosis induced by aflatoxin B1. AB - Aflatoxin B1 (AFB1) is a potent immunosuppressive agent in endotherms, which can be related to the up-regulated apoptosis of immune organs. In this study, we investigated the roles of the mitochondrial, death receptor, and endoplasmic reticulum pathways in Aflatoxin B1 induced thymocytes apoptosis. Chickens were fed an aflatoxin B1 containing diet (0.6 mg/kg AFB1) for 3 weeks. Our results showed that (1) AFB1 diet induced the decrease of T-cell subsets, morphological changes, and excessive apoptosis of thymus. (2) The excessive apoptosis involved the mitochondrial pathway (up-regulation of Bax, Bak, cytC and down-regulation of Bcl-2 and Bcl-xL) and death receptor pathway (up-regulation of FasL, Fas and FADD). (3) Oxidative stress, an apoptosis inducer, was confirmed in the thymus. In conclusion, this is the first study to demonstrate that mitochondrial and death receptor pathways involved in AFB1 induced thymocytes apoptosis in broilers. PMID- 26933816 TI - Beneficial bacteria inhibit cachexia. AB - Muscle wasting, known as cachexia, is a debilitating condition associated with chronic inflammation such as during cancer. Beneficial microbes have been shown to optimize systemic inflammatory tone during good health; however, interactions between microbes and host immunity in the context of cachexia are incompletely understood. Here we use mouse models to test roles for bacteria in muscle wasting syndromes. We find that feeding of a human commensal microbe, Lactobacillus reuteri, to mice is sufficient to lower systemic indices of inflammation and inhibit cachexia. Further, the microbial muscle-building phenomenon extends to normal aging as wild type animals exhibited increased growth hormone levels and up-regulation of transcription factor Forkhead Box N1 [FoxN1] associated with thymus gland retention and longevity. Interestingly, mice with a defective FoxN1 gene (athymic nude) fail to inhibit sarcopenia after L. reuteri therapy, indicating a FoxN1-mediated mechanism. In conclusion, symbiotic bacteria may serve to stimulate FoxN1 and thymic functions that regulate inflammation, offering possible alternatives for cachexia prevention and novel insights into roles for microbiota in mammalian ontogeny and phylogeny. PMID- 26933819 TI - Sixth BHD Symposium and First International Upstate Kidney Cancer Symposium: latest scientific and clinical discoveries. AB - The Sixth BHD Symposium and First International Upstate Kidney Cancer Symposium concluded in September 2015, in Syracuse, NY, USA. The program highlighted recent findings in a variety of areas, including drug development, therapeutics and surgical management of patients with BHD and multi-focal renal tumors, as well as multidisciplinary approaches for patients with localized, locally advanced and metastatic renal cell carcinoma. PMID- 26933818 TI - Squamous cell carcinomas of the lung and of the head and neck: new insights on molecular characterization. AB - Squamous cell carcinomas of the lung and of the head and neck district share strong association with smoking habits and are characterized by smoke-related genetic alterations. Driver mutations have been identified in small percentage of lung squamous cell carcinoma. In parallel, squamous head and neck tumors are classified according to the HPV positivity, thus identifying two different clinical and molecular subgroups of disease.This review depicts different molecular portraits and potential clinical application in the field of targeted therapy, immunotherapy and chemotherapy personalization. PMID- 26933820 TI - The matricellular protein CCN6 (WISP3) decreases Notch1 and suppresses breast cancer initiating cells. AB - Increasing evidence supports that the epithelial to mesenchymal transition (EMT) in breast cancer cells generates tumor initiating cells (TICs) but the contribution of the tumor microenvironment to these programs needs further elucidation. CCN6 (WISP3) is a secreted matrix-associated protein (36.9 kDa) of the CCN family (named after CTGF, Cyr61 and Nov) that is reduced or lost in invasive carcinomas of the breast with lymph node metastasis and in inflammatory breast cancer. CCN6 exerts breast cancer growth and invasion inhibitory functions, but the mechanisms remain to be defined. In the present study we discovered that ectopic CCN6 overexpression in triple negative (TN) breast cancer cells and in cells derived from patients is sufficient to induce a mesenchymal to epithelial transition (MET) and to reduce TICs. In vivo, CCN6 overexpression in the TIC population of MDA-MB-231 cells delayed tumor initiation, reduced tumor volume, and inhibited the development of metastasis. Our studies reveal a novel CCN6/Slug signaling axis that regulates Notch1 signaling activation, epithelial cell phenotype and breast TICs, which requires the conserved thrombospondin type 1 (TSP1) motif of CCN6. The relevance of these data to human breast cancer is highlighted by the finding that CCN6 protein levels are inversely correlated with Notch1 intracellular activated form (NICD1) in 69.5% of invasive breast carcinomas. These results demonstrate that CCN6 regulates epithelial and mesenchymal states transition and TIC programs, and pinpoint one responsible mechanism. PMID- 26933821 TI - Decellularized allogeneic intervertebral disc: natural biomaterials for regenerating disc degeneration. AB - Intervertebral disc degeneration is associated with back pain and disc herniation. This study established a modified protocol for intervertebral disc (IVD) decellularization and prepared its extracellular matrix (ECM). By culturing mesenchymal stem cells (MSCs)(3, 7, 14 and 21 days) and human degenerative IVD cells (7 days) in the ECM, implanting it subcutaneously in rabbit and injecting ECM microparticles into degenerative disc, the biological safety and efficacy of decellularized IVD was evaluated both in vitro and in vivo. Here, we demonstrated that cellular components can be removed completely after decellularization and maximally retain the structure and biomechanics of native IVD. We revealed that allogeneic ECM did not evoke any apparent inflammatory reaction in vivo and no cytotoxicity was found in vitro. Moreover, IVD ECM can induce differentiation of MSCs into IVD-like cells in vitro. Furthermore, allogeneic ECM microparticles are effective on the treatment of rabbit disc degeneration in vivo. In conclusion, our study developed an optimized method for IVD decellularization and we proved decellularized IVD is safe and effective for the treatment of degenerated disc diseases. PMID- 26933823 TI - Prevalence and correlates of painful conditions and multimorbidity in national sample of overweight/obese Veterans. AB - Chronic pain and overweight/obesity are prevalent public health concerns and occur at particularly high rates among Veterans. This study examined the prevalence and correlates of two common painful conditions (back pain and arthritis/joint pain) among overweight/obese Veterans in Veterans Health Administration (VHA) care. Participants (N = 45,477) completed the MOVE!23, a survey intended to tailor treatment for Veterans in VHA's MOVE! weight-management program. Overall, 72% of the sample reported painful conditions, with 10% reporting back pain, 26% reporting arthritis/joint pain, and 35% reporting both. We used multinomial logistic regression with "no pain" as the reference category to examine the association between painful conditions and participant characteristics. After multivariable adjustment, female Veterans had higher odds of reporting arthritis/joint pain and combined back and arthritis/joint pain than no pain. Participants with higher body mass index had higher odds of reporting arthritis/joint pain and both back and arthritis/joint pain. The likelihood of painful conditions was higher in Veterans with comorbidities (hypertension, hyperlipidemia, lung disease, depression, anxiety, or posttraumatic stress disorder) and generally increased with the number of comorbidities reported (i.e., 5 or more). Overweight/obese Veterans frequently report painful conditions and, among those with pain, often have multiple comorbidities. These factors may increase the complexity of clinical management and necessitate refinements to weight-management programs. PMID- 26933825 TI - Lack of association between MC1R variants and Parkinson disease in European descent. PMID- 26933822 TI - Downregulation of miR-137 and miR-6500-3p promotes cell proliferation in pediatric high-grade gliomas. AB - Pediatric high-grade gliomas (pHGGs) are aggressive brain tumors affecting children, and outcomes have remained dismal, even with access to new multimodal therapies. In this study, we compared the miRNomes and transcriptomes of pediatric low- (pLGGs) and high-grade gliomas (pHGGs) using small RNA sequencing (smRNA-Seq) and gene expression microarray, respectively. Through integrated bioinformatics analyses and experimental validation, we identified miR-137 and miR-6500-3p as significantly downregulated in pHGGs. miR-137 or miR-6500-3p overexpression reduced cell proliferation in two pHGG cell lines, SF188 and UW479. CENPE, KIF14 and NCAPG levels were significantly higher in pHGGs than pLGGs, and were direct targets of miR-137 or miR-6500-3p. Furthermore, knockdown of CENPE, KIF14 or NCAPG combined with temozolomide treatment resulted in a combined suppressive effect on pHGG cell proliferation. In summary, our results identify novel mRNA/miRNA interactions that contribute to pediatric glioma malignancy and represent potential targets for the development of new therapeutic strategies. PMID- 26933826 TI - Quantifying creatinine and urea in human urine through Raman spectroscopy aiming at diagnosis of kidney disease. AB - Due to their importance in the regulation of metabolites, the kidneys need continuous monitoring to check for correct functioning, mainly by urea and creatinine urinalysis. This study aimed to develop a model to estimate the concentrations of urea and creatinine in urine by means of Raman spectroscopy (RS) that could be used to diagnose kidney disease. Midstream urine samples were obtained from 54 volunteers with no kidney complaints. Samples were subjected to a standard colorimetric assay of urea and creatinine and submitted to spectroscopic analysis by means of a dispersive Raman spectrometer (830 nm, 350 mW, 30 s). The Raman spectra of urine showed peaks related mainly to urea and creatinine. Partial least squares models were developed using selected Raman bands related to urea and creatinine and the biochemical concentrations in urine measured by the colorimetric method, resulting in r = 0.90 and 0.91 for urea and creatinine, respectively, with root mean square error of cross-validation (RMSEcv) of 312 and 25.2 mg/dL, respectively. RS may become a technique for rapid urinalysis, with concentration errors suitable for population screening aimed at the prevention of renal diseases. PMID- 26933828 TI - A Lysosome-Compatible Near-Infrared Fluorescent Probe for Targeted Monitoring of Nitric Oxide. AB - The requirement for nitric oxide (NO) of lysosomes has motivated the development of a sophisticated fluorescent probe to monitor the distribution of this important biomolecule at the subcellular level in living cells. A near-infrared (NIR) fluorescent Si-rhodamine (SiRB)-NO probe was designed based on the NO induced ring-opening process of Si-rhodamine. The probe exhibits fast chromogenic and fluorogenic responses, and high sensitivity and selectivity toward trace amounts of NO. Significantly, the spirolactam in Si-rhodamine exhibits very good tolerance to H(+), which in turn brings extremely low background fluorescence not only in the physiological environment but also under acidic conditions. The stability of the highly fluorescent product in acidic solution provides persistent fluorescence emission for long-term imaging experiments. To achieve targeted imaging with improved spatial resolution and sensitivity, an efficient lysosome-targeting moiety was conjugated to a SiRB-NO probe, affording a tailored lysosome-targeting NIR fluorescent Lyso-SiRB-NO probe. Inheriting the key advantages of its parent SiRB-NO probe, Lyso-SiRB-NO is a functional probe that is suited for monitoring lysosomal NO with excellent lysosome compatibility. Imaging experiments demonstrated the monitoring of both exogenous and endogenous NO in real time by using the Lyso-SiRB-NO probe. PMID- 26933827 TI - Integrated sensor-augmented pump therapy systems [the MiniMed(r) ParadigmTM Veo system and the VibeTM and G4(r) PLATINUM CGM (continuous glucose monitoring) system] for managing blood glucose levels in type 1 diabetes: a systematic review and economic evaluation. AB - BACKGROUND: In recent years, meters for continuous monitoring of interstitial fluid glucose have been introduced to help people with type 1 diabetes mellitus (T1DM) to achieve better control of their disease. OBJECTIVE: The objective of this project was to summarise the evidence on the clinical effectiveness and cost effectiveness of the MiniMed((r)) ParadigmTM Veo system (Medtronic Inc., Northridge, CA, USA) and the VibeTM (Animas((r)) Corporation, West Chester, PA, USA) and G4((r)) PLATINUM CGM (continuous glucose monitoring) system (Dexcom Inc., San Diego, CA, USA) in comparison with multiple daily insulin injections (MDIs) or continuous subcutaneous insulin infusion (CSII), both with either self monitoring of blood glucose (SMBG) or CGM, for the management of T1DM in adults and children. DATA SOURCES: A systematic review was conducted in accordance with the principles of the Centre for Reviews and Dissemination guidance and the National Institute for Health and Care Excellence Diagnostic Assessment Programme manual. We searched 14 databases, three trial registries and two conference proceedings from study inception up to September 2014. In addition, reference lists of relevant systematic reviews were checked. In the absence of randomised controlled trials directly comparing Veo or an integrated CSII + CGM system, such as Vibe, with comparator interventions, indirect treatment comparisons were performed if possible. METHODS: A commercially available cost-effectiveness model, the IMS Centre for Outcomes Research and Effectiveness diabetes model version 8.5 (IMS Health, Danbury, CT, USA), was used for this assessment. This model is an internet-based, interactive simulation model that predicts the long term health outcomes and costs associated with the management of T1DM and type 2 diabetes. The model consists of 15 submodels designed to simulate diabetes related complications, non-specific mortality and costs over time. As the model simulates individual patients over time, it updates risk factors and complications to account for disease progression. RESULTS: Fifty-four publications resulting from 19 studies were included in the review. Overall, the evidence suggests that the Veo system reduces hypoglycaemic events more than other treatments, without any differences in other outcomes, including glycated haemoglobin (HbA1c) levels. We also found significant results in favour of the integrated CSII + CGM system over MDIs with SMBG with regard to HbA1c levels and quality of life. However, the evidence base was poor. The quality of the included studies was generally low, often with only one study comparing treatments in a specific population at a specific follow-up time. In particular, there was only one study comparing Veo with an integrated CSII + CGM system and only one study comparing Veo with a CSII + SMBG system in a mixed population. Cost-effectiveness analyses indicated that MDI + SMBG is the option most likely to be cost effective, given the current threshold of L30,000 per quality-adjusted life-year gained, whereas integrated CSII + CGM systems and Veo are dominated and extendedly dominated, respectively, by stand-alone, non-integrated CSII with CGM. Scenario analyses did not alter these conclusions. No cost-effectiveness modelling was conducted for children or pregnant women. CONCLUSIONS: The Veo system does appear to be better than the other systems considered at reducing hypoglycaemic events. However, in adults, it is unlikely to be cost-effective. Integrated systems are also generally unlikely to be cost-effective given that stand-alone systems are cheaper and, possibly, no less effective. However, evidence in this regard is generally lacking, in particular for children. Future trials in specific child, adolescent and adult populations should include longer term follow-up and ratings on the European Quality of Life-5 Dimensions scale at various time points with a view to informing improved cost-effectiveness modelling. STUDY REGISTRATION: PROSPERO Registration Number CRD42014013764. FUNDING: The National Institute for Health Research Health Technology Assessment programme. PMID- 26933824 TI - Neutrophil migration into the placenta: Good, bad or deadly? AB - Almost 2 decades have passed since the discovery that pregnancy is associated with a basal inflammatory state involving neutrophil activation, and that this is more overt in cases with preeclampsia, than in instances with sepsis. This pivotal observation paved the way for our report, made almost a decade ago, describing the first involvement of neutrophil extracellular traps (NETs) in a non-infectious human pathology, namely preeclampsia, where an abundance of these structures were detected directly in the placental intervillous space. Despite these remarkable findings, there remains a paucity of interest among reproductive biologists in further exploring the role or involvement of neutrophils in pregnancy and related pathologies. In this review we attempt to redress this deficit by highlighting novel recent findings including the discovery of a novel neutrophil subset in the decidua, the interaction of placental protein 13 (PP13) and neutrophils in modulating spiral artery modification, as well as the use of animal model systems to elucidate neutrophil function in implantation, gestation and parturition. These model systems have been particularly useful in identifying key components implicated in recurrent fetal loss, preeclampsia or new signaling molecules such as sphingolipids. Finally, the recent discovery that anti phospolipid antibodies can trigger NETosis, supports our hypothesis that these structures may contribute to placental dysfunction in pertinent cases with recurrent fetal loss. PMID- 26933829 TI - Initial destination hospital of paediatric prehospital patients in rural Victoria. AB - OBJECTIVE: The objective of this present study was to describe the initial destination hospital of paediatric patients transported by Ambulance Victoria paramedics within the South Western area of Victoria to determine the proportion of patients that bypassed their closest hospital. METHODS: All Ambulance Victoria primary ambulance transports for paediatric patients aged 1 month to 14 years in the Barwon South West region between 1 April 2008 and 28 February 2011 were reviewed. Each case was examined to determine the destination hospital location relative to the case scene location, and the overall nature of each case was grouped into one of seven categories (medical respiratory, medical cardiac, medical neurological, medical other, trauma time critical, and trauma non-time critical). RESULTS: There were 1191 cases identified, with 978 (82%) being taken to the closest hospital and 213 (18%) to a more distant facility. The average distance travelled from the scene to the destination hospital was 15.2 km, and almost 90% of patients transported to the nearest hospital were within 15 km of that hospital. Time critical trauma cases and respiratory-related medical cases had higher rates of transport to more distant hospitals as their initial destination (26% to non-closest and 23% to non-closest, respectively). CONCLUSION: The patient's condition and their location relative to the larger medical facilities appear to influence the decision of destination hospital. Uncertainty regarding the availability of 24 h hospital services and staffing details may contribute to longer transfers. PMID- 26933830 TI - Photosensitized 2-amino-3-hydroxypyridine-induced mitochondrial apoptosis via Smac/DIABLO in human skin cells. AB - The popularity of hair dyes use has been increasing regularly throughout the world as per the demand of hair coloring fashion trends and other cosmetic products. 2-Amino-3-hydroxypyridine (A132) is widely used as a hair dye ingredient around the world. We are reporting first time the phototoxicity mechanism of A132 under ambient environmental UV-B radiation. It showed maximum absorption in UV-B region (317 nm) and forms a photoproduct within an hour exposure of UV-B irradiation. Photocytotoxicity of A132 in human keratinocytes (HaCaT) was measured by mitochondrial (MTT), lysosomal (NRU) and LDH assays which illustrated the significant reduction in cell viability. The role of reactive oxygen species (ROS) generation for A132 phototoxicity was established photo- chemically as well as intracellularly. Noteworthy, formation of tail DNA (comet assay), micronuclei and cyclobutane pyrimidine dimers (CPDs) (immunocytochemistry) formation confirmed the photogenotoxic potential of dye. Cell cycle study (sub-G1peak) and staining with EB/AO revealed the cell cycle arrest and apoptosis. Further, mitochondrial mediated apoptosis was corroborated by reduced MMP, release of cytochrome c and upregulation of caspase-3. Release of mitochondrial Smac/DIABLO in cytoplasm demonstrated the caspase dependent apoptotic cell death by photolabile A132 dye. In-addition increased Bax/Bcl2 ratio again proved the apoptosis. Thus, study suggests that A132 induces photogenotoxicity, phototoxicity and apoptotic cell death through the involvement of Smac/DIABLO in mitochondrial apoptosis via caspase dependent manner. Therefore, the long term use of A132 dye and sunlight exposure jointly increased the oxidative stress in skin which causes premature hair loss, damage to progenitor cells of hair follicles. PMID- 26933831 TI - Highly Enantioselective Rhodium-Catalyzed Addition of Arylboroxines to Simple Aryl Ketones: Efficient Synthesis of Escitalopram. AB - Highly enantioselective additions of arylboroxines to simple aryl ketones have been achieved for the first time with a Rh/(R,R,R,R)-WingPhos catalyst, thus providing a range of chiral diaryl alkyl carbinols with excellent ee values and yields. (R,R,R,R)-WingPhos has been proven to be crucial for the high reactivity and enantioselectivity. The method has enabled a new, concise, and enantioselective synthesis of the antidepressant drug escitalopram. PMID- 26933833 TI - Abrupt Onset of Ulcerative Papules and Nodules on the Face and Genitals. PMID- 26933836 TI - Correction: ATP hydrolysis by the viral RNA sensor RIG-I prevents unintentional recognition of self-RNA. PMID- 26933835 TI - Alzheimer's Disease therapeutics: current and future therapies. AB - Pathologically, Alzheimer's Disease is characterized by amyloidal protein plaques that lead to dementia in the elderly population. While advances have been made in therapeutics over the course of the last 20 years, the drugs generally target the symptoms rather than the underlying pathology. Unfortunately, despite the advances, the mechanisms behind Alzheimer's Disease have still not been clearly identified. Some of these current treatments include acetylcholinesterase inhibitors and N-methyl-D-aspartate receptor agonists. Recently, the pathophysiology behind this disease is becoming more clearly understood and this has led to some novel therapeutic targets that may be able to break the barrier and target the underlying disease. In this review, we will discuss Alzheimer's Disease pathology and the pharmacological therapy that has been in use for a long time as well as novel therapies. PMID- 26933834 TI - Age-Dependent Susceptibility to Pulmonary Fibrosis Is Associated with NLRP3 Inflammasome Activation. AB - Aging has been implicated in the development of pulmonary fibrosis, which has seen a sharp increase in incidence in those older than 50 years. Recent studies demonstrate a role for the nucleotide-binding domain and leucine rich repeat containing family, pyrin domain containing 3 (NLRP3) inflammasome and its regulated cytokines in experimental lung fibrosis. In this study, we tested the hypothesis that age-related NLRP3 inflammasome activation is an important predisposing factor in the development of pulmonary fibrosis. Briefly, young and aged wild-type and NLRP3(-/-) mice were subjected to bleomycin-induced lung injury. Pulmonary fibrosis was determined by histology and hydroxyproline accumulation. Bone marrow and alveolar macrophages were isolated from these mice. NLRP3 inflammasome activation was assessed by co-immunoprecipitation experiments. IL-1beta and IL-18 production was measured by ELISA. The current study demonstrated that aged wild-type mice developed more lung fibrosis and exhibited increased morbidity and mortality after bleomycin-induced lung injury, when compared with young mice. Bleomycin-exposed aged NLRP3(-/-) mice had reduced fibrosis compared with their wild-type age-matched counterparts. Bone marrow derived and alveolar macrophages from aged mice displayed higher levels of NLRP3 inflammasome activation and caspase-1-dependent IL-1beta and IL-18 production, which was associated with altered mitochondrial function and increased production of reactive oxygen species. Our study demonstrated that age-dependent increases in alveolar macrophage mitochondrial reactive oxygen species production and NLRP3 inflammasome activation contribute to the development of experimental fibrosis. PMID- 26933837 TI - Dimensional analysis and scaling relevant to flow models of thrombus formation: communication from the SSC of the ISTH. PMID- 26933839 TI - Finding what works: Predicting health or social service linkage in drug using, African American, female sex workers in Miami, FL. AB - Female sex workers (FSWs) encounter numerous challenges in accessing health and social services. In this study of drug using, African American FSWs, the authors examine specific factors associated with health or social service linkage among participants in a randomized intervention trial. Respondent linkage was significantly associated with individual factors (living alone, severe internal mental distress, and traumatic victimization) and project-related variables (attending five case management sessions and client engagement rating). In the multivariate model, higher client engagement and session attendance remained significant. The researchers conclude by discussing the importance of intervention attendance and engagement as key contributors to health and social service linkage among FSWs. PMID- 26933838 TI - Suppression of a deletion mutation in the gene encoding essential PBP2b reveals a new lytic transglycosylase involved in peripheral peptidoglycan synthesis in Streptococcus pneumoniae D39. AB - In ellipsoid-shaped ovococcus bacteria, such as the pathogen Streptococcus pneumoniae (pneumococcus), side-wall (peripheral) peptidoglycan (PG) synthesis emanates from midcells and is catalyzed by the essential class B penicillin binding protein PBP2b transpeptidase (TP). We report that mutations that inactivate the pneumococcal YceG-domain protein, Spd_1346 (renamed MltG), remove the requirement for PBP2b. DeltamltG mutants in unencapsulated strains accumulate inactivation mutations of class A PBP1a, which possesses TP and transglycosylase (TG) activities. The 'synthetic viable' genetic relationship between Deltapbp1a and DeltamltG mutations extends to essential DeltamreCD and DeltarodZ mutations that misregulate peripheral PG synthesis. Remarkably, the single MltG(Y488D) change suppresses the requirement for PBP2b, MreCD, RodZ and RodA. Structural modeling and comparisons, catalytic-site changes and an interspecies chimera indicate that pneumococcal MltG is the functional homologue of the recently reported MltG endo-lytic transglycosylase of Escherichia coli. Depletion of pneumococcal MltG or mltG(Y488D) increases sphericity of cells, and MltG localizes with peripheral PG synthesis proteins during division. Finally, growth of Deltapbp1a DeltamltG or mltG(Y488D) mutants depends on induction of expression of the WalRK TCS regulon of PG hydrolases. These results fit a model in which MltG releases anchored PG glycan strands synthesized by PBP1a for crosslinking by a PBP2b:RodA complex in peripheral PG synthesis. PMID- 26933840 TI - Photocatalytic/Cu-Promoted C-H Activations: Visible-light-Induced ortho-Selective Perfluoroalkylation of Benzamides. AB - A visible-light-induced and copper-promoted perfluoroalkylation of benzamides was successfully developed under the assistance of an 8-aminoquinoline directing group. It provides a straightforward method for the synthesis of ortho perfluoroalkyl-substituted benzoic acid derivatives. The reaction employs a cheap organic dye eosin Y as the photoredox catalyst and is run under the irradiation of a 26 W fluorescent LED light bulb. PMID- 26933841 TI - The Effect of Deworming on Tests of Tuberculosis Infection in Children With Recent Tuberculosis Exposure: A Randomized Controlled Trial. AB - BACKGROUND: Helminth infestations are associated with T-helper cell type 2 (Th2) immune responses, leading to suppression of Th1 responses required to control Mycobacterium tuberculosis infection. We hypothesized that deworming after documented M. tuberculosis exposure might improve Th1 immune responses. METHODS: This was a randomized controlled trial comparing the effect of early versus delayed (after 3 months) deworming on tuberculin skin testing (TST) and Quantiferon-Gold-in-tube responses among children from a setting with a known high burden of M. tuberculosis and helminth co-infection in Cape Town, South Africa. Children aged 6 to 15 years with documented M. tuberculosis exposure were enrolled. Ascaris lumbricoides status was measured by Ascaris-specific IgE and stool microscopy. RESULTS: A total of 250 children (mean age, 9.6 years) were enrolled; 11.9% (27/227) were Ascaris stool microscopy positive and 54.2% (135/249) were Ascaris stool and/or IgE positive (Ascaris status). In univariable analysis, deworming at enrollment was not associated with a negative TST at 3 months (odds ratio, 0.61; 95% confidence interval, 0.35-1.07; P = 0.08). In stratified analysis, children with a positive Ascaris status were more likely to be TST negative at 3 months if dewormed early (odds ratio, 0.49; 95% confidence interval, 0.23-1.04; P = 0.06). In multivariable analysis, deworming was not associated with TST status (adjusted odds ratios, 0.62; 95% confidence interval, 0.34-1.10; P = 0.10). There was no association between deworming and Quantiferon Gold-in-tube status. CONCLUSIONS: Deworming in children with recent M. tuberculosis exposure is associated with a trend toward a negative TST result. Timing of deworming might influence interpretation of TST in settings with high burdens of tuberculosis and helminths. PMID- 26933842 TI - Frequency-specific disruptions of neuronal oscillations reveal aberrant auditory processing in schizophrenia. AB - Individuals with schizophrenia exhibit abnormalities in evoked brain responses in oddball paradigms. These could result from (a) insufficient salience-related cortical signaling (P300), (b) insufficient suppression of irrelevant aspects of the auditory environment, or (c) excessive neural noise. We tested whether disruption of ongoing auditory steady-state responses at predetermined frequencies informed which of these issues contribute to auditory stimulus relevance processing abnormalities in schizophrenia. Magnetoencephalography data were collected for 15 schizophrenia and 15 healthy subjects during an auditory oddball paradigm (25% targets; 1-s interstimulus interval). Auditory stimuli (pure tones: 1 kHz standards, 2 kHz targets) were administered during four continuous background (auditory steady-state) stimulation conditions: (1) no stimulation, (2) 24 Hz, (3) 40 Hz, and (4) 88 Hz. The modulation of the auditory steady-state response (aSSR) and the evoked responses to the transient stimuli were quantified and compared across groups. In comparison to healthy participants, the schizophrenia group showed greater disruption of the ongoing aSSR by targets regardless of steady-state frequency, and reduced amplitude of both M100 and M300 event-related field components. During the no-stimulation condition, schizophrenia patients showed accentuation of left hemisphere 40 Hz response to both standard and target stimuli, indicating an effort to enhance local stimulus processing. Together, these findings suggest abnormalities in auditory stimulus relevance processing in schizophrenia patients stem from insufficient amplification of salient stimuli. PMID- 26933843 TI - Determination of Autosomal Dominant or Recessive Methionine Adenosyltransferase I/III Deficiencies Based on Clinical and Molecular Studies. AB - Methionine adenosyltransferase (MAT) I/III deficiency can be inherited as autosomal dominant (AD) or as recessive (AR) traits in which mono- or biallelic MAT1A mutations have been identified, respectively. Although most patients have benign clinical outcomes, some with the AR form have neurological deficits. Here we describe 16 Korean patients with MAT I/III deficiency from 15 unrelated families identified by newborn screening. Ten probands had the AD MAT I/III deficiency, while six had AR MAT I/III deficiency. Plasma methionine (145.7 MUmol/L versus 733.2 MUmol/L, P < 0.05) and homocysteine levels (12.3 MUmol/L versus 18.6 MUmol/L, P < 0.05) were lower in the AD type than in AR type. In addition to the only reported AD MAT1A mutation, p.Arg264His, we identified two novel AD mutations, p.Arg249Gln and p.Gly280Arg. In the AR type, four previously reported and two novel mutations, p.Arg163Trp and p.Tyr335*, were identified. No exonic deletions were found by quantitative genomic polymerase chain reaction (PCR). Three-dimensional structural prediction programs indicated that the AD type mutations were located on the dimer interface or in the substrate binding site, hindering MAT I/III dimerization or substrate binding, respectively, whereas the AR mutations were distant from the interface or substrate binding site. These results indicate that the AD or AR MAT I/III deficiency is correlated with clinical findings, substrate levels and structural features of the mutant proteins, which is important for the neurological management and genetic counseling of the patients. PMID- 26933845 TI - Pharmaceutical Policy Reform--Balancing Affordability with Incentives for Innovation. PMID- 26933844 TI - Copy Number Variants Associated with 14 Cases of Self-Injurious Behavior. AB - Copy number variants (CNVs) were detected and analyzed in 14 probands with autism and intellectual disability with self-injurious behavior (SIB) resulting in tissue damage. For each proband we obtained a clinical history and detailed behavioral descriptions. Genetic anomalies were observed in all probands, and likely clinical significance could be established in four cases. This included two cases having novel, de novo copy number variants and two cases having variants likely to have functional significance. These cases included segmental trisomy 14, segmental monosomy 21, and variants predicted to disrupt the function of ZEB2 (encoding a transcription factor) and HTR2C (encoding a serotonin receptor). Our results identify variants in regions previously implicated in intellectual disability and suggest candidate genes that could contribute to the etiology of SIB. PMID- 26933846 TI - "An Uncommonly Silly Law"--Contraception and Disparities in the United States. PMID- 26933847 TI - Dealing with Racist Patients. PMID- 26933848 TI - Stopping vs. Continuing Aspirin before Coronary Artery Surgery. AB - BACKGROUND: Most patients with coronary artery disease receive aspirin for primary or secondary prevention of myocardial infarction, stroke, and death. Aspirin poses a risk of bleeding in patients undergoing surgery, but it is unclear whether aspirin should be stopped before coronary artery surgery. METHODS: We used a 2-by-2 factorial trial design to randomly assign patients who were scheduled to undergo coronary artery surgery and were at risk for perioperative complications to receive aspirin or placebo and tranexamic acid or placebo. The results of the aspirin trial are reported here. Patients were randomly assigned to receive 100 mg of aspirin or matched placebo preoperatively. The primary outcome was a composite of death and thrombotic complications (nonfatal myocardial infarction, stroke, pulmonary embolism, renal failure, or bowel infarction) within 30 days after surgery. RESULTS: Among 5784 eligible patients, 2100 were enrolled; 1047 were randomly assigned to receive aspirin and 1053 to receive placebo. A primary outcome event occurred in 202 patients in the aspirin group (19.3%) and in 215 patients in the placebo group (20.4%) (relative risk, 0.94; 95% confidence interval, 0.80 to 1.12; P=0.55). Major hemorrhage leading to reoperation occurred in 1.8% of patients in the aspirin group and in 2.1% of patients in the placebo group (P=0.75), and cardiac tamponade occurred at rates of 1.1% and 0.4%, respectively (P=0.08). CONCLUSIONS: Among patients undergoing coronary artery surgery, the administration of preoperative aspirin resulted in neither a lower risk of death or thrombotic complications nor a higher risk of bleeding than that with placebo. (Funded by the Australian National Health and Medical Research Council and others; Australia New Zealand Clinical Trials Registry number, ACTRN12605000557639.). PMID- 26933850 TI - Challenges in the Elimination of Pediatric HIV-1 Infection. PMID- 26933849 TI - Weekly vs. Every-3-Week Paclitaxel and Carboplatin for Ovarian Cancer. AB - BACKGROUND: A dose-dense weekly schedule of paclitaxel (resulting in a greater frequency of drug delivery) plus carboplatin every 3 weeks or the addition of bevacizumab to paclitaxel and carboplatin administered every 3 weeks has shown efficacy in ovarian cancer. We proposed to determine whether dose-dense weekly paclitaxel and carboplatin would prolong progression-free survival as compared with paclitaxel and carboplatin administered every 3 weeks among patients receiving and those not receiving bevacizumab. METHODS: We prospectively stratified patients according to whether they elected to receive bevacizumab and then randomly assigned them to receive either paclitaxel, administered intravenously at a dose of 175 mg per square meter of body-surface area every 3 weeks, plus carboplatin (dose equivalent to an area under the curve [AUC] of 6) for six cycles or paclitaxel, administered weekly at a dose of 80 mg per square meter, plus carboplatin (AUC, 6) for six cycles. The primary end point was progression-free survival. RESULTS: A total of 692 patients were enrolled, 84% of whom opted to receive bevacizumab. In the intention-to-treat analysis, weekly paclitaxel was not associated with longer progression-free survival than paclitaxel administered every 3 weeks (14.7 months and 14.0 months, respectively; hazard ratio for disease progression or death, 0.89; 95% confidence interval [CI], 0.74 to 1.06; P=0.18). Among patients who did not receive bevacizumab, weekly paclitaxel was associated with progression-free survival that was 3.9 months longer than that observed with paclitaxel administered every 3 weeks (14.2 vs. 10.3 months; hazard ratio, 0.62; 95% CI, 0.40 to 0.95; P=0.03). However, among patients who received bevacizumab, weekly paclitaxel did not significantly prolong progression-free survival, as compared with paclitaxel administered every 3 weeks (14.9 months and 14.7 months, respectively; hazard ratio, 0.99; 95% CI, 0.83 to 1.20; P=0.60). A test for interaction that assessed homogeneity of the treatment effect showed a significant difference between treatment with bevacizumab and without bevacizumab (P=0.047). Patients who received weekly paclitaxel had a higher rate of grade 3 or 4 anemia than did those who received paclitaxel every 3 weeks (36% vs. 16%), as well as a higher rate of grade 2 to 4 sensory neuropathy (26% vs. 18%); however, they had a lower rate of grade 3 or 4 neutropenia (72% vs. 83%). CONCLUSIONS: Overall, weekly paclitaxel, as compared with paclitaxel administered every 3 weeks, did not prolong progression-free survival among patients with ovarian cancer. (Funded by the National Cancer Institute and Genentech; GOG-0262 ClinicalTrials.gov number, NCT01167712.). PMID- 26933851 TI - IMAGES IN CLINICAL MEDICINE. Ocular Rosacea. PMID- 26933852 TI - CASE RECORDS of the MASSACHUSETTS GENERAL HOSPITAL. Case 6-2016. A 10-Year-Old Boy with Abdominal Cramping and Fevers. PMID- 26933853 TI - Excess Mortality among Persons with Type 2 Diabetes. PMID- 26933854 TI - Excess Mortality among Persons with Type 2 Diabetes. PMID- 26933855 TI - Excess Mortality among Persons with Type 2 Diabetes. PMID- 26933856 TI - Nicotinamide for Skin-Cancer Chemoprevention. PMID- 26933857 TI - Nicotinamide for Skin-Cancer Chemoprevention. PMID- 26933858 TI - Nicotinamide for Skin-Cancer Chemoprevention. PMID- 26933859 TI - Calcium and Vitamin D for the Prevention of Colorectal Adenomas. PMID- 26933860 TI - Calcium and Vitamin D for the Prevention of Colorectal Adenomas. PMID- 26933861 TI - Calcium and Vitamin D for the Prevention of Colorectal Adenomas. PMID- 26933862 TI - Lenalidomide plus Rituximab for Mantle-Cell Lymphoma. PMID- 26933863 TI - Lenalidomide plus Rituximab for Mantle-Cell Lymphoma. PMID- 26933864 TI - Invasive Candidiasis. PMID- 26933865 TI - Invasive Candidiasis. PMID- 26933866 TI - Invasive Candidiasis. PMID- 26933867 TI - Invasive Candidiasis. PMID- 26933868 TI - SLC25A32 Mutations and Riboflavin-Responsive Exercise Intolerance. PMID- 26933869 TI - Marijuana Tourism and Emergency Department Visits in Colorado. PMID- 26933870 TI - IMAGES IN CLINICAL MEDICINE. Eggshell Calcifications of the Bladder. PMID- 26933872 TI - Eye-movement strategies in developmental prosopagnosia and "super" face recognition. AB - Developmental prosopagnosia (DP) is a cognitive condition characterized by a severe deficit in face recognition. Few investigations have examined whether impairments at the early stages of processing may underpin the condition, and it is also unknown whether DP is simply the "bottom end" of the typical face processing spectrum. To address these issues, we monitored the eye-movements of DPs, typical perceivers, and "super recognizers" (SRs) while they viewed a set of static images displaying people engaged in naturalistic social scenarios. Three key findings emerged: (a) Individuals with more severe prosopagnosia spent less time examining the internal facial region, (b) as observed in acquired prosopagnosia, some DPs spent less time examining the eyes and more time examining the mouth than controls, and (c) SRs spent more time examining the nose a measure that also correlated with face recognition ability in controls. These findings support previous suggestions that DP is a heterogeneous condition, but suggest that at least the most severe cases represent a group of individuals that qualitatively differ from the typical population. While SRs seem to merely be those at the "top end" of normal, this work identifies the nose as a critical region for successful face recognition. PMID- 26933871 TI - Meta-Analysis of Transcriptional Responses to Mastitis-Causing Escherichia coli. AB - Bovine mastitis is a widespread disease in dairy cows, and is often caused by bacterial mammary gland infection. Mastitis causes reduced milk production and leads to excessive use of antibiotics. We present meta-analysis of transcriptional profiles of bovine mastitis from 10 studies and 307 microarrays, allowing identification of much larger sets of affected genes than any individual study. Combining multiple studies provides insight into the molecular effects of Escherichia coli infection in vivo and uncovers differences between the consequences of E. coli vs. Staphylococcus aureus infection of primary mammary epithelial cells (PMECs). In udders, live E. coli elicits inflammatory and immune defenses through numerous cytokines and chemokines. Importantly, E. coli infection causes downregulation of genes encoding lipid biosynthesis enzymes that are involved in milk production. Additionally, host metabolism is generally suppressed. Finally, defensins and bacteria-recognition genes are upregulated, while the expression of the extracellular matrix protein transcripts is silenced. In PMECs, heat-inactivated E. coli elicits expression of ribosomal, cytoskeletal and angiogenic signaling genes, and causes suppression of the cell cycle and energy production genes. We hypothesize that heat-inactivated E. coli may have prophylactic effects against mastitis. Heat-inactivated S. aureus promotes stronger inflammatory and immune defenses than E. coli. Lipopolysaccharide by itself induces MHC antigen presentation components, an effect not seen in response to E. coli bacteria. These results provide the basis for strategies to prevent and treat mastitis and may lead to the reduction in the use of antibiotics. PMID- 26933873 TI - Facing the challenge of pain management and opioid misuse, abuse and opioid related fatalities. PMID- 26933874 TI - Mobile Phone Messaging During Unobserved "Home" Induction to Buprenorphine. AB - The deployment of health information technologies promises to optimize clinical outcomes for populations with substance use disorders. Electronic health records, web-based counseling interventions, and mobile phone applications enhance the delivery of evidence-based behavioral and pharmacological treatments, with minimal burden to clinical personnel, infrastructure, and work flows. This clinical case shares a recent experience utilizing mobile phone text messaging between an office-based buprenorphine provider in a safety net ambulatory clinic and a patient seeking buprenorphine treatment for opioid use disorder. The case highlights the use of text message-based physician-patient communication to facilitate unobserved "home" induction onto buprenorphine. PMID- 26933875 TI - Specifying and Pilot Testing Quality Measures for the American Society of Addiction Medicine's Standards of Care. AB - OBJECTIVES: In 2013, the American Society of Addiction Medicine (ASAM) approved its Standards of Care for the Addiction Specialist Physician. Subsequently, an ASAM Performance Measures Panel identified and prioritized the standards to be operationalized into performance measures. The goal of this study is to describe the process of operationalizing 3 of these standards into quality measures, and to present the initial measure specifications and results of pilot testing these measures in a large health care system. By presenting the process rather than just the end results, we hope to shed light on the measure development process to educate, and also to stimulate debate about the decisions that were made. METHODS: Each measure was decomposed into major concepts. Then each concept was operationalized using commonly available administrative data sources. Alternative specifications examined and sensitivity analyses were conducted to inform decisions that balanced accuracy, clinical nuance, and simplicity. Using data from the US Veterans Health Administration (VHA), overall performance and variation in performance across 119 VHA facilities were calculated. RESULTS: Three measures were operationalized and pilot tested: pharmacotherapy for alcohol use disorder, pharmacotherapy for opioid use disorder, and timely follow-up after medically managed withdrawal (aka detoxification). Each measure was calculable with available data, and showed ample room for improvement (no ceiling effects) and wide facility-level variability. CONCLUSIONS: Next steps include conducting feasibility and pilot testing in other health care systems and other contexts such as standalone addiction treatment programs, and also to study the specification and predictive validity of these measures. PMID- 26933876 TI - Abuse Potential of Oral Phendimetrazine in Cocaine-dependent Individuals: Implications for Agonist-like Replacement Therapy. AB - OBJECTIVES: Phendimetrazine is a prodrug for the monoamine releaser phenmetrazine a drug with known abuse potential. Preclinical studies suggest that phendimetrazine has limited abuse potential and may have promise as an agonist like replacement therapy for cocaine dependence. This study evaluated the abuse potential of phendimetrazine in humans. METHODS: Nine cocaine-dependent individuals (N = 9) were enrolled to investigate the abuse potential of phendimetrazine and d-amphetamine, using a double-blind, placebo-controlled, within-subject design. Subjective and cardiovascular effects of oral phendimetrazine (35, 70, and 105 mg), d-amphetamine (10, 20, and 30 mg), and placebo were assessed in quasi-random order across 8 sessions lasting for approximately 8 hours each. RESULTS: d-Amphetamine (20 and 30 mg) significantly increased cardiovascular measures in a time and dose-related manner, but phendimetrazine did not systematically alter cardiovascular measures. Although d amphetamine and phendimetrazine significantly increased ratings indicative of abuse potential (eg, drug liking) and stimulant-like effects relative to placebo, these increases were generally small in magnitude, with phendimetrazine producing significant effects on fewer abuse-related measures and at fewer time points than d-amphetamine. CONCLUSIONS: These preliminary findings suggest that oral phendimetrazine and d-amphetamine may have limited abuse potential in cocaine dependent individuals. These findings collectively emphasize that the clinical utility of medications to treat cocaine-use disorders should be weighed carefully against their potential for abuse and diversion, with careful attention paid to evaluating abuse potential in a clinically relevant population of interest. Future studies are needed to further elucidate the potential utility of phendimetrazine as an agonist-like replacement therapy for cocaine dependence. PMID- 26933877 TI - Determination of Femoral Neck Angle and Torsion Angle Utilizing a Novel Three Dimensional Modeling and Analytical Technology Based on CT Datasets. AB - INTRODUCTION: Exact knowledge of femoral neck inclination and torsion angles is important in recognizing, understanding and treating pathologic conditions in the hip joint. However, published results vary widely between different studies, which indicates that there are persistent difficulties in carrying out exact measurements. METHODS: A three dimensional modeling and analytical technology was used for the analysis of 1070 CT datasets of skeletally mature femurs. Individual femoral neck angles and torsion angles were precisely computed, in order to establish whether gender, age, body mass index and ethnicity influence femoral neck angles and torsion angles. RESULTS: The median femoral neck angle was 122.2 degrees (range 100.1-146.2 degrees , IQR 117.9-125.6 degrees ). There are significant gender (female 123.0 degrees vs. male 121.5 degrees ; p = 0.007) and ethnic (Asian 123.2 degrees vs. Caucasian 121.9 degrees ; p = 0.0009) differences. The median femoral torsion angle was 14.2 degrees (-23.6-48.7 degrees , IQR 7.4-20.4 degrees ). There are significant gender differences (female 16.4 degrees vs. male 12.1 degrees ; p = 0.0001). Femoral retroversion was found in 7.8% of the subjects. CONCLUSION: Precise femoral neck and torsion angles were obtained in over one thousand cases. Systematic deviations in measurement due to human error were eliminated by using automated high accuracy morphometric analysis. Small but significant gender and ethnic differences were found in femoral neck and torsion angles. PMID- 26933878 TI - Incidence and Mortality Trends in German Women with Breast Cancer Using Age, Period and Cohort 1999 to 2008. AB - Longitudinal analysis investigates period (P), often as years. Additional scales of time are age (A) and birth cohort (C) Aim of our study was to use ecological APC analysis for women breast cancer incidence and mortality in Germany. Nation wide new cases and deaths were obtained from Robert Koch Institute and female population from federal statistics, 1999-2008. Data was stratified into ten 5 years age-groups starting 20-24 years, ten birth cohorts starting 1939-43, and two calendar periods 1999-2003 and 2004-2008. Annual incidence and mortality were calculated: cases to 100,000 women per year. Data was analyzed using glm and apc packages of R. Breast cancer incidence and mortality increased with age. Secular rise in breast cancer incidence and decline in mortality was observed for period 1999-2008. Breast cancer incidence and mortality declined with cohorts; cohorts 1950s showed highest incidence and mortality. Age-cohort best explained incidence and mortality followed by age-period-cohort with overall declining trends. Declining age-cohort mortality could be probable. Declining age-cohort incidence would require future biological explanations or rendered statistical artefact. Cohorts 1949-1958 could be unique in having highest incidence and mortality in recent time or future period associations could emerge relatively stronger to cohort to provide additional explanation of temporal change over cohorts. PMID- 26933879 TI - Carotid Intima-Media Thickness Is Associated with Increased Androgens in Adolescents and Young Adults with Classical Congenital Adrenal Hyperplasia. AB - BACKGROUND/AIMS: Youth with congenital adrenal hyperplasia (CAH) due to 21 hydroxylase deficiency develop cardiovascular disease (CVD) risk factors of obesity and hypertension. Carotid intima-media thickness (CIMT), a marker of CVD risk, is increased in CAH young adults. We examined CIMT and its relationship with androgens and obesity in adolescents/young adults with CAH. METHODS: Twenty CAH subjects (age 16 +/- 3.3 years, 50% female) and 20 matched controls were studied cross-sectionally. Eight additional obese patients with CAH were included in within-group comparisons. CIMT by high-resolution ultrasound, androgens, anthropometry, bone age (BA), and metabolic/inflammatory markers were assessed. RESULTS: Within the CAH group, CIMT correlated with 17-hydroxyprogesterone (r = 0.48, p < 0.05) and androstenedione (r = 0.46, p < 0.05), and was greater in obese subjects. CIMT was greater in CAH males than females, but similar among CAH females with advanced BA, CAH males with normal BA, and control males. There was no difference in CIMT between CAH and controls, although high-density lipoprotein was inversely correlated with CIMT in both groups. CONCLUSION: CIMT is associated with increased androgens in CAH adolescents and young adults, with loss of sex differences in CAH females with excess androgen exposure. Our findings highlight the importance of hormonal control for CVD prevention in CAH. PMID- 26933880 TI - Are School Absences Correlated with Influenza Surveillance Data in England? Results from Decipher My Data-A Research Project Conducted through Scientific Engagement with Schools. AB - BACKGROUND: School aged children are a key link in the transmission of influenza. Most cases have little or no interaction with health services and are therefore missed by the majority of existing surveillance systems. As part of a public engagement with science project, this study aimed to establish a web-based system for the collection of routine school absence data and determine if school absence prevalence was correlated with established surveillance measures for circulating influenza. METHODS: We collected data for two influenza seasons (2011/12 and 2012/13). The primary outcome was daily school absence prevalence (weighted to make it nationally representative) for children aged 11 to 16. School absence prevalence was triangulated graphically and through univariable linear regression to Royal College of General Practitioners (RCGP) influenza like illness (ILI) episode incidence rate, national microbiological surveillance data on the proportion of samples positive for influenza (A+B) and with Rhinovirus, RSV and laboratory confirmed cases of Norovirus. RESULTS: 27 schools submitted data over two respiratory seasons. During the first season, levels of influenza measured by school absence prevalence and established surveillance were low. In the 2012/13 season, a peak of school absence prevalence occurred in week 51, and week 1 in RCGP ILI surveillance data. Linear regression showed a strong association between the school absence prevalence and RCGP ILI (All ages, and 5-14 year olds), laboratory confirmed cases of influenza A & B, and weak evidence for a linear association with Rhinovirus and Norovirus. INTERPRETATION: This study provides initial evidence for using routine school illness absence prevalence as a novel tool for influenza surveillance. The network of web-based data collection platforms we established through active engagement provides an innovative model of conducting scientific research and could be used for a wide range of infectious disease studies in the future. PMID- 26933882 TI - Factors Associated with Fear of Falling among Community-Dwelling Older Adults in the Shih-Pai Study in Taiwan. AB - BACKGROUND: Fear of falling is an important risk indicator for adverse health related outcomes in older adults. However, factors associated with fear of falling among community-dwelling older adults are not well-explored. OBJECTIVES: To explore the quality of life and associated factors in fear of falling among older people in the Shih-Pai area in Taiwan. METHODS: This community-based survey recruited three thousand eight hundred and twenty-four older adults aged >= 65 years. The measurements included a structured questionnaire, including quality of life by using Short-Form 36, and information of fear of falling, fall history, demographics, medical conditions, insomnia, sleep quality, depression and subjective health through face-to-face interviews. RESULTS: A total of 53.4% of participants reported a fear of falling. The rate of fear of falling was higher in female subjects. Subjects with fear of falling had lower Short Form-36 scores both for men and women. Falls in the previous year, older age, insomnia, depression and worse subjective health were correlates of fear of falling for both sexes. Male-specific associations with fear of falling were the accessibility of medical help in an emergency, diabetes mellitus and stroke. In parallel, cardiovascular diseases were a female-specific correlate for fear of falling. CONCLUSIONS: Fear of falling is prevalent among community-dwelling older adults. It is seems that there are gender differences in fear of falling with respect to the prevalence and associated factors in older adults. Gender differences should be considered when planning prevention and intervention strategies for fear of falling among older people. PMID- 26933881 TI - Reactivation of Latent HIV-1 Expression by Engineered TALE Transcription Factors. AB - The presence of replication-competent HIV-1 -which resides mainly in resting CD4+ T cells--is a major hurdle to its eradication. While pharmacological approaches have been useful for inducing the expression of this latent population of virus, they have been unable to purge HIV-1 from all its reservoirs. Additionally, many of these strategies have been associated with adverse effects, underscoring the need for alternative approaches capable of reactivating viral expression. Here we show that engineered transcriptional modulators based on customizable transcription activator-like effector (TALE) proteins can induce gene expression from the HIV-1 long terminal repeat promoter, and that combinations of TALE transcription factors can synergistically reactivate latent viral expression in cell line models of HIV-1 latency. We further show that complementing TALE transcription factors with Vorinostat, a histone deacetylase inhibitor, enhances HIV-1 expression in latency models. Collectively, these findings demonstrate that TALE transcription factors are a potentially effective alternative to current pharmacological routes for reactivating latent virus and that combining synthetic transcriptional activators with histone deacetylase inhibitors could lead to the development of improved therapies for latent HIV-1 infection. PMID- 26933883 TI - Translational Research for Tuberculosis Elimination: Priorities, Challenges, and Actions. PMID- 26933884 TI - Effect of Physical Violence on Sexually Transmitted Infections and Treatment Seeking Behaviour among Female Sex Workers in Thane District, Maharashtra, India. AB - BACKGROUND: Violence against sex workers can heighten their vulnerability to HIV and other sexually transmitted infections (STIs). Evidence suggests the risk of acquiring STI/HIV infections among female sex workers (FSWs) who have experienced violence to be almost three-times higher than FSWs, who have not experienced violence. Moreover, an experience of physical and sexual violence makes it difficult for them to negotiate safer sex with their partners and often act as a barrier to utilization of prevention services. METHODS: This study utilizes data from 2785 FSWs aged 18 years and above who participated in a cross-sectional behavioural study conducted during 2013-14 in Thane district, Maharashtra. A probability-based two-stage cluster sampling method was used for data collection. This study assesses the effect of physical violence on self-reported STI symptoms (any STI and multiple STIs) and treatment seeking for the last STI symptom using propensity score matching method. RESULTS: About 18% of sampled FSWs reported physical violence at the time of the survey. The likelihood of experiencing such violence was significantly higher among FSWs who solicited clients at public places, engaged in other economic activities apart from sex work, had savings, and reported high client volume per week. FSWs experiencing violence were also inconsistent condom users while engaging in sex with regular partners and clients. The average adjusted effect of violence clearly depicted an increase in the risk of any STI (11%, p<0.05) and multiple STIs (8%, p<0.10) and reduction in treatment seeking (10%, p<0.05). CONCLUSIONS: This study demonstrates a significant effect of physical violence on reporting of any STI symptom and treatment seeking. Findings call for the immediate inclusion of strategies aimed to address violence related challenges in HIV prevention program currently being provided at Thane district. Such strategies would further help in enhancing the access to tailored STI prevention and care services among FSWs in the district. PMID- 26933885 TI - Intestinal Cell Tight Junctions Limit Invasion of Candida albicans through Active Penetration and Endocytosis in the Early Stages of the Interaction of the Fungus with the Intestinal Barrier. AB - C. albicans is a commensal yeast of the mucous membranes in healthy humans that can also cause disseminated candidiasis, mainly originating from the digestive tract, in vulnerable patients. It is necessary to understand the cellular and molecular mechanisms of the interaction of C. albicans with enterocytes to better understand the basis of commensalism and pathogenicity of the yeast and to improve the management of disseminated candidiasis. In this study, we investigated the kinetics of tight junction (TJ) formation in parallel with the invasion of C. albicans into the Caco-2 intestinal cell line. Using invasiveness assays on Caco-2 cells displaying pharmacologically altered TJ (i.e. differentiated epithelial cells treated with EGTA or patulin), we were able to demonstrate that TJ protect enterocytes against invasion of C. albicans. Moreover, treatment with a pharmacological inhibitor of endocytosis decreased invasion of the fungus into Caco-2 cells displaying altered TJ, suggesting that facilitating access of the yeast to the basolateral side of intestinal cells promotes endocytosis of C. albicans in its hyphal form. These data were supported by SEM observations of differentiated Caco-2 cells displaying altered TJ, which highlighted membrane protrusions engulfing C. albicans hyphae. We furthermore demonstrated that Als3, a hypha-specific C. albicans invasin, facilitates internalization of the fungus by active penetration and induced endocytosis by differentiated Caco-2 cells displaying altered TJ. However, our observations failed to demonstrate binding of Als3 to E-cadherin as the trigger mechanism of endocytosis of C. albicans into differentiated Caco-2 cells displaying altered TJ. PMID- 26933887 TI - Children Use Wealth Cues to Evaluate Others. AB - Wealth differences between individuals are ubiquitous in modern society, and often serve as the basis for biased social evaluations among adults. The present research probed whether children use cues that are commonly associated with wealth differences in society to guide their consideration of others. In Study 1, 4-5-year-old participants from diverse racial backgrounds expressed preferences for children who were paired with high-wealth cues; White children in Study 1 also matched high-wealth stimuli with White faces. Study 2 conceptually replicated the preference effect from Study 1, and showed that young children (4 6 years) also use material wealth indicators to guide their inferences about people's relative standing in other domains (i.e., competence and popularity). Study 3 revealed that children (5-9 years) use a broad range of wealth cues to guide their evaluations of, and actions toward, unfamiliar people. Further, biased responses were not attenuated among children whose families were lower in socioeconomic status. Often overlooked by those who study children's attitudes and stereotypes, social class markers appear to influence evaluations, inferences, and behavior early in development. PMID- 26933886 TI - Effect of a Medicinal Agaricus blazei Murill-Based Mushroom Extract, AndoSanTM, on Symptoms, Fatigue and Quality of Life in Patients with Ulcerative Colitis in a Randomized Single-Blinded Placebo Controlled Study. AB - BACKGROUND: Ingestion of AndoSanTM, based on the mushroom Agaricus blazei Murill, has previously been shown to exhibit anti-inflammatory effects because of reduction of pro-inflammatory cytokines in healthy individuals and patients with ulcerative colitis. In this randomized single-blinded placebo controlled study we examined whether intake of AndoSanTM also resulted in clinical effects. METHODS AND FINDINGS: 50 patients with symptomatic ulcerative colitis were block randomized and blinded for oral daily intake of AndoSanTM or placebo for the 21 days' experimental period. The patients reported scores for symptoms, fatigue and health related quality of life (HRQoL) at days 0, 14 and 21. Fecal calprotectin and general blood parameters were also analyzed. In the AndoSanTM group (n = 24) symptoms improved from baseline (day 0) to days 14 and 21, with respective mean scores (95% CI) of 5.88 (4.92-6.83), 4.71 (3.90-5.52) (p = 0.002) and 4.50 (3.70 5.30) (p = 0.001). Corresponding improved mean scores (+/-SD) for total fatigue were 16.6 (5.59), 14.1 (4.50) (p = 0.001) and 15.1 (4.09) (p = 0.023). These scores in the placebo group (n = 26) were not improved. When comparing the two study groups using mixed model statistics, we found significant better scores for the AndoSanTM-patients. HRQoL for dimensions bodily pain, vitality, social functioning and mental health improved in the AndoSanTM group. There were no alterations in general blood samples and fecal calprotectin. CONCLUSIONS: Beneficiary effects on symptoms, fatigue and HRQoL from AndoSanTM consumption were demonstrated in this per-protocol study, supporting its use as a supplement to conventional medication for patients with mild to moderate symptoms from ulcerative colitis. The patients did not report any harms or unintended effects of AndoSanTM in this study. TRIAL REGISTRATION: ClinicalTrials.gov NCT01496053. PMID- 26933888 TI - Defensins Potentiate a Neutralizing Antibody Response to Enteric Viral Infection. AB - alpha-defensins are abundant antimicrobial peptides with broad, potent antibacterial, antifungal, and antiviral activities in vitro. Although their contribution to host defense against bacteria in vivo has been demonstrated, comparable studies of their antiviral activity in vivo are lacking. Using a mouse model deficient in activated alpha-defensins in the small intestine, we show that Paneth cell alpha-defensins protect mice from oral infection by a pathogenic virus, mouse adenovirus 1 (MAdV-1). Survival differences between mouse genotypes are lost upon parenteral MAdV-1 infection, strongly implicating a role for intestinal defenses in attenuating pathogenesis. Although differences in alpha defensin expression impact the composition of the ileal commensal bacterial population, depletion studies using broad-spectrum antibiotics revealed no effect of the microbiota on alpha-defensin-dependent viral pathogenesis. Moreover, despite the sensitivity of MAdV-1 infection to alpha-defensin neutralization in cell culture, we observed no barrier effect due to Paneth cell alpha-defensin activation on the kinetics and magnitude of MAdV-1 dissemination to the brain. Rather, a protective neutralizing antibody response was delayed in the absence of alpha-defensins. This effect was specific to oral viral infection, because antibody responses to parenteral or mucosal ovalbumin exposure were not affected by alpha-defensin deficiency. Thus, alpha-defensins play an important role as adjuvants in antiviral immunity in vivo that is distinct from their direct antiviral activity observed in cell culture. PMID- 26933890 TI - The Grand Convergence: Closing the Divide between Public Health Funding and Global Health Needs. AB - The Global Health 2035 report notes that the "grand convergence"--closure of the infectious, maternal, and child mortality gap between rich and poor countries--is dependent on research and development (R&D) of new drugs, vaccines, diagnostics, and other health tools. However, this convergence (and the R&D underpinning it) will first require an even more fundamental convergence of the different worlds of public health and innovation, where a largely historical gap between global health experts and innovation experts is hindering achievement of the grand convergence in health. PMID- 26933889 TI - Environmental DNA as a 'Snapshot' of Fish Distribution: A Case Study of Japanese Jack Mackerel in Maizuru Bay, Sea of Japan. AB - Recent studies in streams and ponds have demonstrated that the distribution and biomass of aquatic organisms can be estimated by detection and quantification of environmental DNA (eDNA). In more open systems such as seas, it is not evident whether eDNA can represent the distribution and biomass of aquatic organisms because various environmental factors (e.g., water flow) are expected to affect eDNA distribution and concentration. To test the relationships between the distribution of fish and eDNA, we conducted a grid survey in Maizuru Bay, Sea of Japan, and sampled surface and bottom waters while monitoring biomass of the Japanese jack mackerel (Trachurus japonicus) using echo sounder technology. A linear model showed a high R(2) value (0.665) without outlier data points, and the association between estimated eDNA concentrations from the surface water samples and echo intensity was significantly positive, suggesting that the estimated spatial variation in eDNA concentration can reflect the local biomass of the jack mackerel. We also found that a best-fit model included echo intensity obtained within 10-150 m from water sampling sites, indicating that the estimated eDNA concentration most likely reflects fish biomass within 150 m in the bay. Although eDNA from a wholesale fish market partially affected eDNA concentration, we conclude that eDNA generally provides a 'snapshot' of fish distribution and biomass in a large area. Further studies in which dynamics of eDNA under field conditions (e.g., patterns of release, degradation, and diffusion of eDNA) are taken into account will provide a better estimate of fish distribution and biomass based on eDNA. PMID- 26933891 TI - Recent advances in the identification of Tat-mediated transactivation inhibitors: progressing toward a functional cure of HIV. AB - The current anti-HIV combination therapy does not eradicate the virus that persists mainly in quiescent infected CD4(+) T cells as a latent integrated provirus that resumes after therapy interruption. The Tat-mediated transactivation (TMT) is a critical step in the HIV replication cycle that could give the opportunity to reduce the size of latent reservoirs. More than two decades of research led to the identification of various TMT inhibitors. While none of them met the criteria to reach the market, the search for a suitable TMT inhibitor is still actively pursued. Really promising compounds, including one in a Phase III clinical trial, have been recently identified, thus warranting an update. PMID- 26933892 TI - The Differential Outcomes Effect in Pigeons (Columba livia): Is It Truly Anticipatory? AB - We used delay-interval interference to investigate the nature of the differential outcomes effect (DOE) in pigeons. Birds were trained on a delayed matching-to sample (DMS) task under either common outcome or differential outcome conditions, and then presented with visual interference during the delay period. Consistent with previous literature, the common outcomes birds were slower to learn the DMS task than the differential outcomes birds. The common outcome birds were also more impaired by the visual interference than the differential outcomes birds. Our findings are consistent with the view that the birds trained with common outcomes were likely remembering the sample stimulus during the delay period, and hence were disrupted by the visual interference, whereas the birds trained with differential outcomes were likely relying on the different emotional reactions elicited by the different outcomes to guide their choice behaviour, and hence were less affected by the visual interference. Our findings suggest that the DOE is not truly evidence of anticipatory mediation of short-term retention in pigeons, but rather emotionally driven decision making, which is not truly anticipatory in nature. PMID- 26933893 TI - Mutations in ATOH7 gene in patients with nonsyndromic congenital retinal nonattachment and familial exudative vitreoretinopathy. PMID- 26933894 TI - Age at the onset of menopause and its influencing factors in Turkish women in a rural area. AB - This study was performed to identify menopausal age and its determining factors in women over 40 residing in the Dogubeyazit district of Agri, located in Eastern Turkey. This cross-sectional study was performed on a sample of 1,068 women, selected by simple random sampling among all district health center records of women aged 40 and greater, who were each attributed a random serial number. While 35.6% of the subjects had not yet reached menopause, 60.5% had entered it spontaneously and 3.9% surgically. Average age at spontaneous menopause was 47.4 +/- 3.7 years and that of surgical menopause 45.1 +/- 5.0. Age at marriage, age of last pregnancy, and the age of the subject's mother at menopause affected menopausal status. Identifying menopausal age and its determining factors may modify the menopausal status of women and their management of the perimenopausal period. PMID- 26933895 TI - Abstracts from the ISGE World Congress 2016. PMID- 26933896 TI - Grazoprevir + elbasvir for the treatment of hepatitis C virus infection. AB - INTRODUCTION: Hepatitis C virus (HCV)-related liver disease is a cause of significant morbidity and mortality worldwide. Currently, direct-acting antiviral drugs (DAAs) are associated with an increased sustained virologic response (SVR) and are the gold standard for treating HCV infection. AREAS COVERED: The new combination of grazoprevir, an inhibitor of HCV NS3/4A, and elbasvir, an inhibitor of HCV NS5A, once daily will be available for the treatment of HCV infection. This combination therapy has a high efficacy in HCV genotype 1 and 4 infections, inducing a SVR up to 95%, even in difficult to treat patients such as cirrhotic, HIV co-infected, or dialysis-dependent patients, and patients with stage 4-5 chronic kidney disease or those who failed previous therapy. The safety of grazoprevir combined with elbasvir is very good and without significant adverse effects in phase 2 or 3 studies. For patients who failed prior DAA therapy, in vitro and in vivo studies showed that the grazoprevir and elbasvir combination is fully active against resistance to NS3/4A protease inhibitors. Resistance to NS5B inhibitors is least susceptible to grazoprevir or elbasvir. EXPERT OPINION: This new combination of gazoprevir with elbasvir offers an opportunity to cure HCV infection with short interferon-free therapy, even in difficult to treat patients. PMID- 26933897 TI - Effects of l-Carnitine Supplementation on Serum Inflammatory Factors and Matrix Metalloproteinase Enzymes in Females with Knee Osteoarthritis: A Randomized, Double-Blind, Placebo-Controlled Pilot Study. AB - OBJECTIVE: Considering the importance of inflammation in the pathogenesis of osteoarthritis (OA) and induction of pain, this study was aimed to investigate the effect of L-carnitine supplementation on serum inflammatory mediators and OA associated pain in females with knee OA. METHODS: In this clinical trial, 72 females with mild to moderate knee osteoarthritis started the study, divided into 2 groups to receive 750 mg/day L-carnitine (n = 36) or placebo (n = 36) for 8 weeks. Serum levels of Interleukine-1beta (IL-1beta), high-sensitivity C-reactive protein (hs-CRP), matrix metalloproteinases (MMPs)-1 and -13, and visual analog scale (VAS) for pain were assessed before and after supplementation. Data were analyzed by t test, Wilcoxon signed rank test, Mann-Whitney U test, and analysis of covariance. RESULTS: Only 69 patients (33 in the L-carnitine group and 36 in the placebo group) completed the study. L-Carnitine supplementation decreased serum IL-1beta and MMP-1 levels significantly (p = 0.001 and p = 0.021, respectively); however, serum hs-CRP and MMP-13 levels did not change significantly (p > 0.05). In the placebo group, serum IL-1beta levels increased significantly (p = 0.011), whereas other studied biomarkers did not change significantly. The mean VAS score decreased significantly in the L-carnitine and placebo groups by 52.67% and 21.82%, respectively (p < 0.001). Significant differences were only observed between the 2 groups in serum IL-1beta (p < 0.001) and MMP-1 (p = 0.006) levels and mean VAS score (p = 0.002) after adjusting for baseline values and covariates. CONCLUSION: Despite observed beneficial effects of short-term supplementation of L-carnitine in decreasing serum inflammatory mediators and improving pain in knee OA patients, further studies are needed to achieve concise conclusions. PMID- 26933898 TI - Prophylactic HPV vaccination and anal cancer. AB - The incidence of anal cancer is increasing. High risk populations include HIV positive men who have sex with men (MSM), HIV-negative MSM, HIV-positive women and heterosexual men and women with a history of cervical cancer. HPV has been detected in over 90% of anal cancers. HPV16 is the most common genotype detected in about 70% of anal cancers. The quadrivalent HPV (qHPV) vaccine has been demonstrated to prevent vaccine associated persistent anal HPV infections as well as anal intraepithelial neoplasia grades 2-3 (AIN2+) in young MSM not previously infected. A retrospective analysis also suggests that qHPV vaccination of older MSM treated for AIN2+ may significantly decrease the risk of recurrence of the AIN2+. The HPV types detected in anal cancer are included in the 9-valent vaccine. Thus, the 9-valent HPV vaccine, when administered to boys and girls prior to the onset of sexual activity, should effectively prevent anal cancer. PMID- 26933900 TI - In vivo visual evaluation of nanoparticle transfer in a three-species terrestrial food chain. AB - Nanoparticles (NPs) are increasingly being used, and they present the risk of being introduced into food webs. Numerous studies have been conducted to evaluate the toxicological effects of NPs in the aquatic and freshwater environments and their transfer to upper-level trophic organisms. However, information on the transfer and consequent effects of NPs on soil invertebrates is still limited. In this study, we assessed the transfer of quantum dots (QDs) through a three species terrestrial food chain that consisted of the yeast Saccharomyces cerevisiae, the collembolan Folsomia candida, and the pill bug Armadillidium vulgare, as well as their biodistribution in vital organs using fluorescence analytical techniques. To visualize QD incorporation and biodistribution in F. candida, longitudinal and transversal sections were observed after short-term (3 d) and long-term (12 d) feeding with QD-treated yeast. QDs were located only in the intestine of F. candida and excreted within 1-2 d. QDs were also transferred to the pill bug by feeding, and remained in its intestine. This study showed the transfer of NPs through a model terrestrial food chain and indicated the potential hazards of released NPs for organisms at different trophic levels. PMID- 26933901 TI - The fate of arsenic adsorbed on iron oxides in the presence of arsenite-oxidizing bacteria. AB - Arsenic (As) is a redox-active metalloid whose toxicity and mobility in soil depend on its oxidation state. Arsenite [As(III)] can be oxidized by microbes and adsorbed by minerals in the soil. However, the combined effects of these abiotic and biotic processes are not well understood. In this study, the fate of arsenic in the presence of an isolated As(III)-oxidizing bacterium (Pseudomonas sp. HN-1, 10(9) colony-forming units (CFUs).ml(-1)) and three iron oxides (goethite, hematite, and magnetite at 1.6 g L(-1)) was determined using batch experiments. The total As adsorption by iron oxides was lower with bacteria present and was higher with iron oxides alone. The total As adsorption decreased by 78.6%, 36.0% and 79.7% for goethite, hematite and magnetite, respectively, due to the presence of bacteria. As(III) adsorbed on iron oxides could also be oxidized by Pseudomonas sp. HN-1, but the oxidation rate (1.3 MUmol h(-1)) was much slower than the rate in the aqueous phase (96.2 MUmol h(-1)). Therefore, the results of other studies with minerals only might overestimate the adsorptive capacity of solids in natural systems; the presence of minerals might hinder As(III) oxidation by microbes. Under aerobic conditions, in the presence of iron oxides and As(III)-oxidizing bacteria, arsenic is adsorbed onto iron oxides within the adsorption capacity, and As(V) is the primary form in the solid and aqueous phases. PMID- 26933899 TI - Creation of the Prevention of Organ Failure Checklist. A Multidisciplinary Approach Using the Modified Delphi Technique. AB - RATIONALE: Respiratory failure represents a major risk for morbidity and mortality. Although generally managed in the intensive care unit (ICU), respiratory failure often begins elsewhere. Checklists of care processes to minimize the duration of mechanical ventilation and adverse events are routinely used in the ICU, but are uncommonly used outside the ICU. OBJECTIVES: To develop consensus among a multidisciplinary expert panel on care practices to include in a checklist of best practices for critically ill patients with respiratory failure before and after ICU admission. METHODS: A multidisciplinary expert panel was assembled. The panel was tasked with creating a checklist of care processes aimed at decreasing progression to respiratory failure, duration of mechanical ventilation, mortality in mechanical ventilation, and adverse events. Over the course of multiple teleconferences and e-mail communications, the Prevention of Organ Failure Checklist list was reviewed, refined, and voted upon. Items that received greater than 75% of the vote were included in the final checklist. MEASUREMENTS AND MAIN RESULTS: Using a modified Delphi process, the expert panel was able to compile Prevention of Organ Failure Checklist into 20 items that aimed to decrease mechanical ventilation by assessing the causes of acute respiratory failure, ventilation strategies, sedation, and general critical care processes, as well as to avoid unwanted or nonbeneficial interventions. CONCLUSIONS: The modified Delphi process identified readily available preventative interventions suitable for checklist implementation in patients with or progressing to respiratory failure even before ICU admission. PMID- 26933902 TI - Concept model of the formation process of humic acid-kaolin complexes deduced by trichloroethylene sorption experiments and various characterizations. AB - To explore the interactions between soil organic matter and minerals, humic acid (HA, as organic matter), kaolin (as a mineral component) and Ca(2+) (as metal ions) were used to prepare HA-kaolin and Ca-HA-kaolin complexes. These complexes were used in trichloroethylene (TCE) sorption experiments and various characterizations. Interactions between HA and kaolin during the formation of their complexes were confirmed by the obvious differences between the Qe (experimental sorbed TCE) and Qe_p (predicted sorbed TCE) values of all detected samples. The partition coefficient kd obtained for the different samples indicated that both the organic content (fom) and Ca(2+) could significantly impact the interactions. Based on experimental results and various characterizations, a concept model was developed. In the absence of Ca(2+), HA molecules first patched onto charged sites of kaolin surfaces, filling the pores. Subsequently, as the HA content increased and the first HA layer reached saturation, an outer layer of HA began to form, compressing the inner HA layer. As HA loading continued, the second layer reached saturation, such that an outer third layer began to form, compressing the inner layers. In the presence of Ca(2+), which not only can promote kaolin self-aggregation but can also boost HA attachment to kaolin, HA molecules were first surrounded by kaolin. Subsequently, first and second layers formed (with inner layer compression) via the same process as described above in the absence of Ca(2+), except that the second layer continued to load rather than reach saturation, within the investigated conditions, because of enhanced HA aggregation caused by Ca(2+). PMID- 26933903 TI - Phosphorus and cadmium availability in soil fertilized with biosolids and ashes. AB - The recycling of hygienized municipal sewage sludge (biosolids) to soil as the source of phosphorus (P) is generally encouraged. The use of biosolids, however, has some concerns, such as the presence of elevated concentrations of potentially toxic trace elements, and the possible presence of pathogens, hormones and antibiotics. Organic substances are destroyed during combustion whereas trace elements could partly be separated from P in different ash fractions. Biomass combustion waste (ash) can instead be considered as an alternative P source. This study evaluates and compares the impact of biosolids and their combustion residues (ashes), when used as fertilizers, on P and Cd solubility in soil, plant growth and plant uptake of these elements. Biosolids were also amended with K and Ca to improve the composition and properties of P in ashes, and incinerated at either 800 degrees C or 950 degrees C. Combustion of biosolids improved the Cd/P ratio in ashes by 2-5 times, compared with the initial biosolids. The low Cd content in ashes (4-9 mg Cd (kg P)(-1)) makes this material a particularly attractive alternative to mineral fertilizers. Significantly higher pore water P (as well as total N) was measured in soils containing biosolids, but plants produced a higher biomass in soil fertilized with ashes. The K and Ca amendments prior to biosolids combustion generally decreased the total Cd in ash, but had little effect on P and Cd uptake and biomass growth. Similarly, the combustion temperature had negligible effect on these factors as well. PMID- 26933904 TI - Risk assessment, cross-resistance potential, and biochemical mechanism of resistance to emamectin benzoate in a field strain of house fly (Musca domestica Linnaeus). AB - Reduced sensitivity to insecticides in insect pests often results in control failures and increases in the dose and frequency of applications, ultimately polluting the environment. Reduced sensitivity to emamectin benzoate, a broad spectrum agrochemical belonging to the avermectin group of pesticides, was reported in house flies (Musca domestica L.) collected from Punjab, Pakistan, in 2013. The aim of the present study was to investigate the risk for resistance development, biochemical mechanism, and cross-resistance potential to other insecticides in an emamectin benzoate selected (EB-SEL) strain of house flies. A field-collected strain showing reduced sensitivity to emamectin was re-selected in the laboratory for five consecutive generations and compared with a laboratory susceptible (Lab-Susceptible) reference strain, using bioassays. The field strain showed rapid development of resistance to emamectin (resistance ratio (RR) increased from 35.15 to 149.26-fold) as a result of selection experiments; however, resistance declined when the selection pressure uplifted. The EB-SEL strain showed reduction in resistance to abamectin, indoxacarb, and thiamethoxam. The results of synergism experiments using piperonyl butoxide (PBO) and S,S,S tributylphosphorotrithioate (DEF) enzyme inhibitors and biochemical analyses revealed that the metabolic resistance mechanism was not responsible in developing emamectin resistance in the EB-SEL strain. In conclusion, the risk for the rapid development of emamectin resistance under continuous selection pressure suggests using a multifaceted integrated pest management approach for house flies. Moreover, the instable nature of emamectin resistance in the EB-SEL strain and lack of cross-resistance to other insecticides provide windows for the rotational use of insecticides with different modes of action. This will ultimately reduce emamectin selection pressure and help improving management programs for house flies without polluting the environment. PMID- 26933905 TI - Mobility and speciation of arsenic in the coal fly ashes collected from the Savannah River Site (SRS). AB - Arsenic (As) leaching from coal fly ash stockpiled at waste disposal sites is a source of environmental concern. An array of techniques including batch extraction and column leaching tests, in combination with speciation analysis of chemically specific As species, was employed to evaluate the mobility of As in fly ashes collected from the U.S. DOE Savannah River Site. The results obtained using the U.S. EPA Toxicity Characteristic Leaching Procedure (TCLP), a two-step sequential extraction technique, and continuous column leaching experiments suggest that only a small portion of total As in the fly ashes was mobile, but mobilizable As could be a considerable fraction (3.1-43%), varying inversely with alkalinity of fly ash. Speciation analysis by using phosphate extraction suggests that arsenate (As(V)) was the major extractable species in the fly ash samples. During the column leaching experiment, however, it was observed that arsenite (As(III)) was an important species leached out of the fly ashes, indicating species conversion during the leaching process. The matrix-bound As(V) within the fly ash, once being released from the solid matrix, could be converted to As(III) during its transport inside the column. The pHs of leachates and fly ashes (both acidic in column leaching experiments here) could be related to the dominance of As(III) in the effluents. PMID- 26933906 TI - Facebook use and negative body image among U.S. college women. AB - Young women increasingly spend time on social media, but the relationship of this exposure to body image is still in the initial stages of exploration. In this study the authors used social comparison theory to examine the relationship between time spent on Facebook and body image. A survey of 881 U.S. college women was conducted in April-May 2013. Findings showed that 10.1% had posted about weight, body image, exercise, or dieting, and 27.4% had commented on friends' posts or photos. More time on Facebook related to more frequent body and weight comparisons, more attention to the physical appearance of others, and more negative feelings about their bodies for all women. For women who wanted to lose weight, more time on Facebook also related to more disordered eating symptoms. PMID- 26933907 TI - Validation of a liquid chromatography-tandem mass spectrometry method for the simultaneous determination of sulfonamides, trimethoprim and dapsone in muscle, egg, milk and honey. AB - A quantitative multi-residue method that includes 13 sulfonamides, trimethoprim and dapsone was developed and validated according to Commission Decision 2002/657/EC for muscle, milk egg and honey samples. For all matrices, the same extraction procedure was used. Samples were extracted with an acetone/dichloromethane mixture and cleaned up on aromatic sulfonic acid (SO3H) SPE cartridges. After elution and concentration steps, analytes were identified and quantified by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Data were acquired according to the multiple reaction-monitoring approach (MRM) and analytes were quantified both by the isotope dilution and the matrix-matched approaches calculating the response factors for the scanned product ions. The developed method shows good linearity, specificity, precision (repeatability and within-laboratory reproducibility), and trueness. Estimated CCbeta for sulfonamides ranged between 5.6 and 8.2 ug kg(-1) for eggs, between 11.1 and 69.9 ug kg(-1) for milk, between 64.7 and 87.9 ug kg(-1) for muscle, and between 2.7 and 5.3 ug kg(-1) for honey. CCbeta values for dapsone were 3.1, 0.6, 0.7 and 1.5 ug kg(-1) and for trimethoprim were 3.1, 6.7, 81.7 and 3.0 ug kg(-1) calculated for eggs, milk, muscle and honey, respectively. Recovery for all matrices was in the range from 89.1% and 109.7%. In matrix effect testing, no significant deviations were found between different samples of muscle and milk; however, a matrix effect was observed when testing different types of honey. The validation results demonstrate that the method is suitable for routine veterinary drug analysis and confirmation of suspect samples. PMID- 26933908 TI - NMR relaxation induced by iron oxide particles: testing theoretical models. AB - Superparamagnetic iron oxide particles find their main application as contrast agents for cellular and molecular magnetic resonance imaging. The contrast they bring is due to the shortening of the transverse relaxation time T 2 of water protons. In order to understand their influence on proton relaxation, different theoretical relaxation models have been developed, each of them presenting a certain validity domain, which depends on the particle characteristics and proton dynamics. The validation of these models is crucial since they allow for predicting the ideal particle characteristics for obtaining the best contrast but also because the fitting of T 1 experimental data by the theory constitutes an interesting tool for the characterization of the nanoparticles. In this work, T 2 of suspensions of iron oxide particles in different solvents and at different temperatures, corresponding to different proton diffusion properties, were measured and were compared to the three main theoretical models (the motional averaging regime, the static dephasing regime, and the partial refocusing model) with good qualitative agreement. However, a real quantitative agreement was not observed, probably because of the complexity of these nanoparticulate systems. The Roch theory, developed in the motional averaging regime (MAR), was also successfully used to fit T 1 nuclear magnetic relaxation dispersion (NMRD) profiles, even outside the MAR validity range, and provided a good estimate of the particle size. On the other hand, the simultaneous fitting of T 1 and T 2 NMRD profiles by the theory was impossible, and this occurrence constitutes a clear limitation of the Roch model. Finally, the theory was shown to satisfactorily fit the deuterium T 1 NMRD profile of superparamagnetic particle suspensions in heavy water. PMID- 26933909 TI - Thermal behavior in the magnetic phase diagram of the easy axis antiferromagnet Cs2FeCl5.H2O. AB - The specific heat at a constant applied field C(H)(T) and at fixed temperatures C(T)(H) of single crystals of the low anisotropy antiferromagnet Cs2FeCl5.H2O was measured across the different boundaries of its magnetic phase diagram, in magnetic fields up to 9 T applied parallel and perpendicular to the easy axis direction and to temperatures down to 0.3 K. The specific heat data indicate that the critical behavior along the antiferromagnetic to paramagnetic phase boundary and the spin-flop to paramagnetic phase boundary, are basically the same. We also measured the specific heat when the first order antiferromagnetic to spin-flop phase boundary is crossed at a fixed temperature. The entropy of the different magnetic phases is discussed. PMID- 26933911 TI - 2D shear-wave ultrasound elastography (SWE) evaluation of ablation zone following radiofrequency ablation of liver lesions: is it more accurate? AB - OBJECTIVE: To evaluate the usefulness of two-dimensional quantitative ultrasound shear-wave elastography (2D-SWE) [i.e. virtual touch imaging quantification (VTIQ)] in assessing the ablation zone after radiofrequency ablation (RFA) for ex vivo swine livers. METHODS: RFA was performed in 10 pieces of fresh ex vivo swine livers with a T20 electrode needle and 20-W output power. Conventional ultrasound, conventional strain elastography (SE) and VTIQ were performed to depict the ablation zone 0 min, 10 min, 30 min and 60 min after ablation. On VTIQ, the ablation zones were evaluated qualitatively by evaluating the shear wave velocity (SWV) map and quantitatively by measuring the SWV. The ultrasound, SE and VTIQ results were compared against gross pathological and histopathological specimens. RESULTS: VTIQ SWV maps gave more details about the ablation zone, the central necrotic zone appeared as red, lateral necrotic zone as green and transitional zone as light green, from inner to exterior, while the peripheral unablated liver appeared as blue. Conventional ultrasound and SE, however, only marginally depicted the whole ablation zone. The volumes of the whole ablation zone (central necrotic zone + lateral necrotic zone + transitional zone) and necrotic zone (central necrotic zone + lateral necrotic zone) measured by VTIQ showed excellent correlation (r = 0.915, p < 0.001, and 0.856, p = 0.002, respectively) with those by gross pathological specimen, whereas both conventional ultrasound and SE underestimated the volume of the whole ablation zone. The SWV values of the central necrotic zone, lateral necrotic zone, transitional zone and unablated liver parenchyma were 7.54-8.03 m s(-1), 5.13 5.28 m s(-1), 3.31-3.53 m s(-1) and 2.11-2.21 m s(-1), respectively (p < 0.001 for all the comparisons). The SWV value for each ablation zone did not change significantly at different observation times within an hour after RFA (all p > 0.05). CONCLUSION: The quantitative 2D-SWE of VTIQ is useful for the depiction of the ablation zone after RFA and it facilitates discrimination of different areas in the ablation zone qualitatively and quantitatively. This elastography technique might be useful for the therapeutic response evaluation instantly after RFA. ADVANCES IN KNOWLEDGE: A new quantitative 2D-SWE (i.e. VTIQ) for evaluation treatment response after RFA is demonstrated. It facilitates discrimination of the different areas in the ablation zone qualitatively and quantitatively and may be useful for the therapeutic response evaluation instantly after RFA in the future. PMID- 26933912 TI - Ezrin contributes to cervical cancer progression through induction of epithelial mesenchymal transition. AB - Cervical cancer is the third most common cancer in females worldwide. The treatment options for advanced cervical cancer are limited, leading to high mortality. Ezrin is a membrane-cytoskeleton-binding protein recently reported to act as a tumor promoter, and we previously indicated that the aberrant localization and overexpression of Ezrin could be an independent effective biomarker for prognostic evaluation of cervical cancers. In this study, we identified Ezrin as a regulator of epithelial-mesenchymal transition (EMT) and metastasis in cervical cancer. Ezrin knock-down inhibited anchorage-independent growth, cell migration, and invasion of cervical cancer cell lines in vitro and in vivo. EMT was inhibited in Ezrin-depleted cells, with up-regulation of E cadherin and Cytokeratin-18 (CK-18) and down-regulation of mesenchymal markers. Ezrin knock-down also induced Akt phosphorylation. These results implicate Ezrin as an EMT regulator and tumor promoter in cervical cancer, and down-regulation of Ezrin suppressed cervical cancer progression, possibly via the phosphoinositide 3 kinase/Akt pathway. Furthermore, the expression pattern of Ezrin protein was closely related with the lymphovascular invasion status of cervical cancer by immunohistochemistry, and the survival analysis revealed that the cervical cancer patients with the perinuclear Ezrin expression pattern had longer survival time than those with the cytoplasmic Ezrin expression pattern. Ezrin thus represents a promising target for the development of novel and effective strategies aimed at preventing the progression of cervical cancer. PMID- 26933913 TI - Identification of a six microRNA signature as a novel potential prognostic biomarker in patients with head and neck squamous cell carcinoma. AB - The 5-year survival rate of patients with head and neck squamous cell carcinoma (HNSCC) was only 40%-50%. To investigate the prognostic and predictive value of specific mircoRNAs (miRNAs) in HNSCC. We identified 19 miRNAs associated with over survival (OS) of patients with HNSCC in different clinical classes between 492 HNSCC tissues and 44 normal tissues from The Cancer Genome Atlas (TCGA) dataset. A signature of six miRNAs was identified by the supervised principal component method in the training set. The AUC of the ROC curve for the six microRNA signature predicting 5-year survival was 0.737 (95%CI, 0.627-0.825) in the testing set and 0.708 (95%CI, 0.616-0.785) in the total dataset. In the multivariate Cox regression analysis, patients with high-risk scores had shorter OS (HR, 2.380, 95%CI, 1.361-4.303) than patients with low-risk scores in the total dataset. Therefore, these results provided a new prospect for prognostic biomarker of HNSCC. PMID- 26933914 TI - Fibroblast growth factor receptor 2 expression, but not its genetic amplification, is associated with tumor growth and worse survival in esophagogastric junction adenocarcinoma. AB - BACKGROUND: Fibroblast growth factor receptor 2 (FGFR2) genetic alterations lead to tumor cell proliferation in various types of cancer. We hypothesized that FGFR2 amplification is associated with FGFR2 expression, resulting in tumor growth and poorer outcome in esophagogastric junction (EGJ) adenocarcinoma. PATIENTS AND METHODS: A total of 176 consecutive chemo-naive patients with EGJ adenocarcinoma were enrolled from two academic institutions. FGFR2 amplification was examined by real-time PCR (N = 140) and FGFR2 expression with immunohistochemical staining (N = 176), and compared against clinicopathological factors and patient outcomes. The effects of FGFR2 inhibition or overexpression on cell proliferation, cell cycle, and apoptosis assays were investigated in EGJ adenocarcinoma cell lines. Downstream FGFR2, AKT and ERK were also examined. RESULTS: Based on the correlation between FGFR2 levels and FGFR2 overexpression in vitro, FGFR2 amplification was defined as copy number > 3.0. In clinical samples, FGFR2 amplification and FGFR2 IHC expression were 15% and 61%, respectively. Although these two statuses were significantly correlated (P < 0.05), only FGFR2 IHC expression was significantly associated with tumor depth (multivariate P < 0.001) and overall survival of patients (univariate P = 0.007). Supporting these findings, FGFR2 overexpression was associated with tumor cell proliferation, cell cycle progression, and anti-apoptosis. Selective inhibition of FGFR2 sufficiently suppressed tumor cell proliferation through de phosphorylation of AKT and ERK. CONCLUSIONS: FGFR2 amplification was significantly associated with FGFR2 expression. FGFR2 expression (but not FGFR2 amplification) was associated with tumor growth and patient outcomes. Our findings support FGFR2 as a novel therapeutic target for EGJ adenocarcinoma. PMID- 26933916 TI - Galectin signatures contribute to the heterogeneity of breast cancer and provide new prognostic information and therapeutic targets. AB - Because of their ability to induce local immunosuppression and to confer cancer cells with resistance to apoptosis, members of the galectin family are emerging as a new class of actionable targets in cancer. Unfortunately, we have yet to obtain a clear picture of the galectin signatures in cancer cells and the surrounding tumor microenvironment. The aim of this study was to provide the first detailed analysis of the galectin signature in molecular subtypes of breast cancer. Expression signatures of galectins were obtained at the mRNA and protein levels. A particular attention was paid to stromal versus epithelial staining and to subcellular compartmentalization. Analysis of the stromal signature showed that gal-1, -3, -9-positive stroma were preferentially found in triple-negative (TN) and HER2 subtypes. In cancer cells, gal-1, -3, -8, and -9 showed a dual expression pattern, being found either in the cytosol or in the cytosol and the nucleus. TN patients with gal-8-positive nuclei had significantly better disease free survival (DFS), distant-disease-free survival (DDFS), and overall survival (OS). In contrast, high expression of nuclear gal-1 correlated with poor DDFS and OS. TNBC patients who were positive for both nuclear gal-1 and gal-8 had 5-year DFS and DDFS of 100%, suggesting a dominance of the gal-8 phenotype. Overall, the results indicate that specific galectin expression signatures contribute to the phenotypic heterogeneity of aggressive subtypes of breast cancer. Our data also suggest that galectins have clinical utility as indicators of disease progression and therapeutic targets in aggressive molecular subtypes of breast cancer. PMID- 26933915 TI - Antitumor effects of calgranulin B internalized in human colon cancer cells. AB - Calgranulin B is a small, calcium-binding protein expressed in neutrophils that is secreted into the tumor microenvironment in cancer cases. We previously showed that calgranulin B levels are increased in the stools of colorectal cancer patients. In patient tumor tissues, calgranulin B protein levels correlated with the presence of stromal inflammatory cells surrounding tumor cells, and calgranulin B promoter methylation was observed in both paired human tissues and colon cancer cell lines. Cell lines did not express calgranulin B, but in vitro studies showed that colon cancer cells internalized extracellular calgranulin B, while other types of cancer cells did not. Calgranulin B internalization led to reduced cell proliferation and increased apoptotic cell death. AKT and ERK signals were also increased after calgranulin B treatment, as were p53, beta catenin, E-cadherin and cleaved caspase-3 levels. Additionally, a human protein microarray identified aurora A kinase as a calgranulin B binding partner, and binding inhibited aurora A kinase activity in a dose-dependent manner. Our findings demonstrate the antitumor effects of calgranulin B in the inflammatory microenvironment and suggest that calgranulin B could be potentially efficacious in the treatment of colon cancer. PMID- 26933917 TI - SH3-domain binding protein 1 in the tumor microenvironment promotes hepatocellular carcinoma metastasis through WAVE2 pathway. AB - SH3-domain binding protein-1 (SH3BP1) specifically inactivating Rac1 and its target WAVE2 is required for cell motility. The present study shows SH3BP1 expression patterns in human HCC tissues and cell lines were examined. The regulation of SH3BP1 on HCC cell migration and invasion related to Rac1-WAVE2 signaling was characterized using in vitro and in vivo models. SH3BP1 overexpressed in HCC tissues and highly metastatic HCC cells was significantly associated vascular invasion (VI). SH3BP1 promoted VEGF secretion via Rac1-WAVE2 signaling, so as to exert an augmentation on cell invasion and microvessel formation. In three study cohorts with a total of 516 HCC patients, high SH3BP1 expression combined with high microvessel density (MVD) was confirmed as a powerful independent predictor of HCC prognosis in both training cohorts and validation cohort. Being an important angiogenic factor of HCC through Rac1-WAVE2 signaling, SH3BP1 promotes tumor invasion and microvessel formation contributing to HCC metastasis and recurrence. SH3BP1 is a novel WAVE2 regulator, a prognostic marker and a potential therapeutic target of HCC. PMID- 26933918 TI - Practical considerations for the use of sodium-glucose co-transporter type 2 inhibitors in treating hyperglycemia in type 2 diabetes. AB - Sodium-glucose co-transporter type 2 (SGLT2) inhibitors are a new class of oral anti-diabetic agents with a unique, insulin-independent mode of action. In patients with diabetes who have adequate renal function, SGLT2 inhibitors reduce hyperglycemia by blocking renal glucose reabsorption and increasing urinary glucose excretion. These agents are indicated for the treatment of hyperglycemia in type 2 diabetes mellitus (T2DM), as an adjunct to diet and exercise. In terms of efficacy, they are comparable to most other oral agents, and carry a low risk of hypoglycemia unless combined with sulfonylureas or insulin. They may be used in combination regimens with metformin, sulfonylureas, or insulin. Beyond glucose lowering, SGLT2 inhibitors are associated with modest weight loss and mild anti hypertensive effects. Emerging cardiovascular and renal outcomes data suggest other potentially beneficial non-glycemic effects, although these findings await confirmation from further studies. The main adverse effects are increased risk of volume depletion and of genitourinary infections, although these can be managed with standard interventions. Rare cases of euglycemic ketoacidosis have been reported in a subset of patients treated with these agents, an issue currently under investigation. SGLT2 inhibitors represent a promising alternative treatment option for T2DM patients in whom the effectiveness of oral anti-hyperglycemic therapy is limited by the risk of hypoglycemia, weight gain, or other adverse effects. Safety and efficacy (up to 4 years) have been demonstrated in a range of T2DM patient populations, although more studies will be needed to determine whether treatment with SGLT2 inhibitors improves patient-important outcomes in the longer term. PMID- 26933919 TI - Oxaliplatin immunohybrid nanoparticles in vitro synergistic suppression evaluation in treatment of colorectal cancer. AB - In the present study, we have investigated the enhanced synergistic and apoptotic activity of immunohybrid nanoparticles encapsulating oxaliplatin and covalently conjugated with TRAIL (Apo-2L/CD-253). Time-dependent cytotoxicity activity of nanoparticles was determined by MTT assay in HT-29 cells. Nuclear morphological changes and assessment of apoptotic ratio was analyzed by DAPI (4'6-diamidino-2 phenylindole) staining and annexin-propidium iodide (PI) assay. Cell-cycle analysis of oxaliplatin in HT-29 cell was analyzed by flow cytometry at 72 h. Furthermore, molecular mechanisms related to oxaliplatin-induced anticancer activity was explored by western blot analysis. Our study revealed appreciable time-dependent cytotoxicity, apoptotic, and synergistic activity of oxaliplatin immunohybrid nanoparticles. PMID- 26933920 TI - National Strength and Conditioning Association Position Statement on Long-Term Athletic Development. AB - There has recently been a growing interest in long-term athletic development for youth. Because of their unique physical, psychological, and social differences, children and adolescents should engage in appropriately prescribed exercise programs that promote physical development to prevent injury and enhance fitness behaviors that can be retained later in life. Irrespective of whether a child is involved in organized sport or engages in recreational physical activity, there remains a need to adopt a structured, logical, and evidence-based approach to the long-term development of athleticism. This is of particular importance considering the alarmingly high number of youth who fail to meet global physical activity recommendations and consequently present with negative health profiles. However, appropriate exercise prescription is also crucial for those young athletes who are physically underprepared and at risk of overuse injury because of high volumes of competition and an absence of preparatory conditioning. Whether the child accumulates insufficient or excessive amounts of exercise, or falls somewhere between these opposing ends of the spectrum, it is generally accepted that the young bodies of modern day youth are often ill-prepared to tolerate the rigors of sports or physical activity. All youth should engage in regular physical activity and thus should be viewed as "athletes" and afforded the opportunity to enhance athleticism in an individualized, holistic, and child centered manner. Because of emerging interest in long-term athletic development, an authorship team was tasked on behalf of the National Strength and Conditioning Association (NSCA) to critically synthesize existing literature and current practices within the field and to compose a relevant position statement. This document was subsequently reviewed and formally ratified by the NSCA Board of Directors. A list of 10 pillars of successful long-term athletic development are presented, which summarize the key recommendations detailed within the position statement. With these pillars in place, it is believed that the NSCA can (a) help foster a more unified and holistic approach to long-term athletic development, (b) promote the benefits of a lifetime of healthy physical activity, and PMID- 26933921 TI - Association between pain outcomes and race and opioid treatment: Retrospective cohort study of Veterans. AB - We examined whether pain outcomes (pain interference, perceived pain treatment effectiveness) vary by race and then whether opioid use moderates these associations. These analyses are part of a retrospective cohort study among 3,505 black and 46,203 non-Hispanic, white Department of Veterans Affairs (VA) patients with diagnoses of chronic musculoskeletal pain who responded to the 2007 VA Survey of Healthcare Experiences of Patients (SHEP). We used electronic medical record data to identify prescriptions for pharmacologic pain treatments in the year after diagnosis (Pain Diagnosis index visit) and before the SHEP index visit (the visit that made one eligible to complete the SHEP); pain outcomes came from the SHEP. We found no significant associations between race and pain interference or perceived effectiveness of pain treatment. VA patients with opioid prescriptions between the Pain Diagnosis index visit and the SHEP index visit reported greater pain interference on the SHEP than those without opioid prescriptions during that period. Opioid prescriptions were not associated with perceived treatment effectiveness for most patients. Findings raise questions about benefits of opioids for musculoskeletal pain and point to the need for alternative treatments for addressing chronic noncancer pain. PMID- 26933922 TI - Oncogenic roles of TOPK and MELK, and effective growth suppression by small molecular inhibitors in kidney cancer cells. AB - T-lymphokine-activated killer cell-originated protein kinase (TOPK) and maternal embryonic leucine zipper kinase (MELK) have been reported to play critical roles in cancer cell proliferation and maintenance of stemness. In this study, we investigated possible roles of TOPK and MELK in kidney cancer cells and found their growth promotive effect as well as some feedback mechanism between these two molecules. Interestingly, the blockade of either of these two kinases effectively caused downregulation of forkhead box protein M1 (FOXM1) activity which is known as an oncogenic transcriptional factor in various types of cancer cells. Small molecular compound inhibitors against TOPK (OTS514) and MELK (OTS167) effectively suppressed the kidney cancer cell growth, and the combination of these two compounds additively worked and showed the very strong growth suppressive effect on kidney cancer cells. Collectively, our results suggest that both TOPK and MELK are promising molecular targets for kidney cancer treatment and that dual blockade of OTS514 and OTS167 may bring additive anti tumor effects with low risk of side effects. PMID- 26933923 TI - Erythema Dyschromicum Perstans Response to Isotretinoin. PMID- 26933925 TI - Correction: Copper-catalyzed, hypervalent iodine mediated C=C bond activation of enaminones for the synthesis of alpha-keto amides. AB - Correction for 'Copper-catalyzed, hypervalent iodine mediated C=C bond activation of enaminones for the synthesis of alpha-keto amides' by Jie-Ping Wan et al., Chem. Commun., 2016, 52, 1270-1273. PMID- 26933926 TI - Antiangiogenesis and vascular disrupting agents in cancer: circumventing resistance and augmenting their therapeutic utility. AB - Angiogenesis is a process essential for tumor growth and metastasis. Inhibition of angiogenesis as an anticancer strategy has shown only moderately improved results and is beset with practical limitations, despite theoretical therapeutic advantages. Inevitably resistance develops, through redundancy of signaling pathways and selection for subclonal populations adapted for hypoxic conditions, with more invasive phenotypes. Antiangiogenic-targeted therapies may find improved efficacy in combination therapies; with others in this class, that directly or indirectly target separate pathways or different components of the same pathway, or with a separate class of tumor vasculature-disrupting agents. This review discusses the challenges and strategies for optimization of combination therapies including metronomic administration of drugs and the need for suitable prognostic and surrogate response biomarkers. PMID- 26933929 TI - Being "easy": Women's desire to accept help in later life. AB - This article examines the concept of being "easy" as a quality that female caregivers aspire to as they envision their potential care in later life. It draws on data from a qualitative study exploring the significance of caregiving to adult daughters' perspectives and plans for their own aging. Caregivers' experiences differ based upon their perception of how easy or difficult it was to care for their loved one. The former exemplifies a positive way to approach aging and the receiving of care. Being easy describes an attitude that these caregivers desired for their own later life. PMID- 26933928 TI - The Double-Bond Configuration of Corynanthean Alkaloids and Its Impact on Monoterpenoid Indole Alkaloid Biosynthesis. AB - Experimental evidence is provided for the coherence of the double-bond geometry and the occurrence of "secondary cyclizations" in the biosynthesis of monoterpenoid indole alkaloids. Biosynthetically, akuammiline, C-mavacurine, and Strychnos alkaloids are proposed to be derived from the corynanthean alkaloid geissoschizine, a key intermediate in the biosynthetic pathway of these monoterpenoid indole alkaloids. This process occurs by so-called "secondary cyclizations" from geissoschizine or its derivatives. Although corynanthean alkaloids like geissoschizine incorporate E or Z double bonds located at C19-C20, the alkaloids downstream in the biosynthesis exclusively exhibit the E double bond. This study shows that secondary cyclizations preferentially occur with the E isomer of geissoschizine or its derivatives. This is attributed to the flexibility of the quinolizidine system of the corynanthean alkaloids, which can adopt a cis or trans conformation. For the secondary cyclization to take place, the cis-quinolizidine conformation is required. Experimental evidence supports the hypothesis that the E double bond of geissoschizine induces the cis conformation, whereas the Z double bond induces the trans conformation, which prohibits secondary cyclization of the Z compounds. PMID- 26933930 TI - Neuroprotective effect of the marine macroalga Gelidiella acerosa: identification of active compounds through bioactivity-guided fractionation. AB - Context Gelidiella acerosa (Forsskal) Feldmann & G. Hamel (Rhodophyta-Gelidiales) is a marine red macroalga. Our previous work found that a benzene extract of G. acerosa possesses noticeable neuroprotective activity, when evaluated through in vitro and in vivo systems. Objective Bioactive-guided fractionation and identification of active compounds by column chromatography using solvents of varying polarity. Materials and methods Fractionation was done by column chromatography, antioxidant and anticholinesterase activity was assessed by DPPH and cholinesterase inhibition assays (50-200 MUg/ml), compound identification was done by LC-MS analysis, the mode of interaction of active compound was analyzed through docking studies and quantification was done by high-performance thin layer chromatography (HPTLC) analysis. Results The results suggest that fractions F9-F13 exhibited significant (p < 0.05) antioxidant and anticholinesterase activities. Hence, these fractions were pooled together and verified for neuroprotective activity. The pooled fraction was subjected to LC-MS analysis and among all the compounds, phytol was previously reported to possess excellent neuroprotective potential. Hence, the neuroprotective potential of phytol was assessed. The results suggest that phytol showed significant (p < 0.05) antioxidant activities (25-125 MUg/ml) with an IC50 value of 95.27 +/- 1.65 MUg/ml and cholinesterase inhibitory potential (5-25 MUg/ml) with IC50 values of 2.704 +/- 0.07 and 5.798 +/- 0.72 MUg/ml for AChE and BuChE, respectively. Molecular docking studies suggest that phytol interacts with cholinesterase through the arginine residue of the enzyme. HPTLC quantification showed that about 6.266 MUg of phytol was present per mg of pooled fraction. Conclusion The study suggests that phytol might act as the key compound in contributing to the neuroprotective potential of G. acerosa. PMID- 26933931 TI - Synthesis and Characterization of New Conjugated Fluorenyl-Porphyrin Dendrimers for Optics. AB - A new family of conjugated meso-tetraphenylporphyrin-based dendrimers with four (TPP1, TPP2), eight (TPP3, TPP4, TPP5) and up to sixteen (TPP6) fluorenyl groups has been synthesized and fully characterized. These tetraphenylporphyrin-cored dendrimers present peripheral alkynyl pi-conjugated dendrons with fluorenyl termini. The meso-aryl rings of these porphyrins are functionalized either in para- (TPP1, TPP2, and TPP3) or meta-positions (TPP4, TPP5, and TPP6). Their detailed luminescence properties are discussed in reference to two porphyrins lacking fluorenyl dendrons (TPP-H1,2,3 and TPP-H4,5,6). A strong dependence of their luminescence quantum yield and lifetime on their structures is stated, their nonlinear optical properties were also discussed. PMID- 26933933 TI - Rhodium-Catalyzed Synthesis of 4-Bromo-1,2-dihydroisoquinolines: Access to Bromonium Ylides by the Intramolecular Reaction of a Benzyl Bromide and an alpha Imino Carbene. AB - Highly functionalized 4-bromo-1,2-dihydroisoquinolines were synthesized from readily available 4-(2-(bromomethyl)phenyl)-1-sulfonyl-1,2,3-triazoles. A bromonium ylide is proposed as the key intermediate, which can be formed by the intramolecular nucleophilic attack of the benzyl bromide on the alpha-imino rhodium carbene formed in the presence of the rhodium catalyst. PMID- 26933932 TI - Nomograms for predicting prognostic value of inflammatory biomarkers in colorectal cancer patients after radical resection. AB - Increasing evidence indicates that inflammation plays a vital role in tumorigenesis and progression. However, the prognostic value of inflammatory biomarkers in colorectal cancer (CRC) has not been established. In this study, a retrospective analysis was conducted in patients with CRC in Fudan University Shanghai Cancer Center (FUSCC) between April 1, 2007 and April 30, 2014, and 5,336 patients were identified eligible. Neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), and albumin/globulin ratio (AGR) were analyzed. Kaplan-Meier analysis was used to calculate the 5-year overall survival (OS) and disease-free survival (DFS). Cox regression analysis was performed to assess the prognostic factors. Nomograms were established to predict OS and DFS, and Harrell's concordance index (c-index) was adopted to evaluate prediction accuracy. As results, the 5-year OS was 79.2% and the 5-year DFS was 56.0% in the cohort. Patients were stratified into 2 groups by NLR (<=2.72 and >2.72), PLR (<=219.00 and >219.00), LMR (<=2.83 and >2.83) and AGR (<1.50 and >=1.50). Patients with NLR > 2.72, PLR > 219.00, LMR <= 2.83 and AGR < 1.50 were significantly associated with decreased OS and DFS (p < 0.001). Multivariate analysis indicated that NLR, LMR and AGR were independent factors of OS (p = 0.047, p = 0.008 and p < 0.001, respectively) and DFS (p = 0.009, p < 0.001 and p = 0.008, respectively). In addition, nomograms on OS and DFS were established according to all significant factors, and c-indexes were 0.765 (95% CI: 0.744-0.785) and 0.735 (95% CI: 0.721-0.749), respectively. Nomograms based on OS and DFS can be recommended as practical models to evaluate prognosis for CRC patients. PMID- 26933934 TI - Genotyping-by-sequencing-based genome-wide association studies on Verticillium wilt resistance in autotetraploid alfalfa (Medicago sativa L.). AB - Verticillium wilt (VW) is a fungal disease that causes severe yield losses in alfalfa. The most effective method to control the disease is through the development and use of resistant varieties. The identification of marker loci linked to VW resistance can facilitate breeding for disease-resistant alfalfa. In the present investigation, we applied an integrated framework of genome-wide association with genotyping-by-sequencing (GBS) to identify VW resistance loci in a panel of elite alfalfa breeding lines. Phenotyping was performed by manual inoculation of the pathogen to healthy seedlings, and scoring for disease resistance was carried out according to the standard test of the North America Alfalfa Improvement Conference (NAAIC). Marker-trait association by linkage disequilibrium identified 10 single nucleotide polymorphism (SNP) markers significantly associated with VW resistance. Alignment of the SNP marker sequences to the M. truncatula genome revealed multiple quantitative trait loci (QTLs). Three, two, one and five markers were located on chromosomes 5, 6, 7 and 8, respectively. Resistance loci found on chromosomes 7 and 8 in the present study co-localized with the QTLs reported previously. A pairwise alignment (blastn) using the flanking sequences of the resistance loci against the M. truncatula genome identified potential candidate genes with putative disease resistance function. With further investigation, these markers may be implemented into breeding programmes using marker-assisted selection, ultimately leading to improved VW resistance in alfalfa. PMID- 26933935 TI - Special issue: Microbial biodiversity. PMID- 26933936 TI - Cold active hydrolytic enzymes production by psychrotrophic Bacilli isolated from three sub-glacial lakes of NW Indian Himalayas. AB - The diversity of culturable, cold-active enzymes producing Bacilli was investigated from three sub-glacial lakes of north western Indian Himalayas. Amplified ribosomal DNA restriction analysis (ARDRA) using three restriction enzymes Alu I, Msp I, and Hae III led to the clustering of 136 Bacilli into 26, 23, and 22 clusters at 75% similarity index from Chandratal Lake, Dashair Lake, and Pangong Lake, respectively. Phylogenetic analysis based on 16S rRNA gene sequencing led to the identification of 35 Bacilli that could be grouped in seven families viz.: Bacillaceae (48%), Staphylococcaceae (14%), Bacillales incertae sedis (13%), Planococcaceae (12%), Paenibacillaceae (9%), Sporolactobacillaceae (3%), and Carnobacteriaceae (1%), which included twelve different genera Bacillus, Desemzia, Exiguobacterium, Jeotgalicoccus, Lysinibacillus, Paenibacillus, Planococcus, Pontibacillus, Sinobaca, Sporosarcina, Staphylococcus, and Virgibacillus. Based on their optimal temperature for growth, 35 Bacilli were grouped as psychrophilic (11 strains), psychrotrophic (17 strains), or psychrotolerant (7 strains), respectively. The representative isolates from each cluster were screened for cold-active enzyme activities. Amylase, beta-glucosidase, pectinase, and protease activities at 4 degrees C were detected in more than 80% of the strains while approximately 40, 31, 23, 14, 11, and 9% of strains possessed cellulase, xylanase, beta-galactosidase, laccase, chitinase, and lipase activity, respectively. Among 35 Bacilli, Bacillus amyloliquefaciens, Bacillus marisflavi, Exiguobacterium indicum, Paenibacillus terrae, Pontibacillus sp., Sporosarcina globispora, and Sporosarcina psychrophila were efficient producers of different cold-active enzymes. These cold-adapted Bacilli could play an important role in industrial and agricultural processes. PMID- 26933937 TI - The case for an ultrasound mandate. AB - Emergency Medicine pioneered the use of ultrasound at the bedside. All of the Colleges of Emergency Medicine in the Anglo-American system have incorporated Emergency Ultrasound into their training curriculum, and all but ACEM have made training and proficiency mandatory. Emergency Ultrasound has not taken hold in Australasia the way it has in other parts of the world. It is a unique procedure that requires a College mandate to overcome the political and financial arguments that have kept it from flourishing in our hospitals. ACEM needs to instate such a mandate. PMID- 26933938 TI - Outcome of hypocalcaemia after thyroidectomy treated only in symptomatic patients. AB - BACKGROUND: Calcium supplementation has been proposed after bilateral thyroid surgery, either to all patients or to those with biochemical hypocalcaemia. It has also been suggested that supplementation aids parathyroid recovery and prevents permanent hypoparathyroidism. This single-centre study investigated the feasibility of a restrictive management of post-thyroidectomy hypocalcaemia. METHODS: Serum calcium was checked before surgery, on postoperative day 1 (POD) 1, at a follow-up visit 6-8 weeks after surgery and after a minimum of 12 months in all patients. Regardless of serum calcium levels, patients with symptoms of hypocalcaemia were prescribed oral calcium supplementation (0.5-1.0 g twice daily) and asymptomatic patients were not. Asymptomatic patients were informed about hypocalcaemic symptoms and instructed to contact the surgical ward should symptoms appear. RESULTS: Some 640 patients underwent bilateral thyroid surgery without previous or intentional simultaneous parathyroidectomy. A subnormal serum calcium level (below 2.15 mmol/l) was observed in 412 patients (64.4 per cent) on POD 1. By comparison, only 63 patients (9.8 per cent) experienced symptoms of hypocalcaemia in the postoperative period, all but one with a corresponding biochemical hypocalcaemia on POD 1. Calcium levels in all patients with asymptomatic postoperative hypocalcaemia recovered to normal without supplementation. Serum calcium was also normalized during follow-up in all symptomatic patients, except 22 (3.4 per cent) who became permanently hypoparathyroid. No patient without early hypocalcaemic symptoms developed permanent hypoparathyroidism. CONCLUSION: The proposed restrictive management of postoperative hypocalcaemia after bilateral thyroid surgery avoids unnecessary supplementation for most patients. PMID- 26933939 TI - Developmental quotient to estimate intelligence in autism spectrum disorder. AB - BACKGROUND: Autism spectrum disorders (ASD) are characterized by persistent deficits in social communication and social interaction across contexts, and are associated with restricted patterns of behavior. The developmental quotient (DQ) is based on the developmental age and chronological age of children. This study investigated the utility of the DQ to estimate cognitive ability in young children with ASD. METHODS: The DQ and intelligence quotient (IQ) were assessed using the Kyoto Scale of Psychological Development 2001 (KSPD) and Wechsler Intelligence Scale for Children-III (WISC-III), respectively. The correlation between the DQ and IQ was then analyzed among children with ASD. RESULTS: We enrolled 18 children with ASD (16 boys, two girls; age, 63.6 +/- 9.4 months; age range, 45-83 months). Overall, Cognitive-Adaptive and Language-Social DQ scores were significantly correlated with IQ score in the full scale, verbal, and performance domains. Full-scale IQ and overall DQ had a linear correlation (y = 22.747 + 1.177x, R2 = 0.677, R = 0.823). CONCLUSIONS: The DQ scores obtained using the KSPD were a reasonable estimate of cognitive ability in children with ASD. The KSPD may be a useful alternative to the WISC-III for young children with ASD and could facilitate earlier assessment. PMID- 26933941 TI - Magnet recognition in the United Kingdom: recognising international evidence or remaining in splendid isolation? PMID- 26933940 TI - Stiripentol and vigabatrin current roles in the treatment of epilepsy. AB - INTRODUCTION: Stiripentol and vigabatrin are the two anticonvulsant drugs currently approved in severe infantile-onset epilepsies, respectively Dravet syndrome and infantile spasms. AREAS COVERED: For both, the indication was discovered by chance thanks to an exploratory study. Both demonstrated indisputable efficacy through randomized-controlled trials. Stiripentol as adjunctive therapy to clobazam and valproate performed better than placebo, and vigabatrin as first-line monotherapy better than the reference steroid therapy in spasms due to tuberous sclerosis. At one-year treatment vigabatrin and steroids were equally efficient in the other etiologies of spasms. However, it took more than 20 years for both drugs to be approved world-wide. EXPERT OPINION: Stiripentol suffered from pharmacokinetic potentiation of clobazam, thus raising the question whether it was efficient per se. Finally, animal models and pharmacogenetic data on CYP2C19 confirmed its specific anticonvulsant effect. Stiripentol (in comedication with clobazam and valproate) is therefore to be recommended for Dravet patients. Vigabatrin was found to have a frequent and irreversible retinal toxicity, which required an alternative visual testing to be detected in young children. Today the benefit/risk ratio of vigabatrin as first line is considered to be positive in infantile spasms, given the severity of this epilepsy and the lack of a safer alternative therapy. PMID- 26933944 TI - Assessing fundamental motor skills in Belgian children aged 3-8 years highlights differences to US reference sample. AB - AIM: This study aimed to understand the fundamental motor skills (FMS) of Belgian children using the process-oriented Test of Gross Motor Development, Second Edition (TGMD-2) and to investigate the suitability of using the United States (USA) test norms in Belgium. METHODS: FMS were assessed using the TGMD-2. Gender, age and motor performance were examined in 1614 Belgian children aged 3-8 years (52.1% boys) and compared with the US reference sample. RESULTS: More proficient FMS performance was found with increasing age, from 3 to 6 years for locomotor skills and 3 to 7 years for object control skills. Gender differences were observed in object control skills, with boys performing better than girls. In general, Belgian children had lower levels of motor competence than the US reference sample, specifically for object control skills. The score distribution of the Belgian sample was skewed, with 37.4% scoring below average and only 6.9% scoring above average. CONCLUSION: This study supported the usefulness of the TGMD-2 as a process-oriented instrument to measure gross motor development in early childhood in Belgium. However, it also demonstrated that caution is warranted when using the US reference norms. PMID- 26933943 TI - Understanding motivations to participate in an observational research study: Why do patients enroll? AB - By understanding common motivations for participating in observational research studies, clinicians may better understand the perceived benefits of research participation from their clients' perspective. We enrolled 164 cardiac patients in a study about the effects of gratitude and optimism. Two weeks post enrollment, participants completed a four-item questionnaire regarding motivations for study enrollment. Altruistic motivation ranked highest, while intellectual, health-related, and financial motivations rated lower. Four subgroups of participants emerged, each with distinct characteristics and different priorities for participating. These findings may help front-line clinicians to understand which motivations for participation apply to their clients who enroll in non-treatment-based research projects. PMID- 26933942 TI - APOE2 eases cognitive decline during Aging: Clinical and preclinical evaluations. AB - OBJECTIVE: Apolipoprotein E (apoE), a major cholesterol carrier in the brain, is associated with a strong risk for Alzheimer disease. Compared to the risky APOE4 gene allele, the effects of the protective APOE2 gene allele are vastly understudied, and thus need to be further clarified. METHODS: We reviewed National Alzheimer's Coordinating Center clinical records and performed preclinical experiments using human apoE-targeted replacement (apoE-TR) mice, which do not show amyloid pathology. RESULTS: Clinically, the APOE2 allele was associated with less cognitive decline during aging. This effect was also seen in subjects with little amyloid pathology, or after adjusting for Alzheimer disease related pathologies. In animal studies, aged apoE2-TR mice also exhibited preserved memory function in water maze tests. Regardless, apoE2-TR mice showed similar or greater age-related changes in synaptic loss, neuroinflammation, and oxidative stress compared to apoE3-TR or apoE4-TR mice. Interestingly, apoE concentrations in the cortex, hippocampus, plasma, and cerebrospinal fluid (CSF) were positively correlated with memory performance across apoE isoforms, where apoE2-TR mice had higher apoE levels. Moreover, apoE2-TR mice exhibited the lowest levels of cholesterol in the cortex, despite higher levels in CSF and plasma. These cholesterol levels were associated with apoE levels and memory performance across apoE isoforms. INTERPRETATION: APOE2 is associated with less cognitive decline during aging. This can occur independently of age-related synaptic/neuroinflammatory changes and amyloid accumulation. Higher levels of apoE and associated cholesterol metabolism in APOE2 carriers might contribute to this protective effect. Ann Neurol 2016;79:758-774. PMID- 26933945 TI - Spatially Directional Resorcin[4]arene Cavitand Glycoconjugates for Organic Catalysis. AB - The synthesis of novel spatially directional multivalent resorcin[4]arene cavitand glycoconjugates (RCGs) and their ability to catalyze organic reactions is reported. The beta-d-glucopyranoside moieties on the upper rim of the "bowl" shaped resorcin[4]arene cavitand core are capable of multiple hydrogen-bond interactions resulting in a pseudo-cavity, which has been investigated for organic transformations in aqueous media. The RCGs have been demonstrated to catalyze thiazole formation, thiocyanation, copper(I)-catalyzed azide alkyne cycloaddition (CuAAC), and Mannich reactions; they impart stereoselectivity in the three-component Mannich reaction. Thermodynamic values obtained from (1) H diffusion-ordered spectroscopy (DOSY) experiments suggest that the upper saccharide cavity of the RCG and not the resorcin[4]arene cavity is the site of the complexation event. PMID- 26933946 TI - The ovarian response to standard gonadotropin stimulation is influenced by AMHRII genotypes. AB - The aim of the current study was to explore whether anti-Mullerian hormone receptor II (AMHRII) genetic variants influence the hormonal profile and the ovarian response to standard gonadotropin stimulation of women undergoing medically assisted reproduction. Three hundred in vitro fertilization or intracytoplasmic sperm injection patients constituted the study population, while 300 women with at least one spontaneous pregnancy participated as controls. The follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2) and AMH levels were determined at the third day of the menstrual cycle. AMHRII 10A > G (rs11170555), 1749C > T (rs2071558) and -482A > G (rs2002555) polymorphisms were genotyped. The follicle and oocyte numbers, the follicle size and the clinical pregnancies were recorded. Regarding the AMHRII 1749C > T polymorphism, 1749CT women presented with higher total follicle and small follicle numbers compared to 1749CC women (p = 0.04 and p = 0.01, respectively). Whereas, as concerns the -482A > G polymorphism, -482AG women were characterized by higher total follicle and small follicle numbers comparing with -482AA women (p = 0.07 and p = 0.004, respectively). Finally, -482AG women presented with increased FSH levels compared to -482AA women (p < 0.05). However, no associations of AMHRII gene polymorphisms with serum AMH levels or clinical pregnancy rates were observed. AMHRII 1749C > T and -482A > G genetic variants were associated with the ovarian response to standard gonadotropin stimulation, affecting mainly the follicular growth. PMID- 26933948 TI - Evaluation of patient quality of life and satisfaction with home enteral feeding and oral nutrition support services: a cross-sectional study. AB - Objective The aims of the present study, in home enteral nutrition (HEN) patients, were to assess patient satisfaction with the service and quality of life (QOL) scores, and to compare QOL scores in HEN patients with general Australian population values. Methods Self-administered voluntary questionnaires for the present cross-sectional study were mailed out to 322 eligible participants registered with HEN for >5 months. The questionnaires used included a patient satisfaction survey and a validated QOL questionnaire. Data analysis consisted of cross-tabulation, Chi-squared tests and t-tests. Results There were 112 participants. Patients reported satisfaction with information received before discharge (86%), support received after discharge (74%), expertise of the health professional (87%), access to health professionals experienced with HEN (74%), communication between health professionals (74%), costs of HEN supplies (52%) and delivery of HEN supplies (88%). QOL scores related to physical, psychological, social and environment domains were significantly lower in HEN patients than in the Australian reference population (P<0.001). There was no significant difference in QOL and health satisfaction across different clinical areas (0.737 and 0.316, respectively). Conclusion Overall, participants were satisfied with HEN services. Participants had lower QOL scores compared with the Australian general population. Improvements to the HEN service were suggested, including sooner follow-up after hospital discharge; more frequent reviews for long-term patients; and the availability of a multidisciplinary team to manage HEN patients. What is known about the topic? Malnutrition is a common problem in Australian hospitals. Many patients require nutrition support to maintain or improve their nutrition status because of inadequate oral intake, malabsorption of nutrients or because of a disease process. Nutrition support is commonly started in the in-patient setting and, because of faster patient discharge from hospital, HEN is a cost-effective and reliable way of treating patients who continue to need nutrition support after hospital discharge. Inconsistencies exist in service provision of HEN because there is no national or state-wide standardisation of services. Australian studies that have evaluated patient satisfaction with HEN services are lacking. This is of particular importance because HEN service use is increasing. What does this paper add? This study reveals that patients receiving HEN therapy are mostly satisfied with the service provided. Patients surveyed have expressed important aspects of the HEN service include follow-up and advice from health care professionals, low price and home delivery of supplies, emphasising the importance of adequate clinical services, supply and delivery of HEN. QOL is poorer in the HEN patient population compared with the general Australian population. What are the implications for practitioners? Standardisation of HEN services is important to ensure uniformity in service provision to HEN patients. Health services adhering to best practice guidelines for HEN will result in the provision of adequate quality of care, and subsequently improved patient satisfaction and adherence to HEN therapy. Adequate service provision and appropriate monitoring and review of HEN patients in the community may also contribute to better health outcomes and better QOL for patients. PMID- 26933947 TI - miRNA Profiling Reveals Dysregulation of RET and RET-Regulating Pathways in Hirschsprung's Disease. AB - Hirschsprung's disease (HSCR), the most common congenital malformation of the gut, is regulated by multiple signal transduction pathways. Several components of these pathways are important targets for microRNAs (miRNAs). Multiple miRNAs have been associated with the pathophysiology of HSCR, and serum miRNAs profiles of HSCR patients have been reported, but miRNA expression in HSCR colon tissue is almost completely unexplored. Using microarray technology, we screened colon tissue to detect miRNAs whose expression profiles were altered in HSCR and identify targets of differentially expressed miRNAs. Following filtering of low intensity signals, data normalization, and volcano plot filtering, we identified 168 differentially expressed miRNAs (104 up-regulated and 64 down-regulated). Fifty of these mRNAs represent major targets of dysegulated miRNAs and may thus important roles in the pathophysiology of HSCR. Pathway analysis revealed that 7 of the miRNA targets encode proteins involved in regulation of cell proliferation and migration via RET and related signaling pathways (MAPK and PI3K/AKT). Our results identify miRNAs that play key roles in the pathophysiology of the complex multi-factorial disease HSCR. PMID- 26933949 TI - ESA Hyporesponsiveness Is Associated with Adverse Events in Maintenance Hemodialysis (MHD) Patients, But Not with Iron Storage. AB - OBJECTIVE: It has been reported that hyporesponsiveness to erythropoiesis stimulating agent (ESA) is associated with adverse events in patients on maintenance hemodialysis (MHD). However, it has not been determined whether higher iron storage is associated with an improved response, including better survival, to ESA. DESIGN AND METHOD: We measured serum ferritin, hemoglobin (Hb), and transferrin saturation (TSAT) levels every three months for two years in 1,095 MHD patients. The weekly dose of ESA to Hb ratio was also calculated as an index of ESA responsiveness (ERI). RESULTS: A significant correlation (p<0.001, R = 0.89) between ferritin and Hb was only observed in the patients with ferritin levels <50 ng/mL. High-dose (>=50 mg/week) intravenous iron administration, female sex, low serum albumin, and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use were significant predictors of a high ERI value (>280); however, serum ferritin and TSAT levels did not predict a higher ERI. In the time-dependent Cox hazard model, the risk for a composite event in the patients with a high ERI (>=280) and a high ferritin level (>=100 ng/mL) was significantly greater (hazard ratio [HR], 2.09, P = 0.033) than that for patients with a high ERI and a low ferritin (<100 ng/mL) level. CONCLUSION: Hb was dependent upon ferritin levels in patients with ferritin levels <50 ng/mL but not in patients with ferritin levels >=50 ng/mL. Patients with hyporesponsiveness to ESA had a greater risk of composite events, but ERI was unrelated to iron storage. PMID- 26933950 TI - Forelimb Kinematics of Rats Using XROMM, with Implications for Small Eutherians and Their Fossil Relatives. AB - The earliest eutherian mammals were small-bodied locomotor generalists with a forelimb morphology that strongly resembles that of extant rats. Understanding the kinematics of the humerus, radius, and ulna of extant rats can inform and constrain hypotheses concerning typical posture and mobility in early eutherian forelimbs. The locomotion of Rattus norvegicus has been extensively studied, but the three-dimensional kinematics of the bones themselves remains under-explored. Here, for the first time, we use markerless XROMM (Scientific Rotoscoping) to explore the three-dimensional long bone movements in Rattus norvegicus during a normal, symmetrical gait (walking). Our data show a basic kinematic profile that agrees with previous studies on rats and other small therians: rats maintain a crouched forelimb posture throughout the step cycle, and the ulna is confined to flexion/extension in a parasagittal plane. However, our three-dimensional data illuminate long-axis rotation (LAR) movements for both the humerus and the radius for the first time. Medial LAR of the humerus throughout stance maintains an adducted elbow with a caudally-facing olecranon process, which in turn maintains a cranially-directed manus orientation (pronation). The radius also shows significant LAR correlated with manus pronation and supination. Moreover, we report that elbow flexion and manus orientation are correlated in R. norvegicus: as the elbow angle becomes more acute, manus supination increases. Our data also suggest that manus pronation and orientation in R. norvegicus rely on a divided system of labor between the ulna and radius. Given that the radius follows the flexion and extension trajectory of the ulna, it must rotate at the elbow (on the capitulum) so that during the stance phase its distal end lies medial to ulna, ensuring that the manus remains pronated while the forelimb is supporting the body. We suggest that forelimb posture and kinematics in Juramaia, Eomaia, and other basal eutherians were grossly similar to those of rats, and that humerus and radius LAR may have always played a significant role in forelimb and manus posture in small eutherian mammals. PMID- 26933953 TI - Energy Balance-Related Behaviors, Perinatal, Sociodemographic, and Parental Risk Factors Associated with Obesity in Italian Preschoolers. AB - OBJECTIVE: The obesity epidemic stems from the complex interplay between genetics and environmental factors. Identifying age-specific risk factors in preschoolers may allow implementing more effective intervention strategies. The aim of the present investigation was to examine the association of overweight/obesity with several perinatal, parental, socioeconomic status (SES), and lifestyle-related risk factors in a large sample of Italian preschoolers. METHODS: One thousand eleven children (age 2.0 to 5.7 years) were included in the study. Family pediatricians measured weight and height and collected information on obesity risk factors by means of questionnaires. Perinatal risk factors were recalled from electronic medical records. Weight status was defined according to cutoffs of the International Obesity Task Force (IOTF). RESULTS: Seven hundred sixty-four children (75.6%) were normal weight, and 247 (24.4%) were overweight/obese. Multivariate analysis showed that skipping breakfast (odds ratio [OR] = 3.7; 95% confidence interval [CI], 1.32-10.51), daily drinking of sugar-sweetened beverages (OR = 2.0; 95% CI, 1.02-4.03), meat consumption <5 times/week (OR = 2.2; 95% CI, 1.11-4.57), and formula feeding (OR = 2.1; 95% CI, 0.8-4.5) were significantly (p < 0.05) associated with increased risk of obesity. CONCLUSIONS: Though exclusive formula or mixed feeding represents an age-specific risk factor for overweight/obesity, lifestyle factors associated with increased risk in Italian preschoolers include habits that are common to school-age children, such as skipping breakfast and consumption of sugar-sweetened beverages. The reduced consumption of meat emerged as a risk factor for overweight/obesity, but future research is required to better understand this relationship. Our data suggest, on the whole, that prevention of such unhealthy behaviors must be pursued in preschoolers by means of age-specific interventions. PMID- 26933954 TI - Uracil Nucleosides with Reactive Group at C5 Position: 5-(1-Halo-2 sulfonylvinyl)uridine Analogues. AB - The transition-metal-catalyzed or radical-mediated halosulfonylation of 5 ethynyluridine provided (E)-(1-halo-2-tosylvinyl)uridines. These (beta-halo)vinyl sulfones undergo efficient stereoselective addition-elimination with amines or thiols to provide Z-beta-aminovinyl or E-beta-thiovinyl sulfones tethered to the C5 position of the uracil ring. PMID- 26933951 TI - Transformative Innovations in Reproductive, Maternal, Newborn, and Child Health over the Next 20 Years. AB - As part of the "Grand Convergence: Aligning Technologies and Realities in Global Health" Collection, Cyril Engmann and colleagues discuss promising innovations that have the potential to move the RMNCH agenda forward. PMID- 26933952 TI - Major Transcriptome Changes Accompany the Growth of Pseudomonas aeruginosa in Blood from Patients with Severe Thermal Injuries. AB - Pseudomonas aeruginosa is a Gram-negative opportunistic pathogen that causes serious infections in immunocompromised hosts including severely burned patients. After multiplying within the burn wound, P. aeruginosa translocate into the bloodstream causing bacterial sepsis frequently leading to organ dysfunction and septic shock. Although the pathogenesis of P. aeruginosa infection of thermally injured wounds has been extensively analyzed, little is known regarding the ability of P. aeruginosa to adapt and survive within the blood of severely burned patients during systemic infection. To identify such adaptations, transcriptome analyses (RNA-seq) were conducted on P. aeruginosa strain PA14 that was grown in whole blood from a healthy volunteer or three severely burned patients. Compared with growth in blood from healthy volunteers, growth of PA14 in the blood from severely burned patients significantly altered the expression of 2596 genes, with expression of 1060 genes enhanced, while that of 1536 genes was reduced. Genes whose expression was significantly reduced included genes related to quorum sensing, quorum sensing-controlled virulence factors and transport of heme, phosphate, and phosphonate. Genes whose expression was significantly enhanced were related to the type III secretion system, the pyochelin iron-acquisition system, flagellum synthesis, and pyocyanin production. We confirmed changes in expression of many of these genes using qRT-PCR. Although severe burns altered the levels of different blood components in each patient, the growth of PA14 in their blood produced similar changes in the expression of each gene. These results suggest that, in response to changes in the blood of severely burned patients and as part of its survival strategy, P. aeruginosa enhances the expression of certain virulence genes and reduces the expression of others. PMID- 26933956 TI - Inter-Coder Agreement in One-to-Many Classification: Fuzzy Kappa. AB - Content analysis involves classification of textual, visual, or audio data. The inter-coder agreement is estimated by making two or more coders to classify the same data units, with subsequent comparison of their results. The existing methods of agreement estimation, e.g., Cohen's kappa, require that coders place each unit of content into one and only one category (one-to-one coding) from the pre-established set of categories. However, in certain data domains (e.g., maps, photographs, databases of texts and images), this requirement seems overly restrictive. The restriction could be lifted, provided that there is a measure to calculate the inter-coder agreement in the one-to-many protocol. Building on the existing approaches to one-to-many coding in geography and biomedicine, such measure, fuzzy kappa, which is an extension of Cohen's kappa, is proposed. It is argued that the measure is especially compatible with data from certain domains, when holistic reasoning of human coders is utilized in order to describe the data and access the meaning of communication. PMID- 26933955 TI - A Family of Salmonella Type III Secretion Effector Proteins Selectively Targets the NF-kappaB Signaling Pathway to Preserve Host Homeostasis. AB - Microbial infections usually lead to host innate immune responses and inflammation. These responses most often limit pathogen replication although they can also result in host-tissue damage. The enteropathogenic bacteria Salmonella Typhimurium utilizes a type III secretion system to induce intestinal inflammation by delivering specific effector proteins that stimulate signal transduction pathways resulting in the production of pro-inflammatory cytokines. We show here that a family of related Salmonella Typhimurium effector proteins PipA, GogA and GtgA redundantly target components of the NF-kappaB signaling pathway to inhibit transcriptional responses leading to inflammation. We show that these effector proteins are proteases that cleave both the RelA (p65) and RelB transcription factors but do not target p100 (NF-kappaB2) or p105 (NF kappaB1). A Salmonella Typhimurium strain lacking these effectors showed increased ability to stimulate NF-kappaB and increased virulence in an animal model of infection. These results indicate that bacterial pathogens can evolve determinants to preserve host homeostasis and that those determinants can reduce the pathogen's virulence. PMID- 26933958 TI - Adherence to treatment and monitoring tools: what's new? AB - Asthma is a serious global health problem affecting all age groups, with global prevalence. Although controller medications are usually highly-effective asthma treatments, patient adherence remains poor, and under-use is associated with greater health resource use, morbidity, and mortality. Up to 70-80% of patients cannot use their inhaler correctly, and similar proportions of health professionals are unable to demonstrate its correct use. A recent paper by Foster et al. explored the effectiveness of two briefs GPs' delivered intervention in improving adherence to asthma treatment and diseases control in patients with uncontrolled moderate/severe persistent asthma, in real-community setting. The results suggested that inhaler reminders may represent an effective strategy for improving adherence in primary care compared with a behavioral intervention or usual care, although this may not be reflected in differences in levels of asthma control. Studies in larger population are needed in order to test the efficacy of available technology on asthma outcomes in all age stages. PMID- 26933957 TI - Asthma in pregnancy: one more piece of the puzzle. AB - Asthma is the most commonly occurring respiratory complication during pregnancy, and is associated with a wide range of adverse maternal and perinatal outcomes. However, there is strong evidence that an adequate control of asthma can improve the health of both mothers and their babies. Despite the well-known risks of poorly-controlled asthma during pregnancy, a large proportion of women have sub optimal asthma control, due to concerns surrounding risks related to pharmacological agents and uncertainties regarding the effectiveness and safety of different management strategies. A recent retrospective study showed that step up therapy with low-dose inhaled corticosteroids / long-acting beta2-agonist inhalers (ICS/LABA) or high-dose ICS presents the same risk profile in terms of major congenital malformations. These results are consistent with asthma management guidelines and provide scientific evidence to help physicians and mothers make evidence-based treatment decisions during pregnancy, particularly when stepping up to higher doses of ICS or addition of a LABA are required. These reassuring results should encourage women to continue their asthma medications when required to control their asthma during pregnancy and increase the likelihood of healthy pregnancies and newborns. This commentary focuses on some critical issues of this recent work and to the need of future study to evaluate the safety during pregnancy of novel molecules recently introduced for asthma treatment. PMID- 26933959 TI - Telomeropathies: an emerging spectrum of disorders with important implications for patients with interstitial lung disease. AB - Growing evidence demonstrates that a number of clinical disorders may be related to genetic defects in telomere replication and extension. Overall, these syndromes are referred to as "telomeropathies" or "telomere disorders/syndromes"; they are increasingly being identified. In adulthood, idiopathic pulmonary fibrosis (IPF) is the most common symptom of telomeropathy. IPF is a progressive and fatal disease characterized by scarring of the lungs that thickens the interstitium ultimately leading to irreversible respiratory failure. Starting from this basis, the present review analyzes and discusses the findings of a relevant paper by Gautam George and colleagues from the Division of Pulmonary and Critical Care Medicine at Brigham and Women's Hospital and Harvard Medical School in Boston, MA, recently appeared on the prestigious journal CHEST. In a cohort of patients addressed to lung transplantation, authors were able to demonstrate that subclinical bone marrow and liver abnormalities can be seen in patients with interstitial lung disease (ILD) and short telomeres, in some cases in the absence of clinically significant abnormalities in peripheral blood count and liver function tests. This observation sustains the rationale for further studies aimed to validate telomere length testing as a useful parameter as part of the evaluation for transplant candidacy. A deeper clarification of the complex link between IPF and short telomeres and telomeropathies is required for a new ILD classification, aimed to a fully personalized approach to the disease. PMID- 26933960 TI - Long-term outcome of molecular subgroups of gastrointestinal stromal tumour patients treated with standard-dose imatinib in the BFR14 trial: The wild-type gastrointestinal stromal tumours are not a single group yet. PMID- 26933961 TI - Less than 3 doses of the HPV vaccine - Review of efficacy against virological and disease end points. AB - World Health Organization (WHO) recommended 2 doses of the Human Papillomavirus (HPV) vaccine for girls below 15 y on the basis of the immune-bridging studies demonstrating non-inferior immune response of 2 doses in the adolescent girls compared to 3 doses in the young adult women in whom the efficacy against disease is established. The biological nature of the antigens (virus-like particles) constituting the HPV vaccine is responsible for the vigorous antibody response that may make the third dose redundant. The protection offered by 2 doses has been demonstrated in non-randomized clinical trials to be comparable to that offered by 3 doses against incident and persistent infections of vaccine targeted HPV types. However, results emerging from the ecological and nested case-control studies embedded in the population based screening programs of different countries indicate reduced efficacy of 2 doses against virological and disease end points. Some recent studies observed the protective effect of single dose of the vaccine against incident and persistent infections of the vaccine targeted HPV types to be similar to 3 doses in spite of immunological inferiority. The sample size, duration of follow-ups and number of events were limited in these studies. Longer follow ups of the less than 3 doses cohorts in the ongoing studies as well as appropriately designed and ethically justifiable randomized studies are needed to establish the protection offered by the alternative schedules at least beyond 10 y of vaccination. PMID- 26933962 TI - Which New Health Technologies Do We Need to Achieve an End to HIV/AIDS? AB - In the last 15 years, antiretroviral therapy (ART) has been the most globally impactful life-saving development of medical research. Antiretrovirals (ARVs) are used with great success for both the treatment and prevention of HIV infection. Despite these remarkable advances, this epidemic grows relentlessly worldwide. Over 2.1 million new infections occur each year, two-thirds in women and 240,000 in children. The widespread elimination of HIV will require the development of new, more potent prevention tools. Such efforts are imperative on a global scale. However, it must also be recognised that true containment of the epidemic requires the development and widespread implementation of a scientific advancement that has eluded us to date--a highly effective vaccine. Striving for such medical advances is what is required to achieve the end of AIDS. PMID- 26933964 TI - Human exposure to per- and polyfluoroalkyl substances (PFASs) via house dust in Korea: Implication to exposure pathway. AB - A wide range of per- and polyfluoroalkyl substances (PFASs), including fluorotelomer alcohols (FTOHs), perfluorooctane sulfonamidoethanols (FOSEs), perfluoroalkyl carboxylic acids (PFCAs), and perfluoroalkane sulfonic acids (PFSAs), were measured in fifteen house dust and two nonresidential indoor dust of Korea. Total concentrations of PFASs in house dust ranged from 29.9 to 97.6 ng g(-1), with a dominance of perfluorooctane sulfonic acid (PFOS), followed by 8:2 FTOH, N-Ethyl perfluorooctane sulfonamidoethanol (EtFOSE), perfluoroctanoic acid (PFOA). In a typical exposure scenario, the estimated daily intakes (EDIs) of total PFASs via house dust ingestion were 2.83 ng d(-1) for toddlers and 1.13 ng d(-1) for adults, which were within the range of the mean EDIs reported from several countries. For PFOA and PFOS exposure via house dust ingestion, indirect exposure (via precursors) was a minor contributor, accounting for 5% and 12%, respectively. An aggregated exposure (hereafter, overall-EDIs) of PFOA and PFOS occurring via all pathways, estimated using data compiled from the literature, were 53.6 and 14.8 ng d(-1) for toddlers, and 20.5 and 40.6 ng d(-1) for adults, respectively, in a typical scenario. These overall-EDIs corresponded to 82% (PFOA) and 92% (PFOS) of a pharmacokinetic model-based EDIs estimated from adults' serum data. Direct dietary exposure was a major contributor (>89% of overall-EDI) to PFOS in both toddlers and adults, and PFOA in toddlers. As for PFOA exposure of adults, however direct exposure via tap water drinking (37%) and indirect exposure via inhalation (22%) were as important as direct dietary exposure (41%). House dust-ingested exposure (direct+indirect) was responsible for 5% (PFOS in toddlers) and <1% (PFOS in adults, and PFOA in both toddlers and adults) of the overall-EDIs. In conclusion, house-dust ingestion was a minor contributor in this study, but should not be ignored for toddlers' PFOS exposure due to its significance in the worst-case scenario. PMID- 26933965 TI - Warming increases isoprene emissions from an arctic fen. AB - Emissions of biogenic volatile organic compounds (BVOCs) from dry ecosystems at high latitudes respond strongly to small increases in temperature, and warm canopy surface temperatures drive emissions to higher levels than expected. However, it is not known whether emissions from wetlands, cooled by through flowing water and higher evapotranspiration show similar response to warming as in drier ecosystems. Climate change will cause parts of the Arctic to experience increased snow fall, which delays the start of the growing season, insulates soil from low temperatures in winter, and increases soil moisture and possibly nutrient availability. Currently the effects of increasing snow depth on BVOC emissions are unknown. BVOC emissions were measured in situ across the growing season in a climate experiment, which used open top chambers to increase temperature and snow fences to increase winter snow depth. The treatments were arranged in a full factorial design. Measurements took place during two growing seasons in a fen ecosystem in west Greenland. BVOC samples collected by an enclosure technique in adsorbent cartridges were analysed using gas chromatography-mass spectrometry. Gross ecosystem production (GEP) was measured with a closed chamber technique, to reveal any immediate effect of treatments on photosynthesis, which could further influence BVOC emissions. Isoprene made up 84 92% of the emitted BVOCs. Isoprene emission increased 240 and 340% due to an increase in temperature of 1.3 and 1.6 degrees C in 2014 and 2015, respectively. Isoprene emissions were 25 times higher in 2015 than in 2014 most likely due to a 2.4 degrees C higher canopy air temperature during sampling in 2015. Snow addition had no significant effect on isoprene emissions even though GEP was increased by 24%. Arctic BVOC emissions respond strongly to rising temperatures in wet ecosystems, suggesting a large increase in arctic emissions in a future warmer climate. PMID- 26933963 TI - Hepatitis B and C Co-Infection in HIV Patients from the TREAT Asia HIV Observational Database: Analysis of Risk Factors and Survival. AB - BACKGROUND: We assessed the effects of hepatitis B (HBV) or hepatitis C (HCV) co infection on outcomes of antiretroviral therapy (ART) in HIV-infected patients enrolled in the TREAT Asia HIV Observational Database (TAHOD), a multi-center cohort of HIV-infected patients in the Asia-Pacific region. METHODS: Patients testing HBs antigen (Ag) or HCV antibody (Ab) positive within enrollment into TAHOD were considered HBV or HCV co-infected. Factors associated with HBV and/or HCV co-infection were assessed by logistic regression models. Factors associated with post-ART HIV immunological response (CD4 change after six months) and virological response (HIV RNA <400 copies/ml after 12 months) were also determined. Survival was assessed by the Kaplan-Meier method and log rank test. RESULTS: A total of 7,455 subjects were recruited by December 2012. Of patients tested, 591/5656 (10.4%) were HBsAg positive, 794/5215 (15.2%) were HCVAb positive, and 88/4966 (1.8%) were positive for both markers. In multivariate analysis, HCV co-infection, age, route of HIV infection, baseline CD4 count, baseline HIV RNA, and HIV-1 subtype were associated with immunological recovery. Age, route of HIV infection, baseline CD4 count, baseline HIV RNA, ART regimen, prior ART and HIV-1 subtype, but not HBV or HCV co-infection, affected HIV RNA suppression. Risk factors affecting mortality included HCV co-infection, age, CDC stage, baseline CD4 count, baseline HIV RNA and prior mono/dual ART. Shortest survival was seen in subjects who were both HBV- and HCV-positive. CONCLUSION: In this Asian cohort of HIV-infected patients, HCV co-infection, but not HBV co infection, was associated with lower CD4 cell recovery after ART and increased mortality. PMID- 26933966 TI - Coral reefs chronically exposed to river sediment plumes in the southwestern Caribbean: Rosario Islands, Colombia. AB - Politicians do not acknowledge the devastating impacts riverine sediments can have on healthy coral reef ecosystems during environmental debates in Caribbean countries. Therefore, regional and/or local decision makers do not implement the necessary measures to reduce fluvial sediment fluxes on coral reefs. The Magdalena River, the main contributor of continental fluxes into the Caribbean Sea, delivers water and sediment fluxes into the Rosario Islands National Park, an important marine protected area in the southwestern Caribbean. Until now, there is no scientific consensus on the presence of sediment fluxes from the Magdalena River in the coral reefs of the Rosario Islands. Our hypothesis is that high sediment and freshwater inputs from the Magdalena have been present at higher acute levels during the last decade than previously thought, and that these runoff pulses are not flashy. We use in-situ calibrated MODIS satellite images to capture the spatiotemporal variability of the distribution of suspended sediment over the coral reefs. Furthermore, geochemical data are analyzed to detect associated sedimentation rates and pollutant dispersion into the coastal zone. Results confirm that turbidity levels have been much higher than previous values presented by national environmental authorities on coral reefs off Colombia over the last decade. During the 2003-2013-period most of the Total Suspended Sediments (TSS) values witnessed in the sampled regions were above 10mg/l, a threshold value of turbidity for healthy coral reef waters. TSS concentrations throughout the analyzed time were up to 62.3mg/l. Plume pulses were more pronounced during wet seasons of La Nina events in 2002-2003, 2007 2008, and 2009-2010. Reconstructed time series of MODIS TSS indicates that coral reef waters were exposed to river plumes between 19.6 and 47.8% of the entire period of analysis (2000-2013). Further analyses of time series of water discharge and sediment load into the coastal zone during the last two decades show temporal increases in water discharge and sediment load of 28% and 48%, respectively. (210)Pb dating results from two cores indicate sedimentation rates of ~0.75 cm/y of continentally exported clastic muddy sediments that are being deposited on the carbonatic shelf. The cores contain sediments with heavy metals and their concentrations are frequently above the ecologically accepted standards. Overall, the last decade has witnessed stronger magnitudes in fluvial fluxes to the coastal region, which probably coincide with associated declines in healthy coral cover and water quality. Our results emphasize the importance of local stressors, such as runoff and dispersion of turbid plumes, as opposed to ocean warming, disease and hurricanes, which have played a larger role on other coral reefs in the Caribbean. Coral reef management across the southwestern Caribbean, a coastal region influenced by continental fluxes of numerous rivers flowing from the Andes, may only be effective when land and marine-based stressors are simultaneously mitigated. PMID- 26933967 TI - Incidental nutrient transfers: Assessing critical times in agricultural catchments using high-resolution data. AB - Managing incidental losses associated with liquid slurry applications during closed periods has significant cost and policy implications and the environmental data required to review such a measure are difficult to capture due to storm dependencies. Over four years (2010-2014) in five intensive agricultural catchments, this study used high-resolution total and total reactive phosphorus (TP and TRP), total oxidised nitrogen (TON) and suspended sediment (SS) concentrations with river discharge data to investigate the magnitude and timing of nutrient losses. A large dataset of storm events (defined as 90th percentile discharges), and associated flow-weighted mean (FWM) nutrient concentrations and TP/SS ratios, was used to indicate when losses were indicative of residual or incidental nutrient transfers. The beginning of the slurry closed period was reflective of incidental and residual transfers with high storm FWM P (TP and TRP) concentrations, with some catchments also showing elevated storm TP:SS ratios. This pattern diminished at the end of the closed period in all catchments. Total oxidised N behaved similarly to P during storms in the poorly drained catchments and revealed a long lag time in other catchments. Low storm FWM P concentrations and TP:SS ratios during the weeks following the closed period suggests that nutrients either weren't applied during this time (best times chosen) or that they were applied to less risky areas (best places chosen). For other periods such as late autumn and during wet summers, where storm FWM P concentrations and TP:SS ratios were high, it is recommended that an augmentation of farmer knowledge of soil drainage characteristics with local and detailed current and forecast soil moisture conditions will help to strengthen existing regulatory frameworks to avoid storm driven incidental nutrient transfers. PMID- 26933968 TI - Is precipitation a predictor of mortality in Bangladesh? A multi-stratified analysis in a South Asian monsoon climate. AB - While numerous studies have assessed the association between temperature and mortality in various locations, few have addressed the relationship between precipitation and mortality. Given the high amounts of rainfall in many tropical monsoon areas and the often seasonally pronounced differences, there might be a potentially strong impact on health outcomes and death. In this study, we investigated the association between precipitation and daily death counts in Bangladesh from 2003 to 2007 using regression models with a quasipoisson distribution adjusting for long-term time and seasonal trends, day of the month, age and perceived temperature. Effects were assessed for all ages, the elderly and by gender. During the dry season a sharp increase in death risk was found at very high precipitation amounts which are most likely to be cyclone-related. This cyclone effect was most pronounced for females at the immediate day with an increase of 18.7% (3.8-35.6%) in non-external cause mortality per mm precipitation above 5mm. At longer lags we found a negative association between precipitation and mortality indicating some kind of dry effect which was more pronounced for the elderly with a mortality increase of 4.4% (2.6-6.2%) per mm decrease in precipitation. During the rainy season, we observed a protective effect of rainfall which was strongest during periods of seasonally high equivalent temperatures with a decrease in mortality of 4.0% (2.3-5.6%) per mm increase in precipitation on the immediate day. The observed associations between precipitation and mortality differed by season, age and gender. Generally, a strong short-term increase in mortality was associated with cyclonic activity during the dry season, while ongoing low rainfall seemed to have an adverse impact at higher lags. During the rainy season, precipitation seemed to mitigate heat effects. PMID- 26933969 TI - Dissecting a Hub for Immune Response: Modeling the Structure of MyD88. AB - Immune cells sense foreign organisms through the evolutionarily conserved family of Toll-like receptors. Signaling from these receptors relies on oligomerization of adaptor molecules. In this issue of Structure, Vynke et al. (2016) shed light on the dynamical structure of the homo- and hetero-dimerization domain of MyD88, the main adaptor utilized by Toll-like receptors. PMID- 26933970 TI - Interacting with the Human Insulin Receptor. AB - Insulin is an essential regulator of glucose homeostasis. In this issue of Structure, Croll et al. (2016) reports a significantly improved model of the Fab complexed IR ectodomain refined against a dataset extending to 3.3 A. PMID- 26933971 TI - Structure-Based Identification of HDAC8 Non-histone Substrates. AB - HDAC8 is a member of the family of histone deacetylases (HDACs) that catalyze the deacetylation of acetyl lysine residues within histone and non-histone proteins. The recent identification of novel non-histone HDAC8 substrates such as SMC3, ERRalpha, and ARID1A indicates a complex functionality of this enzyme in cellular homeostasis. To discover additional HDAC8 substrates, we developed a comprehensive, structure-based approach based on Rosetta FlexPepBind, a protocol that evaluates peptide-binding ability to a receptor from structural models of this interaction. Here we adapt this protocol to identify HDAC8 substrates using peptide sequences extracted from proteins with known acetylated sites. The many new in vitro HDAC8 peptide substrates identified in this study suggest that numerous cellular proteins are HDAC8 substrates, thus expanding our view of the acetylome and its regulation by HDAC8. PMID- 26933975 TI - Enhanced magnetic anisotropy and heating efficiency in multi-functional manganese ferrite/graphene oxide nanostructures. AB - A promising nanocomposite material composed of MnFe2O4 (MFO) nanoparticles of ~17 nm diameter deposited onto graphene oxide (GO) nanosheets was successfully synthesized using a modified co-precipitation method. X-ray diffraction, transmission electron microscopy, and selected area electron diffraction confirmed the quality of the synthesized samples. Fourier transform infrared measurements and analysis evidenced that the MFO nanoparticles were attached to the GO surface. Magnetic measurements and analysis using the modified Langevin model evidenced the superparamagnetic characteristic of both the bare MFO nanoparticles and the MFO-GO nanocomposite at room temperature, and an appreciable increase of the effective anisotropy for the MFO-GO sample. Magnetic hyperthermia experiments performed by both calorimetric and ac magnetometry methods indicated that relative to the bare MFO nanoparticles, the heating efficiency of the MFO-GO nanocomposite was similar at low ac fields (0-300 Oe) but became progressively larger with increasing ac fields (>300 Oe). This has been related to the higher effective anisotropy of the MFO-GO nanocomposite. In comparison with the bare MFO nanoparticles, a smaller reduction in the heating efficiency was observed in the MFO-GO composites when embedded in agar or when their concentration was increased, indicating that the GO helped minimize the physical rotation and aggregation of the MFO nanoparticles. These findings can be of practical importance in exploiting this type of nanocomposite for advanced hyperthermia. Magnetoimpedance-based biodetection studies also indicated that the MFO-GO nanocomposite could be used as a promising magnetic biomarker in biosensing applications. PMID- 26933973 TI - Development of a sensitive monoclonal-based enzyme-linked immunosorbent assay for monitoring T-2 toxin in food and feed. AB - The consumption of food or feed contaminated with high levels of T-2 toxin may cause adverse health effects in humans and other animals. In this study, to monitor T-2 toxin rapidly in food and feed, a sensitive and specific monoclonal antibody (mAb) against T-2 toxin was generated and a simple and rapid indirect competitive enzyme-linked immunosorbent assay (ic-ELISA) developed. T-2 toxin was first converted to T-2-hemisuccinate (T-2HS) and T-2-hemiglutarate (T-2HG), which were then conjugated to bovine serum albumin (BSA) and ovalbumin (OVA) to prepare an immunogen and coating antigen, respectively. After the inoculation of female Balb/c mice and cell fusions, one cell line, 4D8, with the IgG1 isotype was obtained. The 4D8 antibody exhibited the ability specifically to recognise T-2 toxin with IC50 1.46 ug l(-1). Based on this 4D8 mAb, an optimised ic-ELISA protocol was developed using only methanol-water (7:3, v/v) in feed and cereal samples and ethyl acetate in muscle samples. The limits of detection of T-2 toxin in various sample matrices varied from 0.07 to 15.8 ug kg(-1); the recoveries ranged from 50.3% to 113.6%; and the CVs were less than 19.0%. These results suggest that the prepared mAb and the developed ic-ELISA method will be a useful tool for detecting T-2 toxin in foods and feeds. PMID- 26933976 TI - Subharmonic Shapiro steps of sliding colloidal monolayers in optical lattices. AB - We investigate theoretically the possibility to observe dynamical mode locking, in the form of Shapiro steps, when a time-periodic potential or force modulation is applied to a two-dimensional (2D) lattice of colloidal particles that are dragged by an external force over an optically generated periodic potential. Here we present realistic molecular dynamics simulations of a 2D experimental setup, where the colloid sliding is realized through the motion of soliton lines between locally commensurate patches or domains, and where the Shapiro steps are predicted and analyzed. Interestingly, the jump between one step and the next is seen to correspond to a fixed number of colloids jumping from one patch to the next, across the soliton line boundary, during each ac cycle. In addition to ordinary 'integer' steps, coinciding here with the synchronous rigid advancement of the whole colloid monolayer, our main prediction is the existence of additional smaller 'subharmonic' steps due to localized solitonic regions of incommensurate layers executing synchronized slips, while the majority of the colloids remains pinned to a potential minimum. The current availability and wide parameter tunability of colloid monolayers makes these predictions potentially easy to access in an experimentally rich 2D geometrical configuration. PMID- 26933972 TI - Factors related to obesity and overweight among Black adolescent girls in the United States. AB - In the United States, Black adolescents have the highest prevalence of pediatric obesity and overweight among girls. While Black girls are disproportionately affected, the reasons for this health disparity remain unclear. The authors conducted a systematic review to investigate the factors related to obesity and overweight among Black adolescent girls. The authors searched four databases for relevant English-language publications using all publication years through 2015. Fifty-one studies met the inclusion criteria and were used for this review. Using a configuration approach to synthesis, three categories were identified, paralleling the bioecological theory of human development: (1) individual, (2) interpersonal, and (3) community and societal factors. A description of each factor's association with obesity among Black adolescent girls is presented. From this review, the authors identified a diverse and vast set of individual, interpersonal, and community and societal factors explored for their relationship with obesity and overweight. Given the insufficient repetition and limited significant findings among most factors, the authors believe that multiple gaps in knowledge exist across all categories regarding the factors related to obesity and overweight among Black adolescent girls. To improve the quality of research in this area, suggested research directions and methodological recommendations are provided. PMID- 26933977 TI - A Year in Review. PMID- 26933978 TI - The Foundation--Pay It Forward. PMID- 26933979 TI - 2015 Certification "Hall of Fame". PMID- 26933980 TI - Middle-Range Theories: Frameworks for Examining a Nonsurgical Cosmetic Problem. AB - The advent of evidence-based research has called for nursing to focus and create additional pathways that enable exploration of specific practice problems. This change of direction has presented an increased opportunity for analysis and scientific research that are pertinent to nursing. Although grand theory has historically been used to define and guide nursing research, currently many theorists have applied middle-range theories for these purposes. This level of theory provides substantive structures and foundations that may facilitate the ability to observe, test, and interpret phenomena so that a higher level of evidence-based research may be translated into practice. This article addresses and describes a selected clinical practice problem, reviews and assesses 2 middle range theories, and finally, provides evaluation of the theories that will reaffirm how they support the practice problem. PMID- 26933981 TI - Understanding the Perioral Anatomy. AB - Rejuvenation of the perioral region can be very challenging because of the many factors that affect the appearance of this area, such as repeated muscle movement causing radial lip lines, loss of the maxillary and mandibular bony support, and decrease and descent of the adipose tissue causing the formation of "jowls." Environmental issues must also be addressed, such as smoking, sun damage, and poor dental health. When assessing a client for perioral rejuvenation, it is critical that the provider understands the perioral anatomy so that high-risk areas may be identified and precautions are taken to prevent serious adverse events from occurring. PMID- 26933982 TI - Leadership and Management in Aesthetic Medicine. AB - The aesthetic provider is obligated to leverage their leadership, management, and teamwork skills on a daily basis in order to deliver optimum aesthetic outcomes for their clients. This article discusses leadership and motivational theories, leadership and management traits, complexity theory, Gardner's tasks of leadership, and the role of emotional intelligence in leading, managing, and following, so the aesthetic provider can identify and align with a particular leadership and management style that suits their practice philosophy. PMID- 26933983 TI - The Dilution Confusion: Easy Dosing for Botulinum Toxins. AB - Aesthetic practitioners prefer various reconstitution volumes for botulinum toxins (BoNTAs). Some injectors prefer larger volumes of bacteriostatic normal saline (NaCl) to achieve a larger diffusion in certain areas and a smaller volume for more precise administration of the BoNTA. Some practitioners believe dilution volumes do not matter at all in relation to spread or diffusion, asserting the diffusion area is simply dose-related. It can get confusing when there is more than one injector in an office, different volumes of saline, and more than one type of syringe to administer the neurotoxin. This leaves possibilities for confusion and dosage errors. This article explores four steps to take the confusion out of reconstituting BoNTAs and delivering accurate and consistent doses within a medical office. PMID- 26933984 TI - Biopsychosocial Issues in Cleft Lip and Palate. PMID- 26933985 TI - The Changing World of Breast Cancer: A Radiologist's Perspective. AB - Compared with other fields of medicine, there is hardly an area that has seen such fast development as the world of breast cancer. Indeed, the way we treat breast cancer has changed fundamentally over the past decades. Breast imaging has always been an integral part of this change, and it undergoes constant adjustment to new ways of thinking. This relates not only to the technical tools we use for diagnosing breast cancer but also to the way diagnostic information is used to guide treatment. There is a constant change of concepts for and attitudes toward breast cancer, and a constant flux of new ideas, new treatment approaches, and new insights into the molecular and biological behavior of this disease. Clinical breast radiologists and even more so, clinician scientists, interested in breast imaging need to keep abreast with this rapidly changing world. Diagnostic or treatment approaches that are considered useful today may be abandoned tomorrow. Approaches that seem irrelevant or far too extravagant today may prove clinically useful and adequate next year. Radiologists must constantly question what they do, and align their clinical aims and research objectives with the changing needs of contemporary breast oncology. Moreover, knowledge about the past helps better understand present debates and controversies. Accordingly, in this article, we provide an overview on the evolution of breast imaging and breast cancer treatment, describe current areas of research, and offer an outlook regarding the years to come. PMID- 26933988 TI - Hepatitis C in Australian prisons: a national needs assessment. AB - PURPOSE: Hepatitis C (HCV) infections are prevalent in custodial settings worldwide, yet provision of antiviral therapies is uncommon. Approximately 30,000 prisoners are held in Australian prisons at any one time, with more than 30 per cent testing positive for HCV antibodies. Prisoners have been identified in the National Hepatitis C Strategy as a priority population for assessment and treatment. The purpose of this paper is to examine the rates of HCV testing and treatment, as well as barriers and opportunities for development of infrastructure for enhanced services. DESIGN/METHODOLOGY/APPROACH: Interviews were conducted with 55 stakeholders from the correctional sector in each state and territory in Australia in two stages: service directors to gather quantitative data regarding rates of testing and treatment; and other stakeholders for qualitative information regarding barriers and opportunities. FINDINGS: Of more than 50,000 individuals put in in custody in Australian prisons in 2013, approximately 8,000 individuals were HCV antibody positive, yet only 313 prisoners received antiviral treatment. The barriers identified to assessment and treatment at the prisoner-level included: fear of side effects and the stigma of being identified to custodial authorities as HCV infected and a likely injecting drug user. Prisoners who came forward may be considered unsuitable for treatment because of prevalent mental health problems and ongoing injecting drug use. Provision of specialist hepatitis nurses and consultants were the most frequently recommended approaches to how prison hepatitis services could be improved. ORIGINALITY/VALUE: Many personal and systems-level barriers relevant to the delivery of HCV treatment services in the custodial setting were identified. Ready access to skilled nursing and medical staff as well as direct acting antiviral therapies will allow the prison-sector to make a major contribution to control of the growing burden of HCV disease. PMID- 26933989 TI - Routine or targeted HIV screening of Indonesian prisoners. AB - PURPOSE: Routine HIV screening of prisoners is generally recommended, but rarely implemented in low-resource settings. Targeted screening can be used as an alternative. Both strategies may provide an opportunity to start HIV treatment but no formal comparisons have been done of these two strategies. The paper aims to discuss these issues. DESIGN/METHODOLOGY/APPROACH: The authors compared yield and costs of routine and targeted screening in a narcotic prison in Indonesia. Routine HIV screening was done for all incoming prisoners from August 2007 February 2009, after it was switched for budgetary reasons to targeted ("opt out") HIV screening of inmates classified as people who inject drugs (PWIDs), and "opt-in" HIV testing for all non-PWIDs. FINDINGS: During routine screening 662 inmates were included. All 115 PWIDs and 93.2 percent of non-PWIDs agreed to be tested, 37.4 percent and 0.4 percent respectively were HIV-positive. During targeted screening (March 2009-October 2010), of 888 inmates who entered prison, 107 reported injecting drug use and were offered HIV testing, of whom 31 (29 percent) chose not to be tested and 25.0 percent of those tested were HIV positive. Of 781 non-PWIDs, 187 (24 percent) came for testing (opt-in), and 2.1 percent were infected. During targeted screening fewer people admitted drug use (12.0 vs 17.4 percent). Routine screening yielded twice as many HIV-infected subjects (45 vs 23). The estimated cost per detected HIV infection was 338 USD for routine and 263 USD for targeted screening. ORIGINALITY/VALUE: In a resource limited setting like Indonesia, routine HIV screening in prison is feasible and more effective than targeted screening, which may be stigmatizing. HIV infections that remain unrecognized can fuel ongoing transmission in prison and lead to unnecessary disease progression and deaths. PMID- 26933990 TI - Injecting drug use, sexual risk, HIV knowledge and harm reduction uptake in a large prison in Bali, Indonesia. AB - PURPOSE: The purpose of this paper is to describe HIV-related risk behavior and knowledge of HIV among inmates of Kerobokan prison Bali, Indonesia. DESIGN/METHODOLOGY/APPROACH: A cross-sectional survey of inmates of using a structured questionnaire and sample framework to reflect narcotic use among inmates and the prison gender mix. FINDINGS: Among 230 inmates recruited to the study self-reported prevalence of injecting drug use was 7.4 percent (95 percent CI 4.0-10.8 percent). Respondents who participated in a prison based methadone treatment program were all still injecting drugs, these made up 13/17 of the IDU. In total, 47 percent (95 percent CIs 45-55 percent) of respondents who reported injecting also reported sharing needles within the last week. Sexual intercourse while in prison was reported by 3.0 percent (95 percent CI 0.82-5.26 percent) of study respondents. One-third of non-injectors were unaware of the preventative role of condom use. This study suggests that despite harm reduction initiatives within Kerobokan prison HIV risk behavior continues and there is a considerable lack of awareness of the importance of condom use in preventing HIV. RESEARCH LIMITATIONS/IMPLICATIONS: The authors relied on self-reported risk behavior that may be subject to reporting bias. The sampling strategy may not reflect the true ratio inmates using or not using narcotics. PRACTICAL IMPLICATIONS: The current harm reduction approach, including methadone substitution treatment should be optimized within the Indonesian prison setting. ORIGINALITY/VALUE: This is the first study reporting HIV-related risk behavior from an Indonesian prison with an established methadone substitution program. PMID- 26933991 TI - Self-harm and overcrowding among prisoners in Geneva, Switzerland. AB - PURPOSE: Prison institutional conditions affect risk for self-harm among detainees. In particular, prison overcrowding may increase the likelihood of self harm by creating competition for resources, space, and enhancing a "deprivation state." The purpose of this paper is to examine the association between overcrowding and prisoner acts of self-harm. DESIGN/METHODOLOGY/APPROACH: This cross-sectional study took place at Geneva's pre-trial prison (capacity:376) between 2006 and 2014. Outcomes were acts of self-harm that required medical attention, and self-strangulation/hanging events (combined into one group, as these are difficult to differentiate). Dichotomous predictors were overcrowding index- annual mean daily population divided by capacity ( > 200 percent vs < 200 percent), and year group (2006-2009 vs 2011-2014). FINDINGS: Self-harm and self strangulations/hangings increased in 2011-2014 compared to 2006-2010 (p < 0.001). Overcrowding in excess of 200 percent was associated with self strangulation/hangings (p < 0.001) but not with all self-harm events. In terms of pertinent demographics that would affect self-harm, there was no prison change in gender, area of origin, foreign residency, religion, or psychiatric treatment. RESEARCH LIMITATIONS/IMPLICATIONS: The present study is limited by the definition and identification of self-harm. The distinction between self-strangulation and self-hanging, and the precise classification of an intent to die is difficult to make in practice, especially with limited prison data records available. The relevant literature addresses the complexity of the association between non suicidal and suicidal behavior. Despite this, the combined category self strangulations/hangings gives some indication of severe self-harm events, especially since the methodology of categorization employed was consistent throughout the entire period of the study. Other limitations include the small sample size and the lack of individual patient data and prison data to help control for confounding factors. Despite these drawbacks, pertinent data (socio demographics and number of prisoners treated for mental health and drug abuse) remained stable over the years. Thus, there are no apparent changes in the inmate population that could be linked to an increase in self-harm. High-security placements and mean prisoner stay have increased over time, with a decrease in staff to prisoner ratio - and these must be looked into further as contributors. Additionally, qualitative methods such as semi-structured interviews and focus groups could delineate the impact of overcrowding on prisoner well-being and self harm potential. PRACTICAL IMPLICATIONS: The authors observed a significant increase in self-harm and self-strangulation/hangings over time, and overcrowding was significantly associated with self-strangulation/hangings (but not with all self-harm events). Overcrowding can impose destructive effects on the psychological and behavioral well being of inmates in prison, influencing a myriad of emotional and livelihood factors that predispose to harmful behavior. ORIGINALITY/VALUE: This report should alert public health and prison authorities to this issue, and garner resources to address such an alarming rise. The findings from this short report demonstrate the need for a further examination of the mechanisms affecting self-harm among prisoners in this population, particularly the relationship between self-strangulations/hangings and overcrowding. PMID- 26933992 TI - Prisons as a source of tuberculosis in Russia. AB - PURPOSE: The purpose of this paper is to analyze poor management of tuberculosis (TB) prevention and treatment and explore parameters and causes of this problem drawing on qualitative interviews with former prisoners and medical specialists in Kaliningrad Oblast in Russia. DESIGN/METHODOLOGY/APPROACH: The authors undertook a qualitative study, to explore access to HIV and TB treatment for people who inject drugs in Kaliningrad. The authors interviewed (outside of prisons) 15 patients and eight health specialists using a semi-structured guide. The authors analyzed the accounts thematically and health consequences of imprisonment emerged as a major theme. FINDINGS: Prisons are overcrowded and lack basic hygiene and infection control. Demand for medical services outstrip supply, HIV and TB prevention lacking, HIV and TB treatment is patchy, with no second line drugs available for resistant forms. The prison conditions are generally degrading and unhealthy and many respondents perceived surviving prisons as a miracle. Cooperation with medical services in the community is poor. RESEARCH LIMITATIONS/IMPLICATIONS: The authors used qualitative research methods, which do not rely on a representative sample. However, many of the structural barriers preventing effective TB treatment and prevention highlighted in this paper have been noted elsewhere, suggesting that findings are likely to reflect conditions elsewhere in Russia. The authors tried to include all possible points of view, as of the medical staff and the patients. However, due to resistance of the officials the authors were unable to conduct interviews with employees of the FCS. Since all the interviews are recalling past experience, the situation may have changed. This does not undermine importance of the findings, as they shed light on particular treatment experiences, and development of prison health system. ORIGINALITY/VALUE: The paper contributes to the literature on prisons as a contributor to TB epidemic, including drug resistant forms. An urgent penitentiary reform in Russia should focus on HIV and TB prevention, case detection, availability of medications and effective treatments. Key to decreasing prison population and improving health is political reform aimed at introduction of effective drug treatment, de-penalization and de-criminalization of drug users and application of alternatives to incarceration. PMID- 26933993 TI - A rapid systematic review of what we know about alcohol use disorders and brief interventions in the criminal justice system. AB - PURPOSE: The purpose of this paper is to review the evidence of alcohol use disorders within the different stages of the criminal justice system in the UK. Furthermore it reviewed the worldwide evidence of alcohol brief interventions in the various stages of the criminal justice system. DESIGN/METHODOLOGY/APPROACH: A rapid systematic review of publications was conducted from the year 2000 to 2014 regarding the prevalence of alcohol use disorders in the various stages of the criminal justice system. The second part of the work was a rapid review of effectiveness studies of interventions for alcohol brief interventions. Studies were included if they had a comparison group. Worldwide evidence was included that consisted of up to three hours of face-to-face brief intervention either in one session or numerous sessions. FINDINGS: This review found that 64-88 per cent of adults in the police custody setting; 95 per cent in the magistrate court setting; 53-69 per cent in the probation setting and 5,913-863 per cent in the prison system and 64 per cent of young people in the criminal justice system in the UK scored positive for an alcohol use disorder. There is very little evidence of effectiveness of brief interventions in the various stages of the criminal justice system mainly due to the lack of follow-up data. SOCIAL IMPLICATIONS: Brief alcohol interventions have a large and robust evidence base for reducing alcohol use in risky drinkers, particularly in primary care settings. However, there is little evidence of effect upon drinking levels in criminal justice settings. Whilst the approach shows promise with some effects being shown on alcohol-related harm as well as with young people in the USA, more robust research is needed to ascertain effectiveness of alcohol brief interventions in this setting. ORIGINALITY/VALUE: This paper provides evidence of alcohol use disorders in the different stages of the criminal justice system in the UK using a validated tool as well as reviewing the worldwide evidence for short ( < three hours) alcohol brief intervention in this setting. PMID- 26933994 TI - Iodinated contrast media inhibit oxygen consumption in freshly isolated proximal tubular cells from elderly humans and diabetic rats: Influence of nitric oxide. AB - Objectives Mechanisms underlying contrast medium (CM)-induced nephropathy remain elusive, but recent attention has been directed to oxygen availability. The purpose of this study was to evaluate the effect of the low-osmolar CM iopromide and the iso-osmolar CM iodixanol on oxygen consumption (QO2) in freshly isolated proximal tubular cells (PTC) from kidneys ablated from elderly humans undergoing nephrectomy for renal carcinomas and from normoglycemic or streptozotocin diabetic rats. Materials PTC were isolated from human kidneys, or kidneys of normoglycemic or streptozotocin-diabetic rats. QO2 was measured with Clark-type microelectrodes in a gas-tight chamber with and without each CM (10 mg I/mL medium). L-NAME was used to inhibit nitric oxide (NO) production caused by nitric oxide synthase. Results Both CM reduced QO2 in human PTC (about -35%) which was prevented by L-NAME. PTC from normoglycemic rats were unaffected by iopromide, whereas iodixanol decreased QO2 (-34%). Both CM decreased QO2 in PTC from diabetic rats (-38% and -36%, respectively). L-NAME only prevented the effect of iopromide in the diabetic rat PTC. Conclusions These observations demonstrate that CM can induce NO release from isolated PTC in vitro, which affects QO2. Our results suggest that the induction of NO release and subsequent effect on the cellular oxygen metabolism are dependent on several factors, including CM type and pre-existing risk factors for the development of CM-induced nephropathy. PMID- 26933995 TI - Chronic inflammation contributes to the development of hepatocellular carcinoma by decreasing miR-122 levels. AB - Persistent inflammation in chronic hepatitis plays a major role in the development of hepatocellular carcinoma (HCC). In this study, the major inflammatory cytokines expressed in chronic hepatitis, IL-6 and TNF-alpha, induced a marked decrease in microRNA-122 (miR-122) levels, and miR-122 expression was downregulated in the livers of chronic hepatitis B (CHB) patients. The decrease of miR-122 caused upregulation of the proinflammatory chemokine CCL2. IL-6 and TNF-alpha suppressed miR-122 both by directly downregulating the transcription factor C/EBPalpha and indirectly upregulating c-myc, which blocks C/EBPalpha-mediated miR-122 transcription. In addition, IL-6 and TNF-alpha levels were elevated and miR-122 levels were decreased in mouse and rat models of diethylnitrosamine (DEN)-induced HCC. Restoration of miR-122 levels through delivery of agomir-122 suppressed DEN-induced hepatocarcinogenesis in mice. Our results show that inflammation-induced miR-122 downregulation in hepatitis contributes to carcinogenesis and suggest that increasing miR-122 may be an effective strategy for preventing HCC development in CHB patients. PMID- 26933996 TI - Serum sphingolipidomic analyses reveal an upregulation of C16-ceramide and sphingosine-1-phosphate in hepatocellular carcinoma. AB - We have recently shown that major alterations of serum sphingolipid metabolites in chronic liver disease associate significantly with the stage of liver fibrosis in corresponding patients. In the current study we assessed via mass spectrometry serum concentrations of sphingolipid metabolites in a series of 122 patients with hepatocellular carcinoma (HCC) compared to an age- and sex-matched series of 127 patients with cirrhosis. We observed a highly significant upregulation of long and very long chain ceramides (C16-C24) in the serum of patients with HCC as compared to patients with cirrhosis (P < 0.001). Accordingly, dihydro-ceramides, synthetic precursors of ceramides and notably sphingosine, sphingosine-1 phosphate (S1P) and sphinganine-1-phosphate (SA1P) were upregulated in patients with HCC (P < 0.001). Especially the diagnostic accuracy of C16-ceramide and S1P, assessed by receiver operating curve (ROC) analysis, showed a higher area under the curve (AUC) value as compared to alpha fetoprotein (AFP) (0.999 and 0.985 versus 0.823, P < 0.001 respectively). In conclusion, serum levels of sphingolipid metabolites show a significant upregulation in patients with HCC as compared to patients with cirrhosis. Particularly C16-ceramide and S1P may serve as novel diagnostic markers for the identification of HCC in patients with liver diseases. Our data justify further investigations on the role of sphingolipids in HCC. PMID- 26933997 TI - KU-0060648 inhibits hepatocellular carcinoma cells through DNA-PKcs-dependent and DNA-PKcs-independent mechanisms. AB - Here we tested anti-tumor activity of KU-0060648 in preclinical hepatocellular carcinoma (HCC) models. Our results demonstrated that KU-0060648 was anti proliferative and pro-apoptotic in established (HepG2, Huh-7 and KYN-2 lines) and primary human HCC cells, but was non-cytotoxic to non-cancerous HL-7702 hepatocytes. DNA-PKcs (DNA-activated protein kinase catalytic subunit) is an important but not exclusive target of KU-0060648. DNA-PKcs knockdown or dominant negative mutation inhibited HCC cell proliferation. On the other hand, overexpression of wild-type DNA-PKcs enhanced HepG2 cell proliferation. Importantly, KU-0060648 was still cytotoxic to DNA-PKcs-silenced or -mutated HepG2 cells, although its activity in these cells was relatively weak. Further studies showed that KU-0060648 inhibited PI3K-AKT-mTOR activation, independent of DNA-PKcs. Introduction of constitutively-active AKT1 (CA-AKT1) restored AKT-mTOR activation after KU-0060648 treatment in HepG2 cells, and alleviated subsequent cytotoxicity. In vivo, intraperitoneal (i.p.) injection of KU-0060648 significantly inhibited HepG2 xenograft growth in nude mice. AKT-mTOR activation was also inhibited in xenografted tumors. Finally, we showed that DNA-PKcs expression was significantly upregulated in human HCC tissues. Yet miRNA-101, an anti-DNA-PKcs miRNA, was downregulated. Over-expression of miR-101 in HepG2 cells inhibited DNA-PKcs expression and cell proliferation. Together, these results indicate that KU-0060648 inhibits HCC cells through DNA-PKcs-dependent and independent mechanisms. PMID- 26933998 TI - Dosimetric impact of intermediate dose calculation for optimization convergence error. AB - Intensity-modulated radiation therapy (IMRT) provides the protection of the normal organs and a precise treatment plan through its optimization process. However, the final dose-volume histogram (DVH) obtained by this technique differs from the optimal DVH, owing to optimization convergence errors. Herein, intermediate dose calculation was applied to IMRT plans during the optimization process to solve these issues.Homogeneous and heterogeneous targets were delineated on a virtual phantom, and the final DVH for the target volume was assessed on the target coverage. The IMRT plans of 30 patients were established to evaluate the usefulness of intermediate dose calculation.The target coverage results were analogous in the three plans with homogeneous targets. Conversely, conformity indices (conformity index [CI], heterogeneity index [HI], and uniformity index [UI]) of plans with intermediate dose calculation were estimated to be more homogenous than plans without this option for heterogeneous targets (CI, 0.371 vs. 1.000; HI, 0.104 vs. 0.036; UI, 1.099 vs. 1.031 for Phantom B; and CI, 0.318 vs. 0.956; HI, 0.167 vs. 0.076; UI, 1.165 vs. 1.057 for Phantom C). In brain and prostate cancers, a slight difference between plans calculated with anisotropic analytical algorithm (AAA) was observed (HI, p = 0.043, UI, p = 0.043 for brain; HI, p = 0.042, UI, p = 0.043 for prostate). All target coverage indices were improved by intermediate dose calculation in lung cancer cases (p = 0.043).In conclusion, intermediate dose calculation in IMRT plans improves the target coverage in the target volume around heterogeneous materials. Moreover, the optimization time can be reduced. PMID- 26933999 TI - Suppression of miR-204 enables oral squamous cell carcinomas to promote cancer stemness, EMT traits, and lymph node metastasis. AB - The feature of oral squamous cell carcinomas (OSCC) is commonly metastasizing to locoreginal lymph nodes, and the involvement of lymph nodes metastasis represents the one of important prognostic factors of poor clinical outcome. MicroRNAs (miRNAs) have been shown to be key players of cancer-related hallmarks including cancer stemness, EMT (epithelial-mesenchymal transition), and metastaisis. Herein we showed that OSCC-derived ALDH1+ cancer stem cells (OSCC-CSCs) express lower level of miR-204, and miR-204 over-expression suppresses cancer stemness and in vivo tumor-growth of OSCC-CSCs. miR-204 binds on their 3'UTR-regions of Slug and Sox4 and suppressing their expression in OSCC-CSCs. On the contrary, down regulation of miR-204 significantly increased cancer stemness and the lymph nodes incidence of orthotopic animal models. Furthermore, co-knockdown with sh-Slug and sh-Sox4 synergistically rescued miR-204-supressing cancer stemness and EMT properties. Clinical results further revealed that a miR-204lowSlughighSox4high signature predicted the worse survival prognosis of OSCC patients by Kaplan-Meier survival analyses. Up-regulated miR-204-targeting Slug and Sox4 by epigallocatechin-3-gallate (EGCG) treatment significantly inhibited the proliferation rate, self-renewal capacity, and the percentage of ALDH1+ and CD44+ cells in OSCC-CSCs Oral-feeding of EGCG effectively alleviated tumor-progression in OSCC-CSCs-xenotransplanted immunocompromised mice through miR-204 activation. In conclusion, miR-204-mediated suppression of cancer stemness and EMT properties could be partially augmented by the anti-CSCs effect of EGCG. PMID- 26934000 TI - The afatinib resistance of in vivo generated H1975 lung cancer cell clones is mediated by SRC/ERBB3/c-KIT/c-MET compensatory survival signaling. AB - We generated afatinib resistant clones of H1975 lung cancer cells by transient exposure of established tumors to the drug and collected the re-grown tumors. Afatinib resistant H1975 clones did not exhibit any additional mutations in proto oncogenes when compared to control clones. Afatinib resistant H1975 tumor clones expressed less PTEN than control clones and in afatinib resistant clones this correlated with increased basal SRC Y416, ERBB3 Y1289, AKT T308 and mTOR S2448 phosphorylation, decreased expression of ERBB1, ERBB2 and ERBB3 and increased total expression of c-MET, c-KIT and PDGFRbeta. Afatinib resistant clones were selectively killed by knock down of [ERBB3 + c-MET + c-KIT] but not by the individual or doublet knock down combinations. The combination of the ERBB1/2/4 inhibitor afatinib with the SRC family inhibitor dasatinib killed afatinib resistant H1975 cells in a greater than additive fashion; other drugs used in combination with dasatinib such as sunitinib, crizotinib and amufatinib were less effective. [Afatinib + dasatinib] treatment profoundly inactivated ERBB3, AKT and mTOR in the H1975 afatinib resistant clones and increased ATG13 S318 phosphorylation. Knock down of ATG13, Beclin1 or eIF2alpha strong suppressed killing by [ERBB3 + c-MET + c-KIT] knock down, but were only modestly protective against [afatinib + dasatinib] lethality. Thus afatinib resistant H1975 NSCLC cells rely on ERBB1- and SRC-dependent hyper-activation of residual ERBB3 and elevated signaling, due to elevated protein expression, from wild type c-MET and c-KIT to remain alive. Inhibition of ERBB3 signaling via both blockade of SRC and ERBB1 results in tumor cell death. PMID- 26934001 TI - MicroRNA-92b represses invasion-metastasis cascade of esophageal squamous cell carcinoma. AB - Invasion and metastasis are major contributors to cancer-caused death in patients suffered from esophageal squamous cell carcinoma (ESCC). To explore the microRNAs involved in regulating invasion-metastasis cascade of ESCC, we established two pairs of sublines (30-U/D and 180-U/D) with distinct motility capacity from two ESCC cell lines (KYSE30 and KYSE180). Screening of the differentially expressed microRNAs identified that microRNA-92b-3p (miR-92b) could dramatically inhibit invasion and metastasis of ESCC cells in vitro and in vivo. Subsequent studies showed that miR-92b exerted its inhibitory function through suppressing the expression of integrin alphaV (ITGAV), which further reduced phosphrylated FAK and impaired Rac1 activation. Moreover, higher expression of miR-92b in ESCC tissues correlated inversely with lymph node metastasis and indicated better prognosis. Together, these results for the first time describe how miR-92b suppresses the motility of ESCC cells and provide a promise for diagnosis or therapy of ESCC invasion and metastasis. PMID- 26934003 TI - Rates of major bleeding with rivaroxaban in real-world studies of nonvalvular atrial fibrillation patients: a meta-analysis. AB - Numerous real-world studies estimating major bleeding rates in rivaroxaban patients with nonvalvular atrial fibrillation have been published. We performed a meta-analysis to better quantify the rates of different types of major bleeding seen with rivaroxaban in observational studies. The pooled rates of major bleeding with rivaroxaban were generally low and consistent with those reported in its pivotal randomized controlled trial. PMID- 26934002 TI - Reproduction of the FC/DFC units in nucleoli. AB - The essential structural components of the nucleoli, Fibrillar Centers (FC) and Dense Fibrillar Components (DFC), together compose FC/DFC units, loci of rDNA transcription and early RNA processing. In the present study we followed cell cycle related changes of these units in 2 human sarcoma derived cell lines with stable expression of RFP-PCNA (the sliding clamp protein) and GFP-RPA43 (a subunit of RNA polymerase I, pol I) or GFP-fibrillarin. Correlative light and electron microscopy analysis showed that the pol I and fibrillarin positive nucleolar beads correspond to individual FC/DFC units. In vivo observations showed that at early S phase, when transcriptionally active ribosomal genes were replicated, the number of the units in each cell increased by 60-80%. During that period the units transiently lost pol I, but not fibrillarin. Then, until the end of interphase, number of the units did not change, and their duplication was completed only after the cell division, by mid G1 phase. This peculiar mode of reproduction suggests that a considerable subset of ribosomal genes remain transcriptionally silent from mid S phase to mitosis, but become again active in the postmitotic daughter cells. PMID- 26934004 TI - Utility of the ImPACT test with deaf adolescents. AB - OBJECTIVE: The goals of the study included empirical examination of the utility of the Immediate and Post-Concussion Assessment and Cognitive Testing (ImPACT) test with adolescents who are deaf or hard-of-hearing and to investigate patterns of performance at baseline that may arise in the assessment of this population. Baseline assessment of student-athletes has been conducted on a widespread scale with focus on performance of typically developing student-athletes and some clinical groups, though to date no studies have examined adolescents who are deaf or hard-of-hearing. METHOD: Retrospective and de-identified ImPACT baseline test used with deaf and hard-of-hearing high-school student-athletes (N = 143; 66% male, mean age = 16.11) was examined. RESULTS: Review indicated significant differences in some composite scores between the deaf and hard-of-hearing group and hearing normative comparisons. A possible marker of task misunderstanding was identified to occur more frequently within the deaf and hard-of-hearing sample (13% in deaf sample vs. .31% in hearing sample). CONCLUSIONS: Results may provide support for the consideration and use of additional measures to ensure comprehension of task demands when considering this tool for use with deaf and hard-of-hearing adolescents. PMID- 26934005 TI - Determination of methemoglobin and hemoglobin levels in small volume samples. AB - Background/aims Hemoglobin-based oxygen carriers (HBOCs) have been previously studied as resuscitation fluids. Due to HBOCs specific molecular conformation, hemoglobin (Hb) and methemoglobin (MetHb) determination is not always possible with automated apparatus. A practical technique was designed that allows simultaneous reading of MetHb and Hb in small volume samples. Methods A spectrophotometric method for measuring low levels of MetHb and Hb from limited volume samples was developed using a 96-well-plate by downsizing the Evelyn Malloy and Drabkin methods. Either blood or buffer samples were spiked with one of five HBOCs (HBOC-201, M101, MP4CO-NP, Sanguinate and Oxyvita C). After treatment with cyanides, the samples were read at 540, 630, and 680 nm, and Hb and MetHb results were compared to certificate-of-analysis. Results Hb levels ranging from 0.2 to 2.8 g/dl were detected accurately with the 96-well-plate method with HBOC-201. Similarly, this method accurately measured Hb from either plasma or buffer samples containing any of the HBOCs. The MetHb plasma samples with HBOC-201 were also in agreement with ABL results (R = 0.99719). MetHb from all HBOCs in buffer measured with this method was comparable to reference but the accuracy was compromised for HBOCs in blood. Conclusions A useful 96-well-plate method of measuring HBOCs' Hb was designed for small-volume plasma samples. It was accurate for measuring MetHb from samples, that contained M101, MP4CO-NP, Sanguinate, and Oxyvita C diluted in buffer. This well-plate method allows reading of batch samples, multiple replicates, and using small volumes to accommodate limited animal blood collection which would not be otherwise detected by automated instrumentation. PMID- 26934006 TI - [Endometriosis - the chameleon of gynecology]. PMID- 26934007 TI - [Palliative radiotherapy - alleviating symptoms and improving quality of life]. PMID- 26934009 TI - [Endometriosis Update 2016]. AB - Endometriosis is a common gynecologic benign disease, affecting 6-10% of women of reproductive age. The disease is often associated with dysmenorrhea, dyspareunia, chronic pelvic pain and infertility. The exact mechanism of the pathogenesis of endometriosis has not yet been fully elucidated, therefore, current medical therapeutic options are more symptom-oriented than causal. The aim of the present work is to summarize the current diagnostic and therapeutic options. PMID- 26934010 TI - [Nephrotic Syndrome in Adult Patients--Etiology and Complications]. AB - The nephrotic syndrome (NS) in adult patients is a rare entity. It is characterized by a tetrad consisting of edema, proteinuria, hypoalbuminemia and hypercholesterolemia. NS can be caused by intrinsic glomerular disorders or secondary damage to the glomerulus triggered by systemic diseases, infections or drugs. The responsibility of the primary care physician is to distinguish NS from other edematous disorders. Patients should be referred to a nephrologist for further diagnosis and treatment. NS is associated with various complications. Affected individuals are prone to infections and may suffer from thrombophilia, acute renal failure and Vitamin D deficiency. Immunosuppressive therapy of the underlying disorder may cause late onset complications such as skin cancer or urothelial carcinoma. Aside from causative therapy adequate management of these complications is crucial for the treatment of patients suffering from NS. PMID- 26934011 TI - [Male Urinary Incontinence--a Taboo Issue]. AB - Male urinary incontinence is an underestimated and frequently not broached issue. The urinary incontinence is divided into stress-, urge incontinence and hybrid forms as well as overflow incontinence. The fact that there are increasingly more men over 60 means that the prevalence of the urinary incontinence is up to 40%, and urinary incontinence will increasingly gain importance in daily routine practice. Many investigations and therapies can be realized by the general practitioner. Already simple therapy approaches can lead to a considerable clinical improvement of male urinary incontinence. If the initial therapy fails or pathological results (i. e. microhaematuria, recurrent urinary tract infections, raised residual urine and so on) are found, the patient should be referred to a urologist. PMID- 26934012 TI - ["Why am I Deaf and my Vision is Blurred?" Thinking of a Horse or a Zebra?]. AB - We present the case of a 66 year old patient with a heterogeneous clinical course over ten months, particularly worsening of vision, hearing and hip pain. She finally died of multi-organ failure. The increased wear of a metal-on-metal hip implant lead to cobalt intoxication. The crucial therapy consists in removing the cobalt source. In the future, physicians need to be aware of this insidious and life-threatening disease possibly affecting thousands of patients after total hip replacement. PMID- 26934013 TI - [Depression - recognizing and treating a depressive episode]. PMID- 26934014 TI - [Resumption of antithrombotic therapy after gastrointestinal bleeding]. PMID- 26934015 TI - [Dietary supplements - blessing or curse?]. PMID- 26934017 TI - [ECG 52. Incidental finding]. PMID- 26934019 TI - Use of combined polarization-sensitive optical coherence tomography and Mueller matrix imaging for the polarimetric characterization of excised biological tissue. AB - Mueller matrix polarimetry and polarization-sensitive optical coherence tomography (PS-OCT) are two emerging techniques utilized in the assessment of tissue anisotropy. While PS-OCT can provide cross-sectional images of local tissue birefringence through its polarimetric sensitivity, Mueller matrix polarimetry can be used to measure bulk polarimetric properties such as depolarization, diattenuation, and retardance. To this day true quantification of PS-OCT data can be elusive, partly due to the reliance on inverse models for the characterization of tissue birefringence and the influence of instrumentation noise. Similarly for Mueller matrix polarimetry, calculation of retardance or depolarization may be influenced by tissue heterogeneities that could be monitored with PS-OCT. Here, we propose an instrument that combines Mueller matrix polarimetry and PS-OCT. Through the co-registration of the two systems, we aim at achieving a better understanding of both modalities. PMID- 26934021 TI - Spacetime. PMID- 26934022 TI - Case 2/2016 - Scimitar Sign with Right Pulmonary Vein Drainage into the Right Atrium. PMID- 26934023 TI - Drug-Induced Long-QT and Torsades de Pointes in Elderly Polymedicated Patients. PMID- 26934024 TI - Multimodality Images of a Mixed Atrial Septal Defect. PMID- 26934025 TI - The Fontan Operation is Not the End of the Road. PMID- 26934027 TI - Clinical significance of white-coat hypertension. PMID- 26934028 TI - Microalbuminuria--an important marker of residual risk: evidence from a primary care setting. PMID- 26934029 TI - Precision medicine should become more 'sympathetic' in managing hypertension. PMID- 26934026 TI - Heterogeneity in 10-Year Course Trajectories of Moderate to Severe Major Depressive Disorder: A Danish National Register-Based Study. AB - IMPORTANCE: Evidence suggests that long-term trajectories of major depressive disorder (MDD) are heterogeneous. The Danish Psychiatric Central Research Register (DPCRR) provides a rare opportunity to examine patterns and correlates of long-term trajectories in a large sample of patients with moderate to severe MDD. OBJECTIVE: To characterize patterns and correlates of 10-year course trajectories of MDD in the DPCRR. DESIGN, SETTING, AND PARTICIPANTS: A cohort containing 11 640 individuals born in Denmark in 1955 or later with their first recorded MDD diagnosis in the DPCRR between 1995 and 2002 was established. Patients were followed for 10 years from the date of their initial MDD diagnosis. Data were obtained from Danish civil and psychiatric national registers in June 2013 and were analyzed from April 4, 2014, to December 17, 2015. Correlates of trajectory class membership were sex, characteristics of the first recorded MDD episode (ie, age, severity, inpatient treatment, and record of suicide attempt or self-harm), and psychiatric diagnoses in parents (ie, depression, bipolar disorder, schizophrenia-spectrum disorders, substance abuse, and anxiety or somatoform disorders). MAIN OUTCOMES AND MEASURES: The outcome variable was past year contact at a psychiatric hospital with a main diagnosis of MDD during each of the 10 years following the initial MDD diagnosis. Trajectories were modeled using latent class growth analysis. RESULTS: The sample included 11 640 individuals (7493 [64.4%] women) aged 18 to 48 years (mean [SD], 31.4 [7.3]) at their first recorded MDD diagnosis. Four trajectory classes were identified: brief contact (77.0%) (characterized by low probability of contact after 2 years); prolonged initial contact (12.8%) (characterized by high decreasing probability of contact during the first 5 years); later reentry (7.1%) (characterized by moderate probability of contact during the second 5 years); and persistent contact (3.1%) (characterized by high or moderate probability of contact throughout). Female sex (odds ratio [OR] range, 1.82-2.22), inpatient treatment (OR range, 1.40-1.50), and severity at first recorded MDD episode (OR range: moderate, 1.61-1.84; severe, 1.93-2.23; and psychotic, 2.73-3.07) were associated with more severe trajectories. Parental anxiety (OR, 1.34 [95% CI, 1.10-1.63]) and depression (OR, 1.63 [95% CI, 1.28-2.09]) were associated with the prolonged initial contact and later reentry classes, respectively. Parental schizophrenia was associated with the persistent contact class (OR range, 2.55 3.04). CONCLUSIONS AND RELEVANCE: Most people treated for moderate to severe MDD in Danish psychiatric hospitals do not receive additional MDD treatment after 2 years; however, a minority receive specialty treatment for up to a decade. Observable heterogeneity in the course may be indicative of underlying etiologic differences. PMID- 26934030 TI - Relationship between systolic blood pressure and mortality in patients with severe cognitive impairment: extremes are bad. PMID- 26934032 TI - Seven-day/24-h ambulatory blood pressure monitoring: night-time blood pressure and dipping status. PMID- 26934031 TI - Indices of central aortic pressure waveform and ventricular function: an intimate conversation changing direction with age. PMID- 26934033 TI - Dietary nitrate decreased blood pressure in obstructive sleep apnoea syndrome: a series of N-of-1 trials. PMID- 26934034 TI - Fibromyalgia syndrome care of Iraq- and Afghanistan-deployed Veterans in Veterans Health Administration. AB - Little is known regarding fibromyalgia syndrome (FMS) care among Operation Iraqi Freedom/Operation Enduring Freedom/Operation New Dawn (OIF/OEF/OND) Veterans. Current recommendations include interdisciplinary, team-based combined care approaches and limited opioid use. In this study of OIF/OEF/OND Veterans who accessed Veterans Health Administration services between 2002 and 2012, we hypothesized that combined care (defined as at least 4 primary care visits/yr with visits to mental health and/or rheumatology) versus <4 primary care visits/yr only would be associated with lower risk of at least 2 opioid prescriptions 12 mo following an FMS diagnosis. Using generalized linear models with a log-link, the Poisson family, and robust standard errors, we estimated risk ratios (RRs) and 95% confidence intervals (CIs). We found that 1% of Veterans had at least 2 FMS diagnoses (International Classification of Diseases 9th Revision-Clinical Modification code 729.1) or at least 1 FMS diagnosis by rheumatology. Veterans with (vs without) FMS were more likely to be female, older, Hispanic, and never/currently married. Combined primary, mental health, and rheumatology care was associated with at least 2 opioid prescriptions (RR [95% CI] for males 2.2 [1.1-4.4] and females 2.8 [0.4-18.6]). Also, combined care was associated with at least 2 nonopioid pain-related prescriptions, a practice supported by evidence-based clinical practice guidelines. In tandem, these results provide mixed evidence of benefit of combined care for FMS. Future studies of healthcare encounter characteristics, care coordination, and benefits for Veterans with FMS are needed. PMID- 26934035 TI - Diagnosing lactose malabsorption in children: difficulties in interpreting hydrogen breath test results. AB - Lactose malabsorption (LM) is caused by insufficient enzymatic degradation of the disaccharide by intestinal lactase. Although hydrogen (H2) breath tests (HBTs) are routinely applied to diagnose LM, false-negative results are not uncommon. Thirty-two pediatric patients (19 females, 13 males) were included in this prospective study. After oral lactose administration (1 g kg(-1) bodyweight to a maximum of 25 g), breath H2 was measured by electrochemical detection. HBT was considered positive if H2 concentration exceeded an increase of ?20 ppm from baseline. In addition to H2, exhaled methane (CH4), blood glucose concentrations and clinical symptoms (flatulence, abdominal pain, diarrhea) were monitored. A positive HBT indicating LM was found in 12/32 (37.5%) patients. Only five (41.7%, 5/12) of these had clinical symptoms during HBT indicating lactose intolerance (LI). Decreased blood glucose concentration increments (?20 mg dL(-1) (?1.1 mmol L(-1))) were found in 3/5 of these patients. CH4 concentrations ?10 ppm at any time during the test were observed in 5/32 (15.6%) patients and in 9/32 (28.1%) between 1 ppm and 9 ppm above baseline after lactose ingestion. In patients with positive HBT 10/12 (83.3%) showed elevated CH4 (>1 ppm) above baseline in breath gas, whereas in patients with negative HBT this figure was only 4/17 (23.5%). In addition to determining H2 in exhaled air, documentation of clinical symptoms, measurement of blood glucose and breath CH4 concentrations may be helpful in deciding whether in a given case an HBT correctly identifies patients with clinically relevant LM. PMID- 26934036 TI - Treatment of Eosinophilic Fasciitis With Sirolimus. PMID- 26934038 TI - Targeting the JAK-STAT pathway in the treatment of 'Th2-high' severe asthma. AB - Severe asthma is a heterogeneous disease characterized by reversible airway obstruction, chronic inflammation and airway remodeling. Phenotyping and/or endotyping can lead to a more personalized treatment strategy, improving the efficacy of novel drugs. Atopic asthma is associated with high levels of Th2 cells, implicated in a number of inflammatory responses. Differentiation of these cells from naive T cells occurs primarily via the JAK-STAT signaling pathway. Targeting this pathway through inhibition of activating cytokines (IL-4 and IL 13) and their receptors, the JAKs or the STATs, has been shown to have a therapeutic effect on asthma pathology. There are a number of novel drugs currently in development, which target various pathway components; these include both biologics and small molecules at various stages of development. PMID- 26934039 TI - Mo2 C as Non-Noble Metal Co-Catalyst in Mo2 C/CdS Composite for Enhanced Photocatalytic H2 Evolution under Visible Light Irradiation. AB - Co-catalysts are a major factor to enhance photocatalytic H2 activity; they are mainly composed of expensive noble metals. Here, we reported a new non-noble metal co-catalyst Mo2 C that efficiently improves the photocatalytic H2 evolution of CdS under visible light irradiation. Mo2 C is prepared by temperature programmed reaction with molybdenum oxide as precursor, and the Mo2 C/CdS composite is prepared by deposition of CdS on Mo2 C. The optimum composite 2.0 % Mo2 C/CdS shows a high H2 evolution rate of 161 MUmol h(-1) , which is ten times higher than that of CdS alone and 2.3 times higher than the optimum for 1.0 % Pt/CdS. Moreover, the Mo2 C/CdS is stable for 50 h. This study presents a new low cost non-noble-metal co-catalyst as a photocatalyst to achieve highly efficient H2 evolution. PMID- 26934041 TI - Great myths of aging, by Joan Erber and Lenore Szuchman. PMID- 26934040 TI - Extraordinary Separation of Acetylene-Containing Mixtures with Microporous Metal Organic Frameworks with Open O Donor Sites and Tunable Robustness through Control of the Helical Chain Secondary Building Units. AB - Acetylene separation is a very important but challenging industrial separation task. Here, through the solvothermal reaction of CuI and 5-triazole isophthalic acid in different solvents, two metal-organic frameworks (MOFs, FJU-21 and FJU 22) with open O donor sites and controllable robustness have been obtained for acetylene separation. They contain the same paddle-wheel {Cu2(COO2)4} nodes and metal-ligand connection modes, but with different helical chains as secondary building units (SBUs), leading to different structural robustness for the MOFs. FJU-21 and FJU-22 are the first examples in which the MOFs' robustness is controlled by adjusting the helical chain SBUs. Good robustness gives the activated FJU-22 a, which has higher surface area and gas uptakes than the flexible FJU-21 a. Importantly, FJU-22 a shows extraordinary separation of acetylene mixtures under ambient conditions. The separation capacity of FJU-22 a for 50:50 C2H2/CO2 mixtures is about twice that of the high-capacity HOF-3, and its actual separation selectivity for C2H2/C2H4 mixtures containing 1% acetylene is the highest among reported porous materials. Based on first-principles calculations, the extraordinary separation performance of C2H2 for FJU-22 a was attributed to hydrogen-bonding interactions between the C2H2 molecules with the open O donors on the wall, which provide better recognition ability for C2H2 than other functional sites, including open metal sites and amino groups. PMID- 26934042 TI - Exploring social media for patient perspectives of sickle cell disease. PMID- 26934043 TI - Self-Assembly and Compartmentalization of Nanozymes in Mesoporous Silica-Based Nanoreactors. AB - Herein, to mimic complex natural system, polyelectrolyte multilayer (PEM)-coated mesoporous silica nanoreactors were used to compartmentalize two different artificial enzymes. PEMs coated on the surface of mesoporous silica could serve as a permeable membrane to control the flow of molecules. When assembling hemin on the surface of mesoporous silica, the hemin-based mesoporous silica system possessed remarkable peroxidase-like activity, especially at physiological pH, and could be recycled more easily than traditional graphene-hemin nanocompounds. The hope is that these new findings may pave the way for exploring novel nanoreactors to achieve compartmentalization of nanozymes and applying artificial cascade catalytic systems to mimic cell organelles or important biochemical transformations. PMID- 26934044 TI - Variation of Bacterial Community Diversity in Rhizosphere Soil of Sole-Cropped versus Intercropped Wheat Field after Harvest. AB - As the major crops in north China, spring crops are usually planted from April through May every spring and harvested in fall. Wheat is also a very common crop traditionally planted in fall or spring and harvested in summer year by year. This continuous cropping system exhibited the disadvantages of reducing the fertility of soil through decreasing microbial diversity. Thus, management of microbial diversity in the rhizosphere plays a vital role in sustainable crop production. In this study, ten common spring crops in north China were chosen sole-cropped and four were chosen intercropped with peanut in wheat fields after harvest. Denaturing gradient gel electrophoresis (DGGE) and DNA sequencing of one 16S rDNA fragment were used to analyze the bacterial diversity and species identification. DGGE profiles showed the bacterial community diversity in rhizosphere soil samples varied among various crops under different cropping systems, more diverse under intercropping system than under sole-cropping. Some intercropping-specific bands in DGGE profiles suggested that several bacterial species were stimulated by intercropping systems specifically. Furthermore, the identification of these dominant and functional bacteria by DNA sequencing indicated that intercropping systems are more beneficial to improve soil fertility. Compared to intercropping systems, we also observed changes in microbial community of rhizosphere soil under sole-crops. The rhizosphere bacterial community structure in spring crops showed a strong crop species specific pattern. More importantly, Empedobacter brevis, a typical plant pathogen, was only found in the carrot rhizosphere, suggesting carrot should be sown prudently. In conclusion, our study demonstrated that crop species and cropping systems had significant effects on bacterial community diversity in the rhizosphere soils. We strongly suggest sorghum, glutinous millet and buckwheat could be taken into account as intercropping crops with peanut; while hulled oat, mung bean or foxtail millet could be considered for sowing in wheat fields after harvest in North China. PMID- 26934046 TI - An In Vitro Study of Factors Influencing the Performance of Digital Intraoral Impressions Operating on Active Wavefront Sampling Technology with Multiple Implants in the Edentulous Maxilla. AB - PURPOSE: To evaluate the performance (accuracy and repeatability) and the factors affecting the clinical performance of a recently released intraoral scanner based on active wavefront sampling technology. MATERIALS AND METHODS: A single resin model of an edentulous maxilla fitted with six implants inserted at various depths and angulations was measured with a coordinated measuring machine (CMM) at 3 to 5 MUm, and this acted as the "true," or reference, values of the study. Six corresponding cylindrical PEEK scanbodies were then mounted onto the implants, and four calibrated observers independently repeated the digital intraoral scan five times with a True Definition (TrueDef) scanner. Using implant position #15 as a reference, five linear and angular measurements were compared with the reference values (CMM), and the data were analyzed via one-way ANOVA and two sample t-test. RESULTS: Mean linear and angular deviations for the TrueDef from CMM measurements were from 5.38 +/- 12.61 MUm to -26.97 +/- 50.56 MUm and from 0.16o +/- 0.04o to -0.43o +/- 0.1o, respectively. Experienced observers performed significantly better than inexperienced ones (p = 0.006), and scan distance (quadrant) significantly affected scanning accuracy (p = 0.003). Visible length of the scanbody affected measurement accuracy (p = 0.0001), while implant angulation did not (p = 0.757). CONCLUSIONS: The TrueDef scanner provides measurements within clinically accepted limits. Yet scanbody visibility, observer experience, and scan length remain relevant factors affecting accuracy. PMID- 26934045 TI - An Efficient Correction Algorithm for Eliminating Image Misalignment Effects on Co-Phasing Measurement Accuracy for Segmented Active Optics Systems. AB - The misalignment between recorded in-focus and out-of-focus images using the Phase Diversity (PD) algorithm leads to a dramatic decline in wavefront detection accuracy and image recovery quality for segmented active optics systems. This paper demonstrates the theoretical relationship between the image misalignment and tip-tilt terms in Zernike polynomials of the wavefront phase for the first time, and an efficient two-step alignment correction algorithm is proposed to eliminate these misalignment effects. This algorithm processes a spatial 2-D cross-correlation of the misaligned images, revising the offset to 1 or 2 pixels and narrowing the search range for alignment. Then, it eliminates the need for subpixel fine alignment to achieve adaptive correction by adding additional tip tilt terms to the Optical Transfer Function (OTF) of the out-of-focus channel. The experimental results demonstrate the feasibility and validity of the proposed correction algorithm to improve the measurement accuracy during the co-phasing of segmented mirrors. With this alignment correction, the reconstructed wavefront is more accurate, and the recovered image is of higher quality. PMID- 26934047 TI - Does comorbid anxiety counteract emotion recognition deficits in conduct disorder? AB - BACKGROUND: Previous research has reported altered emotion recognition in both conduct disorder (CD) and anxiety disorders (ADs) - but these effects appear to be of different kinds. Adolescents with CD often show a generalised pattern of deficits, while those with ADs show hypersensitivity to specific negative emotions. Although these conditions often cooccur, little is known regarding emotion recognition performance in comorbid CD+ADs. Here, we test the hypothesis that in the comorbid case, anxiety-related emotion hypersensitivity counteracts the emotion recognition deficits typically observed in CD. METHOD: We compared facial emotion recognition across four groups of adolescents aged 12-18 years: those with CD alone (n = 28), ADs alone (n = 23), cooccurring CD+ADs (n = 20) and typically developing controls (n = 28). The emotion recognition task we used systematically manipulated the emotional intensity of facial expressions as well as fixation location (eye, nose or mouth region). RESULTS: Conduct disorder was associated with a generalised impairment in emotion recognition; however, this may have been modulated by group differences in IQ. AD was associated with increased sensitivity to low-intensity happiness, disgust and sadness. In general, the comorbid CD+ADs group performed similarly to typically developing controls. CONCLUSIONS: Although CD alone was associated with emotion recognition impairments, ADs and comorbid CD+ADs were associated with normal or enhanced emotion recognition performance. The presence of comorbid ADs appeared to counteract the effects of CD, suggesting a potentially protective role, although future research should examine the contribution of IQ and gender to these effects. PMID- 26934048 TI - Association between Tooth Loss and Gastric Cancer: A Meta-Analysis of Observational Studies. AB - Observational studies showed that tooth loss is associated with gastric cancer, but the findings are inconsistent. In this study, a meta-analysis was conducted to evaluate the relationship between tooth loss and gastric cancer. Relevant studies were screened in PubMed and Embase databases, and nine observational studies were considered eligible for the analysis. The combined relative risks for the highest versus the lowest categories of tooth loss were 1.86 (95% CI: 1.08-3.21) and 1.31 (95% CI: 1.12-1.53) in case control and cohort studies, respectively. However, unstable results were observed in the stratified and sensitivity analysis. The current evidence, based solely on four case-control studies and five cohort studies, suggested that tooth loss is a potential marker of gastric cancer. However, we can not concluded at this time that tooth loss may be a risk factor for gastric cancer due to significant heterogeneity among studies and mixed results between case-control studies and cohort studies. Additional large-scale and high-quality prospective studies are required to evaluate the association between tooth loss and risk of gastric cancer. PMID- 26934050 TI - Correction: Bioinformatics Analysis of the Effects of Tobacco Smoke on Gene Expression. PMID- 26934049 TI - Expression Atlas of the Deubiquitinating Enzymes in the Adult Mouse Retina, Their Evolutionary Diversification and Phenotypic Roles. AB - Ubiquitination is a relevant cell regulatory mechanism to determine protein fate and function. Most data has focused on the role of ubiquitin as a tag molecule to target substrates to proteasome degradation, and on its impact in the control of cell cycle, protein homeostasis and cancer. Only recently, systematic assays have pointed to the relevance of the ubiquitin pathway in the development and differentiation of tissues and organs, and its implication in hereditary diseases. Moreover, although the activity and composition of ubiquitin ligases has been largely addressed, the role of the deubiquitinating enzymes (DUBs) in specific tissues, such as the retina, remains mainly unknown. In this work, we undertook a systematic analysis of the transcriptional levels of DUB genes in the adult mouse retina by RT-qPCR and analyzed the expression pattern by in situ hybridization and fluorescent immunohistochemistry, thus providing a unique spatial reference map of retinal DUB expression. We also performed a systematic phylogenetic analysis to understand the origin and the presence/absence of DUB genes in the genomes of diverse animal taxa that represent most of the known animal diversity. The expression landscape obtained supports the potential subfunctionalization of paralogs in those families that expanded in vertebrates. Overall, our results constitute a reference framework for further characterization of the DUB roles in the retina and suggest new candidates for inherited retinal disorders. PMID- 26934051 TI - Obstructive Sleep Apnoea Modulates Airway Inflammation and Remodelling in Severe Asthma. AB - BACKGROUND: Obstructive sleep apnoea (OSA) is frequently observed in severe asthma but the causal link between the 2 diseases remains hypothetical. The role of OSA-related systemic and airway neutrophilic inflammation in asthma bronchial inflammation or remodelling has been rarely investigated. The aim of this study was to compare hallmarks of inflammation in induced sputum and features of airway remodelling in bronchial biopsies from adult patients with severe asthma with and without OSA. MATERIALS AND METHODS: An overnight polygraphy was performed in 55 patients referred for difficult-to-treat asthma, who complained of nocturnal respiratory symptoms, poor sleep quality or fatigue. We compared sputum analysis, reticular basement membrane (RBM) thickness, smooth muscle area, vascular density and inflammatory cell infiltration in bronchial biopsies. RESULTS: In total, 27/55 patients (49%) had OSA diagnosed by overnight polygraphy. Despite a moderate increase in apnoea-hypopnoea index (AHI; 14.2 +/- 1.6 event/h [5-35]), the proportion of sputum neutrophils was higher and that of macrophages lower in OSA than non-OSA patients, with higher levels of interleukin 8 and matrix metalloproteinase 9. The RBM was significantly thinner in OSA than non-OSA patients (5.8 +/- 0.4 vs. 7.8 +/- 0.4 MUm, p<0.05). RBM thickness and OSA severity assessed by the AHI were negatively correlated (rho = -0.65, p<0.05). OSA and non-OSA patients did not differ in age, sex, BMI, lung function, asthma control findings or treatment. CONCLUSION: Mild OSA in patients with severe asthma is associated with increased proportion of neutrophils in sputum and changes in airway remodelling. PMID- 26934053 TI - A Health Threat to Bystanders Living in the Homes of Smokers: How Smoke Toxins Deposited on Surfaces Can Cause Insulin Resistance. AB - Thirdhand smoke (THS) is the accumulation of secondhand smoke on environmental surfaces. THS is found on the clothing and hair of smokers as well as on surfaces in homes and cars of smokers. Exposure occurs by ingestion, inhalation and dermal absorption. Children living in homes of smokers are at highest risk because they crawl on the floor, touch parents' clothing/hair and household objects. Using mice exposed to THS under conditions that mimic exposure of humans, we show that THS increases cellular oxidative stress by increasing superoxide dismutase (SOD) activity and hydrogen peroxide (H2O2) levels while reducing the activity of antioxidant enzymes catalase and glutathione peroxidase (GPx) that break down H2O2 into H2O and O2. This results in lipid peroxidation, protein nitrosylation and DNA damage. Consequences of these cell and molecular changes are hyperglycemia and insulinemia. Indeed, we found reduced levels of insulin receptor, PI3K, AKT, all important molecules in insulin signaling and glucose uptake by cells. To determine whether these effects on THS-induced insulin resistance are due to increase in oxidative stress, we treated mice exposed to THS with the antioxidants N-acetyl cysteine (NAC) and alpha-tocopherol (alpha toc) and showed that the oxidative stress, the molecular damage, and the insulin resistance, were significantly reversed. Conversely, feeding the mice with chow that mimics "western diet", which is known to increase oxidative stress, while exposing the mice to THS, further increased the oxidative stress and aggravated hyperglycemia and insulinemia. In conclusion, THS exposure results in insulin resistance in the form of non-obese type II diabetes (NODII) through oxidative stress. If confirmed in humans, these studies could have a major impact on how people view exposure to environmental tobacco toxins, in particular to children, elderly and workers in environments where tobacco smoke has taken place. PMID- 26934052 TI - Novel Acylguanidine Derivatives Targeting Smoothened Induce Antiproliferative and Pro-Apoptotic Effects in Chronic Myeloid Leukemia Cells. AB - The most relevant therapeutic approaches to treat CML rely on the administration of tyrosine kinase inhibitors (TKIs) like Imatinib, which are able to counteract the activity of Bcr-Abl protein increasing patient's life expectancy and survival. Unfortunately, there are some issues TKIs are not able to address; first of all TKIs are not so effective in increasing survival of patients in blast crisis, second they are not able to eradicate leukemic stem cells (LSC) which represent the major cause of disease relapse, and third patients often develop resistance to TKIs due to mutations in the drug binding site. For all these reasons it's of primary interest to find alternative strategies to treat CML. Literature shows that Hedgehog signaling pathway is involved in LSC maintenance, and pharmacological inhibition of Smoothened (SMO), one of the key molecules of the pathway, has been demonstrated to reduce Bcr-Abl positive bone marrow cells and LSC. Consequently, targeting SMO could be a promising way to develop a new treatment strategy for CML overcoming the limitations of current therapies. In our work we have tested some compounds able to inhibit SMO, and among them MRT92 appears to be a very potent SMO antagonist. We found that almost all our compounds were able to reduce Gli1 protein levels in K-562 and in KU-812 CML cell lines. Furthermore, they were also able to increase Gli1 and SMO RNA levels, and to reduce cell proliferation and induce apoptosis/autophagy in both the tested cell lines. Finally, we demonstrated that our compounds were able to modulate the expression of some miRNAs related to Hedgehog pathway such as miR 324-5p and miR-326. Being Hedgehog pathway deeply implicated in the mechanisms of CML we may conclude that it could be a good therapeutic target for CML and our compounds seem to be promising antagonists of such pathway. PMID- 26934055 TI - Chemoselective Reduction of Tertiary Amides under Thermal Control: Formation of either Aldehydes or Amines. AB - The chemoselective reduction of amides in the presence of other more reactive reducible functional groups is a highly challenging transformation, and successful examples thereof are most valuable in synthetic organic chemistry. Only a limited number of systems have demonstrated the chemoselective reduction of amides over ketones. Until now, the aldehyde functionality has not been shown to be compatible in any catalytic reduction protocol. Described herein is a [Mo(CO)6 ]-catalyzed protocol with an unprecedented chemoselectivity and allows for the reduction of amides in the presence of aldehydes and imines. Furthermore, the system proved to be tunable by variation of the temperature, which enabled for either C-O or C-N bond cleavage that ultimately led to the isolation of both amines and aldehydes, respectively, in high chemical yields. PMID- 26934056 TI - Photooxygenation of Furylalkylamines: Easy Access to Pyrrolizidine and Indolizidine Scaffolds. AB - A highly adaptable method targeting the ubiquitous and very important pyrrolizidine and indolizidine scaffolds is presented. The general synthetic utility of the method is underscored by its application to the rapid and easy synthesis of five natural products starting from readily accessible alkylfuran precursors. These unprotected primary furylalkylamines are subjected to photooxygenation conditions, which initiate a complex cascade reaction sequence concluding with the production of high value motifs. This sequence can be tailored to need by varying the choice of both photosensitizer and base additive. PMID- 26934054 TI - CHOP Chemotherapy for Aggressive Non-Hodgkin Lymphoma with and without HIV in the Antiretroviral Therapy Era in Malawi. AB - There are no prospective studies of aggressive non-Hodgkin lymphoma (NHL) treated with CHOP in sub-Saharan Africa. We enrolled adults with aggressive NHL in Malawi between June 2013 and May 2015. Chemotherapy and supportive care were standardized, and HIV+ patients received antiretroviral therapy (ART). Thirty seven of 58 patients (64%) were HIV+. Median age was 47 years (IQR 39-56), and 35 (60%) were male. Thirty-five patients (60%) had stage III/IV, 43 (74%) B symptoms, and 28 (48%) performance status >= 2. B-cell NHL predominated among HIV+ patients, and all T-cell NHL occurred among HIV- individuals. Thirty-one HIV+ patients (84%) were on ART for a median 9.9 months (IQR 1.1-31.7) before NHL diagnosis, median CD4 was 121 cells/MUL (IQR 61-244), and 43% had suppressed HIV RNA. HIV+ patients received a similar number of CHOP cycles compared to HIV- patients, but more frequently developed grade 3/4 neutropenia (84% vs 31%, p = 0.001), resulting in modestly lower cyclophosphamide and doxorubicin doses with longer intervals between cycles. Twelve-month overall survival (OS) was 45% (95% CI 31-57%). T-cell NHL (HR 3.90, p = 0.017), hemoglobin (HR 0.82 per g/dL, p = 0.017), albumin (HR 0.57 per g/dL, p = 0.019), and IPI (HR 2.02 per unit, p<0.001) were associated with mortality. HIV was not associated with mortality, and findings were similar among patients with diffuse large B-cell lymphoma. Twenty-three deaths were from NHL (12 HIV+, 11 HIV-), and 12 from CHOP (9 HIV+, 3 HIV-). CHOP can be safe, effective, and feasible for aggressive NHL in Malawi with and without HIV. PMID- 26934057 TI - Characterization of muscle oxygenation response to vascular occlusion: implications for remote ischaemic preconditioning and physical Performance. AB - Remote ischaemic preconditioning is a non-invasive intervention with potential to protect a number of organs against ischaemia-reperfusion injury and possibly improve athletic performance. Little mechanistic evidence exists to support either limb choice or cuff inflation pressure that is most effective. This preliminary study aimed to establish the dose-response effect of different occlusion pressures on skeletal muscle oxygenation and blood flow in healthy males (n = 6). In a randomized controlled crossover study, cuff inflation pressures (140,160 and 180 mmHg) were used to induce limb ischaemia (* 3 cycles of 5-min) in upper (UL) and lower (LL) limbs on three separate occasions. Muscle oxygenation and blood flow properties of UL (flexor carpi ulnaris) and LL (vastus lateralis) were assessed using near infrared spectroscopy. Higher deoxyhaemoglobin (DeltaHHb) values were consistently observed in UL (versus LL; P<0.05), no difference between pressures. Occlusion at 140 mm Hg failed to elicit decreases in tissue oxyhaemoglobin (DeltaHbO2 ) from resting baseline (UL and LL), with significant HbO2 decreases only observed at 180 mmHg in LL (P<0.05). Increases in DeltaHbO2 and muscle oxygenation index (Hbdiff ) above baseline were observed with cuff deflation, lasting up to 15 min into recovery in LL irrespective of occlusion pressure (P<0.05). Muscle oxygenation properties are influenced by choice of limb occluded and findings show that tissue ischaemia can be induced at much lower absolute pressures than traditionally used in RIPC studies. Blood flow and muscle oxygenation may be enhanced for at least 15 min following the last occlusion. PMID- 26934058 TI - Early metabolomics changes in heart and plasma during chronic doxorubicin treatment in B6C3F1 mice. AB - The present study aimed to identify molecular markers of early stages of cardiotoxicity induced by a potent chemotherapeutic agent, doxorubicin (DOX). Male B6C3F1 mice were dosed with 3 mg kg(-1) DOX or saline via tail vein weekly for 2, 3, 4, 6 or 8 weeks (cumulative DOX doses of 6, 9, 12, 18 or 24 mg kg(-1) , respectively) and euthanized a week after the last dose. Mass spectrometry-based and nuclear magnetic resonance spectrometry-based metabolic profiling were employed to identify initial biomarkers of cardiotoxicity before myocardial injury and cardiac pathology, which were not noted until after the 18 and 24 mg kg(-1) cumulative doses, respectively. After a cumulative dose of 6 mg kg(-1) , 18 amino acids and four biogenic amines (acetylornithine, kynurenine, putrescine and serotonin) were significantly increased in cardiac tissue; 16 amino acids and two biogenic amines (acetylornithine and hydroxyproline) were significantly altered in plasma. In addition, 16 acylcarnitines were significantly increased in plasma and five were significantly decreased in cardiac tissue compared to saline treated controls. Plasma lactate and succinate, involved in the Krebs cycle, were significantly altered after a cumulative dose of 6 mg kg(-1) . A few metabolites remained altered at higher cumulative DOX doses, which could partly indicate a transition from injury processes at 2 weeks to repair processes with additional injury happening concurrently before myocardial injury at 8 weeks. These altered metabolic profiles in mouse heart and plasma during the initial stages of injury progression due to DOX treatment may suggest these metabolites as candidate early biomarkers of cardiotoxicity. Published 2016. This article is a U.S. Government work and is in the public domain in the USA. PMID- 26934059 TI - The clinical value of exhaled nitric oxide in patients with lung cancer. AB - INTRODUCTION AND OBJECTIVES: To investigate the clinical value of fractional exhaled nitric oxide (FeNO) in lung cancer patients. METHODS: A total of 172 healthy control subjects and 164 patients with histopathologically confirmed lung cancer were enrolled in this study. The FeNO measurements and pulmonary function tests were conducted in the Chinese PLA General Hospital. The recorded data included FeNO, the forced expiratory volume in one second (FEV1 ), the forced vital capacity (FVC), FEV1 /FVC, the FEV1 (% predicted), the demographic characteristics, the presence of complications and the smoking status. RESULTS: The patients with lung cancer had a significantly higher level of eNO than the healthy control subjects (33.85 +/- 15.63 ppb, n = 163; 16.83 +/- 4.17 ppb, n = 172; P < 0.01). The areas under receiver operating characteristic curves for eNO predicting airway inflammation in lung cancer subjects and healthy control subjects was 0.932 (95% confidence interval: 0.904-0.961). In the lung cancer group, the eNO levels in the squamous cell carcinoma, adenocarcinoma, small-cell lung cancer and lung carcinoid tumor groups were significantly different (P < 0.01). Lung cancer patients with a predicted FEV1 % value <80% had a higher level of eNO than the patients with a predicted FEV1 % value >=80%. CONCLUSIONS: The eNO levels in patients with lung cancer were higher than the normal level, especially in the patients with squamous cell carcinoma and small-cell lung cancer. The differences in eNO among the lung cancer subtypes were statistically significant. Measuring eNO will be helpful in diagnosing airway inflammation in lung cancer and in the classification of lung cancer. PMID- 26934061 TI - The Wnt7's Tale: A story of an orphan who finds her tie to a famous family. AB - The transformation suppressor gene RECK was isolated by cDNA expression cloning (1998), and GPR124/TEM5 was detected as a tumor endothelial marker by differential screening (2000). The importance of Wnt7a/b and Gpr124 in brain angiogenesis was demonstrated by reverse genetics in mice (2008-2010). A series of recent studies using genetically engineered mice and zebrafish as well as luciferase reporter assays in cultured cells led to the discovery of functional interactions among Reck, Gpr124, and Wnt7a/b in triggering canonical Wnt signaling with relevance to embryonic brain angiogenesis and blood-brain barrier formation. PMID- 26934060 TI - The impact of disease activity and tumour necrosis factor-alpha inhibitor therapy on cytokine levels in juvenile idiopathic arthritis. AB - The aim of this study was to evaluate prospectively cytokine levels and disease activity in juvenile idiopathic arthritis (JIA) patients treated with and without tumour necrosis factor (TNF)-alpha inhibitors. TNF-alpha inhibitor-naive JIA subjects were followed prospectively for 6 months. Cytokine levels of TNF-alpha, interleukin (IL)-1beta, IL-6, IL-8, IL-10 and IL-17 were measured at baseline for JIA subjects and healthy controls (HCs). Cytokine levels were then measured at four time-points after initiation of TNF-alpha inhibition for anti-TNF-alpha treated (anti-TNF) JIA subjects, and at two subsequent time-points for other JIA (non-TNF) subjects. JIA disease activity by Childhood Health Assessment Questionnaire (CHAQ) disability index/pain score and physician joint count/global assessment was recorded. Sixteen anti-TNF, 31 non-TNF and 16 HCs were analysed. Among JIA subjects, those with higher baseline disease activity (subsequent anti TNFs) had higher baseline TNF-alpha, IL-6 and IL-8 than those with lower disease activity (non-TNFs) (P < 0.05). TNF-alpha and IL-10 increased, and IL-6 and IL-8 no longer remained significantly higher after TNF-alpha inhibitor initiation in anti-TNF subjects. Subgroup analysis of etanercept versus adalimumab-treated subjects showed that TNF-alpha and IL-17 increased significantly in etanercept but not adalimumab-treated subjects, despite clinical improvement in both groups of subjects. JIA subjects with increased disease activity at baseline had higher serum proinflammatory cytokines. TNF-alpha inhibition resulted in suppression of IL-6 and IL-8 in parallel with clinical improvement in all anti-TNF-treated subjects, but was also associated with elevated TNF-alpha and IL-17 in etanercept treated subjects. PMID- 26934063 TI - Impaired Hemorheological Parameters and Increased Carotid Intima-Media Thickness in Children with Subclinical Hypothyroidism. AB - BACKGROUND: Subclinical hypothyroidism (SH) is defined as elevated serum thyroid stimulating hormone (TSH) concentration associated with normal serum-free thyroxine levels. Effects of hypothyroidism on hemorheology had widely attracted the attention of researchers during the last decade. OBJECTIVE: The purpose of this study is to determine alterations in hemorheological parameters and carotid intima-media thickness (CIMT) in children with SH. METHODS: Fifty-three SH children and 31 healthy controls were enrolled. Erythrocyte deformability and aggregation were determined by an ektacytometer and plasma viscosity (PV) by a cone-plate rotational viscometer. CIMT was evaluated sonographically. RESULTS: Erythrocyte deformability of the SH group measured at 0.53 and 1.69-30 Pa was lower than that of the control group. The erythrocyte aggregation index, aggregation half time and PV were not different between the groups. However, the aggregation amplitude and mean corpuscular hemoglobin concentration were significantly higher in SH compared to the control group. There was a negative correlation between TSH and deformability values measured at 5.33-30.0 Pa. CIMT in patients with SH was significantly higher than in the control group (p = 0.001; SH = 0.48 +/- 0.04 mm, control group = 0.43 +/- 0.03 mm). CONCLUSION: Impaired hemorheology and increased CIMT are well-known risk factors for developing cardiovascular pathologies. The results of the current study suggest the treatment of children with SH in order to avoid early circulatory problems. PMID- 26934062 TI - Paliperidone for the treatment of schizoaffective disorder. AB - INTRODUCTION: Schizoaffective disorder (SCA) is a complex mental illness characterized by psychosis and affective symptoms. Treatment usually involves concomitant therapy with antipsychotics, mood stabilizers, and/or antidepressants. Effective treatment must address acute symptoms, maintain long term stability, promote recovery, and improve patient functioning. AREAS COVERED: Data from 3 pivotal studies evaluating the acute and maintenance treatment of SCA with paliperidone are reviewed. Two formulations of paliperidone have been studied for these indications: an extended-release oral formulation (NCT00397033, NCT00412373) and long-acting injectable once-monthly paliperidone palmitate (NCT01193153). The reported effects of these formulations on psychotic, depressive, and manic symptoms are discussed. EXPERT OPINION: Both formulations were found to be safe and effective for the acute and maintenance treatment of SCA. Of critical importance for this treatment population is that rapid improvement was seen in all major symptoms of SCA, including psychosis, depression, and mania. Mediation analyses suggest that the known antipsychotic effects of paliperidone occur independently of its antidepressant effects. Both formulations of the drug are effective when used as monotherapy or adjunctively with antidepressants or mood stabilizers. Beyond symptom control, both formulations improved patient functioning and increased patient satisfaction. PMID- 26934067 TI - Reply. PMID- 26934068 TI - Development of an interprofessional and interdisciplinary collaborative research practice for clinical faculty. AB - This article describes an interprofessional collaborative research practice fellowship designed to foster the research skills of clinical faculty. The year long fellowship was grounded in big data analysis and the triangle of informatics -knowledge, information, and data. Fellows were selected to include diverse perspectives, training, and knowledge but had limited experience in team science or being a member of an interprofessional research team. The underlying philosophy of the fellowship was experiential learning. Protected time and formal mentorship were necessary factors for developing the interprofessional research practice and the skills to participate in an interprofessional research team. We believe that this innovative interprofessional faculty research fellowship is a viable option for supporting scholarly activity and research collaboration. The findings could inform interprofessional clinical practice and be implemented for patient care. Engagement in interprofessional collaborative research and incorporation of the perspectives, knowledge and expertise of multiple professions, is a model to de silo knowledge creation. PMID- 26934069 TI - Current international flow cytometric practices for the detection and monitoring of paroxysmal nocturnal haemoglobinuria clones: A UK NEQAS survey. AB - BACKGROUND: Paroxysmal nocturnal haemoglobinuria (PNH) is a rare acquired genetic disorder, with an incidence of approximately 1.3 new cases per million population per year. Evidence from the UK National External Quality Assessment Service for Leucocyte Immunophenotyping (UK NEQAS LI) programme suggested major discrepancies on how PNH testing is undertaken. To investigate this we surveyed laboratories in the UK NEQAS LI PNH programme and report here the findings. METHODS: A questionnaire was distributed to all centres registered in UK NEQAS LI flow cytometry programmes (n = 1587). Comprising several subsections, it covered the majority of clinical flow cytometric practices. Participants completed a general section and then the subsections relevant to their laboratory repertoire. One subsection contained 34 questions regarding practices in PNH clone detection. RESULTS: A total of 105 laboratories returned results for the PNH section; the results demonstrated lack of consensus in all areas of PNH testing. Variation was seen in gating and testing strategies, sensitivity levels and final reporting of test results. Several incorrect practices were highlighted such as inappropriate antibody selection and failure to wash the red blood cells (RBCs) prior to analysis. CONCLUSION: Despite the availability of consensus guidelines there appears to be no agreement in the detection and monitoring of PNH. We found only fourteen centres using methods compatible with the International Clinical Cytometry Society guidelines. Of specific note we found that no two laboratories used the same method. This technical variation could lead to incorrect diagnoses, highlighting the need for better adoption and understanding of consensus practices. (c) 2016 International Clinical Cytometry Society. PMID- 26934070 TI - Transforming Health Professions Education: Are We There Yet? PMID- 26934071 TI - Ditch The Verb List!? AB - For many years, one of the mainstays of continuing education has been the development and documentation of objectives to identify the behavioral expectations of learners. However, recent changes to American Nurses Credentialing Center Accreditation Program criteria shift the focus from objectives to outcomes. Implications for providers are addressed in this article. PMID- 26934072 TI - Continuing Nursing Education and Outcomes: Making a Difference in Patient Care. AB - As a large provider unit of contact hour education to more than 16,000 nurses, a continuously growing health system needed to ensure that the education provided to their nursing staff was of significance when meeting evaluation outcome criteria. The education team came together to explore some options. PMID- 26934073 TI - Interprofessional Education: Selecting Faculty and Course Design, Part II. AB - Selecting faculty and designing a course to accomplish the goals of interprofessional education are addressed in this article. Respect for other disciplines, knowledge of the paradigm from which the health professions have evolved, and creating learning outcomes that express complementary benefit to leadership development are described. PMID- 26934074 TI - Storytelling: A Strategy for Providing Context for Learning. AB - Storytelling--a narrative of events related to nursing and linked to evidence- provides a context for learning, particularly for learners who require a rich context to understand and integrate concepts related to patient care. This article offers suggestions for developing and using stories in nursing education. PMID- 26934075 TI - From Chaos to Competency: Implementing a New Competency Model in a Multihospital System. AB - The demonstration of nurses' competency has been a challenge for nurse educators for a multitude of reasons. Standardizing competencies across a health care system is especially challenging. One multihospital health care system embarked on a journey to standardize and implement competencies across the system. Using a collaborative approach, the Wright model of competency assessment was selected and implemented across the system. Lessons learned include (a) the full engagement of Wright's model by all nursing stakeholders is essential, (b) indicators and outcomes must align with quality improvement data, and (c) the needs of each unit must be individualized, and the methods of verification must be closely aligned with the measurable competency. After implementation of this model, the health system now has a standard definition, identification, methodology, and evaluation for competencies. In addition, there are now standard time frames for assessment and evaluation and increased accountability for staff involvement. PMID- 26934076 TI - Factors Affecting Turnover Intention for New Graduate Nurses in Three Transition Periods for Job and Work Environment Satisfaction. AB - BACKGROUND: The turnover rate of new graduate nurses in Korea is twice that of all Korean nurses; job/work environment satisfaction is a known risk factor. The authors examined these factors in new graduate nurses at various transition periods. METHOD: A cross-sectional survey was conducted using stratified sampling from nine regions of Korea, and 443 new graduate nurses were enrolled. Job/work environment satisfaction and turnover intention were measured. Stepwise multiple regression analysis identified the factors affecting turnover intention. RESULTS: The factors differed through the transition periods. At 0 to 6 months, the factors were work schedule, desired hospital, orientation duration, becoming part of a team, professional development, and practical support; at 7 to 12 months, the factors were work schedule and desired hospital; and at 13 to 18 months, the factor was professional development, which accounted for 31%, 22.9%, and 12.6%, respectively, of the reasons for turnover intention. CONCLUSION: Reducing turnover intention requires consideration of the influential factors at each transition period. PMID- 26934077 TI - The Role of Preceptorship and Group Cohesion on Newly Licensed Registered Nurses' Satisfaction and Intent to Stay. AB - BACKGROUND: Thirteen percent of newly licensed registered nurses (NLRNs) vacate their first job after 1 year, and 37% report that they feel ready to change jobs. Turnover can lead to consistent and detrimental nursing shortages in nursing units, as well as increased costs for health care systems. METHOD: A descriptive, prospective, cross-sectional design was used to understand how preceptor role effectiveness and group cohesion affect NLRNs' satisfaction and intent to stay. RESULTS: NLRNs reported high levels of perceived preceptor role effectiveness, group cohesion, and job satisfaction, with only moderate levels of intent to stay. Statistically significant relationships were found among preceptor role effectiveness, job satisfaction, and intent to stay, as well as among group cohesion, job satisfaction, and intent to stay. Preceptor role effectiveness and group cohesion are predictors of NLRNs' level of job satisfaction. Job satisfaction is a predictor of NLRNs' intent to stay. CONCLUSION: Effective preceptors and positive group cohesion are factors that are important to NLRNs' job satisfaction and intent to stay. PMID- 26934078 TI - Preparing New Graduates for Interprofessional Teamwork: Effectiveness of a Nurse Residency Program. AB - The purpose of this project was to determine whether a nurse residency program was effective in improving satisfaction with new graduates' performance competence in interprofessional collaboration. This was a cross-sectional survey design, comparing the satisfaction ratings of nurse leaders and staff nurses at a mid-western academic medical center to national benchmark data obtained from the 2007 Nursing Practice Readiness Tool. The sample consisted of 149 nurses who worked in inpatient units where new graduates practice. Thirty-five had 1 year or less of experience in nursing and 114 had at least 2 years of experience. Managers, experienced nurses, and new graduate nurses varied in their satisfaction ratings regarding interprofessional collaboration. Satisfaction of new graduates' competencies by nurse managers and staff nurses were rated higher in each category, compared with the national study, with 63% of nurse leaders satisfied with new graduates' ability to communicate with the interprofessional team, compared with the national average of 38%. Participants reported 56% satisfaction in the ability to work as a team, compared with 37% reported in the national study. PMID- 26934079 TI - Covalently Assembled Dipeptide Nanospheres as Intrinsic Photosensitizers for Efficient Photodynamic Therapy in Vitro. AB - Monodispersed diphenylalanine-based nanospheres with excellent biocompatibility are fabricated through a facile covalent reaction-induced assembly. Interestingly, the nanospheres exhibit red autofluorescence. Most importantly, such assembled dipeptide nanospheres can serve as intrinsic photosensitizer to convert O2 to singlet oxygen ((1) O2 ). Thus, photodynamic therapy in vitro can be achieved effectively. The versatile strategy could be extended to other biomolecules containing a primary amine group for the fabrication of potential intrinsic photosensitizers. PMID- 26934080 TI - Transcriptomics-assisted quantitative trait locus fine mapping for the rapid identification of a nodulin 26-like intrinsic protein gene regulating boron efficiency in allotetraploid rapeseed. AB - Allotetraploid rapeseed (Brassica napus L., An An Cn Cn , 2n = 4x = 38) is extraordinarily susceptible to boron (B) deficiency, a ubiquitous problem causing severe losses in seed yield. The breeding of B-efficient rapeseed germ plasm is a cost-effective and environmentally friendly strategy for the agricultural industry; however, genes regulating B efficiency in allotetraploid rapeseed have not yet been isolated. In this research, quantitative trait locus (QTL) fine mapping and digital gene expression (DGE) profiling were combined to identify the candidate genes underlying the major-effect QTL qBEC-A3a, which regulates B efficiency. Comparative phenotype analyses of the near-isogenic lines (NILs) indicated that qBEC-A3a plays a significant role in improving B efficiency under B deficiency. Exploiting QTL fine mapping and DGE analyses revealed a nodulin 26 like intrinsic protein (NIP) gene, which encodes a likely boric acid channel. The gene co-expression network for putative B transporters also highlighted its central role in the efficiency of B uptake. An integration of whole-genome re sequencing (WGS) with bulked segregant analysis (BSA) authenticated the emerging availability of QTL-seq for the QTL analyses in allotetraploid rapeseed. Transcriptomics-assisted QTL mapping and comparative genomics provided novel insights into the rapid identification of quantitative trait genes (QTGs) in plant species with complex genomes. PMID- 26934082 TI - Phosphorothiolation of Aryl Boronic Acids Using P(O)H Compounds and Elemental Sulfur. AB - The first multicomponent reaction (MCR) involving aryl boronic acids, elemental sulfur, and P(O)H compounds is presented. It proceeds with excellent yields and provides an attractive approach for the construction of valuable S-aryl phosphorothioates and S-aryl phosphorodithioates using a one-step strategy. Moreover, this method can be easily adapted to large-scale preparation. PMID- 26934081 TI - Screening for important unwarranted variation in clinical practice: a triple-test of processes of care, costs and patient outcomes. AB - Objective Unwarranted variation in clinical practice is a target for quality improvement in health care, but there is no consensus on how to identify such variation or to assess the potential value of initiatives to improve quality in these areas. This study illustrates the use of a triple test, namely the comparative analysis of processes of care, costs and outcomes, to identify and assess the burden of unwarranted variation in clinical practice. Methods Routinely collected hospital and mortality data were linked for patients presenting with symptoms suggestive of acute coronary syndromes at the emergency departments of four public hospitals in South Australia. Multiple regression models analysed variation in re-admissions and mortality at 30 days and 12 months, patient costs and multiple process indicators. Results After casemix adjustment, an outlier hospital with statistically significantly poorer outcomes and higher costs was identified. Key process indicators included admission patterns, use of invasive diagnostic procedures and length of stay. Performance varied according to patients' presenting characteristics and time of presentation. Conclusions The joint analysis of processes, outcomes and costs as alternative measures of performance inform the importance of reducing variation in clinical practice, as well as identifying specific targets for quality improvement along clinical pathways. Such analyses could be undertaken across a wide range of clinical areas to inform the potential value and prioritisation of quality improvement initiatives. What is known about the topic? Variation in clinical practice is a long-standing issue that has been analysed from many different perspectives. It is neither possible nor desirable to address all forms of variation in clinical practice: the focus should be on identifying important unwarranted variation to inform actions to reduce variation and improve quality. What does this paper add? This paper proposes the comparative analysis of processes of care, costs and outcomes for patients with similar diagnoses presenting at alternative hospitals, using linked, routinely collected data. This triple test of performance indicators extracts maximum value from routine data to identify priority areas for quality improvement to reduce important and unwarranted variations in clinical practice. What are the implications for practitioners? The proposed analyses need to be applied to other clinical areas to demonstrate the general application of the methods. The outputs can then be validated through the application of quality improvement initiatives in clinical areas with identified important and unwarranted variation. Validated frameworks for the comparative analysis of clinical practice provide an efficient approach to valuing and prioritising actions to improve health service quality. PMID- 26934084 TI - Supplementation with Watermelon Extract Reduces Total Cholesterol and LDL Cholesterol in Adults with Dyslipidemia under the Influence of the MTHFR C677T Polymorphism. AB - : Dyslipidemia and genetic polymorphisms are associated with increased risk for developing cardiovascular diseases, and watermelon appears to have the potential to improve hyperlipidemia due to the presence of nutrients such as arginine and citrulline. OBJECTIVE: To test the hypolipidemic effect of watermelon extract (Citrullus lanatus) and the influence of the methylenetetrahydrofolate reductase genotype (MTHFR C677T) on supplementation response. METHODS: This is an experimental clinical phase II randomized and double-blind study. Forty-three subjects with dyslipidemia were randomly divided into 2 groups: experimental (n = 22) and control (n = 21) groups. The subjects were supplemented daily for 42 days with 6 g of watermelon extract or a mixture of carbohydrates (sucrose/glucose/fructose). RESULTS: The use of watermelon extract reduced plasma total cholesterol (p < 0.05) and low-density lipoprotein (p < 0.01) without modifying triglycerides, high-density lipoprotein, and very low-density lipoprotein values. Only carriers of the T allele (MTHFR C677T) showed decreasing concentrations of low-density lipoprotein (p < 0.01). No changes in anthropometric parameters analyzed were observed. This is the first study to demonstrate the beneficial effect of the consumption of watermelon extract in reducing plasma levels of lipids in humans. The MTHFR C677T polymorphism did not affect the plasma lipid concentration but made individuals more responsive to treatment with watermelon. CONCLUSIONS: The consumption of this functional food represents an alternative therapy in the combined treatment of patients with dyslipidemia, promoting health and minimizing the development of risk factors for cardiovascular diseases. PMID- 26934083 TI - Association between depression, parameters of adiposity and genetic polymorphisms of pro-inflammatory cytokines: IL-1alpha, IL-1beta, IL-2 and IL-6 in subjects over 55 years old. AB - BACKGROUND: During the last few decades, adiposity has become a relatively common phenomenon worldwide. The available data on the effects of pro-inflammatory factors in both depression and adiposity has been attracting great attention. AIM: We sought to assess the prevalence of -889C>T IL-1alpha, -31T>C and -511C>T IL-1beta, -330T>G IL-2 and -174G>C IL-6 genes and their association with adiposity and depression in Polish subjects. METHODS: A cohort study was conducted in 2013/2014, covering a sample of 297 individuals (217 female and 80 male). Anthropometric data was handled using the BIA analysis method, while for genotyping PCR-RFLP techniques were used. RESULTS: A positive correlation between depression and anthropometric parameters: adipose tissue (in kg) and adipose tissue (in %) (R=0.135 and p=0.02, R=0.114 and p<0.05, respectively) was found. No association between studied polymorphisms and depression was observed. CONCLUSION: Although it was not possible to demonstrate any influence of the studied polymorphisms as the genetic modulator of depression, authors believe that the presented data are noticeable and may provide the basis for future studies on larger groups. PMID- 26934085 TI - Effect of Reaction Pathway on the Extent and Mechanism of Uranium(VI) Immobilization with Calcium and Phosphate. AB - Phosphate addition to subsurface environments contaminated with uranium can be used as an in situ remediation approach. Batch experiments were conducted to evaluate the dependence of the extent and mechanism of uranium uptake on the pathway for reaction with calcium phosphates. At pH 4.0 and 6.0 uranium uptake from solution occurred via autunite (Ca(UO2)2(PO4)2) precipitation irrespective of the starting forms of calcium and phosphate. At pH 7.5, a condition at which calcium phosphate solids could form, the uptake mechanism depended on the nature of the calcium and phosphate as determined by X-ray absorption spectroscopy and laser-induced fluorescence spectroscopy. When dissolved uranium, calcium, and phosphate were added simultaneously, uranium was structurally incorporated into a newly formed amorphous calcium phosphate solid. Adsorption was the dominant removal mechanism for uranium contacted with preformed amorphous calcium phosphate solids. When U(VI) was added to a suspension containing amorphous calcium phosphate solids as well as dissolved calcium and phosphate, then removal occurred through precipitation (57 +/- 4%) of autunite and adsorption (43 +/- 4%) onto calcium phosphate. Dissolved uranium, calcium, and phosphate concentrations with saturation index calculations helped identify removal mechanisms and determine thermodynamically favorable solid phases. PMID- 26934086 TI - Survival during the Breeding Season: Nest Stage, Parental Sex, and Season Advancement Affect Reed Warbler Survival. AB - Avian annual survival has received much attention, yet little is known about seasonal patterns in survival, especially of migratory passerines. In order to evaluate survival rates and timing of mortality within the breeding season of adult reed warblers (Acrocephalus scirpaceus), mark-recapture data were collected in southwest Poland, between 2006 and 2012. A total of 612 individuals (304 females and 308 males) were monitored throughout the entire breeding season, and their capture-recapture histories were used to model survival rates. Males showed higher survival during the breeding season (0.985, 95% CI: 0.941-0.996) than females (0.869, 95% CI: 0.727-0.937). Survival rates of females declined with the progression of the breeding season (from May to August), while males showed constant survival during this period. We also found a clear pattern within the female (but not male) nesting cycle: survival was significantly lower during the laying, incubation, and nestling periods (0.934, 95% CI: 0.898-0.958), when birds spent much time on the nest, compared to the nest building and fledgling periods (1.000, 95% CI: 1.00-1.000), when we did not record any female mortality. These data (coupled with some direct evidence, like bird corpses or blood remains found next to/on the nest) may suggest that the main cause of adult mortality was on nest predation. The calculated survival rates for both sexes during the breeding season were high compared to annual rates reported for this species, suggesting that a majority of mortality occurs at other times of the year, during migration or wintering. These results have implications for understanding survival variation within the reproductive period as well as general trends of avian mortality. PMID- 26934087 TI - Influence of pyrolytic and non-pyrolytic rice and castor straws on the immobilization of Pb and Cu in contaminated soil. AB - Soil contamination with heavy metals has become a global environmental health concern. In the present study, European Community Bureau of Reference (BCR) sequential extraction and toxicity characteristic leaching procedure (TCLP) techniques were used to evaluate the Pb and Cu subsequent transformations, immobilizing impact of pyrolytic and non-pyrolytic rice and castor straws and their efficiency to reduce the metals mobility and leachability in the polluted soil. Obtained results highlight the potential of biochar over non-pyrolytic residues to enhance the immobilization of Pb and Cu in the soil. Castor leaves derived biochar (CLB), castor stem-derived biochar (CSB), and rice straw-derived biochar (RSB) prominently decreased the mobility (acid-soluble fraction) of Pb 49.8%, 31.1%, and 31.9%, respectively, while Cu decreased 15.8%, 11.5%, and 12%, respectively, as compare to control. Sequential extraction showed that biochar treatments prominently modified the proportioning of Pb and Cu from acid soluble to a less bioavailable fraction and increased the geochemical stability in the polluted soil as compared to relative feedstocks as well as the controlled soil. Additionally, the soil pH increased markedly after the addition of biochar. Compared with control, the TCLP-extractable Pb and Cu were reduced to 29.2-41.4% and 5.7-22.8% from the soil respectively by the application of CLB. The immobilization and reduction in leachability of Pb and Cu were correlated with the soil pH. The biochar effect on the Pb immobilization was much better as compared to Cu in co-contaminated soil. Overall addition of CLB offered the best results and could be effective in both Pb and Cu immobilization thereby reducing their mobility and bioavailability in the co-contaminated soil. PMID- 26934089 TI - Computational Design of a Circular RNA with Prionlike Behavior. AB - RNA molecules engineered to fold into predefined conformations have enabled the design of a multitude of functional RNA devices in the field of synthetic biology and nanotechnology. More complex designs require efficient computational methods, which need to consider not only equilibrium thermodynamics but also the kinetics of structure formation. Here we present a novel type of RNA design that mimics the behavior of prions, that is, sequences capable of interaction-triggered autocatalytic replication of conformations. Our design was computed with the ViennaRNA package and is based on circular RNA that embeds domains amenable to intermolecular kissing interactions. PMID- 26934090 TI - Exploring the Space of Viable Configurations in a Model of Metabolism-Boundary Co construction. AB - We introduce a spatial model of concentration dynamics that supports the emergence of spatiotemporal inhomogeneities that engage in metabolism-boundary co construction. These configurations exhibit disintegration following some perturbations, and self-repair in response to others. We define robustness as a viable configuration's tendency to return to its prior configuration in response to perturbations, and plasticity as a viable configuration's tendency to change to other viable configurations. These properties are demonstrated and quantified in the model, allowing us to map a space of viable configurations and their possible transitions. Combining robustness and plasticity provides a measure of viability as the average expected survival time under ongoing perturbation, and allows us to measure how viability is affected as the configuration undergoes transitions. The framework introduced here is independent of the specific model we used, and is applicable for quantifying robustness, plasticity, and viability in any computational model of artificial life that demonstrates the conditions for viability that we promote. PMID- 26934088 TI - QTL Location and Epistatic Effect Analysis of 100-Seed Weight Using Wild Soybean (Glycine soja Sieb. & Zucc.) Chromosome Segment Substitution Lines. AB - Increasing the yield of soybean (Glycine max L. Merrill) is a main aim of soybean breeding. The 100-seed weight is a critical factor for soybean yield. To facilitate genetic analysis of quantitative traits and to improve the accuracy of marker-assisted breeding in soybean, a valuable mapping population consisting of 194 chromosome segment substitution lines (CSSLs) was developed. In these lines, different chromosomal segments of the Chinese cultivar Suinong 14 were substituted into the genetic background of wild soybean (Glycine soja Sieb. & Zucc.) ZYD00006. Based on these CSSLs, a genetic map covering the full genome was generated using 121 simple sequence repeat (SSR) markers. In the quantitative trait loci (QTL) analysis, twelve main effect QTLs (qSW-B1-1/2/3, qSW-D1b-1/2, qSW-D2-1/2, qSW-G-1/2/3, qSW-M-2 and qSW-N-2) underlying 100-seed weight were identified in 2011 and 2012. The epistatic effects of pairwise interactions between markers were analyzed in 2011 and 2012. The results clearly demonstrated that these CSSLs could be used to identify QTLs, and that an epistatic analysis was able to detect several sites with important epistatic effects on 100-seed weight. Thus, we identified loci that will be valuable for improving soybean 100 seed weight. These results provide a valuable foundation for identifying the precise location of genes of interest, and for designing cloning and marker assisted selection breeding strategies targeting the 100-seed weight of soybean. PMID- 26934091 TI - Complex Autocatalysis in Simple Chemistries. AB - Life on Earth must originally have arisen from abiotic chemistry. Since the details of this chemistry are unknown, we wish to understand, in general, which types of chemistry can lead to complex, lifelike behavior. Here we show that even very simple chemistries in the thermodynamically reversible regime can self organize to form complex autocatalytic cycles, with the catalytic effects emerging from the network structure. We demonstrate this with a very simple but thermodynamically reasonable artificial chemistry model. By suppressing the direct reaction from reactants to products, we obtain the simplest kind of autocatalytic cycle, resulting in exponential growth. When these simple first order cycles are prevented from forming, the system achieves superexponential growth through more complex, higher-order autocatalytic cycles. This leads to nonlinear phenomena such as oscillations and bistability, the latter of which is of particular interest regarding the origins of life. PMID- 26934092 TI - Active Shape Discrimination with Compliant Bodies as Reservoir Computers. AB - Compliant bodies with complex dynamics can be used both to simplify control problems and to lead to adaptive reflexive behavior when engaged with the environment in the sensorimotor loop. By revisiting an experiment introduced by Beer and replacing the continuous-time recurrent neural network therein with reservoir computing networks abstracted from compliant bodies, we demonstrate that adaptive behavior can be produced by an agent in which the body is the main computational locus. We show that bodies with complex dynamics are capable of integrating, storing, and processing information in meaningful and useful ways, and furthermore that with the addition of the simplest of nervous systems such bodies can generate behavior that could equally be described as reflexive or minimally cognitive. PMID- 26934093 TI - Population and Evolutionary Dynamics based on Predator-Prey Relationships in a 3D Physical Simulation. AB - Recent studies have reported that population dynamics and evolutionary dynamics, occurring at different time scales, can be affected by each other. Our purpose is to explore the interaction between population and evolutionary dynamics using an artificial life approach based on a 3D physically simulated environment in the context of predator-prey and morphology-behavior coevolution. The morphologies and behaviors of virtual prey creatures are evolved using a genetic algorithm based on the predation interactions between predators and prey. Both population sizes are also changed, depending on the fitness. We observe two types of cyclic behaviors, corresponding to short-term and long-term dynamics. The former can be interpreted as a simple population dynamics of Lotka-Volterra type. It is shown that the latter cycle is based on the interaction between the changes in the prey strategy against predators and the long-term change in both population sizes, resulting partly from a tradeoff between their defensive success and the cost of defense. PMID- 26934094 TI - A General Statistical Method for Identifying Adaptations by Parameterizing Trait Space. AB - It is obviously useful to think of evolved individuals in terms of their adaptations, yet the task of empirically classifying traits as adaptations has been claimed by some to be impossible in principle. I reject that claim by construction, introducing a formal method to empirically test whether a trait is an adaptation. The method presented is general, intuitive, and effective at identifying adaptations while remaining agnostic about their adaptive function. The test follows directly from the notion that adaptations arise from variation, heritability, and differential fitness in an evolving population: I operationalize these three concepts at the trait level, formally defining measures of individual traits. To test whether a trait is an adaptation, these measures are evaluated, locating the trait within a three-dimensional parameterized trait space. Within this space, I identify a region containing all adaptations; a trait's position relative to this adaptive region of trait space describes its status as an adaptation. The test can be applied in any evolving system where a few domain-specific statistical measures can be constructed; I demonstrate the construction of these measures, most notably a measure of an individual's hypothetical fitness if it were born with a different trait, in Packard's Bugs ALife model. The test is applied in Bugs, and shown to conform with our intuitive classification of adaptations. PMID- 26934095 TI - Compartmentalization of an all-E. coli Cell-Free Expression System for the Construction of a Minimal Cell. AB - Cell-free expression is a technology used to synthesize minimal biological cells from natural molecular components. We have developed a versatile and powerful all E. coli cell-free transcription-translation system energized by a robust metabolism, with the far objective of constructing a synthetic cell capable of self-reproduction. Inorganic phosphate (iP), a byproduct of protein synthesis, is recycled through polysugar catabolism to regenerate ATP (adenosine triphosphate) and thus supports long-lived and highly efficient protein synthesis in vitro. This cell-free TX-TL system is encapsulated into cell-sized unilamellar liposomes to express synthetic DNA programs. In this work, we study the compartmentalization of cell-free TX-TL reactions, one of the aspects of minimal cell module integration. We analyze the signals of various liposome populations by fluorescence microscopy for one and for two reporter genes, and for an inducible genetic circuit. We show that small nutrient molecules and proteins are encapsulated uniformly in the liposomes with small fluctuations. However, cell free expression displays large fluctuations in signals among the same population, which are due to heterogeneous encapsulation of the DNA template. Consequently, the correlations of gene expression with the compartment dimension are difficult to predict accurately. Larger vesicles can have either low or high protein yields. PMID- 26934096 TI - An Informational Study of the Evolution of Codes and of Emerging Concepts in Populations of Agents. AB - We consider the problem of the evolution of a code within a structured population of agents. The agents try to maximize their information about their environment by acquiring information from the outputs of other agents in the population. A naive use of information-theoretic methods would assume that every agent knows how to interpret the information offered by other agents. However, this assumes that it knows which other agents it observes, and thus which code they use. In our model, however, we wish to preclude that: It is not clear which other agents an agent is observing, and the resulting usable information is therefore influenced by the universality of the code used and by which agents an agent is listening to. We further investigate whether an agent that does not directly perceive the environment can distinguish states by observing other agents' outputs. For this purpose, we consider a population of different types of agents talking about different concepts, and try to extract new ones by considering their outputs only. PMID- 26934098 TI - Antibiotic Resistance in India: Drivers and Opportunities for Action. AB - Ramanan Laxminarayan and Ranjit Roy Chaudhury examine the factors encouraging the emergence of antibiotic resistance in India, the implications nationally and internationally, and what might be done to help. PMID- 26934097 TI - Thymic Stromal Lymphopoietin Improves Survival and Reduces Inflammation in Sepsis. AB - The mechanisms that contribute to homeostasis of the immune system in sepsis are largely unknown. One study suggests a potential detrimental role for thymic stromal lymphopoietin (TSLP) in sepsis; however, the immune-regulatory effects of TSLP on myeloid cells within the intestinal microenvironment suggest the contrary. Our objective was to clarify TSLP's role in sepsis. Cecal ligation and puncture was performed in mice with total or myeloid-specific deficiency in the TSLP receptor (TSLPR). Survival was monitored closely, peritoneal fluids and plasma were analyzed for markers of inflammation, and myeloid cell numbers and their ability to produce inflammatory mediators was determined. The interaction of TSLP with TSLPR in myeloid cells contributed to mouse survival after septic peritonitis. Mice with TSLPR deficiency in myeloid cells displayed excessive local and systemic inflammation levels (e.g., increased inflammatory cell and cytokine levels) relative to control mice. Moreover, hepatic injury was exacerbated in mice with TSLPR deficiency in their myeloid cells. However, the enhanced inflammatory response did not affect the ability of these mice to clear bacteria. Resident neutrophils and macrophages from septic mice with TSLPR deficiency exhibited an increased ability to produce proinflammatory cytokines. Collectively, our findings suggest that the effects of TSLP on myeloid cells are crucial in reducing the multiple organ failure that is associated with systemic inflammation, which highlights the significance of this cytokine in modulating the host response to infection and in reducing the risks of sepsis development. PMID- 26934099 TI - Opposing effects of Sca-1(+) cell-based systemic FGF2 gene transfer strategy on lumbar versus caudal vertebrae in the mouse. AB - Our previous work showed that a Sca-1(+) cell-based FGF2 therapy was capable of promoting robust increases in trabecular bone formation and connectivity on the endosteum of long bones. Past work reported that administration of FGF2 protein promoted bone formation in red marrow but not in yellow marrow. The issue as to whether the Sca-1(+) cell-based FGF2 therapy is effective in yellow marrow is highly relevant to its clinical potential for osteoporosis, as most red marrows in a person of an advanced age are converted to yellow marrows. Accordingly, this study sought to compare the osteogenic effects of this stem cell-based FGF2 therapy on red marrow-filled lumbar vertebrae with those on yellow marrow-filled caudal vertebrae of young adult W(41)/W(41) mice. The Sca-1(+) cell-based FGF2 therapy drastically increased trabecular bone formation in lumbar vertebrae, but the therapy not only did not promote bone formation but instead caused substantial loss of trabecular bone in caudal vertebrae. The lack of an osteogenic response was not due to insufficient engraftment of FGF2-expressing Sca-1(+) cells or inadequate FGF2 expression in caudal vertebrae. Previous studies have demonstrated that recipient mice of this stem cell-based FGF2 therapy developed secondary hyperparathyroidism and increased bone resorption. Thus, the loss of bone mass in caudal vertebrae might in part be due to an increase in resorption without a corresponding increase in bone formation. In conclusion, the Sca-1(+) cell-based FGF2 therapy is osteogenic in red marrow but not in yellow marrow. PMID- 26934101 TI - VvMJE1 of the grapevine (Vitis vinifera) VvMES methylesterase family encodes for methyl jasmonate esterase and has a role in stress response. AB - The known members of plant methyl esterase (MES) family catalyze the hydrolysis of a C-O ester linkage of methyl esters of several phytohormones including indole 3-acetic acid, salicylic acid and jasmonic acid. The genome of grapevine (Vitis vinifera) was found to contain 15 MES genes, designated VvMES1-15. In this report, VvMES5 was selected for molecular, biochemical and structural studies. VvMES5 is most similar to tomato methyl jasmonate esterase. E. coli-expressed recombinant VvMES5 displayed methyl jasmonate (MeJA) esterase activity, it was renamed VvMJE1. Under steady-state conditions, VvMJE1 exhibited an apparent Km value of 92.9 MUM with MeJA. VvMJE1 was also shown to have lower activity with methyl salicylate (MeSA), another known substrate of the MES family, and only at high concentrations of the substrate. To understand the structural basis of VvMJE1 in discriminating MeJA and MeSA, a homolog model of VvMJE1 was made using the X-ray structure of tobacco SABP2, which encodes for methyl salicylate esterase, as a template. Interestingly, two bulky residues at the binding site and near the surface of tobacco SABP2 are replaced by relatively small residues in VvMJE1. Such a change enables the accommodation of a larger substrate MeJA in VvMJE1. The expression of VvMJE1 was compared in control grape plants and grape plants treated with one of the three stresses: heat, cold and UV-B. While the expression of VvMJE1 was not affected by heat treatment, its expression was significantly up-regulated by cold treatment and UV-B treatment. This result suggests that VvMJE1 has a role in response of grape plants to these two abiotic stresses. PMID- 26934102 TI - Differential hormonal and gene expression dynamics in two inbred sunflower lines with contrasting dormancy level. AB - Seed germination and dormancy are tightly regulated by hormone metabolism and signaling pathway. We investigated the endogenous content of abscisic acid (ABA), its catabolites, and gibberellins (GAs), as well as the expression level of certain ABA and GAs metabolic and signaling genes in embryo of dry and imbibed cypselas of inbred sunflower (Helianthus annuus L., Asteraceae) lines: B123 (dormant) and B91 (non-dormant). Under our experimental conditions, the expression of RGL2 gene might be related to the ABA peak in B123 line at 3 h of imbibition. Indeed, RGL2 transcripts are absent in dry and early embedded cypselas of the non-dormant line B91. ABA increase was accompanied by a significant ABA-Glucosyl ester (ABA-GE) and phaseic acid (PA) (two ABA catabolites) decrease in B123 line (3 h) which indicates that ABA metabolism seems to be more active in this line, and that it would be involved in the imposition and maintenance of sunflower seed dormancy, as it has been reported for many species. Finally, an increase of bioactive GAs (GA1 and GA3) occurs at 12 h of imbibition in both lines after a decrease in ABA content. This study shows the first report about the RGL2 tissue-specific gene expression in sunflower inbred lines with contrasting dormancy level. Furthermore, our results provide evidence that ABA and GAs content and differential expression of metabolism and signaling genes would be interacting in seed dormancy regulation through a mechanism of action related to embryo itself. PMID- 26934100 TI - A new plasmid-based microRNA inhibitor system that inhibits microRNA families in transgenic mice and cells: a potential new therapeutic reagent. AB - Current tools for the inhibition of microRNA (miR) function are limited to modified antisense oligonucleotides, sponges and decoy RNA molecules and none have been used to understand miR function during development. CRISPR/Cas-mediated deletion of miR sequences within the genome requires multiple chromosomal deletions to remove all functional miR family members because of duplications. Here, we report a novel plasmid-based miR inhibitor system (PMIS) that expresses a new RNA molecule, which inhibits miR family members in cells and mice. The PMIS engineered RNA optimal secondary structure, flanking sequences and specific antisense miR oligonucleotide sequence bind the miR in a stable complex to inhibit miR activity. In cells, one PMIS can effectively inhibit miR family members that share the same seed sequence. The PMIS shows no off-target effects or toxicity and is highly specific for miRs sharing identical seed sequences. Transgenic mice expressing both PMIS-miR-17-18 and PMIS-miR-19-92 show similar phenotypes of miR-17-92-knockout mice. Interestingly, mice only expressing PMIS miR-17-18 have developmental defects distinct from mice only expressing PMIS-miR 19-92 demonstrating usefulness of the PMIS system to dissect different functions of miRs within clusters. Different PMIS miR inhibitors can be linked together to knock down multiple miRs expressed from different chromosomes. Inhibition of the miR-17-92, miR-106a-363 and miR-106b-25 clusters reveals new mechanisms and developmental defects for these miRs. We report a new tool to dissect the role of miRs in development without genome editing, inhibit miR function in cells and as a potential new therapeutic reagent. PMID- 26934104 TI - Morphological Variations of Leading-Edge Serrations in Owls (Strigiformes). AB - BACKGROUND: Owls have developed serrations, comb-like structures, along the leading edge of their wings. Serrations were investigated from a morphological and a mechanical point of view, but were not yet quantitatively compared for different species. Such a comparative investigation of serrations from species of different sizes and activity patterns may provide new information about the function of the serrations. RESULTS: Serrations on complete wings and on tenth primary remiges of seven owl species were investigated. Small, middle-sized, and large owl species were investigated as well as species being more active during the day and owls being more active during the night. Serrations occurred at the outer parts of the wings, predominantly at tenth primary remiges, but also on further wing feathers in most species. Serration tips were oriented away from the feather rachis so that they faced into the air stream during flight. The serrations of nocturnal owl species were higher developed as demonstrated by a larger inclination angle (the angle between the base of the barb and the rachis), a larger tip displacement angle (the angle between the tip of the serration and the base of the serration) and a longer length. Putting the measured data into a clustering algorithm yielded dendrograms that suggested a strong influence of activity pattern, but only a weak influence of size on the development of the serrations. CONCLUSIONS: Serrations are supposed to be involved in noise reduction during flight and also depend on the aerodynamic properties that in turn depend on body size. Since especially nocturnal owls have to rely on hearing during prey capture, the more pronounced serrations of nocturnal species lend further support to the notion that serrations have an important function in noise reduction. The differences in shape of the serrations investigated indicate that a silent flight requires well-developed serrations. PMID- 26934103 TI - Identification of Interactions in the NMD Complex Using Proximity-Dependent Biotinylation (BioID). AB - Proximity-dependent trans-biotinylation by the Escherichia coli biotin ligase BirA mutant R118G (BirA*) allows stringent streptavidin affinity purification of proximal proteins. This so-called BioID method provides an alternative to the widely used co-immunoprecipitation (co-IP) to identify protein-protein interactions. Here, we used BioID, on its own and combined with co-IP, to identify proteins involved in nonsense-mediated mRNA decay (NMD), a post transcriptional mRNA turnover pathway that targets mRNAs that fail to terminate translation properly. In particular, we expressed BirA* fused to the well characterized NMD factors UPF1, UPF2 and SMG5 and detected by liquid chromatography-coupled tandem mass spectrometry (LC-MS/MS) the streptavidin purified biotinylated proteins. While the identified already known interactors confirmed the usefulness of BioID, we also found new potentially important interactors that have escaped previous detection by co-IP, presumably because they associate only weakly and/or very transiently with the NMD machinery. Our results suggest that SMG5 only transiently contacts the UPF1-UPF2-UPF3 complex and that it provides a physical link to the decapping complex. In addition, BioID revealed among others CRKL and EIF4A2 as putative novel transient interactors with NMD factors, but whether or not they have a function in NMD remains to be elucidated. PMID- 26934105 TI - Minor Pyranonaphthoquinones from the Apothecia of the Lichen Ophioparma ventosa. AB - Four new quinonoid naphthopyranones, ophioparmin (1), 4-methoxyhaemoventosins (2a and 2b), and 4-hydroxyhaemoventosin (3), together with anhydrofusarubin lactone (4) and haemoventosin (5) were isolated from the fruiting bodies of Ophioparma ventosa, a crustose lichen. Their structures were determined by spectroscopic analyses, and the absolute configurations of 1 and 2 were elucidated through experimental and calculated electronic circular dichroism analyses. Compounds 1, 2, and 5 exhibited moderate to strong antioxidant activities. The main pigment haemoventosin exhibited significant cytotoxicity toward a panel of nine cell lines. PMID- 26934107 TI - Adolescents' intention and self-efficacy to follow Pap testing recommendations after receiving the HPV vaccine. AB - Human papillomavirus (HPV) vaccines are recommended in the US for girls and women 11-26 y of age. Because these vaccines do not prevent all cervical cancers, Papanicolaou (Pap) screening is still recommended after vaccination. Young women who have been vaccinated may perceive themselves at lower risk for HPV infection and cervical cancer, which could lead to lower intention and self-efficacy to follow cervical cancer screening guidelines, and subsequent nonadherence to Pap testing. The aim of this study was to examine whether perceived risk of human papillomavirus (HPV) after vaccination and other factors are associated with adolescents' intention and self-efficacy to get Pap testing after HPV vaccination. Women 13-21 y of age (N = 339) receiving their first HPV vaccine dose completed a survey. Multivariable logistic regression examined associations between perceived risk of HPV and intention/self-efficacy to get a Pap test while adjusting for other factors. Approximately half of participants reported high intention and half reported high self-efficacy to get a Pap test. Factors significantly associated with high intention were Pap testing history and knowledge about HPV/HPV vaccines; factors significantly associated with high self efficacy included insurance plan, Pap testing history, communication with clinician about needing a Pap test after vaccination, lifetime number of male sexual partners, and recent smoking. In conclusion, educating adolescents about HPV/HPV vaccines and the need for Pap testing may increase self efficacy/intention to get a Pap test after vaccination. PMID- 26934108 TI - C5a of Cynoglossus semilaevis has anaphylatoxin-like properties and promotes antibacterial and antiviral defense. AB - Activation of the complement system leads to the cleavage of component factor C5 into C5a and C5b. C5a can induce chemotaxis and inflammatory responses in mammals. The function of C5a in fish is poorly understood. In this study, we report the identification and analysis of a C5 homologue, CsC5, from tongue sole (Cynoglossus semilaevis). CsC5 is composed of 1683 amino acid residues that include an anaphylatoxin homologous domain. Expression of CsC5 could be detected in a variety of tissues and was up-regulated by bacterial or viral pathogen infection. Purified recombinant CsC5a (rCsC5a) could bind to peripheral blood leukocytes (PBL) and stimulate PBL chemotaxis, proliferation, respiratory burst, acid phosphatase activity, and phagocytosis. Tongue sole administered rCsC5a exhibited enhanced resistance against bacterial and viral infections. These results indicate that CsC5a is an anaphylatoxin with a role in innate immune defense against bacterial and viral infections. PMID- 26934109 TI - Monogamy in a Hyper-Symbiotic Shrimp. AB - Theory predicts that monogamy is adaptive in resource-specialist symbiotic crustaceans inhabiting relatively small and morphologically simple hosts in tropical environments where predation risk away from hosts is high. We tested this prediction in Pontonia manningi, a hyper-symbiotic shrimp that dwells in the mantle cavity of the Atlantic winged oyster Pteria colymbus that, in turn, infects gorgonians from the genus Pseudopterogorgia in the Caribbean Sea. In agreement with theory, P. manningi were found dwelling as heterosexual pairs in oysters more frequently than expected by chance alone. Males and females also inhabited the same host individual independent of the female gravid condition or of the developmental stage of brooded embryos. While the observations above argue in favor of monogamy in P. manningi, there is evidence to suggest that males of the studied species are moderately promiscuous. That females found living solitary in oysters most often brooded embryos, and that males allocated more to weaponry (major claw size) than females at any given size suggest that males might be roaming among host individuals in search of and, fighting for, receptive females. All available information depicts a rather complex mating system in P. manningi: primarily monogamous but with moderately promiscuous males. PMID- 26934110 TI - Mediational pathways connecting secondary education and age at marriage to maternal mortality: A comparison between developing and developed countries. AB - While studies have shown that maternal mortality rates have been improving worldwide, rates are still high across developing nations. In general, poor health of women is associated with higher maternal mortality rates in developing countries. Understanding country-level risk factors can inform intervention and prevention efforts that could bring high maternal mortality rates down. Specifically, the authors were interested in investigating whether: (1) secondary education participation (SEP) or age at marriage (AM) of women were related to maternal mortality rates, and (2) adolescent birth rate and contraceptive use (CU) acted as mediators of this association. The authors add to the literature with this current article by showing the relation of SEP and AM to maternal mortality rates globally (both directly and indirectly through mediators) and then by comparing differences between developed and developing/least developed countries. Path analysis was used to test the hypothesized model using country level longitudinal data from 2000 to 2010 obtained from United Nations publications, World Health Organization materials, and World Bank development reports. Findings include a significant correlation between SEP and AM for developing countries; for developed countries the relation was not significant. As well, SEP in developing countries was associated with increased CU. Women in developing countries who finish school before marriage may have important social capital gains. PMID- 26934111 TI - Transfer of thallium from rape seed to rape oil is negligible and oil is fit for human consumption. AB - Rape and other Brassicaceae family plants can accumulate appreciable amounts of thallium from the soil. Because some species of this family are common crops utilised as food for direct consumption or raw materials for food production, thallium can enter the food chain. A useful method for thallium determination is inductively coupled plasma mass spectrometry. The limit of detection (0.2 pg ml( 1) Tl or 0.02 ng g(-1) Tl, taking in the account dilution during sample decomposition) found in the current study was very low, and the method can be used for ultra-trace analysis. Possible transfer of thallium from rape seed to the rape oil was investigated in two ways. The balance of thallium in rape seed meal (content 140-200 ng g(-1) Tl) and defatted rape seed meal indicated that thallium did not pass into the oil (p < 0.05). Moreover, the analyses of thallium in six kinds of edible rape seed oil and three kinds of margarines showed that the amount of thallium in rape seed oil is negligible. PMID- 26934112 TI - Honing the Priorities and Making the Investment Case for Global Health. AB - In the aftermath of the Ebola crisis, the global health community has a unique opportunity to reflect on the lessons learned and apply them to prepare the world for the next crisis. Part of that preparation will entail knowing, with greater precision, what the scale and scope of our specific global health challenges are and what resources are needed to address them. However, how can we know the magnitude of the challenge, and what resources are needed without knowing the current status of the world through accurate primary data? Once we know the current status, how can we decide on an intervention today with a predicted impact decades out if we cannot project into that future? Making a case for more investments will require not just better data generation and sharing but a whole new level of sophistication in our analytical capability--a fundamental shift in our thinking to set expectations to match the reality. In this current status of a distributed world, being transparent with our assumptions and specific with the case for investing in global health is a powerful approach to finding solutions to the problems that have plagued us for centuries. PMID- 26934114 TI - Excitation dependent multicolor emission and photoconductivity of Mn, Cu doped In2S3 monodisperse quantum dots. AB - Indium sulphide (In2S3) quantum dots (QDs) of average size 6 +/- 2 nm and hexagonal nanoplatelets of average size 37 +/- 4 nm have been synthesized from indium myristate and indium diethyl dithiocarbamate precursors respectively. The absorbance and emission band was tuned with variation of nanocrytal size from very small in the strong confinement regime to very large in the weak confinement regime. The blue emission and its shifting with size has been explained with the donor-acceptor recombination process. The 3d element doping (Mn(2+) and Cu(2+)) is found to be effective for formation of new emission bands at higher wavelengths. The characteristic peaks of Mn(2+) and Cu(2+) and the modification of In(3+) peaks in the x-ray photoelectric spectrum (XPS) confirm the incorporation of Mn(2+) and Cu(2+) into the In2S3 matrix. The simulation of the electron paramagnetic resonance signal indicates the coexistence of isotropic and axial symmetry for In and S vacancies. Moreover, the majority of Mn(2+) ions and sulphur vacancies (VS ) reside on the surface of nanocrystals. The quantum confinement effect leads to an enhancement of band gap up to 3.65 eV in QDs. The formation of Mn 3d levels between conduction band edge and shallow donor states is evidenced from a systematic variation of emission spectra with the excitation wavelength. In2S3 QDs have been established as efficient sensitizers to Mn and Cu emission centers. Fast and slow components of photoluminescence (PL) decay dynamics in Mn and Cu doped QDs are interpreted in terms of surface and bulk recombination processes. Fast and stable photodetctors with high photocurrent gain are fabricated with Mn and Cu doped QDs and are found to be faster than pure In2S3. The fastest response time in Cu doped QDs is an indication of the most suitable system for photodetector devices. PMID- 26934113 TI - Land Use Influences Niche Size and the Assimilation of Resources by Benthic Macroinvertebrates in Tropical Headwater Streams. AB - It is well recognized that assemblage structure of stream macroinvertebrates changes with alterations in catchment or local land use. Our objective was to understand how the trophic ecology of benthic macroinvertebrate assemblages responds to land use changes in tropical streams. We used the isotope methodology to assess how energy flow and trophic relations among macroinvertebrates were affected in environments affected by different land uses (natural cover, pasture, sugar cane plantation). Macroinvertebrates were sampled and categorized into functional feeding groups, and available trophic resources were sampled and evaluated for the isotopic composition of 13C and 15N along streams located in the Cerrado (neotropical savanna). Streams altered by pasture or sugar cane had wider and more overlapped trophic niches, which corresponded to more generalist feeding habits. In contrast, trophic groups in streams with native vegetation had narrower trophic niches with smaller overlaps, suggesting greater specialization. Pasture sites had greater ranges of resources exploited, indicating higher trophic diversity than sites with natural cover and sugar cane plantation. We conclude that agricultural land uses appears to alter the food base and shift macroinvertebrate assemblages towards more generalist feeding behaviors and greater overlap of the trophic niches. PMID- 26934115 TI - Collective superlubricity of graphene flakes. AB - We investigate solid lubrication of graphene and graphene flakes using atomistic molecular-dynamics simulations. We find that graphene flakes yield lower friction than graphene as a result of a collective mechanism that emerges from the independent behaviour of the flakes. By freezing out different degrees of freedom of the flakes, we are able to attribute the low friction to non-simultaneous slipping of the individual flakes. We also compare the results of the atomistic simulations to those of a simplified two-dimensional model and find that the behaviour of the latter is strongly dependent on parameters, which emerge naturally from the atomistic simulations. PMID- 26934117 TI - Fiber analysis vignettes: Electron microscopy to the rescue! AB - There has been considerable interest in the exposure doses that contribute to the various asbestos-associated diseases. Epidemiological studies have shown important differences in the contributions of the various fiber types to asbestos related diseases, with the amphiboles showing a greater degree of potency as compared to chrysotile. However, epidemiological studies have occasionally provided misleading results. Over the past several decades, there have been several examples where fiber analysis using electron microscopy produced unexpected results which were important to our understanding of disease-exposure relationships. It is the purpose of this article to summarize these fiber analysis vignettes. PMID- 26934118 TI - Commentary on 'Transnational connections of health professionals: medicoscapes and assisted reproduction in Ghana and Uganda', by Viola Horbst and Trudie Gerrits. PMID- 26934116 TI - Clinical and structural remission rates increased annually and radiographic progression was continuously inhibited during a 3-year administration of tocilizumab in patients with rheumatoid arthritis: A multi-center, prospective cohort study by the Michinoku Tocilizumab Study Group. AB - OBJECTIVE: To evaluate the clinical and structural efficacy of tocilizumab (TCZ) during its long-term administration in patients with rheumatoid arthritis (RA). METHODS: In total, 693 patients with RA who started TCZ therapy were followed for 3 years. Clinical efficacy was evaluated by DAS28-ESR and Boolean remission rates in 544 patients. Joint damage was assessed by calculating the modified total Sharp score (mTSS) in 50 patients. RESULTS: When the reason for discontinuation was limited to inadequate response or adverse events, the 1-, 2-, and 3-year continuation rates were 84.0%, 76.8%, and 72.2%, respectively. The mean DAS28-ESR was initially 5.1 and decreased to 2.5 at 6 months and to 2.2 at 36 months. The Boolean remission rate was initially 0.9% and increased to 21.7% at 6 months and to 32.2% at 36 months. The structural remission rates (DeltamTSS/year <= 0.5) were 68.8%, 78.6%, and 88.9% within the first, second, and third years, respectively. The structural remission rate at 3 years (DeltamTSS <= 1.5) was 66.0%, and earlier achievement of swollen joint count (SJC) of 1 or less resulted in better outcomes. CONCLUSIONS: TCZ was highly efficacious, and bone destruction was strongly prevented. SJC was an easy-to-use indicator of joint destruction. PMID- 26934119 TI - Radiation-induced brachial plexopathy in patients with nasopharyngeal carcinoma: a retrospective study. AB - Radiation-induced brachial plexopathy (RIBP) is one of the late complications in nasopharyngeal carcinoma (NPC) patients who received radiotherapy. We conducted a retrospective study to investigate its clinical characteristics and risk factors.Thirty-onepatients with RIBP after radiotherapy for NPC were enrolled. Clinical manifestations of RIBP, electrophysiologic data, magnetic resonance imaging (MRI), and the correlation between irradiation strategy and incidence of RIBP were evaluated. The mean latency at the onset of RIBP was 4.26 years. Of the symptoms, paraesthesia usually presented first (51.6%), followed by pain (22.6%) and weakness (22.6%). The major symptoms included paraesthesia (90.3%), pain (54.8%), weakness (48.4%), fasciculation (19.3%) and muscle atrophy (9.7%). Nerve conduction velocity (NCV) and electromyography (EMG) disclosed that pathological changes of brachial plexus involved predominantly in the upper and middle trunks in distribution. MRI of the brachial plexus showed hyper-intensity on T1, T2, post-contrast T1 and diffusion weighted whole body imaging with background body signal suppression (DWIBS) images in lower cervical nerves. Radiotherapy with Gross Tumor volume (GTVnd) and therapeutic dose (mean 66.8+/-2.8Gy) for patients with lower cervical lymph node metastasis was related to a significantly higher incidence of RIBP (P<0.001).Thus, RIBP is a severe and progressive complication of NPC after radiotherapy. The clinical symptoms are predominantly involved in upper and middle trunk of the brachial plexus in distribution. Lower cervical lymph node metastasis and corresponding radiotherapy might cause a significant increase of the RIBP incidence. PMID- 26934120 TI - Protein arginine methyltransferase 1 may be involved in pregnane x receptor activated overexpression of multidrug resistance 1 gene during acquired multidrug resistant. AB - PURPOSE: Pregnane x receptor (PXR) - activated overexpression of the multidrug resistance 1 (MDR1) gene is an important way for tumor cells to acquire drug resistance. However, the detailed mechanism still remains unclear. In the present study, we aimed to investigate whether protein arginine methyl transferase 1(PRMT1) is involved in PXR - activated overexpression of MDR1 during acquired multidrug resistant. EXPERIMENTAL DESIGN: Arginine methyltransferase inhibitor 1 (AMI-1) was used to pharmacologically block PRMT1 in resistant breast cancer cells (MCF7/adr). The mRNA and protein levels of MDR1 were detected by real-time PCR and western blotting analysis. Immunofluorescence microscopy and co immunoprecipitation were used to investigate the physical interaction between PXR and PRMT1. Then, 136 candidate compounds were screened for PRMT1 inhibitors. Lastly, luciferase reporter gene and nude mice bearing resistant breast cancer xenografts were adopted to investigate the anti-tumor effect of PRMT1 inhibitors when combined with adriamycin. RESULTS: AMI-1 significantly suppressed the expression of MDR1 in MCF7/adr cells and increased cells sensitivity of MCF7/adr to adriamycin. Physical interaction between PRMT1 and PXR exists in MCF7/adr cells, which could be disrupted by AMI-1. Those results suggest that PRMT1 may be involved in PXR-activated overexpression of MDR1 in resistant breast cancer cells, and AMI-1 may suppress MDR1 by disrupting the interaction between PRMT1 and PXR. Then, five compounds including rutin, isoquercitrin, salvianolic acid A, naproxen, and felodipline were identified to be PRMT1 inhibitors. Finally, those PRMT1 inhibitors were observed to significantly decrease MDR1 promoter activity in vitro and enhance the antitumor effect of adriamycin in nude mice that bearing resistant breast cancer xenografts. CONCLUSIONS: PRMT1 may be an important co activator of PXR in activating MDR1 gene during acquired resistance, and PRMT1 inhibitor combined with chemotherapy drugs may be a new strategy for overcoming tumor MDR. PMID- 26934122 TI - The effects of curcumin (diferuloylmethane) on body composition of patients with advanced pancreatic cancer. AB - BACKGROUND: Curcumin is a natural product that is often explored by patients with cancer. Weight loss due to fat and muscle depletion is a hallmark of pancreatic cancer and is associated with worse outcomes. Studies of curcumin's effects on muscularity show conflicting results in animal models. METHODS AND RESULTS: Retrospective matched 1:2 case-control study to evaluate the effects of curcumin on body composition (determined by computerized tomography) of 66 patients with advanced pancreatic cancer (22 treated,44 controls). Average age (SEM) was 63(1.8) years, 30/66(45%) women, median number of prior therapies was 2, median (IQR) time from advanced pancreatic cancer diagnosis to baseline image was 7(2 13.5) months (p>0.2, all variables). All patients lost weight (3.3% and 1.3%, treated vs. control, p=0.13). Treated patients lost more muscle (median [IQR] percent change -4.8[-9.1,-0.1] vs. -0.05%[-4.2, 2.6] in controls,p<0.001) and fat (median [IQR] percent change -6.8%[-15,-0.6] vs. -4.0%[-7.6, 1.3] in controls,p=0.04). Subcutaneous fat was more affected in the treated patients. Sarcopenic patients treated with curcumin(n=15) had survival of 169(115-223) days vs. 299(229-369) sarcopenic controls(p=0.024). No survival difference was found amongst non-sarcopenic patients. CONCLUSIONS: Patients with advanced pancreatic cancer treated with curcumin showed significantly greater loss of subcutaneous fat and muscle than matched untreated controls. PMID- 26934121 TI - Reactivation of epigenetically silenced miR-124 reverses the epithelial-to mesenchymal transition and inhibits invasion in endometrial cancer cells via the direct repression of IQGAP1 expression. AB - Overexpression of IQGAP1 and microRNA (miRNA) dysregulation are frequent in human tumors, but little is known about the role of IQGAP1 and its relationship to miRNA in endometrial carcinogenesis. We demonstrate that IQGAP1 activates the epithelial-mesenchymal transition (EMT) program and that miR-124 directly represses IQGAP1 expression in endometrial cancer (EC) cells. The overexpression of IQGAP1 stimulates EMT features and enhances migration, invasion and proliferation of EC cells, whereas knocking down IQGAP1 expression reverses EMT and inhibits these malignant properties. Using miRNA microarray profiling, we identified 29 miRNAs (let-7b, let-7f, miR-10b, miR-15b, miR-23a, miR-24, miR-25, miR-27a, miR-29b, miR-30a-5p, miR-34a, miR-124, miR-127, miR-130b, miR-148a, miR 155, miR-191*, miR-194, miR-224, miR-362, miR-409-3p, miR-422b, miR-424, miR-453, miR-497, miR-518d, miR-518f*, miR-526a and miR-656) that are significantly down regulated in an in vitro-selected highly invasive derivative cell line (HEC-50 HI) relative to the parental HEC-50 cells. We further identified miR-124 as a direct regulator of IQGAP1 in EC cells. Enforced expression of miR-124 suppresses EC cell invasion and proliferation. The expression of IQGAP1 mRNA was significantly elevated in EC tissues, while the expression of miR-124 was decreased. The downregulation of miR-124 correlates with a poor survival outcome for patients with EC. Treating EC cells with the demethylating agent 5-aza-2' deoxycytidine increased miR-124 expression and down-regulated IQGAP1 levels. Our data suggest that IQGAP1 promotes EMT, migration and invasion of EC cells. MiR 124, a novel tumor suppressor miRNA that is epigenetically silenced in EC, can reverse EMT and the invasive properties, by attenuating the expression of the IQGAP1 oncogene. PMID- 26934123 TI - Gene modules associated with breast cancer distant metastasis-free survival in the PAM50 molecular subtypes. AB - To identify PAM50 subtype-specific associations between distant metastasis-free survival (DMFS) in breast cancer (BC) patients and gene modules describing potentially targetable oncogenic pathways, a comprehensive analysis evaluating the prognostic efficacy of published gene signatures in 2027 BC patients from 13 studies was conducted. We calculated 21 gene modules and computed hazard ratios (HRs) for DMFS for one-unit increases in module score, with and without adjustment for clinical characteristics. By comparing gene expression to survival outcomes, we derived four subtype-specific prognostic signatures for BC. Univariate and multivariate analyses showed that in the luminal A subgroup, E2F3, PTEN and GGI gene module scores were associated with clinical outcome. In the luminal B tumors, RAS was associated with DMFS and in the basal-like tumors, ER was associated with DMFS. Our defined gene modules predicted high-risk patients in multivariate analyses for the basal-like (HR: 2.19, p=2.5*10-4), luminal A (HR: 3.03, p=7.2*10-5), luminal B (HR: 3.00, p=2.4*10-10) and HER2+ (HR: 5.49, p=9.7*10-10) subgroups. We found that different modules are associated with DMFS in different BC subtypes. The results of this study could help to identify new therapeutic strategies for specific molecular subgroups of BC, and could enhance efforts to improve patient-specific therapy options. PMID- 26934124 TI - The roles of AKR1C1 and AKR1C2 in ethyl-3,4-dihydroxybenzoate induced esophageal squamous cell carcinoma cell death. AB - The aldo-keto reductase (AKR) superfamily of enzymes is critical for the detoxification of drugs and toxins in the human body; these enzymes are involved not only in the development of drug resistance in cancer cells but also in the metabolism of polycyclic aromatic hydrocarbons. Here, we demonstrated that AKR1C1/C2 increased the metabolism of ethyl-3,4-dihydroxybenzoate (EDHB) in esophageal squamous cell carcinoma (ESCC) cells. Previous studies have shown that EDHB can effectively induce esophageal cancer cell autophagy and apoptosis, and the AKR1C family represents one set of highly expressed genes after EDHB treatment. To explore the cytotoxic effects of EDHB, esophageal cancer cells with higher (KYSE180) or lower (KYSE510) AKR1C expression levels were evaluated in this study. The proliferation of KYSE180 cells was inhibited more effectively than that of KYSE510 cells by EDHB treatment. Furthermore, the effective subunits of the AKR superfamily, AKR1C1/C2, were quantitatively identified using multiple reaction monitoring (MRM) assays. The sensitivity of esophageal cancer cells to EDHB was significantly attenuated by the siRNA knockdown of AKR1C1/C2. Moreover, the expression of autophagy inducers (Beclin, LC3II and BNIP3) and NDRG1 was significantly elevated in KYSE180 cells, but not in KYSE510 cells, after EDHB treatment. When autophagy was inhibited by 3-methyladenine, KYSE180 cells exhibited an increased sensitivity to EDHB, which may be a metabolic substrate of AKR1C1/C2. These results indicated that ESCC patients with high AKR1C1/C2 expression may be more sensitive to EDHB, and AKR1C1/C2 may facilitate EDHB induced autophagy and apoptosis, thus providing potential guidance for the chemoprevention of ESCC. PMID- 26934126 TI - The role of ethylene in the regulation of ovary senescence and fruit set in tomato (Solanum lycopersicum). AB - Fruit set is the developmental transition from ovary to young fruit, and generally requires pollination and fertilization. Although the mechanism for fruit set remains elusive, several lines of evidence have demonstrated that fruit set is triggered by activated metabolism of or increased sensitivity to the plant hormones auxin or gibberellins (GAs), which stimulate cell division and expansion within the ovary. Our recent study with tomato (Solanum lycopersicum) suggested that the gaseous hormone ethylene connects auxin and GA, suppressing initiation of fruit set by down-regulating GA accumulation. By contrast, reduced sensitivity to ethylene triggers accumulation of GA, but not auxin, through increasing bioactive GA biosynthesis and decreasing GA inactivation. These changes induce parthenocarpy accompanied by pollination-independent cell expansion in the ovary. Here, we provide evidence that ethylene likely promotes mRNA expression of the senescence-associated genes SlSAG12 and SlNAP in unpollinated ovaries. These results suggest that ethylene acts downstream of auxin and upstream of GA, and also suggest that ethylene promotes senescence of ovary that fail to set fruit in tomato. PMID- 26934125 TI - The association between the TERT rs2736100 AC genotype and reduced risk of upper tract urothelial carcinomas in a Han Chinese population. AB - Upper tract urothelial carcinomas (UTUCs) are originated from urothelium, and consist of renal pelvic carcinomas (RPCs) and ureter carcinomas (UCs). Most UTUCs have already become invasive when diagnosed and there is thus a need to identify high-risk populations for preventive intervention. Recent evidence has accumulated supporting common single nucleotide polymorphisms (SNPs) to be associated with increased risk of various malignancies. However, little is known about susceptibility loci in relation to UTUC development. We genotyped telomerase reverse transcriptase (TERT) rs2736100 variants, the SNP associated with a risk of multiple-types of cancer, in patients with UTUC (n = 212) and evaluated the relationship between the rs2736100 and UTUC risk by comparing to 289 healthy controls. Neither AA nor CC genotypes differed significantly between cases and controls, while the AC-carriers were associated with a reduced risk of UTUC compared to the homozygous AA (OR = 0.583; 95% CI: 0.388 - 0.875; P = 0.012) or AA + CC genotypes (0.613; 95% CI: 0.428 - 0.879; P = 0.010). Further analyses showed that the AC variant conferred a lower risk for early stage UTUCs or those with a wt TERT promoter. When UTUCs were sub-grouped into UCs and RPCs, the AC genotype still predicts a significantly lower risk for UC (P = 0.045, OR = 0.597, 95% CI: 0.370 - 0.963), while at a border line significance for RPC (P = 0.055, OR = 0.597, 95% CI: 0.324 - 0.976). Collectively, the rs2736100 AC variant predicts a reduced risk to develop UTUC. PMID- 26934128 TI - Efficacy and safety of a premixed versus a basal-plus insulin regimen as intensification for type 2 diabetes by timing of the main meal. AB - OBJECTIVE: To describe the efficacy and safety of premixed insulin lispro protamine suspension 75%/insulin lispro solution 25% (LM25) twice daily (bid) versus basal insulin glargine plus prandial insulin lispro (IGL), both once daily, according to main meal timing. METHODS: Data were obtained post hoc from a 24 week, randomized, open-label study comparing LM25 and IGL as insulin intensification in patients with type 2 diabetes inadequately controlled with once daily basal insulin glargine plus metformin and/or pioglitazone (ClinicalTrials.gov identifier: NCT01175824). Patients administered LM25 bid before breakfast and the evening meal, insulin glargine at bedtime and insulin lispro before the day's main meal (meal with the highest 2 hour postprandial glucose level during screening). Patients were grouped by main meal. Changes in glycosylated hemoglobin (HbA1c) and bodyweight were summarized using likelihood based mixed models; hypoglycemia incidence was compared between treatments using Fisher's exact test. RESULTS: Overall, 476 patients (LM25, n = 236; IGL, n = 240) were randomized. In all main meal groups, with both insulin regimens, mean HbA1c significantly decreased from baseline to 24 weeks (p < 0.0001). Patients whose main meal was in the evening had a greater bodyweight increase with LM25 than with IGL (p = 0.015), and a smaller proportion of these patients experienced total (p = 0.027) and nocturnal (p = 0.006) hypoglycemia with LM25 compared with IGL. Patients whose main meal was lunch experienced more nocturnal hypoglycemia with LM25 than with IGL (p = 0.030). Study limitations include that this was a post hoc analysis and no assessments ensured that: SMBG results determined timing of the main meal, each patient's main meal remained unchanged throughout the study, or patients administered insulin lispro with that meal. CONCLUSIONS: Glycemic control improved in patients receiving either LM25 or IGL, irrespective of main meal timing. Both regimens can be used in patients with inadequate glycemic control who are in need of insulin intensification. PMID- 26934127 TI - Body mass index and treatment outcomes following neoadjuvant therapy in women aged 45 y or younger: Evidence from a historic cohort. AB - PURPOSE: Large and consistent evidence supports the role of body mass index (BMI) as a prognostic and predictive indicator in breast cancer. However, there is paucity of data specifically referred to women diagnosed at a young age across the different disease settings. We investigated the impact of BMI on treatment outcomes in 86 breast cancer patients aged 45 y or less treated with neoadjuvant chemotherapy (CT) followed by surgery. METHODS: Pathologic complete response (pCR) was defined as the eradication of cancer from both breast and lymph nodes. Overall survival (OS) and disease-free survival (DFS) were calculated using the Kaplan-Meier product-limit method. Curves were compared by long rank test for significance. Potential predictors of survival were tested in Cox models. RESULTS: We observed a pCR in 19 patients (22%). Lower values of BMI were more commonly associated with pCR (p = 0.05). Results from univariate, but not multivariate, models were somewhat supportive of higher pCR rates in leaner women (p = 0.06). None of the variables impacted DFS. OS was longer in leaner patients (medians and 95%CI: 74.6 months, 66.2-82.9 and 58.5 months, 49.6-67.4, p = 0.009). Longer OS was also related to lower T-stage, adjuvant radiotherapy (RT), and non triple negative (TN) subtype (p = 0.046, p = 0.024, and p = 0.015, respectively). Cox models confirmed the protective role of lower BMI (Hazard Ratios: 0.30, 95%CI: 0.12-0.71, p = 0.007), non TN subtype and adjuvant RT (p = 0.008 and p = 0.024). CONCLUSIONS: In young breast cancer patients treated with neoadjuvant CT followed by surgery, lower values of BMI are associated with longer OS. Our data also showed longer OS in association with a non TN molecular subtype and adjuvant RT. The modifiable nature of BMI and aggressive biologic behavior of the disease diagnosed at a young age encourage further studies to corroborate our findings. PMID- 26934129 TI - Soluble CD40L is associated with insulin resistance, but not with glucose tolerance in obese nondiabetic patients. AB - OBJECTIVE: The soluble platelet secreted ligand CD40 (sCD40L) has a role in atherosclerosis progression. The aim of the present study was to investigate the link between the levels of sCD40L and some classical cardiovascular risk factors in obese nondiabetic patients. METHODS: In the present cross-sectional study, we included76 patients with mean age of 50.7 +/- 10.7 years. Oral glucose tolerance test (OGTT) was performed in all participants and levels of sCD40L were measured using enzyme-linked immunosorbent assay (ELISA) method. RESULTS: We found significantly higher levels in patients with insulin resistance compared to those without (6.4 +/- 3.7 vs. 4.1 +/- 2.4 ng/ml, r = 0.025) and only a tendency toward higher levels in prediabetes compared to normoglycemic patients (5.9 +/- 3.6 vs. 5.3 +/- 3.4 ng/ml). There was no correlation between sCD40L and platelet count, systolic and diastolic blood pressure and lipid profile. CONCLUSIONS: The main factor for increased sCD40L plasma levels was the presence of insulin resistance and not the state of glucose tolerance. PMID- 26934132 TI - Author Response: Choroidal Abnormalities Detected by Near-Infrared Imaging (NIR) in Pediatric Patients With Neurofibromatosis Type 1 (NF1). PMID- 26934131 TI - Choroidal Abnormalities Detected by Near-Infrared Imaging (NIR) in Pediatric Patients With Neurofibromatosis Type 1 (NF1). PMID- 26934133 TI - The Effect of A2A Receptor Antagonist on Microglial Activation in Experimental Glaucoma. AB - PURPOSE: We investigated the effect of A2A receptor (A2AR) antagonist on microglial activation and retinal ganglion cell (RGC) survival under chronic ocular hypertension (COH), and explored the relationship between microglial activation and RGC survival by means of in vitro and in vivo experiments. METHODS: An animal model of COH was induced in one eye of male Sprague-Dawley (SD) rats by ligation of three episcleral veins. The survival of RGCs and the activation of microglia under COH without or with intravitreous injection of A2AR antagonist ZM241385 were assessed by fluorescent labeling, real time PCR and Western blot. ELISA was used to measure the secretion of inflammatory mediators by microglia when glutamate and/or ZM241385 was added into the culture system. RESULTS: Compared to the baseline, RGC density 2 weeks after COH induction decreased at the central (2436 +/- 143 cells/mm2 pre- and 2130 +/- 148 cells/mm2 post-COH induction) and peripheral (2219 +/- 140 cells/mm2 pre- and 1953 +/- 142 cells/mm2 post-COH induction) retina. The microglia changed their ramified morphology to an amoeboid form with increase in TNF-alpha and IL-1beta expression after COH. These changes, however, were ameliorated with intravitreous ZM241385 (RGC density only dropped to 2287 +/- 135 cells/mm2). The upregulation of those proinflammatory cytokines secreted by microglia in vitro under high concentration of glutamate was downregulated when ZM241385 was added into the culture system. CONCLUSIONS: A2AR antagonist ZM241385 could reduce the activation of microglia and downregulate the proinflammatory cytokines expression under the conditions of COH and high concentration of glutamate, which may be one of the mechanisms that protected RGCs in experimental glaucoma. PMID- 26934135 TI - A Robust and Reliable Test to Measure Stereopsis in the Clinic. AB - PURPOSE: The purpose of this study was to develop a convenient test of stereopsis in the clinic that is both robust and reliable and capable of providing a measure of variability necessary to make valid comparisons between measurements obtained at different occasions or under different conditions. METHODS: Stereo acuity was measured based on principles derived from the laboratory measurement of stereopsis (i.e., staircase method). Potential premeasurement compensations are described if there is a significant degree of ocular misalignment, reduced visual acuity, or aniseikonia. Forty-six adults at McGill University, 44 adults at Auckland University, and 51 adults from the University of Bradford, with an age range of 20 to 65 years old and normal or corrected-to-normal vision participated in this study. RESULTS: Stereo acuity within this normal population was widely distributed, with a significant percentage (28%) of the population with only coarse stereo (>300 arc seconds). Across subjects, the SD was approximately 25% of the mean. Measurements at two different times were strongly (r = 0.79) and significantly (P < 0.001) correlated, with little to no significant (P = 0.79) bias (0.01) between test and retest measures of stereopsis. CONCLUSIONS: The application enables measurements over the wide disparity range and not just at the finest disparities. In addition, it allows changes in stereopsis of the order of 1.9 to be statistically distinguished. PMID- 26934134 TI - Role of RDS and Rhodopsin in Cngb1-Related Retinal Degeneration. AB - PURPOSE: Rod photoreceptor outer segment (OS) morphogenesis, structural integrity, and proper signal transduction rely on critical proteins found in the different OS membrane domains (e.g., plasma, disc, and disc rim membrane). Among these key elements are retinal degeneration slow (RDS, also known as peripherin 2), rhodopsin, and the beta subunit of the cyclic nucleotide gated channel (CNGB1a), which have been found to interact in a complex. The purpose of this study was to evaluate the potential interplay between these three proteins by examining retinal disease phenotypes in animal models expressing varying amounts of CNGB1a, rhodopsin, and RDS. METHODS: Outer segment trafficking, retinal function, and photoreceptor structure were evaluated using knockout mouse lines. RESULTS: Eliminating Cngb1 and reducing RDS leads to additive defects in RDS expression levels and rod electroretinogram (ERG) function, (e.g., Cngb1-/-/rds+/ versus rds+/- or Cngb1-/-) but not to additive defects in rod ultrastructure. These additive effects also manifested in cone function: Photopic ERG responses were significantly lower in the Cngb1-/-/rds+/- versus rds+/- or Cngb1-/-, suggesting that eliminating Cngb1 can accelerate the cone degeneration that usually presents later in the rds+/-. This was not the case with rhodopsin; reducing rhodopsin levels in concert with eliminating CNGB1a did not lead to phenotypes more severe than those observed in the Cngb1 knockout alone. CONCLUSIONS: These data support a role for RDS as the core component of a multiprotein plasma membrane-rim-disc complex that has both a structural role in photoreceptor OS formation and maintenance and a functional role in orienting proteins for optimal signal transduction. PMID- 26934130 TI - Neurobehavioral assessment of maternal odor in developing rat pups: implications for social buffering. AB - Social support can attenuate the behavioral and stress hormone response to threat, a phenomenon called social buffering. The mother's social buffering of the infant is one of the more robust examples; yet we understand little about the neurobiology. Using a rodent model, we explore the neurobiology of social buffering by assessing neural processing of the maternal odor, a major cue controlling social buffering in rat pups. We used pups before (postnatal day (PN) 7) and after (PN14, PN23) the functional emergence of social buffering. Pups were injected with 14C 2-deoxyglucose (2-DG) and presented with the maternal odor, a control preferred odor incapable of social buffering (acetophenone), or no odor. Brains were removed, processed for autoradiography and brain areas identified as important in adult social buffering were assessed, including the amygdala basolateral complex (Basolateral Amygdala [BLA]), medial prefrontal cortex (mPFC), and anterior cingulate cortex (ACC). Results suggest dramatic changes in the processing of maternal odor. PN7 pups show mPFC and ACC activation, although PN14 pups showed no activation of the mPFC, ACC, or BLA. All brain areas assessed were recruited by PN23. Additional analysis suggests substantial changes in functional connectivity across development. Together, these results imply complex nonlinear transitions in the neurobiology of social buffering in early life that may provide insight into the changing role of the mother in supporting social buffering. PMID- 26934138 TI - Light Levels and the Development of Deprivation Myopia. PMID- 26934137 TI - Natural Killer T Cells Contribute to Neutrophil Recruitment and Ocular Tissue Damage in a Model of Intraocular Tumor Rejection. AB - PURPOSE: Immune privilege of the eye protects the nonregenerative ocular tissues from innate and adaptive immune-mediated inflammation. In the case of intraocular tumors, immune privilege can be arrested to allow for immune-mediated rejection. Activation of innate immune cells can contribute to necrosis of the intraocular tumor and bystander ocular tissue. Identifying the cellular components of the innate immune system that contribute to ocular destruction, but are not needed for tumor rejection, provides insights into the immunopathological sequelae in intraocular tumor rejection. METHODS: Wild-type (WT), Jalpha18 knockout (KO) mice lacking type I natural killer T (NKT) cells, and CD1d KO mice lacking all NKT cells, were used to identify the role of type II NKT cells in intraocular tumor rejection immunopathology. RESULTS: CD1d KO mice had significantly lowered rates of necrotic eye destruction during tumor rejection compared to WT or Jalpha18 KO mice. Transcriptome and protein analyses revealed that CD1d KO mice had significantly lower expression of CXCL3 compared to WT or Jalpha18 KO mice, and this was associated with decreased neutrophil recruitment. The presence of type II NKT cells in WT or Jalpha18 KO mice led to increased CXCL3, which attracted neutrophils to the intraocular tumor and culminated in destruction of the eye. CONCLUSIONS: We found that type II NKT cells are critical in initiating a damaging inflammatory antitumor response involving the recruitment of neutrophils that compromises the integrity of the eye. Loss of type II NKT cells or depleting neutrophils allows for a productive intraocular tumor response that converts the rejection phenotype to preserve the eye. PMID- 26934139 TI - Author Response: Light Levels and the Development of Deprivation Myopia. PMID- 26934141 TI - Fluorescence Lifetime Imaging in Stargardt Disease: Potential Marker for Disease Progression. AB - PURPOSE: The purpose of this study was to describe autofluorescence lifetime characteristics in Stargardt disease (STGD) using fluorescence lifetime imaging ophthalmoscopy (FLIO) and to investigate potential prognostic markers for disease activity and progression. METHODS: Fluorescence lifetime data of 16 patients with STGD (mean age, 40 years; range, 22-56 years) and 15 age-matched controls were acquired using a fluorescence lifetime imaging ophthalmoscope based on a Heidelberg Engineering Spectralis system. Autofluorescence was excited with a 473 nm laser, and decay times were measured in a short (498-560 nm) and long (560-720 nm) spectral channel. Clinical features, autofluorescence lifetimes and intensity, and corresponding optical coherence tomography images were analyzed. One-year follow-up examination was performed in eight STGD patients. Acquired data were correlated with in vitro measured decay times of all-trans retinal and N-retinylidene-N-retinylethanolamine. RESULTS: Patients with STGD displayed characteristic autofluorescence lifetimes within yellow flecks (446 ps) compared with 297 ps in unaffected areas. In 15% of the STGD eyes, some flecks showed very short fluorescence lifetimes (242 ps). Atrophic areas were characterized by long lifetimes (474 ps), with some remaining areas of normal to short lifetimes (322 ps) toward the macular center. CONCLUSIONS: Patients with recent disease onset showed flecks with very short autofluorescence lifetimes, which is possible evidence of accumulation of retinoids deriving from the visual cycle. During the study period, many of these flecks changed to longer lifetimes, possibly due to accumulation of lipofuscin. Therefore, FLIO might serve as a useful tool for monitoring of disease progression. (ClinicalTrials.gov number, NCT01981148.). PMID- 26934140 TI - Effects of Dorzolamide on Retinal and Choroidal Blood Flow in the DBA/2J Mouse Model of Glaucoma. AB - PURPOSE: To test the hypothesis that acute topical dorzolamide (DZ) decreases intraocular pressure (IOP) and increases retinal and choroidal blood flow in the DBA/2J mouse model of glaucoma. METHODS: Retinal and choroidal blood flow were measured in 4- and 9-month-old DBA/2J mice, and 4-month C57BL/6 (control) mice under isoflurane anesthesia using magnetic resonance imaging. Ocular blood flow was measured at baseline, and 1 and 2 hours after topical dorzolamide. Intraocular pressure was measured using a rebound tonometer in a subset of animals at the same time points. RESULTS: Baseline IOP in the 4-month-old DBA/2J mice and C57BL/6 mice was not significantly different (P > 0.05), and IOP in both groups was less than in the 9-month-old DBA/2J mice (P < 0.05 for both). Compared to baseline, dorzolamide reduced IOP at 1 and 2 hours after dorzolamide in the 4- (P < 0.05) and 9-month-old (P < 0.01) DBA/2J mice, but not in the C57BL/6J mice (P > 0.05). Baseline retinal blood flow was lower in the 4-month and 9-month-old DBA/2J mice compared with the 4-month-old C57BL/6J mice (P < 0.05). Baseline choroidal blood flow in the 9-month-old DBA/2J mice was less than in the C57BL/6J mice (P < 0.05). Compared with baseline, both retinal and choroidal blood flow increased at 1-hour post-dorzolamide and remained elevated 2 hours later in the 9 month-old DBA/2J mice (P < 0.05). CONCLUSIONS: Dorzolamide lowers IOP and raises retinal and choroidal blood flow in older DBA/2J mice, consistent with the study hypothesis. PMID- 26934142 TI - Platelet-Derived Growth Factor Preserves Retinal Synapses in a Rat Model of Ocular Hypertension. AB - PURPOSE: Platelet-derived growth factor (PDGF) promotes neuronal survival in experimental glaucoma and recruits glial cells that regulate synapses. We investigated the effects of intravitreal PDGF on the inflammatory milieu and retinal synapses in the presence of raised IOP. METHODS: Animals with laser induced IOP elevation received intravitreal injections of either saline or 1.5 MUg PDGF. At 7 days, a further intravitreal injection was administered so groups received "PDGF-saline" (n = 15), "PDGF-PDGF" (n = 13), or "saline-saline" (n = 20). Platelet-derived growth factor receptor activation was assessed after 2 weeks using Western blot for PI3 kinase. Immunohistochemistry was performed for markers of synapses in the inner plexiform layer (IPL): PSD-95, GluR1, SY38; RGCs: betaIII-tubulin, and glial cells: Iba-1, CD45. Real-time quantitative polymerase chain reaction (qPCR) was performed for Arc, selp, MCP-1, IL-6, IL-10, and CX3CR1 (n = 13). RESULTS: A single injection of PDGF increased IPL synaptic density in high IOP eyes (PSD-95 = 8.65 +/- 0.43, SY38 = 8.68 +/- 0.51, GluR1 = 9.03 +/- 0.60 puncta/MUm3, P < 0.001) and expression of synaptic modulator Arc (6.92 +/- 3.71-fold change/control, P < 0.05) in comparison with vehicle (PSD-95 = 4.59 +/- 0.41, SY38 = 4.46 +/- 0.38, GluR1 = 5.94 +/- 0.50 puncta/MUm3, Arc = 1.46 +/- 0.31-fold/control). This was associated with more resident microglia (8.16 +/- 1.34-fold change/control, P < 0.001) and infiltrating monocyte-derived macrophages in the retina as well as increased Selp expression (26.8 +/- 14.12 fold change/control, P < 0.05). Optic nerve head (ONH) showed an increased microglia (saline = 1.44 +/- 0.13 versus PDGF = 2.23 +/- 0.18-fold change/control, P < 0.01) but not infiltrating macrophages. IL-10 expression was significantly increased in PDGF-treated eyes (5.43 +/- 0.47-fold change/control, P < 0.05) relative to vehicle (2.51 +/- 0.67-fold change/control). CONCLUSIONS: Platelet-derived growth factor increased microglial and monocyte-derived macrophage populations in the eye and protected intraretinal synapses from degeneration in our experimental glaucoma model. PMID- 26934136 TI - Visual Field Outcomes for the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT). AB - PURPOSE: The Idiopathic Intracranial Hypertension Treatment Trial (IIHTT) showed that acetazolamide provided a modest, significant improvement in mean deviation (MD). Here, we further analyze visual field changes over the 6-month study period. METHODS: Of 165 subjects with mild visual loss in the IIHTT, 125 had perimetry at baseline and 6 months. We evaluated pointwise linear regression of visual sensitivity versus time to classify test locations in the worst MD (study) eye as improving or not; pointwise changes from baseline to month 6 in decibels; and clinical consensus of change from baseline to 6 months. RESULTS: The average study eye had 36 of 52 test locations with improving sensitivity over 6 months using pointwise linear regression, but differences between the acetazolamide and placebo groups were not significant. Pointwise results mostly improved in both treatment groups with the magnitude of the mean change within groups greatest and statistically significant around the blind spot and the nasal area, especially in the acetazolamide group. The consensus classification of visual field change from baseline to 6 months in the study eye yielded percentages (acetazolamide, placebo) of 7.2% and 17.5% worse, 35.1% and 31.7% with no change, and 56.1% and 50.8% improved; group differences were not statistically significant. CONCLUSIONS: In the IIHTT, compared to the placebo group, the acetazolamide group had a significant pointwise improvement in visual field function, particularly in the nasal and pericecal areas; the latter is likely due to reduction in blind spot size related to improvement in papilledema. (ClinicalTrials.gov number, NCT01003639.). PMID- 26934143 TI - Iron Parameters Determine the Prognosis of Critically Ill Patients. AB - OBJECTIVE: Because iron is both an essential and toxic micronutrient influencing the development of microbial infections, we evaluated the usefulness of iron parameters as outcome predictors in ICU patients. DESIGN: Prospective clinical single-center non-interventional study. SETTING: General internal medicine ICU; German University hospital. PATIENTS: One hundred and twelve septic and 43 nonseptic ICU patients, 156 healthy blood donors. MEASUREMENTS AND MAIN RESULTS: Serum iron parameters at admission were correlated with short and long term mortality in ICU subjects. Both hepcidin and ferritin concentrations were significantly elevated in ICU patients compared with blood donors and were the highest in septic patients. On the contrary, serum iron and transferrin levels were decreased in ICU subjects with lowest values among septic patients. Hepcidin values correlated with ferritin levels, and serum iron correlated strongly with transferrin saturation. A moderate correlation of hepcidin, ferritin, and transferrin with inflammatory parameters was noted. Both short- and long-term survivors displayed higher ferritin/transferrin levels and lower transferrin saturation. In Kaplan-Meier analyses, low iron levels (cutoff 10.5 MUmol/mL), low transferrin saturation (cutoff 55%), and high serum transferrin concentrations (cutoff 1.6 g/L) were associated with short- and long-term survival. In the subgroup of septic ICU subjects, low iron levels and transferrin saturation went along with a nonlethal outcome. CONCLUSIONS: Our findings demonstrate that parameters of iron metabolism, particularly transferrin saturation, that reflect serum iron availability, are strong outcome predictors in ICU patients. These data suggest that a failure of iron homeostasis with increased iron availability in serum occurs in lethally ill ICU patients and should trigger prospective clinical trials evaluating the usefulness of iron-chelating therapy in critical illness and sepsis. PMID- 26934144 TI - Adjuvant Corticosteroid Treatment in Adults With Influenza A (H7N9) Viral Pneumonia. AB - OBJECTIVE: To determine the impact of adjuvant corticosteroids administered to patients hospitalized with influenza A (H7N9) viral pneumonia. DESIGN: The effects of adjuvant corticosteroids on mortality were assessed using multivariate Cox regression and a propensity score-matched case-control study. Nosocomial infections and viral shedding were also compared. SETTING: Hospitals with influenza A (H7N9) viral pneumonia patient admission in 84 cities and 16 provinces of Mainland China. PATIENTS: Adolescent and Adult patients aged >14 yr with severe laboratory-confirmed influenza A (H7N9) virus infections were screened from April 2013 to March 2015. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The study population comprised 288 cases who were hospitalized with influenza A (H7N9) viral pneumonia. The median age of the study population was 58 years, 69.8% of the cohort comprised male patients, and 51.4% had at least one type of underlying diseases. The in-hospital mortality was 31.9%. Two hundred and four patients (70.8%) received adjuvant corticosteroids; among them, 193 had hypoxemia and lung infiltrates, 11 had chronic obstructive pulmonary disease, and 11 had pneumonia only. Corticosteroids were initiated within 7 days (interquartile range, 5.0-9.4 d) of the onset of illness and the maximum dose administered was equivalent to 80-mg methylprednisolone (interquartile range, 40 120 mg). The patients were treated with corticosteroids for a median duration of 7 days (interquartile range, 4.0-11.3 d). Cox regression analysis showed that compared with the patients who did not receive corticosteroid, those who received corticosteroid had a significantly higher 60-day mortality (adjusted hazards ratio, 1.98; 95% CI, 1.03-3.79; p = 0.04). Subgroup analysis showed that high dose corticosteroid therapy (> 150 mg/d methylprednisolone or equivalent) significantly increased both 30-day and 60-day mortality, whereas no significant impact was observed for low-to-moderate doses of corticosteroids (25-150 mg/d methylprednisolone or equivalent). The propensity score-matched case-control analysis showed that the median viral shedding time was much longer in the group that received high-dose corticosteroids (15 d), compared with patients who did not receive corticosteroids (13 d; p = 0.039). CONCLUSIONS: High-dose corticosteroids were associated with increased mortality and longer viral shedding in patients with influenza A (H7N9) viral pneumonia. PMID- 26934146 TI - The US Preventive Services Task Force Recommendation on Vision Screening in Older Adults: A Narrow View. PMID- 26934145 TI - Burned Adults Develop Profound Glucose Intolerance. AB - OBJECTIVES: Metabolic alterations after burn injury have been well described in children; however, in adult patients, glucose metabolism and insulin sensitivity are essentially unknown. We sought to characterize metabolic alterations and insulin resistance after burn injury and determine their magnitude and persistence at discharge. DESIGN: Prospective, cohort study. SETTING: Tertiary burn centre. PATIENTS: Nondiabetic adults with an acute burn involving greater than or equal to 20% total body surface area. INTERVENTIONS: An oral glucose tolerance test was administered at discharge. MEASUREMENTS AND MAIN RESULTS: Glucose, insulin, and C-peptide levels were measured to derive surrogate measures of insulin resistance and beta-cell function, including quantitative insulin sensitivity check index, homeostasis model assessment of beta-cell function, homeostasis model assessment of insulin sensitivity, homeostasis model assessment of insulin resistance, and the composite whole-body insulin sensitivity index. Patients were grouped according to the degree of glucose tolerance: normal glucose tolerance, impaired fasting glucose/impaired glucose tolerance, or diabetes. Forty-five adults, 44 +/- 15 years old and with 38% +/- 14% total body surface area burned, underwent an oral glucose tolerance test at discharge. Median quantitative insulin sensitivity check index (0.348 [0.332-0.375]) and median homeostasis model assessment of insulin resistance (1.13 [0.69-1.45]) were abnormal, indicating insulin resistance and impaired insulin production at discharge. Two-thirds of patients (n = 28) met criteria for impaired fasting glucose/impaired glucose tolerance or diabetes. CONCLUSIONS: We have demonstrated that burn-injured adults remain hyperglycemic, are insulin resistant, and express defects in insulin secretion at discharge. Patients with lower burn severity (total body surface area, 20-30%) express similar metabolic alterations as patients with larger burns (total body surface area, >= 30%). Glucose tolerance testing at discharge offers an opportunity for early identification of burn patients who may be at high risk of prediabetes and diabetes. Our findings demonstrated that two-thirds of burn patients had some degree of glucose intolerance. With this in mind, surveillance of glucose intolerance post discharge should be considered. As hyperglycemia and insulin resistance are associated with poor outcomes, studies should focus on how long these profound alterations persist. PMID- 26934147 TI - Impact of damming on the Chironomidae of the upper zone of a tropical run-of-the river reservoir. AB - We examined the effects of the Mogi-Guacu river damming (Sao Paulo State, Brazil) on the Chironomidae fauna. Pre, during, and post-filling sampling was carried out in the main channel and margins of one site in the upper zone of the reservoir, using a modified Petersen grab (325 cm2). We evaluated the total, subfamily, and tribe densities and also their relative abundance. Analysis of genera included densities, relative abundance, richness, and dominance. The Rosso's ecological value index (EVI) determined the ecological importance of each genus. There was a tendency of decrease of the total Chironomidae density, increase in the percentage of Chironomini, and decrease in densities and percentages of Orthocladiinae and Tanytarsini. These changes in percentage were respectively related to Polypedilum, Lopescladius, and Rheotanytarsus, the genera with the highest EVI values. After-filling richness was lower in the margins and dominance of genera did not change significantly. Chironomidae in the margins was more sensitive to damming than in the main channel. This difference in sensibility sustains the use of Chironomidae as bioindicators. Damming impact was indicated by the reduction of both genera richness in the margins and relative abundance of groups typical of faster waters. The results have highlighted the need for multi habitat analysis combined with a before-after sampling approach in the environmental impact studies concerning the damming impact on the benthic fauna. PMID- 26934148 TI - Survival and preference of cotton boll weevil adults for alternative food sources. AB - Plants that have potential as alternative food source (floral nectar, pollen and plant tissues) to the boll weevil during the intercropping season were evaluated considering the prevalent conditions of Cerrado in the Central Brazil. Initially, we tested the nutritional adequacy for the survival of the insect of flower resource (pollen and nectar) provided by eight plant species (fennel, mexican sunflower, castor bean, okra, hibiscus, sorghum, pigeonpea and sunn hemp). Subsequently, we tested if the resources provided by the selected plants continued to be exploited by the boll weevil in the presence of cotton plant, its main food source average longevity of boll weevil adults was significantly longer when they were fed on hibiscus' flowers (166.6 +/- 74.4) and okra flowers (34.7 +/- 28.9) than when they fed on flowers of other six species. Subsequently, the preference of the boll weevil in the use of resources was compared between okra or hibiscus and cotton plants, in dual choice experiments. Boll weevils preferred plants of the three species in the reproductive stages than those in vegetative stages. Although the cotton plant in the reproductive stage was the most preferred plant of all, boll weevils preferred flowering okra and hibiscus than cotton at the vegetative stage. PMID- 26934149 TI - Antioxidant potential of yerba mate (Ilex paraguariensis St. Hil.) extracts in Saccharomyces cerevisae deficient in oxidant defense genes. AB - Yerba-mate (Ilex paraguariensis St. Hil) is mainly consumed as "chimarrao", a hot drink highly appreciated in Brazil, Argentina, Paraguay and Uruguay. This study evaluated the antioxidant potential of aqueous extracts of I. paraguariensis precipitated with ethanol. The leaves were processed as for tea product (TM) and oxidized (OX). The antioxidant potential was evaluated in cells of Saccharomyces cerevisiae deficient in antioxidant defense genes. Three strains evaluated were: a wild (EG) and two mutants (ctt1Delta e ctt1Deltasod1Delta). These strains were pre-treated with the yerba-mate extracts (TM e OX) and submitted to oxidative stress induced by hydrogen peroxide. None of the extracts produced loss of cell viability. The extracts exerted antioxidant activity, protecting the strains (except sod1?ctt1?). The TM extract was more effective than OX. I. paraguariensis extracts showed a potential to be explored in the development of new products. PMID- 26934150 TI - Physical characterization of Rhipsalis (Cactaceae) fruits and seeds germination in different temperatures and light regimes. AB - The germination characteristics of the native cactus species are poorly known, being the temperature and the light the factors that the most interferes in that process. Thus, the objective of the present work was to characterize the fruits and evaluate the influence of the temperature and the light in the seed germination of Rhipsalis floccosa, Rhipsalis pilocarpa and Rhipsalis teres. The tested constant temperatures were 15, 20, 25, 30 and 35 degrees C and the alternate of 20-30 degrees C and 25-35 degrees C in a photoperiod of 10 hours, and with determination of the most appropriate temperature, the germination was tested in light absence. The germination percentage, the index of germination speed and medium time of germination were evaluated. For R. floccosa, the highest germination percentage was at 20 degrees C. For R. pilocarpa and R. teres, the highest germination percentages occurred in 15 degrees C and 20 degrees C. There was correlation to germination percentage between the three species, indicating that they had similar germination behavior. Total absence of germination was verified for the three species in condition of light absence. In conclusion, the temperature of 20 degrees C is the most suitable for the seed germination of R. floccosa. For the species R. pilocarpa and R. teres, the temperatures of 15 and 20 degrees C are the most suitable. PMID- 26934151 TI - Reproductive periods of Lucina pectinata (BIVALVE; LUCINIDAE) in the Paranagua Estuarine Complex, Parana - Brazil. AB - The objectives of the present study is to describe the size for exploitation and gonadal maturation of L. pectinata in Pecas Island in Parana coast. Twenty two individuals were sampled every month, from an intertidal flat of the Pecas River, Municipality of Guaraquecaba, during two periods - summer/autumn and winter of the 2009. Environmental parameter data was obtained at the same time of the biological sampling: temperature, salinity and seawater transparency at the Pecas River mouth. The animals' height, length, width, gross weight, wet weight of meat and dry weight of meat were measured at the lab. The gonad development stages (GDS), condition index (CI) and yield index (Y) were calculated. Sex identification was conducted by direct observation of the gonads and gametes under an optic microscope. Individuals were classified as males (M), females (F) or undetermined (U). The medium height observed was of 49.62 +/- 6.84 mm. Period of more expressive gonad repletion were observed in summer when water temperature was higher. Results of GDS in both periods showed a predominance of partially filled gonad stages. This may be related with the fact that L. pectinata has intense gametogenesis activity, that is, the organisms do not have a resting interval, but go back to gonad restructuring rapidly after releasing the gametes. The continuity of the reproductive cycle of the specimens found in both studied periods could demonstrate a possible continuous reproduction of the species and a size for exploitation above 40.00 mm of height. PMID- 26934152 TI - Effects of seasonal variations and collection methods on the mineral composition of propolis from Apis mellifera Linnaeus Beehives. AB - The effects of seasonal variations and the methods of collection of propolis produced by Africanized honey bees Apis mellifera Linnaeus, 1758, on the composition of constituent minerals such as magnesium (Mg), zinc (Zn), iron (Fe), sodium (Na), calcium (Ca), copper (Cu), and potassium (K) were evaluated. Propolis was harvested from 25 beehives by scraping or by means of propolis collectors (screen, "intelligent" collector propolis [ICP], lateral opening of the super [LOS], and underlay method). During the one-year study, the propolis produced was harvested each month, ground, homogenized, and stored in a freezer at -10 oC. Seasonal analyses of the mineral composition were carried out by atomic absorption spectrophotometry and the results were evaluated by analysis of variance (ANOVA), followed by Tukey-Kramer's test to compare the mean values (p<0.05). The results showed that seasonal variations influence the contents of 5 minerals (Mg, Fe, Na, Ca, and Cu), and the propolis harvesting method affects the contents of 4 minerals (Mg, Zn, Fe, and Ca). PMID- 26934153 TI - Karyotypic diversity among three species of the genus Astyanax (Characiformes: Characidae). AB - The group Incertae sedis within the Characidae family currently includes 88 genera, previously included in the subfamily Tetragonopterinae. Among them is the genus Astyanax comprising a group of species with similar morphology and widely distributed in the Neotropics. Thus, the present study aimed to analyze the karyotype diversity in Astyanax species from different watersheds by conventional Giemsa staining, C-banding and fluorescence in situ hybridization (FISH rDNA 18S) probe.specimens of Astyanax aff. paranae belonging to the "scabripinnis complex", Astyanax asunsionensis and Astyanax aff. bimaculatus were analyzed". Two sympatric karyomorphs were observed in Astyanax.aff paranae, one of them having2n=48andthe other one with 2n=50 chromosomes. Other population of this same species also presented 2n=50 chromosomes, but differing in the karyotype formula and with macro supernumerary chromosome found in 100% of the cells in about 80%of females analyzed. Two population of A. asuncionensis and one population of Astyanax. aff. bimaculatus, also showed a diploid number of 50 chromosomes, but also differing in their karyotype formulas. Therefore, A. asuncionensis was also characterized by intraspecific chromosome diversity. The C-banding analysis was able to demonstrate a distinctable to demonstrate a distinct pattern of heterochromatin differing A. asuncionensis from Astyanax aff. paranae and Astyanax aff. bimaculatus. The supernumerary chromosome of Astyanax aff. paranae proved completely heterochromatic. Only Astyanax.aff. bimaculatus multiple showed multiple sites of nucleolar organizing regions. The other species were characterized by having a simple system of NOR. These data contributes to the know ledge of the existing biodiversity in our fish fauna, here highlighted by the inter- and intraspecific chromosomal diversity in the genus Astyanax. PMID- 26934154 TI - Selectivity curves of the capture of mangrove crab (Ucides cordatus) on the northern coast of Brazil using bayesian inference. AB - Fishing selectivity of the mangrove crab Ucides cordatus in the north coast of Brazil can be defined as the fisherman's ability to capture and select individuals from a certain size or sex (or a combination of these factors) which suggests an empirical selectivity. Considering this hypothesis, we calculated the selectivity curves for males and females crabs using the logit function of the logistic model in the formulation. The Bayesian inference consisted of obtaining the posterior distribution by applying the Markov chain Monte Carlo (MCMC) method to software R using the OpenBUGS, BRugs, and R2WinBUGS libraries. The estimated results of width average carapace selection for males and females compared with previous studies reporting the average width of the carapace of sexual maturity allow us to confirm the hypothesis that most mature individuals do not suffer from fishing pressure; thus, ensuring their sustainability. PMID- 26934155 TI - What are the most important factors determining different vegetation types in the Chapada Diamantina, Brazil? AB - A transect was used to examine the environmental and biological descriptors of a compact vegetation mosaic in the Chapada Diamantina in northeastern Brazil, including the floristic composition, spectrum of plant life forms, rainfall, and soil properties that defined areas of cerrado (Brazilian savanna), caatinga (seasonally dry tropical forest thorny, deciduous shrub/arboreal vegetation) and cerrado-caatinga transition vegetation. The floristic survey was made monthly from April/2009 to March/2012. A dendrogram of similarity was generated using the Jaccard Index based on a matrix of the species that occurred in at least two of the vegetation types examined. The proportions of life forms in each vegetation type were compared using the chi-square test. Composite soil samples were analyzed by simple variance (ANOVA) to examine relationships between soil parameters of each vegetation type and the transition area. The monthly precipitation levels in each vegetation type were measured and compared using the chi-square test. A total of 323 species of angiosperms were collected distributed in 193 genera and 54 families. The dendrogram demonstrated strong difference between the floristic compositions of the cerrado and caatinga, sharing 2% similarity. The chi-square test did not demonstrate any significant statistical differences between the monthly values of recorded rainfall. The organic matter and clay contents of the soilsin the caatinga increased while sand decreased, and the proportions of therophyte, hemicryptophyte, and chamaephyte life forms decreased and phanerophytes increased. We can therefore conclude that the floristic composition and the spectrum of life forms combined to define the cerrado and caatinga vegetation along the transect examined, with soil being the principal conditioning factor determining the different vegetation types, independent of precipitation levels. PMID- 26934156 TI - The population density of Lymnaea columella (Say, 1817) (Mollusca, Lymnaeidae) an intermediate host of Fasciola hepatica (Linnaeus, 1758), in the Caparao microregion, ES, Brazil. AB - The aim of this study was to monitor the population density of Lymnaea columella, an intermediate host of Fasciola hepatica, in various aquatic habitats and in drinking water in the area of the Instituto Federal de Educacao, Ciencia e Tecnologia do Espirito Santo, on Caparao Microregion, municipality of Alegre, state of Espirito Santo, Brazil. Monthly samplings were performed at certain points between drainage areas and drinking water in cattle and goat production systems during the years 2010 to 2013. The mean temperature, precipitation and the frequency of samples of L. columella were analysed graphically according the monthly average during the study period. A total of 2,038 molluscs were collected, 1558 of which were L. columella, that predominated in all sampled points. The highest average of specimens observed for L. columella was in the years 2010 and 2013 (51.0), and occurred decreased in 2011 (19.8). The temperature and precipitation averaged is 23.7 degrees C and 141 mm/year, respectively. Rainfall peak occurred in March (2011, 2013) and November (2012), during these periods the population of L. columella growth. There was no significant difference in the relationship between the specimens observed with seasons (dry-wet), thus the population of L. columella remained stable and can be found throughout the year. PMID- 26934157 TI - A new species of Tripartiella (Ciliophora: Trichodinidae) from Aequidens tetramerus (Perciformes: Cichlidae) in north Brazil. AB - A new species of Tripartiella is described from the gills of the wild saddle cichlid Aequidens tetramerus in north Brazil. Wet smears of skin and gills of examined fish were air-dried at room temperature and impregnated with Klein's dry silver method for examination of the adhesive disc's structures and denticles. Total prevalence of parasitism was 65%. This ciliate is characterized as a small sized trichodinid, body diameter 37.03 +/- 4.9 MUm, adhesive disc 30.50 +/- 2.71 MUm, denticulate ring 13.28 +/- 0.8 MUm and 24 +/- 2.0 denticles. Taxonomic and morphometric data for the new species are discussed. PMID- 26934158 TI - Structure and dynamics of the planktonic diatom community in the Iguassu River, Parana State, Brazil. AB - The evaluation of abiotic and biotic variables can provide information for understanding the structure and function of lotic systems. To obtain this information, measurements of 15 chemical and physical variables and of phytoplankton were conducted at two sampling stations. The present study aims to evaluate the temporal and spatial variation of planktonic diatoms in terms of abiotic variables and the trophic level of the river water and to select diatom species as descriptors of the physical and chemical conditions of the water upstream (S1) and downstream (S2) of the Iguassu River over an annual cycle. Sampling station S1 was classified as oligotrophic to mesotrophic, and S2 was classified as ultra-oligotrophic to oligotrophic. A total of 98 diatom species distributed among 39 genera was recorded, showing no dominant species but 36 abundant species. Although the differences of chemical and physical variables between S1 and S2 were limited to greater turbulence and turbidity, processes triggered by heavy rainfall exerted a significant influence on community structure, and a temporal change in composition was observed. At the end of the dry period, due to the recovery of nutrients and high transparency, there was an abundance of Cocconeis placentula var. lineata. In the rainy period, with increased turbulence and turbidity processes resulting from higher rainfall, there was an abundance of Aulacoseira granulata var. granulata. PMID- 26934160 TI - Research: You Can Do It. PMID- 26934159 TI - Selection of prey to improve biological parameters of the predator Podisus nigrispinus (Dallas, 1851) (Hemiptera: Pentatomidae) in laboratory conditions. AB - Mass production of predatory stinkbugs in the laboratory is prioritized to release them into the field as part of IPM programs. Therefore, the aim of this study was to identify the best prey for rearing the predator Podisus nigrispinus (Dallas, 1851) (Hemiptera: Pentatomidae) among five different species of insect (three of Lepidoptera, one of Coleoptera, and one of Diptera). Second-instar P. nigrispinus nymphs were conditioned in transparent 1000-mL plastic pots, adults were placed in Petri dishes for mating, and both stages were maintained under controlled conditions (25 +/- 1 degrees C, 12 hours of photophase, 70 +/- 10% RH). Nymphs and adults of P. nigrispinus consumed more Musca domestica (Linnaeus, 1758) (Diptera: Muscidae) larvae than the other tested prey. The consumption of fly larvae was 1.5 larvae/day/nymph and adults 1.7 larvae/day/adult. However, the number of eggs per female was less when the predator consumed M. domestica larvae (407.8 eggs/female) and most when consumed the Diatraea saccharalis (Fabricius, 1794) (Lepidoptera: Crambidae) larvae (797.7 eggs/female). Furthermore, the percentage of hatched eggs was greater when the predator females consumed D. saccharalis larvae (90.0%). D. saccharalis larvae is the best prey to rearing P. nigrispinus. PMID- 26934161 TI - Cultural Congruence and Infusion Nursing Practice. AB - The importance of cultural competence in every nursing practice setting in today's world cannot be understated. Unconscious bias can have detrimental effects on therapeutic relationships and health outcomes. Nursing models of cultural competence by Purnell, Leininger, and Campinha-Bacote are reviewed. The Kleinman Model and LEARN Model offer questions and guidelines to facilitate assessment of patients' understanding of illness and treatment. The Infusion Nursing Standards of Practice contains elements of diversity and cultural competence throughout. Self-reflection of one's own values, beliefs, biases, and practice as an infusion nurse will promote the development of cultural competence. PMID- 26934162 TI - Oral Parenteral Antimicrobial Therapy Administration in a Homeless Population. AB - Outpatient parenteral antimicrobial therapy (OPAT) is increasingly used to treat serious infections. Patients who identify themselves as homeless may receive OPAT less often, and little is known about their treatment outcomes. The purpose of this study was to describe challenges, treatment completion rates, and cost savings of OPAT in homeless patients discharged from a public safety-net hospital. PMID- 26934163 TI - The Importance of Glycemic Control in the Hospital and the Role of the Infusion Nurse. AB - Diabetes is reaching epidemic proportions. Patients undergoing surgery, regardless of diabetes history, are at high risk for complications of poor glycemic control, including infection, mortality, and longer lengths of stay. This article provides an overview of the evidence about glycemic control in the hospital, risk factors for hyperglycemia and hypoglycemia, and the role of infusion nurses in improving outcomes for hospitalized patients with diabetes. PMID- 26934164 TI - Using Ultrasonography for Vessel Diameter Assessment to Prevent Infiltration. AB - Small veins are a risk factor for infiltration. However, there are no data regarding the ideal vein diameter for preventing infiltration. Using ultrasound, vessel diameter and calculated ratios of the vessel diameter to the catheter gauge were measured. The relationship between the ratio and infiltration was assessed to establish a cutoff point. The mean ratio of the infiltration group was significantly smaller than that of the no-infiltration group (P < .01), and the ratio was an independent risk factor according to the multivariable analysis. The ratio of 3.3 was determined to be the cutoff point that enables health care professionals to identify veins appropriately. PMID- 26934165 TI - Mathematical modeling for local trans-round window membrane drug transport in the inner ear. AB - The structure and composition of the round window membrane (RWM) make it a particularly effective pathway for drug delivery to the inner ear. Therefore, predicting the efficiency of RWM transport would provide useful information for enhancing local application. In the present study, a mathematical model was established to achieve this goal. A series of drugs with different physicochemical properties were introduced in the inner ear cavity of guinea pigs via RWM by intratympanic application. The perilymphatic drug concentration (C) data were used to calculate the permeability coefficient (Kp) of different drugs diffusing through the RWM. The experimental data were fitted using the Matlab software to set up the numerical model based on Fick's diffusion law and the single-compartment model following extravascular administration, which facilitated the prediction of the permeation profiles of different drugs while trans-RWM. In summary, this mathematical model is a contribution toward developing potentially useful RWM administration simulating tools. PMID- 26934166 TI - VHA Pain Research Working Group and VHA Pain Care. PMID- 26934167 TI - Exhaled nitric oxide and carbon monoxide in mechanically ventilated brain-injured patients. AB - The inflammatory influence and biological markers of prolonged mechanical ventilation in uninjured human lungs remains controversial. We investigated exhaled nitric oxide (NO) and carbon monoxide (CO) in mechanically-ventilated, brain-injured patients in the absence of lung injury or sepsis at two different levels of positive end-expiratory pressure (PEEP). Exhaled NO and CO were assessed in 27 patients, without lung injury or sepsis, who were ventilated with 8 ml kg(-1) tidal volumes under zero end-expiratory pressure (ZEEP group, n = 12) or 8 cm H2O PEEP (PEEP group, n = 15). Exhaled NO and CO was analysed on days 1, 3 and 5 of mechanical ventilation and correlated with previously reported markers of inflammation and gas exchange. Exhaled NO was higher on day 3 and 5 in both patient groups compared to day 1: (PEEP group: 5.8 (4.4-9.7) versus 11.7 (6.9-13.9) versus 10.7 (5.6-16.6) ppb (p < 0.05); ZEEP group: 5.3 (3.8-8.8) versus 9.8 (5.3-12.4) versus 9.6 (6.2-13.5) ppb NO peak levels for days 1, 3 and 5, respectively, p < 0.05). Exhaled CO remained stable on day 3 but significantly decreased by day 5 in the ZEEP group only (6.3 (4.3-9.0) versus 8.1 (5.8-12.1) ppm CO peak levels for day 5 versus 1, p < 0.05). The change scores for peak exhaled CO over day 1 and 5 showed significant correlations with arterial blood pH and plasma TNF levels (r s = 0.49, p = 0.02 and r s = 0.51 p = 0.02, respectively). Exhaled NO correlated with blood pH in the ZEEP group and with plasma levels of IL-6 in the PEEP group. We observed differential changes in exhaled NO and CO in mechanically-ventilated patients even in the absence of manifest lung injury or sepsis. These may suggest subtle pulmonary inflammation and support application of real time breath analysis for molecular monitoring in critically ill patients. PMID- 26934168 TI - Misdiagnosed Periocular Pyoderma Gangrenosum Requiring Ectropion Repair With Development of Second Lesion of Pyoderma Gangrenosum at Graft Site. PMID- 26934170 TI - Bosom Buddies: The Symbiotic Relationship Between Infants and Bifidobacterium longum ssp. longum and ssp. infantis. Genetic and Probiotic Features. AB - The intestinal microbiota is a complex community that plays an important role in human health from the initial steps of its establishment. Its microbial composition has been suggested to result from selective pressures imposed by the host and is modulated by competition among its members. Bifidobacterium longum is one of the most abundant species of the Bifidobacterium genus in the gut microbiota of healthy breast-fed infants and adults. The recent advancements of 'omics techniques have facilitated the genetic and functional studies of different gut microbiota members. They have revealed the complex genetic pathways used to metabolize different compounds that likely contribute to the competitiveness and persistence of B. longum in the colon. The discovery of a genomic island in B. longum ssp. infantis that encodes specific enzymes for the metabolism of human milk oligosaccharides suggests a specific ecological adaptation. Moreover, B. longum is widely used as probiotic, and beneficial effects in infant health have been reported in several studies. PMID- 26934171 TI - Designing Whey Protein-Polysaccharide Particles for Colloidal Stability. AB - Interactions between whey proteins and polysaccharides, in particular the formation of food-grade soluble complexes, are of interest because of potential functional and health benefits. A specific application that has not received much attention is the use of complexes for enhanced colloidal stability of protein sols, such as protein-containing beverages. In beverages, the primary goal is the formation of complexes that remain dispersed after thermal processing and extended storage. This review highlights recent progress in the area of forming whey protein-polysaccharide soluble complexes that would be appropriate for beverage applications. Research in this area indicates that soluble complexes can be formed and stabilized that are reasonably small in size and possess a large surface charge that would predict colloidal stability. Selection of specific proteins and polysaccharides can be tailored to desired conditions. The principal challenges involve overcoming restrictions on protein concentration and ensuring that protein remains bioavailable. PMID- 26934172 TI - Infant Formula Fat Analogs and Human Milk Fat: New Focus on Infant Developmental Needs. AB - Human breast milk is generally and universally recognized as the optimal choice for nutrition during the first year of life. In certain cases in which it is not feasible to breast-feed the infant or the breast milk is not sufficient, especially in the case of preterm infants, infant formula is the next best alternative to provide nutrition to nurture the infant. Therefore, it is highly important that the nutrient composition of the infant formula is as close to breast milk as possible for proper growth and development of the infant. However, human milk is a complex dynamic matrix, and therefore significant research has been done and is still ongoing to fully understand and mimic human breast milk, particularly its fat composition. Lipids play a critical role in infant nutrition. A number of advances have been made in infant formula lipid content and composition so that formula can better simulate or mimic the nutritional functions of human maternal milk. PMID- 26934173 TI - Food Allergy. AB - Food allergy is receiving increased attention in recent years. Because there is currently no known cure for food allergy, avoiding the offending food is the best defense for sensitive individuals. Type I food allergy is mediated by food proteins, and thus, theoretically, any food protein is a potential allergen. Variability of an individual's immune system further complicates attempts to understand allergen-antibody interaction. In this article, we briefly review food allergy occurrence, prevalence, mechanisms, and detection. Efforts aimed at reducing/eliminating allergens through food processing are discussed. Future research needs are addressed. PMID- 26934174 TI - Bacterial Spores in Food: Survival, Emergence, and Outgrowth. AB - Spore-forming bacteria are ubiquitous in nature. The resistance properties of bacterial spores lie at the heart of their widespread occurrence in food ingredients and foods. The efficacy of inactivation by food-processing conditions is largely determined by the characteristics of the different types of spores, whereas food composition and storage conditions determine the eventual germination and outgrowth of surviving spores. Here, we review the current knowledge on variation in spore resistance, in germination, and in the outgrowth capacity of spores relevant to foods. This includes novel findings on key parameters in spore survival and outgrowth obtained by gene-trait matching approaches using genome-sequenced Bacillus spp. food isolates, which represent notorious food spoilage and pathogenic species. Additionally, the impact of strain diversity on heat inactivation of spores and the variability therein is discussed. Knowledge and quantification of factors that influence variability can be applied to improve predictive models, ultimately supporting effective control of spore-forming bacteria in foods. PMID- 26934175 TI - Organogenesis of the Musculoskeletal System in Horse Embryos and Early Fetuses. AB - Musculoskeletal system development involves heterotypical inductive interactions between tendons, muscles, and cartilage and knowledge on organogenesis is required for clarification of its function. The aim of this study was to describe the organogenesis of horse musculoskeletal system between 21 and 105 days of gestation, using detailed macroscopic and histological analyses focusing on essential developmental steps. At day 21 of gestation the skin was translucid, but epithelial condensation and fibrocartilaginous tissues were observed on day 25 of pregnancy. Smooth muscle was seen in lymphatic and blood vessel walls and the beginning of cartilaginous chondrocranium was detected at day 30 of gestation. At day 45, typical chondroblasts and chondrocytes were observed and at day 55, mandibular processes expanded toward the ventral midline of the pharynx. At day 75, muscles became thicker and muscle fibers were seen developing in carpal and metacarpal joints with the beginning of the ossification process. At day 105, major muscle groups, similar to those seen in an adult equine, were observed. The caudal area of the nasal capsule and trabecular cartilages increased in size and became ossified, developing into the ethmoid bone. The presence of nasal, frontal, parietal, and occipital bones was observed. In conclusion, novel features of equine musculoskeletal system development have been described here and each process was linked with an early musculoskeletal event. Data presented herein will facilitate a better understanding of the equine muscular system organogenesis and aid in the detection of congenital deformities. Anat Rec, 299:722-729, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26934176 TI - Magnetic N-Enriched Fe3C/Graphitic Carbon instead of Pt as an Electrocatalyst for the Oxygen Reduction Reaction. AB - A series of Fe3C/C-Nx nanoparticles (NPs) with different nitrogen content are prepared by a simple one-pot route. In the synthetic procedure, aniline and acetonitrile are simultaneously used as the carbon and nitrogen source. The effect of calcination temperature on the structural and functional properties of the materials is investigated. Magnetic measurement shows that the sample prepared at 800 degrees C (Fe3 C/C-N800 NPs) possesses the highest Ms value of 77.2 emu g(-1). On testing as oxygen reduction reaction (ORR) catalysts, the sample prepared at 750 degrees C (Fe3C/C-N750 NPs) shows the best ORR performance among the series, with a more positive onset potential (+0.99 V vs. RHE), higher selectivity (number of electron transfer n~3.93), longer durability, and stronger tolerance against methanol crossover than commercial Pt/C catalysts in a 0.1 m KOH solution. Moreover, in acidic solution, the excellent ORR activity and stability are also exhibited. PMID- 26934177 TI - Health literacy and disease-specific knowledge of caregivers for children with sickle cell disease. AB - This study was conducted to measure the health literacy (HL) and disease-specific knowledge (DSK) of caregivers for children with sickle cell disease (SCD) and relate them to their child's health care utilization. The authors conducted a cross-sectional study of caregiver-child dyads attending an urban pediatric sickle cell clinic. Caregivers were administered the Shortened Test of Functional Health Literacy (S-TOFHLA) and a locally developed DSK questionnaire. Retrospective review of the child's electronic medical record (EMR) was performed to determine annual emergency department (ED) visits and hospitalizations. A total of 142 caregiver-child dyads were recruited for the study. Less than 5% of caregivers had limited HL, with less education (P =.03) and primary language other than English (P =.04) being the only risk factors. Although caregiver HL was not associated with ED visits or hospitalizations, surprisingly DSK was. Caregivers with higher DSK scores had children with higher annual rates of ED utilization (P =.002) and hospitalizations (P =.001), and these children were also more likely to be classified as high ED utilizers (>=4 visits per year; P =.01). Further, caregiver adherence to medication and clinic visits was associated with their child's age (P =.01). Although HL and DSK are both constructs that measure basic health understanding, they differently affect caregivers' ability to navigate and understand the health care system of children with chronic illnesses. This study suggests that the DSK/health care utilization relationship may be a more important measure than HL for programs following children with sickle cell disease and could also have applications in other pediatric chronic diseases. PMID- 26934178 TI - Single-Point Remote Control of Flapping Motion in Clothespin-Shaped Bimetallic Palladium Complexes Based on the N(sp(2))-N(sp(3)) Interconversion in Amide Functionalities. AB - The synthesis, structure, and flapping motion of clothespin-shaped binuclear trans-bis(salicylaldiminato)palladium(II) complexes (anti-1) with 4 azaheptamethylene linkers bearing amide (a-g), urethane (h), or urea (i) functionalities are described in this report. Various 2D (1)H NMR experiments and XRD analyses indicate that the amide- and urethane-linked anti-1 a,b,d-h complexes exist as equilibrated mixtures of major and minor conformers I and II in CDCl3, whereas the complexes anti-1 c and i were observed as a single species. The mapping of NOESY cross-peaks between conformers I and II revealed that the equilibration of the major and minor conformers of anti-1 a,b,d-h proceeds by two pathways, namely a nonrotatory flapping motion of the coordinated blades and a nonflapping rotation of C-N bonds, whereas the equilibration of anti-1 c proceeds by simultaneous flapping and rotation motions. Kinetic studies carried out by means of (1)H-(1)H EXSY experiments revealed that 1) the DeltaG(?) 298K values for the flapping motion are controlled remotely by the steric and electronic effects of the RCON functionalities and 2) the activation parameters for the nonrotatory flapping process are identical to those for the nonflapping peptide rotation in the complexes anti-1 a,b,d-h, which indicates that the present multistep conformational transformation induced by the flapping motion is controlled by the rate-determining pyramidalization/depyramidalization (i.e., sp(2)/sp(3) interconversion) of the nitrogen atoms of the functionalities. The static and controllable molecular mobility of anti-1 bearing peptide linkers has been discussed by comparison with the dynamic behavior of its analogues anti-2-4 with flexible polymethylene linkers. PMID- 26934179 TI - miR-126-3p Promotes Matrix-Dependent Perivascular Cell Attachment, Migration and Intercellular Interaction. AB - microRNAs (miRNAs) can regulate the interplay between perivascular cells (PVC) and endothelial cells (EC) during angiogenesis, but the relevant PVC-specific miRNAs are not yet defined. Here, we identified miR-126-3p and miR-146a to be exclusively upregulated in PVC upon interaction with EC, determined their influence on the PVC phenotype and elucidate their molecular mechanisms of action. Specifically the increase of miR-126-3p strongly promoted the motility of PVC on the basement membrane-like composite and stabilized networks of EC. Subsequent miRNA target analysis showed that miR-126-3p inhibits SPRED1 and PLK2 expression, induces ERK1/2 phosphorylation and stimulates TLR3 expression to modulate cell-cell and cell-matrix contacts of PVC. Gain of expression experiments in vivo demonstrated that miR-126-3p stimulates PVC coverage of newly formed vessels and transform immature into mature, less permeable vessels. In conclusion we showed that miR-126-3p regulates matrix-dependent PVC migration and intercellular interaction to modulate vascular integrity. Stem Cells 2016;34:1297 1309. PMID- 26934180 TI - Preterm birth is associated with atypical social orienting in infancy detected using eye tracking. AB - BACKGROUND: Preterm birth is closely associated with neurocognitive impairment in childhood including increased risk for social difficulties. Eye tracking objectively assesses eye-gaze behaviour in response to visual stimuli, which permits inference about underlying cognitive processes. We tested the hypothesis that social orienting in infancy is altered by preterm birth. METHODS: Fifty preterm infants with mean (range) gestational age (GA) at birth of 29(+1) (23(+2) -33(+0) ) weeks and 50 term infants with mean (range) GA at birth 40(+2) (37(+0) 42(+3) ) weeks underwent eye tracking at median age of 7 months. Infants were presented with three categories of social stimuli of increasing complexity. Time to first fixate (TFF) and looking time (LT) on areas of interest (AoIs) were recorded using remote eye tracking. RESULTS: Preterm infants consistently fixated for a shorter time on social content than term infants across all three tasks: face-scanning (fixation to eyes minus mouth 0.61s vs. 1.47s, p = .013); face pop out task (fixation to face 0.8s vs. 1.34s, p = .023); and social preferential looking (1.16s vs. 1.5s p = .02). Time given to AoIs containing social content as a proportion of LT at the whole stimulus was lower in preterm infants across all three tasks. These results were not explained by differences in overall looking time between the groups. CONCLUSIONS: Eye tracking provides early evidence of atypical cognition after preterm birth, and may be a useful tool for stratifying infants at risk of impairment for early interventions designed to improve outcome. PMID- 26934181 TI - A Global Population Genetic Study of Pantala flavescens. AB - Among terrestrial arthropods, the dragonfly species Pantala flavescens is remarkable due to their nearly global distribution and extensive migratory ranges; the largest of any known insect. Capable of migrating across oceans, the potential for high rates of gene flow among geographically distant populations is significant. It has been hypothesized that P. flavescens may be a global panmictic population but no sufficient genetic evidence has been collected thus far. Through a population genetic analysis of P. flavescens samples from North America, South America, and Asia, the current study aimed to examine the extent at which gene flow is occurring on a global scale and discusses the implications of the genetic patterns we uncovered on population structure and genetic diversity of the species. This was accomplished using PCR-amplified cytochrome oxidase one (CO1) mitochondrial DNA data to reconstruct phylogenetic trees, a haplotype network, and perform molecular variance analyses. Our results suggested high rates of gene flow are occurring among all included geographic regions; providing the first significant evidence that Pantala flavescens should be considered a global panmictic population. PMID- 26934183 TI - Synthesis of Monodisperse Bi-Compartmentalized Amphiphilic Janus Microparticles for Tailored Assembly at the Oil-Water Interface. AB - Janus particles endowed with controlled anisotropies represent promising building blocks and assembly materials because of their asymmetric functionalities. Herein, we show that using the seeded monomer swelling and polymerization technique allows us to obtain bi-compartmentalized Janus microparticles that are generated depending on the phase miscibility of the poly (alkyl acrylate) chains against the polystyrene seed, thus minimizing the interfacial free energy. When tetradecyl acrylate is used, complete compartmentalization into two distinct bulbs can be achieved, while tuning the relative dimension ratio of compartmented bulb against the whole particle. Finally, we have demonstrated that selectively patching the silica nanoparticles onto one of the bulb surfaces gives amphiphilicity to the particles that can assemble at the oil-water interface with a designated level of adhesion, thus leading to development of a highly stable Pickering emulsion system. PMID- 26934182 TI - Comparable Efficacy of Tigecycline versus Colistin Therapy for Multidrug Resistant and Extensively Drug-Resistant Acinetobacter baumannii Pneumonia in Critically Ill Patients. AB - Tigecycline has in vitro activity against multidrug-resistant and extensively drug-resistant Acinetobacter baumannii (MDR/XDRAB), and may constitute an alternative therapy for treating pneumonia caused by MDR/XDRAB. The aim of this study was to compare the efficacy of tigecycline-based therapy with colistin based therapy in patients with MDR/XDRAB pneumonia. Between January 2009 and December 2010, patients in the intensive care unit who were diagnosed with MDR/XDRAB pneumonia and treated with either tigecycline or colistin mono /combination therapy were reviewed. A total of 70 patients were included in our analysis. Among them, 30 patients received tigecycline-based therapy, and 40 patients received colistin-based therapy. Baseline characteristics were similar in the two groups. Clinical success rate was 47% in the tigecycline group and 48% in the colistin group (P = 0.95). There were no differences between the groups with regard to other clinical outcomes, with the exception that nephrotoxicity was observed only in the colistin group (0% vs. 20%; P = 0.009). Clinical and microbiological success rates were numerically higher, and mortality rates were numerically lower in combination therapy group than in the monotherapy group. Multivariate analysis indicated that monotherapy was independently associated with increased clinical failure (aOR, 3.96; 95% CI, 1.03-15.26; P = 0.046). Our results suggest that tigecycline-based therapy was tolerable and the clinical outcome was comparable to that of colistin-based therapy for patients with MDR/XDRAB pneumonia. In addition, combination therapy may be more useful than monotherapy in treatment of MDR/XDRAB pneumonia. PMID- 26934184 TI - Towards Truly Sustainable Polymers: A Metal-Free Recyclable Polyester from Biorenewable Non-Strained gamma-Butyrolactone. AB - The first effective organopolymerization of the biorenewable "non-polymerizable" gamma-butyrolactone (gamma-BL) to a high-molecular-weight metal-free recyclable polyester is reported. The superbase tert-Bu-P4 is found to directly initiate this polymerization through deprotonation of gamma-BL to generate reactive enolate species. When combined with a suitable alcohol, the tert-Bu-P4 -based system rapidly converts gamma-BL into polyesters with high monomer conversions (up to 90 %), high molecular weights (Mn up to 26.7 kg mol(-1) ), and complete recyclability (quantitative gamma-BL recovery). PMID- 26934185 TI - Reproducibility of blood oxygen level-dependent signal changes with end-tidal carbon dioxide alterations. AB - Hypercapnia has been utilized as a stimulus to elicit changes in cerebral blood flow (CBF). However, in many instances it has been delivered in a non-controlled method that is often difficult to reproduce. The purpose of this study was to examine the within- and between-visit reproducibility of blood oxygen level dependent (BOLD) signal changes to an iso-oxic square wave alteration in end tidal carbon dioxide partial pressure (Pet CO2 ). Two 3-Tesla (3T) MRI scans were performed on the same visit, with two square wave alterations administered per scan. The protocol was repeated on a separate visit with minimum of 3 days between scanning sessions. Pet CO2 was altered to stimulate changes in cerebral vascular reactivity (CVR), while Pet O2 was held constant. Eleven subjects (six females; mean age 26.5 +/- 5.7 years) completed the full testing protocol. Excellent within-visit square wave reproducibility (ICC > 0.75) was observed. Similarly, square waves were reproducible between scanning sessions (ICC > 0.7). This study demonstrates BOLD signal changes in response to alterations in Pet CO2 are reproducible both within- and between-visit MRI scans. PMID- 26934186 TI - Evaluation of the effects of deltamethrin on the fetal rat testis. AB - Pregnant Sprague-Dawley rats were administered deltamethrin, at doses 0.1, 1, 5 or 10 mg kg(-1) day(-1) , or di-n-hexyl phthalate (DnHP) (250 mg kg(-1) day(-1) ), by gavage, from gestational day 13 to 19. Maternal toxicity was observed at 10 mg kg(-1) day(-1) , as evidenced by transient clinical signs of neurotoxicity and reductions in body weight, body weight gain and corrected weight gain. Deltamethrin had no statistically significant effect on the incidence of post implantation loss, fetal weight or anogenital distance in the male fetuses. Unlike DnHP, deltamethrin induced no changes in the expression of several genes involved in cholesterol transport or in the steroid synthesis pathway in the testes of gestational day 19.5 male fetuses (SRB1, StAR, P450scc, 3betaHSD, P450 17 A1, 17betaHSD). Fetal testicular levels of P450scc and P450 17 A1 protein were also unaffected by deltamethrin. No statistically significant differences were observed in the ex vivo fetal testicular production of testosterone and androstenedione after deltamethrin exposure, whereas DnHP markedly reduced these parameters. The deltamethrin metabolite, 3-phenoxybenzoic acid, was detected in amniotic fluid. In summary, our results demonstrate that in utero exposure to deltamethrin during the period of sexual differentiation had no significant effect on the testosterone synthesis pathway in the male rat fetus up to a maternal toxic dose. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26934187 TI - Shaping the Growth Behaviour of Biofilms Initiated from Bacterial Aggregates. AB - Bacterial biofilms are usually assumed to originate from individual cells deposited on a surface. However, many biofilm-forming bacteria tend to aggregate in the planktonic phase so that it is possible that many natural and infectious biofilms originate wholly or partially from pre-formed cell aggregates. Here, we use agent-based computer simulations to investigate the role of pre-formed aggregates in biofilm development. Focusing on the initial shape the aggregate forms on the surface, we find that the degree of spreading of an aggregate on a surface can play an important role in determining its eventual fate during biofilm development. Specifically, initially spread aggregates perform better when competition with surrounding unaggregated bacterial cells is low, while initially rounded aggregates perform better when competition with surrounding unaggregated cells is high. These contrasting outcomes are governed by a trade off between aggregate surface area and height. Our results provide new insight into biofilm formation and development, and reveal new factors that may be at play in the social evolution of biofilm communities. PMID- 26934190 TI - Improving Protein Expression Prediction Using Extra Features and Ensemble Averaging. AB - The article focus is the improvement of machine learning models capable of predicting protein expression levels based on their codon encoding. Support vector regression (SVR) and partial least squares (PLS) were used to create the models. SVR yields predictions that surpass those of PLS. It is shown that it is possible to improve the models predictive ability by using two more input features, codon identification number and codon count, besides the already used codon bias and minimum free energy. In addition, applying ensemble averaging to the SVR or PLS models also improves the results even further. The present work motivates the test of different ensembles and features with the aim of improving the prediction models whose correlation coefficients are still far from perfect. These results are relevant for the optimization of codon usage and enhancement of protein expression levels in synthetic biology problems. PMID- 26934191 TI - A Qualitative Study to Examine Feasibility and Design of an Online Social Networking Intervention to Increase Physical Activity in Teenage Girls. AB - BACKGROUND: Online social networks present wide-reaching and flexible platforms through which to deliver health interventions to targeted populations. This study used a social marketing approach to explore teenage girls' perceptions of physical activity and the potential use of online social networks to receive a physical activity intervention. METHODS: Six focus groups were conducted with 19 Australian teenage girls (ages 13 to 18 years) with varying levels of physical activity and socioeconomic status. A semi-structured format was used, with groups discussion transcribed verbatim. Content analysis identified emergent themes, with triangulation and memos used to ensure accuracy. RESULTS: Physical activity was most appealing when it emphasised sport, exercise and fitness, along with opportunities for socialisation with friends and self-improvement. Participants were receptive to delivery of a physical activity intervention via online social networks, with Facebook the most widely reported site. Participants commonly accessed online social networks via mobile devices and particularly smartphones. Undesirable features included promotion of physical activity in terms of walking; use of cartoon imagery; use of humour; and promotion of the intervention via schools, each of which were considered "uncool". Participants noted that their parents were likely to be supportive of them using an online social networking physical activity intervention, particularly if not promoted as a weight loss intervention. CONCLUSION: This study identified key features likely to increase the feasibility and retention of an online social networking physical activity intervention for teenage girls. Guidelines for the design of interventions for teenage girls are provided for future applications. PMID- 26934189 TI - Fragmentation of CagA Reduces Hummingbird Phenotype Induction by Helicobactor pylori. AB - Infection with Helicobacter pylori (H. pylori) has been linked to various gastro intestinal diseases; nevertheless it remains to be clarified why only a minority of infected individuals develop illness. Studies from the West have indicated that the cagA gene and the associated EPIYA genotype of H. pylori is closely linked to the development of severe gastritis and gastric carcinoma; however, as yet no consistent correlation has been found among the bacteria from East Asia. In addition to genotype variation, the CagA protein undergoes fragmentation; however, the functional significance of fragmentation with respect to H. pylori infection remains unknown. In this study, we isolated 594 H. pylori colonies from 99 patients and examined the fragmentation patterns of CagA protein using immunoblotting. By analyzing the ability of the isolates to induce the host cell morphological transition to the highly invasive hummingbird phenotype, we demonstrated that H. pylori colonies with substantial CagA fragmentation are less potent in terms of causing this morphological transition. Our results uncovered a functional role for CagA fragmentation with respect to H. pylori-induced hummingbird phenotype formation and these findings suggest the possibility that the post-translational processing of CagA may be involved in H. pylori infection pathogenesis. PMID- 26934193 TI - How Variability and Effort Determine Coordination at Large Forces. AB - Motor control is a challenging task for the central nervous system, since it involves redundant degrees of freedom, nonlinear dynamics of actuators and limbs, as well as noise. When an action is carried out, which factors does your nervous system consider to determine the appropriate set of muscle forces between redundant degrees-of-freedom? Important factors determining motor output likely encompass effort and the resulting motor noise. However, the tasks used in many previous motor control studies could not identify these two factors uniquely, as signal-dependent noise monotonically increases as a function of the effort. To address this, a recent paper introduced a force control paradigm involving one finger in each hand that can disambiguate these two factors. It showed that the central nervous system considers both force noise and amplitude, with a larger weight on the absolute force and lower weights on both noise and normalized force. While these results are valid for the relatively low force range considered in that paper, the magnitude of the force shared between the fingers for large forces is not known. This paper investigates this question experimentally, and develops an appropriate Markov chain Monte Carlo method in order to estimate the weightings given to these factors. Our results demonstrate that the force sharing strongly depends on the force level required, so that for higher force levels the normalized force is considered as much as the absolute force, whereas the role of noise minimization becomes negligible. PMID- 26934192 TI - Prevalence and Predisposing Factors for Depressive Status in Chinese Patients with Obstructive Sleep Apnoea: A Large-Sample Survey. AB - BACKGROUND AND OBJECTIVE: Recently, there are few studies reporting on depressive status and obstructive sleep apnoea (OSA) in China. A large-sample survey was to be performed to explore the prevalence of depressive status and related factors in Chinese patients with OSA. METHODS: From among a randomly-selected group of OSA patients, 1,327 met inclusion criteria. After screening with the Symptom Checklist 90 (SCL-90) and Self-Rating Depression Scale (SDS), patients were assigned to OSA without depressive status (control group, n = 698) and OSA with depressive status (n = 629) groups. Using chi-squared testing, the correlation analyses between the depressive status and OSA patient demographic and clinical variables were tested. Then depression-related risk factors in OSA patients were analysed using stepwise linear regression analysis. The effects of family and social factors on depressive status in OSA patients were investigated using Mann Whitney U (one of nonparametric test). RESULTS: The prevalence of depressive status was 47.4% in OSA patients. Depressive status was significantly associated with female gender, single status, Family Burden Scale of Disease (FBS), Family APGAR Index (APGAR), apnoea-hypopnea index (AHI), and Perceived Social Support Scale (PSSS). Stepwise linear regression analysis further indicated that single status, hypoxemia, APGAR, AHI, PSSS, AHI, and FBS were all risk factors for depressive status in OSA patients. The total of the FBS score and three of its sub-factors scores (family daily activities, family relationships and mental health of family members) were higher, and the total of the APGAR score and two of its sub-factors scores (adaptability and affection) were lower in OSA with depressive status compared with the control group. Besides, the total score for the PSSS and scores for its two sub-factors (family support and social support) were all lower in OSA patients with depressive status than those of the control group. CONCLUSIONS: Depressive status has high comorbid rate in Chinese OSA patients and is significantly associated with single status, apnoea-hypopnea index, hypoxemia, family and social supports. PMID- 26934194 TI - Accumulating evidence for a role of TCF7L2 variants in bipolar disorder with elevated body mass index. AB - OBJECTIVES: Bipolar disorder (BD) is a complex disease associated with various hereditary traits, including a higher body mass index (BMI). In a prior genome wide association study, we found that BMI modified the association of rs12772424 a common variant in the gene encoding transcription factor 7-like 2 (TCF7L2) - with risk for BD. TCF7L2 is a transcription factor in the canonical Wnt pathway, involved in multiple disorders, including diabetes, cancer and psychiatric conditions. Here, using an independent sample, we evaluated 26 TCF7L2 single nucleotide polymorphisms (SNPs) to explore further the association of BD with the TCF7L2-BMI interaction. METHODS: Using a sample of 662 BD cases and 616 controls, we conducted SNP-level and gene-level tests to assess the evidence for an association between BD and the interaction of BMI and genetic variation in TCF7L2. We also explored the potential mechanism behind the detected associations using human brain expression quantitative trait loci (eQTL) analysis. RESULTS: The analysis provided independent evidence of an rs12772424-BMI interaction (p = 0.011). Furthermore, while overall there was no evidence for SNP marginal effects on BD, the TCF7L2-BMI interaction was significant at the gene level (p = 0.042), with seven of the 26 SNPs showing SNP-BMI interaction effects with p < 0.05. The strongest evidence of interaction was observed for rs7895307 (p = 0.006). TCF7L2 expression showed a significant enrichment of association with the expression of other genes in the Wnt canonical pathway. CONCLUSIONS: The current study provides further evidence suggesting that TCF7L2 involvement in BD risk may be regulated by BMI. Detailed, prospective assessment of BMI, comorbidity, and other possible contributing factors is necessary to explain fully the mechanisms underlying this association. PMID- 26934195 TI - Hypomagnesemia linked to new-onset diabetes mellitus after kidney transplantation: A systematic review and meta-analysis. AB - BACKGROUND: New-onset diabetes after kidney transplantation (NODAT) is associated with both renal allograft failure and increased mortality. The objective of this meta-analysis was to evaluate the risk of NODAT in patients with hypomagnesemia. METHODS: A literature search was performed using MEDLINE, EMBASE, and Cochrane Database of Systematic Reviews from inception through May, 2015. Studies that reported relative risks, odd ratios or hazard ratios comparing the risk of NODAT in patients with hypomagnesemia were included. Pooled risk ratios (RR) and 95% confidence interval (CI) were calculated using a random-effect, generic inverse variance method. RESULTS: Five cohort studies with 1699 patients were included in the analysis to assess the risk of NODAT in patients with hypomagnesemia. The pooled RR of NODAT in patients with hypomagnesemia was 1.25 (95% CI, 1.08-1.45). When meta-analysis was limited only to studies with the post-transplant hypomagnesemia, the pooled RR of NODAT was 1.22 (95% CI, 1.09-1.38). CONCLUSION: Our meta-analysis demonstrates a significant association between hypomagnesemia and NODAT in kidney transplant recipients. This finding suggests the need for a large randomized controlled trial-with very careful attention to assess the effects of normalizing Mg levels and the risk of NODAT. PMID- 26934197 TI - Prognostic impact of pathological response to neoadjuvant chemotherapy followed by definitive surgery in sinonasal squamous cell carcinoma. AB - BACKGROUND: The significance of neoadjuvant chemotherapy followed by definitive surgery for sinonasal squamous cell carcinoma (SCC) was investigated using surgical specimens. METHODS: Surgery was performed in 58 patients, including 43 patients who had received neoadjuvant chemotherapy. The pathological response was classified as grades 0 (no effect), 1 (slight effect), 2 (moderate effect), and 3 (marked effect), and its correlation with prognosis was investigated. RESULTS: Grade 2 or 3 response was observed in 34.9% of cases that received neoadjuvant chemotherapy. Overall survival (OS), disease-free survival (DFS), locoregional control, and freedom from distant metastasis were significantly better in the effective neoadjuvant chemotherapy group (grades 2 and 3) than in the less effective neoadjuvant chemotherapy group (grades 0 and 1) and the non-neoadjuvant chemotherapy group combined. CONCLUSION: Pathological response to neoadjuvant chemotherapy in sinonasal SCC was related to disease prognosis. (c) 2016 Wiley Periodicals, Inc. Head Neck 38: E1305-E1311, 2016. PMID- 26934198 TI - Design and Development of Novel 4-(4-(1H-Tetrazol-5-yl)-1H-pyrazol-1-yl)-6 morpholino-N-(4-nitrophenyl)-1,3,5-triazin-2-amine as Cardiotonic Agent via Inhibition of PDE3. AB - The classical phosphodiesterase 3A (PDE3A) inhibitors provide relaxation of the vasculature system via increasing the cellular level of cyclic adenosine monophosphate (cAMP) and proved to be useful in the management of congestive heart failure. Consequently, the present paper deals with the development of novel pyrazole derivatives tethered with substituted 1,3,5-triazine derivatives in search for novel PDE3 inhibitors. The synthesis of designed inhibitors was realized in a multi-step reaction and the structures were ascertained with the help of various spectroscopic techniques. Subsequently, these analogs were tested for their inhibitory activities against PDE3 enzymes, where they exhibited considerable inhibition, revealing 9g as the most promising inhibitor of the class. In a docking study, the morpholine fragment of compound 9g was efficiently engulfed in the small pocket of the active site lined by Gly940 and Pro941. The substituted aromatic ring of the core scaffold was found to be positioned deep in the cavity bordered by Tyr829, Asn830, Leu850, Glu851, and Thr893. Moreover, it considerably improved the contractility of cardiac muscles without altering the heart beat frequency in experimental subjects. PMID- 26934196 TI - Streptococcus mutans Can Modulate Biofilm Formation and Attenuate the Virulence of Candida albicans. AB - Streptococcus mutans and Candida albicans are found together in the oral biofilms on dental surfaces, but little is known about the ecological interactions between these species. Here, we studied the effects of S. mutans UA159 on the growth and pathogencity of C. albicans. Initially, the effects of S. mutans on the biofilm formation and morphogenesis of C. albicans were tested in vitro. Next, we investigate the influence of S. mutans on pathogenicity of C. albicans using in vivo host models, in which the experimental candidiasis was induced in G. mellonella larvae and analyzed by survival curves, C. albicans count in hemolymph, and quantification of hyphae in the host tissues. In all the tests, we evaluated the direct effects of S. mutans cells, as well as the indirect effects of the subproducts secreted by this microorganism using a bacterial culture filtrate. The in vitro analysis showed that S. mutans cells favored biofilm formation by C. albicans. However, a reduction in biofilm viable cells and inhibition of hyphal growth was observed when C. albicans was in contact with the S. mutans culture filtrate. In the in vivo study, injection of S. mutans cells or S. mutans culture filtrate into G. mellonella larvae infected with C. albicans increased the survival of these animals. Furthermore, a reduction in hyphal formation was observed in larval tissues when C. albicans was associated with S. mutans culture filtrate. These findings suggest that S. mutans can secrete subproducts capable to inhibit the biofilm formation, morphogenesis and pathogenicity of C. albicans, attenuating the experimental candidiasis in G. mellonella model. PMID- 26934199 TI - Serotonin Syndrome Following Methylene Blue Administration for Vasoplegic Syndrome. AB - Methylene blue (MB) has been used for additional blood pressure support in patients who develop severe, refractory vasoplegia; however, MB can induce serotonin syndrome, especially when used in conjunction with other serotonergic agents. We describe a case of serotonin syndrome in a patient who received MB for vasoplegic syndrome after left ventricular assist device implantation and discuss its presentation and management. PMID- 26934200 TI - Evaluation of an interprofessional team-based learning nutrition and lifestyle modification course. AB - An interprofessional, team-based learning elective was developed, implemented, and evaluated to determine the knowledge gained, attitude changes towards interprofessional education, and overall satisfaction with the course. Thirty participants, 14 osteopathic medicine students and 16 pharmacy students, completed the course. The majority of students (88-96%) responded favourably to the team-based learning aspects of the course. Knowledge about nutrition and lifestyle modification was significantly improved by taking the course. Overall, students' readiness for and perception of interprofessional learning improved by taking the course, although not all improvements were statistically significant. In conclusion, the benefits of team-based learning, such as enhancing communication and teamwork skills, can enhance interprofessional education. PMID- 26934202 TI - Subclinical Tick-Borne Encephalitis Virus in Experimentally Infected Apodemus agrarius. AB - OBJECTIVES: In this study, we investigated the dose dependence of tick-borne encephalitis virus (TBEV) infection in one of the reservoirs, i.e. Apodemus agrarius, a small rodent species. METHODS: The animals were challenged with TBEV per os and intramuscularly with infectious doses ranging from 1 to 1,500 plaque forming units (pfu). Clinical signs were recorded and clinical and pathological features were evaluated by histological, immunohistochemical, and serological methods. RESULTS: High perorally administered infectious doses resulted in virus replication in the brain, which is the first sign of subclinical viral encephalitis in the Apodemus genus. The animals seroconverted at infectious doses greater than 100 pfu, and all animals remained asymptomatic. CONCLUSION: Our work shows the first evidence that subclinical TBEV encephalitis may occur in Apodemus species, depending on the virus load of the inoculum. The antiviral response of the local innate immune system may influence the resistance of Apodemus individuals to lower infectious doses. Per oral/nasal infection seems to be more dangerous for the host than other routes of infection. PMID- 26934203 TI - Catalase-Modified Carbon Electrodes: Persuading Oxygen To Accept Four Electrons Rather Than Two. AB - We successfully exploited the natural highly efficient activity of an enzyme (catalase) together with carbon electrodes to produce a hybrid electrode for oxygen reduction, very appropriate for energy transformation. Carbon electrodes, in principle, are cheap but poor oxygen reduction materials, because only two electron reduction of oxygen occurs at low potentials, whereas four-electron reduction is key for energy-transformation technology. With the immobilization of catalase on the surface, the hydrogen peroxide produced electrochemically is decomposed back to oxygen by the enzyme; the enzyme natural activity on the surface regenerates oxygen, which is further reduced by the carbon electrode with no direct electron transfer between the enzyme and the electrode. Near full four electron reduction of oxygen is realised on a carbon electrode, which is modified with ease by a commercially available enzyme. The value of such enzyme-modified electrode for energy-transformation devices is evident. PMID- 26934201 TI - AMP-activated protein kinase: a cellular energy sensor that comes in 12 flavours. AB - The AMP-activated protein kinase (AMPK) is a sensor of cellular energy status that is expressed in essentially all eukaryotic cells, suggesting that it arose during early eukaryotic evolution. It occurs universally as heterotrimeric complexes containing catalytic alpha subunits and regulatory beta and gamma subunits. Although Drosophila melanogaster contains single genes encoding each subunit, in mammals, each subunit exists as multiple isoforms encoded by distinct genes, giving rise to up to 12 heterotrimeric combinations. The multiple isoforms of each subunit are 2R-ohnologues generated by the two rounds of whole genome duplication that occurred at the evolutionary origin of the vertebrates. Although the differential roles of these isoform combinations remain only partly understood, there are indications that they may have different subcellular locations, different inputs and outputs, and different functions. The multiple isoforms are of particular interest with respect to the roles of AMPK in cancer because the genes encoding some isoforms, such as PRKAA1 and PRKAB2 (encoding alpha1 and beta2), are quite frequently amplified in tumour cells, whereas the genes encoding others, such as PRKAA2 (encoding alpha2), tend to be mutated, which, in some but not all cases, may result in a loss of function. Thus, although AMPK acts downstream of the tumour suppressor liver kinase B1, and some of its isoform combinations may act as tumour suppressors that restrain the growth and proliferation of tumour cells, other isoform combinations may paradoxically act as oncogenes, perhaps by aiding the survival of tumour cells undergoing environmental stresses such as hypoxia or nutrient deprivation. PMID- 26934204 TI - Cyanidin 3-O-beta-Glucoside Ameliorates Ethanol-Induced Acute Liver Injury by Attenuating Oxidative Stress and Apoptosis: The Role of SIRT1/FOXO1 Signaling. AB - BACKGROUND: The aim of this study was to examine the effects of Cyanidin 3-O-beta glucoside (C3G) on ethanol (EtOH)-induced acute liver injury in mice as well as in cultured hepatic cells exposed to EtOH, with a focus on the involvement of Silent Mating Type Information Regulation 2 Homolog 1 (SIRT1)/Forkhead fox-O-1 (FOXO1) signaling pathway, and to explore the underlying molecular mechanisms. METHODS: C57BL/6 adolescent male mice were given EtOH via intraperitoneal injection for 2 consecutive days, and the changes in the livers were detected via hematoxylin-eosin staining. The levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured by biochemical methods. Protein expression of SIRT1, FOXO1, acetylated FOXO1 (ac-FOXO1), GRP78, p-eukaryotic initiation factor-2 (eIF2alpha), and apoptosis (p-JNK, p-c-Jun, and Bax) parameters was determined by Western blot. Reactive oxygen species (ROS) was detected by flow cytometry. Human hepatocytes Chang cell line was used to assay cell apoptosis by Annexin V and propidium iodide. In addition, mRNA levels of SIRT1, tumor necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6), and monocyte chemoattractant protein 1 in liver tissues were detected by real-time polymerase chain reaction. RESULTS: This study demonstrated that C3G (10 mg/kg) administration diminished EtOH-induced acute liver injury compared to control group, as evidenced by the significant decreases in ALT and AST levels. Pretreatment with C3G exerted anti-inflammatory effects as indicated by the decreased TNF-alpha and IL-6 levels, as well as decreased inflammatory foci and ballooning cells in liver tissue. The lessened hepatic injury was associated with enhanced SIRT1 protein expression and activity by C3G in vitro and in vivo. C3G treatment also provoked significant attenuation of endoplasmic reticulum stress parameters (GRP78, p-eIF2alpha), which was consistent with reduced levels of both p-c-Jun and Bax. Interestingly, EX527 inhibitor did not affect the protective function of C3G on alcohol-induced cell apoptosis. Moreover, alcohol exposure increased ROS level and decreased ac-FOXO1, while C3G intervention reversed this abnormality, and this may be related to SIRT1 activity by C3G. CONCLUSIONS: Anthocyanin C3G has significant potency in antioxidant, anti-inflammatory, and anti-apoptotic effects on hepatocytes exposed to EtOH by modulating the SIRT1/FOXO1 signaling pathway. Our findings illustrate a novel and definitive therapeutic action of C3G and represent an economically feasible therapeutic intervention to treat alcoholic liver disease. PMID- 26934206 TI - Laboratory investigation of three distinct emissions monitors for hydrochloric acid. AB - : The measurement of hydrochloric acid (HCl) on a continuous basis in coal-fired plants is expected to become more important if HCl standards become implemented as part of the Federal Mercury and Air Toxics Standards (MATS) standards that are under consideration. For this study, the operational performance of three methods/instruments, including tunable diode laser absorption spectroscopy (TDLAS), cavity ring down spectroscopy (CRDS), and Fourier transform infrared (FTIR) spectroscopy, were evaluated over a range of real-world operating environments. Evaluations were done over an HCl concentration range of 0-25 ppmv and temperatures of 25, 100, and 185 degrees C. The average differences with respect to temperature were 3.0% for the TDL for values over 2.0 ppmv and 6.9% of all concentrations, 3.3% for the CRDS, and 4.5% for the FTIR. Interference tests for H2O, SO2, and CO, CO2, and NO for a range of concentrations typical of flue gases from coal-fired power plants did not show any strong interferences. The possible exception was an interference from H2O with the FTIR. The instrument average precision over the entire range was 4.4% for the TDL with better precision seen for concentrations levels of 2.0 ppmv and above, 2.5% for the CRDS, and 3.5% for the FTIR. The minimum detection limits were all on the order of 0.25 ppmv, or less, utilizing the TDL values with a 5-m path. Zero drift was found to be 1.48% for the TDL, 0.88% for the CRDS, and 1.28% for the FTIR. IMPLICATIONS: This study provides an evaluation of the operational performance of three methods/instruments, including TDL absorption spectroscopy (TDLAS), cavity ring down spectroscopy (CRDS), and FTIR spectroscopy, for the measurement of hydrochloric acid (HCl) over a range of real-world operating environments. The results showed good instrument accuracy as a function of temperature and no strong interferences for flue gases typical to coal-fired power plants. The results show that these instruments would be viable for the measurement of HCl in coal-fired plants if HCl standards become implemented as part of the Federal Mercury and Air Toxics Standards (MATS) standards that are under consideration. PMID- 26934205 TI - Diversity-Oriented Combinatorial Biosynthesis of Hybrid Polyketide Scaffolds from Azaphilone and Benzenediol Lactone Biosynthons. AB - Two disparate polyketide families, the benzenediol lactones and the azaphilones, are produced by fungi using iterative polyketide synthase (iPKS) enzymes consisting of collaborating partner subunits. Exploitation of this common biosynthetic logic using iPKS subunit shuffling allowed the diversity-oriented combinatorial biosynthesis of unprecedented polyketide scaffolds new to nature, bearing structural motifs from both of these orthogonal natural product families. Starter unit acyltransferase domain replacements proved necessary but not sufficient to guarantee communication between iPKS subunits. PMID- 26934207 TI - L-arginine, an active component of salmon milt nucleoprotein, promotes thermotolerance via Sirtuin in Caenorhabditis elegans. AB - We previously showed that salmon milt nucleoprotein (NP) promotes thermotolerance in Caenorhabditis elegans; however, the active component and physiological mechanism of this effect has remained unclear. l-arginine (AR) is a major component of protamine and thus it has been proposed as the possible active component of NP. In this study, the viability of C. elegans treated with AR under heat stress was assessed and AR was shown to extend the survival term of the heat stressed organisms. Additionally, AR was shown to restore the thrashing movement of the worms that is suppressed by heat stress. Treatment with AR was furthermore shown to promote thermotolerance in a DAF-16- and SIR-2.1-dependent manner, where DAF-16 and SIR-2.1 are homologs of FoxO and SirT1, respectively. Taken together, these data suggest that AR is one of the active components of NP and promotes thermotolerance via the activation of DAF-16 and SIR-2.1. PMID- 26934208 TI - Does evidence influence policy? Resource allocation and the Indigenous Burden of Disease study. AB - Objective The Indigenous Burden of Disease (IBoD) report is the most comprehensive assessment of Indigenous disease burden in Australia. The aim of the present study was to investigate the potential effect of the IBoD report on Australian Indigenous health policy, service expenditure and research funding. Findings have significance for understanding factors that may influence Indigenous health policy. Methods The potential effect of the IBoD report was considered by: (1) conducting a text search of pertinent documents published by the federal government, Council of Australian Governments and the National Health and Medical Research Council of Australia (NHMRC) and observing the quantity and quality of references to IBoD; (2) examining data on government Indigenous healthcare expenditure for trends consistent with the findings and policy implications of the IBoD report; and (3) examining NHMRC Indigenous grant allocation trends consistent with the findings and policy implications of the IBoD report. Results Of 110 government and NHMRC documents found, IBoD was cited in 27. Immediately after publication of the IBoD report, federal and state governments increased Indigenous health spending (relative to non-Indigenous), notably for community health and public health at the state level. Expenditure on Indigenous hospital separations for chronic diseases also increased. These changes are broadly consistent with the findings of the IBoD report on the significance of chronic disease and the need to address certain risk factors. However, there is no evidence that such changes had a causal connection with the IBoD study. After publication of the IBoD report, changes in NHMRC Indigenous research funding showed little consistency with the findings of the IBoD report. Conclusions The present study found only indirect and inconsistent correlational evidence of the potential influence of the IBoD report on Indigenous health expenditure and research funding. Further assessment of the potential influence of the IBoD report on Indigenous health policy will require more targeted research, including interviews with key informants involved in developing health policy. What is known about the topic? There are currently no publications that consider the potential effed of the IBoD study on Indigenous health expenditure and research funding. What does this paper add? This paper offers the first consideration of the potential effect of the IBoD report. It contains analyses of data from readily available sources, examining national expenditures on Indigenous health and NHMRC Indigenous research, before and after the publication of the IBoD report. What are the implications for practitioners? The paper is relevant to analysts interested in drivers of Indigenous health policy. Although it finds correlations between the release of the IBoD report and some subsequent health spending decisions, other factors should be investigated to better understand the complexity of processes that drive government efforts to improve Indigenous health. PMID- 26934209 TI - Linked Nickel Metallacrowns from a Phosphonate/2-Pyridyloximate Blend of Ligands: Structure and Magnetic Properties. AB - In the present work, four new Ni(II) clusters with nuclearities ranging between Ni4 and Na2Ni8 were synthesized, employing the versatile ligand phenylphosphonate and 6-methylpyridylaldoximate as the coligand. Crystallographic data show that the tetranuclear complex [Ni4(6-MepaoH)4(PhPO3)2(OH)2(MeOH)4](OH)2 (1) consists of two dimers linked by phosphonate bridges, whereas [Cs2Ni6(6 Mepao)6(PhPO3)3(OH)2(H2O)8] (2), Cs[Ni8(6-MepaoH)6(6-Mepao)6(PhPO3)3](ClO4)5 (3), and [Ni8Na2(BzO)6(6-Mepao)6(PhPO3)3] (4) are built from phosphonato-linked {Ni3(6 Mepao)3} metallacycles. The [9-MC(Ni(II)(6-Mepao))-3] fragments in 2-4 show the unusual coordination of additional Cs(+), Na(+), and/or Ni(II) cations. Direct current magnetic measurements were carried in the 300-2 K range. Analysis of the experimental data revealed a complex response with strong antiferromagnetic interactions mediated by the oximato bridges and weak interactions mediated by the phosphonate ones. PMID- 26934210 TI - Microbial diversity in an anaerobic digester with biogeographical proximity to geothermally active region. AB - Anaerobic digestion of agricultural biomass or wastes can offer renewable energy, to help meet the rise in energy demands. The performance of an anaerobic digester considerably depends upon the complex interactions between bacterial and archaeal microbiome, which is greatly influenced by environmental factors. In the present study, we evaluate a microbial community of digester located at two different geographical locations, to understand whether the biogeographical proximity of a digester to a geothermally active region has any influence on microbial composition. The comparative microbial community profiling, highlights coexistence of specific bacterial and archaeal representatives (especially, Prosthecochloris sp., Conexibacter sp., Crenarchaeota isolate (Caldivirga sp.), Metallosphaera sp., Pyrobaculum sp. and Acidianus sp.) in a digester with close proximity to geothermally active region (Site I) and their absence in a digester located far-off from geothermally active region (Site II). A Sorensen's index of similarity of 83.33% and 66.66% for bacterial and archaeal community was observed in both the reactors, respectively. PMID- 26934211 TI - Rehabilitation for Chronic Ankle Instability With or Without Destabilization Devices: A Randomized Controlled Trial. AB - CONTEXT: Individuals with chronic ankle instability (CAI) have deficits in neuromuscular control and altered movement patterns. Ankle-destabilization devices have been shown to increase lower extremity muscle activity during functional tasks and may be useful tools for improving common deficits and self reported function. OBJECTIVE: To determine whether a 4-week rehabilitation program that includes destabilization devices has greater effects on self reported function, range of motion (ROM), strength, and balance than rehabilitation without devices in patients with CAI. DESIGN: Randomized controlled clinical trial. SETTING: Laboratory. PATIENTS OR OTHER PARTICIPANTS: A total of 26 patients with CAI (7 men, 19 women; age = 21.34 +/- 3.06 years, height = 168.96 +/- 8.77 cm, mass = 70.73 +/- 13.86 kg). INTERVENTION(S): Patients completed baseline measures and were randomized into no-device and device groups. Both groups completed 4 weeks of supervised, impairment-based progressive rehabilitation with or without devices and then repeated baseline measures. MAIN OUTCOME MEASURE(S): We assessed self-reported function using the Foot and Ankle Ability Measure. Ankle ROM was measured with an inclinometer. Ankle strength was assessed using a handheld dynamometer during maximal voluntary isometric contractions. Balance was measured using a composite score of 3 reach directions from the Star Excursion Balance Test and a force plate to calculate center of pressure during eyes-open and eyes-closed single-limb balance. We compared each dependent variable using a 2 * 2 (group * time) analysis of variance and post hoc tests as appropriate and set an a priori alpha level at .05. The Hedges g effect sizes and associated 95% confidence intervals were calculated. RESULTS: We observed no differences between the no-device and device groups for any measure. However, both groups had large improvements in self reported function and ankle strength. CONCLUSIONS: Incorporating destabilization devices into rehabilitation did not improve ankle function more effectively than traditional rehabilitation tools because both interventions resulted in similar improvements. Impairment-based progressive rehabilitation improved clinical outcomes associated with CAI. PMID- 26934212 TI - Diagnostic Performance of Split-Bolus Portal Venous Phase Dual-Energy CT Urography in Patients With Hematuria. AB - OBJECTIVE: The purpose of this study is to evaluate the diagnostic performance of split-bolus portal venous phase dual-energy CT (DECT) urography in patients with hematuria. MATERIALS AND METHODS: True unenhanced and split-bolus portal venous phase contrast-enhanced weighted-average images were obtained in 171 patients with hematuria. Virtual unenhanced and iodine-overlay images were reconstructed from contrast-enhanced 80-kVp and tin-filtered 140-kVp scans. Images were independently reviewed by two radiologists who were blinded to the final diagnoses in two separate reading sessions: virtual unenhanced and iodine-overlay images (single phase) in the first session and true unenhanced and contrast enhanced weighted-average images (dual phase) in the second session (mean +/- SD, 52 +/- 8 days later). Sensitivity, specificity, and accuracy of mass detection were calculated from the data of both reading sessions. The number of calculi detected on virtual unenhanced images was compared with the number detected on true unenhanced images. The difference in radiation dose between the single- and dual-phase protocols was calculated. The statistical significance was determined by ANOVA. RESULTS: The sensitivity, specificity, and accuracy were 98.7%, 98.9%, and 98.8%, respectively, for the single-phase approach to malignant mass detection and 98.7%, 97.9%, and 98.3%, respectively, for the dual-phase approach (p > 0.05 for all comparisons). The overall sensitivity of stone detection was 86.7% (39/45) for virtual unenhanced images. Omitting the unenhanced scan reduced the mean radiation dose from 15.4 to 6.7 mSv. CONCLUSION: The diagnostic performance of both the single- and dual-phase approaches of portal venous phase split-bolus DECT urography is equally good in patients with hematuria, and single phase acquisition has the added benefit of radiation reduction. PMID- 26934213 TI - Integrative Taxonomic Approach for Describing a New Cryptic Species of Bush Frog (Raorchestes: Anura: Rhacophoridae) from the Western Ghats, India. AB - A new cryptic species of bush frog Raorchestes honnametti sp. nov. is described from the south-eastern part of the Western Ghats, India. This newly described species belongs to the Charius clade and is morphologically similar to other clade members--R. charius and R. griet. Therefore, an integrative taxonomic approach based on molecular and bioacoustic analysis along with morphology was used to delimit the new species. Raorchestes honnametti sp. nov., is currently known only from Biligiri Rangaswamy Temple Tiger Reserve, a part of Biligiri Rangaswamy horst mountain range (a mountain formed due movement of two faults) formed during the Late Quaternary period (1.8-2.58 Ma). Discovery of cryptic species from a highly speciose and well-studied genus Raorchestes hints at the possible existence of several more cryptic species in this genus. We discuss the possible reasons for crypsis and emphasize the need for continued systematic surveys of amphibians across the Western Ghats. PMID- 26934217 TI - AFM-based tribological study of nanopatterned surfaces: the influence of contact area instabilities. AB - Although the importance of morphology on the tribological properties of surfaces has long been proved, an exhaustive understanding of nanopatterning effects is still lacking due to the difficulty in both fabricating 'really nano-' structures and detecting their tribological properties. In the present work we show how the probe-surface contact area can be a critical parameter due to its remarkable local variability, making a correct interpretation of the data very difficult in the case of extremely small nanofeatures. Regular arrays of parallel 1D straight nanoprotrusions were fabricated by means of a low-dose focused ion beam, taking advantage of the amorphization-related swelling effect. The tribological properties of the patterns were detected in the presence of air and in vacuum (dry ambient) by atomic force microscopy. We have introduced a novel procedure and data analysis to reduce the uncertainties related to contact instabilities. The real time estimation of the radius of curvature of the contacting asperity enables us to study the dependence of the tribological properties of the patterns from their geometrical characteristics. The effect of the patterns on both adhesion and the coefficient of friction strongly depends on the contact area, which is linked to the local radius of curvature of the probe. However, a detectable hydrophobic character induced on the hydrophilic native SiO2 has been observed as well. The results suggest a scenario for capillary formation on the patterns. PMID- 26934216 TI - Assessing use of a printed lifestyle intervention tool by women with borderline gestational diabetes and their achievement of diet and exercise goals: a descriptive study. AB - BACKGROUND: The purpose of this study is to assess use of a booklet by pregnant women to record and assist dietary and lifestyle changes; to describe diet and exercise goals set during the initial lifestyle discussions; and to assess achievement of goals. METHODS: Participants were women with borderline gestational diabetes who received a printed pregnancy record booklet, as part of a randomised trial, to record and set monthly goals for diet and exercise. Outcomes included women's use of the booklets and their achievement of dietary and exercise goals after 1 month. RESULTS: Fifty-six women returned their used pregnancy record booklets and were included in this study. These women set a total of 197 dietary goals and 65 exercise goals. In the first month, over 80% of dietary goals that targeted grains, dairy and overall diet were achieved, but only 20-30% of goals about vegetables, and foods high in fat, sugar and/or salt were achieved. After 1 month, women had achieved 86.4% of their exercise goals to maintain their current level of activity, but only 25.0 % exercise goals to increase walking during pregnancy. CONCLUSIONS: Women who used pregnancy record booklets reported good achievement rates for goals related to grains, fruits, dairy and overall diet, but they were less likely to be successful in achieving goals to increase intake of vegetables, and limit foods that high in fat, sugar and/or salt. Maintaining an active lifestyle during pregnancy was feasible for women although increases in physical activity were less often achieved. Using a pregnancy record booklet may be helpful in assisting and encouraging behavioural changes, although further investigations of long-term effects and in different populations are warranted. PMID- 26934218 TI - Ultrastructural hepatocytic alterations induced by silver nanoparticle toxicity. AB - Silver nanoparticles (SNPs) are widely used in nanomedicine and consuming products with potential risk to human health. While considerable work was carried out on the molecular, biochemical, and physiological alterations induced by these particles, little is known of the ultrastructural pathological alterations that might be induced by nanosilver materials. The aim of the present work is to investigate the hepatocyte ultrastructural alterations that might be induced by SNP exposure. Male rats were subjected to a daily single dose (2 mg/kg) of SNPs (15-35 nm diameter) for 21 days. Liver biopsies from all rats under study were processed for transmission electron microscopy examination. The following hepatic ultrastructural alterations were demonstrated: mitochondria swelling and crystolysis, endoplasmic reticulum disruption, cytoplasmic vacuolization, lipid droplets accumulation, glycogen depletion, karyopyknosis, apoptosis, sinusoidal dilatation, Kupffer cells activation, and myelin figures formation. The current findings may indicate that SNPs can induce hepatocyte organelles alteration, leading to cellular damage that may affect the function of the liver. These findings might indicate that SNPs potentially trigger heptocyte ultrastructural alterations that may affect the function of the liver with potential risk on human health in relation to numerous applications of these particles. More work is needed to elucidate probable ultrastructural alterations in the vital organs that might result from nanosilver toxicity. PMID- 26934219 TI - Continuity of Private Health Insurance Coverage After Traumatic Brain Injury. PMID- 26934214 TI - Raised Intracellular Calcium Contributes to Ischemia-Induced Depression of Evoked Synaptic Transmission. AB - Oxygen-glucose deprivation (OGD) leads to depression of evoked synaptic transmission, for which the mechanisms remain unclear. We hypothesized that increased presynaptic [Ca2+]i during transient OGD contributes to the depression of evoked field excitatory postsynaptic potentials (fEPSPs). Additionally, we hypothesized that increased buffering of intracellular calcium would shorten electrophysiological recovery after transient ischemia. Mouse hippocampal slices were exposed to 2 to 8 min of OGD. fEPSPs evoked by Schaffer collateral stimulation were recorded in the stratum radiatum, and whole cell current or voltage clamp recordings were performed in CA1 neurons. Transient ischemia led to increased presynaptic [Ca2+]i, (shown by calcium imaging), increased spontaneous miniature EPSP/Cs, and depressed evoked fEPSPs, partially mediated by adenosine. Buffering of intracellular Ca2+ during OGD by membrane-permeant chelators (BAPTA AM or EGTA-AM) partially prevented fEPSP depression and promoted faster electrophysiological recovery when the OGD challenge was stopped. The blocker of BK channels, charybdotoxin (ChTX), also prevented fEPSP depression, but did not accelerate post-ischemic recovery. These results suggest that OGD leads to elevated presynaptic [Ca2+]i, which reduces evoked transmitter release; this effect can be reversed by increased intracellular Ca2+ buffering which also speeds recovery. PMID- 26934222 TI - Corrigendum: Observation of polar vortices in oxide superlattices. PMID- 26934221 TI - Vast assembly of vocal marine mammals from diverse species on fish spawning ground. AB - Observing marine mammal (MM) populations continuously in time and space over the immense ocean areas they inhabit is challenging but essential for gathering an unambiguous record of their distribution, as well as understanding their behaviour and interaction with prey species. Here we use passive ocean acoustic waveguide remote sensing (POAWRS) in an important North Atlantic feeding ground to instantaneously detect, localize and classify MM vocalizations from diverse species over an approximately 100,000 km(2) region. More than eight species of vocal MMs are found to spatially converge on fish spawning areas containing massive densely populated herring shoals at night-time and diffuse herring distributions during daytime. We find the vocal MMs divide the enormous fish prey field into species-specific foraging areas with varying degrees of spatial overlap, maintained for at least two weeks of the herring spawning period. The recorded vocalization rates are diel (24 h)-dependent for all MM species, with some significantly more vocal at night and others more vocal during the day. The four key baleen whale species of the region: fin, humpback, blue and minke have vocalization rate trends that are highly correlated to trends in fish shoaling density and to each other over the diel cycle. These results reveal the temporospatial dynamics of combined multi-species MM foraging activities in the vicinity of an extensive fish prey field that forms a massive ecological hotspot, and would be unattainable with conventional methodologies. Understanding MM behaviour and distributions is essential for management of marine ecosystems and for accessing anthropogenic impacts on these protected marine species. PMID- 26934220 TI - Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys. AB - The most recent Ebola virus outbreak in West Africa, which was unprecedented in the number of cases and fatalities, geographic distribution, and number of nations affected, highlights the need for safe, effective, and readily available antiviral agents for treatment and prevention of acute Ebola virus (EBOV) disease (EVD) or sequelae. No antiviral therapeutics have yet received regulatory approval or demonstrated clinical efficacy. Here we report the discovery of a novel small molecule GS-5734, a monophosphoramidate prodrug of an adenosine analogue, with antiviral activity against EBOV. GS-5734 exhibits antiviral activity against multiple variants of EBOV and other filoviruses in cell-based assays. The pharmacologically active nucleoside triphosphate (NTP) is efficiently formed in multiple human cell types incubated with GS-5734 in vitro, and the NTP acts as an alternative substrate and RNA-chain terminator in primer-extension assays using a surrogate respiratory syncytial virus RNA polymerase. Intravenous administration of GS-5734 to nonhuman primates resulted in persistent NTP levels in peripheral blood mononuclear cells (half-life, 14 h) and distribution to sanctuary sites for viral replication including testes, eyes, and brain. In a rhesus monkey model of EVD, once-daily intravenous administration of 10 mg kg(-1) GS-5734 for 12 days resulted in profound suppression of EBOV replication and protected 100% of EBOV-infected animals against lethal disease, ameliorating clinical disease signs and pathophysiological markers, even when treatments were initiated three days after virus exposure when systemic viral RNA was detected in two out of six treated animals. These results show the first substantive post exposure protection by a small-molecule antiviral compound against EBOV in nonhuman primates. The broad-spectrum antiviral activity of GS-5734 in vitro against other pathogenic RNA viruses, including filoviruses, arenaviruses, and coronaviruses, suggests the potential for wider medical use. GS-5734 is amenable to large-scale manufacturing, and clinical studies investigating the drug safety and pharmacokinetics are ongoing. PMID- 26934223 TI - Failure of RQC machinery causes protein aggregation and proteotoxic stress. AB - Translation of messenger RNAs lacking a stop codon results in the addition of a carboxy-terminal poly-lysine tract to the nascent polypeptide, causing ribosome stalling. Non-stop proteins and other stalled nascent chains are recognized by the ribosome quality control (RQC) machinery and targeted for proteasomal degradation. Failure of this process leads to neurodegeneration by unknown mechanisms. Here we show that deletion of the E3 ubiquitin ligase Ltn1p in yeast, a key RQC component, causes stalled proteins to form detergent-resistant aggregates and inclusions. Aggregation is dependent on a C-terminal alanine/threonine tail that is added to stalled polypeptides by the RQC component, Rqc2p. Formation of inclusions additionally requires the poly-lysine tract present in non-stop proteins. The aggregates sequester multiple cytosolic chaperones and thereby interfere with general protein quality control pathways. These findings can explain the proteotoxicity of ribosome-stalled polypeptides and demonstrate the essential role of the RQC in maintaining proteostasis. PMID- 26934225 TI - MARCKS-like protein is an initiating molecule in axolotl appendage regeneration. AB - Identifying key molecules that launch regeneration has been a long-sought goal. Multiple regenerative animals show an initial wound-associated proliferative response that transits into sustained proliferation if a considerable portion of the body part has been removed. In the axolotl, appendage amputation initiates a round of wound-associated cell cycle induction followed by continued proliferation that is dependent on nerve-derived signals. A wound-associated molecule that triggers the initial proliferative response to launch regeneration has remained obscure. Here, using an expression cloning strategy followed by in vivo gain- and loss-of-function assays, we identified axolotl MARCKS-like protein (MLP) as an extracellularly released factor that induces the initial cell cycle response during axolotl appendage regeneration. The identification of a regeneration-initiating molecule opens the possibility of understanding how to elicit regeneration in other animals. PMID- 26934224 TI - A hippocampal network for spatial coding during immobility and sleep. AB - How does an animal know where it is when it stops moving? Hippocampal place cells fire at discrete locations as subjects traverse space, thereby providing an explicit neural code for current location during locomotion. In contrast, during awake immobility, the hippocampus is thought to be dominated by neural firing representing past and possible future experience. The question of whether and how the hippocampus constructs a representation of current location in the absence of locomotion has been unresolved. Here we report that a distinct population of hippocampal neurons, located in the CA2 subregion, signals current location during immobility, and does so in association with a previously unidentified hippocampus-wide network pattern. In addition, signalling of location persists into brief periods of desynchronization prevalent in slow-wave sleep. The hippocampus thus generates a distinct representation of current location during immobility, pointing to mnemonic processing specific to experience occurring in the absence of locomotion. PMID- 26934226 TI - A repeating fast radio burst. AB - Fast radio bursts are millisecond-duration astronomical radio pulses of unknown physical origin that appear to come from extragalactic distances. Previous follow up observations have failed to find additional bursts at the same dispersion measure (that is, the integrated column density of free electrons between source and telescope) and sky position as the original detections. The apparent non repeating nature of these bursts has led to the suggestion that they originate in cataclysmic events. Here we report observations of ten additional bursts from the direction of the fast radio burst FRB 121102. These bursts have dispersion measures and sky positions consistent with the original burst. This unambiguously identifies FRB 121102 as repeating and demonstrates that its source survives the energetic events that cause the bursts. Additionally, the bursts from FRB 121102 show a wide range of spectral shapes that appear to be predominantly intrinsic to the source and which vary on timescales of minutes or less. Although there may be multiple physical origins for the population of fast radio bursts, these repeat bursts with high dispersion measure and variable spectra specifically seen from the direction of FRB 121102 support an origin in a young, highly magnetized, extragalactic neutron star. PMID- 26934228 TI - Neurodevelopment: Regeneration switch is a gas. PMID- 26934227 TI - NAFLD causes selective CD4(+) T lymphocyte loss and promotes hepatocarcinogenesis. AB - Hepatocellular carcinoma (HCC) is the second most common cause of cancer-related death. Non-alcoholic fatty liver disease (NAFLD) affects a large proportion of the US population and is considered to be a metabolic predisposition to liver cancer. However, the role of adaptive immune responses in NAFLD-promoted HCC is largely unknown. Here we show, in mouse models and human samples, that dysregulation of lipid metabolism in NAFLD causes a selective loss of intrahepatic CD4(+) but not CD8(+) T lymphocytes, leading to accelerated hepatocarcinogenesis. We also demonstrate that CD4(+) T lymphocytes have greater mitochondrial mass than CD8(+) T lymphocytes and generate higher levels of mitochondrially derived reactive oxygen species (ROS). Disruption of mitochondrial function by linoleic acid, a fatty acid accumulated in NAFLD, causes more oxidative damage than other free fatty acids such as palmitic acid, and mediates selective loss of intrahepatic CD4(+) T lymphocytes. In vivo blockade of ROS reversed NAFLD-induced hepatic CD4(+) T lymphocyte decrease and delayed NAFLD-promoted HCC. Our results provide an unexpected link between lipid dysregulation and impaired anti-tumour surveillance. PMID- 26934230 TI - Late Tharsis formation and implications for early Mars. AB - The Tharsis region is the largest volcanic complex on Mars and in the Solar System. Young lava flows cover its surface (from the Amazonian period, less than 3 billion years ago) but its growth started during the Noachian era (more than 3.7 billion years ago). Its position has induced a reorientation of the planet with respect to its spin axis (true polar wander, TPW), which is responsible for the present equatorial position of the volcanic province. It has been suggested that the Tharsis load on the lithosphere influenced the orientation of the Noachian/Early Hesperian (more than 3.5 billion years ago) valley networks and therefore that most of the topography of Tharsis was completed before fluvial incision. Here we calculate the rotational figure of Mars (that is, its equilibrium shape) and its surface topography before Tharsis formed, when the spin axis of the planet was controlled by the difference in elevation between the northern and southern hemispheres (hemispheric dichotomy). We show that the observed directions of valley networks are also consistent with topographic gradients in this configuration and thus do not require the presence of the Tharsis load. Furthermore, the distribution of the valleys along a small circle tilted with respect to the equator is found to correspond to a southern hemisphere latitudinal band in the pre-TPW geographical frame. Preferential accumulation of ice or water in a south tropical band is predicted by climate model simulations of early Mars applied to the pre-TPW topography. A late growth of Tharsis, contemporaneous with valley incision, has several implications for the early geological history of Mars, including the existence of glacial environments near the locations of the pre-TPW poles of rotation, and a possible link between volcanic outgassing from Tharsis and the stability of liquid water at the surface of Mars. PMID- 26934229 TI - MIMIVIRE is a defence system in mimivirus that confers resistance to virophage. AB - Since their discovery, giant viruses have revealed several unique features that challenge the conventional definition of a virus, such as their large and complex genomes, their infection by virophages and their presence of transferable short element transpovirons. Here we investigate the sensitivity of mimivirus to virophage infection in a collection of 59 viral strains and demonstrate lineage specificity in the resistance of mimivirus to Zamilon, a unique virophage that can infect lineages B and C of mimivirus but not lineage A. We hypothesized that mimiviruses harbour a defence mechanism resembling the clustered regularly interspaced short palindromic repeat (CRISPR)-Cas system that is widely present in bacteria and archaea. We performed de novo sequencing of 45 new mimivirus strains and searched for sequences specific to Zamilon in a total of 60 mimivirus genomes. We found that lineage A strains are resistant to Zamilon and contain the insertion of a repeated Zamilon sequence within an operon, here named the 'mimivirus virophage resistance element' (MIMIVIRE). Further analyses of the surrounding sequences showed that this locus is reminiscent of a defence mechanism related to the CRISPR-Cas system. Silencing the repeated sequence and the MIMIVIRE genes restores mimivirus susceptibility to Zamilon. The MIMIVIRE proteins possess the typical functions (nuclease and helicase) involved in the degradation of foreign nucleic acids. The viral defence system, MIMIVIRE, represents a nucleic-acid-based immunity against virophage infection. PMID- 26934231 TI - Positron annihilation signatures associated with the outburst of the microquasar V404 Cygni. AB - Microquasars are stellar-mass black holes accreting matter from a companion star and ejecting plasma jets at almost the speed of light. They are analogues of quasars that contain supermassive black holes of 10(6) to 10(10) solar masses. Accretion in microquasars varies on much shorter timescales than in quasars and occasionally produces exceptionally bright X-ray flares. How the flares are produced is unclear, as is the mechanism for launching the relativistic jets and their composition. An emission line near 511 kiloelectronvolts has long been sought in the emission spectrum of microquasars as evidence for the expected electron-positron plasma. Transient high-energy spectral features have been reported in two objects, but their positron interpretation remains contentious. Here we report observations of gamma-ray emission from the microquasar V404 Cygni during a recent period of strong flaring activity. The emission spectrum around 511 kiloelectronvolts shows clear signatures of variable positron annihilation, which implies a high rate of positron production. This supports the earlier conjecture that microquasars may be the main sources of the electron-positron plasma responsible for the bright diffuse emission of annihilation gamma-rays in the bulge region of our Galaxy. Additionally, microquasars could be the origin of the observed megaelectronvolt continuum excess in the inner Galaxy. PMID- 26934232 TI - Domperidone, Parkinson disease and sudden cardiac death: Mice and men show the way. PMID- 26934233 TI - The influence of (central) auditory processing disorder on the severity of speech sound disorders in children. AB - OBJECTIVE: To identify a cutoff value based on the Percentage of Consonants Correct-Revised index that could indicate the likelihood of a child with a speech sound disorder also having a (central) auditory processing disorder . METHODS: Language, audiological and (central) auditory processing evaluations were administered. The participants were 27 subjects with speech-sound disorders aged 7 to 10 years and 11 months who were divided into two different groups according to their (central) auditory processing evaluation results. RESULTS: When a (central) auditory processing disorder was present in association with a speech disorder, the children tended to have lower scores on phonological assessments. A greater severity of speech disorder was related to a greater probability of the child having a (central) auditory processing disorder. The use of a cutoff value for the Percentage of Consonants Correct-Revised index successfully distinguished between children with and without a (central) auditory processing disorder. CONCLUSIONS: The severity of speech-sound disorder in children was influenced by the presence of (central) auditory processing disorder. The attempt to identify a cutoff value based on a severity index was successful. PMID- 26934234 TI - Comparison between refraction measured by Spot Vision ScreeningTM and subjective clinical refractometry. AB - OBJECTIVE: The purpose of this study was to evaluate the accuracy of Spot Vision ScreeningTM as an autorefractor by comparing refraction measurements to subjective clinical refractometry results in children and adult patients. METHODS: One-hundred and thirty-four eyes of 134 patients were submitted to refractometry by Spot and clinical refractometry under cycloplegia. Patients, students, physicians, staff and children of staff from the Hospital das Clinicas (School of Medicine, University of Sao Paulo) aged 7-50 years without signs of ocular disease were examined. Only right-eye refraction data were analyzed. The findings were converted in magnitude vectors for analysis. RESULTS: The difference between Spot Vision ScreeningTM and subjective clinical refractometry expressed in spherical equivalents was +0.66+/-0.56 diopters (D), +0.16+/-0.27 D for the vector projected on the 90 axis and +0.02+/-0.15 D for the oblique vector. CONCLUSIONS: Despite the statistical significance of the difference between the two methods, we consider the difference non-relevant in a clinical setting, supporting the use of Spot Vision ScreeningTM as an ancillary method for estimating refraction. PMID- 26934235 TI - Associations of HIV testing and late diagnosis at a Japanese university hospital. AB - OBJECTIVES: This study was conducted to clarify the rate of late diagnosis of HIV infection and to identify relationships between the reasons for HIV testing and a late diagnosis. METHODS: This retrospective cohort study was conducted among HIV positive patients at the Jikei University Hospital between 2001 and 2014. Patient characteristics from medical records, including age, sex, sexuality, the reason for HIV testing and the number of CD4-positive lymphocytes at HIV diagnosis, were assessed. RESULTS: A total of 459 patients (men, n=437; 95.2%) were included in this study and the median age at HIV diagnosis was 36 years (range, 18-71 years). Late (CD4 cell count <350/mm3) and very late (CD4 cell count <200/mm3) diagnoses were observed in 61.4% (282/459) and 36.6% (168/459) of patients, respectively. The most common reason for HIV diagnosis was voluntary testing (38.6%, 177/459 patients), followed by AIDS-defining illness (18.3%, 84/459 patients). Multivariate analysis revealed a significant association of voluntary HIV testing with non-late and non-very-late diagnoses and there was a high proportion of AIDS defining illness in the late and very late diagnosis groups compared with other groups. Men who have sex with men was a relative factor for non-late diagnosis, whereas nonspecific abnormal blood test results, such as hypergammaglobulinemia and thrombocytopenia, were risk factors for very late diagnosis. CONCLUSIONS: Voluntary HIV testing should be encouraged and physicians should screen all patients who have symptoms or signs and particularly hypergammaglobulinemia and thrombocytopenia, that may nonspecifically indicate HIV infection. PMID- 26934236 TI - Analyses of balance and flexibility of obese patients undergoing bariatric surgery. AB - OBJECTIVE: To assess the postural control and flexibility of obese subjects before and both six and 12 months after bariatric surgery. To verify whether postural control is related to flexibility following weight reductions resulting from bariatric surgery. METHODS: The sample consisted of 16 subjects who had undergone bariatric surgery. All assessments were performed before and six and 12 months after bariatric surgery. Postural balance was assessed using an Accusuway(r) portable force platform, and flexibility was assessed using a standard chair sit and reach test (Wells' chair). RESULTS: With the force platform, no differences were observed in the displacement area or velocity from the center of pressure in the mediolateral and anteroposterior directions. The displacement speed from the center of pressure was decreased at the six month after the surgery; however, unchanged from baseline at 12 months post-surgery. Flexibility increased over time according to the three measurements tested. CONCLUSIONS: Static postural balance did not change. The velocity of postural adjustment responses were increased at six months after surgery. Therefore, weight loss promotes increased flexibility. Yet, improvements in flexibility are not related to improvements in balance. PMID- 26934237 TI - Clinical evaluation, biochemistry and genetic polymorphism analysis for the diagnosis of lactose intolerance in a population from northeastern Brazil. AB - OBJECTIVE: This work aimed to evaluate and correlate symptoms, biochemical blood test results and single nucleotide polymorphisms for lactose intolerance diagnosis. METHOD: A cross-sectional study was conducted in Fortaleza, Ceara, Brazil, with a total of 119 patients, 54 of whom were lactose intolerant. Clinical evaluation and biochemical blood tests were conducted after lactose ingestion and blood samples were collected for genotyping evaluation. In particular, the single nucleotide polymorphisms C>T-13910 and G>A-22018 were analyzed by restriction fragment length polymorphism/polymerase chain reaction and validated by DNA sequencing. RESULTS: Lactose-intolerant patients presented with more symptoms of flatulence (81.4%), bloating (68.5%), borborygmus (59.3%) and diarrhea (46.3%) compared with non-lactose-intolerant patients (p<0.05). We observed a significant association between the presence of the alleles T-13910 and A-22018 and the lactose-tolerant phenotype (p<0.05). After evaluation of the biochemical blood test results for lactose, we found that the most effective cutoff for glucose levels obtained for lactose malabsorbers was <15 mg/dL, presenting an area under the receiver operating characteristic curve greater than 80.3%, with satisfactory values for sensitivity and specificity. CONCLUSIONS: These data corroborate the association of these single nucleotide polymorphisms (C>T-13910 and G>A-22018) with lactose tolerance in this population and suggest clinical management for patients with lactose intolerance that considers single nucleotide polymorphism detection and a change in the biochemical blood test cutoff from <25 mg/dL to <15 mg/dL. PMID- 26934238 TI - Analysis of the Ki-67 index in the vaginal epithelium of castrated rats treated with tamoxifen. AB - OBJECTIVES: Vaginal atrophy and breast cancer are common conditions in postmenopausal women and tamoxifen is the standard endocrine treatment for hormone-sensitive tumors. The present study aimed to assess the effect of tamoxifen on Ki-67 protein expression in the vaginal epithelium of castrated rats. MATERIAL AND METHODS: Forty Wistar-Hannover adult, virgin, castrated rats were randomly divided into two groups, group I (control, n=20) and group II (tamoxifen, n=20), receiving 0.5 ml of propylene glycol and 250 ug of tamoxifen diluted in 0.5 ml of propylene glycol, respectively, daily by gavage for 30 days. On the 31st day, the rats were euthanized and their vaginas were removed and fixed in 10% buffered formalin for the immunohistochemical study of Ki-67 protein expression. Data were analyzed by the Levene and Student's t tests (p<0.05). RESULTS: The mean index of Ki-67 expression in the rat vagina of groups I and II was 4.04+/-0.96 and 26.86+/-2.19, respectively (p<0.001). CONCLUSIONS: According to the results of the present study, tamoxifen, at the dose and treatment length used, induced a significant increase in the cell proliferation of the vaginal mucosa in castrated rats, as evaluated by Ki-67 protein expression. PMID- 26934244 TI - March 1957 (Starbotton): Wilhelmina Barns-Graham. PMID- 26934239 TI - The efficacy and safety of urethral injection therapy for urinary incontinence in women: a systematic review. AB - To evaluate the efficacy and safety of different bulking agents for treating urinary incontinence in women, a systematic review including only randomized controlled trials was performed. The subjects were women with urinary incontinence. The primary outcomes were clinical and urodynamic parameters. The results were presented as a weighted mean difference for non-continuous variables and as relative risk for continuous variables, both with 95% confidence intervals. Initially, 942 studies were identified. However, only fourteen eligible trials fulfilled the prerequisites. Altogether, the review included 1814 patients in trials of eight different types of bulking agents, and all studies were described and analyzed. The measured outcomes were evaluated using a large variety of instruments. The most common complications of the bulking agents were urinary retention and urinary tract infection. Additionally, there were certain major complications, such as one case of death after use of autologous fat. However, the lack of adequate studies, the heterogeneous populations studied, the wide variety of materials used and the lack of long-term follow-up limit guidance of practice. To determine which substance is the most suitable, there is a need for more randomized clinical trials that compare existing bulking agents based on standardized clinical outcomes. PMID- 26934245 TI - Quality of Care Will Be a "Sweet Spot" for JAMA Cardiology Says New Editor-in Chief. PMID- 26934240 TI - Spine radiosurgery for the local treatment of spine metastases: Intensity modulated radiotherapy, image guidance, clinical aspects and future directions. AB - Many cancer patients will develop spinal metastases. Local control is important for preventing neurologic compromise and to relieve pain. Stereotactic body radiotherapy or spinal radiosurgery is a new radiation therapy technique for spinal metastasis that can deliver a high dose of radiation to a tumor while minimizing the radiation delivered to healthy, neighboring tissues. This treatment is based on intensity-modulated radiotherapy, image guidance and rigid immobilization. Spinal radiosurgery is an increasingly utilized treatment method that improves local control and pain relief after delivering ablative doses of radiation. Here, we present a review highlighting the use of spinal radiosurgery for the treatment of metastatic tumors of the spine. The data used in the review were collected from both published studies and ongoing trials. We found that spinal radiosurgery is safe and provides excellent tumor control (up to 94% local control) and pain relief (up to 96%), independent of histology. Extensive data regarding clinical outcomes are available; however, this information has primarily been generated from retrospective and nonrandomized prospective series. Currently, two randomized trials are enrolling patients to study clinical applications of fractionation schedules spinal Radiosurgery. Additionally, a phase I clinical trial is being conducted to assess the safety of concurrent stereotactic body radiotherapy and ipilimumab for spinal metastases. Clinical trials to refine clinical indications and dose fractionation are ongoing. The concomitant use of targeted agents may produce better outcomes in the future. PMID- 26934241 TI - Clinical outcomes of osteonecrosis of the femoral head after autologous bone marrow stem cell implantation: a meta-analysis of seven case-control studies. AB - The purpose of this study was to evaluate the clinical outcomes of osteonecrosis of the femoral head after autologous bone marrow stem cell implantation. We searched the PubMed, Embase and Web of Science databases and included all case control trials that reported on the clinical outcomes of osteonecrosis progression, incidence of total hip arthroplasty and improvement in Harris hip scores. Overall, seven case-control trials were included. Compared with the controls, patients treated with the bone marrow stem cells implantation treatment showed improved clinical outcomes with delayed osteonecrosis progression (odds ratio = 0.17, 95% CI: 0.09 - 0.32; p <0.001), a lower total hip arthroplasty incidence (odds ratio = 0.30, 95% CI: 0.12 - 0.72; p <0.01) and increased Harris hip scores (mean difference = 4.76, 95% CI: 1.24 - 8.28; p<0.01). The heterogeneity, publication bias, and sensitivity analyses showed no statistical difference significant differences between studies. Thus, our study suggests that autologous bone marrow stem cells implantation has a good therapeutic effect on osteonecrosis of the femoral, resulting in beneficial clinical outcomes. However, trials with larger sample sizes are needed to confirm these findings. PMID- 26934246 TI - Promoting Therapeutic Innovation: What Do We Do About Drug-Device Combinations? PMID- 26934255 TI - Health System Loyalty Programs: An Innovation in Customer Care and Service. PMID- 26934256 TI - A PIECE OF MY MIND. A Place to Stay. PMID- 26934257 TI - Visual Acuity Screening Among Asymptomatic Older Adults. PMID- 26934258 TI - Association of Red Blood Cell Transfusion, Anemia, and Necrotizing Enterocolitis in Very Low-Birth-Weight Infants. AB - IMPORTANCE: Data regarding the contribution of red blood cell (RBC) transfusion and anemia to necrotizing enterocolitis (NEC) are conflicting. These associations have not been prospectively evaluated, accounting for repeated, time-varying exposures. OBJECTIVE: To determine the relationship between RBC transfusion, severe anemia, and NEC. DESIGN, SETTING, AND PARTICIPANTS: In a secondary, prospective, multicenter observational cohort study from January 2010 to February 2014, very low-birth-weight (VLBW, <=1500 g) infants, within 5 days of birth, were enrolled at 3 level III neonatal intensive care units in Atlanta, Georgia. Two hospitals were academically affiliated and 1 was a community hospital. Infants received follow-up until 90 days, hospital discharge, transfer to a non study-affiliated hospital, or death (whichever came first). Multivariable competing-risks Cox regression was used, including adjustment for birth weight, center, breastfeeding, illness severity, and duration of initial antibiotic treatment, to evaluate the association between RBC transfusion, severe anemia, and NEC. EXPOSURES: The primary exposure was RBC transfusion. The secondary exposure was severe anemia, defined a priori as a hemoglobin level of 8 g/dL or less. Both exposures were evaluated as time-varying covariates at weekly intervals. MAIN OUTCOMES AND MEASURES: Necrotizing enterocolitis, defined as Bell stage 2 or greater by preplanned adjudication. Mortality was evaluated as a competing risk. RESULTS: Of 600 VLBW infants enrolled, 598 were evaluated. Forty four (7.4%) infants developed NEC. Thirty-two (5.4%) infants died (all cause). Fifty-three percent of infants (319) received a total of 1430 RBC transfusion exposures. The unadjusted cumulative incidence of NEC at week 8 among RBC transfusion-exposed infants was 9.9% (95% CI, 6.9%-14.2%) vs 4.6% (95% CI, 2.6% 8.0%) among those who were unexposed. In multivariable analysis, RBC transfusion in a given week was not significantly related to the rate of NEC (adjusted cause specific hazard ratio, 0.44 [95% CI, 0.17-1.12]; P = .09). Based on evaluation of 4565 longitudinal measurements of hemoglobin (median, 7 per infant), the rate of NEC was significantly increased among VLBW infants with severe anemia in a given week compared with those who did not have severe anemia (adjusted cause-specific hazard ratio, 5.99 [95% CI, 2.00-18.0]; P = .001). CONCLUSIONS AND RELEVANCE: Among VLBW infants, severe anemia, but not RBC transfusion, was associated with an increased risk of NEC. Further studies are needed to evaluate whether preventing severe anemia is more important than minimizing RBC transfusion. PMID- 26934261 TI - Screening for Impaired Visual Acuity in Older Adults: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force. AB - IMPORTANCE: Impaired visual acuity is common among older adults and can adversely affect function and quality of life. OBJECTIVE: To update a 2009 systematic review on screening for impaired visual acuity among older adults for the US Preventive Services Task Force (USPSTF). DATA SOURCES: Ovid MEDLINE (2008 to January 2016), Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews. STUDY SELECTION: Randomized clinical trials of screening; diagnostic accuracy studies of screening tests in primary care settings; and randomized clinical trials of treatment vs placebo or no treatment for uncorrected refractive errors, cataracts, and dry (atrophic) or wet (exudative) age-related macular degeneration (AMD). Studies of screening and diagnostic accuracy were limited to asymptomatic adults 65 years or older; studies of treatment included asymptomatic adults of any age. DATA EXTRACTION AND SYNTHESIS: One investigator abstracted data, a second checked data for accuracy, and 2 investigators independently assessed study quality using predefined criteria. Random-effects meta-analysis was used to estimate the relative and absolute benefits of vascular endothelial growth factor inhibitors (anti-VEGF) for wet AMD. MAIN OUTCOMES AND MEASURES: Visual acuity, vision-related function, functional capacity, harms, and diagnostic accuracy. RESULTS: Three trials (n = 4728) from the 2009 USPSTF review found that screening for impaired visual acuity was not associated with improved visual or clinical outcomes. In 1 good-quality trial (n = 3346), universal screening identified 27% of persons with impaired visual acuity and correctable impairment vs 3.1% with targeted screening, but there was no difference in the likelihood of visual acuity worse than 20/60 after 3 to 5 years (37% vs 35%; relative risk [RR], 1.07; 95% CI, 0.84-1.36). The 2009 review found that effective treatments are available for uncorrected refractive errors and cataracts. Ten-year trial results of dry AMD found an antioxidant/zinc combination was associated with decreased risk of visual acuity loss (46% vs 54%; odds ratio, 0.71; 95% CI, 0.57-0.88). An updated meta-analysis found anti-VEGF for wet AMD was associated with greater likelihood of having vision 20/200 or better vs sham injection (4 trials; RR, 1.47; 95% CI, 1.30-1.66; I2 = 42%; absolute risk difference, 24%; 95% CI, 12%-37% after 1 year). New evidence on the diagnostic accuracy of visual acuity screening tests was limited and consistent with previous findings that screening questions or a visual acuity test was associated with suboptimal accuracy. CONCLUSIONS AND RELEVANCE: Screening can identify persons with impaired visual acuity, and effective treatments are available for common causes of impaired visual acuity, such as uncorrected refractive error, cataracts, and dry or wet AMD. However, direct evidence found no significant difference between vision screening in older adults in primary care settings vs no screening for improving visual acuity or other clinical outcomes. PMID- 26934262 TI - Sudden Onset of Generalized Pustules in a Newborn. PMID- 26934259 TI - Effect of Insulin Glargine Up-titration vs Insulin Degludec/Liraglutide on Glycated Hemoglobin Levels in Patients With Uncontrolled Type 2 Diabetes: The DUAL V Randomized Clinical Trial. AB - IMPORTANCE: Achieving glycemic control remains a challenge for patients with type 2 diabetes, even with insulin therapy. OBJECTIVE: To assess whether a fixed ratio of insulin degludec/liraglutide was noninferior to continued titration of insulin glargine in patients with uncontrolled type 2 diabetes treated with insulin glargine and metformin. DESIGN, SETTING, AND PARTICIPANTS: Phase 3, multinational, multicenter, 26-week, randomized, open-label, 2-group, treat-to target trial conducted at 75 centers in 10 countries from September 2013 to November 2014 among 557 patients with uncontrolled diabetes treated with glargine (20-50 U) and metformin (>=1500 mg/d) with glycated hemoglobin (HbA1c) levels of 7% to 10% and a body mass index of 40 or lower. INTERVENTIONS: 1:1 randomization to degludec/liraglutide (n = 278; maximum dose, 50 U of degludec/1.8 mg of liraglutide) or glargine (n = 279; no maximum dose), with twice-weekly titration to a glucose target of 72 to 90 mg/dL. MAIN OUTCOMES AND MEASURES: Primary outcome measure was change in HbA1c level after 26 weeks, with a noninferiority margin of 0.3% (upper bound of 95% CI, <0.3%). If noninferiority of degludec/liraglutide was achieved, secondary end points were tested for statistical superiority and included change in HbA1c level, change in body weight, and rate of confirmed hypoglycemic episodes. RESULTS: Among 557 randomized patients (mean: age, 58.8 years; women, 49.7%), 92.5% of patients completed the trial and provided data at 26 weeks. Baseline HbA1c level was 8.4% for the degludec/liraglutide group and 8.2% for the glargine group. HbA1c level reduction was greater with degludec/liraglutide vs glargine (-1.81% for the degludec/liraglutide group vs -1.13% for the glargine group; estimated treatment difference [ETD], -0.59% [95% CI, -0.74% to -0.45%]), meeting criteria for noninferiority (P < .001), and also meeting criteria for statistical superiority (P < .001). Treatment with degludec/liraglutide was also associated with weight loss compared with weight gain with glargine (-1.4 kg for degludec/liraglutide vs 1.8 kg for glargine; ETD, -3.20 kg [95% CI, -3.77 to -2.64],P < .001) and fewer confirmed hypoglycemic episodes (episodes/patient-year exposure, 2.23 for degludec/liraglutide vs 5.05 for glargine; estimated rate ratio, 0.43 [95% CI, 0.30 to 0.61],P < .001). Overall and serious adverse event rates were similar in the 2 groups, except for more nonserious gastrointestinal adverse events reported with degludec/liraglutide (adverse events, 79 for degludec/liraglutide vs 18 for glargine). CONCLUSIONS AND RELEVANCE: Among patients with uncontrolled type 2 diabetes taking glargine and metformin, treatment with degludec/liraglutide compared with up-titration of glargine resulted in noninferior HbA1c levels, with secondary analyses indicating greater HbA1c level reduction after 26 weeks of treatment. Further studies are needed to assess longer-term efficacy and safety. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01952145. PMID- 26934260 TI - Screening for Impaired Visual Acuity in Older Adults: US Preventive Services Task Force Recommendation Statement. AB - DESCRIPTION: Update of the US Preventive Services Task Force (USPSTF) recommendation on screening for impaired visual acuity in older adults. METHODS: The USPSTF reviewed the evidence on screening for visual acuity impairment associated with uncorrected refractive error, cataracts, and age-related macular degeneration among adults 65 years or older in the primary care setting; the benefits and harms of screening; the accuracy of screening; and the benefits and harms of treatment of early vision impairment due to uncorrected refractive error, cataracts, and age-related macular degeneration. POPULATION: This recommendation applies to asymptomatic adults 65 years or older who do not present to their primary care clinician with vision problems. RECOMMENDATION: The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for impaired visual acuity in older adults. (I statement). PMID- 26934263 TI - Gonadotropin Interpretation in a 25-Year-Old Man. PMID- 26934264 TI - Association Between Having a Highly Educated Spouse and Physician Practice in Rural Underserved Areas. PMID- 26934265 TI - Hip Fracture Surgery vs Elective Total Hip Replacement. PMID- 26934266 TI - Hip Fracture Surgery vs Elective Total Hip Replacement. PMID- 26934267 TI - Hip Fracture Surgery vs Elective Total Hip Replacement--Reply. PMID- 26934268 TI - Implementing Quality Improvement for Psychosocial Interventions. PMID- 26934269 TI - Implementing Quality Improvement for Psychosocial Interventions--Reply. PMID- 26934270 TI - Coordinating Clinical Site Omitted. PMID- 26934272 TI - The Examination of School Children's Eyes and Ears. PMID- 26934273 TI - JAMA PATIENT PAGE. Screening for Impaired Visual Acuity in Older Adults. PMID- 26934274 TI - General Anesthesia in a Patient With Urticaria Pigmentosa Referred for Electroconvulsive Therapy. AB - Urticaria pigmentosa is a rare disorder characterized by an abnormal systemic proliferation of mast cells. In this condition, various triggers can induce either cutaneous histamine release, resulting in rash, or generalized histamine release, resulting in symptomatic hypotension, syncope, or in its severest form, an anaphylactoid reaction resistant to most resuscitative measures. Many anesthetic agents and adjuncts are known potential triggers, and patients who require surgery or procedures under anesthesia must be managed carefully. In this review, we describe the safe use of general anesthesia for electroconvulsive therapy in a patient with urticaria pigmentosa and discuss the association between psychiatric disorders and mastocytoses. PMID- 26934275 TI - Assessing the Effects of Repetitive Transcranial Magnetic Stimulation on Cognition in Major Depressive Disorder Using Computerized Cognitive Testing. AB - OBJECTIVES: A range of different treatment approaches are available for depression; however, there is an ongoing concern about the cognitive impairment associated with many treatments. This study investigated the effect of treatment with repetitive transcranial magnetic stimulation (rTMS) on cognition in patients with major depressive disorder. Cognition before and after treatment was assessed using a computerized cognitive testing battery, which provided comprehensive assessment across a range of cognitive domains. This was a naturalistic study involving patients attending an outpatient clinical rTMS service. METHODS: A total of 63 patients with treatment-resistant depression completed the IntegNeuro cognitive test battery, a well-validated comprehensive computerized assessment tool before and after receiving 18 or 20 treatments of sequential bilateral rTMS. Change in the various cognitive domains was assessed, and analyses were undertaken to determine whether any change in cognition was associated with a change in rating of depression severity. RESULTS: There was a significant decrease in Hamilton Depression Rating Scale scores from baseline to posttreatment. There was no decline in performance on any of the cognitive tests. There were significant improvements in maze completion time and the number of errors in the maze task. However, these were accounted for by improvement in mood when change in depressive symptoms was included as a covariate. CONCLUSIONS: This open-label study provides further support for the efficacy and safety of rTMS as a treatment option for people with major depressive disorder in a naturalistic clinical setting. Using a comprehensive, robust computerized battery of cognitive tests, the current study indicated that there was no significant cognitive impairment associated with rTMS and that any improvements in cognitive functioning were associated with a reduction in depressive symptoms. PMID- 26934276 TI - Electroconvulsive Therapy in a Patient With Pulmonary Embolism: A Case Report. PMID- 26934277 TI - Intensive care medicine: new insights to improve care. PMID- 26934278 TI - Ethics, economics and outcome editorial. PMID- 26934280 TI - Bleeding and damage control surgery. AB - PURPOSE OF REVIEW: Bleeding is still a major cause of death in trauma patients. Damage control surgery is a strategy that aims to control bleeding and avoid secondary contamination of the cavity. This article checks the principles and indications of damage control surgery, bleeding management, and the role of the anesthesiologist in trauma context. The efficient treatment of severe trauma and exsanguinated patients includes a surgical approach to the patient performed as quickly as possible. Volemic resuscitation, hemostatic transfusion, prevention and/or treatment of coagulopathy, hypothermia, and acidosis are strategies that reduce bleeding, as well as permissive hypotension. RECENT FINDINGS: Specialized literature shows us that the adoption of all of these principles along with reduced surgical time has led to a broader concept called damage control resuscitation. SUMMARY: Damage control resuscitation is a treatment strategy in which the recovery of physiological variables is initially prioritized over anatomical variables and can be required in severe trauma patients. PMID- 26934279 TI - Management of direct oral anticoagulants-associated bleeding in the trauma patient. AB - PURPOSE OF REVIEW: This article emphasizes the differentiated management of direct oral anticoagulants (DOACs)-associated bleeding in trauma patients to generate a severity adjusted treatment protocol. RECENT FINDINGS: The management of DOAC-associated bleeding should take severity, mortality risk, and haemodynamic effects of the trauma-induced bleeding into account. SUMMARY: The different pharmacological properties of DOACs are important for the management of trauma-induced bleeding. Comorbidities like renal impairment and liver dysfunction prolong their half-life. Patients with minor bleeding in stable clinical condition can be managed by a 'wait and see' approach. Moderate bleeding is suggested to be managed by a primarily conservative approach. In life threatening bleeding, the administration of activated or nonactivated factor concentrates seems justified, together with supportive measures as part of an advanced management protocol. The administration of specific antidotes may be an alternative in the future. A monoclonal antibody to dabigatran (idarucizumab) has recently been approved by the Food and Drug Administration, whereas antidotes to Factor X activated inhibitors (andexanet and aripazine) are still under development. Sufficiently powered studies with clinical and safety outcome measures are still missing for all specific antidotes at this time. PMID- 26934283 TI - Study of Impingement Types and Printing Quality during Laser Printing of Viscoelastic Alginate Solutions. AB - Laser-induced forward transfer-based laser printing has been being implemented as a promising orifice-free direct-write strategy for different printing applications. The printing quality during laser printing is largely affected by the jet and droplet formation process and subsequential impingement. The objective of this study is to investigate the impingement-based printing type and resulting printing quality during the laser printing of viscoelastic alginate solutions, which are representative inks for soft structure printing such as bioprinting. Three printing types are identified: droplet-impingement printing, jet-impingement printing with multiple breakups, and jet-impingement printing with a single breakup. Printing quality, in terms of printed droplet morphology and size, has been investigated as a function of alginate concentration, laser fluence, and direct-writing height based on a time-resolved imaging approach and microarrays of printed droplets. Of these, the best printing quality is achieved with single-breakup jet-impingement printing, followed by multiple-breakup jet impingement printing, with droplet-impingement printing producing the lowest quality printing. The printing quality can be improved by using high concentration alginate solutions. The increase of laser fluence may lead to a well-defined primary droplet for low-concentration alginate solutions; however, this can cause the droplet diameter to increase, which may not be desirable. The direct-writing height (i.e., ribbon coating-receiving substrate distance) also influences the print quality. For example, an increase in direct-writing height can cause the printing type to change from the ideal jet-impingement with a single breakup, to the jet-impingement with multiple breakups, and even the least desired droplet-impingement printing, with only slight variations in droplet diameter. PMID- 26934282 TI - Cardiovascular safety of antipsychotics: a clinical overview. AB - INTRODUCTION: Although antipsychotics have been associated with sudden cardiac death (SCD), they still remain a cornerstone in the treatment of psychiatric patients. Most antipsychotics have an unfavorable cardiovascular adverse effect profile, and SCD may occur even in patients with no cardiovascular risk factors. AREAS COVERED: This clinical overview summarizes the cardiovascular safety of antipsychotics by focusing on the wide range of associated adverse effects. In addition, we also discuss current guidelines regarding routine electrocardiogram (ECG) monitoring. EXPERT OPINION: As SCD in psychiatric patients is multifactorial, the contribution from antipsychotic treatment remains largely unknown. Cardiovascular adverse effects of antipsychotics vary substantially, even when used in therapeutic doses. Currently, most clinical concern focuses on antipsychotic-induced corrected QT prolongation, as this may increase risk of Torsades de Pointes and eventually SCD. However, other serious cardiovascular adverse effects of antipsychotics also include Brugada syndrome phenotype, myocardial infarction, and myocarditis. Increased awareness of the cardiovascular safety of antipsychotics can allow physicians to better manage and monitor high risk patients. In this patient group, ECG monitoring may be warranted and other examinations symptom driven. Prescription of antipsychotics should always be a balance between the perceived clinical effect and the burden of adverse effects. PMID- 26934284 TI - ERPs evidence for the relationship between fluid intelligence and cognitive control. AB - The relationship between two components of cognitive control, that is, proactive control and reactive control, and fluid intelligence was investigated by measuring 75 participants' event-related potentials in the AX version of the continuous performance test. The results showed that the mean amplitudes of N2 associated with the two components of cognitive control are highly correlated with fluid intelligence. Specifically, a larger N2 was shown in participants with higher fluid intelligence scores. No significant correlation was found in the peak latencies of the N2 and fluid intelligence. These results enrich our understanding of the relationship between cognitive control and fluid intelligence by using the N2 component as an index and also indicate that cognitive control may be a component of intelligence. PMID- 26934285 TI - Detection of independent functional networks during music listening using electroencephalogram and sLORETA-ICA. AB - The measurement of brain activation during music listening is a topic that is attracting increased attention from many researchers. Because of their high spatial accuracy, functional MRI measurements are often used for measuring brain activation in the context of music listening. However, this technique faces the issues of contaminating scanner noise and an uncomfortable experimental environment. Electroencephalogram (EEG), however, is a neural registration technique that allows the measurement of neurophysiological activation in silent and more comfortable experimental environments. Thus, it is optimal for recording brain activations during pleasant music stimulation. Using a new mathematical approach to calculate intracortical independent components (sLORETA-IC) on the basis of scalp-recorded EEG, we identified specific intracortical independent components during listening of a musical piece and scales, which differ substantially from intracortical independent components calculated from the resting state EEG. Most intracortical independent components are located bilaterally in perisylvian brain areas known to be involved in auditory processing and specifically in music perception. Some intracortical independent components differ between the music and scale listening conditions. The most prominent difference is found in the anterior part of the perisylvian brain region, with stronger activations seen in the left-sided anterior perisylvian regions during music listening, most likely indicating semantic processing during music listening. A further finding is that the intracortical independent components obtained for the music and scale listening are most prominent in higher frequency bands (e.g. beta-2 and beta-3), whereas the resting state intracortical independent components are active in lower frequency bands (alpha-1 and theta). This new technique for calculating intracortical independent components is able to differentiate independent neural networks associated with music and scale listening. Thus, this tool offers new opportunities for studying neural activations during music listening using the silent and more convenient EEG technology. PMID- 26934286 TI - Pitfalls and Key Features of a Case of Sclerosing Pneumocytoma: A Cytological Challenge? AB - BACKGROUND: The aim of the current case report is to re-evaluate the key features and pitfalls of fine-needle aspiration cytology (FNAC) in the diagnosis of sclerosing pneumocytoma (previously named sclerosing hemangioma) and to establish the importance of FNAC in addressing a proper surgical strategy. CASE: Herein we documented a case of a 70- year-old man with a lung nodule which showed a hypermetabolic uptake on positron emission tomography. He therefore underwent FNAC under computed tomography scan guidance with a 22-gauge needle. The cytopathological examination allowed a diagnosis of sclerosing pneumocytoma. A wedge surgical excision was performed and the histological examination confirmed the cytological diagnosis. CONCLUSION: FNAC is a fundamental tool for distinguishing sclerosing pneumocytoma from a malignant lung tumour and together with clinical, radiological and pathological multidisciplinary assessment is indispensable in planning appropriate surgical management. Cytopathologists should be aware of the pitfalls and key features of the cytopathological diagnosis of sclerosing pneumocytoma, which can significantly change the surgical approach to the patient and protect him from aggressive overtreatment. PMID- 26934287 TI - SDF-1 controls the muscle and blood vessel formation of the somite. AB - Stromal-cell-derived factor-1 (SDF-1), the only ligand of the chemokine receptor CXCR4, is involved in skeletal muscle development. However, its role in the proliferation, differentiation and migration of somite cells is not well understood. Here, we investigated its function during somite development in chicken embryos by using gain-of-function and loss-of-function experiments. Overexpression of SDF-1 was performed by electroporating SDF-1 constructs into the ventrolateral part of the somite, or by injecting SDF-1-expressing cells into the somites of stages HH14-16 chicken embryos. We found that enhanced SDF-1 signaling induced cell proliferation in the somite. This resulted in an increase in number of both myotomal and endothelial cells. In contrast, inhibition of SDF 1/CXCR4 signaling led to a reduction of myotomal cells. Injection of SDF-1 producing cells into the somite induced ectopic localization of myotomal cells in the sclerotome. Although many SDF-1-expressing somite cells colonized the limb, only a few of them developed into muscle cells. This resulted in a reduction of the limb muscle mass. This means that most myogenic progenitors were stopped on their migration towards the limb due to the high concentration of the SDF-1 signal in the somite. Most of the SDF-1-expressing somite cells found in the limb were of endothelial cell fate and they contributed to the increase in limb blood vessels. These results reveal that SDF-1 promotes the proliferation of both myogenic and angiogenic progenitor cells of the somite and controls myotome formation. Furthermore, SDF-1 controls muscle and blood vessel formation in the limb in different ways. PMID- 26934288 TI - Coordinate involvement of Nodal-dependent inhibition and Wnt-dependent activation in the maintenance of organizer-specific bmp2b in zebrafish. AB - A vertebrate signaling center, known in zebrafish as the organizer, is essential for axis patterning and formation and is regulated by multiple cell signaling pathways, including Wnt, Nodal, and Bmp. Organizer-specific Bmp2b plays important roles in the maintenance of the Bmp activity gradient and dorsal-ventral patterning. However, it is unknown how transcription of bmp2b in the organizer is regulated. In this study, we generated a bmp2b transgenic line Tsg( 2.272bmp2b:gfp) that reproduced organizer-specific bmp2b expression. Dissection analysis revealed that a 0.273-kb minimal promoter was indispensable for bmp2b expression in the dorsal organizer. Reporter assays showed that organizer specific bmp2b is negatively regulated by the Nodal signal and positively regulated by the Wnt signal in both embryos and cell lines. Promoter analysis and chromatin-immunoprecipitation (ChIP) indicated that one consensus Smad-binding element (SBE) (CAGAC) and one Lef/Tcf-binding element (LBE) (AGATAA) were present in the 0.273-kb promoter, and could be directly bound by Smad2 and beta-catenin proteins. Together, these results suggest that maintenance of organizer-specific bmp2b expression involves opposite and concerted regulation by Nodal and Wnt signaling. PMID- 26934289 TI - Live imaging reveals spatial separation of parental chromatin until the four-cell stage in Caenorhabditis elegans embryos. AB - The parental genomes are initially spatially separated in each pronucleus after fertilization. Here we have used green-to-red photoconversion of Dendra2-H2B labeled pronuclei to distinguish maternal and paternal chromatin domains and to track their spatial distribution in living Caenorhabditis elegans embryos starting shortly after fertilization. Intermingling of the parental chromatin did not occur until after the division of the AB and P1 blastomeres, at the 4-cell stage. Unexpectedly, we observed that the intermingling of chromatin did not take place during mitosis or during chromatin decondensation, but rather ~ 3-5 minutes into the cell cycle. Furthermore, unlike what has been observed in mammalian cells, the relative spatial positioning of chromatin domains remained largely unchanged during prometaphase in the early C. elegans embryo. Live imaging of photoconverted chromatin also allowed us to detect a reproducible 180 degrees rotation of the nuclei during cytokinesis of the one-cell embryo. Imaging of fluorescently-labeled P granules and polar bodies showed that the entire embryo rotates during the first cell division. To our knowledge, we report here the first live observation of the initial separation and subsequent mixing of parental chromatin domains during embryogenesis. PMID- 26934290 TI - Nucleolar protein 4-like has a complex expression pattern in zebrafish embryos. AB - The nucleolar protein 4-like (NOL4L) gene is present on chromosome 20 (20q11.21) in humans. Parts of this gene have been shown to fuse with RUNX1 and PAX5 in acute myeloid leukemia and acute lymphoblastic leukemia, respectively. The normal function of NOL4L in humans and other organisms is not well understood. The expression patterns and functions of NOL4L homologs during vertebrate development have not been reported. We sought to address these questions by studying the expression pattern of zebrafish nol4l during embryogenesis. Our data show that Znol4l mRNA is expressed in multiple organs in zebrafish embryos. The sites of expression include parts of the brain, spinal cord, pronephros, hematopoietic cells and gut. PMID- 26934291 TI - Matrix Gla Protein expression pattern in the early avian embryo. AB - MGP (Matrix Gla Protein) is an extracellular matrix vitamin K dependent protein previously identified as a physiological inhibitor of calcification and shown to be well conserved among vertebrates during evolution. MGP is involved in other mechanisms such as TGF-beta and BMP activity, and a proposed modulator of cell matrix interactions. MGP is expressed early in vertebrate development although its role has not been clarified. Previous work in the chicken embryo found MGP localization predominantly in the aorta and aortic valve base, but no data is available earlier in development. Here we examined MGP expression pattern using whole-mount in situ hybridization and histological sectioning during the initial stages of chick development. MGP was first detected at HH10 in the head and in the forming dorsal aorta. At the moment of the onset of blood circulation, MGP was expressed additionally in the venous plexus which will remodel into the vitelline arteries. By E2.25, it is clear that the vitelline arteries are MGP positive. MGP expression progresses centrifugally throughout the area vasculosa of the yolk sac. Between stages HH17 and HH19 MGP is seen in the dorsal aorta, heart, notochord, nephric duct, roof plate, vitelline arteries and in the yolk sac, beneath main arterial branches and in the vicinity of several vessels and venules. MGP expression persists in these areas at least until E4.5. These data suggest that MGP expression could be associated with cell migration and differentiation and to the onset of angiogenesis in the developing chick embryo. This data has biomedical relevance by pointing to the potential use of chick embryo explants to study molecules involved in artery calcification. PMID- 26934292 TI - pdzrn3 is required for pronephros morphogenesis in Xenopus laevis. AB - Pdzrn3, a multidomain protein with E3-ubiquitin ligase activity, has been reported to play a role in myoblast and osteoblast differentiation and, more recently, in neuronal and endothelial cell development. The expression of the pdzrn3 gene is developmentally regulated in various vertebrate tissues, including muscular, neural and vascular system. Little is known about its expression during kidney development, although genetic polymorphisms and alterations around the human pdzrn3 chromosomal region have been found to be associated with renal cell carcinomas and other kidney diseases. We investigated the pdzrn3 spatio-temporal expression pattern in Xenopus laevis embryos by in situ hybridization. We focused our study on the development of the pronephros, which is the embryonic amphibian kidney, functionally similar to the most primitive nephric structures of human kidney. To explore the role of pdzrn3 during renal morphogenesis, we performed loss-of-function experiments, through antisense morpholino injections and analysed the morphants using specific pronephric markers. Dynamic pdzrn3 expression was observed in embryonic tissues, such as somites, brain, eye, blood islands, heart, liver and pronephros. Loss of function experiments resulted in specific alterations of pronephros development. In particular, at early stages, pdzrn3 depletion was associated with a reduction of the pronephros anlagen and later, with perturbations of the tubulogenesis, including deformation of the proximal tubules. Rescue experiments, in which mRNA of the zebrafish pdzrn3 orthologue was injected together with the morpholino, allowed recovery of the kidney phenotypes. These results underline the importance of pdzrn3 expression for correct nephrogenesis. PMID- 26934293 TI - Bone morphogenetic protein 4 promotes craniofacial neural crest induction from human pluripotent stem cells. AB - Neural crest (NC) cells are a group of cells located in the neural folds at the boundary between the neural and epidermal ectoderm. Cranial NC cells migrate to the branchial arches and give rise to the majority of the craniofacial region, whereas trunk and tail NC cells contribute to the heart, enteric ganglia of the gut, melanocytes, sympathetic ganglia, and adrenal chromaffin cells. Positional information is indispensable for the regulation of cranial or trunk and tail NC cells. However, the mechanisms underlying the regulation of positional information during human NC induction have yet to be fully elucidated. In the present study, supplementation of bone morphogenetic protein (BMP) 4 in defined serum-free culture conditions including fibroblast growth factor-2 and Wnt3a from day 8 after NC specification induced the expression of cranial NC markers, AP2alpha, MSX1, and DLX1, during NC cell differentiation from human pluripotent stem cells. On the other hand, the proportion of cells expressing p75(NTR) or HNK1 decreased compared with that of cells cultured without BMP4, whereas gene expression analysis demonstrated that the expression levels of cranial NC associated genes increased in BMP4-treated NC cells. These BMP4-treated NC cells were capable of differentiation into osteocytes and chondrocytes. The results of the present study indicate that BMP4 regulates cranial positioning during NC development. PMID- 26934294 TI - Development and Psychometric Validation of the FACE-Q Skin, Lips, and Facial Rhytids Appearance Scales and Adverse Effects Checklists for Cosmetic Procedures. AB - IMPORTANCE: Patient-reported outcomes data are needed to determine the efficacy of cosmetic procedures. OBJECTIVE: To describe the development and psychometric evaluation of 8 appearance scales and 2 adverse effect checklists for use in minimally invasive cosmetic procedures. DESIGN, SETTING, AND PARTICIPANTS: We performed a psychometric study to select the most clinically sensitive items for inclusion in item-reduced scales and to examine reliability and validity with patients. Recruitment of the sample for this study took place from June 6, 2010, through July 28, 2014. Data analysis was performed from December 11, 2014, to December 22, 2015. Pretreatment and posttreatment patients 18 years and older who were consulting for any type of facial aesthetic treatment were studied. Patients were from plastic surgery and dermatology outpatient clinics in the United States and Canada (field-test sample) and a clinical trial of a minimally invasive lip treatment in the United Kingdom and France (clinical trial sample). MAIN OUTCOMES AND MEASURES: The FACE-Q scales that measure appearance of the skin, lips, and facial rhytids (ie, overall, forehead, glabella, lateral periorbital area, lips, and marionette lines), with scores ranging from 0 (lowest) to 100 (highest), and the FACE-Q adverse effects checklists for problems after skin and lip treatment. RESULTS: Of 783 patients recruited, 503 field-test patients (response rate, 90%) and 280 clinical trial participants were studied. The mean (SD) age of the patients was 47.4 (14.0) years in the field-test sample and 47.7 (12.3) years in the clinical trial sample. Most of the patients were female (429 [85.3%] in the field-test sample and 274 [97.9%] in the clinical trial sample). Rasch Measurement Theory analyses led to the refinement of 8 appearance scales with 66 total items. All FACE-Q scale items had ordered thresholds and acceptable item fit. Reliability, measured with the Personal Separation Index (range, 0.88-0.95) and Cronbach alpha (range, 0.93-0.98), was high. Lower scores for appearance scales that measured the skin (r = -0.48, P < .001), lips (r = -0.21, P = .001), and lip rhytids (r = -0.32, P < .001) correlated with the reporting of more skin- and lip-related adverse effects. Higher scores for the 8 appearance scales correlated (range, 0.70-0.28; P < .001) with higher scores on the core 10-item FACE-Q satisfaction with facial appearance scale. In the pretreatment group, older age was significantly correlated with lower scores on 5 of the 6 rhytids scales (exception was forehead rhytids) (range, -0.28 to -0.65; P = .03 to <.001). Pretreatment patients reported significantly lower scores on 7 of the 8 appearance scales compared with posttreatment patients (exception was skin) (P < .001 to .005 on independent sample t tests). CONCLUSIONS AND RELEVANCE: The FACE Q appearance scales and adverse effects checklists can be used in clinical practice, research, and quality improvement to incorporate cosmetic patients' perspective in outcome assessments. PMID- 26934297 TI - Antimicrobial activity of four cationic peptides immobilised to poly hydroxyethylmethacrylate. AB - The objective of this study was to immobilise and characterise a variety of antimicrobial peptides (AMPs) onto poly-hydroxyethylmethacrylate (pHEMA) surfaces to achieve an antibacterial effect. Four AMPs, viz. LL-37, melimine, lactoferricin and Mel-4 were immobilised on pHEMA by 1-ethyl-3-(3 dimethylaminopropyl) carbodiimide hydrochloride (EDC) which assisted covalent attachment. Increasing concentrations of AMPs were immobilised to determine the effect on the adhesion of Pseudomonas aeruginosa and Staphylococcus aureus. The AMP immobilised pHEMAs were characterised by X-ray photoelectron spectroscopy (XPS) to determine the surface elemental composition and by amino acid analysis to determine the total amount of AMP attached. In vitro cytotoxicity of the immobilised pHEMA samples to mouse L929 cells was investigated. Melimine and Mel 4 when immobilised at the highest concentrations showed 3.1 +/- 0.6 log and 1.3 +/- 0.2 log inhibition against P. aeruginosa, and 3.9 +/- 0.6 log and 2.4 +/- 0.5 log inhibition against S. aureus, respectively. Immobilisation of LL-37 resulted in up to 2.6 +/- 1.0 log inhibition against only P. aeruginosa, but no activity against S. aureus. LFc attachment showed no antibacterial activity. Upon XPS analysis, immobilised melimine, LL-37, LFc and Mel-4 had 1.57 +/- 0.38%, 1.13 +/- 1.36%, 0.66 +/- 0.47% and 0.73 +/- 0.32% amide nitrogen attached to pHEMA compared to 0.12 +/- 0.14% in the untreated controls. Amino acid analysis determined that the total amount of AMP attachment to pHEMA was 44.3 +/- 7.4 nmol, 3.8 +/- 0.2 nmol, 6.5 +/- 0.6 nmol and 48.9 +/- 2.3 nmol for the same peptides respectively. None of the AMP immobilised pHEMA surfaces showed any toxicity towards mouse L929 cells. The immobilisation of certain AMPs at nanomolar concentration to pHEMA is an effective option to develop a stable antimicrobial surface. PMID- 26934296 TI - Cleavage of Type I Collagen by Fibroblast Activation Protein-alpha Enhances Class A Scavenger Receptor Mediated Macrophage Adhesion. AB - Pathophysiological conditions such as fibrosis, inflammation, and tumor progression are associated with modification of the extracellular matrix (ECM). These modifications create ligands that differentially interact with cells to promote responses that drive pathological processes. Within the tumor stroma, fibroblasts are activated and increase the expression of type I collagen. In addition, activated fibroblasts specifically express fibroblast activation protein-alpha (FAP), a post-prolyl peptidase. Although FAP reportedly cleaves type I collagen and contributes to tumor progression, the specific pathophysiologic role of FAP is not clear. In this study, the possibility that FAP-mediated cleavage of type I collagen modulates macrophage interaction with collagen was examined using macrophage adhesion assays. Our results demonstrate that FAP selectively cleaves type I collagen resulting in increased macrophage adhesion. Increased macrophage adhesion to FAP-cleaved collagen was not affected by inhibiting integrin-mediated interactions, but was abolished in macrophages lacking the class A scavenger receptor (SR-A/CD204). Further, SR-A expressing macrophages localize with activated fibroblasts in breast tumors of MMTV-PyMT mice. Together, these results demonstrate that FAP-cleaved collagen is a substrate for SR-A-dependent macrophage adhesion, and suggest that by modifying the ECM, FAP plays a novel role in mediating communication between activated fibroblasts and macrophages. PMID- 26934300 TI - Corticosteroid-free treatment of tocilizumab monotherapy for microscopic polyangiitis: a single-arm, single-center, clinical trial. AB - OBJECTIVES: To assess the efficacy of tocilizumab (TCZ) monotherapy for the remission induction of microscopic polyangiitis (MPA) in a prospective single arm, single-center, cohort, pilot study. METHODS: Eligible patients were aged between 20 and 80 years and were newly diagnosed with MPA according to Watts' classification algorithm. Seven patients received 8 mg/kg of intravenous TCZ fortnightly for the first 2 months (5 courses), and monthly for the next 10 months (10 courses). One year after TCZ monotherapy, the patients were followed up without any treatment. The protocol did not permit the use corticosteroids or any other immunosuppressants. Complete remission (CR) was defined as the Birmingham Vasculitis Activity Score of 0 at two consecutive visits made at least a month apart. RESULTS: CR was achieved in two of six patients (33.3%) at 6 months and three patients (50.0%) at 12 months. Two patients were withdrawn: one because of inefficacy at 6 weeks and the other because of flare at 6 months. One patient voluntarily withdrew after CR at 3 months. Four patients (66.7%) could be kept drug-free after 1 year of TCZ without relapse for 6-15 months at the last visit. CONCLUSION: TCZ monotherapy may be an alternative treatment strategy in some patients with MPA. PMID- 26934299 TI - Tumor Autonomous Effects of Vitamin D Deficiency Promote Breast Cancer Metastasis. AB - Patients with breast cancer (BCa) frequently have preexisting vitamin D deficiency (low serum 25-hydroxyvitamin D) when their cancer develops. A number of epidemiological studies show an inverse association between BCa risk and vitamin D status in humans, although some studies have failed to find an association. In addition, several studies have reported that BCa patients with vitamin D deficiency have a more aggressive molecular phenotype and worse prognostic indicators. However, it is unknown whether this association is mechanistically causative and, if so, whether it results from systemic or tumor autonomous effects of vitamin D signaling. We found that ablation of vitamin D receptor expression within BCa cells accelerates primary tumor growth and enables the development of metastases, demonstrating a tumor autonomous effect of vitamin D signaling to suppress BCa metastases. We show that vitamin D signaling inhibits the expression of the tumor progression gene Id1, and this pathway is abrogated in vitamin D deficiency in vivo in 2 murine models of BCa. These findings are relevant to humans, because we discovered that the mechanism of VDR regulation of Inhibitor of differentiation 1 (ID1) is conserved in human BCa cells, and there is a negative correlation between serum 25-hydroxyvitamin D levels and the level of ID1 in primary tumors from patients with BCa. PMID- 26934301 TI - Modeling transcranial magnetic stimulation from the induced electric fields to the membrane potentials along tractography-based white matter fiber tracts. AB - OBJECTIVE: Transcranial magnetic stimulation (TMS) is a promising non-invasive tool for modulating the brain activity. Despite the widespread therapeutic and diagnostic use of TMS in neurology and psychiatry, its observed response remains hard to predict, limiting its further development and applications. Although the stimulation intensity is always maximum at the cortical surface near the coil, experiments reveal that TMS can affect deeper brain regions as well. APPROACH: The explanation of this spread might be found in the white matter fiber tracts, connecting cortical and subcortical structures. When applying an electric field on neurons, their membrane potential is altered. If this change is significant, more likely near the TMS coil, action potentials might be initiated and propagated along the fiber tracts towards deeper regions. In order to understand and apply TMS more effectively, it is important to capture and account for this interaction as accurately as possible. Therefore, we compute, next to the induced electric fields in the brain, the spatial distribution of the membrane potentials along the fiber tracts and its temporal dynamics. MAIN RESULTS: This paper introduces a computational TMS model in which electromagnetism and neurophysiology are combined. Realistic geometry and tissue anisotropy are included using magnetic resonance imaging and targeted white matter fiber tracts are traced using tractography based on diffusion tensor imaging. The position and orientation of the coil can directly be retrieved from the neuronavigation system. Incorporating these features warrants both patient- and case-specific results. SIGNIFICANCE: The presented model gives insight in the activity propagation through the brain and can therefore explain the observed clinical responses to TMS and their inter- and/or intra-subject variability. We aspire to advance towards an accurate, flexible and personalized TMS model that helps to understand stimulation in the connected brain and to target more focused and deeper brain regions. PMID- 26934298 TI - BPA Directly Decreases GnRH Neuronal Activity via Noncanonical Pathway. AB - Peripheral feedback of gonadal estrogen to the hypothalamus is critical for reproduction. Bisphenol A (BPA), an environmental pollutant with estrogenic actions, can disrupt this feedback and lead to infertility in both humans and animals. GnRH neurons are essential for reproduction, serving as an important link between brain, pituitary, and gonads. Because GnRH neurons express several receptors that bind estrogen, they are potential targets for endocrine disruptors. However, to date, direct effects of BPA on GnRH neurons have not been shown. This study investigated the effects of BPA on GnRH neuronal activity using an explant model in which large numbers of primary GnRH neurons are maintained and express many of the receptors found in vivo. Because oscillations in intracellular calcium have been shown to correlate with electrical activity in GnRH neurons, calcium imaging was used to assay the effects of BPA. Exposure to 50MUM BPA significantly decreased GnRH calcium activity. Blockage of gamma aminobutyric acid ergic and glutamatergic input did not abrogate the inhibitory BPA effect, suggesting direct regulation of GnRH neurons by BPA. In addition to estrogen receptor-beta, single-cell RT-PCR analysis confirmed that GnRH neurons express G protein-coupled receptor 30 (G protein-coupled estrogen receptor 1) and estrogen-related receptor-gamma, all potential targets for BPA. Perturbation studies of the signaling pathway revealed that the BPA-mediated inhibition of GnRH neuronal activity occurred independent of estrogen receptors, GPER, or estrogen-related receptor-gamma, via a noncanonical pathway. These results provide the first evidence of a direct effect of BPA on GnRH neurons. PMID- 26934302 TI - ATYPICAL MACULOPATHY IN A PATIENT WITH LIGHT CHAIN DEPOSITION DISEASE MIMICKING ADVANCED GEOGRAPHIC ATROPHY. AB - PURPOSE: To report a previously unreported presentation of advanced geographic atrophy of the macula mimicking nonneovascular (dry) age-related macular degeneration in a patient with light chain deposition disease. METHODS: Ocular examination included dilated fundus examination, fundus autofluorescence, full field electroretinography, and spectral domain optical coherence tomography. PATIENTS: Single-patient case report. RESULTS: Dilated fundus examination demonstrated diffuse loss of the retinal pigment epithelium in a geographic atrophy pattern in the macula and drusenlike deposits localized to the outer retina and retinal pigment epithelium. There were no signs of choroidal neovascularization or retinal pigment epithelium detachments. Fundus autofluorescence demonstrated wide areas of retinal pigment epithelium loss. Full field electroretinography was normal. Spectral domain optical coherence tomography displayed atrophy of the outer retinal layers. DISCUSSION: This is the first documented case of drusenlike deposits and maculopathy in a patient with light chain deposition disease that mimics advanced geographic atrophy that is typically observed in nonneovascular age-related macular degeneration. Physicians should be aware of the macular changes that can be associated with light chain deposition disease, and patients with light chain deposition disease should be regularly evaluated for associated macular disease. PMID- 26934303 TI - CENTRAL SEROUS CHORIORETINOPATHY IN POSTMENOPAUSAL WOMEN RECEIVING EXOGENOUS TESTOSTERONE. AB - PURPOSE: Central serous chorioretinopathy (CSR) is a serous detachment of the neurosensory retina commonly associated with male sex, Type-A personality and corticosteroid use. Exogenous administration of androgens and development of CSR in men has been reported. Only one case of CSR in a postmenopausal woman receiving exogenous androgen therapy has been reported. The authors describe three cases of chronic CSR in postmenopausal women receiving exogenous testosterone therapy. METHODS: Diagnosis was based on characteristic clinical, fluorescein angiographic, and optical coherence tomography findings. The three women were being treated with exogenous testosterone and progesterone therapy for symptoms of menopause and libido loss. RESULTS: Average age at presentation was 54.7 years (53-56 years), average duration of exogenous androgen use was 61 months (36-87 months), with average 19.7-month follow-up. Resolution of symptoms seemed correlated with cessation of androgen use despite treatment with oscillatory photodynamic therapy and intravitreal pharmacotherapy with antivascular endothelial growth factor agents. CONCLUSION: Exogenous testosterone is increasingly prescribed for menopausal symptoms and libido loss. Treatment with oscillatory photodynamic therapy, supplemental bevacizumab intravitreal pharmacotherapy, and cessation of exogenous androgen therapy was successful in three cases of chronic, therapy-resistant CSR. Ophthalmologists should inquire about androgen usage in patients who present with CSR, especially in the setting of therapy resistance. PMID- 26934305 TI - Enhancing Metal-Support Interactions by Molybdenum Carbide: An Efficient Strategy toward the Chemoselective Hydrogenation of alpha,beta-Unsaturated Aldehydes. AB - Metal-support interactions are desired to optimize the catalytic turnover on metals. Herein, the enhanced interactions by using a Mo2C nanowires support were utilized to modify the charge density of an Ir surface, accomplishing the selective hydrogenation of alpha,beta-unsaturated aldehydes on negatively charged Ir(delta-) species. The combined experimental and theoretical investigations showed that the Ir(delta-) species derive from the higher work function of Ir (vs. Mo2C) and the consequently electron transfer. In crotonaldehyde hydrogenation, Ir/Mo2C delivered a crotyl alcohol selectivity as high as 80%, outperforming those of counterparts (<30%) on silica. Moreover, such electronic metal-support interactions were also confirmed for Pt and Au, as compared with which, Ir/Mo2C was highlighted by its higher selectivity as well as the better activity. Additionally, the efficacy for various substrates further verified our Ir/Mo2C system to be competitive for chemoselective hydrogenation. PMID- 26934304 TI - SPECTRAL DOMAIN-OPTICAL COHERENCE TOMOGRAPHY FINDINGS OF COMMOTIO RETINAE WITH ASSOCIATED SEROUS RETINAL DETACHMENT. AB - PURPOSE: To describe the appearance of a serous retinal detachment associated with commotio retinae on spectral domain optical coherence tomography. METHODS: Case report. RESULTS: This case demonstrates the rare presentation of subretinal fluid in commotio retinae. Characteristic outer retinal changes associated with commotio retinae were also seen. Treatment was deferred and the subretinal fluid resolved within 1 week. CONCLUSION: Commotio retinae is rarely associated with a serous retinal detachment. This presentation is important to identify as it can avoid unnecessary workup and treatment. PMID- 26934306 TI - Drivers of change: Learning from the lived experiences of nursing home social workers. AB - In response to the growing attention to integrated health care and the cultural change movement in nursing homes, this study examines the lived experiences of nursing home social workers to better understand their role perceptions, job satisfaction, and relationship with other staff members. Hermeneutic phenomenology was used in order to understand the lived experience of being a nursing home social worker. Ten nursing home social workers were recruited from a southern state and individual interviews were conducted. From the interviews, four themes emerged: challenge, coping, mattering, and rewarding. Guided by identity negotiation theory and social identity theory, these findings are discussed. Also, implications for social work education, nursing home administration, and policy is discussed. PMID- 26934308 TI - Insights into centromeric transcription in mitosis. AB - The major role of RNA polymerase II (RNAP II) is to generate mRNAs. I recently uncovered a novel function of RNAP II in chromosome segregation in mitosis, installing the cohesin protector, Shugoshin, at centromeres. Here I will discuss the current understanding of RNAP II-dependent centromeric transcription in mitosis. PMID- 26934307 TI - The essential role of acetyllysine binding by the YEATS domain in transcriptional regulation. AB - The YEATS domains of AF9 and Taf14 have recently been found to recognize the histone H3K9ac modification. In this commentary, we discuss the mechanistic and biological implications of this interaction. We compare structures of the YEATS H3K9ac complexes the highlighting a novel mechanism for the acetyllysine recognition through the aromatic cage. We also summarize the latest findings underscoring a critical role of the acetyllysine binding function of AF9 and Taf14 in transcriptional regulation and DNA repair. PMID- 26934309 TI - Transcriptional enhancers: Transcription, function and flexibility. AB - Active transcriptional enhancers are often transcribed to eRNAs, whose changing levels mirror those of the target gene mRNA. We discuss some of the reported functions of these eRNAs and their likely diversity to allow utilization of distinct cis regulatory regions to enhance transcription in diverse developmental and cellular contexts. PMID- 26934311 TI - Fibroma of a tendon sheath causing Guyon's canal syndrome: case report. AB - This report presents a rare case of a 41-year-old woman with decreased sensation and weakness of grip of her left hand. On examination she had a well-defined mass on the ulnar-volar aspect of the wrist. Magnetic resonance imaging showed a focal nodular mass in Guyon's canal. Examination showed that the mass, 2.1 * 1.1 * 1.0 cm in size, originated in the proximal portion of the canal and was loosely associated with the tendon sheath of the flexor carpi ulnaris. The mass was removed and Guyon's canal released. Histological examination confirmed a diagnosis of fibroma of tendon sheath. Postoperatively, she had fully restored sensory and motor function of her left hand. The tumor has not recurred. PMID- 26934310 TI - Factors contributing to the immunogenicity of meningococcal conjugate vaccines. AB - Various glycoprotein conjugate vaccines have been developed for the prevention of invasive meningococcal disease, having significant advantages over pure polysaccharide vaccines. One of the most important features of the conjugate vaccines is the induction of a T-cell dependent immune response, which enables both the induction of immune memory and a booster response after repeated immunization. The nature of the carrier protein to which the polysaccharides are chemically linked, is often regarded as the main component of the vaccine in determining its immunogenicity. However, other factors can have a significant impact on the vaccine's profile. In this review, we explore the physico-chemical properties of meningococcal conjugate vaccines, which can significantly contribute to the vaccine's immunogenicity. We demonstrate that the carrier is not the sole determining factor of the vaccine's profile, but, moreover, that the conjugate vaccine's immunogenicity is the result of multiple physico-chemical structures and characteristics. PMID- 26934312 TI - No association between ZNF804A rs1344706 and schizophrenia in a case-control study of Han Chinese. AB - Previous studies indicated that the single nucleotide polymorphism (SNP) rs1344706 within the gene ZNF804A was a promising risk variant for schizophrenia in European populations. However, existing results are inconsistent in Han Chinese. Hoping to validate the association of rs1344706 with schizophrenia susceptibility in Han Chinese, we conducted a case-control study in 1284 cases and 990 healthy controls from Jiangsu Province, China. We did not detect any significant between-group difference (all P>0.05) in either allele or genotype frequency under any genetic model between cases and controls. Stratified analysis by sex also failed to find any significant association. Our results did not support the association of rs1344706 with schizophrenia in Han Chinese, and further association studies with large samples from other ethnic backgrounds and focus on more SNPs of ZNF804A are warranted. PMID- 26934313 TI - Structure-Dependent Anchoring of Organic Molecules to Atomically Defined Oxide Surfaces: Phthalic Acid on Co3O4(111), CoO(100), and CoO(111). AB - We have performed a model study to explore the influence of surface structure on the anchoring of organic molecules on oxide materials. Specifically, we have investigated the adsorption of phthalic acid (PA) on three different, well ordered, and atomically defined cobalt oxide surfaces, namely 1) Co3O4(111), 2) CoO(111), and 3) CoO(100) on Ir(100). PA was deposited by physical vapor deposition (PVD). The formation of the PA films and interfacial reactions were monitored in situ during growth by isothermal time-resolved IR reflection absorption spectroscopy (TR-IRAS) under ultrahigh vacuum (UHV) conditions. We observed a pronounced structure dependence on the three surfaces with three distinctively different binding geometries and characteristic differences depending on the temperature and coverage. 1) PA initially binds to Co3O4(111) through the formation of a chelating bis-carboxylate with the molecular plane oriented perpendicularly to the surface. Similar species were observed both at low temperature (130 K) and at room temperature (300 K). With increasing exposure, chelating mono-carboxylates became more abundant and partially replaced the bis-carboxylate. 2) PA binds to CoO(100) in the form of a bridging bis carboxylate for low coverage. Upon prolonged deposition of PA at low temperature, the bis-carboxylates were converted into mono-carboxylate species. In contrast, the bis-carboxylate layer was very stable at 300 K. 3) For CoO(111) we observed a temperature-dependent change in the adsorption mechanism. Although PA binds as a mono-carboxylate in a bridging bidentate fashion at low temperature (130 K), a strongly distorted bis-carboxylate was formed at 300 K, possibly as a result of temperature-dependent restructuring of the surface. The results show that the adsorption geometry of PA depends on the atomic structure of the oxide surface. The structure dependence can be rationalized by the different arrangements of cobalt ions at the three surfaces. PMID- 26934314 TI - Point-of-care test for cervical cancer in LMICs. AB - Cervical cancer screening using Papanicolaou's smear test has been highly effective in reducing death from this disease. However, this test is unaffordable in low- and middle-income countries, and its complexity has limited wide-scale uptake. Alternative tests, such as visual inspection with acetic acid or Lugol's iodine and human papillomavirus DNA, are sub-optimal in terms of specificity and sensitivity, thus sensitive and affordable tests with high specificity for on site reporting are needed. Using proteomics and bioinformatics, we have identified valosin-containing protein (VCP) as differentially expressed between normal specimens and those with cervical intra-epithelial neoplasia grade 2/3 (CIN2/CIN3+) or worse. VCP-specific immunohistochemical staining (validated by a point-of-care technology) provided sensitive (93%) and specific (88%) identification of CIN2/CIN3+ and may serve as a critical biomarker for cervical cancer screening. Future efforts will focus on further refinements to enhance analytic sensitivity and specificity of our proposed test, as well as on prototype development. PMID- 26934315 TI - PARP6 acts as a tumor suppressor via downregulating Survivin expression in colorectal cancer. AB - Poly (ADP-ribose) polymerases (PARPs) are enzymes that transfer ADP-ribose groups to target proteins and are involved in a variety of biological processes. PARP6 is a novel member, and our previous findings suggest that PARP6 may act as a tumor suppressor via suppressing cell cycle progression. However, it is still unclear that PARP6 function besides growth suppression in colorectal cancer (CRC). In this study, we examined tumor suppressive roles of PAPR6 in CRC cells both in vitro and in vivo. We found that PARP6 inhibited colony formation, invasion and migration as well as cell proliferation. Moreover, ectopic overexpression of PARP6 decreased Survivin expression, which acts as an oncogene and is involved in apoptosis and mitosis. We confirmed the inverse correlation between PARP6 and Survivin expression in CRC cases by immunohistochemistry. Importantly, CRC cases with downregulation of PARP6 and upregulation of Survivin showed poor prognosis. In summary, PARP6 acts as a tumor suppressor via downregulating Survivin expression in CRC. PARP6 can be a novel diagnostic and therapeutic target together with Survivin for CRC. PMID- 26934317 TI - Tumor deposits counted as positive lymph nodes in TNM staging for advanced colorectal cancer: a retrospective multicenter study. AB - We investigated the possibility of counting tumor deposits (TDs) as positive lymph nodes (pLNs) in the pN category and evaluated its prognostic value for colorectal cancer (CRC) patients. A new pN category (npN category) was calculated using the numbers of pLNs plus TDs. The npN category included 4 tiers: npN1a (1 tumor node), npN1b (2-3 tumor nodes), npN2a (4-6 tumor nodes), and npN2b (>=7 tumor nodes). We identified 4,121 locally advanced CRC patients, including 717 (11.02%) cases with TDs. Univariate and multivariate analyses were performed to evaluate the disease-free and overall survival (DFS and OS) for npN and pN categories. Multivariate analysis showed that the npN and pN categories were both independent prognostic factors for DFS (HR 1.614, 95% CI 1.541 to 1.673; HR 1.604, 95% CI 1.533 to 1.679) and OS (HR 1.633, 95% CI 1.550 to 1.720; HR 1.470, 95% CI 1.410 to 1.532). However, the npN category was superior to the pN category by Harrell's C statistic. We conclude that it is thus feasible to consider TDs as positive lymph nodes in the pN category when evaluating the prognoses of CRC patients, and the npN category is potentially superior to the TNM (7th edition) pN category for predicting DFS and OS among advanced CRC patients. PMID- 26934316 TI - MiR-449a promotes breast cancer progression by targeting CRIP2. AB - The identification of prognostic biomarkers and their underlying mechanisms of action remain of great interest in breast cancer biology. Using global miRNA profiling of 71 lymph node-negative invasive ductal breast cancers and 5 normal mammary epithelial tissues, we identified miR-449a to be highly overexpressed in the malignant breast tissue. Its expression was significantly associated with increased incidence of patient relapse, decreased overall survival, and decreased disease-free survival. In vitro, miR-449a promoted breast cancer cell proliferation, clonogenic survival, migration, and invasion. By utilizing a tri modal in silico approach for target identification, Cysteine-Rich Protein 2 (CRIP2; a transcription factor) was identified as a direct target of miR-449a, corroborated using qRT-PCR, Western blot, and luciferase reporter assays. MDA-MB 231 cells stably transfected with CRIP2 demonstrated a significant reduction in cell viability, migration, and invasion, as well as decreased tumor growth and angiogenesis in mouse xenograft models. Our data revealed that overexpression of miR-449a suppresses CRIP2, which then affects the tumor vasculature, likely via NF-kappaB/p65 complex-mediated transcription of VEGF. These finding define an oncogenic function of miR-449a in human breast cancer, and highlight the importance of this pathway in driving aggressive behaviour. PMID- 26934318 TI - Predictive role of microRNA-related genetic polymorphisms in the pathological complete response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer patients. AB - In rectal cancer, a pathologic complete response (pCR) to pre-operative treatment is a favourable prognostic marker, but is reported in a minority of the patients. We aimed at identifying microRNA-related host genetic polymorphisms predictive of pCR. A panel of 114 microRNA-related tagging polymorphisms was selected and analyzed on 265 locally advanced rectal cancer patients treated with neoadjuvant chemo-radiotherapy. Patients were stratified in two subgroups according to the radiotherapy dose (50.4Gy for 202 patients, 55.0Gy for 78 patients). Interactions among genetic and clinical-pathological variants were investigated by recursive partitioning analysis. Only polymorphisms with a consistent significant effect in the two subgroups of patients were selected as predictive markers of pCR. The results were validated by bootstrap analysis. SMAD3-rs744910, SMAD3-rs745103, and TRBP-rs6088619 were associated to an increased chance of pCR (p=0.0153, p=0.0471, p=0.0125). DROSHA-rs10719 and SMAD3-rs17228212 had an opposite detrimental effect on pathological tumour response (p=0.0274, p=0.0049). Recursive partitioning analysis highlighted that a longer interval time between the end of radiotherapy and surgery increases the chance of pCR in patients with a specific combination of SMAD3-rs744910 and TRBP-rs6088619 genotypes. This study demonstrated that microRNA-related host genetic polymorphisms can predict pCR to neo-adjuvant chemo radiotherapy, and could be used to personalize the interval time between the end of radiotherapy and surgery. PMID- 26934319 TI - A multimodal assessment of balance in elderly and young adults. AB - Falling is a significant health issue among elderly adults. Given the multifactorial nature of falls, effective balance and fall risk assessment must take into account factors from multiple sources. Here we investigate the relationship between fall risk and a diverse set of biochemical and biomechanical variables including: skeletal muscle-specific troponin T (sTnT), maximal strength measures derived from isometric grip and leg extension tasks, and postural sway captured from a force platform during a quiet stance task. These measures were performed in eight young and eleven elderly adults, along with estimates of fall risk derived from the Tinetti Balance Assessment. We observed age-related effects in all measurements, including a trend toward increased sTnT levels, increased postural sway, reduced upper and lower extremity strength, and reduced balance scores. We observed a negative correlation between balance scores and sTnT levels, suggesting its use as a biomarker for fall risk. We observed a significant positive correlation between balance scores and strength measures, adding support to the notion that muscle strength plays a significant role in postural control. We observed a significant negative correlation between balance scores and postural sway, suggesting that fall risk is associated with more loosely controlled center of mass regulation. PMID- 26934320 TI - Carfilzomib potentiates CUDC-101-induced apoptosis in anaplastic thyroid cancer. AB - Anaplastic thyroid cancer (ATC) is one of the most aggressive human malignancies, with no effective treatment currently available. Previously, we identified agents active against ATC cells, both in vitro and in vivo, using quantitative high throughput screening of 3282 clinically approved drugs and small molecules. Here, we report that combining two of these active agents, carfilzomib, a second generation proteasome inhibitor, and CUDC-101, a histone deacetylase and multi kinase inhibitor, results in increased, synergistic activity in ATC cells. The combination of carfilzomib and CUDC-101 synergistically inhibited cellular proliferation and caused cell death in multiple ATC cell lines harboring various driver mutations observed in human ATC tumors. This increased anti-ATC effect was associated with a synergistically enhanced G2/M cell cycle arrest and increased caspase 3/7 activity induced by the drug combination. Mechanistically, treatment with carfilzomib and CUDC-101 increased p21 expression and poly (ADP-ribose) polymerase protein cleavage. Our results suggest that combining carfilzomib and CUDC-101 would offer an effective therapeutic strategy to treat ATC. PMID- 26934322 TI - Resveratrol suppresses myofibroblast activity of human buccal mucosal fibroblasts through the epigenetic inhibition of ZEB1 expression. AB - Oral submucous fibrosis (OSF) is a precancerous condition of the oral mucosa without specific therapeutic drugs. We previously demonstrated that the zinc finger E-box binding homeobox 1 (ZEB1) plays a pathogenic role in the induction of the myofibroblast activity of buccal mucosal fibroblasts (BMFs) and contributes to the pathogenesis of OSF. Resveratrol is a natural polyphenolic flavonoid with anti-fibrosis activity in various tissues and has the capability to inhibit ZEB1 in oral cancer cells. We examined the effect of resveratrol on the myofibroblast activity of human primary fibrotic BMFs (fBMFs) derived from OSF tissues. With the collagen contraction assay, resveratrol displayed anti myofibroblast activity in three fBMF lines. Resveratrol also inhibited the expression of fibrogenic genes at the mRNA and protein levels in a dose- and time dependent manner. The downregulation of ZEB1 in fBMFs by resveratrol was mediated by epigenetic mechanisms, such as the upregulated expression of miR-200c and the enhancer of zeste homolog 2 (EZH2), as well as the trimethylated lysine 27 of histone H3 (H3K27me3). Resveratrol also increased the binding of H3K27me3 to the ZEB1 promoter. The knockdown of EZH2 in fBMFs caused the upregulation of ZEB1 and suppressed the inhibitory effect of resveratrol. Furthermore, the reversed expression pattern between EZH2 and ZEB1 was observed in 6/8 OSF tissues with twofold upregulation of ZEB1 expression compared with the adjacent normal mucosa. In conclusion, our data suggest that resveratrol epigenetically inhibits ZEB1 expression to suppress the myofibroblast activity of fBMFs and may serve as a dietary supplement for OSF patients. PMID- 26934323 TI - Associations between polymorphisms of long non-coding RNA MEG3 and risk of colorectal cancer in Chinese. AB - Maternally expressed gene 3 (MEG3), a long non-coding RNA (lncRNA), is involved in cancer development and metastasis. The objective of the present study was to evaluate whether common single nucleotide polymorphisms (SNPs) in MEG3 could be related with colorectal cancer risk in Chinese. We genotyped six tagSNPs of MEG3 in a colorectal cancer case-control study including 518 cases and 527 control subjects. Multivariate logistic regression analysis was applied to calculate adjusted odds ratios (ORs). We found that MEG3 rs7158663 AA genotype, but not GA genotype, had significant increased colorectal cancer risk, compared with GG genotype (OR = 1.96 and P = 0.006 for AA versus GG, and OR = 1.20 and P = 0.171 for GA versus GG). Further stratified analysis indicated that the increased risk was significantly correlated with individuals with age <= 60 and family history of cancer. However, there was no significant association between rs7158663 and colorectal tumor site and stage (P = 0.842 for tumor site, and P = 0.601 for tumor stage). These results demonstrate that genetic variants in MEG3 may contribute to the development and risk of colorectal cancer. Further studies are required to confirm these findings. PMID- 26934321 TI - Class II phosphoinositide 3-kinase C2beta regulates a novel signaling pathway involved in breast cancer progression. AB - It is now well established that the enzymes phosphoinositide 3-kinases (PI3Ks) have a key role in the development and progression of many cancer types and indeed PI3Ks inhibitors are currently being tested in clinical trials. Although eight distinct PI3K isoforms exist, grouped into three classes, most of the evidence currently available are focused on one specific isoform with very little known about the potential role of the other members of this family in cancer. Here we demonstrate that the class II enzyme PI3K-C2beta is overexpressed in several human breast cancer cell lines and in human breast cancer specimens. Our data indicate that PI3K-C2beta regulates breast cancer cell growth in vitro and in vivo and that PI3K-C2beta expression in breast tissues is correlated with the proliferative status of the tumor. Specifically we show that downregulation of PI3K-C2beta in breast cancer cell lines reduces colony formation, induces cell cycle arrest and inhibits tumor growth, in particular in an estrogen-dependent in vivo xenograft. Investigation of the mechanism of the PI3K-C2beta-dependent regulation of cell cycle progression and cell growth revealed that PI3K-C2beta regulates cyclin B1 protein levels through modulation of microRNA miR-449a levels. Our data further demonstrate that downregulation of PI3K-C2beta inhibits breast cancer cell invasion in vitro and breast cancer metastasis in vivo. Consistent with this, PI3K-C2beta is highly expressed in lymph-nodes metastases compared to matching primary tumors. These data demonstrate that PI3K-C2beta plays a pivotal role in breast cancer progression and in metastasis development. Our data indicate that PI3K-C2beta may represent a key molecular switch that regulates a rate-limiting step in breast tumor progression and therefore it may be targeted to limit breast cancer spread. PMID- 26934325 TI - Autophagy: a decisive process for stemness. AB - Mature skeletal muscle is a stable tissue imposing low homeostatic demand on its stem cells, which remain in a quiescent state in their niche over time. We have shown that these long-lived resting stem cells attenuate proteotoxicity and avoid senescence through basal autophagy. This protective "clean-up" system is lost during aging, resulting in stem cell regenerative decline. Thus, autophagy is required for muscle stem cell homeostasis maintenance. PMID- 26934324 TI - Role of multifaceted regulators in cancer glucose metabolism and their clinical significance. AB - Aberrant glucose metabolism, "aerobic glycolysis" or "Warburg effect", is a hallmark of human cancers. There is a cluster of "multifaceted regulators", which plays a pivotal role in the regulation of glucose metabolism. They can not only modulate the activities of specific enzymes, but also act as transcriptional activators to regulate the expression of metabolism related genes. Additionally, they can crosstalk with other key factors involved in glucose metabolism and work together to initiate multiple oncogenic processes. These "multifaceted regulators", especially p53, HIF-1, TIGAR and microRNA, will be focused in this review. And we will comprehensively illustrate their regulatory effects on cancer glucose metabolism, and further elaborate on their clinical significance. In depth elucidation the role of "multifaceted regulators" in cancer glucose metabolism will provide us novel insights in cancer research field and offer promising therapeutic targets for anti-cancer therapies. PMID- 26934326 TI - miR-155-5p inhibition promotes the transition of bone marrow mesenchymal stem cells to gastric cancer tissue derived MSC-like cells via NF-kappaB p65 activation. AB - Gastric cancer tissue-derived MSC-like cells (GC-MSC) share similar characteristics to bone marrow MSC (BM-MSC); however, the phenotypical and functional differences and the molecular mechanism of transition between the two cell types remain unclear. Compared to BM-MSC, GC-MSC exhibited the classic phenotype of reactive stroma cells, a stronger gastric cancer promoting capacity and lower expression of miR-155-5p. Inhibition of miR-155-5p by transfecting miRNA inhibitor induced a phenotypical and functional transition of BM-MSC into GC-MSC-like cells, and the reverse experiment deprived GC-MSC of tumor-promoting phenotype and function. NF-kappa B p65 (NF-kappaB p65) and inhibitor of NF-kappa B kinase subunit epsilon (IKBKE/IKKepsilon) were identified as targets of miR-155 5p and important for miRNA inhibitor activating NF-kappaB p65 in the transition. Inactivation of NF-kappaB by pyrrolidine dithiocarbamic acid (PDTC) significantly blocked the effect of miR-155-5p inhibitor on BM-MSC. IKBKE, NF-kappaB p65 and phospho-NF-kappaB p65 proteins were highly enriched in MSC-like cells of gastric cancer tissues, and the latter two were correlated with the pathological progression of gastric cancer. In GC-MSC, the expression of miR-155-5p was downregulated and NF-kappaB p65 protein was increased and activated. NF-kappaB inactivation by PDTC or knockdown of its downstream cytokines reversed the phenotype and function of GC-MSC. Taken together, our findings revealed that miR 155-5p downregulation induces BM-MSC to acquire a GC-MSC-like phenotype and function depending on NF-kappaB p65 activation, which suggests a novel mechanism underlying the cancer associated MSC remodeling in the tumor microenvironment and offers an effective target and approach for gastric cancer therapy. PMID- 26934327 TI - Exploration of the recurrence in radiation brain necrosis after bevacizumab discontinuation. AB - OBJECTIVE: The aim of the paper was to investigate the recurrence and its causes of radiation brain necrosis following bevacizumab discontinuation. METHODS: This study included 14 patients with radiation brain necrosis (confirmed through imaging) after stereotactic radiotherapy for a primary or metastatic brain tumor and who received bevacizumab treatment from June 2011 through December 2014. The patients received bevacizumab at 5 mg/kg, q3-4w, for at least 3 cycles. The T1 signal intensity from enhanced MRI images was used as the evaluation criteria for the brain necrosis treatment efficacy. RESULTS: brain necrosis improved in 13 of the 14 cases (92.9%). However, during follow-up, 10 of the 13 responsive patients (76.9%) exhibited a recurrence in brain necrosis, and a multiple linear regression analysis shows that brain necrosis recurrence was related to the follow-up time after the initial bevacizumab treatment discontinuation. CONCLUSION: bevacizumab produced good short-term effects for radiation brain necrosis; however, most of the patients would recurrence after bevacizumab is discontinued. Thus, brain necrosis was irreversible. PMID- 26934328 TI - Stress resistance and lifespan are increased in C. elegans but decreased in S. cerevisiae by mafr-1/maf1 deletion. AB - Maf1 is a conserved effector of the mechanistic target of rapamycin (mTOR), an aging promoting kinase. However, whether Maf1 is required for lifespan extension caused by mTOR inhibition, such as dietary restriction (DR) or calorie restriction (CR) remains elusive. Here we show that deletion of maf1 in the budding yeast S. cerevisiae but not mafr-1 in C. elegans prevents DR or CR to extend lifespan. Interestingly, mafr-1 deletion increases stress tolerance and extends lifespan. MAFR-1 is phosphorylated in a mTOR-dependent manner and mafr-1 deletion alleviates the inhibition of tRNA synthesis caused by reduced mTOR activity. We find that the opposite effect of mafr-1 deletion on lifespan is due to an enhancement of stress response, including oxidative stress response, mitochondrial unfolded protein response (UPRmt) and autophagy. mafr-1 deletion also attenuates the paralysis of a C. elegans model of Alzheimer's disease. Our study reveals distinct mechanisms of lifespan regulation by Maf1 and MAFR-1. PMID- 26934329 TI - New pathogen-specific immunoPET/MR tracer for molecular imaging of a systemic bacterial infection. AB - The specific and rapid detection of Enterobacteriaceae, the most frequent cause of gram-negative bacterial infections in humans, remains a major challenge. We developed a non-invasive method to rapidly detect systemic Yersinia enterocolitica infections using immunoPET (antibody-targeted positron emission tomography) with [64Cu]NODAGA-labeled Yersinia-specific polyclonal antibodies targeting the outer membrane protein YadA. In contrast to the tracer [18F]FDG, [64Cu]NODAGA-YadA uptake co-localized in a dose dependent manner with bacterial lesions of Yersinia-infected mice, as detected by magnetic resonance (MR) imaging. This was accompanied by elevated uptake of [64Cu]NODAGA-YadA in infected tissues, in ex vivo biodistribution studies, whereas reduced uptake was observed following blocking with unlabeled anti-YadA antibody. We show, for the first time, a bacteria-specific, antibody-based, in vivo imaging method for the diagnosis of a Gram-negative enterobacterial infection as a proof of concept, which may provide new insights into pathogen-host interactions. PMID- 26934330 TI - A bovine herpesvirus 1 pUL51 deletion mutant shows impaired viral growth in vitro and reduced virulence in rabbits. AB - Bovine herpesvirus 1 (BoHV-1) UL51 protein (pUL51) is a tegument protein of BoHV 1 whose function is currently unknown. Here, we aimed to illustrate the specific role of pUL51 in virion morphogenesis and its importance in BoHV-1 virulence. To do so, we constructed a BoHV-1 bacterial artificial chromosome (BAC). We used recombinant BAC and transgenic techniques to delete a major part of the UL51 open reading frame. Deletion of pUL51 resulted in severe viral growth defects, as evidenced by lower single and multi-step growth kinetics, reduced plaque size, and the accumulation of non-enveloped capsids in the cytoplasm of infected cells. Using tagged BoHV-1 recombinant viruses, it was determined that the pUL51 protein completely co-localized with the cis-Golgi marker protein GM-130. Taken altogether, pUL51 was demonstrated to play a critical role in BoHV-1 growth and it is involved in viral maturation and egress. Moreover, an in vivo analysis showed that the pUL51 mutant exhibited reduced virulence in rabbits, with no clinical signs, no nasal shedding of the virus, and no detectable serum neutralizing antibodies. Therefore, we conclude that the BoHV-1 pUL51 is indispensable for efficient viral growth in vitro and is essential for virulence in vivo. PMID- 26934334 TI - Risk of cross-contamination due to the use of antimicrobial medicated feed throughout the trail of feed from the feed mill to the farm. AB - The cross-contamination of non-medicated feed with residues of antimicrobials causes an animal and public health concern associated with the potential for the selection and dissemination of resistance in commensal bacteria and potentially zoonotic bacteria. To identify the extent of this situation, we built a risk model that provides a way to estimate the percentage of cross-contaminated feed in total and at the different levels at which cross-contamination may occur (i.e. the feed mill, the transport truck, the farm), for different levels of antimicrobial medicated feed produced in a country per year. The model, estimated that when antimicrobial medicated feed represents a hypothetical xi = 2% of the total feed produced in a country per year, then 5.5% (95% CI = 3.4%; 11.4%) of the total feed produced in a year could be cross-contaminated with different levels of antimicrobials due to practices related to medicated feed. In detail, 1.80% (95% CI = 0.2%; 7.7%) of the total feed produced in such a country would be cross-contaminated due to antimicrobial carryover occurring at the feed mill level, 1.83% (95% CI = 1.3%; 2.0%) at the transport truck level and 1.84% (95% CI = 1.2%; 2.0%) at the farm level. The model also demonstrated that even in cases where antimicrobial medicated feed would be produced in end-of-line mixers or a fine dosing system on trucks, the risk of cross-contamination would not be negligible; the percentage of cross-contaminated feed produced in a country (where xi = 2%) per year would be 3.7% (95% CI = 2.9%; 4.0%) and 2.4% (95% CI = 1.6%; 2.7%), respectively. It is hard to reduce the risk to zero as it is the result of factors occurring at different levels. Thus, the use of antimicrobial medicated feed should be avoided as much as possible to reduce selection pressure. PMID- 26934332 TI - Genetic Tagging During Human Mesoderm Differentiation Reveals Tripotent Lateral Plate Mesodermal Progenitors. AB - Although clonal studies of lineage potential have been extensively applied to organ specific stem and progenitor cells, much less is known about the clonal origins of lineages formed from the germ layers in early embryogenesis. We applied lentiviral tagging followed by vector integration site analysis (VISA) with high-throughput sequencing to investigate the ontogeny of the hematopoietic, endothelial and mesenchymal lineages as they emerge from human embryonic mesoderm. In contrast to studies that have used VISA to track differentiation of self-renewing stem cell clones that amplify significantly over time, we focused on a population of progenitor clones with limited self-renewal capability. Our analyses uncovered the critical influence of sampling on the interpretation of lentiviral tag sharing, particularly among complex populations with minimal clonal duplication. By applying a quantitative framework to estimate the degree of undersampling we revealed the existence of tripotent mesodermal progenitors derived from pluripotent stem cells, and the subsequent bifurcation of their differentiation into bipotent endothelial/hematopoietic or endothelial/mesenchymal progenitors. Stem Cells 2016;34:1239-1250. PMID- 26934333 TI - Predictors of Depression Treatment Response in an Intensive CBT Partial Hospital. AB - OBJECTIVE: Despite the effectiveness of cognitive behavioral therapy (CBT) for depression, a significant number of patients do not respond. Data examining predictors of treatment response in settings in which CBT is delivered naturalistically are lacking. METHOD: Treatment outcome data collected at a CBT based partial hospital (n = 956) were used to examine predictors of two types of treatment response: (a) a reliable and clinically significant change in depressive symptoms and (b) a self-rating of "very much" or "much" improved. In multiple logistic regression models, we examined predictors of response in the total sample and separately for patients with a primary diagnosis of major depressive disorder (MDD) versus patients with other primary diagnoses. RESULTS: In the total sample, higher treatment outcome expectations and fewer past hospitalizations predicted clinically significant improvement in depression symptoms, and higher treatment expectations and ethnoracial minority background predicted global improvement. In patients with primary MDD, higher treatment outcome expectations and being referred from the community (vs. inpatient hospitalization) predicted better depression response, and higher treatment outcome expectations predicted global improvement. In patients with other primary diagnoses, higher treatment outcome expectations and fewer borderline personality disorder traits predicted depression reduction, and higher treatment outcome expectations, less relationship difficulty, and female gender predicted global improvement. CONCLUSIONS: Results are generally consistent with data from randomized controlled trials on longer term outpatient CBT. Interventions that increase treatment expectancy and modifications to better target men may enhance treatment outcome. Future research should include objective outcome measures and examine mechanisms underlying treatment response. PMID- 26934331 TI - Notch signaling: its roles and therapeutic potential in hematological malignancies. AB - Notch is a highly conserved signaling system that allows neighboring cells to communicate, thereby controlling their differentiation, proliferation and apoptosis, with the outcome of its activation being highly dependent on signal strength and cell type. As such, there is growing evidence that disturbances in physiological Notch signaling contribute to cancer development and growth through various mechanisms. Notch was first reported to contribute to tumorigenesis in the early 90s, through identification of the involvement of the Notch1 gene in the chromosomal translocation t(7;9)(q34;q34.3), found in a small subset of T cell acute lymphoblastic leukemia. Since then, Notch mutations and aberrant Notch signaling have been reported in numerous other precursor and mature hematological malignancies, of both myeloid and lymphoid origin, as well as many epithelial tumor types. Of note, Notch has been reported to have both oncogenic and tumor suppressor roles, dependent on the cancer cell type. In this review, we will first give a general description of the Notch signaling pathway, and its physiologic role in hematopoiesis. Next, we will review the role of aberrant Notch signaling in several hematological malignancies. Finally, we will discuss current and potential future therapeutic approaches targeting this pathway. PMID- 26934335 TI - alpha-Arylation of Ketimines with Aryl Sulfides at a Low Palladium Catalyst Loading. AB - Instead of using aryl halides, aryl sulfides, typically poisonous to transition metal catalysts, were found to serve as aryl electrophiles in the catalytic alpha arylation of ketimines, a class of carbonyl derivatives. Low catalyst loadings (down to 0.5 mol %) of a palladium-NHC complex are sufficient for efficient arylation. alpha-Arylated ketimine products are useful for the synthesis of various azaarenes, including 2,3-diarylpyrroles, an indole, and pyrrolediones. PMID- 26934336 TI - Potential Biomarkers in Diagnosis of Human Gastric Cancer. AB - The high incidence of gastric cancer (GC) and its consequent mortality rate severely threaten human's health. It is not frequently diagnosed until a relatively advanced stage. Surgery is the only potentially curative treatment. Thus, early screening and diagnosis are critical for patients with GC. The tumor marker assays used currently for detecting GC are simple and rapid, but the usage is limited by its low sensitivity and specificity. Here, we provide a brief description of some new potential markers and new biotechnological methods for the diagnosis of GC, hoping to find out more effective approaches for early detection of GC. PMID- 26934338 TI - Evidence and potential in vivo functions for biofluid miRNAs: From expression profiling to functional testing: Potential roles of extracellular miRNAs as indicators of physiological change and as agents of intercellular information exchange. AB - A controversial hypothesis in RNA biology is that extracellular microRNAs (miRNAs), including those in biofluids, have non-cell-autonomous activities. Several studies have characterized biofluid miRNA profiles in healthy or diseased individuals but generally have failed to identify distinct disease signatures. It remains unclear whether alterations in fluid miRNA levels are simply indicators of physiological change or whether miRNAs are taken up by new cells at concentrations sufficient to affect gene expression. There are limitations to biofluid miRNA studies performed to date: methodology for isolating and quantifying biofluid miRNAs is not standardized across studies; mechanistic details of miRNA release and uptake are incomplete; and efforts to assess non cell-autonomous effects of extracellular miRNAs have employed predominantly in vitro strategies. We describe controversies and questions that need to be addressed to test possible in vivo roles of extracellular miRNAs and propose model organisms with rich genetic toolkits for carrying out in vivo functional analyses. PMID- 26934337 TI - Acute heat shock leads to cortical domain internalization and polarity loss in the C. elegans embryo. AB - Many developmental processes are inherently robust due to network organization of the participating factors and functional redundancy. The heterogeneity of the factors involved and their connectivity puts these processes at risk of abrupt system collapse under stress. The polarization of the one-cell C. elegans embryo constitutes such an inherently robust process with functional redundancy. However, how polarization is affected by acute stress has not been thoroughly investigated. Here, we report that heat shock (34 degrees C, 1 h) triggers a highly reproducible loss of the anterior and collapse of the posterior polarity domains. Temperature-dependent loss of cortical non-muscle myosin II drastically reduces cortical tension and leads to internalization of large plasma membrane domains including the membrane-associated polarity factor PAR-2. After internalization, plasma membrane vesicles and associated factors cluster around centrosomes and are thereby withdrawn from the polarization process. Transient formation of the posterior polarity domain suggests that microtubule-induced self organization of this domain is not compromised after heat shock. Hence, our data uncover that the polarization system undergoes a temperature-dependent collapse under acute stress. PMID- 26934340 TI - High Speed Imaging of Cavitation around Dental Ultrasonic Scaler Tips. AB - Cavitation occurs around dental ultrasonic scalers, which are used clinically for removing dental biofilm and calculus. However it is not known if this contributes to the cleaning process. Characterisation of the cavitation around ultrasonic scalers will assist in assessing its contribution and in developing new clinical devices for removing biofilm with cavitation. The aim is to use high speed camera imaging to quantify cavitation patterns around an ultrasonic scaler. A Satelec ultrasonic scaler operating at 29 kHz with three different shaped tips has been studied at medium and high operating power using high speed imaging at 15,000, 90,000 and 250,000 frames per second. The tip displacement has been recorded using scanning laser vibrometry. Cavitation occurs at the free end of the tip and increases with power while the area and width of the cavitation cloud varies for different shaped tips. The cavitation starts at the antinodes, with little or no cavitation at the node. High speed image sequences combined with scanning laser vibrometry show individual microbubbles imploding and bubble clouds lifting and moving away from the ultrasonic scaler tip, with larger tip displacement causing more cavitation. PMID- 26934341 TI - N-Benzyl-4-((heteroaryl)methyl)benzamides: A New Class of Direct NADH-Dependent 2 trans Enoyl-Acyl Carrier Protein Reductase (InhA) Inhibitors with Antitubercular Activity. AB - Isoniazid (INH) remains one of the cornerstones of antitubercular chemotherapy for drug-sensitive strains of M. tuberculosis bacteria. However, the increasing prevalence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains containing mutations in the KatG enzyme, which is responsible for the activation of INH into its antitubercular form, have rendered this drug of little or no use in many cases of drug-resistant tuberculosis. Presented herein is a novel family of antitubercular direct NADH-dependent 2-trans enoyl-acyl carrier protein reductase (InhA) inhibitors based on an N-benzyl-4 ((heteroaryl)methyl)benzamide template; unlike INH, these do not require prior activation by KatG. Given their direct InhA target engagement, these compounds should be able to circumvent KatG-related resistance in the clinic. The lead molecules were shown to be potent inhibitors of InhA and showed activity against M. tuberculosis bacteria. This new family of inhibitors was found to be chemically tractable, as exemplified by the facile synthesis of analogues and the establishment of structure-activity relationships. Furthermore, a co-crystal structure of the initial hit with the enzyme is disclosed, providing valuable information toward the design of new InhA inhibitors for the treatment of MDR/XDR tuberculosis. PMID- 26934343 TI - Use of a Florida Gulf Coast Barrier Island by Spring Trans-Gulf Migrants and the Projected Effects of Sea Level Rise on Habitat Availability. AB - Barrier islands on the north coast of the Gulf of Mexico are an internationally important coastal resource. Each spring hundreds of thousands of Nearctic Neotropical songbirds crossing the Gulf of Mexico during spring migration use these islands because they provide the first landfall for individuals following a trans-Gulf migratory route. The effects of climate change, particularly sea level rise, may negatively impact habitat availability for migrants on barrier islands. Our objectives were (1) to confirm the use of St. George Island, Florida by trans Gulf migrants and (2) to determine whether forested stopover habitat will be available for migrants on St. George Island following sea level rise. We used avian transect data, geographic information systems, remote sensing, and simulation modelling to investigate the potential effects of three different sea level rise scenarios (0.28 m, 0.82 m, and 2 m) on habitat availability for trans Gulf migrants. We found considerable use of the island by spring trans-Gulf migrants. Migrants were most abundant in areas with low elevation, high canopy height, and high coverage of forests and scrub/shrub. A substantial percentage of forest (44%) will be lost by 2100 assuming moderate sea level rise (0.82 m). Thus, as sea level rise progresses, less forests will be available for migrants during stopover. Many migratory bird species' populations are declining, and degradation of barrier island stopover habitat may further increase the cost of migration for many individuals. To preserve this coastal resource, conservation and wise management of migratory stopover areas, especially near ecological barriers like the Gulf of Mexico, will be essential as sea levels rise. PMID- 26934344 TI - [Immunologic biomarkers in predicting the efficacy of cancer therapy]. AB - Immune checkpoint agents, representing a new class of immunotherapeutic modalities, have proven their beneficial effect inducing durable clinical response in a widening spectrum of tumor types. To enhance their efficacy it is of primary importance to search for biomarkers that could help predict the likelihood of therapeutic effect. Results of studies on potential predictive immunological parameters suggest that the existing antitumor immune activity detectable in the patients, although not sufficient to control tumor progression in itself, could increase the efficacy of different immunotherapies. Moreover, the contribution of immune reactions to the effect of other antitumor treatment modalities as chemo-, radio-, and targeted therapy has also been demonstrated. Combinations of immunotherapies with these and with each other will probably represent treatment approaches resulting in the highest therapeutic effect, which may necessitate the development of biomarker panels with multiple components characterizing the immune status of the patient and the tumor as well. PMID- 26934345 TI - [Clinical studies and accepted therapies of advanced melanoma]. AB - The objective of the work is presentation of the available therapeutic results of the clinical trials with anti CTLA-4 and anti PD-1 treatment, which are operating on the immune checkpoints registered in advanced melanoma, and the results of T VEC vaccination (NCT00094653, NCT00324155, KEYNOTE-001, -002, -006, CheckMate 066, -037, -067, NCT00769704). With ipilimumab therapy, long-term survival can be achieved in the case of 20% of patients, with low (10%) therapeutic response, and grade 3-4 treatment related, predominantly autoimmune adverse events occurring in 10-15% of patients. Anti-PD-1 therapy proved more effective compared to ipilimumab, resulting in 21-40% therapeutic response, with 60-74% one-year survival rate and significantly less severe and frequent side effects. Progression-free survival achieved with ipilimumab/nivolumab combination was 11.5 months with grade 3-4 side effects occurring in 55% of patients. T-VEC therapy resulted in 26.4% objective response rate without a significant survival advantage. In the possession of the new immunotherapeutic possibilities, knowledge of the results of clinical studies is essential for the optimal complex therapy of melanoma. PMID- 26934342 TI - Anti-myeloma effect of pharmacological inhibition of Notch/gamma-secretase with RO4929097 is mediated by modulation of tumor microenvironment. AB - Multiple myeloma (MM), a blood cancer characterized by the uncontrolled proliferation of plasma cells, remains incurable by current therapy. Notch signaling has been implicated in the growth and chemoresistance of various cancer types including MM, and therefore we hypothesized that targeting the Notch pathway could be beneficial for the treatment of this disease. Here, we report an anti-tumor effect of Notch/gamma-secretase inhibitor RO4929097 in a pre-clinical model of MM. We demonstrate that this effect was associated with decreased angiogenesis and significant down-regulation of TGF-beta1. In addition, we also show that treatment with RO4929097 results in decreased number and functional activity of osteoclasts. Taken together, our data indicate that targeting Notch may be considered as a new strategy to be tested for MM therapy. PMID- 26934346 TI - [How to choose the optimal therapy? New issues in the treatment of metastatic melanoma]. AB - The last few years brought about a complete paradigm-shift in the field of melanoma therapy: eight new drugs, including three immunooncologic, four targeted and one oncolytic virus, became available in the daily practice. These new treatments provide a significantly increased overall survival potential for patients with metastatic melanoma. Choosing the optimal treatment for the individual patient, however, requires the careful evaluation of several patient- and drug-related factors, and poses a great challenge for the oncologists. This review summarizes the practical aspects of the selection of the optimal melanoma treatment. PMID- 26934347 TI - [Psychological aspects of immunotherapies in the treatment of malignant melanoma]. AB - Psychological problems may arise in connection with oncomedical treatments in three ways: 1. acute and/or 2. chronic ways, as well as 3. co-morbid psychiatric diseases that already exist must also be taken into account. Immunotherapies have the most common and also clinically relevant psychological side effects. Fatigue, anhedonia, social isolation, psychomotor slowness is reported during treatment. Anti-CTLA-4 antibody (ipilimumab) immunotherapy can present one of the most modern opportunities for adequate treatment for patients having distant metastasis or unresectable tumour. In relation to immunotherapies, acute psychological side effects (acute stress) emerging during treatments develop in a way that can mostly be linked to environmental factors, e.g. notification of diagnosis, hospitalisation, progression, deterioration in quality of life, imminent dates of control. Crisis is a temporary and threatening condition that endangers psychological balance. In such conditions, enhanced psychological vulnerability must be taken into account and doctors play a key role in the rapid recognition of the condition. Chronic psychological problems, which may arise from the depressogenic effect of the applied treatment or originated from a pre melanoma psychiatric condition, may exceed the diagnostic and psychotherapeutic competences of a clinical psychologist. Even in case of a well-defined depressogenic biological mechanism such as the activation of the pro-inflammatory cytokine pathway, positive environmental effects can reduce symptoms and thus increase compliance. Side effects can be treated successfully using psychotherapeutic methods and/or psychiatric medicines. The application of routinely used complex psychosocial screening packages can provide the easiest method to identify worsening psychological condition during immunotherapy and give rapid feedback to the oncologist and the patient. Team work is of particular importance in a situation like this as it requires complex, interdisciplinary and high-level professional collaboration. Multidisciplinarity is the basic framework for modern tumour therapy where, under the guidance of oncologists, the work of specialist nurses, social workers, physiotherapists, dieticians and last but not least psychiatrists/psychologists are indispensable and play a significant role. PMID- 26934348 TI - [Self defense instead of offense - Immunotherapy in lung cancer]. AB - Lung cancer is the leading cause of cancer death worldwide and also in Hungary, therefore new therapeutic strategies are of great importance. Among immunotherapeutic approaches immune checkpoint inhibition appears to be the most promising. Recent studies have shown efficacy of immunotherapy, especially in squamous cell lung cancer, which is a big step forward in the treatment of this histological subtype. Unlike in the molecularly targeted therapies, the patient selection method has not yet been developed, although some studies indicate the predictive value of tumor cell PD-L1 immunopositivity, especially in lung adenocarcinoma. Introduction of immunotherapy carries challenge for clinicians regarding the radiological assessment of therapeutic efficiency as well as the management of side effects of new profile. The favorable results of recent studies, however, provide hope in this malignancy still presenting a major therapeutic challenge. PMID- 26934349 TI - [Immunotherapy opportunities in breast cancer]. AB - The prognostic value of tumor infiltrating lymphocytes in breast cancer has long been recognized by histopathologists. These observations were reaffirmed by recent immunohistochemistry and gene expression profiling studies that also revealed an association between greater chemotherapy sensitivity and extensive lymphocytic infiltration in early stage breast cancers treated with neoadjuvant chemotherapy. These results suggest that local anti-tumor immune response can at least partially control cancer growth and may mediate the antitumor effects of chemotherapy. However, until recently, there was no direct clinical evidence to demonstrate that enhancing anti-tumor immune response could lead to clinical benefit in breast cancer patients. The recent development of clinically effective immune checkpoint inhibitors made it possible to test the therapeutic impact of augmenting the local anti-tumor immune response. Two Phase I clinical trials using single agent anti-PD-1 (MK-3475, pembrolizumab) and anti-PD-L1 (MPDL3280A, atezolizumab) antibodies demonstrated close to 20% tumor response rates in heavily pretreated, metastatic, triple negative breast cancers. The most remarkable feature of the responses was their long duration. Several patients had disease control close to a year, or longer, which has not previously been seen with chemotherapy regimens in this patient population. A large number of clinical trials are currently underway with these and similar drugs in the neoadjuvant, adjuvant and metastatic settings to define the role of this new treatment modality in breast cancer. PMID- 26934350 TI - [Immunotherapy in the treatment of genitourinary cancers]. AB - In this clinical review we provide information regarding advance and main achievements in the immunotherapy of genitourinary, particularly renal cell and prostate cancer. Nivolumab treatment became the new standard of care in locally advanced or metastatic renal cell cancer after failure on tyrosine kinase inhibitor treatment. Sipuleucel-T prolonged survival in patients with asymptomatic or minimally symptomatic metastatic castration resistant prostate cancer but had no effect on progression-free survival. Based on the results of phase I/II trials anti-PD-1/PD-L1 monoclonal antibodies are a new hope in the treatment of urothelial bladder cancer. Regarding germ cell tumors basic research is ongoing. PMID- 26934351 TI - [The effect of radiotherapy on the antitumor immune response. Possibilities to combine radiotherapy with immunotherapy]. AB - The past three decades of immunology research led to a drastic increase in the knowledge of antitumor immune response mechanisms and in parallel to a rapid development in various antitumor immune therapy strategies. This will most probably result in the implementation of immunotherapeutic protocols within the standard anticancer regimens in a very near future. Though, it is obvious that combination of immunotherapy with traditional anticancer treatment modalities will only be legitimate if the combination has at least an additive, or perhaps a synergistic effect. The similarly dynamic progress in the radiobiological knowledge proved that ionizing radiation does not have a general immune suppressing effect, as it has been thought for decades, but might possess certain immune stimulatory effects, as well. It is also known by now that local irradiation due to its out-of-field effects has systemic immune modulatory capacity, too. In the light of all these novel findings the optimal combination between antitumor immunotherapy and radiotherapy has become an increasing option. The first part of the present review summarizes the main antitumor mechanisms that can be influenced by ionizing radiation, and the second part attempts to provide a comprehensive overview of those antitumor immunotherapeutic modalities that are currently being used in combination with radiotherapy in preclinical and/or clinical trials for the treatment of various tumors. PMID- 26934352 TI - [Tumorigenesis: interplay of pattern recognition receptors and autophagy]. AB - According to recent data, the involvement of autophagy in tumor development is unquestionable. Nevertheless, cell-derived pathogen/danger-associated molecular pattern (PAMP/DAMP)-sensing Toll-like receptors (TLRs) are also able to contribute to tumorigenesis and immune escape of malignantly transformed cells. Besides immunocompetent cells, several types of tumors also exhibit TLRs. TLR- and autophagy-related signaling pathways, on the other hand, may evolve anti tumor effects in a context dependent cell- and microenvironment-specific mode. Nowadays, the autophagy machinery has been considered as a crucial homeostatic process of eukaryotic cells, and as essential constituent of the immune system influencing antimicrobial and inflammation-related immune responses. Accumulating evidence indicates that TLRs and autophagy are interdependent in response to PAMPs and DAMPs, in addition there is a bi-directional controling cross modulation between them. Regarding personalized medicine, theoretically, it is reasonable that manipulation of the TLR-autophagy regulatory loop might be adaptable for anti-cancer therapy. PMID- 26934353 TI - [Genetic information from tumor-infiltrating B lymphocytes as a driver tool ("GPS") for anti-tumor T cell CARs]. AB - The rapidly growing field of gene therapy techniques to modify T cells with chimeric antigen receptors (CARs) for cancer care solutions, reached considerable achievements. However, there is an urgent need of reliable, well tolerable tumor associated antigen specific antibodies. Tumor-infiltrating B (TIL-B) cell originated single chain Fv (scFv) gene regions could be selected with tumor specificity. DNA sequences of these antibody variable regions were subjects to get engineered into new CAR constructs. Our novel strategy harnesses tumor infiltrating B cells' unique capacity to reveal highly tumor-associated disialylated glycosphingolipids (GD3 gangliosides). We used these human antibody fragments for generating GD3 ganglioside specific CAR gene constructs for potential usage in solid tumors. PMID- 26934354 TI - [Diagnostic problems and prognostic factors in prostate cancer]. AB - We aimed to refine the methodology for discriminating ductal (DAP) and acinar adenocarcinomas (AAP) of the prostate preoperatively with a high degree of accuracy, and confirm that prostate carcinoma of ductal origin is a more aggressive subtype. Moreover, we intended to evaluate the clinical utility of transrectal ultrasound-guided systematic sextant or octant biopsies in prediction of extracapsular extension (ECE) at radical prostatectomy. A blinded retrospective analysis of 3-dimensional histology specimens from 110 consecutive radical prostatectomy (RP) cases operated between 2000 and 2006 was carried out (average follow-up: 5.1 years). The samples were also analyzed for 9 different biomarkers. We performed a retrospective analysis of 84 cases of patients who underwent transrectal ultrasound-guided systematic sextant (in 60 cases) or octant (in 24 cases) biopsy. The presence of ECE was correlated to the number of positive biopsies on each side of the prostate by chi-square analysis. Sensitivity, specificity, positive and negative predictive values were calculated for both positive (two or three positive biopsies per side) and negative (no or only one positive biopsy per side) test results. The number of positive cores was thereafter combined with two other parameters: prostate-specific antigen (PSA) and Gleason score. 3-dimensional and conventional histology classified 97 cases of AAP and 13 cases of DAP. DAP cases had a significantly greater frequency of pT3a and more advanced cancers (p<0.0001), >20 mm tumor focus (p=0.0020), highgrade PIN (p=0.0079), Gleason score >=7 (p<0.0001), positive surgical margin (p=0.0219), ECE (p<0.0001), vascular invasion (p=0.0033), seminal vesicle infiltration (p=0.0213), biochemical/local recurrence (p=0.0015), regional lymph node metastases and distant metastases (p<0.0001). Three biomarkers in combination (chromogranine A, EGFR, p53) distinguished DAP from AAP with an accuracy of 94% (AUC 0.94; 95% CI: 0.88-0.99). ECE was evidenced at RP in 24% (20/84) of the patients. Chi-square analysis demonstrated a significant correlation between the number of positive biopsies and presence of ECE. Analysis of the 168 prostate sides and dominant sides revealed that systematic needle biopsies had a positive predictive value of 46.7% and 37% and a negative predictive value of 89%, and 94%, respectively. Combination of parameters (biopsy Gleason score >=7 vs. <7, PSA >10 ng/ml vs. <=10 ng/ml and more than one positive cores vs. 0 or 1 positives) identified patients at high or low risk of ECE, respectively. On the extremes, with only lowrisk parameters none of the 10 patients, while 77% of those with high-risk group had ECE at RP. Both 3 dimensional histology and the three selected biomarkers can accurately distinguish DAP from AAP. This discriminatory ability offers AAP cases less radical treatment regimens and emphasizes the need to develop more effective treatment regimens for DAP cases. The probability of ECE at radical prostatectomy can be accurately predicted based on the number of positive sextant and octant biopsies, solely or in combination with other parameters. PMID- 26934355 TI - [Necessity of the development of a melanoma prevention program in Hungary - in the light of epidemiological data]. AB - The prevention and the early diagnosis of melanoma malignum are essential because of the aggressive spreading and poor therapeutic response of the tumor. Since survival mainly depends on the tumor stage, in the first part of the Ph.D. thesis the stage distribution of melanomas was assessed in the melanoma patients treated at the Department of Dermatology, Dermatooncology and Venerology, Semmelweis University. This work filled a gap, because the Hungarian National Cancer Registry, similarly to other cancer registries, does not include the tumor stages. The results of the assessment showed that most of the patients (43.8%) belonged to stage IA, while only 0.4% of them were in stage IV. In comparison with international studies from Western Europe, Australia and the United States, the distribution of our patients was highly favorable concerning stages IA and IV. To assess the risk of melanoma among special work circumstances (Nuclear Power Plant of Paks) the Department of Dermatology, Dermatooncology and Venerology organized an oncodermatological screening. The results of the screening confirmed that melanoma incidence was not elevated among the nuclear industry workers compared to the general Hungarian population. Among the 556 examined workers we found one melanoma in situ, and the medical history of this patient suggested that UV exposure rather than ionizing radiation could have been the cause of this tumor. Our results also underline the necessity of analyzing skin effects of UV light to avoid false positive correlations. The risk of second primary cancers among melanoma survivors was also assessed in our Department. The findings suggest that the risk of all second primary tumors significantly, 11-15 times increased after having a former melanoma, compared to the general population. The higher risk was mostly caused by the elevated incidence of second primary melanoma and non-melanoma skin cancers. Besides skin tumors, the risk of some internal malignancies was also significantly higher. Our results emphasize that the regular oncologic control is crucial after having melanoma in order to diagnose a second skin or internal malignancy early. Melanoma awareness, primary and secondary prevention programs would be highly necessary to decrease the number of new melanomas, to increase the rate of the early diagnosed tumors and to improve survival. PMID- 26934356 TI - Efficient Targeted Next Generation Sequencing-Based Workflow for Differential Diagnosis of Alport-Related Disorders. AB - Alport syndrome (AS) is an inherited type IV collagen nephropathies characterized by microscopic hematuria during early childhood, the development of proteinuria and progression to end-stage renal disease. Since choosing the right therapy, even before the onset of proteinuria, can delay the onset of end-stage renal failure and improve life expectancy, the earliest possible differential diagnosis is desired. Practically, this means the identification of mutation(s) in COL4A3 A4-A5 genes. We used an efficient, next generation sequencing based workflow for simultaneous analysis of all three COL4A genes in three individuals and fourteen families involved by AS or showing different level of Alport-related symptoms. We successfully identified mutations in all investigated cases, including 14 unpublished mutations in our Hungarian cohort. We present an easy to use unified clinical/diagnostic terminology and workflow not only for X-linked but for autosomal AS, but also for Alport-related diseases. In families where a diagnosis has been established by molecular genetic analysis, the renal biopsy may be rendered unnecessary. PMID- 26934357 TI - Can Pacing Be Regulated by Post-Activation Potentiation? Insights from a Self Paced 30 km Trial in Half-Marathon Runners. AB - PURPOSE: Given the co-existence of post-activation potentiation (PAP) and fatigue within muscle, it is not known whether PAP could influence performance and pacing during distance running by moderating fatigue. The aim of this study was to assess the influence of PAP on pacing, jumping and other physiological measures during a self-paced 30 km trial. METHODS: Eleven male endurance-trained runners (half-marathon runners) volunteered to participate in this study. Runners participated in a multi-stage 30 km trial. Before the trial started, determination of baseline blood lactate (bLa) and countermovement jump (CMJ) height was performed. The self-paced 30 km trial consisted of 6 * 5 km splits. At the end of each 5 km split (60 s break), data on time to complete the split, CMJ height, Rating of Perceived Exertion (RPE) and blood lactate were collected while heart rate was continuously monitored. RESULTS: There was a significant decrease in speed (e.g. positive pacing strategy after the 4th split, p<0.05) with a progressive increase in RPE throughout the trial. Compared with baseline, CMJ height was significantly (p<0.05) greater than baseline and was maintained until the end of the trial with an increase after the 5th split, concomitant with a significant reduction in speed and an increase in RPE. Significant correlations were found between DeltaCMJ and DeltaSPEED (r = 0.77 to 0.87, p<0.05) at different time points as well as between RPE and speed (r = -0.61 to -0.82, p<0.05). CONCLUSION: Our results indicates that fatigue and potentiation co-exist during long lasting endurance events, and that the observed increase in jump performance towards the end of the trial could be reflecting a greater potentiation potentially perhaps counteracting the effects of fatigue and preventing further reductions in speed. PMID- 26934358 TI - Hypertension, use of antihypertensive medications, and risk of epithelial ovarian cancer. AB - Few studies have examined the associations of hypertension and antihypertensive medications with ovarian cancer. In particular, beta-blockers, one of the most commonly prescribed medications to treat hypertension, may reduce ovarian cancer risk by inhibiting beta-adrenergic signaling. We prospectively followed 90,384 women in the Nurses' Health Study (NHS) between 1988-2012 and 113,121 NHSII participants between 1989-2011. Hypertension and use of antihypertensive medications were self-reported biennially. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). We documented 948 ovarian cancer cases during follow-up. Similar results were observed in the two cohorts. While hypertension was not associated with ovarian cancer risk (Pooled HR = 1.01; 95% CI = 0.88, 1.16), current use of any antihypertensive medication was associated with slightly increased risk compared to never users (Pooled HR = 1.18; 95% CI: 1.02, 1.37). This increased risk was primarily due to use of thiazide diuretics (Pooled HR = 1.37; 95% CI: 1.13, 1.68). No associations were observed for beta-blockers or angiotensin-converting enzyme inhibitors. Calcium channel blockers (CCBs) were associated with suggestively reduced risk (NHS HR = 0.73; 95% CI: 0.53, 1.01), after adjusting for all antihypertensive medications. Associations were similar among hypertensive women and stronger for longer use of thiazide diuretics and CCBs. In conclusion, our results provided no evidence that beta-blockers were associated with reduced ovarian cancer risk. In contrast, we observed an increased risk for use of thiazide diuretics that should be confirmed in other studies. PMID- 26934359 TI - Molecular Structure of Human-Liver Glycogen. AB - Glycogen is a highly branched glucose polymer which is involved in maintaining blood-sugar homeostasis. Liver glycogen contains large composite alpha particles made up of linked beta particles. Previous studies have shown that the binding which links beta particles into alpha particles is impaired in diabetic mice. The present study reports the first molecular structural characterization of human liver glycogen from non-diabetic patients, using transmission electron microscopy for morphology and size-exclusion chromatography for the molecular size distribution; the latter is also studied as a function of time during acid hydrolysis in vitro, which is sensitive to certain structural features, particularly glycosidic vs. proteinaceous linkages. The results are compared with those seen in mice and pigs. The molecular structural change during acid hydrolysis is similar in each case, and indicates that the linkage of beta into alpha particles is not glycosidic. This result, and the similar morphology in each case, together imply that human liver glycogen has similar molecular structure to those of mice and pigs. This knowledge will be useful for future diabetes drug targets. PMID- 26934360 TI - Effect of Dietary Patterns on Muscle Strength and Physical Performance in the Very Old: Findings from the Newcastle 85+ Study. AB - BACKGROUND: Healthy diet has been associated with better muscle strength and physical performance in cross-sectional studies of older adults but the effect of dietary patterns (DP) on subsequent decline, particularly in the very old (aged 85+), has not been determined. OBJECTIVE: We investigated the association between previously established DP and decline in muscle strength and physical performance in the very old. DESIGN: 791 participants (61.8% women) from the Newcastle 85+ Study were followed-up for change in hand grip strength (HGS) and Timed Up-and Go (TUG) test over 5 years (four waves 1.5 years apart). Mixed models were used to determine the effects of DP on muscle strength and physical performance in the entire cohort and separately by sex. RESULTS: Previously we have established three DP that varied in intake of red meats, potato, gravy and butter and differed with key health and social factors. HGS declined linearly by 1.59 kgF in men and 1.08 kgF in women (both p<0.001), and TUG slowed by 0.13 log10 transformed seconds (log10-s) in men and 0.11 log10-s in women per wave after adjusting for important covariates (both p<0.001), and also showed a nonlinear change (p<0.001). Men in DP1 ('High Red Meat') had worse overall HGS (beta = 1.70, p = 0.05), but men in DP3 ('High Butter') had a steeper decline (beta = 0.63, p = 0.05) than men in DP2 ('Low Meat'). Men in DP1 and women in DP3 also had overall slower TUG than those in DP2 (beta = 0.08, p = 0.001 and beta = 0.06, p = 0.01, respectively), but similar rate of decline after adjusting for sociodemographic, lifestyle, health, and functioning factors. The results for HGS and TUG were not affected by participants' cognitive status. CONCLUSIONS: DP high in red meats, potato and gravy (DP1), or butter (DP3) may adversely affect muscle strength and physical performance in later life, independently of important covariates and cognitive status. PMID- 26934363 TI - Urocortin attenuates myocardial fibrosis in diabetic rats via the Akt/GSK-3beta signaling pathway. AB - OBJECTIVE: Urocortin, a novel identified corticotropin-releasing factor-related endocrinal peptide, has been shown to play an essential role in cardioprotection. Until recently, whether urocortin can protect the heart against diabetic cardiomyopathy (DCM) remained unclear. Herein, we evaluated the cardioprotective effect of urocortin on cardiac dysfunction, inflammation, and fibrosis and demonstrated the potential mechanism in a diabetic rat model. METHODS: Diabetic rats were randomly divided into 4 groups: diabetic control group, urocortin, urocortin + astressin (a selective CRF receptor 2 antagonist) and urocortin + triciribine (an Akt pathway blocker). Cardiac catheterization was performed to evaluate cardiac function. The levels of creatine phosphokinase isoenzyme (CK MB), plasma brain natriuretic peptide (BNP), myocardial collagen volume fraction (CVF) and left ventricular mass index (LVWI) were measured. Inflammatory factors (transforming growth factor beta 1, TGF-beta1; connective tissue growth factor, CTGF) and activation of signaling proteins (Akt, GSK-3beta) were also detected using western blot. RESULTS: DCM was successfully induced by the injection of streptozotocin (STZ) as evidenced by abnormal heart mass and cardiac function as well as the imbalance of extracellular matrix homeostasis. Rats in the DCM group showed increased mRNA and protein levels of LVWI, BNP, CK-MB, CVF, TGF-beta1 and CTGF compared to the control group, which were accompanied with diminished phosphorylation of Akt and GSK-3beta. Interestingly, myocardial dysfunction, cardiac fibrosis, and inflammation were suppressed by urocortin in the heart of diabetic rats. Moreover, inhibition of phosphorylation of Akt and GSK-3beta was also reversed by urocortin. These effects of urocortin were suppressed by astressin. In addition, triciribine partially reduced the effects of urocortin on myocardial dysfunction, inflammation, and cardiac fibrosis. CONCLUSIONS: These results suggest that urocortin exhibits a therapeutic benefit in the treatment of DCM by attenuating fibrosis and inflammation. Furthermore, inhibition of the Akt/GSK-3beta signaling pathway may be partially responsible for these effects. PMID- 26934361 TI - Tools and Strategies for Malaria Control and Elimination: What Do We Need to Achieve a Grand Convergence in Malaria? AB - Progress made in malaria control during the past decade has prompted increasing global dialogue on malaria elimination and eradication. The product development pipeline for malaria has never been stronger, with promising new tools to detect, treat, and prevent malaria, including innovative diagnostics, medicines, vaccines, vector control products, and improved mechanisms for surveillance and response. There are at least 25 projects in the global malaria vaccine pipeline, as well as 47 medicines and 13 vector control products. In addition, there are several next-generation diagnostic tools and reference methods currently in development, with many expected to be introduced in the next decade. The development and adoption of these tools, bolstered by strategies that ensure rapid uptake in target populations, intensified mechanisms for information management, surveillance, and response, and continued financial and political commitment are all essential to achieving global eradication. PMID- 26934362 TI - Exponential state transition dynamics in the rest-activity architecture of patients with bipolar disorder. AB - OBJECTIVE: Our goal was to model the temporal dynamics of sleep-wake transitions, represented by transitions between rest and activity obtained from actigraphic data, in patients with bipolar disorder using a probabilistic state transition approach. METHODS: We collected actigraphic data for 14 days from 20 euthymic patients with bipolar disorder, who had been characterized clinically, demographically, and with respect to their circadian preferences (chronotype). We processed each activity record to generate a series of transitions in both directions between the states of rest (R) and activity (A) and plotted the estimated transition probabilities (pRA and pAR). Each 24-hour period was also divided into a rest phase consisting of the eight consecutive least active hours in each day and an active phase consisting of the 16 consecutive most active hours in each day. We then calculated separate transition probabilities for each of these phases for each participant. We subsequently modeled the rest phase data to find the best fit for rest-activity transitions using maximum likelihood estimation. We also examined the association of transition probabilities with clinical and demographic variables. RESULTS: The best-fit model for rest-activity transitions during the rest phase was a mixture (bimodal) of exponential functions. Of those patients with rapid cycling, 75% had an evening-type chronotype. Patients with bipolar II disorder taking antidepressants had a lower probability of transitioning back to rest than those not on antidepressants [mean +/- SD = 0.050 +/- 0.006 versus 0.141 +/- 0.058, F(1,15) = 3.40, p < 0.05]. CONCLUSIONS: The dynamics of transitions between rest and activity in bipolar disorder can be accounted for by a mixture (bimodal) of exponential functions. Patients taking antidepressants had a reduced probability of sustaining and returning to sleep. PMID- 26934364 TI - Activation of cardiac renin-angiotensin system and plasminogen activator inhibitor-1 gene expressions in oral contraceptive-induced cardiometabolic disorder. AB - CONTEXT: Clinical studies have shown that combined oral contraceptive (COC) use is associated with cardiometabolic disturbances. Elevated renin-angiotensin system (RAS) and plasminogen activator inhibitor-1 (PAI-1) have also been implicated in the development of cardiometabolic events. OBJECTIVE: To determine the effect of COC treatment on cardiac RAS and PAI-1 gene expressions, and whether the effect is circulating aldosterone or corticosterone dependent. METHODS: Female rats were treated (p.o.) with olive oil (vehicle) or COC (1.0 ug ethinylestradiol and 10.0 ug norgestrel) daily for six weeks. RESULTS: COC treatment led to increases in blood pressure, HOMA-IR, Ace1 mRNA, Atr1 mRNA, Pai1 mRNA, cardiac PAI-1, plasma PAI-1, C-reactive protein, uric acid, insulin and corticosterone. COC treatment also led to dyslipidemia, decreased glucose tolerance and plasma 17beta-estradiol. CONCLUSION: These results demonstrates that hypertension and insulin resistance induced by COC is associated with increased cardiac RAS and PAI-1 gene expression, which is likely to be through corticosterone-dependent but not aldosterone-dependent mechanism. PMID- 26934365 TI - Calcitonin Receptor-Zonula Occludens-1 Interaction Is Critical for Calcitonin Stimulated Prostate Cancer Metastasis. AB - The role of neuroendocrine peptide calcitonin (CT) and its receptor (CTR) in epithelial cancer progression is an emerging concept with great clinical potential. Expression of CT and CTR is frequently elevated in prostate cancers (PCs) and activation of CT-CTR axis in non-invasive PC cells induces an invasive phenotype. Here we show by yeast-two hybrid screens that CTR associates with the tight junction protein Zonula Occludens-1 (ZO-1) via the interaction between the type 1 PDZ motif at the carboxy-terminus of CTR and the PDZ3 domain of ZO-1. Mutation of either the CTR C-PDZ-binding motif or the ZO-1-PDZ3 domain did not affect binding of CTR with its ligand or G-protein-mediated signaling but abrogated destabilizing actions of CT on tight junctions and formation of distant metastases by orthotopically implanted PC cells in nude mice, indicating that these PDZ domain interactions were pathologically relevant. Further, we observed CTR-ZO-1 interactions in PC specimens by proximity ligation immunohistochemistry, and identified that the number of interactions in metastatic PC specimens was several-fold larger than in non-metastatic PC. Our results for the first time demonstrate a mechanism by which PDZ-mediated interaction between CTR and ZO1 is required for CT-stimulated metastasis of prostate cancer. Since many receptors contain PDZ-binding motifs, this would suggest that PDZ-binding motif-adaptor protein interactions constitute a common mechanism for cancer metastasis. PMID- 26934367 TI - The implicit cognition of reciprocal exchange: automatic retrieval of positive and negative experiences with partners in a prisoner's dilemma game. AB - Models of reciprocity imply that cheater detection is an important prerequisite for successful social exchange. Considering the fundamental role of memory in reciprocal exchange, these theories lead to the prediction that memory for cheaters should be preferentially enhanced. Here, we examine whether information of a partner's previous behaviour in an interaction is automatically retrieved when encountering the face of a partner who previously cheated or cooperated. In two studies, participants played a sequential prisoner's dilemma game with cheaters and cooperative partners. Alternating with the game blocks, participants were asked to classify the smiling or angry facial expressions of cooperators and cheaters. Both experiments revealed congruence effects, reflecting faster identification of the smiles of cooperators (Experiments 1 and 2) and faster identification of the angry facial expressions of cheaters (Experiment 2). Our study provides evidence for the automatic retrieval of the partner's behaviour in the game, regardless of whether partners cheated or cooperated, and thus provides further evidence against the cheater detection hypothesis. PMID- 26934366 TI - Placing memories in context: Hippocampal representations promote retrieval of appropriate memories. AB - Returning to a familiar context triggers retrieval of relevant memories, making memories from other contexts less likely to intrude and cause interference. We investigated the physiology that underlies the use of context to prevent interference by recording hippocampal neurons while rats learned two conflicting sets of discrimination problems, either in the same context or in two distinct contexts. Rats that learned the conflicting problem sets in the same context maintained similar neural representations, and performed poorly because conflicting memories interfered with new learning. In contrast, rats that learned in different contexts formed distinct ensemble representations and performed significantly better. We also measured trial-to-trial variation in representations and found that hippocampal activity was directly linked with performance: on trials where an old representation was active, rats were far more likely to make errors. These results show that the formation of distinct hippocampal representations is critical for contextually appropriate memory retrieval. (c) 2016 Wiley Periodicals, Inc. PMID- 26934370 TI - Neuronal Orphan G-Protein Coupled Receptor Proteins Mediate Plasmalogens-Induced Activation of ERK and Akt Signaling. AB - The special glycerophospholipids plasmalogens (Pls) are enriched in the brain and reported to prevent neuronal cell death by enhancing phosphorylation of Akt and ERK signaling in neuronal cells. Though the activation of Akt and ERK was found to be necessary for the neuronal cells survival, it was not known how Pls enhanced cellular signaling. To answer this question, we searched for neuronal specific orphan GPCR (G-protein coupled receptor) proteins, since these proteins were believed to play a role in cellular signal transduction through the lipid rafts, where both Pls and some GPCRs were found to be enriched. In the present study, pan GPCR inhibitor significantly reduced Pls-induced ERK signaling in neuronal cells, suggesting that Pls could activate GPCRs to induce signaling. We then checked mRNA expression of 19 orphan GPCRs and 10 of them were found to be highly expressed in neuronal cells. The knockdown of these 10 neuronal specific GPCRs by short hairpin (sh)-RNA lentiviral particles revealed that the Pls mediated phosphorylation of ERK was inhibited in GPR1, GPR19, GPR21, GPR27 and GPR61 knockdown cells. We further found that the overexpression of these GPCRs enhanced Pls-mediated phosphorylation of ERK and Akt in cells. Most interestingly, the GPCRs-mediated cellular signaling was reduced significantly when the endogenous Pls were reduced. Our cumulative data, for the first time, suggest a possible mechanism for Pls-induced cellular signaling in the nervous system. PMID- 26934371 TI - Risk factors predicting upper urinary tract deterioration in patients with spinal cord injury: A retrospective study. AB - AIMS: To determine the risk factors predicting upper urinary tract (UUT) deterioration in patients with spinal cord injury (SCI). METHODS: Medical records of 303 SCI patients who referred to the urodynamic unit of a rehabilitation hospital between 1996 and 2003 were retrospectively reviewed. The data included general patient demographics, SCI characteristics, bladder management methods, serum creatinine level, presence of urinary tract infection, indwelling catheter time, radiological findings of upper and lower urinary tract, and video urodynamic (VUD) findings. Univariate and multivariate analyses were used to determine the risk factors predicting UUT deterioration. ROC analysis was done to determine the cut-off values of detrusor pressure and cystometric bladder capacity volume predicting UUT deterioration. RESULTS: Complete data were available on 255 patients. Median patient age was 33 years (18-75). The leading causes of SCI were motor vehicle accidents (40%) and falls (29%). Upper urinary tract deterioration was determined in 63 patients (25%). Abnormal radiological LUT findings, the absence of antimuscarinic drug usage in the history, detrusor pressures greater than 75 cmH2 O and cystometric bladder capacity less than 200 ml were found to be independent risk factors in logistic regression analysis. ROC analysis revealed that values >=75 cmH2 O for maximum detrusor pressure, <200 ml for bladder capacity, and >6 months for indwelling catheter time were cutoff values for UUT deterioration. CONCLUSION: Abnormal radiological LUT findings, the absence of antimuscarinic drug usage, detrusor pressures >=75 cmH2 O, and cystometric bladder capacity <200 ml were independent risk factors predicting UUT deterioration SCI patients. Neurourol. Urodynam. 36:653-658, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 26934369 TI - Cigarette Smoke Enhances the Expression of Profibrotic Molecules in Alveolar Epithelial Cells. AB - Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal disease of unknown etiology. A growing body of evidence indicates that it may result from an aberrant activation of alveolar epithelium, which induces the expansion of the fibroblast population, their differentiation to myofibroblasts and the excessive accumulation of extracellular matrix. The mechanisms that activate the alveolar epithelium are unknown, but several studies indicate that smoking is the main environmental risk factor for the development of IPF. In this study we explored the effect of cigarette smoke on the gene expression profile and signaling pathways in alveolar epithelial cells. Lung epithelial cell line from human (A549), was exposed to cigarette smoke extract (CSE) for 1, 3, and 5 weeks at 1, 5 and 10% and gene expression was evaluated by complete transcriptome microarrays. Signaling networks were analyzed with the Ingenuity Pathway Analysis software. At 5 weeks of exposure, alveolar epithelial cells acquired a fibroblast like phenotype. At this time, gene expression profile revealed a significant increase of more than 1000 genes and deregulation of canonical signaling pathways such as TGF-beta and Wnt. Several profibrotic genes involved in EMT were over expressed, and incomplete EMT was observed in these cells, and corroborated in mouse (MLE-12) and rat (RLE-6TN) epithelial cells. The secretion of activated TGF beta1 increased in cells exposed to cigarette smoke, which decreased when the integrin alpha v gene was silenced. These findings suggest that the exposure of alveolar epithelial cells to CSE induces the expression and release of a variety of profibrotic genes, and the activation of TGF-beta1, which may explain at least partially, the increased risk of developing IPF in smokers. PMID- 26934368 TI - Radiosensitization by PARP Inhibition in DNA Repair Proficient and Deficient Tumor Cells: Proliferative Recovery in Senescent Cells. AB - Radiotherapy continues to be a primary modality in the treatment of cancer. In addition to promoting apoptosis, radiation-induced DNA damage can promote autophagy and senescence, both of which can theoretically function to prolong tumor survival. In this work, we tested the hypothesis that autophagy and/or senescence could be permissive for DNA repair, thereby facilitating tumor cell recovery from radiation-induced growth arrest and/or cell death. In addition, studies were designed to elucidate the involvement of autophagy and senescence in radiosensitization by PARP inhibitors and the re-emergence of a proliferating tumor cell population. In the context of this work, the relationship between radiation-induced autophagy and senescence was also determined. Studies were performed using DNA repair-proficient HCT116 colon carcinoma cells and a repair deficient ligase IV(-/-) isogenic cell line. Exposure to radiation promoted a parallel induction of autophagy and senescence that was strongly correlated with the extent of persistent H2AX phosphorylation in both cell lines, however, inhibition of autophagy failed to suppress senescence, indicating that the two responses were dissociable. Exposure to radiation resulted in a transient arrest in the HCT116 cells while arrest was prolonged in the ligase IV(-/-) cells, however, both cell lines ultimately recovered proliferative function, which may reflect maintenance of DNA repair capacity. The PARP inhibitors, olaparib and niraparib, increased the extent of persistent DNA damage induced by radiation exposure as well as the extent of both autophagy and senescence. Neither cell line underwent significant apoptosis by radiation exposure alone or in the presence of the PARP inhibitors. Inhibition of autophagy failed to attenuate radiosensitization, indicating that autophagy was not involved in the action of the PARP inhibitors. As with radiation alone, despite sensitization by PARP inhibition, proliferative recovery was evident within a period of 10-20 days. While inhibition of DNA repair via PARP inhibition may initially sensitize tumor cells to radiation via the promotion of senescence, this strategy does not appear to interfere with proliferative recovery, which could ultimately contribute to disease recurrence. PMID- 26934372 TI - Immunization Coverage Surveys and Linked Biomarker Serosurveys in Three Regions in Ethiopia. AB - OBJECTIVE: Demographic and health surveys, immunization coverage surveys and administrative data often divergently estimate vaccination coverage, which hinders pinpointing districts where immunization services require strengthening. We assayed vaccination coverage in three regions in Ethiopia by coverage surveys and linked serosurveys. METHODS: Households with children aged 12-23 (N = 300) or 6-8 months (N = 100) in each of three districts (woredas) were randomly selected for immunization coverage surveys (inspection of vaccination cards and immunization clinic records and maternal recall) and linked serosurveys. IgG ELISA serologic biomarkers included tetanus antitoxin >= 0.15 IU/ml in toddlers (receipt of tetanus toxoid) and Haemophilus influenzae type b (Hib) anti-capsular titers >= 1.0 mcg/ml in infants (timely receipt of Hib vaccine). FINDINGS: Coverage surveys enrolled 1,181 children across three woredas; 1,023 (87%) also enrolled in linked serosurveys. Administrative data over-estimated coverage compared to surveys, while maternal recall was unreliable. Serologic biomarkers documented a hierarchy among the districts. Biomarker measurement in infants provided insight on timeliness of vaccination not deducible from toddler results. CONCLUSION: Neither administrative projections, vaccination card or EPI register inspections, nor parental recall, substitute for objective serological biomarker measurement. Including infants in serosurveys informs on vaccination timeliness. PMID- 26934373 TI - What Can the National Broadband Map Tell Us About the Health Care Connectivity Gap? AB - PURPOSE: Internet connection speeds are generally slower in rural areas, and this issue is rising in importance for health care facilities as technologies such as Electronic Health Records and Health Information Exchanges become more common. However, the extent of the rural-urban divide in terms of health care connectivity has not been fully quantified. This report uses data compiled from the National Broadband Map (NBM) to compare levels of health care facility connectivity across metropolitan and nonmetropolitan counties. METHODS: The number of health and medical entries in the Community Anchor Institution (CAI) data collected as part of the NBM grew from 35,000 to 63,000 between 2010 and 2014. About one-fifth provided information on the speed of their connections in 2014. Comparisons across metro and nonmetro counties and over time provide insight into trends associated with the health care connectivity gap. FINDINGS: The data clearly show that health-related institutions in nonmetro counties connect with lower speeds than do their more urban counterparts. At the aggregate level, over 55% of metro institutions who provided speed information had download speeds in excess of 50 megabytes per second in 2014, compared with only 12% of nonmetro institutions (P < .001). More importantly, the connectivity gap has grown significantly during 2010-2014, particularly for nonhospital facilities. CONCLUSIONS: The NBM CAI data are a publicly available and easy to use asset that rural health advocates should be aware of. The fact that the connectivity gap increased during 2010-2014, despite policies focusing on this issue, is a cause for concern. PMID- 26934374 TI - 'Smelling' the cerebrospinal fluid: olfactory signaling molecules are expressed in and mediate chemosensory signaling from the choroid plexus. AB - The olfactory-type signaling machinery has been known to be involved not only in odorant detection but also in other tissues with unsuspected sensory roles. As a barrier, the choroid plexus (CP) is an active participant in the monitoring of the cerebrospinal fluid (CSF), promptly responding to alterations in its composition. We hypothesized that olfactory signaling could be active in CP, contributing to the surveillance of the CSF composition. We determined the mRNA and protein expression of the major components of the olfactory transduction pathway in the rat CP, including odorant receptors, the olfactory G-protein (Galphaolf), adenylate cyclase 3 and cyclic nucleotide-gated channel 2. The functionality of the transduction pathway and the intracellular mechanisms involved were analyzed by DC field potential recording electrophysiological analysis, in an ex vivo CP-brain setup, using polyamines as stimuli and blockers of the downstream signaling pathways. Concentration-dependent responses were obtained for the polyamines studied (cadaverine, putrescine, spermine and spermidine), all known to be present in the CSF. Transfection of a CP epithelial cell line with siRNA against Galphaolf effectively knocked down protein expression and reduced the CP cells' response to spermine. Thus, the key components of the olfactory chemosensory apparatus are present and are functional in murine CP, and polyamines seem to trigger both the cAMP and the phospholipase C-inositol 1,4,5-trisphosphate pathways. Olfactory-like chemosensory signaling may be an essential component of the CP chemical surveillance apparatus to detect alterations in the CSF composition, and to elicit responses to modulate and maintain brain homeostasis. PMID- 26934376 TI - Catalytic Asymmetric Prins Bicyclization for the endo-Selective Formation of 2,6 dioxabicyclo[2.2.2]octanes. AB - A new Lewis acid-catalyzed endo-selective Prins bicyclization of gamma,delta unsaturated aldehydes or ketones with a broad range of aldehydes to dioxabicyclo[2.2.2]octanes is disclosed. When using a chiral BINOL-derived N triflylphosphoramide (NTPA) as catalyst and glyoxylate esters as substrates, the cross-dimerization afford functionalized bicyclic acetals with excellent diastereo- and enantioselectivities. PMID- 26934375 TI - Mechanism of Copper Uptake from Blood Plasma Ceruloplasmin by Mammalian Cells. AB - Ceruloplasmin, the main copper binding protein in blood plasma, has been of particular interest for its role in efflux of iron from cells, but has additional functions. Here we tested the hypothesis that it releases its copper for cell uptake by interacting with a cell surface reductase and transporters, producing apoceruloplasmin. Uptake and transepithelial transport of copper from ceruloplasmin was demonstrated with mammary epithelial cell monolayers (PMC42) with tight junctions grown in bicameral chambers, and purified human (64)Cu labeled ceruloplasmin secreted by HepG2 cells. Monolayers took up virtually all the (64)Cu over 16h and secreted half into the apical (milk) fluid. This was partly inhibited by Ag(I). The (64)Cu in ceruloplasmin purified from plasma of (64)Cu-injected mice accumulated linearly in mouse embryonic fibroblasts (MEFs) over 3-6h. Rates were somewhat higher in Ctr1+/+ versus Ctr1-/- cells, and 3-fold lower at 2 degrees C. The ceruloplasmin-derived (64)Cu could not be removed by extensive washing or trypsin treatment, and most was recovered in the cytosol. Actual cell copper (determined by furnace atomic absorption) increased markedly upon 24h exposure to holoceruloplasmin. This was accompanied by a conversion of holo to apoceruloplasmin in the culture medium and did not occur during incubation in the absence of cells. Four different endocytosis inhibitors failed to prevent 64Cu uptake from ceruloplasmin. High concentrations of non-radioactive Cu(II)- or Fe(III)-NTA (substrates for cell surface reductases), or Cu(I)-NTA (to compete for transporter uptake) almost eliminated uptake of (64)Cu from ceruloplasmin. MEFs had cell surface reductase activity and expressed Steap 2 (but not Steaps 3 and 4 or dCytB). However, six-day siRNA treatment was insufficient to reduce activity or uptake. We conclude that ceruloplasmin is a circulating copper transport protein that may interact with Steap2 on the cell surface, forming apoceruloplasmin, and Cu(I) that enters cells through CTR1 and an unknown copper uptake transporter. PMID- 26934378 TI - Pd(II)-Catalyzed ortho-C-H Olefination/Dearomatization of N-Aryl Ureas: An Approach to Imine Derivatives. AB - An unprecedented approach for the synthesis of imine derivatives was achieved via a Pd(II)-catalyzed dearomatization reaction of N-aryl ureas with internal alkynes. The corresponding spirocyclic imine derivatives were obtained with 20 examples in good to excellent yields. Mechanistic investigation indicated that an interesting 1,3-palladium migration process led to the alpha-regioselective dearomatization when 2-naphthyl ureas were used as the substrates. Fused ring products could also be obtained to further prove this migration process. PMID- 26934377 TI - Flowering-Related RING Protein 1 (FRRP1) Regulates Flowering Time and Yield Potential by Affecting Histone H2B Monoubiquitination in Rice (Oryza Sativa). AB - Flowering time is a critical trait for crops cultivated under various temperature/photoperiod conditions around the world. To understand better the flowering time of rice, we used the vector pTCK303 to produce several lines of RNAi knockdown transgenic rice and investigated their flowering times and other agronomic traits. Among them, the heading date of FRRP1-RNAi knockdown transgenic rice was 23-26 days earlier than that of wild-type plants. FRRP1 is a novel rice gene that encodes a C3HC4-type Really Interesting Novel Gene (RING) finger domain protein. In addition to the early flowering time, FRRP1-RNAi knockdown transgenic rice caused changes on an array of agronomic traits, including plant height, panicle length and grain length. We analyzed the expression of some key genes associated with the flowering time and other agronomic traits in the FRRP1-RNAi knockdown lines and compared with that in wild-type lines. The expression of Hd3a increased significantly, which was the key factor in the early flowering time. Further experiments showed that the level of histone H2B monoubiquitination (H2Bub1) was noticeably reduced in the FRRP1-RNAi knockdown transgenic rice lines compared with wild-type plants and MBP-FRRP1-F1 was capable of self ubiquitination. The results indicate that Flowering Related RING Protein 1 (FRRP1) is involved in histone H2B monoubiquitination and suggest that FRRP1 functions as an E3 ligase in vivo and in vitro. In conclusion, FRRP1 probably regulates flowering time and yield potential in rice by affecting histone H2B monoubiquitination, which leads to changes in gene expression in multiple processes. PMID- 26934380 TI - Enhancement of nitric oxide decomposition efficiency achieved with lanthanum based perovskite-type catalyst. AB - Direct decompositions of nitric oxide (NO) by La0.7Ce0.3SrNiO4, La0.4Ba0.4Ce0.2SrNiO4, and Pr0.4Ba0.4Ce0.2SrNiO4 are experimentally investigated, and the catalysts are tested with different operating parameters to evaluate their activities. Experimental results indicate that the physical and chemical properties of La0.7Ce0.3SrNiO4 are significantly improved by doping with Ba and partial substitution with Pr. NO decomposition efficiencies achieved with La0.4Ba0.4Ce0.2SrNiO4 and Pr0.4Ba0.4Ce0.2SrNiO4 are 32% and 68%, respectively, at 400 degrees C with He as carrier gas. As the temperature is increased to 600 degrees C, NO decomposition efficiencies achieved with La0.4Ba0.4Ce0.2SrNiO4 and Pr0.4Ba0.4Ce0.2SrNiO4, respectively, reach 100% with the inlet NO concentration of 1000 ppm while the space velocity is fixed at 8000 hr(-1). Effects of O2, H2O(g), and CO2 contents and space velocity on NO decomposition are also explored. The results indicate that NO decomposition efficiencies achieved with La0.4Ba0.4Ce0.2SrNiO4 and Pr0.4Ba0.4Ce0.2SrNiO4, respectively, are slightly reduced as space velocity is increased from 8000 to 20,000 hr(-1) at 500 degrees C. In addition, the activities of both catalysts (La0.4Ba0.4Ce0.2SrNiO4 and Pr0.4Ba0.4Ce0.2SrNiO4) for NO decomposition are slightly reduced in the presence of 5% O2, 5% CO2, or 5% H2O(g). For durability test, with the space velocity of 8000 hr(-1) and operating temperature of 600 degrees C, high N2 yield is maintained throughout the durability test of 60 hr, revealing the long-term stability of Pr0.4Ba0.4Ce0.2SrNiO4 for NO decomposition. Overall, Pr0.4Ba0.4Ce0.2SrNiO4 shows good catalytic activity for NO decomposition. IMPLICATIONS: Nitrous oxide (NO) not only causes adverse environmental effects such as acid rain, photochemical smog, and deterioration of visibility and water quality, but also harms human lungs and respiratory system. Pervoskite-type catalysts, including La0.7Ce0.3SrNiO4, La0.4Ba0.4Ce0.2SrNiO4, and Pr0.4Ba0.4Ce0.2SrNiO4, are applied for direct NO decomposition. The results show that NO decomposition can be enhanced as La0.7Ce0.3SrNiO4 is substituted with Ba and/or Pr. At 600 degrees C, NO decomposition efficiencies achieved with La0.4Ba0.4Ce0.2SrNiO4 and Pr0.4Ba0.4Ce0.2SrNiO4 reach 100%, demonstrating high activity and good potential for direct NO decomposition. Effects of O2, H2O(g), and CO2 contents on catalytic activities are also evaluated and discussed. PMID- 26934379 TI - Homozygous nonsense mutation in SGCA is a common cause of limb-girdle muscular dystrophy in Assiut, Egypt. AB - INTRODUCTION: The genetic causes of limb-girdle muscular dystrophy (LGMD) have been studied in numerous countries, but such investigations have been limited in Egypt. METHODS: A cohort of 30 families with suspected LGMD from Assiut, Egypt, was studied using immunohistochemistry, homozygosity mapping, Sanger sequencing, and whole exome sequencing. RESULTS: Six families were confirmed to have pathogenic mutations, 4 in SGCA and 2 in DMD. Of these, 3 families harbored a single nonsense mutation in SGCA, suggesting that this may be a common mutation in Assiut, Egypt, originating from a founder effect. CONCLUSIONS: The Assiut region in Egypt appears to share at least several of the common LGMD genes found in other parts of the world. It is notable that 4 of the 6 mutations were ascertained by means of whole exome sequencing, even though it was the last approach adopted. This illustrates the power of this technique for identifying causative mutations for muscular dystrophies. Muscle Nerve 54: 690-695, 2016. PMID- 26934381 TI - Epithelial Wnt/betacatenin signalling is essential for epididymal coiling. AB - Organ shape and size are important determinants of their physiological functions. Epithelial tubes are anlagen of many complex organs. How these tubes acquire their complex shape and size is a fundamental question in biology. In male mice, the Wolffian duct (WD; postnatally known as epididymis) undergoes an astonishing transformation, where a straight tube only a few millimetres long elongates to over 1000 times its original length and fits into a very small space, due to extensive coiling of epithelium, to perform the highly specialized function of sperm maturation. Defective coiling disrupts sperm maturation and leads to male infertility. Recent work has shown that epithelial cell proliferation is a major driver of WD coiling. Still, very little is known about the molecular signals involved in this process. Testicular androgens are known regulators of WD development. However, epithelial androgen receptor signalling is dispensable for WD coiling. In this study, we have shown that Wnt signalling is highly active in the entire WD epithelium during its coiling, and is limited to only a few segments of the epididymis in later life. Pharmacological and genetic suppression of Wnt signalling inhibited WD coiling by decreasing cell proliferation and promoting apoptosis. Comparative gene expression analysis identified Fibroblast growth factor 7 (Fgf7) as a prime Wnt target gene involved in WD coiling and in vitro treatment with Fgf7 protein increased coiling of WDs. In summary, our work has established that epithelial canonical Wnt signalling is a critical regulator of WD coiling and its precise regulation is essential for WD/epididymal differentiation. PMID- 26934382 TI - The role of technology in Australian youth mental health reform. AB - This paper describes the extent and nature of Internet use by young people, with specific reference to psychological distress and help-seeking behaviour. It draws on data from an Australian cross-sectional study of 1400 young people aged 16 to 25 years. Nearly all of these young people used the Internet, both as a source of trusted information and as a means of connecting with their peers and discussing problems. A new model of e-mental health care is introduced that is directly informed by these findings. The model creates a system of mental health service delivery spanning the spectrum from general health and wellbeing (including mental health) promotion and prevention to recovery. It is designed to promote health and wellbeing and to complement face-to-face services to enhance clinical care. The model has the potential to improve reach and access to quality mental health care for young people, so that they can receive the right care, at the right time, in the right way. PMID- 26934383 TI - Naturally Occurring IgG Antibodies Provide Innate Protection against Vibrio cholerae Bacteremia by Recognition of the Outer Membrane Protein U. AB - Cholera epidemics are caused by Vibrio cholerae serogroups O1 and O139, whereas strains collectively known as non-O1/non-O139 V. cholerae are found in cases of extraintestinal infections and bacteremia. The mechanisms and factors influencing the occurrence of bacteremia and survival of V. cholerae in normal human serum have remained unclear. We found that naturally occurring IgG recognizing V. cholerae outer membrane protein U (OmpU) mediates a serum-killing effect in a complement C1q-dependent manner. Moreover, outer membrane vesicles (OMVs) containing OmpU caused enhanced survival of highly serum-sensitive classical V. cholerae in a dose-dependent manner. OMVs from wild-type and ompU mutant V. cholerae thereby provided a novel means to verify by extracellular transcomplementation the involvement of OmpU. Our data conclusively indicate that loss, or reduced expression, of OmpU imparts resistance to V. cholerae towards serum killing. We propose that the difference in OmpU protein levels is a plausible reason for differences in serum resistance and the ability to cause bacteremia observed among V. cholerae biotypes. Our findings provide a new perspective on how naturally occurring antibodies, perhaps induced by members of the microbiome, may play a role in the recognition of pathogens and the provocation of innate immune defense against bacteremia. PMID- 26934384 TI - Theoretical Proposal for the Whole Phosphate Diester Hydrolysis Mechanism Promoted by a Catalytic Promiscuous Dinuclear Copper(II) Complex. AB - The catalytic mechanism that involves the cleavage of the phosphate diester model BDNPP (bis(2,4-dinitrophenyl) phosphate) catalyzed through a dinuclear copper complex is investigated in the current study. The metal complex was originally designed to catalyze catechol oxidation, and it showed an interesting catalytic promiscuity case in biomimetic systems. The current study investigates two different reaction mechanisms through quantum mechanics calculations in the gas phase, and it also includes the solvent effect through PCM (polarizable continuum model) single-point calculations using water as solvent. Two mechanisms are presented in order to fully describe the phosphate diester hydrolysis. Mechanism 1 is of the S(N)2 type, which involves the direct attack of the MU-OH bridge between the two copper(II) ions toward the phosphorus center, whereas mechanism 2 is the process in which hydrolysis takes place through proton transfer between the oxygen atom in the bridging hydroxo ligand and the other oxygen atom in the phosphate model. Actually, the present theoretical study shows two possible reaction paths in mechanism 1. Its first reaction path (p1) involves a proton transfer that occurs immediately after the hydrolytic cleavage, so that the proton transfer is the rate-determining step, which is followed by the entry of two water molecules. Its second reaction path (p2) consists of the entry of two water molecules right after the hydrolytic cleavage, but with no proton transfer; thus, hydrolytic cleavage is the rate-limiting step. The most likely catalytic path occurs in mechanism 1, following the second reaction path (p2), since it involves the lowest free energy activation barrier (DeltaG(?) = 23.7 kcal mol( 1), in aqueous solution). A kinetic analysis showed that the experimental k(obs) value of 1.7 * 10(-5) s(-1) agrees with the calculated value k1 = 2.6 * 10(-5) s( 1); the concerted mechanism is kinetically favorable. The KIE (kinetic isotope effect) analysis applied to the second reaction path (p2) in mechanism 1 was also taken into account to assess the changes that take place in TS1-i (transition state of mechanism 1) and to perfectly characterize the mechanism described herein. PMID- 26934386 TI - Use of two grasses for the phytoremediation of aqueous solutions polluted with terbuthylazine. AB - The capacity of two grasses, tall fescue (Festuca arundinacea) and orchardgrass (Dactylis glomerata), to remove terbuthylazine (TBA) from polluted solutions has been assessed in hydroponic cultures. Different TBA concentrations (0.06, 0.31, 0.62, and 1.24 mg/L) were chosen to test the capacity of the two grasses to resist the chemical. Aerial biomass, effective concentrations (to cause reductions of 10, 50, and 90% of plant aerial biomass) and chlorophylls contents of orchardgrass were found to be more affected. Tall fescue was found to be more capable of removing the TBA from the growth media. Furthermore, enzymes involved both in the herbicide detoxification and in the response to herbicide-induced oxidative stress were investigated. Glutathione S-transferase (GST, EC. 2.5.1.18) and ascorbate peroxidase (APX, EC. 1.11.1.11) of tall fescue were found to be unaffected by the chemical. GST and APX levels of orchardgrass were decreased by the treatment. These negative modulations exerted by the TBA on the enzyme of orchardgrass explained its lower capacity to cope with the negative effects of the TBA. PMID- 26934385 TI - Central composite design optimization of pilot plant fluidized-bed heterogeneous Fenton process for degradation of an azo dye. AB - Optimization of Acid Yellow 36 (AY36) degradation by heterogeneous Fenton process in a recirculated fluidized-bed reactor was studied using central composite design (CCD). Natural pyrite was applied as the catalyst characterized by X-ray diffraction and scanning electron microscopy. The CCD model was developed for the estimation of degradation efficiency as a function of independent operational parameters including hydrogen peroxide concentration (0.5-2.5 mmol/L), initial AY36 concentration (5-25 mg/L), pH (3-9) and catalyst dosage (0.4-1.2 mg/L). The obtained data from the model are in good agreement with the experimental data (R(2 )= 0.964). Moreover, this model is applicable not only to determine the optimized experimental conditions for maximum AY36 degradation, but also to find individual and interactive effects of the mentioned parameters. Finally, gas chromatography-mass spectroscopy (GC-MS) was utilized for the identification of some degradation intermediates and a plausible degradation pathway was proposed. PMID- 26934387 TI - How Secure Is Your Radiology Department? Mapping Digital Radiology Adoption and Security Worldwide. AB - OBJECTIVE: Despite the long history of digital radiology, one of its most critical aspects--information security--still remains extremely underdeveloped and poorly standardized. To study the current state of radiology security, we explored the worldwide security of medical image archives. MATERIALS AND METHODS: Using the DICOM data-transmitting standard, we implemented a highly parallel application to scan the entire World Wide Web of networked computers and devices, locating open and unprotected radiology servers. We used only legal and radiology compliant tools. Our security-probing application initiated a standard DICOM handshake to remote computer or device addresses, and then assessed their security posture on the basis of handshake replies. RESULTS: The scan discovered a total of 2774 unprotected radiology or DICOM servers worldwide. Of those, 719 were fully open to patient data communications. Geolocation was used to analyze and rank our findings according to country utilization. As a result, we built maps and world ranking of clinical security, suggesting that even the most radiology-advanced countries have hospitals with serious security gaps. CONCLUSION: Despite more than two decades of active development and implementation, our radiology data still remains insecure. The results provided should be applied to raise awareness and begin an earnest dialogue toward elimination of the problem. The application we designed and the novel scanning approach we developed can be used to identify security breaches and to eliminate them before they are compromised. PMID- 26934389 TI - Flexible Strategies for Coping with Rainfall Variability: Seasonal Adjustments in Cropped Area in the Ganges Basin. AB - One of the main manifestations of climate change will be increased rainfall variability. How to deal with this in agriculture will be a major societal challenge. In this paper we explore flexibility in land use, through deliberate seasonal adjustments in cropped area, as a specific strategy for coping with rainfall variability. Such adjustments are not incorporated in hydro meteorological crop models commonly used for food security analyses. Our paper contributes to the literature by making a comprehensive model assessment of inter annual variability in crop production, including both variations in crop yield and cropped area. The Ganges basin is used as a case study. First, we assessed the contribution of cropped area variability to overall variability in rice and wheat production by applying hierarchical partitioning on time-series of agricultural statistics. We then introduced cropped area as an endogenous decision variable in a hydro-economic optimization model (WaterWise), coupled to a hydrology-vegetation model (LPJmL), and analyzed to what extent its performance in the estimation of inter-annual variability in crop production improved. From the statistics, we found that in the period 1999-2009 seasonal adjustment in cropped area can explain almost 50% of variability in wheat production and 40% of variability in rice production in the Indian part of the Ganges basin. Our improved model was well capable of mimicking existing variability at different spatial aggregation levels, especially for wheat. The value of flexibility, i.e. the foregone costs of choosing not to crop in years when water is scarce, was quantified at 4% of gross margin of wheat in the Indian part of the Ganges basin and as high as 34% of gross margin of wheat in the drought-prone state of Rajasthan. We argue that flexibility in land use is an important coping strategy to rainfall variability in water stressed regions. PMID- 26934391 TI - Probing plasmons in three dimensions by combining complementary spectroscopies in a scanning transmission electron microscope. AB - The nanoscale optical response of surface plasmons in three-dimensional metallic nanostructures plays an important role in many nanotechnology applications, where precise spatial and spectral characteristics of plasmonic elements control device performance. Electron energy loss spectroscopy (EELS) and cathodoluminescence (CL) within a scanning transmission electron microscope have proven to be valuable tools for studying plasmonics at the nanoscale. Each technique has been used separately, producing three-dimensional reconstructions through tomography, often aided by simulations for complete characterization. Here we demonstrate that the complementary nature of the two techniques, namely that EELS probes beam induced electronic excitations while CL probes radiative decay, allows us to directly obtain a spatially- and spectrally-resolved picture of the plasmonic characteristics of nanostructures in three dimensions. The approach enables nanoparticle-by-nanoparticle plasmonic analysis in three dimensions to aid in the design of diverse nanoplasmonic applications. PMID- 26934390 TI - Prospective Study of Optimal Obesity Index Cut-Off Values for Predicting Incidence of Hypertension in 18-65-Year-Old Chinese Adults. AB - BACKGROUND: Overweight and obesity increase the risk of elevated blood pressure; most of the studies that serve as a background for the debates on the optimal obesity index cut-off values used cross-sectional samples. The aim of this study was to determine the cut-off values of anthropometric markers for detecting hypertension in Chinese adults with data from prospective cohort. METHODS: This study determines the best cut-off values for the obesity indices that represent elevated incidence of hypertension in 18-65-year-old Chinese adults using data from the China Health and Nutrition Survey (CHNS) 2006-2011 prospective cohort. Individual body mass index (BMI), waist circumference (WC), waist:hip ratio (WHR) and waist:stature ratio (WSR) were assessed. ROC curves for these obesity indices were plotted to estimate and compare the usefulness of these obesity indices and the corresponding values for the maximum of the Youden indices were considered the optimal cut-off values. RESULTS: Five-year cumulative incidences of hypertension were 21.5% (95% CI: 19.4-23.6) in men and 16.5% (95% CI: 14.7-18.2) in women, and there was a significant trend of increased incidence of hypertension with an increase in BMI, WC, WHR or WSR (P for trend < 0.001) in both men and women. The Youden index indicated that the optimal BMI, WC, WHR, WSR cut-off values were 23.53 kg/m2, 83.7 cm, 0.90, and 0.51 among men. The optimal BMI, WC, WHR, WSR cut-off values were 24.25 kg/m2, 79.9 cm, 0.85 and 0.52 among women. CONCLUSIONS: Our study supported the hypothesis that the cut-off values for BMI and WC that were recently developed by the Working Group on Obesity in China (WGOC), the cut-off values for WHR that were developed by the World Health Organization (WHO), and a global WSR cut-off value of 0.50 may be the appropriate upper limits for Chinese adults. PMID- 26934392 TI - Local Regeneration of Cortisol by 11beta-HSD1 Contributes to Insulin Resistance of the Granulosa Cells in PCOS. AB - CONTEXT: Insulin resistance (IR) of the granulosa cells may account for the ovarian dysfunctions observed in polycystic ovarian syndrome (PCOS). The underlying mechanism remains largely unresolved. OBJECTIVE: The objective of the study was to investigate the relationship of IR of the granulosa cells with cortisol in the follicular fluid and 11beta-hydroxysteroid dehydrogenase 1 and 2 (11beta-HSD1 and -2) in the granulosa cells in PCOS. DESIGN: Follicular fluid and granulosa cells were collected from non-PCOS and PCOS patients with and without IR to measure cortisol concentration and the amounts of 11beta-HSD1 and -2, which were then correlated with IR status. The effects of cortisol on the expression of genes pertinent to IR were studied in cultured human granulosa cells. RESULTS: Cortisol concentration in the follicular fluid, 11beta-HSD1 but not 11beta-HSD2 mRNA in the granulosa cells were significantly elevated in PCOS with IR. Increased reductase and decreased oxidase activities of 11beta-HSD were observed in granulosa cells in PCOS with IR. In cultured granulosa cells, insulin-induced Akt phosphorylation was significantly attenuated by cortisol. Cortisol not only increased phosphatase and tensin homolog deleted on chromosome 10, an inhibitor of Akt phosphorylation, but also 11beta-HSD1 in the cells. CONCLUSIONS: Increased 11beta-HSD1 expression and its reductase activity in granulosa cells are the major causes of increased cortisol concentration in the follicular fluid of PCOS with IR. The consequent excessive cortisol might contribute to IR of the granulosa cells in PCOS patients by attenuating Akt phosphorylation via induction of phosphatase and tensin homolog deleted on chromosome 10 expression, which might be further exacerbated by the induction of 11beta-HSD1. PMID- 26934393 TI - The Management of Primary Aldosteronism: Case Detection, Diagnosis, and Treatment: An Endocrine Society Clinical Practice Guideline. AB - OBJECTIVE: To develop clinical practice guidelines for the management of patients with primary aldosteronism. PARTICIPANTS: The Task Force included a chair, selected by the Clinical Guidelines Subcommittee of the Endocrine Society, six additional experts, a methodologist, and a medical writer. The guideline was cosponsored by American Heart Association, American Association of Endocrine Surgeons, European Society of Endocrinology, European Society of Hypertension, International Association of Endocrine Surgeons, International Society of Endocrinology, International Society of Hypertension, Japan Endocrine Society, and The Japanese Society of Hypertension. The Task Force received no corporate funding or remuneration. EVIDENCE: We searched for systematic reviews and primary studies to formulate the key treatment and prevention recommendations. We used the Grading of Recommendations, Assessment, Development, and Evaluation group criteria to describe both the quality of evidence and the strength of recommendations. We used "recommend" for strong recommendations and "suggest" for weak recommendations. CONSENSUS PROCESS: We achieved consensus by collecting the best available evidence and conducting one group meeting, several conference calls, and multiple e-mail communications. With the help of a medical writer, the Endocrine Society's Clinical Guidelines Subcommittee, Clinical Affairs Core Committee, and Council successfully reviewed the drafts prepared by the Task Force. We placed the version approved by the Clinical Guidelines Subcommittee and Clinical Affairs Core Committee on the Endocrine Society's website for comments by members. At each stage of review, the Task Force received written comments and incorporated necessary changes. CONCLUSIONS: For high-risk groups of hypertensive patients and those with hypokalemia, we recommend case detection of primary aldosteronism by determining the aldosterone-renin ratio under standard conditions and recommend that a commonly used confirmatory test should confirm/exclude the condition. We recommend that all patients with primary aldosteronism undergo adrenal computed tomography as the initial study in subtype testing and to exclude adrenocortical carcinoma. We recommend that an experienced radiologist should establish/exclude unilateral primary aldosteronism using bilateral adrenal venous sampling, and if confirmed, this should optimally be treated by laparoscopic adrenalectomy. We recommend that patients with bilateral adrenal hyperplasia or those unsuitable for surgery should be treated primarily with a mineralocorticoid receptor antagonist. PMID- 26934394 TI - Median Arcuate Ligament Syndrome-Review of This Rare Disease. AB - IMPORTANCE: Median arcuate ligament (MAL) syndrome is a rare disease resulting from compression of the celiac axis by fibrous attachments of the diaphragmatic crura, the median arcuate ligament. Diagnostic workup and therapeutic intervention can be challenging. OBJECTIVE: To review the literature to define an algorithm for accurate diagnosis and successful treatment for patients with MAL syndrome. EVIDENCE REVIEW: A search of PubMed (1995-September 28, 2015) was conducted, using the key terms median arcuate ligament syndrome and celiac artery compression syndrome. FINDINGS: Typically a diagnosis of exclusion, MAL syndrome involves a vague constellation of symptoms including epigastric pain, postprandial pain, nausea, vomiting, and weight loss. Extrinsic compression of the vasculature and surrounding neural ganglion has been implicated as the cause of these symptoms. Multiple imaging techniques can be used to demonstrate celiac artery compression by the MAL including mesenteric duplex ultrasonography, computed tomography angiography, magnetic resonance angiography, gastric tonometry, and mesenteric arteriography. Surgical intervention involves open, laparoscopic, or robotic ligament release; celiac ganglionectomy; and celiac artery revascularization. There remains a limited role for angioplasty because this intervention does not address the underlying extrinsic compression resulting in symptoms, although angioplasty with stenting may be used in recalcitrant cases. CONCLUSIONS AND RELEVANCE: Median arcuate ligament syndrome is rare, and as a diagnosis of exclusion, diagnosis and treatment paradigms can be unclear. Based on previously published studies, symptom relief can be achieved with a variety of interventions including celiac ganglionectomy as well as open, laparoscopic, or robotic intervention. PMID- 26934396 TI - 2015: Year of Transition. PMID- 26934395 TI - Eliminating the Neglected Tropical Diseases: Translational Science and New Technologies. AB - Today, the World Health Organization recognizes 17 major parasitic and related infections as the neglected tropical diseases (NTDs). Despite recent gains in the understanding of the nature and prevalence of NTDs, as well as successes in recent scaled-up preventive chemotherapy strategies and other health interventions, the NTDs continue to rank among the world's greatest global health problems. For virtually all of the NTDs (including those slated for elimination under the auspices of a 2012 London Declaration for NTDs and a 2013 World Health Assembly resolution [WHA 66.12]), additional control mechanisms and tools are needed, including new NTD drugs, vaccines, diagnostics, and vector control agents and strategies. Elimination will not be possible without these new tools. Here we summarize some of the key challenges in translational science to develop and introduce these new technologies in order to ensure success in global NTD elimination efforts. PMID- 26934397 TI - Effects of Cardiopulmonary Bypass on Mediastinal Drainage and the Use of Blood Products in the Intensive Care Unit in 60- to 80-Year-Old Patients Who Have Undergone Coronary Artery Bypass Grafting. AB - OBJECTIVE: The present study consisted of patients who underwent on-pump coronary artery bypass grafting (CABG) and off-pump CABG and investigated effect of using cardiopulmonary bypass (CPB) on the amount of postoperative drainage and blood products, red blood cell (RBC), free frozen plasma (FFP) given in the intensive care unit in 60-80-year-old patients who underwent CABG. METHODS: The present study comprises a total of 174 patients who have undergone coronary artery bypass graft (off-pump or on-pump CABG) surgery in our clinic in between 2012-2015 year. RESULTS: It was observed that the amount of drainage in the first 24 postoperative hours was lower in the on-pump CABG group (Group 1) when compared to off-pump group (Group 2) (Group 1 vs . Group 2; 703.5+/-253.8 ml vs . 719.6+/ 209.4 ml;P =0.716). However, the amount of drainage in the second 24 hours was statistically significantly lower in the off-pump CABG group (Group 1 vs . Group 2; 259.8+/-170.6 mlvs . 190.1+/-129.1 ml; P =0.016). With regard to the amount of overall drainage, no statistically significant difference was observed between the two groups. Group 1 needed RBC transfusion higher than Group 2 (Group 1 vs . Group 2; 2.2+/-1.3 bag vs . 1.2+/-0.9 bag;P <0.001). CONCLUSION: We can say that CPB influences the amount of second 24-hour drainage which indexed body surface area. In addition, CPB decreases hct, hb, thrombocyte count in ICU arrived, after 24 hours in postoperative period. Reduced thrombocyte counting effect can be appeared after 48 hours in the postoperative period of CPB. PMID- 26934398 TI - Application of Mechanical Ventilation Weaning Predictors After Elective Cardiac Surgery. AB - OBJECTIVE: To test several weaning predictors as determinants of successful extubation after elective cardiac surgery. METHODS: The study was conducted at a tertiary hospital with 100 adult patients undergoing elective cardiac surgery from September to December 2014. We recorded demographic, clinical and surgical data, plus the following predictive indexes: static compliance (Cstat), tidal volume (Vt), respiratory rate (f), f/ Vt ratio, arterial partial oxygen pressure to fraction of inspired oxygen ratio (PaO2/FiO2), and the integrative weaning index (IWI). Extubation was considered successful when there was no need for reintubation within 48 hours. Sensitivity (SE), specificity (SP), positive predictive value (PPV), negative predictive value (NPV), positive likelihood ratio (LR+), and negative likelihood ratio (LR-) were used to evaluate each index. RESULTS: The majority of the patients were male (60%), with mean age of 55.4+/-14.9 years and low risk of death (62%), according to InsCor. All of the patients were successfully extubated. Tobin Index presented the highest SE (0.99) and LR+ (0.99), followed by IWI (SE=0.98; LR+ =0.98). Other scores, such as SP, NPV and LR-were nullified due to lack of extubation failure. CONCLUSION: All of the weaning predictors tested in this sample of patients submitted to elective cardiac surgery showed high sensitivity, highlighting f/Vt and IWI. PMID- 26934399 TI - Sex Differences in Mortality After CABG Surgery. AB - INTRODUCTION: Numerous studies have shown that women undergoing coronary artery bypass graft surgery present higher mortality rate during hospitalization, and often complications when compared to men. OBJECTIVE: To compare the mortality of men and women undergoing coronary artery bypass graft surgery and identify factors related to differences occasionally found. METHODS: Retrospective cohort study conducted with 215 consecutive patients who underwent coronary bypass surgery. RESULTS: Women had a higher average age. Low body surface and dyslipidemia were more prevalent in women (1.65 vs . 1.85, P<0.001: 53% vs . 30%, P =0.001), whereas history of smoking and previous myocardial infarction were more prevalent in men (35% vs .14.7%, P =0.001; 20% vs . 2.7%, P =0.007). Regarding complications in the postoperative period, there was a higher rate of blood transfusions in women. The overall mortality rate was 5.6%, however there was no statistically significant difference in mortality between men and women. It was observed that among the patients who died, the average body surface area was lower than that of patients who did not have this complication. CONCLUSION: There was no difference in mortality between the sexes after coronary artery bypass graft in this service. PMID- 26934400 TI - Alternative Physical Therapy Protocol Using a Cycle Ergometer During Hospital Rehabilitation of Coronary Artery Bypass Grafting: a Clinical Trial. AB - OBJECTIVE: To compare the efficacy of a cycle ergometer-based exercise program to a standard protocol on the increment of the maximum distance walked during the six-minute walk test in the postoperative rehabilitation of patients submitted to coronary artery bypass grafting. METHODS: A controlled clinical trial pilot, blinded to the outcome, enrolled subjects who underwent coronary artery bypass grafting in a hospital from Southern Brazil. Subjects were designated for the standard physical rehabilitation protocol or to an alternative cycle ergometer based protocol through simple random sampling. The primary outcome was the difference in the maximum distance walked in the six-minute walk test before and after the allocated intervention. RESULTS: Twenty-four patients were included in the analysis, 10 in the standard protocol and 14 in the alternative protocol group. There was an increment in the maximum distance walked in both groups, and borderline superiority in the intervention group comparing to the control group (312.2 vs. 249.7; P=0.06). CONCLUSION: There was an increase in the maximum distance walked in the alternative protocol compared to the standard protocol. Thus, it is postulated that the use of a cycle ergometer can be included in physical rehabilitation in the hospital phase of postoperative coronary artery bypass grafting. However, randomized studies with larger sample size should be conducted to assess the significance of these findings. PMID- 26934401 TI - Effects of Resistance Exercise Applied Early After Coronary Artery Bypass Grafting: a Randomized Controlled Trial. AB - OBJECTIVE: To evaluate the effects of resistance exercise applied early after coronary artery bypass grafting. METHODS: It is a randomized controlled trial with 34 patients undergoing coronary artery bypass grafting between August 2013 and May 2014. Patients were randomized into two groups by simple draw: a control group (n=17), who received conventional physical therapy and an intervention group (n=17), who received, additionally, resistance exercise. Pulmonary function and functional capacity were evaluated in preoperative period and hospital discharge by spirometry and the six-minute walk test. For statistical analysis, we used the following tests: Shapiro-Wilk, Mann-Whitney, Student'st and Fisher's exact. Variables with P<0.05 were considered significant. RESULTS: Groups were homogeneous in terms of demographic, clinical and surgical variables. Resistance exercise exerted no effect on pulmonary function of intervention group compared to control group. However, intervention group maintained functional capacity at hospital discharge measured by percentage of predict distance in 6MWT (54.122.7% vs. 52.515.5%,P=0.42), while control group had a significant decrease (59.211.1% vs. 50.69.9%, P<0.016). CONCLUSION: Our results indicate that resistance exercise, applied early, may promote maintenance of functional capacity on coronary artery bypass grafting patients, having no impact on pulmonary function when compared to conventional physical therapy. PMID- 26934402 TI - Impact of Cardiovascular Interventions on the Quality of Life in the Elderly. AB - INTRODUCTION: The elderly population is growing rapidly. Political and socio economic changes led to the demographic transition in this population with the highest number of surgeries and as well as many comorbidities. OBJECTIVE: To evaluate the impact of cardiovascular intervention on quality of life of elderly patients after three and six months. METHODS: Analytical prospective cohort study with elderly between 60 and 80 years of age, of both sexes, with a diagnosis of coronary artery disease and underwent cardiovascular intervention during the period June 2010 to June 2011. Data were collected by individual interviews in the pre and postoperative periods (after three and six months) by telephone. We used the SF-36 to analyse quality of life in order to assess the physical and mental health of the study population. RESULTS: Of the 44 individuals evaluated, 59.1% were men, 75% in the range of 65 to 74 years, 38.6% were white and 38.6% were black, 31.8% were uneducated, 43.2% were married and 68.2% had less than a minimum wage. Prevailed patients: non-diabetics (68.2%), non-obese (81.8%), hypertensive (84.1%), non-alcoholic and non-smokers (68.2% and 61.4%, respectively). A significant increase in the average of the SF-36 scores between pre and post-surgical periods (three and six months) for the domains: functional capacity, pain, general health, vitality and emotional aspect. CONCLUSION: The elderly population undergoing intervention may have cardiovascular benefits and improvements of quality of life. Physical fitness improvement measures can be taken to resume that capability. PMID- 26934403 TI - Factors Associated with Intubation Time and ICU Stay After CABG. AB - OBJECTIVE: The aim of this study was to identify factors associated with intubation time and intensive care unit stay after coronary artery bypass grafting with cardiopulmonary bypass. METHODS: This was a retrospective study, whose data collection was performed in the hospital charts of 160 patients over 18 years, who underwent surgery from September 2009 to July of 2013 in a hospital in the state of Espirito Santo, Brazil. RESULTS: The mean age of the subjects was 61.44+/-8.93 years old and 68.8% were male. Subjects had a mean of 5.17+/-8.42 days of intensive care unit stay and mean intubation time of 10.99+/-8.41 hours. We observed statistically significant positive correlation between the following variables: patients' age and intubation time; patients' age and intensive care unit stay; intubation time and intensive care unit stay. CONCLUSION: In conclusion, the study showed that older patients had longer intubation time and increased intensive care unit stay. Furthermore, patients with longer intubation time had increased intensive care unit stay. PMID- 26934405 TI - alpha-Smooth Muscle Actin and ACTA2 Gene Expressions in Vasculopathies. AB - alpha-smooth muscle actin, encoded by ACTA2 gene, is an isoform of the vascular smooth muscle actins, typically expressed in the vascular smooth muscle cells contributing to vascular motility and contraction. ACTA2 gene mutations cause a diversity of diffuse vasculopathies such as thoracic aortic aneurysms and dissections as well as occlusive vascular diseases, including premature coronary artery disease and ischemic stroke. Dynamics of differentiation-specific alpha smooth muscle actin in arterial smooth muscle cells and proliferation of the proteins have been well described. Although a variety of research works have been undertaken in terms of modifications of alpha-smooth muscle actin and mutations of ACTA2 gene and myosin, the underlying mechanisms towards the pathological processes by way of gene mutations are yet to be clarified. The purpose of the present article is to describe the phenotypes of alpha-smooth muscle actin and implications of ACTA2 mutations in vasculopathies in order to enhance the understanding of potential mechanisms of aortic and coronary disorders. PMID- 26934404 TI - Surgical Ablation of Atrial Fibrillation Using Energy Sources. AB - Surgical ablation, concomitant with other operations, is an option for treatment in patients with chronic atrial fibrillation. The aim of this study is to present a literature review on surgical ablation of atrial fibrillation in patients undergoing cardiac surgery, considering energy sources and return to sinus rhythm. A comprehensive survey was performed in the literature on surgical ablation of atrial fibrillation considering energy sources, sample size, study type, outcome (early and late), and return to sinus rhythm. Analyzing studies with immediate results (n=5), the percentage of return to sinus rhythm ranged from 73% to 96%, while those with long-term results (n=20) (from 12 months on) ranged from 62% to 97.7%. In both of them, there was subsequent clinical improvement of patients who underwent ablation, regardless of the energy source used. Surgical ablation of atrial fibrillation is essential for the treatment of this arrhythmia. With current technology, it may be minimally invasive, making it mandatory to perform a procedure in an attempt to revert to sinus rhythm in patients requiring heart surgery. PMID- 26934406 TI - Efficacy Analysis of a Script-based Guide for EVAR Execution: is it Possible to Reduce Patient Exposure to Contrast, Operative Time and Blood Loss even when Advanced Technologies are not Available? AB - INTRODUCTION: Despite the patient and medical staff exposure to radiation in endovascular aneurysm repair, the benefits of this abdominal aortic aneurysm type of surgical management are justified by minor recovery time and hospitalization, as well as an option for patients not elected to conventional open repair. In this minimally invasive surgical approach, time of procedure and radiation doses can be substantial--and the increasing frequency of these procedures and it's complexity have impelled vascular surgeons to face additional and successive risk to occupational radiation exposure. Meticulous study of the computed tomography angiography during the endovascular aneurysm repair preparation allows reduction of unnecessary radiation exposure, as also reduces consecutive image acquisition and contrast use (that may be related to renal overload in susceptible patients). Some studies have proposed strategies to optimize endovascular intervention to reduce contrast use and X-ray exposure. Although they might prove to be effective, they rely on use of additional specific and advanced equipment, available only in major centers. As an alternative to this expensive and restrict technology, it is presented a simpler technique through image manipulation on software OsiriX, aiming to reduce both exposures. OBJECTIVE: To analyze the efficacy of the adoption of a study protocol and a script-based guide in preparation for endovascular aneurysm repair through verifying its impact over the surgical procedure--as referred to intravascular contrast infuse, effects over renal function, blood loss and operatory time. METHODS: A longitudinal prospective study from March 2014 through March 2015, where 30 performed endovascular aneurysm repair were compared to a historic control group. The planning for endovascular aneurysm repair through the patient's tomographic image manipulation in the prospective group was performed with OsiriX MD software. A script-based guide upon gathering detailed computed tomography angiography images was elaborated by the author and distributed to the performing surgical team for appreciation, instruction and pre operatory judgment. Based upon the script, the C-arm gantry angle was specifically corrected in each case of endovascular aneurysm repair, for image optimization and aneurysm's neck visualization. Arteriography was performed under digital subtraction angiography after catheters were positioned according to predicted level description in the referred guide. Statistical analysis were performed with a significance level of 5% (P value<0.05). RESULTS: There was a statistically significant relationship between the two studied periods and the variables: contrast volume (284.5 vs. 31.8 mL), operative time (207.5 vs. 140.4 min.) and blood loss (798.1 vs. 204.4 mL), revealing that they are considerably larger in the historical control group than in the script guided current group. There was no difference related to the volume of contrast used in the two groups and the occurrence of renal impairment. CONCLUSION: In the present paper it was possible to demonstrate the impact of the ability to manipulate digital formats of medical images without the need of sophisticated equipment, in adoption of a guide based on the compilation of informations collected with assistance of an accessible software performed on a personal computer. Although we could not prove relation to occurrence of renal impairment, there were direct results on reduction of intravascular contrast use, even as surgical time and blood loss, compared to a previous historical period. PMID- 26934407 TI - ECMO: Improving our Results by Chasing the Rabbits. AB - As Marcelo Giugale published in the Financial Times, Latin America, on the whole, has not excelled at innovation - doing the same things in a new and better way or at doing new things. It has been slow to acquire, adopt and adapt technologies by this time available in other places[1]. Although extracorporeal membrane oxygenation (ECMO) is not a new technology, its use in Latin America is not widespread as needed. Furthermore, we still have a number centers doing ECMO, not reporting their cases, lacking a structured training program and not registered with the extracorporeal life support organization (ELSO). With this scenario, and accepting that ECMO is the first step in any circulatory support program, it is difficult to anticipate the incorporation of new and more complex devices as the technologically advanced world is currently doing. However, the good news is that with the support of experts from USA, Europe and Canada the results in Latin America ELSO'S centers are improving by following its guidelines for training, and using a standard educational process. There is no doubt that we can learn a great deal from the high velocity organizations - the rabbits - whom everyone chases but never catches, that manage to stay ahead because of their endurance, responsiveness, and their velocity in self-correction[2]. PMID- 26934409 TI - Technological Devices Improving System of Translating Languages: What About their Usefulness on the Applicability in Medicine and Health Sciences? AB - INTRODUCTION: In a world in which global communication is becoming ever more important and in which English is increasingly positioned as the pre-eminent international language, that is, English as a Lingua Franca refers to the use of English as a medium of communication between peoples of different languages. It is important to highlight the positive advances in communication in health, provided by technology. OBJECTIVE: To present an overview on some technological devices of translating languages provided by the Web as well as to point out some advantages and disadvantages specially using Google Translate in Medicine and Health Sciences. METHODS: A bibliographical survey was performed to provide an overview on the usefulness of online translators for applicability using written and spoken languages. RESULTS: As we have to consider this question to be further surely answered, this study could present some advantages and disadvantages in using translating online devices. CONCLUSION: Considering Medicine and Health Sciences as expressive into the human scientific knowledge to be spread worldwidely; technological devices available on communication should be used to overcome some language barriers either written or spoken, but with some caution depending on the context of their applicability. PMID- 26934408 TI - Improving Indicators in a Brazilian Hospital Through Quality-Improvement Programs Based on STS Database Reports. AB - OBJECTIVE: To report the initial changes after quality-improvement programs based on STS-database in a Brazilian hospital. METHODS: Since 2011 a Brazilian hospital has joined STS-Database and in 2012 multifaceted actions based on STS reports were implemented aiming reductions in the time of mechanical ventilation and in the intensive care stay and also improvements in evidence-based perioperative therapies among patients who underwent coronary artery bypass graft surgeries. RESULTS: All the 947 patients submitted to coronary artery bypass graft surgeries from July 2011 to June 2014 were analyzed and there was an improvement in all the three target endpoints after the implementation of the quality-improvement program but the reduction in time on mechanical ventilation was not statistically significant after adjusting for prognostic characteristics. CONCLUSION: The initial experience with STS registry in a Brazilian hospital was associated with improvement in most of targeted quality-indicators. PMID- 26934410 TI - Evaluation of the Efficiency of the Atraumatic Endotracheal Tube in the Pulmonary Gas Exchange: an Experimental Study. AB - OBJECTIVE: Mechanical ventilation is frequently necessary, in which case the use of an endotracheal tube is mandatory. The tube has an inflatable balloon in its distal extremity, whose aim is, among other functions, an efficient arterialization. However, serious injuries in the place of contact of the balloon with the trachea can be frequent. Some studies point out that balloons with permanent pressure may reduce this complication. Nevertheless, air scape, expressed by the inspiratory (IV) and expiratory volume (EV) variation (Delta IV EV), may occur, possibly leading to hypoxemia. Thus, the goal of this study was to verify the efficiency of a modified endotracheal tube on arterializations compared to the traditional endotracheal tube. METHODS: The modified endotracheal tube presents intermittent insufflation, with three drillings in the internal region of the cuff, allowing for insufflation in the inspiratory phase of the mechanical ventilation. Three animals were used for the control group, with a cuff pressure of 30 cmH2O, and seven pigs had the modified endotracheal tube. Each animal was kept under mechanical ventilation (FIO2=0.21) for 6 hours. Arterial and venous gases were measured every three hours (T0; T3; T6). RESULTS: The gases confirmed the lack of hypoxia between the Groups, with a difference in the DeltaIV-EV at T0 (P=0.0486). CONCLUSIONS: In this study, the lack of hypoxia showed the efficiency of the modified endotracheal tube. However, new studies are necessary, particularly in diseased lungs, in order to evaluate the real efficiency of the mentioned device on the pulmonary gas exchange. PMID- 26934411 TI - Use of Bovine Pericardium and Sutureless Biological Glue in Left Ventricular Rupture After Mitral Valve Replacement, Five Years of Follow-up. AB - Rupture of the left ventricular wall after mitral valve replacement is an infrequent but lethal complication. Reporting correction technique of ventricular rupture with bovine pericardium patch secured with glue and without suturing: a 51 years-old female patient, with double rheumatic mitral lesion, severe stenosis and discrete insufficiency, who had a mitral valve replacement. During surgery, the patient presented a ventricular rupture of the posterior wall (atrioventricular disruption), which was successfully repaired using bovine pericardium with sutureless biological glue over the epicardium of the damaged area. Sixty months after surgery the patient has no symptoms. PMID- 26934412 TI - Circulatory Assistance: the Challenges of Technological Incorporation in Brazil. PMID- 26934415 TI - Cytolytic hepatitis related to simeprevir overdose in a patient with cirrhosis and HIV-HCV genotype 1 coinfection. PMID- 26934416 TI - Betatrophin in nonalcoholic fatty liver disease. PMID- 26934418 TI - Treatment for Vestibular Disorders: How Does Your Physical Therapist Treat Dizziness Related to Vestibular Problems? PMID- 26934419 TI - Investigational direct-acting antivirals in hepatitis C treatment: the latest drugs in clinical development. AB - INTRODUCTION: Therapeutic options for patients with HCV-related liver disease have increased over the last two decades. In fact, the old standard of care based on the combination of pegylated interferon and ribavirin did not result in satisfactory eradication rates, particularly in patients with liver cirrhosis. With the advent of direct-acting antivirals (DAAs), higher rates of viral clearance became possible and, patients with contraindications to interferon obtained access to treatment. However, several concerns have been raised regarding first-generation DAAs, namely their high costs, and the emergence of resistant-associated variants with low susceptibility to these drugs. AREAS COVERED: In this review, the authors discuss the data about the efficacy and safety of the main anti-HCV direct-acting antivirals currently in the pipeline. Furthermore, they evaluate the impact of these drugs on the therapeutic options currently available for HCV patients. EXPERT OPINION: The results of trials evaluating the effectiveness of new DAAs are encouraging. These new antivirals lead to high rates of viral eradication without relevant adverse reactions and seem to be effective regardless of viral genotypes, presence of resistant associated variants or advanced liver disease. Consequently, with the advent of this new family of drugs, chronic HCV-related hepatitis may become a curable disease. PMID- 26934420 TI - Reading Achievement in Boys With Non-Syndromic Cleft Palate Only: Relationship to Neuropsychological Skill and Neurocircuitry. AB - Reading achievement and neural activation during a reading task were evaluated among boys with isolated cleft palate only (iCP) in comparison to unaffected controls. Ten boys with iCP and 10 unaffected boys between the ages of 8 and 16 years old were assessed. Standardized assessments of intelligence and reading achievement were administered and participants underwent a block-design functional magnetic resonance imaging protocol using non-word rhyming and judgment of line tasks. Among the 10 boys with iCP, reading fluency correlated with phonological awareness and visual memory. Neural activation was increased in regions of the brain associated with a non-fluent/dyslexic reading pattern. PMID- 26934421 TI - Parents' and providers' attitudes toward school-located provision and school entry requirements for HPV vaccines. AB - OBJECTIVE: To determine parents' and providers' attitudes toward school-located provision and school-entry requirements for HPV vaccination. METHODS: Parents/guardians of 11-17 y old girls and pediatric healthcare providers at one inner-city public clinic and three private practices completed semi-structured interviews in 2012-2013. Participants were asked open-ended questions regarding their attitudes toward school-located provision and school-entry requirements for HPV vaccination. Parents' answers were analyzed with relationship to whether their daughters had not initiated, initiated but not completed, or completed the HPV vaccine series. Qualitative analysis was used to identify themes related to shared views. RESULTS: 129 parents/guardians and 34 providers participated. 61% of parents supported providing HPV vaccinations in schools, citing reasons of convenience, improved access, and positive peer pressure. Those who opposed school-located provision raised concerns related to privacy and the capacity of school nurses to manage vaccine-related reactions. Parents whose daughters had not completed the series were more likely to intend to vaccinate their daughters in schools (70%) and support requirements (64%) than parents who had not initiated vaccination (42% would vaccinate at school, 46% support requirements) or completed the series (42% would vaccinate at school, 32% support requirements; p < 0 .05 for all comparisons). 81% of providers supported offering vaccination in schools, wanting to take advantage of the captive audience, improve vaccine completion rates, and decrease the administrative burden on medical office staff, but were concerned about adequate information transfer between schools and medical offices. Only 32% of providers supported school-entry requirements, largely because they felt that a requirement might provoke a public backlash that could further hinder vaccination efforts. CONCLUSIONS: School-located provision of HPV vaccination was widely accepted by healthcare providers and parents whose children have not completed the series, indicating that this venue might be a valuable addition to improve completion rates. Support for school-entry requirements was limited among both parents and healthcare providers. PMID- 26934423 TI - Food Safety, Food Fraud, and Food Defense: A Fast Evolving Literature. AB - Intentional food crime is plural in nature in terms of the types of crime and the differing levels of financial gain. Successful models of food crime are dependent on how well the crime has been executed and at what point, or even if, detection actually occurs. The aim of this paper is to undertake a literature review and critique the often contradictory definitions that can be found in the literature in order to compare and contrast existing food crime risk assessment tools and their application. Food safety, food defense, and food fraud risk assessments consider different criteria in order to determine the degree of situational risk for each criteria and the measures that need to be implemented to mitigate that risk. Further research is required to support the development of global countermeasures, that are of value in reducing overall risk even when the potential hazards may be largely unknown, and specific countermeasures that can act against unique risks. PMID- 26934422 TI - Calcium d-Saccharate: Aqueous Solubility, Complex Formation, and Stabilization of Supersaturation. AB - Molar conductivity of saturated aqueous solutions of calcium d-saccharate, used as a stabilizer of beverages fortified with calcium d-gluconate, increases strongly upon dilution, indicating complex formation between calcium and d saccharate ions, for which, at 25 degrees C, Kassoc = 1032 +/- 80, DeltaHassoc degrees = -34 +/- 6 kJ mol-1, and DeltaSassoc degrees = -55 +/- 9 J mol-1 K-1, were determined electrochemically. Calcium d-saccharate is sparingly soluble, with a solubility product, Ksp, of (6.17 +/- 0.32) * 10-7 at 25 degrees C, only moderately increasing with the temperature: DeltaHsol degrees = 48 +/- 2 kJ mol 1, and DeltaSassoc degrees = 42 +/- 7 J mol-1 K-1. Equilibria in supersaturated solutions of calcium d-saccharate seem only to adjust slowly, as seen from calcium activity measurements in calcium d-saccharate solutions made supersaturated by cooling. Solutions formed by isothermal dissolution of calcium d-gluconate in aqueous potassium d-saccharate becomes spontaneously supersaturated with both d-gluconate and d-saccharate calcium salts, from which only calcium d-saccharate slowly precipitates. Calcium d-saccharate is suggested to act as a stabilizer of supersaturated solutions of other calcium hydroxycarboxylates with endothermic complex formation through a heat-induced shift in calcium complex distribution with slow equilibration upon cooling. PMID- 26934424 TI - Glucose availability enhances lipopolysaccharide production and immunogenicity in the opportunistic pathogen Acinetobacter baumannii. AB - AIM: Acinetobacter baumannii can cause sepsis with high mortality rates. We investigated whether glucose sensing might play a role in A. baumannii pathogenesis. MATERIALS & METHODS: We carried out transcriptome analysis and extracellular polysaccharide determination in an A. baumannii clinical isolate grown on complex medium with or without glucose supplementation, and assessed its ability to induce production of inflammatory cytokines in human macrophages. RESULTS: Growth in glucose-supplemented medium strongly enhanced A. baumannii sugar anabolism, resulting in increasing lipopolysaccharide biosynthesis. In addition, glucose induced active shedding of lipopolysaccharide, in turn triggering a strong induction of inflammatory cytokines in human macrophages. Finally, hemolytic activity was strongly enhanced by growth in glucose supplemented medium. CONCLUSION: We propose that sensing of exogenous glucose might trigger A. baumannii pathogenesis during sepsis. PMID- 26934425 TI - Place matters: Mitigating obesity with the person-in-environment approach. AB - Research demonstrates that environmental and community-level variables contribute to obesity. Many of these variables are outside of personal volitional control, such as the characteristics of the places in which people live. Social work's unique person-in-environment (PIE) approach is an ideal perspective from which to address obesity. This study employs the PIE perspective to examine sprawl, one environmental-level factor. We employed secondary data analysis to examine the effect of sprawl on obesity while controlling for covariates. Region of residence and sprawl significantly predicted obesity, net of covariates. Given that obesity varies among communities, social workers can respond with PIE-oriented solutions. PMID- 26934426 TI - Influence of metallic artifact filtering on MEG signals for source localization during interictal epileptiform activity. AB - OBJECTIVE: Medical intractable epilepsy is a common condition that affects 40% of epileptic patients that generally have to undergo resective surgery. Magnetoencephalography (MEG) has been increasingly used to identify the epileptogenic foci through equivalent current dipole (ECD) modeling, one of the most accepted methods to obtain an accurate localization of interictal epileptiform discharges (IEDs). Modeling requires that MEG signals are adequately preprocessed to reduce interferences, a task that has been greatly improved by the use of blind source separation (BSS) methods. MEG recordings are highly sensitive to metallic interferences originated inside the head by implanted intracranial electrodes, dental prosthesis, etc and also coming from external sources such as pacemakers or vagal stimulators. To reduce these artifacts, a BSS based fully automatic procedure was recently developed and validated, showing an effective reduction of metallic artifacts in simulated and real signals (Migliorelli et al 2015 J. Neural Eng. 12 046001). The main objective of this study was to evaluate its effects in the detection of IEDs and ECD modeling of patients with focal epilepsy and metallic interference. APPROACH: A comparison between the resulting positions of ECDs was performed: without removing metallic interference; rejecting only channels with large metallic artifacts; and after BSS-based reduction. Measures of dispersion and distance of ECDs were defined to analyze the results. MAIN RESULTS: The relationship between the artifact-to signal ratio and ECD fitting showed that higher values of metallic interference produced highly scattered dipoles. Results revealed a significant reduction on dispersion using the BSS-based reduction procedure, yielding feasible locations of ECDs in contrast to the other two approaches. SIGNIFICANCE: The automatic BSS based method can be applied to MEG datasets affected by metallic artifacts as a processing step to improve the localization of epileptic foci. PMID- 26934428 TI - Malignant melanoma arising in sebaceous naevus (of Jadassohn): a case report. AB - Sebaceous naevus are associated with malignant transformation. They commonly occur in the head and neck region and are associated with malignant transformation into basal cell and squamous cell carcinomas. This case report describes a case of a malignant melanoma arising from a longstanding sebaceous naevus. PMID- 26934427 TI - Enantiospecific Alkynylation of Alkylboronic Esters. AB - Enantioenriched secondary and tertiary alkyl pinacolboronic esters undergo enantiospecific deborylative alkynylation through a Zweifel-type alkenylation followed by a 1,2-elimination reaction. The process involves use of alpha-lithio vinyl bromide or vinyl carbamate species, for which application to Zweifel-type reactions has not previously been explored. The resulting functionalized 1,1 disubstituted alkenes undergo facile base-mediated elimination to generate terminal alkyne products in high yield and excellent levels of enantiospecificity over a wide range of pinacolboronic ester substrates. Furthermore, along with terminal alkynes, internal and silyl-protected alkynes can be formed by simply introducing a suitable carbon- or silicon-based electrophile after the base mediated 1,2-elimination reaction. PMID- 26934429 TI - Ultrasonography for diagnosis of alcoholic cirrhosis in people with alcoholic liver disease. AB - BACKGROUND: Heavy alcohol consumption causes alcoholic liver disease and is a causal factor of many types of liver injuries and concomitant diseases. It is a true systemic disease that may damage the digestive tract, the nervous system, the heart and vascular system, the bone and skeletal muscle system, and the endocrine and immune system, and can lead to cancer. Liver damage in turn, can present as multiple alcoholic liver diseases, including fatty liver, steatohepatitis, fibrosis, alcoholic cirrhosis, and hepatocellular carcinoma, with presence or absence of hepatitis B or C virus infection. There are three scarring types (fibrosis) that are most commonly found in alcoholic liver disease: centrilobular scarring, pericellular fibrosis, and periportal fibrosis. When liver fibrosis progresses, alcoholic cirrhosis occurs. Hepatocellular carcinoma occurs in 5% to 15% of people with alcoholic cirrhosis, but people in whom hepatocellular carcinoma has developed are often co-infected with hepatitis B or C virus.Abstinence from alcohol may help people with alcoholic disease in improving their prognosis of survival at any stage of their disease; however, the more advanced the stage, the higher the risk of complications, co-morbidities, and mortality, and lesser the effect of abstinence. Being abstinent one month after diagnosis of early cirrhosis will improve the chance of a seven-year life expectancy by 1.6 times. Liver transplantation is the only radical method that may change the prognosis of a person with alcoholic liver disease; however, besides the difficulties of finding a suitable liver transplant organ, there are many other factors that may influence a person's survival.Ultrasound is an inexpensive method that has been used for years in clinical practice to diagnose alcoholic cirrhosis. Ultrasound parameters for assessing cirrhosis in people with alcoholic liver disease encompass among others liver size, bluntness of the liver edge, coarseness of the liver parenchyma, nodularity of the liver surface, size of the lymph nodes around the hepatic artery, irregularity and narrowness of the inferior vena cava, portal vein velocity, and spleen size.Diagnosis of cirrhosis by ultrasound, especially in people who are asymptomatic, may have its advantages for the prognosis, motivation, and treatment of these people to decrease their alcohol consumption or become abstinent.Timely diagnosis of alcoholic cirrhosis in people with alcoholic liver disease is the cornerstone for evaluation of prognosis or choosing treatment strategies. OBJECTIVES: To determine the diagnostic accuracy of ultrasonography for detecting the presence or absence of cirrhosis in people with alcoholic liver disease compared with liver biopsy as reference standard.To determine the diagnostic accuracy of any of the ultrasonography tests, B-mode or echo-colour Doppler ultrasonography, used singly or combined, or plus ultrasonography signs, or a combination of these, for detecting hepatic cirrhosis in people with alcoholic liver disease compared with liver biopsy as a reference standard, irrespective of sequence. SEARCH METHODS: We performed searches in The Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Hepato-Biliary Group Diagnostic Test Accuracy Studies Register, The Cochrane Library (Wiley), MEDLINE (OvidSP), EMBASE (OvidSP), and the Science Citation Index Expanded to 8 January 2015. We applied no language limitations.We screened study references of the retrieved studies to identify other potentially relevant studies for inclusion in the review and read abstract and poster publications. SELECTION CRITERIA: Three review authors independently identified studies for possible inclusion in the review. We excluded references not fulfilling the inclusion criteria of the review protocol. We sent e-mails to study authors.The included studies had to evaluate ultrasound in the diagnosis of hepatic cirrhosis using only liver biopsy as the reference standard.The maximum time interval of investigation with liver biopsy and ultrasonography should not have exceeded six months. In addition, ultrasonography could have been performed before or after liver biopsy. DATA COLLECTION AND ANALYSIS: We followed the Cochrane Handbook for Systematic Reviews of Diagnostic Test Accuracy. MAIN RESULTS: The review included two studies that provided numerical data regarding alcoholic cirrhosis in 205 men and women with alcoholic liver disease. Although there were no applicability concerns in terms of participant selection, index text, and reference standard, we judged the two studies at high risk of bias. Participants in both studies had undergone both liver biopsy and ultrasonography investigations. The studies shared only a few comparable clinical signs and symptoms (index tests).We decided to not perform a meta-analysis due to the high risk of bias and the high degree of heterogeneity of the included studies. AUTHORS' CONCLUSIONS: As the accuracy of ultrasonography in the two included studies was not informative enough, we could not recommend the use of ultrasonography as a diagnostic tool for liver cirrhosis in people with alcoholic liver disease. In order to be able to answer the review questions, we need diagnostic ultrasonography prospective studies of adequate sample size, enrolling only participants with alcoholic liver disease.The design and report of the studies should follow the Standards for Reporting of Diagnostic Accuracy. The sonographic features, with validated cut-offs, which may help identify clinical signs used for diagnosis of fibrosis in alcoholic liver disease, should be carefully selected to achieve maximum diagnostic accuracy on ultrasonography. PMID- 26934430 TI - Total Nevi, Atypical Nevi, and Melanoma Thickness: An Analysis of 566 Patients at 2 US Centers. AB - IMPORTANCE: Nevi are among the strongest risk factors for melanoma. However, little is known about the association of many total nevi (TN) or atypical nevi (AN) with tumor thickness. OBJECTIVES: To examine the association between age and the number of TN and AN and to explore whether there was a relationship between TN or AN and tumor thickness, controlling for multiple variables. DESIGN, SETTING, AND PARTICIPANTS: Survey of patients with melanoma at 2 academic sites and an affiliated Veteran Affairs medical center. Participants included 566 patients surveyed within 3 months of diagnosis. Patients were surveyed in the melanoma clinics from May 17, 2006, through March 31, 2009, within 3 months of diagnostic biopsy. The dates of the analysis were April 1, 2015, to August 1, 2015. MAIN OUTCOMES AND MEASURES: Counts of TN and AN were performed at the first visit after diagnosis and were categorized as 0 to 20, 20 to 50, or more than 50 for TN and as 0, 1 to 5, or more than 5 for AN. Tumor thickness was categorized as 2.00 mm or less or as 2.01 mm or greater. All analyses were stratified by patient age (<60 or >=60 years). Logistic regression was used to test associations, controlling for age, sex, anatomic location of melanoma, institution, histologic subtype, marital status, performance of skin self examination, number of health care visits in the past year, mode of melanoma discovery, and receipt of skin examination by a physician. RESULTS: The study population included 566 patients. Their mean (SD) age was 56.7 (15.9) years, and 39.0% (n = 221) were female. Of 566 patients, the number of TN was classified as 0 to 20 (66.4% [n = 376]), 20 to 50 (20.5% [n = 116]), or more than 50 (13.1% [n = 74]). Atypical nevus counts were 0 (73.3% [n = 415]), 1 to 5 (14.5% [n = 82]), or more than 5 (12.2% [n = 69]). For those younger than 60 years, the presence of more than 50 TN was associated with a sharply reduced risk of thick melanoma (odds ratio, 0.32; 95% CI, 0.12-0.81), and the presence of more than 5 AN compared with no AN was associated with thicker melanoma (odds ratio, 2.43; 95% CI, 1.02-5.75). CONCLUSIONS AND RELEVANCE: Most patients with melanoma had few nevi and no AN. In younger patients (<60 years), thick melanomas were commonly found in those with fewer TN but more AN, suggesting that physicians and patients should not rely on the total nevus count as a sole reason to perform skin examinations or to determine a patient's at-risk status. Younger patients should be educated on the increased risk of thicker melanomas that is associated with having more AN. PMID- 26934431 TI - Copper oxide nanoparticle induces inflammatory response and mucus production via MAPK signaling in human bronchial epithelial cells. AB - Copper nanoparticles (CuONPs) can pose risks to industrial workers. With increase of its applications especially in electronic fields, it is necessary to assess the toxicity of CuONPs, including pulmonary toxicity. In this study, we investigated the effect of CuONPs on human epithelial cell line H292. CuONPs treatment caused a significant increase in IL-6 and IL-8 mRNA expression and protein levels in H292 cells in a concentration-dependent manner. The mRNA expression and protein levels of MUC5AC were consistent with those of proinflammatory mediators. Additionally, CuONPs treatment increased phosphorylation of mitogen-activated protein kinases (MAPKs), Erk, JNK, and p-38 compared to that of control in a concentration-dependent manner. However, co treatment with CuONPs and each MAPK inhibitor significantly decreased the phosphorylation of each MAPK, resulting in decreased mRNA expression and protein levels of proinflammatory mediators and MUC5AC compared to that in H292 cells only treated with CuONPs. In summary, CuONPs-induced inflammatory mediators and MUC5AC associated with MAPKs phosphorylation. Our results will provide useful information on CuONPs-induced pulmonary toxicity. PMID- 26934432 TI - Concentration effects on biotic and abiotic processes in the removal of 1,1,2 trichloroethane and vinyl chloride using carbon-amended ZVI. AB - A permeable reactive barrier, consisting of both zero valent iron (ZVI) and a biodegradable organic carbon, was evaluated for the remediation of 1,1,2 trichloroethane (1,1,2-TCA) contaminated groundwater. During an 888 day laboratory column study, degradation rates initially stabilized with a degradation half-life of 4.4+/-0.4 days. Based on the accumulation of vinyl chloride (VC) and limited production of 1,1-dichloroethene (1,1-DCE) and 1,2 dichloroethane (1,2-DCA), the dominant degradation pathway was likely abiotic dichloroelimination to form VC. Degradation of VC was not observed based on the accumulation of VC and limited ethene production. After a step reduction in the influent concentration of 1,1,2-TCA from 170+/-20 mg L(-1) to 39+/-11 mg L(-1), the degradation half-life decreased 5-fold to 0.83+/-0.17 days. The isotopic enrichment factor of 1,1,2-TCA also changed after the step reduction from -14.6+/ 0.70/00 to -0.72+/-0.120/00, suggesting a possible change in the degradation mechanism from abiotic reductive degradation to biodegradation. Microbiological data suggested a co-culture of Desulfitobacterium and Dehalococcoides was responsible for the biodegradation of 1,1,2-TCA to ethene. PMID- 26934433 TI - [A woman with a seat belt sign after a car accident]. AB - A 48-year-old woman presented with a cervicothoracic seat belt sign after a car accident as a front seat passenger. The CT scan showed right common carotid artery dissection with a pseudoaneurysm, a right clavicle fracture, sternal fracture, multiple rib fractures left and a laceration of the spleen. She did not develop any neurologic deficits. PMID- 26934434 TI - [A woman with a painful swelling in the groin: the cyst of Nuck, a forgotten diagnosis]. AB - BACKGROUND: The cyst of Nuck is a swelling in the inguinal canal caused by a hydrocele of the round ligament. This abnormality is a result of the absence or incomplete obliteration of the processus vaginalis during foetal development. CASE DESCRIPTION: A 44-year-old woman had suffered from a painful swelling in her right groin for 4 years. Extensive imaging and multiple punctures of the supposed cyst had no lasting results. Eventually, the swelling was identified as a cyst of Nuck, which was confirmed on operative exploration. After excision, the patient was relieved of all her symptoms. CONCLUSION: The cyst of Nuck is a clinical diagnosis. Imaging the swelling may give a misleading result and cause a delay in treatment. PMID- 26934435 TI - [An infant with remarkable soles of his feet]. AB - We describe a 4-month-old male infant with a ridge across the soles of both feet without clinical signs of illness. The abnormality was diagnosed as a precalcaneal congenital fibrolipomatous hamartoma. PMID- 26934436 TI - [Sir Harold D. Gillies, pioneer of plastic surgery]. AB - In the First World War, large numbers of soldiers perished because machine guns and artillery bombardments had rendered the old techniques of combat and weapons hopelessly outdated. In addition to the many deaths, many soldiers were also seriously injured. At the outbreak of the First World War, ENT surgeon Harold D. Gillies signed up with the Royal Army Medical Corps. He used his knowledge of reconstructive surgery in a creative and innovative manner to treat the severely mutilating facial injuries. He thus improved the established techniques of nose reconstruction, skin grafts and facial reconstruction. At the end of the First World War, he had operated on about 11,000 casualties. Surgeons from every part of the world adopted his new principles and Gillies thus created the specialism of plastic and reconstructive surgery. Some of the techniques developed by Gillies are even still in use today. PMID- 26934437 TI - [Adults with chickenpox in the tropics]. AB - In our hospital in the Dutch Caribbean, it is not uncommon for adults to be admitted for chickenpox infection. In contrast to the situation in temperate climates, not all adults are infected during childhood. Therefore, hospital staff are tested when first employed; of those aged between 20-29 years, 40% do not have antibodies against the varicella-zoster virus (VZV). We describe three cases of adults, aged 37, 51 and 90 years respectively, who presented with chickenpox. Compared to children, the clinical course in adults is more severe with the potential risk of life-threatening complications. In pregnancy or concomitant T cell immune deficiency, risk of a fulminant course is even higher. Treatment with aciclovir or valaciclovir is effective and associated with few side-effects. Passive immunization with VZV-immunoglobulin is indicated within 96 hours of exposure, typically followed by acyclovir or valaciclovir. As migration occurs from low endemic tropical areas to high endemic temperate areas, we should be aware of the risk of adult chickenpox in these migrants. PMID- 26934438 TI - [A girl with abdominal pain and progressive vomiting]. AB - An 11-year-old girl with a history of trichophagia presented with abdominal pain and progressive vomiting. The MRI scan showed a gastric mass and multiple masses in the small intestine. A large trichobezoar was removed from the stomach by laparotomy. PMID- 26934439 TI - Parotid area lymph node metastases from preliminarily diagnosed patients with nasopharyngeal carcinoma: report on tumor characteristics and oncologic outcomes. AB - The parotid area lymph node (PLN) is an uncommon site of metastasis originating from nasopharyngeal carcinoma (NPC). The study aimed to investigate clinical characteristics and outcomes of patients with preliminarily diagnosed NPC with PLN metastases. Here we retrospectively reviewed Magnetic resonance imaging (MRI) scans of 2221 patients with untreated nonmetastatic NPC who received intensity modulated radiation therapy (IMRT). Finally, 64 (2.9%) patients were identified with PLN metastases, of which, 34 received PLN-sparing IMRT and 30 received PLN radical IMRT. We also found that 42.2% had N3 disease and 95.3% had stages III IVb. PLN metastases on MRI were characterized by ipsilateral retropharyngeal lymph node (RLN) or level II nodal extracapsular spread (ECS), ipsilateral giant cervical nodes, ipsilateral parapharyngeal extension, or solitary parotid metastasis. The 5-year overall survival, distant metastasis-free survival, regional relapse-free survival, and parotid relapse-free survival rates were 70.4%, 64.3%, 76.7%, and 87.9%, respectively. Distant metastases were the main cause of treatment failure and death. Using PLN-sparing IMRT, sparing PLN with minimal axial diameter of <10 mm, could increase the risk of parotid recurrence. However, it was not an independent prognostic factor. N classification and concurrent-based chemotherapy were almost statistically significant for distant failure and death. Overall, we demonstrated that the PLN metastases might be derived from RLN or level II nodal ECS, giant cervical nodes in a retrograde fashion, or parapharyngeal extension. Sparing PLN of <10 mm by IMRT should consider the risk of parotid recurrence. Distant metastases remained the dominant treatment failure. Further effective systemic chemotherapy should be explored. PMID- 26934440 TI - Increased IL-6 secretion by aged human mesenchymal stromal cells disrupts hematopoietic stem and progenitor cells' homeostasis. AB - Hematopoietic stem and progenitor cell (HSPC) homeostasis declines with age, leading to impaired hematopoiesis. Mesenchymal stromal cells (MSC) are critical components of the bone marrow niche and key regulators of the balance between HSPC proliferation and quiescence. Accrual of DNA damage, a hallmark of cellular aging, occurs in aged MSC. Whether MSC aging alters the bone marrow niche triggering HSPC dysfunction is unknown. Using a human MSC-HSPC co-culture system, we demonstrated that DNA damaged MSC have impaired capacity to maintain CD34+CD38 HSPC quiescence. Furthermore, human MSC from adult donors display some hallmarks of cellular senescence and have a decreased capacity to maintain HSPC quiescence and the most primitive CD34+CD38- subset compared to MSC from pediatric donors. IL-6 neutralization restores the MSC-HPSC crosstalk in senescent and adult MSC HSPC co-cultures highlighting the relevance of the local microenvironment in maintaining HSPC homeostasis. These results provide new evidence implicating components of the MSC secretome in HSPC aging. PMID- 26934441 TI - Comprehensive genetic testing identifies targetable genomic alterations in most patients with non-small cell lung cancer, specifically adenocarcinoma, single institute investigation. AB - This study reviews extensive genetic analysis in advanced non-small cell lung cancer (NSCLC) patients in order to: describe how targetable mutation genes interrelate with the genes identified as variants of unknown significance; assess the percentage of patients with a potentially targetable genetic alterations; evaluate the percentage of patients who had concurrent alterations, previously considered to be mutually exclusive; and characterize the molecular subset of KRAS. Thoracic Oncology Research Program Databases at the University of Chicago provided patient demographics, pathology, and results of genetic testing. 364 patients including 289 adenocarcinoma underwent genotype testing by various platforms such as FoundationOne, Caris Molecular Intelligence, and Response Genetics Inc. For the entire adenocarcinoma cohort, 25% of patients were African Americans; 90% of KRAS mutations were detected in smokers, including current and former smokers; 46% of EGFR and 61% of ALK alterations were detected in never smokers. 99.4% of patients, whose samples were analyzed by next-generation sequencing (NGS), had genetic alterations identified with an average of 10.8 alterations/tumor throughout different tumor subtypes. However, mutations were not mutually exclusive. NGS in this study identified potentially targetable genetic alterations in the majority of patients tested, detected concurrent alterations and provided information on variants of unknown significance at this time but potentially targetable in the future. PMID- 26934442 TI - Preferential targeting of cancer stem cells in the radiosensitizing effect of ABT 737 on HNSCC. AB - Head and neck squamous cell carcinomas (HNSCC) are common human malignancies with poor clinical outcomes. The 5-year survival rates for patients with advanced stage HNSCC have not changed appreciably in the past few decades, underscoring a dire need for improved therapeutic options. HNSCC is frequently characterized by overexpression of anti-apoptotic Bcl-2 family members. Increased levels of these anti-apoptotic proteins have been associated with radio- and chemoresistance and poor clinical outcome. The aim of this study was to evaluate combined effects of radiation and ABT-737, a BH3-mimetic molecule, in HNSCC. Although ABT-737, as a single agent, was largely ineffective at promoting HNSCC cell death, we found that combining ABT-737 and radiation induced strong synergistic apoptosis in HNSCC cell lines and delayed tumoral growth in vivo. Moreover, we demonstrated for the first time that ABT-737, alone or in combination with radiation, can efficiently eliminate cancer stem cells (CSCs). Altogether, our results indicate that therapy targeting anti-apoptotic Bcl-2 family members could be a highly effective potential adjuvant to radiotherapy capable of targeting CSCs in HNSCC and therefore overcoming cancer recurrence and metastasis. PMID- 26934443 TI - Exogenous p53 and ASPP2 expression enhances rAdV-TK/ GCV-induced death in hepatocellular carcinoma cells lacking functional p53. AB - Suicide gene therapy using herpes simplex virus-1 thymidine kinase (HSV-TK) in combination with ganciclovir (GCV) has emerged as a potential new method for treating cancer. We hypothesize that the efficacy of HSV-TK/GCV therapy is at least partially dependent on p53 status in hepatocellular carcinoma (HCC) patients. Using recombinant adenoviral vectors (rAdV), TK, p53, and ASPP2 were overexpressed individually and in combination in Hep3B (p53 null) and HepG2 (p53 wild-type) cell lines and in primary HCC tumor cells. p53 overexpression induced death in Hep3B cells, but not HepG2 cells. ASPP2 overexpression increased rAdV TK/GCV-induced HepG2 cell death by interacting with endogenous p53. Similarly, ASPP2 reduced survival in rAdV-TK/GCV-treated primary HCC cells expressing p53 wild-type but not a p53 R249S mutant. Mutated p53 was unable to bind to ASPP2, suggesting that the increase in rAdV-TK/GCV-induced cell death resulting from ASPP2 overexpression was dependent on its interaction with p53. Additionally, gamma-H2AX foci, ATM phosphorylation, Bax, and p21 expression increased in rAdV TK/GCV-treated HepG2 cells as compared to Hep3B cells. This suggests that the combined use of HSV-TK, GCV, rAdV-p53 and rAdV-ASPP2 may improve therapeutic efficacy in HCC patients lacking functional p53. PMID- 26934444 TI - An increase in galectin-3 causes cellular unresponsiveness to IFN-gamma-induced signal transduction and growth inhibition in gastric cancer cells. AB - Glycogen synthase kinase (GSK)-3beta facilitates interferon (IFN)-gamma signaling by inhibiting Src homology-2 domain-containing phosphatase (SHP) 2. Mutated phosphoinositide 3-kinase (PI3K) and phosphatase and tensin homolog (PTEN) cause AKT activation and GSK-3beta inactivation to induce SHP2-activated cellular unresponsiveness to IFN-gamma in human gastric cancer AGS cells. This study investigated the potential role of galectin-3, which acts upstream of AKT/GSK 3beta/SHP2, in gastric cancer cells. Increasing or decreasing galectin-3 altered IFN-gamma signaling. Following cisplatin-induced galectin-3 upregulation, surviving cells showed cellular unresponsiveness to IFN-gamma. Galectin-3 induced IFN-gamma resistance independent of its extracellular beta-galactoside-binding activity. Galectin-3 expression was not regulated by PI3K activation or by a decrease in PTEN. Increased galectin-3 may cause GSK-3beta inactivation and SHP2 activation by promoting PDK1-induced AKT phosphorylation at a threonine residue. Overexpression of AKT, inactive GSK-3betaR96A, SHP2, or active SHP2D61A caused cellular unresponsiveness to IFN-gamma in IFN-gamma-sensitive MKN45 cells. IFN gamma-induced growth inhibition and apoptosis in AGS cells were observed until galectin-3 expression was downregulated. These results demonstrate that an increase in galectin-3 facilitates AKT/GSK-3beta/SHP2 signaling, causing cellular unresponsiveness to IFN-gamma. PMID- 26934445 TI - ER maleate is a novel anticancer agent in oral cancer: implications for cancer therapy. AB - ER maleate [10-(3-Aminopropyl)-3, 4-dimethyl-9(10H)-acridinone maleate] identified in a kinome screen was investigated as a novel anticancer agent for oral squamous cell carcinoma (OSCC). Our aim was to demonstrate its anticancer effects, identify putative molecular targets and determine their clinical relevance and investigate its chemosensitization potential for platinum drugs to aid in OSCC management. Biologic effects of ER maleate were determined using oral cancer cell lines in vitro and oral tumor xenografts in vivo. mRNA profiling, real time PCR and western blot revealed ER maleate modulated the expression of polo-like kinase 1 (PLK1) and spleen tyrosine kinase (Syk). Their clinical significance was determined in oral SCC patients by immunohistochemistry and correlated with prognosis by Kaplan-Meier survival and multivariate Cox regression analyses. ER maleate induced cell apoptosis, inhibited proliferation, colony formation, migration and invasion in oral cancer cells. Imagestream analysis revealed cell cycle arrest in G2/M phase and increased polyploidy, unravelling deregulation of cell division and cell death. Mechanistically, ER maleate decreased expression of PLK1 and Syk, induced cleavage of PARP, caspase9 and caspase3, and increased chemosensitivity to carboplatin; significantly suppressed tumor growth and increased antitumor activity of carboplatin in tumor xenografts. ER maleate treated tumor xenografts showed reduced PLK1 and Syk expression. Clinical investigations revealed overexpression of PLK1 and Syk in oral SCC patients that correlated with disease prognosis. Our in vitro and in vivo findings provide a strong rationale for pre-clinical efficacy of ER maleate as a novel anticancer agent and chemosensitizer of platinum drugs for OSCC. PMID- 26934446 TI - Pancreatic stellate cells contribute pancreatic cancer pain via activation of sHH signaling pathway. AB - Abdominal pain is a critical clinical symptom in pancreatic cancer (PC) that affects the quality of life for PC patients. However, the pathogenesis of PC pain is largely unknown. In this study, we show that PC pain is initiated by the sonic hedgehog (sHH) signaling pathway in pancreatic stellate cells (PSCs), which is activated by sHH secreted from PC cells, and then, neurotrophic factors derived from PSCs mediate the pain. The different culture systems were established in vitro, and the expression of sHH pathway molecules, neurotrophic factors, TRPV1, and pain factors were examined. Capsaicin-evoked TRPV1 currents in dorsal root ganglion (DRG) neurons were examined by the patch-clamp technique. Pain-related behavior was observed in an orthotopic tumor model. sHH and PSCs increased the expression and secretion of TRPV1, SP, and CGRP by inducing NGF and BDNF in a co culture system, also increasing TRPV1 current. But, suppressing sHH pathway or NGF reduced the expression of TRPV1, SP, and CGRP. In vivo, PSCs and PC cells that expressed high levels of sHH could enhance pain behavior. Furthermore, the blockade of NGF or TRPV1 significantly attenuated the pain response to mechanical stimulation compared with the control. Our results demonstrate that sHH signaling pathway is involved in PC pain, and PSCs play an essential role in the process greatly by inducing NGF. PMID- 26934447 TI - Significance of the NOR1-FOXA1/HDAC2-Slug regulatory network in epithelial mesenchymal transition of tumor cells. AB - The epithelial-mesenchymal transition (EMT) process is believed to play a crucial role in nasopharyngeal carcinoma (NPC) progression, a squamous cell carcinoma of the head and neck with the tendency to metastasize early. At present, much attention has been given to the inducer of EMT involved in NPC progression, while antagonists have been less intensively characterized. In this study, unbiased analysis of EMT-associated gene expression patterns was performed using data mining of global gene expression profiles derived from NPC samples, leading to the successful identification of NOR1, FOXA1, and Slug, all of which showed aberrant expression during NPC progression. The effect of tumor suppressor NOR1 on Slug-induced NPC cells during the EMT process was investigated by use of ectopic expression and RNA interference methods. The molecular mechanisms underlying the tumor-suppressing effect of NOR1 on Slug-induced EMT were thought to be dependent on the cooperation of NOR1 with the FOXA1-HDAC2 complex. We also showed that FOXA1 and HDAC2 bind the slug promoter and directly repress its transcription. Our data revealed a previously unrecognized role of the NOR1 FOXA1/HDAC2-Slug network in the regulation of the EMT process and aggressiveness of NPC. PMID- 26934448 TI - Development of a specific affinity-matured exosite inhibitor to MT1-MMP that efficiently inhibits tumor cell invasion in vitro and metastasis in vivo. AB - The membrane-associated matrix metalloproteinase-14, MT1-MMP, has been implicated in pericellular proteolysis with an important role in cellular invasion of collagenous tissues. It is substantially upregulated in various cancers and rheumatoid arthritis, and has been considered as a potential therapeutic target. Here, we report the identification of antibody fragments to MT1-MMP that potently and specifically inhibit its cell surface functions. Lead antibody clones displayed inhibitory activity towards pro-MMP-2 activation, collagen-film degradation and gelatin-film degradation, and were shown to bind to the MT1-MMP catalytic domain outside the active site cleft, inhibiting binding to triple helical collagen. Affinity maturation using CDR3 randomization created a second generation of antibody fragments with dissociation constants down to 0.11 nM, corresponding to an improved affinity of 332-fold with the ability to interfere with cell-surface MT1-MMP functions, displaying IC50 values down to 5 nM. Importantly, the new inhibitors were able to inhibit collagen invasion by tumor cells in vitro and in vivo primary tumor growth and metastasis of MDA-MB-231 cells in a mouse orthotopic xenograft model. Herein is the first demonstration that an inhibitory antibody targeting sites outside the catalytic cleft of MT1 MMP can effectively abrogate its in vivo activity during tumorigenesis and metastasis. PMID- 26934449 TI - Steamed root of Rehmannia glutinosa Libosch (Plantaginaceae) alleviates methotrexate-induced intestinal mucositis in rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Intestinal mucositis induced by chemotherapy is a severe clinical problem in cancer patients that currently lack effective interventions. In traditional Chinese medicine, chemotherapeutic toxicity is diagnosed as Qi and Yin deficiency, and steamed rehmannia root (SRR) is frequently prescribed to these patients. Whether SRR can prevent the adverse effects remains to be confirmed experimentally. The present study used a rat model to investigate potential efficacy and action mechanisms of SRR in attenuating the adverse effects caused by chemotherapy. MATERIALS AND METHODS: Intraperitoneal injection of a single dose of anti-metabolite methotrexate (MTX, 25mg/kg) was given to adult Wistar rats, which also received oral gavage of water or SRR (1.08g/kg twice daily 3 days before and 4 days after MTX treatment), or calcium folinate (CF, a clinically used MTX antidote as a comparison, at 1mg/kg twice daily 36h after MTX treatment), or SRR and CF in combination. Animals were sacrificed 4 days after MTX treatment. Complete blood cell counting was carried out. Jejunum was analyzed histologically for mucosal damage, immunohistochemically for proliferating cell nuclear antigen (PCNA), and biochemically for thiobarbituric acid reactive substances (TBARS) and reduced glutathione (GSH), as well as for tumor necrosis factor alpha (TNF-alpha). RESULTS: MTX treatment led to weight loss, leucopenia, polycythemia, increase in large thrombocyte ratio, intestinal villus atrophy, crypt loss and reduction in PCNA positive crypt cells, increases in mucosal TBARS and TNF-alpha and decrease in GSH. All these alterations were inhibited by SRR administration except leucopenia, and the effects of CF or CF plus SRR supplementation were found to be inferior to those of SRR. CONCLUSIONS: SRR can alleviate MTX-induced gut mucositis, which may be achieved by inhibiting MTX-induced oxidative stress and inflammatory response. These findings support the application of SRR in chemotherapy but not the combined application of SRR and CF. PMID- 26934450 TI - The emerging role of the tubulin code: From the tubulin molecule to neuronal function and disease. AB - Across different cell types and tissues, microtubules are assembled from highly conserved dimers of alpha- and beta-tubulin. Despite their highly similar structures, microtubules have functional heterogeneity, generated either by the expression of different tubulin genes, encoding distinct isotypes, or by posttranslational modifications of tubulin. This genetically encoded and posttranslational generated heterogeneity of tubulin-the "tubulin code"-has the potential to modulate microtubule structure, dynamics, and interactions with associated proteins. The tubulin code is therefore believed to regulate microtubule functions on a cellular and sub-cellular level. This review highlights the importance of the tubulin code for tubulin structure, as well as on microtubule dynamics and functions in neurons. It further summarizes recent developments in the understanding of mutations in tubulin genes, and how they are linked to neurodegenerative and neurodevelopmental disorders. The current advances in the knowledge of the tubulin code on the molecular and the functional level will certainly lead to a better understanding of how complex signaling events control microtubule functions, especially in cells of the nervous system. (c) 2016 Wiley Periodicals, Inc. PMID- 26934451 TI - CHOROIDAL THICKNESS IN PATIENTS WITH CENTRAL SEROUS CHORIORETINOPATHY: Assessment of Haller and Sattler Layers. AB - PURPOSE: To investigate subfoveal choroidal thickness and subanalyze Haller and Sattler layers in eyes with central serous chorioretinopathy (CSC), uninvolved fellow eyes, and eyes of healthy controls using enhanced depth imaging optical coherence tomography. METHODS: Ocular findings and clinical features of 31 eyes with CSC, 24 fellow eyes and eyes of 30 healthy controls were analyzed retrospectively from October, 2014 to March, 2015. Subfoveal choroidal thickness was measured using enhanced depth imaging optical coherence tomography, and the thicknesses of Haller and Sattler layers were analyzed. RESULTS: Mean subfoveal choroidal thickness and mean thickness of Haller layer were significantly greater in CSC than in fellow eyes (P = 0.043 and P = 0.036, respectively) and in normal control eyes (P < 0.001 each), and those of fellow eyes in CSC patients were significantly thicker than those in normal control eyes (P = 0.018 and P = 0.017, respectively). The thickness of Sattler layer did not differ significantly among these groups (P = 0.519). CONCLUSION: Subfoveal choroidal thickness and the thickness of Haller layer were increased not only in affected but also in uninvolved fellow eyes of CSC patients. Nonvascular smooth muscle cells of the choroid may play a role in the pathophysiology of CSC, in response to increased sympathetic tone. PMID- 26934452 TI - PREDICTION OF MORPHOLOGIC DETERIORATION IN PATIENTS WITH LAMELLAR MACULAR HOLES. AB - PURPOSE: To analyze the morphologic evolution of idiopathic lamellar macular holes (LMHs) as determined by spectral domain optical coherence tomography, and evaluate the utility of retinal function assessments through multifocal electroretinography for predicting the likelihood of morphologic deterioration in LMHs. METHODS: Twenty-eight eyes of 28 patients with LMHs were examined by spectral domain optical coherence tomography at the initial visit and after 12 months. Lamellar macular holes were subdivided into morphologic deterioration (DET) and morphologic maintenance (MAI) groups based on the change in central retinal thickness during the follow-up period. Patients with LMHs were also examined by multifocal electroretinography at the initial visit. Multifocal electroretinography amplitudes were compared between DET and MAI groups, and discriminant function was calculated to predict morphologic deterioration in LMH eyes. RESULTS: During the follow-up period, morphologic deterioration was found in 8 (28.6%) of LMH cases. On multifocal electroretinography, amplitudes in the central ring (R1) and first paracentral ring (R2) were significantly lower in the DET than in the MAI group. Discriminant analysis performed on these two variables yielded a discriminant function with 75% of cases classified correctly. CONCLUSION: Multifocal electroretinography is a useful tool for predicting morphologic deterioration of LMHs. Lower multifocal electroretinography amplitudes in R1 and R2 predict an increased risk of subsequent deterioration. PMID- 26934453 TI - EPIRETINAL MEMBRANE-INDUCED FULL-THICKNESS MACULAR HOLES: The Clinical Features and Surgical Outcomes. AB - PURPOSE: To investigate the clinical features and surgical outcomes in patients with epiretinal membrane-induced full-thickness macular holes (FTMHs). METHODS: Consecutive cases with epiretinal membrane-induced FTMH followed by a single surgeon were retrospectively reviewed (study group, 24 cases). The criteria of epiretinal membrane-induced FTMH selection were 1) documented lamellar macular hole before FTMH formation, 2) FTMH with lamellar hole-associated epiretinal proliferation at the hole edge, and 3) FTMH with wider inner opening and narrower base. Consecutively treated Stage 2 (Control A, 20 cases) and Stage 4 (Control B, 22 cases) MH patients served as controls. All patients were followed up for at least 12 months after treatment. RESULTS: Patients in the study group were younger and had a higher rate of high myopia than Controls A and B. The average hole size (203.6 +/- 104.9 MUm) was similar to that in Control A group and smaller than that in Control B group; the postoperative visual improvement (2-3 lines in Early Treatment Diabetic Retinopathy Study) was lower than that in Control A and B groups. Similar results were found when excluding high myopia cases from the study group. CONCLUSION: Epiretinal membrane-induced FTMH has distinct features from the typical Stage 2 or 4 FTMH. Despite the small size, visual improvement is not as good as that in Stage 2 FTMH. PMID- 26934454 TI - Effectiveness of tacrolimus in comparison with methotrexate or biologics in propensity score-matched patients with rheumatoid arthritis. AB - OBJECTIVE: To analyze the effectiveness of tacrolimus (TAC) in comparison with methotrexate (MTX) or biologics in propensity score (PS)-matched rheumatoid arthritis (RA) patients. METHODS: RA patients with moderate or high disease activity as defined by the 28-joint disease activity score (DAS28) and who had completed at least two successive biannual RA cohort surveys were analyzed. Patients were assigned in a stepwise fashion to one of four groups (Biologics, MTX, TAC, or Control) according to medication changes during a 6-month period. A PS was generated for each of three conditions (Biologics, MTX or Control group versus the TAC group, respectively), followed by the assignment of PS-matched patients. At 1 year, the DAS28 in each treatment versus TAC group was analyzed using a mixed effect model with repeated measures. RESULTS: Compared with the respective PS-matched TAC group, the difference in DAS28 at 1 year was -0.398 [95% confidence interval (CI) - 0.660 to -0.136, p < 0.005] in the Biologics group (N = 120), -0.045 (95% CI -0.222 to 0.133, p = 0.622) in the MTX group (N = 465), and 0.182 (95% CI 0.010 to 0.353, p < 0.05) in the Control group (N = 462). CONCLUSION: TAC may provide a potential therapeutic option for RA patients with moderate to high disease activity. PMID- 26934455 TI - Rhodium(II)-Catalyzed and Thermally Induced Intramolecular Migration of N Sulfonyl-1,2,3-triazoles: New Approaches to 1,2-Dihydroisoquinolines and 1 Indanones. AB - New rhodium(II)-catalyzed or thermally induced intramolecular alkoxy group migration of N-sulfonyl-1,2,3-triazoles has been developed, affording divergent synthesis of 1,2-dihydroisoquinoline and 1-indanone derivatives according to different conditions. N-Sulfonyl keteneimine is the key intermediate for the synthesis of dihydroisoquinoline, whereas the aza-vinyl carbene intermediate results in the formation of 1-indanone. PMID- 26934456 TI - Nurse practitioners & genetic counselors: Collaborative roles in a complex system. AB - In the United States, the lifetime risk of cancer is approximately 50% for men and 33% for women. Approximately 10% of these individuals have an inherited predisposition and substantially increased cancer risk. This article discusses an approach to identifying and managing patients based on a high-risk breast clinic model. PMID- 26934457 TI - Perinatal depression: A clinical update. AB - Perinatal depression is a common condition with significant adverse maternal, fetal, neonatal, and early childhood outcomes. The perinatal period is an opportune time to screen, diagnose, and treat depression. Improved recognition of perinatal depression, particularly among low-income women, can lead to improved perinatal health outcomes. PMID- 26934458 TI - A technical note regarding hemorrhoid banding. PMID- 26934459 TI - Erratum. PMID- 26934460 TI - Corrigendum. PMID- 26934461 TI - Inhibitor Response to HER2 G776(YVMA) In-frame Insertion in HER2-positive Breast Cancer. AB - Human epidermal growth factor receptor 2 (HER2/neu or HER2) has long been recognized as an attractive therapeutic target for breast cancer. The YVMA in frame insertion at the residue G776 (G776(YVMA)) of HER2 kinase domain is a frequently observed mutation that can largely shift drug sensitivity in targeted therapy of HER2-positive breast cancer. Here, the molecular mechanism and biological significance of tyrosine kinase inhibitor (TKI) response to HER2 G776(YVMA) insertion were investigated in detail. An established protocol that integrated bioinformatics modeling and kinase inhibition assay was employed to examine the structural basis, energetic property, and biological implication underlying the intermolecular interaction between HER2 kinase domain and three representative TKIs, i.e. two FDA-approved drugs lapatinib and gefitinib as well as a pan-kinase inhibitor staurosporine. It was found that the insertion mutation can moderately sensitize lapatinib, but cannot influence the inhibitory capability of staurosporine essentially, suggesting that the two inhibitors exhibit differentiated selectivity between the wild-type HER2 (HER2(WT)) and HER2 G776(YVMA) (HER2(YVMA)) variant. In addition, the gefitinib, which was originally developed as EGFR inhibitor, only possesses modest potency against its noncogate target HER2(WT), and the insertion can further impair the potency, causing a strong resistance for the agent to HER2(YVMA) variant. PMID- 26934462 TI - The Caenorhabditis elegans Q neuroblasts: A powerful system to study cell migration at single-cell resolution in vivo. AB - During development, cell migration plays a central role in the formation of tissues and organs. Understanding the molecular mechanisms that drive and control these migrations is a key challenge in developmental biology that will provide important insights into disease processes, including cancer cell metastasis. In this article, we discuss the Caenorhabditis elegans Q neuroblasts and their descendants as a tool to study cell migration at single-cell resolution in vivo. The highly stereotypical migration of these cells provides a powerful system to study the dynamic cytoskeletal processes that drive migration as well as the evolutionarily conserved signaling pathways (including different Wnt signaling cascades) that guide the cells along their specific trajectories. Here, we provide an overview of what is currently known about Q neuroblast migration and highlight the live-cell imaging, genome editing, and quantitative gene expression techniques that have been developed to study this process. PMID- 26934464 TI - A Convenient Palladium-Catalyzed Reductive Carbonylation of Aryl Iodides with Dual Role of Formic Acid. AB - Palladium-catalyzed reductive carbonylation of aryl halides represents a straightforward pathway for the synthesis of aromatic aldehydes. The known reductive carbonylation procedures either require CO gas or complexed compounds as CO sources. In this communication, we developed a palladium-catalyzed reductive carbonylation of aryl iodides with formic acid as the formyl source. As a convenient, practical, and environmental friendly methodology, no additional silane or H2 was required. A variety of aromatic aldehydes were isolated in moderate to excellent yields under mild reaction conditions. Notably, this is the first procedure on using formic acid as the formyl source. PMID- 26934463 TI - Platelets: No longer bystanders in liver disease. AB - : Growing lines of evidence recognize that platelets play a central role in liver homeostasis and pathobiology. Platelets have important roles at every stage during the continuum of liver injury and healing. These cells contribute to the initiation of liver inflammation by promoting leukocyte recruitment through sinusoidal endothelium. They can activate effector cells, thus amplifying liver damage, and by modifying the hepatic cellular and cytokine milieu drive both hepatoprotective and hepatotoxic processes. CONCLUSION: In this review we summarize how platelets drive such pleiotropic actions and attempt to reconcile the paradox of platelets being both deleterious and beneficial to liver function; with increasingly novel methods of manipulating platelet function at our disposal, we highlight avenues for future therapeutic intervention in liver disease. (Hepatology 2016;64:1774-1784). PMID- 26934466 TI - Endometrial Adenocarcinoma in SurePathTM Cervical Samples: Cytological Features Revisited. AB - OBJECTIVE: The cytomorphological criteria of malignant endometrial lesions in cervical samples are less well described than those of cervical lesions. We wished to investigate if there were features in SurePathTM liquid-based cytology samples that would facilitate more accurate differentiation between benign and malignant endometrial cells. STUDY DESIGN: This was a two-phase study, with a review of all SurePathTM samples reported as endometrial adenocarcinoma (n = 42) evaluating 12 cytological features in the first phase. In phase 2 (test set), all initial cases plus an additional 83 cases were reviewed using these 12 cytological features to predict the outcome. RESULTS: Out of 12 cytological features evaluated in phase 1 (training set), nuclear chromatin pattern, apoptotic bodies and tingible body macrophages were found to be the most significant features determining malignant histological outcome. These 12 cytological features were re-evaluated in phase 2 (n = 125). Of 125 cases, 54 had a benign and 71 had a malignant or premalignant histological outcome, with a positive predictive value of 56.8%. CONCLUSION: Granular nuclear chromatin, tingible body macrophages and apoptosis in the background are the most significant factors in determining whether endometrial cells present in cervical samples represent malignancy or are benign. Using these features, relatively accurate predictions of endometrial pathology can be made. PMID- 26934465 TI - Mathematical Modelling of a Brain Tumour Initiation and Early Development: A Coupled Model of Glioblastoma Growth, Pre-Existing Vessel Co-Option, Angiogenesis and Blood Perfusion. AB - We propose a coupled mathematical modelling system to investigate glioblastoma growth in response to dynamic changes in chemical and haemodynamic microenvironments caused by pre-existing vessel co-option, remodelling, collapse and angiogenesis. A typical tree-like architecture network with different orders for vessel diameter is designed to model pre-existing vasculature in host tissue. The chemical substances including oxygen, vascular endothelial growth factor, extra-cellular matrix and matrix degradation enzymes are calculated based on the haemodynamic environment which is obtained by coupled modelling of intravascular blood flow with interstitial fluid flow. The haemodynamic changes, including vessel diameter and permeability, are introduced to reflect a series of pathological characteristics of abnormal tumour vessels including vessel dilation, leakage, angiogenesis, regression and collapse. Migrating cells are included as a new phenotype to describe the migration behaviour of malignant tumour cells. The simulation focuses on the avascular phase of tumour development and stops at an early phase of angiogenesis. The model is able to demonstrate the main features of glioblastoma growth in this phase such as the formation of pseudopalisades, cell migration along the host vessels, the pre-existing vasculature co-option, angiogenesis and remodelling. The model also enables us to examine the influence of initial conditions and local environment on the early phase of glioblastoma growth. PMID- 26934469 TI - Targeting blockage of STAT3 inhibits hepatitis B virus-related hepatocellular carcinoma. AB - Hepatitis B virus (HBV) infection is a significant cause of liver disease pathogenesis, which results in the development of hepatic dysfunction, cirrhosis and hepatocellular carcinoma (HCC). Our previous studies showed that oncogene STAT3 might be an ideal target for HCC therapy. Here, we investigated whether targeting blockage of STAT3 signaling is efficient for HBV-related HCC. Based on the refractory of HCC and the persistence of HBV, in this study, we designed shRNAs targeting STAT3. The results showed that blocking STAT3 signaling by shRNAs could promote HBV positive HCC cell apoptosis and induce cell cycle arrest, resulting in HCC cell growth inhibition in vitro. Importantly, STAT3 shRNAs efficiently suppressed HBV replication, which would reduce HBV-derived stimulation to STAT3 signaling and augment STAT3-shRNAs-mediated anti-HCC effect. Finally, STAT3-shRNAs-mediated anti-HBV positive HCC effect was confirmed in xenograft nude mice. This study suggested that targeting STAT3 therapies such as STAT3-shRNAs may be an efficacious strategy for HBV-related HCC. PMID- 26934470 TI - Defining appropriateness criteria for endoscopic sinus surgery during management of uncomplicated adult chronic rhinosinusitis: a RAND/UCLA appropriateness study. AB - INTRODUCTION: Appropriate indications for endoscopic sinus surgery (ESS) for chronic rhinosinusitis (CRS) are currently poorly defined. The lack of clear surgical indications for ESS likely contributes to the large geographic variation in surgical rates and contributes to reduced quality of care. The objective of this study was to define appropriateness criteria for ESS during management of adult patients with uncomplicated CRS. METHODS: The RAND/UCLA appropriateness methodology was performed. An international, multi-disciplinary panel of 10 experts in CRS was formed and completed two rounds of a modified Delphi ranking process along with a face-to-face meeting. RESULTS: A total of 624 clinical scenarios were ranked, 312 scenarios each for CRS with and CRS without nasal polyps. For adult patients with uncomplicated CRS with nasal polyps, ESS can be appropriately offered when the CT Lund-Mackay score is >= 1 and there has been a minimum trial of a topical intranasal corticosteroid plus a short-course of systemic corticosteroid with a post-treatment total SNOT-22 score >= 20. For adult patients with uncomplicated CRS without nasal polyps, ESS can be appropriately offered when the CT Lund-Mackay score is >= 1 and there has been a minimum trial of a topical intranasal corticosteroid plus either a short-course of a broad spectrum/culture-directed systemic antibiotic or the use of a prolonged course of systemic low-dose anti-inflammatory antibiotic with a post treatment total SNOT-22 score >= 20. CONCLUSION: This study has developed and reported of list of appropriateness criteria to offer ESS as a treatment option during management of uncomplicated adult CRS. The extent or technique of ESS was not addressed in this study and will depend on surgeon and patient factors. Furthermore, these criteria are the minimal threshold to make ESS a treatment option and do not imply that all patients meeting these criteria require surgery. The decision to perform ESS should be made after an informed patient makes a preference-sensitive decision to proceed with surgery. Applying these appropriateness criteria for ESS may optimize patient selection, reduce the incidence of unwarranted surgery, and assist clinicians in providing high quality, patient-centered care to patients with CRS. PMID- 26934468 TI - Quantitative Detection of Nucleoside Analogues by Multi-enzyme Biosensors using Time-Resolved Kinetic Measurements. AB - Fast, simple and cost-effective methods for detecting and quantifying pharmaceutical agents in patients are highly sought after to replace equipment and labor-intensive analytical procedures. The development of new diagnostic technology including portable detection devices also enables point-of-care by non specialists in resource-limited environments. We have focused on the detection and dose monitoring of nucleoside analogues used in viral and cancer therapies. Using deoxyribonucleoside kinases (dNKs) as biosensors, our chemometric model compares observed time-resolved kinetics of unknown analytes to known substrate interactions across multiple enzymes. The resulting dataset can simultaneously identify and quantify multiple nucleosides and nucleoside analogues in complex sample mixtures. PMID- 26934471 TI - Tumour angiogenesis-Origin of blood vessels. AB - The conventional view of tumour vascularization is that tumours acquire their blood supply from neighbouring normal stroma. Additional methods of tumour vascularization such as intussusceptive angiogenesis, vasculogenic mimicry, vessel co-option and vasculogenesis have been demonstrated to occur. However, the origin of the endothelial cells and pericytes in the tumour vasculature is not fully understood. Their origin from malignant cells has been shown indirectly in lymphoma and neuroblastoma by immuno-FISH experiments. It is now evident that tumours arise from a small population of cells called cancer stem cells (CSCs) or tumour initiating cells. Recent data suggest that a proportion of tumour endothelial cells arise from cancer stem cells in glioblastoma. This was demonstrated both in vitro and in vivo. The analysis of chromosomal abnormalities in endothelial cells showed identical genetic changes to those identified in tumour cells. However, another report contradicted these results from the earlier studies in glioblastoma and had shown that CSCs give rise to pericytes and not endothelial cells. The main thrust of this review is the critical analysis of the conflicting data from different studies and the remaining questions in this field of research. The mechanism by which this phenomenon occurs is also discussed in detail. The transdifferentiation of CSCs to endothelial cells/pericytes has many implications in the progression and metastasis of the tumours and hence it would be a novel target for antiangiogenic therapy. PMID- 26934472 TI - EspP, an Extracellular Serine Protease from Enterohemorrhagic E. coli, Reduces Coagulation Factor Activities, Reduces Clot Strength, and Promotes Clot Lysis. AB - BACKGROUND: EspP (E. coli secreted serine protease, large plasmid encoded) is an extracellular serine protease produced by enterohemorrhagic E. coli (EHEC) O157:H7, a causative agent of diarrhea-associated Hemolytic Uremic Syndrome (D+HUS). The mechanism by which EHEC induces D+HUS has not been fully elucidated. OBJECTIVES: We investigated the effects of EspP on clot formation and lysis in human blood. METHODS: Human whole blood and plasma were incubated with EspP(WT )at various concentrations and sampled at various time points. Thrombin time (TT), prothrombin time (PT), and activated partial thromboplastin time (aPTT), coagulation factor activities, and thrombelastgraphy (TEG) were measured. RESULTS AND CONCLUSIONS: Human whole blood or plasma incubated with EspP(WT) was found to have prolonged PT, aPTT, and TT. Furthermore, human whole blood or plasma incubated with EspP(WT) had reduced activities of coagulation factors V, VII, VIII, and XII, as well as prothrombin. EspP did not alter the activities of coagulation factors IX, X, or XI. When analyzed by whole blood TEG, EspP decreased the maximum amplitude of the clot, and increased the clot lysis. Our results indicate that EspP alters hemostasis in vitro by decreasing the activities of coagulation factors V, VII, VIII, and XII, and of prothrombin, by reducing the clot strength and accelerating fibrinolysis, and provide further evidence of a functional role for this protease in the virulence of EHEC and the development of D+HUS. PMID- 26934474 TI - Harnessing the Electrophilicity of Keteniminium Ions: A Simple and Straightforward Entry to Tetrahydropyridines and Piperidines from Ynamides. AB - An efficient, modular and straightforward entry to tetrahydropyridines and piperidines is reported. This reaction is based on a formal intramolecular hydroalkylation of readily available, properly substituted ynamides which, upon simple activation under acidic conditions, generate highly reactive activated keteniminium ions whose reactivity can be finely controlled to induce a remarkably efficient [1,5]-hydride shift from unactivated C-H bonds and trigger a cationic cyclization which is complete within minutes. PMID- 26934473 TI - Spatial and Temporal Variations in the Occurrence and Foraging Activity of Coastal Dolphins in Menai Bay, Zanzibar, Tanzania. AB - Understanding temporal patterns in distribution, occurrence and behaviour is vital for the effective conservation of cetaceans. This study used cetacean click detectors (C-PODs) to investigate spatial and temporal variation in occurrence and foraging activity of the Indo-Pacific bottlenose (Tursiops aduncus) and Indian Ocean humpback (Sousa plumbea) dolphins resident in the Menai Bay Conservation Area (MBCA), Zanzibar, Tanzania. Occurrence was measured using detection positive minutes. Inter-click intervals were used to identify terminal buzz vocalisations, allowing for analysis of foraging activity. Data were analysed in relation to spatial (location) and temporal (monsoon season, diel phase and tidal phase) variables. Results showed significantly increased occurrence and foraging activity of dolphins in southern areas and during hours of darkness. Higher occurrence at night was not explained by diel variation in echolocation rate and so were considered representative of occurrence patterns. Both tidal phase and monsoon season influenced occurrence but results varied among sites, with no general patterns found. Foraging activity was greatest during hours of darkness, High water and Flood tidal phases. Comparisons of echolocation data among sites suggested differences in the broadband click spectra of MBCA dolphins, possibly indicative of species differences. These dolphin populations are threatened by unsustainable fisheries bycatch and tourism activities. The spatial and temporal patterns identified in this study have implications for future conservation and management actions with regards to these two threats. Further, the results indicate future potential for using passive acoustics to identify and monitor the occurrence of these two species in areas where they co-exist. PMID- 26934475 TI - Subclinical hypothyroidism and the risk of metabolic syndrome: A meta-analysis of observational studies. AB - BACKGROUND: Observational studies on the association between subclinical hypothyroidism (SCH) and metabolic syndrome (MetS) have produced inconsistent results. Therefore, we performed a meta-analysis to evaluate the effect of SCH on the risk of MetS. METHODS: Multiple databases were searched to identify studies on the association between SCH and the risk of MetS, up to February 2015. Relevant information for analysis was extracted. A random-effects model was used to calculate the pooled risk estimates. RESULTS: 9 studies (7 cross-sectional and 2 case-control studies) were included. The pooled odds ratio (OR) for MetS comparing SCH with euthyroid subjects was 1.31 (95%CI: 1.08 to 1.60, p = 0.006, I(2) = 50%). Subgroup analyses by countries revealed a significant association for the studies from Asian (OR = 1.244, 95% CI: 1.030-1.503, I(2) = 25%) other than non-Asian (OR = 1.548, 95% CI: 0.925-2.591, I(2) = 73.5%) countries. A positive association was identified in the IDF subgroup (OR = 1.288, 95% CI: 1.055-1.572, I(2) = 0%), but not in the NCEP-ATP III (OR = 1.351, 95% CI: 0.950 1.923, I(2) = 66.4%), Chinese (OR = 1.430, 95% CI: 0.891-2.294) and Japanese (OR = 1.542, 95% CI: 0.594-4.005, I(2) = 78.3%) subgroup. A certain degree of heterogeneity was observed among studies which cannot be explained by study design, diagnostic criteria and location. CONCLUSION: Our results demonstrated that SCH was significantly associated with a higher risk of MetS. Well-designed cohort studies were warranted to confirm our findings. PMID- 26934476 TI - Protective effect of rhEPO on tight junctions of cerebral microvascular endothelial cells early following traumatic brain injury in rats. AB - OBJECTIVE: The goal of this study was to investigate the protective effect of recombinant human EPO(rhEPO) on cerebral microvascular endothelial cells and the mechanisms by which rhEPO interacts with TJs proteins, claudin-5, Occludin and ZO 1 during the early period following traumatic brain injury. RESEARCH DESIGN: Rats (n = 81) were randomly divided into sham-operated group, TBI group and rhEPO+TBI group. Traumatic brain injury was induced by the Marmarou method. METHODS AND PROCEDURES: Rats were killed at 3, 24, 72 and 168 hours after TBI. The integrity of the blood-brain barrier was investigated by using a spectrophotometer to assess extravasation of Evans blue dye. The expression of Claudin-5, Occludin and ZO-1 were determined by immunohistochemistry and real-time fluorescence quantitative PCR. RESULTS: From 3 hours to 3 days, rats in the TBI group demonstrated a remarkable increase in Evans blue content in the brain, relative to rats in the sham-operated group (p < 0.05). The expression of Claudin-5 and Occludin was significantly lower than those in the sham-operated group (p < 0.05). In contrast, rats in the TBI+rhEPO group demonstrated a significant decrease in brain levels. CONCLUSION: It was found that administration of rhEPO protected cerebral microvascular endothelial cells and reduced permeability of BBB and the mechanisms may be due to increasing the expression of TJs proteins. PMID- 26934477 TI - Spiral and Rotor Patterns Produced by Fairy Ring Fungi. AB - A broad class of soil fungi form the annular patterns known as 'fairy rings' and provide one of the only means to observe spatio-temporal dynamics of otherwise cryptic fungal growth processes in natural environments. We present observations of novel spiral and rotor patterns produced by fairy ring fungi and explain these behaviors mathematically by first showing that a well known model of fairy ring fungal growth and the Gray-Scott reaction-diffusion model are mathematically equivalent. We then use bifurcation analysis and numerical simulations to identify the conditions under which spiral waves and rotors can arise. We demonstrate that the region of dimensionless parameter space supporting these more complex dynamics is adjacent to that which produces the more familiar fairy rings, and identify experimental manipulations to test the transitions between these spatial modes. These same manipulations could also feasibly induce fungal colonies to transition from rotor/spiral formation to a set of richer, as yet unobserved, spatial patterns. PMID- 26934479 TI - Cognitive trait anxiety, stress and effort interact to predict inhibitory control. AB - Few studies have focussed on the link between anxiety and inhibitory control in the absence of stimulus-driven external threat. This two-part experiment examined the interactions between (1) somatic trait anxiety, somatic situational stress (i.e. threat of electric shock), and effort, and (2) cognitive trait anxiety, cognitive situational stress (i.e. ego-threat instructions), and effort, on inhibitory processes using a Go-No-Go paradigm. Trait anxiety was operationalised using questionnaire scores and effort was operationalised using a visual analogue scale. Performance effectiveness was measured using the d' parameter from signal detection theory and processing efficiency was indexed by the ratio of d' to response time on correct trials. Results indicated that somatic trait anxiety and stress did not predict effectiveness or efficiency. Cognitive trait anxiety and stress were associated with both inhibitory effectiveness and efficiency deficits; however, contrary to expectations these deficits were evident at higher rather than lower mental effort. Results suggest a distinction between how somatic and cognitive anxiety manifest on tasks involving inhibitory control. PMID- 26934478 TI - Synergistic stress exacerbation in hippocampal neurons: Evidence favoring the dual-hit hypothesis of neurodegeneration. AB - The dual-hit hypothesis of neurodegeneration states that severe stress sensitizes vulnerable cells to subsequent challenges so that the two hits are synergistic in their toxic effects. Although the hippocampus is vulnerable to a number of neurodegenerative disorders, there are no models of synergistic cell death in hippocampal neurons in response to combined proteotoxic and oxidative stressors, the two major characteristics of these diseases. Therefore, a relatively high throughput dual-hit model of stress synergy was developed in primary hippocampal neurons. In order to increase the rigor of the study and strengthen the interpretations, three independent, unbiased viability assays were employed at multiple timepoints. Stress synergy was elicited when hippocampal neurons were treated with the proteasome inhibitor MG132 followed by exposure to the oxidative toxicant paraquat, but only after 48 h. MG132 and paraquat only elicited additive effects 24 h after the final hit and even loss of heat shock protein 70 activity and glutathione did not promote stress synergy at this early timepoint. Dual hits of MG132 elicited modest glutathione loss and slightly synergistic toxic effects 48 h after the second hit, but only at some concentrations and only according to two viability assays (metabolic fitness and cytoskeletal integrity). The thiol N acetyl cysteine protected hippocampal neurons against dual MG132/MG132 hits but not dual MG132/paraquat hits. These findings support the view that proteotoxic and oxidative stress propel and propagate each other in hippocampal neurons, leading to synergistically toxic effects, but not as the default response and only after a delay. The neuronal stress synergy observed here lies in contrast to astrocytic responses to dual hits, because astrocytes that survive severe proteotoxic stress resist additional cell loss following second hits. In conclusion, a new model of hippocampal vulnerability was developed for the testing of therapies, because neuroprotective treatments that are effective against severe, synergistic stress are more likely to succeed in the clinic. (c) 2016 Wiley Periodicals, Inc. PMID- 26934480 TI - Effects of UCP4 on the Proliferation and Apoptosis of Chondrocytes: Its Possible Involvement and Regulation in Osteoarthritis. AB - Reactive oxygen species (ROS)-induced chondrocytes apoptosis plays a key role in osteoarthritis (OA) pathogenesis. Uncoupling protein 4 (UCP4) can protect cells against oxidative stress via reducing ROS production and cell apoptosis. Here, silencing of UCP4 in primary chondrocytes significantly inhibited cell survival, but induced ROS production and cell apoptosis. UCP4 mRNA of cartilage tissues was decreased in osteoarthritis patients, which was negatively correlated with synovial fluid (SF) leptin concentration. Moreover, leptin treatment (5, 10 and 20 ng/ml) of primary cultured chondrocytes significantly decreased mRNA and protein levels of UCP4, but increased ROS production and cell apoptosis in a dose dependent manner. The effects of leptin treatment (20 ng/ml) on chondrocytes was partially reversed by ectopic expression of UCP4. More importantly, intraarticularly injection of UCP4 adenovirus remarkably alleviate OA progression and cell apoptosis in a rat OA model induced by anterior cruciate ligament transection (ACLT). In conclusion, UCP4, whose expression was suppressed by leptin, may be involved in the ROS production and apoptosis of chondrocytes, thus contributing to the OA pathogenesis. PMID- 26934482 TI - Differential Response and Priming Dose Effect on the Proteome of Human Fibroblast and Stem Cells Induced by Exposure to Low Doses of Ionizing Radiation. AB - It has been suggested that a mechanistic understanding of the cellular responses to low dose and dose rate may be valuable in reducing some of the uncertainties involved in current risk estimates for cancer- and non-cancer-related radiation effects that are inherited in the linear no-threshold hypothesis. In this study, the effects of low-dose radiation on the proteome in both human fibroblasts and stem cells were investigated. Particular emphasis was placed on examining: 1. the dose-response relationships for the differential expression of proteins in the low-dose range (40-140 mGy) of low-linear energy transfer (LET) radiation; and 2. the effect on differential expression of proteins of a priming dose given prior to a challenge dose (adaptive response effects). These studies were performed on cultured human fibroblasts (VH10) and human adipose-derived stem cells (ADSC). The results from the VH10 cell experiments demonstrated that low-doses of low-LET radiation induced unique patterns of differentially expressed proteins for each dose investigated. In addition, a low priming radiation dose significantly changed the protein expression induced by the subsequent challenge exposure. In the ADSC the number of differentially expressed proteins was markedly less compared to VH10 cells, indicating that ADSC differ in their intrinsic response to low doses of radiation. The proteomic results are further discussed in terms of possible pathways influenced by low-dose irradiation. PMID- 26934481 TI - Uncovering the Ancestry of B Chromosomes in Moenkhausia sanctaefilomenae (Teleostei, Characidae). AB - B chromosomes constitute a heterogeneous mixture of genomic parasites that are sometimes derived intraspecifically from the standard genome of the host species, but result from interspecific hybridization in other cases. The mode of origin determines the DNA content, with the B chromosomes showing high similarity with the A genome in the first case, but presenting higher similarity with a different species in the second. The characid fish Moenkhausia sanctaefilomenae harbours highly invasive B chromosomes, which are present in all populations analyzed to date in the Parana and Tiete rivers. To investigate the origin of these B chromosomes, we analyzed two natural populations: one carrying B chromosomes and the other lacking them, using a combination of molecular cytogenetic techniques, nucleotide sequence analysis and high-throughput sequencing (Illumina HiSeq2000). Our results showed that i) B chromosomes have not yet reached the Paranapanema River basin; ii) B chromosomes are mitotically unstable; iii) there are two types of B chromosomes, the most frequent of which is lightly C-banded (similar to euchromatin in A chromosomes) (B1), while the other is darkly C-banded (heterochromatin-like) (B2); iv) the two B types contain the same tandem repeat DNA sequences (18S ribosomal DNA, H3 histone genes, MS3 and MS7 satellite DNA), with a higher content of 18S rDNA in the heterochromatic variant; v) all of these repetitive DNAs are present together only in the paracentromeric region of autosome pair no. 6, suggesting that the B chromosomes are derived from this A chromosome; vi) the two B chromosome variants show MS3 sequences that are highly divergent from each other and from the 0B genome, although the B2-derived sequences exhibit higher similarity with the 0B genome (this suggests an independent origin of the two B variants, with the less frequent, B2 type presumably being younger); and vii) the dN/dS ratio for the H3.2 histone gene is almost 4-6 times higher for B chromosomes than for A chromosome sequences, suggesting that purifying selection is relaxed for the DNA sequences located on the B chromosomes, presumably because they are mostly inactive. PMID- 26934483 TI - Clinically Relevant Doses of Enalapril Mitigate Multiple Organ Radiation Injury. AB - Angiotensin-converting enzyme inhibitors (ACEi) are effective mitigators of radiation nephropathy. To date, their experimental use has been in fixed-dose regimens. In clinical use, doses of ACEi and other medication may be escalated to achieve greater benefit. We therefore used a rodent model to test the ACEi enalapril as a mitigator of radiation injury in an escalating-dose regimen. Single-fraction partial-body irradiation (PBI) with one hind limb out of the radiation field was used to model accidental or belligerent radiation exposures. PBI doses of 12.5, 12.75 and 13 Gy were used to establish multi-organ injury. One third of the rats underwent PBI alone, and two thirds of the rats had enalapril started five days after PBI at a dose of 30 mg/l in the drinking water. When there was established azotemic renal injury enalapril was escalated to a 60 mg/l dose in half of the animals and then later to a 120 mg/l dose. Irradiated rats on enalapril had significant mitigation of combined pulmonary and renal morbidity and had significantly less azotemia. Dose escalation of enalapril did not significantly improve outcomes compared to fixed-dose enalapril. The current data support use of the ACEi enalapril at a fixed and clinically usable dose to mitigate radiation injury after partial-body radiation exposure. PMID- 26934484 TI - Stunted at 10 Years. Linear Growth Trajectories and Stunting from Birth to Pre Adolescence in a Rural Bangladeshi Cohort. AB - BACKGROUND: Few studies in low-income settings analyse linear growth trajectories from foetal life to pre-adolescence. The aim of this study is to describe linear growth and stunting from birth to 10 years in rural Bangladesh and to analyse whether maternal and environmental determinants at conception are associated with linear growth throughout childhood and stunting at 10 years. METHODS AND FINDINGS: Pregnant women participating in the MINIMat trial were identified in early pregnancy and a birth cohort (n = 1054) was followed with 19 growth measurements from birth to 10 years. Analyses of baseline predictors and mean height-for-age Z-scores (HAZ) over time were modelled using GLMM. Logistic regression analysis was used to investigate the associations between baseline predictors and stunting (HAZ<-2) at 10 years. HAZ decreased to 2 years, followed by an increase up to 10 years, while the average height-for-age difference in cm (HAD) to the WHO reference median continued to increase up to 10 years. Prevalence of stunting was highest at 2 years (50%) decreasing to 29% at 10 years. Maternal height, maternal educational level and season of conception were all independent predictors of HAZ from birth to pre-adolescence (p<0.001) and stunting at 10 years. The highest probability to be stunted at 10 years was for children born by short mothers (<147.5 cm) (ORadj 2.93, 95% CI: 2.06-4.20), mothers with no education (ORadj 1.74, 95% CI 1.17-2.81) or those conceived in the pre-monsoon season (ORadj 1.94, 95% CI 1.37-2.77). CONCLUSIONS: Height growth trajectories and prevalence of stunting in pre-adolescence showed strong intergenerational associations, social differentials, and environmental influence from foetal life. Targeting women before and during pregnancy is needed for the prevention of impaired child growth. PMID- 26934485 TI - Investing in Health Innovation: A Cornerstone to Achieving Global Health Convergence. PMID- 26934486 TI - Editorial comment to "Risk factors predicting upper urinary tract deterioration in patients with spinal cord injury: A retrospective study". PMID- 26934487 TI - The Effectiveness of Eye Movement Desensitization and Reprocessing Therapy to Treat Symptoms Following Trauma in Timor Leste. AB - The effectiveness of eye movement desensitization and reprocessing (EMDR) therapy for treating trauma symptoms was examined in a postwar/conflict, developing nation, Timor Leste. Participants were 21 Timorese adults with symptoms of posttraumatic stress disorder (PTSD), assessed as those who scored >=2 on the Harvard Trauma Questionnaire (HTQ). Participants were treated with EMDR therapy. Depression and anxiety symptoms were assessed using the Hopkins Symptom Checklist. Symptom changes post-EMDR treatment were compared to a stabilization control intervention period in which participants served as their own waitlist control. Sessions were 60-90 mins. The average number of sessions was 4.15 (SD = 2.06). Despite difficulties providing treatment cross-culturally (i.e., language barriers), EMDR therapy was followed by significant and large reductions in trauma symptoms (Cohen's d = 2.48), depression (d = 2.09), and anxiety (d = 1.77). At posttreatment, 20 (95.2%) participants scored below the HTQ PTSD cutoff of 2. Reliable reductions in trauma symptoms were reported by 18 participants (85.7%) posttreatment and 16 (76.2%) at 3-month follow-up. Symptoms did not improve during the control period. Findings support the use of EMDR therapy for treatment of adults with PTSD in a cross-cultural, postwar/conflict setting, and suggest that structured trauma treatments can be applied in Timor Leste. PMID- 26934488 TI - Non-Breeding Eusocial Mole-Rats Produce Viable Sperm--Spermiogram and Functional Testicular Morphology of Fukomys anselli. AB - Ansell's mole-rats (Fukomys anselli) are subterranean rodents living in families composed of about 20 members with a single breeding pair and their non-breeding offspring. Most of them remain with their parents for their lifetime and help to maintain and defend the natal burrow system, forage, and care for younger siblings. Since incest avoidance is based on individual recognition (and not on social suppression) we expect that non-breeders produce viable sperm spontaneously. We compared the sperm of breeding and non-breeding males, obtained by electroejaculation and found no significant differences in sperm parameters between both groups. Here, we used electroejaculation to obtain semen for the first time in a subterranean mammal. Spermiogram analysis revealed no significant differences in sperm parameters between breeders and non-breeders. We found significantly larger testes (measured on autopsies and on living animals per ultrasonography) of breeders compared to non-breeders (with body mass having a significant effect). There were no marked histological differences between breeding and non-breeding males, and the relative area occupied by Leydig cells and seminiferous tubules on histological sections, respectively, was not significantly different between both groups. The seminiferous epithelium and to a lesser degree the interstitial testicular tissue are characterized by lesions (vacuolar degenerations), however, this feature does not hinder fertilization even in advanced stages of life. The continuous production of viable sperm also in sexually abstinent non-breeders might be best understood in light of the mating and social system of Fukomys anselli, and the potential to found a new family following an unpredictable and rare encounter with an unfamiliar female ("provoked or induced dispersal"). Apparently, the non-breeders do not reproduce because they do not copulate but not because they would be physiologically infertile. The significantly increased testes volume of breeding males (compared to non-breeders) is in agreement with previously found higher testosterone levels of breeders. PMID- 26934491 TI - Promoting the Hydrosilylation of Benzaldehyde by Using a Dicationic Antimony Based Lewis Acid: Evidence for the Double Electrophilic Activation of the Carbonyl Substrate. AB - The concomitant activation of carbonyl substrates by two Lewis acids has been investigated by using [1,2-(Ph2 MeSb)2 C6 H4 ](2+) ([1](2+) ), an antimony-based bidentate Lewis acid obtained by methylation of the corresponding distibine. Unlike the simple stibonium cation [Ph3 MeSb](+) , dication [1](2+) efficiently catalyzes the hydrosilylation of benzaldehyde under mild conditions. The catalytic activity of this dication is correlated to its ability to doubly activate the carbonyl functionality of the organic substrate. This view is supported by the isolation of [1-MU2 -DMF][OTf]2 , an adduct, in which the DMF oxygen atom bridges the two antimony centers. PMID- 26934489 TI - Transforming growth factor beta1 antagonizes the transcription, expression and vascular signaling of guanylyl cyclase/natriuretic peptide receptor A - role of deltaEF1. AB - The objective of this study was to determine the role of transforming growth factor beta1 (TGF-beta1) in transcriptional regulation and function of the guanylyl cyclase A/natriuretic peptide receptor A gene (Npr1) and whether cross talk exists between these two hormonal systems in target cells. After treatment of primary cultured rat thoracic aortic vascular smooth muscle cells and mouse mesangial cells with TGF-beta1, the Npr1 promoter construct containing a delta crystallin enhancer binding factor 1 (deltaEF1) site showed 85% reduction in luciferase activity in a time- and dose-dependent manner. TGF-beta1 also significantly attenuated luciferase activity of the Npr1 promoter by 62%, and decreased atrial natriuretic peptide-mediated relaxation of mouse denuded aortic rings ex vivo. Treatment of cells with TGF-beta1 increased the protein levels of deltaEF1 by 2.4-2.8-fold, and also significantly enhanced the phosphorylation of Smad 2/3, but markedly reduced Npr1 mRNA and receptor protein levels. Over expression of deltaEF1 showed a reduction in Npr1 promoter activity by 75%, while deletion or site-directed mutagenesis of deltaEF1 sites in the Npr1 promoter eliminated the TGF-beta1-mediated repression of Npr1 transcription. TGF-beta1 significantly increased the expression of alpha-smooth muscle actin and collagen type I alpha2 in rat thoracic aortic vascular smooth muscle cells, which was markedly attenuated by atrial natriuretic peptide in cells over-expressing natriuretic peptide receptor A. Together, the present results suggest that an antagonistic cascade exists between the TGF-beta1/Smad/deltaEF1 pathways and Npr1 expression and receptor signaling that is relevant to renal and vascular remodeling, and may be critical in the regulation of blood pressure and cardiovascular homeostasis. PMID- 26934490 TI - EasyCloneMulti: A Set of Vectors for Simultaneous and Multiple Genomic Integrations in Saccharomyces cerevisiae. AB - Saccharomyces cerevisiae is widely used in the biotechnology industry for production of ethanol, recombinant proteins, food ingredients and other chemicals. In order to generate highly producing and stable strains, genome integration of genes encoding metabolic pathway enzymes is the preferred option. However, integration of pathway genes in single or few copies, especially those encoding rate-controlling steps, is often not sufficient to sustain high metabolic fluxes. By exploiting the sequence diversity in the long terminal repeats (LTR) of Ty retrotransposons, we developed a new set of integrative vectors, EasyCloneMulti, that enables multiple and simultaneous integration of genes in S. cerevisiae. By creating vector backbones that combine consensus sequences that aim at targeting subsets of Ty sequences and a quickly degrading selective marker, integrations at multiple genomic loci and a range of expression levels were obtained, as assessed with the green fluorescent protein (GFP) reporter system. The EasyCloneMulti vector set was applied to balance the expression of the rate-controlling step in the beta-alanine pathway for biosynthesis of 3-hydroxypropionic acid (3HP). The best 3HP producing clone, with 5.45 g.L(-1) of 3HP, produced 11 times more 3HP than the lowest producing clone, which demonstrates the capability of EasyCloneMulti vectors to impact metabolic pathway enzyme activity. PMID- 26934493 TI - Palladium-Catalyzed N-Arylation of Cyclopropylamines. AB - A general method has been developed for the previously challenging arylation of cyclopropylamine and N-arylcyclopropylamines. Highly active, air-stable, and commercially available R-allylpalladium precatalysts provide access to a wide range of (hetero)arylated cyclopropylanilines in high yields. Precatalysts [(tBuBrettPhos)Pd(allyl)]OTf and [(BrettPhos)Pd(crotyl)]OTf, deliver monoarylated products, while (PtBu3)Pd(crotyl)Cl is suited for preparing unsymmetrical diarylated products. The developed conditions tolerate a range of functional groups and heterocycles, allowing access to an array of arylated cyclopropylamines, a motif present in prominent drug molecules. PMID- 26934494 TI - First trimester cystic hygroma: does early detection matter? AB - OBJECTIVE: To describe the association of abnormal outcomes with fetal cystic hygroma detected when crown-rump length measures less than 45 mm, and to compare them to outcomes among fetuses with cystic hygroma detected when crown-rump length measures 45-84 mm. METHODS: We performed a retrospective cohort study of fetuses with first trimester nuchal cystic hygroma from 2005 to 2015. RESULTS: A total of 212 fetuses were included. Abnormal karyotype was found in 20 of 46 (43.4%) fetuses with cystic hygroma detected when crown-rump length measured below 45 mm, compared to 108 of 148 (73%) fetuses with cystic hygroma detected at crown-rump lengths of 45-84 mm (p = 0.001). There were no differences in rates of major structural anomaly (27% vs 36%; p = 0.53) or pregnancy loss (23% vs 7%; p = 0.22) among fetuses with normal karyotype. Those with cystic hygroma diagnosed at crown-rump lengths below 45 mm were more likely to have a normal neonatal outcome compared to cases diagnosed with crown-rump lengths of 45-84 mm (25% vs 11%; p = 0.02). CONCLUSION: Cystic hygroma detected when crown-rump length measures below 45 mm have lower rates of chromosomal abnormalities and a higher proportion of normal birth outcomes when compared to those detected later in the first trimester. (c) 2016 John Wiley & Sons, Ltd. PMID- 26934492 TI - Bacterial Communities of Three Saline Meromictic Lakes in Central Asia. AB - Meromictic lakes located in landlocked steppes of central Asia (~2500 km inland) have unique geophysiochemical characteristics compared to other meromictic lakes. To characterize their bacteria and elucidate relationships between those bacteria and surrounding environments, water samples were collected from three saline meromictic lakes (Lakes Shira, Shunet and Oigon) in the border between Siberia and the West Mongolia, near the center of Asia. Based on in-depth tag pyrosequencing, bacterial communities were highly variable and dissimilar among lakes and between oxic and anoxic layers within individual lakes. Proteobacteria, Bacteroidetes, Cyanobacteria, Actinobacteria and Firmicutes were the most abundant phyla, whereas three genera of purple sulfur bacteria (a novel genus, Thiocapsa and Halochromatium) were predominant bacterial components in the anoxic layer of Lake Shira (~20.6% of relative abundance), Lake Shunet (~27.1%) and Lake Oigon (~9.25%), respectively. However, few known green sulfur bacteria were detected. Notably, 3.94% of all sequencing reads were classified into 19 candidate divisions, which was especially high (23.12%) in the anoxic layer of Lake Shunet. Furthermore, several hydro-parameters (temperature, pH, dissolved oxygen, H2S and salinity) were associated (P< 0.05) with variations in dominant bacterial groups. In conclusion, based on highly variable bacterial composition in water layers or lakes, we inferred that the meromictic ecosystem was characterized by high diversity and heterogenous niches. PMID- 26934495 TI - Application of Fluorescent Protein Expressing Strains to Evaluation of Anti Tuberculosis Therapeutic Efficacy In Vitro and In Vivo. AB - The slow growth of Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), hinders development of new diagnostics, therapeutics and vaccines. Using non-invasive real-time imaging technologies to monitor the disease process in live animals would facilitate TB research in all areas. We developed fluorescent protein (FP) expressing Mycobacterium bovis BCG strains for in vivo imaging, which can be used to track bacterial location, and to quantify bacterial load in live animals. We selected an optimal FP for in vivo imaging, by first cloning six FPs: tdTomato, mCherry, mPlum, mKate, Katushka and mKeima, into mycobacteria under either a mycobacterial Hsp60 or L5 promoter, and compared their fluorescent signals in vitro and in vivo. Fluorescence from each FP expressing strain was measured with a multimode reader using the optimal excitation and emission wavelengths for the FP. After normalizing bacterial numbers with optical density, the strain expressing L5-tdTomato displayed the highest fluorescence. We used the tdTomato-labeled M. bovis BCG to obtain real time images of pulmonary infections in living mice and rapidly determined the number of bacteria present. Further comparison between L5-tdTomato and Hsp60 tdTomato revealed that L5-tdTomato carried four-fold more tdTomato gene copies than Hsp60-tdTomato, which eventually led to higher protein expression of tdTomato. Evaluating anti-TB efficacy of rifampicin and isoniazid therapy in vitro and in vivo using the L5-tdTomato strain demonstrated that this strain can be used to identify anti-TB therapeutic efficacy as quickly as 24 h post treatment. These M. bovis BCG reporter strains represent a valuable new tool for evaluation of therapeutics, vaccines and virulence. PMID- 26934496 TI - The FireWork air quality forecast system with near-real-time biomass burning emissions: Recent developments and evaluation of performance for the 2015 North American wildfire season. AB - Environment and Climate Change Canada's FireWork air quality (AQ) forecast system for North America with near-real-time biomass burning emissions has been running experimentally during the Canadian wildfire season since 2013. The system runs twice per day with model initializations at 00 UTC and 12 UTC, and produces numerical AQ forecast guidance with 48-hr lead time. In this work we describe the FireWork system, which incorporates near-real-time biomass burning emissions based on the Canadian Wildland Fire Information System (CWFIS) as an input to the operational Regional Air Quality Deterministic Prediction System (RAQDPS). To demonstrate the capability of the system we analyzed two forecast periods in 2015 (June 2-July 15, and August 15-31) when fire activity was high, and observed fire smoke-impacted areas in western Canada and the western United States. Modeled PM2.5 surface concentrations were compared with surface measurements and benchmarked with results from the operational RAQDPS, which did not consider near real-time biomass burning emissions. Model performance statistics showed that FireWork outperformed RAQDPS with improvements in forecast hourly PM2.5 across the region; the results were especially significant for stations near the path of fire plume trajectories. Although the hourly PM2.5 concentrations predicted by FireWork still displayed bias for areas with active fires for these two periods (mean bias [MB] of -7.3 ug m(-3) and 3.1 ug m(-3)), it showed better forecast skill than the RAQDPS (MB of -11.7 ug m(-3) and -5.8 ug m(-3)) and demonstrated a greater ability to capture temporal variability of episodic PM2.5 events (correlation coefficient values of 0.50 and 0.69 for FireWork compared to 0.03 and 0.11 for RAQDPS). A categorical forecast comparison based on an hourly PM2.5 threshold of 30 ug m(-3) also showed improved scores for probability of detection (POD), critical success index (CSI), and false alarm rate (FAR). IMPLICATIONS: Smoke from wildfires can have a large impact on regional air quality (AQ) and can expose populations to elevated pollution levels. Environment and Climate Change Canada has been producing operational air quality forecasts for all of Canada since 2009 and is now working to include near-real-time wildfire emissions (NRTWE) in its operational AQ forecasting system. An experimental forecast system named FireWork, which includes NRTWE, has been undergoing testing and evaluation since 2013. A performance analysis of FireWork forecasts for the 2015 wildfire season shows that FireWork provides significant improvements to surface PM2.5 forecasts and valuable guidance to regional forecasters and first responders. PMID- 26934497 TI - The PIM1 kinase promotes prostate cancer cell migration and adhesion via multiple signalling pathways. AB - The ability of cells to migrate and form metastases is one of the fatal hallmarks of cancer that can be conquered only with better understanding of the molecules and regulatory mechanisms involved. The oncogenic PIM kinases have been shown to support cancer cell survival and motility, but the PIM-regulated pathways stimulating cell migration and invasion are less well characterized than those affecting cell survival. Here we have identified the glycogen synthase kinase 3beta (GSK3B) and the forkhead box P3 (FOXP3) transcription factor as direct PIM targets, whose tumour-suppressive effects in prostate cancer cells are inhibited by PIM-induced phosphorylation, resulting in increased cell migration. Targeting GSK3B is also essential for the observed PIM-enhanced expression of the prostaglandin-endoperoxide synthase 2 (PTGS2), which is an important regulator of both cell migration and adhesion. Accordingly, selective inhibition of PIM activity not only reduces cell migration, but also affects integrin-mediated cell adhesion. Taken together, these data provide novel mechanistic insights on how and why patients with metastatic prostate cancer may benefit from therapies targeting PIM kinases, and how such approaches may also be applicable to inflammatory conditions. PMID- 26934498 TI - Consumers' and their supporters' perspectives on barriers and strategies to reducing seclusion and restraint in mental health settings. AB - Objective This paper examines the perspectives of consumers and their supporters regarding the use of seclusion and restraint in mental health settings. Methods Five focus groups for consumers and five focus groups for supporters were conducted in four Australian cities and in one rural location. The 66 participants were asked about strategies to reduce or eliminate the use of seclusion and restraint in mental health settings. Results All participants supported the reduction of the use of seclusion and restraint. Barriers to reducing these practices related to the environment, the effects of drug and alcohol issues, lack of a human rights focus and poor recognition of trauma, stigma and discrimination. Strategies for reducing or eliminating seclusion and restraint included workforce development, environmental and cultural changes. Conclusions Participants clearly identified that the status quo needs to change and conveyed urgency for action. Participants suggested that the involvement of supporters and a range of consumer roles are integral to reducing the use of seclusion and restraint. The findings support the current policy emphasis of working towards the elimination of these practices. What is known about the topic? Mental health policies across many jurisdictions support the reduction and elimination of restraint and seclusion. Evidence suggests those subjected to restraint and seclusion largely experience a range of harmful consequences. No studies focus on the views of supporters of consumers regarding the reduction and elimination of seclusion and restraint, whereas the views of consumers appear in a minority of international studies. What does this paper add? The research enabled an opportunity to hear from people who have been personally affected by and/or have lived experience of these coercive practices. Participants identified local reforms that can uphold the human rights of consumers. They suggested practices to increase accountability, peer support and family involvement, areas that have not been analysed in depth in any of the seclusion and restraint literature. What are the implications for practitioners? This paper will give healthcare services a deeper insight into how to reduce or eliminate restraint or seclusion from the perspective of those with lived experience. PMID- 26934499 TI - German Translation and Validation of the Cognitive Style Questionnaire Short Form (CSQ-SF-D). AB - BACKGROUND: The Cognitive Style Questionnaire is a valuable tool for the assessment of hopeless cognitive styles in depression research, with predictive power in longitudinal studies. However, it is very burdensome to administer. Even the short form is still long, and neither this nor the original version exist in validated German translations. METHODS: The questionnaire was translated from English to German, back-translated and commented on by clinicians. The reliability, factor structure and external validity of an online form of the questionnaire were examined on 214 participants. External validity was measured on a subset of 90 subjects. RESULTS: The resulting CSQ-SF-D had good to excellent reliability, both across items and subscales, and similar external validity to the original English version. The internality subscale appeared less robust than other subscales. A detailed analysis of individual item performance suggests that stable results could be achieved with a very short form (CSQ-VSF-D) including only 27 of the 72 items. CONCLUSIONS: The CSQ-SF-D is a validated and freely distributed translation of the CSQ-SF into German. This should make efficient assessment of cognitive style in German samples more accessible to researchers. PMID- 26934500 TI - A Study on Electrolytic Corrosion of Boron-Doped Diamond Electrodes when Decomposing Organic Compounds. AB - Electrolytic corrosion of boron-doped diamond (BDD) electrodes after applying a high positive potential to decompose organic compounds in aqueous solution was studied. Scanning electron microscopy images, Raman spectra, and glow discharge optical emission spectroscopy revealed that relatively highly boron-doped domains were primarily corroded and relatively low boron-doped domains remained after electrolysis. The corrosion due to electrolysis was observed especially in aqueous solutions of acetic acid or propionic acid, while it was not observed in other organic compounds such as formic acid, glucose, and methanol. Electron spin resonance measurements after electrolysis in the acetic acid solution revealed the generation of methyl radicals on the BDD electrodes. Here, the possible mechanisms for the corrosion are discussed. Dangling bonds may be formed due to abstraction of OH groups from C-OH functional groups by methyl radicals generated on the surface of the BDD electrodes. As a result, the sp3 diamond structure would be converted to the sp2 carbon structure, which can be easily etched. Furthermore, to prevent electrolytic corrosion during electrolysis, both the current density and the pH condition in the aqueous solution were optimized. At low current densities or high pH, the BDD electrodes were stable without electrolytic corrosion even in the acetic acid aqueous solution. PMID- 26934502 TI - Self-directed learning. PMID- 26934501 TI - Can Urine Metabolomics Be Helpful in Differentiating Neuropathic and Nociceptive Pain? A Proof-of-Concept Study. AB - The diagnosis of pain nature is a troublesome task and a wrong attribution often leads to an increase of costs and to avoidable pharmaceutical adverse reactions. An objective and specific approach to achieve this diagnosis is highly desirable. The aim of this work was to investigate urine samples collected from patients suffering from pain of different nature by a metabolomics approach based on (1)H NMR spectroscopy and multivariate statistical analysis. We performed a prospective study on 74 subjects: 37 suffering from pain (12 with nociceptive and 25 with neuropathic pain), and 37 controls not suffering from any kind of chronic pain. The application of discriminant analysis on the urine spectral profiles allowed us to classify these two types of pain with high sensibility and specificity. Although the classification relies on the global urine metabolic profile, the individual contribution in discriminating neuropathic pain patients of metabolites such as choline and phosphocholine, taurine and alanine, suggests potential lesions to the nervous system. To the best of our knowledge, this is the first time that a urine metabolomics profile is used to classify these two kinds of pain. This methodology, although based on a limited sample, may constitute the basis for a new helpful tool in the clinical diagnosis. PMID- 26934503 TI - Two-Step Antiferromagnetic Transitions and Ferroelectricity in Spin-1 Triangular Lattice Antiferromagnetic Sr3NiTa2O9. AB - We report the low-temperature characterizations on structural, specific heat, magnetic, and ferroelectric behaviors of transition metal oxide compound Sr3NiTa2O9. It is suggested that Sr3NiTa2O9 is a spin-1 triangular lattice Heisenberg quantum antiferromagnet which may have weak easy-axis anisotropy. At zero magnetic field, a two-step transition sequence at T(N1) = 3.35 K and T(N2) = 2.74 K, respectively, is observed, corresponding to the up-up-down (uud) spin ordering and 120 degrees spin ordering, respectively. The two transition points shift gradually with increasing magnetic field toward the low temperature, accompanying an evolution from the 120 degrees spin structure (phase) to the normal oblique phases. Ferroelectricity in the 120 degrees phase is clearly identified. The first-principles calculations confirm the 120 degrees phase as the ground state whose ferroelectricity originates mainly from the electronic polarization. PMID- 26934505 TI - Utility of Prediction Scores for Hepatocellular Carcinoma in Patients with Chronic Hepatitis B Treated with Nucleos(t)ide Analogues. AB - OBJECTIVE: The utility of risk scores to predict the development of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients treated with nucleos(t)ide analogue (NA) remains to be elucidated. METHODS: CU-HCC (The Chinese University of Hong Kong-HCC) and GAG-HCC (Guide with Age, Gender, HBV DNA, Core promoter mutations and Cirrhosis) scores of 225 Japanese patients treated with NAs for at least 2 years were calculated before and 2 years after the NA treatment. According to the cutoff values, the patients were categorized into high-score or low-score groups. RESULTS: Sixteen of 225 patients developed HCC. Patients with a high score before the NA treatment showed a significantly higher HCC incidence than those with a low score using both score models (p < 0.001). Time-dependent receiver operating characteristic analyses based on scores before and 2 years after the NA treatment showed that both models exhibited moderate accuracy in predicting HCC development. The HCC incidence was significantly lower in the patients whose scores decreased below the cutoff values in response to the NA treatment than in those whose scores remained high using both models (p < 0.01). CONCLUSIONS: The predictive performance of the CU HCC and GAG-HCC scores in the CHB patients treated with NAs is comparable to that in the NA-naive patients. The patients with sustained high scores after the NA treatment showed a higher incidence of HCC development. PMID- 26934506 TI - "Because I never was a damn geneticist" - the unique scientific approach and career of Eric H. Davidson. PMID- 26934504 TI - Randomized clinical trial on 7-days-a-week post-operative radiotherapy vs concurrent post-operative radiochemotherapy in locally advanced cancer of the oral cavity/oropharynx: a report on acute normal tissue reactions. AB - OBJECTIVE: The purpose of the study was to evaluate acute normal tissue reactions and treatment compliance in a randomized clinical trial on 7-days-a-week post operative radiotherapy (p-CAIR) vs post-operative concurrent radiochemotherapy (p RTCT) in locally advanced cancer of the oral cavity/oropharynx. The sample analyzed at present represents approximately 30% of the intended future trial size. METHODS: The patients were randomly assigned to receive 63 Gy in 1.8-Gy fractions 7 days a week (n = 44) or 63 Gy in 1.8-Gy fractions 5 days a week with concurrent cisplatin 80-100 mg per square metre of body surface area on Days 1, 22 and 43 of the course of radiotherapy (n = 40). Acute mucosal reactions were scored using the modified Dische system. RESULTS: 15 (17.9%) patients, including 5 patients in p-CAIR and 10 patients in p-RTCT, did not comply with the assigned radiation treatment, mostly because of rapid tumour progression or deteriorating general performance. In p-RTCT, 22 (55%) patients received less than the intended three courses of chemotherapy mostly owing to haematological toxicity. The average maximum mucosal severity score was 14.2 in p-CAIR compared with 13.4 in p RTCT; the difference was not statistically significant (p = 0.31). CONCLUSION: The schedules compared (p-CAIR and p-RTCT) did not differ considerably with respect to acute mucosal reactions. Haematological toxicity in p-RTCT was elevated compared with p-CAIR. Both schedules were considered tolerable with respect to acute toxicity, which justifies further recruitment to the trial. ADVANCES IN KNOWLEDGE: The results show that early mucosal reactions are comparable in both trial arms but haematological toxicity is more pronounced during radiochemotherapy. PMID- 26934507 TI - Clinical profile, nursing diagnoses and nursing care for postoperative bariatric surgery patients. AB - Objective To analyze the clinical profile, nursing diagnoses, and nursing care established for postoperative bariatric surgery patients. Method Cross-sectional study carried out in a hospital in southern Brazil with a sample of 143 patients. Data were collected retrospectively from electronic medical records between 2011 and 2012 and analyzed statistically. Results We found a predominance of adult female patients (84%) with class III obesity (59.4%) and hypertension (72%). Thirty-five nursing diagnoses were reported, among which the most frequent were: Acute Pain (99.3%), Risk for perioperative positioning injury (98.6%), and Impaired tissue integrity (93%). The most frequently prescribed nursing care were: to use protection mechanisms in the surgical patient positioning, to record pain as 5th vital sign, and to take vital signs. There was an association between age and comorbidities. Conclusion The nursing diagnoses supported the nursing care prescription, which enables the qualification of nursing assistance. PMID- 26934509 TI - A New Miocene-Divergent Lineage of Old World Racer Snake from India. AB - A distinctive early Miocene-divergent lineage of Old world racer snakes is described as a new genus and species based on three specimens collected from the western Indian state of Gujarat. Wallaceophis gen. et. gujaratenesis sp. nov. is a members of a clade of old world racers. The monotypic genus represents a distinct lineage among old world racers is recovered as a sister taxa to Lytorhynchus based on ~3047bp of combined nuclear (cmos) and mitochondrial molecular data (cytb, ND4, 12s, 16s). The snake is distinct morphologically in having a unique dorsal scale reduction formula not reported from any known colubrid snake genus. Uncorrected pairwise sequence divergence for nuclear gene cmos between Wallaceophis gen. et. gujaratenesis sp. nov. other members of the clade containing old world racers and whip snake is 21-36%. PMID- 26934508 TI - Strategies used by nurses to promote teamwork in an emergency room. AB - Objective to analyze the strategies used by nurses to promote teamwork in a hospital emergency room. Method qualitative case study research with 20 nurses in the emergency unit of a university hospital in southern Brazil. Data were collected between June and September 2009 through participant observation and semi-structured interviews, and analyzed using thematic analysis. Results the strategies used by the nurses to promote teamwork in the emergency unit were articulating professional actions; establishing relationships of cooperation; building and maintaining friendly ties; and managing conflict. Conclusion nurses notably make the connections between the practices of the health teams and mediate the relationships established between health professionals to improve care practices. PMID- 26934511 TI - Defeating the stigma of chronic pain. PMID- 26934510 TI - Loss of inhibitory tone on spinal cord dorsal horn spontaneously and nonspontaneously active neurons in a mouse model of neuropathic pain. AB - Plasticity of inhibitory transmission in the spinal dorsal horn (SDH) is believed to be a key mechanism responsible for pain hypersensitivity in neuropathic pain syndromes. We evaluated this plasticity by recording responses to mechanical stimuli in silent neurons (nonspontaneously active [NSA]) and neurons showing ongoing activity (spontaneously active [SA]) in the SDH of control and nerve injured mice (cuff model). The SA and NSA neurons represented 59% and 41% of recorded neurons, respectively, and were predominantly wide dynamic range (WDR) in naive mice. Nerve-injured mice displayed a marked decrease in the mechanical threshold of the injured paw. After nerve injury, the proportion of SA neurons was increased to 78%, which suggests that some NSA neurons became SA. In addition, the response to touch (but not pinch) was dramatically increased in SA neurons, and high-threshold (nociceptive specific) neurons were no longer observed. Pharmacological blockade of spinal inhibition with a mixture of GABAA and glycine receptor antagonists significantly increased responses to innocuous mechanical stimuli in SA and NSA neurons from sham animals, but had no effect in sciatic nerve-injured animals, revealing a dramatic loss of spinal inhibitory tone in this situation. Moreover, in nerve-injured mice, local spinal administration of acetazolamide, a carbonic anhydrase inhibitor, restored responses to touch similar to those observed in naive or sham mice. These results suggest that a shift in the reversal potential for anions is an important component of the abnormal mechanical responses and of the loss of inhibitory tone recorded in a model of nerve injury-induced neuropathic pain. PMID- 26934512 TI - Health care providers' judgments in chronic pain: the influence of gender and trustworthiness. AB - Estimates of patients' pain, and judgments of their pain expression, are affected by characteristics of the observer and of the patient. In this study, we investigated the impact of high or low trustworthiness, a rapid and automatic decision made about another, and of gender and depression history on judgments made by pain clinicians and by medical students. Judges viewed a video of a patient in pain presented with a brief history and rated his or her pain, and the likelihood that it was being exaggerated, minimized, or hidden. Judges also recommended various medical and treatment options. Contrary to expectations, trustworthiness had no main effect on pain estimates or judgments, but interacted with gender producing pervasive bias. Women, particularly those rated of low trustworthiness, were estimated to have less pain and to be more likely to exaggerate it. Unexpectedly, judgments of exaggeration and pain estimates were independent. Consistent with those judgments, men were more likely to be recommended analgesics, and women to be recommended psychological treatment. Effects of depression history were inconsistent and hard to interpret. Contrary to expectations, clinicians' pain estimates were higher than medical students', and indicated less scepticism. Empathy was unrelated to these judgments. Trustworthiness merits further exploration in healthcare providers' judgments of pain authenticity and how it interacts with other characteristics of patients. Furthermore, systematic disadvantage to women showing pain is of serious concern in healthcare settings. PMID- 26934513 TI - Therapies on the horizon for Clostridium difficile infections. AB - INTRODUCTION: Clostridium difficile infections are a leading cause of healthcare facility outbreaks of gastrointestinal illness that may have serious complications and a high rate of recurrent disease. Despite the availability of standard antibiotic treatments, data from national surveillance programs indicate that the incidence of this disease continues to increase, placing a heavy burden on healthcare systems. New emerging strategies are being tested to replace or augment these standard antibiotics. AREAS COVERED: Thirty-two current investigational agents focusing on different strategies for both prevention and treatment of C. difficile infections are reviewed. Data was gathered from a literature search of public databases for published trials from 1999-November 13, 2015 and from the author's compendium of knowledge. Agents reviewed included 13 antibiotics, two antibiotic inactivators, seven bacteria or yeasts acting to enhance the normal microbiome, seven immunizing agents and three toxin binders. Of the 32 investigational treatments reviewed, 8 (25%) showed significant efficacy in phase II or III clinical trials and are actively being developed as new therapies for C. difficile infections. EXPERT OPINION: A number of potential treatments have floundered during their development process, while others have shown promising results. The strongest efficacy has been in the areas of newer antibiotics, probiotics, monoclonal antibodies and vaccines. By targeting the pathogenic pathway of C. difficile infections, multiple strategies for prevention and treatment have been developed. PMID- 26934515 TI - Medical end-of-life decisions in Switzerland 2001 and 2013: Who is involved and how does the decision-making capacity of the patient impact? AB - QUESTIONS UNDER STUDY: In Switzerland, the prevalence of medical end-of-life practices had been assessed on a population level only once - in 2001 - until in 2013/14 an identical study was conducted. We aimed to compare the results of the 2001 and 2013 studies with a special focus on shared decision-making and patients' decision-making capacity. METHODS: Our study encompassed a 21.3% sample of deaths among residents of the German-speaking part of Switzerland aged 1 year or older. From 4998 mailed questionnaires, 3173 (63.5%) were returned. All data were weighted to adjust for age- and sex-specific differences in response rates. RESULTS: Cases with at least one reported end-of-life practice significantly increased from 74.5% (2001) to 82.3% (2013) of all deaths eligible for an end-of life decision (p <0.001). In 51.2% there was a combination of at least two different end-of-life decisions in one case. In relation to discussion with patients or relatives and otherwise expressed preferences of the patient, 76.5% (74.5-78.4%) of all cases with reported medical end-of-life practice in 2013 (2001: 74.4%) relied on shared decision-making, varying from 79.8% (76.5-82.7%) among not at all capable patients to 87.8% (85.0-90.2%) among fully capable patients. In contrast to a generally increasing trend, the prevalence of end-of life practices discussed with fully capable patients decreased from 79.0% (75.3 82.3%) in 2001 to 73.2% (69.6-76.0%) in 2013 (p = 0.037). CONCLUSIONS: Despite a generally high incidence of end-of-life practices in Switzerland, there remains potential for further improvement in shared decision-making. Efforts to motivate physicians to involve patients and relatives may be a win-win situation. PMID- 26934514 TI - Clear Cell Renal Cell Carcinoma: Associations Between CT Features and Patient Survival. AB - OBJECTIVE: The objective of this study was to investigate associations between CT features and survival in patients with clear cell renal cell carcinoma (ccRCC). MATERIALS AND METHODS: The study included 763 patients with histopathologically confirmed ccRCC who underwent preoperative contrast-enhanced CT between 1999 and 2011. Imaging features, both qualitative (cystic tumor, necrosis, tumor contact with renal sinus, renal vein invasion, peritumoral stranding, and peritumoral neovascularity) and quantitative (maximal tumor diameter and distance from the tumor to the renal sinus), were evaluated. Univariate and multivariable Cox regressions were used to assess associations of imaging features with disease specific survival (DSS) and disease-specific progression-free survival (PFS). RESULTS: Greater tumor size and the presence of renal vein invasion on CT were associated with decreased DSS and disease-specific PFS (p < 0.05), and the presence of extensive necrosis (more than two-thirds of the tumor volume) was associated with decreased disease-specific PFS (p < 0.05); this association remained statistically significant when we controlled for pathologic tumor stage. In contrast, no disease-specific death or progression was seen in patients with purely cystic tumors. Greater distance between the tumor and the renal sinus was not statistically significantly associated with longer survival. CONCLUSION: In patients with ccRCC, observation of extensive necrosis on CT was statistically significantly associated with decreased disease-specific PFS, whereas greater tumor size and the presence of renal vein invasion on CT were statistically significantly associated with decreased DSS and disease-specific PFS. No disease progression was observed in tumors with a cystic appearance. Therefore, selected CT features could potentially aid in risk assessment for and counseling of patients with ccRCC and could provide prognostic information beyond the established tumor staging system. PMID- 26934516 TI - LiFePO4 nanoparticles enveloped in freestanding sandwich-like graphitized carbon sheets as enhanced remarkable lithium-ion battery cathode. AB - A novel nanostructure where LiFePO4 nanoparticles are enveloped in sandwich-like carbon sheets as an enhanced cathode in lithium-ion batteries has successfully been synthesized for the first time. Compared to previous carbon-based nanocomposites, the achieved sandwich-like LiFePO4 nanocomposites exhibit totally different architecture, in which LiFePO4 nanoparticles are tightly entrapped between two carbon layers, instead of being anchored on the carbon sheet surfaces. In other words, the achieved sandwich-like LiFePO4 nanocomposite carbon layers are actually freestanding and can be operated and separated from each other. This is a great breakthrough in the design and synthesis of carbon-based functional materials. The obtained sandwich-like LiFePO4 nanocomposites present excellent electrochemical performance, which is rationally ascribed to the superb and unique structure and architecture. Of particular note is that the freestanding sandwich-like LiFePO4 nanocomposites exhibit enhanced cyclability and rate capability. At a high current density of 0.1 A g(-1), a stable specific capacity of approximately 168.5 mAh g(-1) can be delivered over 1000 cycles, and when the charge-discharge rates increase to 0.6, 2, 5 and 10 A g(-1), the specific capacities still survive at 149, 129, 114 and 91 mAh g(-1), respectively. Meanwhile, the sandwiched nanocomposite demonstrates a significantly improved low-temperature electrochemical energy storage performance. With respect to the excellent Li storage performance, and facility and reliability of production, the freestanding sandwich-like LiFePO4 nanocomposites are reasonably believed to have a great potential for multiple electrochemical energy storage applications. PMID- 26934517 TI - Cognitive health. PMID- 26934518 TI - Brain training: Memory games. PMID- 26934519 TI - Brain food: Clever eating. PMID- 26934520 TI - Social networks: Better together. PMID- 26934521 TI - Neural modelling: Abstractions of the mind. PMID- 26934522 TI - Neurobiology: Rise of resilience. PMID- 26934523 TI - Smart drugs: A dose of intelligence. PMID- 26934525 TI - Neurostimulation: Bright sparks. PMID- 26934524 TI - Ageing: Restoration project. PMID- 26934526 TI - Perspective: Time to expand the mind. PMID- 26934527 TI - Chemerin, visfatin, and vaspin serum levels in relation to bone mineral density in patients with inflammatory bowel disease. AB - BACKGROUND: There is evidence that fat mass is correlated with bone mineral density (BMD) in inflammatory bowel disease (IBD), but data on the role of adipokines on this association are limited. The aim of this study was to investigate the serum levels of chemerin, visfatin, and vaspin, hormones that act as adipokines, in relation to BMD in patients with ulcerative colitis (UC) and Crohn's disease (CD). PATIENTS AND METHODS: Serum from 120 IBD patients (68 CD, 52 UC) and 98 matched healthy controls (HC) was collected. Chemerin, visfatin, and vaspin levels were assessed using an enzyme-linked immunosorbent assay. BMD was determined for the lumbar spine and the proximal femur using dual-energy X ray absorptiometry. Full-body composition scans were analyzed using enCORE software based on the absorptiometry system. RESULTS: Serum chemerin was higher in IBD patients than HC [CD 13.67.1+/-5.8, UC 13.9+/-4.3 vs. HC 7.8+/-2.6 ng/ml, odds ratio (OR): 0.95, 95% confidence interval (CI) 0.93-0.98, P<0.0001]. Serum visfatin levels in CD patients were significantly higher than those in UC patients (9.3+/-14.01 vs. 6.5+/-7.2 ng/ml, OR: 0.86, 95% CI 0.80-0.92, P=0.039). In multivariate logistic regression analysis, a significant independent association of osteoporosis (T-score <=2.5 SD) with age (OR: 1.04, 95% CI 1.01 1.08, P=0.02), visfatin (OR: 0.78, 95% CI 0.63-0.97, P=0.02), and chemerin levels (OR: 0.83, 95% CI 0.70-0.98, P=0.03), but not with BMI or body composition, was found. CONCLUSION: Serum visfatin and chemerin levels are associated with the development of osteoporosis in IBD. These results suggest a role of visfatin and chemerin in the pathophysiology of osteoporosis in IBD. PMID- 26934528 TI - Predictors of fecal transplant failure. AB - BACKGROUND: Clostridium difficile infection (CDI) is a significant healthcare burden, with increased morbidity and mortality. Traditional treatment regimens using antibiotics for recurrent CDI are significantly less successful compared with 80-90% with fecal microbiota transplantation (FMT). There is a paucity of data on failure rates and mortality after FMT in CDI. This study aims to identify the rates of failure, relapse, and mortality associated with FMT as well as the risk factors for FMT failure. METHODS: A large retrospective cohort study was carried out including all patients who underwent FMT from December 2012 through May 2014. Patient factors (demographics, comorbidities, immune-suppression, transplant history, antibiotics used, hospitalization, and surgeries), disease factors (number of episodes of CDI, treatments, and severity), and transplant factors (route and number of FMT) were examined. Failure of treatment was defined as no resolution of diarrhea in patients who had been treated with one or more fecal microbiota transplantation within 90 days of FMT. RESULTS: A total of 201 patients (age 66.6+/-18.3 years, 62.2% women) were included. The overall failure rate was 12.4%. Patients with failed fecal transplant had increased number of FMTs compared with those who responded (mean 1.92+/-0.997 vs. 1.29+/-0.615; P=0.004). No colectomies or death related to CDI were found in our patient population. Significant predictors of failure were female sex (P=0.016), previous hospitalization (P=0.006), and surgery before FMT (P=0.005). The overall mortality rate was 9.0% and failure of FMT was associated with an increased risk of death (odds ratio=5.833, confidence interval 2.01-16.925; P<0.05). CONCLUSION: FMT is a suitable alterative to antibiotic use for recurrent CDIs, with a high success rate. The results indicate that hospital-acquired CDI may be a predictor of failure of FMT. PMID- 26934529 TI - Integrated Taxonomy Reveals Hidden Diversity in Northern Australian Fishes: A New Species of Seamoth (Genus Pegasus). AB - Fishes are one of the most intensively studied marine taxonomic groups yet cryptic species are still being discovered. An integrated taxonomic approach is used herein to delineate and describe a new cryptic seamoth (genus Pegasus) from what was previously a wide-ranging species. Preliminary mitochondrial DNA barcoding indicated possible speciation in Pegasus volitans specimens collected in surveys of the Torres Strait and Great Barrier Reef off Queensland in Australia. Morphological and meristic investigations found key differences in a number of characters between P. volitans and the new species, P. tetrabelos. Further mt DNA barcoding of both the COI and the slower mutating 16S genes of additional specimens provided strong support for two separate species. Pegasus tetrabelos and P. volitans are sympatric in northern Australia and were frequently caught together in trawls at the same depths. PMID- 26934530 TI - Dinutuximab for the treatment of pediatric patients with high-risk neuroblastoma. AB - Neuroblastoma (NB) is the most common extra cranial solid tumor of childhood, with 60% of patients presenting with high risk (HR) NB by means of clinical, pathological and biological features. The 5-year survival rate for HR-NB remains below 40%, with the majority of patients suffering relapse from chemorefractory tumor. Immunotherapy is the main strategy against minimal residual disease and clinical experience has mostly focused on monoclonal antibodies (MoAb) against the glycolipid disialoganglioside GD2. Three anti-GD2 antibodies have been tested in the clinic including murine 14G2a, human-mouse chimeric ch14.18 and 3F8. Anti GD2 MoAb induces cellular cytoxicity against NB and is most effective when effector cells like natural killer cells, granulocytes and macrophages are amplified by cytokines. The combination of cytokines IL-2 and GM-CSF with the anti-GD2 MoAb ch14.18 (Dinutuximab) has shown a significant improvement in outcome for HR-NB. The FDA and EMA approved dinutuximab (Unituxin(R)) in 2015 for the treatment of patients with HR-NB who achieved at least a partial response after multimodality therapy. PMID- 26934533 TI - Surgical Mesh Should Be Made Affordable to Low- and Middle-Income Countries. PMID- 26934534 TI - Characterization and Modulation of the Bitterness of Polymethoxyflavones Using Sensory and Receptor-Based Methods. AB - An obstacle in the application of many "health ingredients" is their alleged off flavor. We used a combination of chemical, sensory, and biological analyses to identify the bitter components in citrus peel-derived polymethoxyflavone preparations, claimed to be functional in the lowering of cholesterol. Nobiletin (56-81%) and tangeretin (10-33%) were found to be the main bitter components. Using in vitro receptor assays, hTAS2R14 was shown to be the main bitter receptor involved in their perception, with EC50 values of 14 and 63 MUM, respectively. Our analysis provided several routes for off-flavor reduction. Purification is an option because a purified, single PMF species proved to be considerably less bitter upon application in emulsified foods, due to limited solubility in the aqueous phase. A second route, also demonstrated in vivo, is C5-specific demethoxylation, in line with the finding that 5-desmethylnobiletin does not activate hTAS2R14. A third route could be the use of TAS2R14 antagonists. As a proof of principle, several antagonists, with IC50 values ranging from 10 to 50 MUM, were identified. PMID- 26934535 TI - Quantum anomalous Hall effect in time-reversal-symmetry breaking topological insulators. AB - The quantum anomalous Hall effect (QAHE), the last member of Hall family, was predicted to exhibit quantized Hall conductivity sigma(yx) = e2/h without any external magnetic field. The QAHE shares a similar physical phenomenon with the integer quantum Hall effect (QHE), whereas its physical origin relies on the intrinsic topological inverted band structure and ferromagnetism. Since the QAHE does not require external energy input in the form of magnetic field, it is believed that this effect has unique potential for applications in future electronic devices with low-power consumption. More recently, the QAHE has been experimentally observed in thin films of the time-reversal symmetry breaking ferromagnetic (FM) topological insulators (TI), Cr- and V- doped (Bi,Sb)2Te3. In this topical review, we review the history of TI based QAHE, the route to the experimental observation of the QAHE in the above two systems, the current status of the research of the QAHE, and finally the prospects for future studies. PMID- 26934531 TI - Zika Virus: Medical Countermeasure Development Challenges. AB - INTRODUCTION: Reports of high rates of primary microcephaly and Guillain-Barre syndrome associated with Zika virus infection in French Polynesia and Brazil have raised concerns that the virus circulating in these regions is a rapidly developing neuropathic, teratogenic, emerging infectious public health threat. There are no licensed medical countermeasures (vaccines, therapies or preventive drugs) available for Zika virus infection and disease. The Pan American Health Organization (PAHO) predicts that Zika virus will continue to spread and eventually reach all countries and territories in the Americas with endemic Aedes mosquitoes. This paper reviews the status of the Zika virus outbreak, including medical countermeasure options, with a focus on how the epidemiology, insect vectors, neuropathology, virology and immunology inform options and strategies available for medical countermeasure development and deployment. METHODS: Multiple information sources were employed to support the review. These included publically available literature, patents, official communications, English and Lusophone lay press. Online surveys were distributed to physicians in the US, Mexico and Argentina and responses analyzed. Computational epitope analysis as well as infectious disease outbreak modeling and forecasting were implemented. Field observations in Brazil were compiled and interviews conducted with public health officials. PMID- 26934536 TI - Whole-genome duplications followed by tandem duplications drive diversification of the protein modifier SUMO in Angiosperms. AB - The ubiquitin-like modifier (UBL) SUMO (Small Ubiquitin-Like Modifier) regulates protein function. Structural rather than sequence homology typifies UBL families. However, individual UBL types, such as SUMO, show remarkable sequence conservation. Selection pressure also operates at the SUMO gene copy number, as increased SUMO levels activate immunity and alter flowering time in Arabidopsis. We show how, despite this selection pressure, the SUMO family has diversified into eight paralogues in Arabidopsis. Relationships between the paralogues were investigated using genome collinearity and gene tree analysis. We show that palaeopolyploidy followed by tandem duplications allowed expansion and then diversification of the SUMO genes. For example, Arabidopsis SUMO5 evolved from the pan-eudicot palaeohexaploidy event (gamma), which yielded three SUMO copies. Two gamma copies were preserved as archetype SUMOs, suggesting subfunctionalization, whereas the third copy served as a hotspot for SUMO diversification. The Brassicaceae-specific alpha duplication then caused the duplication of one archetype gamma copy, which, by subfunctionalization, allowed the retention of both SUMO1 and SUMO2. The other archetype gamma copy was simultaneously pseudogenized (SUMO4/6). A tandem duplication of SUMO2 subsequently yielded SUMO3 in the Brassicaceae crown group. SUMO3 potentially neofunctionalized in Arabidopsis, but it is lost in many Brassicaceae. Our advanced methodology allows the study of the birth and fixation of other paralogues in plants. PMID- 26934537 TI - Error in Affiliation. PMID- 26934538 TI - Results of the PAS Study: A Randomized Controlled Trial Evaluating the Effectiveness of a Web-Based Multiple Tailored Smoking Cessation Program Combined With Tailored Counseling by Practice Nurses. AB - This study investigated the effects of Web-based multiple computer tailoring and counseling by a practice nurse (MTC) compared with computer tailoring without counseling (MT) and usual care (UC) on smoking cessation rates, via a randomized controlled trial with 414 Dutch adult smokers, recruited by 91 practice nurses from May 2009 to June 2010. Logistic multilevel regression analyses were conducted with 24-hour point prevalence, 7-day point prevalence, and prolonged abstinence after 6 and 12 months as dependent variables and experimental condition as the independent variable. After 6 and 12 months, 38% and 56% of respondents were followed up, respectively. At both follow-ups, no main effects of the interventions could be identified when comparing them with care as usual and with each other-neither in analyses using available data nor in analyses using a negative scenario in which respondents lost to follow-up were considered to still be smoking. A Web-based multiple computer-tailored smoking cessation program combined with a single face-to-face counseling session by a practice nurse may not be more effective than this computer-tailored program alone or than usual smoking cessation care in the general practice setting. Yet before concluding that the addition of counseling to Web-based computer tailoring cannot be successful, more research needs to be conducted to identify the optimal number of counseling sessions to be combined with the Web-based program and to how to best attune the two modalities. PMID- 26934539 TI - Carborane Substituents Promote Direct Electrophilic Insertion over Reduction Metalation Reactions. AB - Two-electron reduction of 1,1'-bis(o-carborane) followed by reaction with [Ru(eta mes)Cl2 ]2 affords [8-(1'-1',2'-closo-C2 B10 H11 )-4-(eta-mes)-4,1,8-closo-RuC2 B10 H11 ]. Subsequent two-electron reduction of this species and treatment with [Ru(eta-arene)Cl2 ]2 results in the 14-vertex/12-vertex species [1-(eta-mes)-9 (1'-1',2'-closo-C2 B10 H11 )-13-(eta-arene)-1,13,2,9-closo-Ru2 C2 B10 H11 ] by direct electrophilic insertion, promoted by the carborane substituent in the 13 vertex/12-vertex precursor. When arene=mesitylene (mes), the diruthenium species is fluxional in solution at room temperature in a process that makes the metal ligand fragments equivalent. A unique mechanism for this fluxionality is proposed and is shown to be fully consistent with the observed fluxionality or nonfluxionality of a series of previously reported 14-vertex dicobaltacarboranes. PMID- 26934540 TI - Clinical metagenomics for the management of hospital- and healthcare-acquired pneumonia. AB - The increasing burden of multidrug-resistant bacteria affects the management of several infections. In order to prescribe adequate antibiotics, clinicians facing severe infections such as hospital-acquired pneumonia (HAP) need to promptly identify the pathogens and know their antibiotic susceptibility profiles (AST), which with conventional microbiology currently requires 24 and 48 h, respectively. Clinical metagenomics, based on whole genome sequencing of clinical samples, could improve the diagnosis of HAP, however, many obstacles remain to be overcome, namely the turn-around time, the quantification of pathogens, the choice of antibiotic resistance determinants (ARDs), the inference of the AST from metagenomic data and the linkage between ARDs and their host. Here, we propose to tackle those issues in a bottom-up, clinically driven approach. PMID- 26934541 TI - Long-term effects of weight-reducing diets in people with hypertension. AB - BACKGROUND: All major guidelines for antihypertensive therapy recommend weight loss. Thus dietary interventions that aim to reduce body weight might be a useful intervention to reduce blood pressure and adverse cardiovascular events associated with hypertension. OBJECTIVES: Primary objectivesTo assess the long term effects of weight-reducing diets in people with hypertension on all-cause mortality, cardiovascular morbidity, and adverse events (including total serious adverse events, withdrawal due to adverse events, and total non-serious adverse events). Secondary objectivesTo assess the long-term effects of weight-reducing diets in people with hypertension on change from baseline in systolic blood pressure, change from baseline in diastolic blood pressure, and body weight reduction. SEARCH METHODS: We obtained studies from computerised searches of the Cochrane Central Register of Controlled Trials (CENTRAL), the Cochrane Hypertension Specialised Register, Ovid MEDLINE, and Ovid EMBASE, and from searches in reference lists, systematic reviews, and the clinical trials registry ClinicalTrials.gov (status as of 2 February 2015). SELECTION CRITERIA: We included randomised controlled trials (RCTs) of at least 24 weeks' duration that compared weight-reducing dietary interventions to no dietary intervention in adults with primary hypertension. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed risk of bias and extracted data. We pooled studies using fixed-effect meta-analysis. In case of moderate or larger heterogeneity as measured by Higgins I(2), we used a random-effects model. MAIN RESULTS: This review update did not reveal any new studies, so the number of included studies remained the same: 8 studies involving a total of 2100 participants with high blood pressure and a mean age of 45 to 66 years. Mean treatment duration was 6 to 36 months. We judged the risk of bias as unclear or high for all but two trials. No study included mortality as a predefined outcome. One RCT evaluated the effects of dietary weight loss on a combined endpoint consisting of the necessity of reinstating antihypertensive therapy and severe cardiovascular complications. In this RCT, weight-reducing diet lowered the endpoint compared to no diet: hazard ratio 0.70 (95% confidence interval (CI), 0.57 to 0.87). None of the studies evaluated adverse events as designated in our protocol. There was low quality evidence for a blood pressure reduction in participants assigned to weight loss diets as compared to controls: systolic blood pressure: mean difference (MD) -4.5 mm Hg (95% CI -7.2 to -1.8 mm Hg) (3 of 8 studies included in analysis), and diastolic blood pressure: MD -3.2 mm Hg (95% CI -4.8 to -1.5 mm Hg) (3 of 8 studies included in analysis). There was moderate-quality evidence for weight reduction in dietary weight loss groups as compared to controls: MD 4.0 kg (95% CI -4.8 to -3.2) (5 of 8 studies included in analysis). Two studies used withdrawal of antihypertensive medication as their primary outcome. Even though we did not consider this a relevant outcome for our review, the results of these studies strengthen the finding of reduction of blood pressure by dietary weight loss interventions. AUTHORS' CONCLUSIONS: In this update, the conclusions remain the same, as we found no new trials. In people with primary hypertension, weight loss diets reduced body weight and blood pressure, however the magnitude of the effects are uncertain due to the small number of participants and studies included in the analyses. Whether weight loss reduces mortality and morbidity is unknown. No useful information on adverse effects was reported in the relevant trials. PMID- 26934542 TI - Effects of Duration on Perceptions of Teacher Sexual Misconduct. AB - This study explored how respondent gender, gender dyad (male teacher-female student versus female teacher-male student) and duration/frequency (weekly sexual contact over 4 months versus a single incident) affected perceptions of teacher adolescent student sexual involvement. Respondents were 224 undergraduates (104 men, 120 women) recruited from a psychology research pool. Most (87%) were 18-21 years old, and 59% were Caucasian. Each respondent read one of four scenarios (varied by gender dyad and duration/frequency) depicting a teacher-adolescent student sexual interaction and then completed a series of questions about his or her perceptions. Results indicated that men perceived these experiences less negatively than did women, and the female teacher-male student dyad was viewed less negatively than the male teacher-female student dyad. Relatively few significant interactions emerged, and the only main effect for duration/frequency was for commitment. Results are discussed in terms of the need for more research and education. PMID- 26934543 TI - The Levels of Cortisol, Oxidative Stress, and DNA Damage in the Victims of Childhood Sexual Abuse: A Preliminary Study. AB - In this study we aimed to investigate serum cortisol, oxidative stress, and DNA damage in children who are sexual abuse victims. The study included 38 children who sustained child sexual abuse and 38 age- and gender-matched children who did not have a history of trauma. Cortisol levels reflecting the status of the hypothalamic-pituitary-adrenal axis, anti-oxidant enzymes glutathione peroxidase, superoxide dismutase, natural anti-oxidant coenzyme Q, and 8-hydroxy-2 deoxyguanosine as the indicator of DNA damage were analyzed in serum samples using the enzyme linked immunosorbent assay method. Cortisol levels were significantly higher in the child sexual abuse group compared to the control group. There were no significant differences between the groups in terms of oxidative stress and DNA damage. Cortisol and 8-hydroxy-2-deoxyguanosine levels decreased as the time elapsed since the sexual abuse increased. Coenzyme Q level was lower in victims who sustained multiple assaults than in the victims of a single assault. Cortisol and superoxide dismutase levels were lower in the victims of familial sexual abuse. Decreases in cortisol and 8-hydroxy-2 deoxyguanosine levels as time elapsed may be an adaptation to the toxic effects of high cortisol levels over a prolonged period of time. Child sexual abuse did not result in oxidative stress and DNA damage; however, some features of sexual abuse raised the level of oxidative stress. PMID- 26934544 TI - Psychophysiological Reactivity in Child Sexual Abuse. AB - Sexual abuse has physiological and emotional implications. The purpose of this study is to evaluate the neurobiological sequels of childhood sexual trauma by monitoring physiological variables among sexually abused girls and women compared to controls. We assessed posttrauma and traumatic life events of 35 females sexually abused in their childhood (age range 7-51 years) and 25 control females (age range 7-54 years). Electroencephalography, frontalis electromyography, electrodermal activity, and heart rate parameters were recorded while watching sets of pictures representing neutral and trauma-suggestive stimuli. A minority of participants met the Diagnostic and Statistical Manual of Mental Disorders criteria for post-traumatic stress disorder. Abused females displayed significant elevations in heart rate, electromyography, and electroencephalography while viewing allusive stimuli and elevated heart rate while viewing neutral stimuli. The dysfunctional regulation of the physiological stress system associated with child sexual abuse may endanger the victims with various stress and anxiety disorders. PMID- 26934545 TI - The Nature of Posttraumatic Growth in Adult Survivors of Child Sexual Abuse. AB - Potential negative sequelae for survivors of child sexual abuse is well documented. However, growing evidence suggests that some individuals who actively cope with traumatic events can progress from a negative trajectory toward positive psychological change, often termed posttraumatic growth. Current posttraumatic growth theories may be of limited applicability to developmental considerations involved in child sexual abuse. This explorative study examines posttraumatic growth among adult female survivors of child sexual abuse. In-depth interviews were conducted with six participants who believed they had grown through coping with their abuse. Data was analyzed using interpretative phenomenological analysis. Three superordinate and nine subordinate themes were identified and explored. Some participants reported experiencing growth and distress simultaneously. Theoretical and clinical implications are examined in relation to the study's findings. PMID- 26934546 TI - The Disclosure Experiences of Male Child Sexual Abuse Survivors. AB - This article explores the diversity in the disclosure process of male survivors of child sexual abuse. Disclosure is a complex process for victims of both genders, however masculine norms and stereotypes have contributed to an environment that often negates the experiences of men. The disclosure process of 17 adult male survivors of child sexual abuse was explored using transcripts of telephone interviews. A combination of two qualitative methodologies, the phenomenological method and interpretive description approach, was used to analyze this secondary data. The results indicated that the majority of the men in the study waited until adulthood to disclose their abuse, with negative stereotypes contributing to their delayed disclosures. In terms of specific experiences with disclosure, the participants found they received both positive and negative responses. These results were consistent with the literature. PMID- 26934547 TI - Connecting Socially Isolated Older Rural Adults with Older Volunteers through Expressive Arts. AB - Employing a participatory arts-based research approach, we examined an innovative program from rural Ontario, Canada, designed to address social isolation among older people. Older socially isolated adults were matched to trained volunteers, where in dyads, the eight pairs created expressive art in their home setting over the course of 10 home visits. With thematic and narrative inquiry, we analysed the experiences and perceptions of the program leader, older participants, and older volunteers via their artistic creations, weekly logs, evaluations, and field notes. The findings reveal a successful intervention that positively influenced the well-being of older adult participants and older volunteers, especially in regards to relationships, personal development, and creating meaning as well as extending the intervention's impact beyond the program's duration. We also discuss opportunities for similar programs to inform policy and enable positive community-based health and social service responses to rural social isolation. PMID- 26934548 TI - [Not Available]. AB - This research examines obstacles faced by older people living with HIV in maintaining their significant social ties (family, friends) in the light of a double theoretical framework, inter-sectionality and the course of life. Favoring a qualitative methodology, this research is based on in-depth, semi-directed interviews with a diverse sample of 38 people living with HIV, aged 50-73 years. Analysis reveals that a significant proportion of participants have experienced ruptures or deterioration of close ties with intimates at the level of family or friends. The principal factors behind these difficulties are the past and present stigma associated with HIV and /or other social positions, long-term effects of HIV, issues related to aging and crosscutting effects of HIV and aging. PMID- 26934549 TI - Evidence-based medicine has been hijacked: a report to David Sackett. AB - This is a confession building on a conversation with David Sackett in 2004 when I shared with him some personal adventures in evidence-based medicine (EBM), the movement that he had spearheaded. The narrative is expanded with what ensued in the subsequent 12 years. EBM has become far more recognized and adopted in many places, but not everywhere, for example, it never acquired much influence in the USA. As EBM became more influential, it was also hijacked to serve agendas different from what it originally aimed for. Influential randomized trials are largely done by and for the benefit of the industry. Meta-analyses and guidelines have become a factory, mostly also serving vested interests. National and federal research funds are funneled almost exclusively to research with little relevance to health outcomes. We have supported the growth of principal investigators who excel primarily as managers absorbing more money. Diagnosis and prognosis research and efforts to individualize treatment have fueled recurrent spurious promises. Risk factor epidemiology has excelled in salami-sliced data-dredged articles with gift authorship and has become adept to dictating policy from spurious evidence. Under market pressure, clinical medicine has been transformed to finance-based medicine. In many places, medicine and health care are wasting societal resources and becoming a threat to human well-being. Science denialism and quacks are also flourishing and leading more people astray in their life choices, including health. EBM still remains an unmet goal, worthy to be attained. PMID- 26934550 TI - Dave Sackett and the ethos of the EBM community. PMID- 26934551 TI - The targeted histone deacetylase inhibitor tefinostat (CHR-2845) shows selective in vitro efficacy in monocytoid-lineage leukaemias. AB - Tefinostat (CHR-2845) is a novel monocyte/macrophage-targeted histone deacetylase (HDAC) inhibitor which is cleaved into its active acid by the intracellular esterase human carboxylesterase-1 (hCE-1). The in vitro efficacy of tefinostat was characterised in cell lines and in a cohort of 73 primary AML and CMML samples. Dose-dependent induction of apoptosis and significant growth inhibitory effects were seen in myelomonocytic (M4), monocytic/monoblastic (M5) and CMML samples in comparison to non-monocytoid AML sub-types (p = 0.007). Importantly, no growth inhibitory effects were seen in normal bone marrow CD34+ cells exposed to AML-toxic doses of tefinostat in clonogenic assays. Expression of hCE-1 was measured by intracellular flow cytometry and immunoblotting across the cohort, with highest levels seen in M5 AML patients. hCE-1 levels correlated with significantly increased tefinostat sensitivity (low EC50) as measured by growth inhibition assays (p = 0.001) and concomitant elevation of the mature monocytoid marker CD14+. Strong induction of intracellular histone protein acetylation was observed in tefinostat-responsive samples, as were high levels of the DNA damage sensor gamma-H2A.X, highlighting potential biomarkers of patient responsiveness. Synergistic interaction between tefinostat and the current standard treatment cytarabine was demonstrated in dose response and clonogenic assays using simultaneous drug addition in primary samples (median Combination Index value = 0.51). These data provide a strong rationale for the further clinical evaluation of tefinostat in monocytoid-lineage haematological neoplasms including CMML and monocyte-lineage AMLs. PMID- 26934553 TI - Prostate stromal cell proteomics analysis discriminates normal from tumour reactive stromal phenotypes. AB - Changes within interstitial stromal compartments often accompany carcinogenesis, and this is true of prostate cancer. Typically, the tissue becomes populated by myofibroblasts that can promote progression. Not all myofibroblasts exhibit the same negative influence, however, and identifying the aggressive form of myofibroblast may provide useful information at diagnosis. A means of molecularly defining such myofibroblasts is unknown. We compared protein profiles of normal and diseased stroma isolated from prostate cancer patients to identify discriminating hallmarks of disease-associated stroma. We included the stimulation of normal stromal cells with known myofibroblast inducers namely soluble TGFbeta and exosome-associated-TGFbeta and compared the function and protein profiles arising. In all 6-patients examined, diseased stroma exhibited a pro-angiogenic influence on endothelial cells, generating large multicellular vessel-like structures. Identical structures were apparent following stimulation of normal stroma with exosomes (5/6 patients), but TGFbeta-stimulation generated a non-angiogenic stroma. Proteomics highlighted disease-related cytoskeleton alterations such as elevated Transgelin (TAGLN). Many of these were also changed following TGFbeta or exosome stimulation and did not well discriminate the nature of the stimulus. Soluble TGFbeta, however triggered differential expression of proteins related to mitochondrial function including voltage dependent ion channels VDAC1 and 2, and this was not found in the other stromal types studied. Surprisingly, Aldehyde Dehydrogenase (ALDH1A1), a stem-cell associated protein was detected in normal stromal cells and found to decrease in disease. In summary, we have discovered a set of proteins that contribute to defining disease associated myofibroblasts, and emphasise the similarity between exosome-generated myofibroblasts and those naturally arising in situ. PMID- 26934552 TI - Immunogenomics reveal molecular circuits of diclofenac induced liver injury in mice. AB - Diclofenac is a non-steroidal anti-inflammatory drug and its use can be associated with severe adverse reactions, notably myocardial infarction, stroke and drug-induced liver injury (DILI). In pursue of immune-mediated DILI mechanisms an immunogenomic study was carried out. Diclofenac treatment of mice at 30 mg/kg for 3 days caused significant serum ALT and AST elevations, hepatomegaly and degenerative changes including hepatic glycogen depletion, hydropic swelling, cholesterolosis and eosinophilic hepatocytes with one animal presenting subsegmental infarction due to portal vein thrombosis. Furthermore, portal/periportal induction of the rate limiting enzyme in ammonia detoxification, i.e. carbamoyl phosphate synthetase 1 was observed. The performed microarray studies informed on > 600 differential expressed genes of which 35, 37 and 50 coded for inflammation, 51, 44 and 61 for immune and 116, 129 and 169 for stress response, respectively after single and repeated dosing for 3 and 14 days. Bioinformatic analysis defined molecular circuits of hepatic inflammation with the growth hormone (Ghr)- and leptin receptor, the protein-tyrosine-phosphatase, selectin and the suppressor-of-cytokine-signaling (Socs) to function as key nodes in gene regulatory networks. Western blotting confirmed induction of fibronectin and M-CSF to hallmark tissue repair and differentiation of monocytes and macrophages. Transcript expression of the macrophage receptor with collagenous structure increased > 7-fold and immunohistochemistry of CD68 evidenced activation of tissue-resident macrophages. Importantly, diclofenac treatment prompted strong expression of phosphorylated Stat3 amongst individual animals and the associated 8- and 4-fold Soc3 and Il-6 induction reinforced Ghr degradation as evidenced by immunoblotting. Moreover, immunohistochemistry confirmed regulation of master regulatory proteins of diclofenac treated mice to suggest complex pro-and anti-inflammatory reactions in immune-mediated hepatic injury. The findings encourage translational research. PMID- 26934554 TI - VEGF promotes gastric cancer development by upregulating CRMP4. AB - This study aimed to investigate the precise role of CRMP4 in gastric tumor growth and patient survival. The mRNA and protein expression levels of CRMP4, VEGF and VEGFR2 were validated by qRT-PCR and immunohistochemistry. We investigated the effects on tumor growth of overexpression and knockdown of CRMP4 both in vitro and in vivo by constructing stable gastric cell lines using lentiviral-mediated transduction and shRNA interference-mediated knockdown of CRMP4 expression. We further validated the role of the ERK/AKT signaling pathways in VEGF and CRMP4 expression using ERK and PI3K inhibitors. Increased expression of VEGF and CRMP4 were observed in gastric cancer tissues compared with tumor-adjacent tissue. We found that higher CRPM4 expression was associated with lymph node metastasis, TNM stage, tumor differentiation and poorer prognosis in gastric cancer patients. In HGC27 and SGC7901 gastric cancer cells, VEGF upregulated CRMP4 in time and dose dependent manners. Overexpression of CRMP4 increased cell proliferation, migration and invasion, whereas knockdown of CRMP4 expression had opposite effects. VEGF activated CRMP4 expression in gastric cancer cells, and this effect was significantly inhibited by MAPK and PI3K inhibitors (PD98059 and LY294002). In mice, CRMP4 overexpression also resulted in increased tumor growth. These results suggest that increased CRMP4 expression mediated by the activation of VEGF signaling facilitates gastric tumor growth and metastasis, which may have clinical implications associated with a reduced survival rate in gastric cancer patients. PMID- 26934555 TI - Genomic characterization of patient-derived xenograft models established from fine needle aspirate biopsies of a primary pancreatic ductal adenocarcinoma and from patient-matched metastatic sites. AB - N-of-1 trials target actionable mutations, yet such approaches do not test genomically-informed therapies in patient tumor models prior to patient treatment. To address this, we developed patient-derived xenograft (PDX) models from fine needle aspiration (FNA) biopsies (FNA-PDX) obtained from primary pancreatic ductal adenocarcinoma (PDAC) at the time of diagnosis. Here, we characterize PDX models established from one primary and two metastatic sites of one patient. We identified an activating KRAS G12R mutation among other mutations in these models. In explant cells derived from these PDX tumor models with a KRAS G12R mutation, treatment with inhibitors of CDKs (including CDK9) reduced phosphorylation of a marker of CDK9 activity (phospho-RNAPII CTD Ser2/5) and reduced viability/growth of explant cells derived from PDAC PDX models. Similarly, a CDK inhibitor reduced phospho-RNAPII CTD Ser2/5, increased apoptosis, and inhibited tumor growth in FNA-PDX and patient-matched metastatic PDX models. In summary, PDX models can be constructed from FNA biopsies of PDAC which in turn can enable genomic characterization and identification of potential therapies. PMID- 26934556 TI - High blood sugar levels significantly impact the prognosis of colorectal cancer patients through down-regulation of microRNA-16 by targeting Myb and VEGFR2. AB - The high prevalence of type 2 diabetes mellitus in colorectal cancer patients is a crucial public health issue worldwide. The deregulation of microRNAs has been shown to be associated with the progression of CRC; however, the effects of high blood sugar levels on miR deregulation and, in turn, CRC remain unexplored. In this study, 520 CRC patients were classified into two groups according to their blood sugar levels (?110 or <110 mg/dL). Clinicopathologic features, clinical outcomes, and serum miR-16 levels of the two groups were then analyzed, while cell cycles, cell proliferation, migration, and cellular miR-16 expression were investigated via D-(+)-glucose administration. Additionally, the target genes of miR-16 were identified. Through multivariate analysis, both the disease-free survival and overall survival of the CRC patients were found to be associated with the UICC stage, perineural invasion, and blood glucose levels (P < 0.05). Serum miR-16 levels were significantly lower in the high blood glucose patients than in the normal blood glucose patients (P = 0.0329). With D-(+)-glucose administration, the proliferation and migration of CRC cells in vitro increased remarkably (P < 0.05), while their accumulation in the G1 phase decreased significantly. Cellular miR-16 expression was suppressed by D-(+)-glucose administration. The expression levels of two target genes, Myb and VEGFR2, were affected significantly by miR-16, while glucose administration inhibited miR-16 expression and enhanced tumor cell proliferation and migration. Hyperglycemia can impact the clinical outcomes of CRC patients, likely by inhibiting miR-16 expression and the expression of its downstream genes Myb and VEGFR2. PMID- 26934557 TI - CD40-activated B cells induce anti-tumor immunity in vivo. AB - The introduction of checkpoint inhibitors represents a major advance in cancer immunotherapy. Some studies on checkpoint inhibition demonstrate that combinatorial immunotherapies with secondary drivers of anti-tumor immunity provide beneficial effects for patients that do not show a strong endogenous immune response. CD40-activated B cells (CD40B cells) are potent antigen presenting cells by activating and expanding naive and memory CD4+ and CD8+ and homing to the secondary lymphoid organs. In contrast to dendritic cells, the generation of highly pure CD40B cells is simple and time efficient and they can be expanded almost limitlessly from small blood samples of cancer patients. Here, we show that the vaccination with antigen-loaded CD40B cells induces a specific T cell response in vivo comparable to that of dendritic cells. Moreover, we identify vaccination parameters, including injection route, cell dose and vaccination repetitions to optimize immunization and demonstrate that application of CD40B cells is safe in terms of toxicity in the recipient. We furthermore show that preventive immunization of tumor-bearing mice with tumor antigen-pulsed CD40B cells induces a protective anti-tumor immunity against B16.F10 melanomas and E.G7 lymphomas leading to reduced tumor growth. These results and our straightforward method of CD40B-cell generation underline the potential of CD40B cells for cancer immunotherapy. PMID- 26934558 TI - Control of CREB expression in tumors: from molecular mechanisms and signal transduction pathways to therapeutic target. AB - The cyclic AMP response element binding (CREB) protein has pleiotropic activities in physiologic processes. Due to its central position downstream of many growth signaling pathways CREB has the ability to influence cell survival, growth and differentiation of normal, but also of tumor cells suggesting an oncogenic potential of CREB. Indeed, increased CREB expression and activation is associated with tumor progression, chemotherapy resistance and reduced patients' survival. We summarize here the different cellular functions of CREB in tumors of distinct histology as well as its use as potential prognostic marker. In addition, the underlying molecular mechanisms to achieve constitutive activation of CREB including structural alterations, such as gene amplification and chromosomal translocation, and deregulation, which could occur at the transcriptional, post transcriptional and post-translational level, will be described. Since downregulation of CREB by different strategies resulted in inhibition of cell proliferation, invasion and induction of apoptosis, the role of CREB as a promising target for cancer therapy will be also discussed. PMID- 26934561 TI - Measurement of blood flow in the deep veins of the lower limb using the gekoTM neuromuscular electro-stimulation device. AB - BACKGROUND: A previous study using electrical stimulation of the common peroneal nerve (gekoTM) to activate the venous muscle pump measured blood flow in both the femoral and popliteal veins. Increased blood flow by as much as 60% was demonstrated in the femoral vein. Such an increase is assumed to be as a result of an increase in venous flow from the deep calf veins; however this has yet to be confirmed. The aim of this study was to conduct direct measurements in these deep calf veins to confirm this assumption in healthy individuals. METHODS: This was a single centre open-label intra-subject healthy volunteer comparison of blood flow in the peroneal, posterior tibial and gastrocnemial veins with and without the gekoTM device. The device was applied to 18 volunteers. Peak venous velocity (PV) and ejected volume per individual stimulus (VS) and volume flow (VF) was determined using ultrasound. RESULTS: Peak velocity (PV) increased 216% in the peroneal vein, by 112% in the posterior tibial vein and by 137% in the gastrocnemial vein (P<0.001). Ejected volume per stimulus increased by 113% in the peroneal vein, by 38% in the posterior tibial vein and by 50% in the gastrocnemial vein (P<0.003). Associated volume flows during the muscle contraction were increased by 36%, 25% and 17%, respectively (P=0.05) CONCLUSIONS: This is the first time that neuromuscular electro-stimulation has been shown to be an effective method of increasing flow in the axial deep veins of the calf. Significant increases in velocity and volume flow in response to the electrical stimulus were seen in all three veins studied. Enhancements of both blood velocity and volume flow are key factors in the prevention of venous stasis and ultimately deep vein thrombosis (DVT). Further studies are justified to determine the efficacy of the device in the prevention of DVT. PMID- 26934559 TI - CXCR4/CXCL12/CXCR7 axis is functional in neuroendocrine tumors and signals on mTOR. AB - OBJECTIVE: To evaluate the possible crosstalk between C-X-C chemokine receptor 4 (CXCR4)/C-X-C motif chemokine 12 (CXCL12)/C-X-C chemokine receptor 7 (CXCR7) axis with the mammalian target of rapamycin (mTOR) pathway in neuroendocrine tumors (NETs). METHODS: Sixty-one human NETs were included into the study. CXCR4/CXCL12/CXCR7 axis and mTOR pathway were assessed by qRT-PCR and immunohistochemistry (IHC). The effect of mTOR inhibitor, RAD001, was evaluated on CXCR4 pathway through proliferation and p-Erk and p-AKT induction. RESULTS: CXCR4/CXCL12/CXCR7 axis and p-mTOR were found to be active and correlated with grading, Ki67 index and tumor stage. mTOR pathway activation significantly correlated with poor prognosis. In human NET cells, CXCL12 induced mTOR signalling while AMD3100 (CXCR4-antagonist) impaired it. The mTOR-antagonist, RAD001, impaired the CXCL12-dependent induction of CXCR4 downstream effectors. Combination of AMD3100 and RAD001 potentiate cell growth inhibition. CONCLUSIONS: CXCR4/CXCL12/CXCR7 axis is active in NETs and signals on mTOR. CXCR4 might be considered a prognostic factor in NETs. Combined treatment with AMD3100 and RAD001 may provide clinical benefits in NET patients with drug-resistant. PMID- 26934562 TI - Corrigendum. PMID- 26934560 TI - A new immunization and treatment strategy for mouse mammary tumor virus (MMTV) associated cancers. AB - Mouse Mammary Tumor Virus (MMTV) causes mammary carcinoma or lymphoma in mice. An increasing body of evidence in recent years supports its involvement also in human sporadic breast cancer. It is thus of importance to develop new strategies to impair the development, growth and metastasis of MMTV-associated cancers. The signal peptide of the envelope precursor protein of this virus: MMTV-p14 (p14) is an excellent target for such strategies, due to unique characteristics distinct from its regular endoplasmic reticulum targeting function. These include cell surface expression in: murine cancer cells that harbor the virus, human breast cancer (MCF-7) cells that ectopically express p14, as well as cultured human cells derived from an invasive ductal breast carcinoma positive for MMTV sequences. These findings support its use in signal peptide-based immune targeting. Indeed, priming and boosting mice with p14 elicits a specific anti signal peptide immune response sufficient for protective vaccination against MMTV associated tumors. Furthermore, passive immunization using a combination of anti p14 monoclonal antibodies or the transfer of T-cells from immunized mice (Adoptive Cell Transfer) is also therapeutically effective. With reports demonstrating involvement of MMTV in human breast cancer, we propose the immune mediated targeting of p14 as a strategy for prevention, treatment and diagnosis of MMTV-associated cancers. PMID- 26934563 TI - Spontaneous Double Hydrometallation Induced by N->M Coordination in Organometallic Hydrides of Group 14 Elements. AB - Our attempts to synthesise N->M intramolecularly coordinated diorganometallic hydrides L2MH2 [M=Si (4), Ge (5), Sn (6)] containing the CH=N imine group (in which L is C,N-chelating ligand {2-[(2,6-iPr2C6H3)N=CH]C6 H4}(-)) yielded 1,1' bis(2,6-diisopropylphenyl)-2,2'-spriobi[benzo[c][1,2]azasilole] (7), 1,1'-bis(2,6 diisopropylphenyl)-2,2'-spriobi[benzo[c][1,2]azagermole] (8) and C,N-chelated homoleptic stannylene L2Sn (10), respectively. Compounds 7 and 8 are an outcome of a spontaneous double hydrometallation of the two CH=N imine moieties induced by N->M intramolecular coordination (M=Si, Ge) in the absence of any catalyst. In contrast, the diorganotin hydride L2SnH2 (6) is redox-unstable and the reduction of the tin centre with the elimination of H2 provided the C,N-chelated homoleptic stannylene L2Sn (10). Compounds 7 and 8 were characterised by NMR spectroscopy and X-ray diffraction analysis. Because the proposed N->M intramolecularly coordinated diorganometallic hydrides L2MH2 [M=Si (4), Ge (5), Sn (6)] revealed two different types of reduction reactions, DFT calculations were performed to gain an insight into the structures and bonding of the non-isolable diorganometallic hydrides as well as the products of their subsequent reactions. Furthermore, the thermodynamic profiles of the different reaction pathways with respect to the central metal atom were also investigated. PMID- 26934565 TI - Lacrimal Sac Wall Granuloma Simulating a Neoplasm. PMID- 26934564 TI - A Unique Ocular Presentation of Extragenital Lichen Sclerosus. AB - Lichen sclerosus is a chronic, debilitating, and recurring disease that is most commonly seen affecting the anogenital region. Extragenital locations of lichen sclerosus has been well documented, frequently seen in the shoulders, neck, trunk, breasts, and arms, however, infrequently of the face. Specifically, extragenital lichen sclerosus has been reported in several cases to be involving the infraorbital region, but to our knowledge it has never been found affecting the adnexa of the eye. To our understanding, this is the first documented report of a patient with extragenital lichen sclerosus of an eyelid. PMID- 26934566 TI - Carcinoma Ex Pleomorphic Adenoma of the Lacrimal Gland with Epithelial Myoepithelial Carcinoma Histologic Type. AB - A 53-year-old woman presented with a 1-month history of decreased vision and progressive left periorbital fullness. Exam and radiography confirmed a left lacrimal gland mass causing mass effect on the globe and a compressive optic neuropathy. Orbitotomy with excisional biopsy confirmed carcinoma ex pleomorphic adenoma with epithelial and myoepithelial differentiation. Following a negative systemic workup, the patient underwent radiation therapy and remains free of clinical or radiographic disease 24 months following surgery. Herein the presentation, radiography, histopathology, and treatment outcome of a rare case of lacrimal gland epithelial-myoepithelial carcinoma ex pleomorphic adenoma is described. PMID- 26934568 TI - Suitability of Bioelectrical Based Methods to Assess Water Compartments in Recreational and Elite Athletes. AB - OBJECTIVE: It is important for highly active individuals to easily and accurately assess their hydration level. Bioelectrical impedance (BIA) can potentially meet these needs but its validity in active individuals is not well established. We aim to validate total body water (TBW), extracellular water (ECW), and intracellular water (ICW) estimates obtained from 50 kHz BIA, bioelectrical impedance spectroscopy (BIS), and BIA-based models against dilution techniques in 2 populations: active adults and elite athletes. METHODS: Active males (N = 28, 20-39 years) involved in recreational sports and elite athletes (females: N = 57, 16-35 years; males: N = 127, 16-38 years) participated in this study. TBW and ECW were assessed with deuterium and bromide dilution, respectively. ICW was assessed as their difference. Body water compartments were also assessed by BIA (BIA-101), BIS (model 4200), and BIA-based equations. RESULTS: Small but significant differences were observed between alternative methods and the criterion in all subsamples. In female athletes, r(2) > 0.69, r(2) > 0.57, and r(2) > 0.65 were observed between methods in the TBW, ECW, and ICW estimates. In males, r(2) > 0.75, r(2) > 0.65, and r(2) > 0.68 were found between alternative and reference methods in the TBW, ECW, and ICW estimates, respectively, whereas for male recreational exercisers, r(2) > 0.58, r(2) > 0.73, and r(2) > 0.75 were observed. Pure errors ranged between 0.19 to 3.32 kg for TBW, 0.64 to 1.63 for ECW, and 1.98 to 2.64 in ICW. The highest limits of agreement (LoA) were observed in Van Loan and Mayclin equation and the BIA method, respectively, for TBW and ECW assessment and the lowest LoA were observed in BIS for both TBW and ECW estimates. CONCLUSIONS: The higher accuracy of BIS in predicting individual TBW, ECW, and ICW highlights its utility in water assessment of recreational and elite athletes. PMID- 26934569 TI - Incidence, Predictors, and Clinical Implications of Discontinuing Therapy with Inhaled Long-Acting Bronchodilators among Patients with Chronic Obstructive Pulmonary Disease. AB - Incidence, predictors and effect of discontinuation of long-acting bronchodilators on the risk of death or hospital admission among adults with Chronic Obstructive Pulmonary Disease (COPD) were assessed in a large population based prospective study carried out by linking Italian healthcare utilization databases. Specifically, the cohort of 17,490 beneficiaries of the National Health Service in the Italian Region of Lombardy, aged 40 years or older, who started long-acting bronchodilators therapy during 2005-2008 was followed from first dispensation until 2012. During this period, patients who experienced discontinuation of long-acting bronchodilators were identified. Hospitalizations for COPD and deaths for any cause (composite clinical outcome) were also identified during follow-up. A Cox proportional hazards model was fitted to identify predictors of discontinuation. The case-crossover design was used to assess the implications of treatment discontinuation on the clinical outcome risk. Cumulative incidences of discontinuation were, respectively, 67%, 80%, and 92% at 6 months, 1 year, and 5 years since initial treatment. Significant predictors of discontinuation were female gender, younger age, starting treatment with fixed-dose combination of inhaled bronchodilators and corticosteroids, using antibiotics, inhaled long-acting bronchodilators and corticosteroids and not using short-acting bronchodilators, other respiratory drugs and systemic corticosteroids during follow-up. Odds ratios (95% confidence intervals) for the clinical outcome associated with not discontinuing long-acting bronchodilators was 0.64 (0.50 to 0.82). In conclusion, in the real-life setting, discontinuation of inhaled long-acting bronchodilators in adults with COPD is high even after just 6 months, even though persistence to these drugs reduces the risk of severe outcomes. PMID- 26934570 TI - The application of somatic CRISPR-Cas9 to conditional genome editing in Caenorhabditis elegans. AB - Forward and reverse genetic approaches have been well developed in the nematode Caenorhabditis elegans; however, efficient genetic tools to generate conditional gene mutations are still in high demand. Recently, the Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR-associated protein 9 (CRISPR-Cas9) system for genome modification has provided an additional tool for C. elegans researchers to achieve simple and efficient conditional targeted mutagenesis. Here, we review recent advances in the somatic expression of Cas9 endonuclease for conditional gene editing. We present some practical considerations for improving the efficiency and reducing the off-target effects of somatic CRISPR Cas9 and highlight a strategy to analyze somatic mutation at single-cell resolution. Finally, we outline future applications and consider challenges for this emerging genome editing platform that will need to be addressed in the future. PMID- 26934567 TI - Coding Variation in ANGPTL4, LPL, and SVEP1 and the Risk of Coronary Disease. AB - BACKGROUND: The discovery of low-frequency coding variants affecting the risk of coronary artery disease has facilitated the identification of therapeutic targets. METHODS: Through DNA genotyping, we tested 54,003 coding-sequence variants covering 13,715 human genes in up to 72,868 patients with coronary artery disease and 120,770 controls who did not have coronary artery disease. Through DNA sequencing, we studied the effects of loss-of-function mutations in selected genes. RESULTS: We confirmed previously observed significant associations between coronary artery disease and low-frequency missense variants in the genes LPA and PCSK9. We also found significant associations between coronary artery disease and low-frequency missense variants in the genes SVEP1 (p.D2702G; minor-allele frequency, 3.60%; odds ratio for disease, 1.14; P=4.2*10( 10)) and ANGPTL4 (p.E40K; minor-allele frequency, 2.01%; odds ratio, 0.86; P=4.0*10(-8)), which encodes angiopoietin-like 4. Through sequencing of ANGPTL4, we identified 9 carriers of loss-of-function mutations among 6924 patients with myocardial infarction, as compared with 19 carriers among 6834 controls (odds ratio, 0.47; P=0.04); carriers of ANGPTL4 loss-of-function alleles had triglyceride levels that were 35% lower than the levels among persons who did not carry a loss-of-function allele (P=0.003). ANGPTL4 inhibits lipoprotein lipase; we therefore searched for mutations in LPL and identified a loss-of-function variant that was associated with an increased risk of coronary artery disease (p.D36N; minor-allele frequency, 1.9%; odds ratio, 1.13; P=2.0*10(-4)) and a gain of-function variant that was associated with protection from coronary artery disease (p.S447*; minor-allele frequency, 9.9%; odds ratio, 0.94; P=2.5*10(-7)). CONCLUSIONS: We found that carriers of loss-of-function mutations in ANGPTL4 had triglyceride levels that were lower than those among noncarriers; these mutations were also associated with protection from coronary artery disease. (Funded by the National Institutes of Health and others.). PMID- 26934571 TI - N-Heterocyclic Carbene-Ytterbium Amide as a Recyclable Homogeneous Precatalyst for Hydrophosphination of Alkenes and Alkynes. AB - The N-heterocyclic carbene-ytterbium(II) amides (NHC)2Yb[N(SiMe3)2]2 (1: NHC: 1,3,4,5-tetramethylimidazo-2-ylidene (IMe4); 2: NHC: 1,3-diisopropyl-4,5 dimethylimidazol-2-ylidene (IiPr)) and the NHC-stabilized rare-earth phosphide (IMe4)3Yb(PPh2)2 (3) have been synthesized and fully characterized. Complexes 1-3 are active precatalysts for the hydrophosphination of alkenes, alkynes, and dienes and exhibited much superior catalytic activity to that of the NHC-free amide (THF)2Yb[N(SiMe)2]2. Complex 1 is the most active precursor among the three complexes. In particular, complex 1 can be recycled and recovered from the reaction media after the catalytic reactions. Furthermore, it was found that complex 3 could catalyze the polymerization of styrene to yield atactic polystyrenes with low molecular weights. To the best of our knowledge, complex 1 represents the first rare-earth complex that can be recovered after catalytic reactions. PMID- 26934573 TI - Pulling Together as a Community to Ensure the Quality of the Literature. AB - Pulling up our socks! In this Editorial, ChemMedChem Editor-in-Chief Natalia Ortuzar discusses how editors, reviewers and authors might all pull together to address the issue of reproducibility of data reported in the literature. PMID- 26934572 TI - Stable Ultrathin-Shell Double Emulsions for Controlled Release. AB - Double emulsions are normally considered as metastable systems and this limit in stability restricts their applications. To enhance their stability, the outer shell can be converted into a mechanically strong layer, for example, a polymeric layer, thus allowing improved performance. This conversion can be problematic for food and drug applications, as a toxic solvent is needed to dissolve the polymer in the middle phase and a high temperature is required to remove the solvent. This process can also be highly complex, for example, involving UV initiation of polymeric monomer crosslinking. In this study, we report the formation of biocompatible, water-in-oil-in-water (W/O/W) double emulsions with an ultrathin layer of fish oil. We demonstrate their application for the encapsulation and controlled release of small hydrophilic molecules. Without a trigger, the double emulsions remained stable for months, and the release of small molecules was extremely slow. In contrast, rapid release was achieved by osmolarity shock, leading to complete release within 2 h. This work demonstrates the significant potential of double emulsions, and provides new insights into their stability and practical applications. PMID- 26934574 TI - Evaluation of Chosen Cytokine Levels among Patients with Herpes Zoster as Ability to Provide Immune Response. AB - AIM AND BACKGROUND: Herpes zoster is a viral disease caused by the reactivation of varicella-zoster virus (VZV) which remained latent in the cranial nerve or dorsal root ganglia. Cell-mediated immunity is known to decline with age as part of immunosenescence and can lead to the reactivation of VZV. Whereas herpes zoster is usually mild in healthy young persons, older patients are at increased risk for complications. In the present study we investigated the serum cytokine profile (IL-17, IL-23, IL-21, IL-4, IL-12), representing cellular and humoral immunity and assessed the level of VZV IgG antibodies in patients with herpes zoster. METHODS: We investigated the serum concentrations of IL-17, IL-23, IL-21, IL-4, IL-12 and the level of VZV IgG antibodies in 23 patients with herpes zoster who did not develop superinfection. The control group was represented by 21 individuals in similar age with no inflammatory and infectious diseases. Cytokine and antibodies levels were measured by ELISA method. Statistical analysis was performed using the ROC curve (receiver operating characteristic), t-test, Welch's t-test, and nonparametric tests with STATISTICA 10 software. RESULTS: In patients with herpes zoster, the serum level of IL-17, IL-23, IL-21, IL-4 and IL 12 as well as VZV IgG antibodies titer were statistically significantly increased compared to control group. CONCLUSION: Our results confirm the broad activation of the immune system involving humoral and cell-mediated immunity. PMID- 26934575 TI - Predictive Capacity of Biomarkers for Severe Acute Pancreatitis. AB - BACKGROUND: Early prediction of severe acute pancreatitis (SAP) substantially improves treatment of patients. A large amount of biomarkers have been studied with this objective. The aim of this work was to study predictive biomarkers using preset cut-off levels in an unselected population of patients with acute pancreatitis (AP). METHODS: 232 patients (52.2% males, median age 66 years) with AP admitted to Skane University Hospital, Malmo, were consecutively enrolled. Blood samples were collected upon admission and clinical data were gathered both prospectively at inclusion and through review of medical notes. Cut-off levels were defined based on the reports of prior studies, and through their results eight biomarkers (IL-1beta, IL-6, IL-8, IL-10, TNF-alpha, MCP-1, procalcitonin and D-dimer) were selected for analysis. RESULTS: Of the patients, 83.2% had mild AP and 16.8% had SAP. Levels of IL-1beta, IL-6 and IL-10 were significantly (p < 0.05) higher upon admission in the group with SAP. When applying the preset cut off levels on our material, sensitivity and specificity for prediction of severity were low. Receiver operating characteristic curves showed that selected cut-off levels were acceptable, but areas under the curves were inferior compared to other studies. The results did not improve when using the revised Atlanta 2012 classification. CONCLUSIONS: Previous studies on severity prediction of AP are difficult to compare due to large variations in setups and outcomes. Calculated cut-offs in our cohort were in acceptable range from preset levels, however areas under the curves were low, indicating suboptimal biomarkers for the unselected population investigated. For comparable results and possible clinical implementations, future studies need large consecutive series with a reasonable percentage of severe cases. Additionally, novel biomarkers need to be explored. PMID- 26934576 TI - KLF4 is downregulated but not mutated during human esophageal squamous cell carcinogenesis and has tumor stage-specific functions. AB - The transcriptional regulator Kruppel-like factor 4 (KLF4) is decreased in human esophageal squamous cell cancer (ESCC), and Klf4 deletion in mice produces squamous cell dysplasia. Nonetheless the mechanisms of KLF4 downregulation in ESCC and the functions of KLF4 during ESCC development and progression are not well understood. Here, we sought to define the regulation of KLF4 and delineate the stage-specific effects of KLF4 in ESCC. We found that KLF4 expression was decreased in human ESCC and in 8 of 9 human ESCC cell lines. However, by genomic sequencing, we observed no KLF4 mutations or copy number changes in any of 52 human ESCC, suggesting other mechanisms for KLF4 silencing. In fact, KLF4 expression in human ESCC cell lines was increased by the DNA methylation inhibitor 5-azacytidine, suggesting an epigenetic mechanism for KLF4 silencing. Surprisingly, while KLF4 decreased in high-grade dysplasia and early stage tumors, KLF4 increased with advanced cancer stage, and KLF4 expression in ESCC was inversely correlated with survival. Interestingly, KLF4 promoted invasion of human ESCC cells, providing a functional link to the stage-specific expression of KLF4. Taken together, these findings suggest that KLF4 loss is necessary for esophageal tumorigenesis but that restored KLF4 expression in ESCC promotes tumor spread. Thus, the use of KLF4 as a diagnostic and therapeutic target in cancer requires careful consideration of context. PMID- 26934577 TI - Exome sequencing of oral squamous cell carcinoma in users of Arabian snuff reveals novel candidates for driver genes. AB - The study sought to identify genetic aberrations driving oral squamous cell carcinoma (OSCC) development among users of shammah, an Arabian preparation of smokeless tobacco. Twenty archival OSCC samples, 15 of which with a history of shammah exposure, were whole-exome sequenced at an average depth of 127*. Somatic mutations were identified using a novel, matched controls-independent filtration algorithm. CODEX and Exomedepth coupled with a novel, Database of Genomic Variant based filter were employed to call somatic gene-copy number variations. Significantly mutated genes were identified with Oncodrive FM and the Youn and Simon's method. Candidate driver genes were nominated based on Gene Set Enrichment Analysis. The observed mutational spectrum was similar to that reported by the TCGA project. In addition to confirming known genes of OSCC (TP53, CDKNA2, CASP8, PIK3CA, HRAS, FAT1, TP63, CCND1 and FADD) the analysis identified several candidate novel driver events including mutations of NOTCH3, CSMD3, CRB1, CLTCL1, OSMR and TRPM2, amplification of the proto-oncogenes FOSL1, RELA, TRAF6, MDM2, FRS2 and BAG1, and deletion of the recently described tumor suppressor SMARCC1. Analysis also revealed significantly altered pathways not previously implicated in OSCC including Oncostatin-M signalling pathway, AP-1 and C-MYB transcription networks and endocytosis. There was a trend for higher number of mutations, amplifications and driver events in samples with history of shammah exposure particularly those that tested EBV positive, suggesting an interaction between tobacco exposure and EBV. The work provides further evidence for the genetic heterogeneity of oral cancer and suggests shammah-associated OSCC is characterized by extensive amplification of oncogenes. PMID- 26934578 TI - Transition-Metal-Free Borylation of Allylic and Propargylic Alcohols. AB - The base-catalyzed allylic borylation of tertiary allylic alcohols allows the synthesis of 1,1-disubstituted allyl boronates, in moderate to high yield. The unexpected tandem performance of the Lewis acid-base adduct, [Hbase](+) [MeO-B2 pin2 ](-) favored the formation of 1,2,3-triborylated species from the tertiary allylic alcohols and 1-propargylic cyclohexanol at 90 degrees C. PMID- 26934579 TI - Slowing after Observed Error Transfers across Tasks. AB - After committing an error, participants tend to perform more slowly. This phenomenon is called post-error slowing (PES). Although previous studies have explored the PES effect in the context of observed errors, the issue as to whether the slowing effect generalizes across tasksets remains unclear. Further, the generation mechanisms of PES following observed errors must be examined. To address the above issues, we employed an observation-execution task in three experiments. During each trial, participants were required to mentally observe the outcomes of their partners in the observation task and then to perform their own key-press according to the mapping rules in the execution task. In Experiment 1, the same tasksets were utilized in the observation task and the execution task, and three error rate conditions (20%, 50% and 80%) were established in the observation task. The results revealed that the PES effect after observed errors was obtained in all three error rate conditions, replicating and extending previous studies. In Experiment 2, distinct stimuli and response rules were utilized in the observation task and the execution task. The result pattern was the same as that in Experiment 1, suggesting that the PES effect after observed errors was a generic adjustment process. In Experiment 3, the response deadline was shortened in the execution task to rule out the ceiling effect, and two error rate conditions (50% and 80%) were established in the observation task. The PES effect after observed errors was still obtained in the 50% and 80% error rate conditions. However, the accuracy in the post-observed error trials was comparable to that in the post-observed correct trials, suggesting that the slowing effect and improved accuracy did not rely on the same underlying mechanism. Current findings indicate that the occurrence of PES after observed errors is not dependent on the probability of observed errors, consistent with the assumption of cognitive control account. Moreover, the PES effect appears across tasksets with distinct stimuli and response rules in the context of observed errors, reflecting a generic process. Additionally, the slowing effect and improved accuracy in the post-observed error trial do not occur together, suggesting that they are independent behavioral adjustments in the context of observed errors. PMID- 26934581 TI - Brain metastases detection on MR by means of three-dimensional tumor-appearance template matching. AB - PURPOSE: To develop and evaluate a method for an automatic detection of brain metastases in MR images. MATERIALS AND METHODS: Nineteen patients were scanned using a 1.5 Tesla MR scanner. Two radiologists and a radiation oncologist marked the location of the brain metastases. The training group consisted of eight patients harboring 20 metastases. First, three-dimensional (3D) tumor-appearance templates were cross-correlated with MR brain images to evaluate their similarity, and a correlation threshold was established for metastasis candidates. Afterward, a method to reduce false positive rate (FPR) was applied: each detected object was segmented and its degree of anisotropy (DA) was obtained, removing the elongated structures with a DA above the optimal value from the receiver operating characteristic curve. Finally, the method was statistically validated in two groups: 11 patients with 42 brain metastases and 11 patients without metastases. RESULTS: The method led to a sensitivity of 80% and an FPR per slice of 0.023 and 2.75 per patient in the training group. In the first validation group, a sensitivity of 88.10% and an FPR per slice of 0.05 corresponding to 6.91 false positives per patient were obtained. DA implementation decreased 3.5 times FPR compared with templates alone. It improved the radiologist's performance in metastases less than 10 mm from 89-93% to 100%. In the second validation group the FPR was 0.04 per slice and 5.18 per patient. CONCLUSION: This method demonstrates that 3D template matching applying DA technique has high sensitivity and low FPR for detecting brain metastases in MR images. J. Magn. Reson. Imaging 2016;44:642-652. PMID- 26934580 TI - Autism Linked to Increased Oncogene Mutations but Decreased Cancer Rate. AB - Autism spectrum disorder (ASD) is one phenotypic aspect of many monogenic, hereditary cancer syndromes. Pleiotropic effects of cancer genes on the autism phenotype could lead to repurposing of oncology medications to treat this increasingly prevalent neurodevelopmental condition for which there is currently no treatment. To explore this hypothesis we sought to discover whether autistic patients more often have rare coding, single-nucleotide variants within tumor suppressor and oncogenes and whether autistic patients are more often diagnosed with neoplasms. Exome-sequencing data from the ARRA Autism Sequencing Collaboration was compared to that of a control cohort from the Exome Variant Server database revealing that rare, coding variants within oncogenes were enriched for in the ARRA ASD cohort (p<1.0 x 10(-8)). In contrast, variants were not significantly enriched in tumor suppressor genes. Phenotypically, children and adults with ASD exhibited a protective effect against cancer, with a frequency of 1.3% vs. 3.9% (p<0.001), but the protective effect decreased with age. The odds ratio of neoplasm for those with ASD relative to controls was 0.06 (95% CI: 0.02, 0.19; p<0.0001) in the 0 to 14 age group; 0.35 (95% CI: 0.14, 0.87; p = 0.024) in the 15 to 29 age group; 0.41 (95% CI: 0.15, 1.17; p = 0.095) in the 30 to 54 age group; and 0.49 (95% CI: 0.14, 1.74; p = 0.267) in those 55 and older. Both males and females demonstrated the protective effect. These findings suggest that defects in cellular proliferation, and potentially senescence, might influence both autism and neoplasm, and already approved drugs targeting oncogenic pathways might also have therapeutic value for treating autism. PMID- 26934582 TI - Differences in Moral Judgment on Animal and Human Ethics Issues between University Students in Animal-Related, Human Medical and Arts Programs. AB - Moral judgment in relation to animal ethics issues has rarely been investigated. Among the research that has been conducted, studies of veterinary students have shown greater use of reasoning based on universal principles for animal than human ethics issues. This study aimed to identify if this was unique to students of veterinary and other animal-related professions. The moral reasoning of first year students of veterinary medicine, veterinary technology, and production animal science was compared with that of students in non-animal related disciplines of human medicine and arts. All students (n = 531) completed a moral reasoning test, the VetDIT, with animal and human scenarios. When compared with reasoning on human ethics issues, the combined group of students evaluating animal ethics issues showed higher levels of Universal Principles reasoning, lower levels of Personal Interest reasoning and similar levels of Maintaining Norms reasoning. Arts students showed more personal interest reasoning than students in most animal-related programs on both animal and human ethics issues, and less norms-based reasoning on animal ethics issues. Medical students showed more norms-based reasoning on animal ethics issues than all of the animal-related groups. There were no differences in principled reasoning on animal ethics issues between program groups. This has implications for animal-related professions and education programs showing that students' preference for principled reasoning on animal ethics issues is not unique to animal-related disciplines, and highlighting the need to develop student (and professional) capacity to apply principled reasoning to address ethics issues in animal industries to reduce the risk of moral distress. PMID- 26934584 TI - Exploring social inclusion strategies for public health research and practice: The use of participatory visual methods to counter stigmas surrounding street based substance abuse in Colombia. AB - This paper presents the participatory visual research design and findings from a qualitative assessment of the social impact of bazuco and inhalant/glue consumption among street youth in Bogota, Colombia. The paper presents the visual methodologies our participatory action research (PAR) team employed in order to identify and overcome the stigmas and discrimination that street youth experience in society and within state-sponsored drug rehabilitation programmes. I call for critical reflection regarding the broad application of the terms 'participation' and 'participatory' in visual research and urge scholars and public health practitioners to consider the transformative potential of PAR for both the research and practice of global public health in general and rehabilitation programmes for street-based substance abuse in Colombia in particular. The paper concludes with recommendations as to how participatory visual methods can be used to promote social inclusion practices and to work against stigma and discrimination in health-related research and within health institutions. PMID- 26934585 TI - Survey of U.S. zoo and aquarium animal care staff attitudes regarding humane euthanasia for population management. AB - The humane euthanasia of animals for population management, or culling, has been suggested as one possible tool for managing animal populations for sustainability, and recent, highly publicized euthanasia of zoo animals in Copenhagen has stimulated global conversation about population management in zoos. We conducted a nationwide survey of U.S. zoo and aquarium personnel, including keepers, managers, and leaders of AZA animal programs, to assess their overall attitudes regarding population management euthanasia. The surveyed populations were generally very aware of the concept of population management euthanasia. Managers and animal program leaders were more supportive of euthanasia than keepers. We found that regardless of role, men were more supportive of euthanasia than women. Those personnel who were aware of instances of population management euthanasia at their institutions before were more supportive of it than those who were not. Support for culling varied with the kind of animal being considered for it, with three general taxon acceptability groupings emerging. Education, tenure in the profession, taxonomic expertise, and whether or not the responder took the survey before or after the Copenhagen events were not strong predictors of attitudes. Overall, the surveyed populations were approximately evenly split in terms of being in favor of euthanasia, not supporting euthanasia, or being unsure. Most responders indicated that they would be more likely to accept culling if more information was provided on its rationale. These results will form the basis for further discussions on the role of humane euthanasia for population management. Zoo Biol. 35:187-200, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26934586 TI - Double Stereodifferentiation in the Asymmetric Dihydroxylation of Optically Active Olefins. AB - A study of the stereochemical control on the asymmetric dihydroxylation of the double bond of optically active vinyl epoxides and their derivatives (bromo derivatives, azido derivatives, and vinyl aziridines) was carried out and the obtained results are herein reported. The most interesting results were obtained on trans alpha,beta-unsaturated epoxy esters, which were successfully converted with a diastereomeric ratio >80% into the corresponding diols using either the matched or the mismatched conditions, depending on the ligand used. Unprotected bromo derivatives and unprotected aziridines did not afford significant results, while for the protected bromo derivatives, azido derivatives, and N-Boc protected aziridines the matched conditions led to a diastereomeric ratio >95%. Chirality 28:387-393, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26934587 TI - Assessing Fish and Motile Fauna around Offshore Windfarms Using Stereo Baited Video. AB - There remains limited knowledge of how offshore windfarm developments influence fish assemblages, particularly at a local scale around the turbine structures. Considering the existing levels of anthropogenic pressures on coastal fish populations it is becoming increasingly important for developers and environmental regulators to gain a more comprehensive understanding of the factors influencing fish assemblages. Improving our ability to assess such fish populations in close proximity to structures will assist in increasing this knowledge. In the present study we provide the first trial use of Baited Remote Underwater Stereo-Video systems (stereo BRUVs) for the quantification of motile fauna in close proximity to offshore wind turbines. The study was conducted in the Irish Sea and finds the technique to be a viable means of assessing the motile fauna of such environments. The present study found a mixture of species including bottom dwellers, motile crustaceans and large predatory fish. The majority of taxa observed were found to be immature individuals with few adult individuals recorded. The most abundant species were the angular crab (Goneplax rhomboides) and the small-spotted catshark (Scyliorhinus canicula). Of note in this study was the generally low abundance and diversity of taxa recorded across all samples, we hypothesise that this reflects the generally poor state of the local fauna of the Irish Sea. The faunal assemblages sampled in close proximity to turbines were observed to alter with increasing distance from the structure, species more characteristic of hard bottom environments were in abundance at the turbines (e.g. Homarus gammarus, Cancer pagarus, Scyliorhinus spp.) and those further away more characteristic of soft bottoms (e.g. Norwegian Lobster). This study highlights the need for the environmental impacts of offshore renewables on motile fauna to be assessed using targeted and appropriate tools. Stereo BRUVs provide one of those tools, but like the majority of methods for sampling marine biota, they have limitations. We conclude our paper by providing a discussion of the benefits and limitations of using this BRUV technique for assessing fauna within areas close to offshore windfarms. PMID- 26934588 TI - Human Monocyte-Derived Osteoclasts Are Targeted by Staphylococcal Pore-Forming Toxins and Superantigens. AB - Staphylococcus aureus is the leading cause of bone and joint infections (BJIs). Staphylococcal pathogenesis involves numerous virulence factors including secreted toxins such as pore-forming toxins (PFTs) and superantigens. The role of these toxins on BJI outcome is largely unknown. In particular, few studies have examined how osteoclasts, the bone-resorbing cells, respond to exposure to staphylococcal PFTs and superantigens. We investigated the direct impact of recombinant staphylococcal toxins on human primary mature monocyte-derived osteoclasts, in terms of cytotoxicity and cell activation with cell death and bone resorption assays, using macrophages of the corresponding donors as a reference. Monocyte-derived osteoclasts displayed similar toxin susceptibility profiles compared to macrophages. Specifically, we demonstrated that the Panton Valentine leukocidin, known as one of the most powerful PFT which lyses myeloid cells after binding to the C5a receptor, was able to induce the death of osteoclasts. The archetypal superantigen TSST-1 was not cytotoxic but enhanced the bone resorption activity of osteoclasts, suggesting a novel mechanism by which superantigen-producing S. aureus can accelerate the destruction of bone tissue during BJI. Altogether, our data indicate that the diverse clinical presentations of BJIs could be related, at least partly, to the toxin profiles of S. aureus isolates involved in these severe infections. PMID- 26934589 TI - Structural mechanisms of plant glucan phosphatases in starch metabolism. AB - Glucan phosphatases are a recently discovered class of enzymes that dephosphorylate starch and glycogen, thereby regulating energy metabolism. Plant genomes encode two glucan phosphatases, called Starch EXcess4 (SEX4) and Like Sex Four2 (LSF2), that regulate starch metabolism by selectively dephosphorylating glucose moieties within starch glucan chains. Recently, the structures of both SEX4 and LSF2 were determined, with and without phosphoglucan products bound, revealing the mechanism for their unique activities. This review explores the structural and enzymatic features of the plant glucan phosphatases, and outlines how they are uniquely adapted to perform their cellular functions. We outline the physical mechanisms used by SEX4 and LSF2 to interact with starch glucans: SEX4 binds glucan chains via a continuous glucan-binding platform comprising its dual specificity phosphatase domain and carbohydrate-binding module, while LSF2 utilizes surface binding sites. SEX4 and LSF2 both contain a unique network of aromatic residues in their catalytic dual-specificity phosphatase domains that serve as glucan engagement platforms and are unique to the glucan phosphatases. We also discuss the phosphoglucan substrate specificities inherent to SEX4 and LSF2, and outline structural features within the active site that govern glucan orientation. This review defines the structural mechanism of the plant glucan phosphatases with respect to phosphatases, starch metabolism and protein-glucan interaction, thereby providing a framework for their application in both agricultural and industrial settings. PMID- 26934591 TI - Bacterial Community Associated with Organs of Shallow Hydrothermal Vent Crab Xenograpsus testudinatus near Kuishan Island, Taiwan. AB - Shallow-water hydrothermal vents off Kueishan Island (northeastern Taiwan) provide a unique, sulfur-rich, highly acidic (pH 1.75-4.6) and variable temperature environment. In this species-poor habitat, the crab Xenograpsus testudinatus is dominant, as it mainly feeds on zooplankton killed by sulfurous plumes. In this study, 16S ribosomal RNA gene amplicon pyrosequencing was used to investigate diversity and composition of bacteria residing in digestive gland, gill, stomach, heart, and mid-gut of X. testudinatus, as well as in surrounding seawater. Dominant bacteria were Gamma- and Epsilonproteobacteria that might be capable of autotrophic growth by oxidizing reduced sulfur compounds and are usually resident in deep-sea hydrothermal systems. Dominant bacterial OTUs in X. testudinatus had both host and potential organ specificities, consistent with a potential trophic symbiotic relationship (nutrient transfer between host and bacteria). We inferred that versatile ways to obtain nutrients may provide an adaptive advantage for X. testudinatus in this demanding environment. To our knowledge, this is the first study of bacterial communities in various organs/tissues of a crustacean in a shallow-water hydrothermal system, and as such, may be a convenient animal model for studying these systems. PMID- 26934592 TI - Amyloid-beta(25-35) peptides aggregate into cross-beta sheets in unsaturated anionic lipid membranes at high peptide concentrations. AB - One of the hallmarks of Alzheimer's disease is the formation of protein plaques in the brain, which mainly consist of amyloid-beta peptides of different lengths. While the role of these plaques in the pathology of the disease is not clear, the mechanism behind peptide aggregation is a topic of intense research and discussion. Because of their simplicity, synthetic membranes are promising model systems to identify the elementary processes involved. We prepared unsaturated zwitterionic/anionic lipid membranes made of 1-palmitoyl-2-oleoyl-sn-glycero phosphocholine (POPC) and 1,2-dimyristoyl-sn-glycero-3-phospho-l-serine (DMPS) at concentrations of POPC/3 mol% DMPS containing 0 mol%, 3 mol%, 10 mol%, and 20 mol% amyloid-beta25-35 peptides. Membrane-embedded peptide clusters were observed at peptide concentrations of 10 and 20 mol% with a typical cluster size of ~11 MUm. Cluster density increased with peptide concentration from 59 (+/-3) clusters per mm(2) to 920 (+/-64) clusters per mm(2), respectively. While monomeric peptides take an alpha-helical state when embedded in lipid bilayers at low peptide concentrations, the peptides in peptide clusters were found to form cross beta sheets and showed the characteristic pattern in X-ray experiments. The presence of the peptides was accompanied by an elastic distortion of the bilayers, which can induce a long range interaction between the peptides. The experimentally observed cluster patterns agree well with Monte Carlo simulations of long-range interacting peptides. This interaction may be the fundamental process behind cross-beta sheet formation in membranes and these sheets may serve as seeds for further growth into amyloid fibrils. PMID- 26934590 TI - Horizontal DNA Transfer Mechanisms of Bacteria as Weapons of Intragenomic Conflict. AB - Horizontal DNA transfer (HDT) is a pervasive mechanism of diversification in many microbial species, but its primary evolutionary role remains controversial. Much recent research has emphasised the adaptive benefit of acquiring novel DNA, but here we argue instead that intragenomic conflict provides a coherent framework for understanding the evolutionary origins of HDT. To test this hypothesis, we developed a mathematical model of a clonally descended bacterial population undergoing HDT through transmission of mobile genetic elements (MGEs) and genetic transformation. Including the known bias of transformation toward the acquisition of shorter alleles into the model suggested it could be an effective means of counteracting the spread of MGEs. Both constitutive and transient competence for transformation were found to provide an effective defence against parasitic MGEs; transient competence could also be effective at permitting the selective spread of MGEs conferring a benefit on their host bacterium. The coordination of transient competence with cell-cell killing, observed in multiple species, was found to result in synergistic blocking of MGE transmission through releasing genomic DNA for homologous recombination while simultaneously reducing horizontal MGE spread by lowering the local cell density. To evaluate the feasibility of the functions suggested by the modelling analysis, we analysed genomic data from longitudinal sampling of individuals carrying Streptococcus pneumoniae. This revealed the frequent within-host coexistence of clonally descended cells that differed in their MGE infection status, a necessary condition for the proposed mechanism to operate. Additionally, we found multiple examples of MGEs inhibiting transformation through integrative disruption of genes encoding the competence machinery across many species, providing evidence of an ongoing "arms race." Reduced rates of transformation have also been observed in cells infected by MGEs that reduce the concentration of extracellular DNA through secretion of DNases. Simulations predicted that either mechanism of limiting transformation would benefit individual MGEs, but also that this tactic's effectiveness was limited by competition with other MGEs coinfecting the same cell. A further observed behaviour we hypothesised to reduce elimination by transformation was MGE activation when cells become competent. Our model predicted that this response was effective at counteracting transformation independently of competing MGEs. Therefore, this framework is able to explain both common properties of MGEs, and the seemingly paradoxical bacterial behaviours of transformation and cell-cell killing within clonally related populations, as the consequences of intragenomic conflict between self-replicating chromosomes and parasitic MGEs. The antagonistic nature of the different mechanisms of HDT over short timescales means their contribution to bacterial evolution is likely to be substantially greater than previously appreciated. PMID- 26934594 TI - Autoregulation of the tufB operon in Salmonella. AB - In Salmonella enterica and related species, translation elongation factor EF-Tu is encoded by two widely separated but near-identical genes, tufA and tufB. Two thirds of EF-Tu is expressed from tufA with the remaining one third coming from tufB. Inactivation of tufA is partly compensated by a doubling in the amount of EF-TuB but the mechanism of this up-regulation is unknown. By experimental evolution selecting for improved growth rate in a strain with an inactive tufA we selected six different noncoding or synonymous point mutations close to the tufB start codon. Based on these results we constructed a total of 161 different point mutations around the tufB start codon, as well as tufB 3'-truncations, and measured tufB expression using tufB-yfp transcriptional and translational fusions. The expression data support the presence of two competing stem-loop structures that can form in the 5'-end of the tufB mRNA. Formation of the 'closed' structure leads to Rho-dependent transcriptional termination of the tufB mRNA. We propose a model in which translational speed is used as a sensor for EF Tu concentration and where the expression of tufB is post-transcriptionally regulated. This model describes for the first time how expression of the most abundant Salmonella protein is autoregulated. PMID- 26934593 TI - "See One, Sim One, Do One"- A National Pre-Internship Boot-Camp to Ensure a Safer "Student to Doctor" Transition. AB - INTRODUCTION: The transition for being a medical student to a full functioning intern is accompanied by considerable stress and sense of unpreparedness. Simulation based workshops were previously reported to be effective in improving the readiness of interns and residents to their daily needed skills but only few programs were implemented on a large scale. METHODS: A nationally endorsed and mandated pre-internship simulation based workshop is reported. We hypothesized that this intervention will have a meaningful and sustained impact on trainees' perception of their readiness to internship with regard to patient safety and quality of care skills. Main outcome measure was the workshop's contribution to professional training in general and to critical skills and error prevention in particular, as perceived by participants. RESULTS: Between 2004 and 2011, 85 workshops were conducted for a total of 4,172 trainees. Eight-hundred and six of the 2,700 participants approached by e-mail, returned feedback evaluation forms, which were analyzed. Eighty five percent of trainees perceived the workshop as an essential component of their professional training, and 87% agreed it should be mandatory. These ratings peaked during internship and were generally sustained 3 years following the workshop. Contribution to emergency care skills was especially highly ranked (83%). CONCLUSION: Implementation of a mandatory, simulation-based, pre-internship workshop on a national scale made a significant perceived impact on interns and residents. The sustained impact should encourage adopting this approach to facilitate the student to doctor transition. PMID- 26934595 TI - How Often Are Antibiotic-Resistant Bacteria Said to "Evolve" in the News? AB - Media plays an important role in informing the general public about scientific ideas. We examine whether the word "evolve," sometimes considered controversial by the general public, is frequently used in the popular press. Specifically, we ask how often articles discussing antibiotic resistance use the word "evolve" (or its lexemes) as opposed to alternative terms such as "emerge" or "develop." We chose the topic of antibiotic resistance because it is a medically important issue; bacterial evolution is a central player in human morbidity and mortality. We focused on the most widely-distributed newspapers written in English in the United States, United Kingdom, Canada, India, and Australia. We examined all articles that focused primarily on the evolution of antibiotic resistance, were published in 2014 or earlier, and were accessible in online archives, for a total of 1639 articles. The total years examined per newspaper ranged from 5 to 37 years with a median of 27 years, and the overall range was 1978-2014. We quantified how many articles included the term "evolve" and analyzed how this varied with newspaper, country, and time. We found that an overall rate of 18% of articles used the term "evolve" but with significant variation among countries. Newspapers in the United Kingdom had the highest rate (24%), more than double of those in India (9%), the country with the lowest rate. These frequencies were lower than those found in scientific papers from both evolutionary journals and biomedical journals. There were no statistically significant changes in frequency and no trends when "evolve" usage was compared against variables such as newspaper circulation, liberal/conservative bias, time, and state evolution acceptance in U.S. newspapers. This study highlights the globally low usage of the word "evolve" in the popular press. We suggest this low usage may affect public understanding and acceptance of evolutionary concepts. PMID- 26934596 TI - Correction: Immunological Characterization of Whole Tumour Lysate-Loaded Dendritic Cells for Cancer Immunotherapy. PMID- 26934597 TI - Dynamic comparison on the usage of probiotics in organic wastewater treatment under aerobic conditions in a diurnal environment. AB - : This study aims at evaluating and comparing pollution removal in wastewater treatment via the use of probiotics alone or in combination under aerobic conditions in diurnal cycles. Herein, 650 mL of organic wastewater was stored in 1-L conical flasks and then randomly divided into three treatment groups, each experiment was repeated three times. Group A was supplemented with 2% (v/v) photosynthetic bacteria (PSB; Rhodopseudomonas palustris) alone; group B was supplemented with 2% (v/v) B. subtilis alone; and group C was supplemented with 1% (v/v) PSB and 1% (v/v) B. subtilis. Results showed that the pH increases were in the order: group A < group C < group B. The performance of the probiotics in terms of ammonia nitrogen and total nitrogen (TN) removal was in the order: group A < group C < group B, whereas in terms of total organic matter (TOC) and total carbon (TC) removal, the order was group C < group B < group A. These results showed that the effect of probiotics combination treatment on ammonia nitrogen and TN removal was better than that of using B. subtilis alone, but worse than that of using PSB alone. The effect of B. subtilis alone treatment on TOC and TC removal was better than that of using PSB alone, but the combination of PSB and B. subtilis showed greater benefits on TOC and TC removal. IMPLICATIONS: Photosynthetic bacteria and B. subtilis were used in this study to investigate carbon and nitrogen metabolism via the use of different probiotics and then study further on comparing and achieving the best pollution removal performance in probiotics alone or in combination treatment. To make observations realistic, the experiments were conducted under aerobic conditions in a diurnal cycle environment. PMID- 26934598 TI - Forty cases of twin reversed arterial perfusion sequence treated with radio frequency ablation using the multistep coagulation method: a single-center experience. AB - OBJECTIVE: To report the pregnancy outcomes of patients with twin reversed arterial perfusion (TRAP) sequence treated by radiofrequency ablation (RFA). METHODS: This was a retrospective study of TRAP sequences treated in a single center between March 2002 and February 2015. Forty patients underwent RFA with expandable tines through a multistep coagulation method between 15 and 26 gestational weeks. The primary outcome was neonatal survival to discharge. RESULTS: The overall survival of the pump twin was 85%. The survival rates in monochorionic-monoamniotic (MCMA) pregnancies and monochorionic-diamniotic pregnancies were 66.7% (4/6) and 87.9% (29/33), respectively. One triplet was treated successfully and delivered at 36 weeks of gestation. One of 35 live births (2.9%) had preterm premature rupture of membranes less than 34 weeks, resulting in infant death. In five intrauterine pump twin deaths, two cases were MCMA twins with cord entanglement, and three cases were MCDA twins with acardius anceps. CONCLUSIONS: Our study supports the effectiveness of RFA for TRAP sequence after 15 weeks of gestation. The presence of MCMA twins or acardius anceps is associated with a high risk of pump twin death after RFA. (c) 2016 John Wiley & Sons, Ltd. PMID- 26934599 TI - Selective Rho Kinase Inhibitor Allows for Expansion of Human Primary Sebocytes In Vitro. PMID- 26934601 TI - Reversible Inter- and Intramolecular Carbon-Hydrogen Activation, Hydrogen Addition, and Catalysis by the Unsaturated Complex Pt(IPr)(SnBu(t)3)(H). AB - The complex Pt(IPr)(SnBu(t)3)(H) (1) was obtained from the reaction of Pt(COD)2 with Bu(t)3SnH and IPr [IPr = N,N'-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]. Complex 1 undergoes exchange reactions with deuterated solvents (C6D6, toluene d8, and CD2Cl2), where the hydride ligand and the methyl hydrogen atoms on the isopropyl group of the IPr ligand have been replaced by deuterium atoms. Complex 1 reacts with H2 gas reversibly at room temperature to yield the complex Pt(IPr)(SnBu(t)3)(H)3 (2). Complex 2 also undergoes exchange reactions with deuterated solvents as in 1 to deuterate the hydride ligands and the methyl hydrogen atoms on the isopropyl group of the IPr ligand. Complex 1 catalyzes the hydrogenation of styrene to ethylbenzene at room temperature. The reaction of 1 with 1 equiv of styrene at -20 degrees C yields the eta(2)-coordinated product Pt(IPr)(SnBu(t)3)(eta(2)-CH2CHPh)(H) (3), and with 2 equiv of styrene, it forms Pt(IPr)(eta(2)-CH2CHPh)2 (4). PMID- 26934600 TI - Paenibacillus lentimorbus Inoculation Enhances Tobacco Growth and Extenuates the Virulence of Cucumber mosaic virus. AB - Previous studies with Paenibacillus lentimorbus B-30488" (hereafter referred as B 30488), a plant growth promoting rhizobacteria (PGPR) isolated from cow's milk, revealed its capabilities to improve plant quality under normal and stress conditions. Present study investigates its potential as a biocontrol agent against an economically important virus, Cucumber mosaic virus (CMV), in Nicotiana tabacum cv. White Burley plants and delineates the physical, biophysical, biochemical and molecular perturbations due to the trilateral interactions of PGPR-host-CMV. Soil inoculation of B-30488 enhanced the plant vigor while significantly decreased the virulence and virus RNA accumulation by ~12 fold (91%) in systemic leaves of CMV infected tobacco plants as compared to the control ones. Histology of these leaves revealed the improved tissue's health and least aging signs in B-30488 inoculated tobacco plants, with or without CMV infection, and showed lesser intercellular spaces between collenchyma cells, reduced amount of xyloglucans and pectins in connecting primary cells, and higher polyphenol accumulation in hypodermis layer extending to collenchyma cells. B 30488 inoculation has favorably maneuvered the essential biophysical (ion leakage and photosynthetic efficiency) and biochemical (sugar, proline, chlorophyll, malondialdehyde, acid phosphatase and alkaline phosphatase) attributes of tobacco plants to positively regulate and release the virus stress. Moreover, activities of defense related enzymes (ascorbate peroxidase, guaiacol peroxidase, superoxide dismutase and catalase) induced due to CMV-infection were ameliorated with inoculation of B-30488, suggesting systemic induced resistance mediated protection against CMV in tobacco. The quantitative RT-PCR analyses of the genes related to normal plant development, stress and pathogenesis also corroborate well with the biochemical data and revealed the regulation (either up or down) of these genes in favor of plant to combat the CMV mediated stress. These improvements led tobacco plant to produce more flowers and seeds with no negative impact on plant health. The present study may advocate the applicability of B 30488 for crop yield improvement in virus infested areas. PMID- 26934602 TI - Presence of Breeding Birds Improves Body Condition for a Crocodilian Nest Protector. AB - Ecological associations where one species enhances habitat for another nearby species (facilitations) shape fundamental community dynamics and can promote niche expansion, thereby influencing how and where species persist and coexist. For the many breeding birds facing high nest-predation pressure, enemy-free space can be gained by nesting near more formidable animals for physical protection. While the benefits to protected species seem well documented, very few studies have explored whether and how protector species are affected by nest protection associations. Long-legged wading birds (Pelecaniformes and Ciconiiformes) actively choose nesting sites above resident American alligators (Alligator mississippiensis), apparently to take advantage of the protection from mammalian nest predators that alligator presence offers. Previous research has shown that wading bird nesting colonies could provide substantial food for alligators in the form of dropped chicks. We compared alligator body condition in similar habitat with and without wading bird nesting colonies present. Alligator morphometric body condition indices were significantly higher in colony than in non-colony locations, an effect that was statistically independent of a range of environmental variables. Since colonially nesting birds and crocodilians co-occur in many tropical and subtropical wetlands, our results highlight a potentially widespread keystone process between two ecologically important species-groups. These findings suggest the interaction is highly beneficial for both groups of actors, and illustrate how selective pressures may have acted to form and reinforce a strongly positive ecological interaction. PMID- 26934604 TI - Difficult Ventilation After Successful Intubation in the Emergency Setting due to a Ball Valve Clot. AB - The inability to ventilate a patient after successful intubation is a rare but emergent situation and may be caused by obstruction of the endotracheal tube, bilateral tension pneumothorax, esophageal intubation, severe bronchospasm, or mainstem bronchus intubation. We describe an increase in mean airway pressure, inability to ventilate, and loss of cardiac output secondary to a blood clot acting as a ball valve at the end of an endotracheal tube. PMID- 26934603 TI - Middle cerebral artery stenosis in patients with nasopharyngeal carcinoma after radiotherapy: the incidence of stenosis and the risk factors. AB - OBJECTIVE: The purpose of the present study was to investigate the incidence of middle cerebral artery (MCA) stenosis by contrast-enhanced MR angiography (CE MRA), and to evaluate the risk factors for significant (>50%) MCA stenosis in patients with nasopharyngeal carcinoma (NPC) after radiotherapy. METHODS: 116 patients with NPC after radiotherapy were recruited into the irradiation group to investigate the incidence and degree of MCA stenosis by CE-MRA. The results were compared with those of the control group, which comprised 57 newly diagnosed patients with NPC who did not receive radiotherapy. Furthermore, the risk factors for significant MCA stenosis were evaluated. RESULTS: There was a higher incidence of MCA stenosis in the irradiation group than in the control group in terms of patient number (p = 0.000) and vessel involvement (p = 0.000), respectively. The incidence of significant MCA stenosis in the irradiation group was 8.6% (10/116 patients) and 5.2% (12/232 patients) in terms of patient number and vessel involvement, respectively. However, no significant MCA stenosis was found in the control group. Univariate analysis showed that hypercholesterolaemia, T(3-4) stage and longer time interval from radiotherapy were the risk factors related to significant MCA stenosis. Multivariate analysis demonstrated that only T stage was the independent risk factor for significant MCA stenosis development. CONCLUSION: The results showed that radiation can cause MCA stenosis in patients with NPC after radiotherapy, especially in those with T(3-4) stage, and further study is needed. ADVANCES IN KNOWLEDGE: Radiation induced MCA stenosis exists in patients with NPC after radiotherapy, and its prevalence is more common in patients with clinical T(3-4) stage. PMID- 26934605 TI - Postoperative Epidural Abscess in an Infant. AB - In the pediatric population, development of an abscess after epidural analgesia is a rare event. We report who is believed to be the youngest patient with development of an epidural abscess secondary to epidural catheter placement. We detail the infant's symptoms, radiographic workup, surgical treatment, and follow up. PMID- 26934606 TI - Patient Positioning and Skin Sequelae: Ischemic Epidermal Necrosis from Tight Padding During Cardiac Surgery. AB - Careful positioning and padding of pressure points during surgery are recommended to prevent pressure ulcers, vascular injury, and nerve damage in an immobilized patient. However, overpadding may have unintended consequences. We report a case of ischemia-induced full-thickness epidermal necrosis secondary to tight foam padding during a cardiac surgery. PMID- 26934607 TI - Ultrasound-Guided Serratus Anterior Plane Block in Breast Reconstruction Surgery. AB - Pecs block and its variations have been used for various breast surgeries. We describe 2 cases of mastectomy and breast reconstruction by latissimus dorsi (LD) flap where regional analgesia was provided by a combination of ultrasound-guided Pecs-I block and serratus anterior plane block, a recently described technique in which local anesthetic is deposited in the plane between the LD and serratus anterior muscle. This resulted in excellent intraoperative and postoperative analgesia and a minimum of systemic analgesics. The described technique is safe to administer and provides good analgesia for breast reconstruction surgery by LD flap. PMID- 26934608 TI - Acute Hypotension After 50% Dextrose Injections. AB - The hemodynamic effects of small-volume boluses of hyperosmotic solutions are often deemed negligible in the clinical setting. However, animal studies have reported decreases in systemic arterial blood pressure and bradycardia with the administration of hyperosmotic solutions. This is a report of a 60-year-old woman, intubated and sedated, who developed acute decreases in systemic arterial blood pressure with the administration of <=50 mL of 50% dextrose. Animal studies suggest that hyperosmolar-induced hypotension may be avoided by administering the hyperosmotic solution slowly. This allows for admixture and therefore a decreased osmotic load at the proposed osmoreceptor involved in the neural reflex. PMID- 26934609 TI - A Survey of Simulation Utilization in Anesthesiology Residency Programs in the United States. AB - Given the evolution of competency-based education and evidence supporting the benefits of incorporating simulation into anesthesiology residency training, simulation will likely play an important role in the training and assessment of anesthesiology residents. Currently, there are little data available regarding the current status of simulation-based curricula across US residency programs. In this study, we assessed simulation-based training and assessment in US anesthesiology programs using a survey designed to elicit information regarding the type, frequency, and content of the simulation courses offered at the 132 Accreditation Council of Graduate Medical Education-certified anesthesiology training programs. The response rate for the survey was 66%. Although most of the responding programs offered simulation-based courses for interns and residents and during CA-1 orientation, the curriculum varied greatly among programs. Approximately 40% of responding programs use simulation for resident assessment and remediation. The majority of responding programs favored standard simulation based training as part of residency training (89%), and the most common perceived obstacles to doing so were time, money, and human resources. The results from this survey highlight that there are currently large variations in simulation based training and assessment among training programs. It also confirms that many program directors feel that standardizing some components of simulation-based education and assessment would be beneficial. Given the positive impact simulation has on skill retention and operating room preparedness, it may be worthwhile to consider developing a standard curriculum. PMID- 26934610 TI - Monitoring and assessment of outcome in cases of tuberculosis in a municipality of Southern Brazil. AB - Objectives To monitor and assess the outcome of treatment for pulmonary tuberculosis in the tuberculosis control program in a prioritized municipality in Southern Brazil. Methods a quantitative study, descriptive, documentary, using records of people with tuberculosis in treatment between 2009-2013, the collection took place between June and July 2014 in the Tuberculosis Control Program. Descriptive statistics was used. Results The average number of consultations among the 629 patients was 7.2 per patient, with a mean interval of 1.03 months between visits. The average of smears was 2.7 tests per patient during the study period. The outcome of treatment was a cure rate of 87.8%, an abandonment rate of 8.3% and 6.5% of deaths. Conclusions despite the cure rate, abandonment is still high, thus, it is necessary to explore strategies for better adherence to treatment, and the commitment of the municipal administration in articulating monitoring in primary health care. PMID- 26934611 TI - Care of cancer patients in the Family Health Strategy: the user's view. AB - Objective understand the experiences of cancer patients regarding the care received and the relationship with Family Health Strategy professionals. Method qualitative research based on Heidegger's phenomenology held with ten cancer patients living in the coverage area of three healthcare centers in a city in northwestern Parana. Data were collected at the patients' homes from November 2012 to February 2013 through open interviews. Results some patients were faced with the impersonality of professionals and lack of empathy, interaction, and singling in care whereas others had their expectations met since they experienced a comprehensive care permeated with concern, sharing of feelings, and respect. Conclusions the understanding of these experiences raises a reflection on the support that is provided in this instance of care and the importance of overcoming impersonal and inauthentic attitudes in order to transcend to a new level of relationship and care. PMID- 26934612 TI - Association of socioeconomic and clinical factors and tissue integrity outcome of patients with ulcers. AB - Objective to analyze the association between socioeconomic and clinical factors and indicators of the tissue integrity outcome in nursing among patients with venous ulcers. Methods a cross-sectional study at a university hospital in Natal, RN, Brazil, from February to June 2012, with 50 individuals. To analyze the variables, we used the Spearman correlation test and the Mann-Whitney and Kruskal Wallis tests at a level of 5%. Results there was a correlation of low intensity between age and the indicators hydration and skin peeling, and family income and necrosis. There was also an association between gender and the indicators temperature, amount of body hair and exudation. Conclusion the associated variables provide important information for the treatment of patients with venous ulcers, and can help reduce ulcer time and the consequent discomfort, limitations and costs. This information should be considered when providing care for patients with a nursing diagnosis of impaired skin integrity and/or impaired tissue integrity. PMID- 26934613 TI - Representation of nurse's managerial practice in inpatient units: nursing staff perspective. AB - Objective To understand the meanings that nursing staff gives to nurse's managerial practice in the inpatient unit. Methods This is an exploratory and descriptive research with qualitative approach, conducted in a general hospital in a Southern city of Minas Gerais State. We used the Theory of Social Representations as theoretical framework. The study sample were composed by 23 nursing technicians and five nursing assistants. Data collection was conducted through semi-structured interviews, from December 2011 to January 2012. For data analysis we used the discourse analysis, according to social psychology framework. Results The meanings attributed to management occurred from the closeness/distance to staff and to patients' care actions. Conclusions The managerial nurse, perceived as a process apart from care, is classified as non familiar practice, of hard understanding and valuation. PMID- 26934614 TI - Professional attitudes toward patient safety culture in a bone marrow transplant unit. AB - Objective To identify the attitude of health professionals toward the patient safety culture at a bone marrow transplant unit. Methods Quantitative research approach, cross-sectional survey conducted at a bone marrow transplant unit in Santa Catarina, Brazil. Data were collected using a Safety Attitudes Questionnaire with 33 health professionals in August and September of 2013. A total of 37 attitudes were assessed according to six safety dimensions of patient safety culture. Data were analysed by applying descriptive and inferential statistics, ANOVA and the Kruskal-Wallis test with a p value equal to or under 0.05. Results Attitudes regarding the dimension "job satisfaction" were positive for the patient safety culture, and there was a significant difference between the professionals in this dimension (p-value 0.05). The other dimensions were not assessed positively. Conclusion The attitudes of health professionals toward patient safety must be strengthened. PMID- 26934615 TI - Collecting Protein Biomarkers in Breath Using Electret Filters: A Preliminary Method on New Technical Model and Human Study. AB - Biomarkers in exhaled breath are useful for respiratory disease diagnosis in human volunteers. Conventional methods that collect non-volatile biomarkers, however, necessitate an extensive dilution and sanitation processes that lowers collection efficiencies and convenience of use. Electret filter emerged in recent decade to collect virus biomarkers in exhaled breath given its simplicity and effectiveness. To investigate the capability of electret filters to collect protein biomarkers, a model that consists of an atomizer that produces protein aerosol and an electret filter that collects albumin and carcinoembryonic antigen a typical biomarker in lung cancer development- from the atomizer is developed. A device using electret filter as the collecting medium is designed to collect human albumin from exhaled breath of 6 volunteers. Comparison of the collecting ability between the electret filter method and other 2 reported methods is finally performed based on the amounts of albumin collected from human exhaled breath. In conclusion, a decreasing collection efficiency ranging from 17.6% to 2.3% for atomized albumin aerosol and 42% to 12.5% for atomized carcinoembryonic antigen particles is found; moreover, an optimum volume of sampling human exhaled breath ranging from 100 L to 200 L is also observed; finally, the self-designed collecting device shows a significantly better performance in collecting albumin from human exhaled breath than the exhaled breath condensate method (p<0.05) but is not significantly more effective than reported 3-stage impactor method (p>0.05). In summary, electret filters are potential in collecting non-volatile biomarkers in human exhaled breath not only because it was simpler, cheaper and easier to use than traditional methods but also for its better collecting performance. PMID- 26934616 TI - Therapies in early development for the treatment of urinary tract inflammation. AB - INTRODUCTION: Urinary tract inflammation is a very common clinical condition. It is caused by several pathogens and antibiotic treatment is the mainstay of therapy. Increasing antimicrobial resistance and high recurrence rates represent a challenge. Consequently, there is an unmet need for new therapeutic options. AREAS COVERED: The authors discuss the rationale of emerging management strategies and current experimentation. Furthermore, they focus on both acute and recurrent urinary tract infections (UTIs) and examine a range of therapeutics, including new antibiotics, vaccines, mannosides, hyaluronic acid, probiotics, immunomodulant agents and novel compounds derived from nanotechnology. EXPERT OPINION: Basic science studies have elucidated the pathogenesis of UTIs and built up the ground for the development of new therapies. Evidence is mainly derived from animal studies on murine models of bacterial cystitis. However, clinical trials are scanty and cannot provide us with robust evidence. Hetereogeneity and virulence of uropathogens pose a threat that scientists and clinicians are struggling to overcome. PMID- 26934617 TI - Does Real-Time Monitoring of Patient Dose With Dose Management Software Increase CT Technologists' Radiation Awareness? AB - OBJECTIVE: Dose management software can be used to increase patient safety. The purpose of the current study was to evaluate whether real-time monitoring of patient dose in CT examinations increases CT technologists' dose awareness. MATERIALS AND METHODS: Dose data of two scanners (clinical routine CT scanner, mainly outpatients; emergency CT scanner, predominantly emergency department and ICU patients) were analyzed before (period 1) and after (period 2) dose management software was implemented in clinical routine and technologists were advised to check for dose notifications (dose values above reference levels) after each examination (i.e., real-time monitoring). To assess statistically significant differences between both the scanners and the study periods, we used chi-square tests. RESULTS: A total of 6413 examinations were performed (period 1 = 3214 examinations, period 2 = 3199 examinations). Dose notifications were mainly because of patient miscentering (period 1 = 45% of examinations, period 2 = 23%), overweight patients (period 1 = 35%, period 2 = 49%), and scanning repetition (period 1 = 10%, period 2 = 15%). Overall, the number of dose notifications significantly declined in period 2 (period 1, n = 210; period 2, n = 120; p < 0.001). Miscentering was more often seen on the clinical routine CT examinations (period 1 = 46%, period 2 = 23%) than on the emergency CT examinations (period 1 = 44%, period 2 = 22%) and occurred significantly less frequently on both scanners in period 2 (period 1: n = 94; period 2: n = 27; p < 0.001). The relative values of dose notifications due to overweight patients or scanning repetition were higher in period 2, but these differences did not reach statistical significance (p > 0.05). CONCLUSION: Real-time monitoring of patient dose with dose management software increases CT technologists' dose awareness and leads to a reduced number of dose notifications due to human error. PMID- 26934618 TI - Gold Quantum Boxes: On the Periodicities and the Quantum Confinement in the Au28, Au36, Au44 , and Au52 Magic Series. AB - Revealing the size-dependent periodicities (including formula, growth pattern, and property evolution) is an important task in metal nanocluster research. However, investigation on this major issue has been complicated, as the size change is often accompanied by a structural change. Herein, with the successful determination of the Au44(TBBT)28 structure, where TBBT = 4-tert butylbenzenethiolate, the missing size in the family of Au28(TBBT)20, Au36(TBBT)24, and Au52(TBBT)32 nanoclusters is filled, and a neat "magic series" with a unified formula of Au8n+4(TBBT)4n+8 (n = 3-6) is identified. Such a periodicity in magic numbers is a reflection of the uniform anisotropic growth patterns in this magic series, and the n value is correlated with the number of (001) layers in the face-centered cubic lattice. The size-dependent quantum confinement nature of this magic series is further understood by empirical scaling law, classical "particle in a box" model, and the density functional theory calculations. PMID- 26934619 TI - Controllable nanoscale rotating actuator system based on carbon nanotube and graphene. AB - A controllable nanoscale rotating actuator system consisting of a double carbon nanotube and graphene driven by a temperature gradient is proposed, and its rotating dynamics performance and driving mechanism are investigated through molecular dynamics simulations. The outer tube exhibits stable pure rotation with certain orientation under temperature gradient and the steady rotational speed rises as the temperature gradient increases. It reveals that the driving torque is caused by the difference of atomic van der Waals potentials due to the temperature gradient and geometrical features of carbon nanotube. A theoretical model for driving torque is established based on lattice dynamics theory and its predicted results agree well with molecular dynamics simulations. Further discussion is taken according to the theoretical model. The work in this study would be a guide for design and application of controllable nanoscale rotating devices based on carbon nanotubes and graphene. PMID- 26934621 TI - Needs Assessment Survey for Nurse Practitioner and Physician Assistant Colonoscopists for a Gastroenterology Community of Practice. AB - Demand for colonoscopy exceeds capacity in the Veterans Health Administration and the private sector. A small number of innovative Veterans Affairs and private sector facilities have created colonoscopy-training fellowships for nurse practitioners and physician assistants (nonphysicians). Additionally, a gastroenterology community of practice might provide knowledge sharing and professional networking opportunities for nonphysician colonoscopists based on assessment of their need for professional activities. A critical appraisal of related literature pointed out key motivational and structural elements of communities of practice. The survey draft was reviewed by content experts and piloted by four nurse practitioner colonoscopists. Using snowball sampling, the survey was sent to nonphysician endoscopists to capture training experiences, interest in membership, and identified preferences for the structure and delivery of a community of practice. Although the sample size was small (N = 7), results validated similar training experiences and confirmed strong interest in launching a gastroenterology community of practice. PMID- 26934620 TI - Opioid use and walking among patients with chronic low back pain. AB - This study examined the effect of a walking intervention on step counts among patients with chronic back pain who report opioid use. Data were collected as part of a randomized trial to reduce back-pain-related disability. Participants (n = 118 usual care, 111 intervention) were Veterans receiving care within one healthcare system. Step counts were collected at baseline, 6 mo, and 12 mo via an uploading pedometer. Self-reported opioid use was collected by survey. More than 40% (n = 99) of participants reported opioid use at baseline. After adjustment, the predicted mean step count for baseline opioid users assigned to the intervention increased by more than 1,200 steps compared with a reduction of nearly 400 steps for those assigned to usual care (between-group difference = 1,625 steps, p = 0.004). Among nonopioid users, there was no change for those in the intervention (-16 steps) and an increase of about 660 steps for those assigned to usual care (between-group difference = 683 steps, p = 0.17). These data show that patients taking opioids may engage in walking to help manage their back pain. This finding emphasizes the importance of encouraging the use of alternative pain management strategies for these patients. PMID- 26934622 TI - Addressing Potential Cumulative Impacts of Development on Threatened Species: The Case of the Endangered Black-Throated Finch. AB - Where threatened biodiversity is adversely affected by development, policies often state that "no net loss" should be the goal and biodiversity offsetting is one mechanism available to achieve this. However, developments are often approved on an ad hoc basis and cumulative impacts are not sufficiently examined. We demonstrate the potential for serious threat to an endangered subspecies when multiple developments are planned. We modelled the distribution of the black throated finch (Poephila cincta cincta) using bioclimatic data and Queensland's Regional Ecosystem classification. We overlaid granted, extant extractive and exploratory mining tenures within the known and modelled ranges of black-throated finches to examine the level of incipient threat to this subspecies in central Queensland, Australia. Our models indicate that more than half of the remaining P. cincta cincta habitat is currently under extractive or exploratory tenure. Therefore, insufficient habitat exists to offset all potential development so "no net loss" is not possible. This has implications for future conservation of this and similarly distributed species and for resource development planning, especially the use of legislated offsets for biodiversity protection. PMID- 26934623 TI - Host resistance to visceral leishmaniasis: prevalence and prevention. AB - Visceral leishmaniasis (VL) is a chronic parasitic disease caused by the vector borne Leishmania donovani and Leishmania (L.) infantum chagasi parasites. The disease affects about 12 million humans in more than 90 countries worldwide. If not treated, the visceral form of Leishmania infection is potentially fatal, yielding about 50000 deaths per year. In the vertebrate host, the Leishmania species causing VL spread systematically to propagate in macrophage reservoirs distributed in the tissues of internal organs, primarily the liver, spleen, bone marrow and the lymph nodes. The infection is associated with evolved mechanisms from the parasite to subvert the host immune system in order to establish a persistent infection. Currently, efforts are being deployed to develop new anti leishmanial therapies in VL combining immunomodulatory treatment regimens that burst the host immune responses together with leishmanicidal drugs that target the parasite growth. Discoveries in this field are discussed in this article. PMID- 26934624 TI - Association of Age to Mortality and Repeat Revascularization in End-Stage Renal Disease Patients: Implications for Clinicians and Future Health Policies. AB - BACKGROUND: The clinical effects of age occur over an age continuum, yet age as a primary predictor is often analyzed using arbitrary age cut-points. OBJECTIVE: To assess whether transformation of a continuous variable such as age using a spline function can uncover nonlinear associations between age and cardiovascular outcomes. DESIGN: Observational retrospective cohort study in 1015 Kaiser Permanente Northern California patients with end-stage renal disease after index coronary revascularization. Age, the primary predictor, was modeled by 5 different techniques: 1) dichotomized at 65 years or older; 2) at 80 years or older (as a sensitivity analysis); 3) categorized as younger than 55 years (reference), 55 to 64, 65 to 74, and 75 years or older; 4) linear (every 5 years) variable; and 5) nonlinear by transformation into a cubic spline. Age categories were changed in a sensitivity analysis. MAIN OUTCOME MEASURES: Primary and secondary outcomes were all-cause mortality and repeat revascularization, respectively. RESULTS: Graphical assessment demonstrated that age dichotomized at either 65 years and older or 80 years and older led to loss of information. Categorized age underestimated or overestimated risk at the extremes of age. A sensitivity analysis demonstrated that an arbitrary change in the age category led to a different conclusion. Age modeled linearly adequately represented mortality risk but was suboptimal with repeat revascularization. Only the cubic spline demonstrated the nonlinear association between age and repeat revascularization. CONCLUSION: Employing the continuous variable age as a case study, we have demonstrated that the use of flexible transformations, such as spline functions, can unearth clinically meaningful associations that would not have been possible otherwise. Future research should determine whether incorporation of these methods can improve decision making at a population level. PMID- 26934625 TI - Addressing the Child and Maternal Mortality Crisis in Haiti through a Central Referral Hospital Providing Countrywide Care. AB - The neonatal, infant, child, and maternal mortality rates in Haiti are the highest in the Western Hemisphere, with rates similar to those found in Afghanistan and several African countries. We identify several factors that have perpetuated this health care crisis and summarize the literature highlighting the most cost-effective, evidence-based interventions proved to decrease these mortality rates in low- and middle-income countries.To create a major change in Haiti's health care infrastructure, we are implementing two strategies that are unique for low-income countries: development of a countrywide network of geographic "community care grids" to facilitate implementation of frontline interventions, and the construction of a centrally located referral and teaching hospital to provide specialty care for communities throughout the country. This hospital strategy will leverage the proximity of Haiti to North America by mobilizing large numbers of North American medical volunteers to provide one-on one mentoring for the Haitian medical staff. The first phase of this strategy will address the child and maternal health crisis.We have begun implementation of these evidence-based strategies that we believe will fast-track improvement in the child and maternal mortality rates throughout the country. We anticipate that, as we partner with private and public groups already working in Haiti, one day Haiti's health care system will be among the leaders in that region. PMID- 26934627 TI - The effect of epilepsy and antiepileptic drugs on sexual, reproductive and gonadal health of adults with epilepsy. AB - Epilepsy is a common chronic medical illness. Hyposexuality is the most frequent abnormality in men and women with epilepsy. In men with epilepsy, hypoandrogenimia, hypogonadism and sperm abnormalities are common. Testicular atrophy was also infrequently reported. In women with epilepsy, hyperandrogenism, polycystic ovaries (PCOs) and PCO syndrome are frequent. Decreased serum free testosterone, dehydroepiandrosterone levels, free androgen index and free testosterone/leutinizing hormone (LH) ratio and increased sex hormone binding globulin, estradiol, prolactin, LH, follicle stimulating hormone (FSH) levels and LH/FSH ratio are common with epilepsy. Disturbance of central and/or peripheral control of hypothalamic-pituitary-gonadal axis and alteration of central neurotrasmitters (GABA, glutamate and serotonin) by epileptic discharges or antiepileptic drugs (AEDs), direct gonadal toxicity by AEDs and pcyshicatric/psychosocial factors are all incriminated in sexual, reproductive and gonadal abnormalities associated with epilepsy. Patients may benefit from multidisplinary evaluation, tight seizure control, change the AED, androgen therapy, genital vasodilators, L-carnitine supplementation and psychotherapy. PMID- 26934626 TI - Low Back Imaging When Not Indicated: A Descriptive Cross-System Analysis. AB - CONTEXT: Guideline-discordant imaging to evaluate incident low back pain is common. OBJECTIVE: We compared rates of guideline-discordant imaging in patients with low back pain in two care delivery systems with differing abilities to track care through an electronic health record (EHR), and in their patients' insurance status, to measure the association between these factors and rates of ordered low back imaging. DESIGN: We used data from two Kaiser Permanente (KP) Regions and from OCHIN, a community health center network. We extracted data on imaging performed after index visits for low back pain from June 1, 2011, to May 31, 2012, in these systems. Adjusted logistic regression measured associations between system-level factors and imaging rates. MAIN OUTCOME MEASURES: Imaging rates for incident low back pain using 2 national quality metrics: Clinical Quality Measure 0052, a measure for assessing Meaningful Use of EHRs, and the Healthcare Effectiveness Data and Information Set measure "Use of Imaging Studies for Low Back Pain." RESULTS: Among 19,503 KP patients and 2694 OCHIN patients with incident low back pain, ordered imaging was higher among men and whites but did not differ across health care systems. OCHIN's publicly insured patients had higher rates of imaging compared with those with private or no insurance. CONCLUSION: Rates of ordered imaging to evaluate incident low back pain among uninsured OCHIN patients were lower than in KP overall; among insured OCHIN patients, rates were higher than in KP overall. Research is needed to establish causality and develop interventions. PMID- 26934630 TI - Chemical Components for the Design of Temperature-Responsive Vesicles as Cancer Therapeutics. AB - In this Review, we attempt to offer a thorough description of all of the chemical components and the rationale behind the design of temperature-sensitive vesicle systems, as well as the critical pharmacological parameters that need to be combined to achieve their successful clinical translation. The focus of this Review will be predominantly on the design principles around the construction of temperature-sensitive liposomes (TSL) and their use in combination with external local hyperthermia to achieve heat-triggered drug release. The emphasis lies on the chemical components synthesized and incorporated in the design and engineering of TSL. We conclude that the development of TSL with ultrafast drug release capabilities needs to progress in parallel with vesicle pharmacokinetic profiling, imaging, and monitoring capacity and technologies for accurate temperature elevation and control. The development of heat-triggered liposome systems offer the greatest opportunity for clinical translation of the next generation, nanoscale "smart" vesicle systems of enhanced functionality, following from the successful legacy and rich clinical history from multiple earlier liposome technologies. PMID- 26934631 TI - Evolving Approaches in Research and Care for Ovarian Cancers: A Report From the National Academies of Sciences, Engineering, and Medicine. PMID- 26934628 TI - Autophagy interaction with herpes simplex virus type-1 infection. AB - More than 50% of the U.S. population is infected with herpes simplex virus type-I (HSV-1) and global infectious estimates are nearly 90%. HSV-1 is normally seen as a harmless virus but debilitating diseases can arise, including encephalitis and ocular diseases. HSV-1 is unique in that it can undermine host defenses and establish lifelong infection in neurons. Viral reactivation from latency may allow HSV-1 to lay siege to the brain (Herpes encephalitis). Recent advances maintain that HSV-1 proteins act to suppress and/or control the lysosome dependent degradation pathway of macroautophagy (hereafter autophagy) and consequently, in neurons, may be coupled with the advancement of HSV-1-associated pathogenesis. Furthermore, increasing evidence suggests that HSV-1 infection may constitute a gradual risk factor for neurodegenerative disorders. The relationship between HSV-1 infection and autophagy manipulation combined with neuropathogenesis may be intimately intertwined demanding further investigation. PMID- 26934633 TI - Magnetic critical properties and basal-plane anisotropy of Sr2IrO4. AB - The anisotropic magnetic properties of Sr2IrO4 are investigated, using longitudinal and torque magnetometry. The critical scaling across T(c) of the longitudinal magnetization is that expected for the 2D XY universality class. Modeling the torque for a magnetic field in the basal plane, and taking into account all in-plane and out-of-plane magnetic couplings, we derive the effective fourfold anisotropy K4 ~ 1 * 10(5) erg mol(-1). Although larger than for the cuprates, it is found to be too small to account for a significant departure from the isotropic 2D XY model. The in-plane torque also allows us to set an upper bound for the anisotropy of a field-induced shift of the antiferromagnetic ordering temperature. PMID- 26934632 TI - Identification of Essential Genetic Baculoviral Elements for Recombinant Protein Expression by Transactivation in Sf21 Insect Cells. AB - The Baculovirus Expression Vector System (BEVS) is widely used to produce high amounts of recombinant proteins. Nevertheless, generating recombinant baculovirus in high quality is rather time-consuming and labor-intensive. Alternatively, virus-free expression in insect cells did not achieve similar expression levels for most proteins so far. The transactivation method is a promising approach for protein expression in Sf21 cells. It combines advantages of BEVS and plasmid based expression by activating strong virus-dependent promoters on a transfected plasmid by baculoviral coinfection. Here, we identified expression elements required for transactivation. Therefore, we designed several vectors comprising different viral promoters or promoter combinations and tested them for eGFP expression using the automated BioLector microcultivation system. Remarkably, only the combination of the very late promoter p10 together with the homologous region 5 (hr5) could boost expression during transactivation. Other elements, like p10 alone or the late viral promoter polH, did not respond to transactivation. A new combination of hr5 and p10 with the strongest immediate early OpMNPV viral promoter OpIE2 improved the yield of eGFP by ~25% in comparison to the previous applied hr5-IE1-p10 expression cassette. Furthermore, we observed a strong influence of the transcription termination sequence and vector backbone on the level of expression. Finally, the expression levels for transactivation, BEVS and solely plasmid-based expression were compared for the marker protein eGFP, underlining the potential of transactivation for fast recombinant protein expression in Sf21 cells. In conclusion, essential elements for transactivation could be identified. The optimal elements were applied to generate an improved vector applicable in virus-free plasmid-based expression, transactivation and BEVS. PMID- 26934634 TI - The Course of Illness After Initial Diagnosis of Major Depression. PMID- 26934635 TI - Sympathetic and hypothalamic-pituitary-adrenal asymmetry in generalized anxiety disorder. AB - Physiologic investigations of generalized anxiety disorder (GAD) have skewed toward assessment of the autonomic nervous system, largely neglecting hypothalamic-pituitary-adrenal (HPA) axis variables. Although these systems coordinate-suggesting a degree of symmetry-to promote adaptive functioning, most studies opt to monitor either one system or the other. Using a ratio of salivary alpha-amylase (sAA) over salivary cortisol, the present study examined symmetry between the sympathetic nervous system (SNS) and HPA axis in individuals with GAD (n = 71) and healthy controls (n = 37). Compared to healthy controls, individuals with GAD exhibited greater baseline ratios of sAA/cortisol and smaller ratios of sAA/cortisol following a mental arithmetic challenge. We propose that the present study provides evidence for SNS-HPA asymmetry in GAD. Further, these results suggest that increased SNS suppression in GAD may be partially mediated by cortisol activity. PMID- 26934636 TI - A Corpus Investigation of Syntactic Embedding in Piraha. AB - The Piraha language has been at the center of recent debates in linguistics, in large part because it is claimed not to exhibit recursion, a purported universal of human language. Here, we present an analysis of a novel corpus of natural Piraha speech that was originally collected by Dan Everett and Steve Sheldon. We make the corpus freely available for further research. In the corpus, Piraha sentences have been shallowly parsed and given morpheme-aligned English translations. We use the corpus to investigate the formal complexity of Piraha syntax by searching for evidence of syntactic embedding. In particular, we search for sentences which could be analyzed as containing center-embedding, sentential complements, adverbials, complementizers, embedded possessors, conjunction or disjunction. We do not find unambiguous evidence for recursive embedding of sentences or noun phrases in the corpus. We find that the corpus is plausibly consistent with an analysis of Piraha as a regular language, although this is not the only plausible analysis. PMID- 26934637 TI - Selective CO2 Adsorption in a Supramolecular Organic Framework. AB - Considering the rapidly rising CO2 level, there is a constant need for versatile materials which can selectively adsorb CO2 at low cost. The quest for efficient sorptive materials is still on since the practical applications of conventional porous materials possess certain limitations. In that context, we designed, synthesized, and characterized two novel supramolecular organic frameworks based on C-pentylpyrogallol[4]arene (PgC5 ) with spacer molecules, such as 4,4' bipyridine (bpy). Highly optimized and symmetric intermolecular hydrogen-bonding interactions between the main building blocks and comparatively weak van der Waals interactions between solvent molecules and PgC5 leads to the formation of robust extended frameworks, which withstand solvent evacuation from the crystal lattice. The evacuated framework shows excellent affinity for carbon dioxide over nitrogen and adsorbs ca. 3 wt % of CO2 at ambient temperature and pressure. PMID- 26934638 TI - Effects of age on motor excitability measures from children and adolescents with Tourette syndrome. AB - Tourette syndrome (TS) is a neurological disorder characterised by vocal and motor tics. It is associated with cortical-striatal-thalamic-cortical circuit [CSTC] dysfunction and hyper-excitability of cortical motor regions. TS follows a developmental time course, in which tics often become increasingly more controlled during adolescence. Importantly, however, a substantial minority of patients continue to have debilitating tics into adulthood. This indicates that there may be important differences between adult TS patients and children and adolescents with the disorder. We use TMS to examine cortical motor excitability in a sample of children, adolescents and young adults with TS. We demonstrate that, in contrast to studies of adult patients, resting motor threshold and the variability of MEP responses are increased in children with TS, while the gain of motor excitability in reduced. Importantly, we demonstrate that these differences normalise with age over adolescence. We conclude that these effects are likely due to a developmental delay in the maturation of key brain networks in TS, consistent with recent brain imaging studies of structural and functional brain connectivity. Importantly, these findings suggest that the alterations in brain network structure and function associated with TS may be quite different in children and adult patients with the condition. PMID- 26934639 TI - HLA-G expression and regulation during Pseudomonas aeruginosa infection in cystic fibrosis patients. AB - BACKGROUND: Deregulated immune response fails to control biofilm-forming bacteria, as Pseudomonas aeruginosa, in the lungs of cystic fibrosis (CF) patients. HLA-G is an immune-modulatory molecule involved in respiratory diseases and infections. MATERIALS & METHODS: HLA-G mRNA and protein were analyzed in plasma and exhaled breath condensate from CF patients undergoing intravenous antibiotic treatment, CF cell line and murine model. RESULTS: Therapy normalizes HLA-G plasmatic in CF patients suggesting a systemic anti-inflammatory role while in CF airway system, higher expression of HLA-G is associated with P. aeruginosa infection. CF cell line and murine model expressed higher HLA-G molecules in the presence of P. aeruginosa. CONCLUSION: Plasmatic and lung HLA-G expression suggest a role in reducing systemic inflammation and supporting P. aeruginosa infection. PMID- 26934640 TI - Long-term effects of weight-reducing drugs in people with hypertension. AB - BACKGROUND: All major guidelines on antihypertensive therapy recommend weight loss; anti-obesity drugs may be able to help in this respect. OBJECTIVES: PRIMARY OBJECTIVES: To assess the long-term effects of pharmacologically induced reduction in body weight in adults with essential hypertension on all-cause mortality, cardiovascular morbidity, and adverse events (including total serious adverse events, withdrawal due to adverse events, and total non-serious adverse events). SECONDARY OBJECTIVES: To assess the long-term effects of pharmacologically induced reduction in body weight in adults with essential hypertension on change from baseline in systolic blood pressure, change from baseline in diastolic blood pressure, and body weight reduction. SEARCH METHODS: We obtained studies using computerised searches of the Cochrane Hypertension Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), Ovid MEDLINE, Ovid EMBASE, the clinical trials registry ClinicalTrials.gov, and from handsearches in reference lists and systematic reviews (status as of 13 April 2015). SELECTION CRITERIA: Randomised controlled trials in hypertensive adults of at least 24 weeks' duration that compared long term pharmacologic interventions for weight loss with placebo. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies, assessed risk of bias, and extracted data. Where appropriate and in the absence of significant heterogeneity between studies (P > 0.1), we pooled studies using fixed-effect meta-analysis. When heterogeneity was present, we used the random-effects method and investigated the cause of heterogeneity. MAIN RESULTS: After updating the literature search, which was extended to include four new weight-reducing drugs, we identified one additional study of phentermine/topiramate, bringing the total number of studies to nine that compare orlistat, sibutramine, or phentermine/topiramate to placebo and thus fulfil our inclusion criteria. We identified no relevant studies investigating rimonabant, liraglutide, lorcaserin, or naltrexone/bupropion. No study included mortality and cardiovascular morbidity as predefined outcomes. Incidence of gastrointestinal side effects was consistently higher in those participants treated with orlistat versus those treated with placebo. The most frequent side effects were dry mouth, constipation, and headache with sibutramine, and dry mouth and paresthaesia with phentermine/topiramate. In participants assigned to orlistat, sibutramine, or phentermine/topiramate body weight was reduced more effectively than in participants in the usual-care/placebo groups. Orlistat reduced systolic blood pressure as compared to placebo by -2.5 mm Hg (mean difference (MD); 95% confidence interval (CI): -4.0 to -0.9 mm Hg) and diastolic blood pressure by 1.9 mm Hg (MD; 95% CI: -3.0 to -0.9 mm Hg). Sibutramine increased diastolic blood pressure compared to placebo by +3.2 mm Hg (MD; 95% CI: +1.4 to +4.9 mm Hg). The one trial that investigated phentermine/topiramate suggested it lowered blood pressure. AUTHORS' CONCLUSIONS: In people with elevated blood pressure, orlistat and sibutramine reduced body weight to a similar degree, while phentermine/topiramate reduced body weight to a greater extent. In the same trials, orlistat and phentermine/topiramate reduced blood pressure, while sibutramine increased it. We could include no trials investigating rimonabant, liraglutide, lorcaserin, or naltrexone/bupropion in people with elevated blood pressure. Long-term trials assessing the effect of orlistat, liraglutide, lorcaserin, phentermine/topiramate, or naltrexone/bupropion on mortality and morbidity are unavailable and needed. Rimonabant and sibutramine have been withdrawn from the market, after long-term trials on mortality and morbidity have confirmed concerns about the potential severe side effects of these two drugs. The European Medicines Agency refused marketing authorisation for phentermine/topiramate due to safety concerns, while the application for European marketing authorisation for lorcaserin was withdrawn by the manufacturer after the Committee for Medicinal Products for Human Use judged the overall benefit/risk balance to be negative. PMID- 26934641 TI - Using turbidity for designing water networks. AB - Some methods to design water networks with minimum fresh water consumption are based on the selection of a key contaminant. In most of these "single contaminant methods", a maximum allowable concentration of contaminants must be established in water demands and water sources. Turbidity is not a contaminant concentration but is a property that represents the "sum" of other contaminants, with the advantage that it can be cheaper and easily measured than biological oxygen demand, chemical oxygen demand, suspended solids, dissolved solids, among others. The objective of this paper is to demonstrate that turbidity can be used directly in the design of water networks just like any other contaminant concentration. A mathematical demonstration is presented and in order to validate the mathematical results, the design of a water network for a guava fudge production process is performed. The material recovery pinch diagram and nearest neighbors algorithm were used for the design of the water network. Nevertheless, this water network could be designed using other single contaminant methodologies. The maximum error between the expected and the real turbidity values in the water network was 3.3%. These results corroborate the usefulness of turbidity in the design of water networks. PMID- 26934642 TI - Reclamation of DPK hydrocarbon polluted agricultural soil using a selected bulking agent. AB - In the present study, laboratory scale bioremediation of dual purpose kerosene (DPK) hydrocarbon polluted soil using bulking agent (saw dust) was carried out. The effect of different parameters such as total petroleum hydrocarbon (TPH), dehydrogenase activity (DHase) and pH on bioremediation performance were evaluated. Studied parameters such as microbial dynamics, percentage degradation (95.20%), DHase (8.20 +/- 0.43) were found to be higher in saw dust amended system and significantly differed with control at p < 0.05. Experimental data adequately fitted the first order kinetic thus, generated r(2) values (0.966), first order degradation constant (0.659 d(-1)), and degradation half-life t1/2 = ln2/k (1.05 d). Micrococcus luteus, Bacillus sp., Rhizopus arrhizus and Aspergillus sp. were isolated from the study. The use of saw dust as bulking agent greatly increased biodegradation rate and resulted in effective DPK hydrocarbon clean up. Therefore, saw dust could serve as an effective biostimulant towards improved bioremediation of hydrocarbon polluted environment. PMID- 26934643 TI - The effect of lameness on the environmental performance of milk production by rotational grazing. AB - Dairy production leads to significant environmental impacts and increased production will only be feasible if the environmental performance at farm level permits a sustainable milk supply. Lameness is believed to become more prevalent and severe as herd sizes increase, and can significantly reduce milk output per cow while not influencing other attributes of the production system. The objective of this work was to quantify the effect of lameness on the environmental performance of a typical grazed grass dairy farm and evaluate the theoretical value of sensor-based real-time lameness management. Life cycle assessment was used to compare a typical baseline farm with scenarios assuming increased lameness severity and prevalence. It was found that lameness could increase the farm level global warming potential, acidification potential, eutrophication potential and fossil fuel depletion by 7-9%. As increased herd sizes will increase cow: handler ratio, this result was interpreted to suggest that the use of sensors and information and communication technology for lameness detection could improve management on dairy farms to reduce the adverse impact on environmental performance that is associated with lameness. PMID- 26934645 TI - Proteasomal degradation of sphingosine kinase 1 and inhibition of dihydroceramide desaturase by the sphingosine kinase inhibitors, SKi or ABC294640, induces growth arrest in androgen-independent LNCaP-AI prostate cancer cells. AB - Sphingosine kinases (two isoforms termed SK1 and SK2) catalyse the formation of the bioactive lipid sphingosine 1-phosphate. We demonstrate here that the SK2 inhibitor, ABC294640 (3-(4-chlorophenyl)-adamantane-1-carboxylic acid (pyridin-4 ylmethyl)amide) or the SK1/SK2 inhibitor, SKi (2-(p-hydroxyanilino)-4-(p chlorophenyl)thiazole)) induce the proteasomal degradation of SK1a (Mr = 42 kDa) and inhibit DNA synthesis in androgen-independent LNCaP-AI prostate cancer cells. These effects are recapitulated by the dihydroceramide desaturase (Des1) inhibitor, fenretinide. Moreover, SKi or ABC294640 reduce Des1 activity in Jurkat cells and ABC294640 induces the proteasomal degradation of Des1 (Mr = 38 kDa) in LNCaP-AI prostate cancer cells. Furthermore, SKi or ABC294640 or fenretinide increase the expression of the senescence markers, p53 and p21 in LNCaP-AI prostate cancer cells. The siRNA knockdown of SK1 or SK2 failed to increase p53 and p21 expression, but the former did reduce DNA synthesis in LNCaP-AI prostate cancer cells. Moreover, N-acetylcysteine (reactive oxygen species scavenger) blocked the SK inhibitor-induced increase in p21 and p53 expression but had no effect on the proteasomal degradation of SK1a. In addition, siRNA knockdown of Des1 increased p53 expression while a combination of Des1/SK1 siRNA increased the expression of p21. Therefore, Des1 and SK1 participate in regulating LNCaP-AI prostate cancer cell growth and this involves p53/p21-dependent and -independent pathways. Therefore, we propose targeting androgen-independent prostate cancer cells with compounds that affect Des1/SK1 to modulate both de novo and sphingolipid rheostat pathways in order to induce growth arrest. PMID- 26934644 TI - Combining optogenetic stimulation and fMRI to validate a multivariate dynamical systems model for estimating causal brain interactions. AB - State-space multivariate dynamical systems (MDS) (Ryali et al. 2011) and other causal estimation models are being increasingly used to identify directed functional interactions between brain regions. However, the validity and accuracy of such methods are poorly understood. Performance evaluation based on computer simulations of small artificial causal networks can address this problem to some extent, but they often involve simplifying assumptions that reduce biological validity of the resulting data. Here, we use a novel approach taking advantage of recently developed optogenetic fMRI (ofMRI) techniques to selectively stimulate brain regions while simultaneously recording high-resolution whole-brain fMRI data. ofMRI allows for a more direct investigation of causal influences from the stimulated site to brain regions activated downstream and is therefore ideal for evaluating causal estimation methods in vivo. We used ofMRI to investigate whether MDS models for fMRI can accurately estimate causal functional interactions between brain regions. Two cohorts of ofMRI data were acquired, one at Stanford University and the University of California Los Angeles (Cohort 1) and the other at the University of North Carolina Chapel Hill (Cohort 2). In each cohort, optical stimulation was delivered to the right primary motor cortex (M1). General linear model analysis revealed prominent downstream thalamic activation in Cohort 1, and caudate-putamen (CPu) activation in Cohort 2. MDS accurately estimated causal interactions from M1 to thalamus and from M1 to CPu in Cohort 1 and Cohort 2, respectively. As predicted, no causal influences were found in the reverse direction. Additional control analyses demonstrated the specificity of causal interactions between stimulated and target sites. Our findings suggest that MDS state-space models can accurately and reliably estimate causal interactions in ofMRI data and further validate their use for estimating causal interactions in fMRI. More generally, our study demonstrates that the combined use of optogenetics and fMRI provides a powerful new tool for evaluating computational methods designed to estimate causal interactions between distributed brain regions. PMID- 26934646 TI - Predicting hot spots in protein interfaces based on protrusion index, pseudo hydrophobicity and electron-ion interaction pseudopotential features. AB - The identification of hot spots, a small subset of protein interfaces that accounts for the majority of binding free energy, is becoming more important for the research of drug design and cancer development. Based on our previous methods (APIS and KFC2), here we proposed a novel hot spot prediction method. For each hot spot residue, we firstly constructed a wide variety of 108 sequence, structural, and neighborhood features to characterize potential hot spot residues, including conventional ones and new one (pseudo hydrophobicity) exploited in this study. We then selected 3 top-ranking features that contribute the most in the classification by a two-step feature selection process consisting of minimal-redundancy-maximal-relevance algorithm and an exhaustive search method. We used support vector machines to build our final prediction model. When testing our model on an independent test set, our method showed the highest F1 score of 0.70 and MCC of 0.46 comparing with the existing state-of-the-art hot spot prediction methods. Our results indicate that these features are more effective than the conventional features considered previously, and that the combination of our and traditional features may support the creation of a discriminative feature set for efficient prediction of hot spots in protein interfaces. PMID- 26934647 TI - APE1-mediated DNA damage repair provides survival advantage for esophageal adenocarcinoma cells in response to acidic bile salts. AB - Chronic Gastroesophageal Reflux Disease (GERD) is the main risk factor for the development of Barrett's esophagus (BE) and its progression to esophageal adenocarcinoma (EAC). Accordingly, EAC cells are subjected to high levels of oxidative stress and subsequent DNA damage. In this study, we investigated the expression and role of Apurinic/apyrimidinic endonuclease 1 (APE1) protein in promoting cancer cell survival by counteracting the lethal effects of acidic bile salts (ABS)-induced DNA damage. Immunohistochemistry analysis of human tissue samples demonstrated overexpression of APE1 in more than half of EACs (70 of 130), as compared to normal esophagus and non-dysplastic BE samples (P < 0.01). To mimic in vivo conditions, we treated in vitro cell models with a cocktail of ABS. The knockdown of endogenous APE1 in EAC FLO-1 cells significantly increased oxidative DNA damage (P < 0.01) and DNA single- and double-strand breaks (P < 0.01), whereas overexpression of APE1 in EAC OE33 cells reversed these effects. Annexin V/PI staining indicated that the APE1 expression in OE33 cells protects against ABS-induced apoptosis. In contrast, knockdown of endogenous APE1 in FLO-1 cells increased apoptosis under the same conditions. Mechanistic investigations indicated that the pro-survival function of APE1 was associated with the regulation of stress response c-Jun N-terminal protein kinase (JNK) and p38 kinases. Pharmacological inhibition of APE1 base excision repair (BER) function decreased cell survival and enhanced activation of JNK and p38 kinases by ABS. Our findings suggest that constitutive overexpression of APE1 in EAC may be an adaptive pro-survival mechanism that protects against the genotoxic lethal effects of bile reflux episodes. PMID- 26934648 TI - MiR-652-3p is upregulated in non-small cell lung cancer and promotes proliferation and metastasis by directly targeting Lgl1. AB - Our previous study found that miR-652-3p is markedly upregulated in the serum of patients with NSCLC and suggesting that miR-652-3p is a potential biomarker for the early diagnosis of NSCLC. In this study, we detected the expression of miR 652-3p in NSCLC tumor tissues and cell lines and investigated the effect of miR 652-3p on the proliferation and metastasis of NSCLC cells. Our results showed that the expression of miR-652-3p was significantly upregulated in tumor tissues of 50 patients with NSCLC, and it was significantly higher in patients with positive lymph node metastasis, advanced TNM stage and poor prognosis. Using functional analyses by overexpressing or suppressing miR-652-3p in NSCLC cells, we demonstrated that miR-652-3p promoted cell proliferation, migration, invasion and inhibited cell apoptosis. Moreover, the lethal(2) giant larvae 1 (Lgl1) was identified as a direct and functional target of miR-652-3p. Overexpression or knockdown of miR-652-3p led to decreased or increased expression of Lgl1 protein, and the binding site mutation of LLGL1 3'UTR abrogated the responsiveness of the luciferase reporters to miR-652-3p. Overexpression of Lgl1 partially attenuated the function of miR-652-3p. Collectively, these results revealed that miR-652-3p execute a tumor-promoter function in NSCLC through direct binding and regulating the expression of Lgl1. PMID- 26934649 TI - Primary tumor inflammation in gross tumor volume as a prognostic factor for nasopharyngeal carcinoma patients. AB - PURPOSE: The objective of this study is to investigate the prognostic value of primary tumor inflammation (PTI) in nasopharyngeal carcinoma (NPC) in the era of intensity-modulated radiation therapy (IMRT). RESULTS: PTI was observed in 376/1708 (22.0%) patients, and was present in the sphenoid sinus in 289/376 (76.9%), in the nasal cavity in 27 (7.2%), and in both places in 60 (15.9%). The estimated 4-year local relapse-free survival (LRFS), disease-free survival (DFS), overall survival (OS) and distant metastasis-free survival (DMFS) rates for PTI vs. non-PTI group were 89.2% vs. 96.1% (P < 0.001), 73.4% vs. 85.1% (P < 0.001), 85.0% vs. 92.1% (P < 0.001) and 83.6% vs. 91.4% (P < 0.001), respectively. After adjustment for these known prognostic factors, PTI was confirmed as an independent prognostic factor for LRFS (HR 2.152, 95% CI 1.318-3.516, P = 0.002), DFS (HR 1.581, 95% CI 1.204-2.077, P = 0.001) and DMFS (HR 1.682, 95% CI 1.177 2.402, P = 0.004). CONCLUSIONS: Primary tumor inflammation was identified as a strong prognostic factor for patients with NPC in the era of IMRT and should be considered when devising future treatment strategies aimed at improving survival in NPC patients. MATERIALS AND METHODS: Data on 1708 patients with nonmetastatic, histologically-confirmed NPC treated with IMRT between November 2009 and February 2012 at Sun Yat-Sen University Cancer Center were retrospectively reviewed. Patient survival between PTI and non-PTI groups were compared. PMID- 26934651 TI - Lymph nodes regression grade is a predictive marker for rectal cancer after neoadjuvant therapy and radical surgery. AB - Neoadjuvant therapy (NT) for rectal cancer (RC) reduces primary tumors and involved lymph nodes. While a prognostic value of tumor regression grade (TRG) has been identified, involved lymph node regression grade (LRG) has not been systematically evaluated. Here, we evaluated the association of LRG with oncologic outcomes of RC patients after NT followed by radical surgery. 347 patients with locally advanced RC who received NT and then underwent radical surgery were retrospectively recruited between 2004 and 2011. Response to NT was evaluated by a 3-tier LRG and TRG based on the ratio of residual tumor to fibrosis. LRG was assessed in all patients (LRG 0, 170 patients [49.0%]; LRG 1, 100 patients [28.8%]; and LRG 2, 77 patients [22.2%]). LRG correlated with 5-year distant metastasis and 5-year disease free survival (p=0.029 and 0.023, respectively). LRG also correlated with TRG (p=0.017). We conclude that the LRG system may be an independent predictive factor of long-term oncologic outcomes of rectal cancer patients after NT and radical surgery. PMID- 26934652 TI - Survival following segmentectomy or lobectomy in elderly patients with early stage lung cancer. AB - PURPOSE: To determine the survival following segmentectomy versus lobectomy in elderly patients with early-stage non-small cell lung cancer (NSCLC). METHODS: We identified 12324 elderly (>= 70 years) patients with stage I <= 3 cm NSCLC in the Surveillance, Epidemiology and End Results (SEER) database. Propensity score methods were used to balance baseline characteristics of patients undergoing segmentectomy or lobectomy. Overall survival (OS) and lung cancer-specific survival (LCSS) of patients treated with segmentectomy versus lobectomy were compared in Cox regression models after adjusting, stratifying or matching patients based on propensity scores. RESULTS: Cox models adjusting, stratifying or matching propensity scores all showed that patients treated with segmentectomy had significantly worse OS and LCSS compared to lobectomy. Subgroup analysis of patients with tumors <= 2cm, aged >= 75 years, or had >= 7 lymph nodes examined also revealed survival advantage associated with lobectomy. CONCLUSION: Elder age alone could not justify the application of segmentectomy in early-stage lung cancer. Prospective randomized trials are warranted to validate our results. PMID- 26934650 TI - Inhibition of IRE1alpha-driven pro-survival pathways is a promising therapeutic application in acute myeloid leukemia. AB - Survival of cancer cells relies on the unfolded protein response (UPR) to resist stress triggered by the accumulation of misfolded proteins within the endoplasmic reticulum (ER). The IRE1alpha-XBP1 pathway, a key branch of the UPR, is activated in many cancers. Here, we show that the expression of both mature and spliced forms of XBP1 (XBP1s) is up-regulated in acute myeloid leukemia (AML) cell lines and AML patient samples. IRE1alpha RNase inhibitors [MKC-3946, 2-hydroxy-1 naphthaldehyde (HNA), STF-083010 and toyocamycin] blocked XBP1 mRNA splicing and exhibited cytotoxicity against AML cells. IRE1alpha inhibition induced caspase dependent apoptosis and G1 cell cycle arrest at least partially by regulation of Bcl-2 family proteins, G1 phase controlling proteins (p21cip1, p27kip1 and cyclin D1), as well as chaperone proteins. Xbp1 deleted murine bone marrow cells were resistant to growth inhibition by IRE1alpha inhibitors. Combination of HNA with either bortezomib or AS2O3 was synergistic in AML cytotoxicity associated with induction of p-JNK and reduction of p-PI3K and p-MAPK. Inhibition of IRE1alpha RNase activity increased expression of many miRs in AML cells including miR-34a. Inhibition of miR-34a conferred cellular resistance to HNA. Our results strongly suggest that targeting IRE1alpha driven pro-survival pathways represent an exciting therapeutic approach for the treatment of AML. PMID- 26934653 TI - Tumor-associated antigen CAPERalpha and microvessel density in hepatocellular carcinoma. AB - PURPOSE: CAPERalpha, a tumor-associated antigen, was identified from a cDNA clone with autoantibody from a patient with hepatocellular carcinoma (HCC). It has been implicated, by way of alternative splicing of VEGF pre-mRNA, in the regulation of microvessel formation in Ewing's sarcoma. In this study, we looked for possible association of alterations in CAPERalpha with microvessel density in HCC. METHODS: Enzyme-linked immunosorbent assay using recombinant CAPERalpha as antigen were used to detect antibody against CAPERalpha. Immunohistochemistry (IHC) on liver sections was performed to analyze expression profiles of CAPERalpha, VEGF and CD34 in HCC and control tissues and was further used to assess the correlation of expression among CAPERalpha, VEGF and CD34 in HCC development. RESULTS: Autoantibody to CAPERalpha was highest in HCC (22/76, 28.9%), not detected in prostate cancer (0/79) and at 3.4% (3/88) in breast cancer. In immunohistochemical analysis of grades II and III HCC tissues, significantly decreased immunostaining for CAPERalpha was observed and this correlated directly with decreased immunostaining for VEGF (R=0.534, P=0.0003). Using CD34 immunostaining for detecting newly formed microvessels, strong staining was observed in grades II and III HCC. Normal liver sections, all of which have high expression of CAPERalpha were totally negative for CD34 immunostaining. A significant inverse correlation was seen between CAPERalpha and CD34 immunostaining (R=-0.481, P=0.0012). CONCLUSIONS: Decreased expression of CAPERalpha appears to be correlated with appearance of microvessels. It would be of interest to elucidate the cause of altered CAPERalpha since new formation of microvessels is important in progression of HCC. PMID- 26934654 TI - Hypotaurine evokes a malignant phenotype in glioma through aberrant hypoxic signaling. AB - Metabolomics has shown significant potential in identifying small molecules specific to tumor phenotypes. In this study we analyzed resected tissue metabolites using capillary electrophoresis-mass spectrometry and found that tissue hypotaurine levels strongly and positively correlated with glioma grade. In vitro studies were conducted to show that hypotaurine activates hypoxia signaling through the competitive inhibition of prolyl hydroxylase domain-2. This leads to the activation of hypoxia signaling as well as to the enhancement of glioma cell proliferation and invasion. In contrast, taurine, the oxidation metabolite of hypotaurine, decreased intracellular hypotaurine and resulted in glioma cell growth arrest. Lastly, a glioblastoma xenograft mice model was supplemented with taurine feed and exhibited impaired tumor growth. Taken together, these findings suggest that hypotaurine is an aberrantly produced oncometabolite, mediating tumor molecular pathophysiology and progression. The hypotaurine metabolic pathway may provide a potentially new target for glioblastoma diagnosis and therapy. PMID- 26934655 TI - Improved therapy for neuroblastoma using a combination approach: superior efficacy with vismodegib and topotecan. AB - Aberrant activation/expression of pathways/molecules including NF-kB, mTOR, hedgehog and polo-like-kinase-1 (PLK1) are correlated with poor-prognosis neuroblastoma. Therefore, to identify a most efficacious treatment for neuroblastoma, we investigated the efficacy of NF-kB/mTOR dual-inhibitor 13-197, hedgehog inhibitor vismodegib and PLK1 inhibitor BI2536 alone or combined with topotecan against high-risk neuroblastoma. The in vitro efficacy of the inhibitors alone or combined with topotecan on cell growth/apoptosis and molecular mechanism(s) were investigated. Results showed that as single agents 13 197, BI2536 and vismodegib significantly decreased neuroblastoma cell growth and induced apoptosis by targeting associated pathways/molecules. In combination with topotecan, 13-197 did not show significant additive/synergistic effects against neuroblastoma. However, BI2536 or vismodegib further significantly decreased neuroblastoma cell growth/survival. These results clearly showed that vismodegib combination with topotecan was synergistic and more efficacious compared with BI2536 in combination. Together, in vitro data demonstrated that vismodegib was most efficacious in potentiating topotecan-induced antineuroblastoma effects. Therefore, we tested the combined efficacy of vismodegib and topotecan against neuroblastoma in vivo using NSG mice. This resulted in significantly (p<0.001) reduced tumor growth and increased survival of mice. Together, the combination of vismodegib and topotecan showed a significant enhanced antineuroblastoma efficacy by targeting associated pathways/molecules which warrants further preclinical evaluation for translation to the clinic. PMID- 26934656 TI - P300 acetyltransferase regulates fatty acid synthase expression, lipid metabolism and prostate cancer growth. AB - De novo fatty acid (FA) synthesis is required for prostate cancer (PCa) survival and progression. As a key enzyme for FA synthesis fatty acid synthase (FASN) is often overexpressed in human prostate cancers and its expression correlates with worse prognosis and poor survival. P300 is an acetyltransferase that acts as a transcription co-activator. Increasing evidence suggests that P300 is a major PCa promoter, although the underlying mechanism remains poorly understood. Here, we demonstrated that P300 binds to and increases histone H3 lysine 27 acetylation (H3K27Ac) in the FASN gene promoter. We provided evidence that P300 transcriptionally upregulates FASN expression and promotes lipid accumulation in human PCa cells in culture and Pten knockout prostate tumors in mice. Pharmacological inhibition of P300 decreased FASN expression and lipid droplet accumulation in PCa cells. Immunohistochemistry analysis revealed that expression of P300 protein positively correlates with FASN protein levels in a cohort of human PCa specimens. We further showed that FASN is a key mediator of P300 induced growth of PCa cells in culture and in mice. Together, our findings demonstrate P300 as a key factor that regulates FASN expression, lipid accumulation and cell growth in PCa. They also suggest that this regulatory pathway can serve as a new therapeutic target for PCa treatment. PMID- 26934658 TI - Choosing the right stent for patients with ST-segment elevation myocardial infarction: the evidence-based approach. AB - Primary percutaneous coronary intervention (PCI) with the implantation of new generation drug-eluting stents (DES) is the preferred method of reperfusion in ST segment elevation myocardial infarction (STEMI). More importantly, new-generation DES are recommended as the default option in all clinical conditions and lesion subsets. On the other hand, the interest in fully bioresorbable scaffolds (BRS) implantation, also in the setting of STEMI is growing. Also, dedicated stents technologies, i.e. mesh-covered stents and self-expanding stents may play role in the treatment of STEMI and thrombus containing lesions. This review discusses the evidence for different stent options in STEMI with a proposed selection strategy in contemporary primary PCI. PMID- 26934659 TI - Long-term antithrombotic pharmacotherapy following ST-elevation myocardial infarction. AB - The selection and optimal duration of pharmacological agents to counteract thrombotic processes activated in patients with ST-elevation myocardial infarction (STEMI) still remain a debated issue in current clinical practice. Recently published trials have highlighted the potential benefits of dual antiplatelet therapy (DAPT) extended beyond the currently recommended 12-months term. Anticoagulation with non-vitamin K oral anticoagulants in addition to DAPT has also been explored. Importantly, benefits of prolonged antithrombotic management strategies could be offset by harms following bleeding complications, therefore careful assessment of a patient benefit-risk profile must be used to drive individualized medical decisions. Appraising current available evidence is useful to inform clinical practice and to optimize the pharmacological management of patients with STEMI. Accordingly, we provide an overview of the literature focusing on long-term antithrombotic management strategies in patients with a recent or prior myocardial infarction, with a primary focus on STEMI. PMID- 26934657 TI - Liberation from home mechanical ventilation and decannulation in children. AB - BACKGROUND: The prevalence of children requiring outpatient invasive long-term mechanical ventilation is increasing. For some children, liberation from home mechanical ventilation (HMV) and decannulation is the desired outcome. This study describes our experience liberating tracheostomy and HMV (T-HMV) dependent children from respiratory technologies. METHODS: We reviewed charts of T-HMV dependent children who were cared for at our institution and decannulated between July 1999 and December 2011. Patient characteristics, diagnoses, and important steps leading to decannulation were recorded. RESULTS: Forty-six children achieved HMV independence and decannulation. The most common indications for T HMV were lower airway and parenchymal lung disease. The median ages at tracheotomy, initiation of HMV, initiation of tracheostomy collar (TC) trials, HMV independence, and decannulation were 3.5, 6.0, 12.0, 25.5, and 40.5 months, respectively. Twenty-five children (54%) skipped either using a speaking valve, tracheostomy capping, or both without increased likelihood of recannulation. (P = 0.03). Common procedures prior to decannulation were airway surgery, bronchoscopy, and polysomnography (n = 30, 46, and 46 children, respectively). A median of 9.5 clinic visits and 5 hospitalizations occurred from initial hospital discharge to just prior to decannulation. HMV was primarily weaned as an outpatient. CONCLUSION: Liberation from respiratory technology is a complex, multi-step process that can be accomplished in medically complex children with varying underlying disease processes at relatively young ages. Five major steps (tracheotomy, initiation of HMV, initiation of TC trials, HMV independence, and decannulation) performed in conjunction with clinic visits, procedures, and home nursing support were integral in the successful decannulation process. Pediatr Pulmonol. 2016;51:838-849. (c) 2016 Wiley Periodicals, Inc. PMID- 26934661 TI - Advances in dual therapy stenting. AB - Interventional cardiovascular medicine is in continuous evolution. Introduction of drug-eluting stents (DES) in clinical practice drastically improved the efficacy of percutaneous coronary intervention by reducing the risk of in-stent restenosis through the abluminal elution of an antiproliferative drug to suppress neointimal hyperplasia. Unfortunately, safety issues rose with first-generation DES due to incomplete luminal stent strut endothelialization and subsequent risk of late and very-late thrombosis. While 2nd-generation DES addressed some of the safety issues observed with 1st-generation DES, some limitations remain. Dual therapy stenting is an innovative technology developed with the rationale of combining a highly effective antiproliferative drug elution on the abluminal side and an endothelial progenitor cell capture system on the luminal side to accelerate stent strut endothelialization; thus potentially preventing the early and late complications of incomplete endothelial coverage while maintaining an antirestenotic effectiveness. Additionally, a DES platform associated with more predictable and faster endothelialization pattern may be an important therapeutic option in patients at high-risk for bleeding who cannot tolerate even short regimens of dual antiplatelet therapy. The present article reviews the most recent developments in dual therapy stenting from its rationale to the preclinical and clinical studies. PMID- 26934660 TI - Radial versus femoral approach in STEMI: what do we know so far? AB - Radial approach has been used since 1989 to perform coronary angiography as an alternative to femoral access. During past decades, the development of dedicated equipment has led to high efficacy also in complex procedures. ST elevation myocardial infarction (STEMI) is known to be a high bleeding risk setting and in turn bleeding events can negatively impact on outcomes. Observational studies have demonstrated feasibility, efficacy and safety of radial approach when compared to femoral access in STEMI patients, with benefit in bleeding rates. These advantages have also been described in specific populations such as in the elderly and in patients with cardiogenic shock. Some large randomized trials have been conducted to assess outcomes of transradial access versus transfemoral access, with RIVAL and MATRIX representing the largest two studies. The RIVAL documented a significant reduction in access site-related complications in the global population of acute coronary syndrome (ACS) patients, with also lower mortality and net clinical adverse events (NACE), mainly driven by significant reduction of bleeding and all-cause mortality, in the STEMI sub-group. Overall, the MATRIX trial confirmed that radial access decreased bleeding and all-cause death thus reducing the rate of NACE and supporting the transradial access as the one to be preferred in ACS patients. Clinical advantages of radial access have been also tested in smaller randomized trials corroborating the evidence of radial access as a highly recommendable alternative to femoral access in the setting of primary percutaneous coronary intervention (p-PCI). The current evidence suggests that radial access should become the default access for patients with ACS undergoing invasive management. PMID- 26934662 TI - Optimizing adjunctive antithrombotic and anticoagulant therapy in primary PCI for STEMI. AB - The pharmacological management of patients with ST elevation myocardial infarction (STEMI) poses a significant challenge to the clinician. While mechanical reperfusion with primary percutaneous coronary intervention (PPCI) has proved its superiority over fibrinolysis, the best antithrombotic strategy surrounding the procedure remains a matter of debate. Due to the high risk of bleeding induced by antithrombotic drugs, the pharmacological management of STEMI needs to focus on an optimal strategy that reduces the rate of coronary thrombotic events without leading to excess bleeding. Intravenous anticoagulants are recommended for all patients presenting with STEMI. Low molecular heparin may be preferred over unfractionated heparin in the setting of PPCI. Recent data suggest that anticoagulation with bivalirudin can be utilized as an alternative strategy to heparin and Gp2b3a but this should be limited to patients at high risk of bleeding. Dual antiplatelet therapy comprising aspirin and P2Y12 inhibitor represents the cornerstone treatment for STEMI. New P2Y12 inhibitors (prasugrel and ticagrelor) have restricted clopidogrel use to situations where these potent agents are contraindicated. Whilst all oral antiplatelet agents have been used with an initial loading dose in STEMI, the time of their administration remains a controversial issue. In everyday practice, intravenous antiplatelet agents appear less consensual. While Gp2b3a receptor inhibitors use has been restricted to bailout situations, the place of cangrelor is not yet defined in real life daily practice. PMID- 26934663 TI - Advances with polymer-free amphilimus-eluting stents. AB - Despite the improved clinical outcomes following the availability of second generation drug eluting stents (DES), percutaneous coronary intervention (PCI) is associated with worse clinical and angiographic outcomes among the patients with diabetes mellitus (DM) than among non-diabetics. The Cre8 Amphilimus-eluting DES is polymer-free, resulting in a reduced inflammatory response and lower risk of stent thrombosis. In a clinical study, it showed equivalent efficacy and safety in diabetic and non-diabetic populations, a unique finding among DES studies. These findings were confirmed in a real-world study, Investig8, and another real world study, Particip8, is ongoing. The RESERVOIR Clinical Trial recruited patients with DM and showed noninferiority of the Cre8 DES compared to an everolimus eluting DES (EES) in the overall group but showed a statistical superiority of Cre8 in diabetic patients with higher metabolic dysfunctions. The Cre8 DES is therefore a valuable option for this important patient population. PMID- 26934664 TI - Guideline Adherence and Hospital Costs in Pediatric Severe Traumatic Brain Injury. AB - OBJECTIVES: Adherence to pediatric traumatic brain injury guidelines has been associated with improved survival and better functional outcome. However, the relationship between guideline adherence and hospitalization costs has not been examined. To evaluate the relationship between adherence to pediatric severe traumatic brain injury guidelines, measured by acute care clinical indicators, and the total costs of hospitalization associated with severe traumatic brain injury. DESIGN: Retrospective cohort study. SETTING: Five regional pediatric trauma centers affiliated with academic medical centers. PATIENTS: Demographic, injury, treatment, and charge data were included for pediatric patients (17 yr) with severe traumatic brain injury. INTERVENTIONS: Percent adherence to clinical indicators was determined for each patient. Cost-to-charge ratios were used to estimate ICU and total hospital costs for each patient. Generalized linear models evaluated the association between healthcare costs and adherence rate. MEASUREMENTS AND MAIN RESULTS: Cost data for 235 patients were examined. Estimated mean adjusted hospital costs were $103,485 (95% CI, 98,553-108,416); adjusted ICU costs were $82,071 (95% CI, 78,559-85,582). No association was found between adherence to guidelines and total hospital or ICU costs, after adjusting for patient and injury characteristics. Adjusted regression model results provided cost ratio equal to 1.01 for hospital and ICU costs (95% CI, 0.99-1.03 and 0.99-1.02, respectively). CONCLUSIONS: Adherence to severe pediatric traumatic brain injury guidelines at these five leading pediatric trauma centers was not associated with increased hospitalization and ICU costs. Therefore, cost should not be a factor as institutions and providers strive to provide evidence based guideline driven care of children with severe traumatic brain injury. PMID- 26934665 TI - Patterns of subretinal fluid resolution in Group D eyes treated with chemoreduction: Experience from the Children's Hospital Los Angeles/University of Southern California. AB - The purpose of this study was to evaluate patterns of subretinal fluid (SRF) resolution in Group D retinoblastoma eyes. Fifty-three Group D eyes were evaluated for the presence of SRF at diagnosis. They were subsequently treated with systemic chemoreduction (CRD) and the duration of SRF was evaluated. Logistic regression analysis was used to assess the association between duration of SRF and enucleation. Among the 53 Group D eyes, 42 eyes exhibited SRF at diagnosis (79%). After the first cycle of CRD, 27/42 eyes showed SRF (64%); 8/42 eyes demonstrated SRF after three cycles of CRD (19%), and only 3/42 eyes had SRF after six cycles (7%). Ten eyes were enucleated (10/53 or 19%). Only 1 of 10 eyes demonstrated persistent SRF at the time of enucleation. This retrospective analysis of patterns of subretinal fluid in retinoblastoma eyes demonstrates that 80% of Group D eyes present with SRF. Of these eyes, approximately 60% have persistent fluid after one cycle of CRD and less than 10% have persistent fluid after six cycles. However, presence or persistence of SRF during chemoreduction was not found to be a risk factor for enucleation in Group D retinoblastoma eyes. PMID- 26934666 TI - Expansion of the Concept of Nonlinear Effects in Catalytic Reactions Beyond Asymmetric Catalysis. AB - The observation and investigation of nonlinear effects in catalytic reactions provides valuable mechanistic insight. However, the applicability of this method was, until now, limited to molecules possessing chirality and therefore to asymmetric synthesis. The concept of nonlinear effects is expanded to catalytic reactions beyond asymmetric catalysis by using derivatives instead of enantiomers and by considering rates instead of enantiomeric excess. Additionally, its systematic application to investigate the mechanism of catalytic reactions is presented. By exceeding the limitation to asymmetric reactions, the study of nonlinear effects can become a general tool to elucidate reaction mechanisms. PMID- 26934667 TI - The Genetics of Dyslipidemia--When Less Is More. PMID- 26934668 TI - Is the Exhaled Breath Temperature Sensitive to Cigarette Smoking? AB - The smoking habit is accompanied by an acute inflammatory response which follows tissue injury. It would be desirable to find a non-invasive inflammatory marker that would simplify the task of studying and monitoring smokers more simply and allow us to identify populations at risk of contracting Chronic Obstructive Pulmonary Disease (COPD). Today's expectations regarding research focus on issues ranging from inflammatory markers to those of exhaled breath temperature (EBT) are considerable. That said, although the EBT has been largely studied in asthma and COPD, there have not been any studies thus far that have analysed the effect of cigarette smoking on the EBT. Bearing this in mind, in this longitudinal study we aim to analyse the EBT in current smokers, monitor the effects both of cigarette smoking on EBT and of what happens after smoking cessation. Twenty-five (25) smokers (59.5 +/- 3.1 yrs, 12 M) who participated in a multi-disciplinary smoking cessation programme and 25 healthy never-smokers (58.7 +/- 2.9, 13 M) underwent EBT measurement. EBT values were higher in smokers before smoking (T0) than in never-smokers [34.6 (34.2-35) vs 33.2 (32.4-33.7) degrees C, p < 0.001. The smokers repeated measurement 5 minutes after smoking a cigarette (T1) and 2 hours after (T2). They repeated EBC measurement after 1 week (T3) and then after 3 months (T4) from smoking cessation. EBT is higher in smokers compared to controls. EBT increases after cigarette smoking and progressively decreases with the increase of time from when the last cigarette was smoked. Thus, we can conclude that EBT is increased in smokers and also sensitive to the acute effect of cigarette smoke. PMID- 26934669 TI - The CpxRA two-component system contributes to Legionella pneumophila virulence. AB - The bacterium Legionella pneumophila is capable of intracellular replication within freshwater protozoa as well as human macrophages, the latter of which results in the serious pneumonia Legionnaires' disease. A primary factor involved in these host cell interactions is the Dot/Icm Type IV secretion system responsible for translocating effector proteins needed to establish and maintain the bacterial replicative niche. Several regulatory factors have been identified to control the expression of the Dot/Icm system and effectors, one of which is the CpxRA two-component system, suggesting essentiality for virulence. In this study, we generated cpxR, cpxA and cpxRA in-frame null mutant strains to further delineate the role of the CpxRA system in bacterial survival and virulence. We found that cpxR is essential for intracellular replication within Acanthamoeba castellanii, but not in U937-derived macrophages. Transcriptome analysis revealed that CpxRA regulates a large number of virulence-associated proteins including Dot/Icm effectors as well as Type II secreted substrates. Furthermore, the cpxR and cpxRA mutant strains were more sodium resistant than the parental strain Lp02, and cpxRA expression reaches maximal levels during postexponential phase. Taken together, our findings suggest the CpxRA system is a key contributor to L. pneumophila virulence in protozoa via virulence factor regulation. PMID- 26934671 TI - Strawberries Added to the Usual Diet Suppress Fasting Plasma Paraoxonase Activity and Have a Weak Transient Decreasing Effect on Cholesterol Levels in Healthy Nonobese Subjects. AB - OBJECTIVE: Strawberries can improve oxidants-antioxidants balance and reduce some cardiovascular risk factors in obese subjects. Paraoxonase-1 (PON-1) is a high density lipoprotein-associated enzyme with antioxidant properties that can protect from coronary artery disease in humans. We examined the effect of strawberry consumption on plasma PON-1 activity and lipid profile in healthy nonobese subjects. METHODS: Thirty-one subjects (body mass index [BMI] 24.4 +/- 4.0 kg/m(2)) on their usual diet consumed 500 g of strawberry pulp daily for 30 days (first course) and after a 10-day washout the cycle was repeated (second course). Fasting blood and spot morning urine samples were collected before, during, and after each strawberry course (8 time points) for determination of paraoxonase and arylesterase PON-1 activities and lipid profile. Twenty subjects served as controls with respect to cholesterol and PON-1 activities changes over the study period. RESULTS: Strawberries decreased mean plasma paraoxonase PON-1 activity and this effect was more evident after the second course (by 11.6%, p < 0.05) than after the first course (5.4%, p = 0.06), whereas arylesterase activity was constant. Strawberries altered total cholesterol levels (p < 0.05) with a tendency to transiently decrease it (by 5.1%) only after 15 days of the first course. Triglycerides and high- and low-density lipoprotein cholesterol did not change in response to fruit consumption. No changes in PON-1 activities and lipid profile were noted in controls. Paraoxonase correlated with arylesterase activity (p from 0.33 to 0.46 at the first 7 time points, p < 0.05). This association disappeared at the end of study (p = 0.07) when the strongest inhibition of paraoxonase was noted. CONCLUSIONS: Supplementation of the usual diet with strawberries decreased paraoxonase PON-1 activity and did not improve lipid profiles in healthy nonobese subjects. Further studies are necessary to establish the clinical significance of paraoxonase suppression and to define a group of healthy subjects who can benefit from strawberry consumption with respect to cholesterol levels. PMID- 26934673 TI - The evolving threat of carbapenem-resistant infections after liver transplantation: The case of Acinetobacter baumannii. PMID- 26934670 TI - Shedding of Syndecan-1/CXCL1 Complexes by Matrix Metalloproteinase 7 Functions as an Epithelial Checkpoint of Neutrophil Activation. AB - Although neutrophils play critical roles in innate immunity, in excess these cells cause severe tissue damage. Thus, neutrophil activation must be tightly regulated to prevent indiscriminant damage. Previously, we reported that mice lacking matrix metalloproteinase (MMP) 7 are protected from lung injury owing to markedly impaired neutrophil movement from the interstitium into mucosal lumenal spaces. This phenotype resulted from a lack of MMP7 shedding of syndecan-1, a heparan sulfate proteoglycan that carries the neutrophil chemokine CXCL1 as cargo. Here, we assessed if shedding syndecan-1/CXCL1 complexes affects neutrophil activation. Whereas injured monolayers of wild-type alveolar type II cells potently stimulated neutrophil activation, as gauged by release of myeloperoxidase, cells from Mmp7(-/-) or syndecan-1-null (Sdc1(-/-)) mice or human cells with MMP7 knockdown did not. In vivo, we observed reduced myeloperoxidase release relative to neutrophil numbers in bleomycin-injured Mmp7( /-) and Sdc1(-/-) mice. Furthermore, we determined that soluble syndecan-1 directly stimulated neutrophil activation in the absence of cellular damage. These data indicate that MMP7 shedding of syndecan-1/CXCL1 complexes functions as a checkpoint that restricts neutrophil activation at sites of epithelial injury. PMID- 26934672 TI - Evaluation of Five Tests for Sensitivity to Functional Deficits following Cervical or Thoracic Dorsal Column Transection in the Rat. AB - The dorsal column lesion model of spinal cord injury targets sensory fibres which originate from the dorsal root ganglia and ascend in the dorsal funiculus. It has the advantages that fibres can be specifically traced from the sciatic nerve, verifiably complete lesions can be performed of the labelled fibres, and it can be used to study sprouting in the central nervous system from the conditioning lesion effect. However, functional deficits from this type of lesion are mild, making assessment of experimental treatment-induced functional recovery difficult. Here, five functional tests were compared for their sensitivity to functional deficits, and hence their suitability to reliably measure recovery of function after dorsal column injury. We assessed the tape removal test, the rope crossing test, CatWalk gait analysis, and the horizontal ladder, and introduce a new test, the inclined rolling ladder. Animals with dorsal column injuries at C4 or T7 level were compared to sham-operated animals for a duration of eight weeks. As well as comparing groups at individual timepoints we also compared the longitudinal data over the whole time course with linear mixed models (LMMs), and for tests where steps are scored as success/error, using generalized LMMs for binomial data. Although, generally, function recovered to sham levels within 2-6 weeks, in most tests we were able to detect significant deficits with whole time course comparisons. On the horizontal ladder deficits were detected until 5-6 weeks. With the new inclined rolling ladder functional deficits were somewhat more consistent over the testing period and appeared to last for 6-7 weeks. Of the CatWalk parameters base of support was sensitive to cervical and thoracic lesions while hind-paw print-width was affected by cervical lesion only. The inclined rolling ladder test in combination with the horizontal ladder and the CatWalk may prove useful to monitor functional recovery after experimental treatment in this lesion model. PMID- 26934674 TI - Recent Progress in Molecular Recognition Imaging Using Atomic Force Microscopy. AB - Atomic force microscopy (AFM) is an extremely powerful tool in the field of bionanotechnology because of its ability to image single molecules and make measurements of molecular interaction forces with piconewton sensitivity. It works in aqueous media, enabling studies of molecular phenomenon taking place under physiological conditions. Samples can be imaged in their near-native state without any further modifications such as staining or tagging. The combination of AFM imaging with the force measurement added a new feature to the AFM technique, that is, molecular recognition imaging. Molecular recognition imaging enables mapping of specific interactions between two molecules (one attached to the AFM tip and the other to the imaging substrate) by generating simultaneous topography and recognition images (TREC). Since its discovery, the recognition imaging technique has been successfully applied to different systems such as antibody protein, aptamer-protein, peptide-protein, chromatin, antigen-antibody, cells, and so forth. Because the technique is based on specific binding between the ligand and receptor, it has the ability to detect a particular protein in a mixture of proteins or monitor a biological phenomenon in the native physiological state. One key step for recognition imaging technique is the functionalization of the AFM tips (generally, silicon, silicon nitrides, gold, etc.). Several different functionalization methods have been reported in the literature depending on the molecules of interest and the material of the tip. Polyethylene glycol is routinely used to provide flexibility needed for proper binding as a part of the linker that carries the affinity molecule. Recently, a heterofunctional triarm linker has been synthesized and successfully attached with two different affinity molecules. This novel linker, when attached to AFM tip, helped to detect two different proteins simultaneously from a mixture of proteins using a so-called "two-color" recognition image. Biological phenomena in nature often involve multimolecular interactions, and this new linker could be ideal for studying them using AFM recognition imaging. It also has the potential to be used extensively in the diagnostics technique. This Account includes fundamentals behind AFM recognition imaging, a brief discussion on tip functionalization, recent advancements, and future directions and possibilities. PMID- 26934675 TI - Clinical characteristics of prenatally diagnosed persistent left superior vena cava in low-risk pregnancies. AB - OBJECTIVE: To determine the incidence and clinical characteristics of persistent left superior vena cava (PLSVC) among low-risk pregnancies. We have also compared electrocardiography (ECG) parameters of infants with PLSVC with those of normal controls. METHOD: At our institute, fetal echocardiogram is routinely performed in the midtrimester. We retrospectively reviewed the records of prenatally diagnosed PLSVC cases from 2010 to 2014. The ECG findings in infants with isolated PLSVC were compared with those of age-matched controls. RESULTS: Sixty five cases of fetal PLSVC were detected during the study period. It represents 0.36% (65/18 188) of all fetal echocardiographic examinations during the study period. Twenty cases (30.8%) had other cardiac anomalies, seven cases (10.8%) were associated with extracardiac anomalies, and four cases (6.2%) had both cardiac and extracardiac anomalies, whereas in 34 cases (52.3%), the anomaly was isolated. There were no significant differences in ECG parameters between neonates with PLSVC and normal controls. CONCLUSION: Detection of PLSVC should prompt careful search for associated anomalies. Isolated PLSVC is a benign vascular anomaly and the outcomes are excellent. (c) 2016 The Authors. Prenatal Diagnosis published by John Wiley & Sons, Ltd. PMID- 26934677 TI - Correction: Blindness and Glaucoma: A Multicenter Data Review from 7 Academic Eye Clinics. PMID- 26934678 TI - Nonword Repetition in Spanish-Speaking Toddlers with and without Early Language Delays. AB - BACKGROUND/AIMS: Nonword repetition (NWR) studies with English-speaking toddlers indicate favorable diagnostic accuracy for identifying early language delays and strong associations with early vocabulary. While scarce, studies of Spanish NWR have revealed strong diagnostic accuracy with preschool- and school-age children. This study aimed to (1) establish the association between Spanish NWR and early linguistic measures, (2) compare the Spanish NWR skills of typical Spanish speaking toddlers and those of toddlers with early language delays (ELD), and (3) establish the diagnostic accuracy of a Spanish NWR task. METHODS: Sixty-five Spanish-speaking toddlers were given a NWR task and a language assessment while parents completed a vocabulary checklist and reported their child's longest utterances. RESULTS: NWR scores were moderately correlated with vocabulary and language. The ELD group had significantly lower NWR scores than peers, and 68% of the sample was classified correctly, with desirable sensitivity but inadequate specificity obtained. CONCLUSION: Findings from this study revealed developmental trends in Spanish-speaking toddlers' ability to repeat nonwords and that most toddlers were not able to repeat 4- and 5-syllable nonwords. Furthermore, Spanish speaking children with ELD had more difficulties with NWR than typical peers. The diagnostic accuracy results indicated that the clinical use of a Spanish NWR task for toddlers can serve to detect early language-learning difficulties, especially if used as one of multiple diagnostic sources of information to establish ELD. PMID- 26934676 TI - EDAG-1 promotes proliferation and invasion of human thyroid cancer cells by activating MAPK/Erk and AKT signal pathways. AB - Erythroid differentiation-associated gene (EDAG) is differentially expressed in normal hematopoietic progenitor/stem cells and a variety of embryonic tissues. High EDAG-1 expression is also found in human thyroid cancer cells and peripheral blood of patients with leukemia, but its functional significance was unclear. Current study aims to further clarify the expression pattern of EDAG-1 and tests its roles in proliferation and invasion of human thyroid cancer cells in vitro and in vivo. To this end, we have performed gain-of-function and loss-of-function studies to clarify how EDAG-1 regulates the proliferation, invasion, and adhesion ability of human thyroid cancer cells SW579cells. We found that overexpression of EDAG-1 promoted the proliferation, invasion, and adhesion of human thyroid cancer cells, whereas silencing of EDAG-1 reversed all these changes and reduced the tumorigenesis risk of nude mice. Mechanistically, we found that overexpression of EDAG-1 activated the MAPK/Erk and AKT signal pathways. These findings provide novel insights of the role of EDAG-1 in thyroid tumors, and may have direct clinical implication. PMID- 26934680 TI - The prognostic value of hematogones in patients with acute myeloid leukemia. AB - In acute myeloid leukemia (AML), new prognostic tools are needed to assess the risk of relapse. Hematogones (HGs) are normal B-lymphocyte precursors that increase in hematological diseases and may influence remission duration in AML. HG detection was prospectively investigated in 262 AML patients to determine its prognostic value. Flow cytometric HG detection was performed in bone marrow aspiration after intensive chemotherapy at the time of hematological recovery. Patients with HGs in bone marrow samples had a significantly better relapse-free survival (RFS) and overall survival (OS) than patients without HGs (P = 0.0021, and P = 0.0016). Detectable HGs independently predicted RFS (HR = 0.61, 95%CI: 0.42 - 0.89, P = 0.012) and OS (HR = 0.59, 95%CI: 0.38 - 0.92, 0.019) controlling for age, ELN classification, the number of chemotherapy cycles to achieve CR, performance status, secondary AML and flow cytometric minimal residual disease (MRD). In intensively treated AML, individual determination of HGs could be useful to stratify the optimal risk-adapted therapeutic strategy after induction chemotherapy. Am. J. Hematol. 91:566-570, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26934679 TI - Effect of Melatonin in Epithelial Mesenchymal Transition Markers and Invasive Properties of Breast Cancer Stem Cells of Canine and Human Cell Lines. AB - Cancer stem cells (CSCs) have been associated with metastasis and therapeutic resistance and can be generated via epithelial mesenchymal transition (EMT). Some studies suggest that the hormone melatonin acts in CSCs and may participate in the inhibition of the EMT. The objectives of this study were to evaluate the formation of mammospheres from the canine and human breast cancer cell lines, CMT U229 and MCF-7, and the effects of melatonin treatment on the modulation of stem cell and EMT molecular markers: OCT4, E-cadherin, N-cadherin and vimentin, as well as on cell viability and invasiveness of the cells from mammospheres. The CMT-U229 and MCF-7 cell lines were subjected to three-dimensional culture in special medium for stem cells. The phenotype of mammospheres was first evaluated by flow cytometry (CD44(+)/CD24(low/-) marking). Cell viability was measured by MTT colorimetric assay and the expression of the proteins OCT4, E-cadherin, N cadherin and vimentin was evaluated by immunofluorescence and quantified by optical densitometry. The analysis of cell migration and invasion was performed in Boyden Chamber. Flow cytometry proved the stem cell phenotype with CD44(+)/CD24(low/-) positive marking for both cell lines. Cell viability of CMT U229 and MCF-7 cells was reduced after treatment with 1mM melatonin for 24 h (P<0.05). Immunofluorescence staining showed increased E-cadherin expression (P<0.05) and decreased expression of OCT4, N-cadherin and vimentin (P<0.05) in both cell lines after treatment with 1 mM melatonin for 24 hours. Moreover, treatment with melatonin was able to reduce cell migration and invasion in both cell lines when compared to control group (P<0.05). Our results demonstrate that melatonin shows an inhibitory role in the viability and invasiveness of breast cancer mammospheres as well as in modulating the expression of proteins related to EMT in breast CSCs, suggesting its potential anti-metastatic role in canine and human breast cancer cell lines. PMID- 26934681 TI - LOC283731 promoter hypermethylation prognosticates survival after radiochemotherapy in IDH1 wild-type glioblastoma patients. AB - MGMT promoter methylation status is currently the only established molecular prognosticator in IDH wild-type glioblastoma multiforme (GBM). Therefore, we aimed to discover novel therapy-associated epigenetic biomarkers. After enrichment for hypermethylated fractions using methyl-CpG-immunoprecipitation (MCIp), we performed global DNA methylation profiling for 14 long-term (LTS; >36 months) and 15 short-term (STS; 6-10 months) surviving GBM patients. Even after exclusion of the G-CIMP phenotype, we observed marked differences between the LTS and STS methylome. A total of 1,247 probes in 706 genes were hypermethylated in LTS and 463 probes in 305 genes were found to be hypermethylated in STS patients (p values < 0.05, log2 fold change +/- 0.5). We identified 13 differentially methylated regions (DMRs) with a minimum of four differentially methylated probes per gene. Indeed, we were able to validate a subset of these DMRs through a second, independent method (MassARRAY) in our LTS/STS training set (ADCY1, GPC3, LOC283731/ISLR2). These DMRs were further assessed for their prognostic capability in an independent validation cohort (n = 62) of non-G-CIMP GBMs from the TCGA. Hypermethylation of multiple CpGs mapping to the promoter region of LOC283731 correlated with improved patient outcome (p = 0.03). The prognostic performance of LOC283731 promoter hypermethylation was confirmed in a third independent study cohort (n = 89), and was independent of gender, performance (KPS) and MGMT status (p = 0.0485, HR = 0.63). Intriguingly, the prediction was most pronounced in younger GBM patients (<60 years). In conclusion, we provide compelling evidence that promoter methylation status of this novel gene is a prognostic biomarker in IDH1 wild-type/non-G-CIMP GBMs. PMID- 26934682 TI - A Tissue-Penetrating Double Network Restores the Mechanical Properties of Degenerated Articular Cartilage. AB - Incorporation of an interpenetrating polymer network into an existing single polymer network enables augmentation of the original substrate's mechanical properties, and translation of this concept from purely synthetic materials to natural-synthetic hybrid systems provides the opportunity to reinforce mechanical properties of bulk biological substrates. In many disease states, the mechanical properties of bodily tissues deteriorate rendering them prone to further material failure. Herein, a tissue-supplementing technique is described in which an interpenetrating biomimetic hydrogel is polymerized in situ throughout cartilage tissue. The treatment restores the inferior compressive properties of osteoarthritic cartilage to that of healthy cartilage, preferentially localizing to weaker regions of tissue. Furthermore, the treatment technique preserves cartilage under harsh articulation conditions, showing promise as a materials based treatment for early-stage osteoarthritis. PMID- 26934683 TI - Immobilization of multivalent glycoprobes on gold surfaces for sensing proteins and macrophages. AB - The multivalent display of carbohydrates on the cell surface provides cooperative binding to improve the specific biological events. In addition to multivalency, the spatial arrangement and orientation of sugars with respect to external stimuli also trigger carbohydrate-protein interactions. Herein, we report a non covalent host-guest strategy to immobilize heptavalent glyco-beta-cyclodextrin on gold-coated glass slides to study multivalent carbohydrate-protein interactions. We have found that the localization of sugar entities on surfaces using beta cyclodextrin (beta-CD) chemistry increased the avidity of carbohydrate-protein and carbohydrate-macrophage interactions compared to monovalent-beta-CD sugar coated surfaces. This platform is expected to be a promising tool to amplify the avidity of sugar-mediated interactions on surfaces and contribute to the development of next generation bio-medical products. PMID- 26934684 TI - The USPSTF Position on Vision Screening of Adults-Seeing Is Believing? PMID- 26934685 TI - Diffusion-weighted MRI and in-phase/opposed-phase sequences in the assessment of bone tumors. AB - PURPOSE: To evaluate the role of diffusion-weighted apparent diffusion coefficient (ADC) and in-phase/opposed-phase sequences in the differentiation of benign and malignant osseous tumors. MATERIALS AND METHODS: At 1.5T, routine sequences were compared to diffusion-weighted and in-phase/opposed-phase in 63 patients. Routine sequence magnetic resonance imaging (MRI) scoring, mean ADC value, and in-phase/opposed-phase signal intensity ratio (SIR) was obtained. Statistical analysis included significance, receiver operating characteristic (ROC), and linear correlation between the three parameters. RESULTS: In all, 38 patients had malignant tumors and 25 patients had benign tumors. Benign and malignant tumors showed different routine sequence scores (P < 0.001). Mean ADC of the benign lesions ranged 0.9-3.2 * 10(-3) mm(2) /sec of mean +/- SD (1.9 +/- 0.6). In malignant tumors, the mean ADC ranged 0.6-1.9 * 10(-3) mm(2) /sec of mean +/- SD (1.1 +/- 0.4) (P < 0.0001). There was a possible differentiation between malignant and benign tumors at a threshold of 1.1 * 10(-3) mm(2) /sec of sensitivity and specificity of 94.1% and 70.3%, respectively. SIR for benign tumors ranged 0.2-1.0 of mean +/- SD (0.6 +/- 0.3). For malignant lesions SIR ranged 0.4-1.2 of mean +/- SD (0.8 +/- 0.3). Benign and malignant tumors show statistically significant SIR at P < 0.022 with possible differentiation at a threshold of 0.75 of sensitivity and specificity of 70.3% and 76.5%, respectively. Simple linear correlation between both ADC and SIR was significant at P < 0.01 with correlation coefficient (r) = 0.45. CONCLUSION: Diffusion weighted and in-phase/opposed-phase imaging might be used in addition to conventional MRI as a routine tool for differentiation of benign and malignant tumors. J. Magn. Reson. Imaging 2016;44:565-572. PMID- 26934686 TI - Salivary testosterone levels are unrelated to handedness or cerebral lateralization for language. AB - Behavioural and cerebral lateralization are thought to be controlled, at least in part, by prenatal testosterone (T) levels, explaining why sex differences are found in both laterality traits. The present study investigated hormonal effects on laterality using adult salivary T levels, to explore the adequacy of competing theories: the Geschwind, Behan and Galaburda, the callosal, and the sexual differentiation hypotheses. Sixty participants (15 right-handers and 15 left handers of each sex) participated. Behavioural lateralization was studied by means of hand preference tests (i.e., the Edinburgh Handedness Inventory and the Quantification of Hand Preference test) and a hand skill test (i.e., the Peg Moving test) whereas cerebral lateralization for language was studied using the Consonant-Vowel Dichotic Listening test and the Visual Half-Field Lexical Decision test. Salivary T and cortisol (C) concentrations were measured by luminescence immunoassay. Canonical correlations did not reveal significant relationships between T levels and measures of hand preference, hand skill, or language laterality. Thus, our findings add to the growing literature showing no relationship between T concentrations with behavioural or cerebral lateralization. It is claimed that prenatal T is not a major determinant of individual variability in either behavioural or cerebral lateralization. PMID- 26934688 TI - EVIDENCE THAT ECDYSIS IN THE LARVAL COCKROACH, Periplaneta americana L. IS TRIGGERED BY AN INCREASE IN THE CONCENTRATION OF HEMOLYMPH SUGAR. AB - Ecdysis in insects can be defined as shedding of the cuticle at the end of a larval stadium. This event can only occur after the peak titer of ecdysteroid in the hemolymph has returned to a low level. In the cockroach Periplaneta americana, ecdysis is strongly correlated with a rise in the concentration of trehalose and glucose in the hemolymph, leading to the idea that a causal relationship may exist between both events. The objective in this study was to determine if an increase in hemolymph sugar level would shorten the time to ecdysis in cockroach larvae with experimentally delayed ecdysis. The last larval stadium of P. americana averages 33.5 days but this increases significantly if the larva is injected with a small volume of saline. Injection of 10 MUl of saline on day 20 and on four successive days lengthened the stadium by as much as 2 weeks. If, however, trehalose or glucose is incorporated into the saline, approximately 40% of the treated larvae undergo ecdysis at the same time as uninjected larvae. Injection of Peram-AKH, the hypertrehalosemic hormone, also decreases the time for ecdysis to occur. This suggests that peak levels of ecdysteroid trigger the release of Peram-AKH, which then leads to activation of trehalose synthesis. The results support the hypothesis that elevated hemolymph sugar is a contributing factor in the removal of ecdysteroid from the hemolymph. PMID- 26934687 TI - Effects of high-intensity interval training on cardiometabolic risk factors in overweight/obese women. AB - The purpose of this study was to evaluate two practical interval training protocols on cardiorespiratory fitness, lipids and body composition in overweight/obese women. Thirty women (mean +/- SD; weight: 88.1 +/- 15.9 kg; BMI: 32.0 +/- 6.0 kg . m(2)) were randomly assigned to ten 1-min high-intensity intervals (90%VO2 peak, 1 min recovery) or five 2-min high-intensity intervals (80-100% VO2 peak, 1 min recovery) or control. Peak oxygen uptake (VO2 peak), peak power output (PPO), body composition and fasting blood lipids were evaluated before and after 3 weeks of training, completed 3 days per week. Results from ANCOVA analyses demonstrated no significant training group differences for any primary variables (P > 0.05). When training groups were collapsed, 1MIN and 2MIN resulted in a significant increase in PPO (?18.9 +/- 8.5 watts; P = 0.014) and time to exhaustion (?55.1 +/- 16.4 s; P = 0.001); non-significant increase in VO2 peak (?2.36 +/- 1.34 ml . kg(-)(1) . min(-)(1); P = 0.185); and a significant decrease in fat mass (FM) (-?1.96 +/- 0.99 kg; P = 0.011). Short-term interval exercise training may be effective for decreasing FM and improving exercise tolerance in overweight and obese women. PMID- 26934689 TI - Automated Volumetric Breast Density Measurements in the Era of the BI-RADS Fifth Edition: A Comparison With Visual Assessment. AB - OBJECTIVE: The purpose of this study is to evaluate automated volumetric measurements in comparison with visual assessment of mammographic breast density by use of the fifth edition of BI-RADS. MATERIALS AND METHODS: A total of 1185 full-field digital mammography examinations with standard views were retrospectively analyzed. All images were visually assessed by two blinded radiologists according to breast density category in the fifth edition of the BI RADS lexicon. Automated volumetric breast density assessment was performed using two different software programs, Quantra and Volpara. A weighted kappa value was calculated to assess the degree of agreement among the visual and volumetric assessments of the density category. The volumes of fibroglandular tissue or total breast and the percentage breast density provided by the two software programs were compared. RESULTS: Compared with a visual assessment, the agreement of density category ranged from moderate to substantial in Quantra (kappa = 0.54 0.61) and fair to moderate in Volpara (kappa = 0.32-0.43). The distribution of density category was statistically significantly different among visual and volumetric measurements (p < 0.0001). Quantra assigned category A and B (43.5%) more frequently than did the radiologists (25.6%) or Volpara (16.0%). Volpara assigned category D (42.1%) more frequently than did the radiologists (19.5%) or Quantra (15.4%). Between the two software programs, the means of all volumetric data were statistically significantly different (p < 0.0001), but were well correlated (gamma = 0.79-0.99; p < 0.0001). CONCLUSION: More mammographic examinations were classified as nondense breast tissue using the Quantra software and as dense breast tissue using the Volpara software, as compared with visual assessments according to the BI-RADS fifth edition. PMID- 26934690 TI - A Model for Integrating Ambulatory Surgery Centers Into an Academic Health System Using a Novel Ambulatory Surgery Coordinating Council. AB - PROBLEM: An increasing volume of ambulatory surgeries has led to an increase in the number of ambulatory surgery centers (ASCs). Some academic health systems have aligned with ASCs to create a more integrated care delivery system. Yet, these centers are diverse in many areas, including specialty types, ownership models, management, physician employment, and regulatory oversight. Academic health systems then face challenges in integrating these ASCs into their organizations. APPROACH: Johns Hopkins Medicine created the Ambulatory Surgery Coordinating Council in 2014 to manage, standardize, and promote peer learning among its eight ASCs. The Armstrong Institute for Patient Safety and Quality provided support and a model for this organization through its quality management infrastructure. The physician-led council defined a mission and created goals to identify best practices, uniformly provide the highest-quality patient-centered care, and continuously improve patient outcomes and experience across ASCs. OUTCOMES: Council members built trust and agreed on a standardized patient safety and quality dashboard to report measures that include regulatory, care process, patient experience, and outcomes data. The council addressed unintentional outcomes and process variation across the system and agreed to standard approaches to optimize quality. Council members also developed a process for identifying future goals, standardizing care practices and electronic medical record documentation, and creating quality and safety policies. NEXT STEPS: The early success of the council supports the continuation of the Armstrong Institute model for physician-led quality management. Other academic health systems can learn from this model as they integrate ASCs into their complex organizations. PMID- 26934691 TI - Important Skills for Internship and the Fourth-Year Medical School Courses to Acquire Them: A National Survey of Internal Medicine Residents. AB - PURPOSE: To obtain feedback from internal medicine residents, a key stakeholder group, regarding both the skills needed for internship and the fourth-year medical school courses that prepared them for residency. This feedback could inform fourth-year curriculum redesign efforts. METHOD: All internal medicine residents taking the 2013-2014 Internal Medicine In-Training Examination were asked to rank the importance of learning 10 predefined skills prior to internship and to use a dropdown menu of 11 common fourth-year courses to rank the 3 most helpful in preparing for internship. The predefined skills were chosen based on a review of the literature, a national subinternship curriculum, and expert consensus. Chi-square statistics were used to test for differences in responses between training levels. RESULTS: Of the 24,820 internal medicine residents who completed the exam, 20,484 (83%) completed the survey, had complete identification numbers, and consented to have their responses used for research. The three skills most frequently rated as very important were identifying when to seek additional help and expertise, prioritizing clinical tasks and managing time efficiently, and communicating with other providers around care transitions. The subinternship/acting internship was most often selected as being the most helpful course in preparing for internship. CONCLUSIONS: These findings indicate which skills and fourth-year medical school courses internal medicine residents found most helpful in preparing for internship and confirm the findings of prior studies highlighting the perceived value of subinternships. Internal medicine residents and medical educators agree on the skills students should learn prior to internship. PMID- 26934692 TI - The Johns Hopkins Hunterian Laboratory Philosophy: Mentoring Students in a Scientific Neurosurgical Research Laboratory. AB - After over 50 years of scientific contribution under the leadership of Harvey Cushing and later Walter Dandy, the Johns Hopkins Hunterian Laboratory entered a period of dormancy between the 1960s and early 1980s. In 1984, Henry Brem reinstituted the Hunterian Neurosurgical Laboratory, with a new focus on localized delivery of therapies for brain tumors, leading to several discoveries such as new antiangiogenic agents and Gliadel chemotherapy wafers for the treatment of malignant gliomas. Since that time, it has been the training ground for 310 trainees who have dedicated their time to scientific exploration in the lab, resulting in numerous discoveries in the area of neurosurgical research. The Hunterian Neurosurgical Laboratory has been a unique example of successful mentoring in a translational research environment. The laboratory's philosophy emphasizes mentorship, independence, self-directed learning, creativity, and people-centered collaboration, while maintaining productivity with a focus on improving clinical outcomes. This focus has been served by the diverse backgrounds of its trainees, both in regard to educational status as well as culturally. Through this philosophy and strong legacy of scientific contribution, the Hunterian Laboratory has maintained a positive and productive research environment that supports highly motivated students and trainees. In this article, the authors discuss the laboratory's training philosophy, linked to the principles of adult learning (andragogy), as well as the successes and the limitations of including a wide educational range of students in a neurosurgical translational laboratory and the phenomenon of combining clinical expertise with rigorous scientific training. PMID- 26934693 TI - Burnout and Alcohol Abuse/Dependence Among U.S. Medical Students. AB - PURPOSE: To explore the relationship between alcohol abuse/dependence with burnout and other forms of distress among a national cohort of medical students. METHOD: In 2012, the authors completed a national survey of medical students from the American Medical Association's Physician Masterfile containing validated items assessing alcohol abuse/dependence, burnout, depression, suicidality, quality of life (QOL), and fatigue. Descriptive and comparative statistical analyses were computed, including chi-square and multivariate logistic regression, to determine relationships between variables. RESULTS: Of the 12,500 students, 4,402 (35.2%) responded. Of these, 1,411 (32.4%) met diagnostic criteria for alcohol abuse/dependence. Students who were burned out (P = .01), depressed (P = .01), or reported low mental (P =.03) or emotional (P = .016) QOL were more likely to have alcohol abuse/dependence. Emotional exhaustion and depersonalization domains of burnout were strongly associated with alcohol abuse/dependence. On multivariate analysis, burnout (OR 1.20; 95% CI 1.05-1.37; P < .01), having $50,000 to $100,000 (OR 1.21 versus < $50,000; CI 1.02-1.44; P < .05) or > $100,000 (OR 1.27 versus < $50,000; CI 1.08-1.48; P < .01) of educational debt, being unmarried (OR 1.89; CI 1.57-2.27; P < .001), and being younger (for every five years, OR 1.15; CI 1.02-1.28; P = .01) were independently associated with increased risk for alcohol abuse/dependence. CONCLUSIONS: Burnout was strongly related to alcohol abuse/dependence among sampled medical students and increased educational debt predicted a higher risk. A multifaceted approach addressing burnout, medical education costs, and alcohol use is needed. PMID- 26934694 TI - See More, Do More, Teach More: Surgical Resident Autonomy and the Transition to Independent Practice. AB - The graduate medical education system is tasked with training competent and autonomous health care providers while also improving patient safety, delivering more efficient care, and cutting costs. Concerns about resident autonomy and preparation for independent and safe practice appear to be growing, and the field of surgery faces unique challenges in preparing graduates for independent practice. Multiple factors are contributing to an erosion of resident autonomy and decreased operative experience, including differing views of autonomy, financial forces, duty hours regulations, and diverse community health care needs. Identifying these barriers and developing solutions to overcome them are vital first steps in reversing the trend of diminishing autonomy in surgical residency training. This Commentary highlights the problem of decreasing autonomy, outlines specific threats to resident autonomy, and discusses potential solutions to mitigate their impact on the successful transition to independent practice. PMID- 26934695 TI - Stereoselective Behavior of the Fungicide Benalaxyl During Grape Growth and the Wine-Making Process. AB - Benalaxyl is widely applied as a fungicide during grape planting processing. In this experiment, the stereoselective behavior of benalaxyl was studied during the grape growth and wine-making process. A simple method based on high-performance liquid chromatography (HPLC) equipped with a chiral column and UV detector was established to separate and determine the enantiomers of benalaxyl. Stereoselective degradation of the two enantiomers of benalaxyl was found in grapes. The degradation of both enantiomers followed pseudofirst-order kinetics, and the degradation rate of R-(-)-benalaxyl was faster than S-(+)-benalaxyl. The half-life of R-(-)-benalaxyl was 27 h, while the half-life of S-(+)-benalaxyl was 31 h. The enantiomer fraction value decreased from 0.50 to 0.34 and finally only S-(+)-benalaxyl could be detected. In the fermentation process, both enantiomers of benalaxyl were hardly degraded, and no configuration interconversion was observed. Meanwhile, both enantiomers of benalaxyl showed little influence on the growth of the yeast, consumption of carbon sources, or production of alcohol. The result of this study might provide more sufficient data for the evaluation of food safety and potential risk. Chirality 28:394-398, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26934696 TI - Implementation of telementoring for pain management in Veterans Health Administration: Spatial analysis. AB - In 2011, the Veterans Health Administration (VHA) implemented a pilot telementoring program across seven healthcare networks called the Specialty Care Access Network-Extension for Community Healthcare Outcomes (SCAN-ECHO) for pain management. A VHA healthcare network is a group of hospitals and clinics administratively linked in a geographic area. We created a series of county-level maps in one network displaying (1) the location of Veterans with chronic pain, (2) VHA sites (i.e., coordinating center, other medical centers, outpatient clinics), (3) proportion of Veterans being seen in-person at pain specialty clinics, and (4) proportion of Veterans with access to a primary care provider participating in Pain SCAN-ECHO. We calculated the geodesic distance from Veterans' homes to nearest VHA pain specialty care clinics. We used logistic regression to determine the association between distance and Pain SCAN-ECHO primary care provider participation. Mapping showed counties closer to the Pain SCAN-ECHO coordinating center had a higher rate of Veterans whose providers participated in Pain SCAN-ECHO than those further away. Regression models within networks revealed wide heterogeneity in the reach of Pain SCAN-ECHO to Veterans with low spatial access to pain care. Using geographic information systems can reveal the spatial reach of technology-based healthcare programs and inform future expansion. PMID- 26934698 TI - Sex-Based Differences in Adelie Penguin (Pygoscelis adeliae) Chick Growth Rates and Diet. AB - Sexually size-dimorphic species must show some difference between the sexes in growth rate and/or length of growing period. Such differences in growth parameters can cause the sexes to be impacted by environmental variability in different ways, and understanding these differences allows a better understanding of patterns in productivity between individuals and populations. We investigated differences in growth rate and diet between male and female Adelie Penguin (Pygoscelis adeliae) chicks during two breeding seasons at Cape Crozier, Ross Island, Antarctica. Adelie Penguins are a slightly dimorphic species, with adult males averaging larger than adult females in mass (~11%) as well as bill (~8%) and flipper length (~3%). We measured mass and length of flipper, bill, tibiotarsus, and foot at 5-day intervals for 45 male and 40 female individually marked chicks. Chick sex was molecularly determined from feathers. We used linear mixed effects models to estimate daily growth rate as a function of chick sex, while controlling for hatching order, brood size, year, and potential variation in breeding quality between pairs of parents. Accounting for season and hatching order, male chicks gained mass an average of 15.6 g d(-1) faster than females. Similarly, growth in bill length was faster for males, and the calculated bill size difference at fledging was similar to that observed in adults. There was no evidence for sex-based differences in growth of other morphological features. Adelie diet at Ross Island is composed almost entirely of two species--one krill (Euphausia crystallorophias) and one fish (Pleuragramma antarctica), with fish having a higher caloric value. Using isotopic analyses of feather samples, we also determined that male chicks were fed a higher proportion of fish than female chicks. The related differences in provisioning and growth rates of male and female offspring provides a greater understanding of the ways in which ecological factors may impact the two sexes differently. PMID- 26934697 TI - Biochemical Screening of Five Protein Kinases from Plasmodium falciparum against 14,000 Cell-Active Compounds. AB - In 2010 the identities of thousands of anti-Plasmodium compounds were released publicly to facilitate malaria drug development. Understanding these compounds' mechanisms of action--i.e., the specific molecular targets by which they kill the parasite--would further facilitate the drug development process. Given that kinases are promising anti-malaria targets, we screened ~14,000 cell-active compounds for activity against five different protein kinases. Collections of cell-active compounds from GlaxoSmithKline (the ~13,000-compound Tres Cantos Antimalarial Set, or TCAMS), St. Jude Children's Research Hospital (260 compounds), and the Medicines for Malaria Venture (the 400-compound Malaria Box) were screened in biochemical assays of Plasmodium falciparum calcium-dependent protein kinases 1 and 4 (CDPK1 and CDPK4), mitogen-associated protein kinase 2 (MAPK2/MAP2), protein kinase 6 (PK6), and protein kinase 7 (PK7). Novel potent inhibitors (IC50 < 1 MUM) were discovered for three of the kinases: CDPK1, CDPK4, and PK6. The PK6 inhibitors are the most potent yet discovered for this enzyme and deserve further scrutiny. Additionally, kinome-wide competition assays revealed a compound that inhibits CDPK4 with few effects on ~150 human kinases, and several related compounds that inhibit CDPK1 and CDPK4 yet have limited cytotoxicity to human (HepG2) cells. Our data suggest that inhibiting multiple Plasmodium kinase targets without harming human cells is challenging but feasible. PMID- 26934699 TI - A New Species of Frog (Anura: Dicroglossidae) Discovered from the Mega City of Dhaka. AB - We describe a new species of frog of the genus Zakerana discovered from the urban core of Dhaka, Bangladesh, one of the most densely populated cities in the world. Although the new species is morphologically similar to the geographically proximate congeners in the Bangladeshi cricket frog group, we show that it can be distinguished from all congeners on the basis of morphological characters, advertisement calls and variation in two mitochondrial DNA genes (12S rRNA and 16S rRNA). Apart from several diagnostic differences in body proportions, the new species differs from other Zakerana species in having a flattened snout (from ventral view) projecting over the lower jaw, and diagnostic trapezoid-shaped red markings on the vocal sac in males. Molecular genetic analyses show that the new species is highly divergent (3.1-20.1% sequence divergence) from all congeneric species, and forms a well-supported clade with its sister species, Zakerana asmati. The discovery of a new amphibian species from the urban core of Dhaka together with several recent descriptions of new amphibian species from Bangladesh may indicate that more amphibian species remain to be discovered from this country. PMID- 26934701 TI - European Sitting Championship: Prevalence and Correlates of Self-Reported Sitting Time in the 28 European Union Member States. AB - OBJECTIVE: Sedentary behaviour is increasingly recognized as an important health risk, but comparable data across Europe are scarce. The objective of this study was to explore the prevalence and correlates of self-reported sitting time in adults across and within the 28 European Union Member States. METHODS: This study reports data from the Special Eurobarometer 412. In 2013, 27,919 randomly selected Europeans (approximately 1000 per Member State) were interviewed face-to face. Sitting time on a usual day was self-reported and dichotomised into sitting less- and more than 7.5 hours per day. Uni- and multivariate odds ratios of sitting more than 7.5 hours per day were assessed by country and socio demographic variables using binary logistic regression analyses. The analyses were stratified by country to study the socio-demographic correlates of sitting time within the different countries. RESULTS: A total of 26,617 respondents were included in the analyses. Median sitting time was five hours per day. Across Europe, 18.5 percent of the respondents reported to sit more than 7.5 hours per day, with substantial variation between countries (ranging from 8.9 to 32.1 percent). In general, northern European countries reported more sitting than countries in the south of Europe. 'Current occupation' and 'age when stopped education' were found to be the strongest correlates of sitting time, both across Europe and within most Member States. Compared to manual workers, the odds ratio of sitting more than 7.5 hours per day was 5.00 for people with white collar occupations, 3.84 for students, and 3.65 for managers. CONCLUSIONS: There is substantial variation in self-reported sitting time among European adults across countries as well as socio-demographic groups. While regular surveillance of (objectively measured) sedentary behaviour is needed, the results of this study provide entry points for developing targeted interventions aimed at highly sedentary populations, such as people with sedentary occupations. PMID- 26934702 TI - The ACEM Fellowship Examination: Fit for purpose? PMID- 26934700 TI - Analysis of Comparative Sequence and Genomic Data to Verify Phylogenetic Relationship and Explore a New Subfamily of Bacterial Lipases. AB - Thermostable and organic solvent-tolerant enzymes have significant potential in a wide range of synthetic reactions in industry due to their inherent stability at high temperatures and their ability to endure harsh organic solvents. In this study, a novel gene encoding a true lipase was isolated by construction of a genomic DNA library of thermophilic Aneurinibacillus thermoaerophilus strain HZ into Escherichia coli plasmid vector. Sequence analysis revealed that HZ lipase had 62% identity to putative lipase from Bacillus pseudomycoides. The closely characterized lipases to the HZ lipase gene are from thermostable Bacillus and Geobacillus lipases belonging to the subfamily I.5 with <= 57% identity. The amino acid sequence analysis of HZ lipase determined a conserved pentapeptide containing the active serine, GHSMG and a Ca(2+)-binding motif, GCYGSD in the enzyme. Protein structure modeling showed that HZ lipase consisted of an alpha/beta hydrolase fold and a lid domain. Protein sequence alignment, conserved regions analysis, clustal distance matrix and amino acid composition illustrated differences between HZ lipase and other thermostable lipases. Phylogenetic analysis revealed that this lipase represented a new subfamily of family I of bacterial true lipases, classified as family I.9. The HZ lipase was expressed under promoter Plac using IPTG and was characterized. The recombinant enzyme showed optimal activity at 65 degrees C and retained >= 97% activity after incubation at 50 degrees C for 1h. The HZ lipase was stable in various polar and non-polar organic solvents. PMID- 26934703 TI - Performance of Different Analytical Software Packages in Quantification of DNA Methylation by Pyrosequencing. AB - BACKGROUND: Pyrosequencing has emerged as an alternative method of nucleic acid sequencing, well suited for many applications which aim to characterize single nucleotide polymorphisms, mutations, microbial types and CpG methylation in the target DNA. The commercially available pyrosequencing systems can harbor two different types of software which allow analysis in AQ or CpG mode, respectively, both widely employed for DNA methylation analysis. OBJECTIVE: Aim of the study was to assess the performance for DNA methylation analysis at CpG sites of the two pyrosequencing software which allow analysis in AQ or CpG mode, respectively. Despite CpG mode having been specifically generated for CpG methylation quantification, many investigations on this topic have been carried out with AQ mode. As proof of equivalent performance of the two software for this type of analysis is not available, the focus of this paper was to evaluate if the two modes currently used for CpG methylation assessment by pyrosequencing may give overlapping results. METHODS: We compared the performance of the two software in quantifying DNA methylation in the promoter of selected genes (GSTP1, MGMT, LINE 1) by testing two case series which include DNA from paraffin embedded prostate cancer tissues (PC study, N = 36) and DNA from blood fractions of healthy people (DD study, N = 28), respectively. RESULTS: We found discrepancy in the two pyrosequencing software-based quality assignment of DNA methylation assays. Compared to the software for analysis in the AQ mode, less permissive criteria are supported by the Pyro Q-CpG software, which enables analysis in CpG mode. CpG mode warns the operators about potential unsatisfactory performance of the assay and ensures a more accurate quantitative evaluation of DNA methylation at CpG sites. CONCLUSION: The implementation of CpG mode is strongly advisable in order to improve the reliability of the methylation analysis results achievable by pyrosequencing. PMID- 26934704 TI - Transforming Global Health by Improving the Science of Scale-Up. AB - In its report Global Health 2035, the Commission on Investing in Health proposed that health investments can reduce mortality in nearly all low- and middle-income countries to very low levels, thereby averting 10 million deaths per year from 2035 onward. Many of these gains could be achieved through scale-up of existing technologies and health services. A key instrument to close this gap is policy and implementation research (PIR) that aims to produce generalizable evidence on what works to implement successful interventions at scale. Rigorously designed PIR promotes global learning and local accountability. Much greater national and global investments in PIR capacity will be required to enable the scaling of effective approaches and to prevent the recycling of failed ideas. Sample questions for the PIR research agenda include how to close the gap in the delivery of essential services to the poor, which population interventions for non-communicable diseases are most applicable in different contexts, and how to engage non-state actors in equitable provision of health services in the context of universal health coverage. PMID- 26934705 TI - Interaction of Boron Nitride Nanosheets with Model Cell Membranes. AB - Boron nitride nanomaterials have attracted attention for biomedical applications, due to their improved biocompatibility when compared with carbon nanomaterials. Recently, graphene and graphene oxide nanosheets have been shown, both experimentally and computationally, to destructively extract phospholipids from Escherichia coli. Boron nitride nanosheets (BNNSs) have exciting potential biological and environmental applications, for example the ability to remove oil from water. These applications are likely to increase the exposure of prokaryotes and eukaryotes to BNNSs. Yet, despite their promise, the interaction between BNNSs and cell membranes has not yet been investigated. Here, all-atom molecular dynamics simulations were used to demonstrate that BNNSs are spontaneously attracted to the polar headgroups of the lipid bilayer. The BNNSs do not passively cross the lipid bilayer, most likely due to the large forces experienced by the BNNSs. This study provides insight into the interaction of BNNSs with cell membranes and may aid our understanding of their improved biocompatibility. PMID- 26934706 TI - Association of Complement C5 Gene Polymorphisms with Proliferative Diabetic Retinopathy of Type 2 Diabetes in a Chinese Han Population. AB - PURPOSE: To investigate the association of C5 SNPs with proliferative diabetic retinopathy (PDR) of type 2 diabetes (T2D). METHODS: A total of four C5 SNPs including rs2269067, rs7040033, rs1017119 and rs7027797 were genotyped in 400 PDR patients with T2D (cases) and 600 non- proliferative diabetic retinopathy PDR (NPDR) with T2D patients (controls) by using PCR-RFLP method. mRNA expression was examined by real-time PCR. Cytokine production was detected by ELISA. RESULTS: The frequency of GG genotype of C5 rs2269067 was significantly increased in cases compared with controls (Pc = 3.4 * 10(-5), OR = 1.87). And C5 mRNA expression was significantly increased in rs2269067 GG cases as compared with CG or CC cases (P = 0.003, P = 0.001, respectively). Moreover, the production of IL-6 was significantly increased in rs2269067 GG cases compared to CG cases or CC cases (P = 0.002, P = 0.001, respectively). CONCLUSIONS: C5 rs2269067 GG genotype confers risk for PDR of T2D in Chinese han population and is associated with an elevated C5 mRNA expression and an increased IL-6 production. PMID- 26934707 TI - Variation of Soil Organic Carbon and Its Major Constraints in East Central Asia. AB - Variation of soil organic carbon (SOC) and its major constraints in large spatial scale are critical for estimating global SOC inventory and projecting its future at environmental changes. By analyzing SOC and its environment at 210 sites in uncultivated land along a 3020km latitudinal transect in East Central Asia, we examined the effect of environmental factors on the dynamics of SOC. We found that SOC changes dramatically with the difference as high as 5 times in north China and 17 times in Mongolia. Regardless, C:N remains consistent about 12. Path analysis indicated that temperature is the dominant factor in the variation of SOC with a direct effect much higher than the indirect one, the former breaks SOC down the year round while the latter results in its growth mainly via precipitation in the winter half year. Precipitation helps accumulate SOC, a large part of the effect, however, is taken via temperature. NH4+-N and topography also affect SOC, their roles are played primarily via climatic factors. pH correlates significantly with SOC, the effect, however, is taken only in the winter months, contributing to the decay of SOC primarily via temperature. These factors explained as much as 79% of SOC variations, especially in the summer months, representing the major constraints on the SOC stock. Soil texture gets increasingly fine southward, it does not, however, constitute an apparent factor. Our results suggested that recent global warming should have been adversely affecting SOC stock in the mid-latitude as temperature dominates other factors as the constraint. PMID- 26934708 TI - Bio-SCoRes: A Smorgasbord Architecture for Coreference Resolution in Biomedical Text. AB - Coreference resolution is one of the fundamental and challenging tasks in natural language processing. Resolving coreference successfully can have a significant positive effect on downstream natural language processing tasks, such as information extraction and question answering. The importance of coreference resolution for biomedical text analysis applications has increasingly been acknowledged. One of the difficulties in coreference resolution stems from the fact that distinct types of coreference (e.g., anaphora, appositive) are expressed with a variety of lexical and syntactic means (e.g., personal pronouns, definite noun phrases), and that resolution of each combination often requires a different approach. In the biomedical domain, it is common for coreference annotation and resolution efforts to focus on specific subcategories of coreference deemed important for the downstream task. In the current work, we aim to address some of these concerns regarding coreference resolution in biomedical text. We propose a general, modular framework underpinned by a smorgasbord architecture (Bio-SCoRes), which incorporates a variety of coreference types, their mentions and allows fine-grained specification of resolution strategies to resolve coreference of distinct coreference type-mention pairs. For development and evaluation, we used a corpus of structured drug labels annotated with fine grained coreference information. In addition, we evaluated our approach on two other corpora (i2b2/VA discharge summaries and protein coreference dataset) to investigate its generality and ease of adaptation to other biomedical text types. Our results demonstrate the usefulness of our novel smorgasbord architecture. The specific pipelines based on the architecture perform successfully in linking coreferential mention pairs, while we find that recognition of full mention clusters is more challenging. The corpus of structured drug labels (SPL) as well as the components of Bio-SCoRes and some of the pipelines based on it are publicly available at https://github.com/kilicogluh/Bio-SCoRes. We believe that Bio-SCoRes can serve as a strong and extensible baseline system for coreference resolution of biomedical text. PMID- 26934709 TI - Correction: A Downy Mildew Effector Attenuates Salicylic Acid-Triggered Immunity in Arabidopsis by Interacting with the Host Mediator Complex. PMID- 26934710 TI - Analytical Methods in Toxicology. PMID- 26934712 TI - Soil Respiration and Bacterial Structure and Function after 17 Years of a Reciprocal Soil Transplant Experiment. AB - The effects of climate change on soil organic matter-its structure, microbial community, carbon storage, and respiration response-remain uncertain and widely debated. In addition, the effects of climate changes on ecosystem structure and function are often modulated or delayed, meaning that short-term experiments are not sufficient to characterize ecosystem responses. This study capitalized on a long-term reciprocal soil transplant experiment to examine the response of dryland soils to climate change. The two transplant sites were separated by 500 m of elevation on the same mountain slope in eastern Washington state, USA, and had similar plant species and soil types. We resampled the original 1994 soil transplants and controls, measuring CO2 production, temperature response, enzyme activity, and bacterial community structure after 17 years. Over a laboratory incubation of 100 days, reciprocally transplanted soils respired roughly equal cumulative amounts of carbon as non-transplanted controls from the same site. Soils transplanted from the hot, dry, lower site to the cooler and wetter (difference of -5 degrees C monthly maximum air temperature, +50 mm yr-1 precipitation) upper site exhibited almost no respiratory response to temperature (Q10 of 1.1), but soils originally from the upper, cooler site had generally higher respiration rates. The bacterial community structure of transplants did not differ significantly from that of untransplanted controls, however. Slight differences in local climate between the upper and lower Rattlesnake locations, simulated with environmental control chambers during the incubation, thus prompted significant differences in microbial activity, with no observed change to bacterial structure. These results support the idea that environmental shifts can influence soil C through metabolic changes, and suggest that microbial populations responsible for soil heterotrophic respiration may be constrained in surprising ways, even as shorter- and longer-term soil microbial dynamics may be significantly different under changing climate. PMID- 26934713 TI - Validation of the Chinese Translation of the Spatial Hearing Questionnaire and Its Short Form. AB - PURPOSE: Few questionnaires address how to measure spatial hearing ability in complex listening situations. The purpose of the study was (a) to validate the Chinese translation of the Spatial Hearing Questionnaire (C-SHQ) among Chinese participants and (b) to provide a shortened version for the purpose of clinical screening. METHOD: This was a cross-sectional study. The C-SHQ was developed from the process of translation and back-translation of the original 24-item, English version (Tyler, Perreau, & Ji, 2009). The C-SHQ was administered to 146 patients at the Department of Otolaryngology Clinic of Sichuan Provincial People's Hospital between October 2013 and May 2014 at Sichuan, China. Exploratory factor analysis and reliability tests were performed for the full version, and confirmatory factor analysis was applied for the shortened version of the C-SHQ. RESULTS: The exploratory factor analysis revealed scores loaded on 3 similar factors compared with the original SHQ. The internal consistency reliability was high (Cronbach's alpha = 0.99). The confirmatory factor analysis indicated that a shortened version of 12 items is sufficient to measure spatial hearing abilities. CONCLUSIONS: The C-SHQ and its short form are both reliable and valid questionnaires, which are suitable for both research and clinical settings to measure spatial hearing ability in the Chinese population. PMID- 26934716 TI - An Evaluation of the Non-Neutrality of Money. AB - This paper evaluates the effect of a change in the quantity of money on relative prices in the U.S. economy based on quarterly time-series for the period of 1959 to 2013. We also estimate the implication of a change in relative prices on the rate of inflation and macroeconomic variables. The empirical results indicate that the change of money supply not only affects relative prices but also affects the inflation rate and real variables, such as investment, natural rate of unemployment and potential GDP, through the change in relative prices. The relevant finding of our study is that money is not neutral in a non-traditional sense because a change in the money supply disturbs relative prices and, consequently, the allocation of resources in the economy. This finding has serious implications that must be considered in the transmission mechanisms of monetary policy. PMID- 26934715 TI - Our Faces in the Dog's Brain: Functional Imaging Reveals Temporal Cortex Activation during Perception of Human Faces. AB - Dogs have a rich social relationship with humans. One fundamental aspect of it is how dogs pay close attention to human faces in order to guide their behavior, for example, by recognizing their owner and his/her emotional state using visual cues. It is well known that humans have specific brain regions for the processing of other human faces, yet it is unclear how dogs' brains process human faces. For this reason, our study focuses on describing the brain correlates of perception of human faces in dogs using functional magnetic resonance imaging (fMRI). We trained seven domestic dogs to remain awake, still and unrestrained inside an MRI scanner. We used a visual stimulation paradigm with block design to compare activity elicited by human faces against everyday objects. Brain activity related to the perception of faces changed significantly in several brain regions, but mainly in the bilateral temporal cortex. The opposite contrast (i.e., everyday objects against human faces) showed no significant brain activity change. The temporal cortex is part of the ventral visual pathway, and our results are consistent with reports in other species like primates and sheep, that suggest a high degree of evolutionary conservation of this pathway for face processing. This study introduces the temporal cortex as candidate to process human faces, a pillar of social cognition in dogs. PMID- 26934717 TI - Rhodium- and Iridium-Catalyzed Asymmetric Addition of Optically Pure P-Chiral H Phosphinates to Aldehydes Leading to Optically Active alpha-Hydroxyphosphinates. AB - Optically active alpha-hydroxyphosphinates with both C- and P-stereogenic centers are obtained by rhodium- or iridium-catalyzed substrate-directed stereoselective addition of the optically pure H-phosphinates to aldehydes. The reaction most probably proceeds by a transition-metal-catalyzed mechanism with hydridometal complexes as key intermediates in the catalytic cycle. PMID- 26934718 TI - Muscimol microinjected in the arcuate nucleus affects metabolism, body temperature & ventilation. AB - Effects of microinjection of 2 doses of gamma-aminobutyric acid (GABA)A receptor agonist, muscimol (M), into the hypothalamic arcuate nucleus on oxygen consumption and control of ventilation over time and body temperature (BT) at the end of the experiment were compared in adult male and female rats. Relative to cerebrospinal fluid (CSF, 0 nmol), BT was decreased only in male rats with both doses of M, while in female rats, the 5 nmol dose depressed oxygen consumption. Ventilation was depressed by 5 nmol M in male and 10 nmol M in female rats by decreasing tidal volume. M did not affect the ventilatory response of male or female rats to hypoxia, whereas in females 5 and 10 nmol M and in males 10 nmol M depressed the ventilatory response to hypercapnia. Thus, in rats GABAA receptors in the arcuate nucleus modulate BT, oxygen consumption, and ventilation in air and in response to hypercapnia in a sexually dimorphic manner. PMID- 26934719 TI - The zebrafish: an emerging animal model for investigating the hypothalamic regulation of reproduction. AB - Gonadotropin-releasing hormone (GnRH) neurons have a pivotal role in the physiological functions of hypotahlamic-pituitary-gonadal (HPG) axis. The pulsatile releasing of GnRH hormone into the hypophyseal portal circulation at the median eminence represent the first domino in the HPG cascade of events that regulate the development, fertility and aging in all vertebrates. These neurons principally originate in the olfactory placode and migrate during early embryonal stages into the hypothalamus. Alterations in developmental processes or in the releasing of GnRH hormone lead to a rare and complex disorder of the reproductive axis called congenital hypogonadotropic hypogonadism (CHH). Genetic screening of human patients and the use of model systems have led to the identification of several genes involved in the CHH pathogenesis underlying its oligogenic nature. Nevertheless CHH remains, for a large cohort of patients, idiopathic and GnRH neurogenesis processes not fully understood. This is due to intrinsic difficulties that exist in the analysis of earliest embryonic developmental stages and in the methodologies developed to study the CHH-causing genes. In this regard, zebrafish embryos, on account of its external fertilization and development, allow a real-time analysis that could overcome some of the above mentioned limitations. Moreover, the recent availability of several transgenic zebrafish reporter lines makes it an excellent model for the study of the oligogenic mechanisms leading to CHH. PMID- 26934720 TI - The complex genetic basis of congenital hypogonadotropic hypogonadism. AB - Congenital hypogonadotropic hypogonadism (CHH) is a rare disease characterized by delayed/absent puberty and infertility due to an inadequate secretion or action of gonadotrophin-releasing hormone (GnRH), with an otherwise structurally and functionally normal hypothalamic-pituitary-gonadal (HPG) axis. CHH is genetically heterogeneous but, due to the infertility of affected individuals, most frequently emerges in a sporadic form, though numerous familial cases have also been registered. In around 50-60% of cases, CHH is associated with a variety of non-reproductive abnormalities, most commonly anosmia/hyposmia, which defines Kallmann Syndrome (KS) by its presence. Broadly-speaking, genetic defects that directly impact on hypothalamic secretion, regulation, or action of GnRH result in a pure neuroendocrine phenotype, normosmic CHH (nCHH), whereas genetic defects that impact of embryonic migration of GnRH neurons to the hypothalamus most commonly result in KS, though nCHH can also arise. Hence, the description of several pedigrees, comprising subjects exhibiting KS and others with nCHH. Although more than 24 genes have been described to be involved in CHH, molecular variants of these do not presently explain more than 35-45% of reported cases. Therefore, numerous other unidentified genes (or conceivably, epigenetic mechanisms) remain to be described to fully understand the pathogenesis of CHH, explaining the emergent idea that CHH is a complex genetic disease characterized by variable expressivity and penetrance. This review summarizes the current state of knowledge on the complex genetic basis of congenital hypogonadotropic hypogonadism and aims to be accessible to both researchers and clinicians. PMID- 26934721 TI - Effects of melt aging and off-stoichiometric melts on CsSrI3:Eu(2+) single crystal scintillators. AB - Ternary halide scintillators are commonly prepared from a mixture of commercially available binary halides. The initial binary halides may contain excess halogen ions or have different volatilities, which could lead to loss of stoichiometry of the resulting ternary halide crystals and potentially negatively affect optical and scintillation properties. In this work, the effects of vacuum aging of the melt (melt aging) and use of off-stoichiometric melts via introduction of excess CsI on the crystal quality and scintillation properties of CsSrI3:Eu(2+), a promising scintillator for gamma-ray detection applications, are investigated. The phase purity of the grown samples was confirmed by powder X-ray diffraction and differential scanning calorimeter measurements, and the existence of matrix composition variations is revealed by energy-dispersive X-ray spectroscopy analyses. An abnormal relationship between the full energy peak and the shaping time, i.e. full energy peak broadening or existence of two full energy peaks, in the melt-aged and off-stoichiometric samples is observed. It is ascribed to a slow scintillation decay event in a time scale between 15 and 50 MUs. For the CsSrI3:Eu(2+) single crystal grown from a stoichiometric melt without melt aging treatment, an energy resolution of 5.0% at 662 keV and a light yield of 48,000 +/ 2000 photons per MeV can be achieved at a size of 1.4 cm(3). PMID- 26934723 TI - Corrigendum: Mechanochromic Luminescence of Fluorenyl-Substituted Ethylenes. PMID- 26934725 TI - Starving for more: Nutrient sensing by LIN-28 in adult intestinal progenitor cells. AB - In this Extra View, we extend our recent work on the protein LIN-28 and its role in adult stem cell divisions. LIN-28 is an mRNA- and microRNA-binding protein that is conserved from worms to humans. When expressed ectopically, it promotes the reprogramming of differentiated vertebrate cells into pluripotent stem cells as well as the regeneration of vertebrate tissues after injury. However, its endogenous function in stem cell populations is less clear. We recently reported that LIN-28 is specifically expressed in progenitor cells in the adult Drosophila intestine and enhances insulin signaling within this population. Loss of lin-28 alters the division patterns of these progenitor cells, limiting the growth of the intestinal epithelium that is ordinarily caused by feeding. Thus, LIN-28 is part of an uncharacterized circuit used to remodel a tissue in response to environmental cues like nutrition. Here, we extend this analysis by reporting that the levels of LIN-28 in progenitor cells are sensitive to nutrient availability. In addition, we speculate about the role of LIN-28 in the translational control of target mRNAs such as Insulin Receptor (InR) and how such translational control may be an important mechanism that underlies the stem cell dynamics needed for tissue homeostasis and growth. PMID- 26934724 TI - GenoType MTBDRplus Assay for Rapid Detection of Multidrug Resistance in Mycobacterium tuberculosis: A Meta-Analysis. AB - BACKGROUND: There is an urgent demand for rapid and accurate drug-susceptibility testing for the detection of multidrug-resistant tuberculosis. The GenoType MTBDRplus assay is a promising molecular kit designed for rapid identification of resistance to first-line anti-tuberculosis drugs, isoniazid and rifampicin. The aim of this meta-analysis was to evaluate the diagnostic accuracy of GenoType MTBDRplus in detecting drug resistance to isoniazid and rifampicin in comparison with the conventional drug susceptibility tests. METHODS: We searched PubMed, EMBASE, and Cochrane Library databases to identify studies according to predetermined criteria. A total of 40 studies were included in the meta-analysis. QUADAS-2 was used to assess the quality of included studies with RevMan 5.2. STATA 13.0 software was used to analyze the tests for sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, diagnostic odds ratio, and area under the summary receiver operating characteristic curves. Heterogeneity in accuracy measures was tested with Spearman correlation coefficient and Chi square. RESULTS: Patient selection bias was observed in most studies. The pooled sensitivity (95% confidence intervals were 0.91 (0.88-0.94) for isoniazid, 0.96 (0.95-0.97) for rifampicin, and 0.91(0.86-0.94) for multidrug-resistance. The pooled specificity (95% CI) was 0.99 (0.98-0.99) for isoniazid, 0.98 (0.97-0.99) for rifampicin and 0.99 (0.99-1.00) for multidrug-resistance, respectively. The area under the summary receiver operating characteristic curves ranged from 0.99 to 1.00. CONCLUSION: This meta-analysis determined that GenoType MTBDRplus had good accuracy for rapid detection of drug resistance to isoniazid and/or rifampicin of M. tuberculosis. MTBDRplus method might be a good alternative to conventional drug susceptibility tests in clinical practice. PMID- 26934727 TI - Correction: When Parents Separate and One Parent 'Comes Out' as Lesbian, Gay or Bisexual: Sons and Daughters Engage with the Tension that Occurs When Their Family Unit Changes. PMID- 26934729 TI - Exploration of Imaging Biomarkers for Predicting Survival of Patients With Advanced Non-Small Cell Lung Cancer Treated With Antiangiogenic Chemotherapy. AB - OBJECTIVE: The objective of this study was to compare imaging biomarkers, including (18)F-FDG PET, CT perfusion (CTP), and CT texture analysis (CTTA), in predicting the survival of patients with advanced non-small cell lung cancer (NSCLC) treated with antiangiogenic chemotherapy. SUBJECTS AND METHODS: A total of 35 patients (17 men and 18 women; median age, 64.0 years) with advanced NSCLC treated with antiangiogenic chemotherapy were evaluated. CTP and FDG PET were performed before the therapy, and blood flow, blood volume, mean transit time, and the maximum standardized uptake value (SUV max) of the tumor were measured. Texture parameters, including the mean value of pixels with positive values (MPP) and entropy (a measure of irregularity), were also measured on pretherapeutic unenhanced CT images, using CTTA software with a medium texture scale filtration. The best percent change in the tumor burden was also measured. These image derived tumor parameters were then compared with progression-free survival (PFS) and overall survival (OS). RESULTS: In univariate Cox regression analysis, MPP and entropy were significantly correlated with PFS (p = 0.01 and p = 0.01, respectively), whereas SUV max, MPP, and entropy were significantly correlated with OS (p = 0.03, p = 0.04, and p = 0.0008, respectively). In Kaplan-Meier analysis, high MPP and low entropy were significantly associated with favorable PFS (p < 0.0001 and p = 0.03, respectively) and OS (p = 0.0009 and p = 0.005, respectively), and low SUV max was significantly associated with favorable OS (p = 0.01). CTP parameters and the best change in the tumor burden had no associations with survival. In multivariate analysis, only entropy was identified as an independent prognostic factor for OS (p = 0.02). CONCLUSION: CTTA is the optimal imaging biomarker for predicting the survival of patients with advanced NSCLC treated with antiangiogenic chemotherapy. PMID- 26934726 TI - Ultradeformable Archaeosomes for Needle Free Nanovaccination with Leishmania braziliensis Antigens. AB - Total antigens from Leishmania braziliensis promastigotes, solubilized with sodium cholate (dsLp), were formulated within ultradeformable nanovesicles (dsLp ultradeformable archaeosomes, (dsLp-UDA), and dsLp-ultradeformable liposomes (dsLp-UDL)) and topically administered to Balb/c mice. Ultradeformable nanovesicles can penetrate the intact stratum corneum up to the viable epidermis, with no aid of classical permeation enhancers that can damage the barrier function of the skin. Briefly, 100 nm unilamellar dsLp-UDA (soybean phosphatidylcholine: Halorubrum tebenquichense total polar lipids (TPL): sodium cholate, 3:3:1 w:w) of -31.45 mV Z potential, containing 4.84 +/- 0.53% w/w protein/lipid dsLp, 235 KPa Young modulus were prepared. In vitro, dsLp-UDA was extensively taken up by J774A1 and bone marrow derive cells, and the only that induced an immediate secretion of IL-6, IL-12p40 and TNF-alpha, followed by IL 1beta, by J774A1 cells. Such extensive uptake is a key feature of UDA ascribed to the highly negatively charged archaeolipids of the TPL, which are recognized by a receptor specialized in uptake and not involved in downstream signaling. Despite dsLp alone was also immunostimulatory on J774A1 cells, applied twice a week on consecutive days along 7 weeks on Balb/c mice, it raised no measurable response unless associated to UDL or UDA. The highest systemic response, IgGa2 mediated, 1 log lower than im dsLp Al2O3, was elicited by dsLp-UDA. Such findings suggest that in vivo, UDL and UDA acted as penetration enhancers for dsLp, but only dsLp UDA, owed to its pronounced uptake by APC, succeeded as topical adjuvants. The actual TPL composition, fully made of sn2,3 ether linked saturated archaeolipids, gives the UDA bilayer resistance against chemical, physical and enzymatic attacks that destroy ordinary phospholipids bilayers. Together, these properties make UDA a promising platform for topical drug targeted delivery and vaccination, that may be of help for countries with a deficient healthcare system. PMID- 26934730 TI - In Vivo Anti-Inflammatory and Analgesic Effects of Aqueous Extract of Cistus ladanifer L. From Morocco. AB - This study is designed to evaluate the analgesic and anti-inflammatory activities of aqueous extract (AE) of Cistus ladanifer L. leaves in experimental animal models. The central analgesic activity of C. ladanifer AE is studied using hot plate method in rats, and the acute anti-Inflammatory activity of C. ladanifer is investigated by rats paw edema induced by subplantar injection of 0.5% carrageenan into the right hind paw. Rats are pretreated with AE of C. ladanifer at different doses (150, 175, and 200 mg/kg, i.p.). The tramadol and indomethacin are used as reference drugs for analgesic and anti-inflammatory studies, respectively. Our results show that the AE of C. ladanifer exhibited anti inflammatory and analgesic effects dose dependent. In anti-inflammatory activity, the AE of C. ladanifer at all doses reduced significantly the edema paw inflammation after carrageenan injection. Furthermore at 200 mg/kg, the effect of AE is highly important than that of other doses. In addition, the same AE demonstrates significant analgesic effect in thermal-induced pain model. So, this activity is proved by significant reduction of pain score after administration of AE at all doses. The nociception protection effects in this case are, respectively, 70.3%, 74.55%, and 93.33% after administration of AE of C. ladanifer at doses 150, 175, and 200 mg/kg b.w. The results of our findings suggest that AE of C. ladanifer has potential analgesic and anti-inflammatory activities with evidence of possible involvement of peripheral and central effects in its actions. PMID- 26934728 TI - CpG Improves Influenza Vaccine Efficacy in Young Adult but Not Aged Mice. AB - Several studies have shown a reduced efficacy of influenza vaccines in the elderly compared to young adults. In this study, we evaluated the immunogenicity and protective efficacy of a commercially available inactivated influenza vaccine (Fluzone(r)) in young adult and aged mice. C57/BL6 mice were administered a single or double immunization of Fluzone(r) with or without CpG and challenged intranasally with H1N1 A/California/09 virus. A double immunization of Fluzone(r) adjuvanted with CpG elicited the highest level of protection in young adult mice which was associated with increases in influenza specific IgG, elevated HAI titres, reduced viral titres and lung inflammation. In contrast, the vaccine schedule which provided fully protective immunity in young adult mice conferred limited protection in aged mice. Antigen presenting cells from aged mice were found to be less responsive to in vitro stimulation by Fluzone and CpG which may partially explain this result. Our data are supportive of studies that have shown limited effectiveness of influenza vaccines in the elderly and provide important information relevant to the design of more immunogenic vaccines in this age group. PMID- 26934731 TI - Association of Coagulation Factors VIII/XI/XIII Polymorphisms With Coagulation Factor Activities and Deep Vein Thrombosis After Artificial Joints Replacement. AB - The study aims at investigating the effects of coagulation factors VIII/XI/XIII polymorphisms in coagulation factor activities and deep vein thrombosis (DVT). A total of 130 patients with history of artificial joint replacement surgery were recruited, including 65 patients with DVT (cases) and 65 patients without DVT (controls). Cases and controls had comparable age, sex, and body mass index. Activities of VIII/XI and XIII were, respectively, detected by 1 phase anticoagulation method and microtitrimetry. Polymorphisms of VIII rs1800291 (3591C>G), XI rs2289252 (25264C>T), and XIII rs5985 (103G>T) were detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Activities of VIII/XI were significantly increased in cases than in controls (P < 0.001 for VIII, P = 0.024 for XI). Activity of XI was significantly increased by 11.11% in CT + TT mutant type (25264C>T) compared with wild-type CC (95% confidence interval (CI), 2.28-19.95). In univariate analysis, incidence of DVT for CT mutant was 2.41-fold compared with wild-type CC (95% CI, 1.16-5.03). T allele had 1.83-fold increased risk of DVT than C allele (95% CI, 1.06-3.14). In multivariate analysis, incidence of DVT for CT + TT mutant type was 2.39-fold compared with wild type (95% CI, 1.07-5.35). Distributions of VIII gene 3951C>G and genotypes were not significant between groups (both P > 0.05). The mutation rate of VIII gene 103G>T was low in study population (0.77%) and was not significant between groups. XI 25264C>T genotype is significantly associated with XI activity. T mutation of this locus significantly increases XI activity and is a risk factor for DVT. PMID- 26934732 TI - Hyaluronic Acid Suppresses the Expression of Metalloproteinases in Osteoarthritic Cartilage Stimulated Simultaneously by Interleukin 1beta and Mechanical Load. AB - PURPOSE: In patients with osteoarthritis (OA), intraarticular injection of hyaluronic acid (HA) frequently results in reduced pain and improved function for prolonged periods of time, i.e. more than 6 months. However, the mechanisms underlying these effects are not fully understood. Our underlying hypothesis is that HA modifies the enzymatic breakdown of joint tissues. METHODS: To test this hypothesis, we examined osteochondral cylinders from 12 OA patients. In a bioreactor, these samples were stimulated by interleukin 1beta (Il1beta) (2 ng/ml) plus mechanical load (2.0 Mpa at 0.5 Hz horizontal and 0.1 Hz vertical rotation), thus the experimental setup recapitulated both catabolic and anabolic clues of the OA joint. RESULTS: Upon addition of HA at either 1 or 3 mg/ml, we observed a significant suppression of expression of metalloproteinase (MMP)-13. A more detailed analysis based on the Kellgren and Lawrence (K&L) OA grade, showed a much greater degree of suppression of MMP-13 expression in grade IV as compared to grade II OA. In contrast to the observed MMP-13 suppression, treatment with HA resulted in a suppression of MMP-1 expression only at 1 mg/ml HA, while MMP-2 expression was not significantly affected by either HA concentration. CONCLUSION: Together, these data suggest that under concurrent catabolic and anabolic stimulation, HA exhibits a pronounced suppressive effect on MMP-13. In the long run these findings may benefit the development of treatment strategies aimed at blocking tissue degradation in OA patients. PMID- 26934733 TI - The Role of Diverse Strategies in Sustainable Knowledge Production. AB - Online communities are becoming increasingly important as platforms for large scale human cooperation. These communities allow users seeking and sharing professional skills to solve problems collaboratively. To investigate how users cooperate to complete a large number of knowledge-producing tasks, we analyze Stack Exchange, one of the largest question and answer systems in the world. We construct attention networks to model the growth of 110 communities in the Stack Exchange system and quantify individual answering strategies using the linking dynamics on attention networks. We identify two answering strategies. Strategy A aims at performing maintenance by doing simple tasks, whereas strategy B aims at investing time in doing challenging tasks. Both strategies are important: empirical evidence shows that strategy A decreases the median waiting time for answers and strategy B increases the acceptance rate of answers. In investigating the strategic persistence of users, we find that users tends to stick on the same strategy over time in a community, but switch from one strategy to the other across communities. This finding reveals the different sets of knowledge and skills between users. A balance between the population of users taking A and B strategies that approximates 2:1, is found to be optimal to the sustainable growth of communities. PMID- 26934734 TI - Comparison of Risk Factor between Lacunar Stroke and Large Artery Atherosclerosis Stroke: A Cross-Sectional Study in China. AB - BACKGROUND: Stroke is the second most common cause of mortality in China. Although most subtypes of ischemic stroke share similar risk factors, they have different etiologies. Our study aimed to evaluate the different risk factor profiles between the stroke subtypes, lacunar infarcts (LI) and large-artery atherosclerosis (LAA), and clarify the characteristics of current acute ischemic stroke in China. METHODS: In this cross-sectional study, we analyzed the clinical characteristics of 1982 patients with acute ischemic stroke who were admitted to the neurology department at the Peking University First Hospital between 2007 and 2014. Ischemic stroke was further classified into LAA, LI, cardioembolism (CE) and undetermined causes of infarction (UDI) according to TOAST classification. Demographic characteristics, risk factors, as well as the findings of laboratory and imaging tests of 1773 patients with LAA and LI, were analyzed by univariate and multivariate logistic analysis. RESULTS: Of the 1982 ischemic stroke patients included in this study, 1207 were diagnosed with LAA, 566 with LI, 173 with cardioembolism (CE) and 36 with undetermined causes of infarction (UDI). By comparing the risk factors in multivariate logistic regression analysis, hypertension [odds ratio (OR) = 1.832] and white matter leukoaraiosis (WML) (OR = 1.865) were found to be more strongly correlated with LI than LAA. Low density lipoprotein- cholesterol (LDL-c) (OR = 0.774) were more strongly related to LAA than LI. CONCLUSIONS: This study found that hypertension and WML were more strongly correlated with LI than LAA. LDL-c was more strongly related to LAA than LI. PMID- 26934735 TI - Impact of Renal Sympathetic Denervation on Left Ventricular Structure and Function at 1-Year Follow-Up. AB - BACKGROUND: Catheter-based sympathetic renal denervation (RDN) is a recent therapeutic option for patients with resistant hypertension. However, the impact of RDN in left ventricular (LV) mass and function is not completely established. Our aim was to evaluate the effects of RDN on LV structure and function (systolic and diastolic) in patients with resistant hypertension (HTN). METHODS AND RESULTS: From a single centre prospective registry including 65 consecutive patients with resistant HTN submitted to RDN between July-2011 and April-2015, 31 patients with baseline and 1-year follow-up echocardiogram were included in this analysis. Mean age was 65 +/- 7 years, 48% were males, 71% had type 2 diabetes. Most had hypertension lasting for more than 10 years (90%), and were being treated with a median number of 6 anti-hypertensive drugs, including 74% on spironolactone. At 1-year, there was a significant decrease both on office SBP (176 +/- 24 to 149 +/- 13 mmHg, p<0.001) and DBP (90 +/- 14 to 79 +/- 11 mmHg, p<0.001), and also in 24h ABPM SBP (150 +/- 20 to 132 +/- 14 mmhg, p<0.001) and DBP (83 +/- 10 to 74 +/- 9 mmHg, p<0.001). There was also a significant decrease in LV mass from 152 +/- 32 to 136 +/- 34 g/m(2) (p<0.001), an increase in LV end diastolic volume (93 +/- 18 to 111 +/- 27 mL, p = 0.004), an increase in LV ejection fraction (65 +/- 9 to 68 +/- 9%, p = 0.001) and mitral valve E deceleration time (225 +/- 49 to 247 +/- 51 ms, p = 0.015) at 1-year follow up. There were no significant changes in left atrium volume index or in the distribution of patients among the different left ventricle geometric patterns and diastolic function subgroups. CONCLUSIONS: In this single centre registry of patients with resistant hypertension, renal denervation was associated with significant reduction in both office and ABPM blood pressure and a significant decrease in left ventricle mass evaluated by transthoracic echocardiogram at 1 year follow-up. PMID- 26934736 TI - Investigating a Novel Activation-Repolarisation Time Metric to Predict Localised Vulnerability to Reentry Using Computational Modelling. AB - Exit sites associated with scar-related reentrant arrhythmias represent important targets for catheter ablation therapy. However, their accurate location in a safe and robust manner remains a significant clinical challenge. We recently proposed a novel quantitative metric (termed the Reentry Vulnerability Index, RVI) to determine the difference between activation and repolarisation intervals measured from pairs of spatial locations during premature stimulation to accurately locate the critical site of reentry formation. In the clinic, the method showed potential to identify regions of low RVI corresponding to areas vulnerable to reentry, subsequently identified as ventricular tachycardia (VT) circuit exit sites. Here, we perform an in silico investigation of the RVI metric in order to aid the acquisition and interpretation of RVI maps and optimise its future usage within the clinic. Within idealised 2D sheet models we show that the RVI produces lower values under correspondingly more arrhythmogenic conditions, with even low resolution (8 mm electrode separation) recordings still able to locate vulnerable regions. When applied to models of infarct scars, the surface RVI maps successfully identified exit sites of the reentrant circuit, even in scenarios where the scar was wholly intramural. Within highly complex infarct scar anatomies with multiple reentrant pathways, the identified exit sites were dependent upon the specific pacing location used to compute the endocardial RVI maps. However, simulated ablation of these sites successfully prevented the reentry re-initiation. We conclude that endocardial surface RVI maps are able to successfully locate regions vulnerable to reentry corresponding to critical exit sites during sustained scar-related VT. The method is robust against highly complex and intramural scar anatomies and low resolution clinical data acquisition. Optimal location of all relevant sites requires RVI maps to be computed from multiple pacing locations. PMID- 26934737 TI - The athlete "out of breath". AB - Athletes often complain about breathing problems. This is a crucial issue due to potential implications not only on their general health, but also on their competing performance. Asthma and exercise-induced bronchoconstriction are prevalent conditions in elite athletes, which leads doctors to rely most of the times on asthma medication to treat athletes feeling "out of breath". However, there are several other conditions that may mimic asthma and cause dyspnea in athletes. Effective treatment of dyspnea requires appropriate identification and treatment of all disorders. Proper knowledge and accurate diagnosis of such entities is mandatory, since asthma medication is not effective in those conditions. Herein we review the most common differential diagnosis of dyspnea in athletes, and describe the diagnostic strategies in order to increase awareness and to improve doctor's confidence on dealing with these patients. PMID- 26934738 TI - Chemical research on red pigments after adverse reactions to tattoo. AB - Currently, the incidence of tattooing is on the rise compared to the past, especially among adolescents, and it leads to the urgency of monitoring the security status of tattooing centers, as well as to inform people about the risks of tattoo practice. In our clinical experience, 20% of tattooed patients presented adverse reactions, like allergic contact dermatitis, psoriasis with Koebner's phenomena and granulomatous reactions, with the latter most prevalent and most often related to red pigment. Adverse reactions to tattoo pigments, especially the red one, are well known and described in literature. Great attention has to be focused on the pigments used, especially for the presence of new substances, often not well known. For this reason, we decided to perform a study on 12 samples of red tattoo ink, obtained by patients affected by different cutaneous reactions in the site of tattoo, to analyze their chemical composition. PMID- 26934739 TI - Italian Multicenter Cross-Sectional Study (AISAG) on light smoking and allergic diseases in adults. AB - Allergic rhinitis, allergic dermatitis, and food allergy are extremely common diseases and are frequently associated to each other and to asthma. Smoking is a potential risk factor for these conditions, but so far, results from individual studies have been conflicting. On the basis of these contradictory data in the literature we have carried out a multicenter cross-sectional study to evaluate the relationship between some allergic conditions and exposure or not to active light smoking. The study was carried out between May 2013 and November 2013 in 22 different Italian hospitals. Patients with respiratory and/or food allergy, and aged 18 years and over, visited at Allergy Outpatient Clinics, were invited to participate. A total of 1586 allergic patients (21.6% smokers) with a mean age of 39.2 years (standard deviation, SD = 15.1) were included. We demonstrated that the prevalence of tobacco smoking was higher in patients with food allergy and in asthmatic patients in stage III-IV. But no other statistical differences were found at univariate analysis. The sensitization patterns of non-smokers and smokers were similar. Furthermore, tobacco smoking was associated with higher risk of food allergy and lower risk of asthma. Moreover, tobacco smoking was an independent risk factor for persistent respect to intermittent rhinitis, and for asthma GINA stage III-IV with respect to stage I-II. PMID- 26934740 TI - Secondary hypogammaglobulinemia in Waldmann's disease treated with subcutaneous immunoglobulins. AB - Primary intestinal lymphangiectasia (PIL) is rare disorder characterized by congenital malformation or obstruction of intestinal lymphatic drainage; it is responsible for protein losing enteropathy leading to lymphopenia, hypoalbuminemia and hypogammaglobulinemia. A low-fat diet associated with medium chain triglyceride supplementation is the cornerstone of PIL management. The administration of intravenous immunoglobulins does not always lead to satisfactory plasma levels and therefore the replacement therapy with immunoglobulins is controversial. We describe here the case of a patient with PIL and severe hypogammaglobulinemia treated with immunoglobulins. The striking aspect of this case is the clinical and serological benefit obtained with the subcutaneous compared to the intravenous immunoglobulins administration. PMID- 26934741 TI - Erythema multiforme caused by sildenafil in an HIV(+) subject. AB - Erythema multiforme is mainly caused by drug allergy and infections. This is the case of a HIV-positive, 49-year-old male, recently cured for syphilis, that presented erythema multiforme minor, five days after taking sildenafil. He had a fast recovery, only with the use of antihistamines. Cell-mediated allergy to sildenafil was confirmed six months later, with the use of patch-tests. PMID- 26934742 TI - Can the presence of cat/dog at home be considered the only criterion of exposure to cat/dog allergens? A likely underestimated bias in clinical practice and in large epidemiological studies. AB - An important aspect of allergic sensitization to furry animals is the association of dog and cat exposure in early childhood with the incidence of respective allergies later in life. This topic is very controversial, because some authors have found a "facilitating" effect, while others have noticed a "protective" or even no significant effect in individuals living in urban areas. It is likely that some biases could be responsible of these contradictory findings. Cat/dog ownership or their presence in indoor environments are considered usually the main criteria to assess the exposure to these pets in studies' questionnaires. Even in clinical practice "are there animals at home?" is the common query usually done when collecting anamnestic data. In our opinion, these commonly used questions should not be considered the main index of exposure to pet allergens, because they can lead to erroneous interpretation of the clinical significance of positive skin prick tests for pet allergens as well as of the real risk of exposure to allergens of dog/cat in epidemiological studies. Consequently, we suggest a new, more realistic, classification of modalities of exposure to pet allergens in "real life" based on five possible conditions. PMID- 26934744 TI - CT Scanning Imaging Method Based on a Spherical Trajectory. AB - In industrial computed tomography (CT), the mismatch between the X-ray energy and the effective thickness makes it difficult to ensure the integrity of projection data using the traditional scanning model, because of the limitations of the object's complex structure. So, we have developed a CT imaging method that is based on a spherical trajectory. Considering an unrestrained trajectory for iterative reconstruction, an iterative algorithm can be used to realise the CT reconstruction of a spherical trajectory for complete projection data only. Also, an inclined circle trajectory is used as an example of a spherical trajectory to illustrate the accuracy and feasibility of this new scanning method. The simulation results indicate that the new method produces superior results for a larger cone-beam angle, a limited angle and tabular objects compared with traditional circle trajectory scanning. PMID- 26934743 TI - Pre-Osteoblasts Stimulate Migration of Breast Cancer Cells via the HGF/MET Pathway. AB - INTRODUCTION: The occurrence of skeletal metastases in cancer, e.g. breast cancer (BC), deteriorates patient life expectancy and quality-of-life. Current treatment options against tumor-associated bone disease are limited to anti-resorptive therapies and aimed towards palliation. There remains a lack of therapeutic approaches, which reverse or even prevent the development of bone metastases. Recent studies demonstrate that not only osteoclasts (OCs), but also osteoblasts (OBs) play a central role in the pathogenesis of skeletal metastases, partly by producing hepatocyte growth factor (HGF), which promotes tumor cell migration and seeding into the bone. OBs consist of a heterogeneous cell pool with respect to their maturation stage and function. Recent studies highlight the critical role of pre-OBs in hematopoiesis. Whether the development of bone metastases can be attributed to a particular OB maturation stage is currently unknown. METHODS AND RESULTS: Pre-OBs were generated from healthy donor (HD)-derived bone marrow stromal cells (BMSC) as well as the BMSC line KM105 and defined as ALPlow OPNlow RUNX2high OSX high CD166high. Conditioned media (CM) of pre-OBs, but not of undifferentiated cells or mature OBs, enhanced migration of metastatic BC cells. Importantly, HGF mRNA was significantly up-regulated in pre-OBs versus mature OBs, and CM of pre-OBs activated the MET signaling pathway. Highlighting a key role for HGF, CM from HGF-negative pre-OBs derived from the BMSC line HS27A did not support migration of BC cells. Genetically (siMET) or pharmacologically (INCB28060) targeting MET inhibited both HGF- and pre-OB CM- mediated BC cell migration. CONCLUSIONS: Our data demonstrate for the first time a role for pre OBs in mediating HGF/MET- dependent migration of BC cells and strongly support the clinical evaluation of INCB28060 and other MET inhibitors to limit and/or prevent BC-associated bone metastases. PMID- 26934745 TI - Complete Plastid Genome of the Recent Holoparasite Lathraea squamaria Reveals Earliest Stages of Plastome Reduction in Orobanchaceae. AB - Plants from the family Orobanchaceae are widely used as a model to study different aspects of parasitic lifestyle including host-parasite interactions and physiological and genomic adaptations. Among the latter, the most prominent are those that occurred due to the loss of photosynthesis; they include the reduction of the photosynthesis-related gene set in both nuclear and plastid genomes. In Orobanchaceae, the transition to non-photosynthetic lifestyle occurred several times independently, but only one lineage has been in the focus of evolutionary studies. These studies included analysis of plastid genomes and transcriptomes and allowed the inference of patterns and mechanisms of genome reduction that are thought to be general for parasitic plants. Here we report the plastid genome of Lathraea squamaria, a holoparasitic plant from Orobanchaceae, clade Rhinantheae. We found that in this plant the degree of plastome reduction is the least among non-photosynthetic plants. Like other parasites, Lathraea possess a plastome with elevated absolute rate of nucleotide substitution. The only gene lost is petL, all other genes typical for the plastid genome are present, but some of them those encoding photosystem components (22 genes), cytochrome b6/f complex proteins (4 genes), plastid-encoded RNA polymerase subunits (2 genes), ribosomal proteins (2 genes), ccsA and cemA-are pseudogenized. Genes for cytochrome b6/f complex and photosystems I and II that do not carry nonsense or frameshift mutations have an increased ratio of non-synonymous to synonymous substitution rates, indicating the relaxation of purifying selection. Our divergence time estimates showed that transition to holoparasitism in Lathraea lineage occurred relatively recently, whereas the holoparasitic lineage Orobancheae is about two times older. PMID- 26934746 TI - Correction: Genetic Architecture of Atherosclerosis in Mice: A Systems Genetics Analysis of Common Inbred Strains. PMID- 26934747 TI - Iron(III) Chloride Catalyzed Formation of 3,4-Dihydro-2H-pyrans from alpha Alkylated 1,3-Dicarbonyls. Selective Synthesis of alpha- and beta-Lapachone. AB - A mild, catalytic method for the synthesis of 3,4-dihydro-2H-pyrans is described. The FeCl3-catalyzed transformation of aryl- and alkyl beta-diketones enables synthetic access to functionalized pyran core structures incorporated in many natural products and biologically active target structures. The method represents a mild alternative to currently available reaction protocols relying on stoichiometric reagents and harsh reaction conditions. This FeCl3-catalyzed transformation has enabled the selective synthesis of alpha-lapachone in two synthetic transformations and subsequently beta-lapachone in three synthetic transformations, which is currently undergoing clinical trials as a potent anticancer agent. PMID- 26934748 TI - Boron Induces Lymphocyte Proliferation and Modulates the Priming Effects of Lipopolysaccharide on Macrophages. AB - Chemical mediators of inflammation (CMI) are important in host defense against infection. The reduced capacity of host to induce the secretion of these mediators following infection is one of the factors in host susceptibility to infection. Boron, which has been suggested for its role in infection, is reported in this study to increase lymphocyte proliferation and the secretion of CMI by the lipopolysaccharide (LPS)-stimulated peritoneal macrophages in BALB/c mice. Boron was administered to mice orally as borax at different doses for 10 consecutive days, followed by the stimulation of animals with ovalbumin and isolation of splenocytes for proliferation assay. The lymphocyte subsets were determined by flow cytometry in spleen cell suspension. The mediators of inflammation, TNF-alpha, IL-6, IL-1beta and nitric oxide (NO), were measured in culture supernatant of LPS-primed macrophages isolated from borax treated mice. TNF and ILs were measured by ELISA. NO was determined by Griess test. The expression of inducible nitric oxide synthase (iNOS) in macrophages was studied by confocal microscopy. Results showed a significant increase in T and B cell populations, as indicated by an increase in CD4 and CD19, but not CD8, cells. Boron further stimulated the secretion of TNF-alpha, IL-6, IL-1beta, NO and the expression of iNOS by the LPS-primed macrophages. The effect was dose dependent and most significant at a dose level of 4.6 mg/kg b. wt. Taken together, the study concludes that boron at physiological concentration induces lymphocyte proliferation and increases the synthesis and secretion of pro-inflammatory mediators by the LPS-primed macrophages, more specifically the M1 macrophages, possibly acting through Toll-like receptor. The study implicates boron as a regulator of the immune and inflammatory reactions and macrophage polarization, thus playing an important role in augmenting host defense against infection, with possible role in cancer and other diseases. PMID- 26934749 TI - Discrimination of Basal Cell Carcinoma from Normal Skin Tissue Using High Resolution Magic Angle Spinning 1H NMR Spectroscopy. AB - High-resolution magic angle spinning nuclear magnetic resonance (HR-MAS NMR) spectroscopy is a useful tool for investigating the metabolism of various cancers. Basal cell carcinoma (BCC) is the most common skin cancer. However, to our knowledge, data on metabolic profiling of BCC have not been reported in the literature. The objective of the present study was to investigate the metabolic profiling of cutaneous BCC using HR-MAS (1)H NMR spectroscopy. HR-MAS (1)H NMR spectroscopy was used to analyze the metabolite profile and metabolite intensity of histopathologically confirmed BCC tissues and normal skin tissue (NST) samples. The metabolic intensity normalized to the total spectral intensities in BCC and NST was compared, and multivariate analysis was performed with orthogonal partial least-squares discriminant analysis (OPLS-DA). P values < 0.05 were considered statistically significant. Univariate analysis revealed 9 metabolites that showed statistically significant difference between BCC and NST. In multivariate analysis, the OPLS-DA models built with the HR-MAS NMR metabolic profiles revealed a clear separation of BCC from NST. The receiver operating characteristic curve generated from the results revealed an excellent discrimination of BCC from NST with an area under the curve (AUC) value of 0.961. The present study demonstrated that the metabolite profile and metabolite intensity differ between BCC and NST, and that HR-MAS (1)H NMR spectroscopy can be a valuable tool in the diagnosis of BCC. PMID- 26934750 TI - Safety, immunogenicity and cross-reactivity of a Northern hemisphere 2013-2014 seasonal trivalent inactivated split influenza virus vaccine, Anflu(r). AB - Anflu(r) is a seasonal trivalent inactivated split-virion influenza vaccine manufactured by Sinovac Biotech Co., Ltd. The objectives of this study were to evaluate the safety of Anflu(r) (2013-14 formulation: H1N1, H3N2 and BYAM) in infants and adults and its immunogenicity and cross-reactivity against mismatched influenza B lineage and avian influenza A(H7N9) viruses (hereafter BVIC and H7N9, respectively) in adults. In this phase IV open label trial, infants 6-35 months old (n=61) each received two injections with 28 days apart; adults 18-60 yrs old (n=60) and elderly >60 yrs old (n=61) each received one injection. Information of adverse events was collected through safety observation and follow-up visits. Pre and post-immune blood samples (day 0 and 21) were collected from subjects >=18 yrs old to detect hemagglutination inhibition antibody titers and calculate seroprotection rates (SPRs) and seroconversion rates (SCRs). The overall adverse reaction incidence was 1.6% (3/182), and no serious adverse event was reported during the study period. For subjects >=18 yrs old, the SCRs, SPRs, and the geometric mean titers (GMTs) met the European criteria for all three strains. In addition, the point estimations of SCR, SPR and GMT for BVIC also met the European criteria. Six subjects were seroconverted against H7N9; however the serological results did not meet the European criteria. In conclusion, the results showed a satisfactory safety and immunogenicity profile of Anflu(r) and cross-reactivity against BVIC, but did not demonstrate cross-reactivity against H7N9 (Clinicaltrials.gov ID: NCT02269852). PMID- 26934751 TI - Chiropractor. PMID- 26934752 TI - Occupational therapist. PMID- 26934755 TI - Vet Centers. Final rule. AB - The Department of Veterans Affairs (VA) adopts as final an interim final rule that amends its medical regulation that governs Vet Center services. The National Defense Authorization Act for Fiscal Year 2013 (the 2013 Act) requires Vet Centers to provide readjustment counseling services to broader groups of veterans, members of the Armed Forces, including a member of a reserve component of the Armed Forces, and family members of such veterans and members. This final rule adopts as final the regulatory criteria to conform to the 2013 Act, to include new and revised definitions. PMID- 26934756 TI - Does Medicare Advantage Cost Less Than Traditional Medicare? AB - The costs of providing benefits to enrollees in private Medicare Advantage (MA) plans are slightly less, on average, than what traditional Medicare spends per beneficiary in the same county. However, MA plans that are able to keep their costs comparatively low are concen-trated in a fairly small number of U.S. counties. In the 25 counties where the cost differences between MA plans and traditional Medicare are largest, MA plans spent a total of $5.2 billion less than what traditional Medicare would have been expected to spend on the same benefi-ciaries, with health maintenance organizations (HMOs) accounting for all of that difference. In the rest of the country, MA plans spent $4.8 billion above the expected costs under tradi-tional Medicare. Broad determinations about the relative efficiency of MA plans and traditional Medicare can therefore be misleading, as they fail to take into account local conditions and individual plans' performance. PMID- 26934757 TI - Mortality Trends Among Working-Age Whites: The Untold Story. AB - Recent research has called attention to an unexpected rise in death rates among middle-aged, white Americans between 1999 and 2014. The full extent of the phenomenon may be underappreciated, however. If one assumes, based on historical trends, that mortality rates should have declined by 1.8 percent per year, then whites in 2014 had higher-than-expected mortality rates from age 19 to age 65. Furthermore, while increased substance abuse and suicides explain the elevated mortality rates for younger adults, middle-aged whites also seem to be experiencing stalled or rising mortality rates for most ailments and diseases. While a national phenomenon, middle-aged whites face much more adverse mortality trends in certain states and regions. The especially broad reach of these negative mortality trends suggests there is an urgent need for further investigation of its causes and potential remedies. PMID- 26934758 TI - Developing a Framework for Evaluating the Patient Engagement, Quality, and Safety of Mobile Health Applications. AB - Rising ownership of smartphones and tablets across social and demographic groups has made mobile applications, or apps, a potentially promising tool for engaging patients in their health care, particularly those with high health care needs. Through a systematic search of iOS (Apple) and Android app stores and an analysis of apps targeting individuals with chronic illnesses, we assessed the degree to which apps are likely to be useful in patient engagement efforts. Usefulness was determined based on the following criteria: description of engagement, relevance to the targeted patient population, consumer ratings and reviews, and most recent app update. Among the 1,046 health care-related, patient-facing applications identified by our search, 43 percent of iOS apps and 27 percent of Android apps appeared likely to be useful. We also developed criteria for evaluating the patient engagement, quality, and safety of mobile apps. PMID- 26934759 TI - Thank You for All You Do. PMID- 26934760 TI - Choosing Wisely in Delaware: Rationale for Evidence-Based Diagnosis & Evaluation of Low Back Pain. PMID- 26934761 TI - State of the Art: Reconstructing Partial Mastectomy Defects with Autologous Fat Grafting. AB - It is estimated that more than 231,840 new cases of invasive breast cancers will be diagnosed in 2015. Many of these patients will be treated with lumpectomy and radiation or with mastectomy. Historically less than 25 percent of patients undergo immediate breast reconstruction, and autologous fat grafting represents a technique to help address some of the difficulties encountered in delayed reconstruction. The use of autologous fat grafting for reconstruction of soft tissue defects is an increasingly common practice. Despite early concerns regarding the safety of autologous fat into the breasts, recent studies have shown this to be both safe and effective. This study examines the use of autologous fat to replace and reconstruct the tissues removed in a left lower pole partial mastectomy for cancer in a patient treated with radiation. This represents a minimally-invasive, staged approach to the correction of a difficult problem. PMID- 26934762 TI - [Estimation of the immersion time in drowned corpses a further study on the reliability of the table of Reh]. AB - Estimation of the time of immersion is a common problem in forensic medicine. In Germany since about 50 years a table for estimating the minimum time interval of immersion is used. This table was developed taking into account signs of progressive putrefaction and maceration and the monthly average water temperature. The reliability of this table was already checked some years ago. In the study presented, 33 further cases were evaluated. When the average monthly water temperatures used in the table are compared to the actual values, the temperatures in the river Rhine have risen during the last 40 years. Therefore, always the actual water temperature has to be measured and to be taken into consideration for the estimation of immersion time. Since there may be also fluctuations of the monthly water temperatures in cases of longer lasting immersion, a temperature profile has to be taken and the mean water temperature has to be calculated. Besides, the table of Reh should be adapted to the increased water temperatures. PMID- 26934763 TI - [On the value of tattoos for identifying unknown bodies - a retrospective study of forensic autopsy cases from Giessen, Germany]. AB - The number of tattooed people in Germany has constantly grown over the past few years. The present study deals with the question if this social trend can be seen in foren- sic autopsy cases as well. In a retrospective study, forensic autopsy cases of two periods (1990-1994 and 2010-2014) have been reviewed and statistically analyzed. Comparison of the two periods revealed a significant increase in tattooed individuals, especially in the female subgroup. Between 2010 and 2014, 14.2 % of the deceased showed tattoos. There are significant differences in the frequency and localization of tattoos dependent on age and sex. About 50 % of the tattooed deceased showed tattoos on body sites that are visible for other persons in everyday life. The resulting value of tattoos for the purpose of identifying unknown bodies is discussed and illustrated. PMID- 26934764 TI - [Forensic age estimation in juveniles and young adults: Reducing the range of scatter in age diagnosis by combining different methods]. AB - The dramatic rise in the number of refugees entering Germany means that age estimation for juveniles and young adults whose age is unclear but relevant to legal and official procedures has become more important than ever. Until now, whether and to what extent the combination of methods recommended by the Study Group on Forensic Age Diagnostics has resulted in a reduction of the range of scatter of the summarized age diagnosis has been unclear. Hand skeletal age, third molar mineralization stage and ossification stage of the medial clavicular epiphyses were determined for 307 individuals aged between 10 and 29 at time of death on whom autopsies were performed at the Institutes of Legal Medicine in Berlin, Frankfurt am Main and Hamburg between 2001 and 2011. To measure the range of scatter, linear regression analysis was used to calculate the standard error of estimate for each of the above methods individually and in combination. It was found that combining the above methods led to a reduction in the range of scatter. Due to various limitations of the study, the statistical parameters determined cannot, however, be used for age estimation practice. PMID- 26934765 TI - [Accidental ingestion of methadone by children and suggestions for better prevention]. AB - Despite the medial attention attracted by the presented case in January 2012 and the determined measures taken to minimize the risk of accidental poisoning for children in the direct surroundings of substituted persons, we recently faced two more cases of methadone-intoxicated children in Hamburg. We believe that the most important step to increase awareness of the dangerous effects of methadone for children might be the storage of methadone in lockable boxes, which would make it safe from access by children and third parties. Moreover this way of storing reminds the patients of the risks resulting from their medication. Repeated and comprehensive instruction appears to be the best protection against cases like this to counteract careless handling of the substitution medication. PMID- 26934766 TI - [Immunohistochemical investigations on pulmonary tissue in cases of sudden infant death syndrome (SIDS)]. AB - Numerous theories on the pathomechanism of SIDS favor a multifactorial genesis whereby infections of the upper respiratory tract and the pulmonary tissue have a trigger function. The aim of the presented study was to prove the presence of inflammatory responses in pulmonary tissue in SIDS cases because various studies revealed contradictory results about the evidence of inflammatory pulmonary responses in SIDS cases. For this purpose, 10 cases with defined causes of death were examined in comparison to 75 cases of sudden infant death syndrome (SIDS) with regard to CD45RO, CD68 and LCA positive cells in pulmonary tissue. Furthermore, the cell adhesion molecules E-selectin, P-selectin and VCAM were investigated. In the study group, the immunohistochemical imaging of CD45RO and LCA positive cells showed mostly negative results. There were no significant differences between study and control group as to the number of cells expressing CD45R0, CD68 and LCA. The same was true for the adhesion molecules E-selectin, P selectin and VCAM. PMID- 26934767 TI - [Sagittal photogrammetric evaluation of the soft tissue profile between two different racial groups: a comparative study]. AB - INTRODUCTION: Facial soft-tissue analyses made from photographic records (photogrammetric analysis of the soft tissues) showed interracial dimorphism. Standard of these facial analyses, originally obtained from Caucasian might not be appropriate for the diagnosis and treatment planning of other groups of orthodontic patients. The purpose of this study was to compare the sagittal photogrammetric soft tissue profile characteristics between Senegalese and Moroccan adults. MATERIALS AND METHODS: A cross-sectional study was performed in a group of Senegalese and Moroccan students in the Faculty of Medicine, Pharmacy and Dentistry of Dakar. Standardized facial-profile photographs were taken with each student in natural head position, centric relation, and relaxed lip posture. Twenty four linear parameters were measured on paper sheet using a graduated ruler. For each variable mean and SD were calculated. In addition independent samples t-test was performed to detect sexual and racial dimorphism. Results were regarded as significant at p = 0.05. RESULTS: Senegalese subjects had significantly more lips protrusion than Moroccan who had significantly a more elongated and more anterior positioned nose, a more chin prominence and a tendency to cutaneous class II than Senegalese. CONCLUSION: Further studies including different age groups subjects would allow having longitudinal data according to age. PMID- 26934768 TI - [Prevalence of dental caries in school in the city of Ouidah in 2013]. AB - INTRODUCTION: The tooth decay is considered according to the WHO as the fourth world plague, after cancers, cardiovascular diseases and HIV infection. It is about a multifactorial affection few studied in Benin. The purpose of this work was to study prevalence of the tooth decay in schools in the city of Ouidah. METHODS: We conducted a descriptive cross-sectional and analytical study from 27th to 31st May 2013. It focused on 497 students aged from 5 to 15 years of primary and secondary schools in Ouidah. Each child received a dental examination and oral interview which allowed us to have the demographic data and those concerning behavior. RESULTS: The study disclosed that 73% of subjects have toothbrush, but only 4% of them brush frequently their teeth (3 three times a day). 96% of subjects stated that they have never consulted a dentist. The decay prevalence was 49.7% and was correlated to factors such as frequency of brushing, frequency of consultation, history family and parents' assistance. The DMFT index was 0.7. On 369 absent and filled decayed teeth, we counted only a single filled tooth that is 0,2% of teeth. CONCLUSION: In Ouidah's schools, tooth decay is a worrying pathology. The fillings are virtually nonexistent. To provide students a better oral hygiene and healthier teeth, an oral health education module in schools and the integration of oral systematic visits of student's examination at school is required. PMID- 26934769 TI - Malocclusion and orthodontic treatment need of patients attending the Lagos University Teaching Hospital, Lagos, Nigeria. AB - OBJECTIVE: To determine the orthodontic treatment needs of patients attending a Nigerian Teaching Hospital using the Dental Aesthetic Index. METHOD: One hundred and fifty study models of patients who attended the Orthodontic clinic of the Lagos University Teaching Hospital were assessed using the DAI. The data was collected using an evaluation form. Descriptive statistics, Chi-square values and t-tests were used to analyze the data. RESULTS: The mean DAI score was 31.5 +/- 9.7. Overall, 32% of the subjects had no need or slight need for orthodontic treatment. In 23.3% the need for treatment was elective. Severe malocclusion with treatment highly desirable was found in 16.7% and 28% had handicapping malocclusion with treatment considered mandatory. There were no significant gender differences with regard to the DAI treatment categories (p > 0.05). There were no statistically significant differences in mean DAI scores between age groups, gender and social class (p > 0.05). CONCLUSIONS: This study showed that close to one-third of the subjects had dental appearance that did not require treatment. A significant proportion (28%) of the subjects had very severe (handicapping) malocclusion and could qualify for publicly subsidized orthodontic treatment. PMID- 26934770 TI - [Impact of the edentulousness on the quality of life related to the oral health of the Congolese]. AB - BACKGROUND: No studies on the perception of tooth loss effects in their daily lives of edentulous were performed in Congolese Bantu. OBJECTIVES: To assess the severity of the impact of edentulism on the quality of life of partially edentulous Congolese and analyze the influence of age, sex, missing teeth, the location of gaps and pairs of posterior dental occlusion in this impact. METHOD: This descriptive cross-sectional study was conducted in the University Clinics of Kinshasa (CUK) and the Centre Boyambi Army Hi Kinshasa/Gombe. One hundred and eighty one edentulous adults and non-denture wearers clinically examined were asked to complete the questionnaire OHIP 14. RESULTS: Average severity was 11.67 +/- 8.74 on a scale of 0-56. Statistically missing teeth, location of gaps and pairs of posterior dental occlusion residual alter this severity. The poor quality of life was noted in patients who had lost more than 5 teeth (17.04 +/- 7.26), anterior losses (17.32 +/- 9.42) and less than 4 pairs of posterior occlusion (17.84 +/- 6.13). Difficult chewing and concern were the most reported items. CONCLUSION: Severity of the influence of tooth loss on the daily life of Congolese people is low. All edentulous does not necessarily cause a very poor quality of life. Increasing the number of lost teeth, presence of anterior gaps and reduction of posterior occlusion pairs below 4 disrupt the quality of life of partially edentulous. PMID- 26934771 TI - Analysis of Nigerian dentists' opinion and consequences on expanded function dental auxiliaries. AB - OBJECTIVE: To examine Nigerian dentists' opinion on expanded function dental auxiliaries. METHODS: This cross-sectional study of Nigerian dentists attending a dental conference was conducting in 2012 using self-administered questionnaire. The data were analyzed using Statistical Package for the Social Sciences version 16.0. P < 0.05 was considered statistically significant. RESULTS: The majority of the 82 dentists that participated in this study were male, aged 31-40 years, either specialist or specializing (residents), practiced for < 10 years, teaching hospital and urban practitioners. Of the participants, 22 (26.8%) reported favorable opinion towards expanded duty dental auxiliaries. The mean scores on consequences, of expanded function dental auxiliaries ranked redundancy of dentist as highest. Males and non-specialist significantly reported expanded function dental auxiliaries would lead to redundancy of dentists. Practitioners working in other hospitals other than teaching hospital significantly reported that appropriate legislation are necessary before expansion of duties of the dental auxiliaries can be done. The dentists with favorable opinion significantly reported that expanded duty dental auxiliaries would not cause redundancy of dentist and the task are not too difficult for dental auxiliaries with necessary training but will increase service delivery and efficiency, increase job satisfaction, lead to dental auxiliary specialization with legislation. CONCLUSION: Data from this study revealed overall unfavorable opinion of Nigerian dentists on the expanded duty dental auxiliaries. However, those with favorable opinion were significantly supportive of expanded function dental auxiliaries. This information would serve as a useful tool for Nigerian oral healthcare policy formulators. PMID- 26934772 TI - [Oral metal foreign bodies]. AB - Oral foreign bodies are most encountered in children. They rarely pose diagnostic problems. But the therapeutic management can use the therapeutic escalation from simple extraction chair to extraction per endoscopic under general anesthesia. We report an unusual case of metal foreign body (umbrella's support) penetrating the oral cavity and measuring 18 cm long in a 5 years-old boy. A radiograph of skull centered on the mouth as great interest in the diagnostic and particulary in the management of the metallic foreign body. The extraction of foreign body was done by oral approaches under general anesthesia. PMID- 26934773 TI - Oral health status of diabetes mellitus patients in Southwest Cameroon. AB - INTRODUCTION: Diabetes mellitus affects virtually all tissues and organs the body including the hard and soft issues of the oral cavity, manifesting with several complications. OBJECTIVE: To assess the prevalence of oral diseases in diabetics and non-diabetics and to correlate oral diseases with glycaemic control. MATERIALS AND METHODS: This was an observational study involving 149 diabetic patients recruited from hospitals in Southwest Region of Cameroon and 102 non diabetic controls drawn from the general population. The study participants were aged 18 years and above. Data were collected using questionnaires, oral examination and laboratory tests. Oral examination was conducted to assess dental plaque, calculus, dental caries, periodontitis, gingivitis and candidiasis. Glycemic status was assessed by measuring glycated hemoglobin (HbA1c) levels using standardized methods. RESULTS: Thirty five out of 149 (23.5%) diabetic patients had gingivitis; 37 (24.8%) had periodontitis; 29 (19.5%) had dental caries and 32 (21.5%) had oral candidiasis. Gingivitis, periodontitis and oral candidiasis was significantly higher in diabetics than non-diabetics (P < 0.001). Also, more diabetic patients presented with poor oral hygiene than non-diabetics. Poorly controlled diabetics presented more with gingivitis and candidiasis than well-controlled diabetics and this relationship was statistically significant. CONCLUSION: The prevalence of oral disease was significantly higher in diabetics than in non-diabetic controls and hyperglycaemia seemed to be a major contributor to oral health in diabetic patients in the study area. Proper management of blood sugar levels might improve on the oral health of diabetes mellitus patients. PMID- 26934774 TI - [To finish with fear of dental care]. AB - The patient facing the dentist knows fear, anxiety. The symbolism of the mouth and teeth from childhood is an entirely specific nature of the human body. The terrifying image of dental treatment and dentist that has long been stigmatized through painting, literature, theater and cinema can change today. Many therapeutic options to the management of anxiety in dental phobia; anesthesia, conscious sedation, combined with a soothing cabinet, a caring dentist, targeted use of medications or milder alternative methods; homeopathy, herbal medicine, acupuncture, psychotherapy, places the patient's interests at the center of the caregiving relationship. But this treatment panel is also offered him the difficulty of the choice. This exercise without systematization, according to the patient with competence and kindness. Some patients may be sent or processed in collaboration with other health professionals. PMID- 26934775 TI - Analysis of Personal and Home Characteristics Associated with the Elemental Composition of PM2.5 in Indoor, Outdoor, and Personal Air in the RIOPA Study. AB - The complex mixture of chemicals and elements that constitute particulate matter (PM*) varies by season and geographic location because source contributors differ over time and place. The composition of PM having an aerodynamic diameter < 2.5 MUm (PM2.5) is hypothesized to be responsible, in part, for its toxicity. Epidemiologic studies have identified specific components and sources of PM2.5 that are associated with adverse health outcomes. The majority of these studies use measures of outdoor concentrations obtained from one or a few central monitoring sites as a surrogate for measures of personal exposure. Personal PM2.5 (and its elemental composition), however, may be different from the PM2.5 measured at stationary outdoor sites. The objectives of this study were (1) to describe the relationships between the concentrations of various elements in indoor, outdoor, and personal PM2.5 samples, (2) to identify groups of individuals with similar exposures to mixtures of elements in personal PM2.5 and to examine personal and home characteristics of these groups, and (3) to evaluate whether concentrations of elements from outdoor PM2.5 samples are appropriate surrogates for personal exposure to PM2.5 and its elements and whether indoor PM2.5 concentrations and information about home characteristics improve the prediction of personal exposure. The objectives of the study were addressed using data collected as part of the Relationships of Indoor, Outdoor, and Personal Air (RIOPA) study. The RIOPA study has previously measured the mass concentrations of PM2.5 and its elemental constituents during 48-hour concurrent indoor, outdoor (directly outside the home), and personal samplings in three urban areas (Los Angeles, California; Houston, Texas; and Elizabeth, New Jersey). The resulting data and information about personal and home characteristics (including air conditioning use, nearby emission sources, time spent indoors, census-tract geography, air-exchange rates, and other information) for each RIOPA participant were downloaded from the RIOPA study database. We performed three sets of analyses to address the study aims. First, we conducted descriptive analyses to describe the relationships between elemental concentrations in the concurrently gathered indoor, outdoor, and personal air samples. We assessed the correlation between personal exposure and indoor concentrations as well as personal exposure and outdoor concentrations of each element and calculated ratios between them. In addition, we performed principal component analysis (PCA) and calculated principal component scores (PCSs) to examine the heterogeneity of the elemental composition and then tested whether the mixture of elements in indoor, outdoor, and personal PM2.5 was significantly different within each study site and across study sites. Secondly, we performed model-based clustering analysis to group RIOPA participants with similar exposures to mixtures of elements in personal PM2.5. We examined the association between cluster membership and the concentrations of elements in indoor and outdoor PM2.5 samples and personal and home characteristics. Finally, we developed a series of linear regression models and random forest models to examine the association between personal exposure to elements in PM2.5 and (1) outdoor measurements, (2) outdoor and indoor measurements, and (3) outdoor and indoor measurements and home characteristics. As we developed each model, the improvement in prediction of personal exposure when including additional information was assessed. Personal exposures to PM2.5 and to most elements were significantly correlated with both indoor and outdoor concentrations, although concentrations in personal samples frequently exceeded those of indoor and outdoor samples. In general, for most PM2.5 elements indoor concentrations were more highly correlated with personal exposure than were outdoor concentrations. PCA showed that the mixture of elements in indoor, outdoor, and personal PM2.5 varied significantly across sample types within each study site and also across study sites within each sample type. Using model-based clustering, we identified seven clusters of RIOPA participants whose personal PM2.5 samples had similar patterns of elemental composition. Using this approach, subsets of RIOPA participants were identified whose personal exposures to PM2.5 (and its elements) were significantly higher than their indoor and outdoor concentrations (and vice versa). The results of linear and random forest regression models were consistent with our correlation analyses and demonstrated that (1) indoor concentrations were more significantly associated with personal exposure than were outdoor concentrations and (2) participant reports of time spent at their home significantly modified many of the associations between indoor and personal concentrations. In linear regression models, the inclusion of indoor concentrations significantly improved the prediction of personal exposures to Ba, Ca, Cl, Cu, K, Sn, Sr, V, and Zn compared with the use of outdoor elemental concentrations alone. Including additional information on personal and home characteristics improved the prediction for only one element, Pb. Our results support the use of outdoor monitoring sites as surrogates of personal exposure for a limited number of individual elements associated with long-range transport and with a few local or indoor sources. Based on our PCA and clustering analyses, we concluded that the overall elemental composition of PM2.5 obtained at outdoor monitoring sites may not accurately represent the elemental composition of personal PM2.5. Although the data used in these analyses compared outdoor PM2.5 composition collected at the home with indoor and personal samples, our results imply that studies examining the complete elemental composition of PM2.5 should be cautious about using data from central outdoor monitoring sites because of the potential for exposure misclassification. The inclusion of personal and home characteristics only marginally improved the prediction of personal exposure for a small number of elements in PM2.5. We concluded that the additional cost and burden of indoor and personal sampling may be justified for studies examining elements because neither outdoor monitoring nor questionnaire data on home and personal characteristics were able to represent adequately the overall elemental composition of personal PM2.5. PMID- 26934776 TI - A glucose-centric perspective of hyperglycemia. AB - Digestion of food in the intestines converts the compacted storage carbohydrates, starch and glycogen, to glucose. After each meal, a flux of glucose (> 200 g) passes through the blood pool (4-6 g) in a short period of 2 h, keeping its concentration ideally in the range of 80-120 mg/100 mL. Tissue-specific glucose transporters (GLUTs) aid in the distribution of glucose to all tissues. The balance glucose after meeting the immediate energy needs is converted into glycogen and stored in liver (up to 100 g) and skeletal muscle (up to 300 g) for later use. High blood glucose gives the signal for increased release of insulin from pancreas. Insulin binds to insulin receptor on the plasma membrane and activates its autophosphorylation. This initiates the post-insulin-receptor signal cascade that accelerates synthesis of glycogen and triglyceride. Parallel control by phos-dephos and redox regulation of proteins exists for some of these steps. A major action of insulin is to inhibit gluconeogensis in the liver decreasing glucose output into blood. Cases with failed control of blood glucose have alarmingly increased since 1960 coinciding with changed life-styles and large scale food processing. Many of these turned out to be resistant to insulin, usually accompanied by dysfunctional glycogen storage. Glucose has an extended stay in blood at 8 mM and above and then indiscriminately adds on to surface protein-amino groups. Fructose in common sugar is 10-fold more active. This random glycation process interferes with the functions of many proteins (e.g., hemoglobin, eye lens proteins) and causes progressive damage to heart, kidneys, eyes and nerves. Some compounds are known to act as insulin mimics. Vanadium peroxide complexes act at post-receptor level but are toxic. The fungus-derived 2,5-dihydroxybenzoquinone derivative is the first one known to act on the insulin receptor. The safe herbal products in use for centuries for glucose control have multiple active principles and targets. Some are effective in slowing formation of glucose in intestines by inhibiting alpha-glucosidases (e.g., salacia/saptarangi). Knowledge gained from French lilac on active guanidine group helped developing Metformin (1,1-dimethylbiguanide) one of the popular drugs in use. One strategy of keeping sugar content in diets in check is to use artificial sweeteners with no calories, no glucose or fructose and no effect on blood glucose (e.g., steviol, erythrytol). However, the three commonly used non-caloric artificial sweeteners, saccharin, sucralose and aspartame later developed glucose intolerance, the very condition they are expected to evade. Ideal way of keeping blood glucose under 6 mM and HbA1c, the glycation marker of hemoglobin, under 7% in blood is to correct the defects in signals that allow glucose flow into glycogen, still a difficult task with drugs and diets. PMID- 26934777 TI - mRNA and Protein levels of rat pancreas specific protein disulphide isomerase are downregulated during Hyperglycemia. AB - Diabetes (Type I and Type II) which affects nearly every organ in the body is a multi-factorial non-communicable disorder. Hyperglycemia is the most characteristic feature of this disease. Loss of beta cells is common in both types of diabetes whose detailed cellular and molecular mechanisms are yet to be elucidated. As this disease is complex, identification of specific biomarkers for its early detection, management and devising new therapies is challenging. Based on the fact that functionally defective proteins provide the biochemical basis for many diseases, in this study, we tried to identify differentially expressed proteins during hyperglycemia. For that, hyperglycemia was induced in overnight fasted rats by intra-peritoneal injection of streptozotocin (STZ). The pancreas was isolated from control and treated rats for subsequent analyses. The 2D-gel electrophoresis followed by MALDI-TOF-MS-MS analyses revealed several up- and down-regulated proteins in hyperglycemic rat pancreas including the downregulation of a pancreas specific isoform of protein disulphide isomerase a2 (Pdia2).This observation was validated by western blot. Quantitative PCR experiments showed that the level of Pdia2 mRNA is also proportionally reduced in hyperglycemic pancreas. PMID- 26934778 TI - Prevalence and identification of extended spectrum beta-lactamases (ESBL) in Escherichia coli isolated from a tertiary care hospital in North-East India. AB - Extended-spectrum beta-lactamases (ESBLs) are rapidly evolving group of beta lactamase enzymes produced by the Gram negative bacteria. In this study, we determined the antimicrobial sensitivity pattern of Escherichia coli isolates and prevalence of TEM, SHV and CTX-M genes in ESBL positive E. coli isolated from the patients admitted to a tertiary care hospital in North-East India. A total of 85 multidrug-resistant isolates of E. coli obtained from clinical samples; urine (n = 80), sputum (n = 3), body fluid (n = 1), vaginal discharge (n = 1) were screened for resistance to third generation cephalosporins. ESBL production in resistant isolates was determined by double disk synergy test (DDST) and phenotypic confirmatory test (PCT). ESBL positive isolates were subjected to PCR for detection of TEM, SHV and CTX-M genes. Imipenem was found to be most effective against E. coli (susceptible isolates 96.47%) while ciprofloxacin was the least effective antibiotic (resistant isolates 60%). Among 33 ESBL positive isolates confirmed via PCT, preponderance in female population (60.6%) was noted. The most prevalent gene was bla(SHV) (63.04%) followed by bla(TEM) and bla(CTX-M) (60.86 and 54.34%, respectively) in ESBL positive E. coli. Most of the extensively used antibiotics, appear to be ineffective against the ever-mutating bacteria. This resistance urges cautious antimicrobial management on priority. Further, it helps in effectively designing the chemotherapeutic regimen for patients of a particular geographic area. PMID- 26934779 TI - Assessment of haemolytic, cytotoxic and free radical scavenging activities of an underutilized fruit, Baccaurea ramiflora Lour. (Roxb.) Muell. Arg. AB - Baccaurea ramiflora Lour. (Roxb.) Muell. Arg. is an underutilized juicy fruit bearing plant found in sub-Himalayan area, South China, Indo-Burma region, etc. The fruit is considered to be nutritive, and in this study, we evaluated its antioxidant, haemolytic and cytotoxic properties. The juice was examined for the quenching activity of hydroxyl radical, nitric oxide, singlet oxygen, peroxynitrite, total antioxidant activity (TAA), erythrocyte membrane stabilizing activity (EMSA) along with quantification of phenolic and flavonoid contents and also tested for its potential activity as iron chelator, inhibitor of lipid peroxidation and total reducing power. Principal component analysis (PCA) and hierarchical cluster analysis (HCA) were also performed to correlate antioxidant capacities with the phenolic and flavonoid content. Haemolytic activity on murine erythrocyte and MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) cytotoxic test was performed on murine splenocytes, thymocytes, hepatocytes and peritoneal exudates macrophage to examine the cytotoxic effect of its juice. The result exhibited its potent free radical scavenging activity. In case of TAA, DPPH (2, 2-diphenyl-1-picrylhydrazyl), EMSA and lipid peroxidation, the fruit juice was found to have significant (P < 0.001) antioxidant capacity, which is evident from low IC50 (half maximal inhibitory concentration) value. Results obtained from haemolytic inhibition assay and MTT cytotoxic test confirms that the juice does not contain any cytotoxic effect and the fruit is safe for consumption. Fourier transform infrared (FTIR) spectra analysis exhibited high possibility of presence of flavonoid compounds in the juice. PMID- 26934780 TI - Effect of Capparis spinosa Linn. extract on lipopolysaccharide-induced cognitive impairment in rats. AB - Cognitive disorders in mankind are not uncommon. Apart from neurodegenerative diseases such as Alzheimer's (AD), various stresses also affect cognitive functions. Plants are known to be potential source of compounds that ameliorate several diseases including cognitive impairment. Here, we evaluated effect of aqueous extract of caper (Capparis spinosa) buds on lipopolysaccharide-induced cognitive impairment in rats using two different oral doses i.e. 10 (pre treatment) and 30 mg/rat(post-treatment) through assessment of behavioural (Morris Water maze test and Y maze test), biochemical (Cholinesterase assay) and histopathological (H&E staining) parameters. Lipopolysaccharide (from E. coli) administration resulted in an increased neurodegeneration and time taken to reach the platform (in Morris water maze). The increased neurodegeneration in CA1 region of hippocampus was significantly reduced in animals which received caper bud extract; they showed marked reduction in time taken to reach the platform at both the dose levels. The experiment demonstrated that caper bud extract exhibits potential protective effect against learning and memory damage induced by chronic administration of lipopolysaccharide (175 MUg/kg) for 7 days. The results suggest that the caper bud extract could be explored for its use in the treatment of cognitive disorders. PMID- 26934781 TI - Antiapoptotic and neuroprotective role of Curcumin in Pentylenetetrazole (PTZ) induced kindling model in rat. AB - Kindling, a sub threshold chemical or electrical stimulation, increases seizure duration and enhances accompanied behavior until it reaches a sort of equilibrium state. The present study aimed to explore the effect of curcumin on the development of kindling in PTZ kindled rats and its role in apoptosis and neuronal damage. In a PTZ kindled Wistar rat model, different doses of curcumin (100, 200 and 300 mg/kg) were administrated orally one hour before the PTZ injections on alternate day during the whole kindling days. The following parameters were compared between control and experimental groups: the course of kindling, stages of seizures, Histopathological scoring of hippocampus, antioxidant parameters in the hippocampus, DNA fragmentation and caspase-3 expression in hippocampus, and neuron-specific enolase in the blood. One way ANOVA followed by Bonferroni post hoc analysis and Fischer's Exact test were used for statistical analyses. PTZ, 30 mg/kg, induced kindling in rats after 32.0 +/- 1.4 days. Curcumin showed dose-dependent anti-seizure effect. Curcumin (300 mg/kg) significantly increased the latency to myoclonic jerks, clonic seizures as well as generalized tonic-clonic seizures, improved the seizure score and decreased the number of myoclonic jerks. PTZ kindling induced a significant neuronal injury, oxidative stress and apoptosis which were reversed by pretreatment with curcumin in a dose-dependent manner. Our study suggests that curcumin has a potential antiepileptogenic effect on kindling-induced epileptogenesis. PMID- 26934782 TI - Bioprospecting of plant growth promoting psychrotrophic Bacilli from the cold desert of north western Indian Himalayas. AB - The plant growth promoting psychrotrophic Bacilli were investigated from different sites in north western Indian Himalayas. A total of 247 morphotypes were obtained from different soil and water samples and were grouped into 43 clusters based on 16S rDNA-RFLP analysis with three restriction endonucleases. Sequencing of representative isolates has revealed that these 43 Bacilli belonged to different species of 11 genera viz., Desemzia, Exiguobacterium, Jeotgalicoccus, Lysinibacillus, Paenibacillus, Planococcus, Pontibacillus, Sinobaca, Sporosarcina, Staphylococcus and Virgibacillus. With an aim to develop microbial inoculants that can perform efficiently at low temperatures, all representative isolates were screened for different plant growth promoting traits at low temperatures (5-15 degrees C). Among the strains, variations were observed for production (%) of indole-3-acetic acid (20), ammonia (19), siderophores (11), gibberellic acid (4) and hydrogen cyanide (2); solubilisation (%) of zinc (14), phosphate (13) and potassium (7); 1-aminocyclopropane-1-carboxylate deaminase activity (6%) and biocontrol activity (4%) against Rhizoctonia solani and Macrophomina phaseolina. Among all the strains, Bacillus licheniformis, Bacillus muralis, Desemzia incerta, Paenibacillus tylopili and Sporosarcina globispora were found to be potent candidates to be developed as inoculants as they exhibited multiple PGP traits at low temperature. PMID- 26934783 TI - Small scale production and characterization of xanthan gum synthesized by local isolates of Xanthomonas campestris. AB - Xanthan gum is a commercially important microbial exopolysaccharide (EPS) produced by Xanthomonas campestris. X. campestris is a plant pathogen causing various plant diseases such as black rot of crucifers, bacterial leaf blight and citrus canker disease resulting in crop damage. In this study, we isolated efficient local bacterial isolates which are capable to produce xanthan gum utilizing different sources of carbon (maltose, sucrose and glucose). Bacterial isolates from different plant leaves and fruits were identified as Xanthomonas campestris based on their morphological and biochemical characteristics. Among the 23 isolates, 70% were capable of producing gum. Taro plant, considered as new bacterial host, also have the capability to produce xanthan gum. Production conditions of xanthan gum and their relative viscosity by these bacterial isolates were optimized using basal medium containing commercial carbon and nitrogen sources and various temperature and rotation. Highest level of xanthan gum (18.286 g/l) with relative viscosity (7.2) was produced (Host, Citrus macroptera) at 28 degrees C, pH 7.0, 150 rpm using sucrose as a carbon source at orbital shaker. Whereas, in lab fermenter, same conditions gave best result (19.587 g/l gum) with 7.8 relative viscosity. Chilled alcohol (96%) was used to recover the xanthan gum. FTIR studies also carried out for further confirmation of compatibility by detecting the chemical groups. PMID- 26934784 TI - [BIOLOGICAL EFFECTIVENESS OF FISSION SPECTRUM NEUTRONS AND PROTONS WITH ENERGIES OF 60-126 MEV DURING ACUTE AND PROLONGED IRRADIATION]. AB - Neutrons of the fission spectrum are characterized by relatively high values of linear energy transfer (LET). Data about their effects on biological objects are used to evaluate the risk of delayed effects of accelerated ions within the same LET range that serve as an experimental model of the nuclei component of galactic cosmic rays (GCR). Additionally, risks of delayed consequences to cosmonaut's health and average lifetime from certain GCR fluxes and secondary neutrons can be also prognosticated. The article deals with comparative analysis of the literature on reduction of average lifespan (ALS) of animals exposed to neutron reactor spectrum, 60-126 MeV protons, and X- and gamma-rays in a broad range of radiation intensity and duration. It was shown that a minimal lifespan reduction by 5% occurs due to a brief exposure to neutrons with the absorbed dose of 5 cGy, whereas same lifespan reduction due to hard X- and gamma-radiation occurs after absorption of a minimal dose of 100 cGy. Therefore, according to the estimated minimal ALS reduction in mice, neutron effectiveness is 20-fold higher. Biological effectiveness of protons as regards ALS reduction is virtually equal to that of standard types of radiation. Exposure to X- and gamma-radiation with decreasing daily doses, and increasing number of fractions and duration gives rise to an apparent trend toward a less dramatic ALS reduction in mice; on the contrary, exposure to neutrons of varying duration had no effect on threshold doses for the specified ALS reductions. Factors of relative biological effectiveness of neutrons reached 40. PMID- 26934785 TI - [SYMPTOMS OF NEGATIVE EFFECTS CUMULATION IN HUMANS AND ANIMALS UNDER THE ACTION OF G-LOADS OF VARYING DIRECTION IN CONTEXT OF AVIATION AND SPACE FLIGHTS]. AB - Author's and literary data are analyzed to evince symptoms of cumulation in humans and animals of the negative effects caused by g-forces of different directions experienced in aviation and space flights. The author cites evidence for the decisive importance of g-duration for the development of negative effects. Functional indices of g-tolerance do not rule out possible latent changes in visceral organs and body tissues. PMID- 26934786 TI - [NUTRITIONAL STATUS IN THE EXPERIMENT WITH 105-DAY ISOLATION AS THE FIRST PHASE OF PROJECT MARS-500]. AB - In a 105-day experiment simulating crew life in a space exploration vehicle, shifts in the nutritional status were assessed in 6 test subjects differing in the body mass index, basal metabolism, attitude to the diet, physical exercise and workload. Results of the investigation showed that because of the hard physical work the nutritional status of test subjects was described by more intensive basal metabolism, elevated metabolism of carbohydrates and lipids, and their increased mobilization from depots. Food ration, though it was sufficient to sustain health and fairly high performance, failed to meet fully individual taste preferences and energy needs for physical activities. The heavy workloads required mobilization of lipids from adipose depots, and a decrease of the hepatic detoxification and metabolic capacities. Self-limitation of eating protein-rich desserts led to a relative deficiency of protein intake. These faults of the diet were the reason why 4 out of 6 test subjects reduced their basal metabolism and lost body mass. Recovery of metabolism and slowdown of the body mass loss were achieved by supplementing meals with available protein containing products. PMID- 26934787 TI - [VESTIBULAR AND THERMOPROTECTIVE PROPERTIES OF A NEW ACTOPROTECTOR]. AB - In experiments with rats, a new 3-hydroxypyridine (3-HP) derivative--2-ethyl-6 methyl-3-hydroxypyridine L-asparaginate (30 mg/kg)--exhibited a strong vestibuloprotective effect which was better than of promethazine (50 mg/kg), a well-known vestibuloprotector Besides the new actoprotector was competitive with another 3-HP derivative, namely, mexidol (ethyl-methyl-hydroxypyridine succinate) (100 mg/kg). Moreover, a distinct thermoprotective effect of 2-ethyl-6-methyl-3 hydroxypyridine L-asparaginate (30 mg/kg) in mice was not worse than that of mexidol or metaprot (ethylthiobenzimidasol, former name bimethy), an actoprotector with good thermoprotective properties. To conclude, owing to the membrane-protective and antioxidative qualities, the vestibuloprotective and thermoprotective properties of 2-ethyl-6-methyl-3-hydroxypyridine L-asparaginate are better or competitive with the reference preparations. PMID- 26934788 TI - [VESTIBULAR FUNCTION AFTER REPEATED SPACE FLIGHTS]. AB - Results of the vestibular function testing of 32 cosmonauts on return from repeated 125- to 215-day space flights (SF) on the International space station are presented. The cosmonauts were tested twice before flight (baseline data collection) and on days 1-2, 4-5 and 8-9 after landing. Electro- and video oculography were used to register simultaneously eye and head movements. It was found that deadaptation following a repeated stay in long-duration SF takes statistically much shorter time. Most often, atypical vestibular disorders and changed patterns of the otolith-semicircular canal interaction are observed in cosmonauts who have made their maiden flights to microgravity. PMID- 26934789 TI - [PROFILE OF THE MARROW-DERIVED STROMAL PRECURSORS POPULATION IN C57BL/6N MICE FLOWN ON BIOSATELLITE BION-M1]. AB - The CFU-F number, proliferative activity and spontaneous differentiation potential of stromal cells derived from the tibia marrow of C57BL/6N mice readapted to the 1-g gravity following a long-term flight on biosatellite Bion-M1 were evaluated. The CFU-F number, proliferative activity and spontaneous adipogenic and osteogenic differentiation of marrow-derived stromal cells from the space flown group were no different from the group of vivarium control. However, the proliferative activity and adhesion properties of the cells were down-regulated on day 7 of readaptation. These results suggest that space flight factors did not impact the stromal differon of the mouse marrow. The decline of stromal cells activity indicates the decompensation of their functions under 1g gravity. PMID- 26934790 TI - [TOLL-LIKE RECEPTORS IN COSMONAUT'S PERIPHERAL BLOOD CELLS AFTER LONG-DURATION MISSIONS TO THE INTERNATIONAL SPACE STATION]. AB - Studies of Toll-like receptors (TLR) in 20 cosmonauts-members of long-duration (124-199-day) missions to the International space station evidenced changes in relative and absolute counts of peripheral blood monocytes with TLR2, TLR4 and TLR6 on the surface, expression of TLR2 and TLR6 genes, and genes of molecules involved in the TLR signaling pathway and TLR-related NF-KB-, JNK/p38- and IRF pathways on the day of return to Earth. The observed changes displayed individual variability. PMID- 26934791 TI - [NEUROSEMANTIC AND PSYCHOPHYSIOLOGICAL CORRELATES OF RHYTHM-SUGGESTIVE CORRECTION OF STRESS CONDITIONS]. AB - Correlates of successful rhythm-suggestive compensation of stress in sportsmen with neurotic symptoms developed in consequence of painful experience of failure were studied. Effectiveness of the rhythm-suggestive and rational psychological methods was compared by measuring the evoked potentials response to emotionally significant extramental verbal stimuli and images, and using psychophysiological test MASTER to track dynamics of a number of body functional parameters. The rational compensation has been shown to reduce the psychic tension and to set right the voluntary control process. Rhythm-suggestive programs are good for compensation of post-stress emotions and affectations, and the involuntary control process. It was found that correction potentialities of the rhythm suggestive programs together with the psychodiagnostic advantages of test MASTER are promising instruments for dynamic monitoring of the mental state with the aim to prevent workplace stresses and to provide rehabilitation treatment of aftermaths. PMID- 26934792 TI - [HEALTH PREDICTION INDICES OBTAINED WITH LOW-DOSE COMPUTER TOMOGRAPHY SCANS]. AB - Purpose of the investigation was to make prognostic estimations of reductions in somatic morbidity and temporal disability, and tumor pathology using low-dose computer tomography (CT) scans and to compare with standard protocols. Mean effective radiation doses were determined based on the results of 1627 diagnostic CT investigations made in 2012-2014 at the Treatment and Rehabilitation Center of the Russian Ministry of Health. Low-dose CT scans of the head and thoracic, abdominal and small pelvis organs were obtained on a GE Discovery CT750 HD, and with the help of the ASIR and MBIR algorithms of iterative reconstruction. In comparison with a standard dose, a single CT scan with a dose reduced by 10-12 mSv predicts a decrease in total morbidity by 0.84-5.52% and temporal disability by 0.55-1.65% per 100 employees over a year; total risk of tumors and genetic effects reduced in 5 to 10 times, which may be equal to 40-90 cases per 100,000 of 30 y.o. males. PMID- 26934793 TI - [PSYCHOPHYSIOLOGICAL ASPECTS OF THE STRESS PROBLEM]. AB - In the review of literature on stress phenomenology and mechanisms stress is defined as a holistic adaptive psychophysiological reaction in response to a physical or emotiogenic stimulus. Physiological and psychological approaches to stress analysis are demonstrated. Stress is regarded as a nonspecific reaction to stimuli characterized by particular changes in responses of organism. Stress is a part of physiological and personality adaptation. Stress-reaction may produce equally a negative and positive effect on human health and performance. PMID- 26934794 TI - [PROMISING OPTIONS FOR MEDICAL ROBOTICS APPLICATION IN SUPPORT OF CREW LIFE ACTIVITIES AND MITIGATION OF MEDICAL RISKS DURING SPACE FLIGHT]. AB - Theme of the article is integration of robotics, medical robots that embody the bio-engineering technology specifically, into the spacecrew medical care system. PMID- 26934795 TI - Using new non-invasive quick method to detect Borrelia Burgdorferi (B.B.) infection from specific parts of the heart in "seemingly normal" ECGs, and from the ECGs of Atrial Fibrillation (AF), a majority of AF ECGs are found to have: 1) Significant B.B. infection, 2) Markedly increased ANP, 3) Increased Cardiac Troponin I & 4) Markedly reduced Taurine. These 4 factors were mainly localized at infected areas of the SA node area, R-&L-Atria & pulmonary veins at the L atrium. AB - Lyme disease is found in a majority of people we tested. Once Borrelia Burgdorferi (B.B.) spirochete enters human body, it not only causes pain by infecting joints, but it also often enters the brain and the heart. Infection of brain can be quickly detected from the pupil and infection of the heart by ECGs non-invasively. By evaluating recorded ECGs of atrial fibrillation (AF), using U.S. patented non-invasive highly sensitive electromagnetic field (EMF) resonance phenomenon between 2 identical molecules or between a molecule and its antibody, we examined 25 different AF patients' ECGs and found the majority of them suffer from various degrees of B.B. spirochete infection in SA node areas, also in the right & left atria, and pulmonary vein near and around its junction at left atrium & lesser degrees of infection at the AV node & His Bundle. When B.B. infection reaches over 224-600ng or higher at these areas, AF often appears in the majority of all AF analyzed. In order to develop AF, the 4 abnormal factors must be present simultaneously: 1) B.B. infection must be increased to 224-600ng or higher, 2) Atrial Natriuretic Peptide (ANP) must be markedly reduced from normal value of less than 4ng to over 100-400ng, 3) A significant increase of Cardiac Troponin I from normal value of less than 3ng to over 12ng and 4) Taurine must also be markedly reduced from normal value of 4-6ng to 0.25ng. These 4 changes were mainly found only at infected sites of the SA node area, both atria and between the end of the T wave & the beginning of the SA node area, which corresponds to U waves at recorded ECG. Origin of the U wave is mainly due to abnormal electrical potential of pulmonary vein at L-atrium. If all 4 factors do not occur at the infection site, no AF will develop. In seemingly normal ECGs, if using this method, one can detect invisible B.B. infection in early stages. Long before AF appears, AF can be prevented by improved treatment with Amoxicillin 500ng 3 times/day + Taurine 175mg x 3 times/day, with or without EPA 180 mg & DHA 120 mg, to avoid serious current limitations in the use of Doxycycline 100 mg 2 times/day, for 4 weeks. PMID- 26934796 TI - The Beneficial Effects of Electro-acupuncture at PC6 (Neiguan-point) of Gene and Protein Expressions of Classical Inward-rectifier Potassium Channels in Myocardial Ischemic Rats. AB - This study is aim to investigate the effect of electro-acupuncture at PC6 (Neiguan-point) on the gene and protein expressions of classical inward-rectifier potassium channels (Kir) in myocardial ischemia (MI) rats induced by isoproterenol (ISO). With ten for each one, 50 rats were divided into 5 groups which were control group, MI group, PC6 group, LU7 (Lieque-point) group and non acupoint group. The control group was injected normal saline solution (85 mg/kg), the other groups were injected ISO (85 mg/kg). All the rats were injected once daily for two days and recorded electrocardiograms (ECGs) after every injection. Electro-acupuncture (EA) was operated at PC6, LU7 and non-acupoint respectively in the rats of PC6 group, LU7 group and non-acupoint group after twice injections. EA was performed to these three groups with disperse-dense wave (4-20 Hz), pulse amplitude of 14V, 20 mins a day remaining 7 days. The gene and protein expressions of Kir2.1, Kir2.2 and Kir2.3 were analyzed by Western Immunoblotting Technology (Western Blot) and Real-time Fluorescence Quantitative Polymerase Chain Reaction (RT-PCR). But it is regrettable that we did not detect meaningful gene and protein expressions Kir2.3, and the expressions of Kir2.1 and Kir2.2 in MI induced groups were lower [The gene and protein decreased 39.4 +/- 27.3% and 38.7 +/- 17.1% respectively.] than control group (P < 0.05). Compared with MI group, the results of PC6 group and LU7 group increased [PC6 group: the gene and protein increased 42.9 25.0% and 42.2 +/- 10.0% respectively. LU7 group: the gene and protein increased 23.8 +/- 50.1% and 21.1 +/- 32.5% respectively.] obviously (P < 0.05) after EA, furthermore the expressions of PC6 group were higher [The gene and protein increased 15.4 +/- 16.7% and 17.3 +/- 60% respectively.] than LU7 group (P < 0.05). The results show that PC6 has a better positive effect than LU7 on MI rats, and the mechanism is probably that EA at PC6 can significantly increase the gene and protein expressions of Kir2.1 and Kir2.2. PMID- 26934797 TI - Electro-Acupuncture at GV.4 Improves Functional Recovery in paralyzed rats after a Traumatic Spinal Cord Injury. AB - In the present study, the effect of electro-acupuncture (EA) on the oxidative stress, the spinal cord tissue preservation and the recovery of motor function was evaluated after a traumatic spinal cord injury (TSCI). Long Evans rats were randomized into five groups: 1. Sham; 2. TSCI without treatment; 3. TSCI + EA (acupoint GV.4); 4. TSCI + EA (acupoint GV.26) and 5.TSCI + EA (GV.4 + GV.26). The EA was performed with an Electro-Acupunctoscope, AWQ-104L Digital, wave dense dispersed, current intensity 2.5mA and frequency 2-100Hz for 30 minutes. The biochemical results showed a significant increase in the hydroxyl radical concentration in group 2 (3.1 +/- 1.4 nmol) compared with groups 1 (1.8 +/- 0.5 nmol) and 4 (2.4 +/- 1.1 nmol) (p< 0.05), whereas in group 4 (4.8 +/- 1.8 nmol), there was a significant increase in lipid peroxidation when compared with group 1 (1.7 +/- 0.5 nmol) (p < 0.05). The BBB motor function score in the paralyzed hind limbs (normal BBB = 21points) was greater in groups 3 (15.2 points) and 5 (13.5 points) in comparison with groups 2 (11.4 points) and 4 (9.3 points) (p < 0.05). The quantity of preserved spinal cord tissue was greater in group 3 (6582.7+/- 20 MUm2) than in groups 2 (5262.4 20 MUm2), 4 (3995.6 +/- 26MUm2) and 5 (4266.7+/- 22 MUm2). Although EA in GV.26 decreases hydroxyl radical concentration (50%), it significantly increases lipid peroxidation (45%), while stimulation of GV.4 decreases oxidative stress (15%), preserves spinal cord tissue (25%) and improves recovery of motor function in the hind limbs of rats with paralysis (18.1%) compared with untreated group. These findings suggest that EA in GV.4 may be a therapeutic alternative on TSCI. PMID- 26934798 TI - [Between life and death]. PMID- 26934799 TI - [Problems of drug therapy in pediatrics]. PMID- 26934800 TI - [Influenza vaccination for skeptics]. PMID- 26934801 TI - [Education of chronically ill children, adolescents and their families as well as other caregivers: status and prospects]. PMID- 26934802 TI - [Specialty congress of early childhood prevention: tail wind for expanded preventive counseling within the scope preventive health screening]. PMID- 26934803 TI - [Staphylococcus epidermidis on the neonatal care unit: from innocent colonization to sepsis pathogen]. PMID- 26934804 TI - [Petition for the German Parliament regarding the nursing career legislation]. PMID- 26934805 TI - [The health surveillance of workers previously exposed to asbestos: criticality of intervention protocols]. AB - The health surveillance of former-exposed asbestos workers is today a current theme, as well as a social and healthcare need. The long latency periods of asbestos related diseases have determined and determine a constant development of cases of these pathologies. To face with these issues, it is necessary to have available adequate diagnostic, clinical and epidemiological tools, that allow efficient health interventions as well as an acceptance of social and medico legal requests, claimed by workers exposed to asbestos during their work career. To date, health surveillance protocols available for different Italian regions are uneven. This paper aims to synthetically resume contents of some of these protocols and to discuss them, on the light of emerging literature evidence. Based on these considerations, it is finally proposed a scheme for the health surveillance of former-exposed asbestos workers. This proposal is not intended as a comprehensive treatise, rather than as a preliminary approach of this specific healthcare issue. PMID- 26934806 TI - [Organizational well-being and work-related stress in health care organizations: validation of the Work-related Stress Assessment Scale]. AB - The issue of the assessment of work-related stress has stimulated in recent years, the production of several theoretical paradigms and assessment tools. In this paper we present a new scale for the assessment of organizational well-being and work-related stress specific for healthcare organizations (Work-related Stress Assessment Scale - WSAS). The goal of the authors is to examine the psychometric properties of the scale, so that it can be used in the healthcare setting as a work-related stress assessment tool. The answers of 230 healthcare professionals belonging to different roles have been analyzed. The study was realized in 16 Units of the University Hospital "S. Maria alle Scotte "of Siena. The exploratory factor analysis (EFA) revealed the presence of five factors with good internal consistency and reliability, "relationship to the structure of proximity" (alpha = 0.93) "change" (alpha = 0.92), "organization of work "(alpha = 0.81)," relationship with the company / Governance "(alpha = 0.87)" working environment "(alpha = 0.83). The analysis of SEM (Structural Equation Models) has confirmed the goodness of the factor solution (NNFI = 0.835, CFI = 0.921, RMSEA = 0.060). The good psychometric qualities, the shortness and simplicity of the scale WSAS makes it a useful aid in the assessment of work-related stress in health care organizations. PMID- 26934807 TI - [STRATEGY AND METHODS FOR THE RISK ASSESSMENT OF THERMAL COMFORT IN THE WORKPLACE]. AB - This paper examines the problem of assessing thermal conditions in moderate working environments. We reviewed all the laws and technical standards on the focus to propose a method of evaluation by steps including a subjective assessment and technical measurements. PMID- 26934808 TI - [Shield the work]. AB - Many workers are exposed to direct solar radiation. In these conditions the workers may suffer damage to health due to an excessive increase in body temperature, or to the loss of liquids. Were carried out tests to determine if the use of screens made of various materials can reduce the physiological effects. Using the indexes WBGT and PHS were calculated the internal body temperature and the amount of fluids lost, before and after use of the screen. The best screens were those made of cardboard, newspaper paper and beach umbrellas. PMID- 26934809 TI - Functional and quality of life evaluation after single level cervical discectomy and fusion or cervical artificial disc replacement. AB - PURPOSE: To evaluate and compare clinical, functional and quality of life (QOL) outcomes after two types of surgical approach for single level cervical disc herniation: anterior cervical discectomy andfusion (ACDF) with cage and cervical artificial disc replacement (C-ADR). METHOD: 119 patients with cervical disc herniation underwent surgery from January 2007 to December 2010; 55 patients were included in the study (27 ACDF, 28 C-ADR). We performed: a pre and postoperative clinical evaluation of cervicobrachial pain, motor and sensory deficit in the upper limbs; a functional and QOL evaluation with self assessment scales (VAS, NPNQ, SF-36); a postoperative instrumental evaluation of cervical ROM and pain. Mean follow-up period was 24 months. RESULTS: After surgery both groups showed clinical, functional and QOL improvement. No pre and postoperative differences were found between the groups. The postoperative instrumental evaluation showed a globally reduced cervical ROM and a decreased pain threshold in comparison with normal values in both groups. CONCLUSION: Our results demonstrate the clinical equivalence of the two surgical techniques and the satisfaction of the two groups of patients two years after surgery. Although functional changes persist after surgery they do not affect quality of life. PMID- 26934810 TI - [Informed consent in physiotherapy: proposal of a form]. AB - The aim of the work is to highlight the need, the duty and the obligation also for the physiotherapist to obtain a valid informed consent of the patient. MATERIALS AND METHODS: The authors, starting with the informed consent forms that already exist for physicians, offer four modules tailored to the needs of the physiotherapist, specific to each field of rehabilitation. RESULTS AND CONCLUSIONS: Such informed consent may be very useful to physiotherapists to fulfill the obligations of giving information and obtaining consent from patients. At the same time it allows physiotherapists to obtain all information they need about patient's condition and permit patient to understand the proposed treatment and adhere to it. PMID- 26934811 TI - [A MULTIDISCIPLINARY BIOPSYCHOSOCIAL INTEGRATED APPROACH IN ORGANIZATION OF REHABILITATIVE ACTIVITY IN NURSING HOMES (RSA)]. AB - Objectives, social role and organization of Italian nursing homes (RSA) are characterized by a pronounced regional differentiation that causes situations which are difficult to compare about expected outcomes. The definition of a functional outcome is particularly difficult in institutionalized patients and this is due to the failure of a conclusive moment of the rehabilitative treatment. Furthermore we often take care of patients who have already been admitted to intensive and/or extensive rehabilitation units time after time, without further functional profit margin. The inconstant presence of professional figures of rehabilitation in nursing homes' staff makes difficult the drafting of an adequate rehabilitative project, especially for the multiple needs of frail old people. Starting with these assumptions, authors hypothesize and adopt a model of sanitary organization to consent a correct allocation of available resources, according to the patient's needs. They stratified all nursing home patients, using the Multidimensional Prognostic Index (MPI) and "Scheda di osservazione intermedia assistenza" (SOSIA), and measured the residual function. They concluded that a multidimensional evaluation of patients allows to identify wellness (of the sick person and of caregivers) as the main objective; nursing home organization could be think as a "complex supportive prosthesis for old people", made by the interaction among structure, operators and activities. PMID- 26934812 TI - Excessive daytime sleepiness in patients on intrathecal analgesia for chronic pain. AB - OBJECTIVES: Intrathecal (IT) drug administration is an advanced technique in pain treatment algorithm for patients poorly responsive to systemic pharmacological treatment or less invasive techniques. The aim is to improve analgesia lowering side effects; despite this premise, many side effects of long-term IT therapy have been described, mainly related to opioid administration. We observed, in some of the patients regularly followed for pump refills in our Pain Unit, the appearance of excessive daytime sleepiness (EDS) interfering with daily life and work activity; this study aims to investigate the incidence of EDS in patients on IT analgesia with opioid or non-opioid drugs and its possible relationship with respiratory problems during sleep. MATERIALS AND METHODS: 21 patients on IT therapy for chronic pain answered the Epworth Sleepiness Scale (ESS). The incidence of EDS in patients receiving IT opioids was compared to a control group not receiving opioids. In 10 patients, who performed polysomnography (PSG) and maintenance of wakefulness test (MWT) for sleep complaints, we studied the relationship between PSG data and ESS scores and we verified the concordance of ESS and MWT results. RESULTS: 38% of the patients reported EDS, according to ESS data; all the patients with EDS were receiving an IT opioid. Even if some patients presented sleep apneas, we failed to correlate this data with daytime sleepiness. Subjective sleepiness is confirmed by the results of MWT. CONCLUSION: Our data demonstrate that EDS is a frequent and important side effect of IT analgesia and it seems related to opioids administration. PMID- 26934813 TI - AGENTS OF CHANGE. IT enabling healthcare's transformation to value-based care. PMID- 26934814 TI - RAPID SHIFT TO VALUE-BASED CARE FORCING PROVIDERS TO REVAMP IT PLANS. PMID- 26934815 TI - DIFFERENT ROLES FOR NEW CMIOS. Mix of skills, cultural fit is crucial for a successful selection. PMID- 26934816 TI - WHAT WORKS BEST FOR POP HEALTH? Providers look to new options to manage patients' care. PMID- 26934817 TI - BETTER PREDICTING HEALTH. Analytics are keeping populations healthier. PMID- 26934818 TI - Change Master. PMID- 26934819 TI - Geographic Distribution and Evolution of Thyroid Cancer Epidemic in South Korea. PMID- 26934820 TI - [Formula: see text]The Relative Utility of Three English Language Dominance Measures in Predicting the Neuropsychological Performance of HIV+ Bilingual Latino/a Adults. AB - OBJECTIVE: Given the disproportionate impact of neurologic disorders such as HIV on racial/ethnic minorities, neuropsychologists are increasingly evaluating individuals of diverse linguistic backgrounds. This study compares the utility of two brief and one comprehensive language measure to account for variation in English neuropsychological performance within a bilingual population. METHOD: Sixty-two HIV+ English/Spanish bilingual Latino adults completed three language measures in English and Spanish: Self-Reported Language Ability; Verbal Fluency (FAS/PMR); and the Woodcock Munoz Language Survey-Revised (WMLS-R). All participants also completed an English language neuropsychological (NP) battery. RESULTS: It was hypothesized that the comprehensive English/Spanish WMLS-R language dominance index (LDI) would be significantly correlated with NP performance, as well as the best predictor of NP performance over and above the two brief language measures. Contrary to our hypothesis, the WMLS-R LDI was not significantly correlated to NP performance, whereas the easily administered Verbal Fluency and Self-Report LDIs were each correlated with global NP performance and multiple NP domains. After accounting for Verbal Fluency and Self Report LDI in a multivariate regression predicting NP performance, the WMLS-R LDI did not provide a unique contribution to the model. CONCLUSIONS: These findings suggest that the more comprehensive WMLS-R does not improve understanding of the effects of language on NP performance in an HIV+ bilingual Latino population. PMID- 26934821 TI - Dosimetric advantages of proton therapy compared with photon therapy using an adaptive strategy in cervical cancer. AB - Background Image-guided adaptive proton therapy (IGAPT) can potentially be applied to take into account interfraction motion while limiting organ at risk (OAR) dose in cervical cancer radiation therapy (RT). In this study, the potential dosimetric advantages of IGAPT compared with photon-based image-guided adaptive RT (IGART) were investigated. Material and methods For 13 cervical cancer patients, full and empty bladder planning computed tomography (CT) images and weekly CTs were acquired. Based on both primary clinical target volumes (pCTVs) [i.e. gross tumor volume (GTV), cervix, corpus-uterus and upper part of the vagina] on planning CTs, the pretreatment observed full range primary internal target volume (pITV) was interpolated to derive pITV subranges. Given corresponding ITVs (i.e. pITVs including lymph nodes), patient-specific photon and proton plan libraries were generated. Using all weekly CTs, IGART and IGAPT treatments were simulated by selecting library plans and recalculating the dose. For each recalculated IGART and IGAPT fraction, CTV (i.e. pCTV including lymph nodes) coverage was assessed and differences in fractionated substitutes of dose volume histogram (DVH) parameters (V15Gy, V30Gy, V45Gy, Dmean, D2cc) for bladder, bowel and rectum were tested for significance (Wilcoxon signed-rank test). Also, differences in toxicity-related DVH parameters (rectum V30Gy, bowel V45Gy) were approximated based on accumulated dose distributions. Results In 92% (96%) of all recalculated IGAPT (IGART) fractions adequate CTV coverage (V95% >98%) was obtained. All dose parameters for bladder, bowel and rectum, except the fractionated substitute for rectum V45Gy, were improved using IGAPT. Also, IGAPT reduced the mean dose to bowel, bladder and rectum significantly (p < 0.01). In addition, an average decrease of rectum V30Gy and bowel V45Gy indicated reductions in toxicity probabilities when using IGAPT. Conclusion This study demonstrates the feasibility of IGAPT in cervical cancer using a plan-library based plan-of-the-day approach. Compared to photon-based IGART, IGAPT maintains target coverage while significant dose reductions for the bladder, bowel and rectum can be achieved. PMID- 26934823 TI - Plasma apolipoprotein C1 concentration is associated with plasma triglyceride concentration, but not visceral fat, in patients with type 2 diabetes. AB - INTRODUCTION: Apolipoprotein C1 (apoC1) is likely to play an important role in triglyceride (TG) metabolism. Mice overexpressing human apoC1 present decreased adipose tissue stores. This study aimed to determine whether apoC1 concentration influences fat mass and distribution and liver fat content (LFC) in patients with type 2 diabetes (T2D). METHODS: ApoC1 concentrations were measured by ELISA in 113 T2D patients and 56 normolipidaemic-normoglycaemic subjects. Visceral and subcutaneous fat areas were determined by single-slice axial T1-weighted magnetic resonance imaging (MRI), while LFC was measured by hydrogen-1 ((1)H) MR spectroscopy. RESULTS: ApoC1 concentrations were higher in T2D patients than in normolipidaemic-normoglycaemic subjects (P<0.0001), and did not correlate with visceral or subcutaneous fat areas, but significantly correlated with TG (P<0.0001) and LFC (P=0.02) in T2D patients. However, the correlation between apoC1 and LFC was lost after adjusting for TG. ApoC1 concentration was also significantly higher in T2D patients with TG<1.5mmol/L than in control subjects (P<0.0001), although both groups had similar TG levels. On multivariate analysis performed in T2D patients with TG<1.5mmol/L and control subjects, apoC1 concentration was independently and positively associated with type 2 diabetes (P<0.0001) and TG levels (P=0.03). CONCLUSION: This study reports, for the first time, that apoC1 is increased in T2D patients and is significantly correlated with TG, whereas no association was found between apoC1 and adipose tissue. This indicates that, in T2D, apoC1 may play a role in TG metabolism, but is unlikely to modulate fat mass and distribution. This increased apoC1 concentration in T2D patients is not only explained by the increased TG level in T2D patients. PMID- 26934824 TI - Twin Legacies: Victor and Vincent McKusick/Twin Studies: Twinning Rates I; Twinning Rates II; MZ Twin Discordance for Russell-Silver Syndrome; Twins' Language Skills/Headlines: Babies Born to Identical Twin Couples; Identity Exchange; Death of Princess Ashraf (Twin); Yahoo CEO Delivers Identical Twins. AB - The lives of the illustrious monozygotic (MZ) twins, Victor A. and Vincent L. McKusick, are described. Victor earned the distinction as the 'Father of Medical Genetics', while Vincent was a legendary Chief Justice of the Maine Supreme Court. This dual biographical account is followed by two timely reports of twinning rates, a study of MZ twin discordance for Russell-Silver Syndrome (RSS) and a study of twins' language skills. Twin stories in the news include babies born to identical twin couples, a case of switched identity, the death of Princess Ashraf (Twin) and a new mother of twins who is also Yahoo's CEO. PMID- 26934825 TI - Inhibition of cyclooxygenase-2 by NS398 attenuates noise-induced hearing loss in mice. AB - Noise-induced hearing loss (NIHL) is an important occupational disorder. However, the molecular mechanisms underlying NIHL have not been fully clarified; therefore, the condition lacks effective therapeutic methods. Cyclooxygenase-2 (Cox-2) is an inducible enzyme involved in the synthesis of prostaglandins, and has been implicated in many pathophysiological events, such as oxidative stress and inflammation. In this study, we investigated the possible role of Cox-2 in the mechanisms of NIHL and the therapeutic effect of the Cox-2 inhibitor NS398 on NIHL using a mouse model. We demonstrated that Cox-2 is constitutively expressed in the mouse cochlea, and its expression could be dramatically up-regulated by high levels of noise exposure. Furthermore, we demonstrated that pre-treatment with the Cox-2 inhibitor NS398 could inhibit Cox-2 expression during noise overstimulation; and could attenuate noise-induced hearing loss and hair cell damage. Our results suggest that Cox-2 is involved in the pathogenesis of NIHL; and pharmacological inhibition of Cox-2 has considerable therapeutic potential in NIHL. PMID- 26934826 TI - Trends in food consumption and nutrient intake in Germany between 2006 and 2012: results of the German National Nutrition Monitoring (NEMONIT). AB - The German National Nutrition Monitoring (NEMONIT) is a longitudinal and nationwide study to assess changes in food consumption and nutrient intake in Germany. A sample of 1840 participants (baseline age: 14-80 years) was drawn from the nationally representative German National Nutrition Survey (NVS) II (2005 2007). The participants have been interviewed by telephone annually since 2008. Food consumption was assessed by two 24-h recalls in the NVS II and the 4 years of NEMONIT (2008-2012/2013), respectively. Energy and nutrient intakes were calculated using the German Nutrient Database 3.02. Diet quality was evaluated using the Healthy Eating Index-NVS (HEI-NVS) II. Time trends were analysed by generalised estimating equation. Consumption of fruit/fruit products and fruit juice/nectar among men and women decreased, whereas consumption of water, soft drinks and coffee/tea increased over the 6-year period. Furthermore, increased consumption of confectionery and animal fats was observed among women. HEI-NVS II did not change since NVS II in both sexes. There were no changes in energy and protein intakes, but carbohydrate intake declined while fat intake increased over time. Regarding micronutrients, a decreasing intake of thiamin, riboflavin and vitamin B6 was observed in both sexes, but intake of Mg, Fe and niacin increased among women over time. In conclusion, food consumption and nutrient intake remained relatively stable between 2005-2007 and 2012/2013 within this German cohort. A few favourable and unfavourable changes were observed. Compared with national dietary guidelines, consumption of food of plant origin remained too low and consumption of meat/meat products remained too high in Germany. PMID- 26934827 TI - Solid Cancers in the Premature and the Newborn: Report of Three National Referral Centers. AB - BACKGROUND: Advances in multidisciplinary care for pediatric cancer have resulted in significant improvement in cure rates over the last decades; however, these advances have not been uniform across all age groups. Cancer is an important cause of perinatal mortality, yet the full spectrum of malignant neoplasms in newborns is not well defined. METHODS: The authors have reviewed the clinical features and outcomes of 37 newborns with congenital malignant tumors treated at three referral centers in North, Central, and South Poland between 1980 and 2014. Event-free survival (EFS) and overall survival (OS) rates were estimated by Kaplan-Meier methods and compared using long-rank test and Cox models. RESULTS: Twenty-two patients were diagnosed prenatally. The most common diagnoses were neuroblastoma (48.7%), followed by malignant germ-cell tumor (16.2%), and Wilms' tumor (8.1%). Neuroblastoma was the most common malignancy among full-term infants, and malignant sacrococcygeal teratoma was the most common malignancy in premature infants. Thirty patients (81%) are alive with a median follow-up of 4.8 years from diagnosis. Patients with Wilms' tumor and malignant germ-cell tumors had the best outcomes (5-year OS 100% for both), whereas the worst prognosis was observed for sarcoma patients (5-year OS 72.92%). Premature infants had better outcome than full-term infants (5-year OS 92.8% vs. 72.58%, respectively). CONCLUSION: Although rare, neonatal cancers can present with an aggressive clinical behavior, but they have a generally good outcome. Early diagnosis and management by expert multidisciplinary teams that integrate perinatal medicine experts with pediatric and surgical oncologists are critical. Centralized care with clear referral pathways that facilitate early initiation of specialized treatment should be prioritized. PMID- 26934828 TI - Personal History and Physical Examination in Judgment of Urinary Tract Infection in Children Aged 3 Months to 2 Years. AB - BACKGROUND: Pediatricians ubiquitously rely on urine analysis for diagnosing urinary tract infection (UTI) in young febrile children due to discrepancies in symptom presentation. This study aimed to identify the determinants of physical examination and personal history for diagnosing UTI. METHODS: Four hundred and ten patients aged between 3 months and 2 years presenting with a tympanic temperature of >38 degrees C for >24 hours were requested to undergo urinary tests. Pediatricians completed patient record charts before the test results were generated, examined the final results of the tests, and compared the results with those reported in the medical records. Multivariate logistic regression analysis was performed to detect potential confounding factors. RESULTS: An age of <1 year [odds ratio (OR): 5.05; p < 0.01], female sex (OR: 2.117; p < 0.05), and the absence of throat redness (OR: 1.907; p < 0.05) were risk factors for UTI. Patients defecating <=3 times/day (OR: 8.80; p < 0.05) were more likely to have pyuria than those who defecated >3 times/day. CONCLUSION: For febrile patients in the age group examined, the absence of throat redness and female sex were independent predictors of UTI. Moreover, the risk of UTI was higher in younger patients. PMID- 26934829 TI - Pretreatment of BMSCs with TZD solution decreases the proliferation rate of MCF-7 cells by reducing FGF4 protein expression. AB - The present study aimed to investigate the effects of bone marrow-derived mesenchymal stem cells (BMSCs) that had been pretreated with pioglitazone and/or rosiglitazone on the growth and proliferation rate of MCF-7 cells. The adhesive interaction between the BMSCs and the MCF-7 cancer cells revealed that the pretreatment of BMSCs with a combination of two types of thiazolidinedione drug reduced the growth and proliferation rate of the MCF-7 cells. The proliferation rate of the MCF-7 cells could also be reduced by the non-adhesive interaction of the cancer cells with BMSCs pretreated with pioglitazone and/or rosiglitazone. The growth and proliferation rate reduction effects on the MCF-7 cells may be attributed to the reduction in the protein level of fibroblast growth factor 4 (FGF4) in the conditioned medium of the pretreated BMSCs. The evidence that the low protein level of FGF4 in the conditioned medium of the pretreated BMSCs perturbed the proliferation rate of the MCF-7 cells by reducing the levels of Ki 67 and proliferating cell nuclear antigen transcripts in the cancer cells was also demonstrated in the present study using a FGF4-neutralizing antibody. All the above findings demonstrate that future studies on the correlation between FGF4 and pretreated BMSCs would be beneficial. PMID- 26934830 TI - Topographic Cues Reveal Two Distinct Spreading Mechanisms in Blood Platelets. AB - Blood platelets are instrumental in blood clotting and are thus heavily involved in early wound closure. After adhering to a substrate they spread by forming protrusions like lamellipodia and filopodia. However, the interaction of these protrusions with the physical environment of platelets while spreading is not fully understood. Here we dynamically image platelets during this spreading process and compare their behavior on smooth and on structured substrates. In particular we analyze the temporal evolution of the spread area, the cell morphology and the dynamics of individual filopodia. Interestingly, the topographic cues enable us to distinguish two spreading mechanisms, one that is based on numerous persistent filopodia and one that rather involves lamellipodia. Filopodia-driven spreading coincides with a strong response of platelet morphology to the substrate topography during spreading, whereas lamellipodia driven spreading does not. Thus, we quantify different degrees of filopodia formation in platelets and the influence of filopodia in spreading on structured substrates. PMID- 26934831 TI - Acid-suppressive medications during pregnancy and risk of asthma and allergy in the offspring: protocol for a systematic review. PMID- 26934832 TI - Expression and purification of FGF21 in Pichia pastoris and its effect on fibroblast-cell migration. AB - Fibroblast growth factor (FGF)21 functions in the maintenance of glucose homeostasis and exerts protective effects on the liver, heat and kidneys. However, the roles of FGF21 in other tissue types are yet to be fully elucidated. The present study detected elevated expression levels of FGF21 in skin tissue. Furthermore, it was revealed that FGF21 expression in the skin was induced upon wounding. In addition, beta-klotho expression was detected in the skin tissue. To examine the role of FGF21 in the wound healing process, recombinant human (h)FGF21 was expressed in a the yeast strain Pichia (P.) pastoris, a well-known system for recombinant protein production. Based on the sequence of hFGF21 and the optimal codon of P. pastoris, codon-optimized FGF21 open reading frame sequences were obtained using seven pairs of 55-59-nt primers with seven rounds of PCR. The recombinant FGF21 was purified and its function was examined in human fibroblast cells using a wound healing cell migration assay. Treatment with FGF21 promoted cell migration, which is an important step in wound healing. Furthermore, FGF21 treatment enhanced the activity of c-Jun N-terminal kinase, a key regulator in fibroblast-cell migration. In conclusion, FGF21 is induced after wounding and FGF21 expressed and purified from yeast markedly accelerates wound healing. The present study was the first to elucidate the function of FGF21 in skin tissues and provided a theoretical basis for the use of FGF21 in the treatment of skin wounds. PMID- 26934833 TI - In-situ Quasi-Instantaneous e-beam Driven Catalyst-Free Formation Of Crystalline Aluminum Borate Nanowires. AB - The catalyst-assisted nucleation and growth mechanisms for many kinds of nanowires and nanotubes are pretty well understood. At times, though, 1D nanostructures form without a catalyst and the argued growth modes have inconsistencies. One such example is the catalyst-free growth of aluminium borate nanowires. Here we develop an in-situ catalyst-free room temperature growth route for aluminium nanowires using the electron beam in a transmission electron microscope. We provide strong experimental evidence that supports a formation process that can be viewed as a phase transition in which the generation of free volume induced by the electron beam irradiation enhances the atomic mobility within the precursor material. The enhanced atomic mobility and specific features of the crystal structure of Al5BO9 drive the atomic rearrangement that results in the large scale formation of highly crystalline aluminium borate nanowires. The whole formation process can be completed within fractions of a second. Our developed growth mechanism might also be extended to describe the catalyst-free formation of other nanowires. PMID- 26934834 TI - The effects of different levels of brush end rounding on gingival abrasion: a double-blind randomized clinical trial. AB - OBJECTIVE: The objective of this study was to evaluate the effect of different levels of filament end rounding on gingival abrasions (GAs). METHODS: The study was a crossover, split-mouth, contra-lateral, double-blinded, randomized design using professional brushing. Three manual toothbrushes, with 0%, 40-50% and >90% end-rounded filaments, were investigated. Participants refrained from all oral hygiene procedures for 48 h prior to each of the three visits. Prior to brushing, oral soft tissue (OST) and GAs were assessed. Based on the randomization, during every visit contra-lateral quadrants were brushed with one of the three test brushes. After brushing, GAs were re-assessed. The means of the GAs prebrushing and post-brushing and differences per brush were calculated. Subanalyses were performed based on the size of the abrasion and its location. RESULTS: A total of 46 generally healthy participants without periodontitis completed the study and provided a full data set. All brushes had statistically significant increases of abrasions following their use (P < 0.001). Non-end-rounded brushes provided significantly more GAs than did the 40-50% and the >90% brushes (P >= 0.001). A subanalysis showed that significantly more small-sized (P >= 0.002) abrasions located at the gingival margin (P < 0.001) occurred when a non-end-rounded brush was used. No significant differences were found between the 40-50% and >90% end rounded brushes in any of the analyses. OST deviations were not observed. CONCLUSIONS: Based on the results of this experiment involving professional brushing, it can be concluded that 40-50% or greater end-rounded filaments can provide a significant reduction in gingival abrasions compared to non-end-rounded filaments. PMID- 26934835 TI - Estimating restricted mean treatment effects with stacked survival models. AB - The difference in restricted mean survival times between two groups is a clinically relevant summary measure. With observational data, there may be imbalances in confounding variables between the two groups. One approach to account for such imbalances is estimating a covariate-adjusted restricted mean difference by modeling the covariate-adjusted survival distribution and then marginalizing over the covariate distribution. Because the estimator for the restricted mean difference is defined by the estimator for the covariate-adjusted survival distribution, it is natural to expect that a better estimator of the covariate-adjusted survival distribution is associated with a better estimator of the restricted mean difference. We therefore propose estimating restricted mean differences with stacked survival models. Stacked survival models estimate a weighted average of several survival models by minimizing predicted error. By including a range of parametric, semi-parametric, and non-parametric models, stacked survival models can robustly estimate a covariate-adjusted survival distribution and, therefore, the restricted mean treatment effect in a wide range of scenarios. We demonstrate through a simulation study that better performance of the covariate-adjusted survival distribution often leads to better mean squared error of the restricted mean difference although there are notable exceptions. In addition, we demonstrate that the proposed estimator can perform nearly as well as Cox regression when the proportional hazards assumption is satisfied and significantly better when proportional hazards is violated. Finally, the proposed estimator is illustrated with data from the United Network for Organ Sharing to evaluate post-lung transplant survival between large-volume and small-volume centers. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26934836 TI - Upconversion-luminescent/magnetic dual-functional sub-20 nm core-shell SrF2:Yb,Tm@CaF2:Gd heteronanoparticles. AB - Sub-20 nm core-shell and water-soluble SrF2:Yb,Tm@CaF2:Gd heteronanoparticles with both upconversion luminescence (UCL) and magnetic resonance imaging (MRI) capabilities were designed and synthesized via a two-step hydrothermal method. In the design of the heteronanoparticles, SrF2:Yb,Tm nanoparticles with high UCL efficiency are chosen as the core material for strong UCL output; and by epitaxially coating the SrF2:Yb,Tm core particles with inert and biocompatible shells of CaF2:Gd, the core-shell heteronanoparticles are endowed with a magnetic capability (longitudinal relaxivity of 2.4 mM(-1) s(-1)) for MRI, as well as an enhancement of the near infrared (NIR) UCL by 9.2 times. The aqueous dispersion of SrF2:Yb,Tm@CaF2:Gd heteronanoparticles with a concentration of 2.6 wt% can emit NIR UCL so as to be easily detected with a fiber optical spectrometer under illumination of a 975 nm laser diode with a power density of 8.8 W cm(-2). Such a dispersion with a Gd(3+) concentration of 0.0143 mM in the shell region of the heteronanoparticles can also generate the detectable quickening of longitudinal relaxation. The results promise the strong potential of this nanomaterial for applications in bioimaging as a dual-functional probe. PMID- 26934837 TI - Effect of exercise-induced neurogenesis on cognitive function deficit in a rat model of vascular dementia. AB - Chronic cerebral hypoperfusion (CCH) is strongly correlated with progressive cognitive decline in neurological diseases, such as vascular dementia (VaD) and Alzheimer's disease. Exercise can enhance learning and memory, and delay age related cognitive decline. However, exercise-induced hippocampal neurogenesis in experimental animals submitted to CCH has not been investigated. The present study aimed to investigate whether hippocampal neurogenesis induced by exercise can improve cognitive deficit in a rat model of VaD. Male Wistar rats (age, 8 weeks; weight, 292+/-3.05 g; n=12-13/group) were subjected to bilateral common carotid artery occlusion (2VO) or sham-surgery and each group was then subdivided randomly into no exercise and treadmill exercise groups. Exercise groups performed treadmill exercise daily at 15 m/min for 30 min for 4 weeks from the third to the seventh week after 2VO. It was demonstrated that the number of neural progenitor cells and mature neurons in the subgranular zone of 2VO rats was increased by exercise, and cognitive impairment in 2VO rats was attenuated by treadmill exercise. In addition, mature brain-derived neurotrophic factor (BDNF) levels in the hippocampus were increased in the exercise groups. Thus the present study suggests that exercise delays cognitive decline by the enhancing neurogenesis and increasing BDNF expression in the context of VaD. PMID- 26934838 TI - The effect of localized surface plasmon resonance on the emission color change in organic light emitting diodes. AB - Three primary colors, cyan, yellow, and green, are obtained from Ag nano-dot embedded organic light emitting diodes (OLEDs) by localized surface plasmon resonance (LSPR). By changing the thickness of the Ag film, the size and spacing of Ag nano-dots are controlled. The generated light from the emissive layer in the OLEDs interacts with the free electrons near the surface of the Ag nano-dots, which leads to LSPR absorption and scattering. The UV-visible absorption spectra of glass/ITO/Ag nano-dot samples show intense peaks from 430 nm to 520 nm with an increase of Ag nano-dot size. And also, the Rayleigh scattering spectra results show the plasmon resonance wavelength in the range of 470-550 nm. The effect of the LSPR of Ag nano-dots on the change of emission color in OLEDs is demonstrated using 2 dimensional finite-difference time-domain simulations. The intensity of the electro-magnetic field in the sample with 5 nm-thick Ag is low at the incident wavelength of 500 nm, but it increases with the incident wavelength. This provides evidence that the emission color change in OLEDs originates from LSPR at the Ag nano-dots. As a result, the emission peak wavelength of OLEDs shifted toward longer wavelengths, from cyan to yellow-green, with the increase of Ag nano-dot size. PMID- 26934839 TI - Attenuated frontal and sensory inputs to the basal ganglia in cannabis users. AB - Heavy cannabis use is associated with reduced motivation. The basal ganglia, central in the motivation system, have the brain's highest cannabinoid receptor density. The frontal lobe is functionally coupled to the basal ganglia via segregated frontal-subcortical circuits conveying information from internal, self generated activity. The basal ganglia, however, receive additional influence from the sensory system to further modulate purposeful behaviors according to the context. We postulated that cannabis use would impact functional connectivity between the basal ganglia and both internal (frontal cortex) and external (sensory cortices) sources of influence. Resting-state functional connectivity was measured in 28 chronic cannabis users and 29 controls. Selected behavioral tests included reaction time, verbal fluency and exposition to affective pictures. Assessments were repeated after one month of abstinence. Cannabis exposure was associated with (1) attenuation of the positive correlation between the striatum and areas pertaining to the 'limbic' frontal-basal ganglia circuit, and (2) attenuation of the negative correlation between the striatum and the fusiform gyrus, which is critical in recognizing significant visual features. Connectivity alterations were associated with lower arousal in response to affective pictures. Functional connectivity changes had a tendency to normalize after abstinence. The results overall indicate that frontal and sensory inputs to the basal ganglia are attenuated after chronic exposure to cannabis. This effect is consistent with the common behavioral consequences of chronic cannabis use concerning diminished responsiveness to both internal and external motivation signals. Such an impairment of the fine-tuning in the motivation system notably reverts after abstinence. PMID- 26934840 TI - Measuring Graded Membership: The Case of Color. AB - This paper considers Kamp and Partee's account of graded membership within a conceptual spaces framework and puts the account to the test in the domain of colors. Three experiments are reported that are meant to determine, on the one hand, the regions in color space where the typical instances of blue and green are located and, on the other hand, the degrees of blueness/greenness of various shades in the blue-green region as judged by human observers. From the locations of the typical blue and typical green regions in conjunction with Kamp and Partee's account follow degrees of blueness/greenness for the color shades we are interested in. These predicted degrees are compared with the judged degrees, as obtained in the experiments. The results of the comparison support the account of graded membership at issue. PMID- 26934841 TI - Cancer testis antigen SPAG9 is a promising marker for the diagnosis and treatment of lung cancer. AB - Cancer testis antigen sperm-associated antigen 9 (SPAG9) is highly expressed in many types of cancers. In the present study, to obtain a better understanding of the relevance of SPAG9 in cancer diagnosis and treatment, the expression of SPAG9 mRNA and protein in lung cancer specimens was evaluated by RT-PCR, western blotting and immunohistochemistry. ELISA was used to quantify the SPAG9 autoantibody in the peripheral blood of lung cancer patients. The results showed that the expression of SPAG9 mRNA and protein in the lung cancer tissues was significantly higher than that in the adjacent non-cancerous tissues (P<0.01). The level of the SPAG9 autoantibody in the serum of lung cancer patients was significantly higher than the level in the healthy controls (P<0.001), and the level of the SPAG9 autoantibody in the serum of untreated patients was significantly higher than that in treated patients (P=0.002). SPAG9 IgG antibody levels were significantly lower in treated adenocarcinoma and small cell lung cancer patients than these levels in the untreated patients (P=0.006, P=0.026, respectively), while no statistical difference was found between treated and untreated squamous cell carcinoma patients. Our results suggest that the SPAG9 antibody in serum is a promising marker for the diagnosis of lung cancer, and the level of the humoral immune response to this antigen appears to be related to the type of lung cancer. PMID- 26934842 TI - Aqueous Terminalia arjuna extract modulates expression of key atherosclerosis related proteins in a hypercholesterolemic rabbit: A proteomic-based study. AB - PURPOSE: The present study evaluates the effect of an aqueous extract of Terminalia arjuna (aqTAE) on protein expression in aortic plaques of hypercholesterolemic rabbits using a proteomic approach. EXPERIMENTAL DESIGN: Thirty male New Zealand rabbits (n = 6) were employed as Gp1 (stock diet); Gp2 (high-fat diet [HFD]); Gp3 (stock diet + aqTAE); Gp4 (HFD + aqTAE); and Gp5 (HFD + atorvastatin) and followed for 6 months. Protein lysates of aortic tissues were separated by 2DE and proteins were identified by MALDI-TOF/MS. RESULTS: Serum lipids were found to be significantly increased by an HFD and reduced by aqTAE both at 3 and 6 months (Gp4 vs. Gp2; p < 0.05). Total 79 spots were differentially expressed, among which 60 individual proteins were identified, 31 grouped as atherosclerosis-related proteins and 29 classified as others. aqTAE significantly attenuated the protein expression of tumor necrosis factor alpha, cyclooxygenase-2, MMP-9, HSP60, ICAM-5, Endothelin-3, Vimentin, Protein S100-A9 besides others. Many of the observed proteins are known to be consistently associated with endothelial dysfunction, inflammation, plaque rupture, and immune imbalance. CONCLUSIONS AND CLINICAL RELEVANCE: Strong hypolipidemic effects of aqTAE and attenuation of these signature atherogenic biomarkers using proteomics highlights the fact that aqTAE may be useful in the prevention and management of atherosclerosis. PMID- 26934843 TI - Trends in sensitivity analysis practice in the last decade. AB - The majority of published sensitivity analyses (SAs) are either local or one factor-at-a-time (OAT) analyses, relying on unjustified assumptions of model linearity and additivity. Global approaches to sensitivity analyses (GSA) which would obviate these shortcomings, are applied by a minority of researchers. By reviewing the academic literature on SA, we here present a bibliometric analysis of the trends of different SA practices in last decade. The review has been conducted both on some top ranking journals (Nature and Science) and through an extended analysis in the Elsevier's Scopus database of scientific publications. After correcting for the global growth in publications, the amount of papers performing a generic SA has notably increased over the last decade. Even if OAT is still the most largely used technique in SA, there is a clear increase in the use of GSA with preference respectively for regression and variance-based techniques. Even after adjusting for the growth of publications in the sole modelling field, to which SA and GSA normally apply, the trend is confirmed. Data about regions of origin and discipline are also briefly discussed. The results above are confirmed when zooming on the sole articles published in chemical modelling, a field historically proficient in the use of SA methods. PMID- 26934844 TI - Widening the spectrum of autoantibodies in pediatric brainstem encephalitis. PMID- 26934845 TI - Point of care testing for group A streptococci in patients presenting with pharyngitis will improve appropriate antibiotic prescription. AB - OBJECTIVE: History, clinical examination and throat culture may be inadequate to rule in or out the presence of group A streptococci (GAS) infection in patients with sore throat in a remote location. We correlated the diagnostic accuracy for guiding antibiotic prescription of clinical decision and physiological scoring systems to a rapid diagnostic point of care (POC) test result in paediatric patients presenting with sore throat. METHODS: Prospective diagnostic accuracy study conducted between 30 June 2014 and 27 February 2015 in a remote Australian ED using a convenience sample. Among paediatric patients presenting with sore throat, the Centor criteria and clinical decision were documented. Simultaneously, patients without sore throat or respiratory tract infection were tested to determine the number of carriers. A throat swab on all patients was tested using a POC test (Alere TestPack +Plus Strep A with on board control), considered as reference standard to detect GAS infection. RESULTS: A total of 101 patients with sore throat were tested with 26 (25.7%) positive for GAS. One hundred and forty-seven patients without sore throat were tested with one positive POC test result (specificity 99%; 95% CI 96-100). Positive predictive value for clinician decision-making for a positive GAS swab (bacterial infection) was 29% (95% CI 17-43), negative predictive value 78% (95% CI 63-88). Area under ROC for the Centor score was 0.70 (95% CI 0.58-0.81). CONCLUSION: Clinician judgement and Centor score are inadequate tools for clinical decision-making for children presenting with sore throat. Adjunctive POC testing provides sufficient accuracy to guide antibiotic prescription on first presentation. PMID- 26934846 TI - Voice outcome according to surgical extent of transoral laser microsurgery for T1 glottic carcinoma. AB - OBJECTIVES/HYPOTHESIS: To evaluate the outcomes of transoral laser microsurgery (TLM) for T1 glottic carcinoma using longitudinal voice analysis. STUDY DESIGN: Retrospective analysis of medical records. METHODS: We conducted a retrospective review of 57 patients (50 T1a, seven T1b) who underwent TLM for T1 glottic carcinoma, and longitudinal voice analysis was performed before surgery, during the early postoperative period (within 3 months), and during the late postoperative period (more than 6 months). Acoustic, perceptual (Grade, Roughness, Breathiness, Asthenia, Strain scale), and subjective voice analysis using the Voice Handicap Index (VHI) was conducted. RESULTS: Voice quality deteriorated in the early postoperative period in terms of several parameters. However, no significant differences in voice quality were observed in the late postoperative period, whereas Grade (from 1.85 +/- 0.83 to 1.50 +/- 0.90) and Roughness (from 1.74 +/- 0.73 to 1.48 +/- 0.87) had improved significantly. Patients who underwent lesser-extent cordectomy (type I, II) showed improvement in VHI-Physical (from 12.93 +/- 11.10 to 6.07 +/- 8.69) and Grade (from 1.60 +/- 0.68 to 0.98 +/- 0.83), whereas improvement was not identified in those who underwent larger-extent cordectomy (type III, IV, V). Improvement in Grade (from 1.70 +/- 0.80 to 1.23 +/- 0.91) and Roughness (from 1.77 +/- 0.73 to 1.25 +/- 0.76) was identified in patients who had unilateral tumor without involvement of anterior commissure. However, those with involvement of the anterior commissure or bilateral vocal cord showed a tendency toward deterioration in voice quality. CONCLUSIONS: Voice quality of patients following TLM for T1 glottic carcinoma may improve significantly over time in cases with lesser-extent types of cordectomy or unilateral tumor without involvement of the anterior commissure. LEVEL OF EVIDENCE: 4 Laryngoscope, 126:2051-2056, 2016. PMID- 26934847 TI - Downregulation of importin-9 protects MCF-7 cells against apoptosis induced by the combination of garlic-derived alliin and paclitaxel. AB - Numerous studies on the biological mechanism of breast cancer have identified a number of potential therapeutic molecular targets. In this context, one type of potential candidates appears to be agents that target the actin cytoskeleton of cancer cells or regulate actin cytoskeleton dynamics. The aim of the present study was to study the impact of altered actin transport between the cytoplasm and nucleus by the downregulation of importin-9 (IPO9) in breast adenocarcinoma MCF-7 cells exposed to an apoptosis-inducing combination of garlic-derived S allyl-L-cysteine sulfoxide (alliin) and paclitaxel (PTX). The expression of IPO9 was downregulated by the transfection of non-aggressive breast cancer MCF-7 cells with siRNA against IPO9. The altered expression of IPO9 and cofilin-1 (CFL1) was examined using western blotting. Moreover, the effect of the downregulation of IPO9 on cell death induced by the combination of PTX and alliin was also investigated. The alterations of IPO9 and CFL1 levels were also related with F actin organizational changes and F-actin fluorescence intensity in the nuclear/perinuclear area of the cells. The results presented here indicate that alliin and PTX act synergistically to promote and potentiate apoptosis in MCF-7 cells. Furthermore, using RNA interference technique, we showed that downregulation of IPO9 expression was correlated with a significant reduction in the apoptotic cell population as well as with a decrease in F-actin content in whole cells, and in the cortical and nuclear/perinuclear areas of the cells. Simultaneously, the downregulation of IPO9 was also accompanied by the increased post-translational expression of CFL1. Furthermore, the data obtained in the present study allow us to conclude that CFL1 itself does not translocate actin into the cell nucleus but this transport requires the functional expression of IPO9. PMID- 26934849 TI - Laparoscopic rectal cancer resection: inferior to open or not? PMID- 26934850 TI - Role of icodextrin in the prevention of small bowel obstruction. Safety randomized patients control of the first 300 in the ADEPT trial. AB - AIM: Adhesions are the most common cause of small bowel obstruction (SBO). The costs of hospitalization and surgery for SBO are substantial for the health-care system. The adhesion-limiting potential of icodextrin has been shown in patients undergoing surgery for gynaecological diseases. A randomized, multicentre trial in colorectal cancer surgery started in 2009 with the aim of evaluating whether icodextrin could reduce the long-term risk of surgery for SBO. Because of some concerns about complications (especially anastomotic leakage) after icodextrin use, a preplanned interim analysis of morbidity and mortality was conducted. METHOD: Patients with colorectal cancer without metastasis were randomized 1:1 to receive standard surgery, with or without instillation of icodextrin in the abdominal cavity. For the first 300 patients, the 30-day follow-up data were collected from the Swedish ColoRectal Cancer Registry (SCRCR). Pre-, per- and postoperative data, morbidity and mortality were analysed. RESULTS: Of the 300 randomized patients, 288 had a data file in the SCRCR. Twelve patients did not have cancer and another five did not have a resection, leaving 283 for analysis. The authors were blinded to the randomization groups. Demographic data were similar in both groups. The overall complication rate was 24% in Group 1 and 23% in Group 2 (P = 0.89). Four cases of anastomotic leakage were reported in Group 1 and five were reported in Group 2 (P = 1.0). Mortality, intensive care unit (ICU) stay and re-operations did not differ between the groups. CONCLUSION: The pre planned safety analysis of the first 300 patients enrolled in this randomized trial did not show any differences in adverse effects related to the use of icodextrin. All data were gathered from the SCRCR, giving us a strong message that we can continue to include patients in the trial. PMID- 26934854 TI - Validation in colorectal procedures of a useful novel approach for the use of C reactive protein in postoperative infectious complications. AB - AIM: Our aim was to validate a novel use of C-reactive protein (CRP) measurement to identify postoperative infectious complications in patients undergoing colorectal surgery, and to compare the predictive value in this setting against white blood cell (WBC) count and neutrophil-to-lymphocyte ratio (NLR). METHOD: This was a retrospective study of CRP, NLR and WBC measurements in patients undergoing colorectal surgery. CRP, NLR and WBC were recorded on the second postoperative day and on the day of infectious complication (patients who developed infectious complications) or within 3 days prior to discharge (subjects with no complications). The test for detecting infectious complications consisted of comparing the value of the inflammatory marker on the day on which a complication was suspected against the value recorded on the second postoperative day. The test was considered positive if a given value was higher than the registered peak at postoperative day 2. Factors influencing the postoperative peak CRP were also studied. RESULTS: A total of 254 patients were retrospectively studied. Patients whose CRP value was higher than on the second postoperative day had a diagnostic accuracy for infectious complications of up to 94.4% and sensitivity, specificity, positive predictive value and negative predictive value of up to 97.4%, 93.4%, 85.7% and 99.1%, respectively. Poorer results were observed when WBC count and NLR were used rather than CRP measurement. Multiple linear regression analysis showed that surgical procedure and approach, as well as additional resections, were independent factors for 48 h peak CRP. CONCLUSION: C-reactive protein is a better parameter than WBC count and NLR for detecting infectious complications. Our proposed methodology presents good diagnostic accuracy and performance and could potentially be used for any surgical procedure. PMID- 26934856 TI - The human ovarian cancer cell line CABA I: A peculiar genetic evolution. AB - The objective of this study was to study the human ovarian cancer cell line CABA I by means of short tandem repeats (STR) profiling and cytogenetic analysis in order to prevent future misidentification or cross-contamination and verify its stability during in vitro cultivation. To this end, cells at passages 18 and 38 were analyzed using cytogenetic techniques in order to verify possible chromosomal aberrations and the karyotypic evolution of this cell line; GTG banding and FISH were also performed. For STR analysis, DNA was extracted using the automated extractor MagNA pure and analyzed by means of PowerPlex 16 HS. STR profiles were analyzed by GeneMapper 3.2.1 software. Whereas comparative cytogenetic analysis of CABA I cells at passage 18 and 38 has demonstrated considerable genetic instability, we found that STR profiles were essentially unaltered in both analyzed passages, suggesting that the STR profile is reliable and could be used for the regular authentication of CABA I over time. It should be emphasized, however, that of the 16 loci generally used in human STR profiles, only 3 were properly detectable in CABA I. The data highlight that the CABA I cell line demonstrates an anomalous STR profile that does not fully adjust the criteria currently used for the identification of human cells; in spite of this, it remains stable during the in vitro maintainance. Moreover, the genetic instability of the CABA I cell line overlaps with those observed in vivo in tumor cells, making it a suitable candidate to analyze, in vitro, the peculiar genetic evolution of ovarian cancer cells. PMID- 26934855 TI - DNA methylation in endometriosis (Review). AB - Endometriosis is defined by the presence and growth of functional endometrial tissue, outside the uterine cavity, primarily in the ovaries, pelvic peritoneum and rectovaginal septum. Although it is a benign disease, it presents with malignant characteristics, such as invasion to surrounding tissues, metastasis to distant locations and recurrence following treatment. Accumulating evidence suggests that various epigenetic aberrations may play an essential role in the pathogenesis of endometriosis. Aberrant DNA methylation represents a possible mechanism repsonsible for this disease, linking gene expression alterations observed in endometriosis with hormonal and environmental factors. Several lines of evidence indicate that endometriosis may partially be due to selective epigenetic deregulations influenced by extrinsic factors. Previous studies have shed light into the epigenetic component of endometriosis, reporting variations in the epigenetic patterns of genes known to be involved in the aberrant hormonal, immunologic and inflammatory status of endometriosis. Although recent studies, utilizing advanced molecular techniques, have allowed us to further elucidate the possible association of DNA methylation with altered gene expression, whether these molecular changes represent the cause or merely the consequence of the disease is a question which remains to be answered. This review provides an overview of the current literature on the role of DNA methylation in the pathophysiology and malignant evolution of endometriosis. We also provide insight into the mechanisms through which DNA methylation-modifying agents may be the next step in the research of the pharmaceutical treatment of endometriosis. PMID- 26934857 TI - Serum Cobalamin and Methylmalonic Acid Concentrations in Hyperthyroid Cats Before and After Radioiodine Treatment. AB - BACKGROUND: Hyperthyroidism, the most common endocrine disorder in cats, has been associated with low serum cobalamin concentrations. Whether this is a functional cobalamin deficiency of clinical importance has not been assessed. HYPOTHESIS/OBJECTIVES: Cats with hyperthyroidism experience a functional cobalamin deficiency which correlates with their clinical catabolic state and is reversible with return of the euthyroid state. ANIMALS: Thirty-nine client-owned hyperthyroid cats. METHODS: Prospective observational study. Serum cobalamin, methylmalonic acid, and clinical scores were determined in each hyperthyroid cat at enrollment and when euthyroid (60 days after radioiodine treatment). RESULTS: Five of the 39 hyperthyroid cats (13%) had a low serum cobalamin concentration ranging from <150 to 290 ng/L. Serum cobalamin concentrations normalized to >350 ng/L in 2 of the hypocobalaminemic cats once euthyroid. None of the hyperthyroid/hypocobalaminemic cats had increased serum methylmalonic acid concentrations (175-601 nmol/L). In cats with clinical and biochemical hyperthyroidism, there was no correlation between serum cobalamin concentrations with total T4 concentration (P = .12) or clinical scores including body weight (P = .11) and BCS (P = .54). CONCLUSIONS AND CLINICAL IMPORTANCE: In this population of hyperthyroid cats, the prevalence of hypocobalaminemia was low. Specifically, hyperthyroid cats, in which concurrent gastrointestinal disease is unlikely. Hypocobalaminemia is not a functional deficiency requiring supplementation in hyperthyroid cats without gastrointestinal disease. PMID- 26934858 TI - Downregulation of long non-coding RNA TRIM52-AS1 functions as a tumor suppressor in renal cell carcinoma. AB - Long non-coding RNAs (lncRNAs) are important regulators of gene expression, interacting with the major pathways of cell growth, proliferation, differentiation and survival. Alterations in the function of lncRNAs promote tumor formation, progression and metastasis. The purpose of the present study was to identify novel tumor suppressor lncRNAs, and elucidate their physiological function and mechanism in renal cell carcinoma (RCC). The results of the present study revealed that the expression of the lncRNA, TRIM52-AS1, was downregulated in RCC, which was demonstrated using reverse transcription-quantitative polymerase chain reaction analysis. Furthermore, the effects of TRIM52-AS1 on proliferation, cell migration and apoptosis were analyzed using a wound scratch assay, a 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyl tetrazolium bromide assay and flow cytometric analysis, respectively. The overexpression of TRIM52-AS1 using a synthesized vector significantly suppressed cell migration and proliferation, and induced apoptosis of the RCC cells in vitro, and interference of its expression led to the opposite effects. The present study was the first, to the best of our knowledge, to demonstrate that TRIM52-AS1 functions as a tumor suppressor in RCC. Further investigation is required to elucidate the molecular mechanisms underlying the effects of TRIM52-AS1 in the development of RCC. PMID- 26934859 TI - Letter to the Editor: Physical examination tests for screening and diagnosis of cervicogenic headache: A systematic review by Rubio-Ochoa et al. (2015). PMID- 26934860 TI - Maternal serum cadmium level during pregnancy and its association with small for gestational age infants: a population-based birth cohort study. AB - The association between maternal cadmium (Cd) exposure during pregnancy and the increased risk of fetal growth restriction (FGR) remains controversial. The present study evaluated the association between maternal serum Cd level and risk of small for gestational age (SGA) infants in a Chinese population. The present study analyzed a subsample of the C-ABCS cohort that recruited 3254 eligible mother-and-singleton-offspring pairs. Maternal serum Cd level during pregnancy was measured by graphite furnace atomic absorption spectrometry. The rate and odds ratio (OR) for SGA infant were calculated. The rate for SGA infant was 10.6% among subjects with H-Cd (>=1.06 MUg/L), significantly higher than 7.5% among subjects with L-Cd (<1.06 MUg/L). OR was 1.45 (95% CI: 1.11, 1.90; P = 0.007) among subjects with H-Cd. Adjusted OR for SGA infants was 1.43 (95% CI: 1.09, 1.88; P = 0.007) among subjects with H-Cd. Taken together, we observe the fact that maternal Cd exposure at middle gestational stage, elevates the risk of SGA in contrast to early gestational stage. The present results might be interesting and worth more discussing, and guarantee to further studies. PMID- 26934862 TI - Lipopolysaccharide Structure and Biosynthesis in Helicobacter pylori. AB - This review covers the current knowledge and gaps in Helicobacter pylori lipopolysaccharide (LPS) structure and biosynthesis. H. pylori is a Gram-negative bacterium which colonizes the luminal surface of the human gastric epithelium. Both a constitutive alteration of the lipid A preventing TLR4 elicitation and host mimicry of the Lewis antigen decorated O-antigen of H. pylori LPS promote immune escape and chronic infection. To date, the complete structure of H. pylori LPS is not available, and the proposed model is a linear arrangement composed of the inner core defined as the hexa-saccharide (Kdo-LD-Hep-LD-Hep-DD-Hep-Gal-Glc), the outer core composed of a conserved trisaccharide (-GlcNAc-Fuc-DD-Hep-) linked to the third heptose of the inner core, the glucan, the heptan and a variable O antigen, generally consisting of a poly-LacNAc decorated with Lewis antigens. Although the glycosyltransferases (GTs) responsible for the biosynthesis of the H. pylori O-antigen chains have been identified and characterized, there are many gaps in regard to the biosynthesis of the core LPS. These limitations warrant additional mutagenesis and structural studies to obtain the complete LPS structure and corresponding biosynthetic pathway of this important gastric bacterium. PMID- 26934861 TI - 4C-seq revealed long-range interactions of a functional enhancer at the 8q24 prostate cancer risk locus. AB - Genome-wide association studies (GWAS) have identified >100 independent susceptibility loci for prostate cancer, including the hot spot at 8q24. However, how genetic variants at this locus confer disease risk hasn't been fully characterized. Using circularized chromosome conformation capture (4C) coupled with next-generation sequencing and an enhancer at 8q24 as "bait", we identified genome-wide partners interacting with this enhancer in cell lines LNCaP and C4 2B. These 4C-identified regions are distributed in open nuclear compartments, featuring active histone marks (H3K4me1, H3K4me2 and H3K27Ac). Transcription factors NKX3-1, FOXA1 and AR (androgen receptor) tend to occupy these 4C regions. We identified genes located at the interacting regions, and found them linked to positive regulation of mesenchymal cell proliferation in LNCaP and C4-2B, and several pathways (TGF beta signaling pathway in LNCaP and p53 pathway in C4-2B). Common genes (e.g. MYC and POU5F1B) were identified in both prostate cancer cell lines. However, each cell line also had exclusive genes (e.g. ELAC2 and PTEN in LNCaP and BRCA2 and ZFHX3 in C4-2B). In addition, BCL-2 identified in C4-2B might contribute to the progression of androgen-refractory prostate cancer. Overall, our work reveals key genes and pathways involved in prostate cancer onset and progression. PMID- 26934863 TI - miR-135b, upregulated in breast cancer, promotes cell growth and disrupts the cell cycle by regulating LATS2. AB - Dysregulation of microRNAs (miRNAs) plays a critical role in cancer progression. They can act as either oncogenes or tumor suppressor genes in human cancer. The purpose of this study was to investigate the crucial role of miR-135b in breast cancer and to validate whether miR-135b could regulate proliferation of breast cancer cells by effecting specific targets in the Hippo pathway. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was carried out to quantify the expression levels of miR-135b in both breast cancer tissues and cell lines. To characterize the function of miR-135b, MTT assays, colony formation assays, cell migration assays, cell invasion assays, and cell cycle assays were used. Luciferase reporter assays were performed to validate the regulation of a putative target of miR-135b, in corroboration with western blot assays. Finally, we verified the changes of cellular function after transfection of LATS2-siRNA. Our experiments indicate that expression of miR-135b was commonly upregulated in breast cancer specimens and breast cancer cells when compared with that in adjacent normal tissues and non-malignant breast epithelial cells. Enforced expression of miR-135b can regulate cellular proliferation, migration and invasion as well as disrupt the cell cycle of breast cancer cells. Luciferase assays revealed that miR-135b directly bound to the 3'-untranslated region (3' UTR) of LATS2 (large tumor suppressor kinase 2), a critical gene in the Hippo pathway. Western blot analysis verified that miR-135b regulated the expression of LATS2 at protein levels. Further study demonstrated that the downstream gene of LATS2 in the Hippo pathway, such as cyclin-dependent kinase 2 (CDK2) and Phospho Yes-associated protein (p-YAP), can also be regulated by miR-135b and LATS2 axis. Knockdown of endogenous LATS2 can mimic the result of miR-135b up-regulation in breast cancer. Taken together, our findings reveal that the miR-135b and LATS2 axis may be a potential therapeutic target for breast cancer in the future. PMID- 26934864 TI - Binding of caffeine with caffeic acid and chlorogenic acid using fluorescence quenching, UV/vis and FTIR spectroscopic techniques. AB - The interactions of caffeine (CF) with chlorogenic acid (CGA) and caffeic acid (CFA) were investigated by fluorescence quenching, UV/vis and Fourier transform infrared (FTIR) spectroscopic techniques. The results of the study indicated that the fluorescence quenching between caffeine and hydroxycinnamic acids could be rationalized in terms of static quenching or the formation of non-fluorescent CF CFA and CF-CGA complexes. From fluorescence quenching spectral analysis, the quenching constant (KSV), quenching rate constant (kq), number of binding sites (n), thermodynamic properties and conformational changes of the interaction were determined. The quenching constants (KSV) between CF and CGA, CFA are 1.84 * 10(4) and 1.04 * 10(4) L/mol at 298 K and their binding site n is ~ 1. Thermodynamic parameters determined using the Van't Hoff equation indicated that hydrogen bonds and van der Waal's forces have a major role in the reaction of caffeine with caffeic acid and chlorogenic acid. The 3D fluorescence, UV/vis and FTIR spectra also showed that the binding of CF with CFA and CGA induces conformational changes in CFA and CGA. PMID- 26934865 TI - Consumer Directed Care in Australia: early perceptions and experiences of staff, clients and carers. AB - The study aimed to identify the shared issues and challenges being experienced by staff, their clients and informal carers, with the introduction of Consumer Directed Care (CDC). Secondary analysis was undertaken of data that had been initially collected, via semi-structured in-depth interviews, to inform the development of a discrete choice experiment. The raw staff and client/carer data were re-examined using an iterative inductive process. The analysis focused on locating the shared themes and differences between the participant groups based on their CDC experience. The data were also assessed for difficulties or barriers that impacted on the service. Four broad shared themes were derived: culture, role change, operational systems and resourcing, but with a range of diverse and sometimes conflicting sub-themes between the different participant groups. Differences can be linked to participant role in the service chain, with discordance emerging between what has been traditionally offered and what might be possible. This investigation occurred during the period in which services were transitioning from a traditional aged care service model to a new model of service provision requiring considerable industry change. We conclude that existing industry regulation, culture and practice supports an established service model in Australia that arguably makes translation of the objectives of CDC difficult. PMID- 26934866 TI - [German S3 practice guidelines on prevention of venous thromboembolism--New and established evidence]. AB - Any recommendations of the previous practice guidelines on prevention of venous thromboembolism have been put to the test and have been revised in the latest edition in case new evidence had become available. Recommendations which have proven themselves in clinical practice have remained unchanged such as algorithms for risk assessment, however there are now updates on the recommendations of novel oral anticoagulants for prevention of venous thromboembolism, on the use of mechanical prophylaxis, on heparin-induced thrombocytopenia and on prophylaxis in outpatients after surgical procedures. PMID- 26934867 TI - L-carnitine Mediated Reduction in Oxidative Stress and Alteration in Transcript Level of Antioxidant Enzymes in Sheep Embryos Produced In Vitro. AB - The objective of this study was to find out the effect of L-carnitine on oocyte maturation and subsequent embryo development, with L-carnitine-mediated alteration if any in transcript level of antioxidant enzymes (GPx, Cu/Zn-SOD (SOD1) and Mn-SOD (SOD2) in oocytes and developing sheep embryos produced in vitro. Different concentrations of L-carnitine (0 mm, 2.5 mm, 5 mm, 7.5 mm and 10 mm) were used in maturation medium. Oocytes matured with 10 mm L-carnitine showed significantly (p < 0.05) higher cleavage (66.80% vs 39.66, 41.76, 44.64, 64.31%), morula (48.50% vs 20.88, 26.01, 26.99, 44.72%) and blastocyst (33.22% vs 7.66, 9.19, 10.71, 28.57%) percentage as compared to lower concentrations (0 mm, 2.5 mm, 5 mm and 7.5 mm). Cleavage percentage between 10 mm and 7.5 mm L-carnitine were not significantly different. Maturation rate was not influenced by supplementation of any experimental concentration of L-carnitine. There was a significant (p < 0.05) decrease in intracellular ROS and increase in intracellular GSH in 10 mm L-carnitine-treated oocytes and embryos than control group. Antioxidant effect of L-carnitine was proved by culturing oocytes and embryos with H2O2 in the presence of L-carnitine which could be able to protect oocytes and embryos from H2O2-induced oxidative damage. L-carnitine supplementation significantly (p < 0.05) upregulated the expression of GPx and downregulated the expression of SOD2 genes, whereas the expression pattern of SOD1 and GAPDH (housekeeping gene) genes was unaffected in oocytes and embryos. It was concluded from the study that L-carnitine supplementation during in vitro maturation reduces oxidative stress-induced embryo toxicity by decreasing intracellular ROS and increasing intracellular GSH that in turn improved developmental potential of oocytes and embryos and alters transcript level of antioxidant enzymes. PMID- 26934868 TI - Topical Calcineurin Inhibitors, Topical Glucocorticoids and Cancer in Children: A Nationwide Study. PMID- 26934869 TI - Mating competitiveness of sterile genetic sexing strain males (GAMA) under laboratory and semi-field conditions: Steps towards the use of the Sterile Insect Technique to control the major malaria vector Anopheles arabiensis in South Africa. AB - BACKGROUND: Anopheles arabiensis Patton is primarily responsible for malaria transmission in South Africa after successful suppression of other major vector species using indoor spraying of residual insecticides. Control of An. arabiensis using current insecticide based approaches is proving difficult owing to the development of insecticide resistance, and variable feeding and resting behaviours. The use of the sterile insect technique as an area-wide integrated pest management system to supplement the control of An. arabiensis was proposed for South Africa and is currently under investigation. The success of this technique is dependent on the ability of laboratory-reared sterile males to compete with wild males for mates. As part of the research and development of the SIT technique for use against An. arabiensis in South Africa, radio-sensitivity and mating competitiveness of a local An. arabiensis sexing strain were assessed. METHODS: The optimal irradiation dose inducing male sterility without compromising mating vigour was tested using Cobalt 60 irradiation doses ranging from 70-100 Gy. Relative mating competitiveness of sterile laboratory-reared males (GAMA strain) compared to fertile wild-type males (AMAL strain) for virgin wild-type females (AMAL) was investigated under laboratory and semi-field conditions using large outdoor cages. Three different sterile male to fertile male to wild-type female ratios were evaluated [1:1:1, 5:1:1 and 10:1:1 (sterile males: fertile, wild-type males: fertile, wild-type females)]. RESULTS: Irradiation at the doses tested did not affect adult emergence but had a moderate effect on adult survivorship and mating vigour. A dose of 75 Gy was selected for the competitiveness assays. Mating competitiveness experiments showed that irradiated GAMA male mosquitoes are a third as competitive as their fertile AMAL counterparts under semi-field conditions. However, they were not as competitive under laboratory conditions. An inundative ratio of 10:1 induced the highest sterility in the representative wild-type population, with potential to effectively suppress reproduction. CONCLUSION: Laboratory-reared and sterilised GAMA male An. arabiensis at a release ratio of 3:1 (3 sterile males to 1 wild, fertile male) can successfully compete for insemination of wild-type females. These results will be used to inform subsequent small-scale pilot field releases in South Africa. PMID- 26934870 TI - Erratum to: Factors associated with adherence to Antiretroviral Therapy (ART) among adult people living with HIV and attending their clinical care, Eastern Ethiopia. PMID- 26934871 TI - Regeneration of a thiolated and antibody functionalized GaAs (001) surface using wet chemical processes. AB - Wet chemical processes were investigated to remove alkanethiol self-assembled monolayers (SAMs) and regenerate GaAs (001) samples studied in the context of the development of reusable devices for biosensing applications. The authors focused on 16-mercaptohexadecanoic acid (MHDA) SAMs that are commonly used to produce an interface between antibodies or others proteins and metallic or semiconductor substrates. As determined by Fourier transform infrared absorption spectroscopy, among the investigated solutions of HCl, H2O2, and NH4OH, the highest efficiency in removing alkanethiol SAM from GaAs was shown by NH4OH:H2O2 (3:1 volume ratio) diluted in H2O. The authors observed that this result was related to chemical etching of GaAs that even in a weak solution of NH4OH:H2O2:H2O (3:1:100) proceeded at a rate of 130 nm/min. The surface revealed by a 2-min etching under these conditions allowed depositing successfully a new MHDA SAM with comparable quality and density to the initial coating. This work provides an important view on the perspective of the development of a family of cost-effective GaAs-based biosensors designed for repetitive detection of a variety of biomolecules immobilized with dedicated antibody architectures. PMID- 26934873 TI - Development and assessment of a website presenting evidence-based information for people with multiple sclerosis: the IN-DEEP project. AB - BACKGROUND: People with multiple sclerosis (MS) are increasingly using the Internet in the daily management of their condition. They search for high-quality information in plain language, from independent sources, based on reliable and up to-date evidence. The Integrating and Deriving Evidence, Experiences and Preferences (IN-DEEP) project in Italy and Australia aimed to provide people with MS and family members with an online source of evidence-based information, starting from their information needs. This paper reports on the Italian project's website. METHODS: Contents, layout and wording were developed with people with MS and pilot-tested. The website was evaluated using an online 29 item questionnaire for ease of language, contents, navigation, and usefulness of information aimed at people with MS, family members and the general population. RESULTS: The website ( http://indeep.istituto-besta.it/) is structured in multiple levels of information. The first topic was interferons-beta for people with relapsing-remitting MS. In all, 433 people responded to the survey (276 people with MS, 68 family members and 89 others). The mean age was 45 years, almost 90% had a high school diploma, about 80% had relapsing-remitting MS, and the median disease duration was seven years. About 90% judged the website clear, understandable, useful, and easy to navigate. Ninety percent of people with MS and family members would recommend it to others. Sixty-two percent reported they felt confident in making decisions on interferons-beta after reading the website. CONCLUSIONS: The model was judged clear and useful. It could be adapted to other topics and diseases. Clinicians may find it useful in their relationship with patients. PMID- 26934874 TI - Tolerant and Susceptible Sesame Genotypes Reveal Waterlogging Stress Response Patterns. AB - Waterlogging is a common adverse environmental condition that limits plant growth. Sesame (Sesamum indicum) is considered a drought-tolerant oil crop but is typically susceptible to harmful effects from waterlogging. The present study used comparative analysis to explore the waterlogging stress response associated with two sesame genotypes. The RNA-seq dataset generated during a time course of 0, 3, 9 and 15 h of waterlogging as well as 20 h post-drainage indicated that stress gradually suppressed the expression of sesame genes, with 9 h as the critical time point for the response of sesame to waterlogging stress. Of the 19,316 genes expressed during waterlogging, 72.1% were affected significantly. Sesame of both tolerant and susceptible genotypes showed decreased numbers of upregulated differentially expressed genes (DEGs) but increased numbers of downregulated DEGs at the onset of waterlogging. However, the tolerant-genotype sesame exhibited 25.5% more upregulated DEGs and 29.7% fewer downregulated DEGs than those of the susceptible-genotype strain between 3 and 15 h. The results indicated that the tolerant sesame displayed a more positive gene response to waterlogging. A total of 1,379 genes were significantly induced and commonly expressed in sesame under waterlogging conditions from 3 to 15 h regardless of tolerance level; of these genes, 98 are known homologous stress responsive genes, while the remaining 1,281 are newly reported here. This gene set may represent the core genes that function in response to waterlogging, including those related mainly to energy metabolism and phenylpropanoid biosynthesis. Furthermore, a set of 3,016 genes functioning in energy supply and cell repair or formation was activated in sesame recovery from waterlogging stress. A comparative analysis between sesame of the tolerant and susceptible genotypes revealed 66 genes that may be candidates for improving sesame tolerance to waterlogging. This study provided a comprehensive picture of the sesame gene expression pattern in response to waterlogging stress. These results will help dissect the mechanism of the sesame response to waterlogging and identify candidate genes to improve its tolerance. PMID- 26934875 TI - The Italian approach to diverticular perforation complicated by diffuse peritonitis: report of the Annual UCP-SICCR Meeting 2015. PMID- 26934876 TI - HIV-tat alters Connexin43 expression and trafficking in human astrocytes: role in NeuroAIDS. AB - BACKGROUND: HIV-associated neurocognitive disorders (HAND) are a major complication in at least half of the infected population despite effective antiretroviral treatment and immune reconstitution. HIV-associated CNS damage is not correlated with active viral replication but instead is associated with mechanisms that regulate inflammation and neuronal compromise. Our data indicate that one of these mechanisms is mediated by gap junction channels and/or hemichannels. Normally, gap junction channels shutdown under inflammatory conditions, including viral diseases. However, HIV infection upregulates Connexin43 (Cx43) expression and maintains gap junctional communication by unknown mechanism(s). METHODS: Human primary astrocytes were exposed to several HIV proteins as well as to HIV, and expression and function of Connexin43- and Connexin30-containing channels were determined by western blot, immunofluorescence, microinjection of a fluorescent tracer and chromatin immunoprecipitation (ChIP). RESULTS: Here, we demonstrate that HIV infection increases Cx43 expression in vivo. HIV-tat, the transactivator of the virus, and no other HIV proteins tested, increases Cx43 expression and maintains functional gap junctional communication in human astrocytes. Cx43 upregulation is mediated by binding of the HIV-tat protein to the Cx43 promoter, but not to the Cx30 promoter, resulting in increased Cx43 messenger RNA (mRNA) and protein as well as gap junctional communication. CONCLUSIONS: We propose that HIV-tat contributes to the spread of intracellular toxic signals generated in a few HIV-infected cells into surrounding uninfected cells by upregulating gap junctional communication. In the current antiretroviral era, where HIV replication is often completely suppressed, viral factors such as HIV-tat are still produced and released from infected cells. Thus, blocking the effects of HIV-tat could result in new strategies to reduce the damaging consequences of HIV infection of the CNS. PMID- 26934877 TI - Temporal correlation between two channels EEG of bipolar lead in the head midline is associated with sleep-wake stages. AB - Whether the temporal correlation between inter-leads Electroencephalogram (EEG) that located on the boundary between left and right brain hemispheres is associated with sleep stages or not is still unknown. The purpose of this paper is to evaluate the role of correlation coefficients between EEG leads Fpz-Cz and Pz-Oz for automatic classification of sleep stages. A total number of 39 EEG recordings (about 20 h each) were selected from the expanded sleep database in European data format for temporal correlation analysis. Original waveform of EEG was decomposed into sub-bands delta (1-4 Hz), theta (4-8 Hz), alpha (8-13 Hz) and beta (13-30 Hz). The correlation coefficient between original EEG leads Fpz-Cz and Pz-Oz within frequency band 0.5-30 Hz was defined as r(EEG) and was calculated every 30 s, while that between the two leads EEG in sub-bands delta, theta, alpha and beta were defined as r(delta), r(theta), r(alpha) and r(beta), respectively. Classification of wakefulness and sleep was processed by fixed threshold that derived from the probability density function of correlation coefficients. There was no correlation between EEG leads Fpz-Cz and Pz-Oz during wakefulness (|r| < 0.1 for r(theta), r(alpha) and r(beta), while 0.3 > r > 0.1 for r(EEG) and r(delta)), while low correlation existed during sleep (r ~ -0.4 for r(EEG), r(delta), r(theta), r(alpha) and r(beta)). There were significant differences (analysis of variance, P < 0.001) for r(EEG), r(delta), r(theta), r(alpha) and r(beta) during sleep when in comparison with that during wakefulness, respectively. The accuracy for distinguishing states between wakefulness and sleep was 94.2, 93.4, 89.4, 85.2 and 91.4% in terms of r(EEG), r(delta), r(theta), r(alpha) and r(beta), respectively. However, no correlation index between EEG leads Fpz-Cz and Pz-Oz could distinguish all five types of wakefulness, rapid eye movement (REM) sleep, N1 sleep, N2 sleep and N3 sleep. In conclusion, the temporal correlation between EEG bipolar leads Fpz-Cz and Pz-Oz are highly associated with sleep-wake stages. Moreover, high accuracy of sleep wake classification could be achieved by the temporal correlation within frequency band 0.5-30 Hz between EEG leads Fpz-Cz and Pz-Oz. PMID- 26934878 TI - Accelerating Monte Carlo power studies through parametric power estimation. AB - Estimating the power for a non-linear mixed-effects model-based analysis is challenging due to the lack of a closed form analytic expression. Often, computationally intensive Monte Carlo studies need to be employed to evaluate the power of a planned experiment. This is especially time consuming if full power versus sample size curves are to be obtained. A novel parametric power estimation (PPE) algorithm utilizing the theoretical distribution of the alternative hypothesis is presented in this work. The PPE algorithm estimates the unknown non centrality parameter in the theoretical distribution from a limited number of Monte Carlo simulation and estimations. The estimated parameter linearly scales with study size allowing a quick generation of the full power versus study size curve. A comparison of the PPE with the classical, purely Monte Carlo-based power estimation (MCPE) algorithm for five diverse pharmacometric models showed an excellent agreement between both algorithms, with a low bias of less than 1.2 % and higher precision for the PPE. The power extrapolated from a specific study size was in a very good agreement with power curves obtained with the MCPE algorithm. PPE represents a promising approach to accelerate the power calculation for non-linear mixed effect models. PMID- 26934879 TI - Must-Have Knowledge about the Helicobacter pylori-Negative Gastric Cancer. PMID- 26934880 TI - Low Volume Polyethylene Glycol (PEG) Plus Ascorbic Acid, a Valid Alternative to Standard PEG. PMID- 26934881 TI - Understanding the Role of Adalimumab in the Treatment of Moderately to Severely Active Ulcerative Colitis. PMID- 26934882 TI - Is the Use of Intensity-Modulated Radiotherapy Beneficial for Pancreatic Cancer Patients? PMID- 26934883 TI - The Role of Mesothelial Cells in Liver Development, Injury, and Regeneration. AB - Mesothelial cells (MCs) cover the surface of visceral organs and the parietal walls of cavities, and they synthesize lubricating fluids to create a slippery surface that facilitates movement between organs without friction. Recent studies have indicated that MCs play active roles in liver development, fibrosis, and regeneration. During liver development, the mesoderm produces MCs that form a single epithelial layer of the mesothelium. MCs exhibit an intermediate phenotype between epithelial cells and mesenchymal cells. Lineage tracing studies have indicated that during liver development, MCs act as mesenchymal progenitor cells that produce hepatic stellate cells, fibroblasts around blood vessels, and smooth muscle cells. Upon liver injury, MCs migrate inward from the liver surface and produce hepatic stellate cells or myofibroblast depending on the etiology, suggesting that MCs are the source of myofibroblasts in capsular fibrosis. Similar to the activation of hepatic stellate cells, transforming growth factor beta induces the conversion of MCs into myofibroblasts. Further elucidation of the biological and molecular changes involved in MC activation and fibrogenesis will contribute to the development of novel approaches for the prevention and therapy of liver fibrosis. PMID- 26934885 TI - Colorectal Cancer Screening: Stool DNA and Other Noninvasive Modalities. AB - Colorectal cancer screening dates to the discovery of precancerous adenomatous tissue. Screening modalities and guidelines directed at prevention and early detection have evolved and resulted in a significant decrease in the prevalence and mortality of colorectal cancer via direct visualization or using specific markers. Despite continued efforts and an overall reduction in deaths attributed to colorectal cancer over the last 25 years, colorectal cancer remains one of the most common causes of malignancy-associated deaths. In attempt to further reduce the prevalence of colorectal cancer and associated deaths, continued improvement in screening quality and adherence remains key. Noninvasive screening modalities are actively being explored. Identification of specific genetic alterations in the adenoma-cancer sequence allow for the study and development of noninvasive screening modalities beyond guaiac-based fecal occult blood testing which target specific alterations or a panel of alterations. The stool DNA test is the first noninvasive screening tool that targets both human hemoglobin and specific genetic alterations. In this review we discuss stool DNA and other commercially available noninvasive colorectal cancer screening modalities in addition to other targets which previously have been or are currently under study. PMID- 26934886 TI - Multicellular Mathematical Modelling of Mesendoderm Formation in Amphibians. AB - The earliest cell fate decisions in a developing embryo are those associated with establishing the germ layers. The specification of the mesoderm and endoderm is of particular interest as the mesoderm is induced from the endoderm, potentially from an underlying bipotential group of cells, the mesendoderm. Mesendoderm formation has been well studied in an amphibian model frog, Xenopus laevis, and its formation is driven by a gene regulatory network (GRN) induced by maternal factors deposited in the egg. We have recently demonstrated that the axolotl, a urodele amphibian, utilises a different topology in its GRN to specify the mesendoderm. In this paper, we develop spatially structured mathematical models of the GRNs governing mesendoderm formation in a line of cells. We explore several versions of the model of mesendoderm formation in both Xenopus and the axolotl, incorporating the key differences between these two systems. Model simulations are able to reproduce known experimental data, such as Nodal expression domains in Xenopus, and also make predictions about how the positional information derived from maternal factors may be interpreted to drive cell fate decisions. We find that whilst cell-cell signalling plays a minor role in Xenopus, it is crucial for correct patterning domains in axolotl. PMID- 26934887 TI - Minimal Model of Plankton Systems Revisited with Spatial Diffusion and Maturation Delay. AB - This study revisits the minimal model for a plankton ecosystem proposed by Scheffer with spatial diffusion of plankton and the delay of the maturation period of herbivorous zooplankton. It deepens our understanding of effects of the nutrients and the predation of fish upon zooplankton on the dynamical patterns of the plankton system and also presents new phenomena induced by the delay with spatial diffusion. When the nutrient level is sufficient low, the zooplankton population collapses and the phytoplankton population reaches its carrying capacity. Mathematically, the global stability of the boundary equilibrium is proved. As the nutrient level increases, the system switches to coexistent equilibria or oscillations depending on the maturation period of zooplankton and the predation rate of fish on herbivorous zooplankton. Under an eutrophic condition, there is a unique coexistent homogeneous equilibrium, and the equilibrium density of phytoplankton increases, while the equilibrium density of herbivorous zooplankton decreases as the fish predation rate on herbivorous zooplankton is increasing. The study shows that the system will never collapses under the eutrophic condition unless the fish predation rate approaches infinite. The study also finds a functional bifurcation relation between the delay parameter of the maturation period of herbivorous zooplankton and the fish predation rate on herbivorous zooplankton that, above a critical value of the fish predation rate, the system stays at the coexistent equilibrium, and below that value, the system switches its dynamical patterns among stable and unstable equilibria and oscillations. The oscillations emerge from Hopf bifurcations, and a detailed mathematical analysis about the Hopf bifurcations is carried out to give relevant ecological predications. PMID- 26934884 TI - Diagnosis and Management of Autoimmune Hepatitis: Current Status and Future Directions. AB - Autoimmune hepatitis is characterized by autoantibodies, hypergammaglobulinemia, and interface hepatitis on histological examination. The features lack diagnostic specificity, and other diseases that may resemble autoimmune hepatitis must be excluded. The clinical presentation may be acute, acute severe (fulminant), or asymptomatic; conventional autoantibodies may be absent; centrilobular necrosis and bile duct changes may be present; and the disease may occur after liver transplantation or with features that suggest overlapping disorders. The diagnostic criteria have been codified, and diagnostic scoring systems can support clinical judgment. Nonstandard autoantibodies, including antibodies to actin, alpha-actinin, soluble liver antigen, perinuclear antineutrophil antigen, asialoglycoprotein receptor, and liver cytosol type 1, are tools that can support the diagnosis, especially in patients with atypical features. Prednisone or prednisolone in combination with azathioprine is the preferred treatment, and strategies using these medications in various doses can ameliorate treatment failure, incomplete response, drug intolerance, and relapse after drug withdrawal. Budesonide, mycophenolate mofetil, and calcineurin inhibitors can be considered in selected patients as frontline or salvage therapies. Molecular (recombinant proteins and monoclonal antibodies), cellular (adoptive transfer and antigenic manipulation), and pharmacological (antioxidants, antifibrotics, and antiapoptotic agents) interventions constitute future directions in management. The evolving knowledge of the pathogenic pathways and the advances in technology promise new management algorithms. PMID- 26934888 TI - The effect of chronic tianeptine administration on the brain mitochondria: direct links with an animal model of depression. AB - A growing body of evidence has focused on the impact of mitochondrial disturbances in the development of depression, but little data exist regarding the effects of chronic administration of antidepressant drugs on the brain's mitochondrial protein profile. The aim of this study was to investigate the impact of chronic treatment with an atypical antidepressant drug-tianeptine-on the mitochondria-enriched subproteome profile in the hippocampus and the frontal cortex of 3-month-old male rats following a prenatal stress procedure. Rats that were exposed to a prenatal stress procedure displayed depressive- and anxiety like disturbances based on the elevated plus-maze and Porsolt tests. Moreover, two-dimensional electrophoresis coupled with mass spectrometry showed structure dependent mitoproteome changes in brains of prenatally stressed rats after chronic tianeptine administration. A component of 2-oxoglutarate and succinate flavoprotein subunit dehydrogenases, isocitrate subunit alpha, was upregulated in the hippocampus. In the frontal cortex, there was a striking increase in the expression of glutamate dehydrogenase and cytochrome bc1 complex subunit 2. These findings suggest that mitochondria are underappreciated targets for therapeutic interventions, and mitochondrial function may be crucial for the effective treatment of stress-related diseases. PMID- 26934889 TI - Map-based cloning, identification and characterization of the w gene controlling white immature fruit color in cucumber (Cucumis sativus L.). AB - KEY MESSAGE: A single-nucleotide insertion resulted in a premature stop codon that is responsible for white immature fruit color in cucumber. Despite our previous progress in the mapping of the gene controlling white color in immature cucumber fruit and the identification of candidate genes, the specific gene that governs chlorophyll metabolism and its regulatory mechanism remains unknown. Here, we generated a mapping population consisting of 9497 F2 plants to delimit the controlling gene to an 8.2-kb physical interval that defines a sole candidate gene, APRR2. Sequencing the full-length DNA and cDNA of APRR2 allowed for identification of an allele, aprr2, encoding a truncated 101-amino acid protein due to a frameshift mutation and a premature stop codon. Gene structure prediction indicated that these 101 residues are located in a domain necessary for the function of the protein. The expression patterns of APRR2 were entirely consistent with the visual changes in green color intensity during fruit development. A microscopic observation of the fruit pericarp revealed fewer chloroplasts and a lower chloroplast chlorophyll storage capacity in Q24 (white) than in Q30 (green). A single-base insertion in the white color gene w, which leads to a premature stop codon, is hypothesized to have disabled the function of this gene in chlorophyll accumulation and chloroplast development. These findings contribute to basic research and the genetic improvement of fruit color. PMID- 26934890 TI - Identification and genetic mapping of PmAF7DS a powdery mildew resistance gene in bread wheat (Triticum aestivum L.). AB - KEY MESSAGE: Gene PmAF7DS confers resistance to wheat powdery mildew (isolate Bgt#211 ); it was mapped to a 14.6-cM interval ( Xgwm350 a- Xbarc184 ) on chromosome 7DS. The flanking markers could be applied in MAS breeding. Wheat powdery mildew (Pm) is caused by the biotrophic pathogen Blumeria graminis tritici (DC.) (Bgt). An ongoing threat of breakdown of race-specific resistance to Pm requires a continuous effort to discover new alleles in the wheat gene pool. Developing new cultivars with improved disease resistance is an economically and environmentally safe approach to reduce yield losses. To identify and characterize genes for resistance against Pm in bread wheat we used the (Arina * Forno) RILs population. Initially, the two parental lines were screened with a collection of 61 isolates of Bgt from Israel. Three Pm isolates Bgt#210 , Bgt#211 and Bgt#213 showed differential reactions in the parents: Arina was resistant (IT = 0), whereas Forno was moderately susceptible (IT = -3). Isolate Bgt#211 was then used to inoculate the RIL population. The segregation pattern of plant reactions among the RILs indicates that a single dominant gene controls the conferred resistance. A genetic map of the region containing this gene was assembled with DNA markers and assigned to the 7D physical bin map. The gene, temporarily designated PmAF7DS, was located in the distal region of chromosome arm 7DS. The RILs were also inoculated with Bgt#210 and Bgt#213. The plant reactions to these isolates showed high identity with the reaction to Bgt#211, indicating the involvement of the same gene or closely linked, but distinct single genes. The genomic location of PmAF7DS, in light of other Pm genes on 7DS is discussed. PMID- 26934891 TI - Recent advances in the management of pulmonary embolism: focus on the critically ill patients. AB - The aim of this narrative review is to summarize for intensivists or any physicians managing "severe" pulmonary embolism (PE) the main recent advances or recommendations in the care of patients including risk stratification, diagnostic algorithm, hemodynamic management in the intensive care unit (ICU), recent data regarding the use of thrombolytic treatment and retrievable vena cava filters and finally results of direct oral anticoagulants. Thanks to the improvements achieved in the risk stratification of patients with PE, a better therapeutic approach is now recommended from diagnosis algorithm and indication to admission in ICU to indication of thrombolysis and general hemodynamic support in patients with shock. Given at current dosage, thrombolytic therapy is associated with a reduction in the combined end-point of mortality and hemodynamic decompensation in patients with intermediate-risk PE, but this is obtained without a decrease in overall mortality and with a significant increase in major extracranial and intracranial bleeding. In patients with high-intermediate-risk PE, thrombolytic therapy should be given in case of hemodynamic worsening. Vena cava filters are of little help when anticoagulant treatment is not contraindicated, even in patients with PE and features of clinical severity. Finally, direct oral anticoagulants have been shown to be as effective as and safer than the combination of low molecular weight heparin and vitamin K antagonist(s) in patients with venous thromboembolism and low- to intermediate-risk PE. PMID- 26934892 TI - Cross-sectional imaging following surgical interventions for stress urinary incontinence in females. AB - Stress urinary incontinence (SUI) is a condition in which the weakness of the pelvic floor muscles causes unintentional loss of urine. For patients who are unable to achieve symptomatic improvement from lifestyle modification and pharmacotherapy, surgical placement of the pelvic slings or the use of urethral bulking agents has been shown to provide tremendous symptomatic improvement. Learning to recognize the pelvic slings and to identify their complications on imaging is invaluable; however, this is challenging because of the change in the local anatomy after surgical placement of the sling. In this paper, we present CT and MR imaging to demonstrate the surgical and non-surgical treatments of female SUI and their complications. Through this pictorial essay, our goal is to familiarize radiologists with recognizing the various forms of treatment for SUIs, the relevant pelvic anatomy, and complications that may occur secondary to the surgical placement of the pelvic slings. PMID- 26934893 TI - Quality assurance methodology and applications to abdominal imaging PQI. AB - Quality assurance has increasingly become an integral part of medicine, with tandem goals of increasing patient safety and procedural quality, improving efficiency, lowering cost, and ultimately improving patient outcomes. This article reviews quality assurance methodology, ranging from the PDSA cycle to the application of lean techniques, aimed at operational efficiency, to continually evaluate and revise the health care environment. Alignment of goals for practices, hospitals, and healthcare organizations is critical, requiring clear objectives, adequate resources, and transparent reporting. In addition, there is a significant role played by regulatory bodies and oversight organizations in determining external benchmarks of quality, practice, and individual certification and reimbursement. Finally, practical application of quality principles to practice improvement projects in abdominal imaging will be presented. PMID- 26934894 TI - Interventional oncology: pictorial review of post-ablation imaging of liver and renal tumors. AB - Percutaneous image-guided ablation is now commonly performed in many institutions for the treatment of hepatocellular carcinoma, liver metastases, and renal cell carcinoma in select patients. Accurate interpretation of post-ablation imaging is of supreme importance because treatment algorithms for these diseases rely heavily on imaging to guide management decisions. The purpose of this pictorial essay is to provide abdominal imagers with a review of the indications for percutaneous ablation in the abdomen, a basic overview of ablation modalities in clinical use today, the expected post-ablation imaging findings in the liver and kidney, and potential complications of hepatic and renal ablation procedures. PMID- 26934895 TI - Validation of an endothelial roll preparation for Descemet Membrane Endothelial Keratoplasty by a cornea bank using "no touch" dissection technique. AB - Descemet Membrane Endothelial Keratoplasty (DMEK) selectively replaces the damaged posterior part of the cornea. However, the DMEK technique relies on a manually-performed dissection that is time-consuming, requires training and presents a potential risk of endothelial graft damages leading to surgery postponement when performed by surgeons in the operative room. To validate precut corneal tissue preparation for DMEK provided by a cornea bank in order to supply a quality and security precut endothelial tissue. The protocol was a technology transfer from the Netherlands Institute for Innovative Ocular Surgery (NIIOS) to Lyon Cornea Bank, after formation in NIIOS to the DMEK "no touch" dissection technique. The technique has been validated in selected conditions (materials, microscope) and after a learning curve, cornea bank technicians prepared endothelial tissue for DMEK. Endothelial cells densities (ECD) were evaluated before and after preparation, after storage and transport to the surgery room. Microbiological and histological controls have been done. Twenty corneas were manually dissected; 18 without tears. Nineteen endothelial grafts formed a double roll. The ECD loss after cutting was 3.3 % (n = 19). After transportation 7 days later, we found an ECD loss of 25 % (n = 12). Three days after cutting and transportation, we found 2.1 % of ECD loss (n = 7). Histology found an endothelial cells monolayer lying on Descemet membrane. The mean thickness was 12 +/- 2.2 um (n = 4). No microbial contamination was found (n = 19). Endothelial roll stability has been validated at 3 days in our cornea bank. Cornea bank technicians trained can deliver to surgeons an ECD controlled, safety and ready to use endothelial tissue, for DMEK by "no touch" technique, allowing time saving, quality and security for surgeons. PMID- 26934896 TI - Airborne Pollen Concentrations and Emergency Room Visits for Myocardial Infarction: A Multicity Case-Crossover Study in Ontario, Canada. AB - Few studies have examined the acute cardiovascular effects of airborne allergens. We conducted a case-crossover study to evaluate the relationship between airborne allergen concentrations and emergency room visits for myocardial infarction (MI) in Ontario, Canada. In total, 17,960 cases of MI were identified between the months of April and October during the years 2004-2011. Daily mean aeroallergen concentrations (pollen and mold spores) were assigned to case and control periods using central-site monitors in each city along with daily measurements of meteorological data and air pollution (nitrogen dioxide and ozone). Odds ratios and their 95% confidence intervals were estimated using conditional logistic regression models adjusting for time-varying covariates. Risk of MI was 5.5% higher (95% confidence interval (CI): 3.4, 7.6) on days in the highest tertile of total pollen concentrations compared with days in the lowest tertile, and a significant concentration-response trend was observed (P < 0.001). Higher MI risk was limited to same-day pollen concentrations, with the largest risks being observed during May (odds ratio = 1.16, 95% CI: 1.00, 1.35) and June (odds ratio = 1.10, 95% CI: 1.00, 1.22), when tree and grass pollen are most common. Mold spore concentrations were not associated with MI. Our findings suggest that airborne pollen might represent a previously unidentified environmental risk factor for myocardial infarction. PMID- 26934897 TI - The value of preoperative embolization in large and giant solid cerebellar hemangioblastomas. AB - BACKGROUND: Solid cerebellar hemangioblastomas are highly vascular lesions and may cause catastrophic hemorrhage during excision. METHODS: This retrospective study enrolled 10 patients (7 men and 3 women, with a mean age of 38.2 +/- 12.5 years) with solid cerebellar hemangioblastomas. All patients had a solitary tumor and underwent surgical resection of the lesion through a suboccipital approach. The basic features, serial radiographic examinations, and operative records were analyzed. RESULTS: The most common presenting symptoms were headache (100%), ataxia (100%), and long tract manifestations (60%). Three patients had experienced failed surgery previously due to massive intraoperative bleeding. Three patients were confirmed as having Von Hippel-Lindau disease. The average size of the tumor was 40.7 +/- 8.7 mm in its maximal diameter (range 25-58 mm). Total endovascular occlusion obtained in six patients, near total occlusion in three patients, and incomplete occlusion in one patient. Nine (90.0%) patients underwent gross total resection and one (10.0%) underwent partial resection. After the primary surgery, eight (80.0%) patients experienced improvement in their symptoms, two (20.0%) maintained their pre-treatment status, and none showed neurological deterioration following tumor resection. Blood loss during surgery after embolization was minimal and controllable. CONCLUSION: Preoperative embolization improves safety and efficacy of the microsurgical excision of such tightly located very vascular tumors. Embolization changes the concept of this lesion surgery into piecemeal removal rather than a total mass extraction technique. Liquid agents are superior to particles in obliteration of such lesions. PMID- 26934898 TI - Complex lifestyle differences make study on potato consumption and risk of gestational diabetes difficult to interpret. PMID- 26934899 TI - 'She was a foster mother who said she didn't give cuddles': The adverse early foster care experiences of children who later struggle with adoptive family life. AB - Foster care remains a valuable and safe intervention for many children unable to live with their birth family. When birth family reunification is not considered possible, a small proportion of children in foster care will go on to achieve permanency by way of adoption. This article reports on some unexpected findings to emerge from two national adoption studies of previously looked after children in England and Wales. Focussing on a subset of families who had experienced or were at risk of an adoption disruption, the findings revealed that not only did children carry elevated risks for disruption due to their older age at entry to care, multiple foster care placements and traumatic early histories, but once in care, many of the children whose placements had disrupted were considered by their adoptive parents to have had very poor, even harmful fostering experiences before being placed for adoption. Possible explanations for these findings are discussed, together with the implications for social work practice. PMID- 26934900 TI - [Nasogastric intubation in patients with upper gastrointestinal bleeding?]. PMID- 26934901 TI - [Malignant intracerebral nerve sheath tumours: Two case reports and complete review of the literature cases]. AB - Malignant peripheral nerve sheath tumours are extremely rare and can be associated with neurofibramatosis type 1. Their prognosis is poor and surgery remains the mainstay of therapy and should be the first line of treatment. Radiotherapy and chemotherapy are second line treatment and their effectiveness remains to demonstrate. The diagnosis is clinical, radiological, histological and immunohistochemical. Malignant peripheral nerve sheath tumours have a potential of local tumour recurrence very high and can metastasize. They often occur in extremity of the members but also rarely into brain. We report two cases of intracerebral nerve sheath tumour. The first was a 68-year-old woman who was admitted with progressive symptoms of headache and diplopia. A left frontotemporal malignant peripheral nerve sheath tumours was diagnosed and was treated by surgery and irradiation. Ten months later, she presented a local recurrence and spine bone's metastases were treated by vertebroplasty and irradiation. The patient died 15 months after the diagnosis. The second case was a 47-year-old woman who was referred because headache and vomiting symptoms. A right frontal malignant peripheral nerve sheath tumours was diagnosed and treated by surgery and irradiation. After that, the patient had three local recurrence operated and pulmonary and cranial bone's metastases. She was still alive after 20 months. We propose a literature review with 25 cases of intracerebral nerve sheath tumour identified, including the two current cases. PMID- 26934902 TI - The diapsid origin of turtles. AB - The origin of turtles has been a persistent unresolved problem involving unsettled questions in embryology, morphology, and paleontology. New fossil taxa from the early Late Triassic of China (Odontochelys) and the Late Middle Triassic of Germany (Pappochelys) now add to the understanding of (i) the evolutionary origin of the turtle shell, (ii) the ancestral structural pattern of the turtle skull, and (iii) the phylogenetic position of Testudines. As has long been postulated on the basis of molecular data, turtles evolved from diapsid reptiles and are more closely related to extant diapsids than to parareptiles, which had been suggested as stem group by some paleontologists. The turtle cranium with its secondarily closed temporal region represents a derived rather than a primitive condition and the plastron partially evolved through the fusion of gastralia. PMID- 26934903 TI - Fatal intoxication with synthetic cannabinoid MDMB-CHMICA. AB - MDMB-CHMICA is a synthetic cannabinoid that appeared on the European drug market in September 2014. This substance was found in Poland in the herbal mixture "Mocarz" ("Strongman"), which caused a large outbreak of intoxications at the beginning of July 2015. This paper describes the circumstances of death and toxicological findings in a fatal intoxication with MDMB-CHMICA (in combination with alcohol). Loss of consciousness and asystole occurred a few minutes after smoking the 'legal high'. The man died after 4 days of hospitalisation. The cause of death accepted by the medical examiner was multiple organ failure. MDMB-CHMICA was detected and quantified in blood (ante- and postmortem) and internal organs tissues. The samples were analysed using liquid chromatography with mass spectrometry (LC-MS/MS). The concentration of MDMB-CHMICA in antemortem blood was 5.6 ng/mL. Although the death occurred after 4 days from administration a relatively high concentration (2.6 ng/g) was estimated in the brain. Traces of this compound were also found in other postmortem materials (blood, stomach, liver, bile, and kidney). The presented case shows the health risks associated with MDMB-CHMICA use. The administration of this substance can lead to the number of organ failures, cardiac arrest and consequently death. PMID- 26934904 TI - Uncertainty: The Problem With Restricting the Use of Selected Phrases in Image Reporting. PMID- 26934905 TI - The Night Relative Value Unit: A Weighted Relative Value Unit to Equate Day and Night Interpretations. PMID- 26934906 TI - United States Medical Licensing Examination Step 1 and 2 Scores Predict Neuroradiology Fellowship Success. AB - PURPOSE: Many neuroradiology programs use United States Medical Licensing Examination (USMLE) scores to assess fellowship candidates. The authors hypothesized that because they are taken several years before fellowship, USMLE scores would correlate poorly with success in fellowship training as measured by faculty evaluations. METHODS: USMLE scores from 10 years of neuroradiology fellows (n = 73) were compared with their cumulative mean E*Value scores from their fellowship years and their best-to-worst rankings within their fellowship years. If available, subspecialty certification scores were also factored as an outcome. Linear correlation and regression analyses were performed adjusting for gender, medical school site, and practice setting after fellowship. RESULTS: USMLE Step 1, 2, and 3 scores were available for 69, 64, and 56 fellows, respectively. Fellowship E*Value scores and rankings showed statistically significant (P < .05) correlations with all USMLE scores, but most strongly for Step 1 scores and E*Value grade (r = 0.443) and rank (r = 0.370). The mean USMLE Step 1 score of the top-ranked fellows (234.5) was significantly higher than that of the bottom-ranked fellows (217.7). The correlations of E*Value score and rank with USMLE Step 1 and 2 scores remained after adjusting for gender and American versus foreign medical school, but the medical school site attended also was an independent predictor of fellowship evaluations. Subspecialty certification scores did not show correlations but were underpowered (n = 28). CONCLUSIONS: USMLE Step 1 and 2 scores correlated significantly with success in neuroradiology fellowship, measured by faculty assessments of the six core competencies. Using the scores as a means of assessing candidates for positions is justified. PMID- 26934907 TI - Solitary and combined negative influences of diabetes, obesity and hypertension on health-related quality of life of elderly individuals: A population-based cross-sectional study. AB - AIMS: The health-related quality of life (HRQoL) is a matter of concern in elderly people with chronic diseases. The objective of this study was to investigate the impact of obesity, hypertension and diabetes on HRQoL among elderly. METHODS: A population based cross sectional study was conducted with 750 representative sample of elderly people aged 60-90 years in Babol, the northern Iran. The demographic data and the measurement of blood pressure and other anthropometric measures were collected. The validated short form (SF-36) questionnaire was used to assess the HRQoL. A multiple linear regression model was applied to assess the impact of obesity, abdominal obesity, hypertension and diabetes on QoL. RESULTS: The mean age (SD) of participants was 68.0+/-7.6 and 67.7+/-7.9 years for men and women respectively. Diabetes exerted the most negative effect on QoL score (adjusted coefficient=-9.2, 95% CI: -11.7, -6.5 points) followed by abdominal obesity and hypertension. Whereas a combination of three conditions was associated with a greater significant reduction in QoL scores in both sexes(adjusted coefficient=-14.5, 95% CI: -19.0, -9.9 points). However, the negative influence of obesity and hypertension on QoL was significant only in women. CONCLUSION: Most components of the QoL is affected by diabetes, obesity and hypertension particularly in women. Diabetes alone or in combination with other conditions has a negative influence in both sexes with greater effect in women. These findings justify further professional support to compensate the negative influences chronic conditions on health-related QoL especially for older obese diabetic women. PMID- 26934908 TI - The Nice knot as an improvement on current knot options: A mechanical analysis. AB - PURPOSE: There is currently a wide range of suture knots used in rotator cuff repair. The purpose of this study was to compare a new type of self-locking sliding knot called the Nice knot to the self-locking and sliding Nicky's knot. METHODS: Nice knots and Nicky's knots were tied and subjected to mechanical testing including a pure traction stress and a series of dynamic stresses. Both knots were tied using standard braided suture and reinforced braided suture. The responses to these stresses were measured in the amount of elongation of the knot, maximum effort needed for failure, stiffness of construct and dynamic stiffness. RESULTS: With both knots the standard suture had a lower amount of elongation during the dynamic tests than the reinforced braided suture. The reinforced braided suture showed superior results during maximal effort in the pure traction tests. An increased failure rate occurred due to elongation when a dynamic stress was applied to the reinforced suture in both knot types. During dynamic testing the Nice knot showed a decrease in the amount of elongation (P<0.001). CONCLUSIONS: The Nice knot provides a sliding locking knot option which can decrease the risk of elongation during dynamic stress. LEVEL OF EVIDENCE: Basic Science Study, Biomechanical Study. PMID- 26934909 TI - Stakes and methods in economic evaluation. PMID- 26934910 TI - The price of our illusions and myths about the dead donor rule. PMID- 26934911 TI - Complicity and torture. AB - One of the great merits of On Complicity and Compromise is that it wades into specific swamps where ordinary theorists fear to slog. It is persuasive that in general it can be right sometimes to be complicit in wrongdoing by others through causally contributing to the wrongdoing, but not sharing its purpose, if by being involved one can reasonably expect to lessen the extent of the wrong that would otherwise be suffered by the victims. I focus on whether the book's general thesis is applicable to torture, which depends on what torture and the torture situation are in fact like. I focus on the case to which the chapter several times refers: the innovative CIA paradigm of torture. First, to the extent that the paradigm, which is predominantly mental, or psychological, torture succeeds in its goal of producing regression to a compliant state, the physician would be unable to rely on the torture victim's expressions of preferences or interests as authentically his own. Second, since disorientation plays such a large role in the CIA's style of torture (adopted at Guantanamo by the military), the authorities would refuse to allow a stable relationship to be built up with any one doctor by any victim, making comprehension of the victim's preferences difficult. Third, even if the doctor could somehow judge what the victim's genuine interests were, the control of the situation is much too totalistic to allow the physician any action independent of what the torture regime requires. PMID- 26934912 TI - Endothelin-1 induces oncostatin M expression in osteoarthritis osteoblasts by trans-activating the oncostatin M gene promoter via Ets-1. AB - Oncostatin M (OSM) contributes to cartilage degeneration in osteoarthritis (OA) and was demonstrated to be expressed in OA osteoblasts. Endothelin-1 (ET-1) is implicated in the degradation of OA articular cartilage, and osteoblast proliferation and bone development. In the present study, the effects of ET-1 on OSM expression in human OA osteoblasts were investigated, to the best of our knowledge, for the first time. Primary human OA osteoblasts were treated with ET 1 (1, 5, 10, 20 and 30 nM) for 0.5, 1, 2, 3 and 4 h with or without the selective ETA receptor (ETAR) antagonist, BQ123, ETB receptor antagonist, BQ788 or the phosphatidylinositol 3-kinase (PI3K) inhibitor, BKM120. ET-1 treatment induced OSM mRNA expression, and the intracellular and secreted protein levels of OA osteoblasts in a dose-dependent manner. This effect was suppressed by BQ123 and BKM120, but not BQ788 administration. In combination with electrophoretic mobility shift assays, deletional and mutational analyses on the activity of a human OSM promoter/luciferase reporter demonstrated that ET-1 induced OSM expression in OA osteoblasts by trans-activating the OSM gene promoter through specific binding of Ets-1 to an Ets-1 binding site in the OSM promoter in an ETAR and PI3K-dependent manner. Furthermore, ET-1 treatment increased the expression of Ets-1 in a dose-dependent manner, however the knockdown of Ets-1 suppressed the ET1-induced expression of OSM in OA osteoblasts. In conclusion, the present study demonstrated that ET-1 induces the expression of OSM in OA osteoblasts by trans-activating the OSM gene promoter primarily through increasing the expression level of Ets-1 in an ETAR- and PI3K-dependent manner. The current study suggested novel insights into the mechanistic role of ET-1 in the pathophysiology of OA. PMID- 26934913 TI - Integrated analysis of DNA methylation profiles and gene expression profiles to identify genes associated with pilocytic astrocytomas. AB - The present study performed an integral analysis of the gene expression and DNA methylation profile of pilocytic astrocytomas (PAs). Weighted gene co-expression network analysis (WGCNA) was also performed to examine and identify the genes correlated to PAs, to identify candidate therapeutic targets for the treatment of PAs. The DNA methylation profile and gene expression profile were downloaded from the Gene Expression Omnibus database. Following screening of the differentially expressed genes (DEGs) and differentially methylated regions (DMRs), respectively, integrated analysis of the DEGs and DMRs was performed to detect their correlation. Subsequently, the WGCNA algorithm was applied to identify the significant modules and construct the co-expression network associated with PAs. Furthermore, Gene Ontology enrichment analysis of the associated genes was performed using the Database for Annotation, Visualization and Integrated Discovery. A total number of 2,259 DEGs and 235 DMRs were screened out. Integrated analysis revealed that 30 DEGs were DMRs with prominent negative correlation (cor=-0.82; P=0.02). Based on the DEGs, the gene co-expression network was constructed, and nine network modules associated with PAs were identified. The functional analysis results showed that genes relevant to PAs were closely associated with cell differentiation modulation. The screened PA associated genes were significantly different at the expression and methylation levels. These genes may be used as reliable candidate target genes for the treatment of PAs. PMID- 26934914 TI - [Formula: see text] Effects of screening for postconcussive syndrome (PCS) on PCS symptom self-report and neuropsychological test performance. AB - OBJECTIVE: Many non-neurological factors are related to postconcussive syndrome (PCS) symptom report and neuropsychological test performance in mild traumatic brain injury (mTBI). Use of mTBI screening instruments may also contribute to report of PCS symptoms and neuropsychological performance. We examined the impact of randomized PCS screening feedback on PCS symptom report and neuropsychological performance in 152 young adults with no history of mTBI. METHOD: Participants were 158 undergraduates attending a medium-sized Midwestern university who completed the Postconcussive Syndrome Questionnaire (PCSQ) prior to the study and were randomly assigned to one of three conditions. Participants were either given feedback that they endorsed more symptoms than average, feedback that they endorsed fewer symptoms than average, or neutral information. Participants then completed the PCSQ for a second time as well as the Auditory Verbal Learning Test and Paced Auditory Serial Addition Test. RESULTS: Contrary to expectations, participants receiving feedback that they endorsed more symptoms than average did not endorse more PCSQ symptoms post-feedback than participants in other conditions (p = .12); however, consistent with expectations, they demonstrated poorer verbal learning (p = .005) and delayed recall (p = .04) than participants in the below average feedback condition and reported higher rates of retrospective recall of prior mTBI than participants in the neutral condition (p = .01). CONCLUSION: Results suggest that feedback from screening measures can influence individuals' performance and retrospective recall of their personal TBI history. Findings have implications for use of screening measures for PCS in clinical and research settings. PMID- 26934915 TI - Decreased miR-143 and increased miR-21 placental expression levels are associated with macrosomia. AB - Macrosomia, a birth weight >= 4,000 g, is associated with maternal and infant health problems. The dysregulation of microRNAs (miRNAs) in the placenta is associated with adverse birth outcomes, yet whether aberrantly expressed placental miRNAs are associated with macrosomia remains unknown. The aim of the current study was to characterize the expression of three placental miRNAs (miR 6, -21 and -143) and evaluate their association with macrosomia. The miRNA expression in placental tissues from 67 macrosomic pregnancies and 64 normal pregnancies were analyzed using reverse transcription-quantitative polymerase chain reaction. The expression of miR-21 was observed to be elevated in macrosomic placenta compared with control samples, while miR-143 expression was significantly lower than in control placenta (P<0.05). No significant differences were identified in the miR-16 expression levels between the groups (P=0.955). Following division of miRNA expression levels by quartile, logistic regression models demonstrated that the odds of macrosomia increased with miR-21 expression quartile: Q2, odds ratio (OR)=6.67 [95% confidence interval (CI), 1.39-32.05]; Q3, OR=4.10 (95% CI, 0.88-19.11); Q4, OR=16.19 (95% CI, 2.46-106.68). Conversely, higher levels of miR-143 expression were protective against macrosomia: Q2, OR=0.22 (95% CI, 0.049-0.98); Q3, OR=0.11 (95% CI, 0.024-0.55), and Q4, OR=0.16 (95% CI, 0.032-0.79). Thus, statistical analysis demonstrated that high levels of miR-21 expression and low levels of miR-143 expression predict the risk for macrosomia, indicating an interaction between the two miRNAs. Bioinformatic analysis suggested that they are likely to function in the mitogen-activated protein kinases signaling pathway to influence the risk of macrosomia. The results of the present study provide evidence that placental miR-21 and -143 are important in the formation of macrosomia. PMID- 26934916 TI - Testing the methodology for dosimetry audit of heterogeneity corrections and small MLC-shaped fields: Results of IAEA multi-center studies. AB - The International Atomic Energy Agency (IAEA) has a long tradition of supporting development of methodologies for national networks providing quality audits in radiotherapy. A series of co-ordinated research projects (CRPs) has been conducted by the IAEA since 1995 assisting national external audit groups developing national audit programs. The CRP 'Development of Quality Audits for Radiotherapy Dosimetry for Complex Treatment Techniques' was conducted in 2009 2012 as an extension of previously developed audit programs. MATERIAL AND METHODS: The CRP work described in this paper focused on developing and testing two steps of dosimetry audit: verification of heterogeneity corrections, and treatment planning system (TPS) modeling of small MLC fields, which are important for the initial stages of complex radiation treatments, such as IMRT. The project involved development of a new solid slab phantom with heterogeneities containing special measurement inserts for thermoluminescent dosimeters (TLD) and radiochromic films. The phantom and the audit methodology has been developed at the IAEA and tested in multi-center studies involving the CRP participants. RESULTS: The results of multi-center testing of methodology for two steps of dosimetry audit show that the design of audit procedures is adequate and the methodology is feasible for meeting the audit objectives. A total of 97% TLD results in heterogeneity situations obtained in the study were within 3% and all results within 5% agreement with the TPS predicted doses. In contrast, only 64% small beam profiles were within 3 mm agreement between the TPS calculated and film measured doses. Film dosimetry results have highlighted some limitations in TPS modeling of small beam profiles in the direction of MLC leave movements. DISCUSSION: Through multi-center testing, any challenges or difficulties in the proposed audit methodology were identified, and the methodology improved. Using the experience of these studies, the participants could incorporate the auditing procedures in their national programs. PMID- 26934917 TI - Cyclophilin-B Modulates Collagen Cross-linking by Differentially Affecting Lysine Hydroxylation in the Helical and Telopeptidyl Domains of Tendon Type I Collagen. AB - Covalent intermolecular cross-linking provides collagen fibrils with stability. The cross-linking chemistry is tissue-specific and determined primarily by the state of lysine hydroxylation at specific sites. A recent study on cyclophilin B (CypB) null mice, a model of recessive osteogenesis imperfecta, demonstrated that lysine hydroxylation at the helical cross-linking site of bone type I collagen was diminished in these animals (Cabral, W. A., Perdivara, I., Weis, M., Terajima, M., Blissett, A. R., Chang, W., Perosky, J. E., Makareeva, E. N., Mertz, E. L., Leikin, S., Tomer, K. B., Kozloff, K. M., Eyre, D. R., Yamauchi, M., and Marini, J. C. (2014) PLoS Genet 10, e1004465). However, the extent of decrease appears to be tissue- and molecular site-specific, the mechanism of which is unknown. Here we report that although CypB deficiency resulted in lower lysine hydroxylation in the helical cross-linking sites, it was increased in the telopeptide cross-linking sites in tendon type I collagen. This resulted in a decrease in the lysine aldehyde-derived cross-links but generation of hydroxylysine aldehyde-derived cross-links. The latter were absent from the wild type and heterozygous mice. Glycosylation of hydroxylysine residues was moderately increased in the CypB null tendon. We found that CypB interacted with all lysyl hydroxylase isoforms (isoforms 1-3) and a putative lysyl hydroxylase-2 chaperone, 65-kDa FK506-binding protein. Tendon collagen in CypB null mice showed severe size and organizational abnormalities. The data indicate that CypB modulates collagen cross-linking by differentially affecting lysine hydroxylation in a site-specific manner, possibly via its interaction with lysyl hydroxylases and associated molecules. This study underscores the critical importance of collagen post-translational modifications in connective tissue formation. PMID- 26934918 TI - Tubulin Dimer Reversible Dissociation: AFFINITY, KINETICS, AND DEMONSTRATION OF A STABLE MONOMER. AB - Tubulins are evolutionarily conserved proteins that reversibly polymerize and direct intracellular traffic. Of the tubulin family only alphabeta-tubulin forms stable dimers. We investigated the monomer-dimer equilibrium of rat brain alphabeta-tubulin using analytical ultracentrifugation and fluorescence anisotropy, observing tubulin in virtually fully monomeric and dimeric states. Monomeric tubulin was stable for a few hours and exchanged into preformed dimers, demonstrating reversibility of dimer dissociation. Global analysis combining sedimentation velocity and fluorescence anisotropy yielded Kd = 84 (54-123) nm Dimer dissociation kinetics were measured by analyzing the shape of the sedimentation boundary and by the relaxation of fluorescence anisotropy following rapid dilution of labeled tubulin, yielding koff in the range 10(-3)-10(-2) s(-1) Thus, tubulin dimers reversibly dissociate with moderately fast kinetics. Monomer monomer association is much less sensitive than dimer-dimer association to solution changes (GTP/GDP, urea, and trimethylamine oxide). PMID- 26934919 TI - The Klebsiella pneumoniae O12 ATP-binding Cassette (ABC) Transporter Recognizes the Terminal Residue of Its O-antigen Polysaccharide Substrate. AB - Export of the Escherichia coli serotype O9a O-antigenic polysaccharides (O-PS) involves an ATP-binding cassette (ABC) transporter. The process requires a non reducing terminal residue, which is recognized by a carbohydrate-binding module (CBM) appended to the C terminus of the nucleotide-binding domain of the transporter. Here, we investigate the process in Klebsiella pneumoniae serotype O12 (and Raoultella terrigena ATCC 33257). The O12 polysaccharide is terminated at the non-reducing end by a beta-linked 3-deoxy-d-manno-oct-2-ulosonic acid (Kdo) residue. The O12 ABC transporter also binds its cognate O-PS via a CBM, and export is dependent on the presence of the terminal beta-Kdo residue. The overall structural architecture of the O12 CBM resembles the O9a prototype, but they share only weak sequence similarity, and the putative binding pocket for the O12 glycan is different. Removal of the CBM abrogated O-PS transport, but export was restored when the CBM was expressed in trans with the mutant CBM-deficient ABC transporter. These results demonstrate that the CBM-mediated substrate recognition mechanism is evolutionarily conserved and can operate with glycans of widely differing structures. PMID- 26934920 TI - Genome-wide A-to-I RNA editing in fungi independent of ADAR enzymes. AB - Yeasts and filamentous fungi do not have adenosine deaminase acting on RNA (ADAR) orthologs and are believed to lack A-to-I RNA editing, which is the most prevalent editing of mRNA in animals. However, during this study with the PUK1(FGRRES_01058) pseudokinase gene important for sexual reproduction in Fusarium graminearum, we found that two tandem stop codons, UA(1831)GUA(1834)G, in its kinase domain were changed to UG(1831)GUG(1834)G by RNA editing in perithecia. To confirm A-to-I editing of PUK1 transcripts, strand-specific RNA seq data were generated with RNA isolated from conidia, hyphae, and perithecia. PUK1 was almost specifically expressed in perithecia, and 90% of transcripts were edited to UG(1831)GUG(1834)G. Genome-wide analysis identified 26,056 perithecium specific A-to-I editing sites. Unlike those in animals, 70.5% of A-to-I editing sites inF. graminearum occur in coding regions, and more than two-thirds of them result in amino acid changes, including editing of 69PUK1-like pseudogenes with stop codons in ORFs.PUK1orthologs and other pseudogenes also displayed stage specific expression and editing in Neurospora crassa and F. verticillioides Furthermore,F. graminearum differs from animals in the sequence preference and structure selectivity of A-to-I editing sites. Whereas A's embedded in RNA stems are targeted by ADARs, RNA editing inF. graminearum preferentially targets A's in hairpin loops, which is similar to the anticodon loop of tRNA targeted by adenosine deaminases acting on tRNA (ADATs). Overall, our results showed that A to-I RNA editing occurs specifically during sexual reproduction and mainly in the coding regions in filamentous ascomycetes, involving adenosine deamination mechanisms distinct from metazoan ADARs. PMID- 26934921 TI - A time- and cost-effective strategy to sequence mammalian Y Chromosomes: an application to the de novo assembly of gorilla Y. AB - The mammalian Y Chromosome sequence, critical for studying male fertility and dispersal, is enriched in repeats and palindromes, and thus, is the most difficult component of the genome to assemble. Previously, expensive and labor intensive BAC-based techniques were used to sequence the Y for a handful of mammalian species. Here, we present a much faster and more affordable strategy for sequencing and assembling mammalian Y Chromosomes of sufficient quality for most comparative genomics analyses and for conservation genetics applications. The strategy combines flow sorting, short- and long-read genome and transcriptome sequencing, and droplet digital PCR with novel and existing computational methods. It can be used to reconstruct sex chromosomes in a heterogametic sex of any species. We applied our strategy to produce a draft of the gorilla Y sequence. The resulting assembly allowed us to refine gene content, evaluate copy number of ampliconic gene families, locate species-specific palindromes, examine the repetitive element content, and produce sequence alignments with human and chimpanzee Y Chromosomes. Our results inform the evolution of the hominine (human, chimpanzee, and gorilla) Y Chromosomes. Surprisingly, we found the gorilla Y Chromosome to be similar to the human Y Chromosome, but not to the chimpanzee Y Chromosome. Moreover, we have utilized the assembled gorilla Y Chromosome sequence to design genetic markers for studying the male-specific dispersal of this endangered species. PMID- 26934922 TI - In vivo and in vitro studies of MUC1 regulation in sheep endometrium. AB - In this study, we investigated the expression of mucin 1 (MUC1) mRNA and protein in sheep endometrium at different time points during follicular and luteal phases of estrous cycle, and also determined the effect of steroid hormone treatments and interferon tau (IFNtau) on MUC1 mRNA expression in endometrial cell culture in vitro. In experiment one, 15 Welsh mountain ewes were synchronized to a common estrus and killed at precise stages of estrous cycle corresponding to (1) pre-LH peak, (2) LH peak, (3) post-LH peak, (4) early luteal, and (5) mid-luteal. Reproductive tracts were harvested and mRNA was extracted from the endometrial tissues. Parts of the uterine horns were fixed for immunohistochemistry. In experiment two, mixed populations of ovine endometrial cells (from slaughterhouse material collected at the postovulatory stage of the estrous cycle) were cultured to 70% confluence before treatment with (1) progesterone (P4, 10 ng/mL, for 48 hours), (2) estradiol (E2, 100 pg/mL, for 48 hours), or with (3) E2 priming for 12 hours (100 pg/mL) followed by P4 (10 ng/mL) for 36 hours. These were compared with: (4) IFNtau (10 ng/mL, for 48 hours), and (5) basic medium (Dulbecco Modified Eagle Medium /F12) as control. The results showed that MUC1 mRNA and protein expression in sheep endometrium were highest during the midluteal stage and very low during the post-LH period compared with the other stages (P < 0.05). MUC1 immunostaining in the luminal epithelium was apically restricted and was not significantly different across all stages of estrous cycle except at the post-LH peak where it was significantly low. In cell culture, MUC1 mRNA expression was significantly upregulated by both steroids either singly or in combination (P < 0.05), and downregulated in the presence of IFNtau. In conclusion, endometrial MUC1 expression is cyclically regulated by both E2 and P4in vivo and in vitro, and directly downregulated by IFNtau treatment in vitro. PMID- 26934923 TI - An Approach to Improve Intestinal Absorption of Poorly Absorbed Water-Insoluble Components via Niemann-Pick C1-Like 1. AB - Dietary and biliary cholesterol absorption contributes to the maintenance of tight control of cholesterol homeostasis. Cholesterol is present as mixed micelles formed by bile salts and phospholipids in the intestinal lumen. Recently, Niemann-Pick C1-Like 1 (NPC1L1) transporter was identified as being critical for cholesterol absorption. However, the uptake mechanism of an enveloped substrate of NPC1L1 in whole lipid emulsion particles remains unclear. In this study, we investigated the uptake mechanism of a substrate of NPC1L1 in lipid emulsion particles. We also investigated whether these particles containing cholesterol can improve the intestinal absorption of other lipophilic components via NPC1L1. The uptake of lysophosphatidylcholine (LPC)-4,4-difluoro-5-(4-phenyl 1,3-butadienyl)-4-bora-3a,4a-diaza-s-indacene-3-propionic acid saccinimidyl ester (BODIPY), a fluorescently labeled phospholipid, in lipid emulsion particles containing cholesterol (1 uM) was significantly increased compared to that without cholesterol in Caco-2 cells. On the other hand, its increased uptake was significantly inhibited by ezetimibe, a selective inhibitor of NPC1L1. These results suggested that not only cholesterol but also some components in lipid emulsion particles are taken up into enterocytes via NPC1L1. We also examined an approach to improve intestinal absorption of a poorly absorbed water-insoluble component, coenzyme Q10 (CoQ10), by this mechanism. The uptake of CoQ10 in lipid emulsion particles containing cholesterol was significantly increased compared to that without cholesterol. Its increased uptake was significantly inhibited by ezetimibe. Though it is still not clear whether CoQ10 is a substrate of NPC1L1, there is a potential for improvement of the absorption of poorly absorbed components by lipid emulsion particles containing cholesterol. PMID- 26934924 TI - The Effect of a Retinoic Acid Derivative on Cell-Growth Inhibition in a Pulmonary Carcinoma Cell Line. AB - Pulmonary carcinoma is a major cause of cancer-related death worldwide. Because the prognosis remains poor, the development of novel therapeutic approaches is highly desirable. In this study, we investigated the effect of Tamibarotene (Am80), a retinoic acid derivative, on the growth of human lung adenocarcinoma cell line A549. Our ultimate goal in this study is to provide pulmonary carcinoma therapy with a new approach. First, we treated A549 cells with Am80 to clarify the effect of cell-growth inhibition. Am80 significantly reduced the viability of A549 cells in a dose- and time-dependent manner. The IC50 value, which was determined using CellTiter-Glo Luminescent Cell Viability assay, of Am80 and all trans retinoic acid (ATRA) against A549 cells at 6 d was 49.1+/-8.1 uM and 92.3+/ 8.0 uM, respectively. Furthermore, Am80 reduced the anchorage-independent cell growth ability of A549 cells. However, it was not an apoptosis-mediated mechanism. These results suggest that Am80 can be used as an effective, novel cell-growth inhibitor in lung adenocarcinoma. PMID- 26934925 TI - Interaction between Bisphosphonates and Mineral Water: Study of Oral Risedronate Absorption in Rats. AB - Bisphosphonates are antiosteoporotic agents prescribed for patients with osteoporosis. Drug package inserts for bisphosphonate supplements indicate that their bioavailability is reduced by high levels of metal cations (Ca(2+), Mg(2+), etc.). However, standards for these cations in water used for taking risedronate have not been defined. Here, we examined the effect of calcium and magnesium in mineral waters on the bioavailability of the third-generation bisphosphonate, risedronate, following oral administration in rats. As risedronate is unchanged and eliminated renally, risedronate absorption was estimated from the amount excreted in the urine. Risedronate was dissolved in mineral water samples and administered orally at 0.35 mg/kg. Urine samples were collected for 24 h after dosing. Risedronate was extracted from urine using ion-pair solid-phase cartridges and quantified by HPLC with UV detection (262 nm). Cumulative recovery of risedronate was calculated from the amount excreted in the urine. The 24-h recovery of risedronate from evian(r) (0.32+/-0.02% [mean+/-standard deviation (S.D.)], n=4) and Contrex((r)) (0.22+/-0.05%) mineral waters was significantly lower than that from tap water (0.47+/-0.04%, p<0.01). Absorption of risedronate in calcium chloride and magnesium chloride aqueous solutions of the same hardness (822 mg/L) was 54% (0.27+/-0.04%) and 12% (0.51+/-0.08%) lower, respectively, compared with ultrapure water; suggesting that absorption of risedronate declines as the calcium concentration of mineral waters increases. Consumption of mineral waters containing high levels of calcium (80 mg/L or above), such as evian(r) and Contrex((r)), is therefore not recommended when taking risedronate. PMID- 26934926 TI - Neuroprotection of Osthole against Cerebral Ischemia/Reperfusion Injury through an Anti-apoptotic Pathway in Rats. AB - Cerebral ischemia/reperfusion (I/R) injury is a major cause of acute brain injury. The pathogenetic mechanisms underlying I/R injury involve apoptosis, inflammation and oxidative stress. Osthole-a plant coumarin compound-has been reported to protect against focal cerebral I/R-induced injury in rats. However, the mechanism remains unknown. Here we hypothesize that osthole acts through inhibition of apoptosis during focal cerebral I/R injury in rats. We induced cerebral I/R injury by middle cerebral artery occlusion (MCAO) for 2 h followed by reperfusion. We randomly assigned 60 rats to three groups (20 rats per group): sham-operated, vehicle-treated I/R, and osthole-treated I/R. We treated rats intraperitoneally with osthole (40 mg/kg) or vehicle 30 min before cerebral ischemia. We harvested the brains for infarct volume, brain water content, histological changes and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) staining as well as cleaved caspase-3, bax, and bcl-2 levels 24 h after reperfusion. Osthole treatment significantly attenuated cerebral dysfunction and histologic damage induced by I/R injury. Moreover, osthole-treated rats had a dramatic decrease in apoptotic neuronal cells along with a decrease in bax and cleaved caspase-3. The bcl-2 levels increased. Osthole treatment protects the brain from cerebral I/R injury by suppressing cell apoptosis. Thus, osthole may represent a novel practical strategy to prevent cerebral I/R injury. PMID- 26934927 TI - Effect of Physiological Changes in the Skin on Systemic Absorption of Tacrolimus Following Topical Application in Rats. AB - Tacrolimus (TL) ointment is a topical treatment for atopic dermatitis, a disease that exhibits various skin conditions. The effect of skin pathologies on the systemic absorption of TL and related side effects remains unknown. This study aimed to investigate factors affecting the cutaneous absorption of TL. We prepared various skin models in hairless rats by tape stripping, injection of prophlogistic material solution (PMS), and continuous subcutaneous adrenaline (Adr) infusion. In vivo absorption studies were conducted, with measurements of transepidermal water loss (TEWL) and skin blood flow as physiological parameters. Very little TL absorption was observed through intact skin. Greater TL absorption was noted in skins with high TEWL values and fully stripped skin with PMS injections. In contrast, Adr infusion, which reduced skin blood flow, resulted in decreased TL absorption through fully stripped skin. Combined use of TL and Adr on skin with PMS injections resulted in suppression of TL absorption. Our results revealed that TL absorption following topical application is affected by alterations in the skin barrier, blood flow, and vascular permeability. We propose an administration plan for TL in a flowchart as a means of preventing systemic side effects. PMID- 26934928 TI - Effect of Metabolic Inhibitors on the Hepatic Disposition of 5-Fluorouracil after Application to the Rat Liver Surface. AB - We evaluated the effects of 5-fluorouracil (5-FU) metabolic inhibitors, gimeracil or uridine, on the hepatic disposition of 5-FU after application to the liver surface in rats, aiming to enhance the availability of 5-FU in the liver. 5-FU solution with or without metabolic inhibitors was applied to the rat liver surface using a cylindrical diffusion cell. The liver, blood and the remaining solution in the diffusion cell were collected at specified times, and assayed for 5-FU content. 5-FU absorption properties were not altered by addition of gimeracil and uridine. The 5-FU concentration in the diffusion cell attachment site of the rat liver (site 1) at 0.1-0.4 M ratios of gimeracil to 5-FU was significantly higher than that of the control. On the contrary, the addition of uridine did not increase the 5-FU concentration at site 1. At a 0.1 M ratio of gimeracil to 5-FU, the maximum 5-FU plasma concentration was the lowest, and the area under the 5-FU concentration-time curve at site 1 was 3.4 times greater than that of the control. We demonstrated that applying 5-FU with gimeracil to the rat liver surface could increase the availability of 5-FU in the liver. PMID- 26934929 TI - Rhein 8-O-beta-D-Glucopyranoside Elicited the Purgative Action of Daiokanzoto (Da Huang-Gan-Cao-Tang), Despite Dysbiosis by Ampicillin. AB - Sennoside A (SA), the main purgative constituent of Daiokanzoto (da-huang-gan-cao tang; DKT), is generally regarded as a prodrug that is transformed into an active metabolite by beta-glucosidase derived from Bifidobacterium spp. It has been suggested that antibiotics would promote dysbiosis, and thereby inhibit the purgative activity of DKT. In this study, ampicillin was administered to mice for 8 d, and the changes in the SA metabolism of SA alone and of DKT were investigated. The results showed that the SA metabolism of SA singly continued to be inhibited by ampicillin, but that of DKT was activated from day 3 under the same conditions. In order to investigate the mechanism of SA metabolism activated by DKT in the mice administered ampicillin, changes in the SA metabolism were observed in the presence of rhein 8-O-beta-D-glucopyranoside (RG) in rhubarb and liquiritin in glycyrrhiza, both of which accelerated the SA metabolism. In fact, RG achieved an activation of SA metabolism similar to that by DKT. The purgative action of DKT, which was continued treatment of the ampicillin, was significantly greater than that by SA alone, and it was shown that RG was involved in this effect. We also analyzed changes in the intestinal microbiota before and after administration of ampicillin. No Bifidobacteria were detected throughout the treatment, but the population of Bacteroides was significantly increased after 3 d under the same conditions. Taken together, these results strongly suggested that the RG in DKT changed the function of Bacteroides and thereby allowed DKT to metabolize SA. PMID- 26934930 TI - Mechanisms Underlying Enhanced Noradrenaline-Induced Femoral Arterial Contractions of Spontaneously Hypertensive Rats: Involvement of Endothelium Derived Factors and Cyclooxygenase-Derived Prostanoids. AB - We investigated the relationship between noradrenaline (NAd)-induced contractions, endothelial function, and hypertension in femoral arteries isolated from spontaneously hypertensive rats (SHR). In the femoral arteries of SHR, vs. age-matched control Wistar Kyoto (WKY) rats, contractions induced by NAd were increased. These effects were enhanced by endothelial denudation, which abolished the differences between the two groups. NAd-induced contractions were enhanced by nitric oxide (NO) synthase inhibition, and further increased by the blockade of endothelium-derived hyperpolarizing factor (EDHF). Conversely, NAd-induced contractions were inhibited by cyclooxygenase (COX) inhibition. In addition, in SHR arteries, acetylcholine-induced relaxation was reduced, and components of endothelium-derived factors were altered, such as increased COX-derived vasoconstrictor prostanoids, reduced EDHF, and preserved NO-mediated relaxation. In the femoral arteries of SHR, the production of prostanoids [6-keto prostaglandin (PG)F1alpha (a metabolite of prostacyclin (PGI2), PGE2, and PGF2alpha] and COX-2 protein were increased compared with that in WKY rats. By contrast, contractions induced by beraprost (a stable PGI2 analogue), PGE2, and U46619 (thromboxane/prostanoid receptor agonist) were similar between the SHR and WKY groups. Thus, NAd-induced femoral arterial contractions are augmented in SHR resulting from endothelial dysfunction and increased COX-derived vasoconstrictor prostanoid levels. PMID- 26934931 TI - Comparison of Air Pollution in Metropolises in China (Beijing) and Japan (Osaka and Nagoya) on the Basis of the Levels of Contaminants and Mutagenicity. AB - Public concern regarding the transport of air pollutants from mainland East Asia to the leeward area by the prevailing westerlies in spring and winter monsoon has been growing in recent years. We collected total suspended particle (TSP) in Beijing, a metropolis of China located windward of Japan, in spring (late February 2011-May 2011) and in winter (November 2012-early February 2013), then analyzed metals, ions, and organic compounds and mutagenicity, and compared the pollution levels with samples collected at two Japanese metropolises (Osaka and Nagoya) during the same periods. The medians of concentration of TSP and other factors in Beijing were much larger than those in the Japanese metropolises. Especially, the concentrations of polycyclic aromatic hydrocarbons (PAHs) were remarkably high in Beijing in winter, and the median of total PAHs concentration in Beijing was 62-63 times larger than that in the Japanese sites. The mutagenicity of TSP from Beijing toward Salmonella typhimurium YG1024, with and without a mammalian metabolic system (S9 mix), was 13-25 times higher than that from the Japanese sites in winter. These results suggest that air pollution levels in Beijing are very high compared with those at the two Japanese metropolises we evaluated. The diagnostic ratios of PAHs and nitrated polycyclic aromatic hydrocarbons (NPAHs) suggest that the major sources of PAHs and NPAHs in Beijing are different from those at the two Japanese sites in winter, and that the major source in Beijing is coal/biomass combustion. PMID- 26934932 TI - Development and Clinical Evaluation of New Topical Anesthetic Formulations for Dental Care. AB - To provide safe dental care, it is important to minimize the pain associated with the initial injection of the local anesthetic. For this purpose, a topical anesthetic is preliminarily applied to the area where a needle will be inserted in a clinical setting. In this study, we prepared new topical anesthetic formulations with favorable intra-oral retentivity and an excellent anesthetic effect, and clinically evaluated their efficacy. We used 4% lidocaine solution as an anesthetic drug and gelatin, agar, and a food thickener as a base to prepare new topical anesthetic formulations. The subjects rested in a supine position on a chair for dental practice prior to the following experiments. Firstly, about 0.2 g of the sample was applied at a test site. One minute later, the sample was removed, and a 30 G dental injection needle was inserted into the test site. The agar/gelatin-based formulation containing gelatin of 2% and agar of 1% had a moderate solidity at 25 degrees C and a moderate fluidity at 37 degrees C. This formulation showed a significantly greater depth than any of the commercially available topical anesthetics. The results of the present study demonstrated that the agar/gelatin-based formulation showed an excellent analgesic effect against pain associated with needle insertion. PMID- 26934933 TI - Absorption and Urinary Excretion of Peptides after Collagen Tripeptide Ingestion in Humans. AB - Collagen tripeptide (CTP) is a collagen hydrolysate containing a high concentration of tripeptides with a Gly-X-Y sequence, such as Gly-Pro-Hyp. To test the effects of this preparation, we compared the absorption of peptides in humans after ingestion of a tripeptide fraction of CTP (CTP-100), a CTP preparation containing ca. 50% Gly-X-Y tripeptides (CTP-50), and a collagen peptide that did not contain tripeptides (CP). The postprandial levels of Gly-Pro Hyp and Pro-Hyp in the plasma increased in those subjects who ingested CTP-100 and CTP-50, and were higher with greater Gly-Pro-Hyp ingestion. This demonstrated that collagen hydrolysates were efficiently absorbed when the collagen was ingested in the tripeptide form. Gly-Pro-Hyp and Pro-Hyp were also found in the urine after ingestion of CTP-100 or CTP-50. Similar to the results for the plasma concentration, the urinary excretion of Gly-Pro-Hyp and Pro-Hyp was also dependent on the amount of Gly-Pro-Hyp ingested. This indicates that ingested Gly Pro-Hyp and generated Pro-Hyp were relatively stable in the body and were transported to the urine in the peptide form. The concentration of Hyp-Gly in the plasma was low after the ingestion of CP and CTP-100 but higher after the ingestion of CTP-50. Overall, our results suggest that tripeptides derived from collagen are absorbed efficiently by the body. PMID- 26934934 TI - Soluble Human Intestinal Lactoferrin Receptor: Ca(2+)-Dependent Binding to Sepharose-Based Matrices. AB - A soluble form of human intestinal lactoferrin receptor (shLFR) is identical to human intelectin-1 (hITLN-1), a galactofuranose-binding protein that acts as a host defense against invading pathogenic microorganisms. We found that recombinant shLFR, expressed in mammalian cells (CHO DG44, COS-1, and RK13), binds tightly to Sepharose 4 Fast Flow (FF)-based matrices in a Ca(2+)-dependent manner. This binding of shLFR to Sepharose 4 FF-based matrices was inhibited by excess D-galactose, but not by D-glucose, suggesting that shLFR recognizes repeating units of alpha-1,6-linked D-galactose in Sepharose 4 FF. Furthermore, shLFR could bind to both Sepharose 4B- and Sepharose 6B-based matrices that were not crosslinked in a similar manner as to Sepharose 4 FF-based matrices. Therefore, shLFR (hITLN-1) binds to Sepharose-based matrices in a Ca(2+) dependent manner. This binding property is most likely related to the ability, as host defense lectins, to recognize sepharose (agarobiose)-like structures present on the surface of invading pathogenic microorganisms. PMID- 26934935 TI - Effect of Complexin II on Membrane Fusion between Liposomes Containing Mast Cell SNARE Proteins. AB - Mast cells are involved in allergic responses and undergo exocytotic release of inflammatory mediators in response to antigen stimulation. Soluble N ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins are involved in this membrane fusion process; some SNARE-binding proteins regulate SNARE-dependent liposome membrane fusion. SNARE-binding protein complexin II is expressed in mast cells, where it positively regulates exocytotic release after antigen stimulation. We found that complexin II suppressed SNARE-dependent membrane fusion between mast cell SNARE-containing liposomes. This inhibitory effect of complexin II was abolished when we used a structurally divergent mutant (R59H) complexin II, where Arg59 is substituted with histidine. These results suggest that complexin II negatively regulates SNARE-dependent exocytotic membrane fusion in mast cells, and this inhibitory effect is dependent upon Arg59. PMID- 26934936 TI - Mass Spectrometric Characterization of HIV-1 Reverse Transcriptase Interactions with Non-nucleoside Reverse Transcriptase Inhibitors. AB - Non-nucleoside reverse transcriptase inhibitors (NNRTIs) of human immunodeficiency virus type 1 reverse transcriptase (HIV-1 RT) have been developed for the treatment of acquired immunodeficiency syndrome. HIV-1 RT binding to NNRTIs has been characterized by various biophysical techniques. However, these techniques are often hampered by the low water solubility of the inhibitors, such as the current promising diarylpyrimidine-based inhibitors rilpivirine and etravirine. Hence, a conventional and rapid method that requires small sample amounts is desirable for studying NNRTIs with low water solubility. Here we successfully applied a recently developed mass spectrometric technique under non-denaturing conditions to characterize the interactions between the heterodimeric HIV-1 RT enzyme and NNRTIs with different inhibitory activities. Our data demonstrate that mass spectrometry serves as a semi-quantitative indicator of NNRTI binding affinity for HIV-1 RT using low and small amounts of samples, offering a new high-throughput screening tool for identifying novel RT inhibitors as anti-HIV drugs. PMID- 26934937 TI - Errata for Biological and Pharmaceutical Bulletin. PMID- 26934938 TI - Silencing of CerS6 increases the invasion and glycolysis of melanoma WM35, WM451 and SK28 cell lines via increased GLUT1-induced downregulation of WNT5A. AB - Ceramide synthases (CerSs) have been shown to regulate numerous aspects of cancer development. CerS6 has been suggested to be involved in cancer etiology. However, little is known concerning the exact effect of CerS6 on the malignant behavior of melanoma, including glycolysis, proliferation and invasion. In the present study, we found that the expression of CerS6 was low in the melanoma cell lines, including WM35, WM451 and SK-28, and the expression level was related to the malignanct behavior of the melanoma cell lines. We constructed overexpression and silencing models of CerS6 in three melanoma cell lines and found that silencing of CerS6 promoted the ability of proliferation and invasion in the melanoma cell lines. Additionally, downregulation of CerS6 upregulated the activity of glycolysis-related enzyme, and enhanced the expression of glycolysis-related genes, including GLUT1 and MCT1. Furthermore, we identified the genes whose expression levels were changed after silencing of CerS6 by gene microarray. The expression of glycolysis-related gene SLC2A1 (also known as GLUT1) was found to be upregulated, while notably WNT5A was downregulated. The altered expression of GLUT1 and WNT5A was verified by qPCR and western blotting. Furthermore, silencing of GLUT1 in the melanoma cells resulted in the increased expression of WNT5A and the decreased ability of invasion and proliferation in the melanoma cells. Collectively, silencing of CerS6 induced the increased expression of GLUT1, which downregulated the expression of WNT5A and enhanced the invasion and proliferation of melanoma cells. Thus, CerS6 may provide a novel therapeutic target for melanoma treatment. PMID- 26934939 TI - Filaggrin-null mutations are associated with increased maturation markers on Langerhans cells. AB - BACKGROUND: Mutations in the gene encoding filaggrin (FLG), an epidermal structural protein, are the strongest risk factor identified for the development of atopic dermatitis (AD). Up to 50% of patients with moderate-to-severe AD in European populations have FLG-null alleles compared with a general population frequency of 7% to 10%. OBJECTIVE: This study aimed to investigate the relationship between FLG-null mutations and epidermal antigen-presenting cell (APC) maturation in subjects with and without AD. Additionally, we investigated whether the cis isomer of urocanic acid (UCA), a filaggrin breakdown product, exerts immunomodulatory effects on dendritic cells. METHODS: Epidermal APCs from nonlesional skin were assessed by using flow cytometry (n = 27) and confocal microscopy (n = 16). Monocyte-derived dendritic cells from healthy volunteers were used to assess the effects of cis- and trans-UCA on dendritic cell phenotype by using flow cytometry (n = 11). RESULTS: Epidermal APCs from FLG-null subjects had increased CD11c expression. Confocal microscopy confirmed this and additionally revealed an increased number of epidermal CD83(+) Langerhans cells in FLG-null subjects. In vitro differentiation in the presence of cis-UCA significantly reduced costimulatory molecule expression on monocyte-derived dendritic cells from healthy volunteers and increased their ability to induce a regulatory T-cell phenotype in mixed lymphocyte reactions. CONCLUSIONS: We show that subjects with FLG-null mutations have more mature Langerhans cells in nonlesional skin irrespective of whether they have AD. We also demonstrate that cis-UCA reduces maturation of dendritic cells and increases their capacity to induce regulatory T cells, suggesting a novel link between filaggrin deficiency and immune dysregulation. PMID- 26934940 TI - In vitro and in vivo magnetic resonance imaging with chlorotoxin-conjugated superparamagnetic nanoprobes for targeting hepatocarcinoma. AB - The present study aimed to assess the in vitro and in vivo magnetic resonance imaging (MRI) features of chlorotoxin (CTX)-conjugated superparamagnetic iron oxide (SPIO) nanoprobes. CTX-conjugated nanoprobes were composed of SPIO coated with polyethylene glycol (PEG) and conjugated with CTX. The nanoprobes were termed SPIO-PEG-CTX. MRI of the SPIO and SPIO-PEG-CTX solutions at a different concentration was performed with a 3.0-T MRI scanner (Philips Achieva 3.0T X Series; Phillips Healthcare, The Netherlands). Rabbit VX2 hepatocarcinoma was established by a traditional laparotomy method (injection of the tumor particles into the liver using a 15G syringe needle) following approval by the institutional animal care and use committee. Contrast-enhanced MRI of VX2 rabbits (n=8) was performed using the same MRI scanner with SPIO-PEG-CTX solutions as the contrast agent. Data were analyzed with calibration curve and a paired t-test. The SPIO-PEG-CTX nanoparticles were successfully prepared. With increasing concentrations of the solutions, the MRI signal intensity was increased at T1WI, but decreased at T2WI, which were the same as that for SPIO. Rabbit VX2 carcinoma appeared as a low MRI signal at T1WI, and high at T2WI. After injection of the contrast agent, the MRI signal of carcinoma was decreased relative to that before injection at T2WI (1,161+/-331.5 vs. 1,346+/-300.5; P=0.004<0.05), while the signal of the adjacent normal hepatic tissues was unchanged (480.6+/-165.1 vs. 563.4+/-67.8; P=0.202>0.05). The SPIO-PEG-CTX nanoparticles showed MRI negative enhancement at T2WI and a targeting effect in liver cancer, which provides the theoretical basis for further study of the early diagnosis of hepatocellular carcinoma. PMID- 26934941 TI - Gradual withdrawal of remifentanil infusion may prevent opioid-induced hyperalgesia. AB - BACKGROUND: The aim of this study was to examine if gradual withdrawal of remifentanil infusion prevented opioid-induced hyperalgesia (OIH) as opposed to abrupt withdrawal. OIH duration was also evaluated. METHODS: Nineteen volunteers were enrolled in this randomized, double-blinded, placebo-controlled, crossover study. All went through three sessions: abrupt or gradual withdrawal of remifentanil infusion and placebo. Remifentanil was administered at 2.5 ng ml(-1) for 30 min before abrupt withdrawal or gradual withdrawal by 0.6 ng ml(-1) every five min. Pain was assessed at baseline, during infusion, 45-50 min and 105-110 min after end of infusions using the heat pain test (HPT) and the cold pressor test (CPT). RESULTS: The HPT 45 min after infusion indicated OIH development in the abrupt withdrawal session with higher pain scores compared with the gradual withdrawal and placebo sessions (both P<0.01. Marginal mean scores: placebo 2.90; abrupt 3.39; gradual 2.88), but no OIH after gradual withdrawal compared with placebo (P=0.93). In the CPT 50 min after end of infusion there was OIH in both remifentanil sessions compared with placebo (gradual P=0.01, abrupt P<0.01. Marginal mean scores: placebo 4.56; abrupt 5.25; gradual 5.04). There were no differences between the three sessions 105-110 min after infusion. CONCLUSIONS: We found no development of OIH after gradual withdrawal of remifentanil infusion in the HPT. After abrupt withdrawal OIH was present in the HPT. In the CPT there was OIH after both gradual and abrupt withdrawal of infusion. The duration of OIH was less than 105 min for both pain modalities. CLINICAL TRIAL REGISTRATION: NCT 01702389. EudraCT number 2011-002734-39. PMID- 26934942 TI - Comparison between thrombelastography and thromboelastometry in hyperfibrinolysis detection during adult liver transplantation. AB - BACKGROUND: Hyperfibrinolysis is one of the main causes of non-surgical bleeding during liver transplantation (LT). Viscoelastic haemostatic assays, including thromboelastometry (ROTEM((r))) and thrombelastography (TEG((r))), can detect hyperfibrinolysis at the bedside. No study has yet demonstrated which device or assay is more suitable for detecting hyperfibrinolysis. METHODS: This prospective observational study compared ROTEM((r)) and TEG((r)) in isolated adult LT. ROTEM((r)) (EXTEM((r)) [tissue factor activation], FIBTEM((r)) [tissue factor activation with platelet inhibition], and APTEM((r)) [tissue factor activation with tranexamic acid/aprotinin]) and TEG((r)) (kaolin-TEG((r))) were simultaneously performed using arterial blood samples at eight time-points during LT: induction of general anaesthesia, 60 min after skin incision, 10 and 45 min after portal vein clamp, 15 min before graft reperfusion, and five, 30, and 90 min after graft reperfusion. Hyperfibrinolysis was identified per the manufacturers' definitions (maximum lysis >15% in ROTEM((r)) or Lysis30>8% in TEG((r))) and confirmed with APTEM((r)); incidence was compared between assays McNemar's test. RESULTS: Among 296 possible measurement points from 376 consecutive LT recipients, 250 underwent final analysis: 46 measurement points were excluded because of missing assays or flat line. Hyperfibrinolysis was confirmed at 89 (36%) of 250 measurement points: FIBTEM((r)), EXTEM((r)), and kaolin-TEG((r)) detected 84 (94%), 41 (46%), and 21 (24%) hyperfibrinolysis, respectively. These hyperfibrinolysis detection rates significantly differed from each other (P<0.001). CONCLUSIONS: Tissue factor-triggered ROTEM((r)) tests were more sensitive than contact-activated k-TEG((r)) in identifying hyperfibrinolysis in LT patients. Inhibition of platelet-fibrin interaction in FIBTEM((r)) enhanced sensitivity to hyperfibrinolysis detection compared with EXTEM((r)). PMID- 26934943 TI - Are neuromuscular blocking agents being misused in laboratory pigs? AB - The literature (2012-4) describing experimental pig surgery was reviewed to estimate the extent to which neuromuscular block (NMB) is used, to examine methods for ensuring unconsciousness, and to identify the rationale for use of NMB and establish the anaesthetist's training. In the first stage of a two-stage review, NMB use was estimated using Web of Knowledge to identify articles describing NMB during pig surgeries. In the second stage, PubMed and Google Scholar were used to increase the number of articles for determining measures taken to prevent accidental awareness during general anaesthesia (AAGA). The corresponding authors of screened articles were emailed four times to establish the reason for using NMB and the anaesthetists' backgrounds (medical, veterinary, or technical). The first search revealed NMB use in 80 of 411 (20%) studies. Of the 153 articles analysed in the second stage, two described strategies to reduce AAGA. Some (6%) papers did not provide information on anaesthetic doses; citations supporting anaesthetic efficacy were found in only 13. Five of 69 papers using inhalation agents measured end-tidal anaesthetic concentrations based on human, not porcine, minimal alveolar concentrations. The methods in 13% of articles reporting anaesthetic depth assessment were incomplete or questionable, or both; four described using somatic motor reflexes. Corresponding authors of 121 articles reported that the principal reason for NMB was improved 'surgical visualization' (26%). Medical or veterinary anaesthetists supervised anaesthesia in 70% of studies; non-anaesthetists provided NMB, unsupervised, in 23. Nine respondents prioritized experimental expediency over pig welfare. In laboratory pig studies, AAGA may be prevalent; reported details of its attempted prevention are woefully inadequate. PMID- 26934944 TI - Feasibility of a 'reversed' isolated forearm technique by regional antagonization of rocuronium-induced neuromuscular block: a pilot study. AB - BACKGROUND: The isolated forearm technique is used to monitor intraoperative awareness. However, this technique cannot be applied to patients who must be kept deeply paralysed for >1h, because the tourniquet preventing the neuromuscular blocking agent from paralysing the forearm must be deflated from time to time. To overcome this problem, we tested the feasibility of a 'reversed' isolated forearm technique. METHODS: Patients received rocuronium 0.6 mg kg(-1) i.v. to achieve muscle paralysis. A tourniquet was then inflated around one upper arm to prevent further blood supply to the forearm. Sugammadex was injected into a vein of this isolated forearm to antagonize muscle paralysis regionally. A dose titration of sugammadex to antagonize muscle paralysis in the isolated forearm was performed in 10 patients, and the effects of the selected dose were observed in 10 additional patients. RESULTS: The sugammadex dose required to antagonize muscle paralysis in the isolated forearm was 0.03 mg kg(-1) in 30 ml of 0.9% saline. Muscle paralysis was antagonized in the isolated forearm within 3.2 min in nine of 10 patients; the rest of the patients' bodies remained paralysed. Releasing the tourniquet 15 min later did not affect the train-of-four count in the isolated forearm but significantly increased the train-of-four count in the other arm by 7%. CONCLUSIONS: Regional antagonization of rocuronium-induced muscle paralysis using a sugammadex dose of 0.03 mg kg(-1) injected into an isolated forearm was feasible and did not have relevant systemic effects. CLINICAL TRIAL REGISTRATION: The trial was registered at EudraCT (ref. no. 2013-002164-53) before patient enrolment began. PMID- 26934945 TI - Factors influencing the initiation of intensive care in elderly patients and their families: A retrospective cohort study. AB - BACKGROUND: The number of elderly patients admitted to the intensive care unit is constantly growing. However, a decision regarding intensive care in these populations remains a challenge. AIM: To identify factors that influences the decision of elderly patients and their families about whether to initiate intensive care in case of an acute event. DESIGN/PARTICIPANTS: Medical records of patients (>80 years), who were admitted to general wards and referred for intensive care, were retrospectively reviewed. Patients who received intensive care were compared with those not agreeing to the initiation of intensive care. RESULTS: Among the 125 patients, 45 agreed to receiving intensive care. Baseline characteristics at the time of intensive care unit referral were similar between the intensive care and non-intensive care groups. Only one patient had advance directives before the intensive care unit referral. Lower economic status (odds ratio = 0.27, 95% confidence interval = 0.08-0.94) and cognitive impairment (odds ratio = 0.20, 95% confidence interval = 0.07-0.56) were found associated with a lower likelihood of agreeing to intensive care, while a large number of participants involved in the decision-making process were associated with a higher likelihood of intensive care unit use (odds ratio = 1.82, 95% confidence interval = 1.08-3.09). Mean duration of hospital stay was longer for the intensive care group as compared with the non-intensive care group (28.8 days and 19.8 days, respectively, p = 0.03). However, there was no significant difference in the survival rate. CONCLUSION: The initiation of intensive care in elderly patients was influenced not only by medical conditions but also by the patient's economic status and the number of family members involved in the decision-making process. PMID- 26934946 TI - End-of-life care for HIV-infected patients with malignancies: A questionnaire based survey. AB - BACKGROUND: The number of HIV-infected patients who require palliative or end-of life care is increasing, and the status of end-of-life care for HIV patients with malignancies is unclear. AIM: This study aimed to evaluate the end-of-life care provided to HIV patients with malignancies in Japan. DESIGN: National cross sectional questionnaire-based survey. SETTING/PARTICIPANTS: Questionnaires were delivered to the medical staff of 378 regional core hospitals/core hospitals for AIDS and 285 palliative care units in Japan. Data were collected between August and October 2013. RESULTS: Overall, 226 regional core hospitals/core hospitals for AIDS (59.8%) responded. A total of 55 institutions (24.3%) provided end-of life care to HIV patients with malignancies. Regarding the place of death of the patients, 69.1% died at the institution whereas 18.2% were transferred to palliative care units. The requests of 16 (29.1%) institutions to transfer patients to palliative care units were rejected. Of the 378 palliative care units, 179 (62.8%) responded. While 13 palliative care units (4.6%) provided care to hospitalized HIV patients with malignancies, 20 (11.2%) refused to accept these patients for treatment because of a lack of experience in treating these patients and a lack of knowledge regarding HIV infection. CONCLUSION: Our findings suggest that in Japan, HIV patients with malignancies have difficulties obtaining hospitalization at a palliative care unit, which is likely due to a lack of experience among the professionals in treating such patients as well as a lack of knowledge about HIV. PMID- 26934947 TI - A descriptive report of end-of-life care practices occurring in two neonatal intensive care units. AB - BACKGROUND: In Canada and other developed countries, the majority of neonatal deaths occur in tertiary neonatal intensive care units. Most deaths occur following the withdrawal of life-sustaining treatments. AIM: To explore neonatal death events and end-of-life care practices in two tertiary neonatal intensive care settings. DESIGN: A structured, retrospective, cohort study. SETTING/PARTICIPANTS: All infants who died under tertiary neonatal intensive care from January 2009 to December 2013 in a regional Canadian neonatal program. Deaths occurring outside the neonatal intensive care unit in delivery rooms, hospital wards, or family homes were not included. Overall, 227 infant deaths were identified. RESULTS: The most common reasons for admission included prematurity (53.7%), prematurity with congenital anomaly/syndrome (20.3%), term congenital anomaly (11.5%), and hypoxic ischemic encephalopathy (12.3%). The median age at death was 7 days. Death tended to follow a decision to withdraw life-sustaining treatment with anticipated poor developmental outcome or perceived quality of life, or in the context of a moribund dying infant. Time to death after withdrawal of life-sustaining treatment was uncommonly a protracted event but did vary widely. Most dying infants were held by family members in the neonatal intensive care unit or in a parent room off cardiorespiratory monitors. Analgesic and sedative medications were variably given and not associated with a hastening of death. CONCLUSION: Variability exists in end-of-life care practices such as provision of analgesic and sedative medications. Other practices such as discontinuation of cardiorespiratory monitors and use of parent rooms are more uniform. More research is needed to understand variation in neonatal end-of-life care. PMID- 26934948 TI - Measuring healthcare integration: Operationalization of a framework for a systems evaluation of palliative care structures, processes, and outcomes. AB - BACKGROUND: Healthcare integration is a priority in many countries, yet there remains little direction on how to systematically evaluate this construct to inform further development. The examination of community-based palliative care networks provides an ideal opportunity for the advancement of integration measures, in consideration of how fundamental provider cohesion is to effective care at end of life. AIM: This article presents a variable-oriented analysis from a theory-based case study of a palliative care network to help bridge the knowledge gap in integration measurement. DESIGN: Data from a mixed-methods case study were mapped to a conceptual framework for evaluating integrated palliative care and a visual array depicting the extent of key factors in the represented palliative care network was formulated. SETTING/PARTICIPANTS: The study included data from 21 palliative care network administrators, 86 healthcare professionals, and 111 family caregivers, all from an established palliative care network in Ontario, Canada. RESULTS: The framework used to guide this research proved useful in assessing qualities of integration and functioning in the palliative care network. The resulting visual array of elements illustrates that while this network performed relatively well at the multiple levels considered, room for improvement exists, particularly in terms of interventions that could facilitate the sharing of information. CONCLUSION: This study, along with the other evaluative examples mentioned, represents important initial attempts at empirically and comprehensively examining network-integrated palliative care and healthcare integration in general. PMID- 26934949 TI - Apr3 accelerates the senescence of human retinal pigment epithelial cells. AB - Senescence of retinal pigment epithelium (RPE) cells is a major contributor to age-related macular degeneration (AMD). However, the molecular mechanisms underlying RPE dysfunction are not well understood. Apoptosis related protein 3 (Apr3) was originally cloned from HL-60 cells induced by all-trans retinoic acid (ATRA). Preliminary data revealed elevated Apr3 expression in the tissues of aged mice, suggesting that it is involved in the aging process. The present study demonstrated that Apr3 mRNA and protein levels were markedly increased in aged mouse RPE cells. Elevated Apr3 expression was also observed during premature senescence induced by oxidative stress (H2O2 and tert-BHP) in ARPE-19 cells. Moreover, Apr3 overexpression promoted cellular senescence in ARPE-19 cells, as characterized by enhanced senescence-associated beta-galactosidase activity, reduced cell proliferation and increased expression of the senescence markers p53 and p21. In addition, it was demonstrated that overexpression of Apr3-N, a truncated counterpart of Apr3, abrogated Apr3-induced phenotypes. It was concluded that Apr3 expression was induced in replicative and premature senescence of RPE cells and its overexpression accelerated senescence of ARPE-19 cells, which provides important insights into the function of Apr3 in senescence associated diseases. PMID- 26934950 TI - VEGF-C and TGF-beta reciprocally regulate mesenchymal stem cell commitment to differentiation into lymphatic endothelial or osteoblastic phenotypes. AB - The direction of mesenchymal stem cell (MSC) differentiation is regulated by stimulation with various growth factors and cytokines. We recently established MSC lines, [transforming growth factor-beta (TGF-beta)-responsive SG-2 cells, bone morphogenetic protein (BMP)-responsive SG-3 cells, and TGF-beta/BMP-non responsive SG-5 cells], derived from the bone marrow of green fluorescent protein transgenic mice. In this study, to compare gene expression profiles in these MSC lines, we used DNA microarray analysis to characterize the specific gene expression profiles observed in the TGF-beta-responsive SG-2 cells. Among the genes that were highly expressed in the SG-2 cells, we focused on vascular endothelial growth factor (VEGF) receptor 3 (VEGFR3), the gene product of FMS like tyrosine kinase 4 (Flt4). We found that VEGF-C, a specific ligand of VEGFR3, significantly induced the cell proliferative activity, migratory ability (as shown by Transwell migration assay), as well as the phosphorylation of extracellular signal-regulated kinase (ERK)1/2 in the SG-2 cells. Additionally, VEGF-C significantly increased the expression of prospero homeobox 1 (Prox1) and lymphatic vessel endothelial hyaluronan receptor 1 (Lyve1), which are lymphatic endothelial cell markers, and decreased the expression of osteogenic differentiation marker genes in these cells. By contrast, TGF-beta significantly increased the expression of early-phase osteogenic differentiation marker genes in the SG-2 cells and markedly decreased the expression of lymphatic endothelial cell markers. The findings of our study strongly suggest the following: i) that VEGF-C promotes the proliferative activity and migratory ability of MSCs; and ii) VEGF-C and TGF-beta reciprocally regulate MSC commitment to differentiation into lymphatic endothelial or osteoblastic phenotypes, respectively. Our findings provide new insight into the molecular mechanisms underlying the regenerative ability of MSCs. PMID- 26934951 TI - Impact of anti-inflammatory nutrients on obesity-associated metabolic inflammation from childhood through to adulthood. AB - Obesity-related metabolic conditions such as insulin resistance (IR), type 2 diabetes and CVD share a number of pathological features, one of which is metabolic-inflammation. Metabolic-inflammation results from the infiltration of immune cells into the adipose tissue, driving a pro-inflammatory environment, which can induce IR. Furthermore, resolution of inflammation, an active process wherein the immune system counteracts pro-inflammatory states, may be dysregulated in obesity. Anti-inflammatory nutritional interventions have focused on attenuating this pro-inflammatory environment. Furthermore, with inherent variability among individuals, establishing at-risk populations who respond favourably to nutritional intervention strategies is important. This review will focus on chronic low-grade metabolic-inflammation, resolution of inflammation and the putative role anti-inflammatory nutrients have as a potential therapy. Finally, in the context of personalised nutrition, the approaches used in defining individuals who respond favourably to nutritional interventions will be highlighted. With increasing prevalence of obesity in younger people, age dependent biological processes, preventative strategies and therapeutic options are important to help protect against development of obesity-associated co morbidities. PMID- 26934952 TI - To Grow or not to Grow? AB - The seed to seedling transition in plants is initiated following the termination of seed dormancy. Here, I present a simplified developmental framework describing the events underlying this transition. I discuss putative mechanisms of signal integration and their relation to a global developmental fate switch in seeds within this framework. I delineate the events that occur before and after the flipping of this switch, marking an important distinction between these different developmental states. To end, I propose that the final fate switch resides within the embryo, and is informed by the endosperm in arabidopsis (Arabidopsis thaliana). This framework can serve as a template to focus future research in seed science. PMID- 26934953 TI - Polydatin-induced cell apoptosis and cell cycle arrest are potentiated by Janus kinase 2 inhibition in leukemia cells. AB - Polydatin (PD), a natural precursor of resveratrol, has a variety of biological activities, including anti-tumor effects. However, the underlying molecular mechanisms of the anti-cancer activity of PD has not been fully elucidated. The present study demonstrated that PD significantly inhibited the proliferation of the MOLT-4 leukemia cell line in a dose- and time-dependent manner by using Cell Counting Kit-8 assay. PD also dose-dependently increased the apoptotic rate and caused cell cycle arrest in S phase in MOLT-4 cells, as revealed by flow cytometry. In addition, PD dose-dependently decreased the mitochondrial membrane potential and led to the generation of reactive oxygen species in MOLT-4 cells. Western blot analysis revealed that the expression of anti-apoptotic protein B cell lymphoma 2 (Bcl-2) was decreased, whereas that of pro-apoptotic protein Bcl 2-associated X was increased by PD. Furthermore, the expression of two cell cycle regulatory proteins, cyclin D1 and cyclin B1, was suppressed by PD. Of note, the pro-apoptotic and cell cycle-inhibitory effects of PD were potentiated by Janus kinase 2 (JAK2) inhibition. In conclusion, the results of the present study strongly suggested that PD is a promising therapeutic compound for the treatment of leukemia, particularly in combination with JAK inhibitors. PMID- 26934954 TI - Skyrmion Creation and Manipulation by Nano-Second Current Pulses. AB - Easy creation and manipulation of skyrmions is important in skyrmion based devices for data storage and information processing. We show that a nano-second current pulse alone is capable of creating/deleting and manipulating skyrmions in a spin valve with a perpendicularly magnetized free layer and broken chiral symmetry. Interestingly, for an in-plane magnetized fixed layer, the free layer changes from a single domain at zero current to a Neel wall at an intermediate current density. Reverse the current polarity, the Neel wall changes to its image inversion. A properly designed nano-second current pulse, that tends to convert one type of Neel walls to its image inversion, ends up to create a stable skyrmion without assistance of external fields. For a perpendicularly magnetized fixed layer, the skyrmion size can be effectively tuned by a current density. PMID- 26934956 TI - Extended string-like binding of the phosphorylated HP1alpha N-terminal tail to the lysine 9-methylated histone H3 tail. AB - The chromodomain of HP1alpha binds directly to lysine 9-methylated histone H3 (H3K9me). This interaction is enhanced by phosphorylation of serine residues in the N-terminal tail of HP1alpha by unknown mechanism. Here we show that phosphorylation modulates flexibility of HP1alpha's N-terminal tail, which strengthens the interaction with H3. NMR analysis of HP1alpha's chromodomain with N-terminal tail reveals that phosphorylation does not change the overall tertiary structure, but apparently reduces the tail dynamics. Small angle X-ray scattering confirms that phosphorylation contributes to extending HP1alpha's N-terminal tail. Systematic analysis using deletion mutants and replica exchange molecular dynamics simulations indicate that the phosphorylated serines and following acidic segment behave like an extended string and dynamically bind to H3 basic residues; without phosphorylation, the most N-terminal basic segment of HP1alpha inhibits interaction of the acidic segment with H3. Thus, the dynamic string-like behavior of HP1alpha's N-terminal tail underlies the enhancement in H3 binding due to phosphorylation. PMID- 26934957 TI - Integrated Molecular Profiling of Human Gastric Cancer Identifies DDR2 as a Potential Regulator of Peritoneal Dissemination. AB - Peritoneal dissemination is the most frequent, incurable metastasis occurring in patients with advanced gastric cancer (GC). However, molecular mechanisms driving peritoneal dissemination still remain poorly understood. Here, we aimed to provide novel insights into the molecular mechanisms that drive the peritoneal dissemination of GC. We performed combined expression analysis with in vivo selected metastatic cell lines and samples from 200 GC patients to identify driver genes of peritoneal dissemination. The driver-gene functions associated with GC dissemination were examined using a mouse xenograft model. We identified a peritoneal dissemination-associated expression signature, whose profile correlated with those of genes related to development, focal adhesion, and the extracellular matrix. Among the genes comprising the expression signature, we identified that discoidin-domain receptor 2 (DDR2) as a potential regulator of peritoneal dissemination. The DDR2 was upregulated by the loss of DNA methylation and that DDR2 knockdown reduced peritoneal metastasis in a xenograft model. Dasatinib, an inhibitor of the DDR2 signaling pathway, effectively suppressed peritoneal dissemination. DDR2 was identified as a driver gene for GC dissemination from the combined expression signature and can potentially serve as a novel therapeutic target for inhibiting GC peritoneal dissemination. PMID- 26934955 TI - Diversity of Dopaminergic Neural Circuits in Response to Drug Exposure. AB - Addictive substances are known to increase dopaminergic signaling in the mesocorticolimbic system. The origin of this dopamine (DA) signaling originates in the ventral tegmental area (VTA), which sends afferents to various targets, including the nucleus accumbens, the medial prefrontal cortex, and the basolateral amygdala. VTA DA neurons mediate stimuli saliency and goal-directed behaviors. These neurons undergo robust drug-induced intrinsic and extrinsic synaptic mechanisms following acute and chronic drug exposure, which are part of brain-wide adaptations that ultimately lead to the transition into a drug dependent state. Interestingly, recent investigations of the differential subpopulations of VTA DA neurons have revealed projection-specific functional roles in mediating reward, aversion, and stress. It is now critical to view drug induced neuroadaptations from a circuit-level perspective to gain insight into how differential dopaminergic adaptations and signaling to targets of the mesocorticolimbic system mediates drug reward. This review hopes to describe the projection-specific intrinsic characteristics of these subpopulations, the differential afferent inputs onto these VTA DA neuron subpopulations, and consolidate findings of drug-induced plasticity of VTA DA neurons and highlight the importance of future projection-based studies of this system. PMID- 26934958 TI - Toll-like Receptor 9 Can be Activated by Endogenous Mitochondrial DNA to Induce Podocyte Apoptosis. AB - Toll-like receptor 9 (TLR9) senses bacterial DNA characteristic of unmethylated CpG motifs to induce innate immune response. TLR9 is de novo expressed in podocytes of some patients with glomerular diseases, but its role in podocyte injury remains undetermined. Since TLR9 activates p38 MAPK and NFkB that are known to mediate podocyte apoptosis, we hypothesized that TLR9 induces podocyte apoptosis in glomerular diseases. We treated immortalized podocytes with puromycin aminonucleosides (PAN) and observed podocyte apoptosis, accompanied by TLR9 upregulation. Prevention of TLR9 upregulation by siRNA significantly attenuated NFkappaB p65 or p38 activity and apoptosis, demonstrating that TLR9 mediates podocyte apoptosis. We next showed that endogenous mitochondrial DNA (mtDNA), whose CpG motifs are also unmethylated, is the ligand for TLR9, because PAN induced mtDNA accumulation in endolysosomes where TLR9 is localized, overexpression of endolysosomal DNase 2 attenuated PAN-induced p38 or p65 activity and podocyte apoptosis, and DNase 2 silencing was sufficient to activate p38 or p65 and induce apoptosis. In PAN-treated rats, TLR9 was upregulated in the podocytes, accompanied by increase of apoptosis markers. Thus, de novo expressed TLR9 may utilize endogenous mtDNA as the ligand to facilitate podocyte apoptosis, a novel mechanism underlying podocyte injury in glomerular diseases. PMID- 26934959 TI - Efficient delivery of lentiviral vectors into resting human CD4 T cells. PMID- 26934960 TI - Interaction between hexon and L4-100K determines virus rescue and growth of hexon chimeric recombinant Ad5 vectors. AB - The immunogenicity of recombinant adenovirus serotype 5 (rAd5) vectors has been shown to be suppressed by neutralizing antibodies (NAbs) directed primarily against hexon hypervariable regions (HVRs). Preexisting immunity can be circumvented by replacing HVRs of rAd5 hexon with those derived from alternate adenovirus serotypes. However, chimeric modification of rAd5 hexon HVRs tends to cause low packaging efficiency or low proliferation of rAd5 vectors, but the related mechanism remains unclear. In this study, several Ad5-based vectors with precise replacement of HVRs with those derived from Ad37 and Ad43 were generated. We first observed that a HVR-exchanged rAd5 vector displayed a higher efficacy of the recombinant virus rescue and growth improvement compared with the rAd5 vector, although most hexon-chimeric rAd5 vectors constructed by us and other groups have proven to be nonviable or growth defective. We therefore evaluated the structural stability of the chimeric hexons and their interactions with the L4-100K chaperone. We showed that the viability of hexon-chimeric Ad5 vectors was not attributed to the structural stability of the chimeric hexon, but rather to the hexon maturation which was assisted by L4-100K. Our results suggested that the intricate interaction between hexon and L4-100K would determine the virus rescue and proliferation efficiency of hexon-chimeric rAd5 vectors. PMID- 26934961 TI - PEG10 promotes human breast cancer cell proliferation, migration and invasion. AB - Paternally expressed imprinted gene 10 (PEG10), derived from the Ty3/Gypsy family of retrotransposons, has been implicated as a genetic imprinted gene. Accumulating evidence suggests that PEG10 plays an important role in tumor growth in various cancers, including hepatocellular carcinoma, lung cancer and prostate cancer. However, the correlation between PEG10 and breast cancer remains unclear. In the present study, we evaluated and characterized the role of PEG10 in human breast cancer proliferation, cell cycle, clone formation, migration and invasion. The expression level of PEG10 was significantly elevated in breast cancer tissues and associated with distant metastasis and poor clinical outcome. Gene set enrichment analysis indicated that high expression of PEG10 could enrich cell cycle-related processes in breast cancer tissues. Ectopic overexpression of PEG10 in breast cancer cells enhanced cell proliferation, cell cycle, clone formation along with migration and invasion. Cell-to-cell junction molecule E-cadherin was downregulated and matrix degradation proteases MMP-1, MMP-2, MMP-9 were up regulated after PEG10 overexpression. Our results demonstrated that PEG10 is a crucial oncogene and has prognostic value for breast cancer, which could be applied in breast cancer diagnosis and targeting therapy in future. PMID- 26934962 TI - Increasing Incidence within PubMed of the Use of the Misspelling "Pruritis" (sic) Instead of "Pruritus" for Itch. PMID- 26934963 TI - A Randomized Control Trial Exploring the Effect of Mental Rehearsal and Cognitive Visualization on Microsurgery Skills. AB - Background Many factors are known to influence the performance of surgeons within the operating theater, including tiredness, previous experience, and stress levels. The effects of mental rehearsal and cognitive visualization on microsurgical skills have not been assessed. Methods Thirty-six subjects recruited from the Northwick Park Microsurgery Skills Course were randomized into three groups; (1) a control group (C) with no mental rehearsal script, (2) a visual anastomosis group (VA), with a detailed rat anastomosis script, and (3) a visual relaxation (VR) group with a relaxation script, unrelated to the anastomosis. Participants ran through relevant scripts from day 2 to 5 and were assessed through recorded arterial rat anastomosis, scored using the structured assessment of microsurgery skills. Results Results were analyzed by double blinded assessors. No statistical significance was found on Monday and Tuesday (first day post intervention), p = 0.326 (VA vs. C) and p = 0.283 (VR vs. C). A statistically significant difference was noted at the end of day 4; p < 0.001 (VA vs. VR) and p = 0.001 (VA vs. C). Further analysis demonstrated that domains within the global rating scoring system showed statistical significance for (1) dexterity: VA versus VR, p = 0.001, (2) visuospatial skills: VA versus VR, p = 0.001, and VA versus C, p = 0.002, and (3) operative flow: VA versus VR, p = 0.044, and VA versus C, p = 0.026. Conclusion The benefits of cognitive visualization and mental rehearsal in microsurgery may result in fewer complications from errors and thus lead to enhanced patient safety and better operative outcomes. PMID- 26934964 TI - Are medical students satisfied with rural community posting? A survey among final year students in medical schools of south-east Nigeria. AB - INTRODUCTION: The aim of the study was to determine whether final year medical students in medical schools of south-east Nigeria were satisfied with rural community posting. METHODS: A cross-sectional descriptive study design was used. All final year medical students in the six medical schools in south-east Nigeria who had completed their rural community posting and were willing to participate were included in the study. The students were interviewed using a pretested, self administered questionnaire. RESULTS: A total of 457 medical students participated in the study, representing a response rate of 86.7%. Only a minor proportion of the students (22.5%) were satisfied with rural community posting. The most common reason for dissatisfaction among the students was lack of interest in rural communities. Most students (68.7%) were of the opinion that a good rural community posting could influence the students to practise in a rural area after graduation. Factors associated with satisfaction with rural community posting included being a student in a federal institution (adjusted odds ratio (AOR)=0.6, 95% confidence interval (CI)=0.4-0.9), being a male student (AOR=2.4, 95%CI=1.5 3.9) and intention to specialize in community medicine after graduation (AOR=2.7, 95%CI=1.2-6.0). CONCLUSIONS: Most students were dissatisfied with rural community postings and the major reason for dissatisfaction was lack of interest in rural communities. A properly organized rural community posting is capable of changing the negative attitude of the students towards life and medical practice in the rural area. Adequate orientation of the students on the relevance of the posting, good community exposure and enhanced student lecturer interactions during the posting period could ensure satisfaction of the students. There should be a targeted evaluation of the rural community posting at the various medical schools in the country with the aim of strengthening and modifying the posting where necessary so as to ensure its purpose is realized. PMID- 26934965 TI - Effective Nonpharmacological Interventions: Needed Now! PMID- 26934968 TI - A Case Exemplar for National Policy Leadership: Expanding Program of All Inclusive Care for the Elderly (PACE). AB - In November 2015, President Obama signed the Program of All-Inclusive Care for the Elderly (PACE) Innovation Act, which expands a proven model of care to serve high-cost and high-need populations. Specifically, the law provides the Centers for Medicare & Medicaid Services with the authority to waive Medicaid requirements that could not be waived without additional statutory authority. Those requirements include the age of the beneficiary to be served and nursing home eligibility as a condition for PACE enrollment. The law also allows providers and other entities who are not current PACE providers the opportunity to become PACE providers and serve a predominately dually eligible population that has high needs and high cost through a coordinated, integrated model. The current article describes the impact of nursing on the legislation and policy that has shaped the evolution of the PACE program for more than 40 years. [Journal of Gerontological Nursing, 42(3), 9-14.]. PMID- 26934969 TI - Maturation of the MOUTh Intervention: From Reducing Threat to Relationship Centered Care. AB - The purpose of the current article is to describe a personalized practice originally conceived as a way to prevent and minimize care-resistant behavior to provide mouth care to older adults with dementia. The original intervention, Managing Oral Hygiene Using Threat Reduction Strategies (MOUTh), matured during the clinical trial study into a relationship-centered intervention, with emphasis on developing strategies that support residents' behavioral health and staff involved in care. Relationships that were initially pragmatic (i.e., focused on the task of completing mouth care) developed into more personal and responsive relationships that involved deeper engagement between mouth care providers and nursing home (NH) residents. Mouth care was accomplished and completed in a manner enjoyable to NH residents and mouth care providers. The MOUTh intervention may also concurrently affirm the dignity and personhood of the care recipient because of its emphasis on connecting with older adults. PMID- 26934971 TI - Nursing Home Staff Intentions for Learned Communication Skills: Knowledge to Practice. AB - Staff education is critical to improving nursing home dementia care practice. However, a lag in translation to practice is a barrier to improving care. As part of a clinical trial testing effects of a communication intervention on behaviors of residents with dementia, participant-reported likelihood of using learned skills in practice was evaluated in relation to organizational and individual factors in 10 nursing homes. The authors hypothesized that organizational and individual factors would influence staff intention to use new skills in practice. Pre-and post-training comparisons confirmed that staff gained knowledge about communication effectiveness. Staff reported high likelihood for using skills in practice based on modified Duke Diffusion of Innovation (DOI) Scale scores. Care organization was correlated with total DOI scores (r = 0.82, p < 0.01). DOI subscales correlations to organizational and individual attitudes are reported. Evaluating quality improvement interventions in relation to translation to practice is essential in today's nursing home environment. PMID- 26934972 TI - Creating a Supportive Environment Using Cues for Wayfinding in Dementia. AB - The ability to find one's way in the world, known as wayfinding, is impaired in individuals with Alzheimer's disease (AD). Older adult residential environments (e.g., independent living, assisted living, nursing home residences) are often especially difficult for wayfinding, with long, non-distinctive hallways and poorly differentiated routes. Wayfinding problems can cause anxiety, distress, and decreased interaction in individuals with dementia. Visual cues are one promising intervention to help this population find their way more easily. The current article reviews research studies that examine the influence of visual cues on wayfinding. The literature shows evidence that individuals with AD have difficulty wayfinding, yet can still learn their way if the environment is supportive of wayfinding. There is beginning evidence that colorful, familiar (easily identified), and personally meaningful cues placed at key decision points and residents' rooms can help individuals with AD find their way. PMID- 26934973 TI - Feasibility and Effect Sizes of the Revised Daily Engagement of Meaningful Activities Intervention for Individuals With Mild Cognitive Impairment and Their Caregivers. AB - A nurse-led intervention, Daily Engagement of Meaningful Activities (DEMA), was evaluated for feasibility and effect sizes in a two-group randomized pilot study with 36 patient-caregiver dyads (17 DEMA and 19 attention control). Effect sizes were estimated on 10 outcomes: dyad functional ability awareness congruence; patients' meaningful activity performance and satisfaction, confidence, depressive symptoms, communication satisfaction, physical function, and life satisfaction; and caregivers' depressive symptoms and life changes. High feasibility of DEMA was supported by the following indicators: consent (97.7%), session completion (91.7%), and Time 3 measure completion (97.2%). Compared to the attention control group, the DEMA group had higher dyad congruence in functional ability awareness and life satisfaction 3 months post-intervention and improved physical function at 2 weeks post-intervention. Although DEMA showed high feasibility and benefits on some health-related outcomes, further testing of DEMA in a larger randomized controlled clinical trial is needed. PMID- 26934974 TI - AGS and Geriatrics Health Professionals Aim High for the Year Ahead. PMID- 26934975 TI - First report of Cryptosporidium canis in farmed Arctic foxes (Vulpes lagopus) in China. AB - BACKGROUND: Cryptosporidium is an important genus of enteric zoonotic parasites, which can infect a wide range of animals including foxes. Little information is available concerning the prevalence and molecular characterisation of Cryptosporidium spp. in farmed Arctic foxes (Vulpes lagopus) in China. Thus, the objective of the present study was to investigate the prevalence of Cryptosporidium spp. in Arctic foxes in China using nested PCR amplification of the small subunit ribosomal RNA (SSU rRNA) gene. FINDINGS: The overall prevalence of Cryptosporidium spp. in Arctic foxes was 15.9 % (48/302), with 12.9 % in male (18/139) and 18.4 % in female (30/163) foxes, respectively. The prevalence in different farms varied from 0 to 31.43 %. The prevalence of infection in different age groups varied from 14.1 % to 19.0 %. Foxes from Hebei Province (7.8 %, 11/141) had a significantly lower Cryptosporidium spp. prevalence than those from Heilongjiang Province (22.9 %, 16/70) and Jilin Province (23.1 %, 21/91) (P= 0.0015). Sequence analysis of the SSU rRNA gene indicated that all the 48 isolates represented C. canis. CONCLUSIONS: This is the first report of C. canis infection in farmed Arctic foxes in China, which also provides foundation data for preventing and controlling Cryptosporidium infection in foxes, other animals and humans. PMID- 26934976 TI - The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion. AB - BACKGROUND: The immunity-related GTPases (IRGs) constitute a powerful cell autonomous resistance system against several intracellular pathogens. Irga6 is a dynamin-like protein that oligomerizes at the parasitophorous vacuolar membrane (PVM) of Toxoplasma gondii leading to its vesiculation. Based on a previous biochemical analysis, it has been proposed that the GTPase domains of Irga6 dimerize in an antiparallel fashion during oligomerization. RESULTS: We determined the crystal structure of an oligomerization-impaired Irga6 mutant bound to a non-hydrolyzable GTP analog. Contrary to the previous model, the structure shows that the GTPase domains dimerize in a parallel fashion. The nucleotides in the center of the interface participate in dimerization by forming symmetric contacts with each other and with the switch I region of the opposing Irga6 molecule. The latter contact appears to activate GTP hydrolysis by stabilizing the position of the catalytic glutamate 106 in switch I close to the active site. Further dimerization contacts involve switch II, the G4 helix and the trans stabilizing loop. CONCLUSIONS: The Irga6 structure features a parallel GTPase domain dimer, which appears to be a unifying feature of all dynamin and septin superfamily members. This study contributes important insights into the assembly and catalytic mechanisms of IRG proteins as prerequisite to understand their anti-microbial action. PMID- 26934977 TI - Plasma levels of oxidative stress-responsive apoptosis inducing protein (ORAIP) in rats subjected to physicochemical oxidative stresses. AB - Oxidative stress is known to play a pivotal role in the pathogenesis of various disorders including atherosclerosis, aging and especially ischaemia/reperfusion injury. It causes cell damage that leads to apoptosis. However, the precise mechanism has been uncertain. Recently, we identified an apoptosis-inducing humoral factor in a hypoxia/reoxygenated medium of cardiac myocytes. We named this novel post-translationally modified secreted form of eukaryotic translation initiation factor 5A (eIF5A) as oxidative stress-responsive apoptosis inducing protein (ORAIP). We developed a sandwich ELISA and confirmed that myocardial ischaemia/reperfusion markedly increased plasma levels of ORAIP. To investigate whether the role of ORAIP is common to various types of oxidative stress, we measured plasma ORAIP levels in rats subjected to three physicochemical models of oxidative stress including N2/O2 inhalation, cold/warm-stress (heat shock) and blood acidification. In all three models, plasma ORAIP levels significantly increased and reached a peak level at 10-30 min after stimulation, then decreased within 60 min. The (mean+/-S.E.M.) plasma ORAIP levels before and after (peak) stimulation were (16.4+/-9.6) and (55.2+/-34.2) ng/ml in N2/O2 inhalation, (14.1+/-12.4) and (34.3+/-14.6) ng/ml in cold/warm-stress, and (18.9+/-14.3) and (134.0+/-67.2) ng/ml in blood acidification study. These data strongly suggest that secretion of ORAIP in response to oxidative stress is universal mechanism and plays an essential role. ORAIP will be an important novel biomarker as well as a specific therapeutic target of these oxidative stress-induced cell injuries. PMID- 26934978 TI - Development of a stable ERroGFP variant suitable for monitoring redox dynamics in the ER. AB - The endoplasmic reticulum (ER) is an essential organelle for cellular metabolic homeostasis including folding and maturation of secretory and membrane proteins. Disruption of ER proteostasis has been implicated in the pathogenesis of various diseases such as diabetes and neurodegenerative diseases. The ER redox state, which is an oxidative environment suitable for disulfide-bond formation, is essential for ER protein quality control. Hence, detection of the ER redox state, especially in living cells, is essential to understand the mechanism by which the redox state of the ER is maintained. However, methods to detect the redox state of the ER have not been well-established because of inefficient folding and stability of roGFP variants with oxidative redox potential like roGFP-iL. Here we have improved the folding efficiency of ER-targeted roGFP-iL (ERroGFP-iL) in cells by introducing superfolder GFP (sfGFP) mutations. Four specific amino acid substitutions (S30R, Y39N, T105N and I171V) greatly improved folding efficiency in Escherichia coli and in the ER of HeLa cells, as well as the thermostability of the purified proteins. Introduction of these mutations also enhanced the dynamic range for redox change both in vitro and in the ER of living cells. ER targeted roGFP-S4 (ERroGFP-S4) possessing these four mutations could detect physiological redox changes within the ER. ERroGFP-S4 is therefore a novel probe suitable for monitoring redox change in the ER. ERroGFP-S4 can be applied to detect aberrant ER redox states associated with various pathological conditions and to identify the mechanisms used to maintain the redox state of the ER. PMID- 26934979 TI - ATP increases the migration of microglia across the brain endothelial cell monolayer. AB - The cerebral microcapillary endothelium, known as the blood-brain barrier (BBB), acts as a barrier between the blood and the interstitial fluid of the brain. The BBB therefore controls the passage of nutrients into the central nervous system (CNS). Microglia show a specific affinity for migration into the CNS, and this migration appears to occur independently of BBB integrity. To study the migration of microglia across the BBB, we developed an in vitro co-culture system of mouse brain endothelial cells (MBECs) and Ra2 microglia using Transwell inserts. We first investigated the influence of microglia or ATP, a microglial chemotactic factor, on MBEC barrier integrity. The addition of microglia or ATP led to the disruption of the MBEC monolayer and significantly decreased barrier function as measured by trans-endothelial electrical resistance (TEER) and electric cell substrate impedance sensing (ECIS). Furthermore, ATP promoted the migration of microglia but not macrophages across the MBEC monolayer. An inhibitor of matrix metalloproteinases (MMPs) decreased the transmigration of microglia in our system, indicating that MMPs play a role in microglial chemotaxis. We specifically identify a role for microglia-derived MMP-2. In conclusion, we offer evidence that microglia migration across the brain endothelial cell monolayer is increased in the presence of ATP in a manner that involves MMP secretion. PMID- 26934980 TI - LncRNA DQ786243 contributes to proliferation and metastasis of colorectal cancer both in vitro and in vivo. AB - Accumulating evidence demonstrates that long non-coding RNAs (LncRNAs) play important roles in regulating gene expression and are involved in various cancers, including colorectal cancer (CRC). However, LncRNA profiles in CRC remain largely unknown. The present study aims to find the key LncRNA associated with CRC and to study its biological functions in CRC progression. We focused on LncRNA DQ786243, one of LncRNAs which promoted development of CRC from the Gene Expression Omnibus (GEO) and validated using quantitative real-time PCR among about 20 paired CRC tissues. The effects of LncRNA DQ786243 were assessed by silencing the LncRNA in vitro and in vivo Results showed that the expression level LncRNA DQ786243 was significantly higher in CRC tissues and cell lines. We also found LncRNA DQ786243 knockdown by RNA interference with siRNA significantly arrested the cell cycle in the G2/M-phase, promoted apoptosis and weaken the abilities of cell proliferation and invasion in vitro Further investigation into the mechanisms responsible for the growth inhibitory effects by DQ786243 silencing revealed that its knockdown resulted in the induction of cell cycle arrest and apoptosis through certain cell cycle-related and apoptosis-related proteins. Finally, xenograft experiments confirmed that the growth of xenograft tumours formed by CRC cells was suppressed after silencing LncRNA DQ786243 expression. In conclusion, the present study suggests that LncRNA DQ786243 is an oncogene that promotes tumour progression and leads us to propose that LncRNAs may serve as key regulatory hubs in CRC progression. PMID- 26934981 TI - A cell-permeable tool for analysing APP intracellular domain function and manipulation of PIKfyve activity. AB - The mechanisms for regulating PIKfyve complex activity are currently emerging. The PIKfyve complex, consisting of the phosphoinositide kinase PIKfyve (also known as FAB1), VAC14 and FIG4, is required for the production of phosphatidylinositol 3,5-bisphosphate [PI(3,5)P2]. PIKfyve function is required for homoeostasis of the endo/lysosomal system and is crucially implicated in neuronal function and integrity, as loss of function mutations in the PIKfyve complex lead to neurodegeneration in mouse models and human patients. Our recent work has shown that the intracellular domain of the amyloid precursor protein (APP), a molecule central to the aetiology of Alzheimer's disease binds to VAC14 and enhances PIKfyve function. In the present study, we utilize this recent advance to create an easy-to-use tool for increasing PIKfyve activity in cells. We fused APP intracellular domain (AICD) to the HIV TAT domain, a cell-permeable peptide allowing proteins to penetrate cells. The resultant TAT-AICD fusion protein is cell permeable and triggers an increase in PI(3,5)P2 Using the PI(3,5)P2 specific GFP-ML1Nx2 probe, we show that cell-permeable AICD alters PI(3,5)P2 dynamics. TAT-AICD also provides partial protection from pharmacological inhibition of PIKfyve. All three lines of evidence show that the AICD activates the PIKfyve complex in cells, a finding that is important for our understanding of the mechanism of neurodegeneration in Alzheimer's disease. PMID- 26934982 TI - Structural model of FeoB, the iron transporter from Pseudomonas aeruginosa, predicts a cysteine lined, GTP-gated pore. AB - Iron is essential for the survival and virulence of pathogenic bacteria. The FeoB transporter allows the bacterial cell to acquire ferrous iron from its environment, making it an excellent drug target in intractable pathogens. The protein consists of an N-terminal GTP-binding domain and a C-terminal membrane domain. Despite the availability of X-ray crystal structures of the N-terminal domain, many aspects of the structure and function of FeoB remain unclear, such as the structure of the membrane domain, the oligomeric state of the protein, the molecular mechanism of iron transport, and how this is coupled to GTP hydrolysis at the N-terminal domain. In the present study, we describe the first homology model of FeoB. Due to the lack of sequence homology between FeoB and other transporters, the structures of four different proteins were used as templates to generate the homology model of full-length FeoB, which predicts a trimeric structure. We confirmed this trimeric structure by both blue-native-PAGE (BN PAGE) and AFM. According to our model, the membrane domain of the trimeric protein forms a central pore lined by highly conserved cysteine residues. This pore aligns with a central pore in the N-terminal GTPase domain (G-domain) lined by aspartate residues. Biochemical analysis of FeoB from Pseudomonas aeruginosa further reveals a putative iron sensor domain that could connect GTP binding/hydrolysis to the opening of the pore. These results indicate that FeoB might not act as a transporter, but rather as a GTP-gated channel. PMID- 26934983 TI - Manipulating three-dimensional gel network entanglement by thin film shearing. AB - Vortex fluidic mediated shearing of supramolecular gels in thin films leads to complete disruption of fluorous bis-urea derived gels. Hydrocarbon analogues however, are only partially disrupted, which emphasizes the resistance of non fluorous bis-urea gelators towards shear. The gel structures have been studied by combining the thin film shearing with small angle neutron scattering. This technique represents a novel approach to study the effects of external stimuli on self-assembled supramolecular gel networks. PMID- 26934984 TI - Biointeractions of ultrasmall glutathione-coated gold nanoparticles: effect of small size variations. AB - Recent in vivo studies have established ultrasmall (<3 nm) gold nanoparticles coated with glutathione (AuGSH) as a promising platform for applications in nanomedicine. However, systematic in vitro investigations to gain a more fundamental understanding of the particles' biointeractions are still lacking. Herein we examined the behavior of ultrasmall AuGSH in vitro, focusing on their ability to resist aggregation and adsorption from serum proteins. Despite having net negative charge, AuGSH particles were colloidally stable in biological media and able to resist binding from serum proteins, in agreement with the favorable bioresponses reported for AuGSH in vivo. However, our results revealed disparate behaviors depending on nanoparticle size: particles between 2 and 3 nm in core diameter were found to readily aggregate in biological media, whereas those strictly under 2 nm were exceptionally stable. Molecular dynamics simulations provided microscopic insight into interparticle interactions leading to aggregation and their sensitivity to the solution composition and particle size. These results have important implications, in that seemingly small variations in size can impact the biointeractions of ultrasmall AuGSH, and potentially of other ultrasmall nanoparticles as well. PMID- 26934985 TI - Thermal reactionomes reveal divergent responses to thermal extremes in warm and cool-climate ant species. AB - BACKGROUND: The distributions of species and their responses to climate change are in part determined by their thermal tolerances. However, little is known about how thermal tolerance evolves. To test whether evolutionary extension of thermal limits is accomplished through enhanced cellular stress response (enhanced response), constitutively elevated expression of protective genes (genetic assimilation) or a shift from damage resistance to passive mechanisms of thermal stability (tolerance), we conducted an analysis of the reactionome: the reaction norm for all genes in an organism's transcriptome measured across an experimental gradient. We characterized thermal reactionomes of two common ant species in the eastern U.S, the northern cool-climate Aphaenogaster picea and the southern warm-climate Aphaenogaster carolinensis, across 12 temperatures that spanned their entire thermal breadth. RESULTS: We found that at least 2 % of all genes changed expression with temperature. The majority of upregulation was specific to exposure to low temperatures. The cool-adapted A. picea induced expression of more genes in response to extreme temperatures than did A. carolinensis, consistent with the enhanced response hypothesis. In contrast, under high temperatures the warm-adapted A. carolinensis downregulated many of the genes upregulated in A. picea, and required more extreme temperatures to induce down-regulation in gene expression, consistent with the tolerance hypothesis. We found no evidence for a trade-off between constitutive and inducible gene expression as predicted by the genetic assimilation hypothesis. CONCLUSIONS: These results suggest that increases in upper thermal limits may require an evolutionary shift in response mechanism away from damage repair toward tolerance and prevention. PMID- 26934987 TI - Flow measurements of a polyphenyl ether oil in an elastohydrodynamic contact. AB - A novel methodology, based on the use of phosphorescence imaging, is applied to determine the local through-thickness velocity profile of lubricant in an elastohydrodynamic contact. The technique has spatial and temporal resolutions of 40 MUm and 340 MUs respectively and thus allows lubricant rheology to be investigated at conditions close to service conditions. The capability of the newly-developed method is verified by examining the flow of 5P4E polyphenyl ether, a lubricant base fluid used in very high temperature applications and is well-known for its high viscosity-pressure coefficient. Experimental results highlight the effect of the contact pressure on the velocity profile of this fluid in lubricated contacts. At low pressures, the velocity profile of 5P4E is close to linear, characteristic of Couette flow. As the local pressure increases, its velocity profile progressively deviates from a Couette profile and shear banding is evident at high pressure. PMID- 26934986 TI - Cerebrolysin combined with rehabilitation promotes motor recovery in patients with severe motor impairment after stroke. AB - BACKGROUND: Cerebrolysin is a neuropeptide preparation with neuroprotective and neurorestorative effects. Combining Cerebrolysin treatment with a standardized rehabilitation program may have a potential synergistic effect in the subacute stage of stroke. This study aims to evaluate whether Cerebrolysin provides additional motor recovery on top of rehabilitation therapy in the subacute stroke patients with moderate to severe motor impairment. METHODS: This phase IV trial was designed as a prospective, multicenter, randomized, double-blind, placebo controlled, parallel-group study. A total of 70 patients (Cerebrolysin n = 35, placebo n = 35) with moderate to severe motor function impairment were included within 7 days after stroke onset and were randomized to receive a 21-day treatment course of either Cerebrolysin or placebo, given in addition to standardized rehabilitation therapy. Assessments were performed at baseline, immediately after treatment as well as 2 and 3 months after stroke onset. The plasticity of motor system was assessed by diffusion tensor imaging and with resting state functional magnetic resonance imaging. RESULTS: Both groups demonstrated significant improvement in motor function (p < 0.05); however, no significant difference was found between the two groups. In the stroke patients with severe motor impairment, the Cerebrolysin group exhibited significantly more improvement in motor function compared with the placebo group (p < 0.05). Effects of Cerebrolysin were demonstrated as restricted increments of corticospinal diffusivity and as recovery of the sensorimotor connectivity. CONCLUSION: The combination of standard rehabilitation therapy with Cerebrolysin treatment in the subacute stroke has shown additional benefit on motor recovery and plastic changes of the corticospinal tract in patients with severe motor impairment. TRIAL REGISTRATION: NCT01996761 (November 5, 2013). PMID- 26934988 TI - Long-chain NHC-stabilized RuNPs as versatile catalysts for one-pot oxidation/hydrogenation reactions. AB - The synthesis and catalytic activity of long-chain NHC-stabilized RuNPs are presented. Full characterization of these novel nanostructures including surface state studies show that the ligand influences the number and the location of Ru active sites which impacts the NP catalytic activity, especially in hydrogenation reactions. The high stability and versatility of these nanosystems make them successful catalysts for both oxidation and hydrogenation reactions that can even be performed successively in a one pot-fashion. PMID- 26934989 TI - Coordination and supramolecular assembly of {Cd2Ge8V12O48} building block and cucurbit[6] to form rotaxane-shaped hybrids. AB - Assembly of cucurbit[6] and a {Cd2Ge8V12O48} cluster produced two rotaxane-shaped and polyrotaxane-shaped solids by changing the ratio of starting precursors in the system. The high oxygen density of the polyoxoanion surface provides active sites to extend a single rotaxane-shaped hybrid 1 to a 1D polyrotaxane-shaped hybrid 2. This construction strategy may afford an entirely new methodology for polyoxometalate-based hybrid chemistry. PMID- 26934990 TI - Modeling glucose and free fatty acid kinetics in glucose and meal tolerance test. AB - BACKGROUND: Quantitative evaluation of insulin regulation on plasma glucose and free fatty acid (FFA) in response to external glucose challenge is clinically important to assess the development of insulin resistance (World J Diabetes 1:36 47, 2010). Mathematical minimal models (MMs) based on insulin modified frequently sampled intravenous glucose tolerance tests (IM-FSIGT) are widely applied to ascertain an insulin sensitivity index (IEEE Rev Biomed Eng 2:54-96, 2009). Furthermore, it is important to investigate insulin regulation on glucose and FFA in postprandial state as a normal physiological condition. A simple way to calculate the appearance rate (Ra) of glucose and FFA would be especially helpful to evaluate glucose and FFA kinetics for clinical applications. METHODS: A new MM is developed to simulate the insulin modulation of plasma glucose and FFA, combining IM-FSIGT with a mixed meal tolerance test (MT). A novel simple functional form for the appearance rate (Ra) of glucose or FFA in the MT is developed. Model results are compared with two other models for data obtained from 28 non-diabetic women (13 African American, 15 white). RESULTS: The new functional form for Ra of glucose is an acceptable empirical approximation to the experimental Ra for a subset of individuals. When both glucose and FFA are included in FSIGT and MT, the new model is preferred using the Bayes Information Criterion (BIC). CONCLUSIONS: Model simulations show that the new MM allows consistent application to both IM-FSIGT and MT data, balancing model complexity and data fitting. While the appearance of glucose in the circulation has an important effect on FFA kinetics in MT, the rate of appearance of FFA can be neglected for the time-period modeled. PMID- 26934991 TI - MicroRNA-20a negatively regulates expression of NLRP3-inflammasome by targeting TXNIP in adjuvant-induced arthritis fibroblast-like synoviocytes. AB - OBJECTIVES: Rheumatoid arthritis (RA) is a heterogenic and systemic autoimmune disease characterized by synovitis and joint structural damage. However, the pathogenesis of RA is still obscure. It has been reported microRNA-20a (miRNA 20a) was significantly associated with the regulation of pro-inflammatory cytokines release in RA FLS. The purpose of this study was to explore the function and underlying mechanisms of miRNA-20a on NLRP3-inflammasome in adjuvant induced arthritis (AA) fibroblast-like synoviocytes (FLSs) in vitro. METHODS: In this study, using a combination of Western blotting, Q-PCR, and ELISA analysis, we investigated the influence and function of miRNA-20a on NLRP3-inflammasome by targeting TXNIP in AA FLSs. RESULTS: In the present study, the expression of NLRP3-inflammasome was significant up-regulated in AA model in vitro. Our study indicated that silence of NLRP3 down-regulated the expression of NLRP3 inflammasome and the secretion of IL-1beta and MMP-1. Moreover, over-expression of miR-20a decreased formation of NLRP3-inflammasome, including NLRP3, ASC and caspase-1, and suppressed the secretion of IL-1beta and MMP-1, along with down regulated the expressions of TXNIP in primary FLSs isolated from AA. With the combined use of prediction programs and luciferase assay, the rat TXNIP mRNA 3'UTR predicted to be targeted by miR-20a. Similarly, inhibitor TXNIP expression by TXNIP-siRNA markedly repressed formation of NLRP3-inflammasome and the secretion of IL-1beta and MMP-1. CONCLUSION: Taken together, these results indicate that miR-20a may play a pivotal role in the NLRP3-inflammasome by targeted inhibit TXNIP expression in AA FLSs. PMID- 26934992 TI - Myositis ossificans traumatica (circumscripta) and return to sport: A retrospective series of 19 cases. AB - OBJECTIVE: Myositis ossificans is a worrisome complication of muscle lesions in sports medicine. Our goal is to specify clinical, paraclinical and therapeutic elements to guide a myositis ossificans traumatica patient back into sport. METHOD: All patients having consulted between January 2006 and December 2012 presenting myositis ossificans with a recent muscle injury from playing sports were included. We excluded patients with myositis ossificans without an identified trauma, or from an old injury (>6 months). Ultrasound images were captured on a Philips((r)) Sparq ultrasound machine with a linear probe (4 12MHz). The diagnosis of myositis ossificans was performed on 2 ultrasound criteria in context of recent muscle trauma: presence of ossification or calcification within a muscle on axial and longitudinal sections using B-mode and hyperactivity in power Doppler mode around the ossification/calcification. Clinical signs and treatment were collected systematically at inclusion, 6 months and 1 year. RESULTS: Among the 22 myositis ossificans cases diagnosed between January 2006 and December 2012, 19 were of traumatic origin, on a recent muscle lesion and were included in the study. Our patients resumed light physical activities 3 months after diagnosis for 89.5% of them (100% at 10 months) and returned to their earlier level 6 months after myositis ossificans diagnosis for also 89.5% of them (all patients having resumed sport at their earlier levels 12 months after diagnosis). CONCLUSION: Therapeutic abstention and persistence of ossification do not seem to be detrimental factors for resuming a sport at the earlier level with ultrasound monitoring. PMID- 26934993 TI - [Woman with macrocytic anaemia, hyperkalaemia and hyponatraemia]. PMID- 26934994 TI - Direct evidence of recombination in the recA gene of Aeromonas bestiarum. AB - Two hundred and twenty-one strains representative of all Aeromonas species were characterized using the recA gene sequence, assessing its potential as a molecular marker for the genus Aeromonas. The inter-species distance values obtained demonstrated that recA has a high discriminatory power. Phylogenetic analysis, based on full-length gene nucleotide sequences, revealed a robust topology with clearly separated clusters for each species. The maximum likelihood tree showed the Aeromonas bestiarum strains in a well-defined cluster, containing a subset of four strains of different geographical origins in a deep internal branch. Data analysis provided strong evidence of recombination at the end of the recA sequences in these four strains. Intergenomic recombination corresponding to partial regions of the two adjacent genes recA and recX (248 bp) was identified between A. bestiarum (major parent) and Aeromonas eucrenophila (minor parent). The low number of recombinant strains detected (1.8%) suggests that horizontal flow between recA sequences is relatively uncommon in this genus. Moreover, only a few nucleotide differences were detected among these fragments, indicating that recombination has occurred recently. Finally, we also determined if the recombinant fragment could have influenced the structure and basic functions of the RecA protein, comparing models reconstructed from the translated amino acid sequences of our A. bestiarum strains with known Escherichia coli RecA structures. PMID- 26934995 TI - Unravelling the effects of gene flow and selection in highly connected populations of the silver-lip pearl oyster (Pinctada maxima). AB - Many marine organisms often display weak levels of population genetic structuring as a result of both environmental characteristics (e.g., ocean currents) and life history traits (e.g., widely dispersed planktonic larval stages) maintaining high levels of gene flow. This can lead to the assumption that these organisms can be managed as a single stock based on high levels of population connectivity. However, this neglects to account for other micro-evolutionary forces such as selection, which also shape these populations. This study utilizes 1130 genome wide SNP loci to unravel the effects of gene flow and selection shaping three highly connected populations of the silver-lip pearl oyster (Pinctada maxima) in the ecologically and economically important Indo-Pacific region (Aru, Bali, and West Papua). Twenty-two loci under directional selection were identified amongst the populations, providing further supporting evidence of strong local adaptation (i.e., G*E effects) among populations in this region. Global Fst values for directional outliers (0.348) were up to eight times greater than for neutral markers (0.043). Pairwise Fst comparisons between Aru and Bali revealed the largest directional differences (0.488), while Bali and West Papua had the least (0.062). Unrooted neighbour-joining (NJ) distance trees and genetic diversity indices of directional outliers revealed that individuals from Bali and West Papua had reduced allelic variation (MAFavg=0.144, Ho=0.238 and MAFavg=0.232, Ho=0.369, respectively) compared to Aru (MAFavg=0.292, Ho=0.412). This indicates that directional selection is most likely acting upon genetic variation within the Bali and West Papua populations. NJ distance trees, discriminant analysis of principal components, and Fst analyses of directional outliers revealed two divergent groups ("Bali/West Papua"; "Aru") that had previously gone unrecognized. This study not only illustrates that relatively strong local adaptive forces are occurring despite high gene flow, but identifies the populations that are most likely experiencing selection. Additionally, this study highlights the need to understand all micro-evolutionary forces acting on populations when resolving stock structure. PMID- 26934996 TI - Update on ivabradine for heart failure. AB - Despite dramatic advances in therapy for heart failure (HF) during the past 3 decades, hospitalization and mortality rates remain relatively high. In recent decades, it has become apparent that HF is divisible into two equally lethal but pathophysiologically different sub-classes, the first comprising patients with LV systolic dysfunction [heart failure with reduced ejection fraction (HFrEF)] and the other, approximately equal in size, involving patients with "preserved" systolic function [heart failure with preserved ejection fraction (HFpEF)]. Evidence-based event reducing therapy currently is available only for HFrEF. With the completion of seminal trials of beta blockers, now part of standard therapy for HFrEF, it was apparent that heart rate slowing is an underlying basis of clinical effectiveness of HFrEF therapy. With the discovery of the "f current" that modulates the slope of spontaneous diastolic depolarization of the sino atrial node, a non-beta blockade approach to heart rate slowing became available. Ivabradine, the first FDA-approved f-current blocker for HFrEF, markedly reduces hospitalizations for worsening heart failure, while also progressively reducing mortality as pre-therapy heart rate increases, and also promotes beneficial left ventricular remodeling, improves health-related quality of life and is effective despite a wide range of comorbidities. The drug is well tolerated and adverse effects are relatively few. Ivabradine represents an important addition to the armamentarium for mitigation of HFrEF. PMID- 26934997 TI - Molecular detection of Rickettsia, Anaplasma, Coxiella and Francisella bacteria in ticks collected from Artiodactyla in Thailand. AB - A total of 79 ticks collected from Sambar deer (Cervus unicolor), Barking deer (Muntiacus muntjak) and Wild boar (Sus scrofa) were examined by PCR for the presence of Rickettsia, Anaplasma, Coxiella, and Francisella bacteria. Of the 79 ticks, 13% tested positive for Rickettsia, 15% tested positive for Anaplasma, 4% tested positive for Coxiella, and 3% tested positive for Francisella. Interestingly, triple infection with Anaplasma, Rickettsia and Francisella was determined in a Dermacentor auratus tick. Moreover, another triple infection with Rickettsia, Anaplasma, and Coxiella was found in a Haemaphysalis lagrangei tick. Double infection of Rickettsia with Coxiella was also detected in another H. lagrangei tick. From the phylogenetic analyses, we found a Rickettsia sp. with a close evolutionary relationship to Rickettsia bellii in the H. lagrangei tick. We also found the first evidence of a Rickettsia sp. that is closely related to Rickettsia tamurae in Rhipicephalus (Boophilus) microplus ticks from Thailand. H. lagrangei and Haemaphysalis obesa ticks collected from Sambar deer tested positive for Anaplasma species form the same clade with Anaplasma bovis. In contrast, other H. lagrangei ticks collected from Sambar deer and D. auratus ticks collected from Wild boar were also reported for the first time to be infected with an Anaplasma species that is closely related to Anaplasma platys. The phylogenetic analysis of the 16S rRNA gene of Coxiella bacteria revealed that Coxiella symbionts from H. lagrangei formed a distinctly different lineage from Coxiella burnetii (a human pathogen). Additionally, Francisella bacteria identified in D. auratus ticks were found to be distantly related to a group of pathogenic Francisella species. The identification of these bacteria in several feeding ticks suggests the risk of various emerging tick-borne diseases and endosymbionts in humans, wildlife, and domestic animals in Thailand. PMID- 26934998 TI - CuSO4-Mediated Decarboxylative Difluoroacetamidation of alpha,beta-Unsaturated Carboxylic Acids. AB - The first example of decarboxylative difluoroacetamidation of alpha,beta unsaturated carboxylic acids by using difluoromethyl-substituted carbonyl compounds was disclosed. The procedure, which was mediated by low-cost and benign CuSO4, furnished a broad range of difluorinated alkenes in remarkable yields with only the E configuration in most of the cases. Moreover, the product could be smoothly transformed to the corresponding difluorofunctionalized ester and alcohol in high yields. PMID- 26934999 TI - Rank-preserving regression: a more robust rank regression model against outliers. AB - Mean-based semi-parametric regression models such as the popular generalized estimating equations are widely used to improve robustness of inference over parametric models. Unfortunately, such models are quite sensitive to outlying observations. The Wilcoxon-score-based rank regression (RR) provides more robust estimates over generalized estimating equations against outliers. However, the RR and its extensions do not sufficiently address missing data arising in longitudinal studies. In this paper, we propose a new approach to address outliers under a different framework based on the functional response models. This functional-response-model-based alternative not only addresses limitations of the RR and its extensions for longitudinal data, but, with its rank-preserving property, even provides more robust estimates than these alternatives. The proposed approach is illustrated with both real and simulated data. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26935000 TI - Pathological gambling: a review of the neurobiological evidence relevant for its classification as an addictive disorder. AB - In light of the upcoming eleventh edition of the International Classification of Diseases (ICD-11), the question arises as to the most appropriate classification of 'Pathological Gambling' ('PG'). Some academic opinion favors leaving PG in the 'Impulse Control Disorder' ('ICD') category, as in ICD-10, whereas others argue that new data especially from the neurobiological area favor allocating it to the category of 'Substance-related and Addictive Disorders' ('SADs'), following the decision in the fifth revision of the Diagnostic and Statistical Manual of Mental Disorders. The current review examines important findings in relation to PG, with the aim of enabling a well-informed decision to be made with respect to the classification of PG as a SAD or ICD in ICD-11. Particular attention is given to cognitive deficits and underlying neurobiological mechanisms that play a role in SADs and ICDs. These processes are impulsivity, compulsivity, reward/punishment processing and decision-making. In summary, the strongest arguments for subsuming PG under a larger SAD category relate to the existence of similar diagnostic characteristics; the high co-morbidity rates between the disorders; their common core features including reward-related aspects (positive reinforcement: behaviors are pleasurable at the beginning which is not the case for ICDs); the findings that the same brain structures are involved in PG and SADs, including the ventral striatum. Research on compulsivity suggests a relationship with PG and SAD, particularly in later stages of the disorders. Although research is limited for ICDs, current data do not support continuing to classify PG as an ICD. PMID- 26935001 TI - Cannabinoid CB2 receptors are involved in the regulation of fibrogenesis during skin wound repair in mice. AB - Studies have shown that cannabinoid CB2 receptors are involved in wound repair, however, its physiological roles in fibrogenesis remain to be elucidated. In the present study, the capacity of cannabinoid CB2 receptors in the regulation of skin fibrogenesis during skin wound healing was investigated. To assess the function of cannabinoid CB2 receptors, skin excisional BALB/c mice were treated with either the cannabinoid CB2 receptor selective agonist, GP1a, or antagonist, AM630. Skin fibrosis was assessed by histological analysis and profibrotic cytokines were determined by immunohistochemistry, immunofluorescence staining, reverse transcription-quantitative polymerase chain reaction and immunoblotting in these animals. GP1a decreased collagen deposition, reduced the levels of transforming growth factor (TGF)-beta1, TGF-beta receptor I (TbetaRI) and phosphorylated small mothers against decapentaplegic homolog 3 (P-Smad3), but elevated the expression of its inhibitor, Smad7. By contrast, AM630 increased collagen deposition and the expression levels of TGF-beta1, TbetaRI and P-Smad3. These results indicated that cannabinoid CB2 receptors modulate fibrogenesis and the TGF-beta/Smad profibrotic signaling pathway during skin wound repair in the mouse. PMID- 26935002 TI - Bull's eye dermatoscopy pattern at bacillus Calmette-Guerin inoculation site correlates with systemic involvements in patients with Kawasaki disease. AB - For the past decades, although the rash at the bacillus Calmette-Guerin (BCG) inoculation site has been recognized as a diagnostic clue in Kawasaki disease, the present study is the first known one attempting to characterize BCG inoculation by dermatoscopy in Kawasaki disease and correlate the grade of BCG reaction with systemic involvement. Thirty-four patients diagnosed with Kawasaki disease by pediatric specialists were enrolled. We performed detailed history taking, laboratory examination, physical examination and dermatoscopy examinations. Based on the BCG reaction pattern by dermatoscopy, we were able to characterize three patterns: (A) Bull's eye pattern in 18 patients; (B) faint homogenous erythema in nine; and (C) central white patch in seven. Patients from group A exhibited the highest elevation of blood aspartate aminotransferase levels (P < 0.05). Notably, three patients from group A had a significantly dilated coronary artery despite i.v. immunoglobulin injection. We concluded that the bull's eye dermatoscopy sign is not only a useful diagnostic clue but also a severity biomarker in patients with Kawasaki disease. PMID- 26935003 TI - Localizing Perturbations of the Racemic Equilibria Involving Dipicolinate-Derived Lanthanide(III) Complexes. AB - Helical D3 tris(4-amino-2,6-pyridine-dicarboxylate)terbium(III) and europium(III) complexes, which form a racemic equilibrium in aqueous solution, were prepared to study their secondary coordination sphere interactions with chiral amino acids. These interactions were probed using a combination of circularly polarized luminescence (CPL) and 13C NMR spectroscopy. The results indicate that, regardless of the interaction between the chiral molecule and the complex, without an accessible hydrogen-bond donor on the associating molecule, perturbation of the racemic equilibrium cannot occur. A generalized conclusion is established that indicates that the mechanism of chiral recognition by tris(dipicolinate)lanthanide(III) complexes is similar across a variety of analogous ligands. PMID- 26935004 TI - Radiotherapy for brainstem gliomas in children and adults: A single-institution experience and literature review. AB - AIM: To evaluate the treatment results of radiotherapy (RT) in children and adults with brainstem gliomas (BSGs) and review the previous literature. METHODS: Thirty patients (14 children, 16 adults) with BSG treated using RT were retrospectively evaluated. The median ages of the children and adults were 8 years (range: 2-16 years) and 49 years (range: 19-75 years), respectively. A histological diagnosis was obtained in 11 patients. The median total radiation dose was 56 Gy (range: 50-70 Gy) with a single fraction size of 1.8-2.0 Gy. Temozolomide was administered concurrently with RT in 14 patients. RESULTS: Tumor progression after RT occurred in 26 patients (14 children and 12 adults). Four adults survived without tumor progression. The median survival times for children and adults were 8.5 and 39 months, respectively. The 1-, 2- and 3-year overall survival rates for children/adults were 29%/75%, 14%/68% and 0%/53%, respectively (P = 0.001), and the 1-, 2- and 3-year progression-free survival rates for children/adults were 14%/69%, 0%/49% and 0%/35%, respectively (P < 0.001). Grade 3 or higher acute and late toxicities did not occur. CONCLUSION: In this study, the prognosis of children with BSGs was considerably poorer than that of adults, and our results are consistent with those of previous studies. Efforts should be made to improve the survival outcomes of patients with BSGs, especially children. PMID- 26935005 TI - How is anxiety related to math performance in young students? A longitudinal study of Grade 2 to Grade 3 children. AB - Both general and math-specific anxiety are related to proficiency in mathematics. However, it is not clear when math anxiety arises in young children, nor how it relates to early math performance. This study therefore investigated the early association between math anxiety and math performance in Grades 2 and 3, by accounting for general anxiety and by further inspecting the prevalent directionality of the anxiety-performance link. Results revealed that this link was significant in Grade 3, with a prevalent direction from math anxiety to performance, rather than the reverse. Longitudinal analyses also showed an indirect effect of math anxiety in Grade 2 on subsequent math performance in Grade 3. Overall, these findings highlight the importance of monitoring anxiety from the early stages of schooling in order to promote proficient academic performance. PMID- 26935007 TI - Effect of transforming growth factor-beta3 on the expression of Smad3 and Smad7 in tenocytes. AB - Tendon adhesion is a common problem in the healing of injured tendons. The molecular mechanisms of the TGF-beta/Smad signaling pathway have been determined, and the role of TGF-beta has been well characterized in wound healing. However, the intracellular mechanism or downstream signals by which TGF-beta3 modulates its effects on tendon healing have not been well elucidated. The aim of this study was to determine the effect of TGF-beta3 on the TGF-beta/Smad signaling pathway in tenocytes. Quantitative polymerase chain reaction and western blot analysis were used to analyze the effect of TGF-beta3 on the regulation of the expression of Smad proteins in tenocytes. The results demonstrated that TGF-beta3 has no significant effect on the proliferation of tendon cells. The addition of TGF-beta3 to tenocytes can significantly downregulate the expression of Smad3 and upregulate the expression of Smad7 at the gene and protein levels. The results demonstrate that TGF-beta3 may regulate Smad3 and Smad7 proteins through the TGF beta/Smad signaling pathway to minimize extrinsic scarring. Thus, it may provide a novel approach to decrease tendon adhesion and promote tendon healing. PMID- 26935006 TI - Relationship between plasma bilirubin level and oxidative stress markers in HIV infected patients on atazanavir- vs. efavirenz-based antiretroviral therapy. AB - OBJECTIVES: Chronic oxidative stress (OS) may play a role in cardiovascular disease in HIV-infected patients, and increased bilirubin levels may have a beneficial role in counteracting OS. Atazanavir (ATV) inhibits UDP-glucuronosyl transferase 1A1 (UGT1A1), thus increasing unconjugated bilirubin levels. We aimed to compare changes in OS markers in patients on ATV/ritonavir (ATV/r)- vs. efavirenz (EFV)-based first-line antiretroviral therapy (ART). METHODS: A multicentre, prospective cohort study of HIV-infected patients who started first line ART with either ATV/r or EFV was conducted. Lipoprotein-associated phospholipase A2 (Lp-PLA2), myeloperoxidase (MPO) and oxidized low-density lipoprotein (oxLDL) were measured for 145 patients in samples obtained at baseline and after at least 9 months of ART during which the initial regimen was maintained and the patient was virologically suppressed. The change in OS markers was modelled using multiple linear regressions adjusting for baseline values and confounders. RESULTS: After adjustment for baseline variables, patients on ATV/r had a significantly greater decrease in Lp-PLA2 [estimated difference -16.3; 95% confidence interval (CI) -31.4, -1.25; P = 0.03] and a significantly smaller increase in OxLDL (estimated difference -21.8; 95% CI -38.0, -5.6; P < 0.01) relative to those on EFV, whereas changes in MPO were not significantly different (estimated difference 1.2; 95% CI -14.3, 16.7; P = 0.88). Adjusted changes in bilirubin were significantly greater for the ATV/r group than for the EFV group (estimated difference 1.33 mg/dL; 95% CI 1.03, 1.52 mg/dL; P < 0.01). Changes in bilirubin and changes in OS markers were significantly correlated. CONCLUSIONS: When compared with EFV, ATV/r-based therapy was associated with lower levels of oxidative stress biomarkers, which was in part attributable to increased bilirubin levels. PMID- 26935008 TI - Inverse association between altitude and obesity: A prevalence study among andean and low-altitude adult individuals of Peru. AB - OBJECTIVE: To determine the association between altitude and obesity in a nationally representative sample of the Peruvian adult population. METHODS: This is a cross-sectional analysis of publicly available data from the Food and Nutrition National Center (CENAN, Peru), period 2009-2010. The Prevalence ratio of obesity and abdominal obesity was determined as a measure of association. Obesity and abdominal obesity were diagnosed based on direct anthropometric measurements. RESULTS: The final data set consisted of 31,549 individuals >=20 years old. The prevalence ratio of obesity was as follows: 1.00 between 0 and 499 m (reference category), 1.00 (95% confidence interval 0.87-1.16) between 500 1,499 m, 0.74 (0.63-0.86) between 1,500-2,999 m, and 0.54 (0.45-0.64) at >=3,000 m, adjusting for age, sex, self-reported physical activity, out-migration rate, urbanization, poverty, education, and geographical latitude and longitude. In the same order, the adjusted prevalence ratio of abdominal obesity was 1.00, 1.01 (0.94-1.07), 0.93 (0.87-0.99), and 0.89 (0.82-0.95), respectively. We found an interaction between altitude and sex and between altitude and age (P < 0.001, for both interactions) on the association with obesity and abdominal obesity. CONCLUSIONS: Among Peruvian adult individuals, we found an inverse association between altitude and obesity, adjusting for multiple covariates. This adjusted association varied by sex and age. PMID- 26935009 TI - Mother-offspring recognition in the domestic cat: Kittens recognize their own mother's call. AB - Acoustic communication can play an important part in mother-young recognition in many mammals. This, however, has still only been investigated in a small range mainly of herd- or colony-living species. Here we report on the behavioral response of kittens of the domestic cat, a typically solitary carnivore, to playbacks of "greeting chirps" and "meows" from their own versus alien mothers. We found significantly stronger responses to the chirps from kittens' own mother than to her meows or to the chirps or meows of alien mothers. Acoustic analysis revealed greater variation between vocalizations from different mothers than for vocalizations from the same mother. We conclude that chirps emitted by mother cats at the nest represent a specific form of vocal communication with their young, and that kittens learn and respond positively to these and distinguish them from chirps of other mothers and from other cat vocalizations while still in the nest. (c) 2016 Wiley Periodicals, Inc. Dev Psychobiol 58: 568-577, 2016. PMID- 26935010 TI - Nitrogen remobilization and conservation, and underlying senescence-associated gene expression in the perennial switchgrass Panicum virgatum. AB - Improving nitrogen (N) remobilization from aboveground to underground organs during yearly shoot senescence is an important goal for sustainable production of switchgrass (Panicum virgatum) as a biofuel crop. Little is known about the genetic control of senescence and N use efficiency in perennial grasses such as switchgrass, which limits our ability to improve the process. Switchgrass aboveground organs (leaves, stems and inflorescences) and underground organs (crowns and roots) were harvested every month over a 3-yr period. Transcriptome analysis was performed to identify genes differentially expressed in various organs during development. Total N content in aboveground organs increased from spring until the end of summer, then decreased concomitant with senescence, while N content in underground organs exhibited an increase roughly matching the decrease in shoot N during fall. Hundreds of senescence-associated genes were identified in leaves and stems. Functional grouping indicated that regulation of transcription and protein degradation play important roles in shoot senescence. Coexpression networks predict important roles for five switchgrass NAC (NAM, ATAF1,2, CUC2) transcription factors (TFs) and other TF family members in orchestrating metabolism of carbohydrates, N and lipids, protein modification/degradation, and transport processes during senescence. This study establishes a molecular basis for understanding and enhancing N remobilization and conservation in switchgrass. PMID- 26935011 TI - A T7exonuclease-assisted target recycling amplification with graphene oxide acting as the signal amplifier for fluorescence polarization detection of human immunodeficiency virus (HIV) DNA. AB - We report a fluorescence polarization (FP) platform for human immunodeficiency virus (HIV) DNA detection based on T7exonuclease-assisted target recycling amplification with graphene oxide (GO) acting as a FP signal amplifier. In the sensing method, the presence of the target DNA leads to target recycling with the assistance of T7exonuclease, furthermore, the amplification products are absorbed onto the surface of GO, so the all FP values are enhanced by GO. More importantly, this FP sensor exhibits high detection sensitivity; under optimal conditions, the change in FP is linear with the concentration of the target DNA within a concentration range of 50-2000 pmol/L, and the detection limit of this method is as low as 38.6 pmol/L. This FP sensor also exhibits high selectivity, even single-base mismatched DNA can be effectively discriminated from complementary target DNA. Above all, the proposed FP sensor may serve as a general platform for the sensitive assay of disease-related genes. PMID- 26935012 TI - Perioperative progesterone for obese women with breast cancer may improve survival. PMID- 26935013 TI - Validation of the Italian version of the Stanford Presenteeism Scale in nurses. AB - AIMS: To ascertain the validity and reliability of the Italian version of the Stanford Presenteeism Scale (SPS-6). BACKGROUND: Presenteeism has been associated with a work productivity reduction, a lower quality of work and an increased risk of developing health disorders. It is particularly high among nurses and needs valid tools to be assessed. METHODS: A validation study was carried out from July to September 2014. A three-section tool, made of a demographic form, the Stanford Presenteeism Scale (SPS-6) and the Perceived Stress Scale (PSS-10) was administered to a sample of nurses, enrolled in three Italian hospitals. RESULTS: Cronbach's alpha for the entire sample (229 nurses) was found to be 0.72. A significant negative correlation between SPS and perceived stress scores evidenced the external validity. The factor analysis showed a two-component solution, accounting for 71.2% of the variance. The confirmatory factor analysis showed an adequate fit. CONCLUSION: The Italian SPS-6 is a valid and reliable tool for workplace surveys. IMPLICATIONS FOR NURSING MANAGEMENT: Since the validity and reliability of SPS-6 has been confirmed for the Italian version, we have now a valid tool that can measure the levels of presenteeism among Italian nurses. PMID- 26935014 TI - Folate and Inflammatory Markers Moderate the Association Between Helicobacter pylori Exposure and Cognitive Function in US Adults. AB - BACKGROUND: Helicobacter pylori (H. pylori) infection is associated with cognitive deficits in humans, an association potentially mediated or moderated by folate concentration or inflammation. MATERIALS AND METHODS: We used the National Health and Nutrition Examination Survey (NHANES) datasets to examine whether folate concentration or inflammation mediates or moderates the relationship between H. pylori and cognitive function. Models were performed using linear, Poisson, and zero-inflated Poisson regression, and we performed separate analyses for groups aged 20-59 and 60-90 years with sample sizes ranging from 700 to 1700. RESULTS: We did not find evidence of mediation in either age group. In the 20- to 59-year group, interactions between H. pylori and ferritin (p values ranging from .004 to .039) were associated with worse processing speed, better working memory, and worse reaction time. Interactions between H. pylori and fibrinogen (p values ranging from .023 to .045), C-reactive protein (CRP) (p = .023), and the inflammatory index (p = .045) were associated with worse processing speed. In 60- to 90-year-olds, H. pylori interacted with ferritin and the inflammatory index to predict fewer mathematical errors (p values of .036 and .023). Interactions with folate (p values of .016 and .006) and C-reactive protein (p values ranging from <.001 to .048) were inconsistent in directionality. CONCLUSIONS: In this dataset, representative of the US population, inflammation and folate concentrations moderated but did not mediate the association between H. pylori seropositivity and cognition. PMID- 26935015 TI - Release mechanism of high mobility group nucleosome binding domain 1 from lipopolysaccharide-stimulated macrophages. AB - Alarmins are identified as endogenous mediators that have potent immune activating abilities. High mobility group nucleosome binding domain 1 (HMGN1), a highly conserved, non-histone chromosomal protein, which binds to the inner side of the nucleosomal DNA, regulates chromatin dynamics and transcription in cells. Furthermore, HMGN1 acts as a cytokine in the extracellular milieu by inducing the recruitment and maturation of antigen-presenting cells (dendritic cells) to enhance Th1-type antigen-specific immune responses. Thus, HMGN1 is expected to act as an alarmin, when released into the extracellular milieu. The present study investigated the release mechanism of HMGN1 from macrophages using mouse macrophage-like RAW264.7 cells. The results indicated that HMGN1 was released from lipopolysaccharide (LPS)-stimulated RAW264.7 cells, accompanied by cell death as assessed by the release of lactate dehydrogenase (LDH). Subsequently, the patterns of cell death involved in HMGN1 release from LPS-stimulated RAW264.7 cells were determined using a caspase-1 inhibitor, YVAD, and a necroptosis inhibitor, Nec-1. YVAD and Nec-1 did not alter LPS-induced HMGN1 and LDH release, suggesting that pyroptosis (caspase-1-activated cell death) and necroptosis are not involved in the release of HMGN1 from LPS-stimulated RAW264.7 cells. In addition, flow cytometric analysis indicated that LPS stimulation did not induce apoptosis but substantially augmented necrosis, as evidenced by staining with annexin V/propidium iodide. Together these findings suggest that HMGN1 is extracellularly released from LPS-stimulated RAW264.7 macrophage-like cells, accompanied by unprogrammed necrotic cell death but not pyroptosis, necroptosis or apoptosis. PMID- 26935016 TI - AAV2 and Hepatocellular Carcinoma. PMID- 26935017 TI - Deep inspiration breath-hold volumetric modulated arc radiotherapy decreases dose to mediastinal structures in locally advanced lung cancer. PMID- 26935018 TI - Fracture strength, failure type and Weibull characteristics of lithium disilicate and multiphase resin composite endocrowns under axial and lateral forces. AB - OBJECTIVE: Multiphase resin composite materials have been advocated as an alternative to reinforced ceramics but limited information is available to date on their stability. This in vitro study evaluated the effect of axial and lateral forces on the strength of endocrowns made of Li2Si2O5 and multiphase resin composite. METHODS: Sound human molars (N=60, n=10 per group) were randomly divided into 6 groups: Group C: Control, no preparation or restoration; Group LI: Endocrown made of Li2Si2O5 (IPS e.max CAD) and Group LA: Endocrown made of multiphase resin composite material (Lava Ultimate). After decapitation and endodontic preparation, immediate dentin sealing was performed. Following CAD/CAM fabrication, their cementation surfaces were silica coated (CoJet System) and silanized (ESPE-Sil). Endocrowns were then adhesively cemented (Variolink II). All specimens were thermocycled (*10,000 cycles). While half of the specimens in each group were subjected to axial (C(A), LI(A), LA(A)), the other half was subjected to lateral static (C(L), LI(L), LA(L)) loading (1mm/min). Failure type and location after debonding/fracture were classified. Data were analyzed using ANOVA and Tukey's post hoc test (alpha=0.05). Two-parameter Weibull distribution values including the Weibull modulus, scale (m) and shape (0), values were calculated. RESULTS: Under axial loading, mean fracture strength (N) did not show significant difference between groups: LAA (2675+/-588)(a), LIA (2428+/-566)(a), CA (2151+/-672)(a) (p>0.05) and under lateral loading, LAL (838+/-169)(A) presented significantly lower mean values than those of other groups: CL (1499+/ 418)(B), LIL (1118+/-173)(B) (p<0.05). Both endocrown materials and the control group were more vulnerable to lateral loading than axial loading. Under axial loading, Weibull distribution presented higher shape (0) for Groups LIA (5.35) and LAA (5.08) than that of the control (3.97) and under lateral loading LIL (7.5) showed higher shape (0) than those of other groups (4.69-6.46). After axial loading, failure types were mainly cohesive in the material and after lateral loading primarily adhesive between the material and dentin for both LI and LA, most of which were repairable. SIGNIFICANCE: Under axial loading, molars restored with endocrowns performed similar with both Li2Si2O5 and multiphase resin composite but the latter was less durable under lateral loading. PMID- 26935019 TI - Malnutrition assessed by phase angle determines outcomes in low-risk cardiac surgery patients. AB - BACKGROUND & AIMS: Phase angle (PA), which is obtained from bioelectrical impedance analysis (BIA), is a non-invasive method for measuring altered electrical properties of biological tissues. It has been recognised as an objective prognostic marker of disease severity and frailty. The aim of this study is to determine whether PA is a marker of malnutrition and postoperative morbidity in low operative risk patients undergoing cardiac surgery. METHODS: A prospective study was conducted in a tertiary hospital. The nutritional state of the cardiac surgery patients was evaluated using BIA the day before the scheduled surgery. After applying selection criteria, 342 low operative risk patients were selected and classified into two groups in accordance with the PA value: a low PA group and a normal PA group. The correlation between low PA and low fat-free mass index (FFMI), a marker of malnutrition, was assessed. Associations between low PA and adverse postoperative outcomes, defined by the Society of Thoracic Surgeons postoperative risk evaluation model, were analysed. The impact of low PA on length of stay in an ICU and hospital was evaluated. RESULTS: Low PA was detected in 61 (17.8%) patients in the selected group, which consisted of low operative risk patients with a median Euroscore II value of 1.46 (IQR: 0.97-2.03) and was associated with FFMI with Pearson's R of 0.515 (p < 0.001). Low PA was associated with higher rates (13 [21.3%] vs. 30 [10.7%] p = 0.023) and risk of postoperative morbidity in univariate regression analysis (OR = 2.27, Cl 95% = 1.10-4.66, p = 0.026). Furthermore, low PA persisted as an independent factor in multivariate regression analysis (OR = 2.50, CI 95% 1.18-5.29, p = 0.016) adjusted for preoperative risk factors of postoperative morbidity. Evaluation of hospitalisation length revealed a tendency of a prolonged hospitalisation (>14 days) rate (31 [50.8%] vs. 105 [37.8%], p = 0.063) in the group with low PA. CONCLUSION: A low preoperative PA is an indicator of malnutrition and determines adverse outcomes after cardiac surgery. Further research is needed to evaluate clinical applications of the PA, such as a more accurate identification of malnourished cardiac surgery patients. PMID- 26935020 TI - Cannabinoid-Elicited Conditioned Place Preference in a Modified Behavioral Paradigm. AB - Cannabinoids are the active ingredients in marijuana, which is among the most widely used addictive drugs despite the well-documented harmfulness related to its abuse. The mechanism underlying cannabinoid addiction remains unclear, which is attributed partially to the difficulty in behavioral testing of high-dose cannabinoids using the conditioned place preference (CPP) model. Here, we optimized conditions for establishing CPP with the synthetic cannabinoid HU210 intraperitoneally administered at a high dose. We found that the natural place preference of rats could be exploited for establishing a biased CPP model, and that the adverse effect of HU210 could be ameliorated by adding four daily pre injections before the conditioning program. Thus, 0.1 mg/kg HU210 induced CPP when pre-injections were administered before traditional conditioning with HU210 administration paired with the non-preferred compartment. The present study provides a useful CPP model for behavioral measurement of the rewarding effects of cannabinoids. PMID- 26935021 TI - SIRT1 exerts protective effects against paraquat-induced injury in mouse type II alveolar epithelial cells by deacetylating NRF2 in vitro. AB - Silent information regulator 2-related enzyme 1 (SIRT1), a protein deacetylase, is known to strongly protect cells against oxidative stress-induced injury. The nuclear factor E2-related factor 2 (NRF2)-antioxidant response element (ARE) antioxidant pathway plays important regulatory roles in the antioxidant therapy of paraquat (PQ) poisoning. In the present study, we investigated whether the SIRT1/NRF2/ARE signaling pathway plays an important role in lung injury induced by PQ. For this purpose, mouse type II alveolar epithelial cells (AECs-II) were exposed to various concentrations of PQ. The overexpression or silencing of SIRT1 was induced by transfecting the cells with a SIRT1 overexpression vector or shRNA targeting SIRT1, respectively. The protein expression levels of SIRT1 and NRF2 were measured by western blot analysis. The superoxide dismutase (SOD) and catalase (CAT) activities, as well as the glutathione (GSH) and malondialdehyde (MDA) levels were measured using respective kits. Heme oxygenase-1 (HO-1) activity was also determined by ELISA. In addition, cell apoptosis was determined by flow cytometry. The protein stability of NRF2 was analyzed using cycloheximide and its acetylation in the cells was also determined. The following findings were obtained: i) SIRT1 overexpression markedly increased NRF2 protein expression; ii) SIRT1 promoted the transcriptional activity of NRF2 and upregulated the expression of the NRF2 downstream genes, SOD, CAT, GSH and HO-1, thus inhibiting the apoptosis of AECs-II; iii) the inhibition of SIRT1 activity further induced the production of malondialdehyde (MDA), which resulted in increased oxidative damage; iv) SIRT1 promoted the stability of NRF2 by regulating the deacetylation and activation of the NRF2/ARE antioxidant pathway. The findings of this study demonstrate that the protective effects of SIRT1 are associated with the activation of the NRF2/ARE antioxidant pathway in lung injury induced by PQ poisoning. PMID- 26935022 TI - Downregulation of miR-129-2 by promoter hypermethylation regulates breast cancer cell proliferation and apoptosis. AB - Aberrant expression of the miR-129 family has been found in several types of cancer, yet its expression and potential biologic role in breast cancer remain largely unknown. In the present study, we found that miR-129-2 was consistently downregulated in the breast cancer specimens and cell lines. Overexpression of miR-129-2-3p markedly suppressed breast cancer cell proliferation and induced its apoptosis. In addition, a luciferase reporter assay revealed that miR-129-2-3p suppressed BCL2L2 expression. Furthermore, BCL2L2 was able to reverse miR-129-2 3p-mediated cell apoptosis, indicating that BCL2L2 plays a crucial role in mediating the tumor-suppressive role of miR-129-2-3p. Moreover, bisulfite DNA sequencing PCR (BSP) analysis identified that promoter hypermethylation was responsible for the downregulation of miR-129-2 in breast cancer. Collectively, our findings indicate that miR-129-2 is downregulated in breast cancer cells by promoter hypermethylation. Moreover, downregulation of miR-129-2 results in BCL2L2 overexpression and disease progression in breast cancer patients. PMID- 26935023 TI - Therapeutic effects of various methods of MSC transplantation on cerebral resuscitation following cardiac arrest in rats. AB - In the present study, mesenchymal stem cells (MSCs) were transplanted into the brain of rats following cardiopulmonary resuscitation (CPR) by three different methods: Direct stereotaxic injection into the lateral cerebral ventricle (LV), intra-carotid administration (A), and femoral venous infusion (V). The three different methods were compared by observing the effects of MSCs on neurological function following global cerebral hypoxia-ischemia, in order to determine the optimum method for MSC transplantation. MSCs were transplanted in groups A, V and LV following the restoration of spontaneous circulation. Neurological deficit scale scores were higher in the transplantation groups, as compared with the control group. Neuronal damage, brain water content and serum levels of S100 calcium-binding protein B were reduced in the hippocampus and temporal cortex of the transplantation groups, as compared with the control rats following resuscitation. MSCs were able to migrate inside the brain tissue following transplantation, and were predominantly distributed in the hippocampus and temporal cortex where the neurons were vulnerable during global cerebral ischemia. These results suggest that transplantation of MSCs may notably improve neurological function following CPR in a rat model. Of the three different methods of MSC transplantation tested in the present study, LV induced the highest concentration of MSCs in brain areas vulnerable to global cerebral ischemia, and therefore, produced the best neurological outcome. PMID- 26935024 TI - Radiosensitization effect of Huaier on breast cancer cells. AB - Radiotherapy is a critical treatment strategy for breast cancer. However, its wide application is sometimes restricted by radioresistance and radiotoxicity. Trametes robiniophila Murr. (Huaier), an officinal fungus used as a traditional Chinese medicine (TCM), is reported to have multi-biological functions during cancer treatment. Yet, its radiosensitization effects have not been evaluated to date. In the present study, using HTA 2.0 transcriptome microarray assay, Huaier was found to downregulate genes related to the cell cycle, cell division, cell cycle phases and DNA repair. This investigation utilized a colony formation assay to confirm the ability of Huaier to sensitize breast cancer cells to radiotherapy. Flow cytometry, immunofluorescence staining and western blotting were used to illustrate the sensitization mechanism. Our findings suggest that Huaier causes G0/G1 arrest through downregulation of cell cycle-regulating proteins in MCF-7 and MDA-MB-468 cells, prolongs the persistence of gamma-H2Ax foci after radiotherapy and interferes with the homologous recombination (HR) pathway of DNA repair by downregulating RAD51. These results suggest that Huaier has the ability to sensitize breast cancer cells to radiotherapy through regulation of the cell cycle and DNA repair pathway. Thus, Huaier may be a promising radiosensitizer for the treatment of breast cancer. PMID- 26935025 TI - How can we improve the environmental sustainability of poultry production? AB - The review presents results of recent life cycle assessment studies aiming to quantify and improve the environmental performance of UK poultry production systems, including broiler meat, egg and turkey meat production. Although poultry production has been found to be relatively environmentally friendly compared with the production of other livestock commodities, it still contributes to environmental impacts, such as global warming, eutrophication and acidification. Amongst different sub-processes, feed production and transport contributes about 70 % to the global warming potential of poultry systems, whereas manure management contributes about 40-60 % to their eutrophication potential and acidification potential, respectively. All these impacts can be reduced by improving the feed efficiency, either by changing the birds through genetic selection or by making the feed more digestible (e.g. by using additives such as enzymes). However, although genetic selection has the potential to reduce the resources needed for broiler production (including feed consumption), the changing need of certain feed ingredients, most notably protein sources as a result of changes in bird requirements may limit the benefits of this strategy. The use of alternative feed ingredients, such as locally grown protein crops and agricultural by-products, as a replacement of South American grown soya, can potentially also lead to improvements in several environmental impact categories, as long as such feeding strategies have no negative effect on bird performance. Other management options, such as improving poultry housing and new strategies for manure management have also the potential to further improve the environmental sustainability of the poultry industries in Europe. PMID- 26935026 TI - Genetic features of human and bovine Escherichia coli O157:H7 strains isolated in Argentina. AB - Shiga toxin-producing Escherichia coli (STEC) are important food-borne pathogens associated with human diseases. In Argentina, O157:H7 is the dominant serotype in hemolytic uremic syndrome (HUS) cases. Previously, we have described the almost exclusive circulation of human E. coli O157 strains belonging to the hypervirulent clade 8 in Neuquen Province. The aim of the present study was to investigate, by a broad molecular characterization, if this particular distribution of E. coli O157 clades in Neuquen is similar to the situation in other regions of the country and if it may be originated in a similar profile in cattle, its main reservoir. Two-hundred and eighty O157 strains (54 bovine and 226 human) isolated between 2006 and 2008 in different regions of Argentina were studied. All strains harbored rfbO157, fliCH7, eae, and ehxA genes. The predominant genotype was stx2a/stx2c in human (76.1%) and bovine (55.5%) strains. All human isolates tested by Lineage-Specific Polymorphism Assay (LSPA-6), were lineage I/II; among bovine strains, 94.1% belonged to lineage I/II and 5.9% to lineage I. No LSPA-6 lineage II isolates were detected. Single nucleotide polymorphism (SNP) analysis has revealed the existence of nine clade phylogenetic groups. In our clinical strains collection, 87.6% belonged to the hypervirulent clade 8, and 12.4% were classified as clade 4/5. In bovine isolates, 59.3% strains were clade 8, 33.3% clade 4/5 and 7.4% clade 3. More than 80% of human strains showed the presence of 6 of the 7 virulence determinants described in the TW14359 O157 strain associated with the raw spinach outbreak in the U.S. in 2006. More than 80% of bovine strains showed the presence of 3 of these factors. The q933 allele, which has been related to high toxin production, was present in 98.2% of clinical strains and 75.9% of the bovine isolates. The molecular characterization of human STEC O157 strains allows us to conclude that the particular situation previously described for Neuquen Province, may actually be a characteristic of the whole country. These genetic features are quite similar to those observed in the bovine reservoir and may be derived from it. This data confirms that, unlike the rest of the world, in Argentina most of the STEC O157 strains present in cattle may cause human infections of varying severity and the marked virulence described for these strains may be related to the high incidence of HUS in our country. PMID- 26935027 TI - Characterization of the malaria parasite protein PfTip, a novel invasion-related protein. AB - Malaria is one of the most common infective diseases in the world. Invasion of host erythrocytes by the malaria parasite is crucial for pathogen survival and pathogenesis. Various proteins mediate parasite invasion and identification of novel invasion-related proteins may aid in elucidating the underlying molecular mechanism and new intervention strategies for malaria control. This study characterized the PfTip protein, a homolog of the human T-cell immunomodulatory protein, and examined its function in preventing parasite infection. Bioinformatics analysis and experimental validation were adopted in the present study. Bioinformatics analysis showed that PfTip has a beta-propeller fold in its structure and is highly expressed at the early ring stage. TNFRSF14 was predicted to be a candidate interactant of PfTip. Further analyses showed that PfTip blockage by sera inhibited erythrocyte invasion by the malaria parasite. The protective effect of PfTip was further confirmed through in vivo analysis. To the best of our knowledge, this study is the first to provide evidence on the function of PfTip in erythrocyte parasite invasion. Additional assays involving the receptor of this protein are currently underway. PMID- 26935028 TI - Long noncoding RNA MALAT1 promotes hepatic steatosis and insulin resistance by increasing nuclear SREBP-1c protein stability. AB - Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is implicated in liver cell proliferation. However, its role in hepatic steatosis and insulin resistance remain poorly understood. The aim of this study was to investigate the effects of MALAT1 on hepatic lipid accumulation and its potential targets. As expected, MALAT1 expression is increased in hepatocytes exposed to palmitate and livers of ob/ob mice. Knockdown of MALAT1 expression dramatically suppressed palmitate-induced lipid accumulation and the increase of nuclear SREBP-1c protein in HepG2 cells. In addition, RNA immunoprecipitation and RNA pull-down assay confirmed that MALAT1 interacted with SREBP-1c to stabilize nuclear SREBP-1c protein. Finally, injection of si-MALAT1 prevented hepatic lipid accumulation and insulin resistance in ob/ob mice. In conclusion, our observations suggest that MALAT1 promotes hepatic steatosis and insulin resistance by increasing nuclear SREBP-1c protein stability. PMID- 26935029 TI - Weak antilocalization in Cd3As2 thin films. AB - Recently, it has been theoretically predicted that Cd3As2 is a three dimensional Dirac material, a new topological phase discovered after topological insulators, which exhibits a linear energy dispersion in the bulk with massless Dirac fermions. Here, we report on the low-temperature magnetoresistance measurements on a ~50 nm-thick Cd3As2 film. The weak antilocalization under perpendicular magnetic field is discussed based on the two-dimensional Hikami-Larkin-Nagaoka (HLN) theory. The electron-electron interaction is addressed as the source of the dephasing based on the temperature-dependent scaling behavior. The weak antilocalization can be also observed while the magnetic field is parallel to the electric field due to the strong interaction between the different conductance channels in this quasi-two-dimensional film. PMID- 26935030 TI - Heat Shock Protein 27 is down-regulated in Ballooned Hepatocytes of Patients with Nonalcoholic Steatohepatitis (NASH). AB - Ballooning degeneration (BD) of hepatocytes is a distinguishing histological feature associated with the progression of nonalcoholic fatty liver disease (NAFLD). Under the assumption that NAFLD severity is associated with metabolic stress we explored the hypothesis that heat shock 27 kDa protein 1 (HSP27), a protein chaperone involved in stress resistance and cytoskeletal-remodeling, might be deregulated in ballooned hepatocytes. We observed that fasting plasma glucose (fpG) (p = 0.00002), total cholesterol (p = 0.02) and triglycerides (p = 0.01) levels, and female sex (p = 0.01) were significantly associated with the presence of BD. A logistic regression model showed that BD was independently associated with fpG (p = 0.002); OR per unit of glucose concentration 1.05, 95% confidence interval 1.02-1.09. Furthermore, BD was associated with a significant 2.24-fold decrease in the expression level of HSP27-mRNA in comparison with absence of ballooning, p = 0.002. Ballooned hepatocytes showed very low HSP27 immunoreactivity compared with hepatocyes without ballooning (p = 0.009); HSP27 immunoreactivity was inversely correlated with fpG levels (R: -0.49, p = 0.01). In conclusion, BD is associated with down-regulation of liver HSP27 gene and protein expression, suggesting that ballooned hepatocytes fail to ensure a robust physiological response to metabolic-induced stress. PMID- 26935032 TI - Health policy: Reducing rheumatic heart disease in Africa -- time for action. AB - Rheumatic heart disease (RHD) key opinion leaders, health ministers, clinicians, and industry representatives gathered in Ethiopia in February 2015. The question: how to eradicate RHD in Africa. The response: the Addis Ababa communique, a practical document outlining seven major barriers to RHD control in Africa and seven strategies to address them. PMID- 26935033 TI - Vascular disease: Carotid artery stenosis - stenting or endarterectomy? PMID- 26935036 TI - Arrhythmias: Opening Pandora's Box -- incidental genetic findings. AB - A major goal of precision medicine is to improve disease prevention and therapy by using big data provided by genomic technology and electronic health records. In a new study, assessment of a patient population without a history of cardiac disease revealed that genetic variants putatively associated with a risk of sudden death were not linked with arrhythmia phenotypes. PMID- 26935037 TI - Valvular disease: Benefit of early surgery for infective endocarditis. PMID- 26935038 TI - Epidemiology and aetiology of heart failure. AB - Heart failure (HF) is a rapidly growing public health issue with an estimated prevalence of >37.7 million individuals globally. HF is a shared chronic phase of cardiac functional impairment secondary to many aetiologies, and patients with HF experience numerous symptoms that affect their quality of life, including dyspnoea, fatigue, poor exercise tolerance, and fluid retention. Although the underlying causes of HF vary according to sex, age, ethnicity, comorbidities, and environment, the majority of cases remain preventable. HF is associated with increased morbidity and mortality, and confers a substantial burden to the health care system. HF is a leading cause of hospitalization among adults and the elderly. In the USA, the total medical costs for patients with HF are expected to rise from US$20.9 billion in 2012 to $53.1 billion by 2030. Improvements in the medical management of risk factors and HF have stabilized the incidence of this disease in many countries. In this Review, we provide an overview of the latest epidemiological data on HF, and propose future directions for reducing the ever increasing HF burden. PMID- 26935039 TI - Abnormal correlation of circulating endothelial progenitor cells and endothelin-1 concentration may contribute to the development of arterial hypertension in childhood acute lymphoblastic leukemia survivors. AB - It is well known that the rate of arterial hypertension (AH) in childhood acute lymphoblastic leukemia (ALL) survivors is significantly higher than that in the healthy pediatric population; however, the mechanism of this phenomenon is not fully understood. The developing cardiovascular system in children is thought to be highly susceptible to the toxic effects of chemotherapy, which causes damage to the blood vessel wall, including the endothelium. Endothelin-1 (ET-1) is a marker of endothelial damage, and it contributes to AH. Endothelial progenitor cells (EPCs) are derived from the bone marrow and participate in the process of blood vessel repair. The aim of this study was to determine the relationship between the rate of circulating EPCs and plasma levels of ET-1 with respect to hypertension in childhood ALL survivors. The study included 88 childhood ALL survivors and 44 healthy children as controls. All patients and controls had 24-h blood pressure monitoring with a HolCARD CR-07 device. The number of EPCs and the ET-1 serum concentration were measured in the peripheral blood of patients and controls using flow cytometry and enzyme-linked immunosorbent assay, respectively. A correlation was found between the number of EPCs and the ET-1 concentration in the peripheral blood of healthy children and normotensive ALL survivors. However, such a correlation was not found in hypertensive childhood ALL survivors. We conclude that dysregulation of the 'ET-1 and EPC axis' may contribute to the development of AH in some childhood ALL survivors. PMID- 26935040 TI - Twenty-four-hour urinary sodium and potassium excretion and associated factors in Japanese secondary school students. AB - Data on the sodium and potassium intake using dietary records among schoolchildren are sorely lacking in the Japanese literature. Some evidence indicates that sodium and potassium intake has been correctly measured, but information concerning these associated factors is scarce. The 24-h urine samples and first morning voiding (overnight) samples were collected twice from 68 secondary schoolchildren in Suo-Oshima Town, Japan. Sodium, potassium and creatinine concentrations were analyzed. Body height and weight were measured, and menstruation and physical activity were assessed via questionnaires. We analyzed the 24-h samples with a >20-h collecting period and no missed voiding. The 24-h sodium excretion was 163.2+/-36.8 and 149.8+/-45.1 mmol per 24 h for the boys and girls, respectively. Considering daily habits and loss from sweat, intake was assumed to be 10.6+/-1.2 and 10.0+/-2.4 g per day for the boys and girls, respectively. The 24-h potassium excretion was 43.4+/-10.8 and 45.8+/-14.4 mmol per 24 h for the boys and girls, respectively. Estimated usual potassium intake was 2195+/-401 and 2330+/-630 mg per day for the boys and girls, respectively. Sodium excretion was associated with sodium and potassium concentrations in overnight urine samples and physical activity. Potassium excretion was associated with height and physical activity. We described daily sodium and potassium excretion in Japanese secondary schoolchildren. Excretion was associated more with physical activity than with bodyweight. Therefore, the estimation methods used in adults are not applicable for use in adolescents. PMID- 26935041 TI - Differential root transcriptomics in a polyploid non-model crop: the importance of respiration during osmotic stress. AB - To explore the transcriptomic global response to osmotic stress in roots, 18 mRNA seq libraries were generated from three triploid banana genotypes grown under mild osmotic stress (5% PEG) and control conditions. Illumina sequencing produced 568 million high quality reads, of which 70-84% were mapped to the banana diploid reference genome. Using different uni- and multivariate statistics, 92 genes were commonly identified as differentially expressed in the three genotypes. Using our in house workflow to analyze GO enriched and underlying biochemical pathways, we present the general processes affected by mild osmotic stress in the root and focus subsequently on the most significantly overrepresented classes associated with: respiration, glycolysis and fermentation. We hypothesize that in fast growing and oxygen demanding tissues, mild osmotic stress leads to a lower energy level, which induces a metabolic shift towards (i) a higher oxidative respiration, (ii) alternative respiration and (iii) fermentation. To confirm the mRNA-seq results, a subset of twenty up-regulated transcripts were further analysed by RT-qPCR in an independent experiment at three different time points. The identification and annotation of this set of genes provides a valuable resource to understand the importance of energy sensing during mild osmotic stress. PMID- 26935043 TI - Deciphering DNA replication dynamics in eukaryotic cell populations in relation with their averaged chromatin conformations. AB - We propose a non-local model of DNA replication that takes into account the observed uncertainty on the position and time of replication initiation in eukaryote cell populations. By picturing replication initiation as a two-state system and considering all possible transition configurations, and by taking into account the chromatin's fractal dimension, we derive an analytical expression for the rate of replication initiation. This model predicts with no free parameter the temporal profiles of initiation rate, replication fork density and fraction of replicated DNA, in quantitative agreement with corresponding experimental data from both S. cerevisiae and human cells and provides a quantitative estimate of initiation site redundancy. This study shows that, to a large extent, the program that regulates the dynamics of eukaryotic DNA replication is a collective phenomenon that emerges from the stochastic nature of replication origins initiation. PMID- 26935042 TI - Physiological, Diurnal and Stress-Related Variability of Cadmium-Metallothionein Gene Expression in Land Snails. AB - The terrestrial Roman snail Helix pomatia has successfully adapted to strongly fluctuating conditions in its natural soil habitat. Part of the snail's stress defense strategy is its ability to express Metallothioneins (MTs). These are multifunctional, cysteine-rich proteins that bind and inactivate transition metal ions (Cd(2+), Zn(2+), Cu(+)) with high affinity. In Helix pomatia a Cadmium (Cd) selective, inducible Metallothionein Isoform (CdMT) is mainly involved in detoxification of this harmful metal. In addition, the snail CdMT has been shown to also respond to certain physiological stressors. The aim of the present study was to investigate the physiological and diurnal variability of CdMT gene expression in snails exposed to Cd and non-metallic stressors such as desiccation and oxygen depletion. CdMT gene expression was upregulated by Cd exposure and desiccation, whereas no significant impact on the expression of CdMT was measured due to oxygen depletion. Overall, Cd was clearly more effective as an inducer of the CdMT gene expression compared to the applied non-metallic stressors. In unexposed snails, diurnal rhythmicity of CdMT gene expression was observed with higher mRNA concentrations at night compared to daytime. This rhythmicity was severely disrupted in Cd-exposed snails which exhibited highest CdMT gene transcription rates in the morning. Apart from diurnal rhythmicity, feeding activity also had a strong impact on CdMT gene expression. Although underlying mechanisms are not completely understood, it is clear that factors increasing MT expression variability have to be considered when using MT mRNA quantification as a biomarker for environmental stressors. PMID- 26935044 TI - The Effect of Chloroquine on Immune Activation and Interferon Signatures Associated with HIV-1. AB - Immune activation associated with HIV-1 infection contributes to morbidity and mortality. We studied whether chloroquine, through Toll-like receptor (TLR) antagonist properties, could reduce immune activation thought to be driven by TLR ligands, such as gut-derived bacterial elements and HIV-1 RNAs. AIDS Clinical Trials Group A5258 was a randomized, double-blind, placebo-controlled study in 33 HIV-1-infected participants off antiretroviral therapy (ART) and 37 participants on ART. Study participants in each cohort were randomized 1:1 to receive chloroquine 250 mg orally for the first 12 weeks then cross over to placebo for 12 weeks or placebo first and then chloroquine. Combining the periods of chloroquine use in both arms of the on-ART cohort yielded a modest reduction in the proportions of CD8 T cells co-expressing CD38 and DR (median decrease = 3.0%, p = .003). The effect on immune activation in the off-ART cohort was likely confounded by increased plasma HIV-1 RNA during chloroquine administration (median 0.29 log10 increase, p < .001). Transcriptional analyses in the off-ART cohort showed decreased expression of interferon-stimulated genes in 5 of 10 chloroquine-treated participants and modest decreases in CD38 and CCR5 RNAs in all chloroquine-treated participants. Chloroquine modestly reduced immune activation in ART-treated HIV-infected participants. Clinical Trials Registry Number: NCT00819390. PMID- 26935045 TI - Describing functioning and health after spinal cord injury in the light of psychological-personal factors. AB - OBJECTIVE: To describe and explore functioning and health of persons with spinal cord injury from the perspective of psychological-personal factors in the light of the International Classification of Functioning, Disability and Health (ICF) framework. METHODS: Data from 511 participants regarding feelings, thoughts and beliefs, motives, and patterns of experience and behaviour were analysed. Measurement instruments included the Mental Health Index-5, Positive and Negative Affect Schedule, Hospital Anxiety and Depression Scale, Appraisal of Life Events Scale, 5 items from the World Health Organization Quality of Life Scale, Purpose in Life Test-Short Form, General Self-Efficacy Scale, Big Five Inventory-21, Social Skills Inventory-SF, Brief COPE. The distribution of the selected psychological-personal factors-indicators was examined using descriptive statistics. Differences between SCI subgroups by sex, age, age at injury, time since injury, aetiology and severity of injury were explored using analysis of variance (ANOVA) and F-tests. RESULTS: Participants who were older and sustained their spinal cord injury more recently experienced more depressed mood, less positive affect, less challenge appraisal, lower life satisfaction, lower purpose in life, and lower self-efficacy. They reported lower social skills, less usage of the coping strategies humour, positive reframing, and acceptance, and more usage of the coping strategies denial and self-distraction. Overall, effect sizes were small. DISCUSSION: Although study participants appeared to be well adjusted to spinal cord injury, those who sustained their injury at an older age and more recently reported more negative experiences. Quantitative description and exploration of the psychological-personal aspects of health will enable hypotheses to be formulated for further research, and suggest a need for tailored interventions for those at risk of less favourable outcomes. PMID- 26935046 TI - [Cannabis--Position Paper of the German Respiratory Society (DGP)]. AB - In this position paper, the adverse health effects of cannabis are reviewed based on the existing scientific literature; in addition possible symptom-relieving effects on some diseases are depicted. In Germany, cannabis is the most widely used illicit drug. Approximately 600,000 adult persons show abusive or addictive cannabis consumption. In 12 to 17 year old adolescents, cannabis use increased from 2011 to 2014 from 2.8 to 6.4%, and the frequency of regular use from 0.2 to 1.5%. Currently, handling of cannabinoids is much debated in politics as well as in general public. Health aspects have to be incorporated into this debate. Besides analysing mental and neurological side effects, this position paper will mainly focus on the influences on the bronchopulmonary and cardiovascular system. There is strong evidence for the induction of chronic bronchitis. Allergic reactions including asthma are known, too. Associations with other diseases like pulmonary emphysema, lung cancer and pneumonia are not sufficiently proven, however cannot be excluded either. In connection with the use of cannabis cardiovascular events such as coronary syndromes, peripheral vascular diseases and cerebral complications have been noted. Often, the evidence is insufficient due to various reasons; most notably, the overlapping effects of tobacco and cannabis use can frequently not be separated adequately. Empirically, early beginning, high-dosed, long-lasting and regular cannabis consumption increase the risk of various psychological and physical impairments and negatively affect age based development. Concerns therefore relate especially to children and adolescents. There is only little scientific evidence for medical benefits through cannabis as a remedy; systematic research of good quality, in particular prospective, randomised, placebo-controlled double-blinded studies are rare. The medical societies signing this position paper conclude that cannabis consumption is linked to adverse health effects which have to be taken into consideration in the debate about the social attitude towards cannabinoids. The societies agree that many aspects regarding health effects of cannabis are still uncertain and need clarification, preferably through research provided by controlled studies. PMID- 26935047 TI - Integrated analysis of long non-coding RNA competing interactions reveals the potential role in progression of human gastric cancer. AB - Abnormal expression of long non-coding RNAs (lncRNAs) have been shown to play an important role in tumor biology. The Cancer Genome Atlas (TCGA) platform is a large sample sequencing database of lncRNAs, and further analysis of the associations between these data and patients' clinical related information can provide new approaches to find the functions of lncRNA. In the present study, 361 RNA sequencing profiles of gastric cancer (GC) patients were selected from TCGA. Then, we constructed the lncRNA-miRNA-mRNA competitive endogenous RNA (ceRNA) network of GC. There were 25 GC specific lncRNAs (fold change >2, p<0.05) identified, 19 of them were included in ceRNA network. Subsequently, we selected these 19 key lncRNAs and analyzed the correlations with clinical features and overall survival, 14 of them were discriminatively expressed with tumor size, tumor grade, TNM stage and lymphatic metastasis (p<0.05). In addition, eight lncRNAs (RPLP0P2, FOXD2-AS1, H19, TINCR, SLC26A4-AS1, SMIM10L2A, SMIM10L2B and SNORD116-4) were found to be significantly associated with overall survival (log rank p<0.05). Finally, two key lncRNAs HOTAIR and UCA1 were selected for validation of their expression levels in 82 newly diagnosed GC patients by qRT PCR. Results showed that the fold changes between TCGA and qRT-PCR were 100% in agreement. In addition, we also found that HOTAIR was significantly correlated with tumor size and lymphatic metastasis (p<0.05), and UCA1 was significantly correlated with tumor size, TNM stage and lymphatic metastasis (p<0.05). The clinical relevance of the two lncRNAs and the bioinformatics analysis results were almost the same. Overall, our study showed the GC specific lncRNAs expression patterns and a ceRNA network in GC. Clinical features related to GC specific lncRNAs also suggested these lncRNAs are worthwhile for further study as novel candidate biomarkers for the clinical diagnosis of GC and potential indicators for prognosis. PMID- 26935048 TI - Critical length scales and strain localization govern the mechanical performance of multi-layer graphene assemblies. AB - Multi-layer graphene assemblies (MLGs) or fibers with a staggered architecture exhibit high toughness and failure strain that surpass those of the constituent single sheets. However, how the architectural parameters such as the sheet overlap length affect these mechanical properties remains unknown due in part to the limitations of mechanical continuum models. By exploring the mechanics of MLG assemblies under tensile deformation using our established coarse-grained molecular modeling framework, we have identified three different critical interlayer overlap lengths controlling the strength, plastic stress, and toughness of MLGs, respectively. The shortest critical length scale L(C)(S) governs the strength of the assembly as predicted by the shear-lag model. The intermediate critical length L(C)(P) is associated with a dynamic frictional process that governs the strain localization propensity of the assembly, and hence the failure strain. The largest critical length scale L(C)(T) corresponds to the overlap length necessary to achieve 90% of the maximum theoretical toughness of the material. Our analyses provide the general guidelines for tuning the constitutive properties and toughness of multilayer 2D nanomaterials using elasticity, interlayer adhesion energy and geometry as molecular design parameters. PMID- 26935049 TI - Stimulation of V1a receptor increases renal uric acid clearance via urate transporters: insight into pathogenesis of hypouricemia in SIADH. AB - BACKGROUND: Hypouricemia is pathognomonic in syndrome of inappropriate secretion of antidiuretic hormone (SIADH) but the underlying mechanism remains unclear. Based on the previous studies, we hypothesized that V1a receptor may play a principal role in inducing hypouricemia in SIADH and examined uric acid metabolism using a rat model. METHODS: Terlipressin (25 ng/h), a selective V1a agonist, was subcutaneously infused to 7-week-old male Wistar rats (n = 9). Control rats were infused with normal saline (n = 9). The rats were sacrificed to obtain kidney tissues 3 days after treatment. In addition to electrolyte metabolism, changes in expressions of the urate transporters including URAT1 (SLC22A12), GLUT9 (SLC2A9), ABCG2 and NPT1 (SLC17A1) were examined by western blotting and immunohistochemistry. RESULTS: In the terlipressin-treated rats, serum uric acid (UA) significantly decreased and the excretion of urinary UA significantly increased, resulting in marked increase in fractional excretion of UA. Although no change in the expression of URAT1, GLUT9 expression significantly decreased whereas the expressions of ABCG2 and NPT1 significantly increased in the terlipressin group. The results of immunohistochemistry corroborated with those of the western blotting. Aquaporin 2 expression did not change in the medulla, suggesting the independence of V2 receptor stimulation. CONCLUSION: Stimulation of V1a receptor induces the downregulation of GLUT9, reabsorption urate transporter, together with the upregulation of ABCG2 and NPT1, secretion urate transporters, all changes of which clearly lead to increase in renal UA clearance. Hypouricemia seen in SIADH is attributable to V1a receptor stimulation. PMID- 26935050 TI - Chronic Pain and Prescription Drug Use and Abuse: Emerging Research in General Internal Medicine. PMID- 26935051 TI - Factors associated with (non-)participation of cancer survivors with job loss in a supportive return to work program. AB - PURPOSE: To evaluate and implement supportive programs, it is important to understand which cancer survivors (CSs) are participating in these programs and which motives exist for declining participation. Recently, a supportive return-to work (RTW) program was offered to CSs with job loss. The purpose of this study was to identify factors and motives associated with (non-)participation of CSs with job loss in the RTW program. METHODS: In this cross-sectional study (N = 286), information on socio-demographic, health-related, psychosocial, and work related characteristics of CSs in the program was collected. Similar data were collected from those who declined participation. Multivariable logistic regression analyses were conducted (p < 0.05) to identify factors associated with (non-)participation. Motives for declining participation were identified using descriptive analysis. RESULTS: Being married (odds ratio (OR) 0.23; 95 % confidence interval (CI) 0.08-0.69) or living together (OR 0.25; 95 % CI 0.07 0.96) decreased the likelihood of participation in the RTW program. Having a temporary employment contract prior to unemployment (OR 2.60; 95 % CI 1.20-5.63), a clear intention to RTW (OR 2.65; 95 % CI 1.20-5.82), and higher scores on a readiness to RTW instrument, i.e., contemplation scale (OR 2.00; 95 % CI 1.65 2.40) and prepared for action-self-evaluative scale (OR 1.27; 95 % CI 1.04-1.54), increased the likelihood of participation. Physical (50 %) and mental problems (36 %) were leading motives for declining participation. CONCLUSIONS: The results from this study help to distinguish CSs that may not need RTW support, from those who are most in need of RTW support. Practitioners and researchers should tailor RTW support to CSs' socio-demographic, health-related, and work-related characteristics. PMID- 26935052 TI - HBV culture and infectious systems. AB - While an effective vaccine against hepatitis B virus (HBV) has long been available, chronic HBV infection remains a severe global public health concern. Current treatment options have limited effectiveness, and long-term therapy is required to suppress HBV replication; however, complete elimination of the virus is rare. The lack of suitable animal models and infection systems has hindered efforts to unravel the HBV life cycle, particularly the early events in HBV entry, which appear to be highly species- and tissue-specific. Human primary hepatocytes remain the gold standard for HBV replication studies but are limited by availability and variability. While the HepaRG cell line is permissive for HBV replication, other hepatoma cell lines such as HepG2 do not support HBV replication. The recent discovery of sodium taurocholate transporting peptide (NTCP) as a primary receptor for HBV binding has led to the development of replication-competent cell lines such as HepG2-NTCP. Human hepatocytes grown in chimeric mice have provided another approach that allows primary human hepatocytes to be used while overcoming many of their limitations. Although the difficulty in developing HBV infection systems has hindered development of effective treatments, the variability and limited replication efficiency among cell lines point to additional liver-specific factors involved in HBV infection. It is hoped that HBV infection studies will lead to novel drug targets and therapeutic options for the treatment of chronic HBV infection. PMID- 26935053 TI - A glossary of ARDS for beginners. PMID- 26935054 TI - Otologic evaluation of patients with primary antibody deficiency. AB - Common variable immunodeficiency (CVID) represents the most frequent primary immunodeficiency, often encountered in the ENT clinical practice. The clinical spectrum of CVID is quite broad, but otitis media are certainly among the most common clinical manifestations. This prospective study enrolled 60 patients (34 males, 26 females) with a previous diagnosis of CVID with the aim of performing an otologic evaluation and a more precision characterization of incidence, diagnosis, and treatment of otitis media in this group of patients. In consideration that Eustachian tube dysfunction (ETD) could be the 'primum movens' of otitis media, we wanted to assess whether a Eustachian tube dysfunction was present in these patients. Besides, we propose a possible diagnostic algorithm of middle ear pathologies to use in all cases of primary antibody deficiency patients. Results of our otologic examination showed that: 5 % of patients had chronic suppurative otitis media, 25 % bilateral otitis media with effusion and 10 % reported unilateral OME with associated contralateral ETD. There was bilateral isolated ETD and unilateral isolated ETD in 5 and 15 % of patients, respectively. All patients with unilateral OME had associated contralateral ETD. Finally, 40 % of patients were bilaterally negative at otoscopic examination and all otologic tests. PMID- 26935055 TI - The functional outcome of blow-out fractures managed surgically and conservatively: our experience in 100 patients. AB - The proportion of orbital blow-out fractures (BOFs) which are operated upon varies. The purpose of this study was to determine the treatment pattern of BOFs at our tertiary trauma centre and to evaluate the functional outcomes in patients according to whether they were managed surgically or conservatively. The study design is a retrospective cohort study and the setting is Tertiary care University Hospital. The participants include patients with isolated BOFs admitted to our Trauma Unit from 2010 to 2013. Of the 100 consecutive patients included, 60 had available follow-up data. The presence of diplopia and enophthalmus was determined by reviewing the medical records. Data from the patients' initial consultation and their 3-month follow-up were also collected. Of the 60 patients whose data could be analysed, 36 had been managed surgically and 24 conservatively. Of the patients managed surgically, 25 had diplopia in peripheral gaze before surgery and 12 at 3-month follow-up. Nine had diplopia in primary gaze before surgery and none at 3-month follow-up. Five had enophthalmus before surgery and two at 3-month follow-up. Of the patients managed conservatively, eight had diplopia in peripheral gaze initially and seven at 3 month follow-up. Three had diplopia in primary gaze initially and one at 3-month follow-up. One had enophthalmus initially which was still present at 3-month follow-up. Primary gaze diplopia disappeared while secondary gaze diplopia was present in about a third of patients, whether managed surgically or conservatively at the 3-month follow-up. Standardised follow-up as well as clear indications for and against surgery are warranted. PMID- 26935056 TI - Technology in Muslim Moral Philosophy. AB - The article explores the place, role and status of technology in Muslim moral philosophy. Invoking early Muslim encounters with technology the author makes the case why technology is already deeply embedded in contemporary Muslim bioethical thinking. Due to an absence of the philosophical grounding there remains some ambivalence as to why technology is essential to Muslim ethical thinking. Countering the techno-pessimists, the author makes a case in favor of compositional thinking, namely that our thinking itself is altered by our tools and our environment. Compositional thinking opposes the representational mode of thinking that creates a dichotomy between nature versus culture, and technology versus nature. One should, however, anticipate an environment in which technology would be beneficial and not be viewed as potentially harmful. PMID- 26935057 TI - Local delivery of CpG-B and GM-CSF induces concerted activation of effector and regulatory T cells in the human melanoma sentinel lymph node. AB - Impaired immune effector functions in the melanoma sentinel lymph node (SLN) may allow for early metastatic events. In an effort to determine the optimal way to strengthen immune defenses, 28 clinical stage I-II melanoma patients were randomized in a 3-arm Phase II study to receive, prior to excision and sampling of the SLN, i.d. injections of saline or low-dose CpG-B (CpG), alone or combined with GM-CSF (GM), around the melanoma excision site. We previously described the combined administration of these DC-targeting agents to result in activation and recruitment of potentially cross-presenting BDCA3(+) DCs to the SLN. In this report we describe the effects on effector and regulatory T and NK cell subsets. Local low-dose CpG administration resulted in lower CD4/CD8 ratios, Th1 skewing, increased frequencies of melanoma-specific CD8(+) T cells and possible recruitment of effector NK cells, irrespective of GM co-administration. These immune-potentiating effects were counterbalanced by increased IL-10 production by T cells and significantly higher levels of FoxP3 and CTLA4 in regulatory T cells (Tregs) with correspondingly higher suppressive activity in the SLN. Notably, CpG +/- GM-administered patients showed significantly lower numbers of SLN metastases (saline: 4/9, CpG + GM: 1/9, CpG: 0/10, p = 0.04). These findings indicate that i.d. delivery of low-dose CpG +/- GM potentially arms the SLN of early-stage melanoma patients against metastatic spread, but that antitumor efficacy may be further boosted by counteracting the collateral activation of Tregs. PMID- 26935058 TI - Highly and moderately aggressive mouse ovarian cancer cell lines exhibit differential gene expression. AB - Patients with advanced epithelial ovarian cancer often experience disease recurrence after standard therapies, a critical factor in determining their five year survival rate. Recent reports indicated that long-term or short-term survival is associated with varied gene expression of cancer cells. Thus, identification of novel prognostic biomarkers should be considered. Since the mouse genome is similar to the human genome, we explored potential prognostic biomarkers using two groups of mouse ovarian cancer cell lines (group 1: IG-10, IG-10pw, and IG-10pw/agar; group 2: IG-10 clones 2, 3, and 11) which display highly and moderately aggressive phenotypes in vivo. Mice injected with these cell lines have different survival time and rates, capacities of tumor, and ascites formations, reflecting different prognostic potentials. Using an Affymetrix Mouse Genome 430 2.0 Array, a total of 181 genes were differentially expressed (P < 0.01) by at least twofold between two groups of the cell lines. Of the 181 genes, 109 and 72 genes were overexpressed in highly and moderately aggressive cell lines, respectively. Analysis of the 109 and 72 genes using Ingenuity Pathway Analysis (IPA) tool revealed two cancer-related gene networks. One was associated with the highly aggressive cell lines and affiliated with MYC gene, and another was associated with the moderately aggressive cell lines and affiliated with the androgen receptor (AR). Finally, the gene enrichment analysis indicated that the overexpressed 89 genes (out of 109 genes) in highly aggressive cell lines had a function annotation in the David database. The cancer-relevant significant gene ontology (GO) terms included Cell cycle, DNA metabolic process, and Programmed cell death. None of the genes from a set of the 72 genes overexpressed in the moderately aggressive cell lines had a function annotation in the David database. Our results suggested that the overexpressed MYC and 109 gene set represented highly aggressive ovarian cancer potential biomarkers while overexpressed AR and 72 gene set represented moderately aggressive ovarian cancer potential biomarkers. Based on our knowledge, the current study is first time to report the potential biomarkers relevant to different aggressive ovarian cancer. These potential biomarkers provide important information for investigating human ovarian cancer prognosis. PMID- 26935059 TI - Metabolomics of papillary thyroid carcinoma tissues: potential biomarkers for diagnosis and promising targets for therapy. AB - Papillary thyroid carcinoma (PTC) is the most common pathological type of thyroid cancer. Our study was to construct a tissue-targeted metabolomics analysis method based on untargeted and targeted metabolic multi-platforms to identify a comprehensive PTC metabolic network in clinical samples. We applied untargeted gas chromatography-time-of-flight mass spectrometry (GC-TOF-MS) for preliminary screening of potential biomarkers. With diagnostic models constructed using principal component analysis (PCA), partial least squares discriminant analysis (PLS-DA) and orthogonal partial least squares discriminant analysis (OPLS-DA), 45 differentially abundant metabolites with a variable importance in the projection (VIP) value greater than 1 and a P value less than 0.05 were identified, and we show that our approach was able to discriminate PTC tissues from healthy tissues. We then performed validation experiments based on targeted GC-TOF-MS combined with ultra-high-performance liquid chromatography-triple-quadrupole mass spectrometry (UHPLC-QqQ-MS) through constructing linear standard curves of analytes. Ultimately, galactinol, melibiose, and melatonin were validated as significantly altered metabolites (p < 0.05). These three metabolites were defined as a combinatorial biomarker to assist needle biopsy for PTC diagnosis as demonstrated by receiver operating characteristic (ROC) curve analysis, which revealed an area under the ROC curve (AUC) value of 0.96. Based on the metabolite enrichment analysis results, the galactose metabolism pathway was regarded as an important factor influencing PTC development by affecting energy metabolism. Alpha-galactosidase (GLA) was considered to be a potential target for PTC therapy. PMID- 26935060 TI - miRNA-204 suppresses human non-small cell lung cancer by targeting ATF2. AB - MicroRNAs (miRNAs) play a critical role in cancer development and progression. Deregulated expression of miR-204 has been reported in several cancers, but the mechanism through which miR-204 modulates human non-small cell lung cancer (NSCLC) is largely unknown. In this study, we investigate the expression and functional role of miR-204 in human NSCLC tissues and cell lines. RNA isolation, qRT-PCR, MTT, colony formation assay, cell cycle assay, cell apoptosis assay, cell migration assay, and Western blot were performed. Statistical analysis was performed using SPSS 18.0 software and statistical significance was accepted at p value <0.05. miR-204 level was significantly reduced in NSCLC tissues as compared to that of non-neoplastic tissues. Transient over-expression of miR-204 by transfecting with miR-204 mimics suppressed NSCLC cell proliferation, migration, and induced apoptosis and G1 arrest, whereas inhibition of miR-204 showed the converse effects. Additionally, activating transcription factor 2 (ATF2), an important transcription factor, was demonstrated as a potential target gene of miR-204. Subsequent investigations found a negative correlation between miR-204 level and ATF2 expression in NSCLC tissue samples. Moreover, we observed that miR 204 expression inversely affected endogenous ATF2 expression at both mRNA and protein levels in vitro. Taken together, miR-204 may act as a tumor suppressor by directly targeting ATF2 in NSCLC. PMID- 26935061 TI - Unwrapping Neurotrophic Cytokines and Histone Modification. AB - The conventional view that neuroinflammatory lesions contain strictly pro- and anti-inflammatory cytokines is being challenged. Some proinflammatory products e.g. TNF-alpha are crucial intermediates in axon regeneration, oligodendroglial renewal and remyelination. A more functional system of nomenclature classifies cytokines by their neuro 'protective' or 'suppressive' properties. Beyond the balance of these 'environmental' or 'extrinsic' signals, specific 'intrinsic' determinants of cytokine signalling appear to influence the outcome of axoglial regeneration. In this commentary, we examine the potential importance of cytokine induced histone modification on oligodendrocyte differentiation. Neuroinflammation mediates the release of astrocytic leukaemia inhibitory factor (LIF) and erythropoietin (EPO) which potentiates oligodendrocyte differentiation and myelin production. Meanwhile, histone deacetylation strongly suppresses important inhibitors of oligodendrocyte differentiation. Given that LIF and EPO induce histone deacetylases in other systems, future studies should examine whether this mechanism significantly influences the outcome of cytokine-induced remyelination, and whether epigenetic drug targets could potentiate the effects of exogenous cytokine therapy. PMID- 26935062 TI - Primary Cilia in the Murine Cerebellum and in Mutant Models of Medulloblastoma. AB - Cellular primary cilia crucially sense and transduce extracellular physicochemical stimuli. Cilium-mediated developmental signaling is tissue and cell type specific. Primary cilia are required for cerebellar differentiation and sonic hedgehog (Shh)-dependent proliferation of neuronal granule precursors. The mammalian G-protein-coupled receptor 37-like 1 is specifically expressed in cerebellar Bergmann glia astrocytes and participates in regulating postnatal cerebellar granule neuron proliferation/differentiation and Bergmann glia and Purkinje neuron maturation. The mouse receptor protein interacts with the patched 1 component of the cilium-associated Shh receptor complex. Mice heterozygous for patched homolog 1 mutations, like heterozygous patched 1 humans, have a higher incidence of Shh subgroup medulloblastoma (MB) and other tumors. Cerebellar cells bearing primary cilia were identified during postnatal development and in adulthood in two mouse strains with altered Shh signaling: a G-protein-coupled receptor 37-like 1 null mutant and an MB-susceptible, heterozygous patched homolog 1 mutant. In addition to granule and Purkinje neurons, primary cilia were also expressed by Bergmann glia astrocytes in both wild-type and mutant animals, from birth to adulthood. Variations in ciliary number and length were related to the different levels of neuronal and glial cell proliferation and maturation, during postnatal cerebellar development. Primary cilia were also detected in pre neoplastic MB lesions in heterozygous patched homolog 1 mutant mice and they could represent specific markers for the development and analysis of novel cerebellar oncogenic models. PMID- 26935063 TI - Short-Term Ketamine Treatment Decreases Oxidative Stress Without Influencing TRPM2 and TRPV1 Channel Gating in the Hippocampus and Dorsal Root Ganglion of Rats. AB - Calcium ions (Ca2+) are important second messengers in neurons. Ketamine (KETAM) is an anesthetic and analgesic, with psychotomimetic effects and abuse potential. KETAM modulates the entry of Ca2+ in neurons through glutamate receptors, but its effect on transient receptor potential melastatin 2 (TRPM2) and transient receptor potential vanilloid 1 (TRPV1) channels has not been clarified. This study investigated the short-term effects of KETAM on oxidative stress and TRPM2 and TRPV1 channel gating in hippocampal and dorsal root ganglion (DRG) neurons of rats. Freshly isolated hippocampal and DRG neurons were incubated for 24 h with KETAM (0.3 mM). The TRPM2 channel antagonist, N-(p-amylcinnamoyl)anthranilic acid (ACA), inhibited cumene hydroperoxide and ADP-ribose-induced TRPM2 currents in the neurons, and capsazepine (CPZ) inhibited capsaicin-induced TRPV1 currents. The TRPM2 and TRPV1 channel current densities and intracellular free calcium ion concentration of the neurons were lower in the neurons exposed to ACA and CPZ compared to the control neurons, respectively. However, the values were not further decreased by the KETAM + CPZ and KETAM + ACA treatments. KETAM decreased lipid peroxidation levels in the neurons but increased glutathione peroxidase activity. In conclusion, short-term KETAM treatment decreased oxidative stress levels but did not seem to influence TRPM2- and TRPV1-mediated Ca2+ entry. PMID- 26935064 TI - A Single Intrathecal or Intraperitoneal Injection of CB2 Receptor Agonist Attenuates Bone Cancer Pain and Induces a Time-Dependent Modification of GRK2. AB - The objective of this study was to explore the potential role of G-protein coupled receptor kinase 2 (GRK2) in the progression of cannabinoid 2 receptor (CB2) agonist-induced analgesic effects of bone cancer pain. Female Sprague Dawley rats, weighing 160-180 g, were utilized to establish a model of bone cancer pain induced by intra-tibia inoculation of Walker 256 mammary gland carcinoma cells. JWH-015, a selective CB2 agonist, was injected intrathecally or intraperitoneally on postoperative day 10. Bone cancer-induced pain behaviors mechanical allodynia and ambulatory pain-were assessed on postoperative days -1 (baseline), 4, 7, and 10 and at post-treatment hours 2, 6, 24, 48, and 72. The expressions of spinal CB2 and GRK2 protein were detected by Western Blotting on postoperative days -1 (baseline), 4, 7, and 10 and at post-treatment hours 6, 24, and 72. The procedure produced prolonged mechanical allodynia, ambulatory pain, and different changes in spinal CB2 and GRK2 expression levels. Intrathecal or intraperitoneal administration of JWH-015 alleviated the induced mechanical allodynia and ambulatory pain, and inhibited the downregulation of spinal GRK2 expression. These effects were in a time-dependent manner and reversed by pretreatment of CB2 selective antagonist AM630. The results affirmed CB2 receptor agonists might serve as new treatment targets for bone cancer pain. Moreover, spinal GRK2 was an important regulator of CB2 receptor agonist-analgesia pathway. PMID- 26935065 TI - Efficacy and reinfection with soil-transmitted helminths 18-weeks post-treatment with albendazole-ivermectin, albendazole-mebendazole, albendazole-oxantel pamoate and mebendazole. AB - BACKGROUND: Preventive chemotherapy with albendazole or mebendazole is the current strategy to control soil-transmitted helminth (STH) infections (i.e. Ascaris lumbricoides, hookworm and Trichuris trichiura). STH reinfections, in particular A. lumbricoides and T. trichiura occur rapidly after treatment with the standard drugs. However, their low efficacy against T. trichiura, made an accurate assessment of reinfection patterns impossible. METHODS: In 2013 a randomised controlled trial was conducted on Pemba Island, Tanzania. School-aged children diagnosed positive for T. trichiura, were randomly allocated to (i) albendazole-ivermectin; (ii) albendazole-mebendazole; (iii) albendazole-oxantel pamoate; or (iv) mebendazole. Here we report the efficacy [cure rates (CR) and egg-reduction rates (ERR)], reinfection rates and new infections determined 18 weeks post-treatment. RESULTS: For a total of 405 children complete baseline and follow-up data were available. Similar to the efficacy determined after 3 weeks, 18 weeks after treatment albendazole-oxantel pamoate showed a significantly higher efficacy against T. trichiura (CR: 54.0 %, 95 % CI: 43.7-64.0; ERR: 98.6 %, 95 % CI: 97.8-99.2) compared to the other treatment arms. Children treated with albendazole-oxantel pamoate or albendazole-ivermectin had fewer moderate infections compared to children treated with albendazole. The reinfection rates 18 weeks post-treatment among all treatment arms were 37.2 % for T. trichiura (95 % CI: 28.3-46.8), 34.6 % for A. lumbricoides (95 % CI: 27.3-42.3) and 25.0 % for hookworms (95 % CI: 15.5-36.6). CONCLUSION: The moderate reinfection rates with STHs 18 weeks post-treatment support the concept of regular anthelminthic treatment in highly endemic settings. Combination chemotherapy might achieve decreased morbidity in children since in the albendazole plus oxantel pamoate and albendazole plus ivermectin treatment arms only few moderate T. trichiura infections remained. Further trials should investigate the long term efficacy of albendazole-oxantel pamoate (i.e. 6 and 12 month post-treatment) and after several rounds of treatment in order to develop recommendations for appropriate control approaches for STH infections. TRIAL REGISTRATION: Current Controlled Trials ISRCTN80245406. PMID- 26935067 TI - A systematic molecular dynamics approach to the study of peptide Keap1-Nrf2 protein-protein interaction inhibitors and its application to p62 peptides. AB - Protein-protein interactions (PPIs) as drug targets have been gaining growing interest, though developing drug-like small molecule PPI inhibitors remains challenging. Peptide PPI inhibitors, which can provide informative data on the PPI interface, are good starting points to develop small molecule modulators. Computational methods combining molecular dynamics simulations and binding energy calculations could give both the structural and the energetic perspective of peptide PPI inhibitors. Herein, we set up a computational workflow to investigate Keap1-Nrf2 peptide PPI inhibitors and predict the activity of novel sequences. Furthermore, we applied this method to investigate p62 peptides as PPI inhibitors of Keap1-Nrf2 and explored the activity change induced by the phosphorylation of serine. Our results showed that because of the unfavorable solvation effects, the binding affinity of the phosphorylated p62 peptide is lower than the Nrf2 ETGE peptide. Our research results not only provide a useful method to investigate the Keap1-Nrf2 peptide inhibitors, but also give a good example to show how to incorporate computational methods into the study of peptide PPI inhibitors. Besides, applying this method to p62 peptides provides a detailed explanation for the expression of cytoprotective Nrf2 targets induced by p62 phosphorylation, which may benefit the further study of the crosstalk between the Keap1-Nrf2 pathway and p62-mediated selective autophagy. PMID- 26935066 TI - The relative importance of kinetic mechanisms and variable enzyme abundances for the regulation of hepatic glucose metabolism--insights from mathematical modeling. AB - BACKGROUND: Adaptation of the cellular metabolism to varying external conditions is brought about by regulated changes in the activity of enzymes and transporters. Hormone-dependent reversible enzyme phosphorylation and concentration changes of reactants and allosteric effectors are the major types of rapid kinetic enzyme regulation, whereas on longer time scales changes in protein abundance may also become operative. Here, we used a comprehensive mathematical model of the hepatic glucose metabolism of rat hepatocytes to decipher the relative importance of different regulatory modes and their mutual interdependencies in the hepatic control of plasma glucose homeostasis. RESULTS: Model simulations reveal significant differences in the capability of liver metabolism to counteract variations of plasma glucose in different physiological settings (starvation, ad libitum nutrient supply, diabetes). Changes in enzyme abundances adjust the metabolic output to the anticipated physiological demand but may turn into a regulatory disadvantage if sudden unexpected changes of the external conditions occur. Allosteric and hormonal control of enzyme activities allow the liver to assume a broad range of metabolic states and may even fully reverse flux changes resulting from changes of enzyme abundances alone. Metabolic control analysis reveals that control of the hepatic glucose metabolism is mainly exerted by enzymes alone, which are differently controlled by alterations in enzyme abundance, reversible phosphorylation, and allosteric effects. CONCLUSION: In hepatic glucose metabolism, regulation of enzyme activities by changes of reactants, allosteric effects, and reversible phosphorylation is equally important as changes in protein abundance of key regulatory enzymes. PMID- 26935068 TI - Lithium ion intercalation of 3-D vertical hierarchical TiO2 nanotubes on a titanium mesh for efficient photoelectrochemical water splitting. AB - In this communication, we report for the first time the demonstration of a lithium ion intercalation strategy to significantly enhance the photoelectrochemical water splitting performance on 3-dimensional vertical hierarchical top-porous-bottom-tubular TiO2 nanotubes on a fabricable titanium mesh. PMID- 26935069 TI - Comparative transcriptomics and proteomics of three different aphid species identifies core and diverse effector sets. AB - BACKGROUND: Aphids are phloem-feeding insects that cause significant economic losses to agriculture worldwide. While feeding and probing these insects deliver molecules, called effectors, inside their host to enable infestation. The identification and characterization of these effectors from different species that vary in their host range is an important step in understanding the infestation success of aphids and aphid host range variation. This study employs a multi-disciplinary approach based on transcriptome sequencing and proteomics to identify and compare effector candidates from the broad host range aphid Myzus persicae (green peach aphid) (genotypes O, J and F), and narrow host range aphids Myzus cerasi (black cherry aphid) and Rhopalosiphum padi (bird-cherry oat aphid). RESULTS: Using a combination of aphid transcriptome sequencing on libraries derived from head versus body tissues as well as saliva proteomics we were able to predict candidate effectors repertoires from the different aphid species and genotypes. Among the identified conserved or core effector sets, we identified a significant number of previously identified aphid candidate effectors indicating these proteins may be involved in general infestation strategies. Moreover, we identified aphid candidate effector sequences that were specific to one species, which are interesting candidates for further validation and characterization with regards to species-specific functions during infestation. We assessed our candidate effector repertoires for evidence of positive selection, and identified 49 candidates with DN/DS ratios >1. We noted higher rates of DN/DS ratios in predicted aphid effectors than non-effectors. Whether this reflects positive selection due to co-evolution with host plants, or increased neofunctionalization upon gene duplication remains to be investigated. CONCLUSION: Our work provides a comprehensive overview of the candidate effector repertoires from three different aphid species with varying host ranges. Comparative analyses revealed candidate effectors that are most likely are involved in general aspects of infestation, whereas others, that are highly divergent, may be involved in specific processes important for certain aphid species. Insights into the overlap and differences in aphid effector repertoires are important in understanding how different species successfully infest different ranges of plant species. PMID- 26935070 TI - Constructing maternal morbidity - towards a standard tool to measure and monitor maternal health beyond mortality. AB - BACKGROUND: Maternal morbidity is a complex entity and its presentation and severity are on a spectrum. This paper describes the conceptualization and development of a definition for maternal morbidity, and the framework for its measurement: the maternal morbidity matrix, which is the foundation for measuring maternal morbidity, thus, the assessment tool. DISCUSSION: We define maternal morbidity and associated disability as "any health condition attributed to and/or complicating pregnancy and childbirth that has a negative impact on the woman's wellbeing and/or functioning." A matrix of 121 conditions was generated through expert meetings, review of the International Classification of Diseases and related health problems (ICD-10), literature reviews, applying the definition of maternal morbidity and a cut-off of >0.1% prevalence. This matrix has three dimensions: identified morbidity category, reported functioning impact and maternal history. The identification criteria for morbidity include 58 symptoms, 29 signs, 44 investigations and 35 management strategies; these criteria are aimed at recognizing the medical condition, or the functional impact/disability component that will capture the negative impact experienced by the woman. The maternal morbidity matrix is a practical framework for assessing maternal morbidity beyond near-miss. In light of the emerging attention to Universal Health Coverage (UHC) as part of the post-2015 Sustainable Development Goals (SDGs) planning, a definition and standard identification criteria are essential to measuring its extent and impact. PMID- 26935071 TI - [New Developments to Break the Limitations of the Integrated Program--Inclusive Reform of Teaching and Learning by the Jigsaw Method]. PMID- 26935072 TI - [Introduction and Evaluation of an Integrated Program to Develop Pharmacotherapeutic Management Skills]. AB - Pharmacists must be able to select and collect important information for patient care, to accurately assess and monitor the status of patients, to develop care plans, propose optimal formulations, and provide advice to patients about pharmacotherapy. The core curriculum of Japan's pharmacy education model was revised in 2013 based on the "Basic competencies required of a pharmacist" that should be developed by the time of a student's graduation. Specific behavioral objectives to be acquired include competency in "The ability to implement pharmacotherapeutic management", which involves gaining the ability to understand patient information, to design and propose prescriptions, and to conduct pharmacotherapeutic assessments. We thus introduced an integrated program for fifth-year students at Hokkaido Pharmaceutical University using problem-based learning and role-playing with simulated patients to teach clinical communication skills and the ability to design pharmaceutical care plans for patients. A survey of students who completed the program after pharmacy practical training revealed that most of them realized the value of the program: they were able to develop precise care plans for medical problems and learned good communication skills to collect information about patients. PMID- 26935073 TI - [Theory and Practice of the Constructive Jigsaw Method in Advancing Domain Knowledge and Skills in Parallel]. AB - The Learning Sciences constitute a rapidly expanding discipline that focuses on the learning potential of humans. In this paper, I will discuss the particular learning mechanism involved in the concomitant advancement of domain knowledge and 21st century skills, as well as the Constructive Jigsaw Method of knowledge construction through collaboration-that is, collaborative problem solving. An especially important focus on knowledge construction separates routine experts from adaptive experts. While routine experts develop a core set of skills that they apply throughout their lives with increasing efficiency, adaptive experts are much more likely to change their core skills and continually expand the depth of their expertise. This restructuring of core ideas and skills may reduce their efficiency in the short run but make them more flexible in the long run. The Constructive Jigsaw Method employs a learning mechanism that encourages the development of adaptive experts. Under this method, students first study a piece of material in an expert group. One member from each of several expert groups then joins a new study group, a jigsaw group. The members of this new group then combine what they have learned, creating new knowledge and a deeper understanding of the concept through collaboration, communication, and innovation. PMID- 26935074 TI - [Jigsaw Method Is Used to Promote a First Year-student's Understanding of Integrated Subjects at Kobe Pharmaceutical University]. AB - In the School of Pharmacy, collaborative learning that includes both problem based learning (PBL) and team-based learning (TBL) methods, has been introduced as an active learning method into the education of first-year pharmacy students. These methods are an educational approach to teaching and learning that involve groups of students working collaboratively to resolve a problem, complete a task, or develop a product. However, these methods might not aid students who focus more on the results than on the problem-solving process. In addition, the self efficacy and learning motivation of students who dislike these learning methods might decrease. The Jigsaw Method respects the individuality of students and is a collaborative learning approach that decreases conflict among students with varied learning styles. Upon applying this method in the first-year course at Kobe Pharmaceutical University, it was observed that most students who attended the life science class increased their self-efficacy, and their passive learning attitudes transformed into active ones. The introduction of the Jigsaw Method to the education of first-year students can help them acquire an effective technique for learning integrated subjects. PMID- 26935075 TI - [The Synergistic Effect of Problem-based Learning Combined with the Jigsaw Method in a Pharmacotherapy Course]. AB - To promote problem-solving ability within a pharmacotherapy course, we developed new problem-based learning (PBL) and information and communication technologies (ICT) support systems, and introduced the "Jigsaw Method," an active learning method in which, similar to parts of a jigsaw puzzle, students are dependent on each other to create the full picture, to succeed. We conducted 10 PBL modules (one case per module), each lasting one week. To encourage constructive group work, information sharing, and student understanding in the individual modules, we implemented a Jigsaw Method-based wiki worksheet system in which students were to identify patient problems and check each other's work on an e-portfolio system. After completing this new curriculum, students were able to create comprehensive therapeutic care plans. A significant correlation was observed between the students' care plan evaluation scores and their module test results, suggesting that constructive group work can enhance problem-solving ability in therapeutics. These results clearly indicate the benefit of combining our new PBL ICT support system with the Jigsaw Method. PMID- 26935076 TI - [Approach to the Education of Kampo Medicine by Pharmacognosy Faculty]. PMID- 26935077 TI - [Kampo Education in the Faculty of Pharmaceutical Sciences at Toho University]. AB - In the Faculty of Pharmaceutical Sciences at Toho University, Kampo education commenced 40 years ago through a course titeled "Kampo", which has since been renamed as "Kampo Pharmacology". The current university curriculum offers courses in subjects such as Pharmacognosy and Practical Pharmacognosy for sophomores, Kampo Pharmacology for juniors, and Clinical Kampo Medicine for seniors. Kampo Pharmacology is a subject that bridges "Pharmacognosy" to "Clinical Kampo Medicine". The functions of the crude drugs included in Kampo prescriptions are explained both in terms of efficacy from the perspective of Kampo and by contemporary evidence. Furthermore, the "Clinical Kampo Therapeutics" course offered for seniors involves lectures on the fundamentals of Kampo, determination of evidence and prescriptions, case analysis, and prescription analysis by physicians affiliated with our university's medical center. Acquiring an understanding of the effectiveness of crude drugs in herbal medicine and gaining practical clinical knowledge are considered beneficial for future pharmacists. PMID- 26935078 TI - [Approach to Teaching Kampo Medicine at Kyoto Pharmaceutical University]. AB - An approach to educating our pharmaceutical students about Kampo medicine in the six-year system of undergraduate pharmacy education at Kyoto Pharmaceutical University is introduced, including the author's opinions. Curriculum revisions have been made in our university for students entering after 2012. In teaching Kampo medicine at present, a medical doctor and an on-site pharmacist share information difficult to give in a lecture with the teaching staff in my laboratory. For example, before the curriculum revision, we conferred with a pharmacist and a doctor in the course "Kampo Medicine A, B" for 4th year students, in which students were presented a basic knowledge of Kampo medicine, the application of important Kampo medicines, combinations of crude drugs, etc. Further, in our "Introduction to Kampo Medicine" for 6th year students, presented after they have practiced in hospitals and community pharmacies, we again lecture on the pharmacological characteristics of Kampo medicines, on "pattern (Sho)", and on evidence-based medicine (EBM) and research studies of important Kampo medicines. After our curriculum revision, "Kampo Medicine A, B" was rearranged into the courses "Kampo and Pharmacognosy" and "Clinical Kampo Medicine". "Kampo and Pharmacognosy" is now provided in the second semester of the 3rd year, and in this course we lecture on the basic knowledge of Kampo medicine. An advanced lecture will be given on "Clinical Kampo Medicine" in the 6th year. We are searching for the best way to interest students in Kampo medicine, and to counteract any misunderstandings about Kampo medicine. PMID- 26935079 TI - [How to Teach Kampo Medicine in the Age of Internationalization?]. AB - Given the universal prevalence of complementary and alternative medicines, as well as integrative medicine, the usage of traditional medicine has been gaining in popularity worldwide. Japanese Kampo medicine and traditional Chinese medicine (TCM) are both derived from ancient medicines used in East Asia in the 5th-7th centuries, and have developed independently since the 14th century. Now Kampo medicine and TCM have different theories for the diagnosis and use of crude drugs. Unfortunately, Kampo medicine is not well known in Europe and the Americas; as a matter of practice, TCM is the international standard for traditional medicines derived from ancient East Asia. In the teaching of Kampo medicines to undergraduate students in a school of pharmacy, the author considers that a minimum requirement is to explain the differences between TCM and Kampo medicine. For graduate students of pharmaceutical science, the students must know the distinct medical theories of both TCM and Kampo medicine, and furthermore, must be able to read and write articles in English about traditional medicines, in order to help put Kampo medicine on the world map. PMID- 26935080 TI - [Education Program of Kampo-medicine for Undergraduates in Preparation for Clinical Setting]. AB - Kampo-medicine has become popular in Japanese medical practice combined with western medicine. For example, Daikenchu-To for intestinal obstruction after surgical operation, Shakuyakukanzo-To and Goshajinki-Gan for anti-cancer agents induced neuropathy, and Yokkan-San for behavioral psychological symptoms of dementia are alternatively used in addition to conventional treatments in Japan. However, combined use of Kampo-medicine and western medicine may cause unexpected adverse events including undesirable drug-drug interactions because Kampo medicine was not originally developed to be used with western medicine. Although adverse effects of Kampo-medicine are rare compared with those of western medicine, severe events such as liver dysfunction and interstitial pneumonia have been reported in increasing trends. Medical staff including pharmacists, therefore, should be aware of the onset of adverse events before the patients' symptoms become severe. Several adverse effects are caused by chemical constituents such as glycyrrhizin in licorice for pseudoaldosteronism and geniposide in Gardeniae fructus for mesenteric phlebosclerosis. To understand the adverse effects of Kampo-medicine, pharmacists should learn trends in current medication as well as pharmacology and toxicology of the chemical constituents in pharmacognosy. These issues should also be addressed in educational materials for students of clinical pharmacy and pharmacy practice. PMID- 26935081 TI - [Kampo Medicine in the New Model Core Curriculum of Pharmaceutical Education]. AB - What should we educate for Kampo medicine in the model core curriculum of pharmaceutical education? The curricular core should be discussed considering the points mentioned below. (1) Positioning of Kampo medicine in the Japanese medical care system. Kampo medicine is an authorized medical care category in the National Health Insurance (NHI) program in Japan. The NHI drug price list carries 148 Kampo formulations. According to the report of the Japan Kampo Medicines Manufacturers Association in 2011, approximately 90% of Japanese physicians prescribe Kampo medicines. (2) Differences between Kampo medicine and western medicine: In Kampo medicine, the most suitable formula among various Kampo formulas to normalize the psychophysical state of individual patients is selected. In other words, if there is a complaint, there are always some treatments. (3) A strong point of Kampo medicine: Kampo medicine enables physicians to deal with difficult-to-treat conditions by western medicine alone. Also, by using the scale of Kampo medicine, each patient can grasp his or her own systemic state and improve their lifestyle. To extend healthy life expectancy, a basic knowledge of Kampo medicine may play a significant role in integrated health care. "The guide book of the approval standards for OTC Kampo products", "the pharmaceutical advanced educational guideline", and "the manual of the exam questions preparation for registered sales clerks" should also be consulted before selecting the area and contents that should be covered. PMID- 26935082 TI - [Evaluation and Exploring Technique for Drug Target Discovery]. PMID- 26935083 TI - [Development of a Drug Discovery Method Targeted to Stromal Tissue]. AB - Several diseases are characterized by alterations in the molecular distribution of vascular structures, presenting the opportunity to use monoclonal antibodies for clinical therapies. This pharmaceutical strategy, often referred to as "vascular targeting", has promise in promoting the discovery and development of selective biological drugs to regulate angiogenesis-related diseases such as cancer. Various experimental approaches have been utilized to discover accessible vascular markers of health and disease at the protein level. Our group has developed a new chemical proteomics technology to identify and quantify accessible vascular proteins in normal organs and at disease sites. Our developed methodology relies on the perfusion of animal models with suitable ester derivatives of biotin, which react with the primary amine groups of proteins as soon as the molecules are attached. This presentation reports biomedical applications based on vascular targeting strategies, as well as methodologies that have been used to discover new vascular targets. The identification of antigens located in the stromal tissue of pathological blood vessels may provide attractive targets for the development of antibody drugs. This method will also provide an efficient discovery target that could lead to the development of novel antibody drugs. PMID- 26935084 TI - [Biophysical Characterization of Biopharmaceuticals, Including Antibody Drugs]. AB - Biopharmaceuticals, including antibody drugs, are now popular because of their high specificity with low adverse effects, especially in the treatment of cancer and autoimmune diseases. However, because the active pharmaceutical ingredients of biopharmaceuticals are proteins, biophysical characterization of these therapeutic proteins should be required. In this manuscript, methods of chemical and physical characterization of therapeutic proteins are described. In terms of chemical characterization, analysis of chemical modifications of the constituent amino acids is explained. Physical characterization includes higher order structural analysis and assessment of protein aggregates. Quantification methods of aggregates with different sizes, recently encouraged by the U.S. Food and Drug Administration (FDA), are introduced. As for the stability of therapeutic proteins, the importance of chemical and physical stability is explained. Finally, the contribution of colloidal and structural stability to the production of an antibody drug less prone to aggregation is introduced. PMID- 26935085 TI - [Structural Study in the Platform for Drug Discovery, Informatics, and Structural Life Science]. AB - The Platform for Drug Discovery, Informatics, and Structural Life Science (PDIS), which has been launched since FY2012, is a national project in the field of structural biology. The PDIS consists of three cores - structural analysis, control, and informatics - and aims to support life science researchers who are not familiar with structural biology. The PDIS project is able to provide full scale support for structural biology research. The support provided by the PDIS project includes protein purification with various expression systems, large scale protein crystallization, crystal structure determination, small angle scattering (SAXS), NMR, electron microscopy, bioinformatics, etc. In order to utilize these methods of support, PDIS users need to submit an application form to the one-stop service office. Submitted applications will be reviewed by three referees. It is strongly encouraged that PDIS users have sufficient discussion with researchers in the PDIS project before submitting the application. This discussion is very useful in the process of project design, particularly for beginners in structural biology. In addition to this user support, the PDIS project has conducted R&D, which includes the development of synchrotron beamlines. In the PDIS project, PF and SPring-8 have developed beamlines for micro-crystallography, high-throughput data collection, supramolecular assembly, and native single anomalous dispersion (SAD) phasing. The newly developed beamlines have been open to all users, and have accelerated structural biology research. Beamlines for SAXS have also been developed, which has dramatically increased bio-SAXS users. PMID- 26935086 TI - [Novel Therapeutic Targets for Diseases of Endocrine or Immune System Developed through the Analysis of Cross-talk between Ca(2+) and Disease-related Cell Signaling]. PMID- 26935087 TI - [Regulation of Lipid Metabolism by Diacylglycerol Kinases in Pancreatic beta cells]. AB - The appropriate secretion of insulin from pancreatic beta-cells is essential for regulating blood glucose levels. Glucose-stimulated insulin secretion (GSIS) involves the following steps: Glucose uptake by pancreatic beta-cells is metabolized to produce ATP. Increased ATP levels result in the closure of ATP sensitive K(+) (KATP) channels, resulting in membrane depolarization that activates voltage-dependent Ca(2+) channels to subsequently trigger insulin secretion. In addition to this primary mechanism through KATP channels, insulin secretion is regulated by cyclic AMP and diacylglycerol (DAG), which mediate the effects of receptor agonists such as GLP-1 and acetylcholine. Glucose by itself can also increase the levels of these second messengers. Recently, we have shown an obligatory role of diacylglycerol kinase (DGK), an enzyme catalyzing the conversion of DAG to phosphatidic acid, in GSIS. Of the 10 known DGK isoforms, we focused on type-I DGK isoforms (i.e., DGKalpha, DGKbeta, and DGKgamma), which are activated by Ca(2+). The protein expression of DGKalpha and DGKgamma was detected in mouse pancreatic islets and the pancreatic beta-cell line MIN6. Depletion of these DGKs by a specific inhibitor or siRNA decreased both [Ca(2+)]i and insulin secretion in MIN6 cells. Similar [Ca(2+)]i responses were induced by DiC8, a membrane-permeable DAG analog. These results suggest that DGKalpha and DGKgamma play crucial roles in insulin secretion, and that their depletion impairs insulin secretion through DAG accumulation. In this article, we review the current understanding of the roles of DAG- and DGK-signaling in pancreatic beta-cells, and discuss their pathophysiological roles in the progression of type-2 diabetes. PMID- 26935088 TI - [Theoretical Investigations into the Quantitative Mechanisms Underlying the Regulation of [cAMP]i, Membrane Excitability and [Ca(2+)]i during GLP-1 Stimulation in Pancreatic beta Cells]. AB - Upon elevation of plasma glucose concentration, pancreatic beta-cells generate bursts of action potentials to induce cyclic changes in [Ca(2+)]i regulating insulin release. Glucose-dependent insulin secretion is synergistically enhanced by glucagon-like peptide-1 (GLP-1), which increases [cAMP]i and activates protein kinase A (PKA) and exchange protein activated by cAMP (Epac). The insulinotropic effect of GLP-1 is mediated, at least in part, by modulating multiple ion channels/transporters at the plasma membrane and ER through PKA- and EPAC dependent mechanisms, which increase membrane excitability and intracellular Ca(2+) release. However, because of complex interactions between multiple cellular factors involved in the GLP-1 effects, quantitative aspects of the molecular/ionic mechanisms have not yet been determined. We thus performed simulation studies and mathematical analysis to investigate how GLP-1 signals control [cAMP]i and subsequently modify the bursting activities and Ca(2+) dynamics. First, a GLP-1 receptor signal transduction model was developed and introduced to our beta-cells model. Secondly, modulatory effects of PKA/Epac on ion channels/transporters were incorporated based on experimental studies. Increases in the frequency and duration of the bursting activity observed during GLP-1 stimulation were well reconstructed by our model, and lead potential analysis quantitatively determined the functional role of each ion channel/transporter in modifying the burst pattern. Finally, an IP3R model was developed to reproduce GLP-1-induced Ca(2+) transients/oscillations. Instantaneous equilibrium analysis and bifurcation analysis also elucidated the quantitative mechanisms involved in generating IP3R-mediated Ca(2+) mobilization. The results of this theoretical analysis of the effects of GLP-1 on membrane excitability/Ca(2+) dynamics are discussed in this review. PMID- 26935089 TI - [Store-operated Calcium Entry into B Cells Regulates Autoimmune Inflammation]. AB - Alterations in the cytosolic concentration of calcium ions (Ca(2+)) are important signals for various physiological events. The engagement of B cell receptors (BCR) results in the transient release of Ca(2+) into cytosol from endoplasmic reticulum (ER) stores. In turn, this decrease in ER luminal Ca(2+) concentration triggers the opening of Ca(2+) channels in the plasma membrane, inducing a sustained influx of extracellular Ca(2+) into cells. These processes are referred to as store-operated Ca(2+) entry (SOCE), which is an essential pathway for continuous Ca(2+) signaling. While the ER calcium sensor stromal interaction molecule (STIM) 1 and STIM2 are crucial components for SOCE activation, their physiological roles in B cells are unknown. Here we uncover the physiological function of SOCE in B cells by analyzing mice with B cell-specific deletions of STIM1 and STIM2. Our findings indicate that STIM1 and STIM2 are critical for BCR induced SOCE, as well as the activation of nuclear factors of activated T cells (NFAT), and the subsequent production of interleukin-10 (IL-10). Although STIM proteins are not essential for B cell development and antibody responses, these molecules are required to suppress experimental autoimmune encephalomyelitis (EAE) via an IL-10-dependent mechanism. Accumulating evidence underscores the importance of IL-10-producing B cells in autoimmunity, although the identity of IL-10-producing B cells with a regulatory function in vivo remains unclear. We addressed this issue and identified plasmablasts as IL-10-producing B cells that can suppress EAE inflammation. Our data established STIM-dependent SOCE as a key signal for the regulatory plasmablasts required to limit autoimmunity. PMID- 26935090 TI - [Physiological Role of K(+) Channels in the Regulation of T Cell Function]. AB - Potassium ion (K(+)) channels play an important role in the modulation of calcium ion (Ca(2+)) signaling via control of the membrane potential. In T-lymphocytes, the voltage-gated K(+) channel, KV1.3, and the intermediate-conductance Ca(2+) activated K(+) channel, KCa3.1, predominantly contribute to K(+) conductance, and are responsible for cell proliferation, differentiation, apoptosis and infiltration. Inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease, afflicts more than 0.1% of the population worldwide. In the chemically-induced IBD model mouse, an increase in KCa3.1 activity was observed in mesenteric lymph node CD4(+) T-lymphocytes, concomitant with an upregulation of KCa3.1 and a positive KCa3.1 regulator, NDPK-B. Pharmacological blockade of the KCa3.1 K(+) channel by TRAM-34 and/or ICA17043 elicited 1) a significant decrease in IBD severity, as assessed by diarrhea, visible fecal blood, inflammation and crypt damage of the colon; and 2) restoration of the expression levels of KCa3.1 and Th1 cytokines in CD4(+) T-lymphocytes in the IBD model. Recent studies have indicated the impact of K2P5.1 upregulation in T lymphocytes on the pathogenesis of autoimmune diseases such as rheumatoid arthritis and multiple sclerosis. The K2P5.1 K(+) channel is therefore highlighted as a potent therapeutic target in managing the pathogenesis of autoimmune diseases. Alternatively, pre-mRNA splicing of ion channels is associated with the development and progression of various diseases, including autoimmune diseases. Therefore, mRNA-splicing mechanisms underlying the transcriptional regulation of K2P5.1 K(+) channels may be a new strategic therapeutic target for autoimmune and inflammatory diseases. PMID- 26935091 TI - [Functional Expression of a Ca(2+)-activated Cl(-) Channel Modulator Involved in Ion Transport and Epithelial Cell Differentiation]. AB - Cl(-)-permeable channels and transporters expressed on the cell membranes of various mammalian cell types play pivotal roles in the transport of electrolytes and water, pH regulation, cell volume and membrane excitability, and are therefore expected to be useful molecular targets for drug discovery. Both TMEM16A (a possible candidate for Ca(2+)-regulated Cl(-) channels recently identified) and cystic fibrosis transmembrane conductance regulator (CFTR) (or cAMP-regulated Cl(-) channels) have been known to be involved in Cl(-) secretion and reabsorption in the rat salivary gland. Crosstalk between two types of regulatory pathways through these two types of channels has also been described. Previously, we demonstrated that CLCA, a Ca(2+)-activated Cl(-) channel modulator, was involved in Cl(-) absorption in rat salivary ducts. In addition to Ca(2+), basal NF-kappaB activity in a mouse keratinocyte line was shown to be involved in the transcriptional regulation of CLCA. Conversely, a truncated isoform of CLCA was found in undifferentiated epithelial cells present in the rat epidermal basal layers. Under regulation by Ca(2+) and PKC, the surface expression of beta1-integrin and cell adhesion were decreased in the CLCA overexpressing cells. Knockdown of this isoform elevated the expression of beta1 integrin in rat epidermis in vivo. These results indicate that the specific differentiation-dependent localization of CLCA, and transcriptional regulation through Ca(2+), are likely to affect ion permeability and the adhesive potential of epithelial cells. In summary, these types of Cl(-) channels and their modulators may function in a coordinated manner in regulating the functions of epithelial cells under different physiological conditions. PMID- 26935092 TI - [Development of Molecular Probes for Spatio-temporal Analysis of in Vivo Tumor with Photoacoustic Imaging]. AB - Photoacoustic imaging (PA imaging or PAI) has been focused on as a new technique to provide images of high spatial resolution, at depths of up to 5 cm, and the development of novel PAI probes for tumor imaging is of marked interest. Although nanomaterials such as gold nanorods have been reported as PAI probes, dyes are required to aid their ease of preparation, cost-effectiveness, and safety. However, because PAI has relatively low intrinsic sensitivity compared to optical imaging, and requires high-energy laser pulse exposure, an appropriate probe design, high tumor accumulation, and photostability are required for PAI probes. We developed some dyes and evaluated their usefulness as PAI probes. We first developed a high tumor-accumulation dye probe, IC7-1-Bu, which utilizes serum albumin as a tumor-targeting carrier to deliver an adequate PA signal at the tumor. Although IC7-1-Bu showed strong tumor targeting ability and a sufficient PA signal at the tumor in in vivo studies, IC7-1-Bu lacks photostability against multiple laser irradiations of PAI. In order to improve dye photostablity, we focused on the effect of singlet oxygen ((1)O2) generated by excited PAI probes on probe degeneration, and developed a triplet-state quencher conjugated dye probe, IC-5-T. IC-5-T reduced (1)O2 generation and improved photostability against multiple irradiations compared to IC7-1-Bu. IC-5-T also showed a sufficient PA signal at the tumor, and 1.5-fold higher photostabillity compared to IC7-1-Bu in sequential in vivo PAI studies. These results suggest that IC-5-T is a potential PAI probe for tumor imaging. PMID- 26935093 TI - [Methodology for Estimating the Risk of Adverse Drug Reactions in Pregnant Women: Analysis of the Japanese Adverse Drug Event Report Database]. AB - Safety information regarding drug use during pregnancy is insufficient. The present study aimed to establish an optimal signal detection method to identify adverse drug reactions in pregnant women and to evaluate information in the Japanese Adverse Drug Event Report (JADER) database between April 2004 and November 2014. We identified reports on pregnant women using the Standardised MedDRA Queries. We calculated the proportional reporting ratio (PRR) and reporting odds ratio (ROR) of the risk factors for the two known risks of antithyroid drugs and methimazole (MMI) embryopathy, and ritodrine and fetal/infant cardiovascular events. The PRR and ROR values differed between all reports in the JADER database and those on pregnant women, affecting whether signal detection criteria were met. Therefore we considered that reports on pregnant women should be used when risks associated with pregnancy were determined using signal detection. Analyses of MMI embryopathy revealed MMI signals [PRR, 159.7; ROR, 669.9; 95% confidence interval (CI), 282.4-1588.7] but no propylthiouracil signals (PRR, 1.98; ROR, 2.0; 95%CI, 0.3-15.4). These findings were consistent with those of reported risks. Analyses of fetal/infant cardiovascular events revealed ritodrine signals (PRR, 2.1; ROR, 2.1; 95%CI, 1.4 3.3). These findings were also consistent with reported risks. Mining the JADER database was helpful for analyzing adverse drug reactions in pregnant women. PMID- 26935094 TI - [Evaluation of the Association of Hand-Foot Syndrome with Anticancer Drugs Using the US Food and Drug Administration Adverse Event Reporting System (FAERS) and Japanese Adverse Drug Event Report (JADER) Databases]. AB - The Japanese Ministry of Health, Labor, and Welfare lists hand-foot syndrome as a serious adverse drug event. Therefore, we evaluated its association with anticancer drug therapy using case reports in the Japanese Adverse Drug Event Report (JADER) and the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). In addition, we calculated the reporting odds ratio (ROR) of anticancer drugs potentially associated with hand-foot syndrome, and applied the Weibull shape parameter to time-to-event data from JADER. We found that JADER contained 338224 reports from April 2004 to November 2014, while FAERS contained 5821354 reports from January 2004 to June 2014. In JADER, the RORs [95% confidence interval (CI)] of hand-foot syndrome for capecitabine, tegafur gimeracil-oteracil, fluorouracil, sorafenib, and regorafenib were 63.60 (95%CI, 56.19-71.99), 1.30 (95%CI, 0.89-1.89), 0.48 (95%CI, 0.30-0.77), 26.10 (95%CI, 22.86-29.80), and 133.27 (95%CI, 112.85-157.39), respectively. Adverse event symptoms of hand-foot syndrome were observed with most anticancer drugs, which carry warnings of the propensity to cause these effects in their drug information literature. The time-to-event analysis using the Weibull shape parameter revealed differences in the time-dependency of the adverse events of each drug. Therefore, anticancer drugs should be used carefully in clinical practice, and patients may require careful monitoring for symptoms of hand-foot syndrome. PMID- 26935095 TI - Stabilization of the Serum Lithium Concentration by Regulation of Sodium Chloride Intake: Case Report. AB - To avoid fluctuation of the serum lithium concentration (CLi), sodium chloride (NaCl) intake was regulated in oral alimentation. A 62-year-old woman was hospitalized and orally administered 400 mg of lithium carbonate a day to treat her mania. Her CLi was found to be 0.75-0.81 mEq/L. Vomiting made it difficult for the patient to ingest meals orally, and therefore parenteral nutrition with additional oral intake of protein-fortified food was initiated. On day 22, parenteral nutrition was switched to oral alimentation to enable oral intake of food. The total NaCl equivalent amount was decreased to 1.2 g/d, and the CLi increased to 1.15 mEq/L on day 26. Oral alimentation with semi-solid food blended in a mixer was immediately initiated. Although the total NaCl equivalent amount was increased to 4.5-5.0 g/d, her CLi remained high at 1.14-1.17 mEq/L on days 33 and 49, respectively. We investigated oral administration of NaCl (1.8 g/d) on day 52. The total NaCl equivalent amount was increased to 6.3-6.8 g/d, and the CLi decreased to 1.08-0.97 mEq/L on days 63 and 104, respectively. After the start of the orally administered NaCl, her diet was changed to a completely blended diet on day 125. The total NaCl equivalent amount was increased to 9.0 14.5 g/d, and the CLi decreased to 0.53 mEq/L on day 152; therefore, the oral administration of NaCl was discontinued on day 166. The CLi was found to be 0.70 0.85 mEq/L on days 176 and 220. PMID- 26935096 TI - Circadian variation of cardiogenic pulmonary oedema. AB - INTRODUCTION: Circadian variation of in-hospital acute cardiogenic pulmonary oedema (CPE) with the highest occurrence in the early morning has been reported repeatedly. However, no study evaluating circadian variation of CPE in the field has been published. Therefore, we decided to evaluate the circadian variation of CPE in the Central Bohemian Region of the Czech Republic in the patients treated by regional emergency medical service (EMS) and analyse its association with baseline blood pressure in the field. METHODS: We extracted all dispatches to CPE cases from EMS database for the period from 1.11.2008 to 30.6.2014 and analysed for circadian variation. We identified the patients presenting with CPE coupled with arterial hypertension (systolic blood pressure >140mmHg) and hypotension (systolic blood pressure <90mmHg) and compared the subgroups (both subgroups include 2744 subjects). RESULTS: In 4747 episodes of CPE, maximal occurrence was detected in the ninth hour in the morning, representing 7.7% of all CPE episodes (p<0.05). While CPE with hypertension (2463 subjects) reached maximal occurrence also in the ninth hour (7.4% of all cases, p<0.05), CPE with hypotension (281 patients) was most frequent in the fourteenth hour (8.6% of all cases, p<0.05). CONCLUSION: The highest occurrence of CPE was observed in the ninth hour in the morning in our study. Moreover, differences in circadian variation between CPE with hypertension and hypotension were identified. Knowledge of these patterns may have an impact on the logistic of prehospital emergency care and on preventive measures in the patients who have previously undergone CPE. PMID- 26935097 TI - Differential associations between glomerular filtration rate and duration of obesity depending on the presence or absence of left ventricular diastolic dysfunction. AB - BACKGROUND: A robust and consistent association between increasing body mass index (BMI) and chronic kidney disease (CKD) has been reported in several observational studies. Obesity remains the main preventable risk factor for CKD because it largely mediates diabetes and hypertension, the 2 most common etiologies for end-stage kidney disease (ESKD). Obesity is associated weakly with early stages of kidney disease but strongly with kidney progression to ESKD, even after adjustment for hypertension and diabetes. AIM: To assess the relationship between estimated glomerular filtration rate (eGFR) and trans-thoracic echocardiography left ventricular function parameters in a cohort of patients with obesity. MATERIALS & METHODS: Cross-sectional study involving 324 obese (BMI=44.0+/-2.2Kg/m(2)) apparently healthy asymptomatic patients with an eGFR >60ml/min/1.73m(2). Each patient underwent transthoracic echocardiography and a blood testing. The eGFR was addressed by the CKD-EPI formula. RESULTS: All patients had a normal systolic function whereas 24.5% disclosed diastolic dysfunction (DD). Hypertension and type 2 diabetes mellitus prevalence were 34.5% and 4.5% (respectively). All patients disclosed an eGFR >60ml/min while none of them disclosed hyperfiltration (eGFR >120ml/min). eGFR correlated inversely with BMI and the duration of obesity and positively with diastolic function parameters (P<0.001 for all, respectively). Patients with diastolic dysfunction displayed lower eGFR (P<0.0005) and longer duration of obesity (P<0.0005). CONCLUSIONS: Obesity and its duration are likely to impose hemodynamic changes affecting simultaneously both heart (diastolic dysfunction) and kidney (decreased glomerular filtration rate). Larger prospective studies are warranted. PMID- 26935099 TI - Effectiveness of preventive and treatment interventions for primary headaches in the workplace: A systematic review of the literature. AB - Aim The purpose of this systematic literature review is to assess the benefits of workplace-based occupational therapies and interventions, including acute and preventive medication, on headache intensity and frequency, related disability as well as work-related outcomes. Methods A search of the literature was conducted in PubMed, MEDLINE, Cochrane library, CINAHL and Embase using terms related to headache, workplace and occupational health. The Cochrane Collaboration's risk of bias assessment tool was used on individual studies to assess internal validity and the Grading of Recommendations Assessment, Development, and Evaluation system was applied to studies by clinical outcome and used to rate quality of evidence. Results Fifteen articles were included in the systematic review. None of them were classified as low risk of bias according to the Cochrane Collaboration's tool for assessing risk of bias. This systematic review found preliminary low quality evidence suggesting that exercise and acupuncture can reduce workers' headache pain intensity, frequency and related disability. Conclusion Although this systematic review provided preliminary low evidence in favour of work-based intervention, studies with more rigorous designs and methodologies are needed to provide further evidence of the effectiveness of workplace-based headache management strategies. PMID- 26935098 TI - 2-thio-6-azauridine inhibits Vpu mediated BST-2 degradation. AB - BACKGROUD: BST-2 is an interferon-induced host restriction factor that inhibits the release of diverse mammalian enveloped viruses from infected cells by physically trapping the newly formed virions onto the host cell surface. Human Immunodeficiency Virus-1 (HIV-1) encodes an accessory protein Vpu that antagonizes BST-2 by down-regulating BST-2 from the cell surface. RESULTS: Using a cell-based ELISA screening system, we have discovered a lead compound, 2-thio-6 azauridine, that restores cell surface BST-2 level in the presence of Vpu. This compound has no effect on the expression of BST-2 and Vpu, but inhibits Vpu mediated BST-2 down-regulation and exerts no effect on Vpu-induced down regulation of CD4 or KSHV K5 protein induced BST-2 down-regulation. 2-thio-6 azauridine suppresses HIV-1 production in a BST-2-dependent manner. Further results indicate that 2-thio-6-azauridine does not interrupt the interaction of BST-2 with Vpu and beta-TrCP2, but decreases BST-2 ubiquitination. CONCLUSION: Our study demonstrates the feasibility of using small molecules to target Vpu function and sensitize wild type HIV-1 to BST-2-mediated host restriction. PMID- 26935100 TI - Trends and comparison of female first authorship in high impact medical journals: observational study (1994-2014). AB - OBJECTIVE: To examine changes in representation of women among first authors of original research published in high impact general medical journals from 1994 to 2014 and investigate differences between journals. DESIGN: Observational study. STUDY SAMPLE: All original research articles published in Annals of Internal Medicine, Archives of Internal Medicine, The BMJ, JAMA, The Lancet, and the New England Journal of Medicine (NEJM) for one issue every alternate month from February 1994 to June 2014. MAIN EXPOSURES: Time and journal of publication. MAIN OUTCOME MEASURES: Prevalence of female first authorship and its adjusted association with time of publication and journal, assessed using a multivariable logistic regression model that accounted for number of authors, study type and specialty/topic, continent where the study was conducted, and the interactions between journal and time of publication, study type, and continent. Estimates from this model were used to calculate adjusted odds ratios against the mean across the six journals, with 95% confidence intervals and P values to describe the associations of interest. RESULTS: The gender of the first author was determined for 3758 of the 3860 articles considered; 1273 (34%) were women. After adjustment, female first authorship increased significantly from 27% in 1994 to 37% in 2014 (P<0.001). The NEJM seemed to follow a different pattern, with female first authorship decreasing; it also seemed to decline in recent years in The BMJ but started substantially higher (approximately 40%), and The BMJ had the highest total proportion of female first authors. Compared with the mean across all six journals, first authors were significantly less likely to be female in the NEJM (adjusted odds ratio 0.68, 95% confidence interval 0.53 to 0.89) and significantly more likely to be female in The BMJ (1.30, 1.01 to 1.66) over the study period. CONCLUSIONS: The representation of women among first authors of original research in high impact general medical journals was significantly higher in 2014 than 20 years ago, but it has plateaued in recent years and has declined in some journals. These results, along with the significant differences seen between journals, suggest that underrepresentation of research by women in high impact journals is still an important concern. The underlying causes need to be investigated to help to identify practices and strategies to increase women's influence on and contributions to the evidence that will determine future healthcare policies and standards of clinical practice. PMID- 26935101 TI - Fruit flies on the front line: the translational impact of Drosophila. AB - Drosophila melanogaster has been adopted as one of the most-used model systems since it was first introduced by Thomas Morgan for the study of heredity in the early 20th century. Its experimental tractability and similarity of its biological pathways to those of humans have placed the model at the forefront of research into human development and disease. With the ongoing accumulation of genetic tools and assays, the fly community has at its fingertips the resources to generate diverse Drosophila disease models for the study of genes and pathways involved in a wide range of disorders. In recent years, the fly has also been used successfully for drug screening. In this Editorial, we introduce a Special Collection of reviews, interviews and original research articles that highlight some of the many ways that Drosophila has made, and continues to make, an impact on basic biological insights and translational science. PMID- 26935102 TI - Drosophila tools and assays for the study of human diseases. AB - Many of the internal organ systems of Drosophila melanogaster are functionally analogous to those in vertebrates, including humans. Although humans and flies differ greatly in terms of their gross morphological and cellular features, many of the molecular mechanisms that govern development and drive cellular and physiological processes are conserved between both organisms. The morphological differences are deceiving and have led researchers to undervalue the study of invertebrate organs in unraveling pathogenic mechanisms of diseases. In this review and accompanying poster, we highlight the physiological and molecular parallels between fly and human organs that validate the use of Drosophila to study the molecular pathogenesis underlying human diseases. We discuss assays that have been developed in flies to study the function of specific genes in the central nervous system, heart, liver and kidney, and provide examples of the use of these assays to address questions related to human diseases. These assays provide us with simple yet powerful tools to study the pathogenic mechanisms associated with human disease-causing genes. PMID- 26935103 TI - FlyBase portals to human disease research using Drosophila models. AB - The use of Drosophila melanogaster as a model for studying human disease is well established, reflected by the steady increase in both the number and proportion of fly papers describing human disease models in recent years. In this article, we highlight recent efforts to improve the availability and accessibility of the disease model information in FlyBase (http://flybase.org), the model organism database for Drosophila. FlyBase has recently introduced Human Disease Model Reports, each of which presents background information on a specific disease, a tabulation of related disease subtypes, and summaries of experimental data and results using fruit flies. Integrated presentations of relevant data and reagents described in other sections of FlyBase are incorporated into these reports, which are specifically designed to be accessible to non-fly researchers in order to promote collaboration across model organism communities working in translational science. Another key component of disease model information in FlyBase is that data are collected in a consistent format --- using the evolving Disease Ontology (an open-source standardized ontology for human-disease-associated biomedical data) - to allow robust and intuitive searches. To facilitate this, FlyBase has developed a dedicated tool for querying and navigating relevant data, which include mutations that model a disease and any associated interacting modifiers. In this article, we describe how data related to fly models of human disease are presented in individual Gene Reports and in the Human Disease Model Reports. Finally, we discuss search strategies and new query tools that are available to access the disease model data in FlyBase. PMID- 26935104 TI - Modeling congenital disease and inborn errors of development in Drosophila melanogaster. AB - Fly models that faithfully recapitulate various aspects of human disease and human health-related biology are being used for research into disease diagnosis and prevention. Established and new genetic strategies in Drosophila have yielded numerous substantial successes in modeling congenital disorders or inborn errors of human development, as well as neurodegenerative disease and cancer. Moreover, although our ability to generate sequence datasets continues to outpace our ability to analyze these datasets, the development of high-throughput analysis platforms in Drosophila has provided access through the bottleneck in the identification of disease gene candidates. In this Review, we describe both the traditional and newer methods that are facilitating the incorporation of Drosophila into the human disease discovery process, with a focus on the models that have enhanced our understanding of human developmental disorders and congenital disease. Enviable features of the Drosophila experimental system, which make it particularly useful in facilitating the much anticipated move from genotype to phenotype (understanding and predicting phenotypes directly from the primary DNA sequence), include its genetic tractability, the low cost for high throughput discovery, and a genome and underlying biology that are highly evolutionarily conserved. In embracing the fly in the human disease-gene discovery process, we can expect to speed up and reduce the cost of this process, allowing experimental scales that are not feasible and/or would be too costly in higher eukaryotes. PMID- 26935105 TI - The interplay between intestinal bacteria and host metabolism in health and disease: lessons from Drosophila melanogaster. AB - All higher organisms negotiate a truce with their commensal microbes and battle pathogenic microbes on a daily basis. Much attention has been given to the role of the innate immune system in controlling intestinal microbes and to the strategies used by intestinal microbes to overcome the host immune response. However, it is becoming increasingly clear that the metabolisms of intestinal microbes and their hosts are linked and that this interaction is equally important for host health and well-being. For instance, an individual's array of commensal microbes can influence their predisposition to chronic metabolic diseases such as diabetes and obesity. A better understanding of host-microbe metabolic interactions is important in defining the molecular bases of these disorders and could potentially lead to new therapeutic avenues. Key advances in this area have been made using Drosophila melanogaster. Here, we review studies that have explored the impact of both commensal and pathogenic intestinal microbes on Drosophila carbohydrate and lipid metabolism. These studies have helped to elucidate the metabolites produced by intestinal microbes, the intestinal receptors that sense these metabolites, and the signaling pathways through which these metabolites manipulate host metabolism. Furthermore, they suggest that targeting microbial metabolism could represent an effective therapeutic strategy for human metabolic diseases and intestinal infection. PMID- 26935106 TI - Cardiomyocyte-specific conditional knockout of the histone chaperone HIRA in mice results in hypertrophy, sarcolemmal damage and focal replacement fibrosis. AB - HIRA is the histone chaperone responsible for replication-independent incorporation of histone variant H3.3 within gene bodies and regulatory regions of actively transcribed genes, and within the bivalent promoter regions of developmentally regulated genes. The HIRA gene lies within the 22q11.2 deletion syndrome critical region; individuals with this syndrome have multiple congenital heart defects. Because terminally differentiated cardiomyocytes have exited the cell cycle, histone variants should be utilized for the bulk of chromatin remodeling. Thus, HIRA is likely to play an important role in epigenetically defining the cardiac gene expression program. In this study, we determined the consequence of HIRA deficiency in cardiomyocytes in vivo by studying the phenotype of cardiomyocyte-specific Hira conditional-knockout mice. Loss of HIRA did not perturb heart development, but instead resulted in cardiomyocyte hypertrophy and susceptibility to sarcolemmal damage. Cardiomyocyte degeneration gave way to focal replacement fibrosis and impaired cardiac function. Gene expression was widely altered in Hira conditional-knockout hearts. Significantly affected pathways included responses to cellular stress, DNA repair and transcription. Consistent with heart failure, fetal cardiac genes were re expressed in the Hira conditional knockout. Our results suggest that transcriptional regulation by HIRA is crucial for cardiomyocyte homeostasis. PMID- 26935108 TI - Comparative evaluation of whole blood versus plasma for quantitative detection of cytomegalovirus using an automated system. AB - Peripheral blood samples were separated into aliquots of whole blood and plasma and tested using an automated PCR system. More positive results were obtained from plasma (43), compared to whole blood (34). Plasma results did not correlate well with those in whole blood and tended to produce higher viral loads. PMID- 26935107 TI - Mouse myofibers lacking the SMYD1 methyltransferase are susceptible to atrophy, internalization of nuclei and myofibrillar disarray. AB - The Smyd1 gene encodes a lysine methyltransferase specifically expressed in striated muscle. Because Smyd1-null mouse embryos die from heart malformation prior to formation of skeletal muscle, we developed a Smyd1 conditional-knockout allele to determine the consequence of SMYD1 loss in mammalian skeletal muscle. Ablation of SMYD1 specifically in skeletal myocytes after myofiber differentiation using Myf6(cre) produced a non-degenerative myopathy. Mutant mice exhibited weakness, myofiber hypotrophy, prevalence of oxidative myofibers, reduction in triad numbers, regional myofibrillar disorganization/breakdown and a high percentage of myofibers with centralized nuclei. Notably, we found broad upregulation of muscle development genes in the absence of regenerating or degenerating myofibers. These data suggest that the afflicted fibers are in a continual state of repair in an attempt to restore damaged myofibrils. Disease severity was greater for males than females. Despite equivalent expression in all fiber types, loss of SMYD1 primarily affected fast-twitch muscle, illustrating fiber-type-specific functions for SMYD1. This work illustrates a crucial role for SMYD1 in skeletal muscle physiology and myofibril integrity. PMID- 26935109 TI - Ptp1b deletion in pro-opiomelanocortin neurons increases energy expenditure and impairs endothelial function via TNF-alpha dependent mechanisms. AB - Protein tyrosine phosphatase 1b (Ptp1b) is a negative regulator of leptin and insulin-signalling pathways. Its targeted deletion in proopiomelanocortin (POMC) neurons protects mice from obesity and diabetes by increasing energy expenditure. Inflammation accompanies increased energy expenditure. Therefore, the present study aimed to determine whether POMC-Ptp1b deletion increases energy expenditure via an inflammatory process, which would impair endothelial function. We characterized the metabolic and cardiovascular phenotypes of Ptp1b+/+ and POMC Ptp1b-/- mice. Clamp studies revealed that POMC-Ptp1b deletion reduced body fat and increased energy expenditure as evidenced by a decrease in feed efficiency and an increase in oxygen consumption and respiratory exchange ratio. POMC-Ptp1b deletion induced a 2.5-fold increase in plasma tumour necrosis factor alpha (TNF alpha) levels and elevated body temperature. Vascular studies revealed an endothelial dysfunction in POMC-Ptp1b-/- mice. Nitric oxide synthase inhibition [N-nitro-L-arginine methyl ester (L-NAME)] reduced relaxation to a similar extent in Ptp1b+/+ and POMC-Ptp1b-/- mice. POMC-Ptp1b deletion decreased ROS-scavenging enzymes [superoxide dismutases (SODs)] whereas it increased ROS-generating enzymes [NADPH oxidases (NOXs)] and cyclooxygenase-2 (COX-1) expression, in aorta. ROS scavenging or NADPH oxidase inhibition only partially improved relaxation whereas COX-2 inhibition and thromboxane-A2 (TXA2) antagonism fully restored relaxation in POMC-Ptp1b-/- mice Chronic treatment with the soluble TNF alpha receptor etanercept decreased body temperature, restored endothelial function and reestablished aortic COX-2, NOXs and SOD expression to their baseline levels in POMC-Ptp1b-/- mice. However, etanercept promoted body weight gain and decreased energy expenditure in POMC-Ptp1b-/- mice. POMC-Ptp1b deletion increases plasma TNF-alpha levels, which contribute to body weight regulation via increased energy expenditure and impair endothelial function via COX-2 and ROS dependent mechanisms. PMID- 26935110 TI - Prevalence of Combined Somatic and Mental Health Multimorbidity: Patterns by Age, Sex, and Race/Ethnicity. AB - BACKGROUND: The coexistence of chronic mental health conditions with somatic conditions (somatic-mental multimorbidity, or SMM) is common and has been associated with greater symptom burden and functional impairment, higher costs, and excess mortality. However, most existing literature focused on the co occurrence of an index mental health condition with specific additional conditions. By contrast, we studied the prevalence and patterns of SMM more broadly considering 19 selected conditions, and we focused on differences by age, sex, and race/ethnicity. METHODS: The Rochester Epidemiology Project (REP) records-linkage system was used to identify all residents of Olmsted County, MN, on April 1, 2010. We identified individuals with each of 19 common chronic conditions, including 5 mental health conditions, using the International Classification of Diseases, ninth revision (ICD-9) codes received from any health care provider between April 1, 2005 and March 31, 2010. RESULTS: Among the 138,858 residents of the county, 52.4% were women, and 7.9% had SMM. SMM increased steeply with older age, was 1.7 times more common in women, and was lower in Asians compared with whites. Of the 10,903 persons with SMM, 7,739 (71.0%) were younger than 65 years. Depressive and anxiety disorders were the most common conditions involved in SMM. The dyads that were observed more frequently or less frequently than expected by chance varied in composition by age and sex. CONCLUSIONS: SMM that reaches medical attention is highly prevalent across all age groups, is more frequent in women, is less frequent in Asians, and encompasses a wide range of conditions. PMID- 26935111 TI - Motor Output Variability Impairs Driving Ability in Older Adults. AB - BACKGROUND: The functional declines with aging relate to deficits in motor control and strength. In this study, we determine whether older adults exhibit impaired driving as a consequence of declines in motor control or strength. METHODS: Young and older adults performed the following tasks: (i) maximum voluntary contractions of ankle dorsiflexion and plantarflexion; (ii) sinusoidal tracking with isolated ankle dorsiflexion; and (iii) a reactive driving task that required responding to unexpected brake lights of the car ahead. We quantified motor control with ankle force variability, gas position variability, and brake force variability. We quantified reactive driving performance with a combination of gas pedal error, premotor and motor response times, and brake pedal error. RESULTS: Reactive driving performance was ~30% more impaired (t = 3.38; p < .01) in older adults compared with young adults. Older adults exhibited greater motor output variability during both isolated ankle dorsiflexion contractions (t = 2.76; p < .05) and reactive driving (gas pedal variability: t = 1.87; p < .03; brake pedal variability: t = 4.55; p < .01). Deficits in reactive driving were strongly correlated to greater motor output variability (R 2 = .48; p < .01) but not strength (p > .05). CONCLUSIONS: This study provides novel evidence that age related declines in motor control but not strength impair reactive driving. These findings have implications on rehabilitation and suggest that interventions should focus on improving motor control to enhance driving-related function in older adults. PMID- 26935112 TI - Novel phleboviruses detected in ticks, Greece. AB - Since 2009, when severe fever with thrombocytopenia syndrome virus and Heartland virus have been identified and associated with disease in humans, the interest on tick-borne phleboviruses is increasing rapidly. The aim of the present study was to investigate the presence of tick-borne phleboviruses in Greece and compare them with respective ones detected worldwide. Ticks collected from goats and sheep in 60 sites of 13 regional units of Greece were grouped in pools (1-3 ticks per pool) and tested for the presence of phleboviral RNA. Six of 210 pools were positive; they consisted of Rhipicephalus sanguineus ticks collected from sheep in 3 regional units of Greece: Pella (2/30, 6.7%), Imathia (2/21, 9.5%), and Ioannina (2/28, 7.1%). The overall tick minimum infection rate was 2.1%. The sequences of the Greek phlebovirus (provisionally named Antigone virus) form a distinct clade in the tick-borne phleboviruses, differing by >40% from the currently known phleboviruses. Any probable implication of these viruses to public health remains to be elucidated. PMID- 26935113 TI - B-Vitamin Serum Concentrations Predicting Long-Term Overall and Stroke-Free Survival after Carotid Endarterectomy. AB - BACKGROUND: Both deficiency and, according to recent reports, excess of vitamin B12 (B12) are associated with increased mortality. Thus, it is difficult to estimate the effect of B12 on overall survival, which also depends on folate (FA) in homocysteine lowering. This study aimed to assess FA and B12 serum concentrations associated with long-term survival of vascular surgery patients by means of a prognostic index (PI). METHODS: This single-center, prospective cohort study comprised 485 consecutive carotid surgery patients. B-vitamin baseline concentrations of B12 and FA were used to compute a PI for postoperative overall survival from January 2003 to January 2012 (mean observation period 102.3 months). RESULTS: Increasing B12 serum concentrations showed a nonlinear association with overall survival (P = .033). A B vitamin-based PI significantly predicted overall (hazard ratio [HR] per standard deviation = 1.97, confidence interval [CI] 1.37-2.82; P < .001), cardiovascular (HR = 3.03, CI 1.78-5.14; P < .001), and stroke-free survival (HR = 2.20, CI 1.22-3.98; P = .009), and revealed that the highest adverse event-free survival was predicted by high FA (16.3 +/- 12.9 ng/mL) but only moderate B12 (360.3 +/- 156.0 pmol/L) baseline concentrations. CONCLUSIONS: Prediction of increased long-term overall, cardiovascular, and stroke-free survival is based on high FA but only moderate B12 serum concentrations. Excessive B12 concentrations might harbor a potential harm and are no requisite for low homocysteine concentrations. The association between B vitamins and survival might serve either as a tool for risk stratification or, if causative, as effective therapy, if optimal dosing of B vitamins is provided and on-treatment concentrations, including homocysteine and renal functions, are closely monitored. PMID- 26935114 TI - Clopidogrel Resistance Increases Rate of Recurrent Stroke and Other Vascular Events in Chinese Population. AB - BACKGROUND: Research regarding clopidogrel resistance (CR) and ischemic stroke (IS) recurrence related to IS is scanty. The aim of the present study was to determine the incidence of CR and the association between CR and IS recurrence and other vascular events in patients with IS receiving clopidogrel. METHODS: CR was assessed by platelet aggregation assay in 535 IS patients receiving clopidogrel. All patients continued taking clopidogrel after discharge and were followed up for 6 months. The primary outcome was a composite of recurrent ischemic stroke (RIS), myocardial infarction, and death. The secondary outcome was the degree of disability as measured by modified Rankin Scale (mRS). RESULTS: Out of 535 IS patients, 208 (38.88%) were CR and 327 (61.12%) were clopidogrel sensitive (CS). Diabetes was independently associated with risk of CR (odds ratio: 2.42, 95% confidence interval [CI], 1.22-4.97, P <.01). During the follow up period, the incidence of ischemic vascular events was higher in the CR group than in the CS group; the proportion of patients with mRS score of 0-2 points at 6 months was significantly lower in CR group than in CS group. CR (hazard ratio [HR]: 2.82, 95% CI, 1.23-6.94, P <.01), diabetes (HR: 1.61, 95% CI, 1.01-3.49, P = .02), and hypertension (HR: 1.84, 95% CI, 1.12-4.72, P = .03) were independent risk factors for ischemic vascular events. CONCLUSION: The incidence of CR in IS patients taking clopidogrel is relatively high in the Chinese population. CR is associated with ischemic vascular events, including RIS, and poor neurological recovery. PMID- 26935115 TI - Comprehensive Outpatient Rehabilitation Program: Hospital-Based Stroke Outpatient Rehabilitation. AB - BACKGROUND: Few studies have considered the effectiveness of outpatient rehabilitation programs for stroke patients. The objective of this study was to assess the effectiveness of a hospital-based interdisciplinary outpatient stroke rehabilitation program with respect to physical functioning, mobility, and balance. METHODS: The Comprehensive Outpatient Rehabilitation Program provides a hospital-based interdisciplinary approach to stroke rehabilitation in Southwestern Ontario. Outcome measures from physiotherapy and occupational therapy sessions were available at intake and discharge from the program. A series of paired sample t-tests were performed to assess patient changes between time points for each outcome measure. RESULTS: A total of 271 patients met the inclusion criteria for analysis (56.1% male; mean age = 62.9 +/- 13.9 years). Significant improvements were found between admission and discharge for the Functional Independence Measure, grip strength, Chedoke-McMaster Stroke Assessment, two-minute walk test, maximum walk test, Timed Up and Go, Berg Balance Scale, and one-legged stance (P < .003 for all). CONCLUSIONS: The findings indicate that an interdisciplinary rehabilitation program was effective at improving the physical functioning, mobility, and balance of individuals after a stroke. A hospital-based, stroke-specific rehabilitation program should be considered when patients continue to experience deficits after inpatient rehabilitation. PMID- 26935116 TI - National Institutes of Health Stroke Scale-Time Score Predicts Outcome after Endovascular Therapy in Acute Ischemic Stroke: A Retrospective Single-Center Study. AB - BACKGROUND: Outcomes after successful endovascular therapy in acute ischemic stroke are associated with onset-to-reperfusion time (ORT) and the National Institutes of Health Stroke Scale (NIHSS) score. In intravenous recombinant tissue plasminogen activator therapy, the NIHSS-time score, calculated by multiplying onset-to-treatment time with the NIHSS score, has been shown to predict clinical outcomes. In this study, we assessed whether a similar combination of the ORT and the NIHSS score can be applied to predict the outcomes after endovascular therapy. METHODS: We retrospectively reviewed the charts of 128 consecutive ischemic stroke patients with successful reperfusion after endovascular therapy. We analyzed the association of the ORT, the NIHSS score, and the NIHSS-time score with good outcome (modified Rankin Scale score <= 2 at 3 months). RESULTS: Good outcome rates for patients with NIHSS-time scores of 84.7 or lower, scores higher than 84.7 up to 127.5 or lower, and scores higher than 127.5 were 72.1%, 44.2%, and 14.3%, respectively (P < .01). Multivariate logistic regression analysis revealed that the NIHSS-time score was an independent predictor of good outcomes (odds ratio, .372; 95% confidence interval, .175-.789) after adjusting for age, sex, internal carotid artery occlusion, plasma glucose level, ORT, and NIHSS score. CONCLUSIONS: The NIHSS-time score can predict good clinical outcomes after endovascular treatment. PMID- 26935117 TI - Curcumin Attenuates Inflammation, Oxidative Stress, and Ultrastructural Damage Induced by Spinal Cord Ischemia-Reperfusion Injury in Rats. AB - OBJECTIVES: Curcumin is a molecule found in turmeric root that possesses anti inflammatory and antioxidant properties and has been widely used to treat neurodegenerative diseases. We investigated whether curcumin stimulates the neurorepair process and improves locomotor function in a rat model of spinal cord ischemia-reperfusion injury. METHODS: Thirty-two Wistar albino rats (190-220 g) were randomly allocated into 4 groups of 8 rats each: 1 sham-operated group and 3 ischemia-reperfusion injury groups that received intraperitoneal injections of saline vehicle, methylprednisolone (MP, 30 mg/kg following induction of ischemia reperfusion [IR] injury), or curcumin (200 mg/kg for 7 days before induction of IR injury). Spinal cord IR injury was induced by occlusion of the abdominal aorta for 30 minutes. After 24 hours of reperfusion, locomotor function was assessed using the Basso, Beattie, and Bresnahan scale. All animals were sacrificed. Spinal cord tissues were harvested to evaluate histopathological and ultrastructural alterations and to analyze levels of malondialdehyde, tumor necrosis factor-alpha, interleukin-1 beta, nitric oxide, and caspase-3, as well as enzyme activities of superoxide dismutase and glutathione peroxidase. RESULTS: Intraperitoneal administration of curcumin significantly reduced inflammatory cytokine expression, attenuated oxidative stress and lipid peroxidation, prevented apoptosis, and increased antioxidant defense mechanism activity in comparison to treatment with MP or saline. Histopathological and ultrastructural abnormalities were significantly reduced in curcumin-treated rats compared to the MP- and saline-treated groups. Furthermore, curcumin significantly improved locomotor function. CONCLUSIONS: Curcumin treatment preserves neuronal viability against inflammation, oxidative stress, and apoptosis associated with ischemia reperfusion injury. PMID- 26935118 TI - Red Meat Consumption and the Risk of Stroke: A Dose-Response Meta-analysis of Prospective Cohort Studies. AB - BACKGROUND: Prospective studies of red meat consumption and risk of stroke have provided inconsistent results. We aimed to assess this association by conducting a meta-analysis of prospective cohort studies. METHODS: Relevant studies were identified by searching PubMed and EMBASE through April 1, 2013. Summary relative risks (RR) and the corresponding 95% confidence intervals (CIs) were estimated by random-effect or fixed-effect models. RESULTS: Seven prospective cohort studies were included in the analyses, involving 2,079,236 subjects and 21,730 strokes cases. Total red meat consumption was associated with total stroke (RR = 1.14, 95% CI 1.05-1.24), cerebral infarction (RR = 1.13, 95% CI 1.0-1.28), and ischemic stroke (RR = 1.22, 95% CI 1.01-1.46). A significant association was found between consumption of processed red meat and total stroke (RR = 1.17, 95% CI 1.09-1.27). Consumption of fresh red meat was significantly associated with total stroke (RR = 1.13, 95% CI 1.04-1.22) and ischemic stroke (RR = 1.15, 95% CI 1.03-1.29). However, no evidence suggests that any type of meat was associated with hemorrhagic stroke. Also, no association was found between consumption of processed red meat and ischemic stroke (RR = 1.15, 95% CI .98-1.36) and between consumption of fresh red meat and cerebral infarction (RR = 1.06, 95% CI [.94, 1.20]). A significant risk for total stroke could be observed when the consumption of total red meat was above 50 g/day, processed red meat was just above 0 g/day, and fresh red meat was above 70 g/day. CONCLUSION: Our findings indicate that high consumption of red meat, especially processed red meat, will increase the risk of stroke. PMID- 26935119 TI - Atypical Presentation of Aneurysmal Subarachnoid Hemorrhage: Incidence and Clinical Importance. AB - BACKGROUND: The symptoms of sudden severe headache and/or diminished consciousness characterize the onset of aneurysmal subarachnoid hemorrhage (SAH). However, several studies have suggested that some patients show an atypical presentation at the onset: symptoms lacking sudden headache and diminished consciousness. The aim of this study was to investigate the incidence and clinical features of cases with atypical onset. METHODS: Retrospective observational study based on the data collected prospectively from all patients with SAH admitted to our hospital was performed. Cases with a sudden headache at the onset were classified as the headache onset group, and cases with onset symptoms other than headache were classified as the atypical onset group. The clinical parameters were compared between the two groups. RESULTS: Of the 368 patients with SAH, 75 (20.4%) showed diminished consciousness from onset, 279 (75.8%) comprised the headache onset group, and 14 (3.8%) comprised the atypical onset group. The main symptoms in the atypical onset group were nausea or vomiting, vertigo or dizziness, and neck pain or back pain. The rate of misdiagnosis of SAH and the rate of rebleeding after misdiagnosis were higher in the atypical onset group (P = .045 and P = .043, respectively). The interval from onset to diagnosis was longer in the atypical onset group (P = .033). The atypical onset group demonstrated a more severe clinical grade on admission (P = .009), a lower rate of ruptured aneurysm repair (P < .001), and a poorer outcome (P = .003). CONCLUSIONS: Atypical onset is rare but has a great impact on the clinical course through rebleeding exacerbated by misdiagnosis or delayed diagnosis, resulting in poor outcomes. PMID- 26935120 TI - Pulse Blood Pressure Correlates with Late Outcome in Acute Ischemic Stroke without Significant Culprit Artery Stenosis. AB - BACKGROUND: This study was conducted to test the hypothesis that elevated blood pressure at the early stage is associated with unfavorable outcome in acute ischemic stroke patients with stenosis of less than 50% of the culprit artery. METHODS: Patients with acute ischemic stroke onset within 48 hours and stenosis of less than 50% of the culprit artery from a prospective stroke registry were analyzed. A modified Rankin Scale score of 1 or lower at 3 months was defined as a favorable late outcome. Univariate and multivariate logistic regression analyses were used to analyze the association between hemodynamic parameters and outcome. RESULTS: One hundred thirty-six patients fulfilled the selection criteria. Patients with favorable outcome had lower pulse pressure at emergency department (ED) triage, lower systolic blood pressure (SBP) at 24 hours, lower pulse pressure at 24 hours, and lower heart rate (HR) at 24 hours. The univariate logistic regression analysis showed that history of stroke, elevated SBP at 24 hours, elevated HR at 24 hours, elevated pulse pressure at 24 hours, and higher National Institutes of Health Stroke Scale score at ED triage were associated with a less favorable late outcome. Two separate models of multivariate logistic regression analyses showed that pulse pressure at ED triage and pulse pressure at 24 hours, respectively, were significantly associated with less favorable outcome. CONCLUSIONS: Elevated pulse pressure at the early stage is independently associated with unfavorable late outcome in acute ischemic stroke patients with culprit artery stenosis less than 50%. PMID- 26935121 TI - Cerebral Aneurysm Size before and after Rupture: Case Series and Literature Review. AB - BACKGROUND: The conclusions of the International Study of Unruptured Intracranial Aneurysms (ISUIA) demonstrating that anterior circulation aneurysms less than 7 mm in maximal diameter have a 0% risk of rupture continue to be widely cited despite discordance with the anecdotal observation that the majority of ruptured cerebral aneurysms are less than 7 mm. The leading hypothesis to reconcile this discrepancy is that cerebral aneurysms shrink after rupture. Our case series of 6 subjects adds to the scarce published literature that addresses our limited understanding of aneurysm size before and after rupture. METHODS: Our institutional database was evaluated for patients with brain vascular imaging before and after cerebral aneurysm rupture. We evaluated clinical and anatomic features as well as aneurysm dimensions using a submillimeter measurement tool with adjudication between 2 physicians. RESULTS: Among our 6 subjects who met the inclusion criteria, and even when combined with the 17 subjects published in the literature with similar information before rupture, no aneurysms decreased in size more than 2 mm. In total, 17 out of 23 aneurysms studied increased in size after rupture. CONCLUSIONS: Our data add additional evidence that unruptured aneurysms do not shrink in size after rupture. The discrepancy between the ISUIA conclusion on aneurysm size and rupture risk and what is observed anecdotally remains an area in need of additional study. PMID- 26935122 TI - Routine Troponin Measurements Are Unnecessary to Exclude Asymptomatic Coronary Events in Acute Ischemic Stroke Patients. AB - BACKGROUND: Obtaining serum troponin levels in every patient with acute stroke is recommended in recent stroke guidelines, but there is no evidence that these contribute positively to clinical care. We sought to determine the clinical significance of measuring troponin levels in acute ischemic stroke patients. METHODS: We reviewed 398 consecutive patients with acute ischemic stroke at a large academic institution from 2010 to 2012. Troponin levels were measured as a result of protocol in place during part of the study period. The mean age was 70 years (standard deviation +/-16 years) and 197 (49.5%) were men. RESULTS: Chronic kidney disease was present in 78 (19.6%), coronary artery disease in 107 (26.9%), and atrial fibrillation in 107 (26.9%). Serum troponin T was measured in 246 of 398 patients (61.8%). Troponin was elevated (>.01 ng/mL) at any point in 38 of 246 patients (15.5%) and was elevated in 28 patients at all 3 measurements (11.3% of those with troponin measured). Only 4 of 246 patients (1.6%) had a significant uptrend. Two were iatrogenic in the setting of hemodynamic augmentation using vasopressors to maintain cerebral perfusion. One case was attributed to stroke and chronic kidney disease and another case to heart failure from inflammatory fibrocalcific mitral valvular heart disease. CONCLUSIONS: Serum troponin elevation in patients with ischemic stroke is not usually caused by clinically significant acute myocardial ischemia unless iatrogenic in the setting of vasopressor administration. Serum troponin levels should be measured judicially, based on clinical context, rather than routinely in all stroke patients. PMID- 26935123 TI - Higher Incidence of Stroke on the Last Day of the Month in Hungary-a Role for Psychosocial Factors and Financial Insecurity? AB - BACKGROUND: The seasonal cumulation of acute ischemic stroke events is a well known phenomenon. Critical days are determined by both biological and psychosocial factors. We hypothesized that the financial stability of those with a monthly income living in an economically unpredictable environment rises upon the arrival of their salary and decreases in the preceding days, leading to anxiety and existential insecurity, which may increase the incidence of acute ischemic stroke. METHODS: We assessed the daily average number of thrombolytic treatments due to acute ischemic stroke in Hungary between December 1, 2005, and November 30, 2013, calculating the ratio of thrombolytic treatments on the last day of the month (irrespectively whether it was the 28th-31st days) to thrombolytic treatments on the other days, and determined 95% confidence intervals. RESULTS: In this period, 7880 thrombolytic treatments were performed nationwide (2.70/day), out of which 1867 occurred on the last day of the month (19.45/day). If the 28th, 29th, or 30th was not the last day of the month, 15.8, 20.6, and 22 times less thrombolytic treatments, respectively, were performed than on the last day of that month. CONCLUSION: We propose that financial insecurity on the days prior to the receipt of a salary might play a role in the elevation of stroke incidence observed on the last day of the month in Hungary. Further analysis of this phenomenon and its psychosocial effects is needed to adequately allocate healthcare resources and to take preventive measures in the high-risk population. PMID- 26935124 TI - Abstracts of the Endocrine Society of Australia Annual Scientific Meeting 2015, 23-26 August 2015. PMID- 26935126 TI - Low levels of inflammation and the absence of subclinical atherosclerosis in rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease. Patients with RA have an increased risk for the development of cardiovascular diseases, however, the pathophysiological mechanisms of arterial complications in RA remain to be fully elucidated. Understanding the early markers of vascular damage may aid in preventing cardiovascular complications in patients with RA. The current study investigated this by recruiting 30 patients with RA and 30 healthy subjects. Intima-media thickness (IMT) was used to detect the presence of atherosclerotic disease and was measured in the carotid and femoral arteries. Tumor necrosis factor alpha, interleukin-6 (IL-6), IL-8, IL-10 and matrix metalloproteinase-2 were measured as markers of inflammation. An IMT >=0.9 mm was observed in 7/30 patients with RA, however, no significant differences between patients with RA and the controls were observed in the inflammatory markers analyzed. Of note, these results indicated that the appropriate management of RA may have affected the inflammatory status of these patients and consequently may have impacted upon subclinical atherosclerosis. PMID- 26935125 TI - Inhibiting subthalamic nucleus decreases cocaine demand and relapse: therapeutic potential. AB - Preclinical evidence indicates that inactivation of subthalamic nucleus (STN) may be effective for treating cocaine addiction, and therapies that target STN, e.g. deep brain stimulation, are available indicating that this may have clinical promise. Here, we assessed the therapeutic potential of STN inactivation using a translationally relevant economic approach that quantitatively describes drug taking behavior, and tested these results with drug-seeking tasks. Economic demand for cocaine was assessed in rats (n = 11) using a within-session threshold procedure in which cocaine price (responses/mg cocaine) was sequentially increased throughout the session. Cocaine demand was assessed in this manner immediately after bilateral microinfusions into STN of either vehicle (artificial cerebrospinal fluid) or the GABAA receptor agonist muscimol. A separate group of animals (n = 8) was tested for changes in cocaine seeking either during extinction or in response to cocaine-associated cues. Muscimol-induced inhibition of STN significantly attenuated cocaine consumption at high prices, drug seeking during extinction and cued reinstatement of cocaine seeking. In contrast, STN inhibition did not reduce cocaine consumption at low prices or locomotor activity. Thus, STN inactivation reduced economic demand for cocaine and multiple measures of drug seeking during extinction. In view of the association between economic demand and addiction severity in both rat and human, these results indicate that STN inactivation has substantial clinical potential for treatment of cocaine addiction. PMID- 26935127 TI - Triterpene alcohols and sterols from rice bran reduce postprandial hyperglycemia in rodents and humans. AB - SCOPE: Hyperglycemia is a major public health problem worldwide and there is increasing demand for prevention of postprandial hyperglycemia in diabetic, prediabetic, and healthy humans. METHODS AND RESULTS: We investigated whether rice bran and triterpene alcohol and sterol preparation (TASP) lowered hyperglycemia in mice and humans. Brown rice and white rice supplemented with TASP lowered the postprandial hyperglycemia in humans. TASP and its components (cycloartenol [CA], 24-methylene cycloartanol, beta-sitosterol, and campesterol) decreased postprandial hyperglycemia in C57BL/6J mice. Glucose transport into everted rat intestinal sacs and human HuTu80 cells transfected with sodium glucose cotransporter-1 (SGLT1) was significantly reduced by the addition of CA. Intracellular localization analysis suggested that SGLT1 translocation to the apical plasma membrane was inhibited when the cells were treated with CA. CONCLUSIONS: We demonstrated for the first time that TASP from rice bran lowered postprandial hyperglycemia in mice and humans. The smaller increase in blood glucose following TASP consumption may be due to the CA-induced decrease in glucose absorption from the intestine, which may be related to decreased membrane translocation of SGLT1. PMID- 26935128 TI - Species-specific differences in the ability of feline lentiviral Vif to degrade feline APOBEC3 proteins. AB - How host-virus co-evolutionary relationships manifest is one of the most intriguing issues in virology. To address this topic, the mammal-lentivirus relationship can be considered as an interplay of cellular and viral proteins, particularly apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3 (APOBEC3) and viral infectivity factor (Vif). APOBEC3s enzymatically restrict lentivirus replication, whereas Vif antagonizes the host anti-viral action mediated by APOBEC3. In this study, the focus was on the interplay between feline APOBEC3 proteins and two feline immunodeficiency viruses in cats and pumas. To our knowledge, this study provides the first evidence of non-primate lentiviral Vif being incapable of counteracting a natural host's anti-viral activity mediated via APOBEC3 protein. PMID- 26935129 TI - Cardiac non-Hodgkin's lymphoma: clinical characteristics and trends in survival. AB - OBJECTIVES: The purpose of this study was to describe the clinical characteristics and outcomes in cardiac non-Hodgkin's lymphoma (NHL). METHODS: A retrospective analysis of 94 cases of NHL with biopsy-proven cardiac involvement in PubMed between 1990 and 2015. RESULTS: Among cases with cardiac involvement, diffuse large B-cell lymphoma was the most common histologic subtype (58%), followed by T-cell lymphoma (16%), Burkitt's lymphoma (9%), and small lymphocytic lymphoma (6%). Symptomatic heart failure was the most common clinical presentation (34%), and 20% of patients had no cardiac symptoms. Median survival was 3 months (range, 0-72) among all patients. Patients who presented with heart failure had inferior outcomes. Patients with primary, vs. secondary, cardiac involvement had a trend toward superior outcomes. Importantly, chemotherapy treatment was associated with a prolongation in median survival (18 vs. 1 month, HR 0.16, 95% CI, 0.47-0.54, P = 0.0003), and patients diagnosed in the chemo immunotherapy era demonstrated a trend toward better outcomes. Median survival was not reached among patients with B-cell malignancies who were alive for 1 month after the diagnosis. CONCLUSION: Pathologic lymphomatous involvement of cardiac tissue should be considered in the evaluation of patients with NHL. Durable remissions can be achieved in B-cell NHL with cardiac involvement, and thus, therapy should be considered in such cases. PMID- 26935131 TI - Factors associated with self-esteem following acquired brain injury in adults: A systematic review. AB - Self-esteem is potentially a key factor in psychological and psychosocial well being following acquired brain injury (ABI). The current review aimed to identify, synthesise and appraise all existing quantitative empirical studies on predictors or correlates of self-esteem following ABI in adulthood. In total, 27 papers met the inclusion criteria. A range of clinical factors were related to self-esteem after ABI, including the degree of physical and functional impairment. It is unclear if cognitive impairment is related to high or low self esteem. Additionally, psychological variables such as coping styles, adjustment and perception of problems or rehabilitation are related to self-esteem following ABI. Depression is strongly associated with low self-esteem, alongside anxiety, psychological distress and quality of life. Limitations of the available research and recommendations for clinical practice and further research are discussed. In particular, there is a need to engage with contemporary theoretical understandings of self-esteem, integrated with and supported by developments in how self-esteem is conceptualised and measured over time in an ABI population. The findings of the review suggest that self-esteem is an important factor to consider following ABI, particularly in the context of developing individualised, formulation-driven rehabilitation interventions that take into account biological, social and psychological factors. PMID- 26935130 TI - Primary tumor location is an important predictive factor for wild-type KRAS metastatic colon cancer treated with cetuximab as front-line bio-therapy. AB - INTRODUCTION: Left- and right-sided colon cancers were significantly different in epidemiologic, clinical and histological parameters. However, the impact of primary tumor location in metastatic colon cancer treated with front-line targeted triplet regimens is unclear, particularly in Asian populations. METHODS: A total of 121 patients with KRAS exon 2 codon 12/13 wild-type metastatic colon cancer were enrolled between January 2007 and December 2013. All patients received one target agent, such as cetuximab or bevacizumab, as a front-line targeted triplet regimen. The impact of primary tumor location for cetuximab and bevacizumab groups was analyzed, respectively. RESULTS: In cetuximab group, left sided metastatic colon cancer was superior to right-sided metastatic colon cancer in objective response rate (70.1% vs 33.3%, P = 0.024), progression-free survival (15.0 vs 5.3 months, P < 0.001) and overall survival (35.8 vs 14.4 months, P = 0.031). Primary tumor location was an independent prognostic factor for progression-free survival (hazard ratio 0.240, 95% confidence interval 0.114 0.508, P < 0.001). However, in the bevacizumab group, there were no differences in outcomes for either side. Primary tumor location was insignificant for progression-free survival and overall survival in univariate analysis. CONCLUSION: Left-sided primary tumors were favored in cetuximab-based front-line targeted triplet regimen for metastatic colon cancer. PMID- 26935132 TI - Statistical analyses in trials for the comprehensive understanding of organogenesis and histogenesis in humans and mice. AB - Statistical analyses based on the quantitative data from real multicellular organisms are useful as inductive-type studies to analyse complex morphogenetic events in addition to deductive-type analyses using mathematical models. Here, we introduce several of our trials for the statistical analysis of organogenesis and histogenesis of human and mouse embryos and foetuses. Multidimensional scaling has been applied to prove the existence and examine the mode of interkinetic nuclear migration, a regulatory mechanism of stem cell proliferation/differentiation in epithelial tubular tissues. Several statistical methods were used on morphometric data from human foetuses to establish the multidimensional standard growth curve and to describe the relation among the developing organs and body parts. Although the results are still limited, we show that these analyses are not only useful to understand the normal and abnormal morphogenesis in humans and mice but also to provide clues that could correlate aspects of prenatal developmental events with postnatal diseases. PMID- 26935133 TI - Direct comparison of multiparametric magnetic resonance imaging (MRI) results with final histopathology in patients with proven prostate cancer in MRI/ultrasonography-fusion biopsy. AB - OBJECTIVE: To compare multiparametric magnetic resonance imaging (mpMRI) of the prostate and histological findings of both targeted MRI/ultrasonography-fusion prostate biopsy (PBx) and systematic PBx with final histology of the radical prostatectomy (RP) specimen. PATIENTS AND METHODS: A total of 105 patients with prostate cancer (PCa) histopathologically proven using a combination of fusion Pbx and systematic PBx, who underwent RP, were investigated. All patients had been examined using mpMRI, applying the European Society of Urogenital Radiology criteria. Histological findings from the RP specimen were compared with those from the PBx. Whole-mount RP specimen and mpMRI results were directly compared by a uro-pathologist and a uro-radiologist in step-section analysis. RESULTS: In the 105 patients with histopathologically proven PCa by combination of fusion PBx and systematic PBx, the detection rate of PCa was 90% (94/105) in fusion PBx alone and 68% (72/105) in systematic PBx alone (P = 0.001). The combination PBx detected 23 (22%) Gleason score (GS) 6, 69 (66%) GS 7 and 13 (12%) GS >=8 tumours. Fusion PBx alone detected 25 (26%) GS 6, 57 (61%) GS 7 and 12 (13%) GS >=8 tumours. Systematic PBx alone detected 17 (24%) GS 6, 49 (68%) GS 7 and 6 (8%) GS >=8 tumours. Fusion PBx alone would have missed 11 tumours (4% [4/105] of GS 6, 6% [6/105] of GS 7 and 1% [1/105] of GS >=8 tumours). Systematic PBx alone would have missed 33 tumours (10% [10/105] of GS 6, 20% [21/105] of GS 7 and 2% [2/105] of GS >=8 tumours). The rates of concordance with regard to GS between the PBx and RP specimen were 63% (n = 65), 54% (n = 56) and 75% (n = 78) in fusion, systematic and combination PBx (fusion and systematic PBx combined), respectively. Upgrading of the GS between PBx and RP specimen occurred in 33% (n = 34), 44% (n = 46) and 18% (n = 19) in fusion, systematic and combination PBx, respectively. gamma-correlation for detection of any cancer was 0.76 for combination PBx, 0.68 for fusion PBx alone and 0.23 for systematic PBx alone. In all, 84% (n = 88) of index tumours were identified by mpMRI; 86% (n = 91) of index lesions on the mpMRI were proven in the RP specimen. CONCLUSIONS: Fusion PBx of tumour-suspicious lesions on mpMRI was associated with a higher detection rate of more aggressive PCa and a better tumour prediction in final histopathology than systematic PBx alone; however, combination PBx had the best concordance for the prediction of GS. Furthermore, the additional findings of systematic PBx reflect the multifocality of PCa, therefore, the combination of both biopsy methods would still represent the best approach for the prediction of the final tumour grading in PCa. PMID- 26935134 TI - Characterization of bone marrow-derived mesenchymal stem cells from dimethyloxallyl glycine-preconditioned mice: Evaluation of the feasibility of dimethyloxallyl glycine as a mobilization agent. AB - The prolyl hydroxylase inhibitor dimethyloxallyl glycine (DMOG) has been increasingly studied with regards to stem cell therapy. Previous studies have demonstrated that endogenous mesenchymal stem cells (MSCs) may be mobilized into peripheral circulation by pharmaceutical preconditioning. In addition, our previous study confirmed that DMOG, as a novel mobilization agent, could induce mouse/rat MSC migration into peripheral blood circulation. Therefore, the present study conducted studies to characterize bone marrow-derived MSCs (BM-MSCs) collected from mice following DMOG intraperitoneal injection. The surface antigen immune phenotype, differentiation capability, proliferative ability, migratory capacity and paracrine capacity of the BM-MSCs collected from DMOG-preconditioned mice (DBM-MSCs) or normal saline-treated mice (NBM-MSCs) were evaluated by means of flow cytometry, differentiation induction, Cell Counting kit-8, Transwell assay and enzyme-linked immunosorbent assay, respectively. Compared with NBM MSCs, DBM-MSCs displayed a similar immune phenotype and multilineage differentiation capability, reduced proliferative ability and migratory capacity, and similar transforming growth factor and platelet-derived growth factor secretion capacity. These results provide a novel insight into the biological properties of BM-MSCs from mice preconditioned with DMOG. DBM-MSCs exhibited slightly distinct characteristics to NBM-MSCs; however, they may have therapeutic potential for future stem cell therapy. In addition, the present study suggested that DMOG may be used as a novel mobilization agent in future clinical trials as no adverse effects were observed. PMID- 26935135 TI - Bacterial Vegetative Insecticidal Proteins (Vip) from Entomopathogenic Bacteria. AB - Entomopathogenic bacteria produce insecticidal proteins that accumulate in inclusion bodies or parasporal crystals (such as the Cry and Cyt proteins) as well as insecticidal proteins that are secreted into the culture medium. Among the latter are the Vip proteins, which are divided into four families according to their amino acid identity. The Vip1 and Vip2 proteins act as binary toxins and are toxic to some members of the Coleoptera and Hemiptera. The Vip1 component is thought to bind to receptors in the membrane of the insect midgut, and the Vip2 component enters the cell, where it displays its ADP-ribosyltransferase activity against actin, preventing microfilament formation. Vip3 has no sequence similarity to Vip1 or Vip2 and is toxic to a wide variety of members of the Lepidoptera. Its mode of action has been shown to resemble that of the Cry proteins in terms of proteolytic activation, binding to the midgut epithelial membrane, and pore formation, although Vip3A proteins do not share binding sites with Cry proteins. The latter property makes them good candidates to be combined with Cry proteins in transgenic plants (Bacillus thuringiensis-treated crops [Bt crops]) to prevent or delay insect resistance and to broaden the insecticidal spectrum. There are commercially grown varieties of Bt cotton and Bt maize that express the Vip3Aa protein in combination with Cry proteins. For the most recently reported Vip4 family, no target insects have been found yet. PMID- 26935138 TI - Effects of clinically significant weight loss with exercise training on insulin resistance and cardiometabolic adaptations. AB - OBJECTIVE: To determine response rates for clinically significant weight loss (CWL) following different aerobic exercise training amounts and whether enhanced cardiometabolic adaptations are observed with CWL compared to modest weight loss (MWL) or neither. METHODS: Participants (N = 330) performed 6 months of aerobic training at 4 kcal per kilogram per week (KKW), 8 KKW, or 12 KKW (50%, 100%, and 150% of recommended levels respectively). Weight loss was categorized as CWL (>=5%) or MWL (3.0% to 4.9%) or neither. RESULTS: The CWL response rate was greater in the 8 KKW group (20.2%, CI: 13.0% to 27.5%) compared to 4 KKW (10.3%, CI: 4.6% to 16.0%), but not compared to the 12 KKW group (14.6%, CI: 7.6% to 21.6%). Reductions in HOMA-IR were observed in participants with CWL (-0.60, CI: 0.98 to -0.22) and with MWL (-0.48, CI: -0.87 to -0.10), but not those who achieved neither (-0.06, CI -0.22 to 0.10). No changes between groups were observed for cholesterol, fitness, or blood pressure. CONCLUSIONS: Low response rates for CWL were observed following training, even at levels above recommended levels. Achieving MWL with exercise may represent a reasonable initial weight loss target since the improvement in insulin resistance with MWL is similar to what is achieved with CWL. PMID- 26935139 TI - Tightly congruent bursts of lineage and phenotypic diversification identified in a continental ant radiation. AB - Adaptive diversification is thought to be shaped by ecological opportunity. A prediction of this ecological process of diversification is that it should result in congruent bursts of lineage and phenotypic diversification, but few studies have found this expected association. Here, we study the relationship between rates of lineage diversification and body size evolution in the turtle ants, a diverse Neotropical clade. Using a near complete, time-calibrated phylogeny we investigated lineage diversification dynamics and body size disparity through model fitting analyses and estimation of per-lineage rates of cladogenesis and phenotypic evolution. We identify an exceptionally high degree of congruence between the high rates of lineage and body size diversification in a young clade undergoing renewed diversification in the ecologically distinct Chacoan biogeographical region of South America. It is likely that the region presented turtle ants with novel ecological opportunity, which facilitated a nested burst of diversification and phenotypic evolution within the group. Our results provide a compelling quantitative example of tight congruence between rates of lineage and phenotypic diversification, meeting the key predicted pattern of adaptive diversification shaped by ecological opportunity. PMID- 26935136 TI - Strengths and Limitations of Model Systems for the Study of Urinary Tract Infections and Related Pathologies. AB - Urinary tract infections (UTIs) are some of the most common bacterial infections worldwide and are a source of substantial morbidity among otherwise healthy women. UTIs can be caused by a variety of microbes, but the predominant etiologic agent of these infections is uropathogenic Escherichia coli (UPEC). An especially troubling feature of UPEC-associated UTIs is their high rate of recurrence. This problem is compounded by the drastic increase in the global incidence of antibiotic-resistant UPEC strains over the past 15 years. The need for more effective treatments for UTIs is driving research aimed at bettering our understanding of the virulence mechanisms and host-pathogen interactions that occur during the course of these infections. Surrogate models of human infection, including cell culture systems and the use of murine, porcine, avian, teleost (zebrafish), and nematode hosts, are being employed to define host and bacterial factors that modulate the pathogenesis of UTIs. These model systems are revealing how UPEC strains can avoid or overcome host defenses and acquire scarce nutrients while also providing insight into the virulence mechanisms used by UPEC within compromised individuals, such as catheterized patients. Here, we summarize our current understanding of UTI pathogenesis while also giving an overview of the model systems used to study the initiation, persistence, and recurrence of UTIs and life-threatening sequelae like urosepsis. Although we focus on UPEC, the experimental systems described here can also provide valuable insight into the disease processes associated with other bacterial pathogens both within the urinary tract and elsewhere within the host. PMID- 26935137 TI - Extracellular Vesicles Exploit Viral Entry Routes for Cargo Delivery. AB - Extracellular vesicles (EVs) have emerged as crucial mediators of intercellular communication, being involved in a wide array of key biological processes. Eukaryotic cells, and also bacteria, actively release heterogeneous subtypes of EVs into the extracellular space, where their contents reflect their (sub)cellular origin and the physiologic state of the parent cell. Within the past 20 years, presumed subtypes of EVs have been given a rather confusing diversity of names, including exosomes, microvesicles, ectosomes, microparticles, virosomes, virus-like particles, and oncosomes, and these names are variously defined by biogenesis, physical characteristics, or function. The latter category, functions, in particular the transmission of biological signals between cells in vivo and how EVs control biological processes, has garnered much interest. EVs have pathophysiological properties in cancer, neurodegenerative disorders, infectious disease, and cardiovascular disease, highlighting possibilities not only for minimally invasive diagnostic applications but also for therapeutic interventions, like macromolecular drug delivery. Yet, in order to pursue therapies involving EVs and delivering their cargo, a better grasp of EV targeting is needed. Here, we review recent progress in understanding the molecular mechanisms underpinning EV uptake by receptor-ligand interactions with recipient cells, highlighting once again the overlap of EVs and viruses. Despite their highly heterogeneous nature, EVs require common viral entry pathways, and an unanticipated specificity for cargo delivery is being revealed. We discuss the challenges ahead in delineating specific roles for EV-associated ligands and cellular receptors. PMID- 26935140 TI - Effect of storage time and donor sex of transfused red blood cells on 1-year survival in patients undergoing cardiac surgery: an observational study. AB - BACKGROUND: Red blood cell (RBC) storage lesions and RBCs from females transfused into male recipients may have adverse effects on transfusion recipients' survival. We hypothesized that the effect of donor sex and the effect of age of blood on mortality would be most apparent in cardiac surgery patients. STUDY DESIGN AND METHODS: Using data from French Blood Services and two university hospitals, we conducted a retrospective cohort study on cardiac surgery patients whose first transfusion occurred between 2007 and 2011. The age of blood and donor sex effects on 1-year survival were studied using Cox regression modeling, with time-dependent stratification on the number of RBCs and adjustments for the type of surgery and other products transfused. RESULTS: Among the 2715 cardiac surgery patients, 85.1% were alive after 1 year. Age of blood and donor sex were associated with survival before adjustments (p < 0.0001). However, the adjusted hazard ratios (HRs) for patients transfused with blood stored for 29 days or more versus 14 days or less were 0.97 (95% confidence interval [95% CI], 0.69-1.35; p = 0.98) and 1.22 (95% CI, 0.81-1.82) for patients who received only sex mismatched RBCs versus all matched units (p = 0.27). For males transfused solely with female RBCs, the HR was 0.96 (95% CI, 0.57-1.61; p = 0.69); in females transfused only with male RBCs, it was 2.03 (95% CI, 0.87-4.73; p = 0.17). CONCLUSIONS: In this first study of survival after transfusion in France, there was no significant effect for age of blood or donor sex. Contrary to previously reported data, female RBCs appear to be safe for male recipients. PMID- 26935141 TI - Fracto-mechanoluminescence induced by impulsive deformation of II-VI semiconductors. PMID- 26935142 TI - Maximal expiratory pressure and Valsalva manoeuvre do not produce similar cardiovascular responses in healthy men. AB - NEW FINDINGS: What is the central question of this study? This is the first study to evaluate and describe the cardiovascular responses during maximal expiratory pressure compared with the Valsalva manoeuvre, and whether those responses are similar. What is the main finding and its importance? This study showed that the duration of the manoeuvres appears to be responsible for the different physiological mechanisms involved in the cardiovascular responses to each manoeuvre and that the intensity of expiratory effort was related to the response in maximal expiratory pressure. These results are important to identify the risks to which subjects are exposed when performing these manoeuvres. The main purpose of this study was to compare the cardiovascular responses between the Valsalva manoeuvre (VM) and maximal expiratory pressure (MEP) and to evaluate the effect of age on these responses. Twenty-eight healthy men were evaluated and divided into two groups, younger (n = 15, 25 +/- 5 years) and middle aged (n = 13, 50 +/- 5 years), and they performed the VM and MEP measurement. The VM consisted of an expiratory effort (40 mmHg) against a manometer for 15 s, and the MEP was performed according to American Thoracic Society guidelines. The cardiovascular responses were analysed at rest, isotime (3 s), peak, nadir and recovery, and the cardiovascular variations (Delta) were calculated as peak or isotime minus resting values. For the statistical analysis, we used two-way ANOVA (P < 0.05). We observed that MEP and the VM generate similar changes in cardiac output (P > 0.05), but MEP presents higher values for mean arterial pressure (MAPPeak , MAPIsotime , DeltaMAP and DeltaMAPIsotime ) than those observed in the VM (P < 0.05). The execution time of the manoeuvres (VM ~15 s and MEP ~5 s) appears to be largely responsible for the activation of different physiological mechanisms involved in the cardiovascular control for each manoeuvre, and the intensity of expiratory effort is related to the higher response of MAP and peripheral vascular resistance (PVRIsotime and DeltaPVRIsotime ) during MEP (P < 0.05). Moreover, it appears that age affects only the heart rate and PVR responses (P < 0.05), which were higher in the young and middle-aged group, respectively. Based on these findings, we can conclude that MEP and the VM do not generate similar cardiovascular responses, except for cardiac output. PMID- 26935143 TI - Proceedings of the XIIth World Congress of Perinatal Medicine, Madrid, Spain, 3-6 November 2015. AB - XIIth World Congress of Perinatal Medicine, Madrid, Spain, 3-6 November 2015 The World Association of Perinatal Medicine convened its XIIth meeting in Madrid, Spain, 3-6 November 2015. More than 3000 health professionals from the world over and 200 speakers presented up-to-date clinical and basic material related to the care of pregnant women, fetus and neonate. Preceding the formal Congress several individual mini courses were offered. They were well attended and the audience had the opportunity to relate very closely to the speakers, an issue of great importance for young clinicians to share relevant clinical information. The identification and alternative treatments of threatened preterm birth and the care of the growth restricted newborn occupied significant amount of the speakers' efforts. Obesity, postpartum hemorrhage, maternal infections and morbidly adherent placenta were also addressed. 4 days of intensive learning and experience sharing were the result. PMID- 26935144 TI - Investment in attending to cues and the evolution of amplifiers. AB - Signals and cues are extensively used in social interactions across diverse communication systems. Here, we extend an existing theoretical framework to explore investment by emitters and perceivers in the fidelity with which cues and signals associated with the former are detected by the latter. Traits of the emitter that improve cue or signal fidelity without adding information are termed 'amplifiers'. We assume that each party can invest in improving fidelity but that it is increasingly costly the more fidelity is improved. Our model predicts that evolution of amplifier traits of a pre-existing cue occurs over a broader range of circumstances than evolution of signalling in situations where the emitter offered no pre-existing cue to the perceiver. It further predicts that the greater the intrinsic informational value of a cue, the more likely it is that the perceiver (and not the emitter) will invest in the fidelity of detecting that cue. A consequence of this predicted asymmetry is that true communication with reciprocal adaptations in emitters and perceivers to improve signal fidelity is likely to occur predominantly for traits of intermediate reliability. The corollary is that uncertainty of the perceiver will then be a key feature of communication. Uncertainty can arise because perceivers misinterpret signals or do not perceive them correctly, but here we argue that uncertainty is more fundamentally at the root of communication because traits that are intrinsically highly informative will induce only the perceiver and not the emitter to invest in improved fidelity of perception of that trait. PMID- 26935145 TI - The Helicobacter heilmannii hofE and hofF Genes are Essential for Colonization of the Gastric Mucosa and Play a Role in IL-1beta-Induced Gastric MUC13 Expression. AB - BACKGROUND: Helicobacter heilmannii is a zoonotic bacterium associated with gastric disease in humans. We recently showed that H. heilmannii binds to human gastric mucins and epithelial cells and highlighted a potential role for the murine Muc13 mucin in gastric Helicobacter colonization. The aims of this study were to investigate the role of the H. heilmannii hof gene locus encoding HofH/F/E/G/C/D in adhesion to the gastric mucosa and induction of increased gastric Muc13 expression. METHODS: Bacterial hof gene and host gene expression experiments, Helicobacter binding assays and experimental infection studies in mice were performed. H. pylori and its DeltahofF mutant were included for comparison. RESULTS: Helicobacter heilmannii strains lacking HofE or HofF showed a clear decrease in binding to gastric mucins and epithelial cells as well as a lower gastric colonization level in the stomach of Balb/c mice at 4 and 9 weeks post-infection compared to the H. heilmannii wildtype strain. Interestingly, H. heilmannii DeltahofE and DeltahofF and H. pylori DeltahofF did not induce an increased expression of MUC13 in human gastric epithelial cells and of Muc13 in the stomach of mice. Finally, we demonstrated that IL-1beta is induced in the stomach as a response to Helicobacter colonization which on its turn is involved in the expression of MUC13/Muc13 in the gastric epithelium. CONCLUSION: These novel results in Helicobacter research identified H. heilmannii HofE and HofF as adhesins and suggest an important role of H. heilmannii HofE and HofF and H. pylori HofF in IL-1beta-induced gastric MUC13/Muc13 expression. PMID- 26935146 TI - Identification of long-non coding RNA UCA1 as an oncogene in renal cell carcinoma. AB - Renal cell carcinoma (RCC) is the most common type of kidney cancer in adults, which is associated with poor prognosis and high recurrence. Long non-coding RNAs (lncRNAs) have been reported to be dysregulated in cancer and to be important in the regulation of carcinogenesis, thus suggesting that this class of molecules may be used as biomarkers in cancer. The lncRNA urothelial carcinoma associated 1 (UCA1) has been observed to be upregulated and to function as an oncogene in certain types of cancer; however, the role of UCA1 in RCC remains to be elucidated. The present study aimed to determine the expression and function of UCA1 in RCC. Quantitative polymerase chain reaction (qPCR) was used to determine the expression levels of UCA1 in 46 paired RCC and adjacent normal tissue samples. Furthermore, qPCR was used to determine the expression levels of UCA1 in four RCC cell lines compared with the human embryonic kidney 293T cell line. The impact of UCA1 on cell migration, proliferation and apoptosis was investigated by wound scratch assay, MTT and flow cytometry, respectively. The results of the present study demonstrated that UCA1 expression levels were significantly increased in RCC tissues and cells, as compared with the controls. Ectopic expression and gene silencing of UCA1 in RCC cell lines exerted opposite effects on cellular proliferation, migration and apoptosis, and the results suggested that UCA1 may function as an oncogene in RCC. These results indicated that UCA1 may be considered as a promising biomarker for diagnosis, and a therapeutic target in RCC. Further research is required to elucidate the role and target genes of UCA1 in RCC. PMID- 26935147 TI - Risk structures for radiation-induced trismus in head and neck cancer. PMID- 26935148 TI - NOP receptors in the prelimbic cortex have an inhibitory influence on cardiovascular responses induced by restraint stress. AB - Nociceptin/orphanin FQ (N/OFQ) and its receptor (NOP) have structural homology with classic opioids, but constitute a distinct neurotransmitter system because they lack affinity for the opioid peptides and receptors. This neurotransmission is implicated in several physiologic processes, but the role played by NOP receptors during stress situations remains unclear. The acute restraint stress (RS) is a model of unavoidable stress, characterized by sustained increases in mean arterial pressure (MAP), heart rate (HR) and a drop in tail temperature. On another side, the prelimbic (PL) and infralimbic (IL) cortices, subdivisions of the medial prefrontal cortex (MPFC), are implicated in the modulation of functional responses caused by RS. Considering that, the objective of the present study was to investigate the involvement of PL and IL NOP receptors in the control of autonomic responses induced by RS. Bilateral microinjection of nociceptin (NOP agonist) into the PL reduced the cardiovascular responses evoked by RS. Bilateral microinjection of UPF-101 (NOP antagonist) into the PL potentiated the pressor and tachycardiac responses evoked by RS, in a dose dependent manner. Local pretreatment with UPF-101 blocked the RS-evoked changes following nociceptin administration into the PL. None of these treatments affected the drop in tail temperature induced by RS. Otherwise, the administration of nociceptin or UPF-101 into the IL had no effect on RS-evoked autonomic changes. To investigate the peripheral mechanism involved in the increase in the RS-evoked cardiovascular responses induced by the blockade of PL NOP receptors, rats were intravenous pretreated with either homatropine or atenolol. The intravenous treatment with homatropine blunted the increase in the RS-evoked pressor and tachycardiac response induced by the PL treatment with UPF 101, while the intravenous treatment with atenolol did not affect the RS-evoked pressor and tachycardiac response induced by the PL treatment with UPF-101. In conclusion, our study shows an influence of the PL N/OFQ neurotransmission, but not the IL NOP receptors, in the control of cardiovascular responses observed during acute stress, by increasing cardiac parasympathetic activity. PMID- 26935149 TI - Waste bones ash as an alternative source of P for struvite precipitation. AB - Struvite precipitation has been widely applied for the removal of ammonium nitrogen (NH4-N) from wastewater. Due to the high cost of phosphorus (P) reagents, the current research trend was directed to find alternative sources of P, in order to maintain a sustainable NH4-N removal process. The current study investigated waste bones ashes as alternative sources of P. Different types of bones' ashes were characterized, in which the ash produced from waste fish bones was the highest in P content (17%wt.). The optimization of the factors affecting P extraction from ash by acidic leaching showed that applying 2M H2SO4 and 1.25 kg H2SO4/kg ash achieved the highest P recovery (95%). Thereafter, the recovered P was successfully used in struvite precipitation, which achieved more than 90% NH4-N removal and high purity struvite. PMID- 26935150 TI - Enhanced Oral Bioavailability of Pueraria Flavones by a Novel Solid Self microemulsifying Drug Delivery System (SMEDDS) Dropping Pills. AB - To improve bioavailability of pueraria flavones (PF), a self-microemulsifying drug delivery system (SMEDDS) dropping pills composed of PF, Crodamol GTCC, Maisine 35-1, Cremophor RH 40, 1,2-propylene glycol and polyethylene glycol 6000 (PEG6000) was developed. Particle size, zeta potential, morphology and in vitro drug release were investigated, respectively. Pharmacokinetics, bioavailability of PF-SMEDDS dropping pills and commercial Yufengningxin dropping pills were also evaluated and compared in rats. Puerarin treated as the representative component of PF was analyzed. Dynamic light scattering showed the ability of PF-SMEDDS dropping pills to form a nanoemulsion droplet size in aqueous media. The type of media showed no significant effects on the release rate of PF. PF-SMEDDS dropping pills were able to improve the in vitro release rate of PF, and the in vitro release of these dropping pills was significantly faster than that of Yufengningxin dropping pills. There was a dramatic difference between the mean value of t1/2, peak concentration (Cmax), the area of concentration-time curve from 0 to 6 h (AUC0-6 h) of PF-SMEDDS dropping pills and that of commercial Yufengningxin dropping pills. A pharmacokinetic study showed that the bioavailability of PF was greatly enhanced by PF-SMEDDS dropping pills. The value of Cmax and relative bioavailability of PF-SMEDDS dropping pills were dramatically improved by an average of 1.69- and 2.36-fold compared with that of Yufengningxin dropping pills after gavage administration, respectively. It was concluded that bioavailability of PF was greatly improved and that PF-SMEDDS dropping pills might be an encouraging strategy to enhance the oral bioavailability of PF. PMID- 26935151 TI - Rosa hybrida extract suppresses vascular smooth muscle cell responses by the targeting of signaling pathways, cell cycle regulation and matrix metalloproteinase-9 expression. AB - The pharmacological effects of Rosa hybrida are well known in the cosmetics industry. However, the role of Rosa hybrida in cardiovascular biology had not previously been investigated, to the best of our knowledge. The aim of the present study was to elucidate the effect of water extract of Rosa hybrida (WERH) on platelet-derived growth factor (PDGF)-stimulated vascular smooth muscle cells (VSMCs). VSMC proliferation, which was stimulated by PDGF, was inhibited in a non toxic manner by WERH treatment, which also diminished the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and AKT. Treatment with WERH also induced G1-phase cell cycle arrest, which was due to the decreased expression of cyclins and cyclin-dependent kinases (CDKs), and induced p21WAF1 expression in PDGF-stimulated VSMCs. Moreover, WERH treatment suppressed the migration and invasion of VSMCs stimulated with PDGF. Treatment with WERH abolished the expression of matrix metalloproteinase-9 (MMP-9) and decreased the binding activity of nuclear factor-kappaB (NF-kappaB), activator protein-1 (AP 1), and specificity protein 1 (Sp1) motifs in PDGF-stimulated VSMCs. WERH treatment inhibited the proliferation of PDGF-stimulated VSMCs through p21WAF1 mediated G1-phase cell cycle arrest, by decreasing the kinase activity of cyclin/CDK complexes. Furthermore, WERH suppressed the PDGF-induced phosphorylation of ERK1/2 and AKT in VSMCs. Finally, treatment with WERH impeded the migration and invasion of VSMCs stimulated by PDGF by downregulating MMP-9 expression and a reduction in NF-kappaB, AP-1 and Sp1 activity. These results provide new insights into the effects of WERH on PDGF-stimulated VSMCs, and we suggest that WERH has the potential to act as a novel agent for the prevention and/or treatment of vascular diseases. PMID- 26935152 TI - MiR-124 inhibits cell proliferation, migration and invasion by directly targeting SOX9 in lung adenocarcinoma. AB - Accumulating evidence indicates that dysregulation of microRNAs (miRNAs) may contribute to the initiation and progression of cancer. However, the role of miR 124 in lung adenocarcinoma (ADC) and the underlying mechanisms through which miR 124 exerts its functions are not completely understood. In the present study, we detected miR-124 and SOX9 expression in lung ADC tissues. The results showed that miR-124 was significantly downregulated in the lung ADC tissues compared with that noted in the corresponding non-cancerous lung tissues and the level of SOX9 protein was inversely associated with the expression of miR-124. The study in human lung ADC cell line A549 demonstrated that upregulation of miR-124 could inhibit cell proliferation, migration and invasion. The bioinformatic analysis showed that there was a putative miR-124 binding site in the 3' untranslated region (3'UTR) of SOX9. Using a luciferase reporter assay, we verified that SOX9 is a direct target of miR-124. Furthermore, overexpression of miR-124 repressed SOX9 expression, whereas inhibition of miR-124 increased expression of SOX9 in the A549 cells. Finally, we identified that SOX9 was a functional mediator of miR 124 in A549 cells. Taken together, our results suggest that miR-124 functions as a tumor suppressor in lung ADC by directly targeting SOX9 and it may be a promising candidate for miR-based therapy against lung ADC. PMID- 26935153 TI - Protective effect of grape seed extract against cadmium-induced testicular dysfunction. AB - Cadmium (Cd) is the most prevalent toxic metal present in livestock feed; therefore, the present study aimed to examine the ameliorative effects of grape seed extract (GSE) on cadmium chloride (CdCl2)-induced testicular dysfunction of Wistar rats. Male adult Wistar rats (40 rats; n=10/group) were divided into four equal groups. Group one was used as a control, and was given ad libitum access to food and water. Groups 2-4 were treated with CdCl2 [5 mg/kg body weight (BW)], GSE (400 mg/kg BW, orally), and GSE plus CdCl2, respectively. Blood and testicular tissues were collected and assayed for biochemical and histopathological changes, respectively. Testicular genes were expressed using semi-quantitative RT-PCR analysis. The results of the present study demonstrated that there was a decrease in serum testosterone levels following CdCl2 toxicity, which were normalized after GSE co-administration. Furthermore, CdCl2 significantly increased the serum levels of malondialdehyde, and decreased levels of antioxidants. At the histopathological level, the testes of the CdCl2 group exhibited congestion, edema in the interstitial blood vessels, irregular arrangement of the epithelial lining of the seminiferous tubules, and degeneration and sloughing of the spermatogenic cells, which accumulated in the center of the seminiferous tubules. Such pathological alterations were ameliorated following treatment with GSE in the CdCl2 plus GSE group. The immunohistochemical expression of B-cell lymphoma 2-associated X protein was high in the CdCl2 group, and low in the control and GSE groups. Co-treatment with GSE and CdCl2 exhibited ameliorative effects on the immunoreactivity of B-cell lymphoma 2-associated X protein. CdCl2 toxicity induced a significant downregulation in the mRNA expression levels of cytochrome P450 cholesterol side chain cleavage enzyme, cytochrome P450 17A1, 3beta-hydroxysteroid dehydrogenase (3beta-HSD), 17beta-HSD, androgen receptor, steroidogenic acute regulatory protein, and follicle-stimulating hormone receptor. GSE administration exhibited a stimulatory effect on steroidogenesis-associated enzymes, and co-treatment with GSE and CdCl2 normalized and upregulated the mRNA expression levels of these examined genes. This study concluded that GSE has beneficial protective effects against the deleterious effects of CdCl2 on the testis. PMID- 26935154 TI - MiR-183 functions as an oncogene by targeting ABCA1 in colon cancer. AB - Colon cancer remains the second most common cause of cancer-related death, indicating that a proportion of cancer cells are not eradicated by current therapies. Investigation of the molecular mechanisms involved in the development and progression of the disease will aid in the further understanding of the pathogenesis and progression and offer new targets for effective therapies. In the present study, we initially confirmed that ABCA1 was aberrantly expressed in colon cancer tissues and colon cancer cells. Its overexpression inhibited the proliferation of colon cancer HCT116 cells while silencing of ABCA1 promoted the proliferation and inhibited the apoptosis of colon cancer LDL1 cells. Upregulation of specific miRNAs can contribute to the downregulation of tumor suppressive genes. Thus, we aimed to ascertain whether ABCA1 is downregulated by overexpression of a specific miRNA in colon cancer. We screened microRNAs that may target ABCA1 by miRanda which is a commonly used prediction algorithm. We found that miR-183 targets the 3'UTR of ABCA1 mRNA. Subsequent experiments confirmed that miR-183 degraded ABCA1 mRNA in the colon cancer cells. Finally, we demonstrated that miR-183 promoted the proliferation and inhibited the apoptosis of colon cancer cells. Thus, we conclude that miR-183 promotes proliferation and inhibits apoptosis by degrading ABCA1 in colon cancer. PMID- 26935155 TI - Strongyloides ratti and S. venezuelensis - rodent models of Strongyloides infection. AB - Strongyloides spp. are common parasites of vertebrates and two species, S. ratti and S. venezuelensis, parasitize rats; there are no known species that naturally infect mice. Strongyloides ratti and S. venezuelensis overlap in their geographical range and in these regions co-infections appear to be common. These species have been widely used as tractable laboratory systems in rats as well as mice. The core biology of these two species is similar, but there are clear differences in aspects of their within-host biology as well as in their free living generation. Phylogenetic evidence suggests that S. ratti and S. venezuelensis are the result of two independent evolutionary transitions to parasitism of rats, which therefore presents an ideal opportunity to begin to investigate the basis of host specificity in Strongyloides spp. PMID- 26935156 TI - MicroRNA-200b suppresses cell invasion and metastasis by inhibiting the epithelial-mesenchymal transition in cervical carcinoma. AB - The expression of microRNA (miR)-200b is suppressed in numerous tumor types, leading to epithelial-mesenchymal transition, which enables solid tissue epithelial cancers to invade and metastasize. The present study assessed the role of miR-200b in cervical cancer with the aim of clarifying the underlying pathophysiological mechanisms and to identify potential strategies for its prevention and treatment of cervical cancer. Reverse-transcription quantitative PCR revealed that miR-200b was downregulated in invasive cervical carcinoma tissues compared with that in normal adjacent tissues. A Transwell migration assay indicated that transfection of cervical cancer cells with miR-200b mimics significantly inhibited their migratory potential, while migration was enhanced in cells transfected with miR-200b inhibitor. Furthermore, western blot analysis indicated a negative correlation between miR-200b and mesenchymal marker vimentin as well as matrix metalloproteinase-9, which has a key role in tumor invasion and metastasis. In addition, a positive correlation between miR-200b and the epithelial marker E-cadherin was revealed by western blot and immunofluorescence. The results of the present study suggested that miR-200b suppressed the migratory potential of cervical carcinoma cells and therefore their ability to metastasize by inhibiting the epithelial-mesenchymal transition, which may be utilized for the treatment of cervical cancer. PMID- 26935157 TI - Computed Tomography-guided Pericardiocentesis: An alternative approach for accessing the pericardium. AB - Pericardial effusions compress the heart, decrease cardiac output, and lead to haemodynamic collapse. Ultrasound (US)-guided pericardiocentesis is the gold standard for treating pericardial effusions. Recently, the incorporation of computed tomography (CT) guidance has increased patient safety while entering the pericardium. Despite the superior performance of CT-guided pericardiocentesis in smaller, complex effusions, this procedure is not routinely performed by cardiologists and surgeons. Unlike those with an intact pericardium, patients with mediastinal trauma, pericardial adhesions, temporary pacing wires, and vascular conduits are high risk for pericardiocentesis. Tamponade physiology also increases patient susceptibility to the hypotensive effects of anaesthesia during surgical drainage. Here we illustrate the technique of CT-guided pericardiocentesis and demonstrate its application in specific clinical scenarios. We conclude that CT-guided pericardiocentesis provides a useful, alternative strategy for treating cardiac tamponade in high risk patients. PMID- 26935159 TI - Complementary and Alternative Medicine in Cardiac Surgery: Prevalence and Modality of use. AB - BACKGROUND: Complementary and alternative medicines are developing at a growing rate but their use in the hospital setting is little known, ignoring risk or benefit in practice. The objectives of the study were to quantify the prevalence of complementary and alternative medicines used by patients admitted to a cardiac surgery department. METHODS: Patients and staff at the Cardiac Surgery unit of Angers University Hospital (France) were surveyed regarding their modality of complementary and alternative medicines use, between April 01, 2013, and April 18, 2014, by means of an anonymous questionnaire. RESULTS: Of 154 patients included in the study, 58% used a complementary and alternative medicine at least once in their lifetime, 38% during the preceding year, and 14% between the consultation and surgery. In all, 71% used them as a complement to their conventional medical treatment. Of those who used a complementary and alternative medicine during the year of their surgery procedure, only 29% informed their physicians and paramedical staff about it. CONCLUSIONS: Complementary and alternative medicines use among patients admitted to cardiac surgery units is common. Yet there is a real lack of knowledge regarding these health practices among physicians and paramedical staff. PMID- 26935158 TI - Association of Age, Sex, Body Size and Ethnicity with Electrocardiographic Values in Community-based Older Asian Adults. AB - BACKGROUND: Existing electrocardiographic (ECG) reference values were derived in middle-aged Caucasian adults. We aimed to assess the association of age, sex, body size and ethnicity on ECG parameters in a multi-ethnic Asian population. METHODS: Resting 12-lead ECG and anthropometric measurements were performed in a community-based cohort of 3777 older Asians (age 64.7+/-9.1 years, 1467 men, 88.8% Chinese, 7.7% Malay, 3.5% Indian, body mass index [BMI] 24.0+/-3.9kg/m(2)). RESULTS: Men had longer PR interval, wider QRS, shorter QTc interval and taller SV3. In both sexes, older age was associated with longer PR interval, wider QRS, larger R aVL and more leftward QRS axis, while higher BMI was associated with longer PR interval, wider QRS, larger RaVL and more negative QRS axis. There were significant inter-ethnic differences in QRS duration among men, as well as in PR and QTc intervals among women (all adjusted p<0.05). Findings were similar in a healthy subset of 1158 adults (age 61.2+/-9.1 years, 365 men) without cardiovascular risk factors. CONCLUSIONS: These first community-based ECG data in multi-ethnic older Asians highlight the independent effects of age, sex, body size and ethnicity on ECG parameters. PMID- 26935160 TI - Effects of Different Limb Remote Ischaemic Preconditioning on Ischaemia Reperfusion Injury in an Acute Left Anterior Descending Artery Occlusion Rat Model. AB - BACKGROUND: The aim is to compare effects of three different protocols of limb remote ischaemic preconditioning (LRIP) on ischaemia reperfusion injury in an acute left anterior descending artery (LAD) occlusion model rat. METHODS: Forty adult male Wistar rats were randomly assigned into four groups: group A, control; group B, LRIP in bilateral upper-limb (BUL) IP; group C, LRIP in bilateral lower limb (BLL) IP; group D, LRIP in bilateral upper and lower limbs (ULL) IP. The 60min ligation and 180min reperfusion in LAD were applied to all rats. Limb remote ischaemic preconditioning was performed using 5min occlusion and 15min reperfusion (six cycles). Heart rate, blood pressure and electrogastrography (EGG) were recorded. Creatine kinase isoenzyme (CK-MB) level and infarct size were measured. RESULTS: Limb remote ischaemic preconditioning did not significantly affect heart rate, systolic blood pressure and arrhythmia score. However, LRIP significantly increased DBP value and decreased CK-MB levels and infarct size in group B, C, and D. Moreover, LRIP in ULL had a significantly better effect on reducing infarct size than LRIP in BUL and BLL. CONCLUSIONS: Limb remote ischaemic preconditioning at limbs could significantly reduce reperfusion injury in the heart. Moreover, LRIP in ULL indicated a better effect in reducing infarct size than LRIP in BUL and BLL. PMID- 26935161 TI - Pulmonary Protective Effect of Remote Ischaemic Preconditioning with Postconditioning in Patients Undergoing Cardiac Surgery. PMID- 26935162 TI - Cardiovascular Nursing: From Florence to Melbourne. AB - This paper, based on the 2015 CSANZ Cardiovascular Nursing Lecture, takes its title from the invitation to give this lecture in Melbourne being received when the author was visiting Florence, after whom Florence Nightingale, the founder of modern nursing, is named. Her work has indirectly shaped and influenced cardiovascular nursing, which has developed over the past 50 years. Despite its relatively short history, cardiovascular nursing has made a major contribution to improving the cardiovascular health and well-being of patients and families through health promotion, risk reduction and disease prevention. Examples include cardiac rehabilitation and secondary prevention and chronic heart failure disease management. Challenges, however, remain, including nurses practising to the full extent of their education and training, working as full partners with physicians and other health professionals in redesigning healthcare, ensuring better data collection and being more active in advocacy and policy initiatives. Cardiovascular nursing has a strong record of innovation but should always remember that it is there to serve the public and, bearing in mind the risk of potential harm versus benefit, be mindful of Florence Nightingale's wise counsel, "First, do no harm". PMID- 26935163 TI - Massive Pulmonary Embolism Mimicking Acute Myocardial Infarction: Successful use of extracorporeal membrane oxygenation support as bridge to diagnosis. AB - Prolonged cardiac arrest with pulseless electrical activity (PEA) results in death if its aetiology cannot be corrected immediately. We describe the case of a 75-year-old man with chest pain and his electrocardiogram (ECG) revealing ST segment elevation in leads II, III, and aVf. Inferior wall myocardial infarction was subsequently diagnosed. Before performing emergency coronary angiography, however, a sudden cardiac arrest with PEA developed and the patient was placed on advanced cardiac life support. Oxygenation support for the extracorporeal membrane was initiated approximately 65min after prolonged cardiopulmonary resuscitation. Emergency coronary arteriogram showed no obstructive lesions in the right coronary artery. This result, however, was not consistent with the ECG findings, and thus, a massive pulmonary embolism was suspected. Subsequent pulmonary artery angiography showed severe emboli in bilateral branches of the pulmonary arteries. Catheter-directed thrombolysis with urokinase was administered, which ultimately failed, and surgical embolectomy was performed with extracorporeal membrane oxygenation support. After the above intervention, the patient was discharged on hospital day 60 without any sequelae or neurological deficits. PMID- 26935164 TI - Association of Neutrophil-to-lymphocyte Ratio with Contrast-induced Nephropathy in Patients with Non-ST-elevation Acute Coronary Syndrome Treated with Percutaneous Coronary Intervention. AB - BACKGROUND: A higher neutrophil-to-lymphocyte ratio (NLR) is associated with poor clinical outcomes in various cardiovascular diseases, including acute coronary syndromes. However, the relationship between NLR and contrast-induced nephropathy (CIN) in patients with non-ST-elevation acute coronary syndrome (NSTE-ACS) undergoing percutaneous coronary intervention (PCI) has not been known. Hence, we investigated whether admission NLR is associated with CIN after PCI in patients with NSTE-ACS. METHODS: A total of 478 patients (mean age 62.8+/-12.6 years, and 64.2% men), who were admitted to our hospital for NSTEACS and underwent PCI with stent, were recruited. Neutrophil-to-lymphocyte ratio was calculated via dividing neutrophil count by lymphocyte count. The patients were divided into two groups: CIN (+) and CIN (-). Contrast-induced nephropathy was defined as a >=0.5mg/dL and/or a >=25% increase in serum creatinine within 48-72hours post-PCI. RESULTS: Admission NLR was significantly higher in patients with CIN than in patients without CIN (median 5.43, interquartile range 3.23-7.73 vs. median 2.59, interquartile range 1.83-3.88, P<0.001). On multivariate analysis, NLR >= 3.46 value (OR=2.631, 95%CI 1.146-6.060, P=0.022), estimated glomerular filtration rate (OR=0.963, P=0.004), high sensitivity C-reactive protein (OR=1.028, P=0.016) were independent factors of CIN. CONCLUSION: Increased NLR is independently associated with risk of CIN in NSTE-ACS patients treated by PCI. PMID- 26935165 TI - Direct formation of peritectic phase but no primary phase appearance within Ni83.25Zr16.75 peritectic alloy during free fall. AB - Ni83.25Zr16.75 peritectic alloy was containerlessly solidified in a drop tube. When the droplet diameter exceeds a critical value (Dcrit), Ni7Zr2 phase primarily solidifies, followed by the peritectic reaction of Ni7Zr2 + L -> Ni5Zr. Once the droplet diameter is smaller than the critical value (Dcrit), peritectic phase Ni5Zr directly solidifies from the undercooled melt by completely suppressing the nucleation and growth of Ni7Zr2 phase, which is ascribed to high undercooling and cooling rate. Additionally, peritectic phase Ni5Zr grows equiaxially in the sample solidified in a DSC at a cooling rate of 0.167 K/s. PMID- 26935166 TI - Fully analogue photonic reservoir computer. AB - Introduced a decade ago, reservoir computing is an efficient approach for signal processing. State of the art capabilities have already been demonstrated with both computer simulations and physical implementations. If photonic reservoir computing appears to be promising a solution for ultrafast nontrivial computing, all the implementations presented up to now require digital pre or post processing, which prevents them from exploiting their full potential, in particular in terms of processing speed. We address here the possibility to get rid simultaneously of both digital pre and post processing. The standalone fully analogue reservoir computer resulting from our endeavour is compared to previous experiments and only exhibits rather limited degradation of performances. Our experiment constitutes a proof of concept for standalone physical reservoir computers. PMID- 26935167 TI - Diagnosis of the phase function of random media from light reflectance. AB - Light reflectance has been widely used to diagnose random media in both in situ and in vivo applications. The quantification of the phase function of the medium from reflectance measurements, however, remains elusive due to the lack of an explicit connection between the light reflectance profile and the phase function. Here we first present an analytical model for reflectance of scattered light at an arbitrary source-detector separation by forward-peaked scattering media such as biological tissue and cells. The model incorporates the improved small-angle scattering approximation (SAA) to radiative transfer for sub-diffusive light reflectance and expresses the dependence of the light reflectance on the phase function of the scattering medium in a closed form. A spreading length scale, lTheta, is found to characterise subdiffusive light reflectance at the high spatial frequency (close separation) limit. After validation by Monte Carlo simulations, we then demonstrate the application of the model in accurate determination of the complete set of optical properties and the phase function of a turbid medium from the profile of subdiffusive and diffusive light reflectance. PMID- 26935169 TI - Behavioural Neuroscience: Only the lonely. PMID- 26935168 TI - Decoding the organization of spinal circuits that control locomotion. AB - Unravelling the functional operation of neuronal networks and linking cellular activity to specific behavioural outcomes are among the biggest challenges in neuroscience. In this broad field of research, substantial progress has been made in studies of the spinal networks that control locomotion. Through united efforts using electrophysiological and molecular genetic network approaches and behavioural studies in phylogenetically diverse experimental models, the organization of locomotor networks has begun to be decoded. The emergent themes from this research are that the locomotor networks have a modular organization with distinct transmitter and molecular codes and that their organization is reconfigured with changes to the speed of locomotion or changes in gait. PMID- 26935170 TI - Enigmatic in vivo GlcNAc-1-phosphotransferase (GNPTG) transcript correction to wild type in two mucolipidosis III gamma siblings homozygous for nonsense mutations. AB - Mucolipidosis (ML) III gamma is a rare autosomal-recessive disorder caused by pathogenic mutations in the GNPTG gene. GNPTG encodes the gamma-subunit of GlcNAc 1-phosphotransferase that catalyzes mannose 6-phosphate targeting signal synthesis on soluble lysosomal enzymes. ML III gamma patients are characterized by missorting of lysosomal enzymes. In this report, we describe the probable occurrence of mRNA editing in two ML III gamma patients. Patients A and B (siblings) presented at the adult age with a typical clinical picture of ML III gamma, mainly compromising bone and joints, and high levels of lysosomal enzymes in plasma and low levels in fibroblasts. Both were found to be homozygous for c. 112C>G and c.328G>T (p.Glu110Ter) mutations in genomic DNA (gDNA) analysis of GNPTG. Analysis of complementary DNA (cDNA), however, showed normal genotypes for both patients. Low GNPTG mRNA expression was observed in both patients. The mRNA editing can explain the differences found in patients A and B regarding gDNA and cDNA analysis, and the mild clinical phenotype associated with homozygosity for a nonsense mutation. Our results suggest that mRNA editing can be more frequent than expected in monogenic disorders and that GNPTG analysis should be performed on gDNA. PMID- 26935171 TI - Clinical manifestations and growth of patients with urea cycle disorders in Japan. AB - We have previously examined the clinical manifestations, treatments and prognosis of 177 patients with urea cycle disorders (UCDs) from January 1999 to March 2009 in Japan. In this study, we investigated the incidence of clinical manifestations in different peak blood ammonia level at onset in UCD patients, and examined the growth of OTCD (ornithine transcarbamylase deficiency) patients. The UCD patients who had a high peak blood ammonia level at onset showed significantly high incidence of convulsion and abnormal head computed tomography or magnetic resonance imaging. The patients also showed significantly high incidence of hemodialysis and liver transplantation. Choice of therapeutic agents for long term treatment is not different between peak blood ammonia levels at the onset, except for the use of special amino-acid formulas. Growth retardation is not affected by high peak blood ammonia level at onset; however, 32% of male and 52% of female OTCD patients over 1 year old were plotted under the 10th percentile, and showed growth failure. The final height of the male and female OTCD patients were 166.2+/-5.5 and 150.3+/-7.2 cm, respectively. Although the prognosis of UCDs was improved significantly, it is considered that there are still many difficulties in the UCD patient's life. PMID- 26935172 TI - In vitro model of bone to facilitate measurement of adhesion forces and super resolution imaging of osteoclasts. AB - To elucidate processes in the osteoclastic bone resorption, visualise resorption and related actin reorganisation, a combination of imaging technologies and an applicable in vitro model is needed. Nanosized bone powder from matching species is deposited on any biocompatible surface in order to form a thin, translucent, smooth and elastic representation of injured bone. Osteoclasts cultured on the layer expressed matching morphology to ones cultured on sawed cortical bone slices. Resorption pits were easily identified by reflectance microscopy. The coating allowed actin structures on the bone interface to be visualised with super-resolution microscopy along with a detailed interlinked actin networks and actin branching in conjunction with V-ATPase, dynamin and Arp2/3 at actin patches. Furthermore, we measured the timescale of an adaptive osteoclast adhesion to bone by force spectroscopy experiments on live osteoclasts with bone coated AFM cantilevers. Utilising the in vitro model and the advanced imaging technologies we localised immunofluorescence signals in respect to bone with high precision and detected resorption at its early stages. Put together, our data supports a cyclic model for resorption in human osteoclasts. PMID- 26935173 TI - Functioning free gracilis transfer to reconstruct elbow flexion and quality of life in global brachial plexus injured patients. AB - In the study, the functional recovery and relative comprehensive quality of life of cases of global brachial plexus treated with free functioning muscle transfers were investigated. Patients who received functioning gracilis muscle transfer between August 1999 and October 2014 to reconstruct elbow flexion, wrist and fingers extension were recruited. The mean age of the patients was 26.36 (range, 16-42) years. The mean period of time from gracilis transfer to the last follow up was 54.5 months (range, 12-185 months). Muscle power, active range of motion of the elbow flexion, wrist extension, and total active fingers extension were recorded. SDS, SAS and DASH questionnaires were given to estimate patients' quality of life. 35.71% reported good elbow flexion and 50.00% reported excellent elbow flexion. The average ROM of the elbow flexion was 106.5 degrees (range, 0 142 degrees ) and was 17.00 degrees (range, 0-72 degrees ) for wrist extension. The average DASH score was 51.14 (range, 17.5-90.8). The prevalence of anxiety and depression were 42.86% and 45.24%. Thrombosis and bowstringing were the most common short and long-term complications. Based on these findings, free gracilis transfer using accessory nerve as donor nerve is a satisfactory treatment to reconstruct the elbow flexion and wrist extension in global-brachial-plexus injured patients. PMID- 26935175 TI - Corrigendum: Nematodes from terrestrial and freshwater habitats in the Arctic. AB - [This corrects the article DOI: 10.3897/bdj.2.e1165.]. PMID- 26935174 TI - Manganese Superoxide Dismutase Acetylation and Dysregulation, Due to Loss of SIRT3 Activity, Promote a Luminal B-Like Breast Carcinogenic-Permissive Phenotype. AB - SIGNIFICANCE: Breast cancer is the most common nondermatologic malignancy among women in the United States, among which endocrine receptor-positive breast cancer accounts for up to 80%. Endocrine receptor-positive breast cancers can be categorized molecularly into luminal A and B subtypes, of which the latter is an aggressive form that is less responsive to endocrine therapy with inferior prognosis. RECENT ADVANCES: Sirtuin, an aging-related gene involved in mitochondrial metabolism, is associated with life span, and more importantly, murine models lacking Sirt3 spontaneously develop tumors that resemble human luminal B breast cancer. Furthermore, these tumors exhibit aberrant manganese superoxide dismutase (MnSOD) acetylation at lysine 68 and lysine 122 and have abnormally high reactive oxygen species (ROS) levels, which have been observed in many types of breast cancer. CRITICAL ISSUES: The mechanism of how luminal B breast cancer develops resistance to endocrine therapy remains unclear. MnSOD, a primary mitochondrial detoxification enzyme, functions by scavenging excessive ROS from the mitochondria and maintaining mitochondrial and cellular homeostasis. Sirt3, a mitochondrial fidelity protein, can regulate the activity of MnSOD through deacetylation. In this study, we discuss a possible mechanism of how loss of SIRT3-guided MnSOD acetylation results in endocrine therapy resistance of human luminal B breast cancer. FUTURE DIRECTIONS: Acetylation of MnSOD and other mitochondrial proteins, due to loss of SIRT3, may explain the connection between ROS and development of luminal B breast cancer and how luminal B breast cancer becomes resistant to endocrine therapy. Antioxid. Redox Signal. 25, 326-336. PMID- 26935176 TI - Bacterial-excreted small volatile molecule 2-aminoacetophenone induces oxidative stress and apoptosis in murine skeletal muscle. AB - Oxidative stress induces mitochondrial dysfunction and facilitates apoptosis, tissue damage or metabolic alterations following infection. We have previously discovered that the Pseudomonas aeruginosa (PA) quorum sensing (QS)-excreted small volatile molecule, 2-aminoacetophenone (2-AA), which is produced in infected human tissue, promotes bacterial phenotypes that favor chronic infection, while also dampening the pathogen-induced innate immune response, thus compromising muscle function and promoting host tolerance to infection. In this study, murine whole-genome expression data have demonstrated that 2-AA affects the expression of genes involved in reactive oxygen species (ROS) homeostasis, thus producing an oxidative stress signature in skeletal muscle. The results of the present study demonstrated that the expression levels of genes involved in apoptosis signaling pathways were upregulated in the skeletal muscle of 2-AA treated mice. To confirm the results of our transcriptome analysis, we used a novel high-resolution magic-angle-spinning (HRMAS), proton (1H) nuclear magnetic resonance (NMR) method and observed increased levels of bisallylic methylene fatty acyl protons and vinyl protons, suggesting that 2-AA induces skeletal muscle cell apoptosis. This effect was corroborated by our results demonstrating the downregulation of mitochondrial membrane potential in vivo in response to 2 AA. The findings of the present study indicate that the bacterial infochemical, 2 AA, disrupts mitochondrial functions by inducing oxidative stress and apoptosis signaling and likely promotes skeletal muscle dysfunction, which may favor chronic/persistent infection. PMID- 26935177 TI - Anatomical Classifications of the Coronary Arteries in Complete Transposition of the Great Arteries and Double Outlet Right Ventricle with Subpulmonary Ventricular Septal Defect. AB - Objective To discuss the anatomical morphologies of the coronary arteries and frequencies of unusual coronary arteries in complete transposition of the great arteries and double outlet right ventricle (DORV) associated with a subpulmonic ventricular septal defect (VSD). Methods Between March 1999 and August 2012, 1,078 patients with complete transposition of the great arteries or DORV with subpulmonary VSD underwent arterial switch operations (ASOs) and were visually evaluated to classify their coronary artery morphology during open heart surgery. Results The coronary arteries could be classified into five patterns with several subtypes. Unusual coronary arteries were observed in 248 of the 1,078 cases, providing a frequency of 23.01%. The frequencies of the patients with transposition of the great arteries with intact ventricular septum (TGA/IVS), TGA/VSD, and DORV with subpulmonary VSD were 17.65, 23.28, and 31.84%, respectively. The most common morphologies were the right coronary artery (RCA) originating from sinus 1 and circumflex (CX) originating from sinus 2 (1R, AD; 2CX; 26.50%); the CX originating from sinus 2 (1AD; 2R, CX; 21.36%); the RCA, left anterior descending artery, and CX originating from single sinus 2 (2R, AD, CX; 13.24%). The in-hospital mortalities of the patients with or without unusual coronary arteries after ASO were 14.1 and 6.02%, respectively. Conclusion Patients with complete transposition of the great arteries or DORV with subpulmonary VSD have a high frequency of unusual coronary arteries, which might greatly impact on the mortality for ASO. Improving the preoperative diagnostic criteria for coronary artery morphology may significantly increase the success rate for ASOs. PMID- 26935179 TI - Hierarchical CuCo2S4 hollow nanoneedle arrays as novel binder-free electrodes for high-performance asymmetric supercapacitors. AB - Hierarchical CuCo2S4 hollow nanoneedle arrays have been firstly synthesized on a Ni foam using a facile template-free hydrothermal method and applied as novel binder-free electrodes for high-performance asymmetric supercapacitors with ultrahigh specific capacitance, high energy density, excellent rate capability and outstanding long-term cycling stability. PMID- 26935178 TI - The membrane complement regulatory protein CD59 promotes tumor growth and predicts poor prognosis in breast cancer. AB - Breast cancer is the most prevalent type of cancer among women. CD59, a membrane complement regulatory protein, has been demonstrated to be overexpressed in most solid tumors, where it facilitates tumor cell escape from complement surveillance. However, the role of CD59 in breast cancer growth and clinical prognosis is not fully revealed. To investigate the role of CD59 in breast cancer growth and prognostic significance, we knocked down CD59 in a breast cancer cell line that is highly metastatic to the lungs, MDA-MB-231-HM. Cell growth was measured in vitro and in vivo using a xenograft model. In addition, clinical data on a cohort of 120 patients with or without lung metastasis was analyzed based on CD59 expression, which was detected by immunohistochemistry. Knockdown of CD59 significantly inhibited MDA-MB-231-HM cell growth both in vitro and in vivo. An analysis of clinical data on 120 patients revealed that patients with CD59 overexpression may have a worse prognosis. CD59 may therefore be a prognostic biomarker for poor outcome in breast cancer patients. PMID- 26935180 TI - Highly enhanced transverse plasmon resonance and tunable double Fano resonances in gold@titania nanorods. AB - Gold nanorods have attracted intensive interest owing to their localized surface plasmon resonance properties and enormous potential applications. The transverse plasmon of Au nanorods is usually weaker than the longitudinal one, hampering certain plasmonic applications. Herein we report on the intensification of the transverse plasmon resonance by coating TiO2 onto Au nanorods. The transverse plasmon mode of the resultant Au@TiO2 nanorods with a sufficiently thick shell can be comparable to or even stronger than the longitudinal one in intensity. Moreover, both the transverse and longitudinal plasmon resonances of the Au@TiO2 nanorods exhibit an asymmetric line shape on their scattering spectra. Electrodynamic simulations and analyses based on a coupled oscillator model suggest that the asymmetric line shape originates from the coupling between the Au core and TiO2 shell. Apart from the shell thickness, the plasmonic properties of the Au@TiO2 nanorods can also be tuned by the dimension of the Au nanorod core. In addition, the polarization-dependent light scattering from the individual Au@TiO2 nanorods has also been investigated. These results will be of high importance for understanding the interactions between noble metals and semiconductors in plasmonic hybrid nanosystems, and for designing novel plasmonic nanostructures with desired optical properties and functions. PMID- 26935181 TI - Economic crisis and suicides in Spain. Socio-demographic and regional variability. AB - BACKGROUND: Evidence from previous recessions suggests that at times of economic deterioration, suicides increase. Spain has been one of the European countries hardest hit by the financial crisis that started in 2008. The aim of this paper is to examine the impact of the double-dip recession in Spain on the most recent trends in suicide. METHODS: Suicide data from the years 2002-2012 were obtained from the 'Death Statistic according to Cause of Death' of the National Statistics Institute (NSI). Population figures were obtained from the population estimates of the NSI. RESULTS: While the suicide rate decreased between 2002 and 2012, the downward trend has reversed twice, in 2008-2009, and in 2012. This rise was particularly pronounced in males, with the rate ratio of 1.12 (95 % CI 1.05-1.20) in 2008 and 1.10 (95 % CI 1.03-1.18) in 2009. Following a decrease in 2010 and 2011, suicides among males have increased again in 2012-with RR of 1.10 (95 % CI 1.03-1.18) compared to 2007, however the difference between 2011 amounted to 14 % rise-the biggest interannual change in a decade. There was a similar but less pronounced pattern in females. Regional data showed variable results. CONCLUSIONS: These results suggest that the Spanish economic crisis has been associated with suicide rates in 2008, 2009, and 2012. These findings are consistent with the double-dip recession that Spain experienced. PMID- 26935182 TI - Frances Hughes: New CEO of the International Council of Nurses (ICN). PMID- 26935183 TI - Problematic Internet Experiences and Depression. PMID- 26935184 TI - Developmental Neuroscience Explaining Why Adolescents Engage in Risky Behaviors. PMID- 26935187 TI - Can Declining Rates of Dementia Be Explained by the Increased and Widespread Use of Psychotropic Medications? AB - Dementia, once described as the "silent epidemic," is now well known and greatly feared. Although the total number of dementia cases will increase worldwide because of increased life expectancy, eight population-based studies of dementia incidence or prevalence have suggested a declining age-specific risk in the United States and Europe during the past three decades. Many different psychotropic drugs have been introduced since the mid-1950s, and their clinical use has broadened and increased dramatically over time. Antidepressant drugs, second-generation antipsychotic drugs, lithium, valproate, carbamazepine, lamotrigine, electroconvulsive therapy, and exercise have all been found to activate or regulate various intracellular neurotrophic and neuroprotective processes. They promote neurogenesis and are protective in models of neurodegenerative diseases and ischemia. Because of their neurotrophic and neuroprotective effects, the widespread use of psychotropic drugs provides a plausible explanation for declining rates of dementia that have been observed. PMID- 26935188 TI - Dance for Individuals With Dementia. AB - The movement and music associated with dance plays an important role in many individuals' lives and can become imprinted upon the body and mind. Dance is thus closely associated with memory because of these deep connections. Without conscious thought, dance has the potential to be initiated as individuals age. In the current article, the authors share narrative reflections about their experiences with, and the potential of, dance as an intervention for aging populations diagnosed with dementia-related diseases. They draw upon their experiences in working with the aging population and a dance program currently being developed by Canada's National Ballet School and Baycrest Health Sciences for individuals with dementia-related diseases in long-term care. The current article is structured as dialogue between the authors because it mimics dance as a dialogical encounter between movement and music, and/or between individuals. PMID- 26935189 TI - Cancer Screening Among Peer-Led Community Wellness Center Enrollees. AB - Growing evidence suggests health disparities exist in services for individuals with mental disorders served by the public mental health system. The current study assessed the use of cancer screening services among New Jersey residents in publicly funded mental health programs. Self-administered written surveys were completed by 148 adults using peer-led community wellness centers throughout New Jersey. Information was collected on (a) the use of breast, cervical, and colorectal cancer screening services; (b) barriers to receiving preventive services; and (c) perceptions of overall health. More males than females participated in the study, with equal participation among White and African American individuals. Schizophrenia spectrum disorders were the most common self reported psychiatric condition. Colorectal cancers had lower screening levels compared to those of the general population. Physicians not advising patients to complete tests emerged as a main cause of low screening rates. Wellness initiatives designed by peers collaborating with health care providers may improve adherence to preventive cancer screening measures. PMID- 26935190 TI - Kleine-Levin Syndrome: An Overview and Relevance to Nursing Practice. AB - Kleine-Levin syndrome (KLS) is a neuropsychiatric sleep disorder primarily affecting adolescent males. Onset is insidious, idiopathic, and hastened by neurological incident or infection. Typically, the initial onset occurs during the teen years or after the second decade, although cases have been documented in early childhood, adulthood, and senescence. KLS is marked by unexpected debilitating, yet reversible, episodic hypersomnia, with varying recurrence rates; cognitive and behavioral impairment; compulsive eating; and feelings of derealization, hypersexuality, apathy, and depressed mood. Diagnosis is problematic due to the syndrome's rarity, disparity of presenting clinical symptoms, and misdiagnosis. Correct diagnosis can take up to 4 years. The clinical course is approximately 8 to 14 years from initial onset, yet may be longer in the adult form of the disorder. KLS has been shown to impact activities of daily living, usurping an adolescent of his/her social relations with peers, experiences, and time. PMID- 26935191 TI - Transition-Aged Youths With Dual Diagnoses. AB - The current study provides an overview of the research knowledge about unique problems encountered by transition-aged youths with dual diagnoses. A description of the considerable physical and emotional changes experienced by transition-aged youths provides a foundation for exploring the pressures and challenges compounded by mental health issues and substance abuse. Programs that provide intensive support throughout the transition years pay valuable dividends. However, transition-aged youths with dual diagnoses of mental disorders and substance abuse find themselves faced with limited or nonexistent options. There is a confusing lack of continuity and consistency of supports and services, which complicates the already perplexing circumstances that beleaguer the lives of young adults with dual diagnoses. PMID- 26935193 TI - Flavone inhibits migration through DLC1/RhoA pathway by decreasing ROS generation in breast cancer cells. AB - Tumor suppressor protein deleted in liver cancer 1 (DLC1) is a RhoGTPase activating protein (RhoGAP) and inhibits cancer cell migration by inactivating downstream target protein RhoA. A few studies have reported the regulations of reactive oxygen species (ROS) on RhoGAP. In this study, we investigated flavone (the core structure of flavonoids)-induced regulation on ROS generation and DLC1/RhoA pathway in MCF-7 and MDA-MB-231 breast cancer cells and explored whether flavone-induced upregulation of DLC1 is mediated by ROS. Our results showed that flavone decreased ROS production and inhibited cell migration through DLC1/RhoA pathway. To further investigate the role of ROS in flavone-induced regulation on DLC1/RhoA pathway, hydrogen peroxide was added to restore the ROS levels. Flavone-induced upregulation of DLC1 expression, downregulation of RhoA activity, and inhibition of cell migration were all restrained by hydrogen peroxide. We also found that flavone increased DLC1 stability by inhibiting DLC1 protein degradation in breast cancer cells. In summary, our study demonstrated that flavone inhibited cell migration through DLC1/RhoA pathway by decreasing ROS generation and suppressed DLC1 degradation in MCF-7 and MDA-MB-231 breast cancer cells. PMID- 26935194 TI - Reply to the letter to the editor of J. Domenech et al. concerning "A new approach to corpus callosum anomalies in idiopathic scoliosis using diffusion tensor magnetic resonance imaging" by O. Joly et al. (2014) Eur Spine J; 23:2643 9. PMID- 26935196 TI - Italian Spine Society National Congress Firenze, Italy 5th-7th May, 2016 ABSTRACTS. PMID- 26935195 TI - Letter to the editor concerning "A new approach to corpus callosum anomalies in idiopathic scoliosis using diffusion tensor magnetic resonance imaging" by Joly O et al. (2014) Eur Spine J 23:2643-9. PMID- 26935197 TI - Small Contribution in Rural India may have Big Impact on Child Health. PMID- 26935198 TI - Genetic Studies in Autism. AB - Autism is a complex neurodevelopmental disorder, which has captured the attention of not only pediatricians but also the parents. From the symptoms until the final diagnosis, parents undergo a diagnostic odyssey that involves a battery of tests without much yield. This has led to an increase in the referrals to the clinical geneticists to rule out the possible genetic etiology that can have implications for the parents for future pregnancy. This chapter focuses on the various genetic causes and their appropriate application in the evaluation of a child with Autism Spectrum Disorders (ASDs). PMID- 26935199 TI - Predictive Accuracy of Chest Radiographs in Diagnosing Tachypneic Children. AB - OBJECTIVE: To test the predictive accuracy and reporting reproducibility of digital chest radiographs under low-resource conditions. METHODS: One hundred thirty four tachypneic children who presented to two Indian hospitals were enrolled. Based on review of 16 variables recorded in the Emergency Room (ER) by a senior pediatrician, children were given one of the four clinical diagnoses: pneumonia, wheezy disease, mixed and non-respiratory. Every child also had a digital CXR. It was interpreted by ER physician, pediatrician and two independent radiologists. All used the same standardized interpretation system (one or more of: normal, minor patches, major patches, hyperinflation, lobar change, pleural effusion). RESULTS: The 10 % of CXRs showing pleural effusions reliably predicted pneumonia and disease severity. For all other CXR findings, the correlation between CXR interpretation and clinical diagnosis was moderate to poor. Apart from pleural effusions, inter-observer agreements between interpretations made by ER physician, pediatrician and radiologist were also poor (kappa <0.4). CONCLUSIONS: With the exception of pleural effusions, CXR findings, interpreted by a radiologist, had moderate to poor power to predict respiratory diagnosis or disease severity defined by a pediatrician. Value of CXRs was further reduced by poor inter-observer agreement. When investigating tachypneic children under low resource conditions, CXRs should be used with a clear understanding of their limitations. PMID- 26935200 TI - Association of Breakfast Intake with Psychiatric Distress and Violent Behaviors in Iranian Children and Adolescents: The CASPIAN- IV Study. AB - OBJECTIVE: To assess the relationship of breakfast intake with psychiatric distress and violent behaviors among Iranian children and adolescents. METHODS: This national survey was conducted among 14,880 students, aged 6-18 y. They were selected by stratified multistage sampling method from urban and rural areas of 30 provinces of Iran. Breakfast intake, psychiatric distress, and violent behaviors were assessed by a questionnaire prepared based on the Global school based student health survey of the World Health Organization. The data were analyzed by the STATA package. RESULTS: The participation rate was 90.6 %. The percentage of psychiatric distress among breakfast skippers, semi-skippers and non-skippers was 13.4-50.4, 10.1-41.9, and 7.0-33.3 % respectively. The prevalence of psychiatric distress was significantly higher among breakfast skippers than semi-skippers and non-skippers (P value < 0.001). The frequency of psychiatric distress had a significant decreasing trend from breakfast skippers to non-skippers. The prevalence of violent behaviors was significantly higher among breakfast skippers than non-skippers. Students who skipped breakfast reported to be more victimized (29.2 % vs. 26.7 %, respectively, P = 0.04), bullied (21.0 % vs. 16.2 %, respectively, P < 0.001), and had more physical fight (42.6 % vs. 38.5 %, respectively, P = 0.0001) than their other counterparts. CONCLUSIONS: Students who regularly consumed breakfast were less likely to experience mental health disorders and violent behavior. Adhering to a regular and balanced diet, besides the awareness of parents on the importance of breakfast eating, may be an appropriate approach for preventing mental health problems and violent behavior in children and adolescents. PMID- 26935201 TI - Hypertriglyceridemia Thalassemia Syndrome: Common Disease, Uncommon Association. AB - Hypertriglyceridemia has been rarely described with thalassemia, an entity called hypertriglyceridemia-thalassemia syndrome. The authors describe a young infant diagnosed with thalassemia major with severe hypertriglyceridemia. The presence of severe hypertriglyceridemia in this child which rapidly resolved after transfusion, probably suggests a self limited mechanism which may not require therapy. Though hypertriglyceridemia has been reported with hemolytic anemias, the mechanism is unclear. This case illustrates that thalassemia may be associated with hypertriglyceridemia; once familial and secondary causes are ruled out, clinicians may wait for spontaneous resolution before considering specific therapy. PMID- 26935202 TI - Role of preoperative cycloplegic refraction in LASIK treatment of hyperopia. AB - BACKGROUND: Previous studies have suggested that, to improve refractive predictability in hyperopic LASIK treatments, preoperative cycloplegic or manifest refraction, or a combination of both, could be used in the laser nomogram. We set out to investigate (1) the prevalence of a high difference between manifest and cycloplegic spherical equivalent in hyperopic eyes preoperatively, and (2) the related predictability of postoperative keratometry. METHODS: Retrospective cross-sectional data analysis of consecutive treated 186 eyes from 186 consecutive hyperopic patients (mean age 42 [+/-12] years) were analyzed. Excimer ablation for all eyes was performed using a mechanical microkeratome (SBK, Moria, France) and an Allegretto excimer laser platform. Two groups were defined according to the difference between manifest and cycloplegic spherical equivalent which was defined as >=1.00 diopter (D); the data was analyzed according to refractive outcome in terms of refractive predictability, efficacy, and safety. RESULTS: In 24 eyes (13 %), a preoperative difference of >=1.00D between manifest spherical equivalent and cycloplegic spherical equivalent (= MCD) occurred. With increasing preoperative MCD, the postoperative achieved spherical equivalent showed hyperopic regression after 3 months. There was no statistically significant effect of age (accommodation) or optical zone size on the achieved spherical equivalent. CONCLUSIONS: A difference of >=1.00D occurs in about 13 % of hyperopia cases. We suggest that hyperopic correction should be based on the manifest spherical equivalent in eyes with preoperative MCD <1.00D. If the preoperative MCD is >=1.00D, treatment may produce manifest undercorrection, and therefore we advise that the patient should be warrned about lower predictability, and suggest basing conclusions on the arithmetic mean calculated from the preoperative manifest and cycloplegic spheres. PMID- 26935203 TI - Femoral shortening osteotomy in total hip arthroplasty for severe dysplasia: a comparison of two fixation techniques. AB - PURPOSE: The purpose of this study was to compare two distinct fixation methods for a total hip replacement performed via transverse femoral shortening osteotomy for patients with severe hip dysplasia. METHODS: In this retrospective study we compared two fixation methods for total hip replacement of 78 hips in 76 patients exhibiting Crowe type IV developmental hip dysplasia (DDH). The hip replacements were performed via a transverse femoral shortening osteotomy and carried out between September 2009 and December 2013. Group I patients underwent fixation of the shortened femoral segment via a cable attached to the osteotomied segment, and group II patients underwent fixation with a plate and screw. We compared the two techniques based on operating time, osteotomy site union time, Harris hip score, hip loosening signs, and overall clinical outcomes. RESULTS: The mean operating time for groups I and II was determined to be 116.5 +/- 12.8 min and 137.7 +/- 14 min, respectively (p < 0.05), while the average union time was 113 +/- 51 days for group I and 152 +/- 37 days for group II (p < 0.05). Fixation of the femur with a cable (group I) is therefore faster and results in more rapid union time when compared to plate osteosynthesis at the osteotomy site (group II). We observed only one non-union in group I compared with three in group II (p = 0.49). Harris hip scores at the final patient follow-up were 82.8 +/- 7.8 and 80.8 +/- 6.7 for groups I and II, respectively (p = 0.23). Thus, notably no significant differences were observed between the groups with regard to clinical outcomes such as the Harris hip score or loosening of the replacement components. CONCLUSION: Fixation of the removed femoral segment with a cable provided adequate rotational stability and decreased the operating time, leading to early union at the osteotomy site. PMID- 26935204 TI - A Site-Specific, Sustained-Release Drug Delivery System for Aneurysmal Subarachnoid Hemorrhage. AB - Nimodipine is the only drug approved for use by the Food and Drug Administration for improving outcome after aneurysmal subarachnoid hemorrhage (SAH). It has less than optimal efficacy, causes dose-limiting hypotension in a substantial proportion of patients, and is administered enterally 6 times daily. We describe development of site-specific, sustained-release nimodipine microparticles that can be delivered once directly into the subarachnoid space or cerebral ventricles for potential improvement in outcome of patients with aneurysmal SAH. Eight injectable microparticle formulations of nimodipine in poly(DL-lactide-co glycolide) (PLGA) polymers of varying composition were tested in vitro, and 1 was advanced into preclinical studies and clinical application. Intracisternal or intraventricular injection of nimodipine-PLGA microparticles in rats and beagles demonstrated dose-dependent, sustained concentrations of nimodipine in plasma and cerebrospinal fluid for up to 29 days with minimal toxicity in the brain or systemic tissues at doses <2 mg in rats and 51 mg in beagles, which would be equivalent of up to 612-1200 mg in humans, based on scaling relative to cerebrospinal fluid volumes. Efficacy was tested in the double-hemorrhage dog model of SAH. Nimodipine-PLGA microparticles significantly attenuated angiographic vasospasm. This therapeutic approach shows promise for improving outcome after SAH and may have broader applicability for similar diseases that are confined to body cavities or spaces, are self-limited, and lack effective treatments. PMID- 26935205 TI - Factors associated with tick bites and pathogen prevalence in ticks parasitizing humans in Georgia, USA. AB - BACKGROUND: The incidence and emergence of tick-borne diseases has increased dramatically in the United States during the past 30 years, yet few large-scale epidemiological studies have been performed on individuals bitten by ticks. Epidemiological information, including disease development, may provide valuable information regarding effectiveness of tick bite prevention education, pathogen transmission, human-disease dynamics, and potential implications for under reporting of tick-borne diseases. METHODS: Ticks found attached to Georgia residents were submitted for identification and polymerase chain reaction (PCR) testing for Francisella tularensis, Ehrlichia, Anaplasma, Borrelia, and Rickettsia spp. Tick bite victims were interviewed three weeks after the tick bite to identify various epidemiologic factors associated with infestation and if signs suggestive of a tick-borne disease had developed. Fisher's exact test of independence was used to evaluate associations between various factors evaluated in the study. A multivariable logistic regression model was used for the prediction of non-specific illness post-tick bite. RESULTS: From April 2005 December 2006, 444 participants submitted 597 ticks (426 Amblyomma americanum, 142 Dermacentor variabilis, 19 A. maculatum, 7 Ixodes scapularis, 3 Amblyomma sp.) which originated from 95 counties. Only 25 (34 %) of 74 interviewed individuals purposely took tick bite prevention measures. Ticks that were PCR positive for bacterial organisms were attached to 136 participants. Of the 77 participants who developed non-specific illness, 50 did not have PCR positive ticks, whereas 27 did have PCR positive tick (s). Of those 27 individuals, 12 fit the criteria for a possible tick-borne illness (i.e., tick attached >6 h [if known], >=4 day incubation period, and the individual exhibited clinical symptoms typical of a tick-borne illness without exhibiting cough, sore throat, or sinus congestion). Ticks from these individuals were positive for R. amblyommii (n = 8), E. ewingii (n = 1), R. montana (n = 1), R. rhiphicephali (n = 1), and Rickettsia sp. TR-39 (n = 1). CONCLUSIONS: Although illnesses reported in this study cannot definitively be connected with tick bites, it does provide insight into development, diagnosis, and treatment of possible tick-borne diseases post tick bite. The study also provided data on pathogen prevalence, and epidemiologic factors associated with tick bites, as well as tick presence by county in Georgia. PMID- 26935207 TI - The ruthenium-catalysed selective synthesis of mono-deuterated terminal alkynes. AB - We report an efficient catalytic method for the synthesis of mono-deuterated terminal alkynes directly from deuterium oxide, catalysed by a Ru(II) pincer complex in which the reaction proceeds via Ru-acetylide intermediates and amine amide metal-ligand cooperation. PMID- 26935206 TI - Combinatorial phenotypic screen uncovers unrecognized family of extended thiourea inhibitors with copper-dependent anti-staphylococcal activity. AB - The continuous rise of multi-drug resistant pathogenic bacteria has become a significant challenge for the health care system. In particular, novel drugs to treat infections of methicillin-resistant Staphylococcus aureus strains (MRSA) are needed, but traditional drug discovery campaigns have largely failed to deliver clinically suitable antibiotics. More than simply new drugs, new drug discovery approaches are needed to combat bacterial resistance. The recently described phenomenon of copper-dependent inhibitors has galvanized research exploring the use of metal-coordinating molecules to harness copper's natural antibacterial properties for therapeutic purposes. Here, we describe the results of the first concerted screening effort to identify copper-dependent inhibitors of Staphylococcus aureus. A standard library of 10 000 compounds was assayed for anti-staphylococcal activity, with hits defined as those compounds with a strict copper-dependent inhibitory activity. A total of 53 copper-dependent hit molecules were uncovered, similar to the copper independent hit rate of a traditionally executed campaign conducted in parallel on the same library. Most prominent was a hit family with an extended thiourea core structure, termed the NNSN motif. This motif resulted in copper-dependent and copper-specific S. aureus inhibition, while simultaneously being well tolerated by eukaryotic cells. Importantly, we could demonstrate that copper binding by the NNSN motif is highly unusual and likely responsible for the promising biological qualities of these compounds. A subsequent chemoinformatic meta-analysis of the ChEMBL chemical database confirmed the NNSNs as an unrecognized staphylococcal inhibitor, despite the family's presence in many chemical screening libraries. Thus, our copper biased screen has proven able to discover inhibitors within previously screened libraries, offering a mechanism to reinvigorate exhausted molecular collections. PMID- 26935208 TI - Small-Scale Spatio-Temporal Distribution of Bactrocera minax (Enderlein) (Diptera: Tephritidae) Using Probability Kriging. AB - Understanding spatio-temporal distribution of pest in orchards can provide important information that could be used to design monitoring schemes and establish better means for pest control. In this study, the spatial and temporal distribution of Bactrocera minax (Enderlein) (Diptera: Tephritidae) was assessed, and activity trends were evaluated by using probability kriging. Adults of B. minax were captured in two successive occurrences in a small-scale citrus orchard by using food bait traps, which were placed both inside and outside the orchard. The weekly spatial distribution of B. minax within the orchard and adjacent woods was examined using semivariogram parameters. The edge concentration was discovered during the most weeks in adult occurrence, and the population of the adults aggregated with high probability within a less-than-100-m-wide band on both of the sides of the orchard and the woods. The sequential probability kriged maps showed that the adults were estimated in the marginal zone with higher probability, especially in the early and peak stages. The feeding, ovipositing, and mating behaviors of B. minax are possible explanations for these spatio temporal patterns. Therefore, spatial arrangement and distance to the forest edge of traps or spraying spot should be considered to enhance pest control on B. minax in small-scale orchards. PMID- 26935209 TI - Analysis of Johne's disease ELISA status and associated performance parameters in Irish dairy cows. AB - BACKGROUND: Infection with Mycobacterium avium subspecies paratuberculosis (MAP) has been associated with reductions in milk production in dairy cows and sub optimal fertility. The aim of this study was to highlight the production losses associated with testing MAP ELISA positive in Irish dairy cows. Secondary objectives included investigation of risk factors associated with testing MAP ELISA positive. A survey of management practices on study farms was also conducted, with examination of associations between management practices and herd MAP status. Blood samples were collected from 4188 breeding animals on 22 farms. Samples were ELISA tested using the ID Screen Paratuberculosis Indirect Screening Test. Production parameters examined included milk yield, milk fat, milk protein, somatic cell count, and calving interval. The association between MAP ELISA status and production data was investigated using multi-level mixed models. Logistic regression was used to identify risk factors for testing JD blood ELISA positive at individual cow level and to identify associations between farm management practices and herd MAP status. RESULTS: Data were available for 3528 cows. The apparent prevalence recorded was 7.4%. Mixed model analysis revealed no statistically significant association between testing MAP ELISA positive and dairy cow production parameters. Risk factors associated with testing positive included larger sized herds being over twice more likely to test positive than smaller herds (OR 2.4 P = <0.001). Friesians were less likely to test positive relative to other breeds. A number of study farmers were engaged in management practices that have previously been identified as high risk for MAP transmission e.g., 73.1% pooled colostrum and 84.6% of study farmers used the calving area to house sick animals throughout the year. No significant associations however, were identified between farm management practices and herd MAP status. CONCLUSION: No production losses were identified; however an apparent prevalence of 7.4% was recorded. With the abolition of EU milk quotas herd size in Ireland is expanding, as herds included in this study were larger than the national average, results may be indicative of future JD levels if no JD control programmes are implemented to minimise transmission. PMID- 26935211 TI - Minimal-show orthognathic surgical splint. PMID- 26935210 TI - The impact of structural genomics: the first quindecennial. AB - The period 2000-2015 brought the advent of high-throughput approaches to protein structure determination. With the overall funding on the order of $2 billion (in 2010 dollars), the structural genomics (SG) consortia established worldwide have developed pipelines for target selection, protein production, sample preparation, crystallization, and structure determination by X-ray crystallography and NMR. These efforts resulted in the determination of over 13,500 protein structures, mostly from unique protein families, and increased the structural coverage of the expanding protein universe. SG programs contributed over 4400 publications to the scientific literature. The NIH-funded Protein Structure Initiatives alone have produced over 2000 scientific publications, which to date have attracted more than 93,000 citations. Software and database developments that were necessary to handle high-throughput structure determination workflows have led to structures of better quality and improved integrity of the associated data. Organized and accessible data have a positive impact on the reproducibility of scientific experiments. Most of the experimental data generated by the SG centers are freely available to the community and has been utilized by scientists in various fields of research. SG projects have created, improved, streamlined, and validated many protocols for protein production and crystallization, data collection, and functional analysis, significantly benefiting biological and biomedical research. PMID- 26935212 TI - The index of orthognathic functional treatment need accurately prioritises those patients already selected for orthognathic surgery within the NHS. AB - The index of orthognathic functional treatment need (IOFTN) is a newly-proposed system to help to prioritise patients for orthognathic treatment. The five categories are similar to those used in orthodontics, but include additional parameters such as sleep apnoea and facial asymmetry. The aim of this audit was to validate the index and find out the potential future implications, should such a system ever be adopted by commissioners. We calculated the IOFTN category of 100 consecutive patients who had orthognathic surgery between 2010-14 using clinical notes, photographs, study models, and radiographs, and determined the number in categories 4 or 5, analogous to the current indications for orthodontic treatment within the NHS. Sufficient clinical information was available to categorise 59/100 patients, and 56 of the 59 (95%) were in either category 4 or 5. All three of the remaining patients (in categories 1-3) who were operated on were treated because of the anticipated favourable impact on their quality of life. The IOFTN has been proposed for use in future commissioning of orthognathic services within the NHS, and this study has confirmed its efficacy in prioritising treatment accurately, with 95% of patients being in categories 4 or 5. We recommend that the orthognathic treatment index be adapted to include additional psychosocial assessment so that patients who fall into the lower functional categories are not automatically excluded from this potentially life changing treatment. PMID- 26935213 TI - Nerve injury associated with orthognathic surgery. Part 1: UK practice and motor nerve injuries. AB - The head and neck is anatomically complex, and several nerves are at risk during orthognathic operations. Some injuries to nerves are reported more commonly than others. To find out what consultant surgeons tell their patients about the prevalence of common nerve injuries before orthognathic operations, we did a postal survey of fellows of the British Association of Oral and Maxillofacial Surgeons (BAOMS). We also reviewed published papers to find out the reported incidence of injuries to cranial motor nerves during orthognathic operations. Only injuries to the facial nerve were commonly reported, and we found only case reports about injuries to the oculomotor, abducens, and trochlear nerves. The risk of temporary facial nerve palsy reported was 0.30/100 nerves (95% CI 0.23 to 0.50) and permanent facial nerve palsy was 0.06/100 nerves (95% CI 0.02 to 0.15). PMID- 26935214 TI - Kinetics of gene expression of alkaline phosphatase during healing of alveolar bone in rats. AB - Immunohistochemical studies and molecular biology have enabled us to identify numerous proteins that are involved in the metabolism of bone, and their encoding genes. Among these is alkaline phosphatase (ALP), an enzyme that is responsible for the initiation of mineralisation of the extracellular matrix during alveolar bone repair. To evaluate the gene expression of ALP during this process, we studied nine healthy adult male rats, which had their maxillary central incisors extracted from the right side and were randomly divided into three groups. During three experimental periods, 7 days, 14 days, and 28 days, the alveoli were curetted, the rats killed, and samples analysed by real-time reverse transcription polymerase chain reaction (qRT-PCR). The RNAm that encodes the gene for the synthesis of ALP was expressed during the three periods analysed, but its concentration was significantly increased at 14 and 28 days compared with at 7 days. There was no significant difference between 14 and 28 days (p=0.0005). We conclude that genes related to ALP are expressed throughout the healing process and more intensively during the later periods (14 and 28 days), which coincides with the increased formation of mineralised bone. PMID- 26935215 TI - In vivo imaging in autoimmune diseases in the central nervous system. AB - Intravital imaging is becoming more popular and is being used to visualize cellular motility and functions. In contrast to in vitro analysis, which resembles in vivo analysis, intravital imaging can be used to observe and analyze cells directly in vivo. In this review, I will summarize recent imaging studies of autoreactive T cell infiltration into the central nervous system (CNS) and provide technical background. During their in vivo journey, autoreactive T cells interact with many different cells. At first, autoreactive T cells interact with endothelial cells in the airways of the lung or with splenocytes, where they acquire a migratory phenotype to infiltrate into the CNS. After arriving at the CNS, they interact with endothelial cells of the leptomeningeal vessels or the choroid plexus before passing through the blood-brain barrier. CNS-infiltrating T cells become activated by recognizing endogenous autoantigens presented by local antigen-presenting cells (APCs). This activation was visualized in vivo by using protein-based sensors. One such sensor detects changes in intracellular calcium concentration as an early marker of T cell activation. Another sensor detects translocation of Nuclear factor of activated T-cells (NFAT) from cytosol to nucleus as a definitive sign of T cell activation. Importantly, intravital imaging is not just used to visualize cellular behavior. Together with precise analysis, intravital imaging deepens our knowledge of cellular functions in living organs and also provides a platform for developing therapeutic treatments. PMID- 26935216 TI - Anaphylaxis caused by casein used in artificially marbled beef: A case report. PMID- 26935217 TI - Identification and characterization of the Populus trichocarpa CLE family. AB - BACKGROUND: The CLE (CLAVATA3/Endosperm Surrounding Region-related) gene family encodes small signaling peptides that are primarily involved in coordinating stem cell fate in different types of plant meristems. Their roles in vascular cambium have highlighted their potential function in wood formation. Apart from recent advances on identification and characterization of CLE genes, little is known about this gene family in a tree species. RESULTS: Fifty PtCLE genes were identified from the Populus trichocarpa genome and were classified into four major groups based on sequence similarity. Analysis of the genomic organization of PtCLE genes indicates that genome duplication, as well as the diversity in the CLE motif, have contributed to the expansion of CLE gene family in poplar. A comparison with functionally characterized Arabidopsis CLE protein sequences showed that many PtCLE proteins are closely related to their predicted Arabidopsis counterparts. Particularly, PtCLE3, PtCLE12, PtCLE14 and PtCLE38 comprised an identical CLE motif to AtCLE41/TDIF, which is known as a regulator of vascular cambium homeostasis, strongly supporting the idea that similar signaling pathways exist in both species to regulate wood formation and secondary growth. Transcriptome profiling revealed that PtCLE genes generally were differentially expressed while some PtCLE genes exhibited tissue-specific expression patterns. Moreover, compared to their Arabidopsis counterparts, PtCLE genes showed either similar or distinct expression patterns, implying functional conservation in some cases and functional divergence in others. CONCLUSIONS: Our study provides a genome-wide analysis of the CLE gene family in poplar, and highlights the potential roles of key PtCLE genes in the regulation of secondary growth and wood formation. The comparative analysis revealed that functional conservation may exist between PtCLEs and their AtCLE orthologues, which was further supported by transcriptomic analysis. Transcriptional profiling provided further insights into possible functional divergence, evidenced by differential expression patterns of various PtCLE genes. PMID- 26935218 TI - Association between p53-binding protein 1 expression and genomic instability in oncocytic follicular adenoma of the thyroid. AB - Oncocytic follicular adenomas (FAs) of the thyroid are neoplasms of follicular cell origin that are predominantly composed of large polygonal cells with eosinophilic and granular cytoplasm. However, the pathological characteristics of these tumors are largely unexplored. Both the initiation and progression of cancer can be caused by an accumulation of genetic mutations that can induce genomic instability. Thus, the aim of this study was to evaluate the extent of genomic instability in oncocytic FA. As the presence of p53-binding protein 1 (53BP1) in nuclear foci has been found to reflect DNA double-strand breaks that are triggered by various stresses, the immunofluorescence expression pattern of 53BP-1 was assessed in oncocytic and conventional FA. The association with the degree of DNA copy number aberration (CNA) was also evaluated using array-based comparative genomic hybridization. Data from this study demonstrated increased 53BP1 expression (i.e., "unstable" expression) in nuclear foci of oncocytic FA and a higher incidence of CNAs compared with conventional FA. There was also a particular focus on the amplification of chromosome 1p36 in oncocytic FA, which includes the locus for Tumor protein 73, a member of the p53 family implicated as a factor in the development of malignancies. Further evaluations revealed that unstable 53BP1 expression had a significant positive correlation with the levels of expression of Tumor protein 73. These data suggest a higher level of genomic instability in oncocytic FA compared with conventional FA, and a possible relationship between oncocytic FA and abnormal amplification of Tumor protein 73. PMID- 26935220 TI - Characteristics of clients using a community-based drug treatment service ('CAPS AD') in Brazil: An exploratory study. AB - BACKGROUND: Substance use is common in Brazil. In order to improve availability of substance misuse care services, over 400 Psycho-Social Care Centres for Alcohol and Drugs (CAPS-AD) - providing community-based care - have been established following mental health care reform (2001). Information on CAPS-AD clients and outcomes is limited. The present study examined select characteristics of local CAPS-AD clients. METHODS: N=143 adult CAPS-AD clients in Ceilandia (suburb of Brasilia, Federal District) participated in a 1-week 'snapshot' assessment of service users (February 2015). Following consent, descriptive data were collected by a brief, anonymous interviewer-administered questionnaire that included socio-demographic, drug use, treatment history and needs/barriers information. RESULTS: Participants were predominantly male; middle aged; unemployed; married; with middle-school education; primary problem drugs indicated were alcohol and cocaine/crack; half had prior treatment histories and indicated that treatment was externally motivated; 60% reported ways to improve treatment and possible reasons for treatment discontinuation; in multi-variate analyses, the latter was associated with employment and education status (both p<.05). CONCLUSION: CAPS-AD services appear to have increased low-barrier substance misuse treatment availability in Brazil, as well as attract individuals new to the treatment system. Various potential barriers to continuing in treatment should be addressed and more research on CAPS-AD clients and outcomes is needed. PMID- 26935219 TI - The anti-fibrotic agent pirfenidone synergizes with cisplatin in killing tumor cells and cancer-associated fibroblasts. AB - BACKGROUND: Anti-fibrotic drugs such as pirfenidone have been developed for the treatment of idiopathic pulmonary fibrosis. Because activated fibroblasts in inflammatory conditions have similar characteristics as cancer-associated fibroblasts (CAFs) and CAFs contribute actively to the malignant phenotype, we believe that anti-fibrotic drugs have the potential to be repurposed as anti cancer drugs. METHODS: The effects of pirfenidone alone and in combination with cisplatin on human patient-derived CAF cell lines and non-small cell lung cancer (NSCLC) cell lines were examined. The impact on cell death in vitro as well as tumor growth in a mouse model was determined. Annexin V/PI staining and Western blot analysis were used to characterize cell death. Synergy was assessed with the combination index method using Calcusyn software. RESULTS: Pirfenidone alone induced apoptotic cell death in lung CAFs at a high concentration (1.5 mg/mL). However, co-culture in vitro experiments and co-implantation in vivo experiments showed that the combination of low doses of cisplatin (10 MUM) and low doses of pirfenidone (0.5 mg/mL), in both CAFs and tumors, lead to increased cell death and decreased tumor progression, respectively. Furthermore, the combination of cisplatin and pirfenidone in NSCLC cells (A549 and H157 cells) leads to increased apoptosis and synergistic cell death. CONCLUSIONS: Our studies reveal for the first time that the combination of cisplatin and pirfenidone is active in preclinical models of NSCLC and therefore may be a new therapeutic approach in this disease. PMID- 26935221 TI - Usefulness of new and traditional serum biomarkers in children with suspected appendicitis. AB - OBJECTIVE: The objective of the study is to evaluate the usefulness of the leukocyte (white blood count [WBC]) and neutrophil (absolute neutrophil count [ANC]) counts; the values of C-reactive protein (CRP), procalcitonin, and calprotectin (CP); and the APPY1 Test panel of biomarkers, to identify children with abdominal pain at low risk for appendicitis. METHOD: Children 2 to 14 years of age with abdominal pain suggesting acute appendicitis (AA) were prospectively included. Procalcitonin, calprotectin, C-reactive protein, white blood count, ANC, and the new plasma APPY1 Test were performed. The final diagnosis was determined by histopathology in cases of AA and telephone follow-up in children discharged without AA. RESULTS: Between February 2012 and June 2013, 185 children were enrolled with an average age of 9.32+/-2.7 years. Eighty-nine (48.1%) were finally diagnosed with AA. The APPY1 Test panel showed the highest discriminatory power, sensitivity of 97.8 (95% confidence interval [CI], 92.2-99.4), negative predictive value of 95.1 (95% CI, 83.9-98.7), negative likelihood ratio of 0.06 (95% CI, 0.01-0.22), and specificity of 40.6 (95% CI, 31.3-50.5). A negative APPY1 Test and ANC less than 7500 per milliliter provided a sensitivity of 100 (95% CI, 95.9-100), negative predictive value of 100 (95% CI, 89.8-100), and specificity of 35.4 (95% CI, 26.6-45.4). In the multivariate analysis, only the APPY1 Test and ANC greater than 7500 per milliliter were significant risk factors for AA (odds ratio, 13.76; 95% CI, 3.02-62.57, and odds ratio, 6.37; 95% CI, 2.89 14.28, respectively). CONCLUSIONS: The APPY1 Test panel with ANC could be useful in identifying children with abdominal pain suggestive of AA who are at low risk for this disease. PMID- 26935222 TI - A 5-year comparison of ED visits by homeless and nonhomeless patients. AB - BACKGROUND: A 2005 study examined emergency department (ED) utilization by homeless patients in the United States. Within the following 5 years, unemployment increased by 5%. OBJECTIVE: The objective was to analyze changes in ED utilization between 2005 and 2010 by homeless patients and compare with nonhomeless visits. METHODS: Data from the 2010 National Hospital Ambulatory Medical Care Survey were evaluated. RESULTS: Approximately 679854 visits were made by homeless patients, the majority of which were made by men (72.3%) and patients between the ages of 45 and 64 (50.5%). Homeless patients were twice as likely to be uninsured. ED visits by homeless patients had increased by 44% during the 5-year period. Arrival to the ED by ambulance increased by 14% between the study years, and homeless patients were less likely to be admitted. CONCLUSION: The number of visits by homeless patients in the ED increased proportionally to an overall increase in ED visits between 2005 and 2010. PMID- 26935223 TI - Hypertensive brainstem encephalopathy mimicking central pontine myelinolysis: a potential pitfall. PMID- 26935224 TI - Partial resuscitative endovascular balloon occlusion of the aorta as a hemorrhagic shock adjunct for ectopic pregnancy. PMID- 26935225 TI - Point-of-care ultrasonography for the management of shoulder dislocation in ED. AB - OBJECTIVE: Point-of-care ultrasonography (POCUS) is an easily available and noninvasive tool without radiation exposure that is also gaining a broad range of use in emergency departments. The aim of this study is to evaluate the value of POCUS in the diagnosis of shoulder dislocation by comparing with plain radiography. METHODS: This prospective observational study with a convenience sampling was conducted in emergency departments of 2 hospitals. Patients older than 15 years with possible shoulder dislocation during the physical examination composed the study population. All the study patients underwent POCUS evaluation to detect a shoulder dislocation or fracture before radiography, and the POCUS procedure was also achieved after the reduction attempt. RESULTS: A total of 103 patients were enrolled in the study. The mean age of study subjects was 33.9+/-15 years, and 80.6% (n=83) of them were male. The sensitivity and specificity of POCUS in identifying dislocation were 100% (95% confidence interval [CI], 96% 100%) and 100% (95% CI, 48%-100%), respectively. POCUS also confirmed reduction in 93 of 94 patients with a specificity of 100% (95% CI, 96%-100%). POCUS has a sensitivity of 100% (95% CI, 63%-100%) for excluding a shoulder fracture but a specificity of 84.2% (95% CI, 75%-91%). CONCLUSION: Point-of-care ultrasonography is an effective tool to either rule in or rule out shoulder dislocation in the emergency setting. Furthermore, it is a robust sensitive tool for excluding fractures but with false-positive results. PMID- 26935226 TI - Which out-of-hospital cardiac arrest patients should be thrombolysed? PMID- 26935227 TI - Upper extremity edema caused by sotalol. PMID- 26935228 TI - Serum potassium concentration predicts brain hypoxia on CT after avalanche induced cardiac arrest. AB - BACKGROUND: Brain anoxia after complete avalanche burial and cardiac arrest (CA) may occur despite adequate on-site triage. PURPOSE: To investigate clinical and biological parameters associated with brain hypoxia in a cohort of avalanche victims with whole body computed tomographic (CT) scan. METHODS: Retrospective study of patients with CA and whole body CT scan following complete avalanche burial admitted in a level-I trauma center. MAIN FINDINGS: Out of 19 buried patients with whole body CT scan, eight patients had refractory CA and 11 patients had pre-hospital return of spontaneous circulation. Six patients survived at hospital discharge and only two had good neurologic outcome. Twelve patients had signs of brain hypoxia on initial CT scan, defined as brain edema, loss of gray/white matter differentiation and/or hypodensity of basal ganglia. No clinical pre-hospital parameter was associated with brain anoxia. Serum potassium concentration at admission was higher in patients with brain anoxia as compared to patients with normal CT scan: 5.5 (4.1-7.2) mmol/L versus 3.3 (3.0-4.2) mmol/L, respectively (P<.01). A threshold of 4.35 mmol/L serum potassium had 100% specificity to predict brain anoxia on brain CT scan. CONCLUSIONS: Serum potassium concentration had good predictive value for brain anoxia after complete avalanche burial. This finding further supports the use of serum potassium concentration for extracorporeal life support insertion at hospital admission in this context. PMID- 26935229 TI - Comparing patients who leave the ED prematurely, before vs after medical evaluation: a National Hospital Ambulatory Medical Care Survey analysis. AB - BACKGROUND: Many patients leave the Emergency Department (ED) before beginning or completing medical evaluation. Some of these patients may be at higher medical risk depending on their timing of leaving the ED. OBJECTIVES: To compare patient, hospital, and visit characteristics of patients who leave before completing medical care to patients who leave before ED evaluation. METHODS: Retrospective cross-sectional analysis of ED visits using the 2009-2011 National Hospital Ambulatory Medical Care Survey. RESULTS: A total of 100962 ED visits were documented in the 2009-2011 National Hospital Ambulatory Medical Care Survey, representing a weighted count of 402211907 total ED visits. 2646 (2.62%) resulted in a disposition of left without completing medical care. Of these visits, 1792 (67.7%) left before being seen by a medical provider versus 854 (32.3%) who left after medical provider evaluation but before a final disposition. Patients who left after being assessed by a medical provider were older, had higher acuity visits, were more likely to have visited an ED without nursing triage, arrived more often by ambulance, and were more likely to have private insurance than to be self-paying or to have other payment arrangements (e.g. worker's compensation or charity/no charge). CONCLUSIONS: When comparing all patients who left the ED before completion of care, those who left after versus before medical provider evaluation differed in their patient, hospital, and visit characteristics and may represent a high risk patient group. PMID- 26935231 TI - Epidermal Growth Factor Receptor, Excision-Repair Cross-Complementation Group 1 Protein, and Thymidylate Synthase Expression in Penile Cancer. AB - OBJECTIVE: To describe the expression of tissue epidermal growth factor receptor (EGFR), excision-repair cross-complementation group 1 protein (ERCC1), and thymidylate synthase (TS) in patients with penile cancer and explore their association with stage and outcome. METHODS: A total of 52 patients with penile squamous cell cancer who were treated at the University of Southern California from 1995 to 2010 were identified. Paraffin-embedded tissue underwent mRNA quantitation and immunohistochemistry for expression of EGFR, ERCC1, and TS. KRAS mutations were evaluated using polymerase chain reaction-based sequencing. RESULTS: EGFR overexpression was common by mRNA (median, 5.09; range, 1.92-104.5) and immunohistochemistry. EGFR expression > 7 was associated with advanced stage and poor differentiation (P = .01 and .034 respectively) but not with survival in multivariate analysis. ERCC1 mRNA expression was a median of 0.65 (range, 0.21 1.87). TS expression was a median of 1.88 (range, 0.54-6.47). ERCC1 and TS expression were not associated with grade, stage, or survival. There were no KRAS mutations identified. A total of 17 men received chemotherapy; 8 (47%) had an objective response, including 1 with a pathologic complete response. There was a trend for lower expression of EGFR corresponding to a higher likelihood of response (response rate [RR]) to chemotherapy: 67% RR in EGFR mRNA < 7 versus 33% RR in EGFR > 7 (P = .31). CONCLUSIONS: High expression of EGFR mRNA in squamous cell carcinoma of the penis is associated with advanced stage and poor differentiation, but not survival. In our small heterogeneous subset, molecular marker expression did not show a correlation with the likelihood of chemotherapy response. A prospective evaluation of the role of the EGFR pathway and its regulatory environment in penile cancer is warranted. Given the rarity of this cancer, collaborative prospective cohort evaluations and trials need to be encouraged. PMID- 26935230 TI - EEG response varies with lesion location in patients with chronic stroke. AB - BACKGROUND: Brain activation differs according to lesion location in functional magnetic resonance imaging (fMRI) studies, but lesion location-dependent electroencephalographic (EEG) alterations are unclear. Because of the increasing use of EEG-based brain-computer-interface rehabilitation, we examined lesion location-dependent EEG patterns in patients with stroke while they performed motor tasks. METHODS: Twelve patients with chronic stroke were divided into three subgroups according to their lesion locations: supratentorial lesions that included M1 (SM1+), supratentorial lesions that excluded M1 (SM1-), and infratentorial (INF) lesions. Participants performed three motor tasks [active, passive, and motor imagery (MI)] with supination and grasping movements. The hemispheric asymmetric indexes, which were calculated with laterality coefficients (LCs), the temporal changes in the event-related desynchronization (ERD) patterns in the bilateral motor cortex, and the topographical distributions in the 28-channel EEG patterns around the supplementary motor area and bilateral motor cortex of the three participant subgroups were compared with those of the 12 age-matched healthy controls. RESULTS: The SM1+ group exhibited negative LC values in the active and MI motor tasks, while the other patient subgroups exhibited positive LC values. Negative LC values indicate that the ERD/ERS intensity of the ipsilateral hemisphere is higher than the contralateral hemisphere, whereas positive LC values indicate that the ERD/ERS intensity of the contralateral hemisphere is higher than the ipsilateral hemisphere. The LC values of SM1+ and healthy controls differed significantly (rank-sum test, p < 0.05) in both the supination and grasping movements in the active task. The three patient subgroups differed distinctly from each other in the topography analysis. CONCLUSIONS: The hemispheric asymmetry and topographic characteristics of the beta band power patterns in the patients with stroke differed according to the location of the lesion, which suggested that EEG analyses of neurorehabilitation should be implemented according to lesion location. PMID- 26935232 TI - The tall and the short: Repainting the landscape about the growth effects of inhaled and intranasal corticosteroids. AB - BACKGROUND: Earlier 1-year growth studies that used older inhaled corticosteroid (ICS) formulations consistently showed that ICS, but not intranasal corticosteroids (INCS), produced a small ~1 cm/y growth effect that appeared to be nonprogressive and noncumulative. Studies that lasted for >1 year showed that such treatment during childhood did not affect final adult height. Collectively, these studies led to the beliefs that (1) the small short-term effect on growth is unimportant, (2) there is no long-term harm, and (3) any small risk is easily outweighed by the benefit. This led to the cavalier use of ICS and INCS in children and approval of some INCS for over-the-counter sales for children as young as 2 years of age. METHODS: Literature search using Pub-Med. RESULTS: More recent studies, with improved scientific designs, have challenged and overturned the earlier beliefs. Moreover, some of the newer ICS formulations have negative, robust growth studies (designed per FDA guidance and detected no growth effect). CONCLUSIONS: This review focused on the new evidence and how it will change the way that we use ICS and INCS in children with allergy and asthma in both clinical practice and research, with a renewed focus on safety. There also are significant implications for future iterations of asthma guidelines. The goal was to identify the proper amount of new concern about ICS and INCS, not to generate undue steroid "phobia." PMID- 26935233 TI - Family members' or friends' involvement in self-care for patients with depressive symptoms and co-morbid chronic conditions. AB - OBJECTIVES: To describe the support that patients reported receiving from family or friends (F/F) while participating in a self-care intervention for depressive symptoms; examine associations between patient-reported F/F support and use of self-care materials; and describe F/F perceptions of involvement in a subsample of F/F. METHODS: One hundred eighty-nine of 223 (85%) patients aged 40+ with chronic physical conditions and co-morbid depressive symptoms participating in a randomized self-care intervention trial, completed structured telephone surveys at three months about the F/F support received. Ten F/F participated in post study qualitative interviews on the support provided. RESULTS: 30%, 44%, and 91% of patients reported overall F/F support with self-care, F/F involvement with the self-care intervention and emotional support, respectively. 61% felt positively and 10% felt negatively or conflicted with F/F support. F/F involvement in the self-care intervention was the only variable associated with patient use of self care materials when examined alongside all F/F support variables (Proportional Odds Ratio = 1.21; 95% C.I. = 1.01, 1.45). F/F perceived less involvement in the self-care intervention than patients. DISCUSSION: Patients engaged in a self-care intervention for depressive symptoms use more self-care materials when they perceive F/F involvement in the intervention. Patients and F/F may perceive involvement differently and benefit from discussions about potential F/F roles. PMID- 26935234 TI - A (relatively) risky business: the link between prostatic radiotherapy and second malignancies. PMID- 26935235 TI - Partial orbit irradiation achieves excellent outcomes for primary orbital lymphoma. AB - PURPOSE: Primary radiation therapy (RT) achieves excellent local control and overall survival when treating localized orbital lymphoma. However, evidence supporting irradiation of partial orbit volumes to spare nearby critical structures is lacking. We sought to investigate outcomes for patients with localized orbital lymphoma treated with partial orbit irradiation. METHODS AND MATERIALS: We retrospectively reviewed patients with orbital lymphoma treated with RT at our institution who met our inclusion criteria: biopsy-confirmed, low grade lymphoma, localized disease, partial orbit treatment volumes, and follow-up >3months. The Kaplan-Meier method was used to measure overall survival (OS), and the cumulative incidence function adjusted for the competing risk of death was used to measure local failure (LF), contralateral orbit recurrence (COR), and progression. Patient characteristics were compared with outcomes using Fisher exact test for dichotomous variables and Wilcoxon rank-sum test for continuous variables. RESULTS: Thirty-two patients meeting inclusion criteria were identified with median follow-up of 45.8months (range, 3.6-171.9). The majority had stage IEA disease; their sites included conjunctiva (n=20) and retrobulbar or lacrimal gland (n=12). Median partial orbit RT dose was 30.6Gy (range, 22.5-36). Five-year OS was 100%. Five-year cumulative incidence of LF, COR, and overall disease progression was 5.3%, 5.9%, and 21.4%, respectively. Five-year cumulative incidence of LF was 8.3% for conjunctival disease versus 0.0% for retrobulbar or lacrimal gland involvement (P=.15). No significant association was observed between the outcomes of LF, COR, or progression and pretreatment characteristics. Acute and late toxicity included grade 2 periorbital edema (n=3, 9.4%), dry eye (n=3, 9.4%), retinal vascular disorder (n=1, 3.1%), conjunctivitis (n=2, 6.3%), and grade 3 cataract (n=1, 3.1%). CONCLUSIONS: Use of partial orbit irradiation in treating low-grade, localized orbital lymphoma achieves excellent survival with low rates of LF, COR, or progression. PMID- 26935237 TI - Sex differences in impulsive and compulsive behaviors: a focus on drug addiction. AB - Sex differences in inhibition and self-regulation at a behavioral level have been widely described. From an evolutionary point of view, the different selection pressures placed on male and female hominids led them to differ in their behavioral strategies that allowed our species to survive during natural selection processes. These differences reflect changes in neural and structural plasticity that might be the core of sex differences, and of the susceptibility towards one psychiatric condition rather than another. The goal of the present review is to summarize current evidence for such a dichotomy in impulsive and compulsive behavior with a focus on drug addiction. Sex-dependent differences in drug abuse and dependence will be examined in the context of pathophysiological regulation of impulse and motivation by neuromodulators (i.e. gonadal hormones) and neurotransmitters (i.e. dopamine). Advances in the understanding of the sex differences in the capability to control impulses and motivational states is key for the determination of efficacious biologically based intervention and prevention strategies for several neuropsychiatric disorders where loss of impulse control and compulsivity are the core symptoms. PMID- 26935236 TI - Hormonal evaluation in relation to phenotype and genotype in 286 patients with a disorder of sex development from Indonesia. AB - OBJECTIVE: The objective of this study was to determine the aetiological spectrum of disorders of sex development (DSD) in a large cohort of underprivileged and undiagnosed patients from Indonesia. METHODS: A total of 286 patients with atypical external and/or internal genitalia were evaluated using clinical, hormonal, molecular genetic and histological parameters. RESULTS: The age (years) at presentation was 0-0.5 in 41 (14.3%), >0.5-12 in 181 (63.3%) and >12 in 64 cases (22.4%). 46,XY DSD was most common (68.2%, n = 195), 46,XX DSD was found in 23.4% (n = 67) and sex chromosomal DSD in 8.4% (n = 24). In 61.2% of 46,XX DSD patients, 17.9% of 46,XY DSD patients and all sex chromosome DSD patients (29.4% in total), a final diagnosis was reached based on genetic or histological gonadal tissue evaluation. 17-hydroxyprogesterone and androstenedione levels were the most distinctive parameters in 46,XX DSD patients. In 46,XY DSD, diagnostic groups were identified based on the external masculinization score: androgen action disorder (AAD), unknown male undermasculinization (UMU), and gonadal dysgenesis (GD). LH, FSH and testosterone levels were most informative especially in the older age group. HCG tests were of no additional value as no patients with androgen synthesis disorders were found. Hormonal profiles of patients with sex chromosome DSD and a Y-chromosome sequence containing karyotype showed high levels of LH and FSH, and low levels of AMH, inhibin B and testosterone compared with the normal male range. Gene mutations were found in all patients with CAH, but in only 24.5% and 1.8% of patients with AAD and UMU. In 32% of 46,XY GD patients, copy number variants of different genes were found. CONCLUSION: A stepwise diagnostic approach led to a molecularly or histologically proven final diagnosis in 29.4% of the patients. The most informative parameters were serum levels of 17-hydroxyprogesterone and androstenedione in 46,XX DSD patients, and serum LH, FSH and testosterone levels in 46,XY DSD patients. PMID- 26935238 TI - Expression of lactate dehydrogenase C in MDA-MB-231 cells and its role in tumor invasion and migration. AB - The cancer/testis antigen (CTA) lactate dehydrogenase C (LDHC) is a unique LDH isoenzyme associated with glucose and adenosine triphosphate production in mammalian germ cells. However, the role of LDHC in cancer has thus far largely remained elusive. The present study described the expression status of LDHC in human MDA-MB-231 breast cancer cells as well as its role in tumor invasion and migration. Immunohistochemical analysis revealed endogenous LDHC expression in the cytoplasm and nuclei of MDA-MB-231 cells yielded. In addition, in vitro cell invasion and migration assays revealed that when LDHC expression was blocked by its specific inhibitor, cell invasion and migration were compromised in MDA-MB 231 cells. Of note, inhibition of LDHC was unable to induce apoptosis in MDA-MB 231 cells. The present study provided evidence that the LDHC enzyme acts as a CTA in breast carcinoma and exerts an essential role in tumor invasion and migration. PMID- 26935239 TI - Impact of nanotechnology on the delivery of natural products for cancer prevention and therapy. AB - Chemoprevention of human cancer by dietary products is a practical approach of cancer control, especially when chemoprevention is involved during the early stages of the carcinogenesis process. Research over the last few decades has clearly demonstrated the efficacy of dietary products for chemoprevention in cell culture and preclinical animal model systems. However, these in vitro and in vivo effects have not been able to be translated to bedside for clinical use. Among many reasons, inefficient systemic delivery and bioavailability of promising chemopreventive agents are considered to significantly contribute to such a disconnection. Since its advent in the field of cancer, nanotechnology has provided researchers with expertise to explore new avenues for diagnosis, prevention, and therapy of the disease. In a similar trait, we introduced a novel concept in which nanotechnology was utilized for enhancing the outcome of chemoprevention (Cancer Res. 2009; 69:1712-1716). This idea, which we termed as 'nanochemoprevention', was exploited by several laboratories and has now become an advancing field in chemoprevention research. This review summarizes some of these applications of nanotechnology in medicine, particularly focused on controlled and sustained release of bioactive compounds with emphasis on current and future utilization of nanochemoprevention for prevention and therapy of cancer. PMID- 26935240 TI - Suppressive effect of topoisomerase inhibitors on JC polyomavirus propagation in human neuroblastoma cells. AB - JC polyomavirus (JCPyV) causes progressive multifocal leukoencephalopathy (PML), a fatal demyelinating disease of the central nervous system, in immunocompromised patients. Because no drugs have been approved for treating PML, many antiviral agents are currently being investigated for this purpose. The inhibitory effects of the topoisomerase I inhibitors topotecan and beta-lapachone were assessed by investigating viral replication, propagation and viral protein 1 (VP1) production in cultured cells. JCPyV replication was assayed using the human neuroblastoma cell line IMR-32 transfected with the JCPyV plasmid and RT- PCR combined with Dpn I treatment. Dpn I digests the input plasmid DNA containing methylated adenosine, but not newly replicated JCPyV DNA, in IMR-32 cells. It was found that JCPyV replicates less in IMR-32 cells treated with topotecan or beta-lapachone than in untreated cells. Moreover, drug treatment of JCI cells, which are IMR-32 cells persistently infected with JCPyV, led to a reduction in the amount of JCPyV DNA and population of VP1-positive cells. These results demonstrate that topotecan and beta-lapachone affects JCPyV propagation in human neuroblastoma cell lines, suggesting that topotecan and beta-lapachone could potentially be used to treat PML. PMID- 26935241 TI - Acquisition of genomic events leading to lymphoblastic transformation in a rare case of myeloproliferative neoplasm with BCR-JAK2 fusion transcript. AB - We report a case of myeloproliferative neoplasm (MPN) with an atypical t(9;22;15)(p24;q11;q21) translocation, leading to a BCR-JAK2 fusion, associated with a trisomy of chromosome 8 in clonal evolution at karyotype. Patient's evolution was marked by an aggressive clinical course with rapid progression to blast phase within the first year after diagnosis. Examination of matched chronic phase and blast crisis samples by SNP-array karyotyping identified secondary acquired cryptic genetic events at the time of lymphoblastic transformation, including biallelic IKZF1 alteration and EBF1 and CDKN2A/B codeletions. This case is the first report describing acquisition of secondary genetic events leading to acute lymphoblastic progression in a rare MPN with BCR-JAK2 fusion. PMID- 26935242 TI - Will My Soul Go to Heaven If They Take My Brain? Beliefs and Worries About Brain Donation Among Four Ethnic Groups. AB - Purpose of the Study: Studying the brain through autopsy is an essential component of Alzheimer's disease research. Racial and ethnic minorities are underrepresented in Alzheimer's research generally and, in particular, in the number of completed brain autopsies. We explored beliefs about and attitudes toward brain donation among African American, Chinese, Caucasian, and Latino research subjects and their family members through focus groups at 4 NIH-funded Alzheimer's Disease Centers. Design and Methods: Eighteen focus groups were conducted with 61 research subjects and 34 family members. Because the primary purpose of the focus groups was to identify the range of considerations that may influence the decision to participate in brain donation, data from focus groups were pooled and then analyzed. Results: We found that many of the concerns, attitudes, and beliefs about brain donation were similar across the 4 ethnic groups. Concerns and attitudes fell into 3 categories: (a) concerns and misconceptions about brain research and the process of brain removal, (b) religious beliefs, and (c) the role of the family. Implications: Our findings suggest that interventions to enhance enrollment in brain donation that target factors identified in this study are likely to be relevant to people from a broad range of backgrounds and ethnicities. Nonetheless, we observed some potential differences among racial/ethnic groups that may affect how research volunteers and their families approach a decision about donating their brain for research. Further study is warranted to explore these and other possible culturally distinct attitudes and beliefs about brain donation. PMID- 26935243 TI - Compression use during an exercise intervention and associated changes in breast cancer-related lymphedema. AB - AIM: This study assessed the association between compression use and changes in lymphedema observed in women with breast cancer-related lymphedema who completed a 12-week exercise intervention. METHODS: This work uses data collected from a 12 week exercise trial, whereby women were randomly allocated into either aerobic based only (n = 21) or resistance-based only (n = 20) exercise. Compression use during the trial was at the participants discretion. Differences in lymphedema (measured by lymphedema index [L-Dex] score and interlimb circumference difference [%]) and associated symptoms between those who wore, and did not wear compression during the 12-week intervention were assessed. We also explored participants' reasons surrounding compression during exercise. RESULTS: No significant interaction effect between time and compression use for lymphedema was observed. There was no difference between groups over time in the number or severity of lymphedema symptoms. Irrespective of compression use, there were trends for reductions in the proportion of women reporting severe symptoms, but lymphedema status did not change. Individual reasons for the use of compression, or lack thereof, varied markedly. CONCLUSION: Our findings demonstrated an absence of a positive or negative effect from compression use during exercise on lymphedema. Current and previous findings suggest the clinical recommendation that garments must be worn during exercise is questionable, and its application requires an individualized approach. PMID- 26935244 TI - Do people have insight into their face recognition abilities? AB - Diagnosis of developmental or congenital prosopagnosia (CP) involves self-report of everyday face recognition difficulties, which are corroborated with poor performance on behavioural tests. This approach requires accurate self evaluation. We examine the extent to which typical adults have insight into their face recognition abilities across four experiments involving nearly 300 participants. The experiments used five tests of face recognition ability: two that tap into the ability to learn and recognize previously unfamiliar faces [the Cambridge Face Memory Test, CFMT; Duchaine, B., & Nakayama, K. (2006). The Cambridge Face Memory Test: Results for neurologically intact individuals and an investigation of its validity using inverted face stimuli and prosopagnosic participants. Neuropsychologia, 44(4), 576-585. doi:10.1016/j.neuropsychologia.2005.07.001; and a newly devised test based on the CFMT but where the study phases involve watching short movies rather than viewing static faces-the CFMT-Films] and three that tap face matching [Benton Facial Recognition Test, BFRT; Benton, A., Sivan, A., Hamsher, K., Varney, N., & Spreen, O. (1983). Contribution to neuropsychological assessment. New York: Oxford University Press; and two recently devised sequential face matching tests]. Self reported ability was measured with the 15-item Kennerknecht et al. questionnaire [Kennerknecht, I., Ho, N. Y., & Wong, V. C. (2008). Prevalence of hereditary prosopagnosia (HPA) in Hong Kong Chinese population. American Journal of Medical Genetics Part A, 146A(22), 2863-2870. doi:10.1002/ajmg.a.32552]; two single-item questions assessing face recognition ability; and a new 77-item meta-cognition questionnaire. Overall, we find that adults with typical face recognition abilities have only modest insight into their ability to recognize faces on behavioural tests. In a fifth experiment, we assess self-reported face recognition ability in people with CP and find that some people who expect to perform poorly on behavioural tests of face recognition do indeed perform poorly. However, it is not yet clear whether individuals within this group of poor performers have greater levels of insight (i.e., into their degree of impairment) than those with more typical levels of performance. PMID- 26935245 TI - Complications and quality of life in elderly patients with several comorbidities undergoing cutaneous ureterostomy with single stoma or ileal conduit after radical cystectomy. AB - OBJECTIVES: To compare peri-operative outcomes and quality of life (QoL) in a series of elderly patients with high comorbidity status who underwent single stoma cutaneous ureterostomy (CU) or ileal conduit (IC) after radical cystectomy (RC). PATIENTS AND METHODS: The clinical records of patients aged >75 years with an American Society of Anesthesiologists (ASA) score >2 who underwent RC at a single institution between March 2009 and March 2014 were retrospectively analysed. After RC, all patients included in the study received an IC urinary diversion or a CU with single stoma urinary diversion. Preoperative clinical characteristics as well as intra- and postoperative outcomes were evaluated and compared between the two groups. In addition, the Bladder Cancer Index (BCI) was used to assess QoL. RESULTS: A total of 70 patients were included in the final comparative analyses. Of these, 35 underwent IC diversion and 35 CU single stoma diversion. The two groups were similar with regard to age, gender, ASA score, type of indication and pathological features. Operating times (P < 0.001), estimated blood loss (P < 0.001), need for intensive care unit stay (P = 0.01), time to drain removal (P < 0.001) and length of hospital stay (P < 0.001) were significantly higher in patients undergoing IC diversion. The number of patients with intra- (P = 0.04) and early postoperative (P = 0.02) complications was also significantly higher among those undergoing IC diversion. Interestingly, the mean BCI scores were overlapping in the two groups. CONCLUSIONS: The present results show that CU with a single stoma can represent a valid alternative to IC in elderly patients with relevant comorbidities, reducing peri-operative complications without a significant impairment of QoL. PMID- 26935246 TI - SASH1 inhibits cervical cancer cell proliferation and invasion by suppressing the FAK pathway. AB - SAM and SH3 domain containing 1 (SASH1), a member of the SLY-family of signal adapter proteins, is a candidate tumor suppressor in several types of cancer. However, the role of SASH1 in cervical cancer remains to be elucidated. Therefore, in the present study, the role of SASH1 in cervical cancer and the underlying mechanism was investigated. Cell proliferation was detected by the MTT assay. Cell invasion was measured by Transwell assay. The mRNA expression levels of SASH1, matrix metalloproteinase (MMP)-2 and MMP-9 were determined by reverse transcription quantitative polymerase chain reaction. The protein expression levels of SASH1, MMP-2, MMP-9 and focal adhesion kinase (FAK) were determined by western blot analysis. The results demonstrated that SASH1 was downregulated in cervical cancer tissues and cell lines. Subsequently, a vector that overexpresses SASH1 was constructed. Overexpression of SASH1 was found to significantly inhibit cervical cancer cell proliferation and invasion, and also significantly reduce the expression of MMP-2 and MMP-9 in cancer cells. In addition, SASH1 modulated the FAK signaling pathway. Overexpression of SASH1 suppressed the expression of FAK in cancer cells. Taken together, the results suggested that SASH1 inhibits cervical cancer cell proliferation and invasion by suppressing the FAK pathway. PMID- 26935247 TI - Unexpected capacity for organic carbon assimilation by Thermosynechococcus elongatus, a crucial photosynthetic model organism. AB - Genetic modification of key residues of photosystems is essential to identify functionally crucial processes by spectroscopic and crystallographic investigation; the required protein stability favours use of thermophilic species. The currently unique thermophilic photosynthetic model organism is the cyanobacterial genus Thermosynechococcus. We report the ability of Thermosynechococcus elongatus to assimilate organic carbon, specifically D fructose. Growth in the presence of a photosynthesis inhibitor opens the door towards crucial amino acid substitutions in photosystems by the rescue of otherwise lethal mutations. Yet depression of batch-culture growth after 7 days implies that additional developments are needed. PMID- 26935248 TI - Epidermal carbonic anhydrase activity and exoskeletal metal content during the molting cycle of the blue crab, Callinectes sapidus. AB - During the crustacean molting cycle, the exoskeleton is first mineralized in postmolt and intermolt and then presumably demineralized in premolt in order for epidermal retraction to occur. The mineralization process calls for divalent metal ions, such as Ca(2+) and Mg(2+) , and bicarbonate ions whereas protons are necessary for dissolution of carbonate salts. Carbonic anhydrase (CA) has been suggested to be involved in exoskeletal mineralization by providing bicarbonate ions through catalyzing the reaction of carbon dioxide hydration. However, results of earlier studies on the role of epidermal CA in metal incorporation in crustacean exoskeleton are not consistent. This study was aimed to provide further evidence to support the notion that epidermal CA is involved in exoskeletal mineralization using the blue crab, Callinectes sapidus (Rathbun 1896), as the model crustacean. Significant increases first in calcium and magnesium then in manganese post-ecdysis indicate significant metal deposition during postmolt and intermolt. Significant positive correlation between calcium or magnesium content and epidermal CA activity in postmolt and intermolt constitutes evidence that CA is involved in the mineralization of the crustacean exoskeleton. Additionally, we proposed a hypothetical model to describe the role of epidermal CA in both mineralization and demineralization of the exoskeleton based on the results of epidermal CA activity and exoskeletal metal content during the molting cycle. Furthermore, we found that the pattern of epidermal CA activity during the molting cycle of C. sapidus is similar to that of ecdysteroids reported for the same species, suggesting that epidermal CA activity may be under control of the molting hormones. PMID- 26935249 TI - Functional recovery of stored platelets after transfusion. AB - BACKGROUND: Platelet (PLT) concentrates are prophylactically given to prevent major bleeding complications. The corrected count increment (CCI) is currently the only tool to monitor PLT transfusion efficacy. PLT function tests cannot be performed in patients with thrombocytopenia. Therefore, an optimized agonist induced assay was used to determine PLT function, in patients with severe thrombocytopenia before and after transfusion. STUDY DESIGN AND METHODS: PLT reactivity toward adenosine diphosphate (ADP), thrombin receptor-activating peptide SFLLRN (TRAP), and convulxin (CVX) was assessed by flow cytometry. P selectin expression was measured on PLTs from 11 patients with thrombocytopenia before and 1 hour after transfusion, on stored PLTs, and on stored PLTs incubated for 1 hour in whole blood from patients ex vivo. RESULTS: The mean (+/-SEM) CCI after 1 hour was 11.4 (+/-1.5). After transfusion, maximal agonist-induced PLT P selectin expression was on average 29% higher for ADP (p = 0.02), 25% higher for TRAP (p = 0.007), and 24% higher for CVX (p = 0.0008). ADP-induced reactivity of stored PLTs increased with 46% after ex vivo incubation (p = 0.007). These PLTs also showed an overall higher P-selectin expression compared to PLTs 1 hour after transfusion (p = 0.005). After normalization for this background expression, a similar responsiveness was observed. CONCLUSIONS: Our study shows recovery of PLT function after transfusion in patients with thrombocytopenia. The majority of functional PLTs measured after transfusion most likely represents stored transfused PLTs that regained functionality in vivo. The difference in baseline P selectin expression in vivo versus ex vivo suggests a rapid clearance from circulation of PLTs with increased P-selectin expression. PMID- 26935250 TI - Ludwig's angina. PMID- 26935251 TI - Investigations on luminescence behaviour of Ce-activated BaMgAl10 O17 phosphor. AB - The present paper describes the synthesis of cerium-doped barium magnesium aluminate phosphor by combustion method. The crystal structure of synthesized phosphor belongs to the P63 /mmc space group and is related to the beta-alumina structure. The photoluminescence emission spectra exhibited a broad peak centered at 440 nm showing the Ce3+ emission. The thermoluminescence properties of phosphors under ultraviolet irradiation were investigated. The activation energy was calculated by Chen's empirical method. Fracto-mechanoluminescence properties were also investigated. The phosphor showed mechanoluminescence (ML) properties without irradiation and the ML intensity increased linearly with the impact height of the moving piston. Therefore this compound may have a use as a damage sensor. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26935252 TI - Structural insights and membrane binding properties of MGD1, the major galactolipid synthase in plants. AB - Monogalactosyldiacylglycerol (MGDG) and digalactosyldiacylglycerol (DGDG) are the major lipid components of photosynthetic membranes, and hence the most abundant lipids in the biosphere. They are essential for assembly and function of the photosynthetic apparatus. In Arabidopsis, the first step of galactolipid synthesis is catalyzed by MGDG synthase 1 (MGD1), which transfers a galactosyl residue from UDP-galactose to diacylglycerol (DAG). MGD1 is a monotopic protein that is embedded in the inner envelope membrane of chloroplasts. Once produced, MGDG is transferred to the outer envelope membrane, where DGDG synthesis occurs, and to thylakoids. Here we present two crystal structures of MGD1: one unliganded and one complexed with UDP. MGD1 has a long and flexible region (approximately 50 amino acids) that is required for DAG binding. The structures reveal critical features of the MGD1 catalytic mechanism and its membrane binding mode, tested on biomimetic Langmuir monolayers, giving insights into chloroplast membrane biogenesis. The structural plasticity of MGD1, ensuring very rapid capture and utilization of DAG, and its interaction with anionic lipids, possibly driving the construction of lipoproteic clusters, are consistent with the role of this enzyme, not only in expansion of the inner envelope membrane, but also in supplying MGDG to the outer envelope and nascent thylakoid membranes. PMID- 26935253 TI - Brain Volume Loss During the First Year of Interferon-Beta Treatment in Multiple Sclerosis: Baseline Inflammation and Regional Brain Volume Dynamics. AB - OBJECTIVE: A pseudoatrophy effect, mostly affecting white matter, can be observed in patients with multiple sclerosis (MS) early on natalizumab therapy. We aimed to investigate whether a similar pattern could be found after interferon-beta treatment onset. METHODS: From a prospective, ongoing cohort, 123 patients treated with interferon-beta were included. A brain MRI was performed at baseline (3 months prior) and 12 months after therapy onset in all patients. SPM8 software was used for volumetric analysis. Brain parenchymal, gray and white matter volumes at baseline and follow-up were obtained, allowing calculation of percentage of volume changes (BVc, GMVc, and WMVc, respectively). Descriptive statistics and linear regression models were performed. RESULTS: Eighty-four patients were analyzed (39 patients were excluded mostly due to incomplete MRI protocol or segmentation errors); baseline mean age was 33.6 years (SD 8.7), median disease duration was 2.8 years (.3-14), and median EDSS was 1.5 (0-6). Forty-nine patients (58.3%) had baseline gadolinium-enhancing (Gd+) lesions with a median number of 1 (0-18). The regression analysis (adjusted by the number of Gd+ at follow-up MRI, age, disease duration, and baseline EDSS) showed that a higher baseline number of Gd+ lesions was predictive of larger decreases in BVc and WMVc (P = .013 and P = .003, respectively) but not GMVc (P = .777). CONCLUSION: Concurrent inflammation has an impact on brain volume measurements (especially white matter) during the first year of interferon-beta therapy, and should be taken into account when interpreting early brain volume changes on therapy. PMID- 26935254 TI - Neuropathic low back pain in clinical practice. AB - BACKGROUND AND OBJECTIVE: Low back pain (LBP) is one of the most common chronic pain conditions. This paper reviews the available literature on the role of neuropathic mechanisms in chronic LBP and discusses implications for its clinical management, with a particular focus on pharmacological treatments. DATABASES AND DATA TREATMENT: Literature searches were performed in PubMed, key pain congresses and ProQuest Dialog to identify published evidence on neuropathic back pain and its management. All titles were assessed for relevant literature. RESULTS: Chronic LBP comprises both nociceptive and neuropathic components, however, the neuropathic component appears under-recognized and undertreated. Neuropathic pain (NP) is challenging to manage. Many patients with chronic LBP have pain that is refractory to existing treatments. Typically, less than half of patients experience clinically meaningful analgesia with oral pharmacotherapies; these are also associated with risks of adverse effects. Paracetamol and NSAIDs, although widely used for LBP, are unlikely to ameliorate the neuropathic component and data on the use of NP medications such as antidepressants and gabapentin/pregabalin are limited. While there is an unmet need for improved treatment options, recent data have shown tapentadol to have efficacy in the neuropathic component of LBP, and studies suggest that the capsaicin 8% patch and lidocaine 5% medicated plaster, topical analgesics available for the treatment of peripheral NP, may be a valuable additional approach for the management of neuropathic LBP. CONCLUSIONS: Chronic LBP often has an under-recognized neuropathic component, which can be challenging to manage, and requires improved understanding and better diagnosis and treatment. WHAT DOES THIS REVIEW ADD?: Increased recognition and improved understanding of the neuropathic component of low back pain raises the potential for the development of mechanism-based therapies. Open and retrospective studies suggest that agents like tapentadol and topical analgesics - such as the capsaicin 8% patch and the lidocaine 5% medicated plaster - may be effective options for the treatment of neuropathic low back pain in defined patient groups. PMID- 26935255 TI - Connexin32-mediated antitumor effects of suicide gene therapy against hepatocellular carcinoma: In vitro and in vivo anticancer activity. AB - Normal hepatocytes express connexin32 (Cx32), which forms gap junctions at cell cell contact areas. The aim of the present study was to investigate whether Cx32 mediates the cell death-inducing effects of ultrasound microbubbles carrying the herpes simplex virus thymidine kinase (HSV-TK) suicide gene against hepatocellular carcinoma cells in vitro and in vivo. HepG2 cells were exposed to different concentrations of trans-retinoic acid (ATRA) in culture, to evaluate the intrinsic antitumor effect of ATRA. Detailed in-vitro and in-vivo investigations on the antitumor effects of ATRA via Cx32 mediation were performed, and the possible underlying mechanisms of action of the compound were then examined. The gene expression of HSV-TK transfected by ultrasound wave irradiation in the HepG2 cells was quantified using reverse transcription quantitative polymerase chain reaction analysis. The effects on cell death were assessed using an MTT assay. The protein expression levels of Cx32 in ATRA untreated or ATRA-treated tissues were quantified by immunohistochemical analysis and Western blot assays. The HSV-TK gene was successfully transfected into the HepG2 cell using ultrasound wave irradiation, and was stably expressed. Compared with the other groups, the HSV-TK gene group treated with ATRA exhibited an increased number of apoptotic cells (P<0.05) and improved tumor suppression (P<0.05). ATRA significantly increased the expression of Cx32 in the hepatoma tissues (P<0.01). The present study demonstrated that ATRA elevated the protein expression of Cx32 and enhanced the bystander effect of the HSV-TK/GCV suicide gene therapy system, which may provide a potential strategy for hepatocellular carcinoma treatment. PMID- 26935256 TI - Role of adiponectin on antioxidant profile: evaluation during healthy and hypertensive disorders of pregnancy. AB - The study of adipokines and oxidative stress has aided in understanding pre eclampsia physiopathology. Therefore, our group aimed to evaluate the correlation between the adipokines (adiponectin and leptin) and the oxidative stress marker malondialdehyde-thiobarbituric acid reactive substances (MDA-TBARS) and antioxidant activity of plasma [ferric reducing ability of plasma (FRAP)] in healthy pregnant women and patients with gestational hypertension and pre eclampsia. We found a significant negative correlation between MDA-TBARS and adiponectin (r = -0.40, p = 0.0042), suggesting a relationship between antioxidant levels and this adipokine in healthy pregnancies which is altered in patients with gestational hypertension or pre-eclampsia. PMID- 26935257 TI - Effect of socioeconomic position on survival after childhood cancer in Denmark. AB - Background One fifth of all deaths among children in Europe are accounted for by cancer. If this is to be reduced there is a need for studies on not only biology and treatment approaches but also on how social factors influence cure rates. We investigated how various socioeconomic characteristics were associated with survival after childhood cancer. Material and methods In a nationwide cohort of 3797 children diagnosed with cancer [hematological cancer, central nervous system (CNS) tumors, non-CNS solid tumors] before age 20 between 1990 and 2009 we identified parents and siblings and obtained individual level parental socioeconomic variables and vital status through 2012 by linkage to population based registries. Hazard ratios (HR) and 95% confidence intervals (CI) for dying were estimated using multivariate Cox proportional hazard models. Results For all children with cancer combined, survival was slightly but not statistically significantly better the higher the education of the mother or the father, and with maternal income. Significantly better survival was observed when parents were living together compared to living alone and worse survival when the child had siblings compared to none. Young (<20) or older (>=40) maternal age showed non-significant associations, but based on small numbers. For hematological cancers, no significant associations were observed. For CNS tumors, better survival was seen with parents living together (HR 0.70, CI 0.51-0.97). For non CNS solid tumors, survival was better with high education of the mother (HR 0.66, CI 0.44-0.99) compared to basic and worse for children with one (HR 1.45, CI 1.11 1.89) or two or more siblings (HR 1.29, CI 0.93-1.79) (p for trend 0.02) compared to none. Conclusion The impact of socioeconomic characteristics on childhood cancer survival, despite equal access to protocolled and free-of-charge treatment, warrants further and more direct studies of underlying mechanisms in order to target these as a means to improve survival rates. PMID- 26935258 TI - Bioactive Secondary Metabolites from a Thai Collection of Soil and Marine-Derived Fungi of the Genera Neosartorya and Aspergillus. AB - BACKGROUND: Fungi are microorganisms which can produce interesting secondary metabolites with structural diversity. Although terrestrial fungi have been extensively investigated for their bioactive secondary metabolites such as antibiotics, marine-derived fungi have only recently attracted attention of Natural Products chemists. METHODS: Our group has been working on the secondary metabolites produced by the cultures of the fungi of the genera Neosartorya and Aspergillus, collected from soil and marine environments from the tropical region for the purpose of finding new leads for anticancer and antibacterial drugs. RESULTS: This review covers only the secondary metabolites of four soil and six marine-derived species of Neosarorya as well as a new species of marine-derived Aspergillus, investigated by our group. In total, we have isolated fifty three secondary metabolites which can be categorized as polyketides (two), isocoumarins (six), terpenoids (two), meroterpenes (fourteen), alkaloids (twenty eight) and cyclic peptide (one). The anticancer and antibacterial activities of these fungal metabolites are also discussed. CONCLUSION: Among fifty three secondary metabolites isolated, only the alkaloid eurochevalierine and the cadinene sesquiterpene, isolated from the soil fungus N. pseudofisheri, showed relevant in vitro cytostatic activity against glioblastoma (U373) and non-small cell lung cancer (A549) cell lines while the meroditerpene aszonapyrone A exhibited strong antibacterial activity against multidrug-resistant Gram-positive bacteria and also strong antibiofilm activity in these isolates. PMID- 26935259 TI - Enhanced Pro-Apoptotic Effect of Tetrandrine Loaded Nanoparticles Against Osteosarcoma Cells. AB - BACKGROUND: Tetrandrine (Tet), a kind of herbal medicine belonging to the family of bis-benzylisoquinoline alkaloid, has gained more attraction for its potential anti-tumor effects. However, its potential utilization in clinic is greatly hampered by the poor pharmacokinetcs profile due to its insolubility. Recently, biodegradable polymeric nanoparticles with amphilic copolymers as drug carriers have shown better bioavailability against tumor as promising tumor-targeted drug delivery system. METHODS: In the current study, Tet-loaded nanoparticles (Tet NPs) was prepared with amphiphilic block copolymer as drug carriers. The physiochemical characterization, in vitro and in vivo antitumor effect of nanoparticles were evaluated. RESULTS: In vitro study demonstrated the superior cell inhibitory effect of Tet-NPs. Most importantly, the viability of cells exposed to Tet-NPs was significant lower than that of cells treated with free Tet at lower equivalent doses. Moreover, Tet- NPs induced apoptosis and inhibited the proliferation of cells more effectively than free did at the equivalent concentration. Western blot showed that the expression of anti-apoptotic protein Bcl-2, Bcl-XL was significantly promoted while the pro-apoptotic Bax was significantly inhibited by the treatment of Tet-NPs. CONCLUSION: Data from the current study suggested that Tet-NPs is a promising delivery nano-system for the treatment of osteosarcoma. PMID- 26935260 TI - Comment on: Therapeutic hypothermia for severe adult community-acquired bacterial meningitis. PMID- 26935261 TI - Importance of Cardiopulmonary Bypass Period on Systemic Inflammatory Response. PMID- 26935262 TI - Impact of Airflow Limitation on Comorbidities and Postoperative Complications in Patients Undergoing Thoracic Surgery: A Retrospective Observational Study. AB - PURPOSE: To assess the frequency of airflow limitation (AFL), and the relationship between AFL and preoperative comorbidities or postoperative complications in patients who had undergone thoracic surgery. METHODS: The medical records of patients who underwent non-cardiac thoracic surgery at our institution between August 1996 and January 2013 were retrospectively reviewed. On the basis of preoperative pulmonary function tests, patients were classified with those with FEV1/FVC <70% [AFL(+) group] or with FEV1/FVC >=70% [AFL(-) group]. Patient characteristics, preoperative comorbidities and postoperative complications were compared between the groups. RESULTS: Of the 3667 patients assessed, 738 (20.1%) were allocated to the AFL(+) group. AFL was an independent risk factor for three preoperative comorbidities: chronic obstructive pulmonary disease (odds ratio [OR]: 4.65), bronchial asthma (OR 4.30) and cardiac diseases (OR 1.41). Airflow limitation was also an independent risk factor for postoperative respiratory failure including long-term oxygen therapy (OR 2.14) and atelectasis (OR 1.90) in the patients who underwent lobectomy or partial resection of the lung. CONCLUSIONS: Our retrospective study revealed that careful attention needs to be paid to airflow limitation in patients who undergo non cardiac thoracic surgery since it appears to be an important feature of preoperative comorbidities and to increase postoperative complications. PMID- 26935263 TI - Atorvastatin ameliorates early brain injury after subarachnoid hemorrhage via inhibition of AQP4 expression in rabbits. AB - The therapeutic effects of atorvastatin on early brain injury (EBI), cerebral edema and its association with aquaporin 4 (AQP4) were studied in rabbits after subarachnoid hemorrhage (SAH) using western blot analysis and the dry-wet method. Seventy-two healthy male New Zealand rabbits weighing between 2.5 and 3.2 kg were randomly divided into three groups: the SAH group (n=24), sham-operated group (n=24) and the SAH + atorvastatin group (n=24). A double SAH model was employed. The sham-operated group were injected with the same dose of saline solution, the SAH + atorvastatin group received atorvastatin 20 mg/kg/day after SAH. All rabbit brain samples were taken at 72 h after the SAH model was established successfully. Brain edema was detected using the dry-wet method after experimental SAH was induced; AQP4 and caspase-3 expression was measured by western blot analysis, and neuronal apoptosis was detected by terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling (TUNEL) staining at 72 h after SAH. The results indicated that brain edema and injury appeared soon after SAH, while brain edema and EBI were ameliorated and increased behavior scores were noted after prophylactic use of atorvastatin. Compared with the SAH group, the level of AQP4 and the cerebral content of water was significantly decreased (P<0.01) by atorvastatin, and TUNEL staining and studying the expression of caspase-3 showed that the apoptosis of neurons was reduced markedly both in the hippocampus and brain cortex by atorvastatin. The results suggest that atorvastatin ameliorated brain edema and EBI after SAH, which was related to its inhibition of AQP4 expression. Our findings provide evidence that atorvastatin is an effective and well-tolerated approach for treating SAH in various clinical settings. PMID- 26935264 TI - Tetrandrine suppresses metastatic phenotype of prostate cancer cells by regulating Akt/mTOR/MMP-9 signaling pathway. AB - Tetrandrine (TET), a bisbenzylisoquinoline alkaloid found in traditional Chinese medicines, exerts anticancer activity in vitro and in vivo. However, its potential role in the prostate cancer metastatic process has not yet been elucidated. Thus, we investigated the inhibition effect of tetrandrine on prostate cancer migration and invasion and the corresponding molecular basis underlying its anticancer activity. Cell migration and invasion were determined using the Transwell chamber model. The protein expression of Akt, phosphorylated Akt, the mammalian target of rapamycin (mTOR), phosphorylated mTOR and matrix metalloproteinases 9 (MMP-9) was detected by western blot in the presence or absence of tetrandrine or in the group tetrandrine combination with LY294002 (inhibitor of Akt) and rapamycin (inhibitor of mTOR). Our studies showed that excluding the effect of tetrandrine on cell proliferation, tetrandrine significantly inhibited cell migration and invasion in prostate cancer DU145 and PC3 cells. Furthermore, tetrandrine decreased the protein levels of p-Akt, p mTOR, and MMP-9. While the inhibition of Akt or mTOR by the respective inhibitors could potentiate this effect of tetrandrine on prostate cancer cells, the studies indicate that tetrandrine inhibits the metastasis process by negatively regulating the Akt/mTOR/MMP-9 signaling pathway. These results suggest that tetrandrine might serve as a potential metastasis suppressor to treat cancer cells that have escaped surgical removal or that have disseminated widely. PMID- 26935265 TI - Nitidine chloride inhibits ovarian cancer cell migration and invasion by suppressing MMP-2/9 production via the ERK signaling pathway. AB - Nitidine chloride (NC) has been demonstrated to exert anti-tumor effects on various types of tumor. However, no studies have investigated the anti-metastatic effect of NC on ovarian cancer cells, and the underlying mechanisms have not yet been clearly established. The present study aimed to determine the effect of NC on the migration and invasion of ovarian cancer cells. Cell viability and proliferation of ovarian cancer cells were assessed by MTT assay. A scratch wound healing assay and Transwell assays were performed to detect migration and invasion of cells, respectively. The expression levels of matrix metalloproteinase (MMP)-2 and 9 were detected at the mRNA and protein level following stimulation with NC. Subsequently, the expression of mitogen-activated protein kinases was detected by western blot analysis. Finally, an inhibitor of extracellular signal-regulated kinase (ERK) was applied to investigate the effect of NC on the expression of MMP-2/9 as well as the migration and invasion of cells. It was found that NC suppressed the proliferation, migration and invasion of A2780 ovarian cancer cells. NC downregulated MMP-2 and MMP-9 in a dose- and time-dependent manner. In addition, NC was also able to downregulate phosphorylation of ERK. Furthermore, by applying an ERK inhibitor, U0126, the effect of NC on the expression of MMP-2/9 and inhibition of cell migration and invasion was verified. Taken together, these results demonstrated that NC inhibited the migration and invasion of ovarian cancer cells via the ERK signaling pathway. PMID- 26935266 TI - Insulin resistance contributes to multidrug resistance in HepG2 cells via activation of the PERK signaling pathway and upregulation of Bcl-2 and P-gp. AB - Liver tumorigenesis frequently causes insulin resistance which may be used as an independent risk factor for evaluation of survival and post-surgery relapse of liver cancer patients. In the present study, HepG2/IR, an insulin resistant HepG2 cell line, was established by exposing HepG2 cells to 0.5 umol/l of insulin for 72 h, and comparison of HepG2/IR with the parental HepG2 cells indicated that the HepG2/IR cells showed significantly enhanced resistance to the most frequently used chemotherapeutics for solid tumors, such as cisplatin, 5-fluorouracil, vincristine and mitomycin. Flow cytometric analysis of cisplatin-treated HepG2/IR cells showed a significantly decreased hypodiploid peak and a significantly downregulated expression level of pro-apoptotic protein caspase-3 compared with the parental HepG2 cells. Our data further showed swollen endoplasmic reticulum (ER) in the cisplatin-treated HepG2/IR cells with significantly increased levels of glucose-regulated protein 78 (GRP78), phosphorylated protein kinase R-like ER kinase (p-PERK) and P-glycoprotein (P-gp). There was also an upregulated expression of anti-apoptotic protein B-cell lymphoma 2 (Bcl-2) whereas no significant change was observed for CCAAT-enhancer-binding protein homologous protein (CHOP), which is known to be induced by ER stress and to mediate apoptosis. Our results demonstrated that insulin resistance in HepG2 cells promoted a protective unfolded protein response and upregulated the expression of ER chaperone protein GRP78, which resulted in the phosphorylation of PERK kinase to activate the PERK-mediated ER stress signal transduction pathway and the upregulation of Bcl-2 and P-gp, leading to the inhibition of the caspase-3 dependent apoptosis pathway and to the survival of liver tumor cells. PMID- 26935268 TI - In human alloreactive CD4+ T-cells, dichloroacetate inhibits aerobic glycolysis, induces apoptosis and favors differentiation towards the regulatory T-cell subset instead of effector T-cell subsets. AB - Although kidney transplantation is the best therapy for end-stage renal disease, rejection remains a concern, and currently available immunosuppressive agents contribute to morbidity and mortality. Thus, novel immunosuppressive drugs are required. Dichloroacetate (DCA) is already used in the treatment of congenital lactic acidosis and characterized by limited toxicity. As DCA inhibits aerobic glycolysis, which is a prerequisite for CD4+ T-cell proliferation and differentiation into effector T-cells, its possible immunosuppressive role in mixed lymphocyte reaction (MLR), a model of alloreactivity, was investigated. Glucose and lactate concentrations were measured in the supernatants, and cell proliferation was assessed immunoenzymatically. CD4+ T-cells were then isolated from the MLRs and the expression of cleaved caspase-3, various enzymes involved in glycolysis, and the signature transcription factors of CD4+ T-cell subsets were evaluated by western blotting. In MLRs, DCA decreased glucose consumption and aerobic glycolysis, while it exerted a negligible effect on cell proliferation. In CD4+ T-cells, DCA induced apoptosis, and decreased the expression of glucose trasporter-1, hexokinase II, lactate dehydrogenase-A and phosphorylated pyruvate dehydrogenase, while it increased total pyruvate dehydrogenase. In addition, DCA increased the expression of transcription factor forkhead box P3, whereas it decreased the expression of T-box transcription factor TBX21, trans-acting T-cell-specific transcription factor GATA-3 and retinoic acid receptor related orphan receptor-gammat. In conclusion, in alloreactive CD4+ T-cells, DCA inhibits aerobic glycolysis, induces apoptosis and favors differentiation towards the regulatory T-cell subset. These characteristics render it a promising immunosuppressive agent in the field of transplantation. PMID- 26935267 TI - Integrating serological and genetic data to quantify cross-species transmission: brucellosis as a case study. AB - Epidemiological data are often fragmented, partial, and/or ambiguous and unable to yield the desired level of understanding of infectious disease dynamics to adequately inform control measures. Here, we show how the information contained in widely available serology data can be enhanced by integration with less common type-specific data, to improve the understanding of the transmission dynamics of complex multi-species pathogens and host communities. Using brucellosis in northern Tanzania as a case study, we developed a latent process model based on serology data obtained from the field, to reconstruct Brucella transmission dynamics. We were able to identify sheep and goats as a more likely source of human and animal infection than cattle; however, the highly cross-reactive nature of Brucella spp. meant that it was not possible to determine which Brucella species (B. abortus or B. melitensis) is responsible for human infection. We extended our model to integrate simulated serology and typing data, and show that although serology alone can identify the host source of human infection under certain restrictive conditions, the integration of even small amounts (5%) of typing data can improve understanding of complex epidemiological dynamics. We show that data integration will often be essential when more than one pathogen is present and when the distinction between exposed and infectious individuals is not clear from serology data. With increasing epidemiological complexity, serology data become less informative. However, we show how this weakness can be mitigated by integrating such data with typing data, thereby enhancing the inference from these data and improving understanding of the underlying dynamics. PMID- 26935269 TI - A bead-based cleavage method for large-scale identification of protease substrates. AB - Proteolysis is a major form of post translational modification which occurs when a protease cleaves peptide bonds in a target protein to modify its activity. Tracking protease substrates is indispensable for understanding its cellular functions. However, it is difficult to directly identify protease substrates because the end products of proteolysis, the cleaved protein fragments, must be identified among the pool of cellular proteins. Here we present a bead-based cleavage approach using immobilized proteome as the screening library to identify protease substrates. This method enables efficient separation of proteolyzed proteins from background protein mixture. Using caspase-3 as the model protease, we have identified 1159 high confident substrates, among which, strikingly, 43.9% of substrates undergo degradation during apoptosis. The huge number of substrates and positive support of in vivo evidence indicate that the BBC method is a powerful tool for protease substrates identification. PMID- 26935271 TI - Epicardial fat and atrial fibrillation: current evidence, potential mechanisms, clinical implications, and future directions. AB - Obesity is increasingly recognized as a major modifiable determinant of atrial fibrillation (AF). Although body mass index and other clinical measures are useful indications of general adiposity, much recent interest has focused on epicardial fat, a distinct adipose tissue depot that can be readily assessed using non-invasive imaging techniques. A growing body of data from epidemiological and clinical studies has demonstrated that epicardial fat is consistently associated with the presence, severity, and recurrence of AF across a range of clinical settings. Evidence from basic science and translational studies has also suggested that arrhythmogenic mechanisms may involve adipocyte infiltration, pro-fibrotic, and pro-inflammatory paracrine effects, oxidative stress, and other pathways. Despite these advances, however, significant uncertainty exists and many questions remain unanswered. In this article, we review our present understanding of epicardial fat, including its classification and quantification, existing evidence implicating its role in AF, potential mechanisms, implications for clinicians, and future directions for research. PMID- 26935270 TI - Happy heart syndrome: role of positive emotional stress in takotsubo syndrome. AB - AIMS: Takotsubo syndrome (TTS) is typically provoked by negative stressors such as grief, anger, or fear leading to the popular term 'broken heart syndrome'. However, the role of positive emotions triggering TTS remains unclear. The aim of the present study was to analyse the prevalence and characteristics of patients with TTS following pleasant events, which are distinct from the stressful or undesirable episodes commonly triggering TTS. METHODS AND RESULTS: Takotsubo syndrome patients with preceding pleasant events were compared to those with negative emotional triggers from the International Takotsubo Registry. Of 1750 TTS patients, we identified a total of 485 with a definite emotional trigger. Of these, 4.1% (n = 20) presented with pleasant preceding events and 95.9% (n = 465) with unequivocal negative emotional events associated with TTS. Interestingly, clinical presentation of patients with 'happy heart syndrome' was similar to those with the 'broken heart syndrome' including symptoms such as chest pain [89.5% (17/19) vs. 90.2% (412/457), P = 1.0]. Similarly, electrocardiographic parameters, laboratory findings, and 1-year outcome did not differ. However, in a post hoc analysis, a disproportionate higher prevalence of midventricular involvement was noted in 'happy hearts' compared with 'broken hearts' (35.0 vs. 16.3%, P = 0.030). CONCLUSION: Our data illustrate that TTS can be triggered by not only negative but also positive life events. While patient characteristics were similar between groups, the midventricular TTS type was more prevalent among the 'happy hearts' than among the 'broken hearts'. Presumably, despite their distinct nature, happy and sad life events may share similar final common emotional pathways, which can ultimately trigger TTS. PMID- 26935272 TI - Acute myocardial infarction with cardiogenic shock from a left coronary cusp thrombus. PMID- 26935274 TI - Stable room-temperature ferromagnetic phase at the FeRh(100) surface. AB - Interfaces and low dimensionality are sources of strong modifications of electronic, structural, and magnetic properties of materials. FeRh alloys are an excellent example because of the first-order phase transition taking place at ~400 K from an antiferromagnetic phase at room temperature to a high temperature ferromagnetic one. It is accompanied by a resistance change and volume expansion of about 1%. We have investigated the electronic and magnetic properties of FeRh(100) epitaxially grown on MgO by combining spectroscopies characterized by different probing depths, namely X-ray magnetic circular dichroism and photoelectron spectroscopy. We find that the symmetry breaking induced at the Rh terminated surface stabilizes a surface ferromagnetic layer involving five planes of Fe and Rh atoms in the nominally antiferromagnetic phase at room temperature. First-principles calculations provide a microscopic description of the structural relaxation and the electron spin-density distribution that support the experimental findings. PMID- 26935273 TI - Outcomes and costs of left atrial appendage closure from randomized controlled trial and real-world experience relative to oral anticoagulation. AB - AIMS: The aim of this study was to analyse randomized controlled study and real world outcomes of patients with non-valvular atrial fibrillation (NVAF) undergoing left atrial appendage closure (LAAC) with the Watchman device and to compare costs with available antithrombotic therapies. METHODS AND RESULTS: Registry data of LAAC from two centres were prospectively collected from 110 patients with NVAF at risk of stroke, suitable and unsuitable for long-term anticoagulation (age 71.3 +/- 9.2 years, CHADS2 2.8 +/- 1.2, CHA2DS2-VASc 4.5 +/- 1.6, and HAS-BLED 3.8 +/- 1.1). Outcomes from PROTECT AF and registry study LAAC were compared with warfarin, dabigatran, rivaroxaban, apixaban, aspirin, and no treatment using a network meta-analysis. Costs were estimated over a 10-year horizon. Uncertainty was assessed using sensitivity analyses. The procedural success rate was 92% (103/112). Follow-up was 24.1 +/- 4.6 months, during which annual rates of stroke, major bleeding, and all-cause mortality were 0.9% (2/223 patient-years), 0.9% (2/223 patient-years), and 1.8% (4/223 patient-years), respectively. Anticoagulant therapy was successfully stopped in 91.2% (93/102) of implanted patients by 12 months. Registry study LAAC stroke and major bleeding rates were significantly lower than PROTECT AF results: mean absolute difference of stroke, 0.89% (P = 0.02) and major bleeding, 5.48% (P < 0.001). Left atrial appendage closure achieved cost parity between 4.9 years vs. dabigatran 110 mg and 8.4 years vs. warfarin. At 10 years, LAAC was cost-saving against all therapies (range L1162-L7194). CONCLUSION: Left atrial appendage closure in NVAF in a real-world setting may result in lower stroke and major bleeding rates than reported in LAAC clinical trials. Left atrial appendage closure in both settings achieves cost parity in a relatively short period of time and may offer substantial savings compared with current therapies. Savings are most pronounced among higher risk patients and those unsuitable for anticoagulation. PMID- 26935275 TI - Population Code Dynamics in Categorical Perception. AB - Categorical perception is a ubiquitous function in sensory information processing, and is reported to have important influences on the recognition of presented and/or memorized stimuli. However, such complex interactions among categorical perception and other aspects of sensory processing have not been explained well in a unified manner. Here, we propose a recurrent neural network model to process categorical information of stimuli, which approximately realizes a hierarchical Bayesian estimation on stimuli. The model accounts for a wide variety of neurophysiological and cognitive phenomena in a consistent framework. In particular, the reported complexity of categorical effects, including (i) task dependent modulation of neural response, (ii) clustering of neural population representation, (iii) temporal evolution of perceptual color memory, and (iv) a non-uniform discrimination threshold, are explained as different aspects of a single model. Moreover, we directly examine key model behaviors in the monkey visual cortex by analyzing neural population dynamics during categorization and discrimination of color stimuli. We find that the categorical task causes temporally-evolving biases in the neuronal population representations toward the focal colors, which supports the proposed model. These results suggest that categorical perception can be achieved by recurrent neural dynamics that approximates optimal probabilistic inference in the changing environment. PMID- 26935277 TI - Regenerative medicine: The future of 3D printing of human tissues is taking shape. PMID- 26935279 TI - Connective tissue diseases: Mitochondria drive NETosis and inflammation in SLE. AB - Mitochondria are the powerhouses of the cell, providing energy through oxidative respiration. Possibly owing to their similarities with bacteria, however, mitochondria extruded from cells promote inflammation. New research demonstrates that in systemic lupus erythematosus, mitochondrial respiration is critical in neutrophil extracellular trap formation, and that mitochondria released by neutrophils induce inflammatory cytokine production. PMID- 26935280 TI - Neuroinflammation in fibromyalgia and CRPS: top-down or bottom-up? PMID- 26935281 TI - Autoimmunity: Nanomedicine, meet autoimmune disease. PMID- 26935282 TI - Neuroinflammation in fibromyalgia and CRPS is multifactorial. PMID- 26935285 TI - Performance of blood pressure-to-height ratio as a screening tool for elevated blood pressure in pediatric population: a systematic meta-analysis. AB - The aim of this study was to assess the performance of the blood pressure-to height ratio (BPHR) for screening elevated blood pressure (BP) in children and adolescents using a meta-analysis of eligible published studies. We retrieved studies that investigated the performance of the BPHR for identifying elevated BP from Pubmed and other databases. We performed meta-analyses by subgroups of sex, age and ethnicity using a fixed or random effect model based on whether there was between-study heterogeneity. A total of 13 publications including 262 830 children and adolescents aged 6-18 years on BPHR and a total of three publications including 95 343 children on the modified BPHR were included in this meta-analysis. The summary results suggested that BPHR performed well to identify pre-high BP and high BP for children aged 6-11 years and adolescents aged 12-18 years. The performance of BPHR was perfect for identifying severe high BP in adolescents aged 12-18 years. However, the modified BPHR did not improve accuracy for screening high BP in children aged 6-12 years. In summary, BPHR performed well for identifying elevated BP in children and adolescents, independently of sex, age and ethnicity group. In addition, the modified BPHR performed similarly with BPHR for screening high BP in childhood. PMID- 26935283 TI - Metabolomics in rheumatic diseases: desperately seeking biomarkers. AB - Metabolomics enables the profiling of large numbers of small molecules in cells, tissues and biological fluids. These molecules, which include amino acids, carbohydrates, lipids, nucleotides and their metabolites, can be detected quantitatively. Metabolomic methods, often focused on the information-rich analytical techniques of NMR spectroscopy and mass spectrometry, have potential for early diagnosis, monitoring therapy and defining disease pathogenesis in many therapeutic areas, including rheumatic diseases. By performing global metabolite profiling, also known as untargeted metabolomics, new discoveries linking cellular pathways to biological mechanisms are being revealed and are shaping our understanding of cell biology, physiology and medicine. These pathways can potentially be targeted to diagnose and treat patients with immune-mediated diseases. PMID- 26935286 TI - A comparison study of brachial blood pressure recorded with Spacelabs 90217A and Mobil-O-Graph NG devices under static and ambulatory conditions. AB - Ambulatory blood pressure monitoring is an important tool in hypertension diagnosis and management. Although several ambulatory devices exist, comparative studies are scarce. This study aimed to compare for the first time brachial blood pressure levels of Spacelabs 90217A and Mobil-O-Graph NG, under static and ambulatory conditions. We examined 40 healthy individuals under static (study A) and ambulatory (study B) conditions. In study A, participants were randomized into two groups that included blood pressure measurements with mercury sphygmomanometer, Spacelabs and Mobil-O-Graph devices with reverse order of recordings. In study B, simultaneous 6-h recordings with both devices were performed with participants randomized in two sequences of device positioning with arm reversal at 3 h. Finally, all the participants filled in a questionnaire rating their overall preference for a device. In study A, brachial systolic blood pressure (117.2+/-10.3 vs 117.1+/-9.8 mm Hg, P=0.943) and diastolic blood pressure (73.3+/-9.4 mm Hg vs 74.1+/-9.4 mm Hg, P=0.611) did not differ between Spacelabs and Mobil-O-Graph or vs sphygmomanometer (117.8+/-11.1 mm Hg, P=0.791 vs Spacelabs, P=0.753 vs Mobil-O-Graph). Similarly, no differences were found in ambulatory systolic blood pressure (117.9+/-11.4 vs 118.3+/-11.0 mm Hg, P=0.864), diastolic blood pressure (73.7+/-7.4 vs 74.7+/-8.0 mm Hg, P=0.571), mean blood pressure and heart rate between Spacelabs and Mobil-O-Graph. Correlation analyses and Bland-Altman plots showed agreement between the monitors. Overall, the participants showed a preference for the Mobil-O-Graph. Spacelabs 90217A and Mobil-O-Graph NG provide practically identical measurements during the static and ambulatory conditions in healthy individuals and can be rather used interchangeably in clinical practice. PMID- 26935287 TI - Prevalence and determinants of resistant hypertension in a sample of patients followed in Italian hypertension centers: results from the MINISAL-SIIA study program. AB - The aim of this study was to detect the prevalence of resistant hypertension (RH), allowing for adherence to appropriate lifestyle measures according to European Society of Hypertension-European Society of Cardiology (ESH-ESC) 2013 guidelines, in a sample of 1284 hypertensive subjects participating at the MINISAL-SIIA study. Hypertensive patients were recruited in 47 Italian centres, recognised by the Italian Society of Hypertension. Anthropometric indexes, blood pressure and 24-h urinary sodium (Na24h) and potassium (K24h) excretion were measured. Data on antihypertensive therapy were available for 1177 (92%) subjects. The population was divided into three groups (North, Central and South), according to their geographical location. Accounting only at the treatment criteria, the prevalence of RH was 8.2% (96/1177). RH prevalence in the southern, central and northern regions was respectively: 1, 3.8 and 3.3% (P<0.001). Participants with RH were older and showed a higher body mass index (BMI) and waist circumference compared with other subjects (P<0.005). RH risk was statistically significant (P<0.01) increased of 1.52-fold (95% confidence interval (CI):1.20-1.92) for one unit increase in s.d. score of age (11 years), and 1.50-fold (95% CI:1.22-1.83) for one unit increase in s.d. score of BMI (4.5 kg m-2). Including in RH diagnosis also the adherence to appropriate lifestyle measures, such as dietary salt restriction (Na24h <100 mmol) and normal BMI (18 25 kg m-2), RH prevalence felt respectively to 2.2% (26/1177) and 0.8% (9/1177). In conclusion in this national sample of Italian hypertensive population, among participants following both drug treatment and lifestyle modifications advises, the 'true' RH prevalence appears to be particularly low. PMID- 26935288 TI - miR-34a-5p Inhibition Alleviates Intestinal Ischemia/Reperfusion-Induced Reactive Oxygen Species Accumulation and Apoptosis via Activation of SIRT1 Signaling. AB - AIMS: Reactive oxygen species (ROS) generation and massive epithelial apoptosis are critical in the pathogenesis of intestinal ischemia/reperfusion (I/R) injury. We previously found that the Sirtuin 1 (SIRT1)-mediated antioxidant pathway was impaired in the intestine after I/R. Here, we investigate the potential role of SIRT1-targeting microRNAs (miRNAs) in regulating ROS accumulation and apoptosis in intestinal I/R, and the important role SIRT1 involved in. RESULTS: C57BL/6 mice were subjected to intestinal I/R induced by occlusion of the superior mesenteric artery followed by reperfusion. Caco-2 cells were incubated under hypoxia/reoxygenation condition to mimic I/R in vivo. We find that SIRT1 is gradually repressed during the early reperfusion, and that this repression results in intestinal ROS accumulation and apoptosis. Using bioinformatics analysis and real-time PCR, we demonstrate that miR-34a-5p and miR-495-3p are significantly increased among the 41 putative miRNAs that can target SIRT1. Inhibition of miR-34a-5p, but not miR-495-3p, attenuates intestinal I/R injury, as demonstrated by repressing p66shc upregulation, manganese superoxide dismutase repression, and the caspase-3 activation in vitro and in vivo; it further alleviates systemic injury, as demonstrated by reducing inflammatory cytokine release, attenuating lung and liver lesions, and improving survival. Interestingly, SIRT1 plays an indispensable role in the protection afforded by miR-34a-5p inhibition. INNOVATION: This study provides the first evidence of miRNAs in regulating oxidative stress and apoptosis in intestinal I/R. CONCLUSION: miR-34a-5p knockdown attenuates intestinal I/R injury through promoting SIRT1-mediated suppression of epithelial ROS accumulation and apoptosis. This may represent a novel prophylactic approach to intestinal I/R injury. Antioxid. Redox Signal. 24, 961-973. PMID- 26935289 TI - Macrophage activation and polarization modify P2X7 receptor secretome influencing the inflammatory process. AB - The activation of P2X7 receptor (P2X7R) on M1 polarized macrophages induces the assembly of the NLRP3 inflammasome leading to the release of pro-inflammatory cytokines and the establishment of the inflammatory response. However, P2X7R signaling to the NLRP3 inflammasome is uncoupled on M2 macrophages without changes on receptor activation. In this study, we analyzed P2X7R secretome in wild-type and P2X7R-deficient macrophages polarized either to M1 or M2 and proved that proteins released after P2X7R stimulation goes beyond caspase-1 secretome. The characterization of P2X7R-secretome reveals a new function of this receptor through a fine-tuning of protein release. We found that P2X7R stimulation in macrophages is able to release potent anti-inflammatory proteins, such as Annexin A1, independently of their polarization state suggesting for first time a potential role for P2X7R during resolution of the inflammation and not linked to the release of pro-inflammatory cytokines. These results are of prime importance for the development of therapeutics targeting P2X7R. PMID- 26935290 TI - Prolonged survival in pancreatic cancer patients with increased regucalcin gene expression: Overexpression of regucalcin suppresses the proliferation in human pancreatic cancer MIA PaCa-2 cells in vitro. AB - Approximately 90% of all pancreatic cancers are pancreatic ductal adenocarcinomas (PDAC). PDAC is a highly aggressive malignancy and is one of the deadliest. This poor clinical outcome is due to the prominent resistance of pancreatic cancer to drug and radiation therapies. Regucalcin plays a pivotal role as a suppressor protein in signal transduction in various types of cells including tumor tissues. We demonstrated that the prolonged survival is induced in PDAC patients with increased regucalcin gene expression using a dataset of PDAC obtained from GEO database (GSE17891) together with the clinical annotation data file. Moreover, overexpression of regucalcin with full length was demonstrated to suppress the proliferation, cell death and migration in human pancreatic cancer MIA PaCa-2 (K ras mutated) cells that possess resistance to drug and radiation therapies. Suppressive effects of regucalcin on cell proliferation and death were not seen in the cells overexpressed with regucalcin cDNA alternatively spliced variants (deleted exon 4 or deleted exon 4 and 5). Regucalcin was suggested to induce G1 and G2/M phase cell cycle arrest in MIA PaCa-2 cells. Suppressive effects of regucalcin on cell proliferation were independent of cell death. Overexpression of regucalcin was found to suppress signaling pathways including Akt, MAP kinase and SAPK/JNK, to increase the protein levels of p53, a tumor suppresser, and to decrease K-ras, c-fos and c-jun, a oncogene, by suppressing signaling pathways that are related to signaling of K-ras. Regucalcin may play a potential role as a suppressor protein in human pancreatic cancer. PMID- 26935292 TI - A laterally pi-expanded fluorone dye as an efficient near infrared fluorophore. AB - The synthesis and photophysical properties of new dibenzo[b,i]fluorone dye frameworks (BX and FBX) are described. Both BX and FBX display near-infrared sharp absorption and emission upon the addition of base due to the achievement of efficient pi-conjugation based on the small bond alternation strategy. PMID- 26935291 TI - Role of Alix in miRNA packaging during extracellular vesicle biogenesis. AB - Evidence indicates that Alix, an accessory protein of the endosomal sorting complex required for transport (ESCRT), is involved in the biogenesis of extracellular vesicles (EVs). EVs contain selected patterns of microRNAs (miRNAs or miRs); however, little is known about the mechanisms of miRNA enrichment in EVs. The aim of the present study was to evaluate whether Alix is involved in the packaging of miRNAs within EVs released by human liver stem-like cells (HLSCs). EVs released from HLSCs were enriched with miRNAs and expressed Alix and several RNA-binding proteins, including Argonaute 2 (Ago2), a member of the Argonaute family known to be involved in the transport and the processing of miRNAs. Co immunoprecipitation experiments revealed an association between Alix and Ago2. The results from RT-qPCR indicated that in the Alix/Ago2 immunoprecipitates, miRNAs were detectable. EVs were instrumental in transferring selected miRNAs from HLSCs to human endothelial cells absent in the latter cells. Alix knockdown did not influence the number of EVs released by HLSCs, but it significantly decreased miRNA expression levels in the EVs and consequently their transfer to the endothelium. Our findings indicate that Alix binds to Ago2 and miRNAs, suggesting that it plays a key role in miRNA enrichment during EV biogenesis. These results may represent a novel function of Alix, demonstrating its involvement in the EV-mediated transfer of miRNAs. PMID- 26935293 TI - The nature of inherent bactericidal activity: insights from the nanotopology of three species of dragonfly. AB - While insect wings are widely recognised as multi-functional, recent work showed that this extends to extensive bactericidal activity brought about by cell deformation and lysis on the wing nanotopology. We now quantitatively show that subtle changes to this topography result in substantial changes in bactericidal activity that are able to span an order of magnitude. Notably, the chemical composition of the lipid nanopillars was seen by XPS and synchrotron FTIR microspectroscopy to be similar across these activity differences. Modelling the interaction between bacterial cells and the wing surface lipids of 3 species of dragonflies, that inhabit similar environments, but with distinctly different behavioural repertoires, provided the relationship between surface structure and antibacterial functionality. In doing so, these principal behavioural patterns correlated with the demands for antimicrobial efficiency dictated by differences in their foraging strategies. This work now reveals a new feature in the design elegance of natural multi-functional surfaces as well providing insights into the bactericidal mechanism underlying inherently antimicrobial materials, while suggesting that nanotopology is related to the evolutionary development of a species through the demands of its behavioural repertoire. The underlying relationship between the processes of wetting, adhesion and capillarity of the lipid nanopillars and bactericidal efficiency suggests new prospects for purely mechano-responsive antibacterial surfaces. PMID- 26935294 TI - Fourth Ventricular AVM with Transdural Drainage. AB - Arteriovenous malformations (AVMs) of the fourth ventricle are exceptionally rare subtypes of brainstem AVMs. This report illustrates the case of a young man who suffered intraventricular and subarachnoid hemorrhage. Angiography depicted a fourth ventricular AVM that was supplied by branches of the right posterior inferior cerebellar artery and drained via a posterior medullary midline vein into the marginal sinus and cervical radicular and nuchal veins. The drainage pattern is highly uncommon and constitutes a particular challenge for the operative approach. PMID- 26935295 TI - Diagnostic Value of Magnetic Resonance Spectroscopy Compared with Stereotactic Biopsy of Intra-axial Brain Lesions. AB - Background Magnetic resonance spectroscopy (MRS) is usually added to conventional magnetic resonance imaging (MRI) to refine the diagnosis of different brain lesions. Stereotactic brain biopsy is a well-established method to obtain tissues for histopathologic examination. The purpose of the study is to compare the diagnostic yields of MRS and stereotactic biopsy in the characterization of brain lesions. Material and Methods A prospective study conducted on 27 consecutive patients presenting with multifocal, diffuse, as well as deeply seated intra axial brain lesions. All patients had both brain MRI and MRS prior to stereotactic biopsy. Histopathologic examinations of the obtained tissue specimens, using appropriate stains including immunostains, were performed. Results MRS diagnosed neoplastic brain lesions in 15 cases (56%) and nonneoplastic brain lesions in 12 (44%). Correlation between the preoperative diagnosis by MRS and the histopathologic diagnosis following stereotactic biopsy of either a neoplastic or nonneoplastic lesion revealed matching in 25 of 27 cases (sensitivity 88%; specificity 100%). Within the group of cases (n = 15) diagnosed preoperatively by MRS as neoplastic, 12 patients were diagnosed with brain gliomas of different grades. The MRS grading of gliomas exactly matched the histopathologic grading following stereotactic biopsy in 10 of the 12 cases (sensitivity 89%; specificity 67%). Conclusions MRS is a useful addition to the management armamentarium, providing molecular information that assists in the characterization of various brain lesions. Multivoxel MRS may increase the diagnostic yield of stereotactic biopsy by guidance to target the higher choline and lower N-acetylaspartate areas, expected to have greater tumor activity. PMID- 26935296 TI - Do Long-Term Survivor Primary Glioblastoma Patients Harbor IDH1 Mutations? AB - BACKGROUND: Approximately 3 to 16% of glioblastoma multiforme (GBM) patients are considered long-term survivors (LTS: 3+ years). OBJECTIVE: Given the improved survival conferred by IDH1 mutations and the fact that these mutations are detected in 12% of newly diagnosed GBM cases, could long-term survivorship be explained by IDH1 mutation status? Our aim was to describe GBM LTS with IDH1 mutations and explore its association with overall survival (OS). METHODS: Records of 453 newly diagnosed adult GBM patients treated at a single institution from 2004 to 2010 were reviewed retrospectively for patients who survived at least 36 months postsurgery. Descriptive statistics for clinical characteristics, treatments received, and tumor biomarkers were reported. Estimates for progression-free survival (PFS) and OS were provided. RESULTS: Forty (8.8%) LTS GBM patients were identified, with a median age of 50 years and a median preoperative Karnofsky Performance Score (KPS) of 80. Most patients underwent near-total/gross-total resection (72.5%), postoperative radiation (97.5%), and adjuvant temozolomide (95%). PFS rates at 12, 36, 48, and 72 months were 67.5%, 40%, 32.7%, and 26.2%, respectively. Median OS has not yet been reached; however, the survival rate at 48 months was 62.1%. Among 35 patients with available tumor samples, only 8 (22.9%) had IDH1 mutations. No significant difference in median PFS was found between IDH1 mutation and wild-type patients (46.6 versus 26.3 months; p =0.45). CONCLUSIONS: Less than a quarter of our patients' long-term survivorship was associated with favorable IDH1 status. Therefore, IDH1 status does not explain most of the long-term survivorship in the temozolomide era. PMID- 26935297 TI - Hemoglobins, Hemorphins, and 11p15.5 Chromosomal Region in Cancer Biology and Immunity with Special Emphasis for Brain Tumors. AB - In systemic cancers, increased hemolysis leads to extracellular hemoglobin (HB), and experimental studies have shown its provoking role on tumor growth and metastasis. However, investigations have shown that HB chains presented by tumor vascular pericytes or serum protein complexes of HB could also induce antitumor immunity, which may be harnessed to treat refractory cancers and brain tumors. Mounting recent evidence shows that expression of HBs is not restricted to erythrocytes and that HBs exist in the cells of lung and kidney, in macrophages, and in neurons and glia of the central nervous system (CNS). HBs mediate coping with hypoxia and free radical stress in normal and tumor cells, and they are increased in certain tumors including breast, lung, colon, and squamous cell cancers. Recent studies showed HBs in meningioma, in the cyst fluid of craniopharyngioma, in the cerebrospinal fluid (CSF) of pediatric patients with posterior fossa tumors, and in glioblastoma cell lines. Hemorphins, abundant brain peptides formed via HB-chain cleavage, exert opioid activity and antiproliferative and immunomodifier effects. Hence mutations in HBs may modify brain tumorigenesis via influencing hemorphins and perturbing regulations of immune surveillance and cell growth in the neuroectodermal tissues. The beta globin gene cluster resides in the chromosome region 11p15.5, harboring important immunity genes and IGF2, H19, PHLDA2/TSSC3, TRIM3, and SLC22A18 genes associated with cancers and gliomas. 11p15.5 is a prominent region subject to epigenetic regulation. Thus the beta-globin loci may exert haplotypal interactions with these. Some clues support this theory. It is well established that iron load induces liver cancer in thalassemia major; however iron load-independent associations also exist. Enhanced rates of hematologic malignancies are associated with HB Lepore, association of hemoglobin E with cholangiocarcinoma, and enhanced gastric cancer rates in the thalassemia trait. In the African Herero population, a mutant form of delta-globin is very prevalent, and this population has higher rates of pediatric brain tumors. Globins are also expressed in healthy endothelia and in tumoral vessels, indicating potential involvement in angiogenesis. Studies on HBs and their cleavage peptides in cancers and brain tumors may lead to innovative treatment strategies. PMID- 26935298 TI - Urokinase-Treated Antithrombogenic Drains and Optimized Drain Placement in Endoscopic Lumbar Decompressive Surgery. AB - Background Spinal epidural hematoma (SEH) frequently occurs after microendoscopic decompressive laminotomy (MEDL), and a drain may not be functioning sufficiently. Objective To reduce the incidence of SEH after MEDL. Methods A urokinase-treated antithrombogenic drain, which is available only with a large diameter, was reduced in diameter and used after MEDL. Magnetic resonance imaging (MRI) and computed tomography (CT) were performed 36 to 48 hours after surgery. The size of the SEH was measured by MRI, and the location of the drain tip was assessed by CT scan. After imaging, the drain was removed. Results Use of the urokinase-treated antithrombogenic drain reduced the incidence of SEH. However, the drain was not adequately placed in many cases, limiting the effect of the drainage. When the urokinase-treated antithrombogenic drain was placed contralaterally to the approach side using an unsheathed endoscope, the incidence of SEH was further reduced. Conclusions The urokinase-treated antithrombogenic drain prevented thrombus-related drain obstruction. In addition, unsheathed endoscopic contralateral placement of the drain was effective for SEH prevention. PMID- 26935299 TI - The Use of a "Double-Triple Barrel" Technique during Minimally Invasive Multilevel Tubular Laminectomy. A Technical Note. AB - This report presents a modified use of multiple tubular retractors (that limits issues related to the sequential redocking of tubular systems) that may prove helpful in cases where a minimally invasive approach is utilized for the treatment of multilevel lumbar stenosis. PMID- 26935300 TI - Arthroscopic-assisted latissimus dorsi transfer for subscapularis deficiency. AB - Few salvage procedures have been described in case of irreparable subscapularis tear and with variable outcomes. Latissimus dorsi transfer has been widely proposed as a transfer for irreparable posterio-superior rotator cuff tear with good outcomes. The anatomic feasibility of the latissimus dorsi to reconstruct the antero-superior irreparable rotator cuff tear has been suggested, but no clinical study has ever been published. We hypothesized that it was possible to use an arthroscopic-assisted latissimus dorsi transfer to reconstruct the subscapularis function. Five patients were enrolled. A 5-7-cm axillary incision was performed to release the latissimus dorsi tendon from its humeral insertion, the teres major muscle and the apex of the scapula. Afterwards, under arthroscopic control, a 7-mm-diameter tunnel was drilled at the anterior and superior part of the humeral head with an oblique inferior and posterior direction. The tubularized latissimus dorsi tendon was introduced into the tunnel and fixed with a ZipLoop on the posterior humeral cortex. The authors show overall good experience with this technique. LEVEL OF EVIDENCE: Level IV-a, case series. PMID- 26935301 TI - A multi-scale continuum model of skeletal muscle mechanics predicting force enhancement based on actin-titin interaction. AB - Although recent research emphasises the possible role of titin in skeletal muscle force enhancement, this property is commonly ignored in current computational models. This work presents the first biophysically based continuum-mechanical model of skeletal muscle that considers, in addition to actin-myosin interactions, force enhancement based on actin-titin interactions. During activation, titin attaches to actin filaments, which results in a significant reduction in titin's free molecular spring length and therefore results in increased titin forces during a subsequent stretch. The mechanical behaviour of titin is included on the microscopic half-sarcomere level of a multi-scale chemo electro-mechanical muscle model, which is based on the classic sliding-filament and cross-bridge theories. In addition to titin stress contributions in the muscle fibre direction, the continuum-mechanical constitutive relation accounts for geometrically motivated, titin-induced stresses acting in the muscle's cross fibre directions. Representative simulations of active stretches under maximal and submaximal activation levels predict realistic magnitudes of force enhancement in fibre direction. For example, stretching the model by 20 % from optimal length increased the isometric force at the target length by about 30 %. Predicted titin-induced stresses in the muscle's cross-fibre directions are rather insignificant. Including the presented development in future continuum mechanical models of muscle function in dynamic situations will lead to more accurate model predictions during and after lengthening contractions. PMID- 26935302 TI - Three-dimensional hemodynamics analysis of the circle of Willis in the patient specific nonintegral arterial structures. AB - The hemodynamic alteration in the cerebral circulation caused by the geometric variations in the cerebral circulation arterial network of the circle of Wills (CoW) can lead to fatal ischemic attacks in the brain. The geometric variations due to impairment in the arterial network result in incomplete cerebral arterial structure of CoW and inadequate blood supply to the brain. Therefore, it is of great importance to understand the hemodynamics of the CoW, for efficiently and precisely evaluating the status of blood supply to the brain. In this paper, three-dimensional computational fluid dynamics of the main CoW vasculature coupled with zero-dimensional lumped parameter model boundary condition for the CoW outflow boundaries is developed for analysis of the blood flow distribution in the incomplete CoW cerebral arterial structures. The geometric models in our study cover the arterial segments from the aorta to the cerebral arteries, which can allow us to take into account the innate patient-specific resistance of the arterial trees. Numerical simulations of the governing fluid mechanics are performed to determine the CoW arterial structural hemodynamics, for illustrating the redistribution of the blood flow in CoW due to the structural variations. We have evaluated our coupling methodology in five patient-specific cases that were diagnosed with the absence of efferent vessels or impairment in the connective arteries in their CoWs. The velocity profiles calculated by our approach in the segments of the patient-specific arterial structures are found to be very close to the Doppler ultrasound measurements. The accuracy and consistency of our hemodynamic results have been improved (to [Formula: see text] %) compared to that of the pure-resistance boundary conditions (of 43.5 [Formula: see text] 28 %). Based on our grouping of the five cases according to the occurrence of unilateral occlusion in vertebral arteries, the inter-comparison has shown that (i) the flow reduction in posterior cerebral arteries is the consequence of the unilateral vertebral arterial occlusion, and (ii) the flow rate in the anterior cerebral arteries is correlated with the posterior structural variations. This study shows that our coupling approach is capable of providing comprehensive information of the hemodynamic alterations in the pathological CoW arterial structures. The information generated by our methodology can enable evaluation of both the functional and structural status of the clinically significant symptoms, for assisting the treatment decision-making. PMID- 26935303 TI - Effect of Surface Functionalization on the Cellular Uptake and Toxicity of Nanozeolite A. AB - Extensive use of zeolite nanoparticles in many areas, including medicine, has led to the concern about an impact and possible risk of their use for human health and the environment.In our studies, we investigated an uptake, retention, and cytotoxicity of nanozeolite A (BaA) functionalized with aminopropyl or poly(ethylene glycol) (PEG) of different chain lengths using human cervical carcinoma cell line. For internalization studies, nanozeolite was labeled with (133)Ba radionuclide.The results show that in the case of PEG modification, toxicity and uptake depend on the PEG chain length. The highest toxicity has been observed for nanozeolites coated with short-length chain (Ba-silane-PEGm(MW350). Also, amine-modified nanozeolites exhibited high toxicity, while nanozeolites coated with long PEG molecules, BaA-silane-PEGm(MW1000), and BaA-silane PEGm(MW2000), as well as unmodified nanozeolite, seem to be nontoxic.In conclusion, this study shows that uptake, retention, and toxicity of nanozeolites coated with various length PEG molecules groups depend on the molecular weight of PEG. PMID- 26935304 TI - Photoconductivities in MoS2 Nanoflake Photoconductors. AB - Photoconductivities in molybdenum disulfide (MoS2) layered nanostructures with two-hexagonal crystalline structure prepared by mechanical exfoliation were investigated. The photoconductor-type MoS2 nanoflakes exhibit remarkable photoresponse under the above bandgap excitation wavelength of 532 nm at different optical intensity. The photocurrent responsivity and photoconductive gain of nanoflakes can reach, respectively, 30 AW(-1) and 103 at the intensity of 50 Wm(-2), which are several orders of magnitude higher than those of their bulk counterparts. The vacuum-enhanced photocurrent and power-independent responsivity/gain indicate a surface-controlled photoconduction mechanism in the MoS2 nanomaterial. PMID- 26935305 TI - Surfactant-free Synthesis of CuO with Controllable Morphologies and Enhanced Photocatalytic Property. AB - A green synthesis for nanoleave, nanosheet, spindle-like, rugby-like, dandelion like and flower-like CuO nanostructures (from 2D to 3D) is successfully achieved through simply hydrothermal synthetic method without the assistance of surfactant. The morphology of CuO nanostructures can be easily tailored by adjusting the amount of ammonia and the source of copper. By designing a time varying experiment, it is verified that the flower- and dandelion-like CuO structures are synthesized by the self-assembly and Ostwald ripening mechanism. Structural and morphological evolutions are investigated by X-ray diffraction (XRD), scanning electron microscopy (SEM) and UV-visible diffuse reflectance spectra. Additionally, the CuO nanostructures with different morphologies could serve as a potential photocatalyst on the photodecomposition of rhodamine B (RhB) aqueous solutions in the presence of H2O2 under visible light irradiation. PMID- 26935306 TI - Does the choice of suture material matter in anterior and posterior colporrhaphy? AB - INTRODUCTION AND HYPOTHESIS: The optimal suture material in traditional prolapse surgery is still controversial. Our aim was to investigate the effect of using sutures with rapid (RA) or slow (SA) absorption, on symptomatic recurrence after anterior and posterior colporrhaphy. METHODS: A population-based longitudinal cohort study with data from the Swedish National Quality Register for Gynecological Surgery. A total of 1,107 women who underwent primary anterior colporrhaphy and 577 women who underwent primary posterior colporrhaphy between September 2012 and September 2013 were included. Two groups in each cohort were created based on which suture material was used. Pre- and postoperative prolapse related symptoms and patient satisfaction were assessed. RESULTS: We found a significantly lower rate of symptomatic recurrence 1 year after anterior colporrhaphy in the SA suture group compared with the RA suture group, 50 out of 230 (22 %) vs 152 out of 501 (30 %), odds ratio 1.6 (CI 1.1-2.3; p = 0.01). The SA group also had a significantly higher patient satisfaction rate, 83 % vs 75 %, odds ratio 1.6 (CI 1.04-2.4), (p = 0.03). Urgency improved significantly more in the RA suture group (p < 0.001). In the posterior colporrhaphy cohort there was no significant difference between the suture materials. CONCLUSIONS: This study indicates that the use of slowly absorbable sutures decreases the odds of having a symptomatic recurrence after an anterior colporrhaphy compared with the use of rapidly absorbable sutures. However, the use of RA sutures may result in less urgency 1 year postoperatively. In posterior colporrhaphy the choice of suture material does not affect postoperative symptoms. PMID- 26935307 TI - Performance of field-effect transistors based on Nb(x)W(1-x)S2 monolayers. AB - The Schottky barrier has been detected in many field-effect transistors (FETs) based on transition metal dichalcogenide (TMD) semiconductors and has seriously affected the electronic properties of the devices. In order to decrease the Schottky barrier in WS2 FETs, novel Nb doping in WS2 monolayers has been performed and p-FETs based on Nb-doped WS2 (Nb(x)W(1-x)S2) monolayers as the active channel have been fabricated for the first time. The monolayer Nb0.15W0.85S2 p-FET has a drain current of 330 MUA MUm(-1), an impressive I(ON)/I(OFF) of 10(7), and a high effective hole mobility of ~146 cm(2) V(-1) s( 1). The novel Nb doping in monolayer WS2 has eliminated the ambipolar behavior and reduced the Schottky barrier in WS2 FETs. The reduction of the Schottky barrier is ascribed to the hybridization between W 5d, Nb 4d and S 3p states near the EF and to the enhancement of the metallization of the contact between the Pd metal and monolayer Nb(x)W(1-x)S2 after Nb doping. PMID- 26935308 TI - "I don't know" My Cancer Risk: Implications for Health Behavior Engagement. AB - BACKGROUND: Many people report uncertainty about their cancer risk. We examined whether such uncertainty was related to cancer prevention and detection behaviors. METHODS: National Health Interview Survey data from 2005 to 2010 were analyzed. Participants reported their perceived risk for colorectal and breast cancers. Responses were coded as "valid" (i.e., less/as/more likely than average) or "don't know." RESULTS: In bivariate analyses for both cancer sites and survey years, "don't know" responders (DKR) engaged in less physical activity than "valid" responders (p < 0.05). DKR had lower mammography adherence than "valid" responders in 2005 and lower colorectal screening adherence in 2010 (p < 0.05). DKR had marginally lower colorectal screening adherence and fruit/vegetable consumption in 2005 (p < 0.06). Multivariable models indicated that the DKR behavior relationship could be largely accounted for by education. CONCLUSION: Interventions that help people understand their cancer risk may provide particular benefit to people with low education and might consequently reduce health disparities. PMID- 26935309 TI - Goal Navigation, Approach-Oriented Coping, and Adjustment in Young Men with Testicular Cancer. AB - BACKGROUND: Cancer can challenge important life goals for young adult survivors. Poor goal navigation skills might disrupt self-regulation and interfere with coping efforts, particularly approach-oriented attempts. Two studies are presented that investigated relationships among goal navigation processes, approach-oriented coping, and adjustment (i.e., social, emotional, and functional well-being) in separate samples of young adults with testicular cancer. METHODS: In study 1, in-depth interviews (N = 21) were analyzed using thematic analysis to understand experiences of goal pursuit following cancer. In study 2, 171 men completed measures of goal navigation, coping, and adjustment to cancer. RESULTS: In study 1, three prominent themes emerged: goal clarification, goal engagement and disengagement, and responses to disrupted goals. Regression analyses in study 2 revealed that goal navigation skills were positively associated with emotional (B = .35, p < .001), social (B = .24, p < .01), and functional (B = .28, p < .001) well-being, as was approach-oriented coping (B = .22, p < .01; B = .32, p < .001; B = .26, p < .001, respectively). Goal navigation moderated associations between approach-oriented coping and well-being, such that those with low goal navigation ability and low approach-oriented coping reported lower well-being. CONCLUSIONS: Goal navigation skills and approach-oriented coping have unique and interactive relationships with adjustment to testicular cancer. They likely represent important independent targets for intervention, and goal navigation skills might also buffer the negative consequences of low use of approach oriented coping. PMID- 26935312 TI - Photoswitchable basicity through the use of azoheteroarenes. AB - Azoheteroarene photoswitches offer functional advantages over their more conventional azobenzene counterparts by virtue of their heteroaromatic ring(s). Here we report that azobis(2-imidazole) functions as a photoswitchable base due to the additional proton stabilisation that is possible in the protonated Z isomer, facilitated by the basic imidazole nitrogens. This thermodynamic difference in stability corresponds to a 1.3 unit difference in pK(a) values between the E and Z isomers. This pK(a) difference can be used to reversibly control solution pH. PMID- 26935310 TI - Stigma Predicts Treatment Preferences and Care Engagement Among Veterans Affairs Primary Care Patients with Depression. AB - BACKGROUND: Whereas stigma regarding mental health concerns exists, the evidence for stigma as a depression treatment barrier among patients in Veterans Affairs (VA) primary care (PC) is mixed. PURPOSE: This study tests whether stigma, defined as depression label avoidance, predicted patients' preferences for depression treatment providers, patients' prospective engagement in depression care, and care quality. METHODS: We conducted cross-sectional and prospective analyses of existing data from 761 VA PC patients with probable major depression. RESULTS: Relative to low-stigma patients, those with high stigma were less likely to prefer treatment from mental health specialists. In prospective controlled analyses, high stigma predicted lower likelihood of the following: taking medications for mood, treatment by mental health specialists, treatment for emotional concerns in PC, and appropriate depression care. CONCLUSIONS: High stigma is associated with lower preferences for care from mental health specialists and confers risk for minimal depression treatment engagement. PMID- 26935311 TI - Temporal patterns of sitting at work are associated with neck-shoulder pain in blue-collar workers: a cross-sectional analysis of accelerometer data in the DPHACTO study. AB - BACKGROUND: Our aim was to examine the extent to which temporal patterns of sitting during occupational work and during leisure-time, assessed using accelerometry, are associated with intense neck-shoulder pain (NSP) in blue collar workers. METHODS: The population consisted of 659 Danish blue-collar workers. Accelerometers were attached to the thigh, hip, trunk and upper dominant arm to measure sitting time and physical activity across four consecutive days. Temporal sitting patterns were expressed separately for work and leisure by the proportion of total time spent sitting in brief bursts (0-5 min), moderate (>5-20 min) and prolonged (>20 min) periods. The peak NSP intensity during the previous 3 months was assessed using a numerical rating scale (range 0-10) and dichotomized into a lower (<=4) and higher (>4) NSP score. Logistic regression analyses with multiple adjustments for individual and occupational factors were performed to determine the association between brief, moderate and prolonged sitting periods, and NSP intensity. RESULTS: Time in brief bursts of occupational sitting was negatively associated with NSP intensity (adjusted OR 0.68, 95 % CI 0.48-0.98), while time in moderate periods of occupational sitting showed a positive association with NSP (adjusted OR 1.32, 95 % CI 1.04-1.69). Time in prolonged periods of occupational sitting was not associated with NSP (adjusted OR 0.78, 95 % CI 0.78-1.09). We found no significant association between brief, moderate or prolonged sitting periods during leisure, and NSP. CONCLUSION: Our findings indicate that the association between occupational sitting time and intense NSP among blue-collar workers is sensitive to the temporal pattern of sitting. PMID- 26935313 TI - A Combined Approach To Crooked Nose Deformity. AB - BACKGROUND: Crooked nose deformity is a complex anatomical deformity; therefore, repair remains a challenge. Here, we introduce a new technique for crooked nose deformity repair. MATERIALS AND METHODS: Twenty-two patients underwent intraoperative evaluations and measurements, followed by surgery using the open rhinoplasty technique. Our method involves three major steps. First is the creation of an asymmetric medial oblique osteotomy using piezoelectric ultrasonic surgery and double lateral osteotomies, wherein the asymmetric bony ascending part of the maxillary bone at the base of the nasal vault is fractured, pushed in, and delivered to the face. Second is septoplasty with L-strut preservation. The L-strut is removed as a 1-cm block caudally from the septal stump of the keystone area. A (or double) fabricated batten cartilage graft is placed on the concave side of the deviation and sutured to cover the septal stump. The L-strut is then replaced and sutured on the batten graft, redirecting the septum toward the midline. Third is an overlapping cruroplasty on the side of the long asymmetrical lower lateral cartilage to equalize both wings and correct tip deviation. RESULTS: Our new technique was effective for the treatment of crooked nose deformity. CONCLUSIONS: Our technique of K-stone batten plasty with delivery to the face and overlapping cruroplasty may be an effective surgical method for crooked nose deformity. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 26935314 TI - Total Abdominal Wall Reconstruction with Component Separation, Reinforcement, and Vertical Abdominoplasty in Patients with Complex Ventral Hernias. AB - Large complex ventral hernias act as tissue expanders for skin and subcutaneous fat. The purpose of this study is to evaluate outcomes of total abdominal wall reconstruction with component separation, posterior reinforcement, and vertical abdominoplasty in patients with large complex ventral hernias. Between 2010 and 2014, 58 patients underwent total abdominal wall reconstruction with component separation, intra-abdominal reinforcement, and vertical abdominoplasty. Between 2010 and 2012, patients underwent the conventional technique of component separation, while a perforator-preserving technique was performed during 2013 and 2014. Reinforcement material used was either synthetic mesh in clean cases or biologic mesh if contamination was present. All of the excessive skin and subcutaneous fat was removed in a vertical fashion. Data were analyzed with Mann Whitney's U test or Fisher's exact test, as indicated. There were 27 moderately complex and 31 majorly complex hernias. Mean hernia size was 16 * 12 cm. The mean size of the removed skin island was 21 * 12 cm. Patients with contamination during the repair had longer in-hospital stays. Overall the local wound complication rate was 24 %, and was lower with the perforator-preserving technique compared to the conventional technique of component separation (11 vs. 48 %; OR 0.13, CI 0.03-0.5; p = 0.003). The overall postoperative morbidity rate was higher in the presence of contamination, and in patients with lower preoperative serum albumin levels. Mean total follow-up was 14 months with a 1 year recurrence-free survival of 96 %. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 26935315 TI - Highlights from Faraday Discussion 185: Supramolecular Photochemistry, Cambridge, 2015. PMID- 26935316 TI - The relative merits of therapies being developed to tackle inappropriate ('self' directed) complement activation. AB - The complement system is an enzyme cascade that helps defend against infection. Many complement proteins occur in serum as inactive enzyme precursors or reside on cell surfaces. Complement components have many biologic functions and their activation can eventually damage the plasma membranes of cells and some bacteria. Although a direct link between complement activation and autoimmune diseases has not been found, there is increasing evidence that complement activation significantly contributes to the pathogenesis of a large number of inflammatory diseases that may have autoimmune linkage. The inhibition of complement may therefore be very important in a variety of autoimmune diseases since their activation may be detrimental to the individual involved. However, a complete and long-term inhibition of complement may have some contra side effects such as increased susceptibility to infection. The site of complement activation will, however, determine the type of inhibitor to be used, its route of application and dosage level. Compared with conventional drugs, complement inhibitors may be the best option for treatment of autoimmune diseases. The review takes a critical look at the relative merits of therapies being developed to tackle inappropriate complement activation that are likely to result in sporadic autoimmune diseases or worsen already existing one. It covers the complement system, general aspects of complement inhibition therapy, therapeutic strategies and examples of complement inhibitors. It concludes by highlighting on the possibility that a better inhibitor of complement activation when found will help provide a formidable treatment for autoimmune diseases as well as preventing one. PMID- 26935318 TI - In silico analyses for molecular genetic mechanism and candidate genes in patients with Alzheimer's disease. AB - This study aimed to identify candidate genes and explore the molecular pathogenesis of Alzheimer's disease (AD). Exon microarray data composed by of three human entorhinal cortex samples of AD patients and three non-demented controls (NDC) were analyzed, then expression profile data were preprocessed with the Oligo package and differentially expressed genes (DEGs) were identified by limma package in R/Bioconductor. In addition, protein-protein interaction (PPI) network was predicted and constructed using the STRING database. Finally, gene ontology (GO)-biological processes (BP) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways enriched by DEGs were recognized. A total of 124 up regulated and 218 down-regulated genes were identified. TGF-beta-activated kinase 1/MAP3K7 binding protein 2 (TAB 2) and chromogranin B (secretogranin 1) (CHGB) were the significantly up- and down-regulated genes, respectively. In addition, DEGs of DnaJ (Hsp40) homolog, subfamily B, member 1 (DNAJB1) and heat shock 70 kDa protein 1A (HSPA1A) were in the up-regulated network, while synaptophysin (SYP) and somatostatin (SST) were in the down-regulated network. Furthermore, the up-regulated genes were enriched in GO-BP terms of protein stimulus, unfolding and organic substance, etc., and pathways of ECM-receptor interaction, etc. The down-regulated genes were mainly associated with nerve-related transmission and neuroactive substances transportation. Protein folding abnormality and altered synaptic transmission could have a synergistic effect on the pathomechanism of AD. DEGs including DNAJB1 and HSPA1A may be involved in both the processes, while CHGB, SYP and SST may be important for the regulation of synaptic transmission to contribute to the progress and development of AD. PMID- 26935317 TI - Discovery of a tyrosine-rich sporocyst wall protein in Eimeria tenella. AB - BACKGROUND: Eimeria is an important genus of apicomplexan parasites. A defining feature of these parasites is the oocyst, which is transmitted into the environment via the faeces of definitive hosts. The oocyst wall contains cross linked, tyrosine-rich proteins and protects eight infectious sporozoites, housed in pairs within a second walled structure, the sporocyst. The biochemical basis for sporocyst wall formation is not known. FINDINGS: Here, we report the discovery of a novel tyrosine-rich protein, EtSWP1, in Eimeria tenella. Like the tyrosine-rich proteins of the oocyst wall, EtSWP1 is an intrinsically disordered protein with the tyrosine residues concentrated in a specific region of the protein, located immediately following the region of intrinsic disorder. We engineered E. tenella to express mCherry-tagged EtSWP1 and showed that the tagged protein localises specifically to sporocyst walls, indicating that the biochemistry of sporocyst wall assembly is analagous to that of oocyst walls. CONCLUSIONS: Tyrosine-rich proteins are known to be key components of the oocyst wall and we now demonstrate, using gene and protein analyses combined with genetic manipulation, that a novel tyrosine-rich protein is specific for the sporocyst wall. This finding is important because it shows that the biochemistry of these two distinct walls is similar and, hence, brings targeted disruption of sporulation and, therefore, potential neutralisation of oocysts in the environment, a step closer. PMID- 26935319 TI - Minor blunt cervical spine trauma associated with esophageal perforation and epidural empyema. PMID- 26935320 TI - How measurement artifacts affect cerebral autoregulation outcomes: A technical note on transfer function analysis. AB - Cerebral autoregulation (CA) is the mechanism that aims to maintain adequate cerebral perfusion during changes in blood pressure (BP). Transfer function analysis (TFA), the most reported method in literature to quantify CA, shows large between-study variability in outcomes. The aim of this study is to investigate the role of measurement artifacts in this variation. Specifically, the role of distortion in the BP and/or CBFV measurementon TFA outcomes was investigated. The influence of three types of artifacts on TFA outcomes was studied: loss of signal, motion artifacts, and baseline drifts. TFA metrics of signals without the simulated artifacts were compared with those of signals with artifacts. TFA outcomes scattered highly when more than 10% of BP signal or over 8% of the CBFV signal was lost, or when measurements contained one or more artifacts resulting from head movement. Furthermore, baseline drift affected interpretation of TFA outcomes when the power in the BP signal was 5 times the power in the LF band. In conclusion, loss of signal in BP and loss in CBFV, affects interpretation of TFA outcomes. Therefore, it is vital to validate signal quality to the defined standards before interpreting TFA outcomes. PMID- 26935321 TI - Erratum to: 'Conditional robustness analysis for fragility discovery and target identification in biochemical networks and in cancer systems biology'. PMID- 26935322 TI - Experimental quantification of useful and parasitic absorption of light in plasmon-enhanced thin silicon films for solar cells application. AB - A combination of photocurrent and photothermal spectroscopic techniques is applied to experimentally quantify the useful and parasitic absorption of light in thin hydrogenated microcrystalline silicon (MUc-Si:H) films incorporating optimized metal nanoparticle arrays, located at the rear surface, for improved light trapping via resonant plasmonic scattering. The photothermal technique accounts for the total absorptance and the photocurrent signal accounts only for the photons absorbed in the MUc-Si:H layer (useful absorptance); therefore, the method allows for independent quantification of the useful and parasitic absorptance of the plasmonic (or any other) light trapping structure. We demonstrate that with a 0.9 MUm thick absorber layer the optical losses related to the plasmonic light trapping in the whole structure are insignificant below 730 nm, above which they increase rapidly with increasing illumination wavelength. An average useful absorption of 43% and an average parasitic absorption of 19% over 400-1100 nm wavelength range is measured for MUc-Si:H films deposited on optimized self-assembled Ag nanoparticles coupled with a flat mirror (plasmonic back reflector). For this sample, we demonstrate a significant broadband enhancement of the useful absorption resulting in the achievement of 91% of the maximum theoretical Lambertian limit of absorption. PMID- 26935323 TI - Influence of hepatic load from far-off dry period to early postpartum period on the first postpartum ovulation and accompanying subsequent fertility in dairy cows. AB - The aim of the present study was to investigate nutritional and metabolic parameters during the dry and early postpartum periods of ovulatory and anovulatory cows, as well as their postpartum reproductive performance. Blood samples from 20 multiparous Holstein cows were collected once a week from the far off dry period to 3 weeks postpartum. Early postpartum (0-3 weeks) ovulation was confirmed using plasma progesterone concentration profiles, and cows were considered ovulatory if they had resumed luteal activity by this point (n = 9), whereas cows that had not were considered anovulatory (n = 11). Data from the ovulatory and anovulatory cows were analyzed separately for the far-off dry period (7-4 weeks prepartum), the close-up dry period (3-1 weeks prepartum), and the early postpartum period (0-3 weeks). Serum gamma-glutamyl transpeptidase activity (far-off, P = 0.065; close-up, P = 0.051; and early postpartum, P = 0.030) and aspartate aminotransferase (close-up, P = 0.050 and early postpartum, P = 0.087) activities were higher in anovulatory than in ovulatory cows. The days open period was longer (P = 0.019) in anovulatory than in ovulatory cows, and the number of artificial inseminations per conception (P = 0.025) was greater. In conclusion, we found that continuously high gamma-glutamyl transpeptidase activities in serum, which may be induced by liver disorders, prevent subsequent ovulation and affect subsequent fertility, even if cows obtain sufficient ovulation-related energy and beta-carotene. PMID- 26935324 TI - Is passive transmission of non-viral vectors through artificial insemination of sperm-DNA mixtures sufficient for chicken transgenesis? AB - DNA uptake in the post-acrosomal region of the spermatozoa takes place exclusively in immotile spermatozoa that are naturally unable to fertilize eggs. The present study aimed to assess whether passive transmission of non-viral vectors to the surrounding areas of chicken embryos could be an alternate mechanism in chicken sperm-mediated gene transfer. First, the presence of nucleases in rooster seminal plasma was evaluated. Semen ejaculates from five roosters were centrifuged and the supernatant was incubated with pBL2 for 1 h. A robust nuclease cocktail was detected in the rooster semen. To overcome these nucleases, plasmid-TransIT combinations were incubated with semen for 1 h. Incubation of exogenous DNA in the lipoplex structure could considerably bypass the semen nuclease effect. Then, intravaginal insemination of 1 * 10(9) sperm mixed with lipoplexes (40 ug pBL2:40 ul TransIT) was carried out in 15 virgin hens. Neither the epithelial tissue from the inseminated female reproductive tracts nor the produced embryos following artificial insemination showed the transgene. To remove any bias in the transgene transmission possibility, the plasmid-TransIT admixture was directly injected in close vicinity of the embryos in newly laid eggs. Nonetheless, none of the produced fetuses or chicks carried the transgene. In conclusion, the results of the present study revealed a nuclease admixture in rooster seminal plasma, and passive/active transmission of the non-viral vector into close vicinity of the chicken embryo was inefficient for producing transgenic chicks. PMID- 26935325 TI - Greenhouse gas emission and microbial community dynamics during simultaneous nitrification and denitrification process. AB - This study evaluates greenhouse gas emission and the microbial community dynamics during simultaneous nitrification and denitrification (SND) process. Based on CO2 equivalents, the SND reactor released 4.28g of greenhouse gases each cycle. 2.91% of the incoming nitrogen load was emitted as N2O. The CO2 and N2O emissions mainly occurred in the aerobic stage and CH4 emissions were consistently near zero. Extracellular polymeric substance (EPS) contents in activated sludge increased during start-up the SND process. High-throughput sequencing showed increases in bacterial species richness, leading to changes in EPS content and composition observed using 3D-EEM fluorescence spectra. For denitrifying bacteria, the relative abundance of Pseudomonas significantly increased during the SND process, while Paracoccus decreased significantly. For phosphorus accumulating bacteria, the relative abundance of Rhodocyclaceae also significantly increased. The relative abundance of other functional microbes, such as Nitrosomonadaceae (ammonia oxidizer), Nitrospirales (nitrite oxidizer) and Planctomyces (anammox) decreased significantly during the SND process. PMID- 26935326 TI - Effect of selenite on the morphology and respiratory activity of Phanerochaete chrysosporium biofilms. AB - The temporal and spatial effects of selenite (SeO3(2-)) on the physical properties and respiratory activity of Phanerochaete chrysosporium biofilms, grown in flow-cell reactors, were investigated using oxygen microsensors and confocal laser scanning microscopy (CLSM) imaging. Exposure of the biofilm to a SeO3(2-) load of 1.67mgSeL(-1)h(-1) (10mgSeL(-1) influent concentration), for 24h, resulted in a 20% reduction of the O2 flux, followed by a ~10% decrease in the glucose consumption rate. Long-term exposure (4days) to SeO3(2-) influenced the architecture of the biofilm by creating a more compact and dense hyphal arrangement resulting in a decrease of biofilm thickness compared to fungal biofilms grown without SeO3(2-). To the best of our knowledge, this is the first time that the effect of SeO3(2-) on the aerobic respiratory activity on fungal biofilms is described. PMID- 26935329 TI - Evaluating the Validity of the Client Evaluation of Motivational Interviewing Scale in a Brief Motivational Intervention for College Student Drinkers. AB - The Client Evaluation of Motivational Interviewing scale (CEMI) is a measure for assessing client perceptions of clinicians' use of motivational interviewing (MI). This study explored the factorial, convergent and predictive validity of the CEMI with a sample of 137 college students who completed a brief motivational intervention for alcohol harm reduction. A two factor structure was confirmed, supporting previous findings of relational and technical subscales. The CEMI technical subscale partially mediated an increase in readiness to change drinking, while the relational subscale did not. Higher scores on CEMI technical subscale predicted higher scores on the tasks, bond and goals subscales of the Working Alliance Inventory while higher scores on the CEMI relationship subscale predicted an increase in the goals subscale. Finally, the correlations between the CEMI subscales and observer-rated MI spirit score and MI adherent and non adherent behavioral counts were in the expected directions but did not reach statistical significance. Further revision and evaluation of the CEMI is recommended. Clinical, training and research implications are provided. PMID- 26935327 TI - Exome screening to identify loss-of-function mutations in the rhesus macaque for development of preclinical models of human disease. AB - BACKGROUND: Exome sequencing has been utilized to identify genetic variants associated with disease in humans. Identification of loss-of-function mutations with exome sequencing in rhesus macaques (Macaca mulatta) could lead to valuable animal models of genetic disease. Attempts have been made to identify variants in rhesus macaques by aligning exome data against the rheMac2 draft genome. However, such efforts have been impaired due to the incompleteness and annotation errors associated with rheMac2. We wished to determine whether aligning exome reads against our new, improved rhesus genome, MacaM, could be used to identify high impact, loss-of-function mutations in rhesus macaques that would be relevant to human disease. RESULTS: We compared alignments of exome reads from four rhesus macaques, the reference animal and three unrelated animals, against rheMac2 and MacaM. Substantially more reads aligned against MacaM than rheMac2. We followed the Broad Institute's Best Practice guidelines for variant discovery which utilizes the Genome Analysis Toolkit to identify high impact mutations. When rheMac2 was used as the reference genome, a large number of apparent false positives were identified. When MacaM was used as the reference genome, the number of false positives was greatly reduced. After examining the variant analyses conducted with MacaM as reference genome, we identified two putative loss-of-function mutations, in the heterozygous state, in genes related to human health. Sanger sequencing confirmed the presence of these mutations. We followed the transmission of one of these mutations (in the butyrylthiocholine gene) through three generations of rhesus macaques. Further, we demonstrated a functional decrease in butyrylthiocholinesterase activity similar to that observed in human heterozygotes with loss-of-function mutations in the same gene. CONCLUSIONS: The new MacaM genome can be effectively utilized to identify loss-of function mutations in rhesus macaques without generating a high level of false positives. In some cases, heterozygotes may be immediately useful as models of human disease. For diseases where homozygous mutants are needed, directed breeding of loss-of-function heterozygous animals could be used to create rhesus macaque models of human genetic disease. The approach we describe here could be applied to other mammals, but only if their genomes have been improved beyond draft status. PMID- 26935330 TI - SAMe-TT2R2 Score Does Not Predict Time in Therapeutic Range in Atrial Fibrillation Patients After Hospitalization for Acute Decompensated Heart Failure. PMID- 26935328 TI - Mental health clinician attitudes to the provision of preventive care for chronic disease risk behaviours and association with care provision. AB - BACKGROUND: Preventive care for chronic disease risk behaviours by mental health clinicians is sub-optimal. Little research has examined the association between clinician attitudes and such care delivery. This study aimed to explore: i) the attitudes of a multi-disciplinary group of community mental health clinicians regarding their perceived role, perception of client interest, and perceived self efficacy in the provision of preventive care, ii) whether such attitudes differ by professional discipline, and iii) the association between these attitudes and clinician provision of such care. METHOD: A telephone survey was conducted with 151 Australian community mental health clinicians regarding their attitudes towards provision of assessment, advice and referral addressing smoking, nutrition, alcohol, and physical activity, and their reported provision of such care. Logistic regression was used to examine the association between attitudes and care delivery, and attitudinal differences by professional discipline. RESULTS: Most clinicians reported that: their manager supported provision of preventive care; such care was part of their role; it would not jeopardise their practitioner-client relationships, clients found preventive care acceptable, and that they had the confidence, knowledge and skills to modify client health behaviours. Half reported that clients were not interested in changing their health behaviours, and one third indicated that the provision of preventive care negatively impacted on time available for delivery of acute care. The following attitudes were positively associated with the provision of preventive care: role congruence, client interest in change, and addressing health risk behaviours will not jeopardise the client-clinician relationship. CONCLUSIONS: Strategies are required to translate positive attitudes to improved client care and address attitudes which may hinder the provision of preventive care in community mental health. PMID- 26935331 TI - The dynamics of electric powered wheelchair sideways tips and falls: experimental and computational analysis of impact forces and injury. AB - BACKGROUND: To reduce the occurrence of wheelchair falls and to develop effective protection systems, we aimed to quantify sideways tip and fall dynamics of electric power wheelchairs (EPWs). We hypothesized that driving speed, curb height and angle of approach would affect impact forces and head injury risk for wheelchair riders. We further expected that fall dynamics and head injury risk would be greater for unrestrained riders compared to restrained riders. METHODS: Sideways wheelchair tip and fall dynamics were reconstructed using a remotely operated rear wheel drive EPW and a Hybrid III test dummy driving at different approach angles (5 to 63 degrees ) over an adjustable height curb (0.30 to 0.41 m) at speeds of 0.6-1.5 m/s. Rigid body dynamics models (Madymo, TASS International, Livonia, MI) were developed in parallel with the experiments to systematically study and quantify the impact forces and the sideways tip or fall of an EPW user in different driving conditions. RESULTS: Shallower approach angles (25 degrees ) (p < 0.05) and higher curbs (0.4 m) (p < 0.05) were the most significant predictors of tipping for restrained passengers. Unrestrained passengers were most affected by higher curbs (0.4 m) (p < 0.005) and fell forward from the upright wheelchair when the approach angle was 60 degrees . Head impact forces were greater in unrestrained users (6181 +/- 2372 N) than restrained users (1336 +/- 827 N) (p = 0.00053). Unrestrained users had significantly greater head impact severities than restrained users (HIC = 610 +/- 634 vs HIC = 29 +/- 38, p = 0.00013) and several tip events resulted in HICs > 1000 (severe head injury) in unrestrained users. CONCLUSIONS: Sideways tips and forward falls from wheelchairs were most sensitive to curb height and approach angle but were not affected by driving speed. Sideways tips and falls resulted in impact forces that could result in concussions or traumatic brain injury and require injury prevention strategies. Seat belts eliminated the risk of falling from an upright chair and reduced head impact forces in sideways wheelchair tips in this study; however, their use must be considered within the ethical and legal definitions of restraints. PMID- 26935333 TI - Advancements in CAD/CAM technology: Options for practical implementation. AB - PURPOSE: The purpose of this review is to present a comprehensive review of the current published literature investigating the various methods and techniques for scanning, designing, and fabrication of CAD/CAM generated restorations along with detailing the new classifications of CAD/CAM technology. STUDY SELECTION: I performed a review of a PubMed using the following search terms "CAD/CAM, 3D printing, scanner, digital impression, and zirconia". The articles were screened for further relevant investigations. The search was limited to articles written in English, published from 2001 to 2015. In addition, a manual search was also conducted through articles and reference lists retrieved from the electronic search and peer-reviewed journals. RESULTS: CAD/CAM technology has advantages including digital impressions and models, and use of virtual articulators. However, the implementation of this technology is still considered expensive and requires highly trained personnel. Currently, the design software has more applications including complete dentures and removable partial denture frameworks. The accuracy of restoration fabrication can be best attained with 5 axes milling units. The 3D printing technology has been incorporated into dentistry, but does not include ceramics and is limited to polymers. In the future, optical impressions will be replaced with ultrasound impressions using ultrasonic waves, which have the capability to penetrate the gingiva non invasively without retraction cords and not be affected by fluids. CONCLUSION: The coming trend for most practitioners will be the use of an acquisition camera attached to a computer with the appropriate software and the capability of forwarding the image to the laboratory. PMID- 26935332 TI - Knockout of fractalkine receptor Cx3cr1 does not alter disease or microglial activation in prion-infected mice. AB - Microglial activation is a hallmark of the neuroimmunological response to Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and prion disease. The CX3C chemokine axis consists of fractalkine (CX3CL1) and its receptor (CX3CR1); these are expressed by neurons and microglia respectively, and are known to modulate microglial activation. In prion-infected mice, both Cx3cr1 and Cx3cl1 are altered, suggesting a role in disease. To investigate the influence of CX3C axis signalling on prion disease, we infected Cx3cr1 knockout (Cx3cr1-KO) and control mice with scrapie strains 22L and RML. Deletion of Cx3cr1 had no effect on development of clinical signs or disease incubation period. In addition, comparison of brain tissue from Cx3cr1-KO and control mice revealed no significant differences in cytokine levels, spongiosis, deposition of disease associated prion protein or microglial activation. Thus, microglial activation during prion infection did not require CX3C axis signalling. PMID- 26935334 TI - Safety and efficacy of prolonged levofloxacin inhalation solution (APT-1026) treatment for cystic fibrosis and chronic Pseudomonas aeruginosa airway infection. AB - BACKGROUND: Levofloxacin inhalation solution (LIS) is the first aerosolized fluoroquinolone licensed for treatment of patients with cystic fibrosis (CF) and chronic Pseudomonas aeruginosa lung infection. This study evaluated the safety and efficacy of extended LIS treatment. METHODS: Patients completing a multinational, randomized study comparing LIS and tobramycin inhalation solution (TIS) were enrolled in an open-label extension in which all patients received three additional cycles of 28days of LIS 240mg twice daily followed by 28days off drug. Endpoints included mean relative change in percent predicted forced expiratory volume in 1s (FEV1), time to pulmonary exacerbation, and patient reported quality of life. RESULTS: Extended treatment with LIS in 88 patients was well tolerated with no new safety signals and evidence of positive effects on FEV1 and quality of life. CONCLUSION: Patients receiving extended LIS treatment continued to show favorable efficacy with no additional safety concerns. PMID- 26935335 TI - Acarbose reduces body weight irrespective of glycemic control in patients with diabetes: results of a worldwide, non-interventional, observational study data pool. AB - OBJECTIVE: The objective of this study is to examine the effect of acarbose, an alpha-glucosidase inhibitor, on body weight in a real-life setting by pooling data from post-marketing surveillance. METHODS: Data from 10 studies were pooled (n=67,682) and the effect of acarbose on body weight was analysed taking into account baseline body weight, glycemic parameters and other baseline characteristics. RESULTS: The mean relative reduction in body weight was 1.45 +/- 3.24% at the 3-month visit (n=43,510; mean baseline 73.4 kg) and 1.40 +/- 3.28% at the last visit (n=54,760; mean baseline 73.6 kg) (both p<0.0001). These reductions were dependent on baseline body weight (overweight: -1.33 +/- 2.98% [n=13,498; mean baseline 71.6 kg]; obese: -1.98 +/- 3.40% [n=20,216; mean baseline 81.3 kg]). When analysed by baseline glycemic parameter quartiles, the reduction was independent of fasting plasma glucose (FPG), postprandial plasma glucose (PPG), glycated hemoglobin (HbA1c) and postprandial glucose excursion (PPGE). A bivariate analysis of covariance identified female sex, South East Asian and East Asian ethnicity, younger age, higher body mass index, short duration of diabetes, and no previous treatment as factors likely to impact positively on body weight reduction with acarbose. CONCLUSIONS: This post-hoc analysis showed that acarbose treatment reduces body weight independent of glycemic control status but dependent on baseline body weight. PMID- 26935336 TI - Sociocultural context for sex differences in addiction. AB - In this review, we discuss the importance of investigating both sex and gender differences in addiction and relapse in studies of humans and in animal models. Addiction is both a cultural and biological phenomenon. Sex and gender differences are not solely determined by our biology, nor are they entirely cultural; they are interactions between biology and the environment that are continuously played out throughout development. Lessons from the historical record illustrate how context and attitudes affect the way that substance use in men and women is regarded. Finally, cultural and environmental influences may differentially affect men and women, and affect how they respond to drugs of abuse and to treatment protocols. We recommend that both animal models and clinical research need to be developed to consider how contextual and social factors may influence the biological processes of addiction and relapse differentially in men and women. PMID- 26935337 TI - Assessment of the sensitizing capacity and allergenicity of enzymatic cross linked arginine kinase, the crab allergen. AB - SCOPE: The enzymatic cross-linking of an allergen by food processing may alter its sensitization potential. In this study, the IgE-binding activity and allergenicity of cross-linked thermal polymerized arginine kinase (CL-pAK) were investigated. METHODS AND RESULTS: The IgE-binding activity and stability of CL pAK were analyzed by immunological and proteomics methods. The sensitization and potency to induce oral tolerance of CL-pAK were tested using in vivo assays and a cell model. According to the results of inhibition of ELISA, the half inhibitory concentration of AK after cross-linking changed from 1.13 to 228.36 MUg/mL. The results of in vitro digestion demonstrated that CL-pAK showed more resistance to gastrointestinal digestion than native AK. Low allergenicity and capacity to induce oral tolerance in mice were shown by the sera levels of AK-specific antibodies and T-cell cytokine production. Exposure of RBL-2H3 cells to CL-pAK compared with AK, resulted in lower levels of mast degranulation and histamine. CONCLUSION: Enzymatic cross-linking with thermal polymerization of AK by tyrosinase and caffeic acid had high potential in mitigating IgE-binding activity and allergenicity, which were influenced by altering the molecular and immunological features of the shellfish protein. PMID- 26935338 TI - Mucin 1 and poly I:C activates dendritic cells and effectively eradicates pituitary tumors as a prophylactic vaccine. AB - Pituitary tumors are the most common type of cancer within the central nervous system. In the present study, the expression levels of mucin 1 (Muc1) were examined in invasive and non-invasive pituitary tumor samples, and the results of immunohistochemical staining and Western blot analysis demonstrated marked positive expression of Muc1. In addition, Muc1 + polyinosinic:polycytidylic acid (poly I:C) was found to stimulate the expression levels of the surface molecules cluster of differentiation (CD)40, CD83 and CD80, and HLA-DRm and decreased the expression of CD14 in the dendritic cells, determined using fluorescence activated cell sorting. The secretions of interleukin (IL)-6, tumor necrosis factor-alpha and IL-1beta cytokines were also significantly induced, in a dose dependent manner. In in vivo experiments, a higher percentage of CD3+CD4+ T lymphocytes was detected, and the levels of interferon-gamma and IL-2 in the splenocytes were also upregulated. Furthermore, the combination treatment of Muc1 with poly I:C increased anti-Muc1 IgM and anti-Muc1 IgG titers, and altered the balance of IgG2a and IgG1, all of which increased the T helper (Th)1 polarized immune response. Thus, the tumor antigen, Muc1, with poly I:C may produce potent protective effects, which polarize immune responses towards Th1, and elicit antitumor immunity to inhibit the progression of pituitary tumors. PMID- 26935339 TI - Developmental Changes in Neonatal and Infant Skin Structures During the First 6 Months: In Vivo Observation. AB - BACKGROUND/OBJECTIVES: Developmental changes of structures in neonatal and infant skin have not been well characterized. The purpose of this study was to clarify changes in skin structures during neonatal and infant growth in vivo. METHODS: Fifteen healthy, full-term neonates (seven girls, eight boys) were studied. The measurements were performed 4 to 7 days (neonate) and 1, 3, and 6 months after birth on the buttock, upper thigh, and ventral forearm skin using a confocal laser scanning microscope. Developmental changes in dermoepidermal junction structures, stratum corneum thickness, epidermal thickness, and microvascular development were investigated. RESULTS: A significant decrease in stratum corneum thickness was observed over the 3 months after birth. Dermal papillae were not observed in neonatal skin but were observed gradually over the next 3 months. Epidermal thickness, determined from the skin surface to the bottom of the epidermal layer, increased significantly from 4 to 7 days to 1 month of age, indicating the formation of dermal papillae and rete ridges. Complicated microvascular structures were observed in neonatal skin but disappeared gradually and were observed only at the dermal papillae at 3 months of age. CONCLUSIONS: Our results reveal that infant skin is in a developmental stage structurally up to 3 months of age, paralleling skin functional and developmental maturation. PMID- 26935340 TI - Overexpression of vascular adhesion protein-1 is associated with poor prognosis of astrocytomas. AB - Vascular adhesion protein-1 (VAP-1) is one of the endothelial adhesion molecules that is believed to play a role in tumor progression and metastasis, supporting cancer cell extravasation. Very few studies have been performed on analyzing the contribution of VAP-1 in brain tumor. Astrocytomas are the most common type of brain tumors, which are classified by World Health Organization (WHO) into four grades according to the degree of malignancy. This study was designed to investigate VAP-1 expression level in different astrocytoma grades and its correlation with clinicopathological features as well as prognosis of astrocytoma patients. Eighty-seven patients with different grades of astrocytoma (WHO Grade I Grade IV) were enrolled in this study. The expression of VAP-1 was assayed by immunohistochemistry. The correlation between VAP-1 expression and clinicopathological features was evaluated by Chi-square test, and overall survival was analyzed by Kaplan-Meier method. Cox regression analysis was applied to analyze the independent influence of each parameter on overall survival. The expression level of VAP-1 was significantly higher in diffuse astrocytoma than those of pilocytic astrocytoma (p < 0.0001). In the subgroup analysis, upregulated VAP-1 expression was frequently found in older age patients (>=50 years). The VAP-1 expression was found to be significantly correlated with the overall survival (p = 0.0002). There was a statistical correlation between VAP 1(high) tumors in diffuse astrocytoma and VAP-1(low) tumors in pilocytic astrocytoma (p < 0.0001). Multivariate Cox analysis indicated VAP-1 was an independent predictive marker for poorer prognosis (p = 0.0036). Therefore, VAP-1 could be a promising prognostic biomarker in astrocytoma. PMID- 26935341 TI - Thanks for sharing: the bumpy road towards truly open data. PMID- 26935342 TI - Buyang Huanwu Decoction Vigorously Rescues PC12 Cells Against 6-OHDA-Induced Neurotoxicity via Akt/GSK3beta Pathway Based on Serum Pharmacology Methodology. AB - Buyang Huanwu decoction (BYHWD), as a popular traditional Chinese medicine formula, was widely used for treating ischemic diseases. However, in the area of neurodegenerative diseases, the researches focused on BYHWD are rare but promising, and molecular mechanisms underlying are largely elusive. 6 Hydroxydopamine (6-OHDA), a dopaminergic-specific neurotoxin, is extensively used to establish neurotoxic model in vivo and in vitro. In our present study, we prepared drug-containing serum of BYHWD (Buyang Huanwu drug-containing serum [BYHWS]) based on serum pharmacology methodology. Neurotoxic model in vitro was established in PC12 cells, and innovative experimental grouping method was adopted to investigate neuroprotective effects of BYHWS on neurotoxicity induced by 6-OHDA exposure. Remarkably, BYHWS vigorously rescued PC12 cells from 6-OHDA induced neurotoxicity even to surpass 100% in cell viability. Moreover, Hoechst/propidium iodide (PI) staining revealed that cell apoptotic rate was reduced significantly after incubation of BYHWS. Besides, BYHWS effectively restored the disruption of mitochondrial membrane potential and attenuated the elevation of intracellular reactive oxygen species level caused by 6-OHDA insult. Furthermore, BYHWS remarkably reversed the dephosphorylation of Akt (protein kinase B) and glycogen synthase kinase-3beta (GSK3beta) evoked by 6-OHDA. The above protective effects were attenuated by coculturing with Akt inhibitor LY294002. In summary, we concluded that the BYHWS vigorously blocked 6-OHDA induced neurotoxicity via Akt/GSK3beta pathway and provided a novel insight into roles of BYHWD in the clinical practices on neurodegenerative diseases. PMID- 26935343 TI - An e-health strategy to facilitate care of breast cancer survivors: A pilot study. AB - AIM: Innovative e-health strategies are emerging, to tailor and provide convenient, systematic and high-quality survivorship care for an expanding cancer survivor population. This pilot study tests the application of an e-health platform, "Healthy.me," in a breast cancer survivor cohort at Liverpool and Macarthur Cancer Therapy Centres, New South Wales, Australia. METHODS: Fifty breast cancer patients were recruited to use the Healthy.me website, designed by the Centre of Health Informatics at the University of New South Wales, over a 4 month period. Telephone and online questionnaires were used at 1 and 4 months and a face-to-face feedback at study completion, to gather qualitative and quantitative data regarding feasibility of Healthy.me. RESULTS: Healthy.me was reported to be a useful online resource by most users. Usage declined from 76% at 1 month to 48% at 4 months. Breast cancer survivors enjoyed a variety of tailored information regarding health and life-style issues. Positive aspects of Healthy.me were the convenient access to trusted information, and interaction with their peers and healthcare professionals. Barriers to usage contributing to usage decline were lack of reported patient time to re-access information, limited content updates and technical factors. CONCLUSIONS: This pilot study suggested the potential of an e-health strategy such as Healthy.me in addressing the needs of a growing breast cancer survivor population. Ongoing development of a more robust e-health resource and integration with primary care models is warranted. PMID- 26935344 TI - Impact of tumour size on prognosis of upper urinary tract urothelial carcinoma after radical nephroureterectomy: a multi-institutional analysis of 795 cases. AB - OBJECTIVE: To evaluate the prognostic impact of tumour size on survival outcomes in upper urinary tract urothelial carcinoma (UTUC) treated with radical nephroureterectomy (RNU). PATIENTS AND METHODS: Data on 795 patients treated with RNU for UTUC from seven centres were retrospectively analysed with focus on tumour size. Clinicopathological features and relevant prognostic factors were compared between patients with tumours <=3.0 cm and those with tumours >3.0 cm in size. The primary endpoints were cancer-specific survival (CSS), disease recurrence-free survival (RFS) and overall survival (OS). RESULTS: At a median follow-up of 32 months, 313 (39.4%) patients died from UTUC, 321 (40.4%) developed cancer recurrence, and 359 (45.1%) died from all causes. Tumour size >3.0 cm was associated with unfavourable clinicopathlogical features. Kaplan Meier analysis showed that tumour size was significantly correlated with worse CSS, RFS and OS (all P < 0.001). Multivariate analysis showed that tumour size was an independent predictor of CSS (hazard ratio [HR] 2.296; P < 0.001), RFS (HR 2.193; P < 0.001) and OS (HR 2.417; P < 0.001). CONCLUSIONS: Tumour size >3.0 cm was a significant predictor of CSS, RFS and OS after RNU for patients with UTUC. Further studies are warranted before tumour size is included in risk prediction tools. PMID- 26935345 TI - Nicotine Dependence Measures for Perinatal Women. AB - This integrative review provides an overview of nicotine dependence measures used with perinatal women and an evaluation of their psychometric properties. Fifty five articles that met inclusion and exclusion criteria were identified from five different databases. Most of the studies used the Fagerstrom Test for Nicotine Dependence (FTND). Other approaches included diagnostic tests, the Wisconsin Inventory of Smoking Dependence Motives (WISDM), the Tobacco Dependence Screener, and single-item measures. This review indicated that the FTND may not be the best option for measuring nicotine dependence in this population. The WISDM is a newer instrument that has excellent psychometric properties and captures nonnicotinic dimensions of nicotine dependence relevant to women. Future research is needed to assess its reliability in the perinatal population. Other recommendations from this review include the use of biomarker validation, thorough psychometric reporting on nicotine dependence instruments, and the use of multiple instruments to maximize comparability between nicotine dependence instruments. PMID- 26935346 TI - Using the Five-Level Taiwan Triage and Acuity Scale Computerized System: Factors in Decision Making by Emergency Department Triage Nurses. AB - Triage classifies and prioritizes patients' care based on the acuity of the illness in emergency departments (EDs). In Taiwan, the five-level Taiwan Triage and Acuity Scale (TTAS) computerized system was implemented nationally in 2010. The purpose of this study was to understand which factors affect decision-making practices of triage nurses in the light of the implementation of the new TTAS tool and computerized system. The qualitative data were collected by in-depth interviews. Data saturation was reached with 16 participants. Content analysis was used. The results demonstrated that the factors affecting nurses' decision making in the light of the newly implemented computerized system sit within three main categories: external environmental, patients' health status, and nurses' experiences. This study suggests ensuring the patient's privacy while attending the triage desk, improving the critical thinking of triage nurses, and strengthening the public's understanding of the ED visits. These will make ED triage more efficient. PMID- 26935347 TI - Molecular mechanisms underlying mangiferin-induced apoptosis and cell cycle arrest in A549 human lung carcinoma cells. AB - Mangiferin, which is a C-glucosylxanthone (1,3,6,7-tetrahydroxyxanthone-C2-beta-D glucoside) purified from plant sources, has recently gained attention due to its various biological activities. The present study aimed to determine the apoptotic effects of mangiferin on A549 human lung adenocarcinoma cells. In vitro studies demonstrated that mangiferin exerted growth-inhibitory and apoptosis-inducing effects against A549 cells. In addition, mangiferin exhibited anti-tumor properties in A549 xenograft mice in vivo. Mangiferin triggered G2/M phase cell cycle arrest via downregulating the cyclin-dependent kinase 1-cyclin B1 signaling pathway, and induced apoptotic cell death by inhibiting the protein kinase C nuclear factor-kappaB pathway. In addition, mangiferin was able to enhance the antiproliferative effects of cisplatin on A549 cells, thus indicating the potential for a combined therapy. Notably, mangiferin exerted anticancer effects in vivo, where it was able to markedly decrease the volume and weight of subcutaneous tumor mass, and expand the lifespan of xenograft mice. The present study clarified the molecular mechanisms underlying mangiferin-induced antitumor activities, and suggested that mangiferin may be considered a potential antineoplastic drug for the future treatment of cancer. PMID- 26935348 TI - The Use of Antiepileptics in Migraine Prophylaxis. AB - BACKGROUND: Migraine is a chronic debilitating disorder. Selected antiepileptic drugs (AEDs) are proposed as preventives for migraine. Clinical efficacy and side effects of these AEDs are discussed. SUMMARY OF REVIEW: The American Academy of Neurology and the American Society of Headache classify topiramate (TPM) and divalproex sodium (DVPX) as Level-A medications and recommend offering them to patients for migraine prophylaxis. Their mechanism(s) of actions remains not entirely known. Their recognized action as sodium channel blockers may affect the neural component of migraine pain. TPM or DVPX can be considered an obvious choice for those patients with a concomitant seizure disorder. Care must be taken to plan their treatment with their psychiatrist if a mood disorder is present. DVPX tends not to be prescribed as first/second choice due to its potential for weight gain and hepatotoxicity. TPM is generally first choice, but bears severe contraindications. Both medications require education on teratogenesis in childbearing women. Consideration of gabapentin, acetazolamide, leviteracetam, zonisamide, and carbamazipine may be given later as empiric options and in selected patients. Patients must be made aware that there is insufficient scientific support for their use in migraine. CONCLUSIONS: Available AEDs to prophylactically treat migraine are few but of robust clinical efficacy. Special care needs to be exerted with respect to their side effects. Future research is needed for a better understanding of their mechanisms of action in migraine. Such research has the potential of providing some insight into the pathophysiology of migraine. PMID- 26935349 TI - Pharmacokinetics of tildipirosin in pig tonsils. AB - The penetration of antimicrobials in pig tonsils is hardly known. The objective of the study was to quantify the tildipirosin (TD) penetration in tonsils. Animals were randomly divided into six groups (control, T1, T2 (1), T2(5), T2(10), and T2(15)) of eight animals. T1 and T2 groups received a dose of 2 and 4 mg of TD/kg bw in one shot (Zuprevo(r) MSD Animal Health), respectively, and the control group received 2 mL of saline solution. The animals were sacrificed by intravenous administration of pentobarbital sodium 24 h after finishing the treatment for the control, T1, and T2(1) groups, whereas animals of T2(5), T2(10), and T2(15) groups were sacrificed at 5, 10, and 15 days, post-treatment, respectively. Tonsils and blood samples were taken at necropsy to obtain plasma, and the tildipirosin concentration was determined by high-performance liquid chromatography with tandem mass spectrometry detection. The concentration in plasma was always significantly lower than in tonsil. Average TD tonsil concentrations increased significantly in a dose-dependent manner, and the tonsil TD vs. plasma TD concentration ratio was approximately 75 for the doses of 2 and 4 mg of TD/kg bw at 24 h post-treatment. Moreover, the maximum concentration of tildipirosin in tonsil was observed at 1 day postadministration, and this concentration decreased gradually from this day until 15 days postadministration for the dose of 4 mg of TD/kg bw. Finally, the ratio AUCtonsil/AUCplasma was 97.9, and the T1/2 (h) was clearly higher in tonsil than in plasma. PMID- 26935350 TI - Determination of fluoxetine in pharmaceutical and biological samples based on the silver nanoparticle enhanced fluorescence of fluoxetine-terbium complex. AB - In this study, a simple and sensitive spectrofluorimetric method is presented for the determination of fluoxetine based on the enhancing effect of silver nanoparticles (AgNPs) on the terbium-fluoxetine fluorescence emission. The AgNPs were prepared by a simple reduction method and characterized by UV-Vis spectroscopy and transmission electron microscopy. It was indicated that these AgNPs have a remarkable amplifying effect on the terbium-sensitized fluorescence of fluoxetine. The effects of various parameters such as AgNP and Tb3+ concentration and the pH of the media were investigated. Under obtained optimal conditions, the fluorescence intensity of the terbium-fluoxetine-AgNP system was enhanced linearly by increasing the concentration of fluoxetine in the range of 0.008 to 19 mg/L. The limit of detection (b + 3s) was 8.3 * 10-4 mg/L. The interference effects of common species found in real samples were also studied. The method had good linearity, recovery, reproducibility and sensitivity, and was satisfactorily applied for the determination of fluoxetine in tablet formulations, human urine and plasma samples. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26935351 TI - The role of PLDalpha1 in providing specificity to signal-response coupling by heterotrimeric G-protein components in Arabidopsis. AB - Heterotrimeric G-proteins comprised of Galpha, Gbeta and Ggamma subunits are important signal transducers in all eukaryotes. In plants, G-proteins affect multiple biotic and abiotic stress responses, as well as many developmental processes, even though their repertoire is significantly limited compared with that in metazoan systems. One canonical and three extra-large Galpha, 1 Gbeta and 3 Ggamma proteins represent the heterotrimeric G-protein complex in Arabidopsis, and a single regulatory protein, RGS1, is one of the few known biochemical regulators of this signaling complex. This quantitative disparity between the number of signaling components and the range of processes they influence is rather intriguing. We now present evidence that the phospholipase Dalpha1 protein is a key component and modulator of the G-protein complex in affecting a subset of signaling pathways. We also show that the same G-protein subunits and their modulators exhibit distinct physiological and genetic interactions depending on specific signaling and developmental pathways. Such developmental plasticity and interaction specificity likely compensates for the lack of multiplicity of individual subunits, and helps to fine tune the plants' responses to constantly changing environments. PMID- 26935353 TI - Early life stress induces sex-dependent increases in phosphorylated extracellular signal-regulated kinase in brains of mice with neuropathic pain. AB - BACKGROUND: Both early life stress and neuropathic pain induce morphological and functional abnormalities of the nervous system that are associated with emotional regulation. In our previous study, early life stress enhanced nerve injury induced hyperalgesia in adult male and female mice. In the present study, using phosphorylated extracellular signal-regulated kinase (p-ERK) as a marker of neuronal activation, we examined the effect of early life stress on neuronal function following partial sciatic nerve ligation (PSL). METHODS: Early life stress was induced by maternal separation from 2 to 3 weeks of age and by social isolation after weaning (MSSI). Neuropathic pain was induced by PSL at 9 weeks of age, and p-ERK expression after light touch stimulation to the ipsilateral paw was measured using immunohistochemistry 1 week after nerve injury. RESULTS: Although MSSI increased p-ERK expression in the paraventricular nucleus (PVN) and amygdala of male mice, PSL did not affect p-ERK expression in control and MSSI mice. In female mice, increased p-ERK expression was observed in the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc). Furthermore, p-ERK expression in the PVN and amygdala was increased in MSSI-PSL mice. CONCLUSIONS: The present data suggest that early life stress sex-dependently and site specifically increases neuronal activity in the brain. In addition, increased neuronal activity in multiplebrain regions of mice subjected to early life stress may enhance hyperalgesia after nerve injury. WHAT DOES THIS STUDY ADD?: Maternal separation and social isolation (MSSI) increased p-ERK in the paraventricular nucleus (PVN) and amygdala of male mice. MSSI increased p-ERK in the medial prefrontal cortex and nucleus accumbens of female mice. Neuropathic pain increased p-ERK in the PVN and amygdala of female MSSI mice. PMID- 26935354 TI - Forkhead box O1 promotes INS-1 cell apoptosis by reducing the expression of CD24. AB - Type 2 diabetes seriously affects human health and burdens public health systems. Pancreatic beta-cell apoptosis contributes to a reduction in beta-cell mass, which is responsible for the occurrence of type 2 diabetes. However, the mechanism that underlies this effect remains unclear. In the present study, the role of forkhead box O1 (Foxo1) was investigated (which is a key regulatory factor in beta-cell function) in the apoptotic behavior of beta-cells and a potential underlying mechanism was determined. It was demonstrated that Foxo1 overexpression significantly reduced the proliferation of INS-1 cells and increased the apoptosis of INS-1 cells, in contrast to foxm1, foxp, foxa1, foxc and foxb1 overexpression. The present study aimed to investigate potential underlying mechanisms using bioinformatics, including Gene Set Enrichment Analysis, and biological experiments, including flow cytometry, cell counting kit 8, immunofluorescence, western blotting, reverse transcription-quantitative polymerase chain reaction analysis and lentiviral transfection. Further experiments conclusively showed that cluster of differentiation (CD)24 expression was significantly decreased when INS-1 cells were treated with Foxo1. Animal experiments showed high CD24 expression in the pancreatic islets of diabetic Goto Kakizaki rats. Moreover, Gene Set Enrichment Analysis showed that CD24 expression was associated with the adaptive immune response of beta-cells. Finally, no significant differences in the proliferation and apoptosis of CD24 overexpressing INS-1 cells were observed after Foxo1 treatment. These results suggested that Foxo1 overexpression in beta-cells was able to increase apoptosis by inhibiting CD24 expression. This study may provide an approach for the treatment and prevention of type 2 diabetes. PMID- 26935355 TI - Cutaneous malignant melanoma show geographic and socioeconomic disparities in stage at diagnosis and excess mortality. AB - Background Preventive measures are needed to counteract the increasing burden of cutaneous malignant melanoma (CMM). As a basis for rational melanoma prevention, we investigated geographic differences and impact from socioeconomic factors related to incidence, clinical stage at diagnosis and outcome. Material and methods All patients with primary invasive CMM diagnosed in 2004-2013 in the southern and the western Swedish health care regions with a population of 2.9 million adults were eligible for the study. Population-based data were obtained from the national Cancer Register and the national Melanoma Quality Register. Geographic and socioeconomic differences in incidence per stage at diagnosis were mapped and correlated to excess mortality. Results Disease mapping based on 9743 cases in 99 municipalities and 20 metropolitan districts showed marked, regional disparities in stage-specific incidence of CMM. The incidence of stage I-II tumors was higher in the western health care region, whereas the incidence of stage III-IV CMMs was higher in the southern region. The divergent incidence patterns per stage at diagnosis were consistent across population strata based on educational level. The geographic disparities in CMM stage influenced relative survival with an excess five-year mortality ratio in the southern region versus the western region of 1.49 (95% confidence interval 1.22-1.82). The excess mortality ratio for patients with low versus high educational level was 1.81 (1.37-2.40). Conclusion Residential region and educational level influenced CMM stage and, thereby, excess mortality. These observations suggest that geographic as well as socioeconomic data should be considered in prevention of CMM. PMID- 26935356 TI - Pupillary Reconstruction and Outcome after Artificial Iris Implantation. AB - PURPOSE: Patients with iris defects suffer from severe visual impairment, especially increased glare sensitivity and cosmetic disturbances. This constitutes a great psychological strain for those patients. Until recently, possible treatment options were iris print contact lenses, sunglasses, and simple iris prostheses. The aim of this study was to investigate structural and functional outcome parameters and patient satisfaction after implantation of this new artificial iris prosthesis. DESIGN: Prospective case series investigating functional results and patient satisfaction after surgical iris reconstruction. PARTICIPANTS: Thirty-seven consecutive patients with traumatic iris defects presenting from 2011 through 2014 underwent pupillary reconstruction with a new artificial iris implant at the Department of Ophthalmology, Technical University Munich. METHODS: The custom-made, flexible silicone iris prosthesis ArtificialIris (HumanOptics, Erlangen, Germany) used in this study is a novel and innovative device in the surgical treatment of iris defects. Patients were examined before and after iris reconstruction with the iris implant placed in the ciliary sulcus. MAIN OUTCOME MEASURES: Change of best-corrected visual acuity (BCVA), intraocular pressure (IOP), pupillary aperture, glare, contrast sensitivity, endothelial cell density, anterior chamber depth, anterior chamber angle, and patient satisfaction were assessed. RESULTS: Thirty-two eyes of 32 patients (mean age, 52.9+/-16.0 years) were included. After implantation and during follow-up, BCVA and IOP did not change significantly (BCVA, 0.77+/-0.62 logarithm of the minimum angle of resolution [logMAR] preoperatively vs. 0.68+/ 0.64 logMAR 1 month postoperatively [P = 0.792]; IOP, 14.94+/-3.55 mmHg preoperatively vs. 17.72+/-5.88 mmHg 1 month postoperatively [P = 0.197]). The pupillary aperture was reduced significantly (42.11+/-20.1 mm(2) to 8.7+/-0.3 mm(2); P < 0.001). Contrast sensitivity increased significantly (0.80+/-0.51 to 0.93+/-0.49; P = 0.014). Endothelial cell count revealed a significant decrease postoperatively (1949+/-716 per 1 mm(2) to 1841+/-689 per 1 mm(2); P = 0.003). Anterior chamber depth (4.03+/-1.06 mm preoperatively vs. 4.29+/-0.70 mm postoperatively; P = 0.186) and angle (43.2+/-13.5 degrees preoperatively vs. 40.5+/-10.8 degrees postoperatively; P = 0.772) showed no significant differences. Subjective impairment through glare (9.12+/-1.62 preoperatively vs. 3.07+/-2.29 postoperatively; P < 0.001) and cosmetic disturbance (6.33+/-3.21 preoperatively vs. 1.58+/-0.86 postoperatively; P < 0.001) improved significantly. Patient satisfaction with the overall result was 8.91+/-1.51 of 10 points on an analog scale. CONCLUSIONS: The implantation of the artificial iris is a new and effective therapeutic option for the treatment of distinctive traumatic iris defects and results in an individual, aesthetically appealing, and good functional outcome in addition to high patient satisfaction. PMID- 26935358 TI - Risk Stratification of Elderly Community-acquired Pneumonia by Adding Computed Tomography. PMID- 26935357 TI - Aflibercept, Bevacizumab, or Ranibizumab for Diabetic Macular Edema: Two-Year Results from a Comparative Effectiveness Randomized Clinical Trial. AB - PURPOSE: To provide 2-year results comparing anti-vascular endothelial growth factor (VEGF) agents for center-involved diabetic macular edema (DME) using a standardized follow-up and retreatment regimen. DESIGN: Randomized clinical trial. PARTICIPANTS: Six hundred sixty participants with visual acuity (VA) impairment from DME. METHODS: Randomization to 2.0-mg aflibercept, 1.25-mg repackaged (compounded) bevacizumab, or 0.3-mg ranibizumab intravitreous injections performed up to monthly using a protocol-specific follow-up and retreatment regimen. Focal/grid laser photocoagulation was added after 6 months if DME persisted. Visits occurred every 4 weeks during year 1 and were extended up to every 4 months thereafter when VA and macular thickness were stable. MAIN OUTCOME MEASURES: Change in VA, adverse events, and retreatment frequency. RESULTS: Median numbers of injections were 5, 6, and 6 in year 2 and 15, 16, and 15 over 2 years in the aflibercept, bevacizumab, and ranibizumab groups, respectively (global P = 0.08). Focal/grid laser photocoagulation was administered in 41%, 64%, and 52%, respectively (aflibercept vs. bevacizumab, P < 0.001; aflibercept vs. ranibizumab, P = 0.04; bevacizumab vs. ranibizumab, P = 0.01). At 2 years, mean VA improved by 12.8, 10.0, and 12.3 letters, respectively. Treatment group differences varied by baseline VA (P = 0.02 for interaction). With worse baseline VA (20/50 to 20/320), mean improvement was 18.1, 13.3, and 16.1 letters, respectively (aflibercept vs. bevacizumab, P = 0.02; aflibercept vs. ranibizumab, P = 0.18; ranibizumab vs. bevacizumab, P = 0.18). With better baseline VA (20/32 to 20/40), mean improvement was 7.8, 6.8, and 8.6 letters, respectively (P > 0.10, for pairwise comparisons). Anti-Platelet Trialists' Collaboration (APTC) events occurred in 5% with aflibercept, 8% with bevacizumab, and 12% with ranibizumab (global P = 0.047; aflibercept vs. bevacizumab, P = 0.34; aflibercept vs. ranibizumab, P = 0.047; ranibizumab vs. bevacizumab, P = 0.20; global P = 0.09 adjusted for potential confounders). CONCLUSIONS: All 3 anti-VEGF groups showed VA improvement from baseline to 2 years with a decreased number of injections in year 2. Visual acuity outcomes were similar for eyes with better baseline VA. Among eyes with worse baseline VA, aflibercept had superior 2-year VA outcomes compared with bevacizumab, but superiority of aflibercept over ranibizumab, noted at 1 year, was no longer identified. Higher APTC event rates with ranibizumab over 2 years warrants continued evaluation in future trials. PMID- 26935359 TI - Antihypertensive Efficacy of the Direct Renin Inhibitor Aliskiren as Add-on Therapy in Patients with Poorly Controlled Hypertension. AB - OBJECTIVE: A direct renin inhibitor, aliskiren, has a longer stable antihypertensive effect compared with other renin-angiotensin-aldosterone system (RAAS) inhibitors. METHODS: This study was a 6-month, single-center, open trial conducted between December 2010 and November 2011 to assess the antihypertensive effect of adding aliskiren (300 mg) to the treatment of essential hypertension patients whose target blood pressure (BP) had not been achieved and to assess whether it was possible to reduce the amount of antihypertensive drugs used. RESULTS: The results showed an overall improvement in the target BP achievement rate of 60% for clinic BP and 52% for home BP measurements (75 cases total). The mean number of drugs before treatment with aliskiren was 3.28+/-1.52, whereas at the end of the six months the mean number of drugs prescribed other than aliskiren was 2.85+/-1.72 (p<0.0001). Moreover, no worsening of the renal function was observed in patients with diabetes or chronic kidney disease (CKD) who were being treated with other RAAS inhibitors in combination to aliskiren. CONCLUSION: These results showed that when aliskiren was added to the treatment of poorly controlled hypertension, the BP achievement rate increased, and it was possible to reduce the amount of antihypertensive drugs used in combination with aliskiren. Moreover, as a result of careful monitoring of the renal function or decreasing the amounts of drugs used in combination, no worsening of the renal function was observed even in the cases complicated by diabetes or CKD being treated with other RAAS inhibitors. PMID- 26935360 TI - Computed Tomography for the Diagnosis and Evaluation of the Severity of Community acquired Pneumonia in the Elderly. AB - OBJECTIVE: We herein assessed the utility of computed tomography (CT) for the diagnosis and ascertainment of the severity of community-acquired pneumonia (CAP) in the elderly. METHODS: The utility of CT compared with chest radiography (CR) for the diagnosis of CAP was prospectively studied among elderly inpatients with clinical symptoms and signs indicative of CAP at the Department of Respiratory Medicine in Nissan Tamagawa Hospital during the one-year period from January 2013 to December 2013. Additionally, we evaluated whether the findings of CT were useful as predictive factors related to the mortality rate associated with CAP. RESULTS: One hundred and forty-two patients, 65 years of age or older, were surveyed upon hospital admission for suspected CAP. Of the 142 patients included, 127 (89.4%) had pneumonic infiltration diagnosed by CT, however, CR could not recognize pneumonic infiltration in 9.4% (12/127) of these patients. In 127 CAP positive patients, bilateral pneumonic infiltration was more frequently detected by CT in non-survivors than survivors (79.0% vs. 53.7%; p <0.05). By a multivariable analysis to determine the prognostic factors related to mortality from CAP, oxygen desaturation showed the greatest odds ratio among the other predictive factors, followed by comorbid neoplastic disease, blood urea nitrogen >=21 mg/dL, male gender, and bilateral pneumonic infiltration diagnosed by CT. CONCLUSION: We herein demonstrated that CT was superior to CR for diagnosing and evaluating the severity of CAP in elderly patients. PMID- 26935361 TI - Clinical Experience of the Long-term Use of Pirfenidone for Idiopathic Pulmonary Fibrosis. AB - OBJECTIVE: Long-term effects of pirfenidone have been poorly understood to date. This study investigated the clinical efficacy and safety of long-term pirfenidone use for idiopathic pulmonary fibrosis (IPF) in clinical practice. METHODS: This survey study was a retrospective observational study. A survey was used to collect clinical information on IPF cases that were treated with pirfenidone. This survey sheet came from physicians belonging to the Diffuse Lung Diseases Research Group. RESULTS: 502 patients at 22 institutes received pirfeidone treatment. Of the 502 cases, pirfenidone treatment was terminated in under one year in 186 cases (37.1%); adverse effect was the most frequent reason for termination. The pirfenidone treatment lasted for two years or longer in 111 cases (22.1%). The mean change in the forced vital capacity (FVC) was -30+/-224 (SD) mL in the first year of treatment, -158+/-258 mL in the second year, and 201+/-367 mL in the third year. FVC improved by 10% or more in the first year in 10 (14.7%) of 68 cases, and showed a change of +/-10% in 47 (69.1%) cases. It showed a change of +/-10% in the second and third years in 61.7% and 62.5% of the patients, respectively. CONCLUSION: The FVC improved in only a small percentage of patients who received pirfenidone treatment for a long period of time. However, a decrease in the FVC was prevented for three years in over half of the cases. PMID- 26935362 TI - Prevalence of Autoantibodies and the Efficacy of Immunotherapy for Autoimmune Cerebellar Ataxia. AB - OBJECTIVE: Autoimmune cerebellar ataxias were recently reported to be treatable. However, the proportion of patients with cortical cerebellar atrophy of unknown etiology with autoimmune-associated cerebellar ataxia and the actual effectiveness of immunotherapy in these diseases remain unknown. METHODS: We measured the level of autoantibodies (including anti-gliadin antibody, anti glutamic acid decarboxylase (GAD) antibody, and anti-thyroid antibody) in 58 Japanese patients with cerebellar ataxia, excluding those with multiple system atrophy, hereditary spinocerebellar ataxia, cancer, or those who were receiving phenytoin, and the efficacy of immunotherapy was assessed. RESULTS: Thirty-one of 58 (53%) patients were positive for anti-GAD antibody, anti-gliadin antibody, or anti-thyroid antibody. Seven of the 12 anti-gliadin antibody-positive patients, three of the four anti-GAD antibody-positive patients, and three of the six anti thyroid antibody-positive patients responded well to immunotherapy, indicating that 59% of patients with ataxia-associated antibody-positive cerebellar ataxia undergoing immunotherapy responded well. CONCLUSION: Some patients with cerebellar ataxia have autoimmune conditions and diagnosing autoimmune cerebellar ataxia is therefore an important component in the care of patients with this disease entity. PMID- 26935363 TI - Is There an Increased Arterial Stiffness in Patients with Primary Sjogren's Syndrome? AB - OBJECTIVE: Primary Sjogren's syndrome (pSS) is a common chronic autoimmune disease that primarily affects the salivary and lacrimal glands. Arterial stiffness is one of the earliest detectable manifestations of adverse structural and functional changes within the vessel wall. The aim of this study was to evaluate the relationship between arterial stiffness and pSS. METHODS: In this study, 75 female patients with pSS who fulfilled the American European Consensus Criteria for Sjogren's syndrome, were included. A total of 68 age-, sex- and body mass index-matched subjects were recruited as the control population. Arterial stiffness was assessed by measurement of the carotid-femoral pulse wave velocity (PWV). RESULTS: The mean age of the patients was 54.0+/-9.3 years and the median duration of the disease was 10 years. Compared with the control subjects, patients with pSS had a higher mean PWV (8.2+/-1.5 m/s vs. 7.5+/-1.4 m/s; p=0.01). Correlation analysis showed that the PWV was positively correlated with age, body mass index, serum cholesterol, low-density lipoprotein (LDL) and C reactive protein levels, blood pressure, mean arterial pressure (MAP), pulse pressure and left ventricular mass index. A multiple linear regression analysis revealed that arterial stiffness was associated with age, MAP and LDL levels in pSS patients. CONCLUSION: Although patients with pSS appear to have increased arterial stiffness, risk factors associated with arterial stiffness in these patients are similar to the general population. However, we cannot exclude the possibility that a higher PWV in pSS patients is caused, not by pSS itself, but by the use of steroids, hypertension and dyslipidemia. PMID- 26935364 TI - Thermal Disparity between Fingers after Cold-water Immersion of Hands: A Useful Indicator of Disturbed Peripheral Circulation in Raynaud Phenomenon Patients. AB - OBJECTIVE: To devise an effective method to assess the peripheral circulation using an infrared thermographic analysis. METHODS: Sequential measurements of the skin temperature before and after cold-water immersion of the hands were analyzed by a thermographic examination in healthy controls and patients diagnosed to have Raynaud phenomenon (RP). The skin temperatures of the dorsum of all fingernail folds and the metacarpophalangeal (MCP) joints were measured at baseline. Then the hands were immersed in 10 degrees C water for 10 s, and the skin temperatures were measured at 0, 3, 5, 10, 15, 20 and 30 min after immersion. The mean temperature, recovery rate and disparity (coefficient of variation) of the nail fold temperatures were calculated. The distal-dorsal difference (DDD) was calculated by subtracting the mean MCP temperature from the mean nail fold temperature. Receiver operating characteristic (ROC) curves were generated to compare these parameters in terms of their capability to differentiate patients with RP. RESULTS: Thirty-one RP patients and 25 controls were included in the study. The baseline nail fold temperature was significantly lower in RP patients than in the controls. The RP patients had a lower recovery rate, lower DDD and higher disparity than the controls. The disparity and DDD were negatively correlated (r=-0.63, p<0.01), whereas the recovery rate and DDD were positively correlated (r=0.91, p<0.01). The ROC curve analysis revealed that the disparity in nail fold temperature effectively differentiated RP patients from controls (area under the curve: recovery rate 0.72; disparity 0.88; DDD 0.79). CONCLUSION: The temperature disparity between fingers is a useful thermographic parameter for evaluating disturbed peripheral circulation in patients with Raynaud phenomenon. PMID- 26935365 TI - Renal Insufficiency in Concert with Renin-angiotensin-aldosterone Inhibition Is a Major Risk Factor for Hyperkalemia Associated with Low-dose Trimethoprim sulfamethoxazole in Adults. AB - OBJECTIVE: Low-dose trimethoprim-sulfamethoxazole (TMP-SMX) is commonly used to prevent pneumocystis pneumonia in daily practice. Previous reports have shown a relationship between high- or standard-dose of TMP-SMX and hyperkalemia, however it remains unclear whether this is true for low-dose TMP-SMX. In this study we sought to determine the risk factors for hyperkalemia associated with low-dose TMP-SMX. METHODS: In this retrospective cohort study, 186 consecutive adult patients who received TMP-SMX as prophylaxis for pneumocystis pneumonia from January 2014 to January 2015 were evaluated. Data on the patients' age, gender, baseline estimated glomerular filtration rate (eGFR), baseline serum potassium, maximum serum potassium, duration reaching the maximal serum potassium level, dosage, and concomitant use of angiotensin-converting enzyme inhibitors (ACEi)/angiotensin receptor blockers (ARB), beta-blockers, non-steroidal anti inflammatory drugs and potassium-sparing diuretics were retrospectively collected. Hyperkalemia was defined as a serum potassium level >=5 mEq/L. Univariate and multivariate analyses were performed. RESULTS: The median age of the patients was 66 years and 51.1% were men. Hyperkalemia associated with low dose TMP-SMX was observed in 32 patients (17.2%). The median duration to reach the maximal serum potassium level was 12 days. The multivariate logistic regression analysis identified renal insufficiency to be a major risk factor for hyperkalemia associated with low-dose TMP-SMX (eGFR <60 mL/min/1.73 m(2), adjusted OR 4.62). Moreover, in the subpopulation of patients with renal insufficiency, ACEi/ARB use was considered to be a major risk factor for hyperkalemia (adjusted OR 3.96). CONCLUSION: Renal insufficiency in concert with ACEi/ARB use is a major risk factor for hyperkalemia induced by low-dose TMP-SMX. PMID- 26935366 TI - Reversible Posterior Leukoencephalopathy Syndrome Associated with Treatment for Acute Exacerbation of Ulcerative Colitis. AB - Reversible posterior leukoencephalopathy syndrome (RPLS) is a clinical syndrome of varying etiologies with similar neuroimaging findings. This is a case report of a 25-year-old woman who developed typical, neurological symptoms and magnetic resonance imaging abnormalities after treatment for the acute exacerbation of ulcerative colitis (UC), which included blood transfusion, the systemic administration of prednisolone, and the administration of metronidazole. It has been reported that these treatments may contribute to the development of RPLS. RPLS should therefore be considered in the differential diagnosis of UC patients who exhibit impaired consciousness, seizures or visual deficits during treatment. We report a rare case of RPLS in a patient with UC. PMID- 26935367 TI - Prosthetic Valve Dysfunction 35 Years after Mitral Valve Replacement with a Starr Edwards Caged-disc Valve. AB - A 49-year-old man was admitted to our hospital with a chief complaint of dyspnea. He had a history of mitral valve replacement (MVR) with a Starr-Edwards (SE) caged-disc valve at the age of 14. Echocardiography revealed elevated trans valvular pressure gradient of the mitral prosthetic valve with neither disk motion abnormality nor abnormal structure. Catheterization confirmed an elevation of the mean diastolic gradient of the mitral valve to 12.3 mmHg. Re-MVR was performed, and abnormal tissue attached to the cage of the valve and proliferating beneath the valve was observed. Histologic examination revealed them as fibrinous tissue and mild pannus proliferation, respectively. This rare case report focuses on long-term follow-up and the complication of a SE caged disc valve. A SE caged-disc valve may become stenotic, only detected with a trans valvular pressure gradient without any disk motion abnormality or abnormal structure during a prolonged follow-up period. PMID- 26935368 TI - Rapid Normalization of High Glutamic Acid Decarboxylase Autoantibody Titers and Preserved Endogenous Insulin Secretion in a Patient with Diabetes Mellitus: A Case Report and Literature Review. AB - A 59-year-old Japanese woman developed diabetes mellitus without ketoacidosis in the presence of glutamic acid decarboxylase autoantibody (GADA) (24.7 U/mL). After the amelioration of her hyperglycemia, the patient had a relatively preserved serum C-peptide level. Her endogenous insulin secretion capacity remained almost unchanged during 5 years of insulin therapy. The patient's GADA titers normalized within 15 months. The islet-related autoantibodies, including GADA, are believed to be produced following the autoimmune destruction of pancreatic beta cells and are predictive markers of type 1 diabetes mellitus. Therefore, the transient appearance of GADA in our patient may have reflected pancreatic autoimmune processes that terminated without progression to insulin deficiency. PMID- 26935369 TI - Pulmonary Langerhans Cell Histiocytosis-associated Pulmonary Hypertension Showing a Drastic Improvement Following Smoking Cessation. AB - Pulmonary Langerhans cell histiocytosis (PLCH) is a rare, smoking-related, interstitial lung disease, and pulmonary hypertension (PH) is associated with mortality. We herein report a case of PLCH complicated by severe PH and respiratory impairment. After developing PH, the patient displayed a cystic pattern on chest high-resolution computed tomography (HRCT). This, in turn, corresponded with the scarring stage of PLCH. However, the patient's PH and respiratory impairment improve dramatically following smoking cessation. PLCH patients with a cystic pattern on chest HRCT may still be able to improve their PH and respiratory impairment when they are able to quit smoking. PMID- 26935370 TI - A Patient with Idiopathic Pleuroparenchymal Fibroelastosis Showing a Sustained Pulmonary Function due to Treatment with Pirfenidone. AB - The patient was a 68-year-old man presenting with body weight loss and exertional dyspnea. High-resolution computed tomography of the chest showed dense subpleural consolidation with traction bronchiectasis and volume loss predominantly in bilateral apical lesions and upper lobes. A histopathological analysis of a specimen of the right upper lobe showed histological patterns which were consistent with idiopathic pleuroparenchymal fibroelastotis (IPPFE). Treatment with pirfenidone was introduced with the expectation of its potential benefit. The effect of pirfenidone was satisfactory, and a decline in forced vital capacity was inhibited during treatment. This is the first case report suggesting the efficacy of pirfenidone for patients with IPPFE. PMID- 26935371 TI - Pulmonary Paragonimiasis: The Detection of a Worm Migration Track as a Diagnostic Clue for Uncertain Eosinophilic Pleural Effusion. AB - A 38-year-old woman with sustained right chest pain was referred to our hospital. She showed pleural effusion and peripheral blood eosinophilia. Thoracentesis revealed eosinophilic pleural effusion in which the smear, culture and cytological examinations were all negative. Although she had no notable dietary history, chest CT revealed linear opacities, which suggested the migration tracks of paragonimiasis. The diagnosis was confirmed using enzyme-linked immunosorbent assays, which showed elevated Paragonimus westermani and Paragonimus miyazakii antibody levels. After the initiation of praziquantel therapy, all clinical findings were promptly improved. The detection of a migration track may therefore be useful in the diagnosis of paragonimiasis. PMID- 26935372 TI - Promising Effect of Crizotinib on Anaplastic Lymphoma Kinase (ALK)-Positive Non Small Cell Lung Cancer in an Elderly Patient with a Poor Performance Status: A Case Report and Literature Review. AB - Crizotinib is highly effective for anaplastic lymphoma kinase (ALK)-positive non small cell lung cancer (NSCLC). However, it remains unclear whether crizotinib has a beneficial effect on elderly patients with ALK-positive NSCLC with a poor performance status (PS). We herein present the case of an 85-year-old man with stage IV ALK-positive NSCLC, whose PS score was 4 due to pericardial and pleural effusions. After initiating crizotinib therapy, a drastic response was observed and the PS score improved to 0. Adverse effects were manageable. Our results indicate that crizotinib could be an important choice when treating elderly patients with ALK-positive NSCLC with poor PS. PMID- 26935373 TI - Coombs-negative Autoimmune Hemolytic Anemia Followed by Anti-erythropoetin Receptor Antibody-associated Pure Red Cell Aplasia: A Case Report and Review of Literature. AB - A 76-year-old woman was referred to our hospital because of anemia. The laboratory findings revealed hemolysis. Although a direct Coombs test was negative, a high titer of RBC-bound IgG was detected, and a diagnosis of Coombs negative autoimmune hemolytic anemia was made. She was successfully treated with prednisolone. One year and five months later, she again presented anemia and was diagnosed with pure red cell aplasia. Anti-erythropoietin receptor antibody was detected in the serum. She was treated with cyclosporine and obtained prompt recovery. We herein report this rare case and review the pertinent literature. PMID- 26935374 TI - Tonsillectomy to Effectively Treat a Patient with Behcet's Disease. AB - Behcet's disease (BD) is a polysymptomatic and recurrent systemic vasculitis with a chronic course and unknown cause. We herein report a 27-year-old woman who had suffered from a recurrent fever and tonsillitis for nearly ten years with BD for who tonsillectomy was effective. PMID- 26935375 TI - Psoriatic Arthritis with Annular Pustular Psoriasis. AB - We herein present the case of a 56-year-old woman who presented with symptoms of psoriatic arthritis (PsA) with erythema that progressed to annular pustular psoriasis. The patient had a 15-year history of polyarthritis. Annular pustular psoriasis is not typically observed in cases of arthritis. This is the first reported case of PsA with annular pustular psoriasis. PMID- 26935376 TI - Hypertrophic Pachymeningitis as a Potential Cause of Headache Associated with Temporal Arteritis. AB - We herein describe a rare case of temporal arteritis associated with hypertrophic pachymeningitis. An 81-year-old man presented with a right temporal headache that had persisted for one month. A right superficial temporal artery biopsy revealed intimal hypertrophy with increased elastic fibers, consistent with temporal arteritis. Brain MRI using gadolinium enhancement showed thickened dura mater on the right frontal and temporal lobes, which led to the diagnosis of hypertrophic pachymeningitis. Intravenous methylprednisolone and oral prednisolone improved the patient's symptoms. According to our findings, hypertrophic pachymeningitis may be a potential cause of an ipsilateral temporal headache associated with temporal arteritis. PMID- 26935377 TI - Cytomegalovirus Colitis in a Critically Ill Patient Following Severe Legionella Pneumonia with Multiple Organ Failure. AB - A 68-year-old man visited an emergency department complaining of dyspnea. He was diagnosed to have Legionella pneumonia with multiple organ failure. Although his multiple organ failure improved, he suffered from persistent abdominal pain and diarrhea with continuous minor bleeding. Colonoscopy revealed a longitudinal ulcer of the rectum, below the peritoneal reflection. He was diagnosed with cytomegalovirus (CMV) colitis. Antiviral therapy with ganciclovir was initiated. He finally underwent a colostomy after a bowel stricture caused an intestinal outlet obstruction, which made oral intake impossible. Based on the present case, we believe that CMV colitis must be considered as one of the differential diagnoses when critically ill patients develop continuous diarrhea and abdominal pain. PMID- 26935378 TI - Fatal Encephalopathy Associated with Influenza in a Health Care Professional. AB - A 41-year-old nurse was referred to our hospital with a fever and disturbed consciousness. She tested positive for influenza antigen. CT and MRI findings revealed low density and intensity areas in the right occipital and lateral lobes with remarkable brain edema, which led to a diagnosis of influenza encephalopathy. Influenza A antibodies in the serum were below the detection limit despite the patient receiving previous vaccination three months earlier. A PCR analysis revealed that the influenza HA gene was classified into clade 3C.2a, subclass AH3N2. The present case indicates the potential development of encephalopathy in adults under certain conditions. PMID- 26935379 TI - Good's Syndrome Accompanied by Agranulocytosis Following a Rapid Clinical Course. AB - Good's syndrome is an immunodeficiency disease involving thymoma accompanied by hypogammaglobulinemia. We encountered a case of Good's syndrome accompanied by agranulocytosis that followed a rapid clinical course. A 72-year-old man visited our hospital with a two-week history of a sore throat. Candida albicans was detected in the pharynx, and hypogammaglobulinemia was detected in addition to granulocytopenia. The patient subsequently developed septic shock and followed a rapid clinical course which ended in death. Good's syndrome with agranulocytosis was diagnosed at autopsy. Good's syndrome accompanied by agranulocytosis can follow a rapid clinical course and some cases remain asymptomatic until old age. Its prompt treatment is crucial. PMID- 26935380 TI - A Giant Cecal Tumor with Prolapse through the Anus. PMID- 26935381 TI - Depressed Gastric Adenocarcinoma of the Fundic Gland Type. PMID- 26935382 TI - Hypokalemia and the Disappearance of Giant Negative T Waves. PMID- 26935383 TI - Jugulotympanic Paraganglioma in a Woman with Chronic Hoarseness. PMID- 26935384 TI - Janeway Lesions in Eosinophilic Granulomatosis with Polyangiitis. PMID- 26935385 TI - A Distant Origin of Sternoclavicular Septic Arthritis. PMID- 26935386 TI - Calcific Tendinitis of the Longus Colli. PMID- 26935387 TI - Polysplenia or Left Isomerism? PMID- 26935388 TI - Protective role of nuclear factor erythroid 2-related factor 2 in the hemorrhagic shock-induced inflammatory response. AB - Hemorrhagic shock (HS) following trauma or major surgery significantly contributes to mortality. However, the mechanisms through which HS activates the inflammatory response are not yet fully understood. Nuclear factor-erythroid 2 (NF-E2) p45-related factor-2 (Nrf2), a bZIP transcription factor, is a master regulator of robust cytoprotective defenses. The present study investigated the role of Nrf2 in the pathophysiology of HS. Nrf2 expression in peripheral leukocytes obtained from patients with surgery-associated hemorrhage subjected to resuscitation treatment (termed HS patients) or healthy donors was examined by RT qPCR. A marked increase in Nrf2 expression was detected in the leukocytes obtained from the HS patients, which indicates a correlation between Nrf2 expression and the development of HS. Wild-type (WT; Nrf2+/+) and Nrf2-deficient [Nrf2-/- or Nrf2-knockout (KO)] mice were subjected to surgery to induce HS. Systemic inflammation was significantly elevated in the Nrf2-KO mice compared with the WT mice following HS, as assessed by an increase in serum cytokine levels [interleukin (IL)-6, tumor necrosis factor (TNF)-alpha and IL-1beta], as well as high-mobility group box 1 protein (HMGB1) expression. The Nrf2-KO mice exhibited more severe lung and liver injury following HS as evidenced by increased tissue damage, increased myeloperoxidase (MPO) activity and the increased production of pro-inflammatory cytokines. Additionally, Nrf2 deficiency augmented cytokine production induced by the exposure of peritoneal mouse macrophages to lipopolysaccharide (LPS) following HS. Taken together, these results suggest that Nrf2 is a critical host factor which limits immune dysregulation and organ injury following HS. PMID- 26935389 TI - Assessment of sFRP4 as a bio-marker for predicting aggressiveness and recurrence of growth hormone-secreting pituitary adenomas. AB - The association of sFRP4 expression with aggressiveness and recurrence of growth hormone (GH)-secreting pituitary adenomas was investigated. Ten normal pituitary and 52 GH-secreting pituitary adenoma specimens were classified into three groups: normal pituitary (control) group, non-aggressive group, and aggressive group, according to preoperative evaluation by magnetic resonance imaging (MRI)/computed tomography (CT). Expression of sFRP4 was determined by quantitative real-time polymerase chain reaction (qRT-PCR), western blot analysis, and tissue microarrays, to assess the association between sFRP4 and aggressiveness. Follow-up information of all 52 patients was collected to evaluate the impact of sFRP4 expression on the recurrence/progression of GH secreting pituitary adenomas. qRT-PCR results showed a lower level of sFRP4 mRNA in the aggressive group, as compared to that in the non-aggressive group (P=0.001). A similar trend was observed on western blot analysis for sFRP4 protein expression (P=0.004). On analysis by tissue microarrays, weak sFRP4 expression was detected in the aggressive group (10/15, 66.7%). Univariate analysis showed a significant relationship between low sFRP4 expression and aggressiveness (P=0.024). On multivariate analysis weak sFRP4 expression was found to be an independent factor of recurrence/progression (odds ratio: 0.063, P=0.026). Methylation of the sFRP4 promoter was increased in low sFRP4 staining group compared to that in the high sFRP4 staining group (P<0.001). In this study, weak sFRP4 expression appeared to predict aggressive behavior, and was associated with recurrence/progression of GH-secreting pituitary adenomas. Methylation of the sFRP4 promoter may account for the low sFRP4 expression. PMID- 26935390 TI - Thiopurine Biotransformation and Pharmacological Effects: Contribution of Oxidative Stress. AB - BACKGROUND: Thiopurine antimetabolites are important agents for the treatment of severe diseases, such as acute lymphoblastic leukemia and inflammatory bowel disease. Their pharmacological actions depend on biotransformation into active thioguanine-nucleotides; intracellular metabolism is mediated by enzymes of the salvage pathway of nucleotide synthesis and relies on polymorphic enzymes involved in thiopurines' catabolism such as thiopurine-S-methyl transferase. Given the enzymes involved in thiopurines' metabolism, it is reasonable to hypothesize that these drugs are able to induce significant oxidative stress conditions, possibly altering their pharmacological activity. METHODS: A systemic search of peer-reviewed scientific literature in bibliographic databases has been carried out. Both clinical and preclinical studies as well as mechanistic studies have been included to shed light on the role of oxidative stress in thiopurines' pharmacological effects. RESULTS: Sixty-nine papers were included in our review, allowing us to review the contribution of oxidative stress in the pharmacological action of thiopurines. Thiopurines are catabolized in the liver by xanthine oxidase, with potential production of reactive oxidative species and azathioprine is converted into mercaptopurine by a reaction with reduced glutathione, that, in some tissues, may be facilitated by glutathione- S-transferase (GST). A clear role of GSTM1 in modulating azathioprine cytotoxicity, with a close dependency on superoxide anion production, has been recently demonstrated. Interestingly, recent genome-wide association studies have shown that, for both azathioprine in inflammatory bowel disease and mercaptopurine in acute lymphoblastic leukemia, treatment effects on patients' white blood cells are related to variants of a gene, NUDT15, involved in biotransformation of oxidated nucleotides. CONCLUSIONS: Basing on previous evidences published in literature, oxidative stress may contribute to thiopurine effects in significant ways that, however, are still not completely elucidated. PMID- 26935391 TI - Knockdown of eukaryotic translation initiation factor 4E suppresses cell growth and invasion, and induces apoptosis and cell cycle arrest in a human lung adenocarcinoma cell line. PMID- 26935392 TI - Planar cell polarity: the Dachsous/Fat system contributes differently to the embryonic and larval stages of Drosophila. AB - The epidermal patterns of all three larval instars (L1-L3) ofDrosophilaare made by one unchanging set of cells. The seven rows of cuticular denticles of all larval stages are consistently planar polarised, some pointing forwards, others backwards. In L1 all the predenticles originate at the back of the cells but, in L2 and L3, they form at the front or the back of the cell depending on the polarity of the forthcoming denticles. We find that, to polarise all rows, the Dachsous/Fat system is differentially utilised; in L1 it is active in the placement of the actin-based predenticles but is not crucial for the final orientation of the cuticular denticles, in L2 and L3 it is needed for placement and polarity. We find Four-jointed to be strongly expressed in the tendon cells and show how this might explain the orientation of all seven rows. Unexpectedly, we find that L3 that lack Dachsous differ from larvae lacking Fat and we present evidence that this is due to differently mislocalised Dachs. We make some progress in understanding how Dachs contributes to phenotypes of wildtype and mutant larvae and adults. PMID- 26935393 TI - The neurotoxic effects of hydrogen peroxide and copper in Retzius nerve cells of the leech Haemopis sanguisuga. AB - Oxidative stress and the generation of reactive oxygen species (ROS) play an important role in cellular damage. Electrophysiological analyses have shown that membrane transport proteins are susceptible to ROS. In the present study, oxidative stress was induced in Retzius nerve cells of the leechHaemopis sanguisugaby bath application of 1 mM of hydrogen peroxide (H2O2) and 0.02 mM of copper (Cu) for 20 min. The H2O2/Cu(II) produced considerable changes in the electrical properties of the Retzius nerve cells. Intracellular recording of the resting membrane potential revealed that the neuronal membrane was depolarized in the presence of H2O2/Cu(II). We found that the amplitude of action potentials decreased, while the duration augmented in a progressive way along the drug exposure time. The combined application of H2O2and Cu(II) caused an initial excitation followed by depression of the spontaneous electrical activity. Voltage clamp recordings revealed a second effect of the oxidant, a powerful inhibition of the outward potassium channels responsible for the repolarization of action potentials. The neurotoxic effect of H2O2/Cu(II) on the spontaneous spike electrogenesis and outward K(+)current of Retzius nerve cells was reduced in the presence of hydroxyl radical scavengers, dimethylthiourea and dimethyl sulfoxide, but not mannitol. This study provides evidence for the oxidative modification of outward potassium channels in Retzius nerve cells. The oxidative mechanism of the H2O2/Cu(II) system action on the electrical properties of Retzius neurons proposed in this study might have a wider significance, referring not only to leeches but also to mammalian neurons. PMID- 26935394 TI - Secreted recombinant human IL-24 protein inhibits the proliferation of esophageal squamous cell carcinoma Eca-109 cells in vitro and in vivo. AB - Interleukin-24 (IL-24) displays cancer-specific apoptosis-inducing properties in a broad spectrum of human tumors without harmful effects on normal cells. The human IL-24 protein is secreted as a glycosylated protein and functions as a pro Th1 cytokine and a potent antiangiogenic molecule. However, the function of secreted recombinant human IL-24 (srhIL-24) protein in esophageal squamous cell carcinoma (ESCC) cells has not been studied. In the present study, we prepared a stable site-specific-integrated cell line, Flp-InTMCHO/IL-24 (FCHO/IL-24), which secreted rhIL-24 at a higher level than three random-integrated cell lines. In vitro, we identified that the purified srhIL-24 inhibited proliferation and induced the apoptosis of ESCC Eca-109 cells and activated STAT3, which was related with the IL-20 receptors. In vivo, the tumorigenicity of Eca-109 cells was significantly inhibited by s.c. injection of FCHO/IL-24 cells. Decreased tumor microvessel density and an increased number of TUNEL-positive tumor cells were associated with tumor growth inhibition, indicating the presence of antiangiogenic activity and induction of apoptotic activity. In summary, the present study demonstrated that srhIL-24 induced growth inhibition and apoptosis in ESCC Eca-109 cells in vitro and in vivo, which may be mediated by the receptor pathway. PMID- 26935395 TI - Molecular identification of Entamoeba species in savanna woodland chimpanzees (Pan troglodytes schweinfurthii). AB - To address the molecular diversity and occurrence of pathogenic species of the genus Entamoeba spp. in wild non-human primates (NHP) we conducted molecular phylogenetic analyses on Entamoeba from wild chimpanzees living in the Issa Valley, Tanzania. We compared the sensitivity of molecular [using a genus specific polymerase chain reaction (PCR)] and coproscopic detection (merthiolate iodine-formaldehyde concentration) of Entamoeba spp. We identified Entamoeba spp. in 72 chimpanzee fecal samples (79%) subjected to species-specific PCRs for six Entamoeba species/groups (Entamoeba histolytica, Entamoeba nuttalli, Entamoeba dispar, Entamoeba moshkovskii, Entamoeba coli and Entamoeba polecki ST2). We recorded three Entamoeba species: E. coli (47%), E. dispar (16%), Entamoeba hartmanni (51%). Coproscopically, we could only distinguish the cysts of complex E. histolytica/dispar/moshkovskii/nuttalli and E. coli. Molecular prevalence of entamoebas was higher than the prevalence based on the coproscopic examination. Our molecular phylogenies showed that sequences of E. dispar and E. coli from Issa chimpanzees are closely related to sequences from humans and other NHP from GenBank. The results showed that wild chimpanzees harbour Entamoeba species similar to those occurring in humans; however, no pathogenic species were detected. Molecular-phylogenetic methods are critical to improve diagnostics of entamoebas in wild NHP and for determining an accurate prevalence of Entamoeba species. PMID- 26935397 TI - A Facile and Low-Cost Route to Heteroatom Doped Porous Carbon Derived from Broussonetia Papyrifera Bark with Excellent Supercapacitance and CO2 Capture Performance. AB - In this work, we present a facile and low-cost approach to synthesize heteroatom doped porous carbon via hydrothermal treatment of stem bark of broussonetia papyrifera (BP) as the biomass precursor in diluted sulfuric acid, and following thermal activation by KOH at 800 degrees C. The morphology, structure and textural property of the prepared porous carbon (PC) are investigated by scanning electron microscopy, transmission electron microscopy, N2 sorption isotherms, and X-ray photoelectron spectroscopy. The porous carbon possesses a high BET surface area of 1759 m(2) g(-1) and an average pore size of 3.11 nm as well as hetero oxygen (9.09%) and nitrogen (1.7%) doping. Such porous carbon shows outstanding capacitive performances of 416 F g(-1) and 300 F g(-1) in three and two-electrode systems, respectively. As a solid-state adsorbent, the obtained porous carbon has an excellent CO2 adsorption capacity at ambient pressures of up to 6.71 and 4.45 mmol g(-1) at 0 and 25 degrees C, respectively. The results present one novel precursor-synthesis route for facile large-scale production of high performance porous carbon for a variety of great applications including energy storage and CO2 capture. PMID- 26935396 TI - Long non-coding RNA-Low Expression in Tumor inhibits the invasion and metastasis of esophageal squamous cell carcinoma by regulating p53 expression. AB - Long non-coding RNAs (lncRNAs) are involved in governing fundamental biological processes, and, in many lncRNAs, the expression level is altered and likely to have a functional role in tumorigenesis, including apoptosis, migration and invasion. The lncRNA-Low Expression in Tumor (LET), a recently identified lncRNA, was demonstrated to be downregulated in hepatocellular and gallbladder cancer. However, its role in esophageal squamous cell carcinoma (ESCC) requires investigation. The expression level of lncRNA-LET mRNA in primary ESCC and matched healthy tissues (48 cases) was determined by reverse transcription quantitative polymerase chain reaction. In addition, the effects of lncRNA-LET on cell apoptosis were evaluated by flow cytometric analysis, the regulatory effect of lncRNA-LET on migration was detected using a wound healing assay and cellular invasion was analyzed by Matrigel-coated transwell assay. Furthermore, the effect of lncRNA-LET on cell proliferation was investigated by 5-ethynyl-2'-deoxyuridine cell proliferation assay and protein levels of lncRNA-LET targets were analyzed by western blotting. lncRNA-LET expression was decreased in primary ESCC tissues when compared with paired healthy tissues, and was identified to be associated with the clinical features. Overexpression of lncRNA-LET was observed to inhibit the migration and invasion of ESCC cells, and modulate p53 expression levels in human ESCC cell lines in vitro. These results establish that lncRNA-LET is significant in the regulation of tumor progression and metastasis, and serves as a tumor suppressor in, and therefore has therapeutic potential for, the treatment of human ESCC. PMID- 26935398 TI - Characterizing mutation-expression network relationships in multiple cancers. AB - BACKGROUND: Data made available through large cancer consortia like The Cancer Genome Atlas make for a rich source of information to be studied across and between cancers. In recent years, network approaches have been applied to such data in uncovering the complex interrelationships between mutational and expression profiles, but lack direct testing for expression changes via mutation. In this pan-cancer study we analyze mutation and gene expression information in an integrative manner by considering the networks generated by testing for differences in expression in direct association with specific mutations. We relate our findings among the 19 cancers examined to identify commonalities and differences as well as their characteristics. RESULTS: Using somatic mutation and gene expression information across 19 cancers, we generated mutation-expression networks per cancer. On evaluation we found that our generated networks were significantly enriched for known cancer-related genes, such as skin cutaneous melanoma (p<0.01 using Network of Cancer Genes 4.0). Our framework identified that while different cancers contained commonly mutated genes, there was little concordance between associated gene expression changes among cancers. Comparison between cancers showed a greater overlap of network nodes for cancers with higher overall non-silent mutation load, compared to those with a lower overall non silent mutation load. CONCLUSIONS: This study offers a framework that explores network information through co-analysis of somatic mutations and gene expression profiles. Our pan-cancer application of this approach suggests that while mutations are frequently common among cancer types, the impact they have on the surrounding networks via gene expression changes varies. Despite this finding, there are some cancers for which mutation-associated network behaviour appears to be similar: suggesting a potential framework for uncovering related cancers for which similar therapeutic strategies may be applicable. Our framework for understanding relationships among cancers has been integrated into an interactive R Shiny application, PAn Cancer Mutation Expression Networks (PACMEN), containing dynamic and static network visualization of the mutation-expression networks. PACMEN also features tools for further examination of network topology characteristics among cancers. PMID- 26935399 TI - Protein inference: A protein quantification perspective. AB - In mass spectrometry-based shotgun proteomics, protein quantification and protein identification are two major computational problems. To quantify the protein abundance, a list of proteins must be firstly inferred from the raw data. Then the relative or absolute protein abundance is estimated with quantification methods, such as spectral counting. Until now, most researchers have been dealing with these two processes separately. In fact, the protein inference problem can be regarded as a special protein quantification problem in the sense that truly present proteins are those proteins whose abundance values are not zero. Some recent published papers have conceptually discussed this possibility. However, there is still a lack of rigorous experimental studies to test this hypothesis. In this paper, we investigate the feasibility of using protein quantification methods to solve the protein inference problem. Protein inference methods aim to determine whether each candidate protein is present in the sample or not. Protein quantification methods estimate the abundance value of each inferred protein. Naturally, the abundance value of an absent protein should be zero. Thus, we argue that the protein inference problem can be viewed as a special protein quantification problem in which one protein is considered to be present if its abundance is not zero. Based on this idea, our paper tries to use three simple protein quantification methods to solve the protein inference problem effectively. The experimental results on six data sets show that these three methods are competitive with previous protein inference algorithms. This demonstrates that it is plausible to model the protein inference problem as a special protein quantification task, which opens the door of devising more effective protein inference algorithms from a quantification perspective. The source codes of our methods are available at: http://code.google.com/p/protein inference/. PMID- 26935400 TI - WITHDRAWN: Identification of microRNA precursor based on gapped n-tuple structure status composition kernel. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 26935402 TI - An elegant route to overcome fundamentally-limited light extraction in AlGaN deep ultraviolet light-emitting diodes: Preferential outcoupling of strong in-plane emission. AB - While there is an urgent need for semiconductor-based efficient deep ultraviolet (DUV) sources, the efficiency of AlGaN DUV light-emitting diodes (LEDs) remains very low because the extraction of DUV photons is significantly limited by intrinsic material properties of AlGaN. Here, we present an elegant approach based on a DUV LED having multiple mesa stripes whose inclined sidewalls are covered by a MgF2/Al omni-directional mirror to take advantage of the strongly anisotropic transverse-magnetic polarized emission pattern of AlGaN quantum wells. The sidewall-emission-enhanced DUV LED breaks through the fundamental limitations caused by the intrinsic properties of AlGaN, thus shows a remarkable improvement in light extraction as well as operating voltage. Furthermore, an analytic model is developed to understand and precisely estimate the extraction of DUV photons from AlGaN DUV LEDs, and hence to provide promising routes for maximizing the power conversion efficiency. PMID- 26935403 TI - Oral health knowledge and practice of 12 to 14-year-old Almajaris in Nigeria: A problem of definition and a call to action. AB - We studied oral health knowledge and practices of 12 to 14-year-old Almajiri boys in northern Nigeria because we found few studies on their health, and none on their oral health. We present our study after explaining the desperate life circumstances and context of Nigeria's approximately 10 million Almajiri youth. Our results, when compared with those of previously studied populations (those most similar in terms of environment, age range, and oral health characteristics) show that the Almajiris fare poorly. Although the international community has paid some attention to the Nigerian Almajiri children's educational needs, there has been little support for health, and none for oral health. We argue that the World Health Organization could better assist Nigeria and these children by assuring that the Almajiris are not excluded from programs targeting children classified as 'street children', and make specific recommendations. PMID- 26935401 TI - Predicted molecular signaling guiding photoreceptor cell migration following transplantation into damaged retina. AB - To replace photoreceptors lost to disease or trauma and restore vision, laboratories around the world are investigating photoreceptor replacement strategies using subretinal transplantation of photoreceptor precursor cells (PPCs) and retinal progenitor cells (RPCs). Significant obstacles to advancement of photoreceptor cell-replacement include low migration rates of transplanted cells into host retina and an absence of data describing chemotactic signaling guiding migration of transplanted cells in the damaged retinal microenvironment. To elucidate chemotactic signaling guiding transplanted cell migration, bioinformatics modeling of PPC transplantation into light-damaged retina was performed. The bioinformatics modeling analyzed whole-genome expression data and matched PPC chemotactic cell-surface receptors to cognate ligands expressed in the light-damaged retinal microenvironment. A library of significantly predicted chemotactic ligand-receptor pairs, as well as downstream signaling networks was generated. PPC and RPC migration in microfluidic ligand gradients were analyzed using a highly predicted ligand-receptor pair, SDF-1alpha - CXCR4, and both PPCs and RPCs exhibited significant chemotaxis. This work present a systems level model and begins to elucidate molecular mechanisms involved in PPC and RPC migration within the damaged retinal microenvironment. PMID- 26935404 TI - Building codes: An often overlooked determinant of health. AB - Although the vast majority of the world's population spends most of their time in buildings, building codes are not often thought of as 'determinants of health'. The standards that govern the design, construction, and use of buildings affect our health, security, safety, and well-being. This is true for dwellings, schools, and universities, shopping centers, places of recreation, places of worship, health-care facilities, and workplaces. We urge proactive engagement by the global public health community in developing these codes, and in the design and implementation of health protection and health promotion activities intended to reduce the risk of injury, disability, and death, particularly when due to poor building code adoption/adaption, application, and enforcement. PMID- 26935405 TI - Three-dimensionally Ordered Macroporous Structure Enabled Nanothermite Membrane of Mn2O3/Al. AB - Mn2O3 has been selected to realize nanothermite membrane for the first time in the literature. Mn2O3/Al nanothermite has been synthesized by magnetron sputtering a layer of Al film onto three-dimensionally ordered macroporous (3DOM) Mn2O3 skeleton. The energy release is significantly enhanced owing to the unusual 3DOM structure, which ensures Al and Mn2O3 to integrate compactly in nanoscale and greatly increase effective contact area. The morphology and DSC curve of the nanothermite membrane have been investigated at various aluminizing times. At the optimized aluminizing time of 30 min, energy release reaches a maximum of 2.09 kJ?g(-1), where the Al layer thickness plays a decisive role in the total energy release. This method possesses advantages of high compatibility with MEMS and can be applied to other nanothermite systems easily, which will make great contribution to little-known nanothermite research. PMID- 26935406 TI - Menadione-Induced DNA Damage Leads to Mitochondrial Dysfunction and Fragmentation During Rosette Formation in Fuchs Endothelial Corneal Dystrophy. AB - AIMS: Fuchs endothelial corneal dystrophy (FECD), a leading cause of age-related corneal edema requiring transplantation, is characterized by rosette formation of corneal endothelium with ensuing apoptosis. We sought to determine whether excess of mitochondrial reactive oxygen species leads to chronic accumulation of oxidative DNA damage and mitochondrial dysfunction, instigating cell death. RESULTS: We modeled the pathognomonic rosette formation of postmitotic corneal cells by increasing endogenous cellular oxidative stress with menadione (MN) and performed a temporal analysis of its effect in normal (HCEnC, HCECi) and FECD (FECDi) cells and ex vivo specimens. FECDi and FECD ex vivo specimens exhibited extensive mtDNA and nDNA damage as detected by quantitative PCR. Exposure to MN triggered an increase in mitochondrial superoxide levels and led to mtDNA and nDNA damage, while DNA amplification was restored with NAC pretreatment. Furthermore, MN exposure led to a decrease in DeltaPsim and adenosine triphosphate levels in normal cells, while FECDi exhibited mitochondrial dysfunction at baseline. Mitochondrial fragmentation and cytochrome c release were detected in FECD tissue and after MN treatment of HCEnCs. Furthermore, cleavage of caspase-9 and caspase-3 followed MN-induced cytochrome c release in HCEnCs. INNOVATION: This study provides the first line of evidence that accumulation of oxidative DNA damage leads to rosette formation, loss of functionally intact mitochondria via fragmentation, and subsequent cell death during postmitotic cell degeneration of ocular tissue. CONCLUSION: MN induced rosette formation, along with mtDNA and nDNA damage, mitochondrial dysfunction, and fragmentation, leading to activation of the intrinsic apoptosis via caspase cleavage and cytochrome c release. Antioxid. Redox Signal. 24, 1072-1083. PMID- 26935407 TI - Haemodynamic benefits of rapid deployment aortic valve replacement via a minimally invasive approach: 1-year results of a prospective multicentre randomized controlled trial. AB - OBJECTIVES: Aortic valve replacement (AVR) via minimally invasive surgery (MIS) may provide clinical benefits in patients with aortic valve disease. A new class of bioprosthetic valves that enable rapid deployment AVR (RDAVR) may facilitate MIS. We here report the 1-year results of a randomized, multicentre trial comparing the outcomes for MIS-RDAVR with those for conventional AVR via full sternotomy (FS) with a commercially available stented aortic bioprosthesis. METHODS: A total of 100 patients with aortic stenosis were enrolled in a prospective, multicentre, randomized comparison trial (CADENCE-MIS). Key exclusion criteria included AVR requiring concomitant procedures, ejection fraction of <25% and recent myocardial infarction or stroke. Patients were randomized to undergo MIS-RDAVR via upper hemisternotomy (EDWARDS INTUITY) or AVR via FS with a commercially available stented valve. Procedural, early and late clinical outcomes were assessed for both groups. Haemodynamic performance was evaluated by an echocardiography CoreLaboratory. RESULTS: Technical success was achieved in 94% of MIS-RDAVR patients. MIS-RDAVR was associated with significantly reduced cross-clamp times compared with FS (41.3 +/- 20.3 vs 54.0 +/- 20.3 min, P < 0.001). Clinical and functional outcomes were similar at 30 days and 1 year postoperatively for both groups. While both groups received a similarly sized implanted valve (22.9 +/- 2.1 mm MIS-RDAVR vs 23.0 +/- 2.1 mm FS AVR; P = 0.91), MIS-RDAVR patients had significantly lower peak gradients 1 year postoperatively (16.9 +/- 5.3 vs 21.9 +/- 8.6 mmHg; P = 0.033) and a trend towards lower mean gradients (9.1 +/- 2.9 vs 11.5 +/- 4.3 mmHg; P = 0.082). In addition, MIS-RDAVR patients had a significantly larger effective orifice area 1 year postoperatively (1.9 +/- 0.5 vs 1.7 +/- 0.4 cm2; P = 0.047). Paravalvular leaks, however, were significantly more common in the MIS-RDAVR group (P = 0.027). CONCLUSIONS: MIS-RDAVR is associated with a significantly reduced cross clamp time and better valvular haemodynamic function than FS-AVR. However, paravalvular leak rates are higher with MIS-RDAVR. PMID- 26935408 TI - The pro-social neurohormone oxytocin reverses the actions of the stress hormone cortisol in human ovarian carcinoma cells in vitro. AB - The journey patients with ovarian cancer travel from non-specific symptoms causing delayed diagnosis through surgery and chemotherapy, culminating in a 5 year survival rate of 43%, must have a profound and detrimental psychological impact on patients. Emerging studies link higher levels of oxytocin (OT) and increased social support, an independent prognostic factor in cancer, with a moderating effect on stress. In contrast, there is a known association of tumour cell proliferation with elevated cortisol (stress hormone) levels. We hypothesise therefore that there is cross-talk between cortisol and oxytocin at a molecular level. Three ovarian cancer cell lines, used as in vitro models, were treated with cortisol at concentrations mimicking physiological stress in vivo in the presence or absence of OT. OT reduced cell proliferation and migration, induced apoptosis and autophagy for all three cell lines, partially reversing the effects of cortisol. Quantitative RT-PCR of tissue taken from ovarian cancer patients revealed that the glucocorticoid receptor (splice variant GR-P) and OT receptor (OTR) were significantly upregulated compared to controls. Tissue microarray revealed that the expression of GRalpha was lower in the ovarian cancer samples compared to normal tissue. OT is also shown to drive alternative splicing of the GR gene and cortisol-induced OTR expression. OT was able to transactivate GR in the presence of cortisol, thus providing further evidence of cross-talk in vitro. These data provide explanations for why social support might help distressed ovarian cancer patients and help define novel hypotheses regarding potential therapeutic interventions in socially isolated patients. PMID- 26935409 TI - Synthesis of a new family of ionophores based on aluminum-dipyrrin complexes (ALDIPYs) and their strong recognition of alkaline earth ions. AB - Mononuclear and dinuclear aluminum-dipyrrin complexes (ALDIPYs) were synthesized as a new family of ionophores. They exhibited colorimetric and fluorometric responses to alkaline earth ions in an aqueous mixed solvent. The strong recognition was achieved via multipoint interactions with the oxygen atoms appropriately incorporated into the ligand framework. PMID- 26935411 TI - Colloidal quantum dot lasers built on a passive two-dimensional photonic crystal backbone. AB - We report the room-temperature lasing action from two-dimensional photonic crystal (PC) structures composed of a passive Si3N4 backbone with an over-coat of CdSe/CdS/ZnS colloidal quantum dots (CQDs) for optical gain. When optically excited, devices lased in dual PC band-edge modes, with the modal dominance governed by the thickness of the CQD over-layer. The demonstrated laser platform should have an impact on future photonic integrated circuits as the on-chip coupling between active and passive components is readily achievable. PMID- 26935410 TI - Effect of the harvest procedure and tissue site on the osteogenic function of and gene expression in human mesenchymal stem cells. AB - Evidence has indicated that mesenchymal stem cells (MSCs) harvested with the Reamer/Irrigator/Aspirator (RIA) procedure exhibited an improved osteogenic differentiation capability compared with MSCs obtained by bone marrow aspiration from the iliac crest. In the present study, we hypothesized that the harvest procedure indeed influences the osteogenic activity of human MSCs more than the tissue site itself. Concentration [by colony forming unit-fibroblast (CFU-F) assay], calcification (by von Kossa staining), collagen deposition, gene expression and the gene methylation of the bone morphogenetic protein (BMP)-2 pathway [BMP2, SMAD5 and runt-related transcription factor 2 (RUNX2)], the Wnt pathway [WNT3, dickkopf-1 (DKK1), low-density lipoprotein receptor-related protein 5 (LRP5) and beta-catenin] and osteogenic genes [alkaline phosphatase (ALP), collagen, type I, alpha 1 (COL1A) and osteocalcin] were analyzed in the MSCs isolated intraoperatively from the iliac crest with a spoon (n=14), from the femur with a spoon (n=7), from the femur with the RIA procedure (n=13) and from the iliac crest by fine-needle aspiration (n=8, controls). A Bonferroni-Holm corrected p-value <0.05 indicated a statistically significant difference. The concentration of CFU-F in the MSCs was increased in the RIA debris in comparison with that in the iliac crest aspirates (trend) and the femur (spoon, significant). Calcium deposition was highest in the femur-derived MSCs (by RIA) and was significantly increased in comparison with that in the iliac crest derived MSCs (spoon, aspirate). The gene expression of BMP2, SMAD5, RUNX2, osteocalcin, and COL1A was significantly increased in the femur-derived MSCs (spoon) and the iliac crest aspirate derived-MSCs in comparison with that in the femur-derived MSCs (by RIA). There was no significant diversity between the samples obtained using a spoon (from the femur or iliac crest). Calcium deposition and osteogenic gene expression decreased significantly with the increasing passage number in all the samples. The methylation of genes did not correlate with their respective gene expression and inconsistent differences were observed between the groups. Herein, we provide evidence that the harvest procedure is a critical factor in the osteogenesis of MSCs in vitro. The MSCs isolated from the femur and iliac crest using a spoon exhibit no significant differences. The altered gene expression and function of the femur-derived MSCs (by RIA) may be due to the harsh isolation procedure. The variable differentiation ability of the MSCs, which depends on the harvest site and the harvest technique, as well as the rapid loss of the osteogenic differentiation capacity with the increasing culture duration should be taken into consideration when using MSCs as a potential therapeutic application for bone tissue engineering. PMID- 26935412 TI - Ethanol-induced mitophagy in liver is associated with activation of the PINK1 Parkin pathway triggered by oxidative DNA damage. AB - Mitophagy is a cytoprotective mechanism against mitochondrial damaging agents. Studies demonstrating morphological evidence for the involvement of the PINK1 Parkin pathway in the hepatocyte mitophagic response to ethanol toxicity, and potential links to apoptosis and mitochondrial alterations such as spheroid formation are still lacking. We addressed these unresolved issues using a rat model of binge alcohol exposure. Adult rats were injected with ethanol (5g/kg) and liver samples were taken at 0, 3, 6, and 24 hours after ethanol administration and processed for light and electron microscopic studies. Ethanol induced a low level of hepatocyte apoptosis, peaking at 3 h and decreasing significantly by 24 h. In contrast, there was enhanced formation of mitophagic vacuoles in the majority of normal hepatocytes of ethanol-treated rats (ETRs), which peaked at 6 h and was maintained up to 24 h based on electron microscopy and TUNEL/LC3 double labelling. Moreover, enhanced mitophagy in ETR hepatocytes was confirmed by increased LC3 puncta formation, and co-localization of Parkin and LC3 with mitochondrial and lysosomal markers. Immunoelectron microscopy demonstrated the localization of PINK1 and Parkin to damaged mitochondria of ETR hepatocytes, which was consistent with co-localization of Parkin with 8-OHdG, a marker of oxidative mitochondrial DNA damage. Furthermore, electron microscopy showed enhanced formation of mitochondrial spheroids in ETR hepatocytes. These data are the first direct morphological evidence linking PINK1-Parkin pathway activation to the enhanced mitophagic response of hepatocytes to ethanol toxicity. Ethanol-induced hepatic mitophagy may be a prosurvival mechanism, which may have therapeutic implications. PMID- 26935413 TI - Association of serum uric acid levels with the risk of development or progression of albuminuria among Japanese patients with type 2 diabetes: a prospective cohort study [Diabetes Distress and Care Registry at Tenri (DDCRT 10)]. AB - AIMS: To assess the prospective association between baseline serum uric acid level and subsequent risk of development or progression in albuminuria. METHODS: Longitudinal data were obtained from 2518 patients with type 2 diabetes in the development cohort and registered in a Japanese diabetes registry. To assess the independent correlations between baseline serum uric acid quartiles and either the development or progression of diabetic nephropathy for 2 years, the Cox proportional hazards model was used and adjusted for potential confounders. RESULTS: The mean patient age, body mass index, and glycated hemoglobin (HbA1c) level were 66.1 years, 24.6 kg/m(2), and 7.5 % (57.6 mmol/mol), respectively. The baseline serum uric acid levels, with mean values of 3.6, 4.9, 5.8, and 7.3 mg/dL from the first to fourth quartiles, were significantly associated with the urinary albumin/creatinine ratio at baseline (p < 0.001). Baseline uric acid levels were not significantly associated with the development of nephropathy, but they were with the progression of nephropathy. The multivariable-adjusted hazards ratios for the progression from microalbuminuria to macroalbuminuria were 2.17 [95 % confidence interval (CI) 1.15-4.08; p = 0.016], 3.04 (95 % CI 1.67-5.53; p < 0.001), and 3.56 (95 % CI 1.83-6.93; p < 0.0011) for the first, third, and fourth quartiles of serum uric acid levels, respectively, as compared to that for the second quartile. We did not observe significant association between uric acid levels and change in estimated glomerular filtration rate. CONCLUSIONS: Low and high serum uric levels, independent of possible confounders, were associated with a subsequent risk of progression, not development, in albuminuria in type 2 diabetes patients. Therefore, serum uric acid levels may be useful for predicting the future risk of progression of microalbuminuria. PMID- 26935414 TI - Anti-atherogenic effect of trivalent chromium-loaded CPMV nanoparticles in human aortic smooth muscle cells under hyperglycemic conditions in vitro. AB - Atherosclerosis, a major macrovascular complication associated with diabetes, poses a tremendous burden on national health care expenditure. Despite extensive efforts, cost-effective remedies are unknown. Therapies for atherosclerosis are challenged by a lack of targeted drug delivery approaches. Toward this goal, we turn to a biology-derived drug delivery system utilizing nanoparticles formed by the plant virus, Cowpea mosaic virus (CPMV). The aim herein is to investigate the anti-atherogenic potential of the beneficial mineral nutrient, trivalent chromium, loaded CPMV nanoparticles in human aortic smooth muscle cells (HASMC) under hyperglycemic conditions. A non-covalent loading protocol is established yielding CrCl3-loaded CPMV (CPMV-Cr) carrying 2000 drug molecules per particle. Using immunofluorescence microscopy, we show that CPMV-Cr is readily taken up by HASMC in vitro. In glucose (25 mM)-stimulated cells, 100 nM CPMV-Cr inhibits HASMC proliferation concomitant to attenuated proliferating cell nuclear antigen (PCNA, proliferation marker) expression. This is accompanied by attenuation in high glucose-induced phospho-p38 and pAkt expression. Moreover, CPMV-Cr inhibits the expression of pro-inflammatory cytokines, transforming growth factor-beta (TGF-beta) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF kappaB), in glucose-stimulated HASMCs. Finally glucose-stimulated lipid uptake is remarkably abrogated by CPMV-Cr, revealed by Oil Red O staining. Together, these data provide key cellular evidence for an atheroprotective effect of CPMV-Cr in vascular smooth muscle cells (VSMC) under hyperglycemic conditions that may promote novel therapeutic ventures for diabetic atherosclerosis. PMID- 26935415 TI - The expanding spectrum of HCV-related cryoglobulinemic vasculitis: a narrative review. AB - Cryoglobulinemic vasculitis (CV) is a small-to-medium-vessel vasculitis that appears in 10-15 % of patients chronically infected with hepatitis C virus (HCV). The classic symptom triad of CV, purpura/asthenia/arthralgia, is accompanied by clinical features that include glomerulonephritis, neuropathy, interstitial pneumonitis, and cardiomyopathy, ranging in their severity from mild to life threatening. The risk of developing non-Hodgkin lymphoma is also higher. The cumulative 10-year survival rate of CV patients is significantly lower than in the age- and sex-matched general population, with death typically caused by nephropathy, malignancies, liver involvement, and severe infections. Unfailing serological stigmata include both a cryoglobulin IgM fraction with rheumatoid factor activity and decreased complement C4 levels. On peripheral B cells, the expression of the CD81 B cell receptor is reduced while that of the CD19 receptor is increased. A monoclonal B cell lymphocytosis develops in almost one-third of patients. HCV-related proteins (but not HCV-RNA genomic sequences) can be detected on biopsy samples by immunofluorescence and immunohistochemistry and involve the vessel lumen, vessel walls, and the perivascular spaces of the skin, kidney, and peripheral nerves, supporting the pathogenetic role of HCV in the onset of a widespread microvasculitis. Based on the demonstration of HCV infection in the large majority of CV patients, a therapeutic regimen consisting of once-weekly pegylated interferon-alpha and the daily administration of ribavirin results in a sustained virologic response in ~50 % of patients. In those with refractory and relapsing disease, addition of the anti-CD20 monoclonal antibody rituximab has significantly increased the overall response rates. The extension to CV of latest-generation direct-acting antivirals, strikingly successful in non-CV HCV-positive patients, has yielded high complete response rates according to the few studies published thus far. PMID- 26935416 TI - Transcriptomic Analysis Identifies Candidate Genes and Gene Sets Controlling the Response of Porcine Peripheral Blood Mononuclear Cells to Poly I:C Stimulation. AB - Polyinosinic-polycytidylic acid (poly I:C), a synthetic dsRNA analog, has been demonstrated to have stimulatory effects similar to viral dsRNA. To gain deep knowledge of the host transcriptional response of pigs to poly I:C stimulation, in the present study, we cultured and stimulated peripheral blood mononuclear cells (PBMC) of piglets of one Chinese indigenous breed (Dapulian) and one modern commercial breed (Landrace) with poly I:C, and compared their transcriptional profiling using RNA-sequencing (RNA-seq). Our results indicated that poly I:C stimulation can elicit significantly differentially expressed (DE) genes in Dapulian (g = 290) as well as Landrace (g = 85). We also performed gene set analysis using the Gene Set Enrichment Analysis (GSEA) package, and identified some significantly enriched gene sets in Dapulian (g = 18) and Landrace (g = 21). Most of the shared DE genes and gene sets were immune-related, and may play crucial rules in the immune response of poly I:C stimulation. In addition, we detected large sets of significantly DE genes and enriched gene sets when comparing the gene expression profile between the two breeds, including control and poly I:C stimulation groups. Besides immune-related functions, some of the DE genes and gene sets between the two breeds were involved in development and growth of various tissues, which may be correlated with the different characteristics of the two breeds. The DE genes and gene sets detected herein provide crucial information towards understanding the immune regulation of antiviral responses, and the molecular mechanisms of different genetic resistance to viral infection, in modern and indigenous pigs. PMID- 26935417 TI - Conflation of Short Identity-by-Descent Segments Bias Their Inferred Length Distribution. AB - Identity-by-descent (IBD) is a fundamental concept in genetics with many applications. In a common definition, two haplotypes are said to share an IBD segment if that segment is inherited from a recent shared common ancestor without intervening recombination. Segments several cM long can be efficiently detected by a number of algorithms using high-density SNP array data from a population sample, and there are currently efforts to detect shorter segments from sequencing. Here, we study a problem of identifiability: because existing approaches detect IBD based on contiguous segments of identity-by-state, inferred long segments of IBD may arise from the conflation of smaller, nearby IBD segments. We quantified this effect using coalescent simulations, finding that significant proportions of inferred segments 1-2 cM long are results of conflations of two or more shorter segments, each at least 0.2 cM or longer, under demographic scenarios typical for modern humans for all programs tested. The impact of such conflation is much smaller for longer (> 2 cM) segments. This biases the inferred IBD segment length distribution, and so can affect downstream inferences that depend on the assumption that each segment of IBD derives from a single common ancestor. As an example, we present and analyze an estimator of the de novo mutation rate using IBD segments, and demonstrate that unmodeled conflation leads to underestimates of the ages of the common ancestors on these segments, and hence a significant overestimate of the mutation rate. Understanding the conflation effect in detail will make its correction in future methods more tractable. PMID- 26935418 TI - Chicken gga-miR-103-3p Targets CCNE1 and TFDP2 and Inhibits MDCC-MSB1 Cell Migration. AB - Marek's disease (MD) is a highly contagious viral neoplastic disease caused by Marek's disease virus (MDV), which can lead to huge economic losses in the poultry industry. Recently, microRNAs (miRNAs) have been found in various cancers and tumors. In recent years, 994 mature miRNAs have been identified through deep sequencing in chickens, but only a few miRNAs have been investigated further in terms of their function. Previously, gga-miR-103-3p was found downregulated in MDV-infected samples by using Solexa deep sequencing. In this study, we further verified the expression of gga-miR-103-3p among MDV-infected spleen, MD lymphoma from liver, noninfected spleen, and noninfected liver, by qPCR. The results showed that the expression of gga-miR-103-3p was decreased in MDV-infected tissues, which was consistent with our previous study. Furthermore, two target genes of gga-miR-103-3p, cyclin E1 (CCNE1) and transcription factor Dp-2 (E2F dimerization partner 2) (TFDP2), were predicted and validated by luciferase reporter assay, qPCR, and western blot analysis. The results suggested that CCNE1 and TFDP2 are direct targets of gga-miR-103-3p in chickens. Subsequent cell proliferation and migration assay showed that gga-miR-103-3p suppressed MDCC-MSB1 migration, but did not obviously modulate MDCC-MSB1 cell proliferation. In conclusion, gga-miR-103-3p targets the CCNE1 and TFDP2 genes, and suppresses cell migration, which indicates that it might play an important role in MD tumor transformation. PMID- 26935420 TI - Highly-active oxygen evolution electrocatalyzed by a Fe-doped NiSe nanoflake array electrode. AB - Alkaline water electrolysis offers a simple method for mass production of hydrogen but suffers from the sluggish kinetics of the anodic oxygen evolution reaction (OER), calling for the development of low-cost and durable oxygen evolution electrocatalysts with high activity. In this communication, we report a highly-active robust oxygen evolution electrode, developed by in situ hydrothermal growth of an Fe-doped NiSe nanoflake array directly on a macroporous FeNi foam (Fe-NiSe/FeNi foam). This electrode catalyzes the OER with an onset overpotential as low as 200 mV and needs overpotentials of 245 and 264 mV to achieve 50 and 100 mA cm(-2), respectively, in 1.0 M KOH. Remarkably, it is also highly robust to drive 500 and 1000 mA cm(-2) at overpotentials of 246 and 263 mV, respectively, in 30 wt% KOH. PMID- 26935419 TI - The Genetic Basis of Baculum Size and Shape Variation in Mice. AB - The rapid divergence of male genitalia is a preeminent evolutionary pattern. This rapid divergence is especially striking in the baculum, a bone that occurs in the penis of many mammalian species. Closely related species often display diverse baculum morphology where no other morphological differences can be discerned. While this fundamental pattern of evolution has been appreciated at the level of gross morphology, nearly nothing is known about the genetic basis of size and shape divergence. Quantifying the genetic basis of baculum size and shape variation has been difficult because these structures generally lack obvious landmarks, so comparing them in three dimensions is not straightforward. Here, we develop a novel morphometric approach to quantify size and shape variation from three-dimensional micro-CT scans taken from 369 bacula, representing 75 distinct strains of the BXD family of mice. We identify two quantitative trait loci (QTL) that explain ~50% of the variance in baculum size, and a third QTL that explains more than 20% of the variance in shape. Together, our study demonstrates that baculum morphology may diverge relatively easily, with mutations at a few loci of large effect that independently modulate size and shape. Based on a combination of bioinformatic investigations and new data on RNA expression, we prioritized these QTL to 16 candidate genes, which have hypothesized roles in bone morphogenesis and may enable future genetic manipulation of baculum morphology. PMID- 26935421 TI - Inflammation-Related IL1beta/IL1R Signaling Promotes the Development of Asbestos Induced Malignant Mesothelioma. AB - Exposure to asbestos is causally associated with the development of malignant mesothelioma, a cancer of cells lining the internal body cavities. Malignant mesothelioma is an aggressive cancer resistant to all current therapies. Once inhaled or ingested, asbestos causes inflammation in and around tissues that come in contact with these carcinogenic fibers. Recent studies suggest that inflammation is a major contributing factor in the development of many types of cancer, including malignant mesothelioma. The NALP3/NLRP3 inflammasome, including the component ASC, is thought to be an important mediator of inflammation in cells that sense extracellular insults, such as asbestos, and activate a signaling cascade resulting in release of mature IL1beta and recruitment of inflammatory cells. To determine if inflammasome-mediated inflammation contributes to asbestos-induced malignant mesothelioma, we chronically exposed Asc-deficient mice and wild-type littermates to asbestos and evaluated differences in tumor incidence and latency. The Asc-deficient mice showed significantly delayed tumor onset and reduced malignant mesothelioma incidence compared with wild-type animals. We also tested whether inflammation-related release of IL1beta contributes to tumor development in an accelerated mouse model of asbestos-induced malignant mesothelioma. Nf2(+/-);Cdkn2a(+/-) mice exposed to asbestos in the presence of anakinra, an IL1 receptor (IL1R) antagonist, showed a marked delay in the median time of malignant mesothelioma onset compared with similarly exposed mice given vehicle control (33.1 weeks vs. 22.6 weeks, respectively). Collectively, these studies provide evidence for a link between inflammation-related IL1beta/IL1R signaling and the development of asbestos induced malignant mesothelioma. Furthermore, these findings provide rationale for chemoprevention strategies targeting IL1beta/IL1R signaling in high-risk, asbestos-exposed populations. Cancer Prev Res; 9(5); 406-14. (c)2016 AACR. PMID- 26935422 TI - Cervical Microbiota Associated with Higher Grade Cervical Intraepithelial Neoplasia in Women Infected with High-Risk Human Papillomaviruses. AB - It is increasingly recognized that microbes that reside in and on human body sites play major roles in modifying the pathogenesis of several diseases, including cancer. However, specific microbes or microbial communities that can be mechanistically linked to cervical carcinogenesis remain largely unexplored. The purpose of the study was to examine the association between cervical microbiota and high-grade cervical intraepithelial neoplasia (CIN 2+) in women infected with high-risk (HR) human papillomaviruses (HPV) and to assess whether the cervical microbiota are associated with oxidative DNA damage as indicated by the presence of cervical cells positive for 8-hydroxy-2'-deoxyguanosine. The study included 340 women diagnosed with CIN 2+ (cases) and 90 diagnosed with CIN 1 (non-cases). Microbiota composition was determined by Illumina sequencing of the 16S rRNA gene amplified from DNA extracted from cervical mucus samples. Measures of alpha/beta diversity were not associated with either CIN severity or oxidative DNA damage. However, a cervical mucosal community type (CT) dominated by L. iners and unclassified Lactobacillus spp was associated with CIN 2+ (OR = 3.48; 95% CI, 1.27-9.55). Sequence reads mapping to Lactobacillaceae, Lactobacillus, L. reuteri, and several sub-genus level Lactobacillus operational taxonomic units were also associated with CIN 2+ when examined independently (effect size >2.0; P < 0.05). Our 16S rRNA sequencing results need confirmation in independent studies using whole-genome shotgun sequencing and that would allow sharpening the suggested associations at finer taxonomic levels. Our results provide little evidence that DNA oxidative damage mediates the effect of the microbiome on the natural history of HPV infection and CIN severity. Cancer Prev Res; 9(5); 357-66. (c)2016 AACR. PMID- 26935423 TI - Re-Examining the Origin and Application of Determination of Death by Neurological Criteria (DDNC) : A Commentary on "The Case for Reasonable Accommodation of Conscientious Objections to Declarations of Brain Death" by L. Syd M. Johnson. PMID- 26935424 TI - Erratum to: The National Osteoporosis Foundation's position statement on peak bone mass development and lifestyle factors: a systematic review and implementation recommendations. PMID- 26935427 TI - Controlled Release of Chitosan and Sericin from the Microspheres-Embedded Wound Dressing for the Prolonged Anti-microbial and Wound Healing Efficacy. AB - One approach in wound dressing development is to incorporate active molecules or drugs in the dressing. In order to reduce the frequency of dressing changes as well as to prolong wound healing efficacy, wound dressings that can sustain the release of the active molecules should be developed. In our previous work, we developed chitosan/sericin (CH/SS) microspheres that released sericin in a controlled rate. However, the difficulty of applying the microspheres that easily diffuse and quickly degrade onto the wound was its limitations. In this study, we aimed to develop wound dressing materials which are easier to apply and to provide extended release of sericin. Different amounts of CH/SS microspheres were embedded into various compositions of polyvinyl alcohol/gelatin (PVA/G) scaffolds and fabricated using freeze-drying and glutaraldehyde crosslinking techniques. The obtained CH/SS microspheres-embedded scaffolds with appropriate design and formulation were introduced as a wound dressing material. Sericin was released from the microspheres and the scaffolds in a sustained manner. Furthermore, an optimized formation of the microspheres-embedded scaffolds (2PVA2G+2CHSS) was shown to possess an effective antimicrobial activity against both gram-positive and gram-negative bacteria. These microspheres-embedded scaffolds were not toxic to L929 mouse fibroblast cells, and they did not irritate the tissue when applied to the wound. Finally, probably by the sustained release of sericin, these microspheres-embedded scaffolds could promote wound healing as well as or slightly better than a clinically used wound dressing (Allevyn(r)) in a mouse model. The antimicrobial CH/SS microspheres-embedded PVA/G scaffolds with sustained release of sericin would appear to be a promising candidate for wound dressing application. PMID- 26935426 TI - PRINS, a primate-specific long non-coding RNA, plays a role in the keratinocyte stress response and psoriasis pathogenesis. AB - In the last few years with the recent emergence of high-throughput technologies, thousands of long non-coding RNAs (lncRNAs) have been identified in the human genome. However, assigning functional annotation and determining cellular contexts for these RNAs are still in its infancy. As information gained about lncRNA structure, interacting partners, and roles in human diseases may be helpful in the characterization of novel lncRNAs, we review our knowledge on a selected group of lncRNAs that were identified serendipitously years ago by large scale gene expression methods used to study human diseases. In particular, we focus on the Psoriasis-susceptibility-Related RNA Gene Induced by Stress (PRINS) lncRNA, first identified by our research group as a transcript highest expressed in psoriatic non-lesional epidermis. Results gathered for PRINS in the last 10 years indicate that it is conserved in primates and plays a role in keratinocyte stress response. Elevated levels of PRINS expression in psoriatic non-lesional keratinocytes alter the stress response of non-lesional epidermis and contribute to disease pathogenesis. Finally, we propose a categorization for the PRINS lncRNA based on a recently elaborated system for lncRNA classification. PMID- 26935428 TI - Pediatric Biopharmaceutical Classification System: Using Age-Appropriate Initial Gastric Volume. AB - Development of optimized pediatric formulations for oral administration can be challenging, time consuming, and financially intensive process. Since its inception, the biopharmaceutical classification system (BCS) has facilitated the development of oral drug formulations destined for adults. At least theoretically, the BCS principles are applied also to pediatrics. A comprehensive age-appropriate BCS has not been fully developed. The objective of this work was to provisionally classify oral drugs listed on the latest World Health Organization's Essential Medicines List for Children into an age-appropriate BCS. A total of 38 orally administered drugs were included in this classification. Dose numbers were calculated using age-appropriate initial gastric volume for neonates, 6-month-old infants, and children aging 1 year through adulthood. Using age-appropriate initial gastric volume and British National Formulary age specific dosing recommendations in the calculation of dose numbers, the solubility classes shifted from low to high in pediatric subpopulations of 12 years and older for amoxicillin, 5 years, 12 years and older for cephalexin, 9 years and older for chloramphenicol, 3-4 years, 9-11 and 15 years and older for diazepam, 18 years and older (adult) for doxycycline and erythromycin, 8 years and older for phenobarbital, 10 years and older for prednisolone, and 15 years and older for trimethoprim. Pediatric biopharmaceutics are not fully understood where several knowledge gaps have been recently emphasized. The current biowaiver criteria are not suitable for safe application in all pediatric populations. PMID- 26935429 TI - Resolving a Prickly Situation: Involving Stakeholders in Invasive Cactus Management in South Africa. AB - The regulation and management of alien species can be contentious, particularly when the stakeholders who benefit from alien species are different from those who suffer the costs. We propose a consultative process involving relevant stakeholders in invasive species management decisions. The process involves (1) the identification of relevant stakeholders, (2) assessing their perceptions, (3) enhancing interaction between stakeholders, (4) assessing changes in stakeholders' perceptions following interactions with other stakeholders, and (5) developing management recommendations in collaboration with stakeholders. We demonstrate the application of the process using the family Cactaceae ('cacti') in South Africa. Many species of cacti have been introduced to the country over the past two centuries, mostly for horticulture, food and fodder, and hundreds of other species have been introduced in the past few decades (or are likely to be introduced soon) for horticulture. Using the proposed process enabled the negotiation and participation of all stakeholders in decision making and helped minimize contentious situations by clarifying stakeholder's beliefs and exploring consensus solutions. Consequently, management objectives were broadly supported by all stakeholders. These results will be included in a national cactus management strategy for South Africa. PMID- 26935431 TI - Occurrence and genetic characterisation of Acanthamoeba spp. from environmental and domestic water sources in Queen Elizabeth Protected Area, Uganda. AB - BACKGROUND: Acanthamoeba is an emerging potentially pathogenic amoeba that has been receiving increasing attention worldwide as a reservoir and potential vector for the transmission of pathogenic bacteria. It is also associated with brain cell damage, keratitis and skin irritation in humans. Its effects are more severe in immunocompromised individuals. This study provides for the first time in Uganda, information on the prevalence and genotypes of Acanthamoeba in environmental and domestic (tap) water. METHODS: A total of 324 environmental and 84 tap water samples were collected between November 2013 and September 2014. The samples were centrifuged, cultured (Non-Nutrient agar seeded with gram-negative bacteria) and observed under a microscope. After confirmation of Acanthamoeba, genomic DNA was extracted for PCR assays by chemical lysis and purification with phenol/chloroform/isoamyl alcohol. Samples that showed the strongest positive bands (400-600 bp) were subjected to cycle sequencing. RESULTS: Among environmental and tap water samples, 107 (33 %) and 36 (42.9 %) tested positive for Acanthamoeba spp., respectively. Prevalence of Acanthamoeba from specific environmental locations was as follows; Kazinga channel banks (60.7 %), Fish landing sites (50 %), River Kyambura (39.6 %) and Kazinga mid channel (5.3 %). There was a significant difference (p = 0.001) in the prevalence of Acanthamoeba between sampling sites. The mean (Mean +/- SE) occurrence of the organism was higher in Kazinga channel banks (3.44 +/- 0.49) and Fish landing sites (3.08 +/- 0.53). Correlation between in situ parameters and Acanthamoeba was insignificant except for the Dissolved Oxygen (mg/ML) which was negatively correlated (r = 0.231, p = 0.001) to Acanthamoeba. Six distinct partial Acanthamoeba T-genotype groups T1, T2, T4, T5, T6 and T11 were obtained. Ultimately, Acanthamoeba spp., Acanthamoeba hatchetti and Acanthamoeba polyphaga were isolated in the current study. CONCLUSIONS: There was a high prevalence of Acanthamoeba in communal piped tap and environmental water used by communities, indicating poor environmental and domestic water quality. PMID- 26935432 TI - Progress in orthopedic biomaterials and drug delivery. PMID- 26935430 TI - Cannabis Abuse Is Increasing and Associated with Increased Emergency Department Utilization in Gastroenterology Patients. AB - BACKGROUND: The role of cannabinoids in gastrointestinal diseases is controversial and of great interest, yet their use in patients has not been critically examined. AIM: To determine the prevalence and effects of cannabis abuse on healthcare utilization, as measured by emergency department (ED) visits, in a large, tertiary gastroenterology practice. METHODS: All patients seen in the gastroenterology clinic at a tertiary care center during a 27-year period (1986 2013) were included in our study to determine the overall prevalence of cannabis abuse. We matched cannabis abusers 1:2 with non-abusing controls to determine the effect of cannabis on ED utilization, our primary outcome. We used multivariate linear regression to adjust for confounders and define the independent effect of cannabis abuse on ED utilization. RESULTS: Our prevalence study cohort included 190,303 GI clinic patients with an overall cannabis abuse prevalence of 0.80 % (1520 patients). From 1986 to 2012, the prevalence of cannabis abuse in this clinic increased by 0.73 % (0.03 %/year) (p < 0.0001). From the 1520 cannabis abusers identified, 467 patients were randomly selected as cases and were matched to 934 controls. From this retrospective cohort, the median ED visits/year for cannabis abusers was 1.88 versus 0.89 for non-abusers (p < 0.0001). After multivariate adjustment, cannabis abuse was associated with a 1.47-fold increase (95 % CI 1.23-1.76, p < 0.0001) in median ED visits/year. CONCLUSIONS: Reported cannabis abuse in GI clinic patients is less prevalent than in the adult US population, but is increasing. Cannabis abuse among gastroenterology patients is associated with increased ED visits. PMID- 26935433 TI - TGFbeta signaling regulates the choice between pluripotent and neural fates during reprogramming of human urine derived cells. AB - Human urine cells (HUCs) can be reprogrammed into neural progenitor cells (NPCs) or induced pluripotent stem cells (iPSCs) with defined factors and a small molecule cocktail, but the underlying fate choice remains unresolved. Here, through sequential removal of individual compound from small molecule cocktail, we showed that A8301, a TGFbeta signaling inhibitor, is sufficient to switch the cell fate from iPSCs into NPCs in OSKM-mediated HUCs reprogramming. However, TGFbeta exposure at early stage inhibits HUCs reprogramming by promoting EMT. Base on these data, we developed an optimized approach for generation of NPCs or iPSCs from HUCs with significantly improved efficiency by regulating TGFbeta activity at different reprogramming stages. This approach provides a simplified and improved way for HUCs reprogramming, thus would be valuable for banking human iPSCs or NPCs from people with different genetic background. PMID- 26935434 TI - Edoxaban: A Comprehensive Review of the Pharmacology and Clinical Data for the Management of Atrial Fibrillation and Venous Thromboembolism. AB - Historically, vitamin K antagonists have been the only class of oral anticoagulants available. Despite our experience with warfarin over the past 60 years, its use is associated with several pharmacokinetic and clinical disadvantages including unpredictable dosing, frequent monitoring, and delayed onset and offset. Edoxaban, an oral direct Xa inhibitor, may provide clinicians with an additional option in patients requiring chronic anticoagulation. This review examines the pharmacology and clinical data of edoxaban as a therapeutic alternative. PMID- 26935436 TI - Diagnosing true virtue? Remote scenarios, warranted virtue attributions, and virtuous medical practice. AB - Immanuel Kant argues in the Foundations that remote scenarios are diagnostic of genuine virtue. When agents commonly thought to have a particular virtue fail to exhibit that virtue in an extreme situation, he argues, they do not truly have the virtue at all, and our propensities to fail in such ways indicate that true virtue might never have existed. Kant's suggestion that failure to show, say, courage in extraordinary circumstances necessarily silences one's claim to have genuine courage seems to rely on an implausibly demanding standard for warranted virtue attributions. In contrast to this approach, some philosophers-such as Robert Adams and John Doris-have argued for probabilistic accounts of warranted virtue attributions. But despite the initial plausibility of such accounts, I argue that a sole reliance on probabilistic approaches is inadequate, as they are insufficiently sensitive to considerations of credit and fault, which emerge when agents have developed various insurance strategies and protective capacities against their responding poorly to particular eventualities. I also argue that medical graduates should develop the sorts of virtuous dispositions necessary to protect patient welfare against various countervailing influences (even where such influences might be encountered only rarely), and that repeated failures to uphold the proper goals of medicine in emergency scenarios might indeed be diagnostic of whether an individual practitioner does have the relevant medical virtue. In closing, I consider the dispositions involved in friendship. I seek to develop a principled way of determining when remote scenarios can be illuminating of genuine friendship and genuine virtue. PMID- 26935435 TI - Comparing Alzheimer's and Parkinson's diseases networks using graph communities structure. AB - BACKGROUND: Recent advances in large datasets analysis offer new insights to modern biology allowing system-level investigation of pathologies. Here we describe a novel computational method that exploits the ever-growing amount of "omics" data to shed light on Alzheimer's and Parkinson's diseases. Neurological disorders exhibit a huge number of molecular alterations due to a complex interplay between genetic and environmental factors. Classical reductionist approaches are focused on a few elements, providing a narrow overview of the etiopathogenic complexity of multifactorial diseases. On the other hand, high throughput technologies allow the evaluation of many components of biological systems and their behaviors. Analysis of Parkinson's Disease (PD) and Alzheimer's Disease (AD) from a network perspective can highlight proteins or pathways common but differently represented that can be discriminating between the two pathological conditions, thus highlight similarities and differences. RESULTS: In this work we propose a strategy that exploits network community structure identified with a state-of-the-art network community discovery algorithm called InfoMap, which takes advantage of information theory principles. We used two similarity measurements to quantify functional and topological similarities between the two pathologies. We built a Similarity Matrix to highlight similar communities and we analyzed statistically significant GO terms found in clustered areas of the matrix and in network communities. Our strategy allowed us to identify common known and unknown processes including DNA repair, RNA metabolism and glucose metabolism not detected with simple GO enrichment analysis. In particular, we were able to capture the connection between mitochondrial dysfunction and metabolism (glucose and glutamate/glutamine). CONCLUSIONS: This approach allows the identification of communities present in both pathologies which highlight common biological processes. Conversely, the identification of communities without any counterpart can be used to investigate processes that are characteristic of only one of the two pathologies. In general, the same strategy can be applied to compare any pair of biological networks. PMID- 26935437 TI - On the fragility of medical virtue in a neoliberal context: the case of commercial conflicts of interest in reproductive medicine. AB - Social, political, and economic environments play an active role in nurturing professional virtue. Yet, these environments can also lead to the erosion of virtue. As such, professional virtue is fragile and vulnerable to environmental shifts. While physicians are often considered to be among the most virtuous of professional groups, concern has also always existed about the impact of commercial arrangements on physicians' willingness and capacity to enact their professional virtues. This article examines the ways in which commercial arrangements have been negotiated to secure medical virtue from real or perceived threats of erosion. In particular, we focus on the concern surrounding conflicts of interest arising from commercial arrangements that have developed as a result of neoliberal economic and social policies. The deregulation of medical markets and privatization of services have produced new commercial relationships that are often misunderstood by patients, publics, and physicians themselves. 'Conflicts of interest' policies have been introduced in an attempt to safeguard ethical conduct and medical practice. However, a number of virtue ethicists have critiqued these policies as inadequate for securing virtue. We examine the ways in which commercial arrangements have been seen to impact upon medical virtue, both historically and in the context of modern medicine (using the example of fertility services in Australia). We then describe and critique current efforts to restore clinical virtue through both conflict of interest policies and through virtue ethics. Finally, we suggest some possible ways of addressing the corrosive effects of neoliberalism on medical virtue. PMID- 26935439 TI - Consolidation and Expansion of Perovskite Solar Cell Research. PMID- 26935438 TI - The new enhancement technologies and the place of vulnerability in our lives. AB - What is the place of vulnerability in our lives? The current debate about the ethics of enhancement technologies provides a context in which to think about this question. In my view, the current debate is likely to be fruitless, largely because we bring the wrong ethical resources to bear on its questions. In this article, I recall an important, but currently neglected, role that moral concepts play in our thinking, a role they should especially play in relation to the introduction of new technologies. I call this the 'contemplative role of moral concepts'. I then contrast two approaches to the contemplative role of moral concepts which are found in the current literature, and show why it is important to keep in mind both of these approaches when thinking about human vulnerability. PMID- 26935440 TI - Infective Endocarditis Presenting as Right Shoulder Pain: A Case Report. AB - Although cases of referred shoulder pain due to ischemic heart disease have been well documented, to our knowledge no reports on infective endocarditis accompanied by referred right shoulder pain have been published. A 43-year-old Japanese man presented with severe right shoulder pain and a body temperature of 38 degrees C.Blood tests showed inflammation and liver dysfunction, although magnetic resonance imaging did not indicate septic shoulder arthritis. However, contrast-enhanced computed tomography showed renal, splenic, and hepatic infarctions. Moreover, a labile vegetation was detected on an echocardiogram. The patient was diagnosed with infective endocarditis and antibiotics were administered intravenously. Infective endocarditis is a serious condition that can result in complications if it is not diagnosed and treated at an early stage. Therefore, in cases with referred shoulder pain, physicians should carefully consider the presence of internal diseases that may cause this condition, as in the present case. PMID- 26935441 TI - Comprehensive Health-Related Quality of Life is Influenced by Nocturia and Sleep Disturbance: Investigation Based on the SF-8. AB - We investigated the influence of nocturia and sleep disturbance on health-related quality of life(HRQOL) using the Medical Outcomes Study 8-item Short Form Health Survey (SF-8) in patients with nocturia. We also assessed the effect of therapeutic intervention by means of an anticholinergic agent on the results of the SF-8. One hundred and eighty-four patients who voided at least once per night were surveyed using the SF-8, Overactive Bladder Symptom Score (OABSS), Pittsburgh Sleep Quality Index (PSQI), and Epworth Sleepiness Scale (ESS). These parameters were also evaluated before and after 12 weeks of imidafenacin treatment in 51 patients with OAB accompanied by nocturia. The SF-8 physical component summary score (PCS) showed a significant decrease as nighttime voiding frequency increased. The mental health component summary score was 47.1 and 47.6 (which were lower than the standard value of 50) in the group with a nighttime frequency of once and >=3/night, respectively. The SF-8 PCS and 6 subscales were negatively associated with nighttime voiding frequency, while the PSQI global score was positively associated with it. Imidafenacin significantly improved the OABSS, PSQI, and ESS, as well as the SF-8 score. This is the first study using the SF-8 to show that nocturia and sleep disturbance have a major influence on comprehensive HRQOL and that the SF-8 can be used to monitor HRQOL in OAB patients receiving treatment for nocturia. PMID- 26935442 TI - Definitive Radiotherapy Following Induction Chemotherapy for Hypopharyngeal Cancer: Selecting Candidates for Organ-Preserving Treatment Based on the Response to Induction Chemotherapy. AB - The outcomes of induction chemotherapy followed by radiotherapy for hypopharyngeal carcinoma were analyzed to determine whether response to induction chemotherapy could be a useful parameter for selecting candidates for organ preserving therapy.Forty-three patients with hypopharyngeal carcinoma were treated with definitive radiotherapy with or without concurrent chemotherapy following induction chemotherapy. The predominant induction chemotherapy regimens involved cisplatin and 5-fluorouracil with or without docetaxel. The patients that responded to the induction chemotherapy received definitive organ-preserving treatment. Patients who did not respond to induction chemotherapy were considered for surgery, but only those patients who underwent definitive radiotherapy were analyzed in this study. Conventional radiotherapy was administered in all patients. The associations between clinical parameters including age, sex, performance status (PS), tumor site, T-category, N-category, stage, the regimen of induction chemotherapy, the response to induction chemotherapy, the presence/absence of concurrent chemotherapy, overall survival (OS), and local control (LC) were analyzed.Among the surviving patients, the follow-up period ranged from 10-145 months (median: 46 months). The 3-year OS and LC rates for all 43 patients were 61% and 70%, respectively. The 3-year OS and LC rates of the responders were 73% and 81%, respectively, whereas those of the non-responders were 29% and 40%, respectively. In multivariate analysis, only PS was correlated with overall survival (p=0.03). The complication rates were acceptable in all groups.Responders to induction chemotherapy appear to be good candidates for definitive organ-preserving treatment. Chemoselection appears to aid treatment selection in patients with hypopharyngeal carcinoma. PMID- 26935443 TI - Clinical Usefulness of Bakri Balloon Tamponade in the Treatment of Massive Postpartum Uterine Hemorrhage. AB - Intrauterine globe-shaped metreurynter tamponade has been used for some time to treat massive postpartum hemorrhage (PPH). More recently, the Bakri balloon has come into use to treat PPH. It is made of silicon, possesses a drainage lumen, and has a sausage-like spindle shape. The aim of the present study was to investigate the clinical usefulness of Bakri balloon tamponade for massive PPH. Subjects in the present study comprised 5 patients with uterine atony, 3 with placenta previa, and 2 with low-lying placenta. All patients exhibited massive PPH and resistance to conventional hemostatic managements. Bakri balloon tamponade was appliedto these 10 patients. The mean amounts of uterine bleeding (average +/- SD) before and after Bakri insertion were2,732 +/- 1,397 mL and 380 +/- 376 mL, respectively. The median (third-first quartile ranges) volume of salineinflating the balloon was 200 mL (300-150 mL). The median (third-first quartile ranges) indwelling duration of Bakri balloon was 24 hours (24-11 hrs). The overall success rate of Bakri balloon tamponade was 90% (9/10).There were no cases of slipping out or complications regarding balloon placement. Our findings suggest that Bakri balloon tamponade may be applied to the treatment of massive PPH in uterine atony and placenta previa.The Bakri balloon appears to have the following merits: (1) easy insertion into the uterine cavity and low rate of slipping out, (2) proper conformability to the hemorrhagic area due to its spindle shape, (3) ability to monitor blood loss through the drainage lumen even after insertion. PMID- 26935444 TI - Gross Anatomical Dissection of a Horseshoe Kidney: The Eighth Specimen in Our Medical School. AB - Horseshoe kidney is a known congenital renal anomaly. During a gross anatomy dissection course for students in 2014, a horseshoe kidney was found in an 80 year-old female. The isthmus was formed by the fusion of the right and left kidneys at their lower poles and resulted in a U-shaped kidney. Both sides of the renal hilum opened ventrally. Four surplus renal arteries entered the horseshoe kidney. The first surplus renal artery arose from the right side of the abdominal aorta, and entered the lower part of the renal hilum. The second surplus artery arose from the ventral side of the abdominal aorta, and entered the left inferior part of the left renal hilum.The third surplus artery also arose from the ventral side of the abdominal aorta and entered the inferior border of the left part of the isthmus. The fourth surplus artery arose from the bifurcation of the common iliac arteries and distributed to the inferior border of the middle of the isthmus. One surplus renal vein arose from the lower border of the middle of the isthmus, descended dorsally to the abdominal aorta and the right common iliac artery, and then entered the upper wall of the left common iliac vein. The isthmus was made up of renal parenchymal structures. These findings will be useful as regards research and surgery on the horseshoe kidney. This was the eighth case of horseshoe kidney in our laboratory. PMID- 26935445 TI - In silico exploration for agonists/antagonists of brassinolide. AB - Brassinolide (BL) is a plant steroid hormone that is necessary for stem elongation and cell division. To date more than 70 steroidal BL-like compounds, which are collectively named as brassinosteroids, have been identified. However, non-steroidal compounds that mimic BL have not been reported yet, which can be used as plant growth regulators. Twenty-two non-steroidal compounds were screened from the database containing about 5 million compound structures using a pharmacophore-based in silico screening method. The crystal structure (PDB: 4LSX) of the BL receptor was used to generate a pharmacophore model required for in silico screening. Among 22 hit compounds, 15 compounds that are thought to be physicochemically acceptable were submitted to the in vivo rice lamina inclination assay. Although no compound showed BL like activity, three compounds were detected as BL antagonist. The most potent compound was an ester derivative of 1,4-diphenlenedimethanol and isoxazole-4-carboxylic acid, and the other two compounds contain 2-phenylfuran and pyrimidin-2(1H)-one moieties bridged by an ethenyl substructure. The 50% effective doses (ED50) for the antagonistic activity were in a range of 0.6-5nmol per plant. The inhibition of the lamina inclination by the most potent agonist was recovered by the co-application of BL in a dose-dependent manner. PMID- 26935446 TI - Image guided therapy and the importance of local tumour control. PMID- 26935447 TI - [SPRINT study in clinical practice: The goal is to change control blood pressure?]. PMID- 26935449 TI - Two-incision Technique for Subcutaneous Cardioverter-defibrillator Implantation: Method of Choice? PMID- 26935448 TI - Genome-wide identification and evolutionary analyses of the PP2C gene family with their expression profiling in response to multiple stresses in Brachypodium distachyon. AB - BACKGROUND: The type-2C protein phosphatases (PP2Cs), negatively regulating ABA responses and MAPK cascade pathways, play important roles in stress signal transduction in plants. Brachypodium distachyon is a new model plant for exploring the functional genomics of temperate grasses, cereals and biofuel crops. To date, genome-wide identification and analysis of the PP2C gene family in B. distachyon have not been investigated. RESULTS: In this study, 86 PP2C genes in B. distachyon were identified. Domain-based analyses of PP2C proteins showed that they all contained the phosphatase domains featured as 11 conserved signature motifs. Although not all phosphatase domains of BdPP2C members included all 11 motifs, tertiary structure analysis showed that four residues contributing to magnesium/manganese ions (Mg(2+)/Mn(2+)) coordination were conserved, except for two noncanonical members. The analysis of their chromosomal localizations showed that most of the BdPP2C genes were located within the low CpG density region. Phylogenetic tree and synteny blocks analyses among B. distachyon, Arabidopsis thaliana and Oryza sativa revealed that all PP2C members from the three species can be phylogenetically categorized into 13 subgroups (A-M) and BdPP2Cs were evolutionarily more closely related to OsPP2Cs than to AtPP2Cs. Segmental duplications contributed particularly to the expansion of the BdPP2C gene family and all duplicated BdPP2Cs evolved mainly from purifying selection. Real-time quantitative reverse transcription PCR (qRT-PCR) analysis showed that BdPP2Cs were broadly expressed in disparate tissues. We also found that almost all members displayed up-regulation in response to abiotic stresses such as cold, heat, PEG and NaCl treatments, but down-regulation to biotic stresses such as Ph14, Guy11 and F0968 infection. CONCLUSIONS: In the present study, a comprehensive analysis of genome-wide identification and characterization of protein domains, phylogenetic relationship, gene and protein structure, chromosome location and expression pattern of the PP2C gene family was carried out for the first time in a new model monocot, i.e., B. distachyon. Our results provide a reference for genome-wide identification of the PP2C gene family of other species and also provide a foundation for future functional research on PP2C genes in B. distachyon. PMID- 26935450 TI - Multidetector Computed Tomography Usefulness in Infective Endocarditis. PMID- 26935451 TI - Usefulness of MitraClip for the Treatment of Mitral Regurgitation Secondary to Failed Surgical Annuloplasty. PMID- 26935452 TI - Effect of Mycophenolate Mofetil on Diabetic Cardiomyopathy in db/db Mice. PMID- 26935453 TI - Premature Ventricular Complex-induced Cardiomyopathy. PMID- 26935455 TI - Psychiatric Illness Is Common Among Patients with Orthopaedic Polytrauma and Is Linked with Poor Outcomes. AB - BACKGROUND: Psychiatric disorders are common, and their functional consequences may be underappreciated by non-mental health-care providers. There exist limited data regarding the frequency of psychiatric illness in patients who sustain orthopaedic polytrauma. The purpose of this study was to describe the prevalence of psychiatric illness in patients with orthopaedic polytrauma, to determine whether psychiatric illnesses were identified and were accommodated by trauma providers, and, finally, to investigate any associations between postoperative complications and psychiatric illness. METHODS: Three hundred and thirty-two skeletally mature patients with surgically treated axial and/or femoral fractures and injuries to other body systems (Injury Severity Score of >= 16 points) were identified from a database at a Level-I trauma center. These included 238 men and ninety-four women with a mean value (and standard deviation) of 39 +/- 16 years for age and 27 +/- 12 points for the Injury Severity Score. Records were reviewed for preexisting diagnoses of psychiatric disorders. The inpatient courses and discharge recommendations regarding treatment of psychiatric illness were analyzed. Complications in the six-month postoperative period were determined by an independent committee. RESULTS: Preexisting psychiatric disorders were identified in 130 patients (39.2%), including depression in seventy-four patients (22.3%) and substance abuse in fifty-six patients (16.9%). Patients managed by an orthopaedic surgery service were less likely to receive their home psychiatric medications while hospitalized (p = 0.001) and were less likely to receive instructions for psychiatric follow-up at discharge (p = 0.087). Postoperative complications occurred in sixty-six patients (19.9%) overall; depression was an independent predictor of increased complications, with an odds ratio of 2.956 (95% confidence interval, 1.502 to 5.816). CONCLUSIONS: Psychiatric illness was common among individuals who sustained orthopaedic polytrauma, and patients with depression had more complications. This study highlights the need for greater attention to mental health disorders in this population. PMID- 26935454 TI - Burden of disease and patient-reported outcomes in patients with moderate to severe ulcerative colitis in the last 12 months - Multicenter European cohort study. AB - BACKGROUND: Treatment of ulcerative colitis (UC) is aimed at maintaining corticosteroid-free remission and improving quality of life (QoL). AIM: Assess patients' perception of disease burden and unmet clinical needs in moderate/severe UC patients. METHODS: Adults surgery-free conventionally treated patients with Mayo score >=6 were enrolled in an observational, cross-sectional, retrospective study in 11 European countries. Disease control was defined as Mayo score <=2 with no sub-score >1. No corticosteroid was used the previous two months. Unmet clinical needs were defined as: non-controlled disease, self perception of 'moderate'/'severe' disease, and dissatisfaction with treatments. Disease burden on QoL and work productivity were assessed (EuroQol-5D-5L, Short Inflammatory Bowel Disease Questionnaire (SIBDQ) and Work Productivity and Activity Impairment (WPAI) in UC questionnaire). RESULTS: UC patients (n=253) with mean Mayo score at enrolment of 4.9, 44.3% of patients had Mayo score >=6. Main treatment was 5-ASA (75%). Overall, 25% met the composite endpoint for unmet clinical needs. Mean (SD) questionnaire scores were: EQ-5D-5L-VAS, 71 (19.1), EQ 5D-5L utility, 0.77 (0.19), SIBDQ, 4.8 (1.3), and WPAI, 26% (32%). CONCLUSIONS: Patients with moderate/severe UC in the last 12 months treated with conventional therapies felt that their disease was not controlled and 25% reported unmet clinical needs. QoL and work productivity were seriously impaired. PMID- 26935456 TI - Noninvasive Hemoglobin Monitoring: A Rapid, Reliable, and Cost-Effective Method Following Total Joint Replacement. AB - BACKGROUND: Noninvasive hemoglobin (nHgb) monitoring was initially introduced in the intensive care setting as a means of rapidly assessing Hgb values without performing a blood draw. We conducted a prospective analysis to compare reliability, cost, and patient preference between nHgb monitoring and invasive Hgb (iHgb) monitoring performed via a traditional blood draw. METHODS: We enrolled 100 consecutive patients undergoing primary or revision total hip or total knee arthroplasty. On postoperative day 1, nHgb and iHgb values were obtained within thirty minutes of one another. iHgb and nHgb values, cost, patient satisfaction, and the duration of time required to obtain each reading were recorded. The concordance correlation coefficient (CCC) was utilized to evaluate the agreement of the two Hgb measurement methods. Paired t tests and Wilcoxon signed-rank tests were utilized to compare mean Hgb values, time, and pain for all readings. RESULTS: The mean Hgb values did not differ significantly between the two measurement methods: the mean iHgb value (and standard deviation) was 11.3 +/- 1.4 g/dL (range, 8.2 to 14.3 g/dL), and the mean nHgb value was 11.5 +/- 1.8 g/dL (range, 7.0 to 16.0 g/dL) (p = 0.11). The CCC between the two Hgb methods was 0.69. One hundred percent of the patients with an nHgb value of >= 10.5 g/dL had an iHgb value of >8.0 g/dL. The mean time to obtain an Hgb value was 0.9 minute for the nHgb method and 51.1 minutes for the iHgb method (p < 0.001). At our institution, the cost of iHgb monitoring is approximately $28 per blood draw compared with $2 for each nHgb measurement, resulting in a savings of $26 per Hgb assessment when the noninvasive method is used. CONCLUSIONS: Noninvasive Hgb monitoring was found to be more efficient, less expensive, and preferred by patients compared with iHgb monitoring. Providers could consider screening total joint arthroplasty patients with nHgb monitoring and only order iHgb measurement if the nHgb value is <10.5 g/dL. If this protocol had been applied to the first blood draw in our 100 patients, approximately $2000 would have been saved. Extrapolated to the U.S. total joint arthroplasty practice, approximately $20 million could be saved annually. PMID- 26935457 TI - Effect of a Cast on Short-Term Reproducibility and Bone Parameters Obtained from HR-pQCT Measurements at the Distal End of the Radius. AB - BACKGROUND: High-resolution peripheral quantitative computed tomography (HR-pQCT) is a promising tool to assess the fracture-healing process at the microscale in vivo. Since casts are often used during fracture treatment, they might affect the assessment of bone density, microarchitectural, and biomechanical parameters and the short-term reproducibility of those parameters, e.g., as a result of beam hardening. The aim of this study was to assess the effect of a plaster-of-Paris and/or fiberglass cast on bone parameters and on the short-term reproducibility of the HR-pQCT measurements of those parameters. METHODS: The effects of a cast on HR-pQCT-derived bone parameters were evaluated by comparing HR-pQCT scans of fifteen human cadaveric distal radial specimens from one male and fourteen female donors (median age, eighty-four years [range, sixty-two to ninety years] at the time of death) in three conditions: with a plaster-of-Paris cast, with a fiberglass cast, or without a cast. Short-term reproducibility was assessed using duplicate scans of the distal end of the radius in sixteen healthy volunteers without a fracture (nine men and seven women with a median age of twenty-six years; range, twenty-two to thirty-nine years) while wearing and not wearing a fiberglass cast. RESULTS: Compared with measurements made with no cast, the plaster-of-Paris cast introduced a systematic error in the bone parameters ranging from -2.6% in trabecular separation to -9.8% in cortical thickness. Bone parameters were affected only marginally by fiberglass, with errors between -0.6% and -1.6% in trabecular separation and cortical thickness, respectively. Short term reproducibility with a fiberglass cast was similar to that with no cast: approximately 1% for bone density parameters, 4% to 5% for microarchitectural parameters, and 3% to 4% for biomechanical parameters. CONCLUSIONS: A plaster-of Paris cast has a considerable effect on HR-pQCT measurements. A fiberglass cast only marginally affects the bone parameters, and the short-term reproducibility of HR-pQCT measurements in patients with a fiberglass cast is comparable with that in patients without a cast. In studies on fracture-healing using HR-pQCT, a fiberglass cast is desirable if immobilization is indicated. The use of a plaster of-Paris cast should be avoided if possible; however, if not avoidable, corrections after the scan are desirable to adjust for the error introduced in the bone parameters. PMID- 26935458 TI - Effects of Implant-Associated Osteomyelitis on Cefuroxime Bone Pharmacokinetics: Assessment in a Porcine Model. AB - BACKGROUND: The prolonged antibiotic therapy that is often needed for successful management of osteomyelitis may be related to incomplete penetration of antibiotics into the target site. The objective of this study was to assess the effects of implant-associated osteomyelitis on cefuroxime penetration into bone. METHODS: Implant-associated osteomyelitis using a Staphylococcus aureus strain was induced in the right tibia in ten pigs. After five days and following administration of 1500 mg of cefuroxime, measurements of cefuroxime were obtained using microdialysis for eight hours in the implant-related bone cavity, in the adjacent infected cancellous bone and infected subcutaneous tissue, and in healthy cancellous bone and subcutaneous tissue in the contralateral leg. Measurements of the corresponding free plasma concentrations were also obtained. The extent of the infection was assessed by postmortem computed tomography (CT) scans and cultures of blood, swabs, and bone specimens. RESULTS: Bone destruction was found in the implant cavities. No structural bone changes in the adjacent infected cancellous bone were visible on CT scans. S. aureus was grown on culture of specimens from all implant cavities and from eight of ten swabs and seven of ten bone samples from the infected bone. The areas under the concentration-time curves for the different tissues differed significantly, with the lowest area under the curve found in the implant cavity (analysis of variance; p < 0.001). Although not as notable as for the implant cavity, cefuroxime penetration into infected cancellous bone was incomplete but comparable with that in healthy bone. Despite poorer tissue penetration, slightly increased time with concentrations above the minimal inhibitory concentration (MIC) was achieved in the implant cavity up to MICs of 2 mg/L compared with the other tissues, but the time was shorter for higher MICs. CONCLUSIONS: Cefuroxime penetration into infected cancellous bone was incomplete but comparable with that in healthy bone. The destructive bone processes associated with acute osteomyelitis reduced cefuroxime penetration further. CLINICAL RELEVANCE: These findings support the general clinical perception that fast diagnosis and early initiation of antibiotics before the development of implant-associated cavities is important in nonsurgical management of acute osteomyelitis. PMID- 26935459 TI - Comparison of Outcomes of Surgical Treatment for Ossification of the Posterior Longitudinal Ligament Versus Other Forms of Degenerative Cervical Myelopathy: Results from the Prospective, Multicenter AOSpine CSM-International Study of 479 Patients. AB - BACKGROUND: Degenerative cervical myelopathy (DCM) is an all-encompassing term that includes cervical spondylotic myelopathy (CSM), ossification of the posterior longitudinal ligament (OPLL), and other spinal abnormalities that cause cervical cord compression. It is unclear whether surgery is equally effective and safe for patients with OPLL as it is for those with other forms of DCM. The purpose of this study was to compare surgical outcomes of patients with OPLL and those with other forms of DCM. METHODS: Four hundred and seventy-nine patients with symptomatic DCM were prospectively enrolled in the CSM-International study at sixteen sites. Patients' functional status was evaluated using the modified Japanese Orthopaedic Association scale (mJOA) and the Nurick score. Quality of life was assessed using patient-reported outcome measures, including the Neck Disability Index (NDI) and the Short Form (SF)-36. Postoperative functional and quality-of-life outcomes were assessed at two years of follow-up, and scores were compared between patients with and without OPLL. RESULTS: Of 479 patients, 135 (28.2%) had radiographic evidence of OPLL, and 344 (71.8%) had other forms of DCM. The two groups did not differ significantly in demographics, surgical approach, or baseline myelopathy severity. Patients with OPLL achieved similar functional outcomes by two years following surgery compared with patients with other forms of DCM. With respect to quality of life, the NDI and most of the subscales of the SF-36 were not different between the two diagnostic groups. There was a higher risk of perioperative complications in the OPLL group (p = 0.054), although this relationship did not reach statistical significance. Rates of neurological complications did not differ significantly between diagnostic groups. CONCLUSIONS: Surgical decompression for the treatment of OPLL resulted in improvements in functional status and quality of life comparable to those seen in patients with other forms of DCM. Patients with OPLL were at a higher risk of perioperative complications than patients with other forms of DCM. PMID- 26935460 TI - Characteristics of Prevalent Vertebral Fractures Predict New Fractures in Elderly Men. AB - BACKGROUND: Studies have shown that specific characteristics of prevalent vertebral fractures are associated with a markedly low bone mineral density. This study evaluates if these characteristics also predict subsequent fractures. METHODS: MrOS (Mister Osteoporosis) Sweden is a population-based, prospective observational study that includes 3014 community-living men who are sixty-nine to eighty-one years of age. At baseline, 1453 men underwent lateral thoracic and lumbar spine radiography; radiographs of 1427 men were readable. A radiologist identified and characterized prevalent vertebral fractures. Incident fractures during the next five and ten years were objectively registered with use of radiographs. The annual fracture incidence and relative risk of sustaining new fractures were assessed for men with and without baseline prevalent vertebral fracture. Data are presented as the mean and the 95% confidence interval. RESULTS: There were 215 men (15.1%) with at least one prevalent vertebral fracture. During the five-year follow-up, these men had a relative risk of 3.3 (95% confidence interval, 2.6 to 4.3) of sustaining new fractures. The relative risk of sustaining any fracture was especially high in men with two or more prevalent vertebral fractures at 5.5 (95% confidence interval, 3.7 to 7.8), in men with different types of prevalent vertebral fractures at 5.7 (95% confidence interval, 3.6 to 8.5), in men with prevalent fractures in both the thoracic and lumbar regions at 6.4 (95% confidence interval, 4.5 to 8.8), and in men with prevalent fractures with a degree of vertebral body compression in the three worst quartiles, with the relative risk for the worst quartile at 4.0 (95% confidence interval, 2.6 to 5.9). CONCLUSIONS: Older men with a prevalent vertebral fracture have three times increased risk of sustaining new fractures compared with men without a vertebral fracture. Older men with two or more prevalent vertebral fractures, different types of fractures (wedge, biconcave, and/or crush), fractures in both the thoracic and lumbar regions, and a degree of vertebral body compression in the three worst quartiles are at an especially high risk of sustaining new fractures. Older men with prevalent vertebral fractures should be considered for fracture-prevention efforts. PMID- 26935461 TI - Progression of Hip Dysplasia in Mucopolysaccharidosis Type I Hurler After Successful Hematopoietic Stem Cell Transplantation. AB - BACKGROUND: Dysostosis multiplex contributes substantially to morbidity in patients with Hurler syndrome (mucopolysaccharidosis type I Hurler phenotype [MPS I-H]), even after successful hematopoietic stem cell transplantation (HSCT). One of the hallmarks of dysostosis multiplex in MPS I-H is hip dysplasia, which often requires surgical intervention. We sought to describe in detail the course of hip dysplasia in this group of patients, as assessed by radiographic analysis, and to identify potential outcome predictors. METHODS: Longitudinal data were obtained from digitally scored pelvic radiographs of patients with MPS I-H using OrthoGon software for parameters including, but not limited to, the acetabular index, migration percentage, Smith ratio, and neck-shaft angle. Scoring was performed independently by two blinded observers. Additional information on genotype, enzyme replacement therapy pre-HSCT, donor chimerism, and enzyme activity post HSCT were obtained. General trends and potential correlations were calculated with mixed-model statistics. RESULTS: Fifty-two patients (192 radiographs) were included in this analysis. Intraobserver and interobserver variation analysis showed an intraclass correlation coefficient ranging from 0.78 to 1.00. Among the twenty-one patients with follow-up beyond the age of five years, the acetabular index was in the range of severe hip dysplasia in up to 86% of the patients. Severe coxa valga was seen in 91% of the patients. Lateral and superior femoral displacement were highly prevalent, with the migration percentage outside the reference range in up to 96% of the patients. Finally, anterior pelvic tilt increased with age (p = 0.001). No correlations were identified between clinical parameters and radiographic findings. CONCLUSIONS: Our study shows that progressive acetabular dysplasia as well as coxa valga and hip displacement are highly prevalent and progressive over time in patients with MPS I-H, despite successful HSCT. These data may provide essential natural history determinations for the assessment of efficacy of new therapeutic strategies aimed at improving skeletal outcomes in patients with MPS I-H. PMID- 26935463 TI - Comparison of Registered and Published Primary Outcomes in Randomized Controlled Trials of Orthopaedic Surgical Interventions. AB - BACKGROUND: The selective reporting of a subset of the outcomes that had been originally reported to a registry is a potential threat to the validity of evidence-based medicine. The extent of selective reporting has not been described for randomized controlled trials (RCTs) assessing the effectiveness of orthopaedic surgical interventions. The objective of this study was (1) to determine the percentage of orthopaedic surgical RCTs published in high-impact orthopaedic journals that were reported to have been registered, (2) to evaluate the consistency between the primary outcome measures recorded in the registry and those reported in the article, and (3) to evaluate whether selective reporting favored statistically significant outcomes. METHODS: We searched PubMed for articles on RCTs assessing orthopaedic surgical interventions indexed from January 2010 through December 2014 and published in the ten orthopaedic journals with the highest impact factors. For every article in which the authors reported registration of the RCT, we extracted the number and nature of the outcome measures from the article and the corresponding information from the registry. We then evaluated the consistency between the primary outcome measures reported in the registry and those reported in the published article. Moreover, we evaluated whether selective reporting favored statistically significant outcomes. RESULTS: Of the 362 articles on orthopaedic surgical RCTs, ninety (24.9%) reported that the RCT had been registered and thirty-four (37.8%) of the ninety had been registered adequately (registered before the study end with a clear description of the primary outcome measure and its time frame, with no substantial change after the study end). Twenty-six reports were eligible for our evaluation of the consistency between the registered primary outcome measures and those reported in the published article. This analysis identified one or multiple major discrepancies for fourteen articles, eight of which favored statistically significant results. CONCLUSIONS: Few articles on orthopaedic surgical RCTs reported registration of the trial, and even fewer of these trials were registered adequately. Inconsistencies between registered primary outcome measures and those reported in the published articles, as well as selective outcome reporting favoring statistically significant outcomes, were prevalent. CLINICAL RELEVANCE: Although trial registration is now the rule, it is currently far from optimal for orthopaedic surgical RCTs, and selective outcome reporting is prevalent. Full involvement of authors, editors, and reviewers is necessary to ensure publication of quality, unbiased results. PMID- 26935462 TI - Effect of Surgery on Quality of Life of Patients with Spinal Metastasis from Non Small-Cell Lung Cancer. AB - BACKGROUND: Recently, more clinicians have realized the importance of quality of life in the treatment decision-making process. The goal of this study was to determine whether surgery for patients with spinal metastases from non-small-cell lung cancer (NSCLC) could improve their quality of life and prolong survival. METHODS: The study included 133 patients who had been treated for NSCLC spinal metastases between 2010 and 2014. These patients were divided into two groups according to whether or not they had received spinal surgery. Their quality of life was assessed with use of the Functional Assessment of Cancer Therapy-General (FACT-G) questionnaire at the initial diagnosis (baseline) and at one, three, six, and nine months after the diagnosis. The survival times of all patients were also collected. RESULTS: Of the 133 patients, eighty-six (forty-five in the surgery group and forty-one in the non-surgery group) survived for nine months and were assessed at all of the follow-up intervals. The surgery group had significantly higher total, physical well-being, emotional well-being, and functional well-being quality-of-life scores at each follow-up time point as compared with baseline (p < 0.001) as well as compared with the non-surgery group (p < 0.001). A log-rank test demonstrated that the surgery group had longer survival than the non-surgery group (p = 0.020). CONCLUSIONS: The results of this study indicate that surgical treatment improved the quality of life of patients with NSCLC spinal metastases over the nine-month assessment period. The surgery group had a better quality of life and longer survival than the non-surgery group. PMID- 26935464 TI - Development and Assessment of a Distal Radial Fracture Model as a Clinical Teaching Tool. AB - BACKGROUND: Simulation-based learning is increasingly prevalent in the curricula of many surgical training programs. Newly developed simulators must undergo rigorous validity testing before they are used to assess and evaluate surgical trainees. We describe the development of a model that simulates a distal radial fracture requiring closed reduction and cast application and demonstrate its validity. METHODS: We developed a model for simulated treatment of a distal radial fracture with use of a modified Sawbones forearm. Ten junior and ten senior orthopaedic residents were videotaped performing a closed reduction and applying a cast on the model. After each procedure, standard anteroposterior and lateral radiographs of the forearm model were obtained. Two blinded orthopaedic surgeons then rated each resident using a task-specific checklist (Objective Structured Assessment of Technical Skills [OSATS]) and a global rating scale (GRS) as well as radiographic measurements of palmar tilt and three-point index. RESULTS: Compared with the junior residents, senior residents had significantly higher OSATS (p < 0.001) and GRS scores (p < 0.001). The groups did not differ significantly with respect to radiographic palmar tilt (p = 0.86) and three-point index (p = 0.43). All residents were able to restore anatomical alignment, with a mean palmar tilt of 9.1 degrees . In addition, the mean three-point index of all residents was acceptable (0.76). There was a strong correlation between OSATS and GRS scores (r > 0.87; p < 0.01). The inter-rater reliability was high (>= 0.79) for the OSATS, GRS, and radiographic measurements. CONCLUSIONS: We developed an educational model that simulates a distal radial fracture requiring closed reduction and cast application. We demonstrated construct validity, as the GRS and OSATS tools were able to differentiate senior from junior residents. We were unable to differentiate trainees using radiographic assessment, as all residents restored anatomical alignment and had comparable three-point index scores. PMID- 26935465 TI - An Algorithmic Approach to the Management of Recurrent Lateral Patellar Dislocation. AB - High-level evidence supports nonoperative treatment for first-time lateral acute patellar dislocations. Surgical intervention is often indicated for recurrent dislocations. Recurrent instability is often multifactorial and can be the result of a combination of coronal limb malalignment, patella alta, malrotation secondary to internal femoral or external tibial torsion, a dysplastic trochlea, or disrupted and weakened medial soft tissue, including the medial patellofemoral ligament (MPFL) and the vastus medialis obliquus. MPFL reconstruction requires precise graft placement for restoration of anatomy and minimal graft tension. MPFL reconstruction is safe to perform in skeletally immature patients and in revision surgical settings. Distal realignment procedures should be implemented in recurrent instability associated with patella alta, increased tibial tubercle trochlear groove distances, and lateral and distal patellar chondrosis. Groove deepening trochleoplasty for Dejour type-B and type-D dysplasia or a lateral elevation or proximal recession trochleoplasty for Dejour type-C dysplasia may be a component of the treatment algorithm; however, clinical outcome data are lacking. In addition, trochleoplasty is technically challenging and has a risk of substantial complications. PMID- 26935466 TI - Orthopaedics and the Physician Payments Sunshine Act: An Examination of Payments to U.S. Orthopaedic Surgeons in the Open Payments Database. AB - BACKGROUND: The U.S. Centers for Medicare & Medicaid Services (CMS) recently released the Open Payments database (OPD) detailing payments from industry to physicians and teaching hospitals. We seek here to provide an overview of the data with a focus on the orthopaedic community. METHODS: We analyzed payments in the OPD from August 1 to December 31, 2013. The OPD consists of three individual databases: General Payments, Research Payments, and Ownership. Physician identification number, physician specialty, payment type, and payment value were collected. Physicians assigned to multiple specialties were excluded. Comparisons were made between orthopaedic surgeons and the remainder of the top fifteen specialties by payment value. RESULTS: In all, 2,697,015 payments with physicians were recorded; 491,223 of these payments (18.2%) were made to physicians with multiple listed specialties and were excluded. Excluding these potentially misattributed payments did not have a significant impact on the trends identified, and $394.5 million in payments remained. Orthopaedic surgeons represented 3.4% of payments but 25.6% of value, and 13,347 orthopaedic surgeons (68.9% of all active orthopaedic surgeons) were listed in the OPD. Payments over $10,000 represented only 1.6% of payments to orthopaedic surgeons but 75.5% of value. The majority of these payments (56.1%) were royalties. The median payment value for orthopaedic surgeons listed in the OPD was $38.11, with two payments per surgeon; the median aggregated value was $132.56 per surgeon. Orthopaedic surgeons listed in the OPD were more likely to receive payments for travel compared with all other specialties (p < 0.001) and more likely to receive payments for royalties compared with all other specialties (p < 0.001) except neurological surgery. CONCLUSIONS: Financial interactions between orthopaedic surgeons and industry are highly prevalent. A small subset of orthopaedic surgeons received large royalties, which accounted for a majority of the transactional value provided by industry. Orthopaedic surgeons were the recipients of more payments for travel and for royalties than all other specialties except neurological surgery; however, the median value of these and other payments was similar to that for other specialties. PMID- 26935467 TI - Psychological Distress and Orthopaedic Trauma: Commentary on an article by Douglas S. Weinberg, MD, et al.: "Psychiatric Illness Is Common Among Patients with Orthopaedic Polytrauma and Is Linked with Poor Outcomes". PMID- 26935468 TI - The Social Science of Surgery: Commentary on an article by Yu Tang, MD, et al.: "Effect of Surgery on Quality of Life of Patients with Spinal Metastasis from Non Small-Cell Lung Cancer". PMID- 26935469 TI - Models and Simulation: The Future of Orthopaedic Residency Education? Commentary on an article by Ian P. Mayne, MD, et al.: "Development and Assessment of a Distal Radial Fracture Model as a Clinical Teaching Tool". PMID- 26935470 TI - Chest wall desmoid tumours treated with definitive radiotherapy: a plan comparison of 3D conformal radiotherapy, intensity-modulated radiotherapy and volumetric-modulated arc radiotherapy. AB - PURPOSE: Definitive radiotherapy is often used for chest wall desmoid tumours due to size or anatomical location. The delivery of radiotherapy is challenging due to the large size and constraints of normal surrounding structures. We compared the dosimetry of 3D conformal radiotherapy (3DCRT), intensity-modulated radiotherapy (IMRT) and volumetric-modulated arc radiotherapy (VMAT) to evaluate the best treatment option. METHODS AND MATERIALS: Ten consecutive patients with inoperable chest wall desmoid tumours (PTV range 416-4549 cm(3)) were selected. For each patient, 3DCRT, IMRT and VMAT plans were generated and the Conformity Index (CI), organ at risk (OAR) doses and monitor unit (MU) were evaluated. The Wilcoxon signed-rank test was used to compare dose delivered to both target and OARs. RESULTS: The mean number of fields for 3DCRT and IMRT were 6.3 +/- 2.1, 7.2 +/- 1.8. The mean number of arcs for VMAT was 3.7 +/- 1.1. The mean conformity index of VMAT (0.98 +/- 0.14) was similar to that of IMRT (1.03 +/- 0.13), both of which were significantly better than 3DCRT (1.35 +/- 0.20; p = 0.005). The mean dose to lung was significantly higher for 3DCRT (11.9Gy +/- 7.9) compared to IMRT (9.4Gy +/- 5.4, p = 0.014) and VMAT (8.9Gy +/- 4.5, p = 0.017). For the 3 females, the low dose regions in the ipsilateral breast for VMAT were generally less with VMAT. IMRT plans required 1427 +/- 532 MU per fraction which was almost 4-fold higher than 3DCRT (313 +/- 112, P = 0.005). Compared to IMRT, VMAT plans required 60 % less MU (570 +/- 285, P = 0.005). CONCLUSIONS: For inoperable chest wall desmoid tumours, VMAT delivered equivalent target coverage when compared to IMRT but required 60 % less MU. Both VMAT and IMRT were superior to 3DCRT in terms of better PTV coverage and sparing of lung tissue. PMID- 26935471 TI - Coxsackievirus counters the host innate immune response by blocking type III interferon expression. AB - Type I IFNs play an important role in the immune response to enterovirus infections. Their importance is underscored by observations showing that many enteroviruses including coxsackie B viruses (CVBs) have developed strategies to block type I IFN production. Recent studies have highlighted a role for the type III IFNs (also called IFNlambdas) in reducing permissiveness to infections with enteric viruses including coxsackievirus. However, whether or not CVBs have measures to evade the effects of type III IFNs remains unknown. By combining virus infection studies and different modes of administrating the dsRNA mimic poly I : C, we discovered that CVBs target both TLR3- and MDA5/RIG-I-mediated type III IFN expression. Consistent with this, the cellular protein expression levels of the signal transduction proteins TRIF and IPS1 were reduced and no hyperphosphorylation of IRF-3 was observed following infection with the virus. Notably, decreased expression of full-length TRIF and IPS1 and the appearance of cleavage products was observed upon both CVB3 infection and in cellular protein extracts incubated with recombinant 2Apro, indicating an important role for the viral protease in subverting the cellular immune system. Collectively, our study reveals that CVBs block the expression of type III IFNs, and that this is achieved by a similar mechanism as the virus uses to block type I IFN production. We also demonstrate that the virus blocks several intracellular viral recognition pathways of importance for both type I and III IFN production. The simultaneous targeting of numerous arms of the host immune response may be required for successful viral replication and dissemination. PMID- 26935472 TI - Modelling changes in clinical attachment loss to classify periodontal disease progression. AB - AIM: The goal of this study was to identify progressing periodontal sites by applying linear mixed models (LMM) to longitudinal measurements of clinical attachment loss (CAL). METHODS: Ninety-three periodontally healthy and 236 periodontitis subjects had their CAL measured bi-monthly for 12 months. The proportions of sites demonstrating increases in CAL from baseline above specified thresholds were calculated for each visit. The proportions of sites reversing from the progressing state were also computed. LMM were fitted for each tooth site and the predicted CAL levels used to categorize sites regarding progression or regression. The threshold for progression was established based on the model estimated error in predictions. RESULTS: Over 12 months, 21.2%, 2.8% and 0.3% of sites progressed, according to thresholds of 1, 2 and 3 mm of CAL increase. However, on average, 42.0%, 64.4% and 77.7% of progressing sites for the different thresholds reversed in subsequent visits. Conversely, 97.1%, 76.9% and 23.1% of sites classified as progressing using LMM had observed CAL increases above 1, 2 and 3 mm after 12 months, whereas mean rates of reversal were 10.6%, 30.2% and 53.0% respectively. CONCLUSION: LMM accounted for several sources of error in longitudinal CAL measurement, providing an improved method for classifying progressing sites. PMID- 26935473 TI - CXCR4 antagonist AMD3100 ameliorates thyroid damage in autoimmune thyroiditis in NOD.H-2h4 mice. AB - CXC chemokine ligand 12 (CXCL12) and its receptor, CXC chemokine receptor 4 (CXCR4), are upregulated in mice with autoimmune thyroid diseases. However, whether this interaction is involved in the pathophysiology of autoimmune thyroiditis (AIT) remains to be elucidated. In the present study, the effects of the CXCR4 antagonist, AMD3100, in an iodine-induced autoimmune thyroiditis model were investigated. NOD.H-2h4 mice were randomly separated into a control, AIT and AIT+AMD3100 groups. The mice were fed with 0.05% sodium iodide water for 8 weeks to induce AIT. The AMD3100-treated mice were administered with the CXCR4 antagonist at a dose of 10 mg/kg intraperitoneally three times a week during the experimental period. The percentages of CD19+interleukin (IL)10+ B cells and CD4+IL10+ T cells, and the mRNA expression levels of IL10 in the splenocytes were reduced in the AIT group, compared with the control group, however, they increased following AMD3100 treatment, compared with the untreated AIT group. The percentages of CD4+ T cells, CD8+ T cells, CD19+ B cells and CD8+ interferon (IFN)gamma+ T cells, and the mRNA expression levels of IFNgamma increased in the AIT group, compared with the control group, however, these were reduced in the AMD3100 group, compared with the AIT group. The AMD3100-treated mice also had lower serum thyroglobulin antibody titers and reduced lymphocytic infiltration in the thyroid, compared with the untreated AIT mice. These results suggested that inhibition of this chemokine axis may offer potential as a therapeutic target for the treatment of AIT. PMID- 26935474 TI - Audio Feedback with Reduced Self-focus as an Intervention for Social Anxiety: An Experimental Study. AB - BACKGROUND AND OBJECTIVES: Socially anxious individuals tend to underestimate their performance largely due to attentional bias. Video and audio feedback (AF) with cognitive preparation (CP) have shown to improve socially anxious individuals' evaluation of their performance in previous studies. In the present study, it was hypothesized that one of the three steps in CP, reduced self-focus (RS), is sufficient to cause an improved voice evaluation after AF. This was tested in a single-session randomized controlled experiment. METHOD: Forty-one socially anxious participants were asked to give a speech, then to listen to and evaluate a taped recording of their performance. Half of the sample were instructed to reduce their self-focus prior to AF, the rest received AF only. RS involved asking participants to listen to the audio recording as though they were listening to a stranger. Generalization effects were assessed by a second speech. RESULTS: AF with RS led to more improved voice evaluations than AF-only after the first speech, and the effects remained in the evaluation of the second speech. More positive speech evaluations were associated with corresponding reductions of performance anxiety. LIMITATIONS: small sample, analogue study. CONCLUSION: One component of cognitive preparation-(RS)-appears to be sufficient to cause significant effects on voice evaluation in socially anxious individuals. If the results are replicated in clinical samples, AF with RS may be a promising intervention in the treatment of social anxiety. PMID- 26935475 TI - Distinct types of protease systems are involved in homeostasis regulation of mitochondrial morphology via balanced fusion and fission. AB - Mitochondrial morphology is dynamically regulated by fusion and fission. Several GTPase proteins control fusion and fission, and posttranslational modifications of these proteins are important for the regulation. However, it has not been clarified how the fusion and fission is balanced. Here, we report the molecular mechanism to regulate mitochondrial morphology in mammalian cells. Ablation of the mitochondrial fission, by repression of Drp1 or Mff, or by over-expression of MiD49 or MiD51, results in a reduction in the fusion GTPase mitofusins (Mfn1 and Mfn2) in outer membrane and long form of OPA1 (L-OPA1) in inner membrane. RNAi- or CRISPR-induced ablation of Drp1 in HeLa cells enhanced the degradation of Mfns via the ubiquitin-proteasome system (UPS). We further found that UPS-related protein BAT3/BAG6, here we identified as Mfn2-interacting protein, was implicated in the turnover of Mfns in the absence of mitochondrial fission. Ablation of the mitochondrial fission also enhanced the proteolytic cleavage of L-OPA1 to soluble S-OPA1, and the OPA1 processing was reversed by inhibition of the inner membrane protease OMA1 independent on the mitochondrial membrane potential. Our findings showed that the distinct degradation systems of the mitochondrial fusion proteins in different locations are enhanced in response to the mitochondrial morphology. PMID- 26935476 TI - Maternal vitamin B6 deficient or supplemented diets on expression of genes related to GABAergic, serotonergic, or glutamatergic pathways in hippocampus of rat dams and their offspring. AB - SCOPE: Vitamin B6 plays crucial roles on brain development and its maternal deficiency impacts the gamma-aminobutyric acid (GABA)ergic, serotonergic, glutamatergic, and dopaminergic systems in offspring. However, the molecular mechanisms underlying these neurological changes are not well understood. Thus, we aimed at evaluating which components of those neurotransmitter metabolism and signaling pathways can be modulated by maternal vitamin B6 -deficient or B6 supplementated diets in the hippocampus of rat dams and their offspring. METHODS AND RESULTS: Female Wistar rats were fed three different diets: control (6 mg vitamin B6 /kg), supplemented (30 mg vitamin B6 /kg) or deficient diet (0 mg vitamin B6 /kg), from 4 weeks before pregnancy through lactation. Newborn pups (10 days old) from rat dams fed vitamin B6 -deficient diet presented hyperhomocysteinemia and had a significant increase in mRNA levels of glutamate decarboxylase 1 (Gad1), fibroblast growth factor 2 (Fgf2), and glutamate-ammonia ligase (Glul), while glutaminase (Gls) and tryptophan hydroxylase 1 (Tph1) mRNAs were downregulated. Vitamin B6 supplementation or deficiency did not change hippocampal global DNA methylation. CONCLUSION: A maternal vitamin B6 -deficient diet affects the expression of genes related to GABA, glutamate, and serotonin metabolisms in offspring by regulating Gad1, Glul, Gls, and Tph1 mRNA expression. PMID- 26935477 TI - Evaluating the Imbalance Between Increasing Hemodialysis Patients and Medical Staff Shortage After the Great East Japan Earthquake: Report From a Hemodialysis Center Near the Fukushima Nuclear Power Plants. AB - The Great East Japan Earthquake in 2011 caused an unprecedented imbalance between an increasing number of hemodialysis patients and medical staff shortage in the Sousou area, the site of the Fukushima nuclear power plants. In 2014, capacity of our hemodialysis center reached a critical limit due to such an imbalance. We attempted to evaluate the effort of medical staff to clarify to what extent their burden had increased post-disaster. The ratio of total dialysis sessions over total working days of medical staff was determined as an approximate indicator of effort per month. The mean value of each year was compared. Despite fluctuations of the ratio, the mean value did not differ from 2010 to 2013. However, the ratio steadily increased in 2014, and there was a significant increase in the mean value. This proposed indicator of the effort of medical staff appears to reflect what we experienced, although its validity must be carefully examined in future studies. PMID- 26935478 TI - Role of neuroinflammation in neurodegenerative diseases (Review). AB - Neurodegeneration is a phenomenon that occurs in the central nervous system through the hallmarks associating the loss of neuronal structure and function. Neurodegeneration is observed after viral insult and mostly in various so-called 'neurodegenerative diseases', generally observed in the elderly, such as Alzheimer's disease, multiple sclerosis, Parkinson's disease and amyotrophic lateral sclerosis that negatively affect mental and physical functioning. Causative agents of neurodegeneration have yet to be identified. However, recent data have identified the inflammatory process as being closely linked with multiple neurodegenerative pathways, which are associated with depression, a consequence of neurodegenerative disease. Accordingly, pro-inflammatory cytokines are important in the pathophysiology of depression and dementia. These data suggest that the role of neuroinflammation in neurodegeneration must be fully elucidated, since pro-inflammatory agents, which are the causative effects of neuroinflammation, occur widely, particularly in the elderly in whom inflammatory mechanisms are linked to the pathogenesis of functional and mental impairments. In this review, we investigated the role played by the inflammatory process in neurodegenerative diseases. PMID- 26935480 TI - Pigment Loss in Patients with Large Congenital Melanocytic Nevi: Various Clinical Presentations Documented in a Large Series. AB - BACKGROUND/OBJECTIVES: The association between vitiligo and congenital melanocytic nevi remains incompletely understood. The objective of this study was to investigate the frequency of depigmentation, including vitiligo, in patients with a large congenital melanocytic nevus (LCMN), which is a rare melanocytic tumor variant. METHODS: We retrospectively reviewed the files of 92 patients with an LCMN, including photographic documentation regarding the presence of pigment loss on the nevus mass, around the nevus, around the satellites, and elsewhere on the body. RESULTS: Depigmentation was observed in 8 (8.7%) of 92 patients with an LCMN. Depigmented areas within the main nevus mass were observed in six patients, and adjacent or remote vitiligo was observed in four patients. One patient also demonstrated halo depigmentation around some satellite nevi. CONCLUSION: The coexistence of an LCMN with vitiligo does not appear to be rare and may occur with a spectrum of clinical presentations. PMID- 26935479 TI - Randomized controlled clinical pilot study of all-ceramic single-tooth implant reconstructions: clinical and microbiological outcomes at one year of loading. AB - OBJECTIVE: To test whether or not pink veneering of the submucosal part of zirconia abutments influences clinical, microbiological and histological outcomes of cemented implant-supported single crowns (ISSC). MATERIALS AND METHODS: A total of 20 patients with one single-tooth implant in the esthetic zone were included. Implants were randomly restored with either pink-veneered zirconia abutments (test group; n = 10) or non-veneered white zirconia abutments (control group; n = 10) and with adhesively cemented all-ceramic crowns. At the 6-month follow-up, soft tissue biopsies were prepared for histological evaluation and microbiological samples were collected around abutments and the respective contra lateral teeth (in 10 of 20 patients). One year after the initiation of loading, clinical parameters were assessed. Robust linear mixed model and cumulative linked mixed model analyses were performed to investigate the effect of group and time-point on clinical and biological outcomes. RESULTS: Clinical evaluations revealed stable peri-implant soft tissues in terms of probing pocket depth, but a high BOP index (87.5% control; 80.0% test). No statistically significant differences were observed between the test and control group for any outcome measure (P > 0.05). No major biological complications occurred during the observation period. Histological samples revealed a remarkable degree of inflammation in both groups without clear differences in qualitative histological features. Microbiological evaluation demonstrated a slightly higher bacterial count at implants compared to natural teeth at one year of loading without marked differences between groups. CONCLUSION: Limited by a small sample size and a relatively short observation period, pink-veneered zirconia abutments exhibited similar clinical, histological and microbiological outcomes as non-veneered zirconia abutments supporting cemented single crowns. PMID- 26935481 TI - The safety of robot-assisted cystectomy in patients with previous history of pelvic irradiation. AB - OBJECTIVE: To determine the safety of robot-assisted cystectomy (RAC) in patients with an irradiated pelvis, by comparing perioperative complication outcomes after RAC in patients with and without a history of pelvic irradiation. PATIENTS AND METHODS: In all, 252 consecutive patients underwent RAC at a tertiary referral centre from 2002 to 2013. Of all patients, 46 (18%) had a history of pelvic irradiation. Complications occurring at <=30 days and <=90 days of RAC were graded using the modified Clavien-Dindo classification system and additionally categorised by organ system. Baseline variables and outcomes of irradiated and non-irradiated patients were compared using descriptive statistics. Multivariable logistic regression models were generated to test the effect of previous pelvic irradiation on complications. RESULTS: The indications for RAC in patients with a history of pelvic irradiation were: bladder cancer (30 patients, 65%), prostate cancer (two, 4%), fistulae (five, 11%), and intractable symptoms from radiation cystitis (nine, 20%). In all, 25 (54%) irradiated and 112 (54%) non-irradiated patients had complications at <=90 days (P > 0.9), of which 11 (24%) and 43 (21%) respectively had major complications (P = 0.7). One (2%) patient with and two (1%) patients without a history of irradiation died from surgical complications (P = 0.5). Infectious, bleeding, and gastrointestinal complications were the most common events in both groups. In multivariable analyses, a history of pelvic irradiation was not associated with a higher risk of complications. CONCLUSION: RAC performed by an experienced surgeon is a reasonable option in selected patients with a history of pelvic irradiation, as complication rates do not significantly differ compared with non-irradiated patients. PMID- 26935483 TI - Corrigendum: Exogenous Attention Enables Perceptual Learning. AB - Szpiro, S. F. A., & Carrasco, M. (2015). Exogenous attention enables perceptual learning.Psychological Science, 26, 1854-1862. (Original DOI:10.1177/0956797615598976)In the second paragraph of the Testing Sessions section of this article, thetvalue for the between-group difference in spatial frequency differences was incorrectly reported as 9.49,p> .1, rather than 0.95,p> .1. The sentence should read as follows:There was no significant difference between groups for the orientation differences,t(12) = 1.51,p> .1, or for the spatial-frequency differences,t(12) = 0.95,p> .1.Thus, the conclusion regarding the lack of significance remains the same. PMID- 26935482 TI - Host contact and shedding patterns clarify variation in pathogen exposure and transmission in threatened tortoise Gopherus agassizii: implications for disease modelling and management. AB - Most directly transmitted infections require some form of close contact between infectious and susceptible hosts to spread. Often disease models assume contacts are equal and use mean field estimates of transmission probability for all interactions with infectious hosts. Such methods may inaccurately describe transmission when interactions differ substantially in their ability to cause infection. Understanding this variation in transmission risk may be critical to properly model and manage some infectious diseases. In this study, we investigate how varying exposure and transmission may be key to understanding disease dynamics in the threatened desert tortoise Gopherus agassizii. We created heterogeneity in Mycoplasma agassizii exposure (the putative bacterial agent of a respiratory disease) by varying the duration of interactions between naturally infected and uninfected captive desert tortoises. Using qPCR, we identified new infections and compared models of transmission probability as a function of contact duration and pathogen load. We then examined the contact patterns of a wild tortoise population using proximity loggers to identify heterogeneity in contact duration. The top-ranked model predicting M. agassizii transmission included a dose term defined as the product of the number of days in proximity to an infected host and the infection level of that host. Models predicted low transmission probability for short interactions, unless the infectious host had a high load of M. agassizii: such hosts were predicted to transmit infection at higher rates with any amount of contact. We observed predominantly short-lived interactions in a free-ranging tortoise population and thus, expect transmission patterns in this population to vary considerably with the frequency and duration of high infection levels. Mean field models may misrepresent natural transmission patterns in this and other populations depending on the distribution of high-risk contact and shedding events. Rapid outbreaks in generally solitary species may result from changes to their naturally low-risk contact patterns or due to increases in the frequency of severe infections or super-shedding events - population characteristics that should be further investigated to develop effective management strategies. PMID- 26935484 TI - Toward Systems Science in Rehabilitation. PMID- 26935485 TI - Preparing the Next Generation of Physical Therapists for Transformative Practice and Population Management: Example From Macquarie University. PMID- 26935486 TI - Arrhythmic Burden and Ambulatory Monitoring of Pediatric Patients with Cardiomyopathy. AB - BACKGROUND: Pediatric patients with cardiomyopathy (CM) are at risk for sudden cardiac death (SCD), likely driven by arrhythmic etiologies. OBJECTIVES: Describe arrhythmia burden and Holter utility in pediatric CM including: hypertrophic CM (HCM), dilated CM (DCM), and restrictive CM (RCM). METHODS: Retrospective cohort study of patients <21 years with CM. Patient demographics, arrhythmic history, and genetic status were reviewed including outcomes of death, aborted SCD, and device shocks. Holter findings were analyzed over the prior 5 years including clinically significant findings and resulting changes to management. Analysis for the composite outcomes of death, aborted SCD, and appropriate shock were performed using logistic regression with backward elimination. RESULTS: One hundred and forty-six patients were included: 83 HCM, 54 DCM, and nine RCM (mean 13 +/- 6 years). A total of 23% of patients had defibrillators. There were six deaths (two SCD), four patients with appropriate device therapies, and four aborted SCD episodes. In total, 305 Holter monitors were reviewed. Six Holters had significant findings, all nonsustained ventricular tachycardia. Two Holters resulted in changes in management, both defibrillator implantations. Twelve patients had one or more of the conditions defining the composite outcome. Using logistic regression, clinical history of ventricular arrhythmia, frequent premature ventricular complexes, and CM type were included as potential independent predictors in the final model and clinical ventricular arrhythmia and RCM disease were associated with the composite outcome. CONCLUSIONS: SCD and device therapies were relatively rare. Routine Holter screening rarely demonstrated significant findings or changed clinical care. Clinical history of ventricular arrhythmia was associated with poor clinical outcome. PMID- 26935487 TI - Improving green emission of Tb3+ ions in BaO-B2 O3 -P2 O5 glasses by means of Al3+ ions. AB - BaO-B2 O3 -P2 O5 glasses doped with a fixed concentration of Tb3+ ions and varying concentrations of Al2 O3 were synthesized, and the influence of the Al3+ ion concentration on the luminescence efficiency of the green emission of Tb3+ ions was investigated. The optical absorption, excitation, luminescence spectra and fluorescence decay curves of these glasses were recorded at ambient temperature. The emission spectra of terbium ions when excited at 393 nm exhibited two main groups of bands, corresponding to 5 D3 -> 7 Fj (blue region) and 5 D4 -> 7Fj (green region). From these spectra, the radiative parameters, viz., spontaneous emission probability A, total emission probability AT , radiative lifetime tau and fluorescent branching ratio beta, of different transitions originating from the 5 D4 level of Tb3+ ions were evaluated based on the Judd-Ofelt theory. A clear increase in the quantum efficiency and luminescence of the green emission of Tb3+ ions corresponding to 5 D4 -> 7 F5 transition is observed with increases in the concentration of Al2 O3 up to 3.0 mol%. The improvement in emission is attributed to the de-clustering of terbium ions by Al3+ ions and also to the possible admixing of wave functions of opposite parities. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26935488 TI - Fetal goiter associated with preconception hysterosalpingography using an oil soluble iodinated contrast medium. PMID- 26935489 TI - Treatment and prognosis of bone metastasis from cervical cancer (KCOG-G1202s). AB - AIM: The early and precise diagnosis and proper palliative treatment of bone metastasis is important for improving the quality of life of cervical cancer patients. The aim of this study was to clarify the clinical features, treatment modalities and prognosis of bone metastasis in cervical cancer patients in Japan. METHODS: The medical records of 75 cervical cancer patients with bone metastasis who were treated between January 2000 and December 2010 were retrospectively analyzed in a multi-institutional study. RESULTS: Fifty-four patients (72.0%) had a single bone metastasis. Bone metastases were found in the spine (46.7%) and pelvis (42.7%). Forty-three patients (57.3%) also had extra-osseous metastases. Most of the patients received radiotherapy, chemotherapy or both, but 25 patients (33.3%) received palliative care only. Bisphosphonates were given as palliative therapy to 25 patients (33.3%). The median overall survival after the diagnosis of bone metastasis was significantly shorter in patients with extra-osseous metastases than in those without extra-osseous metastases (14 vs 5 months; P < 0.05). The survival of patients who received chemotherapy following radiotherapy or concurrent chemoradiotherapy was significantly longer than that of the patients who received palliative care. On multivariate analysis, the presence of extra-osseous metastasis was an independent predictor of survival in patients with bone metastasis from cervical cancer. CONCLUSIONS: Multidisciplinary treatment might improve the prognosis of patients with bone metastasis who do not have extra-osseous lesions. PMID- 26935490 TI - Oridonin effectively reverses cisplatin drug resistance in human ovarian cancer cells via induction of cell apoptosis and inhibition of matrix metalloproteinase expression. AB - Cisplatin is a first generation platinum-based chemotherapeutic agent, however, the extensive application of cisplatin inevitably results in drug resistance, which is a major obstacle in cancer chemotherapy. The aim of the present study was to investigate the efficiency of reversing cisplatin-resistance with the use of combination therapy with oridonin and cisplatin in human ovarian cancer cells, and attempt to reduce the side effects of the therapeutic agents when used alone. The half maximal inhibitory concentration (IC50) values of cisplatin were determined in cisplatin-sensitive and cisplatin-resistant ovarian cancer cells using an MTT assay. IC50 values of cisplatin in A2780, A2780/DDP, SKOV3 and SKOV3/DDP cells were significantly decreased in a time-dependent manner. The antitumor effect of oridonin in A2780/DDP cells was also detected by the MTT assay and the inhibitory effects of oridonin increased in a dose- and time dependent manner. A2780/DDP cells were treated with 20 uM oridonin in combination with increasing concentrations of cisplatin for 48 h, and the result demonstrated that oridonin synergistically increased the antitumor effects of cisplatin in A2780/DDP cells. Notably, the combination treatment of oridonin and cisplatin effectively reversed cisplatin resistance and the IC50 values were significantly decreased from 50.97 uM and 135.20 to 26.12 uM and 73.00 uM in A2780/DDP and SKOV3/DDP cells at 48 h, respectively. Furthermore, oridonin induced cell apoptosis in a dose-dependent manner and promoted cell-cycle arrest at the G0/G1 phase in ovarian cancer cells. Oridonin and cisplatin synergistically increased the cell apoptosis rate of A2780/DDP cells, which was detected by fluorescence activated cell sorting analysis. Downregulated expression levels of Bcl-2 and upregulated the expression of Bax protein were demonstrated by western blot analysis, further indicating increased apoptosis. In addition, the expression levels of matrix metalloproteinase (MMP)-2 and MMP-9 decreased in a dose dependent manner with oridonin treatment. The results from the present study demonstrated that oridonin exerted a synergistic effect with cisplatin to inhibit proliferation and induce cell apoptosis in cisplatin-resistant ovarian cancer cells. Thus, combination therapy with oridonin and cisplatin effectively reversed cisplatin resistance in human ovarian cancer cells, which may have useful clinical applications. PMID- 26935491 TI - Sixty seconds on . . . the consultant contract. PMID- 26935492 TI - Extending Myringotomy Patency with Topical Everolimus in Rats. AB - BACKGROUND: Everolimus is an immunosuppressant agent that has antiproliferative properties and negative effects on wound healing. The effect of everolimus use to delay the closure time of myringotomy is not known. OBJECTIVES: The aim of the study was to evaluate the impact of topical everolimus on myringotomy patency and to investigate its histopathologic effects on the tympanic membrane. MATERIAL AND METHODS: Twenty Sprague-Dawley rats were bilaterally myringotomized with a myringotomy knife. Gelfoam soaked in 0.05% everolimus in a microemulsion formulation was applied to the right myringotomy site of the rats for 10 min (the everolimus group). The myringotomy sites of the left ears were treated with sterile saline topically (the control group). The tympanic membranes were routinely examined otomicroscopically every other day for 31 days. The membranes were then harvested and evaluated histologically after 31 days. RESULTS: All tympanic membranes were closed by the 15(th) day in the control group, while in the everolimus group the myringotomy remained open in five rats (25%) on day 31. The mean durations of myringotomy patency in the everolimus group and control group were 20.90 +/- 7.85 and 10.10 +/- 3.14 days, respectively. The difference was found to be statistically significant (p < 0.01). In the histopathological examination of the tympanic membranes, there was less fibrosis and less inflammation in the everolimus group than in the control group (p < 0.01). CONCLUSIONS: Topical everolimus application is effective in extending myringotomy patency in rat tympanic membranes. Inflammatory reactions and fibrosis in the lamina propria were observed to be significantly less when topical everolimus was used. PMID- 26935493 TI - An Assessment of the Number of Cariogenic Bacteria in the Saliva of Children with Chemotherapy-Induced Neutropenia. AB - BACKGROUND: Anticancer therapy entails qualitative and quantitative changes in the physiological bacterial flora of the organism, including the oral microflora. OBJECTIVES: The aim of the study was to assess the number of cariogenic bacteria Streptococcus mutans and Lactobacillus spp. - in the saliva of children with chemotherapy-induced neutropenia, and the relationship between the dynamics of neutrophils in the blood and the number of cariogenic bacteria in the saliva. MATERIAL AND METHODS: The study included 52 children aged 3-17.5 years, diagnosed with cancer and undergoing antineoplastic treatment. The control group comprised 52 generally healthy children matched for age and gender. Both groups underwent microbiological analysis of the saliva. The Dentocult SM Strip Mutans test (Orion Diagnostica, Espoo, Finland) was used to evaluate the number of Streptococcus mutans colonies in the saliva, while the Dentocult LB test (Orion Diagnostica) was used to assess the number of Lactobacillus spp. bacteria. The statistical analysis was carried out using STATISTICA 10 software (StatSoft Inc., Tulsa, USA). RESULTS: The statistical analysis using Kendall's tau test showed a significant inverse correlation between the number of neutrophils in the blood and the number of the Streptococcus mutans and Lactobacillus spp. colonies in the saliva of the children undergoing anticancer therapy. The highest titres of cariogenic bacteria in the saliva were observed during severe neutropenia, which was frequently observed between day 7 and day 21 of the chemotherapy course. CONCLUSIONS: A significant increase in the number of cariogenic bacteria in the saliva during episodes of chemotherapy-induced neutropenia suggests that the activity of dental caries increases in children undergoing antineoplastic treatment. PMID- 26935495 TI - The Influence of GnRH Analog Therapy on Growth in Central Precocious Puberty. AB - BACKGROUND: Children with central precocious puberty (CPP) present various somatic and psychological abnormalities. OBJECTIVES: The aim of the study was to evaluate growth changes in girls with central precocious puberty treated with GnRH analog therapy and to analyze the factors affecting the auxological response to this treatment. MATERIAL AND METHODS: The study group consisted of 40 girls with puberty onset aged 6.0 +/- 1.9 years (mean, +/- SD), treated with 3.75 mg decapeptyl depot intramuscularly every 28 days. The treatment was initiated at the age of 7.5 +/- 2.2 years and continued for 3.3 +/- 2.3 years, until the age of 11.4 +/- 0.9 years. Height (Ht), height standard deviation score (HtSDS), statural age, bone age and Ht prediction. RESULTS: During the treatment a decline in HtSDS from 2.0 +/- 1.36 to 1.24 +/- 1.0 was observed (p = 0.0002); and a deceleration in the maturation of bones of 1.0 +/- 0.29 year in the first year and 0.66 +/- 0.33 year in the following years (p = 0.0008). The HtSDS at the end of the treatment was significantly higher than was predicted in pretreatment (1.33 +/- 1.04 vs. 0.07 +/- 1.39, p = 0.0005). Ht and HtSDS after treatment were positively correlated with the predicted Ht (PAH) before treatment and negatively correlated with the bone age/statural age ratio before treatment (p < 0.05). The PAH before and after treatment correlated inversely with the bone age/statural age ratio (p < 0.05). Two subgroups were analyzed according to the patients' age when therapy was introduced: group 1 included girls who were under the age of 7 when therapy was introduced, and group 2 included girls aged 7 or older. There was a statistically significant difference in the PAH SDS before treatment between these two subgroups: Group I (-) 1.3 +/- 1.8 vs. Group II (-) 0.14 +/- 1.2 and there was no difference in the PAH SDS after treatment: Group I (-) 0.7 +/- 1.1 vs. Group II 0.31 +/- 1.2. CONCLUSIONS: The child's age at the beginning of GnRHa therapy was an important predictor of height prognosis; the therapy introduced under the age of 7 improves the PAH during treatment. Height prediction during the entire treatment period is worse in children with more advanced bone age for their statural age at the onset of treatment. PMID- 26935494 TI - Differential Expression of MicroRNAs in Chronic Obstructive Pulmonary Disease. AB - BACKGROUND: This study aimed to investigate the associations of miRNA with COPD patients. OBJECTIVES: Chronic obstructive pulmonary disease (COPD) is characterized by progressive and largely irreversible airflow limitation. COPD is one of the most common causes of death globally and it is still a serious public health problem worldwide. Pathogenesis of COPD is multifactorial including genetics and environmental factors. MATERIAL AND METHODS: Sixty patients who were diagnosed with COPD according to GOLD guidance and 40 controls were involved in the study. This study was separated into four groups according to GOLD guidance. miR_16, miR_17, miR_29c, miR_92, miR_125, miR_126, miR_146, miR_155, miR_181, mir_122 expressions from the total miRNAs obtained were worked on by using real time-PCR method. The p-values are calculated based on a Student's t-test of the replicate 2^ (- Delta Ct) values for each gene in the control group. RESULTS: The miRNAs expressions in normal and COPD patients were found differentially. The miR 29c (p = 0.043) and -126 (p = 0.012) were found significantly different compared to control group. When their expressions are evaluated according to stage, miR-92 expression showed down regulation stage II and no change was observed in other miRNAs. miR-29c and miR-126 expressions showed significant differences in stage III and only miR-126 expression showed significant difference in stage IV. CONCLUSIONS: These results show that miRNA evaluations may give information about the diagnosis, staging and prognosis of the disease. In this study, we demonstrated that miR-29c and -126 are essential for the development of COPD. PMID- 26935496 TI - The Frequencies of Haplotypes of FTO Gene Variants and Their Association with the Distribution of Body Fat in Non-Obese Poles. AB - BACKGROUND: The minor allele frequencies (MAFs) of the FTO gene vary substantially among different ethnic groups, and this variation may explain, to some degree, the differences between estimates of the effects of these alleles on body fat distribution indicators. OBJECTIVES: The aim of this study was to investigate the prevalence of fat mass and obesity associated (FTO) gene variants characterizing the structure of FTO haplotypes in a large Polish population, and to examine the influence of FTO gene variants on body fat distribution among metabolically obese normal weight (MONW) individuals, i.e. those with a normal BMI and visceral obesity. MATERIAL AND METHODS: A total of 854 non-obese individuals aged from 20 to 40 years, residing in three different regions in Poland, were studied. All the patients from this group were genotyped for four FTO gene variants (rs9939609, rs9930506, rs1421085 and rs1121980). Simultaneous identification of all single nucleotide polymorphisms (SNPs) was conducted using the minisequencing method with a pair of designed specific primers. RESULTS: Over 90% of the diplotypes contain only the two most common haplotypes, in three combinations of haplotype pairs: CTAT/CTAT comprised 26.9% in women and 30.9% in men; CTAT/TCGA comprised 45.0% in women and 44.4% in men; and TCGA/TCGA comprised 19.3% in woman and 14.8% in men. The analysis of the variance in body fat distribution parameters shows no statistically significant differences between the three common haplotype pairs in either men or women. CONCLUSIONS: The young Polish population is characterized by two disparate haplotypes of common FTO gene variants: TCGA (a risk SNP haplotype), and CTAT (a protective haplotype). No significant differences were found between fat distribution indicators in relation to haplotypes in either women and men. PMID- 26935498 TI - Low-Level Vitamin D Is Associated with Atrial Fibrillation in Patients with Chronic Heart Failure. AB - BACKGROUND: Atrial fibrillation (AF) frequently accompanies heart failure (HF), and causes exacerbation of symptoms and treatment failure in such patients. Vitamin D was recently suggested to be an important mediator of cardiovascular disease, including HF. OBJECTIVES: The aim of this study was to evaluate the relationship between vitamin D deficiency and AF in patients with chronic HF. MATERIAL AND METHODS: The study included 180 chronic HF patients that were divided into 2 groups based on having sinus rhythm [AF (-) group] or chronic AF [AF (+) group]. Vitamin D status was assessed via measurement of the serum 25 hydroxyvitamin D (25[OH]D) concentration. RESULTS: Mean age of the patients was 66 +/- 8.7 years and 53.9% were male. There weren't any significant differences in age, gender, body mass index, etiology or chronic HF stage between the 2 groups. The vitamin D level in the AF (+) group was significantly lower than in the AF (-) group (11.05 ng/mL vs. 20 ng/mL, p < 0.001) and the parathyroid hormone level was significantly higher in the AF (+) group (76.7 vs. 55 pq mL, p < 0.001). The left atrium to body surface area ratio (LA/BSA) was significantly higher in the AF (+) group (45.03 mm/m2 vs. 42.05 mm/m2, p < 0.01). Independent predictors (based on multiple regression) of AF were vitamin D level (OR = 0.854, 95% CI: 0.805-0.907, p < 0.001) and LA/BSA ratio (OR = 1.077, 95% CI: 1.003 1.156, p < 0.05). The optimal vitamin D cut-off value for the prediction of AF was 16.50 ng/mL, with a sensitivity of 76.0% and specificity of 65.5% (AUC = 0.75, 95% CI: 0.67-0.82). CONCLUSIONS: A low plasma vitamin D concentration was strongly associated with AF in patients with chronic HF. PMID- 26935497 TI - Disease Activity, Oxidized-LDL Fraction and Anti-Oxidized LDL Antibodies Influence Cardiovascular Risk in Rheumatoid Arthritis. AB - BACKGROUND: Patients with rheumatoid arthritis (RA) have a shortened lifespan compared to the general population. The high rate of premature mortality in the RA population can be attributed to cardiovascular disease (CVD). OBJECTIVES: The aim of the study was to look for non-classic risk factors that can at least partially explain the enhanced cardiovascular (CV) risk in patients with RA. MATERIAL AND METHODS: This was an observational study with 37 RA patients and 24 healthy volunteers as controls. The participants' medical history was taken, and systematic coronary risk evaluation (SCORE) and carotid ultrasonography examinations were performed on all the participants. Laboratory tests included antibodies anti-cyclic citrullinated peptide (anti-CCP), inflammatory markers, lipid level, oxidized low-density lipoprotein (oxLDL) level and the level of anti oxLDL antibodies. RESULTS: Both SCORE and oxLDL fraction were elevated in RA patients as compared to the healthy controls (3.1 +/- 3.7 vs. 0.8 +/- 1.2, p = 0.005; and 0.029 +/- 0.033% vs. 0.014 +/- 0.006%, p = 0.04, respectively). In the RA group, the presence of anti-CCP was associated with thickening of the carotid intima-media complex and SCORE elevation. In the RA group, significant correlations were found between SCORE and mean carotid intima-media thickness (IMT; RP = 0.34, p = 0.040), disease activity score (RP = 0.42, p = 0.011), erythrocyte sedimentation rate (ESR; RP = 0.35, p = 0.036), and disease duration (RP = 0.52, p = 0.002). In RA patients with carotid plaques, the oxLDL fraction was significantly elevated in comparison to those without plaques (0.055 +/- 0.070% vs. 0.022 +/- 0.018%, p = 0.033). In the RA group, there was a significant negative correlation between mean carotid IMT and the serum concentration of anti oxLDL antibodies (RP = -0.38, p = 0.02). No association was noted between the presence of rheumatoid nodules and SCORE or carotid IMT. CONCLUSIONS: Among RA patients, disease activity, ESR, disease duration, the presence of anti-CCP antibodies, the oxLDL fraction and the level of anti-oxLDL antibodies influence CV risk. PMID- 26935499 TI - Evaluation of the Usability of Selected Questionnaires Assessing Physical Activity in the Prophylaxis of Cardiovascular Diseases. AB - BACKGROUND: The main health problem of the Polish population is posed by cardiovascular diseases (CDVD), coronary artery disease (CAD) in particular. Respectively higher physical activity linked with energy expenditure of at least 1000 kcal/week may significantly reduce the risk of CAD development. The protective effect of exercise applies not only to persons from high-risk groups and with diagnosed chronic diseases that increase the risk of the incidence of atherosclerosis and its complications, but also to healthy individuals. OBJECTIVES: The aim of this study was to evaluate the usability of the Seven-Day Physical Activity Recall (SDPAR) and International Physical Activity Questionnaire (IPAQ) in research on the correlation between physical activity and risk factors of cardiovascular diseases. MATERIAL AND METHODS: A screening survey, conducted in 2012, included students (n = 340) of the Division of the Academy of Physical Education in Biala Podlaska, aged 18-29 years. Total cholesterol, triglycerides and glucose levels were analyzed, and arterial blood pressure and heart rate were measured. The physical activity of the students was estimated using IPAQ and SDPAR questionnaires. The effect of physical activity on the biochemical blood markers, arterial blood pressure and heart rate was analyzed in groups differing in weekly energy expenditure (WEE). RESULTS: Along with increasing WEE values, calculated with IPAQ and SDPAR questionnaires, tangible descending tendencies were observed in cholesterol concentration in both genders. Significant differences were demonstrated in mean values of the resting heart rate between terciles of women ranked according to the increasing WEE values calculated using IPAQ (p < 0.05) and SDPAR (p < 0.01). Significant (p < 0.05) negative correlations were demonstrated only between the heart rate of women and WEE value calculated with IPAQ (r = -0.223) and SDPAR (r = -0.238). CONCLUSIONS: Beneficial changes were observed in the blood lipid profile and in mean resting heart rate values as affected by the higher energy expenditure. The IPAQ and SDPAR may be applied to assess the level of physical activity; however the SDPAR seems to be a more useful tool in CDVD prevention screening. PMID- 26935500 TI - The Structure of Fats and Fatty Acid Consumption in Elderly People with Cardiovascular System Diseases. AB - BACKGROUND: Patients with cardiovascular system diseases having their origin in arteriosclerosis require special dietetic treatment. Among many nutritional components, fats in the diet (both their quantity and quality) play a very important role in primary and secondary prevention of these diseases. OBJECTIVES: The aim of the study was the estimation of total fats participation (saturated fatty acids, mono- and polyunsaturated fatty acids and cholesterol) in the Daily Nutritional Ration (DNR) of elderly people with cardiovascular system diseases. MATERIAL AND METHODS: The study included 128 persons (66 women and 62 men, mean age 73.2 +/- 6.9) hospitalized in the 1st Clinic of Cardiology and Hypertension, UJCM in Krakow. Daily intakes of energy were estimated using the 24-h nutritional recall and Food Frequency Questionnaire. RESULTS: A higher consumption of fats and fatty acids was observed in men's diet than in women's diet. The percentage of energy from saturated fatty acids (10.6% M and W) was higher than dietary recommendations. The consumption of monounsaturated fatty acids was in accordance with nutritional recommendations. The participation in the diet of polyunsaturated fatty acids was insufficient versus the newest nutritional recommendations and was determined as 4.6% of energy in DNR in men and 4.1% of energy of DNR in women. CONCLUSIONS: The excessive amount of saturated fatty acids together with the insufficient amount of polyunsaturated fatty acids in the diet are the result of the excessive consumption of products which are a source of animal fat and insufficient consumption of plant fat, fish and seafood. PMID- 26935501 TI - 13C-Methacetin Breath Testing in Patients with Non-Alcoholic Fatty Liver Disease. AB - BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a very common chronic liver condition which may potentially develop into fibrosis and cirrhosis. Liver biopsy is still the gold standard for liver fibrosis detection in these patients. However, non-invasive tools for liver assessment in NAFLD patients, like the (13)C-methacetin breath test, may be useful. OBJECTIVES: The aim of the study was to evaluate the utility of the (13)C-methacetin breath test in NAFLD patients, especially in predicting significant fibrosis. MATERIAL AND METHODS: Thirty three patients (24 male and 9 female (average age 47.9)) with histologically proven NAFLD had the (13)C-methacetin breath test performed. RESULTS: Different forms of NAFLD were found during the histology phase, from simple steatosis to advanced fibrosis. Simple steatosis (SS) was found in 18 subjects (54.5%), in another 15 (45.5%) signs of inflammation and fibrosis (NASH) were observed. However, more than half of the patients with liver fibrosis had only minimal changes described (0/1). The sensitivity of the test was highest for cumulative recovery after 10 min of the test and for a combination of two parameters (the cumulative recovery after 40 min and the time of maximal momentary recovery). The positive predictive value was low for all the parameters under consideration, but the negative predictive value was over 0.8 in significant fibrosis detection. CONCLUSIONS: The (13)C-methacetin breath test could be a promising noninvasive tool for excluding at least F1 fibrosis in NAFLD patients. PMID- 26935502 TI - Venous Stenosis and Occlusion in the Presence of Endocardial Leads. AB - BACKGROUND: Venous stenosis and occlusion in the presence of endocardial leads constitute one of the complications of permanent cardiac pacing either by pacemaker, implantable cardioverter-defibrillator or cardiac resynchronization therapy. OBJECTIVES: The aim of this study was to assess the incidence of stenosis and occlusions and determine the risk factors in patients with endocardial leads in a prospective single-center study. MATERIAL AND METHODS: Two hundred eighty consecutive patients aged 25-95 years (male 68.8%) were included. A contrast venography examination of the ipsilateral access vein was performed. The whole study population was divided into 2 groups, based on the presence (group I) or absence (group II) of endocardial leads. RESULTS: Venous stenosis/occlusion was identified in 51 patients (37.5%) in group I and in 3 patients (3.6%) in group II; p < 0.0001. The lead presence most highly correlated with venous complications (OR = 4.172; p < 0.001). In patients with endocardial leads divided into I A and I B according to venous patency diabetes mellitus was proved in multivariate analysis to be the only protective factor against the development of venous stenosis/occlusion (OR = 0.473; p = 0.010). CONCLUSIONS: The presence of endocardial leads is a predisposing factor for venous stenosis/occlusion and increases the risk 4-fold. The venous lesions in the presence of endocardial leads are less frequent among patients with diabetes mellitus. PMID- 26935503 TI - Ultrasound Guided Fine-Needle Aspiration Biopsy of Thyroid Nodules: Does Radiologist Assistance Decrease the Rate of Unsatisfactory Biopsies? AB - BACKGROUND: Ultrasound guided fine-needle aspiration biopsy (UG-FNAB) is the main presurgical, minimally invasive, accurate and generally safe procedure for the diagnosis of thyroid pathology. At present it is recommended as a valuable diagnostic tool for the management of thyroid nodules. OBJECTIVES: This study aimed to evaluate if a radiologist's assistance in the UG-FNAB procedure decreased the rate of unsatisfactory biopsies. MATERIAL AND METHODS: Over a 3 year period, 385 (100%) patients were enrolled to the study. All individuals had UG-FNAB performed for the first time due to multiple nodules of the thyroid gland. Patients with a family history of thyroid cancer, receiving radioactive iodine and other predispositions for thyroid malignancy were excluded. 184 (47.79%) patients were examined using UG-FNAB with a radiologist's assistance (group 1) and 201 (52.21%) without such support (group 2). All biopsies were performed by the same surgeon. All specimens obtained were examined by two cytologists experienced in thyroid pathology. RESULTS: The specimens from the UG FNAB were more frequently diagnostic when obtained from procedures performed with a radiologist's assistance (77.8% vs. 56.8%, p < 0.0001). The cellularity of the specimens obtained from the UG-FNAB performed with a radiologist's assistance was higher than those obtained without such support (66.7% vs. 56.9%, p < 0.0001). CONCLUSIONS: UG-FNAB of the thyroid nodules performed with a radiologist's assistance makes it possible to obtain more valuable specimens, which may improve diagnostic accuracy in the preoperative management of thyroid pathology. PMID- 26935504 TI - The Comparison of Four-Port, Two-Port Without Suspension Suture and Single Port Laparoscopic Cholecystectomy Results. AB - BACKGROUND: Single-port surgery has recently become popular, however, many surgeons have to use additional ports during the surgery due to difficulties. OBJECTIVES: We performed two-port MCAP (with an additional port using a multi channel device through the umbilicus) without a suspension suture in a group of patients. We compared the results of this technique to the LC and SILC techniques. MATERIAL AND METHODS: A total of 90 patients with gallbladder disease were included in the study. LC (n = 30) and SILC (n = 30) were performed in two groups. The other group underwent cholecystectomy (MCAP) by using an additional 5 mm port through the subxiphoid region with a multi-channel port through the transumblical. A transabdominal suspension suture was not used for the patients in this group. The surgery duration, estimated blood loss, length of hospitalization, visual analogue scale (VAS) score in the postoperative 1st and 7th day, need for analgesia in the postoperative period and complications, and the conversion rate were compared between the three methods. RESULTS: A total of 62 females (68.9%) and 28 males (31.1%) participated in the study. MCAP duration was significantly shorter than LC and SILC (38.1 +/- 16.6, 49.4 +/- 15.8, 77.8 +/ 26.7 min respectively) (p < 0.05). The conversion rate was similar in all three groups. Hernia developed in the port area in two patients after SILC (6.7%). No significant difference was found between the groups for the other data we compared. CONCLUSIONS: MCAP seems to be an easier technique with a shorter operation time compared to the other two techniques. However, there is a need for other studies to evaluate the cosmetic results. PMID- 26935505 TI - Assessment of Magnetic Resonance Enterography in the Diagnosis of Small Bowel Diseases in Children with Crohn's Disease. AB - BACKGROUND: In pediatric patients Crohn's disease most commonly involves the colon and the ileocecal part of the intestine. MR enterography, a new method of small bowel imaging with magnetic resonance, has been introduced in the last decade. OBJECTIVES: The aim of this study was to assess the usefulness of the MR enterography in the diagnosis of small bowel lesions in children with Crohn's disease. MATERIAL AND METHODS: The study included 37 children (18 girls and 19 boys) aged from 5.5 to 18 years (average age, 13.3), diagnosed with Crohn's disease according to the Porto criteria. The disease duration ranged from 1 month to 12 years, on average 3 years. MR eterography was performed according to the Giles et al. protocol. The obtained results were compared with the location and the manifestation of the disease according to the Paris classification. RESULTS: In 13 children (35.1%), the disease began prior to 10 years of age, and in the remaining 24 children (64.9%) between 10 and 17 years of age. The gastrointestinal endoscopy confirmed Crohn's disease in the colon (45.9%) and in the colon and ileum (27.1%). An incomplete colonoscopy examination which did not reveal the location of the disease was conducted in 7 children (18.9%). A comparison of the location of Crohn's disease with the location of lesions in the small bowel as indicated by MR enterography revealed that the most common changes can be found in the final part of ileum, in ileum, and in 4 children in jejunum. MR enterography demonstrated, that 16 children (43.2%) had inflammation, 7 children (18.9%) stenosis, and 14 children (37.8%) had no lesions at all. CONCLUSIONS: MR enterography is a non-invasive and safe procedure well tolerated by children that allows the visualization of lesions in the small bowel in children with Crohn's disease. PMID- 26935506 TI - Methionine Aminopeptidase 2 as a Potential Therapeutic Target for Human Non-Small Cell Lung Cancers. AB - BACKGROUND: Methionine aminopeptidase 2 (MetAP2) is a bi-functional protein that plays a critical role in the regulation of post-translational processing and protein synthesis. OBJECTIVES: We studied whether MetAP2 is activated and expressed in human non-small-cell lung cancer (NSCLC) tissues and whether inactivation of MetAP2 activity, with its specific inhibitor fumagillin, potentially inhibits proliferation of NSCLC cells. MATERIAL AND METHODS: The expression and function of MetAP2 were evaluated in NSCLC tissues, primary cell cultures and cell lines using immunohistochemistry, RT-PCR, Western blot, aminopeptidase activity assay and flow cytometry. MetAP2 expression was also studied in relation to clinicopathological factors. RESULTS: MetAP2 expression in NSCLS, including adenocarcinoma (ADC) and squamous cell carcinoma (SCC), showed a moderate to strong positive reaction while normal appearing bronchial epithelium showed weak staining and normal alveolar epithelial cells were widely negative. A high MetAP2 mRNA and protein expression was found in NSCLC tissues. The aminopeptidase activity in NSCLC was 2-fold higher than that in normal lung tissues. In a series of 41 ADC patients, MetAP2 expression was significantly correlated with patient's outcome or survival time. Inhibition of MetAP2 by fumagillin in SCC cell lines revealed a significant increase in caspase-3 activity as compared to the control (p = 0.001). CONCLUSIONS: Our results indicate that MetAP2 is involved in NSCLC and is an important regulator of proliferative and apoptotic targets. Thus inhibition of MetAP2, such as by fumagillin, may be a potential therapeutic modality for prevention of tumor cell growth, development and progression in NSCLC patients. PMID- 26935507 TI - Evaluation of Soft Tissue Reaction to Corundum Ceramic Implants Infiltrated with Colloidal Silver. AB - BACKGROUND: Corundum ceramic is a biomaterial used as a bone graft substitute. Silver is a well known antiseptic substance with many practical, clinical applications. OBJECTIVES: The aim of this study was to estimate soft tissue (in vivo) reaction to a new kind of ceramic implants. In our experiment, we examined the soft tissue reaction after implantation of corundum ceramic infiltrated with colloidal silver in the back muscles of 18 Wistar rats. The use of colloidal silver as a coating for the implant was designed to protect it against colonization by bacteria and the formation of bacterial biofilm. MATERIAL AND METHODS: In our study, based on the experimental method, we performed implantation operations on 18 Wistar rats. We implanted 18 modified ceramic implants and, as a control group, 18 unmodified implants. As a follow up, we observed the animals operated upon, and did postoperative, autopsy and histopathological examinations 14, 30, 90 and 180 days after implantation. RESULTS: We didn't observe any pathological reactions and significant differences between the soft tissue reaction to the modified implants and the control group. CONCLUSIONS: Lack of pathological reaction to the modified implants in the living organism is the proof of their biocompatibility. This is, of course, the first step on the long path to introduce a new kind of biocompatible ceramic implant with antiseptic cottage. Our experiment has an only introductory character and we plan to perform other, more specific, tests of this new kind of implant. PMID- 26935508 TI - Identification and Comparison of Barriers to Assessing and Combating Acute and Postoperative Pain in Elderly Patients in Surgical Wards of Polish Hospitals: A Multicenter Study. AB - BACKGROUND: Inadequate pain monitoring and management in hospitalized patients poses a serious clinical problem which has been extensively covered in literature for over 25 years. OBJECTIVES: The purpose of the paper was to learn about and compare the existing barriers to effective analgesia controlled by nurses on surgical wards in Polish hospitals. MATERIAL AND METHODS: The study was carried out upon the approval of the study protocol by the Independent Bioethics Committee for Scientific Research of the Medical University of Gdansk. The research project was multi-center and took a year. The study was questionnaire based. It used the Polish version of the Nurses' Perceived Obstacles to Pain Assessment and Management Practices questionnaire. The study included a total of 1300 nurses working on surgical wards. RESULTS: The barriers most frequently observed by the respondents were: disorganization of the healthcare system, physicians' mistrust of pain assessment by nursing staff, difficulty contacting and communicating with physicians to discuss the results of patients' pain assessments and difficulties experienced by elderly patients with completing pain assessment scales. CONCLUSIONS: The barriers most frequently impeding pain therapy in elderly patients are associated with the healthcare system, and they were more frequently present on the anesthesiology and intensive care ward and in the emergency department, and occurred the least frequently on the surgical ward. Patient-related problems were more frequent on the anesthesiology and intensive care wards than in the emergency department. Doctor-related problems most frequently occurred on the gynecological ward, while nurse-related problems were more frequent on the anesthesiology and intensive care ward. PMID- 26935509 TI - Nordic Walking May Safely Increase the Intensity of Exercise Training in Healthy Subjects and in Patients with Chronic Heart Failure. AB - BACKGROUND: Physical activity in patients with chronic heart failure (HF) improves the exercise capacity and quality of life, and may also reduce mortality and hospitalizations. The greatest benefits are achieved through high-intensity aerobic exercises resulting in a stronger cardiorespiratory response. Nordic walking (NW), a walking technique using two poles and mimicking the movements performed while cross-country skiing, is associated with the involvement of more muscle groups than in the case of classic walking, and should therefore make it possible to increase exercise intensity, resulting in more effective training for patients with HF. OBJECTIVES: The aim of the study was to assess the feasibility and safety of the NW technique, and to compare the effort intensity while walking with and without the NW technique in both healthy subjects and in patients with chronic HF. MATERIAL AND METHODS: The study involved 12 healthy individuals (aged 30 +/- 10 years, 5 men) and 12 men with stable chronic systolic HF (aged 63 +/- 11 years, all categorized in New York Heart Association class II, median LVEF 30%, median peak VO(2) 18.25 mL/kg/min). All the participants completed two randomly assigned submaximal walking tests (one with NW poles and one without) conducted on a level treadmill for 6 min at a constant speed of 5 km/h. RESULTS: Walking with the NW technique was feasible, safe and well tolerated in all subjects. In both the control group and the chronic HF group, walking with the NW technique increased peak VO(2), RER, VE, PET CO(2), HR and SBP over walking without the poles; and the fatigue grade according to the abridged Borg scale was higher. Dyspnea did not increase significantly with the NW technique. CONCLUSIONS: The NW technique can increase the intensity of aerobic training in a safe and well-tolerated way in both healthy individuals and in patients with chronic HF. PMID- 26935510 TI - The Nanopharmacology and Nanotoxicology of Nanomaterials: New Opportunities and Challenges. AB - The very dynamic growth of nanotechnology, nanomaterials (sized 1-100 nm) and their medical applications over the past 10 years has promised to add a new impetus to the diagnostics and therapeutics of a wide range of human pathologies, including cancer, cardiovascular diseases and diseases of the central nervous system. This growth in nanomedicine also fuels advances in bioengineering, regenerative medicine and the development of medical devices. However, as with all new pharmaceuticals and medical devices, new opportunities are inherently accompanied by new challenges due to the ability of nanomaterials to interact with the body on the cellular, subcellular and molecular levels. This article reviews some of the most compelling problems related to the nanopharmacology and nanotoxicology of nanomaterials. The overview focuses on opportunities emerging from the development of multifunctional nanomaterials and nanotheranostics for the diagnostics and therapy of both major and rare diseases. Challenges related to the hemocompatibility of nanomaterials are also discussed. PMID- 26935511 TI - Role of Platelets in Thromboembolism in Patients with Atrial Fibrillation. AB - Thromboembolic complications of atrial fibrillation (AF) are a major cause of morbidity and mortality but the mechanism of its process remain poorly understood. There are many as yet unanswered questions surrounding the increased thrombotic tendency in AF. One of the crucial questions is what determines the fact that a thrombus remains in the left atrium in situ in some patients, while in others it breaks off and leads to embolic complications. Recent studies indicated an important role of platelets in the left atrial's thrombus formation and suggest that the embolic potential of left atrial thromboses depends on the involvement of platelets in the process of fibrin stabilization rather than aggregation. New methods for investigating platelets function, such as the analysis of transcription activity of RNA coming from platelets contained in thrombi formed in AF, creates an opportunity for studying populations of platelets that are directly involved in homeostatic clot formation. In this paper we present current opinions on the participation of platelets in the pathogenesis of thromboembolism in patients with AF. PMID- 26935512 TI - Resistant Hypertension. AB - Resistant hypertension is a severe medical condition which is estimated to appear in 9-18% of hypertensive patients. Due to higher cardiovascular risk, this disorder requires special diagnosis and treatment. The heterogeneous etiology, risk factors and comorbidities of resistant hypertension stand in need of sophisticated evaluation to confirm the diagnosis and select the best therapeutic options, which should consider lifestyle modifications as well as pharmacological and interventional treatment. After having excluded pseudohypertension, inappropriate blood pressure measurement and control as well as the white coat effect, suspicion of resistant hypertension requires an analysis of drugs which the hypertensive patient is treated with. According to one definition - ineffective treatment with 3 or more antihypertensive drugs including diuretics makes it possible to diagnose resistant hypertension. A multidrug therapy including angiotensin - converting enzyme inhibitors, angiotensin II receptor blockers, beta blockers, diuretics, long-acting calcium channel blockers and mineralocorticoid receptor antagonists has been demonstrated to be effective in resistant hypertension treatment. Nevertheless, optional, innovative therapies, e.g. a renal denervation or baroreflex activation, may create a novel pathway of blood pressure lowering procedures. The right diagnosis of this disease needs to eliminate the secondary causes of resistant hypertension e.g. obstructive sleep apnea, atherosclerosis and renal or hormonal disorders. This paper briefly summarizes the identification of the causes of resistant hypertension and therapeutic strategies, which may contribute to the proper diagnosis and an improvement of the long term management of resistant hypertension. PMID- 26935513 TI - Osteoporosis in Gastrointestinal Diseases. AB - Secondary osteoporosis occurs as an isolated pathology or co-exists with types I and II osteoporosis. The gastroenterologist may come across osteoporosis or osteopenia in a patient with a gastrointestinal disease. This is often a young patient in whom investigations should be carried out and appropriate treatment initiated, aimed at preventing bone fractures and the formation of the best peak bone mass. Osteoporosis occurs in patients with the following conditions: Crohn's disease, ulcerative colitis, celiac disease, post gastrectomy patients, patients with short bowel syndrome, chronic hepatitis and cirrhosis, treated with steroids (steroid-induced osteoporosis) and patients using proton pump inhibitors chronically (state of achlorhydria). It is therefore necessary to approve a list of risk factors of secondary osteoporosis, the presence of which would be an indication for screening for osteoporosis, including a DXA study and the development of a separate algorithm for the therapeutic management of secondary osteoporosis accompanying gastrointestinal diseases, especially in premenopausal young women and young men, because there are currently no registered drugs with proven antifracture activity for this group of patients. PMID- 26935514 TI - Prevention of Iatrogenic Anemia in Critical and Neonatal Care. AB - Iatrogenic anemia caused by diagnostic blood sampling is a common problem in the intensive care unit, where continuous monitoring of blood parameters is very often required. Cumulative blood loss associated with phlebotomy along with other factors render this group of patients particularly susceptible to anemia. As it has been proven that anemia in this group of patients leads to inferior outcomes, packed red blood cell transfusions are used to alleviate possible threats associated with low hemoglobin concentration. However, the use of blood components is a procedure conferring a set of risks to the patients despite improvements in safety. Iatrogenic blood loss has also gained particular attention in neonatal care, where cumulative blood loss due to samples taken during the first week of life could easily equal or exceed circulating blood volume. This review summarizes the current knowledge on the causes of iatrogenic anemia and discusses the most common preventive measures taken to reduce diagnostic blood loss and the requirement for blood component transfusions in the aforementioned clinical situations. PMID- 26935515 TI - Xerostomia of Various Etiologies: A Review of the Literature. AB - This paper presents the etiopathogenesis, symptomatology, evaluation and treatment of mouth dryness. Xerostomia affects 1-29% of the population, mostly women. It is observed in geriatric patients and in individuals using certain medications, those subjected to radiotherapy of the head and neck region or affected with autoimmune conditions. The main signs of xerostomia include the impression of a dry mouth, problems with food ingestion and dryness of the oral mucosa and skin. Evaluation is based on structured interviews (the Fox test) and determinations of unstimulated and stimulated salivary volume. The signs of xerostomia can be attenuated with saliva substitutes, cevimeline or malic acid. Only palliative treatment of this condition is available at present. Untreated xerostomia significantly impairs the quality of life, which can potentially lead to depression. PMID- 26935516 TI - Lentivirus-mediated PHLDA2 overexpression inhibits trophoblast proliferation, migration and invasion, and induces apoptosis. AB - Inadequate trophoblast invasion and increased trophoblast apoptosis cause serious pregnancy complications. Pleckstrin homology-like domain, family Alpha, member 2 (PHLDA2) has been linked to fetal size at birth and growth restriction in a number of studies. However, the impact of PHLDA2 on trophoblast function had not been studied previously, to the best of our knowledge. In the present study, immunofluorescence staining demonstrated that primary trophoblasts isolated from placental villous tissues were positive for cytokeratin 18 (CK18), vimentin and human placental lactogen (hPL). JEG-3 cells and primary trophoblasts were infected with lentivirus overexpressing PHLDA2. RT-qPCR and western blot analysis detected high levels of PHLDA2. A Cell Counting Kit-8 (CCK-8) assay showed that PHLDA2 overexpression inhibited trophoblast proliferation. In addition, PHLDA2 significantly induced apoptosis, as evidenced by Annexin V-FITC/propidium iodide (PI) and Hoechst staining, along with activation of Bax and caspase-3 and also decreased Bcl-2 expression. Further investigation showed that PHLDA2 effectively induced reactive oxygen species (ROS) generation, caused cytochrome c release from the mitochondria into the cytosol and decreased mitochondrial membrane potential. PHLDA2 likely induced apoptosis through the mitochondrial pathway. Wound healing and Transwell assays indicated that PHLDA2 overexpression efficiently suppressed cell migration and invasion. These data suggest that PHLDA2 plays an important role in the occurrence and development of pregnancy complications by promoting trophoblast apoptosis and suppressing cell invasion. PMID- 26935517 TI - Fear of cancer recurrence in prostate cancer survivors. AB - Background High fear of cancer recurrence (FCR) is an understudied topic in prostate cancer (PCa) survivors. This study aimed to detect the prevalence, consequences and characteristics associated with high FCR in PCa survivors. Material and methods This cross-sectional study included patients diagnosed with localized PCa and treated with curative radical prostatectomy between 1992 and 2012. We administered the Cancer Worry Scale (CWS) to assess FCR severity (primary outcome measure). Secondary outcomes included distress, quality of life (QOL), post-traumatic symptoms, and multidimensional aspects of FCR. chi(2) tests, t-tests and Pearson's correlations examined the relationship between FCR and medical/demographic characteristics. MANOVA analyses and chi2-tests identified differences between PCa survivors with high and low FCR. Results Two hundred eighty-three PCa survivors (median age of 70.0 years) completed the questionnaires a median time of 7.1 years after surgery. About a third (36%) of all PCa survivors experienced high FCR. High FCR was associated with lower QOL, more physical problems, higher distress and more post-traumatic stress symptoms. PCa survivors with high FCR reported disease-related triggers (especially medical examinations), felt helpless and experienced problems in social relationships. High FCR was associated with a younger age and having received adjuvant radiotherapy. Conclusions Results illustrate that FCR is a significant problem in PCa survivors. Younger men and those treated with adjuvant radiotherapy are especially at risk. Those with high FCR experience worse QOL and higher symptom burden. Health care providers should pay specific attention to this problem and provide appropriate psychosocial care when needed. PMID- 26935518 TI - [A clinical analysis of elderly dementia patients with physical comorbidities]. AB - AIM: To investigate the current status of elderly dementia patients with physical illnesses and identify optimal care strategies for this growing population. METHODS: This retrospective study included elderly dementia patients who (i) received in-patient treatment for a physical comorbidity at the dementia ward of the Juntendo Tokyo Koto Geriatric Medical Center, and (ii) who were discharged from April 2009 to March 2011. RESULTS: The study population was 390 patients (144 males, 246 females), with a mean [+/-SD] age of 80.5 [+/-8.1] years. Two hundred thirteen of the patients had Alzheimer's disease; the remaining 177 had other types of dementia. The comorbidities necessitating admission were: malignant neoplasms (n=65), respiratory conditions (n=57), genitourinary conditions (n=50), trauma or fracture (n=41), and other (n=177). Among the 239 subjects who were hospitalized from their homes and who were discharged alive, 157 (65.7%) returned to their homes. The hospital stays of patients who were discharged were significantly shorter (P<0.000) and their N-ADL scores were significantly better at admission (P<0.013) and at discharge (P<0.000). The proportion of subjects who were capable of oral ingestion was significantly higher among the patients who were discharged to their homes (P<0.025). The subjects who lived in their homes alone at the time of hospitalization were significantly less likely to be discharged to their homes (P<0.018). CONCLUSIONS: Elderly dementia patients should ideally return home after hospitalization for comorbid illnesses. This was facilitated by minimizing their hospital stay. During in-patient treatment, efforts should be made to maintain their N-ADL levels and support their oral intake. PMID- 26935519 TI - [Abdominal obesity mediates the association between a low physical activity and a decline in gait speed in community-dwelling elderly people: A cross-sectional study]. AB - AIM: A low physical activity leads to obesity and a decline in the physical function. The aim of this cross-sectional study was to examine whether the association between a low physical activity and low physical function was mediated by obesity. METHODS: A total of 73 community-dwelling elderly people participated in this study. The analysis included 56 participants without knee and hip osteoarthritis, low cognitive function (the Mini Mental State Examination score <24) and rheumatoid arthritis (mean age+/-SD: 73.3+/-4.1, female: 50%). The daily step count was collected as a measure of physical activity by a single axial accelerometer. The physical function was measured by the gait speed. Obesity was measured by the body mass index and waist circumference. To assess whether the association between the physical activity and physical function was mediated by obesity, linear regression models were fitted according to Baron and Kenny procedures for a mediation analysis. A p value <0.05 was considered to be statistically significant. RESULTS: The body mass index did not act as a mediator in the association between the physical activity and gait speed, whereas the waist circumference acted as a full mediator in the association between the physical activity and gait speed. CONCLUSION: An increased waist circumference mediates the association between a low physical activity and a low physical function in community-dwelling elderly people. PMID- 26935520 TI - [A case of gastric endocrine cell carcinoma which was significantly reduced in size by radiotherapy]. AB - In 2010, the World Health Organization classified gastric neuroendocrine tumors (NETs) into three types: NET grade (G) 1, NET G2 and neuroendocrine carcinoma (NEC). NECs are associated with a very poor prognosis. The patient was an 84-year old female who was initially diagnosed by gastrointestinal endoscope with type 3 advanced gastric cancer with stenosis of the gastric cardia. Her overall status and performance status did not allow for operations or intensive chemotherapy. Palliative radiotherapy was performed and resulted in a significant reduction in the size of the tumor as well as the improvement of the obstructive symptoms. She died 9 months after radiotherapy. An autopsy provided a definitive diagnosis of gastric endocrine cell carcinoma, and the effectiveness of radiotherapy was pathologically-confirmed. Palliative radiotherapy may be a useful treatment option for providing symptom relief, especially for old patients with unresectable advanced gastric neuroendocrine carcinoma. PMID- 26935521 TI - [Not Available]. PMID- 26935522 TI - [Not Available]. PMID- 26935526 TI - Suppression of forkhead box Q1 by microRNA-506 represses the proliferation and epithelial-mesenchymal transition of cervical cancer cells. AB - MicroRNAs (miRNAs) play a pivotal role in cancer progression and development, representing novel therapeutic tools for cancer therapy. Forkhead box Q1 (FOXQ1) functions as an oncogene in various cancer types. However, the functional significance of FOXQ1 in cervical cancer remains unknown. In this study, we investigated the biological function of FOXQ1 in cervical cancer and tested whether or not FOXQ1 can be targeted and regulated by specific miRNAs. We found that FOXQ1 was highly expressed in cervical cancer cell lines. Knockdown of FOXQ1 by small interfering RNA (siRNA) significantly suppressed the proliferation and epithelial-mesenchymal transition (EMT) of cervical cancer cells. FOXQ1 was predicted as a target gene of microRNA-506 (miR-506), and this prediction was validated by dual-luciferase reporter assay. Quantitative real-time PCR and western blot analyses demonstrated that mRNA and protein expression was negatively regulated by miR-506. The expression of miR-506 was downregulated in cervical cancer tissues, and miR-506 expression was inversely correlated with FOXQ1 expression in cervical cancer. The overexpression of miR-506 dramatically suppressed the proliferation and EMT of cervical cancer cells that mimicked the suppression of FOXO1 siRNA. Furthermore, the restoration of FOXQ1 expression significantly reversed the inhibitory effect of miR-506. Overall, our study demonstrated that miR-506 inhibited the proliferation and EMT of cervical cancer cells by targeting FOXQ1 and provided evidence that the miR-506/FOXQ1 axis plays an important role in the pathogenesis of cervical cancer, representing potential molecular targets for the development of anticancer agents for cervical cancer treatment. PMID- 26935528 TI - Inhibition of rhotekin exhibits antitumor effects in lung cancer cells. AB - Lung cancer is the leading cause for cancer-related death, however, the pathogenesis mechanism is poorly understood. Although the rhotekin (RTKN) gene has been reported to encode an effector for the Rho protein that has critical roles in regulating cell growth, the role of RTKN in lung cancer has not been investigated. In clinical lung cancer patient tumor samples, we identified that the RTKN gene expression level was significantly higher in tumor tissues compared to that of the adjacent normal tissues. To investigate the molecular mechanisms of RTKN in lung cancer, we established RTKN stable knock-down A549 and SPC-A-1 lung adenocarcinoma cell lines using lentiviral transfection of RTKN shRNA and evaluated the antitumor effects. The results showed that RTKN knock-down inhibited lung adenocarcinoma cell viability, induced S phase arrest and increased cell apoptosis. In addition, RTKN knock-down inhibited lung cancer cell invasion and adhesion. Further analysis showed that the S phase promoting factors cyclin-dependent kinase (CDK)1 and CDK2 levels were decreased in RTKN knock-down cells, and that the DNA replication initiation complex proteins Minichromosome maintenance protein complex (MCM)2 and MCM6 were decreased as well in RTKN knock down cells. These results indicated that the RTKN protein was associated with lung cancer in clinic samples and exerted anticancer activity in lung adenocarcinoma cells through inhibiting cell cycle progression and the DNA replication machinery. These findings suggest that RTKN inhibition may be a novel therapeutic strategy for lung adenocarcinoma. PMID- 26935527 TI - Triptolide sensitizes human breast cancer cells to tumor necrosis factor-alpha induced apoptosis by inhibiting activation of the nuclear factor-kappaB pathway. AB - Tumor necrosis factor-alpha (TNF-alpha) can act as either a tumor promoter, linking inflammation with carcinogenesis, or a tumor inhibitor, inducing cancer cell death. However, several types of cancer, including breast cancer, are resistant to TNF-alpha therapy. Triptolide, a diterpene triepoxide, has been reported to exert anti-inflammatory and antiproliferative effects, associated with the inhibition of nuclear factor-kappaB (NF-kappaB). The present study investigated the effects of triptolide sensitization on human breast cancer cells to TNF-alpha-induced apoptosis by inhibiting activation of the NF-kappaB pathway. Human breast cancer MDA-MB-231 cells and MCF-7 cells were treated with different concentrations of triptolide, with or without 10 ng/ml TNF-alpha, for different durations, followed by measurement of cell proliferation using a 3-[4,5 dimethyltiazol-2-yl]-2.5-diphenyl-tetrazolium bromide assay, apoptosis induction, through determination of caspase-3 activity and poly (ADP-ribose) polymerase (PARP) cleavage, and NF-kappaB pathway activation, through determination of inhibitor of NF-kappaB (IkappaB) and the NF-kappaB downstream genes, X-linked inhibitor of apoptosis protein (XIAP) and cellular inhibitor of apoptosis protein1/2 (cIAP1/2)] using Western blot and reverse transcription-quantitative polymerase chain reaction analyses. TNF-alpha, when combined with triptolide, was observed to inhibit the activation of IkappaBalpha, increase the level of cleaved PARP, and further activate caspase-3 in the breast cancer cells. Triptolide also inhibited the expression levels of the downstream anti-apoptotic genes of NF kappaB activation, XIAP and cIAP1/2. The results of the present study demonstrated that triptolide sensitized human breast cancer cells to TNF-alpha induced apoptosis, which may provide a promising combination strategy for human breast cancer therapeutics. PMID- 26935529 TI - The fine structure of sexual stage development and sporogony of Cryptosporidium parvum in cell-free culture. AB - The sexual stages and new oocysts development of Cryptosporidium parvum were investigated in a cell-free culture system using transmission electron microscopy (TEM). Sexual development was extremely rapid after inoculation of oocysts into the medium. The process began within 1/2-12 h and was completed with new oocyst formation 120 h post-inoculation. The macrogamonts were bounded by two membranes and had amylopectin granules and two distinct types of wall-forming bodies. The microgamonts had a large nucleus showing lobe projections and condensation of chromatin, giving rise to peripherally budding microgametes. The microgametes contained a large area of granular substance containing groups of microtubules surrounding the electron-dense nucleus. In some instances, the dividing microgamy was observed in cell-free cultures with no preceding merogonic process. Fertilization was observed with the bullet-shaped microgamete penetrating an immature macrogamont at 24 and 216 h. The new thin- and thick-walled oocysts had a large residuum with polysaccharide granules and sporogony noted inside these oocysts. Novel immature four-layer walled thick oocysts with irregular knob-like protrusions on the outer layer resembling the immature Eimeria oocysts were also observed. The present study confirms the gametogony and sporogony of C. parvum in cell-free culture and describes their ultra-structure for the first time. PMID- 26935531 TI - Resonant X-ray emission with a standing wave excitation. AB - The Borrmann effect is the anomalous transmission of x-rays in perfect crystals under diffraction conditions. It arises from the interference of the incident and diffracted waves, which creates a standing wave with nodes at strongly absorbing atoms. Dipolar absorption of x-rays is thus diminished, which makes the crystal nearly transparent for certain x-ray wave vectors. Indeed, a relative enhancement of electric quadrupole absorption via the Borrmann effect has been demonstrated recently. Here we show that the Borrmann effect has a significantly larger impact on resonant x-ray emission than is observable in x-ray absorption. Emission from a dipole forbidden intermediate state may even dominate the corresponding x-ray spectra. Our work extends the domain of x-ray standing wave methods to resonant x ray emission spectroscopy and provides means for novel spectroscopic experiments in d- and f-electron systems. PMID- 26935530 TI - Neuroprotective effects of ginsenosides on neural progenitor cells against oxidative injury. AB - Ginsenosides exhibit various neuroprotective effects against oxidative stress. However, which ginsenoside provides optimal effects for the treatment of neurological disorders as a potent antioxidant remains to be elucidated. Therefore, the present study investigated and compared the neuroprotective effects of the Rb1, Rd, Rg1 and Re ginsenosides on neural progenitor cells (NPCs) following tert-Butylhydroperoxide (t-BHP)-induced oxidative injury. Primary rat embryonic cortical NPCs were prepared from E14.5 embryos of Sprague-Dawley rats. The oxidative injury model was established with t-BHP. A lactate dehydrogenase assay and terminal deoxynucleotidyl transferase dUTP nick-end labeling staining were used to measure the viability of the NPCs pre-treated with ginsenosides under oxidative stress. Reverse transcription-quantitative polymerase chain reaction analysis was used to determine the activation of intracellular signaling pathways triggered by the pretreatment of ginsenosides. Among the four ginsenosides, only Rb1 attenuated t-BHP toxicity in the NPCs, and the nuclear factor (erythroizd-derived 2)-like 2/heme oxygenase-1 pathway was found to be key in the intracellular defense against oxidative stress. The present study demonstrated the anti-oxidative effects of ginsenoside Rb1 on NPCs, and suggested that Rb1 may offer potential as a potent antioxidant for the treatment of neurological disorders. PMID- 26935532 TI - Changes in Prescribed Drugs Between Admission and the End of Life in Patients Admitted to Palliative Care Facilities. AB - BACKGROUND: The aim of prescribing medication in palliative end-of-life care should be symptom control. Data are lacking regarding the prescription of medication at the end of life. AIM: To investigate the prescription of medication in patients at the end of life in palliative care facilities. DESIGN, SETTING, AND PARTICIPANTS: An observational multicenter study in 7 inpatient palliative care facilities. Participants were adults with an estimated life expectancy of less than 3 months. The study was conducted from February 1, 2012, to January 1, 2013. RESULTS: A total of 155 patients were enrolled. On average, patients were prescribed 6.1 drugs at the moment of admission and 4.6 drugs on the day of death. The prescription of analgesics, psycholeptics, and drugs for functional gastrointestinal disorders increased from admission until death. In general, these are drug classes prescribed for symptom control. All other drug classes decreased between admission and the day of death, including different drug classes for the treatment of comorbid disease, such as anticoagulants, beta blocking agents, drugs used in diabetes, and lipid-modifying agents. CONCLUSIONS AND RELEVANCE: A reduction in the total amount of medication is seen between admission and death in the palliative care facilities. Although there is an increase in prescribed symptom-specific medication and a reduction in medication prescribed for comorbid disease, there are still patients dying with medication not used for symptom control. This increases pill burden and indicates that physicians need to develop guidelines and educational programs for decreasing medication for comorbidities at the end of life. PMID- 26935533 TI - Antipsychotic Drug Use Is Not Associated With Long-Term Mortality Risk in Norwegian Nursing Home Patients. AB - OBJECTIVES: To assess the long-term mortality risk associated with antipsychotic drug (AP) use in nursing homes. DESIGN: A longitudinal study with 5 assessments over a 75-month follow-up period. SETTING: A representative sample of nursing home patients in 4 Norwegian counties. PARTICIPANTS: At baseline, 1163 patients were included. At the last follow-up, 98 patients were still alive. MEASUREMENTS: Prevalent drug use at each assessment was registered. Level of dementia, neuropsychiatric symptoms, level of functioning, medical health, and use of restraints were recorded at each assessment. A Cox regression model with time dependent psychotropic drug use as the main predictor was estimated and adjusted for confounders. RESULTS: In unadjusted Cox regression, a lower mortality risk was associated with the use of other psychotropic drugs, but not APs, compared with nonusers. In the adjusted analysis, neither use of APs nor other psychiatric drugs was associated with increased mortality risk. Higher age, male gender, not being married, medical disease burden, lower level of functioning, more severe degree of dementia, and a higher number of drugs were all associated with increased mortality risk. CONCLUSION: In this long-term study of nursing home patients, AP drug use was not associated with increased risk of mortality. This is in line with results from earlier studies of clinical samples, but contrasts with results from randomized controlled trials and registry-based studies. The findings should be interpreted with caution. Taking into account the modest benefit and high risk of adverse effects of AP drug use, nonpharmacological treatment remains the first-line treatment approach. PMID- 26935535 TI - Role of Neuromodulation and Optogenetic Manipulation in Pain Treatment. AB - Neuromodulation, including invasive and non-invasive stimulation, has been used to treat intractable chronic pain. However, the mechanisms by which neuromodulation produces antinociceptive effect still remain uncertain. Optogenetic manipulation, a recently developed novel approach, has already proven its value to clinicians by providing new insights into mechanisms of current clinical neuromodulation methods as well as pathophysiology of nervous system diseases at the circuit level. Here, we discuss the principles of two neuromodulation methods (deep brain stimulation and motor cortex stimulation) and their applications in pain treatment. More important, we summarize the new information from recent studies regarding optogenetic manipulation in neuroscience research and its potential utility in pain study. PMID- 26935534 TI - All trans-retinoic acid analogs promote cancer cell apoptosis through non-genomic Crabp1 mediating ERK1/2 phosphorylation. AB - All trans retinoic acid (atRA) is one of the most potent therapeutic agents, but extensive toxicity caused by nuclear RA receptors (RARs) limits its clinical application in treating cancer. AtRA also exerts non-genomic activities for which the mechanism remains poorly understood. We determine that cellular retinoic acid binding protein 1 (Crabp1) mediates the non-genomic activity of atRA, and identify two compounds as the ligands of Crabp1 to rapidly and RAR-independently activate extracellular signal regulated kinase 1/2 (ERK1/2). Non-canonically activated ERK activates protein phosphatase 2A (PP2A) and lengthens cell cycle duration in embryonic stem cells (ESC). This is abolished in Crabp1-null ESCs. Re expressing Crabp1 in Crabp1-negative cancer cells also sensitizes their apoptotic induction by atRA. This study reveals a physiological relevance of the non genomic action of atRA, mediated by Crabp1, in modulating cell cycle progression and apoptosis induction, and provides a new cancer therapeutic strategy whereby compounds specifically targeting Crabp1 can modulate cell cycle and cancer cell apoptosis in a RAR-independent fashion, thereby avoiding atRA's toxicity caused by its genomic effects. PMID- 26935538 TI - Decreased LRIG1 in fulvestrant-treated luminal breast cancer cells permits ErbB3 upregulation and increased growth. PMID- 26935537 TI - A distinct and active bacterial community in cold oxygenated fluids circulating beneath the western flank of the Mid-Atlantic ridge. AB - The rock-hosted, oceanic crustal aquifer is one of the largest ecosystems on Earth, yet little is known about its indigenous microorganisms. Here we provide the first phylogenetic and functional description of an active microbial community residing in the cold oxic crustal aquifer. Using subseafloor observatories, we recovered crustal fluids and found that the geochemical composition is similar to bottom seawater, as are cell abundances. However, based on relative abundances and functional potential of key bacterial groups, the crustal fluid microbial community is heterogeneous and markedly distinct from seawater. Potential rates of autotrophy and heterotrophy in the crust exceeded those of seawater, especially at elevated temperatures (25 degrees C) and deeper in the crust. Together, these results reveal an active, distinct, and diverse bacterial community engaged in both heterotrophy and autotrophy in the oxygenated crustal aquifer, providing key insight into the role of microbial communities in the ubiquitous cold dark subseafloor biosphere. PMID- 26935539 TI - Indole-3-Acetic Acid Produced by Burkholderia heleia Acts as a Phenylacetic Acid Antagonist to Disrupt Tropolone Biosynthesis in Burkholderia plantarii. AB - Burkholderia heleia PAK1-2 is a potent biocontrol agent isolated from rice rhizosphere, as it prevents bacterial rice seedling blight disease caused by Burkholderia plantarii. Here, we isolated a non-antibacterial metabolite from the culture fluid of B. heleia PAK1-2 that was able to suppress B. plantarii virulence and subsequently identified as indole-3-acetic acid (IAA). IAA suppressed the production of tropolone in B. plantarii in a dose-dependent manner without any antibacterial and quorum quenching activity, suggesting that IAA inhibited steps of tropolone biosynthesis. Consistent with this, supplementing cultures of B. plantarii with either L-[ring-(2)H5]phenylalanine or [ring (2)H2~5]phenylacetic acid revealed that phenylacetic acid (PAA), which is the dominant metabolite during the early growth stage, is a direct precursor of tropolone. Exposure of B. plantarii to IAA suppressed production of both PAA and tropolone. These data particularly showed that IAA produced by B. heleia PAK1-2 disrupts tropolone production during bioconversion of PAA to tropolone via the ring-rearrangement on the phenyl group of the precursor to attenuate the virulence of B. plantarii. B. heleia PAK1-2 is thus likely a microbial community coordinating bacterium in rhizosphere ecosystems, which never eliminates phytopathogens but only represses production of phytotoxins or bacteriocidal substances. PMID- 26935536 TI - Role of Cannabinoids in Gastrointestinal Mucosal Defense and Inflammation. AB - Modulating the activity of the endocannabinoid system influences various gastrointestinal physiological and pathophysiological processes, and cannabinoid receptors as well as regulatory enzymes responsible for the synthesis or degradation of endocannabinoids representing potential targets to reduce the development of gastrointestinal mucosal lesions, hemorrhage and inflammation. Direct activation of CB1 receptors by plant-derived, endogenous or synthetic cannabinoids effectively reduces both gastric acid secretion and gastric motor activity, and decreases the formation of gastric mucosal lesions induced by stress, pylorus ligation, nonsteroidal anti-inflammatory drugs (NSAIDs) or alcohol, partly by peripheral, partly by central mechanisms. Similarly, indirect activation of cannabinoid receptors through elevation of endocannabinoid levels by globally acting or peripherally restricted inhibitors of their metabolizing enzymes (FAAH, MAGL) or by inhibitors of their cellular uptake reduces the gastric mucosal lesions induced by NSAIDs in a CB1 receptor-dependent fashion. Dual inhibition of FAAH and cyclooxygenase enzymes induces protection against both NSAID-induced gastrointestinal damage and intestinal inflammation. Moreover, in intestinal inflammation direct or indirect activation of CB1 and CB2 receptors exerts also multiple beneficial effects. Namely, activation of both CB receptors was shown to ameliorate intestinal inflammation in various murine colitis models, to decrease visceral hypersensitivity and abdominal pain, as well as to reduce colitis-associated hypermotility and diarrhea. In addition, CB1 receptors suppress secretory processes and also modulate intestinal epithelial barrier functions. Thus, experimental data suggest that the endocannabinoid system represents a promising target in the treatment of inflammatory bowel diseases, and this assumption is also confirmed by preliminary clinical studies. PMID- 26935540 TI - NQO1 Deficiency Leads Enhanced Autophagy in Cisplatin-Induced Acute Kidney Injury Through the AMPK/TSC2/mTOR Signaling Pathway. AB - AIMS: Recent studies have revealed that autophagy is induced under various disease conditions; however, the role of autophagy in pathological states is controversial. NAD(P)H: quinone oxidoreductase 1 (NQO1) is a highly inducible cytoprotective gene that regulates reactive oxygen species (ROS) generation. In this study, we examined whether NQO1 deficiency affects the autophagy process in response to cisplatin-induced nephrotoxicity. RESULTS: In vitro, NQO1 and autophagy-associated proteins were induced after cisplatin treatment and the autophagosomes markedly increased in the cisplatin-treated NQO1-knockdown ACHN cells together with increased ROS production. In vivo, NQO1-KO mice displayed a significant increase in cisplatin-induced acute kidney injury (AKI), as indicated by elevated tubular damage and apoptosis as well as by suppressed cytoprotective signals. In agreement with the in vitro findings, NQO1-KO cisplatin-treated mice displayed a notable increase in autophagy-associated protein expression compared with their wild-type counterparts. Meanwhile, the expression of Ras-related protein 7, which participates in autophagosome maturation and lysosome fusion, markedly decreased in NQO1-KO mice, indicating hampered progress in late autophagy, and was accompanied by increased p62 protein expression. Moreover, NQO1 deletion enhanced the effect of the mammalian target of the rapamycin inhibitor, rapamycin, and led to enhanced tuberous sclerosis complex 2 phosphorylation through AMP-activated protein kinase activation. INNOVATION AND CONCLUSION: These results indicate that autophagy may be enhanced to counter the increased stress due to NQO1 deficiency, an oxidative stress barrier. The present results demonstrate the significant influence of NQO1 on the autophagy process and support the hypothesis that autophagy plays a protective role under oxidative stress conditions. Antioxid. Redox Signal. 24, 867-883. PMID- 26935541 TI - Comparative study of antitumor effects of bromelain and papain in human cholangiocarcinoma cell lines. AB - Cholangiocarcinoma (CC) worldwide is the most common biliary malignancy with poor prognostic value and new systemic treatments are desirable. Plant extracts like bromelain and papain, which are cysteine proteases from the fruit pineapple and papaya, are known to have antitumor activities. Therefore, in this study for the first time we investigated the anticancer effect of bromelain and papain in intra and extrahepatic human CC cell lines. The effect of bromelain and papain on human CC cell growth, migration, invasion and epithelial plasticity was analyzed using cell proliferation, wound healing, invasion and apoptosis assay, as well as western blotting. Bromelain and papain lead to a decrease in the proliferation, invasion and migration of CC cells. Both plant extracts inhibited NFkappaB/AMPK signalling as well as their downstream signalling proteins such as p-AKT, p-ERK, p-Stat3. Additionally, MMP9 and other epithelial-mesenchymal-transition markers were partially found to be downregulated. Apoptosis was induced after bromelain and papain treatment. Interestingly, bromelain showed an overall more effective inhibition of CC as compared to papain. siRNA mediated silencing of NFkappaB on CC cells indicated that bromelain and papain have cytotoxic effects on human CC cell lines and bromelain and partially papain in comparison impair tumor growth by NFkappaB/AMPK signalling. Especially bromelain can evolve as promising, potential therapeutic option that might open new insights for the treatment of human CC. PMID- 26935544 TI - Bi2O3 nanoparticles encapsulated in surface mounted metal-organic framework thin films. AB - We describe a novel procedure to fabricate a recyclable hybrid-photocatalyst based on Bi2O3@HKUST-1 MOF porous thin films. Bi2O3 nanoparticles (NPs) were synthesized within HKUST-1 (or Cu3(BTC)2) surface-mounted metal-organic frame works (SURMOFs) and characterized using X-ray diffraction (XRD), a quartz crystal microbalance (QCM) and transmission electron microscopy (TEM). The Bi2O3 semiconductor NPs (diameter 1-3 nm)/SURMOF heterostructures exhibit superior photo-efficiencies compared to NPs synthesized using conventional routes, as demonstrated via the photodegradation of the nuclear fast red (NFR) dye. PMID- 26935543 TI - Fluorescent ampicillin analogues as multifunctional disguising agents against opsonization. AB - Cancer nanomedicines are opening new paradigms in cancer management and recent research points to how they can vastly improve imaging and therapy through multimodality and multifunctionality. However, challenges to achieving optimal efficacy are manifold starting from processing materials and evaluating their intended effectiveness on biological tissue, to developing new strategies aimed at improving transport of these materials through the biological milieu to the target tissue. Here, we report a fluorescent derivative of a beta-lactam antibiotic, ampicillin (termed iAmp) and its multifunctional physicobiochemical characteristics and potential as a biocompatible shielding agent and an effective dispersant. Carbon nanotubes (CNTs) were chosen to demonstrate the efficacy of iAmp. CNTs are known for their versatility and have been used extensively for cancer theranostics as photothermal and photoacoustic agents, but have limited solubility in water and biocompatibility. Traditional dispersants are associated with imaging artifacts and are not fully biocompatible. The chemical structure of iAmp is consistent with a deamination product of ampicillin. Although the four membered lactam ring is intact, it does not retain the antibiotic properties. The iAmp is an effective dispersant and simultaneously serves as a fluorescent label for single-walled CNTs (SWNTs) with minimal photobleaching. The iAmp also enables bioconjugation of SWNTs to bio-ligands such as antibodies through functional carboxyl groups. Viability tests show that iAmp-coated SWNTs have minimal toxicity. Bio-stability tests under physiological conditions reveal that iAmp coating not only remains stable in a biologically relevant environment with high protein and salt concentrations, but also renders SWNTs transparent against nonspecific protein adsorption, also known as protein corona. Mammalian tissue culture studies with macrophages and opsonins validate that iAmp coating affords immunological resistance to SWNTs. Furthermore, iAmp coating offers protection to SWNTs against their nonspecific adsorption across disparate cell types, which has precluded a targeted strategy, and enables selective molecular targeting. The iAmp can therefore be used as an efficient dispersant, a photostable fluorescent agent, and a biocompatible disguising agent, alleviating CNTs' drawbacks and rendering them suitable for nanotheranostic and drug delivery applications. PMID- 26935542 TI - Linarin promotes osteogenic differentiation by activating the BMP-2/RUNX2 pathway via protein kinase A signaling. AB - Linarin (LIN), a flavonoid which exerts both anti-inflammatory and antioxidative effects, has been found to promote osteogenic differentiation. However, the molecular mechanism of its effect on osteoblast differentiation was unclear. In the present study, LIN from Flos Chrysanthemi Indici (FCI) was isolated in order to investigate the underlying mechanisms of LIN on MC3T3-E1 cells (a mouse osteoblastic cell line) and the osteoprotective effect of LIN in mice which had undergone an ovariectomy (OVX). The results revealed that LIN enhanced osteoblast proliferation and differentiation in MC3T3-E1 cells dose-dependently, with enhanced alkaline phosphatase (ALP) activity and mineralization of extracellular matrix. LIN upregulated osteogenesis-related gene expression, including that of ALP, runt-related transcription factor 2 (RUNX2), osteocalcin (OCN), bone sialoprotein (BSP), and type I collagen (COL-I). Pretreatment with noggin, a bone morphogenetic protein-2 (BMP-2) antagonist, meant that LIN-induced gene expression levels of COL-1, ALP, OCN, BSP and RUNX2 were significantly reduced, as shown by RT-qPCR. Western blot analysis showed that LIN dose-dependently increased the protein levels of BMP-2 and RUNX2 and enhanced the phosphorylation of SMAD1/5. In addition, LIN dose-dependently upregulated protein kinase A (PKA) expression. H-89 (a PKA inhibitor) partially blocked the LIN-induced protein increase in BMP-2, p-SMAD1/5 and RUNX2. We noted that LIN preserved the trabecular bone microarchitecture of ovariectomized mice in vivo. Moreover, pretreatment with LIN significantly lowered serum levels of ALP and OCN in ovariectomized mice. Our data indicated that LIN induced the osteogenic differentiation and mineralization of MC3T3-E1 osteoblastic cells by activating the BMP-2/RUNX2 pathway through PKA signaling in vitro and protected against OVX induced bone loss in vivo. The results strongly suggest that LIN is a useful natural alternative for the management of postmenopausal osteoporosis. PMID- 26935545 TI - Improving Functional Annotation in the DRE-TIM Metallolyase Superfamily through Identification of Active Site Fingerprints. AB - Within the DRE-TIM metallolyase superfamily, members of the Claisen-like condensation (CC-like) subgroup catalyze C-C bond-forming reactions between various alpha-ketoacids and acetyl-coenzyme A. These reactions are important in the metabolic pathways of many bacterial pathogens and serve as engineering scaffolds for the production of long-chain alcohol biofuels. To improve functional annotation and identify sequences that might use novel substrates in the CC-like subgroup, a combination of structural modeling and multiple-sequence alignments identified active site residues on the third, fourth, and fifth beta strands of the TIM-barrel catalytic domain that are differentially conserved within the substrate-diverse enzyme families. Using alpha-isopropylmalate synthase and citramalate synthase from Methanococcus jannaschii (MjIPMS and MjCMS), site-directed mutagenesis was used to test the role of each identified position in substrate selectivity. Kinetic data suggest that residues at the beta3-5 and beta4-7 positions play a significant role in the selection of alpha ketoisovalerate over pyruvate in MjIPMS. However, complementary substitutions in MjCMS fail to alter substrate specificity, suggesting residues in these positions do not contribute to substrate selectivity in this enzyme. Analysis of the kinetic data with respect to a protein similarity network for the CC-like subgroup suggests that evolutionarily distinct forms of IPMS utilize residues at the beta3-5 and beta4-7 positions to affect substrate selectivity while the different versions of CMS use unique architectures. Importantly, mapping the identities of residues at the beta3-5 and beta4-7 positions onto the protein similarity network allows for rapid annotation of probable IPMS enzymes as well as several outlier sequences that may represent novel functions in the subgroup. PMID- 26935546 TI - Impact of intermittent portal clamping on the early recurrence of hepatocellular carcinoma after surgery. AB - PURPOSE: To evaluate the impact of intermittent portal clamping (IPC) during surgery on the early recurrence of hepatocellular carcinoma (HCC). METHODS: The subjects of this retrospective study were 266 patients who underwent curative liver resection for HCC. The patients were grouped as follows: an intermittent portal clamping (IPC) group, n = 78; a continuous portal clamping (CPC) group, n = 128; and a non-portal clamping (NPC) group, n = 60. RESULTS: The median recurrence-free interval within 2 years of follow-up was significantly shorter in the IPC group (14.2 +/- 4.6 months) than in the CPC group (18.0 +/- 4.8 months, P = 0.008) or the NPC group (19.04 +/- 4.1 months, P = 0.023). Moreover, 2-year recurrence-free survival was much lower in the IPC group than in the CPC group (63.6 vs. 75.8 %, P = 0.025) or the NPC group (63.6 vs. 78.0 %, P = 0.030). However, the 2-year OS rate among the three groups was comparable (72.7 vs. 79.9 %; P = 0.101) and 83.1 %, (P = 0.125). According to univariable analysis, tumor size (>5 cm), tumor number (>=2), tumor grade (low/undifferentiated), TNM stage (III), vascular infiltration, blood transfusion, and IPC were significantly associated with the early postoperative recurrence of HCC. After multivariate analysis, significance of tumor grade (low/undifferentiated) and TNM stage (III) disappeared, whereas tumor size (>5 cm), tumor number (>=2), vascular infiltration, blood transfusion, and IPC remained significant. CONCLUSIONS: IPC is an independent risk factor for the early recurrence of HCC after surgery. PMID- 26935547 TI - Laparoscopic management for prenatally diagnosed choledochal cysts. AB - PURPOSE: The aim of this study was to validate our laparoscopic management strategy for asymptomatic and symptomatic patients with prenatally diagnosed choledochal cysts (CCs). METHODS: Thirteen prenatally diagnosed CC patients from 1997 to 2015 were included. Seven patients (1997-2008) underwent open surgery (OS group), and 6 (2009-2015) underwent laparoscopic surgery (LS group). In the asymptomatic patients, LS was performed when the patients weighed over 5 kg. When the patient had clinical manifestations, early LS was performed irrespective of body weight. A retrospective comparison was conducted between the LS and OS groups in terms of the operative time, blood loss, postoperative fasting period, hospital stay, and intra- and postoperative complications. RESULTS: There was no difference between the demographics of both groups. The operative time was significantly longer (380 vs. 288 min) and blood loss was significantly lower (4 vs. 30 mL) in the LS group. Additionally, the postoperative fasting period (3 vs. 6 days) and hospital stay (11 vs. 20 days) were significantly shorter in the LS group. Intraoperative events and early postoperative complications were not encountered in either group. Small bowel obstruction requiring surgery occurred in two patients, 10 and 13 years after OS, respectively. CONCLUSIONS: LS is as safe and feasible as OS in small children with prenatally diagnosed CC, although sufficient pediatric laparoscopic expertise is mandatory. PMID- 26935548 TI - Genetic, spatial, and social relationships among adults in a group of howler monkeys (Alouatta palliata) from Barro Colorado Island, Panama. AB - Kinship plays an important role in the social behavior of many primate species, including patterns of intra-group affiliation and cooperation. Within social groups, kinship is strongly affected by dispersal patterns, with the degree of relatedness among group-mates expected to decrease as the tendency to disperse increases. In primate species characterized by bisexual dispersal, relatedness among adult group-mates is predicted to be low, with social interactions shaped largely by factors other than kinship. To date, however, few studies have examined the role of kinship in social interactions in bisexually dispersing species. Accordingly, we collected genetic, spatial and behavioral data on all adult members (three males, six females) in a group of free-ranging mantled howler monkeys (Alouatta palliata)--a bisexually dispersing species of atelid primate--from Barro Colorado Island (BCI), Panama. Analyses of microsatellite variation revealed that relatedness was greater among adult males in this group (mean pairwise relatedness = 0.32 for males versus 0.09 for females). Relatedness among individuals, however, was not associated with either spatial proximity or frequency of social interactions. Instead, sex was a better predictor of both of these aspects of social behavior. While relatedness among adults had no discernible effect on the intra-group social interactions documented in this study, we postulate that kinship may facilitate affiliative and cooperative behaviors among male group-mates when interacting competitively with neighboring howler groups over access to food or potential mates. PMID- 26935550 TI - The relationship between microvasculature in white matter hyperintensities and cognitive function. AB - White matter hyperintensities (WMHs) are associated with cognitive decline, but less is known about pathophysiology of cognitive decline in patients with WMHs. We investigated microvasculature and microstructure in WMHs using intravoxel incoherent motion (IVIM) and their associations with cognitive function. Thirty two subjects with WMHs were enrolled in our study. Fast diffusion coefficient (D*), perfusion fraction (f) and slow diffusion coefficient (D) from IVIM model were compared between regions of WMHs (periventricular WMHs, PWMHs and deep WMHs, DWMHs) and surrounding normal white matter. Multivariate linear model was used to determine the independent factors associated with cognitive function assessed by the Mini Mental State Examination (MMSE) and the standardized coefficient (beta) of factors was estimated. D* was significantly lower (4.95 * 10-3 mm2/s versus 8.36 * 10-3 mm2/s in PWMHs and 5.04 * 10-3 mm2/s versus 8.67 * 10-3 mm2/s in DWMHs, both P < 0.001), and f (14.64 % versus 12.01 % in PWMHs and 14.26 % versus 11.31 % in DWMHs, both P < 0.001) and D (1.02 * 10-3 mm2/s versus 0.73 * 10-3 mm2/s in PWMHs and 0.86 * 10-3 mm2/s versus 0.70 * 10-3 mm2/s in DWMHs, both P < 0.001) were significantly higher in WMHs. Only f in PWMHs was independently associated with MMSE (beta = 0.443, P = 0.016). The decreased D* and increased D in WMHs were similar to previous findings. The increased f in PWMHs relating with better cognition provides the pathophysiological basis in understanding cognitive decline in patients with WMHs. PMID- 26935552 TI - Prefrontal hemodynamic after-effects caused by rebreathing may predict affective states - A multimodal functional near-infrared spectroscopy study. AB - Brain activity has been shown to be influenced by respiratory behavior. Here, we evaluated whether respiration-induced hypo- or hypercapnia may support differentiation between physiological versus pathological respiratory behavior. In particular, we investigated whether systemic physiological measures could predict the brain's time-frequency hemodynamics after three respiratory challenges (i.e., breath-holding, rebreathing, and hyperventilation) compared to resting-state. Prefrontal hemodynamics were assessed in healthy subjects (N = 27) using functional near-infrared spectroscopy (fNIRS). Systemic physiological measures were assessed in form of heart rate, partial end-tidal carbon dioxide, respiration rate, and saturation of peripheral oxygen. Time-frequency dynamics were quantified using the wavelet transform coherence (i.e., defined here as cortical-systemic coherence). We found that the three respiratory challenges modulated cortical-systemic coherence differently: (1) After rebreathing, cortical-systemic coherence could be predicted from the amplitude of the heart rate (strong negative correlation). (2) After breath-holding, the same observation was made (moderate negative correlation). (3) After hyperventilation, no significant effect was observed. (4) These effects were found only in the frequency range of very low-frequency oscillations. The presented findings highlight a distinct role of rebreathing in predicting cortical-systemic coupling based on heart rate changes, which may represents a measure of affective states in the brain. The applied multimodal assessment of hemodynamic and systemic physiological measures during respiratory challenges may therefore have potential applications in the differentiation between physiological and pathological respiratory behavior. PMID- 26935551 TI - Early dysfunctions of fronto-parietal praxis networks in Parkinson's disease. AB - In Parkinson's disease (PD) the prevalence of apraxia increases with disease severity implying that patients in early stages may already have subclinical deficits. The aim of this exploratory fMRI study was to investigate if subclinical aberrations of the praxis network are already present in patients with early PD. In previous functional imaging literature only data on basal motor functions in PD exists. Thirteen patients with mild parkinsonian symptoms and without clinically diagnosed apraxia and 14 healthy controls entered this study. During fMRI participants performed a pantomime task in which they imitated the use of visually presented objects. Patients were measured ON and OFF dopaminergic therapy to evaluate a potential medication effect on praxis abilities and related brain functions. Although none of the patients was apraxic according to De Renzi ideomotor scores (range 62-72), patients OFF showed significantly lower praxis scores than controls. Patients exhibited significant hyperactivation in left fronto-parietal core areas of the praxis network. Frontal activations were clearly dominant in patients and were correlated with lower individual praxis scores. We conclude that early PD patients already show characteristic signs of praxis network dysfunctions and rely on specific hyperactivations to avoid clinically evident apraxic symptoms. Subclinical apraxic deficits were shown to correlate with an activation shift from left parietal to left frontal areas implying a prospective individual imaging marker for incipient apraxia. PMID- 26935553 TI - Neuronal correlates of personal space intrusion in violent offenders. AB - Personal space (PS) is defined as the imagery region immediately surrounding our body, which acts as safety zone. It has been suggested that PS is enlarged in violent offenders and that this group shows an enhanced sensitivity to the reduction of interpersonal distance. In the present fMRI study high-risk violent offenders and noncriminal controls were presented with photos of neutral facial expressions by men and women. All images were shown twice, as static photos, and animated (i.e., appearing to approach the subject) in order to simulate PS intrusion. Approaching faces generally provoked activation of a fronto-parietal network and the insula. Offenders responded with greater insula activation to approaching faces, especially when the person was male. Insular activation has been recognized before as a neuronal correlate of potential threat and harm detection in PS. The increased reactivity of violent offenders is possibly a result of their hostile attribution bias. PMID- 26935554 TI - The capacity for generating cognitive reappraisals is reflected in asymmetric activation of frontal brain regions. AB - Encouraging patients to use cognitive reappraisal constitutes the core of modern psychotherapeutic approaches. However, evidence for specific neural correlates of the capacity for cognitive reappraisal, which is a necessary prerequisite for the effective implementation of cognitive reappraisal in everyday life, has been sparse to date. In the present study, the capacity for cognitive reappraisal was studied in terms of the participants' inventiveness in generating alternative appraisals of anger-evoking events, and was correlated with frontal EEG alpha asymmetry recorded while the participants were generating reappraisals as well as during a common creative idea generation task. During cognitive reappraisal efforts, individuals higher on the capacity for generating cognitive reappraisals showed more left-lateralized activity in lateral prefrontal cortex, specifically in ventrolateral prefrontal cortex extending toward the frontal pole. This effect was observed independently from the activation during novel idea generation without emotional component, indicating that specific demands are implicated in the generation of reappraisals of emotional events. Taken together, the results indicate that individuals higher on the capacity for cognitive reappraisal are more capable or more prone to recruit appropriate brain regions when the situation demands coming up with alternative appraisals of stressful events. The findings may stimulate the development of more individually targeted interventions. PMID- 26935555 TI - The functional connectivity in the motor loop of human basal ganglia. AB - Basal ganglia interact in a complex way which is still not completely understood. The model generally used to explain basal ganglia interactions is based on experimental data in animals, but its validation in humans has been hampered by methodological restrictions. The time-relationship (partial correlation) of the fluctuations of the blood-oxygen-level-dependent signals recorded in the main basal ganglia was used here (32 healthy volunteers; 18-72 years of age; 16 males and 16 females) to test whether the interaction of the main basal ganglia in humans follows the pattern of functional connectivity in animals. Data showed that most basal ganglia have a functional connectivity which is compatible with that of the established closed-loop model. The strength of the connectivity of some basal ganglia changed with finger motion, suggesting that the functional interactions between basal ganglia are quickly restructured by the motor tasks. The present study with the motor cortico-BG loop centers supports the circling dynamic of the basal ganglia model in humans, showing that motor tasks may change the functional connectivity of these centers. PMID- 26935557 TI - Re: Christopher J.D. Wallis, Refik Saskin, Richard Choo, et al. Surgery Versus Radiotherapy for Clinically-localized Prostate Cancer: A Systematic Review and Meta-analysis. Eur Urol 2016;70:21-30. PMID- 26935556 TI - Lrig1 is a cell-intrinsic modulator of hippocampal dendrite complexity and BDNF signaling. AB - Even though many extracellular factors have been identified as promoters of general dendritic growth and branching, little is known about the cell-intrinsic modulators that allow neurons to sculpt distinctive patterns of dendrite arborization. Here, we identify Lrig1, a nervous system-enriched LRR protein, as a key physiological regulator of dendrite complexity of hippocampal pyramidal neurons. Lrig1-deficient mice display morphological changes in proximal dendrite arborization and defects in social interaction. Specifically, knockdown of Lrig1 enhances both primary dendrite formation and proximal dendritic branching of hippocampal neurons, two phenotypes that resemble the effect of BDNF on these neurons. In addition, we show that Lrig1 physically interacts with TrkB and attenuates BDNF signaling. Gain and loss of function assays indicate that Lrig1 restricts BDNF-induced dendrite morphology. Together, our findings reveal a novel and essential role of Lrig1 in regulating morphogenic events that shape the hippocampal circuits and establish that the assembly of TrkB with Lrig1 represents a key mechanism for understanding how specific neuronal populations expand the repertoire of responses to BDNF during brain development. PMID- 26935558 TI - Re: Christopher J.D. Wallis, Refik Saskin, Richard Choo, et al. Surgery Versus Radiotherapy for Clinically-localized Prostate Cancer: A Systematic Review and Meta-analysis. Eur Urol 2016;70:21-30: Radical Prostatectomy Versus Radiation for Clinically Localized Prostate Cancer: Two Systematic Reviews and a Randomized Controlled Trial. PMID- 26935559 TI - The 2016 WHO Classification of Tumours of the Urinary System and Male Genital Organs-Part A: Renal, Penile, and Testicular Tumours. AB - The fourth edition of the World Health Organization (WHO) classification of urogenital tumours (WHO "blue book"), published in 2016, contains significant revisions. These revisions were performed after consideration by a large international group of pathologists with special expertise in this area. A subgroup of these persons met at the WHO Consensus Conference in Zurich, Switzerland, in 2015 to finalize the revisions. This review summarizes the most significant differences between the newly published classification and the prior version for renal, penile, and testicular tumours. Newly recognized epithelial renal tumours are hereditary leiomyomatosis and renal cell carcinoma (RCC) syndrome-associated RCC, succinate dehydrogenase-deficient RCC, tubulocystic RCC, acquired cystic disease-associated RCC, and clear cell papillary RCC. The WHO/International Society of Urological Pathology renal tumour grading system was recommended, and the definition of renal papillary adenoma was modified. The new WHO classification of penile squamous cell carcinomas is based on the presence of human papillomavirus and defines histologic subtypes accordingly. Germ cell neoplasia in situ (GCNIS) of the testis is the WHO-recommended term for precursor lesions of invasive germ cell tumours, and testicular germ cell tumours are now separated into two fundamentally different groups: those derived from GCNIS and those unrelated to GCNIS. Spermatocytic seminoma has been designated as a spermatocytic tumour and placed within the group of non-GCNIS-related tumours in the 2016 WHO classification. PATIENT SUMMARY: The 2016 World Health Organization (WHO) classification contains new renal tumour entities. The classification of penile squamous cell carcinomas is based on the presence of human papillomavirus. Germ cell neoplasia in situ of the testis is the WHO-recommended term for precursor lesions of invasive germ cell tumours. PMID- 26935560 TI - Insights into the mode of action of anticandidal herbal monoterpenoid geraniol reveal disruption of multiple MDR mechanisms and virulence attributes in Candida albicans. AB - The anticandidal potential of Geraniol (Ger) against Candida albicans has already been established. The present study reveals deeper insights into the mechanisms of action of Ger. We observed that the repertoire of antifungal activity was not only limited to C. albicans and its clinical isolates but also against non albicans species of Candida. The membrane tampering effect was visualized through transmission electron micrographs, depleted ergosterol levels and altered plasma membrane ATPase activity. Ger also affects cell wall as revealed by spot assays with cell wall-perturbing agents and scanning electron micrographs. Functional calcineurin pathway seems to be indispensable for the antifungal effect of Ger as calcineurin signaling mutant was hypersensitive to Ger while calcineurin overexpressing strain remained resistant. Ger also causes mitochondrial dysfunction, impaired iron homeostasis and genotoxicity. Furthermore, Ger inhibits both virulence attributes of hyphal morphogenesis and biofilm formation. Taken together, our results suggest that Ger is potential antifungal agent that warrants further investigation in clinical applications so that it could be competently employed in therapeutic strategies to treat Candida infections. PMID- 26935561 TI - Increased cognitive demands boost the spatial interference effect in bimanual pointing. AB - It is beyond controversy that in bimanual coordination tasks, parameter planning related to the movements of one hand influences the planning and execution of movements simultaneously performed with the other hand. A well-researched example of such bimanual interference is the finding that reaction times tend to be longer when preparing bimanual pointing movements with different amplitudes than for equal amplitude movements. Interestingly, these reaction time costs were found to increase when movement targets were cued symbolically (e.g., using letters) as compared to spatially. Therefore, it was suggested that interference may be primarily related to cue translation and response selection processes rather than resulting from cross-talk at the motor programming level. Here, we argue that spatial interference effects do not necessarily depend on the type of cues used but instead depend on the general task demands (difficulty). In two experiments we show that bimanual interference effects can (1) be abolished in symbolic cueing conditions when highly compatible cues placing minimal demands on response selection processes are used and (2) occur in direct/spatial cueing conditions when a secondary cognitively demanding, but movement-unrelated task is performed. Thus, our findings suggest that whether or not interference effects emerge during movement planning depends on the overall task difficulty and hence the resources available during movement preparation. PMID- 26935563 TI - Does Delay of Diagnosis and Treatment in Appendicitis Cause Perforation? PMID- 26935562 TI - Monitoring of a Hot Melt Coating Process via a Novel Multipoint Near-Infrared Spectrometer. AB - The aim of the present work was to develop a PAT strategy for the supervision of hot melt coating processes. Optical fibers were placed at various positions in the process chamber of a fluid bed device. Experiments were performed to determine the most suitable position for in-line process monitoring, taking into account such requirements as a good signal to noise ratio, the mitigation of dead zones, the ability to monitor the product over the entire process, and reproducibility. The experimental evidence suggested that the position at medium fluid bed height, looking towards the center, i.e., normal to particle movement, proved to be the most reliable position. In this study, the advantages of multipoint monitoring are shown, and an in-line-implementation was created. This enabled the real-time supervision of the process, including the fast detection of inhomogeneities and disturbances in the process chamber, and the compensation of sensor malfunction. In addition, a model for estimating the particle size distribution via NIR was successfully created. This ensures that the quality of the product and the endpoint of the coating process can be determined correctly. PMID- 26935565 TI - Human health risk assessment of cadmium via dietary intake by children in Jiangsu Province, China. AB - The goal of this study was to quantify the exposure to dietary cadmium (Cd) and analyze the major contributors to total Cd intake of children from Jiangsu Province, China. The Cd concentration data were collected by the National Food Contamination Monitoring Program between 2001 and 2009. Consumption data were derived from the Chinese National Nutrition and Health Survey in 2002. The beta binomial-normal model which included age as a covariate was used to assess the long-term dietary Cd intake assuming lower bound and upper bound concentration scenarios. A tolerable weekly intake of 2.5 ug/kg body weight for Cd was applied in the risk assessment. Cd intake decreased as age increased with almost all mean values and P95 of the estimates exceeding the tolerable weekly intake. Children with high-end exposure may suffer non-carcinogenic effects over a lifetime of exposure. Rice and rice products, wheat flour and wheat flour products, crustaceans, pak-choi, pig meat, and beans and bean products were found to be the major contributors to the total Cd intake in children. These conservative estimates of Cd intake indicate possible public health concerns for children in Jiangsu Province. PMID- 26935564 TI - Accuracy of Surgeon-Performed Ultrasound in Detecting Gallstones: A Validation Study. AB - BACKGROUND: Symptomatic gallstone disease is a common diagnosis in patients with abdominal pain. Ultrasound is considered the gold standard method to identify gallstones. Today the examination may be performed bedside by the treating clinician. Bedside ultrasound could provide a safe and time-saving diagnostic resource for surgeons evaluating patients with suspected symptomatic gallstones; however, large validation studies of the accuracy and reliability are lacking. The aim of this study was to prospectively investigate the accuracy of surgeon performed ultrasound for the detection of gallstones. METHODS: Between October 2011 and November 2012, 179 adult patients, with an acute or elective referral for an abdominal ultrasound examination, were examined with a right upper quadrant ultrasound scan by a radiologist as well as a surgeon. The surgeons had undergone a four-week-long ultrasound education before participating in the study. Ultrasound findings of the surgeon were compared to those of the radiologist, using radiologist-performed ultrasound as reference standard. RESULTS: Surgeon-performed ultrasound agreed with radiologist findings in 169 of 179 patients regarding the detection of gallstones, providing an accuracy of 94 %. The sensitivity was 88 % (67/76), specificity 99 % (102/103), positive predictive value 99 % (67/68), and negative predictive value 92 % (102/111). Agreement between the diagnosis set by the radiologists and the surgeons was high: Cohen's Kappa coefficient = 0.88. CONCLUSIONS: Ultrasound-trained surgeons may accurately diagnose gallstones using ultrasound and reach a high level of agreement with radiologists. PMID- 26935566 TI - Arsenic methylation and skin lesions in migrant and native adult women with chronic exposure to arsenic from drinking groundwater. AB - In order to figure out the prevalence of skin lesions and methylation capacity for migrant and native adult women in an endemic area for arsenic poisoning in Inner Mongolia, China, 207 adult women were selected for study subjects. The results showed that the prevalence of skin lesions for the external group, provincial group and native group was 36.54, 26.15 and 35.56 %, respectively. The nail content of arsenic and urinary concentrations of dimethylarsenic (DMA), monomethylarsenic (MMA) and inorganic arsenic (iAs) were significantly higher in women with skin lesions than in those without skin lesions. The highest urinary concentrations of DMA, MMA and iAs were 213.93, 45.72 and 45.01 MUg/L in the native group. The arsenic methylation capacity index revealed that the external group had the greatest capacity, while the native group had the lowest. The odds ratios of skin lesions in relation to arsenic metabolites and arsenic methylation capacity varied widely among the three groups. Urinary MMA and iAs concentrations were positively associated with risk of skin lesions in the three groups of adult women, while primary and secondary methylation capacities were negatively related to risk of skin lesions in native and provincial groups. The external group might be more susceptible to MMA and iAs, while the provincial and native groups were more tolerance to MMA and iAs. Lower primary and secondary arsenic methylation capacities increased the risk of skin lesions in native and provincial groups. Moreover, higher nail arsenic concentration increased the risk of skin lesions of adult women. PMID- 26935569 TI - Isolated Tricuspid Valve Endocarditis Caused by Infection of an Implanted Central Venous Access Port Device. AB - A 70-year-old man was referred to our hospital for an intermittent high fever attributed to subcutaneous pocket infection of an implanted central venous access port device caused by methicillin-resistant staphylococcus aureus and subsequent bloodstream infection. Echocardiography revealed a large vegetation on the posterior tricuspid leaflet, annular dilatation and moderate-to-severe tricuspid regurgitation. Valve surgery was performed for persistent infection despite 8 weeks of antibiotics therapy. At operation, vegetations and torn chordae tendineae were found on the posterior tricuspid leaflet. After total resection of the posterior tricuspid leaflet, bicuspidalization valvuloplasty with prosthetic ring annuloplasty was achieved without relapse of the infection or residual regurgitation. PMID- 26935567 TI - Cardiac Light-Sheet Fluorescent Microscopy for Multi-Scale and Rapid Imaging of Architecture and Function. AB - Light Sheet Fluorescence Microscopy (LSFM) enables multi-dimensional and multi scale imaging via illuminating specimens with a separate thin sheet of laser. It allows rapid plane illumination for reduced photo-damage and superior axial resolution and contrast. We hereby demonstrate cardiac LSFM (c-LSFM) imaging to assess the functional architecture of zebrafish embryos with a retrospective cardiac synchronization algorithm for four-dimensional reconstruction (3-D space + time). By combining our approach with tissue clearing techniques, we reveal the entire cardiac structures and hypertrabeculation of adult zebrafish hearts in response to doxorubicin treatment. By integrating the resolution enhancement technique with c-LSFM to increase the resolving power under a large field-of view, we demonstrate the use of low power objective to resolve the entire architecture of large-scale neonatal mouse hearts, revealing the helical orientation of individual myocardial fibers. Therefore, our c-LSFM imaging approach provides multi-scale visualization of architecture and function to drive cardiovascular research with translational implication in congenital heart diseases. PMID- 26935570 TI - Patients with Posttraumatic Stress Disorder with Comorbid Major Depressive Disorder Require a Higher Dose of Psychotropic Drugs. AB - Major depressive disorder (MDD) has been associated with stressful life events and with posttraumatic stress disorder (PTSD). PTSD and MDD comorbidity was also reported to be associated with greater symptom severity and lower levels of functioning. However, the characteristics of pharmacotherapy for PTSD with MDD are not fully understood. To understand this relationship, we conducted a retrospective review using medical charts at the Department of Neuropsychiatry, Kurume University Hospital. Information from 55 patients with PTSD was analyzed. Five cases were excluded after re-evaluation of the PTSD diagnosis. A higher rate of type II trauma was observed in the PTSD with MDD group (50.0%) than in the PTSD-only group [13.6%; chi(2) (1, n =50) = 7.26, p<0.01]. Patients with comorbid MDD were significantly older, had more severe PTSD symptomatology, and a longer duration of treatment. They also received higher doses of psychotropic drugs, regardless of the type (antidepressants, antipsychotics, benzodiazepines), than the PTSD-only group. Our results showed that comorbid MDD is associated with higher doses of psychotropic drugs, suggesting difficulties in treatment. PMID- 26935571 TI - Level of Clinical Evidence Presented at the Arthroscopy Association of North America Annual Meeting Over 10 Years (2006-2015). AB - PURPOSE: To evaluate any trends in the level of clinical evidence in the papers presented at the Arthroscopy Association of North America (AANA) annual scientific meetings from 2006 to 2015. METHODS: The online abstracts of the paper presentations presented at the AANA meetings were independently evaluated by 2 reviewers (664 total presentations). The reviewers independently screened these results for clinical studies and graded their level of evidence from Level I (i.e., randomized trials) to IV (i.e., case series) based on the American Academy of Orthopaedic Surgeons classification system. RESULTS: Five hundred thirteen presentations met the inclusion criteria and were evaluated. Overall, 16% of the presentations were Level I evidence, 15% were Level II, 26% were Level III, and 43% were Level IV. We observed a significant non-random improvement in the level of evidence of presentations at the AANA meetings (P <= .001) between 2006 and 2015. In particular, the percentage of papers with Level IV evidence presented significantly decreased (P <= .001) and the percentage of papers with Level III evidence increased (P = .004) over the study period. CONCLUSIONS: Statistical trends show that the influence of evidence-based medicine in orthopaedics has had a positive impact on the quality of research presented at the AANA meetings. LEVEL OF EVIDENCE: Level IV, review of abstracts of Level I to Level IV evidence. PMID- 26935572 TI - Effect of Coracoid Drilling for Acromioclavicular Joint Reconstruction Techniques on Coracoid Fracture Risk: A Biomechanical Study. AB - PURPOSE: To biomechanically compare the stability of the coracoid process after an anatomic double-tunnel technique using two 4-mm drill holes or a single-tunnel technique using one 4-mm or one 2.4-mm drill hole. METHODS: For biomechanical testing, 18 fresh-frozen cadaveric scapulae were used and randomly assigned to one of the following groups: two 4-mm drill holes (group 1), one 4-mm drill hole (group 2), or one 2.4-mm drill hole (group 3). After standardized coracoid drilling, load was applied to the conjoined tendons at a rate of 120 mm/min and ultimate failure load, along with the failure mode, was recorded. RESULTS: There was no significant difference between groups regarding load to failure. Mean load to failure in group 1 was 392 N; group 2, 459 N; and group 3, 506 N. The corresponding P values were .55, .74, and .20 for group 1 versus group 2, group 2 versus group 3, and group 1 versus group 3, respectively. However, the failure mode for the group with one 4-mm drill hole and the group with two 4-mm drill holes was coracoid fracture, whereas the group with one 2.4-mm drill hole showed 5 tears of the conjoined tendons and only 1 coracoid fracture (P = .015). CONCLUSIONS: Although there was no significant difference regarding load-to failure testing between groups, the failure mechanism analysis showed that one 2.4-mm drill hole led to less destabilization of the coracoid than one or two 4 mm drill holes. CLINICAL RELEVANCE: Techniques with small, 2.4-mm drill holes might decrease the risk of severe iatrogenic fracture complications. PMID- 26935573 TI - Hip Arthroscopy in Trauma: A Systematic Review of Indications, Efficacy, and Complications. AB - PURPOSE: This systematic review explored the indications, efficacy, and complications of hip arthroscopy in the setting of trauma. METHODS: Databases (PubMed, Medline, Embase, and Web of Science) were searched from database inception to March 2015 for studies using hip arthroscopy in trauma treatment. Systematic screening of eligible studies was undertaken in duplicate. The inclusion criteria included studies pertaining to arthroscopic intervention of all traumatic hip injuries. Abstracted data were organized in table format with descriptive statistics presented. RESULTS: From an initial search yield of 2,809 studies, 32 studies (25 case reports and 7 case series) satisfied the criteria for inclusion. A total of 144 patients (age range, 10 to 53 years) underwent hip arthroscopy for 6 indications associated with trauma: 8 patients for bullet extraction, 6 for femoral head fixation, 82 for loose body removal, 6 for acetabular fracture fixation, 20 for labral intervention, and 23 for ligamentum teres debridement. Patients were followed up postoperatively for a mean of 2.9 years (range, 8 days to 16 years). Successful surgery was achieved in 96% of patients. The rate of major complications (i.e., pulmonary embolism and abdominal compartment syndrome) was 1.4% (2 of 144); avascular necrosis, 1.4% (2 of 144); and nerve palsy, 0.7% (1 of 144). CONCLUSIONS: Hip arthroscopy appears effective and safe in the setting of trauma. These data should be interpreted with caution because of the low-quality evidence of the included studies. Surgeons should be aware of the potential complications such as abdominal compartment syndrome and thromboembolic events when performing hip arthroscopy in the setting of trauma. LEVEL OF EVIDENCE: Level IV, systematic review of Level IV studies. PMID- 26935574 TI - Successful Treatment of Multi-Drug Resistant Pseudomonas aeruginosa Bacteremia with the Recommended Renally Adjusted Ceftolozane/Tazobactam Regimen. AB - INTRODUCTION: Ceftolozane/tazobactam (C/T) is a novel antibiotic approved for complicated intra-abdominal and urinary tract infections caused by Gram-positive and Gram-negative organisms, including some MDR strains. Little is known about the use of this agent for treatment of bacteremia and even less so about the appropriateness of the renally defined regimens. We describe a case of a 66-year old man with a history of chronic kidney disease (baseline Cr = 3-4 mg/dl) and recurrent nephrolithiasis with bilateral stents who had positive concurrent urine and blood cultures for MDR Pseudomonas aeruginosa (PSA), susceptible only to amikacin and colistin. Due to the MDR phenotype and his underlying kidney disease, the 375 mg (250 mg/125 mg) dose of C/T was given as monotherapy every 8 h for his bloodstream infection. METHODS: Once steady state was anticipated, blood was obtained at the end of infusion (1 h), and at 3, 5 and 8 h for drug concentration determination using a validated high-performance liquid chromatography method at the Center for Anti-Infective Research and Development, Hartford Hospital, Hartford. RESULTS: The minimum inhibitory concentration (MIC) for the PSA was 2/4 for C/T, indicating susceptibility. Concentration of ceftolozane of 21.87 ug/ml at 8 h indicated that serum concentrations were maintained above the MIC throughout the dosing interval. The patient was given 25 days of C/T and experienced a successful clinical outcome. Blood cultures obtained at 1 and 3 weeks after completion of treatment remained sterile. No adverse events were attributed to C/T. CONCLUSION: In this patient, the renally adjusted dose of C/T was safe and provided sufficiently high drug concentrations that exceeded the MIC of the infecting organism over the course of therapy. More data are required to determine the clinical utility of C/T in the setting of MDR PSA bacteremia. PMID- 26935575 TI - Enhancing full-length antibody production by signal peptide engineering. AB - BACKGROUND: Protein secretion to the periplasm of Escherichia coli offers an attractive route for producing heterologous proteins including antibodies. In this approach, a signal peptide is fused to the N-terminus of the heterologous protein. The signal peptide mediates translocation of the heterologous protein from the cytoplasm to the periplasm and is cleaved during the translocation process. It was previously shown that optimization of the translation initiation region (TIR) which overlaps with the nucleotide sequence of the signal sequence improves the production of heterologous proteins. Despite the progress, there is still room to improve yields using secretion as a means to produce protein complexes such as full-length monoclonal antibodies (mAbs). RESULTS: In this study we identified the inefficient secretion of heavy chain as the limitation for full-length mAb accumulation in the periplasm. To improve heavy chain secretion we investigated the effects of various signal peptides at controlled TIR strengths. The signal peptide of disulfide oxidoreductase (DsbA) mediated more efficient secretion of heavy chain than the other signal peptides tested. Mutagenesis studies demonstrated that at controlled translational levels, hydrophobicity of the hydrophobic core (H-region) of the signal peptide is a critical factor for heavy chain secretion and full-length mAb accumulation in the periplasm. Increasing the hydrophobicity of a signal peptide enhanced heavy chain secretion and periplasmic levels of assembled full-length mAbs, while decreasing the hydrophobicity had the opposite effect. CONCLUSIONS: This study demonstrates that under similar translational strengths, the hydrophobicity of the signal peptide plays an important role in heavy chain secretion. Increasing the hydrophobicity of the H-region and controlling TIR strengths can serve as an approach to improve heavy chain secretion and full-length mAb production in E. coli. PMID- 26935576 TI - Improved Survival of Calreticulin-Mutated Patients Compared With Janus Kinase 2 in Primary Myelofibrosis: A Meta-Analysis. AB - BACKGROUND: Next to janus kinase 2 (JAK2) and myeloproliferative leukemia protein, calreticulin (CALR) is a recently discovered mutation present in > 20% of patients diagnosed with primary myelofibrosis (PMF). MATERIALS AND METHODS: Six studies published from December 2013 to December 2014 met the inclusion criteria for the present meta-analysis: 2 of an Asian and 4 of a non-Asian population. We assessed the biologic characteristics at diagnosis and investigated overall survival. The analyses were stratified by ethnic origin (Asian vs. non-Asian). RESULTS: A total of 816 patients with the JAK2 mutation and 307 patients with the CALR mutation were included. The patients with the JAK2 mutation were older than those with the CALR mutation, and no statistically significant difference was noted in the gender distribution of the patients with PMF with the JAK2 versus CALR mutation. Patients with JAK2-mutated PMF had a higher white blood cell count, but no statistically significant evidence was found for a difference in the platelet count or hemoglobin level. No difference was found in thrombosis risk or acute leukemic transformation in those 2 populations. Major differences were found between the Asian and non-Asian populations. The difference in characteristics between JAK2 and CALR was larger in the Asian population than in the non-Asian population (P = .007). Also, in the non-Asian population, those with JAK2 mutation had lower platelet counts than the Asians (P = .06). In the non-Asian population, the patients diagnosed with JAK2 positive PMF had worse overall survival than the patients with CALR-positive PMF, with a combined hazard ratio of 2.43 (95% confidence interval, 1.83-3.22). CONCLUSION: The results of the present meta-analysis have confirmed the role of the CALR mutation in the diagnosis of, and as a prognostic tool for, PMF. Our results suggest that patients with the CALR mutation will have better overall survival than patients with the JAK2 mutation in a non-Asian population. PMID- 26935577 TI - Randomized phase II study of axitinib versus physicians best alternative choice of therapy in patients with recurrent glioblastoma. AB - We conducted a randomized, non-comparative, multi center, phase II clinical trial in order to investigate the efficacy of axitinib, an oral small molecule tyrosine kinase inhibitor with high affinity and specificity for the vascular endothelial growth factor receptors, in patients with recurrent glioblastoma following prior treatment with radiation and temozolomide. Forty-four patients were randomly assigned to receive treatment with axitinib (5 mg BID starting dose; N = 22) or "physicians best alternative choice of therapy" that consisted of bevacizumab (N = 20) or lomustine (N = 2). Six-month progression-free survival served as the primary endpoint. The estimated 6-month progression-free survival rate was 34 % (95 % CI 14-54) for patients treated with axitinib and 28 % (95 % CI 8-48) with best alternative treatment; median overall survival was 29 and 17 weeks, respectively. Objective responses according to RANO criteria were documented in 28 % of patients treated with axitinib and 23 % of patients treated with best alternative therapy. A decrease in maximal uptake of 18F-fluoro-ethyL-tyrosine (18F-FET) by the glioblastoma on PET imaging was documented in 85 % of patients at the time of response on axitinib. Corticosteroid treatment could be stopped in four and tapered in seven out of the 15 patients who were treated with steroids at baseline in the axitinib cohort. Most frequent axitinib related grade >=3 adverse events consisted of fatigue (9 %), diarrhea (9 %), and oral hyperesthesia (4.5 %). We conclude that axitinib has single-agent clinical activity and a manageable toxicity profile in patients with recurrent glioblastoma. PMID- 26935579 TI - Excitonic Coupling and Femtosecond Relaxation of Zinc Porphyrin Oligomers Linked with Triazole Bridge: Dynamics and Modeling. AB - The synthesis of new zinc porphyrin oligomers linked by a triazole bridge was carried out via "click" reaction. A split in the porphyrin oligomer B-band was observed. It was considered as evidence of exciton-excitonic coupling. The relaxation of excited states in Q-band porphyrin oligomers was studied by the femtosecond laser spectroscopy technique with a 20 fs pump pulse. The transient oscillations of two B-band excitonic peaks have a pi-radian shift. For explanation of the coherent oscillation, a theoretical model was developed. The model considered the combination of the exciton-excitonic coupling between porphyrin rings in dimer and weak exciton-vibronic coupling in one porphyrin ring. By varying the values of the structural parameters of porphyrins (the strength values of this couplings and measure of symmetry breaking), we obtained correspondence between the experimental data (phase shift and amplitudes of the spectrum oscillations) and the predictions of the model developed here. PMID- 26935578 TI - Cilengitide with metronomic temozolomide, procarbazine, and standard radiotherapy in patients with glioblastoma and unmethylated MGMT gene promoter in ExCentric, an open-label phase II trial. AB - Newly diagnosed glioblastoma multiforme with unmethylated MGMT promoter has a poor prognosis, with a median survival of 12 months. This phase II study investigated the efficacy and safety of combining the selective integrin inhibitor cilengitide with a combination of metronomic temozolomide and procarbazine for these patients. Eligible patients (newly diagnosed, histologically confirmed supratentorial glioblastoma with unmethylated MGMT promoter) were entered into this multicentre study. Cilengitide (2000 mg IV twice weekly) was commenced 1 week prior to radiotherapy combined with daily temozolomide (60 mg/m(2)) and procarbazine (50 or 100 mg) and, after 4 weeks' break, followed by six adjuvant cycles of temozolomide (50-60 mg/m(2)) and procarbazine (50 or 100 mg) on days 1-20, every 28 days. Cilengitide was continued for up to 12 months or until disease progression or unacceptable toxicity. The primary endpoint for efficacy was a 12-month overall survival rate of 65 %. Twenty-nine patients completed study treatment. Sixteen patients survived for 12 months or more, an overall survival rate of 55 %. The median overall survival was 14.5 months (95 % CI 11.1-19.6) and the median progression free survival was 7.4 months (95 % CI 6.1-8). Cilengitide combined with metronomic temozolomide and procarbazine in MGMT-promoter unmethylated glioblastoma did not improve survival compared with historical data and does not warrant further investigation. PMID- 26935582 TI - Quantitative assessment of ribosome drop-off in E. coli. AB - Premature ribosome drop-off is one of the major errors in translation of mRNA by ribosomes. However, repeated analyses of Ribo-seq data failed to quantify its strength inE. coli Relying on a novel highly sensitive data analysis method we show that a significant rate of ribosome drop-off is measurable and can be quantified also when cells are cultured under non-stressing conditions. Moreover, we find that the drop-off rate is highly variable, depending on multiple factors. In particular, under environmental stress such as amino acid starvation or ethanol intoxication, the drop-off rate markedly increases. PMID- 26935580 TI - Promoter-enhancer looping at the PPARgamma2 locus during adipogenic differentiation requires the Prmt5 methyltransferase. AB - PPARgamma2 is a critical lineage-determining transcription factor that is essential for adipogenic differentiation. Here we report characterization of the three-dimensional structure of the PPARgamma2 locus after the onset of adipogenic differentiation and the mechanisms by which it forms. We identified a differentiation-dependent loop between the PPARgamma2 promoter and an enhancer sequence 10 kb upstream that forms at the onset of PPARgamma2 expression. The arginine methyltransferase Prmt5 was required for loop formation, and overexpression of Prmt5 resulted in premature loop formation and earlier onset of PPARgamma2 expression. Kinetic studies of regulatory factor interactions at the PPARgamma2 promoter and enhancer revealed enhanced interaction of Prmt5 with the promoter that preceded stable association of Prmt5 with enhancer sequences. Prmt5 knockdown prevented binding of both MED1, a subunit of Mediator complex that facilitates enhancer-promoter interactions, and Brg1, the ATPase of the mammalian SWI/SNF chromatin remodeling enzyme required for PPARgamma2 activation and adipogenic differentiation. The data indicate a dynamic association of Prmt5 with the regulatory sequences of the PPARgamma2 gene that facilitates differentiation dependent, three-dimensional organization of the locus. In addition, other differentiation-specific, long-range chromatin interactions showed Prmt5 dependence, indicating a more general role for Prmt5 in mediating higher-order chromatin connections in differentiating adipocytes. PMID- 26935581 TI - Cooperative motion of a key positively charged residue and metal ions for DNA replication catalyzed by human DNA Polymerase-eta. AB - Trans-lesion synthesis polymerases, like DNA Polymerase-eta (Pol-eta), are essential for cell survival. Pol-eta bypasses ultraviolet-induced DNA damages via a two-metal-ion mechanism that assures DNA strand elongation, with formation of the leaving group pyrophosphate (PPi). Recent structural and kinetics studies have shown that Pol-eta function depends on the highly flexible and conserved Arg61 and, intriguingly, on a transient third ion resolved at the catalytic site, as lately observed in other nucleic acid-processing metalloenzymes. How these conserved structural features facilitate DNA replication, however, is still poorly understood. Through extended molecular dynamics and free energy simulations, we unravel a highly cooperative and dynamic mechanism for DNA elongation and repair, which is here described by an equilibrium ensemble of structures that connect the reactants to the products in Pol-eta catalysis. We reveal that specific conformations of Arg61 help facilitate the recruitment of the incoming base and favor the proper formation of a pre-reactive complex in Pol eta for efficient DNA editing. Also, we show that a third transient metal ion, which acts concertedly with Arg61, serves as an exit shuttle for the leaving PPi. Finally, we discuss how this effective and cooperative mechanism for DNA repair may be shared by other DNA-repairing polymerases. PMID- 26935583 TI - On the genome base composition of teleosts: the effect of environment and lifestyle. AB - BACKGROUND: The DNA base composition is well known to be highly variable among organisms. Bio-physic studies on the effect of the GC increments on the DNA structure have shown that GC-richer DNA sequences are more bendable. The result was the keystone of the hypothesis proposing the metabolic rate as the major force driving the GC content variability, since an increased resistance to the torsion stress is mainly required during the transcription process to avoid DNA breakage. Hence, the aim of the present work is to test if both salinity and migration, suggested to affect the metabolic rate of teleostean fishes, affect the average genomic GC content as well. Moreover, since the gill surface has been reported to be a major morphological expression of metabolic rate, this parameter was also analyzed in the light of the above hypothesis. RESULTS: Teleosts living in different environments (freshwater and seawater) and with different lifestyles (migratory and non-migratory) were analyzed studying three variables: routine metabolic rate, gill area and genomic GC-content, none of them showing a phylogenetic signal among fish species. Routine metabolic rate, specific gill area and average genomic GC were higher in seawater than freshwater species. The same trend was observed comparing migratory versus non-migratory species. Crossing salinity and lifestyle, the active migratory species living in seawater show coincidentally the highest routine metabolic rate, the highest specific gill area and the highest average genomic GC content. CONCLUSIONS: The results clearly highlight that environmental factors (salinity) and lifestyle (migration) affect not only the physiology (i.e. the routine metabolic rate), and the morphology (i.e. gill area) of teleosts, but also basic genome feature (i.e. the GC content), thus opening to an interesting liaison among the three variables in the light of the metabolic rate hypothesis. PMID- 26935584 TI - Spatiotemporal patterns of particulate matter (PM) and associations between PM and mortality in Shenzhen, China. AB - BACKGROUND: Most studies on air pollution exposure and its associations with human health in China have focused on the heavily polluted industrial areas and/or mega-cities, and studies on cities with comparatively low air pollutant concentrations are still rare. Only a few studies have attempted to analyse particulate matter (PM) for the vibrant economic centre Shenzhen in the Pearl River Delta. So far no systematic investigation of PM spatiotemporal patterns in Shenzhen has been undertaken and the understanding of pollution exposure in urban agglomerations with comparatively low pollution is still limited. METHODS: We analyze daily and hourly particulate matter concentrations and all-cause mortality during 2013 in Shenzhen, China. Temporal patterns of PM (PM2.5 and PM10) with aerodynamic diameters of 2.5 (10) MUm or less (or less (including particles with a diameter that equals to 2.5 (10) MUm) are studied, along with the ratio of PM2.5 to PM10. Spatial distributions of PM10 and PM2.5 are addressed and associations of PM10 or PM2.5 and all-cause mortality are analyzed. RESULTS: Annual average PM10 and PM2.5 concentrations were 61.3 and 39.6 MUg/m(3) in 2013. PM2.5 failed to meet the Class 2 annual limit of the National Ambient Air Quality Standard. PM2.5 was the primary air pollutant, with 8.8 % of days having heavy PM2.5 pollution. The daily PM2.5/PM10 ratios were high. Hourly PM2.5 concentrations in the tourist area were lower than downtown throughout the day. PM10 and PM2.5 concentrations were higher in western parts of Shenzhen than in eastern parts. Excess risks in the number of all-cause mortality with a 10 MUg/m(3) increase of PM were 0.61 % (95 % confidence interval [CI]: 0.50-0.72) for PM10, and 0.69 % (95 % CI: 0.55-0.83) for PM2.5, respectively. The greatest ERs of PM10 and PM2.5 were in 2-day cumulative measures for the all-cause mortality, 2-day lag for females and the young (0-65 years), and L02 for males and the elder (>65 years). PM2.5 had higher risks on all-cause mortality than PM10. Effects of high PM pollution on mortality were stronger in the elder and male. CONCLUSIONS: Our findings provide additional relevant information on air quality monitoring and associations of PM and human health, valuable data for further scientific research in Shenzhen and for the on-going discourse on improving environmental policies. PMID- 26935586 TI - Melanopsin retinal ganglion cell loss and circadian dysfunction in Alzheimer's disease (Review). AB - Alzheimer's disease affects 27 million individuals and is the most common cause of dementia worldwide. The pathology of Alzheimer's disease is primarily due to the beta-amyloid deposits and neurofibrillary tangles. These deposits exist largely in the cerebral blood vessels, but have also been shown to exist in retinal vessels. A new class of cells that were recently identified, known as melanopsin-expressing retinal ganglion cells (mRGCs), are involved in the non image forming functions of the eye. These functions include circadian activities such as temperature rhythms, melatonin release and rest-activity cycles. Circadian dysfunction has been investigated in many cases of Alzheimer's disease. In this review, we outline the current accepted Alzheimer's disease pathology, the role of mRCGs in optic neuropathies and the role of mRCGs, leading to circadian dysfunction, in Alzheimer's disease. PMID- 26935585 TI - Systemic inflammatory impact of periodontitis on acute coronary syndrome. AB - AIM: A causative relationship between acute coronary syndrome (ACS) and periodontitis has yet to be defined. The aim of this study was to assess differences in levels of serum cytokines between individuals with or without ACS or periodontal comorbidity. MATERIAL AND METHODS: In a case-control study, individuals with ACS (78 individuals, 10.3% females) and matching healthy controls (78 individuals, 28.2% females) were included. Medical and dental examinations were performed to diagnose ACS and periodontitis. Serum levels of cytokines were assessed, using Luminex technology. RESULTS: A diagnosis of periodontitis in the ACS and control group was diagnosed in 52.6% and 12.8% of the individuals, respectively. The unadjusted odds-ratio that individuals with ACS also had periodontitis was 7.5 (95% CI: 3.4, 16.8, p < 0.001). Independent of periodontal conditions, individuals with ACS had significantly higher serum levels of IL8 (mean: 44.3 and 40.0 pg/ml) and vascular endothelial growth factor (VEGF) (mean: 82.3 and 55.3 pg/ml) than control individuals. A diagnosis of periodontitis made no difference in serum cytokine expressions. CONCLUSION: Elevated serum levels of VEGF were associated with ACS. Serum cytokine expression in individuals with ACS is unrelated to periodontal conditions. PMID- 26935587 TI - Influence of ATM-Mediated DNA Damage Response on Genomic Variation in Human Induced Pluripotent Stem Cells. AB - Genome instability is a potential limitation to the research and therapeutic application of induced pluripotent stem cells (iPSCs). Observed genomic variations reflect the combined activities of DNA damage, cellular DNA damage response (DDR), and selection pressure in culture. To understand the contribution of DDR on the distribution of copy number variations (CNVs) in iPSCs, we mapped CNVs of iPSCs with mutations in the central DDR gene ATM onto genome organization landscapes defined by genome-wide replication timing profiles. We show that following reprogramming the early and late replicating genome is differentially affected by CNVs in ATM-deficient iPSCs relative to wild-type iPSCs. Specifically, the early replicating regions had increased CNV losses during retroviral (RV) reprogramming. This differential CNV distribution was not present after later passage or after episomal reprogramming. Comparison of different reprogramming methods in the setting of defective DDR reveals unique vulnerability of early replicating open chromatin to RV vectors. PMID- 26935588 TI - Outcomes after surgical resection of pulmonary carcinoid tumors. AB - BACKGROUND: Pulmonary carcinoid tumors make up approximately one percent of all pulmonary tumors, and controversy exists regarding management and prognosis. We undertook a retrospective analysis of all patients who underwent surgical resection of pulmonary carcinoid tumors at our institution. METHODS: From 1992 through 2014, 121 patients who underwent surgical resection of pulmonary carcinoid tumors were retrospectively reviewed. Patient demographics, pathologic data and long-term outcomes were recorded. RESULTS: There were 96 patients with typical carcinoid tumors and 25 patients with atypical carcinoid tumors. All patients received complete resection of their tumors, with 90 % (109/121) of patients undergoing anatomic resection. There were no peri-operative mortalities. Eighty-one percent (98/121) of patients were female. Mean age was 60.7 years. Five and ten year survival rates were 96 % and 88 % respectively for typical carcinoid tumors, as compared to 87 % and 69 % respectively for atypical carcinoid tumors. Tumor size was not associated with survival (p = 0.98). Nodal metastases were evident in 8 % (8/96) of typical carcinoid tumors and 28 % (7/25) percent of atypical carcinoid tumors. Among typical carcinoid cases, the presence of nodal metastases were not associated with overall survival (p = 0.55). Among atypical carcinoid cases, the presence of nodal metastases also was not associated with survival (p = 0.53). No patients received neoadjuvant or adjuvant chemoradiation treatment. CONCLUSIONS: Excellent long-term outcomes can be achieved following surgical resection of pulmonary carcinoid tumors. The presence of nodal metastases was not associated with overall survival. Tumor size was not associated with either recurrence rates or survival. PMID- 26935589 TI - Capillary electrophoretic enantioseparation of basic drugs using a new single isomer cyclodextrin derivative and theoretical study of the chiral recognition mechanism. AB - A novel single-isomer cyclodextrin derivative, heptakis {2,6-di-O-[3-(1,3 dicarboxyl propylamino)-2-hydroxypropyl]}-beta-cyclodextrin (glutamic acid-beta cyclodextrin) was synthesized and used as a chiral selector in capillary electrophoresis for the enantioseparation of 12 basic drugs, including terbutaline, clorprenaline, tulobuterol, clenbuterol, procaterol, carvedilol, econazole, miconazole, homatropine methyl bromide, brompheniramine, chlorpheniramine and pheniramine. The primary factors affecting separation efficiency, which include the background electrolyte pH, the concentration of glutamic acid-beta-cyclodextrin and phosphate buffer concentration, were investigated. Satisfactory enantioseparations were obtained using an uncoated fused-silica capillary of 50 cm (effective length 40 cm) * 50 MUm id with 120 mM phosphate buffer (pH 2.5-4.0) containing 0.5-4.5 mM glutamic acid-beta cyclodextrin as background electrolyte. A voltage of 20 kV was applied and the capillary temperature was kept at 20 degrees C. The results proved that glutamic acid-beta-cyclodextrin was an effective chiral selector for studied 12 basic drugs. Moreover, the possible chiral recognition mechanism of brompheniramine, chlorpheniramine and pheniramine on glutamic acid-beta-cyclodextrin was investigated using the semi-empirical Parametric Method 3. PMID- 26935592 TI - Influenza Vaccination and Other Factors Related to the Development of Influenza Like Illness Among Patients on Chronic Hemodialysis in a Japanese Dialysis Facility. AB - The present study was conducted to evaluate the protective effect of seasonal influenza vaccination on the development of influenza-like illness (ILI), as well as to investigate factors related to the development of ILI among patients in a Japanese dialysis facility. One hundred eighty-three hemodialysis (HD) patients were followed up from November 2008 to March 2009. During the follow-up period, 17 patients developed ILI. We compared the characteristics of these 17 patients to patients without ILI. Compared to the non-ILI group (N = 166), the ILI group (N = 17) showed a non-significantly lower rate of influenza vaccination (70.6% vs. 86.7%, P = 0.07), while any other factor did not differ between the two groups. Influenza vaccination tended to reduce the risk of ILI (Odds ratio = 0.37, 95% CI = 0.12 to 1.14, P = 0.07). The findings of the present study suggested that the influenza vaccine was 60% effective to prevent ILI among HD patients, although the effectiveness was not statistically significant. PMID- 26935590 TI - The significance of naturally occurring neuraminidase quasispecies of H5N1 avian influenza virus on resistance to oseltamivir: a point of concern. AB - Viral adaptability and survival arise due to the presence of quasispecies populations that are able to escape the immune response or produce drug-resistant variants. However, the presence of H5N1 virus with natural mutations acquired without any drug selection pressure poses a great threat. Cloacal samples collected from the 2004-2005 epidemics in Thailand from Asian open-billed storks revealed one major and several minor quasispecies populations with mutations on the oseltamivir (OTV)-binding site of the neuraminidase gene (NA) without prior exposure to a drug. Therefore, this study investigated the binding between the NA containing novel mutations and OTV drug using molecular dynamic simulations and plaque inhibition assay. The results revealed that the mutant populations, S236F mutant, S236F/C278Y mutant, A250V/V266A/P271H/G285S mutant and C278Y mutant, had a lower binding affinity with OTV as compared with the WT virus due to rearrangement of amino acid residues and increased flexibility in the 150-loop. This result was further emphasized through the IC50 values obtained for the major population and WT virus, 104.74 nM and 18.30 nM, respectively. Taken together, these data suggest that H5N1 viruses isolated from wild birds have already acquired OTV-resistant point mutations without any exposure to a drug. PMID- 26935593 TI - Plasmacytoid Dendritic Cells and Type I Interferon Signature in Lichen Striatus. AB - BACKGROUND/OBJECTIVES: In addition to several infectious and neoplastic cutaneous entities, plasmacytoid dendritic cells (pDCs) have been shown to be involved in the pathogenesis of multiple cutaneous inflammatory and autoimmune disorders, including those characterized histologically by an "interface dermatitis" pattern such as lupus or lichen planus (LP), but their role in lichen striatus (LS), which is also known to have this histologic inflammatory pattern, has never been studied. The objective of the study was to investigate the role of pDCs in LS. METHODS: Fifteen LS patients were found in our database and were immunohistochemically tested for pDC occurrence and activity using anti-blood derived dendritic cell antigen-2 and anti-myxovirus resistance protein A (MxA) antibodies, respectively. These individuals were also compared with 15 individuals with LP. RESULTS: pDCs were present in all individuals with LS and LP, but they were less abundant in those with LS, although MxA (surrogate marker of local type I interferon production and thus an indirect assessment of pDC activity) was similarly intense and diffuse in all individuals with LS and LP. In addition to being part of the upper dermal inflammatory bandlike infiltrate as in LP, LS cases, unlike LP, also showed perieccrine pDCs. CONCLUSIONS: pDCs constitute a central component of the inflammatory infiltrate in LS, suggesting a significant role in its pathogenesis. pDC distribution (perieccrine distribution) could also help in microscopically differentiating LS from LP. PMID- 26935591 TI - Enhanced autophagy in cytarabine arabinoside-resistant U937 leukemia cells and its potential as a target for overcoming resistance. AB - Autophagy is a lysosomal degradation mechanism that is essential for cell survival, differentiation, development, and homeostasis. Autophagy protects cells from various stresses, including protecting normal cells from harmful metabolic conditions, and cancer cells from chemotherapeutics. In the current study, a cytarabine arabinoside (Ara-C)-sensitive U937 leukemia cell line and an Ara-C resistant U937 (U937/AR) cell line were assessed for baseline autophagy activity by investigating the LC3-I conversion to LC3-II, performing EGFP-LC3 puncta, an acidic autophagolysosome assay, and measuring the expression of various autophagy related genes. The results demonstrated significantly higher autophagic activity in the U937/AR cells compared with the U937 cells, when the cells were cultured with or without serum. Furthermore, an increase in the autophagic activity in starved U937/AR cells was demonstrated, compared with that in the starved U937 cells. Administration of an autophagy inhibitor demonstrated no change in cell death in the two cell lines when cultured with serum, however, it induced cell death regardless of the Ara-C sensitivity when the cell lines were cultured without serum. In addition, the U937 cells demonstrated an Ara-C resistance when cultured without serum. Co-treatment with Ara-C and the autophagy inhibitor significantly induced cell death in the U937/AR and Ara-C-sensitive U937 cells. In conclusion, autophagy serves an important role in protecting U937 cells from Ara-C and in the development of Ara-C resistance. Inhibition of autophagy combined with the Ara-C treatment in the U937 cells augmented the anti-leukemic effect of Ara-C and overcame Ara-C resistance, suggesting that autophagy may be an important therapeutic target to further improve the treatment outcome in patients with acute myeloid leukemia. PMID- 26935594 TI - Combination of prostate imaging reporting and data system (PI-RADS) score and prostate-specific antigen (PSA) density predicts biopsy outcome in prostate biopsy naive patients. AB - OBJECTIVE: To assess the value of the Prostate Imaging Reporting and Data System (PI-RADS) scoring system, for prostate multi-parametric magnetic resonance imaging (mpMRI) to detect prostate cancer, and classical parameters, such as prostate-specific antigen (PSA) level, prostate volume and PSA density, for predicting biopsy outcome in biopsy naive patients who have suspected prostate cancer. PATIENTS AND METHODS: Patients who underwent mpMRI at our hospital, and who had their first prostate biopsy between July 2010 and April 2014, were analysed retrospectively. The prostate biopsies were taken transperineally under transrectal ultrasonography guidance. In all, 14 cores were biopsied as a systematic biopsy in all patients. Two cognitive fusion-targeted biopsy cores were added for each lesion in patients who had suspicious or equivocal lesions on mpMRI. The PI-RADS scoring system version 2.0 (PI-RADS v2) was used to describe the MRI findings. Univariate and multivariate analyses were performed to determine significant predictors of prostate cancer and clinically significant prostate cancer. RESULTS: In all, 288 patients were analysed. The median patient age, PSA level, prostate volume and PSA density were 69 years, 7.5 ng/mL, 28.7 mL, and 0.26 ng/mL/mL, respectively. The biopsy results were benign, clinically insignificant, and clinically significant prostate cancer in 129 (45%), 18 (6%) and 141 (49%) patients, respectively. The multivariate analysis revealed that PI RADS v2 score and PSA density were independent predictors for prostate cancer and clinically significant prostate cancer. When PI-RADS v2 score and PSA density were combined, a PI-RADS v2 score of >=4 and PSA density >=0.15 ng/mL/mL, or PI RADS v2 score of 3 and PSA density of >=0.30 ng/mL/mL, was associated with the highest clinically significant prostate cancer detection rates (76-97%) on the first biopsy. Of the patients in this group with negative biopsy results, 22% were subsequently diagnosed as prostate cancer. In contrast, a PI-RADS v2 score of <=3 and PSA density of <0.15 ng/mL/mL yielded no clinically significant prostate cancer and no additional detection of prostate cancer on further biopsies. CONCLUSIONS: A combination of PI-RADS v2 score and PSA density can help in the decision-making process before prostate biopsy and in the follow-up strategy in biopsy naive patients. Patients with a PI-RADS v2 score of <=3 and PSA density of <0.15 ng/mL/mL may avoid unnecessary biopsies. PMID- 26935595 TI - Shape plasticity in response to water velocity in the freshwater blenny Salaria fluviatilis. AB - A non-random association between an environmental factor and a given trait could be explained by directional selection (genetic determinism) and by phenotypic plasticity (environmental determinism). A previous study showed a significant relationship between morphology and water velocity in Salaria fluviatilis that conformed to functional expectations. The objective of this study was to test whether this relationship could be explained by phenotypic plasticity. Salaria fluviatilis from a Corsican stream were placed in four experimental channels with different water velocities (0, 10, 20 and 30 cm s(-1)) to test whether there was a morphological response associated with this environmental factor. After 28 days, fish shape changed in response to water velocity without any significant growth. Fish in higher water velocities exhibited a more slender body shape and longer anal and caudal fins. These results indicate a high degree of morphological plasticity in riverine populations of S. fluviatilis and suggest that the previous relationship between morphology and water velocity observed in the field may largely be due to an environmental determinism. PMID- 26935596 TI - Systematic Identification of Long Noncoding RNAs in Immature and Mature Porcine Testes. AB - Thousands of long noncoding RNAs (lncRNAs) have been identified in mouse, rat, and human testes, some of which play important roles in testis development and spermatogenesis. However, systematic analysis of lncRNAs expressed in postnatal pig testes has not been reported. Thus, in this study, we present the expression and characterization of lncRNAs in immature (30-day-old [D30]) and mature (180 day-old [D180]) pig testes. A total of 90 440 168 (85.75%) and 97 001 700 (95.35%) 150-base-pair paired-end clean reads were generated in D30 and D180 cDNA libraries, respectively, using the Illumina HiSeq 4000 platform; 36 727 transcripts were assembled in those two libraries, 777 lncRNA transcripts from 752 lncRNA gene loci were identified using the highly stringent pipeline, and 101 of those lncRNA transcripts were significantly differentially expressed. Those lncRNAs shared some characteristics with other mammals, including fewer exons, shorter length and exon length, and lower expression level compared with those of protein-coding genes; 402 protein-coding genes (<10 kb) were found as nearest neighbors of 294 out of 752 lncRNA genes, and gene ontology enrichment showed that they were enriched in transcription- and development-related processes. Fifteen differentially expressed and 10 novel lncRNAs were randomly selected and validated by quantitative polymerase chain reaction (PCR) and reverse transcriptase PCR. In addition, one of the 10 novel lncRNAs was further confirmed using RACE clone technology. This study provides a catalog of porcine testes lncRNAs for further understanding their regulation roles in pig testis development and spermatogenesis. PMID- 26935597 TI - Changes of Phospholipids in Fetal Liver of Mice Conceived by In Vitro Fertilization. AB - Environmental influences during early development increase the susceptibility to metabolism diseases in adulthood. Assisted reproductive techniques (ART) expose the gametes or preimplantation embryo to a nonphysiological environment that increases the risk of metabolism diseases in later life. However, the precise underlying causes of ART-related metabolism disease remain unclear. In our previous study, by using a mouse model, we found that ART resulted in placental maldevelopment and dysfunction that led to reduced fetal growth. The lipid metabolism and lipid transporters in the placenta were also affected by ART. Based on these findings, we hypothesized that ART may hamper fetal lipid metabolism, which could predispose to metabolic diseases in later life. In the present examination, by lipidomic analysis, we investigated for the first time the effect of ART on phospholipid profiles in the fetal liver in a mouse model and presented it in a detailed overview. We revealed that ART increased significantly the level of lysophosphatidylcholine (LPC), phosphatidic acid (PA), and lysophosphatidylethanolamine in the livers of fetuses compared with those in the controls. LPC and PA acts as signaling molecules involved in the majority of cellular processes regulating many crucial physiological and pathophysiological processes. LPC has been shown to play a crucial role in the development of atherosclerosis and type 2 diabetes, and an increase in PA can result in insulin resistance. We proposed that changes of LPC and PA may be one of the causes of the changes in glucose metabolism and vascular dysfunction in the mouse model of ART. PMID- 26935598 TI - Epigenetic Modulation of Collagen 1A1: Therapeutic Implications in Fibrosis and Endometriosis. AB - Progressive fibrosis is recalcitrant to conventional therapy and commonly complicates chronic diseases and surgical healing. We evaluate here a novel mechanism that regulates scar-tissue collagen (COL1A1/Col1a1) expression and characterizes its translational relevance as a targeted therapy for fibrosis in an endometriosis disease model. Endometriosis is caused by displacement and implantation of uterine endometrium onto abdominal organs and spreads with progressive scarring. Transcription factor KLF11 is specifically diminished in endometriosis lesions. Loss of KLF11-mediated repression of COL1A1/Col1a1 expression resulted in increased fibrosis. To determine the biological significance of COL1A1/Col1a1 expression on fibrosis, we modulated its expression. In human endometrial-stromal fibroblasts, KLF11 recruited SIN3A/HDAC (histone deacetylase), resulting in COL1A1-promoter deacetylation and repression. This role of KLF11 was pharmacologically replicated by a histone acetyl transferase inhibitor (garcinol). In contrast, opposite effects were obtained with a HDAC inhibitor (suberoyl anilide hydroxamic acid), confirming regulatory specificity for these reciprocally active epigenetic mechanisms. Fibrosis was concordantly reversed in Klf11(-/-)animals by histone acetyl transferase inhibitor and in wild-type animals by HDAC inhibitor treatments. Aberrant lesional COL1A1 regulation is significant because fibrosis depended on lesion rather than host genotype. This is the first report demonstrating feasibility for targeted pharmacological reversal of fibrosis, an intractable phenotype of diverse chronic diseases. PMID- 26935599 TI - Plasminogen Improves Mouse IVF by Interactions with Inner Acrosomal Membrane Bound MMP2 and SAMP14. AB - Spermatozoa must penetrate the outer investments of the oocyte, the cumulus oophorus and the zona pellucida (ZP), in order for fertilization to occur. This may require exposure of enzymes on the sperm's inner acrosomal membrane (IAM), one of which is matrix metalloproteinase (MMP) 2, to factors in oviductal fluid. Plasminogen is present in oviductal fluid and activates MMP2 in somatic tissues. The objectives of this study were: 1) to examine possible interactions between plasminogen and IAM-bound plasminogen activator receptor (SAMP14) and -MMP2, 2) to demonstrate plasminogen's presence in the extracellular environment at the site of fertilization, and 3) to provide evidence that plasminogen plays a role in fertilization. Zymographs of sonicated bull and rat sperm extracts incubated with plasmin and/or plasminogen (plasmin/ogen) showed acceleration of initiation of MMP2 activity in concentrations as low as 1 MUg/ml. Immunohistochemical and immunofluorescence analysis of plasmin/ogen revealed its presence in the cytoplasm of mouse ovarian and oviductal oocytes, oviductal epithelium, around the ZP, and amongst the cumulus cells. We modified the standard in vitro fertilization (IVF) approach to more closely mimic natural fertilization by reducing sperm concentration during insemination by ~100* and also comparing cumulus-intact and denuded oocytes. In mice, addition of plasminogen in IVF medium significantly improved fertilization, while MMP2 antibody significantly inhibited sperm penetration in these conditions. IVF improvement by plasminogen was blocked by SAMP14 antibody. Furthermore, MMP2 antibody inhibition was coincident with a failure by spermatozoa to disperse the cumulus oophorus. We provide evidence that plasminogen on its own and through an MMP2-related mechanism improves the ability of oocytes to be fertilized, and demonstrate its effect in sperm penetration of oocyte investments. PMID- 26935600 TI - Nucleolus Precursor Bodies and Ribosome Biogenesis in Early Mammalian Embryos: Old Theories and New Discoveries. AB - In mammals, mature oocytes and early preimplantation embryos contain transcriptionally inactive structures termed nucleolus precursor bodies instead of the typical fibrillo-granular nucleoli. These nuclear organelles are essential and strictly of maternal origin. If they are removed from oocytes, the resulting embryos are unable to replace them and consequently fail to develop. Historically, nucleolus precursor bodies have been perceived as a passive repository site of nucleolar proteins that are required for embryos to form fully functional nucleoli. Recent results, however, contradict this long-standing dogma and show that these organelles are dispensable for nucleologenesis and ribosome biogenesis. In this article, we discuss the possible roles of nucleolus precursor bodies and propose how they might be involved in embryogenesis. Furthermore, we argue that these organelles are essential only shortly after fertilization and suggest that they might actively participate in centromeric chromatin establishment. PMID- 26935601 TI - Biology of Preimplantation Conceptus at the Onset of Elongation in Dairy Cows. AB - The objectives of this study were to characterize changes in transcriptome of preimplantation conceptuses at the onset of elongation and associated changes in uterine histotroph composition and endometrial physiology. Lactating dairy cows (n = 160) had their ovulation synchronized by artificial insemination (study Day 0). On Day 15, uteri were flushed and endometrium tissue collected. Recovered conceptuses were classified based on morphology/length as ovoid (1-4 mm), tubular (5-19 mm), and filamentous (20-60 mm). Total RNA (n = 48) was subjected to transcriptome analysis. The uterine fluid (n = 30) was evaluated by mass spectrophotometry. Transcriptome analyses revealed drastic changes in the transition from ovoid to tubular and from tubular to filamentous. Differentially expressed genes were associated with cellular movement, cell-to-cell signaling, cellular assembly and organization, lipid metabolism, small molecule biochemistry, and molecular transport. Specific changes included reorganization of cytoskeleton and cell migration, arginine metabolism, growth factors signaling, and lipid metabolism. Functional analysis revealed fatty acids and peroxisome proliferator activated receptor gamma as upstream regulators of transcriptome changes. Expression of PPARG increased 17-fold during the onset of elongation and was highly correlated with genes involved in lipid metabolism. The histotroph was rich in amino acids, lipids, saccharides, and other intermediate metabolites, and important changes in composition occurred in the presence of a conceptus. Pregnancy had a major impact on the concentrations of important lipids in the uterine fluid and expression of genes in the endometrium. Collectively, conceptus elongation involves remarkable changes in transcriptome, composition of the histotroph, and endometrial physiology, which help elucidate important events in uterine and conceptus biology at the onset of elongation. PMID- 26935602 TI - An efficient and rapid method for enrichment of lipophilic proteins from Mycobacterium tuberculosis H37Rv for two-dimensional gel electrophoresis. AB - Lipophilic proteome profiling is crucial because they have an anticipated role in biological processes and pathogenesis of Mycobacterium tuberculosis. These lipophilic proteins might be used as potential targets for the development of newer diagnostic markers and drug targets due to their association with membranes and drugs. We developed an efficient and rapid method to enrich the lipophilic proteins extraction from M. tuberculosis H37Rv for 2DE. In the extraction of lipophilic proteins, nonionic detergent (Triton X-100) was added in sonication buffer that augmented the solubilization of the proteins at the time of sonication. Enriched whole cell lysate was subjected to direct phase separation using Triton X-114, without the need for preisolation of membranes. In this study, we report that our optimized extraction buffer increased the lipophilic proteins extraction and their improved resolution on 2D gel up to two- to threefolds (quantitatively and qualitatively) as compared to standard extraction buffer. Some proteins were identified by MALDI-TOF/MS. PMID- 26935603 TI - Reaction-based probe for hydrogen sulfite: dual-channel and good ratiometric response. AB - We designed and synthesized a new series of intramolecular charge transfer (ICT) molecules (compounds T1, T2 and T3) by attaching various electron-donating thiophene groups to the triphenylamine backbone with aldehyde group as the electron acceptor. Based on the nucleophilic addition reaction between hydrogen sulfite and aldehyde, all compounds could act as ratiometric optical probe for hydrogen sulfite and displayed efficient chromogenic and fluorogenic signaling. Upon the addition of hydrogen sulfite anions, probe T3 displayed apparent fluorescent color changes from yellowish-green to blue, with a large emission wavelength shift (Deltalambda = 120 nm). T3 responded to hydrogen sulfite with high sensitivity and the detection limit was determined to be as low as 0.9 MUM. At the same time, apparent changes in UV-vis spectra could also be observed. By virtue of the special nucleophilic addition reaction with aldehyde, T3 displayed high selectivity over other anions. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26935604 TI - Relationship between general movements in neonates who were growth restricted in utero and prenatal Doppler flow patterns. AB - OBJECTIVE: To investigate whether Doppler pulsatility indices (PIs) of the fetal circulation in cases of fetal growth restriction (FGR) are associated with the general movements (GMs) of the neonate after birth. METHODS: This was a prospective observational cohort study including pregnancies with FGR diagnosed between June 2012 and September 2014. A diagnosis of FGR was based on an abdominal circumference or estimated fetal weight < 10th percentile (in conjuction with abnormal Doppler) or declining fetal growth of at least 30 percentiles with respect to previous size measurements. Doppler parameters of the umbilical artery (UA), fetal middle cerebral artery (MCA) and ductus venosus (DV) were measured maximally 1 week prior to delivery. Cerebroplacental ratio (CPR) was calculated as MCA-PI divided by UA-PI. We assessed the quality of neonatal GMs 7 days after birth, around the due date if cases were born preterm, and at 3 months post-term. We performed a detailed analysis of the motor repertoire by calculating a motor optimality score (MOS). RESULTS: Forty-eight FGR cases were included with a median gestational age at delivery of 35 (range, 26-40) weeks. UA PI, MCA-PI and CPR correlated strongly (rho, -0.374 to 0.472; P < 0.01) with the MOS on day 7 after birth, but DV-PI did not. Doppler PI measurements did not correlate with MOS at 3 months post-term. CONCLUSION: Fetal arterial Doppler measurements are associated with the quality of neonatal GMs 1 week after birth, but this association is no longer evident at 3 months post-term. Brain sparing in particular is associated strongly with GMs of an abnormal quality. Copyright (c) 2016 ISUOG. Published by John Wiley & Sons Ltd. PMID- 26935605 TI - Occult fetomaternal hemorrhage in women with pathological placenta with respect to permeability. AB - AIM: Women with pre-eclampsia (PE), placenta previa (PP), placental abruption (PA), and placental mesenchymal dysplasia (PMD) have been described as having placental permeability dysfunction. This study was performed to determine whether occult fetomaternal hemorrhage (FMH) is common in women with such complications and in women with non-reassuring fetal status. METHODS: Forty-one antenatal and 39 postnatal blood samples were obtained from 46 women, including 11 with placental permeability dysfunction (5, 3, 2, and 1 with PE, PP, PA, and PMD, respectively) and 35 controls without such complications. To estimate the amount of fetal red blood cells, flow cytometry was performed using the fetal cell count system with two antibodies against fetal hemoglobin and carbonic anhydrase and the beta-gamma system with two monoclonal antibodies against hemoglobin beta chain and hemoglobin gamma-chain. A diagnosis of FMH was made when the fraction size of the isolated cell population on scatter plots expressing fetal hemoglobin alone or hemoglobin gamma-chain alone accounted for >=0.02% of the total cell population on scatter plots. RESULTS: FMH was identified in five women, including one each with PE, PA, PP, PMD, and no complications. Thus, the prevalence rate of FMH was significantly higher in women with complications than in controls (36% [4/11] vs 2.9% [1/35], respectively, P = 0.009). The FMH occurrence rate did not differ between women with and without non-reassuring fetal status (7.7% [1/13] vs 12% [4/33], respectively, P = 1.000). CONCLUSION: The risk of fetal red blood cells trafficking into the maternal circulation may be increased in women complicated with PE, PA, PP, and PMD. PMID- 26935606 TI - Functional analysis of the TMPRSS2:ERG fusion gene in cisplatin-induced cell death. AB - The TMPRSS2:E-twenty-six (ETS) gene fusion occurs frequently in a high proportion of patients with prostate cancer (PCa) in Western countries, and the aberrant expression of TMPRSS2: v-ETS avian erythroblastosis virus E26 oncogene homolog (ERG), the most common form of the corresponding protein, can regulate cell migration and contribute to tumor invasion and metastasis. However, its association with other cellular events, and in particular, cell death, remain unknown. To examine the function of such fusion genes, an expression plasmid containing the TMPRSS2:ERG (T1/E5) sequence (DeltaERG) from a patient sample was constructed and transiently transfected into DU145 cells, which do not express the fusion gene. It was found that the overexpression of DeltaERG significantly inhibited the ability of cisplatin to induce apoptosis in DU145 cells. By contrast, VCaP cells, which do contain TMPRSS2:ERG, were sensitized to cisplatin induced apoptosis through siRNA inhibition of the fusion gene. To elucidate the underlying mechanism, a stable cell line expressing the DeltaERG gene was constructed. Expression of DeltaERG did not affect cell migration, but did protect cells from DNA damage and apoptosis induced by cisplatin. Furthermore, knockdown of DeltaERG by short interfering RNA resulted in cells regaining their sensitivity to cisplatin. Finally, the gene coding for activating transcription factor 5, which is important for cell survival, may be upregulated by DeltaERG. Taken together, these data point to a new function of the TMPRSS2:ERG fusion gene in regulating the apoptotic pathway. PMID- 26935608 TI - Chronic graft-vs-host disease in 2016: a major challenge and an opportunity. PMID- 26935607 TI - Effects of short-term mechanical hyperventilation on cerebral blood flow and dynamic cerebral autoregulation in critically ill patients with sepsis. AB - In sepsis, higher PaCO2 levels are associated with impaired dynamic cerebral autoregulation (dCA), which may expose the brain to hypo- and hyperperfusion during acute fluctuations in blood pressure. We hypothesised that short-term mechanical hyperventilation would dCA in critically ill patients with sepsis. Seven mechanically ventilated septic patients were included. We assessed dCA before and after 30 min of mechanical hyperventilation. Transfer function analysis of spontaneous oscillations in transcranial Doppler-based middle cerebral artery blood flow velocity (MCAv) and invasive mean arterial blood pressure was used to assess dCA. Mechanical enhance hyperventilation reduced the median PaCO2 from 5.3 (IQR, 5.0-6.5) to 4.7 (IQR, 4.2-5.1) kPa (p < 0.05). This was associated with a reduction in the median MCAv from 57 (IQR, 33-68) to 32 (IQR, 21-40) cm sec(-1) (p < 0.05). Apart from a small increase in gain in the low frequency range (2.32 [IQR 1.80-2.41] vs. 2.59 (2.40-4.64) cm mmHg(-1) sec( 1); p < 0.05), this was not associated with any enhancement in dCA. In conclusion, cerebral CO2 vasoreactivity was found to be preserved in septic patients; nevertheless, and in contrast to our working hypothesis, short-term mechanical hyperventilation did not enhance dCA. PMID- 26935609 TI - Amblyopia screening: a new screening protocol implemented in Croatia. PMID- 26935611 TI - The lung function score and its components as predictors of overall survival and chronic graft-vs-host disease after allogeneic stem cell transplantation. AB - AIM: To retrospectively assess if the modified lung function score (LFS) and/or its components, forced expiratory volume within the first second (FEV1) and diffusion capacity for carbon monoxide corrected for hemoglobin level (cDLCO), predict overall survival (OS) and chronic graft-vs-host-disease (cGvHD). METHODS: We evaluated 241 patients receiving allogeneic hematopoietic stem cell transplantation (allo-HSCT) at the University of Regensburg Transplant Center between June 1998 and July 2005 in relation to their LFS, FEV1 and cDLCO, before and after HSCT. RESULTS: Decreased OS after allo-HSCT was related to decreased pre-transplantation values of FEV1<60% (P=0.040), cDLCO<50% of predicted value (P=0.025), and LFS>=III (P=0.037). It was also related to decreased FEV1 at 3 and 12 months after HSCT (P<0.001 and P=0.001, respectively) and increased LFS at 3 and 12 months after HSCT (P=.028 and P=0.002, respectively), but not to changes of cDLCO. A higher incidence of cGvHD was related to decreased FEV1 at 6, 12, and 18 months (P=0.069, P=0.054, and P=0.009, respectively) and increased LFS at 12 months (P=0.002), but not to changes in cDLCO. CONCLUSIONS: OS was related to both LFS and FEV1, but cGvHD had a stronger relation to FEV1 than to cDLCO or LFS. FEV1 alone offered more information on the outcome after allo-HSCT than LFS or cDLCO, suggesting limited value of LFS for the patients' assessment after allo HSCT. PMID- 26935610 TI - Which questionnaires should we use to evaluate quality of life in patients with chronic graft-vs-host disease? AB - AIM: To investigate the ability of two standard quality of life (QOL) questionnaires - The Short Form (36-item) Health Survey (SF-36) and The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ C30) to evaluate QOL in patients with chronic graft-vs-host disease (cGVHD) graded according to National Institutes of Health (NIH) consensus criteria. METHODS: In this cross-sectional study, QOL was assessed in patients who underwent allogeneic stem cell transplantation (allo-SCT) at the University Hospital Centre Zagreb and were alive and in complete remission for more than one year after allo-SCT. RESULTS: The study included 58 patients, 38 patients with cGVHD and 20 controls, patients without cGVHD. Patients with cGVHD scored according to the NIH criteria had significantly lower scores of global health status and lower QOL on all SF-36 subscales and most of QLQ C30 functional subscales (P<0.050 for all comparisons). Furthermore, patients with active cGVHD had significantly lower QOL scores than patients with inactive cGVHD, and this difference was most evident in physical functioning subscale of SF-36 (P=0.0007) and social functioning subscale of QLQ C30 (P=0.009). CONCLUSION: cGVHD scored according to the NIH criteria is correlated with patient-reported QOL, particularly in the physical domains as detected by SF-36. QLQ C30 questionnaire adds more information on social functioning and should be used as a valuable tool in the evaluation of social domains in cGVHD patients. PMID- 26935613 TI - Shear-wave sonoelastographic features of invasive lobular breast cancers. AB - AIM: To evaluate shear-wave elastographic (SWE) and related gray-scale features of pure invasive lobular breast carcinoma (ILC) and compare them with invasive ductal breast cancers (IDC). METHODS: Quantitative SWE features of mean (El mean), maximum (El-max), minimum (El-min) elasticity values of the stiffest portion of the mass, and lesion-to-fat elasticity ratio (E-ratio) were measured in 40 patients with pure ILC and compared with 75 patients with IDC. Qualitative gray-scale features of lesion size, echogenicity, orientation, and presence of distal shadowing were determined and compared between the groups. RESULTS: ILC were significantly larger than IDC (P=0.008) and exhibited significantly higher El-max (P=0.015) and higher El-mean (P=0.008) than IDC. ILC were significantly more often horizontally oriented, while IDC were significantly more often vertically oriented (P<0.001); ILC were significantly more often hyperechoic than IDC (P<0.001). Differences in stiffness between ILC and IDC determined by quantitative SWE parameters were present only in small tumors (<=1.5 cm in size), ie, small ILC had significantly higher El-max (P=0.030), El-mean (P=0.014), and El-min (P=0.045) than small IDC, while tumors larger than 1.5 cm had almost equal stiffness, without significant differences between the groups. CONCLUSION: Specific histopathologic features of ILC are translated into their qualitative sonographic and quantitative sonoelastographic appearance, with higher stiffness of small ILC compared to small IDC. Gray-scale and sonoelastographic features may help in diagnosing ILC. PMID- 26935612 TI - Zagreb Amblyopia Preschool Screening Study: near and distance visual acuity testing increase the diagnostic accuracy of screening for amblyopia. AB - AIM: To present and evaluate a new screening protocol for amblyopia in preschool children. METHODS: Zagreb Amblyopia Preschool Screening (ZAPS) study protocol performed screening for amblyopia by near and distance visual acuity (VA) testing of 15 648 children aged 48-54 months attending kindergartens in the City of Zagreb County between September 2011 and June 2014 using Lea Symbols in lines test. If VA in either eye was >0.1 logMAR, the child was re-tested, if failed at re-test, the child was referred to comprehensive eye examination at the Eye Clinic. RESULTS: 78.04% of children passed the screening test. Estimated prevalence of amblyopia was 8.08%. Testability, sensitivity, and specificity of the ZAPS study protocol were 99.19%, 100.00%, and 96.68% respectively. CONCLUSION: The ZAPS study used the most discriminative VA test with optotypes in line as they do not underestimate amblyopia. The estimated prevalence of amblyopia was considerably higher than reported elsewhere. To the best of our knowledge, the ZAPS study protocol reached the highest sensitivity and specificity when evaluating diagnostic accuracy of VA tests for screening. The pass level defined at <=0.1 logMAR for 4-year-old children, using Lea Symbols in lines missed no amblyopia cases, advocating that both near and distance VA testing should be performed when screening for amblyopia. PMID- 26935614 TI - Hyperbaric oxygen preconditioning ameliorates blood-brain barrier damage induced by hypoxia through modulation of tight junction proteins in an in vitro model. AB - AIM: To explore the effects of hyperbaric oxygen preconditioning (HBOP) on the permeability of blood-brain barrier (BBB) and expression of tight junction proteins under hypoxic conditions in vitro. METHODS: A BBB in vitro model was constructed using the hCMEC/D3 cell line and used when its trans-endothelial electrical resistance (TEER) reached 80-120 Omega . cm2 (tested by Millicell Electrical Resistance System). The cells were randomly divided into the control group cultured under normal conditions, the group cultured under hypoxic conditions (2%O2) for 24 h (hypoxia group), and the group first subjected to HBOP for 2 h and then to hypoxia (HBOP group). Occludin and ZO-1 expression were analyzed by immunofluorescence assay. RESULTS: Normal hCMEC/D3 was spindle-shaped and tightly integrated. TEER was significantly reduced in the hypoxia (P=0.001) and HBOP group (P=0.014) compared to control group, with a greater decrease in the hypoxia group. Occludin membranous expression was significantly decreased in the hypoxia group (P=0.001) compared to the control group, but there was no change in the HBOP group. ZO-1 membranous expression was significantly decreased (P=0.002) and cytoplasmic expression was significantly increased (P=0.001) in the hypoxia group compared to the control group, although overall expression levels did not change. In the HBOP group, there was no significant change in ZO-1 expression compared to the control group. CONCLUSION: Hyperbaric oxygen preconditioning protected the integrity of BBB in an in vitro model through modulation of occludin and ZO-1 expression under hypoxic conditions. PMID- 26935615 TI - Association between social capital, health-related quality of life, and mental health: a structural-equation modeling approach. AB - AIM: To explore the association(s) between demographic factors, socioeconomic status (SES), social capital, health-related quality of life (HRQoL), and mental health among residents of Tehran, Iran. METHODS: The pooled data (n=31519) were extracted from a population-based survey Urban Health Equity Assessment and Response Tool-2 (Urban HEART-2) conducted in Tehran in 2011. Mental health, social capital, and HRQoL were assessed using the 28-item General Health Questionnaire (GHQ-28), social capital questionnaire, and Short-Form Health Survey (SF-12), respectively. The study used a multistage sampling method. Social capital, HRQoL, and SES were considered as latent variables. The association between these latent variables, demographic factors, and mental health was determined by structural-equation modeling (SEM). RESULTS: The mean age and mental health score were 44.48+/-15.87 years and 23.33+/-11.10 (range, 0-84), respectively. The prevalence of mental disorders was 41.76% (95% confidence interval 41.21-42.30). The SEM model showed that age was directly associated with social capital (P=0.016) and mental health (P=0.001). Sex was indirectly related to mental health through social capital (P=0.018). SES, HRQoL, and social capital were associated both directly and indirectly with mental health status. CONCLUSION: This study suggests that changes in social capital and SES can lead to positive changes in mental health status and that individual and contextual determinants influence HRQoL and mental health. PMID- 26935616 TI - Mapping capacity to conduct health technology assessment in Central, Eastern and South-Eastern Europe. AB - AIM: To provide insights into the capacity to conduct health technology assessment (HTA) in Central, Eastern, and South-Eastern Europe (CESEE), taking account of technical, financial, networking, and human resources. METHODS: An e mail survey of 257 CESEE key informants involved in HTA was undertaken between March and April 2014. Contact e-mail addresses were identified from the internet. The survey questionnaire consisted of 3 sections: i) characteristics of the organization performing HTA, (ii) networking in HTA, and (iii) resources allocated for HTA. RESULTS: The survey was completed by 41 respondents representing a wide range of institutions from CESEE countries (response rate of 19.8%). Less than a quarter of respondents reported that their institutions had HTA-specific budgets, whereas the majority indicated that their institutions participated in HTA networks either at domestic or international levels. Although almost half of respondents indicated that their institutions offered HTA training, a shortage in skills training was suggested as the main barrier to HTA. CONCLUSION: This is the first survey to thoroughly assess the state of HTA capacity in the CESEE region. To strengthen HTA capacity, CESEE countries should increase financial, technical, and training resources. To strengthen collaboration, the European Union and other international bodies should assist existing HTA networks in fulfilling their regional activities through leadership, advocacy to local policymakers, funding, and technical assistance. PMID- 26935617 TI - Current state of open access to journal publications from the University of Zagreb School of Medicine. AB - AIMS: To identify the share of open access (OA) papers in the total number of journal publications authored by the members of the University of Zagreb School of Medicine (UZSM) in 2014. METHODS: Bibliographic data on 543 UZSM papers published in 2014 were collected using PubMed advanced search strategies and manual data collection methods. The items that had "free full text" icons were considered as gold OA papers. Their OA availability was checked using the provided link to full-text. The rest of the UZSM papers were analyzed for potential green OA through self-archiving in institutional repository. Papers published by Croatian journals were particularly analyzed. RESULTS: Full texts of approximately 65% of all UZSM papers were freely available. Most of them were published in gold OA journals (55% of all UZSM papers or 85% of all UZSM OA papers). In the UZSM repository, there were additional 52 freely available authors' manuscripts from subscription-based journals (10% of all UZSM papers or 15% of all UZSM OA papers). CONCLUSION: The overall proportion of OA in our study is higher than in similar studies, but only half of gold OA papers are accessible via PubMed directly. The results of our study indicate that increased quality of metadata and linking of the bibliographic records to full texts could assure better visibility. Moreover, only a quarter of papers from subscription-based journals that allow self-archiving are deposited in the UZSM repository. We believe that UZSM should consider mandating all faculty members to deposit their publications in UZSM OA repository to increase visibility and improve access to its scientific output. PMID- 26935618 TI - Survival analysis in clinical practice: analyze your own data using an Excel workbook. PMID- 26935619 TI - Patient autonomy in a digitalized world: supporting patients' autonomous choice. PMID- 26935621 TI - [Not Available]. PMID- 26935620 TI - Exendin-4 protects bone marrow-derived mesenchymal stem cells against oxygen/glucose and serum deprivation-induced apoptosis through the activation of the cAMP/PKA signaling pathway and the attenuation of ER stress. AB - Exendin-4 (ex-4) is a long-acting glucagon-like peptide-1 receptor (GLP-1R) agonist which exerts beneficial effects on glycemic control and promotes cell viability. In the present study, we investigated the anti-apoptotic effects of ex 4, as well as the potential mechanisms responsible for these effects in rat bone marrow-derived mesenchymal stem cells (BM-MSCs) under conditions of oxygen, glucose and serum deprivation (OGD). The apoptosis of the MSCs was induced by subjecting the cells to OGD conditions for 4 h and was detected by Annexin V/PI and Hoechst 33258 staining. The MSCs were pre-conditioned with ex-4 for 12 h prior to being subjected to OGD conditions, and the expression levels of an apoptotic marker (cleaved caspase-3), endoplasmic reticulum (ER) stress markers [phosphorylated (p-)protein kinase RNA-like endoplasmic reticulum kinase (PERK), PERK, binding immunoglobulin protein (BIP), activating transcription factor 4 (ATF-4) and C/EBP homologous protein (CHOP)], as well as those of a survival marker (Bcl-2) were measured by western blot analysis. Furthermore, the mRNA levels of ATF-4 and CHOP were determined by RT-qPCR. ELISA was used to examine the activity of intracellular cAMP. Moreover, the GLP-1R antagonist, exendin9-39 (ex9-39), the protein kinase A (PKA) inhibitor, H89, and small interfering RNA (siRNA) targeting rat ATF-4 and CHOP were co-incubated with the MSCs. The apoptotic rate was markedly diminished following pre-conditioning with ex-4 in a dose-dependent manner (P<0.05). The ER stress markers, p-PERK, BIP, ATF-4 and CHOP, were upregulated in the cells subjected to OGD conditions. Ex-4 pre conditioning significantly decreased the mRNA and protein levels of ATF-4 and CHOP (P<0.05), and increased the activity of intracellular cAMP (P<0.05). Furthermore, the anti-apoptotic effects of ex-4 were almost reversed by treatment with either H89 or ex9-39 (P<0.05); transfection with siRNA-CHOP significantly reduced the apoptotic rate of the MSCs and did not impair the cytoprotective effects of ex-4. Taken together, these findings suggest that ex-4 protects rat BM MSCs from OGD-induced apoptosis through the activation of the PKA/cAMP pathway and the attenuation of the ER stress signaling pathway. Ex-4 may thus prove to be a therapeutic agent with the potential to improve the viability of MSCs in the ischemic milieu, and consequently, to optimize the therapeutic effects of MSC therapy in acute myocardial infarction. PMID- 26935622 TI - [Preface]. PMID- 26935623 TI - [Overview]. PMID- 26935625 TI - [Inherited bone marrow failure syndromes]. AB - Inherited bone marrow failure syndromes comprise a series of disorders caused by various gene mutations. Genetic tests were formerly difficult to perform because of the large size and number of causative genes. However, recent advances in next generation sequencing has enabled simultaneous testing of all causative genes to be performed at an acceptable cost. We collaboratively conducted a series of whole-exome sequencing studies of patients with inherited bone marrow failure syndromes and discovered RPS27/RPL27 and FANCT as causative genes of Diamond Blackfan anemia and Fanconi anemia, respectively. Furthermore, we established a target gene sequencing system to cover 189 genes associated with pediatric blood diseases to assist genetic diagnoses in clinical practice. In this review, discovery of new causative genes and possible roles of next-generation sequencing in the genetic diagnosis of inherited bone marrow failure syndromes are discussed. PMID- 26935624 TI - [Acquired aplastic anemia]. AB - Idiopathic aplastic anemia (AA) is an autoimmune disease caused by T cells. An increase in the percentage of glycosylphosphatidylinositol-anchored protein deficient cells and the presence of HLA allele-lacking leukocytes due to 6pUPD provide indirect evidence that T cells contribute to the pathophysiology of AA. Recent studies have revealed the presence of somatic mutations in MDS and/or AML candidate genes in one third of AA patients. Current treatment topics include the efficacy of eltrombopag for AA found to be refractory to immunosuppressive therapy as well as for newly diagnosed AA when administered in combination with ATG and cyclosporine. Furthermore, improved outcomes of allogeneic bone marrow transplantation from unrelated donors using reduced-intensity conditioning regimens have been obtained with eltrombopag. Fludarabine-based regimens are now the mainstream approach for preconditioning and have lowered the transplant related mortality rate. However, new problems such as mixed chimerism and secondary graft failure have arisen. Attempts to prevent GVHD more efficiently by including ATG and alemtuzumab in the preconditioning regimen are being investigated. PMID- 26935626 TI - [Iron-refractory iron deficiency anemia]. AB - The major causes of iron deficiency anemia (IDA) include iron loss due to bleeding, increased iron requirements, and decreased iron absorption by the intestine. The most common cause of IDA in Japanese women is iron loss during menstruation. Autoimmune atrophic gastritis and Helicobacter pylori infection can also cause IDA by reducing intestinal iron absorption. In addition to these common etiologies, germline mutations of TMPRSS6 can cause iron-refractory IDA (IRIDA). TMPRSS6 encodes matriptase-2, a membrane-bound serine protease primarily expressed in the liver. Functional loss of matriptase-2 due to homozygous mutations results in an increase in the expression of hepcidin, which is the key regulator of systemic iron homeostasis. The serum hepcidin increase in turn leads to a decrease in iron supply from the intestine and macrophages to erythropoietic cells. IRIDA is microcytic and hypochromic, but decreased serum ferritin is not observed as in IDA. IRIDA is refractory to oral iron supplementation, but does respond to intravenous iron supplementation to some extent. Because genetic testing is required for the diagnoses of IRIDA, a considerable number of cases may go undiagnosed and may thus be overlooked. PMID- 26935627 TI - [Progress in the clinical management of pure red cell aplasia and future prospects]. AB - Pure red cell aplasia (PRCA) is a type of bone marrow failure syndrome (stem cell failure) and is characterized by severe normocytic, normochromic anemia associated with reticulocytopenia and the absence of erythroblasts in otherwise normal bone marrow. The acquired form of chronic PRCA may present as a primary hematological disease in the absence of any other diseases or secondary to thymoma, lymphoproliferative disorders, infections and collagen vascular diseases or after exposure to various drugs or chemicals. Thus, identifying the cause of PRCA is crucial for the optimal management of this disorder. Idiopathic PRCA and secondary PRCA refractory to treatment of the underlying diseases are both generally treated as an immune-mediated disorder. Most chronic PRCA patients successfully treated with immunosuppressants require maintenance immunosuppressive therapy. Refractoriness to induction immunosuppressive therapy and relapse of anemia may be risk factors for death in idiopathic, thymoma associated and large granular lymphocyte leukemia-associated PRCA. The major causes of death are infections and organ failure. Standard treatment options for refractory and relapsed PRCA patients and the immunopathophysiology of acquired chronic PRCA merit further research. PMID- 26935628 TI - [Overview]. PMID- 26935629 TI - [Acute myeloid leukemia: molecular pathogenesis and new therapeutic strategies]. AB - Acute myeloid leukemia (AML) is a form of blood cancer that is characterized by the rapid growth of abnormal myeloid cells. Although the general therapeutic strategy in patients with AML has not changed substantially in more than 30 years, remarkable progress has been achieved in understanding the pathogenesis of AML. Genome-wide analyses have revealed genetic mutations and epigenetic dysregulations that are present in AML cells. Studies of leukemia stem cells have clarified their complex properties and functions in the development of AML, and have also led to the recent identification of pre-leukemic hematopoietic stem cells that undergo clonal evolution in healthy people. Translation of these new findings into the clinical setting is just beginning. This article focuses on recent advances in basic research on the molecular pathogenesis of AML. New strategies under investigation, including epigenetic therapies and immunotherapies, to provide better therapeutic options for AML patients, are also summarized. PMID- 26935630 TI - [Chemokines in chronic myeloid leukemia]. AB - Several tyrosine kinase inhibitors have been developed to target the BCR-ABL fusion gene, a pathognomonic genetic change in chronic myeloid leukemia (CML), and have dramatically improved the outcomes of CML patients. BCR-ABL-expressing CML cells compete with normal hematopoietic cells over the limited space in the bone marrow to proliferate. Moreover, CML cells can gain resistance to tyrosine kinase inhibitors by utilizing bone marrow microenvironments. Thus, in order to develop a novel treatment strategy for CML, it is necessary to elucidate the cellular and molecular basis underlying the interactions between CML and normal hematopoietic cells. Herein, we discuss the roles of chemokines, particularly CXCL12 and CCL3, in reconstruction processes of bone marrow microenvironments by CML cells and the possibility of novel treatment modalities against CML, based on targeting these chemokines. PMID- 26935631 TI - [Juvenile myelomonocytic leukemia (JMML): recent advances in molecular pathogenesis and treatment]. AB - Juvenile myelomonocytic leukemia (JMML) is a rare myelodysplastic/myeloproliferative disorder that occurs during infancy and early childhood; this disorder is characterized by hypersensitivity of the myeloid progenitor cells to granulocyte-macrophage colony-stimulating factor (GM-CSF) in vitro. JMML usually involves somatic and/or germline mutations in the genes of the RAS pathway, including PTPN11, NRAS, KRAS, NF1, and CBL, in the leukemic cells. Recently, additional genetic and/or epigenetic alterations have been identified in JMML, and these alterations appear to be prognostic indicators. Moreover, analyses of JMML stem cells and induced pluripotent stem cells (iPSCs) technology are expected to identify new targets for therapeutic interventions. Almost all patients with JMML experience an aggressive clinical course, and hematopoietic stem cell transplantation (HSCT) is the only curative treatment. The most suitable therapeutic regimen after diagnosis and the optimal conditioning regimen prior to HSCT have yet to be identified, though several clinical trials have been initiated worldwide. Taken together, these new findings indicate that genetic and/or epigenetic alteration-specific risk management may be introduced, and that suitable pre- or post-allogeneic HSCT treatments which are less toxic and can improve outcomes will be developed in the near future. PMID- 26935632 TI - [Chronic myelomonocytic leukemia (CMML): recent advances in molecular pathogenesis and treatment]. AB - Chronic myelomonocytic leukemia (CMML) is one of the clonal myeloid neoplasms characterized by persistent monocytosis and dysplasia of myeloid lineage cells. Thus, CMML includes characteristics of both myelodysplastic syndromes and myeloproliferative neoplasms. Clinical features of CMML are quite heterogeneous. There are no disease-specific gene mutations although more than 90% of CMML patients have one or more gene mutations, and most mutations detected in CMML are also seen in other myeloid malignancies. Among these mutations, ASXL1 mutations negatively affect the disease outcome. Moreover, it has been clarified that the clonal architecture of CMML is characterized by linear accumulation of mutations. Recently, international consortium perspectives in diagnostic recommendations and response criteria were published, and clinical reports on CMML, including a new diagnostic method, molecularly integrated CMML-specific prognostic models and therapeutic trials, are increasing. However, despite the existence of several prognostic models of CMML, formal guidelines for the management of CMML are still lacking. An international consortium proposal of uniform guidelines for management of CMML based on a uniform prognostic scoring system is eagerly awaited. PMID- 26935633 TI - [Recent advances in molecular pathogenesis of myeloproliferative neoplasms]. AB - Myeloproliferative neoplasms (MPNs) are characterized by activation of the JAK STAT pathway due to driver mutations including JAK2V617F and MPLW515K/L, as well as to mutations in CALR. Driver mutations phosphorylate multiple STAT proteins that lead to proliferations, differentiations and cytokine secretions of various hematopoietic cells. However, hematopoietic cells carrying JAK2V617F, which causes excessive cellular proliferation and differentiation, do not necessarily have a clonal growth advantage in terms of hematopoietic repopulation. Alterations of epigenetic modifiers involving histone modifications and DNA methylations, which often co-exist with driver mutations and eventually upregulate several oncogenes, may play crucial roles in long-term clinical courses characterized by progression to myelofibrosis or acute leukemia in MPNs. In addition to JAK2 inhibition, molecules altered by abnormal epigenetic modifications may be worth exploring as potential new therapeutic targets in MPNs. PMID- 26935634 TI - [Correlation between serum L-carnitine concentration and neutrophil engraftment in patients treated with cord blood transplantation]. AB - In cord blood transplantation (CBT), the amount of time elapsing until hematological engraftment has effects on the transplantation results. Carnitine deficiency has been reported to cause erythropoietin refractory anemia in chronic hemodialysis patients and thrombocytopenia or leukopenia of cirrhosis, and carnitine supplementation can improve hematopoiesis in patients with hepatic or renal failure. Patients who receive CBT may suffer from carnitine deficiency, but no studies have investigated the carnitine status of such patients. Herein, we determined the concentration of free carnitine (FC) and investigated the correlation between FC and engraftment in patients who received CBT. Twenty-three patients who received CBT at our hospital during the period from April 2013 to January 2015 were enrolled in this study. One patient was excluded because of graft failure, such that 22 patients were ultimately evaluable. FC concentrations of the patients were sequentially monitored at 4 time points (before conditioning therapy, day 0, day 7, and day 14), basic laboratory data were collected, and their correlations with engraftment were analyzed. FC concentrations of the patients were generally low (before conditioning therapy: 33.1, day 0: 43.2, day 7: 38.3, and day 14: 37.8 MUmol/l). Significant inverse correlations were observed between FC concentrations and the number of days required for neutrophil engraftment on day 0 and day 14 (before conditioning therapy: P=0.15, r=-0.33, day 0: P=0.04, r=-0.43, day 7: P=0.30, r=-0.23, and day 14: P=0.01, r=-0.55). These results suggest carnitine to be an important nutrient that promotes hematopoietic recovery after CBT. PMID- 26935635 TI - [Diffuse large B-cell lymphoma developed newly after 9-year remission of a follicular lymphoma]. AB - Follicular lymphoma (FL) occasionally transforms into diffuse large B-cell lymphoma (DLBCL). This is generally associated with a poor prognosis, necessitating more potent chemotherapy as salvage treatment. However, de novo DLBCL, but not DLBCL transformed from FL, can be treated as primary DLBCL. We encountered a 63-year-old woman who developed DLBCL after a 9-year remission following treatment of FL. To differentiate DLBCL transformed from FL and de novo DLBCL, VDJ gene rearrangements in IgH were examined by PCR using biopsy specimens from both lymphomas. The results revealed the two lymphomas to be different clones. Thus, she was diagnosed with primary DLBCL. Therefore, routine chemotherapy and radiation therapy were conducted for the primary DLBCL with a limited stage, achieving complete remission. Treatment based on the clonality assessment of VDJ gene rearrangements is potentially useful for treating late relapse of B-cell lymphoma according to the pathological conditions of patients. PMID- 26935636 TI - [Cellulitis due to Achromobacter xylosoxidans during bortezomib therapy for multiple myeloma]. AB - Achromobacter xylosoxidans (A. xylosoxidans) is a non-fermentative gram-negative rod. This organism is reportedly a causative pathogen of bacteremia mainly in patients with hematological disorders. However, only one case of cellulitis due to A. xylosoxidans associated with hematological malignancy has been reported. An 80-year-old man developed cellulitis and subsequent bacteremia due to A. xylosoxidans during bortezomib therapy for multiple myeloma. Although his condition was serious enough to require intensive care, he fully recovered with appropriate antimicrobial agents and supportive care. The isolate was broadly resistant to antimicrobial agents, including cefepime, amikacin, and ciprofloxacin. Therefore, the identification and selection of appropriate antimicrobial agents were considered to have contributed to the successful outcome in this case. Physicians should recognize A. xylosoxidans as a possible pathogen causing cellulitis and secondary bacteremia, as well as being aware of its broad resistance to antimicrobial agents. PMID- 26935637 TI - [Successful induction therapy for acute myeloid leukemia complicated with brain hemorrhage and hyperleukocytosis]. AB - Adequate management of hyperleukocytosis in patients with acute myeloid leukemia (AML) is essential for the prevention of life-threatening complications related to leukostasis and tumor lysis syndrome, but the optimal therapeutic strategy remains unclear. We report a 15-year-old girl with newly diagnosed AML who had extreme hyperleukocytosis (leukocyte count at diagnosis, 733,000/MUl) leading to a brain hemorrhage. She was initially treated with hydroxyurea, but presented with brain hemorrhage due to leukostasis and underwent leukapheresis emergently with intensive care and mechanical ventilation. Full-dose standard induction chemotherapy was initiated after achieving gradual cytoreduction (leukocyte count, 465,000/MUl) within five days after the initiation of therapy with hydroxyurea and leukapheresis. These treatments were successful and she experienced no complications. The patient ultimately recovered fully and was discharged with complete remission of AML. Although the effects of hydroxyurea and leukapheresis in the setting of hyperleukocytosis are still controversial, these initial treatments may contribute to successful bridging therapy followed by subsequent induction chemotherapy, especially in AML cases with extreme hyperleukocytosis or life-threatening leukostasis. PMID- 26935640 TI - The gender gap in first authorship of research papers. PMID- 26935643 TI - Drug Tolerance: A Known Unknown in Translational Neuroscience. AB - In neuropsychiatric drug development, the rate of successful translation of preclinical to clinical efficacy has been disappointingly low. Tolerance, defined as a loss of efficacy with repeated drug exposure, is rarely addressed as a potential source of clinical failures. In this review, we argue that preclinical methods of tolerance development may have predictive validity and, therefore, inclusion of studies using repeated drug exposure early during the drug discovery and development process should serve to mitigate a proportion of clinical failures. Our analysis indicates that many published preclinical efficacy studies in the neuropsychiatry arena are conducted with acute drug administration only. Furthermore, specifically in the field of schizophrenia, there are several examples where tolerance development may be suspected as a factor contributing to translational failures. These and other examples highlight the need for built-for purpose tolerance studies to be conducted, regardless of the target interaction mode of the drugs (i.e., agonist or antagonist, allosteric or orthosteric). We suggest that, for compounds that have failed in clinical studies, preclinical efficacy data sets need to be revisited to estimate the potential impact of tolerance development, one of the most significant known unknowns in the preclinical-to-clinical translation. PMID- 26935642 TI - MiR-608 inhibits the migration and invasion of glioma stem cells by targeting macrophage migration inhibitory factor. AB - Glioma stem cells (GSCs) contribute to the malignant biological behavior of these tumors and have also been shown to be resistant to radiation and chemotherapy. Recently, a variety of microRNAs (miRNAs) has been found to present altered expression and to play an important oncogenic role or tumor-suppressive function in cancer stem cells (CSCs). microRNA-608 (miR-608) is one of the newly discovered microRNAs, and its biological functions remain unclear. Human macrophage migration inhibitory factor (MIF) is a well known oncogene associated with tumor recurrence and the poor prognosis of gliomas. In the present study, we found that miR-608 negatively regulated the gene expression of MIF at the post transcriptional level and plays a tumor-suppressive role by targeting MIF in GSCs. We found that miR-608 expression was significantly downregulated and the expression levels of the MIF gene and protein showed an increase in the GSCs. miR 608 overexpression significantly attenuated the proliferation, migration and invasion, and induced the apoptosis of GSCs. The dual-luciferase reporter system revealed that the 3'UTR of MIF is a direct target of miR-608, and miR-608 negatively regulates the gene expression of MIF at the post-transcriptional level by targeting its 3'UTR. Furthermore, we demonstrated that miR-608 overexpression inhibited the malignant behavior of GSCs by downregulating MIF. Western blot results showed that the inhibition of MIF resulted in the inactivation of the PI3K/AKT and JNK pathways. These results demonstrate that miR-608 acts as a potential tumor suppressor and provide insight into new therapeutic targets for malignant glioma. PMID- 26935641 TI - Vanillin and 4-hydroxybenzyl alcohol promotes cell proliferation and neuroblast differentiation in the dentate gyrus of mice via the increase of brain-derived neurotrophic factor and tropomyosin-related kinase B. AB - 4-Hydroxy-3-methoxybenzaldehyde (vanillin) and 4-hydroxybenzyl alcohol (4-HBA) are well-known phenolic compounds, which possess various therapeutic properties and are widely found in a variety of plants. In the present study, the effects of vanillin and 4-HBA were first investigated on cell proliferation, as well as neuronal differentiation and integration of granule cells in the dentate gyrus (DG) of adolescent mice using Ki-67, doublecortin (DCX) immunohistochemistry and 5-bromo-2'-deoxyuridine (BrdU)/feminizing Locus on X 3 (NeuN) double immunofluorescence. In both the vanillin and 4-HBA groups, the number of Ki-67+ cells, DCX+ neuroblasts and BrdU+/NeuN+ neurons were significantly increased in the subgranular zone of the DG, as compared with the vehicle group. In addition, the levels of brain-derived neurotrophic factor (BDNF) and tropomyosin-related kinase B (TrkB), a BDNF receptor, were significantly increased in the DG in the vanillin and 4-HBA groups compared with the vehicle group. These results indicated that vanillin and 4-HBA enhanced cell proliferation, neuroblast differentiation and integration of granule cells in the DG of adolescent mice . These neurogenic effects of vanillin and 4-HBA may be closely associated with increases in BDNF and TrkB. PMID- 26935644 TI - Anthelmintic activity of chicory (Cichorium intybus): in vitro effects on swine nematodes and relationship to sesquiterpene lactone composition. AB - Chicory is a perennial crop that has been investigated as a forage source for outdoor-reared ruminants and pigs, and has been reported to have anthelmintic properties. Here, we investigated in vitro anthelmintic effects of forage chicory extracts against the highly prevalent swine parasites Ascaris suum and Oesophagostomum dentatum. Methanol extracts were prepared and purified from two different cultivars of chicory (Spadona and Puna II). Marked differences were observed between the anthelmintic activity of extracts from the two cultivars. Spadona extracts had potent activity against A. suum third (L3) and fourth (L4) - stage larvae, as well as O. dentatum L4 and adults, whereas Puna II extracts had less activity against A. suum and no activity towards O. dentatum L4. Transmission-electron microscopy of A. suum L4 exposed to Spadona extracts revealed only subtle changes, perhaps indicative of a specific anthelmintic effect rather than generalized toxicity. Ultra-high liquid chromatography-mass spectrometry analysis revealed that the purified extracts were rich in sesquiterpene lactones (SL), and that the SL profile differed significantly between cultivars. This is the first report of anthelmintic activity of forage chicory towards swine nematodes. Our results indicate a significant anthelmintic effect, which may possibly be related to SL composition. PMID- 26935645 TI - Pyropia yezoensis glycoprotein regulates antioxidant status and prevents hepatotoxicity in a rat model of D-galactosamine/lipopolysaccharide-induced acute liver failure. AB - The present study aimed to investigate the effects of Pyropia yezoensis glycoprotein (PYGP) on hepatic antioxidative enzyme activity and mitogen activated protein kinase (MAPK) phosphorylation in a rat model of D galactosamine/lipopolysaccharide (D-GalN/LPS)-induced hepatotoxicity. Glutamic oxaloacetic transaminase (GOT) and glutamic-pyruvic transaminase (GPT) were measured to determine the severity of hepatotoxicity. Treatment with D-GalN/LPS significantly increased the GOT, GPT and lipid peroxidation levels, and decreased the antioxidant capacity of the rats. Treatment with PYGP (150 and 300 mg/kg/body weight) decreased the levels of GOT, GPT and lipid peroxidation levels. The activities of antioxidative enzymes, including catalase, glutathione S transferase and glutathione were upregulated following PYGP treatment. Furthermore, D-GalN/LPS-induced MAPK phosphorylation, and inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) protein expression were downregulated by PYGP. These results indicated that PYGP may exert hepatoprotective effects via the upregulation of antioxidative enzymes, and the downregulation of the MAPK signaling pathway and iNOS and COX-2 expression. PMID- 26935646 TI - Electronic Health Record Patient Portal Adoption by Health Care Consumers: An Acceptance Model and Survey. AB - BACKGROUND: The future of health care delivery is becoming more citizen centered, as today's user is more active, better informed, and more demanding. Worldwide governments are promoting online health services, such as electronic health record (EHR) patient portals and, as a result, the deployment and use of these services. Overall, this makes the adoption of patient-accessible EHR portals an important field to study and understand. OBJECTIVE: The aim of this study is to understand the factors that drive individuals to adopt EHR portals. METHODS: We applied a new adoption model using, as a starting point, Ventkatesh's Unified Theory of Acceptance and Use of Technology in a consumer context (UTAUT2) by integrating a new construct specific to health care, a new moderator, and new relationships. To test the research model, we used the partial least squares (PLS) causal modelling approach. An online questionnaire was administrated. We collected 360 valid responses. RESULTS: The statistically significant drivers of behavioral intention are performance expectancy (beta=.200; t=3.619), effort expectancy (beta=.185; t=2.907), habit (beta=.388; t=7.320), and self-perception (beta=.098; t=2.285). The predictors of use behavior are habit (beta=0.206; t=2.752) and behavioral intention (beta=0.258; t=4.036). The model explained 49.7% of the variance in behavioral intention and 26.8% of the variance in use behavior. CONCLUSIONS: Our research helps to understand the desired technology characteristics of EHR portals. By testing an information technology acceptance model, we are able to determine what is more valued by patients when it comes to deciding whether to adopt EHR portals or not. The inclusion of specific constructs and relationships related to the health care consumer area also had a significant impact on understanding the adoption of EHR portals. PMID- 26935647 TI - A new histological therapeutic classification system to predict eradicated and residual lymph nodes in breast cancer after neoadjuvant chemotherapy. AB - The indication for neoadjuvant chemotherapy (NAC) has recently broadened to include its use in the treatment of initial stage breast cancer. Axillary lymph node metastasis after NAC in breast cancer is a poor prognostic factor. Thus, the prediction of lymph node metastasis is important to estimate the prognosis of breast cancer patients after NAC. Therefore, we focused on residual carcinoma patterns of primary breast tumors after NAC and examined the correlation between the patterns and lymph node metastasis. In this study, we examined 50 breast cancer specimens and associated dissected lymph nodes after NAC. We divided 40 cases into an eradicated lymph node group and a residual lymph node group to analyze residual carcinoma patterns of primary breast tumors. Residual carcinoma patterns were classified according to the cell density of carcinoma cells: dense, focal/nested and sporadic/in-situ. There were significant differences in residual carcinoma patterns (P<0.01) among the three pattern groups. There was a high incidence of dense patterns in the residual lymph node group and a high incidence of sporadic/in-situ patterns in the eradicated lymph node group. Analysis of residual carcinoma patterns of primary breast tumors and clinicopathological factors demonstrated that there were significant differences in tumor reduced ratio on CT (P<0.001), primary tumor area before NAC (P<0.01), primary tumor area after NAC (P<0.00001), intrinsic subtype (P<0.01), Ki-67 labeling index (P<0.01), histological grade (P<0.05) and mitotic count (P<0.01) between the dense and non dense groups. Therefore, our results suggest that the residual carcinoma pattern is useful for predicting eradicated or residual lymph nodes and the malignant potential in breast cancer after NAC. PMID- 26935648 TI - Enhanced external quantum efficiency in GaN-based vertical-type light-emitting diodes by localized surface plasmons. AB - Enhancement of the external quantum efficiency of a GaN-based vertical-type light emitting diode (VLED) through the coupling of localized surface plasmon (LSP) resonance with the wave-guided mode light is studied. To achieve this experimentally, Ag nanoparticles (NPs), as the LSP resonant source, are drop casted on the most top layer of waveguide channel, which is composed of hydrothermally synthesized ZnO nanorods capped on the top of GaN-based VLED. Enhanced light-output power and external quantum efficiency are observed, and the amount of enhancement remains steady with the increase of the injected currents. To understand the observations theoretically, the absorption spectra and the electric field distributions of the VLED with and without Ag NPs decorated on ZnO NRs are determined using the finite-difference time-domain (FDTD) method. The results prove that the observation of enhancement of the external quantum efficiency can be attributed to the creation of an extra escape channel for trapped light due to the coupling of the LSP with wave-guided mode light, by which the energy of wave-guided mode light can be transferred to the efficient light scattering center of the LSP. PMID- 26935649 TI - Have we had a paradigm change in the treatment of rheumatoid arthritis after the American Congress of Rheumatology 2015? PMID- 26935650 TI - Closing the pregnancy-related information gap for women with rheumatoid arthritis. PMID- 26935651 TI - Intranasal Delivery of Recombinant AAV Containing BDNF Fused with HA2TAT: a Potential Promising Therapy Strategy for Major Depressive Disorder. AB - Depression is a disturbing psychiatric disease with unsatisfied therapy. Not all patients are sensitive to anti-depressants currently in use, side-effects are unavoidable during therapy, and the cases with effectiveness are always accompanied with delayed onset of clinical efficacy. Delivering brain-derived neurotrophic factor (BDNF) to brain seems to be a promising therapy. However, a better approach to delivery is still rudimentary. The purpose of our present work is to look for a rapid-onset and long-lasting therapeutic strategy for major depressive disorder (MDD) by effectively delivering BDNF to brain. BDNF, fused with cell-penetrating peptides (TAT and HA2), was packaged in adenovirus associated virus (AAV) to construct the BDNF-HA2TAT/AAV for intranasally delivering BDNF to central nervous system (CNS) via nose-brain pathway. Intranasal administration of BDNF-HA2TAT/AAV to normal mice displayed anti depression effect in forced swimming test when the delivery lasted relatively longer. The AAV applied to mice subjected to chronic mild stress (CMS) through intranasal administration for 10 days also alleviated depression-like behaviors. Western-blotting analysis revealed that BDNF-HA2TAT/AAV nasal administration enhanced hippocampal BDNF content. These results indicate intranasal administration of constructed BDNF-HA2TAT/AAV exerts anti-depression effect in CMS mice by increasing hippocampal BDNF, suggesting that this strategy holds a promising therapeutic potential for MDD. PMID- 26935653 TI - Spinal Cord authors have a moral obligation to share their data. PMID- 26935652 TI - Neurophysiological responses to unpleasant stimuli (acute electrical stimulations and emotional pictures) are increased in patients with schizophrenia. AB - Patients with schizophrenia have often been described as insensitive to nociceptive signals, but objective evidence is sparse. We address this question by combining subjective behavioral and objective neurochemical and neurophysiological measures. The present study involved 21 stabilized and mildly symptomatic patients with schizophrenia and 21 control subjects. We applied electrical stimulations below the pain threshold and assessed sensations of pain and unpleasantness with rating scales, and Somatosensory Evoked Potentials (SEPs/EEG). We also measured attention, two neurochemical stress indices (ACTH/cortisol), and subjective VEPs/EEG responses to visual emotional stimuli. Our results revealed that, subjectively, patients' evaluations do not differ from controls. However, the amplitude of EEG evoked potentials was greater in patients than controls as early as 50 ms after electrical stimulations and beyond one second after visual processing of emotional pictures. Such responses could not be linked to the stress induced by the stimulations, since stress hormone levels were stable. Nor was there a difference between patients and controls in respect of attention performance and tactile sensitivity. Taken together, all indices measured in patients in our study were either heightened or equivalent relative to healthy volunteers. PMID- 26935654 TI - A comparison of high vs standard tidal volumes in ventilator weaning for individuals with sub-acute spinal cord injuries: a site-specific randomized clinical trial. PMID- 26935655 TI - The association between chronological age, age at injury and employment: Is there a mediating effect of secondary health conditions? PMID- 26935657 TI - Oscillation control of carbon nanotube mechanical resonator by electrostatic interaction induced retardation. AB - Despite the superb intrinsic properties of carbon nanotube mechanical resonators, the quality factors at room temperature are 1,000 or less, even in vacuum, which is much lower than that of mechanical resonators fabricated using a top-down approach. This study demonstrates the improvement of the quality factor and the control of nonlinearity of the mechanical resonance of the cantilevered nanotube by electrostatic interaction. The apparent quality factor of the nanotube supported by insulator is improved drastically from approximately 630 to 3200 at room temperature. Results show that retardation of the electrostatic force induced by the contact resistance between the nanotube and the insulator support improves the quality factor. Finite element method calculation reveals that the nonuniform pileup charge on the insulator support strongly influences the nonlinearity of the resonance. PMID- 26935656 TI - Human acetyl-CoA:glucosamine-6-phosphate N-acetyltransferase 1 has a relaxed donor specificity and transfers acyl groups up to four carbons in length. AB - Glucosamine-6-phosphate N-acetyltransferase1 (GNA1) catalyses the transfer of an acetyl group from acetyl coenzyme A (AcCoA) to glucosamine-6-phosphate (GlcN6P) to form N-acetylglucosamine-6-phosphate (GlcNAc6P), which is an essential intermediate in UDP-GlcNAc biosynthesis. An analog of GlcNAc, N butyrylglucosamine (GlcNBu) has shown healing properties for bone and articular cartilage in animal models of arthritis. The goal of this work was to examine whether GNA1 has the ability to transfer a butyryl group from butyryl-CoA to GlcN6P to form GlcNBu6P, which can then be converted to GlcNBu. We developed fluorescent and radioactive assays and examined the donor specificity of human GNA1. Acetyl, propionyl, n-butyryl, and isobutyryl groups were all transferred to GlcN6P, but isovaleryl-CoA and decanoyl-CoA did not serve as donor substrates. Site-specific mutants were produced to examine the role of amino acids potentially affecting the size and properties of the AcCoA binding pocket. All of the wild type and mutant enzymes showed activities of both acetyl and butyryl transfer and can therefore be used for the enzymatic synthesis of GlcNBu for biomedical applications. PMID- 26935658 TI - Future present. PMID- 26935659 TI - Unintended consequences. PMID- 26935660 TI - Brain power. PMID- 26935673 TI - Speedier Arctic data as warm winter shrinks sea ice. PMID- 26935661 TI - Stop needless dispute of science in the courts. PMID- 26935674 TI - India's budget keeps dream of genomics hub alive. PMID- 26935675 TI - Conflicting laws threaten Ukrainian science. PMID- 26935676 TI - Spectre of Ebola haunts Zika response. PMID- 26935677 TI - Epic El Nino yields massive data trove. PMID- 26935678 TI - Can fracking power Europe? PMID- 26935679 TI - The nanolight revolution is coming. PMID- 26935680 TI - Research management: Five years on from Fukushima. PMID- 26935681 TI - Successful test drive for space-based gravitational-wave detector. PMID- 26935682 TI - Correction. PMID- 26935686 TI - Transparency: an opaque illustration. PMID- 26935687 TI - Research data: Japan justifies whaling stance. PMID- 26935688 TI - Transparency: issues are not that simple. PMID- 26935689 TI - Policy: NIH push to stop sexual harassment. PMID- 26935690 TI - Animal research: Australians rush to reject primate bill. PMID- 26935691 TI - Organic chemistry: Reactions triggered electrically. PMID- 26935693 TI - Stem cells: Dietary fat promotes intestinal dysregulation. PMID- 26935694 TI - Space science: Cosmic rays beyond the knees. PMID- 26935695 TI - High-fat diet enhances stemness and tumorigenicity of intestinal progenitors. AB - Little is known about how pro-obesity diets regulate tissue stem and progenitor cell function. Here we show that high-fat diet (HFD)-induced obesity augments the numbers and function of Lgr5(+) intestinal stem cells of the mammalian intestine. Mechanistically, a HFD induces a robust peroxisome proliferator-activated receptor delta (PPAR-delta) signature in intestinal stem cells and progenitor cells (non-intestinal stem cells), and pharmacological activation of PPAR-delta recapitulates the effects of a HFD on these cells. Like a HFD, ex vivo treatment of intestinal organoid cultures with fatty acid constituents of the HFD enhances the self-renewal potential of these organoid bodies in a PPAR-delta-dependent manner. Notably, HFD- and agonist-activated PPAR-delta signalling endow organoid initiating capacity to progenitors, and enforced PPAR-delta signalling permits these progenitors to form in vivo tumours after loss of the tumour suppressor Apc. These findings highlight how diet-modulated PPAR-delta activation alters not only the function of intestinal stem and progenitor cells, but also their capacity to initiate tumours. PMID- 26935697 TI - Electrostatic catalysis of a Diels-Alder reaction. AB - It is often thought that the ability to control reaction rates with an applied electrical potential gradient is unique to redox systems. However, recent theoretical studies suggest that oriented electric fields could affect the outcomes of a range of chemical reactions, regardless of whether a redox system is involved. This possibility arises because many formally covalent species can be stabilized via minor charge-separated resonance contributors. When an applied electric field is aligned in such a way as to electrostatically stabilize one of these minor forms, the degree of resonance increases, resulting in the overall stabilization of the molecule or transition state. This means that it should be possible to manipulate the kinetics and thermodynamics of non-redox processes using an external electric field, as long as the orientation of the approaching reactants with respect to the field stimulus can be controlled. Here, we provide experimental evidence that the formation of carbon-carbon bonds is accelerated by an electric field. We have designed a surface model system to probe the Diels Alder reaction, and coupled it with a scanning tunnelling microscopy break junction approach. This technique, performed at the single-molecule level, is perfectly suited to deliver an electric-field stimulus across approaching reactants. We find a fivefold increase in the frequency of formation of single molecule junctions, resulting from the reaction that occurs when the electric field is present and aligned so as to favour electron flow from the dienophile to the diene. Our results are qualitatively consistent with those predicted by quantum-chemical calculations in a theoretical model of this system, and herald a new approach to chemical catalysis. PMID- 26935698 TI - Upper-plate controls on co-seismic slip in the 2011 magnitude 9.0 Tohoku-oki earthquake. AB - The March 2011 Tohoku-oki earthquake was only the second giant (moment magnitude Mw >= 9.0) earthquake to occur in the last 50 years and is the most recent to be recorded using modern geophysical techniques. Available data place high resolution constraints on the kinematics of earthquake rupture, which have challenged prior knowledge about how much a fault can slip in a single earthquake and the seismic potential of a partially coupled megathrust interface. But it is not clear what physical or structural characteristics controlled either the rupture extent or the amplitude of slip in this earthquake. Here we use residual topography and gravity anomalies to constrain the geological structure of the overthrusting (upper) plate offshore northeast Japan. These data reveal an abrupt southwest-northeast-striking boundary in upper-plate structure, across which gravity modelling indicates a south-to-north increase in the density of rocks overlying the megathrust of 150-200 kilograms per cubic metre. We suggest that this boundary represents the offshore continuation of the Median Tectonic Line, which onshore juxtaposes geological terranes composed of granite batholiths (in the north) and accretionary complexes (in the south). The megathrust north of the Median Tectonic Line is interseismically locked, has a history of large earthquakes (18 with Mw > 7 since 1896) and produced peak slip exceeding 40 metres in the Tohoku-oki earthquake. In contrast, the megathrust south of this boundary has higher rates of interseismic creep, has not generated an earthquake with MJ > 7 (local magnitude estimated by the Japan Meteorological Agency) since 1923, and experienced relatively minor (if any) co-seismic slip in 2011. We propose that the structure and frictional properties of the overthrusting plate control megathrust coupling and seismogenic behaviour in northeast Japan. PMID- 26935701 TI - Brief Admissions During Prolonged Treatment in a Case Involving Borderline Personality Disorder and Posttraumatic Stress Disorder: Use and Functions. AB - BACKGROUND: This study describes the use of brief admissions to a psychiatric ward by a single patient across a period of 7 years. The patient suffered from a borderline personality disorder and a complex posttraumatic stress disorder. OBJECTIVE: The purpose of this study was to describe how brief admission may be used during a long-term treatment process. DESIGN: A single-case descriptive study with triangulation of the data was undertaken. Semistructured interviews were conducted with the patient and the patient's spouse, psychiatrist, ward nurse, and community psychiatric nurse. Other data were retrieved from the medical records of the patient. RESULTS: Four phases could be distinguished in the treatment of the patient: crisis, treatment of posttraumatic stress disorder, treatment of borderline personality disorder, and recovery. The use of brief admissions positively influenced the course of treatment. CONCLUSIONS: Brief admissions were initially used to prevent self-harm and suicide. The goals and functions expanded to prevention of prolonged admission, prevention of dropout from evidence-based therapy, and practicing with newly acquired skills and promotion of autonomy. PMID- 26935702 TI - The Potential Use of Piglets as Human Pediatric Surrogate for Preclinical Pharmacokinetic and Pharmacodynamic Drug Testing. AB - Pediatric drug research is still substandard, not reaching the same quality level as adult drug research. Despite the efforts made by the Food and Drug Administration and European Medicines Agency to reduce off-label use in children, the lack of clinical studies involving the pediatric population still stands. Pharmacokinetic and pharmacodynamics studies (PK/PD) taking growth and maturation into account are necessary to rationalize dosing strategies in children. Currently, traditional animal models such as rats, mice, dogs and primates are used to conduct pharmacokinetic and pharmacodynamic studies, however age-related trials are rather uncommon. Moreover, these species have several shortcomings as animal models, such as a different physiology and anatomy of the gastrointestinal tract in dogs or the ethical aspects for the use of primates. In contrast, piglets might be potential biomedical pediatric animal models because of the good resemblance with humans, anatomically, physiologically and biochemically. This review summarizes the comparative anatomy and physiology and postnatal development of piglets and infants, focusing on six major topics, namely growth, cardiovascular system, gastrointestinal tract, liver, kidney and integument. Furthermore, the application of piglets as animal model in pediatric PK/PD research is discussed. PMID- 26935696 TI - A large light-mass component of cosmic rays at 10(17)-10(17.5) electronvolts from radio observations. AB - Cosmic rays are the highest-energy particles found in nature. Measurements of the mass composition of cosmic rays with energies of 10(17)-10(18) electronvolts are essential to understanding whether they have galactic or extragalactic sources. It has also been proposed that the astrophysical neutrino signal comes from accelerators capable of producing cosmic rays of these energies. Cosmic rays initiate air showers--cascades of secondary particles in the atmosphere-and their masses can be inferred from measurements of the atmospheric depth of the shower maximum (Xmax; the depth of the air shower when it contains the most particles) or of the composition of shower particles reaching the ground. Current measurements have either high uncertainty, or a low duty cycle and a high energy threshold. Radio detection of cosmic rays is a rapidly developing technique for determining Xmax (refs 10, 11) with a duty cycle of, in principle, nearly 100 per cent. The radiation is generated by the separation of relativistic electrons and positrons in the geomagnetic field and a negative charge excess in the shower front. Here we report radio measurements of Xmax with a mean uncertainty of 16 grams per square centimetre for air showers initiated by cosmic rays with energies of 10(17)-10(17.5) electronvolts. This high resolution in Xmax enables us to determine the mass spectrum of the cosmic rays: we find a mixed composition, with a light-mass fraction (protons and helium nuclei) of about 80 per cent. Unless, contrary to current expectations, the extragalactic component of cosmic rays contributes substantially to the total flux below 10(17.5) electronvolts, our measurements indicate the existence of an additional galactic component, to account for the light composition that we measured in the 10(17) 10(17.5) electronvolt range. PMID- 26935699 TI - Pre-fusion structure of a human coronavirus spike protein. AB - HKU1 is a human betacoronavirus that causes mild yet prevalent respiratory disease, and is related to the zoonotic SARS and MERS betacoronaviruses, which have high fatality rates and pandemic potential. Cell tropism and host range is determined in part by the coronavirus spike (S) protein, which binds cellular receptors and mediates membrane fusion. As the largest known class I fusion protein, its size and extensive glycosylation have hindered structural studies of the full ectodomain, thus preventing a molecular understanding of its function and limiting development of effective interventions. Here we present the 4.0 A resolution structure of the trimeric HKU1 S protein determined using single particle cryo-electron microscopy. In the pre-fusion conformation, the receptor binding subunits, S1, rest above the fusion-mediating subunits, S2, preventing their conformational rearrangement. Surprisingly, the S1 C-terminal domains are interdigitated and form extensive quaternary interactions that occlude surfaces known in other coronaviruses to bind protein receptors. These features, along with the location of the two protease sites known to be important for coronavirus entry, provide a structural basis to support a model of membrane fusion mediated by progressive S protein destabilization through receptor binding and proteolytic cleavage. These studies should also serve as a foundation for the structure-based design of betacoronavirus vaccine immunogens. PMID- 26935703 TI - Circulating microRNAs in Hepatocellular Carcinoma: Potential Diagnostic and Prognostic Biomarkers. AB - Hepatocellular carcinoma (HCC) is one of the most common types of malignancies worldwide. There is little information on the mechanisms involved in the pathogenesis of this disease. Diagnosis of HCC at early stages would be crucial for increasing the survival of patients. Circulating miRNAs have emerged as one of the most attractive tools for an early diagnosis of cancers. Various studies have shown that there is an aberrant expression of miRNAs such as miR-25, miR 375, miR-206, miR-223, miR- 92a, miR-222, miR-1, let- 7f and miR-21 in HCC. Circulating and tissue miRNAs have also key roles in the pathogenesis of HCC by affecting several biologically important pathways such as p53, p21, PTEN, PI3K AKT, c-Myc and STAT3. In this review, we summarize the current knowledge on the role of miRNAs in diagnosis, prognosis, and treatment of HCC. PMID- 26935705 TI - Expression, clinical significance and mechanism of Slit2 in papillary thyroid cancer. AB - Thyroid cancer is a common endocrine malignancy. The last decade has seen exciting progress in understanding thyroid cancer molecular pathogenesis. Several major signaling pathways and related molecular derangements have been elucidated, which represent novel diagnostic and prognostic molecular markers for thyroid cancer. Based on the molecular biology of thyroid cancer, a series of therapeutic targets have been developed, which provide unprecedented opportunities. Thus, histological characterization of subgroups of patients and the correct molecular characterization of patients are thought to be key aspects for future clinical management of these patients. In the present study, we identified Slit2 as a prognostic marker for thyroid cancer oncogenesis and recurrence. Mechanistically, Slit2 regulated Warburg effect in thyroid cancer cells through regulation of HIF1alpha and HIF1alpha transcriptional activity. Taken together, our present data uncovered Slit2 as a novel predictive marker for thyroid cancer. The mechanism study indicated that Slit2 regulated the Warburg effect. Additional study on the function of Slit2 in thyroid cancer is required to provide new insights into the potential mechanisms of oncogenesis and recurrence potential of thyroid cancer. PMID- 26935706 TI - Applications of Continuous-Flow Photochemistry in Organic Synthesis, Material Science, and Water Treatment. AB - Continuous-flow photochemistry in microreactors receives a lot of attention from researchers in academia and industry as this technology provides reduced reaction times, higher selectivities, straightforward scalability, and the possibility to safely use hazardous intermediates and gaseous reactants. In this review, an up to-date overview is given of photochemical transformations in continuous-flow reactors, including applications in organic synthesis, material science, and water treatment. In addition, the advantages of continuous-flow photochemistry are pointed out and a thorough comparison with batch processing is presented. PMID- 26935704 TI - Uric acid enhances PKC-dependent eNOS phosphorylation and mediates cellular ER stress: A mechanism for uric acid-induced endothelial dysfunction. AB - The mechanism by which hyperuricemia induced-endothelial dysfunction contributes to cardiovascular diseases (CVDs) is not yet fully understood. In the present study, we used uric acid (UA) to trigger endothelial dysfunction in cultured endothelial cells, and investigated the effects of induced reactive oxygen species (ROS) generation, endoplasmic reticulum (ER) stress induction, and the protein kinase C (PKC)-dependent endothelial nitric oxide synthase (eNOS) signaling pathway. Human umbilical vein endothelial cells (HUVECs) were incubated with 6, 9 or 12 mg/dl UA, ROS scavenger polyethylene glycol-superoxide dismutase (PEG-SOD), ER stress inhibitor 4-phenylbutyric acid (4-PBA), and PKC inhibitor polymyxin B for 6-48 h. Nitric oxide (NO) production, eNOS activity, intracellular ROS, ER stress levels, and the interaction between eNOS and calmodulin (CaM) and cytosolic calcium levels were assessed using fluorescence microscopy and western blot analysis. Apoptosis was assessed by annexin V staining. UA increased HUVEC apoptosis and reduced eNOS activity and NO production in a dose- and time-dependent manner. Intracellular ROS was elevated after 3 h, while ER stress level increased after 6 h. UA did not alter intracellular Ca2+, CaM, or eNOS concentration, or eNOS Ser1177 phosphorylation. However, PKC-dependent eNOS phosphorylation at Thr495 was greatly enhanced, and consequently interaction between eNOS and CaM was reduced. Cellular ROS depletion, ER stress inhibition and PKC activity reduction inhibited the effect of UA on eNOS activity, NO release and apoptosis in HUVECs. Thus, we concluded that UA induced HUVEC apoptosis and endothelial dysfunction by triggering oxidative and ER stress through PKC/eNOS-mediated eNOS activity and NO production. PMID- 26935707 TI - Rapid capillary filling via ion-water interactions over the nanoscale. AB - Giant frictional resistances are grand challenges against the rapid filling of nanoscale capillaries, as encountered in a wide variety of applications ranging from nature to energy. It is commonly believed that partially wettable charged nanocapillaries fill up considerably slower, compared to completely wettable ones, under the influence of a complex interplay between interfacial tension and electrical interactions. In sharp contrast to this common belief, here we discover a new non-intuitive regime of rapid filling of charged capillaries over the nanometer scale, by virtue of which a partially wettable capillary may fill up comparatively faster than a completely wettable one. We attribute the fundamental origin of this remarkable behavior to ion-water interactions over interfacial scales. The underlying novel electro-hydrodynamic mechanism, as unveiled here, may provide deeper insights into the physico-chemical interactions leading to augmentations in the rates of nanocapillary filling over hydrophobic regimes, bearing far-reaching implications in the transport of biological fluids, enhanced oil recovery, and miniaturized energy harvesting applications. PMID- 26935709 TI - [Metatarsalgia: Differential diagnosis and therapy]. AB - Metatarsalgia refers to localized or generalized forefoot pain in the region of the metatarsal heads. Symptoms can be isolated or in combination with accompanying deformities occurring in the forefoot and/or hindfoot. Anamnesis and clinical investigation usually yield to the diagnosis, the underlying cause on the other hand is not always easy to identify. In the foreground of the treatment is the exhaustion of conservative forms of therapy to minimize the symptoms of local pressure increase and callus under the metatarsal heads. In addition, various surgical methods are available, such as corrective osteotomy of the metatarsale bone, soft tissue interventions and the correction of associated deformities. The indications for surgical intervention should be made with caution in order to avoid failures and complaints persisting after surgery. The most common problems are an inadequate indication for surgery, technical problems and insufficient postoperative treatment. PMID- 26935710 TI - Optical extinction and scattering cross sections of plasmonic nanoparticle dimers in aqueous suspension. AB - Absolute extinction and scattering cross sections for gold nanoparticle dimers were determined experimentally using a chemometric approach involving singular value decomposition of the extinction and scattering spectra of slowly aggregating gold nanospheres in aqueous suspension. Quantitative spectroscopic data on plasmonic nanoparticle assemblies in liquid suspension are rare, in particular for particles larger than 40 nm, and in this work we demonstrate how such data can be obtained directly from the aggregating suspension. Our method can analyse, non invasively, the evolution of several sub-populations of nanoparticle assemblies. It may be applied to other self-assembling nanoparticle systems with an evolving optical response. The colloidal systems studied here are based on 20, 50 and 80 nm gold nanospheres in aqueous solutions containing sodium lipoate. In these systems, the reversible dimerisation process can be controlled using pH and ionic strength, and this control is rationalised in terms of DLVO theory. The dimers were identified in suspension by their translational and rotational diffusion through scattering correlation spectroscopy. Moreover, their gigadalton molecular weight was measured using electrospray charge-detection mass spectrometry, demonstrating that mass spectrometry can be used to study nanoparticles assemblies of very high molecular mass. The extinction and scattering cross sections calculated in the discrete-dipole approximation (DDA) agree very well with those obtained experimentally using our approach. PMID- 26935711 TI - Loop Duodenojejunal Bypass with Sleeve Gastrectomy: Comparative Study with Roux en-Y Gastric Bypass in Type 2 Diabetic Patients with a BMI <35 kg/m(2), First Year Results. AB - BACKGROUND: Roux-en-Y gastric bypass (RYGB) has shown good diabetes remission in obese patients with type 2 diabetes mellitus (T2DM), but long-term complications were observed. We developed loop duodenojejunal bypass with sleeve gastrectomy (LDJB-SG) to achieve diabetes remission and avoid the drawbacks of RYGB. We compare 1-year results between LDJB-SG and RYGB with body mass index (BMI) <35 kg/m(2) of T2DM patients. METHODS: We conducted a case-matched study of BMI < 35 kg/m(2) T2DM patients who underwent RYGB and LDJB-SG matching on age, BMI, and duration of diabetes. The 1-year surgical results were compared. RESULTS: Sixty patients were included from March 2010 to August 2012. Thirty patients underwent RYGB and 30 underwent LDJB-SG. The operative time (mean +/- SD) and length of stay (median [IQR]) were significantly longer in the LDJB-SG group than in the RYGB group (127.0 +/- 40.2 vs. 105.0 +/- 64.7 min and 3[3, 4] vs. 3[2, 3] days, respectively). There were no statistical differences between the groups in the mean BMI, fasting plasma glucose, and %HbA1c either at baseline or at 1 year. However, these parameters dropped significantly from the preoperative values (p < 0.01). The level of HOMA-%B at 1 year was significantly higher in the LDJB-SG group than in the RYGB group (p = 0.004). The resolution of comorbidities was similar. Late complications seemed higher in the RYGB group (12 vs. 5, p = 0.08). There were no deaths, but two patients in each group required reoperation. CONCLUSIONS: LDJB-SG was comparable to RYGB in terms of weight loss, glycemic control, and comorbidity resolution in BMI <35 kg/m(2) T2DM patients in the short term. PMID- 26935713 TI - Blood pressure lowering efficacy of coenzyme Q10 for primary hypertension. AB - BACKGROUND: Blood pressure is a commonly measured risk factor for non-fatal and fatal cardiovascular adverse events such as heart attacks and strokes. Clinical trials have suggested that coenzyme Q10, a non-prescription nutritional supplement, can effectively lower blood pressure (BP). When this review was completed and published in October 2009, it concluded that "due to the possible unreliability of the 3 included studies, it is uncertain whether or not coenzyme Q10 reduces blood pressure in the long-term management of primary hypertension." OBJECTIVES: To determine the blood pressure lowering effect of coenzyme Q10 in primary hypertension. SEARCH METHODS: We searched the Hypertension Group Specialised Register (1946 to November 2015), The Cochrane Central Register of Controlled Trials (The Cochrane Library 2015, Issue 10), MEDLINE (1946 to November 2015), MEDLINE In-Process (accessed 10 November 2015), EMBASE (1974 to November 2015), Web of Science (1899 to November 2015), CINAHL (1970 to November 2015), and ClinicalTrials.gov (accessed 10 November 2015). We also searched reference lists of articles for relevant clinical trials in any language. SELECTION CRITERIA: Double blind, randomized, placebo-controlled parallel or cross-over trials evaluating the blood pressure (BP) lowering efficacy of coenzyme Q10 for a duration of at least three weeks, in patients with primary hypertension. DATA COLLECTION AND ANALYSIS: The primary author determined trial inclusion, extracted the data and assessed the risk of bias. The second author independently verified trial inclusion and data extraction. MAIN RESULTS: In this update of the review, one new randomized, controlled cross-over trial with a total of 30 participants was added, and one trial included in the initial review was excluded. Only two of the three included trials were pooled in the meta analysis, as one trial was judged to have an unacceptably high risk of bias. In the meta-analysis of two RCTs (50 participants), coenzyme Q10 did not significantly change systolic BP: -3.68 mm Hg (95% confidence interval (CI) -8.86 to 1.49), or diastolic BP: -2.03 mm Hg (95% CI -4.86 to 0.81] ), based on clinic data. AUTHORS' CONCLUSIONS: This review provides moderate-quality evidence that coenzyme Q10 does not have a clinically significant effect on blood pressure. In one of three trials reporting adverse effects, coenzyme Q10 was well tolerated. Due to the small number of individuals and studies available for analysis, more well-conducted trials are needed. PMID- 26935714 TI - Prospective evaluation of the ability of clinical scoring systems and physician determined likelihood of appendicitis to obviate the need for CT. AB - OBJECTIVE: To determine whether clinical scoring systems or physician gestalt can obviate the need for computed tomography (CT) in patients with possible appendicitis. METHODS: Prospective, observational study of patients with abdominal pain at an academic emergency department (ED) from February 2012 to February 2014. Patients over 11 years old who had a CT ordered for possible appendicitis were eligible. All parameters needed to calculate the scores were recorded on standardised forms prior to CT. Physicians also estimated the likelihood of appendicitis. Test characteristics were calculated using clinical follow-up as the reference standard. Receiver operating characteristic curves were drawn. RESULTS: Of the 287 patients (mean age (range), 31 (12-88) years; 60% women), the prevalence of appendicitis was 33%. The Alvarado score had a positive likelihood ratio (LR(+)) (95% CI) of 2.2 (1.7 to 3) and a negative likelihood ratio (LR(-)) of 0.6 (0.4 to 0.7). The modified Alvarado score (MAS) had LR(+) 2.4 (1.6 to 3.4) and LR(-) 0.7 (0.6 to 0.8). The Raja Isteri Pengiran Anak Saleha Appendicitis (RIPASA) score had LR(+) 1.3 (1.1 to 1.5) and LR(-) 0.5 (0.4 to 0.8). Physician-determined likelihood of appendicitis had LR(+) 1.3 (1.2 to 1.5) and LR(-) 0.3 (0.2 to 0.6). When combined with physician likelihoods, LR(+) and LR(-) was 3.67 and 0.48 (Alvarado), 2.33 and 0.45 (RIPASA), and 3.87 and 0.47 (MAS). The area under the curve was highest for physician-determined likelihood (0.72), but was not statistically significantly different from the clinical scores (RIPASA 0.67, Alvarado 0.72, MAS 0.7). CONCLUSIONS: Clinical scoring systems performed equally well as physician gestalt in predicting appendicitis. These scores do not obviate the need for imaging for possible appendicitis when a physician deems it necessary. PMID- 26935715 TI - Anti-proliferative effect of RCE-4 from Reineckia carnea on human cervical cancer HeLa cells by inhibiting the PI3K/Akt/mTOR signaling pathway and NF-kappaB activation. AB - Cervical cancer is the second leading cause of cancer deaths in women worldwide. In recent years, the studies find that inflammation is a critical component of tumor progression, and the ideal therapeutic methods should be aimed at the inflammation reaction triggers. (1beta,3beta,5beta,25S)-spirostan-1,3-diol1 [alpha-L-rhamnopyranosyl-(1 -> 2)-beta-D-xylopyranoside] (RCE-4) was the main active composition of Reineckia carnea (Andr.) Kunth. It significantly induced apoptosis in cervical cancer Caski cells through the mitochondrial pathway in our previous studies; however, its underlying mechanism remains poorly understood. This study aimed to further evaluate the effect of RCE-4 on human cervical cancer HeLa cells. Based on this observation, we investigated the anti-cervical cancer effect of RCE-4 by modulating phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling pathway, nuclear factor kappa B (NF-kappaB) activation, and inflammation-related key factors in HeLa cells. The results indicated that the HeLa cell was the most sensitive with an IC50 of 7.01 MUM; RCE-4 significantly promoted the release of cellular lactate dehydrogenase (LDH); increased DNA fragmentation and apoptosis; reduced PI3K, Akt, mTOR, and NF-kappaBp65 phosphorylation levels; increased the Bax and cleaved poly (ADP-ribose) polymerase (PARP) protein levels; suppressed Bcl-2 protein expression; elevated the Bax/Bcl-2 expression ratio; and decreased the interleukin-1 beta (IL-1beta) and interleukin-6 (IL-6) mRNA expressions in HeLa cells in a concentration-dependent manner. These findings suggest that RCE-4 exerted beneficially anti-cervical cancer effect on HeLa cells, mainly inhibiting PI3K/Akt/mTOR signaling pathway phosphorylation and NF-kappaB activation, promoting HeLa cell apoptosis. Graphical abstract Anti-tumor effect of RCE-4 on HeLa cells. PMID- 26935716 TI - Gene expression analysis reveals that Delta/Notch signalling is not involved in onychophoran segmentation. AB - Delta/Notch (Dl/N) signalling is involved in the gene regulatory network underlying the segmentation process in vertebrates and possibly also in annelids and arthropods, leading to the hypothesis that segmentation may have evolved in the last common ancestor of bilaterian animals. Because of seemingly contradicting results within the well-studied arthropods, however, the role and origin of Dl/N signalling in segmentation generally is still unclear. In this study, we investigate core components of Dl/N signalling by means of gene expression analysis in the onychophoran Euperipatoides kanangrensis, a close relative to the arthropods. We find that neither Delta or Notch nor any other investigated components of its signalling pathway are likely to be involved in segment addition in onychophorans. We instead suggest that Dl/N signalling may be involved in posterior elongation, another conserved function of these genes. We suggest further that the posterior elongation network, rather than classic Dl/N signalling, may be in the control of the highly conserved segment polarity gene network and the lower-level pair-rule gene network in onychophorans. Consequently, we believe that the pair-rule gene network and its interaction with Dl/N signalling may have evolved within the arthropod lineage and that Dl/N signalling has thus likely been recruited independently for segment addition in different phyla. PMID- 26935717 TI - Molecular cloning, expression pattern, and phylogenetic analysis of a tetraspanin CD82-like molecule in lamprey Lampetra japonica. AB - CD82, a member of the tetraspanins, is originally identified as an accessory molecule in T cell activation, and it participates in the formation of immune synapse both in T cells and antigen-presenting cells of jawed vertebrates. In the present study, a CD82 homologous complementary DNA (cDNA) sequence is identified in the lamprey Lampetra japonica. The open reading frame of this sequence is 801 bp long and encodes a 266-amino acid protein. The multialignment of this sequence with several typical CD82s and CD37s of jawed vertebrates shows that it also possesses their conserved four transmembrane domains and a six-cysteine motif Cys Cys-Gly...Cys-Ser-Cys...Cys...Cys, which is a characteristic motif of CD82 and CD37 vertebrate tetraspanin sequences. Since it is close to CD82s in sequence similarity, we name it as Lja-CD82-like. From the distribution profile of the conserved motifs of CD82-like, CD82, and CD37 molecules from molluscas to mammals, it seems that the CD82s and CD37s evolved from a common ancestral gene through a gene duplication event to their modern forms by a short insertion or substitution approaches. The phylogenetic analysis indicated that CD82 and CD37 molecules of jawed vertebrates originated from a common ancestral gene which is close to agnathan CD82-like and evolved into two distinct paralogous groups maybe after the divergence of jawed and jawless vertebrates. An expression vector with trigger factor (TF) was constructed to ensure that Lja-CD82-like express in prokaryotic expression host. The expressions of Lja-CD82-like messenger RNA (mRNA) and protein in immune-related tissues of lamprey were detected by real time quantitative polymerase chain reaction and western blotting. Results showed that the mRNA and the protein levels of Lja-CD82-like were significantly upregulated in lymphocyte-like cells, gills, and supraneural myeloid bodies after stimulation with mixed antigens, respectively. Our data provided a foundation for the further study of Lja-CD82-like and its role in immune response process of jawless vertebrates. PMID- 26935718 TI - Antifibrinolytic treatment in subarachnoid hemorrhage: Harmful or beneficial? PMID- 26935719 TI - In-Person Versus Online Focus Group Discussions: A Comparative Analysis of Data Quality. AB - Online focus group discussions (FGDs) are becoming popular as a qualitative research method. Methodological examinations regarding the data quality of online versus more traditional in-person FGDs are limited. We compared two online FGDs with two in-person FGDs conducted with gay and bisexual men using a sensitive topic (the experience of intimate partner violence) to examine differences in data quality between the two methods. The online FGDs resulted in larger word count but were shorter in time than the in-person FGDs. There was high overlap in the themes generated across groups; however, the online discussions yielded one additional theme regarding a sensitive topic. In-person FGDs involved less sharing of in-depth stories, whereas sensitive topics were discussed more candidly in the online FGDs. The results illustrate that although theformatof the data generated from each type of FGD may differ, thecontentof the data generated is remarkably similar. PMID- 26935720 TI - Psychosocial Intervention Use in Long-Stay Dementia Care: A Classic Grounded Theory. AB - The objective of this study was to develop a substantive grounded theory of staff psychosocial intervention use with residents with dementia in long-stay care. "Becoming a person again" emerged as the core category accounting for staffs' psychosocial intervention use within long-stay care. Interview data were collected from participants in nine Irish long-stay settings: 14 residents with dementia, 19 staff nurses, one clinical facilitator, seven nurse managers, 21 nursing assistants, and five relatives. Constant comparative method guided the data collection and analysis. The researcher's theoretical memos, based on unstructured observation, and applicable extant literature were also included as data. By identifying the mutuality of the participants' experiences, this classic grounded theory explains staff motivation toward psychosocial intervention use within long-stay care. It also explains how institutional factors interact with those personal factors that incline individuals toward psychosocial intervention use. PMID- 26935721 TI - Portraying Reflexivity in Health Services Research. AB - A model is proposed for supporting reflexivity in qualitative health research, informed by arguments from Bourdieu and Finlay. Bourdieu refers to mastering the subjective relation to the object at three levels-the overall social space, the field of specialists, and the scholastic universe. The model overlays Bourdieu's levels of objectivation with Finlay's three stages of research (pre-research, data collection, and data analysis). The intersections of these two ways of considering reflexivity, displayed as cells of a matrix, pose questions and offer prompts to productively challenge health researchers' reflexivity. Portraiture is used to show how these challenges and prompts can facilitate such reflexivity, as illustrated in a research project. PMID- 26935722 TI - Implementing a Systematic Voiding Program for Patients With Urinary Incontinence After Stroke. AB - We explored health professionals' views of implementing a systematic voiding program (SVP) in a multi-site qualitative process evaluation in stroke services recruited to the intervention arms of a cluster randomized controlled feasibility trial during 2011-2013. We conducted semi-structured group or individual interviews with 38 purposively selected nursing, managerial, and care staff involved in delivering the SVP. Content analysis of transcripts used normalization process theory (NPT) as a pre-specified organization-level exploratory framework. Barriers to implementing the SVP included perceived lack of suitability for some patient groups, patient fear of extending hospital stay, and difficulties with SVP enactment, scheduling, timing, recording, and monitoring. Enablers included the guidance provided by the SVP, patient and relative involvement, extra staff, improved nursing skill and confidence, and experience of success. Three potential mechanisms of consistency, visibility, and individualization linked the SVP process with improvements in outcome, and should be emphasized in SVP implementation. PMID- 26935723 TI - Stepping Back From Crisis Points: The Provision and Acknowledgment of Support in an Online Suicide Discussion Forum. AB - Suicide is a global health concern, though little is known about the social practices that might support those who are contemplating suicide. Online forums provide a unique insight into the anonymous discussion of suicide, including sociocultural norms about suicide and the delicate management of online interaction. In this article, we examine the provision and acknowledgment of support in an online discussion forum about suicide, using discursive psychology to analyze the textual interaction. The analysis illustrates how forum threads function as case studies and enable members to gain support on numerous occasions. In this way, members can gain help at crisis points as and when these occur, while still maintaining authenticity as a valid forum member. The analysis also provides additional evidence for models of suicide which highlight the fluid nature of suicidality and contributes to the preventative work on suicide by demonstrating how support can be provided at crisis points. PMID- 26935724 TI - Radioembolization: Is Prophylactic Embolization of Hepaticoenteric Arteries Necessary? A Systematic Review. AB - PURPOSE: To study the effectiveness of prophylactic embolization of hepaticoenteric arteries to prevent gastrointestinal complications during radioembolization. METHODS: A PubMed, Embase and Cochrane literature search was performed. We included studies assessing both a group of patients with and without embolization. RESULTS: Our search revealed 1401 articles of which title and abstract were screened. Finally, eight studies were included investigating 1237 patients. Of these patients, 456 received embolization of one or more arteries. No difference was seen in the incidence of gastrointestinal complications in patients with prophylactic embolization of the gastroduodenal artery (GDA), right gastric artery (RGA), cystic artery (CA) or hepatic falciform artery (HFA) compared to patients without embolization. Few complications were reported when microspheres were injected distal to the origin of these arteries or when reversed flow of the GDA was present. A high risk of confounding by indication was present because of the non-randomized nature of the included studies. CONCLUSION: It is advisable to restrict embolization to those hepaticoenteric arteries that originate distally or close to the injection site of microspheres. There is no conclusive evidence that embolization of hepaticoenteric arteries influences the risk of complications. PMID- 26935725 TI - Which is the Best Chemotherapeutic Agent for Transarterial Chemoembolization of Hepatocellular Carcinoma? PMID- 26935726 TI - Epidemiological Outbreaks of Pneumocystis jirovecii Pneumonia Are Not Limited to Kidney Transplant Recipients: Genotyping Confirms Common Source of Transmission in a Liver Transplantation Unit. AB - Over a 5-month period, four liver transplant patients at a single hospital were diagnosed with Pneumocystis jirovecii pneumonia (PCP). This unusually high incidence was investigated using molecular genotyping. Bronchoalveolar lavage fluids (BALF) obtained from the four liver recipients diagnosed with PCP were processed for multilocus sequence typing (MLST) at three loci (SOD, mt26s, and CYB). Twenty-four other BALF samples, which were positive for P. jirovecii and collected from 24 epidemiologically unrelated patients with clinical signs of PCP, were studied in parallel by use of the same method. Pneumocystis jirovecii isolates from the four liver recipients all had the same genotype, which was different from those of the isolates from all the epidemiologically unrelated individuals studied. These findings supported the hypothesis of a common source of contamination or even cross-transmission of a single P. jirovecii clone between the four liver recipients. Hospitalization mapping showed several possible encounters between these four patients, including outpatient consultations on one particular date when they all possibly met. This study demonstrates the value of molecular genotyping of P. jirovecii isolated from clinical samples for epidemiological investigation of PCP outbreaks. It is also the first description of a common source of exposure to a single P. jirovecii clone between liver transplant recipients and highlights the importance of prophylaxis in such a population. PMID- 26935727 TI - Microbiology Learning and Education Online. AB - The ubiquity of devices that connect to the Internet has exploded, allowing for easy dissemination of information. Many teachers from kindergarten to universities use the information obtained online or post material they want their students to access. Online media readily places articles, books, videos, and games at our fingertips. The public in general also gathers health information from the Internet. The following review will explore what has been published regarding microbiology education and learning online and the use of electronic media by microbiologists for scientific purposes. PMID- 26935728 TI - Investigation of Linezolid Resistance in Staphylococci and Enterococci. AB - The objective of this study was to investigate an apparent increase in linezolid nonsusceptible staphylococci and enterococci following a laboratory change in antimicrobial susceptibility testing from disk diffusion to an automated susceptibility testing system. Isolates with nonsusceptible results (n = 27) from Vitek2 were subjected to a battery of confirmatory testing which included disk diffusion, Microscan broth microdilution, Clinical and Laboratory Standards Institute (CLSI) reference broth microdilution, gradient diffusion (Etest), 23S rRNA gene sequencing, and cfr PCR. Our results show that there is poor correlation between methods and that only 70 to 75% of isolates were confirmed as linezolid resistant with alternative phenotypic testing methods (disk diffusion, Microscan broth microdilution, CLSI broth microdilution, and Etest). 23S rRNA gene sequencing identified mutations previously associated with linezolid resistance in 16 (59.3%) isolates, and the cfr gene was detected in 3 (11.1%) isolates. Mutations located at positions 2576 and 2534 of the 23S rRNA gene were most common. In addition, two previously undescribed variants (at positions 2083 and 2345 of the 23S rRNA gene) were also identified and may contribute to linezolid resistance. PMID- 26935730 TI - Mapping of Microbiological Procedures by the Members of the International Society of Orthopaedic Centers (ISOC) for Diagnosis of Periprosthetic Infections. PMID- 26935729 TI - Genomic Epidemiology and Molecular Resistance Mechanisms of Azithromycin Resistant Neisseria gonorrhoeae in Canada from 1997 to 2014. AB - The emergence of Neisseria gonorrhoeae strains with decreased susceptibility to cephalosporins and azithromycin (AZM) resistance (AZM(r)) represents a public health threat of untreatable gonorrhea infections. Genomic epidemiology through whole-genome sequencing was used to describe the emergence, dissemination, and spread of AZM(r) strains. The genomes of 213 AZM(r) and 23 AZM-susceptible N. gonorrhoeae isolates collected in Canada from 1989 to 2014 were sequenced. Core single nucleotide polymorphism (SNP) phylogenomic analysis resolved 246 isolates into 13 lineages. High-level AZM(r) (MICs >= 256 MUg/ml) was found in 5 phylogenetically diverse isolates, all of which possessed the A2059G mutation (Escherichia coli numbering) in all four 23S rRNA alleles. One isolate with high level AZM(r) collected in 2009 concurrently had decreased susceptibility to ceftriaxone (MIC = 0.125 MUg/ml). An increase in the number of 23S rRNA alleles with the C2611T mutations (E. coli numbering) conferred low to moderate levels of AZM(r) (MICs = 2 to 4 and 8 to 32 MUg/ml, respectively). Low-level AZM(r) was also associated with mtrR promoter mutations, including the -35A deletion and the presence of Neisseria meningitidis-like sequences. Geographic and temporal phylogenetic clustering indicates that emergent AZM(r) strains arise independently and can then rapidly expand clonally in a region through local sexual networks. PMID- 26935731 TI - Application of Alternative Nucleic Acid Extraction Protocols to ProGastro SSCS Assay for Detection of Bacterial Enteric Pathogens. AB - As an alternative to automated extraction, fecal specimens were processed by investigational lysis/heating (i.e., manual) and by chromatography/centrifugation (i.e., column) methods. ProGastro SSC and Shiga toxin-producing Escherichia coli (i.e., STEC) indeterminate rates for 101 specimens were 1.0% to 3.0% for automated, 11.9% for manual, and 24.8% to 37.6% for column methods. Following freeze-thaw of 247 specimens, indeterminate rates were 1.6% to 2.4% for manual and 0.8 to 5.3% for column methods. Mean processing times for manual and column methods were 30.5 and 69.2 min, respectively. Concordance of investigational methods with automated extraction was >=98.8%. PMID- 26935732 TI - Evaluation of Fluorescent Capillary Electrophoresis for Rapid Identification of Candida Fungal Infections. AB - Early diagnosis of fungal infection is critical for initiating antifungal therapy and reducing the high mortality rate in immunocompromised patients. In this study, we focused on rapid and sensitive identification of clinically important Candida species, utilizing the variability in the length of the ITS2 rRNA gene and fluorescent capillary electrophoresis (f-ITS2-PCR-CE). The method was developed and optimized on 29 various Candida reference strains from which 26 Candida species were clearly identified, while Candida guilliermondii, C. fermentati, and C. carpophila, which are closely related, could not be distinguished. The method was subsequently validated on 143 blinded monofungal clinical isolates (comprising 26 species) and was able to identify 88% of species unambiguously. This indicated a higher resolution power than the classical phenotypic approach which correctly identified 73%. Finally, the culture independent potential of this technique was addressed by the analysis of 55 retrospective DNA samples extracted directly from clinical material. The method showed 100% sensitivity and specificity compared to those of the combined results of cultivation and panfungal PCR followed by sequencing used as a gold standard. In conclusion, this newly developed f-ITS2-PCR-CE analytical approach was shown to be a fast, sensitive, and highly reproducible tool for both culture-dependent and culture-independent identification of clinically important Candida strains, including species of the "psilosis" complex. PMID- 26935733 TI - QUest for the Arrhythmogenic Substrate of Atrial fibRillation in Patients Undergoing Cardiac Surgery (QUASAR Study): Rationale and Design. AB - The heterogeneous presentation and progression of atrial fibrillation (AF) implicate the existence of different pathophysiological processes. Individualized diagnosis and therapy of the arrhythmogenic substrate underlying AF may be required to improve treatment outcomes. Therefore, this single-center study aims to identify the arrhythmogenic areas underlying AF by intra-operative, high resolution, multi-site epicardial mapping in 600 patients with different heart diseases. Participants are divided into 12 groups according to the underlying heart diseases and presence of prior AF episodes. Mapping is performed with a 192 electrode array for 5-10 s during sinus rhythm and (induced) AF of the entire atrial surface. Local activation times are converted into activation and wave maps from which various electrophysiological parameters are derived. Postoperative cardiac rhythm registrations and a 5-year follow-up will show the incidence of postoperative and persistent AF. This project provides the first step in the development of a tool for individual AF diagnosis and treatment. PMID- 26935734 TI - Spatiotemporal analysis of encroachment on wetlands: a case of Nakivubo wetland in Kampala, Uganda. AB - Wetlands provide vital ecosystem services such as water purification, flood control, and climate moderation among others, which enhance environmental quality, promote public health, and contribute to risk reduction. The biggest threat to wetlands is posed by human activities which transform wetlands, often for short-term consumptive benefits. This paper aimed to classify and map recent land cover and provide a multi-temporal analysis of changes from 2002 to 2014 in the Nakivubo wetland through which wastewater from Kampala city drains to Lake Victoria in Uganda. The paper contributes through spatially congruent change maps showing site-specific land cover conversions. In addition, it gives insight into what happened to the wetlands, why it happened, how the changes in the wetlands affect the communities living in them, and how the situation could be better managed or regulated in future. The analysis is based on very high resolution (50 62 cm) aerial photos and satellite imagery, focus group discussions, and key informant interviews. Overall, the analysis of losses and gains showed a 62 % loss of wetland vegetation between 2002 and 2014, mostly attributable to crop cultivation. Cultivation in the wetland buffering the lake shore makes it unstable to anchor. The 2014 data shows large portions of the wetland calved away by receding lake waves. With barely no wetland vegetation buffer around the lake, the heavily polluted wastewater streams will lower the quality of lake water. Furthermore, with increased human activities in the wetland, exposure to flooding and pollution will be likely to have a greater impact on the health and livelihoods of vulnerable communities. This calls for a multi-faceted approach, coordination of the various stakeholders and engagement of wetland-dependent communities as part of the solution, and might require zoning out the wetland and restricting certain activities to specific zones. PMID- 26935736 TI - An integrated spectral-textural approach for environmental change monitoring and assessment: analyzing the dynamics of green covers in a highly developing region. AB - The present study compares the effectiveness of two common preclassification change detection (CD) methods that use two-dimensional data space of spectral textural (S-T) change information. The methods are principal component analysis (PCA) and change vector analysis (CVA) in the Gorgan Township area, Golestn Province, Iran. A series of texture-based information was calculated mainly to separate those land use/land cover (LULC) conversions that are spectrally indistinguishable and also to provide a basis for automatic classification of S-T data space. Both methods were evaluated in terms of accuracy and the required time and expertise. Having the two-dimensional S-T data space generated, support vector machine (SVM) classifier was implemented to automatically extract changed pixels and the receiving operator characteristic (ROC) was employed to assess the accuracy of the output. According to the results, the study area has witnessed substantial mutual transformations between various LULCs among agricultural lands were the most dynamic category in the region. The PCA method applied to the S-T information achieved a ROC of 0.90-indicating an acceptable performance-while the S-T CVA method achieved a lower value of 0.75. The S-T PCA method was considerably less time-consuming and less expertise demanding as well as more accurate in our study area. PMID- 26935735 TI - The investigation of heavy element accumulation in some Hydrophilidae (Coleoptera) species. AB - First of all, this study aimed to find out the measures of some heavy elements (Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, As, Se, Br, Sr, Pb) as heavy element pollution in Erzurum Province, and secondly to observe whether some hydrophilidae (Coleoptera) species can be used as a biomonitor. Insect samples were collected from five different localities of Erzurum in June, July, and August 2014. Heavy element levels in sediment, water, and insect samples were analyzed by energy dispersive X-ray fluorescence (EDXRF) spectrometer device. According to the results of analysis derived through EDXRF spectrometry, heavy element concentrations display differences between stations and also species. The results pointed out that the insects were contaminated by the sediment and water; therefore, some hydrophilidae species accumulate higher concentration of elements than their environment. Results for levels in water were compared to national water quality guidelines. The values of some heavy elements found at higher concentration than acceptable limits. PMID- 26935737 TI - Gout-related inpatient utilization: a study of predictors of outcomes and time trends. AB - BACKGROUND: To assess inpatient healthcare burden of gout in the USA after an Emergency Department (ED) visit and the predictors of gout-related hospitalizations. METHOD: We used the 2009, 2010 and 2012 US National ED Sample (NEDS) data to examine the time trends in inpatient visits with gout as the primary diagnosis. We used the 2012 NEDS data to assess multivariable-adjusted predictors of length of hospital stay, discharge to home (versus other) and total charges for gout-related inpatient visits. RESULTS: Of the 205,152 ED visits for gout as the primary diagnosis in 2012, 7.7 % resulted in hospitalization. In 2009, 2010 and 2012, 63 %, 63 % and 64.5 % of hospitalized patients were discharged home; respective durations of hospital stay were 4.15, 4.00 and 3.86 days. Older age 50 to <65 years (ref <50), renal failure, heart failure, osteoarthritis and diabetes were associated with a longer hospital stay and self pay/uninsured status, hospital location in the Midwest or Western USA with a shorter hospital stay for gout. Similar factors were associated with total charges for gout-related admissions. Older age (65 to <80 and >=80, relative to <50 years), diabetes, self-pay/no charge insurance status, metropolitan area residence, and a longer length of hospital stay were associated with lower odds of discharge to home; and self-pay/no charge (uninsured) status was associated with higher odds of discharge to home, compared to Medicare coverage. CONCLUSIONS: Using a national sample, we noted declining duration of hospital stay and identified factors associated with the length of hospital stay, discharge to home and charges for gout hospitalization following an ED visit. Future studies should examine whether better management of comorbidities in patients with gout can further reduce utilization and cost of gout-related hospitalizations. PMID- 26935738 TI - Molecular basis for the thermostability of Newcastle disease virus. AB - Thermostable Newcastle disease virus (NDV) vaccines have been used widely to protect village chickens against Newcastle disease, due to their decreased dependence on cold chain for transport and storage. However, the genetic basis underlying the NDV thermostability is poorly understood. In this study, we generated chimeric viruses by exchanging viral genes between the thermostable TS09-C strain and thermolabile LaSota strain using reverse genetics technology. Evaluations of these chimeric NDVs demonstrated that the thermostability of NDV was dependent on the origin of HN protein. Chimeras bearing the HN protein derived from thermostable virus exhibited a thermostable phenotype, and vice versa. Both hemagglutinin and neuraminidase activities of viruses bearing the TS09-C HN protein were more thermostable than those containing LaSota HN protein. Furthermore, the newly developed thermostable virus rLS-T-HN, encoding the TS09-C HN protein in LaSota backbone, induced significantly higher antibody response than the TS09-C virus, and conferred complete protection against virulent NDV challenge. Taken together, the data suggest that the HN protein of NDV is a crucial determinant of thermostability, and the HN gene from a thermostable NDV could be engineered into a thermolabile NDV vaccine strain for developing novel thermostable NDV vaccine. PMID- 26935739 TI - Learning to Manage Chronic Pain: The Patients' Perspective. AB - INTRODUCTION: The objective of the present study was to gain insight into patients' experiences in a 4-week interdisciplinary chronic pain management program by determining major themes from patients' written comments on exit questionnaires. METHODS: Upon completion of the program at the Chronic Pain Management Unit (CPMU), patients fill out program satisfaction (Pain Program Satisfaction Questionnaire) and evaluation of goal accomplishment (Self Evaluation Scale) forms, sections of which are open-ended. Questionnaire data from 50 patients, admitted into the CPMU between May 2013 and December 2014, were randomly selected for this study. Written responses to open-ended sections were obtained. Comments were stratified by gender and coded using an inductive approach. Codes were grouped into categories which were further combined into several major themes. RESULTS: Six main themes extracted from comments were (1) impact of a strong interdisciplinary team, (2) learning to adapt in order to manage, (3) the Program as a stepping stone, (4) positive effects of a group effort, (5) improved mental health, and (6) benefits of the program. CONCLUSION: The results of this analysis reinforce the effectiveness of the interdisciplinary CPMU program at improving patients' quality of life. Findings may assist in the promotion of the program to stakeholders such as referral sources. The outcomes may also assist in the development of future programs that have similar goals. Concerns that arise within patients' comments may assist clinicians in this program to make adjustments such that all unique needs are met. PMID- 26935740 TI - Time-Dependent Increase of Chitinase1 in APP/PS1 Double Transgenic Mice. AB - It is reported that chitinase1 increases in Alzheimer's disease (AD). However, the alteration of chitinase1 in the progress of AD is still unclear. Thus, we designed the present study to detect chitinase1 level in different stages of APP/PS1 double transgenic mice. Experimental models were APP/PS1 double transgenic mice with 4, 12 and 22 months. Cognitive function was detected by Morris water maze test in APP/PS1 mice as well as controls. ELISA and the quantitative RT-PCR were used to detect chitinase1 level in different groups. The study displayed that expression of chitinase1 gradually increased in a time dependent manner in APP/PS1 mice, while there were no statistical differences among the wild-type mice in varies ages. Moreover, chitnase1 increased significantly in APP/PS1 mice aged 12 and 22 months compared with the age matched wild-type group, respectively. However, no difference of chitnase1 was found between 4 months-old APP/PS1 mice and wild-type mice. Comparing with the age matched wild type group, the consequences of mRNA on the increase in chitnase1 is in accordance with protein in APP/PS1 mice. Furthermore, Morris water maze showed that 4 months-old APP/PS1 mice have normal spatial learning and impaired spatial memory; both spatial learning and spatial memory in 12 and 22 months-old APP/PS1 mice were declined. Time-dependent increase of chitnase1 in APP/PS1 double transgenic mice indicates that the level of chitinase1 is associated with decline of cognition. Therefore, chitinase1 might be a biomarker of disease progression in AD. PMID- 26935742 TI - Looking Inside the Matrix: Perineuronal Nets in Plasticity, Maladaptive Plasticity and Neurological Disorders. AB - The integrity of the central nervous system (CNS) matrix is crucial for its proper function. Loss of the lattice-like structure compromise synaptic stability and can lead to the disruption of the excitatory/inhibitory balance, astrocytosis, maladaptive plasticity and neuronal death. Perineuronal nets (PNNs) in the extracellular matrix (ECM) provide synaptic integration and control the functional wiring between neurons. These nets are significantly modified during CNS disorders, such as neurodegenerative, cerebrovascular and inflammatory diseases. The breakdown or the modification of PNNs could be due to the activity of matrix metalloproteinases (MMPs) or to the deposition of proteoglycans, glycoproteins, and hyaluronic acid. The expression and the activity of ECM degrading enzymes can be regulated with tissue inhibitors of MMPs or via transcriptional and epigenetic silencing or enhancement (i.e. via histone deacetylases). The identification of molecules and mechanisms able to modify these processes will be essential for a new perspective on brain functioning in health and disease, leading to a target-directed approach with drugs directly interfering with the molecular mechanism underlying neurological disorders. PMID- 26935741 TI - Reaching Out to Send a Message: Proteins Associated with Neurite Outgrowth and Neurotransmission are Altered with Age in the Long-Lived Naked Mole-Rat. AB - Aging is the greatest risk factor for developing neurodegenerative diseases, which are associated with diminished neurotransmission as well as neuronal structure and function. However, several traits seemingly evolved to avert or delay age-related deterioration in the brain of the longest-lived rodent, the naked mole-rat (NMR). The NMR remarkably also exhibits negligible senescence, maintaining an extended healthspan for ~75 % of its life span. Using a proteomic approach, statistically significant changes with age in expression and/or phosphorylation levels of proteins associated with neurite outgrowth and neurotransmission were identified in the brain of the NMR and include: cofilin-1; collapsin response mediator protein 2; actin depolymerizing factor; spectrin alpha chain; septin-7; syntaxin-binding protein 1; synapsin-2 isoform IIB; and dynamin 1. We hypothesize that such changes may contribute to the extended lifespan and healthspan of the NMR. PMID- 26935743 TI - The Effects of Insulin-Induced Hypoglycaemia on Tyrosine Hydroxylase Phosphorylation in Rat Brain and Adrenal Gland. AB - In this study we investigated the effects of insulin-induced hypoglycaemia on tyrosine hydroxylase (TH) protein and TH phosphorylation in the adrenal gland, C1 cell group, locus coeruleus (LC) and midbrain dopaminergic cell groups that are thought to play a role in response to hypoglycaemia and compared the effects of different concentrations of insulin in rats. Insulin (1 and 10 U/kg) treatment caused similar reductions in blood glucose concentration (from 7.5-9 to 2-3 mmol/L); however, plasma adrenaline concentration was increased 20-30 fold in response to 10 U/kg insulin and only 14 fold following 1 U/kg. Time course studies (at 10 U/kg insulin) revealed that in the adrenal gland, Ser31 phosphorylation was increased between 30 and 90 min (4-5 fold), implying that TH was activated to increase catecholamine synthesis in adrenal medulla to replenish the stores. In the brain, Ser19 phosphorylation was limited to certain dopaminergic groups in the midbrain, while Ser31 phosphorylation was increased in most catecholaminergic regions at 60 min (1.3-2 fold), suggesting that Ser31 phosphorylation may be an important mechanism to maintain catecholamine synthesis in the brain. Comparing the effects of 1 and 10 U/kg insulin revealed that Ser31 phosphorylation was increased to similar extent in the adrenal gland and C1 cell group in response to both doses whereas Ser31 and Ser19 phosphorylation were only increased in response to 1 U/kg insulin in LC and in response to 10 U/kg insulin in most midbrain regions. Thus, the adrenal gland and some catecholaminergic brain regions become activated in response to insulin administration and brain catecholamines may be important for initiation of physiological defences against insulin-induced hypoglycaemia. PMID- 26935746 TI - Periorificial Lesions in a Young Girl. PMID- 26935744 TI - Knockdown of SALL4 inhibits the proliferation and reverses the resistance of MCF 7/ADR cells to doxorubicin hydrochloride. AB - BACKGROUND: Breast cancer is the most frequent malignancy in women and drug resistance is the major obstacle for its successful chemotherapy. In the present study, we analyzed the involvement of an oncofetal gene, sal-like 4 (SALL4), in the tumor proliferation and drug resistance of human breast cancer. RESULTS: Our study showed that SALL4 was up-regulated in the drug resistant breast cancer cell line, MCF-7/ADR, compared to the other five cell lines. We established the lentiviral system expressing short hairpin RNA to knockdown SALL4 in MCF-7/ADR cells. Down-regulation of SALL4 inhibited the proliferation of MCF-7/ADR cells and induced the G1 phase arrest in cell cycle, accompanied by an obvious reduction of the expression of cyclinD1 and CDK4. Besides, down-regulating SALL4 can re-sensitize MCF-7/ADR to doxorubicin hydrochloride (ADMh) and had potent synergy with ADMh in MCF-7/ADR cells. Depletion of SALL4 led to a decrease in IC50 for ADMh and an inhibitory effect on the ability to form colonies in MCF 7/ADR cells. With SALL4 knockdown, ADMh accumulation rate of MCF-7/ADR cells was increased, while the expression of BCRP and c-myc was significantly decreased. Furthermore, silencing SALL4 also suppressed the growth of the xenograft tumors and reversed their resistance to ADMh in vivo. CONCLUSION: SALL4 knockdown inhibits the growth of the drug resistant breast cancer due to cell cycle arrest and reverses tumor chemo-resistance through down-regulating the membrane transporter, BCPR. Thus, SALL4 has potential as a novel target for the treatment of breast cancer. PMID- 26935745 TI - Analysis of ex vivo drug response data of Plasmodium clinical isolates: the pros and cons of different computer programs and online platforms. AB - BACKGROUND: In vitro drug susceptibility testing of malaria parasites remains an important component of surveillance for anti-malarial drug resistance. The half maximal inhibition of growth (IC50) is the most commonly reported parameter expressing drug susceptibility, derived by a variety of statistical approaches, each with its own advantages and disadvantages. METHODS: In this study, licensed computer programs WinNonlin and GraphPad Prism 6.0, and the open access programs HN-NonLin, Antimalarial ICEstimator (ICE), and In Vitro Analysis and Reporting Tool (IVART) were tested for their ease of use and ability to estimate reliable IC50 values from raw drug response data from 31 Plasmodium falciparum and 29 P. vivax clinical isolates tested with five anti-malarial agents: chloroquine, amodiaquine, piperaquine, mefloquine, and artesunate. RESULTS: The IC50 and slope estimates were similar across all statistical packages for all drugs tested in both species. There was good correlation of results derived from alternative statistical programs and non-linear mixed-effects modelling (NONMEM) which models all isolate data simultaneously. The user-friendliness varied between packages. While HN-NonLin and IVART allow users to enter the data in 96-well format, IVART and GraphPad Prism 6.0 are capable to analyse multiple isolates and drugs in parallel. WinNonlin, GraphPad Prism 6.0, IVART, and ICE provide alerts for non fitting data and incorrect data entry, facilitating data interpretation. Data analysis using WinNonlin or ICE took the longest computationally, whilst the offline ability of GraphPad Prism 6.0 to analyse multiple isolates and drugs simultaneously made it the fastest among the programs tested. CONCLUSION: IC50 estimates obtained from the programs tested were comparable. In view of processing time and ease of analysis, GraphPad Prism 6.0 or IVART are best suited for routine and large-scale drug susceptibility testing. PMID- 26935747 TI - Emergency revascularization of acute internal carotid artery occlusion: Follow the spike, it guides you. AB - The present study sought to examine the incidence of the angiographic "spike sign" and to assess its predictive significance for achieving carotid revascularization in 54 patients with acute internal carotid artery (ICA) occlusions that required urgent endovascular revascularization. Clinical and imaging files of consecutive patients with ICA occlusion who were treated in a tertiary care academic medical center from 2011-2015 were retrospectively examined under Institutional Review Board approval with a waiver of the requirement for informed consent. All proximal ICA occlusions were treated by stent-assisted carotid angioplasty, and all distal embolic occlusions were managed with stent-assisted mechanical thrombectomy. The study included 24 patients with acute ICA occlusion (group 1) and 30 patients with tandem ICA intracranial occlusions (group 2). The spike sign was seen in 16/24 patients in group 1 (67%), and successful ICA revascularization was achieved in 14/16 (88%). The sign was seen in 26/30 patients in group 2 (87%), and ICA revascularization was successful in all 26 (100%). The remaining 12 patients had no spike sign, and ICA revascularization was successful in only 7/12 (58%). The spike sign is a transient finding that represents the proximal patent remnant of the stenotic corridor in fresh clot. Acute ICA occlusion frequently leaves the spike sign as a marker of the recent thrombotic event. The spike vertex points to the "path of least resistance" for the guidewire to cross the occlusion and engage the true arterial lumen, a critical step during ICA endovascular revascularization. PMID- 26935748 TI - Thin-film optical notch filter spectacle coatings for the treatment of migraine and photophobia. AB - Previous evidence suggests optical treatments hold promise for treating migraine and photophobia. We designed an optical notch filter, centered at 480nm to reduce direct stimulation of intrinsically photosensitive retinal ganglion cells. We used thin-film technology to integrate the filter into spectacle lenses. Our objective was to determine if an optical notch filter, designed to attenuate activity of intrinsically photosensitive retinal ganglion cells, could reduce headache impact in chronic migraine subjects. For this randomized, double-masked study, our primary endpoint was the Headache Impact Test (HIT-6; GlaxoSmithKline, Brentford, Middlesex, UK). We developed two filters: the therapeutic filter blocked visible light at 480nm; a 620nm filter was designed as a sham. Participants were asked to wear lenses with one of the filters for 2weeks; after 2weeks when no lenses were worn, they wore lenses with the other filter for 2weeks. Of 48 subjects, 37 completed the study. Wearing either the 480 or 620nm lenses resulted in clinically and statistically significant HIT-6 reductions. However, there was no significant difference when comparing overall effect of the 480 and 620nm lenses. Although the 620nm filter was designed as a sham intervention, research published following the trial indicated that melanopsin, the photopigment in intrinsically photosensitive retinal ganglion cells, is bi stable. This molecular property may explain the unexpected efficacy of the 620nm filter. These preliminary findings indicate that lenses outfitted with a thin film optical notch filter may be useful in treating chronic migraine. PMID- 26935749 TI - Clinical outcomes in the surgical treatment of idiopathic normal pressure hydrocephalus. AB - Idiopathic normal pressure hydrocephalus (INPH) is a syndrome of gait disturbance, dementia and urinary incontinence. Outcomes after ventriculoperitoneal shunting for INPH are variable due to a lack of reliable, quantitative outcome data and inconsistent methods of selecting shunt candidates. The aim of this retrospective cohort study was to assess objective and quantitative clinical outcomes of ventriculoperitoneal shunting for INPH. From 2008 to 2013, consecutive patients diagnosed with INPH based on clinical and radiological criteria were included in this single-centre study. All patients received programmable-valve ventriculoperitoneal shunts. Outcome measures were assessed at baseline, 3, 6 and 12months post-operatively. Outcomes included gait time and scores on the Unified Parkinson's Disease Rating Scale part III (UPDRS III), the Addenbrooke's Cognitive Examination Revised (ACE-R) and the Mini-Mental State Examination (MMSE). Thresholds for improvements were set a priori as ?20% decrease in gait time, ?10point decrease in UPDRS-III score, ?5point increase in ACE-R score and ?2point increase in MMSE score at last follow-up. The proportion of patients improving varied between measures, being gait time (60%), UPDRS-III (69%), MMSE (63%), and ACE-R (56%). Overall, improvement in at least one outcome measure was observed in 85% of patients and 38% improved in gait time, UPDRS-III score and cognitive scores. Only 15% of patients experienced no improvement on any measure. This study demonstrates that the majority of INPH patients can sustain improvements in multiple symptoms up to 12months after shunting. PMID- 26935750 TI - COPD: A stepwise or a hit hard approach? AB - Current guidelines differ slightly on the recommendations for treatment of Chronic Obstructive Pulmonary Disease (COPD) patients, and although there are some undisputed recommendations, there is still debate regarding the management of COPD. One of the hindrances to deciding which therapeutic approach to choose is late diagnosis or misdiagnosis of COPD. After a proper diagnosis is achieved and severity assessed, the choice between a stepwise or "hit hard" approach has to be made. For GOLD A patients the stepwise approach is recommended, whilst for B, C and D patients this remains debatable. Moreover, in patients for whom inhaled corticosteroids (ICS) are recommended, a step-up or "hit hard" approach with triple therapy will depend on the patient's characteristics and, for patients who are being over-treated with ICS, ICS withdrawal should be performed, in order to optimize therapy and reduce excessive medications. This paper discusses and proposes stepwise, "hit hard", step-up and ICS withdrawal therapeutic approaches for COPD patients based on their GOLD group. We conclude that all approaches have benefits, and only a careful patient selection will determine which approach is better, and which patients will benefit the most from each approach. PMID- 26935751 TI - Critical appraisal of the Portuguese clinical guideline 28/2011. PMID- 26935753 TI - [How much does the choice of new oral anticoagulant matter for reducing the burden of stroke in atrial fibrillation?]. PMID- 26935752 TI - Bio-behavioural HIV and STI surveillance among men who have sex with men in Europe: the Sialon II protocols. AB - BACKGROUND: Globally, the HIV epidemic continues to represent a pressing public health issue in Europe and elsewhere. There is an emerging and progressively urgent need to harmonise HIV and STI behavioural surveillance among MSM across European countries through the adoption of common indicators, as well as the development of trend analysis in order to monitor the HIV-STI epidemic over time. The Sialon II project protocols have been elaborated for the purpose of implementing a large-scale bio-behavioural survey among MSM in Europe in line with a Second Generation Surveillance System (SGSS) approach. METHODS/DESIGN: Sialon II is a multi-centre biological and behavioural cross-sectional survey carried out across 13 European countries (Belgium, Bulgaria, Germany, Italy, Lithuania, Poland, Portugal, Romania, Slovakia, Slovenia, Spain, Sweden, and the UK) in community settings. A total of 4,966 MSM were enrolled in the study (3,661 participants in the TLS survey, 1,305 participants in the RDS survey). Three distinct components are foreseen in the study protocols: first, a preliminary formative research in each participating country. Second, collection of primary data using two sampling methods designed specifically for 'hard-to-reach' populations, namely Time Location Sampling (TLS) and Respondent Driven Sampling (RDS). Third, implementation of a targeted HIV/STI prevention campaign in the broader context of the data collection. DISCUSSION: Through the implementation of combined and targeted prevention complemented by meaningful surveillance among MSM, Sialon II represents a unique opportunity to pilot a bio-behavioural survey in community settings in line with the SGSS approach in a large number of EU countries. Data generated through this survey will not only provide a valuable snapshot of the HIV epidemic in MSM but will also offer an important trend analysis of the epidemiology of HIV and other STIs over time across Europe. Therefore, the Sialon II protocol and findings are likely to contribute significantly to increasing the comparability of data in EU countries through the use of common indicators and in contributing to the development of effective public health strategies and policies in areas of high need. PMID- 26935754 TI - Apoptosis is induced by shikonin through the mitochondrial signaling pathway. AB - The aim of the present study was to investigate the effects of shikonin (SHI) on the induction of apoptosis in human TT medullary thyroid carcinoma cells, and to explore the role of mitochondrial signaling in this process. MTT, Annexin V phycoerythrin/7-aminoactinomycin D staining, electron microscopy and JC-1 probe staining were performed to analyze mitochondrial membrane potential, and western blot analysis was used to examine the activation of the mitochondrial signaling pathway, and the changes in mitochondrial apoptosis pathway-associated protein expression. Following culture for 24-72 h, treatment with various concentrations of SHI inhibited the proliferation of TT cells, in a dose- and time-dependent manner. Transmission electron microscopy demonstrated the presence of typical apoptotic structures, as well as mitochondrial structural changes. The expression levels of apoptosis-associated proteins caspase-9, caspase-3 and poly adenosine triphosphate ribose polymerase increased in a dose-dependent manner following treatment with SHI. In addition, the mitochondrial membrane potential of the experimental group was significantly decreased, and the mitochondrial apoptosis pathway-associated proteins were altered. A possible mechanism underlying SHI induced apoptosis through the mitochondrial signaling pathway is the regulation of B cell lymphoma 2 (Bcl-2)/Bcl-2-associated protein X expression levels, resulting in the decrease in mitochondrial membrane potential and the activation of the caspase-9/caspase-3 enzyme-associated reactions. PMID- 26935755 TI - Effect of portal access system and surgery type on surgery times during laparoscopic ovariectomy and salpingectomy in captive African lions and cheetahs. AB - BACKGROUND: A prospective randomized study was used to compare surgery times for laparoscopic ovariectomy and salpingectomy in female African lion (Panthera leo) (n = 14) and cheetah (Acinonyx jubatus) (n = 20) and to compare the use of a multiple portal access system (MPAS) and single portal access system (SPAS) between groups. Two different portal techniques were used, namely MPAS (three separate ports) in lions and SPAS (SILSTM port) in cheetahs, using standard straight laparoscopic instruments. Portal access system and first ovary was not randomized. Five different surgery times were compared for the two different procedures as well as evaluating the use and application of MPAS and SPAS. Carbon dioxide volumes for lions were recorded. RESULTS: In adult lionesses operative time (OPT) (P = 0.016) and total surgical time (TST) (P = 0.032) were significantly shorter for salpingectomy compared to ovariectomy. Similarly in cheetahs OPT (P = 0.001) and TST (P = 0.005) were also shorter for salpingectomy compared to ovariectomy. In contrast, in lion cubs no difference was found in surgery times for ovariectomy and salpingectomy. Total unilateral procedure time was shorter than the respective bilateral time for both procedures (P = 0.019 and P = 0.001) respectively and unilateral salpingectomy was also faster than unilateral ovariectomy (P = 0.035) in cheetahs. Port placement time, suturing time and TST were significantly shorter for SPAS compared to MPAS (P = 0.008). There was, however, no difference in OPT between SPAS and MPAS. Instrument cluttering with SPAS was found to be negligible. There was no difference in mean volume CO2 required to complete ovariectomy in lions but the correlation between bodyweight and total volume of CO2 in lions was significant (rs = 0.867; P = 0.002). CONCLUSIONS: Laparoscopic salpingectomy was faster than ovariectomy in both adult lions and cheetahs. Using SPAS, both unilateral procedures were faster than bilateral procedures in cheetahs. Placement and suturing of SPAS in cheetahs was easier and faster compared to three separate ports in lions and lion cubs. The use of standard straight instruments during SPAS did not prolong surgery. Surgery was faster in cubs and CO2 required for laparoscopic sterilization in lions could be determined. Predictable surgery times and CO2 volumes will facilitate the accurate planning and execution of surgery in lions and cheetahs. PMID- 26935756 TI - Functional analysis of microRNA-122 binding sequences of hepatitis C virus and identification of variants with high resistance against a specific antagomir. AB - MicroRNA 122 (miR-122) stimulates the replication and translation of hepatitis C virus (HCV) RNA by binding to two adjacent sites, S1 and S2, within the HCV 5'UTR. We demonstrated previously that the miR-122 antagomir miravirsen (SPC3649) suppresses the infection of HCV strain JFH1-based recombinants with HCV genotypes 1-6 5'UTR-NS2 in human hepatoma Huh7.5 cells. However, specific S1 mutations were permitted and conferred virus resistance to miravirsen treatment. Here, using the J6 (genotype 2a) 5'UTR-NS2 JFH1-based recombinant, we performed reverse-genetics analysis of S1 (ACACUCCG, corresponding to miR-122 seed nucleotide positions 8 1), S2 (CACUCC, positions 7-2), and ACCC (positions 1-4) at the 5' end of the HCV genome (5'E); the CC at positions 2-3 of 5'E is involved in miR-122 binding. We demonstrated that the 5'E required four nucleotides for optimal function, and that G or A at position 3 or combined GA at positions 2-3 of 5'E was permitted. In S1 and S2, several single mutations were allowed at specific positions. A UCC > CGA change at positions 4-3-2 of S1, S2, or both S1 and S2 (S1/S2), as well as a C -> G change at position 2 of S1/S2 were permitted. We found that 5'E mutations did not confer virus resistance to miravirsen treatment. However, mutations in S1 and S2 induced virus resistance, and combined S1 and/or S2 mutations conferred higher resistance than single mutations. Identification of miR-122 antagomir resistance-associated mutations will facilitate the study of additional functions of miR-122 in the HCV life cycle and the mechanism of virus escape to host-targeting antiviral approaches. PMID- 26935757 TI - [Overgrowth syndromes and development of embryonic tumours: A review of cases in the last 5 years]. PMID- 26935758 TI - [Stridor in a 10 year-old boy: Unexpected findings]. PMID- 26935759 TI - [Acute accidental poisonings related to non-original containers]. PMID- 26935760 TI - [Is it urgent to update the spanish clinical practice guidelines for acute bronchiolitis management?]. PMID- 26935761 TI - Identification of chemical constituents in traditional Chinese medicine formula using HPLC coupled with linear ion trap-Orbitrap MS from high doses of medicinal materials to equivalent doses of formula: Study on Xiang-Sha-Liu-Jun-Zi-Jia-Jian granules. AB - High-resolution mass spectrometry has been a powerful tool for the research of chemical constituents in traditional Chinese medicine (TCM) formulas. However, the chromatographic peaks were difficult to discriminate clearly in data collection or analysis because of the complexity and the greatly different content of the constituents in TCM formula, which increased the difficulty of identification. In this study, a high-performance liquid chromatography coupled with linear ion trap-Orbitrap mass spectrometry based strategy focused on the comprehensive identification of TCM formula constituents was developed. Identification was carried out from a high dose of medicinal materials to equivalent dose of formula. Meanwhile, combined with mass spectrometry data, chromatographic behaviors, reference standards and previous reports, the identification of constituents in Xiang-Sha-Liu-Jun-Zi-Jia-Jian granules was described. 169 compounds were unambiguously or tentatively characterized, mainly including flavonoids, alkaloids, triterpenic acids, triterpene saponins, lactones, sesquiterpenoids and some other compounds. Among them, 11 compounds were unambiguously confirmed by comparing with reference standards. These results demonstrated that the method was effective and reliable for comprehensive identification of constituents of Xiang-Sha-Liu-Jun-Zi-Jia-Jian granules extracts and reveal the material basis of its therapeutic effects. This strategy might propose a research idea for the characterization of multi-constituents in TCM formula. PMID- 26935762 TI - Controlling S2 Population in Cyanine Dyes Using Shaped Femtosecond Pulses. AB - Fast population transfer from higher to lower excited states occurs via internal conversion (IC) and is the basis of Kasha's rule, which states that spontaneous emission takes place from the lowest excited state of the same multiplicity. Photonic control over IC is of interest because it would allow direct influence over intramolecular nonradiative decay processes occurring in condensed phase. Here we tracked the S2 and S1 fluorescence yield for different cyanine dyes in solution as a function of linear chirp. For the cyanine dyes with polar solvation response IR144 and meso-piperidine substituted IR806, increased S2 emission was observed when using transform limited pulses, whereas chirped pulses led to increased S1 emission. The nonpolar solvated cyanine IR806, on the other hand, did not show S2 emission. A theoretical model, based on a nonperturbative solution of the equation of motion for the density matrix, is offered to explain and simulate the anomalous chirp dependence. Our findings, which depend on pulse properties beyond peak intensity, offer a photonic method to control S2 population thereby opening the door for the exploration of photochemical processes initiated from higher excited states. PMID- 26935764 TI - Enhanced Re-Endothelialization of Decellularized Rat Lungs. AB - Decellularized lung tissue has been recognized as a potential platform to engineer whole lung organs suitable for transplantation or for modeling a variety of lung diseases. However, many technical hurdles remain before this potential may be fully realized. Inability to efficiently re-endothelialize the pulmonary vasculature with a functional endothelium appears to be the primary cause of failure of recellularized lung scaffolds in early transplant studies. Here, we present an optimized approach for enhanced re-endothelialization of decellularized rodent lung scaffolds with rat lung microvascular endothelial cells (ECs). This was achieved by adjusting the posture of the lung to a supine position during cell seeding through the pulmonary artery. The supine position allowed for significantly more homogeneous seeding and better cell retention in the apex regions of all lobes than the traditional upright position, especially in the right upper and left lobes. Additionally, the supine position allowed for greater cell retention within large diameter vessels (proximal 100-5000 MUm) than the upright position, with little to no difference in the small diameter distal vessels. EC adhesion in the proximal regions of the pulmonary vasculature in the decellularized lung was dependent on the binding of EC integrins, specifically alpha1beta1, alpha2beta1, and alpha5beta1 integrins to, respectively, collagen type-I, type-IV, and fibronectin in the residual extracellular matrix. Following in vitro maturation of the seeded constructs under perfusion culture, the seeded ECs spread along the vascular wall, leading to a partial reestablishment of endothelial barrier function as inferred from a custom-designed leakage assay. Our results suggest that attention to cellular distribution within the whole organ is of paramount importance for restoring proper vascular function. PMID- 26935765 TI - Techniques in Hemiarthroplasty of the First Metatarsophalangeal Joint. AB - Surgical intervention for hallux rigidus could be necessitated when conservative attempts fail to alleviate pain and dysfunction. Controversy exists as to which procedure is ideal and will provide lasting relief of hallux rigidus pain. Many arguments have been made for and against hemi-implant arthroplasty. We advocate the use of a low-profile hemimetallic endoprosthesis (Metasurg((r))) and present our technique of using a reamer to sculpt the articular surface of the metatarsal head when necessary. We further advocate for minimal resection of the phalangeal base when using a low-profile device to maintain the soft tissue periarticular intrinsics. We present a 2- to 3-position reamer decompression of the metatarsal and discuss the benefits of maintaining range of motion at the first metatarsophalangeal joint. PMID- 26935763 TI - Modifying the sugar icing on the transplantation cake. AB - As a transplant surgeon, my interest in glycobiology began through my research into ABO-incompatible allotransplantation, and grew when my goal became overcoming the shortage of organs from deceased human donors by the transplantation of pig organs into patients with terminal organ failure (xenotransplantation/cross-species transplantation). The major target for human "natural" (preformed) anti-pig antibodies is galactose-alpha(1,3)-galactose (the "Gal" epitope), which is expressed on many pig cells, including the vascular endothelium. The binding of human IgM and IgG antibodies to Gal antigens initiates the process of hyperacute rejection, resulting in destruction of the pig graft within minutes or hours. This major barrier has been overcome by the production of pigs in which the gene for the enzyme alpha(1,3) galactosyltransferase (GT) has been deleted by genetic engineering, resulting in GT knockout (GTKO) pigs. The two other known carbohydrate antigenic targets on pig cells for human anti-pig antibodies are (i) the product of the cytidine monophosphate-N-acetylneuraminic acid hydroxylase (CMAH) gene, i.e., N glycolylneuraminic acid, and (ii) the product of the beta1,4 N acetylgalactosaminyltransferase gene, i.e., the Sd(a) antigen. Expression of these two has also been deleted in pigs. These genetic manipulations, together with others directed to overcoming primate complement and coagulation activation (the latter of which also relates to glycobiology) have contributed to the prolongation of pig graft survival in nonhuman primate recipients to many months rather than a few minutes. Clinical trials of the transplantation of pig cells are already underway and transplantation of pig organs may be expected within the relatively near future. PMID- 26935766 TI - Narrative competence in children with pragmatic language impairment: a longitudinal study. AB - BACKGROUND: Children with pragmatic language impairment (PLI) show impairments in the use of language in social contexts. Although the issue has been gaining attention in recent literature, not much is known about the developmental trajectories of children who experience pragmatic language problems. Since narrative competence is an important predictor of both academic and social success, evaluating narrative competence in children with PLI is deemed important. AIMS: To examine the development of narrative competence of children with PLI compared with typically developing (TD) children using a prognostic longitudinal design. METHODS & PROCEDURES: Using the Dutch adaptation of the Renfrew Bus Story Test, narrative competence was assessed at ages 5-7 for a group of 84 children with PLI and a group of 81 TD children. Groups were compared on measures of narrative productivity, organization of story content and cohesion. OUTCOMES & RESULTS: Results showed an increase in narrative competence for both groups across most time points. The PLI group obtained lower scores on measures of narrative productivity and story content organization compared with their TD peers at all time points, but did not show more problems related to narrative cohesion. Most problems in the domain of narrative productivity and story content organization were shown to be independent of lower non-verbal intelligence. The developmental trajectory for the PLI group was largely similar to that of their TD peers, and showed a persistent developmental delay of approximately one year. Furthermore, qualitative differences were visible in the proportion of irrelevant T-units, which was consistently higher in the PLI group. The different narrative measures were found to be relatively stable over time. CONCLUSIONS & IMPLICATIONS: The results of this study suggest that narrative difficulties of children identified as pragmatically impaired persist at least until middle childhood. The persistence of the measured developmental delay, combined with the finding of qualitative differences, support the view of PLI as a deficit, which is consistent with the addition of social communication disorder (SCD) to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). PMID- 26935767 TI - Choosing foods for infants: a qualitative study of the factors that influence mothers. AB - BACKGROUND: Examining the experiences of parents making food choices for infants is important because ultimately this influences what infants eat. Infancy is a critical period when food preferences and eating behaviour begin to develop, shaping dietary patterns, growth and health outcomes. There is limited evidence regarding what or why foods are chosen for infants. OBJECTIVE: To describe the experiences of mothers making food choices for their infant children. METHODS: Semi-structured interviews with 32 Australian mothers of infants aged four to 15 months from a range of socioeconomic backgrounds. An inductive thematic analysis through a process of constant comparison was conducted on transcribed interviews. RESULTS: Mothers described many ideas and circumstances which influenced food choices they made for infants. Themes were developed which encapsulate how the wider environment and individual circumstances combine to result in the food choices made for infants. Beliefs, values, norms and knowledge were a central influence on choices. Cost, quality and availabilities of various foods were also key factors. Related to this, and combined with inherent factors such as perishability and infant acceptability, fresh fruits and vegetables were often singled out as an easy or difficult choice. Influences of time, parents' capacities, social connections and different information sources were clearly apparent. Finally infants' own preferences and how parents helped infants with learning to eat were also key influences on food choices. CONCLUSIONS: Choosing foods for infants is a complex social practice. An ecological framework depicting the multiple influences on what people eat and sociological theory on food choice regarding the role of 'social structure' and 'human agency' are both applicable to the process of choosing foods for infants. Equity issues may be key regarding the degree to which mothers can choose particular foods for infants (e.g. choosing foods which promote health). PMID- 26935768 TI - Perfusion MRI in hips with metal-on-metal and metal-on-polyethylene total hip arthroplasty: A pilot study. AB - OBJECTIVES: Hips with metal-on-metal total hip arthroplasty (MoM THA) have a high rate of adverse local tissue reactions (ALTR), often associated with hypersensitivity reactions. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) measures tissue perfusion with the parameter Ktrans (volume transfer constant of contrast agent). Our purpose was 1) to evaluate the feasibility of DCE-MRI in patients with THA and 2) to compare DCE-MRI in patients with MoM bearings with metal-on-polyethylene (MoP) bearings, hypothesising that the perfusion index Ktrans in hips with MoM THA is higher than in hips with MoP THA. METHODS: In this pilot study, 16 patients with primary THA were recruited (eight MoM, eight MoP). DCE-MRI of the hip was performed at 1.5 Tesla (T). For each patient, Ktrans was computed voxel-by-voxel in all tissue lateral to the bladder. The mean Ktrans for all voxels was then calculated. These values were compared with respect to implant type and gender, and further correlated with clinical parameters. RESULTS: There was no significant difference between the two bearing types with both genders combined. However, dividing patients by THA bearing and gender, women with MoM bearings had the highest Ktrans values, exceeding those of women with MoP bearings (0.067 min(-1) versus 0.053 min(-1); p-value < 0.05) and men with MoM bearings (0.067 min(-1) versus 0.034 min(-1); p-value < 0.001). Considering only the men, patients with MoM bearings had lower Ktrans than those with MoP bearings (0.034 min(-1) versus 0.046 min(-1); p < 0.05). CONCLUSION: DCE MRI is feasible to perform in tissues surrounding THA. Females with MoM THA show high Ktrans values in DCE-MRI, suggesting altered tissue perfusion kinematics which may reflect relatively greater inflammation.Cite this article: Dr P. E. Beaule. Perfusion MRI in hips with metal-on-metal and metal-on-polyethylene total hip arthroplasty: A pilot stud. Bone Joint Res 2016;5:73-79. DOI: 10.1302/2046 3758.53.2000572. PMID- 26935769 TI - Omacetaxine mepesuccinate induces apoptosis and cell cycle arrest, promotes cell differentiation, and reduces telomerase activity in diffuse large B-cell lymphoma cells. AB - Clinical studies have demonstrated that omacetaxine mepesuccinate exerts beneficial effects on acute myelogenous leukemia. It has been suggested that omacetaxine mepesuccinate, used alone or with interferon-alpha or cytarabine, induces remission in patients with chronic myelogenous leukemia. These effects are possibly mediated by its ability to induce apoptosis of leukemia cells and inhibit the activity of telomerase. To determine whether omacetaxine mepesuccinate is beneficial in diffuse large B-cell lymphoma (DLBCL), two DLBCL cell lines [a germinal center B cell-like subtype (GCB) and an activated B cell like subtype (ABC)] were treated with omacetaxine mepesuccinate at various concentrations for different durations. The present study indicated that omacetaxine mepesuccinate exerts proapoptotic effects in the two cell types in a dose- and time-dependent manner. The ABC subtype demonstrated increased sensitivity compared with the GCB subtype. At 40 ng/ml, omacetaxine mepesuccinate exhibited a marked proapoptotic effect on DLBCL cells compared with the other tumor cells investigated. Furthermore, omacetaxine mepesuccinate induced cell cycle arrest at G0/G1 phase, and promoted cell terminal differentiation of pro-B cells. The present study also demonstrated that omacetaxine mepesuccinate exerted its antitumor effect by reducing telomerase activity. In conclusion, the present study demonstrated that omacetaxine mepesuccinate may induce apoptosis and cell cycle arrest, promote cell differentiation, and reduce telomerase activity in DLBCL cells, thus aiding the development of omacetaxine mepesuccinate-based DLBCL therapeutic strategies. PMID- 26935772 TI - Flipping the model for access to patient records. PMID- 26935771 TI - Growth inhibition effects of ent-11alpha-hydroxy-15-oxo-kaur-16-en-19-oic-acid on colorectal carcinoma cells and colon carcinoma-bearing mice. AB - The aim of the present study was to investigate the mechanism underlying the antitumor effects of ent-11alpha-hydroxy-15-oxo-kaur-16-en-19-oic-acid (5F) in colorectal cancer (CRC). 5F was isolated and used to treat C26 murine colon carcinoma cells, a xenograft tumor mouse model (induced by C26 cells) and a CRC mouse model [induced by 1,2-dimethylhydrazine (DMH)/dextran sodium sulfate (DSS)]. C26 cell growth was inhibited by 5F in a dose- and time-dependent manner in vitro. In addition, 5F induced cell apoptosis and cell cycle arrest in the G2 phase, increased the activity of caspase-3 and caspase-9, but did not affect the activity of cascase-8, suggesting that 5F induced apoptosis via activation of the mitochondrial signaling pathway rather than the death-receptor signaling pathway. Furthermore, treatment of C26 cells with 5F resulted in upregulation of cyclin dependent kinase inhibitor 1A (p21, Cip1), Bcl-2-associated X protein, nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha and downregulation of B-cell lymphoma 2, nuclear factor kappa-light-chain enhancer of activated B cells and survivin. In vivo animal models demonstrated that 5F treatment protected mice from carcinogenesis induced by DMH/DSS and markedly decreased the xenograft tumor weight with minimal side effects. Therefore, 5F may have potential as an anti-CRC therapeutic agent for use in the clinical setting. PMID- 26935770 TI - Reduced acute myocardial ischemia-reperfusion injury in IL-6-deficient mice employing a closed-chest model. AB - OBJECTIVE AND DESIGN: We examined the role of IL-6 in the temporal development of cardiac ischemia-reperfusion injury employing a closed-chest I/R model. MATERIALS/METHODS: Infarction, local and systemic inflammation, neutrophil infiltration, coagulation and ST elevation/resolution were compared between wild type (WT) and IL-6-deficient (IL-6(-/-)) mice after 1 h ischemia and 0, 1/2, 3, and 24 h reperfusion. RESULTS: IL-6 deficiency reduced infarct size at 3 h reperfusion (28.8 +/- 4.5 % WT vs 17.6 +/- 2.5 % IL-6(-/-)), which reduction persisted and remained similar at 24 h reperfusion (25.1 +/- 3.0 % WT vs 14.6 +/- 4.4 % IL-6(-/-)). Serum Amyloid A was reduced at 24 h reperfusion only (57.5 +/- 4.9 WT vs 24.8 +/- 5.6 ug/ml IL-6(-/-) mice). Cardiac cytokines (IL-6, IL-1beta and TNFalpha) peaked at 3 h reperfusion, but IL-1beta and TNFalpha levels were unaffected by IL-6 deficiency. Significant neutrophil influx was only detected at 24 h reperfusion and was similar for WT and IL-6(-/-). Tissue factor peaked at 24 h reperfusion, whereas fibrin/fibrinogen peaked at 3 h reperfusion and was completely resolved at 24 h reperfusion; both coagulation factors were unaltered by IL-6 deficiency. Prolonged ST elevation was observed during ischemia that completely resolved for both genotypes at early reperfusion. CONCLUSIONS: The data suggest that, in the absence of major surgical intervention, IL-6 contributes to the development of infarct size in the early phase of reperfusion; this contribution did not depend on neutrophil influx, IL-1beta and TNFalpha, tissue factor and fibrin. PMID- 26935773 TI - Evaluation of sample extraction methods for proteomics analysis of green algae Chlorella vulgaris. AB - Many protein extraction methods have been developed for plant proteome analysis but information is limited on the optimal protein extraction method from algae species. This study evaluated four protein extraction methods, i.e. direct lysis buffer method, TCA-acetone method, phenol method, and phenol/TCA-acetone method, using green algae Chlorella vulgaris for proteome analysis. The data presented showed that phenol/TCA-acetone method was superior to the other three tested methods with regards to shotgun proteomics. Proteins identified using shotgun proteomics were validated using sequential window acquisition of all theoretical fragment-ion spectra (SWATH) technique. Additionally, SWATH provides protein quantitation information from different methods and protein abundance using different protein extraction methods was evaluated. These results highlight the importance of green algae protein extraction method for subsequent MS analysis and identification. PMID- 26935775 TI - Effect of weak measurement on entanglement distribution over noisy channels. AB - Being able to implement effective entanglement distribution in noisy environments is a key step towards practical quantum communication, and long-term efforts have been made on the development of it. Recently, it has been found that the null result weak measurement (NRWM) can be used to enhance probabilistically the entanglement of a single copy of amplitude-damped entangled state. This paper investigates remote distributions of bipartite and multipartite entangled states in the amplitudedamping environment by combining NRWMs and entanglement distillation protocols (EDPs). We show that the NRWM has no positive effect on the distribution of bipartite maximally entangled states and multipartite Greenberger-Horne-Zeilinger states, although it is able to increase the amount of entanglement of each source state (noisy entangled state) of EDPs with a certain probability. However, we find that the NRWM would contribute to remote distributions of multipartite W states. We demonstrate that the NRWM can not only reduce the fidelity thresholds for distillability of decohered W states, but also raise the distillation efficiencies of W states. Our results suggest a new idea for quantifying the ability of a local filtering operation in protecting entanglement from decoherence. PMID- 26935774 TI - Antihypertensive Medications and the Survival Rate of Osseointegrated Dental Implants: A Cohort Study. AB - PURPOSE: Antihypertensive drugs in general are beneficial for bone formation and remodeling, and are associated with lower risk of bone fractures. As osseointegration is influenced by bone metabolism, this study aimed to investigate the association between antihypertensive drugs and the survival rate of osseointegrated implants. MATERIALS AND METHODS: This retrospective cohort study included a total of 1,499 dental implants in 728 patients (327 implants in 142 antihypertensive-drugs-users and 1,172 in 586 nonusers). Multilevel mixed effects parametric survival analyses were used to test the association between antihypertensive drugs use and implant failure adjusting for potential confounders. RESULTS: Only 0.6% of the implants failed in patients using antihypertensive drugs while 4.1% failed in nonusers. A higher survival rate of dental implants was observed among users of antihypertensive drugs [HR (95% CI): 0.12 (0.03-0.49)] compared to nonusers. CONCLUSIONS: Our findings suggest that treatment with antihypertensive drugs may be associated with an increased survival rate of osseointegrated implants. To our knowledge, this could be the first study showing that the systemic use of a medication could be associated with higher survival rate of dental implants. PMID- 26935776 TI - iTRAQ-based quantitative proteomic analysis of the anti-apoptotic effect of hyperin, which is mediated by Mcl-1 and Bid, in H2O2-injured EA.hy926 cells. AB - Endothelial injury has been implicated in the pathogenesis of many cardiovascular diseases, including thrombotic disorders. Hyperin (quercetin-3-O-galactoside), a flavonoid compound and major bioactive component of the medicinal herb Apocynum venetum L., is commonly used to prevent endothelium dysfunction. However, its mode of action remains unclear. To the best of our knowledge, we have for the first time investigated the protective effect hyperin exerts against H2O2-induced injury in human endothelium-derived EA.hy926 cells using isobaric tags for relative and absolute quantitation (iTRAQ)-based quantitative proteomic analysis. The results showed that H2O2 exposure induced alterations in the expression of 250 proteins in the cells. We noted that the expression of 52 proteins associated with processes such as cell apoptosis, cell cycle and cytoskeleton organization, was restored by hyperin treatment. Of the proteins differentially regulated following H2O2 stress, the anti-apoptotic protein, myeloid cell leukemia-1 (Mcl 1), and the pro-apoptotic protein, BH3-interacting domain death agonist (Bid), exhibited marked changes in expression. Hyperin increased Mcl-1 expression and decreased that of Bid in a dose-dependent manner. In addition, flow cytometric analysis and western blot analysis of the apoptosis-related proteins, truncated BID (tBid), cleaved caspase-3, cleaved caspase-9, Fas, FasL and caspase-8, demonstrated that the rate of apoptosis and the pro-apoptotic protein levels were decreased by hyperin pre-treatment. In the present study we demonstrate that hyperin effectively prevents H2O2-induced cell injury by regulating the Mcl-1- and Bid-mediated anti-apoptotic mechanism, suggesting that hyperin is a potential candidate for use in the treatment of thrombotic diseases. PMID- 26935777 TI - Uterine perforation and small bowel incarceration 11 months after dilatation and curettage: sonographic and surgical findings. PMID- 26935778 TI - Prevalence, risk factors, management, and treatment outcomes of first-line antituberculous drug-induced liver injury: a prospective cohort study. AB - PURPOSE: Antituberculosis drug-induced liver injury (ATDILI) is one of the most deleterious side effects associated with chemotherapy against tuberculosis (TB). In this study, our objective was to determine the incidence, risk factors, and management of ATDILI and analyze its impact on the treatment outcome in patients receiving standard anti-TB chemotherapy. METHODS: A prospective cohort study of ATDILI prevalence was conducted in 938 enrolled patients of the 1426 TB cases in Shanghai from March 2011 to September 2012. Patients were followed up until February 2014. Univariate and multivariate logistic regression analyses were used to determine the risk factors of ATDILI. Successful therapeutic outcome, rates of drug resistance conversion, sputum smear/culture conversion, and lung cavity closure were analyzed. RESULTS: Hepatitis B surface antigen/hepatitis B e antigen positive hepatitis B carriers, complicated with systemic lupus erythematosus, albumin <= 25 g/L, and chronic alcoholism were independent risk factors for ATDILI. Of the 121 cases with ATDILI (incidence rate of 12.9%), 84 (69.4%) used modified anti-TB therapy after recovery of liver function. Compared with the non ATDILI group, patients with ATDILI exhibited remarkably decreased lung cavity closure rate (84.6% vs. 93.0%, P < 0.001) along with significantly reduced sputum smear/culture conversion rate (85.4% vs. 94.0%, P < 0.001). CONCLUSIONS: Our findings indicated that 12.9% patients developed ATDILI during standard anti-TB therapy, resulting in poor therapeutic outcome. Hepatitis B carriers with systemic lupus erythematosus, albumin <= 25 g/L, and chronic alcoholism manifested increased risks for ATDILI. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26935779 TI - Factor analysis of two versions of the Oral Impacts on Daily Performance scale. AB - The aim of this study was to explore the factorial structure and agreement of two scoring versions of the Oral Impacts on Daily Performance (OIDP) scale, and to compare the fit of the originally proposed factorial structure, as opposed to an alternative model. Exploratory factor analyses (EFA) were conducted to explore the dimensional structure of the OIDP on a convenience sample of 200 adults (S1). Confirmatory factor analyses (CFA) were performed on a random sample of 720 adults (S2). The Cronbach's alpha coefficients for the total and frequency versions of the OIDP scale were, respectively, 0.81 and 0.70 for S1, and 0.82 and 0.79 for S2, with a quadratic Kappa kappa = 0.83 (95% CI: 0.75-0.89) in S1 and kappa = 0.92 (95% CI: 0.89-0.94) in S2. Exploratory factor analyses showed one factor for the total version and three factors (non-interpretable) for the frequency version. Confirmatory factor analyses showed that the frequency version for the one-factor model (Model 1) had the best fit [Root Mean Square Error of Approximation (RMSEA) = 0.04; Comparative Fit Index (CFI) = 0.98; Tucker-Lewis index (TLI) = 0.97, chi(2) P-value < 0.01]. The one-factor model was not significantly different from the original three-factor model. These findings suggest that the scale captures only one overall quality of life dimension, and that the frequency version was the most parsimonious model of the OIDP scale. PMID- 26935780 TI - Point mutation in mitochondrial tRNA gene is associated with polycystic ovary syndrome and insulin resistance. AB - Polycystic ovarian syndrome (PCOS) is characterized by chronic anovulation, hyperandrogenism and polycystic ovaries. To date, the molecular mechanisms underlying PCOS have remained to be fully elucidated. As recent studies have revealed a positive association between mitochondrial dysfunction and PCOS, current investigations focus on mutations in the mitochondrial genome of patients with POCS. The present study reported a Chinese patient with PCOS. Sequence analysis of the mitochondrial genome showed the presence of homoplasmic ND5 T12338C and tRNASer (UCN) C7492T mutations as well as a set of polymorphisms belonging to the human mitochondrial haplogroup F2. The T12338C mutation is known to decrease the ND5 mRNA levels and to inhibit the processing of RNA precursors. The C7492T mutation, which occurred at the highly conserved nucleotide in the anticodon stem of the tRNASer (UCN) gene, is important for the tRNA steady-state level as well as the aminoacylation ability. Therefore, the combination of the ND5 T12338C and tRNASer (UCN) C7492T mutations may lead to mitochondrial dysfunction, and is likely to be involved in the pathogenesis of PCOS. The present study provided novel insight into the molecular mechanisms of PCOS. PMID- 26935781 TI - Basic Principles and Recent Trends of Transcranial Motor Evoked Potentials in Intraoperative Neurophysiologic Monitoring. AB - Transcranial motor evoked potentials (TcMEPs), which are muscle action potentials elicited by transcranial brain stimulation, have been the most popular method for the last decade to monitor the functional integrity of the motor system during surgery. It was originally difficult to record reliable and reproducible potentials under general anesthesia, especially when inhalation-based anesthetic agents that suppressed the firing of anterior horn neurons were used. Advances in anesthesia, including the introduction of intravenous anesthetic agents, and progress in stimulation techniques, including the use of pulse trains, improved the reliability and reproducibility of TcMEP responses. However, TcMEPs are much smaller in amplitude compared with compound muscle action potentials evoked by maximal peripheral nerve stimulation, and vary from one trial to another in clinical practice, suggesting that only a limited number of spinal motor neurons innervating the target muscle are excited in anesthetized patients. Therefore, reliable interpretation of the critical changes in TcMEPs remains difficult and controversial. Additionally, false negative cases have been occasionally encountered. Recently, several facilitative techniques using central or peripheral stimuli, preceding transcranial electrical stimulation, have been employed to achieve sufficient depolarization of motor neurons and augment TcMEP responses. These techniques might have potentials to improve the reliability of intraoperative motor pathway monitoring using TcMEPs. PMID- 26935783 TI - In vitro assessment of the anthelmintic activity of Hedysarum carnosum Desf. at different phenological stages and from six locations in Tunisia. AB - Gastrointestinal nematodes are compromising productivity of grazing sheep and goats. Therefore, scientists have been looking for cost-effective alternative options. Forage legumes (Fabacea Family) contain tannins that could improve livestock performance and their health as well. The present study aimed to (i) determine the in vitro anthelmintic (AH) activity of 19 acetonic extracts of Hedysarum carnosum Desf on Haemonchus contortus by a larval exsheathment assay (LEA); (ii) test the anthelmintic activity of condensed tannins using a deactivating reagent, polyvinylpolypyrrolidone (PVPP); (iii) study the effect of location and the phenological stage on the percentage of exsheathment. The LEA was used at different concentrations (150, 300, 600, 1200 ug mL-1 of acetonic extract/mL of purified buffer solution (PBS)). The larval exsheathment is concentration, location, phenological stage dependent. All extracts, caused a delay of the percentage of exsheathment over 50% so the AH activity of H. carnosum was confirmed. After addition of PVPP, the % exsheathment was similar to the 150 ug mL-1 concentration. The biplot showed that Loc1(S), Loc4(B), Loc 5(PF), Loc 6(BM) and Loc 6(PF) were isolated from other plant extract sample. Our in vitro study showed that H. carnosum seems to be a promising alternative to AH drugs. PMID- 26935782 TI - The New Antiepileptic Drugs: Their Neuropharmacology and Clinical Indications. AB - The administration of antiepileptic drugs (AEDs) is the first treatment of epilepsy, one of the most common neurological diseases. Therapeutic guidelines include newer AEDs as front-line drugs; monotherapy with new AEDs is delivered in Japan. While about 70% of patients obtain good seizure control by taking one to three AEDs, about 60% experience adverse effects and 33% have to change drugs. Compared to traditional AEDs, the prolonged administration of new AEDs elicits fewer adverse effects and fewer drug interactions and their teratogenicity may be lower. These characteristics increase drug compliance and allow combination therapy for drug-resistant epilepsy, although the antiepileptic effects of the new AEDs are not greater than of traditional AEDs. Comorbidities are not rare in epileptics; many adult patients present with stroke and brain tumors. In stroke patients requiring risk control and in chemotherapy-treated brain tumor patients, their fewer drug interactions render the new AEDs advantageous. Also, new AEDs offer favorable side benefits for concurrent diseases and conditions. Patients with stroke and traumatic brain injury often present with psychiatric/behavioral symptoms and cognitive impairment and some new AEDs alleviate such symptoms. This review presents an outline of the new AEDs used to treat adult patients based on the pharmacological activity of the drugs and discusses possible clinical indications from the perspective of underlying causative diseases and comorbidities. PMID- 26935784 TI - Availability of Automated External Defibrillators in Public High Schools. AB - OBJECTIVES: To assess automated external defibrillator (AED) distribution and cardiac emergency preparedness in Michigan secondary schools and investigate for association with school sociodemographic characteristics. STUDY DESIGN: Surveys were sent via electronic mail to representatives from all public high schools in 30 randomly selected Michigan counties, stratified by population. Association of AED-related factors with school sociodemographic characteristics were evaluated using Wilcoxon rank sum test and chi(2) test, as appropriate. RESULTS: Of 188 schools, 133 (71%) responded to the survey and all had AEDs. Larger student population was associated with fewer AEDs per 100 students (P < .0001) and fewer staff with AED training per AED (P = .02), compared with smaller schools. Schools with >20% students from racial minority groups had significantly fewer AEDs available per 100 students than schools with less racial diversity (P = .03). Schools with more students eligible for free and reduced lunch were less likely to have a cardiac emergency response plan (P = .02) and demonstrated less frequent AED maintenance (P = .03). CONCLUSIONS: Although AEDs are available at public high schools across Michigan, the number of AEDs per student varies inversely with minority student population and school size. Unequal distribution of AEDs and lack of cardiac emergency preparedness may contribute to outcomes of sudden cardiac arrest among youth. PMID- 26935785 TI - Genetic Factors Contribute to Risk for Neonatal Respiratory Distress Syndrome among Moderately Preterm, Late Preterm, and Term Infants. AB - OBJECTIVE: To determine the genetic contribution to risk for respiratory distress syndrome (RDS) among moderately preterm, late preterm, and term infants (estimated gestational age >=32 weeks) of African- and European-descent. STUDY DESIGN: We reviewed clinical records for 524 consecutive twin pairs >=32 weeks gestation. We identified pairs in which at least 1 twin had RDS (n = 225) and compared the concordance of RDS between monozygotic and dizygotic twins. Using mixed-effects logistic regression, we identified covariates that increased disease risk. We performed additive genetic, common environmental, and residual effects modeling to estimate genetic variance and used the ratio of genetic variance to total variance to estimate genetic contribution to RDS disease risk. RESULTS: Monozygotic twins were more concordant for RDS than dizygotic twins (P = .0040). Estimated gestational age, European-descent, male sex, delivery by cesarean, and 5-minute Apgar score each independently increased risk for RDS. After adjusting for these covariates, genetic effects accounted for 58% (P = .0002) of the RDS disease risk variance for all twin pairs. CONCLUSIONS: In addition to environmental factors, genetic factors may contribute to RDS risk among moderately preterm, late preterm, and term infants. Discovery of risk alleles may be important for prediction and management of RDS risk. PMID- 26935786 TI - Sustained Effectiveness of Monovalent and Pentavalent Rotavirus Vaccines in Children. AB - OBJECTIVE: Using case-control methodology, we measured the vaccine effectiveness (VE) of the 2-dose monovalent rotavirus vaccine (RV1) and 3-dose pentavalent rotavirus vaccine (RV5) series given in infancy against rotavirus disease resulting in hospital emergency department or inpatient care. STUDY DESIGN: Children were eligible for enrollment if they presented to any 1 of 3 hospitals in Atlanta, Georgia with diarrhea <=10 days duration during January-June 2013 and were born after RV1 introduction. Stool samples were tested for rotavirus by enzyme immunoassay and immunization records were obtained from providers and the state electronic immunization information system. Case-subjects (children testing rotavirus antigen-positive) were compared with children testing rotavirus antigen negative. RESULTS: Overall, 98 rotavirus-case subjects and 175 rotavirus-negative controls were enrolled. Genotype G12P[8] predominated (n = 87, 89%). The VE of 2 RV1 doses was 84% (95% CI 38, 96) among children aged 8-23 months and 82% (95% CI 41, 95) among children aged >=24 months. For the same age groups, the VE of 3 RV5 doses was 80% (95% CI 27, 95) and 87% (95% CI 22, 98), respectively. CONCLUSIONS: Under routine use, the RV1 and RV5 series were both effective against moderate-to severe rotavirus disease during a G12P[8] season, and both vaccines demonstrated sustained protection beyond the first 2 years of life. PMID- 26935788 TI - Exploratory analysis of textual data from the Mother and Child Handbook using the text-mining method: Relationships with maternal traits and post-partum depression. AB - AIM: The aim of the present study was to examine the possibility of screening apprehensive pregnant women and mothers at risk for post-partum depression from an analysis of the textual data in the Mother and Child Handbook by using the text-mining method. METHODS: Uncomplicated pregnant women (n = 58) were divided into two groups according to State-Trait Anxiety Inventory grade (high trait [group I, n = 21] and low trait [group II, n = 37]) or Edinburgh Postnatal Depression Scale score (high score [group III, n = 15] and low score [group IV, n = 43]). An exploratory analysis of the textual data from the Maternal and Child Handbook was conducted using the text-mining method with the Word Miner software program. A comparison of the 'structure elements' was made between the two groups. RESULTS: The number of structure elements extracted by separated words from text data was 20 004 and the number of structure elements with a threshold of 2 or more as an initial value was 1168. Fifteen key words related to maternal anxiety, and six key words related to post-partum depression were extracted. CONCLUSION: The text-mining method is useful for the exploratory analysis of textual data obtained from pregnant woman, and this screening method has been suggested to be useful for apprehensive pregnant women and mothers at risk for post-partum depression. PMID- 26935787 TI - Characteristics of Pediatric Exposures to Antidementia Drugs Reported to a Poison Control System. AB - OBJECTIVE: To characterize pediatric exposures to the antidementia drugs donepezil, memantine, rivastigmine, and galantamine by reviewing a poison control system's database. STUDY DESIGN: A retrospective review of a statewide poison control system's database identified cases of pediatric (less than 19 years of age) exposures to antidementia drugs over an 11-year period. Data collected included age, sex, drug(s) involved, route of exposure, reason for exposure, symptoms, and interventions. RESULTS: There were 189 cases identified (53% male, median age: 2.3 years, 99% unintentional exposures). Donepezil was the most commonly reported exposure (106 cases), followed by memantine (57), galantamine (18), oral rivastigmine (16), and transdermal rivastigmine (3). Coingestants were reported in 68 (36%) cases. Symptoms were reported in 38 (20%) cases. Gastrointestinal symptoms were most common (n = 21) followed by central nervous system depression (n = 15). Oral rivastigmine was associated with higher rates of symptoms. No bradycardia, seizures, or fasciculations were reported. Eighty-nine cases (47%) were evaluated at a health care facility, and 13 (7%) were admitted to a hospital. Oral rivastigmine exposures were associated with increased rate of health care facility evaluation. Activated charcoal was administered in 28 cases. Atropine was given only once, for drooling. There were no serious outcomes or deaths in this series. CONCLUSIONS: Reported pediatric exposures to antidementia drugs resulted in minimal morbidity and no mortality. Oral rivastigmine exposures were found to be associated with more symptoms and health care facility evaluations. PMID- 26935789 TI - Histone deacetylase inhibitor screening identifies HC toxin as the most effective in intrahepatic cholangiocarcinoma cells. AB - Histone deacetylases (HDACs) are highly expressed in intrahepatic cholangiocarcinoma (ICC) and are associated with poor prognosis of these patients. The aim of the present study was to explore the inhibitory effects of HDAC inhibitors on ICC cells and identify effective and sensitive drugs for ICC. Effects of 34 HDAC inhibitors were screened through two rounds of cell viability assays, and HC toxin, a cyclic tetrapeptide first isolated from the secondary metabolite of Helminthosporium carbonum, exhibited an antitumor activity superior to that of the other HDAC inhibitors and gemcitabine. The mechanisms involved in the inhibitory effects of HC toxin on CCLP-1 cells were investigated by cell counting, colony formation assay, cell morphological observation, real-time PCR, western blotting and flow cytometry. It was demonstrated that HC toxin inhibited the cell proliferation and clone formation ability of the CCLP-1 cells. HC toxin increased the acetyl-histone H4 level and this was associated with the inhibitory effect of HC toxin on the CCLP-1 cells. We also found that HC toxin reduced the level of HDAC1 protein in a post-transcriptional manner. Morphological observation showed multiple morphological changes and indicated the possibility of cell differentiation owing to HC toxin. With increasing concentration of HC toxin, the cell cycle was gradually arrested at the G0/G1 stage and the percentage of apoptotic cells increased which was not mainly through the caspase 3-dependent ways. These results indicated that HC toxin was the most effective among the various HDAC inhibitors with multiple functions in the suppression of ICC in vitro. Thus, HC may be a potential chemotherapeutic for ICC. PMID- 26935790 TI - Beyond sodefrin: evidence for a multi-component pheromone system in the model newt Cynops pyrrhogaster (Salamandridae). AB - Sodefrin, a decapeptide isolated from the male dorsal gland of the Japanese fire belly newt Cynops pyrrhogaster, was the first peptide pheromone identified from a vertebrate. The fire belly salamander and sodefrin have become a model for sex pheromone investigation in aquatically courting salamanders ever since. Subsequent studies in other salamanders identified SPF protein courtship pheromones of around 20 kDa belonging to the same gene-family. Although transcripts of these proteins could be PCR-amplified in Cynops, it is currently unknown whether they effectively use full-length SPF pheromones next to sodefrin. Here we combined transcriptomics, proteomics and phylogenetics to investigate SPF pheromone use in Cynops pyrrhogaster. Our data show that not sodefrin transcripts, but multiple SPF transcripts make up the majority of the expression profile in the dorsal gland of this newt. Proteome analyses of water in which a male has been courting confirm that this protein blend is effectively secreted and tail-fanned to the female. By combining phylogenetics and expression data, we show that independent evolutionary lineages of these SPF's were already expressed in ancestral Cynops species before the origin of sodefrin. Extant Cynops species continue to use this multi-component pheromone system, consisting of various proteins in addition to a lineage-specific peptide. PMID- 26935791 TI - Understanding Ammonium Transport in Bioelectrochemical Systems towards its Recovery. AB - We report an integrated experimental and simulation study of ammonia recovery using microbial electrolysis cells (MECs). The transport of various species during the batch-mode operation of an MEC was examined experimentally and the results were used to validate the mathematical model for such an operation. It was found that, while the generated electrical current through the system tends to acidify (or basify) the anolyte (or catholyte), their effects are buffered by a cascade of chemical groups such as the NH3/NH4(+) group, leading to relatively stable pH values in both anolyte and catholyte. The transport of NH4(+) ions accounts for ~90% of the total current, thus quantitatively confirming that the NH4(+) ions serve as effective proton shuttles during MEC operations. Analysis further indicated that, because of the Donnan equilibrium at cation exchange membrane-anolyte/catholyte interfaces, the Na(+) ion in the anolyte actually facilitates the transport of NH4(+) ions during the early stage of a batch cycle and they compete with the NH4(+) ions weakly at later time. These insights, along with a new and simple method for predicting the strength of ammonia diffusion from the catholyte toward the anolyte, will help effective design and operation of bioeletrochemical system-based ammonia recovery systems. PMID- 26935792 TI - Diel variations in the assemblage structure and foraging ecology of larval and 0+ year juvenile fishes in a man-made floodplain waterbody. AB - This study investigated diel variations in zooplankton composition and abundance, and the species composition, density, size structure, feeding activity, diet composition and prey selection of larval and 0+ year juvenile fishes in the littoral of a man-made floodplain waterbody over five 24 h periods within a 57 day period. There was a significant difference in the species composition of diurnal and nocturnal catches, with most species consistently peaking in abundance either during daylight or at night, reflecting their main activity period. There were no consistent diel patterns in assemblage structure or the abundance of some species, however, most likely, respectively, due to the phenology of fish hatching and ontogenetic shifts in diel behaviour or habitat use. There were few clear diel patterns in the diet composition or prey selection of larval and 0+ year juvenile roach Rutilus rutilus and perch Perca fluviatilis, with most taxa consistently selected or avoided irrespective of the time of day or night, and no obvious shift between planktonic and benthic food sources, but dietary overlap suggested that interspecific interactions were probably strongest at night. It is essential that sampling programmes account for the diel ecology of the target species, as diurnal surveys alone could produce inaccurate assessments of resource use. The relative lack of consistent diel patterns in this study suggests that multiple 24 h surveys are required in late spring and early summer to provide accurate assessments of 0+ year fish assemblage structure and foraging ecology. PMID- 26935793 TI - Improving Inpatient Surveys: Web-Based Computer Adaptive Testing Accessed via Mobile Phone QR Codes. AB - BACKGROUND: The National Health Service (NHS) 70-item inpatient questionnaire surveys inpatients on their perceptions of their hospitalization experience. However, it imposes more burden on the patient than other similar surveys. The literature shows that computerized adaptive testing (CAT) based on item response theory can help shorten the item length of a questionnaire without compromising its precision. OBJECTIVE: Our aim was to investigate whether CAT can be (1) efficient with item reduction and (2) used with quick response (QR) codes scanned by mobile phones. METHODS: After downloading the 2008 inpatient survey data from the Picker Institute Europe website and analyzing the difficulties of this 70 item questionnaire, we used an author-made Excel program using the Rasch partial credit model to simulate 1000 patients' true scores followed by a standard normal distribution. The CAT was compared to two other scenarios of answering all items (AAI) and the randomized selection method (RSM), as we investigated item length (efficiency) and measurement accuracy. The author-made Web-based CAT program for gathering patient feedback was effectively accessed from mobile phones by scanning the QR code. RESULTS: We found that the CAT can be more efficient for patients answering questions (ie, fewer items to respond to) than either AAI or RSM without compromising its measurement accuracy. A Web-based CAT inpatient survey accessed by scanning a QR code on a mobile phone was viable for gathering inpatient satisfaction responses. CONCLUSIONS: With advances in technology, patients can now be offered alternatives for providing feedback about hospitalization satisfaction. This Web-based CAT is a possible option in health care settings for reducing the number of survey items, as well as offering an innovative QR code access. PMID- 26935794 TI - Informal learning processes in support of clinical service delivery in a service oriented community pharmacy. AB - The evolving health care system necessitates pharmacy organizations' adjustments by delivering new services and establishing inter-organizational relationships. One approach supporting pharmacy organizations in making changes may be informal learning by technicians, pharmacists, and pharmacy owners. Informal learning is characterized by a four-step cycle including intent to learn, action, feedback, and reflection. This framework helps explain individual and organizational factors that influence learning processes within an organization as well as the individual and organizational outcomes of those learning processes. A case study of an Iowa independent community pharmacy with years of experience in offering patient care services was made. Nine semi-structured interviews with pharmacy personnel revealed initial evidence in support of the informal learning model in practice. Future research could investigate more fully the informal learning model in delivery of patient care services in community pharmacies. PMID- 26935795 TI - Membrane-proximal TRAIL species are incapable of inducing short circuit apoptosis signaling: Implications for drug development and basic cytokine biology. AB - TRAIL continues to garner substantial interest as a recombinant cancer therapeutic while the native cytokine itself serves important tumor surveillance functions when expressed in membrane-anchored form on activated immune effector cells. We have recently developed the genetically stabilized TRAIL platform TR3 in efforts to improve the limitations associated with currently available drug variants. While in the process of characterizing mesothelin-targeted TR3 variants using a single chain antibody (scFv) delivery format (SS-TR3), we discovered that the membrane-tethered cytokine had a substantially increased activity profile compared to non-targeted TR3. However, cell death proceeded exclusively via a bystander mechanism and protected the mesothelin-positive targets from apoptosis rather than leading to their elimination. Incorporation of a spacer-into the mesothelin surface antigen or the cancer drug itself-converted SS-TR3 into a cis acting phenotype. Further experiments with membrane-anchored TR3 variants and the native cytokine confirmed our hypothesis that membrane-proximal TRAIL species lack the capacity to physically engage their cognate receptors coexpressed on the same cell membrane. Our findings not only provide an explanation for the "peaceful" coexistence of ligand and receptor of a representative member of the TNF superfamily but give us vital clues for the design of activity-enhanced TR3 based cancer therapeutics. PMID- 26935796 TI - MicroRNA-200b inhibits epithelial-mesenchymal transition and migration of cervical cancer cells by directly targeting RhoE. AB - Previous studies have identified microRNA-200b (miR-200b) as a powerful regulator of epithelial-mesenchymal transition (EMT) via the control of gene expression. EMT is a critical event that is associated with the initiation of malignant tumor metastasis. A lack of E-cadherin expression and overexpression of vimentin are hallmarks of EMT. It is well-known that RhoE, which is associated with regulation of the actin cytoskeleton and migration via alterations in cell motility, regulates the expression of E-cadherin, matrix metalloproteinase-9 (MMP-9) and vimentin. However, it remains to be elucidated whether miR-200b may alter the molecular behavior of RhoE. The present study aimed to determine whether miR-200b was able to regulate the EMT of cervical cancer, in order to control metastasis. In addition, the correlation between miR-200b and RhoE, E-cadherin and vimentin expression was investigated. Notably, miR-200b was shown to inhibit the function of RhoE and suppress the EMT of cervical cancer. Furthermore, HeLa cells were transfected with miR-200b mimics or inhibitors, and the protein expression levels of E-cadherin, MMP-9, vimentin and RhoE were subsequently detected. A Transwell assay was also conducted, in order to observe the metastatic ability of the HeLa cells. In addition, a luciferase reporter assay was performed using luciferase reporter vectors containing the full length 3'-untranslated region (UTR) of RhoE; miR-200b was able to significantly suppress relative luciferase activity by targeting the 3'-UTR of RhoE. These results suggested that miR-200b may markedly inhibit metastatic potential by regulating cell EMT and inhibiting RhoE; therefore, miR-200b may be considered an effective target for the treatment of patients with highly metastatic cervical cancer. PMID- 26935797 TI - Deciphering the Potential Pharmaceutical Mechanism of Chinese Traditional Medicine (Gui-Zhi-Shao-Yao-Zhi-Mu) on Rheumatoid Arthritis. AB - Gui-Zhi-Shao-Yao-Zhi-Mu (GSZ) decoction is a Traditional Chinese Medicine (TCM) formula commonly used for the treatment of Rheumatoid Arthritis (RA). The therapeutic effect of GSZ for RA treatment is supported by our clinical retrospective study. To uncover the potential mechanism underlying GSZ formula, we identified 1,327 targets of 673 compounds from 9 herbs that involve in Fc epsilon RI signaling pathway and regulation of immunoglobulin production. Comparison between formula targets with 79 RA drug targets and 675 RA disease genes showed that formula targets covered 31.6% RA drug targets and 19.9% RA disease genes. Formula specific targets presented expression patterns highly similar to the disease genes and drug targets based on the expression profiles of RA samples. Investigation of 10 inferred gene clusters from expression profiles with a target association network revealed that formula specific targets directly or indirectly interacted with disease genes that were essential for immune related biological processes (e.g. inflammatory responses, treatment response of rheumatoid arthritis, etc.). Our result indicated that GSZ disrupted the RA disease dysfunction modules and restored homeostasis in the human body. The systemic approach to infer therapeutic mechanisms of GSZ for RA treatment provides a new insight in the understanding of this TCM formula. PMID- 26935805 TI - Mechanism of intermediate filament recognition by plakin repeat domains revealed by envoplakin targeting of vimentin. AB - Plakin proteins form critical connections between cell junctions and the cytoskeleton; their disruption within epithelial and cardiac muscle cells cause skin-blistering diseases and cardiomyopathies. Envoplakin has a single plakin repeat domain (PRD) which recognizes intermediate filaments through an unresolved mechanism. Herein we report the crystal structure of envoplakin's complete PRD fold, revealing binding determinants within its electropositive binding groove. Four of its five internal repeats recognize negatively charged patches within vimentin via five basic determinants that are identified by nuclear magnetic resonance spectroscopy. Mutations of the Lys1901 or Arg1914 binding determinants delocalize heterodimeric envoplakin from intracellular vimentin and keratin filaments in cultured cells. Recognition of vimentin is abolished when its residues Asp112 or Asp119 are mutated. The latter slot intermediate filament rods into basic PRD domain grooves through electrosteric complementarity in a widely applicable mechanism. Together this reveals how plakin family members form dynamic linkages with cytoskeletal frameworks. PMID- 26935806 TI - Estimating oxygen distribution from vasculature in three-dimensional tumour tissue. AB - Regions of tissue which are well oxygenated respond better to radiotherapy than hypoxic regions by up to a factor of three. If these volumes could be accurately estimated, then it might be possible to selectively boost dose to radio-resistant regions, a concept known as dose-painting. While imaging modalities such as 18F fluoromisonidazole positron emission tomography (PET) allow identification of hypoxic regions, they are intrinsically limited by the physics of such systems to the millimetre domain, whereas tumour oxygenation is known to vary over a micrometre scale. Mathematical modelling of microscopic tumour oxygen distribution therefore has the potential to complement and enhance macroscopic information derived from PET. In this work, we develop a general method of estimating oxygen distribution in three dimensions from a source vessel map. The method is applied analytically to line sources and quasi-linear idealized line source maps, and also applied to full three-dimensional vessel distributions through a kernel method and compared with oxygen distribution in tumour sections. The model outlined is flexible and stable, and can readily be applied to estimating likely microscopic oxygen distribution from any source geometry. We also investigate the problem of reconstructing three-dimensional oxygen maps from histological and confocal two-dimensional sections, concluding that two dimensional histological sections are generally inadequate representations of the three-dimensional oxygen distribution. PMID- 26935807 TI - miR-409-3p sensitizes colon cancer cells to oxaliplatin by inhibiting Beclin-1 mediated autophagy. AB - The chemoresistance of colon cancer cells limits the efficacy of chemotherapy. miR-409-3p has been shown to be downregulated in various types of cancer. In the present study, we examined the role of miR-409-3p in colon cancer as well as the effects of miR-409-3p on the sensitivity of colon cancer cells to oxaliplatin. The expression of miR-409 was significantly downregulated in the human colon cancer cell lines compared with the normal colon epithelial cells. Importantly, the miR-409-3p expression levels were lower in human colon cancer patient samples than in normal colon tissues. Moreover, we observed a negative correlation between the miR-409-3p levels and resistance to oxaliplatin: the oxaliplatin resistant colon cancer cells exhibited significantly downregulated miR-409-3p levels, but higher autophagic activity than the oxaliplatin-sensitive cells. Using bioinformatics analysis, we predicted that miR-409-3p miRNA binds to the key autophagy gene encoding Beclin-1. Our findings indicated that the overexpression of miR-409-3p inhibited Beclin-1 expression and autophagic activity by binding to the 3'-untranslated region of Beclin-1 mRNA. In addition, the overexpression of miR-409-3p enhanced the chemosensitivity of the oxaliplatin sensitive and oxaliplatin-resistant colon cancer cells. The restoration of Beclin 1 abrogated these effects of miR-409-3p. In a xenograft model using nude mice, we examined the effects of miR-409-3p on tumor growth during chemotherapy. miR-409 3p overexpression sensitized the tumor to chemotherapy, while inhibiting chemotherapy-induced autophagy in a manner dependent on Beclin-1. The findings of our study suggest that miR-409-3p is capable of enhancing the chemosensitivity of colon cancer cells by inhibiting Beclin-1-mediated autophagy. PMID- 26935808 TI - Corilagin suppresses cholangiocarcinoma progression through Notch signaling pathway in vitro and in vivo. AB - Corilagin is a natural plant polyphenol tannic acid with antitumor, anti inflammatory, and anti-oxidative properties. However, the mechanisms of its actions are largely unknown. Our group reported that corilagin could induce cell inhibition in human breast cancer cell line MCF-7 and human liver hepatocellular carcinoma cell lines HepG2. We report here that corilagin inhibits cholangiocarcinoma (CCA) development through regulating Notch signaling pathway. We found that, in vitro, corilagin inhibited CCA cell proliferation, migration and invasion, promoted CCA cell apoptosis, and inhibited Notch1 and Notch signaling pathway protein expression. Co-immunoprecipitation was used to establish Notch intracellular domain (NICD) interaction with MAML1 and P300 in CCA. Importantly, corilagin reduced Hes1 mRNA level through inhibiting Hes1 promoter activity. In nude mice, corilagin inhibited CCA growth and repressed the expression of Notch1 and mTOR. These results indicate that corilagin may control CCA cell growth by downregulating the expression of Notch1. Therefore, our findings suggest that corilagin may have the potential to become a new therapeutic drug for human CCA. PMID- 26935809 TI - Present perspectives of broadband photodetectors based on nanobelts, nanoribbons, nanosheets and the emerging 2D materials. AB - Recent research on photodetectors has been mainly focused on nanostructured materials that form the building blocks of device fabrication. The selection of a suitable material with well-defined properties forms the key issue for the fabrication of photodetectors that cover different ranges of the electromagnetic spectrum. In this review, the latest progress in light detection using nanobelts, nanoribbons, nanosheets and the emerging two-dimensional (2D) materials is reviewed. Particular emphasis is placed on the detection of light by the hybrid structures of the mentioned nanostructured materials in order to enhance the efficiency of the light-matter interaction. The booming research area of black phosphorus based photo-detection is also reviewed. This review provides an overview of basic concepts and new directions towards photodetectors, and highlights potential for the future development of high performance broadband photodetectors. PMID- 26935810 TI - Atheroprotective properties of human Omentin-1 in experimental atherosclerosis. PMID- 26935811 TI - POEGMA-based disulfide-containing fluorescent probes for imitating and tracing noninternalization-based intracellular drug delivery. AB - POEGMA-based disulfide-containing fluorescent probes were designed and synthesized to enable the real-time and quantitative analysis of the (bio)reduction of disulfides within the polymeric backbones in complex redox media and in the presence of cells. This study lights up the way of exploiting bioreduction in the extracellular spaces for the delivery of hydrophobic drugs. PMID- 26935812 TI - Cu and Cu-Based Nanoparticles: Synthesis and Applications in Catalysis. AB - The applications of copper (Cu) and Cu-based nanoparticles, which are based on the earth-abundant and inexpensive copper metal, have generated a great deal of interest in recent years, especially in the field of catalysis. The possible modification of the chemical and physical properties of these nanoparticles using different synthetic strategies and conditions and/or via postsynthetic chemical treatments has been largely responsible for the rapid growth of interest in these nanomaterials and their applications in catalysis. In addition, the design and development of novel support and/or multimetallic systems (e.g., alloys, etc.) has also made significant contributions to the field. In this comprehensive review, we report different synthetic approaches to Cu and Cu-based nanoparticles (metallic copper, copper oxides, and hybrid copper nanostructures) and copper nanoparticles immobilized into or supported on various support materials (SiO2, magnetic support materials, etc.), along with their applications in catalysis. The synthesis part discusses numerous preparative protocols for Cu and Cu-based nanoparticles, whereas the application sections describe their utility as catalysts, including electrocatalysis, photocatalysis, and gas-phase catalysis. We believe this critical appraisal will provide necessary background information to further advance the applications of Cu-based nanostructured materials in catalysis. PMID- 26935813 TI - Ibuprofen-conjugated hyaluronate/polygalacturonic acid hydrogel for the prevention of epidural fibrosis. AB - The formation of fibrous tissue is part of the natural healing response following a laminectomy. Severe scar tissue adhesion, known as epidural fibrosis, is a common cause of failed back surgery syndrome. In this study, by combining the advantages of drug treatment with a physical barrier, an ibuprofen-conjugated crosslinkable polygalacturonic acid and hyaluronic acid hydrogel was developed for epidural fibrosis prevention. Conjugation was confirmed and measured by 1D(1)H NMR spectroscopy.In vitroanalysis showed that the ibuprofen-conjugated polygalacturonic acid-hyaluronic acid hydrogel showed low cytotoxicity. In addition, the conjugated ibuprofen decreased prostaglandin E2production of the lipopolysaccharide-induced RAW264.7 cells. Histological data inin vivostudies indicated that the scar tissue adhesion of laminectomized male adult rats was reduced by the application of our ibuprofen-conjugated polygalacturonic acid hyaluronic acid hydrogel. Its use also reduced the population of giant cells and collagen deposition of scar tissue without inducing extensive cell recruitment. The results of this study therefore suggest that the local delivery of ibuprofenviaa polygalacturonic acid-hyaluronic acid-based hydrogel reduces the possibility of epidural fibrosis. PMID- 26935814 TI - BF3.OEt2 mediated metal-free one-pot sequential multiple annulation cascade (SMAC) synthesis of complex and diverse tetrahydroisoquinoline fused hybrid molecules. AB - A highly efficient and distinct BF3.OEt2 mediated metal-free SMAC protocol for the synthesis of complex and diverse hybrid molecules viz. indazole fused tetrahydroisoquinolinoquinoxalines, and tetrahydroisoquinolinodiazepine has been developed. The transformation is based on sequential cascade processes involving 2H-indazole formation and deprotection Pictet-Spengler cyclization steps in one pot fashion. The protocol demonstrates the utility of sequential multiple annulations in a cascade fashion. The present one-pot protocol uses the Solid State Melt Reaction (SSMR) strategy for the synthesis of the intermediate 2H indazole. The method is operationally simple and represents a new approach for C C, three C-N and N-N bond formation with a wide substrate scope. PMID- 26935817 TI - Estimated economic impact of pre-filled ephedrine syringes in the operating room. AB - BACKGROUND: Syringes of ephedrine are usually prepared ahead of time in order to reduce the time to injection. Commercial pre-filled syringes of ephedrine have been introduced to minimize the amount of waste. Our primary objective was to determine the economic impact of commercial syringes. We hypothesized that costs could be reduced compared to standard syringes. METHODS: Using data extracted from our medical records system, we retrospectively measured the total dose of ephedrine received per patient in 2013 to estimate the number of administered standard syringes. The proportion of administered standard syringes was calculated as the total number of administered standard syringes divided by the number of delivered ampoules in 2013. Thereafter, we calculated the annual cost difference as the difference between the cost for commercial syringes and the cost for standard syringes. Endpoints were calculated overall and for each operating room. RESULTS: At least one dose of ephedrine was given in 19,422 patients (44,943 administrations). The overall proportion of administered standard syringes was estimated to 52.8%. The threshold proportion of administered standard syringes for which commercial syringes would add no extra cost was 20.4%. In 30/32 operating rooms, the proportion of administered standard syringes was higher than 20.4%. The overall cost increase with commercial syringes was estimated to 51,567 ?. Among operating rooms, incremental costs varied between -703 and 5086 ?. CONCLUSION: Based on our findings, pre-filled ephedrine commercial syringes do not appear to reduce costs. PMID- 26935815 TI - Increased Serum HMGB-1, ICAM-1 and Metalloproteinase-9 Levels in Buerger's Patients. AB - BACKGROUND: Thromboangiitis obliterans (TAO), or Buerger's disease, is an inflammatory occlusive disorder that affects the limb arteries of young smokers. In the aetiology of TAO the immune system appears to play a critical role; however, information on the aspects involved in the evolution of vascular tissue inflammation and of this disease are still limited. OBJECTIVE: This study was carried out to investigate HMGB-1 (high mobility group box-1), MMP (matrix metalloproteinase)- 2, MMP-9, MMP-11 and ICAM (intercellular adhesion molecule)-1 circulating levels in subjects with Buerger's disease. METHODS: Between January 2010 and December 2012, eight patients underwent surgical revascularization of the lower limbs and a specimen of the affected arterial wall was obtained for histological confirmation of Buerger's disease. A blood sample was collected on the same day for measuring HMGB-1, MMP-3, MMP-9 and ICAM-1 by western blot analysis. Controls (n=7) were healthy non-smokers. RESULTS: TAO subjects had a significant increase in HMGB-1, MMP-9 and ICAM-1 compared with controls (P<.0001), while no differences were observed in MMP-2 and MMP-11 levels. Histology confirmed a strong inflammatory infiltrate with signs of necrosis in the arterial wall. CONCLUSION: These data suggest a role for HMGB -1 in the vascular lesions associated with TAO, unveiling HMGB-1 as a potential target for treating this rare disease. PMID- 26935818 TI - Efficiency enhancement of cubic perovskite BaSnO3 nanostructures based dye sensitized solar cells. AB - Cubic perovskite BaSnO3 (BSO) is an important photoelectron transporting material due to its electronic structure that competes with TiO2 in dye-sensitized solar cells (DSCs). Separately, BSO/TiCl4 treated and BSO/scattering layer photoelectrodes have been used in DSCs that effectively increase the photoexcited charge carriers collection resulting in superior photovoltaic performance. In the present work, the different TiCl4 treatment time (1, 3 and 5 min), different scattering layer (tetragonal anatase TiO2 and hexagonal wurtzite ZnO) and different combinations thereof are successfully used on BSO nanocuboids/nanoparticle morphological structure photoelectrodes, and then we systematically inspected their performance in DSCs. Under the optimized conditions, a power conversion efficiency (PCE) of 3.88% is obtained by a BSO/TiCl4 treated photoanode. Furthermore, the BSO photoanodes made using a scattering layer such as anatase TiO2 and hexagonal ZnO i.e., BSO/anatase TiO2 and BSO/hexagonal ZnO, exhibited PCEs of 1.14% and 1.25% respectively. In the end, one of the highest PCEs (5.68%) was achieved using BSO/TiCl4 treated/TiO2 scattering layer photoanode. Another photoelectrode such as BSO/TiCl4 treated/ZnO scattering layer exhibited a PCE of 4.28% that is also higher than the BSO/TiCl4 treated/BSO scattering layer photoanodes. Electron lifetime versus current density studies illustrate the stability of the BSO photoelectrode in DSCs. From the observed results, it is realized that BSO is one of the most important future technological materials. PMID- 26935819 TI - Efficacy of a novel oral formulation of sarolaner (SimparicaTM) against five common tick species infesting dogs in the United States. AB - The efficacy of a single oral treatment with sarolaner (SimparicaTM, Zoetis), a novel isoxazoline compound, was evaluated against five tick species known to infest dogs in the United States. A total of 10 laboratory studies, two against each species, were conducted using adult purpose-bred mongrels or Beagle dogs. In each study, 16 dogs were randomly allocated to one of two treatment groups based on pre-treatment host-suitability tick counts. Dogs were infested with approximately 50 unfed adult Amblyomma americanum, Amblyomma maculatum, Dermacentor variabilis, Ixodes scapularis or Rhipicephalus sanguineus ticks on Days -2, 5, 12, 19, 26 and 33. On Day 0, dogs were treated with a placebo or a sarolaner tablet providing a minimum dose of 2 mg/kg. Tick counts were conducted 48h after treatment and after each subsequent weekly re-infestation. There were no treatment-related adverse reactions during any of the studies. Dogs in the placebo-treated group maintained tick infestations throughout the studies. Geometric mean live tick counts were significantly lower (P<=0.0001) in the sarolaner-treated group compared to the tick counts in the placebo group at all timepoints. Treatment with sarolaner resulted in >=99.6% efficacy against existing infestations of all five tick species within 48h. The efficacy against weekly post-treatment re-infestations of all tick species was >=96.9% for at least 35 days after treatment. Thus, a single dose of sarolaner administered orally at the minimum dosage of 2mg/kg, resulted in excellent efficacy within 48h against existing tick infestations, and against weekly re-infestations for 35 days after treatment. These studies confirmed that administration of the minimum dose of sarolaner will provide rapid treatment of existing infestations and give at least one month of control against re-infestation by the common tick species affecting dogs in the US. PMID- 26935820 TI - Evaluation of the effectiveness of a novel oral formulation of sarolaner (SimparicaTM) for the treatment and control of fleas on dogs. AB - The efficacy of a single oral dose of a novel isoxazoline, sarolaner (SimparicaTM, Zoetis), for the treatment and control of flea infestations on dogs was confirmed in five laboratory studies. The studies were conducted using adult purpose-bred Beagles and/or mixed breed dogs. All animals were individually identified and housed, and were allocated randomly to treatment with either placebo or sarolaner (eight to 10 per group) based on pretreatment parasite counts. Three studies used cat flea (Ctenocephalides felis felis) strains recently isolated from the field from the US, EU, or Australia; in the fourth study a laboratory strain (KS1) with documented tolerance to a number of insecticides such as fipronil, imidacloprid, and permethrin was used. In the fifth study, dogs were infested with dog fleas, Ctenocephalides canis. Dogs were treated orally on Day 0 with a placebo or a sarolaner tablet providing a minimum dose of 2mg/kg. Dogs were infested with approximately 100 unfed, adult fleas prior to treatment and at weekly intervals post-treatment. Comb counts were conducted to determine the numbers of viable fleas at 24h after treatment and after each subsequent infestation. Efficacy against C. felis and C. canis was 99.8-100% from treatment through Day 35. In all five studies, elimination of existing infestations was achieved within 24h after dosing, with only a single live C. felis found on one dog on Day 1. Similarly, control of flea challenges was achieved within 24h after infestation throughout the 35day study periods, with only single live C. felis found on two dogs on Day 28 in one study, and on a single dog on Day 35 in another study. There were no adverse reactions to treatment with sarolaner. These studies confirmed that a single oral dose of sarolaner at 2mg/kg provided highly effective treatment of existing C. felis infestations and persistent control of C. felis on dogs for 35days after treatment. Efficacy equivalent to that seen with C. felis was confirmed against C. canis and a known insecticide-tolerant strain of C. felis. PMID- 26935822 TI - Leaf Litter Inhibits Growth of an Amphibian Fungal Pathogen. AB - Past studies have found a heterogeneous distribution of the amphibian chytrid fungal pathogen, Batrachochytrium dendrobatidis (Bd). Recent studies have accounted for some of this heterogeneity through a positive association between canopy cover and Bd abundance, which is attributed to the cooling effect of canopy cover. We questioned whether leaf litter inputs that are also associated with canopy cover might also alter Bd growth. Leaf litter inputs exhibit tremendous interspecific chemical variation, and we hypothesized that Bd growth varies with leachate chemistry. We also hypothesized that Bd uses leaf litter as a growth substrate. To test these hypotheses, we conducted laboratory trials in which we exposed cultures of Bd to leachate of 12 temperate leaf litter species at varying dilutions. Using a subset of those 12 litter species, we also exposed Bd to pre-leached litter substrate. We found that exposure to litter leachate and substrate reduced Bd spore and sporangia densities, although there was substantial variation among treatments. In particular, Bd densities were inversely correlated with concentrations of phenolic acids. We conducted a field survey of phenolic concentrations in natural wetlands which verified that the leachate concentrations in our lab study are ecologically relevant. Our study reinforces prior indications that positive associations between canopy cover and Bd abundance are likely mediated by water temperature effects, but this phenomenon might be counteracted by changes in aquatic chemistry from leaf litter inputs. PMID- 26935821 TI - Enlarged striatal volume in adults with ADHD carrying the 9-6 haplotype of the dopamine transporter gene DAT1. AB - The dopamine transporter gene, DAT1 (SLC6A3), has been studied extensively as a candidate gene for attention-deficit/hyperactivity disorder (ADHD). Different alleles of variable number of tandem repeats (VNTRs) in this gene have been associated with childhood ADHD (10/10 genotype and haplotype 10-6) and adult ADHD (haplotype 9-6). This suggests a differential association depending on age, and a role of DAT1 in modulating the ADHD phenotype over the lifespan. The DAT1 gene may mediate susceptibility to ADHD through effects on striatal volumes, where it is most highly expressed. In an attempt to clarify its mode of action, we examined the effect of three DAT1 alleles (10/10 genotype, and the haplotypes 10 6 and 9-6) on bilateral striatal volumes (nucleus accumbens, caudate nucleus, and putamen) derived from structural magnetic resonance imaging scans using automated tissue segmentation. Analyses were performed separately in three cohorts with cross-sectional MRI data, a childhood/adolescent sample (NeuroIMAGE, 301 patients with ADHD and 186 healthy participants) and two adult samples (IMpACT, 118 patients with ADHD and 111 healthy participants; BIG, 1718 healthy participants). Regression analyses revealed that in the IMpACT cohort, and not in the other cohorts, carriers of the DAT1 adult ADHD risk haplotype 9-6 had 5.9 % larger striatum volume relative to participants not carrying this haplotype. This effect varied by diagnostic status, with the risk haplotype affecting striatal volumes only in patients with ADHD. An explorative analysis in the cohorts combined (N = 2434) showed a significant gene-by-diagnosis-by-age interaction suggesting that carriership of the 9-6 haplotype predisposes to a slower age-related decay of striatal volume specific to the patient group. This study emphasizes the need of a lifespan approach in genetic studies of ADHD. PMID- 26935823 TI - Prevalence and Seasonality of the Amphibian Chytrid Fungus Batrachochytrium dendrobatidis Along Widely Separated Longitudes Across the United States. AB - The chytrid fungus Batrachochytrium dendrobatidis (Bd) has been implicated in amphibian declines on almost all continents. We report on prevalence and intensity of Bd in the United States amphibian populations across three longitudinally separated north-to-south transects conducted at 15 Department of Defense installations during two sampling periods (late-spring/early summer and mid to late summer). Such a standardized approach minimizes the effects of sampling and analytical bias, as well as human disturbance (by sampling restricted military bases), and therefore permits a cleaner interpretation of environmental variables known to affect chytrid dynamics such as season, temperature, rainfall, latitude, and longitude. Our prevalence of positive samples was 20.4% (137/670), and our mean intensity was 3.21 zoospore equivalents (SE = 1.03; range 0.001-103.59). Of the 28 amphibian species sampled, 15 tested positive. Three sites had no evidence of Bd infection; across the remaining 12 Bd positive sites, neither infection prevalence nor intensity varied systematically. We found a more complicated pattern of Bd prevalence than anticipated. Early season samples showed no trend associated with increasing temperature and precipitation and decreasing (more southerly) latitudes; while in late season samples, the proportion of infected individuals decreased with increasing temperature and precipitation and decreasing latitudes. A similar pattern held for the east-west gradient, with the highest prevalence associated with more easterly/recently warmer sites in the early season then shifting to more westerly/recently cooler sites in the later season. Bd intensity across bases and sampling periods was comparatively low. Some of the trends in our data have been seen in previous studies, and our results offer further continental-level Bd sampling over which more concentrated local sampling efforts can be overlaid. PMID- 26935824 TI - Forced swim stress increases ethanol consumption in C57BL/6J mice with a history of chronic intermittent ethanol exposure. AB - RATIONALE: Stress exposure has been identified as one risk factor for alcohol abuse that may facilitate the transition from social or regulated alcohol use to the development of alcohol dependence. Additionally, stress is a common trigger for relapse and subsequent loss of control of drinking in alcohol-dependent individuals. OBJECTIVES: The present study was designed to characterize effects of repeated forced swim stress (FSS) on ethanol consumption in three rodent drinking models that engender high levels of ethanol consumption. METHODS: Adult male C57BL/6J mice were exposed to 10-min FSS 4 h prior to each drinking session in three different models of high ethanol consumption: chronic intermittent ethanol (CIE) drinking (a model of dependence-like drinking), drinking-in-the dark (DID; a model of binge-like drinking), and intermittent vs. continuous access (a model of escalated drinking). RESULTS: In the CIE drinking paradigm, daily FSS facilitated the escalation of ethanol intake that is typically seen in CIE-exposed mice without altering ethanol consumption in control mice exposed to FSS. FSS prior to drinking sessions did not alter ethanol consumption in the DID or intermittent access paradigms, whereas stressed mice in the continuous access procedure consumed less ethanol than their nonstressed counterparts. CONCLUSIONS: The CIE drinking paradigm may provide a helpful preclinical model of stress induced transition to ethanol dependence that can be used to (1) identify underlying neural mechanisms that facilitate this transition and (2) evaluate the therapeutic potential of various pharmacological agents hypothesized to alleviate stress-induced drinking. PMID- 26935826 TI - Eradication of measles: remaining challenges. AB - Measles virus (MeV) is an aerosol-borne and one of the most contagious pathogenic viruses known. Almost every MeV infection becomes clinically manifest and can lead to serious and even fatal complications, especially under conditions of malnutrition in developing countries, where still 115,000 to 160,000 patients die from measles every year. There is no specific antiviral treatment. In addition, MeV infections cause long-lasting memory B and T cell impairment, predisposing people susceptible to opportunistic infections for years. A rare, but fatal long term consequence of measles is subacute sclerosing panencephalitis. Fifteen years ago (2001), WHO has launched a programme to eliminate measles by a worldwide vaccination strategy. This is promising, because MeV is a human-specific morbillivirus (i.e. without relevant animal reservoir), safe and potent vaccine viruses are sufficiently produced since decades for common application, and millions of vaccine doses have been used globally without any indications of safety and efficacy issues. Though the prevalence of wild-type MeV infection has decreased by >90 % in Europe, measles is still not eliminated and has even re emerged with recurrent outbreaks in developed countries, in which effective vaccination programmes had been installed for decades. Here, we discuss the crucial factors for a worldwide elimination of MeV: (1) efficacy of current vaccines, (2) the extremely high contagiosity of MeV demanding a >95 % vaccination rate based on two doses to avoid primary vaccine failure as well as the installation of catch-up vaccination programmes to fill immunity gaps and to achieve herd immunity, (3) the implications of sporadic cases of secondary vaccine failure, (4) organisation, acceptance and drawbacks of modern vaccination campaigns, (5) waning public attention to measles, but increasing concerns from vaccine-associated adverse reactions in societies with high socio-economic standards and (6) clinical, epidemiological and virological surveillance by the use of modern laboratory diagnostics and reporting systems. By consequent implementation of carefully designed epidemiologic and prophylactic measures, it should be possible to eradicate MeV globally out of mankind, as the closely related morbillivirus of rinderpest could be successfully eliminated out of the cattle on a global scale. PMID- 26935825 TI - Epinephrine increases contextual learning through activation of peripheral beta2 adrenoceptors. AB - RATIONALE: Phenylethanolamine-N-methyltransferase knockout (Pnmt-KO) mice are unable to synthesize epinephrine and display reduced contextual fear. However, the precise mechanism responsible for impaired contextual fear learning in these mice is unknown. OBJECTIVES: Our aim was to study the mechanism of epinephrine dependent contextual learning. METHODS: Wild-type (WT) or Pnmt-KO (129x1/SvJ) mice were submitted to a fear conditioning test either in the absence or in the presence of epinephrine, isoprenaline (non-selective beta-adrenoceptor agonist), fenoterol (selective beta2-adrenoceptor agonist), epinephrine plus sotalol (non selective beta-adrenoceptor antagonist), and dobutamine (selective beta1 adrenoceptor agonist). Catecholamines were separated by reverse-phase HPLC and quantified by electrochemical detection. Blood glucose was measured by coulometry. RESULTS: Re-exposure to shock context induced higher freezing in WT and Pnmt-KO mice treated with epinephrine and fenoterol than in mice treated with vehicle. In addition, freezing response in Pnmt-KO mice was much lower than in WT mice. Freezing induced by epinephrine was blocked by sotalol in Pnmt-KO mice. Epinephrine and fenoterol treatment restored glycemic response in Pnmt-KO mice. Re-exposure to shock context did not induce a significant difference in freezing in Pnmt-KO mice treated with dobutamine and vehicle. CONCLUSIONS: Aversive memories are best retained if moderately high plasma epinephrine concentrations occur at the same moment as the aversive stimulus. In addition, epinephrine increases context fear learning by acting on peripheral beta2-adrenoceptors, which may induce high levels of blood glucose. Since glucose crosses the blood brain barrier, it may enhance hippocampal-dependent contextual learning. PMID- 26935827 TI - The antigen-specific response to Toxoplasma gondii profilin, a TLR11/12 ligand, depends on its intrinsic adjuvant properties. AB - Agonists that activate Toll-like receptors (TLR) are potential vaccine adjuvants. In particular, Toxoplasma gondii profilin (TgPRF) is recognized by TLR11/12 to generate an inflammatory response. Unlike most TLR ligands, TgPRF is also a protein and can therefore simultaneously induce innate and adaptive immune responses. We found that variations in the conformation of TgPRF can affect its ability to induce a TLR11/12-dependent inflammatory response. The secreted recombinant T. gondii (S2-profilin), produced by Schneider 2 cells, has lost its ability to generate an IL-12 response. Reduction of the intramolecular disulfide bonds in S2-profilin rescued the TLR11/12-dependent IL-12 response. Immunization of mice with reduced S2-profilin induced strong cellular and humoral responses compared to mice immunized with unreduced S2-profilin. A mixed Th1/Th2 response was induced with both S2-profilins. However, a more polarized Th1-type response, which was consistent with the IgG2a-polarized humoral response, was observed with reduced S2-profilin. In conclusion, the intrinsic adjuvant properties of TgPRF had significant consequences on the immune response against TgPRF. PMID- 26935828 TI - Anterolateral ligament of the knee: myth or reality? AB - PURPOSE: A ligament of the knee has recently drawn the attention: the rediscovered anterolateral ligament (ALL) of the knee. The tibial insertion of the ALL is torn off in the Segond fracture, pathognomonic of the anterior cruciate ligament tear. The ALL originates from the lateral femoral epicondyle and has fibers inserting on the lateral meniscus. It attaches distally to the tibial plateau, midway between the tip of the fibular head and Gerdy's tubercle. The purpose of this study was to evaluate the visibility of the ALL using routine MRI (1.5T) protocol. MATERIALS AND METHODS: In the first part of our study 10 cadaveric knee joints were examined using MR imaging to evaluate the visibility of the ALL. These cadaveric knees have been dissected to assess the presence of the ALL and to evaluate the accordance between MRI and anatomic dissection. In the second part of the study, 61 knee MRI of patients were examined to evaluate the visibility of the ALL using axial and coronal DP-FS weighted sequences. RESULTS: In all cadaveric knee MRI, the ALL was visualized (full visualization in 75 % and partial visualization in 25 % of the cases), with 100 % accordance between MRI and anatomic dissection. Two cadaveric knees where the ALL was not viewed were excluded of the radio-anatomic analysis. The ALL was visualized in 93.4 % (95 % CI = 84.1-98.2) of the knee MRI studies of the 61 patients included. The whole ligament was visualized in 82 % (95 % CI = 70-90.6) examinations and it was partially visualized in 11.5 % (95 % CI = 4.7-22.2). CONCLUSION: Our results show that the ALL of the knee can be identified using routine 1.5T MR imaging, which suggest that better radiological description of this underestimated anatomical structure may be beneficial in the preoperative planning of ACL tears. PMID- 26935829 TI - Recommendation of treatment strategy for postpancreatectomy hemorrhage: Lessons from a single-center experience in 35 patients. AB - BACKGROUND: Postpancreatectomy hemorrhage (PPH) is a life-threatening complication of pancreatic surgery. The shift from surgical to radiological intervention was recently reported in retrospective cohort studies, but it has remained controversial as to which emergent intervention provides optimal management. METHODS: All 553 patients who underwent standard pancreatic resection at Kobe University Hospital between January 2003 and December 2013 were included. Patient data and complication data were identified from a prospective database. RESULTS: The overall incidence of PPH was 6% (35 of 553 patients). Ten patients underwent endoscopic intervention or observation monitoring, or suffered hemorrhagic sudden death. Among the remaining 25 PPH patients, primary surgical intervention was successful in the 6 hemodynamically unstable PPH patients. Primary radiological intervention could successfully stop the bleeding in 15 of the 17 patients with late-PPH. Nine patients who had bleeding from the hepatic artery after pancreaticoduodenectomy were rescued by endovascular embolization of the artery-trunk. The in-hospital mortality of PPH was 20% (7 of 35). Four of the 5 PPH patients who died following any intervention eventually died due to the other complications associated with prolonged pancreatic fistula. CONCLUSIONS: The leading treatment has been radiological intervention. Endovascular embolization of the hepatic artery-trunk can be securely performed only if blood flow to the liver by an alternate route is confirmed. To reduce mortality of PPH patients, it is necessary to prevent other complications associated with pancreatic fistula following hemostasis. Proactive surgical intervention such as abscess drainage or remnant pancreatectomy is a key consideration. PMID- 26935830 TI - Current Perspectives of Prophylaxis and Management of Acute Infective Endophthalmitis. AB - Endophthalmitis is an intraocular inflammatory condition which may or may not be caused by infective agents. Noninfectious (sterile) endophthalmitis may be attributable to various causes including postoperative retained soft lens matter or toxicity following introduction of other agents into the eye. Infectious endophthalmitis is further subdivided into endogenous and exogenous. In endogenous endophthalmitis there is hematogenous spread of organisms from a distant source of infection whereas in exogenous endophthalmitis direct microbial inoculation may occur usually following ocular surgery or penetrating eye injury with or without intraocular foreign bodies. Acute infective endophthalmitis is usually exogenous induced by inoculation of pathogens following ocular surgery, open-globe injury and intravitreal injections. More infrequently the infective source is internal and septicemia spreads to the eye resulting in endogenous endophthalmitis. Several risk factors have been implicated including immunosuppression, ocular surface abnormalities, poor surgical wound construction, complicated cataract surgery with vitreous loss and certain types of intraocular lens. Comprehensive guidelines and recommendations on prophylaxis and monitoring of surgical cases have been proposed to minimize the risk of acute endophthalmitis. Early diagnosis and prompt management of infective endophthalmitis employing appropriately selected intravitreal antibiotics are essential to optimize visual outcome. PMID- 26935831 TI - Distinct phosphorylation sites on the ghrelin receptor, GHSR1a, establish a code that determines the functions of beta-arrestins. AB - The growth hormone secretagogue receptor, GHSR1a, mediates the biological activities of ghrelin, which includes the secretion of growth hormone, as well as the stimulation of appetite, food intake and maintenance of energy homeostasis. Mapping phosphorylation sites on GHSR1a and knowledge of how these sites control specific functional consequences unlocks new strategies for the development of therapeutic agents targeting individual functions. Herein, we have identified the phosphorylation of different sets of sites within GHSR1a which engender distinct functionality of beta-arrestins. More specifically, the Ser(362), Ser(363) and Thr(366) residues at the carboxyl-terminal tail were primarily responsible for beta-arrestin 1 and 2 binding, internalization and beta-arrestin-mediated proliferation and adipogenesis. The Thr(350) and Ser(349) are not necessary for beta-arrestin recruitment, but are involved in the stabilization of the GHSR1a beta-arrestin complex in a manner that determines the ultimate cellular consequences of beta-arrestin signaling. We further demonstrated that the mitogenic and adipogenic effect of ghrelin were mainly dependent on the beta arrestin bound to the phosphorylated GHSR1a. In contrast, the ghrelin function on GH secretion was entirely mediated by G protein signaling. Our data is consistent with the hypothesis that the phosphorylation pattern on the C terminus of GHSR1a determines the signaling and physiological output. PMID- 26935832 TI - Decentralized colonoscopic surveillance with high patient compliance prevents hereditary and familial colorectal cancer. AB - Although colonoscopic surveillance is recommended both for individuals with known hereditary colorectal cancer (HCRC) syndromes and those with a more moderate familial colorectal cancer (FCRC) history, the evidence for the benefits of surveillance is limited and surveillance practices vary. This study evaluates the preventive effect for individuals with a family history of CRC of decentralized colonoscopic surveillance with the guidance of a cancer prevention clinic. We performed a population based prospective study of 261 patients with HCRC or FCRC, recorded in the colonoscopic surveillance registry at the Cancer genetics clinic, University Hospital of Umea, Sweden. Colonoscopic surveillance was conducted every second (HCRC) or fifth (FCRC) year at local hospitals in Northern Sweden. Main outcome measures were findings of high-risk adenomas (HRA) or CRC, and patient compliance to surveillance. Estimations of the expected numbers of CRC without surveillance were made. During a total of 1256 person years of follow-up, one case of CRC was found. The expected numbers of cancers in the absence of surveillance was between 9.5 and 10.5, resulting in a standardized incidence ratio, observed versus expected cases of CRC, between 0.10 (CI 95 % 0.0012 0.5299) and 0.11 (CI 95 % 0.0014-0.5857). No CRC mortality was reported, but three patients needed surgical intervention. HRA were found in 5.9 % (14/237) of the initial and in 3.4 % (12/356) of the follow-up colonoscopies. Patient compliance to the surveillance program was 90 % as 597 of the planned 662 colonoscopies were performed. The study concludes that colonoscopic surveillance with high patient compliance to the program is effective in preventing CRC when using a decentralized method for colonoscopy surveillance with the guidance of a cancer prevention clinic. PMID- 26935833 TI - IgA vasculitis in adults: the performance of the EULAR/PRINTO/PRES classification criteria in adults. AB - BACKGROUND: In 2010, EULAR/PRINTO/PRES proposed new classification criteria for paediatric IgA vasculitis (IgAV) that have a higher diagnostic sensitivity than the 1990 ACR criteria. These criteria have so far not been evaluated in adults, in whom IgAV is considered as a rare disease. Our main objective was to compare the diagnostic performance of EULAR/PRINTO/PRES and ACR classification criteria in adult IgAV. METHODS: Adult IgAV cases fulfilling the 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides (ICHCCNV) definition of IgAV at a secondary/tertiary rheumatology referral centre were critically reviewed in a partially retrospective and partially prospective manner. First, we compared the diagnostic sensitivity of ACR and EULAR/PRINTO/PRES criteria in this group of patients. Second, the diagnostic specificity of ACR and EULAR/PRINTO/PRES was determined by applying these criteria to a control group of patients with other systemic vasculitides. RESULTS: Between 1 January 2010 and 31 December 2014 350 new cases of systemic vasculitis were identified. IgAV was diagnosed in 129, and other systemic vasculitides in 221 (123 had large, six medium and 92 small vessel vasculitis) cases according to ICHCCNV. The diagnostic sensitivity and specificity of the IgAV EULAR/PRINTO/PRES criteria were 99.2 % (95 % CI 95.4-99.9 %) and 86.0 % (95 % CI 80.7-90.3 %), and of the ACR criteria 86.8 % (95 % CI 79.7-92.1 %) and 81.0 % (95 % CI 75.2-85.9 %), respectively with an inter-criteria agreement of 77.5 % (95 % CI: 70.8-84.1 %). CONCLUSIONS: In the adult population the EULAR/PRINTO/PRES IgAV classification criteria had a higher sensitivity and specificity than the ACR criteria. PMID- 26935834 TI - What are the barriers to care integration for those at the advanced stages of dementia living in care homes in the UK? Health care professional perspective. AB - People with advanced dementia are frequently bed-bound, doubly incontinent and able to speak only a few words. Many reside in care homes and may often have complex needs requiring efficient and timely response by knowledgeable and compassionate staff. The aim of this study is to improve our understanding of health care professionals' attitudes and knowledge of the barriers to integrated care for people with advanced dementia. In-depth, interactive interviews conducted with 14 health care professionals including commissioners, care home managers, nurses and health care assistants in the UK. Barriers to care for people with advanced dementia are influenced by governmental and societal factors which contribute to challenging environments in care homes, poor morale amongst care staff and a fragmentation of health and social care at the end of life. Quality of care for people with dementia as they approach death may be improved by developing collaborative networks to foster improved relationships between health and social care services. PMID- 26935835 TI - 'The stigma attached isn't true of real life': Challenging public perception of dementia through a participatory approach involving people with dementia (Innovative Practice). AB - This paper discusses the potential impact of viewing public performances of an orchestra comprising people with dementia, family members, student volunteers and professional symphony orchestra members in contributing to challenging negative perceptions of dementia. Negative perceptions of dementia abound despite recent policy attempts to challenge the stigma associated with the condition. This paper reports on the findings from the performance element of a music project for people with dementia, known as the BUDI Orchestra, designed to replicate the traditional rehearse and perform cycle of musicians. Data were collected via self completion questionnaires from audience members ( N = 109) at three public performances. The performances exceeded the expectations of the general public, and findings suggest a positive impact on perceptions of dementia, demonstrating the power and potential of participatory approaches showcasing the achievements of those living with dementia when attempting to raise awareness of dementia and challenge negative perceptions. PMID- 26935836 TI - Alirocumab: A Review in Hypercholesterolemia. AB - Alirocumab (Praluent((r))) is a monoclonal antibody against proprotein convertase subtilisin/kexin type 9 (PCSK9) that is administered via subcutaneous injection every 2 weeks. Across ten phase III studies from the ODYSSEY clinical trial program in patients with heterozygous familial hypercholesterolemia (heFH) or nonfamilial hypercholesterolemia (nonFH), including some with mixed dyslipidemia, subcutaneous alirocumab 75 or 150 mg every 2 weeks was significantly more effective with regard to reducing low-density lipoprotein-cholesterol (LDL-C) over 24 weeks than comparator agents (i.e. matching placebo, once-daily oral ezetimibe, or modified oral statin therapy), including when administered as monotherapy or in combination with statin therapy, and when administered with non statin lipid-lowering therapy (LLT) in patients with statin intolerance. Alirocumab provided sustained LDL-C-lowering efficacy over 52-78 weeks' treatment in longer-term trials, and was associated with significantly favorable effects on several other lipid parameters, including non-high-density lipoprotein cholesterol (non-HDL-C) and lipoprotein (a) [Lp(a)]. Alirocumab was generally well tolerated in phase III trials, with no apparent increase in muscle-related adverse events compared with placebo. Thus, alirocumab is a valuable emerging option for use in patients with hypercholesterolemia, particularly patients with statin intolerance or inadequately-controlled LDL-C despite statin therapy; however, more data are needed to establish its potential cardiovascular benefits. PMID- 26935838 TI - FTY720 (Fingolimod) attenuates basal and sphingosine-1-phosphate-evoked thyroid cancer cell invasion. AB - The bioactive lipid sphingosine-1-phosphate (S1P) is a potent inducer of ML-1 thyroid cancer cell migration and invasion. It evokes migration and invasion by activating S1P receptor 1 and 3 (S1P1,3) and downstream signaling intermediates as well as through cross-communication with vascular endothelial growth factor receptor 2 (VEGFR2). However, very little is known about the role of S1P receptors in thyroid cancer. Furthermore, the currently used treatments for thyroid cancer have proven to be rather unsuccessful. Thus, due to the insufficiency of the available treatments for thyroid cancer, novel and targeted therapies are needed. The S1P receptor functional antagonist FTY720, an immunosuppressive drug currently used for treatment of multiple sclerosis, has shown promising effects as an inhibitor of cancer cell proliferation and invasion. In this study, we investigated the effect of FTY720 on invasion and proliferation of several thyroid cancer cell lines. We present evidence that FTY720 attenuated basal as well as S1P-evoked invasion of these cell lines. Furthermore, FTY720 potently downregulated S1P1, protein kinase Calpha(PKCalpha), PKCbetaI, and VEGFR2. It also attenuated S1P-evoked phosphorylation of ERK1/2. Our results also showed that FTY720 attenuated S1P-induced MMP2 intracellular expression, S1P-induced secretion of MMP2 and MMP9, and decreased basal MMP2 and MMP9 activity. Moreover, in FTY720-treated cells, proliferation was attenuated, p21 and p27 were upregulated, and the cells were arrested in the G1 phase of the cell cycle. FTY720 attenuated cancer cell proliferation in the chick embryo chorioallantoic membrane assay. Thus, we suggest that FTY720 could be beneficial in the treatment of thyroid cancer. PMID- 26935837 TI - Somatic mosaicism underlies X-linked acrogigantism syndrome in sporadic male subjects. AB - Somatic mosaicism has been implicated as a causative mechanism in a number of genetic and genomic disorders. X-linked acrogigantism (XLAG) syndrome is a recently characterized genomic form of pediatric gigantism due to aggressive pituitary tumors that is caused by submicroscopic chromosome Xq26.3 duplications that include GPR101 We studied XLAG syndrome patients (n= 18) to determine if somatic mosaicism contributed to the genomic pathophysiology. Eighteen subjects with XLAG syndrome caused by Xq26.3 duplications were identified using high definition array comparative genomic hybridization (HD-aCGH). We noted that males with XLAG had a decreased log2ratio (LR) compared with expected values, suggesting potential mosaicism, whereas females showed no such decrease. Compared with familial male XLAG cases, sporadic males had more marked evidence for mosaicism, with levels of Xq26.3 duplication between 16.1 and 53.8%. These characteristics were replicated using a novel, personalized breakpoint junction specific quantification droplet digital polymerase chain reaction (ddPCR) technique. Using a separate ddPCR technique, we studied the feasibility of identifying XLAG syndrome cases in a distinct patient population of 64 unrelated subjects with acromegaly/gigantism, and identified one female gigantism patient who had had increased copy number variation (CNV) threshold for GPR101 that was subsequently diagnosed as having XLAG syndrome on HD-aCGH. Employing a combination of HD-aCGH and novel ddPCR approaches, we have demonstrated, for the first time, that XLAG syndrome can be caused by variable degrees of somatic mosaicism for duplications at chromosome Xq26.3. Somatic mosaicism was shown to occur in sporadic males but not in females with XLAG syndrome, although the clinical characteristics of the disease were similarly severe in both sexes. PMID- 26935839 TI - Light-Triggered Release of Bioactive Molecules from DNA Nanostructures. AB - Recent innovations in DNA nanofabrication allow the creation of intricately shaped nanostructures ideally suited for many biological applications. To advance the use of DNA nanotechnology for the controlled release of bioactive molecules, we report a general strategy that uses light to liberate encapsulated cargoes from DNA nanostructures with high spatiotemporal precision. Through the incorporation of a custom, photolabile cross-linker, we encapsulated cargoes ranging in size from small molecules to full-sized proteins within DNA nanocages and then released such cargoes upon brief exposure to light. This novel molecular uncaging technique offers a general approach for precisely releasing a large variety of bioactive molecules, allowing investigation into their mechanism of action, or finely tuned delivery with high temporal precision for broad biomedical and materials applications. PMID- 26935840 TI - Genome-wide identification and evolutionary analysis of leucine-rich repeat receptor-like protein kinase genes in soybean. AB - BACKGROUND: Leucine-rich repeat receptor-like kinases (LRR-RLKs) constitute the largest subfamily of receptor-like kinases in plant. A number of reports have demonstrated that plant LRR-RLKs play important roles in growth, development, differentiation, and stress responses. However, no comprehensive analysis of this gene family has been carried out in legume species. RESULTS: Based on the principles of sequence similarity and domain conservation, a total of 467 LRR-RLK genes were identified in soybean genome. The GmLRR-RLKs are non-randomly distributed across all 20 chromosomes of soybean and about 73.3 % of them are located in segmental duplicated regions. The analysis of synonymous substitutions for putative paralogous gene pairs indicated that most of these gene pairs resulted from segmental duplications in soybean genome. Furthermore, the exon/intron organization, motif composition and arrangements were considerably conserved among members of the same groups or subgroups in the constructed phylogenetic tree. The close phylogenetic relationship between soybean LRR-RLK genes with identified Arabidopsis genes in the same group also provided insight into their putative functions. Expression profiling analysis of GmLRR-RLKs suggested that they appeared to be differentially expressed among different tissues and some of duplicated genes exhibited divergent expression patterns. In addition, artificial selected GmLRR-RLKs were also identified by comparing the SNPs between wild and cultivated soybeans and 17 genes were detected in regions previously reported to contain domestication-related QTLs. CONCLUSIONS: Comprehensive and evolutionary analysis of soybean LRR-RLK gene family was performed at whole genome level. The data provides valuable tools in future efforts to identify functional divergence of this gene family and gene diversity among different genotypes in legume species. PMID- 26935841 TI - A trial of semen collection by transrectal electroejaculation method from Amur leopard cat (Prionailurus bengalensis euptilurus). AB - We collected semen from a male Amur leopard cat using the transrectal electroejaculation method and investigated the semen qualities for about four years. In addition, the influence of the season on the spermatogenic function of the Amur leopard cat was investigated with regard to the semen qualities, testicular volume and serum testosterone level. As a result, we could collect semen with good sperm qualities that would be useable for artificial insemination. Some seasonality was noted in the testicular volume and serum testosterone level. We clarified that the semen qualities were favorable before and during the female breeding season compared with those after the breeding season. PMID- 26935842 TI - Establishment of serological test to detect antibody against ferret coronavirus. AB - Since there is no available serological methods to detect antibodies to ferret coronavirus (FRCoV), an enzyme-linked immunosorbent assay (ELISA) using recombinant partial nucleocapsid (N) proteins of the ferret coronavirus (FRCoV) Yamaguchi-1 strain was developed to establish a serological method for detection of FRCoV infection. Many serum samples collected from ferrets recognized both a.a. 1-179 and a.a. 180-374 of the N protein, but two serum samples did not a.a. 180-374 of the N protein. This different reactivity was also confirmed by immunoblot analysis using the serum from the ferret.Therefore, the a.a. 1-179 of the N protein was used as an ELISA antigen. Serological test was carried out using sera or plasma of ferrets in Japan. Surprisingly, 89% ferrets in Japan had been infected with FRCoV. These results indicated that our established ELISA using a.a. 1-179 of the N protein is useful for detection of antibody to FRCoV for diagnosis and seroepidemiology of FRCoV infection. PMID- 26935843 TI - Intermediates of Metabolism: From Bystanders to Signalling Molecules. AB - The integration of biochemistry into immune cell biology has contributed immensely to our understanding of immune cell function and the associated pathologies. So far, most studies have focused on the regulation of metabolic pathways during an immune response and their contribution to its success. More recently, novel signalling functions of metabolic intermediates are being discovered that might play important roles in the regulation of immunity. Here we describe the three long-known small metabolites lactate, acetyl-CoA, and succinate in the context of immunometabolic signalling. Functions of these ubiquitous molecules are largely dependent on their intra- and extracellular concentrations as well as their subcompartmental localisation. Importantly, the signalling functions of these metabolic intermediates extend beyond self regulatory roles and include cell-to-cell communication and sensing of microenvironmental conditions to elicit stress responses and cellular adaptation. PMID- 26935845 TI - Combination or monotherapy for pulmonary arterial hypertension? PMID- 26935844 TI - Combination therapy versus monotherapy for pulmonary arterial hypertension: a meta-analysis. AB - BACKGROUND: Several randomised controlled studies and a previous meta-analysis have reported conflicting results regarding the effect of combined targeted therapy compared with monotherapy for pulmonary arterial hypertension (PAH). We did a systematic review and meta-analysis to assess the effects of a combination of PAH-specific therapies compared with monotherapy on predefined clinical worsening in PAH. METHODS: We searched MEDLINE, Embase, and the Cochrane Library for reports published from Jan 1, 1990, to May 31, 2015, of prospective randomised controlled trials of at least 12 weeks that assessed a combination of PAH-specific therapies (upfront and sequential add-on) compared with background PAH-specific monotherapy in patients older than 12 years. We extracted data from the reports, and assessed the primary outcome of risk of clinical worsening, as defined a priori in each trial, using the Mantel-Haenszel method based on a fixed effects model. FINDINGS: Of 2017 studies that we identified from our search, we included 17 (4095 patients) in our analysis. 15 studies assessed clinical worsening and were included in the primary analysis. Combined therapy was associated with significant risk reduction for clinical worsening compared with monotherapy (combined therapy 17% [332 of 1940 patients] vs monotherapy 28% [517 of 1862 patients], risk ratio [RR] 0.65 [95% CI 0.58-0.72], p<0.00001). We noted no heterogeneity between the studies (I(2)=18%, phomogeneity=0.25). A publication bias was suggested by the results of an Egger test (t=-2.3982, p=0.031), but when we excluded the four studies with the highest SEs, the RR for clinical worsening was identical (0.65 [95% CI 0.58-0.73], p<0.00001). INTERPRETATION: In our analysis, combined therapy for PAH was associated with a significant reduction in clinical worsening compared with monotherapy. However, our study was limited by the variable definition of clinical worsening among the trials and possible publication bias. Because many patients still had clinical worsening with combination therapy, identification of innovative therapeutic targets for PAH is thus urgently needed. FUNDING: None. PMID- 26935846 TI - Predicting factors for malaria re-introduction: an applied model in an elimination setting to prevent malaria outbreaks. AB - BACKGROUND: Malaria re-introduction is a challenge in elimination settings. To prevent re-introduction, receptivity, vulnerability, and health system capacity of foci should be monitored using appropriate tools. This study aimed to design an applicable model to monitor predicting factors of re-introduction of malaria in highly prone areas. METHODS: This exploratory, descriptive study was conducted in a pre-elimination setting with a high-risk of malaria transmission re introduction. By using nominal group technique and literature review, a list of predicting indicators for malaria re-introduction and outbreak was defined. Accordingly, a checklist was developed and completed in the field for foci affected by re-introduction and for cleared-up foci as a control group, for a period of 12 weeks before re-introduction and for the same period in the previous year. Using field data and analytic hierarchical process (AHP), each variable and its sub-categories were weighted, and by calculating geometric means for each sub category, score of corresponding cells of interaction matrices, lower and upper threshold of different risks strata, including low and mild risk of re introduction and moderate and high risk of malaria outbreaks, were determined. The developed predictive model was calibrated through resampling with different sets of explanatory variables using R software. Sensitivity and specificity of the model were calculated based on new samples. RESULTS: Twenty explanatory predictive variables of malaria re-introduction were identified and a predictive model was developed. Unpermitted immigrants from endemic neighbouring countries were determined as a pivotal factor (AHP score: 0.181). Moreover, quality of population movement (0.114), following malaria transmission season (0.088), average daily minimum temperature in the previous 8 weeks (0.062), an outdoor resting shelter for vectors (0.045), and rainfall (0.042) were determined. Positive and negative predictive values of the model were 81.8 and 100 %, respectively. CONCLUSIONS: This study introduced a new, simple, yet reliable model to forecast malaria re-introduction and outbreaks eight weeks in advance in pre-elimination and elimination settings. The model incorporates comprehensive deterministic factors that can easily be measured in the field, thereby facilitating preventive measures. PMID- 26935847 TI - How Climate Change Affects Children's Health. PMID- 26935849 TI - Maternal profiles and social determinants of malnutrition and the MDGs: What have we learnt? AB - BACKGROUND: Maternal socio-demographic and health profiles are important determinants of malnutrition in children. In the 1990s, malnutrition was associated with low-birth-weight, young mothers and low maternal socio-economic status at Princess Marie Louise Children's Hospital (PML). It is not known how this has changed by efforts to achieve the Millennium Development Goals. We examined socio-demographic and health profiles of mothers of children with acute malnutrition and those without the condition to identify risk factors for malnutrition and focus on preventive efforts. METHODS: An unmatched case-control study was conducted in 2013 at PML, the largest facility for treating malnourished children in Ghana in 2013. Mothers of children with moderate and severe acute malnutrition were compared with mothers of well-nourished children. Weight-for-height was used to classify malnutrition. Record forms and a semi structured questionnaire were used for data collection. An analysis was done with Stata 11.0 software. RESULTS: Altogether, 371 mothers were studied consisting of 182 mothers of malnourished children and 189 mothers of well-nourished children. Mothers of malnourished children were more likely to be unmarried or cohabiting, have lower family incomes, HIV infection and chronic disease. They were less likely to stay with or provide alternative care for their child. Awareness and use of social services, health insurance and a cash transfer programme were low. A remarkable reduction in the number of malnourished children occurred when families earned more than $250 USD a month. Over-nutrition was present in both groups of mothers. CONCLUSION: Low family income, unmarried status and type of child care were the main social determinants of malnutrition. There appears to be a reduction in the number of other poor socio-demographic characteristics in both the study and control groups compared to results from a previous study at the same centre, probably because of efforts toward attaining the MDGs. These findings suggest that prevention and optimum management need to involve multidisciplinary teams consisting of health professionals, social workers and/or key workers to enable families at risk to access social care and social protection interventions (MDG 1). This will make the management of malnutrition more effective, prevent relapse, protect the next child and address maternal over nutrition. PMID- 26935851 TI - Characterization of a second physiologically relevant lactose permease gene (lacpB) in Aspergillus nidulans. AB - In Aspergillus nidulans, uptake rather than hydrolysis is the rate-limiting step of lactose catabolism. Deletion of the lactose permease A-encoding gene (lacpA) reduces the growth rate on lactose, while its overexpression enables faster growth than wild-type strains are capable of. We have identified a second physiologically relevant lactose transporter, LacpB. Glycerol-grown mycelia from mutants deleted for lacpB appear to take up only minute amounts of lactose during the first 60 h after a medium transfer, while mycelia of double lacpA/lacpB deletant strains are unable to produce new biomass from lactose. Although transcription of both lacp genes was strongly induced by lactose, their inducer profiles differ markedly. lacpA but not lacpB expression was high in d-galactose cultures. However, lacpB responded strongly also to beta-linked glucopyranose dimers cellobiose and sophorose, while these inducers of the cellulolytic system did not provoke any lacpA response. Nevertheless, lacpB transcript was induced to higher levels on cellobiose in strains that lack the lacpA gene than in a wild type background. Indeed, cellobiose uptake was faster and biomass formation accelerated in lacpA deletants. In contrast, in lacpB knockout strains, growth rate and cellobiose uptake were considerably reduced relative to wild-type, indicating that the cellulose and lactose catabolic systems employ common elements. Nevertheless, our permease mutants still grew on cellobiose, which suggests that its uptake in A. nidulans prominently involves hitherto unknown transport systems. PMID- 26935850 TI - Long-term follow-up of buserelin-induced enteric neuropathy in rats. AB - A few patients have been shown to develop severe abdominal pain and gastrointestinal dysmotility during treatment with gonadotropin-releasing hormone (GnRH) analogs. A rat model of enteric neuropathy has been developed by administration of the GnRH analog buserelin to rats. Loss of enteric neurons and ganglioneuritis throughout the gastrointestinal tract has been described, without other histopathological changes. The aim of the present study was to investigate the long-term effects of this rat model on body weight, and on morphology and inflammatory changes in the gastrointestinal tract. Rats were administered subcutaneous injections of buserelin or saline once daily for 5 days and allowed to recover for 3 weeks. This regimen was repeated four times. The rats were weighed weekly and were sacrificed 16 weeks after the fourth treatment. The bowel wall was measured by morphometry, and the presence of enteric neurons, mast cells, eosinophils and T-lymphocytes was evaluated. Buserelin-treated rats were shown to have a lower body weight at sacrifice, as compared with the controls (P<0.05). Compared with controls, buserelin treatment caused loss of myenteric neurons in the ileum and colon (P<0.01), a thinner circular muscle layer in ileum (P<0.05) and longitudinal muscle layer in colon (P<0.05), increased number of eosinophils in the submucosa of the ileum (P<0.05), and an increased number of T lymphocytes in the submucosa and circular muscle layer of the fundus (P<0.01 and P<0.05, respectively) and circular muscle layer of the colon (P<0.05). Mast cells were equally distributed in the two groups. Thus, long-term follow-up of buserelin-induced enteric neuropathy reveals reduced body weight, loss of myenteric neurons, thinning of muscle layers, and increased numbers of eosinophils and T-lymphocytes in the gastrointestinal tract. PMID- 26935853 TI - Efficacy and safety of traditional Chinese medicine for the treatment of influenza A (H1N1): A meta-analysis. AB - BACKGROUND: In March 2009, the first reported case infected with influenza A (H1N1) virus was identified in Mexico. The World Health Organization officially declared the outbreak to be a pandemic on June 11, 2009. The objective of this study was to evaluate the efficacy and safety of traditional Chinese medicine (TCM) in the treatment of influenza A (H1N1) infection. METHODS: We electronically and manually searched electronic databases, reference lists, and conference compilations to identify randomized clinical trials that compared the treatment of influenza A (H1N1) using TCM with a control group receiving oseltamivir or antivirus therapy. The Jadad score was used to assess trial quality. Duration of viral shedding, time to defervescence, and effective rate were taken as outcome measurements; additionally, heterogeneity analysis and meta analysis were performed. RESULTS: A total of 30 studies were included in our investigation, and these studies together included 3444 cases. Based on the Jadad score, each of these studies were divided as follows: high-quality studies (n = 3), medium-quality studies (n = 2), and low quality studies (n = 25). A meta analysis was performed, which indicated that the time to defervescence between the TCM treatment group and the control group was statistically significant, the duration of viral [Influenza A (H1N1)] shedding in the integrated Chinese and Western medicine subgroups was statistically significant, but it was not statistically significant between the two groups, the effective rate between the two groups was not statistically significant. A total of 18 studies described adverse drug reactions. CONCLUSION: The results of our study indicated that the mean time to defervescence in the TCM treatment group was less than noted in the control group, and that the duration of viral [Influenza A (H1N1)] shedding in the integrated Chinese and Western medicine subgroups was less than that noted in the control group. However, the available evidence does not consider the fact that the difference in duration of viral shedding and effective rate between the two groups was statistically similar. No obvious adverse events were reported in the included studies. PMID- 26935852 TI - Long-term results of stenting versus coronary artery bypass surgery for left main coronary artery disease-A single-center experience. AB - BACKGROUND: Percutaneous coronary intervention (PCI) has emerged as an alternative treatment to coronary artery bypass grafting (CABG) for unprotected left main (LM) coronary artery disease, but the results of both treatments are less clear in real-world practice. We aimed to assess the long-term outcomes of unprotected LM disease treated with CABG or PCI with stenting in high-risk population from a single center. METHODS: We collected 478 consecutive patients with unprotected LM disease (PCI/CABG: 208/270; mean age: 70 +/- 11 years; 85% male), and 252 patients were considered to be at high risk (European System for Cardiac Operative Risk Evaluation >=6). The median follow-up was 4.3 years (interquartile range: 2.7-6.5 years). RESULTS: All-cause death (PCI/CABG: 27.4%/31.5%; p = 0.36) and all-cause death/myocardial infarction (MI)/stroke (PCI/CABG: 30.8%/35.9%; p = 0.49) were comparable between the two groups, whereas the repeat revascularization rate was significantly higher in the PCI group (PCI/CABG: 22.6%/11.0%; p < 0.01). These results remained similar after adjustment with the propensity score. Notably, CABG tended to be associated with higher periprocedural mortality (adjusted p = 0.08) and long-term stroke (adjusted p = 0.05), while PCI was associated with higher long-term MI (adjusted p = 0.09). Analyses of the diabetic subgroup (PCI/CABG: 98/124) yielded similar results. CONCLUSION: PCI was a comparable alternative to CABG for high-risk patients with unprotected LM disease in terms of long-term risks of all-cause death/MI/stroke, but with a significantly higher repeat revascularization rate. PMID- 26935854 TI - The antioxidant effect of Asparagus cochinchinensis (Lour.) Merr. shoot in D galactose induced mice aging model and in vitro. AB - BACKGROUND: An increasing number of plant components and their extracts have been shown to have beneficial health effects in humans. We aimed to explore the antioxidant effects of the aqueous extract of Asparagus cochinchinensis (Lour.) Merr. shoot in vivo and in vitro. METHODS: A total of 80 Kun Ming mice were randomly divided into four groups (20/group). The mice in the control group received a daily subcutaneous injection of saline. A daily injection of D galactose was administered to the aging model group, the vitamin C (Vc) group (positive control group), and the extract treatment group. Regular measurement of blood cells, nitric oxide synthase (NOS), catalase (CAT) activities, superoxide dismutase (SOD) activities, nitric oxide (NO), and malondialdehyde (MDA) concentration, and the expressions of NOS, SOD, and glutathione peroxidase (GPX) in serum levels were obtained. Furthermore, the microstructure of mice viscera was observed using hematoxylin and eosin staining. RESULTS: The aqueous extract of A. cochinchinensis (Lour.) Merr. had similar 1,1-diphenyl-2-picrylhydrazyl radical 2,2-diphenyl-1-(2,4,6-trinitrophenyl) hydrazyl (DPPH.) [or 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS+)] and higher hydroxyl radicals (or superoxide anion; p < 0.05) radical scavenging capabilities to Vc. Moreover, compared with the aging model group, the aqueous extract of A. cochinchinensis (Lour.) Merr. shoot could obviously increase NOS, CAT, and SOD activities and the NO content, and reduce the MDA content (p < 0.05). Additionally, the microstructure of mice viscera was obviously improved and the expressions of NOS, SOD and GPX were also manifestly increased in the treatment group (p < 0.05). CONCLUSION: The aqueous extract of A. cochinchinensis (Lour.) Merr. shoot had a strong radical scavenging capability in vivo and in vitro, and might be used to diminish radicals in the body and consequently prevent aging. PMID- 26935855 TI - Multiplexed protein profiling by sequential affinity capture. AB - Antibody microarrays enable parallelized and miniaturized analysis of clinical samples, and have proven to provide novel insights for the analysis of different proteomes. However, there are concerns that the performance of such direct labeling and single antibody assays are prone to off-target binding due to the sample context. To improve selectivity and sensitivity while maintaining the possibility to conduct multiplexed protein profiling, we developed a multiplexed and semi-automated sequential capture assay. This novel bead-based procedure encompasses a first antigen capture, labeling of captured protein targets on magnetic particles, combinatorial target elution and a read-out by a secondary capture bead array. We demonstrate in a proof-of-concept setting that target detection via two sequential affinity interactions reduced off-target contribution, while lowered background and noise levels, improved correlation to clinical values compared to single binder assays. We also compared sensitivity levels with single binder and classical sandwich assays, explored the possibility for DNA-based signal amplification, and demonstrate the applicability of the dual capture bead-based antibody microarray for biomarker analysis. Hence, the described concept enhances the possibilities for antibody array assays to be utilized for protein profiling in body fluids and beyond. PMID- 26935857 TI - Life cycle assessment and economic analysis of a low concentrating photovoltaic system. AB - Many new photovoltaic (PV) applications, such as the concentrating PV (CPV) systems, are appearing on the market. The main characteristic of CPV systems is to concentrate sunlight on a receiver by means of optical devices and to decrease the solar cells area required. A low CPV (LCPV) system allows optimizing the PV effect with high increase of generated electric power as well as decrease of active surface area. In this paper, an economic analysis and a life cycle assessment (LCA) study of a particular LCPV scheme is presented and its environmental impacts are compared with those of a PV traditional system. The LCA study was performed with the software tool SimaPro 8.0.2, using the Econinvent 3.1 database. A functional unit of 1 kWh of electricity produced was chosen. Carbon Footprint, Ecological Footprint and ReCiPe 2008 were the methods used to assess the environmental impacts of the LCPV plant compared with a corresponding traditional system. All the methods demonstrated the environmental convenience of the LCPV system. The innovative system allowed saving 16.9% of CO2 equivalent in comparison with the traditional PV plant. The environmental impacts saving was 17% in terms of Ecological Footprint, and, finally, 15.8% with the ReCiPe method. PMID- 26935858 TI - Mediterranean diet, dietary polyphenols and low grade inflammation: results from the MOLI-SANI study. AB - Low grade inflammation is characterized by raised concentrations of inflammatory markers in the absence of any overt symptoms and is recognized as a risk factor for a number of chronic diseases including cancer, cardiovascular, cerebrovascular and neurodegenerative diseases. Many studies suggest that low grade inflammation is mitigated by health promoting behaviours such as healthy eating patterns, physical activity, body weight maintenance and tobacco cessation. To date, large scale studies were mainly focused on circulating markers and little evidence is available on cellular biomarkers. The MOLI-SANI study is a prospective cohort study that has recruited 24 325 men and women aged >=35 years from the general population of the Molise Region, a Southern Italian area, with the purpose of investigating genetic and environmental risk/protection factors for cardiovascular and cerebrovascular disease and cancer. Within this cohort, a composite score of low grade inflammation based on the use of plasmatic (C-reactive protein) and cellular (leukocyte and platelet counts and granulocyte : lymphocyte ratio) biomarkers has been proposed and validated. This score accounts for all possible synergistic effects of such inflammatory markers, thus overcoming any potential bias linked to the multi-collinearity of these variables. Of notice, the MOLI-SANI study was the first to address the relationship between the traditional Mediterranean diet and platelet and leucocyte counts as emerging cellular biomarkers of low grade inflammation. The present review paper will discuss the main findings derived from the MOLI-SANI study on the association of low grade inflammation with a Mediterranean eating pattern, with a particular emphasis on the associated dietary polyphenols. PMID- 26935859 TI - No economic benefit of early knee reconstruction over optional delayed reconstruction for ACL tears: registry enriched randomised controlled trial data. AB - BACKGROUND: To analyse 5-year cost-effectiveness of early versus optional delayed acute anterior cruciate ligament (ACL) reconstruction. METHODS: 121 young, active adults with acute ACL injury to a previously uninjured knee were randomised to early ACL reconstruction (n=62, within 10 weeks of injury) or optional delayed ACL reconstruction (n=59; 30 with ACL reconstruction within 6-55 months); all patients received similar structured rehabilitation. Real life data on health care utilisation and sick leave were obtained from regional and national registers. Costs and quality-adjusted life years (QALYs) were discounted at 3%. Full-analysis set (based on study randomisation) and as-treated analysis (according to actual treatment over 5 years) principles were applied. RESULTS: Mean cost of early ACL reconstruction was ?4695 higher than optional delayed ACL reconstruction (p=0.19) and provided an additional 0.13 QALYs (p=0.11). Full analysis set showed incremental net benefit of early versus optional delayed ACL reconstruction was not statistically significantly different from zero at any level. As-treated analysis showed that costs for rehabilitation alone were ?13 650 less than early ACL reconstruction (p<0.001). Results were robust to sensitivity analyses. CONCLUSIONS: In young active adults with acute ACL injury, a strategy of early ACL reconstruction did not provide extra economic value over a strategy of optional delayed ACL reconstruction over a 5-year period. Results from this and previous reports of the KANON-trial imply that early identification of individuals who would benefit from either early ACL reconstruction or rehabilitation alone might reduce resource consumption and decrease risk of unnecessary overtreatment. TRIAL REGISTRATION: ISRCTN84752559. PMID- 26935856 TI - Fusion of Enveloped Viruses in Endosomes. AB - Ari Helenius launched the field of enveloped virus fusion in endosomes with a seminal paper in the Journal of Cell Biology in 1980. In the intervening years, a great deal has been learned about the structures and mechanisms of viral membrane fusion proteins as well as about the endosomes in which different enveloped viruses fuse and the endosomal cues that trigger fusion. We now recognize three classes of viral membrane fusion proteins based on structural criteria and four mechanisms of fusion triggering. After reviewing general features of viral membrane fusion proteins and viral fusion in endosomes, we delve into three characterized mechanisms for viral fusion triggering in endosomes: by low pH, by receptor binding plus low pH and by receptor binding plus the action of a protease. We end with a discussion of viruses that may employ novel endosomal fusion-triggering mechanisms. A key take-home message is that enveloped viruses that enter cells by fusing in endosomes traverse the endocytic pathway until they reach an endosome that has all of the environmental conditions (pH, proteases, ions, intracellular receptors and lipid composition) to (if needed) prime and (in all cases) trigger the fusion protein and to support membrane fusion. PMID- 26935861 TI - Downregulation of epidermal growth factor receptor family receptors and ligands in a mutant K-ras group of patients with colorectal cancer. AB - The present study investigated the expression profiles of the epidermal growth factor receptor (EGFR) family, which consists of four transmembrane tyrosine kinase receptors and their eight ligands, in 122 patients with colorectal cancer (CRC) using reverse transcription-quantitative polymerase chain reaction analysis. On comparison of the CRC primary tumor and matched adjacent normal mucosa (ANM) tissue samples, the mRNA expression levels of ErbB3, but not ErbB1, were significantly increased in CRC tissue samples, compared with those in the ANM tissues. The expression levels of the ligands exhibited opposing trends to their corresponding receptors, including EGF, BTC, AREG, EREG and HB-EGF, which were increased in the CRC tissues, whereas NRG1 and NGR2 were decreased in thee CRC tissues, compared with those in the AMN tissues. Subsequently, the present study investigated the frequency of K-ras mutations in the patients with CRC. The K-ras mutations were found to be present in 36.8% (45/122) of the cases, however, no correlation was observed between K-ras mutations and clinicopathological characteristics. In the CRC tissues, the expression levels of the EGFR family receptors and their ligands were determined in wild-type and mutant K-ras CRC cases. The expression levels of ErbB1, ErbB2, ErbB3, BTC, AREG, EREG, NRG1 and NRG2 were significantly decreased in the mutant K-ras cases, compared with those in the wild-type K-ras cases. These results suggested that the tumorigenesis of CRC with wild-type K-ras was mediated through, not only ErbB1, but also through the ErbB2 and ErbB3 pathways. Notably, although ErbB2 does not bind any ErbB ligands, ErbB2 may activate tumorigenesis via a heterodimer, rather than a homodimer. Therefore, the results of the present study suggest that the most effective strategy to target not only ErbB1, but also ErbB2 and ErbB3, is the use of monoclonal antibody treatment. PMID- 26935862 TI - Optimization of an air-liquid interface exposure system for assessing toxicity of airborne nanoparticles. AB - The use of refined toxicological methods is currently needed for characterizing the risks of airborne nanoparticles (NPs) to human health. To mimic pulmonary exposure, we have developed an air-liquid interface (ALI) exposure system for direct deposition of airborne NPs on to lung cell cultures. Compared to traditional submerged systems, this allows more realistic exposure conditions for characterizing toxicological effects induced by airborne NPs. The purpose of this study was to investigate how the deposition of silver NPs (AgNPs) is affected by different conditions of the ALI system. Additionally, the viability and metabolic activity of A549 cells was studied following AgNP exposure. Particle deposition increased markedly with increasing aerosol flow rate and electrostatic field strength. The highest amount of deposited particles (2.2 MUg cm(-2) ) at cell free conditions following 2 h exposure was observed for the highest flow rate (390 ml min(-1) ) and the strongest electrostatic field (+/-2 kV). This was estimated corresponding to deposition efficiency of 94%. Cell viability was not affected after 2 h exposure to clean air in the ALI system. Cells exposed to AgNPs (0.45 and 0.74 MUg cm(-2) ) showed significantly (P < 0.05) reduced metabolic activities (64 and 46%, respectively). Our study shows that the ALI exposure system can be used for generating conditions that were more realistic for in vitro exposures, which enables improved mechanistic and toxicological studies of NPs in contact with human lung cells.Copyright (c) 2016 The Authors Journal of Applied Toxicology Published by John Wiley & Sons Ltd. PMID- 26935860 TI - Regulatory mechanisms of EGFR signalling during Drosophila eye development. AB - EGFR signalling is a well-conserved signalling pathway playing major roles during development and cancers. This review explores what studying the EGFR pathway during Drosophila eye development has taught us in terms of the diversity of its regulatory mechanisms. This model system has allowed the identification of numerous positive and negative regulators acting at specific time and place, thus participating to the tight control of signalling. EGFR signalling regulation is achieved by a variety of mechanisms, including the control of ligand processing, the availability of the receptor itself and the transduction of the cascade in the cytoplasm. Ultimately, the transcriptional responses contribute to the establishment of positive and negative feedback loops. The combination of these multiple mechanisms employed to regulate the EGFR pathway leads to specific cellular outcomes involved in functions as diverse as the acquisition of cell fate, proliferation, survival, adherens junction remodelling and morphogenesis. PMID- 26935863 TI - Exenatide enhances cognitive performance and upregulates neurotrophic factor gene expression levels in diabetic mice. AB - Exenatide is a potent and selective agonist for the GLP-1 (glucagon-like peptide 1) receptor. Recent studies are focused on the effects of GLP-1 analogues on hippocampal neurogenesis, cognition, learning and memory functions. The aim of this study was to assess the effects of chronic exenatide treatment (0.1 MUg/kg, s.c, twice daily for 2 weeks) on spatial memory functions by using the modified elevated plus maze (mEPM) test and emotional memory functions by using the passive avoidance (PA) test in streptozotocin/nicotinamide (STZ-NA)-induced diabetic mice. As the genes involved in neurite remodelling are among the primary targets of regulation, the effects of diabetes and chronic administration of exenatide on brain-derived neurotrophic factor (BDNF) and cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) messenger ribonucleic acid (mRNA) levels in the hippocampus of mice were also determined using quantitative real-time polymerase chain reaction (RT-PCR). This study revealed that in the mEPM and PA tests, type-2 diabetes-induced mice exhibited significant impairment of learning and memory which were ameliorated by GLP-1 receptor agonist exenatide. Quantitative RT-PCR revealed that CREB and BDNF gene expression levels were downregulated in diabetic mice, and these alterations were increased by exenatide treatment. Since, exenatide improves cognitive ability in STZ/NA-induced diabetic mice and activates molecular mechanisms of memory storage in response to a learning experience, it may be a candidate for alleviation of mood and cognitive disorder. PMID- 26935864 TI - Regulation by AMP-activated protein kinase of PGE2-induced osteoprotegerin synthesis in osteoblasts. AB - Adenosine monophosphate-activated protein kinase (AMPK) is currently recognized to act as a key sensing enzyme in the regulation of cellular energy homeostasis. It has been previously demonstrated that prostaglandin E2 (PGE2) stimulates the synthesis of osteoprotegerin (OPG) through the activation of p38 mitogen activated protein (MAP) kinase, p44/p42 MAP kinase and stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) in osteoblast-like MC3T3-E1 cells. In the present study, it was investigated whether AMPK is implicated in the PGE2 induced OPG synthesis in MC3T3-E1 cells. PGE2 was observed to induce the phosphorylation of AMPKalpha (Thr-172) and AMPKbeta (Ser-108) in a time-dependent manner. PGE2 additionally induced the phosphorylation of acetyl-coenzyme A (CoA) carboxylase, a direct substrate of AMPK. Compound C, an inhibitor of AMPK, which attenuated the phosphorylation of acetyl-CoA carboxylase, significantly suppressed the PGE2-stimulated OPG release and the mRNA expression level. Compound C failed to affect the PGE2-stimulated phosphorylation of p38 MAP kinase or p44/p42 MAP kinase. On the contrary, the phosphorylation of SAPK/JNK was markedly attenuated by compound C. The results of the current study suggest that AMPK acts as a positive regulator in PGE2-stimulated OPG synthesis via SAPK/JNK signaling in osteoblasts. PMID- 26935865 TI - Funding cuts could kill local authorities' enthusiasm for improving public health, experts say. PMID- 26935866 TI - Metabolic profiling during ex vivo machine perfusion of the human liver. AB - As donor organ shortages persist, functional machine perfusion is under investigation to improve preservation of the donor liver. The transplantation of donation after circulatory death (DCD) livers is limited by poor outcomes, but its application may be expanded by ex vivo repair and assessment of the organ before transplantation. Here we employed subnormothermic (21 degrees C) machine perfusion of discarded human livers combined with metabolomics to gain insight into metabolic recovery during machine perfusion. Improvements in energetic cofactors and redox shifts were observed, as well as reversal of ischemia-induced alterations in selected pathways, including lactate metabolism and increased TCA cycle intermediates. We next evaluated whether DCD livers with steatotic and severe ischemic injury could be discriminated from 'transplantable' DCD livers. Metabolomic profiling was able to cluster livers with similar metabolic patterns based on the degree of injury. Moreover, perfusion parameters combined with differences in metabolic factors suggest variable mechanisms that result in poor energy recovery in injured livers. We conclude that machine perfusion combined with metabolomics has significant potential as a clinical instrument for the assessment of preserved livers. PMID- 26935867 TI - The effect of minimally invasive prostatectomy on practice patterns of American urologists. AB - INTRODUCTION AND OBJECTIVES: To determine how robotic prostatectomy affects practice patterns of urologists, we examined the case volume characteristics among certifying urologists for the surgical treatment of prostate cancer. We hypothesized that the utilization of open and robotic prostatectomy as well as lymph node dissection changed dynamically over the last 10 years. METHODS: A total of 6-month case log data of certifying urologists from 2003 to 2013 were obtained for the American Board of Urology. Cases were identified using Current Procedural Terminology codes for open radical prostatectomy (ORP) and laparoscopic or robotic-assisted laparoscopic prostatectomy (RALP) with a corresponding diagnosis of prostate cancer as defined by ICD-9 code 185.0. RESULTS OBTAINED: A total of 6,563 urologists submitted case logs, of which 68% (4,470/6,563) reported performing at least one radical prostatectomy (RP), totaling 46,030 RPs logged. There was a 376% increase in the performance of RALP over the study period with robotic volume increasing from 22% of all RP in 2003 to 85% in 2013. Among surgeons performing ORP, the median number performed was 2; of surgeons who performed RALP, the median number performed was 8 (P<0.001). Overall, 39% of surgeons logging ORP performed 2 or fewer RP, whereas 19% of surgeons who performed RALP performed 2 or less RP (P<0.001). The highest volume robotic surgeons (top 10% surgical volume) performed 41% of all RALP with the highest performing robotic surgeon recording 658 prostatectomies over 6 months. Oncologists represented 4.1% of all surgeons performing RP and performed 15.1% of all RP (P<0.001); general urologists performed the majority of RP (57.8%). When performed open, there was no influence of surgeon specialty on the performance of lymph node dissection (LND); if performed robotically, oncologists were significantly more likely to perform LND compared with general surgeons (47% vs. 25.9%, respectively, P<0.001). CONCLUSIONS: Robotic prostatectomies are performed 5 times more commonly than open prostatectomy and represent 85% of all RP performed by board-certified urologists in 2013. Compared to RALP, ORP are significantly more likely to be performed by lower volume surgeons. Oncologists perform a higher relative percentage of RPs and are significantly more likely to perform LND if performed robotically when compared with general urologists. PMID- 26935869 TI - Slit-miR-218-Robo axis regulates retinal neovascularization. AB - miR-218 is an important intronic microRNA (miRNA or miR) which is known to regulate angiogenesis in tumors. The present study aimed to investigate the effects of miR-218, as well as its host genes, Slit2 and Slit3, on oxygen-induced retinal neovascularization (RNV) and to explore the associated mechanisms of action. For this purpose, a mouse model of oxygen-induced retinopathy (OIR) was established. The expression levels of miR-218-1 and miR-218-2, as well as those of their host genes, Slit2 and Slit3, were determined by RT-qPCR. Fluorescein angiography was performed on the retinas of the mice with OIR, and RNV was quantified by H&E staining in order to evaluate the effect of pCDH-CMV-miR-218 intravitreal injection on RNV in the mouse model of OIR. Roundabout, axon guidance receptor, homolog 1 (Robo1) expression was detected in mouse retinal vascular endothelial cells expressing high or low levels of miR-218 and in retinal tissues from mice with OIR by western blot analysis. Cell migration was evaluated by a scratch wound assay. We noted that in the mice with OIR, the expression level of miR-218 was significantly downregulated. We also noted that Robo1 expression was suppressed by miR-218. Furthermore, in the mice with OIR, the expression level of miR-218 was significantly downregulated, and that of miR 218-1 and its host gene, Slit2, was concomitantly downregulated as well. The restoration of miR-218 inhibited retinal angiogenesis by targeting Robo1. Taken together, our findings suggest that the Slit2-miR-218-Robo1 axis contributes to the inhibition of retinal angiogenesis and that miR-218 may be a new therapeutic target for preventing RNV. PMID- 26935868 TI - EV-D68 infection in children with asthma exacerbation and pneumonia in Mexico City during 2014 autumn. AB - BACKGROUND: Human enterovirus D68 (EV-D68) recently caused an increase in mild-to severe pediatric respiratory cases in North America and some European countries. Even though few of these children presented with acute paralytic disease, direct causal relationship cannot yet be assumed. OBJECTIVES: The purposes of this report were to describe the clinical findings of an outbreak of EV-D68 infection in Mexico City and identify the genetic relationship with previously reported strains. PATIENTS/METHODS: Between September and December 2014, 126 nasopharyngeal samples (NPS) of hospitalized children <15 years of age with ARI were tested for the presence of respiratory viruses using a multiplex RT-qPCR and EV-D68-specific RT-qPCR. Clinical, epidemiological, and demographic data were collected and associated with symptomatology and viral infections. Phylogenetic analyses were performed using VP1 region. RESULTS: Enterovirus/rhinovirus infection was detected in 40 patients (31.7%), of which 24 patients were EV-D68 positive. EV-D68 infection prevailed over September and October 2014 and was associated with neutrophilia and lymphopenia, and patients were more likely to develop hypoxemia. Phylogenetic analyses showed that Mexican EV-D68 belongs to the new B1 clade. CONCLUSIONS: This is the first EV-D68 outbreak described in Mexico and occurred few weeks after the United States reported similar infections. Although EV-D68 belongs to new B1 clade, no neurological affection was observed. PMID- 26935870 TI - Abnormalities of Anthropometric, Hemodynamic, and Autonomic Variables in Offspring of Hypertensive Parents. AB - Young adult offspring of hypertensive parents (pHTN?) are a good model for assessing abnormalities of anthropometric, cardiometabolic, and autonomic variables prior to clinical hypertension. The objectives of this study were to determine whether these variables and autonomic responses to oral carbohydrates were altered in offspring of pHTN?. Two hundred consecutive patients, including 100 pHTN?, were evaluated, with 29 patients, including 14 pHTN?, given a 70-gram carbohydrate load. The pHTN? group had higher blood pressure, pulse pressure, abdominal circumference (AC), weight, body mass index, and basal metabolic rate than offspring of normotensive parents (pHTN?). At baseline, the low-frequency (LF, sympathetic) to high-frequency (HF, parasympathetic) ratio, assessed by spectral analysis of heart rate variability, was similar in both groups. After the carbohydrate load, the LF/HF ratio was greater in offspring of pHTN?. pHTN? individuals have abnormalities of anthropometric and hemodynamic variables at baseline and autonomic responses to oral carbohydrates before developing hypertension. PMID- 26935871 TI - Gambling problems and comorbidity with alcohol use disorders in Chinese-, Korean , and White-American college students. AB - BACKGROUND AND OBJECTIVES: This study examined gambling behaviors and the relationship between gambling problems and alcohol use disorders (AUDs) among Chinese-, Korean-, and White-American college students. METHODS: Participants were 678 (179 Chinese, 194 Korean, and 305 White; 50% female) 21-26 year-old (M = 22.0 +/- 1.36) students attending one university in California. The South Oaks Gambling Screen was administered to assess gambling behavior and the Semi Structured Assessment for the Genetics of Alcoholism was administered to diagnose lifetime AUDs. Chi-squares and multinomial logistic regressions were conducted to test our hypotheses. RESULTS: Rates of lifetime ever gambling and weekly gambling were similar across the three ethnic groups, but participation in five types of gambling behavior differed. Chinese had the highest rates of gambling problems followed by Koreans and then Whites. Univariate odds ratios determined being Chinese or Korean, being male, and having an AUD were risk factors for gambling problems. When stratified by gender and ethnicity, having an AUD was not related to gambling problems in women, but was strongly associated with gambling problems in Chinese and White men and modestly associated in Korean men. This was true despite low rates of AUDs in Chinese men. DISCUSSION AND CONCLUSIONS: Gambling problems were strongly comorbid with AUDs in Chinese- and White-American men, and moderately comorbid in Korean-American men. No relationship of AUD with gambling problems was found in women. SCIENTIFIC SIGNIFICANCE: The results highlight the importance of assessing disaggregated Asian-American subgroups with respect to addictive behaviors and their comorbidity. PMID- 26935872 TI - Novel eosinophilic neuronal cytoplasmic inclusions in the external cuneate nucleus of humans. AB - We report the occurrence of neuronal cytoplasmic inclusions (NCIs) in the external cuneate nucleus of humans. The NCIs appeared as accumulations of eosinophilic rod-like structures in the neuronal somata in 20 (9.5%) of 211 consecutive autopsy cases. Histochemically, the NCIs were stained bright red with Gomori trichrome, Azan-Mallory and methyl green-pyronin, indicating that they contain protein and RNA. Immunohistochemically, the NCIs were positive for stress granule marker proteins, including Hu-antigen R, eukaryotic translation initiation factor 3 and poly(A)-binding protein 1, but negative for ubiquitin- and autophagy-related proteins. Ultrastructurally, the NCIs were composed of randomly oriented arrays of parallel fibrillar crystalline material with a well defined substructure consisting of longitudinal striations, and were often associated with ribosome-like granules. These NCIs are morphologically, immunohistochemically and topographically distinct from any other inclusions previously described. Their incidence was found to increase with age. A high incidence was also observed in individuals with noninfectious inflammatory disease. These findings suggest that eosinophilic NCIs in the external cuneate nucleus are novel inclusions and might be formed under stress conditions. PMID- 26935873 TI - Computed tomographic colonography vs rectal water- contrast transvaginal sonography in diagnosis of rectosigmoid endometriosis: a pilot study. AB - OBJECTIVES: To compare the performance of computed tomographic colonography (CTC) and rectal water-contrast transvaginal sonography (RWC-TVS) in the diagnosis of rectosigmoid endometriosis, and compare precision in estimating the length of the rectosigmoid nodules and the distance between the nodules and the anal verge. METHODS: This prospective study included 70 patients of reproductive age with clinical suspicion of rectosigmoid endometriosis. Patients underwent RWC-TVS and CTC before laparoscopic excision of endometriotic nodules. The findings of RWC TVS and CTC were compared with surgical and histological results. RESULTS: Of the 70 patients included in the study, 40 (57.1%) had rectosigmoid endometriosis. CTC and RWC-TVS had similar accuracy in the diagnosis of rectosigmoid endometriosis (P = 0.508) and similar precision in estimating the length of the endometriotic nodules (P = 0.077). CTC was more precise than RWC-TVS in estimating the distance between the rectosigmoid nodule and the anal verge (P < 0.001). The intensity of pain experienced during CTC was higher than that perceived during RWC-TVS (P < 0.001); however, intestinal distension for CTC was well-tolerated in all patients without significant adverse effects. CONCLUSIONS: RWC-TVS and CTC have similar accuracy in the diagnosis of rectosigmoid endometriosis and similar precision in estimating the size of the nodules; however, CTC is more precise than RWC-TVS in estimating the distance between the nodules and the anal verge, yet patients tolerate RWC-TVS better than CTC. Copyright (c) 2016 ISUOG. Published by John Wiley & Sons Ltd. PMID- 26935874 TI - Shikonin induces apoptosis of HaCaT cells via the mitochondrial, Erk and Akt pathways. AB - Shikonin, which is a major ingredient of the traditional Chinese herb Lithospermum erythrorhizon, possesses various biological functions, including antimicrobial, anti-inflammatory, and antitumor activities. The present study aimed to determine the molecular mechanisms underlying the effects of shikonin on HaCaT cell apoptosis. Treatment with shikonin significantly inhibited the viability of HaCaT cells in a dose- and time-dependent manner, and promoted cell cycle arrest at G0/G1 phase and apoptosis. In addition, shikonin treatment reduced the mitochondrial membrane potential and induced reactive oxygen species generation. The results of a western blot analysis demonstrated that shikonin significantly activated caspase 3 expression, downregulated B-cell lymphoma 2 (Bcl-2) expression, and upregulated Bcl-2-associated X protein and Bcl-2 homologous antagonist killer expression in a dose-dependent manner in HaCaT cells. Furthermore, shikonin decreased extracellular signal-regulated kinase (Erk) and Akt phosphorylation. These results indicated that shikonin may exert its anti-proliferative effects by inducing apoptosis via activation of the mitochondrial signaling pathway and inactivation of the Akt and Erk pathways in HaCaT cells. Therefore, the present study suggested that shikonin may have potential as a component of therapeutic strategies for the treatment of skin diseases. PMID- 26935875 TI - Red signs and not severity of cirrhosis should determine non-selective beta blocker treatment in Child-Pugh C cirrhosis with small varices: increased risk of hepatorenal syndrome and death beyond 6 months of propranolol use. PMID- 26935877 TI - Promoting palliative care in the community: a toolkit to improve and develop primary palliative care throughout Europe. PMID- 26935876 TI - Vonoprazan, a novel potassium-competitive acid blocker, as a component of first line and second-line triple therapy for Helicobacter pylori eradication: a phase III, randomised, double-blind study. AB - OBJECTIVE: The objective of this study was to assess the efficacy, safety and tolerability of vonoprazan, a novel potassium-competitive acid blocker, as a component of Helicobacter pylori eradication therapy. DESIGN: A randomised, double-blind, multicentre, parallel-group study was conducted to verify the non inferiority of vonoprazan 20 mg to lansoprazole 30 mg as part of first-line triple therapy (with amoxicillin 750 mg and clarithromycin 200 or 400 mg) in H pylori-positive patients with gastric or duodenal ulcer history. The first 50 patients failing first-line therapy with good compliance also received second line vonoprazan-based triple therapy (with amoxicillin 750 mg and metronidazole 250 mg) as an open-label treatment. RESULTS: Of the 650 subjects randomly allocated to either first-line triple therapy, 641 subjects completed first-line therapy and 50 subjects completed second-line therapy. The first-line eradication rate (primary end point) was 92.6% (95% CI 89.2% to 95.2%) with vonoprazan versus 75.9% (95% CI 70.9% to 80.5%) with lansoprazole, with the difference being 16.7% (95% CI 11.2% to 22.1%) in favour of vonoprazan, thus confirming the non inferiority of vonoprazan (p<0.0001). The second-line eradication rate (secondary end point) was also high (98.0%; 95% CI 89.4% to 99.9%) in those who received second-line therapy (n=50). Both first-line triple therapies were well tolerated with no notable differences. Second-line triple therapy was also well tolerated. CONCLUSION: Vonoprazan is effective as part of first-line triple therapy and as part of second-line triple therapy in H pylori-positive patients with a history of gastric or duodenal ulcer. TRIAL REGISTRATION NUMBER: NCT01505127. PMID- 26935879 TI - The melioidosis agent Burkholderia pseudomallei and related opportunistic pathogens detected in faecal matter of wildlife and livestock in northern Australia. AB - The Darwin region in northern Australia has experienced rapid population growth in recent years, and with it, an increased incidence of melioidosis. Previous studies in Darwin have associated the environmental presence of Burkholderia pseudomallei, the causative agent of melioidosis, with anthropogenic land usage and proximity to animals. In our study, we estimated the occurrence of B. pseudomallei and Burkholderia spp. relatives in faecal matter of wildlife, livestock and domestic animals in the Darwin region. A total of 357 faecal samples were collected and bacteria isolated through culture and direct DNA extraction after enrichment in selective media. Identification of B. pseudomallei, B. ubonensis, and other Burkholderia spp. was carried out using TTS1, Bu550, and recA BUR3-BUR4 quantitative PCR assays, respectively. B. pseudomallei was detected in seven faecal samples from wallabies and a chicken. B. cepacia complex spp. and Pandoraea spp. were cultured from wallaby faecal samples, and B. cenocepacia and B. cepacia were also isolated from livestock animals. Various bacteria isolated in this study represent opportunistic human pathogens, raising the possibility that faecal shedding contributes to the expanding geographical distribution of not just B. pseudomallei but other Burkholderiaceae that can cause human disease. PMID- 26935878 TI - The vascular clock system generates the intrinsic circadian rhythm of vascular contractility. AB - Many of the cardiovascular parameters or incidences of coronary artery diseases display circadian variations. These day/night time variances may be attributable to the diurnal change in vascular contractility. However, the molecular mechanism of the vascular clock system which generates the circadian variation of vascular contractility has remained largely unknown. Recently we found the existence of the intrinsic circadian rhythm in vascular contractility. A clock gene Roralpha in vascular smooth muscle cells (VSMC) provokes the diurnal oscillatory change in the expression of Rho-associated kinase 2 (ROCK2), which induces the time-of-day dependent variation in the agonist-induced phosphorylation of myosin light chain (MLC) and myofilament Ca(2+) sensitization. In this review, we introduce our recent findings with reference to the molecular basis of the biological clock system and the current literature concerning cardiovascular chronobiology. PMID- 26935880 TI - Exercise oscillatory ventilation in heart failure. AB - Ventilation inefficiency has become a matter of interest for heart failure (HF) specialists, the most remarkable being exertional oscillatory ventilation (EOV). EOV is an abnormal ventilatory phenomenon, originally described as anecdotal, but now considered a marker of disease severity and worst prognosis in HF. EOV is a cyclic fluctuation of minute ventilation (VE) and expired gas kinetics occurring during exercise: it is a slow, prominent, consistent rather than random, fluctuation in VE that may be evanescent or transient and can follow several distinct patterns. In contrast to the periodic breathing observed in Cheyne Stokes respiration and central sleep apnea, the gradual increase and decrease in minute ventilation (VE) are not spaced by periods of apnea. This review will discuss EOV in HF and the overlap with Cheyne-Stokes respiration. PMID- 26935881 TI - Trends in the Assessment of Drug Supersaturation and Precipitation In Vitro Using Lipid-Based Delivery Systems. AB - The generation of drug supersaturation close to the absorptive site is an important mechanism of how several formulation technologies enhance oral absorption and bioavailability. Lipid-based formulations belong to the supersaturating drug delivery systems although this is not the only mechanism of how drug absorption is promoted in vivo. Different methods to determine drug supersaturation and precipitation from lipid-based formulations are described in the literature. Experimental in vitro setups vary according to their complexity and proximity to the in vivo conditions and, therefore, some tests are used for early formulation screening, while others better qualify for a later stage of development. The present commentary discusses this rapidly evolving field of in vitro testing with a special focus on the advancements in analytical techniques and new approaches of mechanistic modeling. The importance of considering a drug absorption sink is particularly emphasized. This commentary should help formulators in the pharmaceutical industry as well as in academia to make informed decisions on how to conduct in vitro tests for lipid-based delivery systems and to decide on the implications of experimental results. PMID- 26935882 TI - Polymorphs and Versatile Solvates of 7-Hydroxyisoflavone. AB - 7-hydroxyisoflavone has been crystallized, identified, and characterized as 2 solvent-free conformational polymorphs and 5 solvates, which differ from each other in the mode of packing and in molecular conformation. All the 7 crystal structures were previously unreported. The conformational polymorphs and solvates were compared by Hirshfeld surface and fingerprint plot analysis and were spectroscopically characterized by powder X-ray diffraction, differential scanning calorimetry, and thermal gravimetric analysis. Hydrogen bond played an important role in the formation of polymorphs. From this study, we can predict that more solvates could be cultivated in other polarity solvents such as isopropanol or 2-butanol at appropriate conditions. PMID- 26935884 TI - Correlation of serum fructosamine and recurrent pregnancy loss: Case-control study. AB - AIM: Pre-gestational diabetes is associated with an elevated risk of pregnancy loss, but it is unclear whether subclinical glucose intolerance is associated with pregnancy loss, especially recurrent pregnancy loss (RPL). The aim of this study was therefore to compare maternal serum fructosamine (a marker of glycemic control) in patients with and without RPL. METHODS: A case-control study was carried out of 117 women with unexplained RPL, defined as two or more pregnancy losses with no more than one live birth, and 117 age-matched controls with at least one full-term uncomplicated pregnancy and no more than one pregnancy loss. No RPL patients or controls had a clinical diagnosis of pre-gestational or gestational diabetes. Maternal serum was analyzed for fructosamine on quantitative spectrophotometry. RESULTS: Mean body mass index (BMI) of RPL patients was 26.0 +/- 6.4 kg/m(2) compared with 26.6 +/- 5.8 kg/m(2) (P = 0.40). Fructosamine was higher in women with RPL (224.1 +/- 28.79 MUmol/mL) compared with controls (188.9 +/- 19.3 MUmol/mL, P < 0.001). This difference persisted when RPL patients and controls were stratified by BMI. The proportion of women with elevated fructosamine considered diagnostic of diabetes (>285 MUmol/L) was similar in RPL patients and controls. CONCLUSION: The RPL patients and controls had a similar proportion of women with elevated fructosamine considered diagnostic of diabetes. Serum fructosamine was increased in women with RPL compared with controls. Thus, subclinical glucose intolerance may be associated with an increased risk of RPL. These data support further investigation into the mechanisms of RPL associated with glucose intolerance, but do not support testing for subclinical glucose intolerance in women with RPL. PMID- 26935883 TI - Involvement of Monocarboxylate Transporter 4 Expression in Statin-Induced Cytotoxicity. AB - Statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, are the most widely used cholesterol-lowering agents for prevention of obstructive cardiovascular events. However, statins can cause a variety of skeletal muscle problems, and exercise leads to an increase in statin-induced muscle injury. Exercise induces the protein content of monocarboxylate transporter 4 (MCT4), which is expressed strongly in skeletal muscle and is thought to play a major role in the transport of metabolically important monocarboxylates such as l lactate. We previously reported that alpha-cyano-4-hydroxycinnamate, an MCT4 inhibitor, increased the inhibition of growth of RD cells, a prototypic embryonal rhabdomyosarcoma cell line (an RD cell line), as a model of in vitro skeletal muscle, induced by a statin. However, it is unclear whether statin-induced RD cell cytotoxicity is associated with MCT4 expression. We, therefore, examined the relationship between statin-induced cytotoxicity and MCT4 expression in RD cells. Atorvastatin reduced the number of viable cells and upregulated MCT4, but not MCT1, mRNA level in a concentration-dependent manner. MCT4 knockdown suppressed atorvastatin-, simvastatin-, and fluvastatin-induced reduction of cell viability and apoptosis compared with negative control-treated cells. In this study, we demonstrated that MCT4 expression is associated with statin-induced cytotoxicity. PMID- 26935885 TI - Reversal of liver cancer-associated stellate cell-induced stem-like characteristics in SMMC-7721 cells by 8-bromo-7-methoxychrysin via inhibiting STAT3 activation. AB - Hepatic stellate cells (HSCs) that are activated by human hepatocellular carcinoma (HCC) cells secrete a variety of cytokines, which are the main component of the HCC microenvironment. We aimed to determine whether 8-bromo-7 methoxychrysin (BrMC) could interfere in cross-talk of the human hepatic stellate cell line LX-2 and liver cancer stem-like cells (LCSLCs) to inhibit the characteristics of LCSLCs endowed with the capacity of sustaining human hepatocellular carcinoma (HCC) self-renewal and progression, and to identify its potential mechanism of action. We found that the levels of fibroblast activation protein (FAP) were augmented in LX-2 cells treated with the conditioned medium of LCSLCs (LCSLC-CM) compared to those cultured with routine medium, indicating that the LCSLC-CM can activate LX-2 cells to become liver cancer-associated stellate cells (LCAHSCs). Furthermore, sphere forming capability of SMMC-7721 cells was enhanced and stem cell-related protein expression was significantly increased following treatment with the conditioned medium of LCAHSCs (LCAHSC-CM). Moreover, the level of p-STAT3 was increased in LX-2 cells treated with LCSLC-CM and BrMC reduced expression of p-STAT3. Combination of BrMC and the selective inhibitor of STAT3 cucurbitacin I (JSI-124) synergistically suppressed the LCSLC characteristics in SMMC-7721 cells. Collectively, our data showed that BrMC inhibited the interaction between LX-2 cells and HCC-derived CSCs, and did so potentially through modulation of the STAT3 pathway. Future therapeutic strategies employing anti-CSC therapy should confirm the potential of cucurbitacin I (JSI-124) and BrMC as potent therapeutic agents. PMID- 26935886 TI - Modulation of MICAL Monooxygenase Activity by its Calponin Homology Domain: Structural and Mechanistic Insights. AB - MICALs (Molecule Interacting with CasL) are conserved multidomain enzymes essential for cytoskeletal reorganization in nerve development, endocytosis, and apoptosis. In these enzymes, a type-2 calponin homology (CH) domain always follows an N-terminal monooxygenase (MO) domain. Although the CH domain is required for MICAL-1 cellular localization and actin-associated function, its contribution to the modulation of MICAL activity towards actin remains unclear. Here, we present the structure of a fragment of MICAL-1 containing the MO and the CH domains-determined by X-ray crystallography and small angle scattering-as well as kinetics experiments designed to probe the contribution of the CH domain to the actin-modification activity. Our results suggest that the CH domain, which is loosely connected to the MO domain by a flexible linker and is far away from the catalytic site, couples F-actin to the enhancement of redox activity of MICALMO CH by a cooperative mechanism involving a trans interaction between adjacently bound molecules. Binding cooperativity is also observed in other proteins regulating actin assembly/disassembly dynamics, such as ADF/Cofilins. PMID- 26935887 TI - Unconventional superconductivity and interaction induced Fermi surface reconstruction in the two-dimensional Edwards model. AB - We study the competition between unconventional superconducting pairing and charge density wave (CDW) formation for the two-dimensional Edwards Hamiltonian at half filling, a very general two-dimensional transport model in which fermionic charge carriers couple to a correlated background medium. Using the projective renormalization method we find that a strong renormalization of the original fermionic band causes a new hole-like Fermi surface to emerge near the center of the Brillouin zone, before it eventually gives rise to the formation of a charge density wave. On the new, disconnected parts of the Fermi surface superconductivity is induced with a sign-changing order parameter. We discuss these findings in the light of recent experiments on iron-based oxypnictide superconductors. PMID- 26935888 TI - Novel susceptibility gene for nonfamilial hypokalemic periodic paralysis. AB - OBJECTIVE: To identify susceptibility genes to nonfamilial hypokalemic periodic paralysis (hypoKPP) consisting of thyrotoxic periodic paralysis (TPP) and sporadic periodic paralysis (SPP) and explore the potential pathogenic mechanisms. METHODS: We enrolled patients with nonfamilial hypoKPP not carrying mutations in CACNA1S, SCN4A, KCNJ18, or KCNJ2 and conducted genome-wide association analyses comparing 77 patients with TPP and 32 patients with SPP with 1,730 controls in a Han Chinese population in Taiwan. Replication was performed using an independent Han Chinese cohort of 50 patients with TPP, 22 patients with SPP, and 376 controls. RESULTS: We identified 4 single nucleotide polymorphisms (rs312692, rs312736, rs992072, rs393743) located about 100 Kb downstream of KCNJ2 on chromosome 17q24.3 associated with both TPP and SPP reaching genome-wide significance (p < 9 * 10(-8)). rs312736 was mapped to CTD-2378E21.1, a lincRNA, and direct sequencing revealed an exon variant rs312732 (risk allele A) highly associated with both TPP (p = 1.81 * 10(-12); odds ratio [OR] 3.22 [95% confidence interval (CI) 2.36-4.40]) and SPP (p = 8.6 * 10(-12); OR 5.4 [95% CI 3.17-9.18]). Overexpression of C (normal allele) CTD-2378E21.1 in C2C12 skeletal muscle cell, but not A (risk allele) CTD-2378E21.1, showed significantly decreased Kcnj2 expression, indicating A-type CTD-2378E21.1 has lost the ability to regulate Kcnj2. CONCLUSIONS: Our study reveals a shared genetic predisposition between TPP and SPP. CTD-2378E21.1 is a novel disease-associated gene for both TPP and SPP and may negatively regulate KCNJ2 expression. These findings provide new insights into the pathogenesis of nonfamilial hypoKPP. PMID- 26935889 TI - Isolated cortical vein thrombosis in autoimmune polyglandular syndrome type 2. PMID- 26935891 TI - Hostile attitudes and effortful coping in young adulthood predict cognition 25 years later. AB - OBJECTIVE: We studied the relation of early-life (mean age 25 years) and mid-life (mean age 50 years) cognitive function to early measures of hostile attitudes and effortful coping. METHODS: In 3,126 black and white men and women (born in 1955 1968) from the Coronary Artery Risk Development in Young Adults Study (CARDIA), we used linear regression to examine the association of hostile attitudes (Cook Medley questionnaire) and effortful coping assessed at baseline (1985-1986) to cognitive ability measured in 1987 and to a composite cognitive Z score of tests of verbal memory, psychomotor speed, and executive function ascertained in midlife (2010-2011). RESULTS: Baseline hostility and effortful coping were prospectively associated with lower cognitive function 25 years later, controlling for age, sex, race, education, long-term exposure to depression, discrimination, negative life events, and baseline cognitive ability. Compared to the lowest quartile, those in the highest quartile of hostility performed 0.21 SD units lower (95% confidence interval [CI] -0.39, -0.02). Those in the highest quartile of effortful coping performed 0.30 SD units lower (95% CI -0.48, -0.12) compared to those in the lowest quartile. Further adjustment for cumulative exposure to cardiovascular risk factors attenuated the association with the cognitive composite Z score for hostility. CONCLUSIONS: Worse cognition in midlife was independently associated with 2 psychological characteristics measured in young adulthood. This suggests that interventions that promote positive social interactions may have a role in reducing risk of late-age cognitive impairment. PMID- 26935892 TI - Vascular gait disorders: What's the matter with the white and gray matter? PMID- 26935890 TI - Spatial-temporal functional mapping of language at the bedside with electrocorticography. AB - OBJECTIVE: To investigate the feasibility and clinical utility of using passive electrocorticography (ECoG) for online spatial-temporal functional mapping (STFM) of language cortex in patients being monitored for epilepsy surgery. METHODS: We developed and tested an online system that exploits ECoG's temporal resolution to display the evolution of statistically significant high gamma (70-110 Hz) responses across all recording sites activated by a discrete cognitive task. We illustrate how this spatial-temporal evolution can be used to study the function of individual recording sites engaged during different language tasks, and how this approach can be particularly useful for mapping eloquent cortex. RESULTS: Using electrocortical stimulation mapping (ESM) as the clinical gold standard for localizing language cortex, the average sensitivity and specificity of online STFM across 7 patients were 69.9% and 83.5%, respectively. Moreover, relative to regions of interest where discrete cortical lesions have most reliably caused language impairments in the literature, the sensitivity of STFM was significantly greater than that of ESM, while its specificity was also greater than that of ESM, though not significantly so. CONCLUSIONS: This study supports the feasibility and clinical utility of online STFM for mapping human language function, particularly under clinical circumstances in which time is limited and comprehensive ESM is impractical. PMID- 26935893 TI - Gray and white matter changes linking cerebral small vessel disease to gait disturbances. AB - OBJECTIVE: To investigate the topographic changes of white matter (WM) integrity and cortical thickness related to gait disturbances and determine whether these neural correlates mediate the association between cerebral small vessel disease (CSVD) and gait disturbances. METHODS: A total of 129 patients with subcortical vascular cognitive impairment were included. CSVD severity was quantified as global and regional WM hyperintensities (WMH) volume and lacune and microbleed numbers. Amyloid burdens were assessed using Pittsburgh compound B (PiB)-PET scanning. Gait score was measured using a standardized scale. WM integrity was assessed by applying tract-based spatial statistics. Cortical thickness was measured using surface-based methods. Path analysis for gait score was performed using regional CSVD markers as predictors and fractional anisotropy (FA) and cortical thickness as mediators. RESULTS: Periventricular WMH (PWMH) volume was associated with gait score, regardless of other CSVD. PiB retention ratio was not associated with gait score. Gait score was correlated with FA in the frontal and parietal WM and bilateral corpus callosum and with cortical thinning in the bilateral frontal and lateral temporo-parieto-occipital regions. Path analysis for gait score showed that PWMH contributed to gait disturbances with the mediation of mean FA or cortical thickness. CONCLUSIONS: Our findings suggest that WMH-related cortical thinning as well as disrupted integrity of periventricular WM is linked to gait disturbances. PMID- 26935895 TI - Diagnostic potential of automated subcortical volume segmentation in atypical parkinsonism. AB - OBJECTIVE: To determine whether automated and observer-independent volumetric MRI analysis is able to discriminate among patients with Parkinson disease (PD), multiple system atrophy (MSA), and progressive supranuclear palsy (PSP) in early to moderately advanced stages of disease. METHODS: T1-weighted volumetric MRI from patients with clinically probable PD (n = 40), MSA (n = 40), and PSP (n = 30) and a mean disease duration of 2.8 +/- 1.7 y were examined using automated volume measures of 22 subcortical regions. The clinical follow-up period was 2.5 +/- 1.2 years. The data were split into a training (n = 72) and a test set (n = 38). The training set was used to build a C4.5 decision tree model in order to classify patients as MSA, PSP, or PD. The classification algorithm was examined by the test set using the final clinical diagnosis at last follow-up as diagnostic gold standard. RESULTS: The midbrain and putaminal volume as well as the cerebellar gray matter compartment were identified as the most significant brain regions to construct a prediction model. The diagnostic accuracy for PD vs MSA or PSP was 97.4%. In contrast, diagnostic accuracy based on validated clinical consensus criteria at the time of MRI acquisition was 62.9%. CONCLUSIONS: Volume segmentation of subcortical brain areas differentiates PD from MSA and PSP and improves diagnostic accuracy in patients presenting with early to moderately advanced stage parkinsonism. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that automated MRI analysis accurately discriminates among early-stage PD, MSA, and PSP. PMID- 26935896 TI - Is electrocorticography-based language mapping ready to replace stimulation? PMID- 26935894 TI - Low-frequency and common genetic variation in ischemic stroke: The METASTROKE collaboration. AB - OBJECTIVE: To investigate the influence of common and low-frequency genetic variants on the risk of ischemic stroke (all IS) and etiologic stroke subtypes. METHODS: We meta-analyzed 12 individual genome-wide association studies comprising 10,307 cases and 19,326 controls imputed to the 1000 Genomes (1 KG) phase I reference panel. We selected variants showing the highest degree of association (p < 1E-5) in the discovery phase for replication in Caucasian (13,435 cases and 29,269 controls) and South Asian (2,385 cases and 5,193 controls) samples followed by a transethnic meta-analysis. We further investigated the p value distribution for different bins of allele frequencies for all IS and stroke subtypes. RESULTS: We showed genome-wide significance for 4 loci: ABO for all IS, HDAC9 for large vessel disease (LVD), and both PITX2 and ZFHX3 for cardioembolic stroke (CE). We further refined the association peaks for ABO and PITX2. Analyzing different allele frequency bins, we showed significant enrichment in low-frequency variants (allele frequency <5%) for both LVD and small vessel disease, and an enrichment of higher frequency variants (allele frequency 10% and 30%) for CE (all p < 1E-5). CONCLUSIONS: Our findings suggest that the missing heritability in IS subtypes can in part be attributed to low frequency and rare variants. Larger sample sizes are needed to identify the variants associated with all IS and stroke subtypes. PMID- 26935897 TI - Primary male development of two sequentially hermaphroditic groupers, Epinephelus akaara and Epinephelus awoara (Perciformes: Epinephelidae). AB - Gonad ontogeny of the Hong Kong grouper Epinephelus akaara (a bi-directional sex changer) and the yellow grouper Epinephelus awoara (a protogynous hermaphrodite) was examined for the first time from post-larval phase until first sexual maturation, by histology. Approximately 20 specimens of each species were collected randomly every 2-7 weeks from rearing tanks with natural sea water and temperature between June 2013 and June 2014. The paired gonadal primordia (GP) were observed at 6 weeks after hatching (wah) for both species; however, gonia were first observed in GP at 16 wah for E. akaara and at 8 wah for E. awoara. The timings for the appearance of primary-growth stage oocytes (O1) and the completion of ovarian lumen (OL) varied; both at 27 wah for E. akaara, and at 18 and 23 wah for E. awoara respectively. A bisexual-phase gonad with an OL, O1 and scattered spermatogenic cysts (SC) was observed at 27-29 wah for both E. akaara and E. awoara. Sexual differentiation was subsequently observed from the bisexual phase gonad at 34 wah for E. akaara, and 41 wah for E. awoara, with the appearance of cortical-alveolus stage oocytes (O2) for developing female and the proliferation of SC for developing primary male (i.e. from juvenile directly). Ovaries of mature females contained the vitellogenic stage oocytes (O3) and scattered SC; testes of mature primary males had sperm in sperm sinuses within the gonadal wall and remained O1. Minimum age of first sexual maturation for both female and primary male of E. akaara was at 41 wah; minimum total length (LT ) of female (143 mm) was larger than that of primary male (137 mm L(T)). Minimum age and size of first sexual maturation for female of E. awoara (47 wah and 149 mm L(T), respectively) were larger than those of E. akaara. Developing primary males of E. awoara were found at 41-58 wah, however, mature males were not observed, indicating inconsistency in first sexual maturation for E. awoara. This study provided strong evidences of primary male pathway in E. akaara and E. awoara; the latter is confirmed to be diandric. PMID- 26935898 TI - Health Behavior Theory in Popular Calorie Counting Apps: A Content Analysis. AB - BACKGROUND: Although the Health & Fitness category of the Apple App Store features hundreds of calorie counting apps, the extent to which popular calorie counting apps include health behavior theory is unknown. OBJECTIVE: This study evaluates the presence of health behavior theory in calorie counting apps. METHODS: Data for this study came from an extensive content analysis of the 10 most popular calorie counting apps in the Health & Fitness category of the Apple App Store. RESULTS: Each app was given a theory score to reflect the extent to which health behavior theory was integrated into the app. The highest possible score was 60. Out of the 10 apps evaluated, My Diet Coach obtained the highest theory score of 15. MapMyFitness and Yumget received the lowest scores of 0. The average theory score among the apps was 5.6. CONCLUSIONS: Most of the calorie counting apps in the sample contained minimal health behavior theory. PMID- 26935899 TI - The development of the asymmetrically dominated decoy effect in young children. AB - One classic example of context-independent violations is the asymmetrically dominated decoy effect, in which adding a decoy option (inferior option) to a set of original options often increases the individual's preference for one option over the other original option. Despite the prevalence of this effect, little is known about its developmental origins. Moreover, it remains contentious whether the decoy effect is a result of biological evolution or is learned from social experience. Here, we investigated the decoy effect in 3- to 7-year-old children (n = 175) and young adults (n = 52) using a simple perceptual task. Results showed that older children (5-year-olds and 7-year-olds), but not younger children (3-year-olds), exhibited a decoy effect. Nevertheless, children as young as age 5 exhibited a decoy effect that was not significantly different from that shown by young adults. These findings suggest that humans start to appreciate the relative values of options at around age 5. PMID- 26935900 TI - Elevated caspase-1 activity and IL-1beta expression are associated with the IPAF inflammasome in an experimental model of allergy. AB - Previous studies have indicated that interleukin (IL)-1beta has an important role in the development of allergic diseases. Therefore, the present study aimed to investigate the upstream pathway underlying IL-1beta production in an experimental model of allergy. BALB/c mice (female, 6-8 weeks old) were sensitized to recombinant (r)Che a 2 by intraperitoneal injection of rChe a 2 adsorbed onto an alum gel suspension on days 0, 7, 14 and 21. In the control group, mice received an injection of 20 mM phosphate-buffered saline absorbed onto alum via the same route. The allergic status of the mice was confirmed serologically by measuring allergen-specific immunoglobulin (Ig)E levels. The protein expression levels of IL-1beta and the mRNA expression levels of inflammasome compartments were measured by enzyme-linked immunosorbent assay and semi-quantitative reverse transcription polymerase chain reaction, respectively. In addition, caspase-1 activity was determined by fluorometric assay. Sensitized mice exhibited significantly increased levels of specific IgE (P<0.05). IL-1beta production and caspase-1 activity were significantly higher in the sensitized mice compared with the control group. In addition, no significant differences were observed between the control and sensitized mice in the expression of genes associated with the inflammasome, including NLR family, pyrin domain containing 3; apoptosis-associated speck-like protein; and NLR family, apoptosis inhibitory protein 5. However, IL-1beta converting enzyme protease-activating factor (IPAF) expression was significantly increased in sensitized mice compared with in the control group (P<0.05). These data indicate that caspase-1 activation and IL 1beta expression are associated with the IPAF inflammasome. Therefore, based on this association, the IPAF inflammasome may be considered for IL-1beta production in the experimental model of allergy. PMID- 26935901 TI - Germplasm dynamics: the role of ecotypic diversity in shaping the patterns of genetic variation in Lolium perenne. AB - Perennial ryegrass (Lolium perenne) is the most widely grown temperate grass species globally. Intensive plant breeding in ryegrass compared to many other crops species is a relatively recent exercise (last 100 years) and provides an interesting experimental system to trace the extent, impact and trajectory of undomesticated ecotypic variation represented in modern ryegrass cultivars. To explore germplasm dynamics in Lolium perenne, 2199 SNPs were genotyped in 716 ecotypes sampled from 90 European locations together with 249 cultivars representing 33 forage/amenity accessions. In addition three pseudo-cross mapping populations (450 individual recombinants) were genotyped to create a consensus genetic linkage map. Multivariate analyses revealed strong differentiation between cultivars with a small proportion of the ecotypic variation captured in improved cultivars. Ryegrass cultivars generated as part of a recurrent selection programme (RSP) are strongly associated with a small number of geographically localised Italian ecotypes which were among the founders of the RSP. Changes in haplotype frequency revealed signatures of selection in genes putatively involved in water-soluble carbohydrate (WSC) accumulation (a trait selected in the RSP). Retrospective analysis of germplasm in breeding programmes (germplasm dynamics) provides an experimental framework for the identification of candidate genes for novel traits such as WSC accumulation in ryegrass. PMID- 26935902 TI - Identification of Resting State Networks Involved in Executive Function. AB - The structural networks in the human brain are consistent across subjects, and this is reflected also in that functional networks across subjects are relatively consistent. These findings are not only present during performance of a goal oriented task but there are also consistent functional networks during resting state. It suggests that goal oriented activation patterns may be a function of component networks identified using resting state. The current study examines the relationship between resting state networks measured and patterns of neural activation elicited during a Stroop task. The association between the Stroop activated networks and the resting state networks was quantified using spatial linear regression. In addition, we investigated if the degree of spatial association of resting state networks with the Stroop task may predict performance on the Stroop task. The results of this investigation demonstrated that the Stroop activated network can be decomposed into a number of resting state networks, which were primarily associated with attention, executive function, visual perception, and the default mode network. The close spatial correspondence between the functional organization of the resting brain and task evoked patterns supports the relevance of resting state networks in cognitive function. PMID- 26935903 TI - EAF2 mediates germinal centre B-cell apoptosis to suppress excessive immune responses and prevent autoimmunity. AB - Regulated apoptosis of germinal centre (GC) B cells is critical for normal humoral immune responses. ELL-associated factor 2 (EAF2) regulates transcription elongation and has been shown to be an androgen-responsive potential tumour suppressor in prostate by inducing apoptosis. Here we show that EAF2 is selectively upregulated in GC B cells among various immune cell types and promotes apoptosis of GC B cells both in vitro and in vivo. EAF2 deficiency results in enlarged GCs and elevated antibody production during a T-dependent immune response. After immunization with type II collagen, mice lacking EAF2 produce high levels of collagen-specific autoantibodies and rapidly develop severe arthritis. Moreover, the mutant mice spontaneously produce anti-dsDNA, rheumatoid factor and anti-nuclear antibodies as they age. These results demonstrate that EAF2-mediated apoptosis in GC B cells limits excessive humoral immune responses and is important for maintaining self-tolerance. PMID- 26935905 TI - Epigenetic silencing of miR-181b contributes to tumorigenicity in colorectal cancer by targeting RASSF1A. AB - Aberrant microRNA expression is common in colorectal cancer and DNA methylation is believed to be responsible for this alteration. In this study, we performed evaluation in vivo and in vitro to determine the role of miR-181b as a potential diagnostic and prognostic biomarker in colorectal cancer. Ninety-seven pairs of colorectal cancer tissues and adjacent normal tissues were collected. The expression level and methylation status of miR-181b was determined in tissue samples and multiple colorectal cancer cell lines. RASSF1A, a predicted target gene of miR-181b, was investigated in vitro. Further mechanistic explorations were conducted. It was found that miR-181b expression was frequently downregulated in cancer samples. This lower expression level resulted from higher hypermethylation in cancer tissue and was closely related to TNM stage. Following artificial synthesis of miR-181b stimulation, colorectal cancer cell proliferation was greatly inhibited in CRC cells while apoptosis percentage markedly increased. miR-181b achieved the tumor suppressive effects via direct targeting of the RASSF1A gene. This study indicated the clinical significance of miR-181b and the influence of miR-181b promoter region in epigenetic silencing of tumorigenicity in colorectal cancer, and implied the possible usage of miR-181b as a diagnostic and prognostic biomarker in colorectal cancer. PMID- 26935906 TI - Acid-promoted bicyclization of arylacetylenes to benzobicyclo[3.2.1]octanes through cationic rearrangements. AB - Acid-promoted efficient, site- and stereo-selective bicyclization of alkynes to polycyclic compounds (benzobicyclo[3.2.1]octanes) was realized with atom- and step-economy. The reaction proceeded through two C-C bonds formed on remote alkyl C-H bonds via twice long-distance cationic rearrangement. PMID- 26935904 TI - Downregulation of vascular endothelial growth factor receptor-2 under oxidative stress conditions is mediated by beta-transduction repeat-containing protein via glycogen synthase kinase-3beta signaling. AB - Vascular endothelial growth factor receptor-2 (VEGFR-2), which is a key determinant of the angiogenecic response, is decreased in diabetic mice under oxidative stress. beta-transduction repeat-containing protein (beta-TrCP) has been reported to participate in VEGFR-2 degradation in thyroid cancer cells. Additionally, glycogen synthase kinase-3beta (GSK-3beta) acts as a mediator in the beta-TrCP-induced degradation of several proteins. However, the role played by beta-TrCP and GSK-3beta in the degradation of VEGFR-2 in endothelial cells where hyperglycemia had been induced was not fully understood. In the present study, we aimed to analyze the mechanisms of VEGFR-2 degradation by studying excess reactive oxygen species (ROS) induced by hyperglycemia or glucose oxidase (GO). Human umbilical vein endothelial cells (HUVECs) were treated with different concentrations of glucose (6.6, 19.8 and 33 mM), mannitol (33 mM) and GO (1 U/ml). Angiogenic function, ROS levels, the co-location of VEGFR-2 and beta-TrCP were evaluated. Cells were collected for RT-qPCR and western blot analysis. We noted that angiogenesis was impaired upon increasing the glucose concentration. When HUVECs were in a hyperglycemic state, ROS production increased, comparable to exposure to GO; GO catalyzes oxidation of glucose into H2O2 and D-glucono delta-lactone. Phosphorylated VEGFR-2 was reduced by hyperglycemia while total VEGFR-2 was almost unaltered. However, VEGFR-2 was reduced when directly exposed to ROS, with resultant co-location of beta-TrCP and VEGFR-2. Through a co immunoprecipitation assay, we noted that ubiquitinated VEGFR-2 was significantly augmented by excess ROS. Decreased VEGFR-2 caused by ROS was ameliorated by beta TrCP siRNA, proteasome inhibitor MG132 and GSK-3beta activity inhibitor (lithium chloride and SB216763). We suggest that redundant ROS reduces VEGFR-2 through beta-TrCP-mediated VEGFR-2 degradation, which is postulated to be regulated by GSK-3beta. PMID- 26935907 TI - One-pot relay catalysis: divergent synthesis of furo[3,4-b]indoles and cyclopenta[b]indoles from 3-(2-aminophenyl)-1,4-enynols. AB - Described herein is an efficient divergent strategy for the synthesis of furo[3,4 b]indoles via a sequential Ag(i)/Bi(iii)/Pd(ii) catalysis and cyclopenta[b]indoles via a one-pot Ag(i)/Bronsted acid relay catalysis from 3-(2 aminophenyl)-4-pentenyn-3-ols, accessible in three simple steps from 2 aminobenzaldehydes. PMID- 26935909 TI - Effective Valsalva maneuvering during TCCD and unrevealed etiology of RLS. AB - Either transcranial color-coded Doppler (TCCD) or contrast echocardiography (CE) is the bests of clinically applicable and reproducible methods to evaluate the functionality of right-to-left shunts that can be found in different localization on atrial septum. As the anatomical features of right-to-left shunts could vary in many forms, detection of RLS by functional tests may aid the clinician to do risk prediction and management of patients. Sensitivity of TCDD or CE can be increased by performing effective Valsalva maneuvering during the test procedure. Timing of RLS during the cardiac cycles may help interpreting about the etiology of RLS, atrial septum or intrapulmonary shunts. Intrapulmonary shunts have been recently reported to be associated with RLS and frequently overlooked unless the tests prolonged up to 10th cardiac beat. Migraine, cryptogenic strokes, and paradoxic embolism are closely associated with RLS which should be evaluated by the collaboration of cardiologists and neurologists. Success of diagnostic procedure depends on high suspicion of index for RLS and application of contrast enhanced tests that are effectively performed at each step. PMID- 26935910 TI - Valsalva manoeuvre and TCCD diagnostic accuracy. PMID- 26935911 TI - Heteroleptic Ru(ii)-bipyridine complexes based on hexylthioether-, hexyloxy- and hexyl-substituted thienylenevinylenes and their application in dye-sensitized solar cells. AB - A series of eight Ru(ii) heteroleptic complexes incorporating an ancillary [2,2']bipyridine functionalised at the [4,4'] positions with one (-type) or two ( type) thienylenevinylenes (nTVs, n = 2 or 4) is reported. Three types of substitutions have been used for nTVs: hexylthioether, hexyloxy and hexyl. The characterisation of the half-sandwich intermediates and final complexes is provided. In particular, the half-sandwich complexes in the -type series are obtained as a racemate, whereas the heteroleptic complexes consist of two regioisomers. Finally, these complexes have been tested as dyes in dye-sensitized solar cells (DSSCs). Counterintuitively, better performances were obtained for type complexes with shorter 2TV moieties. The best performing dye was the Ru(ii) complex mono-functionalized with a 2TV moiety having an hexylthioether substitution (), which achieved a maximum power efficiency of 2.77% under full sun illumination (AM1.5G standard conditions). The structure-performance relationship in DSSCs is discussed based on photovoltaic and electrochemical data and DFT-calculations. PMID- 26935912 TI - Prevalence and antibiotic susceptibility of coagulase-negative Staphylococcus species from bovine subclinical mastitis in dairy herds in the central region of Argentina. AB - Coagulase-negative staphylococci (CNS) are a common cause of bovine subclinical mastitis (SCM). The prevalence of CNS species causing SCM identified by genotyping varies among countries. Overall, the antimicrobial resistance in this group of organisms is increasing worldwide; however, little information exists about a CNS species resistant to antibiotics. The aim of the present study was to genotypically characterize CNS at species level and to determine the prevalence and antibiotic resistance profiles of CNS species isolated from bovine SCM in 51 dairy herds located in the central region of the province of Cordoba, Argentina. In this study, we identified 219 CNS isolates at species level by PCR-restriction fragment length polymorphism of the groEL gene. Staphylococcus chromogenes (46.6%) and Staphylococcus haemolyticus (32%) were the most prevalent species. A minimum of three different CNS species were present in 41.2% of the herds. S. chromogenes was isolated from most of the herds (86.3%), whereas S. haemolyticus was isolated from 66.7% of them. The broth microdilution method was used to test in vitro antimicrobial susceptibility. Resistance to a single compound or two related compounds was expressed in 43.8% of the isolates. S. chromogenes and S. haemolyticus showed a very high proportion of isolates resistant to penicillin. Resistance to two or more non-related antimicrobials was found in 30.6% of all CNS. S. haemolyticus exhibited a higher frequency of resistance to two or more non-related antimicrobials than S. chromogenes. PMID- 26935913 TI - Detection of mumps virus genotype H in two previously vaccinated patients from Mexico City. AB - Infections caused by mumps virus (MuV) have been successfully prevented through vaccination; however, in recent years, an increasing number of mumps outbreaks have been reported within vaccinated populations. In this study, MuV was genotyped for the first time in Mexico. Saliva samples were obtained from two previously vaccinated patients in Mexico City who had developed parotitis. Viral isolation was carried out in Vero cells, and the SH and HN genes were amplified by RT-PCR. Amplicons were sequenced and compared to a set of reference sequences to identify the MuV genotype. PMID- 26935914 TI - Highly pathogenic influenza H5N1 virus of clade 2.3.2.1c in Western Siberia. AB - In the spring of 2015, avian influenza virus surveillance in Western Siberia resulted in isolation of several influenza H5N1 virus strains. The strains were isolated from several wild bird species. Investigation of biological features of those strains demonstrated their high pathogenicity for mammals. Phylogenetic analysis of the HA gene showed that the strains belong to clade 2.3.2.1c. PMID- 26935915 TI - Genotypic evolution and antigenicity of H9N2 influenza viruses in Shanghai, China. AB - H9N2 influenza viruses have been circulating in China since 1994, but a systematic investigation of H9N2 in Shanghai has not previously been undertaken. Here, using 14 viruses we isolated from poultry and pigs in Shanghai during 2002 and 2006-2014, together with the commercial vaccine A/chicken/Shanghai/F/1998 (Ck/SH/F/98), we analyzed the evolution of H9N2 influenza viruses in Shanghai and showed that all 14 isolates originated from Ck/SH/F/98 antigenically. We evaluated the immune protection efficiency of the vaccine. Our findings demonstrate that H9N2 viruses in Shanghai have undergone extensive reassortment. Various genotypes emerged in 2002, 2006 and 2007, while during 2009-2014 only one genotype was found. Four antigenic groups, A-D, could be identified among the 14 isolates and a variety of antigenically distinct H9N2-virus-derived avian influenza viruses (AIVs) circulated simultaneously in Shanghai during this period. Challenge experiments using vaccinated chickens indicated that the vaccine prevented shedding of antigenic group A and B viruses, but not those of the more recent groups C and D. Genetic analysis showed that compared to the vaccine strain, representative viruses of antigenic groups C and D possess greater numbers of amino acid substitutions in the hemagglutinin (HA) protein than viruses in antigenic groups A and B. Many of these substitutions are located in antigenic sites. Our results indicate that the persistence of H9N2 AIV in China might be due to incomplete vaccine protection and that the avian influenza vaccine should be regularly evaluated and updated to maintain optimal protection. PMID- 26935916 TI - Complete genome analysis of coxsackievirus A24 isolated in Yunnan, China, in 2013. AB - Human coxsackievirus A24 (CVA24) belongs to the species Enterovirus C, and variants of this virus frequently cause acute hemorrhagic conjunctivitis (AHC). The complete genome of the K282/YN/CHN/2013 strain, isolated from a healthy child in Yunnan, China, in 2013, is reported here for the first time. The strain showed 80.0 % and 79.9 % nucleotide sequence identity to CVA24 prototype strain Joseph and CVA24 variant prototype EH24, respectively. The K282/YN/CHN/2013 strain belongs to the CVA24 serotype. Twelve amino acid differences, most of which are in structural regions, were found between the CVA24 and CVA24v strains. In the whole-length genome sequence, only the structural region of K282/YN/CHN/2013 was similar to that of the CVA24 strains; the other genome regions were more similar to those of other members of the species Enterovirus C. Recombination analysis showed evidence of recombination with other viruses of the same species. PMID- 26935917 TI - The carboxy-terminal half of nonstructural protein 3A is not essential for foot and-mouth disease virus replication in cultured cell lines. AB - In foot-and-mouth disease (FMD)-endemic parts of the globe, control is mainly implemented by preventive vaccination with an inactivated purified vaccine. ELISAs detecting antibodies to the viral nonstructural proteins (NSP) distinguish FMD virus (FMDV)-infected animals in the vaccinated population (DIVA). However, residual NSPs present in the vaccines are suspected to be a cause of occasional false positive results, and therefore, an epitope-deleted negative marker vaccine strategy is considered a more logical option. In this study, employing a serotype Asia 1 FMDV infectious cDNA clone, it is demonstrated that while large deletions differing in size and location in the carboxy-terminal half of 3A downstream of the putative hydrophobic membrane-binding domain (deletion of residues 86-110, 101-149, 81-149 and 81-153) are tolerated by the virus without affecting its infectivity in cultured cell lines, deletions in the amino-terminal half (residues 5-54, 21-50, 21-80, 55-80 and 5-149) containing the dimerization and the transmembrane domains are deleterious to its multiplication. Most importantly, the virus could dispense with the entire carboxy-terminal half of 3A (residues 81-153) including the residues involved in the formation of the 3A-3B1 cleavage junction. The rescue of a replication-competent FMDV variant carrying the largest deletion ever in 3A (residues 81-153) and the fact that the deleted region contains a series of linear B-cell epitopes inspired us to devise an indirect ELISA based on a recombinant 3A carboxy-terminal fragment and to evaluate its potential to serve as a companion diagnostic assay for differential serosurveillance if the 3A-truncated virus is used as a marker vaccine. PMID- 26935918 TI - Analysis of the entry mechanism of Crimean-Congo hemorrhagic fever virus, using a vesicular stomatitis virus pseudotyping system. AB - Crimean-Congo hemorrhagic fever (CCHF) is a tick-borne disease causing severe hemorrhagic symptoms with a nearly 30 % case-fatality rate in humans. The experimental use of CCHF virus (CCHFV), which causes CCHF, requires high biosafety-level (BSL) containment. In contrast, pseudotyping of various viral glycoproteins (GPs) onto vesicular stomatitis virus (VSV) can be used in facilities with lower BSL containment, and this has facilitated studies on the viral entry mechanism and the measurement of neutralizing activity, especially for highly pathogenic viruses. In the present study, we generated high titers of pseudotyped VSV bearing the CCHFV envelope GP and analyzed the mechanisms involved in CCHFV infection. A partial deletion of the CCHFV GP cytoplasmic domain increased the titer of the pseudotyped VSV, the entry mechanism of which was dependent on the CCHFV envelope GP. Using the pseudotype virus, DC-SIGN (a calcium-dependent [C-type] lectin cell-surface molecule) was revealed to enhance viral infection and act as an entry factor for CCHFV. PMID- 26935919 TI - Characterization and occurrence of squash chlorotic leaf spot virus, a tentative new torradovirus infecting cucurbits in Sudan. AB - During a survey conducted in Sudan in 2012, a virus with spherical particles was isolated from a squash plant showing chlorotic leaf spots. The virus was transmitted mechanically and by two whitefly species, but not by aphids. RT-PCR with generic torradovirus primers yielded a band of expected size from total RNA of a symptomatic plant. Next-generation sequencing confirmed that this is tentatively a new torradovirus, for which we propose the name 'squash chlorotic leaf spot virus'. Using specific RT-PCR primers, the virus was detected in cucurbit samples collected since 1992 at different locations in Sudan. PMID- 26935920 TI - Stability, biophysical properties and effect of ultracentrifugation and diafiltration on measles virus and mumps virus. AB - Measles virus and mumps virus (MeV and MuV) are enveloped RNA viruses used for production of live attenuated vaccines for prophylaxis of measles and mumps disease, respectively. For biotechnological production of and basic research on these viruses, the preparation of highly purified and infectious viruses is a prerequisite, and to meet that aim, knowledge of their stability and biophysical properties is crucial. Our goal was to carry out a detailed investigation of the stability of MeV and MuV under various pH, temperature, shear stress, filtration and storage conditions, as well as to evaluate two commonly used purification techniques, ultracentrifugation and diafiltration, with regard to their efficiency and effect on virus properties. Virus titers were estimated by CCID50 assay, particle size and concentration were measured by Nanoparticle tracking analysis (NTA) measurements, and the host cell protein content was determined by ELISA. The results demonstrated the stability of MuV and MeV at pH <9 and above pH 4 and 5, respectively, and aggregation was observed at pH >9. Storage without stabilizer did not result in structural changes, but the reduction in infectivity after 24 hours was significant at +37 degrees C. Vortexing of the viruses resulted in significant particle degradation, leading to lower virus titers, whereas pipetting had much less impact on virus viability. Diafiltration resulted in higher recovery of both total and infectious virus particles than ultracentrifugation. These results provide important data for research on all upstream and downstream processes on these two viruses regarding biotechnological production and basic research. PMID- 26935921 TI - Biotransformation of Cobicistat: Metabolic Pathways and Enzymes. AB - BACKGROUND: Cobicistat (COBI) is a pharmacoenhancer for antiretroviral therapy. OBJECTIVE: The current study was designed to profile the metabolic pathways of COBI and to determine the enzymes that contribute to COBI metabolism. METHOD: We screened COBI metabolites in mice and human liver microsomes. We also used cDNAexpressed human cytochromes P450 (CYPs) to explore the role of human enzymes in COBI metabolism. RESULTS: Twenty new and three known metabolites of COBI were identified in mouse urine and feces. These new metabolic pathways of COBI include glycine conjugation, N-acetyl cysteine conjugation, morpholine ring-opening, and thiazole ring-opening. Twelve of COBI metabolites were further confirmed in mouse and human liver microsomes, including nine new metabolites. Consistent with the previous report, CYP3A4 and CYP2D6 were determined as the major enzymes that contribute to COBI metabolism. CONCLUSION: This study provided a full map of COBI metabolism. These results can be used to manage CYP-mediated drug-drug interactions and adverse drug reactions that are associated with COBI-containing regimens in human. PMID- 26935922 TI - The Effects of Statin Therapy on the Human Airway. AB - BACKGROUND: Statins have been long known for their lipid-lowering properties however there has been recent interest in their potential to positively influence clinical outcomes in pulmonary disease processes manifesting primarily as airway disorders. OBJECTIVES: We review the potential use of statin therapy in respiratory medicine, with particular emphasis on airway disease. We also explore the possible mechanisms for the observed benefits of statins in conditions of the airway. METHOD: A literary review of published articles related to defining the potential scientific basis for touted clinical efficacy, pertinent clinical data and review articles of statin therapy in airway disease. RESULTS: There was a vast quantity of publications available pertaining to the topic of interest. CONCLUSION: Statins may have beneficial pleiotropic effects in addition to their actions as potent lipid-lowering agents particularly in patients with chronic obstructive pulmonary disease and post lung transplantation. Further human studies are required to substantiate their possible potential as many of the clinical trials performed to date have not demonstrated the translation of results of these promising scientific and observational studies into positive outcomes in well-designed, randomized, placebo-controlled human trials. PMID- 26935923 TI - No adverse effect of outdoor air pollution on HbA1c in children and young adults with type 1 diabetes. AB - BACKGROUND: Evidence is growing that air pollutants deteriorate glucose metabolism and insulin sensitivity by oxidative stress and inflammation. This might affect HbA1c levels and insulin requirements in type 1 diabetes. There are no data available on this association. METHODS: Air pollution values of respirable particulate matter (PM10), nitrogen dioxides (NO2), and accumulated ozone (O3-AOT40) were obtained from the federal environmental agency (Umweltbundesamt II) and assigned to place of residence of 840 participants from a nation-wide population-based type 1 diabetes registry (German Diabetes Center, Dusseldorf, Germany). Information on HbA1c, social status, treatment and co morbidities was collected by self-administered questionnaires. Complete information was available for 771 patients aged 11-21 years at the time of study. RESULTS: In linear regression models, no adverse effects of air pollutants (PM10, NO2 or O3-AOT40 on HbA1c level were found, but O3-AOT40 was inversely associated with HbA1c (mmol/mol) in the crude (estimate per IQR: -1.86; 95% CI: (-3.27; 0.44); p=0.01) and the best model adjusting for lifestyle, socioeconomic factors, clinical information, and season (-1.50; (-2.82; -0.17); 0.034). After adding area of residency as random effect to the crude and the best model, the association was no longer significant (-1.64; (-3.84; 0.56); 0.14); (-1.56; ( 3.67; 0.55); 0.14). Adjustment for further possible confounders did not affect the estimates seriously. None of the pollutants was associated with insulin dose (IU/kg body weight). CONCLUSIONS: Investigated pollutants had no adverse effect on metabolic control in children and young adults with type 1 diabetes in this cross-sectional study. The weak inverse association of accumulated ozone with HbA1c might be due to confounding by regional characteristics or regional aspects of care. PMID- 26935925 TI - On the Dynamical Regimes of Pattern-Accelerated Electroconvection. AB - Recent research has established that electroconvection can enhance ion transport at polarized surfaces such as membranes and electrodes where it would otherwise be limited by diffusion. The onset of such overlimiting transport can be influenced by the surface topology of the ion selective membranes as well as inhomogeneities in their electrochemical properties. However, there is little knowledge regarding the mechanisms through which these surface variations promote transport. We use high-resolution direct numerical simulations to develop a comprehensive analysis of electroconvective flows generated by geometric patterns of impermeable stripes and investigate their potential to regularize electrokinetic instabilities. Counterintuitively, we find that reducing the permeable area of an ion exchange membrane, with appropriate patterning, increases the overall ion transport rate by up to 80%. In addition, we present analysis of nonpatterned membranes, and find a novel regime of electroconvection where a multivalued current is possible due to the coexistence of multiple convective states. PMID- 26935924 TI - Evaluation of Gelatin Microparticles as Adherent-Substrates for Mesenchymal Stem Cells in a Hydrogel Composite. AB - Due to the lack of cell-adhesive moieties in traditional synthetic hydrogels, the present work investigated the use of degradable gelatin microparticles (GMPs) as temporary adherent substrates for anchorage-dependent mesenchymal stem cells (MSCs). MSCs were seeded onto GMPs of varying crosslinking densities and sizes to investigate their role on influencing MSC differentiation and aggregation. The MSC-seeded GMPs were then encapsulated in poly(ethylene glycol)-based hydrogels and cultured in serum-free, growth factor-free osteochondral medium. Non-seeded MSCs co-encapsulated with GMPs in the hydrogels were used as a control for comparison. Over the course of 35 days, MSCs seeded on GMPs exhibited more cell cell contacts, greater chondrogenic potential, and a down-regulation of osteogenic markers compared to the controls. Although the factors of GMP crosslinking and size had nominal influence on MSC differentiation and aggregation, GMPs demonstrate potential as an adherent-substrate for improving cell delivery from hydrogel scaffolds by facilitating cell-cell contacts and improving MSC differentiation. PMID- 26935926 TI - p53 determines prognostic significance of the carbohydrate stem cell marker TF1 (CD176) in ovarian cancer. AB - INTRODUCTION: The oncofoetal Thomsen-Friedenreich (TF1, CD176) epitope is a carbohydrate cancer stem cell (CSC) antigen, and TF1-mediated cancer progression can be widely reversed by anti-TF1 antibodies. Particularly, CSC-like cells are regarded to be tumorigenic and chemoresistant. Aberrant p53 is probably the factor most closely associated with chemoresistance and tumour aggressiveness in ovarian tumours. We thus questioned whether TF1 in combination with p53 or as a single marker may be related to clinico-pathological features and survival of ovarian cancer patients. PATIENTS AND METHODS: Both markers were quantified in ovarian cancer tissue (n = 151) by immunohistochemistry. p53 staining was subdivided into three subgroups [n (completely negative) = 57, n (moderately stained) = 28, n (overexpressing) = 66]. TF1 was scored as positive (n = 30) versus negative (n = 121). RESULTS: Only in those cancers classified with moderate p53 staining-and thus most likely displaying with wild-type TP53-TF1 positivity turned out to be a predictor for shortened overall survival (univariate: p < 0.001, multivariate: p = 0.001). By screening 17 different protein markers for correlation with TF1, only mucin-1 emerged as a potential TF1 carrier protein. CONCLUSION: It is hypothesized that TF1 may confer tumour promoting features, especially in a TP53 wild-type genetic background. In addition, TF1 is an attractive immunotherapeutic target. Whether those cases classified as TF1 positive and at the same time as moderately stained for p53 might particularly benefit from a future anti-TF1 antibody treatment or from TF1 vaccination therapy remains to be determined. PMID- 26935928 TI - Pyrosequencing with di-base addition for single nucleotide polymorphism genotyping. AB - We develop color code-based pyrosequencing with di-base addition for analysis of single nucleotide polymorphisms (SNPs). When a di-base is added into the polymerization, one or several two-color code(s) containing the type and the number of incorporated nucleotides will be produced. The code information obtained in a single run is useful to genotype SNPs as each allelic variant will give a specific pattern compared to the two other variants. Special care has to be taken while designing the di-base dispensation order. Here, we present a detailed protocol for establishing sequence-specific di-base addition to avoid nonsynchronous extension at the SNP sites. By using this technology, as few as 50 copies of DNA templates were accurately sequenced. Higher signals were produced and thus a relatively lower sample amount was required. Furthermore, the read length of per flow was increased, making simultaneous identification of multiple SNPs in a single sequencing run possible. Validation of the method was performed by using templates with two SNPs covering 37 bp and with three SNPs covering 58 bp as well as 82 bp. These SNPs were successfully genotyped by using only a sequencing primer in a single PCR/sequencing run. Our results demonstrated that this technology could be potentially developed into a powerful methodology to accurately determine SNPs so as to diagnose clinical settings. PMID- 26935927 TI - Evaluation of polymorphisms in angiogenesis-related genes as predictive and prognostic markers for sunitinib-treated metastatic renal cell carcinoma patients. AB - PURPOSE: Single nucleotide polymorphisms (SNPs) in angiogenesis-associated genes might play an important role in activity of the tyrosine kinase inhibitor sunitinib and could affect survival of cancer patients treated with this drug. The aim of this retrospective study was to elucidate the role of 10 known SNPs in VEGFA, VEGFR1, VEGFR2 and VEGFR3 as potential prognostic and predictive markers in an independent cohort of patients with metastatic renal cell carcinoma (mRCC). METHODS: DNA from 121 mRCC patients treated with sunitinib was used to analyze SNPs by TaqMan genotyping assays. Disease control rate was evaluated according to RECIST. Adverse effects of sunitinib were registered from medical records. The results of Cox and logistic regression were verified by correction for multiple testing. RESULTS: Kaplan-Meier analysis revealed a reduced progression-free survival in patients with the wild-type (WT) allele of the VEGFA SNP rs699947 compared to variant alleles. Patients with the AA/AC-alleles of the VEGFR1 SNP rs9582036 had an improved median overall survival compared to those with the CC WT allele what could be confirmed by multivariable Cox proportional hazard regression analyses. No statistically significant associations between the analyzed SNPs and higher risk for adverse effects were observed. CONCLUSIONS: The results of this study suggest that most of the selected SNPs in angiogenesis related genes are not associated with survival of mRCC patients after sunitinib therapy or with adverse effects. Only the VEGFR1 SNP rs9582036 showed a statistically significant association with overall survival. The potential of SNPs as prognostic and predictive markers for sunitinib-treated mRCC patients should be finally assessed by prospective studies. PMID- 26935929 TI - Identification of Polish cochineal (Porphyrophora polonica L.) in historical textiles by high-performance liquid chromatography coupled with spectrophotometric and tandem mass spectrometric detection. AB - The present work reports a method for identification of Polish cochineal (Porphyrophora polonica L.) in historical fabrics by the use of high-performance liquid chromatography coupled with diode array and tandem mass spectrometric detection with electrospray ionization (HPLC-DAD-ESI MS/MS). This hyphened technique allows detection and identification of 16 new minor colorants present in the discussed scale insect (including two previously observed by Wouters and Verhecken (Ann Soc Entomol Fr. 1989;25:393-410), but specified only as compounds of unknown structures) that do not occur (e.g., in American cochineal). The MS/MS experiments, complemented with UV-VIS data, enable identification of mono- and di , C- and O-hexosides of kermesic and flavokermesic acids or their derivatives. The present paper introduces a fingerprint of color compounds present in Polish cochineal and defines them, particularly pp6 (ppI, O-hexoside of flavokermesic acid), as its markers allow distinguishing of Polish-cochineal reds from the American ones. Usefulness of the selected set of markers for identification of Polish cochineal has been demonstrated in the examination of textiles from the collection of the National Museum in Warsaw using the multiple reaction monitoring (MRM) method, originally elaborated on the basis of this study. PMID- 26935930 TI - Determination of persimmon leaf chloride contents using near-infrared spectroscopy (NIRS). AB - Early diagnosis of specific chloride toxicity in persimmon trees requires the reliable and fast determination of the leaf chloride content, which is usually performed by means of a cumbersome, expensive and time-consuming wet analysis. A methodology has been developed in this study as an alternative to determine chloride in persimmon leaves using near-infrared spectroscopy (NIRS) in combination with multivariate calibration techniques. Based on a training dataset of 134 samples, a predictive model was developed from their NIR spectral data. For modelling, the partial least squares regression (PLSR) method was used. The best model was obtained with the first derivative of the apparent absorbance and using just 10 latent components. In the subsequent external validation carried out with 35 external data this model reached r(2) = 0.93, RMSE = 0.16% and RPD = 3.6, with standard error of 0.026% and bias of -0.05%. From these results, the model based on NIR spectral readings can be used for speeding up the laboratory determination of chloride in persimmon leaves with only a modest loss of precision. The intermolecular interaction between chloride ions and the peptide bonds in leaf proteins through hydrogen bonding, i.e. N-H...Cl, explains the ability for chloride determinations on the basis of NIR spectra. PMID- 26935931 TI - PEPR: pipelines for evaluating prokaryotic references. AB - The rapid adoption of microbial whole genome sequencing in public health, clinical testing, and forensic laboratories requires the use of validated measurement processes. Well-characterized, homogeneous, and stable microbial genomic reference materials can be used to evaluate measurement processes, improving confidence in microbial whole genome sequencing results. We have developed a reproducible and transparent bioinformatics tool, PEPR, Pipelines for Evaluating Prokaryotic References, for characterizing the reference genome of prokaryotic genomic materials. PEPR evaluates the quality, purity, and homogeneity of the reference material genome, and purity of the genomic material. The quality of the genome is evaluated using high coverage paired-end sequence data; coverage, paired-end read size and direction, as well as soft-clipping rates, are used to identify mis-assemblies. The homogeneity and purity of the material relative to the reference genome are characterized by comparing base calls from replicate datasets generated using multiple sequencing technologies. Genomic purity of the material is assessed by checking for DNA contaminants. We demonstrate the tool and its output using sequencing data while developing a Staphylococcus aureus candidate genomic reference material. PEPR is open source and available at https://github.com/usnistgov/pepr . PMID- 26935932 TI - 3D Raman imaging of systemic endothelial dysfunction in the murine model of metastatic breast cancer. AB - It was recently reported in the murine model of metastatic breast cancer (4T1) that tumor progression and development of metastasis is associated with systemic endothelial dysfunction characterized by impaired nitric oxide (NO) production. Using Raman 3D confocal imaging with the analysis of the individual layers of the vascular wall combined with AFM endothelial surface imaging, we demonstrated that metastasis-induced systemic endothelial dysfunction resulted in distinct chemical changes in the endothelium of the aorta. These changes, manifested as a significant increase in the protein content (18%) and a slight decrease in the lipid content (4%), were limited to the endothelium and did not occur in the deeper layers of the vascular wall. The altered lipid to protein ratio in the endothelium, although more pronounced in the fixed vascular wall, was also observed in the freshly isolated unfixed vascular wall samples in the aqueous environment (12 and 7% change of protein and lipid content, respectively). Our results support the finding that the metastasis induces systemic endothelial dysfunction that may contribute to cancer progression. PMID- 26935933 TI - Metabolites of synthetic cannabinoids in hair--proof of consumption or false friends for interpretation? AB - The detection of drug metabolites in hair is widely accepted as a proof for systemic uptake of the drug, unless the metabolites can be formed as artefacts. However, regarding synthetic cannabinoids, not much is known about mechanisms of incorporation into hair. For a correct interpretation concerning hair findings of these compounds and their metabolites, it is necessary to identify the different routes of incorporation and to assess their contribution to analytical findings. This study presents the results of the LC-ESI-MS/MS analysis of an authentic hair sample taken from a patient with a known history of heavy consumption of synthetic cannabinoids. In the authentic hair sample, 5F-PB-22 and AB-CHMINACA as well as their main metabolites 5F-PB-22 3-carboxyindole, PB-22 5-OH-pentyl, and AB-CHMINACA valine were detected in all segments, comprising segments grown in a time period where the substances had not been distributed on the 'legal high' market. To enable interpretation of the results regarding the distribution of the detected analytes along the hair shaft, the stability of 5F-PB-22 and AB-CHMINACA in hair matrix and under thermal stress was assessed. The stability tests revealed that the three 'metabolites' are also formed in externally contaminated hair after storage of the samples under different conditions. In addition, 5F-PB 22 3-carboxyindole and AB-CHMINACA valine were identified as degradation products in smoke condensate. Therefore, interpretation of 'metabolite' findings of compounds comprising chemically labile amide/ester bonds or 5-fluoro-pentyl side chains should be carried out with utmost care, taking into account the different mechanisms of formation and incorporation into hair. PMID- 26935935 TI - Primary biliary cirrhosis associated with Graves' disease in a male patient. AB - Primary biliary cirrhosis (PBC), which predominantly affects women, has been associated with various autoimmune diseases. Although hypothyroidism accompanying PBC is well documented, the concomitance of PBC and hyperthyroidism is rare. Herein, we report the case of a 62-year-old man who was diagnosed with PBC several years after the development of Graves' disease. This is the first case of a male patient developing PBC with Graves' disease. Both serum alanine aminotransferase levels and serum thyroid hormone levels were normalized after the administration of thiamazole for Graves' disease. However, the cholestatic liver enzyme abnormalities continued, indicating that the PBC was actualized by the administration of thiamazole. After starting ursodeoxycholic acid treatment, cholestatic liver enzyme abnormalities improved. Taken together, when a cholestatic pattern of liver enzymes is observed during follow-up for Graves' disease, an association between Graves' disease and PBC should be considered as a differential diagnosis. PMID- 26935934 TI - Microfabricated, amperometric, enzyme-based biosensors for in vivo applications. AB - Miniaturized electrochemical in vivo biosensors allow the measurement of fast extracellular dynamics of neurotransmitter and energy metabolism directly in the tissue. Enzyme-based amperometric biosensing is characterized by high specificity and precision as well as high spatial and temporal resolution. Aside from glucose monitoring, many systems have been introduced mainly for application in the central nervous system in animal models. We compare the microsensor principle with other methods applied in biomedical research to show advantages and drawbacks. Electrochemical sensor systems are easily miniaturized and fabricated by microtechnology processes. We review different microfabrication approaches for in vivo sensor platforms, ranging from simple modified wires and fibres to fully microfabricated systems on silicon, ceramic or polymer substrates. The various immobilization methods for the enzyme such as chemical cross-linking and entrapment in polymer membranes are discussed. The resulting sensor performance is compared in detail. We also examine different concepts to reject interfering substances by additional membranes, aspects of instrumentation and biocompatibility. Practical considerations are elaborated, and conclusions for future developments are presented. Graphical Abstract ?. PMID- 26935937 TI - Persistent polyclonal binucleated B-cell lymphocytosis and MECOM gene amplification. AB - BACKGROUND: Persistent Polyclonal Binucleated B-cell Lymphocytosis (PPBL) is characterized by a chronic polyclonal B-cell lymphocytosis with binucleated lymphocytes and a polyclonal increase in serum immunoglobulin-M. Cytogenetic is characterized by the presence of a supernumerary isochromosome +i(3)(q10), premature chromosome condensation and chromosomal instability. Outcome of PPBL patients is mostly benign, but subsequent malignancies could occur. The aim of our study is to provide an update of clinical and cytogenetic characteristics of our large cohort of PPBL patients, to describe subsequent malignancies occurring during the follow-up, and to investigate the role of the long arm of chromosome 3 in PPBL. RESULTS: We analyzed clinical, biological and cytogenetic characteristics (conventional cytogenetic analysis and fluorescent in situ hybridization) of 150 patients diagnosed with PPBL. We performed high-resolution SNP arrays in 10 PPBL patients, comparing CD19(+) versus CD19(-) lymphoid cells. We describe the cytogenetic characteristics in 150 PPBL patients consisting in the presence of supernumerary isochromosome +i(3)(q10) (59%) and chromosomal instability (55%). In CD19(+) B-cells, we observed recurrent copy number aberrations of 143 genes with 129 gains (90%) on 3q and a common minimal amplified genomic region in the MECOM gene. After a median follow-up of 60 months, we observed the occurrence of 12 subsequent malignancies (12%), 6 solid tumors and 6 Non-Hodgkin's Lymphomas, and 6 monoclonal gammopathies of undetermined significance (MGUS), requiring a long-term clinical follow-up. CONCLUSIONS: Our clinical and cytogenetic observations lead us to hypothesize that isochromosome 3q, especially MECOM abnormality, could play a key role in PPBL. PMID- 26935936 TI - Dynamic diameter response of intraparenchymal penetrating arteries during cortical spreading depression and elimination of vasoreactivity to hypercapnia in anesthetized mice. AB - Cortical spreading depression (CSD) induces marked hyperemia with a transient decrease of regional cerebral blood flow (rCBF), followed by sustained oligemia. To further understand the microcirculatory mechanisms associated with CSD, we examined the temporal changes of diameter of intraparenchymal penetrating arteries during CSD. In urethane-anesthetized mice, the diameter of single penetrating arteries at three depths was measured using two-photon microscopy during passage of repeated CSD, with continuous recordings of direct current potential and rCBF. The first CSD elicited marked constriction superimposed on the upstrokes of profound dilation throughout each depth of the penetrating artery, and the vasoreaction temporally corresponded to the change of rCBF. Second or later CSD elicited marked dilation with little or no constriction phase throughout each depth, and the vasodilation also temporally corresponded to the increase of rCBF. Furthermore, the peak dilation showed good negative correlations with basal diameter and increase of rCBF. Vasodilation induced by 5% CO2 inhalation was significantly suppressed after CSD passage at any depth as well as hyperperfusion. These results may indicate that CSD-induced rCBF changes mainly reflect the diametric changes of the intraparenchymal arteries, despite the elimination of responsiveness to hypercapnia. PMID- 26935938 TI - The Role of the Nervous System in the Pathophysiology of Psoriasis: A Review of Cases of Psoriasis Remission or Improvement Following Denervation Injury. AB - As most efforts in the last decade have focused on the immunologic basis of inflammatory skin disease, there has been less emphasis on the role of the nervous system in the disease process of psoriasis. Evidence in support of the neurocutaneous pathway has come from observations of patients experiencing unilateral improvement and even complete remission following nerve damage in the affected dermatomal region. The aim of this review was to investigate the role of neuropeptides in the intricate pathophysiology of psoriasis. The PubMed database was searched for individual case reports or case series that reported clearance or significant improvement in psoriatic disease in patients following documented nerve injury. A total of 11 cases were found that reported improvement of psoriatic lesions in areas afflicted by central or peripheral nerve injury. The most common causes of denervation were inadvertent surgical interruption, cerebrovascular accident, and poliomyelitis. In four cases the patients eventually regained neurologic function, which was associated with a recurrence of skin lesions. In cases of permanent nerve damage, there was remission of psoriasis. The cases reported in the literature to date provide clinical evidence that absence of neural input leads to psoriasis improvement, suggesting a crucial role of the nervous system in the pathophysiology of psoriatic disease. In fact, neuropeptides such as nerve growth factor, substance P, calcitonin gene-related peptide, and vasoactive intestinal peptide may be important contributors of psoriatic disease and potential targets for future therapies. PMID- 26935939 TI - Efficacy of peptide nucleic acid and selected conjugates against specific cellular pathologies of amyotrophic lateral sclerosis. AB - Cellular studies have been undertaken on a nonamer peptide nucleic acid (PNA) sequence, which binds to mRNA encoding superoxide dismutase 1, and a series of peptide nucleic acids conjugated to synthetic lipophilic vitamin analogs including a recently prepared menadione (vitamin K) analog. Reduction of both mutant superoxide dismutase 1 inclusion formation and endoplasmic reticulum stress, two of the key cellular pathological hallmarks in amyotrophic lateral sclerosis, by two of the prepared PNA oligomers is reported for the first time. PMID- 26935940 TI - Emerging targets and new small molecule therapies in Parkinson's disease treatment. AB - Parkinson's disease (PD) is a common chronic degenerative disease of the central nervous system. Due to a rapidly aging society worldwide, PD morbidity is on the rise; however, the treatment of PD with conventional drugs carries serious adverse reactions and cannot fix the root cause of PD, the degeneration of dopaminergic neurons, which limits conventional drug usage in clinical practice. In recent years, research on the pathogenesis of PD and its clinical manifestations has led to the discovery of an increasing number of novel targets in PD, including several small molecule targeted compounds. In this paper, we analyze and summarize the most recently published PD literature and review several recently discovered novel targets in PD and their small molecule targeted pharmacologically active agents based on their mechanisms of action and pharmacodynamic profiles. PMID- 26935941 TI - Probing the geometric constraints of RNA binding via dynamic covalent chemistry. AB - Dynamic Combinatorial Chemistry (DCC) has proven to be a reliable method for identifying hit compounds for target nucleic acid (DNA and RNA) sequences. Typically, these hit compounds are subjected to a lengthy process of optimization via traditional medicinal chemistry. Here, we examine the potential of DCC to also generate and test variations on a hit compound as a method for probing the binding site of an RNA-targeted compound. Specifically, we demonstrate that addition of linker dithiols to a disulfide library containing a known binder to the HIV-1 frameshift-stimulatory RNA (a critical regulator of the HIV life cycle) can yield a mixture of new bridged structures incorporating the dithiol, depending on dithiol structure. Equilibration of this library with the HIV FSS RNA resulted in selection of the original disulfide in preference to bridged structures, suggesting incorporation of the bridge is not compatible with this particular binding site. Application of this strategy to other RNA targets should allow for rapidly profiling the affinity of modified compounds. PMID- 26935943 TI - Survivorship After Periprosthetic Femur Fracture: Factors Affecting Outcome. AB - BACKGROUND: Data addressing risk factors predictive of mortality and reoperation after periprosthetic femur fractures (PPFxs) are lacking. This study examined survivorship and risk ratios for mortality and reoperation after surgical treatment for PPFx and associated clinical risk factors. METHODS: A retrospective review was performed for 291 patients treated surgically for PPFx between 2004 and 2013. Primary outcomes were death and reoperation. RESULTS: Mortality at 1 year was 13%, whereas the rate of reoperation was 12%. Greater span of fixation and revision arthroplasty (vs open reduction internal fixation) trended toward a lower likelihood of reoperation. CONCLUSION: After PPFx, patients have a 24% risk of either death or reoperation at 1 year. Factors contributing to increased mortality are nonmodifiable. Risk of reoperation is minimized with greater span of fixation and performance of revision arthroplasty. PMID- 26935942 TI - Synthesis and evaluation of analogs of the phenylpyridazinone NPD-001 as potent trypanosomal TbrPDEB1 phosphodiesterase inhibitors and in vitro trypanocidals. AB - Trypanosomal phosphodiesterases B1 and B2 (TbrPDEB1 and TbrPDEB2) play an important role in the life cycle of Trypanosoma brucei, the causative parasite of human African trypanosomiasis (HAT), also known as African sleeping sickness. Knock down of both enzymes leads to cell cycle arrest and is lethal to the parasite. Recently, we reported the phenylpyridazinone, NPD-001, with low nanomolar IC50 values on both TbrPDEB1 (IC50: 4nM) and TbrPDEB2 (IC50: 3nM) (J. Infect. Dis.2012, 206, 229). In this study, we now report on the first structure activity relationships of a series of phenylpyridazinone analogs as TbrPDEB1 inhibitors. A selection of compounds was also shown to be anti-parasitic. Importantly, a good correlation between TbrPDEB1 IC50 and EC50 against the whole parasite was observed. Preliminary analysis of the SAR of selected compounds on TbrPDEB1 and human PDEs shows large differences which shows the potential for obtaining parasite selective PDE inhibitors. The results of these studies support the pharmacological validation of the Trypanosome PDEB family as novel therapeutic approach for HAT and provide as well valuable information for the design of potent TbrPDEB1 inhibitors that could be used for the treatment of this disease. PMID- 26935944 TI - Predicting Satisfaction for Unicompartmental Knee Arthroplasty Patients in an Asian Population. AB - BACKGROUND: Despite renewed interest in unicompartmental knee arthroplasty (UKA), there is a paucity of published literature with regard to patient satisfaction after UKA within Asian populations. The purpose of this study is to identify characteristics and factors which may contribute to patient dissatisfaction after UKA in a multiracial Asian population. METHODS: Seven hundred twenty-four UKAs were performed between January 2007 and April 2013. Preoperative and postoperative variables were prospectively captured, such as standardized knee scores, knee range of motion, and patient satisfaction scores. These variables were then analyzed with a multiple logistic regression model to determine statistically significant factors contributing to patients' satisfaction. RESULTS: Minimum duration of follow-up was 2 years, with an overall patient satisfaction rate of 92.2%. There was improvement in mean knee range of motion and across various standardized knee scores. Preoperative variables associated with patient dissatisfaction included a poorer preoperative Mental Component Summary, better preoperative knee extension, and better preoperative Oxford Knee Scores. Significant postoperative variables included better Oxford Knee Score at 6 months and Mental Component Summary at 2 years. CONCLUSION: Despite the impressive patient satisfaction rate of UKA in this Asian population, these findings suggest that there is a targeted group of patients with select preoperative factors who would benefit from preoperative counseling. PMID- 26935945 TI - Development of a Prognostic Nomogram for Predicting the Probability of Nonresponse to Total Knee Arthroplasty 1 Year After Surgery. AB - BACKGROUND: Indications for total knee arthroplasty (TKA) currently depend on clinical judgment. Up to one fifth of those who undergo primary TKA do not report a clinically meaningful improvement in pain and function after surgery. Our aim was to develop and internally validate a prognostic tool for predicting the probability of nonresponse to surgery at 12 months. METHODS: Patients from 1 center who underwent primary TKA (N = 615) between 2012 and 2013. The Western Ontario and McMaster Universities Arthritis Index was collected pre- and 12 months after TKA from which nonresponse to surgery was determined using the Outcome Measures in Rheumatology-Osteoarthritis Research Society International responder criteria. Using independent prognostic correlates of postoperative nonresponse observed in adjusted modeling, we derived a prognostic nomogram to estimate the probability of nonresponse to TKA based on this suite of explanatory variables. RESULTS: A total of 90/615 (15%) cases were nonresponders to TKA. The degree of contribution (odds ratio, 95% confidence interval) of each explanatory factor to nonresponse nomogram points was body mass index >=40 kg/m(2) (3.48; 1.97-6.12), Kellgren and Lawrence <4 (2.59; 1.58-4.24), mental disability on Short Form Health Survey (SF-12) mental component score (3.30; 1.44-7.58), and every 10-point increase in preoperative Western Ontario and McMaster Universities Arthritis Index score (0.81; 0.68-0.97). The concordance index for this model was 0.74. CONCLUSION: We have created a prognostic nomogram that displays the predictive probabilities of nonresponse to TKA as a source of decision support for clinicians and patients, about their likely functional outcome from TKA. Although our own internal validation suggested good nomogram performance, external validation in a comparable surgical population is required to confirm generalizability of the nomogram. PMID- 26935946 TI - The development of environmental assessment tools to support the creation of dementia friendly care environments: Innovative practice. AB - The need for more dementia friendly design in hospitals and other care settings is now widely acknowledged. Working with 26 NHS Trusts in England as part of a Department of Health commissioned programme, The King's Fund developed a set of overarching design principles and an environmental assessment tool for hospital wards in 2012. Following requests from other sectors, additional tools were developed for hospitals, care homes, health centres and housing with care. The tools have proven to be effective in both disseminating the principles of dementia friendly design and in enabling the case to be made for improvements that have a positive effect on patient outcomes and staff morale. This paper reports on the development, use and review of the environmental assessment tools, including further work that is now being taken forward by The Association for Dementia Studies, University of Worcester. PMID- 26935947 TI - Procedural characteristics of pulmonary vein isolation using the novel third generation cryoballoon. AB - AIM: A novel third-generation cryoballoon (CB3) to perform pulmonary vein isolation (PVI) has recently been released, featuring a shortened distal balloon tip when compared with the second-generation (CB2), possibly allowing for enhanced intra-ablation pulmonary vein (PV) signal mapping. We aimed to investigate procedural efficacy and safety of the CB3 as compared to the CB2. METHODS AND RESULTS: We studied 472 consecutive patients who underwent CB-PVI for paroxysmal or persistent atrial fibrillation (CB3: 49 patients; CB2: 423 patients). Detailed procedural data and in-hospital complications were registered in a prospective database. Complete PVI using the CB only was achieved in 98% of patients in each group. Single-freeze PVI was observed in 84/88% (CB2/CB3, P = n.s.) of the PVs. Time-to-PVI (TPVI) was 49 +/- 32 (CB2) and 45 +/- 27 s (CB3) (P = n.s.). Time-to-PVI determination rate was higher in the CB3 group (89.5 vs. 82.6%, P = 0.016). Signal noise due to ice formation on mapping electrodes occurred after 70 +/- 46 s using CB3 and did not interfere with TPVI determination. Exchange of the spiral mapping catheter with a guide wire was more frequently required in the CB3 group (8.2 vs. 0.7% patients, P < 0.001). Balloon dislodgement during hockey stick manoeuvres occurred in 6.1% patients of the CB3 group only (P = 0.001). Complication rates were not different between the groups. CONCLUSION: The CB3 offers a higher TPVI determination rate, facilitating dosing schemes based on TPVI, with equally high single-freeze efficacy compared with the CB2. The shortened distal tip of the CB3 requires adaptation of standard catheter manoeuvers to avoid balloon dislodgement. PMID- 26935948 TI - Effects of Triacylglycerol Molecular Species on the Oxidation Behavior of Oils Containing alpha-Linolenic Acid. AB - Two kinds of oils, pure perilla oil and a blend of perilla oil with palm oil, and their enzymatically interesterified oils having the same fatty acid compositions but with different compositions of triacylglycerol (TAG) species, were studied. In particular, the effects of TAG molecular species on the oxidation resistance of oils containing alpha-linolenic acid (Ln) were investigated. The content of TAG binding to three Ln molecules (3Ln-TAG) was found to be different between perilla oil (38.7%) and the interesterified oils (14.5-28.9%) , which were generated using Lipozyme RM-IM((r)) (regiospecificity: sn-1, 3 positional). Oils with lower 3Ln-TAG contents were more stable to oxidation as determined by the conductometric determination method (CDM; 90 degrees C, 20 L/h) than oils with higher 3Ln-TAG contents. This result was also supported by heating oxidation tests (180 degrees C, 7 h) using the interesterified blended oils; the residual ratio of Ln-TAGs in the oils was found to be in the order of 3Ln-TAG<2Ln-TAG<1Ln TAG. Oxidation stability of Lipase OF((r)) (regiospecificity: random) interesterified blended oils also improved on lowering the 3Ln-TAG content. In addition, the oxidation stabilities of Lipozyme RM-IM((r))-interesterified oils were slightly higher than those of the Lipase OF((r))-interesterified oils. We found that the content of 3Ln-TAG was almost the same in both oils, and the content of unsaturated fatty acid at the sn-1, 3 positions of Lipase OF((r)) interesterified oils was higher than that of Lipozyme RM-IM((r))-interesterified oils. These results indicate that oxidation stabilities of oils containing TAG with unsaturated fatty acid such as Ln at sn-2 position were higher than those having unsaturated fatty acids at the sn-1, 3 positions. From these results, the oxidation stability of oils rich in Ln, such as perilla oil and linseed oil, can be improved not only by decreasing 3Ln-TAG but also by enzymatically reducing the unsaturated fatty acid content at the sn-1, 3 positions. PMID- 26935949 TI - Phosphorylation of the amino-terminus of the AGC kinase Gad8 prevents its interaction with TORC2. AB - Cell proliferation, metabolism, migration and survival are coordinated through the tight control of two target of rapamycin (TOR) kinase complexes: TORC1 and TORC2. Here, we show that a novel phosphorylation of fission yeast Gad8 (AGC kinase) on the evolutionarily conserved threonine 6 (Thr6) prevents the physical association between Gad8 and TORC2. Accordingly, this block to protein interactions by Gad8 Thr6 phosphorylation decreases TORC2-controlled activation of Gad8. Likewise, phosphorylation of Gad8 Thr6, possibly by PKC, prevents the association of Gad8 with TORC2 thereby increasing TORC2 activity, because it reduces Gad8-mediated feedback inhibition of TORC2. Consistently, the introduction of a Gad8 T6D mutant, that mimics phosphorylation, increased TORC2 activity. Increased PKC(Pck2) expression prevented Gad8-TORC2 binding and so reduced the TORC2-mediated phosphorylation of Gad8 serine 546 that activates Gad8. Interestingly, independent of the Ser546 phosphorylation status, Gad8 Thr6 phosphorylation is important for remodelling the actin cytoskeleton and survival upon potassium ion and heat stresses. In contrast, Ser546 phosphorylation is required for the control of G1 arrest, mating, cell length at division and vascular size. Finally, these findings reveal a novel mode of TORC2 activation that is essential for cell survival following stress. PMID- 26935952 TI - Correction. PMID- 26935950 TI - TNF-alpha-induced NF-kappaB activation upregulates microRNA-150-3p and inhibits osteogenesis of mesenchymal stem cells by targeting beta-catenin. AB - Although systemic or local inflammation, commonly featured by cytokine activation, is implicated in patients with bone loss, the underlying mechanisms are still elusive. As microRNAs (miR), a class of small non-coding RNAs involved in essential physiological processes, have been found in bone cells, we aimed to investigate the role of miR for modulating osteogenesis in inflammatory milieu using human bone marrow mesenchymal stem cells (hBM-MSCs). Induced by proinflammatory cytokine TNF-alpha, miR-150-3p was identified as a key player in suppressing osteogenic differentiation through downregulating beta-catenin, a transcriptional co-activator promoting bone formation. TNF-alpha treatment increased the levels of miR-150-3p, which directly targeted the 3'-UTR of beta catenin mRNA and in turn repressed its expression. In addition, we observed that miR-150-3p expression was increased by TNF-alpha via IKK-dependent NF-kappaB signalling. There are three putative NF-kappaB binding sites in the promoter region of miR-150, and we identified -686 region as the major NF-kappaB binding site for stimulation of miR-150 expression by TNF-alpha. Finally, the osteogenic differentiation of hBM-MSCs was inhibited by either miR-150-3p overexpression or TNF-alpha treatment, which was prevented by anti-miR-150-3p oligonucleotides. Taken together, our data suggested that miR-150-3p integrated inflammation signalling and osteogenic differentiation and may contribute to the inhibition effects of inflammation on bone formation, thus expanding the pathophysiological functions of microRNAs in bone diseases. PMID- 26935953 TI - Sigmoid volvulus in a patient with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS): a rare occurrence. AB - Mitochondrial diseases are rare and devastating, with a wide spectrum of clinical presentations and systemic symptoms. The majority of the published literature focuses on the neuromuscular manifestations and genetic components of this mitochondrial cytopathy, however, cardiac, renal, endocrine and gastrointestinal manifestations may also be present. The authors report a case detailing a 56-year old woman's final hospitalisation from the gastrointestinal sequelae of mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) (Co Q10 deficiency variant). She presented with abdominal pain and distension associated with lactic acidosis, and was shown on imaging to have a colon perforation. This resulted in emergent surgery at which a necrotic colon secondary to a sigmoid colon was identified. Following four subsequent operations, and the development of multiorgan failure, care was eventually withdrawn. Practitioners of patients with MELAS should be cognisant of the rare but devastating gastrointestinal consequences of mitochondrial diseases. PMID- 26935951 TI - 'Venus trapped, Mars transits': Cu and Fe redox chemistry, cellular topography and in situ ligand binding in terrestrial isopod hepatopancreas. AB - Woodlice efficiently sequester copper (Cu) in 'cuprosomes' within hepatopancreatic 'S' cells. Binuclear 'B' cells in the hepatopancreas form iron (Fe) deposits; these cells apparently undergo an apocrine secretory diurnal cycle linked to nocturnal feeding. Synchrotron-based u-focus X-ray spectroscopy undertaken on thin sections was used to characterize the ligands binding Cu and Fe in S and B cells of Oniscus asellus (Isopoda). Main findings were: (i) morphometry confirmed a diurnal B-cell apocrine cycle; (ii) X-ray fluorescence (XRF) mapping indicated that Cu was co-distributed with sulfur (mainly in S cells), and Fe was co-distributed with phosphate (mainly in B cells); (iii) XRF mapping revealed an intimate morphological relationship between the basal regions of adjacent S and B cells; (iv) molecular modelling and Fourier transform analyses indicated that Cu in the reduced Cu(+) state is mainly coordinated to thiol-rich ligands (Cu-S bond length 2.3 A) in both cell types, while Fe in the oxidized Fe(3+) state is predominantly oxygen coordinated (estimated Fe-O bond length of approx. 2 A), with an outer shell of Fe scatterers at approximately 3.05 A; and (v) no significant differences occur in Cu or Fe speciation at key nodes in the apocrine cycle. Findings imply that S and B cells form integrated unit-pairs; a functional role for secretions from these cellular units in the digestion of recalcitrant dietary components is hypothesized. PMID- 26935954 TI - Giant seminal vesicle cyst: an unusual site for a malignant extragastrointestinal stromal tumour. AB - Mesenchymal tumours with clinicopathological and molecular profiles similar to gastrointestinal stromal tumours (GISTs) are, on occasion, found in extragastrointestinal locations. Extra GIST (EGIST) is a singular occurrence in the genitourinary tract. A 30-year-old man, catheterised following urinary retention, was found to have a complex pelvic retrovesical cyst on imaging. At operation, origin from the right seminal vesicle was evident with histopathology confirming a GIST. The patient received adjuvant therapy with tyrosine kinase inhibitor and is currently disease free at 2 years. This is only the second report of an EGIST at this anatomic locale. The current literature presents significant uncertainty in defining the true origin of EGISTs, particularly those in the pelvis. We propose the designation origin indeterminate stromal tumour (OIST), to facilitate disambiguation and advance accurate profiling of EGIST; a subject in evolution. PMID- 26935955 TI - Re-imagining adherence to treatment from the "other side": local interpretations of adverse anti-malarial drug reactions in the Peruvian Amazon. AB - BACKGROUND: Patients' adherence to malaria treatment is a key issue in malaria control and elimination efforts. Previous studies have reported on problems with adherence to anti-malarials, which in part can be related to adverse drug reactions (ADRs) of anti-malarials. However, there has been a relative inattention to the cultural and social aspects of these anti-malarial side effects and, more broadly, to how cultural representations of body functions may affect people's behaviour. In this article, an in-depth analysis is presented of the cultural logics underlying local interpretations of adverse drug reactions to anti-malarials in the Peruvian Amazon. METHODS: Ethnographic fieldwork was carried out during two periods of 3 months in 2007 and 2008. Fieldwork was carried out in 10 communities in the department of Loreto, the administrative area corresponding to the Peruvian Amazon. Thirty in-depth interviews of key and general informants, focusing on perceived adverse anti-malarial drug reactions, were carried out in Spanish, recorded, transcribed and analysed. RESULTS: Informants reported surprisingly elevated problems of adverse drug reactions. Frequent statements about medication that "shocked", "cut the blood" or provoked "allergic reactions" are difficult to interpret from a biomedical perspective, and only make when considering the underlying cultural logics. The logic of maintaining a 'temperate' physical and moral balance by avoiding excesses of 'hot' or 'cold' or sudden changes of 'body heat' can explain the locally constructed adverse drug reactions to anti-malarials. DISCUSSION: Adherence is a continuous process during which the patient evaluates and re-evaluates the course of his illness and the perceived benefits and risks of the treatment. What counts are the processes, the interpretations and the logics which underlie the decisions to adhere to or to abandon treatment. Adherence can only be adequately addressed if such interpretations are understood and taken into account. PMID- 26935956 TI - Targeting of BMI-1 with PTC-209 shows potent anti-myeloma activity and impairs the tumour microenvironment. AB - BACKGROUND: The polycomb complex protein BMI-1 (BMI-1) is a putative oncogene reported to be overexpressed in multiple myeloma (MM). Silencing of BMI-1 was shown to impair the growth and survival of MM cells. However, therapeutic agents specifically targeting BMI-1 were not available so far. Here, we investigated PTC 209, a novel small molecule inhibitor of BMI-1, for its activity in MM. METHODS: BMI-1 expression was analysed in human MM cell lines and primary MM cells by using publically available gene expression profiling (GEP) data. The anti-MM activity of PTC-209 was investigated by viability testing, cell cycle analysis, annexin V and 7-AAD staining, quantification of cleaved poly(ADP-ribose) polymerase (PARP), JC-1 as well as colony formation assays. Deregulation of central myeloma growth and survival genes was studied by quantitative PCR and flow cytometry, respectively. In addition, the impact of PTC-209 on in vitro osteoclast, osteoblast and tube formation was analysed. RESULTS: We confirmed overexpression of BMI-1 in MM patients by using publically available GEP datasets. Of note, BMI-1 expression was further increased at relapse which translated into significantly shorter overall survival in relapsed/refractory patients treated with bortezomib or dexamethasone. Treatment with PTC-209 significantly decreased viable cell numbers in human MM cell lines, induced a G1 cell cycle arrest, promoted apoptosis and demonstrated synergistic activity with pomalidomide and carfilzomib. The anti-MM activity of PTC-209 was accompanied by a significant decrease of cyclin D1 (CCND1) and v-myc avian myelocytomatosis viral oncogene homolog (MYC) expression as well as upregulation of cyclin dependent kinase inhibitor 1A (CDKN1A) and cyclin-dependent kinase inhibitor 1B (CDKN1B). We also observed upregulation of NOXA (up to 3.6 +/- 1.2-fold induction, P = 0.009) and subsequent downregulation of myeloid cell leukemia 1 (MCL-1) protein levels, which likely mediates the apoptotic effects of PTC-209. Importantly, the anti-MM activity was upheld in the presence of stromal support or myeloma growth factors insulin-like growth factor 1 (IGF-1) and interleukin 6 (IL-6). In the MM microenvironment, PTC-209 impaired tube formation, impaired osteoclast development and decreased osteoblast formation in a dose-dependent manner (P < 0.01 at 1 MUM, respectively). The latter might be attributed to an induction of DKK1 and was reversed by concurrent anti-DKK1 antibody treatment. CONCLUSIONS: We confirmed overexpression of BMI-1 in MM highlighting its role as an attractive drug target and reveal therapeutic targeting of BMI-1 by PTC-209 as a promising novel therapeutic intervention for MM. PMID- 26935957 TI - Evaluating antidepressant treatment prior to adding second-line therapies among patients with treatment-resistant depression. AB - BACKGROUND: Patients with depression can be mistakenly labeled as treatment resistant if they fail to receive an adequate first-line antidepressant trial. Adding second-line agents to the treatment regimens can create an additional burden on both the patients and the healthcare system. OBJECTIVES: To determine if depressed patients receive an adequate antidepressant trial prior to starting second-line therapy and to investigate the association between the type of second line treatment and severity of illness or depression among unipolar versus bipolar patients. SETTING: Oklahoma Medicaid claims data between 2006 and 2011. METHODS: Subjects were depression-diagnosed adult patients with at least two prescriptions of antidepressants followed by a second-line agent. Patients were categorized into one of three groups: an atypical antipsychotic, other augmentation agents (lithium, buspirone, and triiodothyronine), or adding antidepressants, based on the type of second-line therapy. An adequate trial was defined per the American Psychiatric Association guidelines. Factors associated with the type of treatment were tested using multinomial logistic regression models stratified by type of depression (unipolar vs. bipolar patients). MAIN OUTCOME MEASURE: Variables used to measure receiving an adequate antidepressant trial included: trial duration, adherence, dose adequacy, and number of distinct antidepressant trials. RESULTS: A total of 3910 patients were included in the analysis. Most subjects reached the recommended antidepressant dose. However, 28 % of patients had an antidepressant trial duration <4 weeks and only 60 % tried at least two antidepressant regimens prior to adding second-line therapy. Approximately 50 % of the subjects were non-adherent across all groups. Severity of illness and receipt of an adequate antidepressant trial were not predictors of the type of second-line treatment. CONCLUSION: Many patients do not receive an adequate antidepressant trial before starting a second-line agent. The type of second-line treatment was independent of severity of depression. These findings support policies that require reviewing the recommended dose and duration of the first-line antidepressant before adding second-line agents. Healthcare providers need to review the patient's history and reconsider the evidence for prescribing second-line agents. PMID- 26935958 TI - Analysis of antibiotic surgical prophylaxis in hospitalized children suffering upper and lower extremity injuries. AB - BACKGROUND: Surgical prophylaxis may account for one-third of all antibiotic use in paediatric hospitals. OBJECTIVE: To evaluate the appropriateness of surgical prophylaxis and to analyse adherence of surgeons to surgical prophylaxis guidelines. METHOD: Retrospective study at a university paediatric hospital. Patients younger than 18 years with injuries of lower and upper extremities were included. The study period was from January 1st 2011-December 31st 2013 and January 1st 2001-December 31st 2003. The appropriateness of the antibiotic use was analysed in accordance with international and local guidelines. RESULTS: Antibiotic prophylaxis was needed by 1125 (55.0 %) patients in 2011-2013 and by 816 (44.4 %) patients in 2001-2003. However, it was administered to only 66.0 % of those in need of prophylaxis in 2011-2013 and to 70.8 % of those in 2001-2003. A single antibiotic dose was administered to 73.8 % of those who received antibiotics in 2011-2013 and to 34.1 % of those in 2001-2003. The timing of the first dose was correct in 370 (52.9 %) prescriptions in 2011-2013 and in 10 (20.4 %) prescriptions in 2001-2003. The most often used antibiotics for prophylaxis were cefazolin in 2011-2013 and cefuroxime in 2001-2003. CONCLUSION: Overall adherence rate to the international and hospital guidelines was low, indicating that in order to improve this situation, there is a need for multiple interventions. PMID- 26935959 TI - Expression profiling of marker genes responsive to the defence-associated phytohormones salicylic acid, jasmonic acid and ethylene in Brachypodium distachyon. AB - BACKGROUND: Brachypodium distachyon is a promising model plants for grasses. Infections of Brachypodium by various pathogens that severely impair crop production have been reported, and the species accordingly provides an alternative platform for investigating molecular mechanisms of pathogen virulence and plant disease resistance. To date, we have a broad picture of plant immunity only in Arabidopsis and rice; therefore, Brachypodium may constitute a counterpart that displays the commonality and uniqueness of defence systems among plant species. Phytohormones play key roles in plant biotic stress responses, and hormone-responsive genes are used to qualitatively and quantitatively evaluate disease resistance responses during pathogen infection. For these purposes, defence-related phytohormone marker genes expressed at time points suitable for defence-response monitoring are needed. Information about their expression profiles over time as well as their response specificity is also helpful. However, useful marker genes are still rare in Brachypodium. RESULTS: We selected 34 candidates for Brachypodium marker genes on the basis of protein-sequence similarity to known marker genes used in Arabidopsis and rice. Brachypodium plants were treated with the defence-related phytohormones salicylic acid, jasmonic acid and ethylene, and their transcription levels were measured 24 and 48 h after treatment. Two genes for salicylic acid, 7 for jasmonic acid and 2 for ethylene were significantly induced at either or both time points. We then focused on 11 genes encoding pathogenesis-related (PR) 1 protein and compared their expression patterns with those of Arabidopsis and rice. Phylogenetic analysis suggested that Brachypodium contains several PR1-family genes similar to rice genes. Our expression profiling revealed that regulation patterns of some PR1 genes as well as of markers identified for defence-related phytohormones are closely related to those in rice. CONCLUSION: We propose that the Brachypodium immune hormone marker genes identified in this study will be useful to plant pathologists who use Brachypodium as a model pathosystem, because the timing of their transcriptional activation matches that of the disease resistance response. Our results using Brachypodium also suggest that monocots share a characteristic immune system, defined as the common defence system, that is different from that of dicots. PMID- 26935960 TI - Correlates of women's intentions to be screened for human papillomavirus for cervical cancer screening with an extended interval. AB - BACKGROUND: High-risk HPV DNA testing has been proposed as a primary tool for cervical cancer screening (HPV-CCS) as an alternative to the Papanicolaou cytology- method. This study describes factors associated with women's intentions to attend cervical cancer screening if high-risk HPV DNA testing (HPV-CCS) was implemented as a primary screening tool, and if screening were conducted every 4 years starting after age 25. METHODS: This online survey was designed using the Theory of Planned Behaviour to assess factors that impact women's intentions to attend HPV-CCS among women aged 25-69 upon exit of the HPV FOCAL trial. Univariate and regression analyses were performed to compare the demographic, sexual history, and smoking characteristics between women willing and unwilling to screen, and scales for intention to attend HPV-CCS. A qualitative analysis was performed by compiling and coding the comments section of the survey. RESULTS: Of the 981 women who completed the survey in full, only 51.4 % responded that they intended to attend HPV-CCS with a delayed start age and extended screening interval. Women who intended to screen were more likely to have higher education (AOR 0.59, 95 % CI [0.37, 0.93]), while both positive attitudes (AOR 1.26, 95 % CI [1.23, 1.30]) and perceived behavior control (AOR 1.06, 95 % CI [1.02, 1.10]) were significant predictors of intention to screen. Among women who provided comments in the survey, a large number of women expressed fears about not being checked more than every 4 years, but 12 % stated that these fears may be alleviated by having more information. CONCLUSIONS: Acceptability of increased screening intervals and starting age could be improved through enhanced education of benefits. Program planners should consider measures to assess and improve women's knowledge, attitudes and beliefs prior to the implementation of new screening programs to avoid unintended consequences. PMID- 26935961 TI - CATheter Infections in CHildren (CATCH): a randomised controlled trial and economic evaluation comparing impregnated and standard central venous catheters in children. AB - BACKGROUND: Impregnated central venous catheters (CVCs) are recommended for adults to reduce bloodstream infection (BSI) but not for children. OBJECTIVE: To determine the effectiveness of impregnated compared with standard CVCs for reducing BSI in children admitted for intensive care. DESIGN: Multicentre randomised controlled trial, cost-effectiveness analysis from a NHS perspective and a generalisability analysis and cost impact analysis. SETTING: 14 English paediatric intensive care units (PICUs) in England. PARTICIPANTS: Children aged < 16 years admitted to a PICU and expected to require a CVC for >= 3 days. INTERVENTIONS: Heparin-bonded, antibiotic-impregnated (rifampicin and minocycline) or standard polyurethane CVCs, allocated randomly (1 : 1 : 1). The intervention was blinded to all but inserting clinicians. MAIN OUTCOME MEASURE: Time to first BSI sampled between 48 hours after randomisation and 48 hours after CVC removal. The following data were used in the trial: trial case report forms; hospital administrative data for 6 months pre and post randomisation; and national-linked PICU audit and laboratory data. RESULTS: In total, 1859 children were randomised, of whom 501 were randomised prospectively and 1358 were randomised as an emergency; of these, 984 subsequently provided deferred consent for follow-up. Clinical effectiveness - BSIs occurred in 3.59% (18/502) of children randomised to standard CVCs, 1.44% (7/486) of children randomised to antibiotic CVCs and 3.42% (17/497) of children randomised to heparin CVCs. Primary analyses comparing impregnated (antibiotic and heparin CVCs) with standard CVCs showed no effect of impregnated CVCs [hazard ratio (HR) 0.71, 95% confidence interval (CI) 0.37 to 1.34]. Secondary analyses showed that antibiotic CVCs were superior to standard CVCs (HR 0.43, 95% CI 0.20 to 0.96) but heparin CVCs were not (HR 1.04, 95% CI 0.53 to 2.03). Time to thrombosis, mortality by 30 days and minocycline/rifampicin resistance did not differ by CVC. Cost effectiveness - heparin CVCs were not clinically effective and therefore were not cost-effective. The incremental cost of antibiotic CVCs compared with standard CVCs over a 6-month time horizon was L1160 (95% CI -L4743 to L6962), with an incremental cost-effectiveness ratio of L54,057 per BSI avoided. There was considerable uncertainty in costs: antibiotic CVCs had a probability of 0.35 of being dominant. Based on index hospital stay costs only, antibiotic CVCs were associated with a saving of L97,543 per BSI averted. The estimated value of health-care resources associated with each BSI was L10,975 (95% CI -L2801 to L24,751). Generalisability and cost-impact - the baseline risk of BSI in 2012 for PICUs in England was 4.58 (95% CI 4.42 to 4.74) per 1000 bed-days. An estimated 232 BSIs could have been averted in 2012 using antibiotic CVCs. The additional cost of purchasing antibiotic CVCs for all children who require them (L36 per CVC) would be less than the value of resources associated with managing BSIs in PICUs with standard BSI rates of > 1.2 per 1000 CVC-days. CONCLUSIONS: The primary outcome did not differ between impregnated and standard CVCs. However, antibiotic-impregnated CVCs significantly reduced the risk of BSI compared with standard and heparin CVCs. Adoption of antibiotic-impregnated CVCs could be beneficial even for PICUs with low BSI rates, although uncertainty remains whether or not they represent value for money to the NHS. Limitations - inserting clinicians were not blinded to allocation and a lower than expected event rate meant that there was limited power for head-to-head comparisons of each type of impregnation. Future work - adoption of impregnated CVCs in PICUs should be considered and could be monitored through linkage of electronic health-care data and clinical data on CVC use with laboratory surveillance data on BSI. TRIAL REGISTRATION: ClinicalTrials.gov NCT01029717. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 18. See the NIHR Journals Library website for further project information. PMID- 26935962 TI - Compensation of skeletal Class III malocclusion by isolated extraction of mandibular teeth: Part 2: Skeletal, dentoalveolar and soft tissue parameters in comparison with nonextraction Class III therapies. AB - OBJECTIVES: To retrospectively compare two compensatory approaches taken in skeletal Class III patients during the main treatment stage, including a study group of multiband treatment plus isolated extraction of mandibular teeth and a control group of multiband treatment without extraction of teeth. PATIENTS AND METHODS: The extraction group included 22 (12 female, 10 male) patients receiving compensatory multiband treatment for a mean of 3.47 +/- 1.14 years and 16.22 +/- 1.92 years old at debonding. The nonextraction group included 24 (14 female, 10 male) patients undergoing multiband treatment for 2.76 +/- 1.28 years and 15.38 +/- 1.46 years old at debonding. Lateral cephalograms obtained at baseline and upon completion of active treatment were traced for skeletal, dentoalveolar, and soft tissue parameters. Welch and Wilcoxon tests were used to analyze intergroup differences (initial values, final values, initial-to-final changes) and within group differences (p < 0.05). RESULTS: Upon completion of active treatment, the only significant intergroup differences were noted for U1NA and L1ML. Significant within-group changes over the courses of treatment were seen for SNB, MLNL, U1NA, U1NL, L1NB, L1ML, H-angle, ULipEL, and LLipEL (extraction group) or for SNB, ANB, individual ANB, Wits appraisal, U1NA, U1NL, H-angle, Naslab-a, ULipEL, and LLipEL (nonextraction group). Parameters that changed by significantly different amounts in both groups included Wits appraisal, L1NB, L1ML, and LLipEL. CONCLUSION: The added value of isolated extraction therapy basically lies in increasing the potential for retruding the lower incisor inclinations, so that compensatory treatment becomes an option even in selected patients presenting with adverse occlusal situations that would otherwise require orthognathic surgery. Given the successful outcomes in both groups, which had been established by Peer Assessment Rating (PAR) scores, it was possible to define the skeletal, dentoalveolar, and soft tissue characteristics of successful treatment more precisely than before. PMID- 26935963 TI - Occlusal stability after Herbst treatment of patients with retrognathic and prognathic facial types : A pilot study. AB - OBJECTIVES: The purpose of this study was to assess and compare occlusal changes induced by Herbst treatment and the stability of these changes in patients with retrognathic and prognathic facial types. PATIENTS AND METHODS: The sample comprised 11 retrognathic (SNA <=76 degrees , SNB <=72 degrees , ML/NSL >=36 degrees ) and 10 prognathic (SNA >=83 degrees , SNB >=80 degrees , ML/NSL <=32 degrees ) patients with Class II molar relationships of >=0.5 cusp widths bilaterally or >=1.0 cusp width unilaterally. Both groups involved similar distributions of skeletal maturity before treatment. Study parameters were assessed on casts reflecting the situations before treatment (T0), after Herbst treatment (T1), after multibracket treatment immediately following Herbst treatment (T2), and after a mean of 31.1 months of retention (T3). RESULTS: Sagittal molar relationships improved by 0.8 cusp widths in the retrognathic and by 0.7 cusp widths in the prognathic group during active treatment (T0-T2). Insignificant changes of <=0,2 cusp widths were seen in both groups during retention (T2-T3). Overjet decreased by 8.6 mm in the retrognathic and by 5.5 mm in the prognathic group during T0-T2, and both groups showed clinically irrelevant amounts of relapse by 0.7 mm during T2-T3. Overbite improved by 1.2 mm in the retrognathic and by 2.5 mm in the prognathic group during T0-T2, reaching mean values of 1.0 mm or 1.4 mm by T2, which was followed by 0.2 mm or 1.1 mm of relapse during T2-T3. CONCLUSION: Treatment with a Herbst appliance seems to offer stable correction of the sagittal occlusal relationships in Class II patients with retrognathic or prognathic facial types, with the vertical changes being more pronounced in the prognathic cases. PMID- 26935964 TI - Medication adherence to oral anticancer drugs: systematic review. AB - Many studies have demonstrated that non-adherence to oral anticancer drugs (OACDs) has challenged treatment efficacy. Otherwise, few validated tools exist to measure patients' adherence to medication regimen in clinical practice. To synthesize previous studies on adherence by cancer patients taking OACDs, especially in targeted therapy, a systematic search of several electronic databases was conducted. We analyzed existing scales' contents for various cancer patients and outcomes of studies assessing adherence. However, a well-validated scale designed particularly for OACD adherence is still lacking. Most adherence scales used in the studies reviewed contain items focused on measuring patients' medication-taking behavior more than their barriers to medication compliance and beliefs. However, non-adherence to OACDs is a complex phenomenon, and drug-taking barriers and patient beliefs significantly affect patients' non-adherence. To understand the key drivers and predisposing factors for non-adherence, we need to develop a well-validated, multidimensional scale. PMID- 26935965 TI - History "will not thank" NHS leaders who ignore collaborative opportunities. PMID- 26935966 TI - Commentary on 'Peripheral Arterial Disease Incidence and Associated Risk Factors in a Mediterranean Population Based Cohort. The REGICOR Study'. PMID- 26935968 TI - Automatic online buffer capacity (alkalinity) measurement of wastewater using an electrochemical cell. AB - The use of an automatic online electrochemical cell (EC) for measuring the buffer capacity of wastewater is presented. pH titration curves of different solutions (NaHCO3, Na2HPO4, real municipal wastewater, and anaerobic digester liquid) were obtained by conventional chemical titration and compared to the online EC measurements. The results show that the pH titration curves from the EC were comparable to that of the conventional chemical titration. The results show a linear relationship between the response of the online EC detection system and the titrimetric partial alkalinity and total alkalinity of all tested samples. This suggests that an EC can be used as a simple online titration device for monitoring the buffer capacity of different industrial processes including wastewater treatment and anaerobic digestion processes. PMID- 26935967 TI - Type 1 diabetes cadaveric human pancreata exhibit a unique exocrine tissue proteomic profile. AB - Type 1 diabetes (T1D) is an autoimmune disorder resulting from a self-destruction of pancreatic islet beta cells. The complete proteome of the human pancreas, where both the dysfunctional beta cells and their proximal environment co-exist, remains unknown. Here, we used TMT10-based isobaric labeling and multidimensional LC-MS/MS to quantitatively profile the differences between pancreatic head region tissues from T1D (N = 5) and healthy subjects (N = 5). Among the 5357 (1% false discovery rate) confidently identified proteins, 145 showed statistically significant dysregulation between T1D and healthy subjects. The differentially expressed pancreatic proteome supports the growing notion of a potential role for exocrine pancreas involvement in T1D. This study also demonstrates the utility for this approach to analyze dysregulated proteins as a means to investigate islet biology, pancreatic pathology and T1D pathogenesis. PMID- 26935969 TI - Understanding Characteristics Of Likely Marketplace Enrollees And How They Choose Plans. AB - In 2015, adults likely to have enrolled in the Affordable Care Act Marketplace were predominantly non-Hispanic whites and, on average, older and more aware of the availability of Marketplace subsidies than adults who remained uninsured. Enrollees were also significantly more likely than adults who remained uninsured to rely on some type of application assistance instead of exclusively looking for information through the Marketplace website. PMID- 26935970 TI - Regulation of Cell Migration and beta1 Integrin Trafficking by the Endosomal Adaptor GGA3. AB - The integrin family of cell adhesion receptors link extracellular matrices to intracellular signaling pathways and the actin cytoskeleton; and regulate cell migration, proliferation and survival in normal and diseased tissues. The subcellular location of integrin receptors is critical for their function and deregulated trafficking is implicated in various human diseases. Here we identify a role for Golgi-localized gamma-ear containing Arf-binding protein 3 (GGA3), in regulating trafficking of beta1 integrin. GGA3 knockdown reduces cell surface and total levels of alpha2, alpha5 and beta1 integrin subunits, inhibits cell spreading, reduces focal adhesion number, as well as cell migration. In the absence of GGA3, integrins are increasingly retained inside the cell, traffic toward the perinuclear lysosomal compartment and their degradation is enhanced. Integrin traffic and maintenance of integrin levels are dependent on the integrity of the Arf binding site of GGA3. Furthermore, sorting nexin 17 (SNX17), a critical regulator of integrin recycling, becomes mislocalized to enlarged late endosomes upon GGA3 depletion. These data support a model whereby GGA3, through its ability to regulate SNX17 endosomal localization and through interaction with Arf6 diverts integrins from the degradative pathway supporting cell migration. PMID- 26935971 TI - SENP-1 enhances hypoxia-induced proliferation of rat pulmonary artery smooth muscle cells by regulating hypoxia-inducible factor-1alpha. AB - Hypoxic pulmonary vascular remodeling (HPSR) has an important role in the development of hypoxic pulmonary hypertension. HPSR is predominantly mediated by the proliferation of pulmonary artery smooth muscle cells (PASMCs). Our previous study demonstrated that hypoxia-inducible factor (HIF)-1alpha was able to promote the proliferation of PASMCs. Small ubiquitin-like modifier (SUMO)ylation is a post-translational modification that is important in various cellular processes. It has previously been demonstrated that HIF-1alpha may be SUMOylated by SUMO. Conversely, SUMO-specific protease 1 (SENP-1) was able to increase the stability of HIF-1alpha by decreasing SUMOylation of HIF-1alpha. In order to investigate whether SUMOylation of HIF-1alpha has a role in the proliferation of PASMCs, the present study cultured PASMCs in hypoxic and normoxic chambers in vitro. The proliferation ability of PASMCs was measured using the Cell Counting kit-8 and 5 ethynyl-2'-deoxyuridine cell proliferation assays. In addition, short hairpin RNA lentiviral particles were used to knockdown the expression of SENP-1, and the expression levels of HIF-1alpha, SENP-1 and vascular endothelial growth factor (VEGF) were detected at the mRNA and protein levels using semi-quantitative polymerase chain reaction and western blotting, respectively. The present study demonstrated that SENP-1 was able to enhance the proliferative ability of PASMCs by initiating deSUMOylation of HIF-1alpha and increasing the expression of its downstream responsive gene, VEGF. PMID- 26935972 TI - Predicting symptoms in major depression after inpatient treatment: the role of alexithymia. AB - Alexithymia has been considered to have a negative influence on the course of symptoms in various psychiatric disorders. Only a few studies of depressed patients have examined whether alexithymia predicts the outcome of therapeutic interventions or the course of symptoms in naturalistic settings. This prospective study investigated whether alexithymia is associated with depressive symptoms after a multimodal inpatient treatment. Forty-five inpatients suffering from acute major depression were examined in the initial phase of treatment and then again after seven weeks. Patients took part in a multimodal treatment programme comprising psychodynamic-interactional oriented individual and group therapy. The majority of patients were taking antidepressants during study participation. To assess alexithymia and depressive symptoms, the 20-item Toronto Alexithymia Scale (TAS-20), the Beck Depression Inventory II (BDI-II) and the Hamilton Depression Scale (HAMD) were administered at baseline and follow-up. When controlling for baseline depressive symptoms along with trait anxiety, high scores in the externally oriented thinking (EOT) facet of alexithymia at baseline predicted high severity of depressive symptoms at follow-up (for self-reported as well as interviewer-based scores). Inpatients suffering from major depression with a more pronounced external cognitive style might benefit less from a routine multimodal treatment approach (including psychodynamic interactional therapy, antidepressant medication, and complementary therapies). Intervention programmes might modify or account for alexithymic characteristics to improve the course of depressive symptoms in these patients. PMID- 26935974 TI - Correction to "Probing the Salt Concentration Dependent Nucleobase Distribution in a Single-Stranded DNA-Single-Walled Carbon Nanotube Hybrid with Molecular Dynamics". PMID- 26935973 TI - The placebo response of injectable GLP-1 receptor agonists vs. oral DPP-4 inhibitors and SGLT-2 inhibitors: a systematic review and meta-analysis. AB - AIMS: The size of the placebo response in type 2 diabetes (T2DM) treatment and its relation to the route of drug administration have not been systematically reviewed. We aimed to determine weight loss, change in HbA1c and incidence of adverse events after treatment with injectable placebo GLP-1 receptor agonist (GLP-1ra), compared with oral placebo DPP-4 inhibitor (DPP-4i) and placebo SGLT-2 inhibitor (SGLT-2i). METHODS: PubMed, EMBASE and Central were searched up to September 2014 for randomized placebo controlled trials investigating GLP-1ra, DPP-4i or SGLT2-i. Data on placebo groups were extracted and pooled using a generic inverse variance random effects model. RESULTS: Sixty-seven trials were included, involving 2522, 5290 and 2028 patients randomized to placebo GLP-1ra, placebo DPP-4i and placebo SGLT-2i, respectively. Body weight decreased by -0.67 kg (95% CI -1.03, -0.31) after treatment with placebo GLP-1ra (-0.76 kg [95% CI 1.10, -0.43] with placebo short acting GLP-1ra and -0.32 kg [95% CI -1.75, 1.10] with placebo long acting GLP-1ra) and by -0.31 kg (95% CI -0.64, 0.01) with placebo DPP-4i (P = 0.06 for difference with placebo short acting GLP-1ra). Placebo SGLT-2i resulted in an intermediate -0.48 kg (95% CI -0.81, -0.15) weight loss. Weight loss with placebo showed a strong correlation with the active comparator drug (r(2) = 0.40-0.78). HbA1c changed little with placebo treatment (-0.23%, 0.10% and -0.13% for placebo GLP-1ra, DPP-4i and SGLT-2i). Adverse events occurred frequently with placebo, were often similar to the active comparator drug and led to drop-out in 2.0-2.7% of cases. CONCLUSIONS: The response to placebo treatment was related to its active comparator, with injectable placebo GLP-1ra showing a relevant response on weight, whereas oral placebo DPP4i showed no significant response. These findings may suggest that subjective expectations influence T2DM treatment efficacy, which can possibly be employed therapeutically. PMID- 26935975 TI - MicroRNA-200c inhibits the metastasis of non-small cell lung cancer cells by targeting ZEB2, an epithelial-mesenchymal transition regulator. AB - MicroRNAs (miRs) have been demonstrated to regulate various biological processes in human cancer, including non-small cell lung cancer (NSCLC). However, little evidence has been provided regarding the exact role of miR-200c in mediating the malignant progression of NSCLC, as well as the underlying mechanism. The present study aimed to investigate the putative role of miR-200c in the progression of NSCLC. The expression levels of miR-200c were significantly reduced in NSCLC cell lines compared with in normal lung epithelial cells, as determined by reverse transcription-quantitative polymerase chain reaction. Overexpression of miR-200c significantly suppressed cell migration and invasion of A549 NSCLC cells. Results of a luciferase reporter assay further identified zinc finger E-box-binding homeobox 2 (ZEB2) as a direct target gene of miR-200c, and the expression of ZEB2 was shown to be suppressed in A549 cells overexpressing miR-200c. Furthermore, small interfering RNA-mediated inhibition of ZEB2 suppressed the migration and invasion of A549 cells. In addition, since ZEB2 is an epithelial-mesenchymal transition (EMT) regulator, the role of miR-200c in the regulation of EMT in NSCLC cells was further examined. Results of a western blot analysis indicated that overexpression of miR-200c upregulated E-cadherin, and downregulated N cadherin and vimentin expression in A549 cells, thus suggesting that EMT was suppressed. Based on these results, the present study suggested that miR-200c was able to inhibit the metastasis of NSCLC cells by targeting ZEB2. Therefore, miR 200c may be considered as a potential candidate for the treatment of NSCLC. PMID- 26935977 TI - Understanding type I and type II errors, statistical power and sample size. AB - The results of a clinical trial may be subject to random error because of the variability in the measured data, which arises purely by chance. There are two types of random error - type I error and type II error. In this study, type I and type II errors are explained, and the important concepts of statistical power and sample size estimation are discussed. CONCLUSION: The most important way of minimising random errors is to ensure adequate sample size; that is, a sufficient large number of patients should be recruited for the study. PMID- 26935976 TI - Influence of copper on expression of nirS, norB and nosZ and the transcription and activity of NIR, NOR and N2 OR in the denitrifying soil bacteria Pseudomonas stutzeri. AB - Reduction of the potent greenhouse gas nitrous oxide (N(2)O) occurs in soil environments by the action of denitrifying bacteria possessing nitrous oxide reductase (N(2)OR), a dimeric copper (Cu)-dependent enzyme producing environmentally benign dinitrogen (N(2)). We examined the effects of increasing Cu concentrations on the transcription and activity of nitrite reductase (NIR), nitric oxide reductase (NOR) and N2 OR in Pseudomonas stutzeri grown anaerobically in solution over a 10-day period. Gas samples were taken on a daily basis and after 6 days, bacterial RNA was recovered to determine the expression of nirS, norB and nosZ encoding NIR, NOR and N(2)OR respectively. Results revealed that 0.05 mM Cu caused maximum conversion of N(2)O to N(2) via bacterial reduction of N(2)O. As soluble Cu generally makes up less than 0.001% of total soil Cu, extrapolation of 0.05 mg l(-l) soluble Cu would require soils to have a total concentration of Cu in the range of, 150-200 MUg g(-1) to maximize the proportion of N(2)O reduced to N(2). Given that many intensively farmed agricultural soils are deficient in Cu in terms of plant nutrition, providing a sufficient concentration of biologically accessible Cu could provide a potentially useful microbial-based strategy of reducing agricultural N(2)O emissions. PMID- 26935979 TI - miR-155 expression in Primary Cutaneous T-Cell Lymphomas (CTCL). PMID- 26935980 TI - Effects of local structure of Ce(3+) ions on luminescent properties of Y3Al5O12:Ce nanoparticles. AB - Ce(3+)-doped yttrium aluminum garnet (YAG:Ce) nanocrystals were successfully synthesized via a facile sol-gel method. Multiple characterization techniques were employed to study the structure, morphology, composition and photoluminescence properties of YAG:Ce nanophosphors. The YAG:Ce0.0055 sintered at 1030 degrees C exhibited a typical 5d(1)-4f(1) emission band with the maximum peak located at 525 nm, and owned a short fluorescence lifetime tau1 (~28 ns) and a long fluorescence lifetime tau2 (~94 ns). Calcination temperature and Ce(3+) doping concentration have significant effects on the photoluminescence properties of the YAG:Ce nanophosphors. The emission intensity was enhanced as the calcination temperature increased from 830 to 1030 degrees C, but decreased dramatically with the increase of Ce(3+) doping concentration from 0.55 to 5.50 at.% due to the concentration quenching. By optimizing the synthesized condition, the strongest photoluminescence emission intensity was achieved at 1030 degrees C with Ce(3+) concentration of 0.55 at.%. PMID- 26935978 TI - Streptococcus pneumoniae fructose-1,6-bisphosphate aldolase, a protein vaccine candidate, elicits Th1/Th2/Th17-type cytokine responses in mice. AB - Streptococcus pneumoniae (S. pneumoniae) is a major pathogen worldwide. The currently available polysaccharide-based vaccines significantly reduce morbidity and mortality. However, the inherent disadvantages of the currently available polysaccharide-based vaccines have motivated the search for other bacterial immunogens capable of eliciting a protective immune response against S. pneumoniae. Fructose-1,6-bisphosphate aldolase (FBA) is a glycolytic enzyme, which was found to localize to the bacterial surface, where it functions as an adhesin. Previously, immunizing mice with recombinant FBA (rFBA) in the presence of alum elicited a protective immune response against a lethal challenge with S. pneumoniae. Thus, the aim of the present study was to determine the cytokine responses that are indicative of protective immunity following immunization with rFBA. The protective effects against pneumococcal challenge in mice immunized with rFBA with complete Freund's adjuvant (CFA) in the initial immunization and with incomplete Freund's adjuvant (IFA) in booster immunizations surpassed the protective effects observed following immunization with either rFBA + alum or pVACfba. CD4+ T-cells obtained from the rFBA/CFA/IFA/IFA-immunized mice co cultured with rFBA-pulsed antigen-presenting cells (APCs), exhibited a significantly greater proliferative ability than CD4+ T-cells obtained from the adjuvant-immunized mice co-cultured with rFBA-pulsed APCs. The levels of the Th1 type cytokines, interferon (IFN)-gamma, interleukin (IL)-2, tumor necrosis factor (TNF)-alpha and IL-12, the Th2-type cytokines, IL-4, IL-5 and IL-10, and the Th17 type cytokine, IL-17A, significantly increased within 72 h of the initiation of co-culture with CD4+ T-cells obtained from the rFBA-immunized mice, in comparison with the co-cultures with CD4+ T-cells obtained from the adjuvant-immunized mice. Immunizing mice with rFBA resulted in an IgG1/IgG2 ratio of 41, indicating a Th2 response with substantial Th1 involvement. In addition, rabbit and mouse anti rFBA antisera significantly protected the mice against a lethal S. pneumoniae challenge in comparison with preimmune sera. Our results emphasize the mixed involvement of the Th1, Th2 and Th17 arms of the immune system in response to immunization with pneumococcal rFBA, a potential vaccine candidate. PMID- 26935981 TI - Putative modifier genes in mevalonate kinase deficiency. AB - Mevalonate kinase deficiency (MKD) is an autosomal recessive auto-inflammatory disease, caused by impairment of the mevalonate pathway. Although the molecular mechanism remains to be elucidated, there is clinical evidence suggesting that other regulatory genes may be involved in determining the phenotype. The identification of novel target genes may explain non-homogeneous genotype phenotype correlations, and provide evidence in support of the hypothesis that novel regulatory genes predispose or amplify deregulation of the mevalonate pathway in this orphan disease. In the present study, DNA samples were obtained from five patients with MKD, which were then analyzed using whole exome sequencing. A missense variation in the PEX11gamma gene was observed in homozygosis in P2, possibly correlating with visual blurring. The UNG rare gene variant was detected in homozygosis in P5, without correlating with a specific clinical phenotype. A number of other variants were found in the five analyzed DNA samples from the MKD patients, however no correlation with the phenotype was established. The results of the presents study suggested that further analysis, using next generation sequencing approaches, is required on a larger sample size of patients with MKD, who share the same MVK mutations and exhibit 'extreme' clinical phenotypes. As MVK mutations may be associated with MKD, the identification of specific modifier genes may assist in providing an earlier diagnosis. PMID- 26935982 TI - RNA sequencing reveals region-specific molecular mechanisms associated with epileptogenesis in a model of classical hippocampal sclerosis. AB - We report here the first complete transcriptome analysis of the dorsal (dDG) and ventral dentate gyrus (vDG) of a rat epilepsy model presenting a hippocampal lesion with a strict resemblance to classical hippocampal sclerosis (HS). We collected the dDG and vDG by laser microdissection 15 days after electrical stimulation and performed high-throughput RNA-sequencing. There were many differentially regulated genes, some of which were specific to either of the two sub-regions in stimulated animals. Gene ontology analysis indicated an enrichment of inflammation-related processes in both sub-regions and of axonal guidance and calcium signaling processes exclusively in the vDG. There was also a differential regulation of genes encoding molecules involved in synaptic function, neural electrical activity and neuropeptides in stimulated rats. The data presented here suggests, in the time point analyzed, a remarkable interaction among several molecular components which takes place in the damaged hippocampi. Furthermore, even though similar mechanisms may function in different regions of the DG, the molecular components involved seem to be region specific. PMID- 26935983 TI - Understanding the world of dementia. How do people with dementia experience the world? AB - BACKGROUND: There is growing awareness that the subjective experience of people with dementia is important for understanding behavior and improving quality of life. This paper reviews and reflects on the currently available theories on subjective experience in dementia and it explores the possibility of a knowledge gap on the influence of neurological deficits on experience in late stage dementia. METHODS: A literature review on current commonly used theories on experience in dementia was supplemented with a systematic review in PubMed and Psychinfo. For the systematic review, the terms used were Perception and Dementia and Behavior; and Awareness and Dementia and Long term care. RESULTS: Current models emphasize the psychosocial factors that influence subjective experience, but the consequences of neurological deficits are not elaborated upon. The systematic literature search on the neuropsychological functioning in dementia resulted in 631 papers, of which 94 were selected for review. The current knowledge is limited to the early stages of Alzheimer's disease. Next to memory impairments, perception of the direct environment, interpretation of the environment, and inhibition of own responses to the environment seem to be altered in people with dementia. CONCLUSIONS: Without knowledge on how perception, interpretation and the ability for response control are altered, the behavior of people with dementia can easily be misinterpreted. Research into neuropsychological functioning of people in more severe stages and different forms of dementia is needed to be able to develop a model that is truly biopsychosocial. The proposed model can be used in such research as a starting point for developing tests and theories. PMID- 26935984 TI - Uncertainties in estimating heart doses from 2D-tangential breast cancer radiotherapy. AB - BACKGROUND AND PURPOSE: We evaluated the accuracy of three methods of estimating radiation dose to the heart from two-dimensional tangential radiotherapy for breast cancer, as used in Denmark during 1982-2002. MATERIAL AND METHODS: Three tangential radiotherapy regimens were reconstructed using CT-based planning scans for 40 patients with left-sided and 10 with right-sided breast cancer. Setup errors and organ motion were simulated using estimated uncertainties. For left sided patients, mean heart dose was related to maximum heart distance in the medial field. RESULTS: For left-sided breast cancer, mean heart dose estimated from individual CT-scans varied from <1Gy to >8Gy, and maximum dose from 5 to 50Gy for all three regimens, so that estimates based only on regimen had substantial uncertainty. When maximum heart distance was taken into account, the uncertainty was reduced and was comparable to the uncertainty of estimates based on individual CT-scans. For right-sided breast cancer patients, mean heart dose based on individual CT-scans was always <1Gy and maximum dose always <5Gy for all three regimens. CONCLUSIONS: The use of stored individual simulator films provides a method for estimating heart doses in left-tangential radiotherapy for breast cancer that is almost as accurate as estimates based on individual CT scans. PMID- 26935985 TI - Influence of extrusion of corn and broken rice on energy content and growth performance of weaning pigs. AB - Two experiments were conducted to study the effects of extrusion on the energy content of corn and broken rice and on growth performance of weaning pigs. In experiment 1, 24 barrows (28 days old, 7.28 +/- 0.90 kg body weight (BW)) were used to compare the effects of extrusion of corn and broken rice on the values of digestible energy (DE) in weaned pigs. The DE content in extruded corn (17.45 MJ/kg dry matter (DM)) was significantly greater (P < 0.05) by 5.54% compared with that in corn (16.48 MJ/kg DM), while no significant difference in DE content was observed between extruded broken rice (17.66 MJ/kg DM) and broken rice (17.76 MJ/kg DM). In experiment 2, 120 weanling pigs (21 days old, 5.76 +/- 0.07 kg BW) were used to evaluate the influence of substitution corn and extruded corn by different proportions of raw and extruded broken rice on growth performance of pigs. The inclusion of broken rice in the diets improved (P < 0.05) growth performance of pigs during the first week and the 2 weeks post-weaning but not thereafter. However, there was no significant difference in growth performance between treatments in other periods. Overall, this study indicates that feeding weaning pigs with broken rice has beneficial results. PMID- 26935986 TI - The effects of perfluorocarbon on ICAM-1 expression in LPS-induced A549 cells and the potential mechanism. AB - Acute lung injury (ALI)/ARDS is a critical clinical syndrome with high mortality, and the effective therapeutic methods for the treatment remain limited. Previous studies have indicated that liquid ventilation with perfluorocarbon (PFC) may be advantageous over conventional mechanical ventilation in the treatment of ALI/ARDS. Additionally, PFC inhibits the inflammatory response caused by ALI/ARDS. However, the anti-inflammatory mechanism remains to be completely elucidated. In the present study, the aim was to determine the anti-inflammatory mechanism of PFC and the association with microRNA (miR). PFC was used to modulate LPS-induced A549 cells, with the cells divided into four groups: Untreated control group; LPS group, treated with 10 ug/ml LPS; LPS+PFC group, treated with 10 ug/ml LPS and PFC; and PFC group, treated with PFC alone. The intercellular adhesion molecule-1 (ICAM-1) mRNA and protein expression levels of each group were detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blotting, respectively. A549 cells were transfected with miR-17-3p mimics, miR-17-3p inhibitors or negative controls to observe the alterations in the anti-inflammatory effects of PFC. A dual luciferase reporter gene assay was used to determine whether ICAM-1 is a target gene of miR-17-3p. PFC was observed to attenuate the mRNA and protein expression levels of ICAM-1 in LPS-induced A549 cells, with no significant effect on the untreated A549 cells. miR-17-3p was demonstrated to be regulated by PFC. Transfection with miR-17-3p mimics enhanced the anti-inflammatory effects of PFC, whereas the miR-17-3p inhibitor weakened the anti-inflammatory effects of PFC at early time points. To conclude, the current study indicates that ICAM-1 was a target gene of miR-17-3p, and PFC has anti-inflammatory effects. Additionally, the present study is the first report, to the best of our knowledge, that PFC is able to attenuate ICAM-1 expression in LPS-induced A549 cells by increasing miR 17-3p expression. PMID- 26935987 TI - Sulforaphane inhibits TGF-beta-induced epithelial-mesenchymal transition of hepatocellular carcinoma cells via the reactive oxygen species-dependent pathway. AB - Sulforaphane is recognized as a safe antitumor agent derived from various cruciferous vegetables, including broccoli. It has been demonstrated that sulforaphase is a potent antitumor agent in diverse cancers. However, its effect on hepatocellular carcinoma remains largely unknown. Here, we show that sulforaphane inhibits TGF-beta-induced epithelial-mesenchymal transition of hepatocellular carcinoma cell via the reactive oxygen species-dependent pathway. We found sulforaphane inhibited hepatocellular carcinoma cell proliferation in a dose- and time-dependent manner. Sulforaphane induced G0/G1 phase cell cycle arrest and promoted cell apoptosis. A set of experiments showed that sulforaphase inhibited hepatocellular carcinoma cell migration and invasion, inhibited the formation of fibroblast like mesenchymal cells and the expression of Vimentin, but increased the expression of E-cadherin, suggesting sulforaphane suppresses epithelial-mesenchymal transition (EMT) process. Cotreatment with N-acetyl-L cysteine inhibited sulforaphane-inhibited invasion and upregulation of E-cadherin and almost completely abolished the sulforaphane-induced expression of Vimentin. The effect of sulforaphane on the growth of hepatocellular carcinoma cells was confirmed by a xenograft tumor growth model. All our finding indicated that sulforaphane is a promising and safe strategy for treating hepatocellular carcinoma. PMID- 26935988 TI - Prion protein in exosomes: partnering Abeta peptides and driving fibrilization. PMID- 26935989 TI - Is Azilsartan More Effective in Younger Than in Older Patients? An Explorative Analysis of the Prospective EARLY Registry. PMID- 26935990 TI - Activation of innate antiviral immune response via double-stranded RNA-dependent RLR receptor-mediated necroptosis. AB - Viruses induce double-stranded RNA (dsRNA) in the host cells. The mammalian system has developed dsRNA-dependent recognition receptors such as RLRs that recognize the long stretches of dsRNA as PAMPs to activate interferon-mediated antiviral pathways and apoptosis in severe infection. Here we report an efficient antiviral immune response through dsRNA-dependent RLR receptor-mediated necroptosis against infections from different classes of viruses. We demonstrated that virus-infected A549 cells were efficiently killed in the presence of a chimeric RLR receptor, dsCARE. It measurably suppressed the interferon antiviral pathway but promoted IL-1beta production. Canonical cell death analysis by morphologic assessment, phosphatidylserine exposure, caspase cleavage and chemical inhibition excluded the involvement of apoptosis and consistently suggested RLR receptor-mediated necroptosis as the underlying mechanism of infected cell death. The necroptotic pathway was augmented by the formation of RIP1-RIP3 necrosome, recruitment of MLKL protein and the activation of cathepsin D. Contributing roles of RIP1 and RIP3 were confirmed by gene knockdown. Furthermore, the necroptosis inhibitor necrostatin-1 but not the pan-caspase inhibitor zVAD impeded dsCARE-dependent infected cell death. Our data provides compelling evidence that the chimeric RLR receptor shifts the common interferon antiviral responses of infected cells to necroptosis and leads to rapid death of the virus-infected cells. This mechanism could be targeted as an efficient antiviral strategy. PMID- 26935991 TI - Perinatal Exposure to Neuregulin-1 Results in Disinhibition of Adult Midbrain Dopaminergic Neurons: Implication in Schizophrenia Modeling. AB - Aberrant neuregulin-1 (NRG1) signals are suggested to associate with the neuropathophysiology of schizophrenia. Employing a mouse schizophrenia model established by neonatal neuregulin-1 challenge, we analysed postpubertal consequence of the NRG1 pretreatment for the electrophysiological property of nigral dopamine neurons. In vivo single unit recordings from anaesthetized NRG1 pretreated mice revealed increased spike bursting of nigral dopamine neurons. In slice preparations from NRG1-pretreated mice, spontaneous firing was elevated relative to controls. The relative increase in firing rates was abolished by a GABAA receptor antagonist. Whole-cell recording showed that perinatal NRG1 pretreatment diminished inhibitory miniature synaptic currents as well as GABAA receptor sensitivity. These results collectively suggest that perinatal exposure to neuregulin-1 results in the disinhibition of nigral dopamine neurons to influence their firing properties at the adult stage when the behavioral deficits are evident. PMID- 26935992 TI - Direct lower abdominal ureteral jet as sonographic sign of bladder exstrophy. PMID- 26935993 TI - Nuclear distribution of eIF3g and its interacting nuclear proteins in breast cancer cells. AB - Eukaryotic translation initiation factor 3 subunit g (eIF3g) is a core subunit of the eukaryotic translation initiation factor 3 complex, and is important in the initiation of translation. It is also involved in caspase-mediated apoptosis, and is upregulated in multidrug-resistant cancer cells. In the present study, the nuclear distribution of eIF3g was determined by performing co-immunoprecipitation of proteins that potentially interact with eIF3g in the nucleus. Mass spectrometry characterization showed that three proteins, heterogeneous nuclear ribonucleoprotein U/scaffold attachment factor A, HSZFP36/zinc finger protein 823 and beta-actin, were among the candidate eIF3g-interacting proteins in the nucleus. The protein-protein interaction was further confirmed by cross-linking and a glutathione S-transferase pull-down assay, followed by western blotting. The co-localization of these proteins was determined by confocal microscopy. These findings provide novel insight into the possible functions of eIF3g in the nucleus and serves as an important first step for further investigation of the roles of eIF3g in cancer development. PMID- 26935994 TI - A qualitative study exploring health perceptions and factors influencing participation in health behaviors in colorectal cancer survivors. AB - PURPOSE: The purpose of the study was to explore colorectal cancer survivors' health perceptions following cessation of active treatment for cancer and to explore the factors influencing participation in health-promoting behaviors that may help reduce cardiovascular disease risk. METHODS: Face-to-face interviews were conducted with participants that had completed active treatment for cancer within the previous 2 years. Participants were colorectal cancer survivors (N = 24, men = 11, women = 13, M age = 69.38 years, SD = 4.19) recruited from a private hospital in Perth, Australia on the basis that they had existing morbidities that put them at increased risk of cardiovascular disease. Interview transcripts were analyzed using thematic analysis. RESULTS: Five main themes emerged: back to normal; the pleasures in life: 'is it worth it?'; beliefs about health behavior; skepticism of eating guidelines; and lack of motivation. The majority of participants felt they were in good health and had made a full recovery. Participants questioned whether it was worth changing their lifestyle given their life stage and referred to the desire to enjoy life. Lay health beliefs, skepticism of eating guidelines, and a lack of motivation were barriers to change. CONCLUSIONS: Interventions should target lay beliefs and skepticism in relation to health behaviors in order to reinforce the importance and value of participating in health-related behavior. IMPLICATIONS FOR CANCER SURVIVORS: Findings may inform the development of effective, patient-centered interventions that target lay health beliefs and build motivation for health behavior change. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26935995 TI - A Community-Engaged Approach to Developing a Mobile Cancer Prevention App: The mCPA Study Protocol. AB - BACKGROUND: Rapid growth of mobile technologies has resulted in a proliferation of lifestyle-oriented mobile phone apps. However, most do not have a theoretical framework and few have been developed using a community-based participatory research approach. A community academic team will develop a theory-based, culturally tailored, mobile-enabled, Web-based app-the Mobile Cancer Prevention App (mCPA)-to promote adherence to dietary and physical activity guidelines. OBJECTIVE: The aim of this study is to develop mCPA content with input from breast cancer survivors. METHODS: Members of SISTAAH (Survivors Involving Supporters to Take Action in Advancing Health) Talk (N=12), treated for Stages I IIIc breast cancer for less than 1 year, 75 years of age or younger, and English speaking and writing, will be recruited to participate in the study. To develop the app content, breast cancer survivors will engage with researchers in videotaped and audiotaped sessions, including (1) didactic instructions with goals for, benefits of, and strategies to enhance dietary intake and physical activity, (2) guided discussions for setting individualized goals, monitoring progress, and providing or receiving feedback, (3) experiential nutrition education through cooking demonstrations, and (4) interactive physical activity focused on walking, yoga, and strength training. Qualitative (focus group discussions and key informant interviews) and quantitative (sensory evaluation) methods will be used to evaluate the participatory process and outcomes. RESULTS: Investigators and participants anticipate development of an acceptable (frequency and duration of usage) feasible (structure, ease of use, features), and accessible mobile app available for intervention testing in early 2017. CONCLUSIONS: Depending on the availability of research funding, mCPA testing, which will be initiated in Miami, will be extended to Chicago, Houston, Philadelphia, and Los Angeles. PMID- 26935996 TI - Effects of Time to Treatment on Biochemical and Clinical Outcomes for Patients With Prostate Cancer Treated With Definitive Radiation. AB - INTRODUCTION: The purpose of this study was to evaluate if time to treatment (TTT) has an effect on outcomes for patients with localized prostate cancer treated with definitive external beam radiation therapy (EBRT). PATIENTS AND METHODS: We included 4064 patients (1549 low-risk, 1612 intermediate-risk, and 903 high-risk) treated with EBRT. For each National Comprehensive Cancer Network (NCCN) risk group, TTT (defined as the time between initial positive prostate biopsy and start of RT) was analyzed in 4 intervals: < 3, 3-6, 6-9, and 9-24 months. We recorded the use of androgen deprivation therapy among patients with intermediate-risk and high-risk disease. RESULTS: The median TTT was 3.3 months (range, 0.6-23.5 months), and it was similar for each risk group (range, 3.3-3.4 months). The median follow up was 64 months. There were no significant differences in biochemical failure, distant metastasis, or overall survival for patients with TTT < 3, 3-6, 6-9, or 9-24 months for each risk group. There were also no significant differences in the outcomes at 5 years when patients with TTT > 3.3 months were compared with those with TTT <= 3.3 months for each risk group. For high-risk men, 328 of 450 (72.9%) with TTT > 3.3 months were on androgen deprivation therapy (ADT) versus 299 of 453 (66%) with TTT <= 3.3 months. Among men with high-risk cancer treated without ADT, there remained no significant difference in outcomes between TTT > 3.3 months and TTT <= 3.3 months. CONCLUSION: TTT was not associated with significant differences in outcomes among each risk group of men with localized prostate cancer treated with EBRT. Among the high-risk patients, there were no observed detriments in outcomes with TTT > 3.3 months regardless of androgen deprivation therapy use. PMID- 26935997 TI - Prognostic Significance of the Disparity Between Biopsy and Pathologic Gleason Score After Radical Prostatectomy in Clinical Candidates for Active Surveillance According to the Royal Marsden Criteria. AB - INTRODUCTION: We identify the biochemical outcome according to biopsy Gleason score (bGS) among patients who are clinical candidate for active surveillance. We found that different adverse pathologic outcomes and biochemical outcomes were shown according to biopsy pattern although the patients have the same pathologic Gleason score (pGS) 3+4 after RP. BACKGROUND: To identify the biochemical recurrence rate (BCR) according to a pGS upgrade after radical prostatectomy among men with prostate cancer who are clinical candidates for active surveillance (AS) according to the Royal Marsden Hospital criteria. METHODS: Of the 956 patients with prostate cancer who met the Royal Marsden Hospital criteria for AS underwent radical prostatectomy between January 2006 and June 2014, we enrolled the 830 patients whose pGS was <= 3+4 in analysis. We stratified the patients into 3 groups according to the disparity between the bGS and pGS, as follows: group A (n = 211): bGS 3+3 to pGS 3+3; group B (n = 430): bGS 3+3 to pGS 3+4; group C (n = 189): bGS 3+4 to pGS 3+4. RESULTS: The patients in group C had a higher preoperative prostate-specific antigen level, a higher percentage of positive cores, maximum core involvement (P < .001), and higher postoperative levels of extracapsular extension, seminal vesicle invasion, and positive surgical margins compared with the patients in groups A and B (P < .001, P = .002, and P < .001, for patients in groups C, B, and A, respectively). Group C had a significantly lower BCR-free survival rate compared with groups A and B via Kaplan-Meier, and no difference was observed in the BCR between groups A and B (log rank, P = .475). CONCLUSION: Although the patients with the same pGS 3+4 after RP, different adverse outcomes were observed. Because of the significantly different prognosis based on the presence of Gleason pattern 4, patients with this pattern are not suitable for AS. PMID- 26935998 TI - A Case of Gemcitabine and Cisplatin Chemotherapy in a Patient With Metastatic Urothelial Carcinoma Receiving Hemodialysis. PMID- 26935999 TI - TRPA1-dependent regulation of bladder detrusor smooth muscle contractility in normal and type I diabetic rats. AB - TRPA1 is a Ca(2+)-permeable cation channel that is activated by painful low temperatures (<17 degrees C), irritating chemicals, reactive metabolites and mediators of inflammation. In the bladder TRPA1 is predominantly expressed in sensory afferent nerve endings, where it mediates sensory transduction. The contractile effect of its activation on detrusor smooth muscle (DSM) is explained by the release from sensory afferents of inflammatory factors - tachykinins and prostaglandins, which cause smooth muscle cell contraction. Diabetes is a systemic disease, with common complications being diabetic cystopathies and urinary incontinence. However, data on how diabetes affects bladder contractility associated with TRPA1 activation are not available. In this study, by using a rat model with streptozotocin-induced type I diabetes, contractility measurements of DSM strips in response to TRPA1-activating and modulating pharmacological agents and assessment of TRPA1 mRNA expression in bladder-innervating dorsal root ganglia, we have shown that diabetes enhances the TRPA1-dependent mechanism involved in bladder DSM contractility. This is not due to changes in TRPA1 expression, but mainly due to the general inflammatory reaction caused by diabetes. The latter leads to an increase in cyclooxygenase-2-dependent prostaglandin synthesis through the mechanisms associated with substance P activity. This results in the enhanced functional coupling between the tachykinin and prostanoid systems, and the concomitant increase of their impact on DSM contractility in response to TRPA1 activation. PMID- 26936000 TI - Resveratrol can both enhance and relax adrenergic contractions of the rat tail artery. AB - Our aims were to determine 1) if resveratrol's vasorelaxant action is greater in the distal (resistance) versus proximal (conductance) portion of the rat tail artery, and 2) if it can be blocked by agents known to block different potassium (K) channels in arterial smooth muscle. We found that its half-maximally effective concentration values were essentially identical (25 +/- 3 versus 27 +/- 3 MUM) for relaxing adrenergically-precontracted rings prepared from distal versus proximal tissues. This does not confirm a previous report of greater relaxation in resistance versus conductance arteries. We also found that its relaxation could not be blocked by any of seven different K channel blockers. However, we uncovered a novel unanticipated action not yet reported. In half our arterial ring preparations, resveratrol transiently enhanced adrenergically induced precontractions beginning well before its sustained relaxant effect became apparent. This action provides the first reasonable explanation for previously unexplained increases in arterial pressures observed during acute intravenous administration of resveratrol to animal models of traumatic ischemic tissue injury, in which hypotension is often present and in need of correction. Also unanticipated, this same transient enhancement of adrenergic contraction was notably inhibited by some of the same K channel blockers (particularly tetraethylammonium and glibenclamide) that failed to influence its relaxant effect. Although we do not rule out smooth muscle as a possible site for such a paradoxical finding, we suspect resveratrol could also be acting on K-selective mechano-sensitive ion channels located in the endothelium where they may participate in release of contracting factors. PMID- 26936001 TI - Photolysis of Nitric Acid and Nitrate on Natural and Artificial Surfaces. AB - Photolysis of nitric acid and nitrate (HNO3/nitrate) was investigated on the surfaces of natural and artificial materials, including plant leaves, metal sheets, and construction materials. The surfaces were conditioned in the outdoor air prior to experiments to receive natural depositions of ambient HNO3/nitrate and other atmospheric constituents. The photolysis rate constant (JHNO3(s)) of the surface HNO3/nitrate was measured based on the production rates of nitrous acid (HONO) and nitrogen oxides (NOx). The JHNO3(s) values, from 6.0 * 10(-6) s( 1) to 3.7 * 10(-4) s(-1), are 1 to 3 orders of magnitude higher than that of gaseous HNO3. The HONO was the major product from photolysis of HNO3/nitrate on most plant leaves, whereas NOx was the major product on most artificial surfaces. The JHNO3(s) values decreased with HNO3/nitrate surface density and could be described by a simple analytical equation. Within a typical range of HNO3/nitrate surface density in the low-NOx forested areas, photolysis of HNO3/nitrate on the forest canopy can be a significant source for HONO and NOx for the overlying atmosphere. PMID- 26936002 TI - Comparative evaluation of p5+14 with SAP and peptide p5 by dual-energy SPECT imaging of mice with AA amyloidosis. AB - Amyloidosis is a protein-misfolding disorder characterized by the extracellular deposition of amyloid, a complex matrix composed of protein fibrils, hyper sulphated glycosaminoglycans and serum amyloid P component (SAP). Accumulation of amyloid in visceral organs results in the destruction of tissue architecture leading to organ dysfunction and failure. Early differential diagnosis and disease monitoring are critical for improving patient outcomes; thus, whole body amyloid imaging would be beneficial in this regard. Non-invasive molecular imaging of systemic amyloid is performed in Europe by using iodine-123-labelled SAP; however, this tracer is not available in the US. Therefore, we evaluated synthetic, poly-basic peptides, designated p5 and p5+14, as alternative radiotracers for detecting systemic amyloidosis. Herein, we perform a comparative effectiveness evaluation of radiolabelled peptide p5+14 with p5 and SAP, in amyloid-laden mice, using dual-energy SPECT imaging and tissue biodistribution measurements. All three radiotracers selectively bound amyloid in vivo; however, p5+14 was significantly more effective as compared to p5 in certain organs. Moreover, SAP bound principally to hepatosplenic amyloid, whereas p5+14 was broadly distributed in numerous amyloid-laden anatomic sites, including the spleen, liver, pancreas, intestines and heart. These data support clinical validation of p5+14 as an amyloid radiotracer for patients in the US. PMID- 26936003 TI - A complexity scoring system for degenerative mitral valve repair. AB - OBJECTIVE: To develop a score to allow stratification of complexity in degenerative mitral valve repair. METHODS: Retrospective modeling of data from 668 consecutive patients who underwent surgery for mitral valve prolapse. A complexity scoring scale was developed using a consensus approach, assigning a score to each valve, based on the following: prolapsing segments (weight 1 for each posterior segment; weight 2 for each anterior or commissural segment); presence of valve restriction (weight 2); presence of calcification (weight 3 if annulus involved, otherwise weight 2); and prior mitral valve repair (weight 3). Valve repairs were categorized into 3 groups based on the complexity score: 1: Simple (n = 244); 2-4: Intermediate (n = 260); >=5: Complex (n = 164). RESULTS: Mitral valve repair was successfully performed in 667 patients (repair rate: 99.9%). The complexity score was directly correlated with surrogates of technical complexity. The mean cardiopulmonary bypass time increased with lesion complexity ([in minutes] simple: 152; intermediate: 167; complex 195; P < .001). The median number of repair techniques utilized was related to lesion complexity (simple: 3; intermediate: 4; complex: 5; P < .001). Barlow's type etiology was more prevalent in complex cases (63%), compared with simple (9%) and intermediate (35%) cases (P < .001). Advanced repair techniques were required to complete repair in 51% of complex cases, compared with 14% of intermediate and 0% of simple cases (P < .001). Early and late outcomes were similar. CONCLUSIONS: Our scoring system may allow effective stratification of complexity of mitral valve repair. Future studies are required to evaluate the use of our score in a prospective setting. PMID- 26936005 TI - Discussion. PMID- 26936006 TI - Discussion. PMID- 26936004 TI - Are homografts superior to conventional prosthetic valves in the setting of infective endocarditis involving the aortic valve? AB - BACKGROUND: Surgical dogma suggests that homografts should be used preferentially, compared with conventional xenograft or mechanical prostheses, in the setting of infective endocarditis (IE), because they have greater resistance to infection. However, comparative data that support this notion are limited. METHODS: From the prospective databases of 2 tertiary academic centers, we identified 304 consecutive adult patients (age >=17 years) who underwent surgery for active IE involving the aortic valve (AV), in the period 2002 to 2014. Short- and long-term outcomes were evaluated using propensity scores and inverse probability weighting to adjust for selection bias. RESULTS: Homografts, and xenograft and mechanical prostheses, were used in 86 (28.3%), 139 (45.7%), and 79 (26.0%) patients, respectively. Homografts were more often used in the setting of prosthetic valve endocarditis (58.1% vs 28.8%, P = .002) and methicillin resistant Staphylococcus (25.6% vs 12.1%, P = .002), compared with conventional prostheses. Early mortality occurred in 17 (19.8%) in the homograft group, and 20 (9.2%) in the conventional group (P = .019). During follow-up (median: 29.4 months; interquartile-range: 4.7-72.6 months), 60 (19.7%) patients died, and 23 (7.7%) experienced reinfection, with no significant differences in survival (P = .23) or freedom from reinfection rates (P = .65) according to the types of prostheses implanted. After adjustments for baseline characteristics, using propensity-score analyses, use of a homograft did not significantly affect early death (odds ratio 1.61; 95% confidence interval [CI], 0.73-3.40, P = .23), overall death (hazard ratio 1.10; 95% CI, 0.62-1.94, P = .75), or reinfection (hazard ratio 1.04; 95% CI, 0.49-2.18, P = .93). CONCLUSIONS: No significant benefit to use of homografts was demonstrable with regard to resistance to reinfection in the setting of IE. The choice among prosthetic options should be based on technical and patient-specific factors. Lack of availability of homografts should not impede appropriate surgical intervention. PMID- 26936007 TI - Discussion. PMID- 26936008 TI - A contemporary analysis of pulmonary hypertension in patients undergoing mitral valve surgery: Is this a risk factor? AB - OBJECTIVE: Pulmonary hypertension (PHT) has been considered a risk factor for mortality in cardiac surgery. Among mitral valve surgery (MVS) patients, we sought to determine if severe PHT increases mortality risk and if patients who undergo concomitant tricuspid valve surgery (TVS) incur additional risk. METHODS: Preoperative PHT was assessed in 1571 patients undergoing MVS, from 2004 to 2013. Patients were stratified into PHT groups as follows (mm Hg): none (<35); moderate (35-49); severe (50-79); and extreme (>=80). Propensity-score matching resulted in a total of 430 patients, by PHT groups, and 384 patients, by TVS groups. RESULTS: Patients with severe PHT had higher mortality, both 30-day (4% PHT vs 1% no PHT, P < .02) and late (defined as survival at 5 years): 75.5% severe versus 91.9% no PHT (P < .001). In propensity-score-matched groups, severe PHT was not a risk factor for 30-day (3% each, P = 1.0) or late mortality (86.2% severe vs 87.1% no PHT; P = .87). TVS did not increase 30-day (4.7% TVS vs 4.2% no TVS, P = .8) or late mortality (78.7% TVS vs 75.3% no TVS, P = .90). Late survival was lower in extreme PHT (75.4% vs no PHT 91.5%, P = .007), and a trend was found in 30-day mortality (11% extreme vs 3% no PHT, P = .16). CONCLUSIONS: Mortality in MVS is unaffected by severe PHT or the addition of TVS, yet extreme PHT remains a risk factor. Severe PHT (50-79 mm Hg) should not preclude surgery; concomitant TVS does not increase mortality. PMID- 26936010 TI - Discussion. PMID- 26936011 TI - Incidence and management of chylothorax after Ivor Lewis esophagectomy for cancer of the esophagus. AB - OBJECTIVE: Chylothorax is a major complication after esophagectomy. As recent studies refer to heterogeneous patient cohorts and surgical procedures, this study was conducted to report the incidence and evaluate the optimal management of chylous fistula in patients treated with transthoracic esophagectomy and 2 field lymphadenectomy for esophageal cancer. METHODS: From January 2005 to December 2013, a total of 906 patients underwent transthoracic esophageal resection for esophageal carcinoma at our institution. En bloc esophagectomy was performed with routine supradiaphragmatic ligation of the thoracic duct. The incidence of chylothorax, and associated morbidity and mortality, were analyzed, and subsequent therapeutic management was reviewed. RESULTS: Chylothorax after Ivor Lewis esophagectomy was observed in 17 (1.9%) patients. Fifteen patients required surgical intervention with rethoracotomy and repeat duct ligation. Thoracic duct ligation was successful in all patients. Two patients died within 90 days after primary esophageal resection. The median time between initial tumor resection and rethoracotomy was 13 days. Average daily chest-tube output at time of reoperation was 1900 mL. In 2 patients, pleural effusion did not exceed 1000 mL per day. In these cases, conservative management with additional thoracic drainage and total parenteral nutrition led to complete resolution of chylous fistula. CONCLUSIONS: Occurrence of chylothorax after prophylactic thoracic duct ligation during transthoracic esophagectomy for esophageal cancer is rare. In patients with high-output chylous fistula, an early rethoracotomy with repeat ligation of the thoracic duct is safe and helps to shorten recovery time. In cases of low-volume drainage, a conservative approach is feasible. PMID- 26936009 TI - The sutureless aortic valve at 1 year: A large multicenter cohort study. AB - OBJECTIVE: Sutureless aortic valve replacement (AVR) offers an alternative to standard AVR in aortic stenosis. This prospective, single-arm study aimed to demonstrate safety and effectiveness of a bovine pericardial sutureless aortic valve at 1 year. METHODS: From February 2010 to September 2013, 658 patients (mean age 78.3 +/- 5.6 years; 40.0% octogenarian; 64.4% female; mean Society of Thoracic Surgeons score 7.2 +/- 7.4) underwent sutureless AVR in 25 European centers. Concomitant cardiac procedures were performed in 29.5% and minimally invasive cardiac surgery in 33.3%. RESULTS: One-year site-reported event rates were 8.1% for all-cause mortality, 4.5% for cardiac mortality, 3.0% for stroke, 1.9% for valve-related reoperation, 1.4% for endocarditis, and 0.6% for major paravalvular leak. No valve thrombosis, migration, or structural valve deterioration occurred. New York Heart Association class improved at least 1 level in 77.5% and remained stable (70.4% New York Heart Association class I or II at 1 year). Mean effective orifice area was 1.5 +/- 0.4 cm(2); pressure gradient was 9.2 +/- 5.0 mm Hg. Left ventricular mass decreased from 138.5 g/m(2) before surgery to 115.3 g/m(2) at 1 year (P < .001). Echocardiographic core laboratory findings confirmed that paravalvular leak was rare and remained stable during follow-up. CONCLUSIONS: The Perceval sutureless valve resulted in low 1 year event rates in intermediate-risk patients undergoing AVR. New York Heart Association class improved in more than three-quarters of patients and remained stable. These data support the safety and efficacy to 1 year of the Perceval sutureless valve in this intermediate-risk population. PMID- 26936013 TI - LKB1 inhibits the proliferation of gastric cancer cells by suppressing the nuclear translocation of Yap and beta-catenin. AB - Liver kinase B1 (LKB1) is known to suppress the proliferation, energy metabolism and mesenchymal transition of various cancer cells, and is involved in the regulation of Hippo-Yes-associated protein (Yap) and the Wnt/beta-catenin signaling pathways. However, the role of LKB1 in gastric cancer (GC) was not fully understood. Thus, in the present study, we studied LKB1 and found that protein expression (0.37+/-0.061 vs. 0.59+/-0.108, P=0.006) and the protein ratio of p-Yap/Yap (0.179+/-0.085 vs. 0.8+/-0.126, P=0.001) were reduced in 54 gastric adenocarcinoma (GAC) tissues compared with the matched adjacent non-cancerous tissues, using western blotting and RT-qPCR assays. LKB1 expression was also observed decreased in 109 GAC tissues compared with 54 adjacent non-cancerous tissues (chi2=4.678, P=0.0306), and negatively correlated with the nuclear expression of Yap (r=-0.6997) and beta-catenin (r=-0.3510), using immunohistochemical analysis. In GC patients, LKB1 expression was negatively associated with tumor size, tumor infiltration, lymph node metastasis and the TNM stage. LKB1 expression was determined to be positively correlated with longer overall survival of GC patients using Kaplan-Meier analysis (P=0.001). Subsequently, LKB1 expression in human GAC AGS cells was enhanced with a full length LKB1 transfection. In vitro and in vivo proliferation was inhibited in LKB1-overexpressing GC cells compared with the control cells. Yap and beta catenin expression were assessed by western blotting and RT-qPCR, and were found to be increased in the cytoplasm but decreased in the nucleus in LKB1 overexpressing GC cells compared with the control cells. The increase in cytoplasmic beta-catenin was reversed by the silencing of LKB1 or Yap with shRNAs in LKB1-overexpressing GC cells. Moreover, Yap and beta-catenin mRNA were barely altered by LKB1 overexpression. Thus, we concluded that LKB1 expression was reduced in GAC tissues but that it correlated positively with better prognosis for GC patients. LKB1 inhibits the proliferation of GC cells by suppressing the nuclear translocation of Yap and beta-catenin. PMID- 26936014 TI - Dielectric relaxation behavior in antiferroelectric metal organic framework [(CH3)2NH2][Fe(III)Fe(II)(HCOO)6] single crystals. AB - The fundamental aspects of the relaxation dynamics in niccolite-type, mixed valence metal-organic framework, multiferroic [(CH3)2NH2][Fe(3+)Fe(2+)(HCOO)6] single crystals have been reported using dielectric relaxation spectroscopy covering eight decades in frequency (10(-2) <= f <= 10(6)) in the temperature range 120 K <= T <= 250 K. The compound shows antiferroelectric to paraelectric phase transition near T = 154 K with the relaxor nature of electric ordering. The temperature dependent dielectric response in modulus representation indicates three relaxation processes within the experimental window. The variable range hopping model of small polarons explains the bulk non-Debye type conductivity relaxation. The fastest relaxation with activation energy Ea = 0.17 eV is related to progressive freezing of the reorientation motions of DMA(+) cations. X-ray diffraction data revealed that complete freezing of orientational and translational motions of DMA(+) cations occurs well below phase transition temperature. These experimental observations are fundamentally important for the theoretical explanation of relaxation dynamics in niccolite-type metal-organic frameworks. PMID- 26936015 TI - Orientational dynamics of colloidal ribbons self-assembled from microscopic magnetic ellipsoids. AB - We combine experiments and theory to investigate the orientational dynamics of dipolar ellipsoids, which self-assemble into elongated ribbon-like structures due to the presence of a permanent magnetic moment, perpendicular to the long axis in each particle. Monodisperse hematite ellipsoids are synthesized via the sol-gel technique and arrange into ribbons in the presence of static or time-dependent magnetic fields. We find that under an oscillating field, the ribbons reorient perpendicular to the field direction, in contrast with the behaviour observed under a static field. This observation is explained theoretically by treating a chain of interacting ellipsoids as a single particle with orientational and demagnetizing field energy. The model allows us to describe the orientational behaviour of the chain and captures well its dynamics at different strengths of the actuating field. The understanding of the complex dynamics and assembly of anisotropic magnetic colloids is a necessary step for controlling the structure formation, which has direct applications in different fluid-based microscale technologies. PMID- 26936012 TI - Influence of fetal blood flow redistribution on fetal and childhood growth and fat distribution: the Generation R Study. AB - OBJECTIVE: A suboptimal intrauterine environment leads to fetal blood flow redistribution and fetal growth restriction. Not much is known about childhood growth consequences. We examined the associations of fetal blood flow redistribution with birth outcomes, and repeatedly measured fetal and childhood growth and fat mass measures. DESIGN: Prospective cohort study. SETTING: Population-based. POPULATION: One thousand one hundred and ninety-five pregnant women and their children. METHODS: We measured umbilical and cerebral artery blood flow at a gestational age of 30.3 weeks (95% range, 28.5-32.6 weeks). A higher umbilical/cerebral (U/C) pulsatility index ratio is an indicator of preferential blood flow to the brain cerebral circulation at the expense of the lower body parts. MAIN OUTCOME MEASURES: Fetal and childhood growth were repeatedly measured from the third trimester until childhood. We measured the total body fat mass, lean fat mass and android/gynoid fat mass ratio by dual energy X-ray absorptiometry and preperitoneal fat by ultrasound at 6 years. RESULTS: A higher fetal U/C ratio was associated with increased risks of preterm birth and small size for gestational age at birth [odds ratios, 1.41 (95% confidence interval, 1.08-1.85) and 1.63 (95% confidence interval, 1.21-2.19), respectively, per SDS increase in U/C ratio]. Longitudinal growth analyses showed that a higher fetal U/C ratio was associated with persistently lower head circumference, length and weight from third trimester fetal life until childhood (all P < 0.05). The fetal U/C ratio was not associated with total body and abdominal fat measures at 6 years. CONCLUSION: Our results suggest that fetal blood flow redistribution affects fetal development and has persistent consequences for childhood growth. TWEETABLE ABSTRACT: Fetal blood flow redistribution affects fetal development and has persistent consequences for childhood growth. PMID- 26936016 TI - Immobilization of sulfur in microgels for lithium-sulfur battery. AB - Immobilization of sulfur in microgels is achieved via free radical polymerization of commercial poly(ethylene glycol) dimethacrylate in the solution of sulfur terminated poly(3-oligo(ethylene oxide)4-thiophene), a copolymer prepared by the inverse vulcanization of S8 with allyl-terminated poly(3-oligo(ethylene oxide)4 thiophene). This microgelation leads to enhanced Li-S battery performance over the sulfur-terminated polymer. PMID- 26936017 TI - Improvement of the cytotoxic T lymphocyte response against hepatocellular carcinoma by transduction of cancer cells with an adeno-associated virus carrying the interferon-gamma gene. AB - Dendritic cell (DC)-based antigen-targeted immunotherapy may offer effective adjuvant therapy for hepatocellular carcinoma (HCC), in which cytotoxic T lymphocytes (CTLs) are key. However, in a number of cases, the activity of CTLs is completely inhibited due to the downregulated expression of major human leukocyte antigen (HLA) class I molecules by HCC cells. The aim of the present study was to overcome this issue. Hep3B cells were transduced by HCC-specific recombinant adeno-associated virus (rAAV) carrying human alpha-fetoprotein promoter (AFPp) and the interferon-gamma (IFN-gamma) gene (rAAV/AFPp-IFN-gamma). rAAV carrying the cytomegalovirus promoter (CMVp) and human alpha-fetoprotein (AFP) gene (rAAV/CMVp-AFP) was used to transduce professional antigen-presenting DCs for the purpose of stimulating a CTL response. It was observed that transduction of DCs with rAAV/CMVp-AFP resulted in: (i) AFP and interleukin-12 expression; (ii) high expression levels of cluster of differentiation (CD)80, CD83, CD86, CD40, HLA-death receptor and CD1a; (iii) T cell populations with marked IFN-gamma expression; (iv) a high percentage of CD69+/CD8+ T cells; and (v) the activity of CTLs against HLA-A2-expressing Hep3B cells. The transduction of Hep3B cells with rAAV/AFPp-IFN-gamma resulted in: (i) IFN-gamma expression; (ii) upregulated expression of HLA-A2; and (iii) an improved CTL response against HLA-A2-deficient Hep3B cells. rAAV/CMVp-AFP-transduced DCs elicited an AFP specific and HLA-class I-restricted CTL response against Hep3B cells. In conclusion, it was shown that the transduction of Hep3B with rAAV/AFPp-IFN-gamma upregulated the expression of HLA-A2 and improved the sensitivity to CTL response. PMID- 26936018 TI - Potentially traumatic experiences and sexual health among orphaned and separated adolescents in five low- and middle-income countries. AB - Orphans and separated children (OSC) are a vulnerable population whose numbers are increasing, particularly in sub-Saharan Africa and Asia. Over 153 million children worldwide have lost one or both parents, including 17 million orphaned by AIDS, and millions more have been separated from their parents. As younger orphans enter adolescence, their sexual health and HIV-related risk behaviors become key considerations for their overall health. Importantly, their high prevalence of exposure to potentially traumatic events (PTEs) may put OSC at additional risk for adverse sexual health outcomes. The Positive Outcomes for Orphans study followed OSC randomly sampled from institution-based care and from family-based care, as well as a convenience sample of non-OSC, at six sites in five low-and middle-income countries. This analysis focused on the 90-month follow-up, during which adolescents 16 and older were assessed for sexual health, including age at sexual debut, past-year sex, past-year condom use, and perceptions of condom use. We specifically examined the relationship between PTEs and sexual health outcomes. Of the 1258 OSC and 138 non-OSC assessed, 11% reported ever having sex. Approximately 6% of participants reported recent sex and 5% reported having recent unprotected sex. However, 70% of those who had recent sex reported that they did not use a condom every time, and perceptions of condom use tended to be unfavorable for protection against sexual risk behavior. Nearly all (90%) of participants reported experiencing at least one lifetime PTE. For those who experienced "any" PTE, we found increased prevalence of recent sex (PR = 1.39 [0.47, 4.07]) and of recent unprotected sex (PR = 3.47 [0.60, 19.91]). This study highlights the need for caregivers, program managers, and policymakers to promote condom use for sexually active OSC and identify interventions for trauma support services. Orphans living in family-based care may also be particularly vulnerable to early sexual debut and unprotected sexual activity. PMID- 26936019 TI - An atom-efficient and convergent approach to the preparation of NS5A inhibitors by C-H activation. AB - A novel approach of the convergent functionalisation of aryl dibromides to form NS5A type inhibitors using C-H activation is reported. The focus of investigation was to reduce the formation of homodimeric side product, as well as to investigate the scope of different aryl dibromides that were tolerated under the reaction conditions. The C-H activation methodology was found to give a viable synthetic route to NS5A inhibitors, with late stage functionalisation of the core portion of the molecule, albeit with some chemical functionalities not tolerated. PMID- 26936021 TI - Harvest and utilization of chemical energy in wastes by microbial fuel cells. AB - Organic wastes are now increasingly viewed as a resource of energy that can be harvested by suitable biotechnologies. One promising technology is microbial fuel cells (MFC), which can generate electricity from the degradation of organic pollutants. While the environmental benefits of MFC in waste treatment have been recognized, their potential as an energy producer is not fully understood. Although progresses in material and engineering have greatly improved the power output from MFC, how to efficiently utilize the MFC's energy in real-world scenario remains a challenge. In this review, fundamental understandings on the energy-generating capacity of MFC from real waste treatment are provided and the challenges and opportunities are discussed. The limiting factors restricting the energy output and impairing the long-term reliability of MFC are also analyzed. Several energy storage and in situ utilization strategies for the management of MFC's energy are proposed, and future research needs for real-world application of this approach are explored. PMID- 26936020 TI - Elimination of HIV-1-infected cells by broadly neutralizing antibodies. AB - The Fc region of HIV-1 Env-specific broadly neutralizing antibodies (bNAbs) is required for suppressing viraemia, through mechanisms which remain poorly understood. Here, we identify bNAbs that exert antibody-dependent cellular cytotoxicity (ADCC) in cell culture and kill HIV-1-infected lymphocytes through natural killer (NK) engagement. These antibodies target the CD4-binding site, the glycans/V3 and V1/V2 loops on gp120, or the gp41 moiety. The landscape of Env epitope exposure at the surface and the sensitivity of infected cells to ADCC vary considerably between viral strains. Efficient ADCC requires sustained cell surface binding of bNAbs to Env, and combining bNAbs allows a potent killing activity. Furthermore, reactivated infected cells from HIV-positive individuals expose heterogeneous Env epitope patterns, with levels that are often but not always sufficient to trigger killing by bNAbs. Our study delineates the parameters controlling ADCC activity of bNAbs, and supports the use of the most potent antibodies to clear the viral reservoir. PMID- 26936022 TI - A comparison of intranasal dexmedetomidine for sedation in children administered either by atomiser or by drops. AB - Intranasal dexmedetomidine has been used successfully for sedation in children. A mucosal atomisation device delivers an atomised solution to the nasal mucosa which facilitates rapid and effective delivery of medication to the systemic circulation. We compared intranasal delivery of dexmedetomidine in a dose of 3 MUg.kg(-1) by either atomiser or drops from a syringe in children < 3 years old undergoing transthoracic echocardiography. Two hundred and seventy-nine children were randomly assigned to one or other group. One hundred and thirty-seven children received dexmedetomidine by atomiser and 142 by drops. The successful sedation rate was 82.5% (95% CI 75.3-87.9%) and 84.5% (95% CI 77.7-89.5%) for atomiser and drops, respectively (p = 0.569). Sedation tended to be less successful in older children (p = 0.028, OR 0.949, 95% CI 0.916-0.983). There were no significant complications. We conclude that both modes of dexmedetomidine administration are equally effective, although increasing age of the child was associated with a decreased likelihood of successful sedation. PMID- 26936023 TI - Deletion of SIP1 promotes liver regeneration and lipid accumulation. AB - BACKGROUNDS: The function of Smad interacting protein-1 (SIP1) in liver regeneration is not yet known. As it is a key factor linked to the TGF-beta, BMP and Wnt signaling pathways, which are important for liver regeneration, we tested whether SIP1 might also have a critical role in liver regeneration after liver injury. MATERIALS AND METHODS: In this study, the 2/3 partial hepatectomy (2/3 PH) animal model was used to assess wild-type and SIP1 tissue-specific knockout mice. We collected the blood and liver tissue at selected time points after inducing injury. The level of liver regeneration was monitored using several methods, including H&E staining, immunohistochemistry (IHC), Western blotting, and qPCR. RESULTS: There was no difference between adult SIP1 knockout and wild type mice in morphological appearance or liver tissue sections. The peak level of BrdU- and Ki67-positive cells was observed at 36h after PH in both SIP1 knockout and wild-type mice. However, the peak level of BrdU- and Ki67-positivity was higher in SIP1 knockout mice than in wild-type mice (P<0.05). A higher amount of peak cyclin protein expression was also observed in SIP1 knockout mice. Furthermore, lipid accumulation was observed in SIP1 knockout mice during the liver regeneration process. Expression of Plin2, which plays an essential role in adipose differentiation, was found to be significantly higher in SIP1 knockout mice than in wild-type mice after 2/3 PH (P<0.05). CONCLUSION: SIP1 plays an essential role in lipid metabolism during the liver regeneration process and might be a regulator of liver regeneration following PH injury. PMID- 26936024 TI - Expression of Leptin and Sirtuin-1 is associated with poor prognosis in patients with osteosarcoma. AB - Sirtuin-1 (SIRT1) is a downstream target of Leptin, and its inhibition promotes p53-mediated apoptosis. This study aimed to evaluate the expression and prognostic significance of Leptin and SIRT1 in osteosarcoma. Leptin and SIRT1 levels in osteosarcoma samples from 89 patients were evaluated by immunohistochemical staining. The correlations between Leptin and SIRT1 expression with clinical parameters were analyzed by Spearman's test and Pearson's chi-squared test. Prognostic factors were identified by Univariate and multivariate Cox regression analysis. We found that Leptin and SIRT1 expression was low in 23.6% and 20.2%; moderate in 25.8% and 24.7%; and high in 50.5% and 55.1% of patients with osteosarcoma, respectively. Both Leptin and SIRT1 expression were significantly associated with the Enneking stage, distant metastasis and neo-adjuvant chemotherapy. Leptin expression and SIRT1 expression were significantly correlated and they were significantly associated with shorter overall survival. Among osteosarcoma patients who received neo-adjuvant chemotherapy, both Leptin and SIRT1 expression were significantly associated with overall survival of osteosarcoma patients in univariate analysis, but only SIRT1 expression was significantly associated with overall survival of osteosarcoma patients in multivariate analysis. In conclusion, Leptin and SIRT1 expressions are significantly associated with shorter overall survival of osteosarcoma patients, and SIRT1 expression is a significant independent prognostic indicator in patients with osteosarcoma. PMID- 26936025 TI - Six Susceptible-Infected-Susceptible Models on Scale-free Networks. AB - Spreading phenomena are ubiquitous in nature and society. For example, disease and information spread over underlying social and information networks. It is well known that there is no threshold for spreading models on scale-free networks; this suggests that spread can occur on such networks, regardless of how low the contact rate may be. In this paper, I consider six models with different contact and propagation mechanisms, which include models studied so far, but are apt to be confused. To compare these six models, I analyze them by degree-based mean-field theory. I find that the result depends on the details of contact and propagation mechanism. PMID- 26936026 TI - A TNM classification for HPV+ oropharyngeal cancer. PMID- 26936027 TI - Development and validation of a staging system for HPV-related oropharyngeal cancer by the International Collaboration on Oropharyngeal cancer Network for Staging (ICON-S): a multicentre cohort study. AB - BACKGROUND: Human papillomavirus-related (HPV+) oropharyngeal cancer is a rapidly emerging disease with generally good prognosis. Many prognostic algorithms for oropharyngeal cancer incorporate HPV status as a stratification factor, rather than recognising the uniqueness of HPV+ disease. The International Collaboration on Oropharyngeal cancer Network for Staging (ICON-S) aimed to develop a TNM classification specific to HPV+ oropharyngeal cancer. METHODS: The ICON-S study included patients with non-metastatic oropharyngeal cancer from seven cancer centres located across Europe and North America; one centre comprised the training cohort and six formed the validation cohorts. We ascertained patients' HPV status with p16 staining or in-situ hybridisation. We compared overall survival at 5 years between training and validation cohorts according to 7th edition TNM classifications and HPV status. We used recursive partitioning analysis (RPA) and adjusted hazard ratio (AHR) modelling methods to derive new staging classifications for HPV+ oropharyngeal cancer. Recent hypotheses concerning the effect of lower neck lymph nodes and number of lymph nodes were also investigated in an exploratory training cohort to assess relevance within the ICON-S classification. FINDINGS: Of 1907 patients with HPV+ oropharyngeal cancer, 661 (35%) were recruited at the training centre and 1246 (65%) were enrolled at the validation centres. 5-year overall survival was similar for 7th edition TNM stage I, II, III, and IVA (respectively; 88% [95% CI 74-100]; 82% [71 95]; 84% [79-89]; and 81% [79-83]; global p=0.25) but was lower for stage IVB (60% [53-68]; p<0.0001). 5-year overall survival did not differ among N0 (80% [95% CI 73-87]), N1-N2a (87% [83-90]), and N2b (83% [80-86]) subsets, but was significantly lower for those with N3 disease (59% [51-69]; p<0.0001). Stage classifications derived by RPA and AHR models were ranked according to survival performance, and AHR-New was ranked first, followed by AHR-Orig, RPA, and 7th edition TNM. AHR-New was selected as the proposed ICON-S stage classification. Because 5-year overall survival was similar for patients classed as T4a and T4b, T4 is no longer subdivided in the re-termed ICON-S T categories. Since 5-year overall survival was similar among N1, N2a, and N2b, we re-termed the 7th edition N categories as follows: ICON-S N0, no lymph nodes; ICON-S N1, ipsilateral lymph nodes; ICON-S N2, bilateral or contralateral lymph nodes; and ICON-S N3, lymph nodes larger than 6 cm. This resembles the N classification of nasopharyngeal carcinoma but without a lower neck lymph node variable. The proposed ICON-S classification is stage I (T1-T2N0-N1), stage II (T1-T2N2 or T3N0-N2), and stage III (T4 or N3). Metastatic disease (M1) is classified as ICON-S stage IV. In an exploratory training cohort (n=702), lower lymph node neck involvement had a significant effect on survival in ICON-S stage III but had no effect in ICON-S stage I and II and was not significant as an independent factor. Overall survival was similar for patients with fewer than five lymph nodes and those with five or more lymph nodes, within all ICON-S stages. INTERPRETATION: Our proposed ICON-S staging system for HPV+ oropharyngeal cancer is suitable for the 8th edition of the Union for International Cancer Control/American Joint Committee on Cancer TNM classification. Future work is needed to ascertain whether T and N categories should be further refined and whether non-anatomical factors might augment the full classification. FUNDING: None. PMID- 26936028 TI - Implant placement under existing removable dental prostheses and its effect on masticatory performance. AB - OBJECTIVE: The aim of this within-subject study was to evaluate the outcome with implant-tooth-supported removable partial dental prostheses (RPDP group) and implant-supported removable complete dental prostheses (edentulous group) in terms of masticatory performance and self-assessment. MATERIALS AND METHODS: Thirty patients participated in this prospective clinical study (RPDP group: n = 12; edentulous group: n = 18). The prostheses were supported in strategically advantageous regions by placing implants with ball attachments and corresponding matrices in the existing dentures. The masticatory performance was evaluated with the Swallowing Threshold Test Index (STTI), the number of chewing strokes, and the time needed until swallowing at pre-treatment and 6 weeks after integration of ball attachments. Additionally, patients scored chewing satisfaction before and after implantation on a visual analogue scale. RESULTS: The STTI increased significantly (p <= 0.05) after implant therapy in the edentulous group but not in the RPDP group. Furthermore, the STTI was significantly higher (p <= 0.05) in the RPDP group than in the edentulous group at pre-treatment, however, not after therapy (P > 0.05). All patients were very satisfied after therapy concerning ability of speaking, chewing, and stability of their prosthesis. CONCLUSIONS: Patients of the edentulous group benefit more from strategically placed implants under the existing dentures than patients from the RPDP group. However, according to the subjective assessment, the chewing satisfaction generally increased for both groups after implant therapy. CLINICAL RELEVANCE: Patients with a strongly reduced dentition and edentulous patients benefit from strategically placed implants under the existing removable dentures. PMID- 26936029 TI - Influence of Buffer Composition and Calcium Chloride on GdnHCl Denaturation of Bacillus licheniformis alpha-Amylase. AB - The influence of buffer composition on the conformational stability of native and calciumdepleted Bacillus licheniformis alpha-amylase (BLA) was investigated against guanidine hydrochloride (GdnHCl) denaturation using circular dichroism, fluorescence and UV-difference spectroscopy. Differential effect of buffer composition on GdnHCl denaturation of BLA was evident from the magnitude of these spectral signals, which followed the order: sodium phosphate > Tris-HCl > HEPES > MOPS. These effects became more pronounced with calcium-depleted BLA. Sephacryl S 200 gel chromatographic results showed significant BLA aggregation in the presence of 6 M GdnHCl. PMID- 26936030 TI - Number of Drinks to "Feel a Buzz" by HIV Status and Viral Load in Men. AB - The impact of HIV and its treatment on the effects of alcohol remain unclear. Blood alcohol concentrations have been noted to be higher in HIV infected individuals prior to antiretroviral initiation. Our goal was to compare number of drinks to "feel a buzz or high" among HIV infected and uninfected men, stratified by viral load (VL) suppression. Data includes 1478 HIV infected and 1170 uninfected men in the veterans aging cohort study who endorsed current drinking. Mean (SD) number of drinks to feel a buzz was 3.1 (1.7) overall. In multivariable analyses, HIV infected men reported a lower mean number of drinks to feel a buzz compared to uninfected men (coef = -14 for VL < 500; -34 for VL >= 500; p <= .05). Men with HIV, especially those with a detectable VL, reported fewer drinks to feel a buzz. Future research on the relationship between alcohol and HIV should consider the role of VL suppression. PMID- 26936031 TI - Can Nutritional Assessment Tools Predict Response to Nutritional Therapy? AB - Traditional tools and scoring systems for nutritional assessment have focused solely on parameters of poor nutritional status in the past, in an effort to define the elusive concept of malnutrition. Such tools fail to account for the contribution of disease severity to overall nutritional risk. High nutritional risk, caused by either deterioration of nutritional status or greater disease severity (or a combination of both factors), puts the patient in a metabolic stress state characterized by adverse outcome and increased complications. Newer scoring systems for determining nutritional risk, such as the Nutric Score and the Nutritional Risk Score-2002 have created a paradigm shift connecting assessment and treatment with quality outcome measures of success. Clinicians now have the opportunity to identify high risk patients through their initial assessment, provide adequate or sufficient nutrition therapy, and expect improved patient outcomes as a result. These concepts are supported by observational and prospective interventional trials. Greater clinical experience and refinement in these scoring systems are needed in the future to optimize patient response to nutrition therapy. PMID- 26936032 TI - Fighting fish parasites with photodynamically active chlorophyllin. AB - Water-soluble chlorophyll (chlorophyllin) was used in a phototoxic reaction against a number of fish ectoparasites such as Ichtyobodo, Dactylogyrus, Trichodina, and Argulus. Chlorophyllin is applied to the water at concentrations of several micrograms per milliliter for a predefined incubation time, and afterwards, the parasites are exposed to simulated solar radiation. Application in the dark caused only little damage to the parasites; likewise, light exposure without the addition of the photosensitizer was ineffective. In Ichthyobodo, 2 MUg/mL proved sufficient with subsequent simulated solar radiation to almost quantitatively kill the parasites, while in Dactylogyrus, a concentration of about 6 MUg/mL was necessary. The LD50 value for this parasite was 1.02 MUg/mL. Trichodina could be almost completely eliminated at 2 MUg/mL. Only in the parasitic crustacean Argulus, no killing could be achieved by a photodynamic reaction using chlorophyllin. Chlorophyllin is non-toxic, biodegradable, and can be produced at low cost. Therefore, we propose that chlorophyllin (or other photodynamic substances) are a possible effective countermeasure against several ectoparasites in ponds and aquaculture since chemical remedies are either forbidden and/or ineffective. PMID- 26936033 TI - Mass concentration in a nonlocal model of clonal selection. AB - Self-renewal is a constitutive property of stem cells. Testing the cancer stem cell hypothesis requires investigation of the impact of self-renewal on cancer expansion. To better understand this impact, we propose a mathematical model describing the dynamics of a continuum of cell clones structured by the self renewal potential. The model is an extension of the finite multi-compartment models of interactions between normal and cancer cells in acute leukemias. It takes a form of a system of integro-differential equations with a nonlinear and nonlocal coupling which describes regulatory feedback loops of cell proliferation and differentiation. We show that this coupling leads to mass concentration in points corresponding to the maxima of the self-renewal potential and the solutions of the model tend asymptotically to Dirac measures multiplied by positive constants. Furthermore, using a Lyapunov function constructed for the finite dimensional counterpart of the model, we prove that the total mass of the solution converges to a globally stable equilibrium. Additionally, we show stability of the model in the space of positive Radon measures equipped with the flat metric (bounded Lipschitz distance). Analytical results are illustrated by numerical simulations. PMID- 26936035 TI - The value of local normal limits in quantitative Thallium-201 CZT MPI SPECT. AB - BACKGROUND: Considering the distinctive characteristics of CZT detectors, automatic quantification of ischemia using normal limits included with software package may deliver suboptimal results for CAD detection. The present study aims to evaluate the benefits of creating normal limits specific to a local population and laboratory protocol. METHODS AND RESULTS: Two groups were selected from patients who had undergone a CZT MPI. Normal limits were generated with the QPS application based on the population with low likelihood of CAD. Using the vendor supplied and the population-specific normal limits i-TPD and vessel-specific SDS results obtained for patients who had subsequently undergone coronary angiography were compared with coronary angiography data. A weak correlation was observed for low i-TPD (stress TPD minus rest TPD) and SDS values. Both databases gave similar values for the area under the ROC curve concerning i-TPD (0.75 to 0.74) and SDS results (0.72 to 0.75 for the LAD, 0.62 to 0.64 for the LCx, and 0.63 to 0.67 for the RCA). Sensitivity (60%), specificity (78%), and predictive positive (84%) and negative (52%) values were also similar with a diagnostic and prognostic threshold value. CONCLUSION: The use of a population-specific created database did not influence the diagnostic value of thallium-201 MPI QPS results using a CZT camera. PMID- 26936036 TI - Associations between Infant Behaviors during the Face-To-Face Still-Face Paradigm and Oppositional Defiant and Callous-Unemotional Behaviors in Early Childhood. AB - Deficits in social orienting (i.e., gazing toward caregivers) during dyadic interactions and reactivity to stressful stimuli have been identified as behavioral correlates of oppositional defiant disorder (ODD) and callous unemotional (CU) behaviors in older children. The goal of the current study was to investigate infants' mother-directed gaze and reactivity during the face-to face and still-face episodes of the face-to-face stillface paradigm performed at 6 months in the prediction of ODD and CU behaviors in early childhood. Using data from the Durham Child Health and Development study (n = 206), hierarchical regression analyses revealed that infants' negative reactivity during the still face episode and mother-directed gaze during the face-to-face episode predicted fewer ODD behaviors in early childhood. Examination of interaction effects suggested that mother-directed gaze attenuated the negative relation between reactivity and ODD and CU behaviors in early childhood. The current study is one of the first to extend downward the investigation of ODD and CU behaviors into infancy. PMID- 26936038 TI - Septic patients with mitochondrial DNA haplogroup JT have higher respiratory complex IV activity and survival rate. AB - OBJECTIVE: The influence of mitochondrial deoxyribonucleic acid (mtDNA) haplogroup or oxidative phosphorylation system (OXPHOS) function on survival of septic patients has been scarcely studied. However, the association between mtDNA haplogroup, OXPHOS capacity at diagnosis of severe sepsis, and survival has been not previously reported, and that was the objective of the present study. METHODS: This was a prospective, multicenter, observational study. Blood samples from 198 patients at diagnosis of severe sepsis were analyzed to determine mtDNA haplogroup and platelet respiratory complex IV (CIV) specific activity. The end point of the study was 30-day survival. RESULTS: Septic patients with mtDNA haplogroup JT showed higher 30-day survival than those with mtDNA haplogroup non JT (31/38 [81.6%] vs 99/160 [61.9%]; P= .02). Septic patients with mtDNA haplogroup JT showed higher platelet CIV specific activity than those with mtDNA haplogroup non-JT (P= .002). CONCLUSIONS: The main novel finding of our study, including the largest series providing data on platelet CIV specific activity according to mtDNA haplogroup in severe septic patients, was that those with mtDNA haplogroup JT showed higher survival and higher platelet CIV specific activity at diagnosis of severe sepsis than patients with mtDNA haplogroup non JT. PMID- 26936037 TI - Preschool Neuropsychological Measures as Predictors of Later Attention Deficit Hyperactivity Disorder. AB - The present study examined preschool neuropsychological measures as predictors of school-age attention deficit hyperactivity disorder (ADHD). Participants included 168 children (91 males) who completed neuropsychological measures at ages 3 and 4, and who were evaluated for ADHD and oppositional defiant disorder at age 6. The Conners' Kiddie Continuous Performance Test (K-CPT), NEPSY Statue subtest, and a delay aversion task significantly distinguished at-risk children who later did and did not meet criteria for ADHD, with poor to fair overall predictive power, specificity, and sensitivity. However, only the K-CPT ADHD Confidence Index and battery added incremental predictive validity beyond early ADHD symptoms. This battery approach, which required impairment on at least 2 of the 3 significant measures, yielded fair overall predictive power, specificity, and sensitivity, and correctly classified 67 % of children. In addition, there was some support for the specificity hypothesis, with evidence that cool executive function measures (K-CPT and Statue subtest) tended to predict inattentive symptoms. These findings suggest that neuropsychological deficits are evident by preschool-age in children with ADHD, but neuropsychological tests may still misclassify approximately one-third of children if used alone. Thus, neuropsychological measures may be a useful component of early ADHD assessments, but should be used with caution and in combination with other assessment methods. PMID- 26936039 TI - Remote ischemic conditioning for kidney protection: A meta-analysis. AB - BACKGROUND: Results from randomized controlled trials (RCTs) concerning kidney effect of remote ischemic conditioning (RIC) are inconsistent. METHODS: We searched for relevant studies in Medline, Embase, the Cochrane Library, Google Scholar and Chinese database (SinoMed), as well as relevant references from their inception to November 2015. We performed a systematic review and meta-analysis of all eligible RCTs of RIC with kidney events. RESULTS: We included 37 RCTs from 2007 to 2015 involving 8168 patients. Pooled analyses of all RCTs showed RIC significantly reduced the incidence of investigator-defined acute kidney injury (AKI) compared with control groups (RR 0.84, 95% CI 0.73-0.96, P = .009) (I(2) = 25%). However, the difference was not significant when only RIFLE (Risk, Injury, Failure, Loss, End Stage), AKIN (Acute Kidney Injury Network), or KDIGO (Kidney Disease Improving Global Outcomes) criteria were applied to the definition of AKI (RR 0.87, 95% CI 0.74-1.02, P = .08) (I(2) = 22%). In subgroup analysis, RIC showed a significant benefit on reducing investigator-defined AKI in patients following percutaneous coronary intervention (RR 0.64, 95% CI 0.46-0.87), but not after cardiac surgery (RR 0.93, 95% CI 0.82-1.06). There was no difference for changes in the incidence of renal replacement therapy, estimated glomerular filtration rate or serum creatinine. CONCLUSIONS: RIC might be beneficial for the prevention of investigator-defined AKI; however, the effect is likely small. Moreover, due to lack of an effect on use of renal replacement therapy, estimated glomerular filtration rate, RIFLE, AKIN, or KDIGO-defined AKI, and serum creatinine, the evidence for RIC is not robust. Finally, recent large-scale RCTs of RIC focusing on patient-centered outcomes do not support the wider application of RIC. PMID- 26936040 TI - Extended daily dialysis versus intermittent hemodialysis for acute kidney injury: A systematic review. PMID- 26936034 TI - Immune and regulatory functions of neutrophils in inflammatory bone loss. AB - Although historically viewed as merely anti-microbial effectors in acute infection or injury, neutrophils are now appreciated to be functionally versatile with critical roles also in chronic inflammation. Periodontitis, a chronic inflammatory disease that destroys the tooth-supporting gums and bone, is particularly affected by alterations in neutrophil numbers or function, as revealed by observations in monogenic disorders and relevant mouse models. Besides being a significant debilitating disease and health burden in its own right, periodontitis is thus an attractive model to dissect uncharted neutrophil associated (patho)physiological pathways. Here, we summarize recent evidence that neutrophils can contribute to inflammatory bone loss not only through the typical bystander injury dogma but intriguingly also through their absence from the affected tissue, where they normally perform important immunomodulatory functions. Moreover, we discuss recent advances in the interactions of neutrophils with the vascular endothelium and - upon extravasation - with bacteria, and how the dysregulation of these interactions leads to inflammatory tissue damage. Overall, neutrophils have both protective and destructive roles in periodontitis, as they are involved in both the maintenance of periodontal tissue homeostasis and the induction of inflammatory bone loss. This highlights the importance of developing approaches that promote or sustain a fine balance between homeostatic immunity and inflammatory pathology. PMID- 26936041 TI - Measurement of pulmonary artery to aorta ratio in computed tomography is correlated with pulmonary artery pressure in critically ill chronic obstructive pulmonary disease patients. AB - AIM: Chronic obstructive pulmonary disease (COPD) is one of the leading chronic diseases and a common cause of death. Identification of COPD patients at high risk for complications and mortality is of utmost importance. Computed tomography (CT) can be used to measure the ratio of the diameter of the pulmonary artery (PA) to the diameter of the aorta (A), and PA/A ratio was shown to be correlated with PA pressure (PAP). However, the prognostic value of PA size remains unclear in patients with COPD. We hypothesized that PA enlargement, as shown by a PA/A ratio greater than 1, could be associated with a higher risk of mortality in COPD patients admitted to the intensive care unit. METHODS: Data of patients admitted to a medical intensive care unit of a university hospital were retrospectively reviewed between January 2008 and December 2012. Patients who were identified to have a diagnosis of acute exacerbation of COPD and who had an echocardiogram and CT scan were included. Pulmonary artery to aorta ratio was calculated and patients were grouped as PA/A <=1 and PA/A >1. Comparisons were made between the groups and between patients who died and survived. Correlation analysis, survival analysis, and logistic regression analysis were done, where appropriate. RESULTS: One hundred six COPD patients were enrolled. There were 40 (37.4%) patients who had a PA/A >1. Echocardiography measured PAP was higher in the group with PA/A >1 than in those with PA/A <=1 (62.1 +/- 23.2 mm Hg vs 45.3 +/- 17.9 mm Hg, P = .002). Mortality rate of patients with PA/A >1 was higher (50%) than of those patients with PA/A <=1 (36.4%), although the difference did not reach a statistical significance (P = .17). Correlation was found between vmeasured PA diameter and PAP (r = 0.51, P = .001) as well as between the Acute Physiology and Chronic Health Evaluation II values and PAP (r = 0.25, P = .025). CONCLUSION: The PA/A ratio is an easily measured method that can be performed on thorax CT scans. Although, we failed to demonstrate a statistically significant association between higher PA/A and increased mortality, PA/A can be used as a surrogate marker to predict the pulmonary hypertension. PMID- 26936042 TI - High-throughput determination of dissolved free amino acids in unconcentrated freshwater by ion-pairing liquid chromatography and mass spectrometry. AB - We developed a procedure for the direct determination of dissolved free amino acids (DFAAs) in freshwater samples employing ion-pairing liquid chromatography and mass spectrometry. Our approach allowed accurate quantification of subnanomolar concentrations of DFAAs without prior concentration, derivatization or sample clean-up steps, achieving a throughput of three samples per hour. DFAAs were separated on a C-18 resin using tridecafluoroheptanoic acid as an ion pairing agent controlling the overall retention. The relative standard deviation of DFAA measurements was <10% in samples from the mesotrophic Lake Zurich (Switzerland), and across concentrations of 0.5-500nM. Recoveries of DFAAs ranged from 94 to 102% within the range of 0.2-10nM. The limits of quantification for individual DFAAs varied between 50pM to 2nM (median, 0.5nM). The new method was employed to compare the spatial variability of DFAA concentrations in samples obtained by two devices. Epilimnetic samples of different size (ml, l) were collected at various spatial scales (cm, m, km) with a traditional 5l Friedinger sampler and with a custom-made multi-syringe sampling apparatus. Concentrations of total DFAAs ranged from 30 to 330nM. Alanine, serine, glutamic acid, arginine and glycine constituted 65% of the total pool, while methionine and tryptophan occurred at sub-nM concentrations only. Concentrations of individual DFAAs varied spatially over 2 orders of magnitude. Their spatial distribution was positively skewed, as characterized by rare peaks, most strongly so for glutamate, glycine and asparagine. The composition of DFAAs significantly differed at all examined spatial scales, and this could be mainly attributed to alanine, aspartic acid, and glycine. Our new method equals or outperforms existing ones in terms of sensitivity and reproducibility, while its procedural simplicity renders it superior for the high-throughput analysis of freshwater samples. PMID- 26936043 TI - Factors influencing willingness to participate in new drug trial studies: a study among parents whose children were recruited into these trials in northern Ghana. AB - BACKGROUND: During the last decade, the number of clinical trials conducted in sub-Saharan Africa has increased significantly which has helped to address priority health problems in the region. Navrongo health research centre since it was established in 1989, has conducted several trial studies including rectal artesunate trial in the Kassena-Nankana districts. However, there is little evidence-based for assessing the impact of new drug trials. This study explored factors that motivate parents to allow their children to participate in new drug trials in northern Ghana. METHOD: The study used both quantitative and qualitative methods. The participants were randomly selected from among parents whose children were enrolled in a new drug trial conducted in the Kassena-Nankana districts between 2000 and 2003. QSR Nvivo 9 software was used to code the qualitative data into themes before analysis while STATA software Version 11.2(c) was used to analyze the quantitative data. RESULTS: The results showed that majority (95.9%) of the parents were willing to allow their children to be enrolled in future new drug trials. The main factors motivating their willingness to allow their children to be enrolled in these trials were quality of health care services offered to trial participants (92.9%), detail medical examination (90.8%), promptness of care provided (94.4%) and quality of drugs (91.9%). Other factors mentioned included disease prevention (99.5%) and improved living standard (96.1%). Parents reported that the conduct of these trials had reduced the frequency of disease occurrences in the communities because of the quality of health care services provided to the children recruited into these trial studies. CONCLUSION: Though the implementation of clinical trials in the study area is believed to have positive impact on health status of people particularly trial participants, measures should however be taken to address safety and likely side effects of new drugs given to trial participants during these trial studies. PMID- 26936046 TI - Terpenoid Composition and Base Sequences of Ligularia virgaurea (Asteraceae) Grown in the Hengduan Mountain Area in China and a Comment on Drawing Structures. AB - A chemical analysis of 30 samples of Ligularia virgaurea (Asteraceae) collected in Sichuan province and its adjacent territories in China was reviewed. These samples afforded 146 compounds, 73 of which were novel, and the chemical constituents were classified into 8 categories: (1) simple eremophilanes (without ring C) and eudesmanes including nor-derivatives, (2) furanoeremophilanes and lactones with a 1(10)-saturated bond, (3) furanoeremophilanes and lactones with a 1(10)-unsaturated bond, 1,10-epoxide, or 10-ol, (4) furanoeremophilanes and lactones with 1(10)-en-2-one, 1(10)-en-2-ol, or 1-en-3-one, (5) furanoeremophilanes and lactones with 1(10)-en-9-one, 1(10)-en-9-ol, or 1,10 epoxy-9-one, (6) cacalol and their derivatives, (7) bakkanes and their derivatives, and (8) others, as shown in Tables 1-7. In these studies, five chemotypes were identified in addition to three clades from the DNA sequences of L. virgaurea. The structural determination of some compounds was also discussed and a comment on how to express the real structure was proposed, particularly for spiro compounds. PMID- 26936044 TI - Quantitative Prediction of Drug Interactions Caused by CYP1A2 Inhibitors and Inducers. AB - BACKGROUND: A simple method to predict drug-drug interactions mediated by cytochrome P450 enzymes (CYPs) on the basis of in vivo data has been previously applied for several CYP isoforms but not for CYP1A2. The objective of this study was to extend this method to drug interactions caused by CYP1A2 inhibitors and inducers. METHODS: First, initial estimates of the model parameters were obtained using data from the literature. Then, an external validation of these initial estimates was performed by comparing model-based predicted area under the concentration-time curve (AUC) ratios with observations not used in the initial estimation. Third, refined estimates of the model parameters were obtained by Bayesian orthogonal regression using Winbugs software, and predicted AUC ratios were compared with all available observations. Finally, predicted AUC ratios for all possible substrates-inhibitors and substrates-inducers were computed. RESULTS: A total of 100 AUC ratios were retrieved from the literature. Model parameters were estimated for 19 CYP1A2 substrate drugs, 26 inhibitors and seven inducers, including tobacco smoking. In the external validation, the mean prediction error of the AUC ratios was -0.22, while the mean absolute error was 0.97 (37 %). After the Bayesian estimation step, the mean prediction error was 0.11, while the mean absolute error was 0.43 (22 %). The AUC ratios for 625 possible interactions were computed. CONCLUSION: This analysis provides insights into the interaction profiles of drugs poorly studied so far and can help to identify and manage significant interactions in clinical practice. Those results are now available to the community via a web tool ( http://www.ddi-predictor.org ). PMID- 26936047 TI - The Role of an Impurity in Ceftriaxone Sodium Preparation for Injection in Determining Compatibility with Calcium-Containing Solutions. AB - Ceftriaxone sodium preparation for injection is known to form insoluble microparticles with calcium. The purpose of this study was to evaluate the role of an impurity in the ceftriaxone sodium preparation on this incompatibility. Firstly, using HPLC, two impurities were identified in the ceftriaxone sodium solution. The major impurity (impurity 1) was identified as tetrahydro-2-methyl-3 thioxo-1,2,4-triazine-5,6-dione by LC/MS. Secondly, the role played by this impurity in the incompatibility with calcium was examined. Using seven different ceftriaxone preparations for injection, the effect of adding impurity 1 to mixed solutions of ceftriaxone sodium and calcium chloride on the appearance of insoluble microparticles, was examined using a light obscuration particle counter. Although incompatibility was not completely suppressed by the addition of impurity 1, the number of insoluble microparticles formed with calcium chloride solution was decreased in proportion to the concentration of impurity 1, and the concentration of calcium ion decreased as the concentration of added impurity 1 increased. These results show that impurity 1 plays a concentration dependent role in incompatibility between ceftriaxone sodium preparation for injection and calcium-containing solutions. PMID- 26936048 TI - A Novel Scale Up Model for Prediction of Pharmaceutical Film Coating Process Parameters. AB - In the pharmaceutical tablet film coating process, we clarified that a difference in exhaust air relative humidity can be used to detect differences in process parameters values, the relative humidity of exhaust air was different under different atmospheric air humidity conditions even though all setting values of the manufacturing process parameters were the same, and the water content of tablets was correlated with the exhaust air relative humidity. Based on this experimental data, the exhaust air relative humidity index (EHI), which is an empirical equation that includes as functional parameters the pan coater type, heated air flow rate, spray rate of coating suspension, saturated water vapor pressure at heated air temperature, and partial water vapor pressure at atmospheric air pressure, was developed. The predictive values of exhaust relative humidity using EHI were in good correlation with the experimental data (correlation coefficient of 0.966) in all datasets. EHI was verified using the date of seven different drug products of different manufacturing scales. The EHI model will support formulation researchers by enabling them to set film coating process parameters when the batch size or pan coater type changes, and without the time and expense of further extensive testing. PMID- 26936049 TI - Tablet Velocity Measurement and Prediction in the Pharmaceutical Film Coating Process. AB - The purpose of this study was to measure the tablet velocity in pan coating machines during the film coating process in order to understand the impact of the batch size (laboratory to commercial scale), coating machine type (DRIACOATER, HICOATER(r) and AQUA COATER(r)) and manufacturing conditions on tablet velocity. We used a high speed camera and particle image velocimetry to measure the tablet velocity in the coating pans. It was observed that increasing batch sizes resulted in increased tablet velocities under the same rotation number because of the differences in circumferential rotation speeds. We also observed the tendency that increase in the filling ratio of tablets resulted in an increased tablet velocity for all coating machines. Statistical analysis was used to make a tablet velocity predictive equation by employing the filling ratio and rotation speed as the parameters from these measured values. The correlation coefficients of predicted value and experimental value were more than 0.959 in each machine. Using the predictive equation to determine tablet velocities, the manufacturing conditions of previous products were reviewed, and it was found that the tablet velocities of commercial scales, in which tablet chipping and breakage problems had occurred, were higher than those of pilot scales or laboratory scales. PMID- 26936045 TI - Drug Interactions with Lithium: An Update. AB - Lithium has been used for the management of psychiatric illnesses for over 50 years and it continues to be regarded as a first-line agent for the treatment and prevention of bipolar disorder. Lithium possesses a narrow therapeutic index and comparatively minor alterations in plasma concentrations can have significant clinical sequelae. Several drug classes have been implicated in the development of lithium toxicity over the years, including diuretics and non-steroidal anti inflammatory compounds, but much of the anecdotal and experimental evidence supporting these interactions is dated, and many newer medications and medication classes have been introduced during the intervening years. This review is intended to provide an update on the accumulated evidence documenting potential interactions with lithium, with a focus on pharmacokinetic insights gained within the last two decades. The clinical relevance and ramifications of these interactions are discussed. PMID- 26936050 TI - Identification of 2-[2-(4-tert-Butylphenyl)ethyl]-N-[4-(3-cyclopentylpropyl)-2 fluorophenyl]-1,2,3,4-tetrahydroisoquinoline-6-sulfonamide as an Orally Active MGAT2 Inhibitor. AB - We previously reported 2-[2-(4-tert-butylphenyl)ethyl]-N-(4-fluorophenyl)-1,2,3,4 tetrahydroisoquinoline-6-sulfonamide 2 as on orally available monoacylglycerol acyltransferase 2 (MGAT2) inhibitor which exhibited an in vivo efficacy at an oral dose of 100 mg/kg in a mouse oral lipid tolerance test. Further optimization of compound 2 to improve the intrinsic potency culminated in the identification of compound 11. Compound 11 showed a >50-fold lower IC50 against human MGAT2 enzyme than 2. Oral administration of 11 at a dose of 3 mg/kg in the oral lipid tolerance test resulted in significant suppression of triglyceride synthesis. PMID- 26936051 TI - Synthesis and Absolute Configuration of Acanthodendrilline, a New Cytotoxic Bromotyrosine Alkaloid from the Thai Marine Sponge Acanthodendrilla sp. AB - Acanthodendrilline (1), a new bromotyrosine alkaloid, was isolated from the Thai marine sponge Acanthodendrilla sp. The structure of 1 was fully characterized by spectroscopic analysis, in agreement with the synthesized compound used to resolve the single chiral center at C-11. Total synthesis of the enantiomers of 1 allowed for the comparison of specific rotation values and hence the determination of the absolute configuration as 11-S. Cytotoxicity evaluation revealed that (S)-1 exhibited approximately three-fold more potent cytotoxicity against the human non-small cell lung cancer H292 cell line than (R)-1. PMID- 26936052 TI - Four Cytotoxic Spongian Diterpenes from the Sponge Dysidea cf. arenaria. AB - Chemical analysis of the sponge Dysidea cf. arenaria from Irabu Island provided four new diterpenes 1-4. Their structures were elucidated by NMR and other spectroscopic analyses. All the metabolites retained the spongian skeleton and an isovalerate ester, but were different from those previously isolated from a specimen of Okinawa Island, implying geographic variation. The cytotoxicity of compounds 1-4 to NBT-T2 cells was evaluated and their IC50 values were 3.1, 1.9, 8.4, and 3.1 uM, respectively. PMID- 26936053 TI - DNA Topoisomerase Inhibitory Activity of Constituents from the Flowers of Inula japonica. AB - Fourteen compounds were isolated from the flowers of Inula japonica THUNB. (Asteraceae), including two new compounds, (1S,2S,4S,5S,8S,10R)-2-acetoxy-4,3 dihydroxy-pseudoguai-7(11)-en-12,8-olide (1) and (1S,2S,4S,5S,8S,10R)-2,4,13 trihydroxy-pseudoguai-7(11)-en-12,8-olide (2), and twelve known compounds, budlein B (3), 6beta-hydroxytomentosin (4), 6-deacetoxybritanin (5), 4 epipulchellin (6), britanin (7), tomentosin (8), (+)-dihydroquercetin (9), (-) syringaresinol (10), quercetagetin 3,4'-dimethyl ether (11), luteolin (12), britanin G (13) and inuchinenolide C (14). Structures of 1 and 2 were determined based on one and two dimensional (1D)- and (2D)-NMR data and Mosher's esterification method. Compounds 9 and 12 showed inhibitory activities toward DNA topoisomerase I with IC50 values of 55.7 and 37.0 uM, respectively, compared to camptothecin (CPT) with an IC50 of 24.5 uM. Compounds 7-9 and 11-14 exhibited more potent inhibitory activity against topoisomerases II with IC50 values of 6.9, 3.8, 3.0, 6.9, 10.0, 14.7 and 13.8 uM, respectively, than that of etoposide (VP-16) with an IC50 of 26.9 uM. Compounds 4-7 and 10-14 exhibited weak cytotoxicities to the selected cancer cell lines. PMID- 26936054 TI - DNA Interaction and Cytotoxicity of Cyclometalated Ruthenium(II) Complexes as Potential Anticancer Drugs. AB - To evaluate the anticancer activity of the cyclometalated ruthenium(II) complexes [Ru(bpy)2(C^N)]Cl, we have studied the interaction of these complexes using calf thymus DNA (CT-DNA) and cytotoxicity assays with two tumor (L1210 and HeLa) and a non-tumor (BALB/3T3 clone A31) cell lines. It is suggested that the complexes act as intercalators and/or DNA minor groove binders. Moreover, the complexes display favorable cytotoxicity activities with L1210 and HeLa, which in all cases were significantly more favorable than cisplatin. In contrast, the complexes exhibit appreciably lower cytotoxicity toward BALB/3T3 clone A31. PMID- 26936055 TI - Errata for Chemical and Pharmaceutical Bulletin. PMID- 26936056 TI - Erratum to: Structural characteristics of ScBx genes controlling the biosynthesis of hydroxamic acids in rye (Secale cereale L.). PMID- 26936058 TI - Guanfacine Use in Children With Down Syndrome and Comorbid Attention-Deficit Hyperactivity Disorder (ADHD) With Disruptive Behaviors. AB - The purpose of this study was to characterize children with Down syndrome and attention-deficit hyperactivity disorder (ADHD) with disruptive behaviors using the Aberrant Behavior Checklist (ABC), and to measure the treatment effects of guanfacine on maladaptive behaviors. Subjects were enrolled from a group of outpatients who visited our clinic between 2002 and 2007. Subjects (N = 23) were children with Down syndrome ages 4 to 12 years (mean 7.4 +/- 4.1), who met criteria for ADHD according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition The Aberrant Behavior Checklist Irritability and Hyperactivity subscales each showed a significant decrease (P < .0001) at follow up. The mean decline on Hyperactivity was 25% (-7.8 points), and for Irritability, 25% (-3.5 points). The mean composite score also declined by 24% ( 12 points). Effect size differences on Irritability were moderate, whereas differences on Hyperactivity and composite score appeared large. Clinically important target behaviors were reduced. Medication was generally well tolerated and the incidence of treatment emergent side effects remained low. PMID- 26936057 TI - A Canadian qualitative study exploring the diversity of the experience of family caregivers of older adults with multiple chronic conditions using a social location perspective. AB - BACKGROUND: A little-studied issue in the provision of care at home by informal caregivers is the increase in older adult patients with chronic illness, and more specifically, multiple chronic conditions (MCC). We know little about the caregiving experience for this population, particularly as it is affected by social location, which refers to either a group's or individual's place/location in society at a given time, based on their intersecting demographics (age, gender, education, race, immigration status, geography, etc.). We have yet to fully comprehend the combined influence of these intersecting axes on caregivers' health and wellbeing, and attempt to do this by using an intersectionality approach in answering the following research question: How does social location influence the experience of family caregivers of older adults with MCC? METHODS: The data presented herein is a thematic analysis of a qualitative sub-set of a large two-province study conducted using a repeated-measures embedded mixed method design. A survey sub-set of 20 survey participants per province (n = 40 total) were invited to participate in a semi-structured interview. In the first stage of data analysis, Charmaz's (2006) Constructivist Grounded Theory Method (CGTM) was used to develop initial codes, focused codes, categories and descriptive themes. In the second and the third stages of analysis, intersectionality was used to develop final analytical themes. RESULTS: The following four themes describe the overall study findings: (1) Caregiving Trajectory, where three caregiving phases were identified; (2) Work, Family, and Caregiving, where the impact of caregiving was discussed on other areas of caregivers' lives; (3) Personal and Structural Determinants of Caregiving, where caregiving sustainability and coping were deliberated, and; (4) Finding Meaning/Self in Caregiving, where meaning-making was highlighted. CONCLUSIONS: The intersectionality approach presented a number of axes of diversity as comparatively more important than others; these included gender, age, education, employment status, ethnicity, and degree of social connectedness. This can inform caregiver policy and programs to sustain health and well-being. PMID- 26936059 TI - Functional Outcome of School Children With History of Global Developmental Delay. AB - This study aimed to investigate the functional and developmental outcomes in school age children diagnosed with global developmental delay before 2 years old and to verify the association between their final diagnosis and environmental and biological factors. Forty-five Brazilian children (26 boys), mean age 95.84 (7.72) months, who attended regular school and were diagnosed with global developmental delay before they were 2 years old had their functions evaluated. Children with global developmental delay were diagnosed with several conditions at school age. Students with greater chances of receiving a diagnosis were those whose mothers were younger at the time their children were born (OR = 1.47, CI = 1.04-2.09, P = .03), who had impaired motor performance, specially balance (OR = 1.33, CI = 1.01-1.75, P = .04), and who needed help during cognitive and behavioral tasks at school (OR = 1.08, CI = 1.00-1.17, P = .048). Interdisciplinary evaluation contributed to defining the specific diagnosis and to identifying the necessity of specialized support. PMID- 26936060 TI - Osteochondral Fractures of the Knee in Skeletally Immature Patients: Short-Term Results of Operative Fixation using Omnitech Screws. AB - PURPOSE OF THE STUDY: Retrospective case series looking at the use of Omnitech compression screws for the management of osteochondral fractures in skeletally immature patients. MATERIAL AND METHODS: Nine patients with a mean age of 14 were included in the study with a mean follow up of 26 months. RESULTS: The average KOOS, IKDC and Tegner Lysholm Scores were 86.7, 90.34 and 96.1 respectively. CONCLUSION: The use of Omnitech screws in the acute setting for skeletally immature patients shows excellent short-term outcomes. PMID- 26936061 TI - Musculoskeletal Pain and Vitamin D Deficiency in Children: A Pilot Follow-up Study of Vitamin D Therapy in Musculoskeletal/Orthopedic Conditions. AB - PURPOSE OF THE STUDY: The prevalence of vitamin D deficiency in pediatric populations is high. In the present study we analyzed associations between vitamin D therapy and pain, mobility, fatigue, and daily functioning in children with musculoskeletal/orthopedic conditions suffering from chronic and recurrent pain, but also diagnosed with vitamin D deficiency. MATERIAL AND METHODS: Children with different musculoskeletal/orthopedic conditions and vitamin D deficiency were prescribed to receive vitamin D over 6 months. Thirty-five children (18 males; age 10.48 +/- 3.87 years) completed a 6-month follow-up. Self and parent/proxy rating scales were used to evaluate pain, movement, fatigue, and daily functioning. RESULTS: At a six-month follow-up assessment involving child- and parent-reported scores, worst pain intensity significantly decreased (p <= 0.03) after vitamin D therapy, as well as functioning problems related to pain (p <= 0.01). The children reported better movement and balance with less fatigue. The parents reported better functioning in everyday activities of their children. CONCLUSION: This pilot study showed that vitamin D therapy possibly reduces pain intensity and improves mobility and daily functioning in children with musculoskeletal/orthopedic disorders, chronic recurrent pain, and vitamin D deficiency. Further follow-up and randomized studies are required in order to assess the validity of clinical recommendations. PMID- 26936062 TI - [Surgical Treatment for Advanced Rhizarthrosis. Comparison of Results of the Burton-Pellegrini Technique and Trapeziometacarpal Joint Arthroplasty]. AB - PURPOSE OF THE STUDY: The aim of the study was to compare results of the Burton Pellegrini trapeziectomy with ligamentoplasty using the flexor carpi radialis tendon with those of trapeziometacarpal joint replacement in the treatment of advanced rhizarthrosis. MATERIAL AND METHODS: A group of 17 patients, 15 men and two women, underwent trapeziectomy with ligamentoplaty; in 12 of them, the dominant hand was involved. The trapeziometacarpal joint prosthesis Beznoska was implanted in 11 patients (10 men and one woman) with seven dominant and four non dominant hands. All patients pre-operatively experienced pain during thumb movement and hand grip. They were examined before surgery and at 3, 6 and 12 months after it; the values obtained before and at 1 year after surgery were compared. The methods of evaluation included pain intensity assessed using the visual analogue scale (VAS), the Kapandji thumb opposition test and the disabilities of the arm, shoulder and hand (DASH) score (total DASH score and its thumb-targeted module). RESULTS: In the group treated by the Burton-Pellegrini procedure, the average pre- and post-operative Kapandji scores were 6.4 and 8.9, respectively. The average VAS scores were 5/10 pre-operatively and 1/10 post operatively. The average values for the total pre- and post-operative DASH scores were 58 and 19 points, respectively. The DASH score in a thumb-targeted module assessing basal joint-loading in the thumb was 63 points before and 21 points after surgery. In the patients with total joint replacement, the average pre- and post-operative values were as follows: Kapandji score, 7.4 and 9.8; VAS score, 5/10 and 1/10; total DASH score, 56 and 7 points; thumb module DASH score, 60 and 11 points. Two serious complications were recorded, an infection in resection interposition arthroplasty and a trauma associated with total joint replacement loosening. Four patients showed transient paresthesia. DISCUSSION: Several methods for surgical treatment of rhizarthrosis are available today. Arthrodesis is still a widely used procedure although it inhibits thumb movements. Resection arthroplasty provides sufficient pain-free thumb motion, but radial shortening and a loss of grip strength are its disadvantages. Resection interposition arthroplasty results in sufficient painless motion. Tendon interposition provides enough stability for the thumb and for sufficient grip and pinch strength. The disadvantages of this method include a potential for failure of the suspensory tendon during over exercising or a weakened attachment of the autologous tendon to the bone and thus a risk of rupture. Total joint replacement respects the thumb anatomy, preserves the articular capsule and fibrous structures during conservative resection of joint surfaces and keeps the biomechanics of the basal joint of the thumb. It combines advantages of the other surgery procedures, by allowing for a painless range of motion in the joint and vital pinching and gripping abilities, while avoiding their disadvantages such as movement restriction and loss of grip strength. However, the technique may still bear any of the risks associated with foreign material implantation (dislocation, replacement failure, infection, etc.). CONCLUSIONS: The two techniques present valuable contributions to the treatment of advanced rhizarthrosis. In our patients, better outcomes are shown in trapeziometacarpal joint replacement though, in comparison with resection interposition arthroplasty, the indication criteria for this surgery are limited by factors such as the height of the trapezium bone and bone quality necessary for good osseointegration. PMID- 26936063 TI - [Double Osteotomy of the First Metatarsal for Treatment of Juvenile Hallux Valgus Deformity - Our Experience]. AB - PURPOSE OF THE STUDY: The aim of the study was to evaluate the mid-term results in a group of selected patients undergoing corrective surgery for juvenile hallux valgus, using double osteotomy of the first metatarsal. MATERIAL AND METHODS: The group included eight patients, seven girls and one boy, with a more severe form of this deformity treated by double osteotomy of the first metatarsal between 2010 and 2013. The indication for corrective surgery was serious pain when walking; all patients had previously undergone conservative treatment with no effect. All patients had pre-operative clinical examination, the affected foot was X-rayed with the patient standing and radiographic assessments of the intermetatarsal and hallux valgus angles were made. The evaluation of treatment outcomes was based on the scoring system of the American Orthopaedic Foot and Ankle Society (AOFAS) and X-ray images of the foot. The average follow-up was 37 months. RESULTS: Post-operatively, none of the patients reported pain while walking, only two of them experienced pain during sports activities. The average post-operative AOFAS score was 92 points. Both the intermetatarsal angle and the hallux valgus angle improved after surgery in all patients, with two reporting only mild hallux valgus deformity. One patient showed postoperative restriction of motion at the first metatarsophalangeal joint. This was the only complication recorded in association with the surgery. DISCUSSION: Almost all authors dealing with the treatment of hallux valgus deformity primarily prefer conservative therapy. However, this treatment is usually not very effective in severe forms of the disorder. Surgical management is indicated in symptomatic patients or in those with severe juvenile hallux valgus deformity. In paediatric patients it is necessary to respect the presence of an epiphyseal growth plate in the first proximal metatarsal and therefore it is often preferred to use distal first metatarsal osteotomy. At our department, Mitchell's osteotomy for hallux valgus deformity is usually used. However, post-operative outcomes are not satisfactory in severe forms of juvenile hallux valgus in which a high proportion of recurrent deformities is probably related to the growth potential of a juvenile bone. In such cases we use the Peterson and Newman procedure of double first metatarsal osteotomy, which can correct all three components of the deformity while maintaining functional first metatarsal length. This is a great advantage of the method. Although its authors have not reported any post-operative complications, the occurrence of restricted motion in the first metatarsophalangeal joint has been described in the relevant literature. The problem was also recorded in one patient of our group. CONCLUSIONS: Deformities of the forefoot and big toe are frequent orthopaedic disorders in children and adolescents. The results of this study confirm that the double first metatarsal osteotomy is an effective method of surgical treatment for serious hallux valgus deformities in paediatric and adolescent patients. PMID- 26936064 TI - [Anterior Superior and Anterior Interior Iliac Spine Fractures. Comparison of the Results of Conservative and Surgical Treatment]. AB - PURPOSE OF THE STUDY: Avulsion fractures of the anterior superior iliac spine (ASIS) and anterior inferior iliac spine (AIIS) are rare injuries to the skeleton in children. They are most frequent in adolescent athletes, such as sprinters and long-distance runners, and football players. The authors present a group of patients treated at their department and compare the results of procedures used to manage different pelvic avulsion fractures. MATERIAL AND METHODS: Between 2005 and 2012, 38 patients (31 boys and seven girls) with an average age of 15.1 years (range, 4-17 years) were treated. Fourteen patients with minimally displaced fractures were treated conservatively, 24 patients with fractures displaced more than 1 cm underwent surgery. All patients had a standard rehabilitation protocol. Post-operative assessments included: the range of motion in the hip; X-ray at 6 weeks, 3 months and 1 year; duration of bed rest; return to previous activities; occurrence of complications (heterotopic ossification, infection, etc). RESULTS: All patients returned to the pre-injury level of sports activities. Recovery was faster and early rehabilitation was better tolerated in patients treated surgically (p = 0.03), particularly in those with AIIS avulsion fractures. Ambulation with partial weight bearing was possible on average at 7.2 days (range, 2-10 days) in surgically treated patients and at 24.1 days (18-27 days) in conservatively treated patients; the difference was statistically significant (p = 0.02). The range of motion markedly improved in surgically treated patients as early as at 6 weeks while, in conservatively treated patients, the comparable outcome was achieved at 3 months of follow-up (p = 0.02). The time necessary for radiographic evidence of fragment union as well as full recovery was comparable in both patient groups. No deep wound infection was recorded; minor heterotopic ossification was detected in five patients, but no further treatment during follow-up was required. CONCLUSIONS: Indications for surgical treatment are based on the degree of fragment displacement and the patient's demands for sports activities. Although long-term outcomes of both operative and conservative procedures are comparable, the patients treated surgically show faster recovery and need a shorter time of immobilisation. However, removal of osteosynthesis material may be associated with some risk of complications. PMID- 26936065 TI - The Effect of Sagittal Plane Deformities after Tibial Plateau Fractures to Functions and Instability of Knee Joint. AB - PURPOSE OF THE STUDY: The objective of this study is to evaluate the effect of posterior tibial slope after fracture healing on antero-posterior knee laxity, functional outcome and patient satisfaction. MATERIAL AND METHODS: 126 patients who were treated for tibial plateau fractures between 2008-2013 in the orthopedics and traumatology department of our institution were evaluated for the study. Patients were treated with open reduction and internal fixation, arthroscopy assisted minimally invasive osteosynthesis or conservative treatment. RESULTS: Mean posterior tibial slope after the treatment was 6.91 +/- 5.11 and there was no significant difference when compared to the uninvolved side 6.42 +/- 4,21 (p = 0.794). Knee laxity in anterior-posterior plane was 6.14 +/- 2.11 and 5.95 +/- 2.25 respectively on healthy and injured side. The difference of mean laxity in anterior-posterior plane between two sides was statistically significant. DISCUSSION: In this study we found no difference in laxity between the injured and healthy knees. However Tegner score decreased significantly in patients who had greater laxity difference between the knees. We did not find significant difference between fracture type and laxity, IKDC functional scores independent of the ligamentous injury. CONCLUSION: In conclusion despite coronal alignment is taken into consideration in treatment of tibial plateau fractures, sagittal alignment is reasonably important for stability and should not be ignored. PMID- 26936066 TI - Talus Bipartitus Etiology - Is Neonatal Infection Involved? AB - Talus bipartitus is a rare skeletal variation. Several causative factors have been proposed, but none of them seem to be convincing. We hypothesize that talus bipartitus may result from ossification disruption in neonatal period caused possibly by an infection. The observations supporting this link are discussed. The hypothesis is supported by two cases with symptomatic talus bipartitus illustrating the postulated connection. KEY WORDS: ankle, pain etiology, talus abnormalities, talus bipartitus. PMID- 26936067 TI - [Septic Sacroiliitis Complicated by a Pseudoaneurysm of the Internal Iliac Artery. A Case Report]. AB - The case of a 67-year-old woman with a combination of pelvic pyomyositis and left sided sacroiliitis is reported. After a failed two-week antibiotic therapy, CT guided percutaneous drainage of psoas muscle abscesses was performed and methicillin-resistant Staphylococcus aureus (MRSA) was isolated. Subsequently, a regression of symptoms was observed. At 6.5 weeks after the onset of symptoms, progression of sacroiliac joint (SI) destruction was again observed and an open revision of the SI joint was indicated (posterior approach, drainage and lavage). This again was followed by symptom regression. At 9.5 weeks after the patient was admitted, her condition markedly deteriorated and a large gluteal abscess was detected on CT examination. The second revision surgery was complicated by massive bleeding and, due to a septic pseudoaneurysm, internal iliac artery ligation was necessary. A significant subsidence of inflammatory changes and no pseudoaneurysm were shown on the follow-up CT scan. The intravenous antibiotic therapy with clindamycin was continued. At follow-up, repeated microbiological cultures from both tissue samples and drained secretions were all negative and CT scanning detected neither any fluid around the SI joint nor a pseudoaneurysm. PMID- 26936068 TI - [Chronic Locked Posterior Shoulder Dislocation Treated by Anatomical Total Shoulder Arthroplasty]. AB - The aim of this study was to present the results of surgical treatment in two male patients with chronic locked posterior dislocation of the shoulder, who underwent total shoulder arthroplasty due to destruction of more than 45% of the humeral head articular surface and glenoid impairment. The deltopectoral approach was used in both cases. Total shoulder arthroplasty (Epoca-Synthes) was carried out in the standard manner. Case one: A 29-year-old, extremely obese patient suffered injury to his shoulder during an epileptic seizure. At 11 months after injury, surgery was performed using an interscalene plexus block because general anaesthesia presented a high risk for the patient. The total follow-up period was 4 years. Between the 2nd and the 3rd follow-up year, the patient lost about 46% of his body weight. At the first year, when the patient maintained his initial overweight, shoulder elevation was 170 degrees and range of motion was not restricted. The overall Constant Score (CS) was 96. Due to a massive weight loss, muscle strength was reduced and the CS decreased to 82. Case two: A 41- year-old man injured his shoulder in a fall and, due to a late diagnosis, underwent surgery under general anaesthesia at 11 months after injury. At 3-year follow-up the overall result was excellent, with only slightly limited internal rotation of the shoulder. PMID- 26936069 TI - Balancing Success and Risk in Orthopedic Trauma Surgery: The Ridge-Walking between Sound Accepting "Good" and Risky Striving for "Better". AB - Immediate post-operative rating of surgical performance can be a valuable source of learning when trying to analyze the reasons for the difference between "work as planned" and "work as done". There are many reasons for the difference, but they can only be found if complete documentation of the surgical steps allows retrospective scrutiny. Documentation like ICUC1 provides this opportunity for scrutiny and may allow better understanding of some unexpected post-operative evolutions. PMID- 26936071 TI - Systematic analysis of overall survival and interactions between tumor mutations and drug treatment. AB - BACKGROUND: Few exceptional responses in cancer treatment were attributed to a genetic predisposition of the tumor. METHODS: We analyzed a cohort of 3105 patients from 12 different cancer types and systematically sought the existence of a correlation between overall survival and the interaction of 21 antineoplastic treatments with 6 tumor mutations. RESULTS: We identified a single significant correlation resulting in increased overall survival from temozolomide in lower-grade glioma with IDH1 R132H mutations. The trend could not be attributed to either the treatment or the mutation alone. Univariate and multivariate Cox regression demonstrated that this interaction stood as an independent prognostic predictor of survival. CONCLUSION: Our results suggest infrequent instances of exceptional responses ascribable to tumor genomics yet corroborate the existence of an interaction of temozolomide with IDH1 mutations in lower-grade glioma. PMID- 26936070 TI - The transcriptome of NaCl-treated Limonium bicolor leaves reveals the genes controlling salt secretion of salt gland. AB - Limonium bicolor, a typical recretohalophyte that lives in saline environments, excretes excessive salt to the environment through epidermal salt glands to avoid salt stress. The aim of this study was to screen for L. bicolor genes involved in salt secretion by high-throughput RNA sequencing. We established the experimental procedure of salt secretion using detached mature leaves, in which the optimal salt concentration was determined as 200 mM NaCl. The detached salt secretion system combined with Illumina deep sequencing were applied. In total, 27,311 genes were annotated using an L. bicolor database, and 2040 of these genes were differentially expressed, of which 744 were up-regulated and 1260 were down regulated with the NaCl versus the control treatment. A gene ontology enrichment analysis indicated that genes related to ion transport, vesicles, reactive oxygen species scavenging, the abscisic acid-dependent signaling pathway and transcription factors were found to be highly expressed under NaCl treatment. We found that 102 of these genes were likely to be involved in salt secretion, which was confirmed using salt-secretion mutants. The present study identifies the candidate genes in the L. bicolor salt gland that are highly associated with salt secretion. In addition, a salt-transporting pathway is presented to explain how Na(+) is excreted by the salt gland in L. bicolor. These findings will shed light on the molecular mechanism of salt secretion from the salt glands of plants. PMID- 26936072 TI - Erratum to: Pneumococcal lower respiratory tract infections in adults: an observational case-control study in primary care in Belgium. PMID- 26936073 TI - Sexual Behaviors of U.S. Men by Self-Identified Sexual Orientation: Results From the 2012 National Survey of Sexual Health and Behavior. AB - INTRODUCTION: Although a large body of previous research has examined sexual behavior and its relation to risk in men of diverse sexual identities, most studies have relied on convenience sampling. As such, the vast majority of research on the sexual behaviors of gay and bisexual men, in particular, might not be generalizable to the general population of these men in the United States. This is of particular concern because many studies are based on samples of men recruited from relatively "high-risk" venues and environments. AIMS: To provide nationally representative baseline rates for sexual behavior in heterosexual, gay, and bisexual men in the United States and compare findings on sexual behaviors, relationships, and other variables across subgroups. METHODS: Data were obtained from the 2012 National Survey of Sexual Health and Behavior, which involved the administration of an online questionnaire to a nationally representative probability sample of women and men at least 18 years old in the United States, with oversampling of self-identified gay and bisexual men and women. Results from the male participants are included in this article. MAIN OUTCOME MEASURES: Measurements include demographic characteristics, particularly sexual identity, and their relations to diverse sexual behaviors, including masturbation, mutual masturbation, oral sex, vaginal sex, and anal sex. Behaviors with male and female partners were examined. RESULTS: Men of all self-identified sexual identities reported engaging in a range of sexual behaviors (solo and partnered). As in previous studies, sexual identity was not always congruent for gender of lifetime and recent sexual partners. CONCLUSION: Patterns of sexual behaviors and relationships vary among heterosexual, gay, and bisexual men. Several demographic characteristics, including age, were related to men's sexual behaviors. The results from this probability study highlight the diversity in men's sexual behaviors across sexual identities, and these data allow generalizability to the broader population of gay and bisexual men, in particular, in the United States, which is a major advancement in research focused on individuals in a sexual minority. PMID- 26936074 TI - Simplified Interpretation of the Erectile Function Domain of the International Index of Erectile Function. AB - INTRODUCTION: This report describes a post hoc analysis of data from a randomized, double-blinded, placebo-controlled, flexible-dose, sildenafil trial in men with erectile dysfunction. AIMS: To simplify interpretation of erectile function (EF) domain scores of the International Index of Erectile Function (IIEF). METHODS: Men at least 18 years old with erectile dysfunction were randomized to receive sildenafil or placebo for 12 weeks. Men taking nitrates or nitric oxide donors were excluded. Responses for each IIEF EF domain question (questions 1-5 and 15) were combined into two broad categories ("success" for responses of the two most favorable categories of a question and "no success" for other responses). Each question was expressed in a logistic regression model (sildenafil and placebo groups combined) as a function of overall EF domain score. MAIN OUTCOME MEASURES: IIEF EF domain score and items. RESULTS: A four point increase in the IIEF EF domain score was associated with an odds ratio of success of 6.1 for getting an erection, 29.2 for having a firm erection, 10.0 for able to penetrate,12.8 for maintaining erection, 4.0 for maintaining erection to completion, and 3.7 for erection confidence. An EF domain score of 22 was associated with a probability of success of 81% for getting an erection, 86% for having a firm erection, 89% for able to penetrate, 67% for maintaining an erection, 70% for maintaining an erection to completion, and 32% for erection confidence. For an EF domain score of 16, the corresponding probabilities of success were 22%, 4%, 20%, 4%, 22%, and 6%, respectively. CONCLUSION: These results provide stakeholders with a simplified and meaningful interpretation of IIEF EF domain scores based on six key aspects of EF. PMID- 26936075 TI - Altered Appetitive Conditioning and Neural Connectivity in Subjects With Compulsive Sexual Behavior. AB - INTRODUCTION: There has been growing interest in a better understanding of the etiology of compulsive sexual behavior (CSB). It is assumed that facilitated appetitive conditioning might be an important mechanism for the development and maintenance of CSB, but no study thus far has investigated these processes. AIM: To explore group differences in neural activity associated with appetitive conditioning and connectivity in subjects with CSB and a healthy control group. METHODS: Two groups (20 subjects with CSB and 20 controls) were exposed to an appetitive conditioning paradigm during a functional magnetic resonance imaging experiment, in which a neutral stimulus (CS+) predicted visual sexual stimuli and a second stimulus (CS-) did not. MAIN OUTCOME MEASURES: Blood oxygen level dependent responses and psychophysiologic interaction. RESULTS: As a main result, we found increased amygdala activity during appetitive conditioning for the CS+ vs the CS- and decreased coupling between the ventral striatum and prefrontal cortex in the CSB vs control group. CONCLUSION: The findings show that neural correlates of appetitive conditioning and neural connectivity are altered in patients with CSB. The increased amygdala activation might reflect facilitated conditioning processes in patients with CSB. In addition, the observed decreased coupling could be interpreted as a marker for impaired emotion regulation success in this group. PMID- 26936077 TI - Protease activated receptor 2 (PAR2) modulators: a patent review (2010-2015). AB - INTRODUCTION: Protease activated receptor 2 (PAR2) is a self-activated G protein coupled receptor that has been implicated in several diseases, including inflammatory, gastrointestinal, respiratory, metabolic diseases, cancers and others, making it an important prospective drug target. No known endogenous ligands are available for PAR2, so having potent exogenous agonists and antagonists can be helpful for studying physiological functions of PAR2. AREAS COVERED: This review covers agonist-, antagonist-, antibody- and pepducin-based modulators of PAR2 reported in patent applications between 2010-2015, along with their available structure-activity relationships, biological activities and potential uses for studying PAR2. EXPERT OPINION: In the last six years, substantial efforts were made towards developing PAR2 modulators, but most lack potency or selectivity or have poor pharmacokinetic profiles. Many PAR2 modulators were assessed by measuring Galphaq protein-mediated calcium release in cells. This may be insufficient to fully characterize ligand function, since different ligands signal through PAR2 via multiple signaling pathways. It may be feasible to develop biased ligands as drugs that can selectively modulate one or more specific signaling pathways linking PAR2 to a specific diseased state. Accordingly, potent, orally bioavailable, pathway- and receptor-selective PAR2 modulators may be an achievable goal to realizing effective drugs that can treat PAR2-mediated diseases. PMID- 26936076 TI - Awareness and knowledge about human papillomavirus vaccination and its acceptance in China: a meta-analysis of 58 observational studies. AB - BACKGROUND: The human papillomavirus (HPV) vaccines have been widely introduced in immunization programs worldwide, however, it is not accepted in mainland China. We aimed to investigate the awareness and knowledge about HPV vaccines and explore the acceptability of vaccination among the Chinese population. METHODS: A meta-analysis was conducted across two English (PubMed, EMBASE) and three Chinese (China National Knowledge Infrastructure, Wan Fang Database and VIP Database for Chinese Technical Periodicals) electronic databases in order to identify HPV vaccination studies conducted in mainland China. We conducted and reported the analysis in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. RESULTS: Fifty-eight unique studies representing 19 provinces and municipalities in mainland China were assessed. The pooled awareness and knowledge rates about HPV vaccination were 15.95 % (95 % CI: 12.87-19.29, I (2) = 98.9 %) and 17.55 % (95 % CI: 12.38-24.88, I (2) = 99.8 %), respectively. The female population (17.39 %; 95 % CI: 13.06-22.20, I (2) = 98.8 %) and mixed population (18.55 %; 95 % CI: 14.14-23.42, I (2) = 98.8 %) exhibited higher HPV vaccine awareness than the male population (1.82 %; 95 % CI: 0.50-11.20, I (2) = 98.5 %). Populations of mixed ethnicity had lower HPV vaccine awareness (9.61 %; 95 % CI: 5.95-14.03, I (2) = 99.0 %) than the Han population (20.17 %; 95 % CI: 16.42-24.20, I (2) = 98.3 %). Among different regions, the HPV vaccine awareness was higher in EDA (17.57 %; 95 % CI: 13.36-22.21, I (2) = 98.0 %) and CLDA (17.78 %; 95 % CI: 12.18-24.19, I (2) = 97.6 %) than in WUDA (1.80 %; 95 % CI: 0.02-6.33, I (2) = 98.9 %). Furthermore, 67.25 % (95 % CI: 58.75-75.21, I (2) = 99.8 %) of participants were willing to be vaccinated, while this number was lower for their daughters (60.32 %; 95 % CI: 51.25-69.04, I (2) = 99.2 %). The general adult population (64.72 %; 95 % CI: 55.57-73.36, I (2) = 99.2 %) was more willing to vaccinate their daughters than the parent population (33.78 %; 95 % CI: 26.26-41.74, I (2) = 88.3 %). Safety (50.46 %; 95 % CI: 40.00-60.89, I (2) = 96.6 %) was the main concern about vaccination among the adult population whereas the safety and efficacy (68.19 %; 95 % CI: 53.13-81.52, I (2) = 98.6 %) were the main concerns for unwillingness to vaccinate their daughters. CONCLUSIONS: Low HPV vaccine awareness and knowledge was observed among the Chinese population. HPV vaccine awareness differed across sexes, ethnicities, and regions. Given the limited quality and number of studies included, further research with improved study designis necessary. PMID- 26936078 TI - Dp71Delta78-79 dystrophin mutant stimulates neurite outgrowth in PC12 cells via upregulation and phosphorylation of HspB1. AB - PC12 cells acquire a neuronal phenotype in response to nerve growth factor (NGF). However, this phenotype is more efficiently achieved when the Dp71Delta78-79 dystrophin mutant is stably expressed in PC12-C11 cells. To investigate the effect of Dp71Delta78-79 overexpression on the protein profile of PC12-C11 cells, we compared the expression profiles of undifferentiated and NGF-differentiated PC12-C11 and PC12 cells by 2DE. In undifferentiated cultures, one protein was downregulated, and five were upregulated. Dp71Delta78-79 overexpression had a greater effect on differentiated cultures, with ten proteins downregulated and seven upregulated. The protein with the highest upregulation was HspB1. Changes in HspB1 expression were validated by Western blot and immunofluorescence analyses. Interestingly, the neurite outgrowth in PC12-C11 cells was affected by a polyclonal antibody against HspB1, and the level of HspB1 and HspB1Ser86 decreased, suggesting an important role for this protein in this cellular process. Our results show that Dp71Delta78-79 affects the expression level of some proteins and that the stimulated neurite outgrowth produced by this mutant is mainly through upregulation and phosphorylation of HspB1. PMID- 26936079 TI - Using Automated Image Analysis Algorithms to Distinguish Normal, Aberrant, and Degenerate Mitotic Figures Induced by Eg5 Inhibition. AB - Modulation of the cell cycle may underlie the toxicologic or pharmacologic responses of a potential therapeutic agent and contributes to decisions on its preclinical and clinical safety and efficacy. The descriptive and quantitative assessment of normal, aberrant, and degenerate mitotic figures in tissue sections is an important end point characterizing the effect of xenobiotics on the cell cycle. Historically, pathologists used manual counting and special staining visualization techniques such as immunohistochemistry for quantification of normal, aberrant, and degenerate mitotic figures. We designed an automated image analysis algorithm for measuring these mitotic figures in hematoxylin and eosin (H&E)-stained sections. Algorithm validation methods used data generated from a subcutaneous human transitional cell carcinoma xenograft model in nude rats treated with the cell cycle inhibitor Eg5. In these studies, we scanned and digitized H&E-stained xenografts and applied a complex ruleset of sequential mathematical filters and shape discriminators for classification of cell populations demonstrating normal, aberrant, or degenerate mitotic figures. The resultant classification system enabled the representations of three identifiable degrees of morphological change associated with tumor differentiation and compound effects. The numbers of mitotic figure variants and mitotic indices data generated corresponded to a manual assessment by a pathologist and supported automated algorithm verification and application for both efficacy and toxicity studies. PMID- 26936080 TI - Influenza vaccination prevalence and demographic factors of patients and GPs in primary care in Austria and Croatia: a cross-sectional comparative study in the framework of the APRES project. AB - BACKGROUND: The aim of this study was to compare influenza vaccination coverage rates in Austria and Croatia, countries with missing data in the Eurosurveillance and European Centre for Disease Prevention and Control reports. In addition, we assessed demographic factors of GPs and patients and calculated associations regarding vaccination rates. METHODS: This cross-sectional study was conducted within the context of thethe appropriateness of prescribing antibiotics in primary health care in Europe with respect to antibiotic resistance (APRES) project. Between November 2010 and July 2011, 40 GP practices attempted to recruit 200 patients to complete questionnaires about their influenza vaccination status and demographics. Statistical analyses included subgroup analyses and logistic regression models. RESULTS: Data from 7269 patient questionnaires could be analyzed (3309 Austria and 3960 Croatia). The vaccination coverage rates were low (2009/2010: A 18.2 vs. C 20.9%, P < 0.001; 2010/2011: A 13.7 vs. C 18.6%; P < 0.001). The rates were found to be highest in persons aged 65 years and older (2009/2010: A 35.1 vs. C 49.5%, P < 0.001; 2010/2011: A 31.1 vs. C 45.7%, P < 0.001) and lowest in children (2009/2010: A 8.5 vs. C 2.0%, P < 0.001; 2010/2011: A 4.3 vs. C 1.6%, P = 0.002). Besides, demographics in the adjusted regression model for Austria being vaccinated was associated with consulting a female GP (OR, 4.20; P < 0.001) and in Croatia with five or more GP consultations per year (OR, 4.41; P < 0.001). CONCLUSION: The vaccination coverage rates for Austria and Croatia were low, with the highest rates found in persons aged 65 years and older, showing that public coverage of the vaccination costs might increase vaccination rates. However, other factors seem to be relevant, including the engagement of GPs. PMID- 26936081 TI - An examination of unmet health needs as perceived by Roma in Central and Eastern Europe. AB - BACKGROUND: Roma comprise the largest ethnic minority in Europe, with an estimated population of 10-12 million. Roughly 50-60% of European Roma live in the countries of Central and Eastern Europe. In this study, we set out to quantify and explain disparities in unmet health needs for Roma populations relative to non-Roma populations, using self-reported access to health care. METHODS: The United Nations Development Programme/World Bank/European Commission 2011 regional Roma survey was used for this study (12 countries, 8735 Roma and 4572 non-Roma living in same communities), with self-reported unmet health need (did not consult a doctor or health professional when they felt it was necessary in past year) as the primary outcome. Multivariable logistic regressions were performed to study the determinants of unmet health need for Roma populations relative to non-Roma populations. Covariates controlled for included sociodemographic characteristics, economic ability, health status and healthcare access. RESULTS: We found in unadjusted models that Roma throughout Central and Eastern Europe, with the exception of Montenegro, are two to three times more likely to report having an unmet health need in the past 12 months than non-Roma living nearby. These disparities largely remain significant, even after adjusting for gender, age, marital status, employment status, education, number of chronic conditions, health insurance status and geographical proximity to medical providers. CONCLUSIONS: Controlling for conventional measures of access to medical care (i.e. geographic access to providers and health insurance) does not eliminate observed disparities in unmet need. Although improving funding and routine access to healthcare services for Roma is important in its own right as a means of increasing inclusion, there is a need for detailed assessments of the barriers that exist in each country, within and outside the health system, coupled with measures to implement existing commitments on Roma rights. PMID- 26936082 TI - Fast carbonization using fluidized bed for biochar production from reed black liquor: optimization for H2S removal. AB - The biochar was produced from fast pyrolysis of reed black liquor using fluidized bed. Response surface methodology and the central composite design (CCD) were employed for determining optimal adsorbents with maximum H2S removal capacity. The operational parameters such as carbonization temperature ( degrees C), duration (min) and space velocity (SV, L min(-1) kg(-1)) were chosen as independent variables in CCD. The statistical analysis indicates that the effects of carbonization temperature, duration, SV and combined effect of carbonization temperature and duration are all significant to the H2S removal capacity. The optimal condition for achieving the maximum H2S adsorption capacity for biochar is obtained as the follows: carbonization temperature (500 degrees C), duration (5.7 min), SV (7300 L min(-1) kg(-1)) with H2S removal reaching 60 mg g(-1). The dynamic experimental results indicate a good performance in H2S removal by the produced biochar. PMID- 26936083 TI - Original Research: Acute chest syndrome in sickle cell disease: Effect of genotype and asthma. AB - Sickle cell disease is a severe hemoglobinopathy caused by mutations in the beta globin genes. The disorder has protean manifestations and leads to severe morbidity and early mortality. Acute chest syndrome (ACS) is a common complication and in the USA is the leading cause of death in patients with sickle cell disease. Care of patients with sickle cell disease is complex and typically involves both primary care physicians and hematology subspecialists. The purpose of this study was first to attempt to validate in a pediatric sickle cell patient cohort associations between ACS and sickle cell disease genotype and between ACS and asthma as a comorbidity. The second purpose of the study was to study in a typical community the frequency with which asthma associated with ACS was addressed in terms of electronic medical record integration, pulmonary subspecialty consultation for management of asthma, and completion of pulmonary function testing (PFTs). A retrospective study of the electronic medical record of a children's hospital that provides most of the medical care for children in a portion of western New York state was performed. We found that ACS was more common in the sickle cell disease genotypes SS and S/beta-thalassemia-null, and that ACS was more frequent in patients treated for asthma. We also found that despite the use of a comprehensive electronic medical record, there was poor documentation of ACS and asthma episodes in the problem lists of patients with sickle cell disease, and that most patients with sickle cell disease with ACS or asthma failed to receive formal consultation services from pediatric pulmonary subspecialists. PMID- 26936085 TI - Manganese in the human vitreous. PMID- 26936086 TI - Leptin induces the apoptosis of chondrocytes in an in vitro model of osteoarthritis via the JAK2-STAT3 signaling pathway. AB - Emerging data has suggested a high prevalence of osteoarthritis (OA) among obese people. As an important adipokine secreted by white adipose tissue, leptin may be a key mediator in the progression of OA. Leptin exerts a catabolic effect on OA cartilage by increasing the production of metalloproteinase (MMP) enzymes, and contributes to apoptosis in chondrocytes. The current study aimed to explore the role of leptin on the apoptosis of chondrocytes in OA, and its underlying mechanisms. In the in vitro model of OA used in the present study, administration of exogenous leptin induced the generation of reactive oxygen species (ROS) and apoptosis in chondrocytes. It has been demonstrated that leptin is associated with the pathogenesis of OA via the Janus kinase 2 (JAK2)-signal transducer and activator of transcription 3 (STAT3) signaling pathway, and data gathered in the present study demonstrated that suppression of this signaling pathway using a JAK2 inhibitor, AG490, significantly ameliorated leptin-induced apoptosis in damaged chondrocytes in vitro, and reduced the generation of ROS. Furthermore, the protein expression levels of MMP-13 and B-cell lymphoma 2-associated X protein were downregulated in the AG490-treated group. The results of the present study may provide insight into the underlying molecular mechanism by which leptin induces apoptosis in chondrocytes. These findings indicated the importance of leptin as a therapeutic target for the treatment of OA in the overweight population. PMID- 26936084 TI - Minireview: Genetic basis of heterogeneity and severity in sickle cell disease. AB - Sickle cell disease, a common single gene disorder, has a complex pathophysiology that at its root is initiated by the polymerization of deoxy sickle hemoglobin. Sickle vasoocclusion and hemolytic anemia drive the development of disease complications. In this review, we focus on the genetic modifiers of disease heterogeneity. The phenotypic heterogeneity of disease is only partially explained by genetic variability of fetal hemoglobin gene expression and co inheritance of alpha thalassemia. Given the complexity of pathophysiology, many different definitions of severity are possible complicating a full understanding of its genetic foundation. The pathophysiological complexity and the interlocking nature of the biological processes underpinning disease severity are becoming better understood. Nevertheless, useful genetic signatures of severity, regardless of how this is defined, are insufficiently developed to be used for treatment decisions and for counseling. PMID- 26936087 TI - Neurocognitive functioning and outcome of the Illness Management and Recovery Program for clients with schizophrenia and schizoaffective disorder. AB - The relationship between psychosocial programming and neurocognition has been established in previous research, but has not been explored in the context of the Illness Management and Recovery Program (IMR). This study examined associations between neurocognition and illness self-management skills acquisition, based on two previous trials of IMR. Neurocognitive functioning was assessed at baseline and post-treatment in 53 participants with schizophrenia or schizoaffective disorder who completed the IMR. Illness self-management was measured by the client and clinician versions of the Illness Management and Recovery Scale. Statistical analyses investigated improvements in neurocognitive functioning and possible association between illness self-management skills acquisition and neurocognitive functioning. Speed of processing as measured by the Trail Making Test A, was related to client-reported acquisition of illness self-management skills, before and after controlling for psychiatric symptoms and medication, but did not predict improvement in clinician ratings of client illness self management skills. However, when controlling for client session attendance rates, the association between speed of processing and client-reported illness self management skills acquisition ceased to be statistically significant, which suggests that compromised neurocognitive functioning does not reduce response to training in illness self-management in itself. The association between the frequency of attended IMR sessions and outcome of the IMR seems to decrease the negative impact of compromised neurocognition on illness self-management skills acquisition. Also, clients with slower speed of processing may experience less benefit from the IMR and may attend fewer sessions. PMID- 26936088 TI - Male genital lichen sclerosus in recipients of bone marrow transplants. AB - We describe two patients who received haematopoietic stem cell marrow transplantation, and developed male genital lichen sclerosus (MGLSc), one of whom also had squamous carcinoma in situ (Bowen disease). MGLSc has previously been associated with graft-versus-host disease. Various aetiological factors for LSc have been proposed, including a role for chronic occluded epithelial exposure to urine. A number of factors imply that the risk of malignant transformation in this bone marrow transplant group is likely to be higher than the overall figure of 2-9% cited for MGLSc. It is vital, therefore, that clinicians involved in the care of those with haematological malignancies are adequately prepared to examine the genitals of their patients, and to recognize and refer any suspect penile lesions. PMID- 26936089 TI - A seven day NHS. PMID- 26936090 TI - Incretin-based therapy and acute cholecystitis: a review of case reports and EudraVigilance spontaneous adverse drug reaction reporting database. AB - WHAT IS KNOWN AND OBJECTIVE: Glucagon-like peptide-1 (GLP-1) receptor agonists delay gastric and bowel emptying. A similar inhibitory effect of GLP-1 on gallbladder motility has been suggested, possibly leading to an increased risk of cholecystitis related to incretin-based medications, which include GLP-1 antagonists. Our objective was to review evidence in EudraVigilance, the European spontaneous reporting database and the scientific literature on this issue. COMMENT: Increasing evidence suggests an association of incretins with gallbladder adverse events. Pharmacovigilance data from EudraVigilance includes 200 serious ADR reports concerning cholecystitis related to the use of incretin based therapies. Several mechanisms may explain this increased risk of cholecystitis, including rapid weight loss, inhibition of gallbladder contraction and emptying, reduced bile acids production, modulation of inflammation. WHAT IS NEW AND CONCLUSIONS: The available data suggest the possibility of gallbladder disease in diabetic subjects treated with incretins and highlight the importance of evaluating risk factors for cholelithiasis and gallbladder diseases in patients with diabetes before starting this therapy. PMID- 26936091 TI - Overexpression of fatty acid synthase predicts a poor prognosis for human gastric cancer. AB - Fatty acid synthase (FASN), a lipogenic multi-enzyme complex, is reported to be overexpressed in various types of of tumor tissues and serves an important role in tumor development and progression. However, the expression of FASN and its possible role in gastric cancer (GC) remains to be defined. In the present study, FASN expression in a group sample of 167 GC tissues was detected by immunohistochemistry and its correlation with clinicopathological features was analyzed. By clinical analysis, it was identified that FASN overexpression was positively correlated with the overall survival [P=0.008; hazard ratio (HR), 4.412; 95% confidence interval (CI), 1.463-13.305] and recurrence rate (P=0.014; HR, 1.705; 95% CI, 1.116-2.606) in patients with GC. In addition, expression of the FASN protein in GC tissues was correlated with age (P=0.032), clinical stage (P<0.001), gastric wall invasion (P=0.014), lymph node metastasis (P<0.001) and distant metastasis (P<0.001), however not with gender (P>0.05). In addition, FASN was observed to be overexpressed in GC tissues at an mRNA and protein level, compared with the adjacent non-cancerous tissues (P<0.05). Taken together, it was suggested that FASN was closely associated with GC metastasis and survival, which further provided evidence that FASN may be a promising prognostic biomarker for patients with GC. PMID- 26936092 TI - Neoadjuvant chemoradiation (modified Eilber protocol) versus adjuvant radiotherapy in the treatment of extremity soft tissue sarcoma. AB - BACKGROUND: Local control for extremity soft tissue sarcomas (STS) requires surgery combined with radiotherapy, usually given pre-operatively or post operatively. The modified Eilber protocol, a neoadjuvant chemoradiation regimen, has been reported with excellent local control rates. This retrospective single centre study compared outcomes for patients treated with the modified Eilber protocol with those treated with standard adjuvant radiotherapy. METHODS: Patients with a diagnosis of extremity STS were retrospectively reviewed from the Prince of Wales Hospital Sarcoma Database from 1995 to 2012. Sixty-three patients underwent curative surgery with either neoadjuvant Eilber chemoradiotherapy (Eilber) or adjuvant radiotherapy (Adjuvant). RESULTS: Twenty-nine patients were treated with modified Eilber protocol. Thirty-four patients received adjuvant radiotherapy. Three patients (10%) in the Eilber group and five patients (15%) in the Adjuvant group developed local recurrence (P = 0.87). Major acute wound complications were noted in four patients in each group (P = 0.55). One patient (3.4%) in the Eilber group developed Grade 3 or 4 late toxicities after 1 year compared with nine patients (27%) in the Adjuvant group (P = 0.02). CONCLUSION: Neoadjuvant chemoradiation (Eilber protocol) provided similar rates of local control when compared with adjuvant radiotherapy. Acute wound complication rates were similar but there was less severe late toxicity in the Eilber group. PMID- 26936093 TI - Initiating nasal continuous positive airway pressure in preterm neonates at 5 cm as against 7 cm did not decrease the need for mechanical ventilation. AB - AIM: The optimum starting nasal continuous positive airway pressure (nCPAP) for infants on bubble nCPAP is unknown. We compared whether an initial bubble nCPAP of 7 cm rather than 5 cm of water prevented the need for mechanical ventilation among preterm neonates with respiratory distress. METHODS: Preterm neonates born at 27-34 weeks with the onset of respiratory distress within 24 hours of birth were randomised to receive high or standard nCPAP at either 7 cm or 5 cm of water, respectively. The primary outcome was the need for mechanical ventilation in the first week of life. RESULTS: The baseline characteristics were comparable between the two groups. The proportion of infants who required mechanical ventilation during the first week of life was similar between the two groups (standard 29/133, 21.8% versus high 30/138, 21.7%), with a relative risk of 0.99 and range of 0.56-1.77. The secondary outcomes were similar between the two groups, including mortality before discharge, pulmonary air leaks, need of surfactant therapy, bronchopulmonary dysplasia and duration of nCPAP. CONCLUSION: Initiating nCPAP at a higher pressure of 7 cm in preterm neonates with respiratory distress, rather than the standard 5 cm, did not decrease the need for mechanical ventilation during the first week of life. PMID- 26936094 TI - Benefit distribution of social health insurance: evidence from china's urban resident basic medical insurance. AB - Equity is one of the essential objectives of the social health insurance. This article evaluates the benefit distribution of the China's Urban Residents' Basic Medical Insurance (URBMI), covering 300 million urban populations. Using the URBMI Household Survey data fielded between 2007 and 2011, we estimate the benefit distribution by the two-part model, and find that the URBMI beneficiaries from lower income groups benefited less than that of higher income groups. In other words, government subsidy that was supposed to promote the universal coverage of health care flew more to the rich. Our study provides new evidence on China's health insurance system reform, and it bears meaningful policy implication for other developing countries facing similar challenges on the way to universal coverage of health insurance. PMID- 26936095 TI - Downregulation of microRNA-196a enhances the sensitivity of non-small cell lung cancer cells to cisplatin treatment. AB - MicroRNAs (miRNAs or miRs) are a class of small, non-coding RNA molecules that play an important role in the pathogenesis of human diseases through the regulation of gene expression. Although miRNA-196a has been implicated in the progression of human lung cancer, its role in enhancing the sensitivity of non small cell lung cancer (NSCLC) cells to cisplatin has not yet been confirmed. The aim of this study was to evaluate the effects of miRNA-196a on the sensitivity of NSCLC cells to cisplatin in vitro and in vivo. RT-qPCR was used to detect miRNA 196a expression. Synthesized locked nucleic acid (LNA)-anti-miRNA-196a oligonucleotide was transiently transfected into the SPC-A-1 and A549 lung cancer cells to examine the effects of miRNA-196a on the growth of and colony formation inthe cisplatin-treated cells. The effects of miRNA-196a on the sensitivity of SPC-A-1 cells to cisplatin in vivo were determined using BALB/c nude mice. The expression of miRNA-196a was significantly higher in both the lung cancer tissues and cell lines. The LNA-based knockdown of miRNA-196a significantly inhibited SPC A-1 and A549 cell growth and induced apoptosis. Moreover, the downregulation of miRNA-196a sensitized the SPC-A-1 and A549 NSCLC cells to cisplatin in vitro and in vivo, by inducing apoptosis. The findings of this study demonstrate that the administration of cisplatin in combination with miRNA-196a-targeted therapy may be a potential therapeutic strategy for the treatment of NSCLC. PMID- 26936096 TI - Effects of monensin and essential oils on immunological, haematological and biochemical parameters of cows during the transition period. AB - Using a model to generate experimental groups with different manifestations of post-partum (p.p.) fat mobilization and ketogenesis, the effects of a dietary and a medical intervention on biochemical and haematological parameters, antibody titre, leucocytes subsets and function of transition cows were examined. In total, 60 German Holstein cows were allocated 6 weeks antepartum (a.p.) to 3 high body condition score (BCS) groups (BCS 3.95) and 1 low-BCS group (LC, BCS 2.77). High-BCS cows received a monensin controlled-release capsule (HC/MO) or a blend of essential oils (HC/EO) or formed a control group (HC). Parameters were evaluated in 3 periods (day (d) -42 until calving, 1 until 14 days in milk (DIM), 15 until 56 DIM). Over the course of trial, various parameters were influenced by period with greatest variability next to calving. White blood cell count was higher in the HC (8.42 * 103 /MUl) and HC/EO (8.38 * 103 /MUl) groups than in the HC/MO group (6.81 * 103 /MUl) considering the whole trial. Supplementation of monensin decreased aspartate aminotransferase in comparison with the HC group similar to LC treatment. Bilirubin concentration was nearly doubled in all high BCS cows in period 2. In period 3, essential oils increased gamma glutamyltransferase (80.4 Units/l) in comparison with all other groups and glutamine dehydrogenase (61 Units/l) in comparison with the LC (19 Units/l) and the HC/MO group (18 Units/l). Results suggest that parameters were generally characterized by a high variability around calving. Based on biochemical characteristics, it appeared that the HC cows seemed to have compromised hepatocyte integrity when compared to the LC cows. From the immune parameters investigated, the BVDV antibody response was more pronounced in HC/MO compared to HC/EO. PMID- 26936097 TI - Inequality in mortality by occupation related to economic crisis from 1980 to 2010 among working-age Japanese males. AB - The mortality rate for Japanese males aged 30-59 years in managerial and professional spiked in 2000 and remains worse than that of other occupations possibly associated with the economic downturn of the 1990s and the global economic stagnation after 2008. The present study aimed to assess temporal occupation-specific mortality trends from 1980 to 2010 for Japanese males aged 30 59 years for major causes of death. We obtained data from the Occupation-specific Vital Statistics. We calculated age-standardized mortality rates for the four leading causes of death (all cancers, suicide, ischaemic heart disease, and cerebrovascular disease). We used a generalized estimating equation model to determine specific effects of the economic downturn after 2000. The age standardized mortality rate for the total working-age population steadily declined up to 2010 in all major causes of death except suicide. Managers had a higher risk of mortality in all leading causes of death compared with before 1995. Mortality rates among unemployed people steadily decreased for all cancers and ischaemic heart disease. Economic downturn may have caused the prolonged increase in suicide mortality. Unemployed people did not experience any change in mortality due to suicide and cerebrovascular disease and saw a decline in cancer and ischemic heart disease mortality, perhaps because the basic properties of Japan's social welfare system were maintained even during economic recession. PMID- 26936099 TI - Human Immunodeficiency Virus Diagnostic Testing: 30 Years of Evolution. AB - A concern during the early AIDS epidemic was the lack of a test to identify individuals who carried the virus. The first HIV antibody test, developed in 1985, was designed to screen blood products, not to diagnose AIDS. The first generation assays detected IgG antibody and became positive 6 to 12 weeks postinfection. False-positive results occurred; thus, a two-test algorithm was developed using a Western blot or immunofluorescence test as a confirmatory procedure. The second-generation HIV test added recombinant antigens, and the third-generation HIV tests included IgM detection, reducing the test-negative window to approximately 3 weeks postinfection. Fourth- and fifth-generation HIV assays added p24 antigen detection to the screening assay, reducing the test negative window to 11 to 14 days. A new algorithm addressed the fourth-generation assay's ability to detect both antibody and antigen and yet not differentiate between them. The fifth-generation HIV assay provides separate antigen and antibody results and will require yet another algorithm. HIV infection may now be detected approximately 2 weeks postexposure, with a reduced number of false positive results. PMID- 26936098 TI - Collagen metabolic disorder induced by oxidative stress in human uterosacral ligament-derived fibroblasts: A possible pathophysiological mechanism in pelvic organ prolapse. AB - Pelvic organ prolapse (POP) is a global health problem, for which the pathophysiological mechanism remains to be fully elucidated. The loss of extracellular matrix protein has been considered to be the most important molecular basis facilitating the development of POP. Oxidative stress (OS) is a well-recognized mechanism involved in fiber metabolic disorders. The present study aimed to clarify whether OS exists in the uterosacral ligament (USL) with POP, and to investigate the precise role of OS in collagen metabolism in human USL fibroblasts (hUSLFs). In the present study, 8-hydroxyguanosine (8-OHdG) and 4 hydroxynonenal (4-HNE), as oxidative biomarkers, were examined by immunohistochemistry to evaluate oxidative injury in USL sections in POP (n=20) and non-POP (n=20) groups. The primary cultured hUSLFs were treated with exogenous H2O2 to establish an original OS cell model, in which the expression levels of collagen, type 1, alpha1 (COL1A1), matrix metalloproteinase (MMP)-2, tissue inhibitor of metalloproteinase (TIMP)-2 and transforming growth factor (TGF)-beta1 were evaluated by western blot and reverse transcription-quantitative polymerase chain reaction analyses. The results showed that the expression levels of 8-OHdG and 4-HNE in the POP group were significantly higher, compared with those in the control group. Collagen metabolism was regulated by H2O2 exposure in a concentration-dependent manner, in which lower concentrations of H2O2 (0.1-0.2 mM) stimulated the anabolism of COL1A1, whereas a higher concentration (0.4 mM) promoted catabolism. The expression levels of MMP-2, TIMP-2 and TGF-beta1 exhibited corresponding changes with the OS levels. These results suggested that OS may be involved in the pathophysiology of POP by contributing to collagen metabolic disorder in a severity-dependent manner in hUSLFs, possibly through the regulation of MMPs, TIMPs and TGF-beta1 indirectly. PMID- 26936100 TI - Highlights of the 8th International Conference on Vaccines for Enteric Diseases: the Scottish Encounter To Defeat Diarrheal Diseases. AB - Infectious diarrhea is a leading cause of morbidity and of mortality; the burden of disease affects individuals of all ages but particularly young children, especially those living in poor regions where the disease is endemic. It is also a health concern for international travelers to these areas. Experts on vaccines and enteric infections and advocates for global health improvement gathered in Scotland from 8 to 10 July 2015 to discuss recent advances in the assessment and understanding of the burden of enteric diseases and progress in the development and implementation of strategies to prevent these infections. Highlights of the meeting included description of advances in molecular assays to estimate pathogen specific prevalence, methods to model epidemiologic trends, novel approaches to generate broad-spectrum vaccines, new initiatives to evaluate vaccine performance where they are most needed, renewed interest in human challenge models, immunological readouts as predictors of vaccine efficacy, maternal immunization to prevent enteric infections, and the impact of maternal immunity on the vaccine take of infants. A follow-up scientific gathering to advance Shigella and enterotoxigenic Escherichia coli (ETEC) vaccine efforts will be held from 28 to 30 June 2016 in Washington, DC. PMID- 26936101 TI - Springtime for CVI. PMID- 26936103 TI - Startle Modification and P50 Gating in Schizophrenia Patients and Controls: Russian Population. AB - Prepulse modification of the acoustic startle response (ASR) and P50 gating are potential neurophysiological endophenotypes of schizophrenia and may be used in the construction of valid clinical biomarkers. Such approach requires a large amount of data obtained in the representative samples from different gender, socio-typological and ethnic groups, replicating studies using the similar protocols and meta-analyses. This is a replication study of ASR and the first study of P50 suppression in Russian patients with schizophrenia (n = 28) and healthy controls (n = 25). ASR and P50 were estimated according to standard protocols. Patients exhibited increased baseline ASR latency (d = 0.35, p = .026) and reduced prepulse inhibition (PPI) at 60 ms interval (d = 0.39, p = .003) and 120 ms interval (d = 0.37, p = .005) relative to controls. In the P50 test patients displayed greater S2 response amplitude (d = 0.24, p = .036) and deficit of P50 suppression (d = 0.43, p = .001). No correlations of PPI and P50 suppression were found in both groups. Only in controls prepulse ASR facilitation (at 2500 ms interval) positively correlated with P50 suppression (r = -.514, p = .013). In patients PPI displayed significant correlations with Difficulty in abstract thinking (N5: r = -.49, p = .005) and Hallucination (P3: r = .40, p = .036) PANSS scales. Logistic regression showed that the combination of PPI and P50 suppression could serve as a diagnostic predictor. Obtained results demonstrated that both PPI and P50 could be regarded as potential schizophrenia biomarkers in Russian population. PMID- 26936102 TI - The Lipid Bilayer Provides a Site for Cortisone Crystallization at High Cortisone Concentrations. AB - Cortisone is an injected anti-inflammatory drug that can cause painful side effects known as "steroid flares" which are caused by cortisone crystallizing at the injection site. We used molecular dynamics simulations and X-ray diffraction to study the interaction of cortisone with model lipid membranes made of 1 palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) at drug concentrations from 0 mol% to 50 mol%. Cortisone was found to partition in the lipid bilayer and locate in the hydrophilic to hydrophobic interface of the membranes. Cortisone strongly affects the integrity of the membrane, as quantified by a decreased membrane thickness, increased area per lipid, and decreased lipid tail order parameters. At cortisone concentrations of more than 20 mol%, signals from crystallized cortisone were observed. These crystallites are embedded in the bilayers and orient with the membranes. While the cortisone molecules align parallel to the bilayers at low concentrations, they start to penetrate the hydrophobic core at higher concentrations. Trans-membrane crystallites start to nucleate when the membrane thickness has decreased such that cortisone molecules in the different leaflets can find partners from the opposite leaflet resulting in a non-zero density of cortisone molecules in the bilayer center. We suggest that the lipid bilayer provides a site for cortisone crystallization. PMID- 26936104 TI - Paeoniflorin attenuates ultraviolet B-induced apoptosis in human keratinocytes by inhibiting the ROS-p38-p53 pathway. AB - Ultraviolet (UV) light is one of the most harmful environmental factors that contribute to skin damage. Exposure to UV induces extensive generation of reactive oxygen species (ROS), and results in photoaging and skin cancer development. One approach to protecting human skin against UV radiation is the use of antioxidants. In recent years, naturally occurring herbal compounds have gained considerable attention as protective agents for UV exposure. Paeoniflorin (PF) is a novel natural antioxidant, which is isolated from peony root (Radix Paeoniae Alba). The present study evaluated the protective effects of PF on UV induced skin damage in vitro, and demonstrated that the effects were mediated via the ROS-p38-p53 pathway. The results of the present study demonstrated that treatment with PF (25, 50, and 100 uM) significantly increased the percentage of viable keratinocytes after UV-B exposure. In addition, cell death analysis indicated that PF treatment markedly reduced UV-B-radiation-induced apoptosis in keratinocytes, which was accompanied by increased procaspase 3 expression and decreased cleaved caspase 3 expression. Treatment with PF markedly reduced the production of ROS, and inhibited the activation of p38 and p53 in human keratinocytes, thus suggesting that the ROS-p38-p53 pathway has a role in UV-B induced skin damage. In conclusion, the present study reported that PF was able to attenuate UV-B-induced cell damage in human keratinocytes. Notably, these effects were shown to be mediated, at least in part, via inhibition of the ROS p38-p53 pathway. PMID- 26936105 TI - Renin-Angiotensin System Inhibitors: Do They Have the Same Impact at All Ages? PMID- 26936107 TI - 11th International meeting of the Asian Pacific Society of Periodontology. PMID- 26936106 TI - Effect of micronized pea seeds (Pisum sativum L.) as a substitute of soybean meal on tissue fatty acid composition and quality of broiler chicken meat. AB - This study aimed to evaluate the effect of micronized pea seeds introduced into feed mixes for broilers on the slaughter yield, blood lipid parameters, content of fatty acids in selected tissues, and meat quality. The studies involved 150 1 day-old Ross 308 chicks split into three groups (for 42 days). The feed rations differed in terms of the source of proteins: in the control group (C), it was post-extraction soybean meal (SBM) 100%; in group I, SBM 50% and micronized peas 50%; and in group II, micronized peas only, 100%. Irradiated pea seeds added to the feed ration for chicks reduced the fattening grade of carcasses (P < 0.05). Additionally, significant improvement of blood lipid indices was recorded. The share of the irradiated pea seeds in feed mixes decreased the share of saturated fatty acids in the muscles and abdominal fat and had a positive effect on the n 6/n-3 ratio, hypocholesterolemic / hypercholesterolemic ratio, as well as the atherogenic and thrombogenic indices (P < 0.05). PMID- 26936108 TI - Prevalence, incidence estimations, and risk factors of Toxoplasma gondii infection in Germany: a representative, cross-sectional, serological study. AB - Representative data on the extent of endemicity, burden, and risk of human toxoplasmosis are scarce. We assessed the prevalence and determinants of seropositivity of Toxoplasma gondii among adult participants of a nationwide representative cross-sectional survey in Germany. Sera collected from a representative cohort of adults (age 18-79; n = 6,663) in Germany were tested for anti-T. gondii IgG antibodies. Interview-derived data were used to evaluate associated factors. Multivariable logistic regression was applied using sampling weights and accounting for survey design cluster effects. Seroprevalence increased from 20% (95%-CI:17-23%) in the 18-29 age group to 77% (95%-CI:73-81%) in the 70-79 age group. Male gender, keeping cats and BMI >=30 were independent risk factors for seropositivity, while being vegetarian and high socio-economic status were negatively associated. Based on these data, we estimate 1.1% of adults and 1.3% of women aged 18-49 to seroconvert each year. This implies 6,393 seroconversions annually during pregnancies. We conclude that T. gondii infection in Germany is highly prevalent and that eating habits (consuming raw meat) appear to be of high epidemiological relevance. High numbers of seroconversions during pregnancies pose substantial risks for unborn children. Efforts to raise awareness of toxoplasmosis in public health programs targeting to T. gondii transmission control are therefore strongly advocated. PMID- 26936109 TI - Dispersal of Bacillus subtilis and its effect on strawberry phyllosphere microbiota under open field and protection conditions. AB - Using biological control agents (BCAs) is an essential component of integrated pest and diseases management. Despite much research on biocontrol of plant diseases, success in field crops has been limited with most successes being achieved in greenhouse cultivation. This lack of success is often attributed to the complex ecological processes involved in biocontrol. We used next generation sequencing (NGS) technology to study environmental fate of Bacillus subtilis, a widely used BCA, focusing on its dispersal aspect in open field and under protection. The dispersal of B. subtilis was very limited, particularly under protection. The reduction in the BCA population size was relatively small within 8 days; indeed, no overall reduction in the relative abundance was observed under the protected condition. These results suggested that limited dispersal is probably the main reason for its variable (and often low) control efficacy under field conditions. Thus to increase biocontrol efficacy, it is necessary to frequently apply this BCA with the application interval depending on the growth rate of target host tissues. Phyllosphere microbiota differed significantly between plants grown in open field and under protection but were not greatly affected by the introduced BCA. PMID- 26936110 TI - The perceptions of teenagers, young adults and professionals in the participation of bone cancer clinical trials. AB - The reasons why teenagers and young adults (TYA) with cancer do, or do not, participate in clinical trials is not wholly understood. We explored the perceptions and experiences of young people with bone cancer, and health professionals involved in their care, with regard to participation in two clinical trials. We conducted semi-structured interviews using narrative inquiry with 21 young people aged 15-24 years and 18 health professionals. New understandings emerged about perceptions of, and factors that influence participation in, clinical trials. These include perceptions about the importance and design of the clinical trial, communicating with young people in an age specific manner, using language young people are comfortable with, support from family, peers and specialists in teenage and young adult cancer care. We conclude that addressing these factors may increase acceptability of clinical trials and the trial design for TYA with cancer and ultimately improve their participation. Qualitative research has an important role in making explicit the perceptions and practices that ensure trials are patient-centred, appropriate and communicated effectively to TYA. Translating knowledge gained into routine practice, will go some way in ensuring that the disparities affecting this population are more fully understood. PMID- 26936111 TI - Integrated microRNA-gene analysis of coronary artery disease based on miRNA and gene expression profiles. AB - The present study aimed to investigate the key genes and microRNAs (miRNA/miRs) associated with coronary artery disease (CAD) progression. The gene expression profile of GSE20680 and GSE12288, and the miRNA expression profile of GSE28858 were downloaded from the gene expression omnibus database. The differentially expressed genes (DEGs) in GSE20680 and GSE12288, and the differentially expressed miRNAs in GSE28858 were screened using the limma package in R software. Common DEGs between GSE20680 and GSE12288 were selected. Functions and pathways of DEGs and miRNAs were enriched using the DAVID tool from the GO and KEGG databases. The regulatory network of miRNA and selected CAD-associated DEGs was constructed. A total of 270 DEGs (167 upregulated and 103 downregulated) based on the GSE20680 dataset, and 2,268 DEGs (534 upregulated and 1,734 downregulated) based on the GSE12288 dataset, were screened. For the differentially expressed miRNAs, 214 were identified (102 upregulated and 112 downregulated) in CAD samples and were screened. Interferon regulatory factor 2 (IRF2) and cell death-inducing DFFA-like effector b (CIDEB), which are regulated by signal transducer and activator of transcription 3 and myc-associated factor X, were identified as common DEGs for CAD. miR-455-5p, miR-455-3p and miR-1257, which are involved in the major histocompatibility complex (MHC)protein assembly pathway and peptide antigen assembly with MHC class I protein complex pathway, may regulate various miRNAs and target genes, including pro-opiomelancortin (POMC), toll-like receptor 4 (TLR4), interleukin 10 (IL10), activating transcription factor 6 (ATF6) and calreticulin (CALR). The current study identified IRF2 and CIDEB as crucial genes, and miRNA-455-5p, miRNA-455-3p and miR-1257 along with their target genes POMC, TLR4 and CALR, as miRNAs involved in CAD progression. Thus, the present study may provide a basis for future research into the progression mechanism of CAD. PMID- 26936112 TI - Bioelectrodes based on pseudocapacitive cellulose/polypyrrole composite improve performance of biofuel cell. AB - Enzymatic electrodes with high internal capacitance, based on cellulose/polypyrrole composite were optimized and utilized to design improved enzymatic fuel cell. Fructose dehydrogenase Gluconobacter sp. specifically adsorbed on the cellulose/polypyrrole matrix and electrophoretically immobilized and electrochemically entrapped Laccase Trametes versicolor, were used as the anode and cathode bioelectrocatalysts, respectively. The cellulose/polypyrrole composite film exhibited pseudocapacitive properties under mild pH conditions. Following modification with carboxylic groups the composite material enabled highly efficient adsorption of enzyme and provided good electrical contact between the enzymatic active sites and the electrode surface. The modified cellulose/polypyrrole composite based electrode was used for the anode leading to mediatorless fructose oxidation giving large catalytic current density, 12.8mAcm( 2). Laccase and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) as the mediator entrapped in the cellulose/polypyrrole composite film generated dioxygen reduction current density of 2mAcm(-2). Application of pseudocapacitive matrix and decreasing the distance between electrodes to 1mm lead to improvement of the biofuel cell power output and its regeneration ability. The power of the cell was found to increase by introduction of a preconditioning step during which the cell was kept at open circuit voltage under fuel flow. After 24h of preconditioning the matrix was recharged and the device output reached the power, 2.1mWcm(-2) and OCV, 0.59V. PMID- 26936113 TI - Investigation of the metabolic consequences of impregnating spinach leaves with trehalose and applying a pulsed electric field. AB - The impregnation of leafy vegetables with cryoprotectants using a combination of vacuum impregnation (VI) and pulsed electric fields (PEF) has been proposed by our research group as a method of improving their freezing tolerance and consequently their general quality after thawing. In this study, we have investigated the metabolic consequences of the combination of these unit operations on spinach. The vacuum impregnated spinach leaves showed a drastic decrease in the porosity of the extracellular space. However, at maximum weight gain, randomly located air pockets remained, which may account for oxygen consuming pathways in the cells being active after VI. The metabolic activity of the impregnated leaves showed a drastic increase that was further enhanced by the application of PEF to the impregnated tissue. Impregnating the leaves with trehalose by VI led to a significant accumulation of trehalose-6-phosphate (T6P), however, this was not further enhanced by PEF. It is suggested that the accumulation of T6P in the leaves may increase metabolic activity, and increase tissue resistance to abiotic stress. PMID- 26936114 TI - A Distinct Class of Chromoanagenesis Events Characterized by Focal Copy Number Gains. AB - Chromoanagenesis is the process by which a single catastrophic event creates complex rearrangements confined to a single or a few chromosomes. It is usually characterized by the presence of multiple deletions and/or duplications, as well as by copy neutral rearrangements. In contrast, an array CGH screen of patients with developmental anomalies revealed three patients in which a single chromosome carries from 8 to 11 large copy number gains confined to a single chromosome or chromosomal arm, but the absence of deletions. Subsequent fluorescence in situ hybiridization and massive parallel sequencing revealed the duplicons to be clustered together in distinct locations across the altered chromosomes. Breakpoint junction sequences showed both microhomology and non-templated insertions of up to 40 bp. Hence, these patients each demonstrate a single altered chromosome of clustered insertional duplications, no deletions, and breakpoint junction sequences showing microhomology and/or non-templated insertions. These observations are difficult to reconcile with current mechanistic descriptions of chromothripsis and chromoanasynthesis. Therefore, we hypothesize those rearrangements to be of a mechanistically different origin. In addition, we suggest that large untemplated insertional sequences observed at breakpoints are driven by a non-canonical non-homologous end joining mechanism. PMID- 26936115 TI - Impact of Catheter Ablation for Paroxysmal Atrial Fibrillation in Patients With Sick Sinus Syndrome - Important Role of Non-Pulmonary Vein Foci. AB - BACKGROUND: The clinical efficacy of catheter ablation (CA) for paroxysmal atrial fibrillation (PAF) in patients with sick sinus syndrome (SSS) and the mechanism and predictors of recurrence are not yet completely elucidated. METHODS AND RESULTS: Of 963 consecutive patients who underwent PAF ablation during the study period, a total of 108 patients with SSS (SSS group) and 108 matched controls without SSS (non-SSS group) were followed up. During the follow-up period (mean, 32.8+/-17.5 months), the SSS group had significantly higher AF recurrence rate since the last procedure than the non-SSS group (26.9% vs. 12.0%; P=0.02). The SSS group had significantly higher prevalence of non-pulmonary vein (non-PV) foci than the non-SSS group (25.9% vs. 13.9%; P=0.027). On multivariate analysis congestive heart failure (HR, 13.7; 95% CI: 1.57-119; P=0.02) and non-PV foci (HR, 5.75; 95% CI: 1.69-19.6; P=0.005) were independent predictors of recurrence following CA in the SSS group. In the SSS group, 88 patients had bradycardia tachycardia syndrome without prior permanent pacemaker implantation. Of these, 6 required pacemaker implantation because of AF and sinus pause recurrence. CONCLUSIONS: Patients with SSS are at higher risk of AF recurrence after CA. Non PV foci are associated with AF recurrence following PAF with SSS. PMID- 26936116 TI - Forced expression of Nanog with mRNA synthesized in vitro to evaluate the malignancy of HeLa cells through acquiring cancer stem cell phenotypes. AB - Nanog is a pluripotency-related factor. It was also found to play an important role in tumorigenesis. To date, the mechanisms underlying cervical tumorigenesis still need to be elucidated. In the present study, Nanog mRNA was synthesized in vitro and transfected into HeLa cells. After mRNA transfection, the forced expressed of Nanog in HeLa cells led to markedly increased invasion, migration, resistance to chemotherapeutic agents and dedifferentiation. In a subcutaneous xenograft assay, these cells had significantly increased tumorigenic capacity. Real-time PCR indicated that Nanog-induced dedifferentiation was associated with increased expression of endogenous Oct4, Sox2 and FoxD3. In addition, the dedifferentiated HeLa cells acquired features associated with cancer stem cells (CSCs), such as multipotent differentiation capacity, and expression of CSC markers such as CD133. These data imply that Nanog is a positive regulator of cervical cancer dedifferentiation. PMID- 26936117 TI - Bifunctional hairy silica nanoparticles as high-performance additives for lubricant. AB - Bifunctional hairy silica nanoparticles (BHSNs), which are silica nanoparticles covered with alkyl and amino organic chains, were prepared as high-performance additives for lubricants. Compared with hairy silica nanoparticles covered by a single type of organic chain, binary hairy silica nanoparticles exhibit the advantages of both types of organic chains, which exhibit excellent compatibility with lubricants and adsorbability to metal surfaces. Nanoparticles with different ratios of amino and alkyl ligands were investigated. In comparison to an untreated lubricant, BHSNs reduce the friction coefficient and wear scar diameter by 40% and 60%, respectively. The wear mechanism of BHSNs was investigated, and the protective and filling effect of the nanoparticles improved because of collaboration of amino and alkyl ligands. PMID- 26936118 TI - Weathering of field-collected floating and stranded Macondo oils during and shortly after the Deepwater Horizon oil spill. AB - Chemical analysis of large populations of floating (n=62) and stranded (n=1174) Macondo oils collected from the northern Gulf of Mexico sea surface and shorelines during or within seven weeks of the end of the Deepwater Horizon oil spill demonstrates the range, rates, and processes affecting surface oil weathering. Oil collected immediately upon reaching the sea surface had already lost most mass below n-C8 from dissolution of soluble aliphatics, monoaromatics, and naphthalenes during the oil's ascent with further reductions extending up to n-C13 due to the onset of evaporation. With additional time, weathering of the floating and stranded oils advanced with total PAH (TPAH50) depletions averaging 69+/-23% for floating oils and 94+/-3% for stranded oils caused by the combined effects of evaporation, dissolution, and photo-oxidation, the latter of which also reduced triaromatic steroid biomarkers. Biodegradation was not evident among the coalesced floating oils studied, but had commenced in some stranded oils. PMID- 26936119 TI - Bioaccumulation of heavy metals in marine organisms and sediments from Admiralty Bay, King George Island, Antarctica. AB - The Antarctic continent is considered a low-impact environment; however, there is a tendency to increase the contaminants' levels due to human activities in the research stations. In this study, As, Cd, Cr, Cu, Hg, Ni, Pb and Zn levels in sediment and biota were determined in the environmental samples from Admiralty Bay (King George Island, Antarctica) collected in 2003. The results demonstrated high concentrations of Cu and Zn in the sediments. There was bioaccumulation of As in the biota from Admiralty Bay and bioaccumulation of Zn specifically in the biota from Martel Inlet. In addition, the results were useful in order to understand the heavy metal levels for the pre-accident condition of Comandante Ferraz Antarctic Station, where an accident occurred in 2012, and also for the comparison with current conditions within the monitoring work developed by INCT APA (National Institute of Science and Technology for Environmental Research Antarctic). PMID- 26936120 TI - Phosphorus as a driver of nitrogen limitation and sustained eutrophic conditions in Bolinao and Anda, Philippines, a mariculture-impacted tropical coastal area. AB - The dynamics of nitrogen (N) and phosphorus (P) was studied in mariculture areas around Bolinao and Anda, Philippines to examine its possible link to recurring algal blooms, hypoxia and fish kills. They occur despite regulation on number of fish farm structures in Bolinao to improve water quality after 2002, following a massive fish kill in the area. Based on spatiotemporal surveys, coastal waters remained eutrophic a decade after imposing regulation, primarily due to decomposition of uneaten and undigested feeds, and fish excretions. Relative to Redfield ratio (16), these materials are enriched in P, resulting in low N/P ratios (~6.6) of regenerated nutrients. Dissolved inorganic P (DIP) in the water reached 4MUM during the dry season, likely exacerbated by increase in fish farm structures in Anda. DIP enrichment created an N-limited condition that is highly susceptible to sporadic algal blooms whenever N is supplied from freshwater during the wet season. PMID- 26936121 TI - Abiotic factors influencing biomass accumulation of green tide causing Ulva spp. on Pyropia culture rafts in the Yellow Sea, China. AB - Annually recurrent green-tides in the Yellow Sea have been shown to result from direct disposal into the sea of fouling Ulva from Pyropia aquaculture. The role abiotic factors play in Ulva biomass accumulation on rafts was studied to find ways to mitigate this problem. Dissolved inorganic nitrogen (DIN) was very high at all sites, but the highest Ulva biomass was associated with the lowest DIN and anthropogenic N. Under luxuriant background nutrient conditions, variability in temperature and periods of emersion, rather than pH, light and salinity determined Ulva biomass. Two dominant species of Ulva displayed differing tolerances to temperature and desiccation which helped explain why Ulva prolifera dominates floating green-tides. Rather than trying to mitigate green-tides only by reducing nutrient pollution, an earlier harvest of Pyropia in southern Jiangsu Province especially before temperatures increase greatly above 10 degrees C during April, could reduce the biomass of U. prolifera disposed from rafts. PMID- 26936122 TI - Incidence of plastic debris in Sooty Tern nests: A preliminary study on Trindade Island, a remote area of Brazil. AB - Plastic is abundant in the oceans, reaching pelagic zones away from continents. Here we present the first recordings of plastic used as nest material in Sooty Tern nests, on a remote oceanic island. We describe our findings in terms of quantity, size and color of plastic debris. A total of 78 plastics were noted in 54 nests. Four color categories were found: Blue, White, Green and Red. Blue fragments were the most frequent color, present three times as much as white debris. This pattern was present despite blue fragments being smaller and lighter. The plastic debris of lowest frequency were the larger and heavier pieces (red). To our knowledge this is the first record of plastic in Sooty Tern nests. Trindade Island is on an oceanic zone expected to accumulate garbage due to the dynamic ocean currents. Such findings call for a closer inspection of pollution in the Atlantic Ocean. PMID- 26936123 TI - Synergistic effect of elevated temperature, pCO2 and nutrients on marine biofilm. AB - Natural marine biofilms provide signatures of the events that occur over a period of time and can be used as bioindicators of environmental changes. Hence, the effects of temperature (30 and 34 degrees C), pCO2 (400 and 1500MUatm) and nutrients (unenriched and enriched f/2 media) on the marine biofilm were evaluated using a 2*2*2 factorial design. In unenriched condition, acidification significantly increased the abundance of phytoperiphytes whereas reduced that of bacteria and it was vice versa in the enriched condition. Warming had significant negative effect on the abundance of both phytoperiphytes and bacteria, except in unenriched condition wherein it favoured bacterial growth. Synergistically, acidification and warming had deleterious effects resulting in further reduction in the abundance of both phytoperiphytes and bacteria, except in enriched condition wherein bacterial abundance increased. Such changes in biofilm communities in response to warming and acidification can have cascading effect on the subsequent build-up of macrofouling community. PMID- 26936124 TI - The Saudi Law of Ethics of Research on Living Creatures and its Implementing Regulations. AB - The Kingdom of Saudi Arabia passed a Law and Implementing Regulations of Ethics of Research on Living Creatures in 14/09/1431 Hijri (24/08/2010). We have performed an ethical analysis of this law and, accordingly, this paper discusses the major components, key strengths, and weaknesses of this law. The Saudi system considers Islamic Shariah in addition to international research ethics guidelines. The Law and its Implementing Regulations contain all ethical requirements for research. We conclude that this law can serve as an example, not only for other Arab countries in the region that have similar values and social structure to the Kingdom of Saudi Arabia, but also for other Islamic countries. PMID- 26936125 TI - Resveratrol attenuates neuronal autophagy and inflammatory injury by inhibiting the TLR4/NF-kappaB signaling pathway in experimental traumatic brain injury. AB - Previous research has demonstrated that traumatic brain injury (TBI) activates autophagy and a neuroinflammatory cascade that contributes to substantial neuronal damage and behavioral impairment, and Toll-like receptor 4 (TLR4) is an important mediator of this cascade. In the present study, we investigated the hypothesis that resveratrol (RV), a natural polyphenolic compound with potent multifaceted properties, alleviates brain damage mediated by TLR4 following TBI. Adult male Sprague Dawley rats, subjected to controlled cortical impact (CCI) injury, were intraperitoneally injected with RV (100 mg/kg, daily for 3 days) after the onset of TBI. The results demonstrated that RV significantly reduced brain edema, motor deficit, neuronal loss and improved spatial cognitive function. Double immunolabeling demonstrated that RV decreased microtubule associated protein 1 light chain 3 (LC3), TLR4-positive cells co-labeled with the hippocampal neurons, and RV also significantly reduced the number of TLR4 positive neuron-specific nuclear protein (NeuN) cells following TBI. Western blot analysis revealed that RV significantly reduced the protein expression of the autophagy marker proteins, LC3II and Beclin1, in the hippocampus compared with that in the TBI group. Furthermore, the levels of TLR4 and its known downstream signaling molecules, nuclear factor-kappaB (NF-kappaB), and the inflammatory cytokines, interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha were also decreased after RV treatment. Our results suggest that RV reduces neuronal autophagy and inflammatory reactions in a rat model of TBI. Thus, we suggest that the neuroprotective effect of RV is associated with the TLR4/NF-kappaB signaling pathway. PMID- 26936126 TI - 10-pi-Electron arenes a la carte: structure and bonding of the [E-(CnHn)-E](n-6) (E = Ca, Sr, Ba; n = 6-8) complexes. AB - In this paper, we provide solid evidence to show that among an overwhelming structural diversity, alkaline earth metals (Ca, Sr, Ba) have the ability to form inverted sandwich compounds with C6H6, C7H7(+), and C8H8(2+) of Dnh symmetry and general formula [E-(CnHn)-E](n-6) (n = 6-8) with planar 10-pi-electron aromatic cores by virtue of transferring two electrons per metal atom to the ring. However, the origin of the orbital interaction between the metals and the carbon ring is quite different; while [E-(C6H6)-E] complexes are dominated by delta interactions, both pi- and delta-interactions are important in [E-(C7H7)-E](+) and [E-(C8H8)-E](2+) complexes. PMID- 26936127 TI - Water fluxes and encapsulation efficiency in double emulsions: impact of emulsification and osmotic pressure unbalance. AB - We study the influence of the emulsification process on encapsulation efficiency of drugs in double water-in-oil-in-water emulsions. Two drugs were used, first vitamin B12 which can be considered as a model drug and secondly a suspension of Cydia pomonella Granulovirus (CpGV), a virus used in organic agriculture to protect fruits against the Carpocapse insect. Encapsulation is measured by classical UV-Vis spectroscopy method. Additionally we show that rheology is a useful tool to determine water exchanges during emulsification. In a two-step emulsification process, using rotor-stator mixers, encapsulation reaches high levels, close to 100% whatever the flowing regime. This encapsulation decreases only if two conditions are fulfilled simultaneously: (i) during the second emulsification step the flow is turbulent and (ii) it leads to excessive fragmentation inducing formation of too small drops. We also investigate the effect of a deliberate loss of osmotic pressure balance on the encapsulation and characterize the induced water fluxes. We show that encapsulation of vitamin B12 is not affected by the osmotic pressure unbalance, while water exchanges, if they exist, are very fast and aim at restoring equilibrium. As a consequence, the emulsification efficiency is not very sensitive to osmotic stresses provided that the interfaces resist mechanically. PMID- 26936128 TI - mTOR signaling pathway is inhibited downstream of the cyclophilin D-mediated mitochondrial permeability transition in honokiol-triggered regulated necrosis. AB - Honokiol (HNK) is a pharmacologically active small molecule that is isolated from the traditional Chinese medicinal herb, houpu. It may induce diversified types of regulated cell death, which are dependent on different cell types and varying concentrations of therapeutic agent. We previously reported that HNK triggers a cyclophilin D (CypD)-mediated regulated necrosis in various cell lines at certain concentrations (two-fold higher than its half maximal inhibitory concentration). Subsequent study revealed that HNK induced cell death transition from early apoptosis to regulated necrosis in parallel with the increase of HNK dose. In the current study, a lower concentration of HNK (30 ug/ml) than previously reported also induced simplex CypD-mediated mitochondrial permeability transition (MPT) associated regulated necrosis in the HEK-293 human embryonic kidney cell line. HNK, at concentration of 30 ug/ml, induced necrotic cell death in HEK-293 cells, which was demonstrated by positive staining for propidium iodide. No DNA ladder patterns or apoptotic bodies were detected in cells that underwent this type of necrotic cell death. Caspase-8 and -3 were not activated during the process of HNK-induced necrosis. In addition, pan-caspase inhibitor, z-VAD-fmk and receptor interacting protein 1 inhibitor, necrostatin-1 did not inhibit HNK-induced necrosis. However, CypD inhibitor, cyclosporin A (CsA), blocked HNK-induced necrosis. These findings indicate that 30 ug/ml HNK induced simplex CypD-mediated MPT-associated regulated necrosis in HEK-293 cells. Furthermore, the findings demonstrated that during HNK-triggered regulated necrosis the mammalian target of rapamycin (mTOR) signaling pathway is also inhibited. Pretreatment with CsA, therefore, inhibits HNK-triggered regulated necrosis and reverses dephosphorylation of Akt, eIF4E-binding protein 1 and S6 kinase. This indicated that the mTOR signaling pathway is effective downstream of the CypD-mediated MPT and before the onset of plasma membrane breakdown during the regulated necrosis process. Therefore, it has been demonstrated for the first time, to the best of our knowledge, that the mTOR signaling pathway was inhibited downstream of the CypD-mediated MPT in the process of HNK-induced regulated necrosis. PMID- 26936130 TI - Are condom-promotion interventions reaching internal migrants in China? Integrated evidence from two cross-sectional surveys. AB - Behavioral interventions containing behavior change techniques (BCTs) that do not reach the target populations sufficiently will fail to accomplish their desired outcome. To guide sexually transmitted infection prevention policy for internal migrants in China, this study examines the extent to which BCTs aiming at increasing condom use reach the migrants and investigates the preference of the target population for these techniques among 364 migrants and 44 healthcare workers (HCWs) in Shenzhen, China. The results show that condom-promotion techniques that had been offered by HCWs to internal migrants reached a limited proportion of the population (range of reach ratio: 17.6-55.0%), although there appears to be a good match between what is offered and what is preferred by Chinese internal migrants regarding condom-promotion techniques (rank difference <= 1). Our findings highlight the need to increase the reach of condom-promotion techniques among Chinese internal migrants, and suggest techniques that are likely to reach the target population and match their preferred health education approaches. PMID- 26936129 TI - YB-1, a new biomarker of glioma progression, is associated with the prognosis of glioma patients. AB - Y box protein 1 (YB-1) is a multifunctional cellular protein expressed in various cancers, and is a potential target in cancer therapy. Although there is evidence showing that YB-1 plays a role in human cancers, the clinical significance of YB 1 expression in glioma has not been established. In the present study, we investigated the YB-1 level in glioma tumors and analyzed the relationship between the YB-1 level and the grade of malignant glioma, with the aim of providing new ideas for the diagnosis and treatment of gliomas in clinical and basic research settings. A total of 108 patients, comprising 14, 31, 30, and 33 with gliomas of Grades I, II, III, and IV, respectively, were included in this study. The mRNA and protein levels of YB-1 were found to be significantly different between Grade IV and lower-grade tumors. The YB-1 levels in cerebrospinal fluid were significantly higher in Grades III and IV glioma patients than in Grades I and II patients. Immunofluorescence staining was used to detect the levels of YB-1 in the cytoplasm and the nucleus, and results indicated that the intracellular distribution was significantly associated with the pathological grade of glioma. A higher level of YB-1 was associated with shortened survival, suggesting that YB-1 plays a role in the progression of human glioma. PMID- 26936131 TI - Fabricating large two-dimensional single colloidal crystals by doping with active particles. AB - Using simulations we explore the behaviour of two-dimensional colloidal (poly)crystals doped with active particles. We show that these active dopants can provide an elegant new route to removing grain boundaries in polycrystals. Specifically, we show that active dopants both generate and are attracted to defects, such as vacancies and interstitials, which leads to clustering of dopants at grain boundaries. The active particles both broaden and enhance the mobility of the grain boundaries, causing rapid coarsening of the crystal domains. The remaining defects recrystallize upon turning off the activity of the dopants, resulting in a large-scale single-domain crystal. PMID- 26936132 TI - Electronic communication in phosphine substituted bridged dirhenium complexes - clarifying ambiguities raised by the redox non-innocence of the C4H2- and C4 bridges. AB - The mononuclear rhenium carbyne complex trans-[Re(C[triple bond, length as m dash]CSiMe3)([triple bond, length as m-dash]C-Me)(PMe3)4][PF6] (2) was prepared in 90% yield by heating a mixture of the dinitrogen complex trans [ReCl(N2)(PMe3)4] (1), TlPF6, and an excess of HC[triple bond, length as m dash]CSiMe3. 2 could be deprotonated with KOtBu to the vinylidene complex trans [Re(C[triple bond, length as m-dash]CSiMe3)([double bond, length as m dash]C[double bond, length as m-dash]CH2)(PMe3)4] (3) in 98% yield. Oxidation of 3 with 1.2 equiv. of [Cp2Fe][PF6] at -78 degrees C gave the Cbeta-C'beta coupled dinuclear rhenium biscarbyne complex trans-[(Me3SiC[triple bond, length as m dash]C)(PMe3)4Re[triple bond, length as m-dash]C-CH2-CH2-C[triple bond, length as m-dash]Re(PMe3)4(C[triple bond, length as m-dash]CSiMe3)][PF6]2 (5) in 92% yield. Deprotonation of 5 with an excess of KOtBu in THF produced the diamagnetic trans [(Me3SiC[triple bond, length as m-dash]C)(PMe3)4Re[double bond, length as m dash]C[double bond, length as m-dash]CH-CH[double bond, length as m-dash]C[double bond, length as m-dash]Re(PMe3)4(C[triple bond, length as m-dash]CSiMe3)] complex (E-6(S)) in 87% yield with an E-butadienediylidene bridge. Density functional theory (DFT) calculations of E-6(S) confirmed its singlet ground state. The Z form of 6 (Z-6(S)) could not be observed, which is in accord with its DFT calculated 17.8 kJ mol(-1) higher energy. Oxidation of E-6 with 2 equiv. of [Cp2Fe][PF6] resulted in the stable diamagnetic dicationic trans-[(Me3SiC[triple bond, length as m-dash]C)(PMe3)4Re[triple bond, length as m-dash]C-CH[double bond, length as m-dash]CH-C[triple bond, length as m-dash]Re(PMe3)4(C[triple bond, length as m-dash]CSiMe3)][PF6]2 complex (E-6[PF6]2) with an ethylenylidene dicarbyne structure of the bridge. The paramagnetic mixed-valence (MV) complex E 6[PF6] was obtained by comproportionation of E-6(S) and E-6[PF6]2 or by oxidation of E-6(S) with 1 equiv. of [Cp2Fe][PF6]. The dicationic trans-[(Me3SiC[triple bond, length as m-dash]C)(PMe3)4Re[triple bond, length as m-dash]C-C[triple bond, length as m-dash]C-C[triple bond, length as m-dash]Re(PMe3)4(C[triple bond, length as m-dash]CSiMe3)][PF6]2 (7[PF6]2) complex, attributed a butynedi(triyl) bridge structure, was obtained by deprotonation of E-6[PF6]2 with KOtBu followed by oxidation with 2 equiv. of [Cp2Fe][PF6]. The neutral complex 7 could be accessed best by reduction of 7[PF6]2 with KH in the presence of 18-crown-6. According to DFT calculations 7 possesses two equilibrating electronic states: diamagnetic 7(S) and triplet 7(F) with ferromagnetically coupled spins. The latter is calculated to be 5.2 kcal mol(-1) lower in energy than 7(S). There is experimental evidence that 7(S) prevails in solution. 7 could not be isolated in the crystalline state and is unstable transforming mainly by H-abstraction to give E-6(S). UV-Vis-NIR spectroscopy for the dinuclear rhenium complexes E-6(S), E-6[PF6] and E-6[PF6]2, as well as EPR spectroscopic and variable-temperature magnetization measurements for the MV complex E-6[PF6] were also conducted. Spectro-electrochemical reduction studies on 7[PF6]2 allowed the characterization of the mono- and direduced forms of 7(+) and 7 by means of IR- and UV-Vis-NIR spectroscopy and revealed the chemical fate of the higher reduced form. PMID- 26936134 TI - Salt Promotes Passive Overconsumption of Dietary Fat in Humans. AB - BACKGROUND: Excess fat consumption has been linked to the development of obesity. Fat and salt are a common and appetitive combination in food; however, the effect of either on food intake is unclear. Fat taste sensitivity has been negatively associated with dietary fat intake, but how fat taste sensitivity influences the intake of fat within a meal has, to our knowledge, not yet been investigated. OBJECTIVES: Our objectives were, first, to investigate the effects of both fat and salt on ad libitum food intake and, second, to investigate the effects of fat taste sensitivity on satiation responses to fat and whether this was affected by salt. METHODS: Forty-eight healthy adults [16 men and 32 women, aged 18-54 y, body mass index (kg/m(2)): 17.8-34.4] were recruited and their fat taste sensitivity was measured by determination of the detection threshold of oleic acid (18:1n-6). In a randomized 2 * 2 crossover design, participants attended 4 lunchtime sessions after a standardized breakfast. Meals consisted of elbow macaroni (56%) with sauce (44%); sauces were manipulated to be1) low-fat (0.02% fat, wt:wt)/low-salt (0.06% NaCl, wt:wt),2) low-fat/high-salt (0.5% NaCl, wt:wt),3) high-fat (34% fat, wt:/wt)/low-salt, or4) high-fat/high-salt. Ad libitum intake (primary outcome) and eating rate, pleasantness, and subjective ratings of hunger and fullness (secondary outcomes) were measured. RESULTS: Salt increased food and energy intakes by 11%, independent of fat concentration (P= 0.022). There was no effect of fat on food intake (P= 0.6), but high-fat meals increased energy intake by 60% (P< 0.001). A sex * fat interaction was found (P= 0.006), with women consuming 15% less by weight of the high-fat meals than the low-fat meals. Fat taste sensitivity was negatively associated with the intake of high-fat meals but only in the presence of low salt (fat taste * salt interaction on delta intake of high-fat - low-fat meals;P= 0.012). CONCLUSIONS: The results suggest that salt promotes passive overconsumption of energy in adults and that salt may override fat-mediated satiation in individuals who are sensitive to the taste of fat. This trial was registered at the Australian New Zealand Clinical Trials Registry (www.anzctr.org.au) as ACTRN12615000048583. PMID- 26936133 TI - Itk is required for Th9 differentiation via TCR-mediated induction of IL-2 and IRF4. AB - Th9 cells produce interleukin (IL)-9, a cytokine implicated in allergic asthma and autoimmunity. Here we show that Itk, a mediator of T cell receptor signalling required for Th2 immune responses and the development of asthma, is a positive regulator of Th9 differentiation. In a model of allergic lung disease, Itk deficient mice show reduced pulmonary inflammation and IL-9 production by T cells and innate lymphoid type 2 cells (ILC2), despite normal early induction of ILC2s. In vitro, Itk(-/-) CD4(+) T cells do not produce IL-9 and have reduced levels of IRF4 (Interferon Regulator Factor 4), a critical transcription factor for effector T cell function. Both IL-9 and IRF4 expression are rescued by either IL 2 or constitutively active STAT5, but not NFATc1. STAT5 binds the Irf4 promoter, demonstrating one mechanism by which IL-2 rescues weakly activated T cells. Itk inhibition also reduces IL-9 expression by human T cells, implicating ITK as a key regulator of Th9 induction. PMID- 26936135 TI - The Omega-3 Index Is Inversely Associated with Depressive Symptoms among Individuals with Elevated Oxidative Stress Biomarkers. AB - BACKGROUND: Omega-3 (n-3) fatty acid (FA) consumption is thought to improve depressive symptoms. However, current evidence is limited, and whether this association exists among Puerto Ricans, a population burdened by depression, remains uncertain. OBJECTIVES: We examined the association between omega-3 FA biomarkers and depressive symptoms as well as the potential influence of oxidative stress. METHODS: Baseline and longitudinal analyses were conducted in the Boston Puerto Rican Health Study (n= 787; participants aged 57 +/- 0.52 y, 73% women). Urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) concentration, a measure of oxidative stress, and erythrocyte FA composition were collected at baseline. We calculated the omega-3 index as the sum of eicosapentaenoic and docosahexaenoic acids, expressed as a percentage of total FAs. Baseline and 2-y depressive symptoms were characterized by using the Center for Epidemiological Studies-Depression Scale (CES-D). Statistical analyses included linear and logistic regression. RESULTS: Urinary 8-OHdG concentration tended to modify the relation between the erythrocyte omega-3 index and baseline CES-D score (P interaction = 0.10). In stratified analyses, the omega-3 index was inversely associated with CES-D score (beta = -1.74, SE = 0.88;P= 0.02) among those in the top quartile of 8-OHdG concentration but not among those in the lower quartiles. The relation between the omega-3 index and CES-D at 2 y was more clearly modified by 8-OHdG concentration (P-interaction = 0.04), where the omega-3 index was inversely associated with CES-D at 2 y, adjusted for baseline (beta = -1.66, SE = 0.66;P= 0.02), only among those with elevated 8-OHdG concentrations. Among individuals not taking antidepressant medications and in the top tertile of urinary 8-OHdG concentration, the omega-3 index was associated with significantly lower odds of a CES-D score >=16 at baseline (OR: 0.72; 95% CI: 0.53, 0.96) but not at 2 y (OR: 0.83; 95% CI: 0.60, 1.15). CONCLUSIONS: An inverse association between the omega-3 index and depressive symptoms was observed among participants with elevated oxidative stress biomarkers. These data suggest that oxidative stress status may identify those who might benefit from omega-3 FA consumption to improve depressive symptoms. PMID- 26936136 TI - Flavanol-Enriched Cocoa Powder Alters the Intestinal Microbiota, Tissue and Fluid Metabolite Profiles, and Intestinal Gene Expression in Pigs. AB - BACKGROUND: Consumption of cocoa-derived polyphenols has been associated with several health benefits; however, their effects on the intestinal microbiome and related features of host intestinal health are not adequately understood. OBJECTIVE: The objective of this study was to determine the effects of eating flavanol-enriched cocoa powder on the composition of the gut microbiota, tissue metabolite profiles, and intestinal immune status. METHODS: Male pigs (5 mo old, 28 kg mean body weight) were supplemented with 0, 2.5, 10, or 20 g flavanol enriched cocoa powder/d for 27 d. Metabolites in serum, urine, the proximal colon contents, liver, and adipose tissue; bacterial abundance in the intestinal contents and feces; and intestinal tissue gene expression of inflammatory markers and Toll-like receptors (TLRs) were then determined. RESULTS: O-methyl epicatechin-glucuronide conjugates dose-dependently increased (P< 0.01) in the urine (35- to 204-fold), serum (6- to 186-fold), and adipose tissue (34- to 1144 fold) of pigs fed cocoa powder. The concentration of 3-hydroxyphenylpropionic acid isomers in urine decreased as the dose of cocoa powder fed to pigs increased (75-85%,P< 0.05). Compared with the unsupplemented pigs, the abundance ofLactobacillusspecies was greater in the feces (7-fold,P= 0.005) and that ofBifidobacteriumspecies was greater in the proximal colon contents (9-fold,P= 0.01) in pigs fed only 20 or 10 g cocoa powder/d, respectively. Moreover, consumption of cocoa powder reducedTLR9gene expression in ileal Peyer's patches (67-80%,P< 0.05) and mesenteric lymph nodes (43-71%,P< 0.05) of pigs fed 2.5-20 g cocoa powder/d compared with pigs not supplemented with cocoa powder. CONCLUSION: This study demonstrates that consumption of cocoa powder by pigs can contribute to gut health by enhancing the abundance ofLactobacillusandBifidobacteriumspecies and modulating markers of localized intestinal immunity. PMID- 26936137 TI - Dietary Inflammatory Potential during Pregnancy Is Associated with Lower Fetal Growth and Breastfeeding Failure: Results from Project Viva. AB - BACKGROUND: Inflammation during pregnancy has been linked to adverse maternal and infant outcomes. There is limited information available on the contribution of maternal diet to systemic inflammation and pregnancy health. OBJECTIVE: The objective of this study was to examine associations of maternal prenatal dietary inflammatory index (DII), a composite measure of the inflammatory potential of diet, with markers of maternal systemic inflammation and pregnancy outcomes. METHODS: We studied 1808 mother-child pairs from Project Viva, a pre-birth cohort study in Massachusetts. We calculated the DII from first- and second-trimester food-frequency questionnaires by standardizing the dietary intakes of participants to global means, which were multiplied by the inflammatory effect score and summed. We examined associations of DII with maternal plasma C-reactive protein and white blood cell count in the second trimester and the following perinatal outcomes: gestational diabetes, preeclampsia, length of gestation, fetal growth, mode of delivery, and duration of breastfeeding. We used multivariable linear and logistic regression models to analyze the strength of these associations. RESULTS: Maternal age was (mean +/- SD) 32.2 +/- 5.0 y, prepregnancy body mass index (BMI; in kg/m(2)) was 24.9 +/- 5.2, and DII was 2.56 +/- 1.42 units with a range of -5.4 to 3.7. DII was positively correlated with prepregnancy BMI (Pearson'sr= 0.13,P< 0.0001). Higher DII scores, reflecting more proinflammatory dietary potential, were associated with higher second trimester plasma CRP (beta: 0.08 mg/L per 1-unit increase in maternal DII; 95% CI: 0.02, 0.14) and lower birth weight for gestational agezscore in infants born to obese mothers (beta: -0.10zscore per 1-unit increase in maternal DII; 95% CI: 0.18, -0.02). Higher DII scores were associated with lower odds of breastfeeding for at least 1 mo (OR = 0.85; 95% CI: 0.74, 0.98). CONCLUSION: A proinflammatory diet during pregnancy is associated with maternal systemic inflammation and may be associated with impaired fetal growth and breastfeeding failure. PMID- 26936139 TI - High-Molecular-Weight beta-Glucan Decreases Serum Cholesterol Differentially Based on the CYP7A1 rs3808607 Polymorphism in Mildly Hypercholesterolemic Adults. AB - BACKGROUND: beta-Glucan, a soluble fiber with viscous property, has a documented cholesterol-lowering effect. The molecular weight (MW) of beta-glucan, which contributes to viscosity, and an individual's genotype might influence the cholesterol-lowering efficacy of beta-glucan. OBJECTIVES: This study was designed to determine whether the cholesterol-lowering efficacy of barley beta-glucan varied as a function of MW and the daily dose consumed. Our second aim was to determine whether any gene-diet interactions are associated with the cholesterol lowering efficacy of beta-glucan. METHODS: In a randomized controlled crossover trial, 30 mildly hypercholesterolemic adults [12 men and 18 women, aged 27-78 y; body mass index (in kg/m(2)): 20-40; total cholesterol (TC): 5.0-8.0 mmol/L; LDL cholesterol: 2.7-5.0 mmol/L] were randomly assigned to receive a breakfast that contained either barley beta-glucan at 3 g high MW (HMW)/d, 5 g low MW (LMW)/d, or 3 g LMW/d or a control diet, each for 5 wk. The washout period between the phases was 4 wk. Fasting blood samples were collected at the start and end of each phase for blood lipid analysis and genotyping. RESULTS: Consumption of 3 g HMW beta-glucan/d lowered TC by -0.12 mmol/L (95% CI: -0.24, -0.006 mmol/L) compared with the control diet (P= 0.0046), but the LMW beta-glucan, at either 3 g/d or 5 g/d, did not change serum cholesterol concentrations. This effect of HMW beta-glucan was associated with gene-diet interaction, whereby individuals with the single nucleotide polymorphism (SNP) rs3808607-G allele (GG or GT) of the cytochrome P450 family 7 subfamily A member 1 gene (CYP7A1) had greater responses to 3 g HMW beta-glucan/d in lowering TC than TT carriers (P= 0.0006). CONCLUSIONS: The HMW beta-glucan rather than LMW beta-glucan reduced circulating TC effectively in mildly hypercholesterolemic adults. The cholesterol-lowering effect of beta-glucan may also be determined by the genetic characteristics of an individual. These data show that individuals carrying theCYP7A1SNP rs3808607-G allele are more responsive to the cholesterol-lowering effect of beta-glucan with HMW than TT carriers. This trial was registered atclinicaltrials.govasNCT01408719. PMID- 26936138 TI - Sun-Exposed Skin Color Is Associated with Changes in Serum 25-Hydroxyvitamin D in Racially/Ethnically Diverse Children. AB - BACKGROUND: UVB light from the sun increases serum 25-hydroxyvitamin D [25(OH)D] concentration, but this relation may depend on skin pigmentation among different racial/ethnic groups. OBJECTIVE: We used quantitative measures of exposed (facultative) and unexposed (constitutive) skin color to examine relations between serum 25(OH)D concentration, tanning, race/ethnicity, and constitutive skin color over the summer, following winter vitamin D supplementation. METHODS: The subjects (n= 426, mean age 11.7 +/- 1.4 y, 51% female) were racially/ethnically diverse schoolchildren (57% non-white/Caucasian) enrolled in a 6-mo vitamin D supplementation trial (October-December to April-June). In this secondary analysis, measures of serum 25(OH)D concentration and skin color, with the use of reflectance colorimetry, were taken over a 6-mo period after supplementation, from pre-summer (April-June) to post-summer (September December). Multiple linear regression was used to evaluate longitudinal relations. RESULTS: Following supplementation, mean serum 25(OH)D concentration was 29.3 +/- 9.5 ng/mL but fell to 25.6 +/- 7.9 ng/mL (P< 0.0001) by the end of summer. The decrease in white/Caucasian children was less than in black/African American children (P< 0.01) and tended to be less than in Hispanic/Latino, Asian, and multiracial/other children (P= 0.19-0.50) despite similar changes in sun exposed skin color among all groups. Tanning was significantly associated with post-summer serum 25(OH)D concentration (beta = -0.15,P< 0.0001), as was race/ethnicity (P= 0.0002), but the later association disappeared after adjusting for constitutive skin color. CONCLUSIONS: Tanning significantly contributed to serum 25(OH)D concentration over the summer, independent of race/ethnicity, but was not sufficient to maintain serum 25(OH)D concentration attained with supplementation. Much of the variation in serum 25(OH)D concentration between racial/ethnic groups may be explained by skin color. This trial was registered atclinicaltrials.govasNCT01537809. PMID- 26936140 TI - The Form of Choline in the Maternal Diet Affects Immune Development in Suckled Rat Offspring. AB - BACKGROUND: Lipid-soluble phosphatidylcholine (PC) and aqueous free choline are absorbed and metabolized differently, but the metabolic effects of feeding these 2 forms of choline have not been thoroughly investigated. OBJECTIVE: We sought to compare the effects of PC and free choline in the maternal diet on the development of the offspring's immune system. METHODS: During lactation, Sprague Dawley dams (n= 10) were randomly assigned to 1 of 2 diet groups containing the same concentration of total choline (1 g/kg diet) as free choline (choline bitartrate) or PC (egg lecithin). The splenocytes of pups aged 21 d were isolated and stimulated ex vivo with concanavalin A (ConA) or lipopolysaccharide (LPS), and the choline concentrations of stomach content, plasma, and the spleen were measured. RESULTS: Pups from PC-fed dams had a lower proportion of cells involved in antigen presentation but produced 54% more interleukin (IL)-2, 163% more IL-6, and 107% more IFN-gamma after ConA stimulation and 110% more IL-6 and 43% more tumor necrosis factor (TNF)-alpha after LPS stimulation (allP< 0.05). The PC concentrations were significantly higher in the plasma and spleen of pups from PC fed dams (P< 0.05). Increasing the supply of PC in the form of lysophosphatidylcholine to splenocytes in vitro increased the rate of proliferation and IL-2 production and the surface expression of CD25, CD28, CD71, and CD152 on CD8+ T cells, suggesting 1 possible mechanism. CONCLUSIONS: The results of this study demonstrate that providing choline to rats in the form of PC (compared to free choline), possibly by increasing the supply of PC to the suckling pups, promotes maturation and improves function of the offspring's immune system. PMID- 26936142 TI - Sedation in children - is it time to change our practice? PMID- 26936141 TI - Soy Protein Compared with Milk Protein in a Western Diet Increases Gut Microbial Diversity and Reduces Serum Lipids in Golden Syrian Hamsters. AB - BACKGROUND: Diet is a major factor influencing the composition and metabolic activity of the gut microbiota. OBJECTIVE: This study investigated the effect of soy compared with dairy protein on the gut microbiota of hamsters to determine whether changes in microbiota could account for soy protein's lipid lowering properties. METHODS: Thirty-two 6- to 8-wk-old, male Golden Syrian hamsters were fed a Western diet containing 22% (%wt) milk protein isolate (MPI) as the single protein source for 3 wk followed by 6 wk of one of 4 diets containing either [22% protein (%wt)]: MPI, soy protein concentrate (SPC), partially hydrolyzed soy protein isolate (SPI1), or intact soy protein isolate. Serum lipids, hepatic gene expression, and gut microbial populations were evaluated. RESULTS: Serum total and LDL-cholesterol concentrations were lower in the SPC-fed group (183 +/- 9.0 and 50 +/- 4.2 mg/dL, respectively) than in the MPI group (238 +/- 8.7 and 72 +/- 3.9 mg/dL, respectively) (P< 0.05). Triglyceride (TG) concentrations were lower (P< 0.05) in the SPI1-fed group (140 +/- 20.8 mg/dL) than in the MPI-fed group (223 +/- 14.2 mg/dL). VLDL and non-HDL-cholesterol concentrations were lower (by 40-49% and 17-33%, respectively) in all soy-fed groups than in the MPI-fed group (P< 0.05). Sequencing of the 16S ribosomal RNA gene revealed greater microbial diversity in each soy-fed group than in the MPI-fed group (P< 0.05). The cholesterol- and TG-lowering effect of soy protein was associated with higher expression of 3-hydroxy-3-methylglutaryl-CoA reductase (Hmgcr), lanosterol synthase (Lss), and farnesyl-diphosphosphate farnesyl-transferase 1 (Fdft1) (1.6 2.5-fold higher), and lower steroyl-CoA desaturase-1 (Scd1) expression (37-46% lower) in all soy-fed groups (P< 0.05) compared with the MPI-fed group. Gut microbes that showed significant diet differences were significantly correlated (rho = -0.68 to 0.65,P< 0.05) with plasma lipids and hepatic gene expression. CONCLUSION: Dietary protein sources in male Golden Syrian hamsters fed a Western diet affect the gut microbiota, and soy protein may reduce lipogenesis through alterations of the gut microbial community. PMID- 26936143 TI - Torpedo maculopathy: Two case reports and a literature review. AB - CASE REPORTS: The cases concern a 4 year-old boy and 25 year-old female with 20/20 visual acuity, who presented with a unilateral non-pigmented macular lesion, temporal to the fovea, a torpedo shaped defect in the retinal pigment epithelium (RPE). Optical coherence tomography showed attenuation of the RPE signal, and in the second patient there proved to be a neurosensory detachment, RPE atrophy, and thinning of the retinal layers. The lesion was hypoautofluorescent and hyperfluorescent on fluorescein angiography. DISCUSSION: Torpedo maculopathy is an asymptomatic characteristic lesion which should be considered in the differential diagnosis of macular lesions in children and young patients. PMID- 26936144 TI - Oxidized Monolayers of Epitaxial Silicene on Ag(111). AB - The properties of epitaxial silicene monolayers on Ag(111) at various levels of oxidation are determined through complementary density functional theory calculations and soft X-ray spectroscopy experiments. Our calculations indicate that moderate levels of oxidation do not cause a significant bandgap opening in the epitaxial silicene monolayer, suggesting that oxygen functionalization is not a viable mechanism for bandgap tuning while the silicene monolayer remains on its metallic substrate. In addition, moderate oxidation is calculated to strongly distort the hexagonal Si lattice, causing it to cluster in regions of highest oxygen adatom concentration but retain its 2D sheet structure. However, our experiments reveal that beam-induced oxidation is consistent with the formation of islands of bulk-like SiO2. Complete exposure of the monolayer to ambient conditions results in a fully oxidized sample that closely resembles bulk SiO2, of which a significant portion is completely detached from the substrate. PMID- 26936146 TI - Micromanipulation in assisted reproductive technology. AB - Micromanipulation describes a set of tools and techniques for cellular microsurgery and manipulation. Micromanipulation techniques have played an important role in basic research and the development of clinical techniques in assisted reproductive technology. This work provides a review of the development and current practices involving micromanipulation in the human clinical assisted reproduction laboratory. PMID- 26936145 TI - The effect of peri-implantation administration of uterine relaxing agents in assisted reproduction treatment cycles: a systematic review and meta-analysis. AB - Sub-endometrial junctional zone peristalsis is increased by ovarian stimulation and traumatic embryo transfer, and is linked with decreased implantation and pregnancy rates in assisted reproduction treatments. Various agents have been used to inhibit uterine hyper-peristalsis at the time of embryo transfer with conflicting results. This systematic review aimed to identify if uterine relaxants administered in the peri-implantation period during assisted reproduction treatments could improve pregnancy outcomes through literature search with no language restrictions. The review reports on 3546 patients in 17 randomized controlled trials published between 1993 and 2014. Women undergoing assisted reproduction techniques who either received a uterine relaxant agent in the peri-implantation period versus placebo or no treatment were included. Primary outcome was live birth rate. The meta-analyses did not show statistically significant benefit of any uterine relaxing agents on live birth rate. Other meta analyses did not show a significant effect on the clinical pregnancy, spontaneous abortion, ectopic pregnancy and multiple pregnancy rate. Most of the included studies were of low quality and lacked significant power to detect minimally important effect. Evidence is insufficient to recommend using these agents in routine practice. Further methodologically robust randomized controlled trials with more refined selection criteria might reveal a beneficial effect. PMID- 26936147 TI - Crystal structure of a hypothetical protein, TTHA0829 from Thermus thermophilus HB8, composed of cystathionine-beta-synthase (CBS) and aspartate-kinase chorismate-mutase tyrA (ACT) domains. AB - TTHA0829 from Thermus thermophilus HB8 has a molecular mass of 22,754 Da and is composed of 210 amino acid residues. The expression of TTHA0829 is remarkably elevated in the latter half of logarithmic growth phase. TTHA0829 can form either a tetrameric or dimeric structure, and main-chain folding provides an N-terminal cystathionine-beta-synthase (CBS) domain and a C-terminal aspartate-kinase chorismate-mutase tyrA (ACT) domain. Both CBS and ACT are regulatory domains to which a small ligand molecule can bind. The CBS domain is found in proteins from organisms belonging to all kingdoms and is observed frequently as two or four tandem copies. This domain is considered as a small intracellular module with a regulatory function and is typically found adjacent to the active (or functional) site of several enzymes and integral membrane proteins. The ACT domain comprises four beta-strands and two alpha-helices in a betaalphabetabetaalphabeta motif typical of intracellular small molecule binding domains that help control metabolism, solute transport and signal transduction. We discuss the possible role of TTHA0829 based on its structure and expression pattern. The results imply that TTHA0829 acts as a cell-stress sensor or a metabolite acceptor. PMID- 26936149 TI - Reported Church Attendance at the Time of Entry into HIV Care is Associated with Viral Load Suppression at 12 Months. AB - The Southeast has high rates of church attendance and HIV infection rates. We evaluated the relationship between church attendance and HIV viremia in a Southeastern US, HIV-infected cohort. Viremia (viral load >=200 copies/ml) was analyzed 12 months after initiation of care. Univariate and multivariable logistic regression models were fit for variables potentially related to viremia. Of 382 patients, 74 % were virally suppressed at 12 months. Protective variables included church attendance (AOR 0.5; 95 % CI 0.2, 0.9), being on antiretroviral therapy (AOR 0.01; 95 % CI 0.004, 0.04), CD4(+) T lymphocyte count 200-350 cells/mm(3) at care entry (AOR 0.3; 95 % 0.1, 0.9), and education (AOR 0.5; 95 % CI 0.2, 0.9). Variables predicting viremia included black race (AOR 3.2; 95 % CI 1.4, 7.4) and selective disclosure of HIV status (AOR 2.7; 95 % CI 1.2, 5.6). Church attendance may provide needed support for patients entering HIV care for the first time. PMID- 26936150 TI - Erratum to: Exploring motor and visual imagery in Amyotrophic Lateral Sclerosis. PMID- 26936151 TI - Dietary Management of Incremental Transition to Dialysis Therapy: Once-Weekly Hemodialysis Combined With Low-Protein Diet. AB - Initiation of thrice-weekly hemodialysis often results in a rapid loss of residual kidney function (RKF) including reduction in urine output. Preserving RKF longer is associated with better outcomes including greater survival in dialysis patients. An alternative approach aimed at preserving RKF is an incremental transition with less frequent hemodialysis sessions at the beginning with gradual increase in hemodialysis frequency over months. In addition to favorable clinical and economic implications, an incremental transition would also enhance a less stressful adaptation of the patient to dialysis therapy. The current guidelines provide only limited recommendations for incremental hemodialysis approach, whereas the potential role of nutritional management of newly transitioned hemodialysis patients is largely overlooked. We have reviewed previous reports and case studies of once-weekly hemodialysis treatment combined with low-protein, low-phosphorus, and normal-to-high-energy diet especially for nondialysis days, whereas on dialysis days, high protein can be provided. Such an adaptive dietary regimen may elicit more favorable outcomes including better preserved RKF, lower beta2-microglobulin levels, improved phosphorus control, and lower doses of erythropoiesis-stimulating agents. Clinical and nutritional status and RKF should be closely monitored throughout the transition to once and then twice-weekly regimen and eventually thrice-weekly hemodialysis. Further studies are needed to verify the long-term safety and implications of this approach to dialysis transition. PMID- 26936152 TI - Survival in Patients with Degenerative Mitral Stenosis: Results from a Large Retrospective Cohort Study. AB - BACKGROUND: Severe mitral annular calcification causing degenerative mitral stenosis (DMS) is increasingly encountered in patients undergoing mitral and aortic valve interventions. However, its clinical profile and natural history and the factors affecting survival remain poorly characterized. The goal of this study was to characterize the factors affecting survival in patients with DMS. METHODS: An institutional echocardiographic database was searched for patients with DMS, defined as severe mitral annular calcification without commissural fusion and a mean transmitral diastolic gradient of >=2 mm Hg. This resulted in a cohort of 1,004 patients. Survival was analyzed as a function of clinical, pharmacologic, and echocardiographic variables. RESULTS: The patient characteristics were as follows: mean age, 73 +/- 14 years; 73% women; coronary artery disease in 49%; and diabetes mellitus in 50%. The 1- and 5-year survival rates were 78% and 47%, respectively, and were slightly worse with higher DMS grades (P = .02). Risk factors for higher mortality included greater age (P < .0001), atrial fibrillation (P = .0009), renal insufficiency (P = .004), mitral regurgitation (P < .0001), tricuspid regurgitation (P < .0001), elevated right atrial pressure (P < .0001), concomitant aortic stenosis (P = .02), and low serum albumin level (P < .0001). Adjusted for propensity scores, use of renin angiotensin system blockers (P = .02) or statins (P = .04) was associated with better survival, and use of digoxin was associated with higher mortality (P = .007). CONCLUSIONS: Prognosis in patients with DMS is poor, being worse in the aged and those with renal insufficiency, atrial fibrillation, and other concomitant valvular lesions. Renin-angiotensin system blockers and statins may confer a survival benefit, and digoxin use may be associated with higher mortality in these patients. PMID- 26936153 TI - The Rcs regulon in Proteus mirabilis: implications for motility, biofilm formation, and virulence. AB - The overall role of the Rcs phosphorelay in Proteus mirabilis is largely unknown. Previous work had demonstrated that the Rcs phosphorelay represses the flhDC operon and activates the minCDE cell division inhibition system. To identify additional cellular functions regulated by the Rcs phosphorelay, an analysis of RNA-seq data was undertaken. In this report, the results of the RNA-sequencing are discussed with an emphasis on the predicted roles of the Rcs phosphorelay in swarmer cell differentiation, motility, biofilm formation, and virulence. RcsB is shown to activate genes important for differentiation and fimbriae formation, while repressing the expression of genes important for motility and virulence. Additionally, to follow up on the RNA-Seq data, we demonstrate that an rcsB mutant is deficient in its ability to form biofilm and exhibits enhanced virulence in a Galleria mellonella waxworm model. Overall, these results indicate the Rcs regulon in P. mirabilis extends beyond flagellar genes to include those involved in biofilm formation and virulence. Furthermore, the information presented in this study may provide clues to additional roles of the Rcs phosphorelay in other members of the Enterobacteriaceae. PMID- 26936154 TI - Identification of the non-ribosomal peptide synthetase responsible for biosynthesis of the potential anti-cancer drug sansalvamide in Fusarium solani. AB - Sansalvamide is a cyclic pentadepsipeptide produced by Fusarium solani and has shown promising results as potential anti-cancer drug. The biosynthetic pathway has until now remained unidentified, but here we used an Agrobacterium tumefaciens-mediated transformation (ATMT) approach to generate knockout mutants of two candidate non-ribosomal peptide synthetases (NRPS29 and NRPS30). Comparative studies of secondary metabolites in the two deletion mutants and wild type confirmed the absence of sansalvamide in the NRPS30 deletion mutant, implicating this synthetase in the biosynthetic pathway for sansalvamide. Sansalvamide is structurally related to the cyclic hexadepsipeptide destruxin, which both contain an alpha-hydroxyisocaproic acid (HICA) unit. A gene cluster responsible for destruxin production has previously been identified in Metarhizium robertsii together with a hypothetical biosynthetic pathway. Using comparative bioinformatic analyses of the catalytic domains in the destruxin and sansalvamide NRPSs, we were able to propose a model for sansalvamide biosynthesis. Orthologues of the gene clusters were also identified in species from several other genera including Acremonium chrysogenum and Trichoderma virens, which suggests that the ability to produce compounds related to destruxin and sansalvamide is widespread. PMID- 26936155 TI - Bioactive Secondary Metabolites with Unique Aromatic and Heterocyclic Structures Obtained from Terrestrial Actinomycetes Species. AB - Natural products from actinomycetes are important and valuable sources for drug discovery and the development of biological tools. The present review describes our recent study on the isolation of new natural products mainly possessing heterocyclic and aromatic ring structures with biological effects on cancer related cellular pathways such as tumor necrosis factor-alpha-related apoptosis inducing ligand (TRAIL) and Wnt signaling. PMID- 26936156 TI - Cardiac shockwave therapy in patients with chronic refractory angina pectoris. AB - BACKGROUND: Cardiac shockwave therapy (CSWT) might improve symptoms and decrease ischaemia burden by stimulating collateral growth in chronic ischaemic myocardium. This prospective study was performed to evaluate the feasibility and safety of CSWT. METHODS: We included 33 patients (mean age 70 +/- 7 years, mean left ventricular ejection fraction 55 +/- 12 %) with end-stage coronary artery disease, chronic angina pectoris and reversible ischaemia on myocardial scintigraphy. CSWT was applied to the ischaemic zones (3-7 spots/session, 100 impulses/spot, 0.09 mJ/mm(2)) in an echocardiography-guided and ECG-triggered fashion. The protocol included a total of 9 treatment sessions (3 treatment sessions within 1 week at baseline, and after 1 and 2 months). Clinical assessment was performed using exercise testing, angina score (CCS class), nitrate use, myocardial scintigraphy, and cardiac magnetic resonance (CMR) 1 and 4 months after the last treatment session. RESULTS: One and 4 months after CSWT, sublingual nitrate use decreased from 10/week to 2/week (p < 0.01) and the angina symptoms diminished from CCS class III to CCS class II (p < 0.01). This clinical improvement was accompanied by an improved myocardial uptake on stress myocardial scintigraphy (54.2 +/- 7.7 % to 56.4 +/- 9.4 %, p = 0.016) and by increased exercise tolerance at 4-month follow-up (from 7.4 +/- 2.8 to 8.8 +/- 3.6 min p = 0.015). No clinically relevant side effects were observed. CONCLUSION: CSWT improved symptoms and reduced ischaemia burden in patients with end-stage coronary artery disease without relevant side effects. The study provides a solid basis for a randomised multicentre trial to establish CSWT as a new treatment option in end-stage coronary artery disease. PMID- 26936157 TI - Animal models of heart failure with preserved ejection fraction. AB - Heart failure with preserved ejection fraction (HFpEF) constitutes a clinical syndrome in which the diagnostic criteria of heart failure are not accompanied by gross disturbances of systolic function, as assessed by ejection fraction. In turn, under most circumstances, diastolic function is impaired. Although it now represents over 50 % of all patients with heart failure, the mechanisms of HFpEF remain understood, precluding effective therapy. Understanding the pathophysiology of HFpEF has been restricted by both limited access to human myocardial biopsies and by the lack of animal models that fully mimic human pathology. Animal models are valuable research tools to clarify subcellular and molecular mechanisms under conditions where the comorbidities and other confounding factors can be precisely controlled. Although most of the heart failure animal models currently available represent heart failure with reduced ejection fraction, several HFpEF animal models have been proposed. However, few of these fulfil all the features present in human disease. In this review we will provide an overview of the currently available models to study HFpEF from rodents to large animals as well as present advantages and disadvantages of these models. PMID- 26936158 TI - Brief Report: Sensitivity of Children with Autism Spectrum Disorders to Face Appearance in Selective Trust. AB - The current study examined how children with Autism Spectrum Disorders (ASD) could selectively trust others based on three facial cues: the face race, attractiveness, and trustworthiness. In a computer-based hide-and-seek game, two face images, which differed significantly in one of the three facial cues, were presented as two cues for selective trust. Children had to selectively trust the own-race, attractive and trustworthy faces to get the prize. Our findings demonstrate an intact ability of selective trust based on face appearance in ASD compared to typical children: they could selectively trust the informant based on face race and attractiveness. Our results imply that despite their face recognition deficits, children with ASD are still sensitive to some aspects of face appearance. PMID- 26936159 TI - Brief Report: Ages of Language Milestones as Predictors of Developmental Trajectories in Young Children with Autism Spectrum Disorder. AB - Recognizing early risk markers in young children with autism spectrum disorder (ASD) is critical for timely diagnosis and intervention. The purpose of this study was to extend previous findings regarding language milestones to a longitudinal design, in which ages of expressive language milestones (i.e., first words, first phrases) could serve as predictors of developmental trajectories in a heterogeneous sample of young children with ASD (N = 98; age at first assessment: M = 32 months, SD = 5). Age of first words predicted trajectories of expressive language and adaptive skills; number of words predicted each outcome examined. Because these aspects of early language show promise as potential indicators of later functional outcomes, future research on developmental processes as they relate to individual differences will be particularly informative. PMID- 26936161 TI - Preschool Deployment of Evidence-Based Social Communication Intervention: JASPER in the Classroom. AB - Few research-developed early intervention models have been deployed to and tested in real world preschool programs. In this study, teaching staff implemented a social communication modularized intervention, JASPER, in their daily program. Sixty-six preschool children with autism in twelve classrooms (12 teachers) were randomized to receive immediate JASPER training (IT) or were waitlisted (WL) for 3 months with a 1-month follow up. Measures of core deficits (initiations of joint engagement, joint attention gestures and language, play skills) and standardized cognitive measures were improved for IT over WL children. IT teachers achieved and maintained high fidelity. Teachers can implement evidence based interventions with significant improvements in core deficits of their children with ASD. PMID- 26936160 TI - Asperger Syndrome and Schizophrenia: A Comparative Neuropsychological Study. AB - There has been an increasing interest in possible connections between autism spectrum disorder (ASD) and schizophrenia in the last decade. Neuropsychological comparison studies have, however, been few. The present study examined similarities and differences in intellectual and executive functioning between adults with Asperger syndrome (AS) and adults with schizophrenic psychosis (SP). A group with AS and a group with SP were assessed neuropsychologically with WAIS III and D-KEFS. Similarities were found between groups, as displayed by an uneven cognitive profile, limitations in working memory, processing speed and some aspects of executive functioning. Full Scale IQ was higher in the AS group. These results add to the current research illuminating similarities and differences between ASD and schizophrenia on a cognitive level. PMID- 26936162 TI - Comparison of Obesity, Physical Activity, and Sedentary Behaviors Between Adolescents With Autism Spectrum Disorders and Without. AB - Body mass index classification, physical activity (PA), and sedentary behaviors were compared in adolescents with autism spectrum disorder (ASD) to typically developing adolescents. Participants included 42,747 adolescents (ASD, n = 915) from the 2011-2012 National Survey of Children's Health. After controlling for covariates, adolescents were more likely to be overweight and obese, and less likely to engage in regular PA versus typically developing adolescents (p's < 0.05). Increased odds for overweight and obesity were attenuated after adjustment for PA. Higher autism severity was associated with increased odds of overweight and obesity and decreased odds of PA, sport, and club participation. These findings suggest adolescents with ASD are in need of targeted programs to decrease obesity and increase physical activity. PMID- 26936163 TI - Physical activity: what is already being done and how we can avert 1 million deaths annually in future. PMID- 26936165 TI - [Increase the chances of IVF success with preimplantation genetic diagnosis of aneuploidies (PGD-A): myth or reality?]. PMID- 26936164 TI - Severe pain as a possible cause of dropped head syndrome that was attenuated after amputation of an ischemic lower limb. AB - BACKGROUND: Dropped head syndrome (DHS) is defined as weakness of the neck extensor muscles causing a correctable chin-on-the-chest deformity. Here we report the case of a patient with severe pain from lower leg ischemia showing DHS whose symptoms were attenuated by pain relief after amputation of the severely ischemic lower leg. To our knowledge this is the first report indicating that severe pain can cause DHS. CASE PRESENTATION: A 64-year-old Asian woman was referred to our department with a 1-month history of DHS. She also suffered from severe right foot pain because of limb ischemia. She began to complain of DHS as her gangrenous foot pain worsened. She had neck pain and difficulty with forward gaze. We found no clinical or laboratory findings of neuromuscular disorder or isolated neck extensor myopathy. We amputated her leg below the knee because of progressive foot gangrene. Her severe foot pain resolved after the surgery and her DHS was attenuated. CONCLUSION: Severe pain can cause DHS. If a patient with DHS has severe pain in another part of the body, we recommend considering aggressive pain relief as a treatment option. PMID- 26936166 TI - [SUMO paralogs and interferon response]. PMID- 26936167 TI - [Matricellular protein CCN1/CYR61 boosts T-cell output]. PMID- 26936168 TI - [Axonal injury in brain concussions: role of the mechanical duality between neuronal microcompartments]. PMID- 26936169 TI - [SPINK1, hepatic macrophages and progenitor cells: new tools for liver regeneration in alcoholic hepatitis?]. PMID- 26936170 TI - [Sepiapterin reductase as a novel target to treat neuropathic pain]. PMID- 26936172 TI - [Revascularization of the heart after infarct: lessons from embryonic development]. PMID- 26936171 TI - [Mycolactone: the amazing analgesic mycobacterial toxin]. PMID- 26936173 TI - [The Nav1.9 channel is crucial for sensing noxious cold]. PMID- 26936174 TI - [Integration of AAV vectors and insertional mutagenesis]. AB - Recombinant AAV vectors (rAAV) are considered as very efficient tools for in vivo gene transfer. Accordingly, several preclinical and clinical gene therapy trials use these vectors to treat inherited and acquired diseases. rAAV vectors possess the capacity to persist for a long term in the transduced tissue in a transcriptionally active, extra-chromosomal (episomal) form. However, many studies have shown that a significant fraction of the rAAV genomes can also nonspecifically integrate into the host cell genome thus raising the possibility of insertional mutagenesis events. This review summarizes the current knowledge on integration of wild type and rAAV genomes and highlights the major questions which remain unresolved. PMID- 26936175 TI - [How some commensal bacteria would exacerbate colorectal carcinogenesis?]. AB - The gut microbiota maintains a relationship with its host with strong mutual benefits. Changes in the composition of the intestinal microbiota have been detected in colorectal cancer patients to the extent that it is now considered as a real contributing factor in this pathology. In this review, we focus on three commensal bacterial species, namely Bacteroides fragilis, Fusobacterium nucleatum, and Escherichia coli, which seem to emerge as pathogens and to contribute to colorectal carcinogenesis through their inflammatory and oncogenic properties. PMID- 26936176 TI - [Pathophysiology of systemic sclerosis]. AB - Systemic sclerosis (SSc) is an orphan disease affecting the connective tissue. The cause of SSc remains unknown but is likely to involve environmental factors in a genetically primed individual with SSc belonging to the multigenic disorders. Pathogenesis is dominated by early microvascular changes targeting endothelial cells and with the release of several mediators promoting an inflammatory response and vascular remodelling. Several lines of evidence position autoimmunity as a key perpetuating event with activation of both innate and adaptive immunity and with the production of distinct autoantibodies. The cascade ultimates with the fibrosis defined by accumulation of extra-cellular matrix through an imbalance between synthesis and degradation of several components and mesenchymal cell activation and differentiation controlled by a large number of autocrine and paracrine factors. PMID- 26936177 TI - [Epiblast and primitive endoderm cell specification during mouse preimplantation development: a combination between biology and mathematical modeling]. AB - Upon its implantation in the uterus of the mother in mammals, the embryo is composed by three morphologically distinct tissues: the Epiblast (Epi), the Trophectoderm (TE) and the Primitive Endoderm (PrE). Both Epi and PrE are formed from the same cell homogeneous population called the Inner Cell Mass (ICM). Based on our studies, we discuss in this review what molecular interactions are necessary for the specification of these two lineages. For this, we have combined a biological approach with mathematical modeling. We have shown the central role of the gene regulation group composed by NANOG, FGF4, GATA6 and FGFR2 for Epi/PrE cell specification. PMID- 26936178 TI - [Assisted oocyte activation: a new tool for severe male factor infertility treatment]. AB - In severe male infertility, in vitro fertilization (IVF) with intra-cytoplasmic sperm injection (ICSI) represents the sole available therapeutic option. However this technique is not always successful in promoting fertilization, as some couples completely and repeatedly fail to obtain any embryo. In many cases, this failure can be attributed to a defective rise in intracellular calcium, which is required to achieve oocyte activation. Over the last twenty years, several laboratories dedicated to assisted reproduction technologies have been using a calcium ionophore to assist oocyte activation. The aim of this review is to give an overview of the advances and consequences associated with this new technique referred to as assisted oocyte activation. PMID- 26936179 TI - [Healthcare expenditures growth: the red herring of demographic ageing?]. AB - Demographic ageing is often deemed responsible for the massive increase in health expenditures experienced by developed countries. As the elderly consume more medical care than the rest of the population, how could the increase in the share of the 60 + not lead to a marked expansion of healthcare public and private budgets? Despite its apparent logics, such reasoning is fallacious: it ignores that medical care consumption depends on many factors beyond age, which have tremendously evolved in the last decades and may change again in the future. Based on French stylized facts, this article provides an overview of the international literature that aimed at disentangling the respective roles of population ageing and of the non-demographic factors in explaining the dynamics of health expenditures. Paradoxically, technical medical progress has been a major contributor to the increase of healthcare spending. Results from economics research lead to qualify the impact of demographic trends and call for more attention to the public policies decisions that shape healthcare systems. PMID- 26936180 TI - [Humanitarian transition]. AB - In two centuries, modern humanitarian action has experienced several fractures often linked to crises. Although its professionalism and intervention force remain indisputable, it faces, since the 2000s, a new context that limits its ability to act and confronts it with new dilemmas, even though it must deal with needs for aid of unprecedented scale. These difficulties reveal a humanitarian transition period that was not anticipated. This transition period reflects the change from a dominant paradigm of North-South solidarity of Western origin to a much more complex model. This article provides a summary of the current mutations that are dominated by the States' assertion of sovereignty. Among the possible solutions, it argues for an ethical approach and a better integration of the research carried out in the Global South, prerequisites for building a true partnership and placing the victims at the heart of the operations which involve them. PMID- 26936181 TI - [The Washington summit: orange light for genome editing?]. AB - The summit organised in early December 2015 considered in depth the various issues (technical, scientific, societal and ethical) raised by the prospect of genome editing using the extremely effective CRISPR system. Germline editing (for therapeutic or "enhancement" purposes) was stated to be irresponsible under current conditions, but the possibility that this could be considered in the future was not excluded; a mechanism for monitoring progress and possibly revising recommendations was proposed. PMID- 26936182 TI - Allergy-Like Immediate Reactions with Herbal Medicines: A Retrospective Study Using Data from VigiBase(r). AB - INTRODUCTION: Herbal medicines are used worldwide and with an increasing popularity in Western countries. Although often perceived as 'naturally safe', herbals may cause severe adverse drug reactions (ADRs), with immediate allergic reactions being particularly life threatening. OBJECTIVES: The aim of this study was to analyse immediate allergy-like ADRs to herbals documented in VigiBase(r), the WHO international pharmacovigilance database. METHODS: The documentation of all suspected ADRs in association with herbal exposure reported to VigiBase(r) from 1969 to August 2014 was retrieved. Among all reports in which WHO-ART reaction terms were indicative of acute allergic reactions, those classified as 'suspect' with a documented causality assessment and latency time of <=1 day were selected. For the most frequent specific herbal-ADR combinations, the information component (IC) as a measure of disproportionality based on Bayesian statistics was calculated. RESULTS: We identified 757 reports out of 1039 ADRs. Products with mixed herbals (36.0 %) as well as those administered orally (63.2 %) were predominant. The most frequent reactions were urticaria and rash (49.2 %). Anaphylactic reactions accounted for 9.5 %. Disproportionally frequent reporting of mouth edema (IC = 1.81) and anaphylactic reactions (IC = 1.24) to Phleum pretense were noted. CONCLUSION: Our findings indicate that herbal medicines for oral use carry a risk of causing immediate allergy-like ADRs. Studies using the Vigibase(r) database can identify specific combinations of particular herbs and adverse reactions. Healthcare professionals and patients should be aware of these risks and report any serious adverse experiences. PMID- 26936183 TI - Unfolding and Folding of the Three-Helix Bundle Protein KIX in the Absence of Solvent. AB - Electron capture dissociation was used to probe the structure, unfolding, and folding of KIX ions in the gas phase. At energies for vibrational activation that were sufficiently high to cause loss of small molecules such as NH3 and H2O by breaking of covalent bonds in about 5% of the KIX (M + nH)(n+) ions with n = 7-9, only partial unfolding was observed, consistent with our previous hypothesis that salt bridges play an important role in stabilizing the native solution fold after transfer into the gas phase. Folding of the partially unfolded ions on a timescale of up to 10 s was observed only for (M + nH)(n+) ions with n = 9, but not n = 7 and n = 8, which we attribute to differences in the distribution of charges within the (M + nH)(n+) ions. Graphical Abstract ?. PMID- 26936184 TI - Erratum to: 'Mutation of epigenetic regulators TET2 and MLL3 in patients with HTLV-I-induced acute adult T-cell leukemia'. PMID- 26936186 TI - Strategies for the prevention of continuous positive airway pressure failure. AB - Progress in neonatal intensive care is closely linked to improvements in the management of respiratory failure in preterm infants. Current modalities of respiratory support range from the more benign continuous positive airway pressure (CPAP) to various modes of mechanical ventilation. Data from recent randomized control trials suggest that the use of nasal (n)CPAP as the initial mode of respiratory support in critically ill very low birth weight infants is associated with a lower incidence of chronic lung disease. The practice of early initiation of nasal-prong CPAP in all spontaneously breathing infants at Columbia University has resulted in very low rates of chronic lung disease for decades. Many institutions have attempted to replicate the practices and results at Columbia University. However, success rates with nCPAP are highly variable, which may in part be attributable to how well it is utilized. With recent renewed interest in non-invasive respiratory support, particularly bubble nCPAP, it is essential to evaluate strategies for the prevention of CPAP failure. This review discusses strategies that address these issues and shares the practical aspects for replicating success with bubble nCPAP. In addition, it reviews desirable features, major components, and physiological consequences of various bubble CPAP systems along with clinical experience of CPAP use. PMID- 26936185 TI - Understanding the metabolic and health effects of low-calorie sweeteners: methodological considerations and implications for future research. AB - Consumption of foods, beverages, and packets containing low-calorie sweeteners (LCS) has increased markedly across gender, age, race/ethnicity, weight status, and socio-economic subgroups. However, well-controlled intervention studies rigorously evaluating the health effects of LCS in humans are limited. One of the key questions is whether LCS are indeed a beneficial strategy for weight management and prevention of obesity. The current review discusses several methodological considerations in the design and interpretation of these studies. Specifically, we focus on the selection of study participants, inclusion of an appropriate control, importance of considering habitual LCS exposure, selection of specific LCS, dose and route of LCS administration, choice of study outcomes, and the context and generalizability of the study findings. These critical considerations will guide the design of future studies and thus assist in understanding the health effects of LCS. PMID- 26936187 TI - Ancillary therapies to enhance success of non-invasive modes of respiratory support - Approaches to delivery room use of surfactant and caffeine? AB - During recent decades, non-invasive respiratory support has become popular for treating neonates with respiratory failure. Several prospective randomized controlled trials have been performed to compare use of continuous positive airway pressure (CPAP) as primary respiratory support in preterm infants with respiratory distress syndrome (RDS) to endotracheal intubation, mechanical ventilation and surfactant therapy. Systematic reviews of these studies suggest that routine CPAP at delivery is efficacious in decreasing bronchopulmonary dysplasia (BPD), death, or both. This led to the recommendation to consider CPAP to avoid endotracheal intubation. As surfactant therapy is known to reduce BPD and death, several ways to combine CPAP with surfactant have been described. With the increasing use of CPAP immediately after birth, the early use of caffeine to stimulate respiration has become a point of discussion. This review focuses on different modes of surfactant application during CPAP and on the early use of caffeine as ancillary therapies to enhance CPAP success. PMID- 26936188 TI - Maternal microbiome - A pathway to preterm birth. AB - Despite great medical advances in preventing maternal and infant mortality in the past century, one issue remains unresolved: why do so many women give birth prematurely? A major new field of human microbiome studies has begun to shed light on the impact of microbes (of both the commensal and pathogen varieties) on pregnancy outcomes. Recent advances in next-generation sequencing and metagenomic analysis have revealed that maternal microbiomes at a variety of niches including the oral, vaginal, gut, cervical, and even the placenta itself govern pregnancy outcomes. In this review, we describe how alterations in the microbial biomasses impact preterm birth and we discuss the major research questions concerning the cause and/or interdependent relationships between microbiome, infection, and preterm delivery. PMID- 26936189 TI - Non-invasive respiratory support. PMID- 26936190 TI - Increasing incidence of hypotension in the emergency department; a 12 year population-based cohort study. AB - BACKGROUND: The epidemiology of hypotension as presenting symptom among patients in the Emergency Department (ED) is not clarified. The aim of this study was to describe the incidence, etiology, and overall mortality of hypotensive patients in the ED. METHODS: Population-based cohort study at an University Hospital ED in Denmark from January 1, 2000, to December 31, 2011. Patients aged >=18 years living in the hospital catchment area with a first time presentation to the ED with hypotension (systolic blood pressure (SBP) <=100 mm Hg) were included. Outcomes were annual incidence rates (IRs) per 100,000 person years at risk (pyar) and etiological characteristics by means of the International Classification of Diseases, Tenth Revision (ICD-10), as well as 7-day, 30-day, and 90-day all-cause mortality. RESULTS: We identified 3,268 of 438,198 (1 %) cases with a mean overall IR of 125/100,000 pyar (95% CI: 121-130). The IR increased 28% during the period (from 113 to 152 cases per 100,000 pyar). Patients >=65 years had the highest IR compared to age <65 years (rate ratio for men 6.3 (95% CI: 5.6-7.1) and for women 4.2 (95% CI: 3.6-4.9)). The etiology was highly diversified with trauma (17%) and cardiovascular diseases (15%) as the most common. The overall 7-day, 30-day and 90-day mortality rates were 15% (95% CI: 14-16), 22 % (95% CI: 21-24) and 28% (95% CI: 27-30) respectively. CONCLUSION: During 2000-2011 the overall incidence of ED hypotension increased and remained highest among the elderly with a diversified etiology and a 90-day all-cause mortality of 28%. PMID- 26936192 TI - Hereditary spastic paraplegia: Novel mutations and expansion of the phenotype variability in SPG56. AB - We describe a novel sporadic case of SPG56, a rare complicated form of HSP, that expands the clinical and molecular spectrum of the disease, being associated to novel mutations in CYP2U1 and showing as novel feature dorsal hydromyelia at spinal cord MRI. The patient presented an early-onset, slowly progressive paraparesis associated with mild mental retardation. Neurological assessments included the Spastic Paraplegia Rating Scale (SPRS), Mental Deterioration Battery (MDB), and Wechsler Adult Intelligence Scale (WAIS), neurophysiological and neuroimaging studies. Targeted next-generation sequencing panels for the whole set of genes associated with HSP were performed in the probands and her relatives. Neuroimaging studies showed dorsal hydromyelia but no brain MRI abnormalities. Targeted next-generation identified two novel mutations: the c.5C > A/p.S2* on the maternal allele in compound heterozygosity with the paternally inherited c.1288+5G > C in CYP2U1. Both mutations predict early protein truncation and a loss of function. So far, only few SPG56 cases have been reported. This case, expands and further characterize the clinical and molecular spectrum of SPG56. In this regard, in consideration of the putative gene function in neurodevelopment, we suggest a causal association between CYP2U1 mutations and hydromyelia in our patient. PMID- 26936191 TI - Co-distribution and co-infection of chikungunya and dengue viruses. AB - BACKGROUND: Chikungunya and dengue infections are spatio-temporally related. The current review aims to determine the geographic limits of chikungunya, dengue and the principal mosquito vectors for both viruses and to synthesise current epidemiological understanding of their co-distribution. METHODS: Three biomedical databases (PubMed, Scopus and Web of Science) were searched from their inception until May 2015 for studies that reported concurrent detection of chikungunya and dengue viruses in the same patient. Additionally, data from WHO, CDC and Healthmap alerts were extracted to create up-to-date global distribution maps for both dengue and chikungunya. RESULTS: Evidence for chikungunya-dengue co infection has been found in Angola, Gabon, India, Madagascar, Malaysia, Myanmar, Nigeria, Saint Martin, Singapore, Sri Lanka, Tanzania, Thailand and Yemen; these constitute only 13 out of the 98 countries/territories where both chikungunya and dengue epidemic/endemic transmission have been reported. CONCLUSIONS: Understanding the true extent of chikungunya-dengue co-infection is hampered by current diagnosis largely based on their similar symptoms. Heightened awareness of chikungunya among the public and public health practitioners in the advent of the ongoing outbreak in the Americas can be expected to improve diagnostic rigour. Maps generated from the newly compiled lists of the geographic distribution of both pathogens and vectors represent the current geographical limits of chikungunya and dengue, as well as the countries/territories at risk of future incursion by both viruses. These describe regions of co-endemicity in which lab-based diagnosis of suspected cases is of higher priority. PMID- 26936193 TI - Characterization of a SILAC method for proteomic analysis of primary rat microglia. AB - Microglia play important and dynamic roles in mediating a variety of physiological and pathological processes during the development, normal function and degeneration of the central nervous system. Application of SILAC-based proteomic analysis would greatly facilitate the identification of cellular pathways regulating the multifaceted phenotypes of microglia. We and others have successfully SILAC-labeled immortalized murine microglial cell lines in previous studies. In this study, we report the development and evaluation of a SILAC labeled primary rat microglia model. Although the isotope labeling scheme for primary microglia is drastically different from that of immortalized cell lines, our de novo and uninterrupted primary culture labeling protocol (DUP-SILAC) resulted in sufficient incorporation of SILAC labels for mass spectrometry-based proteomic profiling. In addition, label incorporation did not alter their morphology and response to endotoxin stimulation. Proteomic analysis of the endotoxin-stimulated SILAC-labeled primary microglia identified expected as well as potentially novel activation markers and pro-inflammatory pathways that could be quantified in a more physiologically relevant cellular model system compared to immortalized cell lines. The establishment of primary microglia SILAC model will further expand our capacity for global scale proteomic profiling of pathways under various physiological and pathological conditions. Proteomic MS data are available via ProteomeXchange with identifier PXD002759. PMID- 26936194 TI - Effects of interventions on trajectories of health-related quality of life among older patients with hip fracture: a prospective randomized controlled trial. AB - BACKGROUND: Health-related quality of life (HRQoL) has been used to assess subjects' prognosis and recovery following hip fracture. However, evidence is mixed regarding the effectiveness of interventions to improve HRQoL of elders with hip fracture. The purposes of this study were to identify distinct HRQoL trajectories and to evaluate the effects of two care models on these trajectories over 12 months following hip-fracture surgery. METHODS: For this secondary analysis, data came from a randomized controlled trial of subjects with hip fracture receiving three treatment care models: interdisciplinary care (n = 97), comprehensive care (n = 91), and usual care (n = 93). Interdisciplinary care consisted of geriatric consultation, discharge planning, and 4 months of in-home rehabilitation. Comprehensive care consisted of interdisciplinary care plus management of malnutrition and depressive symptoms, fall prevention, and 12 months of in-home rehabilitation. Usual care included only in-hospital rehabilitation and occasional discharge planning, without geriatric consultation and in-home rehabilitation. Mental and physical HRQoL were measured at 1, 3, 6, and 12 months after discharge by the physical component summary scale (PCS) and mental component summary scale (MCS), respectively, of the Medical Outcomes Study Short Form 36, Taiwan version. Latent class growth modeling was used to identify PCS and MCS trajectories and to evaluate how they were affected by the interdisciplinary and comprehensive care models. RESULTS: We identified three quadratic PCS trajectories: poor PCS (n = 103, 36.6 %), moderate PCS (n = 96, 34.2 %), and good PCS (n = 82, 29.2 %). In contrast, we found three linear MCS trajectories: poor MCS (n = 39, 13.9 %), moderate MCS (n = 84, 29.9 %), and good MCS (n = 158, 56.2 %). Subjects in the comprehensive care and interdisciplinary care groups were more likely to experience a good PCS trajectory (b = 0.99, odds ratio [OR] = 2.69, confidence interval [CI] = 7.24-1.00, p = 0.049, and b = 1.32, OR = 3.75, CI = 10.53-1.33, p = 0.012, respectively) than those who received usual care. However, neither care model improved MCS. CONCLUSIONS: The interdisciplinary and comprehensive care models improved recovery from hip fracture by increasing subjects' odds for following a trajectory of good physical functioning after hospitalization. TRIAL REGISTRATION: ClinicalTrials.gov ( NCT01350557 ). PMID- 26936195 TI - Severe intimate partner violence affecting both young and elderly patients of both sexes. AB - BACKGROUND: Intimate partner violence (IPV) affects 25-35 % of women and men in Western countries. Despite the high prevalence of IPV among trauma patients, very little is known about the associated injuries. Most previous studies excluded male victims and IPV is often limited to violence against women. Few reports on IPV among elderly patients exist. METHODS: We examined self-reports of IPV among patients at two major trauma centers of the Helsinki Central Hospital in Finland. Based on previous studies, we hypothesized that we would find the most severe injuries among young and middle-aged women. RESULTS: We identified 29 patients with a total of 105 injuries; patients typically presented with multiple injuries. Half of all patients required hospitalization or surgery. Contrary to previous studies, 17 % of our cohort were male, while 17 % of patients were 65 years or older. We found that 40 % of male victims presented with a New Injury Severity Score (NISS) over 15, indicating severe trauma. Two elderly patients presented with an NISS of 27, the highest in our study. CONCLUSIONS: IPV leads to severe injury across all age groups among both male and female patients. The injury mechanism should be clearly defined for all trauma patients, keeping IPV in mind as a potential cause despite patient age or gender. PMID- 26936197 TI - Evaluation of design factors for a cascade aerator to enhance the efficiency of an oxidation pond for ferruginous mine drainage. AB - This research focused on the optimum design of a cascade aerator to enhance the efficiency of an oxidation pond in a passive treatment system for remediating ferruginous mine drainage. For this purpose, various aeration experiments with aerators of different drop heights (0-4 m) and formations (types A and B) were executed on mine drainage. Type A simply drops the mine drainage into the oxidation pond while type B sprays the mine drainage and retains it for 8 min in each step. The efficiency enhancement of the oxidation pond was strongly dependent on the increase in pH and DO of the mine drainage discharged into the pond. The water quality improved with the increase in drop height but especially showed better effect with type B. The reasons for this result were attributed to the increase of contact surface and retention time of the mine drainage. The cascade aerator, therefore, should be designed to be as high as possible with the assistance of spraying form and retention time of the mine drainage to maximize the efficiency of the oxidation pond. These effects could be evaluated by calculating required areas of the oxidation pond for 95% of Fe(2+) oxidation. PMID- 26936198 TI - Chloride intracellular channel 1 regulates migration and invasion in gastric cancer by triggering the ROS-mediated p38 MAPK signaling pathway. PMID- 26936196 TI - Effects of hemarthrosis on cartilage and synovium in rabbits. AB - PURPOSE: To provide experimental basis for clinic treatment by observing the effects of simple acute hematoma on cartilage and synovium, and improvement of hyaluronic acid (HA) on the damage. METHODS: Twenty-four New Zealand white rabbits were randomly divided 3 groups according to killed time: hematoma group, HA group and control group. These rabbits were killed at 4 days, 2, 4 and 8 weeks, respectively. RESULTS: Knee articular cartilage and synovium were obtained to detect histology, histochemistry and chondroitin proteoglycans (PG). Morphologies of cartilage and synovium in the control group were normal, while cartilage cells were detected hyperplasia of activation and each layer was disorganized in hematoma groups with 4 days and 2 weeks. Compared to the control group, concentrations of PG in 4 days and 2 weeks groups were significantly reduced (p < 0.05), while no significant difference was detected between 4 weeks group and the control group. Morphology was recovered normal in 8 weeks. Compared to hematoma group, morphology and histochemistry were improved in HA group at each time frame. CONCLUSIONS: Simple acute hematoma can lead to temporary change of morphology and biochemistry. Application of HA can reduce damage of hemarthrosis on cartilaginous and shorten the cartilage recovery time. PMID- 26936200 TI - Sex difference in mental well-being among the young-old population: Things that you have left behind might be important in later life. PMID- 26936199 TI - Blastic plasmacytoid dendritic cell neoplasm accompanied by autoimmune hemolytic anemia achieving complete remission with hydroxyurea and steroids. PMID- 26936201 TI - Prevalence and appropriateness of procedures for altering oral dosage forms in a cohort of elderly institutionalized patients. PMID- 26936202 TI - Neutrophil CD64 level. PMID- 26936203 TI - Small bowel obstruction and abdominal pain after robotic versus open radical prostatectomy. AB - Objective The aim of this study was to examine whether intraperitoneal robot assisted surgery leads to small bowel obstruction (SBO), possibly caused by the formation of intra-abdominal adhesions. Materials and methods In total, 7256 men treated by intraperitoneal robot-assisted radical prostatectomy (RARP) and 9787 men treated by retropubic radical prostatectomy (RRP) in 2005-2012 were identified in the Prostate Cancer data Base Sweden (PCBaSe). Multivariable Cox proportional hazards models were used to calculate the risk of readmission for SBO, SBO-related surgery and admissions due to abdominal pain up to 5 years postoperatively. Results During the first postoperative year, the risk of readmission for SBO was higher after RARP than after RRP [hazard ratio (HR) 1.92, 95% confidence interval (CI) 1.14-3.25] but after 5 years there was no significant difference (HR 1.28, 95% CI 0.86-1.91), and there was no difference in the risk of SBO surgery during any period. The risk of admission for abdominal pain was significantly increased after RARP during the first year (HR 2.24, 95% CI 1.50-3.33) but not after 5 years (HR 1.23, 95% CI 0.92-1.63). Conclusion Intraperitoneal RARP had an increased risk of SBO and abdominal pain in the short term during the first year, but not in the long term, compared to RRP. PMID- 26936204 TI - Nuclear magnetic resonance titration of the interaction between pemphigus vulgaris autoantibodies and REWVKFAKPCRE, a therapeutic desmoglein 3 peptide. AB - BACKGROUND: Pemphigus vulgaris (PV) is an autoimmune skin disease, the primary autoantigen of which is the desmosomal cadherin desmoglein (Dsg)3. The exact defin-ition of Dsg3 epitopes and their relationship(s) to the pathophysiology of blister formation are important for the advancement of efforts to develop more effective and specific therapies for PV. AIM: To characterize the binding of autoantibodies from patients with PV to a Dsg3 peptide, REWVKFAKPCRE, which shows therapeutic effectiveness but does not induce pathogenic antibodies. METHODS: We carried out a titration experiment of the reaction between PV autoantibodies and the peptide Dsg349-60REWVKFAKPCRE using nuclear magnetic resonance (NMR) spectroscopy. RESULTS: The interaction between Dsg349-60REWVKFAKPCRE and PV autoantibodies at concentrations of 20, 40 and 60 mg was found to involve R49 and A55 residues. CONCLUSIONS: Our data seem to suggest that the REWVKFAKPCRE peptide may mimic epitopic Dsg3 extracellular sequences related to pathogenic autoantibodies. PMID- 26936205 TI - Enhanced Binding of Phenosafranin to Triblock Copolymer F127 Induced by Sodium Dodecyl Sulfate: A Mixed Micellar System as an Efficient Drug Delivery Vehicle. AB - In this study, we explored the interaction of a cationic phenazinium dye, phenosafranin (PSF, here used as a model drug), with pluronic block copolymer F127, both in the presence and in the absence of the anionic surfactant sodium dodecyl sulfate (SDS), which forms mixed micelles with F127. We applied both steady-state and time-resolved spectroscopic techniques, along with isothermal titration calorimetry (ITC), to demonstrate the binding of the probe PSF to both the pluronic and F127/SDS mixed micelles. Dynamic light scattering (DLS) study revealed that, upon interaction with SDS, the hydrodynamic diameter (dH) of F127 micelles decreased due to the formation of the mixed micelles. The PSF penetrated to the more hydrophobic interior of the mixed micellar system as compared to F127 micelles alone. Micropolarity and fluorescence-quenching experiments revealed that PSF is more deeply seated in the case of F127/SDS mixed micelles. Through a partition coefficient, lifetime measurements, and time-resolved anisotropy experiments, we also established that the partitioning of the probe within the F127 micelles in the presence of SDS is almost double than that in its absence. ITC data corroborates the fact that the binding of PSF is the strongest and most thermodynamically favorable when mixed micelles are formed, which enables our system to serve as an excellent drug delivery vehicle when compared to F127 alone. PMID- 26936206 TI - A change in the trend in dosulepin usage following the introduction of a prescribing indicator but not after two national safety warnings. AB - WHAT IS KNOWN AND OBJECTIVE: The tricyclic antidepressant dosulepin has been associated with an increased risk of toxicity in overdose compared with other antidepressants. In the UK, the MHRA and NICE have issued advice on the prescribing of dosulepin, and a National Prescribing Indicator (NPI) to monitor usage was introduced in Wales in 2011. The aim of this study was to assess whether trends in dosulepin usage in Wales and NE England changed following the two pieces of safety guidance and the introduction of the National Prescribing Indicator in Wales. METHODS: Primary care dosulepin usage in the 12 months prior to and following MHRA safety advice (in 2007), NICE guideline CG90 (in 2009) and the introduction of the NPI (in 2011) was obtained. Usage was measured using defined daily doses (DDDs) per 1000 prescribing units (PUs). The trends in the 12 months prior to and following the introduction of prescribing advice and the NPI were compared using an autoregressive integrated moving average (ARIMA) model. RESULTS AND DISCUSSION: In Wales, the trend in dosulepin usage did not change significantly prior to and following the MHRA advice: -0.18 and -0.43 DDDs/1000PUs per month, respectively (P = 0.07), or prior to and following NICE CG90: -0.30 and -0.49 DDDs/1000PUs per month, respectively (P = 0.35). In the 12 months prior to and following the introduction of the NPI, the trend was -0.45 and -0.98 DDDs/1000PUs per month, respectively (P = 0.001). In NE England, the trend did not alter significantly following the NICE advice or the introduction of the NPI in Wales. WHAT IS NEW AND CONCLUSION: The trend in dosulepin usage in Wales altered significantly following the introduction of the NPI, but not after the other prescribing advice. This association, coupled with the absence of a significant change in NE England over the same period, provided some evidence of the effectiveness of the NPI in prompting a change in prescribing behaviour in Wales. PMID- 26936207 TI - Carbonated soft drinks induce oxidative stress and alter the expression of certain genes in the brains of Wistar rats. AB - In Saudi Arabia, the consumption of carbonated soft drinks is common and often occurs with each meal. Carbonated soft drink consumption has been shown to exhibit effects on the liver, kidney and bone. However, the effects of these soft drinks on brain activity have not been widely examined, particularly at the gene level. Therefore, the current study was conducted with the aim of evaluating the effects of chronic carbonated soft drink consumption on oxidative stress, brain gene biomarkers associated with aggression and brain histology. In total, 40 male Wistar rats were divided into four groups: Group 1 served as a control and was provided access to food and water ad libitum; and groups 2-4 were given free access to food and carbonated soft drinks only (Cola for group 2, Pepsi for group 3 and 7-UP for group 4). Animals were maintained on these diets for 3 consecutive months. Upon completion of the experimental period, animals were sacrificed and serological and histopathological analyses were performed on blood and tissues samples. Reverse transcription-polymerase chain reaction was used to analyze alterations in gene expression levels. Results revealed that carbonated soft drinks increased the serum levels of malondialdehyde (MDA). Carbonated soft drinks were also observed to downregulate the expression of antioxidants glutathione reductase (GR), catalase and glutathione peroxidase (GPx) in the brain when compared with that in the control rats. Rats administered carbonated soft drinks also exhibited decreased monoamine oxidase A (MAO-A) and acetylcholine esterase (AChE) serum and mRNA levels in the brain. In addition, soft drink consumption upregulated mRNA expression of dopamine D2 receptor (DD2R), while 5-hydroxytryptamine transporter (5-HTT) expression was decreased. However, following histological examination, all rats had a normal brain structure. The results of this study demonstrated that that carbonated soft drinks induced oxidative stress and altered the expression of certain genes that are associated with the brain activity and thus should be consumed with caution. PMID- 26936208 TI - Associations between patients' adherence and GPs' attitudes towards risk, statin therapy and management of non-adherence--a survey and register-based study. AB - BACKGROUND: Previous studies suggest that doctors' personal lifestyle, risk taking personality and beliefs about risk reducing therapies may affect their clinical decision-making. Whether such factors are further associated with patients' adherence with medication is largely unknown. OBJECTIVE: To estimate associations between GPs' attitudes towards risk, statin therapy and management of non-adherence and their patients' adherence, and to identify subgroups of GPs with poor patient adherence. METHODS: All Danish GPs were invited to participate in an online survey. We asked whether they regarded statin treatment as important, how they managed non-adherence and whether non-adherence annoyed them. The Jackson Personality Inventory-revised was used to measure risk attitude. The GPs' responses were linked to register data on their patients' redeemed statin prescriptions. Mixed effect logistic regression was used to estimate associations between patient adherence and GPs' attitudes. Adherence was estimated by the proportion of days covered in a 1-year period using an 80% cut-off. RESULTS: We received responses from 1398 GPs (42.2%) who initiated statin therapy in 12 192 patients during the study period. In total 6590 (54.1%) of these patients were adherent. Patients who had GPs rarely assessing their treatment adherence were less likely to be adherent than those who had GPs assessing their patients' treatment adherence now and then, odds ratio (OR) 0.86 [confidence interval (CI) 0.77-0.96]. No other associations were found between patients' adherence and GPs' attitudes. CONCLUSIONS: Our findings suggest that GPs' attitudes to risk, statin therapy or management of non-adherence are not significantly associated with their patients' adherence. PMID- 26936209 TI - The Role of Dairy in Effectiveness and Cost of Treatment of Children With Moderate Acute Malnutrition: A Narrative Review. AB - BACKGROUND: Dairy is recommended in specially formulated supplementary foods to treat children with moderate acute malnutrition (MAM) but with limited evidence and added cost. OBJECTIVE: Review studies of ready-to-use foods (RUFs) versus fortified blended foods (FBFs) to determine whether inclusion of dairy modifies the comparative effectiveness and cost. METHODS: We reviewed literature comparing FBF and RUF in treatment of MAM among children younger than 5 years in developing countries. Outcomes of recovery from MAM, weight, and length gain were compared among treatment categories: FBF with dairy (FBF+), FBF without dairy (FBF-), RUF with dairy (RUF+), and RUF without dairy (RUF-). Supplement cost was compared per 500 kcal. RESULTS: Eight studies were included. Rations were heterogeneous in energy and type of dairy. Overall, RUF+, RUF-, and FBF+ performed similarly, with higher recovery and weight gain compared with FBF-. RUF+ had higher recovery (in 5 of 6 comparisons), weight gain (4 of 4), and length gain (1 of 4) versus FBF-. The RUF+ had higher recovery (1 of 2) versus FBF+, with no other differences. The RUF- versus FBF+ had no differences (0 of 2). The RUF- had higher recovery (1 of 2), weight gain (2 of 2) versus FBF-. Four studies reported supplement costs, which averaged US$0.15 (FBF-), US$0.18 (FBF+), US$0.18 (RUF-), and US$0.37 (RUF+) per 500 kcal. CONCLUSIONS: There is a consistent benefit of FBF that include dairy in treatment of children with MAM. Benefits of dairy in RUF require further investigation. Evidence from rigorous quantitative analysis of existing data, cost-effectiveness, and prospective trials will be essential in determining policy on treatment for children with MAM. PMID- 26936210 TI - Population structure of Atlantic mackerel inferred from RAD-seq-derived SNP markers: effects of sequence clustering parameters and hierarchical SNP selection. AB - Restriction-site-associated DNA sequencing (RAD-seq) and related methods are revolutionizing the field of population genomics in nonmodel organisms as they allow generating an unprecedented number of single nucleotide polymorphisms (SNPs) even when no genomic information is available. Yet, RAD-seq data analyses rely on assumptions on nature and number of nucleotide variants present in a single locus, the choice of which may lead to an under- or overestimated number of SNPs and/or to incorrectly called genotypes. Using the Atlantic mackerel (Scomber scombrus L.) and a close relative, the Atlantic chub mackerel (Scomber colias), as case study, here we explore the sensitivity of population structure inferences to two crucial aspects in RAD-seq data analysis: the maximum number of mismatches allowed to merge reads into a locus and the relatedness of the individuals used for genotype calling and SNP selection. Our study resolves the population structure of the Atlantic mackerel, but, most importantly, provides insights into the effects of alternative RAD-seq data analysis strategies on population structure inferences that are directly applicable to other species. PMID- 26936211 TI - Interferon-gamma release assays can effectively screen migrants for the tuberculosis infection, but urgent, active cases need clinical recognition. AB - AIM: Increasing numbers of migrants to Sweden are screened for tuberculosis (TB), and a rational approach to screening is required. We evaluated positive tuberculin skin tests (TSTs) and interferon-gamma release assays (IGRAs) on paediatric migrants in relation to the TB incidence in the corresponding foreign born populations in Stockholm. METHODS: This study examined the characteristics of migrants under the age of 18 who were referred to a paediatric TB clinic at Karolinska University Hospital from 2008 to 2014 by primary care centres in Stockholm County. RESULTS: We saw 943 TST-positive children with a median age of 14 years at the TB clinic and performed IGRAs on 557. IGRA positivity ranged from 64% in migrants from Somalia to 20% in those from the former Soviet Union and eastern Europe, with an estimated population level prevalence of 18.8% and 4.2%, respectively. These were significantly correlated to TB incidence in foreign-born Stockholm children. We diagnosed active TB in 20 screened migrants, and advanced, symptomatic TB was diagnosed in 10 recently arrived migrants without screening. CONCLUSION: IGRAs showed higher specificity than TST in identifying tuberculosis. TB screening should focus on migrants from high-incidence countries, but this may be inadequate to detect advanced TB cases. PMID- 26936212 TI - The inhibitory effect of A20 on the inflammatory reaction of epidermal keratinocytes. AB - A20 is a negative regulator of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) signaling, and has been implicated in the pathogenesis of psoriasis through genome-wide association study (GWAS). In the present study, we investigated the putative role of A20 in epidermal keratinocytes. Immunohistochemical analysis showed that A20 was expressed in all layers of the epidermis, with an increasing pattern in the upper layers. In our model of calcium-induced keratinocyte differentiation, A20 expression was increased in a time-dependent manner. To investigate whether A20 affected keratinocyte differentiation, we overexpressed A20 in cultured keratinocytes. As a result, we noted that A20 overexpression did not affect keratinocyte differentiation, suggesting that A20 is not a direct modulator of keratinocyte differentiation. Interestingly, we found that A20 levels were decreased in psoriatic lesional skin compared to non-lesional areas. To investigate whether A20 played a role in the innate immune response of keratinocytes, we overexpressed A20 and then examined poly(I:C)-induced cytokine expression. We noted that A20 significantly inhibited poly(I:C)-induced cytokine production, and this effect was related to the inhibition of NF-kappaB signaling. These results suggest that the downregulation of A20 increased the susceptibility of keratinocytes to external stimuli, thus contributing to the development of psoriasis. PMID- 26936214 TI - Identification of Stem Cells in the Secretory Complex of Salivary Glands. AB - Salivary glands have an essential secretory function for maintaining oral and overall health. The epithelial compartment of the gland is composed of several highly specialized cell types that cooperate to secrete and deliver saliva to the oral cavity. The mouse submandibular gland has been used as a model for major salivary glands in human. The secretory complex in this model is composed of 2 secretory compartments, including acini and granular ducts connected by intercalated ducts. Contractile myoepithelial cells surround the secretory complex to facilitate salivary flow. Whether differentiated cells in the secretory complex are maintained by self-duplication or contribution from stem cells has remained an open question. Here, in analyzing the expression of basal cytokeratin (K) 14 in the secretory complex, we discovered a subset of K14(+) ductal cells in the intercalated ducts of the adult gland. These cells are distinct from the K14-expressing basal/myoepithelial cells, proliferate at a significantly higher rate than any other epithelial cell type in the gland, and reside in a spatially defined domain within the intercalated duct. Using inducible genetic lineage tracing, we show that K14(+) ductal cells represent a long-lived yet cycling population of stem cells that are established during development and contribute to the formation and maintenance of the granular ducts throughout life. Our data provide direct evidence for the existence of stem cells contributing to homeostasis of salivary glands, as well as new insights into glandular pathobiology. PMID- 26936213 TI - Levels of Candidate Periodontal Pathogens in Subgingival Biofilm. AB - In recent years, several new periodontal taxa have been associated with the etiology of periodontitis. A recent systematic review provides further support for the pathogenic role of 17 species/phylotypes. Thus, the aim of this study was to assess the prevalence and levels of these species in subjects with generalized chronic periodontitis (GChP; n = 30), generalized aggressive periodontitis (GAgP; n = 30), and periodontal health (PH; n = 30). All subjects underwent clinical and microbiological assessment. Nine subgingival plaque samples were collected from each subject and analyzed for their content of 20 bacterial species/phylotypes through the RNA-oligonucleotide quantification technique. Subjects from the GChP and GAgP groups presented the highest mean values for all clinical parameters in comparison with the PH group (P < 0.05). Subjects with GChP and GAgP showed significantly higher mean levels of Bacteroidetes sp. human oral taxon (HOT) 274, Fretibacterium sp. HOT 360, and TM7 sp. HOT 356 phylotypes, as well as higher mean levels of Filifactor alocis, Fretibacterium fastidiosum, Porphyromonas gingivalis, Tannerella forsythia, and Selenomonas sputigena species than PH subjects (P < 0.05). GAgP subjects presented higher mean levels of TM7 sp. HOT 356 and F. alocis than GChP subjects (P < 0.05). A significantly higher mean prevalence of Bacteroidales sp. HOT 274, Desulfobulbus sp. HOT 041, Fretibacterium sp. HOT 360, and Fretibacterium sp. HOT 362 was found in subjects with GChP and GAgP than in PH subjects. Mean levels of P. gingivalis (r = 0.68), T. forsythia (r = 0.62), F. alocis (r = 0.51, P = 0.001), and Fretibacterium sp. HOT 360 (r = 0.41) were correlated with pocket depth (P < 0.001). In conclusion, Bacteroidales sp. HOT 274, Desulfobulbus sp. HOT 041, Fretibacterium sp. HOT 360, Fretibacterium sp. HOT 362, and TM7 sp. HOT 356 phylotypes, in addition to F. alocis, F. fastidiosum, and S. sputigena, seem to be associated with periodontitis, and their role in periodontal pathogenesis should be further investigated. PMID- 26936216 TI - Graeme Catto: Resilient, realistic, interested. PMID- 26936215 TI - Oral Health-related Beliefs, Behaviors, and Outcomes through the Life Course. AB - Complex associations exist among socioeconomic status (SES) in early life, beliefs about oral health care (held by individuals and their parents), and oral health-related behaviors. The pathways to poor adult oral health are difficult to model and describe, especially due to a lack of longitudinal data. The study aim was to explore possible pathways of oral health from birth to adulthood (age 38 y). We hypothesized that higher socioeconomic position in childhood would predict favorable oral health beliefs in adolescence and early adulthood, which in turn would predict favorable self-care and dental attendance behaviors; those would lead to lower dental caries experience and better self-reported oral health by age 38 y. A generalized structural equation modeling approach was used to investigate the relationship among oral health-related beliefs, behaviors in early adulthood, and dental health outcomes and quality of life in adulthood (age, 38 y), based on longitudinal data from a population-based birth cohort. The current investigation utilized prospectively collected data on early (up to 15 y) and adult (26 and 32 y) SES, oral health-related beliefs (15, 26, and 32 y), self care behaviors (15, 28, and 32 y), oral health outcomes (e.g., number of carious and missing tooth surfaces), and oral health-related quality of life (38 y). Early SES and parental oral health-related beliefs were associated with the study members' oral health-related beliefs, which in turn predicted toothbrushing and dental service use. Toothbrushing and dental service use were associated with the number of untreated carious and missing tooth surfaces in adulthood. The number of untreated carious and missing tooth surfaces were associated with oral health related quality of life. Oral health toward the end of the fourth decade of life is associated with intergenerational factors and various aspects of people's beliefs, SES, dental attendance, and self-care operating since the childhood years. PMID- 26936217 TI - Surface Structure Modification of ZnO and the Impact on Electronic Properties. AB - Zinc oxide (ZnO) is a widely utilized, versatile material implemented in a diverse range of technological applications, particularly in optoelectronic devices, where its inherent transparency, tunable electronic properties, and accessible nanostructures can be combined to confer superior device properties. ZnO is a complex material with a rich and intricate defect chemistry, and its properties can be extremely sensitive to processing methods and conditions; consequently, surface modification of ZnO using both inorganic and organic species has been explored to control and regulate its surface properties, particularly at heterointerfaces in electronic devices. Here, the properties of ZnO are described in detail, particularly its surface chemistry, along with the role of defects in governing its electronic properties, and methods employed to modulate the behavior of as-grown ZnO. An outline is also given on how the native and modified oxide interact with molecular materials. To illustrate the diverse range of surface modification methods and their subsequent influence on electronic properties, a comprehensive review of the modification of ZnO surfaces at molecular interfaces in hybrid photovoltaic (hPV) and organic photovoltaic (OPV) devices is presented. This is a case study rather than a progress report, aiming to highlight the progress made toward controlling and altering the surface properties of ZnO, and to bring attention to the ways in which this may be achieved by using various interfacial modifiers (IMs). PMID- 26936219 TI - Experimental demonstration of topological effects in bianisotropic metamaterials. AB - Existence of robust edge states at interfaces of topologically dissimilar systems is one of the most fascinating manifestations of a novel nontrivial state of matter, a topological insulator. Such nontrivial states were originally predicted and discovered in condensed matter physics, but they find their counterparts in other fields of physics, including the physics of classical waves and electromagnetism. Here, we present the first experimental realization of a topological insulator for electromagnetic waves based on engineered bianisotropic metamaterials. By employing the near-field scanning technique, we demonstrate experimentally the topologically robust propagation of electromagnetic waves around sharp corners without backscattering effects. PMID- 26936220 TI - The Moderator Role of Perceived Emotional Intelligence in the Relationship between Sources of Stress and Mental Health in Teachers. AB - This study analyzes the role of Perceived Emotional Intelligence (PEI) on sources of job stress and mental health in 250 elementary school teachers from Jaen (Spain). The aim of the study was two-fold: (1) to analyze the associations between Perceived Emotional Intelligence (PEI), sources of occupational stress and mental health; and (2) to determine whether PEI moderates the relationship between sources of occupational stress and mental health. An initial sample of 250 teachers was assessed Three questionnaires, the Trait Meta-Mood Scale, the Sources of Stress Scale in Teachers and the Medical Outcomes Study 36-item Short Form Health Survey, were used to evaluate PEI, sources of occupational stress and mental health, respectively. Teachers with higher levels of emotional attention reported lower levels of mental health (r = -.30; p < .001), while teachers showing high emotional clarity reported better emotional role (r = .14; p < .05) and social functioning (r = .15; p < .05). Moreover, PEI components moderate the relationship between sources of occupational stress and emotional role. Specifically, each significant interaction (i.e., deficiencies x attention, adaptation x attention, and adaptation x clarity) made a small and unique contribution in the explanation of emotional role (all p < .05, all sr 2 ~ .02). Finally, our results imply that PEI is an important moderator of teachers' occupational stressors on mental health. PMID- 26936221 TI - Shaking improves the whole bone marrow adherent method of purification. AB - The aim of the present study was to investigate the potential effects of mechanical shaking on the purity, activity, differentiation and possible apoptosis of rat bone marrow mesenchymal stem cells (BMSCs). Based on the whole bone marrow adhesion method, different durations and frequencies of mechanical shaking were used on primary cells. The biomarkers, CD29, CD90, CD45 and CD31, in addition to the apoptosis labels, annexin V-FITC and PI, were investigated using flow-cytometric analysis. The differentiation capability following purification was evaluated. Following shaking treatment, the purity of adherent cells increased, in particular there was an increase in CD29 and CD90 positive cells, with the majority of the detached cells negative for these two markers. In addition, the apoptotic rates increased with the increasing shaking duration and frequency. Furthermore, cells following shaking were induced to differentiate into osteoblasts and adipocytes. The shaking method allows for mesenchymal stem cells at to be obtained with higher positive rates of CD29 and CD90. In addition, horizontal shaking has little influence on cell activity or differentiation, with low levels of apoptosis occurring as a result of shaking. PMID- 26936218 TI - Intracellular kinetics of the androgen receptor shown by multimodal Image Correlation Spectroscopy (mICS). AB - The androgen receptor (AR) pathway plays a central role in prostate cancer (PCa) growth and progression and is a validated therapeutic target. In response to ligand binding AR translocates to the nucleus, though the molecular mechanism is not well understood. We therefore developed multimodal Image Correlation Spectroscopy (mICS) to measure anisotropic molecular motion across a live cell. We applied mICS to AR translocation dynamics to reveal its multimodal motion. By integrating fluorescence imaging methods we observed evidence for diffusion, confined movement, and binding of AR within both the cytoplasm and nucleus of PCa cells. Our findings suggest that in presence of cytoplasmic diffusion, the probability of AR crossing the nuclear membrane is an important factor in determining the AR distribution between cytoplasm and the nucleus, independent of functional microtubule transport. These findings may have implications for the future design of novel therapeutics targeting the AR pathway in PCa. PMID- 26936222 TI - Animal Abuse and Interpersonal Violence: The Cruelty Connection and Its Implications for Veterinary Pathology. AB - The role of the veterinary forensic pathologist in the investigation of animal abuse or neglect can go beyond documenting the condition of animals presented as evidence. Although animal cruelty is a moral concern and a crime in itself, law enforcement response to such crimes is often enhanced by the recognition that crimes against animals can be both indicators of other ongoing crimes against people and predictors of the potential for interpersonal violence. An understanding of common motives underlying animal cruelty can aid the pathologist in asking appropriate questions. The authors review the forms of pathology evidence commonly seen in various presentations of animal cruelty. Understanding these forms of evidence can help the pathologist describe findings that can be significant for assessing the potential risks the alleged perpetrator may pose to other animals and humans. PMID- 26936223 TI - Comparison of Two US Sheep Scrapie Isolates Supports Identification as Separate Strains. AB - Scrapie is a naturally occurring transmissible spongiform encephalopathy of sheep and goats. There are different strains of sheep scrapie that are associated with unique molecular, transmission, and phenotype characteristics. However, in the United States, very little is known about the potential presence of scrapie strains. Scrapie strain and PRNP genotype could both affect susceptibility, potential for transmission, incubation period (IP), and control measures required for eliminating scrapie from a flock. The investigators evaluated 2 US scrapie isolates, No. 13-7 and x124, after intranasal inoculation to compare clinical signs, IPs, spongiform lesions, and patterns of PrPSc deposition in sheep with scrapie-susceptible PRNP genotypes (QQ171). After inoculation with x124, susceptibility and IP were associated with valine at codon 136 (V136) of the prion protein: VV136 sheep had short IPs (6.9 months), those in AV136 sheep were 11.9 months, and AA136 sheep did not develop scrapie. All No. 13-7 inoculated sheep developed scrapie, with IPs of 20.1 months for AA136 sheep, 22.8 months for AV136 sheep, and 26.7 months for VV136 sheep. Patterns of immunoreactivity in the brain were influenced by inoculum isolate and host genotype. Differences in PrPSc profiles versus isolate were most striking when examining brains from sheep with the VV136 genotype. Inoculation into C57BL/6 mice resulted in markedly different attack rates (90.5% for x124 and 5.9% for No. 13-7). Taken together, these data demonstrate that No. 13-7 and x124 represent 2 distinct strains of scrapie with different IPs, genotype susceptibilities, and PrPSc deposition profiles. PMID- 26936224 TI - Hydrogen-rich saline protects against mitochondrial dysfunction and apoptosis in mice with obstructive jaundice. AB - Previous studies have demonstrated that hydrogen-rich saline (HS) protects against bile duct ligation (BDL)-induced liver injury by suppressing oxidative stress and inflammation. Mitochondria, which are targets of excessive reactive oxygen species and central mediators of apoptosis, have a pivotal role in hepatic injury during obstructive jaundice (OJ); however, the implications of HS in the hepatic mitochondria of BDL mice remain unknown. The present study investigated the hypothesis that HS could reduce OJ-induced liver injury through the protection of mitochondrial structure and function, as well as inhibition of the mitochondrial apoptotic pathway. Male C57BL/6 mice were randomly divided into three experimental groups: Sham operation group, BDL injury with normal saline (NS) treatment group, and BDL-injury with HS treatment group. Mitochondrial damage and apoptotic parameters were determined 3 days post-BDL injury and treatment. The results demonstrated that mitochondria isolated from the livers of NS-treated BDL mice exhibited increased mitochondrial swelling, cytochrome c release, and oxidative damage. In addition, liver samples from NS-treated BDL mice exhibited significant increases in B-cell lymphoma 2 (Bcl-2)-associated X protein expression, caspase activities, and hepatocyte apoptosis compared with livers from sham-operated controls. Notably, treatment with HS reduced the levels of these markers and alleviated morphological defects in the mitochondria following injury. In addition, HS markedly increased the antioxidant potential of mitochondria, as evidenced by elevated adenosine triphosphate levels, mitochondrial respiratory function, and increased levels of active Bcl-2. In conclusion, HS attenuates mitochondrial oxidative stress and dysfunction, and inhibits mitochondrial-mediated apoptosis in the livers of BDL mice. PMID- 26936225 TI - Reasons to Conserve Nature. AB - Is it sufficient to base arguments for conservation on the intrinsic value of nature, regardless of the services and economic benefits that biodiversity provides for humans? This question underlies much recent debate that has been at times acrimonious and has led to calls for a more inclusive approach to conservation. Yet melding different ideologies within a unified conceptual framework has proven difficult. Here I describe an approach that recognizes the importance of the level of biological organization and spatial extent in determining the strength of alternative arguments for why we should conserve nature. I argue that the framework helps reconcile contrasting viewpoints and brings clarity to when different conservation management approaches (for instance, regulation versus monetary valuation) are most appropriate. PMID- 26936226 TI - Eradication of common mynas Acridotheres tristis from Denis Island, Seychelles. AB - BACKGROUND: In Seychelles, the common myna has been shown to have a negative impact on endangered endemic birds on Denis Island, interfering with breeding attempts and attacking adult endemic birds at their nests. This stimulated an attempt to eradicate the island's mynas. RESULTS: The eradication was undertaken in three phases, overall killing 1186 mynas and lasting 5 years. Decoy trapping was the most effective method for catching mynas, but the last birds were shot. Decoy trapping was compromised by catches of non-target species. Data collection from killed birds indicated that trapping did not favour either sex, and that most breeding occurred during the wetter season, November to March. CONCLUSIONS: Eradication of mynas from small tropical islands is feasible. The Denis Island eradication was prolonged by difficulties in management and staffing. Using volunteers, the cost of the eradication was similar to that of eradicating rodents from the island. In future eradication attempts in Seychelles, possible food stress during the drier season (May to September) might facilitate trapping at this time. Habitat management, especially the removal of short mown grass, could enhance eradication progress. Continued monitoring is needed to confirm eradication and detect any immigration, and also to record responses in the endemic birds. (c) 2016 Society of Chemical Industry. PMID- 26936227 TI - Recombinant long-acting glycoPEGylated factor IX (nonacog beta pegol) in haemophilia B: assessment of target joints in multinational phase 3 clinical trials. AB - BACKGROUND: The paradigm(TM) 2 and 4 phase 3 clinical trials investigated the safety and efficacy of nonacog beta pegol, a recombinant glycoPEGylated factor IX (FIX) with extended half-life, in previously treated haemophilia B patients. AIM: These post hoc analyses investigated the bleeding patterns in target joints. METHODS: Patients randomized to 40 or 10 IU kg(-1) once weekly prophylaxis who had at least one target joint were included. Baseline demographics and disease specific data were collected. Bleeding patterns were assessed, and an International Society on Thrombosis and Haemostasis (ISTH) definition of target joints was used. RESULTS: A total of 67% and 8% of patients in the 40 and 10 IU kg(-1) arm, respectively, did not experience target joint bleeds during the paradigm(TM) 2 trial. Twenty-four target joints were recorded in each prophylaxis arm at baseline. During the paradigm(TM) 2 trial, no bleeds were reported in 17 (71%) and 7 (29%) target joints in the 40 and 10 IU kg(-1) arms respectively. All target joint bleeds in the 40 IU kg(-1) once weekly prophylaxis arm were controlled with a single injection of 40 IU kg(-1) nonacog beta pegol. By the latest ISTH definition, 90% and 58% of target joints in the 40 and 10 IU kg(-1) arms, respectively, were no longer considered target joints at the end of the paradigm(TM) 2 trial. At the end of the paradigm(TM) 4 extension trial, all target joints in the 40 IU kg(-1) arm were no longer considered target joints. CONCLUSION: Routine prophylaxis with 40 IU kg(-1) once weekly nonacog beta pegol has the potential for effective management of target joint bleeds in haemophilia B patients. PMID- 26936228 TI - Impact of smoking on experimental gingivitis. A clinical, microbiological and immunological prospective study. AB - OBJECTIVE: The present study assessed the effect of smoking on clinical, microbiological and immunological parameters in an experimental gingivitis model. MATERIAL AND METHODS: Twenty-four healthy dental students were divided into two groups: smokers (n = 10); and nonsmokers (n = 14). Stents were used to prevent biofilm removal during brushing. Visible plaque index (VPI) and gingival bleeding index (GBI) were determined 5- on day -7 (running phase), baseline, 21 d (experimental gingivitis) and 28 d (resolution phase). Supragingival biofilm and gingival crevicular fluid were collected and assayed by checkerboard DNA-DNA hybridization and a multiplex analysis, respectively. Intragroup comparison was performed by Friedman and Dunn's multiple comparison tests, whereas the Mann Whitney U-test was applied for intergroup analyses. RESULTS: Cessation of oral hygiene resulted in a significant increase in VPI, GBI and gingival crevicular fluid volume in both groups, which returned to baseline levels 7 d after oral hygiene was resumed. Smokers presented lower GBI than did nonsmokers (p < 0.05) at day 21. Smokers had higher total bacterial counts and higher proportions of red- and orange complex bacteria, as well as lower proportions of Actinomyces spp., and of purple- and yellow-complex bacteria (p < 0.05). Furthermore, the levels of key immune-regulatory cytokines, including interleukin (IL)-8, IL-17 and interferon-gamma, were higher in smokers than in nonsmokers (p < 0.05). CONCLUSION: Smokers and nonsmokers developed gingival inflammation after supragingival biofilm accumulation, but smokers had less bleeding, higher proportions of periodontal pathogens and distinct host-response patterns during the course of experimental gingivitis. PMID- 26936229 TI - Electronic structure and relaxation dynamics in a superconducting topological material. AB - Topological superconductors host new states of quantum matter which show a pairing gap in the bulk and gapless surface states providing a platform to realize Majorana fermions. Recently, alkaline-earth metal Sr intercalated Bi2Se3 has been reported to show superconductivity with a Tc ~ 3 K and a large shielding fraction. Here we report systematic normal state electronic structure studies of Sr0.06Bi2Se3 (Tc ~ 2.5 K) by performing photoemission spectroscopy. Using angle resolved photoemission spectroscopy (ARPES), we observe a quantum well confined two-dimensional (2D) state coexisting with a topological surface state in Sr0.06Bi2Se3. Furthermore, our time-resolved ARPES reveals the relaxation dynamics showing different decay mechanism between the excited topological surface states and the two-dimensional states. Our experimental observation is understood by considering the intra-band scattering for topological surface states and an additional electron phonon scattering for the 2D states, which is responsible for the superconductivity. Our first-principles calculations agree with the more effective scattering and a shorter lifetime of the 2D states. Our results will be helpful in understanding low temperature superconducting states of these topological materials. PMID- 26936230 TI - Berberine Ameliorates Hepatic Steatosis and Suppresses Liver and Adipose Tissue Inflammation in Mice with Diet-induced Obesity. AB - Increasing evidence demonstrates that berberine (BBR) is beneficial for obesity associated non-alcoholic fatty liver disease (NAFLD). However, it remains to be elucidated how BBR improves aspects of NAFLD. Here we revealed an AMP-activated protein kinase (AMPK)-independent mechanism for BBR to suppress obesity associated inflammation and improve hepatic steatosis. In C57BL/6J mice fed a high-fat diet (HFD), treatment with BBR decreased inflammation in both the liver and adipose tissue as indicated by reduction of the phosphorylation state of JNK1 and the mRNA levels of proinflammatory cytokines. BBR treatment also decreased hepatic steatosis, as well as the expression of acetyl-CoA carboxylase and fatty acid synthase. Interestingly, treatment with BBR did not significantly alter the phosphorylation state of AMPK in both the liver and adipose tissue of HFD-fed mice. Consistently, BBR treatment significantly decreased the phosphorylation state of JNK1 in both hepatoma H4IIE cells and mouse primary hepatocytes in both dose-dependent and time-dependent manners, which was independent of AMPK phosphorylation. BBR treatment also caused a decrease in palmitate-induced fat deposition in primary mouse hepatocytes. Taken together, these results suggest that BBR actions on improving aspects of NAFLD are largely attributable to BBR suppression of inflammation, which is independent of AMPK. PMID- 26936232 TI - Duloxetine and escitalopram for hot flushes: efficacy and compliance in breast cancer survivors. AB - Selective serotonin reuptake inhibitors (SSRI) and serotonin-norepinephrine reuptake inhibitors (SNRI) might be an effective treatment for hot flushes (HFs) in breast cancer survivors (BCSs). This study aims to compare the efficacy and tolerability of duloxetine (SNRI) versus escitalopram (SSRI) in reducing frequency and severity of HFs in BCSs and to assess the effect on depression. Thirty-four symptomatic BCSs with emotional impairment received randomly duloxetine 60 mg daily or escitalopram 20 mg daily for 12 weeks. Patients were asked to record in a diary HF frequency and severity at baseline and after 4 and 12 weeks of treatment. Depression was evaluated through validated questionnaires (Beck Depression Inventory and Montgomery Asberg Depression Rating Scale) at baseline and after 4 and 12 weeks of treatment. Both drugs showed a significant reduction of HF frequency and severity after 12 weeks of treatment with no significant difference between the two groups. A significant improvement in depression symptoms was observed at the end of the study period within both the groups, without difference between the two drugs. In conclusion, escitalopram and duloxetine are both effective treatment for the relief of HFs in BCSs, with similar beneficial effect. A significant improvement of depression was obtained with no major side effects. PMID- 26936231 TI - The Pig Olfactory Brain: A Primer. AB - Despite the fact that pigs are reputed to have excellent olfactory abilities, few studies have examined regions of the pig brain involved in the sense of smell. The present study provides an overview of the olfactory bulb, anterior olfactory nucleus, and piriform cortex of adult pigs using several approaches. Nissl, myelin, and Golgi stains were used to produce a general overview of the organization of the regions and confocal microscopy was employed to examine 1) projection neurons, 2) GABAergic local circuit neurons that express somatostatin, parvalbumin, vasoactive intestinal polypeptide, or calretinin, 3) neuromodulatory fibers (cholinergic and serotonergic), and 4) glia (astrocytes and microglia). The findings revealed that pig olfactory structures are quite large, highly organized and follow the general patterns observed in mammals. PMID- 26936233 TI - Treatment with olopatadine and naphazoline hydrochloride reduces allergic conjunctivitis in mice through alterations in inflammation, NGF and VEGF. AB - The aim of the current study was to investigate whether olopatadine and naphazoline hydrochloride reduce allergic conjunctivitis in mice through alterations in inflammation, NGF and VEGF. An allergic conjunctivitis mouse model was established using histamine or an antigen (ovalbumin), following which mice were treated with 1% olopatadine solution and/or 0.2 mg/ml of naphazoline hydrochloride. Histamine or antigen-induced conjunctival vascular hyperpermeability was examined and the levels of inflammatory factors, cytokines, IgE, GMCSF and NGF were analyzed using ELISA in antigen-induced conjunctival vascular hyperpermeability mice. In addition, VEGF protein expression was measured using western blotting in antigen-induced mice. The results indicated that olopatadine and naphazoline hydrochloride significantly suppressed conjunctival dye leakage in mice with histamine or antigen-induced conjunctival vascular hyperpermeability. In addition, treatment with olopatadine and naphazoline hydrochloride was able to reduce the levels of inflammatory factors (TNF-alpha, IL-1beta and IL-6), cytokines (IFN-gamma and IL-4), IgE, GMCSF, and NGF in antigen-induced conjunctival vascular hyperpermeability mice. The protein expression levels of VEGF in antigen-induced conjunctival vascular hyperpermeability mice were reduced following treatment with olopatadine and naphazoline hydrochloride. These results suggest that treatment with olopatadine and naphazoline hydrochloride reduces conjunctivitis in mice via effects on inflammation, NGF and VEGF. PMID- 26936234 TI - Clinical outcomes in cystic fibrosis patients with Trichosporon respiratory infection. AB - BACKGROUND: Relationships between clinical outcomes and novel respiratory pathogens such as Trichosporon are not well understood. METHODS: Respiratory cultures from CF patients were screened for novel pathogens Trichosporon and Chryseobacterium as well as other pathogens over 28months. Relationships between microbiologic and clinical data were assessed using univariate and multivariate methods. RESULTS: Of 4934 respiratory cultures from 474 CF patients, 37 cultures from 10 patients were Trichosporon positive. Patients with positive Trichosproron cultures had a greater decline in FEV1 over time (-3.9%/year vs. -1.3%/year, p<0.05), whereas Chryseobacterium did not influence lung function. These findings were confirmed in multivariate analyses that included age, gender, and other common pathogens as confounders. Treatment of Trichosporon infected patients was associated with improved lung function. CONCLUSIONS: Trichosporon can be recovered from a small but clinically meaningful fraction of CF patients. The presence of Trichosporon, but not Chryseobacterium, is associated with greater declines in lung function. PMID- 26936235 TI - Implementing ICMH-CF (International Committee on Mental Health in CF) guidance on screening for depression and anxiety symptoms: A feasibility and pilot study. PMID- 26936236 TI - Edge Vascular Response After Resorption of the Everolimus-Eluting Bioresorbable Vascular Scaffold - A 5-Year Serial Optical Coherence Tomography Study. AB - BACKGROUND: The edge vascular response (EVR) has been linked to important prognostic implications in patients treated with permanent metallic stents. We aimed to investigate the relationship of EVR with the geometric changes in the everolimus-eluting bioresorbable scaffold using serial optical coherence tomography (OCT) analysis. METHODS AND RESULTS: In the first-in-man ABSORB trial, 28 patients (29 lesions) underwent serial OCT at 4 different time points (Cohort B1: post-procedure, 6, 24, and 60 months [n=13]; Cohort B2: post-procedure, 12, 36, and 60 months [n=15]) following implantation of the scaffold. In Cohort B1, there was no significant luminal change at the distal or proximal edge segment throughout the entire follow-up. In contrast, there was a significant reduction of the lumen flow area (LFA) of the scaffold between post-procedure and 6 months (-1.03+/-0.49 mm(2)[P<0.001]), whereas between 6 and 60 months the LFA remained stable (+0.31+/-1.00 mm(2)[P=0.293]). In Cohort B2, there was a significant luminal reduction of the proximal edge between post-procedure and 12 months ( 0.57+/-0.74 mm(2)[P=0.017]), whereas the lumen area remained stable (-0.26+/-1.22 mm(2)[P=0.462]) between 12 and 60 months. The scaffold LFA showed a change similar to that observed in Cohort B1. CONCLUSIONS: Our study demonstrated a reduction in the scaffold luminal area in the absence of major EVR, suggesting that the physiological continuity of the lumen contour is restored long term. (Circ J 2016; 80: 1131-1141). PMID- 26936237 TI - Prognostic Implications of Non-Invasive Vascular Function Tests in High-Risk Atherosclerosis Patients. AB - BACKGROUND: The aim of this study was to assess the role of clinically available vascular function tests as predictors of cardiovascular events and decline in kidney function. METHODS AND RESULTS: One hundred and fourteen patients who had at least 2 cardiovascular risk factors were recruited for vascular function assessment including ankle-brachial blood pressure index (ABI), brachial-ankle pulse wave velocity (baPWV), cardio-ankle vascular index (CAVI) and flow-mediated vasodilatation (%FMD). During a median period of 51 months, 35 patients reached the primary endpoint (29 cardiovascular events and 6 cardiac deaths), and 30 patients reached the secondary endpoint (decline in kidney function: defined as a 5% per year decline of estimated glomerular filtration rate). In sequential Cox models, a model on the basis of the Framingham risk score, hemoglobin, and high sensitivity C-reactive protein (chi-squared, 16.6) was improved by the ABI (chi squared: 21.5; P=0.047). The baPWV (hazard ratio: 1.42 per 1 SD increase; P=0.025) and the CAVI (hazard ratio: 1.52 per 1 SD increase; P=0.040) were associated with the secondary endpoint. The %FMD was only slightly associated with the primary and secondary endpoints. CONCLUSIONS: Both ABI and baPWV are significantly associated with future cardiovascular events in high-risk patients with cardiovascular disease. The predictive capabilities of these parameters are greater than that of other parameters in this cohort. PMID- 26936238 TI - Intraoperative Factors Cause Postoperative Atrial Fibrillation? PMID- 26936239 TI - Intraoperative Factors Cause Postoperative Atrial Fibrillation? - Reply. PMID- 26936240 TI - A systems approach to animal communication. AB - Why animal communication displays are so complex and how they have evolved are active foci of research with a long and rich history. Progress towards an evolutionary analysis of signal complexity, however, has been constrained by a lack of hypotheses to explain similarities and/or differences in signalling systems across taxa. To address this, we advocate incorporating a systems approach into studies of animal communication--an approach that includes comprehensive experimental designs and data collection in combination with the implementation of systems concepts and tools. A systems approach evaluates overall display architecture, including how components interact to alter function, and how function varies in different states of the system. We provide a brief overview of the current state of the field, including a focus on select studies that highlight the dynamic nature of animal signalling. We then introduce core concepts from systems biology (redundancy, degeneracy, pluripotentiality, and modularity) and discuss their relationships with system properties (e.g. robustness, flexibility, evolvability). We translate systems concepts into an animal communication framework and accentuate their utility through a case study. Finally, we demonstrate how consideration of the system-level organization of animal communication poses new practical research questions that will aid our understanding of how and why animal displays are so complex. PMID- 26936242 TI - A unique feeding strategy of the extinct marine mammal Kolponomos: convergence on sabretooths and sea otters. AB - Mammalian molluscivores feed mainly by shell-crushing or suction-feeding. The extinct marine arctoid, Kolponomos, has been interpreted as an otter-like shell crusher based on similar dentitions. However, neither the masticatory biomechanics of the shell-crushing adaptation nor the way Kolponomos may have captured hard-shelled prey have been tested. Based on mandibular symphyseal morphology shared by Kolponomos and sabre-toothed carnivores, we hypothesize a sabretooth-like mechanism for Kolponomos prey-capture, whereby the mandible functioned as an anchor. Torque generated from jaw closure and head flexion was used to dislodge prey by prying, with prey then crushed using cheek teeth. We test this hypothesized feeding sequence using phylogenetically informed biomechanical simulations and shape analyses, and find a strongly supported, shared high mandibular stiffness in simulated prey-capture bites and mandibular shape in Kolponomos and the sabre-toothed cat Smilodon. These two distantly related taxa converged on using mandibles to anchor cranial torqueing forces when prying substrate-bound prey in the former and sabre-driving forces during prey killing in the latter. Simulated prey-crushing bites indicate that Kolponomos and sea otters exhibit alternative structural stiffness-bite efficiency combinations in mandibular biomechanical adaptation for shell-crushing. This unique feeding system of Kolponomos exemplifies a mosaic of form-function convergence relative to other Carnivora. PMID- 26936241 TI - Selective logging in tropical forests decreases the robustness of liana-tree interaction networks to the loss of host tree species. AB - Selective logging is one of the major drivers of tropical forest degradation, causing important shifts in species composition. Whether such changes modify interactions between species and the networks in which they are embedded remain fundamental questions to assess the 'health' and ecosystem functionality of logged forests. We focus on interactions between lianas and their tree hosts within primary and selectively logged forests in the biodiversity hotspot of Malaysian Borneo. We found that lianas were more abundant, had higher species richness, and different species compositions in logged than in primary forests. Logged forests showed heavier liana loads disparately affecting slow-growing tree species, which could exacerbate the loss of timber value and carbon storage already associated with logging. Moreover, simulation scenarios of host tree local species loss indicated that logging might decrease the robustness of liana tree interaction networks if heavily infested trees (i.e. the most connected ones) were more likely to disappear. This effect is partially mitigated in the short term by the colonization of host trees by a greater diversity of liana species within logged forests, yet this might not compensate for the loss of preferred tree hosts in the long term. As a consequence, species interaction networks may show a lagged response to disturbance, which may trigger sudden collapses in species richness and ecosystem function in response to additional disturbances, representing a new type of 'extinction debt'. PMID- 26936243 TI - Diminished foraging performance of a mutant zebrafish with reduced population of ultraviolet cones. AB - Ultraviolet (UV) cones are photoreceptors that sense light in the range 300-450 nm and are found in the retinas of non-mammalian vertebrates and small mammals. Despite their widespread presence across taxa, the functions that these cones exert in the lives of animals remain largely unknown. In this study, I used the zebrafish lor (lots of rods) mutant, characterized by a diminished UV cone population compared to that of wild-type zebrafish, to test whether its foraging performance differed from that of the wild-type (control). The mean location distance and angle (variables that are reliable indicators of foraging performance) at which control fish detected zooplankton prey were, on average, 24 and 90% greater than corresponding measures for lor fish. Such inferior foraging performance of the mutant could be explained by reduced contrast perception of the prey, resulting from the diminished population of UV cones and associated sensitivity. Thus, UV cones enhance the foraging performance of zebrafish, a crucial ecological function that may explain why small zooplanktivorous fishes retain UV cones throughout their lives. PMID- 26936244 TI - Ocean acidification affects competition for space: projections of community structure using cellular automata. AB - Historical ecological datasets from a coastal marine community of crustose coralline algae (CCA) enabled the documentation of ecological changes in this community over 30 years in the Northeast Pacific. Data on competitive interactions obtained from field surveys showed concordance between the 1980s and 2013, yet also revealed a reduction in how strongly species interact. Here, we extend these empirical findings with a cellular automaton model to forecast ecological dynamics. Our model suggests the emergence of a new dominant competitor in a global change scenario, with a reduced role of herbivory pressure, or trophic control, in regulating competition among CCA. Ocean acidification, due to its energetic demands, may now instead play this role in mediating competitive interactions and thereby promote species diversity within this guild. PMID- 26936245 TI - Reproductive competition triggers mass eviction in cooperative banded mongooses. AB - In many vertebrate societies, forced eviction of group members is an important determinant of population structure, but little is known about what triggers eviction. Three main explanations are: (i) the reproductive competition hypothesis, (ii) the coercion of cooperation hypothesis, and (iii) the adaptive forced dispersal hypothesis. The last hypothesis proposes that dominant individuals use eviction as an adaptive strategy to propagate copies of their alleles through a highly structured population. We tested these hypotheses as explanations for eviction in cooperatively breeding banded mongooses (Mungos mungo), using a 16-year dataset on life history, behaviour and relatedness. In this species, groups of females, or mixed-sex groups, are periodically evicted en masse. Our evidence suggests that reproductive competition is the main ultimate trigger for eviction for both sexes. We find little evidence that mass eviction is used to coerce helping, or as a mechanism to force dispersal of relatives into the population. Eviction of females changes the landscape of reproductive competition for remaining males, which may explain why males are evicted alongside females. Our results show that the consequences of resolving within group conflict resonate through groups and populations to affect population structure, with important implications for social evolution. PMID- 26936247 TI - How social network structure affects decision-making in Drosophila melanogaster. AB - Animals use a number of different mechanisms to acquire crucial information. During social encounters, animals can pass information from one to another but, ideally, they would only use information that benefits survival and reproduction. Therefore, individuals need to be able to determine the value of the information they receive. One cue can come from the behaviour of other individuals that are already using the information. Using a previous extended dataset, we studied how individual decision-making is influenced by the behaviour of conspecifics in Drosophila melanogaster. We analysed how uninformed flies acquire and later use information about oviposition site choice they learn from informed flies. Our results suggest that uninformed flies adjust their future choices based on how coordinated the behaviours of the informed individuals they encounter are. Following social interaction, uninformed flies tended either to collectively follow the choice of the informed flies or to avoid it. Using social network analysis, we show that this selective information use seems to be based on the level of homogeneity of the social network. In particular, we found that the variance of individual centrality parameters among informed flies was lower in the case of a 'follow' outcome compared with the case of an 'avoid' outcome. PMID- 26936246 TI - A cost for high levels of sperm competition in rodents: increased sperm DNA fragmentation. AB - Sperm competition, a prevalent evolutionary process in which the spermatozoa of two or more males compete for the fertilization of the same ovum, leads to morphological and physiological adaptations, including increases in energetic metabolism that may serve to propel sperm faster but that may have negative effects on DNA integrity. Sperm DNA damage is associated with reduced rates of fertilization, embryo and fetal loss, offspring mortality, and mutations leading to genetic disease. We tested whether high levels of sperm competition affect sperm DNA integrity. We evaluated sperm DNA integrity in 18 species of rodents that differ in their levels of sperm competition using the sperm chromatin structure assay. DNA integrity was assessed upon sperm collection, in response to incubation under capacitating or non-capacitating conditions, and after exposure to physical and chemical stressors. Sperm DNA was very resistant to physical and chemical stressors, whereas incubation in non-capacitating and capacitating conditions resulted in only a small increase in sperm DNA damage. Importantly, levels of sperm competition were positively associated with sperm DNA fragmentation across rodent species. This is the first evidence showing that high levels of sperm competition lead to an important cost in the form of increased sperm DNA damage. PMID- 26936248 TI - Myosin filament sliding through the Z-disc relates striated muscle fibre structure to function. AB - Striated muscle contraction requires intricate interactions of microstructures. The classic textbook assumption that myosin filaments are compressed at the meshed Z-disc during striated muscle fibre contraction conflicts with experimental evidence. For example, myosin filaments are too stiff to be compressed sufficiently by the muscular force, and, unlike compressed springs, the muscle fibres do not restore their resting length after contractions to short lengths. Further, the dependence of a fibre's maximum contraction velocity on sarcomere length is unexplained to date. In this paper, we present a structurally consistent model of sarcomere contraction that reconciles these findings with the well-accepted sliding filament and crossbridge theories. The few required model parameters are taken from the literature or obtained from reasoning based on structural arguments. In our model, the transition from hexagonal to tetragonal actin filament arrangement near the Z-disc together with a thoughtful titin arrangement enables myosin filament sliding through the Z-disc. This sliding leads to swivelled crossbridges in the adjacent half-sarcomere that dampen contraction. With no fitting of parameters required, the model predicts straightforwardly the fibre's entire force-length behaviour and the dependence of the maximum contraction velocity on sarcomere length. Our model enables a structurally and functionally consistent view of the contractile machinery of the striated fibre with possible implications for muscle diseases and evolution. PMID- 26936250 TI - Correction to 'Reduced neural sensitivity to social stimuli in infants at risk for autism'. PMID- 26936249 TI - Intensive aquaculture selects for increased virulence and interference competition in bacteria. AB - Although increased disease severity driven by intensive farming practices is problematic in food production, the role of evolutionary change in disease is not well understood in these environments. Experiments on parasite evolution are traditionally conducted using laboratory models, often unrelated to economically important systems. We compared how the virulence, growth and competitive ability of a globally important fish pathogen, Flavobacterium columnare, change under intensive aquaculture. We characterized bacterial isolates from disease outbreaks at fish farms during 2003-2010, and compared F. columnare populations in inlet water and outlet water of a fish farm during the 2010 outbreak. Our data suggest that the farming environment may select for bacterial strains that have high virulence at both long and short time scales, and it seems that these strains have also evolved increased ability for interference competition. Our results are consistent with the suggestion that selection pressures at fish farms can cause rapid changes in pathogen populations, which are likely to have long-lasting evolutionary effects on pathogen virulence. A better understanding of these evolutionary effects will be vital in prevention and control of disease outbreaks to secure food production. PMID- 26936251 TI - ERRATUM. PMID- 26936253 TI - The Construal of Midwives by Pregnant Women with a Body Mass Index Greater Than or Equal to 30 kg/m2 (BMI >= 30 kg/m2 ): A Repertory Grid Study. AB - OBJECTIVE: To explore the construal of midwives by pregnant women with a body mass index greater than 30 kg/m2 (BMI >= 30 kg/m2 ). METHOD: Ten pregnant women with a BMI >= 30 kg/m2 were recruited from antenatal clinics at a maternity hospital in the North West of England. Each participant completed a repertory grid. The participants chose people to match roles including themselves, pregnant women, midwives of different BMIs and hypothetical elements. They also generated psychological constructs to describe them. RESULTS: Pregnant women with a BMI >= 30 kg/m2 construed themselves as vulnerable and self-conscious. Some women endorsed obesity-related stereotypes for themselves and felt responsible for their weight. The midwife with a BMI 18 < 30 kg/m2 was considered to be most similar to the ideal midwife, while the midwife with a BMI <= 18 kg/m2 was construed as having an undesirable interpersonal style. The midwife with a BMI >= 40 kg/m2 was often construed as sharing similar experiences to the pregnant women with a BMI >= 30 kg/m2 , such as struggling with the psychological consequences of a raised BMI. Some women construed the midwife with a BMI 30 < 40 kg/m2 in a positive way, whereas others viewed it as sharing similar feelings about weight as the midwife with a BMI >= 40 kg/m2 . CONCLUSIONS: The pregnant women with a BMI >= 30 kg/m2 in this study described perceptions of themselves and the midwives responsible for their care, which may affect their engagement and satisfaction with services. Pregnant women with a BMI >= 30 kg/m2 should be involved in service development activities to ensure the structure of services and the language used by midwives are acceptable and do not confirm weight related stereotypes. Copyright (c) 2016 John Wiley & Sons, Ltd. KEY PRACTITIONER MESSAGE: Pregnant women with a BMI >= 30 kg/m2 construe themselves as vulnerable and self-conscious and perceive themselves responsible for their weight. Pregnant women with a BMI >= 30 kg/m2 construe midwives with a low BMI as having an undesirable, cold, interpersonal style. Midwives with a raised BMI are construed as similar to the women, because they share the uncomfortable psychological consequences of a raised BMI. The nature of pregnant women's construal may affect their engagement and satisfaction with maternity services and midwifery care. PMID- 26936254 TI - MaGuS: a tool for quality assessment and scaffolding of genome assemblies with Whole Genome ProfilingTM Data. AB - BACKGROUND: Scaffolding is an essential step in the genome assembly process. Current methods based on large fragment paired-end reads or long reads allow an increase in contiguity but often lack consistency in repetitive regions, resulting in fragmented assemblies. Here, we describe a novel tool to link assemblies to a genome map to aid complex genome reconstruction by detecting assembly errors and allowing scaffold ordering and anchoring. RESULTS: We present MaGuS (map-guided scaffolding), a modular tool that uses a draft genome assembly, a Whole Genome ProfilingTM (WGP) map, and high-throughput paired-end sequencing data to estimate the quality and to enhance the contiguity of an assembly. We generated several assemblies of the Arabidopsis genome using different scaffolding programs and applied MaGuS to select the best assembly using quality metrics. Then, we used MaGuS to perform map-guided scaffolding to increase contiguity by creating new scaffold links in low-covered and highly repetitive regions where other commonly used scaffolding methods lack consistency. CONCLUSIONS: MaGuS is a powerful reference-free evaluator of assembly quality and a WGP map-guided scaffolder that is freely available at https://github.com/institut-de-genomique/MaGuS. Its use can be extended to other high-throughput sequencing data (e.g., long-read data) and also to other map data (e.g., genetic maps) to improve the quality and the contiguity of large and complex genome assemblies. PMID- 26936255 TI - Description of Kibdelosporangium banguiense sp. nov., a novel actinomycete isolated from soil of the forest of Pama, on the plateau of Bangui, Central African Republic. AB - A novel actinomycete strain F-240,109(T) from the MEDINA collection was isolated from a soil sample collected in the forest of Pama, on the plateau of Bangui, Central African Republic. The strain was identified according to its 16S rRNA gene sequence as a new member of the genus Kibdelosporangium, being closely related to Kibdelosporangium aridum subsp. aridum (98.6 % sequence similarity), Kibledosporangium phytohabitans (98.3 %), Kibdelosporangium aridum subsp. largum (97.7 %), Kibdelosporangium philippinense (97.6 %) and Kibledosporangium lantanae (96.9 %). In order to resolve its precise taxonomic status, the strain was characterised through a polyphasic approach. The strain is a Gram-stain positive, aerobic, non-motile and catalase-positive actinomycete characterised by formation of extensively branched substrate mycelia and sparse brownish grey aerial mycelia with sporangium-like globular structures. The chemotaxonomic characterisation of strain F-240,109(T) corroborated its affiliation into the genus Kibdelosporangium. The peptidoglycan contains meso-diaminopimelic acid; the major menaquinone is MK-9(H4); the phospholipid profile contains high amounts of phosphatidylethanolamine, hydroxyphosphatidylethanolamine, diphosphatidylglycerol and an unidentified phospholipid; and the predominant cellular fatty acid methyl esters are iso-C16:0, iso-C14:0, iso-C15:0 and 2OH iso-C16:0. However, some key phenotypic differences regarding to its close relatives and DNA-DNA hybridization values indicate that strain F-240,109(T) represents a novel Kibdelosporangium species, for which the name Kibdelosporangium banguiense sp. nov. is proposed. The type strain is strain F-240,109(T) (=DSM 46670(T), =LMG 28181(T)). PMID- 26936256 TI - Kordiimonas sediminis sp. nov., isolated from a sea cucumber culture pond. AB - A marine bacterium, designated strain N39(T), was isolated from a sediment sample collected at a sea cucumber culture pond in Weihai, China. Cells of strain N39(T) were observed to be Gram-stain negative, facultatively anaerobic, motile rods showing catalase and oxidase negative reactions. Strain N39(T) was found to grow optimally at pH 8.0-8.5, 35-37 degrees C and in the presence of approximately 3.0 % (w/v) NaCl. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain N39(T) belongs to the genus Kordiimonas in the family Kordiimonadaceae, appearing closely related to Kordiimonas lacus JCM 16261(T) (95.9 %), Kordiimonas aquimaris MEBiC06554(T) (95.1 %), Kordiimonas gwangyangensis JCM 12864(T) (94.2 %) and Kordiimonas aestuarii 101-1(T) (93.8 %). Ubiquinone 10 (Q-10) was found to be the major respiratory quinone. The dominant cellular fatty acids were identified as iso-C17:1 omega9c, iso-C17:0, iso-C15:0 and C17:1 omega6c. The predominant polar lipids were found to be phosphatidylglycerol, phosphatidylethanolamine and diphosphatidylglycerol. The DNA G + C content of strain N39(T) is 50.8 %. On the basis of genotypic, chemotaxonomic and phenotypic data, strain N39(T) is concluded to represent a novel species within the genus Kordiimonas, for which the name Kordiimonas sediminis sp. nov. is proposed. The type strain is N39(T) (=KCTC 42590(T) = MCCC 1H00112(T)). PMID- 26936257 TI - Erratum to: 'The correlation between pretreatment cytokine expression patterns in peripheral blood mononuclear cells with chronic hepatitis c outcome'. PMID- 26936258 TI - Glutamine metabolism in advanced age. AB - Glutamine, reviewed extensively in the last century, is a key substrate for the splanchnic bed in the whole body and is a nutrient of particular interest in gastrointestinal research. A marked decrease in the plasma glutamine concentration has recently been observed in neonates and adults during acute illness and stress. Although some studies in newborns have shown parenteral and enteral supplementation with glutamine to be of benefit (by decreasing proteolysis and activating the immune system), clinical trials have not demonstrated prolonged advantages such as reductions in mortality or risk of infections in adults. In addition, glutamine is not able to combat the muscle wasting associated with disease or age-related sarcopenia. Oral glutamine supplementation initiated before advanced age in rats increases gut mass and improves the villus height of mucosa, thereby preventing the gut atrophy encountered in advanced age. Enterocytes from very old rats continuously metabolize glutamine into citrulline, which allowed, for the first time, the use of citrulline as a noninvasive marker of intestinal atrophy induced by advanced age. PMID- 26936259 TI - A Review and Update on Tourette Syndrome: Where Is the Field Headed? AB - Tourette syndrome (TS) is a childhood onset neurologic disorder with manifestations including multiple motor and phonic tics, and in most cases a variety of behavioral comorbidities such as attention deficit hyperactivity disorder, obsessive compulsive disorder, and other impulse control disorders. Although it is considered a hereditary disorder, likely modified by environmental factors, genetic studies have yet to uncover relevant causative genes and there is no animal model that mimics the broad clinical phenomenology of TS. There has been a marked increase in the number of neurophysiological, neuroimaging, and other studies on TS. The findings from these studies, however, have been difficult to interpret because of small sample sizes, variability of symptoms across patients, and comorbidities. Although anti-dopaminergic drugs are the most widely used medications in the treatment of TS, there has been increasing interest in other drugs, behavioral therapies, and surgical approaches including deep brain stimulation. Herein, we review the current literature and discuss the complexities of TS and the challenges in understanding its pathophysiology and in selecting the most appropriate treatment. We also offer an expert's view of where the field of TS may be headed. PMID- 26936260 TI - The epidemiology of Takayasu arteritis: a hospital-based study from northwestern part of Turkey. AB - Takayasu arteritis (TA) is a chronic, inflammatory large vessel vasculitis that affects aorta and its main branches. We aimed to evaluate the incidence and prevalence of TA in the northwestern part of Turkey. We retrospectively evaluated 23 TA patients followed by our clinic. Clinical features, treatments and responses were recorded. Our hospital is the single tertiary referral center for rheumatic diseases for a mixed rural and urban population of 620,447 people for >16 years (306,036 males, 314,411 females). Nineteen of the 23 patients were females (82.6 %) and four were males (17.4 %). The annual incidence rate for TA was 0.34/100,000. The overall prevalence of TA in our region was 3.3/100,000 (95 % CI 1.9-4.8) in individuals >16 years. The most common findings at the time of presentation were blood pressure difference (73 %) and headache (60.4 %). The most common angiographic type was type 1 (12 patients, 52.2 %). Median follow-up period was 48 months (range 10-132). Three (13 %) of the patients had stent replacements to different vascular sites. One patient had an operation for aortic aneurysm, and aortic valve replacement surgery has been made. One patient had renal artery bypass operation. Eleven patients (47.8 %) had recurrency at follow up period and two patients (8.7 %) died. In northwestern part of Turkey, the annual incidence and prevalence of TA were higher than western population, but similar to East Asian data. PMID- 26936261 TI - Second-line therapy with biological drugs in rheumatoid arthritis patients in German rheumatologist practices: a retrospective database analysis. AB - The aim of the study was to assess the proportion of German patients with rheumatoid arthritis (RA) who received biological disease-modifying antirheumatic drugs (DMARDs) after initiation of conventional DMARD therapy. Patients aged 18 years or over who had initiated therapy with a conventional DMARD in a rheumatic care practice between 2009 and 2013 were included (IMS LRx database). The main outcome was the first prescription of a biological DMARD within 5 years following the index date. A multivariate Cox regression model was adopted to predict the prescription of biological DMARDs on the basis of patient characteristics. The mean age of the 137,673 patients with RA was 57.8 years (SD = 15.0). 68.3 % of the subjects were women. Most patients started their conventional DMARD therapy with methotrexate (62 %), sulfasalazine (13 %), and hydroxychloroquine (12 %). 20.7 % of the RA patients were given a biological DMARD within 5 years following the index date. Male gender was linked with a 10 % higher likelihood of biologic use whereas age decreased the odds of biological DMARD prescription by 3 % per year. Finally, leflunomide use was associated with increased odds of biologic prescription, whereas sulfasalazine and hydroxychloroquine decreased the chances of receiving biologics, as compared to methotrexate. Around 20 % of patients were being treated with biologics 5 years after prescription of conventional DMARDs. Gender, age, and initial treatment impacted the proportion of subjects treated with biological DMARDs. PMID- 26936262 TI - Inadequate response or intolerability to oral methotrexate: Is it optimal to switch to subcutaneous methotrexate prior to considering therapy with biologics? AB - Methotrexate (MTX) is considered an anchor drug in the treatment of rheumatoid arthritis. It is also the first-line therapy in a multitude of rheumatologic conditions. Low-dose oral MTX is the preliminary modality of treatment for rheumatoid arthritis due to its affordability, favorable outcomes, and limited risks. However, patients refractory to low-dose MTX therapy may require larger doses of oral MTX. Several studies in the past have demonstrated variability in bioavailability of oral MTX at high doses. This warrants a subsequent switch to parenteral MTX. Widely used among the parenteral preparations of MTX is subcutaneous (SC) MTX. SC MTX provides dependable efficacy, predictable bioavailability, sustained clinical outcomes, and minimal GI adverse effects. It is useful either singularly or in combination therapy regimens. Although SC MTX and intramuscular MTX have similar pharmacokinetics, SC MTX may be preferred by most patients. Development of prefilled syringes and auto-injectors have enabled self-administration of the medication providing the patients with a sense of independence and improved general well-being. Hence, SC MTX can prove to be more efficacious in patients refractory to oral MTX therapy or in patients experiencing severe gastrointestinal adverse effects. PMID- 26936263 TI - Utility of strain-echocardiography in current clinical practice. AB - Myocardial strain measurement with two-dimensional speckle-tracking echocardiography (2D-STE) is of paramount importance in the early detection of subclinical left ventricular (LV) systolic dysfunction and the prediction of patient outcomes in various types of heart disease, especially when assessed with global longitudinal strain (GLS). The routine application of myocardial strain parameters requires the definition of normal values and an understanding of their reliabilities. One of the most important potential limitations to widespread clinical application of this technique is inter-vendor differences in normal strain values. Recent clinical reports indicate that the smallest differences were noted in GLS measurements among three orthogonal directions. Because the contribution of circumferential fibers to LV myocardial thickening is greater than that of longitudinal fibers, patients who have a reduced LV ejection fraction can have impaired global circumferential strain (GCS), which reflects more advanced intrinsic myocardial systolic dysfunction and is thus closely related to a poor prognosis. Since STE-derived strain analysis allows us to define the timing of the regional myocardial peak systolic deformation, it permits the assessment of LV mechanical dyssynchrony. The severity of LV mechanical dyssynchrony in the short axis plane, i.e., radial and/or circumferential strain imaging, is favorable for predicting the clinical response to cardiac resynchronization therapy. GLS in the right ventricular (RV) four chamber view has recently been used as a surrogate for global RV function because longitudinal shortening is the major contributor to overall RV performance. Finally, 2D-STE can be used to quantify and characterize RV mechanical dyssynchrony in various diseases including acute pulmonary thromboembolism and chronic pulmonary hypertension. PMID- 26936264 TI - Measuring quality in electrophysiology. AB - The evolving healthcare environment demands optimally measured quality of care. Performance measures are increasingly being used for quality improvement, public reporting, and reimbursement determinations. The National Quality Forum has created rigorous criteria for the evaluation of potential performance measures across medical fields. The Heart Rhythm Society has championed the development of four separate electrophysiology (EP)-specific performance measures: implantable cardioverter defibrillator complication rate, cardiac tamponade and/or pericardiocentesis following atrial fibrillation ablation, infection within 180 days of a cardiac implantable electronic device implantation, replacement, or revision, and in-person evaluation following a cardiac implantable electronic device implantation. National registries serve a key role in developing performance measures and facilitating quality improvement, particularly as they provide improved granularity and accuracy of data compared with administrative claims data. All performance measures demand continued reassessment as technology and performance gaps change and as unintended consequences may arise. PMID- 26936265 TI - Novel usage of the cryoballoon catheter to achieve large area atrial substrate modification in persistent and long-standing persistent atrial fibrillation. AB - BACKGROUND: The cryoballoon catheter has proven to be both safe and effective when used for pulmonary vein (PV) isolation in patients with paroxysmal atrial fibrillation (AF). More recently, the cryoballoon catheter has demonstrated the ability to create durable, transmural, and large areas of PV ablation. However, persistent and long-standing persistent AF can require additional cardiac substrate modification(s) before a patient is returned to normal sinus rhythm. Yet, no study has reported the techniques necessary to achieve extra-PV lesion sets using the cryoballoon catheter. METHODS: Cryoballoon ablation was completed in 225 patients with varying degrees of AF disease. In several cases, the balloon was used for more than PV isolation. This study examines the 11 anatomical cardiac locations where extra-PV lesion sets were utilized. RESULTS: This study demonstrates that these extra-PV ablations can be done safely with the balloon catheter (3.6 % total complication rate). The 12-month efficacy (freedom from all atrial arrhythmia) using these techniques was 88 % in 88 patients with paroxysmal AF, 71 % in 75 patients with persistent AF, and 55 % in 62 patients with long standing persistent AF. While using this protocol, mean procedure time was 2.2 +/ 0.6 h, and average fluoroscopy time was 4.2 +/- 2.2 min. CONCLUSIONS: The cryoballoon catheter can be used to make effective and safe extra-PV lesions. However, these techniques will need to be validated in more multi-center studies with review of complication rates and long-term freedom from AF. PMID- 26936266 TI - Analyzing longitudinal qualitative data: the application of trajectory and recurrent cross-sectional approaches. AB - BACKGROUND: Longitudinal qualitative research methods can add depth and understanding to health care research, especially on topics such as chronic conditions, adherence and changing health policies. In this manuscript we describe when and how to undertake two different applied approaches to analyzing longitudinal qualitative data: a recurrent cross-sectional approach and a trajectory approach. RESULTS: A recurrent cross-sectional approach is most appropriate when the primary interest is comparing two time points, such as before and after a policy change, or when a cohort cannot be maintained, such as a study in which some participants are expected to die. In contrast, a trajectory approach is most appropriate when the purpose of the research is to understand individuals' experiences over time or to understand longitudinal healthcare processes. CONCLUSIONS: Longitudinal qualitative research has the potential to be a powerful approach to understanding the complexities of health care: from relationships between providers and patients, to the experience of chronic disease, to the impact of health policy. Such research will be strengthened by careful consideration of the research question at hand, followed by application of the appropriate analytic approach. PMID- 26936267 TI - Neural Field Models with Threshold Noise. AB - The original neural field model of Wilson and Cowan is often interpreted as the averaged behaviour of a network of switch like neural elements with a distribution of switch thresholds, giving rise to the classic sigmoidal population firing-rate function so prevalent in large scale neuronal modelling. In this paper we explore the effects of such threshold noise without recourse to averaging and show that spatial correlations can have a strong effect on the behaviour of waves and patterns in continuum models. Moreover, for a prescribed spatial covariance function we explore the differences in behaviour that can emerge when the underlying stationary distribution is changed from Gaussian to non-Gaussian. For travelling front solutions, in a system with exponentially decaying spatial interactions, we make use of an interface approach to calculate the instantaneous wave speed analytically as a series expansion in the noise strength. From this we find that, for weak noise, the spatially averaged speed depends only on the choice of covariance function and not on the shape of the stationary distribution. For a system with a Mexican-hat spatial connectivity we further find that noise can induce localised bump solutions, and using an interface stability argument show that there can be multiple stable solution branches. PMID- 26936268 TI - Erratum to: 'Deregulation of the FOXM1 target gene network and its coregulatory partners in oesophageal adenocarcinoma'. PMID- 26936269 TI - Movement Patterns of the Knee During Gait Following ACL Reconstruction: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Altered gait patterns follow ing anterior cruciate ligament reconstruction (ACLR) may be associated with long-term impairments and post traumatic osteoarthritis. OBJECTIVE: This systematic review and meta-analysis compared lower limb kinematics and kinetics of the ACL reconstructed knee with (1) the contralateral limb and (2) healthy age-matched participants during walking, stair climbing, and running. The secondary aim was to describe the differences over time following ACLR for these biomechanical variables. METHOD: Database searches were conducted from inception to July 2014 and updated in August 2015 for studies exploring peak knee angles and moments following ACLR during walking, stair negotiation, and running. Risk of bias was assessed with a modified Downs and Black quality index for all included studies, and meta analyses were performed. Forest plots were explored qualitatively for recovery of gait variables over time after surgery. RESULTS: A total of 40 studies were included in the review; 26 of these were rated as low risk and 14 as high risk of bias. The meta-analysis included 27 studies. Strong to moderate evidence indicated no significant difference in peak flexion angles between ACLR and control groups during walking and stair ascent. Strong evidence was found for lower peak flexion moments in participants with ACLR compared with control groups and contralateral limb during walking and stair activities. Strong to moderate evidence was found for lower peak adduction moment in ACLR participants for the injured compared with the contralateral limbs during walking and stair descent. The qualitative assessment for recovery over time indicated a pattern towards restoration of peak knee flexion angle with increasing time from post-surgery. Peak knee adduction moments were lower within the first year following surgery and higher than controls during later phases (5 years). CONCLUSION: Joint kinematics are restored, on average, 6 years following reconstruction, while knee external flexion moments remain lower than controls. Knee adduction moments are lower during early phases following reconstruction, but are higher than controls, on average, 5 years post-surgery. Findings indicate that knee function is not fully restored following reconstruction, and long-term maintenance programs may be needed. PMID- 26936270 TI - Does Goal Attainment Scaling improve satisfaction regarding performance of activities of younger knee arthroplasty patients? Study protocol of the randomized controlled ACTION trial. AB - BACKGROUND: Knee arthroplasty is being increasingly performed, and also more often in a younger patient population (<65 years of age). Up to 20 % of patients remain dissatisfied after knee arthroplasty, despite the apparent technical success of the operation. Recent studies suggest that the fulfilment of patients' expectations plays an important role in achieving satisfaction. Thus, addressing preoperative expectations more explicitly might improve patient satisfaction. The primary aim of the present study is to investigate the effect of a multidisciplinary, goal attained and individualized rehabilitation on satisfaction of activities of younger patients (<65 years) after knee arthroplasty. METHODS/DESIGN: A single-centre randomized controlled trial will be conducted. In total, 120 patients (<65 years of age) with knee osteoarthritis who will undergo knee arthroplasty, will be randomly allocated to either goal attainment scaling rehabilitation or usual care rehabilitation. Goal attainment scaling rehabilitation includes drafting individually set rehabilitation goals preoperatively and measuring progress of rehabilitation on a six-point scale (-3 to +2). The primary outcome is patient satisfaction concerning activities in daily life, work and leisure time, including sports. Secondary outcome measures include KOOS, OKS, SQUASH and WORQ questionnaires and activity objectively measured with the Activ8(r) activity monitor. DISCUSSION: The findings of this study will help to elucidate whether goal attainment scaling is an effective rehabilitation method for achieving higher levels of patient satisfaction, with a focus on activities, in younger patients after knee arthroplasty. TRIAL REGISTRATION: This trial is since June 15(th) 2015 registered at the Dutch Trial Register: NTR5251 . PMID- 26936271 TI - Comparative modeling and molecular dynamics suggest high carboxylase activity of the Cyanobium sp. CACIAM14 RbcL protein. AB - Rubisco catalyzes the first step reaction in the carbon fixation pathway, bonding atmospheric CO2/O2 to ribulose 1,5-bisphosphate; it is therefore considered one of the most important enzymes in the biosphere. Genetic modifications to increase the carboxylase activity of rubisco are a subject of great interest to agronomy and biotechnology, since this could increase the productivity of biomass in plants, algae and cyanobacteria and give better yields in crops and biofuel production. Thus, the aim of this study was to characterize in silico the catalytic domain of the rubisco large subunit (rbcL gene) of Cyanobium sp. CACIAM14, and identify target sites to improve enzyme affinity for ribulose 1,5 bisphosphate. A three-dimensional model was built using MODELLER 9.14, molecular dynamics was used to generate a 100 ns trajectory by AMBER12, and the binding free energy was calculated using MM-PBSA, MM-GBSA and SIE methods with alanine scanning. The model obtained showed characteristics of form-I rubisco, with 15 beta sheets and 19 alpha helices, and maintained the highly conserved catalytic site encompassing residues Lys175, Lys177, Lys201, Asp203, and Glu204. The binding free energy of the enzyme-substrate complexation of Cyanobium sp. CACIAM14 showed values around -10 kcal mol(-1) using the SIE method. The most important residues for the interaction with ribulose 1,5-bisphosphate were Arg295 followed by Lys334. The generated model was successfully validated, remaining stable during the whole simulation, and demonstrated characteristics of enzymes with high carboxylase activity. The binding analysis revealed candidates for directed mutagenesis sites to improve rubisco's affinity. PMID- 26936272 TI - A combined pharmacokinetic/pharmacodynamic model of levodopa motor response and dyskinesia in Parkinson's disease patients. AB - PURPOSE: Levodopa is the reference treatment for Parkinson's disease. However, after several years of treatment, dyskinesia may occur and strategies to overcome this side effect still need to be explored. We identified a unique population pharmacokinetic/pharmacodynamic model in Parkinson's disease to investigate the relationship and dissociability of motor response and dyskinesia. METHODS: Thirty parkinsonian patients (Hoehn and Yahr stages 3-4), treated with levodopa and suffering from peak-dose dyskinesia, were included in a prospective open-label study. They received a single dose of levodopa equal to 150 % of their usual daily dose. Blood samples, motor evaluations (UPDRS III scale) and peak-dose dyskinesia (Goetz scale) were examined after administration. A population pharmacokinetic/pharmacodynamic (PK/PD) model was developed using NONMEM software. RESULTS: Pharmacokinetic analysis identified a one-compartment model with the following parameter values [bootstrap 95 % CI]: absorption rate constant (KA) 1.86 1/h [1.08-3.25], clearance 36.6 L/h [31.3-42.8], and volume of distribution 42.9 L [34.3-52.3]. Between-subject variability was 122 % [71-183] and 38 % [26-47] for KA and clearance, respectively. Residual variability was 1120 MUg/L [886-1290]. UPDRS III and dyskinesia were best described with an effect compartment and similar KE0 values of 1.37 1/h [1.01-1.77]. For UPDRS III, the E0, EC50, Emax, and Hill coefficient were 31.4 [28.4-35.3], 1410 MUg/L [1200 1700], 0.72 [0.71-0.75], and 4.26 [3.20-5.58], respectively. For dyskinesia, the EC50 and Emax were 6280 MUg/L [3420-37,900] and 17.9 [12.3-80.8], respectively. Residual variability was 3.15 [2.75-3.53] for UPDRS III and 2.66 [1.94-3.51] for dyskinesia. No covariates influenced the parameters. CONCLUSIONS: In patients treated with levodopa and suffering from dyskinesia, the motor response and dyskinesia have close onsets and duration effects. Maximal motor response tends to be inevitably associated with dyskinesia. PMID- 26936274 TI - Nutritional quality and amino acid composition of diets consumed by scavenging hens and cocks across seasons. AB - The objective of the study was to determine the effect of season on nutritional quality and amino acid composition of diets that scavenging hens and cocks consume. Thirty hens and 30 cocks were purchased and slaughtered during each of the rainy, post rainy, cool dry and hot dry seasons. A total of 240 birds were used in the study. Fresh crop content weights were high (P < 0.05) during the cool dry season. Cereal grains, kitchen wastes, green materials, animal protein sources and inorganic materials were the main components of the crop contents. Crop contents varied with season and sex of bird (P < 0.05). The cereal grain weights were high during cool dry and hot dry seasons. Weights of animal protein sources (insects, locusts and termites) were higher (P < 0.05) during the rainy and post rainy seasons. Hens contained more animal protein sources (P < 0.05) than cocks. Hens had a higher (P < 0.05) lysine content during the rainy season than cocks. Histidine, serine, arginine, threonine, cysteine and lysine contents varied with seasons (P < 0.05). Methionine did not vary with season and sex of the bird. Nutritional supplementation of village chickens should, therefore, vary with seasons. PMID- 26936276 TI - [Educating patients about blood transfusion risks : Do we have to rethink?]. PMID- 26936275 TI - Developing mechanical milking in camels? Some main steps to take.... AB - After a first phase of development in the ex-Soviet Union in the 1940s, camel mechanical milking is now developing again in the Arabic peninsula, North and East Africa, Asia, Australia and even in the USA and Europe in a lesser extent, because of the great demand and important health value of camel milk. Nevertheless, such a development remains empirical and uses trial and error methodology, which is generally more time-consuming and more expensive and could create a deadlock in the situation. Nevertheless, developing mechanical milking of camels could be done throughout a step by step well-designed approach rather than this empirical approach. It is the only way to understand the animal/machine interaction and to give us the means to adapt machine milking to the different situations encountered in the world and to animal specificities.After describing the different essential and ancillary steps of this development (knowledge of animal physiology, udder and teat shapes, teat functional characteristics, first functional data of milking including teat reaction, milk emission kinetic, efficiency of milk extraction, weaning procedure, milking procedure, milking behavior of animals, adaptation of material and settings...), we aim to relate, as example, the first results obtained in Tunisian dromedary camels in the last 4 years as basis for more adapted or even specific materials and setting evolution. PMID- 26936277 TI - [Visualization of the superior vena cava in the supraclavicular acoustic window]. AB - BACKGROUND: The ultrasound-guided venipuncture of the internal jugular vein for placement of a central venous catheter is well established. For verification of the catheter tip position mostly intracardiac ECG or chest radiography are used. Previously, we established the right supraclavicular fossa view for ultrasound based verification of the catheter placement in the superior vena cava utilizing a microconvex probe. The microconvex probe has a small footprint. However, not all ultrasound systems used in the operating theater are equipped with a microconvex transducer. AIM: Thus, we systematically compared the visibility of intrathoracic vessels obtained by a linear and a microconvex prone via the right supraclavicular view. MATERIAL AND METHODS: We assessed the visibility of the junction of the brachiocephalic veins, the superior vena cava, the right pulmonary artery, the ascending aorta and the internal jugular vein, comparing a linear with a microconvex probe when using the right supraclavicular view in healthy volunteers. The superior vena cava also was identified using Doppler ultrasound. RESULTS: With the microconvex probe the superior vena cava was visible in all 30 healthy volunteers, but with a linear transducer it was visible in only 53 %. The combined view of the superior vena cava and the right pulmonary artery was possible in all cases when using the microconvex probe, but in only 38 % when using the linear probe. The junction of the brachiocephalic veins was seen in 75 % of the volunteers with the microconvex probe and in 38 % with the linear one. The aorta was visible in 87 % of cases with the microconvex transducer, but only in 30 % with the linear probe. The internal jugular vein was always visible with either probe. CONCLUSION: The microconvex transducer as compared to the linear probe is superior in visualizing the superior vena cava. Possible reasons are a smaller footprint, a better degree of freedom for angulation and a greater penetration depth of the microconvex probe. PMID- 26936278 TI - One in four COPD patients gets no treatment at first diagnosis, study shows. PMID- 26936279 TI - Culture Change From Tobacco Accommodation to Intolerance: Time to Connect the Dots. AB - Broad changes in normative health behavior are critical to overcoming many of the contemporary challenges to public health. Reduction in tobacco use during the last third of the 20th century-one of the greatest improvements in public health illustrates such change. The culture change from accommodation to intolerance of smoking is irrefutable. The role of health communication in predisposing, enabling, and reinforcing the normative social changes that ensued, however, has been less well documented with the linear, cause-and-effect methods of controlled intervention research. We examine the role of mass communication in the cultural transformation that reduced tobacco use, concluding that its influence on reduction in tobacco use follows a pathway as much through secondary transmissions within groups of people as through direct influence on individuals. PMID- 26936280 TI - MicroRNA-141 and its associated gene FUS modulate proliferation, migration and cisplatin chemosensitivity in neuroblastoma cell lines. AB - In the present study, a novel signaling pathway of microRNA-141 (miR-141)/fused in sarcoma (FUS) was investigated in neuroblastoma (NB). Gene expression of miR 141 was evaluated in 6 NB cell lines. IMR-32 and SH-SY5Y cells were transduced with the miR-141 mimic lentivirus. The effects of miR-141 upregulation on cell proliferation, cell division, migration, chemosensitivity and in vivo explants were evaluated by MTT, cell cycle, wound-healing, cisplatin sensitivity and in vivo tumor growth assays, respectively. The correlation between miR-141 and the FUS gene was evaluated by luciferase assay and qRT-PCR. FUS was also downregulated in IMR-32 and SH-SY5Y cells to evaluate its impact on NB regulation. miR-141 was downregulated in both MYCN- and non-MYCN-amplified NB cell lines. In the IMR-32 and SH-SY5Y cells, lentivirus-induced miR-141 upregulation inhibited cancer proliferation, cell cycle progression, migration and increased cisplatin chemosensitivity in vitro. In addition, miR-141 upregulation reduced the in vivo growth of IMR-32 tumor explants. FUS was found to be inversely regulated by miR-141 in NB. Small interfering RNA (siRNA)-induced FUS downregulation had similar tumor-suppressive effects as miR-141 upregulation on NB cell proliferation, cell cycle progression, migration and cisplatin chemosensitivity. Our data indicate that miR-141 and the FUS gene, which are inversely correlated, play significant functional roles in regulating human NB. PMID- 26936281 TI - Self-Assembly of One-Dimensional Nanocrystal Superlattice Chains Mediated by Molecular Clusters. AB - Self-assembly of nanocrystal (NC) building blocks into mesoscopic superstructures with well-defined symmetry and geometry is essential for creating new materials with rationally designed properties. Despite the tremendous progress in colloidal assembly, it remains a fundamental challenge to assemble isotropic spherical NCs into one-dimensional (1D) ordered superstructures. Here, we report a new and general methodology that utilizes molecular clusters to induce the anisotropic assembly of NCs in solution, yielding polymer-like, single-NC-wide linear chains comprising as many as ~1000 close-packed NCs. This cluster-assisted assembly process is applicable to various metallic, semiconductor, and magnetic NCs of different sizes and shapes. Mechanistic investigation reveals that the solvent induced association of clusters plays a key role in driving the anisotropic assembly of NCs. Our work opens a solution-based route for linearly assembling NCs and represents an important step toward the bottom-up construction of 1D ordered NC superstructures. PMID- 26936282 TI - Molecular imprinting: perspectives and applications. AB - Molecular imprinting technology (MIT), often described as a method of making a molecular lock to match a molecular key, is a technique for the creation of molecularly imprinted polymers (MIPs) with tailor-made binding sites complementary to the template molecules in shape, size and functional groups. Owing to their unique features of structure predictability, recognition specificity and application universality, MIPs have found a wide range of applications in various fields. Herein, we propose to comprehensively review the recent advances in molecular imprinting including versatile perspectives and applications, concerning novel preparation technologies and strategies of MIT, and highlight the applications of MIPs. The fundamentals of MIPs involving essential elements, preparation procedures and characterization methods are briefly outlined. Smart MIT for MIPs is especially highlighted including ingenious MIT (surface imprinting, nanoimprinting, etc.), special strategies of MIT (dummy imprinting, segment imprinting, etc.) and stimuli-responsive MIT (single/dual/multi-responsive technology). By virtue of smart MIT, new formatted MIPs gain popularity for versatile applications, including sample pretreatment/chromatographic separation (solid phase extraction, monolithic column chromatography, etc.) and chemical/biological sensing (electrochemical sensing, fluorescence sensing, etc.). Finally, we propose the remaining challenges and future perspectives to accelerate the development of MIT, and to utilize it for further developing versatile MIPs with a wide range of applications (650 references). PMID- 26936273 TI - Consensus Conference on Clinical Management of pediatric Atopic Dermatitis. AB - The Italian Consensus Conference on clinical management of atopic dermatitis in children reflects the best and most recent scientific evidence, with the aim to provide specialists with a useful tool for managing this common, but complex clinical condition. Thanks to the contribution of experts in the field and members of the Italian Society of Pediatric Allergology and Immunology (SIAIP) and the Italian Society of Pediatric Dermatology (SIDerP), this Consensus statement integrates the basic principles of the most recent guidelines for the management of atopic dermatitis to facilitate a practical approach to the disease. The therapeutical approach should be adapted to the clinical severity and requires a tailored strategy to ensure good compliance by children and their parents. In this Consensus, levels and models of intervention are also enriched by the Italian experience to facilitate a practical approach to the disease. PMID- 26936283 TI - Microwave Assisted Synthesis of Porous NiCo2O4 Microspheres: Application as High Performance Asymmetric and Symmetric Supercapacitors with Large Areal Capacitance. AB - Large areal capacitance is essentially required to integrate the energy storage devices at the microscale electronic appliances. Energy storage devices based on metal oxides are mostly fabricated with low mass loading per unit area which demonstrated low areal capacitance. It is still a challenge to fabricate supercapacitor devices of porous metal oxides with large areal capacitance. Herein we report microwave method followed by a pyrolysis of the as-prepared precursor is used to synthesize porous nickel cobaltite microspheres. Porous NiCo2O4 microspheres are capable to deliver large areal capacitance due to their high specific surface area and small crystallite size. The facile strategy is successfully demonstrated to fabricate aqueous-based asymmetric &symmetric supercapacitor devices of porous NiCo2O4 microspheres with high mass loading of electroactive materials. The asymmetric &symmetric devices exhibit maximum areal capacitance and energy density of 380 mF cm(-2) &19.1 Wh Kg(-1) and 194 mF cm(-2) &4.5 Wh Kg(-1) (based on total mass loading of 6.25 &6.0 mg) respectively at current density of 1 mA cm(-2). The successful fabrication of symmetric device also indicates that NiCo2O4 can also be used as the negative electrode material for futuristic asymmetric devices. PMID- 26936284 TI - Growth and growth hormone: An overview. AB - Growth is a good indicator of a child's health. Growth disturbances, including short stature or growth failure, could be indications of illnesses such as chronic disease, nutritional deficits, celiac disease or hormonal abnormalities. Therefore, a careful assessment of the various requirements for normal growth needs to be done by history, physical examination, and screening laboratory tests. More details will be reviewed about the GH-IGF axis, its abnormalities with special emphasis on GH deficiency, its diagnosis and treatment. GH treatment indications in the US will be reviewed and a few only will be highlighted. They will include GH deficiency, as well as the treatment of children born SGA, including the results of a US study using FDA approved dose of 0.48mg/kg/week. GH deficiency in adults will also be briefly reviewed. Treatment of patients with SHOX deficiency will also be discussed. Possible side effects of GH treatment and the importance of monitoring safety will be highlighted. PMID- 26936285 TI - Hepatitis B virus replication is upregulated in proliferated peripheral blood lymphocytes. AB - Increasing evidence indicates that the hepatitis B virus (HBV) replicates in peripheral blood mononuclear cells (PBMCs), but at a low level. The present study aimed to establish a reliable and sensitive method that effectively detects HBV viral products for monitoring antiviral therapy, organ transplantation screening, and diagnosing occult HBV infection. In the present study, PBMCs (obtained from six healthy volunteers) were inoculated with HBV, and cultured with phytohemagglutinin (PHA) and interleukin-2 (IL-2) to stimulate cell proliferation. PBMCs were harvested, and quantitative detection of HBV DNA in cell suspension and intracellular hepatitis B surface antigen (HBsAg) was conducted on days 0, 1, 6 and 12, respectively. In situ hybridization, immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR) were performed to analyze the HBV infection. The results demonstrated that HBV DNA increased concurrently with proliferation of PBMCs isolated from three of six healthy volunteers, and the mean number of PBMCs on day 12 was 13.61 times higher than the initially seeded cell number (P<0.01). The mean copies of HBV DNA at day 12 were 2.98 times higher compared with initial levels (P<0.05). Furthermore, intracellular HBsAg levels increased concurrently with proliferation of PBMCs in one group of cultured PBMCs, which was accompanied by increased HBV DNA levels. In addition, HBV nucleic acids were detected in PBMCs using in situ hybridization. Intracellular HBsAg was observed in PBMCs and HBV RNA was also detected by RT-PCR. The present study demonstrated that HBV replicates in proliferating PBMCs, which were induced by PHA and IL-2. This method offers a novel investigative tool to detect HBV infection in PBMCs and to monitor the course of HBV infection. PMID- 26936286 TI - Advanced treatment of oilfield production wastewater by an integration of coagulation/flotation, catalytic ozonation and biological processes. AB - In this study, advanced treatment of heavily polluted oilfield production wastewater (OPW) was investigated employing the combination of coagulation/dissolved air flotation, heterogeneous catalytic ozonation and sequencing batch reactor (SBR) processes. Two SBR reactors were separately set up before and after the ozonation unit. The results show that microbubble flotation was more efficient than macrobubble flotation in pollutant removal. Catalytic ozonation with the prepared Fe/activated carbon catalyst significantly enhanced pollutant removal in the second SBR by improving wastewater biodegradability and reducing wastewater microtoxicity. The treatment technique decreased oil, chemical oxygen demand and NH3-N by about 97%, 88% and 91%, respectively, allowing the discharge limits to be met. Therefore, the integrated process with efficient, economical and sustainable advantages was suitable for advanced treatment of real OPW. PMID- 26936287 TI - Role of thyroid transcription factor-1 in the diagnosis of feline lung-digit syndrome. AB - Objectives The aim of this study was to investigate the role of thyroid transcription factor-1 (TTF-1) in the diagnosis of feline lung-digit syndrome (FLDS) and to investigate the associations between the morphological features of FLDS and TTF-1 expression. We also compared the reliability of TTF-1 and transmission electron microscopy (TEM) in establishing the diagnosis of FLDS. Methods Histology records of feline digit tumours were retrieved, including patients from 2008-2015. If formalin-fixed, paraffin-embedded tissues were available for review, patients were included in the study. As a control group we included 12 feline primary tumours of the digits. All the histological slides of the study group were blindly reviewed by the same veterinary pathologist. Representative sections of the lesions were selected for immunohistochemistry (IHC) analysis. To confirm the respiratory origin of the neoplastic tissue, TEM was used as a gold standard in all cases. Results Five cases of FLDS were included. TTF-1 was weakly to moderately positive in 60% of the cases, showing no correlation with the microscopic presence of ciliated epithelium. When IHC results were combined with the presence of cilia, 80% of the cases from the study group could be identified as FLDS. TEM confirmed the presence of ciliated epithelium in all five cases, confirming the respiratory origin of the neoplastic tissue and therefore the diagnosis of FLDS. Conclusions and relevance TTF-1 expression is maintained in FLDS. While the combination of TTF-1 and identification of cilia confirms FLDS, TEM should be considered in those cases where diagnosis is uncertain and FLDS is suspected. PMID- 26936288 TI - The reduction of temporal optic nerve head microcirculation in autosomal dominant optic atrophy. AB - PURPOSE: To evaluate the optic nerve head (ONH) microcirculation in autosomal dominant optic atrophy (ADOA) patients. METHODS: This study comprised 22 eyes of 12 ADOA patients, diagnosed according to clinical findings including family history and the presence of mutations in the OPA1 gene. Twenty-four normal eyes of 24 age-matched subjects, with either the right or left eye randomly selected for use, served as controls. Circumpapillary retinal nerve fibre layer thickness (cpRNFLT) and mean blur rate (MBR) in the ONH were determined with optical coherence tomography (OCT) and laser speckle flowgraphy (LSFG), respectively. For each ONH quadrant (superior, temporal, inferior and nasal), the MBR and cpRNFLT ratio was also calculated by dividing tissue MBR in that quadrant by tissue MBR in the entire ONH and by dividing cpRNFLT in that quadrant by cpRNFLT in the entire ONH respectively. RESULTS: Mean blur rate (MBR) in all quadrants was significantly lower in the ADOA patients than in the controls (p < 0.001 in each). The MBR ratio was significantly lower in the ADOA patients only in the temporal quadrant (p < 0.001). Similarly, cpRNFLT was lower in the ADOA patients in all quadrants (p < 0.001 in each), and the cpRNFLT ratio was lower in the temporal quadrant (p < 0.001). CONCLUSION: Reduced blood flow in the temporal optic disc in ADOA patients is associated with reduced temporal cpRNFLT, suggesting that both are caused by damage to the papillomacular bundle. The anatomical characteristics of the papillomacular bundle may make it especially susceptible to mitochondrial dysfunction-induced damage, which occurs in ADOA. PMID- 26936289 TI - Central venous thrombosis in children with intestinal failure on long-term parenteral nutrition. AB - PURPOSE: Central venous thrombosis (CVT) is a serious complication of long-term central venous access for parenteral nutrition (PN) in children with intestinal failure (IF). We reviewed thse incidence of CVT and possible risk factors. METHODS: Children with IF on home PN (2010-2014) with central venous imaging were reviewed. Patient demographics, catheter characteristics and related complications, and markers of liver function were compared between children with and without CVT. Serum thrombophilia markers were reviewed for patients with CVT. RESULTS: Thirty children with central venous imaging were included. Seventeen patients had thrombosis of >=1 central vein, and twelve had >=2 thrombosed central veins. Patients with and without CVT had similar demographics and catheter characteristics. Patients with CVT had a significantly lower albumin level (2.76+/-0.38g/dL vs. 3.12+/-0.41g/dL, p=0.0223). The most common markers of thrombophilia in children with CVT were antithrombin, protein C and S deficiencies, and elevated factor VIII. There was a statistically significant correlation between a combined protein C and S deficiency and having >1 CVT. CONCLUSIONS: Children with IF on long-term PN are at high risk for CVT potentially owing to low levels of natural anticoagulant proteins and elevated factor FVIII activity, likely a reflection of liver insufficiency and chronic inflammation. PMID- 26936290 TI - Outcomes after peritoneal dialysis catheter placement. AB - BACKGROUND: The purpose of this study was to review surgical outcomes after elective placement of peritoneal dialysis (PD) catheters in children with end stage renal disease. METHODS: Children with PD catheters placed between February 2002 and July 2014 were retrospectively reviewed. Outcomes were catheter life, late (>30days post-op) complications (catheter malfunction, catheter malposition, infection), and re-operation rates. Comparison groups included laparoscopic versus open placement, age<2, and weight<10kg. Univariate and multivariate analysis were performed. RESULTS: One hundred sixteen patients had 173 catheters placed (122 open, 51 laparoscopic) with an average patient age of 9.7+/-6.3years. Mean catheter life was similar in the laparoscopic and open groups (581+/-539days versus 574+/-487days, p=0.938). The late complication rate was higher for open procedures (57% versus 37%, p=0.013). Children age<2 or weight<10kg had higher re operation rates (64% versus 42%, p=0.014 and 73% versus 40%, p=0.001, respectively). Adjusted for age and weight, open technique remained a risk factor for late complications (OR 2.44, 95% CI 1.20-4.95) but not re-operation. DISCUSSION: Laparoscopic placement appears to reduce the rate of late complications in children who require PD dialysis catheters. Children <2years age or <10kg remain at risk for complications regardless of technique. PMID- 26936291 TI - The appeasement of Doug: a synthetic approach to enhancer biology. AB - Genetic approaches have been instrumental in dissecting developmental enhancers by characterizing their transcription factor binding sites. Though some enhancers have been well-studied in this regard, we cannot currently build developmental enhancers from scratch. Reconstitution experiments can provide important complementary tests of our understanding of enhancer function, but these experiments are exceedingly rare in the literature, possibly due to the difficulty of publishing negative results. In this perspective, we argue that the time is right for a synthetic approach to enhancer biology. Focusing primarily on Drosophila enhancers as examples, we review classic and modern methods for dissecting enhancer function as well as computational tools for enhancer design. We include our own negative results from attempts to reconstitute the stripe 2 enhancer from the even-skipped locus and discuss possible ways forward. We believe that with a communal effort in open data sharing, we can make substantial progress toward a complete understanding of enhancer function. PMID- 26936293 TI - Interfacial Design of Mixed Matrix Membranes for Improved Gas Separation Performance. AB - High-performance metal-organic framework (MOF)/polyimide (PI) mixed matrix membranes (MMMs) are fabricated by a facile strategy by designing the MOF/PI matrix interface via poly dopamine coating. The overall separation performance of the designed MMMs surpasses the state-of-the-art 2008 Robeson upper bound for the H2 /CH4 and H2 /N2 gas pairs and approaches the 2008 upper bound for the O2 /N2 gas pair. PMID- 26936292 TI - miR-223 reverses the resistance of EGFR-TKIs through IGF1R/PI3K/Akt signaling pathway. AB - Acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib, is a critical issue for the treatment of EGFR mutant-positive non-small cell lung cancer (NSCLC). Recent evidence supports the role of microRNA-223 (miR-223) in modulating chemotherapeutic drug sensitivity, but its role in the resistance to EGFR-TKIs in NSCLC remains unclear. To this end, we investigated the involvement of miR-223 in erlotinib resistance, using two pairs of TKI-sensitive or resistant cell lines, PC9 vs PC9/ER, and HCC827 vs HCC827/ER, as well as PC9/CD133+, which are lung cancer stem-like cells derived from PC9 cells. Downregulation of miR-223 expression in PC9/ER and PC9/CD133+ cells was detected, and the reverse correlation of miR-233 and insulin-like growth factor 1 receptor (IGF1R) in these cells was also revealed. Next, levels of IGF1R mRNA and p-Akt were significantly reduced in miR-223 stably transfected PC9/ER and PC9/CD133+ cells. However, the sensitivity of PC9/ER and PC9/CD133+ cells to erlotinib was partially restored, after overexpression of miR-223 in those cells. Similar results were also observed in vivo. Furthermore, miR-223-mediated inhibition of the IGF1R/PI3K/Akt signaling pathway may have been reversed by the agonist of IGF1R in miR-223 transfected cells. Our findings indicated that downregulation of miR-223, which can induce activation of the IGF1R/phosphatidylinositol 3-kinase (PI3K)/Akt pathway in PC9/ER and PC9/CD133+ cells, may be responsible for the resistance of PC9/ER and PC9/CD133+ cells to erlotinib, suggesting that miR-223 is a potential therapeutic target for overcoming EGFR-TKIs resistance. PMID- 26936295 TI - Decreasing the Viscosity in CO2 Capture by Amino-Functionalized Ionic Liquids through the Formation of Intramolecular Hydrogen Bond. AB - A strategy for decreasing the viscosity variation in the process of CO2 capture by amino-functionalized ionic liquids (ILs) through the formation of intramolecular hydrogen bond was reported. Different with the dramatic increase in viscosity during CO2 uptake by traditional amino-functionalized ILs, slight increase or even decrease in viscosity was achieved through introducing a N or O atom as hydrogen acceptor into amino-functionalized anion, which could stabilize the active hydrogen of produced carbamic acid. Quantum chemical calculations and spectroscopic investigations demonstrated that the formation of intramolecular hydrogen bond between introduced hydrogen acceptor and carbamic acid was the key to avoid the dramatic increase in viscosity during the capture of CO2 by these amino-functionalized ILs. PMID- 26936294 TI - Use of the CryoPredict algorithm to predict live birth from cryopreserved embryos. AB - BACKGROUND: Currently, the viability of cryostored blastocysts that are subsequently re-warmed is determined via the percentage of cell survival. However, the large number of cells that forms the blastocyst can make this estimate difficult and unreliable. Studies have shown that fast re-expanding blastocysts have superior pregnancy rates. AIM: To determine whether the degree and speed of blastocoele re-expansion following cryopreservation and warming correlate with rates of live birth. MATERIALS AND METHODS: A retrospective cohort study of 757 frozen embryo transfer cycles over a 4-year period at Royal Prince Alfred Hospital, Sydney. Clinical and embryology notes were retrieved. Details regarding patient demographics, stimulation cycle from which embryos were derived, frozen embryo transfer cycles, embryology and pregnancy outcomes were recorded. RESULTS: Female (P = 0.01) and male age (P = 0.02) at the time of embryo creation were inversely associated with live birth. Fertilisation method (P = 0.03), embryo type at cryopreservation (P = 0.009), embryo grade at cryopreservation (P < 0.0001), percentage of cell survival post-thaw (P < 0.0001) and the degree of re-expansion (P = 0.003) were the IVF and embryology factors significantly associated with live birth. A predictive model (CryoPredict) was created in order to individualise the probability that the transfer of a given embryo would result in live birth. CONCLUSIONS: The degree and speed of blastocoele re-expansion postcryopreservation and subsequent warming can be used in conjunction with other parameters to predict live birth. PMID- 26936296 TI - Solid capillarity: when and how does surface tension deform soft solids? AB - Soft solids differ from stiff solids in an important way: their surface stresses can drive large deformations. Based on a topical workshop held in the Lorentz Center in Leiden, this Opinion highlights some recent advances in the growing field of solid capillarity and poses key questions for its advancement. PMID- 26936297 TI - Data too important to share: do those who control the data control the message? PMID- 26936298 TI - Rituximab combined with conventional therapy versus conventional therapy alone for the treatment of mucous membrane pemphigoid (MMP). AB - BACKGROUND: The use of rituximab for refractory autoimmune blistering diseases is increasing. Data related to rituximab for the treatment of mucous membrane pemphigoid (MMP) are limited. OBJECTIVE: We sought to compare the efficacy of adding rituximab with traditional immunosuppressive therapies in the treatment of MMP. The primary outcome was achievement and time to disease control. METHODS: Patients with a diagnosis of MMP from August 2001 to June 2015 who had greater than 6 months of follow-up after the initiation of therapy were reviewed. RESULTS: In all, 24 patients were treated with rituximab and 25 were treated with conventional immunosuppression. Of patients, 100% in the rituximab group achieved disease control compared with 40% in the conventional group (P < .01), with a mean time to disease control of 10.17 months and 37.7 months (P = .02). Adverse events were seen in 33% of patients after rituximab, compared with 48% of patients in the conventional group (P = .2). LIMITATIONS: Rituximab dosing was not uniform and the 2 groups were not matched in terms of disease severity, nor were they randomized. CONCLUSIONS: Our study indicates that the addition of rituximab to conventional therapy in patients with MMP results in more rapid and sustained disease control with potentially fewer adverse events. PMID- 26936299 TI - Translational medicine in the field of ablative fractional laser (AFXL)-assisted drug delivery: A critical review from basics to current clinical status. AB - BACKGROUND: Ablative fractional lasers enhance uptake of topical therapeutics and the concept of fractional laser-assisted drug delivery has now been taken into clinical practice. OBJECTIVES: We systematically reviewed preclinical data and clinical evidence for fractional lasers to enhance drug uptake and improve clinical efficacy. METHODS: We searched PubMed and Embase databases; 34 articles met the inclusion criteria. Studies were categorized into experimental preclinical studies and clinical trials, the latter graded according to level of evidence. RESULTS: All preclinical trials (n = 16) documented enhanced topical drug uptake into skin after ablative fractional laser treatment. Clinical evidence encompassed 18 studies, of which 9 were randomized controlled trials and 2 were controlled trials, examining neoplastic lesions, photodamaged skin, scars, onychomycosis, and topical anesthetics. The highest level of evidence was reached for actinic keratoses treated with methylaminolevulinate for photodynamic therapy (level IB, 5 randomized controlled trials), substantiating superior and long lasting efficacy versus conventional photodynamic therapy. No adverse events were reported, but ablative fractional laser-assisted drug delivery implies risks of systemic drug absorption, especially when performed over large skin areas. CONCLUSIONS: Fractional laser-assisted drug delivery is beneficial in enhancing preclinical and clinical outcomes for certain skin conditions. PMID- 26936300 TI - End points in dermatologic clinical trials: A review for clinicians. AB - Clinical trials are critical for the development of new therapies in dermatology, and their results help determine US Food and Drug Administration (FDA) approval and guide care. Of special relevance is the clinical trial efficacy end point, the metric from which statistically significant outcome is derived. Clinicians' understanding of a clinical trial's end point is necessary for critical analysis of the trial results and for applying those results to daily practice. This review provides practical knowledge and critical evaluation of end points used in treatment approvals by the FDA. The end points for actinic keratosis, acne vulgaris, atopic dermatitis, onychomycosis, and cutaneous ulcer serve as examples. PMID- 26936301 TI - An exon skipping in a SEPALLATA-Like gene is associated with perturbed floral and fruits development in cucumber. AB - We isolated a mutant showing perturbations in the development of male and female floral organs and fruits. Analysis of the single nucleotide polymorphisms from bulked F2 pools identified the causative variant occurring in Csa4G126690. Csa4G126690 shows high homology to Arabidopsis SEPALLATA2 (SEP2) thus being designated CsSEP2. The causative variant was located on the splicing site of CsSEP2, resulting in the skipping of exon 6 and abolishment of the transcriptional activity. Our data suggest that CsSEP2 is involved in the floral organ and fruits development by conferring transcriptional activity. PMID- 26936302 TI - Selection of Suitable DNA Extraction Methods for Genetically Modified Maize 3272, and Development and Evaluation of an Event-Specific Quantitative PCR Method for 3272. AB - A novel real-time PCR-based analytical method was developed for the event specific quantification of a genetically modified (GM) maize, 3272. We first attempted to obtain genome DNA from this maize using a DNeasy Plant Maxi kit and a DNeasy Plant Mini kit, which have been widely utilized in our previous studies, but DNA extraction yields from 3272 were markedly lower than those from non-GM maize seeds. However, lowering of DNA extraction yields was not observed with GM quicker or Genomic-tip 20/G. We chose GM quicker for evaluation of the quantitative method. We prepared a standard plasmid for 3272 quantification. The conversion factor (Cf), which is required to calculate the amount of a genetically modified organism (GMO), was experimentally determined for two real time PCR instruments, the Applied Biosystems 7900HT (the ABI 7900) and the Applied Biosystems 7500 (the ABI7500). The determined Cf values were 0.60 and 0.59 for the ABI 7900 and the ABI 7500, respectively. To evaluate the developed method, a blind test was conducted as part of an interlaboratory study. The trueness and precision were evaluated as the bias and reproducibility of the relative standard deviation (RSDr). The determined values were similar to those in our previous validation studies. The limit of quantitation for the method was estimated to be 0.5% or less, and we concluded that the developed method would be suitable and practical for detection and quantification of 3272. PMID- 26936304 TI - [Molecular Identification and Toxicity of Pufferfish Juveniles Contaminating Whitebait Products]. AB - Catches of whitebait, sardine fry, sometimes contains other marine animals, including fishes, mollusks, and crustaceans, and therefore boiled and dried whitebait products may contain these marine animals if sorting is incomplete. In September 2014, contamination of boiled and dried whitebait products with pufferfish juveniles became a serious food safety concern, as tiger pufferfish Takifugu rubripes juveniles are toxic and contain tetrodotoxin (TTX). The toxicity of the juveniles of other pufferfish species, however, is unclear. To evaluate the food safety of whitebait products contaminated with pufferfish juveniles, we identified the species and toxicity of pufferfish juveniles contaminating whitebait products processed between July and September, 2014. Nucleotide sequence analysis of 16S rRNA or cytochrome b gene fragments of the mitochondrial DNA indicated that partial sequences of the polymerase chain reaction products of 15 specimens were identical with those of Lagocephalus spadiceus, and partial sequence from 2 specimens were identical with those of Takifugu vermicularis. We analyzed TTX by liquid chromatography-tandem mass spectrometry. TTX was not detected in the L. spadiceus specimens and was below the quantification limits (30 ng/g) in a T. vermicularis specimen. Based on whitebait product manufacturer's research, 795 individuals and 27.2 g of pufferfish juveniles were detected in 8,245 kg whitebait product. Thus, the ratio of pufferfish to whitebait product was estimated to be 0.096 individual/kg whitebait product and 0.0033 g/kg whitebait product, respectively. PMID- 26936303 TI - [Survey of Radioactive Cesium and Potassium Intake from Food Using Duplicate Diet (Fiscal Years 2011-2014)]. AB - Dietary intake of radioactive substances ((134)Cs, (137)Cs, (40)K) from food in fiscal 2011--2014 was surveyed using the duplicate diet method. 1,612 diet samples were collected from general households of 18 prefectures. (134)Cs and (137)Cs were detected in samples from Fukushima Prefecture, Miyagi Prefecture and Tokyo Prefecture. (134)Cs and (137)Cs were detected in 11 samples in fiscal 2011, 12 samples in fiscal 2012, and 7 samples in fiscal 2013, but none was detected in fiscal 2014. The largest radioactivity in a sample was 12 Bq/kg in Fukushima Prefecture in fiscal 2011. The detected levels gradually decreased and were less than 1.0 Bq/kg in fiscal 2014. The maximum estimated dose of radioactive cecium was 0.14 mSv/year in fiscal 2011. Radioactive potassium was detected in every meal, and showed little change through the four years (median around 30 Bq/kg). PMID- 26936305 TI - [Validation Study for Analytical Method of Diarrhetic Shellfish Poisons in 9 Kinds of Shellfish]. AB - A method was developed for the simultaneous determination of okadaic acid, dinophysistoxin-1 and dinophysistoxin-2 in shellfish using ultra performance liquid chromatography with tandem mass spectrometry. Shellfish poisons in spiked samples were extracted with methanol and 90% methanol, and were hydrolyzed with 2.5 mol/L sodium hydroxide solution. Purification was done on an HLB solid-phase extraction column. This method was validated in accordance with the notification of Ministry of Health, Labour and Welfare of Japan. As a result of the validation study in nine kinds of shellfish, the trueness, repeatability and within laboratory reproducibility were 79-101%, less than 12 and 16%, respectively. The trueness and precision met the target values of notification. PMID- 26936308 TI - Prolonged disease control with MEK inhibitor in neurofibromatosis type I associated glioblastoma. AB - WHAT IS KNOWN AND OBJECTIVE: Neurofibromatosis is associated with overactivation of the RAS-MAPK pathway. MEK inhibitors have been shown to be an effective treatment modality in other malignancies. CASE SUMMARY: We present a 24-year-old male with treatment-refractory neurofibromatosis-associated glioblastoma, who experienced clinical and radiological benefit from the MEK inhibitor, trametinib. WHAT IS NEW AND CONCLUSION: This case highlights the therapeutic success of a MEK inhibitor in neurofibromatosis-associated glioblastoma. As a corollary, this should prompt evaluation of MEK inhibitors in tumours associated with neurofibromatosis. It remains to be elucidated if tumours with somatic NF1 mutations may also benefit from therapy targeting the RAS-MAPK pathway. PMID- 26936306 TI - Estimated insulin sensitivity predicts incident micro- and macrovascular complications in adults with type 1 diabetes over 6 years: the coronary artery calcification in type 1 diabetes study. AB - OBJECTIVE: Reduced insulin sensitivity (IS) is well documented in type 1 diabetes (T1D) and may contribute to vascular complications. We examined the association of estimated IS (eIS) with incident macro- and microvascular complications in adults with T1D in the prospective CACTI study. METHODS: Participants (N=652) were 19-56 years old at baseline and re-examined 6.2+/-0.6years later. Urinary albumin excretion was measured, and categorized as microalbuminuria or greater. Diabetic retinopathy (DR) was based on self-reported history, proliferative DR (PDR) as history of laser eye therapy and coronary artery calcium (CAC) was measured using electron-beam CT. Progression of CAC was defined as a change in the square root transformed CAC volume score of >=2.5. IS was estimated (eIS) by an equation derived from clamp studies. Predictors of each complication were examined using stepwise logistic regression and subjects with complications at baseline excluded. Age, T1D duration, sex, HbA1c, SBP, LDL-C, and eIS were considered for inclusion. RESULTS: Greater eIS at baseline predicted lower odds of developing albuminuria (OR: 0.67, 95% CI 0.51-0.88), DR (OR 0.79, 0.64-0.97), PDR (OR: 0.76, 0.57-0.99) and CACp (OR: 0.71, 0.60-0.85) in multivariable models. CONCLUSIONS: Greater eIS conferred protection from the development of vascular complications over 6-years in T1D. PMID- 26936309 TI - A refractory, cutaneous, subepidermal bullous disease. PMID- 26936307 TI - The impact of diabetes and other metabolic disorders on prostate cancer prognosis. AB - AIMS: To investigate the impact of diabetes mellitus (DM) and other metabolic disorders on the survival of men with prostate cancer (PCa). METHODS: We conducted a retrospective cohort-study based on 715 men with PCa, originally enrolled in an Italian case-control study between 1995 and 2002. Anthropometric measures, self-reported medical conditions, and Gleason score were assessed at enrollment. Adjusted hazard ratios (HRs) of death, with 95% confidence intervals (95% CIs), were estimated using Fine and Gray's regression model. RESULTS: After a median follow-up of 11.6years, 244 (34.1%) deaths occurred, 77 (31.6%) due to PCa. Excess mortality from all causes was reported in PCa patients with DM (HR=1.56, 95% CI: 1.03-2.36), which increased to 1.76 (95% CI: 0.99-3.13) when at least two out of three metabolic disorders (i.e., waist circumference >=102cm, drug-treated hypertension, and hypercholesterolemia) were additionally present. The impact of metabolic disorders was stronger on non-PCa-specific mortality with HRs equal to 2.21 (95% CI: 1.38-3.54) for DM, 1.45 (95% CI: 0.97-2.19) for waist circumference >=102cm, and 1.63 (95% CI: 1.19-2.22) for drug-treated hypertension. CONCLUSIONS: DM and other metabolic disorders unfavorably affected the survival of PCa patients, mainly impacting on the risk of death from causes other than PCa. PMID- 26936310 TI - Influence of different prebiotics and mode of their administration on broiler chicken performance. AB - In the post-antibiotics era, prebiotics are proposed as alternatives to antibiotic growth promoters in poultry production. The goal of this study was to compare in ovo method of prebiotic delivery with in-water supplementation and with both methods combined (in ovo+in-water) in broiler chickens. Two trials were conducted. Trial 1 was carried out to optimize the doses of two prebiotics, DN (DiNovo(r), extract of beta-glucans) and BI (Bi2tos, trans galactooligosaccharides), for in ovo delivery. The estimated parameters were hatchability and bacteriological status of the newly hatched chicks. Prebiotics were dissolved in 0.2 ml of physiological saline, at the doses: 0.18, 0.88, 3.5 and 7.0 mg/embryo; control group (C) was injected in ovo with 0.2 ml of physiological saline. Trial 2 was conducted to evaluate effects of different prebiotics (DN, BI and raffinose family oligosaccharides (RFO)) delivered in ovo, in-water and in a combined way (in ovo+in-water) on broiler chickens performance. The results of the Trial 1 indicated that the optimal dose of DN and BI prebiotics delivered in ovo, that did not reduce chicks' hatchability, was 0.88 mg/embryo (DN) and 3.5 mg/embryo (BI). Both prebiotics numerically increased number of lactobacilli and bifidobacteria in chicken feces (P>0.05). In Trial 2, all prebiotics (DN, BI and RFO) significantly increased BW gain compared with the C group (P<0.05), especially during the first 21 days of life. However, feed intake and feed conversion ratio were increased upon prebiotics delivery irrespective of method used. Injection of prebiotics in ovo combined with in water supplementation did not express synergistic effects on broilers performance compared with in ovo injection only. Taken together, those results confirm that single in ovo prebiotics injection into the chicken embryo can successfully replace prolonged in-water supplementation post hatching. PMID- 26936311 TI - Maximum-Entropy Inference with a Programmable Annealer. AB - Optimisation problems typically involve finding the ground state (i.e. the minimum energy configuration) of a cost function with respect to many variables. If the variables are corrupted by noise then this maximises the likelihood that the solution is correct. The maximum entropy solution on the other hand takes the form of a Boltzmann distribution over the ground and excited states of the cost function to correct for noise. Here we use a programmable annealer for the information decoding problem which we simulate as a random Ising model in a field. We show experimentally that finite temperature maximum entropy decoding can give slightly better bit-error-rates than the maximum likelihood approach, confirming that useful information can be extracted from the excited states of the annealer. Furthermore we introduce a bit-by-bit analytical method which is agnostic to the specific application and use it to show that the annealer samples from a highly Boltzmann-like distribution. Machines of this kind are therefore candidates for use in a variety of machine learning applications which exploit maximum entropy inference, including language processing and image recognition. PMID- 26936312 TI - Early intervention leads to long-term developmental improvements in very preterm infants, especially infants with bronchopulmonary dysplasia. AB - AIM: Various early intervention programmes have been developed in response to the high rate of neurodevelopmental problems in very preterm infants. We investigated longitudinal effects of the Infant Behavioral Assessment and Intervention Program on cognitive and motor development of very preterm infants at the corrected ages of six months to five and a half years. METHODS: This randomised controlled trial divided 176 infants with a gestational age <32 weeks or birthweight <1500 g into intervention (n = 86) and control (n = 90) groups. Cognitive development and motor development were assessed with the Bayley Scales of Infant Development at the CAs of six, 12 and 24 months and at five and a half years with the Wechsler Preschool and Primary Scale of Intelligence and the Movement Assessment Battery for Children. RESULTS: We found significant longitudinal intervention effects (0.4 SD, p = 0.006) on motor development, but no significant impact on cognitive development (p = 0.063). Infants with bronchopulmonary dysplasia showed significant longitudinal intervention effects for cognitive (0.7 SD; p = 0.019) and motor (0.9 SD; p = 0.026) outcomes. Maternal education had little effect on intervention effects over time. CONCLUSION: The Infant Behavioral Assessment and Intervention Program led to long-term developmental improvements in the intervention group, especially in infants with BPD. PMID- 26936313 TI - Copper-Catalyzed trans-Hydroboration of Terminal Aryl Alkynes: Stereodivergent Synthesis of Alkenylboron Compounds. AB - A Cu-catalyzed highly Z-stereoselective hydroboration of alkynes with 1,8 naphthalenediaminatoborane (HB(dan)) is developed. DPEphos (bis[(2 diphenylphosphino)phenyl]ether)-ligated Cu catalysts produced alkenylboron compounds from terminal alkynes with excellent Z-stereoselectivity. In contrast, using a SIPr-CuCl complex as the precatalyst exclusively produced E-hydroboration products at mild conditions. Both catalytic procedures form alkenylboron products stereocomplementary to each other, constituting stereodivergent hydroboration of alkynes through Cu catalysis. Deuterium labeling and isomerization studies support the Z-selective hydroboration via trans-addition of the boron reagent to terminal alkynes as opposed to precedent noble-metal-catalyzed trans hydroborations. PMID- 26936314 TI - Knockdown of ephrin receptor A7 suppresses the proliferation and metastasis of A549 human lung cancer cells. AB - Previous studies have demonstrated that ephrin (Eph) family receptor tyrosine kinases and ligands promote cancer growth, invasion and metastasis. In addition, it has been reported that Eph receptor A7 (EphA7) is transcriptionally activated in lung cancer; however, the effects of silencing EphA7 expression on the growth of lung cancer cells, and the underlying molecular mechanisms, have yet to be determined. Therefore, the present study aimed to investigate whether silencing EphA7 with small interfering (si)RNA could induce apoptosis in non-small cell lung cancer (NSCLC) cells. Furthermore, the effects of siEphA7 on cell migration and invasion were evaluated using Transwell assays. The mechanisms underlying the effects of siEphA7 on the tumorigenic properties of A549 cells were also examined. The results of the present study demonstrated that transfection with siEphA7 inhibited the proliferation, migration and invasion of A549 cells. In addition, siEphA7 significantly increased the protein expression levels of B-cell lymphoma 2 (Bcl-2)-associated X protein and caspase-3, and decreased the protein expression levels of Bcl-2, thus suggesting that siEphA7 was able to induce apoptosis via the intrinsic apoptotic pathway. In addition, the expression levels of phosphatase and tensin homolog (PTEN) were significantly upregulated, and the expression levels of total AKT were not altered, whereas the levels of phosphorylated-AKT were reduced. These findings indicated that EphA7 may have an important role in the pathogenesis of NSCLC by regulating PTEN expression via the PTEN/AKT pathway. Silencing EphA7 may provide a novel approach for the treatment of NSCLC. PMID- 26936316 TI - Methodological Issues on a Clinical Trial to Test Tapentadol Prolonged release vs. Oxycodone/Naloxone Prolonged release. PMID- 26936317 TI - One-stage debulking procedure after flap reconstruction for degloving injury of the hand. AB - AIM: The aim of this study is to evaluate the use of one-stage debulking procedure to separate the fingers after flap reconstruction for degloving injury of the hand. PATIENTS AND METHODS: From January 2009 to June 2014, 15 patients with degloving injuries of the hand were treated at the Kaohsiung Chang Gung Memorial Hospital. Among the 15 patients, 11 sustained degloving injury of the fingers; free flap reconstruction was performed in three patients, and a pedicle flap was used in eight. Four patients sustained complete degloving injuries of the hand; reconstruction was performed with an anterolateral thigh pocketing procedure. One-stage debulking procedure was performed for debulking of the flap and interdigitation from the flap envelope. RESULTS: After the 12-month follow-up and rehabilitation, the fingers could move independently and perform in opposition with the thumb. Protective sensation was also regained. The patients with degloving injury of the fingers could return to daily activity and work after 1-year follow-up, while those with complete degloving injury of the hand could return to daily activities and work after 18-month follow-up. CONCLUSION: The use of ALT pocketing procedure is simple for salvage of complete degloving injury of the hand. One-stage debulking procedure provides thin and durable skin coverage for hand after reconstruction. The fingers can also be separated from the envelope of a bulky flap for independent movement to fulfill functional and aesthetic requirements. PMID- 26936318 TI - Poly Implant ProtheseTM (PIP) experience in the United Kingdom: A prospective cohort study into the accuracy of diagnostic imaging findings in comparison to operative findings of 1029 implants. AB - The Poly Implant ProstheseTM (PIP) implants were withdrawn from market use in the United Kingdom on 31st March 2010 following Government issued advice. In June 2012 a final Government report was issued and during this period the majority of patients elected to have their prostheses removed. This study presents the operative findings of three surgeons. 517 patients were identified retrospectively from the implant database as having received PIP implants with a total of 1029 implants. 62 patients (124 implants) declined explantation after consultation and imaging. The data was recorded prospectively for all patients and included the clinical, imaging and operative findings. A total of 905 implants were removed of which 129 were ruptured at the time of explantation (14.25%). 27 implants were intact but the presence of liquid surrounding the prosthesis was noted. 93 implants were reported as being ruptured after diagnostic imaging but were intact operatively resulting in a test sensitivity of 0.82 and a specificity of 0.92 yielding a positive predictive value of 0.59 and a negative predictive value of 0.97 overall. Capsule formation was noted in 27 breasts (3%). Our study showed that the prevalence of PIP ruptures is comparable to other manufacturers. The prevalence of implant rupture predictably increased over time and the prevalence of abnormal capsule formation was similar to other manufacturers. PMID- 26936320 TI - 53-Year-Old Man With Fever and Back Pain. PMID- 26936321 TI - 40-Year-Old Woman With Breathlessness and Fatigue. PMID- 26936322 TI - The mechanisms of substance P-mediated migration of bone marrow-derived mesenchymal stem cell-like ST2 cells. AB - Substance P (SP) is known to induce the mobilization of bone marrow-derived mesenchymal stem cells (BM-MSCs) and thus participates in wound repair. However, the cellular and molecular mechanisms responsible for the SP-mediated migration of BM-MSCs were not fully understood. In the present study, we studied the molecular mechanisms that mediate the migration of the BM-derived MSC-like cell line ST2 in response to SP. Using a migration assay and western blot analysis, we noted that SP induced the chemotactic migration of ST2 cells through the intrinsic activation of extracellular signal-regulated kinases (ERKs) and protein kinase B (Akt), the phosphorylated expression levels of which were increased. We noted that Src is involved in the SP-mediated migration of ST2 cells and that focal adhesion kinase (FAK) was activated in the ST2 cells following SP treatment. Membrane ruffling increased in the ST2 cells after SP treatment, as was clearly demonstrated by immunocytochemical analysis. Importantly, using a blocking antibody against N-cadherin (GC-4), we studied cell migration and noted that SP mediated the migration of the ST2 cells through N-cadherin. The present study thus advanced our understanding of the mechanisms through which SP induces BM-MSC migration. PMID- 26936319 TI - Single-cell differences in matrix gene expression do not predict matrix deposition. AB - Mesenchymal stem cells (MSCs) display substantial cell-to-cell heterogeneity, complicating their use in regenerative medicine. However, conventional bulk assays mask this variability. Here we show that both chondrocytes and chondrogenically induced MSCs exhibit substantial mRNA expression heterogeneity. Single-molecule RNA FISH to measure mRNA expression of differentiation markers in single cells reveals that sister cell pairs have high levels of mRNA variability, suggesting that marker expression is not heritable. Surprisingly, this variability does not correlate with cell-to-cell differences in cartilage-like matrix production. Transcriptome-wide analysis suggests that no combination of markers can predict functional potential. De-differentiating chondrocytes also show a disconnect between mRNA expression of the cartilage marker aggrecan and cartilage-like matrix accumulation. Altogether, these quantitative analyses suggest that sorting subpopulations based on these markers would only marginally enrich the progenitor population for 'superior' MSCs. Our results suggest that instantaneous mRNA abundance of canonical markers is tenuously linked to the chondrogenic phenotype at the single-cell level. PMID- 26936323 TI - Protein-protein interface prediction based on hexagon structure similarity. AB - Studies on protein-protein interaction are important in proteome research. How to build more effective models based on sequence information, structure information and physicochemical characteristics, is the key technology in protein-protein interface prediction. In this paper, we study the protein-protein interface prediction problem. We propose a novel method for identifying residues on interfaces from an input protein with both sequence and 3D structure information, based on hexagon structure similarity. Experiments show that our method achieves better results than some state-of-the-art methods for identifying protein-protein interface. Comparing to existing methods, our approach improves F-measure value by at least 0.03. On a common dataset consisting of 41 complexes, our method has overall precision and recall values of 63% and 57%. On Benchmark v4.0, our method has overall precision and recall values of 55% and 56%. On CAPRI targets, our method has overall precision and recall values of 52% and 55%. PMID- 26936324 TI - Prediction of drug-drug interactions with carbamazepine-10,11-epoxide using a new in vitro assay for epoxide hydrolase inhibition. AB - 1. Carbamazepine is an antiepileptic drug which is metabolized by CYP3A4 into carbamazepine-10,11-epoxide. This metabolite is then detoxified by epoxide hydrolase. As carbamazepine-10,11-epoxide has been associated with neurotoxicity, it is critical to identify whether a new antiepileptic drug has the potential to inhibit epoxide hydrolase and therefore increase carbamazepine-10,11-epoxide plasma levels. 2. In this study, an in vitro assay was developed to evaluate epoxide hydrolase activity by using carbamazepine-10,11-epoxide as probe substrate. The ability of this assay to predict drug-drug interactions (DDI) at the epoxide hydrolase level was also investigated. 3. To this aim, known inhibitors of epoxide hydrolase for which in vivo data are available were used. Firstly, carbamazepine-10,11-epoxide hydrolase activity was determined in liver microsomes, cytosol and hepatocytes. Thereafter, the IC50 of epoxide hydrolase inhibitors (progabide, valproic acid, valpromide and valnoctamide) was determined in liver microsomes and hepatocytes. Finally, prediction of AUC increase was performed using the in vitro data generated. 4. Interestingly, epoxide hydrolase activity was found to be much higher in human hepatocytes compared to liver microsomes/cytosol. Even though assessed on a limited number of compounds, this study demonstrated that the use of hepatocytes seems to be a more relevant model to assess and predict DDI at the epoxide hydrolase level. PMID- 26936325 TI - Active and adaptive Legionella CRISPR-Cas reveals a recurrent challenge to the pathogen. AB - Clustered regularly interspaced short palindromic repeats with CRISPR-associated gene (CRISPR-Cas) systems are widely recognized as critical genome defense systems that protect microbes from external threats such as bacteriophage infection. Several isolates of the intracellular pathogen Legionella pneumophila possess multiple CRISPR-Cas systems (type I-C, type I-F and type II-B), yet the targets of these systems remain unknown. With the recent observation that at least one of these systems (II-B) plays a non-canonical role in supporting intracellular replication, the possibility remained that these systems are vestigial genome defense systems co-opted for other purposes. Our data indicate that this is not the case. Using an established plasmid transformation assay, we demonstrate that type I-C, I-F and II-B CRISPR-Cas provide protection against spacer targets. We observe efficient laboratory acquisition of new spacers under 'priming' conditions, in which initially incomplete target elimination leads to the generation of new spacers and ultimate loss of the invasive DNA. Critically, we identify the first known target of L. pneumophila CRISPR-Cas: a 30 kb episome of unknown function whose interbacterial transfer is guarded against by CRISPR Cas. We provide evidence that the element can subvert CRISPR-Cas by mutating its targeted sequences - but that primed spacer acquisition may limit this mechanism of escape. Rather than generally impinging on bacterial fitness, this element drives a host specialization event - with improved fitness in Acanthamoeba but a reduced ability to replicate in other hosts and conditions. These observations add to a growing body of evidence that host range restriction can serve as an existential threat to L. pneumophila in the wild. PMID- 26936327 TI - Integrated photonic emitter with a wide switching range of orbital angular momentum modes. AB - Due to the nature of infinite dimensionality, the orbital angular momentum (OAM) has been considered as a new degree of freedom of light and widely expanded the scopes of substantial optical applications such as optical telecommunication, quantum information, particle manipulation and imaging. In recent years, the integrated photonic OAM emitters have been actively investigated due to both compactness and tunability. Essentially, the number of available OAM modes by dynamic switching should be large enough so that the dimensionality of OAM could be explored as much as possible. In this work, an integrated photonic emitter with a wide switching range of OAM modes is theoretically developed, numerically simulated, and experimentally verified. The independence of the micro-ring cavity and the scattering unit provides the flexibility to design the device and optimize the performance. Specifically, the dynamic switching of nine OAM modes (l = -4 ~ 4) with azimuthal polarization has been demonstrated by electrically controlled thermo-optic effect. PMID- 26936326 TI - Effects of tanshinone IIA on fibrosis in a rat model of cirrhosis through heme oxygenase-1, inflammation, oxidative stress and apoptosis. AB - Tanshinone IIA is extracted from the root of Salvia miltiorrhiza and used in traditional Chinese medicine for its anti-inflammatory activity and antioxidant effects. The aim of the present study was to investigate the potential protective effects of tanshinone IIA against fibrosis in a rat model of cirrhosis and to elucidate the underlying mechanisms. Male Sprague Dawley rats were used as the model of cirrhosis in the present study. In the cirrhotic rats, the extent of fibrosis, levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), heme oxygenase-1 (HO-1) protein expression, serum levels of nuclear factor (NF)-kappaB, tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta and IL-6, superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH PX), and the protein expression levels of phosphorylated-p38 mitogen-activated protein kinase (MAPK) were all significantly increased. However, the serum malondialdehyde (MDA) activity and protein kinase B (Akt) protein expression were suppressed in cirrhotic rats compared with the sham (control) group. Compared with the cirrhotic group, administration of tanshinone IIA reduced the extent of fibrosis, levels of ALT and AST, HO-1 protein expression, serum NF-kappaB, TNF alpha, IL-1beta and IL-6 levels, and the activity of SOD, CAT and GSH-PX. Furthermore, administration of tanshinone IIA significantly increased the inhibition of the serum MDA activity and the Akt protein expression in cirrhotic rats compared with those in the cirrhotic group. The protective effect of tanshinone IIA suppresses fibrosis in a rat model of cirrhosis, and reduces inflammation and oxidative stress, via the HO-1, Akt and p38 MAPK signaling pathway. PMID- 26936328 TI - Enhanced diffusion and anomalous transport of magnetic colloids driven above a two-state flashing potential. AB - We combine experiments and theory to investigate the diffusive and the subdiffusive dynamics of paramagnetic colloids driven above a two-state flashing potential. The magnetic potential was realized by periodically modulating the stray field of a magnetic bubble lattice in a uniaxial ferrite garnet film. At large amplitudes H0 of the driving field, the dynamics of the particle resemble an ordinary random walk with a frequency-dependent diffusion coefficient. However, subdiffusive and oscillatory dynamics at short time scales are observed when decreasing H0. We present a persistent random walk model to elucidate the underlying mechanism of motion, and perform numerical simulations to demonstrate that the anomalous motion originates from the dynamic disorder in the structure of the magnetic lattice, induced by the slightly irregular shape of bubbles. PMID- 26936329 TI - Small Molecule Inhibition of Ligand-Stimulated RAGE-DIAPH1 Signal Transduction. AB - The receptor for advanced glycation endproducts (RAGE) binds diverse ligands linked to chronic inflammation and disease. NMR spectroscopy and x-ray crystallization studies of the extracellular domains of RAGE indicate that RAGE ligands bind by distinct charge- and hydrophobicity-dependent mechanisms. The cytoplasmic tail (ct) of RAGE is essential for RAGE ligand-mediated signal transduction and consequent modulation of gene expression and cellular properties. RAGE signaling requires interaction of ctRAGE with the intracellular effector, mammalian diaphanous 1 or DIAPH1. We screened a library of 58,000 small molecules and identified 13 small molecule competitive inhibitors of ctRAGE interaction with DIAPH1. These compounds, which exhibit in vitro and in vivo inhibition of RAGE-dependent molecular processes, present attractive molecular scaffolds for the development of therapeutics against RAGE-mediated diseases, such as those linked to diabetic complications, Alzheimer's disease, and chronic inflammation, and provide support for the feasibility of inhibition of protein protein interaction (PPI). PMID- 26936331 TI - Benzene exposure is associated with epigenetic changes (Review). AB - Benzene is a volatile aromatic hydrocarbon solvent and is known as one of the predominant air pollutants in the environment. Chronic exposure to benzene is known to cause aplastic anemia and increased risk of acute myelogenous leukemia in humans. Although the mechanisms by which benzene causes toxicity remain to be fully elucidated, it is widely accepted that its metabolism is crucial to its toxicity, with involvement of one or more reactive metabolites. Novel approaches aimed at evaluating different mechanisms by which benzene can impact on human health by altering gene regulation have been developed. Among these novel approaches, epigenetics appears to be promising. The present review article summarizes the most important findings, reported from the literature, on epigenetic modifications correlated to benzene exposure. A computerized search in PubMed was performed in November 2014, using search terms, including 'benzene', 'epigenetic', 'histone modifications', 'DNA methylation' and 'microRNA'. Epidemiological and experimental studies have demonstrated the potential epigenetic effects of benzene exposure. Several of the epigenomic changes observed in response to environmental exposures may be mechanistically associated with susceptibility to diseases. However, further elucidation of the mechanisms by which benzene alters gene expression may improve prediction of the toxic potential of novel compounds introduced into the environment, and allow for more targeted and appropriate disease prevention strategies. PMID- 26936330 TI - Neuroprotective effects of Ilexonin A following transient focal cerebral ischemia in rats. AB - Ilexonin A is a compound isolated from the root of a plant commonly used in traditional Chinese medicine. The aim of the present study was to investigate the possible protective mechanism of Ilexonin A in rats subjected to occlusion of the middle cerebral artery (MCAO). Transient focal cerebral ischemia was induced by 2 h of MCAO, followed by reperfusion. Ilexonin A at doses of 20, 40 and 80 mg/kg were administered via intraperitoneal injection immediately following ischemia/reperfusion. The expression levels of glial fibrillary acidic protein (GFAP), ionized calcium-binding adapter molecule-1 (Iba-1), vascular endothelial growth factor (VEGF), fetal liver kinase-1 (Flk-1) and Nestin were examined using immunostaining and Western blot analysis of the peri-infarct region following ischemia/reperfusion. Ilexonin A significantly decreased the infarct volume and improved neurological deficits in a dose-dependent manner. The expression levels of VEGF, Flk-1 and Nestin were significantly increased in the rats treated with Ilexonin A, compared with the rats administered with saline. Following treatment with Ilexonin A, a higher number of GFAP-positive astrocytes were found in the Ilexonin A-treated rats at 1, 3 and 7 days, compared with the rats exposed to ischemia only, however, there were fewer astrocytes at 14 days, compared with the ischemia group. Ilexonin A significantly decreased the protein expression of Iba 1. The results of the present study suggested that the protective effects of Ilexonin A were associated with revascularization, neuronal regeneration, and the regulation of astrocyte and microglia cell activation. PMID- 26936332 TI - Flavonoid intake and incident hypertension in women. AB - BACKGROUND: Intake of flavonoid-containing food has been shown to have a beneficial effect on blood pressure in short-term randomized trials. There are limited data on total flavonoid and flavonoid-subclass consumption over a long period of time and the corresponding incidence of hypertension. OBJECTIVE: We aimed to evaluate the relation between flavonoid subclasses and total flavonoid intakes and incidence of hypertension. DESIGN: In a prospective cohort of 40,574 disease-free French women who responded to a validated dietary questionnaire, we observed 9350 incident cases of hypertension between 1993 and 2008. Cases were identified through self-reports of diagnosed or treated hypertension. Multivariate Cox regression models were adjusted for age, family history of hypertension, body mass index, physical activity, smoking, diabetes, hypercholesterolemia, hormone therapy, and alcohol, caffeine, magnesium, potassium, omega-3 (n-3), and processed meat intakes. RESULTS: Women in the highest quintile of flavonol intake had a 10% lower rate of hypertension than women in the lowest quintile (HR: 0.90; 95% CI: 0.84, 0.97;P-trend = 0.031). Similarly, there was a 9% lower rate for women in the highest category of intake than for women in the lowest category of intake for both anthocyanins and proanthocyanidin polymers [HRs: 0.91 (95% CI: 0.84, 0.97;P-trend = 0.0075) and 0.91 (95% CI: 0.85, 0.97;P-trend = 0.0051), respectively]. An inverse association for total flavonoid intake was observed with a similar magnitude. CONCLUSION: In this large prospective cohort of French middle-aged women, participants with greater flavonol, anthocyanin, and polymeric flavonoid intakes and greater total flavonoid intake were less likely to develop hypertension. PMID- 26936334 TI - All-optical control of three-photon spectra and time asymmetry in a strongly coupled cavity polariton system. AB - Manipulating the nature of photons emission is one of the basic tasks in quantum optics and photonics. The ever growing list of quantum applications requires a robust means of controlling the strongly coupled coherent interaction of photons and matter. Here, we investigate three-photon transmission spectra in a strongly coupled cavity polariton system and show that the correlation functions and transmitted photon stream can be optically manipulated. The dynamics of single photons and photon pairs at the polariton resonances can be changed by light from a single external coupling laser. At the "dark-state polariton," three-photon transmission is a perfectly coherent field in contrast to the strong photon bunching behavior of a typical cavity quantum electrodynamics system. When the detuned probe light is tuned to the "bright polariton," the light exhibits a dramatic photon antibunching effect. Remarkably, the Fano-resonant asymmetric three-photon transmission caused by the interference between the dressed states leads to a new quantum feature that is strongly nonclassical (the third-order correlation function g((3))(0, 0) ? 1) and has a wide and tunable bandwidth. The dependence of the intrinsic third-order correlation and time symmetry of the photon stream on the controlled parameters is also examined. Strongly nonclassical, all-optically controllable multi-photon dynamics are very important for future quantum devices and metrology. PMID- 26936333 TI - Effects of a low-glycemic index diet during pregnancy on offspring growth, body composition, and vascular health: a pilot randomized controlled trial. AB - BACKGROUND: Elevated maternal blood glucose concentrations may contribute to macrosomia, adiposity, and poorer vascular health in the offspring. OBJECTIVE: The aim was to explore the effect of a low-glycemic index (low-GI) diet during pregnancy on offspring growth, adiposity, and arterial wall thickness during infancy. DESIGN: This was a longitudinal follow-up study in a self-selected subgroup of mother-infant pairs (n= 59) participating in a larger randomized trial comparing the effects on perinatal outcomes of a low-GI diet and a conventional high-fiber (HF) diet during pregnancy. Infant anthropometric measurements were taken every month for 6 mo and then at 9 and 12 mo of age. Adiposity was assessed at birth and at 3 mo by air-displacement plethysmography by using the Pea Pod system (Cosmed) and at 6 and 12 mo by bioimpedance analysis (Bodystat). Aortic intima-media thickness was assessed at 12 mo by high resolution ultrasound (Philips). RESULTS: Maternal dietary GI was lower in the low-GI group than in the HF group (51 +/- 1 compared with 57 +/- 1;P< 0.001). No differences in neonatal outcomes were observed in the main trial. In the self selected subsample, birth weight and length z scores were lower in the low-GI group than in the HF group (birth weight z score: 0.2 +/- 0.2 compared with 0.7 +/- 0.2, respectively;P= 0.04; birth length z score: 0.3 +/- 0.2 compared with 0.9 +/- 0.2, respectively;P= 0.04), but adiposity from birth to 12 mo of age and growth trajectories from 1 to 12 mo of age were similar. Aortic intima-media thickness was lower in the low-GI group than in the HF group (657 +/-12 compared with 696 +/- 12 MUm, respectively;P= 0.02), which was partly mediated by differences in birth weight. CONCLUSION: In women at risk of gestational diabetes mellitus, a low-GI diet influences offspring birth weight, birth length, and arterial wall thickness in early childhood, but not adiposity or growth trajectory during the first year of life. This trial was registered at anzctr.org.au as ACTRN12610000681055. PMID- 26936335 TI - Habitat-based cetacean density models for the U.S. Atlantic and Gulf of Mexico. AB - Cetaceans are protected worldwide but vulnerable to incidental harm from an expanding array of human activities at sea. Managing potential hazards to these highly-mobile populations increasingly requires a detailed understanding of their seasonal distributions and habitats. Pursuant to the urgent need for this knowledge for the U.S. Atlantic and Gulf of Mexico, we integrated 23 years of aerial and shipboard cetacean surveys, linked them to environmental covariates obtained from remote sensing and ocean models, and built habitat-based density models for 26 species and 3 multi-species guilds using distance sampling methodology. In the Atlantic, for 11 well-known species, model predictions resembled seasonal movement patterns previously suggested in the literature. For these we produced monthly mean density maps. For lesser-known taxa, and in the Gulf of Mexico, where seasonal movements were less well described, we produced year-round mean density maps. The results revealed high regional differences in small delphinoid densities, confirmed the importance of the continental slope to large delphinoids and of canyons and seamounts to beaked and sperm whales, and quantified seasonal shifts in the densities of migratory baleen whales. The density maps, freely available online, are the first for these regions to be published in the peer-reviewed literature. PMID- 26936336 TI - Development of a tail vein transection bleeding model in fully anaesthetized haemophilia A mice - characterization of two novel FVIII molecules. AB - INTRODUCTION: The tail tip bleeding model and the tail vein transection survival model in mice are important tools for assessment of in vivo effect in haemostasis research. While the tail vein transection model exhibits the best sensitivity to pharmacological intervention it uses death or near-death as endpoint which is fully avoided in the tail tip bleeding model. AIM: The aim of this study was to develop a new tail bleeding model maintaining the sensitivity of the previous survival model but avoiding death/near-death as endpoint. METHODS: Combining the two existing tail bleeding models we developed an optimized version of the survival model with full anaesthetic coverage and short duration of experiments. Using this model, we characterized the effect of turoctocog alfa, a B-domain truncated FVIII molecule (NovoEight((r)) ), as well as the prolonged half-life version of the same molecule (turoctocog alfa pegol, N8-GP). RESULTS: Data showed that the model was sensitive to clinically relevant doses of both turoctocog alfa as well as N8-GP when dosed for 'on demand' treatment. The model also correctly identified a longer duration of effect for N8-GP compared with turoctocog alfa. Moreover, the model allowed the use of mice of both genders and was reproducible over time. CONCLUSION: The optimized tail vein transection bleeding model is sensitive to standard as well as half-life prolonged FVIII molecules and should be a valuable alternative to both the tail tip bleeding model, enhancing sensitivity to pharmacological intervention, as well as to the previously used tail vein transection survival model, avoiding death or near-death as endpoint. PMID- 26936337 TI - Telehealth exercise-based cardiac rehabilitation: a systematic review and meta analysis. AB - OBJECTIVE: Despite proven effectiveness, participation in traditional supervised exercise-based cardiac rehabilitation (exCR) remains low. Telehealth interventions that use information and communication technologies to enable remote exCR programme delivery can overcome common access barriers while preserving clinical supervision and individualised exercise prescription. This meta-analysis aimed to determine the benefits of telehealth exCR on exercise capacity and other modifiable cardiovascular risk factors compared with traditional exCR and usual care, among patients with coronary heart disease (CHD). METHODS: CINAHL, The Cochrane Library, Embase, MEDLINE, PubMed and PsycINFO were searched from inception through 31 May 2015 for randomised controlled trials comparing telehealth exCR with centre-based exCR or usual care among patients with CHD. Outcomes included maximal aerobic exercise capacity, modifiable cardiovascular risk factors and exercise adherence. RESULTS: 11 trials (n=1189) met eligibility criteria and were included in the review. Physical activity level was higher following telehealth exCR than after usual care. Compared with centre-based exCR, telehealth exCR was more effective for enhancing physical activity level, exercise adherence, diastolic blood pressure and low density lipoprotein cholesterol. Telehealth and centre-based exCR were comparably effective for improving maximal aerobic exercise capacity and other modifiable cardiovascular risk factors. CONCLUSIONS: Telehealth exCR appears to be at least as effective as centre-based exCR for improving modifiable cardiovascular risk factors and functional capacity, and could enhance exCR utilisation by providing additional options for patients who cannot attend centre-based exCR. Telehealth exCR must now capitalise on technological advances to provide more comprehensive, responsive and interactive interventions. PMID- 26936338 TI - Surgical ablation of atrial fibrillation in patients with a giant left atrium undergoing mitral valve surgery. AB - OBJECTIVE: As the efficacy of surgical ablation for atrial fibrillation (AF) is reported to be suboptimal for patients with a giant left atrium (LA), its routine use on this population has remained controversial. We sought to evaluate the clinical outcomes of patients with a giant LA undergoing mitral valve (MV) surgery with/without the maze procedure. METHODS: We identified 759 patients with a giant LA (>60 mm) and AF undergoing MV surgery from 1999 through 2012. Of these, 400 underwent MV surgery with the maze procedure (maze group), and the remainder (n=359) underwent MV surgery only (no-maze group). To reduce the impact of selection bias, propensity score analyses were performed based on 25 baseline covariates. RESULTS: Early death occurred in five (1.3%) and nine (2.5%) patients in the maze and the no-maze group, respectively (p=0.28). Freedom from AF at 5 years was 68.9% in the maze group and 9.6% in the no-maze group (p<0.001). After adjustment, the maze group showed a significantly lower risk of death (HR, 0.65; 95% CI 0.44 to 0.98; p=0.038), thromboembolic events (HR, 0.23; 95% CI 0.09 to 0.58; p=0.002) and composite adverse outcomes (death, congestive heart failure and valve-related complications; HR, 0.55; 95% CI 0.42 to 0.71; p<0.001) than the no-maze group. In subgroup analyses, MV surgery with the maze procedure resulted in higher survival and event-free survival in most risk subgroups than without the maze procedure. CONCLUSIONS: The concomitant maze procedure improved postoperative rhythm status, clinical outcomes and cardiac functions in patients with a giant LA undergoing MV surgery. This study indicates that the patients with a giant LA undergoing MV surgery may benefit from an addition of the maze procedure. PMID- 26936339 TI - Chocolate consumption and risk of myocardial infarction: a prospective study and meta-analysis. AB - OBJECTIVE: To examine whether chocolate consumption is associated with a reduced risk of ischaemic heart disease, we used data from a prospective study of Swedish adults and we performed a meta-analysis of available prospective data. METHODS AND RESULTS: The Swedish prospective study included 67 640 women and men from the Cohort of Swedish Men and the Swedish Mammography Cohort who had completed a food frequency questionnaire and were free of cardiovascular disease at baseline. Myocardial infarction (MI) cases were ascertained through linkage with the Swedish National Patient and Cause of Death Registers. PubMed and EMBASE databases were searched from inception until 4 February 2016 to identify prospective studies on chocolate consumption and risk of ischaemic heart disease. RESULTS: The results from eligible studies were combined using a random-effects model. During follow-up (1998-2010), 4417 MI cases were ascertained in the Swedish study. Chocolate consumption was inversely associated with MI risk. Compared with non-consumers, the multivariable relative risk for those who consumed >=3-4 servings/week of chocolate was 0.87 (95% CI 0.77 to 0.98; p for trend =0.04). Five prospective studies on chocolate consumption and ischaemic heart disease were identified. Together with the Swedish study, the meta-analysis included six studies with a total of 6851 ischaemic heart disease cases. The overall relative risk for the highest versus lowest category of chocolate consumption was 0.90 (95% CI 0.82 to 0.97), with little heterogeneity among studies (I(2)=24.3%). CONCLUSIONS: Chocolate consumption is associated with lower risk of MI and ischaemic heart disease. PMID- 26936340 TI - First-degree atrioventricular block: risk marker or innocent finding? PMID- 26936341 TI - Antiproliferative activity of a series of 5-(1H-1,2,3-triazolyl) methyl- and 5 acetamidomethyl-oxazolidinone derivatives. AB - In the face of increasing resistance to the existing antibiotics, oxazolidinones (exemplified by linezolid) have been developed as promising antibacterial agents, but may have other useful actions. In the present study, a series of 5-(1H-1,2,3 triazoly) l-methyl-, 5-acetamidomethyl-morpholino and N-substituted-piperazino oxazolidinone derivatives were investigated to determine whether they are active against eukaryotic cells. An MTT assay, validated by cell counting, was used to assess the effect of nine oxazolidinone derivatives (concentrations 100 nM-10 uM) on the proliferation of MCF7 human breast cancer cells. The three most active compounds were then tested on MDA231 breast cancer cells. Cytotoxicity of the selected derivatives was determined by assessing the extent of apoptosis by flow cytometry. The antimetastatic potential of these compounds was assessed on MDA231 cells using wound healing and agarose invasion assays. The 5-triazolylmethyl piperazino-oxazolidinone derivatives containing 4-N-(2-chlorocinnamoyl), 4-N-(4 nitrobenzoyl) and 4-N-methylsulfonyl moieties exhibited the most potent cytostatic activity against cancer, inhibiting proliferation by up to 70%, in the same order as their reported antibacterial activity against Staphylococcus aureus, but at higher concentrations. Unexpectedly, several derivatives stimulated proliferation at 100 nM, well below their antibacterial minimum inhibitory concentrations. Certain compounds also retarded the motility and invasion of MDA231 cells. Three of the tested derivatives had no effect on the eukaryotic cell lines, demonstrating their preferential activity against bacteria. Two compounds actually stimulated eukaryotic cell proliferation. The remaining three exhibited potent cytostatic activity against and cancer cells, displaying differences in response at low and high concentrations, which may suggest multiple targets on eukaryotic cells. These latter compounds may be useful as anticancer agents. PMID- 26936342 TI - New immunoassays for total, IgA and IgM antibodies against hepatitis E virus: Prevalence in Italian blood donors and patients with chronic liver or kidney diseases. AB - BACKGROUND: Hepatitis E virus (HEV) is a zoonotic agent that causes acute hepatitis in humans with sporadic infections and outbreaks in developing countries worldwide. The global spread of HEV remains underestimated because of subclinical infections and lack of sensitive diagnostic assays. AIMS: To study the prevalence of HEV antibodies (anti-HEV) in sera of blood-donors and patients with chronic-liver-disease and chronic-renal-disease, using newly developed anti HEV assays. METHODS: 396 sera from 199 blood-donors, 109 chronic-liver-disease patients and 88 chronic-renal-disease patients and three standard reference serum panels were tested in parallel with a sensitive reference anti-HEV assay and newly developed assays for IgA, IgM and total anti-HEV based on HEV-like particles produced by recombinant baculo-viruses. RESULTS: Overall, total anti HEV was detected in 12.9% (7.0% blood-donors, 9.2% and 30.7% chronic-liver disease patients and chronic-renal-disease patients, respectively). We observed a higher anti-HEV prevalence in older subjects and in chronic-renal-disease patients in relation with degree on immune-depression (p<0.001). Results from reference serum panels showed an optimal and slightly better performance of the new assay over the commercially available assay. CONCLUSIONS: Newly developed anti-HEV assays using recombinant HEV-like-particles showed optimal diagnostic performances assessing that HEV-infection is endemic in Italy with seroprevalence ranging from 7% to 30% in blood donors and immune-compromised hosts, respectively. PMID- 26936344 TI - Comparative Analysis of Extracellular Polymeric Substances from Cryptococcus gattii VGIIa Strain Isolated for the First Time in Japan. AB - Cryptococcus gattii and C. neoformans are pathogenic yeasts that cause meningoencephalitis. C. gattii has four molecular types: VGI, VGII, VGIII, and VGIV. Furthermore, three genotypes have been reported for VGII, and a high pathogenicity of the VGIIa genotype has been proposed. The VGIIa strain has been isolated from a patient in Japan, but little is known about the characteristics of the polysaccharides in this strain. In this study we examined the induction of interleukin-8(IL-8)transcriptional activation and compared the nuclear magnetic resonance(NMR)spectra of extracellular polymeric substances(EPSs), mainly polysaccharides, from the VGIIa, VGIIb, and VGIIc genotypes. The induction of IL 8 by C. gattii EPSs was weaker than that by C. neoformans EPSs. The anomeric proton signals in the NMR spectra of EPSs obtained from VGII isolates were similar, and the polysaccharides were mainly mannose, xylose, galactose, and glucuronic acid. These results suggest that the extracellular polysaccharides from the VGIIa strain isolated in Japan are almost the same as those from other VGII strains. PMID- 26936345 TI - The Use of Adhesive Tapes to Transfer Skin-scrapings for Sequential Laboratory Diagnosis of Dermatophytosis. AB - BACKGROUND: Dermatophytosis usually causes a skin problem, which requires both clinical findings and laboratory investigations for diagnosis. Whereas, fungal culture is considered as the gold standard procedure, it is more difficult to perform compared to potassium hydroxide(KOH)examination. OBJECTIVE: To evaluate the efficacy of KOH and fungal culture examinations from skin-scraping specimens, which were kept in transparent adhesive tapes at different time intervals. METHODS: Skin-scraping specimens were collected from clinically suspected cases by conventional technique using scalpel blades and kept using transparent adhesive tapes. KOH(10%)preparation and fungal cultures were then performed by highly experienced technicians at different time intervals: day 0(the day of specimen collection, which was set as the standard reference point), day 3 or 4, day 7, day 14, and day 28. Thereafter, the yield for detection of fungal elements by KOH examination and positive fungal cultures from specimens stored in adhesive tape was determined at different time intervals and compared to the results from the standard reference point. RESULTS: The sensitivity of KOH exami-nations from 162 patients at different time intervals showed no significant difference when compared to the standard reference point at day 0. In contrast, the sensitivity of fungal culture progressively decreased as the storage period was prolonged. CONCLUSIONS: KOH examination of skin-scrapings from the adhesive tape storage technique yield good results even when specimens have been kept up to one month. On the other hand, the sensitivity of fungal cultures gradually declines as storage time is extended. PMID- 26936347 TI - [Antifungal Activity of Luliconazole Nail Solution on in vitro and in vivo Onychomycosis Model]. AB - We evaluated luliconazole nail solution, originally generated formulation, for the topical treatment of onychomycosis by two infection models. First, a suspension of Trichophyton mentagrophytes was dropped onto the ventral layer of human nail plate and these nails were set in Franz diffusion cells. After 9-day culture, luliconazole nail solutions (1, 3, and 5%) were applied to the dorsal surface of the nails once a day for 7 days. After application, fungal viability was assessed by measuring the ATP contents of the samples. The dose-dependent efficacy was confirmed, with 3% and 5% luliconazole nail solutions producing significantly lower ATP levels at 7-day treatment. When 3% and 5% luliconazole nail solutions were evaluated in a rabbit model of onychomycosis, both concentrations completely inhibited the recovery of fungi on culture after 4-week treatment. We therefore think these results indicate that 5% luliconazole nail solution is sufficiently potent for treatment of onychomycosis. PMID- 26936346 TI - [In vitro Antifungal Activity of Luliconazole against Trichophyton spp]. AB - The minimum inhibitory concentration (MIC) and the minimum fungicidal concentration (MFC) of luliconazole against Trichophyton rubrum (14 strains) and Trichophyton mentagrophytes (14 strains), which are the most common cause of tinea, were compared with those of 6 topical antifungal drugs of lanoconazole, bifonazole, efinaconazole, liranaftate, naftifine and terbinafine. Luliconazole showed the most potent antifungal activity (MIC90 =0.00098 MUg/ml and MFC90 =0.0078 MUg/ml) among the compounds tested against the two species. Efinaconazole and bifonazole, the drug of azole-class, showed a large MFC/MIC ratio. On the other hand, these ratios of luliconazole and lanoconazole were as small as those of liranaftate, naftifine and terbinafine which are thought to possess fungicidal mechanism. These results suggest that luliconazole possesses fungicidal activity against both species of Trichophyton. In this study, we found that luliconazole had the most potent antifungal activity among the major topical antimycotics used in Japan and the US. Luliconazole would be the best-in-class drug for dermatophytosis in clinics. PMID- 26936348 TI - [Distribution of Luliconazole in Nail Plate by In Vitro Permeation and Efficacy by Zone of Inhibition Test after Treatment of Luliconazole Nail Solution]. AB - To clarify the character of luliconazole nail solution we have developed, we investigated luliconazole distribution and antifungal activity in nail plate. An in vitro permeation study which measured luliconazole concentration of sliced nail in the transverse direction after treatment of luliconazole nail solution was conducted to investigate for concentration dependency and the influences of nail thickness and treatment duration. When 0.2, 1, 3, 5, and 7.5% luliconazole nail solutions were used, luliconazole was detected in the all the layers of nail and there was a concentration gradient from the dorsal side to deep nail layers. The luliconazole concentration was almost same after 14-day treatment with 5% luliconazole nail solution when using nails of different thicknesses. And we confirmed that concentration of luliconazole into the nail was increased depending on the treatment duration. In zone of inhibition test after 14-day treatment, 5% luliconazole nail solution showed statistically high formation rate of zones of inhibition compared to 8% ciclopirox nail lacquer. Above all, these data suggested that 5% luliconazole nail solution has the potential to show high therapeutic effect for onychomycosis. PMID- 26936349 TI - [Mechanism of Cryptococcus Meningoencephalitis]. AB - Cryptococcus neoformans and Cryptococcus gattii are fungal pathogens that cause diseases in humans. Cryptococcal species mainly enter the body by inhalation and in most cases are eliminated by host defense mechanisms. Some cases, however, progress to pneumonia and subsequent dissemination of the infection to the central nervous system (CNS), leading to meningoencephalitis. Cryptococcus can cross the blood-brain barrier transcellularly, paracellularly and through infected phagocytes (the Trojan horse mechanism). The reason for the tropism of Cryptococcus to the CNS could be partially explained by the abundance of inositol in the brain, which causes the hyaluronic acid in fungal cells to bind to host CD44 receptors. There are differences in the clinical characteristics of C. neoformans and C. gattii. HIV infection is the most common risk factor for cryptococcosis due to C. neoformans, whereas C. gattii infection with CNS involvement is frequently found in otherwise healthy individuals exposed to plant propagules found in tropical and subtropical regions. As the virulence traits of C. neoformans contributing to CNS disease, high macrophage uptake and laccase activity are associated with the fungal burden and the rate of clearance of the infection from the brain. Recent reports suggested that the C. gattii VGII strain suppresses host immune responses in the lung and causes more lung infections than CNS diseases. Furthermore, the anti-GM-CSF autoantibodies are a risk factor for CNS infection by the C. gattii VGI strain. To understand the mechanism by which Cryptococcus causes CNS disease, it is important to consider the specific characteristics of the species and the molecular types. PMID- 26936350 TI - [Deep-seated mycosis]. PMID- 26936351 TI - [Term 9]. PMID- 26936352 TI - [Affinity of Luliconazole to Keratin Prepared from Healthy Human Nailand Porcine Hoof]. AB - Luliconazole (LLCZ), an imidazole derivative with a broad spectrum of potent antifungal activity especially for T. rubrum and T. mentagrophytes, is under development as a new drug for treatment of tinea unguium. It is well known that curative effect of an antifungal agent in dermatophytosis is affected by the pharmacokinetics of an agent at the infection loci as well as its antifungal activity, but there is no report about the affinity of LLCZ to nail keratin. We studied LLCZ affinity to keratin powder prepared from healthy human nail and porcine hoof. The LLCZ adsorbed to keratin preparations was washed with phosphate buffer, and its concentration in the buffer supernatant was measured by HPLC. Antifungal titer of the supernatant was also biologically confirmed by disk diffusion assay. Adsorption rate of LLCZ was 80% or more, and LLCZ was gradually liberated into washing buffer. Cumulative liberation rate in 10 times repeated washing against initially adsorbed drug amount was 47.4% for keratin from human nail and was either 52.5% or 50.8% (depending on the LLCZ concentration) for keratin from porcine hoof. The supernatant showed antifungal potential to T. rubrum. These results indicate that LLCZ applied to the nail surface is fully adsorbed to nail keratin and gradually liberated from it. The nail keratin could function as drug reservoir to supply biologically active LLCZ to the nail tissue region of infection loci. The LLCZ delivered to the loci would exert its antifungal potential on tinea unguium. This study also suggests the versatility of porcine hoof powder as an alternative to human nail keratin preparation for non-clinical study. PMID- 26936343 TI - Impact of age- and gender-specific cut-off values for the fecal immunochemical test for hemoglobin in colorectal cancer screening. AB - BACKGROUND: There is no information on the impact of age and gender on the diagnostic yield of different positivity thresholds for the fecal immunochemical test for hemoglobin (FIT). OBJECTIVES: To evaluate the performance of this test at distinct positivity cut-offs in a population-based colorectal cancer (CRC) screening program. METHODS: CRC detection rate (DR), and analysis of resources were evaluated retrospectively, at different cut-offs of FIT (20, 25, 30, 35 and 40MUg Hb/g) respect to a reference value (15MUg Hb/g), according to age and gender, in a screening population of 10,611 participants of the ColonPrev study (Quintero. NEJM 2013). RESULTS: At the reference cut-off value, 36 CRC and 252 advanced adenomas (AA) were diagnosed. Increasing the cut-off in women <=60 years decreases colonoscopies performed by 44.5% without modifying the CRC (DR). Same CRC DR was observed in men <=60 years and women >60 years increasing cut-off at 25-30MUg Hb/g. In men >60 years, all increases in the cut-off affected the CRC DR, especially when the cut-off was increased from 35 to 40MUg Hb/g (CRC miss rate 25%). CONCLUSIONS: To improve the performance of FIT in CRC screening programs, FIT cut-offs could be individualized by age and gender. PMID- 26936353 TI - Association of downregulated HDAC 2 with the impaired mitochondrial function and cytokine secretion in the monocytes/macrophages from gestational diabetes mellitus patients. AB - Gestational diabetes mellitus (GDM) is associated with an increased risk of type 2 diabetes (T2DM) and cardiovascular diseases in later life, yet with underlying mechanisms unclear. The present study was to explore the association of upregulated histone deacetylase 2 (HDAC 2) with the impaired mitochondrial function and the cytokine secretion in the monocytes/macrophages from GDM patients. In this study, we examined the mitochondrial function, proinflamatory cytokine secretion and the HDAC 2 level in the serum or in the monocytes/macrophages from GDM patients, investigated the influence by HDAC 2 inhibitor, AR-42 (N-hydroxy-4-[[(2S)-3-methyl-2-phenylbutanoyl]amino]benzamide), on the mitochondrial function and cytokine secretion in the isolated GDM monocytes/macrophages. Results demonstrated an increased mitochondria size, mitochondrial superoxide and reactive oxygen species (ROS) production, and an undermined mitochondria membrane potential (MMP) in the GDM monocytes/macrophages. And the serum levels of interleukin (IL)-1beta, tumor necrosis factor (TNF)-alpha and IL-6 were also markedly higher in the GDM pregnancies, while the expression and activity of HDAC 2 was downregulated. Moreover, AR-42-mediated HDAC 2 inhibition in vitro contributed to the impaired mitochondrial function and the proinflamatory cytokine secretion. In conclusion, this study suggests an association of the impaired mitochondrial function and the promoted proinflamatory cytokine secretion with the reduced HDAC 2 activity in GDM. These findings may present HDAC 2 as a target for GDM treatment. PMID- 26936355 TI - Introduction to the Special Section on Implementing Feedback from Outcome Measures in Child and Adult Mental Health Services. PMID- 26936354 TI - MetICA: independent component analysis for high-resolution mass-spectrometry based non-targeted metabolomics. AB - BACKGROUND: Interpreting non-targeted metabolomics data remains a challenging task. Signals from non-targeted metabolomics studies stem from a combination of biological causes, complex interactions between them and experimental bias/noise. The resulting data matrix usually contain huge number of variables and only few samples, and classical techniques using nonlinear mapping could result in computational complexity and overfitting. Independent Component Analysis (ICA) as a linear method could potentially bring more meaningful results than Principal Component Analysis (PCA). However, a major problem with most ICA algorithms is the output variations between different runs and the result of a single ICA run should be interpreted with reserve. RESULTS: ICA was applied to simulated and experimental mass spectrometry (MS)-based non-targeted metabolomics data, under the hypothesis that underlying sources are mutually independent. Inspired from the Icasso algorithm, a new ICA method, MetICA was developed to handle the instability of ICA on complex datasets. Like the original Icasso algorithm, MetICA evaluated the algorithmic and statistical reliability of ICA runs. In addition, MetICA suggests two ways to select the optimal number of model components and gives an order of interpretation for the components obtained. CONCLUSIONS: Correlating the components obtained with prior biological knowledge allows understanding how non-targeted metabolomics data reflect biological nature and technical phenomena. We could also extract mass signals related to this information. This novel approach provides meaningful components due to their independent nature. Furthermore, it provides an innovative concept on which to base model selection: that of optimizing the number of reliable components instead of trying to fit the data. The current version of MetICA is available at https://github.com/daniellyz/MetICA. PMID- 26936356 TI - Impact of Middle East Respiratory Syndrome coronavirus (MERS-CoV) on pregnancy and perinatal outcome. AB - BACKGROUND: Middle East Respiratory Syndrome coronavirus (MERS-CoV) is a viral respiratory disease. Most people infected with MERS-CoV develop severe acute respiratory illness. It was first reported in Saudi Arabia in 2012 and has since spread to several other countries. We report the clinical course of MERS-CoV infection in a pregnant woman who acquired the infection during the last trimester. CASE PRESENTATION: The patient is a 33-year-old female working as a critical care nurse. She was 32 weeks pregnant when she presented with respiratory symptoms after direct contact with a MERS-COV patient. Although the patient was in respiratory failure, necessitated mechanical ventilation, and intensive care (ICU) admission, a healthy infant was delivered. The mother recovered. To the best of our knowledge, this is the first reported case of a laboratory-confirmed Middle East Respiratory Syndrome Coronavirus in a pregnant woman. CONCLUSIONS: Middle East Respiratory Syndrome coronavirus (MERS-CoV) known to cause severe acute respiratory illness associated with a high risk of mortality Various factors may have contributed to the successful outcome of this patient such as young age, presentation during the last stages of pregnancy, and possible differences in immune response. PMID- 26936357 TI - Childhood Maltreatment and Headache Disorders. AB - Childhood maltreatment is substantiated in 12 % of children, but nearly 50 % adults recall having been neglected or abused as children. Maltreatment, especially emotional abuse, is associated with migraine. Dysregulation of the HPA axis, autonomic, immune, and metabolic systems appears to be a consequence of maltreatment, and is also reported in migraine. Areas of the brain structurally and functionally affected by childhood abuse and by migraine are also similar, and include the limbic system structures, which connect to pain regions in the brainstem. Putative mechanisms by which early life stress increases the likelihood of developing migraine include gene x environment interactions, in addition to epigenetic modifications via DNA methylation. These modifications are stable and may be transferred across generations, but they may also be reversed by some medications commonly used in migraine, including valproic acid and topiramate. PMID- 26936358 TI - Activation of satellite cells and the regeneration of human skeletal muscle are expedited by ingestion of nonsteroidal anti-inflammatory medication. AB - With this study we investigated the role of nonsteroidal anti-inflammatory drugs (NSAIDs) in human skeletal muscle regeneration. Young men ingested NSAID [1200 mg/d ibuprofen (IBU)] or placebo (PLA) daily for 2 wk before and 4 wk after an electrical stimulation-induced injury to the leg extensor muscles of one leg. Muscle biopsies were collected from the vastus lateralis muscles before and after stimulation (2.5 h and 2, 7, and 30 d) and were assessed for satellite cells and regeneration by immunohistochemistry and real-time RT-PCR, and we also measured telomere length. After injury, and compared with PLA, IBU was found to augment the proportion of ActiveNotch1(+) satellite cells at 2 d [IBU, 29 +/- 3% vs. PLA, 19 +/- 2% (means +/- sem)], satellite cell content at 7 d [IBU, 0.16 +/- 0.01 vs. PLA, 0.12 +/- 0.01 (Pax7(+) cells/fiber)], and to expedite muscle repair at 30 d. The PLA group displayed a greater proportion of embryonic myosin(+) fibers and a residual ~2-fold increase in mRNA levels of matrix proteins (all P < 0.05). Endomysial collagen was also elevated with PLA at 30 d. Minimum telomere length shortening was not observed. In conclusion, ingestion of NSAID has a potentiating effect on Notch activation of satellite cells and muscle remodeling during large scale regeneration of injured human skeletal muscle.-Mackey, A. L., Rasmussen, L. K., Kadi, F., Schjerling, P., Helmark, I. C., Ponsot, E., Aagaard, P., Durigan, J. L. Q., Kjaer, M. Activation of satellite cells and the regeneration of human skeletal muscle are expedited by ingestion of nonsteroidal anti-inflammatory medication. PMID- 26936360 TI - CD13/aminopeptidase N is a negative regulator of mast cell activation. AB - Antigen-induced mast cell (MC) activation via cross-linking of IgE-bound high affinity receptors for IgE (FcepsilonRI) underlies type I allergy and anaphylactic shock. Comprehensive knowledge of FcepsilonRI regulation is thus required. We have identified a functional interaction between FcepsilonRI and CD13 in murine MCs. Antigen-triggered activation of IgE-loaded FcepsilonRI results in cocapping and cointernalization of CD13 and equivalent internalization rates of up to 40%. Cointernalization is not unspecific, because ligand-driven KIT internalization is not accompanied by CD13 internalization. Moreover, antibody-mediated cross-linking of CD13 causes IL-6 production in an FcepsilonRI dependent manner. These data are indicative of a functional interaction between FcepsilonRI and CD13 on MCs. To determine the role of this interaction, CD13 deficient bone marrow-derived MCs (BMMCs) were analyzed. Intriguingly, antigen stimulation of CD13-deficient BMMCs results in significantly increased degranulation and proinflammatory cytokine production compared to wild-type cells. Furthermore, in a low-dose model of passive systemic anaphylaxis, antigen dependent decrease in body temperature, reflecting the anaphylactic reaction, is substantially enhanced by the CD13 inhibitor bestatin (-5.9 +/- 0.6 degrees C) and by CD13 deficiency (-8.8 +/- 0.6 degrees C) in contrast to controls (-1.2 +/- 1.97 degrees C). Importantly, bestatin does not aggravate anaphylaxis in CD13 deficient mice. Thus, we have identified CD13 as a novel negative regulator of MC activation in vitro and in vivo-Zotz, J. S., Wolbing, F., Lassnig, C., Kauffmann, M., Schulte, U., Kolb, A., Whitelaw, B., Muller, M., Biedermann, T., Huber, M. CD13/aminopeptidase N is a negative regulator of mast cell activation. PMID- 26936359 TI - A hemidesmosomal protein regulates actin dynamics and traction forces in motile keratinocytes. AB - During wound healing of the skin, keratinocytes disassemble hemidesmosomes and reorganize their actin cytoskeletons in order to exert traction forces on and move directionally over the dermis. Nonetheless, the transmembrane hemidesmosome component collagen XVII (ColXVII) is found in actin-rich lamella, situated behind the lamellipodium. A set of actin bundles, along which ColXVII colocalizes with actinin4, is present at each lamella. Knockdown of either ColXVII or actinin4 not only inhibits directed migration of keratinocytes but also relieves constraints on actin bundle retrograde movement at the site of lamella, such that actin bundle movement is enhanced more than 5-fold. Moreover, whereas control keratinocytes move in a stepwise fashion over a substrate by generating alternating traction forces, of up to 1.4 kPa, at each flank of the lamellipodium, ColXVII knockdown keratinocytes fail to do so. In summary, our data indicate that ColXVII-actinin4 complexes at the lamella of a moving keratinocyte regulate actin dynamics, thereby determining the direction of cell movement.-Hiroyasu, S., Colburn, Z. T., Jones, J. C. R. A hemidesmosomal protein regulates actin dynamics and traction forces in motile keratinocytes. PMID- 26936361 TI - Tests of ecogeographical relationships in a non-native species: what rules avian morphology? AB - The capacity of non-native species to undergo rapid adaptive change provides opportunities to research contemporary evolution through natural experiments. This capacity is particularly true when considering ecogeographical rules, to which non-native species have been shown to conform within relatively short periods of time. Ecogeographical rules explain predictable spatial patterns of morphology, physiology, life history and behaviour. We tested whether Australian populations of non-native starling, Sturnus vulgaris, introduced to the country approximately 150 years ago, exhibited predicted environmental clines in body size, appendage size and heart size (Bergmann's, Allen's and Hesse's rules, respectively). Adult starlings (n = 411) were collected from 28 localities from across eastern Australia from 2011 to 2012. Linear models were constructed to examine the relationships between morphology and local environment. Patterns of variation in body mass and bill surface area were consistent with Bergmann's and Allen's rules, respectively (small body size and larger bill size in warmer climates), with maximum summer temperature being a strongly weighted predictor of both variables. In the only intraspecific test of Hesse's rule in birds to date, we found no evidence to support the idea that relative heart size will be larger in individuals which live in colder climates. Our study does provide evidence that maximum temperature is a strong driver of morphological adaptation for starlings in Australia. The changes in morphology presented here demonstrate the potential for avian species to make rapid adaptive changes in relation to a changing climate to ameliorate the effects of heat stress. PMID- 26936362 TI - Interventions to increase the reporting of occupational diseases by physicians: a Cochrane systematic review. PMID- 26936363 TI - [Nystagmus. Clinical characteristics and therapeutic options]. AB - This article presents an overview of the pathophysiology of nystagmus and the differential diagnostics of congenital and acquired nystagmus. In addition, the principles of conservative, surgical and pharmacotherapy treatment options are described. The pathophysiological basis of nystagmus deepens the understanding of the etiology of the individual forms of nystagmus. The therapeutic approach to calming of nystagmus aims at an extension of the foveation time, which has the most significant impact on visual acuity. In congenital nystagmus this can be carried out by optimization of the retinal image, prisms or by bilateral surgical muscle repositioning to use the phenomenon of a null or neutral zone. In acquired nystagmus the off-label use of centrally acting medications can sometimes be helpful to calm the nystagmus and the associated oscillopsia. PMID- 26936364 TI - Alpha-stat, beach chair, cerebral autoregulation... But who is at risk? PMID- 26936365 TI - Postoperative awake paralysis in the intensive care unit after cardiac surgery due to residual neuromuscular blockade: a case report and prospective observational study. AB - PURPOSE: We report a case of awake paralysis due to residual neuromuscular blockade (NMB) in the intensive care unit (ICU) in a patient following fast-track cardiac surgery. As a result of this case, we performed a prospective quality assurance audit to investigate the incidence of residual paralysis in the ICU in a similar population of cardiac surgery patients. CLINICAL FEATURES AND AUDIT METHODS: A 73-yr-old woman (69 kg) underwent coronary artery bypass surgery under anesthesia induced with intravenous sufentanil 25 ug, midazolam 5 mg, ketamine 25 mg, and rocuronium 100 mg (followed by two additional 50-mg doses during surgery) and maintained with sevoflurane. Postoperatively in the ICU, the patient was initially sedated with propofol (50 mg.hr(-1)) but failed to awaken 90 min after its cessation. As train-of-four neurostimulation showed residual paralysis, she was re-sedated. Neostigmine 3 mg and glycopyrrolate 0.6 mg were administered, and she was extubated 30 min later. During this episode of residual paralysis, the patient was conscious and reported explicit memory of the events. She was discharged on day 7 without psychological distress related to her postoperative awake paralysis. We subsequently performed a prospective audit in 50 consecutive patients to determine the timing of NMB dosing and to quantify the incidence of residual paralysis after fast-track cardiac surgery. RESULTS: Of the 50 patients studied, 24 (48%) had received an NMB during the last hour of surgery and 33 (66%) had evidence of residual paralysis during the immediate postoperative period. CONCLUSION: Postoperative residual paralysis after fast-track cardiac surgery was common in our institution and likely contributed to the reported case of postoperative awake paralysis. We suggest that an NMB not be administered after intubation in fast-track patients. If given, however, it must be well communicated to the ICU team upon ICU admission. We further recommend routine assessment of neuromuscular function before sedation is weaned prior to extubation. PMID- 26936366 TI - Biological characterization of a new silicon based coating developed for dental implants. AB - Taking into account the influence of Si in osteoblast cell proliferation, a series of sol-gel derived silicon based coating was prepared by controlling the process parameters and varying the different Si-alkoxide precursors molar rate in order to obtain materials able to release Si compounds. For this purpose, methyltrimethoxysilane (MTMOS) and tetraethyl orthosilicate (TEOS) were hydrolysed together and the sol obtained was used to dip-coat the different substrates. The silicon release ability of the coatings was tested finding that it was dependent on the TEOS precursor content, reaching a Si amount value around ninefolds higher for coatings with TEOS than for the pure MTMOS material. To test the effect of this released Si, the in vitro performance of developed coatings was tested with human adipose mesenchymal stem cells finding a significantly higher proliferation and mineralization on the coating with the higher TEOS content. For in vivo evaluation of the biocompatibility, coated implants were placed in the tibia of the rabbit and a histological analysis was performed. The evaluation of parameters such as the bone marrow state, the presence of giant cells and the fibrous capsule proved the biocompatibility of the developed coatings. Furthermore, coated implants seemed to produce a qualitatively higher osteoblastic activity and a higher number of bone spicules than the control (uncoated commercial SLA titanium dental implant). PMID- 26936367 TI - Constructing bio-layer of heparin and type IV collagen on titanium surface for improving its endothelialization and blood compatibility. AB - The modification of cardiovascular stent surface for a better micro-environment has gradually changed to multi-molecule, multi-functional designation. In this study, heparin (Hep) and type IV collagen (IVCol) were used as the functional molecule to construct a bifunctional micro-environment of anticoagulation and promoting endothelialization on titanium (Ti). The surface characterization results (AFM, Alcian Blue 8GX Staining and fluorescence staining of IVCol) indicated that the bio-layer of Hep and IVCol were successfully fabricated on the Ti surface through electrostatic self-assembly. The APTT and platelet adhesion test demonstrated that the bionic layer possessed better blood compatibility compared with Ti surface. The adhesion, proliferation, migration and apoptosis tests of endothelial cells proved that the Hep/IVCol layer was able to enhance the endothelialization of the Ti surface. The in vivo animal implantation results manifested that the bionic surface could encourage new endothelialization. This work provides an important reference for the construction of multifunction micro environment on the cardiovascular scaffold surface. PMID- 26936368 TI - Determinants of infant and young child feeding practices in Rupandehi, Nepal. AB - BACKGROUND: Undernutrition is a major problem in Nepal and meeting the minimum dietary standard is essential for growth and development of young children. Continuous monitoring of such practices is important to inform policy and program formulation. This study aimed to assess complementary feeding practices, and associated factors in Western Nepal. METHODS: This was a cross-sectional study conducted in Rupandehi district of Western Nepal. Face-to-face interviews were conducted among 178 mothers of young children aged 6-23 months using a structured questionnaire and data on complementary feeding practices. These practices were reported as frequency distribution and the factors associated were ascertained using multiple logistic regression. RESULTS: Only 57% of mothers initiated complementary feeding at the age of 6 months. While the proportion of young children receiving minimum meal frequency was reasonably high (84 %), meal diversity (35%) and minimum acceptable diet (33%) remained low. Maternal education and having had their children's growth monitored were independently associated with receiving minimum acceptable diet. CONCLUSION: Few infants and young children received the recommended infant and young children feeding practices. Implementing health promotion programs that educate and enhance the skills of mothers should be a priority for future nutrition interventions. PMID- 26936370 TI - HIV and HCV prevalence and incarceration-related risks among injecting drug users in three West Bank governorates. AB - In the Middle East, the HIV epidemic among injecting drug users (IDUs) seems to be in an early phase, which increases the importance of prevention and systematic risk surveillance. To gain information about HIV and HCV infection rates among IDUs in the West Bank, a biobehavioral survey was conducted using time-location sampling in the Ramallah, Hebron, and Bethlehem governorates in 2013. The researchers recruited 288 Palestinian IDUs ages 16-64 (Mage = 39.2, SD = 11.11). While no HIV cases were found in the sample, 41% of participants tested positive for HCV. Imprisonment was common among participants (83%), so we explored the association of incarceration experience with HCV infection and HIV testing. In multivariate assessments, incarceration was shown to increase the odds of being infected with HCV and ever tested for HIV. HIV prevention should be strengthened in West Bank prisons and correctional facilities, and imprisonment for drug use re-examined. PMID- 26936369 TI - Express photolithographic DNA microarray synthesis with optimized chemistry and high-efficiency photolabile groups. AB - BACKGROUND: DNA microarrays are a core element of modern genomics research and medical diagnostics, allowing the simple and simultaneous determination of the relative abundances of hundreds of thousands to millions of genomic DNA or RNA sequences in a sample. Photolithographic in situ synthesis, using light projection from a digitally-controlled array of micromirrors, has been successful at both commercial and laboratory scales. The advantages of this synthesis method are its ability to reliably produce high-quality custom microarrays with a very high spatial density of DNA features using a compact device with few moving parts. The phosphoramidite chemistry used in photolithographic synthesis is similar to that used in conventional solid-phase synthesis of oligonucleotides, but some unique differences require an independent optimization of the synthesis chemistry to achieve fast and low-cost synthesis without compromising microarray quality. RESULTS: High microarray quality could be maintained while reducing coupling time to a few seconds using DCI activator. Five coupling activators were compared, which resulted in microarray hybridization signals following the order ETT > Activator 42 > DCI ? BTT ? pyridinium chloride, but only the use of DCI led to both high signal and highly uniform feature intensities. The photodeprotection time was also reduced to a few seconds by replacing the NPPOC photolabile group with the new thiophenyl-NPPOC group. Other chemical parameters, such as oxidation and washing steps were also optimized. CONCLUSIONS: Highly optimized and microarray-specific phosphoramidite chemistry, along with the use of the very photosensitive thiophenyl-NPPOC protecting group allow for the synthesis of high complexity DNA arrays using coupling times of 15 s and deprotection times of 9 s. The resulting overall cycle time (coupling to coupling) of about 50 s, results in a three-fold reduction in synthesis time. PMID- 26936371 TI - A correlational study between signature, writing abilities and decision-making capacity among people with initial cognitive impairment. AB - BACKGROUND: Some clinical conditions, including dementia, compromise cognitive functions involved in decision-making processes, with repercussions on the ability to subscribe a will. Because of the increasing number of aged people with cognitive impairment there is an acute and growing need for decision-making capacity evidence-based assessment. AIMS: Our study investigates the relationship between writing abilities and cognitive integrity to see if it is possible to make inferences on decision-making capacity through handwriting analysis. We also investigated the relationship between signature ability and cognitive integrity. METHODS: Thirty-six participants with diagnosis of MCI and 38 participants with diagnosis of initial dementia were recruited. For each subject we collected two samples of signature-an actual and a previous one-and an extract of spontaneous writing. Furthermore, we administered a neuropsychological battery to investigate cognitive functions involved in decision-making. RESULTS: We found significant correlations between spontaneous writing indexes and neuropsychological test results. Nonetheless, the index of signature deterioration does not correlate with the level of cognitive decline. DISCUSSION: Our results suggest that a careful analysis of spontaneous writing can be useful to make inferences on decision-making capacity, whereas great caution should be taken in attributing validity to handwritten signature of subjects with MCI or dementia. CONCLUSIONS: The analysis of spontaneous writing can be a reliable aid in cases of retrospective evaluation of cognitive integrity. On the other side, the ability to sign is not an index of cognitive integrity. PMID- 26936373 TI - Design and implementation of the Americas Hernia Society Quality Collaborative (AHSQC): improving value in hernia care. AB - PURPOSE: Wide variation in care and costs exists regarding the management of abdominal wall hernias, with unproven benefit for many therapies. This work establishes a specialty society-based solution to improve the quality and value of care delivered to hernia patients during routine clinical management on a national scale. METHODS: The Americas Hernia Society Quality Task Force was charged by the Americas Hernia Society leadership to develop an initiative that utilizes the concepts of continuous quality improvement (CQI). A disease-based registry was created to collect information for CQI incorporating real-time outcome reporting, patient reported outcomes, stakeholder engagement, and collaborative learning methods to form a comprehensive quality improvement effort. RESULTS: The Americas Hernia Society Quality Collaborative (AHSQC) was formed with the mission to provide health care professionals real-time information for maximizing value in hernia care. The initial disease areas selected for CQI were incisional and parastomal hernias with ten priorities encompassing the spectrum of care. A prospective registry was created with real time analytic feedback to surgeons. A data assurance process was implemented to ensure maximal data quality and completeness. Four collaborative meetings per year were established to meet the goals of the AHSQC. As of the fourth quarter 2014, the AHSQC includes nearly 2377 patients at 38 institutions with 82 participating surgeons. CONCLUSIONS: The AHSQC has been established as a quality improvement initiative utilizing concepts of CQI. This ongoing effort will continually refine its scope and goals based on stakeholder input to improve care delivered to hernia patients. PMID- 26936374 TI - GRK2 overexpression inhibits IGF1-induced proliferation and migration of human hepatocellular carcinoma cells by downregulating EGR1. AB - G protein-coupled receptor kinase 2 (GRK2) is a serine/threonine kinase that is involved in a variety of important signaling pathways and alternation of GRK2 protein level or activity causes diseases such as heart failure, rheumatoid arthritis, and obesity. However, the role and mechanism of GRK2 in hepatocellular carcinoma (HCC) progression is not fully investigated. In this study we found that GRK2 plays an inhibitory role in IGF1-induced HCC cell proliferation and migration. Overexpression of GRK2 causes a decrease in early growth response-1 (EGR1) expression, while knockdown of GRK2 leads to marked increase in EGR1 expression in the treatment of IGF1. Through co-immunoprecipitation and western blot assay, we confirmed that GRK2 can interact with insulin-like growth factor 1 receptor (IGF-1R) and inhibits IGF1-induced activation of IGF1R signaling pathway. Silencing EGR1 attenuates GRK2 overexpression-caused inhibition of cell proliferation, tumor colony number and migration activity, while overexpressing of EGR1 restores the anti-proliferative and migratory effect by GRK2 overexpression in HCCLM3 cells. Collectively, these results suggest that GRK2 may inhibit IGF1-induced HCC cell growth and migration through downregulation of EGR1 and indicate that enforced GRK2 may offer a potential therapeutic approach against HCC. PMID- 26936375 TI - Inorganic dendrimers: recent advances for catalysis, nanomaterials, and nanomedicine. AB - Dendrimers are hyperbranched polymers having a perfectly defined structure because they are synthesized step-by-step in an iterative fashion, and not by polymerization reactions. Some dendrimers are considered as inorganic, as they possess inorganic atoms at each branching point. Among numerous examples, two families of inorganic dendrimers have emerged as particularly promising: silicon containing dendrimers, particularly carbosilanes, and phosphorus-containing dendrimers, particularly phosphorhydrazones. This tutorial review will display the main properties of both families of dendrimers in the fields of catalysis, materials and biology/nanomedicine. Emphasis will be put on the most recent and promising examples. PMID- 26936372 TI - Abnormal phosphorylation of Tie2/Akt/eNOS signaling pathway and decreased number or function of circulating endothelial progenitor cells in prehypertensive premenopausal women with diabetes mellitus. AB - BACKGROUNDS: The number and activity of circulating endothelial progenitor cells (EPCs) in prehypertension is preserved in premenopausal women. However, whether this favorable effect still exists in prehypertensive premenopausal women with diabetes is not clear. METHODS: This study compared the number and functional activity of circulating EPCs in normotensive or prehypertensive premenopausal women without diabetes mellitus and normotensive or prehypertensive premenopausal women with diabetes mellitus, evaluated the vascular endothelial function in each groups, and investigated the possible underlying mechanism. RESULTS: We found that compared with normotensive premenopausal women, the number and function of circulating EPCs, as well as endothelial function evaluated by flow-mediated dilatation (FMD) in prehypertensive premenopausal women were preserved. In parallel, the Tie2/Akt/eNOS signaling pathway and the plasma NO level or NO secretion of circulating EPCs in prehypertensive premenopausal women was also retained. However, in presence of normotension or prehypertension with diabetes mellitus, the number or function of circulating EPCs and FMD in premenopausal women decreased. Similarly, the phosphorylation of Tie2/Akt/eNOS signaling pathway and the plasma NO level or NO secretion of circulating EPCs was reduced in prehypertension premenopausal with diabetes mellitus. CONCLUSION: The present findings firstly demonstrate that the unfavorable effects of diabetes mellitus on number and activity of circulating EPCs in prehypertension premenopausal women, which is at least partially related to the abnormal phosphorylation of Tie2/Akt/eNOS signaling pathway and subsequently reduced nitric oxide bioavailability. The Tie2/Akt/eNOS signaling pathway may be a potential target of vascular protection in prehypertensive premenopausal women with diabetes mellitus. PMID- 26936377 TI - Bad splits in bilateral sagittal split osteotomy: systematic review of fracture patterns. AB - An unfavourable and unanticipated pattern of the mandibular sagittal split osteotomy is generally referred to as a 'bad split'. Few restorative techniques to manage the situation have been described. In this article, a classification of reported bad split pattern types is proposed and appropriate salvage procedures to manage the different types of undesired fracture are presented. A systematic review was undertaken, yielding a total of 33 studies published between 1971 and 2015. These reported a total of 458 cases of bad splits among 19,527 sagittal ramus osteotomies in 10,271 patients. The total reported incidence of bad split was 2.3% of sagittal splits. The most frequently encountered were buccal plate fractures of the proximal segment (types 1A-F) and lingual fractures of the distal segment (types 2A and 2B). Coronoid fractures (type 3) and condylar neck fractures (type 4) have seldom been reported. The various types of bad split may require different salvage approaches. PMID- 26936376 TI - HSA: integrating multi-track Hi-C data for genome-scale reconstruction of 3D chromatin structure. AB - Genome-wide 3C technologies (Hi-C) are being increasingly employed to study three dimensional (3D) genome conformations. Existing computational approaches are unable to integrate accumulating data to facilitate studying 3D chromatin structure and function. We present HSA ( http://ouyanglab.jax.org/hsa/ ), a flexible tool that jointly analyzes multiple contact maps to infer 3D chromatin structure at the genome scale. HSA globally searches the latent structure underlying different cleavage footprints. Its robustness and accuracy outperform or rival existing tools on extensive simulations and orthogonal experiment validations. Applying HSA to recent in situ Hi-C data, we found the 3D chromatin structures are highly conserved across various human cell types. PMID- 26936378 TI - Comparison of laparoscopic stone surgery and percutaneous nephrolithotomy in the management of large upper urinary stones: a meta-analysis. AB - For the treatment of large upper urinary stones percutaneous nephrolithotomy (PCNL) is generally considered the first choice, and Laparoscopic Stone Surgery (LSS) is an alternative. We aim to compare the efficiency and safety of PCNL with LSS, as far as the management of large upper urinary stones is concerned. A systematic search from Pubmed, Web of Science, Wiley Online Library and Elsevier was performed up to August 1, 2015 for the relevant published studies. After data extraction and quality assessment, meta-analysis was performed using the RevMan 5.3 software. 15 eligible trials evaluating LSS vs. PCNL were identified including 6 prospective and 9 retrospective studies with 473 patients undergoing LSS and 523 patients undergoing PCNL. Although LSS led to longer operative time (p = 0.01) and higher open conversion rate (p = 0.02), patients might benefit from significantly fewer overall complications (p = 0.03), especially lower bleeding rate (p = 0.02), smaller drop in hemoglobin level (p < 0.001), less need of blood transfusion (p = 0.01). The stone free rate was also higher for LSS compared with PCNL (p < 0.001) with less secondary/complementary procedure (p = 0.006). There was no significant difference in other demographic parameters between the two groups. Our data suggests that LSS turns out to be a safe and feasible alternative to PCNL for large upper urinary stones with less bleeding and higher stone free rate. Because of the inherent limitations of the included studies, further large sample prospective, multi-centric studies and randomized control trials should be undertaken to confirm our findings. PMID- 26936379 TI - Hepatitis A virus-encoded miRNAs attenuate the accumulation of viral genomic RNAs in infected cells. AB - The establishment of persistent infection with hepatitis A virus (HAV) is the common result of most HAV/cell culture systems. Previous observations show that the synthesis of viral RNAs is reduced during infection. However, the underlying mechanism is poorly understood. We characterized three HAV-encoded miRNAs in our previous study. In this study, we aim to investigate the impact of these miRNAs on the accumulation of viral RNAs. The results indicated that the synthesis of viral genomic RNAs was dramatically reduced (more than 75 % reduction, P < 0.05) when transfected with one or two viral miRNA mimics. Conversely, they were significantly increased (more than 3.3-fold addition, P < 0.05) when transfected with one or two viral miRNA inhibitors. The luciferase reporter assay of miRNA targets showed that viral miRNAs were fully complementary to specific sites of the viral plus or minus strand RNA and strongly inhibited their expressions. Further data showed that the relative abundance of viral genomic RNA fragments that contain miRNA targets was also dramatically reduced (more than 80 % reduction, P < 0.05) when viral miRNAs were overexpressed with miRNA mimics. In contrast, they were significantly increased (approximately 2-fold addition, P < 0.05) when viral miRNAs were inhibited with miRNA inhibitors. In conclusion, these data suggest a possible mechanism for the reduction of viral RNA synthesis during HAV infection. Thus, we propose that it is likely that RNA virus-derived miRNA could serve as a self-mediated feedback regulator during infection. PMID- 26936380 TI - [Autologous composite grafts from the cavum conchae for reconstruction of multilayer nasal defects]. AB - BACKGROUND: Autologous transplants comprising skin and cartilage, so-called composite grafts (cgs), are an important reconstructive tool for multilayered defects of the nose. A cg from the auricular cavum conchae needs to fulfill both functional and esthetic demands. OBJECTIVE: This article illustrates the indications for and requirements of cgs, and also investigates graft healing and functional-aesthetic results. The current publication is a review article; the original data were published with the award of the 2014 APKO prize under the title "The auricle's cavum conchae composite graft in nasal reconstruction". MATERIALS AND METHODS: At the ENT department of Ulm University Medical School, multilayered defects of different nasal esthetic subunits are reconstructed with cgs. Based on these experiences, the authors report on long-term functional and esthetic results in the areas of the donor and recipient sites. CONCLUSION: Auricular cgs are versatile and reliable autologous transplants. The ease of harvesting, minimal donor site morbidity, and stable convex shape of these grafts render them ideal for reconstruction of multilayered nasal defects. Septal splints and custom-made prosthesis promote healing and prevent stenotic scarring. PMID- 26936381 TI - [The influence of current social, medical, and political trends on the future of otorhinolaryngology]. AB - BACKGROUND: All medical specialties are changing permanently, including otorhinolaryngology. Analyzing trends in social changes, medical progress, and political decisions will allow the effects of these on ENT medicine to be at least partially anticipated. TRENDS: Demographic changes and medical progress lead to an increasing demand for medical treatments. In addition, increasing numbers of female physicians are observed, as are many changes in the lifestyles of young physicians. Medical treatment will develop toward more individualized therapies in the future. ENT surgery will become a more ambulatory medical specialty. Driven by political decisions, digital medicine will become more important. Particular services once provided by physicians will be delegated to non-physician professionals. DISCUSSION: The lack of physicians and the progress in medicine require better networking between in- and outpatient services in the future. The potential of such collaborations is currently not completely realized. However, these developments will also increase the cost of health care. CONCLUSION: These trends will develop otorhinolaryngology into a conservative and surgical ambulatory care driven medical specialty. Embedded in decentralized networks and cooperations, and supported by IT technologies and specialized non physician professionals, ENT physicians will work in hospitals as well as in practices on a permanent basis. Nevertheless, the question of funding these changes has yet to be clarified. PMID- 26936382 TI - Probing Leader Cells in Endothelial Collective Migration by Plasma Lithography Geometric Confinement. AB - When blood vessels are injured, leader cells emerge in the endothelium to heal the wound and restore the vasculature integrity. The characteristics of leader cells during endothelial collective migration under diverse physiological conditions, however, are poorly understood. Here we investigate the regulation and function of endothelial leader cells by plasma lithography geometric confinement generated. Endothelial leader cells display an aggressive phenotype, connect to follower cells via peripheral actin cables and discontinuous adherens junctions, and lead migrating clusters near the leading edge. Time-lapse microscopy, immunostaining, and particle image velocimetry reveal that the density of leader cells and the speed of migrating clusters are tightly regulated in a wide range of geometric patterns. By challenging the cells with converging, diverging and competing patterns, we show that the density of leader cells correlates with the size and coherence of the migrating clusters. Collectively, our data provide evidence that leader cells control endothelial collective migration by regualting the migrating clusters. PMID- 26936383 TI - Should surveillance for liver cancer be modified in hepatitis C patients after treatment-related cirrhosis regression? AB - Surveillance of hepatocellular carcinoma (HCC) with abdominal ultrasound (US) is recommended for patients with advanced liver fibrosis because of hepatitis C virus (HCV) infections who achieve a sustained virological response (SVR) to antiviral therapy. HCC, in fact, may still develop following SVR as a consequence of long-standing carcinogenic activity of either HCV or hepatic fibrosis, whereas HCC risk in non-viraemic patients may also be driven by cofactors like alcohol abuse or diabetes. This explains the debate on whether surveillance for HCC should be continued in patients with documented cirrhosis regression following a SVR too. While regression of cirrhosis was documented to occur in a majority of patients with compensated cirrhosis 5 years after an SVR to interferon, it should be noted that this clinical benefit could be the consequence of treating a selected population with well-compensated liver disease who in fact were interferon able. This may not be the case for most real-life patients with advanced cirrhosis receiving direct antivirals, in whom liver fibrosis may have reached a point of no-return thus potentially preventing the recovery of a normal liver architecture following SVR. Both invasive and non-invasive tools have suboptimal diagnostic accuracy for fibrosis regression in non-viraemic patients, and this prompts to follow international societies' recommendation to perform surveillance in patients with advanced liver fibrosis achieving a SVR, independently on liver histology outcome. PMID- 26936384 TI - Meckel's diverticulum complicated with gastro-intestinal stromal tumor: Case report. AB - INTRODUCTION: Meckel's diverticulum is a common congenital anomaly, mostly asymptomatic. Tumors may arise rarely in these diverticulae. We claim presenting a new problem to the medical staff in Egypt. CASE PRESENTATION: We report a case of a 49year old male patient who attended our center with pelvic mass insinuated between the bladder and the rectum. On exploration the mass was found arising at the tip of a Meckel's diverticulum, Gastro-intestinal stromal tumor (GIST) was confirmed by pathology. DISCUSSION: In review of recently published cases most of these tumors were presented with vague abdominal pain as in our case. Tumors were treated by resection with or without adjuvant Imatinib. CONCLUSION: Surgeons and oncologists should bear in mind this rare diagnosis and know how to treat it. PMID- 26936385 TI - Reduced oxygen saturation is not linked to repeat hospital visits in infant bronchiolitis. PMID- 26936386 TI - The role of cofilin-l in vulvar squamous cell carcinoma: A marker of carcinogenesis, progression and targeted therapy. AB - Numerous studies have revealed that cofilin-l (CFL1) is associated with cancer cell migration and invasion in various types of tumor tissues. We investigated the roles of CFL1 in vulvar squamous cell carcinoma (VSCC). CFL1 expression was detected in VSCC and normal vulvar tissues using immunohistochemistry and western blotting. The vulvar carcinoma SW962 cell line was transfected with CFL1 small interfering RNA (siRNA) and exposed to periplocoside. We then assessed changes in cell proliferation, apoptosis, invasion and metastasis. We detected changes in CFL1 mRNA and protein expression by RT-PCR and western blotting, and alterations in protein expression of various relevant molecules by western blotting. CFL1 expression was found to be significantly upregulated in the VSCC tissues compared with the normal vulvar tissues by immunohistochemistry and western blotting (P<0.05) and was positively correlated with International Federation of Gynecology and Obstetrics (FIGO) stage, differentiation and lymphatic metastasis (P<0.05). After CFL1 knockdown by siRNA transfection, SW962 cells exhibited a decrease in growth, G1 phase cell cycle arrest, induction of apoptotic, low invasion and metastasis, and disrupted lamellipodium formation. We found that the protein expression of Bcl-xL, cyclin A1, MMP2, MMP9 and STAT3 was decreased, while expression of Bax was increased. Periplocoside inhibited SW962 cell growth, promoted apoptosis, suppressed invasion and migration, and lamellipodium formation. Periplocoside exposure resulted in lower CFL1, Bcl-xL, cyclin A1, MMP2, MMP9 and STAT3 levels, but a higher Bax level compared with the control group. We demonstrated that abnormal CFL1 expression may affect vulvar carcinogenesis and subsequent progression. CFL1 silencing by siRNA significantly inhibited VSCC cell progression, which suggests that CFL1 is a potential therapeutic target for vulvar cancer. Periplocoside, which was utilized in the present study for the clinical treatment of vulvar cancer, showed strong antitumor effects by suppression of CFL1 expression. PMID- 26936387 TI - Parametric study of a dyeing wastewater treatment by modified sericite. AB - The aim of this study was to investigate color, suspended solids (SS), chemical oxygen demand (COD) and biological oxygen demand (BOD) removal using modified sericite with magnesium (Mg-Sericite) flocculants in dyeing wastewater. Mg Sericite flocculants successfully removed >95% of color, SS. COD and BOD in dyeing wastewater at the following optimal conditions: Mg-Sericite dosage of 40 mg/L, pH of 11, Mg/Sericite ratio of 1.5, settling time of 20 min, mixing time of 10 min and mixing rate of 100 rpm. The bioflocculant, Mg-Sericite, can be a promising flocculants due to its high efficiency and low dose requirements in dyeing wastewater treatment. In addition, Mg-Sericite does not contaminate treated wastewater, which can be recycled to reduce not only the cost and the demand for water but also the extra operational costs for reusing wastewater. PMID- 26936388 TI - Image Size Influences Visual Search and Perception of Hemorrhages When Reading Cranial CT: An Eye-Tracking Study. AB - OBJECTIVE: The aim of this study was to explore reader gaze, performance, and preference during interpretation of cranial computed tomography (cCT) in stack mode at two different sizes. BACKGROUND: Digital display of medical images allows for the manipulation of many imaging factors, like image size, by the radiologists, yet it is often not known what display parameters better suit human perception. METHOD: Twenty-one radiologists provided informed consent to be eye tracked while reading 20 cCT cases. Half of these cases were presented at a size of 14 * 14 cm (512 * 512 pixels), half at 28 * 28 cm (1,024 * 1,024 pixels). Visual search, performance, and preference for the two image sizes were assessed. RESULTS: When reading small images, significantly fewer, but longer, fixations were observed, and these fixations covered significantly more slices. Time to first fixation of true positive findings was faster in small images, but dwell time on true findings was longer. Readers made more false positive decisions in small images, but no overall difference in either jackknife alternative free response receiver operating characteristic or reading time was found. CONCLUSION: Overall performance is not affected by image size. However, small-stack-mode cCT images may better support the use of motion perception and acquiring an overview, whereas large-stack-mode cCT images seem better suited for detailed analyses. APPLICATION: Subjective and eye-tracking data suggest that image size influences how images are searched and that different search strategies might be beneficial under different circumstances. PMID- 26936389 TI - DNA separation and enrichment using electro-hydrodynamic bidirectional flows in viscoelastic liquids. AB - DNA size separation followed by purification and enrichment constitute essential operations for genetic engineering. These processes are mostly carried out using DNA electrophoresis in gels or in polymer solutions, a well-established yet lengthy technique which has been notably improved using Lab-on-Chip technologies. So far, innovations for DNA separation or enrichment have been mostly undertaken separately, and we present an approach that allows us to perform these two processes simultaneously for DNA fragments spanning 0.2-50 kilo base pairs (kbp) in length. Our technology involves an electric field and a counter hydrodynamic flow in viscoelastic liquids, in which we show the occurrence of transverse forces oriented toward the walls. These forces increase with DNA molecular weight (MW) and hence induce a progressive reduction in DNA migration speed that triggers size separation in microfluidic channels as well as in capillaries. The separation of MW markers in the range 1-50 kbp is achieved in 15 minutes, thus outperforming gel electrophoresis that takes ~3 hours for this sample. Furthermore, the use of a funnel, where electric and flow fields are modulated spatially, enables us to adjust the transverse forces so as to stall the motion of DNA molecules at a position where they accumulate at factors of up to 1000 per minute. In this configuration, we establish that the operations of DNA enrichment and separation can be carried out simultaneously for the bands of a DNA MW marker between 0.2-1.5 kbp diluted at 0.02 ng MUL(-1) in 30 s. Altogether, our technology, which can readily be integrated as an in-line module in Lab-on-Chips, offers unique opportunities for sample preparation and analysis of minute genomic samples. PMID- 26936390 TI - The levels of HDAC1 and thioredoxin1 are related to the death of mesothelioma cells by suberoylanilide hydroxamic acid. AB - Mesothelioma is an aggressive tumor which is mainly derived from the pleura of lung. In the present study, we evaluated the anticancer effect of suberoylanilide hydroxamic acid (SAHA), a histone deacetylase (HDAC) inhibitor on human mesothelioma cells in relation to the levels of HDAC1, reactive oxygen species (ROS) and thioredoxin (Trx). While 1 uM SAHA inhibited cell growth in Phi and ROB cells at 24 h, it did not affect the growth in ADA and Mill cells. Notably, the level of HDAC1 was relatively overexpressed among Phi, REN and ROB cells. SAHA induced necrosis and apoptosis, which was accompanied by the cleavages of PARP and caspase-3 in Phi cells. This agent also increased the loss of mitochondrial membrane potential (MMP, DeltaPsim) in Phi cells. All the tested caspase inhibitors attenuated apoptosis in SAHA-treated Phi cells whereas HDAC1 siRNA enhanced the apoptotic cell death. SAHA increased intracellular ROS levels including O2*- in Phi cells. N-acetyl cysteine (NAC) and vitamin C (Vit.C) significantly reduced the growth inhibition and death of Phi cells caused by SAHA. This drug decreased the mRNA and protein levels of Trx1 in Phi and ROB cells. Furthermore, Trx1 siRNA increased cell death and O2*- level in SAHA treated Phi cells. In conclusion, SAHA selectively inhibited the growth of Phi and ROB mesothelioma cells, which showed the higher basal level of HDAC1. SAHA induced Phi cell death was related to oxidative stress and Trx1 levels. PMID- 26936391 TI - Chemistry of Mesoporous Organosilica in Nanotechnology: Molecularly Organic Inorganic Hybridization into Frameworks. AB - Organic-inorganic hybrid materials aiming to combine the individual advantages of organic and inorganic components while overcoming their intrinsic drawbacks have shown great potential for future applications in broad fields. In particular, the integration of functional organic fragments into the framework of mesoporous silica to fabricate mesoporous organosilica materials has attracted great attention in the scientific community for decades. The development of such mesoporous organosilica materials has shifted from bulk materials to nanosized mesoporous organosilica nanoparticles (designated as MONs, in comparison with traditional mesoporous silica nanoparticles (MSNs)) and corresponding applications in nanoscience and nanotechnology. In this comprehensive review, the state-of-art progress of this important hybrid nanomaterial family is summarized, focusing on the structure/composition-performance relationship of MONs of well defined morphology, nanostructure, and nanoparticulate dimension. The synthetic strategies and the corresponding mechanisms for the design and construction of MONs with varied morphologies, compositions, nanostructures, and functionalities are overviewed initially. Then, the following part specifically concentrates on their broad spectrum of applications in nanotechnology, mainly in nanomedicine, nanocatalysis, and nanofabrication. Finally, some critical issues, presenting challenges and the future development of MONs regarding the rational synthesis and applications in nanotechnology are summarized and discussed. It is highly expected that such a unique molecularly organic-inorganic nanohybrid family will find practical applications in nanotechnology, and promote the advances of this discipline regarding hybrid chemistry and materials. PMID- 26936392 TI - Engineered Theranostic Magnetic Nanostructures: Role of Composition and Surface Coating on Magnetic Resonance Imaging Contrast and Thermal Activation. AB - Magnetic nanostructures (MNS) have emerged as promising functional probes for simultaneous diagnostics and therapeutics (theranostic) applications due to their ability to enhance localized contrast in magnetic resonance imaging (MRI) and heat under external radio frequency (RF) field, respectively. We show that the "theranostic" potential of the MNS can be significantly enhanced by tuning their core composition and architecture of surface coating. Metal ferrite (e.g., MFe2O4) nanoparticles of ~8 nm size and nitrodopamine conjugated polyethylene glycol (NDOPA-PEG) were used as the core and surface coating of the MNS, respectively. The composition was controlled by tuning the stoichiometry of MFe2O4 nanoparticles (M = Fe, Mn, Zn, ZnxMn1-x) while the architecture of surface coating was tuned by changing the molecular weight of PEG, such that larger weight is expected to result in longer length extended away from the MNS surface. Our results suggest that both core as well as surface coating are important factors to take into consideration during the design of MNS as theranostic agents which is illustrated by relaxivity and thermal activation plots of MNS with different core composition and surface coating thickness. After optimization of these parameters, the r2 relaxivity and specific absorption rate (SAR) up to 552 mM(-1) s(-1) and 385 W/g were obtained, respectively, which are among the highest values reported for MNS with core magnetic nanoparticles of size below 10 nm. In addition, NDOPA-PEG coated MFe2O4 nanostructures showed enhanced biocompatibility (up to [Fe] = 200 MUg/mL) and reduced nonspecific uptake in macrophage cells in comparison to other well established FDA approved Fe based MR contrast agents. PMID- 26936393 TI - Nephron Progenitor But Not Stromal Progenitor Cells Give Rise to Wilms Tumors in Mouse Models with beta-Catenin Activation or Wt1 Ablation and Igf2 Upregulation. AB - Wilms tumor, a common childhood tumor of the kidney, is thought to arise from undifferentiated renal mesenchyme. Variable tumor histology and the identification of tumor subsets displaying different gene expression profiles suggest that tumors may arise at different stages of mesenchyme differentiation and that this ontogenic variability impacts tumor pathology, biology, and clinical outcome. To test the tumorigenic potential of different cell types in the developing kidney, we used kidney progenitor-specific Cre recombinase alleles to introduce Wt1 and Ctnnb1 mutations, two alterations observed in Wilms tumor, into embryonic mouse kidney, with and without biallelic Igf2 expression, another alteration that is observed in a majority of tumors. Use of a Cre allele that targets nephron progenitors to introduce a Ctnnb1 mutation that stabilizes beta catenin resulted in the development of tumors with a predominant epithelial histology and a gene expression profile in which genes characteristic of early renal mesenchyme were not expressed. Nephron progenitors with Wt1 ablation and Igf2 biallelic expression were also tumorigenic but displayed a more triphasic histology and expressed early metanephric mesenchyme genes. In contrast, the targeting of these genetic alterations to stromal progenitors did not result in tumors. These data demonstrate that committed nephron progenitors can give rise to Wilms tumors and that committed stromal progenitors are less tumorigenic, suggesting that human Wilms tumors that display a predominantly stromal histology arise from mesenchyme before commitment to a stromal lineage. PMID- 26936394 TI - Evaluation of Concurrent Radiation, Temozolomide and ABT-888 Treatment Followed by Maintenance Therapy with Temozolomide and ABT-888 in a Genetically Engineered Glioblastoma Mouse Model. AB - Despite the use of ionizing radiation (IR) and temozolomide (TMZ), outcome for glioblastoma (GBM) patients remains dismal. Poly (ADP-ribose) polymerase (PARP) is important in repair pathways for IR-induced DNA damage and TMZ-induced alkylation at N7-methylguanine and N3-methyldenine. However, optimized protocols for administration of PARP inhibitors have not been delineated. In this study, the PARP inhibitor ABT-888 was evaluated in combination with and compared to current standard-of-care in a genetically engineered mouse GBM model. Results demonstrated that concomitant TMZ/IR/ABT-888 with adjuvant TMZ/ABT-888 was more effective in inducing apoptosis and reducing proliferation with significant tumor growth delay and improved overall survival over concomitant TMZ/IR with adjuvant TMZ. Diffusion-weighted MRI, an early translatable response biomarker detected changes in tumors reflecting response at 1 day post TMZ/IR/ABT-888 treatment. This study provides strong scientific rationale for the development of an optimized dosing regimen for a PARP inhibitor with TMZ/IR for upfront treatment of GBM. PMID- 26936395 TI - Activation-Induced Cytidine Deaminase Links Ovulation-Induced Inflammation and Serous Carcinogenesis. AB - In recent years, the notion that ovarian carcinoma results from ovulation-induced inflammation of the fallopian tube epithelial cells (FTECs) has gained evidence. However, the mechanistic pathway for this process has not been revealed yet. In the current study, we propose the mutator protein activation-induced cytidine deaminase (AID) as a link between ovulation-induced inflammation in FTECs and genotoxic damage leading to ovarian carcinogenesis. We show that AID, previously shown to be functional only in B lymphocytes, is expressed in FTECs under physiological conditions, and is induced in vitro upon ovulatory-like stimulation and in vivo in carcinoma-associated FTECs. We also report that AID activity results in epigenetic, genetic and genomic damage in FTECs. Overall, our data provides new insights into the etiology of ovarian carcinogenesis and may set the ground for innovative approaches aimed at prevention and early detection. PMID- 26936396 TI - Amplified in Breast Cancer Regulates Transcription and Translation in Breast Cancer Cells. AB - BACKGROUND: Control of mRNA translation is fundamentally altered in cancer. Insulin-like growth factor-I (IGF-I) signaling regulates key translation mediators to modulate protein synthesis (e.g. eIF4E, 4E-BP1, mTOR, and S6K1). Importantly the Amplified in Breast Cancer (AIB1) oncogene regulates transcription and is also a downstream mediator of IGF-I signaling. MATERIALS AND METHODS: To determine if AIB1 also affects mRNA translation, we conducted gain and loss of AIB1 function experiments in estrogen receptor alpha (ERalpha)(+) (MCF-7L) and ERalpha(-) (MDA-MB-231, MDA-MB-435 and LCC6) breast cancer cells. RESULTS: AIB1 positively regulated IGF-I-induced mRNA translation in both ERalpha(+) and ERalpha(-) cells. Formation of the eIF4E-4E-BP1 translational complex was altered in the AIB1 ERalpha(+) and ERalpha(-) knockdown cells, leading to a reduction in the eIF4E/4E-BP1 and eIF4G/4E-BP1 ratios. In basal and IGF-I stimulated MCF-7 and LCC6 cells, knockdown of AIB1 decreased the integrity of the cap-binding complex, reduced global IGF-I stimulated polyribosomal mRNA recruitment with a concomitant decrease in ten of the thirteen genes tested in polysome-bound mRNAs mapping to proliferation, cell cycle, survival, transcription, translation and ribosome biogenesis ontologies. Specifically, knockdown of AIB1 decreased ribosome-bound mRNA and steady-state protein levels of the transcription factors ERalpha and E2F1 in addition to reduced ribosome bound mRNA of the ribosome biogenesis factor BYSL in a cell-line specific manner to regulate mRNA translation. CONCLUSION: The oncogenic transcription factor AIB1 has a novel role in the regulation of polyribosome recruitment and formation of the translational complex. Combinatorial therapies targeting IGF signaling and mRNA translation in AIB1 expressing breast cancers may have clinical benefit and warrants further investigation. PMID- 26936397 TI - Ezrin Enhances EGFR Signaling and Modulates Erlotinib Sensitivity in Non-Small Cell Lung Cancer Cells. AB - Ezrin is a scaffolding protein that is involved in oncogenesis by linking cytoskeletal and membrane proteins. Ezrin interacts with epidermal growth factor receptor (EGFR) in the cell membrane, but little is known about the effects of this interaction on EGFR signaling pathway. In this study, we established the biological and functional significance of ezrin-EGFR interaction in non-small cell lung cancer (NSCLC) cells. Endogenous ezrin and EGRF interaction was confirmed by co-immunoprecipitation and immunofluorescent staining. When expression of ezrin was inhibited, EGFR activity and phosphorylation levels of downstream signaling pathway proteins ERK and STAT3 were decreased. Cell fractionation experiments revealed that nuclear EGFR was significantly diminished in ezrin-knockdown cells. Consequently, mRNA levels of EGFR target genes AURKA, COX-2, cyclin D1, and iNOS were decreased in ezrin-depleted cells. A small molecule inhibitor of ezrin, NSC305787, reduced EGF-induced phosphorylation of EGFR and downstream target proteins, EGFR nuclear translocation, and mRNA levels of nuclear EGFR target genes similar to ezrin suppression. NSC305787 showed synergism with erlotinib in wild-type EGFR-expressing NSCLC cells, whereas no synergy was observed in EGFR-null cells. Phosphorylation of ezrin on Y146 was found as an enhancer of ezrin-EGFR interaction and required for increased proliferation, colony formation, and drug resistance to erlotinib. These findings suggest that ezrin-EGFR interaction augments oncogenic functions of EGFR and that targeting ezrin may provide a potential novel approach to overcome erlotinib resistance in NSCLC cells. PMID- 26936398 TI - Somatic Copy Number Amplification and Hyperactivating Somatic Mutations of EZH2 Correlate With DNA Methylation and Drive Epigenetic Silencing of Genes Involved in Tumor Suppression and Immune Responses in Melanoma. AB - The epigenetic modifier EZH2 is in the center of a repressive complex controlling differentiation of normal cells. In cancer EZH2 has been implicated in silencing tumor suppressor genes. Its role in melanoma as well as target genes affected by EZH2 are poorly understood. In view of this we have used an integrated systems biology approach to analyze 471 cases of skin cutaneous melanoma (SKCM) in The Cancer Genome Atlas (TCGA) for mutations and amplifications of EZH2. Identified changes in target genes were validated by interrogation of microarray data from melanoma cells treated with the EZH2 inhibitor GSK126. We found that EZH2 activation by mutations, gene amplification and increased transcription occurred in about 20% of the cohort. These alterations were associated with significant hypermethylation of DNA and significant downregulation of 11% of transcripts in patient RNASeq data. GSK126 treatment of melanoma lines containing EZH2 activation reversed such transcriptional repression in 98 candidate target genes. Gene enrichment analysis revealed genes associated with tumor suppression, cell differentiation, cell cycle inhibition and repression of metastases as well as antigen processing and presentation pathways. The identified changes in EZH2 were associated with an adverse prognosis in the TCGA dataset. These results suggest that inhibiting of EZH2 is a promising therapeutic avenue for a substantial fraction of melanoma patients. PMID- 26936400 TI - Tribute to Bruce C. Garrett. PMID- 26936399 TI - To select or not to select? The role of B-cell selection in determining the MYD88 mutation status in Waldenstrom Macroglobulinaemia. PMID- 26936401 TI - Autobiography of Bruce C. Garrett. PMID- 26936405 TI - Ophthalmological considerations in necrobiotic xanthogranuloma. PMID- 26936406 TI - An electrochemical sensor for nitrobenzene using pi-conjugated polymer-embedded nanosilver. AB - A novel electrochemical sensing platform for nitrobenzene has been developed using silver nanoparticles (AgNPs) embedded in the poly(amic) acid (PAA) polymer matrix (PAA-AgNPs). PAA was synthesized via the polycondensation reaction of para phenylenediamine and benzene-1,2,4,5-tetracarboxylic dianhydride. PAA-AgNP nanocomposites were synthesized by the in situ reduction of a silver precursor by the polymer at room temperature in a one-step approach without using an extraneous reducing or capping agent. The composite was subsequently characterized in solution and as a thin film. The X-ray diffraction technique revealed the crystalline nature of the PAA films with the embedded AgNPs. Unlike conventional polymers, the synthesized PAA membrane exhibits significant UV/Vis spectroscopic response. The sequestered nanoparticles also show the characteristic surface plasmon resonance (SPR) peaks confirming the presence of AgNPs. Integrated charge areas were 4.826 mC and 2.176 C for PAA/GC and PAA AgNPs/GC respectively. The charge at the PAA-AgNP/GC electrode is 451 times greater than that at the PAA/GC electrode suggesting that the AgNP composite exhibits higher electroactivity. When tested as a sensor for nitrobenzene, the PAA-AgNP modified GC electrode showed promising potential as an electrochemical sensor. The electrochemical sensors exhibit a wide linear dynamic range (10-600 MUM) with a correlation coefficient of 0.9735, a detection limit of 1.68 MUM and a sensitivity of 7.88 MUA MUM(-1). The sensor also exhibited minimal interference effects on structurally-similar nitroaromatic compounds and metal species such as 4-nitroaniline (4-NA), 2-nitrophenol (2-NP), dinitrobenzene (DNB), Pb(2+) and Cd(2+). PMID- 26936407 TI - A New Role for an Old Drug: Metformin Targets MicroRNAs in Treating Diabetes and Cancer. AB - MicroRNAs (miRNAs) are a family of short, noncoding, 19-23 base pair RNA molecules. Due to their unique role in gene regulation in various tissues, miRNAs play important roles in regulating insulin secretion, metabolic disease, and cancer biology. Emerging evidence demonstrates that miRNAs could also be novel diagnostic markers for a variety of disease states. Additionally, miRNAs have been found to function either as oncogenes, or tumor suppressor genes in cerian cancers. An increasing number of studies have been conducted investigating new drugs targeting miRNAs as a potential anticancer therapy. Metformin is the most widely prescribed medication for treating Type 2 diabetes (T2D). Recent clinical data suggests that metformin impacts the miRNA profile in T2D subjects. Most excitingly, studies have found that metformin is protective against cancer. The anticancer activity of metformin is mediated through a direct regulation of miRNAs, which further modulates several downstream genes in metabolic or preoncogenic pathways. These miRNAs are, therefore, prospective therapeutic targets for treating diabetes and cancer which is the topic of this review. Further study on the regulation of miRNAs by metformin could result in novel therapeutic strategies for recurrent or drug-esistant cancer, and as part of combinatorial approaches with conventional anticancer therapies. PMID- 26936409 TI - Increasing Incidence of Tuberculosis Infection in the Coastal Region of Northern Miyagi after the Great East Japan Earthquake. AB - On March 11, 2011, the Great East Japan Earthquake struck off the northeast coast of Japan. Within an hour of the earthquake, devastating tsunamis swept over the coastal region of the Miyagi Prefecture, facing Pacific Ocean. Accordingly, more than 400,000 residents were forced to stay at evacuation shelters. We investigated the changes in tuberculosis prevalence after the disaster. Annual data for all tuberculosis patients between April 1, 2009 and March 31, 2013 were extracted from the database of the Miyagi Prefectural Government. In the coastal region of Northern Miyagi, the number of tuberculosis patients increased in the post-disaster period (p < 0.001, 9.6 vs.19.1 per 100,000 people), compared to the pre-disaster period. In contrast, its prevalence did not change in the inland region of Northern Miyagi and the coastal and inland regions of Southern Miyagi. Importantly, in the inland and coastal regions of Northern Miyagi, the number of patients with latent tuberculosis infection (LTBI) increased in the post-disaster period (p < 0.001). Furthermore, in the coastal shelters, 11 evacuees with the history of contacting tuberculosis patients were diagnosed with LTBI, whereas no cases of LTBI patients were observed in the inland shelters. Thus, staying in the coastal shelters was a risk factor for contracting tuberculosis (OR: 19.31, 95% CI: 1.11-334.80); indeed, twice as many evacuees visited each coastal shelter on April 1, 2011, compared to the inland region. We should prepare the shelters to avoid overcrowding, and long-term observation is required to detect the prevalence of tuberculosis infection. PMID- 26936408 TI - OsGRF4 controls grain shape, panicle length and seed shattering in rice. AB - Traits such as grain shape, panicle length and seed shattering, play important roles in grain yield and harvest. In this study, the cloning and functional analysis of PANICLE TRAITS 2 (PT2), a novel gene from the Indica rice Chuandali (CDL), is reported. PT2 is synonymous with Growth-Regulating Factor 4 (OsGRF4), which encodes a growth-regulating factor that positively regulates grain shape and panicle length and negatively regulates seed shattering. Higher expression of OsGRF4 is correlated with larger grain, longer panicle and lower seed shattering. A unique OsGRF4 mutation, which occurs at the OsmiRNA396 target site of OsGRF4, seems to be associated with high levels of OsGRF4 expression, and results in phenotypic difference. Further research showed that OsGRF4 regulated two cytokinin dehydrogenase precursor genes (CKX5 and CKX1) resulting in increased cytokinin levels, which might affect the panicle traits. High storage capacity and moderate seed shattering of OsGRF4 may be useful in high-yield breeding and mechanized harvesting of rice. Our findings provide additional insight into the molecular basis of panicle growth. PMID- 26936411 TI - Sexual orientation, treatment utilization, and barriers for alcohol related problems: Findings from a nationally representative sample. AB - BACKGROUND: Gay, lesbian, and bisexual (GLB) individuals appear to have an increased likelihood of alcohol use disorders and treatment utilization for alcohol related problems compared to heterosexual individuals. Despite this increase, treatment utilization rates among GLB individuals remain low. In an effort to address this, our paper examined whether or not GLB individuals encounter unique barriers when pursuing treatment for alcohol related problems. METHODS: Using data from the National Epidemiologic Survey on Alcohol Related Conditions (NESARC), we examined service sector specific factors, some of which included (a) utilization rates, (b) self-reported treatment barriers, and (c) whether or not there were emergent differences among GLB individuals, after controlling for socio-demographic and clinical characteristics. RESULTS: Findings indicated that GLB individuals reported higher severity rates for alcohol use disorders when compared to heterosexual individuals, and were significantly more likely to utilize treatment services for alcohol related problems, however, not across all treatment sectors. While similar patterns were observed when examining barriers to treatment, bisexual individuals reported significantly more barriers than heterosexual and gay/lesbian individuals. CONCLUSION: These findings underscored the importance of identifying and developing interventions that addresses treatment barriers associated with alcohol use service utilization among GLB populations, and creating improved outreach and education programs to better address stigmas associated with substance use and sexuality. PMID- 26936410 TI - Second malignancies after radiotherapy for prostate cancer: systematic review and meta-analysis. AB - OBJECTIVE: To determine the association between exposure to radiotherapy for the treatment of prostate cancer and subsequent second malignancies (second primary cancers). DESIGN: Systematic review and meta-analysis of observational studies. DATA SOURCES: Medline and Embase up to 6 April 2015 with no restrictions on year or language. STUDY SELECTION: Comparative studies assessing the risk of second malignancies in patients exposed or unexposed to radiotherapy in the course of treatment for prostate cancer were selected by two reviewers independently with any disagreement resolved by consensus. DATA EXTRACTION AND SYNTHESIS: Two reviewers independently extracted study characteristics and outcomes. Risk of bias was assessed with the Newcastle-Ottawa scale. Outcomes were synthesized with random effects models and Mantel-Haenszel weighting. Unadjusted odds ratios and multivariable adjusted hazard ratios, when available, were pooled. MAIN OUTCOME MEASURES: Second cancers of the bladder, colorectal tract, rectum, lung, and hematologic system. RESULTS: Of 3056 references retrieved, 21 studies were selected for analysis. Most included studies were large multi-institutional reports but had moderate risk of bias. The most common type of radiotherapy was external beam; 13 studies used patients treated with surgery as controls and eight used patients who did not undergo radiotherapy as controls. The length of follow-up among studies varied. There was increased risk of cancers of the bladder (four studies; adjusted hazard ratio 1.67, 95% confidence interval 1.55 to 1.80), colorectum (three studies; 1.79, 1.34 to 2.38), and rectum (three studies; 1.79, 1.34 to 2.38), but not cancers of the hematologic system (one study; 1.64, 0.90 to 2.99) or lung (two studies; 1.45, 0.70 to 3.01), after radiotherapy compared with the risk in those unexposed to radiotherapy. The odds of a second cancer varied depending on type of radiotherapy: treatment with external beam radiotherapy was consistently associated with increased odds while brachytherapy was not. Among the patients who underwent radiotherapy, from individual studies, the highest absolute rates reported for bladder, colorectal, and rectal cancers were 3.8%, 4.2%, and 1.2%, respectively, while the lowest reported rates were 0.1%, 0.3%, and 0.3%. CONCLUSION: Radiotherapy for prostate cancer was associated with higher risks of developing second malignancies of the bladder, colon, and rectum compared with patients unexposed to radiotherapy, but the reported absolute rates were low. Further studies with longer follow-up are required to confirm these findings. PMID- 26936412 TI - Validation of the alcohol use item banks from the Patient-Reported Outcomes Measurement Information System (PROMIS). AB - BACKGROUND: The Patient-Reported Outcomes Measurement Information System (PROMIS) includes five item banks for alcohol use. There are limited data, however, regarding their validity (e.g., convergent validity, responsiveness to change). To provide such data, we conducted a prospective study with 225 outpatients being treated for substance abuse. METHODS: Assessments were completed shortly after intake and at 1-month and 3-month follow-ups. The alcohol item banks were administered as computerized adaptive tests (CATs). Fourteen CATs and one six item short form were also administered from eight other PROMIS domains to generate a comprehensive health status profile. After modeling treatment outcome for the sample as a whole, correlates of outcome from the PROMIS health status profile were examined. RESULTS: For convergent validity, the largest correlation emerged between the PROMIS alcohol use score and the Alcohol Use Disorders Identification Test (r=.79 at intake). Regarding treatment outcome, there were modest changes across the target problem of alcohol use and other domains of the PROMIS health status profile. However, significant heterogeneity was found in initial severity of drinking and in rates of change for both abstinence and severity of drinking during follow-up. This heterogeneity was associated with demographic (e.g., gender) and health-profile (e.g., emotional support, social participation) variables. CONCLUSIONS: The results demonstrated the validity of PROMIS CATs, which require only 4-6 items in each domain. This efficiency makes it feasible to use a comprehensive health status profile within the substance use treatment setting, providing important prognostic information regarding abstinence and severity of drinking. PMID- 26936413 TI - New Insights from Clinical Assessment of Upper Extremities in Cervical Traumatic Spinal Cord Injury. AB - Upper extremity function has a strong impact on the quality of life in cervical spinal cord-injured patients. Upper extremity function depends on many factors, such as muscle strength, level of lesion, and extension of the cord damage in its axial axis produced by the injury. These variables can be obtained by the International Standards for Neurological Classification of Spinal Cord Injury, which is the standard for the functional evaluation of traumatic spinal cord injury (SCI) patients. The aim of this study was to describe the relationship between upper limb muscle strength, level of injury, and axial damage with the functionality of upper limb measured using the Jebsen-Taylor Hand Function Test (JTHFT) and the 9 Hole Peg Test (9HPT) in cervical SCI. Twenty-nine patients were included in this study. Our results suggest that both the JTHFT and 9HPT can be similarly used to quantify functional impairment after cervical SCI. Moreover, our data suggest that the upper extremity motor score, JTHFT, and 9HPT strongly correlate with the American Spinal Injury Association (ASIA) impairment scale (graded from A to E), but not with the lesion level. Our findings can be of great importance for the clinician or researchers whose therapeutic interventions have as a main objective to improve upper limb functionality in patients with cervical SCI. We suggest that ASIA impairment scale, ASIA motor score, and functional tests (including JTHFT and/or 9HPT) could be used as outcome measures in cervical SCI clinical trials. PMID- 26936415 TI - Synthesis of Allenamides by Copper-Catalyzed Coupling of Propargylic Bromides and Nitrogen Nucleophiles. AB - An efficient and general synthesis of allenamides derived from oxazolidinones and hydantoins is reported. Upon activation with a combination of a copper catalyst and a 2,2'-bipyridine derivative in the presence of an inorganic base, propargylic bromides were found to be suitable reagents for the direct allenylation of nitrogen nucleophiles by a formal copper-catalyzed S(N)2' reaction. Besides the availability of the starting materials, notable features of this route to allenamides are its mild reaction conditions, the reaction being performed at room temperature in most cases, and its applicability to the preparation of mono-, di-, as well as trisubstituted allenamides. PMID- 26936414 TI - Magnetoelectric relaxor and reentrant behaviours in multiferroic Pb(Fe2/3W1/3)O3 crystal. AB - Significant quenched disorder in crystal structure can break ferroic (magnetic or electric) long-range order, resulting in the development of ferroic glassy states at low temperatures such as magnetic spin glasses, electric dipolar glasses, relaxor ferroelectrics, etc. These states have been widely studied due to novel physical phenomena they reveal. Much less known are the effects of quenched disorder in multiferroics, i.e. the materials where magnetic and electric correlations coexist. Here we report an unusual behaviour in complex perovskite Pb(Fe2/3W1/3)O3 (PFW) crystals: the coexistence of electric relaxor, magnetic relaxor and antiferromagnetic (AFM) states. The most striking finding is the transformation of the AFM phase into a new reentrant-type magnetic glassy phase below Tg ? 10 K. We show that the behaviour at this transformation contrasts the typical behaviour of canonical spin glasses and is similar to the behaviour of relaxor ferroelectrics. Magnetoelectric effect is also observed in the AFM phase in the temperature range of the transition into electric relaxor phase at Tf ? 200. The mechanism of magnetic relaxor behaviour is supposed to arise from the frustrated interactions among the spins located at the AFM domain walls. Our results should inspire further studies of multirelaxor behaviour in other multiferroic systems. PMID- 26936416 TI - De novo transcriptome assembly and comprehensive expression profiling in Crocus sativus to gain insights into apocarotenoid biosynthesis. AB - Saffron (Crocus sativus L.) is commonly known as world's most expensive spice with rich source of apocarotenoids and possesses magnificent medicinal properties. To understand the molecular basis of apocarotenoid biosynthesis/accumulation, we performed transcriptome sequencing from five different tissues/organs of C. sativus using Illumina platform. After comprehensive optimization of de novo transcriptome assembly, a total of 105, 269 unique transcripts (average length of 1047 bp and N50 length of 1404 bp) were obtained from 206 million high-quality paired-end reads. Functional annotation led to the identification of many genes involved in various biological processes and molecular functions. In total, 54% of C. sativus transcripts could be functionally annotated using public databases. Transcriptome analysis of C. sativus revealed the presence of 16721 SSRs and 3819 transcription factor encoding transcripts. Differential expression analysis revealed preferential/specific expression of many transcripts involved in apocarotenoid biosynthesis in stigma. We have revealed the differential expression of transcripts encoding for transcription factors (MYB, MYB related, WRKY, C2C2 YABBY and bHLH) involved in secondary metabolism. Overall, these results will pave the way for understanding the molecular basis of apocarotenoid biosynthesis and other aspects of stigma development in C. sativus. PMID- 26936418 TI - Anti-inflammatory effects of essential oils extracted from Chamaecyparis obtusa on murine models of inflammation and RAW 264.7 cells. AB - Antimicrobial, antifungal and anti-inflammatory effects of essential oils extracted from Chamaecyparis obtusa (EOCO) have previously been reported. In the present study, the anti-inflammatory effects of EOCO were investigated in two murine models of inflammation: Carrageenan-induced paw edema and thioglycollate induced peritonitis, and in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophage cells. The expression levels of proinflammatory cytokines were analyzed by ELISA, the expression of nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) were determined by western blotting, and nitrite concentration was measured using Griess reagent. In mice with carrageenan-induced edema, paw thickness and the expression levels of interleukin (IL)-1beta and IL-6 in paw homogenates were significantly decreased in the EOCO (5 and 10 mg/kg) group, as compared with the control group. In mice with thioglycollate-induced peritonitis, treatment with EOCO (5 and 10 mg/kg) reduced the number of total cells and suppressed tumor necrosis factor-alpha (TNF-alpha), IL-1beta and IL-6 levels in peritoneal fluid. In addition, EOCO reduced nitric oxide, TNF-alpha and IL-6 production, and suppressed iNOS and COX-2 expression in LPS-stimulated RAW 264.7 cells. These results suggest that EOCO may exert anti-inflammatory effects in vivo and in vitro, and that these effects may be associated with the inhibition of inflammatory mediators. Therefore, EOCO may be considered an effective therapeutic agent for the treatment of inflammatory diseases. PMID- 26936419 TI - Self-rated health and return to work after first-time stroke. AB - OBJECTIVE: Self-rated health is an essential aspect of life after stroke, and return to work is considered one of the most important outcomes for younger stroke patients. The aim of this study was to examine whether self-rated health 3 months after stroke, clinical and demographic determinants are independently associated with return to work and subsequent work-stability. MATERIAL AND METHODS: A total of 590 patients with first-time stroke were included from a Danish population-based cohort study. All patients were younger than 60 years and working or unemployed at the time of stroke. Information on self-rated health (Short Form 12; SF-12) was collected from questionnaires 3 months after stroke. Employment status was defined on a weekly basis using national register-data on transfer payments. RESULTS: Fifty percent were self-supporting or job-seeking 12 months after stroke, and the same proportion was found after 24 months. More than 70% of the patients who returned to work did not receive sickness benefits in the 12 months following return to work. Good self-rated health 3 months after stroke and minor stroke severity were strongly associated with return to work after 12 and 24 months. CONCLUSION: Self-rated health 3 months after stroke was strongly associated with return to work and work-stability after stroke. PMID- 26936417 TI - Vaniprevir plus peginterferon alfa-2b and ribavirin in treatment-experienced Japanese patients with hepatitis C virus genotype 1 (GT1b) infection: Phase 3 studies. AB - BACKGROUND AND AIM: Vaniprevir is a macrocyclic hepatitis C virus (HCV) non structural (NS)3/4A protease inhibitor. The objective of these phase 3 multicenter, open-label trials was to evaluate the safety and efficacy of vaniprevir + peginterferon alfa-2b + ribavirin (PR) in Japanese patients with HCV genotype (GT)1 infection who had previously failed treatment with interferon based regimens. METHODS: Japanese patients with chronic HCV GT1 were enrolled. In PN044, patients with previous relapse or virologic breakthrough were randomized to vaniprevir (300 mg twice daily) + PR for 12 weeks followed by PR for another 12 weeks (12-week arm) or vaniprevir + PR for 24 weeks (24-week arm). In PN045, patients with previous partial/null response received vaniprevir + PR for 24 weeks. The primary endpoint was sustained virologic response at 24 weeks after completing treatment (SVR24 ). RESULTS: In PN044 (n = 51), SVR24 was 92.0% and 96.2% in the 12- and 24-week arms, respectively. In PN045 (n = 42), SVR24 was 61.9% in all patients and 55.2% in previous null responders. In both studies, vaniprevir + PR was generally safe and well tolerated; the majority of adverse events were mild/moderate and included pyrexia, decreased hemoglobin, headache, nausea, pruritus, and decreased platelet count. Polymorphisms in the HCV NS3 gene at baseline (Y56, Q80, and V170) did not impact treatment outcome. Virologic failure was principally associated with the on-treatment emergence of R155 or D168 mutations. CONCLUSIONS: Vaniprevir + PR is an effective, well-tolerated treatment for Japanese patients with HCV GT1 infection who failed previous interferon-based treatment. ClinicalTrials.gov Identifier NCT01405937 and NCT01405560 (Protocols PN044 and PN045). PMID- 26936420 TI - Directly Predicting Water Quality Criteria from Physicochemical Properties of Transition Metals. AB - Transition metals are a group of elements widespread in aquatic environments that can be hazardous when concentrations exceeding threshold values. Due to insufficient data, criteria maximum concentrations (CMCs) of only seven transition metals for protecting aquatic life have been recommended by the USEPA. Hence, it is deemed necessary to develop empirical models for predicting the threshold values of water quality criteria (WQC) for other transition metals for which insufficient information on toxic potency is available. The present study established quantitative relationships between recommended CMCs and physicochemical parameters of seven transition metals, then used the developed relationships to predict CMCs for other transition metals. Seven of 26 physicochemical parameters examined were significantly correlated with the recommended CMCs. Based on this, five of the seven parameters were selected to construct a linear free energy model for predicting CMCs. The most relevant parameters were identified through principle component analysis, and the one with the best correlation with the recommended CMCs was a combination of covalent radius, ionic radius and electron density. Predicted values were largely consistent with their toxic potency values. The present study provides an alternative approach to develop screening threshold level for metals which have insufficient information to use traditional methods. PMID- 26936421 TI - MicroRNA-16 suppresses the activation of inflammatory macrophages in atherosclerosis by targeting PDCD4. AB - Programmed cell death 4 (PDCD4) is involved in a number of bioprocesses, such as apoptosis and inflammation. However, its regulatory mechanisms in atherosclerosis remain unclear. In this study, we investigated the role and mechanisms of action of PDCD4 in high-fat diet-induced atherosclerosis in mice and in foam cells (characteristic pathological cells in atherosclerotic lesions) derived from ox LDL-stimulated macrophages. MicroRNA (miR)-16 was predicted to bind PDCD4 by bioinformatics analysis. In the mice with atherosclerosis and in the foam cells, PDCD4 protein expression (but not the mRNA expression) was enhanced, while that of miR-16 was reduced. Transfection with miR-16 mimic decreased the activity of a luciferase reporter containing the 3' untranslated region (3'UTR) of PDCD4 in the macrophage-derived foam cells. Conversely, treatment with miR-16 inhibitor enhanced the luciferase activity. However, by introducing mutations in the predicted binding site located in the 3'UTR of PDCD4, the miR-16 mimic and inhibitor were unable to alter the level of PDCD4, suggesting that miR-16 is a direct negative regulator of PDCD4 in atherosclerosis. Furthermore, transfection wtih miR-16 mimic and siRNA targeting PDCD4 suppressed the secretion and mRNA expression of pro-inflammatory factors, such as interleukin (IL)-6 and tumor necrosis factor-alpha (TNF-alpha), whereas it enhanced the secretion and mRNA expression of the anti-inflammatory factor, IL-10. Treatment with miR-16 inhibitor exerted the opposite effects. In addition, the phosphorylation of p38 and extracellular signal-regulated kinase (ERK), and nuclear factor-kappaB (NF kappaB) expression were altered by miR-16. In conclusion, our data demonstrate that the targeting of PDCD4 by miR-16 may suppress the activation of inflammatory macrophages though mitogen-activated protein kinase (MAPK) and NF-kappaB signaling in atherosclerosis; thus, PDCD4 may prove to be a potential therapeutic target in the treatment of atherosclerosis. PMID- 26936422 TI - A genome-wide association analysis for susceptibility of pigs to enterotoxigenic Escherichia coli F41. AB - Enterotoxigenic Escherichia coli (ETEC) is a type of pathogenic bacteria that cause diarrhea in piglets through colonizing pig small intestine epithelial cells by their surface fimbriae. Different fimbriae type of ETEC including F4, F18, K99 and F41 have been isolated from diarrheal pigs. In this study, we performed a genome-wide association study to map the loci associated with the susceptibility of pigs to ETEC F41 using 39454 single nucleotide polymorphisms (SNPs) in 667 F2 pigs from a White Duroc*Erhualian F2 cross. The most significant SNP (ALGA0022658, P=5.59*10-13) located at 6.95 Mb on chromosome 4. ALGA0022658 was in high linkage disequilibrium (r 2>0.5) with surrounding SNPs that span a 1.21 Mb interval. Within this 1.21 Mb region, we investigated ZFAT as a positional candidate gene. We re-sequenced cDNA of ZFAT in four pigs with different susceptibility phenotypes, and identified seven coding variants. We genotyped these seven variants in 287 unrelated pigs from 15 diverse breeds that were measured with ETEC F41 susceptibility phenotype. Five variants showed nominal significant association (P<0.05) with ETEC F41 susceptibility phenotype in International commercial pigs. This study provided refined region associated with susceptibility of pigs to ETEC F41 than that reported previously. Further works are needed to uncover the underlying causal mutation(s). PMID- 26936424 TI - Complete transposition of the great arteries with double outlet right ventricle in a dog. AB - A 2-year old intact male Collie dog presented to the cardiology service at Oregon State University for evaluation of cyanosis and suspected congenital cardiac disease. Echocardiography revealed a constellation of cardiac abnormalities including a single large vessel exiting the right ventricle with a diminutive left ventricular outflow tract, a ventricular septal defect, and marked concentric right ventricular hypertrophy with moderate right atrial dilation. Cardiac-gated computed tomography confirmed the previous anomalies in addition to supporting a diagnosis of complete transposition of the great arteries, double outlet right ventricle, and pulmonic hypoplasia with a single coronary ostium. Prominent bronchoesophageal collateral vessels were concurrently identified. Clinically, the dog was stable despite mild cyanosis that worsened with exercise; no intervention was elected at the time. This case report describes a rare combination of congenital cardiac defects and the usefulness of cardiac-gated cross-sectional imaging in the anatomic diagnosis. PMID- 26936425 TI - Ameliorative effects of pomegranate on carbon tetrachloride hepatotoxicity in rats: A molecular and histopathological study. AB - The present study aimed to investigate the molecular mechanism underlying the hepatoprotective effects of pomegranate (POM) against oxidative stress in a rat model of carbon tetrachloride (CCl4)-induced liver damage. Injection of rats with CCl4 resulted in hepatic inflammation and lipid accumulation via the upregulation of interleukin (IL)-6 and sterol regulatory element-binding protein 1c (SREBP-1c) mRNA expression. CCl4 induced downregulation of the anti-inflammatory factors alpha 2-macroglobulin (alpha-2M) and IL-10 in comparison with the POM treated group. In addition, CCl4 induced downregulation of superoxide dismutase (SOD), glutathione S-transferase (GST) and catalase (CAT) expression. Conversely, prior administration of POM counteracted the deleterious alterations induced by CCl4. POM downregulated CCl4-induced IL-6 upregulation, normalized the increase in SREBP-1c expression, and prevented CCl4-induced alpha-2M downregulation. POM counteracted CCL4-induced alterations via immunosuppressive, anti-inflammatory and regenerative effects by upregulating transforming growth factor-beta1, HSP70 and IL-10 mRNA expression. In addition, POM increased reactive oxygen species scavenging activity by augmenting the antioxidant defense mechanism against CCl4 hepatotoxicity, as demonstrated by detecting SOD, CAT and GST expression. These results confirm that, at the molecular level, POM exerts hepatoprotective effects against CCl4-induced oxidative stress and liver tissue damage. PMID- 26936423 TI - The Prevalence and Distribution of Neurodegenerative Compound-Producing Soil Streptomyces spp. AB - Recent work from our labs demonstrated that a metabolite(s) from the soil bacterium Streptomyces venezuelae caused dopaminergic neurodegeneration in Caenorhabditis elegans and human neuroblastoma cells. To evaluate the capacity for metabolite production by naturally occurring streptomycetes in Alabama soils, Streptomyces were isolated from soils under different land uses (agriculture, undeveloped, and urban). More isolates were obtained from agricultural than undeveloped soils; there was no significant difference in the number of isolates from urban soils. The genomic diversity of the isolates was extremely high, with only 112 of the 1509 isolates considered clones. A subset was examined for dopaminergic neurodegeneration in the previously established C. elegans model; 28.3% of the tested Streptomyces spp. caused dopaminergic neurons to degenerate. Notably, the Streptomyces spp. isolates from agricultural soils showed more individual neuron damage than isolates from undeveloped or urban soils. These results suggest a common environmental toxicant(s) within the Streptomyces genus that causes dopaminergic neurodegeneration. It could also provide a possible explanation for diseases such as Parkinson's disease (PD), which is widely accepted to have both genetic and environmental factors. PMID- 26936426 TI - Efficacy and safety of liraglutide, a once-daily human glucagon-like peptide-1 analogue, in Latino/Hispanic patients with type 2 diabetes: post hoc analysis of data from four phase III trials. AB - The aim of the present analysis was to evaluate the efficacy of the glucagon-like peptide-1 receptor agonist liraglutide in Latino/Hispanic individuals with type 2 diabetes, in addition to comparing its treatment effects with those observed in non-Latino/Hispanic individuals. Analyses were performed on patient-level data from a subset of individuals self-defined as Latino/Hispanic from four phase III studies, the LEAD-3, LEAD-4, LEAD-6 and 1860-LIRA-DPP-4 trials. Endpoints included change in glycated haemoglobin (HbA1c) and body weight from baseline. In Latino/Hispanic patients (n = 505; 323 treated with liraglutide) after 26 weeks, mean HbA1c reductions were significantly greater with both liraglutide 1.2 and 1.8 mg versus comparator or placebo in the LEAD-3 and LEAD-4 studies, and with 1.8 mg liraglutide in the 1860-LIRA-DPP-4 trial. In LEAD-3 both doses led to significant differences in body weight change among Latino/Hispanic patients versus the comparator. With 1.8 mg liraglutide, difference in weight change was significant only in the 1860-LIRA-DPP-4 trial versus sitagliptin. For both endpoints Latino/Hispanic and non-Latino/Hispanic patients responded to liraglutide similarly. In summary, liraglutide is efficacious for treatment of type 2 diabetes in Latino/Hispanic patients, with a similar efficacy to that seen in non-Latino/Hispanic patients. PMID- 26936427 TI - Temperature mapping of operating nanoscale devices by scanning probe thermometry. AB - Imaging temperature fields at the nanoscale is a central challenge in various areas of science and technology. Nanoscopic hotspots, such as those observed in integrated circuits or plasmonic nanostructures, can be used to modify the local properties of matter, govern physical processes, activate chemical reactions and trigger biological mechanisms in living organisms. The development of high resolution thermometry techniques is essential for understanding local thermal non-equilibrium processes during the operation of numerous nanoscale devices. Here we present a technique to map temperature fields using a scanning thermal microscope. Our method permits the elimination of tip-sample contact-related artefacts, a major hurdle that so far has limited the use of scanning probe microscopy for nanoscale thermometry. We map local Peltier effects at the metal semiconductor contacts to an indium arsenide nanowire and self-heating of a metal interconnect with 7 mK and sub-10 nm spatial temperature resolution. PMID- 26936428 TI - The importance of surgical margins in renal cell and urothelial carcinomas. AB - This chapter reviews the prevalence, outcomes, and management of positive surgical margins for patients with either renal cell or urothelial carcinomas. Though renal cell carcinoma tends to be resistant to conventional radio- or chemotherapy, kidney cancer patients with positive surgical margins can often be managed with close surveillance with acceptable outcomes. On the other hand, urothelial tumors tend to be more aggressive, and positive surgical margins after radical cystectomy often requires adjuvant therapy. PMID- 26936429 TI - Silybin suppresses cell proliferation and induces apoptosis of multiple myeloma cells via the PI3K/Akt/mTOR signaling pathway. AB - Silybin is a biologically active component extracted from the seeds of Silybum marianum, which has been shown to have inhibitory effects on prostate, skin, bladder, lung and colon cancer cells, in addition to its efficacy in the treatment of liver diseases, including hepatitis and cirrhosis. The aim of the present study was to investigate whether silybin suppresses the proliferation and induces apoptosis of multiple myeloma (MM) cells and to elucidate its molecular targets. The proliferative and apoptotic rates of the U266 MM cell line were assessed using MTT and flow-cytometric assays, respectively. Western blot analysis was used to assess the protein levels of phosphoinositide-3 kinase (PI3K), phosphorylated (p)-Akt and p-mammalian target of rapamycin (mTOR) in U266 cells. In addition, PI3K inhibitor LY294002 or activator insulin-like growth factor 1 were used to investigate the involvement of the PI3K/Akt-mTOR signaling pathway in the effect of silybin on U266 cells. The results revealed that silybin restrained the proliferation and enhanced the apoptosis of U266 cells. Furthermore, silybin inhibited the protein expression of PI3K, p-Akt and p-mTOR in U266 cells. Of note, inhibition of PI3K facilitated silybin-mediated reduction of mTOR activation, cell proliferation and induction of apoptosis in U266 cells, while activation of PI3K attenuated the effects of silybin. In conclusion, silybin suppressed cell proliferation and promoted apoptosis of U266 cells via PI3K/Akt-mTOR signaling pathways. PMID- 26936430 TI - A Comparison of the Sensitivity of Brush Allodynia and Semmes-Weinstein Monofilament Testing in the Detection of Allodynia Within Regions of Secondary Hyperalgesia in Humans. AB - BACKGROUND: Two of the most common Quantitative Sensory Techniques (QST) employed to detect allodynia include mechanical brush allodynia and Semmes-Weinstein monofilaments. However, their relative sensitivity at detecting allodynia is poorly understood. The purpose of this study was to compare the sensitivity of brush allodynia against Semmes-Weinstein monofilament technique for detecting allodynia within regions of secondary hyperalgesia in humans. METHODS: Twenty subjects (10 males, 10 females; 21.1 +/- 0.9 years) were recruited and randomly allocated to allodynia or monofilament groups. Topical capsaicin (Zostrix 0.075%) was applied to a target region defined by C4-C7 dermatomes. Allodynia testing was performed at 0- (baseline) and 10 minutes postcapsaicin. The Semmes-Weinstein group assessed changes in skin sensitivity 8 cm inferior to target region and 2 cm lateral to the spinous process, while brush allodynia was employed to detect the point inferior to the target region where subjects reported changes in skin sensitivity. The distance (cm) from this point to the inferior border of the target region was termed the Allodynia Score. RESULTS: Statistically significant increases in the Allodynia Score were observed at 10 minutes postcapsaicin compared to baseline (P < 0.001). No differences in monofilament scores were observed between 10 minutes postcapsaicin and baseline (P = 0.125). Brush allodynia also demonstrated superior sensitivity, detecting allodynia in 100% of cases compared to 60% in the Semmes-Weinstein group. CONCLUSION: Brush allodynia is more sensitive than Semmes-Weinstein monofilaments for detecting mechanical allodynia in regions of secondary hyperalgesia. Brush allodynia may be preferred over Semmes-Weinstein monofilaments for clinical applications requiring reliable detection of allodynia. PMID- 26936431 TI - Response to letter to the editor re 'Prevalence and predictors of childhood enuresis in southwest Nigeria: Findings from a cross-sectional population study'. PMID- 26936432 TI - Parental interview may not be the best instrument to detect daily voiding symptoms. PMID- 26936434 TI - Introductory editorial. PMID- 26936433 TI - Urinary cytokines as markers of latent inflammation in children with chronic pyelonephritis and anorectal malformations. AB - INTRODUCTION: Anorectal malformations (ARMs) comprise a range of defects in the development of the lowest portion of the intestinal tract that are often associated with anomalies of the urinary tract. We hypothesize that ARMs may specifically predispose the patients to prolonged urinary tract infection (UTI) and transition from a state of active (clinically apparent) inflammation to a state of latent inflammation following antibiotic treatment. Yet diagnosis of latent inflammation in the urinary tract is problematic. OBJECTIVE: The aim was to investigate the urinary levels of proinflammatory (IL-1beta, IL-6, IL-8, and MCP-1), anti-inflammatory (IL-10), and proangiogenic (VEGF) cytokines in the clinical course of chronic pyelonephritis (CP) as potential biomarkers of latent inflammation in the urinary tract in children with ARM. PATIENTS AND METHODS: A total of 34 children (age range 4-120 months) with CP in the active phase of inflammation were divided into two groups: CP with ARM group included 20 patients and CP without ARM group included 14 patients. The control group included 20 healthy children similar by age and gender. Urine samples were collected at the time of enrollment, 5-7 days after institution of antibiotic treatment, and 1.5 months after enrollment. Cytokine concentrations were measured by ELISA. RESULTS: Upon enrollment, we detected increased urinary levels of IL-10 and MCP-1 and normal levels of IL-1beta, IL-6, IL-8, and VEGF in CP with ARM patients as well as normal levels of all of these cytokines in CP without ARM patients. After 5-7 days of antibiotic treatment, despite significant clinical and laboratory improvement observed in both patient groups, we documented a prominent increase in the urinary concentrations of all measured cytokines indicating ongoing inflammation in the urinary tract. Following 1.5 months of enrollment, in CP without ARM patients, IL-8 and MCP-1 were increased, IL-1, IL-6, and VEGF were close to control, and IL-10 was below the control level, indicating partial resolution of the inflammatory process. In contrast, in CP with ARM patients, IL 1beta, IL-6, IL-8, MCP-1, and VEGF were increased suggesting persistent inflammation in the urinary tract (Table). CONCLUSION: Based on the urinary cytokine profile, we conclude that presence of ARM may be associated with transition from active to latent inflammation in the urinary tract after antibiotic treatment for UTI. Follow-up monitoring of the urinary cytokines may provide a better assessment of inflammatory activity in the urinary tract in children with combined urological and anorectal pathologies. PMID- 26936436 TI - Evidence of single-nanoparticle translocation through a solid-state nanopore by plasmon resonance energy transfer. AB - This work proposes a gold nanoparticle (AuNP) based probe to study the single nanoparticle translocation behavior through a silicon nitride (SiNx) solid-state nanopore. The AuNP probe is functionalized with a rhodamine derivative molecule, termed Rhod-DPA, whose fluorescence can be activated in the presence of Cu(2+) due to the binding between Rhod-DPA and Cu(2+). The Cu(2+) triggered configuration change of Rhod-DPA on the probe surface can induce the plasmon resonance energy transfer (PRET) from single AuNPs to the transformed fluorescent molecules, which can be detected by the color change of AuNP probes under dark field microscopy (DFM) and their scattering spectra recorded on a spectrometer. By analyzing the peak shifts before and after the addition of Cu(2+), evidence of single nanoparticle translocation through the nanopore has been obtained, proving the successful establishment of the tracking strategy. PMID- 26936435 TI - Renoprotective effect of curcumin against the combined oxidative stress of diabetes and nicotine in rats. AB - The progression of diabetic nephropathy (DN) is accelerated by smoking. The current study investigated the ability of curcumin to protect the kidneys against damage from oxidative stress induced by diabetes mellitus (DM) and nicotine (NC). A total of 24 male Wistar rats were divided into four groups of six rats each. DM was induced by a single intraperitoneal injection of streptozotocin 60 mg/kg body weight. DM rats were treated with or without NC in the absence or presence of curcumin for 8 weeks. As compared with the controls, DM rats exhibited reduced serum levels of high density lipoprotein, superoxide dismutase and glutathione peroxidase, and decreased renal mRNA expression levels of synaptopodin, connexin 43 and erythropoietin (EPO), which were further suppressed by NC and restored to normal levels by curcumin treatment. Additionally, DM rats exhibited increases in their lipid profiles (cholesterol, triacylglycerol and phospholipids), oxidative markers (malondialdehyde, gamma-glutamyltranspeptidase and nitric oxide), kidney function markers (urea and creatinine) and the mRNA expression levels of vimentin, desmin, SREBP-1, iNOS and TGF-beta1. These effects were further enhanced by NC, but counteracted by curcumin treatment. Kidneys from DM rats displayed glomerular hypertrophy, sclerosis and tubulo-interstitial changes represented by tubular lipid deposition, interstitial mononuclear cell infiltration and fibroplasia. Pancreatic islets exhibited cellular vacuolation, morphological irregularity and damaged or reduced in size beta-cells. These renal and pancreatic changes became more severe following NC treatment and were ameliorated by curcumin. Therefore, NC-induced DN progression may predominantly operate by increasing oxidative stress, reducing the levels of antioxidants, suppressing EPO levels, and causing perturbations to gap junction and podocyte structure. Curcumin may ameliorate the damaging effects of DM and NC on the kidney through normalization of the mRNA expression levels of several genes important in the progression of DN. PMID- 26936438 TI - Selection of reference genes for expression analysis in the potato psyllid, Bactericera cockerelli. AB - The selection of reference genes is a crucial step for quantitative real-time PCR analyses and increasingly the use of more than one reference gene for accurate and reliable normalization is being recommended. In this study, a set of six genes was selected and their stability was assessed in different life stages and female organs of Bactericera cockerelli harbouring or not the bacterial pathogen 'Candidatus Liberibacter solanacearum' (Lso) haplotype B. The stability of each gene was determined using the BestKeeper, NormFinder and GeNorm programs. These analyses identified elongation factor-1a, ribosomal protein subunit L5 and ribosomal protein subunit 18 as the most stable genes to analyse gene expression during the insect life stages irrespective of Lso presence; Lso haplotype B only affected their respective ranking. By contrast, a common set of normalizers could not be found amongst the different female organs tested (bacteriomes, alimentary canals and reproductive organs). PMID- 26936437 TI - Observing the interplay between surface and bulk optical nonlinearities in thin van der Waals crystals. AB - Van der Waals materials, existing in a range of thicknesses from monolayer to bulk, allow for interplay between surface and bulk nonlinearities, which otherwise dominate only at atomically-thin or bulk extremes, respectively. Here, we observe an unexpected peak in intensity of the generated second harmonic signal versus the thickness of Indium Selenide crystals, in contrast to the quadratic increase expected from thin crystals. We explain this by interference effects between surface and bulk nonlinearities, which offer a new handle on engineering the nonlinear optical response of 2D materials and their heterostructures. PMID- 26936439 TI - Radioresistance of granulation tissue-derived cells from skin wounds combined with total body irradiation. AB - Combined radiation and wound injury (CRWI) occurs following nuclear explosions and accidents, radiological or nuclear terrorism, and radiation therapy combined with surgery. CRWI is complicated and more difficult to heal than single injuries. Stem cell-based therapy is a promising treatment strategy for CRWI, however, sourcing stem cells remains a challenge. In the present study, the granulation tissue-derived cells (GTCs) from the skin wounds (SWs) of CRWI mice (C-GTCs) demonstrated a higher radioresistance to the damage caused by combined injury, and were easier to isolate and harvest when compared with bone marrow derived mesenchymal stromal cells (BMSCs). Furthermore, the C-GTCs exhibited similar stem cell-associated properties, such as self-renewal and multilineage differentiation capacity, when compared with neonatal dermal stromal cells (DSCs) and GTCs from unirradiated SWs. Granulation tissue, which is easy to access, may present as an optimal autologous source of stem/progenitor cells for therapeutic applications in CRWI. PMID- 26936440 TI - Penny wise, pound foolish: an assessment of Canadian Hemophilia/inherited bleeding disorder comprehensive care program services and resources. AB - INTRODUCTION: A network of 25 haemophilia/inherited bleeding disorder comprehensive care centres was established in Canada in the 1970s and 1980s. In 2007, standards of care, focused on the structural and resource requirements necessary to effectively provide optimal care, were adopted. AIM: Assess how human and physical resources affect centres' capacity to attain standards of care. METHODS: The Canadian Hemophilia Society (CHS), with the support of the Association of Hemophilia Clinic Directors of Canada (AHCDC), undertook the assessment. Health care providers were interviewed in person by lay CHS volunteers and staff. A comprehensive patient satisfaction survey was mailed to a representative cross-section of patients/caregivers. RESULTS: The CHS observed that, despite competent and dedicated staff, many of the programmes are experiencing serious resource deficiencies. Twenty-three of the 25 programmes lack resources in one or more of the following disciplines: haematology, nursing, physiotherapy, social work and clerical/data entry. In nine of the 25 programmes, no resources are allocated to certain core disciplines, notably physiotherapy and social work. Key standards of care, including regular health assessments and close monitoring of home infusion with factor concentrates, are not always respected. Nevertheless, a high level of satisfaction was observed among patients and their caregivers. The study also discovered that clotting factor concentrates constitute 90-95% of the total cost of care while all other aspects of care delivery represent only 5-10%. CONCLUSIONS: Under-funding of programmes and suboptimal monitoring of valuable clotting factor concentrate utilization and reporting are both 'penny-wise' and 'pound-foolish'. A formal accreditation process is needed. PMID- 26936441 TI - Generation and characterization of bovine bone marrow-derived macrophage cell line. AB - Macrophages, as the forefront of innate immune defense, have an important role in the host responses to mycobacterial infection. Therefore, a stable macrophage cell line is needed for future bovine immune system research on the bacterial infection. In this study, we established a bovine macrophage cell line by introducing the human telomerase reverse transcriptase (hTERT) gene into bovine bone marrow-derived macrophages (bBMMs). The TERT-bBMMs cells expressed macrophage surface antigen (CD11b, CD282) and upregulated expression of the cytokines IL-1beta, IL-6, IL-10, IL-12, TNF-alpha in response to bacterial invasion. These results demonstrate that this cell line provide reliable cell model system for future studies on interactions between the bovine macrophages and Mycobacterium tuberculosis. PMID- 26936442 TI - Tremor in a Bassoonist: Tremor in Dystonia or Essential Tremor? PMID- 26936443 TI - Rapid Eye Movement Sleep Behavior Disorder in Parkinson's Disease: A Preliminary Study. AB - OBJECTIVE: Rapid eye movement sleep behavior disorder (RBD) is associated with alpha-synucleinopathies, such as Parkinson's disease (PD). We aimed to assess the differences in the clinical characteristics of PD with and without RBD. METHODS: Forty-two patients previously diagnosed with PD were evaluated for clinical history, motor and cognitive functioning using the Unified Parkinson's Disease Rating Scale (UPDRS) and Mini-Mental State Examination (MMSE), autonomic symptoms, sleep characteristics using the Pittsburg Sleep Quality Index (PSQI), and the presence of RBD using the Korean version of the RBD screening questionnaire (RBDSQ). The prevalence of RBD and the patients' demographic features were evaluated. The patients were classified into two groups, PD with RBD and PD without RBD, based on the RBDSQ scores. The motor and cognitive functions, as well as other clinical features of the two groups were compared. RESULTS: A total of 42 PD patients were enrolled. Eighteen patients were classified as PD with RBD. Compared to PD without RBD, PD with RBD showed higher scores of rigidity in the UPDRS subscale. Regarding sleep problems, PD with RBD revealed higher sleep disturbance, lower sleep efficiency, and lower overall sleep quality in the PSQI. There was no difference in cognitive dysfunction between the two groups according to the Korean version of the MMSE. CONCLUSIONS: PD with RBD was associated with poorer sleep and motor symptoms. Therefore, RBD symptoms in PD are possibly poor prognostic markers. PMID- 26936444 TI - Physical activity in older age: perspectives for healthy ageing and frailty. AB - Regular physical activity helps to improve physical and mental functions as well as reverse some effects of chronic disease to keep older people mobile and independent. Despite the highly publicised benefits of physical activity, the overwhelming majority of older people in the United Kingdom do not meet the minimum physical activity levels needed to maintain health. The sedentary lifestyles that predominate in older age results in premature onset of ill health, disease and frailty. Local authorities have a responsibility to promote physical activity amongst older people, but knowing how to stimulate regular activity at the population-level is challenging. The physiological rationale for physical activity, risks of adverse events, societal and psychological factors are discussed with a view to inform public health initiatives for the relatively healthy older person as well as those with physical frailty. The evidence shows that regular physical activity is safe for healthy and for frail older people and the risks of developing major cardiovascular and metabolic diseases, obesity, falls, cognitive impairments, osteoporosis and muscular weakness are decreased by regularly completing activities ranging from low intensity walking through to more vigorous sports and resistance exercises. Yet, participation in physical activities remains low amongst older adults, particularly those living in less affluent areas. Older people may be encouraged to increase their activities if influenced by clinicians, family or friends, keeping costs low and enjoyment high, facilitating group-based activities and raising self-efficacy for exercise. PMID- 26936445 TI - Intronic PRRT2 mutation generates novel splice acceptor site and causes paroxysmal kinesigenic dyskinesia with infantile convulsions (PKD/IC) in a three generation family. AB - BACKGROUND: Mutations in PRRT2 cause autosomal dominant paroxysmal kinesigenic dyskinesia with infantile convulsions (PKD/IC). CASE PRESENTATION: A previously not recognized intronic PRRT2 mutation (c.880-35G > A; p.S294Lfs*29) was found in an 18 month old girl with IC and in her mother with classical presentation of PKD. The mutation results in a novel splice acceptor site in intron 2 of PRRT2. Due to frameshift and a subsequent premature stop-codon the resulting transcript appears to render the PRRT2 protein non/dysfunctional and is the likely cause of disease in this family. CONCLUSION: Our findings expand the mutational spectrum of this disease. PMID- 26936446 TI - A Randomized Trial Comparing Two Tongue-Pressure Resistance Training Protocols for Post-Stroke Dysphagia. AB - The objective of this study was to compare the outcomes of two tongue resistance training protocols. One protocol ("tongue-pressure profile training") emphasized the pressure-timing patterns that are typically seen in healthy swallows by focusing on gradual pressure release and saliva swallowing tasks. The second protocol ("tongue-pressure strength and accuracy training") emphasized strength and accuracy in tongue-palate pressure generation and did not include swallowing tasks. A prospective, randomized, parallel allocation trial was conducted. Of 26 participants who were screened for eligibility, 14 received up to 24 sessions of treatment. Outcome measures of posterior tongue strength, oral bolus control, penetration-aspiration and vallecular residue were made based on videofluoroscopy analysis by blinded raters. Complete data were available for 11 participants. Significant improvements were seen in tongue strength and post-swallow vallecular residue with thin liquids, regardless of treatment condition. Stage transition duration (a measure of the duration of the bolus presence in the pharynx prior to swallow initiation, which had been chosen to capture impairments in oral bolus control) showed no significant differences. Similarly, significant improvements were not seen in median scores on the penetration-aspiration scale. This trial suggests that tongue strength can be improved with resistance training for individuals with tongue weakness following stroke. We conclude that improved penetration-aspiration does not necessarily accompany improvements in tongue strength; however, tongue-pressure resistance training does appear to be effective for reducing thin liquid vallecular residue. PMID- 26936447 TI - Bacterial and eukaryotic biodiversity patterns in terrestrial and aquatic habitats in the Sor Rondane Mountains, Dronning Maud Land, East Antarctica. AB - The bacterial and microeukaryotic biodiversity were studied using pyrosequencing analysis on a 454 GS FLX+ platform of partial SSU rRNA genes in terrestrial and aquatic habitats of the Sor Rondane Mountains, including soils, on mosses, endolithic communities, cryoconite holes and supraglacial and subglacial meltwater lenses. This inventory was complemented with Denaturing Gradient Gel Electrophoresis targeting Chlorophyta and Cyanobacteria. OTUs belonging to the Rotifera, Chlorophyta, Tardigrada, Ciliophora, Cercozoa, Fungi, Bryophyta, Bacillariophyta, Collembola and Nematoda were present with a relative abundance of at least 0.1% in the eukaryotic communities. Cyanobacteria, Proteobacteria, Bacteroidetes, Acidobacteria, FBP and Actinobacteria were the most abundant bacterial phyla. Multivariate analyses of the pyrosequencing data revealed a general lack of differentiation of both eukaryotes and prokaryotes according to habitat type. However, the bacterial community structure in the aquatic habitats was dominated by the filamentous cyanobacteria Leptolyngbya and appeared to be significantly different compared with those in dry soils, on mosses, and in endolithic habitats. A striking feature in all datasets was the detection of a relatively large amount of sequences new to science, which underscores the need for additional biodiversity assessments in Antarctic inland locations. PMID- 26936448 TI - Isolation and characterization of yeasts associated with plants growing in heavy metal- and arsenic-contaminated soils. AB - Yeasts were quantified and isolated from the rhizospheres of 5 plant species grown at 2 sites of a Mexican region contaminated with arsenic, lead, and other heavy metals. Yeast abundance was about 10(2) CFU/g of soil and 31 isolates were obtained. On the basis of the phylogenetic analysis of 26S rRNA and internal transcribed spacer fragment, 6 species were identified within the following 5 genera: Cryptococcus (80.64%), Rhodotorula (6.45%), Exophiala (6.45%), Trichosporon (3.22%), and Cystobasidium (3.22%). Cryptococcus spp. was the predominant group. Pectinases (51.6%), proteases (51.6%), and xylanases (41.9%) were the enzymes most common, while poor production of siderophores (16.1%) and indole acetic acid (9.67%) was detected. Isolates of Rhodotorula mucilaginosa and Cystobasidium sloffiae could promote plant growth and seed germination in a bioassay using Brassica juncea. Resistance of isolates by arsenic and heavy metals was as follows: As(3+) >= 100 mmol/L, As(5+) >= 30 mmol/L, Zn(2+) >= 2 mmol/L, Pb(2+) >= 1.2 mmol/L, and Cu(2+) >= 0.5 mmol/L. Strains of Cryptococcus albidus were able to reduce arsenate (As(5+)) into arsenite (As(3+)), but no isolate was capable of oxidizing As(3+). This is the first study on the abundance and identification of rhizosphere yeasts in a heavy-metal- and arsenic contaminated soil, and of the reduction of arsenate by the species C. albidus. PMID- 26936449 TI - A simple and rapid method for identification of lesions at high risk for the no reflow phenomenon immediately before elective coronary stent implantation. AB - We aimed to design a rapid and reliable method to identify coronary lesions at high risk for the no-reflow phenomenon before elective coronary stent implantation using integrated backscatter intravascular ultrasound (IB-IVUS). The no-reflow phenomenon occurring during elective percutaneous coronary intervention (PCI) worsens patient prognosis, regardless of whether the phenomenon is transient or persistent. We retrospectively studied 353 coronary lesions to identify factors potentially promoting the no-reflow phenomenon, including lesion location and severity. We also performed component analysis by two- and three dimensional IB-IVUS before elective stent implantation. The cutoff values of the true lipid volume and estimated lipid volume (lipid area at the minimal lumen diameter site * total stent length) for the no-reflow phenomenon were determined by receiver operating curve analysis. Type C lesions, regardless of location and a thrombolysis in myocardial flow grade of 0, were risk factors for the no-reflow phenomenon during PCI. The estimated lipid volume was significantly correlated with the true lipid volume (R 2 = 0.778, p < 0.0001). The cutoff value of the estimated lipid volume for the no-reflow phenomenon was 132.6 mm3 (area under the curve = 0.719), and the predictive value was equivalent to that of the true lipid volume. Lesions with an estimated lipid volume of >=132.6 mm3 had a significantly higher risk of the no-reflow phenomenon during elective stent implantation (odds ratio, 4.35; 95 % confidence interval, 1.67-12.7; p = 0.0024). The simple and rapid measurement of the estimated lipid volume immediately before stenting during PCI constitutes a reliable predictor of lesions at high risk for the no reflow phenomenon. PMID- 26936450 TI - Comparison of first- and second-generation drug-eluting stent efficacies for treating left main and/or three-vessel disease: a propensity matched study. AB - The efficacy of second-generation drug-eluting stent (DES) for the treatment of left main disease (LM) and/or three vessel disease (3VD) remains unclear. We compared 2-year outcomes of second- versus first -generation DES implantation among patients with LM and/or 3VD and to assess the differential of risk by complexity of coronary artery disease using synergy between percutaneous coronary intervention with taxus and cardiac surgery (SYNTAX) scores. Between April 2007 and December 2012, 341 patients with LM and/or 3VD were treated by percutaneous coronary intervention; 154 with first-generation DES and 137 with second generation DES. After propensity matching, 101 patients remained in each group. The rate of target lesion revascularization (TLR) and major adverse cardiac event (MACE) were compared. TLR and MACE at 2 years were more common in the first- compared with second-generation DES group (TLR 19.8 vs. 8.9 %; p = 0.016, MACE 24.8 vs. 10.9 %; p = 0.008). In patients with low (0-22) and intermediate (23-32) SYNTAX scores, TLR and MACE tended to occur more often with first-generation DES group. In patients with high SYNTAX scores (?33), TLR and MACE were significantly more common with first-generation DES group (TLR 29.0 vs. 11.1 %; p = 0.035, MACE 35.5 vs. 13.9 %; p = 0.034). Compared with first-generation DES, second generation DES proved beneficial in reducing risk of TLR and MACE in patients with LM and/or 3VD, particularly among those with high SYNTAX scores (?33). PMID- 26936451 TI - Filling defects of the left atrial appendage on multidetector computed tomography: their disappearance following catheter ablation of atrial fibrillation and the detection of LAA thrombi by MDCT. AB - Filling defects of the left atrial appendage (LAA) on multidetector computed tomography (MDCT) are known to occur, not only due to LAA thrombi formation, but also due to the disturbance of blood flow in the LAA of patients with atrial fibrillation (AF). The purpose of this study was to evaluate the impact of the maintenance of sinus rhythm via ablation on the incidence of LAA filling defects on MDCT in patients with AF. A total of 459 consecutive patients were included in the present study. Prior to ablation, MDCT and transesophageal echocardiography (TEE) were performed. AF ablation was performed in patients without LAA thrombi confirmed on TEE. The LAA filling defects were evaluated on MDCT at 3 months after ablation. LAA filling defects were detected on MDCT in 51 patients (11.1 %), among whom the absence of LAA thrombi was confirmed in 42 patients using TEE. The LAA Doppler velocity in patients with LAA filling defects was lower than that of patients without filling defects (0.61 +/- 0.19 vs. 0.47 +/- 0.21 m/s; P < 0.0001). The sensitivity, specificity and negative predictive value of MDCT in the detection of thrombi were 100, 91 and 100 %, respectively. No LAA filling defects were observed on MDCT at 3 months after ablation in any of the patients, including the patients in whom filling defects were noted prior to the procedure. MDCT is useful for evaluating the presence of LAA thrombi and the blood flow of the LAA. The catheter ablation of AF not only suppresses AF, but also eliminates LAA filling defect on MDCT suggesting the improvement of LAA blood flow. PMID- 26936452 TI - Lipoprotein(a) levels predict adverse vascular events after acute myocardial infarction. AB - Lipoprotein(a) [Lp(a)], which is genetically determined, has been reported as an independent risk factor for atherosclerotic vascular disease. However, the prognostic value of Lp(a) for secondary vascular events in patients after coronary artery disease has not been fully elucidated. This 3-year observational study included a total of 176 patients with ST-elevated myocardial infarction (STEMI), whose Lp(a) levels were measured within 24 h after primary percutaneous coronary intervention. We divided enrolled patients into two groups according to Lp(a) level and investigated the association between Lp(a) and the incidence of major adverse cardiac and cerebrovascular events (MACCE). A Kaplan-Meier analysis demonstrated that patients with higher Lp(a) levels had a higher incidence of MACCE than those with lower Lp(a) levels (log-rank P = 0.034). A multivariate Cox regression analysis revealed that Lp(a) levels were independently correlated with the occurrence of MACCE after adjusting for other classical risk factors of atherosclerotic vascular diseases (hazard ratio 1.030, 95 % confidence interval: 1.011-1.048, P = 0.002). In receiver-operating curve analysis, the cutoff value to maximize the predictive power of Lp(a) was 19.0 mg/dl (area under the curve = 0.674, sensitivity 69.2 %, specificity 62.0 %). Evaluation of Lp(a) in addition to the established coronary risk factors improved their predictive value for the occurrence of MACCE. In conclusion, Lp(a) levels at admission independently predict secondary vascular events in patients with STEMI. Lp(a) might provide useful information for the development of secondary prevention strategies in patients with myocardial infarction. PMID- 26936453 TI - Development of the Chronic Pain Coding System (CPCS) for Characterizing Patient Clinician Discussions About Chronic Pain and Opioids. AB - OBJECTIVE: To describe the development and initial application of the Chronic Pain Coding System. DESIGN: Secondary analysis of data from a randomized clinical trial. SETTING: Six primary care clinics in northern California. SUBJECTS: Forty five primary care visits involving 33 clinicians and 45 patients on opioids for chronic noncancer pain. METHODS: The authors developed a structured coding system to accurately and objectively characterize discussions about pain and opioids. Two coders applied the final system to visit transcripts. Intercoder agreement for major coding categories was moderate to substantial (kappa = 0.5-0.7). Mixed effects regression was used to test six hypotheses to assess preliminary construct validity. RESULTS: Greater baseline pain interference was associated with longer pain discussions (P = 0.007) and more patient requests for clinician action (P = 0.02) but not more frequent negative patient evaluations of pain (P = 0.15). Greater clinician-reported visit difficulty was associated with more frequent disagreements with clinician recommendations (P = 0.003) and longer discussions of opioid risks (P = 0.049) but not more frequent requests for clinician action (P = 0.11). Rates of agreement versus disagreement with patient requests and clinician recommendations were similar for opioid-related and non opioid-related utterances. CONCLUSIONS: This coding system appears to be a reliable and valid tool for characterizing patient-clinician communication about opioids and chronic pain during clinic visits. Objective data on how patients and clinicians discuss chronic pain and opioids are necessary to identify communication patterns and strategies for improving the quality and productivity of discussions about chronic pain that may lead to more effective pain management and reduce inappropriate opioid prescribing. PMID- 26936455 TI - Correction to A Continuous, Fluorogenic Sirtuin 2 Deacylase Assay: Substrate Screening and Inhibitor Evaluation. PMID- 26936454 TI - Carnosic acid induces apoptosis through inactivation of Src/STAT3 signaling pathway in human renal carcinoma Caki cells. AB - Carnosic acid (CA), the major bioactive compound of Rosmarinus officinalis L., has been reported to possess anti-inflammatory and anticancer activities. However, the molecular mechanisms underlying the anticancer effects of CA remain poorly understood. In the present study, we investigated that CA significantly reduced the viability of human renal carcinoma Caki cells. CA-induced apoptosis was connected with the cleavage of caspase-9, -7 and -3, and that of PARP. Moreover, CA increased the expression of pro-apoptotic protein Bax and diminished the expression of anti-apoptotic protein Bcl-2 and Bcl-xL, thereby releasing cytochrome c into the cytosol. Treatment with CA in Caki cells also induced the expression of p53 and its target gene product, p27, through down-regulation of Murine double minute-2 (Mdm2). Furthermore, CA generated reactive oxygen species (ROS), and pretreatment with ROS scavenger N-acetyl cysteine (NAC) abrogated CA induced cleavage of PARP and expression of p53. One of the key oncogenic signals is mediated through signal transducer and activator of transcription-3 (STAT3), which promotes abnormal cell proliferation. Incubation of cells with CA markedly diminished the phosphorylation of STAT3 and its upstream, Src, and reduced the expression of STAT3 responsive gene products, such as D-series of cyclins and survivin. Taken together, the present study revealed that CA induced apoptosis in Caki cells by induction of p53 and suppression of STAT3 signaling. PMID- 26936456 TI - The impact of common polymorphisms in CETP and ABCA1 genes with the risk of coronary artery disease in Saudi Arabians. AB - BACKGROUND: Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide. Many genetic and environmental risk factors including atherogenic dyslipidemia contribute towards the development of CAD. Functionally relevant mutations in the dyslipidemia-related genes and enzymes involved in the reverse cholesterol transport system are associated with CAD and contribute to increased susceptibility of myocardial infarction (MI). METHOD: Blood samples from 990 angiographically confirmed Saudi CAD patients with at least one event of myocardial infarction were collected between 2012 and 2014. A total of 618 Saudi controls with no history or family history of CAD participated in the study. Four polymorphisms, rs2230806, rs2066715 (ABCA1), rs5882, and rs708272 (CETP), were genotyped using TaqMan Assay. RESULTS: CETP rs5882 (OR = 1.45, P < 0.005) and ABCA1 rs2230806 (OR = 1.42, P = 0.017) polymorphisms were associated with increased risk of CAD. However, rs708272 polymorphism showed protective effect (B1 vs. B2: OR = 0.80, P = 0.003 and B2B2 vs. B1B1: OR = 0.68, P = 0.012) while the ABCA1 variant rs2066715 was not associated. CONCLUSION: This study is the first to report the association of these polymorphisms with CAD in the population of the Eastern Province of Saudi Arabia. The rs5882 polymorphism (CETP) showed a significant association and therefore could be a promising marker for CAD risk estimation while the rs708272 polymorphism had a protective effect from CAD. PMID- 26936458 TI - Alternatively activated macrophages exhibit an anticalcifying activity dependent on extracellular ATP/pyrophosphate metabolism. AB - Calcium-phosphate deposition (CPD) in atherosclerotic lesions, which begins in middle age and increases with aging, is a major independent predictor of future cardiovascular disease morbi-mortality. Remodeling of atherosclerotic vessels during aging is regulated in part by intimal macrophages, which can polarize to phenotypically distinct populations with distinct functions. This study tested the hypothesis that classically activated macrophages (M1phis) and alternatively activated macrophages (M2phis) differently affect vascular smooth muscle cell (VSMC) calcification and investigated the underlying mechanisms. We analyzed mouse VSMC-macrophage cocultures using a transwell system. Coculture of VSMCs with M2phis significantly reduced CPD, but coculture with M1phis had no effect. The anticalcific effect of M2phis was associated with elevated amounts of extracellular ATP and pyrophosphate (PPi), two potent inhibitors of CPD, and was lost upon forced hydrolysis of these metabolites. In M2phis and VSMC-M2phis cocultures, analysis of the ectoenzymes that regulate extracellular ATP/PPi metabolism revealed increased mRNA expression and activity of ectoenzyme nucleotide pyrophosphatase/phosphodiesterase-1, which synthesizes PPi from ATP, without changes in tissue-nonspecific alkaline phosphatase, which hydrolyzes PPi In conclusion, increased accumulation of extracellular ATP and PPi by alternatively activated mouse M2phis inhibits CPD. These results reveal novel mechanisms underlying macrophage-dependent control of intimal calcification. PMID- 26936457 TI - Simulation of the effects of moderate stimulation/inhibition of the beta1 adrenergic signaling system and its components in mouse ventricular myocytes. AB - The beta1-adrenergic signaling system is one of the most important protein signaling systems in cardiac cells. It regulates cardiac action potential duration, intracellular Ca(2+) concentration ([Ca(2+)]i) transients, and contraction force. In this paper, a comprehensive experimentally based mathematical model of the beta1-adrenergic signaling system for mouse ventricular myocytes is explored to simulate the effects of moderate stimulations of beta1 adrenergic receptors (beta1-ARs) on the action potential, Ca(2+) and Na(+) dynamics, as well as the effects of inhibition of protein kinase A (PKA) and phosphodiesterase of type 4 (PDE4). Simulation results show that the action potential prolongations reach saturating values at relatively small concentrations of isoproterenol (~0.01 MUM), while the [Ca(2+)]i transient amplitude saturates at significantly larger concentrations (~0.1-1.0 MUM). The differences in the response of Ca(2+) and Na(+) fluxes to moderate stimulation of beta1-ARs are also observed. Sensitivity analysis of the mathematical model is performed and the model limitations are discussed. The investigated model reproduces most of the experimentally observed effects of moderate stimulation of beta1-ARs, PKA, and PDE4 inhibition on the L-type Ca(2+) current, [Ca(2+)]i transients, and the sarcoplasmic reticulum Ca(2+) load and makes testable predictions for the action potential duration and [Ca(2+)]i transients as functions of isoproterenol concentration. PMID- 26936460 TI - Aggregation of the metallocycles {Cu8} and {Cu20} using [Cu(bp)] units (H2bp = bis(2-hydroxybenzyl)amine): structures and magnetic properties. AB - Two metallocycles, {Cu8(bp)4(OH)4(H2O)4(ClO4)4} (1) and {Cu20(bp)20} (2), were afforded by the reactions of the semi-flexible tridentate ligand bis(2 hydroxybenzyl)amine (H2bp) with Cu(ClO4)2.6H2O and Cu(OAc)2.H2O. Complex 1 has a saddle-shaped cyclic structure and complex 2 has a nanosized wheel-shaped structure. The two compounds consist of [Cu(bp)] units. PMID- 26936461 TI - Is sadness blue? The problem of using figurative language for emotions on psychological tests. AB - Psychological tests sometimes include figurative language like I feel blue. However, figurative language may not mean the same thing cross-culturally. Previous research found cross-cultural evidence for 14 conceptual metaphors and metonymies for emotions (e.g., sadness is blue). Our two studies asked participants (total n = 795) in the USA and India whether happiness, sadness, anger, and fear are associated with certain descriptors (blue, down, bright, etc.). Most participants in both countries endorsed ten of the 14 hypothesized associations; however, the percentage of participants endorsing an association was often far from 100 %. For example, in the USA, only 71.7 % associated hot with anger and only 65.9 % associated blue with sadness. Moreover, descriptors were often associated with more than one emotion. Furthermore, only two associations (happiness is up and bright) were endorsed by more than 90 % of participants in both countries and had descriptors that were not associated with additional emotions. We conclude that figurative language is often ambiguous and should be used with caution on psychological tests unless there is evidence the language is understood cross-culturally. Advice to this effect is currently lacking from psychometrics textbooks and should be added. PMID- 26936459 TI - Hepatic resection provided long-term survival for patients with intermediate and advanced-stage resectable hepatocellular carcinoma. AB - BACKGROUND: Hepatic resection has the highest local controllability that results in long-term survival for hepatocellular carcinoma (HCC). This study aimed to investigate the role of hepatic resection in selected patients of intermediate and advanced stage. METHODS: Clinical, pathological, and outcome data of 542 consecutive patients were retrospectively analyzed from a single center. The Kaplan-Meier method was used to estimate survival. Postoperative prognostic factors were evaluated using univariate and multivariate analyses. RESULTS: The 1 , 3-, and 5-year overall survival rates were 89.0, 64.3, and 53.0%, respectively. The 1-, 3-, and 5-year disease-free survival rates were 72.2, 44.5, and 34.2%, respectively. Preoperative alpha-fetoprotein level >400 ng/mL, macroscopic vascular invasion, microscopic portal vein thrombosis, multiple tumor nodules, and the largest tumor size >5 cm were significantly correlated with overall survival. When these clinical risk factors were used in a postoperative staging system, assigning one point for each factor, the total score was precisely predictive of long-term survival. For patients with surgery plus adjuvant TACE (transarterial chemoembolization), the median overall survival was 56 months (range 1-110 months) and the 5-year OS rate was 48.5%. CONCLUSIONS: Hepatic resection is efficient and safe for HCC patients of intermediate and advanced stage. The adjuvant TACE should be recommended for HCC patients with poor risk factors. PMID- 26936462 TI - Flipping the stimulus: Effects on scanpath coherence? AB - In experiments investigating dynamic tasks, it is often useful to examine eye movement scan patterns. We can present trials repeatedly and compute within subjects/conditions similarity in order to distinguish between signal and noise in gaze data. To avoid obvious repetitions of trials, filler trials must be added to the experimental protocol, resulting in long experiments. Alternatively, trials can be modified to reduce the chances that the participant will notice the repetition, while avoiding significant changes in the scan patterns. In tasks in which the stimuli can be geometrically transformed without any loss of meaning, flipping the stimuli around either of the axes represents a candidate modification. In this study, we examined whether flipping of stimulus object trajectories around the x- and y-axes resulted in comparable scan patterns in a multiple object tracking task. We developed two new strategies for the statistical comparison of similarity between two groups of scan patterns, and then tested those strategies on artificial data. Our results suggest that although the scan patterns in flipped trials differ significantly from those in the original trials, this difference is small (as little as a 13 % increase of overall distance). Therefore, researchers could use geometric transformations to test more complex hypotheses regarding scan pattern coherence while retaining the same duration for experiments. PMID- 26936463 TI - Use of Skin-Whitening Products by Sudanese Undergraduate Females: a Survey. AB - BACKGROUND: Although skin-whitening products are commonly used among dark-skinned women of African descent, research on the frequency with which Sudanese women use skin-whitening products is lacking. METHODS: A cross-sectional study was conducted at the University of Gezira, Sudan, on the use of skin-whitening products among a sample of Sudanese undergraduate females (ages 16-33 years). Sociodemographic characteristics were collected, and students were asked whether they had used skin-whitening products in the past 12 months. RESULTS: Of the 348 undergraduate females surveyed in this study, 74.4 % reported using skin whitening products within the past year. Of this group, 2.7 % reported using injections, 2.4 % pills, 30.6 % bleaching cream, and 76.2 % soap. Illegal sources (e.g., people selling on the sides of roads) of skin-whitening products were reported by 22.8 %. The use of skin-whitening products was common in females who were not satisfied with their skin colors more so than those who were satisfied with their skin colors (83.7 vs. 70.5 %, P = 0.010). Undergraduate females who had mothers, sisters, or other relatives who bleached reported a greater frequency of using skin-whitening products than those who had no family member who bleached (100, 87.7, or 77 % vs. 67.5 %, P = 0.003, respectively). The odds of using skin-whitening products in females who had mothers or sisters bleaching were 7.8 times higher (adjusted odds ratio (aOR) 7.8; 95 % confidence interval (CI) 2.572, 23.828) and two times higher in females who had other relatives bleaching (aOR 2.4; 95 % CI 1.159, 5.115), compared with females who had no family members who bleached. CONCLUSION: It was estimated that a majority (7 out of 10) of Sudanese undergraduate females have tried skin-whitening products. However, because the university population is an elite group, a population-based survey is warranted to address the use of skin-whitening products among the general population of Sudanese women. PMID- 26936464 TI - Erratum to: Measuring motivation for medical treatment: confirming the factor structure of the Achievement Motivation Index for Medical Treatment (AMI-MeT). PMID- 26936465 TI - Antihypertensive drugs and statins must be considered in arterial stiffness evaluation in patients with Alzheimer's disease. PMID- 26936467 TI - Foreign body into a lumbar vertebral body: how did it get in there? PMID- 26936466 TI - The impact of detoxifying and repair gene polymorphisms on oxidative stress in ischemic stroke. AB - Stroke is a multifactorial disease caused by the combination of certain risk factors and genetic factors. There are possible risk factors having important role in the pathogenesis of stroke. The most important environmental factors are cigarette smoking and oxidative stress which have different sources. GST (M1, T1, P1) have major roles in detoxification of the products of oxidative stress and they are polymorphic. DNA damages can also be repaired by repair enzymes such as OGG1 and XRCC1 which are highly polymorphic and have pivotal roles in repair systems. In the present study, we investigated that polymorphisms in genes involved in detoxification and DNA-repair pathways might modify the individual's risk for ischemic stroke. Furthermore, the products of oxidative stress and antioxidant capacity were measured and the impact of gene polymorphism on them was evaluated. Our data showed that OGG1 Ser326Cys and XRCC1 Arg399Gln gene polymorphisms had impacts on the development of stroke. PMID- 26936469 TI - Prognostic implications in patients with symptomatic aortic stenosis and preserved ejection fraction: Japanese multicenter aortic stenosis, retrospective (JUST-R) registry. AB - BACKGROUND: Current prognostic implication of symptomatic patients with aortic stenosis (AS) remains undetermined. This study investigated the current prognostic implications of AS-related symptoms and the effect of aortic valve replacement (AVR) on outcome. METHODS: We enrolled 586 consecutive patients with severe AS (aortic valve area <1.0cm2) with preserved left ventricular ejection fraction (>=50%). All patients were stratified into the following four groups based on the predominant symptoms: Group 1, asymptomatic (n=316); Group 2, chest pain (n=41); Group 3, heart failure (n=192); or Group 4, syncope (n=37). RESULTS: AS-related symptoms were diagnosed in 270 patients (46.1%), among whom 182 patients (32.2%) received AVR. Thirty-nine patients (6.7%) had cardiac death during the mean follow-up of 16+/-14 months. AVR was associated with significant reduction in cardiac death in Groups 3 (p<0.001) and 4 (p=0.004) whereas no significant prognostic advantage of AVR was observed in Groups 1 or 2. Cox proportional-hazard multivariate analysis revealed that age, heart failure, and mean pressure gradient (PG) were associated with increased risk of cardiac death in all patients regardless of AVR [hazard ratio (HR): 1.079, 2.090, and 1.008 respectively, all p<0.05]. In the patients without AVR, age, heart failure, syncope, and mean PG were independently associated with cardiac death (HR: 1.130, 3.639, 4.638, and 1.008, all p<0.05). CONCLUSION: This retrospective study demonstrated the current associations between the types of AS symptoms and prognosis in Japanese patients with severe AS. PMID- 26936468 TI - Norton scale for predicting prognosis in elderly patients undergoing trans catheter aortic valve implantation: A historical prospective study. AB - BACKGROUND: The Norton scale is traditionally used to assess the risk of pressure ulcers. However, recent studies have shown its prognostic utilization in elderly patients with diverse medical conditions. The association between low admission Norton scale scores (ANSS), complications, and mortality in elderly patients following trans-catheter aortic valve implantation (TAVI) has never been studied. We aimed to determine if low ANSS (<=16) is associated with complications and 30 day and 1-year mortality in elderly patients undergoing TAVI. METHODS: The medical charts of elderly (>=70 years) TAVI patients at the Tel-Aviv Medical Center, a tertiary medical center, were studied for the following measurements: ANSS, demographics, co-morbidities, complications during hospitalization, and 30 day and 1-year mortality. Complications included: an atrio-ventricular block, stroke, and vascular complications. RESULTS: The cohort included 302 elderly patients: 179 (59.3%) were women; the mean age was 83.3+/-5.1 years. Following TAVI, 112 (37.1%) patients had complications other than pressure ulcers, 10 (3.3%) patients died within 30 days, and 42 (13.9%) patients died within one year. Overall, 36 (11.9%) patients had low ANSS. 1-year mortality rates were almost three times higher in patients with low ANSS relative to patients with high ANSS (27.8% vs. 12.0%; the relative risk 1.1; p=0.018). A stepwise logistic regression analysis showed that ANSS was independently inversely associated with 1-year mortality (p=0.018). Complications and 30-day mortality rates were similar in both groups. CONCLUSIONS: Low ANSS are associated with 1-year mortality after TAVI. The Norton scale may therefore be used as an additional tool for elderly patient selection before TAVI. PMID- 26936470 TI - A combined method for synthesis of superconducting Cu doped Bi2Se3. AB - We present a two-step technique for the synthesis of superconducting CuxBi2Se3. Cu0.15Bi2Se3 single crystals were synthesized using the melt-growth method. Although these samples are non-superconducting, they can be employed to generate high quality superconducting samples if used as precursors in the following electrochemical synthesis step. Samples made from Cu0.15Bi2Se3 reliably exhibit zero-resistance even under the non-optimal quenching condition, while samples made from pristine Bi2Se3 require fine tuning of the quenching conditions to achieve similar performance. Moreover, under the optimal quenching condition, the average superconducting shielding fraction was still lower in the samples made from pristine Bi2Se3 than in the samples made from Cu0.15Bi2Se3. These results suggest that the pre-doped Cu atoms facilitate the formation of a superconducting percolation network. We also discuss the useful clues that we gathered about the locations of Cu dopants that are responsible for superconductivity. PMID- 26936471 TI - The recommended treatment algorithms of the BCLC and HKLC staging systems: does following these always improve survival rates for HCC patients? AB - BACKGROUND & AIMS: Several staging systems have been proposed for hepatocellular carcinoma (HCC). Among them, only the Barcelona Clinic Liver Cancer (BCLC) and Hong Kong Liver Cancer (HKLC) staging systems also recommend treatment modality. This study was designed to see whether BCLC and HKLC staging can guide treatment strategy, so analyzed whether patients survival is better for those who received recommended therapy by each staging system. METHODS: A total of 3515 treatment naive, newly diagnosed HCC patients at a single centre were analyzed. RESULTS: Five-year survival rates according to BCLC stages: 0 = 79.1%, A = 62.9%, B = 40.3%, C = 21.3% and D = 27.0%; 5-year survival rates according to HKLC stages: I = 72.3%, IIa = 54.9%, IIb = 50.6%, IIIa = 21.3%, IIIb = 10.2%, IVa = 16.7%, IVb = 7.2%, Va = 47.1% and Vb = 11.3%. The C-indices of the BCLC and HKLC staging systems were 0.708 and 0.732 respectively. Patient survival was better when patients received the recommended treatment in stages 0 or A; survival was worse if treatment began at stage B, C or D. For HKLC staging system, survival was better when patients received the recommended treatment in stages I, IIa, IIb, IIIa or Va but was worse when treatment began in stages IIIb, IVa, IVb or Vb. CONCLUSION: Both the BCLC and HKLC staging systems effectively stratified patient prognosis, but neither could direct therapy for a large proportion of patients; for some stages, recommended therapy was associated with worse prognosis. PMID- 26936472 TI - Forty years of The Selfish Gene are not enough. PMID- 26936473 TI - Bioaccumulation and Quantitative Variations of Microcystins in the Swartspruit River, South Africa. AB - The bioaccumulation and quantitative variations of cyanobacterial peptide hepatotoxin intracellular microcystin in floating scums of cyanobacterium microcystis flos aquae collected from predetermined sampling sites in the Swartspruit River was investigated. Three distinct MCs variants (MC-YR, MC-LR, and MC-RR) were isolated, identified, and quantified. Additionally, two minor microcystin congeners (MC-(H4) YR), (D-Asp(3), Dha(7))MC-RR) also were identified but were not quantified. Quantitative analysis was achieved using peak areas substituted on linear regression equations: Y = 10085x - 19698 (R (2) = 0.9998), Y = 201387x + 20328 (R (2) = 0.9929), Y = 2506x + 15659 (R (2) = 0.9999), and 9859x + 208694 (R (2) = 0.9929) of standard curves for 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, and 10.0 MUg/mL MC-LR, MC-RR, MC-YR respectively. Variant dominance followed the order MC-LR > MC-RR > MC-YR across the sampling sites. Analysis of maximum and minimum concentrations of quantified MCs variants showed 270.7, 14.10 (ug/g), 141.5, 1.43 (ug/g), and 72.28, 0.15 (ug/g) for MC-LR, MC-RR, and MC-YR, respectively. This implies there was quantitative variations of microcystin congeners across the sampled sites. Significant differences between means were assessed by an analysis of variance with P < 0.05 being considered significant. Results showed that there were no significant difference between mean MCs concentrations across the sampling periods (P > 0.05) and significant difference between mean MCs concentrations across sampling sites (P < 0.05). PMID- 26936474 TI - TNFalpha-induced M-MDSCs promote transplant immune tolerance via nitric oxide. AB - Efficient induction of functional competent myeloid-derived suppressor cells (MDSCs) will be critical for the clinical application of MDSCs to treat autoimmune diseases and to induce transplantation immune tolerance. In the present study, we tried to establish the MDSC induction system with M-CSF and tumor necrosis factor alpha (TNFalpha) and investigated the immunosuppressive function of M-CSF + TNFalpha-induced MDSCs in transplant mouse models. Monocytic MDSCs (M-MDSCs) were induced by culture of the non-adherent mouse bone marrow cells with M-CSF or M-CSF + TNFalpha, respectively, for 7 days. Phenotype analysis revealed that the majority of M-CSF- and M-CSF + TNFalpha-induced MDSCs express F4/80. The addition of TNFalpha in the induction period increased Gr-1, Ly6C, CD80, and CD274 expressions on these cells. M-CSF + TNFalpha-induced M MDSCs showed poor TNFalpha, IL-12, and IL-6 expressions after lipopolysaccharide (LPS) stimulation and decreased arginase 1 (Arg-1) and Fizz expressions after IL 4 stimulation compared with M-CSF-induced M-MDSCs. M-CSF + TNFalpha-induced M MDSCs showed enhanced ability to suppress T cell proliferation and cytokine production than M-CSF-induced M-MDSCs. M-CSF + TNFalpha-induced M-MDSCs express high levels of inducing nitric oxide synthase (iNOS) and blocking iNOS activity by a chemical inhibitor or gene deficiency significantly reversed the inhibitory effects of M-CSF + TNFalpha-induced M-MDSCs on T cells. Adoptive transfer of M CSF + TNFalpha-induced M-MDSCs promoted immune tolerance in a male-to-female skin grafted mice, but M-CSF + TNFalpha-induced iNOS-deficient M-MDSCs failed to do so. Thus, M-CSF + TNFalpha-induced M-MDSCs have powerful immunosuppressive activity, which is mediated by an iNOS-dependent pathway. M-CSF + TNFalpha induced M-MDSCs can promote immune tolerance to donor antigens in a transplant mouse model. KEY MESSAGE: The combination of M-CSF and TNFalpha efficiently induces functional M-MDSCs in vitro. M-CSF + TNFalpha-induced M-MDSCs promote immune tolerance in a transplant mouse model. The immunosuppressive ability of M CSF + TNFalpha-induced M-MDSCs is dependent on iNOS. PMID- 26936476 TI - Assessment of the relationship between rural non-point source pollution and economic development in the Three Gorges Reservoir Area. AB - This study investigates the relationship between rural non-point source (NPS) pollution and economic development in the Three Gorges Reservoir Area (TGRA) by using the Environmental Kuznets Curve (EKC) hypothesis for the first time. Five types of pollution indicators, namely, fertilizer input density (FD), pesticide input density (PD), agricultural film input density (AD), grain residues impact (GI), and livestock manure impact (MI), were selected as rural NPS pollutant variables. Rural net income per capita was used as the indicator of economic development. Pollution load was generated by agricultural inputs (consumption of fertilizer, pesticide, and agricultural film) and economic growth with invert U shaped features. The predicted turning points for FD, PD, and AD were at rural net income per capita levels of 6167.64, 6205.02, and 4955.29 CNY, respectively, which were all surpassed. However, the features between agricultural waste outputs (grain residues and livestock manure) and economic growth were inconsistent with the EKC hypothesis, which reflected the current trends of agricultural economic structure in the TGRA. Given that several other factors aside from economic development level could influence the pollutant generation in rural NPS, a further examination with long-run data support should be performed to understand the relationship between rural NPS pollution and income level. PMID- 26936475 TI - beta-Estradiol and ethinyl-estradiol contamination in the rivers of the Carpathian Basin. AB - 17beta-Estradiol (E2) and 17alpha-ethinyl estradiol (EE2), which are environmental estrogens, have been determined with LC-MS in freshwater. Their sensitive analysis needs derivatization and therefore is very hard to achieve in multiresidue screening. We analyzed samples from all the large and some small rivers (River Danube, Drava, Mur, Sava, Tisza, and Zala) of the Carpathian Basin and from Lake Balaton. Freshwater was extracted on solid phase and derivatized using dansyl chloride. Separation was performed on a Kinetex XB-C18 column. Detection was achieved with a benchtop orbitrap mass spectrometer using targeted MS analysis for quantification. Limits of quantification were 0.05 ng/L (MS1) and 0.1 ng/L (MS/MS) for E2, and 0.001 ng/L (MS1) and 0.2 ng/L (MS/MS) for EE2. River samples contained n.d.-5.2 ng/L E2 and n.d.-0.68 ng/L EE2. Average levels of E2 and EE2 were 0.61 and 0.084 ng/L, respectively, in rivers, water courses, and Lake Balaton together, but not counting city canal water. EE2 was less abundant, but it was still present in almost all of the samples. In beach water samples from Lake Balaton, we measured 0.076-0.233 E2 and n.d.-0.133 EE2. A relative high amount of EE2 was found in river Zala (0.68 ng/L) and in Heviz-Pahoki canal (0.52 ng/L), which are both in the catchment area of Lake Balaton (Hungary). PMID- 26936477 TI - Polychlorinated biphenyl 126 exposure in L6 myotubes alters glucose metabolism: a pilot study. AB - Polychlorinated biphenyls (PCBs) are increasingly recognized as metabolic disruptors. Due to its mass, skeletal muscle is the major site of glucose disposal. While muscle mitochondrial dysfunction and oxidative stress have been shown to play a central role in metabolic disease development, no studies to date have investigated the effect of PCB exposure on muscle energy metabolism and oxidative stress. In this pilot study, we tested the effect of exposure to PCB126 in L6 myotubes (from 1 to 2500 nM for 24 h) on mitochondrial function, glucose metabolism, and oxidative stress. Exposure to PCB126 had no apparent effect on resting, maximal, and proton leak-dependent oxygen consumption rate in intact L6 myotubes. However, basal glucose uptake and glycolysis were inhibited by 20-30 % in L6 myotubes exposed to PCB126. Exposure to PCB126 did not appear to alter skeletal muscle anti-oxidant defense or oxidative stress. In conclusion, our study shows for the first time that exposure to a dioxin-like PCB adversely affects skeletal muscle glucose metabolism. Given the importance of skeletal muscle in the maintenance of glucose homeostasis, PCB126 could play an important role in the development of metabolic disorders. PMID- 26936478 TI - Aqueous extracts of Mozambican plants as alternative and environmentally safe acid-base indicators. AB - Indicators are substances that change color as the pH of the medium. Many of these substances are dyes of synthetic origin. The mulala plant (Euclea natalensis), which roots are commonly used by rural communities for their oral hygiene, and roseira (Hibiscus rosa-sinensis), an ornamental plant, are abundant in Mozambique. Currently, synthetic acid-base indicators are most commonly used but have environmental implications and, on the other hand, are expensive products, so the demand for natural indicators started. This study investigated the applicability of aqueous extracts of H. rosa-sinensis and E. natalensis as acid-base indicators. Ground on this work, the extracts can be used as acid-base indicators. On the basis of the absorption spectroscopy in both the UV-Vis region and previous studies, it was possible to preliminarily pinpoint anthocyanins and naphthoquinones as responsible for the shifting of colors depending on the pH range of aqueous extracts of H. rosa-sinensis and E. natalensis. These natural indicators are easily accessible, inexpensive, easy to extract, environmentally safe, and locally available. PMID- 26936479 TI - Bisphenol A exposure and healing effects of Adiantum capillus-veneris L. plant extract (APE) in bisphenol A-induced reproductive toxicity in albino rats. AB - The current study presents the bisphenol A exposure and the ameliorative effects of Adiantum capillus-veneris on testicular toxicity induced by bisphenol A. Adult male albino rats were divided into five groups of five animals each: A (control), B (vehicle control), C (toxic), D (protective), and E (ameliorative) were served distilled water, olive oil, bisphenol A (BPA) at 100 mg/kg body weight, A. capillus-veneris plant extract at 25 mg/kg body weight, and BPA + A. capillus veneris, respectively. All of the doses were administered orally for 15 days, and the rats were then sacrificed. Blood samples for the testosterone assay and both testes were collected for histological examination. The body weight, paired testes weight, relative tissue weight index, Johnsen scoring of tubules, and level of serum testosterone decreased in BPA-treated rats. Similarly, histological examination of the testes in BPA-treated animals revealed a lower number of Leydig cells, an irregular basement membrane, sloughing of germinal layers, vacuolization, a lower number of spermatocytes, and debris in the lumen. However, co-administration of A. capillus-veneris with BPA increased the total antioxidative capacity (330.82 +/- 22.46 MUmol/mg protein) of the testes and restored the serum testosterone level (1.70 ng/ml); histological features showed restoration in the stages of spermatogenesis. Conclusively, A. capillus-veneris plant extract overcomes the estrogenic effects of BPA on the reproductive system of rats and protects rats' testes against BPA-induced injury/damage via an antioxidative mechanism that appears to be conciliated. PMID- 26936481 TI - Effects of an awareness raising campaign on intention and behavioural determinants for handwashing. AB - This article assesses the effectiveness of The Great WASH Yatra handwashing awareness raising campaign in India on changing visitors' intention to wash hands with soap after using the toilet and the underlying behavioural determinants. Interviews based on the RANAS (Risk, Attitudes, Norms, Abilities, Self regulation) model of behaviour change were conducted with 687 visitors before and after their visit to the campaign. Data showed that a campaign visit had little effect on the intention to wash hands with soap, even when comparing visitors who had actively participated in handwashing games with those who had not. After a campaign visit, knowledge about the benefits of washing hands had increased by almost half a standard deviation. A multiple linear regression analysis revealed that when considering all behavioural determinants change scores simultaneously, they were able to explain 57% of the variance in the intention change score. These findings suggest that substantively changing behaviour requires more than improving knowledge and emphasizing the importance of washing hands. Identifying the crucial behavioural determinants for handwashing may be an important first step in planning effective large-scale promotion programmes. PMID- 26936480 TI - A youth mentor-led nutritional intervention in urban recreation centers: a promising strategy for childhood obesity prevention in low-income neighborhoods. AB - B'More Healthy Community for Kids (BHCK) is an ongoing multi-level intervention to prevent childhood obesity in African-American low-income neighborhoods in Baltimore city, MD. Although previous nutrition interventions involving peer mentoring of youth have been successful, there is a lack of studies evaluating the influence of cross-age peers within interventions targeting youth. This article evaluates the implementation of the BHCK intervention in recreation centers, and describes lessons learned. Sixteen youth leaders delivered bi weekly, interactive sessions to 10- to 14-y olds. Dose, fidelity and reach are assessed, as is qualitative information regarding what worked well during sessions. Dose is operationalized as the number of interactive sessions, and taste tests, giveaways and handouts per session; fidelity as the number of youth leaders participating in the entire intervention and per session and reach as the number of interactions with the target population. Based on a priori set values, number of interactive sessions was high, and number of taste tests, giveaways and handouts was moderate to high (dose). The number of participating youth leaders was also high (fidelity). Of the 14 planned sessions, the intervention was implemented with high/moderate reach. Data suggest that working with cross-age peers is a promising nutritional intervention for recreation centers. PMID- 26936482 TI - Knowledge and practice of sun protection in schools in South Africa where no national sun protection programme exists. AB - Interventions in primary schools that increase sun-protective behaviours and decrease ultraviolet radiation exposure, sunburn incidence and skin cancer risk can be effective. SunSmart School Accreditation Programmes (SSAP) are recommended. Prior to SSAP implementation in South Africa, we explored the feasibility of obtaining national baseline information and investigated possible associations between strategies regarding sun protection in schools and students' responses to a questionnaire. Principals from randomly selected urban government schools in all nine South African provinces completed a questionnaire and 679 students were surveyed. The mean sun-related knowledge and behaviour scores of students were 4 (range: 1-7) and 3 (range-0-8) out of 9, respectively. The mean school sun protection effort score was 4 out of 14. There were no statistically significant correlations between students' knowledge or behaviour scores and their school score. The World Health Organization recommends an SSAP to address policy, practice and curriculum changes to support sun protection of students. This cross-sectional study demonstrates the feasibility of, and need for, a larger baseline study with longitudinal, multi-variable follow-up which includes other influential factors, such as parent support. Such research could quantify the impact of the SSAP and identify which key factors influence the sun-related knowledge and behaviours of students. PMID- 26936483 TI - Analysis of planar acintigraphic images using the Li-Ma technique. AB - A statistics-based approach to comparison of planar scintigraphic images is introduced to provide additional information to subtraction method. The proposed procedure leads to parametric images with better noise properties allowing subsequent statistical analysis. An example of an application of the technique is given using parathyroid scintigrams. The presented technique is not intended to replace the image subtraction method but offers a tool that may help during a diagnosis-making process. PMID- 26936484 TI - Penicillium purpurogenum cultures under ethanol-induced stress and its correlation with fungal adhesion and biodegrading ability. AB - Fungi are known to be affected by external environmental stimuli, resulting in different stress response effects, which in turn could be used to enhance its biodegrading ability. In a previous study, ethanol was used to manipulate cell cell and cell-surface interaction to prevent cell loss and maximize the usage of Penicillium purpurogenum cells in the media, a correlation was drawn between ethanol oxidative stress, surface-bound proteins and fungal adhesion. The present study focuses on a more detailed study of the effect of ethanol on the same fungus. The results show that the presence of Yap1p gene and the detection of an oxidized form of glutathione (GSSG) suggest that a stress response might be involved in the adhesion process. The process of adhesion could be described as a signaling process and it is affected by the germ tube formation as an initial step in adhesion. Protein profile showed polymorphism in surface-bound proteins for cultures amended with ethanol when compared to control cultures. Ethanol also affected the DNA polymorphic profile of DNA, rendering the fungus genetically variable. P. purpurogenum produced phenol oxidase enzyme and could be used to degrade total phenols in olive mill waste water without the formation of biofilm on the surface of the containers. PMID- 26936485 TI - Inhibitor of growth 4 suppresses colorectal cancer growth and invasion by inducing G1 arrest, inhibiting tumor angiogenesis and reversing epithelial mesenchymal transition. AB - Previous studies have found that inhibitor of growth 4 (ING4), a tumor suppressor, is reduced in human colorectal cancer (CRC), and is inversely correlated with clinical Dukes' stage, histological grade, lymph node metastasis and microvessel density (MVD). However, its underlying mechanism remains undetermined. In the present study, we analyzed ING4 expression in a panel of human CRC cells using low (LS174T and SW480) and high (LoVo and SW620) metastatic cell lines. We demonstrated that both the low and high metastatic CRC cells exhibited a lower level of ING4 compared to the level in normal human colorectal mucous epithelial FHC cells. Furthermore, ING4 expression in high metastatic CRC cells was less than that in low metastatic CRC cells. We then generated a lentivirus construct expressing ING4 and green fluorescent protein (GFP), established a ING4-stably transgenic LoVo CRC cell line, and investigated the effect of lentiviral-mediated ING4 expression on high metastatic LoVo CRC cells. Gain-of-function studies revealed that ING4 significantly inhibited LoVo CRC cell growth and invasion in vitro and induced cell cycle G1 phase arrest. Moreover, ING4 obviously suppressed LoVo CRC subcutaneously xenografted tumor growth and reduced tumor MVD in vivo in athymic BALB/c nude mice. Mechanistically, ING4 markedly upregulated P21 and E-cadherin but downregulated cyclin E, interleukin (IL)-6, IL-8, vascular endothelial growth factor (VEGF), Snail1, N-cadherin and vimentin in the LoVo CRC cells. Our data provide compelling evidence that i) ING4 suppresses CRC growth possibly via induction of G1 phase arrest through upregulation of P21 cyclin-dependent kinase (CDK) inhibitor and downregulation of cyclin E as well as inhibition of tumor angiogenesis through reduction of IL-6, IL-8 and VEGF proangiogenic factors; ii) ING4 inhibits CRC invasion and metastasis probably via a switch from mesenchymal marker N-cadherin to epithelial marker E-cadherin through downregulation of Snail1 epithelial-mesenchymal transition (EMT)-inducing transcription factor (EMT-TF). PMID- 26936486 TI - WHICH PATIENTS WITH CHRONIC KIDNEY DISEASE HAVE THE GREATEST SYMPTOM BURDEN? A COMPARATIVE STUDY OF ADVANCED CKD STAGE AND DIALYSIS MODALITY. AB - BACKGROUND: Chronic kidney disease (CKD) leads to a range of symptoms, which are often under-recognised and little is known about the multidimensional symptom experience in advanced CKD. OBJECTIVES: To examine (1) symptom burden at CKD stages 4 and 5, and dialysis modalities, and (2) demographic and renal history correlates of symptom burden. METHODS: Using a cross-sectional design, a convenience sample of 436 people with CKD was recruited from three hospitals. The CKD Symptom Burden Index (CKD-SBI) was used to measure the prevalence, severity, distress and frequency of 32 symptoms. Demographic and renal history data were also collected. RESULTS: Of the sample, 75.5 % were receiving dialysis (haemodialysis, n = 287; peritoneal dialysis, n = 42) and 24.5 % were not undergoing dialysis (stage 4, n = 69; stage 5, n = 38). Participants reported an average of 13.01 +/- 7.67 symptoms. Fatigue and pain were common and burdensome across all symptom dimensions. While approximately one-third experienced sexual symptoms, when reported these symptoms were frequent, severe and distressing. Haemodialysis, older age and being female were independently associated with greater symptom burden. CONCLUSIONS: In CKD, symptom burden is better understood when capturing the multidimensional aspects of a range of physical and psychological symptoms. Fatigue, pain and sexual dysfunction are key contributors to symptom burden, and these symptoms are often under-recognised and warrant routine assessment. The CKD-SBI offers a valuable tool for renal clinicians to assess symptom burden, leading to the commencement of timely and appropriate interventions. PMID- 26936488 TI - Revisiting and re-engineering the classical zinc finger peptide: consensus peptide-1 (CP-1). AB - Zinc plays key structural and catalytic roles in biology. Structural zinc sites are often referred to as zinc finger (ZF) sites, and the classical ZF contains a Cys2His2 motif that is involved in coordinating Zn(II). An optimized Cys2His2 ZF, named consensus peptide 1 (CP-1), was identified more than 20 years ago using a limited set of sequenced proteins. We have reexamined the CP-1 sequence, using our current, much larger database of sequenced proteins that have been identified from high-throughput sequencing methods, and found the sequence to be largely unchanged. The CCHH ligand set of CP-1 was then altered to a CAHH motif to impart hydrolytic activity. This ligand set mimics the His2Cys ligand set of peptide deformylase (PDF), a hydrolytically active M(II)-centered (M = Zn or Fe) protein. The resultant peptide [CP-1(CAHH)] was evaluated for its ability to coordinate Zn(II) and Co(II) ions, adopt secondary structure, and promote hydrolysis. CP 1(CAHH) was found to coordinate Co(II) and Zn(II) and a pentacoordinate geometry for Co(II)-CP-1(CAHH) was implicated from UV-vis data. This suggests a His2Cys(H2O)2 environment at the metal center. The Zn(II)-bound CP-1(CAHH) was shown to adopt partial secondary structure by 1-D (1)H NMR spectroscopy. Both Zn(II)-CP-1(CAHH) and Co(II)-CP-1(CAHH) show good hydrolytic activity toward the test substrate 4-nitrophenyl acetate, exhibiting faster rates than most active synthetic Zn(II) complexes. PMID- 26936489 TI - p-Type MoS2 and n-Type ZnO Diode and Its Performance Enhancement by the Piezophototronic Effect. AB - A plasma-induced p-type MoS2 flake and n-type ZnO film diode, which exhibits an excellent rectification ratio, is demonstrated. Under 365 nm optical irradiation, this p-n diode shows a strong photoresponse with an external quantum efficiency of 52.7% and a response time of 66 ms. By increasing the pressure on the junction to 23 MPa, the photocurrent can be enhanced by a factor of four through the piezophototronic effect. PMID- 26936490 TI - Tribochemistry of Bismuth and Bismuth Salts for Solid Lubrication. AB - One of the main trends in the past decades is the reduction of wastage and the replacement of toxic compounds in industrial processes. Some soft metallic particles can be used as nontoxic solid lubricants in high-temperature processes. The behavior of bismuth metal particles, bismuth sulfide (Bi2S3), bismuth sulfate (Bi2(SO4)3), and bismuth oxide (Bi2O3) as powder lubricants was studied in a range of temperatures up to 580 degrees C. The mechanical behavior was examined using a high-temperature pin-on-disc setup, with which the friction force between two flat-contact surfaces was recorded. The bismuth-lubricated surfaces showed low coefficients of friction (MU ~ 0.08) below 200 degrees C. Above the melting temperature of the metal powder at 271 degrees C, a layer of bismuth oxide developed and the friction coefficient increased. Bismuth oxide showed higher friction coefficients at all temperatures. Bismuth sulfide exhibited partial oxidation upon heating but the friction coefficient decreased to MU ~ 0.15 above 500 degrees C, with the formation of bismuth oxide-sulfate, while some bismuth sulfate remained. All surfaces were studied by X-ray diffraction (XRD), confocal microscopy, high-resolution scanning electron microscopy (HR-SEM), and energy dispersive X-ray spectroscopy (EDS). This study reveals how the partial oxidation of bismuth compounds at high temperatures affects their lubrication properties, depending on the nature of the bismuth compound. PMID- 26936487 TI - Hepatocellular carcinoma cell sensitivity to Vgamma9Vdelta2 T lymphocyte-mediated killing is increased by zoledronate. AB - The limited efficacy of vaccines in hepatocellular carcinoma (HCC), due to the low frequency of tumor-infiltrating cytotoxic T lymphocytes (CTLs), indicates the importance of innate immune surveillance, which assists acquired immunity by directly recognizing and eliminating HCC. Innate Vgamma9Vdelta2 T cells have major histocompatibility complex-unrestricted antitumor activity and are activated by phosphoantigens, which are upregulated in cancer cells by the nitrogen-containing bisphosphonate, zoledronate (Zol). A better understanding of HCC susceptibility to Zol and downstream gammadelta T cell-mediated killing is essential to optimize gammadelta T cell-mediated immunotherapy. This study systematically examined the interactions between gammadelta T cells and Zol treated HCC cell lines (HepG2, HLE, HLF, HuH-1, JHH5, JHH7, and Li-7) in vitro. All HCC cell lines expressed the DNAX accessory molecule-1 ligands, poliovirus receptor, and Nectin-2, and gammadelta T cell-mediated killing of these cells was significantly enhanced by Zol. Small interfering RNA-mediated knockdown of these ligands did not affect the susceptibility to gammadelta T cell lysis. This killing activity was partly inhibited by mevastatin, an inhibitor of the mevalonate pathway, and markedly reduced by a monoclonal antibody to gamma- and delta-chain T cell receptor, indicating that this is crucial for Zol-induced HCC killing. In addition, Zol-treated HCC cell lines triggered gammadelta T cell proliferation and induced production of Th1 and Th2, but not Th17, cytokines. The Zol concentration that enhanced HCC cell susceptibility to gammadelta T cell killing was lower than that required to directly inhibit HCC proliferation. Thus, gammadelta T cells may be important effector cells in the presence of Zol, especially where there are insufficient number of cancer antigen-specific CTLs to eliminate HCC. Our in vitro data support the proposal that Zol-treatment, combined with adaptive gammadelta T cell immunotherapy, may provide a feasible and effective approach for treatment of HCC. PMID- 26936491 TI - Polylactic acid nanosheets in prevention of postoperative intestinal adhesion and their effects on bacterial propagation in an experimental model. AB - BACKGROUND: Ultrathin films (nanosheets) adhere tightly to organ surfaces but prevent adhesion to other organs. The antiadhesive effect of nanosheets and their effect on bacterial propagation were investigated in a murine intestinal adhesion model. METHODS: Polylactic acid nanosheets (approximately 80 nm thick) were produced. Serosal defects were created by peeling off the intestinal serosa; these were left open or covered with nanosheets or Seprafilm(r) and the formation of intestinal adhesions was analysed. To examine bacterial propagation, a nanosheet or Seprafilm(r) was placed on intact murine jejunum followed by Escherichia coli inoculation at the site. RESULTS: Treatment both with nanosheets and with Seprafilm(r) reduced postoperative intestinal adhesion (mean adhesion score 0.67 for nanosheets, 0.43 for Seprafilm(r) and 2.87 for no antiadhesive treatment; P < 0.001 for nanosheets or Seprafilm(r) versus no adhesive treatment). Nanosheet treatment did not affect bacterial propagation in the peritoneal cavity, whereas Seprafilm(r)-treated mice showed bacterial propagation, leading to increased mortality. CONCLUSION: Nanosheets may be effective novel antiadhesive agents even in the presence of bacterial contamination. Surgical relevance Intra-abdominal adhesions following surgical contamination can trigger postoperative complications and lead to deterioration in long-term quality of life. However, currently there are no effective antiadhesion materials to prevent the formation of adhesions. Treatment with ultrathin nanosheets effectively reduced postoperative intestinal adhesion in an experimental mouse model, and did not affect bacterial propagation in the peritoneal cavity. These nanosheets are potent novel antiadhesive materials that potentially can be applied even in contaminated conditions. PMID- 26936493 TI - Feline hip dysplasia: A challenge to recognise and treat. AB - PRACTICAL RELEVANCE: The reported incidence of hip dysplasia (HD) in cats varies dramatically between studies, but the condition is likely more common than we realise. There is little doubt that cats with HD and associated osteoarthritis (OA) suffer pain, and this warrants appropriate therapy. DIAGNOSTIC CHALLENGES: Clinical signs of HD in cats are often gradual in onset, making them difficult to appreciate, but may include inactivity, pelvic limb lameness, difficulty jumping and climbing stairs, and reluctance to squat to defecate. Often lameness is bilateral, and can be particularly difficult to recognise. The most common radiographic finding is an abnormally shallow acetabulum. Subluxation, however, is not consistently associated with OA in cats and therefore the role that joint laxity plays in disease progression remains uncertain. Degenerative changes of the femoral head and neck seem to develop later than in the dog, and are less marked. THERAPEUTIC CHALLENGES: The majority of cats respond to non-surgical management with environmental modulation, physical therapy, dietary modulation, weight loss, nutraceuticals and drug therapy. Should non-surgical management not provide sufficient relief, two salvage surgical options are available: femoral head and neck excision (FHNE) and total hip replacement (THR). While there is a risk of complications with micro-THR, the positive outcomes that have been reported indicate that it should be considered in the treatment of coxofemoral pathology in cats in the same way that THR is considered for larger dogs, especially given the inconsistent results associated with FHNE. Monitoring the effect of treatment is challenging as the assessment of pain in cats is complex and there is no validated scoring system or owner-completed questionnaire yet available for cats. EVIDENCE BASE: There is a paucity of clinical reports focusing solely on HD in cats. The author draws on a combination of published studies, in cats, dogs and humans, as well as personal clinical experience. PMID- 26936492 TI - Practical urinalysis in the cat: 1: Urine macroscopic examination 'tips and traps'. AB - SERIES OUTLINE: This is the first article in a two-part series on urinalysis in the cat. The focus of Part 1 is urine macroscopic examination. Part 2, to appear in the May 2016 issue, discusses urine microscopic examination. PRACTICAL RELEVANCE: Urinalysis is an essential procedure in feline medicine but often little attention is paid to optimising the data yielded or minimising factors that can affect the results. CLINICAL CHALLENGES: For the best results, appropriately collected urine should be prepared promptly by specialist laboratory personnel for the relevant tests and assessed by a clinical pathologist. This is invariably impractical in clinical settings but careful attention can minimise artefacts and allow maximum useful information to be obtained from this seemingly simple process. AUDIENCE: Clinical pathologists would be familiar with the information provided in this article, but it is rarely available to general or specialist practitioners, and both can potentially benefit. EQUIPMENT: Most of the required equipment is routinely available to veterinarians. However, instructions have been provided to give practical alternatives for specialist procedures in some instances. EVIDENCE BASE: Evidence for much of the data on urinalysis in cats is lacking. Validation of the human equipment used routinely, such as dipsticks, is also lacking. As such, the evidence base for feline urinalysis is quite poor and information has largely been extrapolated from the human literature. Information from feline studies has been included where available. In addition, practical clinicopathological and clinical observations are provided. PMID- 26936494 TI - ISFM Consensus Guidelines on the Diagnosis and Management of Feline Chronic Kidney Disease. AB - PRACTICAL RELEVANCE: Chronic kidney disease (CKD) is one of the most commonly diagnosed diseases in older cats. In most cats, CKD is also a progressive disease and can be accompanied by a wide range of clinical and clinicopathological changes. These ISFM Consensus Guidelines have been developed by an independent panel of clinicians and academics to provide practical advice on the diagnosis and management of this complex disease. CLINICAL CHALLENGES: Although CKD is a common clinical problem in cats, the manifestations of disease vary between individuals. Thus there is a need for careful and repeat evaluation of cats with CKD and adjustment of therapy according to individual needs. In addition to addressing problems arising from CKD and improving quality of life (QoL) for the patient, therapy may also target slowing the underlying progression of disease and hence prolonging life. While maintaining QoL is of paramount importance in our patients, this can be challenging when multiple therapies are indicated. In some cases it is necessary to prioritise therapy, given an understanding of what is likely to most benefit the individual patient. EVIDENCE BASE: In preparing these Guidelines, the Panel has carefully reviewed the existing published literature, and has also graded the quality of evidence for different interventions to help to provide practical recommendations on the therapeutic options for feline CKD. This is a field of veterinary medicine that has benefited from some excellent published clinical research and further research findings will undoubtedly modify the recommendations contained in these Guidelines in the future. PMID- 26936495 TI - Case-based clinical reasoning in feline medicine: 2: Managing cognitive error. AB - AIM: This is Article 2 of a three-part series on clinical reasoning that encourages practitioners to explore and understand how they think and make case based decisions. It is hoped that, in the process, they will learn to trust their intuition but, at the same time, put in place safeguards to diminish the impact of bias and misguided logic on their diagnostic decision-making. SERIES OUTLINE: Article 1, published in the January 2016 issue of JFMS, discussed the relative merits and shortcomings of System 1 thinking (immediate and unconscious) and System 2 thinking (effortful and analytical). This second article examines ways of managing cognitive error, particularly the negative impact of bias, when making a diagnosis. Article 3, to appear in the May 2016 issue, explores the use of heuristics (mental short cuts) and illness scripts in diagnostic reasoning. PMID- 26936496 TI - Use of megestrol in cats. PMID- 26936497 TI - ABVP roundtable regarding management of diabetic cats. PMID- 26936498 TI - 2015 JFMS Resident Best Paper Award winner. PMID- 26936499 TI - Many Americans have problems with cost and access to healthcare, poll finds. PMID- 26936500 TI - Rate, risk factors and assessment of a counselling intervention for antenatal depression by public health nurses in an Israeli ultra-orthodox community. AB - AIM: To investigate the rate of and risk factors for perinatal depression in an Israeli ultra-orthodox Jewish community and assess the contribution of antenatal nursing intervention to reducing symptoms of postpartum depression. BACKGROUND: Perinatal depression is recognized globally as a common complication of pregnancy and childbirth, with negative effects on the mother, infant and family. Among Jewish ultra-orthodox women both religion and childbearing play major roles. DESIGN: Single-group pretest-posttest intervention study. METHOD: Depressive symptoms were assessed by the Edinburgh Postnatal Depression Scale. One-hundred sixty women attending a mother-child healthcare clinic during December 2011 January 2013 completed the Edinburgh Postnatal Depression Scale prenatally and 148 (92.5%) repeated the survey 6 weeks postpartum. Nurses were trained to screen and offer non-directive supportive counselling intervention. Risk factors for antenatal depressive symptoms were analysed using multivariable logistic regression and analysis of changes in score was performed by 2-way analysis of variance. RESULTS: Nineteen participants (11.9%) scored >=10 on the Edinburgh Postnatal Depression Scale antenatally. Nurses provided intervention for 40 women. Postpartum, only one participant scored >=10. The decrease in Edinburgh score was greater for those whose antenatal score was >=10. CONCLUSION: Although the rate of antenatal depressive symptoms was similar to that in other studies, postpartum symptoms may have been underreported, possible due to culturally related reticence. This underscores the importance of understanding the context in which the service is offered and the sensitivities of particular groups. The findings indicate that antenatal nursing intervention is a potentially protective measure for perinatal emotional well-being. PMID- 26936501 TI - Dental stories for children with autism. AB - PURPOSE: To investigate caregivers' preference regarding dental stories to prepare children with autism for dental visits. METHODS: Caregivers of children with autism were allowed use of dental stories available via different media (paper, tablet computer, computer) and image types (comics or drawings, photographs, video). Caregivers completed pre- and postintervention surveys. Fisher's exact tests were used to determine associations between predictive factors and preferences. RESULTS: Forty initial and 16 follow-up surveys were completed. Subjects were primarily male (85%). Mean child age was 6.7 years. Nine (64%) caregivers found the dental story useful for themselves and their child. Two (14%) caregivers found the aid only helpful for themselves. Preferred media type was associated with language understanding (p = .038) and home media preference (p = .002). CONCLUSIONS: Practitioners should consider using dental stories to help prepare families and children for dental visits. Individual preferences for dental stories vary; using prior history can aid in selection. PMID- 26936502 TI - Psychosocial correlates of alcohol and other substance use among low-income adolescents in peri-urban Johannesburg, South Africa: A focus on gender differences. AB - Alcohol and other drug use is prevalent among peri-urban, South African adolescents. We identified correlates of alcohol and other drug use by gender among adolescents (age = 16-18 years; N = 822) in peri-urban Johannesburg. Interviewer-administered surveys assessed sexual activity, alcohol and other drug use, and relevant psychosocial factors. In separate logistic regression models of alcohol and other drug use stratified by gender, violence exposure and sexual activity were associated with alcohol use for both males and females. For females only, depressive symptoms were associated with drug use. For males only, being older and sexually active were associated with drug use. Substance use interventions for South African adolescents should consider psychological health, sexual health, and tailoring by gender. PMID- 26936503 TI - Sociocultural pressure, internalization, BMI, exercise, and body dissatisfaction in Korean female college students. AB - This research investigated the differential effects of sociocultural pressures from media, peers, and parents on the thin ideal internalization and body dissatisfaction of 472 Korean female college students using structural equation modeling. Results indicated that after controlling for body mass index and exercise, media pressure exerted the largest effects, followed by peer pressure and parental pressure, on thin ideal internalization, and in turn, body dissatisfaction. Furthermore, parent and media pressures were found to exert direct effects on body dissatisfaction as well as indirect effects through thin ideal internalization. The results and implications of the study are discussed. PMID- 26936504 TI - Dendritic cell vaccines based on immunogenic cell death elicit danger signals and T cell-driven rejection of high-grade glioma. AB - The promise of dendritic cell (DC)-based immunotherapy has been established by two decades of translational research. Of the four malignancies most targeted with clinical DC immunotherapy, high-grade glioma (HGG) has shown the highest susceptibility. HGG-induced immunosuppression is a roadblock to immunotherapy, but may be overcome by the application of T helper 1 (T(H)1) immunity-biased, next-generation, DC immunotherapy. To this end, we combined DC immunotherapy with immunogenic cell death (ICD; a modality shown to induce T(H)1 immunity) induced by hypericin-based photodynamic therapy. In an orthotopic HGG mouse model involving prophylactic/curative setups, both biologically and clinically relevant versions of ICD-based DC vaccines provided strong anti-HGG survival benefit. We found that the ability of DC vaccines to elicit HGG rejection was significantly blunted if cancer cell-associated reactive oxygen species and emanating danger signals were blocked either singly or concomitantly, showing hierarchical effect on immunogenicity, or if DCs, DC-associated MyD88 signal, or the adaptive immune system (especially CD8(+) T cells) were depleted. In a curative setting, ICD based DC vaccines synergized with standard-of-care chemotherapy (temozolomide) to increase survival of HGG-bearing mice by ~300%, resulting in ~50% long-term survivors. Additionally, DC vaccines also induced an immunostimulatory shift in the brain immune contexture from regulatory T cells to T(H)1/cytotoxic T lymphocyte/T(H)17 cells. Analysis of the The Cancer Genome Atlas glioblastoma cohort confirmed that increased intratumor prevalence of T(H)1/cytotoxic T lymphocyte/T(H)17 cells linked genetic signatures was associated with good patient prognosis. Therefore, pending final preclinical checks, ICD-based vaccines can be clinically translated for glioma treatment. PMID- 26936505 TI - ATRX loss promotes tumor growth and impairs nonhomologous end joining DNA repair in glioma. AB - Recent work in human glioblastoma (GBM) has documented recurrent mutations in the histone chaperone protein ATRX. We developed an animal model of ATRX-deficient GBM and showed that loss of ATRX reduces median survival and increases genetic instability. Further, analysis of genome-wide data for human gliomas showed that ATRX mutation is associated with increased mutation rate at the single-nucleotide variant (SNV) level. In mouse tumors, ATRX deficiency impairs nonhomologous end joining and increases sensitivity to DNA-damaging agents that induce double stranded DNA breaks. We propose that ATRX loss results in a genetically unstable tumor, which is more aggressive when left untreated but is more responsive to double-stranded DNA-damaging agents, resulting in improved overall survival. PMID- 26936506 TI - Therapeutic targeting of oxygen-sensing prolyl hydroxylases abrogates ATF4 dependent neuronal death and improves outcomes after brain hemorrhage in several rodent models. AB - Disability or death due to intracerebral hemorrhage (ICH) is attributed to blood lysis, liberation of iron, and consequent oxidative stress. Iron chelators bind to free iron and prevent neuronal death induced by oxidative stress and disability due to ICH, but the mechanisms for this effect remain unclear. We show that the hypoxia-inducible factor prolyl hydroxylase domain (HIF-PHD) family of iron-dependent, oxygen-sensing enzymes are effectors of iron chelation. Molecular reduction of the three HIF-PHD enzyme isoforms in the mouse striatum improved functional recovery after ICH. A low-molecular-weight hydroxyquinoline inhibitor of the HIF-PHD enzymes, adaptaquin, reduced neuronal death and behavioral deficits after ICH in several rodent models without affecting total iron or zinc distribution in the brain. Unexpectedly, protection from oxidative death in vitro or from ICH in vivo by adaptaquin was associated with suppression of activity of the prodeath factor ATF4 rather than activation of an HIF-dependent prosurvival pathway. Together, these findings demonstrate that brain-specific inactivation of the HIF-PHD metalloenzymes with the blood-brain barrier-permeable inhibitor adaptaquin can improve functional outcomes after ICH in several rodent models. PMID- 26936510 TI - Reversible Hypopituitarism Associated with Intravascular Large B-Cell Lymphoma: Case Report of Successful Immunochemotherapy. AB - Intravascular large B-cell lymphoma (IVLBCL) is a rare subtype of diffuse large B cell lymphoma. There have been only a limited number of reports regarding pituitary dysfunction associated with IVLBCL. We present a 71-year-old woman with hypopituitarism without any hypothalamic/pituitary abnormalities as assessed by magnetic resonance imaging. She presented with edema, abducens palsy, and elevated levels of lactate dehydrogenase and soluble interleukin-2 receptor. Provocative testing showed that the peaks of luteinizing hormone, follicle stimulating hormone, thyroid-stimulating hormone and adrenocorticotropic hormone were evoked to normal levels by simultaneous administration of luteinizing hormone-releasing hormone, thyrotropin-releasing hormone and corticotropin releasing hormone, but the responses of these four pituitary hormones showed a delayed pattern. She was diagnosed with IVLBCL with cerebrospinal invasion by pathological findings of the bone marrow, skin, and cerebrospinal fluid. She achieved hematological remission after immunochemotherapy. Pituitary function was also restored without hormonal replacement, and the improvement of the pituitary function was confirmed by dynamic testing. We reviewed the literature with respect to hypopituitarism associated with IVLBCL. There were less than 20 case reports and most of the patients died. Endocrinological course was described in only two cases, and both of them required hormonal supplementation. To our knowledge, this is the first case of hypopituitarism induced by IVLBCL that was successfully managed by immunochemotherapy alone. This case suggests that early diagnosis and treatment of IVLBCL might improve anterior pituitary function and enable patients to avoid hormone replacement therapy. PMID- 26936509 TI - Microarray analysis of New Green Cocoon associated genes in silkworm, Bombyx mori. AB - Green cocoons in silkworm, Bombyx mori, are caused by flavonoids accumulation in the silk proteins, fibroin and sericin. Despite the economic value of natural green cocoon and medical value of flavonoids, there is limited understanding of the molecular mechanism regulating flavonoids uptake in silkworm, which is tightly associated with the trait of green cocoon. The purpose of this study is to perform a comprehensive analysis to understand the molecular mechanisms of flavonoids uptake in silkworm based on microarray analyses. The study subject was the New Green Cocoon from the silkworm strains, G200 and N100, a new spontaneous dominant green cocoon trait identified in the 2000s. The genes regulating this trait are independent of other green cocoon genes previously reported. Genome wide gene expression was compared between the New Green Cocoon producing silkworm strains, G200 and N100, and the control sample, which is the white cocoon producing strain 872B. Among these strains, N100 and 872B are near-isogenic lines. The results showed that 130 genes have consistently changing expression patterns in the green cocoon strains when compared with the white cocoon strain. Among these, we focused on the genes related to flavonoids metabolism and absorption, such as sugar transporter genes and UDP-glucosyltransferase genes. Based on our findings, we propose the potential mechanisms for flavonoids absorption and metabolism in silkworm. Our results imply that silkworm might be used as an underlying model for flavonoids in pharmaceutical research. PMID- 26936507 TI - A dominant gain-of-function mutation in universal tyrosine kinase SRC causes thrombocytopenia, myelofibrosis, bleeding, and bone pathologies. AB - The Src family kinase (SFK) member SRC is a major target in drug development because it is activated in many human cancers, yet deleterious SRC germline mutations have not been reported. We used genome sequencing and Human Phenotype Ontology patient coding to identify a gain-of-function mutation in SRC causing thrombocytopenia, myelofibrosis, bleeding, and bone pathologies in nine cases. Modeling of the E527K substitution predicts loss of SRC's self-inhibitory capacity, which we confirmed with in vitro studies showing increased SRC kinase activity and enhanced Tyr(419) phosphorylation in COS-7 cells overexpressing E527K SRC. The active form of SRC predominates in patients' platelets, resulting in enhanced overall tyrosine phosphorylation. Patients with myelofibrosis have hypercellular bone marrow with trilineage dysplasia, and their stem cells grown in vitro form more myeloid and megakaryocyte (MK) colonies than control cells. These MKs generate platelets that are dysmorphic, low in number, highly variable in size, and have a paucity of alpha-granules. Overactive SRC in patient-derived MKs causes a reduction in proplatelet formation, which can be rescued by SRC kinase inhibition. Stem cells transduced with lentiviral E527K SRC form MKs with a similar defect and enhanced tyrosine phosphorylation levels. Patient-derived and E527K-transduced MKs show Y419 SRC-positive stained podosomes that induce altered actin organization. Expression of mutated src in zebrafish recapitulates patients' blood and bone phenotypes. Similar studies of platelets and MKs may reveal the mechanism underlying the severe bleeding frequently observed in cancer patients treated with next-generation SFK inhibitors. PMID- 26936511 TI - [Unruptured cerebral aneurysms: Controversies on population screening]. AB - The idea of population screening of unruptured intracranial aneurysms is interesting because, despite recent advances in surgical and endovascular treatment, the mortality related to aneurismal subarachnoid haemorrhage reaches 30%. Screening is justified whenever the morbidity and mortality of the treatment (markedly lower for unruptured compared to ruptured aneurysms) overcomes the inherent risk of harbouring a brain aneurysm. Although, at present, this balance does not seem to favour population-based screening, it is justified in certain sub-populations with an increased risk of rupture. In this review, an analysis is made of the requirements for implementing a screening program, when would it be justified, what is to be expected from treatment (in terms of effectiveness, morbidity and costs), and what medical-legal issues are relevant and to determine the usefulness of the program. A study protocol is proposed aimed at examining the usefulness of population screening for brain aneurysms by magnetic resonance angiography. PMID- 26936512 TI - Evidence for placental compensation in cattle. AB - Prenatal development is known to be extremely sensitive to maternal and environmental challenges. In this study, we hypothesize that body growth and lactation during gestation in cattle reduce nutrient availability for the pregnant uterus, with consequences for placental development. Fetal membranes of 16 growing heifers and 27 fully grown cows of the Belgian Blue (BB) breed were compared to determine the effect of body growth on placental development. Furthermore, the fetal membranes of 49 lactating Holstein Friesian (HF) cows and 27 HF heifers were compared to study the impact of dam lactation compared to dam body growth. After parturition, calf birth weight and body measurements of dam and calf were recorded, as well as weight of total fetal membranes, cotyledons and intercotyledonary membranes. All cotyledons were individually measured to calculate both the surface of each individual cotyledon and the total cotyledonary surface per placenta. Total cotyledonary surface was unaffected by breed or the breed*parity interaction. Besides a 0.3 kg lower cotyledonary weight (P=0.007), heifer placentas had a smaller total cotyledonary surface compared with placentas of cows (0.48+/-0.017 v. 0.54+/-0.014 m2, respectively, P<0.001). Within the BB breed, fetal membranes of heifers had a 1.5 kg lower total weight and 1.0 kg lower intercotyledonary membrane weight (P<0.005) compared with cows. A cotyledon number of only 91+/-5.4 was found in multiparous BB dams, while growing BB heifers had a higher cotyledon number (126+/-6.7, P<0.001), but a greater proportion of smaller cotyledons (<40 cm2). Within the HF breed, no parity effect on intercotyledonary membrane weight, cotyledon number and individual cotyledonary surface was found. Placental efficiency (calf weight/total cotyledonary surface) was similar in HF and BB heifers but significantly higher in multiparous BB compared with multiparous HF dams (106.0+/ 20.45 v. 74.3+/-12.27 kg/m2, respectively, P<0.001). Furthermore, a seasonal effect on placental development was found, with winter and spring placentas having smaller cotyledons than summer and fall placentas (P<0.001). Main findings of the present study are that lactation and maternal growth during gestation entail a comparable nutrient diverting constraint, which might alter placental development. However, results suggest that the placenta is able to manage this situation through two potential compensation mechanisms. In early pregnancy the placenta might cope by establishing a higher number of cotyledons, while in late gestation a compensatory expansion of the cotyledonary surface is suggested to meet the nutrient demand of the fetus. PMID- 26936508 TI - PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: Mechanisms, response biomarkers, and combinations. AB - PD-L1 and PD-1 (PD) pathway blockade is a highly promising therapy and has elicited durable antitumor responses and long-term remissions in a subset of patients with a broad spectrum of cancers. How to improve, widen, and predict the clinical response to anti-PD therapy is a central theme in the field of cancer immunology and immunotherapy. Oncologic, immunologic, genetic, and biological studies focused on the human cancer microenvironment have yielded substantial insight into this issue. Here, we focus on tumor microenvironment and evaluate several potential therapeutic response markers including the PD-L1 and PD-1 expression pattern, genetic mutations within cancer cells and neoantigens, cancer epigenetics and effector T cell landscape, and microbiota. We further clarify the mechanisms of action of these markers and their roles in shaping, being shaped, and/or predicting therapeutic responses. We also discuss a variety of combinations with PD pathway blockade and their scientific rationales for cancer treatment. PMID- 26936514 TI - Diabetic biomarkers and the risk of proximal or distal gastric cancer. AB - BACKGROUND AND AIM: The role of diabetes mellitus as a risk factor for gastric cancer has been controversial. We studied the association between diabetic biomarkers and the risk of gastric cancer and whether these associations depend on cancer location. METHODS: In this retrospective cohort study with subjects with negative initial esophagogastroduodenoscopy findings (n = 23 218) during a routine health checkup, we measured fasting glucose and insulin levels, calculated the homeostatic model assessment insulin resistance (HOMA-IR) values, and analyzed the risk of gastric cancer in relation to diabetic biomarker tertiles and the presence of diabetes mellitus. RESULTS: The incidence rate of gastric cancer was 9.7 per 10 000 person-years during the mean 6.8-year follow up. Patients with diabetes, higher fasting glucose levels, or higher HOMA-IR levels were older; men, current smokers, and heavy alcohol consumers represented larger proportions of these groups. They also had high body mass index and hemoglobin A1c more often. In the multivariate-adjusted Cox regression analyses, the incidence of gastric cancer was not significantly associated with diabetes mellitus or higher diabetic biomarker levels. Compared with normal glucose levels, lower glucose levels were significantly associated with an increased risk of distal gastric cancer. The hazard ratio for fasting glucose level tertile 1 was 2.39 (95% confidence interval, 1.48-3.85) (reference, tertile 2). Lower glucose levels were not associated with a risk of proximal gastric cancer, compared with a normal glucose level. CONCLUSIONS: Our findings suggest that fasting glucose levels have a different effect on distal and proximal gastric cancers. PMID- 26936513 TI - Screening for Post-Traumatic Stress Disorder in a Civilian Emergency Department Population with Traumatic Brain Injury. AB - Post-traumatic stress disorder (PTSD) is a condition associated with traumatic brain injury (TBI). While the importance of PTSD and TBI among military personnel is widely recognized, there is less awareness of PTSD associated with civilian TBI. We examined the incidence and factors associated with PTSD 6 months post injury in a civilian emergency department population using measures from the National Institute of Neurological Disorders and Stroke TBI Common Data Elements Outcome Battery. Participants with mild TBI (mTBI) from the Transforming Research and Clinical Knowledge in Traumatic Brain Injury Pilot study with complete 6 month outcome batteries (n = 280) were analyzed. Screening for PTSD symptoms was conducted using the PTSD Checklist-Civilian Version. Descriptive measures are summarized and predictors for PTSD were examined using logistic regression. Incidence of screening positive for PTSD was 26.8% at 6 months following mTBI. Screening positive for PTSD was significantly associated with concurrent functional disability, post-concussive and psychiatric symptomatology, decreased satisfaction with life, and decreased performance in visual processing and mental flexibility. Multi-variable regression showed injury mechanism of assault (odds ratio [OR] 3.59; 95% confidence interval [CI] 1.69-7.63; p = 0.001) and prior psychiatric history (OR 2.56; 95% CI 1.42-4.61; p = 0.002) remained significant predictors of screening positive for PTSD, while education (per year OR 0.88; 95% CI 0.79-0.98; p = 0.021) was associated with decreased odds of PTSD. Standardized data collection and review of pre-injury education, psychiatric history, and injury mechanism during initial hospital presentation can aid in identifying patients with mTBI at risk for developing PTSD symptoms who may benefit from closer follow-up after initial injury care. PMID- 26936515 TI - Novel mutations in the CYP11B2 gene causing aldosterone synthase deficiency. AB - Aldosterone synthase deficiency (ASD) is a rare, autosomal recessive inherited disease. Mutations in the CYP11B2 gene are responsible for the occurrence of ASD, and the clinical manifestations of ASD vary with age. Affected infants may develop symptoms of mineralocorticoid deficiency, including clinical presentation with frequent vomiting, a variable degree of hyponatremia, hyperkalemia, and metabolic acidosis combined with poor growth, which are easily confused with several other endocrine genopathies, including pseudohypoaldosteronism type 1 and congenital adrenal hyperplasia. In the present study, whole exome sequencing (WES) was used to screen for causal variants in the genome of a Chinese pediatric patient with confusing endocrine disorder symptoms. Clinical symptoms of frequent vomiting, hyponatremia and hyperkalemia were selected as the filtering indices to analyze the WES data. Clinically relevant variants were subsequently verified using Sanger sequencing. Minigene construct analysis was used to assess the consequence of a splicing variant in the CYP11B2 gene. The compound heterozygous mutations, c.1009C>T and c.240-1G>A, in the CYP11B2 gene were identified and confirmed, and represented novel variants. Sequence analysis results revealed that the c.1009C>T mutation at codon 337 of exon 6 was a nonsense mutation, which led to early termination of the protein translation process. In addition, further investigation of the splicing pattern in a minigene construct showed that the c.240-1G>A mutation led to the preservation of intron 1, with the 3'-splice site disappearing during transcriptional processing of the mRNA. Using molecular genetic assessments, the patient was finally diagnosed with ASD. Therefore, the present study identified two novel CYP11B2 gene mutations in a Chinese patient with ASD, indicating exome sequencing as an effective diagnostic tool for rare endocrine-metabolic diseases. PMID- 26936516 TI - A targeted next-generation sequencing method for identifying clinically relevant mutation profiles in lung adenocarcinoma. AB - Molecular profiling of lung cancer has become essential for prediction of an individual's response to targeted therapies. Next-generation sequencing (NGS) is a promising technique for routine diagnostics, but has not been sufficiently evaluated in terms of feasibility, reliability, cost and capacity with routine diagnostic formalin-fixed, paraffin-embedded (FFPE) materials. Here, we report the validation and application of a test based on Ion Proton technology for the rapid characterisation of single nucleotide variations (SNVs), short insertions and deletions (InDels), copy number variations (CNVs), and gene rearrangements in 145 genes with FFPE clinical specimens. The validation study, using 61 previously profiled clinical tumour samples, showed a concordance rate of 100% between results obtained by NGS and conventional test platforms. Analysis of tumour cell lines indicated reliable mutation detection in samples with 5% tumour content. Furthermore, application of the panel to 58 clinical cases, identified at least one actionable mutation in 43 cases, 1.4 times the number of actionable alterations detected by current diagnostic tests. We demonstrated that targeted NGS is a cost-effective and rapid platform to detect multiple mutations simultaneously in various genes with high reproducibility and sensitivity. PMID- 26936517 TI - Trunk muscle activity patterns in a person with spinal cord injury walking with different un-powered exoskeletons: A case study. AB - OBJECTIVE: To investigate trunk muscle activity patterns in a person with thoracic spinal cord injury when walking with different un-powered exoskeletons, and to explore how different un-powered exoskeletons affect trunk muscle activity patterns. CASE REPORT: Data were recorded from a subject with complete spinal cord injury at T10, using an electromyography system on 4 pairs of trunk muscles and a motion capture system simultaneously. RESULTS: The participant generated large muscle force to laterally bend and rotate trunk, and swung his leg through the moments generated, not only by trunk flexion and extension, but by trunk rotation. In an energy-stored exoskeleton without springs condition, the energy generated by erector spinae contraction was stored in the energy-stored component in the stance phase and released in the swing phase to compensate for energy generated by the obliquus externus abdominis and avoid overuse of the obliquus externus abdominis. CONCLUSION: These findings prompt further development of un powered exoskeletons and investigation into trunk muscle functions in patients with spinal cord injury when walking with un-powered exoskeletons. PMID- 26936518 TI - Treatment with bone marrow mesenchymal stem cells combined with plumbagin alleviates spinal cord injury by affecting oxidative stress, inflammation, apoptotis and the activation of the Nrf2 pathway. AB - The aim of the present study was to investigate the protective effect exerted by bone marrow mesenchymal stem cells (BMSCs) in combination with plumbagin on spinal cord injury (SCI) and explore the mechanism behind this protective effect. Firstly, BMSCs were extracted from male Sprague-Dawley rats, cultured in vitro, and identified by hematoxylin. Sprague-Dawley rats were then randomly divided into a control group, SCI model group, BMSC-treated group, a plumbagin-treated group, and a BMSC and plumbagin-treated group. After treatment with BMSCs combined with plumbagin, a Basso, Beattie and Bresnahan (BBB) test was carried out and the spinal cord water content was examined in order to analyze the effect of BMSCs combined with plumbagin on SCI. The myeloperoxidase (MPO), superoxide dismutase (SOD), malondialdehyde (MDA), nuclear factor-kappaB (NF-kappaB) p65 unit, tumor necrosis factor-alpha (TNF-alpha) levels were also detected. Moreover, nuclear factor erythroid 2-related factor 2 (Nrf2), phosphoinositide 3 kinase (PI3K), phosphorylated (p-)Akt, p-p38 mitogen-activated protein kinase (MAPK), and p-extracellular-signal-regulated kinase (ERK) protein expression levels were measured using western blot analysis. Treatment with BMSCs combined with plumbagin significantly improved locomotor recovery and reduced the spinal cord water content after SCI. The increased MPO, MDA, NF-kappaB p65 and TNF-alpha levels were significantly suppressed and the decreased SOD was significantly increased in SCI rats. The suppression of Nrf2, p-Akt and p-ERK, as well as the promotion of p-p38 MAPK, were reversed by treatment with BMSCs combined with plumbagin. These effects suggest that treatment with BMSCs combined with plumbagin alleviates SCI through its effects on oxidative stress, inflammation, apoptotis and activation of the Nrf2 pathway. PMID- 26936519 TI - Dapagliflozin reduces albuminuria in patients with diabetes and hypertension receiving renin-angiotensin blockers. AB - AIMS: To characterize the effect of dapagliflozin on albuminuria and estimated glomerular filtration rate (eGFR) and to determine whether effects on albuminuria were mediated through changes in glycated haemoblogin (HbA1c), systolic blood pressure (SBP), body weight or eGFR. METHODS: We conducted a post hoc analysis of data pooled from two phase III clinical trials in hypertensive patients with type 2 diabetes (T2DM) on stable angiotensin-converting enzyme inhibitor or angiotensin receptor blocker therapy, randomly assigned to dapagliflozin 10 mg/day or matched placebo. This analysis included only patients with microalbuminuria or macroalbuminuria at baseline. RESULTS: Patients were randomized to receive dapagliflozin 10 mg (n = 167) or placebo (n = 189). Dapagliflozin resulted in greater 12-week reductions in albuminuria compared with placebo: -33.2% [95% confidence interval (CI) -45.4, -18.2]. The reduction in albuminuria was also present after adjusting for age, sex and changes in HbA1c, SBP, body weight and eGFR: -23.5% (95% CI -37.6, -6.3). There was a decrease in eGFR with dapagliflozin versus placebo that was readily reversed 1 week after last dose. No serious renal-related adverse events were observed in any group. CONCLUSIONS: Dapagliflozin was effective in lowering albuminuria in patients with T2DM and hypertension using renin-angiotensin system blockade therapy. Reductions in albuminuria were still present after adjusting for changes in HbA1c, SBP, body weight and eGFR. Dapagliflozin-induced improvements in glycaemic control and reductions in SBP, coupled with other potentially beneficial renal effects, may lead to a reduced long-term renal and cardiovascular risk. PMID- 26936521 TI - Fingerprints of Multiple Electron Scatterings in Single-Layer Graphene. AB - The electrons in graphene exhibit unusual behaviours, which can be described by massless Dirac quasiparticles. Understanding electron scattering in graphene has been of significant importance for its future application in electronic devices because electron scattering determines electrical properties such as resistivity and electron transport. There are two types of electron scatterings in graphene: intervalley scattering and intravalley scattering. In single-layer graphene, to date, it has been difficult to observe intravalley scattering because of the suppression of backscattering resulting from the chiral nature of the electrons in graphene. Here, we report the multiple electron scattering behaviours in single-layer graphene on a metallic substrate. By applying one- and two dimensional Fourier transforms to maps of the local density of states, we can distinguish individual scattering processes from complex interference patterns. These techniques enable us to provide direct evidence of intravalley scattering, revealing a linear dispersion relation with a Fermi velocity of ~7.4 * 10(5) m/s. PMID- 26936520 TI - Regulation of global gene expression and cell proliferation by APP. AB - Down syndrome (DS), caused by trisomy of chromosome 21, is one of the most common genetic disorders. Patients with DS display growth retardation and inevitably develop characteristic Alzheimer's disease (AD) neuropathology, including neurofibrillary tangles and neuritic plaques. The expression of amyloid precursor protein (APP) is increased in both DS and AD patients. To reveal the function of APP and elucidate the pathogenic role of increased APP expression in DS and AD, we performed gene expression profiling using microarray method in human cells overexpressing APP. A set of genes are significantly altered, which are involved in cell cycle, cell proliferation and p53 signaling. We found that overexpression of APP inhibits cell proliferation. Furthermore, we confirmed that the downregulation of two validated genes, PSMA5 and PSMB7, inhibits cell proliferation, suggesting that the downregulation of PSMA5 and PSMB7 is involved in APP-induced cell proliferation impairment. Taken together, this study suggests that APP regulates global gene expression and increased APP expression inhibits cell proliferation. Our study provides a novel insight that APP overexpression may contribute to the growth impairment in DS patients and promote AD pathogenesis by inhibiting cell proliferation including neural stem cell proliferation and neurogenesis. PMID- 26936522 TI - Reply: Transfusion reduction in liver surgery is a team sport. PMID- 26936523 TI - Clinical and nutritional outcomes after intestinal autotransplantation. AB - OBJECTIVE: This study describes the operative techniques and early clinical and nutritional outcomes after intestinal autotransplantation (IATx). BACKGROUND: IATx is a novel surgical strategy for patients with abdominal neoplasms involving the root of the superior mesenteric and/or celiac arteries, but the effects of IATx on clinical and nutritional outcomes are not well-known. METHODS: Six patients aged 24-67 years (mean, 54) underwent consecutive IATx in our center from January 2011 to January 2015. In all patients, selection and harvesting of a segmental autograft of bowel was carried out first, and radical en bloc resection of the neoplasm was performed second. RESULTS: One patient lost the autograft owing to arterial thrombosis 48 hours postoperatively, and another succumbed to a pancreatic fistula at 21 days. The remaining 4 patients survived with no evidence of tumor recurrence currently at 9-, 23-, 23-, and 39-months of follow-up. These 4 patients have had well-functioning autografts and have not required any intravenous fluid hydration since discharge. Serum d-xylose levels recovered fully 2 weeks postoperatively, and plasma proteins and cholesterol levels normalized 12-18 months later. The surviving 4 patients gained body weight without major alterations in lifestyle, work habits, or psychosocial conditions. CONCLUSION: Although IATx is associated with considerable operative risk, this aggressive approach allows patients with selected abdominal neoplasms involving the major mesenteric vessels to be completely resected and attain early intestinal autonomy from parenteral nutrition. PMID- 26936524 TI - Intestinal stem cells and intestinal homeostasis in health and in inflammation: A review. AB - BACKGROUND: The human intestine is a complex group of organs, highly specialized in processing food and providing nutrients to the body. It is under constant threat from microbials and toxins and has therefore developed a number of protective mechanisms. One important mechanism is the constant shedding of epithelial cells into the lumen; another is the production and maintenance of a double-layered mucous boundary in which there is continuous sampling of the luminal microbiota and a persistent presence of antimicrobial enzymes. However, the gut needs commensal bacteria to effectively break down food into absorbable nutrients, which necessitates constant communication between the luminal bacteria and the intestinal immune cells in homeostasis. Disruption of homeostasis, for whatever reason, will give rise to (chronic) inflammation. DISCUSSION: Both medical and surgical management of this disruption is discussed. PMID- 26936525 TI - Never give up. PMID- 26936526 TI - Cold-inducible RNA-binding protein plays a central role in the pathogenesis of abdominal aortic aneurysm in a murine experimental model. AB - BACKGROUND: Cold-inducible RNA-binding protein (CIRP) is a recently identified proinflammatory cytokine. We hypothesize that CIRP is involved in the progression of abdominal aortic aneurysms (AAA) and that anti-CIRP treatment could inhibit this progression. METHODS: We investigated CIRP expression in the sera and aneurysmal tissues of human AAA patients and elastase-induced AAA rats. To further examine the role of CIRP in the development of AAA, anti-CIRP antibody (1 mg/kg) or nonimmunized control immunoglobulin (Ig)G (1 mg/kg) was injected via the caudal vein in the experimental AAA model. To further investigate the underlying mechanisms, RAW 267.4 cells were stimulated with recombinant murine CIRP (rmCIRP). RESULTS: In human AAA tissue, CIRP exhibited a 5.6-fold and 93% increase in mRNA and protein expression, respectively. In a rat AAA model, CIRP was upregulated significantly in a time-dependent manner in the serum and AAA tissue. The anti-CIRP antibody treatment significantly suppressed the dilation of experimental AAA. Simultaneously, inhibition of CIRP significantly attenuated the expression of matrix metalloproteinase (MMP)-2, MMP-9, tumor necrosis factor alpha, and monocyte chemoattractant protein-1, and the number of CD68-positive macrophages in the experimental AAA tissue. In vitro, rmCIRP significantly increased MMP-9 messenger RNA expression in a dose-dependent manner by 1.2-fold, 2.9-fold, and 5.5-fold, respectively. Simultaneously, rmCIRP promoted RAW 264.7 cell migration, with an approximately 2.7-fold increase in the number of migrated cells. CONCLUSION: Our findings demonstrate that CIRP mediates experimental AAA development by promoting the inflammatory response and inducing MMP-9 expression, demonstrating its potential as a novel target for inhibiting the progression of AAA. PMID- 26936527 TI - How far can we lower graft-to-recipient weight ratio for living donor liver transplantation under modulation of portal venous pressure? AB - BACKGROUND: Smaller size grafts for living donor liver transplantation (LDLT) can enhance donor safety and expand donor availability. We previously reported that modulation of portal venous pressure (PVP) was key for successful LDLT with small grafts, and that it actively lowered graft-to-recipient weight ratio (GRWR) for adult-to-adult LDLT. This retrospective study investigated the outcome of LDLT using small grafts with PVP modulation. METHOD: This study analyzed 221 adult LDLT patients between March 2008 and December 2013 and divided them into 3 groups based on GRWR: large (L), GRWR >= 0.8% (n = 154), medium (M), >= 0.7% GRWR < 0.8% (n = 38); and small (S) GRWR < 0.7% (n = 29). Donor and recipient factors, PVP, pressure gradient between PVP and central venous pressure (CVP), occurrence of small for size syndrome (SFSS), ascites, and posttransplant laboratory data were compared across the 3 groups. Patient and graft survival were compared using Kaplan-Meier methods. RESULTS: There was no difference in patient or graft survival between the 3 groups. Amount of posttransplant ascites and posttransplant International Normalized Ratio were similar, but the S and M groups had more prolonged cholestasis. SFSS was identified in 17%, 13%, and 13% in the S, M, and L groups, respectively (P = NS). Patients with a final PVP of <=15 mmHg had better survival than patients with a final PVP of >15 mmHg (P < .001). Multivariate analysis showed that donor age >40 years old, final PVP of >15 mmHg, and pressure gradient of PVP-CVP >5 mmHg were risk factors for inferior patient survival. CONCLUSION: We achieved satisfactory outcomes in LDLT with GRWR as low as 0.6% using PVP modulation. Thus, we currently set a lower limit of GRWR at 0.6% while protecting donor safety and expanding donor availability. PMID- 26936528 TI - Comments on: Risk factors for central lymph node metastasis in papillary thyroid carcinoma: A National Cancer Data Base (NCDB) study. PMID- 26936529 TI - Empirical likelihood based detection procedure for change point in mean residual life functions under random censorship. AB - The mean residual life (MRL) function is one of the basic parameters of interest in survival analysis that describes the expected remaining time of an individual after a certain age. The study of changes in the MRL function is practical and interesting because it may help us to identify some factors such as age and gender that may influence the remaining lifetimes of patients after receiving a certain surgery. In this paper, we propose a detection procedure based on the empirical likelihood for the changes in MRL functions with right censored data. Two real examples are also given: Veterans' administration lung cancer study and Stanford heart transplant to illustrate the detecting procedure. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26936530 TI - Bendamustine and stem-cell mobilization: not so bad! PMID- 26936531 TI - Clinicopathological significance of LAT1 and ASCT2 in patients with surgically resected esophageal squamous cell carcinoma. AB - BACKGROUND: Amino acid transporters are highly expressed in various human cancers. L-type amino acid transporter 1 (LAT1) and system alanine-serine cysteine amino acid transporter-2 (ASCT2) play a crucial role in tumor progression and survival. However, the clinicopathological significance of these transporters in patients with esophageal squamous cell carcinoma (ESCC) remains unclear. METHODS: One hundred and fifty-seven patients with surgically resected ESCC were evaluated. Immunohistochemical analysis was performed for LAT1, ASCT2, CD98, Ki-67, and micro-vessel density (MVD), as determined by CD34 expression. RESULTS: LAT1 and ASCT2 were positively expressed in 59% (93/157) and 48% (76/157) of tumors respectively. LAT1 and ASCT2 expression significantly correlated with T factor, N factor, lymphatic permeation, vascular invasion, and CD98 expression. The 5-year survival rates of LAT1-high and -low and ASCT2-high and -low expressing patients were 62.0% and 69.6% (P < 0.05) and 59.6% and 70.1% (P = 0.068), respectively. The combined positive expression of LAT1 and ASCT2 was a significant prognostic factor in univariate analysis. CONCLUSION: High expression of LAT1 and ASCT2 correlates with metastasis and invasion. Accordingly, these proteins could serve as prognostic biomarkers and therapeutic targets for treating patients with surgically resectable ESCC. J. Surg. Oncol. 2016;113:381-389. (c) 2016 Wiley Periodicals, Inc. PMID- 26936533 TI - Corrigendum: DICER1 and microRNA regulation in post-traumatic stress disorder with comorbid depression. PMID- 26936532 TI - Instant rice made from white and pigmented giant embryonic rice reduces lipid levels and body weight in high fat diet-fed mice. AB - PROBLEM: With the growing health problem on obesity and its associated metabolic disorders, functional foods with hypolipidemic and body fat-lowering effects are greatly needed. The effects of instant rice made from a combination of pigmented giant embryonic rice (Keunnunjami) and white rice, in comparison with those of instant non-pigmented giant embryonic brown rice and instant ordinary brown rice, on the lipid metabolism and body weight in mice under high fat diet condition were investigated. METHODS: Male C57BL/6N mice (n=48) were given experimental diets for seven weeks: normal control (NC), high fat (HF), and HF supplemented with instant normal brown rice (HF-NB), non-pigmented giant embryonic brown rice (HF-GB), and white rice with 8% Keununnjami (HF-KJ8) or 18% Keunnunjami (HF KJ18). Their body weight gain, plasma lipid profile, adipokine level, lipid regulating enzymes activities, and mRNA expressions of peroxisome proliferator activated receptors (PPARs) were determined. RESULTS: At the end of the experimental period, the HF mice exhibited significantly higher body weight and fat, plasma triglyceride and total cholesterol levels, and atherogenic index and lower high-density lipoprotein cholesterol concentration than the NC group. However, diet supplementation of instant rice counteracted this high fat-induced body weight gain and hyperlipidemia through inhibition of lipogenesis and adipokine production and alteration of PPARs expressions. CONCLUSION: The instant KJ8 and KJ18 rice showed generally similar hypolipidemic and body weight-lowering effects to instant NB and GB rice. These findings demonstrate that instant white rice with added 8% Keunnunjami may be beneficial as functional food with strong hypolipidemic and anti-obesity properties. PMID- 26936534 TI - Hypoxia increases the heterogeneity of melanoma cell populations and affects the response to vemurafenib. AB - A hypoxic microenvironment is one of the predominant reasons for incomplete response to melanoma treatment. Vemurafenib, which targets the mutated BRAF-V600 kinase, improves melanoma patient survival, however, resistance invariably develops. The present study evaluated the effect of hypoxia on three BRAF-V600E mutant melanoma cell lines, M14, A375 and 518A2, treated with vemurafenib. Compared with the other two cell lines, hypoxic vemurafenib-treated A375 cells exhibited an enhanced cell proliferation rate and migratory capacity compared with normoxic vemurafenib-treated A375 cells. Immunoblotting analyses revealed that the expression levels of hypoxia inducible factor (HIF)1alpha and carbonic anhydrase IX were reduced in vemurafenib-treated M14 and 518A2 cells, however, not in A375 cells. The expression levels of the mitogen-activated protein kinase, Janus kinase-signal transducer and activator of transcription, and phosphatidylinositol-4,5-bisphosphate 3-kinase signaling pathway proteins revealed a cell-type specific response to vemurafenib and hypoxia. Knockdown experiments of HIF1alpha performed in hypoxic A375 cells decreased the expression of phosphorylated (p-)protein kinase B, which was restored following vemurafenib treatment, and increased the expression of p-extracellular-signal-regulated kinases. Therefore, three melanoma cell lines responded to vemurafenib under hypoxia in a cell type-specific manner, suggesting that a subset of cells provides a treatment-resistant pool, from which disease relapse may originate. These data confirmed that vemurafenib may be successful in treating the proliferating cells, whereas the non-proliferating subpopulation must be addressed by a combination of vemurafenib with other treatment strategies. PMID- 26936535 TI - Effects of whole-body vibration training on physical function, bone and muscle mass in adolescents and young adults with cerebral palsy. AB - We performed a clinical trial on the effects of whole-body vibration training (WBVT) on muscle function and bone health of adolescents and young adults with cerebral palsy. Forty participants (11.3-20.8 years) with mild to moderate cerebral palsy (GMFCS II-III) underwent 20-week WBVT on a vibration plate for 9 minutes/day 4 times/week at 20 Hz (without controls). Assessments included 6 minute walk test, whole-body DXA, lower leg pQCT scans, and muscle function (force plate). Twenty weeks of WBVT were associated with increased lean mass in the total body (+770 g; p = 0.0003), trunk (+410 g; p = 0.004), and lower limbs (+240 g; p = 0.012). Bone mineral content increased in total body (+48 g; p = 0.0001), lumbar spine (+2.7 g; p = 0.0003), and lower limbs (+13 g; p < 0.0001). Similarly, bone mineral density increased in total body (+0.008 g/cm(2); p = 0.013), lumbar spine (+0.014 g/cm(2); p = 0.003), and lower limbs (+0.023 g/cm(2); p < 0.0001). Participants reduced the time taken to perform the chair test, and improved the distance walked in the 6-minute walk test by 11% and 35% for those with GMFCS II and III, respectively. WBVT was associated with increases in muscle mass and bone mass and density, and improved mobility of adolescents and young adults with cerebral palsy. PMID- 26936536 TI - Effect and mechanism of fuzhisan and donepezil on the sirtuin 1 pathway and amyloid precursor protein metabolism in PC12 cells. AB - The present study aimed to determine the effect and mechanism of fuzhisan (FZS) and donepezil on the SIRT1 signaling pathway and the metabolism of the amyloid precursor protein (APP) in PC12 cells. An experimental cell model of PC12 cells with Abeta25-35-induced neurotoxicity was established and cell proliferation was determined by the MTT assay following treatment with donepezil and FZS. In addition, cell apoptosis was determined using DAPI staining and light microscopy. Furthermore, western blot analysis and ELISA were utilized to evaluate the expression levels of associated APP, Abeta40, Abeta42, sAPPalpha, sAPPbeta, ADAM10, sirtuin 1 (SIRT1) and forkhead box O (FoxO) protein. The results indicated that the cell model was successfully established and FZS protected the PC12 cells from the neurotoxic effects of Abeta25-35, in a similar effect to donepezil, in a dose-dependent manner. The expression of APP remained at the same level during the experimental period. The levels of Abeta40, Abeta42 and sAPPbeta were downregulated, where as sAPPalpha, ADAM10, SIRT1 and FoxO expression levels were upregulated. In conclusion, FZS treatment attenuated the Abeta25-35-induced neurotoxicity in vitro. The neuroprotective mechanism of FZS was determined, including the induction of ADAM10 and SIRT1-FoxO pathway, which participated in the process of neuroprotection. The present study identified the neuroprotective function of FZS, which may protect against Abeta-induced toxicity. Therefore, FZS may be used clinically as a beneficial therapeutic drug for the development or progression of Alzheimer's disease. PMID- 26936537 TI - Epilepsy and metaphors in literature. AB - This topic has two different aspects: seizures and epilepsy used as metaphors and seizures described in metaphors. Whereas some metaphors are unique and have high literary value, others can be categorized in prototypical groups. These include sexual metaphors; metaphors of strong emotions, of life crises and breakdown, and also of exultation; religious metaphors; and metaphors of weakness which mostly belong to older literature. Writers with epilepsy, in their literary texts, rarely talk about seizures in metaphors. Authors who do this sometimes seem to use reports that they have received from afflicted persons. The most common metaphors for seizures belong to the realms of dreams and of strong sensory impressions (visual, auditory). More rarely, storm and whirlwind are used as literary metaphors for seizures. This article is part of a Special Issue entitled "Epilepsy, Art, and Creativity". PMID- 26936539 TI - Anderson Localization in Degenerate Spin-Orbit Coupled Fermi Gas with Disorder. AB - Competition between superconductivity and disorder plays an essential role in understanding the metal-insulator transition. Based on the Bogoliubov-de Gennes framework, we studied an 2D s-wave fermionic optical lattice system with both spin- orbit coupling and disorder are presented. We find that, with the increase of the strength of disorder, the mean superconducting order parameter will vanish while the energy gap will persist, which indicates that the system undergoes a transition from a superconducting state to a gapped insulating state. This can be confirmed by calculating the inverse participation ratio. We also find that, if the strength of disorder is small, the superconducting order parameter and the energy gap will decrease if we increase the strength of spin-orbit coupling and Zeeman field. In the large disorder limits, the increase of the strength of spin- orbit coupling will increase the mean superconducting order parameter. This phenomenon shows that the system is more insensitive to disorder if the spin orbit coupling is presented. Numerical computing also shows that the whole system breaks up into several superconducting islands instead of being superconductive. PMID- 26936538 TI - Astragaloside IV suppresses inflammatory mediator production in synoviocytes and collagen-induced arthritic rats. AB - The aim of the current study was to investigate the effects of Astragaloside-IV (AS-IV) on inflammatory mediators in synoviocytes and collagen-induced arthritic rats. Synoviocytes were stimulated with lipopolysaccharides (LPS) and Sprague Dawley rats were injected with type II collagen. AS-IV was administered to the LPS-stimulated synoviocytes and collagen-induced arthritis (CIA) rats. The inflammation of LPS-stimulated synoviocytes and CIA rats was assessed using enzyme-linked immunosorbent assays and western blotting. Using Cell Counting Kit 8 analysis, it was demonstrated that AS-IV (5, 20 and 50 mg/ml) inhibited the LPS stimulated synoviocytes proliferation in a dose-dependent manner. AS-IV significantly inhibited the LPS-stimulated inflammatory response, as indicated by the expression levels of TNF-alpha, IL-1beta, IL-6 and IL-8. In addition, treatment with AS-IV significantly reduced the LPS-stimulated cyclooxygenase (COX)-1, COX-2, high mobility group box 1 protein (HMGB1) and intercellular adhesion molecule 1 overexpression, and intranuclear nuclear factor (NF) kappaBp65 subunit accumulation and activation of c-Jun N-terminal kinase (JNK)1/2 and p38. Similar to the protective effects of AS-IV on LPS-stimulated synoviocytes, AS-IV treatment significantly reduced the expression levels of tumor necrosis factor alpha, interleukin (IL)-1beta, IL-6 and IL-8 expression levels, and attenuated intranuclear NF-kappaBp65 subunit accumulation and overexpression of COX-2 and inducible nitric oxide synthase in CIA rats. In conclusion, the results of the present study demonstrated for the first time, to the best of our knowledge, that AS-IV protects synoviocytes against LPS- and collagen-induced inflammatory responses through inhibition of the HMGB1-dependent JNK1/2- and p38-activated NF-kappaB/COX-2 pathway. PMID- 26936540 TI - Understanding the causes of obesity in children with trisomy 21: hyperphagia vs physical inactivity. AB - BACKGROUND: Individuals with intellectual disabilities are at increased risk of becoming overweight or obese. This is particularly evident in people with trisomy 21 and Prader-Willi syndrome (PWS). Although metabolic factors are known to contribute to obesity in trisomy 21 and hyperphagia plays a primary role in PWS, hyperphagia has not yet been investigated as a possible contributing factor to obesity in trisomy 21. METHODS: Participants comprised three diagnostic groups: trisomy 21 (T21 group), PWS (PWS group) and lifestyle-related obesity (LRO group). They were required to be aged 6-18 years and have a body mass index over the 85th percentile for age and gender. A parent of each participant completed the Hyperphagia Questionnaire and the Children's Leisure Activity Study Survey. Mean scores for each domain and across all domains of the Hyperphagia Questionnaire and the Children's Leisure Activity Study Survey were compared between diagnostic groups using linear regression analysis. RESULTS: The study group consisted of 52 young people (23 men and 29 women) aged 6-18 years (mean 12.5 years; T21 group n = 17, PWS group n = 16 and LRO group n = 19). As hypothesised, the PWS group had the highest mean scores across all domains of the Hyperphagia Questionnaire, and the LRO group had the lowest. Food-seeking behaviour was more pronounced in the PWS group than the T21 group (mean score 13.2 vs. 8.6, p = 0.008). The LRO group spent more hours per week engaged in physical activity (14.7) in comparison with the other groups (9.6 and 9.7), whereas between the groups, differences in time spent in sedentary activities were less pronounced. CONCLUSIONS: Preoccupation with food and low levels of physical activity may contribute to the development of overweight and obesity in some individuals with trisomy 21. These factors warrant consideration in the clinical context. PMID- 26936541 TI - An assessment of the direction-finding accuracy of bat biosonar beampatterns. AB - In the biosonar systems of bats, emitted acoustic energy and receiver sensitivity are distributed over direction and frequency through beampattern functions that have diverse and often complicated geometries. This complexity could be used by the animals to determine the direction of incoming sounds based on spectral signatures. The present study has investigated how well bat biosonar beampatterns are suited for direction finding using a measure of the smallest estimator variance that is possible for a given direction [Cramer-Rao lower bound (CRLB)]. CRLB values were estimated for numerical beampattern estimates derived from 330 individual shape samples, 157 noseleaves (used for emission), and 173 outer ears (pinnae). At an assumed 60 dB signal-to-noise ratio, the average value of the CRLB was 3.9 degrees , which is similar to previous behavioral findings. Distribution for the CRLBs in individual beampatterns had a positive skew indicating the existence of regions where a given beampattern does not support a high accuracy. The highest supported accuracies were for direction finding in elevation (with the exception of phyllostomid emission patterns). No large, obvious differences in the CRLB (greater 2 degrees in the mean) were found between the investigated major taxonomic groups, suggesting that different bat species have access to similar direction-finding information. PMID- 26936542 TI - Modeling human echolocation of near-range targets with an audible sonar. AB - Blind humans echolocate nearby targets by emitting palatal clicks and perceiving echoes that the auditory system is not able to resolve temporally. The mechanism for perceiving near-range echoes is not known. This paper models the direct mouth to-ear signal (MES) and the echo to show that the echo enhances the high frequency components in the composite MES/echo signal with features that allow echolocation. The mouth emission beam narrows with increasing frequency and exhibits frequency-dependent transmission notches in the backward direction toward the ears as predicted by the piston-in-sphere model. The ears positioned behind the mouth detect a MES that contains predominantly the low frequencies contained in the emission. Hence the high-frequency components in the emission that are perceived by the ears are enhanced by the echoes. A pulse/echo audible sonar verifies this model by echolocating targets from 5 cm range, where the MES and echo overlap significantly, to 55 cm. The model predicts that unambiguous ranging occurs over a limited range and that there is an optimal range that produces the highest range resolution. PMID- 26936543 TI - Measurement of stiffness of standing trees and felled logs using acoustics: A review. AB - This paper provides a review on the use of acoustics to measure stiffness of standing trees, stems, and logs. An outline is given of the properties of wood and how these are related to stiffness and acoustic velocity throughout the tree. Factors are described that influence the speed of sound in wood, including the different types of acoustic waves which propagate in tree stems and lumber. Acoustic tools and techniques that have been used to measure the stiffness of wood are reviewed. The reasons for a systematic difference between direct and acoustic measurements of stiffness for standing trees, and methods for correction, are discussed. Other techniques, which have been used in addition to acoustics to try to improve stiffness measurements, are also briefly described. Also reviewed are studies which have used acoustic tools to investigate factors that influence the stiffness of trees. These factors include different silvicultural practices, geographic and environmental conditions, and genetics. PMID- 26936544 TI - Perceptual integration of acoustic cues to laryngeal contrasts in Korean fricatives. AB - This paper provides evidence that multiple acoustic cues involving the presence of low-frequency energy integrate in the perception of Korean coronal fricatives. This finding helps explain a surprising asymmetry between the production and perception of these fricatives found in previous studies: lower F0 onset in the following vowel leads to a response bias for plain [s] over fortis [s*], despite the fact that there is no evidence for a corresponding acoustic asymmetry in the production of [s] and [s*]. A fixed classification task using the Garner paradigm provides evidence that low F0 in a following vowel and the presence of voicing during frication perceptually integrate. This suggests that Korean listeners in previous experiments were responding to an "intermediate perceptual property" of stimuli, despite the fact that the individual acoustic components of that property are not all present in typical Korean fricative productions. The finding also broadens empirical support for the general idea of perceptual integration to a language, a different manner of consonant, and a situation where covariance of the acoustic cues under investigation is not generally present in a listener's linguistic input. PMID- 26936546 TI - Acoustic behavior of a rigidly backed poroelastic layer with periodic resonant inclusions by a multiple scattering approach. AB - The acoustic response of a rigidly backed poroelastic layer with a periodic set of elastic cylindrical inclusions embedded is studied. A semi-analytical approach is presented, based on Biot's 1956 theory to account for the deformation of the skeleton, coupling mode matching technique, Bloch wave representation, and multiple scattering theory. This model is validated by comparing the derived absorption coefficients to finite element simulations. Numerical results are further exposed to investigate the influence of the properties of the inclusions (type, material properties, size) of this structure, while a modal analysis is performed to characterize the dynamic behaviors leading to high acoustic absorption. Particularly, in the case of thin viscoelastic membranes, an absorption coefficient larger than 0.8 is observed on a wide frequency band. This property is found to be due to the coupling between the first volume mode of the inclusion and the trapped mode induced by the periodic array and the rigid backing, for a wavelength in the air smaller than 11 times the material thickness. PMID- 26936547 TI - Fast evaluation of transient acoustic fields. AB - The efficient computation of transient fields radiated by non-harmonic source distributions is a problem relevant in numerous areas of acoustics. This paper presents an efficient easily implemented method for the generation of time dependent spherical harmonic expansions for arbitrary sources, which can be used to compute the transient radiated field at arbitrary points outside the source domain. The method depends on the theory of time-domain spherical harmonic expansions and the solution of Vandermonde systems. Results are presented demonstrating the efficiency and accuracy of the method with respect to full evaluation of the field radiated by a randomized source distribution. PMID- 26936548 TI - Multimodal acquisition of articulatory data: Geometrical and temporal registration. AB - Acquisition of dynamic articulatory data is of major importance for studying speech production. It turns out that one technique alone often is not enough to get a correct coverage of the whole vocal tract at a sufficient sampling rate. Ultrasound (US) imaging has been proposed as a good acquisition technique for the tongue surface because it offers a good temporal sampling, does not alter speech production, is cheap, and is widely available. However, it cannot be used alone and this paper describes a multimodal acquisition system which uses electromagnetography sensors to locate the US probe. The paper particularly focuses on the calibration of the US modality which is the key point of the system. This approach enables US data to be merged with other data. The use of the system is illustrated via an experiment consisting of measuring the minimal tongue to palate distance in order to evaluate and design Magnetic Resonance Imaging protocols well suited for the acquisition of three-dimensional images of the vocal tract. Compared to manual registration of acquisition modalities which is often used in acquisition of articulatory data, the approach presented relies on automatic techniques well founded from geometrical and mathematical points of view. PMID- 26936549 TI - Detecting the thickness mode frequency in a concrete plate using backward wave propagation. AB - Material stiffness and plate thickness are the two key parameters when performing quality assurance/quality control on pavement structures. In order to estimate the plate thickness non-destructively, the Impact Echo (IE) method can be utilized to extract the thickness resonance frequency. An alternative to IE for estimating the thickness resonance frequency of a concrete plate, and to subsequently enable thickness determination, is presented in this paper. The thickness resonance is often revealed as a sharp peak in the frequency spectrum when contact receivers are used in seismic testing. Due to a low signal-to-noise ratio, IE is not ideal when using non-contact microphone receivers. In studying the complex Lamb wave dispersion curves at a frequency infinitesimally higher than the thickness frequency, it is seen that two counter-directed waves occur at the same frequency but with phase velocities in opposite directions. Results show that it is possible to detect the wave traveling with a negative phase velocity using both accelerometers and air-coupled microphones as receivers. This alternative technique can possibly be used in non-contact scanning measurements based on air-coupled microphones. PMID- 26936550 TI - Distortion product otoacoustic emission generation mechanisms and their dependence on stimulus level and primary frequency ratio. AB - In this study, a systematic analysis of the dependence on stimulus level and primary frequency ratio r of the different components of human distortion product otoacoustic emissions has been performed, to check the validity of theoretical models of their generation, as regards the localization of the sources and the relative weight of distortion and reflection generation mechanisms. 2f1 - f2 and 2f2 - f1 distortion product otoacoustic emissions of 12 normal hearing ears from six human subjects have been measured at four different levels, in the range [35, 65] dB sound pressure level, at eight different ratios, in the range [1.1, 1.45]. Time-frequency filtering was used to separate distortion and reflection components. Numerical simulations have also been performed using an active nonlinear cochlear model. Both in the experiment and in the simulations, the behavior of the 2f1 - f2 distortion and reflection components was in agreement with previous measurements and with the predictions of the two-source model. The 2f2 - f1 response showed a rotating-phase component only, whose behavior was in general agreement with that predicted for a component generated and reflected within a region basal to the characteristic place of frequency 2f2 - f1, although alternative interpretations, which are also discussed, cannot be ruled out. PMID- 26936551 TI - Cues for auditory stream segregation of birdsong in budgerigars and zebra finches: Effects of location, timing, amplitude, and frequency. AB - Deciphering the auditory scene is a problem faced by many organisms. However, when faced with numerous overlapping sounds from multiple locations, listeners are still able to attribute the individual sound objects to their individual sound-producing sources. Here, the characteristics of sounds important for integrating versus segregating in birds were determined. Budgerigars and zebra finches were trained using operant conditioning procedures on an identification task to peck one key when they heard a whole zebra finch song and to peck another when they heard a zebra finch song missing a middle syllable. Once the birds were trained to a criterion performance level on those stimuli, probe trials were introduced on a small proportion of trials. The probe songs contained modifications of the incomplete training song's missing syllable. When the bird responded as if the probe was a whole song, it suggests they streamed together the altered syllable and the rest of the song. When the bird responded as if the probe was a non-whole song, it suggests they segregated the altered probe from the rest of the song. Results show that some features, such as location and intensity, are more important for segregating than other features, such as timing and frequency. PMID- 26936552 TI - Prediction of break-out sound from a rectangular cavity via an elastically mounted panel. AB - The break-out sound from a cavity via an elastically mounted panel is predicted in this paper. The vibroacoustic system model is derived based on the so-called spectro-geometric method in which the solution over each sub-domain is invariably expressed as a modified Fourier series expansion. Unlike the traditional modal superposition methods, the continuity of the normal velocities is faithfully enforced on the interfaces between the flexible panel and the (interior and exterior) acoustic media. A fully coupled vibro-acoustic system is obtained by taking into account the strong coupling between the vibration of the elastic panel and the sound fields on the both sides. The typical time-consuming calculations of quadruple integrals encountered in determining the sound power radiation from a panel has been effectively avoided by reducing them, via discrete cosine transform, into a number of single integrals which are subsequently calculated analytically in a closed form. Several numerical examples are presented to validate the system model, understand the effects on the sound transmissions of panel mounting conditions, and demonstrate the dependence on the size of source room of the "measured" transmission loss. PMID- 26936553 TI - A model for wave propagation in a porous solid saturated by a three-phase fluid. AB - This paper presents a model to describe the propagation of waves in a poroelastic medium saturated by a three-phase viscous, compressible fluid. Two capillary relations between the three fluid phases are included in the model by introducing Lagrange multipliers in the principle of virtual complementary work. This approach generalizes that of Biot for single-phase fluids and allows to determine the strain energy density, identify the generalized strains and stresses, and derive the constitutive relations of the system. The kinetic and dissipative energy density functions are obtained assuming that the relative flow within the pore space is of laminar type and obeys Darcy's law for three-phase flow in porous media. After deriving the equations of motion, a plane wave analysis predicts the existence of four compressional waves, denoted as type I, II, III, and IV waves, and one shear wave. Numerical examples showing the behavior of all waves as function of saturation and frequency are presented. PMID- 26936554 TI - The benefit of head orientation to speech intelligibility in noise. AB - Spatial release from masking is traditionally measured with speech in front. The effect of head-orientation with respect to the speech direction has rarely been studied. Speech-reception thresholds (SRTs) were measured for eight head orientations and four spatial configurations. Benefits of head orientation away from the speech source of up to 8 dB were measured. These correlated with predictions of a model based on better-ear listening and binaural unmasking (r = 0.96). Use of spontaneous head orientations was measured when listeners attended to long speech clips of gradually diminishing speech-to-noise ratio in a sound deadened room. Speech was presented from the loudspeaker that initially faced the listener and noise from one of four other locations. In an undirected paradigm, listeners spontaneously turned their heads away from the speech in 56% of trials. When instructed to rotate their heads in the diminishing speech-to-noise ratio, all listeners turned away from the speech and reached head orientations associated with lower SRTs. Head orientation may prove valuable for hearing impaired listeners. PMID- 26936557 TI - An experimental application of aeroacoustic time-reversal to the Aeolian tone. AB - This paper presents an experimental application of the aeroacoustic time-reversal (TR) source localization technique for studying flow-induced noise problems and compares the TR results with those obtained using conventional beamforming (CB). Experiments were conducted in an anechoic wind tunnel for the benchmark test-case of a full-span circular cylinder located in subsonic cross-flow wherein the far field acoustic pressure was sampled using two line arrays (LAs) of microphones located above and below the cylinder. The source map obtained using the signals recorded at the two LAs without modeling the reflective surfaces of the contraction-outlet and cylinder during TR simulations revealed the lift-dipole nature of aeroacoustic source generated at the Aeolian tone; however, it indicates an error of 3/20 of Aeolian tone wavelength in the predicted location. Modeling the reflective contraction-outlet during TR was shown to improve the focal-resolution of the source and reduce side-lobe levels, especially in the low frequency range. The experimental TR results were shown to be comparable to (a) the simulation results of an idealized dipole at the cylinder location in wind tunnel flow and (b) that obtained by monopole and dipole CB, thereby demonstrating the suitability of TR method as a diagnostic tool to analyze flow induced noise generation mechanism. PMID- 26936556 TI - Spectral contrast enhancement improves speech intelligibility in noise for cochlear implants. AB - Spectral smearing causes, at least partially, that cochlear implant (CI) users require a higher signal-to-noise ratio to obtain the same speech intelligibility as normal hearing listeners. A spectral contrast enhancement (SCE) algorithm has been designed and evaluated as an additional feature for a standard CI strategy. The algorithm keeps the most prominent peaks within a speech signal constant while attenuating valleys in the spectrum. The goal is to partly compensate for the spectral smearing produced by the limited number of stimulation electrodes and the overlap of electrical fields produced in CIs. Twelve CI users were tested for their speech reception threshold (SRT) using the standard CI coding strategy with and without SCE. No significant differences in SRT were observed between conditions. However, an analysis of the electrical stimulation patterns shows a reduction in stimulation current when using SCE. In a second evaluation, 12 CI users were tested in a similar configuration of the SCE strategy with the stimulation being balanced between the SCE and the non-SCE variants such that the loudness perception delivered by the strategies was the same. Results show a significant improvement in SRT of 0.57 dB (p < 0.0005) for the SCE algorithm. PMID- 26936555 TI - Comparing measurement errors for formants in synthetic and natural vowels. AB - The measurement of formant frequencies of vowels is among the most common measurements in speech studies, but measurements are known to be biased by the particular fundamental frequency (F0) exciting the formants. Approaches to reducing the errors were assessed in two experiments. In the first, synthetic vowels were constructed with five different first formant (F1) values and nine different F0 values; formant bandwidths, and higher formant frequencies, were constant. Input formant values were compared to manual measurements and automatic measures using the linear prediction coding-Burg algorithm, linear prediction closed-phase covariance, the weighted linear prediction-attenuated main excitation (WLP-AME) algorithm [Alku, Pohjalainen, Vainio, Laukkanen, and Story (2013). J. Acoust. Soc. Am. 134(2), 1295-1313], spectra smoothed cepstrally and by averaging repeated discrete Fourier transforms. Formants were also measured manually from pruned reassigned spectrograms (RSs) [Fulop (2011). Speech Spectrum Analysis (Springer, Berlin)]. All but WLP-AME and RS had large errors in the direction of the strongest harmonic; the smallest errors occur with WLP-AME and RS. In the second experiment, these methods were used on vowels in isolated words spoken by four speakers. Results for the natural speech show that F0 bias affects all automatic methods, including WLP-AME; only the formants measured manually from RS appeared to be accurate. In addition, RS coped better with weaker formants and glottal fry. PMID- 26936558 TI - Fano resonance scatterings in waveguides with impedance boundary conditions. AB - The resonance scattering theory is used to study the sound propagation in a waveguide with a portion of its wall lined by a locally reacting material. The objective is to understand the effects of the mode coupling in the lined portion on the transmission. It is shown that a zero in the transmission is present when a real resonance frequency of the open system, i.e., the lined portion of the waveguide that is coupled to the two semi-infinite rigid ducts, is equal to the incident frequency. This transmission zero occurs as a Fano resonance-due to the excitation of a trapped mode in the open system. The trapped mode is formed by the interferences of two neighbored modes with complex resonance frequencies. It is also linked to the avoided crossing of eigenvalues of these two modes that occurs near an exceptional point (a subject that has attracted much attention in recent years in different physical domains). The real and complex resonance frequencies of the open system are determined by an equivalent eigenvalue problem of matrix Heff, which describes the eigenvalue problem defined in the finite lined portion (scattering region). With the aid of the eigenvalues and eigenfunctions of matrix Heff, the usual acoustic resonance scattering formula can be extended to describe the coupling effects between the scattering region and the rigid parts of the waveguide. PMID- 26936559 TI - Assessment of the biomechanical stability of a dental implant with quantitative ultrasound: A three-dimensional finite element study. AB - Dental implant stability is an important determinant of the surgical success. Quantitative ultrasound (QUS) techniques can be used to assess such properties using the implant acting as a waveguide. However, the interaction between an ultrasonic wave and the implant remains poorly understood. The aim of this study is to investigate the sensitivity of the ultrasonic response to the quality and quantity of bone tissue in contact with the implant surface. The 10 MHz ultrasonic response of an implant used in clinical practice was simulated using an axisymmetric three-dimensional finite element model, which was validated experimentally. The amplitude of the echographic response of the implant increases when the depth of a liquid layer located at the implant interface increases. The results show the sensitivity of the QUS technique to the amount of bone in contact with the implant. The quality of bone tissue around the implant is varied by modifying the bone biomechanical properties by 20%. The amplitude of the implant echographic response decreases when bone quality increases, which corresponds to bone healing. In all cases, the amplitude of the implant response decreased when the dental implant stability increased, which is consistent with the experimental results. PMID- 26936560 TI - Separation of non-stationary sound fields with single layer pressure-velocity measurements. AB - This paper examines the feasibility of extracting the non-stationary sound field generated by a target source in the presence of disturbing source from single layer pressure-velocity measurements. Unlike the method described in a previous paper [Bi, Geng, and Zhang, J. Acoust. Soc. Am. 135(6), 3474-3482 (2014)], the proposed method allows measurements of pressure and particle velocity signals on a single plane instead of pressure signals on two planes, and the time-dependent pressure generated by the target source is extracted by a simple superposition of the measured pressure and the convolution between the measured particle velocity and the corresponding impulse response function. Because the particle velocity here is measured directly, the error caused by the finite difference approximation can be avoided, which makes it possible to perform the separation better than the previous method. In this paper, a Microflown pressure-velocity probe is used to perform the experimental measurements, and the calibration procedure of the probe in the time domain is given. The experimental results demonstrate that the proposed method is effective in extracting the desired non stationary sound field generated by the target source from the mixed one in both time and space domains, and it obtains more accurate results than the previous method. PMID- 26936561 TI - Measurement of dispersion curves of circumferential guided waves radiating from curved shells: Theory and numerical validation. AB - A method is proposed to evaluate in a non-contact way the phase velocity dispersion curves of circumferential waves around a shell of arbitrary shape immersed in a fluid. No assumptions are made about the thickness or the material of the shell. A geometrical model is derived to describe the shape of the radiated wavefronts in the surrounding fluid, and predict the positions of its centers of curvature. Then the time-reversal principle is applied to recover these positions and to calculate the phase velocity of the circumferential waves. Numerical finite-difference simulations are performed to evaluate the method on a circular and on an elliptic thin shell. Different dispersion curves can be recovered with an error of less than 10%. PMID- 26936563 TI - Stress-dependent ultrasonic scattering in polycrystalline materials. AB - Stress-dependent elastic moduli of polycrystalline materials are used in a statistically based model for the scattering of ultrasonic waves from randomly oriented grains that are members of a stressed polycrystal. The stress is assumed to be homogeneous and can be either residual or generated from external loads. The stress-dependent elastic properties are incorporated into the definition of the differential scattering cross-section, which defines how strongly an incident wave is scattered into various directions. Nine stress-dependent differential scattering cross-sections or scattering coefficients are defined to include all possibilities of incident and scattered waves, which can be either longitudinal or (two) transverse wave types. The evaluation of the scattering coefficients considers polycrystalline aluminum that is uniaxially stressed. An analysis of the influence of incident wave propagation direction, scattering direction, frequency, and grain size on the stress-dependency of the scattering coefficients follows. Scattering coefficients for aluminum indicate that ultrasonic scattering is much more sensitive to a uniaxial stress than ultrasonic phase velocities. By developing the stress-dependent scattering properties of polycrystals, the influence of acoustoelasticity on the amplitudes of waves propagating in stressed polycrystalline materials can be better understood. This work supports the ongoing development of a technique for monitoring and measuring stresses in metallic materials. PMID- 26936562 TI - Cochlear implant speech intelligibility outcomes with structured and unstructured binary mask errors. AB - It has been shown that intelligibility can be improved for cochlear implant (CI) recipients with the ideal binary mask (IBM). In realistic scenarios where prior information is unavailable, however, the IBM must be estimated, and these estimations will inevitably contain errors. Although the effects of both unstructured and structured binary mask errors have been investigated with normal hearing (NH) listeners, they have not been investigated with CI recipients. This study assesses these effects with CI recipients using masks that have been generated systematically with a statistical model. The results demonstrate that clustering of mask errors substantially decreases the tolerance of errors, that incorrectly removing target-dominated regions can be as detrimental to intelligibility as incorrectly adding interferer-dominated regions, and that the individual tolerances of the different types of errors can change when both are present. These trends follow those of NH listeners. However, analysis with a mixed effects model suggests that CI recipients tend to be less tolerant than NH listeners to mask errors in most conditions, at least with respect to the testing methods in each of the studies. This study clearly demonstrates that structure influences the tolerance of errors and therefore should be considered when analyzing binary-masking algorithms. PMID- 26936564 TI - How clarinettists articulate: The effect of blowing pressure and tonguing on initial and final transients. AB - Articulation, including initial and final note transients, is important to tasteful music performance. Clarinettists' tongue-reed contact, the time variation of the blowing pressure P-mouth, the mouthpiece pressure, the pressure in the instrument bore, and the radiated sound were measured for normal articulation, accents, sforzando, staccato, and for minimal attack, i.e., notes started very softly. All attacks include a phase when the amplitude of the fundamental increases exponentially, with rates r ~1000 dB s(-1) controlled by varying both the rate of increase in P-mouth and the timing of tongue release during this increase. Accented and sforzando notes have shorter attacks (r~1300 dB s(-1)) than normal notes. P-mouth reaches a higher peak value for accented and sforzando notes, followed by a steady decrease for accented notes or a rapid fall to a lower, nearly steady value for sforzando notes. Staccato notes are usually terminated by tongue contact, producing an exponential decrease in sound pressure with rates similar to those calculated from the bandwidths of the bore resonances: ~400 dB s(-1). In all other cases, notes are stopped by decreasing P mouth. Notes played with different dynamics are qualitatively similar, but louder notes have larger P-mouth and larger r. PMID- 26936566 TI - Estimation and simulation of multi-beam sonar noise. AB - Methods for the estimation and modeling of noise present in multi-beam sonar data, including the magnitude, probability distribution, and spatial correlation of the noise, are developed. The methods consider individual acoustic samples and facilitate compensation of highly localized noise as well as subtraction of noise estimates averaged over time. The modeled noise is included in an existing multi beam sonar simulation model [Holmin, Handegard, Korneliussen, and Tjostheim, J. Acoust. Soc. Am. 132, 3720-3734 (2012)], resulting in an improved model that can be used to strengthen interpretation of data collected in situ at any signal to noise ratio. Two experiments, from the former study in which multi-beam sonar data of herring schools were simulated, are repeated with inclusion of noise. These experiments demonstrate (1) the potentially large effect of changes in fish orientation on the backscatter from a school, and (2) the estimation of behavioral characteristics such as the polarization and packing density of fish schools. The latter is achieved by comparing real data with simulated data for different polarizations and packing densities. PMID- 26936565 TI - Wind dependence of ambient noise in a biologically rich coastal area. AB - The wind dependence of acoustic spectrum between 100 Hz and 16 kHz is investigated for coastal biologically rich areas. The analysis of 5 months of continuous measurements run in a 10 m deep shallow water environment off Brittany (France) showed that wind dependence of spectral levels is subject to masking by biological sounds. When dealing with raw data, the wind dependence of spectral levels was not significant for frequencies where biological sounds were present (2 to 10 kHz). An algorithm developed by Kinda, Simard, Gervaise, Mars, and Fortier [J. Acoust. Soc. Am. 134(1), 77-87 (2013)] was used to automatically filter out the loud distinctive biological contribution and estimated the ambient noise spectrum. The wind dependence of ambient noise spectrum was always significant after application of this filter. A mixture model for ambient noise spectrum which accounts for the richness of the soundscape is proposed. This model revealed that wind dependence holds once the wind speed was strong enough to produce sounds higher in amplitude than the biological chorus (9 kn at 3 kHz, 11 kn at 8 kHz). For these higher wind speeds, a logarithmic affine law was adequate and its estimated parameters were compatible with previous studies (average slope 27.1 dB per decade of wind speed increase). PMID- 26936567 TI - Array model interpolation and subband iterative adaptive filters applied to beamforming-based acoustic echo cancellation. AB - In this paper, an evolutionary exposition is given in regard to the enhancing strategies for acoustic echo cancellers (AECs). A fixed beamformer (FBF) is utilized to focus on the near-end speaker while suppressing the echo from the far end. In reality, the array steering vector could differ considerably from the ideal freefield plane wave model. Therefore, an experimental procedure is developed to interpolate a practical array model from the measured frequency responses. Subband (SB) filtering with polyphase implementation is exploited to accelerate the cancellation process. Generalized sidelobe canceller (GSC) composed of an FBF and an adaptive blocking module is combined with AEC to maximize cancellation performance. Another enhancement is an internal iteration (IIT) procedure that enables efficient convergence in the adaptive SB filters within a sample time. Objective tests in terms of echo return loss enhancement (ERLE), perceptual evaluation of speech quality (PESQ), word recognition rate for automatic speech recognition (ASR), and subjective listening tests are conducted to validate the proposed AEC approaches. The results show that the GSC-SB-AEC-IIT approach has attained the highest ERLE without speech quality degradation, even in double-talk scenarios. PMID- 26936568 TI - The role of various structures in the head on the formation of the biosonar beam of the baiji (Lipotes vexillifer). AB - The relative role of the various structures in the head of the baiji (Lipotes vexillifer) is examined. A finite element approach was applied to numerically simulate the acoustic propagation through a dolphin's head to examine the relative role of the skull, air sacs, and melon in the formation of the biosonar beam in the vertical plane. The beam pattern obtained with the whole head in place is compared with the beam pattern when the air sac is removed and the other structures (skull and melon) are in place, with only the skull removed, and finally with only the melon removed. The beam pattern with the air sacs and skull intact and the melon removed closely resembled the beam pattern for the complete head, suggesting that the melon has a minor role in the formation of the beam. The beam pattern for the other two cases had very little resemblance to the beam pattern for the whole head. The air sacs seem to have a role of directing propagation of the signal toward the front and the skull prevents the sound propagating below the rostrum. The beam patterns along with a correlation analysis showed that the melon had only a slight influence on the shape and direction of the beam. The resultant beam exiting the head of the dolphin is the result of complex reflection processes within the head of the animal. PMID- 26936569 TI - Interference pattern of the sound field in the presence of an internal Kelvin wave in a stratified lake. AB - Internal Kelvin waves (IKWs) initiated by rotation of the Earth are one of the main hydrodynamic phenomena in large stratified lakes where baroclinic Rossby radius of deformation is smaller than the horizontal scale of the lake. IKWs can be identified using the spectra of internal waves, where in the presence of IKWs, the inertial frequency is at maximum. IKWs play a rather important role in the lake's dynamics for different processes, both in the water layer and sediment, especially at the periphery of lake. Due to influence of internal waves on the sound propagation, acoustical methods can be used for estimation of behaviour of IKWs. In this paper, the spatiotemporal variability of the mid-frequency (~1 kHz) sound field in the presence of IKWs in a deep stratified Lake Kinneret is studied using numerical simulations based on normal-mode theory. Due to the specific character of perturbation of the water layer, IKWs can cause specific variations of interference pattern, in particular, a significant shift of the sound interference pattern both in spatial and frequency domain. These shifts can be easily measured and used for reconstruction of IKW parameters. PMID- 26936570 TI - An acoustic study of nasal consonants in three Central Australian languages. AB - This study presents nasal consonant data from 21 speakers of three Central Australian languages: Arrernte, Pitjantjatjara and Warlpiri. The six nasals considered are bilabial /m/, dental /n/, alveolar /n/, retroflex /n/, alveo palatal /n/, and velar /n/. Nasal formant and bandwidth values are examined, as are the locations of spectral minima. Several differences are found between the bilabial /m/ and the velar /n/, and also the palatal /n/. The remaining coronal nasals /n n n/ are not well differentiated within the nasal murmur, but their average bandwidths are lower than for the other nasal consonants. Broader spectral shape measures (Centre of Gravity and Standard Deviation) are also considered, and comparisons are made with data for stops and laterals in these languages based on the same spectral measures. It is suggested that nasals are not as easily differentiated using the various measures examined here as are stops and laterals. It is also suggested that existing models of nasal consonants do not fully account for the observed differences between the various nasal places of articulation; and that oral formants, in addition to anti-formants, contribute substantially to the output spectrum of nasal consonants. PMID- 26936571 TI - Utilising temporal signal features in adverse noise conditions: Detection, estimation, and the reassigned spectrogram. AB - Visual displays in passive sonar based on the Fourier spectrogram are underpinned by detection models that rely on signal and noise power statistics. Time frequency representations specialised for sparse signals achieve a sharper signal representation, either by reassigning signal energy based on temporal structure or by conveying temporal structure directly. However, temporal representations involve nonlinear transformations that make it difficult to reason about how they respond to additive noise. This article analyses the effect of noise on temporal fine structure measurements such as zero crossings and instantaneous frequency. Detectors that rely on zero crossing intervals, intervals and peak amplitudes, and instantaneous frequency measurements are developed, and evaluated for the detection of a sinusoid in Gaussian noise, using the power detector as a baseline. Detectors that rely on fine structure outperform the power detector under certain circumstances; and detectors that rely on both fine structure and power measurements are superior. Reassigned spectrograms assume that the statistics used to reassign energy are reliable, but the derivation of the fine structure detectors indicates the opposite. The article closes by proposing and demonstrating the concept of a doubly reassigned spectrogram, wherein temporal measurements are reassigned according to a statistical model of the noise background. PMID- 26936572 TI - Three-dimensional parabolic equation modeling of mesoscale eddy deflection. AB - The impact of mesoscale oceanography, including ocean fronts and eddies, on global scale low-frequency acoustics is examined using a fully three-dimensional parabolic equation model. The narrowband acoustic signal, for frequencies from 2 to 16 Hz, is simulated from a seismic event on the Kerguellen Plateau in the South Indian Ocean to an array of receivers south of Ascension Island in the South Atlantic, a distance of 9100 km. The path was chosen for its relevance to seismic detections from the HA10 Ascension Island station of the International Monitoring System, for its lack of bathymetric interaction, and for the dynamic oceanography encountered as the sound passes the Cape of Good Hope. The acoustic field was propagated through two years (1992 and 1993) of the eddy-permitting ocean state estimation ECCO2 (Estimating the Circulation and Climate of the Ocean, Phase II) system. The range of deflection of the back-azimuth was 1.8 degrees with a root-mean-square of 0.34 degrees . The refraction due to mesoscale oceanography could therefore have significant impacts upon localization of distant low-frequency sources, such as seismic or nuclear test events. PMID- 26936573 TI - Idealized digital models for conical reed instruments, with focus on the internal pressure waveform. AB - Two models for the generation of self-oscillations of reed conical woodwinds are presented. The models use the fewest parameters (of either the resonator or the exciter), whose influence can be quickly explored. The formulation extends iterated maps obtained for lossless cylindrical pipes without reed dynamics. It uses spherical wave variables in idealized resonators, with one parameter more than for cylinders: the missing length of the cone. The mouthpiece volume equals that of the missing part of the cone, and is implemented as either a cylindrical pipe (first model) or a lumped element (second model). Only the first model adds a length parameter for the mouthpiece and leads to the solving of an implicit equation. For the second model, any shape of nonlinear characteristic can be directly considered. The complex characteristic impedance for spherical waves requires sampling times smaller than a round trip in the resonator. The convergence of the two models is shown when the length of the cylindrical mouthpiece tends to zero. The waveform is in semi-quantitative agreement with experiment. It is concluded that the oscillations of the positive episode of the mouthpiece pressure are related to the length of the missing part, not to the reed dynamics. PMID- 26936575 TI - Evolution of the temporal slope density function for waves propagating according to the inviscid Burgers equation. AB - An exact formulation for the evolution of the probability density function of the time derivative of a waveform (slope density) propagating according to the one dimensional inviscid Burgers equation is given. The formulation relies on the implicit Earnshaw solution and therefore is only valid prior to shock formation. As explicit examples, the slope density evolution of an initially sinusoidal plane wave, initially Gaussian-distributed planar noise, and an initially triangular wave are presented. The triangular wave is used to examine weak-shock limits without violating the theoretical assumptions. It is also shown that the moments of the slope density function as a function of distance may be written as an expansion in terms of the moments of the source slope density function. From this expansion, approximate expressions are presented for the above cases as well as a specific non-Gaussian noise case intended to mimic features of jet noise. Finally, analytical predictions of the propagation of initially Gaussian distributed noise are compared favorably with plane-wave tube measurements. PMID- 26936574 TI - Nonlinear frequency compression: Influence of start frequency and input bandwidth on consonant and vowel recognition. AB - By varying parameters that control nonlinear frequency compression (NFC), this study examined how different ways of compressing inaudible mid- and/or high frequency information at lower frequencies influences perception of consonants and vowels. Twenty-eight listeners with mild to moderately severe hearing loss identified consonants and vowels from nonsense syllables in noise following amplification via a hearing aid simulator. Low-pass filtering and the selection of NFC parameters fixed the output bandwidth at a frequency representing a moderately severe (3.3 kHz, group MS) or a mild-to-moderate (5.0 kHz, group MM) high-frequency loss. For each group (n = 14), effects of six combinations of NFC start frequency (SF) and input bandwidth [by varying the compression ratio (CR)] were examined. For both groups, the 1.6 kHz SF significantly reduced vowel and consonant recognition, especially as CR increased; whereas, recognition was generally unaffected if SF increased at the expense of a higher CR. Vowel recognition detriments for group MS were moderately correlated with the size of the second formant frequency shift following NFC. For both groups, significant improvement (33%-50%) with NFC was confined to final /s/ and /z/ and to some VCV tokens, perhaps because of listeners' limited exposure to each setting. No set of parameters simultaneously maximized recognition across all tokens. PMID- 26936576 TI - Transaural experiments and a revised duplex theory for the localization of low frequency tones. AB - The roles of interaural time difference (ITD) and interaural level difference (ILD) were studied in free-field source localization experiments for sine tones of low frequency (250-750 Hz). Experiments combined real-source trials with virtual trials created through transaural synthesis based on real-time ear canal measurements. Experiments showed the following: (1) The naturally occurring ILD is physically large enough to exert an influence on sound localization well below 1000 Hz. (2) An ILD having the same sign as the ITD modestly enhances the perceived azimuth of tones for all values of the ITD, and it eliminates left right confusions that otherwise occur when the interaural phase difference (IPD) passes 180 degrees . (3) Increasing the ILD to large, implausible values can decrease the perceived laterality while also increasing front-back confusions. (4) Tone localization is more directly related to the ITD than to the IPD. (5) An ILD having a sign opposite to the ITD promotes a slipped-cycle ITD, sometimes with dramatic effects on localization. Because the role of the ITD itself is altered by the ILD, the duplex processing of ITD and ILD reflects more than mere trading; the effect of the ITD can be reversed in sign. PMID- 26936577 TI - Pulse-spreading harmonic complex as an alternative carrier for vocoder simulations of cochlear implants. AB - Noise- and sine-carrier vocoders are often used to acoustically simulate the information transmitted by a cochlear implant (CI). However, sine-waves fail to mimic the broad spread of excitation produced by a CI and noise-bands contain intrinsic modulations that are absent in CIs. The present study proposes pulse spreading harmonic complexes (PSHCs) as an alternative acoustic carrier in vocoders. Sentence-in-noise recognition was measured in 12 normal-hearing subjects for noise-, sine-, and PSHC-vocoders. Consistent with the amount of intrinsic modulations present in each vocoder condition, the average speech reception threshold obtained with the PSHC-vocoder was higher than with sine vocoding but lower than with noise-vocoding. PMID- 26936578 TI - Experimental observation of ultrasound fast and slow waves through three dimensional printed trabecular bone phantoms. AB - In this paper, ultrasound measurements of 1:1 scale three-dimensional (3D) printed trabecular bone phantoms are reported. The micro-structure of a trabecular horse bone sample was obtained via synchrotron x-ray microtomography, converted to a 3D binary data set, and successfully 3D-printed at scale 1:1. Ultrasound through-transmission experiments were also performed through a highly anisotropic version of this structure, obtained by elongating the digitized structure prior to 3D printing. As in real anisotropic trabecular bone, both the fast and slow waves were observed. This illustrates the potential of stereolithography and the relevance of such bone phantoms for the study of ultrasound propagation in bone. PMID- 26936579 TI - Behavioural estimates of auditory filter widths in ferrets using notched-noise maskers. AB - Frequency selectivity is a fundamental property of hearing which affects almost all aspects of auditory processing. Here auditory filter widths at 1, 3, 7, and 10 kHz were estimated from behavioural thresholds using the notched-noise method [Patterson, Nimmo-Smith, Weber, and Milroy, J. Acoust. Soc. Am. 72, 1788-1803 (1982)] in ferrets. The mean bandwidth was 21% of the signal frequency, excluding wider bandwidths at 1 kHz (65%). They were comparable although on average broader than equivalent measurements in other mammals (~11%-20%), and wider than bandwidths measured from the auditory nerve in ferrets (~18%). In non-human mammals there is considerable variation between individuals, species, and in the correspondence with auditory nerve tuning. PMID- 26936580 TI - Three-dimensional time reversal communications in elastic media. AB - This letter presents a series of vibrational communication experiments, using time reversal, conducted on a set of cast iron pipes. Time reversal has been used to provide robust, private, and clean communications in many underwater acoustic applications. Here the use of time reversal to communicate along sections of pipes and through a wall is demonstrated to overcome the complications of dispersion and multiple scattering. These demonstrations utilize a single source transducer and a single sensor, a triaxial accelerometer, enabling multiple channels of simultaneous communication streams to a single location. PMID- 26936582 TI - Geoacoustic inversion in shallow tropical waters for a silty and sandy seabed. AB - Seabed parameters are inverted from ambient noise measurements at two shallow tropical environments with dissimilar seabed characteristics, a silty and a sandy seabed, using an approach that matches the measured and modeled complex vertical coherence. Coherence is modeled using the Green's function output from the model oases, along with theoretical formulation, for a range independent environment. Genetic algorithm is used to search the model parameter space consisting of sound speed, density, and attenuation in the sediment layers and half-space. Reasonable estimates have been obtained for the silty site, whereas the sandy site gave relatively poor parameter estimates due to reflective seabed and shipping interference. PMID- 26936581 TI - Dynamic hyperarticulation of coda voicing contrasts. AB - This study investigates the capacity for targeted hyperarticulation of contextually-relevant contrasts. Participants communicated target words with final /s/ or /z/ when a voicing minimal-pair (e.g., target dose, minimal-pair doze) either was or was not available as an alternative in the context. The results indicate that talkers enhance the durational cues associated with the word-final voicing contrast based on whether the context requires it, and that this can involve both elongation as well as shortening, depending on what enhances the contextually-relevant contrast. This suggests that talkers are capable of targeted, context-sensitive temporal enhancements. PMID- 26936583 TI - Compressive sensing with a spherical microphone array. AB - A wave expansion method is proposed in this work, based on measurements with a spherical microphone array, and formulated in the framework provided by Compressive Sensing. The method promotes sparse solutions via l1-norm minimization, so that the measured data are represented by few basis functions. This results in fine spatial resolution and accuracy. This publication covers the theoretical background of the method, including experimental results that illustrate some of the fundamental differences with the "conventional" least squares approach. The proposed methodology is relevant for source localization, sound field reconstruction, and sound field analysis. PMID- 26936584 TI - [Usefulness of brain natriuretic propeptide in the diagnosis and management of patent ductus arteriosus]. AB - INTRODUCTION: Patent ductus arteriosus (PDA) is a prevalent condition in preterm infants, and may be related to increased morbidity and mortality in the most immature newborns. Recent studies have examined the usefulness of brain natriuretic propeptide (proBNP) in the diagnosis of this pathology. The aim of the study was to evaluate the diagnostic efficacy of proBNP as a marker of hemodynamic overload in PDA. PAIENTS AND METHODS: A retrospective study was conducted on preterm infants less than 32 weeks of gestation and/or weight less than 1500 grams. Echocardiogram and determination of proBNP levels were performed on all patients. Comparison was made by subgroups according to the presence of PDA and their haemodynamic characteristics. RESULTS: Of the 60 patients enrolled, 71.7% had PDA, of which 86% had haemodynamically significant patent ductus arteriosus (HS-PDA). All of them, but one, received medical treatment with ibuprofen or acetaminophen. Surgical closure was required in 29.7% of HS-PDA. Higher values of proBNP were found in patients with HS-PDA (33338+/ 34494.47pg/mL; p=.000) compared with patients with closed or non-haemodynamically significant ductus arteriosus. Higher values were also found in patients who required surgical closure of PDA (30596.8+/-14910.9; p=.004). A greater decrease inproBNP levels was found in the group of patients which duct closure after pharmacological treatment (68+/-24.69% vs -12.22+/-99.4%; p=.030). ProBNP cutoff level for HS-PDA was calculated by ROC curve and it was 9321.5pg/mL (Specificity: 100%, Sensitivity: 94.6%). CONCLUSIONS: ProBNP levels are related to the presence or absence of haemodynamically significant patent ductus arteriosus; and its variations with treatment response. High values are also related to the need for surgical closure of PDA. PMID- 26936585 TI - Downregulation of miR-429 and inhibition of cell migration and invasion in nasopharyngeal carcinoma. AB - Viral, dietary and genetic factors have been implicated in nasopharyngeal carcinoma (NPC), however, the molecular mechanism underlying its pathogenesis remains to be fully elucidated. MicroRNAs (miRNAs) have been reported to be important in NPC tumorigenesis, with a previous miRNA microarray study showing the downregulation of miRNA (miR)-429 in NPC cells. However, the possible mechanisms of action of miR-429 have not been examined. In the present study, the expression profiles of miR-429 were detected using reverse transcription quantitative polymerase chain reaction analysis in CNE-1 and CNE-2 cells, which are two generally used NPC cells with different degrees of differentiation. Subsequently, cell proliferation, invasion and migration were analyzed in miR-429 overexpressing CNE-2 cells, and the modulatory function of miR-429 was also investigated using two target genes, zinc finger E-Box-binding homeobox 1 (ZEB1) and CRK-like (CRKL), by transfection with miR-429 mimic or anti-miR-429. Significant changes in the expression of miR-429 were detected, particularly in low-differentiated CNE-2 cells, with higher levels of epidemicity and malignancy. Additional results revealed that miR-429 inhibited the invasion and migration of the CNE-2 cells, whereas no significant effect on cell growth was observed. In addition, the mRNA and protein expression levels of the two target genes, ZEB1 and CRKL, were negatively regulated by miR-429, demonstrated through gain-of function and loss-of-function investigations, indicating that these two functional downstream targets may be involved in the inhibitory effects of miR 429 on NPC migration and invasion. miR-429 may act as a negative regulatory factor of NPC tumorigenesis, involving the functions of its downstream targets, ZEB1 and CRKL. The results suggested miR-429 as a potential candidate for miRNA based prognosis or therapy against NPC. PMID- 26936586 TI - Non-antibiotic effects of ibuprofen in uncomplicated urinary tract infection in women. PMID- 26936587 TI - Viral dynamic modelling of Hepatitis C and resistance-associated variants in haemophiliacs. AB - AIM: Chronic hepatitis C virus (HCV) infection is an important source of morbidity and mortality among haemophiliacs. Limited data are available regarding treatment intervention using direct-acting antivirals (DAAs) and theoretical concerns regarding accumulation of drug-associated resistance variants (RAVs) remain. We conducted a pilot study of treatment with telaprevir/pegylated interferon-alfa/ribavirin to evaluate treatment response and the role of lead-in DAA therapy on mutational selection of resistance variants. METHODS: Ultra-deep sequence analysis was performed at baseline, 48 hours and 168 hours after treatment initiation. RESULTS: No dominant RAVs were identified at baseline, but low-level RAVs were noted at baseline in all subjects. Viral dynamic models were used to assess treatment responses. The efficacy parameter (E) for lead-in ranged from 0 to 0.9745 (mean = 0.514). Subsequent addition of telaprevir resulted in a mean efficacy of more than 0.999. This was comparable to subjects who started all three medications simultaneously. A total of 80% achieved SVR. While rapid shifts in the RAV population following DAA initiation were observed, treatment failure associated with A156V was observed in only one patient. Adverse event profiles were similar to that observed in non-haemophilia cohorts. There was no evidence of factor inhibitor formation. There was no evidence that lead-in provided benefit in terms of response efficacy. CONCLUSION: These data support DAA-based therapy in those with inherited bleeding disorders. PMID- 26936588 TI - Phosphorylation of syntaxin-3 at Thr 14 negatively regulates exocytosis in RBL 2H3 mast cells. AB - Recent studies have revealed that soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins interact with each other, forming a SNARE complex that induces exocytosis in mast cells. Previously, we reported that syntaxin-3, a SNARE protein, regulates mast cell exocytosis and is constantly phosphorylated. In this study, we tried to identify the amino acid residue that is phosphorylated in mast cells, and to elucidate the regulatory mechanism of exocytosis by phosphorylation in syntaxin-3. We found that Thr 14 of syntaxin-3 was a phosphorylation site in mast cells. In addition, the overexpression of a constitutively dephosphorylated syntaxin-3 (T14A) mutant enhanced mast cell exocytosis. We also showed that the phosphomimetic mutation of syntaxin-3 at Thr 14 (T14E) induced structural changes in syntaxin-3, and this mutation inhibited binding of syntaxin-3 to Munc18-2. These results suggest that phosphorylated syntaxin-3 at Thr 14 negatively regulates mast cell exocytosis by impairing the interaction between syntaxin-3 and Munc18-2. PMID- 26936589 TI - Pathogenic Candida species differ in the ability to grow at limiting potassium concentrations. AB - A high intracellular concentration of potassium (200-300 mmol/L) is essential for many yeast cell functions, such as the regulation of cell volume and pH, maintenance of membrane potential, and enzyme activation. Thus, cells use high affinity specific transporters and expend a lot of energy to acquire the necessary amount of potassium from their environment. In Candida genomes, genes encoding 3 types of putative potassium uptake systems were identified: Trk uniporters, Hak symporters, and Acu ATPases. Tests of the tolerance and sensitivity of C. albicans, C. dubliniensis, C. glabrata, C. krusei, C. parapsilosis, and C. tropicalis to various concentrations of potassium showed significant differences among the species, and these differences were partly dependent on external pH. The species most tolerant to potassium-limiting conditions were C. albicans and C. krusei, while C. parapsilosis tolerated the highest KCl concentrations. Also, the morphology of cells changed with the amount of potassium available, with C. krusei and C. tropicalis being the most influenced. Taken together, our results confirm potassium uptake and accumulation as important factors for Candida cell growth and suggest that the sole (and thus probably indispensable) Trk1 potassium uptake system in C. krusei and C. glabrata may serve as a target for the development of new antifungal drugs. PMID- 26936590 TI - Does Immunosuppressive Therapy Affect Markers of Kidney Damage? AB - BACKGROUND: Markers currently used to detect kidney damage are effective in both early (KIM-1, NGAL) and late (MCP-1, MMP, TIMP) stages of renal tubular damage, indicating the progression of chronic kidney disease. Immunosuppressive drugs may damage the transplanted organ through their direct toxic effects and by contributing to the development of chronic fibrosis and tubular atrophy. The aim of this study was to determine if immunosuppressive drugs per se affect the concentration of kidney damage markers, by using concentrations and doses of immunosuppressive within therapeutic, not toxic, levels in rat blood. MATERIAL AND METHODS: The study involved 36 rats grouped according to the immunosuppressive regimen used (tacrolimus, mycophenolate mofetil, cyclosporin A, rapamycin, and prednisone). The rats were treated with a 3-drug protocol for 6 months. No drugs were administered to the control group. The blood samples were collected to determine the concentration of kidney damage markers by using enzyme linked immunosorbent assay (ELISA). RESULTS: 1. In the groups receiving regimens based on cyclosporin A (CyA), significantly higher concentrations of KIM-1 in plasma was observed compared to cases not treated with drugs. 2. The use of tacrolimus was associated with increased concentrations of MCP-1 in plasma and rapamycin was associated with decreased concentrations of MCP-1 in plasma. 3. Rapamycin induces an unfavorable, profibrotic imbalance between metalloproteinase 9 and its inhibitor, TIMP-1. CONCLUSIONS: Commonly used immunosuppressive drugs influence the concentration of blood markers of kidney damage. This fact should be taken into account when analyzing the association between the concentration of these markers and pathological processes occurring in the transplanted kidney. PMID- 26936591 TI - MiR-1284 modulates multidrug resistance of gastric cancer cells by targeting EIF4A1. AB - Routine chemotherapy as an important treatment mode often can not be effective because of multidrug resistance (MDR). MicroRNA (miRNA) modulates the expression of a great number of genes, including MDR. In this study, the expression of miR 1284 was reduced in gastric cancer (GC) tissue specimens with metastasis and in vincristine-resistant (VCR) GC SGC7901 cells (SGC-7901/VCR) compared to that in the controls. Recombinant lentiviral vectors with miR-1284 led to the overexpression of miR-1284 mRNA and reversed the chemoresistance of SGC7901/VCR cells, promoted cell cycle arrested at the G0/G1 phase, accelerated drug-induced apoptosis, and decreased migration and invasiveness of SGC-7901/VCR. In addition, the overexpression of miR-1284 sensitized tumors to chemotherapy in vivo. Our data provide combined evidence that miR-1284 can heighten the expression of MYC and reduce the expression of JUN, MMP12, and EIF4A1 that was the direct target. In conclusion, miR-1284 can function as a new regulator to reduce GC MDR cells by targeting EIF4A1. PMID- 26936592 TI - Limonoids and Triterpenoids as 11beta-HSD1 Inhibitors from Walsura robusta. AB - Nine new cedrelone-type limonoid derivatives, walsunoids A-I (1-9), and 11 known compounds were isolated from the leaves of Walsura robusta. Walsunoid A (1) is a new degradation product of cedrelone-type limonoids, and walsunoid I (9) is a rare cedrelone-type limonoid amide. Their structures and absolute configurations were determined by spectroscopic data, single-crystal X-ray diffraction, and ECD data analyses. Five compounds showed moderate inhibitory activities against human and/or mouse 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) with IC50 values ranging from 0.69 to 9.9 MUM. PMID- 26936593 TI - A Permutation Test for Unbalanced Paired Comparisons of Global Field Power. AB - Global field power is a valuable summary of multi-channel electroencephalography data. However, global field power is biased by the noise typical of electroencephalography experiments, so comparisons of global field power on data with unequal noise are invalid. Here, we demonstrate the relationship between the number of trials that contribute to a global field power measure and the expected value of that global field power measure. We also introduce a statistical testing procedure that can be used for multi-subject, repeated-measures (also called within-subjects) comparisons of global field power when the number of trials per condition is unequal across conditions. Simulations demonstrate the effect of unequal trial numbers on global field power comparisons and show the validity of the proposed test in contrast to conventional approaches. Finally, the proposed test and two alternative tests are applied to data collected in a rapid serial visual presentation target detection experiment. The results show that the proposed test finds global field power differences in the classical P3 range; the other tests find differences in that range but also at other times including at times before stimulus onset. These results are interpreted as showing that the proposed test is valid and sensitive to real within-subject differences in global field power in multi-subject unbalanced data. PMID- 26936594 TI - The Role of Skull Modeling in EEG Source Imaging for Patients with Refractory Temporal Lobe Epilepsy. AB - We investigated the influence of different skull modeling approaches on EEG source imaging (ESI), using data of six patients with refractory temporal lobe epilepsy who later underwent successful epilepsy surgery. Four realistic head models with different skull compartments, based on finite difference methods, were constructed for each patient: (i) Three models had skulls with compact and spongy bone compartments as well as air-filled cavities, segmented from either computed tomography (CT), magnetic resonance imaging (MRI) or a CT-template and (ii) one model included a MRI-based skull with a single compact bone compartment. In all patients we performed ESI of single and averaged spikes marked in the clinical 27-channel EEG by the epileptologist. To analyze at which time point the dipole estimations were closer to the resected zone, ESI was performed at two time instants: the half-rising phase and peak of the spike. The estimated sources for each model were validated against the resected area, as indicated by the postoperative MRI. Our results showed that single spike analysis was highly influenced by the signal-to-noise ratio (SNR), yielding estimations with smaller distances to the resected volume at the peak of the spike. Although averaging reduced the SNR effects, it did not always result in dipole estimations lying closer to the resection. The proposed skull modeling approaches did not lead to significant differences in the localization of the irritative zone from clinical EEG data with low spatial sampling density. Furthermore, we showed that a simple skull model (MRI-based) resulted in similar accuracy in dipole estimation compared to more complex head models (based on CT- or CT-template). Therefore, all the considered head models can be used in the presurgical evaluation of patients with temporal lobe epilepsy to localize the irritative zone from low density clinical EEG recordings. PMID- 26936595 TI - Positive Emotional Experience: Induced by Vibroacoustic Stimulation Using a Body Monochord in Patients with Psychosomatic Disorders: Is Associated with an Increase in EEG-Theta and a Decrease in EEG-Alpha Power. AB - Relaxation and meditation techniques are generally characterized by focusing attention, which is associated with an increase of frontal EEG Theta. Some studies on music perception suggest an activation of Frontal Midline Theta during emotionally positive attribution, others display a lateralization of electrocortical processes in the attribution of music induced emotion of different valence. The present study examined the effects of vibroacoustic stimulation using a Body Monochord and the conventional relaxation music from an audio CD on the spontaneous EEG of patients suffering from psychosomatic disorders (N = 60). Each treatment took about 20 min and was presented to the patients in random order. Subjective experience was recorded via self-rating scale. EEG power spectra of the Theta, Alpha-1 and Alpha-2 bands were analysed and compard between the two treatment conditions. There was no lateralization of electrocortical activity in terms of the emotional experience of the musical pieces. A reduction in Alpha-2 power occurred during both treatments. An emotionally positive attribution of the experience of the vibroacoustically induced relaxation state is characterized by a more pronounced release of control. In the context of focused attention this is interpreted as flow experience. The spontaneous EEG showed an increase in Theta power, particularly in the frontal medial and central medial area, and a greater reduction in Alpha-2 power. The intensity of positive emotional feelings during the CD music showed no significant effect on the increase in Theta power. PMID- 26936596 TI - Independent Vector Analysis for SSVEP Signal Enhancement, Detection, and Topographical Mapping. AB - Steady state visual evoked potentials (SSVEPs) have been identified as an effective solution for brain computer interface (BCI) systems as well as for neurocognitive investigations. SSVEPs can be observed in the scalp-based recordings of electroencephalogram signals, and are one component buried amongst the normal brain signals and complex noise. We present a novel method for enhancing and improving detection of SSVEPs by leveraging the rich joint blind source separation framework using independent vector analysis (IVA). IVA exploits the diversity within each dataset while preserving dependence across all the datasets. This approach is shown to enhance the detection of SSVEP signals across a range of frequencies and subjects for BCI systems. Furthermore, we show that IVA enables improved topographic mapping of the SSVEP propagation providing a promising new tool for neuroscience and neurocognitive research. PMID- 26936597 TI - Novel methods for microCT-based analyses of vasculature in the renal cortex reveal a loss of perfusable arterioles and glomeruli in eNOS-/- mice. AB - BACKGROUND: Two-dimensional measures of vascular architecture provide incomplete information about vascular structure. This study applied a novel rigorous method for 3D microCT-based analysis of total and cortical renal vasculature combined with a novel method to isolate and quantify the number of perfused glomeruli to assess vascular changes in eNOS-/- mice. METHODS: Two month old male wildtype and eNOS-/- mice were perfused with heparinized saline followed by radiopaque Microfil. The Microfil-perfused vasculature of excised kidneys was imaged by MUCT with an isotropic voxel-size of 5.0 MUm. For analysis of renal cortical vasculature, a custom algorithm was created to define the cortical volume of interest (VOI) as the entire volume within 600 MUm of the renal surface. Vessel thickness in the whole kidney or renal cortex was analyzed by plotting the distribution of vascular volume at each measured thickness and examining differences between the genotypes at individual thicknesses. A second image processing algorithm was created to isolate, identify, and extract contrast perfused glomeruli from the cortical vessels. RESULTS: Fractional vascular volume (vascular volume/kidney volume; VV/KV) and Vessel Number/mm (V.N) were significantly lower in eNOS-/- mice vs. WT (p < 0.05). eNOS-/- kidneys had significantly fewer perfusable vessels vs. WT in the range of 20-40 MUm in thickness. The cortex of eNOS-/- kidneys had significantly lower VV, VV/cortical volume, and V.N, with an increase in the distance between vessels (all p < 0.05). The total volume of vessels in the range of 20-30 MUm was significantly lower in the cortex of eNOS-/- mice compared to WT (p < 0.05). Moreover, the total number of perfused glomeruli was significantly decreased in eNOS-/- mice (p < 0.01). CONCLUSIONS: The methods presented here demonstrate a new method to analyze contrast enhanced MUCT images for vascular phenotyping of the murine kidney. These data also demonstrate that kidneys in eNOS-/- mice have severe defects in vascular perfusion/structure in the renal cortex. PMID- 26936598 TI - Post-glacial phylogeography and evolution of a wide-ranging highly-exploited keystone forest tree, eastern white pine (Pinus strobus) in North America: single refugium, multiple routes. AB - BACKGROUND: Knowledge of the historical distribution and postglacial phylogeography and evolution of a species is important to better understand its current distribution and population structure and potential fate in the future, especially under climate change conditions, and conservation of its genetic resources. We have addressed this issue in a wide-ranging and heavily exploited keystone forest tree species of eastern North America, eastern white pine (Pinus strobus). We examined the range-wide population genetic structure, tested various hypothetical population history and evolutionary scenarios and inferred the location of glacial refugium and post-glacial recolonization routes. Our hypothesis was that eastern white pine survived in a single glacial refugium and expanded through multiple post-glacial recolonization routes. RESULTS: We studied the range-wide genetic diversity and population structure of 33 eastern white pine populations using 12 nuclear and 3 chloroplast microsatellite DNA markers. We used Approximate Bayesian Computation approach to test various evolutionary scenarios. We observed high levels of genetic diversity, and significant genetic differentiation (F ST = 0.104) and population structure among eastern white pine populations across its range. A south to north trend of declining genetic diversity existed, consistent with repeated founder effects during post glaciation migration northwards. We observed broad consensus from nuclear and chloroplast genetic markers supporting the presence of two main post-glacial recolonization routes that originated from a single southern refugium in the mid Atlantic plain. One route gave rise to populations at the western margin of the species' range in Minnesota and western Ontario. The second route gave rise to central-eastern populations, which branched into two subgroups: central and eastern. We observed minimal sharing of chloroplast haplotypes between recolonization routes but there was evidence of admixture between the western and west-central populations. CONCLUSIONS: Our study reveals a single southern refugium, two recolonization routes and three genetically distinguishable lineages in eastern white pine that we suggest to be treated as separate Evolutionarily Significant Units. Like many wide-ranging North American species, eastern white pine retains the genetic signatures of post-glacial recolonization and evolution, and its contemporary population genetic structure reflects not just the modern distribution and effects of heavy exploitation but also routes northward from its glacial refugium. PMID- 26936599 TI - Sequential morphological change of Chiari malformation type II following surgical repair of myelomeningocele. AB - PURPOSE: To document long-term morphological changes of Chiari type II malformation (CM-II) following closure of spina bifida manifesta (SBM). METHODS: We retrospectively evaluated postnatal magnetic resonance images of the CM-II and posterior fossa (PF) in 28 consecutive cases. We measured changes in vertebral level and length of the cerebellar peg (CP), cerebrospinal fluid (CSF) spaces anterior and posterior to the cerebrospinal junction, PF area, and the anteroposterior diameters of the foramen magnum (FM) and C1 vertebra. We examined the morphological differences between the cases with and without ventriculoperitoneal (VP) shunting and derived predicted means by nonlinear mixed effect modeling. RESULTS: At birth, there were significant differences in CP length, PF area, and FM and C1 diameters between those who underwent VP shunting and those who did not. In cases with a CP below C1, VP shunting was required in every case but one. In those with visible CSF space at birth, VP shunts were not required. In 17 of 18 cases with a CP below C1, the vertebral level ascended by mean two vertebral levels (range 0-5 levels) within 4-6 months of delivery. In the remaining case, slowly progressive hydrocephalus and delayed CP descent required VP shunting at 8 months. Predicted mean CP length and FM and C1 diameters were greater in those who underwent VP shunting, but there was no difference in predicted mean PF area. CONCLUSION: The morphology of CM-II and the presence of hydrocephalus influence each other in children who have undergone postnatal SBM repair. PMID- 26936600 TI - Syntheses, structures, physical and electronic properties of quaternary semiconductors: Cs[RE9Cd4Se18] (RE = Tb-Tm). AB - Five new quaternary rare-earth selenides, Cs[RE9Cd4Se18] (RE = Tb-Tm), which are the first examples with closed cavities in the quaternary A/RE/Cd/Q (A = alkali metal; RE = rare earth metal; Q = chalcogenide) system, have been synthesized by high-temperature solid state reactions with a modified reactive CsCl flux. Single crystal X-ray diffraction analyses show that these isostructural materials adopted a known BaV13O18-structure type in the trigonal space group R3[combining macron] (no. 148) with cell parameters of a = 17.773(2)-17.489(6) A, c = 9.918(2) 9.765(5) A and Z = 3. The structure is composed of MSe6 (centered by disordered RE and Cd) and RESe6 octahedra that share edges to form a 3D framework, inside which the cuboctahedral Se12 closed cavities accommodate Cs cations. It is interesting to note that these compounds exhibit atomic distributions different from the recently reported Mn-compounds Cs[RE9Mn4Se18]. In Cd-compounds, Cd and RE atoms are statistically mixed only at one of the 18f sites; the rest of the RE atoms are fully occupied at the two framework sites: 18f and 3a. Moreover, the theoretical studies have greatly aided the understanding of the site-preference about a Cd atom in the 3D framework. The synthesis, structural characterization, electronic band structure as well as physical properties of the title compounds are also discussed. PMID- 26936601 TI - Perioperative immunonutrition in normo-nourished patients undergoing laparoscopic colorectal resection. AB - OBJECTIVE: To determine whether the joint implementation of immunonutrition and a laparoscopic approach improves morbidity, mortality, and length of stay (LOS) compared with dietary advice. BACKGROUND: Despite progress in recent years in the surgical management of patients with colorectal cancer, postoperative complications are frequent. Nutritional supplements enriched with immunonutrients have recently been introduced into clinical practice. However, the immunonutrition benefits in patients undergoing colorectal laparoscopic surgery are unknown. METHODS: This study was a prospective, randomized trial with two parallel treatment groups receiving an immune-enhancing dietary supplement for 7 days before colorectal resection and 5 days postoperatively or dietary advice. RESULTS: A total of 128 patients were randomized. At baseline, both groups were comparable with respect to age, sex, surgical risk, comorbidities, and analytical and nutritional parameters. The median postoperative LOS was 5 days and was not significantly different between the groups. Wound infection differed significantly between the groups (11.50 vs. 0.00 %, p = 0.006). No other differences between the groups were identified. CONCLUSIONS: The joint use of laparoscopy and supplementation with immunonutrients reduces surgical wound infection in patients undergoing colorectal surgery. TRIAL REGISTRATION: This study is registered with ClinicalTrial.gov : NCT0239396. PMID- 26936602 TI - The superficial elevated and depressed lesion type is an independent factor associated with non-curative endoscopic submucosal dissection for early gastric cancer. AB - BACKGROUND: The expanded criteria for endoscopic submucosal dissection (ESD) for early gastric cancer (EGC) have led to an increase in the number of EGC patients who receive curative treatment involving endoscopic techniques. Identifying the factors that are associated with treatment outcomes would be helpful in the application of ESD for EGC. METHODS: Potential factors associated with incomplete ESD and with non-curative ESD were investigated using a multiple logistic regression model in EGC patients who consecutively underwent ESD according to the expanded criteria. RESULTS: A total of 363 patients with 398 EGC lesions were enrolled. The rates of complete ESD and curative ESD were 96.2 % (383/398) and 85.7 % (341/398), respectively. No significant factors associated with incomplete ESD were identified. In contrast, a tumor size >20 mm [odds ratio (OR) 3.31; 95 % confidence interval (CI) 1.74-6.29], the superficial elevated and depressed type (0-IIa + IIc or IIc + IIa) (OR 4.37; 95 % CI 1.88-9.88), and the undifferentiated type (OR 5.93; 95 % CI 1.65-19.41) were identified as independent factors associated with non-curative ESD. The superficial elevated and depressed type in particular was found to be highly related to submucosal and lymphovascular invasion. The rate of non-curative ESD in cases of this macroscopic type occurring together with a tumor size >20 mm was 58.3 %, and the adjusted OR was 16.48 (95 % CI 4.69-62.09). CONCLUSION: The results suggest that the superficial elevated and depressed type is an independent factor associated with non-curative ESD and that the risk of non-curative ESD is increased when this macroscopic type is present along with a large tumor size. PMID- 26936603 TI - The HIV Protein gp120 Alters Mitochondrial Dynamics in Neurons. AB - Neurotoxicity of human immunodeficiency virus-1 (HIV) includes synaptic simplification and neuronal apoptosis. However, the mechanisms of HIV-associated neurotoxicity remain unclear, thus precluding an effective treatment of the neurological complications. The present study was undertaken to characterize novel mechanisms of HIV neurotoxicity that may explain how HIV subjects develop neuronal degeneration. Several neurodegenerative disorders are characterized by mitochondrial dysfunction; therefore, we hypothesized that HIV promotes mitochondrial damage. We first analyzed brains from HIV encephalitis (HIVE) by electron microscopy. Several sections of HIVE subjects contained enlarged and damaged mitochondria compared to brains from HIV subjects with no neurological complications. Similar pathologies were observed in mice overexpressing the HIV protein gp120, suggesting that this viral protein may be responsible for mitochondrial pathology found in HIVE. To gain more information about the cellular mechanisms of gp120 neurotoxicity, we exposed rat cortical neurons to gp120 and we determined cellular oxygen consumption rate, mitochondrial distribution, and trafficking. Our data show that gp120 evokes impairment in mitochondrial function and distribution. These data suggest that one of the mechanisms of HIV neurotoxicity includes altered mitochondrial dynamics in neurons. PMID- 26936604 TI - Acute Hyperammonemia Induces NMDA-Mediated Hypophosphorylation of Intermediate Filaments Through PP1 and PP2B in Cerebral Cortex of Young Rats. AB - In the present work, we studied the effects of toxic ammonia levels on the cytoskeleton of neural cells, with emphasis in the homeostasis of the phosphorylating system associated with the intermediate filaments (IFs). We used in vivo and in vitro models of acute hyperammonemia in 10- and 21-day-old rats. In the in vivo model, animals were intraperitoneally injected with ammonium acetate (7 mmol/Kg), and the phosphorylation level of the cytoskeletal proteins was analyzed in the cerebral cortex and hippocampus 30 and 60 min after injection. The injected ammonia altered the IF phosphorylation of astrocytes (GFAP and vimentin) and neurons (neurofilament subunits of low, middle, and high molecular weight, respectively: NFL, NFM, and NFH) from cerebral cortex of 21-day old rats. This was a transitory effect observed 30 min after injection, recovering 30 min afterward. Phosphorylation was not altered in the cerebral cortex of 10-day-old pups. The homeostasis of hippocampal IFs was preserved at the studied ages and times. In the in vitro model, cortical slices of 10- and 21 day-old rats were incubated with 0.5, 1, or 5 mM NH4Cl, and the phosphorylation level of the IF proteins was analyzed after 30 min. The IF phosphorylation was not altered in cortical slices of 10-day-old rats; however, in cortical slices of 21-day-old pups, 5 mM NH4Cl induced hypophosphorylation of GFAP and vimentin, preserving neurofilament phosphorylation levels. Hypophosphorylation was mediated by the protein phosphatases 1 (PP1) and 2B (PP2B), and this event was associated with Ca(2+) influx via N-methyl-D-aspartate (NMDA) glutamate receptors. The aim of this study is to show that acute ammonia toxicity targets the phosphorylating system of IFs in the cerebral cortex of rats in a developmentally regulated manner, and NMDA-mediated Ca(2+) signaling plays a central role in this mechanism. We propose that the disruption of cytoskeletal homeostasis could be an endpoint of the acute hyperammonemia in the developing brain. We believe that these results contribute for better understanding the molecular basis of the ammonia toxicity in brain. PMID- 26936607 TI - MEGAnnotator: a user-friendly pipeline for microbial genomes assembly and annotation. AB - Genome annotation is one of the key actions that must be undertaken in order to decipher the genetic blueprint of organisms. Thus, a correct and reliable annotation is essential in rendering genomic data valuable. Here, we describe a bioinformatics pipeline based on freely available software programs coordinated by a multithreaded script named MEGAnnotator (Multithreaded Enhanced prokaryotic Genome Annotator). This pipeline allows the generation of multiple annotated formats fulfilling the NCBI guidelines for assembled microbial genome submission, based on DNA shotgun sequencing reads, and minimizes manual intervention, while also reducing waiting times between software program executions and improving final quality of both assembly and annotation outputs. MEGAnnotator provides an efficient way to pre-arrange the assembly and annotation work required to process NGS genome sequence data. The script improves the final quality of microbial genome annotation by reducing ambiguous annotations. Moreover, the MEGAnnotator platform allows the user to perform a partial annotation of pre-assembled genomes and includes an option to accomplish metagenomic data set assemblies. MEGAnnotator platform will be useful for microbiologists interested in genome analyses of bacteria as well as those investigating the complexity of microbial communities that do not possess the necessary skills to prepare their own bioinformatics pipeline. PMID- 26936605 TI - C1q-targeted inhibition of the classical complement pathway prevents injury in a novel mouse model of acute motor axonal neuropathy. AB - INTRODUCTION: Guillain-Barre syndrome (GBS) is an autoimmune disease that results in acute paralysis through inflammatory attack on peripheral nerves, and currently has limited, non-specific treatment options. The pathogenesis of the acute motor axonal neuropathy (AMAN) variant is mediated by complement-fixing anti-ganglioside antibodies that directly bind and injure the axon at sites of vulnerability such as nodes of Ranvier and nerve terminals. Consequently, the complement cascade is an attractive target to reduce disease severity. Recently, C5 complement component inhibitors that block the formation of the membrane attack complex and subsequent downstream injury have been shown to be efficacious in an in vivo anti-GQ1b antibody-mediated mouse model of the GBS variant Miller Fisher syndrome (MFS). However, since gangliosides are widely expressed in neurons and glial cells, injury in this model was not targeted exclusively to the axon and there are currently no pure mouse models for AMAN. Additionally, C5 inhibition does not prevent the production of early complement fragments such as C3a and C3b that can be deleterious via their known role in immune cell and macrophage recruitment to sites of neuronal damage. RESULTS AND CONCLUSIONS: In this study, we first developed a new in vivo transgenic mouse model of AMAN using mice that express complex gangliosides exclusively in neurons, thereby enabling specific targeting of axons with anti-ganglioside antibodies. Secondly, we have evaluated the efficacy of a novel anti-C1q antibody (M1) that blocks initiation of the classical complement cascade, in both the newly developed anti-GM1 antibody-mediated AMAN model and our established MFS model in vivo. Anti-C1q monoclonal antibody treatment attenuated complement cascade activation and deposition, reduced immune cell recruitment and axonal injury, in both mouse models of GBS, along with improvement in respiratory function. These results demonstrate that neutralising C1q function attenuates injury with a consequent neuroprotective effect in acute GBS models and promises to be a useful new target for human therapy. PMID- 26936606 TI - Selecting the embryo with the highest implantation potential using a data mining based prediction model. AB - BACKGROUND: Embryo selection has been based on developmental and morphological characteristics. However, the presence of an important intra-and inter-observer variability of standard scoring system (SSS) has been reported. A computer assisted scoring system (CASS) has the potential to overcome most of these disadvantages associated with the SSS. The aims of this study were to construct a prediction model, with data mining approaches, and compare the predictive performance of models in SSS and CASS and to evaluate whether using the prediction model would impact the selection of the embryo for transfer. METHODS: A total of 871 single transferred embryos between 2008 and 2013 were included and evaluated with two scoring systems: SSS and CASS. Prediction models were developed using multivariable logistic regression (LR) and multivariate adaptive regression splines (MARS). The prediction models were externally validated with a test set of 109 single transfers between January and June 2014. Area under the curve (AUC) in training data and validation data was compared to determine the utility of the models. RESULTS: In SSS models, the AUC declined significantly from training data to validation data (p < 0.05). No significant difference was detected in CASS derived models. Two final prediction models derived from CASS were obtained using LR and MARS, which showed moderate discriminative capacity (c statistic 0.64 and 0.69 respectively) on validation data. CONCLUSIONS: The study showed that the introduction of CASS improved the generalizability of the prediction models, and the combination of computer-assisted scoring system with data mining based predictive modeling is a promising approach to improve the selection of embryo with the highest implantation potential. PMID- 26936608 TI - Febrile Neutropenia Rates According to Body Mass Index and Dose Capping in Women Receiving Chemotherapy for Early Breast Cancer. AB - AIMS: Studies suggest worse outcomes in obese women with breast cancer than in non-obese women. One potential reason may be that oncologists 'dose cap' adjuvant chemotherapy in obese patients in order to avoid excessive toxicity. Reductions from standard dosing may compromise survival outcomes in the curative setting. Here we describe the body mass index (BMI) distribution of patients in a non trial population, the frequency with which oncologists dose cap and its effect on febrile neutropenia chemotherapy toxicity. MATERIALS AND METHODS: In this non randomised study, electronic patient records retrospectively identified patients with early breast cancer who initiated neoadjuvant or adjuvant chemotherapy at the Royal Marsden Hospital between 1 January and 31 December 2013. Baseline data included age, BMI, performance status, tumour characteristics, granulocyte colony stimulating factor and comorbidities. Chemotherapy doses, rates of dose capping across BMI groups and rates of febrile neutropenia were reported. RESULTS: In total, 325 patients were eligible: 79 (24.5%) were obese (BMI >= 30), 109 (33.5%) were overweight (BMI >=25 - <30) and 137 (42%) were normal bodyweight (BMI < 25). Sixteen patients (20.5%) in the obese group received dose-capped chemotherapy. Overall, 62 patients (19%) had an episode of febrile neutropenia. Obese patients receiving uncapped chemotherapy did not experience a significant difference in febrile neutropenia rates when compared with overweight or normal bodyweight groups (P = 0.5798). The febrile neutropenia rate in obese patients receiving capped chemotherapy was 6.5%, compared with 24% in obese patients receiving uncapped chemotherapy (P = 0.1216). CONCLUSION: In a non-trial population of obese patients, dose capping is frequently used. Obese patients receiving uncapped chemotherapy do not experience increased febrile neutropenia rates when compared with uncapped overweight or normal bodyweight patients. Furthermore, dose capping was associated with a trend towards lower rates of febrile neutropenia than in other groups and may indicate relative under-dosing of chemotherapy. This supports international guidelines that state that obese patients should not be dose capped. PMID- 26936609 TI - Wide Variation in the Use of Radiotherapy in the Management of Surgically Treated Rectal Cancer Across the English National Health Service. AB - AIMS: Radiotherapy is an important treatment modality in the multidisciplinary management of rectal cancer. It is delivered both in the neoadjuvant setting and postoperatively, but, although it reduces local recurrence, it does not influence overall survival and increases the risk of long-term complications. This has led to a variety of international practice patterns. These variations can have a significant effect on commissioning, but also future clinical research. This study explores its use within the large English National Health Service (NHS). MATERIALS AND METHODS: Information on all individuals diagnosed with a surgically treated rectal cancer between April 2009 and December 2010 were extracted from the Radiotherapy Dataset linked to the National Cancer Data Repository. Individuals were grouped into those receiving no radiotherapy, short-course radiotherapy with immediate surgery (SCRT-I), short-course radiotherapy with delayed surgery (SCRT-D), long-course chemoradiotherapy (LCCRT), other radiotherapy (ORT) and postoperative radiotherapy (PORT). Patterns of use were then investigated. RESULTS: The study consisted of 9201 individuals; 4585 (49.3%) received some form of radiotherapy. SCRT-I was used in 12.1%, SCRT-D in 1.2%, LCCRT in 29.5%, ORT in 4.7% and PORT in 2.3%. Radiotherapy was used more commonly in men and in those receiving an abdominoperineal excision and less commonly in the elderly and those with comorbidity. Significant and substantial variations were also seen in its use across all the multidisciplinary teams managing this disease. CONCLUSION: Despite the same evidence base, wide variation exists in both the use of and type of radiotherapy delivered in the management of rectal cancer across the English NHS. Prospective population-based collection of local recurrence and patient-reported early and late toxicity information is required to further improve patient selection for preoperative radiotherapy. PMID- 26936610 TI - Association between anemia and bronchopulmonary dysplasia in preterm infants. AB - Anemia is commonly seen in preterm infants. It may reduce the capacity of hemoglobin to transport oxygen throughout the body and may result in tissue and organ dysfunction. This study aimed to investigate the effect of anemia on the development of bronchopulmonary dysplasia (BPD) in preterm infants. 243 infants who were admitted to BaYi Children's Hospital Affiliated to Clinical Medical College in Beijing Military General Hospital with gestational age (GA) less than 32 weeks from February, 2014 to February, 2015 were included in the study. Maternal and infant data were recorded. Multivarariate logistic regression analysis was performed to determine the association between anemia and BPD. Of 243 preterm infants, the incidence of anemia was higher in BPD patients than non BPD patients (p < 0.001). Mean Hct in BPD patients was lower than non-BPD patients at different time points in 1d, 7d, 14d, and 21d. Controlling for other confounding factors, early anemia was associated with an increased risk of BPD. Number of transfusions is also a significant risk factor for BPD (p = 0.001). Therefore, prevention and treatment of early anemia is necessary and reducing number of transfusions may reduce the incidence of BPD in preterm infants. PMID- 26936612 TI - Effect of Short-Duration, Localized Carbamide Peroxide Application to Remove Enamel Staining on Bond Strength of Resin Cement to Enamel. AB - Objective Peripheral enamel staining is often noticed after removal of long-term veneer or crown provisional restorations. Application of carbamide peroxide (CP) easily removes the stain, but the potential for immediate bonding with a resin based cement is questionable. This project tested the short-term, shear bond strength of a commercial, photo-curable, resin cement to bovine enamel after application of a 10% concentration of CP placed for different exposure times. MATERIALS AND METHODS: Bovine enamel was flattened and polished. Surfaces had either no CP application (control), or 10% CP applied for 10, 20, or 30 seconds. Teeth were acid-etched, rinsed, dried, and controlled sized stubs of a commercial resin cement were photocured onto the treated surfaces. The shear bond strength of each specimen was determined using a universal testing machine, and results were compared using an analysis of variance at a preset alpha of 0.5 (n = 10/group). RESULTS: No significant differences (p = 0.819) in shear bond strength were found among any CP cleaning treatments or the experimental (nontreated) control. CONCLUSIONS: Short-term application of 10% carbamide peroxide prior to acid etching, to remove enamel stains in teeth prepared to receive ceramic veneers or crowns, does not reduce immediate shear bond strength of resin-based cement to enamel. CLINICAL SIGNIFICANCE: Clinicians can confidently apply 10% CP for short-term, localized stain removal on enamel and not be concerned about affecting subsequent bond strength of a resin-based cement to enamel. (J Esthet Restor Dent, 2016). PMID- 26936611 TI - Estimating the Co-Development of Cognitive Decline and Physical Mobility Limitations in Older U.S. Adults. AB - This study examines the co-development of cognitive and physical function in older Americans using an age-heterogeneous sample drawn from the Health and Retirement Study (1998-2008). We used multiple-group parallel process latent growth models to estimate the association between trajectories of cognitive function as measured by immediate word recall scores, and limitations in physical function as measured as an index of functional mobility limitations. Nested model fit testing was used to assess model fit for the separate trajectories followed by estimation of an unconditional parallel process model. Controls for demographic characteristics, socioeconomic status, and chronic health conditions were added to the best-fitting parallel process model. Pattern mixture models were used to assess the sensitivity of the parameter estimates to the effect of selective attrition. Results indicated that favorable cognitive health and mobility at initial measurement were associated with faster decline in the alternate functional domain. The cross-process associations remained significant when we adjusted estimates for the influence of covariates and selective attrition. Demographic and socioeconomic characteristics were consistently associated with initial cognitive and physical health but had few relations with change in these measures. PMID- 26936613 TI - Radiation exposure from medical imaging in dialyzed patients undergoing renal pre transplant evaluation. AB - BACKGROUND AND AIM: Ionizing radiation exposure from medical procedures is rising sharply-the per-capita annual effective dose in the US is 3.0 millisieverts (mSv). Hemodialyzed and kidney transplanted patients receive still higher doses of ionizing radiation due to the presence of multiple comorbidities. The aim of this study was to assess the cumulative effective dose (CED) among dialyzed patients undergoing renal pre-transplant evaluation. PATIENTS AND METHODS: We evaluated 70 hemodialysis patients between June 2009 and December 2014, aged 46.4 +/- 12.0 years. The number and type of radiologic procedures were collected through the Radiology Information System. CED was expressed as total mSv/patient and annual CED (mSv/patient/year). RESULTS: A total of 744 radiologic procedures were performed, accounting for 3869 mSv of ionizing radiation: conventional radiology, computed tomography and nuclear medicine accounted for 78, 14 and 8 % of the procedures, but they represented, respectively, 8, 83 and 9 % of the total CED. The mean (median) annual CED was 35 (7) mSv/patient/year, while total CED was 72 (32) mSv/patient. Thirty-seven patients were active waitlisted and received 47 (10) mSv during the pre-transplant evaluation and 36 (5) mSv during the waiting phase to maintain active status. Concerning cancer risk, 4 (7 %) patients were classified at low risk (<3 mSv/year), 19 (35 %) at moderate risk (3 to <20 mSv/year), 8 (15 %) at high risk (20 to <50 mSv/year), and 23 (43 %) at very high risk (>=50 mSv/year). CONCLUSIONS: Our study demonstrated that during renal pre-transplant evaluation, dialyzed patients receive a high dose of ionizing radiation. Considering that transplanted individuals have a high incidence of cancer due to multifactorial etiology, it is mandatory to reduce the ionizing radiation imaging. PMID- 26936614 TI - Serum protein electrophoresis: an interesting diagnosis tool to distinguish viral from bacterial community-acquired pneumonia. AB - 29-69 % of pneumonias are microbiologically documented because it can be considered as an invasive procedure with variable test sensitivity. However, it drastically impacts therapeutic strategy in particular the use of antibiotics. Serum protein electrophoresis (SPEP) is a routine and non-invasive test commonly used to identify serum protein disorders. As virus and bacteria may induce different globulins production, we hypothesize that SPEP can be used as an etiological diagnosis test. Retrospective study conducted from 1/1/13 until 5/1/15 among patient hospitalized for an acute community-acquired pneumonia based on fever, crackles and radiological abnormalities. alpha/beta, alpha/gamma, beta/gamma globulins and albumin/globulin (A/G) ratio were calculated from SPEP. Data were analyzed in 3 groups: documented viral (DVP) or bacterial pneumonia (DBP) and supposedly bacterial pneumonia (SBP). We used ANOVA statistic test with multiple comparisons using CI95 and ROC curve to compare them. 109 patients included divided into DBP (n = 16), DVP (n = 26) and SBP (n = 67). Mean age was 62 +/- 18 year-old with a sex ratio M/F of 1.3. Underlying conditions (e.g. COPD, diabetes) were comparable between groups in multivariate analysis. Means of A/G ratio were 0.80 [0.76-0.84], 0.96 [0.91-1.01], 1.08 [0.99-1.16] respectively for DBP, SBP and DVP (p = 0.0002). A/G ratio cut-off value of 0.845 has a sensitivity of 87.5 % and a specificity of 73.1 %. A/G ratio seems to be an easy diagnostic tool to differentiate bacterial from viral pneumonia. A/G ratio cut-off value below 0.845 seems to be predictable of a bacterial origin and support the use of antibiotics. PMID- 26936615 TI - Personalized medicine in severe influenza. AB - Existing therapies against infectious diseases may only be effective in limited subpopulations during specific phases of diseases, incorporating theranostics, and there is a clear need to individualize different therapeutic approaches depending on the host. Influenza A virus infection evolves into a severe respiratory failure in some young adult patients, related to an exaggerated inflammatory response. Mortality rates remain high despite antiviral treatment and aggressive respiratory support. The influenza A virus (IAV) infection will induce a proinflammatory innate immune response through recognition of viral RNA by Toll-like receptor (TLR) 7 and retinoic acid-inducible gene 1 (RIG-I) molecules by nuclear factor kappa-light-chain-enhancer of activated B cells (NF kappaB route). Anti-inflammatory therapies focused on modulating this inflammatory response to "all patients" have not been satisfactory. Steroids should be avoided because they do not improve survival and promote superinfections. Since clinical judgment has often been proven inadequate, interest in the use of biomarkers to monitor host response and to assess severity and complications is growing. It is well known that, if used appropriately, these can be helpful tools to predict not only severity but also mortality. We need more biomarkers that predict host response: it is time to change lactate measurement to proteomics and transcriptomics. Theranostics describes an approach covering both diagnosis and coupled therapy. Death is usually a fatal complication of a dysregulated immune response more than the acute virulence of the infectious agent. Future research demonstrating the usefulness of adjunctive therapy in a subset of critically ill patients with IAV pneumonia is an unmet clinical need. PMID- 26936616 TI - The influence of the type and design of the anesthesia record on ASA physical status scores in surgical patients: paper records vs. electronic anesthesia records. AB - BACKGROUND: The American Society of Anesthesiologists Physical Status classification (ASA PS) of surgical patients is a standard element of the preoperative assessment. In early 2013, the Department of Anesthesia was notified that the distribution of ASA PS scores for sampled patients at the University of Iowa had recently begun to deviate from national comparison data. This change appeared to coincide with the transition from paper records to a new electronic Anesthesia Information Management System (AIMS). We hypothesized that the design of the AIMS was unintentionally influencing how providers assigned ASA PS values. METHODS: Primary analyses were based on 12-month blocks of data from paper records and AIMS. For the purpose of analysis, ASA PS was dichotomized to ASA PS 1 and 2 vs. ASA PS >2. To ensure that changes in ASA PS were not due to "real" changes in our patient mix, we examined other relevant covariates (e.g. age, weight, case distribution across surgical services, emergency vs. elective surgeries etc.). RESULTS: There was a 6.1 % (95 % CI: 5.1-7.1 %) absolute increase in the fraction of ASA PS 1&2 classifications after the transition from paper (54.9 %) to AIMS (61.0 %); p < 0.001. The AIMS was then modified to make ASA PS entry clearer (e.g. clearly highlighting ASA PS on the main anesthesia record). Following the modifications, the AS PS 1&2 fraction decreased by 7.7 % (95 % CI: 6.78-8.76 %) compared to the initial AIMS records (from 61.0 to 53.3 %); p < 0.001. There were no significant or meaningful differences in basic patient characteristics and case distribution during this time. CONCLUSION: The transition from paper to electronic AIMS resulted in an unintended but significant shift in recorded ASA PS scores. Subsequent design changes within the AIMS resulted in resetting of the ASA PS distributions to previous values. These observations highlight the importance of how user interface and cognitive demands introduced by a computational system can impact the recording of important clinical data in the medical record. PMID- 26936617 TI - [Simultaneous diagnosis of pseudomeningocele, tethered cord syndrome and cerebrospinal fluid fistula: Report of a case]. AB - The clinical case is presented on a patient with an extensive sacral dysraphism, a history of myelomeningocele surgical repair in her childhood, as well as tethered cord syndrome. The patient was also diagnosed with pseudomeningocele and a cerebrospinal fluid cutaneous fistula. A surgical approach was used, with encouraging results being obtained in the clinical outcome of the patient. A review of the literature was performed to support the surgical decision in this case. PMID- 26936618 TI - FASN, ErbB2-mediated glycolysis is required for breast cancer cell migration. AB - Both fatty acid synthase (FASN) and ErbB2 have been shown to promote breast cancer cell migration. However, the underlying molecular mechanism remains poorly understood and there is no reported evidence that directly links glycolysis to breast cancer cell migration. In this study, we investigated the role of FASN, ErbB2-mediated glycolysis in breast cancer cell migration. First, we compared lactate dehydrogenase A (LDHA) protein levels, glycolysis and cell migration between FASN, ErbB2-overexpressing SK-BR-3 cells and FASN, ErbB2-low-expressing MCF7 cells. Then, SK-BR-3 cells were treated with cerulenin (Cer), an inhibitor of FASN, and ErbB2, LDHA protein levels, glycolysis, and cell migration were detected. Next, we transiently transfected ErbB2 plasmid into MCF7 cells and detected FASN, LDHA protein levels, glycolysis and cell migration. Heregulin beta1 (HRG-beta1) is an activator of ErbB2 and 2-deoxyglucose (2-DG) and oxamate (OX) are inhibitors of glycolysis. MCF7 cells were treated with HRG-beta1 alone, HRG-beta1 plus 2-DG, OX or cerulenin and glycolysis, and cell migration were measured. We found that FASN, ErbB2-high-expressing SK-BR-3 cells displayed higher levels of glycolysis and migration than FASN, ErbB2-low-expressing MCF7 cells. Inhibition of FASN by cerulenin impaired glycolysis and migration in SK-BR 3 cells. Transient overexpression of ErbB2 in MCF7 cells promotes glycolysis and migration. Moreover, 2-deoxyglucose (2-DG), oxamate (OX), or cerulenin partially reverses heregulin-beta1 (HRG-beta1)-induced glycolysis and migration in MCF7 cells. In conclusion, this study demonstrates that FASN, ErbB2-mediated glycolysis is required for breast cancer cell migration. These novel findings indicate that targeting FASN, ErbB2-mediated glycolysis may be a new approach to reverse breast cancer cell migration. PMID- 26936619 TI - Required barrier efficiency of internal bags against the migration from recycled paperboard packaging into food: a benchmark. AB - The use of recycled paperboard and corrugated board for food packaging is in the interest of the sustainability of resources, but in most applications the food must be protected against contamination from these materials, such as by an internal bag with a functional barrier. Producers of packaging need a specification to find the most suitable and economical barrier for a given application, and the customer needs the confidence that a solution offered to him is adequate. An accurate determination of the barrier efficiency is not possible due to the large number of migrants, most of which have not been evaluated or not even identified. Hence the specification must be based on assumptions and verifiable by a simple test. The proposed benchmark presumes that the migration of all non-evaluated or even unknown substances in recycled paperboard will remain below 0.01 mg kg(-1) food, the conventional detection limit, if their transfer does not exceed 1% of the content in the paperboard. Some substances, such as mineral oil or fatty acids, will exceed the 0.01 mg kg(-1) limit, but they are known, evaluated and of no concern at the reduced migration. Since the critical substances must be assumed to be unknown, the criterion of the 1% migration is tested with three surrogate substances of similar volatility and covering a broad range of polarity. The cornerstones of the method are specified. PMID- 26936620 TI - Relationship of Right Ventricular Size and Function with Respiratory Status in Duchenne Muscular Dystrophy. AB - The relationship between pulmonary function and right ventricle (RV) in Duchenne muscular dystrophy (DMD) has not been evaluated. Using cardiac magnetic resonance (CMR), we describe the relationship of RV size and function with spirometry in a DMD cohort. Fifty-seven boys undergoing CMR and pulmonary function testing within 1 month at a single center (2013-2015) were enrolled. Comparisons of RV ejection fraction (RVEF) and end-diastolic volume index (RVEDVI) were made across categories of percent forced vital capacity (FVC%), and relationships were assessed. Mean age was 15.5 +/- 3.5 years. Spirometry and CMR were performed within 3.9 +/- 4.1 days. Median FVC% was 92.0 % (67.5-116.5 %). Twenty-three (40 %) patients had abnormal FVC% (<80 %) of which 13 (57 %) had mild (FVC% 60-79 %), 6 (26 %) had moderate (FVC% 40-59 %), and 4 (17 %) had severe (FVC <40 %) reductions. Mean RVEF was 58.3 +/- 3.7 %. Patients with abnormal FVC% were older and had lower RVEF and RVEDVI. Both RVEF and RVEDVI were significantly associated with FVC% (r = 0.31, p = 0.02 and r = 0.39, p = 0.003, respectively). In a large DMD cohort, RVEF and RVEDVI were related to FVC%. Worsening respiratory status may guide monitoring of cardiac function in these patients. PMID- 26936621 TI - Comprehensive Versus Targeted Genetic Testing in Children with Hypertrophic Cardiomyopathy. AB - Hypertrophic cardiomyopathy (HCM) is a genetic disease of the sarcomere that can be found in both children and adults and is associated with many causative mutations. In children who are not the index case of HCM in their families, current recommendations call only for targeted genetic testing for familial mutations. However, clinical experience suggests that de novo mutations are possible, as are mutations inherited from apparently an unaffected parent. A chart review was conducted of all patients who received HCM genetic testing at Johns Hopkins from 2004 to 2013. In total, 239 patient charts were analyzed for personal and familial genetic findings. Eighty-one patients with sarcomere gene mutations were identified, of which 66 had a clinical diagnosis of HCM. Importantly, eight patients had >1 pathogenic or likely pathogenic mutation, including six patients who were diagnosed with HCM as children (18 or younger). In this analysis, when a sarcomere mutation is identified in a family, the likelihood of a child with HCM having >1 mutation is 25 % (6/24), compared to 4.8 % (2/42) for adults. The large number of children with multiple mutations suggests that broad panel rather than targeted genetic testing should be considered in HCM presenting during childhood even if the child is not the index case. PMID- 26936622 TI - Modeling Co-evolution of Speech and Biology. AB - Two computer simulations are investigated that model interaction of cultural evolution of language and biological evolution of adaptations to language. Both are agent-based models in which a population of agents imitates each other using realistic vowels. The agents evolve under selective pressure for good imitation. In one model, the evolution of the vocal tract is modeled; in the other, a cognitive mechanism for perceiving speech accurately is modeled. In both cases, biological adaptations to using and learning speech evolve, even though the system of speech sounds itself changes at a more rapid time scale than biological evolution. However, the fact that the available acoustic space is used maximally (a self-organized result of cultural evolution) is constant, and therefore biological evolution does have a stable target. This work shows that when cultural and biological traits are continuous, their co-evolution may lead to cognitive adaptations that are strong enough to detect empirically. PMID- 26936624 TI - Radiosensitization of esophageal carcinoma cells by knockdown of RNF2 expression. AB - Radiotherapy has been widely used for the treatment of cancer patients, especially for esophageal cancer patients. Ring finger protein 2 (RNF2) plays an important role in promoting the growth of cancer cells after exposure to irradiation. The present study aims to characterize the proliferative effects of RNF2 on cancer cells, and its mechanisms on the growth of esophageal cancer cells. We demonstrate that expression of RNF2 was markedly upregulated in esophageal cancer cell lines and surgically resected cancer specimens. In addition, RNF2 expression level is positively correlated with the presence of tumor size, lymph node metastases and negatively correlated with patient survival rates, suggesting that it plays an important role in the progression of esophageal cancer. Furthermore, the expression of RNF2 at both mRNA and protein levels in esophageal cancer ECA109 and TE13 cells was detected by real-time PCR and western blot assay after shRNA targeting RNF2. Co-immunoprecipitation (Co-IP) assay and western blot analysis were employed to detect the interaction between RNF2 and r-H2AX, H2AK119ub, and the expression of proteins associated with cell cycle and apoptosis, respectively. We used flow cytometry assay to analyze cell cycle and apoptosis of transfected cells, and further examined cellular growth in vitro and in vivo. shRNA targeting RNF2 gene and protein downregulated RNF2 expression after transfection for 24 h. The proliferation of tumor cells in RNF2 shRNA group was suppressed after radiotherapy. In addition, the interaction of RNF2, H2AK119ub, r-H2AX was increased after exposure to IR, followed by increasing apoptosis rates and inducing the arrest at G0/G1 phase after irradiation and shRNA targeting RNF2. Expression of the short-hairpin RNA is also correlated with the upregulation of p16 and Bax, and the downregulation of cyclin D2, cyclin-dependent kinase (CDK)-4, H2AX and Bcl-2. RNF2 gene knockdown induces radiosensitivity of esophageal cancer cells in vitro and significantly inhibits the growth of tumor cells. The mechanisms include inducing the cell cycle arrest at G0/G1 phase and promoting apoptosis. PMID- 26936623 TI - On-site bundled rapid HIV/HCV testing in substance use disorder treatment programs: study protocol for a hybrid design randomized controlled trial. AB - BACKGROUND: More than 1.2 million people in the United States are living with human immunodeficiency virus (HIV), and 3.2 million are living with hepatitis C virus (HCV). An estimated 25 % of persons living with HIV also have HCV. It is therefore of great public health importance to ensure the prompt diagnosis of both HIV and HCV in populations that have the highest prevalence of both infections, including individuals with substance use disorders (SUD). METHODS/DESIGN: In this theory-driven, efficacy-effectiveness-implementation hybrid study, we will develop and test an on-site bundled rapid HIV/HCV testing intervention for SUD treatment programs. Its aim is to increase the receipt of HIV and HCV test results among SUD treatment patients. Using a rigorous process involving patients, providers, and program managers, we will incorporate rapid HCV testing into evidence-based HIV testing and linkage to care interventions. We will then test, in a randomized controlled trial, the extent to which this bundled rapid HIV/HCV testing approach increases receipt of HIV and HCV test results. Lastly, we will conduct formative research to understand the barriers to, and facilitators of, the adoption, implementation, and sustainability of the bundled rapid testing strategy in SUD treatment programs. DISCUSSION: Novel approaches that effectively integrate on-site rapid HIV and rapid HCV testing are needed to address both the HIV and HCV epidemics. If feasible and efficacious, bundled rapid HIV/HCV testing may offer a scalable, potentially cost-effective approach to testing high-risk populations, such as patients of SUD treatment programs. It may ultimately lead to improved linkage to care and progress through the HIV and HCV care and treatment cascades. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02355080 . (30 January 2015). PMID- 26936625 TI - Ecological allometries and niche use dynamics across Komodo dragon ontogeny. AB - Ontogenetic allometries in ecological habits and niche use are key responses by which individuals maximize lifetime fitness. Moreover, such allometries have significant implications for how individuals influence population and community dynamics. Here, we examined how body size variation in Komodo dragons (Varanus komodoensis) influenced ecological allometries in their: (1) prey size preference, (2) daily movement rates, (3) home range area, and (4) subsequent niche use across ontogeny. With increased body mass, Komodo dragons increased prey size with a dramatic switch from small (<=10 kg) to large prey (>=50 kg) in lizards heavier than 20 kg. Rates of foraging movement were described by a non linear concave down response with lizard increasing hourly movement rates up until ~20 kg body mass before decreasing daily movement suggesting reduced foraging effort in larger lizards. In contrast, home range area exhibited a sigmoid response with increased body mass. Intrapopulation ecological niche use and overlap were also strongly structured by body size. Thus, ontogenetic allometries suggest Komodo dragon's transition from a highly active foraging mode exploiting small prey through to a less active sit and wait feeding strategy focused on killing large ungulates. Further, our results suggest that as body size increases across ontogeny, the Komodo dragon exhibited marked ontogenetic niche shifts that enabled it to function as an entire vertebrate predator guild by exploiting prey across multiple trophic levels. PMID- 26936626 TI - Implementing Level of Care Criteria for Supported Housing in One Urban County. PMID- 26936627 TI - Needs Assessment for Behavioral Health Workforce: a State-Level Analysis. AB - This study describes trends in the supply and the need for behavioral health professionals in Nebraska. A state-level health workforce database was used to estimate the behavioral health workforce supply and need. Compared with national estimates, Nebraska has a lower proportion of all categories of behavioral health professionals. The majority of Nebraska counties have unusually high needs for mental health professionals, with rural areas experiencing a decline in the supply of psychiatrists over the last decade. Availability of robust state-level health workforce data can assist in crafting effective policy for successful systems change, particularly for behavioral health. PMID- 26936628 TI - Experimental Neospora Caninum Infection in Pregnant Dairy Heifers Raises Concentrations of Pregnancy-Associated Glycoproteins 1 and 2 in Foetal Fluids. AB - Plasma concentrations of PAG-1 are used for pregnancy diagnosis and as a marker of placental/foetal well-being, while those of PAG-2 may be an indicator of abortion risk in Neospora caninum-infected cows. Studies have shown that N. caninum infection modifies PAG-1 and PAG-2 patterns in maternal blood plasma. However, no prior work has examined the effects of N. caninum infection on concentrations of PAGs in foetal fluids. In this study, PAG-1, PAG-2 and pH levels were determined in the amniotic and allantoic fluids of foetuses collected at 152 days of gestation from control uninfected dams and from dams experimentally infected with N. caninum on Day 110 of gestation. Foetal fluids from infected foetuses had significantly higher PAG-2 concentrations (p = 0.026) and pH values (p = 0.02) than fluids from non-infected foetuses. In infected foetuses, significantly higher concentrations of PAG-1 (p < 0.001) and PAG-2 (p < 0.001) were detected in fluid samples showing antibodies against N. caninum than those without antibodies. Moreover, pH values were significantly higher (p = 0.011) in foetal fluid samples with antibodies than in samples from non-infected foetuses. In conclusion, this is the first report on the effect of N. caninum infection on PAG levels in foetal fluids. Our results indicate that following the experimental infection of dams with N. caninum on Day 110 of gestation, foetal fluids collected from the infected foetuses of these dams featured higher PAG-1 and PAG-2 levels and pH values than fluids from non-infected controls, provided that the samples tested showed the presence of antibodies. The clinical implications of these findings are that following infection with N. caninum, most cows will experience some level of placental damage and that this injury correlates with foetal fluid PAG levels and pH. PMID- 26936629 TI - Electrospun Polymeric Core-sheath Yarns as Drug Eluting Surgical Sutures. AB - Drug-coated sutures are widely used as delivery depots for antibiotics and anti inflammatory drugs at surgical wound sites. Although drug-laden coating provides good localized drug concentration, variable loading efficiency and release kinetics limits its use. Alternatively, drug incorporation within suture matrices is hampered by the harsh fabrication conditions required for suture-strength enhancement. To circumvent these limitations, we fabricated mechanically robust electrospun core-sheath yarns as sutures, with a central poly-l-lactic acid core, and a drug-eluting poly-lactic-co-glycolic acid sheath. The electrospun sheath was incorporated with aceclofenac or insulin to demonstrate versatility of the suture in loading both chemical and biological class of drugs. Aceclofenac and insulin incorporated sutures exhibited 15% and 4% loading, and release for 10 and 7 days, respectively. Aceclofenac sutures demonstrated reduced epidermal hyperplasia and cellularity in skin-inflammation animal model, while insulin loaded sutures showed enhanced cellular migration in wound healing assay. In conclusion, we demonstrate an innovative strategy of producing mechanically strong, prolonged drug-release sutures loaded with different classes of drugs. PMID- 26936630 TI - The MECP2 variant c.925C>T (p.Arg309Trp) causes intellectual disability in both males and females without classic features of Rett syndrome. AB - Missense MECP2 variants can have various phenotypic effects ranging from a normal phenotype to typical Rett syndrome (RTT). In females, the phenotype can also be influenced by the X-inactivation pattern. In this study, we present detailed clinical descriptions of six patients with a rare base-pair substitution affecting Arg309 at the C-terminal end of the transcriptional repression domain (TRD). All patients have intellectual disability and present with some RTT features, but they do not fulfill the clinical criteria for typical or atypical RTT. Most of the patients also have mild facial dysmorphism. Intriguingly, the mother of an affected male patient is an asymptomatic carrier of this variant. It is therefore likely that the p.(Arg309Trp) variation does not necessarily lead to male lethality, and it results in a wide range of clinical features in females, probably influenced by different X-inactivation patterns in target tissues. PMID- 26936631 TI - The Role of Moral Beliefs, Memories, and Preferences in Representations of Identity. AB - People perceive that if their memories and moral beliefs changed, they would change. We investigated why individuals respond this way. In Study 1, participants judged that identity would change more after changes to memories and widely shared moral beliefs (e.g., about murder) versus preferences and controversial moral beliefs (e.g., about abortion). The extent to which participants judged that changes would affect their relationships predicted identity change (Study 2) and mediated the relationship between type of moral belief and perceived identity change (Study 3). We discuss the role that social relationships play in judgments of identity and highlight implications for psychology and philosophy. PMID- 26936632 TI - General anesthesia for dental care management of a patient with epidermolysis bullosa: 24-month follow-up. AB - Epidermolysis bullosa comprises a group of uncommon skin-related diseases, characterized by the formation of blisters on mucocutaneous regions occurring spontaneously, following a trauma, exposure to heat, or as a result of minimal mechanical trauma. The dental treatment of the patient with epidermolysis bullosa raises many questions and discussions, due to the difficulty of carrying out the procedures. This report aimed to detail the clinical considerations of the treatment under general anesthesia of a patient with epidermolysis bullosa. The extraction of all deciduous teeth under general anesthesia was recommended based on the clinical and radiographic examinations. At 24-month follow-up, the patient had great improvement in oral hygiene without new caries lesions. The patient has been followed-up at every month for caries lesion prevention and permanent tooth development. The treatment under general anesthesia provided the ideal safe conditions and was beneficial for the patient. PMID- 26936633 TI - Assisting with food glorious food. PMID- 26936635 TI - The 128th Regional Meeting (Kinki Area). PMID- 26936636 TI - The 68th Regional Meeting (Seinan Area). PMID- 26936634 TI - Extracellular granzyme K mediates endothelial activation through the cleavage of protease-activated receptor-1. AB - Granzymes are a family of serine proteases that were once thought to function exclusively as mediators of cytotoxic lymphocyte-induced target cell death. However, non-apoptotic roles for granzymes, including granzyme K (GzK), have been proposed. As recent studies have observed elevated levels of GzK in the plasma of patients diagnosed with clinical sepsis, we hypothesized that extracellular GzK induces a proinflammatory response in endothelial cells. In the present study, extracellular GzK proteolytically activated protease-activated receptor-1 leading to increased interleukin 6 and monocyte chemotactic protein 1 production in endothelial cells. Enhanced expression of intercellular adhesion molecule 1 along with an increased capacity for adherence of THP-1 cells was also observed. Characterization of downstream pathways implicated the mitogen-activated protein kinase p38 pathway for intercellular adhesion molecule 1 expression, and both the p38 and the extracellular signal-regulated protein kinases 1 and 2 pathways in cytokine production. GzK also increased tumour necrosis factor alpha-induced inflammatory adhesion molecule expression. Furthermore, the physiological inhibitor of GzK, inter-alpha-inhibitor protein, significantly inhibited GzK activity in vitro. In summary, extracellular GzK promotes a proinflammatory response in endothelial cells. PMID- 26936637 TI - Does the physiology of chondrichthyan fishes constrain their distribution in the deep sea? AB - The deep sea is the largest ecosystem on Earth but organisms living there must contend with high pressure, low temperature, darkness and scarce food. Chondrichthyan fishes (sharks and their relatives) are important consumers in most marine ecosystems but are uncommon deeper than 3000 m and exceedingly rare, or quite possibly absent, from the vast abyss (depths >4000 m). By contrast, teleost (bony) fishes are commonly found to depths of ~ 8400 m. Why chondrichthyans are scarce at abyssal depths is a major biogeographical puzzle. Here, after outlining the depth-related physiological trends among chondrichthyans, we discuss several existing and new hypotheses that implicate unique physiological and biochemical characteristics of chondrichthyans as potential constraints on their depth distribution. We highlight three major, and not mutually exclusive, working hypotheses: (1) the urea-based osmoregulatory strategy of chondrichthyans might conflict with the interactive effects of low temperature and high pressure on protein and membrane function at great depth; (2) the reliance on lipid accumulation for buoyancy in chondrichthyans has a unique energetic cost, which might increasingly limit growth and reproductive output as food availability decreases with depth; (3) their osmoregulatory strategy may make chondrichthyans unusually nitrogen limited, a potential liability in the food-poor abyss. These hypotheses acting in concert could help to explain the scarcity of chondrichthyans at great depths: the mechanisms of the first hypothesis may place an absolute, pressure-related depth limit on physiological function, while the mechanisms of the second and third hypotheses may limit depth distribution by constraining performance in the oligotrophic abyss, in ways that preclude the establishment of viable populations or lead to competitive exclusion by teleosts. PMID- 26936638 TI - Increased muscular volume and cuticular specialisations enhance jump velocity in solitarious compared with gregarious desert locusts, Schistocerca gregaria. AB - The desert locust, Schistocerca gregaria, shows a strong phenotypic plasticity. It can develop, depending upon population density, into either a solitarious or gregarious phase that differs in many aspects of behaviour, physiology and morphology. Prominent amongst these differences is that solitarious locusts have proportionately longer hind femora than gregarious locusts. The hind femora contain the muscles and energy-storing cuticular structures that propel powerful jumps using a catapult-like mechanism. We show that solitarious locusts jump on average 23% faster and 27% further than gregarious locusts, and attribute this improved performance to three sources: first, a 17.5% increase in the relative volume of their hind femur, and hence muscle volume; second, a 24.3% decrease in the stiffness of the energy-storing semi-lunar processes of the distal femur; and third, a 4.5% decrease in the stiffness of the tendon of the extensor tibiae muscle. These differences mean that solitarious locusts can generate more power and store more energy in preparation for a jump than can gregarious locusts. This improved performance comes at a cost: solitarious locusts expend nearly twice the energy of gregarious locusts during a single jump and the muscular co-contraction that energises the cuticular springs takes twice as long. There is thus a trade off between achieving maximum jump velocity in the solitarious phase against the ability to engage jumping rapidly and repeatedly in the gregarious phase. PMID- 26936639 TI - Evidence for a plasma-accessible carbonic anhydrase in the lumen of salmon heart that may enhance oxygen delivery to the myocardium. AB - Oxygen supply to the heart of most teleosts, including salmonids, relies in part or in whole on oxygen-depleted venous blood. Given that plasma-accessible carbonic anhydrase (CA) in red muscle of rainbow trout has recently been shown to facilitate oxygen unloading from arterial blood under certain physiological conditions, we tested the hypothesis that plasma-accessible CA is present in the lumen of coho salmon (Oncorhynchus kisutch) hearts, and may therefore assist in the luminal oxygen supply to the spongy myocardium, which has no coronary circulation. We demonstrate a widespread distribution of CA throughout the heart chambers, including lumen-facing cells in the atrium, and confirm that the membrane-bound isoform ca4 is expressed in the atrium and ventricle of the heart. Further, we confirm that CA catalytic activity is available to blood in the atrial lumen using a modified electrometric DeltapH assay in intact atria in combination with either a membrane-impermeable CA inhibitor or specific cleavage of the Ca4 membrane anchor. Combined, these results support our hypothesis of the presence of an enhanced oxygen delivery system in the lumen of a salmonid heart, which could help support oxygen delivery when the oxygen content of venous blood becomes greatly reduced, such as after burst exercise and during environmental hypoxia. PMID- 26936640 TI - Surface tension dominates insect flight on fluid interfaces. AB - Flight on the 2D air-water interface, with body weight supported by surface tension, is a unique locomotion strategy well adapted for the environmental niche on the surface of water. Although previously described in aquatic insects like stoneflies, the biomechanics of interfacial flight has never been analysed. Here, we report interfacial flight as an adapted behaviour in waterlily beetles (Galerucella nymphaeae) which are also dexterous airborne fliers. We present the first quantitative biomechanical model of interfacial flight in insects, uncovering an intricate interplay of capillary, aerodynamic and neuromuscular forces. We show that waterlily beetles use their tarsal claws to attach themselves to the interface, via a fluid contact line pinned at the claw. We investigate the kinematics of interfacial flight trajectories using high-speed imaging and construct a mathematical model describing the flight dynamics. Our results show that non-linear surface tension forces make interfacial flight energetically expensive compared with airborne flight at the relatively high speeds characteristic of waterlily beetles, and cause chaotic dynamics to arise naturally in these regimes. We identify the crucial roles of capillary-gravity wave drag and oscillatory surface tension forces which dominate interfacial flight, showing that the air-water interface presents a radically modified force landscape for flapping wing flight compared with air. PMID- 26936641 TI - To boldly gulp: standard metabolic rate and boldness have context-dependent influences on risk-taking to breathe air in a catfish. PMID- 26936642 TI - [Bisalbuminaemia. Presentation of a case]. PMID- 26936643 TI - [Breast cancer in a male patient]. PMID- 26936644 TI - Biological mechanisms related to differences in residual feed intake in dairy cows. AB - Residual feed intake (RFI), defined as the difference between an animal's actual feed intake and expected feed intake over a specific period, is an inheritable character of feed conversion efficiency in dairy cows. Research has shown that a lower RFI could improve the profitability of milk production. This study explored variation in RFI by comparing the differences in body size, milk performance, feeding behavior, and serum metabolites in 29 Holstein cows in mid lactation. The cows were selected from a total of 84 animals based on their RFI following feedlot tests. Selected cows were ranked into high RFI (RFI >1 SD above the mean, n=14) and low RFI (RFI<1 SD below the mean, n=15). The low RFI cows (more efficient) consumed 1.59 kg/day less dry matter than the high RFI group (P<0.01), while they produced nearly equal 4% fat-corrected milk. The milk : feed ratio was higher for the low RFI group than for the high RFI group (P<0.05). The levels of milk protein (P<0.01), total solids (P<0.05), and nonfat solids (P<0.05) were also higher for the low RFI group, whereas milk urea nitrogen was lower (P<0.01). The daily feeding duration was shorter for the low RFI group than for the high RFI group (P<0.01). No significant differences were found in levels of glucose, beta-hydroxybutyrate, prolactin, insulin, IGF-1, growth hormone or ghrelin, but the level of neuropeptide Y was higher (P<0.01) and levels of leptin and non esterified fatty acid (P<0.05) were lower for the low RFI group than for the high RFI group. There were substantial differences between cows with different RFI, which might affect the efficiency of milk protein metabolism and fat mobilization. PMID- 26936645 TI - Engineering islet for improved performance by optimized reaggregation in alginate gel beads. AB - After islet isolation, diffusion has become the main mechanism to transport oxygen and nutrients into the core of islets. However, diffusion has limitations, by which nutrients cannot effectively reach the core of large islets and can eventually cause core cell death and islet loss. This problem can be resolved by dispersing islets into single islet cells, but single islet cells do not exhibit insulin release function in in vitro culture. In this study, we intended to establish a new islet engineering approach by forming islet cell clusters to improve islet survival and function. Therefore, alginate gels were used to encapsulate islet cells to form artificial islets after dispersion of islets into single cells. The shape of the islet cell clusters was similar to native islets, and the size of the islet cell clusters was limited to a maximum diameter of 100 MUm. By limiting the diameter of this engineered islet cell cluster, cell viability was nearly 100%, a significant improvement over natural islets. Importantly, islet cell clusters express the genes of islets, including Isl-1, Gcg, and insulin-1, and insulin secretion ability was maintained in vitro. PMID- 26936647 TI - MicroRNA-133a inhibits the malignant behavior of glioma via downregulation of matrix metallopeptidase 9. AB - MicroRNA (miR)-133a expression has been reported to be downregulated in numerous human malignancies. However, the expression levels and function of miR-133a have not yet been investigated in human glioma. In the present study, the expression of miR-133a was analyzed by reverse transcription-quantitative polymerase chain reaction. Following transfection of miR-133a, cell proliferation, cell migration, cell invasion and luciferase assays, and western blot analysis were conducted in glioma cell lines. The present study demonstrated that miR-133a was downregulated in human glioma tissues compared with in normal adjacent tissues. In addition, the results indicated that miR-133a was likely to directly target matrix metallopeptidase 9 in glioma. These results suggest that miR-133a may be considered as a target for the treatment of human glioma. PMID- 26936646 TI - Test or Rest? Computerized Cognitive Testing in the Emergency Department after Pediatric Mild Traumatic Brain Injury Does Not Delay Symptom Recovery. AB - Rest is commonly prescribed following a mild traumatic brain injury (mTBI). There is concern that cognitive exertion by an acutely or sub-acutely injured brain may negatively alter outcome. The objective of this study was to determine if computerized cognitive testing in the emergency department alters symptom outcome from mTBI. Participants included 77 youth with mTBI who underwent computerized cognitive testing (mean age, 13.6; 95% confidence interval [CI] = 13.0-14.2) and were matched to 77 youth with mTBI who did not participate in cognitive testing (mean age, 13.5; 95% CI = 12.9-14.0). Participants who underwent cognitive testing did not differ from those who did not undergo acute cognitive testing on mean symptom ratings or the proportion who were not recovered at 7-10 days, 1 month, 2 months, or 3 months. There also was no difference in symptom outcome for those who underwent a shortened (four subtests, mean time = 16 min) or full length (seven subtests, mean time = 28 min) version of the computerized test. Brief cognitive exertion using a computerized cognitive assessment after mTBI in youth does not result in worse symptoms at these follow-up periods, does not prolong symptom recovery, should not be considered contraindicated to recovery, and could be considered as another tool to aid in the management of these injuries. Further research with different samples is warranted. PMID- 26936648 TI - Study on potato consumption will increase confusion regarding food and the risk of gestational diabetes. PMID- 26936650 TI - One-year trajectories of motivation and physical activity in persons with disabilities. AB - OBJECTIVE: To assess trajectories of autonomous and controlled motivation and physical activity over one year in subjects with chronic disabilities receiving rehabilitation. In addition, to assess whether improvements in motivation and clinical variables during rehabilitation predict physical activity. DESIGN: Prospective interventional design. METHODS: A total of 214 subjects with physical disabilities admitted to a 4-week rehabilitation stay were included in the study. Multi-level models were performed examining the trajectories of autonomous motivation, controlled motivation and physical activity over one year. Changes in motivation, pain, fatigue, physical and mental functioning and self-efficacy (clinical factors) from admission to discharge from rehabilitation were analysed using paired samples t-tests. Multiple linear regressions were applied to evaluate the influence of changes in clinical factors during rehabilitation on the level of physical activity after one year. RESULTS: A significant effect of time on autonomous motivation was observed over one year. Higher exercise efficacy, physical functioning and education predicted a higher level of physical activity. However, improvement in autonomous motivation, self-efficacy, pain, fatigue, mental and physical functioning during rehabilitation did not predict the level of physical activity after 4 weeks or one year. CONCLUSION: Rehabilitation based on adapted physical activity is associated with improvement in autonomous motivation. However, improvement in motivation was not related to short- or long-term effects on physical activity. PMID- 26936649 TI - dFoxO promotes Wingless signaling in Drosophila. AB - The Wnt/beta-catenin signaling is an evolutionarily conserved pathway that regulates a wide range of physiological functions, including embryogenesis, organ maintenance, cell proliferation and cell fate decision. Dysregulation of Wnt/beta catenin signaling has been implicated in various cancers, but its role in cell death has not yet been fully elucidated. Here we show that activation of Wg signaling induces cell death in Drosophila eyes and wings, which depends on dFoxO, a transcription factor known to be involved in cell death. In addition, dFoxO is required for ectopic and endogenous Wg signaling to regulate wing patterning. Moreover, dFoxO is necessary for activated Wg signaling-induced target genes expression. Furthermore, Arm is reciprocally required for dFoxO induced cell death. Finally, dFoxO physically interacts with Arm both in vitro and in vivo. Thus, we have characterized a previously unknown role of dFoxO in promoting Wg signaling, and that a dFoxO-Arm complex is likely involved in their mutual functions, e.g. cell death. PMID- 26936651 TI - Prevalence and risk factors for atopic disease in a population of preschool children in Rome: Challenges to early intervention. AB - BACKGROUND: Allergic diseases are complex identities determined by an interplay of genetic and environmental factors, resulting in the clinical manifestation of the disease. So far in Italy, updated data about the prevalence and risk factors of respiratory and allergic diseases in preschool children are not available. METHODS: Children aged 3-5 years, attending four different nursery schools in an urban district of the city of Rome. A standardized questionnaire developed under the SIDRIA-2 protocol was administered to the parents of the children for the assessment of the potential risk factors and the outcomes. RESULTS: A total of 494 children were enrolled in the study; 289 of them (60.3%) performed a skin prick test (SPT). In the 12 months preceding the interviews, 15% of children experienced at least one episode of wheezing, 5.5% of allergic rhinitis, 11% of children had a doctor diagnosis of asthma, 12% of children who underwent the SPT were positive to at least one of the tested allergens, being diagnosed as atopic. The univariate analysis for the health outcomes of the study shows that asthma was positively associated with daycare attendance, mother's history of atopy, siblings' history of atopy, recurrent siblings' bronchitis, and dermatitis. Atopy was positively associated with mother's history of atopy and dermatitis, whereas there is a borderline protective association with recurrent siblings' bronchitis. CONCLUSIONS: This study represents a first comprehensive epidemiological evaluation of prevalence of respiratory and allergic diseases in children aged 3 5 years in the city of Rome and an updating of the evolution of allergic diseases. PMID- 26936652 TI - MicroRNA-29a induces insulin resistance by targeting PPARdelta in skeletal muscle cells. AB - Intrauterine growth retardation (IUGR) induces metabolic syndrome, which is often characterized by insulin resistance (IR), in adults. Previous research has shown that microRNAs (miRNAs or miRs) play a role in the target genes involved in this process, but the mechanisms remain unclear. In the present study, we examined miRNA profiles using samples of skeletal muscles from both IUGR and control rat offspring whose mothers were fed either a protein-restricted diet or a diet which involved normal amounts of protein during pregnancy, respectively. miR-29a was found to be upregulated in the skeletal muscles of IUGR offspring. The luciferase reporter assay confirmed the direct interaction between miR-29a and peroxisome proliferator-activated receptor delta (PPARdelta). Overexpression of miR-29a in the skeletal muscle cell line C2C12 suppressed the expression of its target gene PPARdelta, which, in turn, influenced the expression of its coactivator, peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha). Thus, PPARdelta/PGC-1alpha-dependent signals together reduced insulin-dependent glucose uptake and adenosine triphosphate (ATP) production. Overexpression of miR 29a also caused a decrease in levels of glucose transporter 4 (GLUT4), the most important glucose transporter in skeletal muscle, which partially induced a decrease insulin-dependent glucose uptake. These findings provide evidence for a novel micro-RNA-mediated mechanism of PPARdelta regulation, and we also noted the IR-promoting actions of miR-29a in skeletal muscles of IUGR. PMID- 26936653 TI - How to do it: lessons identified from investigating and trying to control an outbreak of gonorrhoea in young heterosexual adults. PMID- 26936654 TI - Metabolic memory and all-cause death in community-based patients with type 2 diabetes: the Fremantle Diabetes Study. AB - AIMS: To validate the findings, in a usual care setting, of glycaemic intervention trials, which have shown that tight control in patients with recently diagnosed type 2 diabetes protects against death during post-study monitoring, but that it may be deleterious in long-duration diabetes with vascular complications. METHODS: A subset of 531 patients with type 2 diabetes from the community-based observational Fremantle Diabetes Study Phase 1, who attended >=5 annual reviews (mean follow-up 15.9 years), were categorized by baseline diabetes duration [<1 year (Group 1); 1 to <5 years (Group 2); and >=5 years (Group 3)]. Glycated haemoglobin (HbA1c) trajectories over the first 5 years were determined [low, medium and high; equivalent to mean HbA1c <=6.6% (<49 mmol/mol), 6.7-8.0% (50-64 mmol/mol) and >=8.0% (>64 mmol/mol), respectively]. Kaplan-Meier analysis was used to assess survival by duration and HbA1c trajectory. Cox proportional hazards modelling identified predictors of all-cause death. RESULTS: There was greater mortality in patients with a medium versus those with a low trajectory in Group 1: hazard ratio (HR) 1.99 [95% confidence interval (CI) 1.003-3.94; p = 0.049], and in patients with a high versus a low trajectory in Group 2: HR 2.02 (95% CI 1.11-3.71; p = 0.022). In Group 3, both medium [HR 0.57 (95% CI 0.35-0.92; p = 0.022)] and high [HR 0.56 (95% CI 0.32 0.96); p = 0.035] trajectories were independently and inversely associated with death. CONCLUSIONS: In community-based patients with newly or recently diagnosed type 2 diabetes, poor glycaemic control was an adverse prognostic indicator. Tight control was independently associated with death in patients with diabetes duration >=5 years. These data parallel intervention trial findings and support individualization of HbA1c targets. PMID- 26936655 TI - Stimulation of translation by human Unr requires cold shock domains 2 and 4, and correlates with poly(A) binding protein interaction. AB - The RNA binding protein Unr, which contains five cold shock domains, has several specific roles in post-transcriptional control of gene expression. It can act as an activator or inhibitor of translation initiation, promote mRNA turnover, or stabilise mRNA. Its role depends on the mRNA and other proteins to which it binds, which includes cytoplasmic poly(A) binding protein 1 (PABP1). Since PABP1 binds to all polyadenylated mRNAs, and is involved in translation initiation by interaction with eukaryotic translation initiation factor 4G (eIF4G), we investigated whether Unr has a general role in translational control. We found that Unr strongly stimulates translation in vitro, and mutation of cold shock domains 2 or 4 inhibited its translation activity. The ability of Unr and its mutants to stimulate translation correlated with its ability to bind RNA, and to interact with PABP1. We found that Unr stimulated the binding of PABP1 to mRNA, and that Unr was required for the stable interaction of PABP1 and eIF4G in cells. siRNA-mediated knockdown of Unr reduced the overall level of cellular translation in cells, as well as that of cap-dependent and IRES-dependent reporters. These data describe a novel role for Unr in regulating cellular gene expression. PMID- 26936657 TI - Effect of restricted suckling on the onset of follicular dynamics and body condition score in Brahman cattle raised under tropical conditions. AB - With the aim of evaluating the effect of restricted suckling on the onset of follicular dynamics and body condition, multiparous Bos indicus cows were distributed in two groups. One group (RS=36) was subjected to a scheme of restricted suckling starting at 21 days postpartum. Calves were allowed to suckle once per day for a period of two h whilst the control group (C=18) remained with their dams at all times. At calving, body condition score, back fat thickness and body weight had similar values (p>0.05) for both groups. By day 85 postpartum both groups had recorded losses in body weight. The cows in the continuous group formed a greater (p<0.05) number of follicles of class size <6mm in both periods before and after synchronization. The proportion of cows showing estrus and ovulation before 45 days, was not different (p>0.05). The number of cows that exhibited estrus after 45 days, was greater (p<0.05) in RS than C group, 72.2% and 55.5%, respectively. Same situation (p<0.05) occurred in cows that ovulated, 88.8 and 66.7%, for groups RS and C, respectively. The subset in the intensive observations showed that the size of the bigger follicle was larger (p<0.05) for RS cows than C cows from 36 h after CIDR withdrawal. At 57 h, the size of the biggest follicle recorded was not different between groups (p>0.05). A regime of restricted suckling favors the earlier growth of follicles and the prompt restoration of ovarian activity. PMID- 26936656 TI - Changes in some pregnancy biomarkers of Yankasa ewes experimentally infected with Trypanosoma evansi. AB - The study was designed to determine the effect of Trypanosoma evansi infection on some pregnancy biomarkers of Yankasa ewes (YE). Twenty pregnant YE were assigned into 3 groups (A, B and C) comprising 7 ewes each in groups A and B, while group C comprise 6 YE. Groups A and B were each inoculated with blood containing approximately 1.0 * 10(6) of T. evansi through the jugular vein on days 59 and 110 of pregnancy, representing second and third trimesters, respectively, while group C served as the uninfected control. Progesterone (P4) and pregnancy specific protein-B (PSPB) of YE in group A were significantly (p < 0.05) high at weeks 4 and 12 post infection (pi) respectively, while there was no significant (p > 0.05) difference in P4 and PSPB of YE in groups B. Estrone sulfate (E1S) significantly (p < 0.05) decrease for YE in group A at weeks 2 and 11 pi. However, it was not significantly (p > 0.05) different in group B. Cortisol concentration of YE in group A was significantly (p < 0.05) decreased at week 12 pi. Conversely, the cortisol concentration of YE in group B significantly (p < 0.05) increased at week 3 pi. There was no significant (p > 0.05) association among the pregnancy biomarkers of YE in groups A and B throughout the study, except between progesterone and cortisol in group B, which were significantly associated (r = 0.77, p < 0.05). It was therefore concluded that T. evansi infection affects pregnancy biomarkers more at mid pregnancy than at late pregnancy. PMID- 26936658 TI - Mode of action of cryoprotectants for sperm preservation. AB - Sperm cryopreservation facilitates storage and transport for use in artificial reproduction technologies. Cryopreservation processing, however, exposes cells to stress resulting in cellular damage compromising sperm function. Cryoprotective agents are needed to minimize cryopreservation injury, but at higher concentration they are toxic to cells. In this review, we describe cryoinjury mechanisms, and modes of action of different types of cryoprotective agents. Furthermore, measures are discussed how to minimize toxic effects caused by adding and removing cryoprotective agents. Cryoprotective agents can be divided into permeating and non-permeating agents. Permeating agents such as glycerol can move across cellular membranes and modulate the rate and extent of cellular dehydration during freezing-induced membrane phase transitions. Permeating protectants provide intracellular protection because they are preferentially excluded from the surface of biomolecules thereby stabilizing the native state. Non-permeating agents can be divided into osmotically active smaller molecules and osmotically inactive macromolecules. Both, permeating and non-permeating protectants form a protective glassy state during freezing preserving biomolecular and cellular structures. Freezing extenders for sperm contain salts, buffer compounds, sugars, proteins and lipids, and typically contain glycerol as the main permeating cryoprotective agent providing intracellular protection. Non permeating protectants including sugars and proteins are used as bulking agents and to increase the glass transition temperature of the freezing extender. Ultra heat-treated milk and egg yolk are frequently added as membrane modifying agents to enhance the inherent sperm cryostability. The protocol how to use and add cryoprotectants is a compromise between their beneficial and potentially detrimental effects. PMID- 26936659 TI - Reduced ovulation rate, failure to be mated and fertilization failure/embryo loss are the underlying causes of poor reproductive performance in juvenile ewes. AB - A ewe that is mated as a juvenile (producing a lamb at 1 year of age) will produce an average of only 0.6 lambs to weaning, compared to an average of 1.2 lambs in adult ewes. Understanding the underlying causes of this low reproductive efficiency and designing methods to improve or mitigate these effects could potentially increase adoption of mating juvenile ewes. In Experiment 1, 2 Cohorts of ewes, born a year apart, were mated in order to lamb at 1 and 2 years of age and the performance of the ewes at each age was compared. Onset of puberty, mating by the fertile ram, ovulation rate, early pregnancy (day 30-35) litter size, number of lambs born and number of lambs weaned were measured. In juvenile ewes, by day 35 of pregnancy, 43% of ova had failed to become a viable embryo and this early loss was the largest contributor to the poor reproductive performance observed. Compared with young adult ewes, ovulation rate was lower (p<0.001), fewer ova were exposed to sperm (p<0.001) and fertilization failure/embryo loss was increased (p<0.001) in juveniles. In Experiment 2, the early pregnancy litter size of juveniles was shown to be greater (p<0.001) in those ewes with a greater ovulation rate (p<0.001). Attaining puberty prior to introduction of the fertile ram was associated with an increased pregnancy rate (p<0.001). In juvenile ewes, failure to mate with the ram, lower ovulation rate and increased fertilisation failure/embryo loss underlie their poor reproductive performance. PMID- 26936661 TI - Comparison of in vitro estrogenic activity and estrogen concentrations in source and treated waters from 25 U.S. drinking water treatment plants. AB - In vitro bioassays have been successfully used to screen for estrogenic activity in wastewater and surface water, however, few have been applied to treated drinking water. Here, extracts of source and treated water samples were assayed for estrogenic activity using T47D-KBluc cells and analyzed by liquid chromatography-Fourier transform mass spectrometry (LC-FTMS) for natural and synthetic estrogens (including estrone, 17beta-estradiol, estriol, and ethinyl estradiol). None of the estrogens were detected above the LC-FTMS quantification limits in treated samples and only 5 source waters had quantifiable concentrations of estrone, whereas 3 treated samples and 16 source samples displayed in vitro estrogenicity. Estrone accounted for the majority of estrogenic activity in respective samples, however the remaining samples that displayed estrogenic activity had no quantitative detections of known estrogenic compounds by chemical analyses. Source water estrogenicity (max, 0.47ng 17beta estradiol equivalents (E2Eq) L-1) was below levels that have been linked to adverse effects in fish and other aquatic organisms. Treated water estrogenicity (max, 0.078ngE2EqL-1) was considerably below levels that are expected to be biologically relevant to human consumers. Overall, the advantage of using in vitro techniques in addition to analytical chemical determinations was displayed by the sensitivity of the T47D-KBluc bioassay, coupled with the ability to measure cumulative effects of mixtures, specifically when unknown chemicals may be present. PMID- 26936660 TI - Antibacterial activity and mechanism of action of auranofin against multi-drug resistant bacterial pathogens. AB - Traditional methods employed to discover new antibiotics are both a time consuming and financially-taxing venture. This has led researchers to mine existing libraries of clinical molecules in order to repurpose old drugs for new applications (as antimicrobials). Such an effort led to the discovery of auranofin, a drug initially approved as an anti-rheumatic agent, which also possesses potent antibacterial activity in a clinically achievable range. The present study demonstrates auranofin's antibacterial activity is a complex process that involves inhibition of multiple biosynthetic pathways including cell wall, DNA, and bacterial protein synthesis. We also confirmed that the lack of activity of auranofin observed against Gram-negative bacteria is due to the permeability barrier conferred by the outer membrane. Auranofin's ability to suppress bacterial protein synthesis leads to significant reduction in the production of key methicillin-resistant Staphylococcus aureus (MRSA) toxins. Additionally, auranofin is capable of eradicating intracellular MRSA present inside infected macrophage cells. Furthermore, auranofin is efficacious in a mouse model of MRSA systemic infection and significantly reduces the bacterial load in murine organs including the spleen and liver. Collectively, this study provides valuable evidence that auranofin has significant promise to be repurposed as a novel antibacterial for treatment of invasive bacterial infections. PMID- 26936662 TI - Benthic algal assessment of ecological status in European lakes and rivers: Challenges and opportunities. AB - This opinion paper introduces a special series of articles dedicated to freshwater benthic algae and their use in assessment and monitoring. This special series was inspired by talks presented at the 9th International Congress on the Use of Algae for Monitoring Rivers and Comparable Habitats (Trento, Italy, 2015), the latest of a series of meetings started in 1991. In this paper, we will first provide a brief overview of phytobenthos methods in Europe. Then, we will turn towards the 'dark side' of phytobenthos and describe four particular problems for phytobenthos assessment in the European Union: (1) over-reliance on a single group of algae (mostly diatoms) to the exclusion of other groups; (2) relatively low adoption of benthic algae for ecological assessments in lakes; (3) absence of measures of phytobenthos abundance; (4) approaches used to define boundaries between ecological classes. Following this, we evaluate the strengths and limitations of current phytobenthos assessment methods against 12 criteria for method evaluation addressing four areas: ecological rationale, performance, feasibility of implementation, and use in communication and management. Using these criteria, we identify and discuss three general challenges for those developing new methods for phytobenthos-based assessment: a weak ecological rationale and insufficient consideration of the role of phytobenthos as a diagnostic tool and for communicating ecosystem health beyond a narrow group of specialists. The papers in the special series allow a comparison with the situation and approaches in the USA, present new methods for the assessment of ecological status and acidification, provide tools for an improved management of headwaters and petrifying springs, discuss the utility of phytobenthos for lake assessments, and test the utility of functional measures (such as biofilm phosphorus uptake capacity, PUC). PMID- 26936663 TI - Surface-air mercury fluxes across Western North America: A synthesis of spatial trends and controlling variables. AB - Mercury (Hg) emission and deposition can occur to and from soils, and are an important component of the global atmospheric Hg budget. This paper focuses on synthesizing existing surface-air Hg flux data collected throughout the Western North American region and is part of a series of geographically focused Hg synthesis projects. A database of existing Hg flux data collected using the dynamic flux chamber (DFC) approach from almost a thousand locations was created for the Western North America region. Statistical analysis was performed on the data to identify the important variables controlling Hg fluxes and to allow spatiotemporal scaling. The results indicated that most of the variability in soil-air Hg fluxes could be explained by variations in soil-Hg concentrations, solar radiation, and soil moisture. This analysis also identified that variations in DFC methodological approaches were detectable among the field studies, with the chamber material and sampling flushing flow rate influencing the magnitude of calculated emissions. The spatiotemporal scaling of soil-air Hg fluxes identified that the largest emissions occurred from irrigated agricultural landscapes in California. Vegetation was shown to have a large impact on surface-air Hg fluxes due to both a reduction in solar radiation reaching the soil as well as from direct uptake of Hg in foliage. Despite high soil Hg emissions from some forested and other heavily vegetated regions, the net ecosystem flux (soil flux+vegetation uptake) was low. Conversely, sparsely vegetated regions showed larger net ecosystem emissions, which were similar in magnitude to atmospheric Hg deposition (except for the Mediterranean California region where soil emissions were higher). The net ecosystem flux results highlight the important role of landscape characteristics in effecting the balance between Hg sequestration and (re )emission to the atmosphere. PMID- 26936664 TI - Causative Organisms and Associated Antimicrobial Resistance in Healthcare Associated, Central Line-Associated Bloodstream Infections From Oncology Settings, 2009-2012. AB - BACKGROUND: Recent antimicrobial resistance data are lacking from inpatient oncology settings to guide infection prophylaxis and treatment recommendations. We describe central line-associated bloodstream infection (CLABSI) pathogens and antimicrobial resistance patterns reported from oncology locations to the Centers for Disease Control and Prevention's National Healthcare Safety Network (NHSN). METHODS: CLABSI data reported to NHSN from 2009 to 2012 from adult inpatient oncology locations were compared to data from nononcology adult locations within the same hospitals. Pathogen profile, antimicrobial resistance rates, and CLABSI incidence rates per 1000 central line-days were calculated. CLABSI incidence rates were compared using Poisson regression. RESULTS: During 2009-2012, 4654 CLABSIs were reported to NHSN from 299 adult oncology units. The most common organisms causing CLABSI in oncology locations were coagulase-negative staphylococci (16.9%), Escherichia coli (11.8%), and Enterococcus faecium (11.4%). Fluoroquinolone resistance was more common among E. coli CLABSI in oncology than nononcology locations (56.5% vs 41.5% of isolates tested; P < .0001) and increased significantly from 2009-2010 to 2011-2012 (49.5% vs 60.4%; P = .01). Furthermore, rates of CLABSI were significantly higher in oncology compared to nononcology locations for fluoroquinolone-resistant E. coli (rate ratio, 7.37; 95% confidence interval [CI], 6.20-8.76) and vancomycin-resistant E. faecium (rate ratio, 2.27, 95% CI, 2.03-2.53). However, resistance rates for some organisms, such as Klebsiella species and Pseudomonas aeruginosa, were lower in oncology than in nononcology locations. CONCLUSIONS: Antimicrobial-resistant E. coli and E. faecium have become significant pathogens in oncology. Practices for antimicrobial prophylaxis and empiric antimicrobial therapy should be regularly assessed in conjunction with contemporary antimicrobial resistance data. PMID- 26936665 TI - Real-World Sustained Virologic Response Rates of Sofosbuvir-Containing Regimens in Patients Coinfected With Hepatitis C and HIV. AB - BACKGROUND: Patients with hepatitis C virus (HCV) with or without human immunodeficiency virus (HIV) achieve high sustained virological response (SVR) rates on sofosbuvir (SOF)-containing regimens in clinical trials. Real world data on patients coinfected with HCV and HIV treated with SOF-based regimens are lacking. METHODS: This observational cohort study included HIV/HCV-coinfected adults with genotype 1 HCV who initiated treatment with a SOF-containing regimen between December 2013 and December 2014 (n = 89) at the Mount Sinai Hospital or the Brooklyn Hospital Center. The primary outcome was SVR at 12 weeks after the end of treatment. The secondary outcomes were risk factors for treatment failure, serious adverse events, and side effects. A post hoc per protocol analysis of SVR was performed on patients who completed treatment and follow-up. RESULTS: In an intention-to-treat analysis, SVR rates were 76% (31/41) for simeprevir (SMV)/SOF, 94% (16/17) for SMV/SOF/ribavirin (RBV), and 52% (16/31) for SOF/RBV. The SVR rates of SMV/SOF/RBV and SMV/SOF did not differ significantly in this small study (P = .15). However the SVR rate of SMV/SOF/RBV was higher than that of SOF/RBV (P < .01). In a per protocol analysis, SMV/SOF/RBV had a higher SVR rate than SOF/RBV: 100% (16/16) vs 57% (16/28) (P < .01). The most commonly reported adverse effects were rash, pruritus, fatigue, and insomnia. One patient who had decompensated cirrhosis prior to treatment initiation died after receiving SMV/SOF. CONCLUSIONS: SMV/SOF +/- RBV is an effective option with minimal adverse effects for most HIV-positive patients with genotype 1 HCV. SMV should be used with caution in patients with decompensated cirrhosis. PMID- 26936666 TI - Laboratory Monitoring of Antiretroviral Therapy for HIV Infection: Cost Effectiveness and Budget Impact of Current and Novel Strategies. AB - BACKGROUND: Optimal laboratory monitoring of antiretroviral therapy (ART) for human immunodeficiency virus (HIV) remains controversial. We evaluated current and novel monitoring strategies in Cote d'Ivoire, West Africa. METHODS: We used the Cost-Effectiveness of Preventing AIDS Complications -International model to compare clinical outcomes, cost-effectiveness, and budget impact of 11 ART monitoring strategies varying by type (CD4 and/or viral load [VL]) and frequency. We included "adaptive" strategies (biannual then annual monitoring for patients on ART/suppressed). Mean CD4 count at ART initiation was 154/MUL. Laboratory test costs were CD4=$11 and VL=$33. The standard of care (SOC; biannual CD4) was the comparator. We assessed cost-effectiveness relative to Cote d'Ivoire's 2013 per capita GDP ($1500). RESULTS: Discounted life expectancy was 16.69 years for SOC, 16.97 years with VL confirmation of immunologic failure, and 17.25 years for adaptive VL. Mean time on failed first-line ART was 3.7 years for SOC and <0.9 years for all routine/adaptive VL strategies. VL failure confirmation was cost saving compared with SOC. Adaptive VL had an incremental cost-effectiveness ratio (ICER) of $4100/year of life saved compared with VL confirmation and increased the 5-year budget by $310/patient compared with SOC. Adaptive VL achieved an ICER <1* GDP if second-line ART and VL costs simultaneously decreased to $156 and $13, respectively. CONCLUSIONS: VL confirmation of immunologic failure is more effective and less costly than CD4 monitoring in Cote d'Ivoire. Adaptive VL monitoring reduces time on failing ART, is cost-effective, and should become standard in Cote d'Ivoire and similar settings. PMID- 26936667 TI - Confronting Ebola as a Sexually Transmitted Infection. AB - The unprecedented Ebola outbreak that devastated West Africa evolved within months from a regional outbreak to a global public health emergency. While the rate of confirmed cases declined dramatically, sporadic clusters of Ebola virus disease (EVD) continue well beyond the double incubation period of 42 days used to declare a nation Ebola-free. At the same time, evidence that the virus persists in genital fluids and can be sexually transmitted, along with the potential for lingering virus in other body compartments to permit recrudescence of EVD, has shaken our thinking of what it takes to achieve lasting control of an Ebola epidemic. A comprehensive response to the threat of persistence and sexual transmission of Ebola is required and should build on accessible longitudinal medical care of survivors and accurate genital fluid testing for Ebola. Control of this and future Ebola outbreaks will depend on our ability to recognize and respond to this persistence of the virus in those who survive. PMID- 26936668 TI - Rising Mortality Associated With Hepatitis C Virus in the United States, 2003 2013. AB - In the United States, hepatitis C virus (HCV)-associated mortality is increasing. From 2003-2013, the number of deaths associated with HCV has now surpassed 60 other nationally notifiable infectious conditions combined. The increasing HCV associated mortality trend underscores the urgency in finding, evaluating, and treating HCV-infected persons. PMID- 26936669 TI - Analysis of Non-AIDS-Defining Events in HIV Controllers. AB - BACKGROUND: Human immunodeficiency virus (HIV) controllers have the striking ability to maintain viremia at extremely low or undetectable levels without antiretroviral treatment. Even though these patients have been widely studied, information about clinical outcomes, especially concerning to non-AIDS-defining events (nADEs), is scarce. We have analyzed the frequency and rate of nADEs and their associated factors in a large multicenter HIV controller cohort. METHODS: Data on nADEs were recorded for 320 HIV controllers within the multicenter Spanish AIDS Research Network HIV Controllers Cohort (ECRIS). Percentages and crude incidence rates (CIRs) per 100 person-years of follow-up (PYFU) were calculated for the entire follow-up period and for 2 separate periods: the period under control and the period after loss of control. These rates were compared with those for 632 noncontrollers. Demographic and immunological data collected from the controllers were included in a multivariate model to assess factors that were independently associated with nADEs in HIV controllers. RESULTS: HIV controllers experience nADEs, albeit at lower rates than patients who do not spontaneously control the virus (1.252 [95% confidence interval {CI}, .974-1.586] per 100 PYFU and 2.481 [95% CI, 2.153-2.845] per 100 PYFU, respectively; P < .001). Hepatitis C virus (HCV) coinfection was the main factor associated with nADEs in all of the studied periods. Although hepatic events were the most prevalent, they represented only approximately 30% of the total events. CIRs of cardiovascular events increased in the post-loss-of-control period. CONCLUSIONS: HCV/HIV coinfection was the main factor associated with hepatic and extrahepatic nADEs in HIV controllers. The eradication of HCV infection may ameliorate the presence of comorbidities in these patients. PMID- 26936670 TI - Healthcare Outbreaks Associated With a Water Reservoir and Infection Prevention Strategies. AB - Hospital water may serve as a reservoir of healthcare-associated pathogens, and contaminated water can lead to outbreaks and severe infections. The clinical features of waterborne outbreaks and infections as well as prevention strategies and control measures are reviewed. The common waterborne pathogens were bacteria, including Legionella and other gram-negative bacteria, and nontuberculous mycobacteria, although fungi and viruses were occasionally described. These pathogens caused a variety of infections, including bacteremia and invasive and disseminated diseases, particularly among immunocompromised hosts and critically ill adults as well as neonates. Waterborne outbreaks occurred in healthcare settings with emergence of new reported reservoirs, including electronic faucets (Pseudomonas aeruginosa and Legionella), decorative water wall fountains (Legionella), and heater-cooler devices used in cardiac surgery (Mycobacterium chimaera). Advanced molecular techniques are useful for achieving a better understanding of reservoirs and transmission pathways of waterborne pathogens. Developing prevention strategies based on water reservoirs provides a practical approach for healthcare personnel. PMID- 26936671 TI - Detection of IFN-gamma Secretion by T Cells Collected Before and After Successful Treatment of Early Lyme Disease. AB - BACKGROUND: Current serodiagnostics for Lyme disease lack sensitivity during early disease, and cannot determine treatment response. We evaluated an assay based on QuantiFERON technology utilizing peptide antigens derived from Borrelia burgdorferi to stimulate interferon-gamma (IFN-gamma) release as an alternative to serodiagnosis for the laboratory detection of Lyme disease. METHODS: Blood was obtained from patients with erythema migrans before (n = 29) and 2 months after (n = 27) antibiotic therapy. IFN-gamma release was measured by enzyme-linked immunosorbent assay (ELISA) following overnight stimulation of whole blood with the peptide antigens, and compared to the results of standard serological assays (C6, ELISA, and Western blot). RESULTS: IFN-gamma release was observed in pretreatment blood of 20 of 29 (69%) patients with Lyme disease. Following antibiotic treatment, IFN-gamma was significantly reduced (P = .0002), and was detectable in only 4 of 20 (20%) initially positive patients. By contrast, anti C6 antibodies were detected in pretreatment sera from 17 of 29 (59%) subjects, whereas only 5 of 29 (17%) patients had positive Western blot seroreactivity. Antibody responses persisted and expanded following treatment. CONCLUSIONS: Our findings suggest that measurement of IFN-gamma after incubating blood with Borrelia antigens could be useful in the laboratory diagnosis of early Lyme disease. Also, after antibiotic treatment, this response appears to be short lived. PMID- 26936672 TI - Reply to Koo et al. PMID- 26936673 TI - Plasmid-Mediated Colistin-Resistant Escherichia coli in Bacteremia in Switzerland. PMID- 26936674 TI - Bone Mineral Content in Neonates. PMID- 26936675 TI - Reply to Hurley. PMID- 26936677 TI - Corrigendum: Gs-coupled GPCR signalling in AgRP neurons triggers sustained increase in food intake. PMID- 26936676 TI - Defining the possible therapeutic benefit of lymphadenectomy among patients undergoing hepatic resection for intrahepatic cholangiocarcinoma. AB - BACKGROUND: The aim of the study was to investigate the therapeutic role of lymphadenectomy (LND) in patients with intrahepatic cholangiocarcinoma. METHODS: 826 patients who underwent liver resection were identified using the SEER database from 1988 to 2011. Two groups of patients were defined: 201 (24%) undergoing potentially therapeutic LND (group A, >3 lymph nodes (LN) removed), and 625 (76%) not receiving therapeutic LND (group B, <=3 LNs removed). A propensity score analysis was performed to create a matched cohort of 402 patients (201 in either group). The survival benefit of therapeutic LND was also estimated using multivariate parametric analysis comparing two simulated cohorts of 826 patients. RESULTS: 1-, 3-, and 5-year survival rates were 71%, 37%, and 27% for group A patients, and 73%, 37%, and 27% for matched group B patients (P = 0.656). When simulation analysis was performed, a moderate survival benefit of LND of 5.46 months was calculated (95%CI, 4.64-6.29). Considerable differences in LND survival benefit predictions were found according to patient's sex (males, 9.90 vs. females 1.16 months), age (<=60 years, 15 vs. >60 years, -1.34 months), and tumor size (>50 mm, 9.20 vs. <=50 mm, -0.28). CONCLUSIONS: LND therapeutic benefit among a subset of patients. Future work is required to investigate the role of routine LND among these patients. J. Surg. Oncol. 2016;113:685-691. (c) 2016 Wiley Periodicals, Inc. PMID- 26936679 TI - The water-land-food nexus of first-generation biofuels. AB - Recent energy security strategies, investment opportunities and energy policies have led to an escalation in biofuel consumption at the expenses of food crops and pastureland. To evaluate the important impacts of biofuels on food security, the food-energy nexus needs to be investigated in the context of its linkages with the overall human appropriation of land and water resources. Here we provide a global assessment of biofuel crop production, reconstruct global patterns of biofuel crop/oil trade and determine the associated displacement of water and land use. We find that bioethanol is mostly produced with domestic crops while 36% of biodiesel consumption relies on international trade, mainly from Southeast Asia. Altogether, biofuels rely on about 2-3% of the global water and land used for agriculture, which could feed about 30% of the malnourished population. We evaluate the food-energy tradeoff and the impact an increased reliance on biofuel would have on the number of people the planet can feed. PMID- 26936678 TI - Sip-jeon-dea-bo-tang, a traditional herbal medicine, ameliorates cisplatin induced anorexia via the activation of JAK1/STAT3-mediated leptin and IL-6 production in the fat tissue of mice. AB - Despite its therapeutic advantages, chemotherapy can also cause adverse effects, including anorexia and loss of appetite. Although numerous patients with cancer have been reported to suffer from anorexia during or following chemotherapy, treatment options for anorexia remain to be determined. In Asian countries, traditional medicines are widely used to treat problems with appetite; sip-jeon dea-bo-tang (SJDBT) is one of those medicines used for the treatment of anorexia. The present study demonstrated that SJDBT ameliorated cisplatin-induced anorexia. In a mouse model of chemotherapy-induced anorexia, oral administration of SJDBT prevented the cisplatin-induced reduction of food intake, inhibiting weight loss. The results of multiplex assays showed that SJDBT only altered the levels of interleukin (IL)-6 and leptin in the serum and fat tissue. In addition, SJDBT maintained the serum leptin level and increased the serum IL-6 level, whereas cisplatin reduced the levels of both serum leptin and IL-6. Furthermore, SJDBT was revealed to increase the levels of leptin and IL-6 in the fat tissue by activating the JAK1/STAT3 signaling pathway. In conclusion, the present results revealed that SJDBT ameliorated cisplatin-induced anorexia, suggesting its usefulness in the prevention of anorexia during chemotherapy. PMID- 26936680 TI - Comparative proteomic analysis of heat stress proteins associated with rat sperm maturation. AB - Heat stress is demonstrated to have an effect on the function of the male testis, however, limited information has been reported on its effects on sperm maturation. In the present study, a comparative proteomic analysis was performed on the rat caput epididymal fluids responsible for sperm maturation, to identify key heat-stress-associated sperm maturation proteins. The results demonstrated 21 proteins corresponding to 29 differential protein spots, including 10 downregulated and 11 upregulated proteins in the heat treatment group. Functional analysis demonstrated that these proteins were primarily involved in enriched reproduction and antioxidant activity. Analysis of western blot and immunohistochemical analysis demonstrated that the expression of antioxidant proteins peroxiredoxin 6 and clusterin were downregulated, and the expression of superoxide dismutase upregulated, in the heat treatment group. Morphological and TUNEL experiments demonstrated that altered nucleus activity occurred in the caput epididymis. The study provided, to the best of our knowledge, novel information for studies on the biological functions of the epididymis and sperm maturation. PMID- 26936681 TI - Downregulation of VEGF and upregulation of TL1A expression induce HUVEC apoptosis in response to high glucose stimuli. AB - High glucose-induced endothelial cell apoptosis is considered to be the initiator of diabetes-associated vascular complications. Experiments in vivo and in vitro have demonstrated that high glucose levels contribute to the apoptosis of endothelial cells by mediating cellular dysfunction and metabolic disorder via the production of various cytokines. As the most important endogenous vascular regulators, the balance between pro-proliferative effector vascular endothelial growth factor (VEGF) and anti-proliferative effector tumor necrosis factor-like cytokine 1A (TL1A) is important in the modulation of endothelial cell survival and proliferation, and neovascularization. The present study aimed to explore whether the imbalance between VEGF and TL1A affected the apoptosis of human umbilical vein endothelial cells (HUVECs) exposed to high glucose conditions and then further investigated the potential mechanism. The results showed that the downregulation of VEGF in combination with the upregulation of TL1A in response to high glucose levels led to enhanced HUVEC apoptosis. Further experiments revealed that silencing high glucose-induced TL1A expression using TL1A small interfering (si)RNA or the overexpression of VEGF by transfection with VEGF DNA resulted in a reduced HUVEC apoptosis rate compared with the controls. The effects occurred by attenuating and activating the phosphoinositide 3 kinase/Akt/endothelial nitric oxide synthase pathway, respectively. In addition, VEGF and TL1A inhibited each other in hyperglycemia. In conclusion, these findings provide theoretical support for the further investigation of novel therapeutic strategies designed to maintain the balance between VEGF and TL1A and, thus, to prevent the onset and progression of endothelial cell apoptosis in response to high glucose stimuli. PMID- 26936682 TI - Evaluating Intensity-Modulated Radiation Therapy in Locally Advanced Non-Small Cell Lung Cancer: Results From the National Cancer Data Base. AB - INTRODUCTION: Reports have suggested improvements in dosimetry, toxicity, and quality of life with intensity-modulated radiation therapy (IMRT) in locally advanced non-small-cell lung cancer (NSCLC). The selection criteria for those patients who may benefit is unclear. This study sought to identify subgroups of patients who may derive survival benefit from intensity modulated radiation therapy (IMRT) compared with 3D conformal radiation therapy (3DCRT). METHODS AND MATERIALS: The National Cancer Data Base was queried for stage III NSCLC treated with radiation and chemotherapy alone with curative intent. All received >= 58 Gy. Kaplan-Meier and log-rank test were performed to compare overall survival (OS) by treatment modality. A multivariable Cox proportional hazards model was used to assess association with OS. Propensity score matching was also implemented. RESULTS: A total of 2543 patients treated between 2003 and 2006 were eligible; 422 (16.6%) received IMRT, 2121 (83.4%) received 3DCRT. In patients with T3 and T4 disease, IMRT was associated with an improvement in median OS and 5-year survival rate (17.2 vs. 14.6 months; 19.9% vs. 13.4%, P = .021.) In multivariable analysis, there was an interaction between treatment type and T stage that was found to be significant (P = .03). In the propensity matched cohort of T3 and T4 patients, the use of IMRT remained associated with improved OS (hazard ratio, 0.80; 95% confidence interval, 0.64-1.00; P = .048). CONCLUSIONS: Use of IMRT in patients with T3 and T4 tumors was associated with improved overall survival in this large population-based analysis. This is a novel finding that is in concordance with the well-described dosimetric benefits of IMRT in NSCLC. PMID- 26936684 TI - Gestural praxis in young adults with mild to moderate intellectual disabilities. AB - BACKGROUND: Praxis functioning in the population with intellectual disabilities (ID) has been poorly studied. The goal of this research was to look for a starting point to study the praxic functioning in young adults with mild to moderate ID. METHOD: Thirty young adults with ID and 30 young adults without ID, between the ages of 18 and 35 years, participated in this study. All participants completed tests that assessed gestural praxis. RESULTS: It was possible to observe similar praxis behaviour in the group with ID in almost all domains studied, albeit showing statistical values lower than those of the group without ID. DISCUSSIONS: Despite the high number of errors committed, the sample of participants with ID was able to reach the goal of praxic tasks performed; such errors may be associated with a deficit in the development of various brain functions and not only with praxis functioning, mainly related to a lower yield in terms of planning, monitoring and correcting intentional movement. PMID- 26936683 TI - SAMHD1 transcript upregulation during SIV infection of the central nervous system does not associate with reduced viral load. AB - Restriction of HIV-1 in myeloid-lineage cells is attributed in part to the nucleotidase activity of the SAM-domain and HD-domain containing protein (SAMHD1), which depletes free nucleotides, blocking reverse transcription. In the same cells, the Vpx protein of HIV-2 and most SIVs counteracts SAMHD1. Both Type I and II interferons may stimulate SAMHD1 transcription. The contributions of SAMHD1 to retroviral restriction in the central nervous system (CNS) have been the subject of limited study. We hypothesized that SAMHD1 would respond to interferon in the SIV-infected CNS but would not control virus due to SIV Vpx. Accordingly, we investigated SAMHD1 transcript abundance and association with the Type I interferon response in an SIV model. SAMHD1 transcript levels were IFN responsive, increasing during acute phase infection and decreasing during a more quiescent phase, but generally remaining elevated at all post-infection time points. In vitro, SAMHD1 transcript was abundant in macaque astrocytes and further induced by Type I interferon, while IFN produced a weaker response in the more permissive environment of the macrophage. We cannot rule out a contribution of SAMHD1 to retroviral restriction in relatively non-permissive CNS cell types. We encourage additional research in this area, particularly in the context of HIV 1 infection. PMID- 26936685 TI - Younger pregnant women have a higher risk of striae gravidarum, the study said. PMID- 26936686 TI - Scutellaria baicalensis Georgi extract protects against alcohol-induced acute liver injury in mice and affects the mechanism of ER stress. AB - The aims of the present study were to examine the hepatoprotective effect of Scutellaria baicalensis Georgi extract (Scutellariae Radix extract; SRE) against acute alcohol-induced liver injury in mice, and investigate the mechanism of endoplasmic reticulum (ER) stress. High performance liquid chromatography was used for the phytochemical analysis of SRE. Animals were administered orally with 50% alcohol (12 ml/kg) 4 h following administration of doses of SRE every day for 14 days, with the exception of normal control group. The protective effect was investigated by measuring the levels of aspartate transaminase (AST), alanine transferase (ALT) and triglyceride (TG) in the serum, and the levels of glutathione (GSH) and malondialdehyde (MDA) in liver tissues. The levels of glucose-related protein 78 (GRP78) were detected using immunohistochemical localization and an enzyme-linked immunosorbent assay. Hepatocyte apoptosis was assessed using terminal-deoxynucleoitidyl transferase mediated nick end labeling. The SRE contained 31.2% baicalin. Pretreatment with SRE had a marked protective effect by reversing the levels of biochemical markers and levels of GRP78 in a dose-dependent manner. The results of the present study demonstrated that pretreatment with SRE exerted a marked hepatoprotective effect by downregulating the expression of GRP78, which is a marker of ER stress. PMID- 26936687 TI - Therapeutic outcome of 6198 interferon-naive Egyptian patients with chronic hepatitis C: a real-life experience and lessons to be learned in DAAs' era. AB - Antiviral therapy for HCV infection has been validated in randomized controlled clinical trials, but its value in the real world is less well studied. There is relatively little data on real-world responses to interferon-based therapies for patients with genotype 4 infection. We aimed to examine experience with large scale access to antiviral therapy in chronic HCV in a real-life clinical setting in Egypt. Detailed pretreatment data of 6198 IFN-naive chronic HCV patients who had received PEG-IFN/RBV therapy at Cairo-Fatemic Hospital, Egypt, between 2009 and 2012 were obtained from the HCV database. At week 12, 95.7% of patients had undetectable HCV RNA, and by week 24 and 48, breakthrough was 6% and 4%, respectively. However, 43.7% of patients discontinued treatment prematurely, and intent to treat end of treatment response was 44.6% (79.3% per protocol). Sustai ned response data were available from only 1281 patients and was 84.9%. Haematological abnormalities were comparable in patients who did or did not comply with therapy. This is the first real-world, large-scale experience of antiviral therapy in chronic HCV in Egypt. Suboptimal response in HCV predominantly genotype 4 was mainly driven by noncompliance as well as gaps in the healthcare system leading to treatment discontinuation. These results need to be considered in the era of all oral antiviral regimes. PMID- 26936688 TI - White matter microstructure and impulsivity in methamphetamine dependence with and without a history of psychosis. AB - BACKGROUND: Methamphetamine (MA) use may lead to white matter injury and to a range of behavioral problems and psychiatric disorders, including psychosis. The present study sought to assess white matter microstructural impairment as well as impulsive behavior in MA dependence and MA-associated psychosis (MAP). METHODS: Thirty patients with a history of MAP, 39 participants with MA dependence and 40 healthy controls underwent diffusion tensor imaging (DTI). Participants also completed the UPPS-P impulsive behavior questionnaire. We applied tract-based spatial statistics (TBSS) to investigate group differences in mean diffusivity (MD), fractional anisotropy (FA), axial (lambda|| ) and radial diffusivity (lambda? ), and their association with impulsivity scores and psychotic symptoms. RESULTS: The MAP group displayed widespread higher MD, lambda|| and lambda? levels compared to both controls and the MA group, and lower FA in extensive white matter areas relative to controls. MD levels correlated positively with negative psychotic symptoms in MAP. No significant DTI group differences were found between the MA group and controls. Both clinical groups showed high levels of impulsivity, and this dysfunction was associated with DTI measures in frontal white matter tracts. CONCLUSIONS: MAP patients show distinct patterns of impaired white matter integrity of global nature relative to controls and the MA group. Future work to investigate the precise nature and timing of alterations in MAP is needed. The results are further suggestive of frontal white matter pathology playing a role in impulsivity in MA dependence and MAP. Hum Brain Mapp 37:2055 2067, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26936689 TI - Effects of flavonoid derivatives on human microvascular endothelial cells. AB - Some natural compounds, including flavonoids, are active in vasculature re-growth during hair follicle disruption, but their effects have not been yet evaluated directly on microvascular endothelial cells. Skin vascularisation regulates the physiological blood supply required for hair growth and its dysregulation is the basis of several human diseases. Follicle-derived vascular endothelial growth factor (VEGF) release from follicular keratinocytes promotes perifollicular vascularisation and increases follicle and hair size, while blockade of VEGF mediated angiogenesis leads to impaired hair growth. Here, we tested three flavonoids, namely visnadin (VSD), hesperidin (HSP) and baicalin (BC), on cultured human microvascular endothelial cells (HMEC), comparing their effects with minoxidil (MXD), a synthetic drug broadly used in the treatment of androgenetic alopecia. The response to these compounds was assayed in terms of endothelial survival, proliferation, tubulogenesis and proangiogenic signalling. We show that BC promotes HMEC proliferation, while both VSD and MXD enhance tubulogenesis. Interestingly, only HSP increases VEGFR-2 phosphorylation. PMID- 26936690 TI - Point/Counterpoint. Radiotherapy using hard wedges is no longer appropriate and should be discontinued. PMID- 26936691 TI - Monte Carlo calculated correction factors for the PTW microDiamond detector in the Gamma Knife-Model C. AB - PURPOSE: Accurate dose measurements in small fields require correction factors when sufficient CPE is not present inside of the field. These factors adjust for perturbation, volume averaging, and other effects; as such, they are field size, detector, and phantom dependent. In this work, Monte Carlo (MC) methods were used to calculate correction factors for PTW's microDiamond detector in Elekta's Gamma Knife Model-C unit. These correction factors allow for accurate measurement of output factors-even in the smallest field sizes where CPE is not present. METHODS: The small field correction factors were calculated as kQclin,Qmsr (fclin,fmsr) correction factors according to the Alfonso formalism. The MC model of the Gamma Knife was built with the EGSnrc code system, using BEAMnrc and DOSRZnrc user codes. Efforts were made to validate the MC model against experimental measurements. Using the model, field output factors and measurement ratios for each of the four helmet sizes were simulated for an ABS plastic phantom and validated against film measurements, detector measurements, and treatment planning system (TPS) data. Once validated against the available ABS phantom, the model was applied to a more waterlike solid water phantom. Using MC results from the solid water phantom, the final k correction factors were determined relative to the machine specific reference field-the 18 mm helmet, which is the largest field size available on the unit. RESULTS: When validating against experimental measurements using the ABS phantom, all MC methods agreed with experiment within the stated uncertainties: MC determined field output factors agreed within 0.6% of the TPS and 1.4% of film; and MC simulated measurement ratios matched physically measured ratios within 1% for all helmet sizes. kQclin,Qmsr (fclin,fmsr) for the PTW microDiamond in the solid water phantom approached unity to within 0.4% +/- 1.7% for all the helmet sizes except the 4 mm; the 4 mm helmet size over-responded by 3.2% +/- 1.7%, resulting in a kQ4mm,Q18mm (f4mm,f18mm) of 0.969. CONCLUSIONS: Similar to what has been found in the Gamma Knife Perfexion, the PTW microDiamond over-responds in the smallest 4 mm field. The over-response can be corrected via the Alfonso formalism using the correction factors determined in this work. Using the MC calculated correction factors, the PTW microDiamond detector is an effective dosimeter in all available helmet sizes. PMID- 26936692 TI - Postoperative 3D spine reconstruction by navigating partitioning manifolds. AB - PURPOSE: The postoperative evaluation of scoliosis patients undergoing corrective treatment is an important task to assess the strategy of the spinal surgery. Using accurate 3D geometric models of the patient's spine is essential to measure longitudinal changes in the patient's anatomy. On the other hand, reconstructing the spine in 3D from postoperative radiographs is a challenging problem due to the presence of instrumentation (metallic rods and screws) occluding vertebrae on the spine. METHODS: This paper describes the reconstruction problem by searching for the optimal model within a manifold space of articulated spines learned from a training dataset of pathological cases who underwent surgery. The manifold structure is implemented based on a multilevel manifold ensemble to structure the data, incorporating connections between nodes within a single manifold, in addition to connections between different multilevel manifolds, representing subregions with similar characteristics. RESULTS: The reconstruction pipeline was evaluated on x-ray datasets from both preoperative patients and patients with spinal surgery. By comparing the method to ground-truth models, a 3D reconstruction accuracy of 2.24 +/- 0.90 mm was obtained from 30 postoperative scoliotic patients, while handling patients with highly deformed spines. CONCLUSIONS: This paper illustrates how this manifold model can accurately identify similar spine models by navigating in the low-dimensional space, as well as computing nonlinear charts within local neighborhoods of the embedded space during the testing phase. This technique allows postoperative follow-ups of spinal surgery using personalized 3D spine models and assess surgical strategies for spinal deformities. PMID- 26936693 TI - Clinical introduction of image lag correction for a cone beam CT system. AB - PURPOSE: Image lag in the flat-panel detector used for Linac integrated cone beam computed tomography (CBCT) has a degrading effect on CBCT image quality. The most prominent visible artifact is the presence of bright semicircular structure in the transverse view of the scans, known also as radar artifact. Several correction strategies have been proposed, but until now the clinical introduction of such corrections remains unreported. In November 2013, the authors have clinically implemented a previously proposed image lag correction on all of their machines at their main site in Amsterdam. The purpose of this study was to retrospectively evaluate the effect of the correction on the quality of CBCT images and evaluate the required calibration frequency. METHODS: Image lag was measured in five clinical CBCT systems (Elekta Synergy 4.6) using an in-house developed beam interrupting device that stops the x-ray beam midway through the data acquisition of an unattenuated beam for calibration. A triple exponential falling edge response was fitted to the measured data and used to correct image lag from projection images with an infinite response. This filter, including an extrapolation for saturated pixels, was incorporated in the authors' in-house developed clinical cbct reconstruction software. To investigate the short-term stability of the lag and associated parameters, a series of five image lag measurement over a period of three months was performed. For quantitative analysis, the authors have retrospectively selected ten patients treated in the pelvic region. The apparent contrast was quantified in polar coordinates for scans reconstructed using the parameters obtained from different dates with and without saturation handling. RESULTS: Visually, the radar artifact was minimal in scans reconstructed using image lag correction especially when saturation handling was used. In patient imaging, there was a significant reduction of the apparent contrast from 43 +/- 16.7 to 15.5 +/- 11.9 HU without the saturation handling and to 9.6 +/- 12.1 HU with the saturation handling, depending on the date of the calibration. The image lag correction parameters were stable over a period of 3 months. The computational load was increased by approximately 10%, not endangering the fast in-line reconstruction. CONCLUSIONS: The lag correction was successfully implemented clinically and removed most image lag artifacts thus improving the image quality. Image lag correction parameters were stable for 3 months indicating low frequency of calibration requirements. PMID- 26936694 TI - Technical Note: Method to correlate whole-specimen histopathology of radical prostatectomy with diagnostic MR imaging. AB - PURPOSE: Validation of MRI-guided tumor boundary delineation for targeted prostate cancer therapy is achieved via correlation with gold-standard histopathology of radical prostatectomy specimens. Challenges to accurate correlation include matching the pathology sectioning plane with the in vivo imaging slice plane and correction for the deformation that occurs between in vivo imaging and histology. A methodology is presented for matching of the histological sectioning angle and position to the in vivo imaging slices. METHODS: Patients (n = 4) with biochemical failure following external beam radiotherapy underwent diagnostic MRI to confirm localized recurrence of prostate cancer, followed by salvage radical prostatectomy. High-resolution 3-D MRI of the ex vivo specimens was acquired to determine the pathology sectioning angle that best matched the in vivo imaging slice plane, using matching anatomical features and implanted fiducials. A novel sectioning device was developed to guide sectioning at the correct angle, and to assist the insertion of reference dye marks to aid in histopathology reconstruction. RESULTS: The percentage difference in the positioning of the urethra in the ex vivo pathology sections compared to the positioning in in vivo images was reduced from 34% to 7% through slicing at the best match angle. Reference dye marks were generated, which were visible in ex vivo imaging, in the tissue sections before and after processing, and in histology sections. CONCLUSIONS: The method achieved an almost fivefold reduction in the slice-matching error and is readily implementable in combination with standard MRI technology. The technique will be employed to generate datasets for correlation of whole-specimen prostate histopathology with in vivo diagnostic MRI using 3-D deformable registration, allowing assessment of the sensitivity and specificity of MRI parameters for prostate cancer. Although developed specifically for prostate, the method is readily adaptable to other types of whole tissue specimen, such as mastectomy or liver resection. PMID- 26936695 TI - Accelerated iterative beam angle selection in IMRT. AB - PURPOSE: Iterative methods for beam angle selection (BAS) for intensity-modulated radiation therapy (IMRT) planning sequentially construct a beneficial ensemble of beam directions. In a naive implementation, the nth beam is selected by adding beam orientations one-by-one from a discrete set of candidates to an existing ensemble of (n - 1) beams. The best beam orientation is identified in a time consuming process by solving the fluence map optimization (FMO) problem for every candidate beam and selecting the beam that yields the largest improvement to the objective function value. This paper evaluates two alternative methods to accelerate iterative BAS based on surrogates for the FMO objective function value. METHODS: We suggest to select candidate beams not based on the FMO objective function value after convergence but (1) based on the objective function value after five FMO iterations of a gradient based algorithm and (2) based on a projected gradient of the FMO problem in the first iteration. The performance of the objective function surrogates is evaluated based on the resulting objective function values and dose statistics in a treatment planning study comprising three intracranial, three pancreas, and three prostate cases. Furthermore, iterative BAS is evaluated for an application in which a small number of noncoplanar beams complement a set of coplanar beam orientations. This scenario is of practical interest as noncoplanar setups may require additional attention of the treatment personnel for every couch rotation. RESULTS: Iterative BAS relying on objective function surrogates yields similar results compared to naive BAS with regard to the objective function values and dose statistics. At the same time, early stopping of the FMO and using the projected gradient during the first iteration enable reductions in computation time by approximately one to two orders of magnitude. With regard to the clinical delivery of noncoplanar IMRT treatments, we could show that optimized beam ensembles using only a few noncoplanar beam orientations often approach the plan quality of fully noncoplanar ensembles. CONCLUSIONS: We conclude that iterative BAS in combination with objective function surrogates can be a viable option to implement automated BAS at clinically acceptable computation times. PMID- 26936696 TI - Automated fluence map optimization based on fuzzy inference systems. AB - PURPOSE: The planning of an intensity modulated radiation therapy treatment requires the optimization of the fluence intensities. The fluence map optimization (FMO) is many times based on a nonlinear continuous programming problem, being necessary for the planner to define a priori weights and/or lower bounds that are iteratively changed within a trial-and-error procedure until an acceptable plan is reached. In this work, the authors describe an alternative approach for FMO that releases the human planner from trial-and-error procedures, contributing for the automation of the planning process. METHODS: The FMO is represented by a voxel-based convex penalty continuous nonlinear model. This model makes use of both weights and lower/upper bounds to guide the optimization process toward interesting solutions that are able to satisfy all the constraints defined for the treatment. All the model's parameters are iteratively changed by resorting to a fuzzy inference system. This system analyzes how far the current solution is from a desirable solution, changing in a completely automated way both weights and lower/upper bounds. The fuzzy inference system is based on fuzzy reasoning that enables the use of common-sense rules within an iterative optimization process. The method is built in two stages: in a first stage, an admissible solution is calculated, trying to guarantee that all the treatment planning constraints are being satisfied. In this first stage, the algorithm tries to improve as much as possible the irradiation of the planning target volumes. In a second stage, the algorithm tries to improve organ sparing, without jeopardizing tumor coverage. RESULTS: The proposed methodology was applied to ten head-and-neck cancer cases already treated in the Portuguese Oncology Institute of Coimbra (IPOCFG) and signalized as complex cases. IMRT treatment was considered, with 7, 9, and 11 equidistant beam angles. It was possible to obtain admissible solutions for all the patients considered and with no human planner intervention. The results obtained were compared with the optimized solution using a similar optimization model but with human planner intervention. For the vast majority of cases, it was possible to improve organ sparing and at the same time to assure better tumor coverage. CONCLUSIONS: Embedding a fuzzy inference system into FMO allows human planner reasoning to be used in the guidance of the optimization process toward interesting regions in a truly automated way. The proposed methodology is capable of calculating high quality plans within reasonable computational times and can be an important contribution toward fully automated radiation therapy treatment planning. PMID- 26936697 TI - Scatter radiation intensities around a clinical digital breast tomosynthesis unit and the impact on radiation shielding considerations. AB - PURPOSE: To measure the scattered radiation intensity around a clinical digital breast tomosynthesis (DBT) unit and to provide updated data for radiation shielding design for DBT systems with tungsten-anode x-ray tubes. METHODS: The continuous distribution of scattered x-rays from a clinical DBT system (Hologic Selenia Dimensions) was measured within an angular range of 0 degrees -180 degrees using a linear-array x-ray detector (X-Scan 0.8f3-512, Detection Technology, Inc., Finland), which was calibrated for the x-ray spectrum range of the DBT unit. The effects of x-ray field size, phantom size, and x-ray kVp/filter combination were investigated. Following a previously developed methodology by Simpkin, scatter fraction was determined for the DBT system as a function of angle around the phantom center. Detailed calculations of the scatter intensity from a DBT system were demonstrated using the measured scatter fraction data. RESULTS: For the 30 and 35 kVp acquisition, the scatter-to-primary-ratio and scatter fraction data closely matched with data previously measured by Simpkin. However, the measured data from this study demonstrated the nonisotropic distribution of the scattered radiation around a DBT system, with two strong peaks around 25 degrees and 160 degrees . The majority scatter radiation (>70%) originated from the imaging detector assembly, instead of the phantom. With a workload from a previous survey performed at MGH, the scatter air kerma at 1 m from the phantom center for wall/door is 1.76 * 10(-2) mGy patient(-1), for floor is 1.64 * 10(-1) mGy patient(-1), and for ceiling is 3.66 * 10(-2) mGy patient( 1). CONCLUSIONS: Comparing to previously measured data for mammographic systems, the scatter air kerma from Holgoic DBT is at least two times higher. The main reasons include the harder primary beam with higher workload (measured with total mAs/week), added tomosynthesis acquisition, and strong small angle forward scattering. Due to the highly conservative initial assumptions, the shielding recommendation from NCRP Report 147 is still sufficient for the Hologic DBT system given the workload from a previous survey at MGH. With the data provided from this study, accurate shielding calculation can be performed for Hologic DBT systems with specific workload and barrier distance. PMID- 26936698 TI - Motion-robust intensity-modulated proton therapy for distal esophageal cancer. AB - PURPOSE: To develop methods for evaluation and mitigation of dosimetric impact due to respiratory and diaphragmatic motion during free breathing in treatment of distal esophageal cancers using intensity-modulated proton therapy (IMPT). METHODS: This was a retrospective study on 11 patients with distal esophageal cancer. For each patient, four-dimensional computed tomography (4D CT) data were acquired, and a nominal dose was calculated on the average phase of the 4D CT. The changes of water equivalent thickness (DeltaWET) to cover the treatment volume from the peak of inspiration to the valley of expiration were calculated for a full range of beam angle rotation. Two IMPT plans were calculated: one at beam angles corresponding to small DeltaWET and one at beam angles corresponding to large DeltaWET. Four patients were selected for the calculation of 4D robustness-optimized IMPT plans due to large motion-induced dose errors generated in conventional IMPT. To quantitatively evaluate motion-induced dose deviation, the authors calculated the lowest dose received by 95% (D95) of the internal clinical target volume for the nominal dose, the D95 calculated on the maximum inhale and exhale phases of 4D CT DCT0 andDCT50 , the 4D composite dose, and the 4D dynamic dose for a single fraction. RESULTS: The dose deviation increased with the average DeltaWET of the implemented beams, DeltaWETave. When DeltaWETave was less than 5 mm, the dose error was less than 1 cobalt gray equivalent based on DCT0 and DCT50 . The dose deviation determined on the basis of DCT0 and DCT50 was proportionally larger than that determined on the basis of the 4D composite dose. The 4D-robustness-optimized IMPT plans notably reduced the overall dose deviation of multiple fractions and the dose deviation caused by the interplay effect in a single fraction. CONCLUSIONS: In IMPT for distal esophageal cancer, DeltaWET analysis can be used to select the beam angles that are least affected by respiratory and diaphragmatic motion. To further reduce dose deviation, the 4D robustness optimization can be implemented for IMPT planning. Calculation of DCT0 and DCT50 is a conservative method to estimate the motion-induced dose errors. PMID- 26936699 TI - Simulation evaluation of NIST air-kerma rate calibration standard for electronic brachytherapy. AB - PURPOSE: Dosimetry for the model S700 50 kV electronic brachytherapy (eBT) source (Xoft, Inc., a subsidiary of iCAD, San Jose, CA) was simulated using Monte Carlo (MC) methods by Rivard et al. ["Calculated and measured brachytherapy dosimetry parameters in water for the Xoft Axxent x-ray source: An electronic brachytherapy source," Med. Phys. 33, 4020-4032 (2006)] and recently by Hiatt et al. ["A revised dosimetric characterization of the model S700 electronic brachytherapy source containing an anode-centering plastic insert and other components not included in the 2006 model," Med. Phys. 42, 2764-2776 (2015)] with improved geometric characterization. While these studies examined the dose distribution in water, there have not previously been reports of the eBT source calibration methods beyond that recently reported by Seltzer et al. ["New national air-kerma standard for low-energy electronic brachytherapy sources," J. Res. Natl. Inst. Stand. Technol. 119, 554-574 (2014)]. Therefore, the motivation for the current study was to provide an independent determination of air-kerma rate at 50 cm in air Kair(d=50 cm) using MC methods for the model S700 eBT source. METHODS: Using CAD information provided by the vendor and disassembled sources, an MC model was created for the S700 eBT source. Simulations were run using the mcnp6 radiation transport code for the NIST Lamperti air ionization chamber according to specifications by Boutillon et al. ["Comparison of exposure standards in the 10 50 kV x-ray region," Metrologia 5, 1-11 (1969)], in air without the Lamperti chamber, and in vacuum without the Lamperti chamber. Kair(d=50 cm) was determined using the *F4 tally with NIST values for the mass energy-absorption coefficients for air. Photon spectra were evaluated over 2 pi azimuthal sampling for polar angles of 0 degrees <= theta <= 180 degrees every 1 degrees . Volume averaging was averted through tight radial binning. Photon energy spectra were determined over all polar angles in both air and vacuum using the F4 tally with 0.1 keV resolution. A total of 10(11) simulated histories were run for the Lamperti chamber geometry (statistical uncertainty of 0.14%), with 10(10) histories for the in-air and in-vacuum simulations (statistical uncertainty of 0.04%). The total standard uncertainty in the calculated air-kerma rate determination amounted to 6.8%. RESULTS: MC simulations determined the air-kerma rate at 50 cm from the source with the modeled Lamperti chamber to be (1.850 +/- 0.126) * 10( 4) Gy/s, which was within the range of Kair(d=50 cm) values (1.67-2.11) * 10(-4) Gy/s measured by NIST. The ratio of the photon spectra in air and in vacuum were in good agreement above 13 keV, and for theta < 150 degrees where the influence of the Kovar sleeve and the Ag epoxy components caused increased scatter in air. Below 13 keV, the ratio of the photon spectra in air to vacuum exhibited a decrease that was attributed to increased attenuation of the photons in air. Across most of the energy range on the source transverse plane, there was good agreement between the authors' simulated spectra and that measured by NIST. Discrepancies were observed above 40 keV where the NIST spectrum had a steeper fall-off towards 50 keV. CONCLUSIONS: Through MC simulations of radiation transport, this study provided an independent validation of the measured air kerma rate at 50 cm in air at NIST for the model S700 eBT source, with mean results in agreement within 3.3%. This difference was smaller than the range (i.e., 23%) of the measured values. PMID- 26936700 TI - Vision 20/20: Magnetic resonance imaging-guided attenuation correction in PET/MRI: Challenges, solutions, and opportunities. AB - Attenuation correction is an essential component of the long chain of data correction techniques required to achieve the full potential of quantitative positron emission tomography (PET) imaging. The development of combined PET/magnetic resonance imaging (MRI) systems mandated the widespread interest in developing novel strategies for deriving accurate attenuation maps with the aim to improve the quantitative accuracy of these emerging hybrid imaging systems. The attenuation map in PET/MRI should ideally be derived from anatomical MR images; however, MRI intensities reflect proton density and relaxation time properties of biological tissues rather than their electron density and photon attenuation properties. Therefore, in contrast to PET/computed tomography, there is a lack of standardized global mapping between the intensities of MRI signal and linear attenuation coefficients at 511 keV. Moreover, in standard MRI sequences, bones and lung tissues do not produce measurable signals owing to their low proton density and short transverse relaxation times. MR images are also inevitably subject to artifacts that degrade their quality, thus compromising their applicability for the task of attenuation correction in PET/MRI. MRI-guided attenuation correction strategies can be classified in three broad categories: (i) segmentation-based approaches, (ii) atlas-registration and machine learning methods, and (iii) emission/transmission-based approaches. This paper summarizes past and current state-of-the-art developments and latest advances in PET/MRI attenuation correction. The advantages and drawbacks of each approach for addressing the challenges of MR-based attenuation correction are comprehensively described. The opportunities brought by both MRI and PET imaging modalities for deriving accurate attenuation maps and improving PET quantification will be elaborated. Future prospects and potential clinical applications of these techniques and their integration in commercial systems will also be discussed. PMID- 26936701 TI - A spectroscopic study of the chromatic properties of GafChromicEBT3 films. AB - PURPOSE: This work provides an interpretation of the chromatic properties of GafChromicEBT3 films based on the chemical nature of the polydiacetylene (PDA) molecules formed upon interaction with ionizing radiation. The EBT3 films become optically less transparent with increasing radiation dose as a result of the radiation-induced polymerization of diacetylene monomers. In contrast to empirical quantification of the chromatic properties, less attention has been given to the underlying molecular mechanism that induces the strong decrease in transparency. METHODS: Unlaminated GafChromicEBT3 films were irradiated with a 6 MV photon beam to dose levels up to 20 Gy. The optical absorption properties of the films were investigated using visible (vis) spectroscopy. The presence of PDA molecules in the active layer of the EBT3 films was investigated using Raman spectroscopy, which probes the vibrational modes of the molecules in the layer. The vibrational modes assigned to PDA's were used in a theoretical vis-absorption model to fit our experimental vis-absorption spectra. From the fit parameters, one can assess the relative contribution of different PDA conformations and the length distribution of PDA's in the film. RESULTS: Vis-spectroscopy shows that the optical density increases with dose in the full region of the visible spectrum. The Raman spectrum is dominated by two vibrational modes, most notably by the nu(C=C) and the nu(C=C) stretching modes of the PDA backbone. By fitting the vis-absorption model to experimental spectra, it is found that the active layer contains two distinct PDA conformations with different absorption properties and reaction kinetics. Furthermore, the mean PDA conjugation length is found to be 2-3 orders of magnitude smaller than the crystals PDA's are embedded in. CONCLUSIONS: Vis- and Raman spectroscopy provided more insight into the molecular nature of the radiochromic properties of EBT3 films through the identification of the excited states of PDA and the presence of two PDA conformations. The improved knowledge on the molecular composition of EBT3's active layer provides a framework for future fundamental modeling of the dose response. PMID- 26936702 TI - A simple method for determining the coagulation threshold temperature of transparent tissue-mimicking thermal therapy gel phantoms: Validated by magnetic resonance imaging thermometry. AB - PURPOSE: Tissue-mimicking thermal therapy phantoms that coagulate at specific temperatures are valuable tools for developing and evaluating treatment strategies related to thermal therapy. Here, the authors propose a simple and efficient method for determining the coagulation threshold temperature of transparent thermal therapy gel phantoms. METHODS: The authors used a previously published gel phantom recipe with 2% (w/v) of bovine serum albumin as the temperature-sensitive protein. Using the programmable heating settings of a polymerase chain reaction (PCR) machine, the authors heated 50 MUl gel samples to various temperatures for 3 min and then imaged them using the BioRad Gel Doc system to determine the coagulation temperature using an opacity quantification method. The estimated coagulation temperatures were then validated for gel phantoms prepared with different pH levels using high-intensity focused ultrasound (HIFU) heating and magnetic resonance imaging (MRI) thermometry methods on a clinical MR-HIFU system. RESULTS: The PCR heating method produced consistent and reproducible coagulation of gel samples in precise correlation with the set incubation temperatures. The resulting coagulation threshold temperatures for gel phantoms of varying pH levels were found to be 44.1 +/- 0.1, 53.4 +/- 0.9, and 60.3 +/- 0.9 degrees C for pH levels of 4.25, 4.50, and 4.75, respectively. This corresponded well with the coagulation threshold temperatures determined by MR-thermometry, with coagulation defined as a 95% decrease in T2 relaxation time, which were estimated at 53.6 +/- 1.9 and 62.9 +/- 2.4 degrees C for a pH of 4.50 and 4.75, respectively. CONCLUSIONS: The opacity quantification method provides a fast and reproducible estimate of the coagulation threshold temperature of transparent temperature-sensitive gel phantoms. The temperatures determined using this method were well within the range of temperatures estimated using MR-thermometry. Due to the specific heating capabilities of the PCR machine, and the robust determination of coagulation threshold temperatures based on the statistically significant increase in the opacity of gel samples, coagulation temperatures can be determined more precisely and with less variability compared to MRI-based methods. PMID- 26936703 TI - Automatic labeling of MR brain images by hierarchical learning of atlas forests. AB - PURPOSE: Automatic brain image labeling is highly demanded in the field of medical image analysis. Multiatlas-based approaches are widely used due to their simplicity and robustness in applications. Also, random forest technique is recognized as an efficient method for labeling, although there are several existing limitations. In this paper, the authors intend to address those limitations by proposing a novel framework based on the hierarchical learning of atlas forests. METHODS: Their proposed framework aims to train a hierarchy of forests to better correlate voxels in the MR images with their corresponding labels. There are two specific novel strategies for improving brain image labeling. First, different from the conventional ways of using a single level of random forests for brain labeling, the authors design a hierarchical structure to incorporate multiple levels of forests. In particular, each atlas forest in the bottom level is trained in accordance with each individual atlas, and then the bottom-level forests are clustered based on their capabilities in labeling. For each clustered group, the authors retrain a new representative forest in the higher level by using all atlases associated with the lower-level atlas forests in the current group, as well as the tentative label maps yielded from the lower level. This clustering and retraining procedure is conducted iteratively to yield a hierarchical structure of forests. Second, in the testing stage, the authors also present a novel atlas forest selection method to determine an optimal set of atlas forests from the constructed hierarchical structure (by disabling those nonoptimal forests) for accurately labeling the test image. RESULTS: For validating their proposed framework, the authors evaluate it on the public datasets, including Alzheimer's disease neuroimaging initiative, Internet brain segmentation repository, and LONI LPBA40. The authors compare the results with the conventional approaches. The experiments show that the use of the two novel strategies can significantly improve the labeling performance. Note that when more levels are constructed in the hierarchy, the labeling performance can be further improved, but more computational time will be also required. CONCLUSIONS: The authors have proposed a novel multiatlas-based framework for automatic and accurate labeling of brain anatomies, which can achieve accurate labeling results for MR brain images. PMID- 26936704 TI - Contour interpolated radial basis functions with spline boundary correction for fast 3D reconstruction of the human articular cartilage from MR images. AB - PURPOSE: The aim of this work is to demonstrate a new image processing technique that can provide a "near real-time" 3D reconstruction of the articular cartilage of the human knee from MR images which is user friendly. This would serve as a point-of-care 3D visualization tool which would benefit a consultant radiologist in the visualization of the human articular cartilage. METHODS: The authors introduce a novel fusion of an adaptation of the contour method known as "contour interpolation (CI)" with radial basis functions (RBFs) which they describe as "CI RBFs." The authors also present a spline boundary correction which further enhances volume estimation of the method. A subject cohort consisting of 17 right nonpathological knees (ten female and seven male) is assessed to validate the quality of the proposed method. The authors demonstrate how the CI-RBF method dramatically reduces the number of data points required for fitting an implicit surface to the entire cartilage, thus, significantly improving the speed of reconstruction over the comparable RBF reconstruction method of Carr. The authors compare the CI-RBF method volume estimation to a typical commercial package (3d doctor), Carr's RBF method, and a benchmark manual method for the reconstruction of the femoral, tibial, and patellar cartilages. RESULTS: The authors demonstrate how the CI-RBF method significantly reduces the number of data points (p-value < 0.0001) required for fitting an implicit surface to the cartilage, by 48%, 31%, and 44% for the patellar, tibial, and femoral cartilages, respectively. Thus, significantly improving the speed of reconstruction (p-value < 0.0001) by 39%, 40%, and 44% for the patellar, tibial, and femoral cartilages over the comparable RBF model of Carr providing a near real-time reconstruction of 6.49, 8.88, and 9.43 min for the patellar, tibial, and femoral cartilages, respectively. In addition, it is demonstrated how the CI-RBF method matches the volume estimation of a typical commercial package (3d doctor), Carr's RBF method, and a benchmark manual method for the reconstruction of the femoral, tibial, and patellar cartilages. Furthermore, the performance of the segmentation method used for the extraction of the femoral, tibial, and patellar cartilages is assessed with a Dice similarity coefficient, sensitivity, and specificity measure providing high agreement to manual segmentation. CONCLUSIONS: The CI-RBF method provides a fast, accurate, and robust 3D model reconstruction that matches Carr's RBF method, 3d doctor, and a manual benchmark method in accuracy and significantly improves upon Carr's RBF method in data requirement and computational speed. In addition, the visualization tool has been designed to quickly segment MR images requiring only four mouse clicks per MR image slice. PMID- 26936705 TI - Theoretical substantiation of biological efficacy enhancement for beta-delayed particle decay (9)C beam: A Monte Carlo study in combination with analysis with the local effect model approach. AB - PURPOSE: To improve the efficacy of heavy ion therapy, beta-delayed particle decay (9)C beam as a double irradiation source for cancer therapy has been proposed. The authors' previous experiment showed that relative biological effectiveness (RBE) values at the depths around the Bragg peak of a (9)C beam were enhanced and compared to its stable counterpart (12)C beam. The purpose of this study was to explore the nature of the biological efficacy enhancement theoretically. METHODS: A Monte Carlo simulation study was conducted in this study. First a simplified cell model was established so as to form a tumor tissue. Subsequently, the tumor tissue was imported into the Monte Carlo simulation software package gate and then the tumor cells were virtually irradiated with comparable (9)C and (12)C beams, respectively, in the simulations. The transportation and particle deposition data of the (9)C and (12)C beams, derived from the gate simulations, were analyzed with the authors' local effect model implementation so as to deduce cell survival fractions. RESULTS: The particles emitted from the decay process of deposited (9)C particles around a cell nucleus increased the dose delivered to the nucleus and elicited clustered damages around the secondary particles' trajectories. Therefore, compared to the (12)C beam, the RBE value of the (9)C beam increased at the depths around their Bragg peaks. CONCLUSIONS: Collectively, the increased local doses and clustered damages due to the decayed particles emitted from deposited (9)C particles led to the RBE enhancement in contrast with the (12)C beam. Thus, the enhanced RBE effect of a (9)C beam for a simplified tumor model was shown theoretically in this study. PMID- 26936706 TI - Sample size requirements for knowledge-based treatment planning. AB - PURPOSE: To determine how training set size affects the accuracy of knowledge based treatment planning (KBP) models. METHODS: The authors selected four models from three classes of KBP approaches, corresponding to three distinct quantities that KBP models may predict: dose-volume histogram (DVH) points, DVH curves, and objective function weights. DVH point prediction is done using the best plan from a database of similar clinical plans; DVH curve prediction employs principal component analysis and multiple linear regression; and objective function weights uses either logistic regression or K-nearest neighbors. The authors trained each KBP model using training sets of sizes n = 10, 20, 30, 50, 75, 100, 150, and 200. The authors set aside 100 randomly selected patients from their cohort of 315 prostate cancer patients from Princess Margaret Cancer Center to serve as a validation set for all experiments. For each value of n, the authors randomly selected 100 different training sets with replacement from the remaining 215 patients. Each of the 100 training sets was used to train a model for each value of n and for each KBT approach. To evaluate the models, the authors predicted the KBP endpoints for each of the 100 patients in the validation set. To estimate the minimum required sample size, the authors used statistical testing to determine if the median error for each sample size from 10 to 150 is equal to the median error for the maximum sample size of 200. RESULTS: The minimum required sample size was different for each model. The DVH point prediction method predicts two dose metrics for the bladder and two for the rectum. The authors found that more than 200 samples were required to achieve consistent model predictions for all four metrics. For DVH curve prediction, the authors found that at least 75 samples were needed to accurately predict the bladder DVH, while only 20 samples were needed to predict the rectum DVH. Finally, for objective function weight prediction, at least 10 samples were needed to train the logistic regression model, while at least 150 samples were required to train the K-nearest neighbor methodology. CONCLUSIONS: In conclusion, the minimum required sample size needed to accurately train KBP models for prostate cancer depends on the specific model and endpoint to be predicted. The authors' results may provide a lower bound for more complicated tumor sites. PMID- 26936707 TI - A Bayesian spatial temporal mixtures approach to kinetic parametric images in dynamic positron emission tomography. AB - PURPOSE: Estimation of parametric maps is challenging for kinetic models in dynamic positron emission tomography. Since voxel kinetics tend to be spatially contiguous, the authors consider groups of homogeneous voxels together. The authors propose a novel algorithm to identify the groups and estimate kinetic parameters simultaneously. Uncertainty estimates for kinetic parameters are also obtained. METHODS: Mixture models were used to fit the time activity curves. In order to borrow information from spatially nearby voxels, the Potts model was adopted. A spatial temporal model was built incorporating both spatial and temporal information in the data. Markov chain Monte Carlo was used to carry out parameter estimation. Evaluation and comparisons with existing methods were carried out on cardiac studies using both simulated data sets and a pig study data. One-compartment kinetic modeling was used, in which K1 is the parameter of interest, providing a measure of local perfusion. RESULTS: Based on simulation experiments, the median standard deviation across all image voxels, of K1 estimates were 0, 0.13, and 0.16 for the proposed spatial mixture models (SMMs), standard curve fitting, and spatial K-means methods, respectively. The corresponding median mean squared biases for K1 were 0.04, 0.06, and 0.06 for abnormal region of interest (ROI); 0.03, 0.03, and 0.04 for normal ROI; and 0.007, 0.02, and 0.05 for the noise region. CONCLUSIONS: SMM is a fully Bayesian algorithm which determines the optimal number of homogeneous voxel groups, voxel group membership, parameter estimation, and parameter uncertainty estimation simultaneously. The voxel membership can also be used for classification purposes. By borrowing information from spatially nearby voxels, SMM substantially reduces the variability of parameter estimates. In some ROIs, SMM also reduces mean squared bias. PMID- 26936708 TI - Marker-free motion correction in weight-bearing cone-beam CT of the knee joint. AB - PURPOSE: To allow for a purely image-based motion estimation and compensation in weight-bearing cone-beam computed tomography of the knee joint. METHODS: Weight bearing imaging of the knee joint in a standing position poses additional requirements for the image reconstruction algorithm. In contrast to supine scans, patient motion needs to be estimated and compensated. The authors propose a method that is based on 2D/3D registration of left and right femur and tibia segmented from a prior, motion-free reconstruction acquired in supine position. Each segmented bone is first roughly aligned to the motion-corrupted reconstruction of a scan in standing or squatting position. Subsequently, a rigid 2D/3D registration is performed for each bone to each of K projection images, estimating 6 * 4 * K motion parameters. The motion of individual bones is combined into global motion fields using thin-plate-spline extrapolation. These can be incorporated into a motion-compensated reconstruction in the backprojection step. The authors performed visual and quantitative comparisons between a state-of-the-art marker-based (MB) method and two variants of the proposed method using gradient correlation (GC) and normalized gradient information (NGI) as similarity measure for the 2D/3D registration. RESULTS: The authors evaluated their method on four acquisitions under different squatting positions of the same patient. All methods showed substantial improvement in image quality compared to the uncorrected reconstructions. Compared to NGI and MB, the GC method showed increased streaking artifacts due to misregistrations in lateral projection images. NGI and MB showed comparable image quality at the bone regions. Because the markers are attached to the skin, the MB method performed better at the surface of the legs where the authors observed slight streaking of the NGI and GC methods. For a quantitative evaluation, the authors computed the universal quality index (UQI) for all bone regions with respect to the motion free reconstruction. The authors quantitative evaluation over regions around the bones yielded a mean UQI of 18.4 for no correction, 53.3 and 56.1 for the proposed method using GC and NGI, respectively, and 53.7 for the MB reference approach. In contrast to the authors registration-based corrections, the MB reference method caused slight nonrigid deformations at bone outlines when compared to a motion-free reference scan. CONCLUSIONS: The authors showed that their method based on the NGI similarity measure yields reconstruction quality close to the MB reference method. In contrast to the MB method, the proposed method does not require any preparation prior to the examination which will improve the clinical workflow and patient comfort. Further, the authors found that the MB method causes small, nonrigid deformations at the bone outline which indicates that markers may not accurately reflect the internal motion close to the knee joint. Therefore, the authors believe that the proposed method is a promising alternative to MB motion management. PMID- 26936709 TI - Quantifying masking in clinical mammograms via local detectability of simulated lesions. AB - PURPOSE: High mammographic density is known to be associated with decreased sensitivity of mammography. Recent changes in the BI-RADS density assessment address the effect of masking by densities, but the BI-RADS assessment remains qualitative and achieves only moderate agreement between radiologists. An automated, quantitative algorithm that estimates the likelihood of masking of simulated masses in a mammogram by dense tissue has been developed. The algorithm considers both the effects of loss of contrast due to density and the distracting texture or appearance of dense tissue. METHODS: A local detectability (dL) map is created by tessellating the mammograms into overlapping regions of interest (ROIs), for which the detectability by a non-prewhitening observer is computed using local estimates of the noise power spectrum and volumetric breast density (VBD). The dL calculation was validated in a 4-alternative forced-choice observer study on the ROIs of 150 craniocaudal digital mammograms. The dL metric was compared against the inverse threshold contrast, (DeltaMUT)(-1) from the observer study, the anatomic noise parameter beta, the radiologist's BI-RADS density category, and a validated measure of VBD (Cumulus). RESULTS: The mean dL had a high correlation of r = 0.915 and r = 0.699 with (DeltaMUT)(-1) in the computerized and human observer study, respectively. In comparison, the local VBD estimate had a low correlation of 0.538 with (DeltaMUT)(-1). The mean dL had a correlation of 0.663, 0.835, and 0.696 with BI-RADS density, beta, and Cumulus VBD, respectively. CONCLUSIONS: The proposed dL metric may be useful in characterizing the potential for lesion masking by dense tissue. Because it uses information about the anatomic noise or tissue appearance, it is more closely linked to lesion detectability than VBD metrics. PMID- 26936710 TI - Technical Note: Compact three-tesla magnetic resonance imager with high performance gradients passes ACR image quality and acoustic noise tests. AB - PURPOSE: A compact, three-tesla magnetic resonance imaging (MRI) system has been developed. It features a 37 cm patient aperture, allowing the use of commercial receiver coils. Its design allows simultaneously for gradient amplitudes of 85 millitesla per meter (mT/m) sustained and 700 tesla per meter per second (T/m/s) slew rates. The size of the gradient system allows for these simultaneous performance targets to be achieved with little or no peripheral nerve stimulation, but also raises a concern about the geometric distortion as much of the imaging will be done near the system's maximum 26 cm field-of-view. Additionally, the fast switching capability raises acoustic noise concerns. This work evaluates the system for both the American College of Radiology's (ACR) MRI image quality protocol and the Food and Drug Administration's (FDA) nonsignificant risk (NSR) acoustic noise limits for MR. Passing these two tests is critical for clinical acceptance. METHODS: In this work, the gradient system was operated at the maximum amplitude and slew rate of 80 mT/m and 500 T/m/s, respectively. The geometric distortion correction was accomplished by iteratively determining up to the tenth order spherical harmonic coefficients using a fiducial phantom and position-tracking software, with seventh order correction utilized in the ACR test. Acoustic noise was measured with several standard clinical pulse sequences. RESULTS: The system passes all the ACR image quality tests. The acoustic noise as measured when the gradient coil was inserted into a whole-body MRI system conforms to the FDA NSR limits. CONCLUSIONS: The compact system simultaneously allows for high gradient amplitude and high slew rate. Geometric distortion concerns have been mitigated by extending the spherical harmonic correction to higher orders. Acoustic noise is within the FDA limits. PMID- 26936711 TI - Effect of reconstruction methods and x-ray tube current-time product on nodule detection in an anthropomorphic thorax phantom: A crossed-modality JAFROC observer study. AB - PURPOSE: To evaluate nodule detection in an anthropomorphic chest phantom in computed tomography (CT) images reconstructed with adaptive iterative dose reduction 3D (AIDR(3D)) and filtered back projection (FBP) over a range of tube current-time product (mAs). METHODS: Two phantoms were used in this study: (i) an anthropomorphic chest phantom was loaded with spherical simulated nodules of 5, 8, 10, and 12 mm in diameter and +100, -630, and -800 Hounsfield units electron density; this would generate CT images for the observer study; (ii) a whole-body dosimetry verification phantom was used to ultimately estimate effective dose and risk according to the model of the BEIR VII committee. Both phantoms were scanned over a mAs range (10, 20, 30, and 40), while all other acquisition parameters remained constant. Images were reconstructed with both AIDR(3D) and FBP. For the observer study, 34 normal cases (no nodules) and 34 abnormal cases (containing 1 3 nodules, mean 1.35 +/- 0.54) were chosen. Eleven observers evaluated images from all mAs and reconstruction methods under the free-response paradigm. A crossed-modality jackknife alternative free-response operating characteristic (JAFROC) analysis method was developed for data analysis, averaging data over the two factors influencing nodule detection in this study: mAs and image reconstruction (AIDR(3D) or FBP). A Bonferroni correction was applied and the threshold for declaring significance was set at 0.025 to maintain the overall probability of Type I error at alpha = 0.05. Contrast-to-noise (CNR) was also measured for all nodules and evaluated by a linear least squares analysis. RESULTS: For random-reader fixed-case crossed-modality JAFROC analysis, there was no significant difference in nodule detection between AIDR(3D) and FBP when data were averaged over mAs [F(1, 10) = 0.08, p = 0.789]. However, when data were averaged over reconstruction methods, a significant difference was seen between multiple pairs of mAs settings [F(3, 30) = 15.96, p < 0.001]. Measurements of effective dose and effective risk showed the expected linear dependence on mAs. Nodule CNR was statistically higher for simulated nodules on images reconstructed with AIDR(3D) (p < 0.001). CONCLUSIONS: No significant difference in nodule detection performance was demonstrated between images reconstructed with FBP and AIDR(3D). mAs was found to influence nodule detection, though further work is required for dose optimization. PMID- 26936712 TI - Tumor radio-sensitivity assessment by means of volume data and magnetic resonance indices measured on prostate tumor bearing rats. AB - PURPOSE: Radiation therapy is one of the most common treatments in the fight against prostate cancer, since it is used to control the tumor (early stages), to slow its progression, and even to control pain (metastasis). Although many factors (e.g., tumor oxygenation) are known to influence treatment efficacy, radiotherapy doses and fractionation schedules are often prescribed according to the principle "one-fits-all," with little personalization. Therefore, the authors aim at predicting the outcome of radiation therapy a priori starting from morphologic and functional information to move a step forward in the treatment customization. METHODS: The authors propose a two-step protocol to predict the effects of radiation therapy on individual basis. First, one macroscopic mathematical model of tumor evolution was trained on tumor volume progression, measured by caliper, of eighteen Dunning R3327-AT1 bearing rats. Nine rats inhaled 100% O2 during irradiation (oxy), while the others were allowed to breathe air. Second, a supervised learning of the weight and biases of two feedforward neural networks was performed to predict the radio-sensitivity (target) from the initial volume and oxygenation-related information (inputs) for each rat group (air and oxygen breathing). To this purpose, four MRI-based indices related to blood and tissue oxygenation were computed, namely, the variation of signal intensity DeltaSI in interleaved blood oxygen level dependent and tissue oxygen level dependent (IBT) sequences as well as changes in longitudinal DeltaR1 and transverse DeltaR2(*) relaxation rates. RESULTS: An inverse correlation of the radio-sensitivity parameter, assessed by the model, was found with respect the DeltaR2(*) (-0.65) for the oxy group. A further subdivision according to positive and negative values of DeltaR2(*) showed a larger average radio-sensitivity for the oxy rats with DeltaR2(*)<0 and a significant difference in the two distributions (p < 0.05). Finally, a leave-one out procedure yielded a radio-sensitivity error lower than 20% in both neural networks. CONCLUSIONS: While preliminary, these specific results suggest that subjects affected by the same pathology can benefit differently from the same irradiation modalities and support the usefulness of IBT in discriminating between different responses. PMID- 26936714 TI - A Fourier approach to pulse pile-up in photon-counting x-ray detectors. AB - PURPOSE: An analytic Fourier approach to predict the expected number of counts registered in a photon-counting detector subject to pulse pile-up for arbitrary photon flux, detector response function, and pulse-shape is presented. The analysis provides a complete forward model for energy-sensitive, photon-counting x-ray detectors for spectral computed tomography. METHODS: The formalism of the stochastic theory of the expected frequency of level crossings of shot noise processes is applied to the pulse pile-up effect and build on a recently published analytic Fourier representation of the level crossing frequency of shot noise processes with piece-wise continuous kernels with jumps. RESULTS: The general analytic result is validated by a Monte Carlo simulation for pulses of the form g(t) = e(-t/tau) (t > 0) and a Gaussian detector response function. The Monte Carlo simulations are in excellent agreement with the analytic predictions of photon counts within the numerical accuracy of the calculations. CONCLUSIONS: The phenomenon of pulse pile-up is identified with the level-crossing problem of shot noise processes and an exact, analytic formula for the expected number of counts in energy-sensitive, photon-counting x-ray detectors for arbitrary photon flux, response function, and pulse-shapes is derived. The framework serves as a theoretical foundation for future works on pulse pile-up. PMID- 26936713 TI - A novel electron accelerator for MRI-Linac radiotherapy. AB - PURPOSE: MRI guided radiotherapy is a rapidly growing field; however, current electron accelerators are not designed to operate in the magnetic fringe fields of MRI scanners. As such, current MRI-Linac systems require magnetic shielding, which can degrade MR image quality and limit system flexibility. The purpose of this work was to develop and test a novel medical electron accelerator concept which is inherently robust to operation within magnetic fields for in-line MRI Linac systems. METHODS: Computational simulations were utilized to model the accelerator, including the thermionic emission process, the electromagnetic fields within the accelerating structure, and resulting particle trajectories through these fields. The spatial and energy characteristics of the electron beam were quantified at the accelerator target and compared to published data for conventional accelerators. The model was then coupled to the fields from a simulated 1 T superconducting magnet and solved for cathode to isocenter distances between 1.0 and 2.4 m; the impact on the electron beam was quantified. RESULTS: For the zero field solution, the average current at the target was 146.3 mA, with a median energy of 5.8 MeV (interquartile spread of 0.1 MeV), and a spot size diameter of 1.5 mm full-width-tenth-maximum. Such an electron beam is suitable for therapy, comparing favorably to published data for conventional systems. The simulated accelerator showed increased robustness to operation in in line magnetic fields, with a maximum current loss of 3% compared to 85% for a conventional system in the same magnetic fields. CONCLUSIONS: Computational simulations suggest that replacing conventional DC electron sources with a RF based source could be used to develop medical electron accelerators which are robust to operation in in-line magnetic fields. This would enable the development of MRI-Linac systems with no magnetic shielding around the Linac and reduce the requirements for optimization of magnetic fringe field, simplify design of the high-field magnet, and increase system flexibility. PMID- 26936715 TI - Systematic feasibility analysis of a quantitative elasticity estimation for breast anatomy using supine/prone patient postures. AB - PURPOSE: Breast elastography is a critical tool for improving the targeted radiotherapy treatment of breast tumors. Current breast radiotherapy imaging protocols only involve prone and supine CT scans. There is a lack of knowledge on the quantitative accuracy with which breast elasticity can be systematically measured using only prone and supine CT datasets. The purpose of this paper is to describe a quantitative elasticity estimation technique for breast anatomy using only these supine/prone patient postures. Using biomechanical, high-resolution breast geometry obtained from CT scans, a systematic assessment was performed in order to determine the feasibility of this methodology for clinically relevant elasticity distributions. METHODS: A model-guided inverse analysis approach is presented in this paper. A graphics processing unit (GPU)-based linear elastic biomechanical model was employed as a forward model for the inverse analysis with the breast geometry in a prone position. The elasticity estimation was performed using a gradient-based iterative optimization scheme and a fast-simulated annealing (FSA) algorithm. Numerical studies were conducted to systematically analyze the feasibility of elasticity estimation. For simulating gravity-induced breast deformation, the breast geometry was anchored at its base, resembling the chest-wall/breast tissue interface. Ground-truth elasticity distributions were assigned to the model, representing tumor presence within breast tissue. Model geometry resolution was varied to estimate its influence on convergence of the system. A priori information was approximated and utilized to record the effect on time and accuracy of convergence. The role of the FSA process was also recorded. A novel error metric that combined elasticity and displacement error was used to quantify the systematic feasibility study. For the authors' purposes, convergence was set to be obtained when each voxel of tissue was within 1 mm of ground-truth deformation. RESULTS: The authors' analyses showed that a ~97% model convergence was systematically observed with no-a priori information. Varying the model geometry resolution showed no significant accuracy improvements. The GPU based forward model enabled the inverse analysis to be completed within 10-70 min. Using a priori information about the underlying anatomy, the computation time decreased by as much as 50%, while accuracy improved from 96.81% to 98.26%. The use of FSA was observed to allow the iterative estimation methodology to converge more precisely. CONCLUSIONS: By utilizing a forward iterative approach to solve the inverse elasticity problem, this work indicates the feasibility and potential of the fast reconstruction of breast tissue elasticity using supine/prone patient postures. PMID- 26936716 TI - Airway tree reconstruction in expiration chest CT scans facilitated by information transfer from corresponding inspiration scans. AB - PURPOSE: Analysis and comparison of airways imaged in pairs of inspiration and expiration lung CT scans provides important information for quantitative assessment of lung diseases like chronic obstructive pulmonary disease. However, airway tree reconstruction in expiration CT scans is a challenging problem. Typically, only a low number of airway branches are found in expiration scans, compared to inspiration scans. To detect more airways in expiration CT scans, the authors introduce a novel airway reconstruction approach and assess its performance. METHODS: The method requires a pair of inspiration and expiration CT scans and utilizes information from the inspiration scan to facilitate reconstructing the airway tree in the expiration lung CT scan. First, an initial airway tree (high confidence) and airway candidates (limited confidence) are reconstructed in the expiration scan by utilizing a 3D graph-based reconstruction method. Then, the 3D airway tree is reconstructed in the inspiration scan. Second, correspondences between expiration and inspiration tree structures are identified by utilizing a novel hierarchical tree matching algorithm that utilizes a local CT image-based similarity criterion. Third, the tree information from the inspiration airway tree is used to select expiration candidates, resulting in the final expiration tree structure. The approach was evaluated on a diverse set of 40 scan pairs and compared to the baseline method, which utilizes only the expiration CT scan. RESULTS: The proposed method produced a significant (p < 0.05) increase in airway tree length by 13.35 cm, on average, which represents an 11.21% increase relative to the baseline result using only the expiration CT scan. A detailed analysis of all additionally identified airways resulted in a true and false positive rate of 94.8% and 5.2%, respectively. The true positive rate was found to be significantly higher than the false positive rate (p < 0.05). CONCLUSIONS: The proposed method allowed increasing the number of found airways in expiration scans significantly. In addition, the algorithm establishes correspondence between inspiration and expiration airway trees, which can facilitate label transfer between airway trees and quantitative assessment of change in airways. The approach can be adapted to facilitate airway reconstruction in several longitudinal lung CT scans by means of mutual information transfer. PMID- 26936717 TI - 4D interventional device reconstruction from biplane fluoroscopy. AB - PURPOSE: Biplane angiography systems provide time resolved 2D fluoroscopic images from two different angles, which can be used for the positioning of interventional devices such as guidewires and catheters. The purpose of this work is to provide a novel algorithm framework, which allows the 3D reconstruction of these curvilinear devices from the 2D projection images for each time frame. This would allow creating virtual projection images from arbitrary view angles without changing the position of the gantries, as well as virtual endoscopic 3D renderings. METHODS: The first frame of each time sequence is registered to and subtracted from the following frame using an elastic grid registration technique. The images are then preprocessed by a noise reduction algorithm using directional adaptive filter kernels and a ridgeness filter that emphasizes curvilinear structures. A threshold based segmentation of the device is then performed, followed by a flux driven topology preserving thinning algorithm to extract the segments of the device centerline. The exact device path is determined using Dijkstra's algorithm to minimize the curvature and distance between adjacent segments as well as the difference to the device path of the previous frame. The 3D device centerline is then reconstructed using epipolar geometry. RESULTS: The accuracy of the reconstruction was measured in a vascular head phantom as well as in a cadaver head and a canine study. The device reconstructions are compared to rotational 3D acquisitions. In the phantom experiments, an average device tip accuracy of 0.35 +/- 0.09 mm, a Hausdorff distance of 0.65 +/- 0.32 mm, and a mean device distance of 0.54 +/- 0.33 mm were achieved. In the cadaver head and canine experiments, the device tip was reconstructed with an average accuracy of 0.26 +/- 0.20 mm, a Hausdorff distance of 0.62 +/- 0.08 mm, and a mean device distance of 0.41 +/- 0.08 mm. Additionally, retrospective reconstruction results of real patient data are presented. CONCLUSIONS: The presented algorithm is a novel approach for the time resolved 3D reconstruction of interventional devices from biplane fluoroscopic images, thus allowing the creation of virtual projection images from arbitrary view angles as well as virtual endoscopic 3D renderings. Availability of this technique would enhance the ability to accurately position devices in minimally invasive endovascular procedures. PMID- 26936718 TI - Dynamic fractal signature dissimilarity analysis for therapeutic response assessment using dynamic contrast-enhanced MRI. AB - PURPOSE: To develop a dynamic fractal signature dissimilarity (FSD) method as a novel image texture analysis technique for the quantification of tumor heterogeneity information for better therapeutic response assessment with dynamic contrast-enhanced (DCE)-MRI. METHODS: A small animal antiangiogenesis drug treatment experiment was used to demonstrate the proposed method. Sixteen LS-174T implanted mice were randomly assigned into treatment and control groups (n = 8/group). All mice received bevacizumab (treatment) or saline (control) three times in two weeks, and one pretreatment and two post-treatment DCE-MRI scans were performed. In the proposed dynamic FSD method, a dynamic FSD curve was generated to characterize the heterogeneity evolution during the contrast agent uptake, and the area under FSD curve (AUCFSD) and the maximum enhancement (MEFSD) were selected as representative parameters. As for comparison, the pharmacokinetic parameter K(trans) map and area under MR intensity enhancement curve AUCMR map were calculated. Besides the tumor's mean value and coefficient of variation, the kurtosis, skewness, and classic Renyi dimensions d1 and d2 of K(trans) and AUCMR maps were evaluated for heterogeneity assessment for comparison. For post-treatment scans, the Mann-Whitney U-test was used to assess the differences of the investigated parameters between treatment/control groups. The support vector machine (SVM) was applied to classify treatment/control groups using the investigated parameters at each post-treatment scan day. RESULTS: The tumor mean K(trans) and its heterogeneity measurements d1 and d2 values showed significant differences between treatment/control groups in the second post treatment scan. In contrast, the relative values (in reference to the pretreatment value) of AUCFSD and MEFSD in both post-treatment scans showed significant differences between treatment/control groups. When using AUCFSD and MEFSD as SVM input for treatment/control classification, the achieved accuracies were 93.8% and 93.8% at first and second post-treatment scan days, respectively. In comparison, the classification accuracies using d1 and d2 of K(trans) map were 87.5% and 100% at first and second post-treatment scan days, respectively. CONCLUSIONS: As quantitative metrics of tumor contrast agent uptake heterogeneity, the selected parameters from the dynamic FSD method accurately captured the therapeutic response in the experiment. The potential application of the proposed method is promising, and its addition to the existing DCE-MRI techniques could improve DCE-MRI performance in early assessment of treatment response. PMID- 26936719 TI - Characterization of optical-surface-imaging-based spirometry for respiratory surrogating in radiotherapy. AB - PURPOSE: To provide a comprehensive characterization of a novel respiratory surrogate that uses optical surface imaging (OSI) for accurate tidal volume (TV) measurement, dynamic airflow (TV') calculation, and quantitative breathing pattern (BP) estimation during free breathing (FB), belly breathing (BB), chest breathing (CB), and breath hold (BH). METHODS: Optical surface imaging, which captures all respiration-induced torso surface motion, was applied to measure respiratory TV, TV', and BP in three common breathing patterns. Eleven healthy volunteers participated in breathing experiments with concurrent OSI-based and conventional spirometric measurements under an institutional review board approved protocol. This OSI-based technique measures dynamic TV from torso volume change (DeltaVtorso = TV) in reference to full exhalation and airflow (TV' = dTV/dt). Volume conservation, excluding exchanging air, was applied for OSI-based measurements under negligible pleural pressure variation in FB, BB, and CB. To demonstrate volume conservation, a constant TV was measured during BH while the chest and belly are moving ("pretended" respiration). To assess the accuracy of OSI-based spirometry, a conventional spirometer was used as the standard for both TV and TV'. Using OSI, BP was measured as BP(OSI) = DeltaVchest/DeltaVtorso and BP can be visualized using BP(SHI) = SHIchest/(SHIchest + SHIbelly), where surface height index (SHI) is defined as the mean vertical distance within a region of interest on the torso surface. A software tool was developed for OSI image processing, volume calculation, and BP visualization, and another tool was implemented for data acquisition using a Bernoulli-type spirometer. RESULTS: The accuracy of the OSI-based spirometry is -21 +/- 33 cm(3) or -3.5% +/- 6.3% averaged from 11 volunteers with 76 +/- 28 breathing cycles on average in FB. Breathing variations between two separate acquisitions with approximate 30-min intervals are substantial: -1% +/- 34% (ranging from -64% to 40%) in TV, 4% +/- 20% (ranging from -50% to 26%) in breathing period (T), and -1% +/- 34% (ranging from -49% to 44%) in BP. The airflow accuracy and variation (between two exercises) are -1 +/- 54 cm(3)/s and -5% +/- 30%, respectively. The slope of linear regression between OSI-TV and spirometric TV is 0.93 (R(2) = 0.95) for FB, 0.96 (R(2) = 0.98) for BB, and 0.95 (R(2) = 0.95) for CB. The correlation between the two spirometric measurements is 0.98 +/- 0.01. BP increases from BB, FB to CB, while TV increases from FB, BB, to CB. Under BH, 4% volume variation (range) on average was observed. CONCLUSIONS: The OSI-based technique provides an accurate measurement of tidal volume, airflow rate, and breathing pattern; all affect internal organ motion. This technique can be applied to various breathing patterns, including FB, BB, and CB. Substantial breathing irregularities and irreproducibility were observed and quantified with the OSI-based technique. These breathing parameters are useful to quantify breathing conditions, which could be used for effective tumor motion predictions. PMID- 26936720 TI - A limit on dose reduction possible with CT reconstruction algorithms without prior knowledge of the scan subject. AB - PURPOSE: To find an upper bound on the maximum dose reduction possible for any reconstruction algorithm, analytic or iterative, that result from the inclusion of the data statistics. The authors do not analyze noise reduction possible from prior knowledge or assumptions about the object. METHODS: The authors examined the task of estimating the density of a circular lesion in a cross section. Raw data were simulated by forward projection of existing images and numerical phantoms. To assess an upper bound on the achievable dose reduction by any algorithm, the authors assume that both the background and the shape of the lesion are completely known. Under these conditions, the best possible estimate of the density can be determined by solving a weighted least squares problem directly in the raw data domain. Any possible reconstruction algorithm that does not use prior knowledge or make assumptions about the object, including filtered backprojection (FBP) or iterative reconstruction methods with this constraint, must be no better than this least squares solution. The authors simulated 10,000 sets of noisy data and compared the variance in density from the least squares solution with those from FBP. Density was estimated from FBP images using either averaging within a ROI, or streak-adaptive averaging with better noise performance. RESULTS: The bound on the possible dose reduction depends on the degree to which the observer can read through the possibly streaky noise. For the described low contrast detection task with the signal shape and background known exactly, the average dose reduction possible compared to FBP with streak-adaptive averaging was 42% and it was 64% if only the ROI average is used with FBP. The exact amount of dose reduction also depends on the background anatomy, with statistically inhomogeneous backgrounds showing greater benefits. CONCLUSIONS: The dose reductions from new, statistical reconstruction methods can be bounded. Larger dose reductions in the density estimation task studied here are only possible with the introduction of prior knowledge, which can introduce bias. PMID- 26936721 TI - Longitudinal diffusion MRI for treatment response assessment: Preliminary experience using an MRI-guided tri-cobalt 60 radiotherapy system. AB - PURPOSE: To demonstrate the preliminary feasibility of a longitudinal diffusion magnetic resonance imaging (MRI) strategy for assessing patient response to radiotherapy at 0.35 T using an MRI-guided radiotherapy system (ViewRay). METHODS: Six patients (three head and neck cancer, three sarcoma) who underwent fractionated radiotherapy were enrolled in this study. A 2D multislice spin echo single-shot echo planar imaging diffusion pulse sequence was implemented on the ViewRay system and tested in phantom studies. The same pulse sequence was used to acquire longitudinal diffusion data (every 2-5 fractions) on the six patients throughout the entire course of radiotherapy. The reproducibility of the apparent diffusion coefficient (ADC) measurements was assessed using reference regions and the temporal variations of the tumor ADC values were evaluated. RESULTS: In diffusion phantom studies, the ADC values measured on the ViewRay system matched well with reference ADC values with <5% error for a range of ground truth diffusion coefficients of 0.4-1.1 * 10(-3) mm(2)/s. The remote reference regions (i.e., brainstem in head and neck patients) had consistent ADC values throughout the therapy for all three head and neck patients, indicating acceptable reproducibility of the diffusion imaging sequence. The tumor ADC values changed throughout therapy, with the change differing between patients, ranging from a 40% drop in ADC within the first week of therapy to gradually increasing throughout therapy. For larger tumors, intratumoral heterogeneity was observed. For one sarcoma patient, postradiotherapy biopsy showed less than 10% necrosis score, which correlated with the observed 40% decrease in ADC from the fifth fraction to the eighth treatment fraction. CONCLUSIONS: This pilot study demonstrated that longitudinal diffusion MRI is feasible using the 0.35 T ViewRay MRI. Larger patient cohort studies are warranted to correlate the longitudinal diffusion measurements to patient outcomes. Such an approach may enable response guided adaptive radiotherapy. PMID- 26936723 TI - Photon counting x-ray imaging with K-edge filtered x-rays: A simulation study. AB - PURPOSE: In photon counting (PC) x-ray imaging and computed tomography (CT), the broad x-ray spectrum can be split into two parts using an x-ray filter with appropriate K-edge energy, which can improve material decomposition. Recent experimental study has demonstrated substantial improvement in material decomposition with PC CT when K-edge filtered x-rays were used. The purpose of the current work was to conduct further investigations of the K-edge filtration method using comprehensive simulation studies. METHODS: The study was performed in the following aspects: (1) optimization of the K-edge filter for a particular imaging configuration, (2) effects of the K-edge filter parameters on material decomposition, (3) trade-off between the energy bin separation, tube load, and beam quality with K-edge filter, (4) image quality of general (unsubtracted) images when a K-edge filter is used to improve dual energy (DE) subtracted images, and (5) improvements with K-edge filtered x-rays when PC detector has limited energy resolution. The PC x-ray images of soft tissue phantoms with 15 and 30 cm thicknesses including iodine, CaCO3, and soft tissue contrast materials, were simulated. The signal to noise ratio (SNR) of the contrast elements was determined in general and material-decomposed images using K-edge filters with different atomic numbers and thicknesses. The effect of the filter atomic number and filter thickness on energy separation factor and SNR was determined. The boundary conditions for the tube load and halfvalue layer were determined when the K-edge filters are used. The material-decomposed images were also simulated using PC detector with limited energy resolution, and improvements with K-edge filtered x-rays were quantified. RESULTS: The K-edge filters with atomic numbers from 56 to 71 and K-edge energies 37.4-63.4 keV, respectively, can be used for tube voltages from 60 to 150 kVp, respectively. For a particular tube voltage of 120 kVp, the Gd and Ho were the optimal filter materials to achieve highest SNR. For a particular K-edge filter of Gd and tube voltage of 120 kVp, the filter thickness 0.6 mm provided maximum SNR for considered imaging applications. While K-edge filtration improved SNR of CaCO3 and iodine by 41% and 36%, respectively, in DE subtracted images, it did not deteriorate SNR in general images. For x-ray imaging with nonideal PC detector, the positive effect of the K edge filter was increased when FWHM energy resolution was degraded, and maximum improvement was at 60% FWHM. CONCLUSIONS: This study has shown that K-edge filtered x-rays can provide substantial improvements of material selective PC x ray and CT imaging for nearly all imaging applications using 60-150 kVp tube voltages. Potential limitations such as tube load, beam hardening, and availability of filter material were shown to not be critical. PMID- 26936722 TI - Phase aberration simulation study of MRgFUS breast treatments. AB - PURPOSE: This simulation study evaluates the effects of phase aberration in breast MR-guided focused ultrasound (MRgFUS) ablation treatments performed with a phased-array transducer positioned laterally to the breast. A quantification of these effects in terms of thermal dose delivery and the potential benefits of phase correction is demonstrated in four heterogeneous breast numerical models. METHODS: To evaluate the effects of varying breast tissue properties on the quality of the focus, four female volunteers with confirmed benign fibroadenomas were imaged using 3T MRI. These images were segmented into numerical models with six tissue types, with each tissue type assigned standard acoustic properties from the literature. Simulations for a single-plane 16-point raster-scan treatment trajectory centered in a fibroadenoma in each modeled breast were performed for a breast-specific MRgFUS system. At each of the 16 points, pressure patterns both with and without applying a phase correction technique were determined with the hybrid-angular spectrum method. Corrected phase patterns were obtained using a simulation-based phase aberration correction technique to adjust each element's transmit phase to obtain maximized constructive interference at the desired focus. Thermal simulations were performed for both the corrected and uncorrected pressure patterns using a finite-difference implementation of the Pennes bioheat equation. The effect of phase correction was evaluated through comparison of thermal dose accumulation both within and outside a defined treatment volume. Treatment results using corrected and uncorrected phase aberration simulations were compared by evaluating the power required to achieve a 20 degrees C temperature rise at the first treatment location. The extent of the volumes that received a minimum thermal dose of 240 CEM at 43 degrees C inside the intended treatment volume as well as the volume in the remaining breast tissues was also evaluated in the form of a dose volume ratio (DVR), a DVR percent change between corrected and uncorrected phases, and an additional metric that measured phase spread. RESULTS: With phase aberration correction applied, there was an improvement in the focus for all breast anatomies as quantified by a reduction in power required (13%-102%) to reach 20 degrees C when compared to uncorrected simulations. Also, the DVR percent change increased by 5%-77% in seven out of eight cases, indicating an improvement to the treatment as measured by a reduction in thermal dose deposited to the nontreatment tissues. Breast compositions with a higher degree of heterogeneity along the ultrasound beam path showed greater reductions in thermal dose delivered outside of the treatment volume with correction applied than beam trajectories that propagated through more homogeneous breast compositions. An increasing linear trend was observed between the DVR percent change and the phase-spread metric (R(2) = 0.68). CONCLUSIONS: These results indicate that performing phase aberration correction for breast MRgFUS treatments is beneficial for the small-aperture transducer (14.4 * 9.8 cm) evaluated in this work. While all breast anatomies could benefit from phase aberration correction, greater benefits are observed in more heterogeneous anatomies. PMID- 26936724 TI - Performance evaluation of a high-speed multileaf collimator in real-time IMRT delivery to moving targets. AB - PURPOSE: Multileaf collimator (MLC) tracking can be used for motion management. However, on account of mechanical constraints, it is a crucial challenge for conventional MLCs (3-4 cm/s in leaf speed) to track fast targets, especially moving in 2D in the beam's eye view (BEV). Our group has recently developed a "high-speed" MLC (HS-MLC) prototype with a maximum leaf speed of 40 cm/s, which makes it possible to track the vast majority of moving targets without violation of mechanical constraints. The major innovation of the HS-MLC design is that it employs linear motors instead of rotary motors to drive leaves. This paper mainly aims to evaluate the performance of the HS-MLC in real-time intensity-modulated radiation therapy delivery to targets moving in 2D in the BEV. METHODS: A 2D real time tracking algorithm was proposed first based on a previous superimposing leaf sequencing method. Then, simulations were performed to evaluate the delivery performance including fluence accuracy, efficiency, delivery time, and number of monitor units under various settings of limiting coefficient and dose rate for four clinical fluence maps and two target speeds. The comparisons between the HS MLC with a "medium-speed" MLC (MS-MLC, 10 cm/s) and a "low-speed" MLC (LS-MLC, 5 cm/s) were also made. For validation, experiments were carried out on the HS-MLC prototype in the lab environment. A camera-based measurement system was set up to detect actual leaf trajectories. RESULTS: Simulation results indicate that a limiting coefficient of 0.5 and a dose rate of 400 MU/min are "optimal" in the sense of getting best compromise between delivery time and number of monitor units. Under the optimal parameters, the HS-MLC achieved 100% in efficiency, 18.1 s in delivery time, and 121.2 MU in number of monitor units on average for the "fast" target speed, compared to 94%, 20.6 s, and 129.9 MU with the MS-MLC, and to 53%, 40.2 s, and 141.1 MU with the LS-MLC. The benefits of increased leaf speed were demonstrated. The experimental results agreed with the simulation ones, which further confirmed the efficacy of the HS-MLC. CONCLUSIONS: The HS-MLC is superior to conventional MLCs when used for tracking, benefiting from its high leaf speed. These results indicate that the novel HS-MLC is feasible for high accuracy and high-efficiency motion management. It also offers guidance for future MLC design. PMID- 26936725 TI - Technical Note: FreeCT_wFBP: A robust, efficient, open-source implementation of weighted filtered backprojection for helical, fan-beam CT. AB - PURPOSE: With growing interest in quantitative imaging, radiomics, and CAD using CT imaging, the need to explore the impacts of acquisition and reconstruction parameters has grown. This usually requires extensive access to the scanner on which the data were acquired and its workflow is not designed for large-scale reconstruction projects. Therefore, the authors have developed a freely available, open-source software package implementing a common reconstruction method, weighted filtered backprojection (wFBP), for helical fan-beam CT applications. METHODS: FreeCT_wFBP is a low-dependency, GPU-based reconstruction program utilizing c for the host code and Nvidia CUDA C for GPU code. The software is capable of reconstructing helical scans acquired with arbitrary pitch values, and sampling techniques such as flying focal spots and a quarter-detector offset. In this work, the software has been described and evaluated for reconstruction speed, image quality, and accuracy. Speed was evaluated based on acquisitions of the ACR CT accreditation phantom under four different flying focal spot configurations. Image quality was assessed using the same phantom by evaluating CT number accuracy, uniformity, and contrast to noise ratio (CNR). Finally, reconstructed mass-attenuation coefficient accuracy was evaluated using a simulated scan of a FORBILD thorax phantom and comparing reconstructed values to the known phantom values. RESULTS: The average reconstruction time evaluated under all flying focal spot configurations was found to be 17.4 +/- 1.0 s for a 512 row * 512 column * 32 slice volume. Reconstructions of the ACR phantom were found to meet all CT Accreditation Program criteria including CT number, CNR, and uniformity tests. Finally, reconstructed mass-attenuation coefficient values of water within the FORBILD thorax phantom agreed with original phantom values to within 0.0001 mm(2)/g (0.01%). CONCLUSIONS: FreeCT_wFBP is a fast, highly configurable reconstruction package for third-generation CT available under the GNU GPL. It shows good performance with both clinical and simulated data. PMID- 26936726 TI - Toward improved target conformity for two spot scanning proton therapy delivery systems using dynamic collimation. AB - PURPOSE: To quantify improvement in target conformity in brain and head and neck tumor treatments resulting from the use of a dynamic collimation system (DCS) with two spot scanning proton therapy delivery systems (universal nozzle, UN, and dedicated nozzle, DN) with median spot sizes of 5.2 and 3.2 mm over a range of energies from 100 to 230 MeV. METHODS: Uncollimated and collimated plans were calculated with both UN and DN beam models implemented within our in-house treatment planning system for five brain and ten head and neck datasets in patients previously treated with spot scanning proton therapy. The prescription dose and beam angles from the clinical plans were used for both the UN and DN plans. The average reduction of the mean dose to the 10-mm ring surrounding the target between the uncollimated and collimated plans was calculated for the UN and the DN. Target conformity was analyzed using the mean dose to 1-mm thickness rings surrounding the target at increasing distances ranging from 1 to 10 mm. RESULTS: The average reductions of the 10-mm ring mean dose for the UN and DN plans were 13.7% (95% CI: 11.6%-15.7%; p < 0.0001) and 11.5% (95% CI: 9.5%-13.5%; p < 0.0001) across all brain cases and 7.1% (95% CI: 4.4%-9.8%; p < 0.001) and 6.3% (95% CI: 3.7%-9.0%; p < 0.001), respectively, across all head and neck cases. The collimated UN plans were either more conformal (all brain cases and 60% of the head and neck cases) than or equivalent (40% of the head and neck cases) to the uncollimated DN plans. The collimated DN plans offered the highest conformity. CONCLUSIONS: The DCS added either to the UN or DN improved the target conformity. The DCS may be of particular interest for sites with UN systems looking for a more economical solution than upgrading the nozzle to improve the target conformity of their spot scanning proton therapy system. PMID- 26936727 TI - A new computer aided diagnosis system for evaluation of chronic liver disease with ultrasound shear wave elastography imaging. AB - PURPOSE: Classify chronic liver disease (CLD) from ultrasound shear-wave elastography (SWE) imaging by means of a computer aided diagnosis (CAD) system. METHODS: The proposed algorithm employs an inverse mapping technique (red-green blue to stiffness) to quantify 85 SWE images (54 healthy and 31 with CLD). Texture analysis is then applied involving the automatic calculation of 330 first and second order textural features from every transformed stiffness value map to determine functional features that characterize liver elasticity and describe liver condition for all available stages. Consequently, a stepwise regression analysis feature selection procedure is utilized toward a reduced feature subset that is fed into the support vector machines (SVMs) classification algorithm in the design of the CAD system. RESULTS: With regard to the mapping procedure accuracy, the stiffness map values had an average difference of 0.01 +/- 0.001 kPa compared to the quantification results derived from the color-box provided by the built-in software of the ultrasound system. Highest classification accuracy from the SVM model was 87.0% with sensitivity and specificity values of 83.3% and 89.1%, respectively. Receiver operating characteristic curves analysis gave an area under the curve value of 0.85 with [0.77-0.89] confidence interval. CONCLUSIONS: The proposed CAD system employing color to stiffness mapping and classification algorithms offered superior results, comparing the already published clinical studies. It could prove to be of value to physicians improving the diagnostic accuracy of CLD and can be employed as a second opinion tool for avoiding unnecessary invasive procedures. PMID- 26936728 TI - Evaluation of the influence of double and triple Gaussian proton kernel models on accuracy of dose calculations for spot scanning technique. AB - PURPOSE: The main purpose in this study was to present the results of beam modeling and how the authors systematically investigated the influence of double and triple Gaussian proton kernel models on the accuracy of dose calculations for spot scanning technique. METHODS: The accuracy of calculations was important for treatment planning software (TPS) because the energy, spot position, and absolute dose had to be determined by TPS for the spot scanning technique. The dose distribution was calculated by convolving in-air fluence with the dose kernel. The dose kernel was the in-water 3D dose distribution of an infinitesimal pencil beam and consisted of an integral depth dose (IDD) and a lateral distribution. Accurate modeling of the low-dose region was important for spot scanning technique because the dose distribution was formed by cumulating hundreds or thousands of delivered beams. The authors employed a double Gaussian function as the in-air fluence model of an individual beam. Double and triple Gaussian kernel models were also prepared for comparison. The parameters of the kernel lateral model were derived by fitting a simulated in-water lateral dose profile induced by an infinitesimal proton beam, whose emittance was zero, at various depths using Monte Carlo (MC) simulation. The fitted parameters were interpolated as a function of depth in water and stored as a separate look-up table. These stored parameters for each energy and depth in water were acquired from the look-up table when incorporating them into the TPS. The modeling process for the in-air fluence and IDD was based on the method proposed in the literature. These were derived using MC simulation and measured data. The authors compared the measured and calculated absolute doses at the center of the spread-out Bragg peak (SOBP) under various volumetric irradiation conditions to systematically investigate the influence of the two types of kernel models on the dose calculations. RESULTS: The authors investigated the difference between double and triple Gaussian kernel models. The authors found that the difference between the two studied kernel models appeared at mid-depths and the accuracy of predicting the double Gaussian model deteriorated at the low-dose bump that appeared at mid-depths. When the authors employed the double Gaussian kernel model, the accuracy of calculations for the absolute dose at the center of the SOBP varied with irradiation conditions and the maximum difference was 3.4%. In contrast, the results obtained from calculations with the triple Gaussian kernel model indicated good agreement with the measurements within +/-1.1%, regardless of the irradiation conditions. CONCLUSIONS: The difference between the results obtained with the two types of studied kernel models was distinct in the high energy region. The accuracy of calculations with the double Gaussian kernel model varied with the field size and SOBP width because the accuracy of prediction with the double Gaussian model was insufficient at the low-dose bump. The evaluation was only qualitative under limited volumetric irradiation conditions. Further accumulation of measured data would be needed to quantitatively comprehend what influence the double and triple Gaussian kernel models had on the accuracy of dose calculations. PMID- 26936729 TI - Frequency based gating: An alternative, conformal, approach to 4D PET data utilization. AB - PURPOSE: Respiratory gating is a strategy for overcoming image degradation caused by patient motion in Positron Emission Tomography (PET) imaging. Traditional methods for sorting data, namely, phase-based gating or amplitude-based gating, come with an inherent trade-off between resolution improvements and added noise present in the subjugated data. If the goal of motion correction in PET is realigned from creating 4D images that attempt to mimic nongated images, towards ideal utilization of the information available, then new paths for data management emerge. In this work, the authors examine the application of a method in a new class of frequency based data subjugation algorithms, termed gating +. This strategy utilizes data driven information to locally adapt signal to its optimal segregation, thereby creating a new approach to 4D data utilization PET. METHODS: 189 (18)F-fluorodeoxyglucose (FDG) PET scans were acquired at a single bed position centered on the thorax region. 4D gated image sets were reconstructed using data driven gating. The gating+ signal optimization algorithm, previously presented in small animal PET images and simulations, was used to segregate data in frequency space to generate optimized 4D images in the population-the first application and analysis of gating+ in human PET scans. The nongated, phase gated, and gating+ representations of the data were compared using FDG uptake analysis in the identified lesions and noise measurements from background regions. RESULTS: Optimized processing required less than 1 min per scan on a standard PC (plus standard reconstruction time), and yielded entire 4D optimized volumes plus motion maps. Optimized scans had noise characteristics similar to nongated images, yet also contained much of the resolution and motion information found in the gated images. The average SUVmax increase in the lesion sample between gated/nongated and gating+/nongated (+/-SD in population) was 35.8% +/- 34.6% and 28.6% +/- 27.9%, respectively. The average percent standard deviation (%SD +/- SD in population) in liver volumes of interest (VOIs) across the sample for the nongated, gated, and gating+ scans was 6.7% +/- 2.4%, 13.6% +/ 3.3%, and 7.1% +/- 2.5%, respectively. In all cases, the noise in the gating+ liver VOIs was closer to the nongated measurements than to the gated. CONCLUSIONS: The gating+ algorithm introduces the notion of conforming 4D data segregation to the local information and statistics that support it. By segregating data in frequency space, the authors are able to generate low noise motion information rich image sets, derived solely from selective use of raw data. Their work shows that the gating+ algorithm can be robustly applied in populations, and across varying qualities of motion and scans statistics, and be integrated as part of a fully automated motion correction workflow. Furthermore, the idea of smart signal utilization underpins a new concept of low risk or even risk-free motion correction application in PET. PMID- 26936730 TI - A Monte Carlo study on the collimation of pencil beam scanning proton therapy beams. AB - PURPOSE: The lateral edge of a proton therapy beam is commonly used to achieve conformality to the treatment volume where critical structures reside close to the target. However, when treating shallow depths, the lateral edge of a pencil beam scanning (PBS) system may be broader than that of a double scattered (DS) system. Use of a range-shifter to degrade the beam and allow treatment of very shallow depths further blurs the lateral edge. The authors investigate the potential use of a collimator with a PBS system for delivery of 3D uniform dose volumes to a water-tank phantom, identifying the key factors controlling the width of the lateral edge. METHODS: The geant4 application for tomographic emission (gate) Monte Carlo (MC) environment was used, following validation against previously published data. Key parameters for PBS beams were investigated to assess their impact on the lateral edge of both monoenergetic beams and uniform dose-volumes. These parameters included nozzle-to-surface distance (NSD), vacuum window-to-surface distance (VSD), use of a range-shifter, and spot optimization parameters. RESULTS: The lateral edge of an uncollimated PBS beam is particularly sensitive to VSD and NSD. While use of a range-shifter blurs the lateral edge, collimation allows the edge to be sharpened to between 2 and 4 mm depending on the depth of the target. Optimization of the spot weightings alone can provide a penumbral width close to that of a single spot, but also leads to poorer uniformity near the edge of the target volume. CONCLUSIONS: Collimation of PBS beams should be considered for superficial targets particularly for beams delivered through a range-shifter, since the resultant sharpening of the lateral edge will allow improved sparing of adjacent normal tissues. Further work is needed to develop collimators which are integrated into both nozzle designs and planning system optimization algorithms. PMID- 26936731 TI - Reducing streak artifacts in computed tomography via sparse representation in coupled dictionaries. AB - PURPOSE: Reducing the number of acquired projections is a simple and efficient way to reduce the radiation dose in computed tomography (CT). Unfortunately, this results in streak artifacts in the reconstructed images that can significantly reduce their diagnostic value. This paper presents a novel algorithm for suppressing these artifacts in 3D CT. METHODS: The proposed algorithm is based on the sparse representation of small blocks of 3D CT images in learned overcomplete dictionaries. It learns two dictionaries, the first dictionary (D(a)) is for artifact-full images that have been reconstructed from a small number (approximately 100) of projections. The other dictionary (D(c)) is for clean artifact-free images. The core idea behind the proposed algorithm is to relate the representation coefficients of an artifact-full block in D(a) to the representation coefficients of the corresponding artifact-free block in D(c). The relation between these coefficients is modeled with a linear mapping. The two dictionaries and the linear relation between the coefficients are learned simultaneously from the training data. To remove the artifacts from a test image, small blocks are extracted from this image and their sparse representation is computed in D(a). The linear map is then used to compute the corresponding coefficients in D(c), which are then used to produce the artifact-suppressed blocks. RESULTS: The authors apply the proposed algorithm on real cone-beam CT images. Their results show that the proposed algorithm can effectively suppress the artifacts and substantially improve the quality of the reconstructed images. The images produced by the proposed algorithm have a higher quality than the images reconstructed by the FDK algorithm from twice as many projections. CONCLUSIONS: The proposed sparsity-based algorithm can be a valuable tool for postprocessing of CT images reconstructed from a small number of projections. Therefore, it has the potential to be an effective tool for low-dose CT. PMID- 26936732 TI - Automatic thoracic anatomy segmentation on CT images using hierarchical fuzzy models and registration. AB - PURPOSE: In an attempt to overcome several hurdles that exist in organ segmentation approaches, the authors previously described a general automatic anatomy recognition (AAR) methodology for segmenting all major organs in multiple body regions body-wide [J. K. Udupa et al., "Body-wide hierarchical fuzzy modeling, recognition, and delineation of anatomy in medical images," Med. Image Anal. 18(5), 752-771 (2014)]. That approach utilized fuzzy modeling strategies, a hierarchical organization of organs, and divided the segmentation task into a recognition step to localize organs which was then followed by a delineation step to demarcate the boundary of organs. It achieved speed and accuracy without employing image/object registration which is commonly utilized in many reported methods, particularly atlas-based. In this paper, our aim is to study how registration may influence performance of the AAR approach. By tightly coupling the recognition and delineation steps, by performing registration in the hierarchical order of the organs, and through several object-specific refinements, the authors demonstrate that improved accuracy for recognition and delineation can be achieved by judicial use of image/object registration. METHODS: The presented approach consists of three processes: model building, hierarchical recognition, and delineation. Labeled binary images for each organ are registered and aligned into a 3D fuzzy set representing the fuzzy shape model for the organ. The hierarchical relation and mean location relation between different organs are captured in the model. The gray intensity distributions of the corresponding regions of the organ in the original image are also recorded in the model. Following the hierarchical structure and location relation, the fuzzy shape model of different organs is registered to the given target image to achieve object recognition. A fuzzy connectedness delineation method is then employed to obtain the final segmentation result of organs with seed points provided by recognition. The authors assess the performance of this method for both nonsparse (compact blob-like) and sparse (thin tubular) objects in the thorax. RESULTS: The results of eight thoracic organs on 30 real images are presented. Overall, the delineation accuracy in terms of mean false positive and false negative volume fractions is 0.34% and 4.02%, respectively, for nonsparse objects, and 0.16% and 12.6%, respectively, for sparse objects. The two object groups achieve mean boundary distance relative to ground truth of 1.31 and 2.28 mm, respectively. CONCLUSIONS: The hierarchical structure and location relation integrated into the model provide the initial pose for registration and make the recognition process efficient and robust. The 3D fuzzy model combined with hierarchical affine registration ensures that accurate recognition can be obtained for both nonsparse and sparse organs. Tailoring the registration process for each organ by specialized similarity criteria and updating the organ intensity properties based on refined recognition improve the overall segmentation process. PMID- 26936733 TI - Technical Note: Relationships between gamma criteria and action levels: Results of a multicenter audit of gamma agreement index results. AB - PURPOSE: The aim of this work was to use a multicenter audit of modulated radiotherapy quality assurance (QA) data to provide a practical examination of gamma evaluation criteria and action level selection. The use of the gamma evaluation method for patient-specific pretreatment QA is widespread, with most commercial solutions implementing the method. METHODS: Gamma agreement indices were calculated using the criteria 1%/1 mm, 2%/2 mm, 2%/3 mm, 3%/2 mm, 3%/3 mm, and 5%/3 mm for 1265 pretreatment QA measurements, planned at seven treatment centers, using four different treatment planning systems, delivered using three different delivery systems (intensity-modulated radiation therapy, volumetric modulated arc therapy, and helical tomotherapy) and measured using three different dose measurement systems. The sensitivity of each pair of gamma criteria was evaluated relative to the gamma agreement indices calculated using 3%/3 mm. RESULTS: A linear relationship was observed for 2%/2 mm, 2%/3 mm, and 3%/2 mm. This result implies that most beams failing at 3%/3 mm would also fail for those criteria, if the action level was adjusted appropriately. Some borderline plans might be passed or failed depending on the relative priority (tighter tolerance) used for dose difference or distance to agreement evaluation. Dosimeter resolution and treatment modality were found to have a smaller effect on the results of QA measurements than the number of dimensions (2D or 3D) over which the gamma evaluation was calculated. CONCLUSIONS: This work provides a method (and a large sample of results) for calculating equivalent action levels for different gamma evaluation criteria. This work constitutes a valuable guide for clinical decision making and a means to compare published gamma evaluation results from studies using different evaluation criteria. More generally, the data provided by this work support the recommendation that gamma criteria that specifically prioritize the property of greatest clinical importance for each treatment modality of anatomical site should be selected when using gamma evaluations for modulated radiotherapy QA. It is therefore suggested that departments using the gamma evaluation as a QA analysis tool should consider the relative importance of dose difference and distance to agreement, when selecting gamma evaluation criteria. PMID- 26936734 TI - Technical Note: Preferred dosimeter size and associated correction factors in commissioning high dose per pulse, flattening filter free x-ray beams. AB - PURPOSE: High dose rate flattening filter free (FFF) beams pose new challenges and considerations for accurate reference and relative dosimetry. The authors report errors associated with commonly used ion chambers and introduce simple methods to mitigate them. METHODS: Dosimetric errors due to (1) ion recombination effects of high dose per pulse (DPP) FFF beams and (2) volume-averaging effects of the radial profile were examined on a TrueBeam STx. Four commonly used cylindrical ion chambers spanning a range of lengths (0.29-2.3 cm) and volumes (0.016-0.6 cm(3)) were used to determine the magnitude of these effects for 6 and 10 MV unflattened x-ray beams (6XFFF and 10XFFF, respectively). Two methods were used to determine the magnitude of ion collection efficiency: (1) direct measurement of the percent depth dose (PDD) for the clinical, high DPP beam in comparison to that obtained after reducing the DPP and (2) measurement of Pion as a function of depth. Two methods were used to quantify the magnitude of volume averaging: (1) direct measurement of volume-averaging via cross-calibration and (2) calculation of volume-averaging from radial profiles of the beam. Finally, a simple analytical expression for the radial profile volume-averaging correction factor, Prp = [OAR(0.29L)](-1), or the inverse of the off-axis ratio of dose at 0.29L, where L is the length of the chamber's sensitive volume, is introduced to mitigate the volume-averaging effect in Farmer-type chambers. RESULTS: Errors in measured PDD for the clinical beams were 1.3% +/- 0.07% and 1.6% +/- 0.07% at 35 cm depth for the 6XFFF and 10XFFF beam, respectively, using an IBA CC13 ion chamber, due to charge recombination with a high DPP. Volume-averaging effects were 0.4% and 0.7% for the 6XFFF and 10XFFF beam, respectively, when measured with a Farmer-type chamber. For the application of TG-51, these errors combine when using a CC13 to measure the PDD and a Farmer for absolute output dosimetry for a total error of up to 2% at dmax for the 10XFFF beam. CONCLUSIONS: Relative and absolute dosimetry in high DPP, unflattened x-ray beams of 10 MV or higher requires corrections for charge recombination and/or volume-averaging when dosimeters with certain geometries are used. Chambers used for PDD measurement are available that do not require a correction for charge recombination. A simple analytical expression of the correction factor Prp was introduced in this work to account for volume-averaging effects in Farmer chambers. Choice of an appropriate dosimeter coupled with application of the established correction factors Pion and Prp reduces the uncertainty in the PDD measurement and the reference dose measurement. PMID- 26936735 TI - Application of systems and control theory-based hazard analysis to radiation oncology. AB - PURPOSE: Both humans and software are notoriously challenging to account for in traditional hazard analysis models. The purpose of this work is to investigate and demonstrate the application of a new, extended accident causality model, called systems theoretic accident model and processes (STAMP), to radiation oncology. Specifically, a hazard analysis technique based on STAMP, system theoretic process analysis (STPA), is used to perform a hazard analysis. METHODS: The STPA procedure starts with the definition of high-level accidents for radiation oncology at the medical center and the hazards leading to those accidents. From there, the hierarchical safety control structure of the radiation oncology clinic is modeled, i.e., the controls that are used to prevent accidents and provide effective treatment. Using STPA, unsafe control actions (behaviors) are identified that can lead to the hazards as well as causal scenarios that can lead to the identified unsafe control. This information can be used to eliminate or mitigate potential hazards. The STPA procedure is demonstrated on a new online adaptive cranial radiosurgery procedure that omits the CT simulation step and uses CBCT for localization, planning, and surface imaging system during treatment. RESULTS: The STPA procedure generated a comprehensive set of causal scenarios that are traced back to system hazards and accidents. Ten control loops were created for the new SRS procedure, which covered the areas of hospital and department management, treatment design and delivery, and vendor service. Eighty three unsafe control actions were identified as well as 472 causal scenarios that could lead to those unsafe control actions. CONCLUSIONS: STPA provides a method for understanding the role of management decisions and hospital operations on system safety and generating process design requirements to prevent hazards and accidents. The interaction of people, hardware, and software is highlighted. The method of STPA produces results that can be used to improve safety and prevent accidents and warrants further investigation. PMID- 26936737 TI - High intensity focused ultrasound induced in vivo large volume hyperthermia under 3D MRI temperature control. AB - PURPOSE: Mild hyperthermia can be used as an adjuvant therapy to enhance radiation therapy or chemotherapy of cancer. However, administering mild hyperthermia is technically challenging due to the high accuracy required of the temperature control. MR guided high-intensity focused ultrasound (MR-HIFU) is a technology that can address this challenge. In this work, accurate and spatially uniform mild hyperthermia is demonstrated for deep-seated clinically relevant heating volumes using a HIFU system under MR guidance. METHODS: Mild hyperthermia heating was evaluated for temperature accuracy and spatial uniformity in 11 in vivo porcine leg experiments. Hyperthermia was induced with a commercial Philips Sonalleve MR-HIFU system embedded in a 1.5T Ingenia MR scanner. The operating software was modified to allow extended duration mild hyperthermia. Heating time varied from 10 min up to 60 min and the assigned target temperature was 42.5 degrees C. Electronic focal point steering, mechanical transducer movement, and dynamic transducer element switch-off were exploited to enlarge the heated volume and obtain uniform heating throughout the acoustic beam path. Multiple temperature mapping images were used to control and monitor the heating. The magnetic field drift and transducer susceptibility artifacts were compensated to enable accurate volumetric MR thermometry. RESULTS: The obtained mean temperature for the target area (the cross sectional area of the heated volume at focal depth primarily used to control the heating) was on average 42.0 +/- 0.6 degrees C. Temperature uniformity in the target area was evaluated using T10 and T90, which were 43.1 +/- 0.6 and 40.9 +/- 0.6 degrees C, respectively. For the near field, the corresponding temperatures were 39.3 +/- 0.8 degrees C (average), 40.6 +/- 1.0 degrees C (T10), and 38.0 +/- 0.9 degrees C (T90). The sonications resulted in a concise heating volume, typically in the shape of a truncated cone. The average depth reached from the skin was 86.9 mm. The results show that the heating algorithm was able to induce deep heating while keeping the near-field temperature uniform and at a safe level. CONCLUSIONS: The capability of MR-HIFU to induce accurate, spatially uniform, and robust mild hyperthermia in large deep seated volumes was successfully demonstrated through a series of in vivo animal experiments. PMID- 26936736 TI - Significant radiation reduction in interventional fluoroscopy using a novel eye controlled movable region of interest. AB - PURPOSE: This paper reports the first results obtained using a novel technology called eye controlled region of interest (ECR) that substantially reduces both staff and patient irradiation during an interventional fluoroscopy procedure without interfering with workflow. Its collimator includes a partially x-ray attenuating plate with a nonattenuating aperture. An eye tracker follows the operator's gaze to automatically position the aperture to the clinical region of interest (CROI) anywhere in the image in real-time. METHODS: Experiments were performed in a swine model using a mobile fluoroscope with a 30 cm image intensifier and manual control of fluoroscopic factors. The factory collimator and image display monitor were replaced with different components for this study. The full 30 cm field-of-view (FOV) of the image intensifier was irradiated at normal levels, and served as a baseline, when ECR was disengaged. With ECR engaged, most of the 30 cm FOV was irradiated to less than 20% of normal levels while the CROI was normally irradiated. Animal irradiation was determined by physical KAP (kerma area product) measurements. Operator irradiation was characterized by air kerma and air kerma rate measurements near the operator. Data were collected from three pairs of interventions in each of five swine models. RESULTS: When ECR was engaged, KAP was reduced to 0.22 (p < 0.001) of baseline and operator irradiation to 0.27 (p < 0.001) of baseline. Overall procedure time had a borderline increase (p = 0.07) but fluoroscopy time was unchanged (p = 0.36) (Wilcoxon signed rank). Measured staff and patient radiation reductions are consistent with this collimator's design. Subjective impressions of imaging improvements are consistent with less scatter reaching the CROI. Engaging ECR reduced irradiation without subjectively or objectively increasing operator workload. CONCLUSIONS: The first in vivo evaluation of ECR demonstrated that this technology has objectively reduced KAP and operator irradiation by approximately 75% without interfering with the performance of fluoroscopically guided interventional procedures. In addition, reduced scatter production subjectively improved device visualization. These findings indicate the practicability of achieving better radiation optimization. PMID- 26936738 TI - Investigation of the 4D composite MR image distortion field associated with tumor motion for MR-guided radiotherapy. AB - PURPOSE: Magnetic resonance (MR) images are affected by geometric distortions due to the specifics of the MR scanner and patient anatomy. Quantifying the distortions associated with mobile tumors is particularly challenging due to real anatomical changes in the tumor's volume, shape, and relative location within the MR imaging volume. In this study, the authors investigate the 4D composite distortion field, which combines the effects of the susceptibility-induced and system-related distortion fields, experienced by mobile lung tumors. METHODS: The susceptibility (chi) effects were numerically simulated for two specific scenarios: (a) a full motion cycle of a lung tumor due to breathing as depicted on ten phases of a 4D CBCT data set and (b) varying the tumor size and location in lung tissue via a synthetically generated sphere with variable diameter (4-80 mm). The chi simulation procedure relied on the segmentation and generation of 3D susceptibility (chi) masks and computation of the magnetic field by means of finite difference methods. A system-related distortion field, determined with a phantom and image processing algorithm, was used as a reference. The 4D composite distortion field was generated as the vector summation of the chi-induced and system-related fields. The analysis was performed for two orientations of the main magnetic field (B0), which correspond to several MRIgRT system configurations. Specifically, B0 was set along the z-axis as in the case of a cylindrical-bore scanner and in the (x,y)-plane as for a biplanar MR. Computations were also performed for a full revolution at 15 degrees increments in the case of a rotating biplanar magnet. Histograms and metrics such as maximum, mean, and range were used to evaluate the characteristics of the 4D distortion field. RESULTS: The chi-induced field depends on the change in volume and shape of the moving tumor as well as the local surrounding anatomy. In the case of system-related distortions, the tumor experiences increased field perturbations as it moves further away from the MR isocenter. For a mobile lung tumor, the 4D composite field, corresponding to a 1.5 T field and a readout gradient of 5 mT/m, amounts to 3.0 and 2.8 mm for the MRIgRT system designs featuring B0 oriented along the z-axis (cylindrical-bore scanner) and in the (x,y)-plane (biplanar scanner), respectively. For a rotating biplanar scanner, the composite distortion field varied nonlinearly with the rotation angle. Overall, the dominant contribution to the composite field was from the system related distortion field. The tumor centroid experienced a systematic shift of 2 mm and showed a negligible perturbation for different B0 values. The dependency on the tumor size was also investigated, namely the max values varied from 1.2 to 2.5 mm for spherical volumes with a diameter between 4 and 80 mm. CONCLUSIONS: The composite distortion field requires adequate quantification for lung radiation therapy applications such as treatment planning, pretreatment patient setup verification, and real-time treatment delivery guidance. For certain scenarios such as small tumor volumes, the spatial distortions may be corrected by applying systematic shifts derived from a single tumor motion phase. In the case of high readout gradients common to fast imaging applications, the chi distortions were found to be less than 1 mm irrespective of scanner configuration. PMID- 26936739 TI - Visual-search observers for assessing tomographic x-ray image quality. AB - PURPOSE: Mathematical model observers commonly used for diagnostic image-quality assessments in x-ray imaging research are generally constrained to relatively simple detection tasks due to their need for statistical prior information. Visual-search (VS) model observers that employ morphological features in sequential search and analysis stages have less need for such information and fewer task constraints. The authors compared four VS observers against human observers and an existing scanning model observer in a pilot study that quantified how mass detection and localization in simulated digital breast tomosynthesis (DBT) can be affected by the number P of acquired projections. METHODS: Digital breast phantoms with embedded spherical masses provided single target cases for a localization receiver operating characteristic (LROC) study. DBT projection sets based on an acquisition arc of 60 degrees were generated for values of P between 3 and 51. DBT volumes were reconstructed using filtered backprojection with a constant 3D Butterworth postfilter; extracted 2D slices were used as test images. Three imaging physicists participated as observers. A scanning channelized nonprewhitening (CNPW) observer had knowledge of the mean lesion-absent images. The VS observers computed an initial single-feature search statistic that identified candidate locations as local maxima of either a template matched-filter (MF) image or a gradient-template MF (GMF) image. Search inefficiencies that modified the statistic were also considered. Subsequent VS candidate analyses were carried out with (i) the CNPW statistical discriminant and (ii) the discriminant computed from GMF training images. These location invariant discriminants did not utilize covariance information. All observers read 36 training images and 108 study images per P value. Performance was scored in terms of area under the LROC curve. RESULTS: Average human-observer performance was stable for P between 7 and 35. In the absence of search inefficiencies, the VS models based on the GMF analysis provided the best correlation (Pearson rho >= 0.62) with the human results. The CNPW-based VS observers deviated from the humans primarily at lower values of P. In this limited study, search inefficiencies allowed for good quantitative agreement with the humans for most of the VS observers. CONCLUSIONS: The computationally efficient training requirements for the VS observer are suitable for high resolution imaging, indicating that the observer framework has the potential to overcome important task limitations of current model observers for x-ray applications. PMID- 26936740 TI - Comment on "Report of improved performance in Talbot-Lau phase-contrast computed tomography" [Med. Phys. 42(6), 2892-2896 (2015)]. PMID- 26936741 TI - Comment on "Large area CMOS active pixel sensor x-ray imager for digital breast tomosynthesis: Analysis, modeling, and characterization" [Med. Phys. 42, 6294 6308 (2015)]. PMID- 26936742 TI - Response to "Comment on 'A protocol for EBT3 radiochromic film dosimetry using reflection scanning' " [Med. Phys. 41(12), 122101 (6pp.) (2014)]. PMID- 26936745 TI - Corrigendum on: Wang H, Chen C, Li J, Yang X, Zhang H and Wang Z. Modified first dorsal metacarpal artery island flap for sensory reconstruction of thumb pulp defects. J Hand Surg Eur. 2016, 41: 177-84. AB - The authors apologise for an error in the presentation of the affiliations of the authors of this published paper. The correct details are:Hui Wang(1,2*), Chao Chen(3*), Jun Li(4), Xiaoxi Yang(5), Hui Zhang(1,6), Zhiqiang Wang(1,7) (1)Graduate School, Southern Medical University, Guangzhou, Guangdong, PR China(2)The department of Hand Surgery, The Second Hospital of Tangshan, Tangshan, Hebei, PR China(3)The department of Orthopedics, Chinese PLA General Hospital, Beijing, PR China(4)The emergency department, The Second Hospital of Tangshan, Tangshan, Hebei, PR China(5)The department of traditional Chinese Medicine, College of traditional Chinese Medicine, North China University of Technology, Tangshan, Hebei, PR China(6)The department of Joint Surgery, The Second Hospital of Tangshan, Tangshan, Hebei, PR China(7)The department of Orthopaedics, Affiliated Hospital, North China University of Technology, Tangshan, Hebei, 063000, PR China*Hui Wang and Chao Chen contributed equally to this work. PMID- 26936744 TI - Protein phosphatase 1gamma regulates the proliferation of human glioma via the NF kappaB pathway. AB - Protein phosphatase 1gamma (PP1gamma), a member of mammalian protein phosphatases, serine/threonine phosphatases, catalyzes the majority of protein dephosphorylation events and regulates diverse cellular processes, such as neuronal signaling, muscle contraction, glycogen synthesis, and cell proliferation. However, its expression and potential functions in human glioma is unclear. In this study, we detected the high expression of PP1gamma and phosphorylated p65 (p-p65) in human glioma tissues. Besides, we demonstrated that upregulation of PP1gamma was tightly related to poor 5-year survival via systemic statistical analysis. Employing serum-starved and re-feeding models of U251 and U87MG, we observed the increasing expression of PP1gamma and p-p65 were accompanied by the cell proliferation markers cyclin D1 and proliferating cell nuclear antigen (PCNA). Employing depletion-PP1gamma models, we found downregulated PP1gamma and p-p65 compared with upregulated IkappaBalpha, which indicates the inhibition of NF-kappaB pathway, and flow cytometry analysis confirmed the weakened cell proliferation. Moreover, we found that the translocation of p65 into the nucleus was impaired. Collectively, we identified the positive correlation between upregulation of PP1gamma and human glioma cell proliferation and that knock-down of PP1gamma alleviated the glioma proliferation by reducing p65 transportation into the nucleus. The results showed that PP1gamma could accelerate human glioma proliferation via the NF-kappaB pathway. PMID- 26936746 TI - A knotless bidirectional-barbed tendon repair is inferior to conventional 4 strand repairs in cyclic loading. AB - We divided 21 flexor digitorum profundus tendons in the index, middle and ring fingers in seven cadaver hands into three groups. The tendons were cut in zone 2 and repaired using a 4-strand cruciate core suture repair with one of the following three materials in each group: (1) a knotless repair with a 2-0 bidirectional-barbed suture, which has similar tensile strength as a 4-0 non barbed suture used in the other two groups; (2) a knotted locking repair with a non-barbed 4-0 conventional suture; and (3) a non-locking repair with a non barbed 4-0 knotless suture. The repaired fingers were cyclically loaded through a simulated active range of motion to a 5 N load. We monitored and recorded the gap sizes at regular intervals during the test. The 2-0 bidirectional-barbed suture group and non-barbed suture groups developed gaps of 2.2 mm after 10 cycles and 2.4 mm after 20 cycles, respectively. Over 1000 cycles, the mean gaps were 3.2 mm in the 4-0 conventional suture group and 9.1 mm in the 2-0 bidirectional-barbed group. The tendons in the 2-0 bidirectional-barbed group gapped earlier, with statistically significant differences compared with those in the locking repair with a non-barbed 4-0 knotless suture group. The repair strength of the barbed suture technique was inferior to the cruciate repairs using a conventional 4-0 non-barbed suture tested in this cyclic-loading model. LEVEL OF EVIDENCE: Level V. PMID- 26936747 TI - Biomechanical investigation of 'figure of 8' flexor tendon repair techniques. AB - This biomechanical study compared the original Al-Qattan repair with other modifications postulated to reduce bulk and friction, thereby potentially improving outcome. A total of 32 cadaveric digits with intact flexor apparatus were used. In each digit, the flexor digitorum profundus and flexor digitorum superficialis tendons were cut cleanly in Zone 2. We tested Al-Qattan's technique along with three modifications using stronger suture material and varying the number of strands across the repair site. Of the four repair techniques, the modified Al-Qattan's technique using two 'figure of 8' 4-0 Fiberwire core sutures (Group 4) had the best balance of ultimate tensile strength (50.9 N), 2 mm gapping force (38 N) and friction. The modified technique provided a stronger repair for early active mobilization and has less friction than the originally described repair. PMID- 26936748 TI - Absence of extensor indicis tendon complicating reconstruction of the extensor pollicis longus. PMID- 26936749 TI - Mir-338-3p Inhibits Malignant Biological Behaviors of Glioma Cells by Targeting MACC1 Gene. AB - BACKGROUND Human brain glioma is the most common endocranial tumor; its mortality and morbidity are very high. The objective of this study was to determine whether miR-338-3p can regulate malignant biological behaviors of glioma cells by targeted silencing of MACC1. MATERIAL AND METHODS The expression of miR-338-3p was detected by quantitative real-time PCR in brain glioma tissues and cell lines. Bioinformatics software was used to predict some potential target genes of miR-338-3p. Luciferase activities assay was used to verify the combination between target genes and miR-338-3p. And MACC1 protein expression was detected by Western blot. The apoptosis and proliferation ability were analyzed by MTT and flow cytometry assay. RESULTS Compared with normal brain tissues and cells, miR 338-3p in glioma tissues and cell lines was confirmed to be expressed at low levels, and down-regulation of miR-338-3p tended to be correlated with worse histological grade. Up-regulation of miR-338-3p promoted apoptosis and sharply inhibited cell proliferation ability of U251 and U87 cells. The luciferase activities assay, biotin-avidin pull-down assay, and western blot analysis verified that MACC1 was a specific target gene of miR-338-3p. Subsequent experiments found that up-regulation of MACC1 significantly inhibited the apoptosis and increased the cell proliferation ability of U251 and U87 cells. The regulation effects of miR-338-3p on malignant biological behaviors of glioma cells can be partly reversed by up-regulation of MACC1. CONCLUSIONS Down regulation of miR-338-3p was an independent prognostic biomarker associated with poor prognosis in glioma patients; miR-338-3p acted as a tumor-suppressing gene whose silencing can inhibit malignant biological behaviors of glioma cells. MACC1 was a specific target gene of miR-338-3p, which regulates malignant biological behaviors of glioma cells partly through directly silencing MACC1 expression. PMID- 26936750 TI - Why Animals Die: An Introduction to the Pathology of Aging. PMID- 26936751 TI - Endocrinopathy and Aging in Ferrets. AB - Ferrets have become more popular as household pets and as animal models in biomedical research in the past 2 decades. The average life span of ferrets is about 5-11 years with onset of geriatric diseases between 3-4 years including endocrinopathies, neoplasia, gastrointestinal diseases, cardiomyopathy, splenomegaly, renal diseases, dental diseases, and cataract. Endocrinopathies are the most common noninfectious disease affecting middle-aged and older ferrets. Spontaneous neoplasms affecting the endocrine system of ferrets appear to be increasing in prevalence with a preponderance toward proliferative lesions in the adrenal cortex and pancreatic islet cells. Diet, gonadectomy, and genetics may predispose ferrets to an increased incidence of these endocrinopathies. These functional proliferative lesions cause hypersecretion of hormones that alter the physiology and metabolism of the affected ferrets resulting in a wide range of clinical manifestations. However, there is an apparent dearth of information available in the literature about the causal relationship between aging and neoplasia in ferrets. This review provides a comprehensive overview of the anatomy and physiology of endocrine organs, disease incidence, age at diagnosis, clinical signs, pathology, and molecular markers available for diagnosis of various endocrine disorders in ferrets. PMID- 26936753 TI - Authors' reply to Kristiansen. PMID- 26936754 TI - Variable coordination modes and catalytic dehydrogenation of B-phenyl amine boranes. AB - The chemistry of N-substituted amine-boranes and their reactivity towards transition metal centres is well established but the chemistry of B-substituted amine-boranes is not. Here we present the coordination chemistry of H2PhB.NMe3 towards a range of Rh(i) fragments with different P-Rh-P ligand bite angles, {Rh(P(i)Pr3)2}(+), {Rh(P(i)Bu3)2}(+), {Rh((i)Pr2P(CH2)3P(i)Pr2)}(+), {Rh(Ph2P(CH2)nPPh2)}(+) (n = 3, 5), as characterised by NMR spectroscopy and single-crystal X-ray diffraction. This reveals a difference in the coordination mode of the amine-borane, with large bite angle fragments favouring eta(2) coordination through a sigma-interaction with BH2, whereas fragments with small bite angles favour eta(6)-coordination through the aryl group of the amine borane. The catalytic dehydrocoupling of H2PhB.NMe2H is also explored, with the aminoborane HPhB[double bond, length as m-dash]NMe2 found to be the sole dehydrogenation product. Stoichiometric reactivity with H2PhB.NMe2H again showed small bite angle fragments to prefer eta(6)-aryl coordination, while the larger bite angle {Rh(P(i)Pr3)2}(+) gave rapid dehydrogenation to form a mixture of the Rh(iii) dihydride [Rh(P(i)Pr3)2(H)2(eta(2)-H2PhB.NMe2H)][BAr(F)4] and the low coordinate aminoboryl complex [Rh(P(i)Pr3)2(H)(BPhNMe2)][BAr(F)4]. These results suggest that precatalysts which eta(6)-bind arenes strongly should be avoided for the dehydrocoupling of amine-boranes bearing aryl substituents. PMID- 26936752 TI - Approaches to Investigating Complex Genetic Traits in a Large-Scale Inbred Mouse Aging Study. AB - Inbred mice are a unique model system for studying aging because of the genetic homogeneity within inbred strains, the short life span of mice relative to humans, and the rich array of analytic tools that are available. A large-scale aging study was conducted on 28 inbred strains representing great genetic diversity to determine, via histopathology, the type and diversity of spontaneous diseases that aging mice develop. A total of 20 885 different diagnoses were made, with an average of 12 diagnoses per mouse in the study. Eighteen inbred strains have had their genomes sequenced, and many others have been partially sequenced to provide large repositories of data on genetic variation among the strains. This vast amount of genomic information can be utilized in genome-wide association studies to find candidate genes that are involved in the pathogenesis of spontaneous diseases. As an illustration, this article presents a genome-wide association study of the genetic associations of age-related intestinal amyloidosis, which implicated 3 candidate genes: translocating chain-associated membrane protein 1 (Tram1); splicing factor 3b, subunit 5 (Sf3b5); and syntaxin 11 (Stx11). Representative photomicrographs are available on the Mouse Tumor Biology Database and Pathbase to serve as a reference when evaluating inbred mice used in other genetic or experimental studies to rule out strain background lesions. Many of the age-related mouse diseases are similar, if not identical, to human diseases; therefore, the genetic discoveries have direct translational benefit. PMID- 26936755 TI - A phase II trial of dose-dense (biweekly) paclitaxel plus carboplatin as neoadjuvant chemotherapy for operable breast cancer. AB - The aim of the present study is to investigate the efficacy and safety of dose dense (biweekly) carboplatin and paclitaxel as a neoadjuvant treatment for operable breast cancer. Patients with previously untreated breast cancer (stages Ic-III) were treated with four cycles of paclitaxel (175 mg/m(2), intravenous drip, D1) and carboplatin (area under the curve of 5, D1). Patients with HER2+ disease simultaneously received trastuzumab (6 mg/kg initial dose with subsequent doses of 4 mg/kg biweekly). The primary endpoint was a pathologically complete response (pCR). Between January 2012 and February 2014, 110 patients were enrolled. The overall pCR rate was 35.45 % (39 of 110). The pCR rates for the different cancer subtypes were as follows: 10.53 % (2 of 19) among the patients with the luminal A subtype, 12.50 % (5 of 40) among the patients with the luminal B (HER2-) subtype, 58.33 % (14 of 24) among the patients with the luminal B (HER2+) subtype, 57.14 % (8 of 14) among the patients with the triple-negative subtype, and 76.92 % (10 of 13) among the patients with the HER2+ subtype. The patients experienced the following toxicity side effects: grade 3/4 neutropenia (N = 27, 24.55 %), grade 3/4 anemia (N = 6, 5.45 %), grade 3/4 thrombocytopenia (N = 2, 1.82 %), grade 3 alanine aminotransferase (ALT) elevation (N = 1, 0.91 %), grade 3 neuropathy (N = 3, 2.73 %), grade 3 pain (N = 2, 1.82 %), and grade 3 fatigue (N = 1, 0.91 %). In total, 19.09 % of the patients experienced treatment delay or discontinuation due to hematological toxicity, and one patient discontinued treatment due to non-hematological toxicity. Neoadjuvant biweekly paclitaxel plus carboplatin is a feasible therapy that achieved high pCR rates in patients with the HER2+, triple-negative, and luminal B (HER2+) cancer subtypes (NCT0205986). PMID- 26936757 TI - Erratum to: 'Identification of candidate gonadal sex differentiation genes in the chicken embryo using RNA-seq'. PMID- 26936756 TI - Cluster analysis and its application to healthcare claims data: a study of end stage renal disease patients who initiated hemodialysis. AB - BACKGROUND: Cluster analysis (CA) is a frequently used applied statistical technique that helps to reveal hidden structures and "clusters" found in large data sets. However, this method has not been widely used in large healthcare claims databases where the distribution of expenditure data is commonly severely skewed. The purpose of this study was to identify cost change patterns of patients with end-stage renal disease (ESRD) who initiated hemodialysis (HD) by applying different clustering methods. METHODS: A retrospective, cross-sectional, observational study was conducted using the Truven Health MarketScan(r) Research Databases. Patients aged >=18 years with >=2 ESRD diagnoses who initiated HD between 2008 and 2010 were included. The K-means CA method and hierarchical CA with various linkage methods were applied to all-cause costs within baseline (12 months pre-HD) and follow-up periods (12-months post-HD) to identify clusters. Demographic, clinical, and cost information was extracted from both periods, and then examined by cluster. RESULTS: A total of 18,380 patients were identified. Meaningful all-cause cost clusters were generated using K-means CA and hierarchical CA with either flexible beta or Ward's methods. Based on cluster sample sizes and change of cost patterns, the K-means CA method and 4 clusters were selected: Cluster 1: Average to High (n = 113); Cluster 2: Very High to High (n = 89); Cluster 3: Average to Average (n = 16,624); or Cluster 4: Increasing Costs, High at Both Points (n = 1554). Median cost changes in the 12-month pre-HD and post-HD periods increased from $185,070 to $884,605 for Cluster 1 (Average to High), decreased from $910,930 to $157,997 for Cluster 2 (Very High to High), were relatively stable and remained low from $15,168 to $13,026 for Cluster 3 (Average to Average), and increased from $57,909 to $193,140 for Cluster 4 (Increasing Costs, High at Both Points). Relatively stable costs after starting HD were associated with more stable scores on comorbidity index scores from the pre-and post-HD periods, while increasing costs were associated with more sharply increasing comorbidity scores. CONCLUSIONS: The K-means CA method appeared to be the most appropriate in healthcare claims data with highly skewed cost information when taking into account both change of cost patterns and sample size in the smallest cluster. PMID- 26936760 TI - HIV Interaction With Human Host: HIV-2 As a Model of a Less Virulent Infection. AB - HIV-1 and HIV-2 are the causal agents of AIDS. While similar in many ways, a significant amount of data suggests that HIV-2 is less virulent than HIV-1. In fact, HIV-2 infection is characterized by a longer asymptomatic stage and lower transmission rate, and the majority of HIV-2-infected patients can be classified as long-term non-progressors or elite controllers. The mechanisms underlying the ability of human host to naturally control HIV-2 infection are far from being completely understood. The identification of the differences between HIV-1 and HIV-2 interactions with human host cells could provide important insights into several aspects of retroviral pathogenesis that remain elusive, with significant implications for HIV vaccine development and therapy. In this review, we delve into some of the differences that notably distinguish HIV-2 from HIV-1, highlighting possible consequences in the pathogenesis and natural history of both infections. PMID- 26936759 TI - Human Immunodeficiency Virus Type 1 Two-Long Terminal Repeat Circles: A Subject for Debate. AB - HIV-1 infections are characterized by the integration of the reverse transcribed genomic RNA into the host chromosomes making up the provirus. In addition to the integrated proviral DNA, there are other forms of linear and circular unintegrated viral DNA in HIV-1-infected cells. One of these forms, known as two long terminal repeat circles, has been extensively studied and characterized both in in vitro infected cells and in cells from patients. Detection of two-long terminal repeat circles has been proposed as a marker of antiretroviral treatment efficacy or ongoing replication in patients with undetectable viral load. But not all authors agree with this use because of the uncertainty about the lifespan of the two-long terminal repeat circles. We review the major studies estimating the half-life of the two-long terminal repeat circles as well as those proposing its detection as a marker of ongoing replication or therapeutic efficacy. We also review the characteristic of these circular forms and the difficulties in its detection and quantification. The variety of approaches and methods used in the two-long terminal repeat quantification as well as the low reliability of some methods make the comparison between results difficult. We conclude that it is not possible to draw a clear supposition about the lifespan of two-long terminal repeat circles and consequently they should not be used as a marker of ongoing replication without a careful analysis of the methods and results. PMID- 26936761 TI - Treatment Options for Visceral Leishmaniasis and HIV Coinfection. AB - Leishmania and HIV coinfection is a major health problem in more than 35 countries worldwide. The impaired immune function of visceral leishmaniasis/HIV coinfected patients may: (i) favor the reactivation of latent Leishmania infection; (ii) induce a more severe presentation of visceral leishmaniasis; (iii) cause a poorer therapeutic response; and (iv) increase the risk of relapse after treatment. One of the major challenges in the management of visceral leishmaniasis/HIV coinfection is developing an effective drug therapy that not only resolves the first episode of visceral leishmaniasis but also prevents relapse. However, scarce evidence and data are available on the optimal therapy for visceral leishmaniasis/HIV coinfection. In our study we reviewed the efficacy of several drugs currently employed for visceral leishmaniasis in HIV patients and current knowledge of secondary prophylaxis. Additionally, we reviewed a set of ongoing clinical trials that are being performed to evaluate the efficacy of new therapeutic regimens for visceral leishmaniasis in patients with and without HIV. Finally, other therapeutic strategies based on immunotherapy, vaccination, or screening for latent leishmaniasis infection in HIV patients are reviewed. Apart from being potentially useful in clinical practice, the results obtained in our study highlight the need for further research on the management of visceral leishmaniasis/HIV coinfection. PMID- 26936763 TI - Diabetes in HIV-infected persons in Cameroon? AB - In the past, the increased prevalence of diabetes in HIV infection has been attributed to antiretroviral drugs. In this study, Cameroonians with HIV infection were shown in a paper in this issue of the Journal to be more likely to have diabetes if they were not on therapy. Future research should examine if the diabetes is related to the host response to infection or to socioeconomic factors that might both contribute to not being on anti-retroviral therapy and predispose to diabetes. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26936762 TI - Diesel Exhaust Worsens Cardiac Conduction Instability in Dobutamine-Challenged Wistar-Kyoto and Spontaneously Hypertensive Rats. AB - Short-term exposure to air pollution, particularly from vehicular sources, increases the risk of acute clinical cardiovascular events. However, cardiotoxicity is not always clearly discernible under ambient conditions; therefore, more subtle measures of cardiac dysfunction are necessary to elucidate the latent effects of exposure. Determine the effect of whole diesel exhaust (DE) exposure on reserve of refractoriness (RoR), an intrinsic electrophysiological measure of the heart's minimum level of refractoriness relative to development of electrical conduction instability, in rats undergoing exercise-like stress. Wistar-Kyoto (WKY) and spontaneously hypertensive (SH) rats implanted with radiotelemeters to continuously collect electrocardiogram (ECG) and heart rate were exposed to 150 ug/m3 of DE and challenged with dobutamine 24 h later to mimic exercise-induced increases of the heart rate. The Chernyak-Starobin-Cohen (CSC) model was then applied to the ECG-derived QT and RR intervals collected during progressive increases in heart rate to calculate RoR for each rat. Filtered air-exposed WKY and SH rats did not have any decrease in RoR, which indicates increased risk of cardiac conduction instability; however, DE caused a significant decrease in both strains. Yet, the decrease in RoR in SH rats was eight times steeper when compared to WKY rats indicating greater cardiac conduction instability in the hypertensive strain. These data indicate that after exposure to DE, risk of cardiac instability increases during increasing stress, particularly in the presence of underlying cardiovascular disease. Furthermore, the CSC model, which was previously shown to reveal cardiac risk in humans, can be applied to rodent toxicology studies. PMID- 26936764 TI - Needs of Patients with Schizophrenia Among an Ethnic Minority Group in Latin America. AB - The aim of the study is to describe the need profile of outpatients with schizophrenia belonging to an Aymara ethnic group in Latin-America and to compare that profile to non-Aymara patients. A sample of 253 patients were evaluated with the Two-Way Communication Checklist (2-COM Checklist) measuring the needs and satisfaction of the patient; Positive and Negative Syndrome scale for Schizophrenia (PANSS) and Attitude to the Drugs (DAI-10). No significant differences were found between Aymara and non-Aymara, either in the total number of needs or in the subscales of satisfaction or in the types of needs. After adjustment for socio-demographic and clinical factors, patients with higher severity (PANSS) had higher number of needs and lower level of satisfaction. Higher score on DAI-10 is related to a higher total number of needs and better satisfaction with medication. Age, sex, ethnicity and employment were also associated with specific needs. The profile of the needs of schizophrenic Aymara patients does not differ from that of non-Aymara patients, and that in both groups it is necessary that the treatment primarily address symptom management and the subjective aspects of quality of life. PMID- 26936766 TI - [Myeloradiculitis due to Schistosoma haematobium: about an observation in Dakar (Senegal)]. AB - Nervous localisations of schistosomiasis are rare. We report the case of a 25 year-old Senegalese patient admitted for a progressive myeloradiculitis onset, over a one week period. The diagnosis of Schistosoma haematobium myeloradiculitis was made in front of a positive serum serology for S. haematobium, presence of S. haematobium eggs in urine, hyperproteinorachia, endemicity of S. haematobium in the region where the patient was originating and a past medical history of macroscopic hematuria in a context of river bathing. There was also no arguments for another cause to these neurological manifestations. Our patient was treated with praziquantel, prednisone and physiotherapy. Evolution was marked 6 weeks after the beginning of treatment by a significant improvement of motor deficit, enabling the patient to walk again. There was also a regression of genitosphincter dysfunction. Work-up for patients presenting with paraplegia in tropical countries, should also include search for S. heamatobium infection. PMID- 26936765 TI - Autophagic and lysosomal defects in human tauopathies: analysis of post-mortem brain from patients with familial Alzheimer disease, corticobasal degeneration and progressive supranuclear palsy. AB - INTRODUCTION: The accumulation of insoluble proteins within neurons and glia cells is a pathological hallmark of several neurodegenerative diseases. Abnormal aggregation of the microtubule-associated protein tau characterizes the neuropathology of tauopathies, such as Alzheimer disease (AD), corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP). An impairment of the lysosomal degradation pathway called macroautophagy, hereafter referred to as autophagy, could contribute to the accumulation of aggregated proteins. The role of autophagy in neurodegeneration has been intensively studied in the context of AD but there are few studies in other tauopathies and it is not known if defects in autophagy is a general feature of tauopathies. In the present study, we analysed autophagic and lysosomal markers in human post-mortem brain samples from patients with early-onset familial AD (FAD) with the APP Swedish mutation (APPswe), CBD and PSP and control individuals. RESULTS: FAD, CBD and PSP patients displayed an increase in LC3-positive vesicles in frontal cortex, indicating an accumulation of autophagic vesicles. Moreover, using double-immunohistochemistry and in situ proximity ligation assay, we observed colocalization of hyperphosphorylated tau with the autophagy marker LC3 in FAD, CBD and PSP patients but not in control individuals. Increased levels of the lysosomal marker LAMP1 was detected in FAD and CBD, and in addition Cathepsin D was diffusely spread in the cytoplasm in all tauopathies suggesting an impaired lysosomal integrity. CONCLUSION: Taken together, our results indicate an accumulation of autophagic and lysosomal markers in human brain tissue from patients with primary tauopathies (CBD and PSP) as well as FAD, suggesting a defect of the autophagosome-lysosome pathway that may contribute to the development of tau pathology. PMID- 26936769 TI - Impact of MR-safe headphones on PET attenuation in combined PET/MRI scans. AB - BACKGROUND: MR headphones are attenuation sources affecting PET quantification in hybrid PET/MRI. Despite potentially better patient communication, usage in PET/MRI scans is not approved by the vendor. This study aims to determine the impact of headphones on PET by means of phantom and patient scans. Additionally, the perceived benefit of using headphones was evaluated. FINDINGS: A cylinder phantom was scanned without and with dedicated MR headphones in a PET/CT scanner. Headphone attenuation was additionally assessed in a clinical setup in 10 patients on a PET/MR scanner using F-18-fluoro-deoxy-glucose. The difference in tracer uptake with and without headset was determined for the various brain regions. Additionally, the patients were asked for differences in noise levels, patient comfort, communication quality, and preference. CT data revealed headphone attenuation values of 350-500 HU. Neglecting headphone attenuation leads to a decrease in PET values between the earcups of about 11 % when compared to the correctly reconstructed data. Regions further away from the headphones were less affected. Patient images demonstrated a decrease of 11 % on average in the cerebellum and temporal lobes, while other regions were less affected. No visual artefacts in the images were noticed. On average, no advantage in terms of noise and patient comfort and only slightly better quality of communication were imparted by the patients. CONCLUSIONS: Using headphones during PET/MR acquisition leads to a negative bias in brain uptake values without introducing obvious image artefacts. Since they lack benefits for the patients, they should be avoided if PET quantification of the brain is needed. PMID- 26936768 TI - An investigation of the relation between tumor-to-liver ratio (TLR) and tumor-to blood standard uptake ratio (SUR) in oncological FDG PET. AB - BACKGROUND: The standardized uptake value (SUV) is the nearly exclusive means for quantitative evaluation of clinical [18F-]fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) whole body investigations. However, the SUV methodology has well-known shortcomings. In this context, it has been recognized that at least part of the problems can be eliminated if tumor SUV is normalized to the SUV of a reference region in the liver (tumor-to-liver [TLR] ratio). In recent publications, we have systematically investigated the tumor-to-blood SUV ratio (SUR) for normalization of tumor SUVs which in our view offers principal advantages in comparison to TLR. The aim of this study was a comprehensive comparison of TLR and SUR in terms of quantification of tumor lesions. METHODS: 18F-FDG PET/CT was performed in 424 patients (557 scans) with different tumor entities prior to radio(chemo)therapy. In the PET images, SUVmax of the primary tumor was determined. SUVliver was calculated in the inferior right lobe of the liver. SUVblood was determined by manually delineating the aorta in the low-dose CT. TLR and SUR were computed and scan time corrected to 60 min p.i. (TLRtc and SURtc). Correlation analysis was performed for SUVliver vs. SUVblood, TLR vs. SUR, SUVliver/SUVblood vs. SUVblood,SURtc/TLR vs. SURtc, and SURtc/TLRtc vs. SURtc. Variability of the respective ratios was assessed via histogram analysis. The prognostic value of TLR and TLRtc for distant metastases-free survival (DM) was investigated with univariate Cox regression in a homogeneous subgroup (N = 130) and compared to previously published results for SUV and SURtc. RESULTS: Correlation analysis revealed a linear correlation of SUVliver vs. SUVblood (R (2)=0.83) and of TLR vs. SURtc (R (2)=0.92). The SUVliver/SUVblood ratio (mean +/ s.d.) was 1.47 +/- 0.18. For the SURtc/TLR ratio, we obtained 1.14 +/- 0.21 and for the SURtc/TLRtc ratio 1.38 +/- 0.17. Survival analysis revealed TLR and TLRtc as significant prognostic factors for DM (hazard ratio [HR] = 3.3 and HR = 3, respectively). Both hazard ratios are lower than that of SURtc (HR = 4.1) although this reduction does not reach statistical significance for the given limited group size. HRs of TLR and SURtc are both significantly higher than HR of SUV (HR = 2.2). CONCLUSIONS: Suitability of the liver as surrogate of arterial tracer supply for SUV normalization via TLR computation is limited. Further studies in sufficiently large patient groups are required to better characterize the relative performance of SUV, TLR, and SUR in different settings. PMID- 26936770 TI - Experience-Dependent Brain Development as a Key to Understanding the Language System. AB - An influential view of the nature of the language system is that of an evolved biological system in which a set of rules is combined with a lexicon that contains the words of the language together with a representation of their context. Alternative views, usually based on connectionist modeling, attempt to explain the structure of language on the basis of complex associative processes. Here, I put forward a third view that stresses experience-dependent structural development of the brain circuits supporting language as a core principle of the organization of the language system. In this view, embodied in a recent neuroconstructivist neural network of past tense development and processing, initial domain-general predispositions enable the development of functionally specialized brain structures through interactions between experience-dependent brain development and statistical learning in a structured environment. Together, these processes shape a biological adult language system that appears to separate into distinct mechanism for processing rules and exceptions, whereas in reality those subsystems co-develop and interact closely. This view puts experience dependent brain development in response to a specific language environment at the heart of understanding not only language development but adult language processing as well. PMID- 26936767 TI - Motif mediated protein-protein interactions as drug targets. AB - Protein-protein interactions (PPI) are involved in virtually every cellular process and thus represent an attractive target for therapeutic interventions. A significant number of protein interactions are frequently formed between globular domains and short linear peptide motifs (DMI). Targeting these DMIs has proven challenging and classical approaches to inhibiting such interactions with small molecules have had limited success. However, recent new approaches have led to the discovery of potent inhibitors, some of them, such as Obatoclax, ABT-199, AEG 40826 and SAH-p53-8 are likely to become approved drugs. These novel inhibitors belong to a wide range of different molecule classes, ranging from small molecules to peptidomimetics and biologicals. This article reviews the main reasons for limited success in targeting PPIs, discusses how successful approaches overcome these obstacles to discovery promising inhibitors for human protein double minute 2 (HDM2), B-cell lymphoma 2 (Bcl-2), X-linked inhibitor of apoptosis protein (XIAP), and provides a summary of the promising approaches currently in development that indicate the future potential of PPI inhibitors in drug discovery. PMID- 26936772 TI - Novel photoswitchable dielectric properties on nanomaterials of electronic core shell gamma-FeOx@Au@fullerosomes for GHz frequency applications. AB - We unexpectedly observed a large amplification of the dielectric properties associated with the photoswitching effect and the new unusual phenomenon of delayed photoinduced capacitor-like (i.e. electric polarization) behavior at the interface on samples of three-layered core-shell (gamma-FeOx@AuNP)@[C60(>DPAF C9)](n)2 nanoparticles (NPs) in frequencies of 0.5-4.0 GHz. The detected relative dielectric constant amplification was initiated upon switching off the light followed by relaxation to give an excellent recyclability. These NPs having e(-) polarizable fullerosomic structures located at the outer layer were fabricated from highly magnetic core-shell gamma-FeOx@AuNPs. Surface-stabilized 2 in a core shell structure was found to be capable of photoinducing the surface plasmonic resonance (SPR) effect by white LED light. The accumulated SPR energy was subsequently transferred to the partially bilayered C60(>DPAF-C9) fullerosomic membrane layer in a near-field (~1.5 nm) region without producing radiation heat. Since the monostatic SAR signal is dielectric property-dependent, we used these measurements to provide evidence of derived reflectivity changes on a surface coated with 2 at 0.5-4.0 GHz upon illumination of LED white light. We found that a high, >99%, efficiency of response amplification in image amplitude can be achieved. PMID- 26936771 TI - Pancreatic Beta Cell Survival and Signaling Pathways: Effects of Type 1 Diabetes Associated Genetic Variants. AB - Type 1 diabetes (T1D) is a complex autoimmune disease in which pancreatic beta cells are specifically destroyed by the immune system. The disease has an important genetic component and more than 50 loci across the genome have been associated with risk of developing T1D. The molecular mechanisms by which these putative T1D candidate genes modulate disease risk, however, remain poorly characterized and little is known about their effects in pancreatic beta cells. Functional studies in in vitro models of pancreatic beta cells, based on techniques to inhibit or overexpress T1D candidate genes, allow the functional characterization of several T1D candidate genes. This requires a multistage procedure comprising two major steps, namely accurate selection of genes of potential interest and then in vitro and/or in vivo mechanistic approaches to characterize their role in pancreatic beta cell dysfunction and death in T1D. This chapter details the methods and settings used by our groups to characterize the role of T1D candidate genes on pancreatic beta cell survival and signaling pathways, with particular focus on potentially relevant pathways in the pathogenesis of T1D, i.e., inflammation and innate immune responses, apoptosis, beta cell metabolism and function. PMID- 26936773 TI - Multiple paths of electron flow to current in microbial electrolysis cells fed with low and high concentrations of propionate. AB - Microbial electrolysis cells (MECs) provide a viable approach for bioenergy generation from fermentable substrates such as propionate. However, the paths of electron flow during propionate oxidation in the anode of MECs are unknown. Here, the paths of electron flow involved in propionate oxidation in the anode of two chambered MECs were examined at low (4.5 mM) and high (36 mM) propionate concentrations. Electron mass balances and microbial community analysis revealed that multiple paths of electron flow (via acetate/H2 or acetate/formate) to current could occur simultaneously during propionate oxidation regardless of the concentration tested. Current (57-96 %) was the largest electron sink and methane (0-2.3 %) production was relatively unimportant at both concentrations based on electron balances. At a low propionate concentration, reactors supplemented with 2-bromoethanesulfonate had slightly higher coulombic efficiencies than reactors lacking this methanogenesis inhibitor. However, an opposite trend was observed at high propionate concentration, where reactors supplemented with 2 bromoethanesulfonate had a lower coulombic efficiency and there was a greater percentage of electron loss (23.5 %) to undefined sinks compared to reactors without 2-bromoethanesulfonate (11.2 %). Propionate removal efficiencies were 98 % (low propionate concentration) and 78 % (high propionate concentration). Analysis of 16S rRNA gene pyrosequencing revealed the dominance of sequences most similar to Geobacter sulfurreducens PCA and G. sulfurreducens subsp. ethanolicus. Collectively, these results provide new insights on the paths of electron flow during propionate oxidation in the anode of MECs fed with low and high propionate concentrations. PMID- 26936775 TI - Can the Genetic Origin Affect Rabbit Seminal Plasma Protein Profile along the Year? AB - The study was designed to evaluate the influence of genetic origin on rabbit seminal plasma protein profile variation along the year. Seminal plasma of rabbits from line A (maternal line) and R (paternal line) collected during a natural year was subjected to polyacrylamide gel electrophoresis (SDS-PAGE). The electrophoretic profile of rabbit seminal plasma resulted in multiple protein bands of different intensity ranging from 9 to 240 kDa. Results showed that seven protein bands were significantly different between genetic lines, and among these, three protein bands were significantly different between seasons. The differentially expressed proteins were identified by MALDI-TOF/TOF or LC-MS/MS analysis and were the following ones: FAM115E-like (220, 113 and 59 kDa), ectonucleoside triphosphate diphosphohydrolase 3 isoform X2 (72 kDa), annexin A5 (32 kDa), lipocalin allergen Ory c 4 precursor (19 kDa), and haemoglobin subunit zetalike (13 kDa) between genetic lines and FAM115E-like (113 kDa), haemoglobin subunit zetalike (13 kDa) and beta-nerve growth factor (12 kDa) between seasons. These results indicate that proteins from rabbit seminal plasma are under both seasonal control and genetic control. Furthermore, the differential presence of these proteins could be one of the causes explaining the differences observed in fertility and seminal parameters between these two lines in earlier studies. PMID- 26936774 TI - Advances in recombinant antibody manufacturing. AB - Since the first use of Chinese hamster ovary (CHO) cells for recombinant protein expression, production processes have steadily improved through numerous advances. In this review, we have highlighted several key milestones that have contributed to the success of CHO cells from the beginning of their use for monoclonal antibody (mAb) expression until today. The main factors influencing the yield of a production process are the time to accumulate a desired amount of biomass, the process duration, and the specific productivity. By comparing maximum cell densities and specific growth rates of various expression systems, we have emphasized the limiting parameters of different cellular systems and comprehensively described scientific approaches and techniques to improve host cell lines. Besides the quantitative evaluation of current systems, the quality determining properties of a host cell line, namely post-translational modifications, were analyzed and compared to naturally occurring polyclonal immunoglobulin fractions from human plasma. In summary, numerous different expression systems for mAbs are available and also under scientific investigation. However, CHO cells are the most frequently investigated cell lines and remain the workhorse for mAb production until today. PMID- 26936777 TI - Evaluation of movement quality: a new tool for children with hyperkinetic movement disorders. PMID- 26936776 TI - Oxford Lithium Trial (OxLith) of the early affective, cognitive, neural and biochemical effects of lithium carbonate in bipolar disorder: study protocol for a randomised controlled trial. AB - BACKGROUND: Despite lithium's being the most effective drug for bipolar disorder and in clinical use for decades, we still know very little about its early effects relevant to its mode of action. METHODS/DESIGN: The Oxford Lithium Trial is a double-blind, randomised, placebo-controlled study of 6-week lithium treatment in participants with bipolar disorder and mood instability. Its aim is to identify early clinical, neurocognitive and biological effects. Participants (n = 40) will undergo an intensive battery of multi-modal investigations, including remote monitoring of mood, activity and physiology, as well as cognitive testing, fMRI and magnetoencephalography, together with biochemical and gene expression measurements to assess renal, inflammatory and circadian effects. DISCUSSION: The findings derived from this trial may be of value in predicting subsequent therapeutic response or side effects, not only relevant to the use of lithium but also providing a potential signature to help in more rapid evaluation of novel mood stabilisers. In this respect, OxLith is a step towards the development of a valid experimental medicine model for bipolar disorder. TRIAL REGISTRATION: ISRCTN91624955 . Registered on 22 January 2015. PMID- 26936778 TI - A single dose of alcohol does not meaningfully alter circadian phase advances and phase delays to light in humans. AB - Central circadian timing influences mental and physical health. Research in nocturnal rodents has demonstrated that when alcohol is consumed, it reaches the central hypothalamic circadian pacemaker (suprachiasmatic nuclei) and can directly alter circadian phase shifts to light. In two separate studies, we examined, for the first time, the effects of a single dose of alcohol on circadian phase advances and phase delays to light in humans. Two 23-day within subjects placebo-controlled counterbalanced design studies were conducted. Both studies consisted of 6 days of fixed baseline sleep to stabilize circadian timing, a 2-day laboratory session, a 6-day break, and a repeat of 6 days of fixed sleep and a 2-day laboratory session. In the phase advance study (n= 10 light drinkers, 24-45 yr), the laboratory sessions consisted of a baseline dim light phase assessment, sleep episode, alcohol (0.6 g/kg) or placebo, 2-h morning bright light pulse, and final phase assessment. In the phase-delay study (n= 14 light drinkers, 22-44 yr), the laboratory sessions consisted of a baseline phase assessment, alcohol (0.8 g/kg) or placebo, 2-h late night bright light pulse, sleep episode, and final phase assessment. In both studies, alcohol either increased or decreased the observed phase shifts to light (interaction P>= 0.46), but the effect of alcohol vs. placebo on phase shifts to light was always on average smaller than 30 min. Thus, no meaningful effects of a single dose of alcohol vs. placebo on circadian phase shifts to light in humans were observed. PMID- 26936779 TI - Hindbrain glucagon-like peptide-1 neurons track intake volume and contribute to injection stress-induced hypophagia in meal-entrained rats. AB - Published research supports a role for central glucagon-like peptide 1 (GLP-1) signaling in suppressing food intake in rodent species. However, it is unclear whether GLP-1 neurons track food intake and contribute to satiety, and/or whether GLP-1 signaling contributes to stress-induced hypophagia. To examine whether GLP 1 neurons track intake volume, rats were trained to consume liquid diet (LD) for 1 h daily until baseline intake stabilized. On test day, schedule-fed rats consumed unrestricted or limited volumes of LD or unrestricted volumes of diluted (calorically matched to LD) or undiluted Ensure. Rats were perfused after the test meal, and brains processed for immunolocalization of cFos and GLP-1. The large majority of GLP-1 neurons expressed cFos in rats that consumed satiating volumes, regardless of diet type, with GLP-1 activation proportional to intake volume. Since GLP-1 signaling may limit intake only when such large proportions of GLP-1 neurons are activated, a second experiment examined the effect of central GLP-1 receptor (R) antagonism on 2 h intake in schedule-fed rats. Compared with baseline, intracerebroventricular vehicle (saline) suppressed Ensure intake by ~11%. Conversely, intracerebroventricular injection of vehicle containing GLP-1R antagonist increased intake by ~14% compared with baseline, partly due to larger second meals. We conclude that GLP-1 neural activation effectively tracks liquid diet intake, that intracerebroventricular injection suppresses intake, and that central GLP-1 signaling contributes to this hypophagic effect. GLP-1 signaling also may contribute to satiety after large volumes have been consumed, but this potential role is difficult to separate from a role in the hypophagic response to intracerebroventricular injection. PMID- 26936780 TI - Vascular smooth muscle-specific deletion of the leptin receptor attenuates leptin induced alterations in vascular relaxation. AB - Obesity is a risk factor for cardiovascular disease and is associated with increased plasma levels of the adipose-derived hormone leptin. Vascular smooth muscle cells (VSMC) express leptin receptors (LepR); however, their physiological role is unclear. We hypothesized that leptin, at levels to mimic morbid obesity, impairs vascular relaxation. To test this, we used control and VSM-LepR knockout mice (VSM-LepR KO) created with a tamoxifen-inducible specific Cre recombinase to delete the LepR gene in VSMC. Control (10-12 wk old) and VSM-LepR KO (10-12 wk old) mice were fed a diet containing tamoxifen (50 mg/kg) for 6 wk, after which vascular reactivity was studied in isolated carotid arteries using an organ chamber bath. Vessels were incubated with leptin (100 ng/ml) or vehicle (0.1 mM Tris.HCl) for 30 min. Leptin treatment resulted in significant impairment of vessel relaxation to the endothelial-specific agonist acetylcholine (ACh). When these experiments were repeated in the presence of the superoxide scavenger tempol, relaxation responses to ACh were restored. VSM-LepR deletion resulted in a significant attenuation of leptin-mediated impaired ACh-induced relaxation. These data show that leptin directly impairs vascular relaxation via a VSM-LepR mediated mechanism, suggesting a potential pathogenic role for leptin to increase cardiovascular risk during obesity. PMID- 26936781 TI - Endothelin, sex, and pregnancy: unique considerations for blood pressure control in females. AB - Endothelin-1 (ET-1) is a potent vasoconstrictor, and dysregulation of the endothelin (ET) system has been implicated in the development of hypertension. Sex differences in the ET system have been identified in ET receptor expression and activation, levels of ET-1, and downstream mediators of the ET system. More specifically, males have greater ET-1/ETA receptor activation, whereas females exhibit greater ETB receptor activation. These differences have been suggested to contribute to the sex differences observed in blood pressure control, with greater ETB receptor activation in females potentially acting as an important pathway contributing to the lower prevalence of hypertension in young females compared with age-matched males. This hypothesis is further supported by studies in pregnancy; the role of the ET system is enhanced during pregnancy, with dysregulation of the ET system resulting in preeclampsia. Further research is necessary to elucidate the relative roles of the ET system in blood pressure control in both sexes and to further explore the potential benefits of pharmacological ET blockade in women. PMID- 26936783 TI - Regulation of lung maturation by prolyl hydroxylase domain inhibition in the lung of the normally grown and placentally restricted fetus in late gestation. AB - Intrauterine growth restriction induced by placental restriction (PR) in sheep leads to chronic hypoxemia and reduced surfactant maturation. The underlying molecular mechanism involves altered regulation of hypoxia signaling by increased prolyl hydroxylase domain (PHD) expression. Here, we evaluated the effect of intratracheal administration of the PHD inhibitor dimethyloxalylglycine (DMOG) on functional, molecular, and structural determinants of lung maturation in the control and PR sheep fetus. There was no effect of DMOG on fetal blood pressure or fetal breathing movements. DMOG reduced lung expression of genes regulating hypoxia signaling (HIF-3alpha, ACE1), antioxidant defense (CAT), lung liquid reabsorption (SCNN1-A, ATP1-A1, AQP-1, AQP-5), and surfactant maturation (SFTP-A, SFTP-B, SFTP-C, PCYT1A, LPCAT, ABCA3, LAMP3) in control fetuses. There were very few effects of DMOG on gene expression in the PR fetal lung (reduced lung expression of angiogenic factor ADM, water channel AQP-5, and increased expression of glucose transporter SLC2A1). DMOG administration in controls reduced total lung lavage phosphatidylcholine to the same degree as in PR fetuses. These changes appear to be regulated at the molecular level as there was no effect of DMOG on the percent tissue, air space, or numerical density of SFTP B positive cells in the control and PR lung. Hence, DMOG administration mimics the effects of PR in reducing surfactant maturation in the lung of control fetuses. The limited responsiveness of the PR fetal lung suggests a potential biochemical limit or reduced plasticity to respond to changes in regulation of hypoxia signaling following exposure to chronic hypoxemia in utero. PMID- 26936782 TI - Ischemic preconditioning reduces hemodynamic response during metaboreflex activation. AB - Ischemic preconditioning (IP) has been shown to improve exercise performance and to delay fatigue. However, the precise mechanisms through which IP operates remain elusive. It has been hypothesized that IP lowers the sensation of fatigue by reducing the discharge of group III and IV nerve endings, which also regulate hemodynamics during the metaboreflex. We hypothesized that IP reduces the blood pressure response during the metaboreflex. Fourteen healthy males (age between 25 and 48 yr) participated in this study. They underwent the following randomly assigned protocol: postexercise muscle ischemia (PEMI) test, during which the metaboreflex was elicited after dynamic handgrip; control exercise recovery session (CER) test; and PEMI after IP (IP-PEMI) test. IP was obtained by occluding forearm circulation for three cycles of 5 min spaced by 5 min of reperfusion. Hemodynamics were evaluated by echocardiography and impedance cardiography. The main results were that after IP the mean arterial pressure response was reduced compared with the PEMI test (means +/- SD +3.37 +/- 6.41 vs. +9.16 +/- 7.09 mmHg, respectively). This was the consequence of an impaired venous return that impaired the stroke volume during the IP-PEMI more than during the PEMI test (-1.43 +/- 15.35 vs. +10.28 +/- 10.479 ml, respectively). It was concluded that during the metaboreflex, IP affects hemodynamics mainly because it impairs the capacity to augment venous return and to recruit the cardiac preload reserve. It was hypothesized that this is the consequence of an increased nitric oxide production, which reduces the possibility to constrict venous capacity vessels. PMID- 26936784 TI - Polycythemia and high levels of erythropoietin in blood and brain blunt the hypercapnic ventilatory response in adult mice. AB - Changes in arterial Po2, Pco2, and pH are the strongest stimuli sensed by peripheral and central chemoreceptors to adjust ventilation to the metabolic demand. Erythropoietin (Epo), the main regulator of red blood cell production, increases the hypoxic ventilatory response, an effect attributed to the presence of Epo receptors in both carotid bodies and key brainstem structures involved in integration of peripheral inputs and control of breathing. However, it is not known whether Epo also has an effect on the hypercapnic chemoreflex. In a first attempt to answer this question, we tested the hypothesis that Epo alters the ventilatory response to increased CO2 levels. Basal ventilation and hypercapnic ventilatory response (HCVR) were recorded from control mice and from two transgenic mouse lines constitutively expressing high levels of human Epo in brain only (Tg21) or in brain and plasma (Tg6), the latter leading to polycythemia. To tease apart the potential effects of polycythemia and levels of plasma Epo in the HCVR, control animals were injected with an Epo analog (Aranesp), and Tg6 mice were treated with the hemolytic agent phenylhydrazine after splenectomy. Ventilatory parameters measured by plethysmography in conscious mice were consistent with data from electrophysiological recordings in anesthetized animals and revealed a blunted HCVR in Tg6 mice. Polycythemia alone and increased levels of plasma Epo blunt the HCVR. In addition, Tg21 mice with an augmented level of cerebral Epo also had a decreased HCVR. We discuss the potential implications of these findings in several physiopathological conditions. PMID- 26936785 TI - Relaxin deficiency attenuates pregnancy-induced adaptation of the mesenteric artery to angiotensin II in mice. AB - Pregnancy is associated with reduced peripheral vascular resistance, underpinned by changes in endothelial and smooth muscle function. Failure of the maternal vasculature to adapt correctly leads to serious pregnancy complications, such as preeclampsia. The peptide hormone relaxin regulates the maternal renal vasculature during pregnancy; however, little is known about its effects in other vascular beds. This study tested the hypothesis that functional adaptation of the mesenteric and uterine arteries during pregnancy will be compromised in relaxin deficient (Rln(-/-)) mice. Smooth muscle and endothelial reactivity were examined in small mesenteric and uterine arteries of nonpregnant (estrus) and late pregnant (day 17.5) wild-type (Rln(+/+)) and Rln(-/-) mice using wire myography. Pregnancy per se was associated with significant reductions in contraction to phenylephrine, endothelin-1, and ANG II in small mesenteric arteries, while sensitivity to endothelin-1 was reduced in uterine arteries of Rln(+/+) mice. The normal pregnancy-associated attenuation of ANG II-mediated vasoconstriction in mesenteric arteries did not occur in Rln(-/-) mice. This adaptive failure was endothelium-independent and did not result from altered expression of ANG II receptors or regulator of G protein signaling 5 (Rgs5) or increases in reactive oxygen species generation. Inhibition of nitric oxide synthase with l-NAME enhanced ANG II-mediated contraction in mesenteric arteries of both genotypes, whereas blockade of prostanoid production with indomethacin only increased ANG II induced contraction in arteries of pregnant Rln(+/+) mice. In conclusion, relaxin deficiency prevents the normal pregnancy-induced attenuation of ANG II-mediated vasoconstriction in small mesenteric arteries. This is associated with reduced smooth muscle-derived vasodilator prostanoids. PMID- 26936786 TI - The hypophagic response to heat stress is not mediated by GPR109A or peripheral beta-OH butyrate. AB - Rising temperatures resulting from climate change will increase the incidence of heat stress, negatively impacting the labor force and food animal production. Heat stress elevates circulating beta-OH butyrate, which induces vasodilation through GPR109a. Interestingly, both heat stress and intraperitoneal beta-OH butyrate administration induce hypophagia. Thus, we aimed to investigate the role of beta-OH butyrate in heat stress hypophagia in mice. We found that niacin, a beta-OH butyrate mimetic that cannot be oxidized to generate ATP, also reduces food intake. Interestingly, the depression in food intake as a result of 8-h intraperitoneal niacin or 48-h heat exposure did not result from changes in hypothalamic expression of orexigenic or anorexigenic signals (AgRP, NPY, or POMC). Genetically eliminating GPR109a expression did not prevent the hypophagic response to heat exposure, intraperitoneal beta-OH butyrate (5.7 mmol/kg), or niacin (0.8 mmol/kg). Hepatic vagotomy eliminated the hypophagic response to beta OH butyrate and niacin but did not affect the hypophagic response to heat exposure. We subsequently hypothesized that the hypophagic response to heat stress may depend on direct effects of beta-OH butyrate at the central nervous system: beta-OH butyrate induced hormonal changes (hyperinsulinemia, hypercorticosteronemia, and hyperleptinemia), or gene expression changes. To test these possibilities, we blocked expression of hepatic hydroxyl methyl glutaryl CoA synthase II (HMGCS2) to prevent hepatic beta-OH butyrate synthesis. Mice that lack HMGCS2 maintain a hypophagic response to heat stress. Herein, we establish that the hypophagia of heat stress is independent of GPR109a, the hepatic vagus afferent nerve, and hepatic ketone body synthesis. PMID- 26936788 TI - Starch Accumulation in the Bundle Sheaths of C3 Plants: A Possible Pre-Condition for C4 Photosynthesis. AB - C4 plants have evolved >60 times from their C3 ancestors. C4 photosynthesis requires a set of closely co-ordinated anatomical and biochemical characteristics. However, it is now recognized that the evolution of C4 plants requires fewer changes than had ever been considered, because of the genetic, biochemical and anatomical pre-conditions of C3 ancestors that were recruited into C4 photosynthesis. Therefore, the pre-conditions in C3 plants are now being actively investigated to clarify the evolutionary trajectory from C3 to C4 plants and to engineer C4 traits efficiently into C3 crops. In the present mini review, the anatomical characteristics of C3 and C4 plants are briefly reviewed and the importance of the bundle sheath for the evolution of C4 photosynthesis is described. For example, while the bundle sheath of C3 rice plants accumulates large amounts of starch in the developing leaf blade and at the lamina joint of the mature leaf, the starch sheath function is also observed during leaf development in starch accumulator grasses regardless of photosynthetic type. The starch sheath function of C3 plants is therefore also implicated as a possible pre-condition for the evolution of C4 photosynthesis. The phylogenetic relationships between the types of storage carbohydrates and of photosynthesis need to be clarified in the future. PMID- 26936787 TI - New potent accelerator of neurite outgrowth from Lawsonia inermis flower under non-fasting condition. AB - The methanolic extract of Lawsonia inermis L. (henna) showed accelerative effects on nerve growth factor-induced neurite outgrowth in PC12 cells under non-fasting conditions. To elucidate the active constituents responsible for the neuronal differentiation, we conducted a search of the constituents and examined their accelerative effects on neurite outgrowth in PC12 cells. We isolated a new acetophenone glycoside, inermioside A, which exerted a significant accelerative effect on neurite outgrowth. We also confirmed the activities of nine known compounds, including quercetin and lalioside. In addition, we found that quercetin, one of the active constituents, increased Vav3 mRNA expression. PMID- 26936789 TI - A Novel Antifouling Defense Strategy from Red Seaweed: Exocytosis and Deposition of Fatty Acid Derivatives at the Cell Wall Surface. AB - We investigated the organelles involved in the biosynthesis of fatty acid (FA) derivatives in the cortical cells of Laurencia translucida (Rhodophyta) and the effect of these compounds as antifouling (AF) agents. A bluish autofluorescence (with emission at 500 nm) within L. translucida cortical cells was observed above the thallus surface via laser scanning confocal microscopy (LSCM). A hexanic extract (HE) from L. translucida was split into two isolated fractions called hydrocarbon (HC) and lipid (LI), which were subjected to HPLC coupled to a fluorescence detector, and the same autofluorescence pattern as observed by LSCM analyses (emission at 500 nm) was revealed in the LI fraction. These fractions were analyzed by gas chromatography-mass spectrometry (GC-MS), which revealed that docosane is the primary constituent of HC, and hexadecanoic acid and cholesterol trimethylsilyl ether are the primary components of LI. Nile red (NR) labeling (lipid fluorochrome) presented a similar cellular localization to that of the autofluorescent molecules. Transmission and scanning electron microscopy (TEM and SEM) revealed vesicle transport processes involving small electron lucent vesicles, from vacuoles to the inner cell wall. Both fractions (HC and LI) inhibited micro-fouling [HC, lower minimum inhibitory concentration (MIC) values of 0.1 ug ml(-1); LI, lower MIC value of 10 ug ml(-1)]. The results suggested that L. translucida cortical cells can produce FA derivatives (e.g. HCs and FAs) and secrete them to the thallus surface, providing a unique and novel protective mechanism against microfouling colonization in red algae. PMID- 26936790 TI - Oil Secretory System in Vegetative Organs of Three Arnica Taxa: Essential Oil Synthesis, Distribution and Accumulation. AB - Arnica, a genus including the medicinal species A. montana, in its Arbo variety, and A. chamissonis, is among the plants richest in essential oils used as pharmaceutical materials. Despite its extensive use, the role of anatomy and histochemistry in the internal secretory system producing the essential oil is poorly understood. Anatomical sections allowed differentiation between two forms of secretory structures which differ according to their distribution in plants. The first axial type is connected to the vascular system of all vegetative organs and forms canals lined with epithelial cells. The second cortical type is represented by elongated intercellular spaces filled with oil formed only between the cortex cells of roots and rhizomes at maturity, with canals lacking an epithelial layer.Only in A. montana rhizomes do secretory structures form huge characteristic reservoirs. Computed tomography illustrates their spatial distribution and fusiform shape. The axial type of root secretory canals is formed at the interface between the endodermis and cortex parenchyma, while, in the stem, they are located in direct contact with veinal parenchyma. The peripheral phloem parenchyma cells are arranged in strands around sieve tube elements which possess a unique ability to accumulate large amounts of oil bodies. The cells of phloem parenchyma give rise to the aforementioned secretory structures while the lipid components (triacylglycerols) stored there support the biosynthesis of essential oils by later becoming a medium in which these oils are dissolved. The results indicate the integrity of axial secretory structures forming a continuous system in vegetative plant organs. PMID- 26936791 TI - Plastid Terminal Oxidase as a Route to Improving Plant Stress Tolerance: Known Knowns and Known Unknowns. AB - A plastid-localized terminal oxidase, PTox, was first described due to its role in chloroplast development, with plants lacking PTox producing white sectors on their leaves. This phenotype is explained as being due to PTox playing a role in carotenoid biosynthesis, as a cofactor of phytoene desaturase. Co-occurrence of PTox with a chloroplast-localized NADPH dehydrogenase (NDH) has suggested the possibility of a functional respiratory pathway in plastids. Evidence has also been found that, in certain stress-tolerant plant species, PTox can act as an electron acceptor from PSII, making it a candidate for engineering stress tolerant crops. However, attempts to induce such a pathway via overexpression of the PTox protein have failed to date. Here we review the current understanding of PTox function in higher plants and discuss possible barriers to inducing PTox activity to improve stress tolerance. PMID- 26936792 TI - Precision Targeted Mutagenesis via Cas9 Paired Nickases in Rice. AB - Recent reports of CRISPR- (clustered regularly interspaced short palindromic repeats)/Cas9 (CRISPR-associated protein 9) mediated heritable mutagenesis in plants highlight the need for accuracy of the mutagenesis directed by this system. Off-target mutations are an important issue when considering functional gene analysis, as well as the molecular breeding of crop plants with large genome size, i.e. with many duplicated genes, and where the whole-genome sequence is still lacking. In mammals, off-target mutations can be suppressed by using Cas9 paired nickases together with paired guide RNAs (gRNAs). However, the performance of Cas9 paired nickases has not yet been fully assessed in plants. Here, we analyzed on- and off-target mutation frequency in rice calli and regenerated plants using Cas9 nuclease or Cas9 nickase with paired gRNAs. When Cas9 paired nickases were used, off-target mutations were fully suppressed in rice calli and regenerated plants. However, on-target mutation frequency also decreased compared with that induced by the Cas9 paired nucleases system. Since the gRNA sequence determines specific binding of Cas9 protein-gRNA ribonucleoproteins at the targeted sequence, the on-target mutation frequency of Cas9 paired nickases depends on the design of paired gRNAs. Our results suggest that a combination of gRNAs that can induce mutations at high efficiency with Cas9 nuclease should be used together with Cas9 nickase. Furthermore, we confirmed that a combination of gRNAs containing a one nucleotide (1 nt) mismatch toward the target sequence could not induce mutations when expressed with Cas9 nickase. Our results clearly show the effectiveness of Cas9 paired nickases in delivering on-target specific mutations. PMID- 26936794 TI - In Vitro Assays of BciC Showing C132-Demethoxycarbonylase Activity Requisite for Biosynthesis of Chlorosomal Chlorophyll Pigments. AB - A BciC enzyme is related to the removal of the C13(2)-methoxycarbonyl group in biosynthesis of bacteriochlorophylls (BChls) c, d and e functioning in green sulfur bacteria, filamentous anoxygenic phototrophs and phototrophic acidobacteria. These photosynthetic bacteria have the largest and the most efficient light-harvesting antenna systems, called chlorosomes, containing unique self-aggregates of BChl c, d or e pigments, that lack the C13(2)-methoxycarbonyl group which disturbs chlorosomal self-aggregation. In this study, we characterized the BciC derived from the green sulfur bacterium Chlorobaculum tepidum, and examined the in vitro enzymatic activities of its recombinant protein. The BciC-catalyzing reactions of various substrates showed that the enzyme recognized chlorophyllide (Chlide) a and 3,8-divinyl(DV)-Chlide a as chlorin substrates to give 3-vinyl-bacteriochlorophyllide (3V-BChlide) d and DV BChlide d, respectively. Since the BciC afforded a higher activity with Chlide a than that with DV-Chlide a and no activity with (DV-)protoChlides a (porphyrin substrates) and 3V-BChlide a (a bacteriochlorin substrate), this enzyme was effective for diverting the chlorosomal pigment biosynthetic pathway at the stage of Chlide a away from syntheses of other pigments such as BChl a and Chl a The addition of methanol to the reaction mixture did not prevent the BciC activity, and we identified this enzyme as Chlide a demethoxycarbonylase, not methylesterase. PMID- 26936793 TI - The Flavodiiron Protein Flv3 Functions as a Homo-Oligomer During Stress Acclimation and is Distinct from the Flv1/Flv3 Hetero-Oligomer Specific to the O2 Photoreduction Pathway. AB - The flavodiiron proteins (FDPs) Flv1 and Flv3 in cyanobacteria function in photoreduction of O2 to H2O, without concomitant formation of reactive oxygen species, known as the Mehler-like reaction. Both Flv1 and Flv3 are essential for growth under fluctuating light (FL) intensities, providing protection for PSI. Here we compared the global transcript profiles of the wild type (WT), Deltaflv1 and Deltaflv1/Deltaflv3 grown under constant light (GL) and FL. In the WT, FL induced the largest down-regulation in transcripts involved in carbon concentrating mechanisms (CCMs), while those of the nitrogen assimilation pathways increased as compared with GL. Already under GL the Deltaflv1/Deltaflv3 double mutant demonstrated a partial down-regulation of transcripts for CCM and nitrogen metabolism, while in FL conditions the transcripts for nitrogen assimilation were strongly down-regulated. Many alterations were specific only for Deltaflv1/Deltaflv3, and not detected in Deltaflv1, suggesting that certain transcripts are affected primarily because of the lack of flv3 By constructing the strains overproducing solely either Flv1 or Flv3, we demonstrate that the homo-oligomers of these proteins also function in acclimation of cells to FL, by catalyzing reactions with as yet unidentified components, while the presence of both Flv1 and Flv3 is a prerequisite for the Mehler-like reaction and thus the electron transfer to O2 Considering the low expression of flv1, it is unlikely that the Flv1 homo-oligomer is present in the WT. PMID- 26936795 TI - "Because It's Hers": When Preschoolers Use Ownership in Their Explanations. AB - Young children show competence in reasoning about how ownership affects object use. In the present experiments, we investigate how influential ownership is for young children by examining their explanations. In three experiments, we asked 3- to 5-year-olds (N = 323) to explain why it was acceptable (Experiments 1-3) or unacceptable (Experiment 2 and 3) for a person to use an object. In Experiments 1 and 2, older preschoolers referenced ownership more than alternative considerations when explaining why it was acceptable or unacceptable for a person to use an object, even though ownership was not mentioned to them. In Experiment 3, ownership was mentioned to children. Here, younger preschoolers frequently referenced ownership when explaining unacceptability of using an object, but not when explaining why using it was acceptable. These findings suggest that ownership is influential in preschoolers' explanations about the acceptability of using objects, but that the scope of its influence increases with age. PMID- 26936796 TI - Prevalence and Diversity of Leptospires in Different Ecological Niches of Urban and Rural Areas of South Andaman Island. AB - Leptospirosis is an emerging disease around the globe. South Andaman Island is an endemic region for leptospirosis. We herein compared the prevalence of leptospires in urban and rural areas of South Andaman Island. The PCR detection and isolation of Leptospira revealed that pathogenic leptospires were prevalent in sewage water and household drainage water in urban areas and in paddy fields, vegetable field water, and stream water in rural areas. These results demonstrate that intermediates are ubiquitously present in the environment and may be responsible for asymptomatic infections, and also provide an insight into disease ecology. PMID- 26936797 TI - Unexpected Diversity of pepA Genes Encoding Leucine Aminopeptidases in Sediments from a Freshwater Lake. AB - We herein designed novel PCR primers for universal detection of the pepA gene, which encodes the representative leucine aminopeptidase gene, and investigated the genetic characteristics and diversity of pepA genes in sediments of hypereutrophic Lake Kasumigaura, Japan. Most of the amino acid sequences deduced from the obtained clones (369 out of 370) were related to PepA-like protein sequences in the M17 family of proteins. The developed primers broadly detected pepA-like clones associated with diverse bacterial phyla-Alpha-, Beta-, Gamma-, and Deltaproteobacteria, Acidobacteria, Actinobacteria, Aquificae, Chlamydiae, Chloroflexi, Cyanobacteria, Firmicutes, Nitrospirae, Planctomycetes, and Spirochetes as well as the archaeal phylum Thaumarchaeota, indicating that prokaryotes in aquatic environments possessing leucine aminopeptidase are more diverse than previously reported. Moreover, prokaryotes related to the obtained pepA-like clones appeared to be r- and K-strategists, which was in contrast to our previous findings showing that the neutral metalloprotease gene clones obtained were related to the r-strategist genus Bacillus. Our results suggest that an unprecedented diversity of prokaryotes with a combination of different proteases participate in sedimentary proteolysis. PMID- 26936798 TI - Incidence and risk factors for venous thromboembolism following surgical treatment of fractures below the hip: a meta-analysis. AB - Venous thromboembolism (VTE) is a common complication after surgical treatment of fractures, which is associated with significant morbidity and mortality. Identifying the risk factors for VTE is important for preventive strategies to reduce the incidence of VTE. Therefore, we conducted a meta-analysis to evaluate the incidence of VTE and the risk factors influencing the development of VTE in patients who underwent surgery for fractures below the hip. PubMed, Embase, Web of Science, SinoMed (Chinese BioMedical Literature Service System, China) and CNKI (National Knowledge Infrastructure, China) databases were systematically searched to identify cohort or case-control studies that investigated the incidence and risk factors for VTE following surgical treatment of fractures below the hip. VTE risk ratios (RRs) were pooled by use of a fixed-effect model or a random-effect model, depending on the heterogeneity among the included studies. Heterogeneity between the studies was assessed by I2 statistics. Twenty three studies with a total of 191 294 patients who met the inclusion criteria were included in this meta-analysis. Our results demonstrated that age (>=60 years) (RR = 1.85, 95% confidence interval (CI): 1.34, 2.55; P = 0.000), previous VTE(RR = 5.25, 95% CI: 2.77, 9.96; P = 0.000), heart failure (RR = 1.74, 95% CI: 1.34, 2.27; P = 0.000), current smoking status (RR = 1.23, 95% CI: 1.07, 1.41; P = 0.004), hypertension (RR = 1.62, 95% CI: 1.27, 2.06; P = 0.000), hyperlipidaemia (RR = 2.16, 95% CI: 1.79, 2.62; P = 0.000), diabetes mellitus (RR = 1.46, 95% CI: 1.27, 1.68; P = 0.000), obesity (RR = 1.58, 95% CI: 1.35,.1.85; P = 0.000), multiple fractures (RR = 2.14, 95% CI: 1.00, 4.60; P = 0.050), varicose veins (RR = 3.07, 95% CI: 1.12, 8.47; P = 0.030), prolonged operation time (weighted mean differences (WMD) = 1.22, 95% CI: 0.63, 1.81; P = 0.000) and prolonged bed rest time (WMD = 3.12, 95% CI: 2.96, 3.29; P = 0.000) were associated with an increased risk of developing VTE. The other variables, including age (<60 years), previous smoking, immobility, pregnancy, cancer, open fractures and combination with trauma were not identified as significant risk factors for VTE. Almost all the risk factors mentioned above are in line with the known risk factors for VTE following surgery for fractures below the hip. Thus, surgeons should pay close attention to patients with these medical conditions in order to reduce the incidence of VTE following surgical treatment of fractures below the hip. PMID- 26936800 TI - Single joint robotic orthoses for gait rehabilitation: An educational technical review. AB - Robot-assisted physical gait therapy is gaining recognition among the rehabilitation engineering community. Several robotic orthoses for the treatment of gait impairments have been developed during the last 2 decades, many of which are designed to provide physical therapy to a single joint of the lower limb; these are reviewed here. The mechanism design and actuation concepts for these single joint robotic orthoses are discussed. The control algorithms developed for these robotic orthoses, which include trajectory tracking control and assist-as needed control, are described. Finally, the mechanism design and control of single joint robotic orthoses are discussed. There is a strong need to develop assist-as-needed control algorithms and to perform clinical evaluation of these robotic orthoses in order to establish their therapeutic efficacy. PMID- 26936799 TI - Long-term Outcome of Irish Wolfhound Dogs with Preclinical Cardiomyopathy, Atrial Fibrillation, or Both Treated with Pimobendan, Benazepril Hydrochloride, or Methyldigoxin Monotherapy. AB - BACKGROUND: Dilated cardiomyopathy (DCM) is a common cause of morbidity and mortality in the Irish Wolfhound (IW). However, the benefit of medical treatment in IW dogs with preclinical DCM, atrial fibrillation (AF), or both has not been demonstrated. OBJECTIVES: Compare the time to develop congestive heart failure (CHF) or sudden death in IW dogs with preclinical DCM, AF, or both receiving monotherapy with pimobendan, methyldigoxin, or benazepril hydrochloride. ANIMALS: Seventy-five client-owned IW dogs. METHODS: Irish Wolfhound dogs were prospectively randomized to receive pimobendan (Vetmedin(r)), benazepril HCl (Fortekor(r)), or methyldigoxin (Lanitop(r)) monotherapy in a 1:1:1 ratio in a blinded clinical trial. The prospectively defined composite primary endpoint was onset of CHF or sudden death. To assure stringent evaluation of treatment effect, data from dogs complying with the study protocol were analyzed. RESULTS: Sixty six IW fulfilling the study protocol included 39 males, 27 females; median (interquartile range) age, 4.0 years (3.0-5.0 years) and weight, 70.0 kg (63.0 75.0 kg). Primary endpoint was reached in 5 of 23 (21.7%) IW receiving pimobendan, 11 of 22 (50.0%) receiving benazepril HCl, and 9 of 21 (42.9%) receiving methyldigoxin. Median time to primary endpoint was significantly longer for pimobendan (1,991 days; 65.4 months) compared to methyldigoxin (1,263 days; 41.5 months; P = .031) or benazepril HCl-(997 days; 32.8 months; P = .008) treated dogs. CONCLUSIONS AND CLINICAL IMPORTANCE: In IW dogs with preclinical DCM, AF or both, pimobendan monotherapy significantly prolonged time to onset of CHF or sudden death than did monotherapy with benazepril HCl or methyldigoxin. PMID- 26936801 TI - Silencing of phosphoglucose isomerase/autocrine motility factor decreases U87 human glioblastoma cell migration. AB - Phosphoglucose isomerase/autocrine motility factor (PGI/AMF) is secreted by tumors and influences tumor growth and metastasis. In order to investigate the effects of silencing PGI/AMF on the migration and the sphere forming abilities of human glioblastoma U87 cells, as well as on the side population cells (SPCs), PGI/AMF was silenced using siRNA. Western blot analysis and RT-qPCR were used to assess the expression of PGI/AMF, Akt and SRY (sex determining region Y)-box 2 (SOX2). Wound healing, migration and tumorsphere formation assays were performed to assess invasion and metastatic potential. The proportion of SPCs was determined using Hoechst 33342 dye and flow cytometric analysis. PGI/AMF silencing inhibited the wound healing capacity and migration ability of U87 cells by 52.6 and 80.4%, respectively, compared with the scrambled siRNA (both P<0.001). Silencing of PGI/AMF decreased the proportion of SPCs in the U87 cells by 80.9% (P<0.01). The silencing of PGI/AMF decreased the number and size of tumorspheres by 53.1 and 39.9%, respectively, compared with the scrambled siRNA (both P<0.01). The silencing of PGI/AMF decreased the levels of phosphorylated Akt (-71.9%, P<0.001) compared with the scrambled siRNA, as well as the levels of the stemness marker, SOX2 (-61.7%, P<0.01). Taken together, these findings suggest that PGI/AMF silencing decreases migration, tumorsphere formation as well as the proportion of SPCs in glioblastoma U87 cells. We suggest that the Akt pathway is involved, and our results provide a potential new target for the treatment of glioblastoma. PMID- 26936802 TI - Evolution of pharmacological obesity treatments: focus on adverse side-effect profiles. AB - Pharmacotherapy directed toward reducing body weight may provide benefits for both curbing obesity and lowering the risk of obesity-associated comorbidities; however, many weight loss medications have been withdrawn from the market because of serious adverse effects. Examples include pulmonary hypertension (aminorex), cardiovascular toxicity, e.g. flenfluramine-induced valvopathy, stroke [phenylpropanolamine (PPA)], excess non-fatal cardiovascular events (sibutramine), and neuro-psychiatric issues (rimonabant; approved in Europe, but not in the USA). This negative experience has helped mould the current drug development and approval process for new anti-obesity drugs. Differences between the US Food and Drug Administration (FDA) and the European Medicines Agency, however, in perceptions of risk-benefit considerations for individual drugs have resulted in discrepancies in approval and/or withdrawal of weight-reducing medications. Thus, two drugs recently approved by the FDA, i.e. lorcaserin and phentermine + topiramate extended release, are not available in Europe. In contrast, naltrexone sustained release (SR)/bupropion SR received FDA approval, and liraglutide 3.0 mg was recently approved in both the USA and Europe. Regulatory strategies adopted by the FDA to manage the potential for uncommon but potentially serious post-marketing toxicity include: (i) risk evaluation and mitigation strategy programmes; (ii) stipulating post-marketing safety trials; (iii) considering responder rates and limiting cumulative exposure by discontinuation if weight loss is not attained within a reasonable timeframe; and (iv) requiring large cardiovascular outcome trials before or after approval. We chronicle the adverse effects of anti-obesity pharmacotherapy and consider how the history of high-profile toxicity issues has shaped the current regulatory landscape for new and future weight-reducing drugs. PMID- 26936805 TI - Distinct ethanol drinking microstructures in two replicate lines of mice selected for drinking to intoxication. PMID- 26936804 TI - An inflammation-independent contraction mechanophenotype of airway smooth muscle in asthma. PMID- 26936803 TI - Mycobacterial disease in patients with chronic granulomatous disease: A retrospective analysis of 71 cases. AB - BACKGROUND: Chronic granulomatous disease (CGD) is a rare primary immunodeficiency caused by inborn errors of the phagocyte nicotinamide adenine dinucleotide phosphate oxidase complex. From the first year of life onward, most affected patients display multiple, severe, and recurrent infections caused by bacteria and fungi. Mycobacterial infections have also been reported in some patients. OBJECTIVE: Our objective was to assess the effect of mycobacterial disease in patients with CGD. METHODS: We analyzed retrospectively the clinical features of mycobacterial disease in 71 patients with CGD. Tuberculosis and BCG disease were diagnosed on the basis of microbiological, pathological, and/or clinical criteria. RESULTS: Thirty-one (44%) patients had tuberculosis, and 53 (75%) presented with adverse effects of BCG vaccination; 13 (18%) had both tuberculosis and BCG infections. None of these patients displayed clinical disease caused by environmental mycobacteria, Mycobacterium leprae, or Mycobacterium ulcerans. Most patients (76%) also had other pyogenic and fungal infections, but 24% presented solely with mycobacterial disease. Most patients presented a single localized episode of mycobacterial disease (37%), but recurrence (18%), disseminated disease (27%), and even death (18%) were also observed. One common feature in these patients was an early age at presentation for BCG disease. Mycobacterial disease was the first clinical manifestation of CGD in 60% of these patients. CONCLUSION: Mycobacterial disease is relatively common in patients with CGD living in countries in which tuberculosis is endemic, BCG vaccine is mandatory, or both. Adverse reactions to BCG and severe forms of tuberculosis should lead to a suspicion of CGD. BCG vaccine is contraindicated in patients with CGD. PMID- 26936806 TI - News coverage of clinical research. PMID- 26936807 TI - Anxiety disorders: A blended treatment approach. AB - Anxiety disorders are common illnesses for patients that can significantly impact quality of life. These conditions are complicated and advanced by chronic illness. It can be a challenge not only for patients to live with but also for providers to evaluate and treat. Several tools exist to support clinicians in their work to manage and improve patient symptoms and reduce the burden of the disease. While there are numerous treatment modalities that are shown to help control and alleviate symptoms, close monitoring and evaluation are essential for improved patient outcomes and proper use of available resources. PMID- 26936809 TI - Controlling an invisible order. PMID- 26936810 TI - Solid qubits. PMID- 26936808 TI - Sarcopenia as a predictor of pulmonary complications after esophagectomy for thoracic esophageal cancer. AB - BACKGROUND AND OBJECTIVES: Sarcopenia or loss of skeletal muscle mass has been identified as a poor prognostic factor for a wide variety of diseases and conditions. We investigated whether preoperative sarcopenia is associated with postoperative complications in patients undergoing esophagectomy for thoracic esophageal cancer. METHODS: We retrospectively reviewed the medical records of consecutive patients with thoracic esophageal cancer who underwent esophagectomy between September 2005 and July 2014 at Kyoto University Hospital. Skeletal muscle mass was assessed using preoperative computed tomographic scans by measuring the cross-sectional muscle area at the third lumbar vertebral level. RESULTS: Among the 199 eligible patients, 149 (75%) were classified as having sarcopenia. There was no difference in the incidence of overall complications between the groups (risk ratio [RR]: 1.10, 95% confidence interval [CI]: 0.80 1.53, P = 0.54). However, pulmonary complications were significantly more frequent in the sarcopenia group than in the nonsarcopenia group (RR: 2.63, 95% CI: 1.20-5.77, P = 0.007). Multivariate analyses demonstrated that sarcopenia was associated with a high adjusted risk of one or more pulmonary complications (odds ratio: 2.96, 95% CI: 1.14-7.69, P = 0.026). CONCLUSIONS: Sarcopenia independently predicts pulmonary complications after esophagectomy for thoracic esophageal cancer. J. Surg. Oncol. 2016;113:678-684. (c) 2016 Wiley Periodicals, Inc. PMID- 26936811 TI - Long-term monitoring for nanomedicine implants and drugs. PMID- 26936812 TI - Correction. PMID- 26936813 TI - Navigating the risk landscape. PMID- 26936815 TI - Quantum information: Violation of Bell's inequality in Si. PMID- 26936818 TI - Academia and industry united. PMID- 26936817 TI - Antiferromagnetic spintronics. AB - Antiferromagnetic materials are internally magnetic, but the direction of their ordered microscopic moments alternates between individual atomic sites. The resulting zero net magnetic moment makes magnetism in antiferromagnets externally invisible. This implies that information stored in antiferromagnetic moments would be invisible to common magnetic probes, insensitive to disturbing magnetic fields, and the antiferromagnetic element would not magnetically affect its neighbours, regardless of how densely the elements are arranged in the device. The intrinsic high frequencies of antiferromagnetic dynamics represent another property that makes antiferromagnets distinct from ferromagnets. Among the outstanding questions is how to manipulate and detect the magnetic state of an antiferromagnet efficiently. In this Review we focus on recent works that have addressed this question. The field of antiferromagnetic spintronics can also be viewed from the general perspectives of spin transport, magnetic textures and dynamics, and materials research. We briefly mention this broader context, together with an outlook of future research and applications of antiferromagnetic spintronics. PMID- 26936816 TI - Catalysis with two-dimensional materials and their heterostructures. AB - Graphene and other 2D atomic crystals are of considerable interest in catalysis because of their unique structural and electronic properties. Over the past decade, the materials have been used in a variety of reactions, including the oxygen reduction reaction, water splitting and CO2 activation, and have been shown to exhibit a range of catalytic mechanisms. Here, we review recent advances in the use of graphene and other 2D materials in catalytic applications, focusing in particular on the catalytic activity of heterogeneous systems such as van der Waals heterostructures (stacks of several 2D crystals). We discuss the advantages of these materials for catalysis and the different routes available to tune their electronic states and active sites. We also explore the future opportunities of these catalytic materials and the challenges they face in terms of both fundamental understanding and the development of industrial applications. PMID- 26936819 TI - Status of Antiarrhythmic Drug Development for Atrial Fibrillation: New Drugs and New Molecular Mechanisms. PMID- 26936820 TI - The heritability and patterns of DNA methylation in normal human colorectum. AB - DNA methylation (DNAm) has been linked to changes in chromatin structure, gene expression and disease. The DNAm level can be affected by genetic variation; although, how this differs by CpG dinucleotide density and genic location of the DNAm site is not well understood. Moreover, the effect of disease causing variants on the DNAm level in a tissue relevant to disease has yet to be fully elucidated. To this end, we investigated the phenotypic profiles, genetic effects and regional genomic heritability for 196080 DNAm sites in healthy colorectum tissue from 132 unrelated Colombian individuals. DNAm sites in regions of low-CpG density were more variable, on average more methylated and were more likely to be significantly heritable when compared with DNAm sites in regions of high-CpG density. DNAm sites located in intergenic regions had a higher mean DNAm level and were more likely to be heritable when compared with DNAm sites in the transcription start site (TSS) of a gene expressed in colon tissue. Within CpG dense regions, the propensity of the DNAm level to be heritable was lower in the TSS of genes expressed in colon tissue than in the TSS of genes not expressed in colon tissue. In addition, regional genetic variation was associated with variation in local DNAm level no more frequently for DNAm sites within colorectal cancer risk regions than it was for DNAm sites outside such regions. Overall, DNAm sites located in different genomic contexts exhibited distinguishable profiles and may have a different biological function. PMID- 26936821 TI - mGlu5 positive allosteric modulation normalizes synaptic plasticity defects and motor phenotypes in a mouse model of Rett syndrome. AB - Rett syndrome (RS) is a neurodevelopmental disorder that shares many symptomatic and pathological commonalities with idiopathic autism. Alterations in protein synthesis-dependent synaptic plasticity (PSDSP) are a hallmark of a number of syndromic forms of autism; in the present work, we explore the consequences of disruption and rescue of PSDSP in a mouse model of RS. We report that expression of a key regulator of synaptic protein synthesis, the metabotropic glutamate receptor 5 (mGlu5) protein, is significantly reduced in both the brains of RS model mice and in the motor cortex of human RS autopsy samples. Furthermore, we demonstrate that reduced mGlu5 expression correlates with attenuated DHPG-induced long-term depression in the hippocampus of RS model mice, and that administration of a novel mGlu5 positive allosteric modulator (PAM), termed VU0462807, can rescue synaptic plasticity defects. Additionally, treatment of Mecp2-deficient mice with VU0462807 improves motor performance (open-field behavior and gait dynamics), corrects repetitive clasping behavior, as well as normalizes cued fear conditioning defects. Importantly, due to the rationale drug discovery approach used in its development, our novel mGlu5 PAM improves RS phenotypes and synaptic plasticity defects without evoking the overt adverse effects commonly associated with potentiation of mGlu5 signaling (i.e. seizures), or affecting cardiorespiratory defects in RS model mice. These findings provide strong support for the continued development of mGlu5 PAMs as potential therapeutic agents for use in RS, and, more broadly, for utility in idiopathic autism. PMID- 26936822 TI - Ciliopathy-associated protein CEP290 modifies the severity of retinal degeneration due to loss of RPGR. AB - Mutations in RPGR (retinitis pigmentosa GTPase regulator) are the most common cause of X-linked RP, a severe blindness disorder. RPGR mutations result in clinically variable disease with early- to late-onset phenotypic presentation. Molecular mechanisms underlying such heterogeneity are unclear. Here we show that phenotypic expression of Rpgr-loss in mice is influenced genetically by the loss of Cep290, a human ciliopathy gene. We found that Rpgrko/Y mice with a heterozygous hypomorphic allele of Cep290 (Cep290rd16/+) but not of a heterozygous null allele of Cep290 (Cep290null/+) or of other ciliopathy genes, Rpgrip1, Nphp1, Nphp4 and Nphp5, exhibit relatively early onset (by 3 months of age) retinal degeneration and dysfunction when compared with the onset at ~7 months of age in the Rpgrko/Y mice. We also observed disorganized photoreceptor outer-segment morphology and defective trafficking of opsins in the Rpgrko/Y::Cep290rd16/+ mice. Together with a physical interaction between RPGR and the C-terminal domain of CEP290, our data suggest that RPGR and CEP290 genetically interact and highlight the involvement of hypomorphic alleles of genes as potential modifiers of heterogeneous retinal ciliopathies. PMID- 26936824 TI - Heterozygous mutation of Ush1g/Sans in mice causes early-onset progressive hearing loss, which is recovered by reconstituting the strain-specific mutation in Cdh23. AB - Most clinical reports have suggested that patients with congenital profound hearing loss have recessive mutations in deafness genes, whereas dominant alleles are associated with progressive hearing loss (PHL). Jackson shaker (Ush1gjs) is a mouse model of recessive deafness that exhibits congenital profound deafness caused by the homozygous mutation of Ush1g/Sans on chromosome 11. We found that C57BL/6J-Ush1gjs/+ heterozygous mice exhibited early-onset PHL (ePHL) accompanied by progressive degeneration of stereocilia in the cochlear outer hair cells. Interestingly, ePHL did not develop in mutant mice with the C3H/HeN background, thus suggesting that other genetic factors are required for ePHL development. Therefore, we performed classical genetic analyses and found that the occurrence of ePHL in Ush1gjs/+ mice was associated with an interval in chromosome 10 that contains the cadherin 23 gene (Cdh23), which is also responsible for human deafness. To confirm this mutation effect, we generated C57BL/6J-Ush1gjs/+, Cdh23c.753A/G double-heterozygous mice by using the CRISPR/Cas9-mediated Cdh23c.753A>G knock-in method. The Cdh23c.753A/G mice harbored a one-base substitution (A for G), and the homozygous A allele caused moderate hearing loss with aging. Analyses revealed the complete recovery of ePHL and stereocilia degeneration in C57BL/6J-Ush1gjs/+ mice. These results clearly show that the development of ePHL requires at least two mutant alleles of the Ush1g and Cdh23 genes. Our results also suggest that because the SANS and CDH23 proteins form a complex in the stereocilia, the interaction between these proteins may play key roles in the maintenance of stereocilia and the prevention of ePHL. PMID- 26936823 TI - Shorter telomere length in Europeans than in Africans due to polygenetic adaptation. AB - Leukocyte telomere length (LTL), which reflects telomere length in other somatic tissues, is a complex genetic trait. Eleven SNPs have been shown in genome-wide association studies to be associated with LTL at a genome-wide level of significance within cohorts of European ancestry. It has been observed that LTL is longer in African Americans than in Europeans. The underlying reason for this difference is unknown. Here we show that LTL is significantly longer in sub Saharan Africans than in both Europeans and African Americans. Based on the 11 LTL-associated alleles and genetic data in phase 3 of the 1000 Genomes Project, we show that the shifts in allele frequency within Europe and between Europe and Africa do not fit the pattern expected by neutral genetic drift. Our findings suggest that differences in LTL within Europeans and between Europeans and Africans is influenced by polygenic adaptation and that differences in LTL between Europeans and Africans might explain, in part, ethnic differences in risks for human diseases that have been linked to LTL. PMID- 26936825 TI - ARL3 regulates trafficking of prenylated phototransduction proteins to the rod outer segment. AB - The small GTPase, ADP-ribosylation factor-like 3 (ARL3), has been proposed to participate in the transport of proteins in photoreceptor cells. Moreover, it has been implicated in the pathogenesis associated with X-linked retinitis pigmentosa (XLRP) resulting from mutations in the ARL3 GTPase activating protein, retinitis pigmentosa 2 (RP2). To determine the importance of ARL3 in rod photoreceptor cells, we generated transgenic mice expressing a dominant active form of ARL3 (ARL3-Q71L) under a rod-specific promoter. ARL3-Q71L animals exhibited extensive rod cell death after post-natal day 30 (PN30) and degeneration was complete by PN70. Prior to the onset of cell death, rod photoresponse was significantly reduced along with a robust decrease in rod phosphodiesterase 6 (PDE6) and G protein receptor kinase-1 (GRK1) levels. Furthermore, assembled phosphodiesterase 6 (PDE6) subunits, rod transducin and G-protein receptor kinase-1 (GRK1) accumulated on large punctate structures within the inner segment in ARL3-Q71L retina. Defective trafficking of prenylated proteins is likely due to sequestration of prenyl binding protein delta (PrBPdelta) by ARL3-Q71L as we demonstrate a specific interaction between these proteins in the retina. Unexpectedly, our studies also revealed a novel role for ARL3 in the migration of photoreceptor nuclei. In conclusion, this study identifies ARL3 as a key player in prenylated protein trafficking in rod photoreceptor cells and establishes the potential role for ARL3 dysregulation in the pathogenesis of RP2-related forms of XLRP. PMID- 26936826 TI - Mimicking titration experiments with MD simulations: A protocol for the investigation of pH-dependent effects on proteins. AB - Protein structure and function are highly dependent on the environmental pH. However, the temporal or spatial resolution of experimental approaches hampers direct observation of pH-induced conformational changes at the atomic level. Molecular dynamics (MD) simulation strategies (e.g. constant pH MD) have been developed to bridge this gap. However, one frequent problem is the sampling of unrealistic conformations, which may also lead to poor pKa predictions. To address this problem, we have developed and benchmarked the pH-titration MD (pHtMD) approach, which is inspired by wet-lab titration experiments. We give several examples how the pHtMD protocol can be applied for pKa calculation including peptide systems, Staphylococcus nuclease (SNase), and the chaperone HdeA. For HdeA, pHtMD is also capable of monitoring pH-dependent dimer dissociation in accordance with experiments. We conclude that pHtMD represents a versatile tool for pKa value calculation and simulation of pH-dependent effects in proteins. PMID- 26936827 TI - TLR4 inhibitor attenuates amyloid-beta-induced angiogenic and inflammatory factors in ARPE-19 cells: Implications for age-related macular degeneration. AB - Subretinally-deposited amyloid-beta (Abeta) is an important factor in age-related macular degradation (AMD) often leading to irreversible blindness in the elderly population. The molecular mechanism underlying Abeta deposition during AMD remains unclear. The expression of inflammatory and angiogenic factors was examined by treatment of retinal pigment epithelial (RPE) cells with the oligomeric form of Abeta (OAbeta1-42). Changes in the mRNA expression levels of various cytokines was detected by the QuantiGenePlex 6.0 Reagent system, and the protein expression level was determined by western blotting. Culture supernatants were detected using a multiplex cytokine assay and enzyme-linked immunosorbent assays. The in vitro tube formation was evaluated by a Matrigel assay. The present study highlights that OAbeta1-42 activates the toll-like receptor 4 (TLR4), myeloid differentiation factor 88 and phosphorylation nuclear factor kappaB signaling pathway in RPE cells. Additionally, it increased the mRNA and protein expression of interleukin (IL)-6, IL-8, IL-33, vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and angiopoietin 2. Furthermore, the TLR4 inhibitor (COBRA) attenuated the expression of inflammatory and angiogenesis factors, particularly IL-6, IL-8, IL-33, bFGF and VEGF. When human umbilical vein endothelial cells (HUVECs) were co-cultured with the COBRA treated RPE cell culture supernatant the length of the endothelial cell network (measured by calculating tip cell lengths of endothelial cells) was impaired when compared with the HUVECs that were co-cultured with the cell supernatant exposed to OAbeta1-42. These results suggest that the TLR4-associated pathway may be a potential target for the treatment of AMD. PMID- 26936829 TI - Genomic dissection of plant development and its impact on thousand grain weight in barley through nested association mapping. AB - Flowering time is a key agronomic trait that plays an important role in crop yield. There is growing interest in dissecting the developmental subphases of flowering to better understand and fine-tune plant development and maximize yield. To do this, we used the wild barley nested association mapping (NAM) population HEB-25, comprising 1420 BC1S3 lines, to map quantitative trait loci (QTLs) controlling five developmental traits, plant height, and thousand grain weight. Genome-wide association studies (GWAS) enabled us to locate a total of 89 QTLs that genetically regulate the seven investigated traits. Several exotic QTL alleles proved to be highly effective and potentially useful in barley breeding. For instance, thousand grain weight was increased by 4.5 g and flowering time was reduced by 9.3 days by substituting Barke elite QTL alleles for exotic QTL alleles at the denso/sdw1 and the Ppd-H1 loci, respectively. We showed that the exotic allele at the semi-dwarf locus denso/sdw1 can be used to increase grain weight since it uncouples the negative correlation between shoot elongation and the ripening phase. Our study demonstrates that nested association mapping of HEB 25 can help unravel the genetic regulation of plant development and yield formation in barley. Moreover, since we detected numerous useful exotic QTL alleles in HEB-25, we conclude that the introgression of these wild barley alleles into the elite barley gene pool may enable developmental phases to be specifically fine-tuned in order to maximize thousand grain weight and, potentially, yield in the long term. PMID- 26936830 TI - Cross-tolerance to biotic and abiotic stresses in plants: a focus on resistance to aphid infestation. AB - Plants co-evolved with an enormous variety of microbial pathogens and insect herbivores under daily and seasonal variations in abiotic environmental conditions. Hence, plant cells display a high capacity to respond to diverse stresses through a flexible and finely balanced response network that involves components such as reduction-oxidation (redox) signalling pathways, stress hormones and growth regulators, as well as calcium and protein kinase cascades. Biotic and abiotic stress responses use common signals, pathways and triggers leading to cross-tolerance phenomena, whereby exposure to one type of stress can activate plant responses that facilitate tolerance to several different types of stress. While the acclimation mechanisms and adaptive responses that facilitate responses to single biotic and abiotic stresses have been extensively characterized, relatively little information is available on the dynamic aspects of combined biotic/abiotic stress response. In this review, we consider how the abiotic environment influences plant responses to attack by phloem-feeding aphids. Unravelling the signalling cascades that underpin cross-tolerance to biotic and abiotic stresses will allow the identification of new targets for increasing environmental resilience in crops. PMID- 26936828 TI - Pepper CabZIP63 acts as a positive regulator during Ralstonia solanacearum or high temperature-high humidity challenge in a positive feedback loop with CaWRKY40. AB - CaWRKY40 is known to act as a positive regulator in the response of pepper (Capsicum annuum) to Ralstonia solanacearum inoculation (RSI) or high temperature high humidity (HTHH), but the underlying mechanism remains elusive. Herein, we report that CabZIP63, a pepper bZIP family member, participates in this process by regulating the expression of CaWRKY40. CabZIP63 was found to localize in the nuclei, be up-regulated by RSI or HTHH, bind to promoters of both CabZIP63(pCabZIP63) and CaWRKY40(pCaWRKY40), and activate pCabZIP63- and pCaWRKY40-driven beta-glucuronidase expression in a C- or G-box-dependent manner. Silencing of CabZIP63 by virus-induced gene silencing (VIGS) in pepper plants significantly attenuated their resistance to RSI and tolerance to HTHH, accompanied by down-regulation of immunity- or thermotolerance-associated CaPR1, CaNPR1, CaDEF1, and CaHSP24. Hypersensitive response-mediated cell death and expression of the tested immunity- and thermotolerance-associated marker genes were induced by transient overexpression (TOE) of CabZIP63, but decreased by that of CabZIP63-SRDX. Additionally, binding of CabZIP63 to pCaWRKY40 was up-regulated by RSI or HTHH, and the transcript level of CaWRKY40 and binding of CaWRKY40 to the promoters of CaPR1, CaNPR1, CaDEF1 and CaHSP24 were up-regulated by TOE of CabZIP63. On the other hand, CabZIP63 was also up-regulated transcriptionally by TOE of CaWRKY40. The data suggest collectively that CabZIP63 directly or indirectly regulates the expression of CaWRKY40 at both the transcriptional and post-transcriptional level, forming a positive feedback loop with CaWRKY40 during pepper's response to RSI or HTHH. Altogether, our data will help to elucidate the underlying mechanism of crosstalk between pepper's response to RSI and HTHH. PMID- 26936831 TI - New synthesis route for ternary transition metal amides as well as ultrafast amide-hydride hydrogen storage materials. AB - K2[Mn(NH2)4] and K2[Zn(NH2)4] were successfully synthesized via a mechanochemical method. The mixture of K2[Mn(NH2)4] and LiH showed excellent rehydrogenation properties. In fact, after dehydrogenation K2[Mn(NH2)4]-8LiH fully rehydrogenates within 60 seconds at ca. 230 degrees C and 5 MPa of H2. This is one of the fastest rehydrogenation rates in amide-hydride systems known to date. This work also shows a strategy for the synthesis of transition metal nitrides by decomposition of the mixtures of M[M'(NH2)n] (where M is an alkali or alkaline earth metal and M' is a transition metal) and metal hydrides. PMID- 26936832 TI - Compulsive sexual behaviour as a behavioural addiction: the impact of the internet and other issues. PMID- 26936833 TI - Temperature effects on fish production across a natural thermal gradient. AB - Global warming is widely predicted to reduce the biomass production of top predators, or even result in species loss. Several exceptions to this expectation have been identified, however, and it is vital that we understand the underlying mechanisms if we are to improve our ability to predict future trends. Here, we used a natural warming experiment in Iceland and quantitative theoretical predictions to investigate the success of brown trout as top predators across a stream temperature gradient (4-25 degrees C). Brown trout are at the northern limit of their geographic distribution in this system, with ambient stream temperatures below their optimum for maximal growth, and above it in the warmest streams. A five-month mark-recapture study revealed that population abundance, biomass, growth rate, and production of trout all increased with stream temperature. We identified two mechanisms that contributed to these responses: (1) trout became more selective in their diet as stream temperature increased, feeding higher in the food web and increasing in trophic position; and (2) trophic transfer through the food web was more efficient in the warmer streams. We found little evidence to support a third potential mechanism: that external subsidies would play a more important role in the diet of trout with increasing stream temperature. Resource availability was also amplified through the trophic levels with warming, as predicted by metabolic theory in nutrient-replete systems. These results highlight circumstances in which top predators can thrive in warmer environments and contribute to our knowledge of warming impacts on natural communities and ecosystem functioning. PMID- 26936834 TI - Motor recovery at 6 months after admission is related to structural and functional reorganization of the spine and brain in patients with spinal cord injury. AB - This study aimed to explore structural and functional reorganization of the brain in the early stages of spinal cord injury (SCI) and identify brain areas that contribute to motor recovery. We studied 25 patients with SCI, including 10 with good motor recovery and 15 with poor motor recovery, along with 25 matched healthy controls. The mean period post-SCI was 9.2 +/- 3.5 weeks in good recoverers and 8.8 +/- 2.6 weeks in poor recoverers. All participants underwent structural and functional MRI on a 3-T magnetic resonance system. We evaluated differences in cross-sectional spinal cord area at the C2/C3 level, brain cortical thickness, white matter microstructure, and functional connectivity during the resting state among the three groups. We also evaluated associations between structural and functional reorganization and the rate of motor recovery. After SCI, compared with good recoverers, poor recoverers had a significantly decreased cross-sectional spinal cord area, cortical thickness in the right supplementary motor area and premotor cortex, and fractional anisotropy (FA) in the right primary motor cortex and posterior limb of the internal capsule. Meanwhile, poor recoverers showed decreased functional connectivity between the primary motor cortex and higher order motor areas (supplementary motor area and premotor cortex), while good recoverers showed increased functional connectivity among these regions. The structural and functional reorganization of the spine and brain was associated with motor recovery rate in all SCI patients. In conclusion, structural and functional reorganization of the spine and brain directly affected the motor recovery of SCI. Less structural atrophy and enhanced functional connectivity are associated with good motor recovery in patients with SCI. Multimodal imaging has the potential to predict motor recovery in the early stage of SCI. Hum Brain Mapp 37:2195-2209, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26936835 TI - Xanthane sesquiterpenoids from the roots and flowers of Xanthium cavanillesii. AB - The sesquiterpene lactones xanthanodiene, 4-epi-xanthanol, 4-epi-isoxanthanol, and 4-epi-xanthinin, as well as the xanthanolide derivative 4-oxo-bedfordia acid were isolated from the chloroform extracts of roots and flowers of Xanthium cavanillesii Schouw. The identities of these compounds were corroborated through comparison of their spectroscopic data, including IR, MS, and (1)H and (13)C NMR assignments, with literature reports. In addition, the structural characterization of 4-oxo-bedfordia acid was revisited and a comprehensive spectroscopic study of the compound is presented. This is to our knowledge the first phytochemical investigation of the roots of X. cavanillesii, and of flowers in the whole Xanthium genus. PMID- 26936836 TI - Late presenting iatrogenic tracheoesophageal fistula. PMID- 26936837 TI - Entrapment of guidewire in left anterior descending artery: Surgical management. AB - Entrapment of a guidewire during coronary artery interventions is rare and requires prompt treatment. A 52-year-old man underwent a primary percutaneous transluminal coronary angioplasty to the left anterior descending artery. A fractured guidewire was retained in the distal left anterior descending artery, which caused left ventricular dysfunction and total occlusion of the left anterior descending artery. He underwent endarterectomy with removal of the guidewire and bypass grafting. He had a normal postoperative period. The modalities for management of an entrapped guidewire are discussed. PMID- 26936838 TI - Double-orifice mitral valve associated with bicuspid aortic valve. AB - Double-orifice mitral valve is a rare congenital anomaly that usually does not cause a significant hemodynamic effect. Double-orifice mitral valve and a bicuspid aortic valve were detected in a 54-year-old lady who presented with dyspnea on exertion for one year. This is a rare association. Three-dimensional echocardiography is helpful to determine the type of malformation. The patient had no significant mitral regurgitation or stenosis, but demonstrated moderate aortic stenosis. She is undergoing periodic monitoring. PMID- 26936839 TI - Infant Mortality and Race in Kansas: Associations With Women, Infants, and Children Services. AB - BACKGROUND: Racial and ethnic minority infants and mothers have worse birth outcomes than Caucasian infants and mothers, specifically infant mortality. The purpose of this pilot study was to compare infant mortality rates from vital statistic data between mothers who participated in the Women, Infants, and Children (WIC) Program and the general population in Kansas. METHODS: A retrospective secondary analysis of data received from the Kansas Department of Health and Environment (KDHE) was conducted. Data were provided on all mothers who delivered a child in the state of Kansas from 2009 to 2011. The data received from KDHE included maternal demographics, infant deaths, infant gestational age, infant weight at birth, and WIC program participation. RESULTS: The overall infant mortality rate was 6.4 per 1000 births. Infant mortality for Caucasians was lower than for non-Caucasians. Infant mortality for blacks was greater than for non-blacks. Being Hispanic was not statistically associated with a difference in infant mortality. WIC program participation was associated with lower infant mortality in both blacks and Hispanics. After adjusting for WIC, infants born to black mothers were still more than twice as likely to die when compared with Caucasian infants. WIC services were not statistically associated with a reduction in infant mortality. Mother's education showed a significant protective effect on the likelihood of infant death. CONCLUSION: The WIC program is associated with positive outcomes at the national level. However, widespread reductions in health disparities have not been reported. Differences in education levels between mothers affected infant mortality to a greater degree than WIC program participation alone in the analysis. The infant mortality rate for black and Hispanic mothers was lower for WIC program participants. The WIC program may be beneficial for reducing infant mortality racial disparities but program participation should be expanded to affect maternal health disparities at the population level. PMID- 26936840 TI - Spectral-converting study of Ba((9-3)(m+n)/2)Er(m)Yb(n)Y2Si6O24 (m = 0.005 - 0.2, n = 0 - 0.3) orthosilicate phosphors. AB - Optical materials composed of Ba((9-3)(m+n)/2)Er(m)Yb(n)Y2Si6O24 (m = 0.005-0.2, n = 0-0.3) were prepared using a solid-state reaction. The X-ray diffraction patterns of the obtained phosphors were examined to index the peak positions. The photoluminescence (PL) excitation and emission spectra of the Er(3+)-activated phosphors and the critical emission quenching as a function of Er(3+) content in the Ba(9-3m/2)Er(m)Y2Si6O24 structure were monitored. The spectral conversion properties of Er(3+) and Er(3+)-Yb(3+) ions doped in Ba9Y2Si6O24 phosphors were elucidated under diode-laser irradiation at 980 nm. Up-conversion emission spectra and the dependence of the emission intensity on pump power for the Ba8.55Er0.1Yb0.2Y2Si6O24 phosphor were investigated. The desired up-conversion of the emitted light, which passed through the green, yellow, orange and red regions of the spectrum, was achieved through the use of appropriate Er(3+) and/or Yb(3+) concentrations in the host structure and 980 nm excitation light. The up conversion mechanism in the phosphors is described by an energy-level schematic. PMID- 26936841 TI - Clinical Profile of Statin Intolerance in the Phase 3 GAUSS-2 Study. AB - PURPOSE: Recent evidence suggests that statin intolerance may be more common than reported in randomized trials. However, the statin-intolerant population is not well characterized. The goal of this report is to characterize the population enrolled in the phase 3 Goal Achievement after Utilizing an anti-PCSK9 antibody in Statin Intolerant Subjects Study (GAUSS-2; NCT 01763905). METHODS: GAUSS-2 compared evolocumab, a fully human monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9) to ezetimibe in hypercholesterolemic patients who discontinued statin therapy due to statin-associated muscle symptoms (SAMS). GAUSS-2 was a 12-week, double-blind, placebo-controlled, randomized study that enrolled patients with elevated LDL-C who were either not on a statin or able to tolerate only a low-dose due to SAMS. Patients had received >=2 statins and were unable to tolerate any statin dose or increase in dose above a specified weekly dose due to SAMS. RESULTS: Three hundred seven patients (mean [SD] age, 62 [10] years; 54 % males) were randomized 2:1 (evolocumab:ezetimibe). Mean (SD) LDL-C was 4.99 (1.51) mmol/L. Patients had used >=2 (100 %), >=3 (55 %), or >=4 (21 %) statins. Coronary artery disease was present in 29 % of patients. Statin intolerant symptoms were myalgia in 80 % of patients, weakness in 39 %, and more serious complications in 20 %. In 98 % of patients, SAMS interfered with normal daily activity; in 52 %, symptoms precluded moderate exertion. CONCLUSION: Evaluation of the GAUSS-2 trial population of statin-intolerant patients demonstrates that most patients were high risk with severely elevated LDL-C and many had statin-associated muscle symptoms that interfered with their quality of life. PMID- 26936842 TI - Wine consumption reduced postprandial platelet sensitivity against platelet activating factor in healthy men. AB - PURPOSE: Platelet activating factor (PAF) is a potent inflammatory and thrombotic mediator that participates in the initiation and prolongation of atherosclerosis. The aim of the present study was to evaluate the potential effect of wine consumption on platelet aggregation against PAF. METHODS: The study had cross over design. Ten healthy men participated in four daily trials on separate days: They consumed a standardized meal along with white wine, Robola variety (trial R), or red wine, Cabernet Sauvignon variety (trial CS), or an ethanol solution (trial E), or water (trial W). Blood samples were collected before and after meal consumption and at several time points during the next 6 h. Platelet aggregation against PAF (EC50 values) and several blood biomarkers were measured, and incremental areas under the curve (iAUC) were calculated. RESULTS: A significant trial effect was found in platelet sensitivity against PAF (p trial = 0.01). Moreover, the iAUC-PAF EC50 of CS trial was higher compared to both iAUC-PAF EC50 of E and W trials (P = 0.04, P = 0.02). Plasminogen activator inhibitor-1 iAUC was higher in all alcoholic beverages compare with the one of W trial (P E = 0.05, P R = 0.01, P CS = 0.01). Triacylglycerol iAUC increased significantly only in E compared to W trial (P = 0.04) and were significantly lower at 60-120 min in wine trials compared to the one of E (P < 0.05). CONCLUSIONS: Wine consumption improved platelet sensitivity independently of alcohol, kept triacylglycerols at lower levels during their postprandial elevation, and did not affect plasminogen activator inhibitor-1 levels more adversely than ethanol per se. PMID- 26936843 TI - Interannual variations in spring phenology and their response to climate change across the Tibetan Plateau from 1982 to 2013. AB - Land surface phenology has been widely used to evaluate the effects of climate change on terrestrial ecosystems in recent decades. Climate warming on the Tibetan Plateau (1960-2010, 0.2 degrees C/decade) has been found to be greater than the global average (1951-2012, 0.12 degrees C/decade), which has had a significant impact on the timing of spring greenup. However, the magnitude and direction of change in spring phenology and its response to warming temperature and precipitation are currently under scientific debate. In an attempt to explore this issue further, we detected the onset of greenup based on the time series of daily two-band enhanced vegetation index (EVI2) from the advanced very high resolution radiometer (AVHRR) long-term data record (LTDR; 1982-1999) and Moderate Resolution Imaging Spectroradiometer (MODIS) Climate Modeling Grid (CMG; 2000-2013) using hybrid piecewise logistic models. Further, we examined the temporal trend in greenup onset in both individual pixels and ecoregions across the entire Tibetan Plateau over the following periods: 1982-1999, 2000-2013, and 1982-2013. The interannual variation in greenup onset was linked to the mean temperature and cumulative precipitation in the preceding month, and total precipitation during winter and spring, respectively. Finally, we investigated the relationship between interannual variation in greenup onset dates and temperature and precipitation from 1982 to 2013 at different elevational zones for different ecoregions. The results revealed no significant trend in the onset of greenup from 1982 to 2013 in more than 86 % of the Tibetan Plateau. For each study period, statistically significant earlier greenup trends were observed mainly in the eastern meadow regions while later greenup trends mainly occurred in the southwestern steppe and meadow regions both with areal coverage of less than 8 %. Although spring phenology was negatively correlated with spring temperature and precipitation in the majority of pixels (>60 %), only 15 % and 10 % of these correlations were significant (P < 0.1), respectively. Climate variables had varying effects on the ecoregions with altitude. In the meadow ecoregion, greenup onset was significantly affected by both temperature and precipitation from 3500 to 4000 m altitude and by temperature alone from 4000 to 4500 m. In contrast, greenup onset across all elevational zones, in the steppe ecoregion, was not directly driven by either spring temperature or precipitation, which was likely impacted by soil moisture associated with warming temperature. These findings highlight the complex impacts of climate change on spring phenology in the Tibetan Plateau. PMID- 26936844 TI - Analysis of the Efficacy of an Intervention to Improve Parent-Adolescent Problem Solving. AB - We conducted a two-group longitudinal partially nested randomized controlled trial to examine whether young adolescent youth-parent dyads participating in Mission Possible: Parents and Kids Who Listen, in contrast to a comparison group, would demonstrate improved problem-solving skill. The intervention is based on the Circumplex Model and Social Problem-Solving Theory. The Circumplex Model posits that families who are balanced, that is characterized by high cohesion and flexibility and open communication, function best. Social Problem-Solving Theory informs the process and skills of problem solving. The Conditional Latent Growth Modeling analysis revealed no statistically significant differences in problem solving among the final sample of 127 dyads in the intervention and comparison groups. Analyses of effect sizes indicated large magnitude group effects for selected scales for youth and dyads portraying a potential for efficacy and identifying for whom the intervention may be efficacious if study limitations and lessons learned were addressed. PMID- 26936845 TI - The Impact of Phosphohistone-H3-Assisted Mitotic Count and Ki67 Score in the Determination of Tumor Grade and Prediction of Distant Metastasis in Well Differentiated Pancreatic Neuroendocrine Tumors. AB - This study investigated the impact of phosphohistone-H3 (PHH3)-assisted mitotic count by comparing its performance with conventional mitotic count and Ki67 score as well as the status of distant metastasis. A total of 43 surgically resected pancreatic neuroendocrine tumors (panNET) with complete follow-up information has been subjected to a standardized assessment with respect to mitotic count (both conventional and PHH3-assisted) and Ki67 score. Five participants assessed mitotic count and the time spent was recorded in both methods. All tumors were assigned to a G1 category of mitotic rate on conventional mitotic count that failed to identify three tumors with a G2 category of mitotic rate on PHH3. Near perfect and fair agreements were achieved among observers when using PHH3 and conventional method, respectively. The mean time spent to determine mitotic count on PHH3-stained slides was significantly shorter (p < 0.001). The performance of PHH3-assisted mitotic grade category was significant as the three cases with a G2 mitotic category were associated with distant metastasis (p = 0.01). Despite its performance, the PHH3-assisted mitotic count downgraded 17 cases that were classified as G2 based on Ki67 scores in this series. The Ki67 grade category was either the same or higher than the mitotic grade category. Ten patients developed distant metastasis. Eleven tumors exhibited vascular invasion characterized by intravascular tumor cells admixed with thrombus. Our results indicate that PHH3 assisted mitotic count facilitates an accurate mitotic count with a perfect agreement among observers. The small size of this cohort is an important limitation of the current study, a G2 mitotic grade category based on PHH3 immunohistochemistry was one of the correlates of panNETs with distant metastasis. While the prognostic impact of PHH3-assisted mitotic count needs to be clarified in larger cohorts, Ki67 scores designated higher grade category in all cases; thus, it was the best determinant of the tumor grade. More importantly, the presence of vascular invasion along with the Ki67 grade category was found to be independent predictors of distant metastasis. PMID- 26936846 TI - Effectiveness of Medical Rehabilitation on Return-to-Work Depends on the Interplay of Occupation Characteristics and Disease. AB - Introduction Work disability causes high costs for economy, organizations, and employees. However, medical rehabilitation does not always enable employees to return to their old jobs. In the present study, we investigated how disease classification and work characteristics interact in predicting the success of medical rehabilitation in terms of one's ability to return to a former job. Methods To this end, we matched 2009 patient data from the German Statutory Pension Insurance agency with job characteristics data from the Occupational Information Network (O*NET) 17.0 database. We used a multilevel approach and a sample of N = 72,029, nested in 194 occupational groups. Results We found that workers are less likely to reenter a former job if mental illnesses coincide with emotionally demanding labor and if musculoskeletal diseases coincide with extreme environmental conditions. We did not find different effects between occupational groups for other types of diseases (circulatory system, neoplasms, injuries, others). Conclusion Thus, the contextual overlap of disease and occupational characteristics notably lowers the chances of a successful return-to-work. These findings should be taken into account by physicians when attempting to set realistic goals for rehabilitation in collaboration with the patient and the funding agency. PMID- 26936848 TI - Saccharification of newspaper waste after ammonia fiber expansion or extractive ammonia. AB - The lignocellulosic fractions of municipal solid waste (MSW) can be used as renewable resources due to the widespread availability, predictable and low pricing and suitability for most conversion technologies. In particular, after the typical paper recycling loop, the newspaper waste (NW) could be further valorized as feedstock in biorefinering industry since it still contains up to 70 % polysaccharides. In this study, two different physicochemical methods-ammonia fiber expansion (AFEX) and extractive ammonia (EA) were tested for the pretraetment of NW. Furthermore, based on the previously demonstrated ability of the recombinant enzymes endocellulase rCelStrep, alpha-L-arabinofuranosidase rPoAbf and its evolved variant rPoAbf F435Y/Y446F to improve the saccharification of different lignocellulosic pretreated biomasses (such as corn stover and Arundo donax), in this study these enzymes were tested for the hydrolysis of pretreated NW, with the aim of valorizing the lignocellulosic fractions of the MSW. In particular, a mixture of purified enzymes containing cellulases, xylanases and accessory hemicellulases, was chosen as reference mix and rCelStrep and rPoAbf or its variant were replaced to EGI and Larb. The results showed that these enzymatic mixes are not suitable for the hydrolysis of NW after AFEX or EA pretreatment. On the other hand, when the enzymes rCelStrep, rPoAbf and rPoAbf F435Y/Y446F were tested for their effect in hydrolysis of pretreated NW by addition to a commercial enzyme mixture, it was shown that the total polysaccharides conversion yield reached 37.32 % for AFEX pretreated NW by adding rPoAbf to the mix whilst the maximum sugars conversion yield for EA pretreated NW was achieved 40.80 % by adding rCelStrep. The maximum glucan conversion yield obtained (45.61 % for EA pretreated NW by adding rCelStrep to the commercial mix) is higher than or comparable to those reported in recent manuscripts adopting hydrolysis conditions similar to those used in this study. PMID- 26936847 TI - Role of Notch signaling in regulating innate immunity and inflammation in health and disease. AB - The Notch signaling pathway is conserved from Drosophila to mammals and is critically involved in developmental processes. In the immune system, it has been established that Notch signaling regulates multiple steps of T and B cell development in both central and peripheral lymphoid organs. Relative to the well documented role of Notch signaling in lymphocyte development, less is known about its role in regulating myeloid lineage development and function, especially in the context of acute and chronic inflammation. In this review article, we will describe the evidence accumulated during the recent years to support a key regulatory role of the Notch pathway in innate immune and inflammatory responses and discuss the potential implications of such regulation for pathogenesis and therapy of inflammatory disorders. PMID- 26936849 TI - Suppression of the toxicity of Bac7 (1-35), a bovine peptide antibiotic, and its production in E. coli. AB - Bac7 (1-35) is an Arg- and Pro-rich peptide antibiotic, produced in bovine cells to protect them from microbial infection. It has been demonstrated to inhibit the protein synthesis in E. coli, leading to cell death. Because of its toxicity, no cost effective methods have been developed for Bac7 production in Escherichia coli for its potential clinical use. Here, we found a method to suppress Bac7 (1 35) toxicity in E. coli to establish its high expression system, in which Bac7 (1 35) was fused to the C-terminal end of protein S, a major spore-coat protein from Myxococcus xanthus, using a linker containing a Factor Xa cleavage site. The resulting His6-PrS2-Bac7 (1-35) (PrS2 is consisted of two N-terminal half domains of protein S connected in tandem) was well expressed using the Single-Protein Production (SPP) system at low temperature and subsequently purified in a single step by using a Ni column. The combination of protein S fusion and its expression in the SPP system at low temperature appeared to suppress Bac7 (1-35) toxicity. Both the purified His6-PrS2-Bac7 (1-35) and His6-PrS2-Bac7 (1-35) treated by Factor Xa were proven to be a potent inhibitor for cell-free protein synthesis. PMID- 26936850 TI - Chronic Oral L-Carnitine Supplementation Drives Marked Plasma TMAO Elevations in Patients with Organic Acidemias Despite Dietary Meat Restrictions. AB - Recent studies have implicated trimethylamine N-oxide (TMAO) in atherosclerosis, raising concern about L-carnitine, a common supplement for patients with inborn errors of metabolism (IEMs) and a TMAO precursor metabolized, in part, by intestinal microbes. Dietary meat restriction attenuates carnitine-to-TMAO conversion, suggesting that TMAO production may not occur in meat-restricted individuals taking supplemental L-carnitine, but this has not been tested. Here, we mine a metabolomic dataset to assess TMAO levels in patients with diverse IEMs, including organic acidemias. These data were correlated with clinical information and confirmed using a quantitative TMAO assay. Marked plasma TMAO elevations were detected in patients treated with supplemental L-carnitine, including those on a meat-free diet. On average, patients with an organic acidemia had ~45-fold elevated [TMAO], as compared to the reference population. This effect was mitigated by metronidazole therapy lasting 7 days each month. Collectively, our data show that TMAO production occurs at high levels in patients with IEMs receiving oral L-carnitine. Further studies are needed to determine the long-term safety and efficacy of chronic oral L-carnitine supplementation and whether suppression or circumvention of intestinal bacteria may improve L-carnitine therapy. PMID- 26936853 TI - Bone scintigraphy in tophaceous gout. PMID- 26936851 TI - Identification of a predictive factor for distant metastasis in esophageal squamous cell carcinoma after definitive chemoradiotherapy. AB - BACKGROUND AND PURPOSE: Distant metastasis (DM) after definitive chemoradiotherapy has not been a focus of research in esophageal carcinoma. At present, local-regional control is improving following advances in salvage treatments after definitive chemoradiotherapy. There is a need to focus on suppressing the development of DM. The aim of this study was to identify pre treatment factors associated with DM after definitive chemoradiotherapy. MATERIALS AND METHODS: This study included 144 patients with thoracic esophageal squamous cell carcinoma (Stage I/II/III/IV; 35/17/69/23) (TNM 7th) who underwent definitive chemoradiotherapy; >50 Gy was prescribed to all gross tumors with concurrent administration of 5-fluorouracil +/- platinum. Pre-treatment factors included age, gender, performance status, tumor location, T/N/M status, tumor length, size of metastatic lymph nodes (LN size), and the presence of intramural metastasis or multiple primary tumors. The effects of pre-treatment factors on overall survival (OS) and DM were evaluated. RESULTS: The median follow-up period was 48 months. DM occurred as an initial progression in 21 % of patients, and LN size correlated with DM development (hazard ratio [HR] = 5.12; p = 0.0013) and poor OS (HR = 2.20; p = 0.0076) in univariate and multivariate analyses. CONCLUSIONS: LN size is a quantitative pre-treatment prognostic factor that should be assessed prior to definitive chemoradiotherapy. Patients with large metastatic lymph nodes are at high risk of DM and should be monitored. PMID- 26936852 TI - Prognostic value of (18)F-fluorodeoxyglucose positron emission tomography/computed tomography in patients with Barcelona Clinic Liver Cancer stages 0 and A hepatocellular carcinomas: a multicenter retrospective cohort study. AB - PURPOSE: We evaluated the prognostic value of pretreatment (18)F fluorodeoxyglucose positron emission tomography with computed tomography (FDG PET/CT) in patients with Barcelona Clinic Liver Cancer (BCLC) stage 0 or A hepatocellular carcinoma (HCC) who had received curative treatment or transarterial chemoembolization (TACE). METHODS: Between 2009 and 2010, 317 patients diagnosed with HCC at seven hospitals were enrolled. Among these, 195 patients underwent curative treatments including resection, liver transplantation, and radiofrequency ablation. TACE was performed in 122 patients. The tumor-to-normal liver standardized uptake value ratio (TLR) of the primary tumor was measured using pretreatment FDG PET/CT. The prognostic significance of TLR and other clinical variables was assessed using Cox regression models. Differences in the overall survival (OS) associated with TLR or other significant clinical factors were examined using the Kaplan-Meier method. RESULTS: Over a median follow-up period of 46 months, 77 patients died from cancer. In the curative cohort, higher TLR (>=2) was significantly associated with death (hazard ratio [HR] = 2.68; 95 % CI, 1.16-6.15; P = 0.020) in multivariable analysis. Patients with a higher TLR had significantly worse OS than patients with a lower TLR (5-year overall survival, 61 % vs. 79.4 %; P = 0.006). In the TACE cohort, the Model for End-Stage Liver Disease (MELD) score (>=8) was a significant independent prognostic factor for OS (HR = 3.34; 95 % CI, 1.49-7.48; P = 0.003), whereas TLR was not associated with OS. The Kaplan-Meier curves showed significantly poorer OS in patients with higher MELD scores (>=8) than in those with lower MELD scores (5-year survival rate, 33.1 % vs. 79.6 %; P < 0.001). CONCLUSIONS: Pretreatment TLR measured using FDG PET/CT was an independent prognostic factor for OS in patients with BCLC stage 0 or A HCC undergoing curative treatment. In contrast, underlying liver function appeared to be important in predicting the prognosis of patients undergoing TACE. PMID- 26936854 TI - Social Media Use and HIV-Related Risk Behaviors in Young Black and Latino Gay and Bi Men and Transgender Individuals in New York City: Implications for Online Interventions. AB - Urban young men who have sex with men (YMSM) and transgender women continue to experience high rates of new HIV infections in the USA, yet most of this population is not reached by current prevention interventions. The rate of Internet and social media use among youth is high. However, continually updated understanding of the associations between social media access and use and HIV risk behaviors is needed to reach and tailor technology-delivered interventions for those most vulnerable to HIV-racially and ethnically diverse urban YMSM and transgender persons. Thus, we conducted an in-person, venue-based cross-sectional survey among young gay, bisexual, and transgender individuals at locations primarily visited by Black and Latino gay and bisexual and transgender individuals in New York City to understand social media use and how it may relate to HIV risk behaviors to inform social media-based interventions. Among 102 primarily Black and Latino gay and bisexual men (75.5 %) and transgender women (19.6 %), over 90 % were under 30 years of age, 18.6 % reported homelessness in the past 6 months, and 10.8 % reported having HIV. All participants used social media, most accessed these platforms most often via a mobile device (67.6 %) and most logged on multiple times per day (87.3 %). Participants used social media to seek sex partners (56.7 %), exchange sex for money or clothes (19.6 %), and exchange sex for drugs (9.8 %). These results confirm prior studies demonstrating the feasibility of using social media platforms to reach at-risk, urban youth. Of particular concern is the association between recent STI and exchanging sex for money/clothes and drugs. Interventions using social media for young, urban minority MSM and transgender populations should incorporate risk reduction modules addressing exchange partners and promote frequent and regular HIV/STI testing. PMID- 26936857 TI - Is It a Dog? Is It a Sea Monster? Is it . . . ? PMID- 26936855 TI - Authors' reply to Gachi, Mullie and colleagues, and Weatherburn. PMID- 26936856 TI - Papillary Renal Cell Carcinoma Arising in a Lymph Node Metastasis of a Testicular Teratoma: A Very Rare Occurrence. AB - We present a case of a teratoma with somatic type malignancy (TSM) in the form of papillary renal cell carcinoma (pRCC) within supraclavicular and retroperitoneal lymph node metastases of a testicular pure teratoma. Resection of both masses revealed a teratoma without any other germ cell tumor component. A papillary carcinoma component was also detected intermingled with the teratomatous elements. The carcinoma cells displayed eosinophilic cytoplasm and prominent nucleoli. Groups of foamy histiocytes in the fibrovascular cores was a striking finding that brought pRCC to mind. Immunoreactivity for CK7, PAX8, AMACR, CD10, napsin, and vimentin along with morphologic findings confirmed renal cell differentiation. No radiological evidence of a primary renal cell carcinoma was found in the kidney. Consequently, pRCC arising in a teratoma was diagnosed. TSM is described as teratoma with a malignant component that is typically encountered in other organs and tissues. TSM in the form of pRCC is an extremely rare entity. Our case is the second example of a testicular germ cell tumor metastasis with a somatic malignancy in the form of pRCC. In conclusion, carcinomas of renal cell differentiation should be kept in mind as a rare form of TSM, especially in metastatic germ cell tumors. PMID- 26936858 TI - Medical Therapy for Inappropriate Sexual Behaviors in a Teen With Autism Spectrum Disorder. AB - Teens with autism spectrum disorder often exhibit sexual behaviors in public that are disturbing to parents, teachers, and peers. Some have proposed that such behaviors can be curtailed with hormonal suppression. There is information on the Internet suggesting that such medications work, and some reports in the peer reviewed medical literature support these claims. Such medications can have serious side effects. In this paper, we present a case in which parents requested such treatment of their teenage son with autism spectrum disorder. PMID- 26936860 TI - A Multifaceted Approach to Improving Outcomes in the NICU: The Pediatrix 100 000 Babies Campaign. AB - BACKGROUND AND OBJECTIVE: Despite advances in neonatal medicine, infants requiring neonatal intensive care continue to experience substantial morbidity and mortality. The purpose of this initiative was to generate large-scale simultaneous improvements in multiple domains of care in a large neonatal network through a program called the "100,000 Babies Campaign." METHODS: Key drivers of neonatal morbidity and mortality were identified. A system for retrospective morbidity and mortality review was used to identify problem areas for project prioritization. NICU system analysis and staff surveys were used to facilitate reengineering of NICU systems in 5 key driver areas. Electronic health record based automated data collection and reporting were used. A quality improvement infrastructure using the Kotter organizational change model was developed to support the program. RESULTS: From 2007 to 2013, data on 422 877 infants, including a subset with birth weight of 501 to 1500 g (n = 58 555) were analyzed. Key driver processes (human milk feeding, medication use, ventilator days, admission temperature) all improved (P < .0001). Mortality, necrotizing enterocolitis, retinopathy of prematurity, bacteremia after 3 days of life, and catheter-associated infection decreased. Survival without significant morbidity (necrotizing enterocolitis, severe intraventricular hemorrhage, severe retinopathy of prematurity, oxygen use at 36 weeks' gestation) improved. CONCLUSIONS: Implementation of a multifaceted quality improvement program that incorporated organizational change theory and automated electronic health record based data collection and reporting program resulted in major simultaneous improvements in key neonatal processes and outcomes. PMID- 26936859 TI - Iron Supplementation in Pregnancy or Infancy and Motor Development: A Randomized Controlled Trial. AB - BACKGROUND AND OBJECTIVE: Insufficient iron levels for optimal fetal and infant development is a concern during pregnancy and infancy. The goal of this study was to assess the effects of iron supplementation in pregnancy and/or infancy on motor development at 9 months. METHODS: The study was a randomized controlled trial (RCT) of infancy iron supplementation linked to an RCT of pregnancy iron supplementation, conducted in Hebei, China. A total of 1482 infants were randomly assigned to receive placebo (n = 730) or supplemental iron (n = 752) from 6 weeks to 9 months. Gross motor development (assessed by using the Peabody Developmental Motor Scale, Second Edition, instrument) was the primary outcome. Neurologic integrity and motor quality were secondary outcomes. RESULTS: Motor outcome was available for 1196 infants, divided into 4 supplementation period groups: (1) placebo in pregnancy/placebo in infancy (n = 288); (2) placebo in pregnancy/iron in infancy (n = 305); (3) iron in pregnancy/placebo in infancy (n = 298); and (4) iron in pregnancy/iron in infancy (n = 305). Using the Peabody Developmental Motor Scale, instrument, iron supplementation in infancy but not pregnancy improved gross motor scores: overall, P < .001; reflexes, P = .03; stationary, P < .001; and locomotion, P < .001. Iron supplementation in infancy improved motor scores by 0.3 SD compared with no supplementation or supplementation during pregnancy alone. Effects of iron supplementation in infancy alone were similar to effects with iron in both pregnancy and infancy. CONCLUSIONS: The RCT design supports the causal inference that iron supplementation in infancy, with or without iron supplementation in pregnancy, improved gross motor test scores at 9 months. PMID- 26936861 TI - Economic Evaluation Plan (EEP) for A Very Early Rehabilitation Trial (AVERT): An international trial to compare the costs and cost-effectiveness of commencing out of bed standing and walking training (very early mobilization) within 24 h of stroke onset with usual stroke unit care. AB - RATIONALE: A key objective of A Very Early Rehabilitation Trial is to determine if the intervention, very early mobilisation following stroke, is cost-effective. Resource use data were collected to enable an economic evaluation to be undertaken and a plan for the main economic analyses was written prior to the completion of follow up data collection. AIM AND HYPOTHESIS: To report methods used to collect resource use data, pre-specify the main economic evaluation analyses and report other intended exploratory analyses of resource use data. SAMPLE SIZE ESTIMATES: Recruitment to the trial has been completed. A total of 2,104 participants from 56 stroke units across three geographic regions participated in the trial. METHODS AND DESIGN: Resource use data were collected prospectively alongside the trial using standardised tools. The primary economic evaluation method is a cost-effectiveness analysis to compare resource use over 12 months with health outcomes of the intervention measured against a usual care comparator. A cost-utility analysis is also intended. STUDY OUTCOME: The primary outcome in the cost-effectiveness analysis will be favourable outcome (modified Rankin Scale score 0-2) at 12 months. Cost-utility analysis will use health related quality of life, reported as quality-adjusted life years gained over a 12 month period, as measured by the modified Rankin Scale and the Assessment of Quality of Life. DISCUSSION: Outcomes of the economic evaluation analysis will inform the cost-effectiveness of very early mobilisation following stroke when compared to usual care. The exploratory analysis will report patterns of resource use in the first year following stroke. PMID- 26936862 TI - Alcohol and Immediate Risk of Cardiovascular Events: A Systematic Review and Dose Response Meta-Analysis. AB - BACKGROUND: Although considerable research describes the cardiovascular effects of habitual moderate and heavy alcohol consumption, the immediate risks following alcohol intake have not been well characterized. Based on its physiological effects, alcohol may have markedly different effects on immediate and long-term risk. METHODS AND RESULTS: We searched CINAHL, Embase, and PubMed from inception to March 12, 2015, supplemented with manual screening for observational studies assessing the association between alcohol intake and cardiovascular events in the following hours and days. We calculated pooled relative risks and 95% confidence intervals for the association between alcohol intake and myocardial infarction, ischemic stroke, and hemorrhagic stroke using DerSimonian and Laird random effects models to model any alcohol intake or dose-response relationships of alcohol intake and cardiovascular events. Among 1056 citations and 37 full-text articles reviewed, 23 studies (29 457 participants) were included. Moderate alcohol consumption was associated with an immediately higher cardiovascular risk that was attenuated after 24 hours, and even protective for myocardial infarction and hemorrhagic stroke (~2-4 drinks: relative risk=30% lower risk) and protective against ischemic stroke within 1 week (~6 drinks: 19% lower risk). In contrast, heavy alcohol drinking was associated with higher cardiovascular risk in the following day (~6-9 drinks: relative risk=1.3-2.3) and week (~19-30 drinks: relative risk=2.25-6.2). CONCLUSIONS: There appears to be a consistent finding of an immediately higher cardiovascular risk following any alcohol consumption, but, by 24 hours, only heavy alcohol intake conferred continued risk. PMID- 26936865 TI - Clinical assessment and management of general surgery patients via synchronous telehealth. AB - Objective This paper describes how a clinical team at Landstuhl Regional Medical Center (LRMC) successfully integrated synchronous telehealth (TH) into their routine clinical practice. Methods and materials Synchronous TH encounters were performed using Polycom(r) software on surgeons' computers with high-definition (HD) cameras on monitors at distant sites and PolyCom HDX9000(r) Telehealth Practitioner Carts at originating sites. Patients provided consented and were presented to general surgeons by nurses and medical technicians at Army health clinics throughout the European Theater. Results In calendar year (CY) 2014, five general surgeons and two surgical physician assistants (PAs) at Landstuhl Regional Medical Center along with registered nurses (RNs) at six originating clinic sites throughout Europe completed 130 synchronous TH encounters for 101 general surgery patients resulting in 73 completed and 16 recommended surgeries. Eighty-eight percent of patients had a completed or recommended surgery. No surgeries or procedures planned after initial TH evaluation were cancelled. Originating site clinics ranged in distance from 68 miles to 517 miles. Acceptance by providers, patients and clinic staff was high. Conclusion Synchronous TH was effective and safe in evaluating common general surgical conditions. We excluded sensitive and complex conditions requiring a nuanced physical examination. The TH efforts of the general surgery staff have resulted in high-quality, seamless and predictable TH activities that continue to expand into other surgical and medical specialties beyond general surgery. Seven surgeons and two PAs use synchronous TH regularly serving patients over a broad geographic area. PMID- 26936864 TI - Telemedicine for ophthalmic consultation services: use of a portable device and layering information for graders. AB - Introduction We compared remote, image-based patient consultations to in-person consultations at emergency department and inpatient hospital settings. Methods Patients evaluated by the ophthalmic consultation services (gold standard) were imaged over a two-week period. A trained study coordinator took anterior segment photographs (AS) and posterior segment photographs (PS) with a portable camera (PictorPlus, Volk Optical, Cleveland, OH). Ophthalmologists (graders) determined photograph quality, presence of pathology, and their confidence in disease detection. At a separate session, graders reassessed photographs accompanied by a one-sentence summary of demographics and chief complaint (CHx). We computed accuracy and reliability statistics. Results We took AS photographs of 24 eyes of 15 patients and PS photographs of 39 eyes of 20 patients. The majority of images were rated as acceptable or excellent in quality (AS: 89-96%; PS: 70-75%). Graders detected AS pathology with 62-81% sensitivity based on photographs, increasing to 87-88% sensitivity with photographs plus CHx. Graders detected PS pathology with 79-86% sensitivity based on a photograph only, increasing to 100% sensitivity with photographs plus CHx. Discussion In this pilot study, there is evidence that portable ophthalmic imaging technologies could enable ophthalmologists to remotely evaluate anterior and posterior segment eye diseases with good sensitivity. The ophthalmologist could detect ocular pathology on photographs more accurately if they were provided brief clinical information. PMID- 26936863 TI - Cardiac Stim1 Silencing Impairs Adaptive Hypertrophy and Promotes Heart Failure Through Inactivation of mTORC2/Akt Signaling. AB - BACKGROUND: Stromal interaction molecule 1 (STIM1) is a dynamic calcium signal transducer implicated in hypertrophic growth of cardiomyocytes. STIM1 is thought to act as an initiator of cardiac hypertrophic response at the level of the sarcolemma, but the pathways underpinning this effect have not been examined. METHODS AND RESULTS: To determine the mechanistic role of STIM1 in cardiac hypertrophy and during the transition to heart failure, we manipulated STIM1 expression in mice cardiomyocytes by using in vivo gene delivery of specific short hairpin RNAs. In 3 different models, we found that Stim1 silencing prevents the development of pressure overload-induced hypertrophy but also reverses preestablished cardiac hypertrophy. Reduction in STIM1 expression promoted a rapid transition to heart failure. We further showed that Stim1 silencing resulted in enhanced activity of the antihypertrophic and proapoptotic GSK-3beta molecule. Pharmacological inhibition of glycogen synthase kinase-3 was sufficient to reverse the cardiac phenotype observed after Stim1 silencing. At the level of ventricular myocytes, Stim1 silencing or inhibition abrogated the capacity for phosphorylation of Akt(S473), a hydrophobic motif of Akt that is directly phosphorylated by mTOR complex 2. We found that Stim1 silencing directly impaired mTOR complex 2 kinase activity, which was supported by a direct interaction between STIM1 and Rictor, a specific component of mTOR complex 2. CONCLUSIONS: These data support a model whereby STIM1 is critical to deactivate a key negative regulator of cardiac hypertrophy. In cardiomyocytes, STIM1 acts by tuning Akt kinase activity through activation of mTOR complex 2, which further results in repression of GSK-3beta activity. PMID- 26936866 TI - Skilled use of the media by vested interests to promote drugs and other health products. PMID- 26936867 TI - Getting to the Outer Leaflet: Physiology of Phosphatidylserine Exposure at the Plasma Membrane. AB - Phosphatidylserine (PS) is a major component of membrane bilayers whose change in distribution between inner and outer leaflets is an important physiological signal. Normally, members of the type IV P-type ATPases spend metabolic energy to create an asymmetric distribution of phospholipids between the two leaflets, with PS confined to the cytoplasmic membrane leaflet. On occasion, membrane enzymes, known as scramblases, are activated to facilitate transbilayer migration of lipids, including PS. Recently, two proteins required for such randomization have been identified: TMEM16F, a scramblase regulated by elevated intracellular Ca(2+), and XKR8, a caspase-sensitive protein required for PS exposure in apoptotic cells. Once exposed at the cell surface, PS regulates biochemical reactions involved in blood coagulation, and bone mineralization, and also regulates a variety of cell-cell interactions. Exposed on the surface of apoptotic cells, PS controls their recognition and engulfment by other cells. This process is exploited by parasites to invade their host, and in specialized form is used to maintain photoreceptors in the eye and modify synaptic connections in the brain. This review discusses what is known about the mechanism of PS exposure at the surface of the plasma membrane of cells, how actors in the extracellular milieu sense surface exposed PS, and how this recognition is translated to downstream consequences of PS exposure. PMID- 26936870 TI - Advice is needed on the benefits of sweet potato in diabetes. PMID- 26936868 TI - A System to Study Aneuploidy In Vivo. AB - Aneuploidy, an imbalanced chromosome number, is associated with both cancer and developmental disorders such as Down syndrome (DS). To determine how aneuploidy affects cellular and organismal physiology, we have developed a system to evaluate aneuploid cell fitness in vivo. By transplanting hematopoietic stem cells (HSCs) into recipient mice after ablation of recipient hematopoiesis by lethal irradiation, we can directly compare the fitness of HSCs derived from a range of aneuploid mouse models with that of euploid HSCs. This experimental system can also be adapted to assess the interplay between aneuploidy and tumorigenesis. We hope that further characterization of aneuploid cells in vivo will provide insight both into the origins of hematopoietic phenotypes observed in DS individuals as well as the role of different types of aneuploid cells in the genesis of cancers of the blood. PMID- 26936869 TI - Activated protein C levels and outcome in patients with cardiogenic shock complicating acute myocardial infarction. AB - INTRODUCTION: In patients with severe sepsis, low levels of activated protein C are associated with high morbidity and mortality. In an observational study we investigated whether patients with cardiogenic shock have decreased circulatory levels of activated protein C, and if these are associated with increased mortality. METHODS: We measured serum activated protein C and interleukin-6 levels in 43 patients with cardiogenic shock following acute myocardial infarction and in 15 control patients with uncomplicated myocardial infarction at days 0-5 and 7 after the onset of shock/myocardial infarction. RESULTS: Activated protein C levels were significantly lower in patients with cardiogenic shock compared to controls. In cardiogenic shock patients, there was no difference in activated protein C levels at baseline, whereas activated protein C levels significantly declined in 28-day non-survivors at day 2, compared with 28-day survivors. Lower levels of activated protein C were associated with a higher degree of vasopressor need, whereas there was no significant association with multiple organ failure in the first days. Regarding the inflammatory response, a strong inverse correlation was observed between interleukin-6 and activated protein C levels. CONCLUSION: Patients with cardiogenic shock who did not survive up to 28 days showed a decline in activated protein C levels during the course of the disease, which was inversely correlated with interleukin-6. This study underlines sustained inflammatory mechanisms in the development and persistence of cardiogenic shock, highlighting a potential effect of anti-inflammatory interventions early during cardiogenic shock. PMID- 26936871 TI - Pronounced kidney hypoxia precedes albuminuria in type 1 diabetic mice. AB - Intrarenal tissue hypoxia has been proposed as a unifying mechanism for the development of chronic kidney disease, including diabetic nephropathy. However, hypoxia has to be present before the onset of kidney disease to be the causal mechanism. To establish whether hypoxia precedes the onset of diabetic nephropathy, we implemented a minimally invasive electron paramagnetic resonance oximetry technique using implanted oxygen sensing probes for repetitive measurements of in vivo kidney tissue oxygen tensions in mice. Kidney cortex oxygen tensions were measured before and up to 15 days after the induction of insulinopenic diabetes in male mice and compared with normoglycemic controls. On day 16, urinary albumin excretions and conscious glomerular filtration rates were determined to define the temporal relationship between intrarenal hypoxia and disease development. Diabetic mice developed pronounced intrarenal hypoxia 3 days after the induction of diabetes, which persisted throughout the study period. On day 16, diabetic mice had glomerular hyperfiltration, but normal urinary albumin excretion. In conclusion, intrarenal tissue hypoxia in diabetes precedes albuminuria thereby being a plausible cause for the onset and progression of diabetic nephropathy. PMID- 26936872 TI - The rebirth of interest in renal tubular function. AB - The measurement of glomerular filtration rate by the clearance of inulin or creatinine has evolved over the past 50 years into an estimated value based solely on plasma creatinine concentration. We have examined some of the misconceptions and misunderstandings of the classification of renal disease and its course, which have followed this evolution. Furthermore, renal plasma flow and tubular function, which in the past were estimated by the clearance of the exogenous aryl amine, para-aminohippurate, are no longer measured. Over the past decade, studies in experimental animals with reduced nephron mass and in patients with reduced renal function have identified small gut-derived, protein-bound uremic retention solutes ("uremic toxins") that are poorly filtered but are secreted into the lumen by organic anion transporters (OATs) in the proximal renal tubule. These are not effectively removed by conventional hemodialysis or peritoneal dialysis. Residual renal function, urine produced in patients with advanced renal failure or undergoing dialysis treatment, may represent, at least in part, secretion of fluid and uremic toxins, such as indoxyl sulfate, mediated by proximal tubule OATs and might serve as a useful survival function. In light of this new evidence of the physiological role of proximal tubule OATs, we suggest that measurement of renal tubular function and renal plasma flow may be of considerable value in understanding and managing chronic kidney disease. Data obtained in normal subjects indicate that renal plasma flow and renal tubular function might be measured by the clearance of the endogenous aryl amine, hippurate. PMID- 26936873 TI - Neuroanatomic and behavioral correlates of urinary dysfunction induced by vaginal distension in rats. AB - The aim of the present study was to use a model of simulated human childbirth in rats to determine the damage to genitourinary structures and behavioral signs of urinary dysfunction induced by vaginal distension (VD) in female rats. In experiment 1, the length of the genitourinary tract and the nerves associated with it were measured immediately after simulated human delivery induced by VD or sham (SH) procedures. Electroneurograms of the dorsal nerve of the clitoris (DNC) were also recorded. In experiment 2, histological characteristics of the bladder and major pelvic ganglion of VD and SH rats were evaluated. In experiment 3, urinary parameters were determined in conscious animals during 6 h of dark and 6 h of light before and 3 days after VD or SH procedures. VD significantly increased distal vagina width (P < 0.001) and the length of the motor branch of the sacral plexus (P < 0.05), DNC (P < 0.05), and vesical nerves (P < 0.01) and decreased DNC frequency and amplitude of firing. VD occluded the pelvic urethra, inducing urinary retention, hematomas in the bladder, and thinness of the epithelial (P < 0.05) and detrusor (P < 0.01) layers of the bladder. Major pelvic ganglion parameters were not modified after VD. Rats dripped urine in unusual places to void, without the stereotyped behavior of micturition after VD. The neuroanatomic injuries after VD occur alongside behavioral signs of urinary incontinence as determined by a new behavioral tool for assessing micturition in conscious animals. PMID- 26936874 TI - Spontaneous one-kidney rats are more susceptible to develop hypertension by DOCA NaCl and subsequent kidney injury compared with uninephrectomized rats. AB - There is little clinical data of how hypertension may influence individuals with nephron deficiency in the context of being born with a single kidney. We recently developed a new rat model (the heterogeneous stock-derived model of unilateral renal agenesis rat) that is born with a single kidney and exhibits progressive kidney injury and decline in kidney function with age. We hypothesized that DOCA salt would induce a greater increase in blood pressure and therefore accelerate the progression of kidney injury in rats born with a solitary kidney compared with rats that have undergone unilateral nephrectomy. Time course evaluation of blood pressure, kidney injury, and renal hemodynamics was performed in the following six groups of animals from weeks 13 to 18: 1) DOCA-treated rats with a solitary kidney (DOCA+S group), 2) placebo-treated rats with a solitary kidney, 3) DOCA-treated control rats with two kidneys (DOCA+C group), 4) placebo-treated control rats with two kidneys, 5) DOCA-treated rats with two kidneys that underwent uninephrectomy (DOCA+UNX8 group), and 6) placebo-treated rats with two kidneys that underwent uninephrectomy. DOCA+S rats demonstrated a significant rise (P < 0.05) in blood pressure (192 +/- 4 mmHg), proteinuria (205 +/- 31 mg/24 h), and a decline in glomerular filtration rate (600 +/- 42 MUl.min(-1).g kidney weight(-1)) relative to the DOCA+UNX8 (173 +/- 3 mmHg, 76 +/- 26 mg/24 h, and 963 +/- 36 MUl.min(-1).g kidney weight(-1)) and DOCA+C (154 +/- 2 mmHg, 7 +/- 1 mg/24 h, and 1,484 +/- 121 MUl.min(-1).g kidney weight(-1)) groups. Placebo-treated groups showed no significant change among the three groups. An assessment of renal injury markers via real-time PCR/Western blot analysis and histological analysis was concordant with the measured physiological parameters. In summary, congenital solitary kidney rats are highly susceptible to the induction of hypertension compared with uninephrectomized rats, suggesting that low nephron endowment is an important driver of elevated blood pressure, hastening nephron injury through the transmission of elevated systemic blood pressure and thereby accelerating decline in kidney function. PMID- 26936875 TI - N-sulfation of heparan sulfate is critical for syndecan-4-mediated podocyte cell matrix interactions. AB - Previous research has shown that podocytes unable to assemble heparan sulfate on cell surface proteoglycan core proteins have compromised cell-matrix interactions. This report further explores the role of N-sulfation of intact heparan chains in podocyte-matrix interactions. For the purposes of this study, a murine model in which the enzyme N-deacetylase/N-sulfotransferase 1 (NDST1) was specifically deleted in podocytes and immortalized podocyte cell lines lacking NDST1 were developed and used to explore the effects of such a mutation on podocyte behavior in vitro. NDST1 is a bifunctional enzyme, ultimately responsible for N-sulfation of heparan glycosaminoglycans produced by cells. Immunostaining of glomeruli from mice whose podocytes were null for Ndst1 (Ndst1( /-)) showed a disrupted pattern of localization for the cell surface proteoglycan, syndecan-4, and for alpha-actinin-4 compared with controls. The pattern of immunostaining for synaptopodin and nephrin did not show as significant alterations. In vitro studies showed that Ndst1(-/-) podocytes attached, spread, and migrated less efficiently than Ndst1(+/+) podocytes. Immunostaining in vitro for several markers for molecules involved in cell-matrix interactions showed that Ndst1(-/-) cells had decreased clustering of syndecan-4 and decreased recruitment of protein kinase-Calpha, alpha-actinin-4, vinculin, and phospho-focal adhesion kinase to focal adhesions. Total intracellular phospho focal adhesion kinase was decreased in Ndst1(-/-) compared with Ndst1(+/+) cells. A significant decrease in the abundance of activated integrin alpha5beta1 on the cell surface of Ndst1(-/-) cells compared with Ndst1(+/+) cells was observed. These results serve to highlight the critical role of heparan sulfate N-sulfation in facilitating normal podocyte-matrix interactions. PMID- 26936877 TI - Nasal high flow: going viral? PMID- 26936876 TI - One-year outcomes of rosuvastatin versus placebo in sepsis-associated acute respiratory distress syndrome: prospective follow-up of SAILS randomised trial. AB - BACKGROUND: Prior randomised trials have evaluated statins in patients with sepsis and acute respiratory distress syndrome (ARDS), but there has been no comprehensive evaluation of long-term effects, despite potential neuromuscular and mental health adverse effects of these drugs. AIM: To evaluate the effect of rosuvastatin versus placebo on survival, physical function and performance, and mental health outcomes in patients with sepsis-associated ARDS. METHODS: Prospective follow-up evaluation of the ARDS Clinical Trials Network Statins for Acutely Injured Lungs from Sepsis trial of rosuvastatin versus placebo in 568 mechanically ventilated patients with sepsis-associated ARDS, with blinded 6 month outcome assessment performed in the 272 eligible survivors for age-adjusted and sex-adjusted 36-Item Short Form Health Survey (SF-36) physical function and mental health domains, and in 84 eligible survivors for the 6 min walk test, along with secondary outcomes evaluations of survival, and additional patient reported and performance-based measures at 6-month and 12-month follow-up. RESULTS: Over 1-year follow-up, there was no significant difference in cumulative survival in the rosuvastatin versus placebo groups (58% vs 61%; p=0.377), with survivors demonstrating substantial impairments in physical function and mental health. Rosuvastatin versus placebo had no effect (mean treatment effect (95% CI)) on SF-36 physical function (0 (-7 to 8), p=0.939) or mental health (-6 (-12 to 1) p=0.085) domains, 6 min walk distance (per cent predicted: 2 (-9 to 14), p=0.679) or the vast majority of secondary outcomes. CONCLUSIONS: Over 1-year follow-up, patients with sepsis-associated ARDS had high cumulative mortality, with survivors commonly experiencing impairments in physical functioning and performance, and mental health. Randomisation to rosuvastatin had no effect on these outcomes. TRIAL REGISTRATION NUMBER: NCT00979121 and NCT00719446. PMID- 26936878 TI - Predictors of expressed breast milk volume in mothers expressing milk for their preterm infant. AB - BACKGROUND: An understanding of predictors of breast milk production may enable the provision of better advice and support to mothers with preterm infants who may need to express milk for long periods. OBJECTIVE: To investigate factors predicting the amount of milk expressed by mothers for their preterm infant (1) during the first 10 days and (2) during the infant's whole hospital stay. METHODS: 62 mothers with preterm infants <34 weeks who participated in a randomised trial comparing two breast pumps completed 10-day diaries including weight of milk expressed and questionnaires giving their opinion of the breast pump; 47 mothers provided data on milk expression up to the infant's hospital discharge. RESULTS: Significant predictors of 10-day milk weight in multivariate models were the number of episodes of 'breast feeding' (17 g (95% CI 8 to 26, p=0.001) increase per episode), the use of double versus single pumping (109 (31 186, p=0.007) g/day more) and the number of complete daily records (17 (1-33, p=0.04) g increase/day). Significant multivariate predictors of total milk production were double versus single pumping (491 (55) mL/day vs 266 (44) mL/day), expressing 500 mL/day by day 10 (525 (53) mL/day vs 232 (43) mL/day) and a higher score for breast pump 'comfort' (best=489 (39) mL/day, middle=335 (57) mL/day, worst=311 (78) mL/day). CONCLUSIONS: These results suggest that relatively simple, modifiable factors can favourably impact milk production in the neonatal intensive care unit setting and emphasise the importance of double pumping, early establishment of milk production and design features of the breast pump that promote comfort. TRIAL REGISTRATION NUMBER: NCT00887991. PMID- 26936879 TI - Clearing Persistent Extracellular Antigen of Hepatitis B Virus: An Immunomodulatory Strategy To Reverse Tolerance for an Effective Therapeutic Vaccination. AB - Development of therapeutic vaccines/strategies to control chronic hepatitis B virus (HBV) infection has been challenging because of HBV-induced tolerance. In this study, we explored strategies for breaking tolerance and restoring the immune response to the HBV surface Ag in tolerant mice. We demonstrated that immune tolerance status is attributed to the level and duration of circulating HBsAg in HBV carrier models. Removal of circulating HBsAg by a monoclonal anti HBsAg Ab in tolerant mice could gradually reduce tolerance and reestablish B cell and CD4(+) T cell responses to subsequent Engerix-B vaccination, producing protective IgG. Furthermore, HBsAg-specific CD8(+) T cells induced by the addition of a TLR agonist resulted in clearance of HBV in both serum and liver. Thus, generation of protective immunity can be achieved by clearing extracellular viral Ag with neutralizing Abs followed by vaccination. PMID- 26936880 TI - Myeloid-Derived Suppressor Cell Survival and Function Are Regulated by the Transcription Factor Nrf2. AB - Tumor-induced myeloid-derived suppressor cells (MDSC) contribute to immune suppression in tumor-bearing individuals and are a major obstacle to effective immunotherapy. Reactive oxygen species (ROS) are one of the mechanisms used by MDSC to suppress T cell activation. Although ROS are toxic to most cells, MDSC survive despite their elevated content and release of ROS. NF erythroid 2-related factor 2 (Nrf2) is a transcription factor that regulates a battery of genes that attenuate oxidative stress. Therefore, we hypothesized that MDSC resistance to ROS may be regulated by Nrf2. To test this hypothesis, we used Nrf2(+/+)and Nrf2( /-)BALB/c and C57BL/6 mice bearing 4T1 mammary carcinoma and MC38 colon carcinoma, respectively. Nrf2 enhanced MDSC suppressive activity by increasing MDSC production of H2O2, and it increased the quantity of tumor-infiltrating MDSC by reducing their oxidative stress and rate of apoptosis. Nrf2 did not affect circulating levels of MDSC in tumor-bearing mice because the decreased apoptotic rate of tumor-infiltrating MDSC was balanced by a decreased rate of differentiation from bone marrow progenitor cells. These results demonstrate that Nrf2 regulates the generation, survival, and suppressive potency of MDSC, and that a feedback homeostatic mechanism maintains a steady-state level of circulating MDSC in tumor-bearing individuals. PMID- 26936881 TI - Usp9X Is Required for Lymphocyte Activation and Homeostasis through Its Control of ZAP70 Ubiquitination and PKCbeta Kinase Activity. AB - To achieve a durable adaptive immune response, lymphocytes must undergo clonal expansion and induce a survival program that enables the persistence of Ag experienced cells and the development of memory. During the priming phase of this response, CD4(+)T lymphocytes either remain tolerized or undergo clonal expansion. In this article, we show that Usp9X functions as a positive regulatory switch during T lymphocyte priming through removal of inhibitory monoubiquitination from ZAP70. In the absence of Usp9X, an increased amount of ZAP70 localized to early endosomes consistent with the role of monoubiquitin in endocytic sorting. Usp9X becomes competent to deubiquitinate ZAP70 through TCR dependent phosphorylation and enhancement of its catalytic activity and association with the LAT signalosome. In B lymphocytes, Usp9X is required for the induction of PKCbeta kinase activity after BCR-dependent activation. Accordingly, inUsp9Xknockout B cells, there was a significant reduction in phospho-CARMA1 levels that resulted in reduced CARMA1/Bcl-10/MALT-1 complex formation and NF kappaB-dependent cell survival. The pleiotropic effect of Usp9X during Ag receptor signaling highlights its importance for the development of an effective and durable adaptive immune response. PMID- 26936882 TI - MicroRNA-487b Is a Negative Regulator of Macrophage Activation by Targeting IL-33 Production. AB - MicroRNAs (miRNAs) are short noncoding RNAs that regulate a broad spectrum of biological processes, including immune responses. Although the contributions of miRNAs to the function of immune cells are beginning to emerge, their specific roles remain largely unknown. IL-33 plays an important role in macrophage activation for innate host defense and proinflammatory responses. In this study, we report that miR-487b can suppress the levels of mRNA and protein for IL-33 during the differentiation of bone marrow-derived macrophages (BMDMs). This results in inhibition of IL-33-induced expression of Ag-presenting and costimulatory molecules and proinflammatory mediators. A luciferase assay showed that miR-487b binds to the IL-33 3'-untranslated region. We also confirmed that IL-33 directly promotes the activation of BMDMs by increasing the expression of MHC class I, MHC class II, CD80/CD86, and inducible NO synthase (iNOS) in a dose dependent manner. Exposure of BMDMs to the TLR4 ligand, LPS, decreased miR-487b expression, increased IL-33 transcript levels, and induced the production of proinflammatory mediators (e.g., iNOS, IL-1beta, IL-6, and TNF-alpha). Treatment with a specific inhibitor of miR-487b function also resulted in increased levels of IL-33 mRNA, which augmented LPS-induced expression of these inflammatory mediators in macrophages. Collectively, our results indicate that miR-487b plays a negative regulatory role in macrophages by controlling the levels of IL-33 transcript and protein to fine-tune innate immune host defense and proinflammatory responses of these cells. Thus, miR-487b plays an important role in the regulation of macrophage homeostasis and activation by targeting IL-33 transcripts. PMID- 26936884 TI - Closed oocyte vitrification and storage in an oocyte donation programme: obstetric and neonatal outcome. AB - STUDY QUESTION: Does closed oocyte vitrification in an oocyte donation programme have an impact on obstetric and neonatal outcome? SUMMARY ANSWER: Obstetric and neonatal outcomes after closed system vitrification of donor oocytes appear to be reassuring. WHAT IS KNOWN ALREADY: The use of fresh oocytes has not been proved to be superior to the use of vitrified donor oocytes in terms of survival, embryo development and clinical pregnancies. Those studies used open devices to prove the non-superiority. Very limited information is available on the comparison of open and closed devices, and the results for survival, embryo development and pregnancy outcomes are conflicting. Data on obstetric and neonatal outcome from vitrified oocytes are scarce. Only one large report is available after the use of donor oocytes vitrified with an open device. STUDY DESIGN, SIZE, DURATION: Retrospective observational study performed at the Centre for Reproductive Medicine, UZ Brussel, Belgium. All 117 oocyte recipient cycles between March 2010 and August 2014 with the use of a closed vitrification device and leading to a pregnancy beyond 20 weeks were included in this study. PARTICIPANTS/MATERIALS, SETTING, METHODS: All recipient warming cycles with a pregnancy beyond 20 weeks from vitrified donor oocytes: results from the fresh embryo transfers. MAIN RESULTS AND THE ROLE OF CHANCE: For 117 recipient cycles, a total of 793 oocytes were warmed of which 657 (82.8%) survived and 499 (76.0%) were fertilized. Nineteen single and 98 double embryo transfers led to 95 singleton and 22 twin pregnancies. Hypertensive disorders, haemorrhages and gestational diabetes were reported in 22/112 (19.6%), 30/112 (26.8%) and 13/112 (11.6%) of the pregnancies, respectively. No major adverse neonatal outcomes were observed. Congenital malformations were observed in 11 out of 139 children; for one an elective termination was performed at 25 weeks. LIMITATIONS, REASONS FOR CAUTION: Since March 2010, almost all oocytes for donation are vitrified in our centre. Therefore, no recent data are available to control the outcomes of fresh oocyte donations. WIDER IMPLICATIONS OF THE FINDINGS: The reassuring results obtained in the current study show that closed system vitrification devices for donor oocytes may be used as an alternative to open devices which have been linked to possible cross-contamination issues. STUDY FUNDING/COMPETING INTERESTS: None. TRIAL REGISTRATION NUMBER: N/A. PMID- 26936887 TI - No hypothesis. PMID- 26936886 TI - Compensated reduction in Leydig cell function is associated with lower semen quality variables: a study of 8182 European young men. AB - STUDY QUESTION: Is the Leydig cell function of young European men associated with semen quality? SUMMARY ANSWER: Compensated reduction in Leydig cell function, defined as increased LH concentration combined with adequate testosterone production is associated with lower semen quality. WHAT IS ALREADY KNOWN: Semen quality of young European men shows a heterogeneous pattern. Many have sperm counts below and in the lower WHO reference where there nevertheless is a significant risk of subfecundity. Little is known about differences in Leydig cell function between men with semen quality below and within the WHO reference range. STUDY DESIGN, SIZE AND DURATION: A coordinated, cross-sectional population based study of 8182 men undertaken in 1996-2010. PARTICIPANTS, SETTING AND METHOD: Young men (median age 19.1 years) were investigated in centres in Denmark, Estonia, Finland, Germany Latvia, Lithuania, and Spain. The men originated from the general populations, all were young, almost all were unaware of their fecundity and each provided a semen and blood sample. Associations between semen parameters and serum levels of testosterone and luteinising hormone (LH), calculated free testosterone, and ratios between serum testosterone and LH were determined. MAIN RESULT AND ROLE OF CHANCE: Serum testosterone levels were not associated with sperm concentrations, total sperm counts, or percentage of motile or morphologically normal spermatozoa. There was an inverse association between the semen parameters and serum LH levels, and accordingly a positive association to testosterone/LH ratio and calculated-free-testosterone/LH ratio. LIMITATIONS, REASON FOR CAUTION: The size of the study mitigates the intra individual variability concern. The distinction between different sub-categories of sperm motility and sperm morphology is subjective despite training. However, inter-observer variation would tend towards non-differential misclassification and would decrease the likelihood of detecting associations between reproductive hormone levels and semen variables, suggesting that the presented associations might in reality be even stronger than shown. Although we adjusted for confounders, we cannot of course exclude that our results can be skewed by selection bias or residual confounding. WIDER IMPLICATIONS OF THE FINDINGS: Compensated reduction in Leydig cell function, defined as increased LH concentration combined with adequate testosterone production is associated with lower semen quality. This is apparent even within the WHO reference range of semen quality. It is unknown whether impaired Leydig cell function in young men may confer an increased risk of acquired testosterone deficiency later in life. STUDY FUNDING/COMPETING INTERESTS: Support from The Research Fund of Rigshospitalet (grant no. R42-A1326) to N.J. made this study possible. The background studies of young men have been supported economically by several grants. ITALIC! Denmark: The European Union (contract numbers BMH4-CT96-0314, QLK4-CT-1999-01422, QLK4-CT-2002-00603 and most recently FP7/2007-2013, DEER Grant agreement no. 212844), The Danish Research Council (grants nos. 9700833 2107-05-0006), The Danish Agency for Science, Technology and Innovation (Grant no. 271070678), Rigshospitalet (Grant no. 961506336), The University of Copenhagen (Grant no. 211-0357/07-3012), The Danish Ministry of Health and the Danish Environmental Protection Agency, A.P. Moller and wife Chastine McKinney Mollers foundation, and Svend Andersens Foundation. ITALIC! Finland: European Union (contract numbers BMH4-CT96-0314, QLK4-CT-1999-01422, QLK4-CT- 2002-00603 and most recently FP7/2008-2012, DEER Grant agreement no. 212844), The Academy of Finland, Turku University Hospital Funds, Sigrid Juselius Foundation. ITALIC! Estonia, Latvia and Lithuania: European Union (QLRT-2001-02911), the Estonian Science Foundation, grant number 2991, Lithuanian Foundation for Research, Organon Agencies B.V. and the Danish Research Council, grant no. 9700833. ITALIC! Germany: European Union (contract numbers QLK4-CT-2002-00603). ITALIC! Spain: European Commission QLK4-1999-01422. M.F. received support from the Spanish Ministry of Science and Innovation (Program Ramon y Cajal). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. None of the authors have any competing interests to declare. PMID- 26936885 TI - Attitudes toward prevention of mtDNA-related diseases through oocyte mitochondrial replacement therapy. AB - STUDY QUESTION: Among women who carry pathogenic mitochondrial DNA (mtDNA) point mutations and healthy oocyte donors, what are the levels of support for developing oocyte mitochondrial replacement therapy (OMRT) to prevent transmission of mtDNA mutations? SUMMARY ANSWER: The majority of mtDNA carriers and oocyte donors support the development of OMRT techniques to prevent transmission of mtDNA diseases. WHAT IS KNOWN ALREADY: Point mutations of mtDNA cause a variety of maternally inherited human diseases that are frequently disabling and often fatal. Recent developments in (OMRT) as well as pronuclear transfer between embryos offer new potential options to prevent transmission of mtDNA disease. However, it is unclear whether the non-scientific community will approve of embryos that contain DNA from three people. STUDY DESIGN, SIZE, DURATION: Between 1 June 2012 through 12 February 2015, we administered surveys in cross-sectional studies of 92 female carriers of mtDNA point mutations and 112 healthy oocyte donors. PARTICIPANTS/MATERIALS, SETTING, METHODS: The OMRT carrier survey was completed by 92 female carriers of an mtDNA point mutation. Carriers were recruited through the North American Mitochondrial Disease Consortium (NAMDC), the United Mitochondrial Disease Foundation (UMDF), patient support groups, research and private patients followed at the Columbia University Medical Center (CUMC) and patients' referrals of maternal relatives. The OMRT donor survey was completed by 112 women who had donated oocytes through a major ITALIC! in vitro fertilization clinic. MAIN RESULTS AND THE ROLE OF CHANCE: All carriers surveyed were aware that they could transmit the mutation to their offspring, with 78% (35/45) of women, who were of childbearing age, indicating that the risk was sufficient to consider not having children, and 95% (87/92) of all carriers designating that the development of this technique was important and worthwhile. Of the 21 surveyed female carriers considering childbearing, 20 (95%) considered having their own biological offspring somewhat or very important and 16 of the 21 respondents (76%) were willing to donate oocytes for research and development. Of 112 healthy oocyte donors who completed the OMRT donor survey, 97 (87%) indicated that they would donate oocytes for generating a viable embryo through OMRT. LIMITATIONS, REASONS FOR CAUTION: Many of the participants were either patients or relatives of patients who were already enrolled in a research-oriented database, or who sought care in a tertiary research university setting, indicating a potential sampling bias. The survey was administered to a select group of individuals, who carry, or are at risk for carrying, mtDNA point mutations. These individuals are more likely to have been affected by the mutation or have witnessed first-hand the devastating effects of these mutations. It has not been established whether the general public would be supportive of this work. This survey did not explicitly address alternatives to OMRT. WIDER IMPLICATIONS OF THE FINDINGS: This is the first study indicating a high level of interest in the development of these methods among women affected by the diseases or who are at risk of carrying mtDNA mutations as well as willingness of most donors to provide oocytes for the development of OMRT. STUDY FUNDING/COMPETING INTERESTS: This work was conducted under the auspices of the NAMDC (Study Protocol 7404). NAMDC (U54NS078059) is part of the NCATS Rare Diseases Clinical Research Network (RDCRN). RDCRN is an initiative of the Office of Rare Diseases Research (ORDR) and NCATS. NAMDC is funded through a collaboration between NCATS, NINDS, NICHD and NIH Office of Dietary Supplements. The work was also supported by the Bernard and Anne Spitzer Fund and the New York Stem Cell Foundation (NYSCF). Dr Hirano has received research support from Santhera Pharmaceuticals and Edison Pharmaceuticals for studies unrelated to this work. None of the other authors have conflicts of interest. TRIAL REGISTRATION NUMBER: Not applicable. PMID- 26936883 TI - Human SR-BI and SR-BII Potentiate Lipopolysaccharide-Induced Inflammation and Acute Liver and Kidney Injury in Mice. AB - The class B scavenger receptors BI (SR-BI) and BII (SR-BII) are high-density lipoprotein receptors that recognize various pathogens, including bacteria and their products. It has been reported that SR-BI/II null mice are more sensitive than normal mice to endotoxin-induced inflammation and sepsis. Because the SR BI/II knockout model demonstrates multiple immune and metabolic disorders, we investigated the role of each receptor in the LPS-induced inflammatory response and tissue damage using transgenic mice with pLiv-11-directed expression of human SR-BI (hSR-BI) or human SR-BII (hSR-BII). At 6 h after i.p. LPS injection, transgenic hSR-BI and hSR-BII mice demonstrated markedly higher serum levels of proinflammatory cytokines and 2- to 3-fold increased expression levels of inflammatory mediators in the liver and kidney, compared with wild-type (WT) mice. LPS-stimulated inducible NO synthase expression was 3- to 6-fold higher in the liver and kidney of both transgenic strains, although serum NO levels were similar in all mice. Despite the lower high-density lipoprotein plasma levels, both transgenic strains responded to LPS by a 5-fold increase of plasma corticosterone levels, which were only moderately lower than in WT animals. LPS treatment resulted in MAPK activation in tissues of all mice; however, the strongest response was detected for hepatic extracellular signal-regulated protein kinase 1 and 2 and kidney JNK of both transgenic mice. Histological examination of hepatic and renal tissue from LPS-challenged mice revealed more injury in hSR-BII, but not hSR-BI, transgenic mice versus WT controls. Our findings demonstrate that hSR-BII, and to a lesser extent hSR-BI, significantly increase LPS-induced inflammation and contribute to LPS-induced tissue injury in the liver and kidney, two major organs susceptible to LPS toxicity. PMID- 26936889 TI - Drunk on risk: how the chief medical officers' alcohol guidelines are demonising drink. PMID- 26936888 TI - Signs and symptoms associated with early pregnancy loss: findings from a population-based preconception cohort. AB - STUDY QUESTION: What is the relationship between signs and symptoms of early pregnancy and pregnancy loss <20 weeks' gestation? SUMMARY ANSWER: Vaginal bleeding is associated with increased incidence of early pregnancy loss, with more severe bleeding and bleeding accompanied by lower abdominal cramping associated with greater incidence of loss; conversely, vomiting is associated with decreased incidence of early pregnancy loss, even in the setting of vaginal bleeding, while nausea alone is not. WHAT IS KNOWN ALREADY: Two previous cohort studies with preconception enrollment suggested that bleeding is associated with loss while nausea is inversely associated with loss though these studies were limited by small study size and reporting after loss ascertainment. No prior preconception cohort study has examined multiple signs and symptoms in relation to pregnancy loss. STUDY DESIGN, SIZE, DURATION: Population-based preconception cohort of 501 couples discontinuing contraception to try for pregnancy in 16 counties in Michigan and Texas, USA. Participants were followed daily until positive home pregnancy test or 12 months of trying without an hCG pregnancy; women who became pregnant were followed daily from 2 to 7 weeks post-conception. PARTICIPANTS, SETTING, METHODS: Three hundred and forty-seven women had a positive home pregnancy test denoting hCG pregnancy. Three hundred and forty-one women remained after excluding ineligible pregnancies. Women recorded daily from 2 to 7 weeks post-conception their signs and symptoms, including vaginal bleeding (none, spotting, light, moderate and heavy), lower abdominal cramping, nausea and vomiting. Pregnancy losses were ascertained by a subsequent negative home pregnancy test, clinical confirmation or onset of menses, depending on gestational age at loss; time-to-loss was measured in days post-conception. Cumulative incidence functions and 95% confidence intervals (CIs) were constructed for each sign or symptom, and hazard ratios (HRs) and 95% CIs for presence compared with absence of signs or symptoms were estimated using Cox proportional hazard models. MAIN RESULTS AND THE ROLE OF CHANCE: Women experienced lower abdominal cramping (85%), nausea (48%), vomiting (46%) and light/moderate/heavy vaginal bleeding (24%) during early pregnancy. Ninety-five (28%) women experienced a loss. Cumulative incidence of pregnancy loss varied by symptomatology: 19% for vomiting, 27% for lower abdominal cramping, 35% for nausea only, 52% for vaginal bleeding, 81% for vaginal bleeding with lower abdominal cramping. Incidence of pregnancy loss was increased among women with vaginal bleeding (HR: 3.62, 95% CI: 2.29-5.74) and among women with vaginal bleeding and lower abdominal cramping (HR: 5.03, 95% CI: 2.07-12.20). Incidence of pregnancy loss was decreased for women with vomiting (HR: 0.51, 95% CI: 0.30 0.86). In the setting of vaginal bleeding with lower abdominal cramping, vomiting reduced the incidence of pregnancy loss (HR: 0.24, 95% CI: 0.11-0.56). LIMITATIONS, REASONS FOR CAUTION: There were few losses beyond 14 weeks gestation; thus, the precision of our findings related to losses occurring after the first trimester is limited. WIDER IMPLICATIONS OF THE FINDINGS: By using sensitive home pregnancy tests, we are able to document and characterize the cumulative incidence of the earliest pregnancy losses, which constitute the majority of losses. The use of daily, prospective capture of signs and symptoms relative to ascertainment of pregnancy loss minimizes potential biases associated with reporting after rather than before a loss, which could potentially distort the relationship between signs and symptoms and pregnancy loss. The findings of our study suggest that it may be useful to develop prognostic models for pregnancy loss based on signs and symptoms. STUDY FUNDING/COMPETING INTERESTS: This study was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (contract numbers N01-HD-3-3355; N01-HD-3-3356; N01-HD-3 3358). The authors have no conflict of interest to declare. PMID- 26936890 TI - Evolution of Chromosomal Clostridium botulinum Type E Neurotoxin Gene Clusters: Evidence Provided by Their Rare Plasmid-Borne Counterparts. AB - Analysis of more than 150 Clostridium botulinum Group II type E genomes identified a small fraction (6%) where neurotoxin-encoding genes were located on plasmids. Seven closely related (134-144 kb) neurotoxigenic plasmids of subtypes E1, E3, and E10 were characterized; all carried genes associated with plasmid mobility via conjugation. Each plasmid contained the same 24-kb neurotoxin cluster cassette (six neurotoxin cluster and six flanking genes) that had split a helicase gene, rather than the more common chromosomal rarA. The neurotoxin cluster cassettes had evolved as separate genetic units which had either exited their chromosomal rarA locus in a series of parallel events, inserting into the plasmid-borne helicase gene, or vice versa. A single intact version of the helicase gene was discovered on a nonneurotoxigenic form of this plasmid. The observed low frequency for the plasmid location may reflect one or more of the following: 1) Less efficient recombination mechanism for the helicase gene target, 2) lack of suitable target plasmids, and 3) loss of neurotoxigenic plasmids. Type E1 and E10 plasmids possessed a Clustered Regularly Interspaced Short Palindromic Repeats locus with spacers that recognized C. botulinum Group II plasmids, but not C. botulinum Group I plasmids, demonstrating their long-term separation. Clostridium botulinum Group II type E strains also carry nonneurotoxigenic plasmids closely related to C. botulinum Group II types B and F plasmids. Here, the absence of neurotoxin cassettes may be because recombination requires both a specific mechanism and specific target sequence, which are rarely found together. PMID- 26936892 TI - An intriguing association of Turner syndrome with severe nephrotic syndrome: searching for a diagnosis. AB - Systemic lupus erythematosus (SLE) is a chronic disease caused by an aberrant autoimmune response, with a large spectrum of clinical manifestations. It strikingly affects women. Recent papers reveal that the men with Klinefelter syndrome (47, XXY) have a higher incidence of lupus than the men in the general population, similar with that of genotypic females. On the other hand, there is a great lack of information regarding the association of SLE with Turner syndrome, but it seems to be a lower risk for females with Turner to develop SLE. We present a rare association of a Turner syndrome with SLE, with negative immunology for SLE and with diagnosis made on renal biopsy. These data suggest that the presence of two X chromosomes may predispose to SLE, the ligand (CD40 ligand) for one of the genes that contributes to the pathogenesis of SLE being located on the X chromosome. PMID- 26936891 TI - Long-term organ damage accrual and safety in patients with SLE treated with belimumab plus standard of care. AB - OBJECTIVE: To examine long-term organ damage and safety following treatment with belimumab plus standard of care (SoC) in patients with systemic lupus erythematosus (SLE). METHODS: Pooled data were examined from two ongoing open label studies that enrolled patients who completed BLISS-52 or BLISS-76. Patients received belimumab every four weeks plus SoC. SLICC Damage Index (SDI) values were assessed every 48 weeks (study years) following belimumab initiation (baseline). The primary endpoint was change in SDI from baseline at study years 5 6. Incidences of adverse events (AEs) were reported for the entire study period. RESULTS: The modified intent-to-treat (MITT) population comprised 998 patients. At baseline, 940 (94.2%) were female, mean (SD) age was 38.7 (11.49) years, and disease duration was 6.7 (6.24) years. The mean (SD) SELENA-SLEDAI and SDI scores were 8.2 (4.18) and 0.7 (1.19), respectively; 411 (41.2%) patients had organ damage (SDI = 1: 235 (23.5%); SDI >= 2: 176 (17.6%)) prior to belimumab. A total of 427 (42.8%) patients withdrew overall; the most common reasons were patient request (16.8%) and AEs (8.5%).The mean (SD) change in SDI was +0.2 (0.48) at study years 5-6 (n = 403); 343 (85.1%) patients had no change from baseline in SDI score (SDI +1: 46 (11.4%), SDI +2: 13 (3.2%), SDI +3: 1 (0.2%)). Of patients without organ damage at baseline, 211/241 (87.6%) had no change in SDI and the mean change (SD) in SDI was +0.2 (0.44). Of patients with organ damage at baseline, 132/162 (81.5%) had no change in SDI and the mean (SD) change in SDI was +0.2 (0.53). The probability of not having a worsening in SDI score was 0.88 (95% CI: 0.85, 0.91) and 0.75 (0.67, 0.81) in those without and with baseline damage, respectively (post hoc analysis).Drug-related AEs were reported for 433 (43.4%) patients; infections/infestations (282, 28.3%) and gastrointestinal disorders (139, 13.9%) were the most common. CONCLUSION: Patients with SLE treated with long-term belimumab plus SoC had a low incidence of organ damage accrual and no unexpected AEs. High-risk patients with pre-existing organ damage also had low accrual, suggesting a favorable effect on future damage development. PMID- 26936893 TI - Urinary osteoprotegerin: a potential biomarker of lupus nephritis disease activity. AB - OBJECTIVES: Urinary biomarkers may help in identification, treatment and assessment of response in patients with lupus nephritis (LN). Osteoprotegerin (OPG) is produced by the kidneys and lymphoid cells and may reflect renal disease activity better. The data on its utility are sparse. METHODS: Fifty-eight patients with active LN (AN), 24 with active non-renal disease (ANR) and 39 with inactive disease (ID) were included. Median disease duration was 32 (1-204) months and median age was 27 (12-50) years. AN patients were followed up every three months for one year. Urine and serum samples were collected for OPG measurement by ELISA (pg/ml) and urinary values were normalised for creatinine excretion (pg/mg). Urine samples from 24 healthy individuals (HCs) and 20 patients each of rheumatoid arthritis (RA) and diabetic nephropathy (DM) served as controls. Variables were expressed as median (range). RESULTS: At baseline, normalised urinary OPG (uOPG) was significantly higher (p < 0.001) in AN (1229 (0 8577)) than ANR (236 (0-14713)), ID (463 (7-4253)), HCs (366 (120-2849)) and DM (350 (127-1577)) but it was not different from RA (1511 (122-8849)). uOPG correlated modestly with rSLEDAI (r = 0.4, p < 0.001) and SLEDAI (r = 0.31, p < 0.001) but not with serum OPG (sOPG). uOPG but not sOPG could differentiate between AN and ANR groups. In the longitudinal study, uOPG and sOPG decreased significantly with treatment at all follow-up visits but the trend of fall in sOPG was erratic. uOPG values at baseline, 3, 6, 9 and 12 months were 1229 (0 8577), 466 (3-4874), 104 (0-1598), 325 (0-4025) and 555 (6-6771) pg/mg, respectively. uOPG but not sOPG rose before conventional markers in three patients who had a relapse of LN. In two patients who developed chronic kidney disease, uOPG remained persistently high. For differentiating AN from ANR patients, uOPG performed the best on receiver operator characteristics analysis (AUC = 0.72) when compared with anti-dsDNA antibodies, C3, C4 and sOPG. CONCLUSION: uOPG is derived from kidneys and helps differentiate active SLE patients with and without LN. It shows modest correlation with disease activity and has a potential to predict poor response to therapy and relapse of LN. PMID- 26936894 TI - Superoxide and Singlet Oxygen Produced within the Thylakoid Membranes Both Cause Photosystem I Photoinhibition. AB - Photosystem I (PSI) photoinhibition suppresses plant photosynthesis and growth. However, the mechanism underlying PSI photoinhibition has not been fully clarified. In this study, in order to investigate the mechanism of PSI photoinhibition in higher plants, we applied repetitive short-pulse (rSP) illumination, which causes PSI-specific photoinhibition in chloroplasts isolated from spinach leaves. We found that rSP treatment caused PSI photoinhibition, but not PSII photoinhibition in isolated chloroplasts in the presence of O2 However, chloroplastic superoxide dismutase and ascorbate peroxidase activities failed to protect PSI from its photoinhibition. Importantly, PSI photoinhibition was largely alleviated in the presence of methyl viologen, which stimulates the production of reactive oxygen species (ROS) at the stromal region by accepting electrons from PSI, even under the conditions where CuZn-superoxide dismutase and ascorbate peroxidase activities were inactivated by KCN. These results suggest that the ROS production site, but not the ROS production rate, is critical for PSI photoinhibition. Furthermore, we found that not only superoxide (O2 (-)) but also singlet oxygen ((1)O2) is involved in PSI photoinhibition induced by rSP treatment. From these results, we suggest that PSI photoinhibition is caused by both O2 (-) and (1)O2 produced within the thylakoid membranes when electron carriers in PSI become highly reduced. Here, we show, to our knowledge, new insight into the PSI photoinhibition in higher plants. PMID- 26936895 TI - Modularity of Conifer Diterpene Resin Acid Biosynthesis: P450 Enzymes of Different CYP720B Clades Use Alternative Substrates and Converge on the Same Products. AB - Cytochrome P450 enzymes of the CYP720B subfamily play a central role in the biosynthesis of diterpene resin acids (DRAs), which are a major component of the conifer oleoresin defense system. CYP720Bs exist in families of up to a dozen different members in conifer genomes and fall into four different clades (I-IV). Only two CYP720B members, loblolly pine (Pinus taeda) PtCYP720B1 and Sitka spruce (Picea sitchensis) PsCYP720B4, have been characterized previously. Both are multisubstrate and multifunctional clade III enzymes, which catalyze consecutive three-step oxidations in the conversion of diterpene olefins to DRAs. These reactions resemble the sequential diterpene oxidations affording ent-kaurenoic acid from ent-kaurene in gibberellin biosynthesis. Here, we functionally characterized the CYP720B clade I enzymes CYP720B2 and CYP720B12 in three different conifer species, Sitka spruce, lodgepole pine (Pinus contorta), and jack pine (Pinus banksiana), and compared their activities with those of the clade III enzymes CYP720B1 and CYP720B4 of the same species. Unlike the clade III enzymes, clade I enzymes were ultimately found not to be active with diterpene olefins but converted the recently discovered, unstable diterpene synthase product 13-hydroxy-8(14)-abietene. Through alternative routes, CYP720B enzymes of both clades produce some of the same profiles of conifer oleoresin DRAs (abietic acid, neoabietic acid, levopimaric acid, and palustric acid), while clade III enzymes also function in the formation of pimaric acid, isopimaric acid, and sandaracopimaric acid. These results highlight the modularity of the specialized (i.e. secondary) diterpene metabolism, which produces conifer defense metabolites through variable combinations of different diterpene synthase and CYP720B enzymes. PMID- 26936897 TI - Economy, efficiency, and the evolution of pollen tube growth rates. AB - PREMISE: Pollen tube growth rate (PTGR) is an important aspect of male gametophyte performance because of its central role in the fertilization process. Theory suggests that under intense competition, PTGRs should evolve to be faster, especially if PTGR accurately reflects gametophyte quality. Oddly, we know remarkably little about how effectively the work of tube construction is translated to elongation (growth and growth rate). Here we test the prediction that pollen tubes grow equally efficiently by comparing the scaling of wall production rate (WPR) to PTGR in three water lilies that flower concurrently: Nymphaea odorata, Nuphar advena and Brasenia schreberi. METHODS: Single-donor pollinations on flower or carpel pairs were fixed just after pollen germination (time A) and 45 min later (time B). Mean PTGR was calculated as the average increase in tube length over that growth period. Tube circumferences (C) and wall thicknesses (W) were measured at time B. For each donor, WPR = mean (C * W) * mean PTGR. KEY RESULTS: Within species, pollen tubes maintained a constant WPR to PTGR ratio, but species had significantly different ratios. N. odorata and N. advena had similar PTGRs, but for any given PTGR, they had the lowest and highest WPRs, respectively. CONCLUSIONS: We showed that growth rate efficiencies evolved by changes in the volume of wall material used for growth and in how that material was partitioned between lateral and length dimensions. The economics of pollen tube growth are determined by tube design, which is consequent on trade offs between efficient growth and other pollen tube functions. PMID- 26936896 TI - Heat stress yields a unique MADS box transcription factor in determining seed size and thermal sensitivity. AB - Early seed development events are highly sensitive to increased temperature. This high sensitivity to a short-duration temperature spike reduces seed viability and seed size at maturity. The molecular basis of heat stress sensitivity during early seed development is not known. We selected rice (Oryza sativa), a highly heat-sensitive species, to explore this phenomenon. Here, we elucidate the molecular pathways that contribute to the heat sensitivity of a critical developmental window during which the endosperm transitions from syncytium to the cellularization stage in young seeds. A transcriptomic comparison of seeds exposed to moderate (35 degrees C) and severe (39 degrees C) heat stress with control (28 degrees C) seeds identified a set of putative imprinted genes, which were down-regulated under severe heat stress. Several type I MADS box genes specifically expressed during the syncytial stage were differentially regulated under moderate and severe heat stress. The suppression and overaccumulation of these genes are associated with precocious and delayed cellularization under moderate and severe stress, respectively. We show that modulating the expression of OsMADS87, one of the heat-sensitive, imprinted genes associated with syncytial stage endosperm, regulates rice seed size. Transgenic seeds deficient in OsMADS87 exhibit accelerated endosperm cellularization. These seeds also have lower sensitivity to a moderate heat stress in terms of seed size reduction compared with seeds from wild-type plants and plants overexpressing OsMADS87 Our findings suggest that OsMADS87 and several other genes identified in this study could be potential targets for improving the thermal resilience of rice during reproductive development. PMID- 26936898 TI - Preparation methods prior to PET/CT scanning that decrease uptake of 18F-FDG by myocardium, brown adipose tissue, and skeletal muscle. AB - BACKGROUND: The hypermetabolic environment of the myocardium, brown adipose tissue (BAT), and muscle will have an effect on the diagnostic accuracy of 18F fluorodeoxyglucose (18F-FDG) positron-emission tomography (PET)/computed tomography (CT). A low carbohydrate, high fat, and protein-permitted diet before PET/CT scanning can reduce the degree of 18F-FDG uptake by the myocardium, brown adipose tissue, and skeletal muscle. PURPOSE: To determine the effect of a low carbohydrate, high fat and protein-permitted diet on 18F-FDG uptake by myocardium, BAT, and muscle during PET/CT. MATERIAL AND METHODS: A total of 126 patients who adhered to two meals before PET/CT scanning (that were prepared using a low carbohydrate, high fat, and protein-permitted diet), i.e. the diet group, were compared with 126 patients who fasted for at least 12 h prior to scanning (i.e. the fasting group). The degree of 18F-FDG uptake within the myocardium, BAT, and muscle were stratified into four grades (range, 0-3) with 0 for negligible uptake, and 3 for intense uptake. Correlations between the diet and fasting groups with respect to degree of 18F-FDG uptake within the myocardium, BAT, and muscle were analyzed. RESULTS: The degree of 18F-FDG uptake within the myocardium, BAT, and muscle in the diet group was significantly lower compared with the 18F-FDG uptake within myocardium, BAT, and muscle in the fasting group (P < 0.001, P = 0.001, P < 0.001). CONCLUSION: A low carbohydrate/high fat diet before 18F-FDG injection can suppress uptake of 18F FDG within the myocardium, BAT, and skeletal muscle. PMID- 26936899 TI - Metal artifact reduction (MAR) based on two-compartment physical modeling: evaluation in patients with hip implants. AB - BACKGROUND: Artifacts from metallic implants can hinder image interpretation in computed tomography (CT). Image quality can be improved using metal artifact reduction (MAR) techniques. PURPOSE: To evaluate the impact of a MAR algorithm on image quality of CT examinations in comparison to filtered back projection (FBP) in patients with hip prostheses. MATERIAL AND METHODS: Twenty-two patients with 25 hip prostheses who underwent clinical abdominopelvic CT on a 64-row CT were included in this retrospective study. Axial images were reconstructed with FBP and five increasing MAR levels (M30-34). Objective artifact strength (OAS) (SIart SInorm) was assessed by region of interest (ROI) measurements in position of the strongest artifact (SIart) and in an osseous structure without artifact (SInorm) (in Hounsfield units [HU]). Two independent readers evaluated subjective image quality regarding metallic hardware, delineation of bone, adjacent muscle, and pelvic organs on a 5-point scale (1, non-diagnostic; 5, excellent image quality). Artifacts in the near field, far field, and newly induced artifacts due to the MAR technique were analyzed. RESULTS: OAS values were: M34: 243.8 +/- 155.4 HU; M33: 294.3 +/- 197.8 HU; M32: 340.5 +/- 210.1 HU; M31: 393.6 +/- 225.2 HU; M30: 446.8 +/- 224.2 HU and FBP: 528.9 +/- 227.7 HU. OAS values were significantly lower for M32-34 compared to FBP (P < 0.01). For overall subjective image quality, results were: FBP, 2.0 +/- 0.2; M30, 2.3 +/- 0.8; M31, 2.6 +/- 0.5; M32, 3.0 +/- 0.6; M33, 3.5 +/- 0.6; and M34, 3.8 +/- 0.4 (P < 0.001 for M30-M34 vs. FBP, respectively). Increasing MAR levels resulted in new artifacts in 17% of reconstructions. CONCLUSION: The investigated MAR algorithm led to a significant reduction of artifacts from metallic hip implants. The highest MAR level provided the least severe artifacts and the best overall image quality. PMID- 26936900 TI - Magnetic resonance imaging characteristics and treatment aspects of ventricular tuberculosis in adult patients. AB - BACKGROUND: Ventricular involvement in neurotuberculosis is rare. The literature regarding the characteristics of magnetic resonance imaging (MRI) in ventricular tuberculosis is very limited. PURPOSE: To describe MRI characteristics of ventricular tuberculosis and discuss the medical treatment along with the clinical outcome. MATERIAL AND METHODS: Ten patients (6 men, 4 women; average age, 39 years) were diagnosed with ventricular tuberculosis during a period of 3 years. Four patients had the history of pulmonary/pleural tuberculosis. The clinical and MRI features of these patients were reviewed retrospectively. RESULTS: On a brain MRI, three patients showed ependymitis associated with contrast enhancement of the ependymal lining of the ventricular walls. One patient had choroid plexitis associated with prominent swollen and marked enhancement of the choroid plexus. One patient had intraventricular tuberculoma associated with an intraventricular nodule. Two patients had both ependymitis and choroid plexitis. Three patients had both intraventricular tuberculoma and choroid plexitis. Four patients had hydrocephalus. All patients underwent intrathecal injection of isoniazid and dexamethasone combined with multidrug anti tuberculosis treatment. All patients had a good clinical recovery, except for one who developed hemi-paralysis due to cerebral infarction. On the repeated MRI of eight patients after therapy, all lesions disappeared or decreased in size, apart from in one patient who showed ventricular separation. CONCLUSION: MRI characteristics of ventricular tuberculosis included ependymal enhancement, swelling, and enhancement of the choroid plexus and intraventricular tuberculomas. Intrathecal injection of isoniazid and dexamethasone along with multidrug chemotherapy showed good efficacy in ventricular tuberculosis. PMID- 26936901 TI - Lay support for pregnant women with social risk: a randomised controlled trial. AB - OBJECTIVES: We sought evidence of effectiveness of lay support to improve maternal and child outcomes in disadvantaged families. DESIGN: Prospective, pragmatic, individually randomised controlled trial. SETTING: 3 Maternity Trusts in West Midlands, UK. PARTICIPANTS: Following routine midwife systematic assessment of social risk factors, 1324 nulliparous women were assigned, using telephone randomisation, to standard maternity care, or addition of referral to a Pregnancy Outreach Worker (POW) service. Those under 16 years and teenagers recruited to the Family Nurse Partnership trial were excluded. INTERVENTIONS: POWs were trained to provide individual support and case management for the women including home visiting from randomisation to 6 weeks after birth. Standard maternity care (control) included provision for referring women with social risk factors to specialist midwifery services, available to both arms. MAIN OUTCOME MEASURES: Primary outcomes were antenatal visits attended and Edinburgh Postnatal Depression Scale (EPDS) 8-12 weeks postpartum. Prespecified, powered, subgroup comparison was among women with 2 or more social risks. Secondary outcomes included maternal and neonatal birth outcomes; maternal self-efficacy, and mother to-infant bonding at 8-12 weeks; child development assessment at 6 weeks, breastfeeding at 6 weeks, and immunisation uptake at 4 months, all collected from routine child health systems. RESULTS: Antenatal attendances were high in the standard care control and did not increase further with addition of the POW intervention (10.1 vs 10.1 (mean difference; MD) -0.00, 95% CI (95% CI -0.37 to 0.37)). In the powered subgroup of women with 2 or more social risk factors, mean EPDS (MD -0.79 (95% CI -1.56 to -0.02) was significantly better, although for all women recruited, no significant differences were seen (MD -0.59 (95% CI -1.24 to 0.06). Mother-to-infant bonding was significantly better in the intervention group for all women (MD -0.30 (95% CI -0.61 to -0.00) p=0.05), and there were no differences in other secondary outcomes. CONCLUSIONS: This trial demonstrates differences in depressive symptomatology with addition of the POW service in the powered subgroup of women with 2 or more social risk factors. Addition to existing evidence indicates benefit from lay interventions in preventing postnatal depression. This finding is important for women and their families given the known effect of maternal depression on longer term childhood outcomes. TRIAL REGISTRATION NUMBER: ISRCTN35027323; Results. PMID- 26936902 TI - Getting our house in order: an audit of the registration and publication of clinical trials supported by the National Institute for Health Research Oxford Biomedical Research Centre and the Musculoskeletal Biomedical Research Unit. AB - OBJECTIVES: To audit the proportion of clinical trials that had been publically registered and, of the completed trials, the proportion published. SETTING: 2 major research institutions supported by the National Institute of Health Research (NIHR). PRIMARY AND SECONDARY OUTCOME MEASURES: The proportion of trials reporting results within 12 months, 24 months and 'ever'. Factors associated with non-publication were analysed using logistic regression. INCLUSION CRITERIA: Phases 2-4 clinical trials identified from internal documents and publication lists. RESULTS: In total, 286 trials were identified. We could not find registration for 4 (1.4%) of these, all of which were completed and published. Of the trials with a registered completion date pre-January 2015, just over half (56%) were published, and half of these were published within 12 months (36/147, 25%). For some trials, information on the public registers was found to be out-of date and/or inaccurate. No clinical trial characteristics were found to be significantly associated with non-publication. We have produced resources to facilitate similar audits elsewhere. CONCLUSIONS: It was feasible to conduct an internal audit of registration and publication in 2 major research institutions. Performance was similar to, or better than, comparable cohorts of trials sampled from registries. The major resource input required was manually seeking information: if all registry entries were maintained, then almost the entire process of audit could be automated--and routinely updated--for all research centres and funders. PMID- 26936903 TI - Adaptation and validation of the Distress Scale for Mexican patients with type 2 diabetes and hypertension: a cross-sectional survey. AB - OBJECTIVES: The aim of this study was to adapt and validate the Distress Scale for Mexican patients with type 2 diabetes and hypertension (DSDH17M). SETTING: Two family medicine clinics affiliated with the Mexican Institute of Social Security. PARTICIPANTS: 722 patients with type 2 diabetes and/or hypertension (235 patients with diabetes, 233 patients with hypertension and 254 patients with both diseases). DESIGN: A cross-sectional survey. METHODS: The validation procedures included: (1) content validity using a group of experts, (2) construct validity from exploratory factor analysis, (3) internal consistency using Cronbach's alpha, (4) convergent validity between DSDH17M and anxiety and depression using the Spearman correlation coefficient, (5) discriminative validity through the Wilcoxon rank-sum test and (6) test-retest reliability using intraclass correlation coefficient. RESULTS: The DSDH17M has 17 items and three factors explaining 67% of the total variance. Cronbach alpha ranged from 0.83 to 0.91 among factors. The first factor of 'Regime-related Distress and Emotional Burden' moderately correlated with anxiety and depression scores. Discriminative validity revealed that patients with obesity, those with stressful events and those who did not adhere to pharmacological treatment had significantly higher distress scores in all DSDH17M domains. Test-retest intraclass correlation coefficient for DSDH17M ranged from 0.92 to 0.97 among factors. CONCLUSIONS: DSDH17M is a valid and reliable tool to identify distress of patients with type 2 diabetes and hypertension. PMID- 26936904 TI - Discovering untapped relationship potential with patients in telehealth: a qualitative interview study. AB - OBJECTIVES: To explore factors that influence relationship building between telehealth professionals and patients with chronic illness over a distance, from a telehealth professional's perspective. DESIGN: 4 focus group interviews were conducted in June 2014. Digital recordings were transcribed verbatim and qualitative content analysis was performed using an iterative process of 3 coding rounds. PARTICIPANTS: 20 telehealth professionals. SETTING: A telehealth service centre in the south of Germany that provided care for 12,000 patients with chronic heart failure across Germany. RESULTS: Non-video telehealth technology creates an atmosphere that fosters sharing of personal information and a non judgemental attitude. This facilitates the delivery of fair and equal healthcare. A combination of a protocol-driven service structure along with shared team and organisational values provide a basis for establishing long-term healthcare relationships. However, each contact between a telehealth professional and a patient has an uncertain outcome and requires skillful negotiation of the relationship. Although care provision was personalised, there was scope to include the patients as 'experts on their own illness' to a greater extent as advocated by person-centred care. Currently, provision of person-centred care is not sufficiently addressed in telehealth professional training. CONCLUSIONS: Telehealth offers a viable environment for the delivery of person-centred care for patients with long-standing disease. Current telehealth training programmes may be enhanced by teaching person-centred care skills. PMID- 26936905 TI - omega-3 Fatty acids for major depressive disorder in adults: an abridged Cochrane review. AB - OBJECTIVE: To assess the effects of n-3 polyunsaturated fatty acids (n-3PUFAs; also known as omega-3 fatty acids) compared with comparator for major depressive disorder (MDD) in adults. DESIGN: Systematic review and meta-analyses. DATA SOURCES: The Cochrane Depression, Anxiety and Neurosis Review Group's Specialised Registers (CCDANCTR) and International Trial Registries searched to May 2015. CINAHL searched to September 2013. TRIAL SELECTION: INCLUSION CRITERIA: a randomised controlled trial (RCT); that provided n-3PUFAs as an intervention; used a comparator; measured depressive symptomology as an outcome; and was conducted in adults with MDD. OUTCOMES: Primary outcomes were depressive symptomology and adverse events. RESULTS: 20 trials encompassing 26 relevant studies were found. For n-3PUFAs versus placebo, n-3PUFA supplementation resulted in a small-to-modest benefit for depressive symptomology: SMD=-0.32 (95% CI -0.52 to -0.12; 25 studies, 1373 participants, very low-quality evidence), but this effect is unlikely to be clinically meaningful, is very imprecise and, based on funnel plot inspection, sensitivity analyses and comparison with large well conducted trials, is likely to be biased. Considerable evidence of heterogeneity between studies was also found, and was not explained by subgroup or sensitivity analyses. Numbers of individuals experiencing adverse events were similar in intervention and placebo groups (OR=1.24, 95% CI 0.95 to 1.62; 19 studies, 1207 participants; very low-quality evidence). For n-3PUFAs versus antidepressants, no differences were found between treatments in depressive symptomology (MD=-0.70 (95% CI -5.88 to 4.48); 1 study, 40 participants, very low-quality evidence). CONCLUSIONS: At present, we do not have sufficient evidence to determine the effects of n-3PUFAs as a treatment for MDD. Further research in the form of adequately powered RCTs is needed. PMID- 26936906 TI - Menstrual hygiene management among adolescent girls in India: a systematic review and meta-analysis. AB - OBJECTIVES: To assess the status of menstrual hygiene management (MHM) among adolescent girls in India to determine unmet needs. DESIGN: Systematic review and meta-analysis. We searched PubMed, The Global Health Database, Google Scholar and references for studies published from 2000 to September 2015 on girls' MHM. SETTING: India. PARTICIPANTS: Adolescent girls. OUTCOME MEASURES: Information on menarche awareness, type of absorbent used, disposal, hygiene, restrictions and school absenteeism was extracted from eligible materials; a quality score was applied. Meta-analysis was used to estimate pooled prevalence (PP), and meta regression to examine the effect of setting, region and time. RESULTS: Data from 138 studies involving 193 subpopulations and 97,070 girls were extracted. In 88 studies, half of the girls reported being informed prior to menarche (PP 48%, 95% CI 43% to 53%, I(2) 98.6%). Commercial pad use was more common among urban (PP 67%, 57% to 76%, I(2) 99.3%, n=38) than rural girls (PP 32%, 25% to 38%, I(2) 98.6%, n=56, p<0.0001), with use increasing over time (p<0.0001). Inappropriate disposal was common (PP 23%, 16% to 31%, I(2) 99.0%, n=34). Menstruating girls experienced many restrictions, especially for religious activities (PP 0.77, 0.71 to 0.83, I(2) 99.1%, n=67). A quarter (PP 24%, 19% to 30%, I(2) 98.5%, n=64) reported missing school during periods. A lower prevalence of absenteeism was associated with higher commercial pad use in univariate (p=0.023) but not in multivariate analysis when adjusted for region (p=0.232, n=53). Approximately a third of girls changed their absorbents in school facilities (PP 37%, 29% to 46%, I(2) 97.8%, n=17). Half of the girls' homes had a toilet (PP 51%, 36% to 67%, I(2) 99.4%, n=21). The quality of studies imposed limitations on analyses and the interpretation of results (mean score 3 on a scale of 0-7). CONCLUSIONS: Strengthening of MHM programmes in India is needed. Education on awareness, access to hygienic absorbents and disposal of MHM items need to be addressed. TRIAL REGISTRATION NUMBER: CRD42015019197. PMID- 26936908 TI - How do authors of systematic reviews deal with research malpractice and misconduct in original studies? A cross-sectional analysis of systematic reviews and survey of their authors. AB - OBJECTIVES: To study whether systematic reviewers apply procedures to counter balance some common forms of research malpractice such as not publishing completed research, duplicate publications, or selective reporting of outcomes, and to see whether they identify and report misconduct. DESIGN: Cross-sectional analysis of systematic reviews and survey of their authors. PARTICIPANTS: 118 systematic reviews published in four journals (Ann Int Med, BMJ, JAMA, Lancet), and the Cochrane Library, in 2013. MAIN OUTCOMES AND MEASURES: Number (%) of reviews that applied procedures to reduce the impact of: (1) publication bias (through searching of unpublished trials), (2) selective outcome reporting (by contacting the authors of the original studies), (3) duplicate publications, (4) sponsors' and (5) authors' conflicts of interest, on the conclusions of the review, and (6) looked for ethical approval of the studies. Number (%) of reviewers who suspected misconduct are reported. The procedures applied were compared across journals. RESULTS: 80 (68%) reviewers confirmed their data. 59 (50%) reviews applied three or more procedures; 11 (9%) applied none. Unpublished trials were searched in 79 (66%) reviews. Authors of original studies were contacted in 73 (62%). Duplicate publications were searched in 81 (69%). 27 reviews (23%) reported sponsors of the included studies; 6 (5%) analysed their impact on the conclusions of the review. Five reviews (4%) looked at conflicts of interest of study authors; none of them analysed their impact. Three reviews (2.5%) looked at ethical approval of the studies. Seven reviews (6%) suspected misconduct; only 2 (2%) reported it explicitly. Procedures applied differed across the journals. CONCLUSIONS: Only half of the systematic reviews applied three or more of the six procedures examined. Sponsors, conflicts of interest of authors and ethical approval remain overlooked. Research misconduct is sometimes identified, but rarely reported. Guidance on when, and how, to report suspected misconduct is needed. PMID- 26936907 TI - Proteomic prediction and Renin angiotensin aldosterone system Inhibition prevention Of early diabetic nephRopathy in TYpe 2 diabetic patients with normoalbuminuria (PRIORITY): essential study design and rationale of a randomised clinical multicentre trial. AB - INTRODUCTION: Diabetes mellitus affects 9% of the European population and accounts for 15% of healthcare expenditure, in particular, due to excess costs related to complications. Clinical trials aiming for earlier prevention of diabetic nephropathy by renin angiotensin system blocking treatment in normoalbumuric patients have given mixed results. This might reflect that the large fraction of normoalbuminuric patients are not at risk of progression, thereby reducing power in previous studies. A specific risk classifier based on urinary proteomics (chronic kidney disease (CKD)273) has been shown to identify normoalbuminuric diabetic patients who later progressed to overt kidney disease, and may hold the potential for selection of high-risk patients for early intervention. Combining the ability of CKD273 to identify patients at highest risk of progression with prescription of preventive aldosterone blockade only to this high-risk population will increase power. We aim to confirm performance of CKD273 in a prospective multicentre clinical trial and test the ability of spironolactone to delay progression of early diabetic nephropathy. METHODS AND ANALYSIS: Investigator-initiated, prospective multicentre clinical trial, with randomised double-masked placebo-controlled intervention and a prospective observational study. We aim to include 3280 type 2 diabetic participants with normoalbuminuria. The CKD273 classifier will be assessed in all participants. Participants with high-risk pattern are randomised to treatment with spironolactone 25 mg once daily, or placebo, whereas, those with low-risk pattern will be observed without intervention other than standard of care. Treatment or observational period is 3 years.The primary endpoint is development of confirmed microalbuminuria in 2 of 3 first morning voids urine samples. ETHICS AND DISSEMINATION: The study will be conducted under International Conference on Harmonisation - Good clinical practice (ICH-GCP) requirements, ethical principles of Declaration of Helsinki and national laws. This first new biomarker-directed intervention trial aiming at primary prevention of diabetic nephropathy may pave the way for personalised medicine approaches in treatment of diabetes complications. TRIAL REGISTRATION NUMBER: NCT02040441; Pre-results. PMID- 26936909 TI - Is the HAS-BLED score useful in predicting post-extraction bleeding in patients taking warfarin? A retrospective cohort study. AB - OBJECTIVE: Unexpected post-extraction bleeding is often experienced in clinical practice. Therefore, determining the risk of post-extraction bleeding in patients receiving anticoagulant therapy prior to surgery is beneficial. This study aimed to verify whether the HAS-BLED score was useful in predicting post-extraction bleeding in patients taking warfarin. DESIGN: Retrospective cohort study. SETTING: Department of Oral and Maxillofacial Surgery, Tokyo Women's Medical University. PARTICIPANTS: Participants included 258 sequential cases (462 teeth) who had undergone tooth extraction between 1 January 2010 and 31 December 2012 while continuing warfarin therapy. MAIN OUTCOME MEASURE: Post-extraction risk factors for bleeding. The following data were collected as the predicting variables for multivariate logistic analysis: the HAS-BLED score, extraction site, tooth type, stability of teeth, extraction procedure, prothrombin time international normalised ratio value, platelet count and the use of concomitant antiplatelet agents. RESULTS: Post-extraction bleeding was noted in 21 (8.1%) of the 258 cases. Haemostasis was achieved with localised haemostatic procedures in all the cases of post-extraction bleeding. The HAS-BLED score was found to be insufficient in predicting post-extraction bleeding (area under the curve=0.548, p=0.867, multivariate analysis). The risk of post-extraction bleeding was approximately three times greater in patients taking concomitant oral antiplatelet agents (risk ratio=2.881, p=0.035, multivariate analysis). CONCLUSIONS: The HAS-BLED score alone could not predict post-extraction bleeding. The concomitant use of oral antiplatelet agents was a risk factor for post extraction bleeding. No episodes of post-extraction bleeding required more than local measures for haemostasis. However, because this was a retrospective study conducted at a single institution, large-scale prospective cohort studies, which include cases of outpatient tooth extraction, will be necessary in the future. PMID- 26936910 TI - Socioeconomic deprivation and barriers to live-donor kidney transplantation: a qualitative study of deceased-donor kidney transplant recipients. AB - OBJECTIVES: Socioeconomically deprived individuals with renal disease are less likely to receive a live-donor kidney transplant than less-deprived individuals. This qualitative study aimed to identify reasons for the observed socioeconomic disparity in live-donor kidney transplantation. DESIGN: A qualitative study using face-to-face in-depth semistructured interviews. SETTING: A UK tertiary renal referral hospital and transplant centre. PARTICIPANTS: Purposive sampling was used to select deceased-donor transplant recipients from areas of high socioeconomic deprivation (SED) (19 participants), followed by a low SED comparison group (13 participants), aiming for maximum diversity in terms of age, gender, ethnicity, primary renal disease and previous renal replacement therapy. METHODS: Participants were interviewed following their routine transplant clinic review. Interviews were digitally audio-recorded and transcribed verbatim. Transcripts were coded using NVivo software and analysed using the constant comparison method described in Grounded Theory. RESULTS: Themes common and distinct to each socioeconomic group emerged. 6 themes appeared to distinguish between individuals from areas of high and low SED. 4 themes were distinct to participants from areas of high SED: (1) Passivity, (2) Disempowerment, (3) Lack of social support and (4) Short-term focus. 2 themes were distinct to the low SED group: (1) Financial concerns and (2) Location of donor. CONCLUSIONS: Several of the emerging themes from the high SED individuals relate to an individual's lack of confidence and skill in managing their health and healthcare; themes that are in keeping with low levels of patient activation. Inadequate empowerment of socioeconomically deprived individuals by healthcare practitioners was also described. Financial concerns did not emerge as a barrier from interviews with the high SED group. Interventions aiming to redress the observed socioeconomic inequity should be targeted at both patients and clinical teams to increase empowerment and ensure shared decision-making. PMID- 26936912 TI - I get height with a little help from my friends: herd protection from sanitation on child growth in rural Ecuador. AB - BACKGROUND: Infectious disease interventions, such as vaccines and bed nets, have the potential to provide herd protection to non-recipients. Similarly, improved sanitation in one household may provide community-wide benefits if it reduces contamination in the shared environment. Sanitation at the household level is an important predictor of child growth, but less is known about the effect of sanitation coverage in the community. METHODS: From 2008 to 2013, we took repeated anthropometric measurements on 1314 children under 5 years of age in 24 rural Ecuadorian villages. Using mixed effects regression, we estimated the association between sanitation coverage in surrounding households and child growth. RESULTS: Sanitation coverage in the surrounding households was strongly associated with child height, as those with 100% coverage in their surroundings had a 67% lower prevalence of stunting [prevalence ratio (PR) 0.32, 95% CI 0.15 0.69] compared with those with 0% coverage. Children from households with improved sanitation had a lower prevalence of stunting (PR 0.86, 95% CI 0.64 1.15). When analysing height as a continuous outcome, the protective effect of sanitation coverage is manifested primarily among girls during the second year of life, the time at which growth faltering is most likely to occur. CONCLUSIONS: Our study highlights that a household's sanitation practices can provide herd protection to the overall community. Studies which fail to account for the positive externalities that sanitation provides will underestimate the overall protective effect. Future studies could seek to identify a threshold of sanitation coverage, similar to a herd immunity threshold, to provide coverage and compliance targets. PMID- 26936911 TI - Interventions to prevent or reduce the level of frailty in community-dwelling older adults: a protocol for a scoping review of the literature and international policies. AB - INTRODUCTION: With ageing comes increased vulnerability such that older adults' ability to recover from acute illnesses, fall-related injuries and other stresses related to the physical ageing processes declines. This increased vulnerability, also known as frailty, is common in older adults and associated with increased healthcare service use and adverse health outcomes. Currently, there is no overview of available interventions to prevent or reduce the level of frailty (as defined by study's authors) which will help healthcare providers in community settings caring for older adults. We will address this gap by reviewing interventions and international policies that are designed to prevent or reduce the level of frailty in community-dwelling older adults. METHODS AND ANALYSIS: We will conduct a scoping review using the updated guidelines of Arksey and O'Malley to systematically search the peer-reviewed journal articles to identify interventions that aimed to prevent or reduce the level of frailty. We will search grey literature for international policies. The 6-stage scoping review model involves: (1) identifying the research question; (2) identifying relevant studies; (3) selecting studies; (4) charting the data; (5) collating, summarising and reporting the results and (6) consulting with key stakeholders. ETHICS AND DISSEMINATION: Our scoping review will use robust methodology to search for available interventions focused on preventing or reducing the level of frailty in community-dwelling older adults. We will consult with stakeholders to find out whether they find the frailty interventions/policies useful and to identify the barriers and facilitators to their implementation in Canada. We will disseminate our findings to relevant stakeholders at local, national and international levels by presenting at relevant meetings and publishing the findings. Our review will identify gaps in research and provide healthcare providers and policymakers with an overview of interventions that can be implemented to prevent or postpone frailty. PMID- 26936913 TI - Immunological Characterization and Neutralizing Ability of Monoclonal Antibodies Directed Against Botulinum Neurotoxin Type H. AB - BACKGROUND: Only Clostridium botulinum strain IBCA10-7060 produces the recently described novel botulinum neurotoxin type H (BoNT/H). BoNT/H (N-terminal two thirds most homologous to BoNT/F and C-terminal one-third most homologous to BoNT/A) requires antitoxin to toxin ratios >=1190:1 for neutralization by existing antitoxins. Hence, more potent and safer antitoxins against BoNT/H are needed. METHODS: We therefore evaluated our existing monoclonal antibodies (mAbs) to BoNT/A and BoNT/F for BoNT/H binding, created yeast-displayed mutants to select for higher-affinity-binding mAbs by using flow cytometry, and evaluated the mAbs' ability to neutralize BoNT/H in the standard mouse bioassay. RESULTS: Anti-BoNT/A HCC-binding mAbs RAZ1 and CR2 bound BoNT/H with high affinity. However, only 1 of 6 BoNT/F mAbs (4E17.2A) bound BoNT/H but with an affinity >800 fold lower (equilibrium dissociation binding constant [KD] = 7.56 * 10(-8)M) than its BoNT/F affinity (KD= 9.1 * 10(-11)M), indicating that the N-terminal two thirds of BoNT/H is immunologically unique. The affinity of 4E17.2A for BoNT/H was increased >500-fold to KD= 1.48 * 10(-10)M (mAb 4E17.2D). A combination of mAbs RAZ1, CR2, and 4E17.2D completely protected mice challenged with 280 mouse median lethal doses of BoNT/H at a mAb dose as low as 5 ug of total antibody. CONCLUSIONS: This 3-mAb combination potently neutralized BoNT/H and represents a potential human antitoxin that could be developed for the prevention and treatment of type H botulism. PMID- 26936916 TI - Molecular Profile and FDG-PET/CT Total Metabolic Tumor Volume Improve Risk Classification at Diagnosis for Patients with Diffuse Large B-Cell Lymphoma. AB - PURPOSE: The prognostic impact of total metabolic tumor volume (TMTV) measured on pretreatment (18)F-FDG PET/CT and its added value to molecular characteristics was investigated in patients with diffuse large B-cell lymphoma (DLBCL). EXPERIMENTAL DESIGN: For 81 newly diagnosed patients with DLBCL treated with rituximab and CHOP/CHOP-like regimen, TMTV was computed using the 41% SUVmax thresholding method. According to the gene expression profile, determined using DASL (cDNA-mediated Annealing, Selection, Ligation and extension) technology, a subset of 57 patients was classified in germinal center B (GCB) or activated B cell (ABC) subtypes and MYC or BCL2 overexpressed. RESULTS: Median follow-up was 64 months. Five-year progression-free survival (PFS) and overall survival (OS) were 60% and 63% in the whole population. Median pretherapy TMTV was 320 cm(3) (25th-75th percentiles 106-668 cm(3)). With a 300 cm(3) cutoff, patients with high TMTV (n = 43) had a 5-year PFS and OS of 43% and 46% compared with 76% and 78% for patients with a low TMTV (P = 0.0023, P = 0.0047). ABC status, MYC, or BCL2 overexpression and both overexpression ("dual expressor," DE) were significantly associated with a worse PFS and OS. TMTV combined with molecular data allowed a significant better risk substratification of ABC/GCB patients, on PFS and OS. High TMTV individualized in molecular-low-risk patients a group with a poor outcome (MYC, PFS=51%, OS=55% BCL2, PFS=49%, OS=49% or DE PFS=50%, OS=50%) and a group with a good outcome (MYC, PFS=93%, OS=93% BCL2, PFS=86%, OS=86%, or DE PFS=81%, OS=81%). CONCLUSIONS: The combination of molecular and imaging characteristics at diagnosis could lead to a more accurate selection of patients, to increase tailor therapy. Clin Cancer Res; 22(15); 3801-9. (c)2016 AACR. PMID- 26936914 TI - ErbB2 Signaling Increases Androgen Receptor Expression in Abiraterone-Resistant Prostate Cancer. AB - PURPOSE: ErbB2 signaling appears to be increased and may enhance androgen receptor (AR) activity in a subset of patients with castration-resistant prostate cancer (CRPC), but agents targeting ErbB2 have not been effective. This study was undertaken to assess ErbB2 activity in abiraterone-resistant prostate cancer and to determine whether it may contribute to AR signaling in these tumors. EXPERIMENTAL DESIGN: AR activity and ErbB2 signaling were examined in the radical prostatectomy specimens from a neoadjuvant clinical trial of leuprolide plus abiraterone and in the specimens from abiraterone-resistant CRPC xenograft models. The effect of ErbB2 signaling on AR activity was determined in two CRPC cell lines. Moreover, the effect of combination treatment with abiraterone and an ErbB2 inhibitor was assessed in a CRPC xenograft model. RESULTS: We found that ErbB2 signaling was elevated in residual tumor following abiraterone treatment in a subset of patients and was associated with higher nuclear AR expression. In xenograft models, we similarly demonstrated that ErbB2 signaling was increased and associated with AR reactivation in abiraterone-resistant tumors. Mechanistically, we show that ErbB2 signaling and subsequent activation of the PI3K/AKT signaling stabilizes AR protein. Furthermore, concomitantly treating CRPC cells with abiraterone and an ErbB2 inhibitor, lapatinib, blocked AR reactivation and suppressed tumor progression. CONCLUSIONS: ErbB2 signaling is elevated in a subset of patients with abiraterone-resistant prostate cancer and stabilizes AR protein. Combination therapy with abiraterone and ErbB2 antagonists may be effective for treating the subset of CRPC with elevated ErbB2 activity. Clin Cancer Res; 22(14); 3672-82. (c)2016 AACR. PMID- 26936915 TI - Targeting MDM2 for Treatment of Adenoid Cystic Carcinoma. AB - PURPOSE: There are no effective treatment options for patients with advanced adenoid cystic carcinoma (ACC). Here, we evaluated the effect of a new small molecule inhibitor of the MDM2-p53 interaction (MI-773) in preclinical models of ACC. EXPERIMENTAL DESIGN: To evaluate the anti-tumor effect of MI-773, we administered it to mice harboring three different patient-derived xenograft (PDX) models of ACC expressing functional p53. The effect of MI-773 on MDM2, p53, phospho-p53, and p21 was examined by Western blots in 5 low passage primary human ACC cell lines and in MI-773-treated PDX tumors. RESULTS: Single-agent MI-773 caused tumor regression in the 3 PDX models of ACC studied here. For example, we observed a tumor growth inhibition index of 127% in UM-PDX-HACC-5 tumors that was associated with an increase in the fraction of apoptotic cells (P = 0.015). The number of p53-positive cells was increased in MI-773-treated PDX tumors (P < 0.001), with a correspondent shift in p53 localization from the nucleus to the cytoplasm. Western blots demonstrated that MI-773 potently induced expression of p53 and its downstream targets p21, MDM2, and induced phosphorylation of p53 (serine 392) in low passage primary human ACC cells. Notably, MI-773 induced a dose-dependent increase in the fraction of apoptotic ACC cells and in the fraction of cells in the G1 phase of cell cycle (P < 0.05). CONCLUSIONS: Collectively, these data demonstrate that therapeutic inhibition of the MDM2-p53 interaction with MI-773 activates downstream effectors of apoptosis and causes robust tumor regression in preclinical models of ACC. Clin Cancer Res; 22(14); 3550-9. (c)2016 AACR. PMID- 26936917 TI - FGFR1 Is a Potential Prognostic Biomarker and Therapeutic Target in Head and Neck Squamous Cell Carcinoma. AB - PURPOSE: FGFR1 is a promising therapeutic target in multiple types of solid tumors, including head and neck squamous cell carcinoma (HNSCC). FGFR inhibitors have shown great therapeutic value in preclinical models. However, resistance remains a major setback. In this study, we have investigated the prognostic value of FGFR1 expression in HNSCC, the therapeutic relevance of targeting FGFR with AZD4547, and potential resistant mechanisms. EXPERIMENTAL DESIGN: IHC and FISH were applied on tissue microarrays to investigate FGFR1 protein expression and FGFR1 gene copy numbers in 452 HNSCCs. The sensitivity of HNSCC cell lines to AZD4547, either as single or combination treatment with the EGFR inhibitor gefitinib, was assessed using long-term colony formation assays, short-term viability assays, and biochemical analysis. RESULTS: FGFR1 protein overexpression occurred in 82% (36/44) of human papillomavirus (HPV)-positive HNSCC and 75% (294/392) of HPV-negative HNSCC and relates with poor overall survival and disease-free survival in HPV-negative HNSCC [HR, 3.07; 95% confidence interval (CI), 1.74-6.90; P = 0.001 and HR, 1.53; 95% CI, 1.04-2.39; P = 0.033]. Moreover, the FGFR1 gene was amplified in 3% (3/110) of HPV-negative HNSCC. Treatment of the high FGFR1-expressing cell line CCL30 with AZD4547 reduced cell proliferation and FGFR signaling. Two FGFR-amplified cell lines, SCC147 and BICR16, were resistant to AZD4547 treatment due to EGFR signaling. Combined AZD4547 and gefitinib treatment synergistically inhibited the proliferation of resistant cell lines. CONCLUSIONS: Here, we identify high FGFR1 expression as a candidate prognostic biomarker in HPV-negative HNSCC. Furthermore, we provide a rationale for treating FGFR1-expressing HNSCC with the FGFR inhibitor AZD4547 and for combining AZD4547 and gefitinib in FGFR inhibitor-resistant HNSCC patients. Clin Cancer Res; 22(15); 3884-93. (c)2016 AACR. PMID- 26936919 TI - KIT Exon 11 Codons 557-558 Deletion Mutation Promotes Liver Metastasis Through the CXCL12/CXCR4 Axis in Gastrointestinal Stromal Tumors. AB - PURPOSE: KIT mutations, the most prevalent genetic event in gastrointestinal stromal tumors (GIST), are associated with malignant features and poor prognosis. Aggressive GISTs possess a high propensity to spread to the liver. This study aimed to explore the role of KIT mutations in GIST liver metastasis. EXPERIMENTAL DESIGN: A total of 170 GISTs were used to determine the association between KIT mutations and liver metastasis. Immunohistochemistry was performed to assess the correlation of KIT mutations with CXCR4 and ETV1 expression. Genetic and pharmacologic methods were used to study the regulation of CXCR4 and ETV1 by KIT mutations. RESULTS: Codons 557 and 558 in KIT exon 11 were deletion hot spots in GISTs. KIT exon 11 deletions involving codons 557-558 were highly associated with liver metastasis. Overexpression of mutant KIT with exon 11 codons 557-558 deletion (KIT Delta557-558) increased GIST cell motility and liver metastasis. Mechanistically, overexpression of KIT Delta557-558 in GIST cells increased ETV1 and CXCR4 expression. CXCR4 knockdown counteracted KIT Delta557-558-mediated cell migration. Moreover, KIT Delta557-558-induced CXCR4 expression could be abolished by silencing ETV1. The chromatin immunoprecipitation assay showed that ETV1 directly bound to the CXCR4 promoter. After ERK inhibitor PD325901 treatment, the upregulation of ETV1 by KIT Delta557-558 was prevented. In addition, KIT exon 11 codons 557-558 deletion enhanced CXCL12-mediated GIST cell migration and invasion. CONCLUSIONS: KIT exon 11 557-558 deletion upregulates CXCR4 through increased binding of ETV1 to the CXCR4 promoter in GIST cells, which thus promotes liver metastasis. These findings highlighted the potential therapeutic targets for metastatic GISTs. Clin Cancer Res; 22(14); 3477-87. (c)2016 AACR. PMID- 26936920 TI - alpha-Fetoprotein level-dependent early hepatitis B surface antigen decline during entecavir therapy in chronic hepatitis B with hepatitis flare. AB - OBJECTIVES: Hepatitis B surface antigen (HBsAg) reduction during nucleos(t)ide analogue therapy is related to ALT level. ALT reflects hepatocytolysis while alpha-fetoprotein (AFP) >=100 ng/mL during hepatitis flare reflects more extensive hepatocytolysis (bridging hepatic necrosis). The impact of AFP levels on early HBsAg kinetics during entecavir therapy was investigated. METHODS: HBsAg level was measured at baseline and months 6 and 12 of entecavir therapy in 149 chronic hepatitis B patients with hepatitis flare, defined as ALT >=5* upper limit of normal (ULN), and 58 patients with ALT <5* ULN. RESULTS: There was a significantly greater HBsAg reduction in an ALT (<5, 5-10, 10-20 and >=20* ULN, P = 0.001) and AFP (<20, 20-99 and >=100 ng/mL, P = 0.000) level-dependent manner. In hepatitis flares with a peak AFP level >=20 ng/mL, the differences in HBsAg reduction across all ALT levels became non-significant. HBsAg reduction was greater in genotype B- than genotype C-infected patients with baseline ALT >=20* ULN, but the difference became non-significant in those with peak AFP >=100 ng/mL. Multivariate linear regression analysis showed that AFP level >=100 ng/mL, baseline HBsAg level and genotype B were independent significant factors for greater HBsAg decline at month 6 of entecavir therapy. CONCLUSIONS: During entecavir therapy, early HBsAg reduction increased in an AFP and ALT level dependent manner, suggesting the impact of hepatocytolysis rather than nucleos(t)ide analogue per se. Notably, a higher AFP level during hepatitis flare, reflecting more extensive hepatic necrosis, was a more powerful factor than ALT and genotype for greater HBsAg decline. PMID- 26936918 TI - Methionine and Kynurenine Activate Oncogenic Kinases in Glioblastoma, and Methionine Deprivation Compromises Proliferation. AB - PURPOSE: We employed a metabolomics-based approach with the goal to better understand the molecular signatures of glioblastoma cells and tissues, with an aim toward identifying potential targetable biomarkers for developing more effective and novel therapies. EXPERIMENTAL DESIGN: We used liquid chromatography coupled with mass spectrometry (LC-MS/Q-TOF and LC-MS/QQQ) for the discovery and validation of metabolites from primary and established glioblastoma cells, glioblastoma tissues, and normal human astrocytes. RESULTS: We identified tryptophan, methionine, kynurenine, and 5-methylthioadenosine as differentially regulated metabolites (DRM) in glioblastoma cells compared with normal human astrocytes (NHAs). Unlike NHAs, glioblastoma cells depend on dietary methionine for proliferation, colony formation, survival, and to maintain a deregulated methylome (SAM:SAH ratio). In methylthioadenosine phosphorylase (MTAP)-deficient glioblastoma cells, expression of MTAP transgene did not alter methionine dependency, but compromised tumor growth in vivo We discovered that a lack of the kynurenine-metabolizing enzymes kynurenine monooxygenase and/or kynureninase promotes the accumulation of kynurenine, which triggers immune evasion in glioblastoma cells. In silico analysis of the identified DRMs mapped the activation of key oncogenic kinases that promotes tumorigenesis in glioblastoma. We validated this result by demonstrating that the exogenous addition of DRMs to glioblastoma cells in vitro results in oncogene activation as well as the simultaneous downregulation of Ser/Thr phosphatase PP2A. CONCLUSIONS: We have connected a four-metabolite signature, implicated in the methionine and kynurenine pathways, to the promotion and maintenance of glioblastoma. Together, our data suggest that these metabolites and their respective metabolic pathways serve as potential therapeutic targets for glioblastoma. Clin Cancer Res; 22(14); 3513-23. (c)2016 AACR. PMID- 26936921 TI - Near-Death and Other Transpersonal Experiences Occurring During Catastrophic Events. AB - The purpose of this article is to describe examples of near-death and other transpersonal experiences occurring during catastrophic events like floods, wars, bombings, and death camps. To date, researchers have limited their investigations of these transpersonal events to those occurring to seriously ill patients in hospitals, those dying from terminal illnesses, or to individuals experiencing a period of grief after the death of a loved one. Missing is awareness by first responders and emergency healthcare professionals about these transpersonal experiences and what to say to the individuals who have them. Some responders experience not only deaths of the victims they assist, but also deaths of their colleagues. Information about these transpersonal experiences can also be of comfort to them. The examples in this article include a near-death experience during the Vietnam War, an out-of-body experience after a bomb explosion during the Iraq War, a near-death visit to a woman imprisoned at Auschwitz, and two after-death communications, one from a person killed in Auschwitz and another from a soldier during World War I. Also included are interviews with two New York City policemen who were September 11, 2001 responders. It is hoped the information will provide knowledge of these experiences to those who care for those near death, or dying, or grieving because of catastrophic events, and encourage researchers to further investigate these experiences during disasters. PMID- 26936922 TI - Features and Role of Minimally Invasive Palliative Procedures for Pain Management in Malignant Pelvic Diseases: A Review. AB - Pain is a common and debilitating symptom in pelvic cancer diseases. Failure in controlling this pain through pharmacological approaches calls for employing multimodal management and invasive techniques. Various strategies are commonly used for this purpose, including palliative radiotherapy, epidural medications and intrathecal administration of analgesic and local anesthetic drugs with pumps, and neural or plexus blockade. This review focuses on the features of minimally invasive palliative procedures (MIPPs), such as radiofrequency ablation, laser-induced thermotherapy, cryoablation, irreversible electroporation, electrochemotherapy, microwave ablation, and cementoplasty as well as their role in palliation of cancer pelvic pain. Despite the evidence of effectiveness and safety of these interventions, there are still many barriers to accessing MIPPs, including the availability of trained staff, the lack of precise criteria of indication, and the high costs. PMID- 26936923 TI - The Technical and Performance Characteristics of a Low-Cost, Simply Constructed, Black Light Moth Trap. AB - The universal mercury vapor black light trap is an effective device used for collecting moth specimens in a wide variety of habitats; yet, they can present challenges for researchers. The mercury vapor trap is often powered by a heavy automotive battery making it difficult to conduct extensive surveys in remote regions. The mercury vapor trap also carries a considerable financial cost per trap unit, making trapping challenging with low research budgets. Here, we describe the development and trapping properties of a lighter, simply constructed, and less expensive trap. The LED funnel trap consists of a funnel, soda bottles with plastic vanes, and is powered by rechargeable 9-V batteries. Two strips of low-wavelength LEDs are used as attractants. We tested the trapping parameters of this trap design compared to a standard mercury vapor trap over 10 trap nights in a suburban woodlot in the summer of 2015. The mercury vapor trap caught significantly more moth individuals than the LED trap (average of 78 vs 40 moths per trap night; P < 0.05), and significantly more species than the LED trap (23 vs 15 per trap night; P < 0.05); the mercury vapor trap caught a total of 104 macromoth species over the duration of the study, compared to a total of 87 by the LED trap. Despite the lower yields, the low cost of the LED trap (<$30 ea.) makes it superior to the mercury vapor trap in cost-acquisition per moth species and per moth individual trapped. The LED trap may be a viable alternative to the standard mercury vapor trap, facilitating insect trapping in more diverse settings. PMID- 26936924 TI - Needles: Toward Large-Scale Genomic Prediction with Marker-by-Environment Interaction. AB - Genomic prediction relies on genotypic marker information to predict the agronomic performance of future hybrid breeds based on trial records. Because the effect of markers may vary substantially under the influence of different environmental conditions, marker-by-environment interaction effects have to be taken into account. However, this may lead to a dramatic increase in the computational resources needed for analyzing large-scale trial data. A high performance computing solution, called Needles, is presented for handling such data sets. Needles is tailored to the particular properties of the underlying algebraic framework by exploiting a sparse matrix formalism where suited and by utilizing distributed computing techniques to enable the use of a dedicated computing cluster. It is demonstrated that large-scale analyses can be performed within reasonable time frames with this framework. Moreover, by analyzing simulated trial data, it is shown that the effects of markers with a high environmental interaction can be predicted more accurately when more records per environment are available in the training data. The availability of such data and their analysis with Needles also may lead to the discovery of highly contributing QTL in specific environmental conditions. Such a framework thus opens the path for plant breeders to select crops based on these QTL, resulting in hybrid lines with optimized agronomic performance in specific environmental conditions. PMID- 26936925 TI - Comprehensive Analysis of the SUL1 Promoter of Saccharomyces cerevisiae. AB - In the yeast Saccharomyces cerevisiae, beneficial mutations selected during sulfate-limited growth are typically amplifications of the SUL1 gene, which encodes the high-affinity sulfate transporter, resulting in fitness increases of >35% . Cis-regulatory mutations have not been observed at this locus; however, it is not clear whether this absence is due to a low mutation rate such that these mutations do not arise, or they arise but have limited fitness effects relative to those of amplification. To address this question directly, we assayed the fitness effects of nearly all possible point mutations in a 493-base segment of the gene's promoter through mutagenesis and selection. While most mutations were either neutral or detrimental during sulfate-limited growth, eight mutations increased fitness >5% and as much as 9.4%. Combinations of these beneficial mutations increased fitness only up to 11%. Thus, in the case of SUL1, promoter mutations could not induce a fitness increase similar to that of gene amplification. Using these data, we identified functionally important regions of the SUL1 promoter and analyzed three sites that correspond to potential binding sites for the transcription factors Met32 and Cbf1 Mutations that create new Met32- or Cbf1-binding sites also increased fitness. Some mutations in the untranslated region of the SUL1 transcript decreased fitness, likely due to the formation of inhibitory upstream open reading frames. Our methodology-saturation mutagenesis, chemostat selection, and DNA sequencing to track variants-should be a broadly applicable approach. PMID- 26936928 TI - Pendred Syndrome in a Newborn with Neck Swelling: A Case Report. AB - BACKGROUND: Pendred syndrome is a rare autosomal recessive condition, characterized by functional impairment of thyroid gland and sensorineural hearing loss. The syndrome presents in patients with homozygous or compound heterozygous mutation. The presentation in the form of neck mass in a newborn is rare. CASE CHARACTERISTICS: A 1 month old baby presented to us with neck mass, which was found to be an enlarged thyroid gland. Thyroid function tests were consistent with hypothyroidism. Further evaluation revealed moderate sensorineural hearing loss; genetic analysis showed that baby was homozygous for the known mutations causing the disease. INTERVENTION: Thyroid hormone replacement and hearing habilitation were done. Follow up showed regression of the neck mass and normalization of thyroid function tests. Genetic counseling of the family was done. MESSAGE: Identification of the exact cause of congenital hypothyroidism can prevent grave consequences later on for the patient as well as for the family. PMID- 26936926 TI - A Novel Candidate Gene for Temperature-Dependent Sex Determination in the Common Snapping Turtle. AB - Temperature-dependent sex determination (TSD) was described nearly 50 years ago. Researchers have since identified many genes that display differential expression at male- vs. female-producing temperatures. Yet, it is unclear whether these genes (1) are involved in sex determination per se, (2) are downstream effectors involved in differentiation of ovaries and testes, or (3) are thermo-sensitive but unrelated to gonad development. Here we present multiple lines of evidence linking CIRBP to sex determination in the snapping turtle, Chelydra serpentina We demonstrate significant associations between a single nucleotide polymorphism (SNP) (c63A > C) in CIRBP, transcript levels in embryonic gonads during specification of gonad fate, and sex in hatchlings from a thermal regime that produces mixed sex ratios. The A allele was induced in embryos exposed to a female-producing temperature, while expression of the C allele did not differ between female- and male-producing temperatures. In accord with this pattern of temperature-dependent, allele-specific expression, AA homozygotes were more likely to develop ovaries than AC heterozygotes, which, in turn, were more likely to develop ovaries than CC homozygotes. Multiple regression using SNPs in CIRBP and adjacent loci suggests that c63A > C may be the causal variant or closely linked to it. Differences in CIRBP allele frequencies among turtles from northern Minnesota, southern Minnesota, and Texas reflect small and large-scale latitudinal differences in TSD pattern. Finally, analysis of CIRBP protein localization reveals that CIRBP is in a position to mediate temperature effects on the developing gonads. Together, these studies strongly suggest that CIRBP is involved in determining the fate of the bipotential gonad. PMID- 26936927 TI - Promotion of Homologous Recombination by SWS-1 in Complex with RAD-51 Paralogs in Caenorhabditis elegans. AB - Homologous recombination (HR) repairs cytotoxic DNA double-strand breaks (DSBs) with high fidelity. Deficiencies in HR result in genome instability. A key early step in HR is the search for and invasion of a homologous DNA template by a single-stranded RAD-51 nucleoprotein filament. The Shu complex, composed of a SWIM domain-containing protein and its interacting RAD51 paralogs, promotes HR by regulating RAD51 filament dynamics. Despite Shu complex orthologs throughout eukaryotes, our understanding of its function has been most extensively characterized in budding yeast. Evolutionary analysis of the SWIM domain identified Caenorhabditis elegans sws-1 as a putative homolog of the yeast Shu complex member Shu2. Using a CRISPR-induced nonsense allele of sws-1, we show that sws-1 promotes HR in mitotic and meiotic nuclei. sws-1 mutants exhibit sensitivity to DSB-inducing agents and fail to form mitotic RAD-51 foci following treatment with camptothecin. Phenotypic similarities between sws-1 and the two RAD-51 paralogs rfs-1 and rip-1 suggest that they function together. Indeed, we detect direct interaction between SWS-1 and RIP-1 by yeast two-hybrid assay that is mediated by the SWIM domain in SWS-1 and the Walker B motif in RIP-1 Furthermore, RIP-1 bridges an interaction between SWS-1 and RFS-1, suggesting that RIP-1 facilitates complex formation with SWS-1 and RFS-1 We propose that SWS 1, RIP-1, and RFS-1 compose a C. elegans Shu complex. Our work provides a new model for studying Shu complex disruption in the context of a multicellular organism that has important implications as to why mutations in the human RAD51 paralogs are associated with genome instability. PMID- 26936929 TI - Waging War on Mosquitoes: Scientific Research and the Formation of Mosquito Brigades in French West Africa, 1899-1920. AB - While the majority of colonial public health officials in Africa intermittently used measures for mosquito containment, the government of French West Africa made the creation of what were called mosquito brigades into a vital element of urban sanitary policy. The project seemed to offer a chance to curb the impact of mosquito-borne disease on the colonial economy. Yet, despite the full support of sanitary policy on the federal, colonial, and local levels, the government found that conducting a "War on Mosquitoes" was far more difficult than they originally envisioned. The colonial government's mosquito brigades were understaffed and often ran into resistance from both the African and European populations. Above all, the government's urban mosquito control programs failed because their goal of controlling the breeding of mosquitoes lay beyond the limited capabilities of the both local government and the Federation's health and sanitation services. This paper will examine the origins and fate of the French West African mosquito brigades and provide a context for analyzing their atypical place among colonial efforts at malaria prevention. PMID- 26936930 TI - Play complexity and toy engagement in preschoolers with autism spectrum disorder: Do girls and boys differ? AB - While sex differences in play have been extensively observed in typical development, only a handful of studies have explored this phenomenon in depth with children with autism spectrum disorders. This study explored sex differences in play complexity and toy engagement within caregiver-child interaction samples for preschool-aged children (2-5 years 11 months) with an autism spectrum disorder who were matched to typically developing children on sex and non-verbal development. Overall we found that girls and boys with autism spectrum disorder were largely equivalent in their play complexity. Despite similar play, girls and boys with autism spectrum disorder differed in a number of ways in their toy engagement, replicating traditional gender differences-girls played more with dolls and domestic items (though at lower rates than typically developing girls) and boys played more with the garage and cars (though at lower rates than typically developing boys). Our findings support the importance and utility of examining sex differences in autism spectrum disorder in light of those observed within typical development. PMID- 26936931 TI - High-Sensitivity Cardiac Troponin I Is a Strong Predictor of Cardiovascular Events and Mortality in the AGES-Reykjavik Community-Based Cohort of Older Individuals. AB - BACKGROUND: The objective of this study was to investigate the predictive power of a high-sensitivity cardiac troponin I (hs-cTnI) assay for cardiovascular events and mortality in a large population of older community dwellers. METHODS: Blood was collected from 5764 individuals (age 66-98 years) during the period of 2002-2006 and the outcome as to all-cause death and incidence of cardiovascular disease (CVD) and coronary heart disease (CHD) followed up to 10 years. hs-cTnI (Abbott) was measured in serum to assess the association of this marker with CVD, CHD and death, and finally, to compare the results with conventional risk factors by multivariable statistical analysis. RESULTS: The median (interquartile range) concentrations of hs-cTnI were 8.4 ng/L (5.6-14.2 ng/L) and 5.3 ng/L (3.8-8.1 ng/L) in men (2416) and women (3275), respectively, and the concentrations increased linearly with age. Outcomes as to all-cause death and incidence of CVD and CHD were significantly associated with increasing concentrations of hs-cTnI beginning well below the 99th percentile concentrations. The associations with outcome remained after adjustments for conventional risk factors and were similar in men and women. CONCLUSIONS: Our findings suggest that hs-cTnI reflects the status of the myocardium even in seemingly healthy individuals and that the measurements of hs-cTnI may be useful for primary prediction of heart disease; this should form the basis for future prospective clinical trials for determining whether measuring hs-cTnI can be used in the prevention of CVD/CHD. PMID- 26936932 TI - Interaction of Galectin-3 Concentrations with the Treatment Effects of beta Blockers and RAS Blockade in Patients with Systolic Heart Failure: A Derivation Validation Study from TIME-CHF and GISSI-HF. AB - BACKGROUND: Galectin-3 predicts prognosis in heart failure (HF) and may help to select HF patients in need of intensified therapy. METHODS: This retrospective post hoc analysis included 219 patients from the Trial of Intensified versus Standard Medical Therapy in Elderly Patients with Congestive Heart Failure (TIME HF) and 631 patients from Gruppo Italiano per lo Studio della Sopravvivenza nell'Insufficienza Cardiaca (GISSI-HF) with HF who had reduced ejection fraction and available galectin-3 plasma concentrations. The interaction between galectin 3, beta-blockers, renin-angiotensin system (RAS) blockade, and spironolactone on outcome was evaluated in TIME-CHF and validated in GISSI-HF. End points were all cause mortality and the composite of mortality with HF hospitalization or any hospitalization. RESULTS: High galectin-3 concentrations were associated with adverse outcome in both cohorts and remained significantly associated with death after multivariate adjustment [hazard ratio 2.42 (95% CI 1.17-5.01), P = 0.02, in TIME-CHF; 1.47 (1.02-2.10), P = 0.04, in GISSI-HF). In TIME-CHF, patients with low galectin-3 plasma concentrations had a better prognosis when beta-blockers were up-titrated, whereas patients with high galectin-3 plasma concentrations did not (interaction P < 0.05 for mortality and death with or without hospitalization). Opposite trends were seen for RAS blockade but were not statistically significant. Patients with high galectin-3 plasma concentrations had neutral prognosis when receiving spironolactone, whereas patients with low galectin-3 plasma concentrations had worse prognosis when receiving spironolactone (interaction P < 0.10 for death with or without hospitalization). In the GISSI-HF validation cohort, these interactions were confirmed for beta blockers (P < 0.05 for all end points) and consistent for RAS blockade (P < 0.10 for death with or without hospitalization), but inconsistent for spironolactone. CONCLUSIONS: Galectin-3 is a mediocre prognostic marker, and galectin-3 concentrations interact with the treatment effect of beta-blockers and possibly RAS blockade in patients with systolic HF. PMID- 26936933 TI - Plasma d-Dimer as a Useful Marker Predicts Severity of Atherosclerotic Lesion and Short-Term Outcome in Patients With Coronary Artery Disease. AB - Increased d-dimer is indicative of a hypercoagulable state and found to be associated with acute coronary syndromes. The present study aimed to evaluate whether plasma d-dimer levels could predict subsequent major clinical events in patients with coronary artery disease (CAD). First, 2209 angiographic-proven patients with CAD were consecutively enrolled. Then, all patients were subjected to follow up for an average of 18 months (ranged from 14 to 1037 days). The relationships of the plasma d-dimer with the severity of CAD and future clinical outcomes were evaluated. We found that plasma d-dimer was higher in patients with prior myocardial infarction (MI) than that in patients with nonprior MI (P = .006). Multivariate linear regression analysis suggested that the plasma d-dimer was linked to the severity of CAD assessed by Gensini score (beta = 0.052, 95% confidence interval [CI]: 1.20-6.84, P = .005) even after adjusting for confounding factors. During the follow-up, 42 patients underwent prespecified outcomes. After adjustment for multiple variables in the Cox regression model, the d-dimer levels remained to be a potential predictor of total outcome (hazard ratio = 1.22, 95% CI: 1.09-1.37, P = .001). Therefore, plasma d-dimer levels appeared to be a useful predictor for the severity of CAD and the subsequent major clinical events. PMID- 26936934 TI - The role of macrophages in obesity-driven chronic liver disease. AB - Overnutrition and a sedentary lifestyle have resulted in the expansion of human obesity and associated metabolic complications. Nonalcoholic fatty liver disease has become the most common chronic liver disease in Western developed countries and can range from simple hepatic steatosis to a combination of steatosis, inflammation, and ballooning degeneration (nonalcoholic steatohepatitis). Obesity and its related liver disease are both risk factors for hepatocellular carcinoma, the incidence of which is expected to increase rapidly. The pathogenesis of nonalcoholic fatty liver disease and its progression to nonalcoholic steatohepatitis and hepatocellular carcinoma involve a deregulated lipid metabolism and a disruption of immune homeostasis and tissue integrity and are associated with a state of chronic inflammation. Macrophages are immune cells essential for maintenance of organ function and homeostasis but can also contribute to tissue damage and maintain a proinflammatory response. Their function depends on their origin, and tissue and can be converted based on local environmental cues. Resident liver macrophages, Kupffer cells, which function as sentinels, provide a first defense and are assisted by infiltrating monocytes in cases of hepatic insult. Until now, the contribution of tissue-residing and infiltrating macrophages to the onset and progression of nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, and hepatocellular carcinoma has been only partially unraveled. This review summarizes the current knowledge on the contribution of macrophage subsets to obesity-driven fatty liver disease and its complications and sheds light on still unexplored areas. PMID- 26936935 TI - Chemokine axes in breast cancer: factors of the tumor microenvironment reshape the CCR7-driven metastatic spread of luminal-A breast tumors. AB - Chemokine axes have been shown to mediate site-specific metastasis in breast cancer, but their relevance to different subtypes has been hardly addressed. Here, with the focus on the CCR7-CCL21 axis, patient datasets demonstrated that luminal-A tumors express relatively low CCR7 levels compared with more aggressive disease subtypes. Furthermore, lymph node metastasis was not associated with high CCR7 levels in luminal-A patients. The metastatic pattern of luminal-A breast tumors may be influenced by the way luminal-A tumor cells interpret signals provided by factors of the primary tumor microenvironment. Thus, CCR7-expressing human luminal-A cells were stimulated simultaneously by factors representing 3 tumor microenvironment arms typical of luminal-A tumors, hormonal, inflammatory, and growth stimulating: estrogen + TNF-alpha + epidermal growth factor. Such tumor microenvironment stimulation down-regulated the migration of CCR7 expressing tumor cells toward CCL21 and inhibited the formation of directional protrusions toward CCL21 in a novel 3-dimensional hydrogel system. CCL21-induced migration of CCR7-expressing tumor cells depended on PI3K and MAPK activation; however, when CCR7-expressing cancer cells were prestimulated by tumor microenvironment factors, CCL21 could not effectively activate these signaling pathways. In vivo, pre-exposure of the tumor cells to tumor microenvironment factors has put restraints on CCL21-mediated lymph node-homing cues and shifted the metastatic pattern of CCR7-expressing cells to the aggressive phenotype of dissemination to bones. Several of the aspects were also studied in the CXCR4 CXCL12 system, demonstrating similar patient and in vitro findings. Thus, we provide novel evidence to subtype-specific regulation of the CCR7-CCL21 axis, with more general implications to chemokine-dependent patterns of metastatic spread, revealing differential regulation in the luminal-A subtype. PMID- 26936936 TI - PLA2G5 regulates transglutaminase activity of human IL-4-activated M2 macrophages through PGE2 generation. AB - Phospholipases A2 are enzymes that liberate membrane-bound lipids in a tissue and cell-specific fashion. Group V secretory phospholipase A2 is necessary for the development of M2 macrophages and their effector functions in a mouse model of the T-helper-2 allergic airway inflammation. However, the function of group V phospholipase A2 in human M2 activation and T-helper-2 inflammation is ill defined. Transglutaminase-2, a protein cross-linking enzyme, is a newly identified marker of both human and mouse interleukin-4-activated M2 macrophages and is also found in the lungs of patients with asthma. We report that group V phospholipase A2 and transglutaminase-2 colocalized in macrophages of human nasal polyp tissue obtained from patients with T-helper-2 eosinophilic inflammation, and their coexpression positively correlated with the number of eosinophils in each tissue specimen. We demonstrate that in human monocyte-derived macrophages activated by interleukin-4, group V phospholipase A2 translocated and colocalized with transglutaminase-2 in the cytoplasm and on the membrane of macrophages. Moreover, knocking down group V phospholipase A2 with small interfering ribonucleic acid reduced macrophage transglutaminase activity, whereas mass spectrometry analysis of lipids also showed reduced prostaglandin E2 production. Finally, exogenous prostaglandin E2 restored transglutaminase activity of group V phospholipase A2-small interfering ribonucleic acid-treated macrophages. Thus, our study shows a novel function of group V phospholipase A2 in regulating the transglutaminase activity of human interleukin-4-activated M2 macrophages through prostaglandin E2 generation and suggests that group V phospholipase A2 is a functionally relevant enzyme that may have therapeutic value for the treatment of human T-helper-2 inflammatory disorders. PMID- 26936937 TI - The heat shock response plays an important role in TDP-43 clearance: evidence for dysfunction in amyotrophic lateral sclerosis. AB - Detergent-resistant, ubiquitinated and hyperphosphorylated Tar DNA binding protein 43 (TDP-43, encoded by TARDBP) neuronal cytoplasmic inclusions are the pathological hallmark in ~95% of amyotrophic lateral sclerosis and ~60% of frontotemporal lobar degeneration cases. We sought to explore the role for the heat shock response in the clearance of insoluble TDP-43 in a cellular model of disease and to validate our findings in transgenic mice and human amyotrophic lateral sclerosis tissues. The heat shock response is a stress-responsive protective mechanism regulated by the transcription factor heat shock factor 1 (HSF1), which increases the expression of chaperones that refold damaged misfolded proteins or facilitate their degradation. Here we show that manipulation of the heat shock response by expression of dominant active HSF1 results in a dramatic reduction of insoluble and hyperphosphorylated TDP-43 that enhances cell survival, whereas expression of dominant negative HSF1 leads to enhanced TDP-43 aggregation and hyperphosphorylation. To determine which chaperones were mediating TDP-43 clearance we over-expressed a range of heat shock proteins (HSPs) and identified DNAJB2a (encoded by DNAJB2, and also known as HSJ1a) as a potent anti-aggregation chaperone for TDP-43. DNAJB2a has a J domain, allowing it to interact with HSP70, and ubiquitin interacting motifs, which enable it to engage the degradation of its client proteins. Using functionally deleted DNAJB2a constructs we demonstrated that TDP-43 clearance was J domain-dependent and was not affected by ubiquitin interacting motif deletion or proteasome inhibition. This indicates that TDP-43 is maintained in a soluble state by DNAJB2a, leaving the total levels of TDP-43 unchanged. Additionally, we have demonstrated that the levels of HSF1 and heat shock proteins are significantly reduced in affected neuronal tissues from a TDP-43 transgenic mouse model of amyotrophic lateral sclerosis and patients with sporadic amyotrophic lateral sclerosis. This implies that the HSF1-mediated DNAJB2a/HSP70 heat shock response pathway is compromised in amyotrophic lateral sclerosis. Defective refolding of TDP-43 is predicted to aggravate the TDP-43 proteinopathy. The finding that the pathological accumulation of insoluble TDP-43 can be reduced by the activation of HSF1/HSP pathways presents an exciting opportunity for the development of novel therapeutics. PMID- 26936938 TI - MRI visual rating scales in the diagnosis of dementia: evaluation in 184 post mortem confirmed cases. AB - Accurately distinguishing between different degenerative dementias during life is challenging but increasingly important with the prospect of disease-modifying therapies. Molecular biomarkers of dementia pathology are becoming available, but are not widely used in clinical practice. Conversely, structural neuroimaging is recommended in the evaluation of cognitive impairment. Visual assessment remains the primary method of scan interpretation, but in the absence of a structured approach, diagnostically relevant information may be under-utilized. This definitive, multi-centre study uses post-mortem confirmed cases as the gold standard to: (i) assess the reliability of six visual rating scales; (ii) determine their associated pattern of atrophy; (iii) compare their diagnostic value with expert scan assessment; and (iv) assess the accuracy of a machine learning approach based on multiple rating scales to predict underlying pathology. The study includes T1-weighted images acquired in three European centres from 184 individuals with histopathologically confirmed dementia (101 patients with Alzheimer's disease, 28 patients with dementia with Lewy bodies, 55 patients with frontotemporal lobar degeneration), and scans from 73 healthy controls. Six visual rating scales (medial temporal, posterior, anterior temporal, orbito-frontal, anterior cingulate and fronto-insula) were applied to 257 scans (two raters), and to a subset of 80 scans (three raters). Six experts also provided a diagnosis based on unstructured assessment of the 80-scan subset. The reliability and time taken to apply each scale was evaluated. Voxel-based morphometry was used to explore the relationship between each rating scale and the pattern of grey matter volume loss. Additionally, the performance of each scale to predict dementia pathology both individually and in combination was evaluated using a support vector classifier, which was compared with expert scan assessment to estimate clinical value. Reliability of scan assessment was generally good (intraclass correlation coefficient > 0.7), and average time to apply all six scales was <3 min. There was a very close association between the pattern of grey matter loss and the regions of interest each scale was designed to assess. Using automated classification based on all six rating scales, the accuracy (estimated using the area under the receiver-operator curves) for distinguishing each pathological group from controls ranged from 0.86-0.97; and from one another, 0.75-0.92. These results were substantially better than the accuracy of any single scale, at least as good as expert reads, and comparable to previous studies using molecular biomarkers. Visual rating scores from magnetic resonance images routinely acquired as part of the investigation of dementias, offer a practical, inexpensive means of improving diagnostic accuracy. PMID- 26936939 TI - Longitudinal patterns of leukoaraiosis and brain atrophy in symptomatic small vessel disease. AB - Cerebral small vessel disease is a common condition associated with lacunar stroke, cognitive impairment and significant functional morbidity. White matter hyperintensities and brain atrophy, seen on magnetic resonance imaging, are correlated with increasing disease severity. However, how the two are related remains an open question. To better define the relationship between white matter hyperintensity growth and brain atrophy, we applied a semi-automated magnetic resonance imaging segmentation analysis pipeline to a 3-year longitudinal cohort of 99 subjects with symptomatic small vessel disease, who were followed-up for >=1 years. Using a novel two-stage warping pipeline with tissue repair step, voxel-by-voxel rate of change maps were calculated for each tissue class (grey matter, white matter, white matter hyperintensities and lacunes) for each individual. These maps capture both the distribution of disease and spatial information showing local rates of growth and atrophy. These were analysed to answer three primary questions: first, is there a relationship between whole brain atrophy and magnetic resonance imaging markers of small vessel disease (white matter hyperintensities or lacune volume)? Second, is there regional variation within the cerebral white matter in the rate of white matter hyperintensity progression? Finally, are there regionally specific relationships between the rates of white matter hyperintensity progression and cortical grey matter atrophy? We demonstrate that the rates of white matter hyperintensity expansion and grey matter atrophy are strongly correlated (Pearson's R = -0.69, P < 1 * 10(-7)), and significant grey matter loss and whole brain atrophy occurs annually (P < 0.05). Additionally, the rate of white matter hyperintensity growth was heterogeneous, occurring more rapidly within long association fasciculi. Using voxel-based quantification (family-wise error corrected P < 0.05), we show the rate of white matter hyperintensity progression is associated with increases in cortical grey matter atrophy rates, in the medial-frontal, orbito-frontal, parietal and occipital regions. Conversely, increased rates of global grey matter atrophy are significantly associated with faster white matter hyperintensity growth in the frontal and parietal regions. Together, these results link the progression of white matter hyperintensities with increasing rates of regional grey matter atrophy, and demonstrate that grey matter atrophy is the major contributor to whole brain atrophy in symptomatic cerebral small vessel disease. These measures provide novel insights into the longitudinal pathogenesis of small vessel disease, and imply that therapies aimed at reducing progression of white matter hyperintensities via end-arteriole damage may protect against secondary brain atrophy and consequent functional morbidity. PMID- 26936942 TI - An introduction to the Endocrine Society Clinical Practice Guideline on treatment of symptoms of the menopause. AB - Treatment of symptoms of menopause remains a challenge for many health care practitioners. In an effort to facilitate this process, the Endocrine Society convened an international Task Force of menopause experts to review the relevant clinical evidence and formulate practical recommendations for relieving the most common menopausal symptoms. The result is a comprehensive evidence-based guideline, which emphasizes an individualized approach to alleviate bothersome vasomotor symptoms and those related to postmenopausal changes of the vagina and urinary tract. Therapies including estrogen, either alone or in combination with progestogen or bazedoxifene, tibolone, antidepressants, gabapentin, as well as complementary approaches are discussed. In this commentary, the chairs of the Task Force highlight the organization and content of the guideline and the processes involved in its development. PMID- 26936940 TI - Regional profiles of the candidate tau PET ligand 18F-AV-1451 recapitulate key features of Braak histopathological stages. AB - SEE THAL AND VANDENBERGHE DOI101093/BRAIN/AWW057 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Post-mortem Braak staging of neurofibrillary tau tangle topographical distribution is one of the core neuropathological criteria for the diagnosis of Alzheimer's disease. The recent development of positron emission tomography tracers targeting neurofibrillary tangles has enabled the distribution of tau pathology to be imaged in living subjects. Methods for extraction of classic Braak staging from in vivo imaging of neurofibrillary tau tangles have not yet been explored. Standardized uptake value ratio images were calculated from 80-100 minute (18)F-AV-1451 (also known as T807) positron emission tomography scans obtained from n = 14 young reference subjects (age 21-39 years, Mini-Mental State Examination 29-30) and n = 173 older test subjects (age 50-95 years) comprising amyloid negative cognitively normal (n = 42), clinically diagnosed mild cognitive impairment (amyloid positive, n = 47, and amyloid negative, n = 40) and Alzheimer's disease (amyloid positive, n = 28, and amyloid negative, n = 16). We defined seven regions of interest in anterior temporal lobe and occipital lobe sections corresponding closely to those used as decision points in Braak staging. An algorithm based on the Braak histological staging procedure was applied to estimate Braak stages directly from the region of interest profiles in each subject. Quantitative region-based analysis of (18)F-AV 1451 images yielded region of interest and voxel level profiles that mirrored key features of neuropathological tau progression including profiles consistent with Braak stages 0 through VI. A simple set of decision rules enabled plausible Braak stages corresponding to stereotypical progression patterns to be objectively estimated in 149 (86%) of test subjects. An additional 12 (7%) subjects presented with predefined variant profiles (relative sparing of the hippocampus and/or occipital lobe). The estimated Braak stage was significantly associated with amyloid status, diagnostic category and measures of global cognition. In vivo (18)F-AV-1451 positron emission tomography images across the Alzheimer's disease spectrum could be classified into patterns similar to those prescribed by Braak neuropathological staging of tau pathology. PMID- 26936944 TI - How journalism works: A minor study upholds the safety of HRT. PMID- 26936941 TI - Cerebrospinal fluid analysis detects cerebral amyloid-beta accumulation earlier than positron emission tomography. AB - Cerebral accumulation of amyloid-beta is thought to be the starting mechanism in Alzheimer's disease. Amyloid-beta can be detected by analysis of cerebrospinal fluid amyloid-beta42 or amyloid positron emission tomography, but it is unknown if any of the methods can identify an abnormal amyloid accumulation prior to the other. Our aim was to determine whether cerebrospinal fluid amyloid-beta42 change before amyloid PET during preclinical stages of Alzheimer's disease. We included 437 non-demented subjects from the prospective, longitudinal Alzheimer's Disease Neuroimaging Initiative (ADNI) study. All underwent (18)F-florbetapir positron emission tomography and cerebrospinal fluid amyloid-beta42 analysis at baseline and at least one additional positron emission tomography after a mean follow-up of 2.1 years (range 1.1-4.4 years). Group classifications were based on normal and abnormal cerebrospinal fluid and positron emission tomography results at baseline. We found that cases with isolated abnormal cerebrospinal fluid amyloid beta and normal positron emission tomography at baseline accumulated amyloid with a mean rate of 1.2%/year, which was similar to the rate in cases with both abnormal cerebrospinal fluid and positron emission tomography (1.2%/year, P = 0.86). The mean accumulation rate of those with isolated abnormal cerebrospinal fluid was more than three times that of those with both normal cerebrospinal fluid and positron emission tomography (0.35%/year, P = 0.018). The group differences were similar when analysing yearly change in standardized uptake value ratio of florbetapir instead of percentage change. Those with both abnormal cerebrospinal fluid and positron emission tomography deteriorated more in memory and hippocampal volume compared with the other groups (P < 0.001), indicating that they were closer to Alzheimer's disease dementia. The results were replicated after adjustments of different factors and when using different cut offs for amyloid-beta abnormality including a positron emission tomography classification based on the florbetapir uptake in regions where the initial amyloid-beta accumulation occurs in Alzheimer's disease. This is the first study to show that individuals who have abnormal cerebrospinal amyloid-beta42 but normal amyloid-beta positron emission tomography have an increased cortical amyloid-beta accumulation rate similar to those with both abnormal cerebrospinal fluid and positron emission tomography and higher rate than subjects where both modalities are normal. The results indicate that cerebrospinal fluid amyloid beta42 becomes abnormal in the earliest stages of Alzheimer's disease, before amyloid positron emission tomography and before neurodegeneration starts. PMID- 26936945 TI - Practice observed. PMID- 26936946 TI - Intradialytic Hypoxemia and Clinical Outcomes in Patients on Hemodialysis. AB - BACKGROUND AND OBJECTIVES: Intradialytic hypoxemia has been recognized for decades, but its associations with outcomes have not yet been assessed in a large patient cohort. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Our retrospective cohort study was conducted between January of 2012 and January of 2015. We recorded blood oxygen saturation every minute during hemodialysis in patients with arteriovenous access. A 6-month baseline period with at least 10 treatments with oxygen saturation measurements preceded a 12-month follow-up. Patients were stratified by the presence or absence of prolonged intradialytic hypoxemia defined as oxygen saturation <90% for at least one third of the treatment time. Demographic, laboratory, and treatment data and hospitalization and mortality rates were compared between the groups. Multivariate Cox regression analysis was used to assess baseline predictors of all-cause mortality during follow-up. RESULTS: In total, 100 (10%) of 983 patients had prolonged intradialytic hypoxemia. These patients were older (+3.6 years; 95% confidence interval, 0.8 to 6.3), had longer dialysis vintage (+1.2 years; 95% confidence interval, 0.3 to 2.1), and had higher prevalence of congestive heart failure (+10.8%; 95% confidence interval, 1.6 to 20.7) and chronic obstructive pulmonary disease (+13%; 95% confidence interval, 5 to 21.2). They also resembled an inflammatory phenotype, with lower serum albumin levels (-0.1 g/dl; 95% confidence interval, 0.2 to 0) and higher neutrophil-to-lymphocyte ratios (+1; 95% confidence interval, 0.5 to 1.6). They had lower hemoglobin levels (-0.2 g/dl; 95% confidence interval, -0.4 to 0) and required more erythropoietin (+1374 U per hemodialysis treatment; 95% confidence interval, 343 to 2405). During follow-up, all-cause hospitalization (1113 hospitalizations; univariate hazard ratio, 1.46; 95% confidence interval, 1.22 to 1.73) and mortality (89 deaths; adjusted hazard ratio, 1.98; 95% confidence interval, 1.14 to 3.43) were higher in patients with prolonged intradialytic hypoxemia. CONCLUSIONS: Prolonged intradialytic hypoxemia was associated with laboratory indicators of inflammation, higher erythropoietin requirements, and higher all-cause hospitalization and mortality. PMID- 26936947 TI - Dying to Feel Better: The Central Role of Dialysis-Induced Tissue Hypoxia. PMID- 26936948 TI - Analysis of data on endangered species consultations reveals nothing regarding their economic impacts. PMID- 26936949 TI - Reply to Rieger and Wagner: Context matters when studying purportedly harmful cultural practices. PMID- 26936950 TI - Polygyny and child health revisited. PMID- 26936951 TI - Leukocyte integrin alphaLbeta2 headpiece structures: The alphaI domain, the pocket for the internal ligand, and concerted movements of its loops. AB - High-resolution crystal structures of the headpiece of lymphocyte function associated antigen-1 (integrin alphaLbeta2) reveal how the alphaI domain interacts with its platform formed by the alpha-subunit beta-propeller and beta subunit betaI domains. The alphaLbeta2 structures compared with alphaXbeta2 structures show that the alphaI domain, tethered through its N-linker and a disulfide to a stable beta-ribbon pillar near the center of the platform, can undergo remarkable pivoting and tilting motions that appear buffered by N-glycan decorations that differ between alphaL and alphaX subunits. Rerefined beta2 integrin structures reveal details including pyroglutamic acid at the beta2 N terminus and bending within the EGF1 domain. Allostery is relayed to the alphaI domain by an internal ligand that binds to a pocket at the interface between the beta-propeller and betaI domains. Marked differences between the alphaL and alphaX subunit beta-propeller domains concentrate near the binding pocket and alphaI domain interfaces. Remarkably, movement in allostery in the betaI domain of specificity determining loop 1 (SDL1) causes concerted movement of SDL2 and thereby tightens the binding pocket for the internal ligand. PMID- 26936952 TI - Novel family of terpene synthases evolved from trans-isoprenyl diphosphate synthases in a flea beetle. AB - Sesquiterpenes play important roles in insect communication, for example as pheromones. However, no sesquiterpene synthases, the enzymes involved in construction of the basic carbon skeleton, have been identified in insects to date. We investigated the biosynthesis of the sesquiterpene (6R,7S)-himachala 9,11-diene in the crucifer flea beetle Phyllotreta striolata, a compound previously identified as a male-produced aggregation pheromone in several Phyllotreta species. A (6R,7S)-himachala-9,11-diene-producing sesquiterpene synthase activity was detected in crude beetle protein extracts, but only when (Z,E)-farnesyl diphosphate [(Z,E)-FPP] was offered as a substrate. No sequences resembling sesquiterpene synthases from plants, fungi, or bacteria were found in the P. striolata transcriptome, but we identified nine divergent putative trans isoprenyl diphosphate synthase (trans-IDS) transcripts. Four of these putative trans-IDSs exhibited terpene synthase (TPS) activity when heterologously expressed. Recombinant PsTPS1 converted (Z,E)-FPP to (6R,7S)-himachala-9,11-diene and other sesquiterpenes observed in beetle extracts. RNAi-mediated knockdown of PsTPS1 mRNA in P. striolata males led to reduced emission of aggregation pheromone, confirming a significant role of PsTPS1 in pheromone biosynthesis. Two expressed enzymes showed genuine IDS activity, with PsIDS1 synthesizing (E,E) FPP, whereas PsIDS3 produced neryl diphosphate, (Z,Z)-FPP, and (Z,E)-FPP. In a phylogenetic analysis, the PsTPS enzymes and PsIDS3 were clearly separated from a clade of known coleopteran trans-IDS enzymes including PsIDS1 and PsIDS2. However, the exon-intron structures of IDS and TPS genes in P. striolata are conserved, suggesting that this TPS gene family evolved from trans-IDS ancestors. PMID- 26936953 TI - Blocking rapid ice crystal growth through nonbasal plane adsorption of antifreeze proteins. AB - Antifreeze proteins (AFPs) are a unique class of proteins that bind to growing ice crystal surfaces and arrest further ice growth. AFPs have gained a large interest for their use in antifreeze formulations for water-based materials, such as foods, waterborne paints, and organ transplants. Instead of commonly used colligative antifreezes such as salts and alcohols, the advantage of using AFPs as an additive is that they do not alter the physicochemical properties of the water-based material. Here, we report the first comprehensive evaluation of thermal hysteresis (TH) and ice recrystallization inhibition (IRI) activity of all major classes of AFPs using cryoscopy, sonocrystallization, and recrystallization assays. The results show that TH activities determined by cryoscopy and sonocrystallization differ markedly, and that TH and IRI activities are not correlated. The absence of a distinct correlation in antifreeze activity points to a mechanistic difference in ice growth inhibition by the different classes of AFPs: blocking fast ice growth requires rapid nonbasal plane adsorption, whereas basal plane adsorption is only relevant at long annealing times and at small undercooling. These findings clearly demonstrate that biomimetic analogs of antifreeze (glyco)proteins should be tailored to the specific requirements of the targeted application. PMID- 26936956 TI - Reply to Weiland et al.: The point is to bring data to inform policy, not to rely solely on anecdotes. PMID- 26936954 TI - Cell-type-restricted anti-cytokine therapy: TNF inhibition from one pathogenic source. AB - Overexpression of TNF contributes to pathogenesis of multiple autoimmune diseases, accounting for a remarkable success of anti-TNF therapy. TNF is produced by a variety of cell types, and it can play either a beneficial or a deleterious role. In particular, in autoimmunity pathogenic TNF may be derived from restricted cellular sources. In this study we evaluated the feasibility of cell-type-restricted TNF inhibition in vivo. To this end, we engineered MYSTI (Myeloid-Specific TNF Inhibitor)--a recombinant bispecific antibody that binds to the F4/80 surface molecule on myeloid cells and to human TNF (hTNF). In macrophage cultures derived from TNF humanized mice MYSTI could capture the secreted hTNF, limiting its bioavailability. Additionally, as evaluated in TNF humanized mice, MYSTI was superior to an otherwise analogous systemic TNF inhibitor in protecting mice from lethal LPS/D-Galactosamine-induced hepatotoxicity. Our results suggest a novel and more specific approach to inhibiting TNF in pathologies primarily driven by macrophage-derived TNF. PMID- 26936957 TI - Science for Reducing Health Inequalities Emerges From Social Justice Movements. AB - Although the health sciences have investigated economic and social inequalities in morbidity and mortality for hundreds of years, health inequalities persist and are, by some measures, increasing. This is not simply a situation in which the knowledge exists but is not implemented. Rather, science in general and epidemiology in particular have focused on quantifying the effects of specific agents considered in isolation. This approach is powerful, but, in the absence of ecological concepts that connect parts and wholes, contributes to maintaining health inequalities. By joining movements for human rights and social justice, health scientists can identify research questions that are relevant to public health, develop methods that are appropriate to answering those questions, and contribute to efforts to reduce health inequalities. PMID- 26936955 TI - Functions for diverse metabolic activities in heterochromatin. AB - Growing evidence demonstrates that metabolism and chromatin dynamics are not separate processes but that they functionally intersect in many ways. For example, the lysine biosynthetic enzyme homocitrate synthase was recently shown to have unexpected functions in DNA damage repair, raising the question of whether other amino acid metabolic enzymes participate in chromatin regulation. Using an in silico screen combined with reporter assays, we discovered that a diverse range of metabolic enzymes function in heterochromatin regulation. Extended analysis of the glutamate dehydrogenase 1 (Gdh1) revealed that it regulates silent information regulator complex recruitment to telomeres and ribosomal DNA. Enhanced N-terminal histone H3 proteolysis is observed in GDH1 mutants, consistent with telomeric silencing defects. A conserved catalytic Asp residue is required for Gdh1's functions in telomeric silencing and H3 clipping. Genetic modulation of alpha-ketoglutarate levels demonstrates a key regulatory role for this metabolite in telomeric silencing. The metabolic activity of glutamate dehydrogenase thus has important and previously unsuspected roles in regulating chromatin-related processes. PMID- 26936958 TI - Lycopene activates antioxidant enzymes and nuclear transcription factor systems in heat-stressed broilers. AB - This study was conducted to evaluate the effects of dietary lycopene supplementation on growth performance, antioxidant status, and muscle nuclear transcription factor [Kelch like-ECH-associated protein 1 (Keap1) and (erythroid derived 2)-like 2 (Nrf2)] expressions in broiler chickens exposed to heat stress (HS). A total of 180 one-day-old male broiler chicks (Ross 308) were assigned randomly to one of 2*3 factorially arranged treatments: two housing temperatures (22 degrees C for 24 h/d; thermoneutral, TN or 34 degrees C for 8 h/d HS) and three dietary lycopene levels (0, 200, or 400 mg/kg). Each treatment consisted of three replicates of 10 birds. Birds were reared to 42 d of age. Heat stress caused reductions in feed intake and weight gain by 12.2 and 20.7% and increased feed efficiency by 10.8% (P<0.0001 for all). Increasing dietary lycopene level improved performance in both environments. Birds reared under the HS environment had lower serum and muscle lycopene concentration (0.34 vs. 0.50 MUg/mL and 2.80 vs. 2.13 MUg/g), activities of superoxide dismutase (151 vs. 126 U/mL and 131 vs. 155 U/mg protein), glutathione peroxidase (184 vs. 154 U/mL and 1.39 vs. 1.74 U/mg protein), and higher malondialdehyde (MDA) concentration (0.53 vs. 0.83 MUg/mL and 0.78 vs. 0.45 MUg/ mg protein) than birds reared under the TN environment. Changes in levels of lycopene and MDA and activities of enzymes in serum and muscle varied by the environmental temperature as dietary lycopene level increased. Moreover, increasing dietary lycopene level suppressed muscle Keap1 expression and enhanced muscle Nrf2 expression, which had increased by 150% and decreased by 40%, respectively in response to HS. In conclusion, lycopene supplementation alleviates adverse effects of HS on performance through modulating expressions of stress-related nuclear transcription factors. PMID- 26936959 TI - Changes in knee kinematics following total knee arthroplasty. AB - Total knee arthroplasty (TKA) changes the knee joint in both intentional and unintentional, known and unknown, ways. Patellofemoral and tibiofemoral kinematics play an important role in postoperative pain, function, satisfaction and revision, yet are largely unknown. Preoperative kinematics, postoperative kinematics or changes in kinematics may help identify causes of poor clinical outcome. Patellofemoral kinematics are challenging to record since the patella is obscured by the metal femoral component in X-ray and moves under the skin. The purpose of this study was to determine the kinematic degrees of freedom having significant changes and to evaluate the variability in individual changes to allow future study of patients with poor clinical outcomes. We prospectively studied the 6 degrees of freedom patellofemoral and tibiofemoral weightbearing kinematics, tibiofemoral contact points and helical axes of rotation of nine subjects before and at least 1 year after total knee arthroplasty using clinically available computed tomography and radiographic imaging systems. Normal kinematics for healthy individuals were identified from the literature. Significant differences existed between pre-TKA and post-TKA kinematics, with the post-TKA kinematics being closer to normal. While on average the pre-total knee arthroplasty knees in this group displayed no pivoting (only translation), individually only five knees displayed this behaviour (of these, two showed lateral pivoting, one showed medial pivoting and one showed central pivoting). There was considerable variability postoperatively as well (five central, two lateral and two medial pivoting). Both preop and postop, flexion behaviour was more hinge-like medially and more rolling laterally. Helical axes were more consistent postop for this group. An inclusive understanding of the pre-TKA and post-TKA kinematics and changes in kinematics due to total knee arthroplasty could improve implant design, patient diagnosis and surgical technique. PMID- 26936960 TI - Inhibition of TGF-beta Signaling Promotes Human Pancreatic beta-Cell Replication. AB - Diabetes is associated with loss of functional pancreatic beta-cells, and restoration of beta-cells is a major goal for regenerative therapies. Endogenous regeneration of beta-cells via beta-cell replication has the potential to restore cellular mass; however, pharmacological agents that promote regeneration or expansion of endogenous beta-cells have been elusive. The regenerative capacity of beta-cells declines rapidly with age, due to accumulation of p16(INK4a), resulting in limited capacity for adult endocrine pancreas regeneration. Here, we show that transforming growth factor-beta (TGF-beta) signaling via Smad3 integrates with the trithorax complex to activate and maintain Ink4a expression to prevent beta-cell replication. Importantly, inhibition of TGF-beta signaling can result in repression of the Ink4a/Arf locus, resulting in increased beta-cell replication in adult mice. Furthermore, small molecule inhibitors of the TGF-beta pathway promote beta-cell replication in human islets transplanted into NOD-scid IL-2Rg(null) mice. These data reveal a novel role for TGF-beta signaling in the regulation of the Ink4a/Arf locus and highlight the potential of using small molecule inhibitors of TGF-beta signaling to promote human beta-cell replication. PMID- 26936961 TI - Retinoic Acid Mediates Visceral-Specific Adipogenic Defects of Human Adipose Derived Stem Cells. AB - Increased visceral fat, rather than subcutaneous fat, during the onset of obesity is associated with a higher risk of developing metabolic diseases. The inherent adipogenic properties of human adipose-derived stem cells (ASCs) from visceral depots are compromised compared with those of ASCs from subcutaneous depots, but little is known about the underlying mechanisms. Using ontological analysis of global gene expression studies, we demonstrate that many genes involved in retinoic acid (RA) synthesis or regulated by RA are differentially expressed in human tissues and ASCs from subcutaneous and visceral fat. The endogenous level of RA is higher in visceral ASCs; this is associated with upregulation of the RA synthesis gene through the visceral-specific developmental factor WT1. Excessive RA-mediated activity impedes the adipogenic capability of ASCs at early but not late stages of adipogenesis, which can be reversed by antagonism of RA receptors or knockdown of WT1. Our results reveal the developmental origin of adipocytic properties and the pathophysiological contributions of visceral fat depots. PMID- 26936962 TI - Antigen Presentation and T-Cell Activation Are Critical for RBP4-Induced Insulin Resistance. AB - Adipose tissue (AT) inflammation contributes to impaired insulin action, which is a major cause of type 2 diabetes. RBP4 is an adipocyte- and liver-derived protein with an important role in insulin resistance, metabolic syndrome, and AT inflammation. RBP4 elevation causes AT inflammation by activating innate immunity, which elicits an adaptive immune response. RBP4-overexpressing mice (RBP4-Ox) are insulin resistant and glucose intolerant and have increased AT macrophages and T-helper 1 cells. We show that high-fat diet-fed RBP4(-/-) mice have reduced AT inflammation and improved insulin sensitivity versus wild type. We also elucidate the mechanism for RBP4-induced macrophage antigen presentation and subsequent T-cell activation. In RBP4-Ox, AT macrophages display enhanced c Jun N-terminal kinase, extracellular signal-related kinase, and p38 phosphorylation. Inhibition of these pathways and of NF-kappaB reduces activation of macrophages and CD4 T cells. MyD88 is an adaptor protein involved in proinflammatory signaling. In macrophages from MyD88(-/-) mice, RBP4 fails to stimulate secretion of tumor necrosis factor, IL-12, and IL-6 and CD4 T-cell activation. In vivo blockade of antigen presentation by treating RBP4-Ox mice with CTLA4-Ig, which blocks costimulation of T cells, is sufficient to reduce AT inflammation and improve insulin resistance. Thus, MyD88 and downstream mitogen activated protein kinase and NF-kappaB pathways are necessary for RBP4-induced macrophage antigen presentation and subsequent T-cell activation. Also, blocking antigen presentation with CTLA4-Ig improves RBP4-induced insulin resistance and macrophage-induced T-cell activation. PMID- 26936963 TI - Glucagon-Like Peptide 1 Receptor Activation Attenuates Platelet Aggregation and Thrombosis. AB - Short-term studies in subjects with diabetes receiving glucagon-like peptide 1 (GLP-1)-targeted therapies have suggested a reduced number of cardiovascular events. The mechanisms underlying this unexpectedly rapid effect are not known. We cloned full-length GLP-1 receptor (GLP-1R) mRNA from a human megakaryocyte cell line (MEG-01), and found expression levels of GLP-1Rs in MEG-01 cells to be higher than those in the human lung but lower than in the human pancreas. Incubation with GLP-1 and the GLP-1R agonist exenatide elicited a cAMP response in MEG-01 cells, and exenatide significantly inhibited thrombin-, ADP-, and collagen-induced platelet aggregation. Incubation with exenatide also inhibited thrombus formation under flow conditions in ex vivo perfusion chambers using human and mouse whole blood. In a mouse cremaster artery laser injury model, a single intravenous injection of exenatide inhibited thrombus formation in normoglycemic and hyperglycemic mice in vivo. Thrombus formation was greater in mice transplanted with bone marrow lacking a functional GLP-1R (Glp1r(-/-)), compared with those receiving wild-type bone marrow. Although antithrombotic effects of exenatide were partly lost in mice transplanted with bone marrow from Glp1r(-/-) mice, they were undetectable in mice with a genetic deficiency of endothelial nitric oxide synthase. The inhibition of platelet function and the prevention of thrombus formation by GLP-1R agonists represent potential mechanisms for reduced atherothrombotic events. PMID- 26936964 TI - A Synergistic Antiobesity Effect by a Combination of Capsinoids and Cold Temperature Through Promoting Beige Adipocyte Biogenesis. AB - Beige adipocytes emerge postnatally within the white adipose tissue in response to certain environmental cues, such as chronic cold exposure. Because of its highly recruitable nature and relevance to adult humans, beige adipocytes have gained much attention as an attractive cellular target for antiobesity therapy. However, molecular circuits that preferentially promote beige adipocyte biogenesis remain poorly understood. We report that a combination of mild cold exposure at 17 degrees C and capsinoids, a nonpungent analog of capsaicin, synergistically and preferentially promotes beige adipocyte biogenesis and ameliorates diet-induced obesity. Gain- and loss-of-function studies show that the combination of capsinoids and cold exposure synergistically promotes beige adipocyte development through the beta2-adrenoceptor signaling pathway. This synergistic effect on beige adipocyte biogenesis occurs through an increased half life of PRDM16, a dominant transcriptional regulator of brown/beige adipocyte development. We document a previously unappreciated molecular circuit that controls beige adipocyte biogenesis and suggest a plausible approach to increase whole-body energy expenditure by combining dietary components and environmental cues. PMID- 26936965 TI - Role of GCN2-Independent Signaling Through a Noncanonical PERK/NRF2 Pathway in the Physiological Responses to Dietary Methionine Restriction. AB - Restricting availability of essential amino acids (EAAs) limits aminoacylation of tRNAs by their cognate EAAs and activates the nutrient-sensing kinase, general control nonderepressible 2 (GCN2). Activated GCN2 phosphorylates eukaryotic initiation factor 2 (eIF2), altering gene-specific translation and initiating a transcriptional program collectively described as the integrated stress response (ISR). Central GCN2 activation by EAA deprivation is also linked to an acute aversive feeding response. Dietary methionine restriction (MR) produces a well documented series of physiological responses (increased energy intake and expenditure, decreased adiposity, and increased insulin sensitivity), but the role of GCN2 in mediating them is unknown. Using Gcn2(-/-) mice, we found that the absence of GCN2 had no effect on the ability of MR to reduce body weight or adiposity, increase energy intake and expenditure, increase hepatic transcription and release of fibroblast growth factor 21, or improve insulin sensitivity. Interestingly, hepatic eIF2 phosphorylation by MR was uncompromised in Gcn2(-/-) mice. Instead, protein kinase R-like endoplasmic reticulum (ER) kinase (PERK) was activated in both intact and Gcn2(-/-) mice. PERK activation corresponded with induction of the ISR and the nuclear respiratory factor 2 antioxidant program but not ER stress. These data uncover a novel glutathione-sensing mechanism that functions independently of GCN2 to link dietary MR to its metabolic phenotype. PMID- 26936967 TI - Long-chain acylcarnitines determine ischaemia/reperfusion-induced damage in heart mitochondria. AB - The accumulation of long-chain fatty acids (FAs) and their CoA and carnitine esters is observed in the ischaemic myocardium after acute ischaemia/reperfusion. The aim of the present study was to identify harmful FA intermediates and their detrimental mechanisms of action in mitochondria and the ischaemic myocardium. In the present study, we found that the long-chain acyl-CoA and acylcarnitine content is increased in mitochondria isolated from an ischaemic area of the myocardium. In analysing the FA derivative content, we discovered that long-chain acylcarnitines, but not acyl-CoAs, accumulate at concentrations that are harmful to mitochondria. Acylcarnitine accumulation in the mitochondrial intermembrane space is a result of increased carnitine palmitoyltransferase 1 (CPT1) and decreased carnitine palmitoyltransferase 2 (CPT2) activity in ischaemic myocardium and it leads to inhibition of oxidative phosphorylation, which in turn induces mitochondrial membrane hyperpolarization and stimulates the production of reactive oxygen species (ROS) in cardiac mitochondria. Thanks to protection mediated by acyl-CoA-binding protein (ACBP), the heart is much better guarded against the damaging effects of acyl-CoAs than against acylcarnitines. Supplementation of perfusion buffer with palmitoylcarnitine (PC) before occlusion resulted in a 2-fold increase in the acylcarnitine content of the heart and increased the infarct size (IS) by 33%. A pharmacologically induced decrease in the mitochondrial acylcarnitine content reduced the IS by 44%. Long-chain acylcarnitines are harmful FA intermediates, accumulating in ischaemic heart mitochondria and inducing inhibition of oxidative phosphorylation. Therefore, decreasing the acylcarnitine content via cardioprotective drugs may represent a novel treatment strategy. PMID- 26936968 TI - Mechanism of chitosan recognition by CBM32 carbohydrate-binding modules from a Paenibacillus sp. IK-5 chitosanase/glucanase. AB - An antifungal chitosanase/glucanase isolated from the soil bacterium Paenibacillus sp. IK-5 has two CBM32 chitosan-binding modules (DD1 and DD2) linked in tandem at the C-terminus. In order to obtain insights into the mechanism of chitosan recognition, the structures of DD1 and DD2 were solved by NMR spectroscopy and crystallography. DD1 and DD2 both adopted a beta-sandwich fold with several loops in solution as well as in crystals. On the basis of chemical shift perturbations in(1)H-(15)N-HSQC resonances, the chitosan tetramer (GlcN)4 was found to bind to the loop region extruded from the core beta-sandwich of DD1 and DD2. The binding site defined by NMR in solution was consistent with the crystal structure of DD2 in complex with (GlcN)3, in which the bound (GlcN)3 stood upright on its non-reducing end at the binding site. Glu(14)of DD2 appeared to make an electrostatic interaction with the amino group of the non-reducing end GlcN, and Arg(31), Tyr(36)and Glu(61)formed several hydrogen bonds predominantly with the non-reducing end GlcN. No interaction was detected with the reducing end GlcN. Since Tyr(36)of DD2 is replaced by glutamic acid in DD1, the mutation of Tyr(36)to glutamic acid was conducted in DD2 (DD2-Y36E), and the reverse mutation was conducted in DD1 (DD1-E36Y). Ligand-binding experiments using the mutant proteins revealed that this substitution of the 36th amino acid differentiates the binding properties of DD1 and DD2, probably enhancing total affinity of the chitosanase/glucanase toward the fungal cell wall. PMID- 26936966 TI - Factors correlated with the resolution of macular oedema after one dose injection of intravitreal triamcinolone acetonide treatment in branch retinal vein occlusion. AB - OBJECTIVE: To investigate the predictive baseline factors for a successful outcome following one dose of intravitreal triamcinolone acetonide (IVTA) in patients with macular oedema (ME) caused by branch retinal vein occlusion (BRVO). METHODS: This retrospective study enrolled patients with ME (macular retinal thickness [MRT] >= 300 um) due to BRVO who still had ME 3 months after grid laser photocoagulation. Patients were divided according to treatment into an IVTA group and a laser-only group. The resolution of ME was documented at months 3 and 6. RESULTS: A total of 154 eyes with ME were investigated: IVTA group (90 eyes) and laser-only group (64 eyes). Predictive factors for successful IVTA treatment were younger age, shorter duration of ME, initial onset ME, accompanied by serous retinal detachment, few concomitant systemic diseases and nonischaemic BRVO. A broken foveal capillary ring was related to a poor treatment outcome. Eyes with cystoid spaces in the outer plexiform layer were more likely to have a good treatment response. CONCLUSION: IVTA is effective for resolving ME due to BRVO after grid laser photocoagulation treatment. PMID- 26936969 TI - The different catalytic roles of the metal-binding ligands in human 4 hydroxyphenylpyruvate dioxygenase. AB - 4-Hydroxyphenylpyruvate dioxygenase (HPPD) is a non-haem iron(II)-dependent oxygenase that catalyses the conversion of 4-hydroxyphenylpyruvate (HPP) to homogentisate (HG). In the active site, a strictly conserved 2-His-1-Glu facial triad co-ordinates the iron ready for catalysis. Substitution of these residues resulted in about a 10-fold decrease in the metal binding affinity, as measured by isothermal titration calorimetry, and a large reduction in enzyme catalytic efficiencies. The present study revealed the vital role of the ligand Glu(349) in enzyme function. Replacing this residue with alanine resulted in loss of activity. The E349G variant retained 5% activity for the coupled reaction, suggesting that co-ordinating water may be able to support activation of the trans-bound dioxygen upon substrate binding. The reaction catalysed by the H183A variant was fully uncoupled. H183A variant catalytic activity resulted in protein cleavage between Ile(267) and Ala(268) and the production of an N-terminal fragment. The H266A variant was able to produce 4-hydroxyphenylacetate (HPA), demonstrating that decarboxylation had occurred but that there was no subsequent product formation. Structural modelling of the variant enzyme with bound dioxygen revealed the rearrangement of the co-ordination environment and the dynamic behaviour of bound dioxygen in the H266A and H183A variants respectively. These models suggest that the residues regulate the geometry of the reactive oxygen intermediate during the oxidation reaction. The mutagenesis and structural simulation studies demonstrate the critical and unique role of each ligand in the function of HPPD, and which correlates with their respective co-ordination position. PMID- 26936970 TI - Calcium-insensitive splice variants of mammalian E1 subunit of 2-oxoglutarate dehydrogenase complex with tissue-specific patterns of expression. AB - The 2-oxoglutarate dehydrogenase (OGDH) complex is an important control point in vertebrate mitochondrial oxidative metabolism, including in the citrate cycle and catabolism of alternative fuels including glutamine. It is subject to allosteric regulation by NADH and the ATP/ADP ratio, and by Ca(2+) through binding to the E1 subunit. The latter involves a unique Ca(2+)-binding site which includes D(114)ADLD (site 1). Here, we describe three splice variants of E1 in which either the exon expressing this site is replaced with another exon (loss of site 1, LS1) or an additional exon is expressed leading to the insertion of 15 amino acids just downstream of site 1 (Insert), or both changes occur together (LS1/Insert). We show that all three variants are essentially Ca(2+)-insensitive. Comparison of massive parallel sequence (RNA-Seq) databases demonstrates predominant expression of the Ca(2+)-sensitive archetype form in heart and skeletal muscle, but substantial expression of the Ca(2+)-insensitive variants in brain, pancreatic islets and other tissues. Detailed proteomic and activity studies comparing OGDH complexes from rat heart and brain confirmed the substantial difference in expression between these tissues. The evolution of OGDH variants was explored using bioinformatics, and this indicated that Ca(2+) sensitivity arose with the emergence of chordates. In all species examined, this was associated with the co-emergence of Ca(2+)-insensitive variants suggesting a retained requirement for the latter in some settings. Tissue-specific expression of OGDH splice variants may thus provide a mechanism that tunes the control of the enzyme to the specialized metabolic and signalling needs of individual cell types. PMID- 26936971 TI - Rab14 limits the sorting of Glut4 from endosomes into insulin-sensitive regulated secretory compartments in adipocytes. AB - Insulin increases glucose uptake by increasing the rate of exocytosis of the facilitative glucose transporter isoform 4 (Glut4) relative to its endocytosis. Insulin also releases Glut4 from highly insulin-regulated secretory compartments (GSVs or Glut4 storage vesicles) into constitutively cycling endosomes. Previously it was shown that both overexpression and knockdown of the small GTP binding protein Rab14 decreased Glut4 translocation to the plasma membrane (PM). To determine the mechanism of this perturbation, we measured the effects of Rab14 knockdown on the trafficking kinetics of Glut4 relative to two proteins that partially co-localize with Glut4, the transferrin (Tf) receptor and low-density lipoprotein-receptor-related protein 1 (LRP1). Our data support the hypothesis that Rab14 limits sorting of proteins from sorting (or 'early') endosomes into the specialized GSV pathway, possibly through regulation of endosomal maturation. This hypothesis is consistent with known Rab14 effectors. Interestingly, the insulin-sensitive Rab GTPase-activating protein Akt substrate of 160 kDa (AS160) affects both sorting into and exocytosis from GSVs. It has previously been shown that exocytosis of GSVs is rate-limited by Rab10, and both Rab10 and Rab14 are in vitro substrates of AS160. Regulation of both entry into and exit from GSVs by AS160 through sequential Rab substrates would provide a mechanism for the finely tuned 'quantal' increases in cycling Glut4 observed in response to increasing concentrations of insulin. PMID- 26936973 TI - Physiologically Based Pharmacokinetic Modeling in Pediatric Oncology Drug Development. AB - Childhood cancer represents more than 100 rare and ultra-rare diseases, with an estimated 12,400 new cases diagnosed each year in the United States. As such, this much smaller patient population has led to pediatric oncology drug development lagging behind that for adult cancers. Developing drugs for pediatric malignancies also brings with it a number of unique trial design considerations, including flexible enrollment approaches, age-appropriate formulation, acceptable sampling schedules, and balancing the need for age-stratified dosing regimens, given the smaller patient populations. The regulatory landscape for pediatric pharmacotherapy has evolved with U.S. Food and Drug Administration (FDA) legislation such as the 2012 FDA Safety and Innovation Act. In parallel, regulatory authorities have recommended the application of physiologically based pharmacokinetic (PBPK) modeling, for example, in the recently issued FDA Strategic Plan for Accelerating the Development of Therapies for Pediatric Rare Diseases. PBPK modeling provides a quantitative and systems-based framework that allows the effects of intrinsic and extrinsic factors on drug exposure to be modeled in a mechanistic fashion. The application of PBPK modeling in drug development for pediatric cancers is relatively nascent, with several retrospective analyses of cytotoxic therapies, and latterly for targeted agents such as obatoclax and imatinib. More recently, we have employed PBPK modeling in a prospective manner to inform the first pediatric trials of pinometostat and tazemetostat in genetically defined populations (mixed lineage leukemia rearranged and integrase interactor-1-deficient sarcomas, respectively). In this review, we evaluate the application of PBPK modeling in pediatric cancer drug development and discuss the important challenges that lie ahead in this field. PMID- 26936972 TI - Evaluating the Disposition of a Mixed Aldehyde Oxidase/Cytochrome P450 Substrate in Rats with Attenuated P450 Activity. AB - Marketed drugs cleared by aldehyde oxidase (AO) are few, with no known clinically relevant pharmacokinetic drug interactions associated with AO inhibition, whereas cytochrome P450 (P450) inhibition or induction mediates a number of clinical drug interactions. Little attention has been given to the consequences of coadministering a P450 inhibitor with a compound metabolized by both AO and P450. Upon discovering that VU0409106 (1) was metabolized by AO (to M1) and P450 enzymes (to M4-M6), we sought to evaluate the in vivo disposition of 1 and its metabolites in rats with attenuated P450 activity. Male rats were orally pretreated with the pan-P450 inactivator, 1-aminobenzotriazole (ABT), before an i.p. dose of 1. Interestingly, the plasma area under the curve (AUC) of M1 was increased 15-fold in ABT-treated rats, indicating a metabolic shunt toward AO resulted from the drug interaction condition. The AUC of 1 also increased 7.8 fold. Accordingly, plasma clearance of 1 decreased from 53.5 to 15.3 ml/min per kilogram in ABT-pretreated rats receiving an i.v. dose of 1. Consistent with these data, M1 formation in hepatic S9 increased with NADPH-exclusion to eliminate P450 activity (50% over reactions containing NADPH). These studies reflect possible consequences of a drug interaction between P450 inhibitors and compounds cleared by both AO and P450 enzymes. Notably, increased exposure to an AO metabolite may hold clinical relevance for active metabolites or those mediating toxicity at elevated concentrations. The recent rise in clinical drug candidates metabolized by AO underscores the importance of these findings and the need for clinical studies to fully understand these risks. PMID- 26936974 TI - Catalytic Activities of Tumor-Specific Human Cytochrome P450 CYP2W1 Toward Endogenous Substrates. AB - CYP2W1 is a recently discovered human cytochrome P450 enzyme with a distinctive tumor-specific expression pattern. We show here that CYP2W1 exhibits tight binding affinities for retinoids, which have low nanomolar binding constants, and much poorer binding constants in the micromolar range for four other ligands. CYP2W1 converts all-transretinoic acid (atRA) to 4-hydroxyatRA and all transretinol to 4-OH all-transretinol, and it also oxidizes retinal. The enzyme much less efficiently oxidizes 17beta-estradiol to 2-hydroxy-(17beta)-estradiol and farnesol to a monohydroxylated product; arachidonic acid is, at best, a negligible substrate. These findings indicate that CYP2W1 probably plays an important role in localized retinoid metabolism that may be intimately linked to its involvement in tumor development. PMID- 26936975 TI - Action potential amplitude as a noninvasive indicator of motor unit-specific hypertrophy. AB - Skeletal muscle fibers hypertrophy in response to strength training, with type II fibers generally demonstrating the greatest plasticity in regards to cross sectional area (CSA). However, assessing fiber type-specific CSA in humans requires invasive muscle biopsies. With advancements in the decomposition of surface electromyographic (sEMG) signals recorded using multichannel electrode arrays, the firing properties of individual motor units (MUs) can now be detected noninvasively. Since action potential amplitude (APSIZE) has a documented relationship with muscle fiber size, as well as with its parent MU's recruitment threshold (RT) force, our purpose was to examine if MU APSIZE, as a function of its RT (i.e., the size principle), could potentially be used as a longitudinal indicator of MU-specific hypertrophy. By decomposing the sEMG signals from the vastus lateralis muscle of 10 subjects during maximal voluntary knee extensions, we noninvasively assessed the relationship between MU APSIZE and RT before and immediately after an 8-wk strength training intervention. In addition to significant increases in muscle size and strength (P < 0.02), our data show that training elicited an increase in MU APSIZE of high-threshold MUs. Additionally, a large portion of the variance (83.6%) in the change in each individual's relationship between MU APSIZE and RT was explained by training-induced changes in whole muscle CSA (obtained via ultrasonography). Our findings suggest that the noninvasive, electrophysiological assessment of longitudinal changes to MU APSIZE appears to reflect hypertrophy specific to MUs across the RT continuum. PMID- 26936976 TI - The predictive roles of neural oscillations in speech motor adaptability. AB - The human speech system exhibits a remarkable flexibility by adapting to alterations in speaking environments. While it is believed that speech motor adaptation under altered sensory feedback involves rapid reorganization of speech motor networks, the mechanisms by which different brain regions communicate and coordinate their activity to mediate adaptation remain unknown, and explanations of outcome differences in adaption remain largely elusive. In this study, under the paradigm of altered auditory feedback with continuous EEG recordings, the differential roles of oscillatory neural processes in motor speech adaptability were investigated. The predictive capacities of different EEG frequency bands were assessed, and it was found that theta-, beta-, and gamma-band activities during speech planning and production contained significant and reliable information about motor speech adaptability. It was further observed that these bands do not work independently but interact with each other suggesting an underlying brain network operating across hierarchically organized frequency bands to support motor speech adaptation. These results provide novel insights into both learning and disorders of speech using time frequency analysis of neural oscillations. PMID- 26936977 TI - Macaque retinal ganglion cell responses to visual patterns: harmonic composition, noise, and psychophysical detectability. AB - The goal of these experiments was to test how well cell responses to visual patterns can be predicted from the sinewave tuning curve. Magnocellular (MC) and parvocellular (PC) ganglion cell responses to different spatial waveforms (sinewave, squarewave, and ramp waveforms) were measured across a range of spatial frequencies. Sinewave spatial tuning curves were fit with standard Gaussian models. From these fits, waveforms and spatial tuning of a cell's responses to the other waveforms were predicted for different harmonics by scaling in amplitude for the power in the waveform's Fourier expansion series over spatial frequency. Since higher spatial harmonics move at a higher temporal frequency, an additional scaling for each harmonic by the MC (bandpass) or PC (lowpass) temporal response was included, together with response phase. Finally, the model included a rectifying nonlinearity. This provided a largely satisfactory estimation of MC and PC cell responses to complex waveforms. As a consequence of their transient responses, MC responses to complex waveforms were found to have significantly more energy in higher spatial harmonic components than PC responses. Response variance (noise) was also quantified as a function of harmonic component. Noise increased to some degree for the higher harmonics. The data are relevant for psychophysical detection or discrimination of visual patterns, and we discuss the results in this context. PMID- 26936979 TI - Gait parameter control timing with dynamic manual contact or visual cues. AB - We investigated the timing of gait parameter changes (stride length, peak toe velocity, and double-, single-support, and complete step duration) to control gait speed. Eleven healthy participants adjusted their gait speed on a treadmill to maintain a constant distance between them and a fore-aft oscillating cue (a place on a conveyor belt surface). The experimental design balanced conditions of cue modality (vision: eyes-open; manual contact: eyes-closed while touching the cue); treadmill speed (0.2, 0.4, 0.85, and 1.3 m/s); and cue motion (none, +/-10 cm at 0.09, 0.11, and 0.18 Hz). Correlation analyses revealed a number of temporal relationships between gait parameters and cue speed. The results suggest that neural control ranged from feedforward to feedback. Specifically, step length preceded cue velocity during double-support duration suggesting anticipatory control. Peak toe velocity nearly coincided with its most-correlated cue velocity during single-support duration. The toe-off concluding step and double-support durations followed their most-correlated cue velocity, suggesting feedback control. Cue-tracking accuracy and cue velocity correlations with timing parameters were higher with the manual contact cue than visual cue. The cue/gait timing relationships generalized across cue modalities, albeit with greater delays of step-cycle events relative to manual contact cue velocity. We conclude that individual kinematic parameters of gait are controlled to achieve a desired velocity at different specific times during the gait cycle. The overall timing pattern of instantaneous cue velocities associated with different gait parameters is conserved across cues that afford different performance accuracies. This timing pattern may be temporally shifted to optimize control. Different cue/gait parameter latencies in our nonadaptation paradigm provide general-case evidence of the independent control of gait parameters previously demonstrated in gait adaptation paradigms. PMID- 26936978 TI - Categorically distinct types of receptive fields in early visual cortex. AB - In the visual cortex, distinct types of neurons have been identified based on cellular morphology, response to injected current, or expression of specific markers, but neurophysiological studies have revealed visual receptive field (RF) properties that appear to be on a continuum, with only two generally recognized classes: simple and complex. Most previous studies have characterized visual responses of neurons using stereotyped stimuli such as bars, gratings, or white noise and simple system identification approaches (e.g., reverse correlation). Here we estimate visual RF models of cortical neurons using visually rich natural image stimuli and regularized regression system identification methods and characterize their spatial tuning, temporal dynamics, spatiotemporal behavior, and spiking properties. We quantitatively demonstrate the existence of three functionally distinct categories of simple cells, distinguished by their degree of orientation selectivity (isotropic or oriented) and the nature of their output nonlinearity (expansive or compressive). In addition, these three types have differing average values of several other properties. Cells with nonoriented RFs tend to have smaller RFs, shorter response durations, no direction selectivity, and high reliability. Orientation-selective neurons with an expansive output nonlinearity have Gabor-like RFs, lower spontaneous activity and responsivity, and spiking responses with higher sparseness. Oriented RFs with a compressive nonlinearity are spatially nondescript and tend to show longer response latency. Our findings indicate multiple physiologically defined types of RFs beyond the simple/complex dichotomy, suggesting that cortical neurons may have more specialized functional roles rather than lying on a multidimensional continuum. PMID- 26936980 TI - Temporal and spatial tuning of dorsal lateral geniculate nucleus neurons in unanesthetized rats. AB - Visual response properties of neurons in the dorsolateral geniculate nucleus (dLGN) have been well described in several species, but not in rats. Analysis of responses from the unanesthetized rat dLGN will be needed to develop quantitative models that account for visual behavior of rats. We recorded visual responses from 130 single units in the dLGN of 7 unanesthetized rats. We report the response amplitudes, temporal frequency, and spatial frequency sensitivities in this population of cells. In response to 2-Hz visual stimulation, dLGN cells fired 15.9 +/- 11.4 spikes/s (mean +/- SD) modulated by 10.7 +/- 8.4 spikes/s about the mean. The optimal temporal frequency for full-field stimulation ranged from 5.8 to 19.6 Hz across cells. The temporal high-frequency cutoff ranged from 11.7 to 33.6 Hz. Some cells responded best to low temporal frequency stimulation (low pass), and others were strictly bandpass; most cells fell between these extremes. At 2- to 4-Hz temporal modulation, the spatial frequency of drifting grating that drove cells best ranged from 0.008 to 0.18 cycles per degree (cpd) across cells. The high-frequency cutoff ranged from 0.01 to 1.07 cpd across cells. The majority of cells were driven best by the lowest spatial frequency tested, but many were partially or strictly bandpass. We conclude that single units in the rat dLGN can respond vigorously to temporal modulation up to at least 30 Hz and spatial detail up to 1 cpd. Tuning properties were heterogeneous, but each fell along a continuum; we found no obvious clustering into discrete cell types along these dimensions. PMID- 26936981 TI - Nicotinic acetylcholine receptor-mediated responses in medial vestibular and prepositus hypoglossi nuclei neurons showing distinct neurotransmitter phenotypes. AB - Cholinergic transmission in both the medial vestibular nucleus (MVN) and prepositus hypoglossi nucleus (PHN) plays an important role in horizontal eye movements. We previously demonstrated that the current responses mediated via nicotinic acetylcholine receptors (nAChRs) were larger than those mediated via muscarinic acetylcholine receptors (mAChRs) in cholinergic MVN and PHN neurons that project to the cerebellum. In this study, to clarify the predominant nAChR responses and the expression patterns of nAChRs in MVN and PHN neurons that exhibit distinct neurotransmitter phenotypes, we identified cholinergic, inhibitory, and glutamatergic neurons using specific transgenic rats and investigated current responses to the application of acetylcholine (ACh) using whole cell recordings in brain stem slices. ACh application induced larger nAChR mediated currents than mAChR-mediated currents in every neuronal phenotype. In the presence of an mAChR antagonist, we found three types of nAChR-mediated currents that exhibited different rise and decay times and designated these as fast (F)-, slow (S)-, and fast and slow (FS)-type currents. F-type currents were the predominant response in inhibitory MVN neurons, whereas S-type currents were observed in the majority of glutamatergic MVN and PHN neurons. No dominant response type was observed in cholinergic neurons. Pharmacological analyses revealed that the F-, S-, and FS-type currents were mainly mediated by alpha7, non-alpha7, and both alpha7 and non-alpha7 nAChRs, respectively. These findings suggest that cholinergic responses in the major neuronal populations of the MVN and PHN are predominantly mediated by nAChRs and that the expression of alpha7 and non-alpha7 nAChRs differ among the neuronal phenotypes. PMID- 26936983 TI - Similar prevalence and magnitude of auditory-evoked and visually evoked activity in the frontal eye fields: implications for multisensory motor control. AB - Saccadic eye movements can be elicited by more than one type of sensory stimulus. This implies substantial transformations of signals originating in different sense organs as they reach a common motor output pathway. In this study, we compared the prevalence and magnitude of auditory- and visually evoked activity in a structure implicated in oculomotor processing, the primate frontal eye fields (FEF). We recorded from 324 single neurons while 2 monkeys performed delayed saccades to visual or auditory targets. We found that 64% of FEF neurons were active on presentation of auditory targets and 87% were active during auditory-guided saccades, compared with 75 and 84% for visual targets and saccades. As saccade onset approached, the average level of population activity in the FEF became indistinguishable on visual and auditory trials. FEF activity was better correlated with the movement vector than with the target location for both modalities. In summary, the large proportion of auditory-responsive neurons in the FEF, the similarity between visual and auditory activity levels at the time of the saccade, and the strong correlation between the activity and the saccade vector suggest that auditory signals undergo tailoring to match roughly the strength of visual signals present in the FEF, facilitating accessing of a common motor output pathway. PMID- 26936982 TI - Sodium channel diversity in the vestibular ganglion: NaV1.5, NaV1.8, and tetrodotoxin-sensitive currents. AB - Firing patterns differ between subpopulations of vestibular primary afferent neurons. The role of sodium (NaV) channels in this diversity has not been investigated because NaV currents in rodent vestibular ganglion neurons (VGNs) were reported to be homogeneous, with the voltage dependence and tetrodotoxin (TTX) sensitivity of most neuronal NaV channels. RT-PCR experiments, however, indicated expression of diverse NaV channel subunits in the vestibular ganglion, motivating a closer look. Whole cell recordings from acutely dissociated postnatal VGNs confirmed that nearly all neurons expressed NaV currents that are TTX-sensitive and have activation midpoints between -30 and -40 mV. In addition, however, many VGNs expressed one of two other NaV currents. Some VGNs had a small current with properties consistent with NaV1.5 channels: low TTX sensitivity, sensitivity to divalent cation block, and a relatively negative voltage range, and some VGNs showed NaV1.5-like immunoreactivity. Other VGNs had a current with the properties of NaV1.8 channels: high TTX resistance, slow time course, and a relatively depolarized voltage range. In two NaV1.8 reporter lines, subsets of VGNs were labeled. VGNs with NaV1.8-like TTX-resistant current also differed from other VGNs in the voltage dependence of their TTX-sensitive currents and in the voltage threshold for spiking and action potential shape. Regulated expression of NaV channels in primary afferent neurons is likely to selectively affect firing properties that contribute to the encoding of vestibular stimuli. PMID- 26936984 TI - Utility of EEG measures of brain function in patients with acute stroke. AB - EEG has been used to study acute stroke for decades; however, because of several limitations EEG-based measures rarely inform clinical decision-making in this setting. Recent advances in EEG hardware, recording electrodes, and EEG software could overcome these limitations. The present study examined how well dense-array (256 electrodes) EEG, acquired with a saline-lead net and analyzed with whole brain partial least squares (PLS) modeling, captured extent of acute stroke behavioral deficits and varied in relation to acute brain injury. In 24 patients admitted for acute ischemic stroke, 3 min of resting-state EEG was acquired at bedside, including in the ER and ICU. Traditional quantitative EEG measures (power in a specific lead, in any frequency band) showed a modest association with behavioral deficits [NIH Stroke Scale (NIHSS) score] in bivariate models. However, PLS models of delta or beta power across whole brain correlated strongly with NIHSS score (R(2) = 0.85-0.90) and remained robust when further analyzed with cross-validation models (R(2) = 0.72-0.73). Larger infarct volume was associated with higher delta power, bilaterally; the contralesional findings were not attributable to mass effect, indicating that EEG captures significant information about acute stroke effects not available from MRI. We conclude that 1) dense-array EEG data are feasible as a bedside measure of brain function in patients with acute stroke; 2) high-dimension EEG data are strongly correlated with acute stroke behavioral deficits and are superior to traditional single-lead metrics in this regard; and 3) EEG captures significant information about acute stroke injury not available from structural brain imaging. PMID- 26936985 TI - Impact of calcium-activated potassium channels on NMDA spikes in cortical layer 5 pyramidal neurons. AB - Active electrical events play an important role in shaping signal processing in dendrites. As these events are usually associated with an increase in intracellular calcium, they are likely to be under the control of calcium activated potassium channels. Here, we investigate the impact of calcium activated potassium channels onN-methyl-d-aspartate (NMDA) receptor-dependent spikes, or NMDA spikes, evoked by glutamate iontophoresis onto basal dendrites of cortical layer 5 pyramidal neurons. We found that small-conductance calcium activated potassium channels (SK channels) act to reduce NMDA spike amplitude but at the same time, also decrease the iontophoretic current required for their generation. This SK-mediated decrease in NMDA spike threshold was dependent on R type voltage-gated calcium channels and indicates a counterintuitive, excitatory effect of SK channels on NMDA spike generation, whereas the capacity of SK channels to suppress NMDA spike amplitude is in line with the expected inhibitory action of potassium channels on dendritic excitability. Large-conductance calcium activated potassium channels had no significant impact on NMDA spikes, indicating that these channels are either absent from basal dendrites or not activated by NMDA spikes. These experiments reveal complex and opposing interactions among NMDA receptors, SK channels, and voltage-gated calcium channels in basal dendrites of cortical layer 5 pyramidal neurons during NMDA spike generation, which are likely to play an important role in regulating the way these neurons integrate the thousands of synaptic inputs they receive. PMID- 26936986 TI - Dendritic spine remodeling following early and late Rac1 inhibition after spinal cord injury: evidence for a pain biomarker. AB - Neuropathic pain is a significant complication following spinal cord injury (SCI) with few effective treatments. Drug development for neuropathic pain often fails because preclinical studies do not always translate well to clinical conditions. Identification of biological characteristics predictive of disease state or drug responsiveness could facilitate more effective clinical translation. Emerging evidence indicates a strong correlation between dendritic spine dysgenesis and neuropathic pain. Because dendritic spines are located on dorsal horn neurons within the spinal cord nociceptive system, dendritic spine remodeling provides a unique opportunity to understand sensory dysfunction after SCI. In this study, we provide support for the postulate that dendritic spine profiles can serve as biomarkers for neuropathic pain. We show that dendritic spine profiles after SCI change to a dysgenic state that is characteristic of neuropathic pain in a Rac1 dependent manner. Suppression of the dysgenic state through inhibition of Rac1 activity is accompanied by attenuation of neuropathic pain. Both dendritic spine dysgenesis and neuropathic pain return when inhibition of Rac1 activity is lifted. These findings suggest the utility of dendritic spines as structural biomarkers for neuropathic pain. PMID- 26936987 TI - Effects of aging on the response of single neurons to amplitude-modulated noise in primary auditory cortex of rhesus macaque. AB - Temporal envelope processing is critical for speech comprehension, which is known to be affected by normal aging. Whereas the macaque is an excellent animal model for human cerebral cortical function, few studies have investigated neural processing in the auditory cortex of aged, nonhuman primates. Therefore, we investigated age-related changes in the spiking activity of neurons in primary auditory cortex (A1) of two aged macaque monkeys using amplitude-modulated (AM) noise and compared these responses with data from a similar study in young monkeys (Yin P, Johnson JS, O'Connor KN, Sutter ML. J Neurophysiol 105: 582-600, 2011). For each neuron, we calculated firing rate (rate code) and phase-locking using phase-projected vector strength (temporal code). We made several key findings where neurons in old monkeys differed from those in young monkeys. Old monkeys had higher spontaneous and driven firing rates, fewer neurons that synchronized with the AM stimulus, and fewer neurons that had differential responses to AM stimuli with both a rate and temporal code. Finally, whereas rate and temporal tuning functions were positively correlated in young monkeys, this relationship was lost in older monkeys at both the population and single neuron levels. These results are consistent with considerable evidence from rodents and primates of an age-related decrease in inhibition throughout the auditory pathway. Furthermore, this dual coding in A1 is thought to underlie the capacity to encode multiple features of an acoustic stimulus. The apparent loss of ability to encode AM with both rate and temporal codes may have consequences for stream segregation and effective speech comprehension in complex listening environments. PMID- 26936988 TI - Intrinsic excitability differs between murine hypoglossal and spinal motoneurons. AB - Motoneurons differ in the behaviors they control and their vulnerability to disease and aging. For example, brain stem motoneurons such as hypoglossal motoneurons (HMs) are involved in licking, suckling, swallowing, respiration, and vocalization. In contrast, spinal motoneurons (SMs) innervating the limbs are involved in postural and locomotor tasks requiring higher loads and lower movement velocities. Surprisingly, the properties of these two motoneuron pools have not been directly compared, even though studies on HMs predominate in the literature compared with SMs, especially for adult animals. Here we used whole cell patch-clamp recording to compare the electrophysiological properties of HMs and SMs in age-matched neonatal mice (P7-P10). Passive membrane properties were remarkably similar in HMs and SMs, and afterhyperpolarization properties did not differ markedly between the two populations. HMs had narrower action potentials (APs) and a faster upstroke on their APs compared with SMs. Furthermore, HMs discharged APs at higher frequencies in response to both step and ramp current injection than SMs. Therefore, while HMs and SMs have similar passive properties, they differ in their response to similar levels of depolarizing current. This suggests that each population possesses differing suites of ion channels that allow them to discharge at rates matched to the different mechanical properties of the muscle fibers that drive their distinct motor functions. PMID- 26936989 TI - The vestibular system does not modulate fusimotor drive to muscle spindles in relaxed leg muscles of subjects in a near-vertical position. AB - It has been shown that sinusoidal galvanic vestibular stimulation (sGVS) has no effect on the firing of spontaneously active muscle spindles in either relaxed or voluntarily contracting human leg muscles. However, all previous studies have been conducted on subjects in a seated position. Given that independent vestibular control of muscle spindle firing would be more valuable during postural threat, we tested the hypothesis that this modulation would become apparent for subjects in a near-vertical position. Unitary recordings were made from 18 muscle spindle afferents via tungsten microelectrodes inserted percutaneously into the common peroneal nerve of awake human subjects laying supine on a motorized tilt table. All recorded spindle afferents were spontaneously active at rest, and each increased its firing rate during a weak static contraction. Sinusoidal bipolar binaural galvanic vestibular stimulation (+/-2 mA, 100 cycles) was applied to the mastoid processes at 0.8 Hz. This continuous stimulation produced a sustained illusion of "rocking in a boat" or "swinging in a hammock." The subject was then moved into a near-vertical position (75 degrees ), and the stimulation repeated. Despite robust vestibular illusions, none of the fusimotor-driven spindles exhibited phase-locked modulation of firing during sinusoidal GVS in either position. We conclude that this dynamic vestibular stimulus was insufficient to modulate the firing of fusimotor neurons in the near-vertical position. However, this does not mean that the vestibular system cannot modulate the sensitivity of muscle spindles via fusimotor neurons in free unsupported standing, when reliance on proprioceptive feedback is higher. PMID- 26936990 TI - "Lucio's Phenomenon" Associated with Mycobacterium lepromatosis. PMID- 26936991 TI - On Bathwater, Babies, and Designing Programs for Impact: Evaluations of the Integrated Community Case Management Strategy in Burkina Faso, Ethiopia, and Malawi. PMID- 26936992 TI - Integrated Community Case Management of Childhood Illness: What Have We Learned? PMID- 26936993 TI - FGFR1 promotes the stem cell-like phenotype of FGFR1-amplified non-small cell lung cancer cells through the Hedgehog pathway. AB - Cancer stem cell-like phenotype is critical for tumor formation and treatment resistance. FGFR1 is found to be amplified in non-small cell lung cancer, particularly in the lung squamous cell cancer (LSCC). Whether FGFR1 contributes to the maintenance of stem cell-like phenotype of FGFR1-amplified lung cancer cells remains elusive. In this study, treatment with FGFR1 inhibitor AZD4547 suppressed the growth of tumor spheres and reduced ALDH positive proportion in FGFR1-amplified lung cancer cells in vitro, as well as inhibited the growth of oncospheres and parental cells in xenograft models. Knockdown of FGFR1 recaptured the similar effect as AZD4547 in vitro. Furthermore, activation of FGFR1 and subsequently its downstream ERK signaling enhanced the expression and transcriptional activity of GLI2, which could be blocked by FGFR1 inhibitor/silencing or ERK inhibitor. Knockdown of GLI2 directly inhibited the stem-like phenotype of FGFR1-amilified cells, whereas overexpression of GLI2 sufficiently rescued the phenotype caused by FGFR1 knockdown. Notably we also identified a correlation between FGFR1 and GLI2 expressions from clinical data, as well as an inverse relationship with progression free survival (PFS). Together our study suggests that the FGFR1/GLI2 axis promotes the lung cancer stem cell like phenotype. These results support a rational strategy of combination of FGFR1 and GLI inhibitors for treatment of FGFR1-amplified lung cancers, especially LSCC. PMID- 26936996 TI - The Hippocampus Contributes to Allocentric Spatial Memory through Coherent Scene Representations. PMID- 26936994 TI - Somatostatin receptor expression in small cell lung cancer as a prognostic marker and a target for peptide receptor radionuclide therapy. AB - Despite initial responsiveness to both chemotherapy and radiotherapy, small cell lung cancer (SCLC) commonly relapses within months. Although neuroendocrine characteristics may be difficult to demonstrate in individual cases, a relevant expression of somatostatin receptors (SSTR) on the cell surface has been described. We aimed to evaluate the prognostic value of SSTR-expression in advanced SCLC. We further examined pre-requisites for successful peptide receptor radionuclide therapy (PRRT). 21 patients with extensive stage SCLC were enrolled. All patients underwent positron emission tomography/computed tomography (PET/CT) with 68Ga-DOTATATE to select patients for SSTR-directed therapy. PET scans were visually and semi-quantitatively assessed and compared to SSTR2a and SSTR5 expression in biopsy samples. Peak standardized uptake values (SUVpeak) of tumors as well as tumor-to-liver ratios were correlated to progression-free (PFS) and overall survival (OS). In 4/21 patients all SCLC lesions were PET-positive. 6/21 subjects were rated "intermediate" with the majority of lesions positive, the remaining 11/21 patients were PET-negative. PET-positivity correlated well with histologic SSTR2a, but not with SSTR5 expression. Neither PET-positivity nor SUVpeak were predictors of PFS or OS. In 4 patients with intensive SSTR2a receptor expression, PRRT was performed with one partial response and one stable disease, respectively. SSTR-expression as detected by 68Ga-DOTATATE-PET and/or histology is not predictive of PFS or OS in patients with advanced SCLC. However, in patients exhibiting sufficient tracer uptake, PRRT might be a treatment option given its low toxicity and the absence of effective alternatives. PMID- 26936997 TI - Understanding the Role of miR-33 in Brain Lipid Metabolism: Implications for Alzheimer's Disease. PMID- 26936995 TI - PDZ-binding kinase/T-LAK cell-originated protein kinase is a target of the fucoidan from brown alga Fucus evanescens in the prevention of EGF-induced neoplastic cell transformation and colon cancer growth. AB - The fucoidan with high anticancer activity was isolated from brown alga Fucus evanescens. The compound effectively prevented EGF-induced neoplastic cell transformation through inhibition of TOPK/ERK1/2/MSK 1 signaling axis. In vitro studies showed that the fucoidan attenuated mitogen-activated protein kinases downstream signaling in a colon cancer cells with different expression level of TOPK, resulting in growth inhibition. The fucoidan exerts its effects by directly interacting with TOPK kinase in vitro and ex vivo and inhibits its kinase activity. In xenograft animal model, oral administration of the fucoidan suppressed HCT 116 colon tumor growth. The phosphorylation of TOPK downstream signaling molecules in tumor tissues was also inhibited by the fucoidan. Taken together, our findings support the cancer preventive efficacy of the fucoidan through its targeting of TOPK for the prevention of neoplastic cell transformation and progression of colon carcinomas in vitro and ex vivo. PMID- 26936998 TI - Identification of Synaptotagmin 10 as Effector of NPAS4-Mediated Protection from Excitotoxic Neurodegeneration. AB - Neuronal degeneration represents a pathogenetic hallmark after different brain insults, such as ischemia and status epilepticus (SE). Excessive release of glutamate triggered by pathophysiologic synaptic activity has been put forward as key mechanism in this context. In response to pathophysiologic synaptic activity, multiple signaling cascades are activated that ultimately initiate expression of specific sets of genes, which may decide between neuronal survival versus death. Recently, a core set of genes ["activity-regulated inhibitor of death" (AID) genes] including the transcription factor (TF) NPAS4 (neuronal PAS domain protein 4) has been found to provide activity-induced protection against neuronal death caused by excitotoxic stimulation. However, the downstream targets of AID action mediating neuroprotection remained so far unknown. Here, we have identified synaptotagmin 10 (Syt10), a vesicular Ca(2+) sensor, as the first neuroprotective effector protein downstream of the TF NPAS4. The expression of Syt10 is strongly upregulated by pathophysiologic synaptic activity after kainic acid (KA) exposure and its absence renders mouse hippocampal neurons highly susceptible to excitotoxic insults. We found NPAS4 as critical for the increase in Syt10 levels and in turn the ability of NPAS4 to confer neuroprotection against KA-induced excitotoxicity to be severely diminished in Syt10 knock-out neurons. In summary, our results point to an important role for signaling of the NPAS4-Syt10 pathway in the neuronal response to strong synaptic activity as a consequence of excitotoxic insults. SIGNIFICANCE STATEMENT: Aberrant synaptic activity is observed in many neurological disorders and has been suggested as an important factor contributing to the pathophysiology. Intriguingly, pathophysiologic activity can also trigger signaling cascades mediating potentially compensatory neuroprotection against excitotoxic insult. Here, we identify a new neuroprotective signaling cascade involving the activity-induced transcriptional regulator NPAS4 and the vesicular Ca(2+)-sensor protein synaptotagmin 10 (Syt10). Syt10 is required for NPAS4 to protect hippocampal neurons against excitotoxic cell death. NPAS4 in turn controls the activity of the Syt10 gene, which is strongly induced by pathophysiologic activity. Our results uncover an entirely unexpected, novel function of Syt10 underlying the response of neurons to pathophysiologic activity and provide new therapeutic perspectives for neurological disorders. PMID- 26936999 TI - Reconstruction of Spatial Thermal Gradient Encoded in Thermosensory Neuron AFD in Caenorhabditis elegans. AB - During navigation, animals process temporal sequences of sensory inputs to evaluate the surrounding environment. Thermotaxis of Caenorhabditis elegans is a favorable sensory behavior to elucidate how navigating animals process sensory signals from the environment. Sensation and storage of temperature information by a bilaterally symmetric pair of thermosensory neurons, AFD, is essential for the animals to migrate toward the memorized temperature on a thermal gradient. However, the encoding mechanisms of the spatial environment with the temporal AFD activity during navigation remain to be elucidated. Here, we show how the AFD neuron encodes sequences of sensory inputs to perceive spatial thermal environment. We used simultaneous calcium imaging and tracking system for a freely moving animal and characterized the response property of AFD to the thermal stimulus during thermotaxis. We show that AFD neurons respond to shallow temperature increases with intermittent calcium pulses and detect temperature differences with a critical time window of 20 s, which is similar to the timescale of behavioral elements of C. elegans, such as turning. Convolution of a thermal stimulus and the identified response property successfully reconstructs AFD activity. Conversely, deconvolution of the identified response kernel and AFD activity reconstructs the shallow thermal gradient with migration trajectory, indicating that AFD activity and the migration trajectory are sufficient as the encoded signals for thermal environment. Our study demonstrates bidirectional transformation between environmental thermal information and encoded neural activity. SIGNIFICANCE STATEMENT: Deciphering how information is encoded in the nervous system is an important challenge for understanding the principles of information processing in neural circuits. During navigation behavior, animals transform spatial information to temporal patterns of neural activity. To elucidate how a sensory system achieves this transformation, we focused on a thermosensory neuron in Caenorhabditis elegans called AFD, which plays a major role in a sensory behavior. Using tracking and calcium imaging system for freely moving animals, we identified the response property of the AFD. The identified response property enabled us to reconstruct both neural activity from a temperature stimulus and a spatial thermal environment from neural activity. These results shed light on how a sensory system encodes the environment. PMID- 26937000 TI - Integration of Visual and Proprioceptive Limb Position Information in Human Posterior Parietal, Premotor, and Extrastriate Cortex. AB - The brain constructs a flexible representation of the body from multisensory information. Previous work on monkeys suggests that the posterior parietal cortex (PPC) and ventral premotor cortex (PMv) represent the position of the upper limbs based on visual and proprioceptive information. Human experiments on the rubber hand illusion implicate similar regions, but since such experiments rely on additional visuo-tactile interactions, they cannot isolate visuo-proprioceptive integration. Here, we independently manipulated the position (palm or back facing) of passive human participants' unseen arm and of a photorealistic virtual 3D arm. Functional magnetic resonance imaging (fMRI) revealed that matching visual and proprioceptive information about arm position engaged the PPC, PMv, and the body-selective extrastriate body area (EBA); activity in the PMv moreover reflected interindividual differences in congruent arm ownership. Further, the PPC, PMv, and EBA increased their coupling with the primary visual cortex during congruent visuo-proprioceptive position information. These results suggest that human PPC, PMv, and EBA evaluate visual and proprioceptive position information and, under sufficient cross-modal congruence, integrate it into a multisensory representation of the upper limb in space. SIGNIFICANCE STATEMENT: The position of our limbs in space constantly changes, yet the brain manages to represent limb position accurately by combining information from vision and proprioception. Electrophysiological recordings in monkeys have revealed neurons in the posterior parietal and premotor cortices that seem to implement and update such a multisensory limb representation, but this has been difficult to demonstrate in humans. Our fMRI experiment shows that human posterior parietal, premotor, and body-selective visual brain areas respond preferentially to a virtual arm seen in a position corresponding to one's unseen hidden arm, while increasing their communication with regions conveying visual information. These brain areas thus likely integrate visual and proprioceptive information into a flexible multisensory body representation. PMID- 26937001 TI - Neuroinflammatory Dynamics Underlie Memory Impairments after Repeated Social Defeat. AB - Repeated social defeat (RSD) is a murine stressor that recapitulates key physiological, immunological, and behavioral alterations observed in humans exposed to chronic psychosocial stress. Psychosocial stress promotes prolonged behavioral adaptations that are associated with neuroinflammatory signaling and impaired neuroplasticity. Here, we show that RSD promoted hippocampal neuroinflammatory activation that was characterized by proinflammatory gene expression and by microglia activation and monocyte trafficking that was particularly pronounced within the caudal extent of the hippocampus. Because the hippocampus is a key area involved in neuroplasticity, behavior, and cognition, we hypothesize that stress-induced neuroinflammation impairs hippocampal neurogenesis and promotes cognitive and affective behavioral deficits. We show here that RSD caused transient impairments in spatial memory recall that resolved within 28 d. In assessment of neurogenesis, the number of proliferating neural progenitor cells (NPCs) and the number of young, developing neurons were not affected initially after RSD. Nonetheless, the neuronal differentiation of NPCs that proliferated during RSD was significantly impaired when examined 10 and 28 d later. In addition, social avoidance, a measure of depressive-like behavior associated with caudal hippocampal circuitry, persisted 28 d after RSD. Treatment with minocycline during RSD prevented both microglia activation and monocyte recruitment. Inhibition of this neuroinflammatory activation in turn prevented impairments in spatial memory after RSD but did not prevent deficits in neurogenesis nor did it prevent the persistence of social avoidance behavior. These findings show that neuroinflammatory activation after psychosocial stress impairs spatial memory performance independent of deficits in neurogenesis and social avoidance. SIGNIFICANCE STATEMENT: Repeated exposure to stress alters the homeostatic environment of the brain, giving rise to various cognitive and mood disorders that impair everyday functioning and overall quality of life. The brain, previously thought of as an immune-privileged organ, is now known to communicate extensively with the peripheral immune system. This brain-body communication plays a significant role in various stress-induced inflammatory conditions, also characterized by psychological impairments. Findings from this study implicate neuroimmune activation rather than impaired neurogenesis in stress-induced cognitive deficits. This idea opens up possibilities for novel immune interventions in the treatment of cognitive and mood disturbances, while also adding to the complexity surrounding the functional implications of adult neurogenesis. PMID- 26937002 TI - Corticospinal Inputs to Primate Motoneurons Innervating the Forelimb from Two Divisions of Primary Motor Cortex and Area 3a. AB - Previous anatomical work in primates has suggested that only corticospinal axons originating in caudal primary motor cortex ("new M1") and area 3a make monosynaptic cortico-motoneuronal connections with limb motoneurons. By contrast, the more rostral "old M1" is proposed to control motoneurons disynaptically via spinal interneurons. In six macaque monkeys, we examined the effects from focal stimulation within old and new M1 and area 3a on 135 antidromically identified motoneurons projecting to the upper limb. EPSPs with segmental latency shorter than 1.2 ms were classified as definitively monosynaptic; these were seen only after stimulation within new M1 or at the new M1/3a border (incidence 6.6% and 1.3%, respectively; total n = 27). However, most responses had longer latencies. Using measures of the response facilitation after a second stimulus compared with the first, and the reduction in response latency after a third stimulus compared with the first, we classified these late responses as likely mediated by either long-latency monosynaptic (n = 108) or non-monosynaptic linkages (n = 108). Both old and new M1 generated putative long-latency monosynaptic and non-monosynaptic effects; the majority of responses from area 3a were non-monosynaptic. Both types of responses from new M1 had significantly greater amplitude than those from old M1. We suggest that slowly conducting corticospinal fibers from old M1 generate weak late monosynaptic effects in motoneurons. These may represent a stage in control of primate motoneurons by the cortex intermediate between disynaptic output via an interposed interneuron seen in nonprimates and the fast direct monosynaptic connections present in new M1. SIGNIFICANCE STATEMENT: The corticospinal tract in Old World primates makes monosynaptic connections to motoneurons; previous anatomical work suggests that these connections come only from corticospinal tract (CST) neurons in the subdivision of primary motor cortex within the central sulcus ("new M1") and area 3a. Here, we show using electrophysiology that cortico-motoneuronal connections from fast conducting CST fibers are indeed made exclusively from new M1 and its border with 3a. However, we also show that all parts of M1 and 3a have cortico-motoneuronal connections over more slowly conducting CST axons, as well as exert disynaptic effects on motoneurons via interposed interneurons. Differences between old and new M1 are thus more subtle than previously thought. PMID- 26937003 TI - A Molecular Determinant of Subtype-Specific Desensitization in Ionotropic Glutamate Receptors. AB - AMPA and NMDA receptors are glutamate-gated ion channels that mediate fast excitatory synaptic transmission throughout the nervous system. In the continual presence of glutamate, AMPA and NMDA receptors containing the GluN2A or GluN2B subunit enter into a nonconducting, desensitized state that can impact synaptic responses and glutamate-mediated excitotoxicity. The process of desensitization is dramatically different between subtypes, but the basis for these differences is unknown. We generated an extensive sequence alignment of ionotropic glutamate receptors (iGluRs) from diverse animal phyla and identified a highly conserved motif, which we termed the "hydrophobic box," located at the extracellular interface of transmembrane helices. A single position in the hydrophobic box differed between mammalian AMPA and NMDA receptors. Surprisingly, we find that an NMDAR-to-AMPAR exchange mutation at this position in the rat GluN2A or GluN2B subunit had a dramatic and highly specific effect on NMDAR desensitization, making it AMPAR-like. In contrast, a reverse exchange mutation in AMPARs had minimal effects on desensitization. These experiments highlight differences in desensitization between iGluR subtypes and the highly specific contribution of the GluN2 subunit to this process. SIGNIFICANCE STATEMENT: Rapid communication between cells in the nervous system depends on ion channels that are directly activated by neurotransmitter molecules. Here, we studied ionotropic glutamate receptors (iGluRs), which are ion channels activated by the neurotransmitter glutamate. By comparing the sequences of a vast number of iGluR proteins from diverse animal species, assisted by available structural information, we identified a highly conserved motif. We showed that a single amino acid difference in this motif between mammalian iGluR subtypes has dramatic effects on receptor function. These results have implications in both the evolution of synaptic function, as well as the role of iGluRs in health and disease. PMID- 26937004 TI - Laminar- and Target-Specific Amygdalar Inputs in Rat Primary Gustatory Cortex. AB - The primary gustatory cortex (GC) receives projections from the basolateral nucleus of the amygdala (BLA). Behavioral and electrophysiological studies demonstrated that this projection is involved in encoding the hedonic value of taste and is a source of anticipatory activity in GC. Anatomically, this projection is largest in the agranular portion of GC; however, its synaptic targets and synaptic properties are currently unknown. In vivo electrophysiological recordings report conflicting evidence about BLA afferents either selectively activating excitatory neurons or driving a compound response consistent with the activation of inhibitory circuits. Here we demonstrate that BLA afferents directly activate excitatory neurons and two distinct populations of inhibitory neurons in both superficial and deep layers of rat GC. BLA afferents recruit different proportions of excitatory and inhibitory neurons and show distinct patterns of circuit activation in the superficial and deep layers of GC. These results provide the first circuit-level analysis of BLA inputs to a sensory area. Laminar- and target-specific differences of BLA inputs likely explain the complexity of amygdalocortical interactions during sensory processing. SIGNIFICANCE STATEMENT: Projections from the basolateral nucleus of the amygdala (BLA) to the cortex convey information about the emotional value and the expectation of a sensory stimulus. Although much work has been done to establish the behavioral role of BLA inputs to sensory cortices, very little is known about the circuit organization of BLA projections. Here we provide the first in-depth analysis of connectivity and synaptic properties of the BLA input to the gustatory cortex. We show that BLA afferents activate excitatory and inhibitory circuits in a layer-specific and pattern-specific manner. Our results provide important new information about how neural circuits establishing the hedonic value of sensory stimuli and driving anticipatory behaviors are organized at the synaptic level. PMID- 26937005 TI - Prefrontal Cortex Structure Predicts Training-Induced Improvements in Multitasking Performance. AB - The ability to perform multiple, concurrent tasks efficiently is a much-desired cognitive skill, but one that remains elusive due to the brain's inherent information-processing limitations. Multitasking performance can, however, be greatly improved through cognitive training (Van Selst et al., 1999, Dux et al., 2009). Previous studies have examined how patterns of brain activity change following training (for review, see Kelly and Garavan, 2005). Here, in a large scale human behavioral and imaging study of 100 healthy adults, we tested whether multitasking training benefits, assessed using a standard dual-task paradigm, are associated with variability in brain structure. We found that the volume of the rostral part of the left dorsolateral prefrontal cortex (DLPFC) predicted an individual's response to training. Critically, this association was observed exclusively in a task-specific training group, and not in an active-training control group. Our findings reveal a link between DLPFC structure and an individual's propensity to gain from training on a task that taps the limits of cognitive control. SIGNIFICANCE STATEMENT: Cognitive "brain" training is a rapidly growing, multibillion dollar industry (Hayden, 2012) that has been touted as the panacea for a variety of disorders that result in cognitive decline. A key process targeted by such training is "cognitive control." Here, we combined an established cognitive control measure, multitasking ability, with structural brain imaging in a sample of 100 participants. Our goal was to determine whether individual differences in brain structure predict the extent to which people derive measurable benefits from a cognitive training regime. Ours is the first study to identify a structural brain marker-volume of left hemisphere dorsolateral prefrontal cortex-associated with the magnitude of multitasking performance benefits induced by training at an individual level. PMID- 26937007 TI - Slow Muscle Precursors Lay Down a Collagen XV Matrix Fingerprint to Guide Motor Axon Navigation. AB - The extracellular matrix (ECM) provides local positional information to guide motoneuron axons toward their muscle target. Collagen XV is a basement membrane component mainly expressed in skeletal muscle. We have identified two zebrafish paralogs of the human COL15A1 gene, col15a1a and col15a1b, which display distinct expression patterns. Here we show that col15a1b is expressed and deposited in the motor path ECM by slow muscle precursors also called adaxial cells. We further demonstrate that collagen XV-B deposition is both temporally and spatially regulated before motor axon extension from the spinal cord in such a way that it remains in this region after the adaxial cells have migrated toward the periphery of the myotome. Loss- and gain-of-function experiments in zebrafish embryos demonstrate that col15a1b expression and subsequent collagen XV-B deposition and organization in the motor path ECM depend on a previously undescribed two-step mechanism involving Hedgehog/Gli and unplugged/MuSK signaling pathways. In silico analysis predicts a putative Gli binding site in the col15a1b proximal promoter. Using col15a1b promoter-reporter constructs, we demonstrate that col15a1b participates in the slow muscle genetic program as a direct target of Hedgehog/Gli signaling. Loss and gain of col15a1b function provoke pathfinding errors in primary and secondary motoneuron axons both at and beyond the choice point where axon pathway selection takes place. These defects result in muscle atrophy and compromised swimming behavior, a phenotype partially rescued by injection of a smyhc1:col15a1b construct. These reveal an unexpected and novel role for collagen XV in motor axon pathfinding and neuromuscular development. SIGNIFICANCE STATEMENT: In addition to the archetypal axon guidance cues, the extracellular matrix provides local information that guides motor axons from the spinal cord to their muscle targets. Many of the proteins involved are unknown. Using the zebrafish model, we identified an unexpected role of the extracellular matrix collagen XV in motor axon pathfinding. We show that the synthesis of collagen XV-B by slow muscle precursors and its deposition in the common motor path are dependent on a novel two-step mechanism that determines axon decisions at a choice point during motor axonogenesis. Zebrafish and humans use common molecular cues and regulatory mechanisms for the neuromuscular system development. And as such, our study reveals COL15A1 as a candidate gene for orphan neuromuscular disorders. PMID- 26937006 TI - Interneurons Differentially Contribute to Spontaneous Network Activity in the Developing Hippocampus Dependent on Their Embryonic Lineage. AB - Spontaneously generated network activity is a hallmark of developing neural circuits, and plays an important role in the formation of synaptic connections. In the rodent hippocampus, this activity is observed in vitro as giant depolarizing potentials (GDPs) during the first postnatal week. Interneurons importantly contribute to GDPs, due to the depolarizing actions of GABA early in development. While they are highly diverse, cortical interneurons can be segregated into two distinct groups based on their embryonic lineage from either the medial or caudal ganglionic eminences (MGE and CGE). There is evidence suggesting CGE-derived interneurons are important for GDP generation; however, their contribution relative to those from the MGE has never been directly tested. Here, we optogenetically inhibited either MGE- or CGE-derived interneurons in a region-specific manner in mouse neonatal hippocampus in vitro. In CA1, where interneurons are the primary source of recurrent excitation, we found that those from the MGE strongly and preferentially contributed to GDP generation. Furthermore, in dual whole-cell patch recordings in neonatal CA1, MGE interneurons formed synaptic connections to and from neighboring pyramidal cells at a much higher rate than those from the CGE. These MGE interneurons were commonly perisomatic targeting, in contrast to those from the CGE, which were dendrite targeting. Finally, inhibiting MGE interneurons in CA1 suppressed GDPs in CA3 and vice versa; conversely, they could also trigger GDPs in CA1 that propagated to CA3 and vice versa. Our data demonstrate a key role for MGE-derived interneurons in both generating and coordinating GDPs across the hippocampus. SIGNIFICANCE STATEMENT: During nervous system development, immature circuits internally generate rhythmic patterns of electrical activity that promote the establishment of synaptic connections. Immature interneurons are excitatory rather than inhibitory and actively contribute to the generation of these spontaneous network events, referred to as giant depolarizing potentials (GDPs) in the hippocampus. Interneurons can be generally separated into two distinct groups based on their origin in the embryo from the medial or caudal ganglionic eminences (MGE and CGE). Here we show that MGE interneurons play a dominant role in generating GDPs compared with their CGE counterparts. They accomplish this due to their high synaptic connectivity within the local circuitry. Finally, they can control network activity across large regions of the developing hippocampus. PMID- 26937008 TI - 17beta-Estradiol Acutely Potentiates Glutamatergic Synaptic Transmission in the Hippocampus through Distinct Mechanisms in Males and Females. AB - Estradiol (E2) acutely potentiates glutamatergic synaptic transmission in the hippocampus of both male and female rats. Here, we investigated whether E2 induced synaptic potentiation occurs via presynaptic and/or postsynaptic mechanisms and which estrogen receptors (ERs) mediate E2's effects in each sex. Whole-cell voltage-clamp recordings of mEPSCs in CA1 pyramidal neurons showed that E2 increases both mEPSC frequency and amplitude within minutes, but often in different cells. This indicated that both presynaptic and postsynaptic mechanisms are involved, but that they occur largely at different synapses. Two-photon (2p) glutamate uncaging at individual dendritic spines showed that E2 increases the amplitude of uncaging-evoked EPSCs (2pEPSCs) and calcium transients (2pCaTs) at a subset of spines on a dendrite, demonstrating synapse specificity of E2's postsynaptic effects. All of these results were essentially the same in males and females. However, additional experiments using ER-selective agonists indicated sex differences in the mechanisms underlying E2-induced potentiation. In males, an ERbeta agonist mimicked the postsynaptic effects of E2 to increase mEPSC, 2pEPSC, and 2pCaT amplitude, whereas in females, these effects were mimicked by an agonist of G protein-coupled ER-1. The presynaptic effect of E2, increased mEPSC frequency, was mimicked by an ERalpha agonist in males, whereas in females, an ERbeta agonist increased mEPSC frequency. Thus, E2 acutely potentiates glutamatergic synapses similarly in both sexes, but distinct ER subtypes mediate the presynaptic and postsynaptic aspects of potentiation in each sex. This indicates a latent sex difference in which different molecular mechanisms converge to the same functional endpoint in males versus females. SIGNIFICANCE STATEMENT: Some sex differences in the brain may be latent differences, in which the same functional endpoint is achieved through distinct underlying mechanisms in males versus females. Here we report a latent sex difference in molecular regulation of excitatory synapses in the hippocampus. The steroid 17beta estradiol is known to acutely potentiate glutamatergic synaptic transmission in both sexes. We find that this occurs through a combination of increased presynaptic glutamate release probability and increased postsynaptic sensitivity to glutamate in both sexes, but that distinct estrogen receptor subtypes underlie each aspect of potentiation in each sex. These results indicate that therapeutics targeting a specific estrogen receptor subtype or its downstream signaling would likely affect synaptic transmission differently in the hippocampus of each sex. PMID- 26937009 TI - Loss of Ptf1a Leads to a Widespread Cell-Fate Misspecification in the Brainstem, Affecting the Development of Somatosensory and Viscerosensory Nuclei. AB - The brainstem contains diverse neuronal populations that regulate a wide range of processes vital to the organism. Proper cell-fate specification decisions are critical to achieve neuronal diversity in the CNS, but the mechanisms regulating cell-fate specification in the developing brainstem are poorly understood. Previously, it has been shown that basic helix-loop-helix transcription factor Ptf1a is required for the differentiation and survival of neurons of the inferior olivary and cochlear brainstem nuclei, which contribute to motor coordination and sound processing, respectively. In this study, we show that the loss of Ptf1a compromises the development of the nucleus of the solitary tract, which processes viscerosensory information, and the spinal and principal trigeminal nuclei, which integrate somatosensory information of the face. Combining genetic fate-mapping, birth-dating, and gene expression studies, we found that at least a subset of brainstem abnormalities in Ptf1a(-/-) mice are mediated by a dramatic cell-fate misspecification in rhombomeres 2-7, which results in the production of supernumerary viscerosensory and somatosensory neurons of the Lmx1b lineage at the expense of Pax2(+) GABAergic viscerosensory and somatosensory neurons, and inferior olivary neurons. Our data identify Ptf1a as a major regulator of cell fate specification decisions in the developing brainstem, and as a previously unrecognized developmental regulator of both viscerosensory and somatosensory brainstem nuclei. SIGNIFICANCE STATEMENT: Cell-fate specification decisions are critical for normal CNS development. Although extensively studied in the cerebellum and spinal cord, the mechanisms mediating cell-fate decisions in the brainstem, which regulates a wide range of processes vital to the organism, remain largely unknown. Here we identified mouse Ptf1a as a novel regulator of cell-fate decisions during both early and late brainstem neurogenesis, which are critical for proper development of several major classes of brainstem cells, including neurons of the somatosensory and viscerosensory nuclei. Since loss-of function PTF1A mutations were described in human patients, we suggest Ptf1a dependent cell-fate misspecification as a novel mechanism of human brainstem pathology. PMID- 26937010 TI - Impaired Serotonergic Brainstem Function during and after Seizures. AB - Impaired breathing, cardiac function, and arousal during and after seizures are important causes of morbidity and mortality. Previous work suggests that these changes are associated with depressed brainstem function in the ictal and post ictal periods. Lower brainstem serotonergic systems are postulated to play an important role in cardiorespiratory changes during and after seizures, whereas upper brainstem serotonergic and other systems regulate arousal. However, direct demonstration of seizure-associated neuronal activity changes in brainstem serotonergic regions has been lacking. Here, we performed multiunit and single unit recordings from medullary raphe and midbrain dorsal raphe nuclei in an established rat seizure model while measuring changes in breathing rate and depth as well as heart rate. Serotonergic neurons were identified by immunohistochemistry. Respiratory rate, tidal volume, and minute ventilation were all significantly decreased during and after seizures in this model. We found that population firing of neurons in the medullary and midbrain raphe on multiunit recordings was significantly decreased during the ictal and post-ictal periods. Single-unit recordings from identified serotonergic neurons in the medullary raphe revealed highly consistently decreased firing during and after seizures. In contrast, firing of midbrain raphe serotonergic neurons was more variable, with a mixture of increases and decreases. The markedly suppressed firing of medullary serotonergic neurons supports their possible role in simultaneously impaired cardiorespiratory function in seizures. Decreased arousal likely arises from depressed population activity of several neuronal pools in the upper brainstem and forebrain. These findings have important implications for preventing morbidity and mortality in people living with epilepsy. SIGNIFICANCE STATEMENT: Seizures often cause impaired breathing, cardiac dysfunction, and loss of consciousness. The brainstem and, specifically, brainstem serotonin neurons are thought to play an important role in controlling breathing, cardiac function, and arousal. We used an established rat seizure model to study the overall neuronal activity in the brainstem as well as firing of specific serotonin neurons while measuring cardiorespiratory function. Our results demonstrated overall decreases in brainstem neuronal activity and marked downregulation of lower brainstem serotonin neuronal firing in association with decreased breathing and heart rate during and after seizures. These findings point the way toward new treatments to augment brainstem function and serotonin, aiming to prevent seizure complications and reduce morbidity and mortality in people living with epilepsy. PMID- 26937013 TI - Brain Regions Influencing Implicit Violent Attitudes: A Lesion-Mapping Study. AB - Increased aggression is common after traumatic brain injuries and may persist after cognitive recovery. Maladaptive aggression and violence are associated with dysfunction in the prefrontal and temporal cortex, but such dysfunctional behaviors are typically measured by explicit scales and history. However, it is well known that answers on explicit scales on sensitive topics--such as aggressive thoughts and behaviors--may not reveal true tendencies. Here, we investigated the neural basis of implicit attitudes toward aggression in humans using a modified version of the Implicit Association Task (IAT) with a unique sample of 112 Vietnam War veterans who suffered penetrating brain injury and 33 healthy controls who also served in combat in Vietnam but had no history of brain injury. We hypothesized that dorsolateral prefrontal cortex (dlPFC) lesions, due to the crucial role of the dlPFC in response inhibition, could influence performance on the IAT. In addition, we investigated the causal contribution of specific brain areas to implicit attitudes toward violence. We found a more positive implicit attitude toward aggression among individuals with lesions to the dlPFC and inferior posterior temporal cortex (ipTC). Furthermore, executive functions were critically involved in regulating implicit attitudes toward violence and aggression. Our findings complement existing evidence on the neural basis of explicit aggression centered on the ventromedial prefrontal cortex. These findings highlight that dlPFC and ipTC play a causal role in modulating implicit attitudes about violence and are crucially involved in the pathogenesis of aggressive behavior. SIGNIFICANCE STATEMENT: Maladaptive aggression and violence can lead to interpersonal conflict and criminal behavior. Surprisingly little is known about implicit attitudes toward violence and aggression. Here, we used a range of techniques, including voxel-based lesion-symptom mapping, to examine the causal role of brain structures underpinning implicit attitudes toward aggression in a unique sample of combat veterans with traumatic brain injury. We found that damage to the dorsolateral prefrontal cortex (dlPFC) led to a more positive implicit attitude toward violence that under most normal situations would be considered inappropriate. These results suggest that treatments aimed at increasing cognitive control using cognitive behavioral therapies dependent on the intact dlPFC could treat aggressive and violent behavior. PMID- 26937012 TI - Effects of Signal-to-Noise Ratio on Auditory Cortical Frequency Processing. AB - The neural mechanisms that support the robust processing of acoustic signals in the presence of background noise in the auditory system remain largely unresolved. Psychophysical experiments have shown that signal detection is influenced by the signal-to-noise ratio (SNR) and the overall stimulus level, but this relationship has not been fully characterized. We evaluated the neural representation of frequency in rat primary auditory cortex by constructing tonal frequency response areas (FRAs) in primary auditory cortex for different SNRs, tone levels, and noise levels. We show that response strength and selectivity for frequency and sound level depend on interactions between SNRs and tone levels. At low SNRs, jointly increasing the tone and noise levels reduced firing rates and narrowed FRA bandwidths; at higher SNRs, however, increasing the tone and noise levels increased firing rates and expanded bandwidths, as is usually seen for FRAs obtained without background noise. These changes in frequency and intensity tuning decreased tone level and tone frequency discriminability at low SNRs. By contrast, neither response onset latencies nor noise-driven steady-state firing rates meaningfully interacted with SNRs or overall sound levels. Speech detection performance in humans was also shown to depend on the interaction between overall sound level and SNR. Together, these results indicate that signal processing difficulties imposed by high noise levels are quite general and suggest that the neurophysiological changes we see for simple sounds generalize to more complex stimuli. SIGNIFICANCE STATEMENT: Effective processing of sounds in background noise is an important feature of the mammalian auditory system and a necessary feature for successful hearing in many listening conditions. Even mild hearing loss strongly affects this ability in humans, seriously degrading the ability to communicate. The mechanisms involved in achieving high performance in background noise are not well understood. We investigated the effects of SNR and overall stimulus level on the frequency tuning of neurons in rat primary auditory cortex. We found that the effects of noise on frequency selectivity are not determined solely by the SNR but depend also on the levels of the foreground tones and background noise. These observations can lead to improvement in therapeutic approaches for hearing-impaired patients. PMID- 26937011 TI - Essential Roles for ARID1B in Dendritic Arborization and Spine Morphology of Developing Pyramidal Neurons. AB - De novo truncating mutations in ARID1B, a chromatin-remodeling gene, cause Coffin Siris syndrome, a developmental disorder characterized by intellectual disability and speech impairment; however, how the genetic elimination leads to cognitive dysfunction remains unknown. Thus, we investigated the neural functions of ARID1B during brain development. Here, we show that ARID1B regulates dendritic differentiation in the developing mouse brain. We knocked down ARID1B expression in mouse pyramidal neurons using in utero gene delivery methodologies. ARID1B knockdown suppressed dendritic arborization of cortical and hippocampal pyramidal neurons in mice. The abnormal development of dendrites accompanied a decrease in dendritic outgrowth into layer I. Furthermore, knockdown of ARID1B resulted in aberrant dendritic spines and synaptic transmission. Finally, ARID1B deficiency led to altered expression of c-Fos and Arc, and overexpression of these factors rescued abnormal differentiation induced by ARID1B knockdown. Our results demonstrate a novel role for ARID1B in neuronal differentiation and provide new insights into the origin of cognitive dysfunction associated with developmental intellectual disability. SIGNIFICANCE STATEMENT: Haploinsufficiency of ARID1B, a component of chromatin remodeling complex, causes intellectual disability. However, the role of ARID1B in brain development is unknown. Here, we demonstrate that ARID1B is required for neuronal differentiation in the developing brain, such as in dendritic arborization and synapse formation. Our findings suggest that ARID1B plays a critical role in the establishment of cognitive circuitry by regulating dendritic complexity. Thus, ARID1B deficiency may cause intellectual disability via abnormal brain wiring induced by the defective differentiation of cortical neurons. PMID- 26937014 TI - Hydroxymethylation of microRNA-365-3p Regulates Nociceptive Behaviors via Kcnh2. AB - DNA 5-hydroxylmethylcytosine (5hmC) catalyzed by ten-eleven translocation methylcytosine dioxygenase (TET) occurs abundantly in neurons of mammals. However, the in vivo causal link between TET dysregulation and nociceptive modulation has not been established. Here, we found that spinal TET1 and TET3 were significantly increased in the model of formalin-induced acute inflammatory pain, which was accompanied with the augment of genome-wide 5hmC content in spinal cord. Knockdown of spinal TET1 or TET3 alleviated the formalin-induced nociceptive behavior and overexpression of spinal TET1 or TET3 in naive mice produced pain-like behavior as evidenced by decreased thermal pain threshold. Furthermore, we found that TET1 or TET3 regulated the nociceptive behavior by targeting microRNA-365-3p (miR-365-3p). Formalin increased 5hmC in the miR-365-3p promoter, which was inhibited by knockdown of TET1 or TET3 and mimicked by overexpression of TET1 or TET3 in naive mice. Nociceptive behavior induced by formalin or overexpression of spinal TET1 or TET3 could be prevented by downregulation of miR-365-3p, and mimicked by overexpression of spinal miR-365 3p. Finally, we demonstrated that a potassium channel, voltage-gated eag-related subfamily H member 2 (Kcnh2), validated as a target of miR-365-3p, played a critical role in nociceptive modulation by spinal TET or miR-365-3p. Together, we concluded that TET-mediated hydroxymethylation of miR-365-3p regulates nociceptive behavior via Kcnh2. SIGNIFICANCE STATEMENT: Mounting evidence indicates that epigenetic modifications in the nociceptive pathway contribute to pain processes and analgesia response. Here, we found that the increase of 5hmC content mediated by TET1 or TET3 in miR-365-3p promoter in the spinal cord is involved in nociceptive modulation through targeting a potassium channel, Kcnh2. Our study reveals a new epigenetic mechanism underlying nociceptive information processing, which may be a novel target for development of antinociceptive drugs. PMID- 26937015 TI - Connectivity Profiles Reveal a Transition Subarea in the Parahippocampal Region That Integrates the Anterior Temporal-Posterior Medial Systems. AB - Traditional anatomical studies of the parahippocampal region (PHR) defined the lateral portion into two subregions, the perirhinal (PRC) and parahippocampal (PHC) cortices. Based on this organization, several models suggested that the PRC and the PHC play different roles in memory through connections with different memory-related brain networks. To identify the key components of the human PHR, we used a well accepted connection-based parcellation method on two independent datasets. Our parcellation divided the PRC and PHC into three subregions, specifically, the rostral PRC, caudal PRC (PRCc), and PHC. The connectivity profile for each subregion showed that the rostral PRC was connected to the anterior temporal (AT) system and the PHC was connected to the posterior medial (PM) system. The transition area (PRCc) integrated the AT-PM systems. These results suggest that the lateral PHR not only contains functionally segregated subregions, but also contains a functionally integrated subregion. SIGNIFICANCE STATEMENT: We redefined the cartography of the human parahippocampal region (PHR) and identified a transition subarea based on distinct anatomical and functional connectivity profiles. This well defined anatomical organization of the PHR is necessary for expanding our understanding and studying the functional relevance of its subregions in recognition memory. We found that the transition subregion [caudal perirhinal cortex (PRCc)] is a functionally integrated subregion that integrates the anterior temporal (AT)-posterior medial (PM) systems. In addition, we found that the core components of the AT and PM systems connect with the PHR in the rostral PRC and parahippocampal cortex (PHC), respectively, rather than connecting with the traditional, larger, and thus less concise PRC and PHC areas. This may lead to new insights into the human memory system and related neurodegenerative diseases. PMID- 26937016 TI - Application of q-Space Diffusion MRI for the Visualization of White Matter. AB - White matter abnormalities in the CNS have been reported recently in various neurological and psychiatric disorders. Quantitation of non-Gaussianity for water diffusion by q-space diffusional MRI (QSI) renders biological diffusion barriers such as myelin sheaths; however, the time-consuming nature of this method hinders its clinical application. In the current study, we aimed to refine QSI protocols to enable their clinical application and to visualize myelin signals in a clinical setting. For this purpose, animal studies were first performed to optimize the acquisition protocol of a non-Gaussian QSI metric. The heat map of standardized kurtosis values derived from optimal QSI (myelin map) was then created. Histological validation of the myelin map was performed in myelin deficient mice and in a nonhuman primate by monitoring its variation during demyelination and remyelination after chemical spinal cord injury. The results demonstrated that it was sensitive enough to depict dysmyelination, demyelination, and remyelination in animal models. Finally, its utility in clinical practice was assessed by a pilot clinical study in a selected group of patients with multiple sclerosis (MS). The human myelin map could be obtained within 10 min with a 3 T MR scanner. Use of the myelin map was practical for visualizing white matter and it sensitively detected reappearance of myelin signals after demyelination, possibly reflecting remyelination in MS patients. Our results together suggest that the myelin map, a kurtosis-related heat map obtainable with time-saving QSI, may be a novel and clinically useful means of visualizing myelin in the human CNS. SIGNIFICANCE STATEMENT: Myelin abnormalities in the CNS have been gaining increasing attention in various neurological and psychiatric diseases. However, appropriate methods with which to monitor CNS myelin in daily clinical practice have been lacking. In the current study, we introduced a novel MRI modality that produces the "myelin map." The myelin map accurately depicted myelin status in mice and nonhuman primates and in a pilot clinical study of multiple sclerosis patients, suggesting that it is useful in detecting possibly remyelinated lesions. A myelin map of the human brain could be obtained in <10 min using a 3 T scanner and it therefore promises to be a powerful tool for researchers and clinicians examining myelin-related diseases. PMID- 26937018 TI - Flexion Reflex Can Interrupt and Reset the Swimming Rhythm. AB - The spinal cord can generate the hip flexor nerve activity underlying leg withdrawal (flexion reflex) and the rhythmic, alternating hip flexor and extensor activities underlying locomotion and scratching, even in the absence of brain inputs and movement-related sensory feedback. It has been hypothesized that a common set of spinal interneurons mediates flexion reflex and the flexion components of locomotion and scratching. Leg cutaneous stimuli that evoke flexion reflex can alter the timing of (i.e., reset) cat walking and turtle scratching rhythms; in addition, reflex responses to leg cutaneous stimuli can be modified during cat and human walking and turtle scratching. Both of these effects depend on the phase (flexion or extension) of the rhythm in which the stimuli occur. However, similar interactions between leg flexion reflex and swimming have not been reported. We show here that a tap to the foot interrupted and reset the rhythm of forward swimming in spinal, immobilized turtles if the tap occurred during the swim hip extensor phase. In addition, the hip flexor nerve response to an electrical foot stimulus was reduced or eliminated during the swim hip extensor phase. These two phase-dependent effects of flexion reflex on the swim rhythm and vice versa together demonstrate that the flexion reflex spinal circuit shares key components with or has strong interactions with the swimming spinal network, as has been shown previously for cat walking and turtle scratching. Therefore, leg flexion reflex circuits likely share key spinal interneurons with locomotion and scratching networks across limbed vertebrates generally. SIGNIFICANCE STATEMENT: The spinal cord can generate leg withdrawal (flexion reflex), locomotion, and scratching in limbed vertebrates. It has been hypothesized that there is a common set of spinal cord neurons that produce hip flexion during flexion reflex, locomotion, and scratching based on evidence from studies of cat and human walking and turtle scratching. We show here that flexion reflex and swimming also share key spinal cord components based on evidence from turtles. Foot stimulation can reset the timing of the swimming rhythm and the response to each foot stimulation can itself be altered by the swim rhythm. Collectively, these studies suggest that spinal cord neuronal networks underlying flexion reflex, multiple forms of locomotion, and scratching share key components. PMID- 26937017 TI - Activation of Alpha 7 Cholinergic Nicotinic Receptors Reduce Blood-Brain Barrier Permeability following Experimental Traumatic Brain Injury. AB - Traumatic brain injury (TBI) is a major human health concern that has the greatest impact on young men and women. The breakdown of the blood-brain barrier (BBB) is an important pathological consequence of TBI that initiates secondary processes, including infiltration of inflammatory cells, which can exacerbate brain inflammation and contribute to poor outcome. While the role of inflammation within the injured brain has been examined in some detail, the contribution of peripheral/systemic inflammation to TBI pathophysiology is largely unknown. Recent studies have implicated vagus nerve regulation of splenic cholinergic nicotinic acetylcholine receptor alpha7 (nAChRa7) signaling in the regulation of systemic inflammation. However, it is not known whether this mechanism plays a role in TBI-triggered inflammation and BBB breakdown. Following TBI, we observed that plasma TNF-alpha and IL-1beta levels, as well as BBB permeability, were significantly increased in nAChRa7 null mice (Chrna7(-/-)) relative to wild-type mice. The administration of exogenous IL-1beta and TNF-alpha to brain-injured animals worsened Evans Blue dye extravasation, suggesting that systemic inflammation contributes to TBI-triggered BBB permeability. Systemic administration of the nAChRa7 agonist PNU-282987 or the positive allosteric modulator PNU-120596 significantly attenuated TBI-triggered BBB compromise. Supporting a role for splenic nAChRa7 receptors, we demonstrate that splenic injection of the nicotinic receptor blocker alpha-bungarotoxin increased BBB permeability in brain-injured rats, while PNU-282987 injection decreased such permeability. These effects were not seen when alpha-bungarotoxin or PNU-282987 were administered to splenectomized, brain-injured rats. Together, these findings support the short-term use of nAChRa7-activating agents as a strategy to reduce TBI-triggered BBB permeability. SIGNIFICANCE STATEMENT: Breakdown of the blood brain barrier (BBB) in response to traumatic brain injury (TBI) allows for the accumulation of circulating fluids and proinflammatory cells in the injured brain. These processes can exacerbate TBI pathology and outcome. While the role of inflammation in the injured tissue has been examined in some detail, the contribution of peripheral inflammation in BBB breakdown and ensuing pathology has not been well defined. We present experimental evidence to indicate that the stimulation of nicotinic acetylcholine alpha7 receptors (nAChRa7s) can reduce peripheral inflammation and BBB breakdown after TBI. These results suggest that activators of nAChRa7 may have therapeutic utility for the treatment of TBI. PMID- 26937019 TI - Requirement for Microglia for the Maintenance of Synaptic Function and Integrity in the Mature Retina. AB - Microglia, the principal resident immune cell of the CNS, exert significant influence on neurons during development and in pathological situations. However, if and how microglia contribute to normal neuronal function in the mature uninjured CNS is not well understood. We used the model of the adult mouse retina, a part of the CNS amenable to structural and functional analysis, to investigate the constitutive role of microglia by depleting microglia from the retina in a sustained manner using genetic methods. We discovered that microglia are not acutely required for the maintenance of adult retinal architecture, the survival of retinal neurons, or the laminar organization of their dendritic and axonal compartments. However, sustained microglial depletion results in the degeneration of photoreceptor synapses in the outer plexiform layer, leading to a progressive functional deterioration in retinal light responses. Our results demonstrate that microglia are constitutively required for the maintenance of synaptic structure in the adult retina and for synaptic transmission underlying normal visual function. Our findings on constitutive microglial function are relevant in understanding microglial contributions to pathology and in the consideration of therapeutic interventions that reduce or perturb constitutive microglial function. SIGNIFICANCE STATEMENT: Microglia, the principal resident immune cell population in the CNS, has been implicated in diseases in the brain and retina. However, how they contribute to the everyday function of the CNS is unclear. Using the model of the adult mouse retina, we examined the constitutive role of microglia by depleting microglia from the retina. We found that in the absence of microglia, retinal neurons did not undergo overt cell death or become structurally disorganized in their processes. However, connections between neurons called synapses begin to break down, leading to a decreased ability of the retina to transmit light responses. Our results indicate that retinal microglia contribute constitutively to the maintenance of synapses underlying healthy vision. PMID- 26937020 TI - Combined Treatment with Morphine and Delta9-Tetrahydrocannabinol in Rhesus Monkeys: Antinociceptive Tolerance and Withdrawal. AB - Opioid receptor agonists are effective for treating pain; however, tolerance and dependence can develop with repeated use. Combining opioids with cannabinoids can enhance their analgesic potency, although it is less clear whether combined treatment alters opioid tolerance and dependence. In this study, four monkeys received 3.2 mg/kg morphine alone or in combination with 1 mg/kg Delta(9) tetrahydrocannabinol (THC) twice daily; the antinociceptive effects (warm water tail withdrawal) of morphine, the cannabinoid receptor agonists WIN 55,212 [(R) (1)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin 6-yl]-1-naphthalenylmethanone mesylate] and CP 55,940 (2-[(1R,2R,5R)-5-hydroxy-2 (3-hydroxypropyl) cyclohexyl]-5-(2-methyloctan-2-yl)phenol), and the kappa opioid receptor agonist U-50,488 (trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl) cyclohexyl]benzenacetamide methanesulfonate) were examined before, during, and after treatment. To determine whether concurrent THC treatment altered morphine dependence, behavioral signs indicative of withdrawal were monitored when treatment was discontinued. Before treatment, each drug increased tail withdrawal latency to 20 seconds (maximum possible effect). During treatment, latencies did not reach 20 seconds for morphine or the cannabinoids up to doses 3- to 10-fold larger than those that were fully effective before treatment. Rightward and downward shifts in antinociceptive dose-effect curves were greater for monkeys receiving the morphine/THC combination than monkeys receiving morphine alone. When treatment was discontinued, heart rate and directly observable withdrawal signs increased, although they were generally similar in monkeys that received morphine alone or with THC. These results demonstrated that antinociceptive tolerance was greater during treatment with the combination, and although treatment conditions were sufficient to result in the development of dependence on morphine, withdrawal was not markedly altered by concurrent treatment with THC. Thus, THC can enhance some (antinociception, tolerance) but not all (dependence) effects of morphine. PMID- 26937022 TI - Angled shots onto body armour using 9 mm ammunition: the effect on potential blunt injury. AB - INTRODUCTION: Some military specialists wear body armour that is more similar to police armour and provides protection from ammunition fired from pistols. During ballistic testing, these armours are mounted on a standardised type of modelling clay and the back face signature (BFS; depth of depression) formed as a result of the non-perforating impact event on to the armour is measured. This study investigated the effect of impact angle on the BFS and on the deformation of the bullet. METHODS: Two commonly worn types of armour (HG1/A+KR1 and HG1+KR1) were considered that provide protection from pistol ammunition and sharp weapons. Armours were tested against two types of pistol ammunition (9 mm full metal jacket and 9 mm hollow point) at eight different impact angles (0 degrees , 15 degrees , 30 degrees , 45 degrees , 60 degrees , 70 degrees , 75 degrees and 80 degrees ). RESULTS: Increased impact angles resulted in smaller BFSs. Impact angle also affected whether bullets were retained in the armour; as the impact angle increased, the probability of a round exiting the side of the armour increased. Bullet deformation was affected by impact angle. CONCLUSIONS: Understanding the deformation of bullets may assist with recreating a shooting incident and interpreting forensic evidence. PMID- 26937021 TI - Identification of Tazarotenic Acid as the First Xenobiotic Substrate of Human Retinoic Acid Hydroxylase CYP26A1 and CYP26B1. AB - Cytochrome P450 (CYP) 26A1 and 26B1 are heme-containing enzymes responsible for metabolizing all-trans retinoic acid (at-RA). No crystal structures have been solved, and therefore homology models that provide structural information are extremely valuable for the development of inhibitors of cytochrome P450 family 26 (CYP26). The objectives of this study were to use homology models of CYP26A1 and CYP26B1 to characterize substrate binding characteristics, to compare structural aspects of their active sites, and to support the role of CYP26 in the metabolism of xenobiotics. Each model was verified by dockingat-RA in the active site and comparing the results to known metabolic profiles ofat-RA. The models were then used to predict the metabolic sites of tazarotenic acid with results verified by in vitro metabolite identification experiments. The CYP26A1 and CYP26B1 homology models predicted that the benzothiopyranyl moiety of tazarotenic acid would be oriented toward the heme of each enzyme and suggested that tazarotenic acid would be a substrate of CYP26A1 and CYP26B1. Metabolite identification experiments indicated that CYP26A1 and CYP26B1 oxidatively metabolized tazarotenic acid on the predicted moiety, with in vitro rates of metabolite formation by CYP26A1 and CYP26B1 being the highest across a panel of enzymes. Molecular analysis of the active sites estimated the active-site volumes of CYP26A1 and CYP26B1 to be 918 A(3)and 977 A(3), respectively. Overall, the homology models presented herein describe the enzyme characteristics leading to the metabolism of tazarotenic acid by CYP26A1 and CYP26B1 and support a potential role for the CYP26 enzymes in the metabolism of xenobiotics. PMID- 26937023 TI - Tissue engineering through the UK Defence Medical Services: lessons learned from the Armed Forces Institute of Regenerative Medicine (AFIRM). PMID- 26937024 TI - Combined effects of alpha particles and depleted uranium on Zebrafish (Danio rerio) embryos. AB - The combined effects of low-dose or high-dose alpha particles and depleted uranium (DU) in Zebrafish (Danio rerio) embryos were studied. Three schemes were examined-(i) [ILUL]: 0.44 mGy alpha-particle dose + 10 ug/l DU exposure, (ii) [IHUH]: 4.4 mGy alpha-particle dose + 100 ug/l DU exposure and (iii) [IHUL]: 4.4 mGy alpha-particle dose + 10 ug/l DU exposure-in which Zebrafish embryos were irradiated with alpha particles at 5 h post fertilization (hpf) and/or exposed to uranium at 5-6 hpf. The results were also compared with our previous work, which studied the effects of [ILUH]: 0.44 mGy alpha-particle dose + 100 ug/l DU exposure. When the Zebrafish embryos developed to 24 hpf, the apoptotic signals in the entire embryos, used as the biological endpoint for this study, were quantified. Our results showed that [ILUL] and [IHUL] led to antagonistic effects, whereas [IHUH] led to an additive effect. The effect found for the previously studied case of [ILUH] was difficult to define because it was synergistic with reference to the 100 ug/l DU exposure, but it was antagonistic with reference to the 0.44 mGy alpha-particle dose. All the findings regarding the four different schemes showed that the combined effects critically depended on the dose response to each individual stressor. We also qualitatively explained these findings in terms of promotion of early death of cells predisposed to spontaneous transformation by alpha particles, interacting with the delay in cell death resulting from various concentrations of DU exposure. PMID- 26937026 TI - Hepatitis C Virus Exploitation of Processing Bodies. AB - During infection, positive-strand RNA viruses subvert cellular machinery involved in RNA metabolism to translate viral proteins and replicate viral genomes to avoid or disable the host defense mechanisms. Cytoplasmic RNA granules modulate the stabilities of cellular and viral RNAs. Understanding how hepatitis C virus and other flaviviruses interact with the host machinery required for protein synthesis, localization, and degradation of mRNAs is important for elucidating how these processes occur in both virus-infected and uninfected cells. PMID- 26937025 TI - The Vaccinia Virus H3 Envelope Protein, a Major Target of Neutralizing Antibodies, Exhibits a Glycosyltransferase Fold and Binds UDP-Glucose. AB - The highly conserved H3 poxvirus protein is a major target of the human antibody response against poxviruses and is likely a key contributor to protection against infection. Here, we present the crystal structure of H3 from vaccinia virus at a 1.9-A resolution. H3 looks like a glycosyltransferase, a family of enzymes that transfer carbohydrate molecules to a variety of acceptor substrates. Like glycosyltransferases, H3 binds UDP-glucose, as shown by saturation transfer difference (STD) nuclear magnetic resonance (NMR) spectroscopy, and this binding requires Mg(2+) Mutation of the glycosyltransferase-like metal ion binding motif in H3 greatly diminished its binding to UDP-glucose. We found by flow cytometry that H3 binds to the surface of human cells but does not bind well to cells that are deficient in surface glycosaminoglycans. STD NMR experiments using a heparin sulfate decasaccharide confirmed that H3 binds heparin sulfate. We propose that a surface of H3 with an excess positive charge may be the binding site for heparin. Heparin binding and glycosyltransferase activity may be involved in the function of H3 in the poxvirus life cycle. IMPORTANCE: Poxviruses are under intense research because of bioterrorism concerns, zoonotic infections, and the side effects of existing smallpox vaccines. The smallpox vaccine using vaccinia virus has been highly successful, but it is still unclear why the vaccine is so effective. Studying the antigens that the immune system recognizes may allow a better understanding of how the vaccine elicits immunity and how improved vaccines can be developed. Poxvirus protein H3 is a major target of the immune system. The H3 crystal structure shows that it has a glycosyltransferase protein fold. We demonstrate that H3 binds the sugar nucleotide UDP-glucose, as do glycosyltransferases. Our experiments also reveal that H3 binds cell surface molecules that are involved in the attachment of poxviruses to cells. These structural and functional studies of H3 will help in designing better vaccines and therapeutics. PMID- 26937028 TI - Dynamic Phosphorylation of VP30 Is Essential for Ebola Virus Life Cycle. AB - Ebola virus is the causative agent of a severe fever with high fatality rates in humans and nonhuman primates. The regulation of Ebola virus transcription and replication currently is not well understood. An important factor regulating viral transcription is VP30, an Ebola virus-specific transcription factor associated with the viral nucleocapsid. Previous studies revealed that the phosphorylation status of VP30 impacts viral transcription. Together with NP, L, and the polymerase cofactor VP35, nonphosphorylated VP30 supports viral transcription. Upon VP30 phosphorylation, viral transcription ceases. Phosphorylation weakens the interaction between VP30 and the polymerase cofactor VP35 and/or the viral RNA. VP30 thereby is excluded from the viral transcription complex, simultaneously leading to increased viral replication which is supported by NP, L, and VP35 alone. Here, we use an infectious virus-like particle assay and recombinant viruses to show that the dynamic phosphorylation of VP30 is critical for the cotransport of VP30 with nucleocapsids to the sites of viral RNA synthesis, where VP30 is required to initiate primary viral transcription. We further demonstrate that a single serine residue at amino acid position 29 was sufficient to render VP30 active in primary transcription and to generate a recombinant virus with characteristics comparable to those of wild-type virus. In contrast, the rescue of a recombinant virus with a single serine at position 30 in VP30 was unsuccessful. Our results indicate critical roles for phosphorylated and dephosphorylated VP30 during the viral life cycle. IMPORTANCE: The current Ebola virus outbreak in West Africa has caused more than 28,000 cases and 11,000 fatalities. Very little is known regarding the molecular mechanisms of how the Ebola virus transcribes and replicates its genome. Previous investigations showed that the transcriptional support activity of VP30 is activated upon VP30 dephosphorylation. The current study reveals that the situation is more complex and that primary transcription as well as the rescue of recombinant Ebola virus also requires the transient phosphorylation of VP30. VP30 encodes six N-proximal serine residues that serve as phosphorylation acceptor sites. The present study shows that the dynamic phosphorylation of serine at position 29 alone is sufficient to activate primary viral transcription. Our results indicate a series of phosphorylation/dephosphorylation events that trigger binding to and release from the nucleocapsid and transcription complex to be essential for the full activity of VP30. PMID- 26937027 TI - Combined HIV-1 Envelope Systemic and Mucosal Immunization of Lactating Rhesus Monkeys Induces a Robust Immunoglobulin A Isotype B Cell Response in Breast Milk. AB - Maternal vaccination to induce anti-HIV immune factors in breast milk is a potential intervention to prevent postnatal HIV-1 mother-to-child transmission (MTCT). We previously demonstrated that immunization of lactating rhesus monkeys with a modified vaccinia Ankara (MVA) prime/intramuscular (i.m.) protein boost regimen induced functional IgG responses in milk, while MVA prime/intranasal (i.n.) boost induced robust milk Env-specific IgA responses. Yet, recent studies have suggested that prevention of postnatal MTCT may require both Env-specific IgA and functional IgG responses in milk. Thus, to investigate whether both responses could be elicited by a combined systemic/mucosal immunization strategy, animals previously immunized with the MVA prime/i.n. boost regimen received an i.n./i.m. combined C.1086 gp120 boost. Remarkably, high-magnitude Env-specific IgA responses were observed in milk, surpassing those in plasma. Furthermore, 29% of vaccine-elicited Env-specific B cells isolated from breast milk were IgA isotype, in stark contrast to the overwhelming predominance of IgG isotype Env specific B cells in breast milk of chronically HIV-infected women. A clonal relationship was identified between Env-specific blood and breast milk B cells, suggesting trafficking of that cell population between the two compartments. Furthermore, IgA and IgG monoclonal antibodies isolated from Env-specific breast milk B cells demonstrated diverse Env epitope specificities and multiple effector functions, including tier 1 neutralization, antibody-dependent cellular cytotoxicity (ADCC), infected cell binding, and inhibition of viral attachment to epithelial cells. Thus, maternal i.n./i.m. combined immunization is a novel strategy to enhance protective Env-specific IgA in milk, which is subsequently transferred to the infant via breastfeeding. IMPORTANCE: Efforts to increase the availability of antiretroviral therapy to pregnant and breastfeeding women in resource-limited areas have proven remarkably successful at reducing HIV vertical transmission rates. However, more than 200,000 children are infected annually due to failures in therapy implementation, monitoring, and adherence, nearly half by postnatal HIV exposure via maternal breast milk. Intriguingly, in the absence of antiretroviral therapy, only 10% of breastfed infants born to HIV-infected mothers acquire the virus, suggesting the existence of naturally protective immune factors in milk. Enhancement of these protective immune factors through maternal vaccination will be a critical strategy to reduce the global pediatric AIDS epidemic. We have previously demonstrated that a high magnitude of HIV Env specific IgA in milk correlates with reduced risk of infant HIV acquisition. In this study, we describe a novel HIV vaccine regimen that induces potent IgA responses in milk and therefore could potentially protect against breast milk HIV MTCT. PMID- 26937031 TI - Coordinated Neutralization and Immune Activation by the Cytosolic Antibody Receptor TRIM21. AB - TRIM21 is a high-affinity antibody receptor uniquely expressed in the cytosol of mammalian cells. Here we summarize its role in extending antibody protection into the intracellular environment and allowing nonprofessional cells to benefit from adaptive immunity. We highlight recent work that has shed light on how TRIM21 acts as both an immune sensor and effector. We also review how TRIM21 synergizes with other innate immune receptors to promote an integrated antiviral response. PMID- 26937029 TI - PrPSc-Specific Antibody Reveals C-Terminal Conformational Differences between Prion Strains. AB - Understanding the structure of PrP(Sc) and its strain variation has been one of the major challenges in prion disease biology. To study the strain-dependent conformations of PrP(Sc), we purified proteinase-resistant PrP(Sc) (PrP(RES)) from mouse brains with three different murine-adapted scrapie strains (Chandler, 22L, and Me7) and systematically tested the accessibility of epitopes of a wide range of anti-PrP and anti-PrP(Sc) specific antibodies by indirect enzyme-linked immunosorbent assay (ELISA). We found that epitopes of most anti-PrP antibodies were hidden in the folded structure of PrP(RES), even though these epitopes are revealed with guanidine denaturation. However, reactivities to a PrP(Sc)-specific conformational C-terminal antibody showed significant differences among the three different prion strains. Our results provide evidence for strain-dependent conformational variation near the C termini of molecules within PrP(Sc) multimers. IMPORTANCE: It has long been apparent that prion strains can have different conformations near the N terminus of the PrP(Sc) protease-resistant core. Here, we show that a C-terminal conformational PrP(Sc)-specific antibody reacts differently to three murine-adapted scrapie strains. These results suggest, in turn, that conformational differences in the C terminus of PrP(Sc) also contribute to the phenotypic distinction between prion strains. PMID- 26937030 TI - The Human Cytomegalovirus UL116 Gene Encodes an Envelope Glycoprotein Forming a Complex with gH Independently from gL. AB - Human cytomegalovirus (HCMV) is a major cause of morbidity and mortality in transplant patients and is the leading viral cause of birth defects after congenital infection. HCMV infection relies on the recognition of cell-specific receptors by one of the viral envelope glycoprotein complexes. Either the gH/gL/gO or the gH/gL/UL128/UL130/UL131A (Pentamer) complex has been found to fulfill this role, accounting for HCMV entry into almost all cell types. We have studied the UL116 gene product, a putative open reading frame identified by in silico analysis and predicted to code for a secreted protein. Virus infection experiments in mammalian cells demonstrated that UL116 is expressed late in the HCMV replication cycle and is a heavily glycosylated protein that first localizes to the cellular site of virus assembly and then inserts into the virion envelope. Transient-transfection studies revealed that UL116 is efficiently transported to the plasma membrane when coexpressed with gH and that gL competes with UL116 for gH binding. Further evidence for gH/UL116 complex formation was obtained by coimmunoprecipitation experiments on both transfected and infected cells and biochemical characterization of the purified complex. In summary, our results show that the product of the UL116 gene is an HCMV envelope glycoprotein that forms a novel gH-based complex alternative to gH/gL. Remarkably, the gH/UL116 complex is the first herpesvirus gH-based gL-less complex. IMPORTANCE: HCMV infection can cause severe disease in immunocompromised adults and infants infected in utero The dissection of the HCMV entry machinery is important to understand the mechanism of viral infection and to identify new vaccine antigens. The gH/gL/gO and gH/gL/UL128/UL130/UL131 (Pentamer) complexes play a key role in HCMV cell entry and tropism. Both complexes are formed by an invariant gH/gL scaffold on which the other subunits assemble. Here, we show that the UL116 gene product is expressed in infected cells and forms a heterodimer with gH. The gH/UL116 complex is carried on the infectious virions, although in smaller amounts than gH/gL complexes. No gH/UL116/gL ternary complex formed in transfected cells, suggesting that the gH/UL116 complex is independent from gL. This new gH-based gL-free complex represents a potential target for a protective HCMV vaccine and opens new perspectives on the comprehension of the HCMV cell entry mechanism and tropism. PMID- 26937032 TI - The RNA Helicase eIF4A Is Required for Sapovirus Translation. AB - The eukaryotic initiation factor 4A (eIF4A) is a DEAD box helicase that unwinds RNA structure in the 5' untranslated region (UTR) of mRNAs. Here, we investigated the role of eIF4A in porcine sapovirus VPg-dependent translation. Using inhibitors and dominant-negative mutants, we found that eIF4A is required for viral translation and infectivity, suggesting that despite the presence of a very short 5' UTR, eIF4A is required to unwind RNA structure in the sapovirus genome to facilitate virus translation. PMID- 26937033 TI - Longitudinal Examination of the Intestinal Lamina Propria Cellular Compartment of Simian Immunodeficiency Virus-Infected Rhesus Macaques Provides Broader and Deeper Insights into the Link between Aberrant MicroRNA Expression and Persistent Immune Activation. AB - Chronic immune activation/inflammation driven by factors like microbial translocation is a key determinant of human immunodeficiency virus/simian immunodeficiency virus (HIV/SIV) disease progression. Although extensive research on inflammation has focused on studying protein regulators, increasing evidence suggests a critical role for microRNAs (miRNAs) in regulating several aspects of the immune/inflammatory response and immune cell proliferation, differentiation, and activation. To understand their immunoregulatory role, we profiled miRNA expression sequentially in intestinal lamina propria leukocytes (LPLs) of eight macaques before and at 21, 90, and 180 days postinfection (dpi). At 21 dpi, ~20 and 9 miRNAs were up- and downregulated, respectively. However, at 90 dpi (n = 60) and 180 dpi (n = 44), >=75% of miRNAs showed decreased expression. Notably, the T-cell activation-associated miR-15b, miR-142-3p, miR-142-5p, and miR-150 expression was significantly downregulated at 90 and 180 dpi. Out of ~10 downregulated miRNAs predicted to regulate CD69, we confirmed miR-92a to directly target CD69. Interestingly, the SIV-induced miR-190b expression was elevated at all time points. Additionally, elevated lipopolysaccharide (LPS)-responsive miR 146b-5p expression at 180 dpi was confirmed in primary intestinal macrophages following LPS treatment in vitro Further, reporter and overexpression assays validated IRAK1 (interleukin-1 receptor 1 kinase) as a direct miR-150 target. Furthermore, IRAK1 protein levels were markedly elevated in intestinal LPLs and epithelium. Finally, blockade of CD8(+) T-cell activation/proliferation with delta-9 tetrahydrocannabinol (Delta(9)-THC) significantly prevented miR-150 downregulation and IRAK1 upregulation. Our findings suggest that miR-150 downregulation during T-cell activation disrupts the translational control of IRAK1, facilitating persistent gastrointestinal (GI) inflammation. Finally, the ability of Delta(9)-THC to block the miR-150-IRAK1 regulatory cascade highlights the potential of cannabinoids to inhibit persistent inflammation/immune activation in HIV/SIV infection. IMPORTANCE: Persistent GI tract disease/inflammation is a cardinal feature of HIV/SIV infection. Increasing evidence points to a critical role for miRNAs in controlling several aspects of the immune/inflammatory response. Here, we show significant dysregulation of miRNA expression exclusively in the intestinal lamina propria cellular compartment through the course of SIV infection. Specifically, the study identified miRNA signatures associated with key pathogenic events, such as viral replication, T-cell activation, and microbial translocation. The T-cell-enriched miR-150 showed significant downregulation throughout SIV infection and was confirmed to target IRAK1, a critical signal-transducing component of the IL-1 receptor and TLR signaling pathways. Reduced miR-150 expression was associated with markedly elevated IRAK1 expression in the intestines of chronically SIV infected macaques. Finally, Delta(9)-THC-mediated blockade of CD8(+) T-cell activation in vitro significantly inhibited miR-150 downregulation and IRAK1 upregulation, suggesting its potential for targeted immune modulation in HIV infection. PMID- 26937034 TI - A North American H7N3 Influenza Virus Supports Reassortment with 2009 Pandemic H1N1 and Induces Disease in Mice without Prior Adaptation. AB - Reassortment between H5 or H9 subtype avian and mammalian influenza A viruses (IAV) can generate a novel virus that causes disease and transmits between mammals. Such information is currently not available for H7 subtype viruses. We evaluated the ability of a low-pathogenicity North American avian H7N3 virus (A/shorebird/Delaware/22/2006) to reassort with mammalian or avian viruses using a plasmid-based competition assay. In addition to genome segments derived from an avian H7N9 virus, the H7N3 virus reassorted efficiently with the PB2, NA, and M segments from the 2009 pandemic H1N1 (PH1N1) virus.In vitro and in vivo evaluation of the H7N3:PH1N1 (7 + 1) reassortant viruses revealed that the PB2, NA, or M segments from PH1N1 largely do not attenuate the H7N3 virus, whereas the PB1, PA, NP, or NS genome segments from PH1N1 do. Additionally, we assessed the functionality of the H7N3:PH1N1 7 + 1 reassortant viruses by measuring the inflammatory response in vivo We found that infection with wild-type H7N3 resulted in increased inflammatory cytokine production relative to that seen with the PH1N1 strain and that the increase was further exacerbated by substitution of PH1N1 PB2 but not NA or M. Finally, we assessed if any adaptations occurred in the individually substituted segments after in vivo inoculation and found no mutations, suggesting that PH1N1 PB2, NA, and M are genetically stable in the background of this H7N3 virus. Taking the data together, we demonstrate that a North American avian H7N3 IAV is genetically and functionally compatible with multiple gene segments from the 2009 pandemic influenza virus strain without prior adaptation. IMPORTANCE: The 2009 pandemic H1N1 virus continues to circulate and reassort with other influenza viruses, creating novel viruses with increased replication and transmission potential in humans. Previous studies have found that this virus can also reassort with H5N1 and H9N2 avian influenza viruses. We now show that several genome segments of the 2009 H1N1 virus are also highly compatible with a low-pathogenicity avian H7N3 virus and that these reassortant viruses are stable and not attenuated in an animal model. These results highlight the potential for reassortment of H1N1 viruses with avian influenza virus and emphasize the need for continued surveillance of influenza viruses in areas of cocirculation between avian, human, and swine viruses. PMID- 26937035 TI - Novel Role for Protein Inhibitor of Activated STAT 4 (PIAS4) in the Restriction of Herpes Simplex Virus 1 by the Cellular Intrinsic Antiviral Immune Response. AB - Small ubiquitin-like modifier (SUMO) is used by the intrinsic antiviral immune response to restrict viral pathogens, such as herpes simplex virus 1 (HSV-1). Despite characterization of the host factors that rely on SUMOylation to exert their antiviral effects, the enzymes that mediate these SUMOylation events remain to be defined. We show that unconjugated SUMO levels are largely maintained throughout infection regardless of the presence of ICP0, the HSV-1 SUMO-targeted ubiquitin ligase. Moreover, in the absence of ICP0, high-molecular-weight SUMO conjugated proteins do not accumulate if HSV-1 DNA does not replicate. These data highlight the continued importance for SUMO signaling throughout infection. We show that the SUMO ligase protein inhibitor of activated STAT 4 (PIAS4) is upregulated during HSV-1 infection and localizes to nuclear domains that contain viral DNA. PIAS4 is recruited to sites associated with HSV-1 genome entry through SUMO interaction motif (SIM)-dependent mechanisms that are destabilized by ICP0. In contrast, PIAS4 accumulates in replication compartments through SIM independent mechanisms irrespective of ICP0 expression. Depletion of PIAS4 enhances the replication of ICP0-null mutant HSV-1, which is susceptible to restriction by the intrinsic antiviral immune response. The mechanisms of PIAS4 mediated restriction are synergistic with the restriction mechanisms of a characterized intrinsic antiviral factor, promyelocytic leukemia protein, and are antagonized by ICP0. We provide the first evidence that PIAS4 is an intrinsic antiviral factor. This novel role for PIAS4 in intrinsic antiviral immunity contrasts with the known roles of PIAS proteins as suppressors of innate immunity. IMPORTANCE: Posttranslational modifications with small ubiquitin-like modifier (SUMO) proteins regulate multiple aspects of host immunity and viral replication. The protein inhibitor of activated STAT (PIAS) family of SUMO ligases is predominantly associated with the suppression of innate immune signaling. We now identify a unique and contrasting role for PIAS proteins as positive regulators of the intrinsic antiviral immune response to herpes simplex virus 1 (HSV-1) infection. We show that PIAS4 relocalizes to nuclear domains that contain viral DNA throughout infection. Depletion of PIAS4, either alone or in combination with the intrinsic antiviral factor promyelocytic leukemia protein, significantly impairs the intrinsic antiviral immune response to HSV-1 infection. Our data reveal a novel and dynamic role for PIAS4 in the cellular-mediated restriction of herpesviruses and establish a new functional role for the PIAS family of SUMO ligases in the intrinsic antiviral immune response to DNA virus infection. PMID- 26937036 TI - MicroRNA-19b-3p Modulates Japanese Encephalitis Virus-Mediated Inflammation via Targeting RNF11. AB - Japanese encephalitis virus (JEV) can invade the central nervous system and consequently induce neuroinflammation, which is characterized by profound neuronal cell damage accompanied by astrogliosis and microgliosis. Albeit microRNAs (miRNAs) have emerged as major regulatory noncoding RNAs with profound effects on inflammatory response, it is unknown how astrocytic miRNAs regulate JEV-induced inflammation. Here, we found the involvement of miR-19b-3p in regulating the JEV-induced inflammatory responsein vitroandin vivo The data demonstrated that miR-19b-3p is upregulated in cultured cells and mouse brain tissues during JEV infection. Overexpression of miR-19b-3p led to increased production of inflammatory cytokines, including tumor necrosis factor alpha, interleukin-6, interleukin-1beta, and chemokine (C-C motif) ligand 5, after JEV infection, whereas knockdown of miR-19b-3p had completely opposite effects. Mechanistically, miR-19b-3p modulated the JEV-induced inflammatory response via targeting ring finger protein 11, a negative regulator of nuclear factor kappa B signaling. We also found that inhibition of ring finger protein 11 by miR-19b-3p resulted in accumulation of nuclear factor kappa B in the nucleus, which in turn led to higher production of inflammatory cytokines.In vivosilencing of miR-19b-3p by a specific antagomir reinvigorates the expression level of RNF11, which in turn reduces the production of inflammatory cytokines, abrogates gliosis and neuronal cell death, and eventually improves the survival rate in the mouse model. Collectively, our results demonstrate that miR-19b-3p positively regulates the JEV-induced inflammatory response. Thus, miR-19b-3p targeting may constitute a thought-provoking approach to rein in JEV-induced inflammation. IMPORTANCE: Japanese encephalitis virus (JEV) is one of the major causes of acute encephalitis in humans worldwide. The pathological features of JEV-induced encephalitis are inflammatory reactions and neurological diseases resulting from glia activation. MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression posttranscriptionally. Accumulating data indicate that miRNAs regulate a variety of cellular processes, including the host inflammatory response under pathological conditions. Recently, a few studies demonstrated the role of miRNAs in a JEV-induced inflammatory response in microglia; however, their role in an astrocyte-derived inflammatory response is largely unknown. The present study reveals that miR-19b-3p targets ring finger protein 11 in glia and promotes inflammatory cytokine production by enhancing nuclear factor kappa B activity in these cells. Moreover, administration of an miR-19b-3p-specific antagomir in JEV infected mice reduces neuroinflammation and lethality. These findings suggest a new insight into the molecular mechanism of the JEV-induced inflammatory response and provide a possible therapeutic entry point for treating viral encephalitis. PMID- 26937038 TI - Molecular Evolutionary Dynamics of Respiratory Syncytial Virus Group A in Recurrent Epidemics in Coastal Kenya. AB - The characteristic recurrent epidemics of human respiratory syncytial virus (RSV) within communities may result from the genetic variability of the virus and associated evolutionary adaptation, reducing the efficiency of preexisting immune responses. We analyzed the molecular evolutionary changes in the attachment (G) glycoprotein of RSV-A viruses collected over 13 epidemic seasons (2000 to 2012) in Kilifi (n = 649), Kenya, and contemporaneous sequences (n = 1,131) collected elsewhere within Kenya and 28 other countries. Genetic diversity in the G gene in Kilifi was dynamic both within and between epidemics, characterized by frequent new variant introductions and limited variant persistence between consecutive epidemics. Four RSV-A genotypes were detected in Kilifi: ON1 (11.9%), GA2 (75.5%), GA5 (12.3%), and GA3 (0.3%), with predominant genotype replacement of GA5 by GA2 and then GA2 by ON1. Within these genotypes, there was considerable variation in potential N-glycosylation sites, with GA2 and ON1 viruses showing up to 15 different patterns involving eight possible sites. Further, we identified 15 positively selected and 34 genotype-distinguishing codon sites, with six of these sites exhibiting both characteristics. The mean substitution rate of the G ectodomain for the Kilifi data set was estimated at 3.58 * 10(-3) (95% highest posterior density interval = 3.04 to 4.16) nucleotide substitutions/site/year. Kilifi viruses were interspersed in the global phylogenetic tree, clustering mostly with Kenyan and European sequences. Our findings highlight ongoing genetic evolution and high diversity of circulating RSV-A strains, locally and globally, with potential antigenic differences. Taken together, these provide a possible explanation on the nature of recurrent local RSV epidemics. IMPORTANCE: The mechanisms underlying recurrent epidemics of RSV are poorly understood. We observe high genetic diversity in circulating strains within and between epidemics in both local and global settings. On longer time scales (~7 years) there is sequential replacement of genotypes, whereas on shorter time scales (one epidemic to the next or within epidemics) there is a high turnover of variants within genotypes. Further, this genetic diversity is predicted to be associated with variation in antigenic profiles. These observations provide an explanation for recurrent RSV epidemics and have potential implications on the long-term effectiveness of vaccines. PMID- 26937037 TI - Derivation and Characterization of a CD4-Independent, Non-CD4-Tropic Simian Immunodeficiency Virus. AB - CD4 tropism is conserved among all primate lentiviruses and likely contributes to viral pathogenesis by targeting cells that are critical for adaptive antiviral immune responses. Although CD4-independent variants of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) have been described that can utilize the coreceptor CCR5 or CXCR4 in the absence of CD4, these viruses typically retain their CD4 binding sites and still can interact with CD4. We describe the derivation of a novel CD4-independent variant of pathogenic SIVmac239, termed iMac239, that was used to derive an infectious R5-tropic SIV lacking a CD4 binding site. Of the seven mutations that differentiate iMac239 from wild-type SIVmac239, a single change (D178G) in the V1/V2 region was sufficient to confer CD4 independence in cell-cell fusion assays, although other mutations were required for replication competence. Like other CD4-independent viruses, iMac239 was highly neutralization sensitive, although mutations were identified that could confer CD4-independent infection without increasing its neutralization sensitivity. Strikingly, iMac239 retained the ability to replicate in cell lines and primary cells even when its CD4 binding site had been ablated by deletion of a highly conserved aspartic acid at position 385, which, for HIV 1, plays a critical role in CD4 binding. iMac239, with and without the D385 deletion, exhibited an expanded host range in primary rhesus peripheral blood mononuclear cells that included CCR5(+) CD8(+) T cells. As the first non-CD4 tropic SIV, iMac239-DeltaD385 will afford the opportunity to directly assess the in vivo role of CD4 targeting on pathogenesis and host immune responses. IMPORTANCE: CD4 tropism is an invariant feature of primate lentiviruses and likely plays a key role in pathogenesis by focusing viral infection onto cells that mediate adaptive immune responses and in protecting virions attached to cells from neutralizing antibodies. Although CD4-independent viruses are well described for HIV and SIV, these viruses characteristically retain their CD4 binding site and can engage CD4 if available. We derived a novel CD4-independent, CCR5-tropic variant of the pathogenic molecular clone SIVmac239, termed iMac239. The genetic determinants of iMac239's CD4 independence provide new insights into mechanisms that underlie this phenotype. This virus remained replication competent even after its CD4 binding site had been ablated by mutagenesis. As the first truly non-CD4-tropic SIV, lacking the capacity to interact with CD4, iMac239 will provide the unique opportunity to evaluate SIV pathogenesis and host immune responses in the absence of the immunomodulatory effects of CD4(+) T cell targeting and infection. PMID- 26937039 TI - Complement Opsonization Promotes Herpes Simplex Virus 2 Infection of Human Dendritic Cells. AB - Herpes simplex virus 2 (HSV-2) is one of the most common sexually transmitted infections globally, with a very high prevalence in many countries. During HSV-2 infection, viral particles become coated with complement proteins and antibodies, both present in genital fluids, which could influence the activation of immune responses. In genital mucosa, the primary target cells for HSV-2 infection are epithelial cells, but resident immune cells, such as dendritic cells (DCs), are also infected. DCs are the activators of the ensuing immune responses directed against HSV-2, and the aim of this study was to examine the effects opsonization of HSV-2, either with complement alone or with complement and antibodies, had on the infection of immature DCs and their ability to mount inflammatory and antiviral responses. Complement opsonization of HSV-2 enhanced both the direct infection of immature DCs and their production of new infectious viral particles. The enhanced infection required activation of the complement cascade and functional complement receptor 3. Furthermore, HSV-2 infection of DCs required endocytosis of viral particles and their delivery into an acid endosomal compartment. The presence of complement in combination with HSV-1- or HSV-2 specific antibodies more or less abolished HSV-2 infection of DCs. Our results clearly demonstrate the importance of studying HSV-2 infection under conditions that ensue in vivo, i.e., conditions under which the virions are covered in complement fragments and complement fragments and antibodies, as these shape the infection and the subsequent immune response and need to be further elucidated. IMPORTANCE: During HSV-2 infection, viral particles should become coated with complement proteins and antibodies, both present in genital fluids, which could influence the activation of the immune responses. The dendritic cells are activators of the immune responses directed against HSV-2, and the aim of this study was to examine the effects of complement alone or complement and antibodies on HSV-2 infection of dendritic cells and their ability to mount inflammatory and antiviral responses. Our results demonstrate that the presence of antibodies and complement in the genital environment can influence HSV-2 infection under in vitro conditions that reflect the in vivo situation. We believe that our findings are highly relevant for the understanding of HSV-2 pathogenesis. PMID- 26937040 TI - Effects of Fecal Microbial Transplantation on Microbiome and Immunity in Simian Immunodeficiency Virus-Infected Macaques. AB - An altered intestinal microbiome during chronic human immunodeficiency virus (HIV) infection is associated with mucosal dysfunction, inflammation, and disease progression. We performed a preclinical evaluation of the safety and efficacy of fecal microbiota transplantation (FMT) as a potential therapeutic in HIV-infected individuals. Antiretroviral-treated, chronically simian immunodeficiency virus (SIV)-infected rhesus macaques received antibiotics followed by FMT. The greatest microbiota shift was observed after antibiotic treatment. The bacterial community composition at 2 weeks post-FMT resembled the pre-FMT community structure, although differences in the abundances of minor bacterial populations remained. Immunologically, we observed significant increases in the number of peripheral Th17 and Th22 cells and reduced CD4(+) T cell activation in gastrointestinal tissues post-FMT. Importantly, the transplant was well tolerated with no negative clinical side effects. Although this pilot study did not control for the differential contributions of antibiotic treatment and FMT to the observed results, the data suggest that FMT may have beneficial effects that should be further evaluated in larger studies. IMPORTANCE: Due to the immunodeficiency and chronic inflammation that occurs during HIV infection, determination of the safety of FMT is crucial to prevent deleterious consequences if it is to be used as a treatment in the future. Here we used the macaque model of HIV infection and performed FMT on six chronically SIV-infected rhesus macaques on antiretroviral treatment. In addition to providing a preclinical demonstration of the safety of FMT in primates infected with a lentivirus, this study provided a unique opportunity to examine the relationships between alterations to the microbiome and immunological parameters. In this study, we found increased numbers of Th17 and Th22 cells as well as decreased activation of CD4(+) T cells post-FMT, and these changes correlated most strongly across all sampling time points with lower abundance taxonomic groups and other taxonomic groups in the colon. Overall, these data provide evidence that changes in the microbiome, particularly in terms of diversity and changes in minor populations, can enhance immunity and do not have adverse consequences. PMID- 26937042 TI - Highly stretchable wrinkled gold thin film wires. AB - With the growing prominence of wearable electronic technology, there is a need to improve the mechanical reliability of electronics for more demanding applications. Conductive wires represent a vital component present in all electronics. Unlike traditional planar and rigid electronics, these new wearable electrical components must conform to curvilinear surfaces, stretch with the body, and remain unobtrusive and low profile. In this paper, the piezoresistive response of shrink induced wrinkled gold thin films under strain demonstrates robust conductive performance in excess of 200% strain. Importantly, the wrinkled metallic thin films displayed negligible change in resistance of up to 100% strain. The wrinkled metallic wires exhibited consistent performance after repetitive strain. Importantly, these wrinkled thin films are inexpensive to fabricate and are compatible with roll to roll manufacturing processes. We propose that these wrinkled metal thin film wires are an attractive alternative to conventional wires for wearable applications. PMID- 26937043 TI - Stability constants for the formation of lead chloride complexes as a function of temperature and ionic strength. AB - The stability constants for the formation of lead (Pb2+) with chloride [Formula: see text] have been determined using a spectrophotometric method in NaClO4 solutions as a function of ionic strength (0-6 m) and temperature (15-45 degrees C). The results have been fitted to the equations: [Formula: see text] with standard errors of 0.05, 0.04 and 0.06, respectively. The thermodynamic values of log beta1, logbeta2 and logbeta3 at 25.0 degrees C and the enthalpies of formation of PbCl+, PbCl20 and PbCl3- are in good agreement with literature values. We have combined our results with the earlier work of Seward (1984) to yield thermodynamic constants that are valid from 15 to 300 degrees C: [Formula: see text] with standard errors of 0.05, 0.08 and 0.10, respectively. PMID- 26937041 TI - The Enduring Association between Education and Mortality: The Role of Widening and Narrowing Disparities. AB - This paper examines how educational disparities in mortality emerge, grow, decline, and disappear across causes of death in the United States and how these change contribute to the enduring association of education and mortality over time. Focusing on adults age 40-64, we first examine the extent to which disparities in all-cause mortality by education persisted from 1989-2007. We then test the "fundamental cause" prediction that mortality disparities persist, in part, by shifting to new health outcomes over time, most importantly for those causes of death that have increasing mortality rates. To test this hypothesis, we focus in depth on the period from 1999-2007, when all causes of death were coded to the same classification system. The results indicate (a) both substantial widening and narrowing of mortality disparities across causes of death, (b) almost all causes of death that had increasing mortality rates also had widening disparities by education, and (c) the total disparity by education in all-cause mortality would be about 25% smaller today were it not for newly widened or emergent disparities since 1999. These results point to the theoretical and policy importance of identifying the social forces that cause health disparities to widen over time. PMID- 26937044 TI - Social affiliation and contact patterns among white-tailed deer in disparate landscapes: implications for disease transmission. AB - In social species, individuals contact members of the same group much more often than those of other groups, particularly for contacts that could directly transmit disease agents. This disparity in contact rates violates the assumptions of simple disease models, hinders disease spread between groups, and could decouple disease transmission from population density. Social behavior of white tailed deer has important implications for the long-term dynamics and impact of diseases such as bovine tuberculosis and chronic wasting disease (CWD), so expanding our understanding of their social system is important. White-tailed deer form matrilineal groups, which inhabit stable home ranges that overlap somewhat with others-a pattern intermediate between mass-action and strict territoriality. To quantify how group membership affects their contact rates and document the spectrum of social affiliation, we analyzed location data from global positioning system (GPS) collars on female and juvenile white-tailed deer in 2 study areas: near Carbondale in forest-dominated southern Illinois (2002 2006) and near Lake Shelbyville in agriculture-dominated central Illinois (2006 2009). For each deer dyad (i.e., 2 individual deer with sufficient overlapping GPS data), we measured space-use overlap, correlation of movements, direct contact rate (simultaneous GPS locations < 10 m apart), and indirect contact rate (GPS locations < 10 m apart when offset by 1 or 3 days). Direct contact rates were substantially higher for within-group dyads than between-group dyads, but group membership had little apparent effect on indirect contact rates. The group membership effect on direct contact rates was strongest in winter and weakest in summer, with no apparent difference between study areas. Social affiliations were not dichotomous, with some deer dyads showing loose but positive affiliation. Even for obvious within-group dyads, their strength of affiliation fluctuated between years, seasons, and even days. Our findings highlight the poor fit between deer behavior and simple models of disease transmission and, combined with previous infection data, suggest that direct contact is the primary driver of CWD transmission among free-living female and juvenile white-tailed deer. PMID- 26937045 TI - Molecular and morphologic data reveal multiple species in Peromyscus pectoralis. AB - DNA sequence and morphometric data were used to re-evaluate the taxonomy and systematics of Peromyscus pectoralis. Phylogenetic analyses (maximum likelihood and Bayesian inference) of DNA sequences from the mitochondrial cytochrome-b gene in 44 samples of P. pectoralis indicated 2 well-supported monophyletic clades. The 1st clade contained specimens from Texas historically assigned to P. p. laceianus; the 2nd was comprised of specimens previously referable to P. p. collinus, P. p. laceianus, and P. p. pectoralis obtained from northern and eastern Mexico. Levels of genetic variation (~7%) between these 2 clades indicated that the genetic divergence typically exceeded that reported for other species of Peromyscus. Samples of P. p. laceianus north and south of the Rio Grande were not monophyletic. In addition, samples representing P. p. collinus and P. p. pectoralis formed 2 clades that differed genetically by 7.14%. Multivariate analyses of external and cranial measurements from 63 populations of P. pectoralis revealed 4 morpho-groups consistent with clades in the DNA sequence analysis: 1 from Texas and New Mexico assignable to P. p. laceianus; a 2nd from western and southern Mexico assignable to P. p. pectoralis; a 3rd from northern and central Mexico previously assigned to P. p. pectoralis but herein shown to represent an undescribed taxon; and a 4th from southeastern Mexico assignable to P. p. collinus. Based on the concordance of these results, populations from the United States are referred to as P. laceianus, whereas populations from Mexico are referred to as P. pectoralis (including some samples historically assigned to P. p. collinus, P. p. laceianus, and P. p. pectoralis). A new subspecies is described to represent populations south of the Rio Grande in northern and central Mexico. Additional research is needed to discern if P. p. collinus warrants species recognition. PMID- 26937046 TI - Temporal segregation of the Australian and Antarctic blue whale call types (Balaenoptera musculus spp.). AB - We examined recordings from a 15-month (May 2009-July 2010) continuous acoustic data set collected from a bottom-mounted passive acoustic recorder at a sample frequency of 6kHz off Portland, Victoria, Australia (38 degrees 33'01"S, 141 degrees 15'13"E) off southern Australia. Analysis revealed that calls from both subspecies were recorded at this site, and general additive modeling revealed that the number of calls varied significantly across seasons. Antarctic blue whales were detected more frequently from July to October 2009 and June to July 2010, corresponding to the suspected breeding season, while Australian blue whales were recorded more frequently from March to June 2010, coinciding with the feeding season. In both subspecies, the number of calls varied with time of day; Antarctic blue whale calls were more prevalent in the night to early morning, while Australian blue whale calls were detected more often from midday to early evening. Using passive acoustic monitoring, we show that each subspecies adopts different seasonal and daily call patterns which may be related to the ecological strategies of these subspecies. This study demonstrates the importance of passive acoustics in enabling us to understand and monitor subtle differences in the behavior and ecology of cryptic sympatric marine mammals. PMID- 26937047 TI - What Is Peromyscus? Evidence from nuclear and mitochondrial DNA sequences suggests the need for a new classification. AB - The evolutionary relationships between Peromyscus, Habromys, Isthmomys, Megadontomys, Neotomodon, Osgoodomys, and Podomys are poorly understood. In order to further explore the evolutionary boundaries of Peromyscus and compare potential taxonomic solutions for this diverse group and its relatives, we conducted phylogenetic analyses of DNA sequence data from alcohol dehydrogenase (Adh1-I2), beta fibrinogen (Fgb-I7), interphotoreceptor retinoid-binding protein (Rbp3), and cytochrome-b (Cytb). Phylogenetic analyses of mitochondrial and nuclear genes produced similar topologies although levels of nodal support varied. The best-supported topology was obtained by combining nuclear and mitochondrial sequences. No monophyletic Peromyscus clade was supported. Instead, support was found for a clade containing Habromys, Megadontomys, Neotomodon, Osgoodomys, Podomys, and Peromyscus suggesting paraphyly of Peromyscus and confirming previous observations. Our analyses indicated an early divergence of Isthmomys from Peromyscus (approximately 8 million years ago), whereas most other peromyscine taxa emerged within the last 6 million years. To recover a monophyletic taxonomy from Peromyscus and affiliated lineages, we detail 3 taxonomic options in which Habromys, Megadontomys, Neotomodon, Osgoodomys, and Podomys are retained as genera, subsumed as subgenera, or subsumed as species groups within Peromyscus. Each option presents distinct taxonomic challenges, and the appropriate taxonomy must reflect the substantial levels of morphological divergence that characterize this group while maintaining the monophyletic relationships obtained from genetic data. PMID- 26937048 TI - Whisker spot patterns: a noninvasive method of individual identification of Australian sea lions (Neophoca cinerea). AB - Reliable methods for identification of individual animals are advantageous for ecological studies of population demographics and movement patterns. Photographic identification, based on distinguishable patterns, unique shapes, or scars, is an effective technique already used for many species. We tested whether photographs of whisker spot patterns could be used to discriminate among individual Australian sea lion (Neophoca cinerea). Based on images of 53 sea lions, we simulated 5,000 patterns before calculating the probability of duplication in a study population. A total of 99% (+/- 1.5 SD) of patterns were considered reliable for a population of 50, 98% (+/- 1.7 SD) for 100, 92% (+/- 4.7 SD) for 500, and 88% (+/- 5.7 SD) for 1,000. We tested a semiautomatic approach by matching 16 known individuals at 3 different angles (70 degrees , 90 degrees , and 110 degrees ), 2 distances (1 and 2 m), and 6 separate times over a 1-year period. A point-pattern matching algorithm for pairwise comparisons produced 90% correct matches of photographs taken on the same day at 90 degrees . Images of individuals at 1 and 2 m resulted in 89% correct matches, those photographed at different angles and different times (at 90 degrees ) resulted in 48% and 73% correct matches, respectively. Our results show that the Chamfer distance transform can effectively be used for individual identification, but only if there is very little variation in photograph angle. This point-pattern recognition application may also work for other otariid species. PMID- 26937050 TI - Diet of a sigmodontine rodent assemblage in a Peruvian montane forest. AB - Knowledge of feeding habits of small rodents is necessary for understanding food webs, trophic structure, and plant-animal interactions in Neotropical forests. Despite several studies that have investigated community structure and feeding behavior of rodents, large gaps remain in our understanding of their guild occupancy. Our objective was to investigate the diets of 7 species of small (< 100g) sympatric sigmodontine rodents in a high (3,500 m) Andean montane rainforest in Peru. We qualitatively and quantitatively assessed diet items in fecal samples from livetrapped rodents from 2009 to 2012. Frequency data for 4 diet categories indicated that all 7 species of rodents contained 4 diet categories in fecal samples: arthropods (88%), remains of leaves and fibers from plants (61%), intact seeds (with or without fruit pulp; 50%), and mycorrhizal spores (45%). Omnivory was found to be a strategy used by all species, although contingency table analysis revealed significant differences among and within species in diet categories. Cluster analysis showed 2 main groupings: that of the Thomasomys spp. plus Calomys sorellus group which included high amounts of intact seeds and plant parts in their fecal samples, and those of the genera Akodon, Microryzomys, Oligoryzomys, which included a greater proportion of arthropods in their fecal samples, but still consumed substantial amounts of fruit and plant parts. Intact seed remains from at least 17 plant species (9 families) were found in fecal samples. We concluded that this assemblage of sigmodontine rodents is omnivorous but that they likely play an important role as frugivores and in seed dispersal in tropical montane forests in Peru. El conocimiento de los habitos alimenticios de roedores pequenos es necesario para comprender cadenas alimenticias, estructura trofica, e interacciones planta-animal en los bosques neotropicales. A pesar de que numerosos estudios han investigado la estructura de comunidades y el comportamiento de forrajeo en roedores, aun existen grandes vacios en nuestra comprension de sus gremios troficos. Nuestro objetivo fue investigar las dietas de siete especies de pequenos (< 100 g) roedores sigmodontinos simpatricos en un bosque montano andino a 3.500] m en Peru. Cualitativamente y cuantitativamente evaluamos la dieta en muestras fecales de roedores capturados entre el 2009 y el 2012. Datos de frecuencia para cuatro categorias de dieta indicaron que las siete especies de roedores consumieron cuatro categorias de dieta: artropodos (88%), pedazos de hojas y fibras de plantas (61%), semillas intactas (con o sin pulpa de frutos; 50%), y esporas de micorrizas (45%). Omnivoria fue la estrategia utilizada por todas las especies, aunque el analisis con tablas de contingencia revelo diferencias significativas entre y dentro de especies en categorias de dieta. El analisis de agrupacion presento 2 grupos principales: el grupo Thomasomys spp. y Calomys sorellus, que incluye una gran proporcion de semillas intactas, y partes de plantas en las muestras fecales y el grupo que incluye los generos Akodon, Microryzomys y Oligoryzomys, el cual incluyo una proporcion mayor de artropodos en sus muestras fecales, pero con niveles altos de semillas intactas. Semillas intactas de al menos 17 especies de plantas (9 familias) fueron encontradas en las muestras fecales. Concluimos que este ensamble de roedores sigmodontinos es omnivoro y que probablemente las especies juegan un rol importante como frugivoros y en la dispersion de semillas en los bosques montanos tropicales en el Peru. PMID- 26937049 TI - Comparisons of life-history parameters between free-ranging and captive killer whale (Orcinus orca) populations for application toward species management. AB - Data collected on life-history parameters of known-age animals from the northern (NR) and southern resident (SR) killer whales (Orcinus orca) of the eastern North Pacific were compared with life-history traits of killer whales located at SeaWorld (SEA) facilities. For captive-born SEA animals, mean age and body length at 1st estrus was 7.5 years and 483.7cm, respectively. Estimated mean age at 1st conception was different (P < 0.001) for the combined data from both northern and southern resident (NSR) free-ranging populations (12.1 years) compared to SEA (9.8 years), as was the estimated mean age at 1st observed calf (SEA: 11.1 years, NSR: 14.2 years, P < 0.001). Average calf survival rate to 2 years of age for SEA animals (0.966) was significantly greater (P = 0.04) than that for SR (0.799). Annual survival rate (ASR) for SEA increased over approximately 15-year increments with rates in the most recent period (2000-2015 ASR: 0.976) improved (P < 0.05) over the first 2 periods of captivity (1965-1985: 0.906; 1985-2000: 0.941). The SR (0.966) and NR ASR (0.977) were higher (P <= 0.05) than that of SEA until 2000, after which there were no inter-population differences. Based on ASR, median and average life expectancy were 28.8 and 41.6 years (SEA: 2000 2015), 20.1 and 29.0 years (SR), and 29.3 and 42.3 years (NR), respectively. The ASR for animals born at SEA (0.979) was higher (P = 0.02) than that of wild caught SEA animals (0.944) with a median and average life expectancy of 33.1 and 47.7 years, respectively. These data present evidence for similar life-history parameters of free-ranging and captive killer whale populations and the reproductive potential and survivorship patterns established herein have application for use in future research concerning the overall health of both populations. PMID- 26937051 TI - Order-Order Morphological Transitions for Dual Stimulus Responsive Diblock Copolymer Vesicles. AB - A series of non-ionic poly(glycerol monomethacrylate)-poly(2-hydroxypropyl methacrylate) (PGMA-PHPMA) diblock copolymer vesicles has been prepared by reversible addition-fragmentation chain transfer (RAFT) aqueous dispersion polymerization of HPMA at 70 degrees C at low pH using a carboxylic acid-based chain transfer agent. The degree of polymerization (DP) of the PGMA block was fixed at 43, and the DP of the PHPMA block was systematically varied from 175 to 250 in order to target vesicle phase space. Based on our recent work describing the analogous PGMA-PHPMA diblock copolymer worms [Lovett J. R.; Angew. Chem.2015, 54, 1279-1283], such diblock copolymer vesicles were expected to undergo an order order morphological transition via ionization of the carboxylic acid end-group on switching the solution pH. Indeed, irreversible vesicle-to-sphere and vesicle-to worm transitions were observed for PHPMA DPs of 175 and 200, respectively, as judged by turbidimetry, transmission electron microscopy (TEM), and dynamic light scattering (DLS) studies. However, such morphological transitions are surprisingly slow, with relatively long time scales (hours) being required at 20 degrees C. Moreover, no order-order morphological transitions were observed for vesicles comprising longer membrane-forming blocks (e.g., PGMA43-PHPMA225-250) on raising the pH from pH 3.5 to pH 6.0. However, in such cases the application of a dual stimulus comprising the same pH switch immediately followed by cooling from 20 to 5 degrees C, induces an irreversible vesicle-to-sphere transition. Finally, TEM and DLS studies conducted in the presence of 100 mM KCl demonstrated that the pH-responsive behavior arising from end-group ionization could be suppressed in the presence of added electrolyte. This is because charge screening suppresses the subtle change in the packing parameter required to drive the morphological transition. PMID- 26937052 TI - Air cleaning performance of a new environmentally controlled primary crusher operator booth. AB - The National Institute for Occupational Safety and Health (NIOSH) cooperated with 3M Company in the design and testing of a new environmentally controlled primary crusher operator booth at the company's Wausau granite quarry near Wausau, WI. This quarry had an older crusher booth without a central heating, ventilation and air conditioning (HVAC) system, and without an air filtration and pressurization system. A new replacement operator booth was designed and installed by 3M based on design considerations from past NIOSH research on enclosed cab filtration systems. NIOSH conducted pre-testing of the old booth and post-testing of the new booth to assess the new filtration and pressurization system's effectiveness in controlling airborne dusts and particulates. The booth's dust and particulate control effectiveness is described by its protection factor, expressed as a ratio of the outside to inside concentrations measured during testing. Results indicate that the old booth provided negligible airborne respirable dust protection and low particulate protection from the outside environment. The newly installed booth provided average respirable dust protection factors from 2 to 25 over five shifts of dust sampling with occasional worker ingress and egress from the booth, allowing some unfiltered contaminants to enter the enclosure. Shorter-term particle count testing outside and inside the booth under near-steady-state conditions, with no workers entering or exiting the booth, resulted in protection factors from 35 to 127 on 0.3- to 1.0-MUm respirable size particulates under various HVAC airflow operating conditions. PMID- 26937053 TI - FUNGIBILITY AND CONSUMER CHOICE: EVIDENCE FROM COMMODITY PRICE SHOCKS. AB - We formulate a test of the fungibility of money based on parallel shifts in the prices of different quality grades of a commodity. We embed the test in a discrete-choice model of product quality choice and estimate the model using panel microdata on gasoline purchases. We find that when gasoline prices rise consumers substitute to lower octane gasoline, to an extent that cannot be explained by income effects. Across a wide range of specifications, we consistently reject the null hypothesis that households treat "gas money" as fungible with other income. We compare the empirical fit of three psychological models of decision-making. A simple model of category budgeting fits the data well, with models of loss aversion and salience both capturing important features of the time series. PMID- 26937054 TI - Digital Games, Design, and Learning: A Systematic Review and Meta-Analysis. AB - In this meta-analysis, we systematically reviewed research on digital games and learning for K-16 students. We synthesized comparisons of game versus nongame conditions (i.e., media comparisons) and comparisons of augmented games versus standard game designs (i.e., value-added comparisons). We used random-effects meta-regression models with robust variance estimates to summarize overall effects and explore potential moderator effects. Results from media comparisons indicated that digital games significantly enhanced student learning relative to nongame conditions ([Formula: see text] = 0.33, 95% confidence interval [0.19, 0.48], k = 57, n = 209). Results from value-added comparisons indicated significant learning benefits associated with augmented game designs ([Formula: see text] = 0.34, 95% confidence interval [0.17, 0.51], k = 20, n = 40). Moderator analyses demonstrated that effects varied across various game mechanics characteristics, visual and narrative characteristics, and research quality characteristics. Taken together, the results highlight the affordances of games for learning as well as the key role of design beyond medium. PMID- 26937055 TI - An entropy-based measure of hydrologic complexity and its applications. AB - Basin hydrologic response is a function of soil moisture distributional featuresAn information-based dimensionless index of hydrologic complexity is appliedThe complexity index characterizes soil moisture distributional features. PMID- 26937056 TI - Hydraulic fracturing water use variability in the United States and potential environmental implications. AB - A U.S. map of water volumes used to hydraulically fracture oil and gas wells, 2011-2014Hydraulic fracturing water volumes differ regionally across the U.S.Discussion of variation in water use and potential environmental implications. PMID- 26937057 TI - Career Readiness: A Potential Pathway through which Urban Youth Exposure to Stress Influences Adult Health. AB - A growing body of research provides support for the detrimental effects of stress during childhood on future adult health, however, less is known about how stress disrupts normal developmental processes. This pathway may be particularly relevant for urban adolescents who are exposed to additional contextual stressors. This study will longitudinally explore how psychological stress from multiple domains influences urban adolescents' career readiness. Two hundred youth (ages 14-21) completed surveys assessing their school, family, neighborhood and health stress. Path analysis using a parallel process model found that school and neighborhood stress at 6 months were significantly associated with decreased career readiness at 15 months. Health stress at baseline was related to an increased report of career readiness at 15 months, which was moderated by parental closeness. These findings suggest that experiences of stress for urban youth negatively impact their planning for the future, particularly in the absence of supportive parental relationships. PMID- 26937058 TI - Radiative flux and forcing parameterization error in aerosol-free clear skies. AB - Radiation parameterizations in GCMs are more accurate than their predecessorsErrors in estimates of 4 *CO2 forcing are large, especially for solar radiationErrors depend on atmospheric state, so global mean error is unknown. PMID- 26937059 TI - To Blame or to Forgive? Reconciling Punishment and Forgiveness in Criminal Justice. AB - What do you do when faced with wrongdoing-do you blame or do you forgive? Especially when confronted with offences that lie on the more severe end of the spectrum and cause terrible psychological or physical trauma or death, nothing can feel more natural than blame. Indeed, in the UK and the USA, increasingly vehement and righteous public expressions of blame and calls for vengeance have become commonplace; correspondingly, contemporary penal philosophy has witnessed a resurgence of the retributive tradition, in the modern form usually known as the 'justice' model. On the other hand, people can and routinely do forgive others, even in cases of severe crime. Evolutionary psychologists argue that both vengeance and forgiveness are universal human adaptations that have evolved as alternative responses to exploitation, and, crucially, strategies for reducing risk of re-offending. We are naturally endowed with both capacities: to blame and retaliate, or to forgive and seek to repair relations. Which should we choose? Drawing on evolutionary psychology, we offer an account of forgiveness and argue that the choice to blame, and not to forgive, is inconsistent with the political values of a broadly liberal society and can be instrumentally counter-productive to reducing the risk of future re-offending. We then sketch the shape of penal philosophy and criminal justice policy and practice with forgiveness in place as a guiding ideal. PMID- 26937060 TI - Evidence for litter differences in play behaviour in pre-weaned pigs. AB - The aim of this study was to analyse spontaneous play behaviour in litters of domestic pigs (Sus scrofa) for sources of variation at individual and litter levels and to relate variation in play to measures of pre and postnatal development. Seven litters of commercially bred piglets (n = 70) were born (farrowed) within a penning system (PigSAFE) that provided opportunities for the performance of spontaneous play behaviours. Individual behaviour was scored based on an established play ethogram for 2 days per week over the 3 week study period. We found strong evidence of litter differences in play behaviour (F(6,63) = 27.30, p < 0.001). Of the variance in total play, 50% was attributable to differences between litters with a lesser proportion (11%) to between piglets within litters. We found similar evidence of litter differences when we analysed the separate play categories (e.g. for locomotor play: F(6,63) = 27.50, p < 0.001). For social and locomotor play the variance was partitioned in a broadly similar way to total play; however for object play the variance was distributed with a more even balance across and within litters. In terms of explanatory factors we found little evidence that at the litter level differences in play were associated with differences in general activity. Of the prenatal factors measured, we found that birth weight was positively associated with total play and the play categories (e.g. with total play: F(1,64) = 12.8, p < 0.001). We also found that postnatal piglet growth up to weaning (as a percentage of birth weight) had a significant positive association with total play and the play categories (e.g. with object play: F(1,66) = 20.55, p < 0.001). As found in other studies, on average males engaged in more social play (e.g. non-injurious play fighting: F(1,63) = 39.8, p < 0.001). Males also initiated more play bouts on average than females (F(1,62) = 4.41, p = 0.040). We conclude that the study of differences between litters and individuals provides a robust approach to understanding factors potentially influencing play behaviour in the pig. This work also provides support for the use of play as a welfare indicator in pre weaned piglets as the litter differences in play we observed were associated positively with physical development. PMID- 26937061 TI - The effect of isoflurane anaesthesia and buprenorphine on the mouse grimace scale and behaviour in CBA and DBA/2 mice. AB - Prevention or alleviation of pain in laboratory mice is a fundamental requirement of in vivo research. The mouse grimace scale (MGS) has the potential to be an effective and rapid means of assessing pain and analgesic efficacy in laboratory mice. Preliminary studies have demonstrated its potential utility for assessing pain in mouse models that involve potentially painful procedures. The next step in validation is to determine if the other procedures that are integral to these models, i.e. anaesthesia or analgesia, result in any changes in MGS score which would need to be taken into account when using this tool to assess post procedural pain. Here, spontaneous behaviour and MGS data for CBA and DBA/2 mice were recorded at baseline and following either isoflurane anaesthesia (suitable to perform abdominal surgery) or 0.05 mg/kg s.c. buprenorphine. In line with previous studies, isoflurane anaesthesia alone had limited effects on the spontaneous behaviour in either strain of mice. Administration of buprenorphine resulted in increased periods of activity e.g. walking and chewing bedding in CBA mice. These effects were not demonstrated in DBA/2 mice. In comparison, buprenorphine alone had no impact on MGS score in either strain of mice, however DBA/2 mice showed a significant increase in MGS score following isoflurane anaesthesia. The presence of this increased MGS score must be taken into account when attempting to use the MGS to assess pain in DBA/2 mice. Further work should be carried out to establish the presence of this isoflurane effect in other strains and the potential influence of gender on the MGS. This further validation is necessary prior to implementation of this technique in clinical scenarios. PMID- 26937062 TI - Simulation of air quality and cost to ventilate swine farrowing facilities in winter. AB - We developed a simulation model to study the effect of ventilation airflow rate with and without filtered recirculation on airborne contaminant concentrations (dust, NH3, CO, and CO2) for swine farrowing facilities. Energy and mass balance equations were used to simulate the indoor air quality and operational cost for a variety of ventilation conditions over a 3-month winter period, using time-varied outdoor temperature. The sensitivity of input and output parameters on indoor air quality and operational cost were evaluated. Significant factors affecting model output included mean winter temperature, generation rate of contaminants, pit-air exchange ratio, and recirculation ratio. As mean outdoor temperature was decreased from -2.5 degrees C to -12.5 degrees C, total operational costs were increased from $872 to $1304. Dust generation rate affected dust concentrations linearly. When dust generation rates changed -50% and +100% from baseline, indoor dust concentrations were changed -50% and +100%, respectively. The selection of a pit-air-exchange ratio was found critical to NH3 concentration, but has little impact on other contaminants or cost. As the pit-air-exchange ratio was increased from 0.1 to 0.3, the NH3 concentration was increased by a factor of 1.5. The recirculation ratio affected both IAQ factors and total operational cost. As the recirculation ratio decreased to 0, inhalable and respirable dust concentrations, humidity, NH3 and CO2 concentrations decreased and total operational cost ($2216) was 104% more than with pit-fan-only ventilation ($1088). When the recirculation ratio was 1, the total operational cost was increased by $573 (53%) compared to pit-fan-only. Simulation provides a useful tool for examining the costs and benefits to installing common ventilation technology to CAFO and, ultimately, making sound management decisions. PMID- 26937063 TI - Orientation to the sun by animals and its interaction with crypsis. AB - Orientation with respect to the sun has been observed in a wide range of species and has generally been interpreted in terms of thermoregulation and/or ultraviolet (UV) protection. For countershaded animals, orientation with respect to the sun may also result from the pressure to exploit the gradient of coloration optimally to enhance crypsis.Here, we use computational modelling to predict the optimal countershading pattern for an oriented body. We assess how camouflage performance declines as orientation varies using a computational model that incorporates realistic lighting environments.Once an optimal countershading pattern for crypsis has been chosen, we determine separately how UV protection/irradiation and solar thermal inflow fluctuate with orientation.We show that body orientations that could optimally use countershading to enhance crypsis are very similar to those that allow optimal solar heat inflow and UV protection.Our findings suggest that crypsis has been overlooked as a selective pressure on orientation and that new experiments should be designed to tease apart the respective roles of these different selective pressures. We propose potential experiments that could achieve this. PMID- 26937065 TI - High-Throughput Microfluidic Device for Rare Cell Isolation. AB - Enumerating and analyzing circulating tumor cells (CTCs)-cells that have been shed from primary solid tumors-can potentially be used to determine patient prognosis and track the progression of disease. There is a great challenge to create an effective platform that can isolate these cells, as they are extremely rare: only 1-10 CTCs are present in a 7.5mL of a cancer patient's peripheral blood. We have developed a novel microfluidic system that can isolate CTC populations label free. Our system consists of a multistage separator that employs inertial migration to sort cells based on size. We demonstrate the feasibility of our device by sorting colloids that are comparable in size to red blood cells (RBCs) and CTCs. PMID- 26937066 TI - The fruits of long endeavors - 200 years of oncology. PMID- 26937064 TI - Structural development of human brain white matter from mid-fetal to perinatal stage. AB - The structures of developing human brain white matter (WM) tracts can be effectively quantified by DTI-derived metrics, including fractional anisotropy (FA), mean, axial and radial diffusivity (MD, AD and RD). However, dynamics of WM microstructure during very early developmental period from mid-fetal to perinatal stage is unknown. It is difficult to accurately measure microstructural properties of these WM tracts due to severe contamination from cerebrospinal fluid (CSF). In this study, high resolution DTI of fetal brains at mid-fetal stage (20 weeks of gestation or 20wg), 19 brains in the middle of 3rd trimester (35wg) and 17 brains around term (40wg) were acquired. We established first population-averaged DTI templates at these three time points and extracted WM skeleton. 16 major WM tracts in limbic, projection, commissural and association tract groups were traced with DTI tractography in native space. The WM skeleton in the template space was inversely transformed back to the native space for measuring core WM microstructures of each individual tract. Continuous microstructural enhancement and volumetric increase of WM tracts were found from 20wg to 40wg. The microstructural enhancement from FA measurement is decelerated in late 3rd trimester compared to mid-fetal to middle 3rd trimester, while volumetric increase of prefrontal WM tracts is accelerated. The microstructural enhancement from 35wg to 40wg is heterogeneous among different tract groups with microstructures of association tracts undergoing most dramatic change. Besides decreases of RD indicating active myelination, the decrease of AD for most WM tracts during late 3rd trimester suggests axonal packing process. PMID- 26937067 TI - Therapeutic Issues with Gay and Lesbian Elders. PMID- 26937068 TI - Improving wheat to remove coeliac epitopes but retain functionality. AB - Coeliac disease is an intolerance triggered by the ingestion of wheat gluten proteins. It is of increasing concern to consumers and health professionals as its incidence appears to be increasing. The amino acid sequences in gluten proteins that are responsible for triggering responses in sensitive individuals have been identified showing that they vary in distribution among and between different groups of gluten proteins. Conventional breeding may therefore be used to select for gluten protein fractions with lower contents of coeliac epitopes. Molecular breeding approaches can also be used to specifically down-regulate coeliac-toxic proteins or mutate coeliac epitopes within individual proteins. A combination of these approaches may therefore be used to develop a "coeliac-safe" wheat. However, this remains a formidable challenge due to the complex multigenic control of gluten protein composition. Furthermore, any modified wheats must retain acceptable properties for making bread and other processed foods. Not surprisingly, such coeliac-safe wheats have not yet been developed despite over a decade of research. PMID- 26937070 TI - Microfluidic gradient device for studying mesothelial cell migration and the effect of chronic carbon nanotube exposure. AB - Cell migration is one of the crucial steps in many physiological and pathological processes, including cancer development. Our recent studies have shown that carbon nanotubes (CNTs), similarly to asbestos, can induce accelerated cell growth and invasiveness that contribute to their mesothelioma pathogenicity. Malignant mesothelioma is a very aggressive tumor that develops from cells of the mesothelium, and is most commonly caused by exposure to asbestos. CNTs have a similar structure and mode of exposure to asbestos. This has raised a concern regarding the potential carcinogenicity of CNTs, especially in the pleural area which is a key target for asbestos-related diseases. In this paper, a static microfluidic gradient device was applied to study the migration of human pleural mesothelial cells which had been through a long-term exposure (4 months) to subcytotoxic concentration (0.02 MUg cm-2) of single-walled CNTs (SWCNTs). Multiple migration signatures of these cells were investigated using the microfluidic gradient device for the first time. During the migration study, we observed that cell morphologies changed from flattened shapes to spindle shapes prior to their migration after their sensing of the chemical gradient. The migration of chronically SWCNT-exposed mesothelial cells was evaluated under different fetal bovine serum (FBS) concentration gradients, and the migration speeds and number of migrating cells were extracted and compared. The results showed that chronically SWCNT-exposed mesothelial cells are more sensitive to the gradient compared to non-SWCNT-exposed cells. The method described here allows simultaneous detection of cell morphology and migration under chemical gradient conditions, and also allows for real-time monitoring of cell motility that resembles in vivo cell migration. This platform would be much needed for supporting the development of more physiologically relevant cell models for better assessment and characterization of the mesothelioma hazard posed by nanomaterials. PMID- 26937071 TI - Cardiac and vascular changes with kidney transplantation. AB - Cardiovascular event rates are high in patients with chronic kidney disease (CKD), increasing with deteriorating kidney function, highest in CKD patients on dialysis, and improve with kidney transplantation (KTx). The cardiovascular events in CKD patients such as myocardial infarction and heart failure are related to abnormalities of vascular and cardiac structure and function. Many studies have investigated the structural and functional abnormalities of the heart and blood vessels in CKD, and the changes that occur with KTx, but the evidence is often sparse and occasionally contradictory. We have reviewed the available evidence and identified areas where more research is required to improve the understanding and mechanisms of these changes. There is enough evidence demonstrating improvement of left ventricular hypertrophy, except in children, and sufficient evidence of improvement of left ventricular function, with KTx. There is reasonable evidence of improvement in vascular function and stiffness. However, the evidence for improvement of vascular structure and atherosclerosis is insufficient. Further studies are necessary to establish the changes in vascular structure, and to understand the mechanisms of vascular and cardiac changes, following KTx. PMID- 26937072 TI - Prevalence and predictors of chronic kidney disease in newly diagnosed human immunodeficiency virus patients in Owerri, Nigeria. AB - Human immunodeficiency virus (HIV) infection is a common cause of chronic kidney disease (CKD) in Sub-Saharan Africa. This study aims at identifying the prevalence and predictors of CKD in newly diagnosed HIV patients in Owerri, South East Nigeria. This was a cross-sectional study consisting of 393 newly diagnosed HIV-seropositive subjects and 136 age- and sex-matched seronegative subjects as controls. CKD was defined as 24-hour urine protein (24-HUP) >=0.3 g and/or glomerular filtration rate (GFR) < 60 ml/min. Subjects were recruited from the HIV clinic and the Medical Outpatient Department of Federal Medical Centre, Owerri. Clinical and anthropometric data were collected. Relevant investigations were performed, including HIV screening and relevant urine and blood investigations. The mean age of the HIV subjects was 38.84 +/- 10.65 years. CKD was present in 86 (22.9%) HIV subjects and 11 (8.l %) controls. Low waist circumference (WC), high serum creatinine, high spot urine protein/creatinine ratio (SUPCR), high 24-HUP/creatinine Ratio (24-HUPCR), high 24-HUP/osmolality Ratio (24-HUPOR) predicted CKD in HIV subjects. CKD prevalence is high (22.9%) among newly diagnosed HIV patients in South East Nigeria. The predictors of CKD included WC, serum creatinine, SUPCR, 24-HUPCR, and 24-HUPOR. PMID- 26937073 TI - Biopsy-proven renal disease in Ile-Ife, Nigeria: A histopathologic review. AB - Although various patterns of renal diseases have been reported from different renal biopsy registries worldwide, data from Nigeria remain scanty. A 10-year retrospective review of renal biopsies was conducted in our tertiary health care facility. All cases were reclassified based on their light microscopic features after the application of standard histochemical stains. A total of 165 cases were reviewed with a male:female ratio of 1.8:1 and a mean age of 15.4 +/- 12.0 years. About 69.7% of the cases were below the age of 16 years, while only 2.4% were older than 50 years. The most common indications for biopsy were nephrotic syndrome (72.1%) and acute renal failure of unknown etiology (11.5%). Overall, glomerulonephritis (80%) was the most common histologic category and occurred only in individuals younger than 50 years old. Minimal change disease (22.9%) and membranoproliferative glomerulonephritis (21.9%) were the most common varieties in children, while membranous glomerulonephritis (30.6%) and focal segmental glomerulosclerosis (27.8%) were the commonest among the adult population. The initial histologic diagnosis was revised in 18 cases while a diagnosis was arrived at in seven cases initially adjudged as inadequate for assessment. This study showed that renal biopsy was predominantly performed in children and adolescents. Although glomerulonephritis was the predominant disease, the predominant histologic patterns varied with the patient age. Despite the scarcity of advanced diagnostic tools in resource-poor environments, routine use of histochemical stains is helpful in the evaluation of renal biopsies. PMID- 26937074 TI - Survival of elderly dialysis patients is not dependent on modality or "older" age. AB - While discussing renal replacement therapy, the choice of modality and survival on dialysis are important considerations. These issues are even more important in elderly group of patients. We studied the survival and factors affecting survival of our elderly dialysis patients. All incident patients who started dialysis from November 2006 to March 2014 were considered for inclusion. Patients who initiated dialysis at or >65 years of age and had completed 90 days of dialysis were included. Overall survival of elderly dialysis patients was determined. Patients were divided into two groups based on the modality of dialysis and age: elderly (65-70 years) and older (>70 years). The baseline data and survival were then compared between groups. Mean age of the study population was 71.8 +/- 6 years with 73.8% males, and 71.4% had diabetes. Median overall survival of the patients was 26.6 months. Median survival of elderly dialysis patients was 26.5 months and of older dialysis patients was 30.1 months (P = 0.9). Median survival of hemodialysis and PD patients was also similar (30.1 and 25.2 months respectively. Multivariate analysis showed diabetes as the only determining factor affecting survival (P = 0.01). To conclude, there is no difference between survival of elderly and "older" or between elderly hemodialysis and PD patients. PMID- 26937075 TI - Validity of nutrition risk index as a malnutrition screening tool compared with subjective global assessment in end-stage renal disease patients on peritoneal dialysis. AB - We undertook this study to compare subjective global assessment (SGA) and nutrition risk index (NRI) as malnutrition screening tools in peritoneal dialysis (PD) patients. Nutrition status of the patients was categorized into low, moderate and high risk of malnutrition based on both NRI and SGA. The sensitivity, specificity and predictive values of NRI were compared with SGA, an already validated tool of nutrition status assessment in PD patients. Two hundred and eighty-three end-stage renal disease patients (age 50.02 +/- 13.76 years; 204 males, 150 diabetic) were included. Based on SGA, 71/283 (25.08%) had normal nutrition, 192/283 (67.84%) mild-moderate and 20/283 (7.07%) severe malnutrition. Based on NRI, 38/283 (13.43%) patients had normal nutritional status, 193/283 (68.20%) mild-moderate and 52/283 (18.37%) severe malnutrition. Twenty-three of 283 (8.1%) were correctly classified as normal by NRI (true negative) and 197/283 (69.6%) as malnourished (true positive), 15/283 (5.3%) as false negative, 48/283 (16.96%) were misclassified as malnourished (false positive). NRI has sensitivity of 92.9% and specificity of 32.39%. Positive predictive value and Negative predictive values (NPVs) of NRI are 80.41% and 60.53%, respectively. Accuracy of the test is 78%. The receiver operating characteristic curve of NRI is 0.63. To conclude, NRI carries high sensitivity but low specificity as compared to SGA. It can be used as screening tool but not as a diagnostic tool for assessment of nutritional status in PD patients because of its low specificity and NPV. PMID- 26937077 TI - Dobrin syndrome: A case report and review of the literature. AB - Dobrin syndrome or tubulointerstitial nephritis and uveitis syndrome is a rare disease with excellent prognosis. We report a 60-year-old male of Indian origin who presented with acute interstitial nephritis (AIN) and unilateral anterior immune-mediated uveitis. The syndrome has been reported sporadically. This is only the third case from a patient of Indian origin. We highlight this case and evaluate the long-term use of nonsteroidal anti-inflammatory drug-induced AIN and uveitis as a potential causative factor. PMID- 26937076 TI - Fetuin-A and vascular calcification in Indian end-stage renal disease population. AB - Fetuin-A levels, its correlation with vascular calcification and other biochemical markers of chronic kidney disease-mineral and bone disorder (CKD-MBD) has not been studied in Indian end-stage renal disease population. Forty patients on dialysis for more than 3 months were studied. Biochemical parameters of CKD MBD, highly sensitive-C reactive protein (hs-CRP), lipid profile and fetuin-A levels were estimated. Multi-slice computed tomography (MSCT) at the level of L1 L4 was done, and calcification score calculated using AJ 130 smart score. Levels of fetuin-A were correlated with calcification score and biochemical markers of CKD-MBD. Mean fetuin-A levels were 0.33 +/- 0.098 g/l. Positive correlation of abdominal aortic calcification scores was found with age (P < 0.01) and duration of dialysis (P = 0.018). No correlation was detected between MSCT score, calcium phosphate product, intact parathyroid hormone, vitamin D, triglycerides and fetuin-A, and there was no correlation between fetuin-A levels, age, dialysis duration and calcium phosphate product but a significant correlations with vitamin D3 (P = 0.034), serum albumin (P = 0.002) was detected. Inverse correlation with hs-CRP was obtained. Patients with ischemic heart disease had numerically lower levels of fetuin-A (P = 0.427) and numerically higher MSCT score (P = 0.135). Patients with low hs-CRP (<10) had numerically higher fetuin-A levels (P = 0.090) and significantly low MSCT scores (P = 0.020). Calcium deposition seen on MSCT increases with age and duration of dialysis but is not related to fetuin-A levels. Inconclusive relationship exists with other parameters of CKD-MBD. Large controlled studies are needed to establish the role of fetuin-A in vascular calcification in Indian population. PMID- 26937078 TI - Plasma exchange in Immunoglobulin A nephropathy with thrombotic microangiopathy and acute cortical necrosis. AB - A 25-year-old female presented with decreased urine output, deranged renal function, thrombocytopenia, and hemolytic anemia. Kidney biopsy was consistent with thrombotic microangiopathy with acute cortical necrosis and Immunoglobulin A nephropathy (IgAN). Hemolytic anemia, thrombocytopenia and urine output improved after five sessions of plasma exchange. Renal function showed a delayed recovery and serum creatinine normalized by 3 months. This is first case of successful use of plasma exchange in hemolytic uremic syndrome with cortical necrosis associated with IgAN. PMID- 26937080 TI - An unusual case of cocoon abdomen in a patient on hemodialysis. AB - "Cocoon abdomen" or sclerosing encapsulating peritonitis is a rare cause of intestinal obstruction. It has been described in patients on continuous ambulatory peritoneal dialysis. The exact etiology is unknown, but pathogenesis rests on chronic peritoneal inflammation. No case has been reported so far in patients on hemodialysis. We hereby report a case of cocoon abdomen presenting as refractory ascites with intestinal obstruction in a patient on maintenance hemodialysis. PMID- 26937079 TI - Cytomegalovirus infection inducing flare of Behcet's disease with possible recurrence of glomerulonephritis after renal transplantation. AB - We present a case of young male with end-stage renal disease due to type III membranoproliferative glomerulonephritis (GN) and clinical features consistent with Behcet's disease (BD). He developed flare of BD 3 months after deceased donor renal transplantation following cytomegalovirus infection, in the form of oral and genital ulcers. He also had GN characterized by mild mesangial proliferation, neutrophilic infiltration and subepithelial, mesangial and intramembranous electron dense deposits, which could possibly be attributed to recurrence of renal disease due to BD. The clinical flare of BD was treated with colchicine with good response. PMID- 26937081 TI - Ataxia in a chronic kidney disease patient on anti-tubercular therapy. AB - Isoniazid is the mainstay of anti-tubercular therapy. Used in isolation or in combination with other anti-tubercular drugs, it is generally well-tolerated. While hepatotoxicity and neurotoxicity are reported, significant neurotoxicity remains uncommon. In this report, we present a case of rare neurological complication secondary to anti-tubercular therapy in a patient with stage 5 chronic kidney disease. PMID- 26937082 TI - An unusual case of nephrotic syndrome. AB - Nephrotic syndrome can be rarely due to inherited disorders of enzymes. One such variety is lecithin cholesterol acyltransferase deficiency. It leads to accumulation of unesterified cholesterol in the eye and other organs. We report a case of nephrotic syndrome with cloudy cornea and hypocholesterolemia with foam cells and lipid deposits on renal biopsy. Awareness about this rare disease may help in the early institution of specific measures to prevent progression to end stage renal disease. PMID- 26937083 TI - Renal lymphangiectasia: One disease, many names! PMID- 26937084 TI - Bladder diverticula. PMID- 26937086 TI - Nephrotic syndrome and acute renal failure as a presenting symptom of acute lymphoblastic leukemia. PMID- 26937085 TI - Pityriasis rubra pilaris and mesangial proliferative glomerulonephritis in a child: Association or coincidence? PMID- 26937087 TI - Chronic active antibody mediated rejection associated with human leukocyte antigen-C*07 antibodies. PMID- 26937088 TI - Adnexal torsion in an adolescent renal transplant recipient. PMID- 26937089 TI - Purple urine bag syndrome in chronic kidney disease. PMID- 26937090 TI - Act faster for your chronic kidney disease patients. PMID- 26937091 TI - Predictors of left ventricular dysfunction with right ventricular pacing: Is paced QRS duration the answer? PMID- 26937092 TI - Paced QRS duration predicts left ventricular function in patients with permanent pacemakers - One-year follow-up study using equilibrium radionuclide angiography (ERNA). AB - Permanent pacing, being non physiological, often results in ventricular dysfunction over time. Narrower paced QRS duration from pacing the right ventricular outflow tract septum, might result in relatively preserved ventricular function over long term follow up. PMID- 26937093 TI - Anesthetic management in atrial fibrillation ablation procedure: Adding non invasive ventilation to deep sedation. AB - Anesthetic management of patients undergoing pulmonary vein isolation for atrial fibrillation has specific requirements. The feasibility of non-invasive ventilation (NIV) added to deep sedation procedure was evaluated. Seventy-two patients who underwent ablation procedure were retrospectively revised, performed with (57%) or without (43%) application of NIV (Respironic((r)) latex-free total face mask connected to Garbin ventilator-Linde Inc.) during deep sedation (Midazolam 0.01-0.02 mg/kg, fentanyl 2.5-5 MUg/kg and propofol: bolus dose 1-1.5 mg/kg, maintenance 2-4 mg/kg/h). In the two groups (NIV vs deep sedation), differences were detected in intraprocedural (pH 7.37 +/- 0.05 vs 7.32 +/- 0.05, p = 0.001; PaO2 117.10 +/- 27.25 vs 148.17 +/- 45.29, p = 0.004; PaCO2 43.37 +/- 6.91 vs 49.33 +/- 7.34, p = 0.002) and in percentage variation with respect to basal values (pH -0.52 +/- 0.83 vs -1.44 +/- 0.87, p = 0.002; PaCO2 7.21 +/- 15.55 vs 34.91 +/- 25.76, p = 0.001) of arterial blood gas parameters. Two episodes of respiratory complications, treated with application of NIV, were reported in deep sedation procedure. Endotracheal intubation was not necessary in any case. Adverse events related to electrophysiological procedures and recurrence of atrial fibrillation were recorded, respectively, in 36% and 29% of cases. NIV proved to be feasible in this context and maintained better respiratory homeostasis and better arterial blood gas balance when added to deep sedation. PMID- 26937095 TI - Overcoming the challenge of venous occlusion for lead implantation. AB - Vein stenosis or occlusion is a frequent finding in patients with previously implanted transvenous leads. This editorial describes the different techniques that may be used to overcome this hurdle in case a new lead needs to be implanted, and discusses two case reports in this issue of the journal. PMID- 26937094 TI - Syncope: Assessment of risk and an approach to evaluation in the emergency department and urgent care clinic. AB - Syncope is among the most frequent forms of transient loss of consciousness (TLOC), and is characterized by a relatively brief and self-limited loss of consciousness that by definition is triggered by transient cerebral hypoperfusion. Most often, syncope is caused by a temporary drop of systemic arterial pressure below that required to maintain cerebral function, but brief enough not to cause permanent structural brain injury. Currently, approximately one-third of syncope/collapse patients seen in the emergency department (ED) or urgent care clinic are admitted to hospital for evaluation. The primary objective of developing syncope/TLOC risk stratification schemes is to provide guidance regarding the immediate prognostic risk of syncope patients presenting to the ED or clinic; thereafter, based on that risk assessment physicians may be better equipped to determine which patients can be safely evaluated as outpatients, and which require hospital care. In general, the need for hospitalization is determined by several key issues: i) the patient's immediate (usually considered 1 week to 1 month) mortality risk and risk for physical injury (e.g., falls risk), ii) the patient's ability to care for him/herself, and iii) whether certain treatments inherently require in-hospital initiation (e.g., pacemaker implantation). However, at present no single risk assessment protocol appears to be satisfactory for universal application, and development of a consensus recommendation is an essential next step. PMID- 26937096 TI - Contralateral transvenous left ventricular lead placement of implantable devices with pre-sternal tunnelling in chronically obstructed subclavian veins. AB - Cardiac resynchronisation therapy (CRT) is a recognised therapy for the management of severe left ventricular dysfunction, advanced congestive cardiac failure (NYHA III or IV), ventricular dyssynchrony (either broad LBBB or mechanical dyssynchrony on echocardiography) and failure of optimal medical therapy to achieve improvement in clinical status. Upgrading right ventricular pacemakers or defibrillators to biventricular devices is common and we describe here, 2 such cases of biventricular upgrade with blocked venous access on the ipsilateral side and successful placement of left ventricular leads following pre sternal tunnelling from the contralateral side. PMID- 26937097 TI - Overcoming a subclavian complete occlusion: Simple single lead extraction by the subclavian vein allowing implantation of two new leads and upgrade to CRT-P with multi-site pacing. AB - Central venous obstruction following pacemaker implantation is not uncommon, and can prove challenging in the case of system upgrade. We report a case of DDDR to CRT-P (with multi-site pacing) upgrade, where a subclavian occlusion was overcome resorting to an atrial lead extraction (using only a locking stylet). This allowed regaining of the venous access with subsequent implantation of not just one, but two new leads and subsequent successful upgrade. PMID- 26937098 TI - Delayed AICD therapy and cardiac arrest resulting from undersensing of ventricular fibrillation in a subject with hypertrophic cardiomyopathy-A case report. AB - Defibrillation testing is no longer routinely performed after automatic implantable cardioverter-defibrillator (AICD) implantation. However, certain subjects undergoing AICD implantation may be at higher risk of undersensing of ventricular arrhythmias resulting in potentially fatal outcomes. We present the case of a 30-year-old woman with hypertrophic cardiomyopathy (HCM; 'asymmetric septal hypertophy' morphologic variant) and prophylactic AICD who experienced an out of hospital cardiac arrest. AICD interrogation revealed undersensing as a result of intermittent high amplitude electrograms during an episode of ventricular fibrillation (VF). The subject underwent replacement and repositioning of the AICD lead along with pulse generator replacement (that utilized a different VF sensing algorithm) with appropriate sensing of VF and successful defibrillation testing. The presence of intermittent high amplitude electrograms during episodes of VF in AICDs using the AGC function should be recognized as a situation that may necessitate interventions to prevent undersensing and consequent delay in therapy. PMID- 26937099 TI - Utility of unipolar recordings for complex Wolff-Parkinson-White ablation. AB - Radiofrequency ablation has been shown to be a safe and effective treatment strategy for the management of symptomatic patients with Wolff-Parkinson-White syndrome. It is supported by a success rate of 95% and a recurrence rate of less than 5%. However, ablation of accessory pathways can be challenging at times. The causes for failure can be grouped into three categories - unusual location of the pathway, technical difficulties in delivering the ablation and localization error [1]. In this case report we are reporting a case of a young male who presented to us with symptomatic Wolff-Parkinson-White syndrome with two failed prior ablations at another institution. This case illustrates the importance of knowing accurate localization and course of the accessory pathway by utilizing the unipolar and bipolar electrograms simultaneously during radiofrequency ablation. PMID- 26937100 TI - Isolation of persistent left superior vena cava during atrial fibrillation ablation. AB - Persistent left superior vena cava is a rarely seen anomaly but it may be an arrhythmogenic source for paroxysmal atrial fibrillation. Furthermore, the complex anatomicregion between the left superior vena cava and the pulmonary veins may leads to misinterpretation of the pulmonary vein recordings during atrial fibrillation ablation. Approaches that might be helpful to overcome these problems are discussed in this case report. PMID- 26937101 TI - Dual chamber pacing mode in an atrial antitachycardia pacing device without a ventricular lead - A necessary evil. AB - We present a case of a single chamber atrial pacemaker implanted for sinus node dysfunction and treatment of macroreentrant atrial tachycardias with atrial antitachycardia pacing. The patient presented with sustained atrial tachycardia above the detection rate, however, the device was unable to detect the tachycardia and did not deliver the programmed therapy. We discuss the nuances of the atrial tachyarrhythmia detection algorithms, and the programming strategies to maximize detection of atrial arrhythmias in a single chamber atrial pacemaker. PMID- 26937102 TI - Successful ablation of premature ventricular contractions originating from the ascending aorta. PMID- 26937103 TI - An unusual course of a pacemaker lead in congenitally corrected transposition of the great arteries. PMID- 26937104 TI - Current research on the relevance of electrocardiography in cardiac resynchronization therapy. PMID- 26937105 TI - IPEJ: A journey of one and half decades. PMID- 26937106 TI - IPEJ: The journey continues. PMID- 26937107 TI - New technologies for catheter based treatment of paroxysmal atrial fibrillation - Everything under control? PMID- 26937108 TI - Pulmonary vein isolation using new technologies to improve ablation lesion formation: Initial results comparing enhanced catheter tip irrigation (Surround Flow((r))) with contact force measurement (Smarttouch((r))). AB - INTRODUCTION: Pulmonary vein reconnection after pulmonary vein isolation (PVI) is a significant problem in the treatment of paroxysmal atrial fibrillation (AF). We report about patients who underwent contact force (CF) guided PVI using CF catheter and compared them to patients with PVI using an ablation catheter with enhanced tip irrigation. METHODS: A total of 59 patients were included in the analysis. In 30 patients circumferential PVI was performed using the Thermocool Smarttouch((r)) ablation catheter (ST) whereas in 29 patients circumferential PVI using the Thermocool Surround Flow SF((r)) ablation catheter (SF) was performed. Patients were compared in regard to procedure time, fluoroscopy time/dose as well as RF-application duration and completeness of PVI. Adverse events (pericardial effusion, PV stenosis, stroke, death) were evaluated. The presence of sinus rhythm off antiarrhythmic medication was assessed during 6 months follow-up using multiple 7 day Holter-ECGs. RESULTS: In both groups, all PVs were isolated without serious adverse events. Procedure time was 2.15 +/- 0.5 h (ST) vs. 2.37 +/- 1.13 h (SF) (p = 0.19). Duration of RF-applications was 46.6 +/- 18 min (ST) and 49.8 +/- 19 min (SF) (p = 0.52). Fluoroscopy time was 25.2 +/- 13 min (ST) vs. 29 +/- 18 min (SF), fluoroscopy dose 2675.6 +/- 1658 versus 3038.3 +/- 1997 cGym(2) (p = 0.36 and 0.46 respectively). Sinus rhythm off antiarrhythmic medication validated with 7 day Holter ECGs was present in both groups in 72% of patients after 6 months of follow up. CONCLUSION: PVI using the new contact force catheter is safe and effective in patients with paroxysmal AF. PMID- 26937109 TI - Recurrent syncope in the Andersen Tawil syndrome - Cardiac or neurological? PMID- 26937110 TI - Case report: Ablation of diffuse inter-trabecular substrate in a patient with isolated ventricular non-compaction. PMID- 26937111 TI - Preferential conduction travelling from the left coronary cusp to the right ventricular outflow tract via the right coronary cusp of the aorta. AB - This report describes a case of premature ventricular contractions with the preferential pathway traveling from the left coronary cusp (LCC) to the right ventricular outflow tract (RVOT) via the right coronary cusp (RCC). The earliest activation was recorded within the LCC, while the successful ablation site was the RCC, where the second earliest prepotential was recorded. The remediable ablation site for ventricular arrhythmias (VAs) arising from the left ventricular (LV) ostium may not necessarily be the site of the earliest activation, but may be the site with the potential representing the preferential pathway. PMID- 26937112 TI - Successful cryoablation of an incessant atrial tachycardia arising from the right atrial appendage. AB - The right atrial appendage can be the origin of focal atrial tachycardias. Their ablation can be challenging owing to the complexity of the appendage anatomy. To our knowledge, we describe the first successful solid tip cryoablation of a focal tachycardia within the right atrial appendage in a patient presenting with tachycardia-induced cardiomyopathy. PMID- 26937113 TI - Double-gap-in-roof reentrant tachycardia following surgical thoracoscopic atrial fibrillation ablation. AB - A case of macro-reentrant tachycardia associated with a box lesion after thoracoscopis left atrial surgical atrial fibrillation (AF) ablation yet to be described. The goal was to clarify the mechanisms and electrophysiological characteristics of this type of tachycardia. A patient was admitted for an EP study following surgical thoracoscopic AF ablation (box lexion formation by right sided Cobra thoracoscopic ablation). Thoracoscopic ablation was done as the first step of the hybrid ablation approach to the persistent AF; the second step was the EP study. At the EP study, he presented with incessant regular tachycardia (cycle length of 226 ms). An EP study with conventional, 3D activation and entrainment mapping was done to assess the tachycardia mechanism. Two conduction gaps in the superior line (roofline) between the superior pulmonary veins were discovered. The tachycardia was successfully treated with a radiofrequency application near the gap close to the left superior pulmonary vein; however, following tachycardia termination, pulmonary vein isolation was absent. A second radiofrequency application, close to the roof of the right superior pulmonary, vein closed the gap in the box and led to the isolation of all 4 pulmonary veins. No atrial tachycardia recurred during the 6-month follow-up. Conduction gaps in box lesion created by thoracospcopic ablation can present as a novel type of man made tachycardia after surgical ablation of atrial fibrillation. Activation and entrainment mapping is necessary for an accurate diagnosis. PMID- 26937114 TI - Atrial sensor, remote monitoring and new anticoagulant drugs: Identification and treatment of a patient with unknown and asymptomatic atrial flutter. AB - This case report describes how new tools and technologies can drive a different approach in the management of arrhythmic patients. An unknown and asymptomatic atrial flutter was detected by the atrial sensor mounted in a single lead implantable cardioverter defibrillator. Moreover daily remote monitoring of the device allowed early notification and prompt clinical reaction. Anticoagulant therapy onset, radiofrequency ablation and the following anticoagulant therapy removal were driven by the device data transmissions. PMID- 26937115 TI - Diagnostic dilemma with a narrow QRS regular rhythm at normal rates in a patient with corrected transposition of great arteries. AB - A 35 year old male, known case of corrected transposition of great arteries presented with exertional dyspnea and recurrent pre-syncope. 12 lead electrocardiogram revealed a regular rhythm at 75 beats per minute, P waves occurring on the upstroke of T waves and apparent 1:1 P-QRS relationship. The possibilities to be considered - complete AV block with junctional escape, junctional rhythm with 1:1 retrograde conduction, junctional rhythm with isorhythmic AV dissociation and prolonged PR interval have been discussed. PMID- 26937116 TI - An inappropriate defibrillator shock during ventricular tachycardia. AB - Ventricular oversensing in patients with defibrillators is an infrequent but deleterious condition. We report a patient with a cardiac resynchronization defibrillation device that presented with hyperkalemia and syncope. Device interrogation revealed ventricular double-counting within the QRS of a slow ventricular tachycardia, resulting detection of the slow ventricular tachycardia in the ventricular fibrillation zone, and delivery of an effective therapy, below device programmed detection rate. This case of defibrillator inappropriate detection emphasizes the relevance of device electrogram interrogation in order to minimize inappropriate therapies. PMID- 26937117 TI - Tilt test in paced patients: Is it worth the effort? PMID- 26937119 TI - Deep breathing-triggered atrial fibrillation: An unusual mechanism terminated by focal RF ablation. PMID- 26937118 TI - Tilt-table testing of patients with pacemaker and recurrent syncope. AB - The diagnosis of recurrent syncope in patients with pacemakers (PM) is quite challenging and the etiology of syncope is often multifactorial. To portray the mechanism of syncope in PM patients, we report the results of head-up tilt table testing (HUT) in a series of patients with PM, originally implanted for reasons other than neurally mediated syncope, referred due to syncope or pre-syncope (aborted syncope, vertigo, suspected orthostatic hypotension). Forty-one patients with PM undergoing a HUT in our syncope unit between January 1st, 2007 and December 31st 2011 were included. A standard HUT protocol with nitroglycerine provocation was used and the test results were classified according to current guidelines. Baseline data were retrieved from the medical records. Overall, 54% of patients had a positive response to HUT. Vasodepressor or orthostatic hypotensive response were the most prevalent responses accounting for 72% of patients with a positive test. There were no differences between groups with positive or negative test result regarding age, gender, resting blood pressure and heart rate, daily fluid intake, pacing mode, pacing indication or pacing rhythm at rest. HUT in patients with pacemakers has a high diagnostic yield. Although, the majority of patients had a vasodepressor or orthostatic hypotensive response, cardioinhibitory response leading to syncope was also seen. PMID- 26937120 TI - Catheter ablation of accessory pathway between the right atrial appendage and the right ventricle: A case report. PMID- 26937121 TI - Successful ablation of frequent atrial premature beats from non-coronary aortic cusp with remote magnetic navigation. AB - A 59-year-old female with structurally normal heart was admitted to our hospital for treatment of highly symptomatic, drug refractory atrial premature beats (APB). ECG revealed atrial parasystolic trigeminy. The arrhythmogenic focus was mapped and ablated using magnetic remote navigation and 3D electroanatomical mapping system. To our knowledge, this is the first report on successful ablation of frequent APBs in the non-coronary aortic cusp. PMID- 26937122 TI - Ablation of an orthodromic reentrant tachycardia via a concealed accessory pathway targeted in the non-coronary sinus. PMID- 26937123 TI - An unusual cause of recurrent syncope in a patient with implantable cardioverter defibrillator. AB - Electromagnetic interferences (EMI) deriving from electrical devices may affect implantable cardioverter defibrillators (ICD). Improved algorithms have been developed in order to minimize adverse effects. However, caution should be still recommended in ICD recipients when handling electrical devices. Here we describe the case of an ICD patient with recurrent syncopal episodes due to inhibition of pacing by oversensing of electrical noise from a not properly grounded washing machine. PMID- 26937124 TI - Acute transient non-physiological over-sensing in the ventricle with a DF4 lead. AB - The DF-4 is a new defibrillator lead technology. We present two cases of non physiological transient ventricular over-sensing in patients who underwent implantation of an ICD for secondary prevention. Case 1 had ventricular over sensing during pacing threshold evaluation post defibrillation testing while Case 2 had the lead integrity alert triggered immediately post discharge with transient over-sensing. No lead-connector issues were found. Case 1 was likely due to improper venting of the header and trapped air. Case 2 was hypothesized to be due to intermittent header pin non-contact secondary to blood in the header. These cases reveal that DF-4 leads are subject to both reported and potentially novel causes of transient acute ventricular over-sensing. PMID- 26937125 TI - An unusual WPW syndrome: What is the preexcitation variant? AB - A 15-year-old female with WPW syndrome and normal heart underwent an electrophysiology study for paroxysmal palpitations and syncope. Intravenous adenosine produced an unexpected response of QRS changes and advanced AV block. During isoproteronol infusion, short-lasting and poorly tolerated wide QRS tachycardia was inducible, but pacing maneuvers were not feasible during tachycardia to determine its definitive mechanism. However, various electrophysiologic phenomena including adenosine response, junctional beats pattern, and multisite atrial pacing were helpful to overcome the diagnosis challenges. Finally, careful evaluation of tachycardia features and the comprehensive electrophysiology study were crucial to establish presence of unusual preexcitation variants, and thus to guide successful catheter ablation of the arrhythmic substrate. PMID- 26937126 TI - Dual atrial rhythm on electrocardiogram. PMID- 26937128 TI - Association of air pollution on birth outcomes in New Delhi - a pilot study on the potential of HMIS data for environmental public health tracking. AB - OBJECTIVES: The study objective was to assess the gaps in current hospital health management information systems (ie. paper based records of prenatal, delivery, neonatal, discharge data) for environmental studies. This study also considers the feasibility of linking patient-level hospital data with ambient air pollution data recorded in real time by air quality monitoring stations. METHODS: This retrospective hospital based cohort study used a semi-ecologic design to explore the association of air pollution with a neonate's birth weight and gestational age. Maternal and neonatal data from 2007-2012 were encoded and linked with air pollution data based on distance to the nearest air quality monitoring station. Completeness and accuracy of neonatal anthropometric measures, maternal demographic information, nutritional status and maternal risk factors (gestational diabetes, anaemia, hypertension, etc.) were assessed. RESULTS: The records of 10,565 births in Sir Ganga Ram hospital in New Delhi were encoded and linked with real time air quality data. These were records of women who reported a New Delhi address during the time of delivery. The distance of each address to all the monitoring stations were recorded. Birth records were assigned pollution exposure levels averaged across records from monitoring stations within 10 kilometers of the address during the pregnancy period. CONCLUSION: This pilot study will highlight the potential of hospital management information system in linking administrative hospital record data with information on environmental exposure. The linked health-exposure dataset can then be used for studying the impact of various environmental exposures on health outcomes. Mother's educational attainment, occupation, residential history, nutritional status, tobacco and alcohol use during pregnancy need to be documented for better health risk assessments or case management. Health institutions can provide data for public health researchers and environmental scientists and can serve as the backbone of an environmental public health tracking system. PMID- 26937127 TI - Alternative polyadenylation can regulate post-translational membrane localization. AB - For many genomic loci, there are more than one potential cleavage and polyadenylation site, resulting in the generation of multiple distinct transcripts. When the proximal polyadenylation site is present within the coding region of the transcript, alternative polyadenylation can result in proteins with distinct amino acid sequences and potentially distinct functions. In most cases, the different possible polyadenylation sites are all present within the 3' untranslated regions (UTRs), and the amino acid sequence of the encoded proteins are not affected by polyadenylation site selection. In individual instances, the selection of the proximal versus distal polyadenylation site in the 3'UTR can dramatically affect transcript stability and translatability. In some instances, UTR alternative polyadenylation generates RNA isoforms that have distinct subcellular localization patterns, and that can regulate the location of the encoded protein in an RNA-guided manner. In a recent paper, the laboratory of Christine Mayr demonstrated that alternative polyadenylation of the transmembrane protein CD47 results in transcripts with the same localization pattern, but the encoded protein localizes to the endoplasmic reticulum when it is encoded by the transcript generated by using the proximal polyadenylation site in 3'UTR, and the identical protein localizes to the plasma membrane when the transcript is encoded by the distal polyadenylation site, also in the 3' UTR. Unlike previous studies, the mechanism of localization does not rely on differential trafficking of the mRNA and is instead, based on RNA-mediated recruitment of proteins to the cytoplasmic side of CD47 that support its plasma membrane localization. Other transmembrane proteins were discovered to be regulated similarly. The results demonstrate that the choice of polyadenylation site can affect protein localization and function, even when the sequence of the protein is unaffected. Further, the transcript encoding a protein can serve as a scaffold to recruit additional proteins that affect the protein's fate. PMID- 26937129 TI - Advanced gastric cancer: Current treatment landscape and future perspectives. AB - Gastric cancer currently ranks fourth in cancer-related mortality worldwide. In the western world, it is most often diagnosed at an advanced stage, after becoming metastatic at distant sites. Patients with advanced disease (locally advanced or metastatic) have a somber prognosis, with a median overall survival of 10-12 mo, and palliative chemotherapy is the mainstay of treatment. In recent years, novel approaches using inhibition of human epidermal growth factor receptor 2 (HER2) have demonstrated significant improvements in progression-free and overall survival, compared with chemotherapy alone, in first-line treatment of patients with overexpression of HER2. In addition, both second-line chemotherapy and treatment with the vascular endothelial growth factor receptor inhibitor ramucirumab demonstrated significant benefits in terms of overall survival, compared with best supportive care, in randomized studies. Moreover, ramucirumab in combination with chemotherapy demonstrated further significant benefits in terms of progression-free and overall survival, compared with chemotherapy alone, in second-line treatment for patients with metastatic gastric cancer. A recently published molecular classification of gastric cancer is expected to improve patient stratification and selection for clinical trials and provide a roadmap for future drug development. Nevertheless, despite these developments the prognosis of patients with advanced gastric cancer remains poor. In this review we discuss current standards of care and outline major topics of drug development in gastric cancer. PMID- 26937130 TI - Fibroblast growth factor receptor signaling as therapeutic targets in gastric cancer. AB - Fibroblast growth factor receptors (FGFRs) regulate a variety of cellular functions, from embryogenesis to adult tissue homeostasis. FGFR signaling also plays significant roles in the proliferation, invasion, and survival of several types of tumor cells. FGFR-induced alterations, including gene amplification, chromosomal translocation, and mutations, have been shown to be associated with the tumor initiation and progression of gastric cancer, especially in diffuse type cancers. Therefore, the FGFR signaling pathway might be one of the therapeutic targets in gastric cancer. This review aims to provide an overview of the role of FGFR signaling in tumorigenesis, tumor progression, proliferation, and chemoresistance. We also discuss the accumulating evidence that demonstrates the effectiveness of using clinical therapeutic agents to inhibit FGFR signaling for the treatment of gastric cancer. PMID- 26937131 TI - Current status in remnant gastric cancer after distal gastrectomy. AB - Remnant gastric cancer (RGC) and gastric stump cancer after distal gastrectomy (DG) are recognized as the same clinical entity. In this review, the current knowledges as well as the non-settled issues of RGC are presented. Duodenogastric reflux and denervation of the gastric mucosa are considered as the two main factors responsible for the development of RGC after benign disease. On the other hand, some precancerous circumstances which already have existed at the time of initial surgery, such as atrophic gastritis and intestinal metaplasia, are the main factors associated with RGC after gastric cancer. Although eradication of Helicobacter pylori (H. pylori) in remnant stomach is promising, it is still uncertain whether it can reduce the risk of carcinogenesis. Periodic endoscopic surveillance after DG was reported useful in detecting RGC at an early stage, which offers a chance to undergo minimally invasive endoscopic treatment or laparoscopic surgery and leads to an improved prognosis in RGC patients. Future challenges may be expected to elucidate the benefit of eradication of H. pylori in the remnant stomach if it could reduce the risk for RGC, to build an optimal endoscopic surveillance strategy after DG by stratifying the risk for development of RGC, and to develop a specific staging system for RGC for the standardization of the treatment by prospecting the prognosis. PMID- 26937132 TI - Emerging molecular basis of hematogenous metastasis in gastric cancer. AB - Lymphatic metastasis is commonly observed in gastric cancer (GC), but hematogenous metastasis is more likely responsible for the cancer-related mortality. Since Stephen Paget first introduced the "seed and soil hypothesis" a century ago, growing evidence recognizes that numerous essential secreted factors and signaling pathway effectors participate in the pre-metastatic niche formation and distant organ metastasis. The cross-talk between GC cells and surrounding microenvironment may consist of a series of interrelated steps, including epithelial mesenchymal transition, intravasation into blood vessels, circulating tumor cell translocation, and secondary organ metastasis. Secreted factors including vascular endothelial growth factor (VEGF), matrix metalloproteinases and cancer-derived extracellular vesicles, especially exosomes, are essential in formation of premetastatic niche. Circulating tumor cells and microRNAs represent as ''metastatic intermediates'' between primary tumors and sites of dissemination. Many biomarkers have been identified as novel metastatic markers and prognostic effectors. In addition, molecular therapy has been designed to target biomarkers such as growth factors (human epidermal growth factor receptor 2, VEGF) and chemokines, although they have not clearly proven to be effective in inhibiting GC metastasis in clinical trials. In this review, we will systematically discuss the emerging molecules and their microenvironment in hematogenous metastasis of GC, which may help us to find new therapeutic strategies in the future. PMID- 26937135 TI - Estrogen receptors in gastric cancer: Advances and perspectives. AB - Worldwide, gastric cancer is one of the most common malignancies with high mortality. Various aspects of the development and progression of gastric cancer continue to be extensively investigated in order to further our understanding and provide more effective means for the prevention, diagnosis, and treatment of the disease. Estrogen receptors (ERs) are steroid hormone receptors that regulate cellular activities in many physiological and pathological processes in different tissues. There are two distinct forms of ERs, namely ERalpha and ERbeta, with several alternative-splicing isoforms for each. They show distinct tissue distribution patterns and exert different biological functions. Dysregulation of ERs has been found to be associated closely with many diseases, including cancer. A number of studies have been conducted to investigate the role of ERs in gastric cancer, the possible mechanisms underlying these roles, and the clinical relevance of deregulated ERs in gastric cancer patients. To date, inconsistent associations of different ERs with gastric cancer have been reported. These inconsistencies may be caused by variations in in vitro cell models and clinical samples, including assay conditions and protocols with regard to different forms of ERs. Given the potential of the deregulated ERs as diagnostic/prognostic markers or therapeutic targets for gastric cancer, it will be important to identify/confirm the association of each ER isoform with gastric cancer, to determine the specific roles and interactions that these individual ER isoforms play under specific conditions in the development and/or progression of gastric cancer, and to elucidate precisely these mechanisms. In this review, we summarize the achievements from early ER studies in gastric cancer to the most up-to-date discoveries, with an effort to provide a comprehensive understanding of the role of ERs roles in gastric cancer and its possible mechanisms. Furthermore, we propose directions for future investigations. PMID- 26937134 TI - Molecular alterations in gastric cancer with special reference to the early-onset subtype. AB - Currently, gastric cancer (GC) is one of the most frequently diagnosed neoplasms, with a global burden of 723000 deaths in 2012. It is the third leading cause of cancer-related death worldwide. There are numerous possible factors that stimulate the pro-carcinogenic activity of important genes. These factors include genetic susceptibility expressed in a single-nucleotide polymorphism, various acquired mutations (chromosomal instability, microsatellite instability, somatic gene mutations, epigenetic alterations) and environmental circumstances (e.g., Helicobcter pylori infection, EBV infection, diet, and smoking). Most of the aforementioned pathways overlap, and authors agree that a clear-cut pathway for GC may not exist. Thus, the categorization of carcinogenic events is complicated. Lately, it has been claimed that research on early-onset gastric carcinoma (EOGC) and hereditary GC may contribute towards unravelling some part of the mystery of the GC molecular pattern because young patients are less exposed to environmental carcinogens and because carcinogenesis in this setting may be more dependent on genetic factors. The comparison of various aspects that differ and coexist in EOGCs and conventional GCs might enable scientists to: distinguish which features in the pathway of gastric carcinogenesis are modifiable, discover specific GC markers and identify a specific target. This review provides a summary of the data published thus far concerning the molecular characteristics of GC and highlights the outstanding features of EOGC. PMID- 26937137 TI - Hepatocellular carcinoma and non-alcoholic steatohepatitis: The state of play. AB - Hepatocellular carcinoma (HCC) is now the fifth cancer of greatest frequency and the second leading cause of cancer related deaths worldwide. Chief amongst the risks of HCC are hepatitis B and C infection, aflatoxin B1 ingestion, alcoholism and obesity. The latter can promote non-alcoholic fatty liver disease (NAFLD), that can lead to the inflammatory form non-alcoholic steatohepatitis (NASH), and can in turn promote HCC. The mechanisms by which NASH promotes HCC are only beginning to be characterized. Here in this review, we give a summary of the recent findings that describe and associate NAFLD and NASH with the subsequent HCC progression. We will focus our discussion on clinical and genomic associations that describe new risks for NAFLD and NASH promoted HCC. In addition, we will consider novel murine models that clarify some of the mechanisms that drive NASH HCC formation. PMID- 26937133 TI - Peroxisome proliferator activated receptors at the crossroad of obesity, diabetes, and pancreatic cancer. AB - Pancreatic ductal adenocarcinoma (PDAC) is the fourth cause of cancer death with an overall survival of 5% at five years. The development of PDAC is characteristically associated to the accumulation of distinctive genetic mutations and is preceded by the exposure to several risk factors. Epidemiology has demonstrated that PDAC risk factors may be non-modifiable risks (sex, age, presence of genetic mutations, ethnicity) and modifiable and co-morbidity factors related to the specific habits and lifestyle. Recently it has become evident that obesity and diabetes are two important modifiable risk factors for PDAC. Obesity and diabetes are complex systemic and intertwined diseases and, over the years, experimental evidence indicate that insulin-resistance, alteration of adipokines, especially leptin and adiponectin, oxidative stress and inflammation may play a role in PDAC. Peroxisome proliferator activated receptor-gamma (PPARgamma) is a nuclear receptor transcription factor that is implicated in the regulation of metabolism, differentiation and inflammation. PPARgamma is a key regulator of adipocytes differentiation, regulates insulin and adipokines production and secretion, may modulate inflammation, and it is implicated in PDAC. PPARgamma agonists are used in the treatment of diabetes and oxidative stress-associated diseases and have been evaluated for the treatment of PDAC. PPARgamma is at the cross-road of diabetes, obesity, and PDAC and it is an interesting target to pharmacologically prevent PDAC in obese and diabetic patients. PMID- 26937138 TI - Sphingosine kinase 1 is upregulated with lysophosphatidic acid receptor 2 in human colorectal cancer. AB - AIM: To examine the expression of SphK1, an oncogenic kinase that produces sphingosine 1-phosphate (S1P), and its correlation with the expression of LPAR2, a major lysophosphatidic acid (LPA) receptor overexpressed in various cancers, in human colorectal cancer. METHODS: Real-time reverse-transcription polymerase chain reaction was used to measure the mRNA expression of SphK1, LPAR2, and the three major S1P receptors in 27 colorectal cancer samples and corresponding normal tissue samples. We also examined the correlation between the expression of SphK1 and LPAR2. RESULTS: Colorectal cancer tissue in 22 of 27 patients had higher levels of SphK1 mRNA than in normal tissue. In two-thirds of the samples, SphK1 mRNA expression was more than two-fold higher than in normal tissue. Consistent with previous reports, LPAR2 mRNA expression in 20 of 27 colorectal cancer tissue samples was higher compared to normal tissue samples. Expression profiles of all three major S1P receptors, S1PR1, S1PR2, and S1PR3, varied without any trend, with no significant difference in expression between cancer and normal tissues. A highly significant positive correlation was found between SphK1 and LPAR2 expression [Pearson's correlation coefficient (r) = 0.784 and P < 0.01]. The mRNA levels of SphK1 and LPAR2 did not correlate with TNM stage. CONCLUSION: Our findings suggest that S1P and LPA may play important roles in the development of colorectal cancer via the upregulation of SphK1 and LPAR2, both of which could serve as new therapeutic targets in the treatment of colorectal cancer. PMID- 26937136 TI - Glycosyltransferases and non-alcoholic fatty liver disease. AB - Non-alcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease and its incidence is increasing worldwide. However, the underlying mechanisms leading to the development of NAFLD are still not fully understood. Glycosyltransferases (GTs) are a diverse class of enzymes involved in catalyzing the transfer of one or multiple sugar residues to a wide range of acceptor molecules. GTs mediate a wide range of functions from structure and storage to signaling, and play a key role in many fundamental biological processes. Therefore, it is anticipated that GTs have a role in the pathogenesis of NAFLD. In this article, we present an overview of the basic information on NAFLD, particularly GTs and glycosylation modification of certain molecules and their association with NAFLD pathogenesis. In addition, the effects and mechanisms of some GTs in the development of NAFLD are summarized. PMID- 26937139 TI - Glucagon-like peptide-1 analogue prevents nonalcoholic steatohepatitis in non obese mice. AB - AIM: To investigate whether a glucagon-like peptide-1 (GLP-1) analogue inhibits nonalcoholic steatohepatitis (NASH), which is being increasingly recognized in Asia, in non-obese mice. METHODS: A methionine-choline-deficient diet (MCD) along with exendin-4 (20 MUg/kg per day, ip), a GLP-1 analogue, or saline was administered to male db/db mice (non-obese NASH model). Four or eight weeks after commencement of the diet, the mice were sacrificed and their livers were excised. The excised livers were examined by histochemistry for evidence of hepatic steatosis and inflammation. Hepatic triglyceride (TG) and free fatty acid (FFA) content was measured, and the expression of hepatic fat metabolism- and inflammation-related genes was evaluated. Oxidative stress-related parameters and macrophage recruitment were also examined using immunohistochemistry. RESULTS: Four weeks of MCD feeding induced hepatic steatosis and inflammation and increased the hepatic TG and FFA content. The expression of fatty acid transport protein 4 (FATP4), a hepatic FFA influx-related gene; macrophage recruitment; and the level of malondialdehyde (MDA), an oxidative stress marker, were significantly augmented by a 4-wk MCD. The levels of hepatic sterol regulatory element-binding protein-1c (SREBP-1c) mRNA (lipogenesis-related gene) and acyl coenzyme A oxidase 1 (ACOX1) mRNA (beta-oxidation-related gene) had decreased at 4 wk and further decreased at 8 wk. However, the level of microsomal triglyceride transfer protein mRNA (a lipid excretion-related gene) remained unchanged. The administration of exendin-4 significantly attenuated the MCD-induced increase in hepatic steatosis, hepatic TG and FFA content, and FATP4 expression as well as the MCD-induced augmentation of hepatic inflammation, macrophage recruitment, and MDA levels. Additionally, it further decreased the hepatic SREBP-1c level and alleviated the MCD-mediated inhibition of the ACOX1 mRNA level. CONCLUSION: These results suggest that GLP-1 inhibits hepatic steatosis and inflammation through the inhibition of hepatic FFA influx and oxidative stress in a non-obese NASH model. PMID- 26937140 TI - Relationship of serum polyunsaturated fatty acids with cytokines in colorectal cancer. AB - AIM: To investigate the relationship of serum levels of polyunsaturated fatty acid (PUFA) with kinds of cytokines in colorectal cancer (CRC). METHODS: Serum samples of 100 CRC patients were collected. The concentration of total n-3 PUFA which included C18:3 n-3, C20:5 n-3, C22:5 n-3, C22:6 n-3 and the total n-6 PUFA included C18:2 n-6, C18:3 n-6, C20:3 n-6, C20:4 n-6, and C22:5 n-6 were detected on GC-2010 Plus Gas Chromatograph with a OmegawaxTM 250 column. Cytokines were detected by MagPlexTM-C microspheres. P values for the trend were estimated by creating a continuous variable using the median value within quartiles. RESULTS: Interleukin-6 (IL-6) showed significantly positive association with the C20:4 n-6 (P for trend = 0.004). Interferon gamma (IFN-gamma) showed significant positive association with the C22:5 n-3 (P for trend = 0.035). IL-8 and matrix metalloproteinase-9 (MMP-9) showed significant inverse association with the C22:6 n-3 (P for trend = 0.049, and 0.021). MMP-2 showed significant inverse association with the C20:5 n-3 (P for trend = 0.008). MMP-7 showed significantly positive association with the ratio of n-6 PUFA and n-3 PUFA (P for trend = 0.008). MMP-7 also showed significantly inverse association with the ratio of C20:4 n-6 and (n-6 PUFA + n-3 PUFA) (P for trend = 0.024). IL-10 (P for trend = 0.023) and IL-6 (P for trend = 0.036) showed significantly positive association with the ratio of C20:4 n-6 and C20:5 n-3. CONCLUSION: Our data suggested that serum levels of PUFA is related to the inflammation of CRC, and also play different role in regulation of immune response. PMID- 26937142 TI - Role of CD56-expressing immature biliary epithelial cells in biliary atresia. AB - AIM: To analyze the clinical and pathological parameters and expression of the neural cell adhesion molecule (CD56) in patients with biliary atresia (BA). METHODS: Established clinical laboratory markers of hepatic function, including enzyme activity, protein synthesis, and bilirubin metabolism, were evaluated in patients with BA and compared with those in patients with choledochal cysts and neonatal hepatitis. Pathological changes in tissue morphology and fibrosis were examined by histological and tissue collagen staining. Immunohistochemical staining for the biliary epithelial cell markers CD56 and CK19 together with the Notch signaling related molecules Notch1 and Notch2 was performed in the context of alterations in the structure of intrahepatic biliary ducts. RESULTS: Differences in some clinical laboratory parameters among the three diseases examined were observed, but they did not correlate with the pathological classification of fibrosis in BA. Immunohistochemical staining showed the presence of CD56-positive immature bile ducts in most patients (74.5%) with BA but not in patients with choledochal cysts or neonatal hepatitis. The number of CD56-expressing cells correlated with disease severity, with more positive cells present in the later stages of liver damage (81.8% vs 18.2%). Furthermore, bile plugs were mainly found in CD56-positive immature biliary ducts. Notch signaling was a key regulatory pathway in biliary duct formation and played a role in tissue fibrosis. Notch1 was co-expressed in CD56-positive cells, whereas Notch2 was found exclusively in blood vessels in the portal area of patients with BA. CONCLUSION: The maturation of biliary epithelial cells and the expression of Notch may play a role in the pathogenesis of BA. PMID- 26937141 TI - Dietary saturated fatty acid and polyunsaturated fatty acid oppositely affect hepatic NOD-like receptor protein 3 inflammasome through regulating nuclear factor-kappa B activation. AB - AIM: To investigate the effect of different dietary fatty acids on hepatic inflammasome activation. METHODS: Wild-type C57BL/6 mice were fed either a high fat diet or polyunsaturated fatty acid (PUFA)-enriched diet. Primary hepatocytes were treated with either saturated fatty acids (SFAs) or PUFAs as well as combined with lipopolysaccharide (LPS). The expression of NOD-like receptor protein 3 (NLRP3) inflammasome, peroxisome proliferator-activated receptor-gamma and nuclear factor-kappa B (NF-kappaB) was determined by real-time PCR and Western blot. The activity of Caspase-1 and interleukine-1beta production were measured. RESULTS: High-fat diet-induced hepatic steatosis was sufficient to induce and activate hepatic NLRP3 inflammasome. SFA palmitic acid (PA) directly activated NLRP3 inflammasome and increased sensitization to LPS-induced inflammasome activation in hepatocytes. In contrast, PUFA docosahexaenoic acid (DHA) had the potential to inhibit NLRP3 inflammasome expression in hepatocytes and partly abolished LPS-induced NLRP3 inflammasome activation. Furthermore, a high-fat diet increased but PUFA-enriched diet decreased sensitization to LPS induced hepatic NLRP3 inflammasome activation in vivo. Moreover, PA increased but DHA decreased phosphorylated NF-kappaB p65 protein expression in hepatocytes. CONCLUSION: Hepatic NLRP3 inflammasome activation played an important role in the development of non-alcoholic fatty liver disease. Dietary SFAs and PUFAs oppositely regulated the activity of NLRP3 inflammasome through direct activation or inhibition of NF-kappaB. PMID- 26937143 TI - Improved prescription of taohechengqi-tang alleviates D-galactosamine acute liver failure in rats. AB - AIM: To investigate the hepatoprotective effect of improved prescription of Taohechengqi-tang (IPTT) against acute liver failure (ALF) in rats. METHODS: Seventy specific pathogen free male Wistar rats were randomly divided into four groups: control group (normal rats, n = 10), ALF group (ALF model, n = 20), Stronger Neo-Minophagen C (SNMC) group (ALF model + SNMC, n = 20), and IPTT group (ALF model + IPTT, n = 20). The ALF model group was administered an intraperitoneal injection of D-galactosamine (1.4 g/kg), and the control group received normal saline intraperitoneally. The SNMC and IPTT groups were treated with SMMC (15.6 mg/kg) or IPTT (28.6 g/kg) by gavage at 24 h intervals, and the ALF and control groups were treated with normal saline. At 36 h after injection, serum alanine aminotransferase, aspartate aminotransferase, total bilirubin, albumin, and cholinesterase and prothrombin time were determined, and liver histopathological scores were observed by microscopy after hematoxylin and eosin staining. mRNA expression of high mobility group box (HMGB) 1, toll-like receptor (TLR) 4, nuclear factor kappa B (NF-kappaB) and caspase-3 were analyzed via fluorescence quantitative reverse transcriptase polymerase chain reaction. Proliferating cell nuclear antigen (PCNA) immunohistochemistry in liver tissue was also performed. RESULTS: D-galactosamine notably decreased the biochemical and coagulation profiles in serum. IPTT not only improved liver function and histopathology but also normalized the gene expression levels in liver tissue. Compared with the model group, in the IPTT and SNMC groups, HMGB1 mRNA/beta-actin (0.06 +/- 0.03, 0.11 +/- 0.04 vs 0.25 +/- 0.04, P < 0.05); TLR4 mRNA/beta-actin (0.07 +/- 0.02, 0.22 +/- 0.08 vs 0.41 +/- 0.22, P < 0.05); NF-kappaB mRNA/beta actin (0.74 +/- 0.41, 1.78 +/- 0.64 vs 2.68 +/- 1.35, P < 0.05); and caspase-3 mRNA/beta-actin levels were all significantly reduced (1.61 +/- 0.45, 2.57 +/- 1.04 vs 3.41 +/- 0.85, P < 0.05). The gene expression levels were significantly lower in the IPTT group than in the SNMC group (P < 0.05). Compared with the model group, the PCNA expression in liver tissue was significantly enhanced in the IPTT and SNMC groups (36.34 +/- 4.91, 25.57 +/- 2.94 vs 17.55 +/- 2.40, P < 0.05). CONCLUSION: IPTT attenuates inflammation in ALF via inhibition of HMGB1 production, which may contribute to limited liver regeneration. PMID- 26937144 TI - Moxibustion regulates inflammatory mediators and colonic mucosal barrier in ulcerative colitis rats. AB - AIM: To observe the efficacy and mechanism of grain-sized moxibustion at different acupoints in a rat model of ulcerative colitis (UC). METHODS: Sprague Dawley rats were randomly divided into control, UC model, grain-sized moxibustion at a single acupoint (CV 12), grain-sized moxibustion at two acupoints (CV 12 and CV 4), grain-sized moxibustion at three acupoints (CV 12, CV 4, and ST 36), and medication groups (n = 8/group). The UC model was established by enema of trinitrobenzene sulfonic acid. Direct moxibustion was used once a day for 7 d. Disease activity index (DAI) was evaluated before and after the treatment. Morphologic changes of intestinal tissue were observed under an optical microscope. The expression of tumor necrosis factor (TNF)-alpha and p38 mitogen activated protein kinase (p38MAPK) in colonic tissue was detected using Western blot, and the levels of occludin and zonula occludens-1 (ZO-1) mRNAs were detected using reverse transcription PCR. RESULTS: Compared with the control group, the intestinal mucosae were incomplete in the model group, glandular structures were irregular, and submucosae were edematous, hyperemic, and infiltrated with inflammatory cells. The DAI scores and expression of TNF-alpha and p38MAPK were increased significantly in the model group compared to controls (Ps < 0.01), while the mRNA levels of occludin and ZO-1 were reduced significantly (Ps < 0.01). Compared with the model group, colonic mucosa and the arrangement of glands were complete and regular in the treatment groups. DAI scores and the expression of TNF-alpha and p38MAPK were reduced significantly in moxibustion groups compared to controls (Ps < 0.01), while the mRNA levels of occludin and ZO-1 were increased significantly (Ps < 0.01). The improvements in the above indices in the three acupoints group and the medication group were superior to those in the single and two acupoints groups (all P < 0.05). CONCLUSION: Reduction of TNF-alpha and p38MAPK and increased expression of occludin and ZO-1 in colonic tissue represent a potential mechanism for improved intestinal mucosal tissue repair with grain-sized moxibustion. PMID- 26937145 TI - Significance and prognostic value of increased serum direct bilirubin level for lymph node metastasis in Chinese rectal cancer patients. AB - AIM: To determine the significance of increased serum direct bilirubin level for lymph node metastasis (LNM) in Chinese rectal cancer patients, after those with known hepatobiliary and pancreatic diseases were excluded. METHODS: A cohort of 469 patients, who were treated at the China-Japan Friendship Hospital, Ministry of Health (Beijing, China), in the period from January 2003 to June 2011, and with a pathological diagnosis of rectal adenocarcinoma, were recruited. They included 231 patients with LNM (49.3%) and 238 patients without LNM. Follow-up for these patients was taken through to December 31, 2012. RESULTS: The baseline serum direct bilirubin concentration was (median/inter-quartile range) 2.30/1.60 3.42 MUmol/L. Univariate analysis showed that compared with patients without LNM, the patients with LNM had an increased level of direct bilirubin (2.50/1.70-3.42 vs 2.10/1.40-3.42, P = 0.025). Multivariate analysis showed that direct bilirubin was independently associated with LNM (OR = 1.602; 95%CI: 1.098-2.338, P = 0.015). Moreover, we found that: (1) serum direct bilirubin differs between male and female patients; a higher concentration was associated with poor tumor classification; (2) as the baseline serum direct bilirubin concentration increased, the percentage of patients with LNM increased; and (3) serum direct bilirubin was associated with the prognosis of rectal cancer patients and higher values indicated poor prognosis. CONCLUSION: Higher serum direct bilirubin concentration was associated with the increased risk of LNM and poor prognosis in our rectal cancers. PMID- 26937146 TI - Risk factors for tuberculosis after gastrectomy in gastric cancer. AB - AIM: To examine incidence of tuberculosis (TB) in gastrectomy patients and investigate the risk factors for developing TB after gastrectomy in patients with gastric cancer. METHODS: A retrospective cohort study of gastrectomy patients with gastric cancer was performed at a university-affiliated hospital in Seoul, South Korea between January 2007 and December 2009. We reviewed patient medical records and collected data associated with the risk of TB, surgery, and gastric cancer. Standardized incidence ratios (SIRs) of TB were calculated to compare the incidence of TB in gastrectomy patients with that in the general Korean population, and risk factors for TB after gastrectomies were analyzed. RESULTS: Among the 1776 gastrectomy patients, 0.9% (16/1776) developed post-gastrectomy TB, with an incidence of 223.7 cases per 100000 patients per year. The overall incidence of TB in gastrectomy patients, adjusted by sex and age, was significantly higher than that in the general population (SIR = 2.22, 95%CI: 1.27 3.60). Previous TB infection [odds ratio (OR) = 7.1, P < 0.001], lower body mass index (BMI) (kg/m(2); OR = 1.21, P = 0.043) and gastrectomy extent (total gastrectomy vs subtotal gastrectomy) (OR = 3.48, P = 0.017) were significant risk factors for TB after gastrectomy in a multivariate analysis. CONCLUSION: TB incidence after gastrectomy is higher than that in the general population. Previous TB infection, lower BMI, and total gastrectomy are risk factors for TB after gastrectomy in patients with gastric cancer. PMID- 26937147 TI - Helicobacter pylori infection is not associated with nonalcoholic fatty liver disease. AB - AIM: To determine whether Helicobacter pylori (H. pylori) infection confers a higher risk of Nonalcoholic fatty liver disease (NAFLD). METHODS: Healthy people who underwent health screening were analyzed retrospectively. Inclusion criteria were age >= 20 years, history of H. pylori infection, and recorded insulin level. Participants were classified as H. pylori positive or negative according to (13)C urea breath tests. NAFLD was defined using the hepatic steatosis index (HSI) and NAFLD liver fat score (NAFLD-LFS). Those with an HSI > 36 or NAFLD-LFS > -0.640 were considered to have NAFLD. Multivariable logistic regression was performed to identify risk factors for NAFLD. RESULTS: Three thousand six hundred and sixty three people were analyzed and 1636 (44.7%) were H. pylori positive. H. pylori infection was associated with older age, male gender, hypertension, higher body mass index, and a dyslipidemic profile. HSI differed significantly between H. pylori positive and negative subjects (median 33.2, interquartile range (IQR) 30.0-36.2 for H. pylori-positive vs median 32.6, IQR 29.8-36.0 for negative participants, P = 0.005), but NAFLD-LSF did not [median -1.7, IQR -2.4 - -0.7 vs median -1.8, IQR -2.4-(-0.7), respectively, P = 0.122]. The percentage of people with NAFLD did not differ between infected and uninfected groups: HIS, 26.9% vs 27.1%, P = 0.173; NAFLD-LFS, 23.5% vs 23.1%, P = 0.778. H. pylori infection was not a risk factor, but C-reactive protein concentration and smoking were significant risk factors for NAFLD. CONCLUSION: H. pylori infection is not a risk factor for NAFLD as indicated by HSI or NAFLD-LFS. Prospective, large-scale studies involving liver biopsies should be considered. PMID- 26937148 TI - Prognostic factors and long-term outcomes of hilar cholangiocarcinoma: A single institution experience in China. AB - AIM: To evaluate the prognostic factors of hilar cholangiocarcinoma in a large series of patients in a single institution. METHODS: Eight hundred and fourteen patients with a diagnosis of hilar cholangiocarcinoma that were evaluated and treated between 1990 and 2014, of which 381 patients underwent curative surgery, were included in this study. Potential factors associated with overall survival (OS) and disease-free survival (DFS) were evaluated by univariate and multivariate analyses. RESULTS: Curative surgery provided the best long-term survival with a median OS of 26.3 mo. The median DFS was 18.1 mo. Multivariate analysis showed that patients with tumor size > 3 cm [hazard ratio (HR) = 1.482, 95%CI: 1.127-1.949; P = 0.005], positive nodal disease (HR = 1.701, 95%CI: 1.346 2.149; P < 0.001), poor differentiation (HR = 2.535, 95%CI: 1.839-3.493; P < 0.001), vascular invasion (HR = 1.542, 95%CI: 1.082-2.197; P = 0.017), and positive margins (HR = 1.798, 95%CI: 1.314-2.461; P < 0.001) had poor OS outcome. The independent factors for DFS were positive nodal disease (HR = 3.383, 95%CI: 2.633-4.348; P < 0.001), poor differentiation (HR = 2.774, 95%CI: 2.012-3.823; P < 0.001), vascular invasion (HR = 2.136, 95%CI: 1.658-3.236; P < 0.001), and positive margins (HR = 1.835, 95%CI: 1.256-2.679; P < 0.001). Multiple logistic regression analysis showed that caudate lobectomy [odds ratio (OR) = 9.771, 95%CI: 4.672-20.433; P < 0.001], tumor diameter (OR = 3.772, 95%CI: 1.914-7.434; P < 0.001), surgical procedures (OR = 10.236, 95%CI: 4.738-22.116; P < 0.001), American Joint Committee On Cancer T stage (OR = 2.010, 95%CI: 1.043-3.870; P = 0.037), and vascular invasion (OR = 2.278, 95%CI: 0.997-5.207; P = 0.051) were independently associated with tumor-free margin, and surgical procedures could indirectly affect survival outcome by influencing the tumor resection margin. CONCLUSION: Tumor margin, tumor differentiation, vascular invasion, and lymph node status were independent factors for OS and DFS. Surgical procedures can indirectly affect survival outcome by influencing the tumor resection margin. PMID- 26937149 TI - Outcomes and patients' perspectives of transition from paediatric to adult care in inflammatory bowel disease. AB - AIM: To describe the disease and psychosocial outcomes of an inflammatory bowel disease (IBD) transition cohort and their perspectives. METHODS: Patients with IBD, aged > 18 years, who had moved from paediatric to adult care within 10 years were identified through IBD databases at three tertiary hospitals. Participants were surveyed regarding demographic and disease specific data and their perspectives on the transition process. Survey response data were compared to contemporaneously recorded information in paediatric service case notes. Data were compared to a similar age cohort who had never received paediatric IBD care and therefore who had not undergone a transition process. RESULTS: There were 81 returned surveys from 46 transition and 35 non-transition patients. No statistically significant differences were found in disease burden, disease outcomes or adult roles and responsibilities between cohorts. Despite a high prevalence of mood disturbance (35%), there was a very low usage (5%) of psychological services in both cohorts. In the transition cohort, knowledge of their transition plan was reported by only 25/46 patients and the majority (54%) felt they were not strongly prepared. A high rate (78%) of discussion about work/study plans was recorded prior to transition, but a near complete absence of discussion regarding sex (8%), and other adult issues was recorded. Both cohorts agreed that their preferred method of future transition practices (of the options offered) was a shared clinic appointment with all key stakeholders. CONCLUSION: Transition did not appear to adversely affect disease or psychosocial outcomes. Current transition care processes could be optimised, with better psychosocial preparation and agreed transition plans. PMID- 26937150 TI - Feasibility of full-spectrum endoscopy: Korea's first full-spectrum endoscopy colonoscopic trial. AB - AIM: To evaluate the full-spectrum endoscopy (FUSE) colonoscopy system as the first report on the utility thereof in a Korean population. METHODS: We explored the efficacy of the FUSE colonoscopy in a retrospective, single-center feasibility study performed between February 1 and July 20, 2015. A total of 262 subjects (age range: 22-80) underwent the FUSE colonoscopy for colorectal cancer screening, polyp surveillance, or diagnostic evaluation. The cecal intubation success rate, the polyp detection rate (PDR), the adenoma detection rate (ADR), and the diverticulum detection rate (DDR), were calculated. Also, the success rates of therapeutic interventions were evaluated with biopsy confirmation. RESULTS: All patients completed the study and the success rates of cecal and terminal ileal intubation were 100% with the FUSE colonoscope; we found 313 polyps in 142 patients and 173 adenomas in 95. The overall PDR, ADR and DDR were 54.2%, 36.3%, and 25.2%, respectively, and were higher in males, and increased with age. The endoscopists and nurses involved considered that the full-spectrum colonoscope improved navigation and orientation within the colon. No colonoscopy was aborted because of colonoscope malfunction. CONCLUSION: The FUSE colonoscopy yielded a higher PDR, ADR, DDR than did traditional colonoscopy, without therapeutic failure or complications, showing feasible, effective, and safe in this first Korean trial. PMID- 26937151 TI - Ombitasvir, paritaprevir, ritonavir, dasabuvir and ribavirin in cirrhosis after complete destruction of hepatocellular carcinoma. AB - We observed a sustained viral response (SVR) of ombitasvir/paritaprevir/ritonavir, dasabuvir and ribavirin therapy, for 12 wk, in two cases with compensated liver cirrhosis and fully destroyed early hepatocellular carcinoma (HCC). Patients were infected with hepatitis C virus (HCV) genotype 1b and were previous null responders/relapsers to interferon alpha/ribavirin (IFN/RBV). There was a rapid suppression of HCV RNA to undetectable levels within the first two treatment weeks. SVR was achieved even after marked reduction of the RBV dose. The treatment was well tolerated. Both subjects experienced worsening of liver disease during therapy, in different patterns: severe, transient, predominantly direct hyperbilirubinemia without cytolysis (case 1) or progressive increase of aminotransferases (grade 4) without severe hyperbilirubinemia (case 2). Adverse events spontaneously resolved. The patients remained in a good clinical condition without hepatic decompensation. There was no re-occurrence of HCC. This is the first report for treatment of HCV cirrhosis after complete HCC destruction. PMID- 26937152 TI - Condyloma acuminatum of the anal canal, treated with endoscopic submucosal dissection. AB - Condyloma acuminatum (CA) is a common sexually transmitted disease caused by human papilloma virus infection. Not all individuals develop persistent, progressive disease, but careful follow up is required with moderate-to-severe dysplasia to prevent progression to malignancy. Standard therapies include surgical treatments (trans-anal resection and trans-anal endoscopic microsurgery) and immunotherapeutic and topical methods (topical imiquimod); however, local recurrence remains a considerable problem. Here, we report a case with superficial CA of the anal canal, treated with endoscopic submucosal dissection (ESD). A 28-year-old man presented with a chief complaint of hematochezia. Digital exam did not detect a tumor. Screening colonoscopy revealed 10-mm long, whitish condyles extending from the anal canal to the lower rectum. The lesion covered almost the whole circumference, and only a small amount of normal mucosa remained. Magnifying endoscopy with narrow band imaging showed brownish hairpin shaped, coiled capillaries. Although histopathological diagnosis by biopsy revealed CA, accurate histological differentiation between CA, papilloma, and squamous cell carcinoma can be difficult with a small specimen. Therefore, we performed diagnostic ESD, which provides a complete specimen for precise histopathological evaluation. The pathological diagnosis was CA, with moderate dysplasia (anal intraepithelial neoplasia 2). There was no recurrence at 16 mo after the initial ESD. Compared to surgical treatment, endoscopic diagnosis and resection could be performed simultaneously and the tumor margin observed clearly with a magnifying chromocolonoscopy, resulting in less recurrence. These findings suggest that endoscopic resection may be an alternative method for CA that prevents recurrence. PMID- 26937155 TI - Choosing Wisely for Birth. AB - In this column, the editor of The Journal of Perinatal Education describes the American Academy of Nursing's engagement in the national Choosing Wisely campaign and how it has implications for promoting normal birth. The editor also describes the contents of this issue, which offer a broad range of resources, research, and inspiration for childbirth educators in their efforts to promote, support, and protect natural, safe, and healthy birth. PMID- 26937153 TI - Terminal ileum gangrene secondary to a type IV paraesophageal hernia. AB - Type IV paraesophageal hernia (PEH) is very rare, and is characterized by the intrathoracic herniation of the abdominal viscera other than the stomach into the chest. We describe a 78-year-old woman who presented at our emergency department because of epigastric pain that she had experienced over the past 24 h. On the day after admission, her pain became severe and was accompanied by right chest pain and dyspnea. Chest radiography revealed an intrathoracic intestinal gas bubble occupying the right lower lung field. Emergency explorative laparotomy identified a type IV PEH with herniation of only the terminal ileum through a hiatal defect into the right thoracic cavity. In this report, we also present a review of similar cases in the literature published between 1980 and 2015 in PubMed. There were four published cases of small bowel herniation into the thoracic cavity during this period. Our patient represents a rare case of an individual diagnosed with type IV PEH with incarceration of only the terminal ileum. PMID- 26937154 TI - Stability of adenine-based cytokinins in aqueous solution. AB - Since the isolation of the first cytokinin almost 60 yr ago, cytokinins have become critically important for ornamental and agricultural crops in plant tissue culture. Despite the extensive research on this class of compounds, little information is available on the chemical stability of cytokinins in solution or following an autoclave cycle with Murashige and Skoog (MS) basal medium. This work describes the stability in aqueous solutions of five widely used adenine based cytokinins: trans-zeatin (tZ), 6-(gamma,gamma-dimethylallylamino) purine (2iP), kinetin, benzyladenine (BA), and m-topolin. High pressure liquid chromatography (HPLC) and electrospray ionization-mass spectrometry (ESI-MS) were used to quantify and identify their degradation. BA, kinetin, 2iP, and m-topolin were stable at 1.0 mg mL-1 in 0.05 N KOH, with no statistically significant concentration changes (p > 0.05) after 90 d of storage at temperatures of -20 degrees C, 2-6 degrees C, or 25 degrees C. The cytokinin tZ was used as a model compound to evaluate stability under alkaline and acid conditions as well as after repeated freeze-thaw cycles. Trans-zeatin retained >90% of the initial concentration of 1.0 mg mL-1 when dissolved in 0.01 N KOH and stored at -20 degrees C and 2-6 degrees C for 90 d, with only the 2-6 degrees C temperature treatment showing a statistical significant concentration change (p = 0.03). The 1.0 mg mL-1 tZ solution in 0.01 N KOH was stable through six repeated freeze-thaw cycles over 90 d without any significant change in concentration compared to the initial freeze-thaw. Yet, tZ showed highly significant concentration changes when dissolved at 50 mg mL-1 and 0.5 N KOH. All of these adenine-based cytokinins showed exceptional stability following an autoclave cycle at 121 degrees C, 110 kPa for 30 min when in solutions of 1.0 mg mL-1 in 0.05 N KOH, with no significant degradation detected. Trans-zeatin was also found to be stable after one autoclave cycle with 1* MS-basal salts. PMID- 26937156 TI - Nora's Story. AB - In this column, Nora Gibbons, 16 years old, describes the home births of four of her siblings. Nora's story captures the wonder and simplicity of home birth and demonstrates the impact the experience of being present at home birth can have on children. Nora's joy and confidence in birth because of her experiences will influence her own birth choices. PMID- 26937157 TI - How Doula Care Can Advance the Goals of the Affordable Care Act: A Snapshot From New York City. AB - Doula care meets each of the triple aims of the Affordable Care Act: improving health outcomes for all, improving the experience of care, and lowering costs by reducing non-beneficial and unwanted medical interventions. Cost is the greatest barrier to use of doula support. Reimbursement for doula services by private insurance, Medicaid, and Medicaid managed care organizations would significantly increase access to doulas. Widespread availability of doula care could significantly reduce cesarean rates, and increased access to community-based doula programs could reduce entrenched health disparities. PMID- 26937158 TI - Reducing Length of Labor and Cesarean Surgery Rate Using a Peanut Ball for Women Laboring With an Epidural. AB - One strategy for reducing the primary cesarean surgery rate and length of labor is using a peanut-shaped exercise ball for women laboring under epidural analgesia. A randomized, controlled study was conducted to determine whether use of a "peanut ball" decreased length of labor and increased the rate of vaginal birth. Women who used the peanut ball (n = 107) versus those who did not (n = 91) demonstrated shorter first stage labor by 29 min (p = .053) and second stage labor by 11 min (p < .001). The intervention was associated with a significantly lower incidence of cesarean surgery (OR = 0.41, p = .04). The peanut ball is potentially a successful nursing intervention to help progress labor and support vaginal birth for women laboring under epidural analgesia. PMID- 26937159 TI - Institutional and Cultural Perspectives on Home Birth in Israel. AB - This study exposes doctors' and midwives' perceptions and misperceptions regarding home birth by examining their views on childbirth in general and on risk associated with home births in particular. It relies on an approach of risk communication and an anthropological framework. In a qualitative-constructive study, 19 in-depth interviews were conducted with hospital doctors, hospital midwives, home-birth midwives, and a home-birth obstetrician. Our findings reveal that hospital midwives and doctors suffer from lack of exposure to home births, leading to disagreement regarding norms and risk; it also revealed sexist or patriarchal worldviews. Recommendations include improving communication between home-birth midwives and hospital counterparts; increased exposure of hospital doctors to home birth, creating new protocols in collaboration with home-birth midwives; and establishing a national database of home births. PMID- 26937160 TI - Building Perinatal Case Manager Capacity Using Quality Improvement. AB - Improving breastfeeding rates among Black women is a potential strategy to address disparities in health outcomes that disproportionately impact Black women and children. This quality improvement (QI) initiative aimed to improve perinatal case manager knowledge and self-efficacy to promote breastfeeding among Black, low-income women who use services through Boston Healthy Start Initiative. QI methodology was used to develop and test a two-part strategy for perinatal case managers to promote and support breastfeeding. A positive change was observed in infant feeding knowledge and case manager self-efficacy to promote breastfeeding. Among the 24 mothers participating in this QI initiative, 100% initiated and continued breastfeeding at 1 week postpartum, and 92% were breastfeeding at 2 weeks postpartum. PMID- 26937161 TI - Social Support, Postpartum Depression, and Professional Assistance: A Survey of Mothers in the Midwestern United States. AB - Transition into motherhood is generally a joyful life event; for some women, however, it is marked by emotional turmoil. Lack of support can be associated with postpartum depression and can compromise both the mother and infant. A descriptive, cross-sectional study (N = 61) was conducted to explore the relationship between social support and postpartum depression and to determine whether mothers overwhelmed with childcare, or overwhelmed with life in general since becoming a mother, sought professional help. The results revealed that screening for depression alone may not be sufficient, that mothers are willing to contact a professional for help in the postpartum period, and that assessments after birth should include a broader assessment of life's difficulties rather than focusing on childcare responsibilities alone. PMID- 26937163 TI - Generation of Human Monoclonal Autoantibody-Producing Cell Lines by Epstein-Barr Virus Transformation of Autoreactive B Lymphocytes and by Somatic Cell Hybridization Techniques: Application to the Analysis of the Autoimmune B Cell Repertoire. AB - Epstein-Barr virus (EBV) was used to immortalize human peripheral B lymphocytes committed to the production of autoantibodies in healthy subjects and in patients with various autoimmune diseases. EBV-transformed B lymphocytes producing human monoclonal autoantibodies were fused with the human-mouse heterohybridoma F3B6 cells to stabilize the production of monoclonal antibodies (mAb). The present method of generating human B cell clones producing mAbs now makes it possible to analyze in detail the nature of human autoantibodies with respect to antigen binding specificity, affinity, corresponding autoepitopes, and the variable (V) region structure. PMID- 26937162 TI - U.S. Nulliparas' Reasons for Expected Provider Type and Childbirth Setting. AB - The objective of this study was to describe nulliparas' reasons for the type of provider (i.e., midwife, physician) and childbirth setting (i.e., home, hospital, hospital-based birth center) that respondents expected for their births. Data were collected via a cross-sectional, descriptive, self-administered, Web-based survey including both close- and open-ended questions and were analyzed using conventional content analysis. Respondents were 220 nulliparous women aged 18-40 years, living in the United States, and pregnant at 20 or fewer weeks' gestation. Women's reasons were categorized broadly as relating to provider/setting attributes, relationship with provider/setting, normative choices, respondent attributes, and practical considerations. Respondents' reasons highlight misconceptions about childbirth care options, especially regarding midwifery and nonhospital settings, which may be addressed by childbirth education. PMID- 26937164 TI - Techniques for Building an OSHA Compliant Guardrail Structure. AB - In the construction industry, workers falling to a lower level has been the primary cause of fatalities according to the Bureau of Labor Statistics Census of Fatal Occupational Injuries database. From 2006 to 2010, an average of 353 construction workers died annually as a result of falling to a lower level. An average of 126 workers (36%) died when falling from unguarded roof edges, and through roof and floor holes or skylights. The National Institute for Occupational Safety and Health evaluated the strength of job-built guardrail structures around an opening. The study focused on a 2'*4' opening typical of residential skylights. Nine full-time residential carpenters built guardrails for strength testing. PMID- 26937165 TI - Lychee flower extract inhibits proliferation and viral replication of HSV-1 infected corneal epithelial cells. AB - PURPOSE: Herpes simplex virus type I (HSV-1) is capable of causing a wide array of human ocular diseases. Herpes simplex virus keratitis (HSK)-induced cytopathogenicity together with the chronic immune-inflammatory reaction can trigger stromal scarring, thinning, and neovascularization which may lead to permanent vision impairment. Lychee flower extract (LFE) is known for its antioxidant and anti-inflammatory effects. Therefore, in this study, we investigated the mechanism of the Statens Seruminstitut rabbit corneal (SIRC) epithelial cells infected by HSV-1 and examined the antiviral capabilities of LFE. METHODS: SIRC cells were pretreated with different concentrations of LFE (0.2, 0.1, and 0.05 MUg/ml) and then infected with 1 MOI of HSV-1 for 24 h. The cell viability or morphology was evaluated in this study. In addition, the supernatants and cell extracts were collected for Cell Counting Kit-8 (CCK), plaque assay, and western blotting. RESULTS: We found that HSV-1-induced cell proliferation is regulated through inhibition of the mammalian target of rapamycin (mTOR) and p70s6k phosphorylation in response to the LFE. In addition, the LFE enhanced the autophagy protein expression (Beclin-1 and light chain 3, LC3) and decreased the viral titers. CONCLUSIONS: These results showed the antiviral capabilities and the protective effects of LFE. Taken together, our data indicate that LFE has potential as an anti-HSK (herpes simplex keratitis) for HSV-1 infection. PMID- 26937167 TI - A new PET system for small-animal imaging. AB - We outline the design of a new small-animal PET system. This system employs modular scintillation cameras composed of nine PMTs coupled by a light guide to a monolithic NaI(Tl) scintillation crystal. The basic principles of the PET system are presented along with an overview of the electronics and position-estimation scheme. The potential advantages of this design are discussed and preliminary reconstructed images are presented. PMID- 26937166 TI - Corneal recovery in a rabbit limbal stem cell deficiency model by autologous grafts of tertiary outgrowths from cultivated limbal biopsy explants. AB - PURPOSE: To determine the corneal regenerative capacity of sequentially generated primary, secondary, and tertiary limbal explant outgrowths in a limbal stem cell deficiency (LSCD) surgical model. METHODS: Two-millimeter-long limbal shallow biopsies were surgically excised from the upper quadrant of the right eye of rabbits and set on preserved amniotic membrane for explant culture. After the generation of primary outgrowth, the biopsies were sequentially transferred to new amniotic membrane to generate secondary and then tertiary outgrowths. Eighteen rabbits were subjected to a 360 degrees limbal peritomy extending into the scleral zone and combined with superficial keratectomy of the corneal periphery and thorough mechanical debridement of the central cornea in their left eye. Right eye outgrowths, six of each generation, were engrafted on the ocular surface. Clinical outcomes (neovascularization, corneal clarity, and corneal fluorescein staining) were graded after 6 months. Post-mortem corneas were compared with histology, immunochemistry for p63 and Krt3, ABCG2-dependent dye exclusion, and capacity for outgrowths in explant culture. RESULTS: Immunohistology and western blot of the outgrowths for p63 and Krt3 indicated no differences in expression between the primary and tertiary outgrowths for these two markers of growth and differentiation. Clinically, all rabbits treated with amniotic membrane alone developed severe LSCD. Most rabbits grafted with cell outgrowths from all three outgrowth generations achieved stable (>6 months) recovery of the ocular surface. There were partial failures of grafts performed with two secondary and tertiary outgrowths. However, Kruskal-Wallis statistical analysis of the clinical scores yielded no significant difference between the three groups (p=0.524). Histology showed full anatomic recovery of grafts made with primary and tertiary outgrowths. Krt3 and p63 expression throughout the whole limbal corneal epithelium with primary or tertiary outgrowths was not distinguishable from each other. The percentage of dye-excluding cells present within this zone and the capacity of the explant epithelial outgrowth of the regenerated peripheral corneal zone were also on par with those of the donor corneas. The Krt3-negative cells that characterize the basal epithelial layer of the normal limbus could not be found in any regenerated cornea from the primary to tertiary outgrowths. CONCLUSIONS: Our results demonstrate that in rabbits post primary explant outgrowths retain the capacity for LSCD recovery found in primary explants. PMID- 26937168 TI - Three-year follow-up of ranibizumab treatment of wet age-related macular degeneration: influence of baseline visual acuity and injection frequency on visual outcomes. AB - PURPOSE: To determine the effect of ranibizumab on visual acuity (VA) following a 3-year treatment period for patients diagnosed with wet age-related macular degeneration. To establish whether baseline VA and injection frequency influence visual outcomes. PATIENTS AND METHODS: Retrospective review of 70 patients (76 eyes) treated with 0.5 mg intravitreal ranibizumab for 3 consecutive months, and pro re nata thereafter (three + pro re nata protocol), over a 3-year period. VA was measured using Early Treatment Diabetic Retinopathy Study (ETDRS) charts at baseline, 12, 24, and 36 months. The number of injections administered at the end of years 1, 2, and 3 were also recorded. Eyes were stratified according to baseline VA, as well as the number of injections administered at the end of year 1. Linear regression analysis determined the relationship between VA and both baseline VA and injection frequency. P<0.05 was considered statistically significant. RESULTS: At 36 months, VA improved by a mean of 5.3 ETDRS letters (P=0.002), with 29% of eyes (n=22) demonstrating a clinically significant improvement in VA (gain of >=15 ETDRS letters). Improvements in VA from baseline to 36 months were inversely proportional to the baseline VA (R=0.414, P=<0.001). A positive correlation was observed between injection frequency and change in VA from baseline to 36 months (R=0.244, P=0.036). CONCLUSION: Mean improvement in VA is inversely proportional to baseline VA, and directly proportional to injection frequency. PMID- 26937170 TI - Biosimilars in the management of neutropenia: focus on filgrastim. AB - Advances in chemotherapy and surgery allows the majority of patients to survive cancer diseases. Yet, the price may be a proportion of patients dying of complications due to treatment-induced infectious complications, such as neutropenia. With the aim of decreasing morbidity and mortality related to infectious complications, recombinant human granulocyte colony-stimulating factor (G-CSF), filgrastim, and pegylated filgrastim have been used to reduce time and degree of neutropenia. A biosimilar is a copy of an approved original biologic medicine whose data protection has expired. The patent for filgrastim expired in Europe in 2006 and in the US in 2013. This review analyses the available evidence to be considered in order to design a strategy of use of G-CSF and its biosimilars. The clinical and safety outcomes of biosimilars are well within the range of historically reported data for originator filgrastim. This underscores the clinical effectiveness and safety of biosimilar filgrastim in daily clinical practice. Biosimilars can play an important role by offering the opportunity to reduce costs, thus contributing to the financial sustainability of treatment programs. PMID- 26937172 TI - Effects of 22 novel CYP2D6 variants found in Chinese population on the metabolism of dapoxetine. AB - BACKGROUND: CYP2D6 is one of the most important members of the cytochrome P450 superfamily. Its genetic polymorphism significantly influences the efficacy and safety of some drugs, which might cause adverse effects and therapeutic failure. METHODS AND RESULTS: The aim of this research was mainly to explore the catalytic activities of 22 newly reported CYP2D6 isoforms (2D6*87, *88, *89, *90, *91, *92, *93, *94, *95, *96,*97, *98, *R25Q, F164L, E215K, F219S, V327M, D336N, V342M, R344Q, R440C, R497C) on dapoxetine in vitro. The research was designed with an appropriate incubation system in test tubes and carried out in the constant temperature water. Through detecting its two metabolites desmethyldapoxetine and dapoxetine-N-oxide, the available data were obtained to explain the influence of CYP2D6 polymorphism on the substrate drug dapoxetine. As a result, the intrinsic clearance (Vmax/Km) values of most variants were significantly altered when compared with the counterpart of CYP2D6*1, with most of these variants exhibiting either reduced Vmax and/or increased Km values. For dapoxetine demethylation pathway (which produces desmethyldapoxetine), 2D6*89 and E215K exhibited no markedly decreased relative clearance of 92.81% and 97.70%, respectively. The relative clearance of rest 20 variants exhibited decrease in different levels, ranging from 20.44% to 90.90%. For the dapoxetine oxidation pathway (which produces dapoxetine-N-oxide), the relative clearance values of three variants, 2D6*90, *94, and V342M, exhibited no markedly increased relative clearance of 106.17%, 107.78%, and 109.98%, respectively; the rest 19 variants exhibited significantly decreased levels ranging from 27.56% to 84.64%. In addition, the kinetic parameters of two CYP2D6 variants (2D6*92 and 2D6*96) could not be detected, due to the defect of the CYP2D6 gene. CONCLUSION: As the first report of all aforementioned alleles for dapoxetine metabolism, these data may help in the clinical assessment of the metabolic elimination of dapoxetine and may provide fundamental information for further clinical studies. PMID- 26937171 TI - Long-term use of amiodarone before heart transplantation significantly reduces early post-transplant atrial fibrillation and is not associated with increased mortality after heart transplantation. AB - BACKGROUND: Amiodarone is a frequently used antiarrhythmic drug in patients with end-stage heart failure. Given its long half-life, pre-transplant use of amiodarone has been controversially discussed, with divergent results regarding morbidity and mortality after heart transplantation (HTX). AIM: The aim of this study was to investigate the effects of long-term use of amiodarone before HTX on early post-transplant atrial fibrillation (AF) and mortality after HTX. METHODS: Five hundred and thirty patients (age >=18 years) receiving HTX between June 1989 and December 2012 were included in this retrospective single-center study. Patients with long-term use of amiodarone before HTX (>=1 year) were compared to those without long-term use (none or <1 year of amiodarone). Primary outcomes were early post-transplant AF and mortality after HTX. The Kaplan-Meier estimator using log-rank tests was applied for freedom from early post-transplant AF and survival. RESULTS: Of the 530 patients, 74 (14.0%) received long-term amiodarone therapy, with a mean duration of 32.3+/-26.3 months. Mean daily dose was 223.0+/ 75.0 mg. Indications included AF, Wolff-Parkinson-White syndrome, ventricular tachycardia, and ventricular fibrillation. Patients with long-term use of amiodarone before HTX had significantly lower rates of early post-transplant AF (P=0.0105). Further, Kaplan-Meier analysis of freedom from early post-transplant AF showed significantly lower rates of AF in this group (P=0.0123). There was no statistically significant difference between patients with and without long-term use of amiodarone prior to HTX in 1-year (P=0.8596), 2-year (P=0.8620), 5-year (P=0.2737), or overall follow-up mortality after HTX (P=0.1049). Moreover, Kaplan Meier survival analysis showed no statistically significant difference in overall survival (P=0.1786). CONCLUSION: Long-term use of amiodarone in patients before HTX significantly reduces early post-transplant AF and is not associated with increased mortality after HTX. PMID- 26937169 TI - Fuchs endothelial corneal dystrophy: current perspectives. AB - Fuchs endothelial corneal dystrophy (FECD) is the most common corneal dystrophy and frequently results in vision loss. Hallmarks of the disease include loss of corneal endothelial cells and formation of excrescences of Descemet's membrane. Later stages involve all layers of the cornea. Impairment of endothelial barrier and pump function and cell death from oxidative and unfolded protein stress contribute to disease progression. The genetic basis of FECD includes numerous genes and chromosomal loci, although alterations in the transcription factor 4 gene are associated with the majority of cases. Definitive treatment of FECD is corneal transplantation. In this paper, we highlight advances that have been made in understanding FECD's clinical features, pathophysiology, and genetics. We also discuss recent advances in endothelial keratoplasty and potential future treatments. PMID- 26937173 TI - 5-(Bis(3-(2-hydroxyethyl)-1H-indol-2-yl)methyl)-2-hydroxybenzoic acid (BHIMHA): showing a strategy of designing drug to block lung metastasis of tumors. AB - Early metastasis is still the most recalcitrant factor in the treatment of lung cancer patients. By analyzing the structures and comparing the docking scores of the known pharmacophores, the authors of this paper designed 5-(bis(3-(2 hydroxyethyl)-1H-indol-2-yl)methyl)-2-hydroxybenzoic acid (BHIMHA) as a promising lead compound to develop metastasis inhibitors. In vitro 5, 10, and 20 uM of BHIMHA concentration dependently inhibited the migration and invasion of A549 cells. In vivo 0.4, 2.0, and 8.9 umol/kg of BHIMHA dose dependently inhibited the metastasis of LLC (Lewis Lung Carcinoma) toward lung. In vivo, 2 umol/kg of BHIMHA showed additional actions of slowing the growth of the primary tumor of C57BL/6 mice and S180 mice as well as inhibiting xylene-induced ear edema of the mice. Therefore, BHIMHA simultaneously blocked tumor metastasis toward lung, slowed the primary tumor growth, and limited the inflammation. These pharmacological actions were correlated with the inhibition of PKCalpha and NF kappaB expression. PMID- 26937174 TI - Treatment with a Ginkgo biloba extract, EGb 761, inhibits excitotoxicity in an animal model of spinocerebellar ataxia type 17. AB - Spinocerebellar ataxia type 17 (SCA 17) is a polyglutamine disease caused by the expansion of CAG/CAA repeats in the TATA box-binding protein (TBP) gene. The Ginkgo biloba extract, EGb 761, contains flavonoids and terpenoids with a potential use for the treatment of neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. The neuroprotective effects of EGb 761 are obvious, but whether the EGb 761 has therapeutic effects in SCA 17 is still unclear. To manage our issues, we have generated TBP/79Q-expressing SH-SY5Y cells and SCA 17 transgenic mice with the mutant hTBP gene. In in vitro experiment, we observed that the EGb 761 treatment decreased the amount of sodium dodecyl sulfate insoluble proteins in the TBP/79Q-expressing SH-SY5Y cells. We further found that the EGb 761 treatment could inhibit excitotoxicity and calcium influx and reduce the expression of apoptotic markers in glutamate-treated SH-SY5Y neuroblastoma cells. In in vivo experiment, we observed that the EGb 761 treatment (100 mg/kg intraperitoneal injection per day) could relieve the motor deficiencies of the SCA 17 transgenic mice. Our findings provide evidence that the EGb 761 treatment can be a remedy for SCA 17 via suppressing excitotoxicity and apoptosis in SCA 17 cell and animal models. Therefore, we suggest that EGb 761 may be a potential therapeutic agent for treating SCA 17. PMID- 26937175 TI - Synergistic roles of p53 and HIF1alpha in human renal cell carcinoma-cell apoptosis responding to the inhibition of mTOR and MDM2 signaling pathways. AB - INTRODUCTION: mTOR and MDM2 signaling pathways are frequently deregulated in cancer development, and inhibition of mTOR or MDM2 independently enhances carcinoma-cell apoptosis. However, responses to mTOR and MDM2 antagonists in renal cell carcinoma (RCC) remain unknown. MATERIALS AND METHODS: A498 cells treated with MDM2 antagonist MI-319 and/or mTOR inhibitor rapamycin were employed in the present study. Cell apoptosis and Western blot analysis were performed. RESULTS AND CONCLUSION: We found that the MDM2 inhibitor MI-319 induced RCC cell apoptosis mainly dependent on p53 overexpression, while the mTOR antagonist rapamycin promoted RCC cell apoptosis primarily through upregulation of HIF1alpha expression. Importantly, strong synergistic effects of MI-319 and rapamycin combinations at relatively low concentrations on RCC cell apoptosis were observed. Depletion of p53 or HIF1alpha impaired both antagonist-elicited apoptoses to differential extents, corresponding to their expression changes responding to chemical treatments, and double knockdown of p53 and HIF1alpha remarkably hindered MI-319- or rapamycin-induced apoptosis, suggesting that both p53 and HIF1alpha are involved in MDM2 or mTOR antagonist-induced apoptosis. Collectively, we propose that concurrent activation of p53 and HIF1alpha may effectively result in cancer-cell apoptosis, and that combined MDM2 antagonists and mTOR inhibitors may be useful in RCC therapy. PMID- 26937176 TI - Potential for bispecific T-cell engagers: role of blinatumomab in acute lymphoblastic leukemia. AB - Patients with relapsed/refractory (R/R) B-precursor acute lymphoblastic leukemia (ALL) and patients whose minimal residual disease persists during treatment have a poor leukemia-free survival. Despite improvements in front-line therapy, the outcome in these patients remains poor, especially after relapse. As there are no standard chemotherapeutic regimens for the treatment of patients with R/R B precursor ALL, T-cell-based therapeutic approaches have recently come to the forefront in ALL therapy. Recently, monoclonal antibodies have been developed to target specific antigens expressed in B-lineage blast cells. In this setting, CD19 is of great interest as this antigen is expressed in B-lineage cells. Therefore, it has been selected as the target antigen for blinatumomab, a new bi specific T-cell engager antibody. This sophisticated antibody binds sites for both CD19 and CD3, leading to T-cell proliferation and activation and B-cell apoptosis. Owing to its short serum half-life, blinatumomab has been administrated by continuous intravenous infusion with a favorable safety profile. The most significant toxicities were central nervous system events and the cytokine release syndrome. This new therapeutic approach using blinatumomab has been shown to be effective in patients with positive minimal residual disease and in patients with R/R B-precursor ALL leading to a recent approval by the US Food and Drug Administration after an accelerated review process. This review focuses on the profile of blinatumomab and its efficacy and safety. PMID- 26937177 TI - How effective is an in-hospital heart failure self-care program in a Japanese setting? Lessons from a randomized controlled pilot study. AB - BACKGROUND: Although the effectiveness of heart failure (HF) disease management programs has been established in Western countries, to date there have been no such programs in Japan. These programs may have different effectiveness due to differences in health care organization and possible cultural differences with regard to self-care. Therefore, the purpose of this study was to evaluate the effectiveness of a pilot HF program in a Japanese setting. METHODS: We developed an HF program focused on enhancing patient self-care before hospital discharge. Patients were randomized 1:1 to receive the new HF program or usual care. The primary outcome was self-care behavior as assessed by the European Heart Failure Self-Care Behavior Scale (EHFScBS). Secondary outcomes included HF knowledge and the 2-year rate of HF hospitalization and/or cardiac death. RESULTS: A total of 32 patients were enrolled (mean age, 63 years; 31% female). There was no difference in the total score of the EHFScBS between the two groups. One specific behavior score regarding a low-salt diet significantly improved compared with baseline in the intervention group. HF knowledge in the intervention group tended to improve more over 6 months than in the control group (a group-by-time effect, F=2.47, P=0.098). During a 2-year follow-up, the HF program was related to better outcomes regarding HF hospitalization and/or cardiac death (14% vs 48%, log-rank test P=0.04). In Cox regression analysis after adjustment for age, sex, and logarithmic of B-type natriuretic peptide, the program was associated with a reduction in HF hospitalization and/or cardiac death (hazard ratio, 0.17; 95% confidence interval, 0.03-0.90; P=0.04). CONCLUSION: The HF program was likely to increase patients' HF knowledge, change their behavior regarding a low-salt diet, and reduce HF hospitalization and/or cardiac events. Further improvement focused on the transition of knowledge to self-care behavior is necessary. PMID- 26937178 TI - Inhaled antibiotics for the treatment of chronic Pseudomonas aeruginosa infection in cystic fibrosis patients: challenges to treatment adherence and strategies to improve outcomes. AB - BACKGROUND: Inhaled antibiotics (ABs) are recommended for use in the therapy of chronic Pseudomonas aeruginosa infection in patients with cystic fibrosis (CF). The aim of this systematic literature review was to identify level of adherence to inhaled ABs and to determine predictors and consequences of nonadherence in CF. METHODS: A systematic literature search of English-language articles was conducted in April 2015 using Medline and Embase. No publication date limit was applied. The literature screening was conducted by two independent reviewers. All of the included studies were assessed for quality. RESULTS: The search yielded 193 publications, of which ten met the inclusion criteria and underwent data extraction. Seven studies focused on inhaled tobramycin, one on inhaled colistimethate, one on inhaled levofloxacin, and one on inhaled aztreonam lysine. Medication adherence to inhaled ABs was analyzed by pharmacy refill history, daily phone diary, parent and child self-reports, vials counting, or electronic monitoring. In randomized controlled trials (n=3), proportion of adherent patients (>75%-80% of required doses taken) ranged from 86% to 97%; in prospective cohort studies (n=3), adherence rates ranged between 36% and 92%, and in retrospective studies (n=4) it ranged between 60% and 70%. The adherence to inhaled ABs in CF was found to be associated with the complexity of treatment, time of drug administration, age of patients, treatment burden (adverse events, taste), and patient satisfaction. CONCLUSION: The high diversity of adherence data was because of the different study designs (randomized controlled trials vs real-world studies) and the lack of a commonly accepted consensus on the definition of adherence in the reviewed articles. Routine adherence monitoring during CF care, discussing the possible reasons of suboptimal adherence with the patient, and changing treatment regimens on the basis of patient burden can individualize CF therapy for patients and may improve the level of adherence. PMID- 26937179 TI - Managing neurogenic bowel dysfunction: what do patients prefer? A discrete choice experiment of patient preferences for transanal irrigation and standard bowel management. AB - BACKGROUND: Most patients with bowel dysfunction secondary to neurological illness are managed by a range of nonsurgical methods, including dietary changes, laxatives, and suppository use to transanal irrigation (TAI). The aim of the present study was to explore individuals' preferences regarding TAI devices and furthermore investigate willingness to pay (WTP) for attributes in devices in the UK. METHODS: A discrete choice experiment survey was conducted to evaluate the patients' perceived value of TAI devices. Attributes were selected based upon a literature review and input from clinicians. Interviews were conducted with three clinicians and the survey was developed and finalized with the input from both patients and professionals. The final attributes were "risk of urinary tract infections" (UTIs), "risk of fecal incontinence" (FI), "frequency of use", "time spent on toilet", "ease of use", "level of control/independence", and "cost". Participants were recruited by a patient panel of TAI device users in the UK. Data were analyzed using the conditional logit model whereby the coefficients obtained from the model provided an estimate of the (log) odds ratios (ORs) of preference for attributes. WTP was also estimated for each attribute. RESULTS: A total of 129 participants were included in the final analyses. Sixty two percent of the participants had suffered from three UTIs in the preceding year and 58% of patients reported currently experiencing FI using their current device. All attributes were significant predictors of choice. The most important attributes for participants were the "risk of FI", "frequency of use", and "risk of UTIs". CONCLUSION: Participants with bowel dysfunction regarded "risk of FI", "frequency of use", and "avoiding UTIs" as the most important features of a TAI device. These preferences are valuable in informing decision makers and clinicians regarding different bowel management solutions as well as for development of future devices. PMID- 26937180 TI - Possible effect of decreased insulin resistance on ferritin levels after Nordic Walking training. PMID- 26937181 TI - Factors associated with decreased bone mineral density in postmenopausal women with schizophrenia. AB - OBJECTIVE: This study examined the risk factors for decreased bone mineral density (BMD) in postmenopausal women with schizophrenia. METHODS: Cluster sampling method was adopted in this large-sample, cross-sectional study. A total of 219 postmenopausal female inpatients with schizophrenia were selected and interviewed in Beijing. The average age of the patients was 60.4+/-7.0 years. Clinical assessment instruments included the Positive and Negative Syndrome Scale (PANSS) and a questionnaire with detailed general information and disease-related investigations. Laboratory measurements included prolactin (PRL), estradiol, progesterone, thyroid stimulating hormone, FT3, and FT4. BMD testing was performed by dual-energy X-ray absorptiometry. RESULTS: The prevalence of osteoporosis or osteopenia was 66.2% (n=145). Decreased BMD was associated with age, illness duration, therapeutic dose (equivalent chlorpromazine dose), treatment duration, PANSS-negative scores, body mass index (BMI), daily exercises (min/d), drinking (unit/wk), PRL, and estradiol. Multiple logistic regression analysis revealed that age, treatment duration, PANSS-negative score, BMI, and PRL were significantly associated with decreased BMD. CONCLUSION: Prevalence of BMD loss was higher in Chinese postmenopausal women with schizophrenia compared to the normal BMD group. A combination of demographic and clinical factors play important roles in determining decreased BMD, including older age, longer treatment duration, more PANSS-negative scores, higher BMI, and higher PRL level. PMID- 26937182 TI - Management of acute perioperative myocardial infarction: a case report of concomitant acute myocardial infarction and tumor bleeding in the transverse colon. AB - Acute myocardial infarction complicated by bleeding colon tumor is problematic with regard to management, and appropriate balance of antiplatelet or anticoagulation therapy and hemostasis or surgery is crucial for effective treatment. Here, we present a case of concomitant acute myocardial infarction and bleeding tumor in the transverse colon, and share our experience of successfully balancing anticoagulation therapy and hemostasis. PMID- 26937184 TI - Highlights and hot topics in the management of COPD: where are we heading? PMID- 26937183 TI - Self-management of health care behaviors for COPD: a systematic review and meta analysis. AB - PURPOSE: This systematic review aimed to identify the most effective components of interventions to facilitate self-management of health care behaviors for patients with COPD. PROSPERO registration number CRD42011001588. METHODS: We used standard review methods with a systematic search to May 2012 for randomized controlled trials of self-management interventions reporting hospital admissions or health-related quality of life (HRQoL). Mean differences (MD), hazard ratios, and 95% confidence intervals (CIs) were calculated and pooled using random effects meta-analyses. Effects among different subgroups of interventions were explored including single/multiple components and multicomponent interventions with/without exercise. RESULTS: One hundred and seventy-three randomized controlled trials were identified. Self-management interventions had a minimal effect on hospital admission rates. Multicomponent interventions improved HRQoL (studies with follow-up >6 months St George's Respiratory Questionnaire (MD 2.40, 95% CI 0.75-4.04, I (2) 57.9). Exercise was an effective individual component (St George's Respiratory Questionnaire at 3 months MD 4.87, 95% CI 3.96-5.79, I (2) 0%). CONCLUSION: While many self-management interventions increased HRQoL, little effect was seen on hospital admissions. More trials should report admissions and follow-up participants beyond the end of the intervention. PMID- 26937185 TI - Diagnosis, assessment, and phenotyping of COPD: beyond FEV1. AB - COPD is now widely recognized as a complex heterogeneous syndrome, having both pulmonary and extrapulmonary features. In clinical practice, the diagnosis of COPD is based on the presence of chronic airflow limitation, as assessed by post bronchodilator spirometry. The severity of the airflow limitation, as measured by percent predicted FEV1, provides important information to the physician to enable optimization of management. However, in order to accurately assess the complexity of COPD, there need to be other measures made beyond FEV1. At present, there is a lack of reliable and simple blood biomarkers to confirm and further assess the diagnosis of COPD. However, it is possible to identify patients who display different phenotypic characteristics of COPD that relate to clinically relevant outcomes. Currently, validated phenotypes of COPD include alpha-1 antitrypsin deficiency, and "frequent exacerbators". Recently, a definition and assessment of a new phenotype comprising patients with overlapping features of asthma and COPD has been suggested and is known as "asthma COPD overlap syndrome". Several other phenotypes have been proposed, but require validation against clinical outcomes. Defining phenotypes requires the assessment of multiple factors indicating disease severity, its impact, and its activity. Recognition and validation of COPD phenotypes has an important role to play in the selection of evidence-based targeted therapy in the future management of COPD, but regardless of the diagnostic terms, patients with COPD should be assessed and treated according to their individual treatable characteristics. PMID- 26937186 TI - COPD: the patient perspective. AB - Chronic obstructive pulmonary disease (COPD) is a highly prevalent disease characterized by nonreversible airway obstruction. Well-characterized symptoms such as exertional dyspnea and fatigue have a negative impact on patients' quality of life (QoL) and restrict physical activity in daily life. The impact of COPD symptoms on QoL is often underestimated; for example, 36% of patients who describe their symptoms as being mild-to-moderate also admit to being too breathless to leave the house. Additionally, early morning and nighttime symptoms are a particular problem. Methods are available to allow clinicians to accurately assess COPD symptoms, including patient questionnaires. Integrated approaches to COPD management, particularly pulmonary rehabilitation, are effective strategies for addressing symptoms, improving exercise capacity and, potentially, also increasing physical activity. Inhaled bronchodilators continue to be the mainstay of drug therapy in COPD, where options can be tailored to meet patients' needs with careful selection of the inhaled medication and the device used for its delivery. Overall, an integrated approach to disease management should be considered for improving QoL and subsequent patient outcomes in COPD. PMID- 26937188 TI - Using basic fibroblast growth factor nanoliposome combined with ultrasound introduced technology to early intervene the diabetic cardiomyopathy. AB - Basic fibroblast growth factor (bFGF)-loaded liposome (bFGF-lip) combined with ultrasound-targeted microbubble destruction (UTMD) technique was investigated to prevent diabetic cardiomyopathy (DCM). Cardiac function and myocardial ultrastructure were assessed. Terminal deoxynucleotidyl transferase (TdT) mediated dUTP nick-end labeling (TUNEL) staining, immunohistochemistry staining, and Western blot assay were used to investigate the signal pathway underlying the expression of bFGF in DCM treatment. From Mason staining and TUNEL staining, bFGF lip + UTMD group showed significant differences from the diabetes group and other groups treated with bFGF or bFGF-lip. The diabetes group showed similar results (myocardial capillary density, collagen volume fraction, and cardiac myocyte apoptosis index) to other bFGF treatment groups. Indexes from transthoracic echocardiography and hemodynamic evaluation also proved the same conclusion. These results confirmed that the abnormalities including diastolic dysfunctions, myocardial fibrosis, and metabolic disturbances could be suppressed by the different extents of twice-weekly bFGF treatments for 12 consecutive weeks (free bFGF or bFGF-lip +/- UTMD), with the strongest improvements observed in the bFGF lip + UTMD group. The group combining bFGF-lip with UTMD demonstrated the highest level of bFGF expression among all the groups. The bFGF activated the PI3K/AKT signal pathway, causing the reduction of myocardial cell apoptosis and increase of microvascular density. This strategy using bFGF-lip and UTMD is a potential strategy in early intervention of DCM in diabetes. PMID- 26937189 TI - Preliminary report of improved sleep quality in patients with dry eye disease after initiation of topical therapy. AB - PURPOSE: Dry eye disease (DED) is potentially associated with sleep and mood disorders. This study evaluated sleep quality in patients with DED using a questionnaire-based survey before and after topical eyedrop treatment. The effectiveness of sleep and ophthalmic services in assisting with sleep problems in patients with eye disease was also assessed. METHODS: Seventy-one consecutive patients with DED visiting eight general eye clinics in various locations answered a questionnaire containing the Pittsburgh Sleep Quality Index and Hospital Anxiety and Depression Scale. Photophobia and chronotype (morningness/eveningness) were also evaluated with two representative questions from established questionnaires (National Eye Institute Visual Function Questionnaire-25 and Morningness/Eveningness questionnaire). Follow-up evaluation was conducted by interview or mail 3-10 months after the initial evaluation. A sleep service was established in two eye clinics to identify possible ocular diseases related to sleep and mood disorders; it comprised a questionnaire, sleep diary, actigram, medical interviews, visual field testing, retinal ganglion cell layer thickness measurement, and DED examination. RESULTS: Patients with newly diagnosed DED exhibited a greater improvement in sleep after DED treatment compared with patients with established DED. Improvement in Pittsburgh Sleep Quality Index was significant (P<0.05) and strongly correlated with improvement in Hospital Anxiety and Depression Scale (P<0.05) for new patients, but not for patients with established DED. Ten eye clinic patients visited the sleep service and nine of them had DED. They were successfully treated with eyedrops and sleep services, which included blue-light-shield eyewear and wearable blue-light therapy lamps according to their problem. CONCLUSION: Sleep quality improved in patients with DED after topical treatment with or without the sleep service. Psychiatric treatment focusing on sleep disorders could be beneficial for patients with DED. PMID- 26937187 TI - Exacerbations of COPD. AB - Exacerbations of chronic obstructive pulmonary disease (COPD) are defined as sustained worsening of a patient's condition beyond normal day-to-day variations that is acute in onset, and that may also require a change in medication and/or hospitalization. Exacerbations have a significant and prolonged impact on health status and outcomes, and negative effects on pulmonary function. A significant proportion of exacerbations are unreported and therefore left untreated, leading to a poorer prognosis than those treated. COPD exacerbations are heterogeneous, and various phenotypes have been proposed which differ in biologic basis, prognosis, and response to therapy. Identification of biomarkers could enable phenotype-driven approaches for the management and prevention of exacerbations. For example, several biomarkers of inflammation can help to identify exacerbations most likely to respond to oral corticosteroids and antibiotics, and patients with a frequent exacerbator phenotype, for whom preventative treatment is appropriate. Reducing the frequency of exacerbations would have a beneficial impact on patient outcomes and prognosis. Preventative strategies include modification of risk factors, treatment of comorbid conditions, the use of bronchodilator therapy with long-acting beta2-agonists or long-acting muscarinic antagonists, and inhaled corticosteroids. A better understanding of the mechanisms underlying COPD exacerbations will help to optimize use of the currently available and new interventions for preventing and treating exacerbations. PMID- 26937190 TI - Sexual dysfunction, mood, anxiety, and personality disorders in female patients with fibromyalgia. AB - BACKGROUND: We aimed to investigate the current prevalence of sexual dysfunction (SD), mood, anxiety, and personality disorders in female patients with fibromyalgia (FM). METHODS: This case-control study involved 96 patients with FM and 94 healthy women. The SD diagnosis was based on a psychiatric interview in accordance with the Diagnostic and Statistical Manual of Mental Disorders, fourth edition criteria. Mood and anxiety disorders were diagnosed using the Structured Clinical Interview. Personality disorders were diagnosed according to the Structured Clinical Interview for DSM, Revised Third Edition Personality Disorders. RESULTS: Fifty of the 96 patients (52.1%) suffered from SD. The most common SD was lack of sexual desire (n=36, 37.5%) and arousal disorder (n=10, 10.4%). Of the 96 patients, 45 (46.9%) had a mood or anxiety disorder and 13 (13.5%) had a personality disorder. The most common mood, anxiety, and personality disorders were major depression (26%), generalized anxiety disorder (8.3%), and histrionic personality disorder (10.4%). CONCLUSION: SD, mood, and anxiety disorders are frequently observed in female patients with FM. Pain plays a greater role in the development of SD in female patients with FM. PMID- 26937191 TI - Global economic burden of schizophrenia: a systematic review. AB - BACKGROUND: Schizophrenia is one of the top 25 leading causes of disability worldwide in 2013. Despite its low prevalence, its health, social, and economic burden has been tremendous, not only for patients but also for families, caregivers, and the wider society. The magnitude of disease burden investigated in an economic burden study is an important source to policymakers in decision making. This study aims to systematically identify studies focusing on the economic burden of schizophrenia, describe the methods and data sources used, and summarize the findings of economic burden of schizophrenia. METHODS: A systematic review was performed for economic burden studies in schizophrenia using four electronic databases (Medline, EMBASE, PsycINFO, and EconLit) from inception to August 31, 2014. RESULTS: A total of 56 articles were included in this review. More than 80% of the studies were conducted in high-income countries. Most studies had undertaken a retrospective- and prevalence-based study design. The bottom-up approach was commonly employed to determine cost, while human capital method was used for indirect cost estimation. Database and literature were the most commonly used data sources in cost estimation in high-income countries, while chart review and interview were the main data sources in low and middle income countries. Annual costs for the schizophrenia population in the country ranged from US$94 million to US$102 billion. Indirect costs contributed to 50% 85% of the total costs associated with schizophrenia. The economic burden of schizophrenia was estimated to range from 0.02% to 1.65% of the gross domestic product. CONCLUSION: The enormous economic burden in schizophrenia is suggestive of the inadequate provision of health care services to these patients. An informed decision is achievable with the increasing recognition among public and policymakers that schizophrenia is burdensome. This results in better resource allocation and the development of policy-oriented research for this highly disabling yet under-recognized mental health disease. PMID- 26937192 TI - DSM-5 PTSD and posttraumatic stress spectrum in Italian emergency personnel: correlations with work and social adjustment. AB - The Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-5) has recently recognized a particular risk for posttraumatic stress disorder (PTSD) among first responders (criterion A4), acknowledging emergency units as stressful places of employment. Little data is yet available on DSM-5 among emergency health operators. The aim of this study was to assess DSM-5 symptomatological PTSD and posttraumatic stress spectrum, as well as their impact on work and social functioning, in the emergency staff of a major university hospital in Italy. One hundred and ten subjects (doctors, nurses, and health-care assistants) were recruited at the Emergency Unit of the Azienda Ospedaliero Universitaria Pisana (Italy) and assessed by the Trauma and Loss Spectrum-Self Report (TALS-SR) and Work and Social Adjustment Scale (WSAS). A 15.7% DSM-5 symptomatological PTSD prevalence rate was found. Nongraduated persons reported significantly higher TALS-SR Domain IV (reaction to loss or traumatic events) scores and a significantly higher proportion of individuals presenting at least one maladaptive behavior (TALS-SR Domain VII), with respect to graduate ones. Women reported significantly higher WSAS scores. Significant correlations emerged between PTSD symptoms and WSAS total scores among health-care assistants, nongraduates and women. Our results showed emergency workers to be at risk for posttraumatic stress spectrum and related work and social impairment, particularly among women and nongraduated subjects. PMID- 26937193 TI - Effect of a nonsurgical treatment program on the gait pattern of idiopathic toe walking: a case report. AB - BACKGROUND: Recent studies have reported many possibilities for the treatment of idiopathic toe walking (ITW); however, none of them have been sufficiently documented. The purpose of this case study was to document the evolution of the gait pattern of a child with severe ITW using the Gillette Gait Index before and after the third and sixth weeks, a nonsurgical treatment program and then every 3 months to 1 year from the start of the treatment. This is significant because the case study shows that a nonsurgical treatment program can be an alternative treatment method for children with severe ITW. CASE DESCRIPTION: The case study involved a 5-year-old boy diagnosed with severe ITW. An orthopedist recommended a surgical treatment, but his parents refused to provide consent. INTERVENTION: The subject participated in a 12-week nonsurgical treatment program that used tone inhibiting casts (TICs) combined with physiotherapy based on neurodevelopmental treatment principles. The treatment protocol included the following: 1) precast preparation; 2) TICs with treatment; and 3) post-cast treatment to improve the gait pattern. OUTCOMES: After treatment with TICs, the range of motion of ankle dorsiflexion during stance had increased, resulting in an almost normalized gait. The patient stopped toe walking for at least 1 year. DISCUSSION: This study demonstrates that nonsurgical treatment should be considered first, with surgical options reserved for resistant cases; however, further research is required given the current lack of knowledge about treatment outcomes using TICs and the wide use of this treatment modality in children with ITW. PMID- 26937194 TI - New developments in the treatment of acute bacterial skin and skin structure infections: considerations for the effective use of dalbavancin. AB - Dalbavancin, an intravenous glycopeptide, was approved by the US Food and Drug Administration in May 2014 for use in adult patients with acute bacterial skin and skin structure infections. The recommended dosing regimen for effective use of dalbavancin is 1,000 mg followed by a 500 mg dose after 1 week. Two multinational, identically designed, non-inferiority trials, DISCOVER 1 and 2, demonstrated similar early clinical success with dalbavancin compared to vancomycin with an option to switch to oral linezolid. In a recently published non-inferiority trial, a single-dose regimen of dalbavancin was compared to the traditional two-dose administration and was found to have a non-inferior clinical response. In the aforementioned trials, dalbavancin was well tolerated, with patients experiencing transient adverse events of mild to moderate severity. The prolonged half-life, excellent skin and soft tissue penetration, bactericidal activity against Gram-positive bacteria including methicillin-resistant Staphylococcus aureus, and convenient dosing make dalbavancin a reasonable option for the treatment of acute bacterial skin and skin structure infections in adult patients who have tried and failed other therapies. PMID- 26937195 TI - Drug-related problems in a sample of outpatients with chronic diseases: a cross sectional study from Jordan. AB - Optimization of drug therapy and preventing drug-related problems (DRPs) are major factors to improve health care, reduce expenditure, and potentially save lives. This study aimed at describing the types, numbers, and frequencies of DRPs in the outpatient settings of a group of hospitals in Jordan. The study was set in the cardiology, endocrine, and respiratory outpatient clinics of five major hospitals in Jordan. Patients who visited the above clinics during the period from September 2012 to December 2013, were candidates for this study. Each included subject was fully assessed for DRPs by clinical pharmacists according to a specially designed and validated pharmaceutical care manual. The main outcome measures were the number and types of DRPs. Data were collected from 2,898 patients (mean age +/- standard deviation: 56.59+/-13.5 years). The total number of identified DRPs was 32,348, with an average of 11.2 DRPs per patient. The most common DRPs were a need for additional or more frequent monitoring, a problem in patients' adherence to self-care activities or nonpharmacological therapy, and that the patient was not given instruction in or did not understand nonpharmacological therapy or self-care advice. The numbers of DRPs per patient in our sample were associated with older age (>57 years), being unmarried, having an education level of high school or less, not having health insurance, and the presence of certain clinical conditions, including hypertension, diabetes mellitus, dyslipidemia, ischemic heart disease, cardiac catheterization, heart failure, and gout. In conclusion, implementation of clinical pharmacy services is a strategy to limit DRPs. Certain patient populations are more vulnerable to DRPs. PMID- 26937196 TI - Effectiveness of the clinical pharmacist in reducing mortality in hospitalized cardiac patients: a propensity score-matched analysis. AB - BACKGROUND: Pharmacist-led medication review services have been assessed in the meta-analyses in hospital. Of the 135 relevant articles located, 21 studies met the inclusion criteria; however, there was no statistically significant difference found between pharmacists' interventions and usual care for mortality (odds ratio 1.50, 95% confidence interval 0.65, 3.46, P=0.34). These analyses may not have found a statistically significant effect because they did not adequately control the wide variation in the delivery of care and patient selection parameters. Additionally, the investigators did not conduct research on the cases of death specifically and did not identify all possible drug-related problems (DRPs) that could cause or contribute to mortality and then convince physicians to correct. So there will be a condition to use a more precise approach to evaluate the effect of clinical pharmacist interventions on the mortality rates of hospitalized cardiac patients. OBJECTIVE: To evaluate the impact of the clinical pharmacist as a direct patient-care team member on the mortality of all patients admitted to the cardiology unit. METHODS: A comparative study was conducted in a cardiology unit of a university-affiliated hospital. The clinical pharmacists did not perform any intervention associated with improper use of medications during Phase I (preintervention) and consulted with the physicians to address the DRPs during Phase II (postintervention). The two phases were compared to evaluate the outcome, and propensity score (PS) matching was applied to enhance the comparability. The primary endpoint of the study was the composite of all-cause mortality during Phase I and Phase II. RESULTS: Pharmacists were consulted by the physicians to correct any drug-related issues that they suspected may cause or contribute to a fatal outcome in the cardiology ward. A total of 1,541 interventions were suggested by the clinical pharmacist in the study group; 1,416 (92.0%) of them were accepted by the cardiology team, and violation of incompatibilities had the highest percentage of acceptance by the cardiology team. All-cause mortality was 1.5% during Phase I (preintervention) and was reduced to 0.9% during Phase II (postintervention), and the difference was statistically significant (P=0.0005). After PS matching, all-cause mortality changed from 1.7% during Phase I down to 1.0% during Phase II, and the difference was also statistically significant (P=0.0074). CONCLUSION: DRPs that were suspected to cause or contribute to a possibly fatal outcome were determined by clinical pharmacist service in patients hospitalized in a cardiology ward. Correction of these DRPs by physicians after pharmacist's advice caused a significant decrease in mortality as analyzed by PS matching. The significant reduction in the mortality rate in this patient population observed in this study is "hypothesis generating" for future randomized studies. PMID- 26937197 TI - Bacterial profile of urinary tract infection and antimicrobial susceptibility pattern among pregnant women attending at Antenatal Clinic in Dil Chora Referral Hospital, Dire Dawa, Eastern Ethiopia. AB - PURPOSE: The aim of this study was to determine the bacterial profile of urinary tract infection (UTI) and antimicrobial susceptibility pattern among pregnant women attending at antenatal clinic in Dil Chora Referral Hospital, Dire Dawa, Eastern Ethiopia. PATIENTS AND METHODS: An institutional-based cross-sectional study was conducted from February 18, 2015 to March 25, 2015. Clean-catch midstream urine specimens were collected from 186 pregnant women using sterile containers. Then, culture and antimicrobial susceptibility tests were performed by standard disk diffusion method. Patient information was obtained using pretested structured questionnaire. Data were entered and cleaned using EpiData Version 3 and then exported to Statistical Package for Social Science (Version 16) for further analysis. RESULTS: The prevalence of significant bacteriuria was 14%. Gram-negative bacteria were more prevalent (73%). Escherichia coli (34.6%), coagulase-negative staphylococci (19.2%), Pseudomonas aeruginosa (15.4%), and Klebsiella spp. (11.5%) were common bacterial isolates, where most of them were resistant against ampicillin, amoxicillin, tetracycline, trimethoprim sulfamethoxazole, and chloramphenicol. Multidrug resistance (resistance in >=2 drugs) was seen in 100% of the isolated bacteria. A majority of the bacterial isolates were sensitive to ciprofloxacin, ceftriaxone, erythromycin, and gentamicin. CONCLUSION: This study found a number of bacterial isolates with very high resistance to the commonly prescribed drugs from pregnant women with and without symptoms of UTI. Therefore, the early routine detection of causative agents of UTI and determining their drug susceptibility pattern are important for pregnant women to avoid complications in mother and fetus. Ciprofloxacin, ceftriaxone, gentamicin, and erythromycin can be used with great care for the empirical treatment of UTI. PMID- 26937199 TI - Postpartum depression screening in the Neonatal Intensive Care Unit: program development, implementation, and lessons learned. AB - OBJECTIVE: The aims of this project were to describe the development of a postpartum depression screening program for mothers of infants in the Neonatal Intensive Care Unit and assess the implementation of the screening program. METHODS: Screening began at 14 days postpartum and was implemented as part of routine medical care. A nurse coordinator facilitated communication with mothers for increasing screen completion, review of critical self-harm items, and making mental health referrals. During the 18-month study period, 385 out of 793 eligible mothers completed the screen. RESULTS: Approximately 36% of mothers had a positive screen that resulted in a mental health referral and an additional 30% of mothers had screening results indicating significant symptoms. CONCLUSION: Several barriers were identified, leading to adjustments in the screening process, and ultimately recommendations for future screening programs and research. Development of a postpartum depression screening process in the Neonatal Intensive Care Unit involves support, training, implementation, and coordination from administrators, medical staff, new mothers, and mental health specialists. Several predictable challenges to program development require ongoing assessment and response to these challenges. RELEVANCE: This study highlights the expanding role of the psychologist and behavioral health providers in health care to intervene as early as possible in the life of a child and family with medical complications through multidisciplinary program development and implementation, as well as key considerations for institutions initiating such a program. PMID- 26937198 TI - Reversing anticoagulant effects of novel oral anticoagulants: role of ciraparantag, andexanet alfa, and idarucizumab. AB - Novel oral anticoagulants (NOACs) are increasingly used in clinical practice, but lack of commercially available reversal agents is a major barrier for mainstream use of these therapies. Specific antidotes to NOACs are under development. Idarucizumab (aDabi-Fab, BI 655075) is a novel humanized mouse monoclonal antibody that binds dabigatran and reverses its anticoagulant effect. In a recent Phase III study (Reversal Effects of Idarucizumab on Active Dabigatran), a 5 g intravenous infusion of idarucizumab resulted in the normalization of dilute thrombin time in 98% and 93% of the two groups studied, with normalization of ecarin-clotting time in 89% and 88% patients. Two other antidotes, andexanet alfa (PRT064445) and ciraparantag (PER977) are also under development for reversal of NOACs. In this review, we discuss commonly encountered management issues with NOACs such as periprocedural management, laboratory monitoring of anticoagulation, and management of bleeding. We review currently available data regarding specific antidotes to NOACs with respect to pharmacology and clinical trials. PMID- 26937200 TI - Comparative analyses of postoperative complications and prognosis of different surgical procedures in stage II endometrial carcinoma treatment. AB - OBJECTIVE: To investigate the impact of surgical resection extent on the postoperative complications and the prognosis in patients with stage II endometrial cancer. METHODS: A total of 54 patients were retrospectively reviewed, 35 patients underwent subradical hysterectomy and 19 patients received radical hysterectomy, both with simultaneous bilateral salpingo-oophorectomy and pelvic and paraaortic lymphadenectomy. RESULTS: Comparing the surgical outcomes in subradical hysterectomy group vs radical hysterectomy group, there were no significant differences in operative time, estimated blood loss, and hospital stay. After surgery, 37.1% vs 36.8% patients received postoperative radiotherapy in the subradical hysterectomy group vs radical hysterectomy group, without statistically significant difference. As for postoperative complications, the early postoperative complication rate in patients who underwent subradical hysterectomy was 14.3%, significantly lower than that in patients submitted to radical hysterectomy (14.3% vs 42.1%), with P=0.043. However, there was no significant difference in late postoperative complication rate between the two surgical procedures. Regarding the clinical prognosis, patients receiving the subradical hysterectomy showed similar survival to their counterparts undergoing the radical procedures. The relapse rate was 5.71% vs 5.26%, respectively, without significant difference. There were no deaths in both surgical groups. CONCLUSION: For stage II endometrial carcinoma, subradical hysterectomy presented with less early postoperative complications and similar survival duration and recurrence compared with radical hysterectomy and should be advocated in clinical treatment. PMID- 26937201 TI - PBOV1 promotes prostate cancer proliferation by promoting G1/S transition. AB - Prostate cancer (PC) is one of the leading causes of cancer death in men, and thus, finding new regulators is critical for PC therapy. Prostate and breast cancer overexpressed 1 (PBOV1) is overexpressed in breast, prostate, and bladder cancers, as it is upregulated in the serum of patients with PC, but the role of PBOV1 in PC has not been studied. In this article, we found that PBOV1 was indeed overexpressed in PC cells; PBOV1 overexpression promoted cell proliferation and colony formation ability and arrested cell cycle in the G0/G1 phase and tumorigenicity ability in vitro, whereas knockdown of PBOV1 reduced these effects. Further analysis of PBOV1 overexpression inhibited cell cycle inhibitors, P21 and P27, and increased the phosphorylation level of Rb and cyclin D1 expression, suggesting that PBOV1 promoted cell proliferation through promoting G1/S transition. PMID- 26937202 TI - Using the geometric mean fluorescence intensity index method to measure ZAP-70 expression in patients with chronic lymphocytic leukemia. AB - Expression of zeta-chain-associated protein kinase 70 kDa (ZAP-70) in chronic lymphocytic leukemia (CLL) is associated with more aggressive disease and can help differentiate CLL from cases expressing mutated or unmutated immunoglobulin heavy chain variable region (IgHV) genes. However, standardizing ZAP-70 expression by flow cytometric analysis has proved unsatisfactory. The key point is that ZAP-70 is weakly expressed with a continuous expression pattern rather than a clear discrimination between positive and negative CLL cells, which means that the resulting judgment is subjective. Thus, in this study, we aimed at assessing the reliability and repeatability of ZAP-70 expression using the geometric mean fluorescence intensity (geo MFI) index method based on flow cytometry with 256-channel resolution in a series of 402 CLL patients and to compare ZAP-70 with other biological and clinical prognosticators. According to IgHV mutational status, we were able to confirm that the optimal cut-off point for the geo MFI index was 3.5 in the test set. In multivariate analyses that included the major clinical and biological prognostic markers for CLL, the prognostic impact of ZAP-70 expression appeared to have stronger discriminatory power when the geo MFI index method was applied. In addition, we found that ZAP 70-positive patients according to the geo MFI index method had shorter time to first treatment or overall survival (P=0.0002, P=0.0491). This is the first report showing that ZAP-70 expression can be evaluated by a new approach, the geo MFI index, which could be a useful prognostic method as it is more reliable, less subjective, and therefore better associated with improvement of CLL prognostication and prediction of clinical course. PMID- 26937203 TI - Sugammadex for reversal of neuromuscular blockade: a retrospective analysis of clinical outcomes and cost-effectiveness in a single center. AB - OBJECTIVE: The aim of the study is to evaluate the clinical and economic impact of introducing a rocuronium-neostigmine-sugammadex strategy into a cisatracurium neostigmine regimen for neuromuscular block (NMB) management. METHODS: We conducted a retrospective analysis of clinical outcomes and cost-effectiveness in five operating rooms at University Hospital of Padova. A clinical outcome evaluation after sugammadex administration as first-choice reversal drug in selected patients (rocuronium-sugammadex) and as rescue therapy after neostigmine reversal (rocuronium-neostigmine-sugammadex) compared to control was performed. A cost-analysis of NMB management accompanying the introduction of a rocuronium neostigmine-sugammadex strategy into a cisatracurium-neostigmine regimen was carried out. To such purpose, two periods were compared: 2011-2012, without sugammadex available; 2013-2014, with sugammadex available. A subsequent analysis was performed to evaluate if sugammadex replacing neostigmine as first choice reversal drug is cost-effective. RESULTS: The introduction of a rocuronium neostigmine-sugammadex strategy into a cisatracurium-neostigmine regimen reduced the average cost of NMB management by 36%, from ?20.8/case to ?13.3/case. Patients receiving sugammadex as a first-choice reversal drug (3%) exhibited significantly better train-of-four ratios at extubation (P<0.001) and were discharged to the surgical ward (P<0.001) more rapidly than controls. The cost saving of sugammadex as first-choice reversal drug has been estimated to be ?2.9/case. Patients receiving sugammadex as rescue therapy after neostigmine reversal (3.2%) showed no difference in time to discharge to the surgical ward (P=0.44) compared to controls. No unplanned intensive care unit (ICU) admissions with rocuronium-neostigmine-sugammadex strategy were observed. The potential economic benefit in avoiding postoperative residual curarization (PORC)-related ICU admission in the 2013-2014 period was estimated at an average value of ?13,548 (?9,316-?23,845). CONCLUSION: Sugammadex eliminated PORC and associated morbidities. In our center, sugammadex reduced the costs of NMB management and promoted rapid turnover of patients in operating rooms, with total cost effectiveness that counteracts the disadvantages of its high cost. PMID- 26937204 TI - Neoadjuvant therapy for early-stage breast cancer: the clinical utility of pertuzumab. AB - Approximately 20% of breast cancer patients harbor tumors that overexpress human epidermal growth factor receptor 2 (HER2; also known as ErbB2), a receptor tyrosine kinase that belongs to the epidermal growth factor receptor family of receptor tyrosine kinases. HER2 amplification and hyperactivation drive the growth and survival of breast cancers through the aberrant activation of proto oncogenic signaling systems, particularly the Ras/MAP kinase and PI3K/AKT pathways. Although HER2-positive (HER2(+)) breast cancer was originally considered to be a highly aggressive form of the disease, the clinical landscape of HER2(+) breast cancers has literally been transformed by the approval of anti HER2 agents for adjuvant and neoadjuvant settings. Indeed, pertuzumab is a novel monoclonal antibody that functions as an anti-HER2 agent by targeting the extracellular dimerization domain of the HER2 receptor; it is also the first drug to receive an accelerated approval by the US Food and Drug Administration for use in neoadjuvant settings in early-stage HER2(+) breast cancer. Here, we review the molecular and cellular factors that contribute to the pathophysiology of HER2 in breast cancer, as well as summarize the landmark preclinical and clinical findings underlying the approval and use of pertuzumab in the neoadjuvant setting. Finally, the molecular mechanisms operant in mediating resistance to anti-HER2 agents, and perhaps to pertuzumab as well, will be discussed, as will the anticipated clinical impact and future directions of pertuzumab in breast cancer patients. PMID- 26937205 TI - Clinical utility, safety, and efficacy of pregabalin in the treatment of fibromyalgia. AB - Fibromyalgia is a chronic debilitating medical syndrome with limited therapeutic options. Pregabalin, an anticonvulsant and alpha-2-Delta subunit receptor ligand, is one of the anchor drugs approved by the US Food and Drug Administration for the treatment of fibromyalgia. The drug has shown clinically meaningful benefits across multiple symptom domains of fibromyalgia. Efficacy of pregabalin in fibromyalgia pain has been evaluated in at least five high-quality randomized trials, two long-term extension studies, a meta-analysis, a Cochrane database systematic review, and several post hoc analyses. These studies also hint towards a meaningful benefit on sleep, functioning, quality of life, and work productivity. Side effects of pregabalin, although common, are mild to moderate in intensity. They are noted early during therapy, improve or disappear with dose reduction, and are not usually life- or organ threatening. In most patients, tolerance develops to the most common side effects, dizziness, and somnolence, with time. With close clinical monitoring at initiation or dose titration, pregabalin can be effectively used in primary care setting. Pregabalin is cost saving with long-term use and its cost-effectiveness profile is comparable, if not better, to that of other drugs used in fibromyalgia. In the present era of limited therapeutic options, pregabalin undoubtedly retains its role as one of cardinal drugs used in the treatment of fibromyalgia. This review intends to discuss the clinical utility of pregabalin in the management of fibromyalgia with a focus on efficacy, safety, and cost-effectiveness. PMID- 26937206 TI - Safety of apixaban for venous thromboembolism prophylaxis: the evidence to date. AB - Apixaban, a direct orally active anticoagulant (selective, direct factor Xa inhibitor) is approved for (primary) prevention of venous thromboembolism (VTE) in patients undergoing elective total-hip or total-knee arthroplasty, for acute treatment/prevention of recurrent events in patients with VTE, and extended prophylaxis in patients with a history of VTE. Another approved use is prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. The present overview focuses on the safety of apixaban specifically in the VTE setting. Apixaban displays favorable pharmacokinetic properties: simple twice daily dosing, low inter- and intrasubject variability, dose and time linearity, and multiple elimination pathways not critically dependent on either renal or metabolic mechanisms. An extensive nonclinical program and the overall clinical development program (all approved and tested indications) provided no signal that would indicate any particular specific safety concern related to apixaban apart from the increased risk of bleeding. With regard to the approved VTE indications, safety (and efficacy) was assessed in five large pivotal Phase III trials. In comparison to currently recommended standard treatments, apixaban shows superior efficacy, while at the same time no excess risk of bleeding in patients undergoing total-hip or total-knee arthroplasty. In treatment of VTE, apixaban shows noninferior efficacy and a reduced risk of bleeding, whereas in extended prophylaxis it reduced the risk of VTE/VTE-related deaths, with no increased risk of relevant bleedings in comparison to placebo. Documented clinical experience with apixaban in daily practice is currently sparse. However, its use is progressively increasing, and there has been no signal so far that would materially change the perception of its safety profile as defined in the premarketing trials. PMID- 26937207 TI - The influence of sex, age, and race experience on pacing profiles during the 90 km Vasaloppet ski race. AB - The purpose of this study was to investigate pacing-profile differences during the 90 km Vasaloppet ski race related to the categories of sex, age, and race experience. Skiing times from eight sections (S1 to S8) were analyzed. For each of the three categories, 400 pairs of skiers were matched to have a finish time within 60 seconds, the same start group, and an assignment to the same group for the other two categories. Paired-samples Student's t-tests were used to investigate sectional pacing-profile differences between the subgroups. Results showed that males skied faster in S2 (P=0.0042), S3 (P=0.0049), S4 (P=0.010), and S1-S4 (P<0.001), whereas females skied faster in S6 (P<0.001), S7 (P<0.001), S8 (P=0.0088), and S5-S8 (P<0.001). For the age category, old subjects (40 to 59 years) skied faster than young subjects (19 to 39 years) in S3 (P=0.0029), and for the other sections, there were no differences. Experienced subjects (>=4 Vasaloppet ski race completions) skied faster in S1 (P<0.001) and S1-S4 (P=0.0054); inexperienced skiers (<4 Vasaloppet ski race completions) had a shorter mean skiing time in S5-S8 (P=0.0063). In conclusion, females had a more even pacing profile than that of males with the same finish time, start group, age, and race experience. No clear age-related pacing-profile difference was identified for the matched subgroups. Moreover, experienced skiers skied faster in the first half whereas inexperienced skiers had higher skiing speeds during the second half of the race. PMID- 26937208 TI - A new method for teaching physical examination to junior medical students. AB - INTRODUCTION: Teaching effective physical examination is a key component in the education of medical students. Preclinical medical students often have insufficient clinical knowledge to apply to physical examination recall, which may hinder their learning when taught through certain understanding-based models. This pilot project aimed to develop a method to teach physical examination to preclinical medical students using "core clinical cases", overcoming the need for "rote" learning. METHODS: This project was developed utilizing three cycles of planning, action, and reflection. Thematic analysis of feedback was used to improve this model, and ensure it met student expectations. RESULTS AND DISCUSSION: A model core clinical case developed in this project is described, with gout as the basis for a "foot and ankle" examination. Key limitations and difficulties encountered on implementation of this pilot are discussed for future users, including the difficulty encountered in "content overload". CONCLUSION: This approach aims to teach junior medical students physical examination through understanding, using a simulated patient environment. Robust research is now required to demonstrate efficacy and repeatability in the physical examination of other systems. PMID- 26937209 TI - Myosin VI contributes to malignant proliferation of human glioma cells. AB - Previously characterized as a backward motor, myosin VI (MYO6), which belongs to myosin family, moves toward the minus end of the actin track, a direction opposite to all other known myosin members. Recent researches have illuminated the role of MYO6 in human cancers, particularly in prostate cancer. However, the role of MYO6 in glioma has not yet been determined. In this study, to explore the role of MYO6 in human glioma, lentivirus-delivered short hairpin RNA (shRNA) targeting MYO6 was designed to stably down-regulate its endogenous expression in glioblastoma cells U251. Knockdown of MYO6 signifi cantly inhibited viability and proliferation of U251 cells in vitro. Moreover, the cell cycle of U251 cells was arrested at G0/G1 phase with the absence of MYO6, which could contribute to the suppression of cell proliferation. In conclusion, we firstly identified the crucial involvement of MYO6 in human glioma. The inhibition of MYO6 by shRNA might be a potential therapeutic method in human glioma. PMID- 26937210 TI - Curcumin protects against the intestinal ischemia-reperfusion injury: involvement of the tight junction protein ZO-1 and TNF-alpha related mechanism. AB - Present study aimed to investigate the eff ect of curcumin-pretreatment on intestinal I/R injury and on intestinal mucosa barrier. Thirty Wistar rats were randomly divided into: sham, I/R, and curcumin groups (n=10). Animals in curcumin group were pretreated with curcumin by gastric gavage (200 mg/kg) for 2 days before I/R. Small intestine tissues were prepared for Haematoxylin & Eosin (H&E) staining. Serum diamine oxidase (DAO) and tumor necrosis factor (TNF)-alpha levels were measured. Expression of intestinal TNF-alpha and tight junction protein (ZO-1) proteins was detected by Western blot and/or immunohistochemistry. Serum DAO level and serum and intestinal TNF-alpha leves were signifi cantly increased after I/R, and the values were markedly reduced by curcumin pretreatment although still higher than that of sham group (p<0.05 or p<0.001). H&E staining showed the significant injury to intestinal mucosa following I/R, and curcumin pretreatment signifi cantly improved the histological structure of intestinal mucosa. I/R insult also induced significantly down-regulated expression of ZO-1, and the eff ect was dramatically attenuated by curcumin pretreatment. Curcumin may protect the intestine from I/R injury through restoration of the epithelial structure, promotion of the recovery of intestinal permeability, as well as enhancement of ZO-1 protein expression, and this eff ect may be partly attributed to the TNF-alpha related pathway. PMID- 26937212 TI - CRM1 inhibitor S109 suppresses cell proliferation and induces cell cycle arrest in renal cancer cells. AB - Abnormal localization of tumor suppressor proteins is a common feature of renal cancer. Nuclear export of these tumor suppressor proteins is mediated by chromosome region maintenance-1 (CRM1). Here, we investigated the antitumor eff ects of a novel reversible inhibitor of CRM1 on renal cancer cells. We found that S109 inhibits the CRM1-mediated nuclear export of RanBP1 and reduces protein levels of CRM1. Furthermore, the inhibitory eff ect of S109 on CRM1 is reversible. Our data demonstrated that S109 signifi cantly inhibits proliferation and colony formation of renal cancer cells. Cell cycle assay showed that S109 induced G1-phase arrest, followed by the reduction of Cyclin D1 and increased expression of p53 and p21. We also found that S109 induces nuclear accumulation of tumor suppressor proteins, Foxo1 and p27. Most importantly, mutation of CRM1 at Cys528 position abolished the eff ects of S109. Taken together, our results indicate that CRM1 is a therapeutic target in renal cancer and the novel reversible CRM1 inhibitor S109 can act as a promising candidate for renal cancer therapy. PMID- 26937211 TI - Anti-diabetic activities of catalpol in db/db mice. AB - The objective was to investigate the hypoglycemic action of catalpol in spontaneous diabetes db/db mice. 40 db/db mice were randomly divided into fi ve groups: model control gourp; db/db plus catalpol 40, 80, 120 mg/kg body wt. groups and db/db plus metformin 250 mg/kg group. Age-matched db/m mice were selected as normal control group. The mice were administered with corresponding drugs or solvent by gavage for 4 weeks. The oral glucose tolerance test was carried out at the end of 3(rd) week. After 4 weeks of treatment, the concentrations of fasting blood glucose (FBG), glycated serum protein (GSP), insulin (INS), triglyceride (TG), total cholesterol (TC) and adiponection (APN) in serum were detected. The protein expressions of phosphorylation-AMPKalpha1/2 in liver, phosphorylation-AMPKalpha1/2 and glucose transporter-4 (GLUT-4) in skeletal muscle and adipose tissues were detected by western blot. Real time RT PCR was used to detect the mRNA expressions of acetyl-CoA carboxylase (ACC) and Hydroxymethyl glutaric acid acyl CoA reductase (HMGCR) in liver. Our results showed that catalpol could significantly improve the insulin resistance, decrease the serum concentrations of INS, GSP, TG, and TC. The concentrations of APN in serum, the protein expression of phosphorylation-AMPKalpha1/2 in liver, phosphorylation-AMPKalpha1/2 and GLUT-4 in peripheral tissue were increased. Catalpol could also down regulate the mRNA expressions of ACC and HMGCR in liver. In conclusion, catalpol ameliorates diabetes in db/db mice. It has benefi t eff ects against lipid/glucose metabolism disorder and insulin resistance. The mechanism may be related to up-regulating the expression of phosphorylation AMPKalpha1/2. PMID- 26937213 TI - High glucose and palmitate increases bone morphogenic protein 4 expression in human endothelial cells. AB - Here, we investigated whether hyperglycemia and/or free fatty acids (palmitate, PAL) aff ect the expression level of bone morphogenic protein 4 (BMP4), a proatherogenic marker, in endothelial cells and the potential role of BMP4 in diabetic vascular complications. To measure BMP4 expression, human umbilical vein endothelial cells (HUVECs) were exposed to high glucose concentrations and/or PAL for 24 or 72 h, and the effects of these treatments on the expression levels of adhesion molecules and reactive oxygen species (ROS) were examined. BMP4 loss-of function status was achieved via transfection of a BMP4-specific siRNA. High glucose levels increased BMP4 expression in HUVECs in a dose-dependent manner. PAL potentiated such expression. The levels of adhesion molecules and ROS production increased upon treatment with high glucose and/or PAL, but this eff ect was negated when BMP4 was knocked down via siRNA. Signaling of BMP4, a proinflammatory and pro-atherogenic cytokine marker, was increased by hyperglycemia and PAL. BMP4 induced the expression of infl ammatory adhesion molecules and ROS production. Our work suggests that BMP4 plays a role in atherogenesis induced by high glucose levels and/or PAL. PMID- 26937214 TI - Identification of Lys49-PLA2 from crude venom of Crotalus atrox as a human neutrophil-calcium modulating protein. AB - We fortuitously observed a human neutrophil intracellular free-calcium concentration ([Ca(2+)]i) increasing activity in the commercially available phosphodiesterase I (PDE I), which is actually dried crude venom of Crotalus atrox. As this activity was not observed with another commercially available pure PDE I, we tried to find out the causative molecule(s) present in 'crude' PDE, and identified Lys49-phospholipase A2 (Lys49-PLA2 or K49-PLA2), a catalytically inactive protein which belongs to the phospholipase A2 family, by activity-driven three HPLC (reverse phase, size exclusion, reverse phase) steps followed by SDS PAGE and LC-MS/MS. K49-PLA2 induced Ca(2+) infl ux in human neutrophils without any cytotoxic eff ect. Two calcium channel inhibitors, 2-aminoetoxydiphenyl borate (2-APB) (30 uM) and SKF-96365 (20 uM) signifi cantly inhibited K49-PLA2 induced [Ca(2+)]i increase. These results suggest that K49-PLA2 modulates [Ca(2+)]i in human neutrophils via 2-APB- and SKF-96365-sensitive calcium channels without causing membrane disruption. PMID- 26937215 TI - The neuroprotective mechanism of ampicillin in a mouse model of transient forebrain ischemia. AB - Ampicillin, a beta-lactam antibiotic, dose-dependently protects neurons against ischemic brain injury. The present study was performed to investigate the neuroprotective mechanism of ampicillin in a mouse model of transient global forebrain ischemia. Male C57BL/6 mice were anesthetized with halothane and subjected to bilateral common carotid artery occlusion for 40 min. Before transient forebrain ischemia, ampicillin (200 mg/kg, intraperitoneally [i.p.]) or penicillin G (6,000 U/kg or 20,000 U/kg, i.p.) was administered daily for 5 days. The pretreatment with ampicillin but not with penicillin G signifi cantly attenuated neuronal damage in the hippocampal CA1 subfield. Mechanistically, the increased activity of matrix metalloproteinases (MMPs) following forebrain ischemia was also attenuated by ampicillin treatment. In addition, the ampicillin treatment reversed increased immunoreactivities to glial fibrillary acidic protein and isolectin B4, markers of astrocytes and microglia, respectively. Furthermore, the ampicillin treatment significantly increased the level of glutamate transporter-1, and dihydrokainic acid (DHK, 10 mg/kg, i.p.), an inhibitor of glutamate transporter-1 (GLT-1), reversed the neuroprotective effect of ampicillin. Taken together, these data indicate that ampicillin provides neuroprotection against ischemia-reperfusion brain injury, possibly through inducing the GLT-1 protein and inhibiting the activity of MMP in the mouse hippocampus. PMID- 26937216 TI - Blockade of Kv1.5 channels by the antidepressant drug sertraline. AB - Sertraline, a selective serotonin reuptake inhibitor (SSRI), has been reported to lead to cardiac toxicity even at therapeutic doses including sudden cardiac death and ventricular arrhythmia. And in a SSRI-independent manner, sertraline has been known to inhibit various voltage-dependent channels, which play an important role in regulation of cardiovascular system. In the present study, we investigated the action of sertraline on Kv1.5, which is one of cardiac ion channels. The eff ect of sertraline on the cloned neuronal rat Kv1.5 channels stably expressed in Chinese hamster ovary cells was investigated using the whole-cell patch-clamp technique. Sertraline reduced Kv1.5 whole-cell currents in a reversible concentration-dependent manner, with an IC 50 value and a Hill coefficient of 0.71 uM and 1.29, respectively. Sertraline accelerated the decay rate of inactivation of Kv1.5 currents without modifying the kinetics of current activation. The inhibition increased steeply between -20 and 0 mV, which corresponded with the voltage range for channel opening. In the voltage range positive to +10 mV, inhibition displayed a weak voltage dependence, consistent with an electrical distance delta of 0.16. Sertraline slowed the deactivation time course, resulting in a tail crossover phenomenon when the tail currents, recorded in the presence and absence of sertraline, were superimposed. Inhibition of Kv1.5 by sertraline was use-dependent. The present results suggest that sertraline acts on Kv1.5 currents as an open-channel blocker. PMID- 26937217 TI - NecroX-5 protects mitochondrial oxidative phosphorylation capacity and preserves PGC1alpha expression levels during hypoxia/reoxygenation injury. AB - Although the antioxidant and cardioprotective effects of NecroX-5 on various in vitro and in vivo models have been demonstrated, the action of this compound on the mitochondrial oxidative phosphorylation system remains unclear. Here we verify the role of NecroX-5 in protecting mitochondrial oxidative phosphorylation capacity during hypoxia-reoxygenation (HR). Necrox-5 treatment (10 uM) and non treatment were employed on isolated rat hearts during hypoxia/reoxygenation treatment using an ex vivo Langendorff system. Proteomic analysis was performed using liquid chromatography-mass spectrometry (LC-MS) and non-labeling peptide count protein quantification. Real-time PCR, western blot, citrate synthases and mitochondrial complex activity assays were then performed to assess heart function. Treatment with NecroX-5 during hypoxia significantly preserved electron transport chain proteins involved in oxidative phosphorylation and metabolic functions. NecroX-5 also improved mitochondrial complex I, II, and V function. Additionally, markedly higher peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC1alpha) expression levels were observed in NecroX-5 treated rat hearts. These novel results provide convincing evidence for the role of NecroX-5 in protecting mitochondrial oxidative phosphorylation capacity and in preserving PGC1alpha during cardiac HR injuries. PMID- 26937218 TI - Mitochondrial calcium uniporter inhibition attenuates mouse bone marrow-derived mast cell degranulation induced by beta-1,3-glucan. AB - Mast cells are primary mediators of allergic inflammation. Beta-1,3-glucan (BG) protects against infection and shock by activating immune cells. Activation of the BG receptor induces an increase in intracellular Ca(2+), which may induce exocytosis. However, little is known about the precise mechanisms underlying BG activation of immune cells and the possible role of mitochondria in this process. The present study examined whether BG induced mast cell degranulation, and evaluated the role of calcium transients during mast cell activation. Our investigation focused on the role of the mitochondrial calcium uniporter (MCU) in BG-induced degranulation. Black mouse (C57) bone marrow-derived mast cells were stimulated with 0.5 ug/ml BG, 100 ug/ml peptidoglycan (PGN), or 10 uM A23187 (calcium ionophore), and dynamic changes in cytosolic and mitochondrial calcium and membrane potential were monitored. BG-induced mast cell degranulation occurred in a time-dependent manner, and was significantly reduced under calcium free conditions. Ruthenium red, a mitochondrial Ca(2+) uniporter blocker, significantly reduced mast cell degranulation induced by BG, PGN, and A23187. These results suggest that the mitochondrial Ca(2+) uniporter has an important regulatory role in BG-induced mast cell degranulation. PMID- 26937219 TI - Effects of prunetin on the proteolytic activity, secretion and gene expression of MMP-3 in vitro and production of MMP-3 in vivo. AB - We investigated whether prunetin affects the proteolytic activity, secretion, and gene expression of matrix metalloproteinase-3 (MMP-3) in primary cultured rabbit articular chondrocytes, as well as in vivo production of MMP-3 in the rat knee joint to evaluate the potential chondroprotective eff ect of prunetin. Rabbit articular chondrocytes were cultured in a monolayer, and reverse transcription polymerase chain reaction (RT-PCR) was used to measure interleukin-1beta (IL 1beta)-induced expression of MMP-3, MMP-1, MMP-13, a disintegrin and metalloproteinase with thrombospondin motifs-4 (ADAMTS-4), and ADAMTS-5. In rabbit articular chondrocytes, the effects of prunetin on IL-1beta-induced secretion and proteolytic activity of MMP-3 were investigated using western blot analysis and casein zymography, respectively. The eff ect of prunetin on MMP-3 protein production was also examined in vivo. The results were as follows: (1) prunetin inhibited the gene expression of MMP-3, MMP-1, MMP-13, ADAMTS-4, and ADAMTS-5; (2) prunetin inhibited the secretion and proteolytic activity of MMP-3; (3) prunetin suppressed the production of MMP-3 protein in vivo. These results suggest that prunetin can regulate the gene expression, secretion, and proteolytic activity of MMP-3, by directly acting on articular chondrocytes. PMID- 26937220 TI - Factors influencing hospitalized patients' perception of individualized nursing care: a cross-sectional study. AB - BACKGROUND: Individualized care is a cornerstone of patient-centered nursing care. To foster individualized care, influencing factors should be known. The aim of this study was to identify the individual and organizational factors influencing hospitalized patients' perception of individualized care. METHODS: A cross-sectional study was conducted of 606 patients from 20 wards from five hospitals across Germany. Individualized care and potential influencing factors were assessed via structured questionnaires. To identify influencing factors, we applied a hierarchical linear model with two levels. RESULTS: Self-rated health, length of ward stay, educational level and shared decision-making process about nursing care were perceived to influence individualized care. A higher rating of health and longer ward stay correlated with improved perceptions of individualized nursing care. In addition, an educational level of nine or fewer years and a perceived shared decision-making process about nursing care positively influenced the perception of nursing care as being tailored to individual needs. CONCLUSIONS: Several factors influence patients' perception of individualized care. However, only the decision-making process can be actively influenced by nurses. Therefore, nurses should be encouraged to promote shared decision-making regarding patients' nursing care. TRIAL NUMBER: DRKS00005174 (Date of registration: 2013/08/01). PMID- 26937221 TI - Association of social support and socio-demographic characteristics with poor self-rated health and depressive symptomatology among single mothers in Cyprus: a descriptive cross-sectional study. AB - BACKGROUND: The number of single-parent families headed by mothers is rapidly growing worldwide. A large part of the international literature reveals that single motherhood is associated with increased levels of chronic stress, mainly due to economic distress and reduced levels of social support, which may eventually lead to physical and psychological illness. Most published research comes from Northern Europe and the US, while it is accepted that both social welfare systems and societal factors vary substantially across countries. These issues haven't been explored in Southern Europe and this study aims to fill this gap by a) assessing the health of single mothers in Cyprus in terms of self assessed general health and the prevalence of clinical depressive symptoms and b) investigating the effect of perceived social support relation to their health status. METHODS: General health was assessed in terms of Self-Rated Health (SRH), while the prevalence of clinical depressive symptoms was assessed with the Center of Epidemiological Studies-Depression Scale (CES-D). Perceived social Support was assessed with the Social Provision Scale. All scales were completed anonymously and voluntary by 316 single mothers. Univariable and multivariable associations between SRH and depressive symptoms with socio-demographic characteristics were investigated using chi-square tests and in multivariable backward stepwise logistic regression models respectively. Odd ratio of clinically significant depressive symptoms and SRH across decreasing levels of social support were estimated in logistic regression models. RESULTS: The prevalence of depressive symptoms (CES-D score >= 22) was 38.9 %, which is almost three times greater than the general population. Strong associations with all health assessment tools were observed with variables relating to the lowest monthly family income and the presence of economic difficulties, unemployment, the single motherhood status and pre-existing illness. Social support as perceived by the mothers displayed a strong negative independent association with all tools, even after adjusting confounders. CONCLUSION: These findings can be a challenge for health care professionals, especially those working in the field of community-family nursing and highlight the necessity of interventions and strategies at community level in order to support this vulnerable population group. PMID- 26937222 TI - RURAL - URBAN DIFFERENCES IN HEALTH CARE QUALITY ASSESSMENT. AB - AIM: To determine the rural-urban differences in primary care practice, hospital inpatient care and total services. METHODS: This cross-sectional study used data from Zenica-Doboj Canton in Federation of Bosnia and Herzegovina (FBiH). The overall sample size for the study was 1,995. Individual interviews were conducted in one randomly selected day of the week, except Monday and Friday, on the basis of EUROPEP (European Task Force on Patient Evaluations of General Practice Care) standardized questionnaire. RESULTS: Out of total number (n=1 995), 47.9% was urban population and median of age was 42 years for both populations. The most of urban residents (81.4%) had finished high school or higher education compared with rural residents (58.5%) (p < 0.001). There are significant differences in employment status between rural and urban population (p < 0.001). Rural residents are more likely to travel more than 15 minutes to see their health facilities compared with urban residents (61.7% vs. 24.4%, respectively). Median of distance (kilometers) from residence location to the nearest hospital was statistically significantly higher in rural Me = 8.0 (5.0 do 14.5) km compared to urban population Me = 1.5 (1.0 to 3.0) km (p < 0.001). The rural population was more likely to buy drugs for medical treatment (p < 0.001) and parenteral injections in primary care practice (p < 0.001). CONCLUSION: There are significant differences in the overall health care assessment of rural populations as compared to urban populations. PMID- 26937224 TI - Adult Attachment and Transgender Identity in the Italian Context: Clinical Implications and Suggestions for Further Research. AB - INTRODUCTION: Although attachment theory has been recognized as one of the main reference for the study of the general wellbeing, little research has been focused on the attachment styles of transgender people. Attachment styles are deeply influenced by the earliest relationships with caregivers, which, for gender nonconforming children, are often characterized by parental rejection. Consequently, transgender children and adults likely internalize societal stigma, developing internalized transphobia. The current research was aimed to explore the link between adult attachment and internalized transphobia. METHOD: 25 male to-female (MtF) and 23 female-to-male (FtM) transgender people participated in the survey filling in two self-report questionnaires: the Attachment Style Questionnaire and the Transgender Identity Survey. A cluster analysis, T-Test and multiple regression analysis were conducted to explore the link between attachment styles and internalized transphobia. RESULTS: A greater prevalence of secure attachment styles was detected. Participants with secure attachment styles reported higher levels of positive transgender identity than those with insecure attachment styles. Secure attachment styles significantly affect positive transgender identity, while insecure attachment styles influence internalized transphobia. CONCLUSIONS: A clinical focus on the redefinition of the Internal Working Models of transgender people can inform psychologically-focused interventions, which transgender people can benefit from. PMID- 26937225 TI - Gene therapy for cardiovascular manifestations of lysosomal storage diseases. AB - Cardiac disease causes morbidity in several lysosomal storage diseases, which are the result of deficient activity of lysosomal enzymes. Mucopolysaccharidosis (MPS) causes aortic and valvular disease, Pompe disease causes cardiac muscle weakness, and Fabry disease causes left ventricular hypertrophy. Enzyme replacement therapy involves intravenous injection of enzyme modified with mannose 6-phosphate, which can be taken up by cells, and is currently approved for some lysosomal storage diseases. Gene therapy can result in secretion of mannose 6-phosphate-modified enzyme into blood, from where it can; similarly, be taken up by cells. Gene therapy has been effective in animal models of lysosomal storage disease, and holds great promise. PMID- 26937226 TI - Metabolite profiling of the ripening of Mangoes Mangifera indica L. cv. 'Tommy Atkins' by real-time measurement of volatile organic compounds. AB - Real-time profiling of mango ripening based on proton transfer reaction-time of flight-mass spectrometry (PTR-ToF-MS) of small molecular weight volatile organic compounds (VOCs), is demonstrated using headspace measurements of 'Tommy Atkins' mangoes. VOC metabolites produced during the ripening process were sampled directly, which enabled simultaneous and rapid detection of a wide range of compounds. Headspace measurements of 'Keitt' mangoes were also conducted for comparison. A principle component analysis of the results indicated that several mass channels were not only key to the ripening process but could also be used to distinguish between mango cultivars. The identities of 22 of these channels, tentatively speciated using contemporaneous GC-MS measurements of sorbent tubes, are rationalized through examination of the biochemical pathways that produce volatile flavour components. Results are discussed with relevance to the potential of headspace analysers and electronic noses in future fruit ripening and quality studies. PMID- 26937223 TI - Regulation of mTORC1 by growth factors, energy status, amino acids and mechanical stimuli at a glance. AB - The mechanistic/mammalian target of rapamycin complex 1 (mTORC1) plays a pivotal role in the regulation of skeletal muscle protein synthesis. Activation of the complex leads to phosphorylation of two important sets of substrates, namely eIF4E binding proteins and ribosomal S6 kinases. Phosphorylation of these substrates then leads to an increase in protein synthesis, mainly by enhancing translation initiation. mTORC1 activity is regulated by several inputs, such as growth factors, energy status, amino acids and mechanical stimuli. Research in this field is rapidly evolving and unraveling how these inputs regulate the complex. Therefore this review attempts to provide a brief and up-to-date narrative on the regulation of this marvelous protein complex. Additionally, some sports supplements which have been shown to regulate mTORC1 activity are discussed. PMID- 26937227 TI - Regulation of Th2 Cell Immunity by Dendritic Cells. AB - Th2 cell immunity is required for host defense against helminths, but it is detrimental in allergic diseases in humans. Unlike Th1 cell and Th17 cell subsets, the mechanism by which dendritic cells modulate Th2 cell responses has been obscure, in part because of the inability of dendritic cells to provide IL 4, which is indispensable for Th2 cell lineage commitment. In this regard, immune cells other than dendritic cells, such as basophils and innate lymphoid cells, have been suggested as Th2 cell inducers. More recently, multiple independent researchers have shown that specialized subsets of dendritic cells mediate Th2 cell responses. This review will discuss the current understanding related to the regulation of Th2 cell responses by dendritic cells and other immune cells. PMID- 26937229 TI - Involvement of Immune Cell Network in Aortic Valve Stenosis: Communication between Valvular Interstitial Cells and Immune Cells. AB - Aortic valve stenosis is a heart disease prevalent in the elderly characterized by valvular calcification, fibrosis, and inflammation, but its exact pathogenesis remains unclear. Previously, aortic valve stenosis was thought to be caused by chronic passive and degenerative changes associated with aging. However, recent studies have demonstrated that atherosclerotic processes and inflammation can induce valvular calcification and bone deposition, leading to valvular stenosis. In particular, the most abundant cell type in cardiac valves, valvular interstitial cells, can differentiate into myofibroblasts and osteoblast-like cells, leading to valvular calcification and stenosis. Differentiation of valvular interstitial cells can be trigged by inflammatory stimuli from several immune cell types, including macrophages, dendritic cells, T cells, B cells, and mast cells. This review indicates that crosstalk between immune cells and valvular interstitial cells plays an important role in the development of aortic valve stenosis. PMID- 26937228 TI - Induction of CD4(+) Regulatory and Polarized Effector/helper T Cells by Dendritic Cells. AB - Dendritic cells (DCs) are considered to play major roles during the induction of T cell immune responses as well as the maintenance of T cell tolerance. Naive CD4(+) T cells have been shown to respond with high plasticity to signals inducing their polarization into effector/helper or regulatory T cells. Data obtained from in vitro generated bone-marrow (BM)-derived DCs as well as genetic mouse models revealed an important but not exclusive role of DCs in shaping CD4(+) T cell responses. Besides the specialization of some conventional DC subsets for the induction of polarized immunity, also the maturation stage, activation of specialized transcription factors and the cytokine production of DCs have major impact on CD4(+) T cells. Since in vitro generated BM-DCs show a high diversity to shape CD4(+) T cells and their high similarity to monocyte derived DCs in vivo, this review reports data mainly on BM-DCs in this process and only touches the roles of transcription factors or of DC subsets, which have been discussed elsewhere. Here, recent findings on 1) the conversion of naive into anergic and further into Foxp3(-) regulatory T cells (Treg) by immature DCs, 2) the role of RelB in steady state migratory DCs (ssmDCs) for conversion of naive T cells into Foxp3(+) Treg, 3) the DC maturation signature for polarized Th2 cell induction and 4) the DC source of IL-12 for Th1 induction are discussed. PMID- 26937230 TI - Use of Cell-Penetrating Peptides in Dendritic Cell-Based Vaccination. AB - Cell-penetrating peptides (CPPs) are short amino acids that have been widely used to deliver macromolecules such as proteins, peptides, DNA, or RNA, to control cellular behavior for therapeutic purposes. CPPs have been used to treat immunological diseases through the delivery of immune modulatory molecules in vivo. Their intracellular delivery efficiency is highly synergistic with the cellular characteristics of the dendritic cells (DCs), which actively uptake foreign antigens. DC-based vaccines are primarily generated by pulsing DCs ex vivo with various immunomodulatory antigens. CPP conjugation to antigens would increase DC uptake as well as antigen processing and presentation on both MHC class II and MHC class I molecules, leading to antigen specific CD4(+) and CD8(+) T cell responses. CPP-antigen based DC vaccination is considered a promising tool for cancer immunotherapy due to the enhanced CTL response. In this review, we discuss the various applications of CPPs in immune modulation and DC vaccination, and highlight the advantages and limitations of the current CPP-based DC vaccination. PMID- 26937231 TI - Dendritic Cell-based Immunotherapy for Rheumatoid Arthritis: from Bench to Bedside. AB - Dendritic cells (DCs) are professional antigen presenting cells, and play an important role in the induction of antigen-specific adaptive immunity. However, some DC populations are involved in immune regulation and immune tolerance. These DC populations are believed to take part in the control of immune exaggeration and immune disorder, and maintain immune homeostasis in the body. Tolerogenic DCs (tolDCs) can be generated in vitro by genetic or pharmacological modification or by controlling the maturation stages of cytokine-derived DCs. These tolDCs have been investigated for the treatment of rheumatoid arthritis (RA) in experimental animal models. In the last decade, several in vitro and in vivo approaches have been translated into clinical trials. As of 2015, three tolDC trials for RA are on the list of ClinicalTrial.gov (www.clinicaltrials.gov). Other trials for RA are in progress and will be listed soon. In this review, we discuss the evolution of tolDC-based immunotherapy for RA and its limitations and future prospects. PMID- 26937233 TI - TCF4-Targeting miR-124 is Differentially Expressed amongst Dendritic Cell Subsets. AB - Dendritic cells (DCs) are professional antigen-presenting cells that sample their environment and present antigens to naive T lymphocytes for the subsequent antigen-specific immune responses. DCs exist in a range of distinct subpopulations including plasmacytoid DCs (pDCs) and classical DCs (cDCs), with the latter consisting of the cDC1 and cDC2 lineages. Although the roles of DC specific transcription factors across the DC subsets have become understood, the posttranscriptional mechanisms that regulate DC development are yet to be elucidated. MicroRNAs (miRNAs) are pivotal posttranscriptional regulators of gene expression in a myriad of biological processes, but their contribution to the immune system is just beginning to surface. In this study, our in-house probe collection was screened to identify miRNAs possibly involved in DC development and function by targeting the transcripts of relevant mouse transcription factors. Examination of DC subsets from the culture of mouse bone marrow with Flt3 ligand identified high expression of miR-124 which was able to target the transcript of TCF4, a transcription factor critical for the development and homeostasis of pDCs. Further expression profiling of mouse DC subsets isolated from in vitro culture as well as via ex vivo purification demonstrated that miR 124 was outstandingly expressed in CD24(+) cDC1 cells compared to in pDCs and CD172alpha(+) cDC2 cells. These results imply that miR-124 is likely involved in the processes of DC subset development by posttranscriptional regulation of a transcription factor(s). PMID- 26937232 TI - Generation of Tolerogenic Dendritic Cells and Their Therapeutic Applications. AB - Dendritic cells (DCs) are professional antigen-presenting cells (APCs) that bridge innate and adaptive immune responses, thereby leading to immune activation. DCs have been known to recognize pathogen-associated molecular patterns such as lipopolysaccharides (LPS) and nucleic acids via their pattern recognition receptors, which trigger signaling of their maturation and effector functions. Furthermore, DCs take up and process antigens as a form of peptide loaded on the major histocompatibility complex (MHC) and present them to T cells, which are responsible for the adaptive immune response. Conversely, DCs can also play a role in inducing immune suppression under specific circumstances. From this perspective, the role of DCs is related to tolerance rather than immunity. Immunologists refer to these special DCs as tolerogenic DCs (tolDCs). However, the definition of tolDCs is controversial, and there is limited information on their development and characteristics. In this review, we discuss the current concept of tolDCs, cutting-edge methods for generating tolDCs in vitro, and future applications of tolDCs, including clinical use. PMID- 26937234 TI - Immunogenic Cell Death Induced by Ginsenoside Rg3: Significance in Dendritic Cell based Anti-tumor Immunotherapy. AB - Cancer is one of the leading causes of morbidity and mortality worldwide; therefore there is a need to discover new therapeutic modules with improved efficacy and safety. Immune-(cell) therapy is a promising therapeutic strategy for the treatment of intractable cancers. The effectiveness of certain chemotherapeutics in inducing immunogenic tumor cell death thus promoting cancer eradication has been reported. Ginsenoside Rg3 is a ginseng saponin that has antitumor and immunomodulatory activity. In this study, we treated tumor cells with Rg3 to verify the significance of inducing immunogenic tumor cell death in antitumor therapy, especially in DC-based immunotherapy. Rg3 killed the both immunogenic (B16F10 melanoma cells) and non-immunogenic (LLC: Lewis Lung Carcinoma cells) tumor cells by inducing apoptosis. Surface expression of immunogenic death markers including calreticulin and heat shock proteins and the transcription of relevant genes were increased in the Rg3-dying tumor. Increased calreticulin expression was directly related to the uptake of dying tumor cells by dendritic cells (DCs): the proportion of CRT(+) CD11c(+) cells was increased in the Rg3-treated group. Interestingly, tumor cells dying by immunogenic cell death secreted IFN-gamma, an effector molecule for antitumor activity in T cells. Along with the Rg3-induced suppression of pro-angiogenic (TNF-alpha) and immunosuppressive cytokine (TGF-beta) secretion, IFN-gamma production from the Rg3-treated tumor cells may also indicate Rg3 as an effective anticancer immunotherapeutic strategy. The data clearly suggests that Rg3-induced immunogenic tumor cell death due its cytotoxic effect and its ability to induce DC function. This indicates that Rg3 may be an effective immunotherapeutic strategy. PMID- 26937235 TI - Analysis of small-angle X-ray scattering data in the presence of significant instrumental smearing. AB - A laboratory-scale small-angle X-ray scattering instrument with pinhole collimation has been used to assess smearing effects due to instrumental resolution. A new, numerically efficient method to smear ideal model intensities is developed and presented. It allows for directly using measured profiles of isotropic but otherwise arbitrary beams in smearing calculations. Samples of low polydispersity polymer spheres have been used to show that scattering data can in this way be quantitatively modeled even when there is substantial distortion due to instrumental resolution. PMID- 26937236 TI - Misfit-induced changes of lattice parameters in two-phase systems: coherent/incoherent precipitates in a matrix. AB - Elastic accommodation of precipitation-induced or thermally induced misfit leads to lattice-parameter changes in crystalline multi-phase systems. Formulae for calculation of such misfit-induced lattice-parameter changes are presented for the aggregate (matrix + second-phase particles) and for the individual matrix and second phase, recognizing the occurrence of either coherent or incoherent diffraction by the matrix and second-phase particles. An overview and an (re)interpretation on the above basis is presented of published lattice-parameter data, obtained by X-ray diffraction analyses of aggregates of matrix plus second phase particles. Examples for three types of systems consisting of a matrix with misfitting second-phase particles are dealt with, which differ in the origin of the misfit (precipitation or thermally induced) and in the type of diffraction (coherent or incoherent diffraction of matrix plus second-phase particles). The experimental data are shown to be in good to very good agreement with predictions according to the current treatment. PMID- 26937237 TI - SENJU: a new time-of-flight single-crystal neutron diffractometer at J-PARC. AB - SENJU is a new single-crystal time-of-flight neutron diffractometer installed at BL18 at the Materials and Life Science Experimental Facility of the Japan Accelerator Research Complex (J-PARC). The diffractometer was designed for precise crystal and magnetic structure analyses under multiple extreme sample environments such as low temperature, high pressure and high magnetic field, and for diffraction measurements of small single crystals down to 0.1 mm3 in volume. SENJU comprises three choppers, an elliptical shape straight supermirror guide, a vacuum sample chamber and 37 scintillator area detectors. The moderator-to-sample distance is 34.8 m, and the sample-to-detector distance is 800 mm. The wavelength of incident neutrons is 0.4-4.4 A (first frame). Because short-wavelength neutrons are available and the large solid angle around the sample position is covered by the area detectors, a large reciprocal space can be simultaneously measured. Furthermore, the vacuum sample chamber and collimator have been designed to produce a very low background level. Thus, the measurement of a small single crystal is possible. As sample environment devices, a newly developed cryostat with a two-axis (omega and phi axes) goniometer and some extreme environment devices, e.g. a vertical-field magnet, high-temperature furnace and high-pressure cell, are available. The structure analysis of a sub-millimetre size (0.1 mm3) single organic crystal, taurine, and a magnetic structure analysis of the antiferromagnetic phase of MnF2 have been performed. These results demonstrate that SENJU can be a powerful tool to promote materials science research. PMID- 26937238 TI - Reduction of lattice disorder in protein crystals by high-pressure cryocooling. AB - High-pressure cryocooling (HPC) has been developed as a technique for reducing the damage that frequently occurs when macromolecular crystals are cryocooled at ambient pressure. Crystals are typically pressurized at around 200 MPa and then cooled to liquid nitrogen temperature under pressure; this process reduces the need for penetrating cryoprotectants, as well as the damage due to cryocooling, but does not improve the diffraction quality of the as-grown crystals. Here it is reported that HPC using a pressure above 300 MPa can reduce lattice disorder, in the form of high mosaicity and/or nonmerohedral twinning, in crystals of three different proteins, namely human glutaminase C, the GTP pyrophosphokinase YjbM and the uncharacterized protein lpg1496. Pressure lower than 250 MPa does not induce this transformation, even with a prolonged pressurization time. These results indicate that HPC at elevated pressures can be a useful tool for improving crystal packing and hence the quality of the diffraction data collected from pressurized crystals. PMID- 26937239 TI - X-ray nanodiffraction analysis of stress oscillations in a W thin film on through silicon via. AB - Synchrotron X-ray nanodiffraction is used to analyse residual stress distributions in a 200 nm-thick W film deposited on the scalloped inner wall of a through-silicon via. The diffraction data are evaluated using a novel dedicated methodology which allows the quantification of axial and tangential stress components under the condition that radial stresses are negligible. The results reveal oscillatory axial stresses in the range of ~445-885 MPa, with a distribution that correlates well with the scallop wavelength and morphology, as well as nearly constant tangential stresses of ~800 MPa. The discrepancy with larger stress values obtained from a finite-element model, as well as from a blanket W film, is attributed to the morphology and microstructural nature of the W film in the via. PMID- 26937240 TI - A visible-light-excited fluorescence method for imaging protein crystals without added dyes. AB - Fluorescence microscopy methods have seen an increase in popularity in recent years for detecting protein crystals in screening trays. The fluorescence-based crystal detection methods have thus far relied on intrinsic UV-inducible tryptophan fluorescence, nonlinear optics or fluorescence in the visible light range dependent on crystals soaked with fluorescent dyes. In this paper data are presented on a novel visible-light-inducible autofluorescence arising from protein crystals as a result of general stabilization of conjugated double-bond systems and increased charge delocalization due to crystal packing. The visible light-inducible autofluorescence serves as a complementary method to bright-field microscopy in beamline applications where accurate crystal centering about the rotation axis is essential. Owing to temperature-dependent chromophore stabilization, protein crystals exhibit tenfold higher fluorescence intensity at cryogenic temperatures, making the method ideal for experiments where crystals are cooled to 100 K with a cryostream. In addition to the non-damaging excitation wavelength and low laser power required for imaging, the method can also serve a useful role for differentiating protein crystals from salt crystals in screening trays. PMID- 26937241 TI - COD::CIF::Parser: an error-correcting CIF parser for the Perl language. AB - A syntax-correcting CIF parser, COD::CIF::Parser, is presented that can parse CIF 1.1 files and accurately report the position and the nature of the discovered syntactic problems. In addition, the parser is able to automatically fix the most common and the most obvious syntactic deficiencies of the input files. Bindings for Perl, C and Python programming environments are available. Based on COD::CIF::Parser, the cod-tools package for manipulating the CIFs in the Crystallography Open Database (COD) has been developed. The cod-tools package has been successfully used for continuous updates of the data in the automated COD data deposition pipeline, and to check the validity of COD data against the IUCr data validation guidelines. The performance, capabilities and applications of different parsers are compared. PMID- 26937242 TI - Extension of the sasCIF format and its applications for data processing and deposition. AB - Recent advances in small-angle scattering (SAS) experimental facilities and data analysis methods have prompted a dramatic increase in the number of users and of projects conducted, causing an upsurge in the number of objects studied, experimental data available and structural models generated. To organize the data and models and make them accessible to the community, the Task Forces on SAS and hybrid methods for the International Union of Crystallography and the Worldwide Protein Data Bank envisage developing a federated approach to SAS data and model archiving. Within the framework of this approach, the existing databases may exchange information and provide independent but synchronized entries to users. At present, ways of exchanging information between the various SAS databases are not established, leading to possible duplication and incompatibility of entries, and limiting the opportunities for data-driven research for SAS users. In this work, a solution is developed to resolve these issues and provide a universal exchange format for the community, based on the use of the widely adopted crystallographic information framework (CIF). The previous version of the sasCIF format, implemented as an extension of the core CIF dictionary, has been available since 2000 to facilitate SAS data exchange between laboratories. The sasCIF format has now been extended to describe comprehensively the necessary experimental information, results and models, including relevant metadata for SAS data analysis and for deposition into a database. Processing tools for these files (sasCIFtools) have been developed, and these are available both as standalone open-source programs and integrated into the SAS Biological Data Bank, allowing the export and import of data entries as sasCIF files. Software modules to save the relevant information directly from beamline data-processing pipelines in sasCIF format are also developed. This update of sasCIF and the relevant tools are an important step in the standardization of the way SAS data are presented and exchanged, to make the results easily accessible to users and to promote further the application of SAS in the structural biology community. PMID- 26937243 TI - Efficacy of growth hormone replacement on anthropometric outcomes, obesity, and lipids in children with optic nerve hypoplasia and growth hormone deficiency. AB - BACKGROUND: Hypopituitarism and obesity are causes of major lifelong morbidity in patients with optic nerve hypoplasia (ONH). Growth hormone deficiency (GHD) affects the majority of children with ONH, though the degree of deficiency and variability of early growth patterns range from early severe retardation to normal initial growth. The utility of early GH replacement for improving anthropometric, body composition, and lipid outcomes in patients with ONH and GHD, especially those with normal initial height velocity, is unknown. This study examines the effects of GH replacement in a cohort of children with ONH and GHD. METHODS: Controlled clinical trial from 2005-2014. The study included 17 children with ONH and untreated GHD. Those meeting criteria for growth deceleration were assigned to treatment with recombinant human growth hormone (n = 5) while those with normal height velocity were randomized either to treatment (n = 5) or to observation (no intervention, n = 7). Study duration was 3 years. Primary outcome measures included stature, weight, weight-for-stature, and BMI standard deviation score (SDS) at study completion. RESULTS: Subjects on GH, irrespective of entry growth trajectory, grew more on average in stature than controls by a difference of 0.98 SDS by study end; this effect persisted after adjusting for baseline overweight status. Treatment had an effect on weight SDS only after adjusting for initial overweight status, resulting in an average increase of 0.83 SDS more than controls. Subjects who were overweight at the outset experienced greater gains in both weight and stature SDS. Treatment had no statistically significant impact on weight-for-stature or BMI SDS. A reduction in body fat percentage was observed in those treated, both before (-6.1 %) and after (-4.3 %) adjustment for initial overweight status. CONCLUSION: Early GH replacement has a positive effect on short-term statural outcomes in children with ONH and GHD, even in those exhibiting normal initial linear growth. Results were less conclusive regarding treatment effects on body composition and lipids. PMID- 26937244 TI - Angiopoietin-2 concentration in serum is associated with severe asthma phenotype. AB - BACKGROUND: Several proangiogenic molecules have been implicated in the pathogenies of asthmatic inflammation and remodeling. The aim of the study was to compare the concentration of proangiogenic factors in the sera of asthmatic patients and in healthy subjects (HS), and to refer the concentrations to both clinical and inflammatory markers of the disease severity. METHODS: Serum was collected from 45 patients with severe/refractory asthma (SRA) and 51 patients with non-severe asthma (nSA). The control group included 30 HS. Serum concentrations of Angiopoietin-1, Angiopoietin-2, vascular endothelial growth factor (VEGF) and osteopontin were assessed by the enzyme-linked immunosorbent assay. RESULTS: The levels of Angiopoietin-1 (68.8 +/- 2.7 vs 56.4 +/- 9.3 ng/ml; p < 0.05), Angiopoietin-2 (4.9 +/- 0.35 vs 1.38 +/- 0.14 ng/ml; p < 0.0001) and VEGF were significantly higher in asthmatic patients (n = 94) as compared to HS (255 +/- 45.4 vs 424.5 +/- 27.8 pg/ml; p < 0.01). The mean serum level of Angiopoietin-2 was found to be significantly higher in patients with SRA as compared to nSA patients (6.04 +/- 0.46 vs 3.84 +/- 0.43; p < 0.001). Angiopoietin-2 serum level correlated with respiratory function and with parameters of asthma severity: the mean number of asthma exacerbations in the preceding 12 months (R = 0.21; p < 0.05), mean number of emergency visits due to severe asthma exacerbation (R = 0.24; p < 0.04) and mean number of hospitalizations (R = 0.21; p < 0.05) or dose of inhaled glucocorticosteroids taken by the patients (R = 0.36; p < 0.001). CONCLUSION: Angiopoietin-2 seems to be a crucial proangiogenic cytokine overproduced in patients with SRA characterized by repeated exacerbations and Angiopoietin-2 serum levels can serve as a biomarker of severe asthma. PMID- 26937245 TI - Phylogenetic relationships of the New World titi monkeys (Callicebus): first appraisal of taxonomy based on molecular evidence. AB - BACKGROUND: Titi monkeys, Callicebus, comprise the most species-rich primate genus-34 species are currently recognised, five of them described since 2005. The lack of molecular data for titi monkeys has meant that little is known of their phylogenetic relationships and divergence times. To clarify their evolutionary history, we assembled a large molecular dataset by sequencing 20 nuclear and two mitochondrial loci for 15 species, including representatives from all recognised species groups. Phylogenetic relationships were inferred using concatenated maximum likelihood and Bayesian analyses, allowing us to evaluate the current taxonomic hypothesis for the genus. RESULTS: Our results show four distinct Callicebus clades, for the most part concordant with the currently recognised morphological species-groups-the torquatus group, the personatus group, the donacophilus group, and the moloch group. The cupreus and moloch groups are not monophyletic, and all species of the formerly recognized cupreus group are reassigned to the moloch group. Two of the major divergence events are dated to the Miocene. The torquatus group, the oldest radiation, diverged c. 11 Ma; and the Atlantic forest personatus group split from the ancestor of all donacophilus and moloch species at 9-8 Ma. There is little molecular evidence for the separation of Callicebus caligatus and C. dubius, and we suggest that C. dubius should be considered a junior synonym of a polymorphic C. caligatus. CONCLUSIONS: Considering molecular, morphological and biogeographic evidence, we propose a new genus level taxonomy for titi monkeys: Cheracebus n. gen. in the Orinoco, Negro and upper Amazon basins (torquatus group), Callicebus Thomas, 1903, in the Atlantic Forest (personatus group), and Plecturocebus n. gen. in the Amazon basin and Chaco region (donacophilus and moloch groups). PMID- 26937247 TI - Improvement in glycemia after glucose or insulin overload in leptin-infused rats is associated with insulin-related activation of hepatic glucose metabolism. AB - BACKGROUND: Insulin regulates glucose homeostasis through direct effects on the liver, among other organs, with leptin modulating insulin's hepatic actions. Since central leptin may modify insulin signaling in the liver, we hypothesized that leptin infusion activates hepatic glycogen synthesis following peripheral administration of a bolus of glucose or insulin, thus regulating glycemia. FINDINGS: Oral glucose and intraperitoneal insulin tolerance tests were performed in control, intracerebroventricular leptin-treated and pair-fed rats during 14 days. An improvement in glycemia and an increase in hepatic free glucose and glycogen concentrations after glucose or insulin overload were observed in leptin treated rats. In order to analyze whether the liver was involved in these changes, we studied activation of insulin signaling by Western blotting and multiplex bead immunoassay after leptin infusion. Our studies revealed an increase in phosphorylation of insulin receptor substrate-1 and Akt in leptin treated rats. Examination of parameters related to glucose uptake and metabolism in the liver revealed an augment in glucose transporter 2 and a decrease in phosphoenolpyruvate carboxylase protein levels in this group. CONCLUSIONS: These results indicate that central leptin increases hepatic insulin signaling, associated with increased glycogen concentrations after glucose or insulin overload, leading to an improvement in glycemia. PMID- 26937246 TI - Weight restoration on a high carbohydrate refeeding diet promotes rapid weight regain and hepatic lipid accumulation in female anorexic rats. AB - BACKGROUND: There is currently no standard clinical refeeding diet for the treatment of anorexia nervosa (AN). To provide the most efficacious AN clinical care, it is necessary to define the metabolic effects of current refeeding diets. METHODS: An activity-based model of anorexia nervosa (AN) was used in female rats. AN was induced over 7d by timed access to low fat (LF) diet with free access to a running wheel. Plasma hormones/metabolites and body composition were assessed at baseline, AN diagnosis (day 0), and following 28d of refeeding on LF diet. Energy balance and expenditure were measured via continuous indirect calorimetry on days -3 to +3. RESULTS: AN induction caused stress as indicated by higher levels of corticosterone versus controls (p < 0.0001). The rate of weight gain during refeeding was higher in AN rats than controls (p = 0.0188), despite lower overall energy intake (p < 0.0001). This was possible due to lower total energy expenditure (TEE) at the time of AN diagnosis which remained significantly lower during the entire refeeding period, driven by markedly lower resting energy expenditure (REE). AN rats exhibited lower lipid accumulation in visceral adipose tissues (VAT) but much higher liver accumulation (62 % higher in AN than control; p < 0.05) while maintaining the same total body weight as controls. It is possible that liver lipid accumulation was caused by overfeeding of carbohydrate suggesting that a lower carbohydrate, higher fat diet may be beneficial during AN treatment. To test whether such a diet would be accepted clinically, we conducted a study in adolescent female AN patients which showed equivalent palatability and acceptability for LF and moderate fat diets. In addition, this diet was feasible to provide clinically during inpatient treatment in this population. CONCLUSION: Refeeding a LF diet to restore body weight in female AN rats caused depressed TEE and REE which facilitated rapid regain. However, this weight gain was metabolically unhealthy as it resulted in elevated lipid accumulation in the liver. It is necessary to investigate the use of other diets, such as lower carbohydrate, moderate fat diets, in pre-clinical models to develop the optimal clinical refeeding diets for AN. PMID- 26937250 TI - Selection and validation of reference genes for normalization of quantitative real-time reverse transcription PCR analysis in Poria cocos (Schw.) Wolf (Fuling). AB - BACKGROUND: Quantitative real-time reverse transcription PCR (qRT-PCR) requires a stable internal control to avoid misinterpretation of data or errors for gene expression normalization. However, there are still no validated reference genes for stable internal control in Poria cocos (Schw.) Wolf (Fuling). This study aims to validate the reference genes of P. cocos. METHODS: This study firstly collected the 14 candidate reference genes by BLASTP from the genome of P. cocos for qRT-PCR analysis to determine the expression levels of 14 housekeeping genes (GAPDH, MAPK, beta-Act, RPB2, RPB1-1, RPB1-2, his3-1, his3-2, APT, SAMDC, RP, beta-Tub, EIF, and CYP) under different temperatures and in response to different plant hormones (indole-3-acetic acid, abscisic acid, 6-benzylaminopurine, methyl jasmonate, and gibberellic acid), and the threshold cycle (Ct) values. The results were analyzed by four programs (i.e., geNorm, NormFinder, BestKeeper, and RefFinder) for evaluating the candidate reference genes. RESULTS: SAMDC, his3-2, RP, RPB2, and his3-1 were recommended as reference genes for treating P. cocos with indole-3-acetic acid, abscisic acid, 6-benzylaminopurine, methyl jasmonate, and gibberellic acid, respectively. Under different temperatures RPB2 was the most stable reference gene. CYP was the most stable gene for all 90 samples by RefFinder. CONCLUSION: SAMDC, his3-2, RP, RPB2, and his3-1 were evaluated to be suitable reference genes for P. cocos following different treatments. RPB2 was the most stable reference gene under different temperatures and CYP was the most stable gene in the mycelia under all six evaluated conditions. PMID- 26937251 TI - Inhibition of IKK-beta by epidioxysterols from the flowers of Calotropis gigantea (Niu jiao gua). AB - BACKGROUND: Calotropis gigantea (Asclepiadaceae) (Niu jiao gua) has been used as a poultice in Chinese medicine for treating inflammatory skin diseases, e.g., neurodermatitis. This study aims to isolate the epidioxysterols from the flowers of C. gigantea, elucidate their structures and evaluate their possible inhibitory effects on the NF-kappaB pathway. METHODS: The two epidioxysterols 9,11 dehydroergosterol peroxide (1) and ergosterol peroxide (2) were isolated from the powdered flowers of C. gigantea by ultrasonic-assisted extraction, followed by the purification of the crude extract by column chromatography (i.e., silica gel and MCI-gel CHP 20P open columns). The chemical structures of these compounds were identified through a comparison of their HRMS, (1)H and (13)C NMR data with those in the literature. The in vitro IKK-beta inhibitory activities of compounds 1 and 2 (1-100 uM) were evaluated using an IKK alpha and beta Assay/Inhibitor Screening Kit, which is a single-site, semi-quantitative immunoassay. Berberine was used as a positive control. The IKK-beta inhibitory activities between compounds 1 and 2 were compared by a two-tailed Student's t test to summarize the structure activity relationship. RESULTS: Compounds 1 and 2 exhibited a dose dependent inhibitory activity towards IKK-beta in a similar manner to that of berberine. The IKK-beta inhibitory activities of these two epidioxysterols were significantly stronger (P = 0.001 for compound 1 and P = 0.028 for compound 2) than that of berberine at the concentration of 100 uM. Furthermore, at the same concentration the suppressive effect of compound 1 towards IKK-beta was greater than that of compound 2 (P = 0.041), while their activities at 10 and 50 uM were comparable. The difference in the results at 100 uM therefore suggested that the double bond between C-9 and C-11 in compound 1 could be responsible for its higher inhibitory activity towards IKK-beta at this concentration. CONCLUSIONS: 9,11-dehydroergosterol peroxide (1) and ergosterol peroxide (2) were isolated from the flowers of C. gigantea and exhibited in vitro inhibitory activities towards IKK-beta. PMID- 26937249 TI - An updated re-analysis of the mortality risk from nasopharyngeal cancer in the National Cancer Institute formaldehyde worker cohort study. AB - BACKGROUND: To determine whether the National Cancer Institute's (NCI) suggestion of a persistent increased mortality risk for nasopharyngeal cancer (NPC) in relation to formaldehyde (FA) exposure is robust with respect to alternative methods of data analysis. METHODS: NCI provided the cohort data updated through 2004. We computed U.S. and local county rate-based standardized mortality ratios (SMRs) and internal cohort rate-based relative risks (RR) in relation to four formaldehyde exposure metrics (highest peak, average intensity, cumulative, and duration of exposure), using both NCI categories and alternative categorizations. We modeled the plant group-related interaction structure using continuous and categorical forms of each FA exposure metric and evaluated the impact of NCI's decision to exclude non-exposed workers from the baseline category. RESULTS: Overall, our results corroborate the findings of our earlier reanalyses of data from the 1994 NCI cohort update. Six of 11 NPC deaths observed in the NCI study occurred in Plant 1, two (including the only additional NPC death) occurred in Plant 3 among workers in the lowest exposure category of highest peak, average intensity and cumulative FA exposure and in the second exposure category of duration of exposure, and the remaining cases occurred individually in three of eight remaining plants. A large, statistically significant, local rate-based NPC SMR of 7.34 (95 % CI = 2.69-15.97) among FA-exposed workers in Plant 1 contrasted with an 18 % deficit in NPC deaths (SMR = 0.82, 95 % CI = .17-2.41) among exposed workers in Plants 2-10. Overall, the new NCI findings led to: (1) reduced SMRs and RRs in the remaining nine study plants in unaffected exposure categories, (2) attenuated exposure-response relations for FA and NPC for all the FA metrics considered and (3) strengthened and expanded evidence that the earlier NCI internal analyses were non-robust and mis-specified as they did not account for a statistically significant interaction structure between plant group (Plant 1 vs. Plants 2-10) and FA exposure. CONCLUSIONS: Our updated reanalysis provided little or no evidence to support NCI's suggestion of a persistent association between FA exposure and mortality from NPC. NCI's suggestion continues to be driven heavily by anomalous findings in one study plant (Plant 1). PMID- 26937252 TI - The meaning of behavioral medicine in the public health field-a review of documents related to medical education in Japan. AB - International standardization of medical education requires Japanese medical schools to restructure their curricula to include "behavioral science." Two influential documents for Japanese medical education, the "Model Core Curriculum for Medical Education in Japan" and the "Scope of the Japanese National Examination for Medical Doctors" include some key terms regarding behavioral science. However, they are not systematic and the phrase "behavioral science" itself could not be found in these documents. The new global standards for medical education, the "Basic Medical Education WFME Global Standards," require medical schools to include behavioral science in their curricula. The definition of "behavioral science" in the global standards emphasizes social aspects and determinants of health, which is also a key concept of public health. From the view point of public health, it is hoped that the systematic introduction of behavioral science into Japanese medical education will strengthen the public health mindset of medical doctors, which in turn will support the healthcare system in communities. PMID- 26937253 TI - Special series on "The meaning of behavioral medicine in the psychosomatic field" establishment of a core curriculum for behavioral science in Japan: The importance of such a curriculum from the perspective of psychology. AB - This article discusses the core curriculum for behavioral science, from the perspective of psychology, recommended by the Japanese Society of Behavioral Medicine and seeks to explain how the curriculum can be effectively implemented in medical and health-related departments. First, the content of the core curriculum is reviewed from the perspective of psychology. We show that the curriculum features both basic and applied components and that the basic components are closely related to various aspects of psychology. Next, we emphasize two points to aid the effective delivery of the curriculum: 1) It is necessary to explain the purpose and significance of basic components of behavioral science to improve student motivation; and 2) it is important to encourage student self-efficacy to facilitate application of the acquired knowledge and skills in clinical practice. PMID- 26937254 TI - DPP-4 inhibition improves early mortality, beta cell function, and adipose tissue inflammation in db/db mice fed a diet containing sucrose and linoleic acid. AB - BACKGROUND: Diabetes therapy that not only lowers glucose levels but also lengthens life spans is required. We previously demonstrated that DPP-4 inhibition ameliorated beta cell apoptosis and adipose tissue inflammation in beta cell-specific glucokinase haploinsufficient mice fed a diet containing a combination of sucrose and linoleic acid (SL). METHODS: In this study, we investigated the effects of DPP-4 inhibition in obese diabetic db/db mice fed an SL diet or a control diet containing sucrose and oleic acid (SO). We also examined the effects of DPP-4 inhibition in IRS-1-deficient mice fed an SL or SO diet as a model of insulin resistance. RESULTS: DPP-4 inhibition efficiently increases the active GLP-1 levels in db/db mice. Unexpectedly, the SL diet, but not the SO diet, markedly increases mortality in the db/db mice. DPP-4 inhibition reduces the early lethality in SL-fed db/db mice. DPP-4 inhibition improves glucose tolerance, beta cell function, and adipose tissue inflammation in db/db mice fed either diet. No significant changes in glycemic control or beta cell mass were observed in any of the IRS-1-deficient mouse groups. CONCLUSIONS: A diet containing a combination of sucrose and linoleic acid causes early lethality in obese diabetic db/db mice, but not in lean and insulin resistant IRS-1 knockout mice. DPP-4 inhibition has protective effects against the diet-induced lethality in db/db mice. PMID- 26937256 TI - Ambipolar inverters with natural origin organic materials as gate dielectric and semiconducting layer. AB - Thin film electronics fabricated with non-toxic and abundant materials are enabling for emerging bioelectronic technologies. Herein complementary-like inverters comprising transistors using 6,6'-dichloroindigo as the semiconductor and trimethylsilyl-cellulose (TMSC) films on anodized aluminum as bilayer dielectric layer are demonstrated. The inverters operate both in the first and third quadrant, exhibiting a maximum static gain of 22 and a noise margin of 58% at a supply voltage of 14 V. ((c) 2015 WILEY-VCH Verlag GmbH &Co. KGaA, Weinheim). PMID- 26937258 TI - Using Residence Time Distributions (RTDs) to Address the Traceability of Raw Materials in Continuous Pharmaceutical Manufacturing. AB - Continuous processing in pharmaceutical manufacturing is a relatively new approach that has generated significant attention. While it has been used for decades in other industries, showing significant advantages, the pharmaceutical industry has been slow in its adoption of continuous processing, primarily due to regulatory uncertainty. This paper aims to help address these concerns by introducing methods for batch definition, raw material traceability, and sensor frequency determination. All of the methods are based on established engineering and mathematical principles, especially the residence time distribution (RTD). This paper introduces a risk-based approach to address content uniformity challenges of continuous manufacturing. All of the detailed methods are discussed using a direct compaction manufacturing line as the main example, but the techniques can easily be applied to other continuous manufacturing methods such as wet and dry granulation, hot melt extrusion, capsule filling, etc. PMID- 26937257 TI - Diagnostic and prognostic value of SHOX2 and SEPT9 DNA methylation and cytology in benign, paramalignant, and malignant ascites. AB - BACKGROUND: Cytology remains the gold standard for the detection of malignant cells in ascites. However, its sensitivity is limited. The aim of this study was to evaluate DNA methylation biomarkers for the differential diagnosis of benign (ascites in patients without malignancy), malignant (ascites in cancer patients directly caused by malignancy), and paramalignant (ascites in cancer patients caused by comorbidities but not by malignancy) ascites. METHODS: A cohort of 283 patients (134 cancer patients, 149 patients with benign diseases) presenting with ascites was prospectively enrolled. Ascites was evaluated by means of cytopathological investigation and DNA methylation of SHOX2 and SEPT9 in the cell free and cellular fraction. DNA methylation in bisulfite-converted DNA was determined using quantitative methylation specific real-time PCR. Cytopathological and DNA methylation results were evaluated with regard to diagnosis and overall survival (OS). RESULTS: Patients with positive DNA methylation had a poor overall survival compared to methylation-negative patients (hazard ratio: HR = 1.97, p = 0.001). In multivariate survival analysis, DNA methylation was an independent prognostic parameter (p = 0.003) together with age (HR = 1.03, p < 0.001) and the presence of malignant disease (HR = 1.87, p < 0.001). The combination of methylation with cytopathological analyses led to a 42 % increase in the detection rate of malignant ascites, resulting in 37 % positively diagnosed cancer patients and a specificity of 97 %. Among cancer patients, patients with DNA methylation-positive ascites showed an adverse clinical course (HR = 1.63, p = 0.039). CONCLUSIONS: DNA methylation testing adds diagnostic and prognostic information and might constitute an effective ancillary method for the differential diagnosis of malignant, paramalignant, and benign ascites. PMID- 26937259 TI - Evalution of Renal Involvement in Patients with Behcet Disease: Need to be Aware About Potential Hypertension in Long Term Follow Up? AB - BACKROUND: The aim of this study was to evaluate frequency and severity of kidney involvement with some clinical, ultrasonography and color Doppler measurements in patients with Behcet disease. MATERIAL/METHODS: This study was including 32 patients with Behcet disease and 32 healthy sex and age-matched control subjects. Patients were divided into two groups as period of disease 0-6 years and 7 years and above to evaluate effect of duration of disease. We evaluated some biochemical tests in both blood and urine related to renal functions, blood pressure values. Gray scale and color Doppler findings were noted. RESULTS: Renal artery volume flow in patients with a duration of 7 years or above was significantly decreased compared to control group (p<0.05). However, gray scale ultrasound and color Doppler measurements reveal there was not statistically significant change compared to control group. There was no biochemical abnormalities in any patient. Four patients had elevated blood pressure but mean blood pressure values were not statistically different compared to volunteers. CONCLUSIONS: Renal involvement ratios varies in different studies but not common. End stage renal failure can be seen very rare. Furthermore, vasculitic changes can lead renal artery narrowness and can result to decrease in renal blood flow. It has a potential to activate renin angiotensin aldosterone cascade to elevate blood pressure. We must be aware about blood pressure of patients with Behcet disease, especially with long term follow up. PMID- 26937260 TI - Radiological Features of Long-Standing Hypoparathyroidism. AB - BACKGROUND: Idiopathic hypoparathyroidism is an extremely rare endocrinal disorder with a prevalence of 37 per 100,000. Herein we presented a case of a 30 year-old male who came with symptoms of muscle weakness, carpopedal spasms and limitation of movement which gradually progressed over 8 years. CASE REPORT: A 30 year-old male patient presented in an outpatient department of a tertiary care centre with a complaint of severe pain in both hip joints. He had generalized muscle weakness, facial discomfort, recurrent episodes of carpopedal spasms and crampy abdominal pains. On clinical examination, the patient had Chvostek sign and Trousseau sign. Biochemical tests revealed hypocalcemia, hyperphosphatemia and hypomagnesemia with low plasma parathyroid hormone level. X-ray of the pelvis and spine revealed spondylarthropathic changes of long-standing hypoparathyroidism. Computed Tomography of the brain revealed bilateral basal ganglia calcifications. The patient was treated with intravenous calcium gluconate, magnesium and oral vitamin D3. On follow-up the patient showed improvement of muscle weakness and carpopedal spasm with near-normal biochemical parameters. However, there was no improvement in symptoms related to spondyloarthropathy. CONCLUSIONS: Idiopathic hypoparathyroidism is a rare endocrine disorder with clinic and biochemical features of hypocalcemia. Long- standing hypoparathyroidism can cause spondyloarthropathic changes closely resembling ankylosing spondylitis and DISH. Skeletal changes of long-standing hypoparathyroidism are irreversible. If left untreated, life-threatening complications like cardiac arrhythmias and broncholaryngospasm may occur. PMID- 26937261 TI - CT Imaging Features in the Characterization of Non-Growing Solid Pulmonary Nodules in Non-Smokers. AB - BACKGROUND: A disappearing or persistent solid pulmonary nodule is a neglected clinical entity that still poses serious interpretative issues to date. Traditional knowledge deriving from previous reports suggests particular features, such as smooth edges or regular shape, to be significantly associated with benignity. A large number of benign nodules are reported among smokers in lung cancer screening programmes. The aim of this single-center retrospective study was to correlate specific imaging features to verify if traditional knowledge as well as more recent acquisitions regarding benign SPNs can be considered reliable in a current case series of nodules collected in a non-smoker cohort of patients. MATERIAL/METHODS: Fifty-three solid SPNs proven as non growing during follow-up imaging were analyzed with regard to their imaging features at thin-section CT, their predicted malignancy risk according to three major risk assessment models, minimum density analysis and contrast enhanced-CT in the relative subgroups of nodules which underwent such tests. RESULTS: Eleven nodules disappeared during follow-up, 29 showed volume loss and 16 had a VDT of 1121 days or higher. There were 48 nodules located peripherally (85.71%). Evaluation of the enhancement after contrast media (n=29) showed mean enhancement +/-SD of 25.72+/-35.03 HU, median of 18 HU, ranging from 0 to 190 HU. Minimum density assessment (n=30) showed mean minimum HU +/-SD of -28.27+/-47.86 HU, median of -25 HU, ranging from -144 to 68 HU. Mean malignancy risk +/-SD was 15.05+/-26.69% for the BIMC model, 17.22+/-19.00% for the Mayo Clinic model and 19.07+/-33.16% for the Gurney's model. CONCLUSIONS: Our analysis suggests caution in using traditional knowledge when dealing with current small solid peripheral indeterminate SPNs and highlights how quantitative growth at follow-up should be the cornerstone of characterization. PMID- 26937262 TI - Effectively Communicating Colorectal Cancer Screening Information to Primary Care Providers: Application for State, Tribe or Territory Comprehensive Cancer Control Coalitions. AB - BACKGROUND: Patients are more likely to be screened for colorectal cancer if it is recommended by a health care provider. Therefore, it is imperative that providers have access to the latest screening guidelines. PURPOSE: This practice based project sought to identify Kentucky primary care providers' preferred sources and methods of receiving colorectal cancer information to improve state comprehensive cancer control provider outreach initiatives. METHODS: Four focus groups were conducted with primary care physicians, nurse practitioners, and physician assistants. Discussion included preferred sources and methods of receiving updated screening guidelines, legislation, and statewide public awareness campaign materials. RESULTS: Providers (N = 17) identified their preferred methods for receiving colorectal cancer information as: routine emails from trusted sources (colleagues, professional societies and research, and advocacy agencies), scientific journals, existing conferences, and the media. DISCUSSION: When delivering colorectal cancer information to primary care providers, multiple approaches are needed. An ideal partner for dissemination of information is state comprehensive cancer control coalitions, considering their prioritization of colorectal cancer screening and existing networks of partners who were identified as trusted sources. TRANSLATION TO HEALTH EDUCATION PRACTICE: Assessment of primary care providers' preferred methods and sources of receiving colorectal cancer information informs strategies for practice among comprehensive cancer control coalitions. PMID- 26937263 TI - MIXED MODEL AND ESTIMATING EQUATION APPROACHES FOR ZERO INFLATION IN CLUSTERED BINARY RESPONSE DATA WITH APPLICATION TO A DATING VIOLENCE STUDY. AB - The NEXT Generation Health study investigates the dating violence of adolescents using a survey questionnaire. Each student is asked to affirm or deny multiple instances of violence in his/her dating relationship. There is, however, evidence suggesting that students not in a relationship responded to the survey, resulting in excessive zeros in the responses. This paper proposes likelihood-based and estimating equation approaches to analyze the zero-inflated clustered binary response data. We adopt a mixed model method to account for the cluster effect, and the model parameters are estimated using a maximum-likelihood (ML) approach that requires a Gaussian-Hermite quadrature (GHQ) approximation for implementation. Since an incorrect assumption on the random effects distribution may bias the results, we construct generalized estimating equations (GEE) that do not require the correct specification of within-cluster correlation. In a series of simulation studies, we examine the performance of ML and GEE methods in terms of their bias, efficiency and robustness. We illustrate the importance of properly accounting for this zero inflation by reanalyzing the NEXT data where this issue has previously been ignored. PMID- 26937264 TI - Understanding Chemical versus Electrostatic Shifts in X-ray Photoelectron Spectra of Organic Self-Assembled Monolayers. AB - The focus of the present article is on understanding the insight that X-ray photoelectron spectroscopy (XPS) measurements can provide when studying self assembled monolayers. Comparing density functional theory calculations to experimental data on deliberately chosen model systems, we show that both the chemical environment and electrostatic effects arising from a superposition of molecular dipoles influence the measured core-level binding energies to a significant degree. The crucial role of the often overlooked electrostatic effects in polar self-assembled monolayers (SAMs) is unambiguously demonstrated by changing the dipole density through varying the SAM coverage. As a consequence of this effect, care has to be taken when extracting chemical information from the XP spectra of ordered organic adsorbate layers. Our results, furthermore, imply that XPS is a powerful tool for probing local variations in the electrostatic energy in nanoscopic systems, especially in SAMs. PMID- 26937265 TI - Challenges in RCC Imaging: Renal Insufficiency, Post-Operative Surveillance, and the Role of Radiomics. PMID- 26937266 TI - Curcumin-encapsulating Nanogels as an Effective Anticancer Formulation for Intracellular Uptake. AB - Nanoscale drug delivery systems represent an attractive strategy to improve both the efficacy and safety of anticancer drugs. In this work, we describe nanoformulation of curcumin, a most potent natural anticancer compound capable of killing cancer cells while sparing the normal tissues. Since curcumin is a natural hydrophobic polyphenol, it has a low aqueous solubility and bioavailability, which are challenging to its therapeutic efficacy. We developed and evaluated a novel colloidal nanogel carrier for encapsulation of curcumin to increase its solubility and cytotoxicity. Amphiphilic Poloxamer-cationic network in the nanogel NG127 was designed to efficiently encapsulate curcumin. Homogenous drug complexes were obtained with 20-25% content of curcumin and the particle size of ca. 150 nm. Using ImageStream multispectral imaging flow cytometry, we demonstrated that the curcumin-nanogel formulation (C-NG) was readily internalized into MDA-231 breast cancer cells. A real-time cell growth electronic sensing assay was used to measure proliferation responses of various breast cancer cells to C-NG treatments. Our results indicated that the C-NG formulation was 70-85% more effective in inhibiting growth, at concentrations lower than IC50 of free curcumin. This was also confirmed morphologically by modified acridine orange/ethidium bromide staining and fluorescent microscopy. Importantly, nanocarrier NG127 alone displayed practically no cytotoxicity. We conclude that nanogel carriers offer an innovative way to encapsulate curcumin and to obtain more effective anticancer therapeutics than curcumin alone with a potential to specific tumor targeting, such as using antibodies against surface receptors specific to breast cancer cells. PMID- 26937267 TI - Draft genome sequences of Pantoea agglomerans and Pantoea vagans isolates associated with termites. AB - The genus Pantoea incorporates many economically and clinically important species. The plant-associated species, Pantoea agglomerans and Pantoea vagans, are closely related and are often isolated from similar environments. Plasmids conferring certain metabolic capabilities are also shared amongst these two species. The genomes of two isolates obtained from fungus-growing termites in South Africa were sequenced, assembled and annotated. A high number of orthologous genes are conserved within and between these species. The difference in genome size between P. agglomerans MP2 (4,733,829 bp) and P. vagans MP7 (4,598,703 bp) can largely be attributed to the differences in plasmid content. The genome sequences of these isolates may shed light on the common traits that enable P. agglomerans and P. vagans to co-occur in plant- and insect-associated niches. PMID- 26937268 TI - CyAnimator: Simple Animations of Cytoscape Networks. AB - CyAnimator (http://apps.cytoscape.org/apps/cyanimator) is a Cytoscape app that provides a tool for simple animations of Cytoscape networks. The tool allows you to take a series of snapshots (CyAnimator calls them frames) of Cytoscape networks. For example, the first frame might be of a network shown from a "zoomed out" viewpoint and the second frame might focus on a specific group of nodes. Once these two frames are captured by the tool, it can animate between them by interpolating the changes in location, zoom, node color, node size, edge thickness, presence or absence of annotations, etc. The animations may be saved as a series of individual frames, animated GIFs, MP4 movies, or H.264/MOV movies. CyAnimator is available from within the Cytoscape App Manager or from the Cytoscape app store. PMID- 26937269 TI - A DNA extraction protocol for improved DNA yield from individual mosquitoes. AB - Typical DNA extraction protocols from commercially available kits provide an adequate amount of DNA from a single individual mosquito sufficient for PCR-based assays. However, next-generation sequencing applications and high-throughput SNP genotyping assays exposed the limitation of DNA quantity one usually gets from a single individual mosquito. Whole genome amplification could alleviate the issue but it also creates bias in genome representation. While trying to find alternative DNA extraction protocols for improved DNA yield, we found that a combination of the tissue lysis protocol from Life Technologies and the DNA extraction protocol from Qiagen yielded a higher DNA amount than the protocol using the Qiagen or Life Technologies kit only. We have not rigorously tested all the possible combinations of extraction protocols; we also only tested this on mosquito samples. Therefore, our finding should be noted as a suggestion for improving people's own DNA extraction protocols and not as an advertisement of a commercially available product. PMID- 26937270 TI - Validating the use of Medicare Australia billing data to examine trends in skin cancer. AB - BACKGROUND: Epidemiological data surrounding non-melanomatous skin cancer (NMSC) is highly variable, in part due to the lack of government cancer registries. Several studies employ the use of Medical Australia (MA) rebate data in assessing such trends, the validity of which has not been studied in the past. Conversely, melanoma skin cancer is a notifiable disease, and thus, MA and cancer registry data is readily available. The aim of the current study is to assess the use of MA for epidemiological measures for skin cancers, by using melanoma as a disease sample. METHODS: Following ethics approval, data from MA and Victorian Cancer Registry (VCR) from 2004-2008 were extracted. Incidence of MA and VCR unique melanoma cases were compared and stratified by age and local government area (LGA). Regression and a paired-samples t-test were performed. RESULTS: During the study period; 15,150 and 13,886 unique melanoma patients were identified through VCR and MA data sources respectively. An outlier in the >80- year age group was noted between MA and VCR data. When stratified by age, significant correlation between MA and VCR was observed for all patients (gradient 0.91, R2= 0.936) and following exclusion of >80 patients (gradient 0.96, R2= 0.995). When stratified by LGA, a high degree of observation was observed for all patients (gradient 0.94, R2= 0.977) and following exclusion of >80 patients (gradient 0.996, R2= 0.975). CONCLUSION: Despite the inclusion of outlier data groups, acceptable correlation between MA and VCR melanoma data was observed, suggesting that MA may be suitable for assessing epidemiological trends. Such principals may be used to validate the use of MA data for similar calculations assessing NMSC trends. PMID- 26937271 TI - Conservation in the face of climate change: recent developments. AB - An increased understanding of the current and potential future impacts of climate change has significantly influenced conservation in practice in recent years. Climate change has necessitated a shift toward longer planning time horizons, moving baselines, and evolving conservation goals and targets. This shift has resulted in new perspectives on, and changes in, the basic approaches practitioners use to conserve biodiversity. Restoration, spatial planning and reserve selection, connectivity modelling, extinction risk assessment, and species translocations have all been reimagined in the face of climate change. Restoration is being conducted with a new acceptance of uncertainty and an understanding that goals will need to shift through time. New conservation targets, such as geophysical settings and climatic refugia, are being incorporated into conservation plans. Risk assessments have begun to consider the potentially synergistic impacts of climate change and other threats. Assisted colonization has gained acceptance in recent years as a viable and necessary conservation tool. This evolution has paralleled a larger trend in conservation-a shift toward conservation actions that benefit both people and nature. As we look forward, it is clear that more change is on the horizon. To protect biodiversity and essential ecosystem services, conservation will need to anticipate the human response to climate change and to focus not only on resistance and resilience but on transitions to new states and new ecosystems. PMID- 26937272 TI - Recent advances in understanding of chronic kidney disease. AB - Chronic kidney disease (CKD) is defined as any condition that causes reduced kidney function over a period of time. Fibrosis, tubular atrophy and interstitial inflammation are the hallmark of pathological features in CKD. Regardless of initial insult, CKD has some common pathways leading CKD to end-stage kidney disease, including hypoxia in the tubulointerstitium and proteinuria. Recent advances in genome editing technologies and stem cell research give great insights to understand the pathogenesis of CKD, including identifications of the origins of renal myofibroblasts and tubular epithelial cells upon injury. Environmental factors such as hypoxia, oxidative stress, and epigenetic factors in relation to CKD are also discussed. PMID- 26937273 TI - Should adults with type 2 diabetes be screened for atherosclerotic cardiovascular disease? AB - Diabetes mellitus is associated with greater risks for cardiovascular diseases (CVD). Multiple noninvasive screening tools for CVD including cardiac CT, carotid intima-media thickness test, myocardial perfusion imaging have been examined in those with diabetes, but the prognostic value of these tests vary and issues remain regarding their cost-benefit ratios, potential harms of radiation, and how they fit into screening algorithms for CVD. We discuss in this report the needs and criteria for screening tests and summarize the evidence from observational studies and clinical trials. We also explore whether there should be more sensitive screening modalities to better detect both short and long-term cardiovascular risk among asymptomatic patients with diabetes. PMID- 26937274 TI - Cancer Genomics. AB - Modern cancer genomics has emerged from the combination of the Human Genome Reference, massively parallel sequencing, and the comparison of tumor to normal DNA sequences, revealing novel insights into the cancer genome and its amazing diversity. Recent developments in applying our knowledge of cancer genomics have focused on the utility of these data for clinical applications. The emergent results of this translation into the clinical setting already are changing the clinical care and monitoring of cancer patients. PMID- 26937275 TI - Early lessons from schistosomiasis mass drug administration programs. AB - Mass drug administration using praziquantel is the backbone of the current strategy for the control of schistosomiasis. As the theoretical plans have moved into practical application, certain challenges with this approach have surfaced, and it is likely that annual mass drug administration alone may not be sufficient to achieve program goals. However, mass drug administration is still the only available intervention that can be readily used in the wide variety of settings where schistosomiasis is endemic. The task then becomes how to improve this approach and identify what adjuncts to mass drug administration are effective, as programs move from morbidity control to elimination goals. Other aspects worthy of consideration include how best to employ new diagnostic tools to more easily identify where treatment is needed, and new formulations of praziquantel to extend the availability of treatment to all age groups. The aim of this review is to highlight both areas of challenge and of opportunity to improve the public health impact of schistosomiasis control programs. PMID- 26937277 TI - Case Report: Ischaemic appendicitis post mesenteric biopsy. AB - A common indication for laparoscopic mesenteric lymph node biopsy is to provide a tissue diagnosis in the absence of palpable peripheral nodes via a minimally invasive approach. There are no reports to date of ischaemia to the appendix as a complication of this procedure. We report the case of a 34-year-old lady who underwent a mesenteric biopsy for a lesion found incidentally on CT to investigate longstanding abdominal pain, and 2 days later required an appendicectomy for ischaemic appendicitis. PMID- 26937278 TI - Continuous Attractor Neural Networks: Candidate of a Canonical Model for Neural Information Representation. AB - Owing to its many computationally desirable properties, the model of continuous attractor neural networks (CANNs) has been successfully applied to describe the encoding of simple continuous features in neural systems, such as orientation, moving direction, head direction, and spatial location of objects. Recent experimental and computational studies revealed that complex features of external inputs may also be encoded by low-dimensional CANNs embedded in the high dimensional space of neural population activity. The new experimental data also confirmed the existence of the M-shaped correlation between neuronal responses, which is a correlation structure associated with the unique dynamics of CANNs. This body of evidence, which is reviewed in this report, suggests that CANNs may serve as a canonical model for neural information representation. PMID- 26937279 TI - Basal body structure in Trichonympha. AB - Trichonympha is a symbiotic flagellate of many species of termites and of the wood-feeding cockroach. Remarkably, this unicellular organism harbors up to over ten thousand flagella on its surface, which serve to propel it through the viscous environment of the host hindgut. In the 1960s, analysis of resin-embedded Trichonympha samples by electron microscopy revealed that the basal bodies that give rise to these flagella are exceptionally long, with a proximal, cartwheel bearing, region some 50 times longer than that of regular centrioles. In recent years, this salient feature has prompted the analysis of the 3D architecture of Trichonympha basal bodies in the native state using cryo-electron tomography. The resulting ~40 A resolution map of the basal body proximal region revealed a number of novel features that may be conserved in centrioles of other systems. These include proximal-distal polarity of the pinhead structure that links the cartwheel to centriolar microtubules, as well as of the linker between the A and the C microtubules. Moreover, this work demonstrated that the cartwheel is made of stacked ring-like structures that likely each comprise 18 molecules of SAS-6 proteins. PMID- 26937276 TI - Advances in the understanding of delayed cerebral ischaemia after aneurysmal subarachnoid haemorrhage. AB - Delayed cerebral ischaemia has been described as the single most important cause of morbidity and mortality in patients who survive the initial aneurysmal subarachnoid haemorrhage. Our understanding of the pathophysiology of delayed cerebral ischaemia is meagre at best and the calcium channel blocker nimodipine remains the only intervention to consistently improve functional outcome after aneurysmal subarachnoid haemorrhage. There is substantial evidence to support cerebral vessel narrowing as a causative factor in delayed cerebral ischaemia, but contemporary research demonstrating improvements in vessel narrowing has failed to show improved functional outcomes. This has encouraged researchers to investigate other potential causes of delayed cerebral ischaemia, such as early brain injury, microthrombosis, and cortical spreading depolarisation. Adherence to a common definition of delayed cerebral ischaemia is needed in order to allow easier assessment of studies using multiple different terms. Furthermore, improved recognition of delayed cerebral ischaemia would not only allow for faster treatment but also better assessment of interventions. Finally, understanding nimodipine's mechanism of action may allow us to develop similar agents with improved efficacy. PMID- 26937280 TI - Integrated metabolomics and phytochemical genomics approaches for studies on rice. AB - Metabolomics is widely employed to monitor the cellular metabolic state and assess the quality of plant-derived foodstuffs because it can be used to manage datasets that include a wide range of metabolites in their analytical samples. In this review, we discuss metabolomics research on rice in order to elucidate the overall regulation of the metabolism as it is related to the growth and mechanisms of adaptation to genetic modifications and environmental stresses such as fungal infections, submergence, and oxidative stress. We also focus on phytochemical genomics studies based on a combination of metabolomics and quantitative trait locus (QTL) mapping techniques. In addition to starch, rice produces many metabolites that also serve as nutrients for human consumers. The outcomes of recent phytochemical genomics studies of diverse natural rice resources suggest there is potential for using further effective breeding strategies to improve the quality of ingredients in rice grains. PMID- 26937281 TI - c-MYB is a transcriptional regulator of ESPL1/Separase in BCR-ABL-positive chronic myeloid leukemia. AB - BACKGROUND: Genomic instability and clonal evolution are hallmarks of progressing chronic myeloid leukemia (CML). Recently, we have shown that clonal evolution and blast crisis correlate with altered expression and activity of Separase, a cysteine endopeptidase that is a mitotic key player in chromosomal segregation and centriole duplication. Hyperactivation of Separase in human hematopoietic cells has been linked to a feedback mechanism that posttranslationally stimulates Separase proteolytic activity after imatinib therapy-induced reduction of Separase protein levels. METHODS AND RESULTS: In search for potential therapy responsive transcriptional mechanisms we have investigated the role of the transcription factor c-MYB for Separase expression in CML cell lines (LAMA-84, K562, BV-173) and in clinical samples. Quantitative RT-PCR and Western blot immunostaining experiments revealed that c-MYB expression levels are decreased in an imatinib-dependent manner and positively correlate with Separase expression levels in cell lines and in clinical CML samples. RNA silencing of c-MYB expression in CML cell lines resulted in reduced Separase protein levels. Gelshift and ChIP assays confirmed that c-MYB binds to a putative c-MYB binding sequence located within the ESPL1 promoter. CONCLUSIONS: Our data suggest that ESPL1/Separase is a regulatory target of c-MYB. Therefore, c-MYB, known to be required for BCR-ABL-dependent transformation of hematopoietic progenitors and leukemogenesis, may also control the Separase-dependent fidelity of mitotic chromosomal segregation and centriole duplication essential for maintenance of genomic stability. PMID- 26937282 TI - Genome sequence and description of Anaerosalibacter massiliensis sp. nov. AB - Anaerosalibacter massiliensis sp. nov. strain ND1(T) (= CSUR P762 = DSM 27308) is the type strain of A. massiliensis sp. nov., a new species within the genus Anaerosalibacter. This strain, the genome of which is described here, was isolated from the faecal flora of a 49-year-old healthy Brazilian man. Anaerosalibacter massiliensis is a Gram-positive, obligate anaerobic rod and member of the family Clostridiaceae. With the complete genome sequence and annotation, we describe here the features of this organism. The 3 197 911 bp long genome (one chromosome but no plasmid) contains 3271 protein-coding and 62 RNA genes, including six rRNA genes. PMID- 26937284 TI - Timing control of gait: a study of essential tremor patients vs. age-matched controls. AB - BACKGROUND: Essential tremor (ET) is a common movement disorder characterized by kinetic, postural and intention tremors. Mounting evidence suggests an underlying dysfunction of the cerebellum or cerebellar system. While few recent studies report impairments in timing control of finger movements in ET, timing control of gait has not been examined to date. We compared timing control of gait in ET patients vs. controls, and further assessed the association of these timing impairments with tremor severity among the ET patients. One-hundred-fifty-five ET patients and 60 age-matched controls underwent a comprehensive neurological assessment and gait analysis, which included walking at a criterion step frequency (cadence) with a metronome (timing production) and walking at a criterion step frequency after the metronome was turned off (timing reproduction). Outcomes of interest for both conditions were timing accuracy (measured by cadence error) and timing precision (measured by cadence variability). We also assessed cadence and step time across conditions. RESULTS: Cadence was lower in ET patients than controls (p < 0.03), whereas step time was similar for ET patients and controls. Accuracy (cadence error) and precision (cadence variability) were not different in ET patients compared with controls. Cranial tremor score was significantly associated with cadence (timing production condition, p = 0.003 and timing reproduction condition, p = 0.0001) and cadence error (timing production condition, p = 0.01). Kinetic tremor and intention tremor scores were not associated with gait measures. CONCLUSIONS: ET patients do not demonstrate impairments in timing control of gait as compared with matched controls. Prior work shows that patients with cerebellar dysfunction demonstrate selective impairments in timing of discrete movements (such as finger tapping) but not continuous movements (such as circle drawing). Taken together, these results support the hypothesis that the cerebellum may be important for timing control of discrete rather than continuous movements. PMID- 26937285 TI - A TMS investigation on the role of the cerebellum in pitch and timbre discrimination. AB - BACKGROUND: Growing neuroimaging and clinical evidence suggests that the cerebellum plays a critical role in perception. In the auditory domain, the cerebellum seems to be important in different aspects of music and sound processing. Here we investigated the possible causal role of the cerebellum in two auditory tasks, a pitch discrimination and a timbre discrimination task. Specifically, participants performed a pitch and a timbre discrimination task prior and after receiving offline low frequency transcranical magnetic stimulation (TMS) over their (right) cerebellum. RESULTS: Suppressing activity in the right cerebellum by means of inhibitory 1 Hz TMS affected participants' ability to discriminate pitch but not timbre. CONCLUSION: These findings point to a causal role of the cerebellum in at least certain aspects of sound processing and are important in a clinical perspective helping understanding the impact of cerebellar lesions on sensory functions. PMID- 26937283 TI - Brown adipose tissue: endocrine determinants of function and therapeutic manipulation as a novel treatment strategy for obesity. AB - INTRODUCTION: Recent observation of brown adipose tissue (BAT) being functional in adult humans provides a rationale for its stimulation to increase energy expenditure through 'adaptive thermogenesis' for an anti-obesity strategy. Many endocrine dysfunctions are associated with changes in metabolic rate that over time may result in changes in body weight. It is likely that human BAT plays a role in such processes. REVIEW: In this brief review article, we explore the endocrine determinants of BAT activity, and discuss how these insights may provide a basis for future developments of novel therapeutic strategies for obesity management. A review of electronic and print data comprising original and review articles retrieved from PubMed search up to December 2013 was conducted (Search terms: brown adipose tissue, brown fat, obesity, hormone). In addition, relevant references from the articles were screened for papers containing original data. CONCLUSION: There is promising data to suggest that targeting endocrine hormones for BAT modulation can yield a cellular bioenergetics answer for successful prevention and management of human obesity. Further understanding of the physiological link between various endocrine hormones and BAT is necessary for the development of new therapeutic options. PMID- 26937288 TI - Who dares, wins? PMID- 26937287 TI - Distal-less induces elemental color patterns in Junonia butterfly wings. AB - BACKGROUND: The border ocellus, or eyespot, is a conspicuous color pattern element in butterfly wings. For two decades, it has been hypothesized that transcription factors such as Distal-less (Dll) are responsible for eyespot pattern development in butterfly wings, based on their expression in the prospective eyespots. In particular, it has been suggested that Dll is a determinant for eyespot size. However, functional evidence for this hypothesis has remained incomplete, due to technical difficulties. RESULTS: Here, we show that ectopically expressed Dll induces ectopic elemental color patterns in the adult wings of the blue pansy butterfly, Junonia orithya (Lepidoptera, Nymphalidae). Using baculovirus-mediated gene transfer, we misexpressed Dll protein fused with green fluorescent protein (GFP) in pupal wings, resulting in ectopic color patterns, but not the formation of intact eyespots. Induced changes included clusters of black and orange scales (a basic feature of eyespot patterns), black and gray scales, and inhibition of cover scale development. In contrast, ectopic expression of GFP alone did not induce any color pattern changes using the same baculovirus-mediated gene transfer system. CONCLUSIONS: These results suggest that Dll plays an instructive role in the development of color pattern elements in butterfly wings, although Dll alone may not be sufficient to induce a complete eyespot. This study thus experimentally supports the hypothesis of Dll function in eyespot development. PMID- 26937286 TI - Investigation of the usefulness of zaleplon at two doses to induce afternoon sleep under noise interference and its effects on psychomotor performance and vestibular function. AB - BACKGROUND: Military operation personnel often suffer from sleep difficulty because of their work requirements. In this study, we investigated the efficacy of zaleplon at two doses to induce afternoon-sleep under noise interference and its effects on psychomotor performance and vestibular function; we subsequently established the optimal dosage regimen for military operation personnel. METHODS: Twenty-two healthy young male volunteers were recruited for the study. Eight subjects took 10 mg or 15 mg of zaleplon and placebo alternately and then were exposed to noise. Changes in polysomnography (PSG) indices, including sleep latency (SL), sleep efficiency (SE) and sleep structure, were recorded after drug administration. After awakening, the volunteers' subjective judgments of sleep quality and sleepiness were measured. Eight volunteers underwent 3 psychomotor performance tests at a one-week interval, and the psychomotor performance tests were conducted before and after taking zaleplon and placebo. Six volunteers participated in the vestibular function test session, and parameters, including optokinetic nystagmus (OKN), vestibular ocular reflex (VOR), visual-vestibular ocular reflex (VVOR) and vestibular ocular reflex fixation suppression (VOR-Fix), were detected by the same experimental design as described above. The data of sleep observations were subjected to one-way variance analysis. RESULTS: Compared with the placebo group, SL was shortened significantly, and the scores of subjective sleep quality and sleep depth were clearly increased in the zaleplon 10 mg group (P < 0.05). Moreover, the SE and the percent of REM (rapid eye movement) sleep were increased remarkably in the zaleplon 15 mg group (P < 0.01). Furthermore, the SE, percent of REM sleep and scores of subjective sleep depth in the zaleplon 15 mg group were significantly higher than in the zaleplon 10 mg group (P < 0.05). The psychomotor performance did not change significantly after ingestion of 10 mg or 15 mg of zaleplon, whereas the OKN and VOR gains were lower in the two dose groups of zaleplon (P < 0.05) and restored to normal 3 h after drug ingestion. CONCLUSION: Zaleplon is an ideal hypnotic for military personnel, and its hypnotic efficiency is dose-related under noise interference; a 15 mg dose of zaleplon could provide significantly better sleep than a 10 mg dose of zaleplon. PMID- 26937289 TI - Surface interactions between two of the main periodontal pathogens: Porphyromonas gingivalis and Tannerella forsythia. AB - PURPOSE: Porphyromonas gingivalis and Tannerella forsythia have been implicated as the major etiologic agents of periodontal disease. These two bacteria are frequently isolated together from the periodontal lesion, and it has been suggested that their interaction may increase each one's virulence potential. The purpose of this study was to identify proteins on the surface of these organisms that are involved in interbacterial binding. METHODS: Biotin labeling of surface proteins of P. gingivalis and T. forsythia and liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis was performed to identify surface proteins involved in the coaggregating activity between P. gingivalis and T. forsythia. RESULTS: It was found that three major T. forsythia proteins sized 161, 100, and 62 kDa were involved in binding to P. gingivalis, and P. gingivalis proteins sized 35, 32, and 26 kDa were involved in binding to T. forsythia cells. CONCLUSIONS: LC-MS/MS analysis identified one T. forsythia surface protein (TonB linked outer membrane protein) involved in interbacterial binding to P. gingivalis. However, the nature of other T. forsythia and P. gingivalis surface proteins identified by biotin labeling could not be determined. Further analysis of these proteins will help elucidate the molecular mechanisms that mediate coaggregation between P. gingivalis and T. forsythia. PMID- 26937290 TI - Diagnostic accuracy of a combination of salivary hemoglobin levels, self-report questionnaires, and age in periodontitis screening. AB - PURPOSE: This study evaluated the predictive performance of a combination of self report questionnaires, salivary hemoglobin levels, and age as a non-invasive screening method for periodontitis. METHODS: The periodontitis status of 202 adults was examined using salivary hemoglobin levels, responses to 10 questions on a self-report questionnaire, and the Community Periodontal Index (CPI). The ability of those two variables and the combination thereof with age to predict the presence of CPI scores of 3-4 and 4 was assessed using logistic regression and receiver operating characteristic (ROC) curve analysis. RESULTS: CPI scores of 3-4 and 4 were present among 79.7% and 46.5% of the sample, respectively. The area under the ROC curves (AUROCs) of salivary hemoglobin levels for predicting prevalence of CPI scores of 3-4 and 4 were 0.63 and 0.67, respectively (with sensitivity values of 71% and 60% and specificity values of 56% and 72%, respectively). Two distinct sets of five questions were associated with CPI scores of 3-4 and 4, with AUROCs of 0.73 and 0.71, sensitivity values of 76% and 66%, and specificity values of 63% and 69%. The combined model incorporating both variables and age showed the best predictive performance, with AUROCs of 0.78 and 0.76, sensitivity values of 71% and 65%, and specificity values of 68% and 77% for CPI scores of 3-4 and 4, respectively. CONCLUSIONS: The combination of salivary hemoglobin levels and self-report questionnaires was shown to be a valuable screening method for detecting periodontitis. PMID- 26937291 TI - Root coverage using a coronally advanced flap with or without acellular dermal matrix: a meta-analysis. AB - PURPOSE: Gingival recession is a major esthetic concern and may lead to root sensitivity during periodontal treatment. Coronally advanced flaps (CAFs) with and without acellular dermal matrix (ADM) are widely used in root coverage procedures. The aim of this study was to analyze the efficacy of CAF in combination with ADM in the treatment of gingival recession. METHODS: PubMed, The Cochrane Library, and Embase were used to identify relevant articles. The articles were screened, data were extracted, and the quality of the studies was assessed by three reviewers with expertise in clinical practice, trials, statistics, and biomedical editing. The clinical endpoints of interest included changes in recession, probing depth (PD), clinical attachment level (CAL), and keratinized tissue (KT). RESULTS: Ten randomized controlled trials were identified, including six studies that compared CAFs with ADM and CAFs using connective tissue grafting (CTG) and four studies that compared CAFs with or without ADM. No statistically significant differences were found between the use of ADM and CTG, whereas statistically significant differences were found between groups in which ADM and CAF were combined and groups that underwent CAF alone with regard to recession coverage, CAL, and KT. The combination of CAF with an ADM allograft achieved more favorable recession coverage and recovery of CAL and KT than CAF alone. CONCLUSIONS: The results from the ADM and CTG groups suggest that both procedures may be equally effective in clinical practice. Given the limitations of this study, further investigation is needed to clarify the effectiveness of ADM and CAF in clinical practice. PMID- 26937292 TI - Prevalence of Porphyromonas gingivalis fimA genotypes in the peri-implant sulcus of Koreans assessed using a new primer. AB - PURPOSE: Porphyromonas gingivalis fimA is a virulence factor associated with periodontal diseases, but its role in the pathogenesis of peri-implantitis remains unclear. We aimed to evaluate the relationship between the condition of peri-implant tissue and the distribution of P. gingivalis fimA genotypes in Koreans using a new primer. METHODS: A total of 248 plaque samples were taken from the peri-implant sulci of 184 subjects. The control group consisted of sound implants with a peri-implant probing depth (PD) of 5 mm or less with no bleeding on probing (BOP). Test group I consisted of implants with a peri-implant PD of 5 mm or less and BOP, and test group II consisted of implants with a peri-implant PD of more than 5 mm and BOP. DNA was extracted from each sample and analyzed a using a polymerase chain reaction (PCR) with P. gingivalis-specific primers, followed by an additional PCR assay to differentiate the fimA genotypes in P. gingivalis-positive subjects. RESULTS: The Prevalence of P. gingivalis in each group did not significantly differ (P>0.05). The most predominant fimA genotype in all groups was type II. The prevalence of type Ib fimA was significantly greater in test group II than in the control group (P<0.05). CONCLUSIONS: The fimA type Ib genotype of P. gingivalis was found to play a critical role in the destruction of peri-implant tissue, suggesting that it may be a distinct risk factor for peri-implantitis. PMID- 26937293 TI - Effects of a mouthwash containing potassium nitrate, sodium fluoride, and cetylpyridinium chloride on dentin hypersensitivity: a randomized, double-blind, placebo-controlled study. AB - PURPOSE: We evaluated the efficacy of a mouthwash containing potassium nitrate (KNO3) as its main component, along with sodium fluoride (NaF) and cetylpyridinium chloride (CPC). The primary endpoint was the relief of dentin hypersensitivity (DH) against the cold stimuli. The effects on other DH tests and periodontal inflammation were also evaluated. METHODS: We used a single-center, double-blind, placebo-controlled, randomized design. A total of 82 patients with DH (40 in the test group, 42 placebo controls) were analyzed using visual analog scales (VASs) for a cold test, a tactile test, a compressive air test, and self reported pain during daily activities, as well as clinical parameters including plaque index, gingival index, modified sulcular bleeding index (mSBI), gingival recession, and probing depth, which were collected at baseline and after four and six weeks of mouthwash use. RESULTS: VAS scores for cold sensations, tactile sensations, the compressive air test, and self-reported pain significantly decreased from baseline during the six weeks in both groups (P<0.01), and no significant differences between the groups were found. In male patients (10 in the test group and 7 in the control group), both groups showed significant reductions in VAS scores for the cold test over the six weeks, and greater reductions were found in the test group than in the control group between four and six weeks (P=0.01) and between baseline and six weeks (P<0.01). In addition, the mSBI in the test group significantly decreased from baseline during the six weeks (P<0.01), and the changes at four and six weeks from baseline were significantly greater in the test group compared to the control group (P=0.03 and P=0.02, respectively). CONCLUSIONS: A mouthwash containing a mixture of KNO3, NaF, and CPC reduced DH and gingival inflammation, however, the efficacy was comparable to the control group. PMID- 26937294 TI - Late-term healing in an augmented sinus with different ratios of biphasic calcium phosphate: a pilot study using a rabbit sinus model. AB - PURPOSE: The aim of this pilot study was to determine the osteoconductivity and dimensional stability of augmented sinuses using different ratios of biphasic calcium phosphate (BCP) in a rabbit sinus model. METHODS: Each sinus of New Zealand white rabbits (2.5-3.5 kg) was assigned to one of two groups: BCP with a hydroxyapatite to beta-tricalcium phosphate (HA:beta-TCP) ratio of 70:30 (group TCP30) and BCP with an HA:beta-TCP ratio of 30:70 (group TCP70). After preparing a window in the antral wall of a sinus, the Schneiderian membrane was elevated, and the applicable material was grafted. A fluorochrome calcein green was injected five days before euthanizing the animals at four months post-surgery. The specimens were analyzed histologically, histomorphometrically, and by using micro-computed tomography (micro-CT). RESULTS: Micro-CT analysis revealed that the total augmented volume and the new bone volume did not differ significantly between the two groups whereas the resorption of materials was greater in the TCP70 group. The trabecular thickness, number, and separation also did not differ significantly between the two groups. Histomorphometrically, the areas of total augmentation, new bone, and residual material, as well as the ratio of new-bone material contact did not differ significantly between the groups. Histologically, the residual particles were more scattered in the TCP70 group than in the TCP30 group. The fluorescence of the calcein green did not differ notably between the two groups. CONCLUSIONS: The osteoconductivity and dimensional stability of the two BCPs with different ratios tested in this study were comparable after four months of healing. Therefore, we conclude that both BCPs show promise as a bone substitute for sinus augmentation. PMID- 26937296 TI - Dynamic coherent backscattering mirror. AB - The phase of multiply scattered light has recently attracted considerable interest. Coherent backscattering is a striking phenomenon of multiple scattered light in which the coherence of light survives multiple scattering in a random medium and is observable in the direction space as an enhancement of the intensity of backscattered light within a cone around the retroreflection direction. Reciprocity also leads to enhancement of backscattering light in the spatial space. The random medium behaves as a reciprocity mirror which robustly converts a diverging incident beam into a converging backscattering one focusing at a conjugate spot in space. Here we first analyze theoretically this coherent backscattering mirror (CBM) phenomenon and then demonstrate the capability of CBM compensating and correcting both static and dynamic phase distortions occurring along the optical path. CBM may offer novel approaches for high speed dynamic phase corrections in optical systems and find applications in sensing and navigation. PMID- 26937295 TI - Improved Method for Isolation of Neonatal Rat Cardiomyocytes with Increased Yield of C-Kit+ Cardiac Progenitor Cells. AB - Cell therapy represents a promising new paradigm for treatment of heart disease, a major cause of death in the industrialized world. The recent discovery of tissue resident c-Kit+ cardiac progenitor cells (CPCs) has fueled scientific efforts to exploit these cells therapeutically for regenerative interventions, and primary culture of cardiomyocytes is a common in-vitro model to investigate basic molecular mechanisms underlying cardiac degeneration and regeneration. Current protocols for cardiomyocyte isolation frequently result in low cell yield and insufficient depletion of fibroblasts, which then overgrow the cardiomyocytes in culture. In this protocol we describe an improved method for the isolation of neonatal rat cardiomyocytes that also enables enhanced yields of CPCs. Gentle techniques of enzymatic and mechanical tissue processing ensure high cell numbers and viability, while subsequent Percoll density gradient centrifugation minimizes fibroblasts. We compared the advantages of different enzymes and found that Collagenase 2 alone leads to very high yields of cardiomyocytes, whereas the application of MatraseTM enzyme blend increases the relative yield of c-Kit+ CPCs to up to 35%. Cardiomyocytes and CPCs isolated with this protocol may constitute an important cell source for investigating heart disease as well as cell based therapeutic approaches. PMID- 26937297 TI - Effect of boron doping on nanostructure and magnetism of rapidly quenched Zr2Co11 based alloys. AB - The role of B on the microstructure and magnetism of Zr16Co82.5-x Mo1.5B x ribbons prepared by arc melting and melt spinning is investigated. Microstructure analysis show that the ribbons consist of a hard-magnetic rhombohedral Zr2Co11 phase and a minor amount of soft-magnetic Co. We show that the addition of B increases the amount of hard-magnetic phase, reduces the amount of soft-magnetic Co and coarsens the grain size from about 35 nm to 110 nm. There is a monotonic increase in the volume of the rhombohedral Zr2Co11 unit cell with increasing B concentration. This is consistent with a previous theoretical prediction that B may occupy a special type of large interstitial sites, called interruption sites. The optimum magnetic properties, obtained for x = 1, are a saturation magnetization of 7.8 kG, a coercivity of 5.4 kOe, and a maximum energy product of 4.1 MGOe. PMID- 26937298 TI - Changing of the guard. PMID- 26937299 TI - Underneath the "apple-jelly". PMID- 26937300 TI - Eccrine syringofibroadenoma (ESFA): a report of two cases. PMID- 26937301 TI - Histiocytoid Sweet's syndrome in a patient with myelodsyplastic syndrome: report and review of the literature. AB - The neutrophilic dermatoses are a group of disorders characterized by skin lesions for which histological examination reveals intense epidermal and/or dermal inflammatory infiltrates composed primarily of neutrophils without evidence of infection. The myelodysplastic syndromes consist of a heterogeneous group of malignant hematopoietic stem cell disorders characterized by dysplastic and inadequate blood cell production with a variable risk of transformation to acute leukemia. Rarely, histiocytoid Sweet's syndrome occurring in patients with myelodysplastic syndrome has been described. We present a case of a 66-year-old woman with a history of myelodysplastic syndrome who developed histiocytoid Sweet's syndrome. We also review the literature and characterize patients with myelodysplastic syndrome who have developed histiocytoid Sweet's syndrome. PMID- 26937302 TI - A rare complication of follicular hair unit extraction: Kaposi's varicelliform eruption. AB - Follicular hair unit extraction (FUE) is becoming a popular type of hair transplantation recently. Kaposi's varicelliform eruption (KVE) is an uncommon skin emergency due to cutaneous dissemination of several types of viruses, most notably herpes virus, over the lesions of preexisting skin disorders. A 34-year old man visited our dermatology outpatient clinic with a blistering, itchy and tender eruption on his head and body. He had undergone follicular FUE for androgenic alopecia 12 days previously, and 5 days after the procedure, umbilicated and/or hemorrhagic vesiculopustules appeared firstly on the occipital scalp skin where the hair units were taken. The lesions had rapidly spread over the upper chest and back. After the operation, he had taken oral methylprednisolone, amoxicillin clavulanate and had used fusidic acid ointment without any benefit. Bacterial culture of the pustules yielded no microorganism, while Tzanck smear from the vesicles revealed multinuclear giant cell groups. Based on a diagnosis of KVE, we treated the patient with oral valacyclovir hydrochloride 1000 mg 3 times a day for 14 days. Symptoms cleared rapidly, pustules and vesicles dried in a few days, and re-epithelialization of the eroded areas started at the end of the first week. The reported complications of FUE include necrosis of the donor site, postoperative hyperesthesia, recipient area folliculitis, keloids, bleeding, infection and pyogenic granuloma. Up to this date there are only three reports of KVE developing just after dermatological surgery, including dermabrasion, laser resurfacing, and skin grafting. According to our knowledge, this is the first case of KVE occurring after the FUE procedure. We think that the traumatic effects and skin barrier disruption due to operation and immune alteration due to postsurgical steroid treatment might have precipitated the activation and dissemination of latent herpesvirus infection. PMID- 26937303 TI - Vasculitis with panniculitis following botulinum toxin A injection for cosmetic use. AB - Botulinum toxin A injection is performed most frequently for facial rejuvenation all over the world. Some bizarre and severe side effects have been reported after botulinum toxin A injection. Herein, we present a case of vasculitis with panniculitis after a patient underwent a cosmetic procedure that included injection of purported botulinum toxin A. PMID- 26937304 TI - Dermoscopic features of conjunctival, mucosal, and nail pigmentations in a case of Laugier-Hunziker syndrome. PMID- 26937305 TI - Comment on "'Tape dermatoscopy': constructing a low-cost dermatoscope using a mobile phone, immersion fluid and transparent adhesive tape". PMID- 26937307 TI - Human Wellbeing and Flourishing: If Not Now, When? PMID- 26937308 TI - Integrative Medicine and Health Disparities. PMID- 26937306 TI - New CD20 alternative splice variants: molecular identification and differential expression within hematological B cell malignancies. AB - BACKGROUND: CD20 is a B cell lineage-specific marker expressed by normal and leukemic B cells and targeted by several antibody immunotherapies. We have previously shown that the protein from a CD20 mRNA splice variant (D393-CD20) is expressed at various levels in leukemic B cells or lymphoma B cells but not in resting, sorted B cells from the peripheral blood of healthy donors. RESULTS: Western blot (WB) analysis of B malignancy primary samples showed additional CD20 signals. Deep molecular PCR analysis revealed four new sequences corresponding to in-frame CD20 splice variants (D657-CD20, D618-CD20, D480-CD20, and D177-CD20) matching the length of WB signals. We demonstrated that the cell spliceosome machinery can process ex vivo D480-, D657-, and D618-CD20 transcript variants by involving canonical sites associated with cryptic splice sites. Results of specific and quantitative RT-PCR assays showed that these CD20 splice variants are differentially expressed in B malignancies. Moreover, Epstein-Barr virus (EBV) transformation modified the CD20 splicing profile and mainly increased the D393-CD20 variant transcripts. Finally, investigation of three cohorts of chronic lymphocytic leukemia (CLL) patients showed that the total CD20 splice variant expression was higher in a stage B and C sample collection compared to routinely collected CLL samples or relapsed refractory stage A, B, or C CLL. CONCLUSION: The involvement of these newly discovered alternative CD20 transcript variants in EBV transformation makes them interesting molecular indicators, as does their association with oncogenesis rather than non-oncogenic B cell diseases, differential expression in B cell malignancies, and correlation with CLL stage and some predictive CLL markers. This potential should be investigated in further studies. PMID- 26937309 TI - Integrative Health and the Emerging Whole-Systems Approach to Dietary Guidelines. PMID- 26937310 TI - My Inspiration. PMID- 26937311 TI - Stories of Growth and Wisdom: A Mixed-Methods Study of People Living Well With Pain. AB - Chronic pain remains a daunting clinical challenge, affecting 30% of people in the United States and 20% of the global population. People meeting this challenge by achieving wellbeing while living with pain are a virtually untapped source of wisdom about this persistent problem. Employing a concurrent mixed-methods design, we studied 80 people living with chronic pain with "positive stories to tell" using semi-structured interviews and standardized questionnaires. In-depth interviews focused on what helped, what hindered, how they changed, and advice for others in similar circumstances. Major qualitative themes included acceptance, openness, self-efficacy, hope, perseverance, self-regulation, kinesthetic awareness, holistic approaches and integrative therapies, self-care, spirituality, social support, and therapeutic lifestyle behaviors such as music, writing, art, gardening, and spending time in nature. Themes of growth and wisdom included enhanced relationships, perspective, clarity, strength, gratitude, compassion, new directions, and spiritual change. Based on narrative analysis of the interviews and Ardelt's Three-Dimensional Wisdom Model, participants were divided into 2 groups: 59 wisdom exemplars and 21 nonexemplars. Non-exemplar themes were largely negative and in direct contrast to the exemplar themes. Quantitatively, wisdom exemplars scored significantly higher in Openness and Agreeableness and lower in Neuroticism compared to non-exemplars. Wisdom exemplars also scored higher in Wisdom, Gratitude, Forgiveness, and Posttraumatic Growth than nonexemplars, and more exemplars used integrative therapies compared to the non-exemplars. As a whole, the exemplar narratives illustrate a Positive Approach Model (PAM) for living well with pain, which allows for a more expansive pain narrative, provides positive role models for patients and clinicians, and contributes to a broader theoretical perspective on persistent pain. PMID- 26937313 TI - Provider Perspective on Integrative Medicine for Pediatric Sickle Cell Disease related Pain. AB - OBJECTIVE: Integrative medicine (IM) approaches are sometimes used to manage sickle cell disease (SCD)-related pain. The purpose of this research is to (1) understand provider perspective towards the use of IM for pain in children with SCD at a large urban children's hospital and (2) provide recommendations on how to better promote IM for children and adolescents with SCD. METHODS: After approval from the institutional review board, a qualitative case study approach was used with criterion-type purposeful sampling to select providers from the division of hematology to adequately inform the study. Semistructured interviews were completed using audiotape to facilitate transcription. NVivo 10 analytic software (QSR International Pty Ltd, Doncaster, Victoria, Australia) was used to organize data into themes to answer the study questions. RESULTS: Ten provider interviews were completed. Attitudes were generally positive, and most providers felt that IM is generally helpful. All providers reported that they do not optimally use integrative therapies for children with SCD. The barriers uncovered focused on lack of process for integration of IM, specifically that IM resources seem transient and based on short-term funding. Provider attitude towards CAM is generally positive, but provider comfort level is highly variable. No providers are completely comfortable with their knowledge base about IM, and increased knowledge is desired. CONCLUSIONS: Creation of protocols and processes to incorporate IM into management plans for patients with SCD could help to promote its use. Education of providers about utility and efficacy of IM for SCD-related pain and about existing resources would aid in promotion of IM for children with SCD. PMID- 26937312 TI - Mindfulness- and Acceptance-based Interventions for Psychosis: A Systematic Review and Meta-analysis. AB - BACKGROUND: Mindfulness- and acceptance-based interventions are increasingly studied as a potential treatment for a variety of mental conditions. OBJECTIVE: To assess the effects of mindfulness- and acceptance-based interventions on psychotic symptoms and hospitalization in patients with psychosis. METHODS: MEDLINE/PubMed, Embase, the Cochrane Library, and PsycINFO were screened from inception through April 2015. Randomized controlled trials (RCTs) were analyzed when they assessed psychotic symptoms or hospitalization in patients with psychosis; affect, acceptance, mindfulness, and safety were defined as secondary outcomes. RESULTS: Eight RCTs with a total of 434 patients comparing mindfulness based (4 RCTs) or acceptance-based interventions (4 RCTs) to treatment as usual or attention control were included. Six RCTs had low risk of bias. Moderate evidence was found for short-term effects on total psychotic symptoms, positive symptoms, hospitalization rates, duration of hospitalization, and mindfulness and for long-term effects on total psychotic symptoms and duration of hospitalization. No evidence was found for effects on negative symptoms, affect, or acceptance. No serious adverse events were reported. CONCLUSION: Mindfulness- and acceptance-based interventions can be recommended as an additional treatment for patients with psychosis. PMID- 26937314 TI - Meeting the Challenge of a More Person-centered Future for US Healthcare. PMID- 26937316 TI - Complementary and Alternative Medicine Use in the US Adult Low Back Pain Population. AB - BACKGROUND: Many people suffering from low back pain (LBP) have found conventional medical treatments to be ineffective for managing their LBP and are increasingly turning to complementary and alternative medicine (CAM) to find pain relief. A comprehensive picture of CAM use in the LBP population, including all of the most commonly used modalities, is needed. STUDY OBJECTIVE: To examine prevalence and perceived benefit of CAM use within the US LBP population by limiting vs nonlimiting LBP and to evaluate the odds of past year CAM use within the LBP population. METHODS: Data are from the 2012 National Health Interview Survey, Alternative Health Supplement. We examined a nationally representative sample of US adults with LBP (N=9665 unweighted). Multiple logistic regression was used to estimate the odds of past year CAM use. RESULTS: In all, 41.2% of the LBP population used CAM in the past year, with higher use reported among those with limiting LBP. The most popular therapies used in the LBP population included herbal supplements, chiropractic manipulation, and massage. The majority of the LBP population used CAM specifically to treat back pain, and 58.1% of those who used CAM for their back pain perceived a great deal of benefit. CONCLUSION: The results are indicative of CAM becoming an increasingly important component of care for people with LBP. Additional understanding of patterns of CAM use among the LBP population will help health professionals make more informed care decisions and guide investigators in development of future back pain-related CAM research. PMID- 26937315 TI - Health-related Culinary Education: A Summary of Representative Emerging Programs for Health Professionals and Patients. AB - BACKGROUND: Beneficial correlations are suggested between food preparation and home food preparation of healthy choices. Therefore, there is an emergence of culinary medicine (CM) programs directed at both patients and medical professionals which deliver education emphasizing skills such as shopping, food storage, and meal preparation. OBJECTIVE: The goal of this article is to provide a description of emerging CM programs and to imagine how this field can mature. METHODS: During April 2015, 10 CM programs were identified by surveying CM and lifestyle medicine leaders. Program directors completed a narrative describing their program's structure, curricula, educational design, modes of delivery, funding, and cost. Interviews were conducted in an effort to optimize data collection. RESULTS: All 10 culinary programs deliver medical education curricula educating 2654 health professionals per year. Educational goals vary within the domains of (1) provider's self-behavior, (2) nutritional knowledge and (3) prescribing nutrition. Six programs deliver patients' curricula, educating 4225 individuals per year. These programs' content varies and focuses on either specific diets or various culinary behaviors. All the programs' directors are health professionals who are also either credentialed chefs or have a strong culinary background. Nine of these programs offer culinary training in either a hands-on or visual demonstration within a teaching kitchen setting, while one delivers remote culinary tele-education. Seven programs track outcomes using various questionnaires and biometric data. CONCLUSIONS: There is currently no consensus about learning objectives, curricular domains, staffing, and facility requirements associated with CM, and there has been little research to explore its impact. A shared strategy is needed to collectively overcome these challenges. PMID- 26937317 TI - China's Other Medical Systems: Recognizing Uyghur, Tibetan, and Mongolian Traditional Medicines. AB - BACKGROUND: Traditional Chinese medicine, as it is understood and adopted by those with a growing interest in complementary and alternative practices to biomedicine, is often used as an umbrella term for traditional medical practices from regions within and bordering the People's Republic of China. However, there are multiple distinct medical traditions in China, including that of the Uyghurs, Tibetans, and Mongolians. OBJECTIVE: It is important to recognize the commonalities and differences of these unique systems of medicine practiced by the 3 different cultures among China's borders. METHODS: Through an in-depth analysis of the individual beliefs and theories that form the foundation of each system, we trace the origins of the concepts that were synthesized into the Uyghur, Tibetan, and Mongolian medical systems. Furthermore, we compare diagnostic techniques and contrast treatment modalities among the 3 systems. DISCUSSION: We discuss humoral theory, constitution theory, elemental theory, organ theory, and yin and yang theory. We find that imbalance is the common cause of disease or illness, but the conditions and external factors that explain such imbalances differ among the Uyghur, Tibetan, and Mongolian systems. Through these comparisons, we seek to highlight the unique beliefs, practices, and treatments utilized by these cultures. CONCLUSION: The features and attributes, while not exclusive to each population, are nonetheless uniquely synthesized by each system and thus demonstrate the distinct nature of Uyghur, Tibetan, and Mongolian medical systems. PMID- 26937319 TI - The Business Case for Optimal Healing Environments. PMID- 26937318 TI - Factors Associated With Excessive Gestational Weight Gain: Review of Current Literature. AB - BACKGROUND: Excessive gestational weight gain (EGWG) places women at increased risk for complications during pregnancy and also increases the likelihood that they will remain overweight after pregnancy. The Institute of Medicine (IOM) has recommended weight gain guidelines based on pre-pregnancy body mass index (BMI), but evidence-based strategies to achieve these goals are limited. OBJECTIVE: This review discusses factors associated with EGWG with the goal of identifying targets for future intervention. METHODS: A search was performed using the PubMed database to identify all English-language papers published between 1995 and 2014 related to excessive weight gain in pregnancy. Papers were grouped by theme: preconception BMI, sociodemographics, diet and exercise, psychosocial characteristics, and type of prenatal care. RESULTS: Studies found that women who were overweight or obese at the time of conception were at higher risk of EGWG and that increased physical activity protected against EGWG. Studies on diet and sociodemographic characteristics were inconclusive. Psychological factors, specifically accurate perceptions of BMI, also appear to play a role in EGWG. Limited studies on methods of prenatal care delivery did not show improvement of weight parameters with group compared to one-on-one visits. CONCLUSION: Pre pregnancy BMI is most strongly associated with EGWG, indicating that healthy weight habits throughout adult life may be especially important in periods of expected weight change, such as pregnancy. To decrease EGWG, providers should focus on improving pre-conception BMI through appropriate counseling on healthy eating and increased physical activity as well as encouraging pregnant women to continue moderate exercise during pregnancy when appropriate. PMID- 26937320 TI - Acupuncture for the Management of Postdural Puncture Headache: A Case Report. AB - Postdural puncture headache (PDPH) is a recognized complication of neuraxial anesthesia. This case report documents 1 patient who developed PDPH following epidural anesthesia for postoperative pain control. The patient declined conventional treatments, including an epidural blood patch and intravenous caffeine. This report documents successful use of adjunct acupuncture for the management of PDPH. Additional research on acupuncture as a potential adjunctive therapy for PDPH is needed, particularly for patients who are reluctant to receive more invasive treatments. PMID- 26937321 TI - Improvement of Asthma and Gastroesophageal Reflux Disease With Oral Pulvis stomachicus cum Belladonna, a Combination of Matricaria recutita, Atropa belladonna, Bismuth, and Antimonite: A Pediatric Case Report. AB - The association between gastroesophageal reflux disease (GERD) and asthma, although well established in adults, is less strong in the pediatric age group. Benefits of proton pump therapy are limited across age ranges. While there is a growing body of literature on the use of complementary treatments for both asthma and GERD, few studies have focused on treatment benefits for the GERD-asthma association. We present the case of a 2-year-old boy with asthma and GERD who was not responding to inhaled, low-dose corticosteroids, beta-mimetic therapy, and a 6-week course of proton pump inhibitor treatment. We noted a gradual disappearance of symptoms when he was given an oral preparation of Pulvis stomachicus cum Belladonna, an anthroposophic medication containing Matricaria recutita, Atropa belladonna, bismuth, and antimonite. Matricaria recutita and bismuth have known gastric protective properties, and Atropa belladonna contains anticholinergic agents that have a bronchodilatory effect. These complementary medications appear promising in terms of relieving the symptoms of GERD associated asthma. PMID- 26937322 TI - Post-gastrectomy Syndrome Successfully Treated With Kampo Medicine: A Case Report. AB - Cancer-related gastrectomy can cause post-gastrectomy syndrome, which includes weight loss, dumping syndrome, and reflux esophagitis and negatively affects the quality of life. Comprehensive and individualized patient management is required; however, there is a limit to Western medicine's ability to treat these symptoms. Kampo, a traditional Japanese medicine, adapts treatments to each individual's symptoms and constitution. We treated a 68-year-old male patient with post gastrectomy syndrome using senpukukataishasekito, a Kampo medicine. He was diagnosed with Stage II-A gastric cancer at age 66 years and underwent a laparoscopic, pylorus-preserving gastrectomy followed by chemotherapy for 13 months. He visited our clinic for chemotherapy-related fatigue, postsurgical weight loss, and limb numbness. He was prescribed both hachimijiogan and hochuekkito. At the second visit, he complained of stomach discomfort, so we prescribed senpukukataishasekito. As his stomach function improved, his body weight increased and his fatigue decreased. We suggest that senpukukataishasekito may be an effective treatment for post-gastrectomy syndrome. PMID- 26937323 TI - Integrative Medicine Approach to Pediatric Obsessive-Compulsive Disorder and Anxiety: A Case Report. AB - Pediatric obsessive-compulsive disorder (OCD) is prevalent in 1% to 2% of the population. Emerging studies have correlated non-celiac gluten sensitivity with psychiatric conditions such as schizophrenia, depression, mania, and anxiety. This case study is the first reported case of OCD associated with non-celiac gluten sensitivity. The objectives of this case report are to (1) identify gluten sensitivity as a possible contributing factor to OCD in some patients; and (2) point out the possible benefit of an integrative medicine approach to the management of OCD in a patient with suboptimal benefit from a standard treatment regime. A 7-year-old male treated at a multi-physician integrative medicine practice in the United States had marked reduction of OCD symptoms and anxiety along with marked improvement of social behavior and school work after treatment consisting of gluten avoidance and other integrative medicine modalities. The patient's rapid response without side effects behooves the medical research community to further investigate the association of non-celiac gluten sensitivity and pediatric OCD. PMID- 26937324 TI - A Case Report of Improvement in Crohn's Disease-related Symptoms Following Participation in a Comprehensive Mind-Body Program. AB - Stress is widely believed to play a role in the development and pathogenesis of inflammatory bowel disease (IBD), and several studies of mind-body programs have suggested benefits in this patient population. Here we describe a case report of a young man with a flare in Crohn's disease-related symptoms that improved in response to a comprehensive, multi-modal, mind-body program and the development of a novel IBD treatment center that incorporates mind-body approaches, nutrition, and other modalities to provide more holistic and patient-centered care for individuals with IBD. PMID- 26937325 TI - Scanning the Global Literature. PMID- 26937326 TI - Response order effects in the Youth Tobacco Survey: Results of a split-ballot experiment. PMID- 26937327 TI - Possible impacts of a future grand solar minimum on climate: Stratospheric and global circulation changes. AB - A future decline in solar activity would not offset projected global warmingA future decline in solar activity could have larger regional effects in winterTop down mechanism contributes to Northern Hemisphere regional response. PMID- 26937328 TI - Mesoscale eddies and Trichodesmium spp. distributions in the southwestern North Atlantic. AB - Trichodesmium abundance was elevated in certain cyclonic and anticyclonic eddiesEnhancement in cyclonic eddies could be driven by Ekman convergenceAnticyclonic eddies with elevated abundance were anomalously fresh. PMID- 26937329 TI - Assessing the role of oxygen on ring current formation and evolution through numerical experiments. AB - Low O+/H+ ratio produced stronger ring currentInclusion of physics-based ionospheric outflow leads to a reduction in the CPCPOxygen presence is linked to a nightside reconnection point closer to the Earth. PMID- 26937331 TI - The 4 June 2011 neutron event at Mercury: A defense of the solar origin hypothesis. AB - We address claim that neutrons from a 4 June 2011 event at Mercury are nonsolarThe claim is based on an erroneous assumption about instrument singles countsThe best interpretation of the neutron event is that the neutrons have a solar origin. PMID- 26937330 TI - A summary of the BARREL campaigns: Technique for studying electron precipitation. AB - BARREL observed electron precipitation over wide range of energy and timescalesPrecipitating electron distribution is determined using spectroscopy for 19 January 2013 eventBARREL timing data has accuracy within sampling interval of 0.05 s. PMID- 26937333 TI - Positive and Negative Predictive Value of PET-CT in Skull Base Lesions: Case Series and Systematic Literature Review. AB - Objectives To study positive (PPV) and negative predictive value (NPV) of positron emission tomography with computed tomography (PET-CT) scans in determining malignancy in skull base lesions and perform a systematic literature review for optimal PET-CT interpretation. Design Retrospective case series and systematic literature review of the current English literature. Setting Tertiary referral academic medical center. Participants All patients with skull base lesions that underwent PET-CT and tissue biopsy from 2010 to 2013. Main Outcome Measures PPV and NPV of radiologist's report and standardized uptake value (SUV) cutoff of 2.5 and 3, biopsy with pathologic interpretation, clinical follow-up. Results A total of 31 PET-CT scans of 16 patients were studied; 10 PET-CT were performed upfront for diagnostic purposes and 21 were post-treatment surveillance scans. The PPV of radiologist's interpretation, SUV cutoff of 2.5, and SUV cutoff of 3.0 was 80%, 60%, and 68.4%, with a NPV of 100%, 83.3%, and 75%, respectively. Literature search yielded 500 abstracts; 7 studies met inclusion criteria for detailed review. No consensus or guidelines for optimal SUV cutoff value was found. Conclusions PET-CT based on SUV cutoff criteria alone has high NPV but low PPV in determining malignancy in skull base lesions. Interpretation by a radiologist experienced in nuclear medicine and neuroradiology, synthesizing clinical, SUV, and radiologic data are of superior value. PMID- 26937332 TI - Mitochondrial Targeted Antioxidant in Cerebral Ischemia. AB - There has been much evidence suggesting that reactive oxygen species (ROS) generated in mitochondria during cerebral ischemia play a major role in programming the senescence of organism. Antioxidants dealing with mitochondria slow down the appearance and progression of symptoms in cerebral ischemia and increase the life span of organisms. The mechanisms of mitochondrial targeted antioxidants, such as SKQ1, Coenzyme Q10, MitoQ, and Methylene blue, include increasing adenosine triphosphate (ATP) production, decreasing production of ROS and increasing antioxidant defenses, providing benefits in neuroprotection following cerebral ischemia. A number of studies have shown the neuroprotective role of these mitochondrial targeted antioxidants in cerebral ischemia. Here in this short review we have compiled the literature supporting consequences of mitochondrial dysfunction, and the protective role of mitochondrial targeted antioxidants. PMID- 26937334 TI - Giant Petrous Bone Cholesteatoma: Combined Microscopic Surgery and an Adjuvant Endoscopic Approach. AB - Petrous bone cholesteatomas (PBCs) are epidermoid cysts, which have developed in the petrous portion of the temporal bone and may be congenital or acquired. Cholesteatomas arising in this region have a tendency to invade bone and functional structures and the middle and posterior fossae reaching an extensive size. Traditionally, surgery of a giant PBC contemplates lateral transtemporal or middle fossa microscopic surgery; however, in recent years, endoscopic surgical techniques (primary or complementary endoscopic approach) are starting to receive a greater consensus for middle ear and mastoid surgeries. We report the rare case of an 83-year-old Caucasian male affected by a giant cholesteatoma that eroded the labyrinth and the posterior fossa dura and extended to the infralabyrinthine region, going beyond the theca and reaching the first cervical vertebra. The giant cholesteatoma was managed through a combined approach (microscopic and, subsequently, complementary endoscopic approach). In this case report, we illustrate some advantages of this surgical choice. PMID- 26937335 TI - Nanofibrous Synthetic Dural Patch for Skull Base Defects: Preliminary Experience for Reconstruction after Extended Endonasal Approaches. AB - Setting One of the consequences of the widespread use of endoscopic endonasal approaches (EEA) to skull base pathologies is the management of complex skull base defects. Nowadays, the gold standard is a multilayer closure that reproduces the physiological tissue barriers. Several techniques have been described in the literature; however, skull base reconstruction after EEA still represents a matter of debate, especially after extended EEA. A watertight closure is paramount to prevent cerebrospinal fluid leak and meningitis. Design Regarding this issue, we present our experience with a new synthetic dural patch, ReDura (Medprin Biotech, La Mirada, California, United States), as a subdural inlay in three patients who underwent endoscopic endonasal removal of sellar and suprasellar lesions. Conclusions ReDura patch showed the same versatility of autologous iliotibial tract. A dural patch that easily adapts to all defects, revealed to be a useful tool for performing watertight closure, possibly in a short operative time, after endoscopic approaches. PMID- 26937336 TI - Denervation of the Eustachian Tube and Hearing Loss Following Trigeminal Schwannoma Resection. AB - Objectives To discuss eustachian tube dysfunction (ETD) as a cause of hearing loss and to discuss its pathogenesis following resection of trigeminal schwannomas. Methods Presented herein are two cases of trigeminal schwannoma that were resected surgically with sacrifice of the motor branch of the trigeminal nerve. Neither of the cases had evidence of extracranial extension nor preoperative ETD. Both patients developed ETD and have been followed without evidence of schwannoma recurrence. Conclusions Trigeminal schwannomas are rare tumors that typically require surgical resection. Hearing loss is a potential postsurgical deficit and warrants evaluation by an otolaryngologist with consideration given to a preoperative audiogram. ETD as a result of trigeminal motor branch sacrifice should be included in the differential diagnosis of postoperative hearing loss in this patient subset as it may be reversed with placement of a tympanostomy tube. PMID- 26937337 TI - Corrigendum to 'Disseminated mucormycosis in a paediatric patient: Lictheimia corymbifera successfully treated with combination antifungal therapy' [Medical Mycology Case Reports (2014) 18-21]. AB - [This corrects the article DOI: 10.1016/j.mmcr.2014.08.002.]. PMID- 26937338 TI - Disseminated Chrysosporium infection in a German shepherd dog. AB - Disseminated Chrysosporium spp. infection was diagnosed in a German shepherd dog based on a positive fungal culture and cytological findings of intralesional fungi associated with granulomatous splenitis and neutrophilic lymphadenitis. The clinical presentation that could mimic a multicentric lymphoma, including markedly enlarged lymph nodes and a very abnormal splenic appearance on ultrasound makes this case even more atypical. The patient showed rapid clinical improvement on oral posaconazole and remains clinically stable ten months after diagnosis. PMID- 26937339 TI - Difficult diagnosis of invasive fungal infection predominantly involving the lower gastrointestinal tract in acute lymphoblastic leukaemia. AB - Invasive fungal infections are most commonly seen in immunocompromised patients and usually affect the respiratory system. Gastrointestinal system involvement of mucormycosis and invasive aspergillosis is rarely reported in childhood. Here we describe a 5 year old boy with acute lymphoblastic leukaemia who developed invasive fungal infection particularly affecting the lower gastrointestinal system to emphasise the difficulties in diagnosis and management of invasive fungal infections in immunocompromised patients. PMID- 26937340 TI - Micafungin in the treatment of candiduria: A case series. AB - Echinocandin antifungal agents are not routinely recommended for the treatment of candiduria due to low urine concentrations and a paucity of clinical data supporting this indication. This report presents five cases describing the use of micafungin for the treatment of candiduria. Each patient received parenteral micafungin for a minimum of 6 days and had resolution of baseline fungal within 30 days of treatment completion. PMID- 26937341 TI - Partial KCNQ1OT1 hypomethylation: A disguised familial Beckwith-Wiedemann syndrome as a sporadic adrenocortical tumor. AB - Beckwith-Wiedemann syndrome has a wide spectrum of complications such as embryonal tumors, namely adrenocortical tumor. Tumor predisposition is one of the most challenging manifestations of this syndrome. A 45-day old female with a family history of adrenocortical tumor presented with adrenocortical tumor. The case raised suspicion of a hereditary Beckwith-Wiedemann syndrome, therefore molecular analysis was undertaken. The results revealed partial KCNQ1OT1 hypomethylation in the infant's blood DNA which was associated with a complete loss of methylation in the infant's adrenocortical tumor tissue. It is unique for familial Beckwith-Wiedemann syndrome caused by KCNQ1OT1 partial hypomethylation to manifest solely through adrenocortical tumor. Incomplete penetrance and specific tissue mosaicism could provide explanations to this novel hereditary Beckwith-Wiedemann syndrome presentation. PMID- 26937343 TI - Precision medicine is here, break out your wallet. PMID- 26937342 TI - NGS meta data analysis for identification of SNP and INDEL patterns in human airway transcriptome: A preliminary indicator for lung cancer. AB - High-throughput sequencing of RNA (RNA-Seq) was developed primarily to analyze global gene expression in different tissues. It is also an efficient way to discover coding SNPs and when multiple individuals with different genetic backgrounds were used, RNA-Seq is very effective for the identification of SNPs. The objective of this study was to perform SNP and INDEL discoveries in human airway transcriptome of healthy never smokers, healthy current smokers, smokers without lung cancer and smokers with lung cancer. By preliminary comparative analysis of these four data sets, it is expected to get SNP and INDEL patterns responsible for lung cancer. A total of 85,028 SNPs and 5738 INDELs in healthy never smokers, 32,671 SNPs and 1561 INDELs in healthy current smokers, 50,205 SNPs and 3008 INDELs in smokers without lung cancer and 51,299 SNPs and 3138 INDELs in smokers with lung cancer were identified. The analysis of the SNPs and INDELs in genes that were reported earlier as differentially expressed was also performed. It has been found that a smoking person has SNPs at position 62,186,542 and 62,190,293 in SCGB1A1 gene and 180,017,251, 180,017,252, and 180,017,597 in SCGB3A1 gene and INDELs at position 35,871,168 in NFKBIA gene and 180,017,797 in SCGB3A1 gene. The SNPs identified in this study provides a resource for genetic studies in smokers and shall contribute to the development of a personalized medicine. This study is only a preliminary kind and more vigorous data analysis and wet lab validation are required. PMID- 26937345 TI - Editorial. PMID- 26937344 TI - Ethics education for clinician-researchers in genetics: The combined approach. AB - Advancements in genomic technology and genetic research have uncovered new and unforeseen ethical and legal issues that must now be faced by clinician researchers. However, lack of adequate ethical training places clinician researchers in a position where they might be unable to effectively assess and resolve the issues presented to them. The literature demonstrates that ethics education is relevant and engaging where it is targeted to the level and context of the learners, and it includes real-world based cases approached in innovative ways. In order to test the feasibility of a combined approach to ethics education, a conference was held in 2012 to raise awareness and familiarize participants with the ethical and legal issues surrounding medical technology in genetics and then to have them apply this to reality-based case studies. The conference included participants from a variety of backgrounds and was divided into three sections: (i) informative presentations by experts in the field; (ii) mock REB deliberations; and (iii) a second mock-REB, conducted by a panel of experts. Feedback from participants was positive and indicated that they felt the learning objectives had been met and that the material was presented in a clear and organized fashion. Although only an example of the combined approach in a particular setting, the success of this conference suggests that combining small group learning, practical cases, role-play and interdisciplinary learning provides a positive experience and is an effective approach to ethics education. PMID- 26937346 TI - Genetics, lifestyle and longevity: Lessons from centenarians. AB - Longevity as a complex life-history trait shares an ontogenetic relationship with other quantitative traits and varies among individuals, families and populations. Heritability estimates of longevity suggest that about a third of the phenotypic variation associated with the trait is attributable to genetic factors, and the rest is influenced by epigenetic and environmental factors. Individuals react differently to the environments that they are a part of, as well as to the environments they construct for their survival and reproduction; the latter phenomenon is known as niche construction. Lifestyle influences longevity at all the stages of development and levels of human diversity. Hence, lifestyle may be viewed as a component of niche construction. Here, we: a) interpret longevity using a combination of genotype-epigenetic-phenotype (GEP) map approach and niche construction theory, and b) discuss the plausible influence of genetic and epigenetic factors in the distribution and maintenance of longevity among individuals with normal life span on the one hand, and centenarians on the other. Although similar genetic and environmental factors appear to be common to both of these groups, exceptional longevity may be influenced by polymorphisms in specific genes, coupled with superior genomic stability and homeostatic mechanisms, maintained by negative frequency-dependent selection. We suggest that a comparative analysis of longevity between individuals with normal life span and centenarians, along with insights from population ecology and evolutionary biology, would not only advance our knowledge of biological mechanisms underlying human longevity, but also provide deeper insights into extending healthy life span. PMID- 26937347 TI - Exercise intensity modulates capillary perfusion in correspondence with ACE I/D modulated serum angiotensin II levels. AB - During exercise the renin-angiotensin system is stimulated. We hypothesized that the increase in serum angiotensin II (AngII) levels after exercise is dependent on exercise intensity and duration and secondly that people with the ACE-II genotype will show a higher increase in AngII serum levels. We also assumed that perfusion of upper limbs is transiently reduced with maximal cycling exercise and that subjects with the ACE-II compared to the ACE-ID/DD genotype will have a higher capillary perfusion due to lower AngII levels. Ten healthy subjects completed a maximal exercise test, a 12-min exercise test at ventilatory threshold and a 3-min test at the respiratory compensation point. AngII serum levels and capillary recruitment of the skin in the third finger were measured before and after exercise and breath-by-breath gas exchange during exercise was assessed. Baseline levels of AngII levels were lower prior to the 3-min test which took place on average 5 days after the last exercise. A two-fold increase compared to baseline levels was found for AngII only immediately after the 3-min test and not after the maximal exercise test and 12-min of exercise. Subjects without the I allele showed a decrease in AngII values after the maximal test in contrast to subjects with the ACE-II/ID genotype. Subjects with the ACE-II genotype had a 1.8 times significant higher capillary perfusion in the finger after exercise. A trend was observed for a 34.3% decreased capillary recruitment in the ACE-ID/DD genotype after exercise. We conclude that the rise in AngII after exercise is intensity dependent and that variability in serum AngII and capillary perfusion is related to the ACE I/D polymorphism. PMID- 26937348 TI - Patients' views on incidental findings from clinical exome sequencing. AB - This article characterizes the opinions of patients and family members of patients undergoing clinical genomic-based testing regarding the return of incidental findings from these tests. Over sixteen months, we conducted 55 in depth interviews with individuals to explore their preferences regarding which types of results they would like returned to them. Responses indicate a diversity of attitudes toward the return of incidental findings and a diversity of justifications for those attitudes. The majority of participants also described an imperative to include the patient in deciding which results to return rather than having universal, predetermined rules governing results disclosure. The results demonstrate the importance of a patient centered-approach to returning incidental findings. PMID- 26937349 TI - The lifestylisation of healthcare? 'Consumer genomics' and mobile health as technologies for healthy lifestyle. AB - Consumer genomics and mobile health provide health-related information to individuals and offer advice for lifestyle change. These 'technologies for healthy lifestyle' occupy an ambiguous space between the highly regulated medical domain and the less regulated consumer market. We argue that this ambiguity challenges implicit distinctions between what is medical and what is related to personal lifestyle choices within current regulatory systems. In this article, we discuss how consumer genomics and mobile health devices give rise to new ways of creating (and making sense of) health-related knowledge. We also address some of the implications of harnessing, rather than denying, the hybridity of mobile health devices, being situated between medical devices and consumer products, between health and lifestyle. PMID- 26937351 TI - Applied and translational neurogenomics. PMID- 26937350 TI - Nutrigenomics: A controversy. AB - Nutrigenomics is an emerging science which investigates a certain area of nutrition that uses molecular tools to search access and understand the several responses obtained through a certain diet applied between individual and population groups. The increased need for the use of personalised nutrition in patients is increasing and research is being made on its possible effects. However, research on nutrigenomics and in particular, obesity is still ongoing. Following a current metanalysis on thirty-eight nutrigenomics genes, it seems that a definite association between the genes usually examined in nutrigenomics testing and several diet-related diseases is lacking, even though there is a limited number of studies associating them. In 2014, literature search results in a great number of studies on several polymorphisms. This heterogeneity could only show the way towards new research aims. Nutrigenomics was born due to the need to move from Epidemiology and Physiology to Molecular Biology and Genetics. Currently, there are steps that need to be considered in order for nutrigenomics to be applied: the genes, the gene/protein network, and the strategy towards the determination of the nutrients' influence on gene/protein expression. It is certainly an interesting evolving science with many areas to be investigated further and from different perspectives, as it involves ethics, medicine, genetics and nutrition. PMID- 26937353 TI - Neurogenomics: An Egyptian perspective. PMID- 26937352 TI - Neurogenomics: An opportunity to integrate neuroscience, genomics and bioinformatics research in Africa. AB - Modern genomic approaches have made enormous contributions to improving our understanding of the function, development and evolution of the nervous system, and the diversity within and between species. However, most of these research advances have been recorded in countries with advanced scientific resources and funding support systems. On the contrary, little is known about, for example, the possible interplay between different genes, non-coding elements and environmental factors in modulating neurological diseases among populations in low-income countries, including many African countries. The unique ancestry of African populations suggests that improved inclusion of these populations in neuroscience related genomic studies would significantly help to identify novel factors that might shape the future of neuroscience research and neurological healthcare. This perspective is strongly supported by the recent identification that diseased individuals and their kindred from specific sub-Saharan African populations lack common neurological disease-associated genetic mutations. This indicates that there may be population-specific causes of neurological diseases, necessitating further investigations into the contribution of additional, presently-unknown genomic factors. Here, we discuss how the development of neurogenomics research in Africa would help to elucidate disease-related genomic variants, and also provide a good basis to develop more effective therapies. Furthermore, neurogenomics would harness African scientists' expertise in neuroscience, genomics and bioinformatics to extend our understanding of the neural basis of behaviour, development and evolution. PMID- 26937354 TI - Neurogenethics: An emerging discipline at the intersection of ethics, neuroscience, and genomics. AB - The analysis of ethical, legal, and social implications (ELSI) associated with genetics ("genethics") has focused on traditional concerns in bioethics, such as privacy and informed consent. The analysis of ELSI associated with neuroscience ("neuroethics") has focused on concerns related to personhood, such as free will or cognitive enhancement. With neurogenomics coming of age, this is an appropriate time to attend to the set of novel concerns that arises when we consider the confluence of these two lines of research. I call this area of ethics inquiry "neurogenethics", map out the problem space, and highlight future areas of inquiry related to genome editing and gene therapy, optogenetics and memory manipulation, and genomic identity and online communities. PMID- 26937356 TI - Investigation of redox status in chronic cerebral hypoperfusion-induced neurodegeneration in rats. AB - Aging related reduction in cerebral blood flow (CBF) has been linked with neurodegenerative disorders including Alzheimer's disease and dementia. Experimentally, a condition of chronic cerebral hypoperfusion due to reduced CBF can be induced by permanent bilateral occlusion of common carotid arteries (2 vessel occlusion, 2VO) in rats. Since oxidative stress, leading to neuronal apoptosis and death, is one of the mechanisms, which is thought to play a significant role in chronic degenerative neurological disorders, the present study was planned to assess the ROS status by measuring the levels of anti oxidant enzymes that might occur during chronic cerebral hypoperfusion. Antioxidant enzymes namely glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase were measured in the brain tissue at eight weeks of 2VO induction in rats. Results show significantly elevated levels of GPx, SOD, and catalase enzymes as compared with the control group. It is possible that compensatory rise in antioxidant enzymes occurs in response to increased oxidative stress following ischemic insult. PMID- 26937355 TI - Ethical issues associated with genetic counseling in the context of adolescent psychiatry. AB - Genetic counseling is a well-established healthcare discipline that provides individuals and families with health information about disorders that have a genetic component in a supportive counseling encounter. It has recently been applied in the context of psychiatric disorders (like schizophrenia, bipolar disorder, schizoaffective disorder, obsessive compulsive disorder, depression and anxiety) that typically appear sometime during later childhood through to early adulthood. Psychiatric genetic counseling is emerging as an important service that fills a growing need to reframe understandings of the causes of mental health disorders. In this review, we will define psychiatric genetic counseling, and address important ethical concerns (we will particularly give attention to the principles of autonomy, beneficence, non-maleficence and justice) that must be considered in the context of its application in adolescent psychiatry, whilst integrating evidence regarding patient outcomes from the literature. We discuss the developing capacity and autonomy of adolescents as an essential and dynamic component of genetic counseling provision in this population and discuss how traditional viewpoints regarding beneficence and non-maleficence should be considered in the unique situation of adolescents with, or at risk for, psychiatric conditions. We argue that thoughtful and tailored counseling in this setting can be done in a manner that addresses the important health needs of this population while respecting the core principles of biomedical ethics, including the ethic of care. PMID- 26937357 TI - Targeted NGS meets expert clinical characterization: Efficient diagnosis of spastic paraplegia type 11. AB - Next generation sequencing (NGS) is transforming the diagnostic approach for neurological disorders, since it allows simultaneous analysis of hundreds of genes, even based on just a broad, syndromic patient categorization. However, such an approach bears a high risk of incidental and uncertain genetic findings. We report a patient with spastic paraplegia whose comprehensive neurological and imaging examination raised a high clinical suspicion of SPG11. Thus, although our NGS pipeline for this group of disorders includes gene panel and exome sequencing, in this sample only the spatacsin gene region was captured and subsequently searched for mutations. Two probably pathogenic variants were quickly and clearly identified, confirming the diagnosis of SPG11. This case illustrates how combination of expert clinical characterization with highly oriented NGS protocols leads to a fast, cost-efficient diagnosis, minimizing the risk of findings with unclear significance. PMID- 26937358 TI - NDUFA12L mitochondrial complex-I assembly factor: Implications for taupathies. AB - There is a strong correlation between taupathies and the development and progression of neurodegenerative disorders. Abnormal tau becomes hyperphosphorylated and dissociated from microtubules with the aggregation of intracellular tau aggregates within the patient's brain. The current review is divided into two broad sections. In the first section we discuss the molecular biology and the clinicopathologic features of taupathies. While in the second section we discuss the relationship between mitochondrial complex-I and taupathies. Polymorphism in NDUFA12L may be a crucial factor for development of neurodegenerative taupathies. Thus NDUFA12L screening may be an early biomarker for identifying risk groups for such disorders. PMID- 26937359 TI - Risperidone-associated adverse drug reactions and CYP2D6 polymorphisms in a South African cohort. AB - BACKGROUND: Contradictory information exists regarding the influence of CYP2D6 polymorphisms on adverse drug reactions (ADRs) (extrapyramidal symptoms (EPS) and weight gain) related to risperidone treatment. This prompted us to evaluate the influence of CYP2D6 genetic variation in a cohort of South African patients who presented with marked movement disorders and/or weight gain while on risperidone treatment. METHODS: Patients who were experiencing marked risperidone ADRs were recruited from Weskoppies Public Psychiatric Hospital. As poor or intermediate metabolism was expected, comprehensive CYP2D6 sequence variations were evaluated using XL-PCR + Sequencing. RESULTS: No statistically significant association was found between CYP2D6 poor metabolism and risperidone ADRs. An inverse relationship between EPS and weight gain was however identified. A novel CYP2D6 allele was identified which is unlikely to affect metabolism based on in silico evaluation. CONCLUSION: CYP2D6 variation appeared not to be a good pharmacogenetic marker for predicting risperidone-related ADRs in this naturalistic South African cohort. Evaluation of a larger cohort would be needed to confirm these observations, including an examination of the role of potential intermediaries between the hypothesised genetic and clinical phenotypes. PMID- 26937360 TI - The clinical validity and utility of combinatorial pharmacogenomics: Enhancing patient outcomes. AB - Prescribing safe and effective medications is a challenge in psychiatry. While clinical use of pharmacogenomic testing for individual genes has provided some clinical benefit, it has largely failed to show clinical utility. However, pharmacogenomic testing that integrates relevant genetic variation from multiple loci for each medication has shown clinical validity, utility and cost savings in multiple clinical trials. While some challenges remain, the evidence for the clinical utility of "combinatorial pharmacogenomics" is mounting. Expanding education of pharmacogenomic testing is vital to implementation efforts in psychiatric treatment settings with the overall goal of improving medication selection decisions. PMID- 26937361 TI - Impact factors and its relevance in dentistry. PMID- 26937362 TI - Surface properties and early murine pre-osteoblastic cell responses of phosphoric acid modified titanium surface. AB - AIMS: The present study investigated the surface properties and murine pre osteoblast cell (MC3T3-E1) responses of phosphoric acid (H3PO4) treated commercially pure titanium. METHODS: Titanium discs were treated with various concentration of H3PO4 (5%, 10%, and 20%; v/v) at 90 degrees C for 30 min. Surface properties were evaluated by profilometer, contact angle meter, and scanning electron microscopy (SEM) with energy dispersive X-rays. MC3T3-E1 attachment and spreading were evaluated by SEM and phalloidin immunohistochemistry staining. RESULTS: Surface roughness and wettability were not statistically difference among all experimental and control groups. Phosphate and oxygen were detected on H3PO4 treated surfaces. At 20 min, cell attachment was significantly higher in 10% and 20% H3PO4 treated groups compared to the control. Cells exhibited orientated-cytoskeleton fibers on 20% H3PO4 modified titanium surface. Though, there was no difference in cell spreading stage among all treatment groups. CONCLUSION: H3PO4 treatment on titanium may influence early cell response, particularly on attachment and spreading. PMID- 26937363 TI - In vivo association of immunophenotyped macrophages expressing CD163 with PDGF-B in gingival overgrowth-induced by three different categories of medications. AB - AIMS: This study was carried out to identify and outline the degree of relationship between immunophenotyped macrophages expressing CD163 and PDGF-B in cyclosporine-A, phenytoin, and nifedipine-induced gingival overgrowth. METHODS: Eighty adult male albino rats were selected and divided into four equal groups. Group I received no treatment. Rats of groups II, III, and IV were administered cyclosporine-A, phenytoin, and nifedipine, respectively. Routine tissue processing was carried out for staining with CD163 and PDGF-B. The results of this study were analyzed statistically. RESULTS: Group I exhibited score 0 gingival overgrowth while group II yielded score 3 with blunt and bulbous gingival crests. Rats of group III showed score 2 with knife edge and group IV revealed less pronounced gingival overgrowth and mostly the gingival crest was knife edge. Group II had the highest mean value for CD163 while group I showed the lowest value. In addition, group II had the highest mean value for PDGF-B while group I showed the lowest value. Statistically, there was an overall significant difference between the studied groups as well as between each two groups. CONCLUSION: Strong association exists between immunophenotyped macrophages expressing CD163 and PDGF-B in GO induced by these medications. In addition, CD163 and PDGF-B upregulated in cyclosporine-A-induced GO compared to phenytoin and nifedipine medications. PMID- 26937364 TI - Clinicopathological correlation of Bcl-2 oncoprotein expression in oral precancer and cancer. AB - Oral squamous cell carcinoma is the most common malignant tumor of the oral cavity. Normally the death of cell and the growth are active processes and depend not only on external factors but also on the expression of genes such as Bcl-2, which activate and inhibit apoptosis. The term Bcl-2 is an acronym for B-cell lymphoma/leukemia-2 genes. It has been reported that there is deregulation of Bcl 2 expression during progression from oral epithelial dysplasia to squamous cell carcinoma. Expression of this oncoprotein can be detected by immunohistochemistry. AIMS AND OBJECTIVES: An attempt was made to evaluate Bcl-2 oncoprotein expression in patients with oral precancer and cancer. MATERIALS AND METHODS: A selective prospective clinical and immunohistochemical study. Clinicopathological examination was correlated with immunohistochemical findings. The immunolocalization of Bcl-2 protein was performed using the labeled streptavidin biotin method. To visualize the reaction, 3,3-diaminobenzidine was used. RESULTS: Bcl-2 expression was positive in 11 [36.66%, low Bcl-2 expression 3 (10.00%), moderate Bcl-2 expression 7 (23.33%), and high Bcl-2 expression 1 (3.33%)] oral cancer cases and 14 [87.50%, low expression 8 (50%), moderate expression 6 (37.50%)] precancer cases. CONCLUSION: On the basis of the results of our study, we conclude that positive Bcl-2 expression may be an indicator of poor prognosis in oral cancer and precancer. PMID- 26937365 TI - Expression of GLUT-1 in oral squamous cell carcinoma in tobacco and non-tobacco users. AB - BACKGROUND: GLUTs are a family of proteins that mediate glucose transport through the membrane, expressed in head and neck squamous cell carcinoma. GLUT-1 positivity in malignant cells indicates increased proliferative activity, energy requirements, aggressive behaviour and poor radiation response. AIM: To observe the expression of GLUT-1 protein in oral squamous cell carcinoma in tobacco and non-tobacco users and to correlate the expression with histopathological grading and pathological staging. METHODS: 50 cases (25 tobacco and 25 non-tobacco) of oral squamous cell carcinoma, selected during period of August 2014 to July 2015. Histopathological grading, TNM and staging were done. Immunohistochemical staining was performed using standard protocol for paraffin embedded sections. Analysis was performed on SPSS software (Windows version 17.0). RESULTS: Significant association of GLUT-1 expression was found with history of tobacco (p < 0.001), Bryne's grade (p < 0.001), tumour size (p = 0.001), nodal metastasis (p = 0.022) and stage (p < 0.001). Higher GLUT-1 expression in stage II, stage III and stage IV was found as compared to stage I. GLUT-1 immunoexpression also shows progressive switch from membranous to cytoplasmic to combined location correlating with histopathologic grade and pTNM stage. CONCLUSION: GLUT-1 expression correlates significantly with histological grade and pTNM staging of oral squamous cell carcinoma. It also significantly correlates with tobacco addiction. Thus, GLUT-1 expression may serve as a biomarker for patients of oral squamous cell carcinoma. PMID- 26937366 TI - Clinico-epidemiological study of oral squamous cell carcinoma: A tertiary care centre study in North India. AB - INTRODUCTION: Oral squamous cell carcinoma (OSCC) ranks 12th most common cancer in the world. OBJECTIVE: The aim of this study was to retrospectively evaluate the OSCC. METHODS: A retrospective study of 611 OSCC patients from January 2010 to December 2013 was carried out in Department of Surgical Oncology, King George's Medical University, Lucknow, India. Details of patient's sex, age, tobacco habit and site of cancer were noted. Data were analyzed by Student's t test and chi-squire (chi (2)) test. RESULTS: The prevalence of OSCC was significantly (p < 0.001) higher in males (75.9%) than females (24.1%). The mean age of female patients was higher than males (p < 0.001). In both the genders, the buccal mucosa and gingivobuccal sulcus were found to be the most affected sites. Moreover, the smokeless form of tobacco was found to be significantly associated with OSCC, especially in females. CONCLUSION: The study concluded that OSCC is more common in men as compared to women, probably due to habit of tobacco consumption. Smokeless tobacco use is an important risk factor, especially in females. PMID- 26937368 TI - Role of salivary malondialdehyde in assessment of oxidative stress among diabetics. AB - AIMS: To evaluate and compare the salivary content of malondialdehyde (MDA) in patients with type 2 diabetes and control subjects. METHODS: We conducted a cross sectional study among 30 freshly diagnosed subjects of diabetes mellitus and 30 volunteers with no diabetes mellitus. Serum and salivary MDS levels were evaluated among all the subjects. RESULTS: The mean serum MDA in group controls and diabetics was 0.95 +/- 0.13 and 3.11 +/- 0.42. The mean salivary MDA in group controls and diabetics was 0.26 +/- 0.05 MUmol/l and 0.81 +/- 0.07 MUmol/l. The mean serum and salivary MDA levels were significantly higher in group diabetics than control group (p < 0.001 and <0.001) respectively. There was significant positive strong correlation between serum and salivary MDA levels in both controls and diabetics groups (r = 0.857, p < 0.001 and r = 0.891, p < 0.001) respectively. CONCLUSION: MDA was detectable in saliva in both diabetic and control groups. There was a positive significant correlation between salivary and serum MDA in diabetic and control subjects. Hence, salivary MDA appears to be an indicator of serum MDA concentration. PMID- 26937367 TI - Management of mandibular angle fractures using a 1.7 mm 3-dimensional strut plate. AB - AIM: We report our experience with the use of 1.7 mm 3-dimentional (3D) strut plate for the management of mandibular angle fractures. METHODS: This prospective study enrolled 15 patients in whom mandibular angle fractures were treated with 1.7 mm 3D plate using trans-buccal trochar. Patients were evaluated at 72 h, 2 weeks, 6 weeks and 12 weeks for fracture stability, occlusion, soft-tissue swelling, infection and post-operative inferior alveolar nerve damage. Other complications like wound dehiscence, non-union, mal-union and hardware failure were also assessed. RESULTS: In the immediate post-operative period, fracture instability was seen in 1 (6.7%) patient which resolved by 2 weeks. Mild occlusal discrepancy was also noted in 1 (6.7%) patient. Wound dehiscence was seen in 5 (33.3%) patients and all resolved by local measures. 1 (6.7%) patient developed post-operative nerve paraesthesia. Immediate post-operative radiographic evaluation demonstrated optimal reduction in all cases with no inferior border gaping. No case of infection, hardware failure, non-union and mal-union was noted. CONCLUSION: Within the limitations of the study, 1.7 mm 3D strut plate was found to be effective for management of non-communited mandibular angle fractures. PMID- 26937369 TI - Comparative antimicrobial efficacy of herbal alternatives (Emblica officinalis, Psidium guajava), MTAD, and 2.5% sodium hypochlorite against Enterococcus faecalis: An in vitro study. AB - AIM: The objective of this study was to evaluate the antimicrobial efficacy of herbal alternatives (Emblica officinalis, Psidium guajava), BioPure MTAD, and 2.5% sodium hypochlorite against Enterococcus faecalis. MATERIALS AND METHOD: The testing of the antimicrobial efficacy of selected medicaments against E. faecalis was done by the agar disk-diffusion method. Whatman paper discs of 6 mm diameter were prepared and soaked with the test solution. These discs were then placed onto the previously seeded agar Petri plates. Later, these plates were incubated for 48 h at 37 degrees C under the appropriate gaseous conditions in a CO2 incubator. A zone of inhibition was recorded in millimeter for each plate and the results were analyzed statistically. RESULT: MTAD was found to be superior in its antibacterial abilities against E. faecalis compared with the other irrigants used. All the other tested irrigants showed significant zone of inhibition. CONCLUSIONS: BioPure MTAD offers better antibacterial efficacy than NaOCl. E. officinalis and P. guajava are effective antibacterial agents against E. faecalis and can be used to reduce root canal microflora and root canal failures. PMID- 26937370 TI - Effect of carbonated drinks on wound healing of oral epithelium. AB - BACKGROUND: Carbonated drinks are the second most consumed non-alcoholic beverages in the world after tea. The effects of these drinks on hard tissues and vital organs of the body have been proved beyond doubt. This study, however, explains the effect of these drinks on wound healing of oral epithelium. METHODS: Thirty-six male Wistar rats were considered for the study. A circular wound of 3.0 mm was created on the buccal mucosa of all animals and they were divided into two groups. Animals in group 1 were fed with chow pellet and water, while those in group 2 were fed with a commercially available carbonated drink instead of water. Six animals from each group were euthanized at 0, 7, and 21 days. Wound site was histologically assessed for differences in thickness and characteristics of the regenerating epithelium between two groups. RESULTS: There was a marked difference in the healing pattern between the two groups. Animals in group 1 showed a normal healing pattern at the end of day 21. In the group 2, the regenerated epithelium showed hyperplasia and hyperkeratosis along with acanthosis at the end of the experiment with a subsequent delayed inflammatory reaction at day 21. CONCLUSION: Consumption of carbonated drinks can disrupt oral wound healing. The contents in carbonated drinks have a proinflammatory action on the soft tissue. Results suggest that epithelial changes seen in experimental group 2 could be a result of constant irritation by the acidic and fizzy nature of carbonated drinks. PMID- 26937371 TI - Effect of Aloe vera, chlorine dioxide, and chlorhexidine mouth rinses on plaque and gingivitis: A randomized controlled trial. AB - OBJECTIVE: To evaluate the effect of Aloe vera, chlorine dioxide, and chlorhexidine mouth rinses on plaque and gingivitis in orthodontic treatment. MATERIALS AND METHODS: A randomized single-center, single-blind, parallel group, controlled trial was conducted among 90 subjects undergoing fixed orthodontic treatment. The subjects were randomly divided into one of the three study groups (Aloe vera, chlorhexidine, chlorine dioxide). Plaque and gingivitis were assessed using modified Silness and Loe Plaque Index and Gingival Index at baseline and at follow-up after 15 days. Paired t-test and ANOVA with post hoc Dunnett test were used. A p-value of <0.05 was considered statistically significant. RESULTS: A total of 85 participants completed the study; among them, 40 were male and 45 were female. There was significant reduction in mean plaque and gingival scores in all the 3 groups at follow-up when compared to baseline. A significantly higher reduction (plaque and gingival scores) was found in chlorhexidine when compared with the Aloe vera group. However, no significant difference was seen between chlorhexidine and chlorine dioxide with respect to mean reduction in plaque and gingival scores. CONCLUSION: Chlorine dioxide can be a suitable and economical alternative for chlorhexidine. Further long-term studies are recommended for evaluating their effectiveness. PMID- 26937372 TI - Proposal for a simple and effective diagrammatic representation of root canal configuration for better communication amongst oral radiologists and clinicians. AB - OBJECTIVES: Root canal anatomy has been proved to be a complex canal configuration system. The negotiation and cleaning of this system is essential for successful root canal treatment. The present root canal classification systems are unable to transfer the clinically relevant information about the canal system from the oral radiologist to the treating clinician. Thus, a simple and effective diagrammatic representation of the canal system, depicting the major canals, important changes during their course along with other relevant information has been presented. METHODS: The proposed representation consists of five horizontal lines dividing the tooth into four segments from the point of reference to apical foramen. Each line has been designated with different line style. The diagrammatic images, one anterior and one posterior multi-rooted tooth, are given for easy understanding of the orientation of image. The whole image can be saved in portable network graphics format and can be imported to any word processing document. The image can be printed in the reporting sheet. RESULT: Applying the same proposal, some of the diagrammatic representations have been showed. CONCLUSION: This proposal for diagrammatic representation of root canal configuration can be helpful in getting an approximate distribution of the canals in a relatively simple manner. This scheme also provides valuable clinical information about the root canal system, which the other classifications fail to represent. PMID- 26937374 TI - The versatility of spandex photographic retractor for transoral surgical procedures. AB - The trend toward transoral access, be it for pathology or facial cosmetic surgery, has become increasingly popular over the last two decades with facial incisions being used more and more sporadically than otherwise. Transoral access because of its inherent limitations, retraction of the oral and perioral tissues without inducing physical or thermal injury makes it a daunting task for the operating surgeon. The use of conventional retractors in conjunction with surgical instruments can lead to inadvertent injury to the perioral tissues resulting in untoward postoperative sequelae leading to patient discomfort and delayed recovery. This article elucidates the versatility of a simple photographic retractor (spandex) as a useful adjunctive tool in the retraction and protection of the perioral tissues for almost all transoral surgical procedures. PMID- 26937373 TI - Saliva as a diagnostic tool for oral and systemic diseases. AB - Early disease detection is not only vital to reduce disease severity and prevent complications, but also critical to increase success rate of therapy. Saliva has been studied extensively as a potential diagnostic tool over the last decade due to its ease and non-invasive accessibility along with its abundance of biomarkers, such as genetic material and proteins. This review will update the clinician on recent advances in salivary biomarkers to diagnose autoimmune diseases (Sjogren's syndrome, cystic fibrosis), cardiovascular diseases, diabetes, HIV, oral cancer, caries and periodontal diseases. Considering their accuracy, efficacy, ease of use and cost effectiveness, salivary diagnostic tests will be available in dental offices. It is expected that the advent of sensitive and specific salivary diagnostic tools and the establishment of defined guidelines and results following rigorous testing will allow salivary diagnostics to be used as chair-side tests for several oral and systemic diseases in the near future. PMID- 26937375 TI - Witkop's syndrome: A case report. AB - Witkop's syndrome is a rare autosomal dominant disorder characterized by tooth and nail abnormalities. It is a variant of ectodermal dysplasia, which is thought to occur in approximately 1 in 100,000 live births. Thus, such a low occurrence and paucity of clearly delineating features make its identification in general population a real challenge. This case report aims to add to the existing literature a commonsense approach of identifying the uncommon thing. PMID- 26937376 TI - Clinical and MRI models predicting amyloid deposition in progressive aphasia and apraxia of speech. AB - Beta-amyloid (Abeta) deposition can be observed in primary progressive aphasia (PPA) and progressive apraxia of speech (PAOS). While it is typically associated with logopenic PPA, there are exceptions that make predicting Abeta status challenging based on clinical diagnosis alone. We aimed to determine whether MRI regional volumes or clinical data could help predict Abeta deposition. One hundred and thirty-nine PPA (n = 97; 15 agrammatic, 53 logopenic, 13 semantic and 16 unclassified) and PAOS (n = 42) subjects were prospectively recruited into a cross-sectional study and underwent speech/language assessments, 3.0 T MRI and C11-Pittsburgh Compound B PET. The presence of Abeta was determined using a 1.5 SUVR cut-point. Atlas-based parcellation was used to calculate gray matter volumes of 42 regions-of-interest across the brain. Penalized binary logistic regression was utilized to determine what combination of MRI regions, and what combination of speech and language tests, best predicts Abeta (+) status. The optimal MRI model and optimal clinical model both performed comparably in their ability to accurately classify subjects according to Abeta status. MRI accurately classified 81% of subjects using 14 regions. Small left superior temporal and inferior parietal volumes and large left Broca's area volumes were particularly predictive of Abeta (+) status. Clinical scores accurately classified 83% of subjects using 12 tests. Phonological errors and repetition deficits, and absence of agrammatism and motor speech deficits were particularly predictive of Abeta (+) status. In comparison, clinical diagnosis was able to accurately classify 89% of subjects. However, the MRI model performed well in predicting Abeta deposition in unclassified PPA. Clinical diagnosis provides optimum prediction of Abeta status at the group level, although regional MRI measurements and speech and language testing also performed well and could have advantages in predicting Abeta status in unclassified PPA subjects. PMID- 26937377 TI - Brain lesion-pattern analysis in patients with olfactory dysfunctions following head trauma. AB - The presence of cerebral lesions in patients with neurosensory alterations provides a unique window into brain function. Using a fuzzy logic based combination of morphological information about 27 olfactory-eloquent brain regions acquired with four different brain imaging techniques, patterns of brain damage were analyzed in 127 patients who displayed anosmia, i.e., complete loss of the sense of smell (n = 81), or other and mechanistically still incompletely understood olfactory dysfunctions including parosmia, i.e., distorted perceptions of olfactory stimuli (n = 50), or phantosmia, i.e., olfactory hallucinations (n = 22). A higher prevalence of parosmia, and as a tendency also phantosmia, was observed in subjects with medium overall brain damage. Further analysis showed a lower frequency of lesions in the right temporal lobe in patients with parosmia than in patients without parosmia. This negative direction of the differences was unique for parosmia. In anosmia, and also in phantosmia, lesions were more frequent in patients displaying the respective symptoms than in those without these dysfunctions. In anosmic patients, lesions in the right olfactory bulb region were much more frequent than in patients with preserved sense of smell, whereas a higher frequency of carriers of lesions in the left frontal lobe was observed for phantosmia. We conclude that anosmia, and phantosmia, are the result of lost function in relevant brain areas whereas parosmia is more complex, requiring damaged and intact brain regions at the same time. PMID- 26937378 TI - Delay of cognitive gamma responses in Alzheimer's disease. AB - Event-related oscillations (EROs) reflect cognitive brain dynamics, while sensory evoked oscillations (SEOs) reflect sensory activities. Previous reports from our lab have shown that those with Alzheimer's disease (AD) or mild cognitive impairment (MCI) have decreased activity and/or coherence in delta, theta, alpha and beta cognitive responses. In the current study, we investigated gamma responses in visual SEO and ERO in 15 patients with AD and in 15 age-, gender- and education-matched healthy controls. The following parameters were analyzed over the parietal-occipital regions in both groups: (i) latency of the maximum gamma response over a 0-800 ms time window; (ii) the maximum peak-to-peak amplitudes for each participant's averaged SEO and ERO gamma responses in 3 frequency ranges (25-30, 30-35, 40-48 Hz); and (iii) the maximum peak-to-peak amplitudes for each participant's averaged SEO and ERO gamma responses over a 0 800 ms time block containing four divided time windows (0-200, 200-400, 400-600, and 600-800 ms). There were main group effects in terms of both latency and peak to-peak amplitudes of gamma ERO. However, peak-to-peak gamma ERO amplitude differences became noticeable only when the time block was divided into four time windows. SEO amplitudes in the 25-30 Hz frequency range of the 0-200 ms time window over the left hemisphere were greater in the healthy controls than in those with AD. Gamma target ERO latency was delayed up to 138 ms in AD patients when compared to healthy controls. This finding may be an effect of lagged neural signaling in cognitive circuits, which is reflected by the delayed gamma responses in those with AD. Based on the results of this study, we propose that gamma responses should be examined in a more detailed fashion using multiple frequency and time windows. PMID- 26937379 TI - The development of automatic emotion regulation in an implicit emotional Go/NoGo paradigm and the association with depressive symptoms and anhedonia during adolescence. AB - Impaired automatic emotion regulation (AER) is closely related to major depressive disorder. Our research in adults has identified two AER-related components, Go N2 and NoGo P3, in an implicit emotional Go/NoGo paradigm. However, it is unclear whether Go N2 and NoGo P3 reflect the development of AER in adolescents and the relationship of these components with subclinical depressive symptoms and trait anhedonia. We collected EEG data from 55 adolescents while they completed the implicit emotional Go/NoGo task. After the experiment, the subjects completed the Chinese version of the Temporal Experience of Pleasure Scale and the Beck Depression Inventory. Consistent with results in adults, we determined that Go N2 represents automatic top-down attention to emotions in Go trials, whereas NoGo P3 represents automatic response inhibition in NoGo trials. These AER components exhibited age-dependent improvement during adolescence. Additionally, NoGo P3 amplitudes elicited by viewing positive faces were positively correlated with trait anhedonia, whereas NoGo P3 amplitudes elicited by viewing negative faces were negatively correlated with depressive symptoms. Our observations provide further understanding of the neurodevelopmental mechanism of AER and yield new insight into dissociable impairments in AER in adolescents with major depressive disorder during positive and negative implicit processing. PMID- 26937380 TI - Wavelet coherence analysis of dynamic cerebral autoregulation in neonatal hypoxic ischemic encephalopathy. AB - Cerebral autoregulation represents the physiological mechanisms that keep brain perfusion relatively constant in the face of changes in blood pressure and thus plays an essential role in normal brain function. This study assessed cerebral autoregulation in nine newborns with moderate-to-severe hypoxic-ischemic encephalopathy (HIE). These neonates received hypothermic therapy during the first 72 h of life while mean arterial pressure (MAP) and cerebral tissue oxygenation saturation (SctO2) were continuously recorded. Wavelet coherence analysis, which is a time-frequency domain approach, was used to characterize the dynamic relationship between spontaneous oscillations in MAP and SctO2. Wavelet based metrics of phase, coherence and gain were derived for quantitative evaluation of cerebral autoregulation. We found cerebral autoregulation in neonates with HIE was time-scale-dependent in nature. Specifically, the spontaneous changes in MAP and SctO2 had in-phase coherence at time scales of less than 80 min (< 0.0002 Hz in frequency), whereas they showed anti-phase coherence at time scales of around 2.5 h (~ 0.0001 Hz in frequency). Both the in phase and anti-phase coherence appeared to be related to worse clinical outcomes. These findings suggest the potential clinical use of wavelet coherence analysis to assess dynamic cerebral autoregulation in neonatal HIE during hypothermia. PMID- 26937381 TI - Profiles of aberrant white matter microstructure in fragile X syndrome. AB - Previous studies attempting to quantify white matter (WM) microstructure in individuals with fragile X syndrome (FXS) have produced inconsistent findings, most likely due to the various control groups employed, differing analysis methods, and failure to examine for potential motion artifact. In addition, analyses have heretofore lacked sufficient specificity to provide regional information. In this study, we used Automated Fiber-tract Quantification (AFQ) to identify specific regions of aberrant WM microstructure along WM tracts in patients with FXS that differed from controls who were matched on age, IQ and degree of autistic symptoms. Participants were 20 patients with FXS, aged 10 to 23 years, and 20 matched controls. Using Automated Fiber-tract Quantification (AFQ), we created Tract Profiles of fractional anisotropy and mean diffusivity along 18 major WM fascicles. We found that fractional anisotropy was significantly increased in the left and right inferior longitudinal fasciculus (ILF), right uncinate fasciculus, and left cingulum hippocampus in individuals with FXS compared to controls. Conversely, mean diffusivity was significantly decreased in the right ILF in patients with FXS compared to controls. Age was significantly negatively associated with MD values across both groups in 11 tracts. Taken together, these findings indicate that FXS results in abnormal WM microstructure in specific regions of the ILF and uncinate fasciculus, most likely caused by inefficient synaptic pruning as a result of decreased or absent Fragile X Mental Retardation Protein (FMRP). Longitudinal studies are needed to confirm these findings. PMID- 26937382 TI - Altered white matter and cortical structure in neonates with antenatally diagnosed isolated ventriculomegaly. AB - Ventriculomegaly (VM) is the most common central nervous system abnormality diagnosed antenatally, and is associated with developmental delay in childhood. We tested the hypothesis that antenatally diagnosed isolated VM represents a biological marker for altered white matter (WM) and cortical grey matter (GM) development in neonates. 25 controls and 21 neonates with antenatally diagnosed isolated VM had magnetic resonance imaging at 41.97(+/- 2.94) and 45.34(+/- 2.14) weeks respectively. T2-weighted scans were segmented for volumetric analyses of the lateral ventricles, WM and cortical GM. Diffusion tensor imaging (DTI) measures were assessed using voxel-wise methods in WM and cortical GM; comparisons were made between cohorts. Ventricular and cortical GM volumes were increased, and WM relative volume was reduced in the VM group. Regional decreases in fractional anisotropy (FA) and increases in mean diffusivity (MD) were demonstrated in WM of the VM group compared to controls. No differences in cortical DTI metrics were observed. At 2 years, neurodevelopmental delays, especially in language, were observed in 6/12 cases in the VM cohort. WM alterations in isolated VM cases may be consistent with abnormal development of WM tracts involved in language and cognition. Alterations in WM FA and MD may represent neural correlates for later neurodevelopmental deficits. PMID- 26937383 TI - Language at rest: A longitudinal study of intrinsic functional connectivity in preterm children. AB - BACKGROUND: Preterm (PT) children show early cognitive and language deficits and display altered cortical connectivity for language compared to term (T) children. Developmentally, functional connectivity networks become more segregated and integrated, through the weakening of short-range and strengthening of long-range connections. METHODS: Longitudinal intrinsic connectivity distribution (ICD) values were assessed in PT (n = 13) compared to T children (n = 12) at ages 8 vs. 16 using a Linear Mixed Effects model. Connectivity values in regions generated by the group * age interaction analysis were then correlated to scores on full IQ (FSIQ), verbal IQ (VIQ), verbal comprehension IQ (VCIQ), performance IQ (PIQ), Peabody picture vocabulary test-revised (PPVT-R), and Rapid Naming Composite (RDRL_Cmp). RESULTS: Nine regions were generated by the group * age interaction analysis. PT connectivity significantly increased over time in all but two regions, and they ultimately displayed greater relative connectivity at age 16 than Ts in all areas except the left occipito-temporal cortex (OTC). PTs underwent significant connectivity reductions in the left OTC, which corresponded with worse performance on FSIQ, VIQ, and PIQ. These findings differed from Ts, who did not undergo any significant changes in connectivity over time. CONCLUSIONS: These findings suggest that the developmental alterations in connectivity in PT children at adolescence are both pervasive and widespread. The persistent and worsening cognitive and language deficits noted in the PT subjects may be attributed to the loss of connections in the left OTC. PMID- 26937386 TI - Methylenetetrahydrofolate reductase deficiency alters levels of glutamate and gamma-aminobutyric acid in brain tissue. AB - Methylenetetrahydrofolate reductase (MTHFR) is an enzyme key regulator in folate metabolism. Deficiencies in MTHFR result in increased levels of homocysteine, which leads to reduced levels of S-adenosylmethionine (SAM). In the brain, SAM donates methyl groups to catechol-O-methyltransferase (COMT), which is involved in neurotransmitter analysis. Using the MTHFR-deficient mouse model the purpose of this study was to investigate levels of monoamine neurotransmitters and amino acid levels in brain tissue. MTHFR deficiency affected levels of both glutamate and gamma-aminobutyric acid in within the cerebellum and hippocampus. Mthfr (-/-) mice had reduced levels of glutamate in the amygdala and gamma-aminobutyric acid in the thalamus. The excitatory mechanisms of homocysteine through activation of the N-methyl-d-aspartate receptor in brain tissue might alter levels of glutamate and gamma-aminobutyric acid. PMID- 26937384 TI - Prefrontal contributions to relational encoding in amnestic mild cognitive impairment. AB - Relational memory declines are well documented as an early marker for amnestic mild cognitive impairment (aMCI). Episodic memory formation relies on relational processing supported by two mnemonic mechanisms, generation and binding. Neuroimaging studies using functional magnetic resonance imaging (fMRI) have primarily focused on binding deficits which are thought to be mediated by medial temporal lobe dysfunction. In this study, prefrontal contributions to relational encoding were also investigated using fMRI by parametrically manipulating generation demands during the encoding of word triads. Participants diagnosed with aMCI and healthy control subjects encoded word triads consisting of a category word with either, zero, one, or two semantically related exemplars. As the need to generate increased (i.e., two- to one- to zero-link triads), both groups recruited a core set of regions associated with the encoding of word triads including the parahippocampal gyrus, superior temporal gyrus, and superior parietal lobule. Participants diagnosed with aMCI also parametrically recruited several frontal regions including the inferior frontal gyrus and middle frontal gyrus as the need to generate increased, whereas the control participants did not show this modulation. While there is some functional overlap in regions recruited by generation demands between the groups, the recruitment of frontal regions in the aMCI participants coincides with worse memory performance, likely representing a form of neural inefficiency associated with Alzheimer's disease. PMID- 26937385 TI - Lenticulostriate arterial distribution pathology may underlie pediatric anoxic brain injury in drowning. AB - Drowning is a leading cause of neurological morbidity and mortality in young children. Anoxic brain injury (ABI) can result from nonfatal drowning and typically entails substantial neurological impairment. The neuropathology of drowning-induced pediatric ABI is not well established. Specifically, quantitative characterization of the spatial extent and tissue distribution of anoxic damage in pediatric nonfatal drowning has not previously been reported but could clarify the underlying pathophysiological processes and inform clinical management. To this end, we used voxel-based morphometric (VBM) analyses to quantify the extent and spatial distribution of consistent, between-subject alterations in gray and white matter volume. Whole-brain, high-resolution T1 weighted MRI datasets were acquired in 11 children with chronic ABI and 11 age- and gender-matched neurotypical controls (4-12 years). Group-wise VBM analyses demonstrated predominantly central subcortical pathology in the ABI group in both gray matter (bilateral basal ganglia nuclei) and white matter (bilateral external and posterior internal capsules) (P < 0.001); minimal damage was found outside of these deep subcortical regions. These highly spatially convergent gray and white matter findings reflect the vascular distribution of perforating lenticulostriate arteries, an end-arterial watershed zone, and suggest that vascular distribution may be a more important determinant of tissue loss than oxygen metabolic rate in pediatric ABI. Further, these results inform future directions for diagnostic and therapeutic modalities. PMID- 26937387 TI - Neonatal mitochondrial hepatoencephalopathy caused by novel GFM1 mutations. AB - Disorders caused by defects in the mitochondrial translation system are clinically and genetically heterogeneous. The elongation phase of mitochondrial protein synthesis requires, among many other components, three nuclear-encoded elongation factors: EFTu (TUFM; 602389), EFTs (TSFM; 604723), and EFG1 (GFM1; 606639). Mutations have been identified in the genes encoding all three elongation factors, and they result in combined respiratory chain deficiencies and severe phenotypes with an early fatal outcome. So far, only eleven patients have been reported with mutations in GFM1. Here we describe an additional three patients with novel GFM1 mutations. Our results confirm the tissue-specific effect of GFM1 mutations, since we found only slightly decreased respiratory chain enzyme activities in muscle and fibroblasts, but a severe deficiency in the liver. Hence, a thorough biochemical evaluation is important to guide genetic investigation in patients suspected for a mitochondrial disorder. PMID- 26937388 TI - Human pulmonary artery endothelial cells in the model of mucopolysaccharidosis VI present a prohypertensive phenotype. AB - BACKGROUND: Mucopolysaccharidosis type VI (MPS VI) is an autosomal recessive lysosomal disorder caused by a deficient activity of N-acetylgalactosamine-4 sulfatase (ARSB). Pulmonary hypertension (PH) occurs in MPS VI patients and is a marker of bad prognosis. Malfunction of endothelium, which regulates vascular tonus and stimulates angiogenesis, can contribute to the occurrence of PH in MPS VI. AIM: The aim of the study was to establish a human MPS VI cellular model of pulmonary artery endothelial cells (HPAECs) and evaluate how it affects factors that may trigger PH such as proliferation, apoptosis, expression of endothelial nitric oxide synthase (eNOS), natriuretic peptide type C (NPPC), and vascular endothelial growth factor A (VEGFA). RESULTS: Increasing concentrations of dermatan sulfate (DS) reduce the viability of the cells in both ARSB deficiency and controls, but hardly influence apoptosis. The expression of eNOS in HPAECs is reduced up to two thirds in the presence of DS. NPPC shows a biphasic expression reaction with an increase at 50 MUg/mL DS and reduction at 0 and 100 MUg/mL DS. The expression of VEGFA decreases with increasing DS concentrations and absence of elastin, and increases with increasing DS in the presence of elastin. CONCLUSION: Our data suggest that MPS VI endothelium presents a prohypertensive phenotype due to the reduction of endothelium's proliferation ability and expression of vasorelaxing factors. PMID- 26937389 TI - A rare case of Niemann-Pick disease type C without neurological involvement in a 66-year-old patient. AB - The case of a 66 year-old female - the oldest known living patient with Niemann Pick disease type C (NP-C) who remains free of any neurological or psychiatric manifestations 18 years after presentation - is presented. An incidental finding of massive splenomegaly was detected during a routine pelvic ultrasound. The pathology report after splenectomy showed the presence of lipid-laden macrophages. Fibroblasts cultured in LDL-enriched medium revealed abnormal filipin staining consistent with cholesterol-filled vesicles and the rate of cholesterol esterification in response to stimulation of LDL-cholesterol uptake was significantly depressed at 6% of that seen in cells from normal controls, but at a level similar to that observed in an NP-C positive control. Molecular genetic testing later revealed a compound heterozygous mutant NP-C genotype comprising two previously described disease-causing mutations in the NPC1 gene, one in exon 8 (c.1133T>C [V378A]) and one in exon 13 (c.1990G>A [V664M]). These findings confirmed the diagnosis of NP-C. Only three patients with this disorder aged > 53 years have previously been reported, all of whom presented with neurological or neuropsychiatric manifestations. Our patient is the first reported NP-C patient, now in her seventh decade of life, who has to date only manifested splenomegaly. This case highlights the extreme clinical variability of NP-C, and the need to consider this disease in the differential diagnosis of organomegaly, even in the absence of neurological, psychiatric and related clinical signs. SYNOPSIS: An elderly female patient with confirmed NP-C and isolated splenomegaly has remained asymptomatic for neurological, cognitive, psychiatric or ophthalmologic abnormailities into her seventh decade of life. PMID- 26937390 TI - Long-term effectiveness of agalsidase alfa enzyme replacement in Fabry disease: A Fabry Outcome Survey analysis. AB - Outcomes from 5 years of treatment with agalsidase alfa enzyme replacement therapy (ERT) for Fabry disease in patients enrolled in the Fabry Outcome Survey (FOS) were compared with published findings for untreated patients with Fabry disease. Data were extracted from FOS, a Shire-sponsored database, for comparison with data from three published studies. Outcomes evaluated were the annualized rate of change in estimated glomerular filtration rate (eGFR) and left ventricular mass indexed to height (LVMI) as well as time to and ages at a composite morbidity endpoint and at death. FOS data were extracted for 740 treated patients who were followed for a median of ~ 5 years. Compared with no treatment, patients treated with agalsidase alfa demonstrated slower decline in renal function and slower progression of left ventricular hypertrophy. Treated male patients with baseline eGFR < 60 mL/min/1.73 m(2) had a mean (standard error of the mean [SEM]) annualized change in eGFR of - 2.86 (0.53) mL/min/1.73 m(2)/y compared with - 6.8 (1.5) in the published untreated cohort. The mean (SEM) rate of LVMI increase with treatment was 0.33 (0.10) g/m(2.7)/y in males and 0.48 (0.09) in females, compared with 4.07 (1.03) in untreated males and 2.31 (0.81) in untreated females. Morbidity occurred later in treated patients, with ~ 16% risk of a composite morbidity event (26% in males) after 24 months with ERT versus ~ 45% without treatment, with first events and deaths also occurring at older ages in patients administered ERT (e.g., estimated median survival in treated males was 77.5 years versus 60 years in untreated males). Findings from these retrospective comparisons of observational data and published literature support the long-term benefits of ERT with agalsidase alfa for Fabry disease in slowing the progression of renal impairment and cardiomyopathy. Treatment also appeared to delay the onset of morbidity and mortality. Interpretation of these findings should take into account that they are based on retrospective comparisons with previously published data. PMID- 26937391 TI - Minimal hepatic glucose-6-phosphatase-alpha activity required to sustain survival and prevent hepatocellular adenoma formation in murine glycogen storage disease type Ia. AB - Glycogen storage disease type Ia (GSD-Ia), characterized by impaired glucose homeostasis and chronic risk of hepatocellular adenoma (HCA), is caused by a deficiency in glucose-6-phosphatase-alpha (G6Pase-alpha or G6PC) activity. In a previous 70-90 week-study, we showed that a recombinant adeno-associated virus (rAAV) vector-mediated gene transfer that restores more than 3% of wild-type hepatic G6Pase-alpha activity in G6pc (-/-) mice corrects hepatic G6Pase-alpha deficiency with no evidence of HCA. We now examine the minimal hepatic G6Pase alpha activity required to confer therapeutic efficacy. We show that rAAV-treated G6pc (-/-) mice expressing 0.2% of wild-type hepatic G6Pase-alpha activity suffered from frequent hypoglycemic seizures at age 63-65 weeks but mice expressing 0.5-1.3% of wild-type hepatic G6Pase-alpha activity (AAV-LL mice) sustain 4-6 h of fast and grow normally to age 75-90 weeks. Despite marked increases in hepatic glycogen accumulation, the AAV-LL mice display no evidence of hepatic abnormalities, hepatic steatosis, or HCA. Interprandial glucose homeostasis is maintained by the G6Pase-alpha/glucose-6-phosphate transporter (G6PT) complex, and G6PT-mediated microsomal G6P uptake is the rate-limiting step in endogenous glucose production. We show that hepatic G6PT activity is increased in AAV-LL mice. These findings are encouraging for clinical studies of G6Pase alpha gene-based therapy for GSD-Ia. PMID- 26937392 TI - Cerebrotendinous xanthomatosis: Possibility of founder mutation in CYP27A1 gene (c.526delG) in Eastern Indian and Surinamese population. AB - Cerebrotendinous xanthomatosis is a lipid storage disease characterized by diarrhea, cataract, tendon xanthoma and neurological regression if untreated. CYP27A1 is the only gene in which mutations are known to cause Cerebrotendinous xanthomatosis. We report two Indian families from different regions of India who underwent molecular testing of CYP27A1. The first family from Eastern India consisting of two affected individuals was found to have the c.526delG homozygous mutation in exon 3, previously reported from our laboratory, also in a patient from Eastern India. However the second affected individual from Southern India that we studied and two previously reported cases from Northern India have different mutations. Interestingly the only previous report of c.526delG mutation was in a Surinamese individual from the Netherlands. To date most of the pathogenic mutations for Cerebrotendinous xanthomatosis have been confined to single population except for R362C mutation which was reported from the Netherlands and the USA (Black). To our knowledge this is the second causal mutation for Cerebrotendinous xanthomatosis which has been reported in two different populations. As human trading was prevalent from Eastern India to Surinam by the Dutch settlers this mutation might suggest a common founder mutation in these populations. PMID- 26937393 TI - Angelman syndrome and isovaleric acidemia: What is the link? AB - We report a toddler affected with Angelman syndrome and isovaleric acidemia (IVA). Such association was due to paternal uniparental isodisomy (UPD) of chromosome 15 in which the proband inherited two paternal copies of an IVA gene point mutation. As both diseases may have severe impact on neurodevelopment, adequate treatment of IVA should be discussed. In our patient however, the variant identified likely causes asymptomatic organic aciduria. Such findings emphasize that paternal UPD 15 can rarely lead to co-occurrence of Angelman syndrome and potentially treatable inborn errors of metabolism. PMID- 26937394 TI - Rhabdomyolysis in a neonate due to very long chain acyl CoA dehydrogenase deficiency. AB - Very long chain acyl CoA dehydrogenase deficiency (VLCADD) is an inborn error in long chain fatty acid oxidation with significant variability in the severity and timing of its clinical presentation. Neonatal presentations of VLCADD have included hypoglycemia and cardiomyopathy while rhabdomyolysis is usually a later onset complication. We describe a neonate with VLCADD presenting with rhabdomyolysis prior to the return of an abnormal newborn screen. This report suggests that evaluating for rhabdomyolysis, in addition to a cardiac and hepatic work-up, is an important part of the initial evaluation of an infant with an abnormal newborn screen suggesting a diagnosis of VLCADD. PMID- 26937395 TI - Molecular mechanisms responsible for neuroinflammation and neurological impairments in mevalonate kinase deficiency. PMID- 26937396 TI - An uncommon clinical presentation of relapsing dilated cardiomyopathy with identification of sequence variations in MYNPC3, KCNH2 and mitochondrial tRNA cysteine. AB - We describe a young girl with dilated cardiomyopathy, long QT syndrome, and possible energy deficiency. Two major sequence changes were identified by whole exome sequencing (WES) and mitochondrial DNA analysis that were interpreted as potentially causative. Changes were identified in the KCNH2 gene and mitochondrial tRNA for cysteine. A variation was also seen in MYPBC3. Since the launch of WES as a clinically available technology in 2010, there has been concern regarding the identification of variants unrelated to the patient's phenotype. However, in cases where targeted sequencing fails to explain the clinical presentation, the underlying etiology could be more complex than anticipated. In this situation, the extensive reach of this tool helped explain both her phenotype and family history. PMID- 26937397 TI - Improved sensitivity of an acid sphingomyelinase activity assay using a C6:0 sphingomyelin substrate. AB - Short-chain C6-sphingomyelin is an artificial substrate that was used in an acid sphingomyelinase activity assay for a pilot screening study of patients with Niemann-Pick disease types A and B. Using previously published multiplex and single assay conditions, normal acid sphingomyelinase activity levels (i.e. false negative results) were observed in two sisters with Niemann-Pick B who were compound heterozygotes for two missense mutations, p.C92W and p.P184L, in the SMPD1 gene. Increasing the sodium taurocholate detergent concentration in the assay buffer lowered the activity levels of these two patients into the range observed with other patients with clear separation from normal controls. PMID- 26937400 TI - Detection of glutaric acidemia type 1 in infants through tandem mass spectrometry. AB - Glutaric acidemia type 1 (GA1) is a rare inherited metabolic disorder which goes underdiagnosed due to its latency period and subtle presentation. A pilot clinical study was conducted to assess the usefulness, specificity and sensitivity of the tandem mass (MS/MS) spectrometer, specifically the Abbott (AB) Sciex 3200, in the screening for GA1 using dried blood spots. A total of 17,100 specimens, comprising pediatric patients and healthy newborns, were screened from June 2012 to June 2014. A selection criterion was applied to increase the range of samples tested. 14 of the total specimens tested presumptive positive for GA1, of whom all were symptomatic. The diagnosis was confirmed in 4 of the 14 cases and they were started on treatment. 4 cases expired before confirmation. The remaining cases were empirically started on treatment. Most of the patients responded favorably to the dietary management. One important observation was that the older symptomatic children diagnosed with GA1 had poorer outcomes in terms of recovery of delayed milestones and mental deterioration, further emphasizing the need for early diagnosis of organic acidemias along with the other biochemical defects. Tandem mass spectrometry was found to be more than 93.33% sensitive and more than 99.42% specific. The screening test proved to be very simple and economical. PMID- 26937398 TI - Muscle imaging data in late-onset Pompe disease reveal a correlation between the pre-existing degree of lipomatous muscle alterations and the efficacy of long term enzyme replacement therapy. AB - BACKGROUND: Late-onset Pompe disease (LOPD) is a metabolic myopathy caused by mutations in GAA and characterized by proximal muscle weakness and respiratory insufficiency. There is evidence from clinical studies that enzyme replacement therapy (ERT) with human recombinant alpha-glucosidase improves motor performance and respiratory function in LOPD. OBJECTIVE: We analyzed quantitative muscle MRI data of lower limbs to evaluate the effects of long-term ERT on muscle parameters. METHODS: Three symptomatic LOPD patients who received ERT for five years and four untreated presymptomatic LOPD patients were included in the study. T1-weighted MRI images were used to determine volumes of thigh and lower leg muscles. In addition, mean gray values of eight individual thigh muscles were calculated to assess the degree of lipomatous muscle alterations. RESULTS: We detected a decrease in thigh muscle volume of 6.7% (p < 0.001) and an increase in lower leg muscle volume of 8.2% (p = 0.049) after five years of ERT. Analysis of individual thigh muscles revealed a positive correlation between the degree of lipomatous muscle alterations at baseline and the increase of gray values after five years of ERT (R(2) = 0.68, p < 0.001). Muscle imaging in presymptomatic patients showed in one case pronounced lipomatous alteration of the adductor magnus muscle and mild to moderate changes in further thigh muscles. CONCLUSIONS: The results demonstrate that fatty muscle degeneration can occur before clinical manifestation of muscle weakness and suggest that mildly affected muscles may respond better to ERT treatment than severely involved muscles. If these findings can be validated by further studies, it should be discussed if muscle alterations detected by muscle MRI may be an objective sign of disease manifestation justifying an early start of ERT in clinically asymptomatic patients in order to improve the long-term outcome. PMID- 26937399 TI - Enzymatic replacement therapy for Hunter disease: Up to 9 years experience with 17 patients. AB - Hunter disease is an X-linked lysosomal storage disorder characterized by progressive storage of glycosaminoglycans (GAGs) and multi-organ impairment. The central nervous system (CNS) is involved in at least 50% of cases. Since 2006, the enzymatic replacement therapy (ERT) is available but with no effect on the cognitive impairment, as the present formulation does not cross the blood-brain barrier. Here we report the outcome of 17 Hunter patients treated in a single center. Most of them (11) started ERT in 2006, 3 had started it earlier in 2004, enrolled in the phase III trial, and 3 after 2006, as soon as the diagnosis was made. The liver and spleen sizes and urinary GAGs significantly decreased and normalized throughout the treatment. Heart parameters improved, in particular the left ventricular mass index/m(2) decreased significantly. Amelioration of hearing was seen in many patients. Joint range of motion improved in all patients. However, no improvement on respiratory function, eye, skeletal and CNS disease was found. The developmental quotient of patients with a CNS involvement showed a fast decline. These patients were no more testable after 6 years of age and, albeit the benefits drawn from ERT, their quality of life worsened throughout the years. The whole group of patients showed a consistent residual disease burden mainly represented by persistent skeletal disease and frequent need of surgery. This study suggests that early diagnosis and treatment and other different therapies which are able to cross the blood-brain barrier, might in the future improve the MPS II outcome. PMID- 26937401 TI - Enzyme replacement therapy in Hurler syndrome after failure of hematopoietic transplant. AB - The most severe form of Mucopolysaccharosidosis type I (MPS-I), Hurler syndrome, presents with progressive respiratory, cardiac and musculoskeletal symptoms and cognitive deterioration. Treatment includes enzyme replacement therapy (ERT) and/or hematopoietic stem cell transplantation (HSCT). We describe the case of an 8-year old boy with MPS-I, homozygous for W402X, treated at 10 months of age with HSCT and after failure of the transplant, with ERT during 2 years showing good results, including a positive neuropsychological development. PMID- 26937403 TI - Refeeding syndrome in a young woman with argininosuccinate lyase deficiency. AB - A severely chronically protein and calorie restricted young woman with argininosuccinate lyase deficiency developed transient refeeding syndrome (RFS) and hyperammonemia after modest diet liberalization following initiation of glycerol phenylbutyrate (GPB). The patient required IV supportive care and supplementation with potassium, magnesium and calcium. She is now doing well on GPB and an appropriate maintenance diet. Susceptibility to RFS should be considered in chronically nutritionally restricted patients with metabolic disorders after liberalization of diet. PMID- 26937402 TI - Oxidative stress parameters of Gaucher disease type I patients. PMID- 26937404 TI - Arrhythmia as a cardiac manifestation in MELAS syndrome. AB - A 44-year-old female with a diagnosis of mitochondrial myopathy, encephalopathy and stroke-like episodes (MELAS) syndrome had progressive left ventricular hypertrophy (LVH) on echocardiogram. A Holter monitor demonstrated episodes of non-sustained atrial tachycardia, a finding not been previously described in this population. This unique case of MELAS syndrome demonstrates the known associated cardiac manifestation of LVH and the new finding of atrial tachycardia which may represent the potential for subclinical arrhythmia in this population. PMID- 26937405 TI - Late onset variants in Fabry disease: Results in high risk population screenings in Argentina. AB - BACKGROUND: Screening for Fabry disease (FD) in high risk populations yields a significant number of individuals with novel, ultra rare genetic variants in the GLA gene, largely without classic manifestations of FD. These variants often have significant residual alpha-galactosidase A activity. The establishment of the pathogenic character of previously unknown or rare variants is challenging but necessary to guide therapeutic decisions. OBJECTIVES: To present 2 cases of non classical presentations of FD with renal involvement as well as to discuss the importance of high risk population screenings for FD. RESULTS: Our patients with non-classical variants were diagnosed through FD screenings in dialysis units. However, organ damage was not limited to kidneys, since LVH, vertebrobasilar dolichoectasia and cornea verticillata were also present. Lyso-Gb3 concentrations in plasma were in the pathologic range, compatible with late onset FD. Structural studies and in silico analysis of p.(Cys174Gly) and p.(Arg363His), employing different tools, suggest that enzyme destabilization and possibly aggregation could play a role in organ damage. CONCLUSIONS: Screening programs for FD in high risk populations are important as FD is a treatable multisystemic disease which is frequently overlooked in patients who present without classical manifestations. PMID- 26937406 TI - Increased apoptosis and hypomyelination in cerebral white matter of macular mutant mouse brain. AB - Hypomyelination in developing brain is often accompanied by congenital metabolic disorders. Menkes kinky hair disease is an X-linked neurodegenerative disease of impaired copper transport, resulting from a mutation of the Menkes disease gene, a transmembrane copper-transporting p-type ATPase gene (ATP7A). In a macular mutant mouse model, the murine ortholog of Menkes gene (mottled gene) is mutated, and widespread neurodegeneration and subsequent death are observed. Although some biochemical analysis of myelin protein in macular mouse has been reported, detailed histological study of myelination in this mouse model is currently lacking. Since myelin abnormality is one of the neuropathologic findings of human Menkes disease, in this study early myelination in macular mouse brain was evaluated by immunohistochemistry. Two-week-old macular mice and normal littermates were perfused with 4% paraformaldehyde. Immunohistochemical staining of paraffin embedded and vibratome sections was performed using antibodies against either CNPase, cleaved caspase-3 or O4 (marker of immature oligodendrocytes). This staining showed that cerebral myelination in macular mouse was generally hypoplastic and that hypomyelination was remarkable in internal capsule, corpus callosum, and cingulate cortex. In addition, an increased number of cleaved caspase-3 positive cells were observed in corpus callosum and internal capsule. Copper deficiency induced by low copper diet has been reported to induce oligodendrocyte dysfunction and leads to hypomyelination in this mouse model. Taken together, hypomyelination observed in this study in a mouse model of Menkes disease is assumed to be induced by increased apoptosis of immature oligodendrocytes in developing cerebrum, through deficient intracellular copper metabolism. PMID- 26937408 TI - Complex III deficiency due to an in-frame MT-CYB deletion presenting as ketotic hypoglycemia and lactic acidosis. AB - Complex III deficiency due to a MT-CYB mutation has been reported in patients with myopathy. Here, we describe a 15-year-old boy who presented with metabolic acidosis, ketotic hypoglycemia and carnitine deficiency. Electron transport chain analysis and mitochondrial DNA sequencing on muscle tissue lead to the eventual diagnosis of complex III deficiency. This case demonstrates the critical role of muscle biopsies in a myopathy work-up, and the clinical efficacy of supplement therapy. PMID- 26937409 TI - Haemodialysis is an effective treatment in acute metabolic decompensation of maple syrup urine disease. AB - Acute metabolic decompensation in maple syrup urine disease can occur during intercurrent illness and is a medical emergency. A handful of reports in the medical literature describe the use of peritoneal dialysis and haemodialysis as therapeutic inventions. We report the only patient from our centre to have haemodialysis performed in this setting. Combined with dietary BCAA restriction and calorific support, haemodialysis allows rapid reduction in plasma leucine concentrations considerably faster than conservative methods. PMID- 26937407 TI - Hereditary fructose intolerance in Brazilian patients. PMID- 26937410 TI - Two consecutive partial liver transplants in a patient with Classic Maple Syrup Urine Disease. AB - Maple syrup urine disease is caused by a deficiency in the branched chain ketoacid dehydrogenase (BCKAD) complex. This results in the accumulation of branched chain amino acids (BCAA) and branched chain ketoacids in the body. Even when aggressively treated with dietary restriction of BCAA, patients experience long term cognitive, neurological and psychosocial problems. Liver transplantation from deceased donors has been shown to be an effective modality in introducing adequate BCKAD activity, attaining a metabolic cure for patients. Here, we report the clinical course of the first known patient with classic MSUD who received two consecutive partial liver grafts from two different living non carrier donors and his five year outcome posttransplant. We also show that despite the failure of the first liver graft, and initial acute cellular rejection of the second liver graft in our patient, his metabolic control remained good without metabolic decompensation. PMID- 26937412 TI - The challenge of long-term tetrahydrobiopterin (BH4) therapy in phenylketonuria: Effects on metabolic control, nutritional habits and nutrient supply. AB - BACKGROUND AND AIMS: BH4-sensitive phenylketonuria (PKU) patients relax their phenylalanine (Phe) restricted diet due to increased Phe tolerance, while keeping dried blood Phe concentrations with in the therapeutic range. We aimed to investigate metabolic control, eating habits and nutrient supply under long-term BH4-therapy. PATIENTS AND METHODS: Retrospective analysis of mean dried blood Phe concentrations and their variability, food and nutrient intake in BH4-sensitive patients (n = 8, 3f, age 6.0-16.6 y) under classical dietary treatment for one year and during the three years after initiation of BH4. RESULTS: Phe concentrations of BH4-sensitve PKU patients remained within therapeutic range throughout the observation period, independent of therapeutic regime. Under BH4, Phe tolerance increased significantly (493.2 +/- 161.8 mg/d under classical diet vs 2021.93 +/- 897.4 mg/d two years under BH4; P = 0.004). Variability of Phe concentrations remained unchanged (mean SD; P = 1.000). Patients adjust their food choice and significantly increased their intake of cereals, potatoes, dairy products and meat (P = 0.019, P = 0.016, P = 0.016 and P = 0.016, respectively). Under diet changes after implementation of BH4 a drop in micronutrient intake (vitamin D, folic acid, iron, calcium, iodine) could be revealed (P = 0.005, P < 0.001, P = 0.004, P = 0.001, P = 0.003, respectively). CONCLUSIONS: BH4-sensitive PKU patients can achieve good metabolic control under an adjuvant BH4- or a BH4 monotherapy. The liberalized diet under BH4 seems to jeopardize the quality of patients' nutrition, and these patients require close follow-up and special nutrition education to minimize the risk for imbalanced diet and nutrient deficiencies. PMID- 26937413 TI - Characterization of a rare Unverricht-Lundborg disease mutation. AB - Cystatin B (CSTB) gene mutations cause Unverricht-Lundborg disease (ULD), a rare form of myoclonic epilepsy. The previous identification of a Portuguese patient, homozygous for a unique splicing defect (c.66G > A; p.Q22Q), provided awareness regarding the existence of variant forms of ULD. In this work we aimed at the characterization of this mutation at the population level and at the cellular level. The cellular fractionation studies here carried out showed mislocalization of the protein and add to the knowledge on this disease. PMID- 26937411 TI - Mutations in ARSB in MPS VI patients in India. AB - Mucopolysaccharidosis VI (MPS VI) is an autosomal recessive inborn error of metabolism caused by mutations in the arylsulfatase B gene (ARSB) and consequent deficient activity of ARSB, a lysosomal enzyme. We present here the results of a study undertaken to identify the mutations in ARSB in MPS VI patients in India. Around 160 ARSB mutations, of which just 4 are from India, have been reported in the literature. Our study covered nine MPS VI patients from eight families. Both familial mutations were found in seven families, and only one mutation was found in one family. Seven mutations were found - four novel (p.G38_G40del3, p.C91R, p.L98R and p.R315P), two previously reported from India (p.D53N and p.W450C), and one reported from outside India (p.R160Q). One mutation, p.W450C, was present in two families, and the other six mutations were present in one family each. Analysis of the molecular structure of the enzyme revealed that most of these mutations either cause loss of an active site residue or destabilize the structure of the enzyme. The only previous study on mutations in ARSB in Indian MPS VI patients, by Kantaputra et al. 2014 [1], reported four novel mutations of which two (p.D53N and p.W450C) were found in our study as well. Till date, nine mutations have been reported from India, through our study and the Kantaputra study. Eight out of these nine mutations have been found only in India. This suggests that the population studied by us might have its own typical set of mutations, with other populations equally likely to have their own set of mutations. PMID- 26937414 TI - Neuraminidase-1 contributes significantly to the degradation of neuronal B-series gangliosides but not to the bypass of the catabolic block in Tay-Sachs mouse models. PMID- 26937415 TI - Pediatric patient with hyperketotic hypoglycemia diagnosed with glycogen synthase deficiency due to the novel homozygous mutation in GYS2. AB - BACKGROUND: Glycogen synthase deficiency (glycogen storage disease 0 - GSD 0) caused by mutations in the GYS2 gene is characterized by a lack of glycogen synthesis in the liver. It is a rare condition of disturbed glycogen homeostasis in the liver with less than 30 cases reported in the literature so far. CASE REPORT: We report a 9 year old boy diagnosed with GSD 0 due to the newly identified, highly pathogenic homozygous mutation: NM_021957.3:p.Phe574Leu/c.1720T > C in ex. 14. A random, asymptomatic hypoglycemia with ketonuria was found in this patient at the age of 7. His developmental parameters were within normal ranges. Oral glucose tolerance test showed normal baseline blood levels of glucose, insulin and lactate, and their increase following glucose intake. Eight-hour fasting plasma glucose test, revealed glucose blood level of 34 mg/dl with no clinical symptoms. The results of these tests suggested GSD 0. Molecular analysis of the GYS2 gene was not feasible, but this particular gene was included in the panel of hypoglycemia of whole exome sequencing (WES) which was at our disposal. PMID- 26937416 TI - Executive function in adolescents with PKU and their siblings: Associations with biochemistry. AB - Previous research shows consistent and marked executive function impairment in children with early and continuously treated phenylketonuria. This between groups analysis (phenylketonuria group vs sibling controls) found no significant differences in executive function (although adolescents with phenylketonuria performed slightly worse than their siblings). Biochemical relationships with executive function were confined to long-term measures of high phenylalanine:tyrosine ratio exposure, as well as tyrosine exposure independent of phenylalanine. This study suggests that early and continuously treated PKU results in non-significant EF differences (compared to siblings), although the influence of long-term exposure to poorer metabolic control is still evident. PMID- 26937417 TI - Building local human resources to implement SLMTA with limited donor funding: The Ghana experience. AB - BACKGROUND: In 2009, Ghana adopted the Strengthening Laboratory Management Toward Accreditation (SLMTA) programme in order to improve laboratory quality. The programme was implemented successfully with limited donor funding and local human resources. OBJECTIVES: To demonstrate how Ghana, which received very limited PEPFAR funding, was able to achieve marked quality improvement using local human resources. METHOD: Local partners led the SLMTA implementation and local mentors were embedded in each laboratory. An in-country training-of-trainers workshop was conducted in order to increase the pool of local SLMTA implementers. Three laboratory cohorts were enrolled in SLMTA in 2011, 2012 and 2013. Participants from each cohort attended in a series of three workshops interspersed with improvement projects and mentorship. Supplemental training on internal audit was provided. Baseline, exit and follow-up audits were conducted using the Stepwise Laboratory Quality Improvement Process Towards Accreditation (SLIPTA) checklist. In November 2013, four laboratories underwent official SLIPTA audits by the African Society for Laboratory Medicine (ASLM). RESULTS: The local SLMTA team successfully implemented three cohorts of SLMTA in 15 laboratories. Seven out of the nine laboratories that underwent follow-up audits have reached at least one star. Three out of the four laboratories that underwent official ASLM audits were awarded four stars. Patient satisfaction increased from 25% to 70% and sample rejection rates decreased from 32% to 10%. On average, $40 000 was spent per laboratory to cover mentors' salaries, SLMTA training and improvement project support. CONCLUSION: Building in-country capacity through local partners is a sustainable model for improving service quality in resource-constrained countries such as Ghana. Such models promote country ownership, capacity building and the use of local human resources for the expansion of SLMTA. PMID- 26937418 TI - Candidate gene analysis supports a role for polymorphisms at TCF7L2 as risk factors for type 2 diabetes in Sudan. AB - BACKGROUND: Genetic susceptibility to type 2 diabetes (T2D) is multifactorial. A growing number of genes have been identified as risk factors for T2D across multiple ethnicities in trans-ancestry meta-analysis of large-scale genome-wide association studies. Few studies have looked at these genes in Sub-Saharan African populations. This study was undertaken to look for associations between T2D and single nucleotide polymorphisms (SNPs) in a number of the top candidate genes in a selected Sudanese population. METHODS: A total 240 T2D cases and 128 unrelated healthy control subjects were included in this study. Age, sex, weight and height were recorded, blood pressure and biochemical profiles of glucose and lipids were analysed. Single nucleotide polymorphism (SNP) genotyping was performed using the Sequenom MassARRAY(r) system. Fourteen SNPs were selected across 7 genes: CAPN10 (rs2975760 and rs5030952), PPARG (rs17036314 and rs1801282), IGF2BP2 (rs4402960 and rs1470579), CDKAL1 (rs9465871), HHEX (rs1111875), TCF7L2 (rs7903146, rs11196205 and rs12255372), and KCNJ11 (rs5215, rs1800467 and rs5219). Allelic and haplotype association analyses were performed under additive models in PLINK. P <= 0.007 (=0.05/7 genes) was the P-value required to achieve correction for multiple testing. RESULTS: A significant genetic association between the SNPs rs7903146 (odds ratio 1.69, 95 % confidence interval 1.21-2.38, P = 0.002) and rs12255372 (odds ratio 1.70, 95 % confidence interval 1.20-2.41, P = 0.003) at TCF7L2 and T2D was found in Sudanese population. These associations were retained after adjusting for age, sex and BMI (e.g. rs7903146: odds ratio 1.70, P adj:age/sex/BMI = 0.005). The strongest haplotype association (odds ratio 2.24; P adj:age/sex/BMI = 0.0003) comprised the two point haplotype T_C across rs7903146 and rs11196205. Stepwise logistic regression demonstrated that SNP rs7903146 added significant main effects to rs11196205 or rs12255372, whereas the reverse was not true, indicating that the main effect for association with T2D in this population is most strongly tagged by SNP rs7903146. Adjusted analyses also provided support for protection from T2D associated with minor alleles at SNPs rs2975760 at CAPN10 (odds ratio 0.44, 95 % confidence interval 0.20-0.97, P adj:age/sex/BMI = 0.042) and rs1111876 at HHEX (odds ratio 0.60, 95 % confidence interval 0.39- 0.93, P adj:age/sex/BMI = 0.022). CONCLUSIONS: Multiethnic associations between T2D and SNPs at TCF7L2, CAPN10 and HHEX extend to Sub-Saharan Africa, specifically Sudan. PMID- 26937419 TI - Predictors of Clinical Anxiety Aggravation at the End of a Cardiac Rehabilitation Program. AB - BACKGROUND: Anxiety is one of the most primary and common reactions to a cardiac event can lead to hypertension, tachycardia, and high cardiac output. OBJECTIVES: To investigate the predictors of clinical anxiety aggravation at the end of a cardiac rehabilitation (CR) program. PATIENTS AND METHODS: This retrospective study used a database of a CR ward of a hospital in Iran. The demographic and clinical information of 574 patients participating in the CR program from April 2005 through April 2010 were analyzed. In order to determine the predictors of anxiety, binary logistic regression was performed. RESULTS: After adjustment for gender, age and education, the results showed that 16.7% of the patients completed their CR program with increased levels of clinical anxiety. The following study variables were independently predictive of increased anxiety at the end of the CR program: male gender (OR = 2.04, 95% CI = 1.11 to 3.33, P = 0.048), no history of diabetes (OR = 4.24, 95% CI = 172 to 10.44, P = 0.002), family history of cardiac disease (OR = 2.63, 95% CI = 1.03 to 6.74, P = 0.043), and not quitting smoking (OR = 3.29, 95% CI = 1.38 to 7.85, P = 0.007). These variables could explain 9% - 15% of the variance in the dependent variable. CONCLUSIONS: It is possible to predict higher anxiety levels at the end of the CR program and implement preventive measures to control anxiety by considering certain demographic and clinical variables. Future studies should assess the predictive power of other variables. PMID- 26937420 TI - Cell-based assays using calcein acetoxymethyl ester show variation in fluorescence with treatment conditions. AB - The use of fluorogenic compounds in cell and molecular biology has increased in both frequency and range of applications. However, such compounds may introduce artifacts in intracellular fluorescence and cell number estimations as a consequence of interaction with exogenous stimulants, necessitating the use of adequate controls for accurate measurements and valid conclusions. Using calcein acetoxymethyl ester (AM) in combination with various exogenous cellular treatments, we report that the standard practice of direct normalization of experimental values to controls is insufficient for fluorogenic measurements. Treatments applied to cells may influence intracellular conversion of the fluorogenic compound, thereby enhancing or decreasing fluorescence relative to controls. We hereby encourage caution and recommend normalization of cellular fluorescence within each treatment group before comparison to controls. PMID- 26937421 TI - Lasing from Glassy Ge Quantum Dots in Crystalline Si. AB - Semiconductor light-emitters compatible with standard Si integration technology (SIT) are of particular interest for overcoming limitations in the operating speed of microelectronic devices. Light sources based on group IV elements would be SIT-compatible, but suffer from the poor optoelectronic properties of bulk Si and Ge. Here we demonstrate that epitaxially grown Ge quantum dots (QDs) in a defect-free Si matrix show extraordinary optical properties if partially amorphized by Ge-ion bombardment (GIB). In contrast to conventional SiGe nanostructures, these QDs exhibit dramatically shortened carrier lifetimes and negligible thermal quenching of the photoluminescence (PL) up to room temperature. Microdisk resonators with embedded GIB-QDs exhibit threshold behavior as well as a superlinear increase of the integrated PL intensity with concomitant line width narrowing as the pump power increases. These findings demonstrate light amplification by stimulated emission in a fully SIT-compatible group IV nanosystem. PMID- 26937422 TI - Conventional videodefecography: Pathologic findings according to gender and age. AB - OBJECTIVES: To review the most common disorders depicted with conventional videodefecography, and to compare the defecographic abnormalities between symptomatic patients according to their gender and age. METHODS: Conventional videodefecography studies of 300 patients (24 men, 266 women; mean age - 57.7) performed in a 32-month period were reviewed for the following parameters: anorectal angle, movement of the pelvic floor, intussusceptions, incontinence and rectocele. The results were analyzed using the chi-square test. RESULTS: Normal findings were observed in 16.7% men and 7.5% women. In women, the most frequent pathological findings were rectocele (62%), descending perineum syndrome (42.8%), intussusceptions (33.8%), incontinence (10.5%), dyskinetic puborectalis syndrome (9.4%) and rectal prolapse (4.5%); in men the most frequent pathology was the dyskinetic puborectalis syndrome (37.5%). This syndrome is more likely in men than in women (p = 0.01; OR 5.78); descending perineum syndrome (p = 0.027; OR 2.8) is more likely to occur in women. Women with perineal descent younger than 50 years frequently present an increased descent during evacuation (81.8%), while those older than 50 years already have a low pelvic floor during rest (60.3%) (p < 0.001; OR 6.8), with little change in evacuation. CONCLUSION: Videodefecographic findings vary with age and gender. PMID- 26937423 TI - MR urography (MRU) of non-dilated ureter with diuretic administration: Static fluid 2D FSE T2-weighted versus 3D gadolinium T1-weighted GE excretory MR. AB - OBJECTIVE: The goal of this prospective study was to compare the efficiency of two types of MRU after diuretic administration to identify the non-dilated ureter. METHODS: MR pelvic examinations were performed in 126 patients after receiving furosemide. Each patient underwent in addition to their protocol for context, two types of MRU: 2D T2-weighted FSE (T2w-MRU) and 3D Gd T1-weighted GE (CE-MRU). Four segments were checked for each ureter. For the first part of the analysis, readers evaluated the whole image quality using a four points subjective scale and for the second part, they were asked to score separately each ureteral segment as present or absent. RESULTS: 1008 ureteral segments were checked. For the image quality, readers did not find any significant difference (3.8 +/- 0.5 vs 3.6 +/- 0.7, p value: 0.13) between MRU methods. The interobserver agreement was excellent with a kappa correlation coefficient as high as 0.89 for T2w-MRU and 0.92 for CE-MRU, respectively. For the detection of the segments and considering the 9 rotations for the T2W MRU, there were no statistically significant differences between the two groups. CONCLUSION: T2 weighted MRU with multiple orientations and diuretic is sufficient to identify the non-dilated ureter. It offers information on ureteral peristaltism. It can be suggested that this sequence is able to detect an initial obstruction before hydronephrosis occurs. PMID- 26937424 TI - An innovative approach to investigate the dynamics of the cerebrospinal fluid in the prepontine cistern: A feasibility study using spatial saturation-prepared cine PC-MRI. AB - PURPOSES: Accurate measurements of the cerebrospinal fluid that flows through the prepontine cistern (PPC) are challenging due to artefacts originating from basilar artery blood flow. We aim to accurately quantify cerebrospinal fluid (CSF) flow and stroke volume in the PPC, which is essential before endoscopic third ventriculostomy. MATERIALS AND METHODS: We developed a new PC-MRI sequence prepared with Hadamard saturation bands to accurately quantify CSF flow in the PPC by suppressing the blood signal in the surrounding vessels. In total, 28 adult hydrocephalic patients (age 59 +/- 20 years) were scanned using conventional PC-MRI and our developed sequence. CSF was separately extracted from the PPC and the foramen of Magendie, and flow (min and max) and stroke volume were quantified. RESULTS: Our modifications result in a complete deletion of signal from flowing blood, resulting in significantly reduced CSF stroke volume (Conv = 446 +/- 113 mm(3), Dev = 390 +/- 119 mm(3), p = 0.006) and flow, both minimum (Conv = -1630 +/- 486 mm(3)/s, Dev = -1430 +/- 406 mm(3)/s, p = 0.005) and maximum (Conv = 2384 +/- 657 mm(3)/s, Dev = 1971 +/- 62 mm(3)/s, p = 0.002) compared with the conventional sequence, whereas no change in the area of interest was noted (Conv = 236 +/- 65 mm(2), Dev = 249 +/- 75 mm(2), p = 0.21). CONCLUSIONS: Accurate and reproducible CSF flow and stroke volume measurements in the PPC can be achieved with sat-band prepared cine PC-MRI. PMID- 26937425 TI - MR-PET of the body: Early experience and insights. AB - MR-PET is a novel imaging modality that combines anatomic and metabolic data acquisition, allowing for simultaneous depiction of morphological and functional abnormalities with an excellent soft tissue contrast and good spatial resolution; as well as accurate temporal and spatial image fusion; while substantially reducing radiation dose when compared with PET-CT. In this review, we will discuss MR-PET basic principles and technical challenges and limitations, explore some practical considerations, and cover the main clinical applications, while shedding some light on some of the future trends regarding this new imaging technique. PMID- 26937426 TI - Current update on combined hepatocellular-cholangiocarcinoma. AB - Combined hepatocellular-cholangiocarcinoma is a rare but unique primary hepatic tumor with characteristic histology and tumor biology. Recent development in genetics and molecular biology support the fact that combined hepatocellular cholangiocarcinoma is closely linked with cholangiocarcinoma, rather than hepatocellular carcinoma. Combined hepatocellular cholangiocarcinoma tends to present with an more aggressive behavior and a poorer prognosis than either hepatocellular carcinoma or cholangiocarcinoma. An accurate preoperative diagnosis and aggressive treatment planning can play crucial roles in appropriate patient management. PMID- 26937427 TI - Magnetic resonance imaging of less common pancreatic malignancies and pancreatic tumors with malignant potential. AB - Pancreatic tumors are an increasingly common finding in abdominal imaging. Various kinds of pathologies of the pancreas are well known, but it often remains difficult to classify the lesions radiologically in respect of type and grade of malignancy. Magnetic resonance imaging (MRI) is the method of choice for the evaluation of pancreatic pathologies due to its superior soft tissue contrast. In this article we present a selection of less common malignant and potentially malignant pancreatic neoplasms with their characteristic appearance on established MRI sequences with and without contrast enhancement. PMID- 26937428 TI - An unusual cause of intra-abdominal calcification: A lithopedion. AB - We report a case of a 77-year-old female who was admitted to the emergency department complaining of diffuse abdominal pain for five days, associated with nausea, vomiting and constipation. Physical examination disclosed a large incarcerated umbilical hernia, which was readily apparent on supine abdominal plain films. These also showed a calcified heterogeneous mass in the mid abdominal region, which was further characterized by CT as a lithopedion (calcified ectopic pregnancy). This is one of the few cases studied on a MDCT equipment, and it clearly enhances the post-processing abilities of this imaging method which allows diagnostic high-quality MIP images. Lithopedion is a rare entity, with less than 300 cases previously described in the medical literature. However, many reported cases corresponded to cases of skeletonization or collections of fetal bone fragments discovered encysted in the pelvic region at surgery or autopsy. It is thus estimated that true lithopedion is a much rarer entity. The diagnosis may be reached by a suggestive clinical history and a palpable mass on physical examination, while the value of modern cross-sectional techniques is still virtually unknown. Ultrasonography may depict an empty uterine cavity and a calcified abdominal mass of non-specific characteristics, and computed tomography or magnetic resonance imaging are able to reach a conclusive diagnosis and may additionally define the involvement of adjacent structures. The differential diagnosis includes other calcified pathologic situations, including ovarian tumors, uterine fibroids, urinary tract neoplasms, inflammatory masses or epiploic calcifications. PMID- 26937429 TI - Tracheal Bronchus: High Resolution Computed Tomography diagnosis in a symptomatic patient. AB - A 75-year-old female underwent a High Resolution Computed Tomography (HRCT) scan for recurrent bronchitis and cough. HRCT images showed an anomalous supernumerary bronchus to the right upper lobe directly arising from the right side of distal trachea, corresponding to Tracheal Bronchus (TrB). TrB can cause recurrent right upper lobe pneumonia and special care is requiring during endotracheal intubation. PMID- 26937430 TI - Metallosis: A diagnosis not only in patients with metal-on-metal prostheses. AB - Although the real actual incidence of metallosis is unknown, it is described as a rare diagnosis with a 5% estimated incidence in the hip prosthetic replacements. The adoption of non-metallic articular prosthetic devices, made of polyethylene and ceramic, is the main reason to the diminishing number of reported cases. We present a case of metallosis with a clinical systemic presentation in a patient with a non-metallic hip prosthesis, which occurred due to a fracture of the acetabular liner component, leading to abnormal metal-metal contact. The metallic debris leads to a massive local and systemic release of cytokines. Revision is necessary whenever osteolysis and loosening of the prosthesis occur. Imaging evaluation, especially CT, has a central role in diagnosis and planning the surgical treatment. PMID- 26937431 TI - An unusual case of extensive peritoneal calcification: A case report. AB - The peritoneum is the largest serous membrane of the body and can be exposed to several injuries that may cause abnormal findings on imaging exams. Linear peritoneal calcification is remarkably rare, usually secondary to long duration peritoneal dialysis. We report an uncommon case of extensive peritoneal calcification in a 39-year-old female without long exposure to peritoneal dialysis solutions, in which peritoneal calcification could be linked to Alport syndrome and previous adverse reaction to intraperitoneal iodinated contrast. Radiologist should be aware of this and related imaging findings, know when to search for them as well as understand their clinical value. PMID- 26937432 TI - Visual assessment of biliary excretion of Gd-EOB-DTPA in patients with suspected diffuse liver disease - A biopsy-verified prospective study. AB - OBJECTIVES: To qualitatively evaluate late dynamic contrast phases, 10, 20 and 30 min, after administration of Gd-EOB-DTPA with regard to biliary excretion in patients presenting with elevated liver enzymes without clinical signs of cirrhosis or hepatic decompensation and to compare the visual assessment of contrast agent excretion with histo-pathological fibrosis stage, contrast uptake parameters and blood tests. METHODS: 29 patients were prospectively examined using 1.5 T MRI. The visually assessed presence or absence of contrast agent for each of five anatomical regions in randomly reviewed time-series was summarized on a four grade scale for each patient. The scores, including a total visual score, were related to the histo-pathological findings, the quantitative contrast agent uptake parameters, expressed as K Hep or LSC_N, and blood tests. RESULTS: No relationship between the fibrosis grade or contrast uptake parameters could be established. A negative correlation between the visual assessment and alkaline phosphatase (ALP) was found. Comparing a sub-group of cholestatic patients with fibrosis score and Gd-EOB-DTPA dynamic parameters did not add any additional significant correlation. CONCLUSIONS: No correlation between visually assessed biliary excretion of Gd-EOB-DTPA and histo-pathological or contrast uptake parameters was found. A negative correlation between the visual assessment and alkaline phosphatase (ALP) was found. PMID- 26937433 TI - Test-positive rate at CT colonography is increased by rectal bleeding and/or unexplained weight loss, unlike other common gastrointestinal symptoms. AB - PURPOSE: We evaluated the rate of significant colonic and extra-colonic abnormalities at computed tomography colonography (CTC), according to symptoms and age. MATERIALS AND METHODS: We retrospectively evaluated 7361 consecutive average-risk subjects (3073 males, average age: 60.3 +/- 13.9; range 18-96 years) for colorectal cancer (CRC) who underwent CTC. They were divided into three groups according to clinical symptoms: 1343 asymptomatic individuals (group A), 899 patients with at least one "alarm" symptom for CRC, including rectal bleeding and unexplained weight loss (group C), and 5119 subjects with other gastrointestinal symptoms (group B). Diagnostic and test-positive rates of CTC were established using optical colonoscopy (OC) and/or surgery as reference standard. In addition, clinically significant extra-colonic findings were noted. RESULTS: 903 out of 7361 (12%, 95% confidence interval (CI) 0.11-0.13) subjects had at least one clinically significant colonic finding at CTC. CTC true positive fraction and false positive fraction were respectively 637/642 (99.2%, 95%CI 0.98 0.99) and 55/692 (7.95%, 95%CI 0.05-0.09). The pooled test-positive rate in group C (138/689, 20.0%, 95%CI 0.17-0.23) was significantly higher than in both groups A (79/1343, 5.9%, 95%CI 0.04-0.07) and B (420/5329, 7.5%, 95%CI 0.07-0.08) (p < 0.001). Aging and male gender were associated to a higher test positive rate. The rate of clinically significant extra-colonic findings was significantly higher in group C (44/689, 6.4%, 95%CI 0.04-0.08) versus groups A (26/1343, 1.9%, 95%CI 0.01-0.02) and B (64/5329, 1.2%, 95%CI 0.01-0.02) (p < 0.001). CONCLUSION: Both test-positive and significant extra-colonic finding rates at CTC are significantly increased in the presence of "alarm" gastrointestinal symptoms especially in older patients. PMID- 26937434 TI - CT features of low grade serous carcinoma of the ovary. AB - OBJECTIVE: To evaluate the CT features of pathologically proven low grade serous carcinoma (LGSC) of the ovary. METHODS: Patients with a pathologic diagnosis of LGSC and CT prior to oophorectomy were retrospectively identified. The CT scans in 14 patients were available and were analyzed for an adnexal mass, peritoneal mass and ascites. The adnexal mass was characterized as complex primarily cystic, mixed cystic solid, or primarily solid. Calcification in the adnexal and peritoneal masses and nodes was noted. RESULTS: Pathology revealed 6 patients had LGSC and 8 patients had a combined diagnosis of LGSC and serous borderline tumor (SBT) of the ovary. Of the 6 patients with only LGSC, 4 had primarily solid or mixed solid cystic adnexal masses and 5 had peritoneal masses. Calcification was present in the adnexal and peritoneal masses in 4 patients, and in nodes in 2 patients. Of the 8 patients with co-existing LGSC and SBT, 7 had complex primarily cystic adnexal masses and 6 had peritoneal masses. Calcification was present in the adnexal and peritoneal masses in 5 patients and in nodes in 2 patients. CONCLUSION: LGSC can appear as a solid, mixed solid cystic, or complex primarily cystic ovarian mass, and the appearance may be due to a co-existing SBT. Calcification of the adnexal and peritoneal masses appears to be common. LGSC is a diagnostic consideration in patients with a calcified adnexal mass and concurrent peritoneal masses or calcified nodes on CT. PMID- 26937435 TI - Volumetric CT perfusion assessment of treatment response in head and neck squamous cell carcinoma: Comparison of CT perfusion parameters before and after chemoradiation therapy. AB - BACKGROUND AND PURPOSE: World Health Organization estimated that there were 600,000 new cases of head and neck cancers and 300,000 deaths each year worldwide. Scientific modalities to predict the treatment outcomes are not available yet. We conducted this study to (1) compare CT perfusion parameters before and after chemoradiation among patients with head and neck squamous cell carcinoma and (2) to evaluate the prognostic value of each perfusion parameter in predicting the response to chemoradiation. MATERIALS AND METHODS: We conducted a prospective study among all patients with head and neck squamous cell carcinoma registered for chemoradiotherapy (CRT) at Regional Cancer Research Center, Shimla, Himachal Pradesh, India during the period June 2012 through June 2013. CTp data were acquired on a 64-slice CT scanner (Light speed VCT Xte; GE Healthcare) with 14 cm z-axis coverage using Volume Helical Shuttle (VHS) feature at baseline, on completion of 40 Gy and 66 Gy of chemoradiation. We dichotomised the treatment outcome as complete response and non-response (partial responders/stable disease/progressive disease) using RECIST 1.1 criteria. We compared all perfusion parameters at baseline, 40 Gy and 66 Gy of CRT between responders and non-responders. We dichotomised the perfusion parameters as high (>median value) and low (<=median value) to analyze association between perfusion parameters and treatment outcome. We calculated the sensitivity, specificity, predictive values, and likelihood ratios for each dichotomized perfusion parameter using Wilson Score method. RESULTS: We followed 24 patients (23 of them men) from start of the treatment till completion of it. All had Stage III or Stage IV of the disease. Blood flow (BF) and blood volume (BV) decreased and Mean Transit Time (MTT) increased significantly (p < 0.05) at 66 Gy among responders to CRT as compared to non-responders. Patients with high BF (>106 ml/100 g/min) at baseline were five times more likely (p = 0.004) to respond to treatment as compared to those with low BF. BF was found to be 83.3% predictive of complete response. Other perfusion parameters were not significantly predictive of outcome (p > 0.05) Combination of high BF (>106 ml/100 g/min) and low (<=47 ml/100 g/min) permeability surface (PS) was 100% predictive of response to CRT irrespective of the stage of tumor. CONCLUSIONS: High BF at baseline is the single best predictor of response to chemoradiaton. A combination of high BF and low PS was found to be 100% predictive of complete response irrespective of the stage of the tumor. PMID- 26937436 TI - Chronic extradural spinal hematoma after previous trauma. PMID- 26937437 TI - Feasibility of low contrast media volume in CT angiography of the aorta. AB - OBJECTIVES: Using smaller volumes of contrast media (CM) in CT angiography (CTA) is desirable in terms of cost reduction and prevention of contrast-induced nephropathy (CIN). The purpose was to evaluate the feasibility of low CM volume in CTA of the aorta. METHODS: 77 patients referred for CTA of the aorta were scanned using a standard MDCT protocol at 100 kV. A bolus of 50 ml CM (Iopromide 300 mg Iodine/ml) at a flow rate of 6 ml/s was applied (Iodine delivery rate IDR = 1.8 g/s; Iodine load 15 g) followed by a saline bolus of 40 ml at the same flow rate. Scan delay was determined by the test bolus method. Subjective image quality was assessed and contrast enhancement was measured at 10 anatomical levels of the aorta. RESULTS: Diagnostic quality images were obtained for all patients, reaching a mean overall contrast enhancement of 324 +/- 28 HU. Mean attenuation was 350 +/- 60 HU at the thoracic aorta and 315 +/- 83 HU at the abdominal aorta. CONCLUSIONS: A straightforward low volume CM protocol proved to be technically feasible and led to CTA examinations reaching diagnostic image quality of the aorta at 100 kV. Based on these findings, the use of a relatively small CM bolus can be incorporated into routine clinical imaging. PMID- 26937438 TI - Comparing hepatic 2D and 3D magnetic resonance elastography methods in a clinical setting - Initial experiences. AB - PURPOSE: Continuous monitoring of liver fibrosis progression in patients is not feasible with the current diagnostic golden standard (needle biopsy). Recently, magnetic resonance elastography (MRE) has emerged as a promising method for such continuous monitoring. Since there are different MRE methods that could be used in a clinical setting there is a need to investigate whether measurements produced by these MRE methods are comparable. Hence, the purpose of this pilot study was to evaluate whether the measurements of the viscoelastic properties produced by 2D (stiffness) and 3D (elasticity and 'G abs,Elastic') MRE are comparable. MATERIALS AND METHODS: Seven patients with diffuse or suspect diffuse liver disease were examined in the same day with the two MRE methods. 2D MRE was performed using an acoustic passive transducer, with a 1.5 T GE 450 W MR system. 3D MRE was performed using an electromagnetic active transducer, with a 1.5 T Philips Achieva MR system. Finally, mean viscoelastic values were extracted from the same anatomical region for both methods by an experienced radiologist. RESULTS: Stiffness correlated well with the elasticity, R (2) = 0.96 (P < 0.001; slope = 1.08, intercept = 0.61 kPa), as well as with 'G abs,Elastic' R (2) = 0.96 (P < 0.001; slope = 0.95, intercept = 0.28 kPa). CONCLUSION: This pilot study shows that different MRE methods can produce comparable measurements of the viscoelastic properties of the liver. The existence of such comparable measurements is important, both from a clinical as well as a research perspective, since it allows for equipment-independent monitoring of disease progression. PMID- 26937439 TI - Diffusion weighted imaging and diffusion tensor imaging in the evaluation of transplanted kidneys. AB - OBJECTIVE: The aim of this study is to investigate the relation between renal indexes and functional MRI in a population of kidney transplant recipients who underwent MR with diffusion-weighted imaging (DWI) and diffusion tensor imaging (DTI) of the transplanted graft. METHOD: Study population included 40 patients with single kidney transplant. The patients were divided into 3 groups, on the basis of creatinine clearance (CrCl) values calculated using Cockcroft-Gault formula: group A, including patients with normal renal function (CrCl >= 60 mL/min); group B, which refers to patients with moderate renal impairment (CrCl > 30 but <60 mL/min); and, finally, group C, which means severe renal deterioration (CrCl <= 30 mL/min). All patients were investigated with a 1.5 Tesla MRI scanner, acquiring DWI and DTI sequences. A Mann-Whitney U test was adopted to compare apparent diffusion coefficients (ADCs) and fractional anisotropy (FA) measurements between groups. Receiver operating characteristic (ROC) curves were created for prediction of normal renal function (group A) and renal failure (group C). Pearson correlation was performed between renal clearance and functional imaging parameter (ADC and FA), obtained for cortical and medullar regions. RESULTS: Mann-Whitney U test revealed a highly significant difference (p < 0.01) between patients with low CrCl (group C) and normal CrCl (group A) considering both medullar ADC and FA and cortical ADC. Regarding contiguous groups, the difference between group B and C was highly significant (p < 0.01) for medullar ADC and significant (p < 0.05) for cortical ADC and medullar FA. No difference between these groups was found considering cortical FA. Analyzing groups A and B, we found a significant difference (p < 0.05) for medullar both ADC and FA, while no difference was found for cortical ADC and FA. Strongest Pearson correlation was found between CrCl and medullar ADC (r = 0.65). For predicting normal renal function or severe renal impairment, highest values of AUC were observed using medullar ADC cut-off values (respectively 0.885 and 0.871); medullar FA showed also high accuracy (respectively 0.831 and 0.853). CONCLUSIONS: DWI and DTI are promising tools for non-invasive monitoring of renal function; medullar ADC proved to be the best parameter for renal function assessment. PMID- 26937440 TI - Magnetic resonance imaging biomarkers of chronic obstructive pulmonary disease prior to radiation therapy for non-small cell lung cancer. AB - OBJECTIVE: In this prospectively planned interim-analysis, the prevalence of chronic obstructive lung disease (COPD) phenotypes was determined using magnetic resonance imaging (MRI) and X-ray computed tomography (CT) in non-small-cell-lung cancer (NSCLC) patients. MATERIALS AND METHODS: Stage-III-NSCLC patients provided written informed consent for pulmonary function tests, imaging and the 6-min-walk test. Ventilation defect percent (VDP) and CT lung density (relative-of-CT density-histogram <-950, RA950) were measured. Patients were classified into three subgroups based on qualitative and quantitative COPD and tumour-specific imaging phenotypes: (1) tumour-specific ventilation defects (TSD), (2) tumour specific and other ventilation defects without emphysema (TSDV), and, (3) tumour specific and other ventilation defects with emphysema (TSDVE). RESULTS: Seventeen stage-III NSCLC patients were evaluated (68 +/- 7 years, 7 M/10 F, mean FEV1 = 77%pred) including seven current and 10 ex-smokers and eight patients with a prior lung disease diagnosis. There was a significant difference for smoking history (p = .02) and FEV1/FVC (p = .04) for subgroups classified using quantitative imaging. Patient subgroups classified using qualitative imaging findings were significantly different for emphysema (RA950, p < .001). There were significant relationships for whole-lung VDP (p < .05), but not RECIST or tumour lobe VDP measurements with pulmonary function and exercise measurements. Preliminary analysis for non-tumour burden ventilation abnormalities using Reader operator-characteristic (ROC) curves reflected a 94% classification rate for smoking pack-years, 93% for FEV1/FVC and 82% for RA950. ROC sensitivity/specificity/positive/negative likelihood ratios were also generated for pack-years, (0.92/0.80/4.6/0.3), FEV1/FVC (0.92/0.80/4.6/0.3), RA950 (0.92/0.80/4.6/0.3) and RECIST (0.58/0.80/2.9/1.1). CONCLUSIONS: In this prospectively planned interim-analysis of a larger clinical trial, NSCLC patients were classified based on COPD imaging phenotypes. A proof-of-concept evaluation showed that FEV1/FVC and smoking history identified NSCLC patients with ventilation abnormalities appropriate for functional lung avoidance radiotherapy. PMID- 26937441 TI - State-of-the-art imaging of liver fibrosis and cirrhosis: A comprehensive review of current applications and future perspectives. AB - OBJECTIVE: The purpose of this article is to provide a comprehensive overview of imaging findings in patients with hepatic fibrosis and cirrhosis; and to describe which radiological/clinical modality is best for staging hepatic fibrosis. CONCLUSION: MR elastography (MRE) appears to be the most reliable method for grading liver fibrosis, although the CT fibrosis score derived from the combination of caudate-to-right-lobe ratio and the diameters of the liver veins significantly correlates with the stage of fibrosis. PMID- 26937442 TI - CT and MR imaging findings of systemic complications occurring during pregnancy and puerperal period, adversely affected by natural changes. AB - Dynamic physiological and anatomical changes for delivery may adversely induce various specific non-obstetric complications during pregnancy and puerperal period. These complications can be fatal to both the mother and the fetus, thus a precise and early diagnosis ensued by an early treatment is essential. Along with ultrasonography, computed tomography (CT) and magnetic resonance imaging (MRI) have assumed an increasing role in the diagnosis. This article aims to discuss the pathophysiology of these complications, the indications for CT and MRI, and the imaging findings. PMID- 26937444 TI - A comparative study of collimation in bedside chest radiography for preterm infants in two teaching hospitals. AB - OBJECTIVE: Unnecessary exposure of the abdomen, arms or head may lead to a substantial increase of the radiation dose in portable chest X-rays on the neonatal intensive care unit. The objective was to identify potential factors influencing inappropriate exposure of non-thoracic structures in two teaching hospitals. METHODS: The study analysed 200 consecutive digital chest radiographs in 20 preterm neonates (mean gestation 25 +/- 1 weeks). Demographical data, tube settings and exposure parameters were recorded. To grade the collimation, we used a scoring system with a maximum of 12 exposed non-thoracic structures. Length of gestation, age, the radiographer, years of experience in performing X-rays and the number of in situ catheters or lines, were correlated with collimation quality. RESULTS: There was no significant difference between the rates of optimal images obtained in the two hospitals (0.32 vs 0.39, n.s.). Scores showed that most suboptimal images had only mildly reduced image quality (1.40 +/- 1.38 vs 1.20 +/- 1.43, n.s.). Length of gestation or presence of surgical drains, catheters and tubes had no obvious effects on the exposure of non-thoracic structures. Large intra-individual variation in optimal collimation (14-86%) was noted for the radiographers in both hospitals; this was unrelated to their respective years of experience. CONCLUSION: In our study, the only identifiable factor influencing the collimation of portable chest radiographs in preterm infants was the radiographer's dedication and awareness. There were no apparent differences between the hospitals investigated. Exposure of non-thoracic structures was relatively frequent and mainly involved the proximal humeri. PMID- 26937443 TI - Craniocaudal tumour extension in uterine cervical cancer on MRI compared to histopathology. AB - PURPOSE: To assess the reliability of magnetic resonance imaging (MRI) for evaluation of craniocaudal tumour extension by comparing the craniocaudal tumour extension on the pre-operative MRI and post-operative hysterectomy specimen in patients with early stage uterine cervical cancer. MATERIALS AND METHODS: After approval of the institutional review board was acquired, pre-operative MRI and hysterectomy specimen of 21 women with early stage cervical cancer were re evaluated. The craniocaudal extension on MRI was measured separately by two experienced radiologists and compared with corresponding measurements from the hysterectomy specimen, which were re-evaluated by an experienced pathologist. RESULTS: Median craniocaudal extension of uterine cervical cancer on MRI was slightly smaller compared to histopathology (2.1 cm vs. 2.5 cm). The median underestimation was 0.4 cm (range -0.6 cm to 2.2 cm, mean 0.4 cm, standard deviation (SD) +/-0.7 cm); Pearson's correlation was 0.83 (p < 0.001). In two patients (9%) MRI underestimated tumour craniocaudal extension by more than 1.8 cm. CONCLUSION: MRI represents the histopathological craniocaudal tumour extension in the majority of patients with early stage uterine cervical cancer, but with a systematic small underestimation of the real craniocaudal tumour extension. PMID- 26937445 TI - How Turkish radiology residents access information related to their profession in this social media and smartphone era. AB - PURPOSE: To evaluate the frequency of mobile technology and social media usage among radiology residents and their access to professional information. MATERIALS AND METHODS: A questionnaire consisting of 24 questions prepared using Google Drive was sent via e-mail to 550 radiology residents throughout the country. Of the 176 participating residents, 74 completed the survey via the internet, and 102 completed it at three different national radiology meetings. Response rates and its relationship with responses given to different questions were assessed. RESULTS: Hundred two male and 74 female residents participated in the survey. 141 (81.3%) residents thought that they had appropriate internet access in their department. The number of residents using a smartphone was 153 (86.9%). The android operating system (70, 45.8%) was the preferred operating system of respondants. Only 24 (15.7%) of the smartphone users thought that there were enough radiology related applications. "Radiology assistant" (18.9%), "Radiopedia" (7.8%) and "Radiographics" (7.8%) were the most utilized applications. Of the smartphone users, 87(56.9%) stated that they used cell phones in order to find radiological information, and the most used web pages were Google (165, 93.8%), Radiopaedia.org (129, 73.3%), Radiologyassistant.nl (135, 76.7%), and Pubmed (114, 64.8%). Social media usages were as follows: None (10, 5.7%), Facebook (139, 79%), Twitter (55, 31.3%), Google + (51, 29%) and YouTube (44, 25%). CONCLUSION: While smartphone usage rates among the residents were high, the use of radiology specific applications was not common. Social media usage was very common among residents. PMID- 26937446 TI - Prioritising the relevant information for learning and decision making within orbital and ventromedial prefrontal cortex. AB - Our environment and internal states are frequently complex, ambiguous and dynamic, meaning we need to have selection mechanisms to ensure we are basing our decisions on currently relevant information. Here, we review evidence that orbitofrontal (OFC) and ventromedial prefrontal cortex (VMPFC) play conserved, critical but distinct roles in this process. While OFC may use specific sensory associations to enhance task-relevant information, particularly in the context of learning, VMPFC plays a role in ensuring irrelevant information does not impinge on the decision in hand. PMID- 26937447 TI - Using Intermediate Cognitive Endpoints to Facilitate Translational Research in Psychosis. AB - Recent advances in the understanding of psychosis have uncovered potential for a paradigm shift in related drug discovery efforts. The study of psychosis is evolving from its origins in serendipity and empiricism to more formal, hypothesis driven accounts of the cognitive substrates underlying hallucinations and delusions. Recent evidence suggests that misattribution of salience and abnormal prediction error might underlie some forms of psychosis. If substantiated, such intermediate constructs could significantly facilitate translational research for drug discovery. Aberrant salience and prediction error can be assayed with simple tests of associative learning in both species, and a convincing back translation of effects, when combined with measures of neurotransmitter release and brain activity could for the first time allow robust, causal connections to be made between molecular mechanisms in rodents and symptoms in patients. PMID- 26937448 TI - Data from camera surveys identifying co-occurrence and occupancy linkages between fishers (Pekania pennanti), rodent prey, mesocarnivores, and larger predators in mixed-conifer forests. AB - These data provide additional information relevant to the frequency of fisher detections by camera traps, and single-season occupancy and local persistence of fishers in small patches of forest habitats detailed elsewhere, "Landscape Fuel Reduction, Forest Fire, and Biophysical Linkages to Local Habitat Use and Local Persistence of Fishers (Pekania pennanti) in Sierra Nevada Mixed-conifer Forests" [10]. The data provides insight on camera trap detections of 3 fisher predators (bobcat [Lynx rufus]). Coyote [Canis latrans], mountain lion [Puma concolor], 5 mesocarnivores in the same foraging guild as fishers (gray fox [Urocyon cinereoargenteus]) ringtail [Bassariscus astutus], marten [Martes americana], striped skunk [Mephitis mephitis] spotted skunk [Spilogale gracilis], and 5 Sciuridae rodents that fishers consume as prey (Douglas squirrel [Tamiasciurus douglasii]), gray squirrel [Sciurus griseus], northern flying squirrel [Glaucomys sabrinus], long-eared chipmunk [Neotamias quadrimaculatus], California ground squirrel [Spermophilus beecheyi]. We used these data to identify basic patterns of co-occurrence with fishers, and to evaluate the relative importance of presence of competing mesocarnivores, rodent prey, and predators for fisher occupancy of small, 1 km(2) grid cells of forest habitat. PMID- 26937449 TI - Data set for comparison of cellular dynamics between human AAVS1 locus-modified and wild-type cells. AB - This data article describes cellular dynamics, such as migration speed and mobility of the cytoskeletal protein, of wild-type human fibroblast cells and cells with a modified adeno-associated virus integration site 1 (AAVS1) locus on human chromosome 19. Insertion of exogenous gene into the AAVS1 locus has been conducted in recent biological researches. Previously, our data showed that the AAVS1-modification changes cellular contractile force (Mizutani et al., 2015 [1]). To assess if this AAVS1-modification affects cell migration, we compared cellular migration speed and turnover of cytoskeletal protein in human fibroblasts and fibroblasts with a green fluorescent protein gene knocked-in at the AAVS1 locus in this data article. Cell nuclei were stained and changes in their position attributable to cell migration were analyzed. Fluorescence recovery was observed after photobleaching for the fluorescent protein-tagged myosin regulatory light chain. Data here are related to the research article "Transgene Integration into the Human AAVS1 Locus Enhances Myosin II-Dependent Contractile Force by Reducing Expression of Myosin Binding Subunit 85" [1]. PMID- 26937450 TI - Proteomic analysis of SETD6 interacting proteins. AB - SETD6 (SET-domain-containing protein 6) is a mono-methyltransferase that has been shown to methylate RelA and H2AZ. Using a proteomic approach we recently identified several new SETD6 substrates. To identify novel SETD6 interacting proteins, SETD6 was immunoprecipitated (IP) from Human erythromyeloblastoid leukemia K562 cells. SETD6 binding proteins were subjected to mass-spectrometry analysis resulting in 115 new SETD6 binding candidates. STRING database was used to map the SETD6 interactome network. Network enrichment analysis of biological processes with Gene Ontology (GO) database, identified three major groups; metabolic processes, muscle contraction and protein folding. PMID- 26937451 TI - Data on cell spread area and directional contraction in human umbilical vein endothelial cells on fibronectin and on collagen type I-coated micro-posts. AB - Fibronectin and collagen type I are abundant extracellular matrix proteins that modulate cell mechanics and they regulate angiogenic sprouting. In this data article, fibronectin- or collagen type I-coated micro-posts were used to examine the traction force, cell spread area and directional contraction of human umbilical vein endothelial cells (HUVECs). PMID- 26937452 TI - Dataset on the effects of CYB5D2 on the distribution of HeLa cervical cancer cell cycle. AB - We have recently reported that CYB5D2 plays a role in suppression of cervical cancer tumorigenesis, "CYB5D2 displays tumor suppression activities towards cervical cancer" [1]. We provide the accompany data here describing the effects of CYB5D2 overexpression and addition of recombinant CYB5D2 on HeLa cell cycle distribution. Furthermore, we will present the conditions used to specifically determine CYB5D2 expression in primary cervical and cervical cancer tissues using immunohistochemistry (IHC) and the patient cohort involved in assessing the CYB5D2 protein levels in primary cervical and cervical cancer tissues. PMID- 26937453 TI - Mobile reminders to improve opportunistic screening of type 2 diabetes mellitus: Data documentation and data analysis plan of a randomized trial data. AB - This Data in Brief article contains individual level data of a randomized trial in a primary care setting. This trial offered mobile reminder to follow up for definitive tests during opportunistic screening of diabetes mellitus in Puducherry, India (2014). ("Effect of mobile reminders on screening yield during opportunistic screening for type 2 diabetes mellitus in a primary health care setting: a randomized trial" (Kumar et al., 2015) [1]) Variables collected included the baseline characteristics of study participants (n=390) and information on initial screening and eligibility for definitive test, study group (intervention/control), follow up for definitive test and definitive test results. The data was double entered with adequate checks and validated in EpiData. Final data after correcting the data entry errors has been shared here. In addition, we have shared data entry plan, EpiData triplet files for data entry and program file for data analysis. They may be used by other researchers who intend to replicate this research in their setting. PMID- 26937454 TI - Data on final calcium concentration in native gel reagents determined accurately through inductively coupled plasma measurements. AB - In this article we present data on the concentration of calcium as determined by Inductively Coupled Plasma (ICP) measurements. Calcium was estimated in the reagents used for native gel electrophoresis of Neuronal Calcium Sensor (NCS) proteins. NCS proteins exhibit calcium-dependent mobility shift in native gels. The sensitivity of this shift to calcium necessitated a precise determination of calcium concentrations in all reagents used. We determined the calcium concentrations in different components used along with the samples in the native gel experiments. These were: 20 mM Tris pH 7.5, loading dye and running buffer, with distilled water as reference. Calcium determinations were through ICP measurements. It was found that the running buffer contained calcium (244 nM) over the blank. PMID- 26937455 TI - Global protein expression dataset acquired during isoniazid-induced cytoprotection against H2O2 challenge in HL-60 cells. AB - Isoniazid (INH) is one of the first-line anti-tuberculosis drugs. Its effect on oxidative stress, however, is unknown. Here we used a model of oxidative stress by employing glucose/glucose oxidase (GOx), which (based on the availability of glucose and oxygen) is known to produce H2O2. This reaction induces oxidative stress culminating in necrotic cell death in HL-60 cells (a human promyelocytic leukemia cell line). The changes in protein levels have been quantified using global proteome expression changes through stable isotope labeling by amino acids in cell culture (SILAC) followed by LC-MS/MS analysis. A total of 1459 and 1712 proteins were identified in forward and reverse experiments, respectively. However, only 390 proteins were reproducibly identified in both samples. These 390 proteins were taken into account for further analysis which has been described in "Cytoprotective effect of isoniazid against H2O2 derived injury in HL-60 cells" [1]. PMID- 26937456 TI - Drivers' merging behavior data in highway work zones. AB - There have been growing research interests in finding a suitable work zone layout to improve work zone safety and traffic efficiency. This paper contains data supporting the research article entitled: Effects of work zone configurations and traffic density on performance variables and subjective workload (Shakouri et al., 2014 [1]). A full factorial experiment was conducted to compare the efficiency of two work zone configurations by using a driving simulator with two levels of work zone configuration, two levels of traffic density and three levels of sign placement as fixed factors. Seven female and 23 male participants completed the experiment. In this paper we present the data relating to demographic information of participants, driving simulator data and subjective workload evaluation of participants for each work zone. PMID- 26937457 TI - X-ray, Cryo-EM, and computationally predicted protein structures used in integrative modeling of HIV Env glycoprotein gp120 in complex with CD4 and 17b. AB - We present the data used for an integrative approach to computational modeling of proteins with large variable domains, specifically applied in this context to model HIV Env glycoprotein gp120 in its CD4 and 17b bound state. The initial data involved X-ray structure PDBID:1GC1 and electron microscopy image EMD:5020. Other existing X-ray structures were used as controls to validate and hierarchically refine partial and complete computational models. A summary of the experiment protocol and data was published (Rasheed et al., 2015) [26], along with detailed analysis of the final model (PDBID:3J70) and its implications. PMID- 26937458 TI - Mean-variance portfolio analysis data for optimizing community-based photovoltaic investment. AB - The amount of electricity generated by Photovoltaic (PV) systems is affected by factors such as shading, building orientation and roof slope. To increase electricity generation and reduce volatility in generation of PV systems, a portfolio of PV systems can be made which takes advantages of the potential synergy among neighboring buildings. This paper contains data supporting the research article entitled: PACPIM: new decision-support model of optimized portfolio analysis for community-based photovoltaic investment [1]. We present a set of data relating to physical properties of 24 houses in Oregon, USA, along with simulated hourly electricity data for the installed PV systems. The developed Matlab code to construct optimized portfolios is also provided in . The application of these files can be generalized to variety of communities interested in investing on PV systems. PMID- 26937459 TI - Comparative proteomics dataset of skimmed milk samples from Holstein and Jersey dairy cattle. AB - Milk samples were collected from Holstein and Jersey breeds of dairy cattle maintained under the same management practices and environmental conditions over a seven-day period. Milk samples were collected twice daily from six cows of each breed as previously described (Tacoma et al., 2016) [1]. Samples were composited within individual cow over the experimental period and skimmed to remove the fat layer. Skimmed milk samples were fractionated using CaCl2 precipitation, ultracentrifugation and ProteoMiner treatment to remove the high abundance milk proteins. Separation of the low abundance proteins was achieved using SDS-PAGE. Differential protein abundances were analyzed by mass spectrometry-based proteomic approaches followed by statistical analyses of the peptide count data. The complete list of low-abundance proteins identified in both breeds is provided in the dataset as well as the total number of distinct sequenced peptides and gene ontology functions for each protein. The relative abundance of a select few proteins is depicted using the SIEVE software. PMID- 26937460 TI - Linearity analysis and comparison study on the epoc((r)) point-of-care blood analysis system in cardiopulmonary bypass patients. AB - The epoc((r)) blood analysis system (Epocal Inc., Ottawa, Ontario, Canada) is a newly developed in vitro diagnostic hand-held analyzer for testing whole blood samples at point-of-care, which provides blood gas, electrolytes, ionized calcium, glucose, lactate, and hematocrit/calculated hemoglobin rapidly. The analytical performance of the epoc((r)) system was evaluated in a tertiary hospital, see related research article "Analytical evaluation of the epoc((r)) point-of-care blood analysis system in cardiopulmonary bypass patients" [1]. Data presented are the linearity analysis for 9 parameters and the comparison study in 40 cardiopulmonary bypass patients on 3 epoc((r)) meters, Instrumentation Laboratory GEM4000, Abbott iSTAT, Nova CCX, and Roche Accu-Chek Inform II and Performa glucose meters. PMID- 26937461 TI - Comprehensive data analysis of human ureter proteome. AB - Comprehensive human ureter proteome dataset was generated from OFFGel fractionated ureter samples. Our result showed that among 2217 non-redundant ureter proteins, 751 protein candidates (33.8%) were detected in urine as urinary protein/polypeptide or exosomal protein. On the other hand, comparing ureter protein hits (48) that are not shown in corresponding databases to urinary bladder and prostate human protein atlas databases pinpointed 21 proteins that might be unique to ureter tissue. In conclusion, this finding offers future perspectives for possible identification of ureter disease-associated biomarkers such as ureter carcinoma. In addition, Cytoscape GO annotation was examined on the final ureter dataset to better understand proteins molecular function, biological processes, and cellular component. The ureter proteomic dataset published in this article will provide a valuable resource for researchers working in the field of urology and urine biomarker discovery. PMID- 26937462 TI - Survey data on entrepreneurs' subjective plan and perceptions of the likelihood of success. AB - Entrepreneurship is an important economic process in both developed and developing worlds. Nonetheless, many of its concepts appear to be difficult to 'operationalize' due to lack of empirical data; and this is particularly true with emerging economy. The data set described in this paper is available in Mendeley Data's "Vietnamese entrepreneurs' decisiveness and perceptions of the likelihood of success/continuity, Vuong (2015) [1]" http://dx.doi.org/10.17632/kbrtrf6hh4.2; and can enable the modeling after useful discrete data models such as BCL. PMID- 26937463 TI - Data from molecular dynamics simulations in support of the role of human CES1 in the hydrolysis of Amplex Red. AB - This data article contains the results of molecular dynamics (MD) simulations performed to assess the stability of the previously computed complex between the hCES1 structure and the Amplex Red (AR) substrate (Miwa et al., 2015) [1] and to compare the dynamic behavior of this complex with that of the corresponding hCES1 deacetylAR product. The study involves both standard molecular dynamics (MD) and steered (SMD) simulations to offer a quantitative comparison of the stability for the two complexes. With regard the standard MD runs, the data article graphically reports the r.m.s.d. profile of the ligand's atoms as well as the dynamic behavior of key contacts involving the catalytic Ser221 residue. The SMD simulations provide a comparison of the pull forces required to undock the two ligands and reveal that Van der Waals and hydrophobic interactions play a key role in complex stabilization. PMID- 26937464 TI - Toxicological data of some antibiotics and pesticides to fish, mosquitoes, cyanobacterial mats and to plants. AB - This article provides toxicological data of antibiotics to fish and mosquito (El Nahhal and El-dahdaouh, 2015) (doi: 10.5132/eec.2015.01.03 [1]), to cyanobacteria (El-Nahhal and Alshanti, 2015)(dx.doi.org/10.4172/2161-0525.1000274 [2]) and pesticides to plants (El-Nahhal and Hamdona, 2015) (doi.10.1186/s40064-015-1148-7 [3]). The data provided herein described the experimental procedure and calculation of the appropriate toxicity parameters, lethal concentrations (LC50) required to kill 50% of tested animal, percentage growth inhibition, relative toxicity (RT) and Mixture toxicity index. Moreover, the data enable the readers to perform future experiments and open future discussion with other authors elsewhere and generate future research guidelines which benefit the young scientific community around the globe in the field of mixture toxicity. PMID- 26937465 TI - Fatigue data for polyether ether ketone (PEEK) under fully-reversed cyclic loading. AB - In this article, the data obtained from the uniaxial fully-reversed fatigue experiments conducted on polyether ether ketone (PEEK), a semi-crystalline thermoplastic, are presented. The tests were performed in either strain controlled or load-controlled mode under various levels of loading. The data are categorized into four subsets according to the type of tests, including (1) strain-controlled fatigue tests with adjusted frequency to obtain the nominal temperature rise of the specimen surface, (2) strain-controlled fatigue tests with various frequencies, (3) load-controlled fatigue tests without step loadings, and (4) load-controlled fatigue tests with step loadings. Accompanied data for each test include the fatigue life, the maximum (peak) and minimum (valley) stress-strain responses for each cycle, and the hysteresis stress-strain responses for each collected cycle in a logarithmic increment. A brief description of the experimental method is also given. PMID- 26937466 TI - Urbanization data of Samara city, Russia. AB - A method has been developed for urbanization by using satellite data and socio economic data. These datasets consists three decade Landsat images and population data. A detailed description using flow chart is given to show how to use this data to produce land use/cove maps. The land use/cove maps were used to know the urban growth in Samara City, Russia. PMID- 26937467 TI - Digital image quantification of siderophores on agar plates. AB - This article presents visual image data and detailed methodology for the use of a new method for quantifying the exudation of siderophores during fungal growth. The data include images showing time series for calibration, fungal exudation, and negative controls, as well as replication accuracy information. In addition, we provide detailed protocols for making CAS assay layer plates, the digital analysis protocol for determining area of color change, and discuss growth media that do and do not work with the layer plate method. The results of these data, their interpretation, and further discussion can be found in Andrews et al., 2016 [1]. PMID- 26937468 TI - Gene expression microarray data from human microvascular endothelial cells supplemented with a low concentration of niacin. AB - The systemic lipid modifying drug, niacin, can directly improve human microvascular endothelial cell angiogenic function under lipotoxic conditions, possibly through activation of niacin receptors "Niacin receptor activation improves human microvascular endothelial cell angiogenic function during lipotoxicity" (Hughes-Large et al. 2014). Here we provide accompanying data collected using Affymetrix GeneChip microarrays to identify changes in gene expression in human microvascular endothelial cells treated with 10 MUM niacin. Statistical analyses of robust multi-array average (RMA) values revealed that only 16 genes exhibited greater than 1.3-fold differential expression. Of these 16, only 5 were identified protein coding genes, while 3 of the remaining 11 genes appeared to be small nuclear/nucleolar RNAs. Altered expression of EFCAB4B, NAP1L2, and OR13C8 was confirmed by real time quantitative PCR. PMID- 26937469 TI - Proteome identification of the silkworm middle silk gland. AB - To investigate the functional differentiation among the anterior (A), middle (M), and posterior (P) regions of silkworm middle silk gland (MSG), their proteomes were characterized by shotgun LC-MS/MS analysis with a LTQ-Orbitrap mass spectrometer. To get better proteome identification and quantification, triplicate replicates of mass spectrometry analysis were performed for each sample. The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium (Vizcaino et al., 2014) [1] via the PRIDE partner repository (Vizcaino, 2013) [2] with the dataset identifier PXD003371. The peptide identifications that were further processed by PeptideProphet program in Trans-Proteomic Pipeline (TPP) after database search with Mascot software were also available in .XML format files. Data presented here are related to a research article published in Journal of Proteomics by Li et al. (2015) [3]. PMID- 26937470 TI - Illumina next generation sequencing data and expression microarrays data from retinoblastoma and medulloblastoma tissues. AB - Retinoblastoma (Rb) is a pediatric intraocular malignancy and probably the most robust clinical model on which genetic predisposition to develop cancer has been demonstrated. Since deletions in chromosome 13 have been described in this tumor, we performed next generation sequencing to test whether recurrent losses could be detected in low coverage data. We used Illumina platform for 13 tumor tissue samples: two pools of 4 retinoblastoma cases each and one pool of 5 medulloblastoma cases (raw data can be found at http://www.ebi.ac.uk/ena/data/view/PRJEB6630). We first created an in silico reference profile generated from a human sequenced genome (GRCh37p5). From this data we calculated an integrity score to get an overview of gains and losses in all chromosomes; we next analyzed each chromosome in windows of 40 kb length, calculating for each window the log2 ratio between reads from tumor pool and in silico reference. Finally we generated panoramic maps with all the windows whether lost or gained along each chromosome associated to its cytogenetic bands to facilitate interpretation. Expression microarrays was done for the same samples and a list of over and under expressed genes is presented here. For this detection a significance analysis was done and a log2 fold change was chosen as significant (raw data can be found at http://www.ncbi.nlm.nih.gov/geo/accession number GSE11488). The complete research article can be found at Cancer Genetics journal (Garcia-Chequer et al., in press) [1]. In summary here we provide an overview with visual graphics of gains and losses chromosome by chromosome in retinoblastoma and medulloblastoma, also the integrity score analysis and a list of genes with relevant expression associated. This material can be useful to researchers that may want to explore gains and losses in other malignant tumors with this approach or compare their data with retinoblastoma. PMID- 26937471 TI - Data on plasma levels of apolipoprotein E, correlations with lipids and lipoproteins stratified by APOE genotype, and risk of ischemic heart disease. AB - Data on correlations of plasma apoE with levels of lipids and lipoproteins stratified by APOE genotypes as well as data exploring the association between plasma levels of apoE and risk of ischemic heart disease (IHD) are wanted. The present data on 91,695 individuals from the general population provides correlations between plasma levels of apoE and lipids and lipoproteins for the three APOE genotypes epsilon33, epsilon44 and epsilon22, representing each of the three apoE isoforms. Further, data on extreme groups of plasma apoE (highest 5%) versus lower levels of apoE at enrollment explores risk of IHD and myocardial infarction (MI) and is given as hazard ratios. In addition, IHD and MI as a function of apoE/high-density lipoprotein (HDL) cholesterol ratio, as well as data on lipids, lipoproteins and apolipoproteins are given as hazard ratios. Data is stratified by gender and presented for the Copenhagen General Population Study and the Copenhagen City Heart Study combined. PMID- 26937472 TI - Data characterizing tensile behavior of cenosphere/HDPE syntactic foam. AB - The data set presented is related to the tensile behavior of cenosphere reinforced high density polyethylene syntactic foam composites "Processing of cenosphere/HDPE syntactic foams using an industrial scale polymer injection molding machine" (Bharath et al., 2016) [1]. The focus of the work is on determining the feasibility of using an industrial scale polymer injection molding (PIM) machine for fabricating syntactic foams. The fabricated syntactic foams are investigated for microstructure and tensile properties. The data presented in this article is related to optimization of the PIM process for syntactic foam manufacture, equations and procedures to develop theoretical estimates for properties of cenospheres, and microstructure of syntactic foams before and after failure. Included dataset contains values obtained from the theoretical model. PMID- 26937473 TI - Proteome stability analysis of snap frozen, RNAlater preserved, and formalin fixed paraffin-embedded human colon mucosal biopsies. AB - Large repositories of well characterized RNAlater preserved samples and formalin fixed, paraffin-embedded samples have been generated worldwide. However, the impact on the proteome of the preservation methods remain poorly described. Therefore, we analyzed the impact on the proteome of preserving samples in RNAlater, and by formalin-fixation, paraffin-embedding on human soft tissue, using directly frozen samples as a control ("Comparing the proteome of snap frozen, RNAlater preserved, and formalin-fixed paraffin-embedded human tissue samples" [1]). We here report the data from the analysis. The comparative analysis was performed on 24 colon mucosa biopsies, extracted from the sigmoideum of two gastroenterologically healthy participants for the purpose of this study. A set of biopsies were additionally stored for 30 min at room temperature prior to formalin-fixation. The samples were analyzed by high throughput gel free quantitative proteomics. The MS proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PRIDE: PXD002029. PMID- 26937474 TI - Data on megakaryocytes in the bone marrow of mice exposed to formaldehyde. AB - Previously, we reported that occupational exposure to formaldehyde (FA) exposure in factory workers reduced platelet counts, http://dx.doi.org/10.1158/1055 9965.EPI-09-0762[1], while exposure in mice increased platelet counts http://dx.doi.org/10.1371/journal.pone.0074974[2]. Bone marrow megakaryocyte (MK) numbers were also increased in exposed mice, as determined qualitatively. The data presented here are from a quantitative evaluation of MK numbers in the bone marrow histopathological slides from the previous FA exposure experiments in mice. Bone marrow slides were prepared using a single 5 MUm section of femur from 2 mice randomly selected from each exposure group (n=9) treated with 0, 0.5 and 3.0 mg/m(3) FA by nose-only inhalation. MKs were systemically counted and average MK frequency was calculated as the total MK per slide divided by the number of fields evaluated. Data are presented visually as microscopy views and graphically as MK frequency. PMID- 26937475 TI - Fast sorption measurements of volatile organic compounds on building materials: Part 1 - Methodology developed for field applications. AB - A Proton Transfer Reaction-Mass Spectrometer (PTR-MS) has been coupled to the outlet of a Field and Laboratory Emission Cell (FLEC), to measure volatile organic compounds (VOC) concentration during a sorption experiments (Rizk et al., this issue) [1]. The limits of detection of the PTR-MS for three VOCs are presented for different time resolution (2, 10 and 20 s). The mass transfer coefficient was calculated in the FLEC cavity for the different flow rates. The concentration profile obtained from a sorption experiment performed on a gypsum board and a vinyl flooring are also presented in comparison with the profile obtained for a Pyrex glass used as a material that do not present any sorption behavior (no sink). Finally, the correlation between the concentration of VOCs adsorbed on the surface of the gypsum board at equilibrium (Cse ) and the concentration of VOCs Ce measured in the gas phase at equilibrium is presented for benzene, C8 aromatics and toluene. PMID- 26937476 TI - Successful pregnancy following myomectomy for uterine smooth muscle tumor of uncertain malignant potential: A case report and review of the literature. AB - *STUMPs are rare smooth muscle tumors with an overall favorable prognosis.*Pregnancy is possible after diagnosis of STUMP treated with myomectomy*Management of patients desiring fertility with STUMPs requires a multidisciplinary approach. PMID- 26937478 TI - Commment on the review entitled "A critical appraisal of hyperthermic intraperitoneal chemotherapy (HIPEC) in the treatment of advanced and recurrent ovarian cancer" by Chiva LM and Gonzalez-Martin A. AB - *We raised some methodological concerns and made some comments on the systematic review by Chiva and colleague.*To state that Cytoreduction & HIPEC is not beneficial in front line and platinum sensitive recurrence is highly disputable.*Anyway, the combined treatment should be offered in the context of clinical trial; randomized data are urgently needed. PMID- 26937477 TI - Prolonged response to exemestane following multiple surgical resections and hormonal therapies in a patient with recurrent endometrial stromal sarcoma. AB - BACKGROUND: Endometrial stromal sarcomas (ESSs) are rare, indolent tumors with high recurrence rates. Management includes surgery and hormonal therapy given high estrogen and progesterone receptor (ER/PR) expression. CASE: A pre menopausal patient with stage II ESSs (ER +/PR +) underwent primary surgery followed by adjuvant megestrol. Recurrence in the bladder/upper vagina (ER +/PR ) was diagnosed one year later and treated with anterior pelvic exenteration and adjuvant letrozole. Two years later she recurred and was treated with radical surgery and adjuvant exemestane therapy (tumor ER strongly +/PR +). The patient then had a five-year disease free interval before being diagnosed with her third recurrence (ER +). CONCLUSION: Exemestane treatment for ESSs can lead to a prolonged response, even in the setting of progression after prior aromatase inhibitor treatment. PMID- 26937479 TI - Pilomatrix carcinoma of the vulva. AB - BACKGROUND: Pilomatrix carcinomas are rare, frequently occurring in older male patients. We report a case of vulvar pilomatrix carcinoma in a 30-year-old woman, the second known reported case occurring on the external genitalia. CASE: A 30 year-old female originally presented at an outside institution for the management of an asymptomatic vulvar mass that was biopsied and read as invasive squamous cell carcinoma. Pathology review at our institution reclassified the vulvar mass as a low-grade pilomatrix carcinoma. The patient underwent radical hemivulvectomy without an inguinal-femoral groin node dissection. She has remained without evidence of disease recurrence for more than 5 years since her diagnosis. CONCLUSION: Pilomatrix carcinoma can be confused for an invasive squamous cell carcinoma. Due to its low risk of metastases, a less radical surgical approach can be taken. Consideration of this unusual malignancy is important in the determination of appropriate management. PMID- 26937481 TI - Sertoli-Leydig cell tumor of the ovary: A diagnostic dilemma. AB - BACKGROUND: Sertoli-Leydig cell tumors are rare sex-cord stromal tumors of the ovary that can present with a variety of histological elements, which may complicate diagnosis and treatment. CASE: A 40-year-old female presenting with pelvic pain is found to have a large complex right adnexal mass and elevated alpha-fetoprotein. The mass was diagnosed as a Sertoli-Leydig cell tumor with heterologous elements including carcinoid and hepatoid components. She was treated with surgical resection followed by adjuvant chemotherapy and remains clear of disease. CONCLUSION: Prognostic indicators for Sertoli-Leydig cell tumors include degree and type of heterologous element differentiation. Thorough characterization of such elements is crucial for adequate diagnosis and treatment. PMID- 26937480 TI - Noninvasive test for the diagnosis of ovarian hormone-secreting-neoplasm in postmenopausal women. AB - CONTEXT: The diagnosis of ovarian hormone-secreting neoplasm in postmenopausal women is currently based on imaging modalities and selective venography. However, these diagnostic tests are not always accurate. In order to improve and simplify the diagnosis, we propose a noninvasive hormonal test. OBJECTIVE: To report our experience using noninvasive hormonal test for the diagnosis of ovarian hormone producing tumor in two postmenopausal women. DESIGN AND INTERVENTION: Evaluation of androgen and estradiol serum levels following 1. Adrenal hormonal depression, 2. ovarian hormonal depression and 3. ovarian hormonal stimulation. SETTING: Tertiary care medical center. MAIN OUTCOME MEASURES: Changes in androgen and estradiol levels. RESULTS: In the first case, total testosterone, free androgen index and estradiol serum levels decreased following ovarian depression by GnRH antagonist (6.9 nmol/L, 67 nmol/L and < 70 pmol/L, respectively) and subsequently increased after ovarian stimulation with LH (11.5 nmol/L, 117 nmol/L and 176 pmol/L, respectively). Histological evaluation revealed steroid cell tumor in one ovary. In the second case, estradiol serum levels decreased following ovarian depression by GnRH-antagonist (73 pmol/L) and subsequently increased following ovarian stimulation with FSH (118 pmol/L). Histological evaluation revealed granulosa cell tumor in one ovary. CONCLUSIONS: To our knowledge, these are the first cases of ovarian hormone-producing tumors in postmenopausal women diagnosed by noninvasive hormonal test. The proposed test can be considered in postmenopausal women suspected of having androgen and/or estrogen producing tumors. PMID- 26937482 TI - Retreatment with aromatase inhibitor therapy in the management of granulosa cell tumor. AB - *Over 90% of granulosa cell tumors have a FOXL2 mutation that contributes to aromatase upregulation.*Chemotherapy has demonstrated limited efficacy in the treatment of granulosa cell tumors.*A patient with recurrent granulosa cell tumor responded briefly to anastrazole treatment.*Retreatment with another aromatase inhibitor letrozole led to a durable response of 24 months. PMID- 26937483 TI - Uterine tumors resembling ovarian sex-cord tumor: A case-report and a review of literature. PMID- 26937484 TI - A prospective pilot study on the incidence of post-operative lymphedema in women with endometrial cancer. AB - To determine the incidence of lower-extremity lymphedema after surgical therapy including lymphadenectomy in endometrial cancer patients using standardized leg measurements. Also, to determine additional risk factors for the development of lymphedema and to study the effect of lymphedema on one's quality of life. In this prospective cohort study, patients with the diagnosis of endometrial cancer who were to undergo definitive surgical management were evaluated pre-operatively and followed post-operatively over the course of two years. Standardized leg measurements were performed by the same individuals at six time-points. Subjects also completed a standardized quality-of-life survey at each time-point. The incidence of lymphedema in 39 women with endometrial cancer using a standardized leg measurement protocol was 12.8% with lymphedema defined as a 20% increase in post-operative leg measurements. There was no significant association between the development of lymphedema and the number of pelvic or para-aortic lymph nodes removed, medical comorbidities, or surgical approach (p > 0.05). Of the five patients who met criteria for lymphedema, only one had worsening quality-of-life concerns post-operatively on the FACT-En, version 4, survey. This is the first prospective study using standardized leg measurements to calculate the incidence of post-operative lymphedema in endometrial cancer. Medical comorbidities, surgical approach, number of lymph nodes removed, and location of lymph nodes removed did not appear to affect the development of lymphedema in this cohort. A prospective, multicenter trial is needed to confirm these findings and to further assess the impact of lymphedema on one's quality of life. PMID- 26937485 TI - Ovarian carcinoma initially presenting as breast cancer two years prior to diagnosis: A case report and review of literature. AB - *Ovarian cancer presenting as a primary breast cancer two years prior*Ovarian cancer with metastases to breast is rare.*Metastases to the breast generally present as a recurrence.*Delay in diagnosis likely due to chemotherapy given for breast disease. PMID- 26937486 TI - Epithelioid sarcoma of the vulva and its clinical implication: A case report and review of the literature. AB - *We present a case of vulva epithelioid sarcoma, and review the articles.*The rarity of this disease causes delay in diagnosis and lack of guideline for optimal treatment.*Physicians should have high suspicions in diagnosing this vulvar disease using prompt biopsy without delay. PMID- 26937487 TI - Unequal burden of sleep-related obesity among black and white Americans. AB - BACKGROUND: This study ascertained whether individuals of the black race/ethnicity are unequally burdened by sleep-related overweight/obesity. METHODS: Analysis was based on data obtained from Americans (ages, 18-85 years) in the National Health Interview Survey (1977-2009). Sleep duration was coded as either very short sleep (VSS) (<=5 hours), short sleep (SS) (5-6 hours), or long sleep (>8 hours), referenced to 7-8-hour sleepers. Overweight was defined as body mass index (BMI) >=25.0 and <=29.9 kg/m2 and obesity, BMI >=30 kg/m2, referenced to normal weight (BMI = 18.5-24.9 kg/m2). RESULTS: Multivariate-adjusted regression analyses indicated that, among whites, VSS was associated with a 10% increased likelihood of being overweight and 51% increased likelihood of being obese, relative to 7-8-hour sleepers. Short sleep was associated with a 13% increased likelihood of being overweight and 45% increased likelihood of being obese. Long sleep was associated with 21% increased likelihood of being obese. Among blacks, VSS was associated with a 76% increased likelihood of being overweight and 81% increased likelihood of being obese. Short sleep was associated with a 16% increased likelihood of being overweight and 32% increased likelihood of being obese. As for the white stratum, long sleep was associated with a 25% increased likelihood of being obese. CONCLUSION: Our investigation demonstrates strong linkages between inadequate sleep and overweight/ obesity among black and white Americans. Although it cannot be said that insufficient sleep causes overweight/obesity, individuals of the black race/ethnicity sleeping <=5 hours may be unequally burdened by sleep-related overweight/obesity. PMID- 26937488 TI - Diversity at the Water-Metal Interface: Metal, Water Thickness, and Confinement Effects. AB - The structure and properties of water films in contact with metal surfaces are crucial to understand the chemical and electrochemical processes involved in energy-related technologies. The nature of thin water films on Pd, Pt, and Ru has been investigated by first-principles molecular dynamics to assess how the chemistry at the water-metal surface is responsible for the diversity in the behavior of the water layers closer to the metal. The characteristics of liquid water: the radial distribution functions, coordination, and fragment speciation appear only for unconfined water layers of a minimum of 1.4 nm thick. In addition, the water layer is denser in the region closest to the metal for Pd and Pt, where seven- and five-membered ring motifs appear. These patterns are identical to those identified by scanning tunneling microscopy for isolated water bilayers. On Ru densification at the interface is not observed, water dissociates, and protons and hydroxyl groups are locked at the surface. Therefore, the acid-base properties in the area close to the metal are not perturbed, in agreement with experiments, and the bulk water resembles an electric double layer. Confinement affects water making it closer to ice for both structural and dynamic properties, thus being responsible for the higher viscosity experimentally found at the nanoscale. All these contributions modify the solvation of reactants and products at the water-metal interface and will affect the catalytic and electrocatalytic properties of the surface. PMID- 26937489 TI - Previous Injury and Chronic Pain are Associated with Side of Onset in Parkinson's Disease. AB - BACKGROUND: Parkinson's disease (PD) motor symptoms are frequently asymmetric and the factors that influence the side of onset are unclear. OBJECTIVE: To explore whether peripheral injury and associated chronic limb pain may influence the side of onset. METHODS: We administered a questionnaire to 128 PD patients in a tertiary movement disorder clinic. Handedness, date and type of limb injury(s) and duration of associated pain, and date and side of onset were ascertained. RESULTS: Sixty-two subjects reported limb injuries prior to the onset of PD symptoms, 30 with and 32 without chronic pain (i.e., >= 2 months). There was no association between injury and PD onset side overall (p=0.334). In subjects with chronic pain associated with limb injuries, however, side of injuries was associated with the side of PD symptom onset (p=0.030). CONCLUSIONS: Limb injury with chronic pain may be related to the side of PD symptom onset. Future studies may shed light on the nature of this observation. PMID- 26937492 TI - Olaparib for the treatment of ovarian cancer. AB - Olaparib, an oral poly(ADP-ribose) polymerase (PARP) inhibitor, is the first FDA approved drug in its class for patients with ovarian cancer, specifically in a subset of patients with BRCA mutations and prior chemotherapy treatments. PARP inhibitors have had other implications in different solid tumor types including breast, gastric and pancreatic malignancies. In light of the recent FDA approval of olaparib for the treatment of ovarian cancer, this article aims to outline the mechanisms and implications of the drug. With a favorable adverse event profile and improved outcomes, including progression-free survival, olaparib has demonstrated augmentation to therapeutic options in the treatment of ovarian cancer. PMID- 26937491 TI - Isavuconazonium sulfate for the treatment of fungal infection. AB - Isavuconazole is a new azole antifungal drug with a broad antifungal spectrum that includes yeasts, molds and dimorphic fungi. Its prodrug, isavuconazonium sulfate, is currently approved in the United States and Europe for the treatment of the two of the most common and most challenging invasive fungal infections in clinical practice, invasive aspergillosis and invasive mucormycosis. It is available in both oral and intravenous formulations for once-a-day dosing and has favorable safety profile and drug interaction potential in comparison to voriconazole. Its role in the treatment of other fungal infections, besides aspergillosis and mucormycosis, remains to be determined. Similarly, its efficacy in prophylaxis against invasive fungal infections or its utility in patients with prior azole exposure is yet to be elucidated in clinical studies. PMID- 26937494 TI - The year's new drugs & biologics 2015: Part I. AB - Nearly 100 new drugs and biologics, including important new line extensions, were approved or launched for the first time globally in 2015. These products are covered in depth in part I of our annual review of the pharma and biotech industry. PMID- 26937493 TI - Suvorexant: efficacy and safety profile of a dual orexin receptor antagonist in treating insomnia. AB - Suvorexant is a hypnotic representing the first-in-class of a new group of agents known as dual orexin receptor antagonists. They target cerebral orexin receptors which, when activated, contribute to arousal and wakefulness. Suvorexant was shown to decrease sleep onset times and increase sleep duration, whether assessed objectively by polysomnography or subjectively by sleep diaries in primary insomnia patients. Overall tolerability was good, with somnolence being the commonest adverse event (<= 7% in 3-month studies). No strong signals for rebound or withdrawal were seen after 1-12 months of treatment and few adverse events suggestive of residual psychomotor or cognitive events have been recorded. Further studies are required in patients with insomnia comorbid with depression and head-to-head studies with established hypnotics such as zolpidem and eszopiclone. Studies augmenting the small number of patients evaluating the initial recommended dose (10 mg) would also be prudent. PMID- 26937495 TI - Advancements of molecularly imprinted polymers in the food safety field. AB - Molecularly imprinted technology (MIT) has been widely employed to produce stable, robust and cheap molecularly imprinted polymer (MIP) materials that possess selective binding sites for recognition of target analytes in food, such as pesticides, veterinary drugs, mycotoxins, illegal drugs and so on. Because of high selectivity and specificity, MIPs have drawn great attention in the food safety field. In this review, the recent developments of MIPs in various applications for food safety, including sample preparation, chromatographic separation, sensing, immunoassay etc., have been summarized. We particularly discuss the advancements and limitations in these applications, as well as attempts carried out for their improvement. PMID- 26937490 TI - Kupffer Cell Metabolism and Function. AB - Kupffer cells are resident liver macrophages and play a critical role in maintaining liver functions. Under physiological conditions, they are the first innate immune cells and protect the liver from bacterial infections. Under pathological conditions, they are activated by different components and can differentiate into M1-like (classical) or M2-like (alternative) macrophages. The metabolism of classical or alternative activated Kupffer cells will determine their functions in liver damage. Special functions and metabolism of Kupffer cells suggest that they are an attractive target for therapy of liver inflammation and related diseases, including cancer and infectious diseases. Here we review the different types of Kupffer cells and their metabolism and functions in physiological and pathological conditions. PMID- 26937496 TI - Hormone glucagon: electrooxidation and determination at carbon nanotubes. AB - The oxidation of glucagon, which is one of the key hormones in glucose homeostasis, was studied at electrodes modified with carbon nanotubes (CNT) that were dispersed in a polysaccharide adhesive chitosan (CHIT). Such electrodes displayed improved resistance to fouling, which allowed for the investigation of both the electrolysis/mass spectrometry and electroanalysis of glucagon. The off line electrospray ionization and tandem mass spectrometric analyses showed that the -4 Da mass change to glucagon upon electrolysis at CNT was due to the electrooxidation of its tryptophan (W25) and dityrosine (Y10, Y13) residues. The methionine residue of glucagon did not contribute to its oxidation. The amperometric determination of glucagon yielded the limit of detection equal to ~20 nM (E = 0.800 V, pH 7.40, S/N = 3), sensitivity of 0.46 A M(-1) cm(-2), linear dynamic range up to 2.0 MUM (R(2) = 0.998), response time <5 s, and good signal stability. Free tryptophan and tyrosine yielded comparable analytical figures of merit. The direct amperometric determination of unlabeled glucagon at CHIT-CNT electrodes is the first example of a rapid alternative to the complex analytical assays of this peptide. PMID- 26937497 TI - [Tribute to the professor Michel Petit]. PMID- 26937500 TI - Preface. PMID- 26937501 TI - Modelling cost-effective therapies. PMID- 26937502 TI - Junior medical researchers: a neglected community with great academic potential. PMID- 26937503 TI - Motsoaledi on 'tide-turning' new HIV treatment guidelines. PMID- 26937504 TI - Medical aids often their own worst enemies with fraud. PMID- 26937505 TI - Council for Medical Schemes braves the tightrope between funders and the poor. PMID- 26937507 TI - Adolescent health. PMID- 26937506 TI - Private hospitals could turbo-boost public sector reform. PMID- 26937509 TI - Understanding and responding to HIV risk in youngSouth African women: Clinical perspectives. AB - Young women (15-24 years) contribute a disproportionate 24% to all new HIV infections in South Africa - more than four times that of their male peers. HIV risk in young women is driven by amplifying cycles of social, behavioural and biological vulnerability. Those most likely to acquire infection are typically from socioeconomically deprived households in high HIV-prevalence communities, have limited or no schooling, engage in transactional sex or other high-risk coping behaviours, and have a history of sexually transmitted infections (STIs)and/or pregnancy. Despite the imperative to prevent HIV acquisition in young women, there is a dearth of evidence-based interventions to do so. However, there are several steps that healthcare workers can take to improve outcomes for this key population at the individual level.These include being able to identify high HIV-risk young women, ensuring that they receive the maximum social support they are eligible for, providing reliable and non-judgemental counselling on sexual and reproductive health and relationships, delivering contraceptives and screening and treating STIs in the context of accessible, youth-friendly services. PMID- 26937508 TI - Improving adolescent maternal health. AB - Each year thousands of adolescent girls and young women in South Africa (SA) become pregnant and many die from complications related to pregnancy and childbirth. Although women of all ages are susceptible, girls<15 years of age are five times as likely, and those aged 15-19 years twice as likely, to die from complications related to childbirth than women in their 20s. In SA, non-pregnancy related infections (e.g. HIV), obstetric haemorrhage and hypertension contributed to almost 70% of avoidable maternal deaths. In addition to the implementation of standardized preventive interventions to reduce obstetric haemorrhage and hypertension, better reproductive health services for adolescents, access to HIV care and treatment for women infected with HIV, and improved access to and uptake of long-acting reversible contraception are important ingredients for reducing maternal mortality among adolescents. PMID- 26937510 TI - Adolescent antiretroviral management: Understanding the complexity of non adherence. AB - This case-based discussion highlights challenges in adolescent antiretroviral management, focusing on non-disclosure of status and the subsequent impact of suboptimal treatment adherence. Despite the scale-up of antiretroviral therapy (ART) and recommendations made by the World Health Organization (WHO) for ART for all human immunodeficiency virus (HIV)-infected paediatric patients, ART coverage in adolescents lags behind that in adults. Challenges of sustaining lifelong ART in children and adolescents require consideration of specific behavioural, physiological and psychosocial complexities associated with this special group. To preserve future drug options and sustain lifelong access to therapy, addressing non-adherence to treatment is critical to minimising acquisition of ART drug resistance and treatment failure. We review the psychosocial and developmental components that influence the course of the disease in adolescents and consider the complexities arising from perinatal exposure to ART and the growing risk of transmitted ART drug resistance in high-burden resource-limited settings. PMID- 26937511 TI - Adolescent HIV treatment issues in South Africa. AB - Following the discovery of the human immunodeficiency virus (HIV), our knowledge of HIV infection and management has increased rapidly, but implementation of interventions has been slow in resource-limited settings. In particular, interventions such as antiretroviral treatment (ART) and prevention of mother-to child transmission were hindered owing to lack of access to antiretroviral drugs. This resulted in ongoing HIV transmission, morbidity and mortality associated with opportunistic infections. Notwithstanding the current progress in HIV prevention and treatment, challenges remain in preventing new infections in adolescents and supporting and treating HIV-infected adolescents. Barriers to successful treatment of infection in adolescents include denial of diagnosis, poor understanding or perception of future benefits of treatment and current orientated thinking that may contribute to non-adherence to ART. Side-effects that lead to stigmatisation, such as lipoatrophy (stavudine, zidovudine), diarrhoea and flatulence (lopinavir/ritonavir) and gynaecomastia (efavirenz), maybe intolerable and prevent adherence to treatment. This article highlights common treatment issues in HIV adolescent care and provides guidance on their management in the South African setting. PMID- 26937512 TI - Human papillomavirus (HPV) vaccination of adolescents in the South African private health sector: Lessons from the HPV demonstration project in KwaZulu Natal. AB - In South Africa (SA), >4,000 women die annually of cervical cancer, a disease caused by the human papillomavirus (HPV). Infections caused by certain genotypes of HPV increase the risk of cervical cancer. HIV-infected women in particular are more likely to have persistent HPV infection, with higher-risk genotypes. In SA, two vaccines (HPV quadrivalent (types 6, 11, 16, and 18) vaccine, recombinant (Gardasil) and HPV bivalent (types 16 and 18) vaccine, recombinant (Cervarix)) are currently registered for the prevention of HPV-related disease. In the past, there have been significant challenges to achieving high coverage and uptake of vaccination-contributory factors include cost and lack of awareness. An HPV demonstration project among schoolgirls in rural KwaZulu-Natal showed that high vaccine uptake is achievable. In 2014, the National Department of Health launched the national HPV vaccination programme among female learners attending public schools. Awareness of HPV vaccination among healthcare providers, education of parents, teachers and learners, and avoidance of missed opportunities for vaccination are vital to the success of the programme. Primary healthcare practitioners may play an important role in cervical cancer prevention by identifying and offering vaccination to girls who miss the opportunity to be vaccinated at school. HPV vaccination should be considered as one arm of a comprehensive programme of cervical cancer prevention and control. PMID- 26937513 TI - Chemo- and radiotherapy-induced urinary side effects: the role of glycosaminoglycans. PMID- 26937514 TI - Chemotherapy and pelvic radiotherapy-induced bladder injury. AB - An understanding of the basics of the anatomy of the bladder mucosa is essential to better understand the pathophysiology of chemo-and radiotherapy-induced cystitis. Following an overview of bladder anatomy and the definitions and causes of bladder injury, the mechanisms of cyclophosphamide (CP)-induced bladder injury are discussed as a specific example. PMID- 26937515 TI - Treatment of bladder urothelium injury. AB - The management of patients with cystitis-related symptoms due to urinary tract infection, bladder pain syndrome (BPS) or radio/chemo-induced cystitis remains challenging. A component in the pathophysiology of these symptoms relates to the fact that the urothelium is a highly metabolically active structure and that alterations in this structure can give rise to a variety of symptoms. PMID- 26937516 TI - Introduction: the Bjorn Ekwall Memorial Award 2015. PMID- 26937517 TI - Dear Editor. PMID- 26937518 TI - Dear Editor. PMID- 26937519 TI - In Reply. PMID- 26937520 TI - In Reply. PMID- 26937522 TI - Making Fair Choices: a symposium. PMID- 26937521 TI - The legacy of a pioneer. PMID- 26937523 TI - Editorial. PMID- 26937524 TI - Sex determination from pulp tissues of teeth subjected to different physical conditions and times after extraction. AB - BACKGROUND: The purpose of this study was to determine the reliability of sex determination from observation of Barr bodies in cells of tooth pulp tissue subjected to different physical conditions and duration of time after extraction. METHOD: The study comprised 150 teeth of subjects (male 50% and female 50%) who were randomly sampled. The teeth were grouped according to the conditions and times they were subjected to before extirpation of pulp tissues as follows: immediately after extraction; after 1 month in stagnant water; after staying at room temperature for 1 month, 3 months and 5 months post extraction and; after being subjected to varied degrees of temperature. The pulp tissues were fixed in 10% formal saline and processed for H&E stain. The presence of a cell with visible Barr body was considered positive for women. RESULTS: Sex chromatin were observable in the female preparations up to a duration of five months after extraction; teeth left in stagnant water for 1 month; and teeth subjected to temperature up to 400 degrees C. There was no positive cell in preparations of male subjects. CONCLUSION: Teeth pulp tissues are reliable evidence in forensic human identification by sex in varied physical conditions and times of death. PMID- 26937525 TI - Effects of induced-kwashiorkor on salivary parameters in Wistar rats. AB - BACKGROUND: This study was undertaken to determine changes induced by protein malnutrition (kwashiorkor). in the secretory functions of salivary glands and biochemical parameters of salivary fluid using rats. METHODS: Eighteen male Wistar rats were randomly divided into two groups (control and kwarshiorkor) of 9 rats each. The rats were fed with normal diet and low protein diet (2% protein) respectively for a period of 6 weeks. Stimulated saliva samples using pilocarpine (10 mg/kg body weight i.p.) were collected and salivary glands (parotid and submandibular) were surgically removed. Biochemical analysis of salivary secretion using salivary lag time, flow rate, pH, total protein and concentrations of electrolytes (Na+, K+, Ca++, Cl-, HCO(2-)3 PO4) were conducted and compared. Morphological assessment of the salivary glands was done using heamatoxyline-eosin and Alcian blue stains. RESULTS: Body weights decreased in the kwashiorkor group. Weights of submandibular and parotid glands (right and left) were lower in the kwashiorkor group compared to the normal diet group. The mean salivary lag time was increased while the salivary flow rate was reduced in the kwashiorkor group compared to normal diet group. Salivary electrolytes and total protein analysis showed reduced concentration of sodium while potassium and bicarbonate concentrations were increased in the kwashiorkor group compared to the normal diet group. Histological analysis of the H-E and alcian blue stained salivary glands in the kwashiorkor group exhibited moderate to severe acinar cell atrophy, periductal fibrosis and reduced mucin content. CONCLUSION: These findings suggest the role of functional and biochemical changes in salivary secretion in the pathophysiology of oral diseases associated with protein malnutrition. PMID- 26937526 TI - Coconut water alters maternal high fat diet induced changes in hormones and pup morphometry of Wistar rats. AB - BACKGROUND: Maternal high fat diet (HFD) during gestation adversely programmes foetal metabolism and cardiovascular function for the development of obesity and its related cardiovascular diseases in adult life. The hypolipidemic actions of coconut water (CW) in the presence of HFD have been reported. This study examined the effects of oral administration of CW on lipid panel, hormone profile, pup and placental morphometry of dams fed HFD during gestation. METHODS: Twenty-four pregnant Wistar rats were assigned to four groups (n = 6) and treated daily from gestation day (GD) 1 to 21 as follows; Group 1: 1 ml/100g b.wt. distilled water; Group 2: 1ml/100g b.wt. CW; Group 3: HFD (70% standard rat feed plus 30% butter); Group 4: HFD + 1 ml/100g b.wt. CW. Animals were sacrificed on GD 21. Random blood glucose was measured using tail blood. Caesarean section was performed to remove the pups and their placentas which were immediately measured. Oxidative stress status of the placentas; serum lipid and hormone profiles of dams were assessed. RESULTS: HFD+CW resulted in significant (P < 0.05) reductions in pup weight and morphometric indices when compared with pups from HFD. These changes were accompanied by significant improvements in maternal serum lipid profile, alterations in hormone levels and higher placental lipid peroxidation. CONCLUSION: These results suggest that coconut water is protective against maternal high fat diet-induced changes. Further studies are on-going to determine the actions of coconut water of maternal high fat diet induced foetal programming of adult health. PMID- 26937527 TI - Effects of methotrexate on serum testosterone level in sleep deprived male Wistar rats. AB - BACKGROUND: Sleep deprivation has been reported to decrease testosterone levels but the mechanism remains unclear. Studies have shown that sleep deprivation increases interleukin 1 beta (IL-1beta), a pro-inflammatory cytokine and that increased IL-1beta levels cause reductions in Leydig cell production of testosterone. This study was therefore designed to determine the effects of methotrexate, an IL-1beta blocker on serum testosterone levels in sleep deprived male Wistar rats. METHODS: Twenty male Wistar rats were randomly assigned into four groups (n = 5); group I (Control) received the vehicle (1% tween 80 solution); group II (methotrexate) received 0.5 mg/kg body weight methotrexate; group III (SD) was sleep deprived and received the vehicle; group IV (SD+Methotrexate) was sleep deprived and received 0.5 mg/kg body weight methotrexate. Sleep deprivation was induced using the modified multiple platform technique for 14 days. Treatments were administered twice weekly by oral gavage for 14 days. Blood was collected on day 14 and serum was obtained for analyses of testosterone, LH and FSH levels. IL-1beta level and histology of the testis were also determined. Data were expressed as Mean +/- SEM and analysed using ANOVA. p < 0.05 was considered significant. RESULTS: Serum testosterone levels were significantly decreased while testicular IL-1beta was increased in SD and SD+Methotrexate compared with Control. FSH and LH levels were not significantly different among the groups. CONCLUSION: Results of this study suggest that reduction in serum testosterone level in sleep deprived rats is not dependent on increased level of IL-1beta. PMID- 26937528 TI - Influence of gender on heart failure among hospitalised Nigerian patients. AB - BACKGROUND: Heart failure is a global phenomenon with poor morbi-mortality statistics. Though data abound in the developed nations, they are just becoming available here. There is a perceived neglect of heart failure epidemiology as it affects women; which is getting some attention in the advanced nations. This work attempts to see how gender impacts on heart failure in our environment and to provide insight on how any peculiarities could be approached. METHOD: As part of a larger study on relationship between 6 minute walk test and left ventricular systolic function in heart failure patients in our centre (July 2012 to June 2013), we dichotomized the cases along the line of gender. This was to see what differences may be related to the genders. All patients had history, physical examination and investigations including echocardiography which formed the bases for comparison. RESULTS: There were 140 patients, 85 (60.7%) of whom were females. Mean age was 48.2 (14.5) years; but males were significantly older [53.8 (12.6) Vs 44.6 (14.6)]. Heart failure under 45 years affected women more. More males drank and smoked. While diabetes was more common in males, more females had hypertension and rheumatic heart disease as aetiologies. Females tended to be more symptomatic but the difference did not attain statistical significance. Renal function tended to be worse in males. CONCLUSION: Women tend to go into heart failure earlier than men in our environment and had more hypertension and rheumatic heart disease as causes. Renal function was worse in males given a greater constellation of cardiovascular disease risk factors namely alcohol use, smoking and diabetes. More effort should go into preventing rheumatic heart disease and hypertension which result in heart failure in women. Obstetric encounters for cerebrovascular disease evaluation should be taken more seriously since these conditions are likely to result in failure related to pregnancy and child-birth. PMID- 26937529 TI - Diagnostic accuracy of tru-cut biopsy of breast lumps at University College Hospital, Ibadan. AB - BACKGROUND: Tru-cut needle biopsies form an integral part of Triple assessment of breast cancer and include clinical assessment, mammography and core needle biopsy. No study has been done to evaluate the validity of the procedure in our environment. This study was done to evaluate the validity of core needle biopsies in our centre. METHOD: A retrospective study of patients with tru-cut needle biopsies of breast lumps and follow-up excisional biopsy or mastectomy done in the Department of Surgery, University College Hospital, Ibadan over a ten year period was done. Fifty one patients who fulfilled the inclusion criteria had their records obtained from the Department of Pathology. The diagnosis was classified into benign and malignant with the excisional biopsy or mastectomy diagnosis used as the gold standard. The sensitivity, specificity and accuracy were calculated and kappa was also done to evaluate the degree of agreement. RESULTS: A total of 51 cases were included in this study. The average age of the patients was 47 +/- 13 years with a range from 19 to 81 years. Thirty of the biopsies (59%) had a definitive diagnosis of malignancy while twenty one (41%) were benign. The overall sensitivity, specificity and accuracy were 86%, 71% and 80.4% respectively. The specificity of malignant biopsies was 68% while benign was 35%. The level of agreement for malignant biopsies was higher than benign biopsies with a kappa of 0.39 for malignant diagnosis as against 0.29 for benign. CONCLUSION: Tru-cut needle biopsies have a comparable sensitivity and specificity to excisional biopsies. Diagnostic accuracy can be further enhanced with the adoption of image guided biopsies. PMID- 26937530 TI - Physicochemical properties and biological evaluation of Yoyo bitters. AB - BACKGROUND: The current widespread distribution and use of Yoyo bitters; an herbal bitters made in Nigeria calls for an assessment of its content, efficacy and extent to which this product achieves the labelled claim of being an herbal cleanser. METHODS: The pH, analysis for trace metal and preliminary phytochemicals screening were assessed. In addition, the total phenolic acid content, antioxidant activity using DPPH inhibition and microbiological assay were evaluated using standard procedures. The biological effect of different doses on weight, blood glucose, haematological parameters, liver function and tissues pathology were investigated in healthy Wistar rats over a 28-day period. RESULTS: Yoyo bitters is a slightly acidic liquid (pH 5.46), containing 0.110 MUg/L of zinc, little quantities of saponins, alkaloids, anthraquinones and cardenolides. Low total phenolic acid content (537.7 +/- 22.38 mgGAE/mL), poor radical scavenging activity; DPPH IC50 of 855.27 +/- 85.8 mg/mL compared with 1.27 +/- 0.03 and 1.24 +/- 0.02 mg/nL for gallic acid and ascorbic acid respectively. There was lack of antibacterial activity. The weight, blood glucose level and liver function were not affected, while only WBC and platelet levels were increased significantly (p = 0.003). Gut associated lymphoid tissues (GALT) was observed in the intestine as well as hepatic lesions with some of the treated groups. CONCLUSION: Yoyo bitters has a weak antioxidant activity, thus may not possess significant effect on the enhancement of general body health. It has immune-potentiating effect with the risk of development of hepatic degeneration. PMID- 26937531 TI - The transverse penile pedicled flap urethroplasty: description of a simplified technique for the dissection of the Fascio-cutaneous flap. AB - INTRODUCTION/OBJECTIVE: Urethroplasty is often required for long urethral strictures or urethral strictures that have recurred after repeated urethral dilatations or urethrotomy. The transvers penile skin pedicled flap is very versatile for the reconstruction of long urethral stricture. However the meticulous sharp dissection required to develop it takes a long time to do and may be associated with button hole injuries to the vascular pedicle and the penile skin. We describe a simplified technique of raising the flap which does not require sharp dissection and is very quick to accomplish. METHOD: Technique involves using a circumcising distal penile shaft skin incision to de-glove the penis by blunt dissection. The skin substitute, adequate to give appropriate urethra calibre is similarly dissected bluntly along with its vascular pedicle from the proximal penile skin. The techniques used to facilitate successful blunt dissection are described. RESULT: In 9 adults with long, multiple urethral strictures, the average time to develop the flap was 15 minutes and complication have been limited to temporary urethro-cutaneous fistula at the ventral part of the circular skin closure. These fistulae closed on conservative treatment. No patient suffered button-hole injuries to either the vascular pedicle or the penile skin. CONCLUSIONS: This modification to the standard sharp dissection is very quick to accomplish. It also avoids the creation of button-hole injuries to either the vascular pedicle or the penile skin. It should make the use of this versatile flap more attractive in the reconstruction of long urethral strictures in those who may wish to use this option for reconstruction of long urethral strictures. PMID- 26937532 TI - Non-surgical extraction of a massive sialolith in the Wharton's duct of a Nigerian. AB - BACKGROUND: Sialolithiasis is the most common salivary gland disorder characterized by calculi formation within the gland and/or its duct. The submandibular gland is most frequently affected due to the peculiar anatomy of the duct and the nature of its secretion. Varying sizes have been described for salivary calculi and unusually large sialoliths measuring above 3.5cm have been reported. Similarly, a few giant sialoliths have been reported in Africans. We therefore report the case of a large sialolith in the Wharton's duct of a Nigerian male. CASE PRESENTATION AND MANAGEMENT: A 54 year old Nigerian man presented with a hard, painless, left floor of mouth swelling of one year duration. There were recurrent episodes of moderate pain at meal times. Intraoral examination revealed a hard, mobile, non tender, creamy mass on the left side of the floor of the mouth protruding out of the Wharton's duct orifice. A lower occlusal radiograph revealed a large radio-opacity in the floor of the mouth and a diagnosis of left submandibular sialolithiasis was made. The sialolith was removed non-surgically and measured 4.4 cm by 1.8 cm. The patient was discharged and follow up period was uneventful. CONCLUSION: Large sialoliths are rarely reported in Africans, non-surgical extraction can be attempted for accessible and mobile sialoliths after full evaluation. Complex cases should be referred to the oral and maxillofacial surgeon. PMID- 26937533 TI - Charge syndrome in a Nigerian infant: a rare genetic disorder. AB - BACKGROUND: Charge syndrome is a rare genetic disorder that arises during early fetal development and affects multiple organ systems. Diagnosis is largely clinical. Mutation at the CHD7 gene located on Chromosome 8 has been identified in a great number of patients reviewed in different parts of the world. Survival depends on the intensity of the medical management as well as an early aggressive approach to the feeding adaptation in these children. CASE REPORT: We report a case of a 42 day old baby with clinical features in keeping with Charge syndrome. He was a product of a full-term uneventful pregnancy period delivered to non consanguineous apparently healthy parents. Two older siblings were normal. He developed respiratory distress shortly after birth. Multiple abnormalities were identified at birth which included genital, ear, eye and cardiovascular as well as skeletal abnormalities. Genetic testing was not carried out due to cost. Child was managed by a multidisciplinary team. Main problems were those of sepsis and feeding adaptation. He later succumbed to death after a month on admission. CONCLUSION: This is the first case of Charge syndrome reported in Nigeria. It is a rare, multisystemic condition with grave health implications and early diagnosis and appropriate management could reduce morbidity and prevent mortality. This report is to increase awareness of this rare condition and to promote better identification and intervention of similar presentation in future. PMID- 26937534 TI - A typical presentations of hypothyroidism and associated problems in Ibadan, Nigeria. AB - BACKGROUND: Hypothyroidism can present atypically making its recognition difficult especially in resource limited settings. CASE PRESENTATION AND MANAGEMENT: Two children presented with atypical features of hypothyroidism with resultant delay in diagnosis. Patient I presented with persistent respiratory distress, facial swelling and recurrent syncopal attacks. Cardiovascular examination was normal except for pulmonary hypertension. He did not respond to conventional supportive therapy and hypothyroidism was discovered much later. Patient II was a seven month old male infant with abdominal swelling, bilateral pitting leg oedema, poor weight gain and delayed developmental milestones. Examination revealed ascites and pericardial effusion. He was being managed for protein energy malnutrition until he was found to have hypothyroidism and was successfully managed with L thyroxin. CONCLUSION: A typical presentations of hypothyroidism in resource limited settings can result in delay in diagnosis and treatment which can lead to unnecessary morbidity and mortality. High index of suspicion and expertise are therefore required. PMID- 26937552 TI - Novel Monoclonal Antibody LpMab-17 Developed by CasMab Technology Distinguishes Human Podoplanin from Monkey Podoplanin. AB - Podoplanin (PDPN) is a type-I transmembrane sialoglycoprotein, which possesses a platelet aggregation-stimulating (PLAG) domain in its N-terminus. Among the three PLAG domains, O-glycan on Thr52 of PLAG3 is critical for the binding with C-type lectin-like receptor-2 (CLEC-2) and is essential for platelet-aggregating activity of PDPN. Although many anti-PDPN monoclonal antibodies (mAbs) have been established, almost all mAbs bind to PLAG domains. We recently established CasMab technology to produce mAbs against membranous proteins. Using CasMab technology, we produced a novel anti-PDPN mAb, LpMab-17, which binds to non-PLAG domains. LpMab-17 clearly detected endogenous PDPN of cancer cells and normal cells in Western-blot, flow cytometry, and immunohistochemistry. LpMab-17 recognized glycan-deficient PDPN in flow cytometry, indicating that the interaction between LpMab-17 and PDPN is independent of its glycosylation. The minimum epitope of LpMab-17 was identified as Gly77-Asp82 of PDPN using enzyme-linked immunosorbent assay. Of interest, LpMab-17 did not bind to monkey PDPN, whereas the homology is 94% between human PDPN and monkey PDPN, indicating that the epitope of LpMab-17 is unique compared with the other anti-PDPN mAbs. The combination of different epitope-possessing mAbs could be advantageous for the PDPN-targeting diagnosis or therapy. PMID- 26937553 TI - Relevance of nerve conduction velocity in the assessment of balance performance in older adults with diabetes mellitus. AB - Purpose This study investigated the relationship between peripheral nerve conduction velocity (NCV) and balance performance in older adults with diabetes. Methods Twenty older adults with diabetes were recruited to evaluate the NCV of their lower limbs and balance performance. The balance assessments comprised the timed up and go (TUG) test, Berg balance scale (BBS), unipedal stance test (UST), multidirectional reach test (MDRT), maximum step length (MSL) test and quiet standing with eyes open and closed. The relationship between NCV and balance performance was evaluated by Pearson's correlation coefficients, and the balance performances of the diabetic patients with and without peripheral neuropathy were compared by using Mann-Whitney U tests. Results The NCV in the lower limbs exhibited a moderate to strong correlation with most of the balance tests including the TUG (r = -0.435 to -0.520, p < 0.05), BBS (r = 0.406-0.554, p < 0.05), UST (r = 0.409-0.647, p < 0.05) and MSL (r = 0.399-0.585, P < 0.05). In addition, patients with diabetic peripheral neuropathy had a poorer TUG (p < 0.05), BBS (p < 0.01), UST (p < 0.05) and MSL performance (p < 0.05) compared with those without peripheral neuropathy (p < 0.05). Conclusion Our findings revealed that a decline in peripheral nerve conduction in the lower limb is not only an indication of nerve dysfunction, but may also be related to the impairment of balance performance in patients with diabetes. Implications for Rehabilitation Nerve conduction velocity in the lower limbs of diabetic older adults showed moderate to strong correlations with most of the results of balance tests, which are commonly used in clinics. Decline in nerve conduction velocity of the lower limbs may be related to the impairment of balance control in patients with diabetes. Diabetic older adults with peripheral neuropathy exhibited greater postural instability than those without peripheral neuropathy. PMID- 26937551 TI - Conformational Flexibility Enables the Function of a BECN1 Region Essential for Starvation-Mediated Autophagy. AB - BECN1 is essential for autophagy, a critical eukaryotic cellular homeostasis pathway. Here we delineate a highly conserved BECN1 domain located between previously characterized BH3 and coiled-coil domains and elucidate its structure and role in autophagy. The 2.0 A sulfur-single-wavelength anomalous dispersion X ray crystal structure of this domain demonstrates that its N-terminal half is unstructured while its C-terminal half is helical; hence, we name it the flexible helical domain (FHD). Circular dichroism spectroscopy, double electron-electron resonance-electron paramagnetic resonance, and small-angle X-ray scattering (SAXS) analyses confirm that the FHD is partially disordered, even in the context of adjacent BECN1 domains. Molecular dynamic simulations fitted to SAXS data indicate that the FHD transiently samples more helical conformations. FHD helicity increases in 2,2,2-trifluoroethanol, suggesting it may become more helical upon binding. Lastly, cellular studies show that conserved FHD residues are required for starvation-induced autophagy. Thus, the FHD likely undergoes a binding-associated disorder-to-helix transition, and conserved residues critical for this interaction are essential for starvation-induced autophagy. PMID- 26937554 TI - Asymmetric Organocatalytic Wittig [2,3]-Rearrangement of Oxindoles. AB - A highly enantioselective organocatalytic [2,3]-rearrangement of oxindole derivatives is presented. The reaction was catalyzed by squaramide, and this provides access to 3-hydroxy 3-substituted oxindoles in high enantiomeric purities. PMID- 26937555 TI - Differential Mobility Spectrometry Coupled with Multiple Ion Monitoring in Regulated LC-MS/MS Bioanalysis of a Therapeutic Cyclic Peptide in Human Plasma. AB - A differential mobility spectrometry (DMS) in combination with a multiple ion monitoring (MIM) method was developed and validated for quantitative LC-MS/MS bioanalysis of pasireotide (SOM230) in human plasma. Pasireotide, a therapeutic cyclic peptide, exhibits poor collision-induced dissociation (CID) efficiency for multiple reaction monitoring (MRM) detection. Therefore, in an effort to increase the overall sensitivity of the assay, a DMS-MIM approach was explored. By selecting the most abundant doubly charged precursor ion in both the Q1 and Q3 of the mass analyzer in MIM and combining the DMS capability to significantly reduce the high matrix/chemical background noise, this new LC-DMS-MIM method overcomes the sensitivity challenge in the typical MRM method due to poor CID fragmentation of the analyte. Human plasma was spiked with pasireotide with concentrations in the range 0.01-50 ng/mL. Weak cation-exchange solid-phase extraction was employed for sample preparation. The sample extracts were analyzed with a SCIEX QTRAP 6500 system equipped with an ESI source and DMS device. The separation voltage and compensation voltage of the DMS and other parameters of the MS system were optimized to maximize signal responses. The performance of the LC-DMS-MIM assay for quantitative analysis of pasireotide in human plasma was evaluated and compared to those obtained via LC-MRM and LC-MIM without DMS. Overall, the assay sensitivity with DMS-MIM was approximately 5-fold better than that observed in MRM or MIM without DMS. The assay was validated with accuracy (% bias) and precision (% CV) of the QC results at eight concentration levels (0.01, 0.02, 0.05, 0.15, 0.3, 1.5, 15, and 37.5 ng/mL) evaluated ranging from -4.8 to 5.0% bias and 0.7 to 8.6% CV for the intraday and interday runs. The current LC-DMS MIM workflow can be expanded to quantitative analysis of other molecules that have poor fragmentation efficiency in CID. PMID- 26937556 TI - Phase Transitions of PYR14-TFSI as a Function of Pressure and Temperature: the Competition between Smaller Volume and Lower Energy Conformer. AB - A detailed Raman study has been carried out on the ionic liquid 1-butyl-1 methylpyrrolidinium bis(trifluoromethanesulfonyl)imide (PYR14-TFSI) over a wide pressure (0-8 GPa) and temperature (100-300 K) range. The explored thermodynamic region allowed us to study the evolution of the system across different solid and liquid phases. Calculated Raman spectra remarkably helped in the spectral data analysis. In particular, the pressure behavior of the most intense Raman peak and the shape analysis of the ruby fluorescence (used as a local pressure gauge) allowed us to identify a liquid-solid transition around 2.2 GPa at T = 300 K. The low-frequency Raman signal as well as the absence of remarkable spectral shape modifications on crossing the above threshold and the comparison with the spectra of the crystalline phase suggest a glassy nature of the high-pressure phase. A detailed analysis of the pressure dependence of the relative concentration of two conformers of TFSI allowed us to obtain an estimate of the volume variation between trans-TFSI and the smaller cis-TFSI, which is the favored configuration on applying the pressure. Finally, the combined use of both visual inspection and Raman spectroscopy confirmed the peculiar sequence of phase transitions observed as a function of temperature at ambient pressure and the different spectral/morphological characteristics of the two crystalline phases. PMID- 26937559 TI - Multiscale Simulation and Modeling of Multilayer Heteroepitactic Growth of C60 on Pentacene. AB - We apply multiscale methods to describe the strained growth of multiple layers of C60 on a thin film of pentacene. We study this growth in the presence of a monolayer pentacene step to compare our simulations to recent experimental studies by Breuer and Witte of submonolayer growth in the presence of monolayer steps. The molecular-level details of this organic semiconductor interface have ramifications on the macroscale structural and electronic behavior of this system and allow us to describe several unexplained experimental observations for this system. The growth of a C60 thin film on a pentacene surface is complicated by the differing crystal habits of the two component species, leading to heteroepitactical growth. In order to probe this growth, we use three computational methods that offer different approaches to coarse-graining the system and differing degrees of computational efficiency. We present a new, efficient reaction-diffusion continuum model for 2D systems whose results compare well with mesoscale kinetic Monte Carlo (KMC) results for submonolayer growth. KMC extends our ability to simulate multiple layers but requires a library of predefined rates for event transitions. Coarse-grained molecular dynamics (CGMD) circumvents KMC's need for predefined lattices, allowing defects and grain boundaries to provide a more realistic thin film morphology. For multilayer growth, in this particularly suitable candidate for coarse-graining, CGMD is a preferable approach to KMC. Combining the results from these three methods, we show that the lattice strain induced by heteroepitactical growth promotes 3D growth and the creation of defects in the first monolayer. The CGMD results are consistent with experimental results on the same system by Conrad et al. and by Breuer and Witte in which C60 aggregates change from a 2D structure at low temperature to 3D clusters along the pentacene step edges at higher temperatures. PMID- 26937557 TI - Preoperative posterior tilt of at least 20 degrees increased the risk of fixation failure in Garden-I and -II femoral neck fractures. AB - Background and purpose - It has been suggested that preoperative posterior tilt of the femoral head may increase the risk of fixation failure in Garden-I and -II femoral neck fractures. To investigate this association, we studied a cohort of 322 such patients. Patients and methods - Patients treated with internal fixation between 2005 and 2012 were retrospectively identified using hospital records and the digital image bank. 2 raters measured the preoperative posterior tilt angle and categorized it into 3 groups: < 10 degrees , 10-20 degrees , and >= 20 degrees . The inter-rater reliability (IRR) was determined. Patients were observed until September 2013 (with a minimum follow-up of 18 months) or until failure of fixation necessitating salvage arthroplasty. The risk of fixation failure was assessed using competing-risk regression analysis, adjusting for time to surgery. Results - Patients with a posterior tilt of >= 20 degrees had a higher risk of fixation failure: 19% (8/43) as compared to 11% (14/127) in the 10 20 degrees category and 6% (9/152) in the < 10 degrees category (p = 0.03). Posterior tilt of >= 20 degrees increased the risk of fixation failure, with an adjusted hazard ratio of 3.4 (95% CI: 1.3-8.9; p = 0.01). The interclass correlation coefficient for angular measurements of posterior tilt was 0.90 (95% CI: 0.87-0.92), and the IRR for the categorization of posterior tilt into 3 groups was 0.76 (95% CI: 0.69-0.81). Interpretation - Preoperative posterior tilt of >= 20 degrees in Garden-I and -II femoral neck fractures increased the risk of fixation failure necessitating salvage arthroplasty. The reliability of the methods that we used to measure posterior tilt ranged from good to excellent. PMID- 26937584 TI - An Fe-N2 Complex That Generates Hydrazine and Ammonia via Fe?NNH2: Demonstrating a Hybrid Distal-to-Alternating Pathway for N2 Reduction. AB - Biological N2 fixation to NH3 may proceed at one or more Fe sites in the active site cofactors of nitrogenases. Modeling individual e(-)/H(+) transfer steps of iron-ligated N2 in well-defined synthetic systems is hence of much interest but remains a significant challenge. While iron complexes have been recently discovered that catalyze the formation of NH3 from N2, mechanistic details remain uncertain. Herein, we report the synthesis and isolation of a diamagnetic, 5 coordinate Fe?NNH2(+) species supported by a tris(phosphino)silyl ligand via the direct protonation of a terminally bound Fe-N2(-) complex. The Fe?NNH2(+) complex is redox-active, and low-temperature spectroscopic data and DFT calculations evidence an accumulation of significant radical character on the hydrazido ligand upon one-electron reduction to S = (1)/2 Fe?NNH2. At warmer temperatures, Fe?NNH2 rapidly converts to an iron hydrazine complex, Fe-NH2NH2(+), via the additional transfer of proton and electron equivalents in solution. Fe-NH2NH2(+) can liberate NH3, and the sequence of reactions described here hence demonstrates that an iron site can shuttle from a distal intermediate (Fe?NNH2(+)) to an alternating intermediate (Fe-NH2NH2(+)) en route to NH3 liberation from N2. It is interesting to consider the possibility that similar hybrid distal/alternating crossover mechanisms for N2 reduction may be operative in biological N2 fixation. PMID- 26937585 TI - o-Quinones Derived from Tribenzotriquinacenes: Functionalization of Inner Bay Positions and Use for Single-Wing Extensions. AB - Through a surprisingly nonregioselective oxidation process, the reaction of two analogous 2-hydroxy-substituted tribenzotriquinacenes (TBTQs) 8a/8b by o iodoxybenzoic acid was found to afford the corresponding Cs- and C1-symmetrical TBTQ-o-quinones 6a/6b and 7a/7b, respectively, in 1:1 ratio and excellent combined yields. This finding represents the first example of direct introduction of a functional group into a sterically hindered, inner bay-positions of a parent TBTQ skeleton. In contrast, the analogous reaction with 1-hydroxy-TBTQ 15 failed to produce the desired o-quinone 7a. After reduction of the quinones 6a and 7a to the corresponding catechols 17 and 23, electrophilic aromatic substitution could also be realized at the activated inner bay-position(s) to afford several tri- and tetrafunctionalized TBTQ compounds 18, 21, and 25. The Cs-symmetrical o quinone 6a was converted into further single-wing extended derivatives such as TBTQ-based phenazines 27a-f, through condensation reactions, and to benzodioxine derivative 32 by Diels-Alder reaction with tetracyclone. The novel TBTQ-quinones and the corresponding TBTQ-catechols offer a variety of new accesses to single wing-extended and -functionalized TBTQ derivatives. PMID- 26937586 TI - Isolation and identification of oxidation products of guaiacol from brines and heated meat matrix. AB - In this study we investigated the formation of the oxidation products of guaiacol in brines and heated meat matrix: 6-nitrosoguaiacol, 4-nitroguaiacol and 6 nitroguaiacol. For this purpose we applied a newly developed HPLC-UV and LC-MS method. For the first time, 6-nitrosoguaiacol was determined in brine and meat (containing guaiacol and sodium nitrite), which had been heated to 80 degrees C and subsequently subjected to simulated digestion. Application of 500mg/L ascorbic acid to the brines reduced guaiacol degradation at pH3 and simultaneously inhibited the formation of 6-nitrosoguaiacol compared to brines containing only 100mg/L of ASC. The oxidation products were isolated with a new extraction method from meat samples containing 400mg/kg sodium nitrite at pH3.6 following simulated digestion. When oxygen was added, 6-nitrosoguaiacol was determined even at legally allowed levels (150mg/kg) of the curing agent. Finally, we developed a new LC-MS method for the separation and qualitative determination of the four main smoke methoxyphenols. PMID- 26937587 TI - Determination of volatile aroma compounds in beef using differences in steak thickness and cook surface temperature. AB - Top loin steaks with a United States Department of Agriculture (USDA) grade of Select were cut 1.3cm, 2.5cm, or 3.8cm thick and cooked on a skillet at 177 degrees C, 204 degrees C, or 232 degrees C. Aroma compounds described as fatty, tallow, and oily are highly related to the identity of beef flavor. These compounds are produced in the highest quantity when steaks are cooked either at low temperatures (177 degrees C) or for short periods of time. Whereas, aroma compounds described as roasted, nutty, or fruity are developed from browning the surface of the steak as a result of cooking at high skillet surface temperatures (232 degrees C) or for long periods of time, as would be seen cooking thick steaks (3.8cm). This study shows that the amount of specific aroma compounds can be predicted (r(2) values up to 0.62) from measured cooking times and temperatures. It may be possible to develop beef steak flavor by recommending steak thickness and cooking temperatures. PMID- 26937588 TI - Self-Assembled Multilayer Structure and Enhanced Thermochromic Performance of Spinodally Decomposed TiO2-VO2 Thin Film. AB - Composite films of VO2-TiO2 were deposited on sapphire (11-20) substrate by cosputtering method. Self-assembled well-ordered multilayer structure with alternating Ti- and V-rich epitaxial thin layer was obtained by thermal annealing via a spinodal decomposition mechanism. The structured thermochromic films demonstrate superior optical modulation upon phase transition, with significantly reduced transition temperature. The results provide a facile and novel approach to fabricate smart structures with excellent performance. PMID- 26937589 TI - Quantification of flavonol glycosides in Camellia sinensis by MRM mode of UPLC QQQ-MS/MS. AB - Phenolic compounds are major components of tea flavour, in which catechins and flavonol glycosides play important roles in the astringent taste of tea infusion. However, the flavonol glycosides are difficult to quantify because of the large variety, as well as the inefficient seperation on chromatography. In this paper, a total of 15 flavonol glycosides in the tea plant (Camellia sinensis) were identified by the high performance liquid chromatography (HPLC) coupled to a time of-flight mass spectrometer (TOF-MS), and a quantitative method was established based on multiple reaction monitoring (MRM) mode of ultra-high performance liquid chromatography (UPLC) coupled to a triple quadrupole mass spectrometer (QQQ MS/MS). It provided the limit of detection and quantification to the order of picogram, which was more sensitive than the HPLC detection of the order of nanogram. The relative standard deviations of the intra- and inter-day variations in retention time and signal intensity (peak area) of six analytes were less than 0.26% and 4%, respectively. The flavonol glycosides of four tea cultivars were relatively quantified using the signal intensity (peak area) of product ion, in which six flavonol glycosides were quantified by the authentic standards. The results showed that the flavonol mono-, di- and tri-glycoside mostly accumulated in young leaves of the four tea cultivars. Notably, the myricetin 3-O-galactoside was the major component among the six flavonol glycosides detected. PMID- 26937558 TI - Canonical Transient Receptor Potential 6 Channel: A New Target of Reactive Oxygen Species in Renal Physiology and Pathology. AB - SIGNIFICANCE: Regulation of Ca2+ signaling cascade by reactive oxygen species (ROS) is becoming increasingly evident and this regulation represents a key mechanism for control of many fundamental cellular functions. Canonical transient receptor potential (TRPC) 6, a member of Ca2+-conductive channel in the TRPC family, is widely expressed in kidney cells, including glomerular mesangial cells, podocytes, tubular epithelial cells, and vascular myocytes in renal microvasculature. Both overproduction of ROS and dysfunction of TRPC6 channel are involved in renal injury in animal models and human subjects. Although regulation of TRPC channel function by ROS has been well described in other tissues and cell types, such as vascular smooth muscle, this important cell regulatory mechanism has not been fully reviewed in kidney cells. Recent Advances: Accumulating evidence has shown that TRPC6 is a redox-sensitive channel, and modulation of TRPC6 Ca2+ signaling by altering TRPC6 protein expression or TRPC6 channel activity in kidney cells is a downstream mechanism by which ROS induce renal damage. CRITICAL ISSUES: This review highlights how recent studies analyzing function and expression of TRPC6 channels in the kidney and their response to ROS improve our mechanistic understanding of oxidative stress-related kidney diseases. FUTURE DIRECTIONS: Although it is evident that ROS regulate TRPC6 mediated Ca2+ signaling in several types of kidney cells, further study is needed to identify the underlying molecular mechanism. We hope that the newly identified ROS/TRPC6 pathway will pave the way to new, promising therapeutic strategies to target kidney diseases such as diabetic nephropathy. Antioxid. Redox Signal. 25, 732-748. PMID- 26937590 TI - Preparation of selective magnetic dispersive solid-phase sorbent and its application for recognition clenbuterol from bovine urine. AB - A new kind of selective magnetic dispersive solid-phase sorbent based on multiple Fe3O4 nanospheres as the core structure and molecular imprinted material as the shell structure was synthesized with tert-butylamine and 2-chloroaniline as the templates. The obtained multicore-shell-structured sorbent was spherical (diameter distribution 25-90MUm) with porous morphologies, thus incorporating strong magnetic properties and specific molecular recognition coupled with rapid adsorption and dynamic equilibrium. The sorbent was applied for rapid and selective screening of clenbuterol (CLB) in bovine urine samples. Good linearity was obtained in the range 1.25-200ngmL(-1) with the average recovery at three spiked levels ranging from 91.4% to 105.3%. The proposed method significantly improved the purification and extraction efficiency of CLB in urine samples and eliminated the effect of template leakage during quantitative analysis. PMID- 26937593 TI - Detection of a single enzyme molecule based on a solid-state nanopore sensor. AB - The nanopore sensor as a high-throughput and low-cost technology can detect a single molecule in a solution. In the present study, relatively large silicon nitride (Si3N4) nanopores with diameters of ~28 and ~88 nm were fabricated successfully using a focused Ga ion beam. We have used solid-state nanopores with various sizes to detect the single horseradish peroxidase (HRP) molecule and for the first time analyzed single HRP molecular translocation events. In addition, a real-time monitored single enzyme molecular biochemical reaction and a translocation of the product of enzyme catalysis substrates were investigated by using a Si3N4 nanopore. Our nanopore system showed a high sensitivity in detecting single enzyme molecules and a real-time monitored single enzyme molecular biochemical reaction. This method could also be significant for studying gene expression or enzyme dynamics at the single-molecule level. PMID- 26937591 TI - Polymeric Prodrug Grafted Hollow Mesoporous Silica Nanoparticles Encapsulating Near-Infrared Absorbing Dye for Potent Combined Photothermal-Chemotherapy. AB - In this study, polymeric prodrug coated hollow mesoporous silica nanoparticles (HMSNs) with encapsulated near-infrared (NIR) absorbing dye were prepared and explored for combined photothermal-chemotherapy. A copolymer integrated with tert butoxycarbonyl protected hydrazide groups and oligoethylene glycols was initially grafted on the surface of HMSNs via reversible addition-fragmentation chain transfer (RAFT) polymerization followed by the deprotection to reactivate the hydrazide groups for the conjugation of anticancer drug doxorubicin (DOX). DOX was covalently bound onto the polymer substrate by acid-labile hydrazone bond and released quickly in weak acidic environment for chemotherapy. The hollow cavity of HMSNs was loaded with an NIR absorbing dye IR825 to form the final multifunctional hybrid denoted as HMSNs-DOX/IR825. The hybrid exhibited good dispersity and stability as well as high light-to-heat conversion efficiency. As revealed by confocal microscopy and flow cytometry analysis, the hybrid was efficiently taken up by cancer cells, and the conjugated DOX could be released under the cellular environment. In vitro cytotoxicity study demonstrated that anticancer activity of HMSNs-DOX/IR825 could be significantly improved by the NIR irradiation, which led to a satisfactory therapeutic efficacy through the combination treatment. Thus, the developed hybrid could be a promising candidate for the combined photothermal-chemotherapy of cancer. PMID- 26937602 TI - Survival From Childhood Hematological Malignancies in Denmark: Is Survival Related to Family Characteristics? AB - BACKGROUND: Due to diverse findings as to the role of family factors for childhood cancer survival even within Europe, we explored a nationwide, register based cohort of Danish children with hematological malignancies. METHODS: All children born between 1973 and 2006 and diagnosed with a hematological malignancy before the age of 20 years (N = 1,819) were followed until 10 years from diagnosis. Kaplan-Meier curves and Cox proportional hazards models estimating hazard ratios (HR) and 95% confidence intervals (CI) were used to assess the impact of family characteristics on overall survival in children with hematological malignancies. RESULTS: Having siblings and increasing birth order were associated with reduced survival from acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Associations with AML were strongest and statistically significant. HRs of 1.62 (CI 0.85; 3.09) and 5.76 (CI 2.01; 16.51) were observed for the fourth or later born children with ALL (N = 41) and AML (N = 9), respectively. Children with older parents showed a tendency toward inferior ALL survival, while for AML young maternal age was related to poorer survival. Based on small numbers, a trend toward poorer survival from non-Hodgkin lymphoma was observed for children having siblings and for children of younger parents. CONCLUSIONS: Further research is warranted to gain further knowledge on the impact of family factors on childhood cancer survival in other populations and to elaborate potential underlying mechanisms and pathways of those survival inequalities. PMID- 26937603 TI - Peptide [4]Catenane by Folding and Assembly. AB - A topologically complex peptide [4]catenane with the crossing number of 12 was synthesized by a folding and assembly strategy wherein the folding and metal directed self-assembly of a short peptide fragment occur simultaneously. The latent Omega-looped conformation of the Pro-Gly-Pro sequence was found only when pyridines at the C- and N-termini coordinatively bind metal ions (Ag(I) or Au(I) ). Crystallographic studies revealed that the Omega-looped motifs formed four M3 L3 macrocycles that were intermolecularly entwined to generate an unprecedented peptide [4]catenane topology. PMID- 26937601 TI - Structure-Based Design of an Iminoheterocyclic beta-Site Amyloid Precursor Protein Cleaving Enzyme (BACE) Inhibitor that Lowers Central Abeta in Nonhuman Primates. AB - We describe successful efforts to optimize the in vivo profile and address off target liabilities of a series of BACE1 inhibitors represented by 6 that embodies the recently validated fused pyrrolidine iminopyrimidinone scaffold. Employing structure-based design, truncation of the cyanophenyl group of 6 that binds in the S3 pocket of BACE1 followed by modification of the thienyl group in S1 was pursued. Optimization of the pyrimidine substituent that binds in the S2'-S2" pocket of BACE1 remediated time-dependent CYP3A4 inhibition of earlier analogues in this series and imparted high BACE1 affinity. These efforts resulted in the discovery of difluorophenyl analogue 9 (MBi-4), which robustly lowered CSF and cortex Abeta40 in both rats and cynomolgus monkeys following a single oral dose. Compound 9 represents a unique molecular shape among BACE inhibitors reported to potently lower central Abeta in nonrodent preclinical species. PMID- 26937604 TI - Patient-led Goal Setting: A Pilot Study Investigating a Promising Approach for the Management of Chronic Low Back Pain. AB - STUDY DESIGN: A prospective, single-arm, pre-postintervention study. OBJECTIVE: The aim of this study was to test the preliminary effectiveness of a patient-led goal-setting intervention on improving disability and pain in chronic low back pain. SUMMARY OF BACKGROUND DATA: An effective intervention for the treatment of chronic low back pain remains elusive despite extensive research into the area.An intervention using patient-centered goal setting to drive intervention strategies and encourage self-management for patients suffering chronic low back was developed. METHODS: A single group longitudinal cohort pilot study was conducted. Twenty participants (male = nine) experiencing chronic low back pain were involved in a patient-led goal-setting intervention, facilitated by a physiotherapist over a 2-month period with two monthly follow-up sessions after treatment conclusion. Participants, guided by the therapist, identified problem areas of personal importance, defined goals, and developed evidence-based strategies to achieve the goals. Participants implemented the strategies independently between sessions. Primary outcome measures of disability and pain intensity were measured at baseline, 2, and 4 months. Secondary measures of quality of life, stress and anxiety, self-efficacy, and fear of movement were also taken. RESULTS: Significant improvements (repeated analysis of variance P < 0.05) were seen in measures of disability, pain, fear avoidance, quality of life, and self-efficacy over the period of intervention and were maintained for a further 2 months after treatment conclusion. CONCLUSION: This intervention is novel because the goals set are based on patients' personal preferences, and not on treatment guidelines. Our findings confirm that a patient-centered goal setting intervention is a potentially effective intervention for the management of chronic low back pain showing significant improvements in both quality of life and pain intensity. LEVEL OF EVIDENCE: 4. PMID- 26937606 TI - In response: Re: Zhu Y, Tian Z, Zhu B, Zhang W, Li Y, Zhu Q. Bryan Cervical Disc Arthroplasty Versus Anterior Cervical Discectomy and Fusion for Treatment of Cervical Disc Diseases: A Meta-Analysis of Prospective Randomized Controlled Trials. Spine (Phila Pa 1976) 2015. PMID- 26937605 TI - Who are the Best Candidates for Decompressive Surgery and Spine Stabilization in Patients With Metastatic Spinal Cord Compression?: A New Scoring System. AB - STUDY DESIGN: A retrospective study. OBJECTIVE: This study aims to develop a new scoring system that can guild surgeons to select the best candidates for decompressive surgery in patients with metastatic spinal cord compression (MSCC). SUMMARY OF BACKGROUND DATA: Predicting survival and functional outcome is essential when selecting the individual treatment for patients with MSCC. The criteria for identifying MSCC patients who are most likely to benefit from decompressive surgery remain unclear. METHODS: We retrospectively analyzed 12 preoperative characteristics for postoperative survival in a series of 206 patients with MSCC who were operated with decompressive surgery and spine stabilization. Characteristics significantly associated with survival in the multivariate analysis were included in the scoring system. Postoperative function outcome was also analyzed on the basis of the scoring system. RESULTS: According to the multivariate analysis, primary site (P < 0.01), preoperative ambulatory status (P < 0.01), visceral metastases (P < 0.01), preoperative chemotherapy (P = 0.02), and bone metastasis at cancer diagnosis (P = 0.03) had a significant impact on postoperative survival and were included in the scoring system. According to the prognostic scores, which ranged from 0 to 10 points, three risk groups were designed: 0 to 2, 3 to 5, and 6 to 10 points. The corresponding 6 months survival rates were 8.2%, 56.5%, and 91.5%, respectively (P < 0.01), and postoperative ambulatory rates were 35.7%, 73.3%, and 95.9%, respectively (P < 0.01). CONCLUSION: We present a new scoring system for predicting survival and function outcome of MSCC patients after surgical decompression and spine stabilization. This new scoring system can help surgeons select the best candidates for surgical treatment. LEVEL OF EVIDENCE: 4. PMID- 26937607 TI - Validity, Reliability, and Responsiveness of SRS-7 as an Outcomes Assessment Instrument for Operatively Treated Patients With Adult Spinal Deformity. AB - STUDY DESIGN: A retrospective analysis. OBJECTIVE: The aim of our study was to compare the normality, concurrent validity, internal consistency, responsiveness, and dimensionality of an item response theory-derived seven-question instrument (SRS-7), against the Scoliosis Research Society-22r (SRS-22r) questionnaire in operatively treated patients with adult spinal deformity (ASD). SUMMARY OF BACKGROUND DATA: Compared with SRS-22r, SRS-7 (which has been validated in operatively treated patients with adolescent idiopathic scoliosis) has advantages of being short, unidimensional, and linear. METHODS: A prospective database of ASD patients was queried for patients 18 years or older who were operatively treated, and who answered pre- and postoperative (at 2-year follow-up) SRS-22r questions (n = 276). Corresponding SRS-7 scores were calculated using answers to SRS-22r items 1, 4, 6, 10, 18, 19, and 20. Significance was set at a P value less than 0.01. RESULTS: SRS-7 and SRS-22r were normally distributed preoperatively but not postoperatively. SRS-7 and SRS-22r scores had high correlation both preoperatively (r = 0.76, P < 0.01) and postoperatively (r = 0.83, P < 0.01). The internal consistency reliability Cronbach alpha values were 0.61 (SRS-7) and 0.83 (SRS-22r) preoperatively and 0.91 (SRS-7) and 0.95 (SRS-22r) postoperatively. SRS 7 was found to be more responsive than SRS-22r with measures of effect size: Cohen d = 1.21 versus 1.13, Hedge g = 1.21 versus 1.13, and effect size correlation r = 0.52 versus 0.49. Iterative principal factor analysis of pre- and postoperative scores showed the presence of one dominant latent factor in SRS-7 (unidimensionality) and four latent factors in SRS-22r (multidimensionality). CONCLUSION: SRS-7 is a valid, reliable, responsive, and unidimensional instrument, which can be used as a short-form alternative to the SRS-22r for assessing global changes in patient-reported outcomes over time in patients with ASD. LEVEL OF EVIDENCE: 3. PMID- 26937609 TI - A modest proposal. PMID- 26937610 TI - Back on TRAC: New trial launched in bid to outpace multidrug-resistant malaria. PMID- 26937608 TI - Circulating cellular adhesion molecules and risk of diabetes: the Multi-Ethnic Study of Atherosclerosis (MESA). AB - AIMS: To test the hypothesis that soluble cellular adhesion molecules would be positively and independently associated with risk of diabetes. METHODS: Soluble levels of six cellular adhesion molecules (ICAM-1, E-selectin, VCAM-1, E cadherin, L-selectin and P-selectin) were measured in participants in the Multi Ethnic Study of Atherosclerosis, a prospective cohort study. Participants were then followed for up to 10 years to ascertain incident diabetes. RESULTS: Sample sizes ranged from 826 to 2185. After adjusting for age, sex, race/ethnicity, BMI and fasting glucose or HbA1c , four cellular adhesion molecules (ICAM-1, E selectin, VCAM-1 and E-cadherin) were positively associated with incident diabetes and there was a statistically significant trend across quartiles. Comparing the incidence of diabetes in the highest and lowest quartiles of each cellular adhesion molecule, the magnitude of association was largest for E selectin (hazard ratio 2.49; 95% CI 1.26-4.93) and ICAM-1 (hazard ratio 1.76; 95% CI 1.22-2.55) in fully adjusted models. Tests of effect modification by racial/ethnic group and sex were not statistically significant for any of the cellular adhesion molecules (P > 0.05). CONCLUSIONS: The finding of significant associations between multiple cellular adhesion molecules and incident diabetes may lend further support to the hypothesis that microvascular endothelial dysfunction contributes to risk of diabetes. PMID- 26937611 TI - Group mentality: Determining if targeted treatments really work for cancer. PMID- 26937612 TI - Missing link: Animal models to study whether Zika causes birth defects. PMID- 26937614 TI - When patients reach out, scientists should reach back carefully. PMID- 26937615 TI - The cellular origins of drug resistance in cancer. PMID- 26937616 TI - Deriving functional beige fat from capillaries. PMID- 26937617 TI - Approaching a cure for type 1 diabetes. PMID- 26937619 TI - Progress Toward Measles Elimination - Nepal, 2007-2014. AB - In 2013, the 66th session of the Regional Committee of the World Health Organization (WHO) South-East Asia Region (SEAR) established a goal to eliminate measles and to control rubella and congenital rubella syndrome (CRS) in SEAR by 2020. Current recommended measles elimination strategies in the region include 1) achieving and maintaining >=95% coverage with 2 doses of measles-containing vaccine (MCV) in every district, delivered through the routine immunization program or through supplementary immunization activities (SIAs); 2) developing and sustaining a sensitive and timely measles case-based surveillance system that meets minimum recommended performance indicators; 3) developing and maintaining an accredited measles laboratory network; and 4) achieving timely identification, investigation, and response to measles outbreaks. In 2013, Nepal, one of the 11 SEAR member states, adopted a goal for national measles elimination by 2019. This report updates a previous report and summarizes progress toward measles elimination in Nepal during 2007-2014. During 2007-2014, estimated coverage with the first MCV dose (MCV1) increased from 81% to 88%. Approximately 3.9 and 9.7 million children were vaccinated in SIAs conducted in 2008 and 2014, respectively. Reported suspected measles incidence declined by 13% during 2007 2014, from 54 to 47 cases per 1 million population. However, in 2014, 81% of districts did not meet the measles case-based surveillance performance indicator target of >=2 discarded non-measles cases per 100,000 population per year. To achieve and maintain measles elimination, additional measures are needed to strengthen routine immunization services to increase coverage with MCV1 and a recently introduced second dose of MCV (MCV2) to >=95% in all districts, and to enhance sensitivity of measles case-based surveillance by adopting a more sensitive case definition, expanding case-based surveillance sites nationwide, and ensuring timely transport of specimens to the accredited national laboratory. PMID- 26937620 TI - The Horizon is Always Ahead. PMID- 26937621 TI - Ag2CrO4 nanoparticles loaded on two-dimensional large surface area graphite-like carbon nitride sheets: simple synthesis and excellent photocatalytic performance. AB - Graphite-like carbon nitride (g-C3N4) with a large surface area was prepared through thermal condensation of guanidine hydrochloride at 650 degrees C. Various amounts of silver chromate (Ag2CrO4) nanoparticles with small size were highly loaded on the g-C3N4 by a simple co-precipitation method at room temperature. The chemical constituents, surface structure and optical properties of the resultant Ag2CrO4/g-C3N4 composites were thoroughly characterized. And the photocatalytic performances were evaluated by degradation of Rhodamine B (RhB) and phenol, the experimental results indicated that the as-prepared Ag2CrO4/g C3N4 composites presented excellent photocatalytic activity under visible-light irradiation. With the mass ratio of Ag2CrO4 to g-C3N4 at 1 : 2, the Ag2CrO4/g C3N4 composites exhibited optimal photocatalytic activity for degrading RhB, approximately 6.1 and 10.4 times higher than those on pure g-C3N4 and bare Ag2CrO4 particles. The improved photocatalytic activity was mainly attributed to the combined effect including the larger surface area, highly dispersed smaller Ag2CrO4 nanoparticles, stronger visible absorption and higher charge separation efficiency of the Ag2CrO4/g-C3N4 composites. Moreover, the possible mechanism for the photocatalytic activity was tentatively proposed. PMID- 26937618 TI - Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants. AB - Depression is a common, devastating illness. Current pharmacotherapies help many patients, but high rates of a partial response or no response, and the delayed onset of the effects of antidepressant therapies, leave many patients inadequately treated. However, new insights into the neurobiology of stress and human mood disorders have shed light on mechanisms underlying the vulnerability of individuals to depression and have pointed to novel antidepressants. Environmental events and other risk factors contribute to depression through converging molecular and cellular mechanisms that disrupt neuronal function and morphology, resulting in dysfunction of the circuitry that is essential for mood regulation and cognitive function. Although current antidepressants, such as serotonin-reuptake inhibitors, produce subtle changes that take effect in weeks or months, it has recently been shown that treatment with new agents results in an improvement in mood ratings within hours of dosing patients who are resistant to typical antidepressants. Within a similar time scale, these new agents have also been shown to reverse the synaptic deficits caused by stress. PMID- 26937622 TI - Perianal Crohn's Disease is Associated with Distal Colonic Disease, Stricturing Disease Behavior, IBD-Associated Serologies and Genetic Variation in the JAK-STAT Pathway. AB - BACKGROUND: Perianal Crohn's Disease (pCD) is a particularly severe phenotype associated with poor quality of life with a reported prevalence of 12%-40%. Previous studies investigating the etiology of pCD have been limited in the numbers of subjects and the intensity of genotyping. The aim of this study was to identify clinical, serological, and genetic factors associated with pCD. METHODS: We performed a case-control study comparing patients with (pCD+) and without perianal (pCD) involvement in CD; defined as the presence of perianal abscesses or fistulae. Data on demographics and clinical features were obtained by chart review. Inflammatory bowel disease-related serology was determined by enzyme linked immunosorbent assay. Genetic data were generated using Illumina genotyping platforms. RESULTS: We included 1721 patients with CD of which 524 (30.4%) were pCD+ and 1197 were pPCD. pCD was associated with distal colonic disease (Odds ratio 5.54 [3.23-9.52], P < 0.001), stricturing disease behavior (1.44 [1.14 1.81], P = 0.002) and family history of inflammatory bowel disease (4.98 [3.30 7.46], P < 0.001). pCD was associated with higher anti-sacharomyces cerevisae antibodies IgA (P < 0.001) and OmpC (P = 0.008) antibody levels. pCD was associated with known inflammatory bowel disease loci, including KIF3B, CRTC3, TRAF3IP2, JAZF1, NRIP1, MST1, FUT2, and PTGER (all P < 0.05). We also identified genetic association with genes involved in autophagy (DAPK1, P = 5.11 * 10), TNF alpha pathways (NUCB2, P = 8.68 * 10; DAPK1), IFNg pathways (DAPK1; NDFIP2, P = 8.74 * 10), and extracellular matrix and scaffolding proteins (USH1C, P = 8.68 * 10; NDFIP2; TMC07, P = 8.87 * 10). Pathway analyses implicated the JAK-Stat pathway (pc = 3.72 * 10). CONCLUSION: We have identified associations between pCD, more distal colonic inflammation, Crohn's disease-associated serologies, and genetic variation in the JAK-Stat pathway. PMID- 26937623 TI - Microbiome Survey of the Inflamed and Noninflamed Gut at Different Compartments Within the Gastrointestinal Tract of Inflammatory Bowel Disease Patients. AB - BACKGROUND: We aimed to contrast the mucosal microbiota in Crohn's disease (CD) and ulcerative colitis (UC). METHODS: We assessed the concept of localized dysbiosis by comparing the bacterial communities of inflamed and noninflamed mucosa of patients with inflammatory bowel disease (IBD) and by analysis of the microbiota composition at distinct gut compartments (ileum, cecum, mid-colon, and rectum). We performed 16S rDNA sequencing to analyze population structures. Quality control and operational taxonomic unit classification of reads were performed using mothur with statistical analyses executed in the R package, phyloseq. RESULTS: There was no variation in any phyla or genera comparing inflamed to noninflamed mucosa within CD (or UC) or when comparing different gut compartments within CD (or UC). There were differences between the inflamed and noninflamed mucosa between CD and UC: analysis of the inflamed IBD gut at the phylum level indicated that Bacteroidetes (P = 0.002) and Fusobacteria (P < 0.05) were detected more frequently in inflamed CD mucosa than in inflamed UC mucosa. Conversely, Proteobacteria and Firmicutes (P < 0.05) were more frequently observed in the inflamed UC mucosa. At the genus level, the abundance of Faecalibacterium (P <= 0.05), Bacteroides (P = 0.003), and Pseudomonas (P < 0.001) were significantly different between the inflamed CD and UC and the abundance of 13 genera were significantly different within the noninflamed mucosa. The noninflamed UC mucosa was the most different from non-IBD mucosa. CONCLUSIONS: Dramatic shifts of microbial communities were not observed between the noninflamed and inflamed mucosa within CD (or UC) although both the inflamed (and noninflamed) mucosa was different between CD and UC. PMID- 26937624 TI - Ulcerative Colitis-Associated Long Noncoding RNA, BC012900, Regulates Intestinal Epithelial Cell Apoptosis. AB - BACKGROUND: Long noncoding RNAs (lncRNAs) were recently found to be key regulators of biological functions and associated with human diseases. Thus far, the roles of lncRNAs in inflammatory bowel disease (IBD) remain unknown. We aimed to determine whether lncRNAs are associated with IBD and regulate epithelial cell physiology. METHODS: lncRNAs microarray and quantitative RT-PCR were performed on 60 sigmoid colon biopsies from patients with active ulcerative colitis (UC) and relevant controls. Localization of lncRNAs was detected by in situ hybridization and on subcellular RNA. The boundaries of BC012900 were assessed by 5' and 3' rapid amplification of cDNA ends. Apoptosis and proliferation assays were performed on BC012900-expressing construct or siRNA-transfected cells. RESULTS: We identified 329 lncRNAs with increased and 126 lncRNAs with decreased expression in active UC tissues compared with normal control tissues, including the most significantly upregulated (BC012900, AK001903, and AK023330) and downregulated (BC029135, CDKN2B-AS1, and BC062296) transcripts. We found that most of the lncRNAs are localized to the nucleus. In particular, BC012900 expression was significantly increased in active UC and stimulated by cytokines and pathogenic molecules. Furthermore, BC012900 overexpression in epithelial cells results in a significant inhibition of cell proliferation and an increased susceptibility to apoptosis, which differ from its adjacent gene DUSP4. CONCLUSIONS: Multiple lncRNAs are differentially expressed in IBD and play a role in regulating cellular physiology. Our results indicate that lncRNAs may be integral modulators of intestinal inflammation associated with IBD and represent novel targets for future therapeutics and diagnostic marker development. PMID- 26937628 TI - HSiCl3-Mediated Reduction of Nitro-Derivatives to Amines: Is Tertiary Amine Stabilized SiCl2 the Actual Reducing Species? AB - The mechanism of a recently reported, highly chemoselective metal-free protocol of wide general applicability for the reduction of aromatic and aliphatic nitro derivatives to amines has been investigated. The reaction is supposed to occur through the generation of a Si(II) reducing species; quantum mechanical calculations, and spectroscopic and experimental data strongly suggest the tertiary amine-stabilized dichlorosilylene to be the most probable reducing agent. PMID- 26937625 TI - Ancient hybridization and genomic stabilization in a swordtail fish. AB - A rapidly increasing body of work is revealing that the genomes of distinct species often exhibit hybrid ancestry, presumably due to postspeciation hybridization between closely related species. Despite the growing number of documented cases, we still know relatively little about how genomes evolve and stabilize following hybridization, and to what extent hybridization is functionally relevant. Here, we examine the case of Xiphophorus nezahualcoyotl, a teleost fish whose genome exhibits significant hybrid ancestry. We show that hybridization was relatively ancient and is unlikely to be ongoing. Strikingly, the genome of X. nezahualcoyotl has largely stabilized following hybridization, distinguishing it from examples such as human-Neanderthal hybridization. Hybridization-derived regions are remarkably distinct from other regions of the genome, tending to be enriched in genomic regions with reduced constraint. These results suggest that selection has played a role in removing hybrid ancestry from certain functionally important regions. Combined with findings in other systems, our results raise many questions about the process of genomic stabilization and the role of selection in shaping patterns of hybrid ancestry in the genome. PMID- 26937627 TI - The contribution of developmental experience vs. condition to life history, trait variation and individual differences. AB - 1. Developmental experience, for example food abundance during juvenile stages, is known to affect life history and behaviour. However, the life history and behavioural consequences of developmental experience have rarely been studied in concert. As a result, it is still unclear whether developmental experience affects behaviour through changes in life history, or independently of it. 2. The effect of developmental experience on life history and behaviour may also be masked or affected by individual condition during adulthood. Thus, it is critical to tease apart the effects of developmental experience and current individual condition on life history and behaviour. 3. In this study, we manipulated food abundance during development in the western black widow spider, Latrodectus hesperus, by rearing spiders on either a restricted or ad lib diet. We separated developmental from condition-dependent effects by assaying adult foraging behaviour (tendency to attack prey and to stay on out of the refuge following an attack) and web structure multiple times under different levels of satiation following different developmental treatments. 4. Spiders reared under food restriction matured slower and at a smaller size than spiders reared in ad lib conditions. Spiders reared on a restricted diet were more aggressive towards prey and built webs structured for prey capture, while spiders reared on an ad lib diet were less aggressive and built safer webs. Developmental treatment affected which traits were plastic as adults: restricted spiders built safer webs when their adult condition increased, while ad lib spiders reduced their aggression when their adult condition increased. The amount of individual variation in behaviour and web structure varied with developmental treatment. Spiders reared on a restricted diet exhibited consistent variation in all aspects of foraging behaviour and web structure, while spiders reared on an ad lib diet exhibited consistent individual variation in aggression and web weight only. 5. Developmental experience affected the average life history, behaviour and web structure of spiders, but also shaped the amount of phenotypic variation observed among individuals. Surprisingly, developmental experience also determined the particular way in which individuals plastically adjusted their behaviour and web structure to changes in adult condition. PMID- 26937629 TI - MicroRNA-3666 Regulates Thyroid Carcinoma Cell Proliferation via MET. AB - BACKGROUND/AIMS: Thyroid carcinoma (TC) is a highly lethal malignant cancer and its carcinogenesis remains undetermined. Dysregulation of microRNAs (miRNAs) is well known to be involved in the development of various cancers, including TC, whereas a role of miR-3666 in the pathogenesis of TC has not been appreciated. METHODS: We analyzed the levels of MET and miR-3666 in TC tissue and the relationship of miR-3666 levels with patients' prognosis. We then overexpressed miR-3666 by miRNA mimics transfection and inhibited miR-3666 by miRNA antisense transfection in TC cells. Cell survival and growth were analyzed by CCK-8 assay and MTT assay, respectively. Cell apoptosis and proliferation were analyzed by flow cytometry. Bioinformatics analyses were applied to predict miR-3666 targets, which was then confirmed using luciferase reporter assay. RESULTS: We detected significantly higher levels of MET, and significantly lower levels of miR-3666 in TC tissue, compared to the adjacent non-tumor tissue. Moreover, the low miR-3666 levels were associated with poor survival of the patients. Overexpression of miR 3666 significantly inhibited cell growth, while depletion of miR-3666 increased cell growth in TC cells. Moreover, the effects of miR-3666 on cell growth appeared to result from alteration in cell proliferation, rather than changes in cell apoptosis. MiR-3666 was found to bind to the 3'-UTR of MET mRNA to inhibit its translation in TC cells. CONCLUSION: Reduced miR-3666 levels in TC tissue may promotes TC growth, possibly through MET-mediated cell proliferation. PMID- 26937630 TI - Indication for liver transplantation in a patient with a history of a gastric lymphoma. AB - The indication for liver transplantation in patients with history of lymphoma is little-known, and the references documented in the medical literature are still limited. We present the case of a 63-year-old man who was diagnosed with chronic hepatopathy due to HBV 15 years ago. He was operated on for hepatocellular carcinoma in the segment VI of the liver 4 years ago, finding a macronodular liver cirrhosis during the surgery. Fifteen months later, the patient was diagnosed with diffuse large B-cell gastric lymphoma (fig.1). After a good response to chemotherapy treatment with R-CHOP scheme, the patient has been in complete remission for 36 months. Currently, the patient has a Child-Pugh score of 5 points, MELD score of 6 points, an undetectable viral load and it does not exist any evidence of hepatocellular carcinoma recurrence. With respect to this case, could it be considered liver transplantation in any assumption or would it be rejected in any case due to the recent history of lymphoma? In this case report, it has decided to do a periodic follow-up of the patient, but because of the good prognosis of the lymphoma, liver transplantation may be performed in the case of hepatocellular recurrence, worsening of liver function (Child-Pugh B or C) or fulminant hepatic failure due to HBV reactivation. There is not yet consensus about the interval between lymphoma remission and liver transplantation, therefore it recommends an individual oncologic evaluation in order to establish the recurrence risk before deciding on the indication for liver transplantation. PMID- 26937631 TI - Comparison of HER2 Expression in Primary Tumor and Disseminated Tumor Cells in the Bone Marrow of Breast Cancer Patients. AB - OBJECTIVE: The aim of this study was to measure the human epidermal growth factor receptor 2 (HER2) status of disseminated tumor cells (DTCs) from bone marrow (BM) aspirates and to assess correspondence or discrepancy with the primary tumor. METHODS: DTCs were isolated from the BM of 156 breast cancer patients. Cytokeratin-positive DTCs were further analyzed by the chromogenic in situ hybridization method to detect HER2 gene amplification. RESULTS: A significant correlation (p = 0.021) was found between the HER2 status of DTCs and the primary tumors. Sixty-one (68.5%) patients had a corresponding status. However, a shift of phenotype between primary tumor and DTCs was found in the remaining patients. CONCLUSION: This study showed a significant grade of discordance of the HER2 status between primary tumors and DTCs in the BM of a relevant subgroup of patients. Detection of HER2 amplification on DTCs could therefore help to better stratify patients for a more tailored therapy, since they would benefit from a HER2-targeted therapy. PMID- 26937632 TI - Agar Sediment Test for Assessing the Suitability of Organic Waste Streams for Recovering Nutrients by the Aquatic Worm Lumbriculus variegatus. AB - An agar sediment test was developed to evaluate the suitability of organic waste streams from the food industry for recovering nutrients by the aquatic worm Lumbriculus variegatus (Lv). The effects of agar gel, sand, and food quantities in the sediment test on worm growth, reproduction, and water quality were studied. Agar gel addition ameliorated growth conditions by reducing food hydrolysis and altering sediment structure. Best results for combined reproduction and growth were obtained with 0.6% agar-gel (20 ml), 10 g. fine sand, 40 g. coarse sand, and 105 mg fish food (Tetramin). With agar gel, ingestion and growth is more the result of addition of food in its original quality. Final tests with secondary potato starch sludge and wheat bran demonstrated that this test is appropriate for the comparison of solid feedstuffs and suspended organic waste streams. This test method is expected to be suitable for organic waste studies using other sediment dwelling invertebrates. PMID- 26937635 TI - Mortality from Congenital Heart Disease in Mexico: A Problem on the Rise. AB - BACKGROUND AND OBJECTIVES: Temporal trends in mortality from congenital heart disease (CHD) vary among regions. It is therefore necessary to study this problem in each country. In Mexico, congenital anomalies were responsible for 24% of infant mortality in 2013 and CHD represented 55% of total deaths from congenital anomalies among children under 1 year of age. The objectives of this study were to analyze the trends in infant mortality from CHD in Mexico (1998 to 2013), its specific causes, age at death and associated socio-demographic factors. METHODS: Population-based study which calculated the compounded annual growth rate of death rom CHD between 1998 and 2013. Specific causes, age at which death from CHD occurred and risk factors associated with mortality were analyzed for the year 2013. RESULTS: Infant mortality from CHD increased 24.8% from 1998 to 2013 (114.4 to 146.4/ 100,000 live births). A total of 3,593 CHD deaths occurred in 2013; the main causes were CHD with left-to-right shunt (n = 487; 19.8/100,000 live births) and cyanotic heart disease (n = 410; 16.7/100,000). A total of 1,049 (29.2%) deaths from CHD occurred during the first week of life. Risk factors associated with mortality from CHD were, in order of magnitude: non-institutional birth, rural area, birth in a public hospital and male sex. CONCLUSIONS: Mortality from CHD has increased in Mexico. The main causes were CHD with left-to-right shunt, which are not necessarily fatal if treated promptly. Populations vulnerable to death from CHD were identified. Approximately one-third of the CHD occurred during the first week of life. It is important to promote early diagnosis, especially for non-institutional births. PMID- 26937634 TI - Insight on Genes Affecting Tuber Development in Potato upon Potato spindle tuber viroid (PSTVd) Infection. AB - Potato (Solanum tuberosum L) is a natural host of Potato spindle tuber viroid (PSTVd) which can cause characteristic symptoms on developing plants including stunting phenotype and distortion of leaves and tubers. PSTVd is the type species of the family Pospiviroidae, and can replicate in the nucleus and move systemically throughout the plant. It is not well understood how the viroid can affect host genes for successful invasion and which genes show altered expression levels upon infection. Our primary focus in this study is the identification of genes which can affect tuber formation since viroid infection can strongly influence tuber development and especially tuber shape. In this study, we used a large-scale method to identify differentially expressed genes in potato. We have identified defence, stress and sugar metabolism related genes having altered expression levels upon infection. Additionally, hormone pathway related genes showed significant up- or down-regulation. DWARF1/DIMINUTO, Gibberellin 7-oxidase and BEL5 transcripts were identified and validated showing differential expression in viroid infected tissues. Our study suggests that gibberellin and brassinosteroid pathways have a possible role in tuber development upon PSTVd infection. PMID- 26937636 TI - Early Diagnosis of Pneumonia in Severe Stroke: Clinical Features and the Diagnostic Role of C-Reactive Protein. AB - BACKGROUND: Accurate diagnosis of pneumonia complicating severe stroke is challenging due to difficulties in physical examination, altered immune responses and delayed manifestations of radiological changes. The aims of this study were to describe early clinical features and to examine C-reactive protein (CRP) as a diagnostic marker of post-stroke pneumonia. METHODS: Patients who required nasogastric feeding and had no evidence of pneumonia within 7 days of stroke onset were included in the study and followed-up for 21 days with a daily clinical examination. Pneumonia was diagnosed using modified British Thoracic Society criteria. RESULTS: 60 patients were recruited (mean age 77 years, mean National Institutes of Health Stroke Scale Score 19.47). Forty-four episodes of pneumonia were identified. Common manifestations on the day of the diagnosis were new onset crackles (43/44, 98%), tachypnoea>25/min (42/44, 95%), and oxygen saturation <90% (41/44, 93%). Cough, purulent sputum, and pyrexia >38 degrees C were observed in 27 (61%), 25 (57%) and 15 (34%) episodes respectively. Leucocytosis (WBC>11,000/ml) and raised CRP (>10 mg/l) were observed in 38 (86%) and 43 (97%) cases of pneumonia respectively. The area under the ROC curve for CRP was 0.827 (95% CI 0.720, 0.933). The diagnostic cut-off for CRP with an acceptable sensitivity (>0.8) was 25.60 mg/L (Youden index (J) 0.515; sensitivity 0.848; specificity 0.667). A cut-off of 64.65 mg/L had the highest diagnostic accuracy (J 0.562; sensitivity 0.636; specificity 0.926). CONCLUSION: Patients with severe stroke frequently do not manifest key diagnostic features of pneumonia such as pyrexia, cough and purulent sputum early in their illness. The most common signs in this group are new-onset crackles, tachypnoea and hypoxia. Our results suggest that a CRP >25 mg/L should prompt investigations for pneumonia while values >65 mg/L have the highest diagnostic accuracy to justify consideration of this threshold as a diagnostic marker of post-stroke pneumonia. PMID- 26937633 TI - Neurotransmitter signaling through heterotrimeric G proteins: insights from studies in C. elegans. AB - Neurotransmitters signal via G protein coupled receptors (GPCRs) to modulate activity of neurons and muscles. C. elegans has ~150 G protein coupled neuropeptide receptor homologs and 28 additional GPCRs for small-molecule neurotransmitters. Genetic studies in C. elegans demonstrate that neurotransmitters diffuse far from their release sites to activate GPCRs on distant cells. Individual receptor types are expressed on limited numbers of cells and thus can provide very specific regulation of an individual neural circuit and behavior. G protein coupled neurotransmitter receptors signal principally via the three types of heterotrimeric G proteins defined by the G alpha subunits Galphao, Galphaq, and Galphas. Each of these G alpha proteins is found in all neurons plus some muscles. Galphao and Galphaq signaling inhibit and activate neurotransmitter release, respectively. Galphas signaling, like Galphaq signaling, promotes neurotransmitter release. Many details of the signaling mechanisms downstream of Galphaq and Galphas have been delineated and are consistent with those of their mammalian orthologs. The details of the signaling mechanism downstream of Galphao remain a mystery. Forward genetic screens in C. elegans have identified new molecular components of neural G protein signaling mechanisms, including Regulators of G protein Signaling (RGS proteins) that inhibit signaling, a new Galphaq effector (the Trio RhoGEF domain), and the RIC-8 protein that is required for neuronal Galpha signaling. A model is presented in which G proteins sum up the variety of neuromodulator signals that impinge on a neuron to calculate its appropriate output level. PMID- 26937638 TI - The German Version of the Gaze Anxiety Rating Scale (GARS): Reliability and Validity. AB - OBJECTIVE: Fear of eye gaze and avoidance of eye contact are core features of social anxiety disorders (SAD). To measure self-reported fear and avoidance of eye gaze, the Gaze Anxiety Rating Scale (GARS) has been developed and validated in recent years in its English version. The main objectives of the present study were to psychometrically evaluate the German translation of the GARS concerning its reliability, factorial structure, and validity. METHODS: Three samples of participants were enrolled in the study. (1) A non-patient sample (n = 353) completed the GARS and a set of trait questionnaires to assess internal consistency, test-retest reliability, factorial structure, and concurrent and divergent validity. (2) A sample of patients with SAD (n = 33) was compared to a healthy control group (n = 30) regarding their scores on the GARS and the trait measures. RESULTS: The German GARS fear and avoidance scales exhibited excellent internal consistency and high stability over 2 and 4 months, as did the original version. The English version's factorial structure was replicated, yielding two categories of situations: (1) everyday situations and (2) situations involving high evaluative threat. GARS fear and avoidance displayed convergent validity with trait measures of social anxiety and were markedly higher in patients with GSAD than in healthy controls. Fear and avoidance of eye contact in situations involving high levels of evaluative threat related more closely to social anxiety than to gaze anxiety in everyday situations. CONCLUSIONS: The German version of the GARS has demonstrated reliability and validity similar to the original version, and is thus well suited to capture fear and avoidance of eye contact in different social situations as a valid self-report measure of social anxiety and related disorders in the social domain for use in both clinical practice and research. PMID- 26937639 TI - Correction: Model-Assisted Analysis of Spatial and Temporal Variations in Fruit Temperature and Transpiration Highlighting the Role of Fruit Development. PMID- 26937637 TI - Metabolic Changes Precede the Development of Pulmonary Hypertension in the Monocrotaline Exposed Rat Lung. AB - There is increasing interest in the potential for metabolic profiling to evaluate the progression of pulmonary hypertension (PH). However, a detailed analysis of the metabolic changes in lungs at the early stage of PH, characterized by increased pulmonary artery pressure but prior to the development of right ventricle hypertrophy and failure, is lacking in a preclinical animal model of PH. Thus, we undertook a study using rats 14 days after exposure to monocrotaline (MCT), to determine whether we could identify early stage metabolic changes prior to the manifestation of developed PH. We observed changes in multiple pathways associated with the development of PH, including activated glycolysis, increased markers of proliferation, disruptions in carnitine homeostasis, increased inflammatory and fibrosis biomarkers, and a reduction in glutathione biosynthesis. Further, our global metabolic profile data compare favorably with prior work carried out in humans with PH. We conclude that despite the MCT-model not recapitulating all the structural changes associated with humans with advanced PH, including endothelial cell proliferation and the formation of plexiform lesions, it is very similar at a metabolic level. Thus, we suggest that despite its limitations it can still serve as a useful preclinical model for the study of PH. PMID- 26937642 TI - With regard to the implementation of the AGREE instrument in atrial fibrillation clinical guidelines. PMID- 26937640 TI - Rainbow Vectors for Broad-Range Bacterial Fluorescence Labeling. AB - Since their discovery, fluorescent proteins have been widely used to study protein function, localization or interaction, promoter activity and regulation, drug discovery or for non-invasive imaging. They have been extensively modified to improve brightness, stability, and oligomerization state. However, only a few studies have focused on understanding the dynamics of fluorescent proteins expression in bacteria. In this work, we developed a set plasmids encoding 12 fluorescent proteins for bacterial labeling to facilitate the study of pathogen host interactions. These broad-spectrum plasmids can be used with a wide variety of Gram-negative microorganisms including Escherichia coli, Pseudomonas aeruginosa, Burkholderia cepacia, Bordetella bronchiseptica, Shigella flexneri or Klebsiella pneumoniae. For comparison, fluorescent protein expression and physical characteristics in Escherichia coli were analyzed using fluorescence microscopy, flow cytometry and in vivo imaging. Fluorescent proteins derived from the Aequorea Victoria family showed high photobleaching, while proteins form the Discosoma sp. and the Fungia coccina family were more photostable for microscopy applications. Only E2-Crimson, mCherry and mKeima were successfully detected for in vivo applications. Overall, E2-Crimson was the fastest maturing protein tested in E. coli with the best overall performance in the study parameters. This study provides a unified comparison and comprehensive characterization of fluorescent protein photostability, maturation and toxicity, and offers general recommendations on the optimal fluorescent proteins for in vitro and in vivo applications. PMID- 26937641 TI - Serum Amyloid A Induces Inflammation, Proliferation and Cell Death in Activated Hepatic Stellate Cells. AB - Serum amyloid A (SAA) is an evolutionary highly conserved acute phase protein that is predominantly secreted by hepatocytes. However, its role in liver injury and fibrogenesis has not been elucidated so far. In this study, we determined the effects of SAA on hepatic stellate cells (HSCs), the main fibrogenic cell type of the liver. Serum amyloid A potently activated IkappaB kinase, c-Jun N-terminal kinase (JNK), Erk and Akt and enhanced NF-kappaB-dependent luciferase activity in primary human and rat HSCs. Serum amyloid A induced the transcription of MCP-1, RANTES and MMP9 in an NF-kappaB- and JNK-dependent manner. Blockade of NF-kappaB revealed cytotoxic effects of SAA in primary HSCs with signs of apoptosis such as caspase 3 and PARP cleavage and Annexin V staining. Serum amyloid A induced HSC proliferation, which depended on JNK, Erk and Akt activity. In primary hepatocytes, SAA also activated MAP kinases, but did not induce relevant cell death after NF-kappaB inhibition. In two models of hepatic fibrogenesis, CCl4 treatment and bile duct ligation, hepatic mRNA levels of SAA1 and SAA3 were strongly increased. In conclusion, SAA may modulate fibrogenic responses in the liver in a positive and negative fashion by inducing inflammation, proliferation and cell death in HSCs. PMID- 26937643 TI - A Novel Tram Stent Method in the Treatment of Coronary Bifurcation Lesions - Finite Element Study. AB - A novel stent was designed for the treatment of coronary bifurcation lesion, and it was investigated for its performance by finite element analysis. This study was performed in search of a novel method of treatment of bifurcation lesion with provisional stenting. A bifurcation model was created with the proximal vessel of 3.2 mm diameter, and the distal vessel after the side branch (2.3 mm) was 2.7 mm. A novel stent was designed with connection links that had a profile of a tram. Laser cutting and shape setting of the stent was performed, and thereafter it was crimped and deployed over a balloon. The contact pressure, stresses on the arterial wall, stresses on the stent, the maximal principal log strain of the main artery and the side-branch were studied. The study was performed in Abaqus, Simulia. The stresses on the main branch and the distal branch were minimally increased after deployment of this novel stent. The side branch was preserved, and the stresses on the side branch were lesser; and at the confluence of bifurcation on either side of the side branch origin the von-Mises stress was marginally increased. The stresses and strain at the bifurcation were significantly lesser than the stresses and strain of the currently existing techniques used in the treatment of bifurcation lesions though the study was primarily focused only on the utility of the new technology. There is a potential for a novel Tram-stent method in the treatment of coronary bifurcation lesions. PMID- 26937645 TI - MicroRNA Expression Profiling to Identify and Validate Reference Genes for the Relative Quantification of microRNA in Rectal Cancer. AB - INTRODUCTION: MicroRNAs (miRNAs) play important roles in regulating biological processes at the post-transcriptional level. Deregulation of miRNAs has been observed in cancer, and miRNAs are being investigated as potential biomarkers regarding diagnosis, prognosis and prediction in cancer management. Real-time quantitative polymerase chain reaction (RT-qPCR) is commonly used, when measuring miRNA expression. Appropriate normalisation of RT-qPCR data is important to ensure reliable results. The aim of the present study was to identify stably expressed miRNAs applicable as normaliser candidates in future studies of miRNA expression in rectal cancer. MATERIALS AND METHODS: We performed high-throughput miRNA profiling (OpenArray(r)) on ten pairs of laser micro-dissected rectal cancer tissue and adjacent stroma. A global mean expression normalisation strategy was applied to identify the most stably expressed miRNAs for subsequent validation. In the first validation experiment, a panel of miRNAs were analysed on 25 pairs of micro dissected rectal cancer tissue and adjacent stroma. Subsequently, the same miRNAs were analysed in 28 pairs of rectal cancer tissue and normal rectal mucosa. RESULTS: From the miRNA profiling experiment, miR-645, miR-193a-5p, miR-27a and let-7g were identified as stably expressed, both in malignant and stromal tissue. In addition, NormFinder confirmed high expression stability for the four miRNAs. In the RT-qPCR based validation experiments, no significant difference between tumour and stroma/normal rectal mucosa was detected for the mean of the normaliser candidates miR-27a, miR-193a-5p and let 7g (first validation P = 0.801, second validation P = 0.321). MiR-645 was excluded from the data analysis, because it was undetected in 35 of 50 samples (first validation) and in 24 of 56 samples (second validation), respectively. Significant difference in expression level of RNU6B was observed between tumour and adjacent stromal (first validation), and between tumour and normal rectal mucosa (second validation). CONCLUSION: We recommend the mean expression of miR 27a, miR-193a-5p and let-7g as normalisation factor, when performing miRNA expression analyses by RT-qPCR on rectal cancer tissue. PMID- 26937647 TI - [New Pathogenetic Concepts and Early Pharmacological Studies in Sarcoidosis]. AB - The etiology of sarcoidosis is still elusive, yet there has been considerable progress in various areas of basic and clinical research. This review focuses on mechanisms of granuloma formation and on new findings in autoimmunity and genetics of sarcoidosis. A new promising concept arose, where serum amyloid A and/or mycobacterial antigens serve as nidus for granuloma formation. Furthermore, autoimmunity in sarcoidosis was neglected for a long time, yet new studies found autoantigens and abnormalities in antigen presentation in sarcoidosis. Last but not least, large genome-wide association studies discovered several new predisposing genes, leading to new hypotheses on pathomechanisms of sarcoidosis.In the second part, we focus on ongoing or recently completed clinical-pharmacological studies in patients with sarcoidosis: Positive studies were published in well characterized and homogenous subcohorts of sarcoid patients. Several drugs have shown a positive effect on sarcoidosis-associated fatigue, on sarcoidosis of the skin and on pulmonary hypertension in sarcoid patients. It seems that the generation of clinically closely defined subcohorts is necessary to achieve positive outcomes in studies on sarcoidosis. PMID- 26937646 TI - The efficacy and safety of a combination of glucosamine hydrochloride, chondroitin sulfate and bio-curcumin with exercise in the treatment of knee osteoarthritis: a randomized, double-blind, placebo-controlled study. AB - BACKGROUND: Knee osteoarthritis (OA) conservative treatment aims to delay cartilage degeneration; chondroprotective agents are a valid approach in this sense. A commercially available dietary supplement, CartiJoint Forte, containing glucosamine hydrochloride (GH), chondroitin sulfate (CS) and Bio-Curcumin BCM 95(r), was used in this trial. AIM: The aim of this study was to assess efficacy and safety of CartiJoint Forte combined with physical therapy in treating subjects with knee OA. DESIGN: A multicenter, prospective, randomized, double blind, placebo-controlled clinical trial. SETTING: Outpatients referred to the Rehabilitation Departments of two University Hospitals. POPULATION: Fifty-three patients were randomly assigned to an experimental group (N=26) or a control group (N.=27). Experimental subjects received two tablets of CartiJoint Forte each day for 8 weeks, while those in the control group were provided with a placebo. Three subjects dropped out during the course of the study. METHODS: The two groups both received 20 sessions of physical therapy during the course of the trial. Primary outcome was pain intensity, measured both at motion and at rest, using the Visual Analogue Scale (VAS). A secondary outcome was an assessment of knee function by Western Ontario and McMaster Universities Arthritis Index and Lequesne Index, knee ROM, and two inflammation markers (C-reactive protein and erythrocyte sedimentation rate). Each assessment was carried out at baseline (T0), at 8 weeks (T1) and at 12 weeks (T2). RESULTS: VAS at rest was found to be reduced between T0 and T1, as well as between T0 and T2 (F=13.712; P=0.0001), with no differences between groups (F=1.724; P=0.191). VAS at motion revealed a significant "group * time-check" interaction (F=2.491; P=0.032), with increasing effect of time on VAS reduction (F=17.748; P=0.0001). This was most pronounced in the experimental group at 8 weeks (F=3.437; P=0.045). The Lequesne Index showed reductions at T1 and T2 compared to T0 (F=9.535; P=0.0001), along with group effect, since the experimental group presented a lower score at T2 (F=7.091; P=0.009). No significant changes were found in the knee ROM and inflammation markers. CONCLUSION: CartiJoint Forte, added to physical therapy, may ameliorate pain and help to improve algofunctional score in knee OA patients. CLINICAL REHABILITATION IMPACT: Treatment of knee OA with curcuminoids plus glycosaminoglycans, added to physical therapy, improves VAS at motion and Lequesne Index scores. PMID- 26937644 TI - A Historical Overview of the Classification, Evolution, and Dispersion of Leishmania Parasites and Sandflies. AB - BACKGROUND: The aim of this study is to describe the major evolutionary historical events among Leishmania, sandflies, and the associated animal reservoirs in detail, in accordance with the geographical evolution of the Earth, which has not been previously discussed on a large scale. METHODOLOGY AND PRINCIPAL FINDINGS: Leishmania and sandfly classification has always been a controversial matter, and the increasing number of species currently described further complicates this issue. Despite several hypotheses on the origin, evolution, and distribution of Leishmania and sandflies in the Old and New World, no consistent agreement exists regarding dissemination of the actors that play roles in leishmaniasis. For this purpose, we present here three centuries of research on sandflies and Leishmania descriptions, as well as a complete description of Leishmania and sandfly fossils and the emergence date of each Leishmania and sandfly group during different geographical periods, from 550 million years ago until now. We discuss critically the different approaches that were used for Leishmana and sandfly classification and their synonymies, proposing an updated classification for each species of Leishmania and sandfly. We update information on the current distribution and dispersion of different species of Leishmania (53), sandflies (more than 800 at genus or subgenus level), and animal reservoirs in each of the following geographical ecozones: Palearctic, Nearctic, Neotropic, Afrotropical, Oriental, Malagasy, and Australian. We propose an updated list of the potential and proven sandfly vectors for each Leishmania species in the Old and New World. Finally, we address a classical question about digenetic Leishmania evolution: which was the first host, a vertebrate or an invertebrate? CONCLUSIONS AND SIGNIFICANCE: We propose an updated view of events that have played important roles in the geographical dispersion of sandflies, in relation to both the Leishmania species they transmit and the animal reservoirs of the parasites. PMID- 26937648 TI - Idiopathic polyhydramnios: persistence across gestation and impact on pregnancy outcomes. AB - PURPOSE: To investigate the likelihood of resolution of idiopathic polyhydramnios in pregnant women and compare outcomes between resolved and persistent cases. METHODS: One hundred and sixty-three women with idiopathic polyhydramnios who delivered at two medical centers during a 3 year period (January 2012-January 2015) were included in the study. Exclusion criteria included congenital fetal anomalies, maternal diabetes, isoimmunization, fetal infection, placental tumors or anomalies, and multiple gestation. Polyhydramnios was defined as SDP>=8cm or AFI>=24cm. Resolved cases were defined as those with AFI and/or SDP falling and remaining below 24cm and 8cm respectively. Pregnancy outcomes were compared between resolved and persistent cases. Two-sample t-test or Wilcoxon rank-sum test was used for continuous variables while chi-square test or Fisher's exact test was used for categorical measures. RESULTS: Resolution was noted in 61 of 163 (37%) patients. There were no differences in maternal age, gravidity or parity between resolved and persistent cases. Mean gestational age at diagnosis of polyhydramnios and overall mean AFI were significantly lower in the cases that resolved (29.7+/-4.5 weeks vs 33.4+/-4.1 weeks, p<0.0001; 23.3+/-3.5cm vs 25.8 23.3+/-4.0cm, p=0.0002). Similar to AFI measurements, mean SDP was also lower in cases with resolution (p=0.002). There was no difference in induction rates, mode of delivery, amnioinfusion rates, meconium staining of amniotic fluid and fetal heart rate abnormalities influencing intrapartum management between the two groups. Induction of labor for fetal indication and rupture of membranes were significantly more common in the persistent group. Cesarean delivery for abnormal lie and fetal distress did not differ between the groups. There was an increased risk of macrosomia (>4000g) and preterm delivery (<37 weeks) in the persistent group (p<0.05). CONCLUSIONS: Resolution rate was approximately 37% and more likely in cases diagnosed earlier in pregnancy and with lower mean amniotic fluid volume. Preterm delivery and macrosomia were more common in cases that persisted across gestation. PMID- 26937649 TI - Introduction. Molecular Imprinting in Separation Science. PMID- 26937650 TI - Determination of donepezil in serum samples using molecularly imprinted polymer nanoparticles followed by high-performance liquid chromatography with ultraviolet detection. AB - A molecularly imprinted polymer designed for the selective extraction of donepezil from serum samples was synthesized using a noncovalent molecular imprinting approach. The molecularly imprinted polymer was evaluated chromatographically and then its affinity for donepezil was confirmed by solid phase extraction. The optimal conditions for solid-phase extraction were provided by cartridge conditioning using acidified water purified from a Milli-Q system, sample loading under basic aqueous conditions, clean-up using acetonitrile, and elution with methanol/tetrahydrofuran. Desirable molecular recognition properties of the molecularly imprinted polymer led to good donepezil recoveries (90-102%). The data indicated that the imprinted polymer has a perfect selectivity and affinity for donepezil and could be used for selective extraction and analysis of donepezil in human serum. PMID- 26937651 TI - Erratum. AB - In the article by Takahashi et al., entitled "Reduced abundance of butyrate producing bacteria species in the fecal microbial community in Crohn's disease" [Digestion 2016;93:59- 65, DOI: 10.1159/000441768], the name sequence of the authors was corrected, missing underlining in table 1 was added, and an error in the legend of figure 1 was corrected. PMID- 26937652 TI - Genetic Correlations Greatly Increase Mutational Robustness and Can Both Reduce and Enhance Evolvability. AB - Mutational neighbourhoods in genotype-phenotype (GP) maps are widely believed to be more likely to share characteristics than expected from random chance. Such genetic correlations should strongly influence evolutionary dynamics. We explore and quantify these intuitions by comparing three GP maps-a model for RNA secondary structure, the HP model for protein tertiary structure, and the Polyomino model for protein quaternary structure-to a simple random null model that maintains the number of genotypes mapping to each phenotype, but assigns genotypes randomly. The mutational neighbourhood of a genotype in these GP maps is much more likely to contain genotypes mapping to the same phenotype than in the random null model. Such neutral correlations can be quantified by the robustness to mutations, which can be many orders of magnitude larger than that of the null model, and crucially, above the critical threshold for the formation of large neutral networks of mutationally connected genotypes which enhance the capacity for the exploration of phenotypic novelty. Thus neutral correlations increase evolvability. We also study non-neutral correlations: Compared to the null model, i) If a particular (non-neutral) phenotype is found once in the 1 mutation neighbourhood of a genotype, then the chance of finding that phenotype multiple times in this neighbourhood is larger than expected; ii) If two genotypes are connected by a single neutral mutation, then their respective non neutral 1-mutation neighbourhoods are more likely to be similar; iii) If a genotype maps to a folding or self-assembling phenotype, then its non-neutral neighbours are less likely to be a potentially deleterious non-folding or non assembling phenotype. Non-neutral correlations of type i) and ii) reduce the rate at which new phenotypes can be found by neutral exploration, and so may diminish evolvability, while non-neutral correlations of type iii) may instead facilitate evolutionary exploration and so increase evolvability. PMID- 26937654 TI - Role Domains of Knowledge Brokering: A Model for the Health Care Setting. AB - Knowledge brokering is a strategy to support collaborations and partnerships within and across clinical, research, and policy worlds to improve the generation and use of research knowledge. Knowledge brokers function in multiple roles to facilitate the use of evidence by leveraging the power of these partnerships. The application of theory can provide clarity in understanding the processes, influences, expected mechanisms of action, and desired outcomes of knowledge brokering. Viewing knowledge brokering from the perspective of its role domains can provide a means of organizing these elements to advance our understanding of knowledge brokering. The objectives of this special interest article are (1) to describe the context for knowledge brokering in health care, (2) to provide an overview of knowledge translation theories applied to knowledge brokering, and (3) to propose a model outlining the role domains assumed in knowledge brokering. The Role Model for Knowledge Brokering is composed of 5 role domains, including information manager, linking agent, capacity builder, facilitator, and evaluator. We provide examples from the literature and our real-world experience to demonstrate the application of the model. This model can be used to inform the practice of knowledge brokering as well as professional development and evaluation strategies. In addition, it may be used to inform theory-driven research examining the effectiveness of knowledge brokering on knowledge generation and translation outcomes in the health care field, as well as on patient health outcomes.Video Abstract is available for more insights from the authors (see Supplemental Digital Content 1, http://links.lww.com/JNPT/A126). PMID- 26937655 TI - Knowledge Translation: The Catalyst for Innovation of Neurologic Physical Therapy. PMID- 26937653 TI - Interleukin-1beta Promoter Polymorphism Enhances the Risk of Sleep Disturbance in Alzheimer's Disease. AB - Sleep alleviates Alzheimer's disease (AD)-related neuropathological processes, whereas sleep disturbance in AD patients is associated with elevated peripheral inflammatory cytokine levels. In the present study, we assessed interleukin (IL) 1beta and APOEepsilon4 polymorphisms for association with susceptibility of sleep disturbances in AD patients. A total of 123 pretreated AD patients and 120 age-, gender- and education level-matched healthy controls were recruited for two consecutive full-night polysomnography and measurement of Epworth Sleepiness Scale (ESS) scores for sleep-wake disturbance. Their genomic DNA was analyzed for IL-1beta and APOEepsilon4 SNPs using ligase detection reaction (LDR) technology. Blood levels of IL-1beta, IL-6, and tumor necrosis factor alpha (TNF-alpha) were measured using ELISA after lipopolysaccharide (LPS) stimulation. The odds ratio and 95% confidence interval for genotype-specific risk were calculated using an unconditional logistic regression model and adjusted by age, gender, educational levels, body mass index (BMI), and activities of daily living (ADL). Compared to the non-APOEepsilon4/epsilon4 genotype, APOEepsilon4/epsilon4 significantly increased the risk of AD (APOEepsilon4/epsilon4 vs. non-APOEepsilon4/epsilon4, adjusted OR = 4.33, 95% CI = 1.33-14.10, p = 0.015). Compared to the IL-1beta CC genotype (-31), the TT genotype significantly increased the risk of AD (TT vs. CC, adjusted OR = 1.72, 95% CI = 1.13-2.61, p = 0.010). AD patients carrying the APOEepsilon4 allele and the IL-1beta TT genotype showed less time in bed, longer sleep latency and REM latency, more awakenings, and a lower SWS percentage than those carrying CC/CT combined genotypes. In addition, blood IL-1beta levels were significantly greater in AD patients carrying both the APOEepsilon4 allele and the IL-1beta-31TT genotype than in those carrying the APOEepsilon4 allele and the -31 TC or CC genotype. In conclusion, this study provides the first evidence indicating that the IL-1beta-31TT genotype and homozygous APOEepsilon4 combined are associated with increased risk of developing AD with sleep disturbance. PMID- 26937657 TI - "Ice" (crystal methamphetamine): concerns and responses. PMID- 26937658 TI - Alcohol and other drug treatment policy in Australia. PMID- 26937656 TI - Immune Responses to the Cancer Testis Antigen XAGE-1b in Non Small Cell Lung Cancer Caucasian Patients. AB - Immunotherapy approaches using checkpoint blockade, alone, or in combination with tumor antigen vaccination, or adoptive cell transfer, are emerging as promising approaches for the treatment of non-small cell lung cancer (NSCLC). In preparation for upcoming combined immunotherapy approaches in NSCLC, here, we have assessed spontaneous immune responses to XAGE-1b, a tumor specific antigen of the Cancer Testis Antigen group that has been previously reported to be spontaneously immunogenic in the Japanese population, in a cohort of Caucasian patients with NSCLC. We found spontaneous serological responses to XAGE-1b in 9% of the patients. Importantly, these responses were limited to, and represented 13% of, patients with adenocarcinoma tumors, the most frequent histological subtype, for which immunotherapy approaches are under development. Using a set of overlapping peptides spanning the entire XAGE-1b protein, and in support of the serological data, we detected significant XAGE-1b specific CD4+ T cell responses in all XAGE-1b seropositive patients and identified several CD4+ T cell epitopes. Altogether, our results support the relevance of the XAGE-1b antigen in Caucasians NSCLC patients with adenocarcinoma, and the implementation of future immunotherapies exploiting the high immunogenicity of the antigen in this patient population. PMID- 26937659 TI - ADHD and psychostimulants - overdiagnosis and overprescription. PMID- 26937661 TI - Managing legal and medical complexities in caring for people with drug and alcohol problems: a call for change. PMID- 26937662 TI - Take-home naloxone programs and calls to emergency services. PMID- 26937664 TI - Australia reschedules naloxone for opioid overdose. PMID- 26937663 TI - Drug checking to improve monitoring of new psychoactive substances in Australia. PMID- 26937665 TI - Prescription drug monitoring in Australia: capacity and coverage issues. PMID- 26937666 TI - Trends in drug use among adolescents admitted to residential treatment in Australia. PMID- 26937667 TI - Trends in methamphetamine residues in wastewater in metropolitan and regional cities in south-east Queensland, 2009-2015. PMID- 26937668 TI - Estimating the number of regular and dependent methamphetamine users in Australia, 2002-2014. AB - OBJECTIVE: To estimate the number of regular and dependent methamphetamine users in Australia. DESIGN: Indirect prevalence estimates were made for each year from 2002-03 to 2013-14. We applied multiplier methods to data on treatment episodes for amphetamines (eg, counselling, rehabilitation, detoxification) and amphetamine-related hospitalisations to estimate the numbers of regular (at least monthly) and dependent methamphetamine users for each year. Dependent users comprised a subgroup of those who used the drug regularly, so that estimates of the sizes of these two populations were not additive. RESULTS: We estimated that during 2013-14 there were 268 000 regular methamphetamine users (95% CI, 187 000 385 000) and 160 000 dependent users (95% CI, 110 000-232 000) aged 15-54 years in Australia. This equated to population rates of 2.09% (95% CI, 1.45-3.00%) for regular and 1.24% (95% CI, 0.85-1.81%) for dependent use. The rate of dependent use had increased since 2009-10 (when the rate was estimated to be 0.74%), and was higher than the previous peak (1.22% in 2006-07). The highest rates were consistently among those aged 25-34 years, in whom the rate of dependent use during 2012-2013 was estimated to be 1.50% (95% CI, 1.05-2.22%). There had also been an increase in the rate of dependent use among those aged 15-24 years (in 2012-13 reaching 1.14%; 95% CI, 0.80-1.69%). CONCLUSIONS: There have been increases over the past 12 years in the numbers of regular and dependent methamphetamine users in Australia. Our estimates suggest that the most recent numbers are the highest for this period, and that the increase has been most marked among young adults (those aged 15-34 years). IMPLICATIONS: There is an increasing need for health services to engage with people who have developed problems related to their methamphetamine use. PMID- 26937669 TI - ADHD medication overdose and misuse: the NSW Poisons Information Centre experience, 2004-2014. AB - OBJECTIVES: To describe Australian trends in overdoses with medications used to treat attention deficit hyperactivity disorder (ADHD). DESIGN, SETTING AND PARTICIPANTS: This was a retrospective observational study of intentional exposures to methylphenidate, dexamphetamine, modafinil and atomoxetine reported to the New South Wales Poisons Information Centre (NSWPIC) from 1 January 2004 to 31 December 2014. The NSWPIC takes calls from New South Wales, Tasmania and the Australian Capital Territory between 6 am and midnight each day, and, as part of a national after-hours roster, from all Australian states between midnight and 6 am on seven nights each fortnight. The target population included Australian residents aged 10-75 years. MAIN OUTCOME MEASURES: Demographic characteristics of the patients, changes in numbers of exposures with time, co-ingestants, route of exposure, and disposition of patients. RESULTS: During the 11-year study period, 1735 intentional exposures to the four medications were reported to NSWPIC. There was a 210% increase in intentional exposures to methylphenidate over this period, whereas the number of dexamphetamine exposures declined by 25%. Illicit use (defined as co-ingestion with alcohol or a street drug) increased by 429% across the study period. At least 93% of overdose patients required hospitalisation. Trends in exposures paralleled trends in the dispensing of these medications, as recorded in Pharmaceutical Benefits Scheme data. CONCLUSIONS: NSWPIC data show a dramatic increase in intentional exposures to ADHD medications between 2004 and 2014, mainly to methylphenidate. Further, the data suggest that illicit use of these substances is increasing. The potential harm related to misuse of prescription stimulants and the close correlation between these exposures and the prescribing of these drugs causes concerns about their diversion, and highlights the importance of the quality use of medicines (ie, ensuring that they are used safely, appropriately and in an evidence-based manner, including considering non medical or non-stimulant alternatives) and of risk assessment for misuse when prescribing ADHD drugs. PMID- 26937670 TI - Perceptions of Australasian emergency department staff of the impact of alcohol related presentations. AB - OBJECTIVES: To survey emergency department (ED) clinical staff about their perceptions of alcohol-related presentations. DESIGN, SETTING AND PARTICIPANTS: A mixed methods online survey of ED clinicians in Australia and New Zealand, conducted from 30 May to 7 July 2014. MAIN OUTCOME MEASURES: The frequency of aggression from alcohol-affected patients or their carers experienced by ED staff; the perceived impact of alcohol-related presentations on ED function, waiting times, other patients and staff. RESULTS: In total, 2002 ED clinical staff completed the survey, including 904 ED nurses (45.2%) and 1016 ED doctors (50.7%). Alcohol-related verbal aggression from patients had been experienced in the past 12 months by 97.9% of respondents, and physical aggression by 92.2%. ED nurses were the group most likely to have felt unsafe because of the behaviour of these patients (92% reported such feelings). Alcohol-related presentations were perceived to negatively or very negatively affect waiting times (noted by 85.5% of respondents), other patients in the waiting room (94.4%), and the care of other patients (88.3%). Alcohol-affected patients were perceived to have a negative or very negative impact on staff workload (94.2%), wellbeing (74.1%) and job satisfaction (80.9%). CONCLUSIONS: Verbal and physical aggression by alcohol affected patients is commonly experienced by ED clinical staff. This has a negative impact on the care of other patients, as well as on staff wellbeing. Managers of health services must ensure a safe environment for staff and patients. More importantly, a comprehensive public health approach to changing the prevailing culture that tolerates alcohol-induced unacceptable behaviour is required. PMID- 26937671 TI - Comparing colorectal cancer treatment and survival for Aboriginal and non Aboriginal people in New South Wales. AB - OBJECTIVES: Our aim was to compare surgical treatment rates and survival rates for Aboriginal and non-Aboriginal people in New South Wales with colorectal cancer, and to describe the medical treatment received by a sample of Aboriginal people with colorectal cancer. DESIGN, SETTING AND PARTICIPANTS: All people diagnosed with colorectal cancer in NSW during 2001-2007 were identified and their cancer registry records linked to hospital admissions data and death records. A medical records audit of a sample of Aboriginal people diagnosed with colorectal cancer during 2000-2011 was also conducted. MAIN OUTCOME MEASURES: Cause-specific survival, odds of surgical treatment, and the proportions of people receiving adjuvant treatments. RESULTS: Of 29 777 eligible colorectal cancer cases, 278 (0.9%) involved Aboriginal people. Similar proportions of Aboriginal (76%) and non-Aboriginal (79%) people had undergone surgical treatment. Colorectal cancer-specific survival was similar for Aboriginal and non Aboriginal people up to 18 months after diagnosis, but 5 years post-diagnosis the risk of death for Aboriginal people who had had surgical treatment was 68% higher than for non-Aboriginal people (adjusted hazards ratio, 1.68; 95% CI, 1.32-2.09). Of 145 Aboriginal people with colorectal cancer identified by the medical records audit, 117 (81%) had undergone surgery, and 56 (48%) had also received adjuvant chemotherapy and/or radiotherapy. CONCLUSIONS: Aboriginal people with colorectal cancer had poorer survival rates than non-Aboriginal people, although rates of surgical treatment, complications and follow-up colonoscopy were similar. More work is needed to identify and understand why outcomes for Aboriginal people with colorectal cancer are different from those of other New South Wales residents. PMID- 26937672 TI - Necrotising myositis presenting as multiple limb myalgia. PMID- 26937673 TI - HLA-B*5801: a genetic susceptibility to allopurinol-induced DRESS. PMID- 26937674 TI - Lessons from Oliver Sacks. PMID- 26937675 TI - The acute care conveyor belt: a personal experience. PMID- 26937678 TI - Lamb Wave-Based Acoustic Radiation Force-Driven Particle Ring Formation Inside a Sessile Droplet. AB - We demonstrate an acoustofluidic device using Lamb waves (LWs) to manipulate polystyrene (PS) microparticles suspended in a sessile droplet of water. The LW based acoustofluidic platform used in this study is advantageous in that the device is actuated over a range of frequencies without changing the device structure or electrode pattern. In addition, the device is simple to operate and cheap to fabricate. The LWs, produced on a piezoelectric substrate, attenuate inside the fluid and create acoustic streaming flow (ASF) in the form of a poloidal flow with toroidal vortices. The PS particles experience direct acoustic radiation force (ARF) in addition to being influenced by the ASF, which drive the concentration of particles to form a ring. This phenomenon was previously attributed to the ASF alone, but the present experimental results confirm that the ARF plays an important role in forming the particle ring, which would not be possible in the presence of only the ASF. We used a range of actuation frequencies (45-280 MHz), PS particle diameters (1-10 MUm), and droplet volumes (5, 7.5, and 10 MUL) to experimentally demonstrate this phenomenon. PMID- 26937679 TI - Visualizing Redox Dynamics of a Single Ag/AgCl Heterogeneous Nanocatalyst at Atomic Resolution. AB - Operando characterization of gas-solid reactions at the atomic scale is of great importance for determining the mechanism of catalysis. This is especially true in the study of heterostructures because of structural correlation between the different parts. However, such experiments are challenging and have rarely been accomplished. In this work, atomic scale redox dynamics of Ag/AgCl heterostructures have been studied using in situ environmental transmission electron microscopy (ETEM) in combination with density function theory (DFT) calculations. The reduction of Ag/AgCl to Ag is likely a result of the formation of Cl vacancies while Ag(+) ions accept electrons. The oxidation process of Ag/AgCl has been observed: rather than direct replacement of Cl by O, the Ag/AgCl nanocatalyst was first reduced to Ag, and then Ag was oxidized to different phases of silver oxide under different O2 partial pressures. Ag2O formed at low O2 partial pressure, whereas AgO formed at atmospheric pressure. By combining in situ ETEM observation and DFT calculations, this structural evolution is characterized in a distinct nanoscale environment. PMID- 26937680 TI - Comparison of Early Changes in Ocular Surface and Inflammatory Mediators between Femtosecond Lenticule Extraction and Small-Incision Lenticule Extraction. AB - PURPOSE: To evaluate the short-term changes in ocular surface measures and tear inflammatory mediators after femtosecond lenticule extraction (FLEx) and small incision lenticule extraction (SMILE) procedures. METHODS: Eighteen subjects (18 eyes) underwent FLEx and 23 subjects (23 eyes) underwent SMILE in this single center and prospective study. Central corneal sensitivity, Schirmer I test (SIT), noninvasive tear breakup time (NI-TBUT), tear meniscus height, corneal fluorescein (FL) staining, and ocular surface disease index (OSDI) were assessed in all patients. Concentrations of interleukin-1alpha (IL-1alpha), tumor necrosis factor-alpha (TNF-alpha), nerve growth factor (NGF), interferon-gamma (IFN gamma), transforming growth factor-beta1 (TGF-beta1) and matrix metalloproteinase 9 (MMP-9) in collected tears were measured by multiplex antibody microarray. RESULTS: Central corneal sensitivity was reduced in both groups, but the scores in the SMILE group were higher than those in the FLEx group at all time points postoperatively (P<0.01). Lower FL scores and longer NI-BUT were observed in the SMILE group 1 week after surgery (P<0.05). OSDI scores in both groups increased rapidly at 1 day and 1 week postoperatively, then returned to their preoperative levels within 1 month (P<0.05). There were no significant differences in SIT or tear meniscus height between the two groups. Lower and faster recovery of tear NGF, TGF-beta1 and IL-1alpha concentration were found in the SMILE group compared to the FLEx group postoperatively. No significant difference was found in tear TNF-alpha, IFN-gamma and MMP-9 for either group before or after surgery. Tear NGF, TGF-beta1 and IL-1alpha show a correlation with ocular surface changes after FLEx or SMILE surgery. CONCLUSION: SMILE has superiority over FLEx in early ocular surface changes and NGF, TGF-beta1 and IL-1alpha may contribute to the process of ocular surface recovery. TRIAL REGISTRATION: ClinicalTrials.gov NCT02540785. PMID- 26937682 TI - Pitfalls of DNA Quantification Using DNA-Binding Fluorescent Dyes and Suggested Solutions. AB - The Qubit fluorometer is a DNA quantification device based on the fluorescence intensity of fluorescent dye binding to double-stranded DNA (dsDNA). Qubit is generally considered useful for checking DNA quality before next-generation sequencing because it measures intact dsDNA. To examine the most accurate and suitable methods for quantifying DNA for quality assessment, we compared three quantification methods: NanoDrop, which measures UV absorbance; Qubit; and quantitative PCR (qPCR), which measures the abundance of a target gene. For the comparison, we used three types of DNA: 1) DNA extracted from fresh frozen liver tissues (Frozen-DNA); 2) DNA extracted from formalin-fixed, paraffin-embedded liver tissues comparable to those used for Frozen-DNA (FFPE-DNA); and 3) DNA extracted from the remaining fractions after RNA extraction with Trizol reagent (Trizol-DNA). These DNAs were serially diluted with distilled water and measured using three quantification methods. For Frozen-DNA, the Qubit values were not proportional to the dilution ratio, in contrast with the NanoDrop and qPCR values. This non-proportional decrease in Qubit values was dependent on a lower salt concentration, and over 1 mM NaCl in the DNA solution was required for the Qubit measurement. For FFPE-DNA, the Qubit values were proportional to the dilution ratio and were lower than the NanoDrop values. However, electrophoresis revealed that qPCR reflected the degree of DNA fragmentation more accurately than Qubit. Thus, qPCR is superior to Qubit for checking the quality of FFPE-DNA. For Trizol-DNA, the Qubit values were proportional to the dilution ratio and were consistently lower than the NanoDrop values, similar to FFPE-DNA. However, the qPCR values were higher than the NanoDrop values. Electrophoresis with SYBR Green I and single-stranded DNA (ssDNA) quantification demonstrated that Trizol-DNA consisted mostly of non-fragmented ssDNA. Therefore, Qubit is not always the most accurate method for quantifying DNA available for PCR. PMID- 26937683 TI - Breaking the Barrier to Slow Water Exchange Rates for Optimal Magnetic Resonance Detection of paraCEST Agents. AB - EuDOTA-tetraamide complexes as paraCEST agents offer an attractive platform for designing biological sensors and responsive agents. The early versions of these agents showed low sensitivity at temperature and power levels suitable for in vivo applications partly due to non-optimal water exchange rates. Here we report two new EuDOTA derivatives having glutamyl-phosphonate side arms that display the slowest water exchange rates of any other paraCEST agent reported so far. The advantages of such systems are demonstrated experimentally both in vitro and in vivo and DFT calculations were performed to help understand the physical-chemical reasons for this interesting behavior. PMID- 26937684 TI - Bioavailability and Chronic Toxicity of Metal Sulfide Minerals to Benthic Marine Invertebrates: Implications for Deep Sea Exploration, Mining and Tailings Disposal. AB - The exploration and proposed mining of sulfide massive deposits in deep-sea environments and increased use deep-sea tailings placement (DSTP) in coastal zones has highlighted the need to better understand the fate and effects of mine derived materials in marine environments. Metal sulfide ores contain high concentrations of metal(loid)s, of which a large portion exist in highly mineralized or sulfidised forms and are predicted to exhibit low bioavailability. In this study, sediments were spiked with a range of natural sulfide minerals (including chalcopyrite, chalcocite, galena, sphalerite) to assess the bioavailability and toxicity to benthic invertebrates (bivalve survival and amphipod survival and reproduction). The metal sulfide phases were considerably less bioavailable than metal contaminants introduced to sediment in dissolved forms, or in urban estuarine sediments contaminated with mixtures of metal(loid)s. Compared to total concentrations, the dilute-acid extractable metal(loid) (AEM) concentrations, which are intended to represent the more oxidized and labile forms, were more effective for predicting the toxicity of the sulfide mineral contaminated sediments. The study indicates that sediment quality guidelines based on AEM concentrations provide a useful tool for assessing and monitoring the risk posed by sediments impacted by mine-derived materials in marine environments. PMID- 26937681 TI - Evaluation of a Decision Support System for Obstructive Sleep Apnea with Nonlinear Analysis of Respiratory Signals. AB - INTRODUCTION: Obstructive Sleep Apnea (OSA) is a common sleep disorder requiring the time/money consuming polysomnography for diagnosis. Alternative methods for initial evaluation are sought. Our aim was the prediction of Apnea-Hypopnea Index (AHI) in patients potentially suffering from OSA based on nonlinear analysis of respiratory biosignals during sleep, a method that is related to the pathophysiology of the disorder. MATERIALS AND METHODS: Patients referred to a Sleep Unit (135) underwent full polysomnography. Three nonlinear indices (Largest Lyapunov Exponent, Detrended Fluctuation Analysis and Approximate Entropy) extracted from two biosignals (airflow from a nasal cannula, thoracic movement) and one linear derived from Oxygen saturation provided input to a data mining application with contemporary classification algorithms for the creation of predictive models for AHI. RESULTS: A linear regression model presented a correlation coefficient of 0.77 in predicting AHI. With a cutoff value of AHI = 8, the sensitivity and specificity were 93% and 71.4% in discrimination between patients and normal subjects. The decision tree for the discrimination between patients and normal had sensitivity and specificity of 91% and 60%, respectively. Certain obtained nonlinear values correlated significantly with commonly accepted physiological parameters of people suffering from OSA. DISCUSSION: We developed a predictive model for the presence/severity of OSA using a simple linear equation and additional decision trees with nonlinear features extracted from 3 respiratory recordings. The accuracy of the methodology is high and the findings provide insight to the underlying pathophysiology of the syndrome. CONCLUSIONS: Reliable predictions of OSA are possible using linear and nonlinear indices from only 3 respiratory signals during sleep. The proposed models could lead to a better study of the pathophysiology of OSA and facilitate initial evaluation/follow up of suspected patients OSA utilizing a practical low cost methodology. TRIAL REGISTRATION: ClinicalTrials.gov NCT01161381. PMID- 26937685 TI - Interactions of Haptoglobin with Monomeric Globin Species: Insights from Molecular Modeling and Native Electrospray Ionization Mass Spectrometry. AB - Haptoglobin (Hp) binds free hemoglobin (Hb) dimers to prevent negative consequences of Hb circulation in the extracellular environment. Although both monomeric Hb and myoglobin (Mb) species also present potential risks, their interactions with Hp have not been extensively studied. Mb is homologous to both the alpha- and beta-chains of Hb and shares many conserved Hb/Hp interface residues, yet whether Hp binds Mb remains unclear. To address this, computational biology tools were used to predict the interactions required for Hp to bind monomeric globins, and the predicted association was tested using native electrospray ionization mass spectrometry (ESI-MS). The Hb/Hp crystal structure was used as the template to create molecular models of two Mb molecules bound to an Hp heterodimer (Mb2/Hp). Molecular modeling suggests that Mb can bind at the Hp alpha-chain binding site, where 73% of the globin/Hp interactions are conserved. By contrast, several ionic beta-chain residues involved in complementary electrostatic interactions with Hp correspond to residues with the opposite charge in Mb, suggesting unfavorable electrostatic Hp/Mb interactions at the beta-chain binding site. As shown by native ESI-MS, isolated monomeric Hbalpha subunits can form 2:1 complexes with Hp heterotetramers in the absence of Hb beta-chains. Native ESI-MS also confirmed that Mb can bind to Hp heterotetramers in solution with stoichiometries of 1:1 and 2:1 at physiological pH and ionic strength. The affinity of Hp for Mb appears to be diminished relative to that of Hb alpha-chains. Our in silico experiments rationalize this change and demonstrate that molecular modeling of protein/protein interactions is a valuable aid for MS experiments. PMID- 26937690 TI - Effect of Cholesterol on Cellular Uptake of Cancer Drugs Pirarubicin and Ellipticine. AB - The cell membrane is a major barrier for drug transport. Given that many cancer drugs must passively cross the cell membrane, understanding drug-membrane interactions is crucial. We used fluorescence-activated cell sorting to investigate how cholesterol influences the transport of the cancer drugs ellipticine and pirarubicin across cell membranes. We showed that cholesterol depletion helped pirarubicin cross the membranes of nonsmall cell lung carcinoma and Chinese hamster ovary cells. In contrast, the uptake of ellipticine was not strongly influenced by cholesterol depletion. To study the microscopic origins of these observations, atomistic molecular dynamics simulations were performed. Doxorubicin (similar in structure to pirarubicin) and ellipticine were simulated in model membranes of POPC and POPC with 40 mol % cholesterol. Atomistic free energy calculations for the translocation of a single ellipticine and doxorubicin across the lipid bilayers qualitatively matched the experiment results. The free energy barrier for doxorubicin crossing the bilayer was strongly increased when cholesterol was present, while for ellipticine the barrier remained similar with and without cholesterol. Molecular dynamics simulations showed that the different hydrogen-bonding propensities of the two drugs are likely the major factor for the different behaviors. The qualitative agreement between cell experiments and atomistic computer simulations illustrates the potential to link observed biological phenomena and single molecule mechanisms of actions. Our results suggest that the traditional understanding of drug permeation and the influence of cholesterol on the small molecule transport is naive and needs to be re examined. PMID- 26937689 TI - Good validity and reliability of the forgotten joint score in evaluating the outcome of total knee arthroplasty. AB - Background and purpose - When evaluating the outcome after total knee arthroplasty (TKA), increasing emphasis has been put on patient satisfaction and ability to perform activities of daily living. To address this, the forgotten joint score (FJS) for assessment of knee awareness has been developed. We investigated the validity and reliability of the FJS. Patients and methods - A Danish version of the FJS questionnaire was created according to internationally accepted standards. 360 participants who underwent primary TKA were invited to participate in the study. Of these, 315 were included in a validity study and 150 in a reliability study. Correlation between the Oxford knee score (OKS) and the FJS was examined and test-retest evaluation was performed. A ceiling effect was defined as participants reaching a score within 15% of the maximum achievable score. Results - The validity study revealed a strong correlation between the FJS and the OKS (intraclass correlation coefficient (ICC) = 0.81, 95% CI: 0.77-0.85; p < 0.001). The test-retest evaluation showed almost perfect reliability for the FJS total score (ICC = 0.91, 95% CI: 0.88-0.94) and substantial reliability or better for individual items of the FJS (ICC? 0.79). We found a high level of internal consistency (Cronbach's? = 0.96). The ceiling effect for the FJS was 16%, as compared to 37% for the OKS. Interpretation - The FJS showed good construct validity and test-retest reliability. It had a lower ceiling effect than the OKS. The FJS appears to be a promising tool for evaluation of small differences in knee performance in groups of patients with good clinical results after TKA. PMID- 26937691 TI - Rapid Recognition and Isolation of Live Colon Cancer Stem Cells by Using Metabolic Labeling of Azido Sugar and Magnetic Beads. AB - New approach for colon cancer stem cells (CSCs) recognition and isolation is reported. Colon CSCs are responsible for colonic tumor growth, metastasis, and resistance for radio-/chemotherapies. An accurate identification and isolation method is critical for understanding and characterization of these cells. In our work, we recognized CSCs' population from colon cancer cells by using metabolic labeling of azido sugar based on the quiescent nature of these cells, which differed fundamentally from previously described methods by using specific cellular markers to recognize and isolate CSCs. Later the putative CSCs were isolated by using commercially available magnetic beads. The isolated cells population had much higher sphere formation efficiency, soft-agar colony formation efficiency, and an mRNA level of colon stem cells marker Lgr5 than the leftover population. Our method provides a new avenue and a general strategy for recognition and isolation of CSCs, which shows great potential for further use in both the fundamental research of CSCs and clinical tests. PMID- 26937706 TI - Enantioselective Synthesis of Spirobarbiturate-Cyclohexenes through Phosphine Catalyzed Asymmetric [4 + 2] Annulation of Barbiturate-Derived Alkenes with Allenoates. AB - An enantioselective synthesis of pharmaceutically important spirobarbiturates has been achieved via spirocyclic chiral phosphine-catalyzed asymmetric [4 + 2] annulation of barbiturate-derived alkenes with allenoates. With the use of this tool, various spirobarbiturate-cyclohexenes are obtained in good to excellent yields with excellent diastereo- and enantioselectivities. A wide range of alpha substituted allenoates and barbiturate-derived alkenes were tolerated. PMID- 26937707 TI - Health-related quality of life in working-age adults with visual impairments in Germany. AB - Purpose The purpose of this study was to gather data about physical activity and quality of life (QoL) for people of working age with visual impairments to optimize upcoming physical activity-based interventions in vocational rehabilitation. Methods Two hundred and seventy-seven former participants of four vocational rehabilitation centres in Germany answered an online questionnaire. The health-related QOL has been assessed by means of the WHOQOL-BREF questionnaire. The data were analysed via multivariate analysis of covariances (MANCOVAs), univariate analysis of covariances (ANCOVAs) and discriminant function analysis. Results Compared to a normative group of adults aged 36-45, the study group showed lower values in all domains of QOL. The MANCOVA (visual acuity) produced no multivariate significant effect. Also, the ANCOVA showed no significant effect for the global dimension of the WHOQOL-BREF. The MANCOVA (leisure time activity) produced a multivariate significant effect. Post-hoc ANCOVAS revealed significant effects for all four domains of QoL. The ANCOVA analysing the global domain showed a similar significant effect as well. The active persons had higher values in all domains of QoL compared to the more passive participants. Conclusion Interventions in vocational rehabilitation should focus on leisure time activity to enhance QoL. At this stage, the role of physical activity is still unclear and further studies are needed. Implications for rehabilitation People with visual impairments often show a worse quality of life than normal-sighted people. The degree of severity of the visual impairment does not affect quality of life. Sport and physical activity are effective means of improving quality of life. An active leisure time activity supports the improvement of the quality of life of visual-impaired people that participated in a vocational rehabilitation. PMID- 26937709 TI - Image Noise, CNR, and Detectability of Low-Contrast, Low-Attenuation Liver Lesions in a Phantom: Effects of Radiation Exposure, Phantom Size, Integrated Circuit Detector, and Iterative Reconstruction. AB - Purpose To assess image noise, contrast-to-noise ratio (CNR) and detectability of low-contrast, low-attenuation liver lesions in a semianthropomorphic phantom by using either a discrete circuit (DC) detector and filtered back projection (FBP) or an integrated circuit (IC) detector and iterative reconstruction (IR) with changes in radiation exposure and phantom size. Materials and Methods An anthropomorphic phantom without or with a 5-cm-thick fat-mimicking ring (widths, 30 and 40 cm) containing liver inserts with four spherical lesions was scanned with five exposure settings on each of two computed tomography scanners, one equipped with a DC detector and the other with an IC detector. Images from the DC and IC detector scanners were reconstructed with FBP and IR, respectively. Image noise and lesion CNR were measured. Four radiologists evaluated lesion presence on a five-point diagnostic confidence scale. Data analyses included receiver operating characteristic (ROC) curve analysis and noninferiority analysis. Results The combination of IC and IR significantly reduced image noise (P < .001) (with the greatest reduction in the 40-cm phantom and at lower exposures) and improved lesion CNR (P < .001). There was no significant difference in area under the ROC curve between detector-reconstruction combinations at fixed exposure for either phantom. Reader accuracy with IC-IR was noninferior at 50% (100 mAs [effective]) and 25% (300 mAs [effective]) exposure reduction for the 30- and 40 cm phantoms, respectively (adjusted P < .001 and .04 respectively). IC-IR improved readers' confidence in the presence of a lesion (P = .029) independent of phantom size or exposure level. Conclusion IC-IR improved objective image quality and lesion detection confidence but did not result in superior diagnostic accuracy when compared with DC-FBP. Moderate exposure reductions maintained comparable diagnostic accuracy for both detector-reconstruction combinations. Lesion detection in the 40-cm phantom was inferior at smaller exposure reduction than in the 30-cm phantom. ((c)) RSNA, 2016 Online supplemental material is available for this article. PMID- 26937708 TI - Assessment of Functional Differences in Malignant and Benign Breast Lesions and Improvement of Diagnostic Accuracy by Using US-guided Diffuse Optical Tomography in Conjunction with Conventional US. AB - Purpose To investigate ultrasonography (US)-guided diffuse optical tomography to distinguish the functional differences of hemoglobin concentrations in a wide range of malignant and benign breast lesions and to improve breast cancer diagnosis in conjunction with conventional US. Materials and Methods The study protocol was approved by the institutional review boards and was HIPAA compliant. Written informed consent was obtained from all patients. Patients (288 women; mean age, 50 years; range, 17-94 years) who underwent US-guided biopsy were imaged with a handheld US and optical probe. The US-imaged lesion was used to guide reconstruction of light absorption maps at four wavelengths, and total hemoglobin (tHb), oxygenated hemoglobin (oxyHb), and deoxygenated hemoglobin (deoxyHb) were computed from the absorption maps. A threshold (80 MUmol/L) was chosen on the basis of this study population. Two radiologists retrospectively evaluated US images on the basis of the US Breast Imaging Reporting and Data System lexicon, and a lesion was considered malignant when a score of 4C or 5 was given or a lesion had tHb greater than 80 MUmol/L. A two-sample t test was used to calculate significance between groups, and Spearman rho was computed between hemoglobin parameters and tumor pathologic grades. Results Three tumors were Tis, 37 were T1, 19 were T2-T4 carcinomas, and 233 were benign lesions. The mean maximum tHb, oxyHb, and deoxyHb of Tis-T1 and T2-T4 groups were 89.3 MUmol/L +/- 20.2 (standard deviation), 65.0 MUmol/L +/- 20.8, and 33.5 MUmol/L +/- 11.3, respectively, and 84.7 MUmol/L +/- 32.8, 57.1 MUmol/L +/- 19.8, and 34.7 MUmol/L +/- 18.9, respectively. The corresponding values of benign lesions were 54.1 MUmol/L +/- 23.5, 38.0 MUmol/L +/- 17.4, and 25.2 MUmol/L +/- 13.8, respectively. The mean maximum tHb, oxyHb, and deoxyHb were significantly higher in the malignant groups than the benign group (P <.001, <.001, and .041, respectively). For malignant lesions, the mean maximum tHb moderately correlated with tumor histologic grade and nuclear grade (rho = 0.283 and 0.315, respectively). The mean maximum oxyHb moderately correlated with tumor nuclear grade (rho = 0.267). When radiologists' US diagnosis and the tHb were used together, the sensitivity, specificity, positive predictive value, and negative predictive value were 96.6% 100%, 77.3%-83.3%, 52.7%-59.4%, and 99.0%-100%, respectively, for the combined malignant group. Conclusion The tHb and oxyHb correlate with breast cancer pathologic grade and can be used as an adjunct to US to improve sensitivity and negative predictive value in breast cancer diagnosis. ((c)) RSNA, 2016 Online supplemental material is available for this article. PMID- 26937710 TI - Predicting Retear after Repair of Full-Thickness Rotator Cuff Tear: Two-Point Dixon MR Imaging Quantification of Fatty Muscle Degeneration-Initial Experience with 1-year Follow-up. AB - Purpose To determine the degree of preoperative fatty degeneration within muscles, postoperative longitudinal changes in fatty degeneration, and differences in fatty degeneration between patients with full-thickness supraspinatus tears who do and those who do not experience a retear after surgery. Materials and Methods This prospective study had institutional review board approval and was conducted in accordance with the Committee for Human Research. Informed consent was obtained. Fifty patients with full-thickness supraspinatus tears (18 men, 32 women; mean age, 67.0 years +/- 8.0; age range, 41-91 years) were recruited. The degrees of preoperative and postoperative fatty degeneration were quantified by using a two-point Dixon magnetic resonance (MR) imaging sequence; two radiologists measured the mean signal intensity on in-phase [S(In)] and fat [S(Fat)] images. Estimates of fatty degeneration were calculated with "fat fraction" values by using the formula S(Fat)/S(In) within the supraspinatus, infraspinatus, and subscapularis muscles at baseline preoperative and at postoperative 1-year follow-up MR imaging. Preoperative fat fractions in the failed-repair group and the intact-repair group were compared by using the Mann-Whitney U test. Results The preoperative fat fractions in the supraspinatus muscle were significantly higher in the failed-repair group than in the intact repair group (37.0% vs 19.5%, P < .001). Fatty degeneration of the supraspinatus muscle tended to progress at 1 year postoperatively in only the failed-repair group. Conclusion MR imaging quantification of preoperative fat fractions by using a two-point Dixon sequence within the rotator cuff muscles may be a viable method for predicting postoperative retear. ((c)) RSNA, 2016. PMID- 26937711 TI - CT Angiography of the Aorta: Prospective Evaluation of Individualized Low-Volume Contrast Media Protocols. AB - Purpose To prospectively develop individualized low-volume contrast media (CM) protocols adapted to tube voltage in patients undergoing computed tomographic (CT) angiography of the aorta. Materials and Methods The study was approved by the institutional review board and local ethics committee. All patients provided written informed consent. CT angiography was performed by using automated attenuation-based tube voltage selection (ATVS) (range, 70-150 kVp; 10-kVp increments). Iodine attenuation curves from an ex vivo experiment in a phantom were used to design CM protocols for CT angiography of the thoracoabdominal aorta in 129 consecutive patients (hereafter, cohort A). Further modified CM protocols based on results in cohort A were designed with the aim of homogeneous vascular attenuation of 300-350 HU across tube voltages and were applied to another 61 consecutive patients (cohort B). Three independent blinded radiologists assessed subjective image quality, and one reader determined objective image quality. The Kruskal-Wallis test was performed to test for differences in subjective image quality, and linear regression was performed to test for differences in objective image quality between the automatically selected tube voltages. Results Experiments revealed tube voltage-dependent iodine attenuation curves, which were used to determine the CM protocols in cohort A; these ranged from 68 mL at 110 kVp to 45 mL at 80 kVp. In both cohorts, ATVS selected 80 kVp in 62 patients, 90 kVp in 84, 100 kVp in 33, and 110 kVp in 11. In cohort A, image quality that was satisfactory or better was attained in 126 (98%) of 129 patients who had no significant differences in subjective image quality between tube voltages (P = .106) but who did have significant differences in attenuation and contrast-to noise ratio (CNR) (P < .001 for both). In cohort B, the further-modified CM protocol (from 33 mL at 80 kVp to 68 mL at 110 kVp) yielded image quality that was satisfactory or better in all 61 (100%) patients, without significant differences in subjective image quality (P = .178), and without significant differences between tube voltage and attenuation (P = .108), noise (P = .250), or CNR (P = .698). Conclusion Individualized low-volume CM protocols based on automatically selected tube voltages are feasible and yield diagnostic image quality for CT angiography of the aorta. ((c)) RSNA, 2016 Online supplemental material is available for this article. PMID- 26937712 TI - Leptin Signaling Is Not Required for Anorexigenic Estradiol Effects in Female Mice. AB - Estradiol and leptin are critical hormones in the regulation of body weight. The aim of this study was to determine whether this cross talk between leptin receptor (LepRb) and estrogen receptor-alpha (ERalpha) signaling is critical for estradiol's anorexigenic effects. Leprb-Cre mice were crossed with Cre-dependent Tau-green fluorescent protein (GFP) reporter, Stat3-flox or Eralpha-flox mice to generate female mice with GFP expression, signal transducer and activator of transcription 3 (STAT3) knockout (KO), or ERalpha KO, specifically in LepRb expressing cells. The proportion of Leprb-GFP cells colocalizing ERalpha was high (~80%) in the preoptic area but low (~10%) in the mediobasal hypothalamus, suggesting that intracellular cross talk between these receptors is minimal for metabolic regulation. To test whether estradiol enhanced arcuate leptin sensitivity, ovarectomized mice received varying levels of estradiol replacement. Increasing estrogenic states did not increase the degree of leptin-induced STAT3 phosphorylation. LepRb-specific STAT3 KO mice and controls were ovarectomized and given either chronic estradiol or vehicle treatment to test whether STAT3 is required for estrogen-induced body weight suppression. Both groups of estradiol treated mice showed an equivalent reduction in body weight and fat content compared with vehicle controls. Finally, mice lacking ERalpha specifically in LepRb-expressing neurons also showed no increase in body weight or impairments in metabolic function compared with controls, indicating that estradiol acts independently of leptin-responsive cells to regulate body weight. However, fecundity was impaired in in Leprb-ERalpha KO females. Contrary to the current dogma, we report that estradiol has minimal direct actions on LepRb cells in the mediodasal hypothalamus and that its anorexigenic effects can occur entirely independently of LepRb-STAT3 signaling in female mice. PMID- 26937717 TI - Ultrasensitive Multiplexed Immunoassay for Tumor Biomarkers Based on DNA Hybridization Chain Reaction Amplifying Signal. AB - In this work, a novel electrochemical immunoassay protocol has been reported for simultaneous determination of multiple tumor biomarkers based on DNA hybridization chain reaction (HCR) for signal amplification. Alpha-fetoprotein (AFP) and prostate specific antigen (PSA) were selected as model biomarkers. The immunoassay protocol contained primary antibodies immobilized on gold nanoparticles (Au NPs), secondary antibodies conjugated with DNA concatemer from HCR of primer, auxiliary probe, and signal probe labeled with signal molecules (methyleneblue (MB) and ferrocene (Fc)). In the presence of target biomarkers, the sandwich immunocomplex was formed between the primary antibodies and secondary antibodies bioconjugates carrying numerous signal molecules. As a result, two well-resolved reduction peaks, one was at -0.35 V (corresponding to MB) and other was at 0.33 V (corresponding to Fc; both vs SCE), were obtained in differential pulse voltammetry, and peak currents changed were related to the level of biomarkers. Under optimal conditions, the electrochemical immunoassay exhibited a wide linear response range (0.5 pg mL(-1) to 50 ng mL(-1)) and low detection limits (PSA, 0.17 pg mL(-1); AFP, 0.25 pg mL(-1)) (at S/N = 3). In addition, the immunoassay was evaluated by analyzing simulate human serum sample, and the recoveries obtained were within 99.4-107.6% for PSA and 97.9-108.2% for AFP, indicating the immnuoassay could be applied to the simultaneous detection of AFP and PSA in human serum samples. PMID- 26937713 TI - Ablation of KNDy Neurons Results in Hypogonadotropic Hypogonadism and Amplifies the Steroid-Induced LH Surge in Female Rats. AB - In the human infundibular (arcuate) nucleus, a subpopulation of neurons coexpress kisspeptin and neurokinin B (NKB), 2 peptides required for normal reproductive function. A homologous group of neurons exists in the arcuate nucleus of rodents, termed KNDy neurons based on the coexpression of kisspeptin, NKB, and dynorphin. To study their function, we recently developed a method to selectively ablate KNDy neurons using NK3-SAP, a neurokinin 3 receptor agonist conjugated to saporin (SAP). Here, we ablated KNDy neurons in female rats to determine whether these neurons are required for estrous cyclicity and the steroid induced LH surge. NK3 SAP or Blank-SAP (control) was microinjected into the arcuate nucleus using stereotaxic surgery. After monitoring vaginal smears for 3-4 weeks, rats were ovariectomized and given 17beta-estradiol and progesterone in a regimen that induced an afternoon LH surge. Rats were killed at the time of peak LH levels, and brains were harvested for NKB and dual labeled GnRH/Fos immunohistochemistry. In ovary-intact rats, ablation of KNDy neurons resulted in hypogonadotropic hypogonadism, characterized by low levels of serum LH, constant diestrus, ovarian atrophy with increased follicular atresia, and uterine atrophy. Surprisingly, the 17beta-estradiol and progesterone-induced LH surge was 3 times higher in KNDy ablated rats. Despite the marked increase in the magnitude of the LH surge, the number of GnRH or anterior ventral periventricular nucleus neurons expressing Fos was not significantly different between groups. Our studies show that KNDy neurons are essential for tonic levels of serum LH and estrous cyclicity and may play a role in limiting the magnitude of the LH surge. PMID- 26937714 TI - Adrenal Demedullation and Oxygen Supplementation Independently Increase Glucose Stimulated Insulin Concentrations in Fetal Sheep With Intrauterine Growth Restriction. AB - In pregnancies complicated by placental insufficiency and intrauterine growth restriction (IUGR), fetal glucose and oxygen concentrations are reduced, whereas plasma norepinephrine and epinephrine concentrations are elevated throughout the final third of gestation. Here we study the effects of chronic hypoxemia and hypercatecholaminemia on beta-cell function in fetal sheep with placental insufficiency-induced IUGR that is produced by maternal hyperthermia. IUGR and control fetuses underwent a sham (intact) or bilateral adrenal demedullation (AD) surgical procedure at 0.65 gestation. As expected, AD-IUGR fetuses had lower norepinephrine concentrations than intact-IUGR fetuses despite being hypoxemic and hypoglycemic. Placental insufficiency reduced fetal weights, but the severity of IUGR was less with AD. Although basal plasma insulin concentrations were lower in intact-IUGR and AD-IUGR fetuses compared with intact-controls, glucose stimulated insulin concentrations were greater in AD-IUGR fetuses compared with intact-IUGR fetuses. Interestingly, AD-controls had lower glucose- and arginine stimulated insulin concentrations than intact-controls, but AD-IUGR and AD control insulin responses were not different. To investigate chronic hypoxemia in the IUGR fetus, arterial oxygen tension was increased to normal levels by increasing the maternal inspired oxygen fraction. Oxygenation of IUGR fetuses enhanced glucose-stimulated insulin concentrations 3.3-fold in intact-IUGR and 1.7-fold in AD-IUGR fetuses but did not lower norepinephrine and epinephrine concentrations. Together these findings show that chronic hypoxemia and hypercatecholaminemia have distinct but complementary roles in the suppression of beta-cell responsiveness in IUGR fetuses. PMID- 26937718 TI - Positional Selectivity in C-H Functionalizations of 2-Benzylfurans with Bimetallic Catalysts. AB - Metal-catalyzed carbon-carbon bond-forming reactions are a mainstay in the synthesis of pharmaceutical agents. A long-standing problem plaguing the field of transition metal catalyzed C-H functionalization chemistry is control of selectivity among inequivalent C-H bonds in organic reactants. Herein we advance an approach to direct site selectivity in the arylation of 2-benzylfurans founded on the idea that modulation of cooperativity in bimetallic catalysts can enable navigation of selectivity. The bimetallic catalysts introduced herein exert a high degree of control, leading to divergent site-selective arylation reactions of both sp(2) and sp(3) C-H bonds of 2-benzylfurans. It is proposed that the selectivity is governed by cation-pi interactions, which can be modulated by choice of base and accompanying additives [MN(SiMe3)2, M = K or Li.12-crown-4]. PMID- 26937737 TI - Co-N Decorated Hierarchically Porous Graphene Aerogel for Efficient Oxygen Reduction Reaction in Acid. AB - Nitrogen-functionalized graphene materials have been demonstrated as promising electrocatalyst for the oxygen reduction reaction (ORR), owning to their respectable activity and excellent stability in alkaline electrolyte. However, they exhibit unacceptable catalytic activity in acid medium. Here, a hierarchically porous Co-N functionalized graphene aerogel is prepared as an efficient catalyst for the ORR in acid electrolyte. In the preparation process, polyaniline (PANI) is introduced as a pore-forming agent to aid in the self assembly of graphene species into a porous aerogel networks, and a nitrogen precursor to induce in situ nitrogen doping. Therefore, a Co-N decorated graphene aerogel framework with a large surface area (485 m(2) g(-1)) and an abundance of meso/macropores is effectively formed after heat treatment. Such highly desired structures can not only expose sufficient active sites for the ORR but also guarantee the fast mass transfer in the catalytic process, which provides significant catalytic activity with positive onset and half wave potentials, low hydrogen peroxide yield, high resistance to methanol crossover, and remarkable stability that is comparable to commercial Pt/C in acid medium. PMID- 26937739 TI - Transmission of Zika Virus Through Sexual Contact with Travelers to Areas of Ongoing Transmission - Continental United States, 2016. AB - Zika virus is a flavivirus closely related to dengue, West Nile, and yellow fever viruses. Although spread is primarily by Aedes species mosquitoes, two instances of sexual transmission of Zika virus have been reported, and replicative virus has been isolated from semen of one man with hematospermia. On February 5, 2016, CDC published recommendations for preventing sexual transmission of Zika virus. Updated prevention guidelines were published on February 23. During February 6 22, 2016, CDC received reports of 14 instances of suspected sexual transmission of Zika virus. Among these, two laboratory-confirmed cases and four probable cases of Zika virus disease have been identified among women whose only known risk factor was sexual contact with a symptomatic male partner with recent travel to an area with ongoing Zika virus transmission. Two instances have been excluded based on additional information, and six others are still under investigation. State, territorial, and local public health departments, clinicians, and the public should be aware of current recommendations for preventing sexual transmission of Zika virus, particularly to pregnant women. Men who reside in or have traveled to an area of ongoing Zika virus transmission and have a pregnant partner should abstain from sexual activity or consistently and correctly use condoms during sex with their pregnant partner for the duration of the pregnancy. PMID- 26937738 TI - Discovery of a New Inhibitor of Myeloid Differentiation 2 from Cinnamamide Derivatives with Anti-Inflammatory Activity in Sepsis and Acute Lung Injury. AB - Acute inflammatory diseases, including acute lung injury and sepsis, remain the most common life-threatening illness in intensive care units worldwide. Cinnamamide has been incorporated in several synthetic compounds with therapeutic potentials including anti-inflammatory properties. However, the possible mechanism and direct molecular target of cinnamamides for their anti-inflammatory effects were rarely investigated. In this study, we synthesized a series of cinnamamides and evaluated their anti-inflammatory activities. The most active compound, 2i, was found to block LPS-induced MD2/TLR4 pro-inflammatory signaling activation in vitro and to attenuate LPS-caused sepsis and acute lung injury in vivo. Mechanistically, we demonstrated that 2i exerts its anti-inflammatory effects by directly targeting and binding MD2 in Arg90 and Tyr102 residues and inhibiting MD2/TLR4 complex formation. Taken together, this work presents a novel MD2 inhibitor, 2i, which has the potential to be developed as a candidate for the treatment of sepsis, and provides a new lead structure for the development of anti-inflammatory agents targeting MD2. PMID- 26937742 TI - Selectively Modulating Triplet Exciton Formation in Host Materials for Highly Efficient Blue Electrophosphorescence. AB - The concept of limiting the triplet exciton formation to fundamentally alleviate triplet-involved quenching effects is introduced to construct host materials for highly efficient and stable blue phosphorescent organic light-emitting diodes (PhOLEDs). The low triplet exciton formation is realized by small triplet exciton formation fraction and rate with high binding energy and high reorganization energy of triplet exciton. Demonstrated in two analogue molecules in conventional donor-acceptor molecule structure for bipolar charge injection and transport with nearly the same frontier orbital energy levels and triplet excited energies, the new concept host material shows significantly suppressed triplet exciton formation in the host to avoid quenching effects, leading to much improved device efficiencies and stabilities. The low-voltage-driving blue PhOLED devices exhibit maximum efficiencies of 43.7 cd A(-1) for current efficiency, 32.7 lm W(-1) for power efficiency, and 20.7% for external quantum efficiency with low roll-off and remarkable relative quenching effect reduction ratio up to 41%. Our fundamental solution for preventing quenching effects of long-lived triplet excitons provides exciting opportunities for fabricating high-performance devices using the advanced host materials with intrinsically small triplet exciton formation cross section. PMID- 26937744 TI - Differentiation between Melanin-Laden Macrophages and Melanoma Cells in Vitreous Aspirates. AB - OBJECTIVE: The differential diagnosis between retinal detachment and melanoma metastatic to the vitreous can be challenging, both clinically and cytologically. We demonstrate the diagnostic features and pitfalls of the cytological assessment. STUDY DESIGN: A case of a metastatic melanoma to the vitreous is compared to a case of retinal detachment initially suspected as melanoma metastasis. Case 1 was a 54-year-old patient with a vague history of pigmented lesions 20 years previously and a current presentation of a visual defect. Case 2 was a 68-year-old patient with a history of melanoma and a presentation of floaters and flashing lights. RESULTS: The vitreous fluid of case 1 contained atypical, pigment-laden cells positive for HMB-45 and assessed as melanoma. On enucleation, a melanoma metastatic to the vitreous was diagnosed. The vitreous fluid of case 2 revealed atypical cells containing pigment granules. The cells were negative for melanocytic markers, while the granules stained positive for melanin. Macrophage marker CD163 was positive in all cells. The interpretation was one of macrophages reactive to the retinal detachment. CONCLUSION: Melanin laden macrophages can mimic melanoma cells. This needs to be considered in the differential diagnosis. Additional stains can help the distinction. PMID- 26937743 TI - Physical activity estimated by the bone-specific physical activity questionnaire is also associated with cardiovascular risk. AB - The nature of physical activity that benefits bone is traditionally thought to differ from that benefiting cardiovascular health. Accordingly, exercise recommendations for improving bone health and cardiovascular health are largely incongruent. Our aim was to determine the associations between high-impact physical activity participation and both cardiovascular disease risk factors and bone mass. We recruited 94 men and women (age 34.0 +/- 13.3 years) to undergo measures of cardiovascular disease risk (BMI, total cholesterol, fasting blood glucose, waist-to-hip ratio, and mean arterial pressure) and dual-energy X-ray absorptiometry (DXA XR-800, Norland) measures of bone mass (femoral neck, lumbar spine, and whole body BMD) and body composition (whole body lean mass and fat mass). Physical activity participation was estimated using the bone-specific physical activity questionnaire (BPAQ). Those in the upper tertile for current BPAQ score exhibited lower total cholesterol, waist-to-hip ratio, and mean arterial pressure than those in the lower tertiles (P < 0.05) with the relationship being mild-to-moderate (r = -0.49 to 0.29, P < 0.01). Those in the upper tertile for BPAQ score also had greater lumbar spine BMD than those in the lower tertile (P = 0.008), with BPAQ score predicting 6% of the variance in BMD (P = 0.02). We conclude that high-impact physical activity as captured by the BPAQ may be beneficial for both bone health and for attenuating cardiovascular disease risk. PMID- 26937745 TI - Probing in Space and Time the Nuclear Motion Driven by Nonequilibrium Electronic Dynamics in Ultrafast Pumped N2. AB - An ultrafast electronic excitation of N2 in the vacuum ultraviolet creates a nonstationary coherent linear superposition of interacting valence and Rydberg states resulting in a net oscillating dipole moment. There is therefore a linear response to an electrical field that can be queried by varying the time delay between the pump and a second optical probe pulse. Both the pump and probe pulses are included in our computation as part of the Hamiltonian, and the time dependent wave function for both electronic and nuclear dynamics is computed using a grid representation for the internuclear coordinate. Even on an ultrafast time scale there are several processes that can be discerned beyond the expected coherence oscillations. In particular, the coupling between the excited valence and Rydberg states of the same symmetry is very evident and can be directly probed by varying the delay between pulse and probe. For quite a number of vibrations the nuclear motion does not dephase the electronic disequilibrium. However, the nuclear motion does modulate the dipolar response by taking the wave packet in and out of the Franck-Condon region and by its strong influence on the coupling of the Rydberg and valence states. A distinct isotope effect arises from the dependence of the interstate coupling on the nuclear mass. PMID- 26937746 TI - Pharmaceutical costs for inflammatory bowel disease units - An issue for department heads? The GESTIONAEII survey. AB - Inflammatory bowel disease (IBD) units have a relevant weight within gastroenterology departments. In order to gain insight into the managerial aspects of IBD diagnosis and treatment, SEPD submitted a survey (GESTIONAEII) to department heads, IBD specialists, and other gastroenterologists. In this letter, we discuss the results obtained from gastroenterology department heads. PMID- 26937747 TI - Single transradial guide catheter retrograde/antegrade recanalization of a complex circumflex artery chronic total occlusion. PMID- 26937748 TI - Comparison of Population Pharmacokinetics Based on Steady-State Assumption Versus Electronically Monitored Adherence to Lopinavir, Atazanavir, Efavirenz, and Etravirine: A Retrospective Study. AB - BACKGROUND: Population pharmacokinetic (PopPK) analyses often rely on steady state and full adherence to prescribed dosage regimen assumptions from data gathered during therapeutic drug monitoring (TDM). Nonadherence is common in chronic diseases such as HIV. This study evaluates the impact of adherence measurement by electronic monitoring on PopPK parameter estimation and individual concentration profile predictions, and also the influence of adherence issues on the clinical interpretation of a concentration measurement. METHODS: Published PopPK models for lopinavir, atazanavir, efavirenz, and etravirine were applied to estimate PK parameters and individual concentrations in 140 HIV patients taking part in a medication adherence program using 2 dosing data sets. The first set included the last dose reported by the patient with steady-state and full adherence assumptions; the second set used detailed electronic dosing history. PopPK parameter estimates and individual predictions were compared between the 2 dosing entries. RESULTS: Clearance estimates and likewise predicted concentrations did not markedly differ between the 2 dosing histories. However, certain patterns of nonadherence such as sparse missed doses or consecutive missed doses lead to suboptimal drug exposure. The interpretation based on self reported information would have concluded on a wrongly appropriate individual exposure. CONCLUSIONS: PopPK analysis assuming steady state with full adherence produced similar results to those based on detailed electronic dosing history reconciled with patients' allegations. Self-reported last dose intake appeared reliable for concentration predictions and therapeutic drug monitoring interpretation for most patients followed at the medication adherence program. Yet, clinicians should be aware that concentration predictions based on self reported last dose intake might be overestimated in case of undetected patterns of nonadherence, increasing the risk of forthcoming therapeutic failure. PMID- 26937749 TI - Predictors of Radiation Field Failure After Definitive Chemoradiation in Patients With Locally Advanced Cervical Cancer. AB - PURPOSE: We identified the predictive factors for locoregional failure after definitive chemoradiation in patients with locally advanced cervical cancer. METHODS: Altogether, 397 patients with locally advanced cervical cancer (stage IB2-IVA) were treated with definitive chemoradiation between June 2001 and February 2010. Platinum-based concurrent chemotherapy was given to all patients with median radiation dose of external beam radiotherapy 50.4 Gy in 28 fractions and intracavitary radiotherapy 30 Gy in 6 fractions. Competing risk regression analysis was used to reveal the predictive factors for locoregional failure. RESULTS: During the median follow-up of 7.2 years, locoregional failure occurred in 51 (12.9%) patients. The estimated 3-year rate of locoregional control was 89%, whereas the overall survival rate was 82%. After univariate and multivariate analyses, large tumor size (>5 cm), young age (<=40 years), nonsquamous histology, positive lymph node on magnetic resonance imaging, and advanced stage (III-IV) were identified as risk factors for locoregional failure (P = 0.003, P = 0.075, P = 0.005, P = 0.055, and P < 0.001, respectively). After risk grouping according to the coefficients from the multivariate model, we identified a high risk group for locoregional failure after treatment with definitive chemoradiation as follows: (1) tumor size larger than 5 cm, and at least 1 other risk factor or (2) tumor size 5 cm or less, and at least 3 other risk factors. The cumulated estimated 3-year rate of locoregional failure of the high-risk group was 26%, which was significantly higher than that of the low-risk group (7%, P < 0.001). The 3-year overall survival rates of the 2 groups were also significantly different (57% vs 86%, P < 0.001). CONCLUSIONS: Large tumor size (>5 cm), young age (<=40 years), nonsquamous histology, positive lymph node on magnetic resonance imaging, and advanced stage are all risk factors for locoregional failure after definitive platinum-based chemoradiation in patients with locally advanced cervical cancer. In the high-risk group, further clinical trials are warranted to improve the locoregional control rate. PMID- 26937750 TI - Surgical Treatment of Metastatic Ovarian Tumors From Extragenital Primary Sites. AB - OBJECTIVE: The purpose of this study was to investigate the outcomes and prognostic factors of metastasectomy in patients with metastatic ovarian tumors from extragenital primary sites. MATERIALS AND METHODS: All patients with pathologically confirmed metastatic ovarian tumors between January 1997 and June 2015 were included in this study. A total of 131 patients were identified. The data were obtained from the patients' medical records. Clinicopathological features were evaluated by both univariate and multivariate analyses. RESULTS: The primary sites were colorectal region (53.4%), stomach (26%), and breast (13%). Preoperative serum CA 125 and CA 19-9 levels were elevated in 29.4% and 39.8% of the patients, respectively. Cytoreductive surgery was performed in 41.2% of the patients. Seventy-three (55.7%) patients had no residual disease after surgery. Sixty-six (49.6%) patients had combined metastases at the time of the surgery to sites including the liver, pancreas, lung, bone, lymph nodes, bladder, or the intestine. With a median follow-up of 33 months, the median survival time was 22 months. The estimated 5-year survival probability is 0.26. On univariate analysis, primary cancer site, combined metastasis outside the ovaries, residual disease, preoperative serum CA 125 and CA 19-9 levels, and histologic type were significant parameters for overall survival. Furthermore, residual disease, preoperative serum CA 19-9 level, and primary cancer site were found to be independent prognostic factors on multivariate analysis. CONCLUSIONS: The most common primary sites for ovarian metastasis are gastrointestinal tract. Metastasectomy may have beneficial effects on survival, especially if the residual disease is less than 5 mm. Prospective studies warranted to evaluate the value of metastasectomy in patients with ovarian metastasis. PMID- 26937751 TI - Restaging and Survival Analysis of 4036 Ovarian Cancer Patients According to the 2013 FIGO Classification for Ovarian, Fallopian Tube, and Primary Peritoneal Cancer. AB - OBJECTIVE: With the 2013 International Federation of Gynecology and Obstetrics (FIGO) staging for ovarian, fallopian tube, and primary peritoneal cancer, the number of substages changed from 10 to 14. Any classification of a malignancy should easily assign patients to prognostic groups, refer patients to individualized treatments, and allow benchmarking and comparison of patients and results between centers. The stage should reflect survival in particular. The objective of the study was to validate these requirements of the revised FIGO staging on a high number of ovarian cancer patients. MATERIALS AND METHODS: Demographic, surgical, histological, and survival data from 4036 ovarian cancer patients were used in the analysis. Five-year survival rates (5YSR) and hazard ratios for the old and revised FIGO staging were calculated using Kaplan-Meier curves and Cox regression. RESULTS: A total of 1532 patients were assigned to new stages. Stages IA and IC1 had similar survival (5YSR, 87%); and stages IB, IC2, and IC3 had similar survival (5YSR, 75%-80%). Stage IIC was omitted, resulting in similar survival in stages IIA and IIB (5YSR, 61% and 65%). Of 1660 patients in stage IIIC, 79 were restaged: In 16 cases, IIIC was down-staged to IIIA1, as they had only been stage IIIC owing to lymph node metastases; and in 63 cases, IIIC was down-staged to IIIB, as they had lymph node metastases and abdominal tumor of less than 2 cm. The 5YSR in stage IIIC was unchanged (22%). Stage IV (5YSR, 14% ) was restaged as IVA (13%) and IVB (13%). Both were different from IIIC; P < 0.0001. CONCLUSION: With introduction of new substages, staging becomes more demanding. Second, as fewer patients are allocated to each substage, statistical power is diminished, resulting in uncertainty in the results. Despite this, and most importantly, the revised coding adequately reflects survival, as there was a clear graphical and statistical tendency for poorer survival with increasing stage. PMID- 26937752 TI - Pelvic Exenterations for Advanced and Recurrent Endometrial Cancer: Clinical Outcomes of 40 Patients. AB - OBJECTIVE: The aim of this study was to analyze the clinical experience and outcome of patients who have undergone pelvic exenteration for primary advanced or recurrent endometrial cancer. METHODS: We analyzed the medical records of 40 women who underwent pelvic exenteration to treat primary advanced or recurrent endometrial cancer. RESULTS: Pelvic exenteration was performed in 40 patients with primary advanced or recurrent endometrial cancer. Three patients (8%) underwent a primary exenteration, and 37 patients (92%) underwent a secondary exenteration. A total exenteration, anterior exenteration, and posterior exenteration was performed in 85%, 5%, and 10% of patients, respectively.In 31 cases, exenteration was performed with a curative aim, and in 9 cases, exenteration was performed with a palliative aim. The overall survival rates were 61.4% at 5 years and 51.1% at 10 years. For the 31 patients who underwent pelvic exenteration with a curative aim, the overall survival rates were higher than those for the entire study population and were 72.6% at 5 years and 59.4% at 10 years. For the 9 patients who underwent a palliative exenteration, the overall survival rates were 19.1% at 5 years and 0% at 10 years. This is to the best of our knowledge the biggest study of pelvic exenteration in patients with endometrial cancer. CONCLUSIONS: Our data show that pelvic exenterations are a valid therapeutic option with long-term survival in select patients. PMID- 26937753 TI - Role of Video-Assisted Thoracoscopy in Advanced Ovarian Cancer: A Literature Review. AB - Tools that accurately predict the presence of metastatic ovarian cancer in the pleura are limited. Thus, we sought to summarize the current literature on video assisted thoracoscopic surgery (VATS) and its applicability in patients with advanced ovarian cancer. A total of 187 patients with suspected ovarian cancer who underwent the VATS procedure were identified for this analysis. The median patient age was 59.4 years (range, 20.3-83 years). The median operative time for VATS was 32 minutes (range, 5-65 minutes). In 89 patients (48%), VATS revealed macroscopic disease in the pleural cavity. After VATS, 44 patients underwent neoadjuvant chemotherapy, and the remaining 143 patients underwent primary cytoreductive surgery. Video-assisted thoracoscopic surgery led to a change in disease stage or management in 76 patients (41%). Among patients with pleural effusions, VATS revealed pleural disease in 57% of patients, and 73% of patients with positive pleural cytology had evidence of pleural disease at the time of VATS. In addition, 23.5% of patients with negative pleural cytology had evidence of pleural disease at the time of VATS. Prospective trials are needed to accurately evaluate the impact of VATS on disease-free and overall survival in patients with advanced ovarian cancer. Video-assisted thoracoscopic surgery can help determine which patients are ideal candidates for surgical cytoreduction. PMID- 26937754 TI - Prognostic Significance of POLE Exonuclease Domain Mutations in High-Grade Endometrioid Endometrial Cancer on Survival and Recurrence: A Subanalysis. AB - OBJECTIVE: POLE mutations in high-grade endometrioid endometrial cancer (EEC) have been associated with improved survival. We sought to investigate the prevalence of POLE tumor mutation and its prognostic significance on outcomes and clinical applications in a subanalysis of women with high-grade EEC from a previously described cohort of 544 EEC patients in which POLE mutation status and survival outcomes were assessed. METHODS: Polymerase chain reaction amplification and Sanger sequencing were used to test for POLE mutations in 72 tumors. Associations between POLE mutation, demographic and clinicopathologic features, and survival were investigated with Cox proportional hazard models. RESULTS: POLE mutations were identified in 7 (9.7%) of 72 grade 3 EECs. No significant differences in the clinicopathologic features between those with POLE mutations and those without were identified. Adjusted for age, a decreased risk of recurrence was suggested in patients with a POLE mutation (adjusted hazard ratio, 0.37; 95% confidence interval, 0.09-1.55), as well as decreased risk of death (adjusted hazard ratio, 0.19; 95% confidence interval, 0.03-1.42). CONCLUSIONS: POLE mutations in tumors of women with grade 3 EEC are associated with a lower risk of recurrence and death, although not statistically significant because of high variability in these estimates. These findings, consistent with recently published combined analyses, support POLE mutation status as a noteworthy prognostic marker and may favor a change in the treatment of women with grade 3 EECs, particularly in those with early-stage disease, in which omission of adjuvant therapy and decreased surveillance could possibly be appropriate. PMID- 26937755 TI - Pattern Recognition to Prognosticate Endometrial Cancer: The Science Behind the Art of Office Hysteroscopy-A Retrospective Study. AB - OBJECTIVE: This study aimed to evaluate a specific glomerular pattern for prognostication of endometrial cancer (EC). MATERIALS AND METHODS: The office hysteroscopy's picture and video of 4197 women were reviewed, 48 women who were suspected of type I EC were analyzed: 26 have glomerular pattern (group 1) and 22 without it (group 2). RESULTS: The histopathological grading after hysterectomy with glomerular pattern had grade 2 or grade 3 disease on final histology (n = 25; 96%). The sensitivity and specificity of this test were 84.6% and 81.8%, respectively, with a likelihood ratio of 4:6 in predicting and prognosticating those women who have high-grade tumor or invasive disease. CONCLUSIONS: This hysteroscopic picture might be used as a novel marker for risk stratification of EC. PMID- 26937756 TI - Molecular Profiling of Clear Cell Ovarian Cancers: Identifying Potential Treatment Targets for Clinical Trials. AB - BACKGROUND: Advanced stage/recurrent clear cell ovarian cancers (CCOCs) are characterized by a low response to chemotherapy and a poor prognosis. There is growing interest in investigating novel/molecular targeted therapies in patients with CCOC in histotype-specific trials. However, CCOCs are not a uniform entity and comprise a number of molecular subtypes and it is unlikely that a single approach to treatment will be appropriate for all patients. The aim of this study was to analyze the results of a multiplatform profiling panel in CCOCs to identify potential therapeutic targets. PATIENTS AND METHODS: Tumor profiling was performed on 521 CCOCs. They were grouped into pure (n = 422) and mixed (n = 99) CCOC for analysis. Testing included a combination of DNA sequencing (including next-generation sequencing) using a 46-gene panel, immunohistochemistry, fluorescent or chromogenic in situ hybridization, and RNA fragment analysis. RESULTS: The most common findings were in the PIK3CA/Akt/mTOR pathway, with 61% of all CCOCs showing a molecular alteration in one of these pathway components. Next-generation sequencing revealed PIK3CA mutations in 50% of pure CCOCs. Significant differences were observed between pure and mixed CCOCs with respect to hormone receptor expression (9% vs 34.7% for ER, 13.45 vs 26.4% for PR), cMET (24.1% vs 11.6%), PD-1 tumor infiltrating lymphocytes (48.1% vs 100%), expression of PD-L1 (7.4% vs 25%), and TOPO1 (41% vs 27.1%) on immunohistochemistry, whereas next-generation sequencing revealed significant differences in mutation frequency in PIK3CA (50% vs 18.5%), TP53 (18.1% vs 57.7%), KRAS (12.4% vs 3.7%), and cMET (1.9% vs 11.1%). CONCLUSIONS: This large study confirms that the PIK3CA/Akt/mTOR pathway is commonly altered in CCOCs, and highlights the significant differences between pure and mixed CCOCs. Clear cell ovarian cancers are molecularly heterogeneous and there are a number of potential therapeutic targets which could be tested in clinical trials. PMID- 26937757 TI - Population-based approaches to treatment and readmission after spinal cord injury. AB - BACKGROUND: Recent studies in surgical and non-surgical specialties have suggested that patients admitted on the weekend may have worse outcomes. In particular, patients with stroke and acute cardiovascular events have shown worse outcomes with weekend treatment. It is unclear whether this extends to patients with spinal cord injury (SCI). This study was designed to evaluate factors for readmission after index hospitalization for spinal cord injury. METHODS: This cohort was constructed from the State Inpatient Databases of California, New York, and Florida. For this study 14,396 patients with SCI were identified. The primary outcome measure evaluated was 30-day readmission. Secondary measures include in-hospital complications. Univariate and multivariate analysis were utilized to evaluate covariates. c2, Fisher's exact, and linear, logistic, and modified Poisson regression methods were utilized for statistical analysis. Propensity score methods were used with matched pairs analysis performed by the McNemar's Test. RESULTS: Weekend admission was not associated with increased 30- day readmission rates in multivariate analysis. Race and discharge to a facility (RR 1.60 [1.43-1.79]) or home with home care (RR 1.23 [1.07-1.42]), were statistically significant risk factors for readmission. Payor status did not affect rates of readmission. In propensity score matched pairs analysis, weekend admission was not associated with increased odds of 30-day readmission (OR 1.04 [0.89-1.21]). Patients admitted to high volume centers had significantly lower risk of readmission when compared with patients admitted to low volume centers. CONCLUSIONS: Our results suggest that the weekend effect, described previously in other patient populations, may not play as important a role in patients with SCI. PMID- 26937759 TI - Latent autoimmune diabetes of the adult: A new kind of diabetes? PMID- 26937758 TI - Chronic cough and a normal chest X-ray - a simple systematic approach to exclude common causes before referral to secondary care: a retrospective cohort study. AB - Chronic cough is common in the community and can cause significant morbidity. It is not clear how closely treatment guidelines are used in general practice, or how often specialist referral is indicated. We aimed to assess the management of chronic cough in primary care before referral to a cough clinic, and to assess the outcome of managing chronic cough with an approach of simple investigation and empirical treatment trials. Data were extracted from the records of all patients attending a district general hospital respiratory clinic over a two-year period with isolated chronic cough lasting ?8 weeks. The clinic assessed symptoms with a cough-severity visual analogue scale and the Leicester Cough Questionnaire. Among 266 patients, the most frequent diagnoses were asthma (29%), gastro-oesophageal reflux (22%) and angiotensin-converting enzyme inhibitor use (14%). In all, 12% had unexplained chronic cough. Common diagnoses had often not been excluded in primary care: only 21% had undergone spirometry, 86% had undergone chest radiography and attempts to exclude asthma with corticosteroids had been made only in 39%. In the clinic few investigations were conducted that were not available in primary care. Substantial improvements in symptoms occurred with a median (interquartile range) total of 2 (2-3) clinic visits. We estimated that 87% of patients could have been managed solely in primary care; we did not identify distinguishing characteristics among this group. Most cases of chronic cough referred to secondary care could be managed with a simple and systematic approach, which is potentially transferrable to a community setting. PMID- 26937760 TI - Correction: A convenient approach to an advanced intermediate toward the naturally occurring, bioactive 6-substituted 5-hydroxy-4-aryl-1H-quinolin-2-ones. PMID- 26937761 TI - Novel aluminum-BODIPY dyads: intriguing dual-emission via photoinduced energy transfer. AB - Three novel BODIPY-based heterodinuclear complexes, [salen(3,5-(t)Bu)2Al-(OC6H4 BODIPY)] (6), [salen(3,5-(t)Bu)2Al-(OC6F2H2-BODIPY)] (7), and [(mq)2Al-(OC6H4 BODIPY)] (8) (salen = N,N'-bis(salicylidene)ethylenediamine, BODIPY = 4,4 difluoro-4-bora-3a,4a-diaza-s-indacene, and mq = methyl-8-quinolinolato) were prepared and characterized by multinuclear NMR spectroscopy. The specific structures of 6-8 were also determined by single crystal X-ray analysis. In particular, the salen-based heterodinuclear complexes 6 and 7 exhibited higher thermal stability (Td5 = 309 and 306 degrees C, respectively) than that of the closely related mononuclear aluminum or BODIPY compounds, except for 8. The UV/vis absorption and PL spectra for 6 and 7 indicated a significant photoinduced energy transfer from the aluminum-salen moiety to the BODIPY group in an intramolecular manner. Theoretical calculations revealed independent transition states of the aluminum-salen moiety or the BODIPY group in the Al(III)-BODIPY dyads, further supporting these experimental results. PMID- 26937766 TI - A Commercial Conducting Polymer as Both Binder and Conductive Additive for Silicon Nanoparticle-Based Lithium-Ion Battery Negative Electrodes. AB - This work describes silicon nanoparticle-based lithium-ion battery negative electrodes where multiple nonactive electrode additives (usually carbon black and an inert polymer binder) are replaced with a single conductive binder, in this case, the conducting polymer PEDOT: PSS. While enabling the production of well mixed slurry-cast electrodes with high silicon content (up to 95 wt %), this combination eliminates the well-known occurrence of capacity losses due to physical separation of the silicon and traditional inorganic conductive additives during repeated lithiation/delithiation processes. Using an in situ secondary doping treatment of the PEDOT: PSS with small quantities of formic acid, electrodes containing 80 wt % SiNPs can be prepared with electrical conductivity as high as 4.2 S/cm. Even at the relatively high areal loading of 1 mg/cm(2), this system demonstrated a first cycle lithiation capacity of 3685 mA.h/g (based on the SiNP mass) and a first cycle efficiency of ~78%. After 100 repeated cycles at 1 A/g this electrode was still able to store an impressive 1950 mA.h/g normalized to Si mass (~75% capacity retention), corresponding to 1542 mA.h/g when the capacity is normalized by the total electrode mass. At the maximum electrode thickness studied (~1.5 mg/cm(2)), a high areal capacity of 3 mA.h/cm(2) was achieved. Importantly, these electrodes are based on commercially available components and are produced by the standard slurry coating methods required for large-scale electrode production. Hence, the results presented here are highly relevant for the realization of commercial LiB negative electrodes that surpass the performance of current graphite-based negative electrode systems. PMID- 26937768 TI - Electromyographic Analysis of Traditional and Kinetic Chain Exercises for Dynamic Shoulder Movements. AB - Oliver, GD, Plummer, HA, and Gascon, SS. Electromyographic analysis of traditional and kinetic chain exercises for dynamic shoulder movements. J Strength Cond Res 30(11): 3146-3154, 2016-Proper utilization of the kinetic chain allows for efficient kinetic energy transfer from the proximal segments to the distal segments. The aims of this study were to describe muscle activations in 4 kinetic chain prethrowing exercises and compare these muscle activations with 3 traditional resistance-band exercises. Twenty-six healthy college students (22.9 +/- 3.4 years; 172.2 +/- 8.6 cm; 74.2 +/- 16.3 kg), regardless of gender, participated. Surface electromyographic data were recorded for selected pelvic and scapular musculature while subjects performed the exercises. The exercises included airplane (single-leg balance with weight-bearing hip flexed to 90 degrees and non-weight-bearing hip extended) while performing alternating repetitions of external and internal shoulder rotation, lunge, Get Up, single-leg balance, and resistance band I, T, and Y. A repeated-measures analysis of variance, with a factor of exercise (8 different levels), was used. Post hoc analyses were used for each muscle to determine the statistically significant differences between exercises. The results reveal the greatest activation occurred during the 2 airplane exercises than all the other exercises. The results of this study help to establish surface electromyographic data for selected pelvis and scapula musculature during a series of kinetic chain and resistance-band exercises. Understanding the muscle activations during these exercises can assist clinicians and coaches in choosing the appropriate exercises to implement for individuals involved in dynamic shoulder movement. PMID- 26937769 TI - A New Method for the Evaluation and Prediction of Base Stealing Performance. AB - Bricker, JC, Bailey, CA, Driggers, AR, McInnis, TC, and Alami, A. A new method for the evaluation and prediction of base stealing performance. J Strength Cond Res 30(11): 3044-3050, 2016-The purposes of this study were to evaluate a new method using electronic timing gates to monitor base stealing performance in terms of reliability, differences between it and traditional stopwatch-collected times, and its ability to predict base stealing performance. Twenty-five healthy collegiate baseball players performed maximal effort base stealing trials with a right and left-handed pitcher. An infrared electronic timing system was used to calculate the reaction time (RT) and total time (TT), whereas coaches' times (CT) were recorded with digital stopwatches. Reliability of the TGM was evaluated with intraclass correlation coefficients (ICCs) and coefficient of variation (CV). Differences between the TGM and traditional CT were calculated with paired samples t tests Cohen's d effect size estimates. Base stealing performance predictability of the TGM was evaluated with Pearson's bivariate correlations. Acceptable relative reliability was observed (ICCs 0.74-0.84). Absolute reliability measures were acceptable for TT (CVs = 4.4-4.8%), but measures were elevated for RT (CVs = 32.3-35.5%). Statistical and practical differences were found between TT and CT (right p = 0.00, d = 1.28 and left p = 0.00, d = 1.49). The TGM TT seems to be a decent predictor of base stealing performance (r = -0.49 to -0.61). The authors recommend using the TGM used in this investigation for athlete monitoring because it was found to be reliable, seems to be more precise than traditional CT measured with a stopwatch, provides an additional variable of value (RT), and may predict future performance. PMID- 26937770 TI - Incremental Testing Design on Slide Board for Speed Skaters: Comparison Between Two Different Protocols. AB - Piucco, T, O'Connell, J, Stefanyshyn, D, and de Lucas, RD. Incremental testing design on slide board for speed skaters: comparison between two different protocols. J Strength Cond Res 30(11): 3116-3121, 2016-The aim of this study was to investigate the effect of stage duration (Long-stage-LS: 3-minute, Short-stage SS: 1-minute) on maximal and submaximal aerobic physiological variables during a simulated skating test performed on a slide board. Ten well-trained male speed skaters performed 2 maximal incremental tests on slide board until voluntary exhaustion. The second ventilatory threshold (VT2) was determined by the ventilatory equivalent method. All participants reached the criteria for maximal oxygen uptake (V[Combining Dot Above]O2max) attainment in both protocols. Maximal cadence (CADmax), V[Combining Dot Above]O2 at VT2 and cadence at VT2 (CADVT2) were significantly higher during SS protocol, but maximal heart rate was significantly lower for the SS protocol. V[Combining Dot Above]O2max was significantly correlated with CADmax for the SS (r = 0.62) and LS protocols (r = 0.61). Strong correlations were found between CADmax and CADVT2 during the SS (r = 0.83) and LS protocols (r = 0.76). The results of the present study suggest that either SS or LS slide board incremental protocol can be used to evaluate skaters, since they elicited maximal physiological responses. Additionally, slide board incremental skating tests may be considered as a more specific and practical alternative than laboratory-based tests, especially when a large number of athletes need to be assessed. PMID- 26937771 TI - Physical Differences Between Forwards and Backs in American Collegiate Rugby Players. AB - La Monica, MB, Fukuda, DH, Miramonti, AA, Beyer, KS, Hoffman, MW, Boone, CH, Tanigawa, S, Wang, R, Church, DD, Stout, JR, and Hoffman, JR. Physical differences between forwards and backs in American collegiate rugby players. J Strength Cond Res 30(9): 2382-2391, 2016-This study examined the anthropometric and physical performance differences between forwards and backs in a championship level American male collegiate rugby team. Twenty-five male rugby athletes (mean +/- SD; age 20.2 +/- 1.6 years) were assessed. Athletes were grouped according to position as forwards (n = 13) and backs (n = 12) and were evaluated on the basis of anthropometrics (height, weight, percent body fat [BF%]), cross-sectional area (CSA), muscle thickness (MT), and pennation angle (PA) of the vastus lateralis (VL), maximal strength (1 repetition maximum [1RM] bench press and squat), vertical jump power, midthigh pull (peak force [PF] and peak rate of force development [PRFD]), maximal aerobic capacity (V[Combining Dot Above]O2peak), agility (pro agility, T test), speed (40-m sprint), and a tethered sprint (peak velocity [PV], time to peak velocity, distance covered, and step rate and length). Comparisons between forwards and backs were analyzed using independent t tests with Cohen's d effect size. Forwards were significantly different from backs for body weight (90.5 +/- 12.4 vs. 73.7 +/- 7.1 kg, p < 0.01; d = 1.60), BF% (12.6 +/- 4.2 vs. 8.8 +/- 2.1%, p <= 0.05; d = 1.10), VL CSA (38.3 +/- 9.1 vs. 28.7 +/- 4.7 cm, p < 0.01; d = 1.26), 1RM bench press (121.1 +/- 30.3 vs. 89.5 +/- 20.4 kg, p <= 0.05; d = 1.17), 1RM squat (164.6 +/- 43.0 vs. 108.5 +/- 31.5 kg, p < 0.01; d = 1.42), PF (2,244.6 +/- 505.2 vs. 1,654.6 +/- 338.8 N, p < 0.01; d = 1.32), PV (5.49 +/- 0.25 vs. 5.14 +/- 0.37 m.s, p <= 0.05; d = 1.04), and step length (1.2 +/- 0.1 vs. 1.1 +/- 0.1 m, p <= 0.05; d = 0.80). V[Combining Dot Above]O2peak was significantly (p <= 0.05, d = -1.20) higher in backs (54.9 +/- 3.9 ml.kg.min) than in forwards (49.4 +/- 4.4 ml.kg.min). No differences in agility performance were found between position groups. The results of this study provide descriptive information on anthropometric and performance measures on American male collegiate championship-level rugby players offering potential standards for coaches to use when developing or recruiting players. PMID- 26937772 TI - Validity of a Wearable Accelerometer Device to Measure Average Acceleration Values During High-Speed Running. AB - Alexander, JP, Hopkinson, TL, Wundersitz, DWT, Serpell, BG, Mara, JK, and Ball, NB. Validity of a wearable accelerometer device to measure average acceleration values during high-speed running. J Strength Cond Res 30(11): 3007-3013, 2016-The aim of this study was to determine the validity of an accelerometer to measure average acceleration values during high-speed running. Thirteen subjects performed three sprint efforts over a 40-m distance (n = 39). Acceleration was measured using a 100-Hz triaxial accelerometer integrated within a wearable tracking device (SPI-HPU; GPSports). To provide a concurrent measure of acceleration, timing gates were positioned at 10-m intervals (0-40 m). Accelerometer data collected during 0-10 m and 10-20 m provided a measure of average acceleration values. Accelerometer data was recorded as the raw output and filtered by applying a 3-point moving average and a 10-point moving average. The accelerometer could not measure average acceleration values during high-speed running. The accelerometer significantly overestimated average acceleration values during both 0-10 m and 10-20 m, regardless of the data filtering technique (p < 0.001). Body mass significantly affected all accelerometer variables (p < 0.10, partial eta = 0.091-0.219). Body mass and the absence of a gravity compensation formula affect the accuracy and practicality of accelerometers. Until GPSports-integrated accelerometers incorporate a gravity compensation formula, the usefulness of any accelerometer-derived algorithms is questionable. PMID- 26937773 TI - Torque and Muscle Activation Impairment Along With Insulin Resistance Are Associated With Falls in Women With Fibromyalgia. AB - Goes, SM, Stefanello, JMF, Homann, D, Lodovico, A, Hubley-Kozey, CL, and Rodacki, ALF. Torque and muscle activation impairment along with insulin resistance are associated with falls in women with fibromyalgia. J Strength Cond Res 30(11): 3155-3164, 2016-Fibromyalgia (FM) is a chronic pain condition associated with reduced muscle strength, which can lead to functional incapacity and higher risk of falls. The purpose of the study was to compare maximal ankle joint torque, muscle activation, and metabolic changes between women with and without FM. In addition, the relationship between those aspects and retrospectively reported falls in women with FM was determined. Twenty-nine middle-aged women with FM and 30 controls were recruited. Fall history, pain intensity, and pain threshold were assessed. Plasma glucose levels and insulin resistance (IR) were determined. Peak torque and rate of torque development (RTD) were calculated, and muscle activation was assessed from maximum isometric voluntary ankle dorsiflexion and plantar flexion contractions. In addition, voluntary muscle activation failure of the anterior tibialis muscle during maximal dorsiflexion was calculated. When compared to controls, women with FM reported higher number of retrospectively reported falls, exhibited higher IR, showed reduced plantar flexion and dorsiflexion RTD, had lower plantar flexion peak torque, and demonstrated more antagonist coactivation and higher muscle activation failure (p <= 0.05). Higher muscle activation failure was explained by glucose level and pain intensity (adj R = 0.28; p <= 0.05). Reduced plantar flexion and dorsiflexion peak torque explained 80% of retrospectively reported falls variance; also, high antagonist coactivation (odds ratio [OR] = 1.6; p <= 0.05) and high IR (OR = 1.8; p <= 0.05) increased the chance of falls in the FM group. A combination of metabolic factors and muscle function increased the odds of retrospectively reporting a fall in FM. Both aspects may be considered in interventions designed for reducing falls in this population. PMID- 26937774 TI - Energy Drinks Improve Five-Kilometer Running Performance in Recreational Endurance Runners. AB - Prins, PJ, Goss, FL, Nagle, EF, Beals, K, Robertson, RJ, Lovalekar, MT, and Welton, GL. Energy drinks improve five-kilometer running performance in recreational endurance runners. J Strength Cond Res 30(11): 2979-2990, 2016-The purpose of this study was to evaluate exercise performance time and related physiological and perceptual responses of recreational endurance runners after they had ingested a commercially available energy drink (Red Bull, Red Bull GmbH, Fuschl am See, Austria) containing caffeine, glucose, and taurine. Recreational endurance runners (n = 18; 13 men and 5 women; age: 20.39 +/- 3.27 years; weight: 71.25 +/- 17.17 kg; height: 178.00 +/- 7.57 cm; V[Combining Dot Above]O2max: 55.94 +/- 7.66 ml.kg.min) participated in a double-blind, crossover, repeated measures study where they were randomized to supplement with 500 ml of the commercially available energy drink Red Bull and a noncaffeinated, sugar-free placebo (PLA) 60 minutes before completing a 5-km time trial on a treadmill, separated by 7 days. Heart rate, rating of perceived exertion (RPE) (RPE-Overall; RPE-Chest; RPE-Legs), and affect were recorded at rest, 1 hour before ingestion, at 5-minute intervals during the 5-km time trial, and immediately after exercise. Session RPE and session affect were obtained 5 minutes after completion of the 5 km time trial. The distance covered at each 5-minute interval during the 5-km time trial was recorded. Performance improved with the energy drink compared with placebo (Red Bull: 1,413.2 +/- 169.7 vs. PLA: 1,443.6 +/- 179.2 seconds; p = 0.016), but there were no differences in RPE, affect, session RPE, session affect, or the distance covered at 5-minute splits between the two 5-km time trials (p > 0.05). These results demonstrate that consuming a commercially available energy drink before exercise can improve 5-km performance. These results may have application for altering pre-exercise nutritional strategies in recreational runners. PMID- 26937775 TI - Highly Sensitive Dual-Phase Nanoglass-Ceramics Self-Calibrated Optical Thermometer. AB - A strategy to achieve high sensitivity of noncontact optical thermometer via the structure design of nanoglass-ceramic and the usage of Ln(3+) (Ln = Eu, Tb, Dy) luminescence as reference signal and Cr(3+) emission as temperature signal was provided. Specifically, the synthesized dual-phase glass-ceramics were evidenced to enable spatially confined doping of Ln(3+) in the hexagonal GdF3 nanocrystals and Cr(3+) in the cubic Ga2O3 nanoparticles, being beneficial to suppressing detrimental energy transfer between Ln(3+) and Cr(3+) and thus significantly enhancing their luminescence. As a consequence, completely different temperature sensitive luminescence of Ln(3+)4f -> 4f transition and Cr(3+) 3d -> 3d transition in the present glass-ceramic resulted in obvious variation of Cr(3+)/Ln(3+) fluorescence intensity ratio with temperature and strikingly high detecting temperature sensitivity of 15-22% per K. We believe that this preliminary study will provide an important advance in exploring other innovative optical thermometry. PMID- 26937776 TI - Diagnostics of common microdeletion syndromes using fluorescence in situ hybridization: single center experience in a developing country. AB - Microdeletion syndromes are caused by chromosomal deletions of less than 5 megabases which can be detected by fluorescence in situ hybridization (FISH). We evaluated the most commonly detected microdeletions for the period from June 01, 2008 to June 01, 2015 in the Federation of Bosnia and Herzegovina, including DiGeorge, Prader-Willi/Angelman, Wolf-Hirschhorn, and Williams syndromes. We report 4 patients with DiGeorge syndromes, 4 patients with Prader-Willi/Angelman, 4 patients with Wolf-Hirschhorn syndrome, and 3 patients with Williams syndrome in the analyzed 7 year period. Based on the positive FISH results for each syndrome, the incidence was calculated for the Federation of Bosnia and Herzegovina. These are the first reported frequencies of the microdeletion syndromes in the Federation of Bosnia and Herzegovina. PMID- 26937777 TI - Structure and Properties of Ir-Containing Oxides with Large Spin-Orbit Coupling: Ba2In(2-x)Ir(x)O(5+delta). AB - In this work, the solid solution series Ba2In(2-x)Ir(x)O5+delta (x = 0-1.4, 2) was synthesized, and its structural, magnetic, and charge-transport properties were measured. With increasing Ir content, three transitions in the room temperature structure were observed: orthorhombic to tetragonal to cubic to a monoclinic distortion of a hexagonal BaTiO3 structure. Neutron diffraction shows Ba2In(1.6)Ir(0.4)O5.4 to be cubic and Ba2InIrO6 to be monoclinic, the latter contrary to previously published X-ray diffraction refinements. Magnetization measurements show Curie-Weiss behavior for x = 0.2-0.6, which arises from nearly 50:50 ratio of Ir(V) and Ir(VI). To our knowledge, this is the first time Ir(VI) has been stabilized with standard solid-state methods under ambient conditions. The electrical resistivity measurements show all the compounds studied are semiconducting and that resistivity decreases with increasing Ir content, suggesting the proximity to a metal-insulator transition. A sign reversal in the high-temperature Seebeck coefficient is observed indicating both electron and hole charge transport. PMID- 26937778 TI - Dermal Uptake from Airborne Organics as an Important Route of Human Exposure to E Waste Combustion Fumes. AB - Skin absorption of gaseous organic contaminants is an important and relevant mechanism in human exposure to such contaminants, but has not been adequately examined. This article demonstrates that dermal uptake from airborne contaminants could be recognized as a significant exposure route for local residents subjecting to combustion fume from e-waste recycling activities. It is particularly true for organic pollutants which have high dermal penetration rates and large skin-air partition coefficients, such as low molecular weight plasticizers and flame retardants. PMID- 26937779 TI - Determination of Stability from Multicomponent Pesticide Mixes. AB - A study was conducted to evaluate the stability of 528 pesticides, metabolites, and contaminants prepared in large multicomponent mixes to enhance laboratory efficiency by allowing maximum use of the useful shelf life of the mixtures. Accelerated aging at 50 degrees C simulated 6 month, 1 year, and 2 year storage periods at -20 degrees C. Initial mixture composition was based on the instrument of analysis. After preliminary stability data had been obtained, mixtures were reformulated and re-evaluated. In all, 344 compounds showed satisfactory stability across all treatment groups, 100 compounds showed statistically significant changes between the control and the 6 month simulated storage period (27 with losses >20%), and the remainder showed borderline stability or were tested in one protocol. Stability behavior for organophosphates agreed with the proposed reaction mechanism responsible for acetylcholinesterase inhibition. A small number of compounds increased in response over time, suggesting the occurrence of degradation of precursor pesticides into these respective compounds. PMID- 26937780 TI - Solution Behavior of the Intrinsically Disordered N-Terminal Domain of Retinoid X Receptor alpha in the Context of the Full-Length Protein. AB - Retinoid X receptors (RXRs) are transcription factors with important functions in embryonic development, metabolic processes, differentiation, and apoptosis. A particular feature of RXRs is their ability to act as obligatory heterodimerization partners of class II nuclear receptors. At the same time, these receptors are also able to form homodimers that bind to direct repeat separated by one nucleotide hormone response elements. Since the discovery of RXRs, most of the studies focused on its ligand binding and DNA binding domains, while its N-terminal domain (NTD) harboring a ligand-independent activation function remained poorly characterized. Here, we investigated the solution properties of the NTD of RXRalpha alone and in the context of the full-length receptor using small-angle X-ray scattering and nuclear magnetic resonance spectroscopy. We report the solution structure of the full-length homodimeric RXRalpha on DNA and show that the NTD remains highly flexible within this complex. PMID- 26937781 TI - Protein Quality Assessment on Saliva Samples for Biobanking Purposes. AB - Biobank saliva sample quality depends on specific criteria applied to collection, processing, and storage. In spite of the growing interest in saliva as a diagnostic fluid, few biobanks currently store large collections of such samples. The development of a standard operating procedure (SOP) for saliva collection and quality control is fundamental for the establishment of a new saliva biobank, which stores samples to be made available to the saliva research community. Different collection methods were tested regarding total volume of protein obtained, protein content, and protein profiles, and the results were used to choose the best method for protein studies. Furthermore, the impact of the circadian variability and inter- and intraindividual differences, as well as the saliva sample stability at room temperature, were also evaluated. Considering our results, a sublingual cotton roll method for saliva collection proved to produce saliva with the best characteristics and should be applied in the morning, whenever possible. In addition, there is more variability in salivary proteins between individuals than in the same individual for a 5-month period. According to the electrophoretic protein profile, protein stability is guaranteed for 24 hours at room temperature and the protein degradation profile and protein identification were characterized. All this information was used to establish an SOP for saliva collection, processing, and storage in a biobank. We conclude that it is possible to collect saliva using an easy and inexpensive protocol, resulting in saliva samples for protein analysis with sufficient quality for biobanking purposes. PMID- 26937782 TI - Renal function after elective total hip replacement. AB - Background and purpose - Acute kidney injury (AKI) is associated with increased short-term and long-term mortality in intensive care populations and in several surgical specialties, but there are very few data concerning orthopedic populations. We have studied the incidence of AKI and the prevalence of chronic kidney disease (CKD) in an elective population of orthopedic patients undergoing primary total hip replacement, hypothesizing that chronic kidney disease predisposes to AKI. Patients and methods - This was a single-center, population based, retrospective, registry-based cohort study involving all primary elective total hip replacements performed from January 2003 through December 2012. Patient demographics and creatinine values were registered. We evaluated the presence of CKD and AKI according to the international guidelines for kidney disease (KDIGO Acute Kidney Injury Workgroup 2013 ). Results - 3,416 patients were included (2,064 females (60%)). AKI (according to KDIGO criteria) was seen in 75 patients (2.2%, 95% CI: 1.7-2.7) in the course of primary total hip replacement. Of these, 26 had pre-existing CKD of class 3-5. Pre-existing CKD of class 3-5, indicating moderately to severely reduced kidney function, was seen in 374 individuals (11%). Interpretation - Development of acute kidney injury appears to be a substantial problem compared to other complications related to elective total hip arthroplasty, i.e. luxation and infection. Patients with pre-existing chronic kidney disease may be especially vulnerable. The clinical impact of acute kidney injury in an elective orthopedic population remains to be elucidated. PMID- 26937786 TI - Quantifying the Distribution of the Stoichiometric Composition of Anticancer Peptide Lycosin-I on the Lipid Membrane with Single Molecule Spectroscopy. AB - Lycosin-I, a peptide toxin derived from spider venom, has been demonstrated to be a promising candidate for the inhibition of tumor cell growth in vitro and in vivo by interacting with and penetrating the cell membrane. Owing to the shortage of an efficient characterization strategy, however, there is still a lack of detailed knowledge about the distribution of the stoichiometric composition information on this peptide in solution and on lipid membrane prior to the cellular uptake process, which is fundamentally important for the understanding of the anticancer mechanism. In this work, with objective-type total internal reflection fluorescence microscopy (TIRF), the distribution of the stoichiometric composition of lycosin-I in different solutions as well as on the lipid membrane was explored extensively on the basis of a statistical single molecule fluorescence intensity analysis for the first time. It was found that lycosin-I is mainly present in a monomer state in diverse physiological solutions regardless of the concentration of the peptide and the incubation time. However, on the lipid membrane, the fraction of small size oligomers increased as a function of time. Fusion of movable peptide molecules to those peptide oligomers with restricted motion on the lipid membrane was also observed. PMID- 26937788 TI - The Psychology of Working Theory. AB - In the current article, we build on research from vocational psychology, multicultural psychology, intersectionality, and the sociology of work to construct an empirically testable Psychology of Working Theory (PWT). Our central aim is to explain the work experiences of all individuals, but particularly people near or in poverty, people who face discrimination and marginalization in their lives, and people facing challenging work-based transitions for which contextual factors are often the primary drivers of the ability to secure decent work. The concept of decent work is defined and positioned as the central variable within the theory. A series of propositions is offered concerning (a) contextual predictors of securing decent work, (b) psychological and economic mediators and moderators of these relations, and (c) outcomes of securing decent work. Recommendations are suggested for researchers seeking to use the theory and practical implications are offered concerning counseling, advocacy, and public policy. PMID- 26937787 TI - Characterization of alpha-Synuclein Multimer Stoichiometry in Complex Biological Samples by Electrophoresis. AB - The aberrant aggregation of alpha-synuclein in the brain is a hallmark of Parkinson's disease (PD). In vivo soluble alpha-synuclein occurs as a monomer and several multimers, the latter of which may be important for the biological function of alpha-synuclein. Currently, there is a lack of reproducible methods to compare alpha-synuclein multimer abundance between complex biological samples. Here we developed a method, termed "multimer-PAGE," that combines in-gel chemical cross-linking with several common electrophoretic techniques to measure the stoichiometry of soluble alpha-synuclein multimers in brain tissue lysates. Results show that soluble alpha-synuclein from the rat brain exists as several high molecular weight species of approximately 56 kDa (alphaS56), 80 kDa (alphaS80), and 100 kDa (alphaS100) that comigrate with endogenous lipids, detergents, and/or micelles during blue native gel electrophoresis (BN-PAGE). Co extraction of endogenous lipids with alpha-synuclein was essential for the detection of soluble alpha-synuclein multimers. Homogenization of brain tissue in small buffer volumes (>50 mg tissue per 1 mL buffer) increased relative lipid extraction and subsequently resulted in abundant soluble multimer detection via multimer-PAGE. alpha-Synuclein multimers captured by directly cross-linking soluble lysates resembled those observed following multimer-PAGE. The ratio of multimer (alphaS80) to monomer (alphaS17) increased linearly with protein input into multimer-PAGE, suggesting to some extent, multimers were also formed during electrophoresis. Overall, soluble alpha-synuclein maintains lipid interactions following tissue disruption and readily forms multimers when this lipid-protein complex is preserved. Once the multimer-PAGE technique was validated, relative stoichiometric comparisons could be conducted simultaneously between 14 biological samples. Multimer-PAGE provides a simple inexpensive biochemical technique to study the molecular factors influencing alpha-synuclein multimerization. PMID- 26937789 TI - Predictors and moderators of between-therapists and within-therapist differences in depressed outpatients' experiences of the Rogerian conditions. AB - The extent to which patients experience their therapists as providing empathy, positive regard and genuineness (the Rogerian Conditions) is an important predictor of outcome in the psychotherapy of depression (Zuroff & Blatt, 2006). Using data from 157 depressed outpatients treated by 27 therapists in the cognitive-behavior therapy, interpersonal therapy, or clinical management with placebo conditions of the Treatment of Depression Collaborative Research Program (Elkin et al., 1989), Zuroff, Kelly, Leybman, Blatt, and Wampold (2010) showed that between-therapists and within-therapist differences in Rogerian Conditions at the second treatment session predicted more rapid reductions in overall maladjustment. We conducted novel analyses intended to identify: 1) predictors of between-therapists and within-therapist differences in Rogerian Conditions and 2) moderators of the effects on maladjustment of between-therapists and within therapist differences in Rogerian Conditions. Patients with lower levels of self critical perfectionism, higher levels of an adaptive form of dependency or higher expectations of warmth from their therapists experienced higher levels of Rogerian Conditions than their therapist's average patient. High baseline self critical perfectionism diminished the between-therapists effect of Rogerian Conditions on maladjustment, whereas baseline adaptive dependency enhanced the within-therapist effect of Rogerian Conditions. Results shed additional light on the centrality of patient characteristics, the Rogerian Conditions, and their transactions and interactions on outcome in brief outpatient therapy for depression. PMID- 26937802 TI - Prediction of Low versus High Recurrence Scores in Estrogen Receptor-Positive, Lymph Node-Negative Invasive Breast Cancer on the Basis of Radiologic-Pathologic Features: Comparison with Oncotype DX Test Recurrence Scores. AB - Purpose To review mammographic, ultrasonographic (US), and magnetic resonance (MR) imaging features and pathologic characteristics of estrogen receptor (ER) positive, lymph node-negative invasive breast cancer and to determine the relationship of these characteristics to Oncotype DX (Genomic Health, Redwood City, Calif) test recurrence scores (ODRS) for breast cancer recurrence. Materials and Methods This institutional review board-approved retrospective study was performed in a single large academic medical center. The study population included patients with ER-positive, lymph node-negative invasive breast cancer who underwent genomic testing from January 1, 2009, to December 31, 2013. Imaging features of the tumor were classified according to the Breast Imaging Reporting and Data System lexicon by breast imagers who were blinded to the ODRS. Mammography was performed in 86% of patients, US was performed in 84%, and MR imaging was performed in 33%, including morphologic and kinetic evaluation. Images from each imaging modality were evaluated. Each imaging finding, progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) status, and tumor grade were then individually correlated with ODRS. Analysis of variance was used to determine differences for each imaging feature. Regression analysis was used to calculate prediction of recurrence on the basis of imaging features combined with histopathologic features. Results The 319 patients had a mean age +/- standard deviation of 55 years +/- 8.7 (range, 31-82 years). Imaging features with a positive correlation with ODRS included a well circumscribed oval mass (P = .024) at mammography, vascularity (P = .047) and posterior enhancement (P = .004) at US, and lobulated mass (P = .002) at MR imaging. Recurrence scores were predicted by using these features in combination with PR and HER2 status and tumor grade by using the threshold of more than 30 as a high recurrence score. With a regression tree, there was correlation (r = 0.79) with 89% sensitivity and 83% specificity. Conclusion On the basis of preliminary data, information obtained routinely for breast cancer diagnosis can reliably be used to predict the ODRS with high sensitivity and specificity. ((c)) RSNA, 2016. PMID- 26937820 TI - Standardization of FT4 and Harmonization of TSH Measurements--A Request for Input from Endocrinologists and Other Physicians. PMID- 26937803 TI - CT Features Associated with Epidermal Growth Factor Receptor Mutation Status in Patients with Lung Adenocarcinoma. AB - Purpose To retrospectively identify the relationship between epidermal growth factor receptor (EGFR) mutation status, predominant histologic subtype, and computed tomographic (CT) characteristics in surgically resected lung adenocarcinomas in a cohort of Asian patients. materials and Methods This study was approved by the institutional review board, with waiver of informed consent. Preoperative chest CT findings were retrospectively evaluated in 385 surgically resected lung adenocarcinomas. A total of 30 CT descriptors were assessed. EGFR mutations at exons 18-21 were determined by using the amplification refractory mutation system. Multiple logistic regression analyses were performed to identify independent factors of harboring EGFR mutation status. The final model was selected by using the backward elimination method, and two areas under the receiver operating characteristic curve (ROC) were compared with the nonparametric approach of DeLong, DeLong, and Clarke-Pearson. Results EGFR mutations were found in 168 (43.6%) of 385 patients. Mutations were found more frequently in (a) female patients (P < .001); (b)those who had never smoked (P < .001); (c)those with lepidic predominant adenocarcinomas (P = .001) or intermediate pathologic grade (P < .001); (e) smaller tumors (P < .001); (f)tumors with spiculation (P = .019), ground-glass opacity (GGO) or mixed GGO (P < .001), air bronchogram (P = .006), bubblelike lucency (P < .001), vascular convergence (P = .024), thickened adjacent bronchovascular bundles (P = .027), or pleural retraction (P < .001); and (g) tumors without pleural attachment (P = .004), a well-defined margin (P = .010), marked heterogeneous enhancement (P = .001), severe peripheral emphysema (P = .002), severe peripheral fibrosis (P = .013), or lymphadenopathy (P = .028). The most important and significantly independent prognostic factors of harboring EGFR-activating mutation for the model with both clinical variables and CT features were those who had never smoked and those with smaller tumors, bubblelike lucency, homogeneous enhancement, or pleural retraction when adjusting for histologic subtype, pathologic grade, or thickened adjacent bronchovascular bundles. ROC curve analysis showed that use of clinical variables combined with CT features (area under the ROC curve = 0.778) was superior to use of clinical variables alone (area under the ROC curve = 0.690). Conclusion CT imaging features of lung adenocarcinomas in combination with clinical variables can be used to prognosticate EGFR mutation status better than use of clinical variables alone. ((c)) RSNA, 2016 Online supplemental material is available for this article. PMID- 26937821 TI - Uptake Mechanism and Direct Translocation of a New CPP for siRNA Delivery. AB - Since their development, cell-penetrating peptides (CPPs) have been used as delivery vehicles for various genetic or therapeutic agents; however, the uptake mechanisms of CPPs and the delivery details are still unclear. Understanding the mechanisms of cellular internalization of CPPs facilitate their development of CPPs as gene delivery vectors. In the present study, we evaluated the internalization process of a previously designed CPP, STR-KV, complexed with small interference RNA (siRNA) targeting at the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) gene. Using heparin treatment and chemical endocytic inhibitors, we elucidated that the electrostatic interaction of STR-KV/siRNA complex with heparin sulfate proteoglycans at the cell membrane surface triggered the energy-independent uptake of the majority of the complexes, which most likely through a direct translocation pathway. The intracellular trafficking and internalization kinetics observed by confocal microscopy also confirmed that the complex was uptaken through a nonendocytic pathway. PMID- 26937822 TI - Correction to Quantitative metrics for assessing positional and orientational order in colloidal crystals. PMID- 26937826 TI - Activities and Stabilities of Au-Modified Stepped-Pt Single-Crystal Electrodes as Model Cathode Catalysts in Polymer Electrolyte Fuel Cells. AB - The purpose of this study is to test the concept of protecting vulnerable sites on cathode catalysts in polymer electrolyte fuel cells. Pt single-crystal surfaces were modified by depositing Au atoms selectively on (100) step sites and their electrocatalytic activities for oxygen reduction reaction (ORR) and stabilities against potential cycles were examined. The ORR activities were raised by 70% by the Au modifications, and this rise in the activity was ascribed to enhanced local ORR activities on Pt(111) terraces by the surface Au atoms. The Au modifications also stabilized the Pt surfaces against potential cycles by protecting the low-coordinated (100) step sites from surface reorganizations. Thus, the surface modification by selective Au depositions on vulnerable sites is a promising method to enhance both the ORR activity and durability of the catalysts. PMID- 26937827 TI - Nitrogen- and Sulfur-Codoped Hierarchically Porous Carbon for Adsorptive and Oxidative Removal of Pharmaceutical Contaminants. AB - Heteroatom (nitrogen and sulfur)-codoped porous carbons (N-S-PCs) with high surface areas and hierarchically porous structures were successfully synthesized via direct pyrolysis of a mixture of glucose, sodium bicarbonate, and thiourea. The resulting N-S-PCs exhibit excellent adsorption abilities and are highly efficient for potassium persulfate activation when employed as catalysts for the oxidative degradation of sulfachloropyridazine (SCP) solutions. The adsorption capacities of N-S-PC-2 (which contains 4.51 atom % nitrogen and 0.22 atom % sulfur and exhibits SBET of 1608 m(2) g(-1)) are 73, 7, and 3 times higher than those of graphene oxide, reduced graphene oxide, and commercial single-walled carbon nanotube, respectively. For oxidation, the reaction rate constant of N-S PC-2 is 0.28 min(-1). This approach not only contributes to the large-scale production and application of high-quality catalysts in water remediation but also provides an innovative strategy for the production of heteroatom-doped PCs for energy applications. PMID- 26937828 TI - Structure-Based Design and Synthesis of Novel Inhibitors Targeting HDAC8 from Schistosoma mansoni for the Treatment of Schistosomiasis. AB - Schistosomiasis is a major neglected parasitic disease that affects more than 265 million people worldwide and for which the control strategy consists of mass treatment with the only available drug, praziquantel. In this study, a series of new benzohydroxamates were prepared as potent inhibitors of Schistosoma mansoni histone deacetylase 8 (smHDAC8). Crystallographic analysis provided insights into the inhibition mode of smHDAC8 activity by these 3-amidobenzohydroxamates. The newly designed inhibitors were evaluated in screens for enzyme inhibitory activity against schistosome and human HDACs. Twenty-seven compounds were found to be active in the nanomolar range, and some of them showed selectivity toward smHDAC8 over the major human HDACs (1 and 6). The active benzohydroxamates were additionally screened for lethality against the schistosome larval stage using a fluorescence-based assay. Four of these showed significant dose-dependent killing of the schistosome larvae and markedly impaired egg laying of adult worm pairs maintained in culture. PMID- 26937844 TI - Total Syntheses of the Tetracyclic Cyclopiane Diterpenes Conidiogenone, Conidiogenol, and Conidiogenone B. AB - Total syntheses of the biologically important and structurally unique tetracyclic diterpenes conidiogenone, conidiogenol, and conidiogenone B of the cyclopiane class are reported. The absolute configuration of naturally occurring conidiogenone B was also corrected. The key step of our strategy involved the highly efficient construction of both ring C and the quaternary carbon center shared by rings A and C through a one-step regioselective and diastereoselective cycloenlargement in the form of a semipinacol-type rearrangement. In particular, the desired regioselectivity was made possible by properly adjusting the migratory aptitude of the migrating carbon atom through the introduction of an electron-donating phenylthio group at this position. PMID- 26937845 TI - New Caledonia: A Hot Spot for Valuable Chemodiversity Part 3: Santalales, Caryophyllales, and Asterids. AB - The flora of New Caledonia encompasses more than 3000 plant species and an endemism of almost 80%. New Caledonia is even considered as one of the 34 'hot spots' for biodiversity. Considering the current global loss of biodiversity and the fact that several drugs and pesticides become obsolete, there is an urgent need to increase sampling and research on new natural products. In this context, here, we reviewed the chemical knowledge available on New Caledonian native flora from economical perspectives. We expect that a better knowledge of the economic potential of plant chemistry will encourage the plantation of native plants for the development of a sustainable economy which will participate in the conservation of biodiversity. This review is divided into three parts, and the third part which is presented here summarizes the scientific literature related to the chemistry of endemic santalales, caryophyllales, and asterids. We show that the high rate of endemism is correlated with the originality of phytochemicals encountered in New Caledonian plants. A total of 176 original natural compounds have been identified from these plants, whereas many species have not been investigated so far. We also discuss the economic potential of plants and molecules with consideration of their medicinal and industrial perspectives. This review finally highlights several groups, such as Sapotaceae, that are unexplored in New Caledonia despite the high chemical interest in them. These plants are considered to have priority in future chemical investigations. PMID- 26937846 TI - Announcement: Sleep Awareness Week - March 6-12, 2016. AB - Sleep Awareness Week, the National Sleep Foundation's annual campaign to educate the public about the importance of sleep in health and safety, will be observed March 6-12, 2016. The American Academy of Sleep Medicine and the Sleep Research Society recommend that adults aged 18-60 years sleep >=7 hours each night to promote optimal health and well-being. However, 35% of U.S. adults report typically sleeping <7 hours Adults who do not get enough sleep on a regular basis are more likely to suffer from chronic conditions, such as obesity, high blood pressure, diabetes, and poor mental health. PMID- 26937847 TI - Assorted Phenoxyl-Radical Polymers and Their Application in Lithium-Organic Batteries. AB - The synthesis and electrochemical characterization of novel polymers bearing phenoxyl-radicals as redox-active side chains is described. The monomers are synthesized from the corresponding phenols and quinones, respectively. These compounds are subsequently poly-merized via ring-opening metathesis polymerization. The electrochemical properties of the phenoxyl-radical polymers are characterized using cyclic voltammetry and the most promising polymer is investigated as active material in a lithium coin-cell, creating the first phenoxyl-lithium battery. These phenoxyl-containing polymers represent interesting anode materials for organic radical and lithium batteries due to their suitable redox-potentials and possibility to create batteries with higher potentials as well as straightforward synthesis procedures. PMID- 26937848 TI - Localization of Narrowband Single Photon Emitters in Nanodiamonds. AB - Diamond nanocrystals that host room temperature narrowband single photon emitters are highly sought after for applications in nanophotonics and bioimaging. However, current understanding of the origin of these emitters is extremely limited. In this work, we demonstrate that the narrowband emitters are point defects localized at extended morphological defects in individual nanodiamonds. In particular, we show that nanocrystals with defects such as twin boundaries and secondary nucleation sites exhibit narrowband emission that is absent from pristine individual nanocrystals grown under the same conditions. Critically, we prove that the narrowband emission lines vanish when extended defects are removed deterministically using highly localized electron beam induced etching. Our results enhance the current understanding of single photon emitters in diamond and are directly relevant to fabrication of novel quantum optics devices and sensors. PMID- 26937849 TI - Cryogenic transmission electron microscopy study: preparation of vesicular dispersions by quenching microemulsions. AB - We previously showed that long-lived nanoemulsions, seeming initially vesicular, might be prepared simply by diluting and cooling (quenching) warm microemulsions with n-hexadecane with precooled water. In this paper, we confirm that these systems are vesicular dispersions when fresh, and they can be made with similar structures and compositional dependence using alkanes with chain lengths ranging from octane to hexadecane. The nanostructures of fresh nanoemulsions are imaged with cryogenic transmission electron microscopy (cryo-TEM). We confirm that water continuous microemulsions give simple dispersions of vesicles (sometimes unilamellar), typically less than 100 nm in diameter; these systems can avoid separation for over 2 months. Selected samples were also prepared using halogenated alkanes to create additional contrast in the cryo-TEM, allowing us to confirm that the oil is located in the observed vesicular structures. PMID- 26937853 TI - Cellular Response to Reagent-Free Electron-Irradiated Gelatin Hydrogels. AB - As a biomaterial, it is well established that gelatin exhibits low cytotoxicity and can promote cellular growth. However, to circumvent the potential toxicity of chemical crosslinkers, reagent-free crosslinking methods such as electron irradiation are highly desirable. While high energy irradiation has been shown to exhibit precise control over the degree of crosslinking, these hydrogels have not been thoroughly investigated for biocompatibility and degradability. Here, NIH 3T3 murine fibroblasts are seeded onto irradiated gelatin hydrogels to examine the hydrogel's influence on cellular viability and morphology. The average projected area of cells seeded onto the hydrogels increases with irradiation dose, which correlates with an increase in the hydrogel's shear modulus up to 10 kPa. Cells on these hydrogels are highly viable and exhibits normal cell cycles, particularly when compared to those grown on glutaraldehyde crosslinked gelatin hydrogels. However, proliferation is reduced on both types of crosslinked samples. To mimic the response of the hydrogels in physiological conditions, degradability is monitored in simulated body fluid to reveal strongly dose dependent degradation times. Overall, given the low cytotoxicity, influence on cellular morphology and variability in degradation times of the electron irradiated gelatin hydrogels, there is significant potential for application in areas ranging from regenerative medicine to mechanobiology. PMID- 26937854 TI - Bioinspired Design and Computational Prediction of Iron Complexes with Pendant Amines for the Production of Methanol from CO2 and H2. AB - Inspired by the active site structure of [FeFe]-hydrogenase, we built a series of iron dicarbonyl diphosphine complexes with pendant amines and predicted their potentials to catalyze the hydrogenation of CO2 to methanol using density functional theory. Among the proposed iron complexes, [(P(tBu)2N(tBu)2H)FeH(CO)2(COOH)](+) (5COOH) is the most active one with a total free energy barrier of 23.7 kcal/mol. Such a low barrier indicates that 5COOH is a very promising low-cost catalyst for high-efficiency conversion of CO2 and H2 to methanol under mild conditions. For comparison, we also examined Bullock's Cp iron diphosphine complex with pendant amines, [(P(tBu)2N(tBu)2H)FeHCp(C5F4N)](+) (5Cp-C5F4N), as a catalyst for hydrogenation of CO2 to methanol and obtained a total free energy barrier of 27.6 kcal/mol, which indicates that 5Cp-C5F4N could also catalyze the conversion of CO2 and H2 to methanol but has a much lower efficiency than our newly designed iron complexes. PMID- 26937855 TI - Different people respond differently to therapy: A demonstration using patient profiling and risk stratification. AB - BACKGROUND: This study aimed to identify patient characteristics associated with poor outcomes in psychological therapy, and to develop a patient profiling method. METHOD: Clinical assessment data for 1347 outpatients was analysed. Final treatment outcome was based on reliable and clinically significant improvement (RCSI) in depression (PHQ-9) and anxiety (GAD-7) measures. Thirteen patient characteristics were explored as potential outcome predictors using logistic regression in a cross-validation design. RESULTS: Disability, employment status, age, functional impairment, baseline depression and outcome expectancy predicted post-treatment RCSI. Regression coefficients for these factors were used to derive a weighting scheme called Leeds Risk Index (LRI), used to assign risk scores to individual cases. After stratifying cases into three levels of LRI scores, we found significant differences in RCSI and treatment completion rates. Furthermore, LRI scores were significantly correlated with the proportion of treatment sessions classified as 'not on track'. CONCLUSIONS: The LRI tool can identify cases at risk of poor progress to inform personalized treatment recommendations for low and high intensity psychological interventions. PMID- 26937856 TI - Desipramine administered chronically inhibits lipopolysaccharide-stimulated production of IL-1beta in the brain and plasma of rats. AB - Nowadays, it is assumed that therapeutic efficacy of antidepressants depends, at least partly, on their anti-inflammatory properties. The present study investigated for the first time the effect of 21-day oral administration of desipramine on the lipopolysaccharide (LPS)-stimulated IL-1beta concentration in the olfactory bulb, hypothalamus, frontal cortex, hippocampus and plasma of rats, and on the LPS-induced IL-1beta mRNA level in the olfactory bulb. Desipramine (15mg/kg/day) reduced significantly the LPS (250 MUg/kg i.p.)-induced IL-1beta concentration in the olfactory bulb, hypothalamus and in plasma, and diminished the LPS effect on IL-1beta mRNA in the olfactory bulb. Plasma concentration of desipramine was comparable to its therapeutic range. By using the alpha1/alpha2 adrenoceptor antagonist prazosin and the unspecific beta-adrenoceptor antagonist propranolol given prior to LPS, we found that the effect of desipramine on LPS induced IL-1beta production was partially mediated by both adrenoceptors in the olfactory bulb and plasma, and that beta-adrenoceptors contributed also to its effect on the stimulated IL-1beta concentration in the hypothalamus. The effect of LPS on the cerebral IL-1beta levels was, in part, mediated by beta adrenoceptors and, in a region-specific manner, by alpha1/alpha2-adrenoceptors. The findings provide evidence for central and peripheral anti-inflammatory activity of desipramine and confirm the impact of the noradrenergic system on IL 1beta production induced by an immunostimulatory challenge. PMID- 26937857 TI - DNA quality and quantity from up to 16 years old post-mortem blood stored on FTA cards. AB - Blood samples preserved on FTA cards offer unique opportunities for genetic research. DNA recovered from these cards should be stable for long periods of time. However, it is not well established as how well the DNA stored on FTA card for substantial time periods meets the demands of forensic or genomic DNA analyses and especially so for from post-mortem (PM) samples in which the quality can vary upon initial collection. The aim of this study was to evaluate the time dependent degradation on DNA quality and quantity extracted from up to 16 years old post-mortem bloodstained FTA cards. Four random FTA samples from eight time points spanning 1998 to 2013 (n=32) were collected and extracted in triplicate. The quantity and quality of the extracted DNA samples were determined with Quantifiler((r)) Human Plus (HP) Quantification kit. Internal sample and sample to-sample variation were evaluated by comparing recovered DNA yields. The DNA from the triplicate samplings were subsequently combined and normalized for further analysis. The practical effect of degradation on DNA quality was evaluated from normalized samples both with forensic and pharmacogenetic target markers. Our results suggest that (1) a PM change, e.g. blood clotting prior to sampling, affects the recovered DNA yield, creating both internal and sample-to sample variation; (2) a negative correlation between the FTA card storage time and DNA quantity (r=-0.836 at the 0.01 level) was observed; (3) a positive correlation (r=0.738 at the level 0.01) was found between FTA card storage time and degradation levels. However, no inhibition was observed with the method used. The effect of degradation was manifested clearly with functional applications. Although complete STR-profiles were obtained for all samples, there was evidence of degradation manifested as decreased peak heights in the larger-sized amplicons. Lower amplification success was notable with the large 5.1 kb CYP2D6 gene fragment which strongly supports degradation of the stored samples. According to our results, DNA stored on FTA cards is rather stable over a long time period. DNA extracted from this storage medium can be used as human identification purposes as the method used is sufficiently sensitive and amplicon sizes tend to be <400 bp. However, DNA integrity was affected during storage. This effect should be taken into account depending on the intended application especially if high quality DNA and long PCR amplicons are required. PMID- 26937858 TI - Beneficial Effects of Early Enteral Nutrition After Major Rectal Surgery: A Possible Role for Conditionally Essential Amino Acids? Results of a Randomized Clinical Trial. AB - OBJECTIVES: To investigate direct postoperative outcome and plasma amino acid concentrations in a study comparing early enteral nutrition versus early parenteral nutrition after major rectal surgery. Previously, it was shown that a low plasma glutamine concentration represents poor prognosis in ICU patients. DESIGN: A preplanned substudy of a previous prospective, randomized, open-label, single-centre study, comparing early enteral nutrition versus early parenteral nutrition in patients at high risk of postoperative ileus after surgery for locally advanced or locally recurrent rectal cancer. Early enteral nutrition reduced postoperative ileus, anastomotic leakage, and hospital stay. SETTING: Tertiary referral centre for locally advanced and recurrent rectal cancer. PATIENTS: A total of 123 patients with locally advanced or recurrent rectal carcinoma requiring major rectal surgery. INTERVENTIONS: Patients were randomized (ALEA web-based external randomization) preoperatively into two groups: early enteral nutrition (early enteral nutrition, intervention) by nasojejunal tube (n = 61) or early parenteral nutrition (early parenteral nutrition, control) by jugular vein catheter (n = 62). Eight hours after the surgical procedure artificial nutrition was started in hemodynamically stable patients, stimulating oral intake in both groups. Blood samples were collected to measure plasma glutamine, citrulline, and arginine concentrations using a validated ultra performance liquid chromatography-tandem mass spectrometric method. MEASUREMENTS AND MAIN RESULTS: Baseline concentrations were comparable for both groups. Directly after rectal surgery, a decrease in plasma amino acids was observed. Plasma glutamine concentrations were higher in the parenteral group than in the enteral group on postoperative day 1 (p = 0.027) and day 5 (p = 0.008). Arginine concentrations were also significantly increased in the parenteral group at day 1 (p < 0.001) and day 5 (p = 0.001). CONCLUSIONS: Lower plasma glutamine and arginine concentrations were measured in the enteral group, whereas a better clinical outcome was observed. We conclude that plasma amino acids do not provide a causal explanation for the observed beneficial effects of early enteral feeding after major rectal surgery. PMID- 26937859 TI - Variations in Case-Mix-Adjusted Duration of Mechanical Ventilation Among ICUs. AB - OBJECTIVES: To develop a model that predicts the duration of mechanical ventilation and then to use this model to compare observed versus expected duration of mechanical ventilation across ICUs. DESIGN: Retrospective cohort analysis. SETTING: Eighty-six eligible ICUs at 48 U.S. hospitals. PATIENTS: ICU patients receiving mechanical ventilation on day 1 (n = 56,336) admitted from January 2013 to September 2014. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We developed and validated a multivariable logistic regression model for predicting duration of mechanical ventilation using ICU day 1 patient characteristics. Mean observed minus expected duration of mechanical ventilation was then obtained across patients and for each ICU. The accuracy of the model was assessed using R. We defined better performing units as ICUs that had an observed minus expected duration of mechanical ventilation less than -0.5 days and a p value of less than 0.01; and poorer performing units as ICUs with an observed minus expected duration of mechanical ventilation greater than +0.5 days and a p value of less than 0.01. The factors accounting for the majority of the model's explanatory power were diagnosis (71%) and physiologic abnormalities (24%). For individual patients, the difference between observed and mean predicted duration of mechanical ventilation was 3.3 hours (95% CI, 2.8-3.9) with R equal to 21.6%. The mean observed minus expected duration of mechanical ventilation across ICUs was 3.8 hours (95% CI, 2.1-5.5), with R equal to 69.9%. Among the 86 ICUs, 66 (76.7%) had an observed mean mechanical ventilation duration that was within 0.5 days of predicted. Five ICUs had significantly (p < 0.01) poorer performance (observed minus expected duration of mechanical ventilation, > 0.5 d) and 14 ICUs significantly (p < 0.01) better performance (observed minus expected duration of mechanical ventilation, < -0.5 d). CONCLUSIONS: Comparison of observed and case mix-adjusted predicted duration of mechanical ventilation can accurately assess and compare duration of mechanical ventilation across ICUs, but cannot accurately predict an individual patient's mechanical ventilation duration. There are substantial differences in duration of mechanical ventilation across ICU and their association with unit practices and processes of care warrants examination. PMID- 26937860 TI - Impact of Proactive Nurse Participation in ICU Family Conferences: A Mixed-Method Study. AB - OBJECTIVES: To investigate family perceptions of having a nurse participating in family conferences and to assess the psychologic well being of the same families after ICU discharge. DESIGN: Mixed-method design with a qualitative study embedded in a single-center randomized study. SETTING: Twelve-bed medical surgical ICU in a 460-bed tertiary hospital. SUBJECTS: One family member for each consecutive patient who received more than 48 hours of mechanical ventilation in the ICU. INTERVENTION: Planned proactive participation of a nurse in family conferences led by a physician. In the control group, conferences were led by a physician without a nurse. MEASUREMENTS AND MAIN RESULTS: Of the 172 eligible family members, 100 (60.2%) were randomized; among them, 88 underwent semistructured interviews at ICU discharge and 86 completed the Peritraumatic Dissociative Experiences Questionnaire at ICU discharge and then the Hospital Anxiety Depression Questionnaire and the Impact of Event Scale (for posttraumatic stress-related symptoms) 3 months later. The intervention and control groups were not significantly different regarding the prevalence of posttraumatic stress related symptoms (52.3 vs 50%, respectively; p = 0.83). Anxiety and depression subscale scores were significantly lower in the intervention group. The qualitative data indicated that the families valued the principle of the conference itself. Perceptions of nurse participation clustered into four main themes: trust that ICU teamwork was effective (50/88; 56.8%), trust that care was centered on the patient (33/88; 37.5%), trust in effective dissemination of information (15/88; 17%), and trust that every effort was made to relieve anxiety in family members (12/88; 13.6%). CONCLUSIONS: Families valued the conferences themselves and valued the proactive participation of a nurse. These positive perceptions were associated with significant anxiety or depression subscale scores but not with changes in posttraumatic stress-related symptoms. PMID- 26937861 TI - Growing Up After Critical Illness: Verbal, Visual-Spatial, and Working Memory Problems in Neonatal Extracorporeal Membrane Oxygenation Survivors. AB - OBJECTIVES: To assess neuropsychologic outcome in 17- and 18-year-old neonatal extracorporeal membrane oxygenation survivors. DESIGN: A prospective longitudinal follow-up study. SETTING: Follow-up program at the Erasmus MC-Sophia Children's Hospital in Rotterdam, The Netherlands. PATIENTS: Thirty adolescents 17 or 18 years old, treated between 1991 and 1997, underwent neuropsychologic assessment. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Attention, memory, executive functioning, visual-spatial functions, social-emotional functioning, and behavior were assessed with validated instruments, and data were compared with reference data. Included predictors for analysis of adverse outcome were diagnosis, age at start extracorporeal membrane oxygenation, convulsions, and use of antiepileptics. Adolescents' performance (expressed as mean [SD] z score) was significantly lower than the norm on short-term and long-term verbal memory (z score = -1.40 [1.58], p = 0.016; z score = -1.54 [1.67], p = 0.010, respectively), visual-spatial memory (z score = -1.65 [1.37], p = 0.008; z score = -1.70 [1.23], p = 0.008, respectively), and working memory (32% vs 9% in the norm population). Parents reported more problems for their children regarding organization of materials (z score = -0.60 [0.90]; p = 0.03) and behavior evaluation (z score = -0.53 [0.88]; p = 0.05) on a questionnaire. Patients reported more withdrawn/depressed behavior (z score = -0.47 [0.54]; p = 0.02), somatic complaints (z score = -0.43 [0.48]; p = 0.03), and social problems (z score = -0.41 [0.46]; p = 0.04). Patients reported more positive feelings of self esteem and an average health status. CONCLUSIONS: Adolescents treated with neonatal extracorporeal membrane oxygenation are at risk of verbal, visual spatial, and working memory problems. Future research should focus on 1) the longitudinal outcome of specific neuropsychologic skills in adolescence and adulthood; 2) identifying risk factors of neuropsychologic dysfunction; 3) evaluating to what extent "severity of illness" is responsible for acquired brain injury; and 4) effects of timely cognitive rehabilitation. PMID- 26937862 TI - Evaluation of Noninvasive Hemoglobin Monitoring in Surgical Critical Care Patients. AB - OBJECTIVE: To assess the clinical utility of noninvasive hemoglobin monitoring based on pulse cooximetry in the ICU setting. DESIGN AND SETTING: A total of 358 surgical patients from a large urban, academic hospital had the noninvasive hemoglobin monitoring pulse cooximeter placed at admission to the ICU. Core and stat laboratory hemoglobin measurements were taken at the discretion of the clinicians, who were blinded to noninvasive hemoglobin monitoring values. MEASUREMENT AND MAIN RESULTS: There was a poor correlation between the 2,465 time matched noninvasive hemoglobin monitoring and laboratory hemoglobin measurements (r = 0.29). Bland-Altman analysis showed a positive bias of 1.0 g/dL and limits of agreement of -2.5 to 4.6 g/dL. Accuracy was best at laboratory values of 10.5 14.5 g/dL and least at laboratory values of 6.5-8 g/dL. At hemoglobin values that would ordinarily identify a patient as requiring a transfusion (< 8 g/dL), noninvasive hemoglobin monitoring consistently overestimated the patient's true hemoglobin. When sequential laboratory values declined below 8 g/dL (n = 102) and 7 g/dL (n = 13), the sensitivity and specificity of noninvasive hemoglobin monitoring at identifying these events were 27% and 7%, respectively. At a threshold of 8 g/dL, continuous noninvasive hemoglobin monitoring values reached the threshold before the labs in 45 of 102 instances (44%) and at 7 g/dL, noninvasive hemoglobin monitoring did so in three of 13 instances (23%). Noninvasive hemoglobin monitoring minus laboratory hemoglobin differences showed an intraclass correlation coefficient of 0.47 within individual patients. Longer length of stay and higher All Patient Refined Diagnostic-Related Groups severity of illness were associated with poor noninvasive hemoglobin monitoring accuracy. CONCLUSIONS: Although noninvasive hemoglobin monitoring technology holds promise, it is not yet an acceptable substitute for laboratory hemoglobin measurements. Noninvasive hemoglobin monitoring performs most poorly in the lower hemoglobin ranges that include commonly used transfusion trigger thresholds and is not consistent within individual patients. Further refinement of the signal acquisition and analysis algorithms and clinical reevaluation are needed. PMID- 26937863 TI - Transfusion of 35-Day Stored RBCs in the Presence of Endotoxemia Does Not Result in Lung Injury in Humans. AB - OBJECTIVE: Transfusion-related acute lung injury is the leading cause of transfusion-related mortality. Preclinical studies have shown that aged RBCs can induce transfusion-related acute lung injury in the presence of a "first hit" (e.g., sepsis). Clinical studies, however, show conflicting results on this matter. We tested whether maximally stored RBCs are able to induce lung injury in the presence of a "first hit" in humans (Dutch Trial Register: NTR4455). DESIGN: Open-label, randomized controlled trial. PATIENTS: Healthy male volunteers. INTERVENTIONS: Eighteen healthy male volunteers donated one unit of autologous RBCs 2 or 35 days before the experiment. The experiment was started by infusion of 2 ng/kg lipopolysaccharide ("first hit"). After 2 hours, volunteers received normal saline (n = 6), 2-day stored transfusion (n = 6), or 35-day stored transfusion (n = 6) ("second hit"). Blood was sampled hourly. Six hours after transfusion, the diffusion capacity of the lungs for carbon monoxide was tested and volunteers underwent spirometry, chest x-ray study, and a bronchoalveolar lavage. MEASUREMENTS AND MAIN RESULTS: All volunteers fulfilled sepsis criteria after lipopolysaccharide injection. The stored blood transfusion did not result in significant changes in either hemodynamic or respiratory variables compared with the control groups. Furthermore, chest x-rays, lung function, and PaO2/FIO2 ratios did not differ between groups. Transfusion of stored autologous RBCs did not result in an increased level of protein in the lungs or neutrophil influx. CONCLUSIONS: Transfusion of 35-day stored autologous RBCs in the presence of endotoxemia does not result in lung injury in humans. PMID- 26937864 TI - Thirty day postoperative outcomes following anterior lumbar interbody fusion using the National Surgical Quality Improvement Program database. AB - OBJECTIVE: Anterior lumbar interbody fusion (ALIF) is a common procedure used to treat various lumbar degenerative pathologies. The purpose of this study is to describe 30-day postoperative outcomes following ALIF on a national scale. METHODS: The American College of Surgeons National Surgery Quality Improvement Program (ACS NSQIP) was searched for ALIF patients between 2005 and 2011. The top preoperative diagnoses were determined using ICD-9 codes. All available 30-day complications were grouped as overall composite morbidity and were compared between preoperative diagnosis groups by univariable and multivariable analyses. RESULTS: There were a total of 1352 ALIF patients. Overall, 6.73% of patients experienced a postoperative complication. Unplanned reoperations (2.48%), urinary tract infection (1.55%), superficial surgical site infection (1.41%), and sepsis (1.11%) were the most common morbidity events. The morbidity rates for each sub group were: intervertebral disc degeneration (4.41%), spondylosis (6.72%), lumbosacral spinal stenosis(8.21%), and spondylolisthesis (8.41%). After extensive adjustment for patient characteristics and preoperative morbidities, multivariable analysis revealed spondylolisthesis (OR=3.29; 95% CI:1.04-10.46) and spinal stenosis (OR=3.76; 95% CI:1.33-10.63) to be associated with significantly higher overall morbidity odds when compared with lumbar disc degeneration. Lumbosacral spondylosis was associated with similar outcomes as degenerative disc disease (OR =1.70; 95% CI:0.48-6.06). CONCLUSIONS: Diverse postoperative complications need to be managed following ALIF. Patients with spondylolisthesis and spinal stenosis may carry increased 30-day postoperative morbidity profiles in ALIF when compared to those with degenerative disc disease. Prospective studies are needed to better delineate the outcomes of ALIF procedures, particularly in the spondylolisthesis and spinal stenosis patient populations. PMID- 26937865 TI - The Expression of Neuropilin-1 in Human Placentas From Normal and Preeclamptic Pregnancies. AB - Preeclampsia (PET) is a hypertensive disorder that affects 2% to 8% of pregnant women. Recent observations support the hypothesis that upregulation of placental anti-angiogenic factors are responsible for the clinical manifestations of the disease. Neuropilin-1 (NP-1) is a transmembrane protein that acts as a coreceptor for vascular endothelial growth factor and as a regulatory protein in the immune system. The aim of the study was to evaluate the expression of NP-1 in PET and normal placentas. Nineteen placental specimens from severe PET pregnancies were compared with 20 placental specimens of women with low-risk pregnancy. All the specimens underwent immunohistochemical staining with anti-human NP-1 antibody. The degree of NP-1 staining was measured both for intensity and extent. Our study demonstrated NP-1 immunoreactivity mainly in the decidual cells, the intermediate trophoblast, and the syncytiotrophoblast, particularly in the areas in the syncytial knots and shed particles. The particles were strongly NP-1 immunoreactive. The expression of NP-1 in the syncytiotrophoblast was lower in placentas of PET compared with control (P=0.017). Shedding of syncytiotrophoblast particles from placenta to maternal blood occurs in normal pregnancies and is enhanced during PET and contributes to the maternal vascular injury that characterizes PET. Our new observation that shows strong NP-1 immunoreactivity of these particles, and decreased NP1 expression in syncytiotrophoblast of PET placentas in comparison to the control group, may imply a role of NP-1 in PET. PMID- 26937866 TI - Intestinal-Type Adenocarcinoma Arising in a Mature Cystic Teratoma of the Ovary. AB - Here, we present a rare case of intestinal type adenocarcinoma arising in mature cystic teratoma (MCT) and review all previously reported similar cases with emphasis on the immunohistochemical characteristics of prior cases. Nine prior cases of intestinal type adenocarcinoma arising in MCT have been previously reported. Two of the prior cases as well as this case have been associated with CA19-9 elevation. CK20 is consistently strongly positive and CK7 is usually negative in cases of intestinal type adenocarcinoma arising in MCT. This contrasts with mucinous tumors of the ovary which are known to be usually CK7 strongly positive and inconsistently CK20 positive. The pattern of strong CK20 staining and often negative or weak CK7 staining is common to mucinous neoplasms arising in MCT. These findings suggest that the less common subset of primary mucinous ovarian tumors that have strong CK20 staining and partial or negative CK7 staining may represent a group of tumors with germ cell origin rather than the more common surface epithelial origin. PMID- 26937868 TI - Lab-scale thermal analysis of electronic waste plastics. AB - In this work, we experimentally revealed the thermochemical decomposition pathway of Decabromodiphenyl ethane (DBDPE) and tetrabromobisphenol A (TBBPA) containing electronic waste plastics using an online thermogravimetric-fourier transform infrared-mass spectroscopy (TG-FTIR-MS) system, a high resolution gas chromatography/high resolution mass (HRGC-MS) spectroscopy, and a fixed-bed reactor. We found the distribution and species of produced bromides can be easily controlled by adjusting pyrolytic temperature, which is particularly crucial to their recycle. From the analysis of the liquid and solid phase obtained from the fixed-bed reactor, we proposed that the Br radicals formed during the pyrolysis process may be captured by organic species derived from the depolymerization of plastics to form brominated compounds or by the inorganic species in the plastics, and that these species remained in the char residue after pyrolysis. Our work for the first time demonstrates intramolecular oxygen atoms play a pivotal role in the formation of PBDD/Fs that pyrolysis of oxygen-free BFRs is PBDD/Fs-free, whereas pyrolysis of oxygen-containing BFRs is PBDD/Fs-reduced. PMID- 26937867 TI - Elevated urinary levels of carcinogenic N-nitrosamines in patients with urinary tract infections measured by isotope dilution online SPE LC-MS/MS. AB - N-nitrosamines (NAms) are well-documented for their carcinogenic potential. Human exposure to NAms may arise from the daily environment and endogenous formation via the reaction of secondary amines with nitrites or from bacteria infection. We describe the use of isotope dilution online solid-phase extraction (SPE) LC-MS/MS to quantify nine NAms in human urine. This method was validated and further applied to healthy subjects and patients with urinary tract infection (UTI). N nitrosodimethylamine (NDMA), N-nitrosomethylethylamine (NMEA), N nitrosopyrrolidine (NPYR) and N-nitrosomorpholine (NMOR) were analyzed with an APCI source, while N-nitrosodiethylamine (NDEA), N-nitrosopiperidine (NPIP), N nitrosodi-n-propylamine (NDPA), N-nitrosodibutylamine (NDBA) and N nitrosodiphenylamine (NDPhA) were quantified with an ESI source, due to their effect on the sensitivity and chromatography. NDMA was the most abundant N nitrosamine, while NDPhA was firstly identified in human. UTI patients had three to twelve-fold higher concentrations for NDMA, NPIP, NDEA, NMOR and NDBA in urine than healthy subjects, and the NAms were significantly decreased after antibiotics treatment. NDMA concentrations were also significantly correlated with the pH value, leukocyte esterase activity or nitrite in urines of UTI patients. Our findings by online SPE LC-MS/MS method evidenced that UTI patients experienced various NAms exposures, especially the potent carcinogen NDMA, which was likely induced by bacteria infection. PMID- 26937869 TI - Microwave-induced carbon nanotubes catalytic degradation of organic pollutants in aqueous solution. AB - In this study, a new catalytic degradation technology using microwave induced carbon nanotubes (MW/CNTs) was proposed and applied in the treatment of organic pollutants in aqueous solution. The catalytic activity of three CNTs of 10-20nm, 20-40nm, and 40-60nm diameters were compared. The results showed that organic pollutants such as methyl orange (MO), methyl parathion (MP), sodium dodecyl benzene sulfonate (SDBS), bisphenol A (BPA), and methylene blue (MB) in aqueous solution could be degraded effectively and rapidly in MW/CNTs system. CNTs with diameter of 10-20nm exhibited the highest catalytic activity of the three CNTs under MW irradiation. Further, complete degradation was obtained using 10-20nm CNTs within 7.0min irradiation when 25mL MO solution (25mg/L), 1.2g/L catalyst dose, 450W, 2450MHz, and pH=6.0 were applied. The rate constants (k) for the degradation of SDBS, MB, MP, MO and BPA using 10-20nm CNTs/MW system were 0.726, 0.679, 0.463, 0.334 and 0.168min(-1), respectively. Therefore, this technology may have potential application for the treatment of targeted organic pollutants in wastewaters. PMID- 26937870 TI - Adsorption behavior and mechanism of chloramphenicols, sulfonamides, and non antibiotic pharmaceuticals on multi-walled carbon nanotubes. AB - The adsorption behavior of different emerging contaminants (3 chloramphenicols, 7 sulfonamides, and 3 non-antibiotic pharmaceuticals) on five types of multi-walled carbon nanotubes (MWCNTs), and the underlying factors were studied. Adsorption equilibriums were reached within 12h for all compounds, and well fitted by the Freundlich isotherm model. The adsorption affinity of pharmaceuticals was positively related to the specific surface area of MWCNTs. The solution pH was an important parameter of pharmaceutical adsorption on MWCNTs, due to its impacts on the chemical speciation of pharmaceuticals and the surface electrical property of MWCNTs. The adsorption of ionizable pharmaceuticals decreased in varying degrees with the increased ionic strength. MWCNT-10 was found to be the strongest adsorbent in this study, and the Freundlich constant (KF) values were 353 2814mmol(1-n)L(n)/kg, 571-618mmol(1-n)L(n)/kg, and 317-1522mmol(1-n)L(n)/kg for sulfonamides, chloramphenicols, and non-antibiotic pharmaceuticals, respectively. The different adsorption affinity of sulfonamides might contribute to the different hydrophobic of heterocyclic substituents, while chloramphenicols adsorption was affected by the charge distribution in aromatic rings via substituent effects. PMID- 26937871 TI - Toxicity of graphene oxide on growth and metabolism of Pseudomonas putida. AB - The increasing consumption of graphene derivatives leads to greater presence of these materials in wastewater treatment plants and ecological systems. The toxicity effect of graphene oxide (GO) on the microbial functions involved in the biological wastewater treatment process is studied, using Pseudomonas putida and salicylic acid (SA) as bacterial and pollutant models. A multiparametric flow cytometry (FC) method has been developed to measure the metabolic activity and viability of P. putida in contact with GO. A continuous reduction in the percentages of viable cells and a slight increase, lower than 5%, in the percentages of damaged and dead cells, suggest that P. putida in contact with GO loses the membrane integrity but preserves metabolic activity. The growth of P. putida was strongly inhibited by GO, since 0.05mgmL(-1) of GO reduced the maximum growth by a third, and the inhibition was considerably greater for GO concentrations higher than 0.1mgmL(-1). The specific SA removal rate decreased with GO concentration up to 0.1mgmL(-1) indicating that while GO always reduces the growth of P. putida, for concentrations higher than 0.1mgmL(-1), it also reduces its activity. Similar behaviour is observed using simulated urban and industrial wastewaters, the observed effects being more acute in the industrial wastewaters. PMID- 26937872 TI - Vaccines for preventing herpes zoster in older adults. AB - BACKGROUND: Herpes zoster, also known as 'shingles', is a neurocutaneous disease characterised by the reactivation of the latent varicella zoster virus (VZV), the virus that causes chickenpox when immunity to VZV declines. It is an extremely painful condition that can last many weeks or months and it can significantly compromise the quality of life of affected individuals. The natural process of aging is associated with a reduction in cellular immunity and this predisposes older people to herpes zoster. Vaccination with an attenuated form of VZV activates specific T cell production avoiding viral reactivation. The Food and Drug Administration has approved a herpes zoster vaccine with an attenuated active virus for clinical use among older adults, which has been tested in large populations. A new adjuvanted recombinant VZV subunit zoster vaccine has also been tested. It consists of recombinant VZV glycoprotein E and a liposome-based AS01B adjuvant system. This new vaccine is not yet available for clinical use. OBJECTIVES: To evaluate the effectiveness and safety of vaccination for preventing herpes zoster in older adults. SEARCH METHODS: For this 2015 update, we searched the Cochrane Central Register of Controlled Trials (CENTRAL 2015, Issue 9), MEDLINE (1948 to the 3rd week of October 2015), EMBASE (2010 to October 2015), CINAHL (1981 to October 2015) and LILACS (1982 to October 2015). SELECTION CRITERIA: Randomised controlled trials (RCTs) or quasi-RCTs comparing zoster vaccine with placebo or no vaccine, to prevent herpes zoster in older adults (mean age > 60 years). DATA COLLECTION AND ANALYSIS: Two review authors independently collected and analysed data using a data extraction form. They also performed 'Risk of bias' assessment. MAIN RESULTS: We identified 13 studies involving 69,916 participants. The largest study included 38,546 participants. All studies were conducted in high-income countries and included only healthy Caucasian individuals >= 60 years of age without immunosuppressive comorbidities. Ten studies used live attenuated varicella zoster virus (VZV) vaccines. Three studies tested a new type of vaccine not yet available for clinical use. We judged five of the included studies to be at low risk of bias.The incidence of herpes zoster, at up to three years of follow-up, was lower in participants who received the vaccine than in those who received a placebo: risk ratio (RR) 0.49; 95% confidence interval (CI) 0.43 to 0.56, risk difference (RD) 2%, number needed to treat to benefit (NNTB) 50; GRADE: moderate quality evidence. The vaccinated group had a higher incidence of mild to moderate intensity adverse events. These date came from one large study that included 38,546 people aged 60 years or older.A study including 8122 participants compared the new vaccine (not yet available) to the placebo; the group that received the new vaccine had a lower incidence of herpes zoster at 3.2 years of follow-up: RR 0.04, 95% CI 0.02 to 0.10, RD 3%, NNTB 33; GRADE: moderate quality evidence. The vaccinated group had a higher incidence of adverse events but most them were of mild to moderate intensity.All studies received funding from the pharmaceutical industry. AUTHORS' CONCLUSIONS: Herpes zoster vaccine is effective in preventing herpes zoster disease and this protection can last three years. In general, zoster vaccine is well tolerated; it produces few systemic adverse events and injection site adverse events of mild to moderate intensity.There are studies of a new vaccine (with a VZV glycoproteic fraction plus adjuvant), which is currently not yet available for clinical use. PMID- 26937874 TI - Looking Toward Improving the Journal. AB - The sine qua non that underlies the success of any publication is the extent to which it satisfies an expectation that it contains articles of interest to readers. With the exception of the production of occasional issues on special topics, the Journal of Allied Health does not solicit articles. Instead of a top down approach that always can be at risk of lacking awareness of the emergence of important new developments in the health care arena, a bottom-up approach provides a reasonable degree of assurance that some novel ideas of considerable interest will appear at regular intervals. Nevertheless, there is value in entertaining suggestions regarding the kinds of manuscripts that will appeal to readers. PMID- 26937873 TI - Combating cough. PMID- 26937875 TI - Inter-rater Agreement on Final Competency Testing Utilizing Standardized Patients. AB - The purpose of this study was to determine whether licensed physical therapists (n=8) serving as standardized patients (SPs) for practical examinations evaluate physical therapy students (n=51) equivalently to the physical therapy course instructor (n=1). METHODS: The SPs completed the same assessment based on the evaluation criteria as did the instructor. The scores for the practical examination, answers to three questions, and the documentation note were summarized separately for the SP and the instructor by means and standard deviations. A paired t-test and an intraclass correlation coefficient (ICC) for each aspect of the score were calculated. ICC(1,1) values were reported along with corresponding 95% confidence intervals. RESULTS: The instructor had significantly higher scores for the practical exam and the overall score compared to the ratings from the SPs. No differences were observed between the instructor and SP scores on the three answers to the questions and documentation note scores. CONCLUSIONS: Based on the ICC values identified in this study, a physical therapist serving as an SP may not be an adequate replacement for an instructor when it comes to grading physical therapy students on all aspects of their competency tests. PMID- 26937876 TI - Developing Agentic Learners for 21st Century Practice: A Pedagogic Approach in Occupational Therapy. AB - In this paper, an approach to teaching occupational therapy students how to create orthoses, whilst at the same time developing higher-order critical thinking, reflective, and clinical reasoning skills is described. The scaffolded nature of the learning activities, incorporating Kolb's reflective learning cycle, was used to support students' capacity for clinical reasoning and better prepare them for clinical placement. The peer-assessment element was also designed to support the experiential learning by allowing students to test their evaluation of hand orthoses, compare their assessment with an expert's, and identify areas for improvement. Students who demonstrated higher grades for the written reflection assessment showed better agreement with the experts (smaller bias, p<0.01). This study concluded there was a correlation between students' capacity for reflective thinking and the development of clinical reasoning. Furthermore, the reflective writing exercise encouraged students to generalise their skills beyond the classroom. The approach and findings of this study are relevant to a range of allied health professions through providing a process to support the development of higher-order critical thinking, reflection, and reasoning skills. Furthermore, the study provides an evidence base to demonstrate that higher reflective skill capacity and critical thinking are crucial to creating agentic learners. PMID- 26937877 TI - Validation of a New Tool to Measure Physiotherapists' Interprofessional Practices. AB - Interprofessional collaboration is recommended in health systems everywhere, but research on its measurement is needed. This psychometric study assessed the construct validity, internal consistency, and test-retest reliability of the Intensity of Interprofessional Practices Questionnaire for Private-Sector Physiotherapists (IIPQ-PT). A random sample of 303 physiotherapists (PTs) completed the 12-item questionnaire, and a subsample of 103 completed it a second time 2 weeks later. Exploratory factor analyses revealed a one-factor solution for the instrument. IIPQ-PT scores showed respectively fair and moderate relationships with the percentage of low back pain clients for whom PTs reported interactions with other professionals (0.30; 95% CI 0.19-0.40; p<0.001) and perceived degree of interactions (0.58; 95% CI 0.50-0.65; p<0.001). The IIPQ-PT had high internal consistency (Cronbach's a= 0.86; 95% CI 0.83-0.88) and good test-retest reliability (ICC=0.69; 95% CI 0.57-0.78). The minimum detectable difference for a 95% CI was 2.52. Although further study of this instrument is warranted, our results are promising for its future use. The IIPQ-PT may prove useful to evaluate the effectiveness of interventions aiming to improve interprofessional practices and to measure the effects of such practices on service users, providers, and the health system. PMID- 26937878 TI - Exploring Students' Perceptions of the Educational Value of Formative Objective Structured Clinical Examination (OSCE) in a Nutrition Program. AB - INTRODUCTION: Objective Structured Clinical Examinations (OSCEs) are valuable teaching tools in various disciplines including nutrition. OSCEs increase students' confidence, improve their communication and counseling skills, and can predict clinical strength and identify weaknesses prior to clinical placement. This study explored the impact of three OSCE experiences with nutrition students and evaluated the use of this type of formative assessment. METHODS: Eleven female students with mean age 27.5+/-7.0 yrs enrolled in a medical nutrition therapy course completed three focus groups, ranging from 2 to 6 participants each, after the completion of three OSCE sessions. DATA ANALYSIS: Two independent reviewers used interpretative phenomenological analysis to analyze verbatim transcriptions. RESULTS: Five themes emerged: bridge to clinical practice, a comprehensive learning tool, realistic experience, student challenges, and curriculum considerations. CONCLUSION: OSCE is an accepted tool by nutrition students and provides a memorable comprehensive learning experience. Students found OSCEs to be more realistic and authentic than hospital visits, and the interprofessional activities made the experience more holistic. The lack of preparation was the most challenging part of OSCE. The OSCE improved students' confidence and bridged the gap to clinical placement, and students recommended to continue using it as part of the curriculum. PMID- 26937879 TI - Do Differences in Programmatic Resource Investments Result in Different 3-Year Pass Rates on the U.S. National Physical Therapy Examination? AB - PURPOSE: The rising cost of health professions education is well documented and a growing concern among educators; however, little is known about the implications of resource investment on student success. The objective of this study was to determine whether programs with higher National Physical Therapist Exam (NPTE) pass rates invested significantly more on programmatic resources. METHODS: This observational study used data from the Commission on Accreditation in Physical Therapy Education's (CAPTE) Annual Accreditation Report including all accredited physical therapist programs from the United States who graduated physical therapist students in 2011. Resource expenditures were recorded as both raw and as an index variable (resources per student). Descriptive statistics and comparisons (using chi-square and t-tests) among programs with <100% and 100% pass rates were analyzed from 2009-2011. An ANCOVA was used to determine differences in raw resource expenditures and resource expenditures per student. RESULTS: There were no differences in raw resource expenditures between programs with <100% and 100% pass rates. Programs with 100% pass rates were provided more resource expenditures per student for personnel, overall budget, and core faculty. CONCLUSIONS: The results of this study suggest programs with 100% pass rates invested significantly more per student for selected resources. PMID- 26937880 TI - Effect of Physical Therapy Students' Clinical Experiences on Clinician Productivity. AB - BACKGROUND: Physical therapy clinical education experiences (CEEs) are difficult to secure, particularly first-level CEEs. Our purpose was to determine 1) what impact student full-time CEEs have on PT clinician productivity and 2) whether there is a productivity difference between first vs final CEEs. METHODS: Productivity logs, including possible factors impacting productivity, were distributed to clinician-student pairings on first and final CEEs. Two-week baseline data (without a student) were compared to weeks 1 and 6 (with a student) for 31 logs using a 2x4 repeated-measures ANOVA. In a subset of 17 logs for CEEs 8 weeks or longer, a 2x5 repeated-measures ANOVA was performed. RESULTS: There was a significant increase in the number of patients seen and CPT units billed by both levels of CEEs comparing weeks 1 and 6. In the subset of CEEs, 8 weeks or longer, there was a significant increase in the number of patients treated per hour at week 6 and a trend toward a change at week 8 when compared to baseline week A. The factors selected as impacting productivity were census (59%) and staffing (32%). CONCLUSION: Physical therapy clinician-student pairings showed an overall increase in productivity during both full-time first and final level CEEs. PMID- 26937881 TI - An Evidence-Based Approach to Influencing Evidence-Based Practice in Allied Health. AB - BACKGROUND: Factors affecting the evidence-based practice (EBP) capabilities of allied health staff are complex and are linked with institutional barriers, personal self-belief, and individual experience and ability. This study's aim was to measure the effect of training and organisational change on EBP measures among allied health staff. METHODS: Sixty-three percent of allied health hospital staff (201/303) completed an online survey measuring constructs of EBP. Results were compared to those from the same survey conducted in the previous year, with a response rate of 72.2% (182/252). Eighty staff completed the survey at both time points. Independent and repeated measures ANOVAs were used to compare levels of self-efficacy, outcome expectancy, knowledge, and use, according to discipline over time. RESULTS: A significant increase in EBP self-efficacy was observed over time (p=0.03), as well as amongst staff who completed the survey at both time points (p=0.013). Significant differences existed between professions at time 2 in EBP-outcome expectancy (p=0.002) and EBP use (p=0.016). CONCLUSIONS: Targeted within-department and general allied health workplace evidence-based interventions to improve EBP constructs have been effective at improving overall allied health EBP self-efficacy. Different departments have demonstrated individual improvements in EBP scores, potentially reflecting different training and organisational strategies implemented across departments. PMID- 26937882 TI - Jefferson Teamwork Observation Guide (JTOG): An Instrument to Observe Teamwork Behaviors. AB - Interprofessional education (IPE) is becoming an integral part of the education of health professions students. However, teaching students to become successful members of interprofessional teams is complex, and it is important for students to learn the combinations of skills necessary for teams to function effectively. There are many instruments available to measure many features related to IPE. However, these instruments are often too cumbersome to use in an observational situation since they tend to be lengthy and contain many abstract characteristics that are difficult to identify. The Jefferson Teamwork Observation Guide (JTOG) is a short tool that was created for students early in their educational program to observe teams in action with a set of guidelines to help them focus their observation on behaviors indicative of good teamwork. The JTOG was developed over a 2-year period based on student and clinician feedback and the input of experts in IPE. While initially developed as a purely educational tool for prelicensure students, it is becoming clear that it is an easy-to-use instrument that assesses the behavior of clinicians in practice. PMID- 26937883 TI - Frequency and Confidence of Healthcare Practitioners in Encountering and Addressing Nutrition-Related Issues. AB - OBJECTIVE: Identify the frequency of nutrition issues encountered by healthcare professionals and their confidence in addressing these issues. METHODS: A survey designed to assess the frequency and type of nutrition issues most often encountered in practice of a variety of healthcare professionals and the practitioners' confidence in addressing nutrition issues was developed and distributed to 5,729 graduates from an academic medical center. Descriptive statistics were calculated for all variables. Logistic regression models were used to find predictors of confidence. RESULTS: The final response rate was 17.2% (n=987). The most common nutrition-related problems encountered included obesity (43.8%), diabetes mellitus (43%), and cardiovascular disease (37.1%). Nutrition issues were encountered daily or weekly by 70.5% of healthcare providers, but only 24.8% felt "very confident" in addressing nutrition issues. Significant predictors of confidence included number of years working, more frequent nutrition-related encounters, and nutrition education in professional programs. CONCLUSION: Healthcare practitioners encounter nutrition issues frequently in practice and often do not have a high level of confidence in addressing these issues. PMID- 26937884 TI - Examiner Fatigue and Ability to Concentrate in Objective Structured Clinical Examinations for Physical Therapist Students. AB - PURPOSE: This study examined the effect of time, method of scoring, and method of recording on examiners' self-perceived fatigue and ability to concentrate, and if those factors have any effect on scoring student performance by the examiners during the administration of an objective structured clinical examination (OSCE). METHODS: Twenty-two clinicians and faculty were recruited to participate as examiners of two OSCEs in this study. The examiners were asked to rate their perceived level of fatigue and ability to concentrate at the end of pre determined blocks of time during two OSCEs using a visual analog scale. Data were analyzed using a mixed-model multi-way ANOVA for repeated measures and paired t tests. RESULTS: In both OSCEs, there was a significant difference over time, with examiner fatigue increasing over time (p<0.05) and the ability to concentrate decreasing over time (p<0.05). In one OSCE, there was a significant difference in student performance scores, with lower performance scores over time (p<0.05). There was a significant difference between paper and electronic recording in fatigue (p>0.009), with paper showing more fatigue than the electronic recording. CONCLUSION: The results of this study demonstrate that fatigue and ability to concentrate are factors to consider when conducting an OSCE. PMID- 26937885 TI - Professionalism in Physician Assistant, Physical Therapist, Occupational Therapist, Clinical Psychology, and Biomedical Sciences Students. AB - Interprofessional collaboration for healthcare requires a better understanding of the commonalities and differences in student perceptions of professionalism. METHODS: 217 students in five programs (PA 71, PT 46, OT 29, CP 12, and BMS 59) completed a 22-item survey (response rate 79.5%). A Likert scale grading from 1 (hardly ever) to 5 (always) was used to assess professional attitudes and behaviors. RESULTS: A mixed-model MANOVA, supplemented with post-hoc analyses, showed significant group by time interactions for 5 items. Sensitivity to differences and diversity of other people increased for BMS students, but decreased for PT students. Timeliness increased for BMS students, but did not change for PA students. Seeking out new learning experiences increased for BMS students, but did not change for PA or PT students. Taking a group leadership role increased for BMS students, decreased for PT students, while PA and OT students showed no change. Volunteering time to serve others decreased for OT and PA students, while BMS and BM students showed no change. CONCLUSION: It is plausible that these findings emerge from differences in program curricula and specific training objectives. The findings provide initial insight to educators on ways that attitudes and behaviors pertaining to professionalism sometimes vary among students in different health science programs. PMID- 26937886 TI - Faculty Perceptions, Knowledge, and Attitudes Toward Interprofessional Education and Practice. AB - As interprofessional education (IPE) is incorporated into health professions programs, it is essential to understand faculty perceptions, knowledge, and attitudes about IPE and interprofessional practice (IPP). A descriptive, cross sectional design was used. Seventy-one faculty from three campuses of two rural public universities representing seven different programs participated. Despite limited IPE experience, faculty appreciated IPE and IPP. Notably, many felt undervalued by other professions. Participants acknowledged the importance of working with other professions (mean 2.69+/-0.53), participating on IP teams (2.61+/-0.52), and integrating IPP in patient care (2.60+/-0.52). Faculty reported low IPE knowledge (1.74+/-0.66) and confidence in IPE teaching ability (1.74+/-0.67). These findings demonstrate a need for faculty development in both IPE and IPP across all health disciplines. PMID- 26937887 TI - Pitfalls in [18F]FDG PET imaging in gynecological malignancies. AB - Gynecologic malignancies are the leading causes of cancer in women and they represent about 10 to 20% of all solid tumors. During the past few decades, technological advancements in the detection and staging have gained a pivotal role in all oncological processes, including the gynecological ones. Beyond ultrasound, computed tomography (CT) and magnetic resonance (MR) imaging that are conventionally used for anatomical imaging, [18F]FDG imaging and its hybrid further development as PET/CT has become a crucial tool due of its ability to combine functional metabolic and anatomic information, and the ability to image the entire whole body in a single examination. Since the introduction of integrated hybrid PET/CT systems into clinical practice the accurate analysis of the images has detected a number of limitations and pitfalls. The purpose of this review was to describe in detail the different pitfalls related to the use of [18F]FDG PET/CT in the gynecological malignancies, providing imaging examples and discussing possible ways to avoid misinterpretations. PMID- 26937888 TI - Community-acquired pneumonia by Legionella pneumophila. Do we need to include new recommendations for inflammatory bowel disease patients under immunomodulators? AB - We present the case of a community-acquired pneumonia by Legionella Pneumophila in a 31-year-old patient with Crohn's disease under anti-TNF agents. Following this and other similar cases reported in literature, we propose to include recommendations to prevent this infection in patients starting treatment with immunosuppressant drugs through simple measures regarding the control of water in the patients' home. PMID- 26937889 TI - Generalized Mechanistic Model for the Chemical Vapor Deposition of 2D Transition Metal Dichalcogenide Monolayers. AB - Transition metal dichalcogenides (TMDs) like molybdenum disulfide (MoS2) and tungsten disulfide (WS2) are layered materials capable of growth to one monolayer thickness via chemical vapor deposition (CVD). Such CVD methods, while powerful, are notoriously difficult to extend across different reactor types and conditions, with subtle variations often confounding reproducibility, particularly for 2D TMD growth. In this work, we formulate the first generalized TMD synthetic theory by constructing a thermodynamic and kinetic growth mechanism linked to CVD reactor parameters that is predictive of specific geometric shape, size, and aspect ratio from triangular to hexagonal growth, depending on specific CVD reactor conditions. We validate our model using experimental data from Wang et al. (Chem. Mater. 2014, 26, 6371-6379) that demonstrate the systemic evolution of MoS2 morphology down the length of a flow CVD reactor where variations in gas phase concentrations can be accurately estimated using a transport model (CSulfur = 9-965 MUmol/m(3); CMoO3 = 15-16 mmol/m(3)) under otherwise isothermal conditions (700 degrees C). A stochastic model which utilizes a site-dependent activation energy barrier based on the intrinsic TMD bond energies and a series of Evans-Polanyi relations leads to remarkable, quantitative agreement with both shape and size evolution along the reactor. The model is shown to extend to the growth of WS2 at 800 degrees C and MoS2 under varied process conditions. Finally, a simplified theory is developed to translate the model into a "kinetic phase diagram" of the growth process. The predictive capability of this model and its extension to other TMD systems promise to significantly increase the controlled synthesis of such materials. PMID- 26937890 TI - [Vegetables as new psychoactive drugs: a narrative review]. AB - There is growing interest in plants with psychoactive effects among consumers with different levels of experience. This has generated a need for updated knowledge among medical professionals and other health workers. These plants, which may be used in shamanic healing ceremonies or rituals or just for traditional purposes, have emerged in the Western world as new psychoactive drugs; largely thanks to the ease of purchase, sale, cultivation and exchange of information that the Internet offers. This review summarizes the current knowledge about the most important psychoactive plants, either by their mention in Internet forums or harm-reduction portals or by their allusion in scientific texts. PMID- 26937891 TI - Nano Liquid Chromatography Directly Coupled to Electron Ionization Mass Spectrometry for Free Fatty Acid Elucidation in Mussel. AB - Recently the miniaturization of liquid chromatography (LC) systems and progresses in mass spectrometry instrumentation have enabled direct introduction of the effluent coming from a nanoLC column into the high-vacuum region of an electron ionization source. In the present research, a nanoLC system was directly coupled to an electron ionization mass spectrometer (EI-MS) without any interface or modification of the ion source. The advantage with respect to atmospheric pressure ionization techniques, normally coupled with LC, is major identification power because of a more extensive and reproducible fragmentation pattern, without any matrix effect or mobile-phase interference. In particular, a nanoLC/EI-MS method was developed for elucidation of the free fatty acid profile in mussel samples, avoiding a previous derivatization step, required when gas chromatographic analysis is involved. A total of 20 fatty acids were reliably identified through the comparison with commercial libraries. A quantitative determination was also carried out by using the response factors approach along with the internal standard method, allowing for quantification of 14 fatty acids. Among them, palmitic acid resulted the most abundant, followed by omega6 arachidonic acid. The quantitative data were compared with those obtained by a well-established technique, such as gas chromatography with flame ionization detection (GC-FID). Both nanoLC/EI-MS and GC-FID methods were validated and similar results were obtained in terms of limit of detection and quantification, resulting in the picomole range, and sensitivity as well was not significantly different, as demonstrated by comparing the slope values of the calibration curves (p < 0.05, from a t-test). PMID- 26937892 TI - Relationship of SELE A561C and G98T Variants With the Susceptibility to CAD. AB - Published genetic association studies have produced controversial results regarding the association of SELE gene polymorphisms (A516C and G98T) and CAD susceptibility. We therefore chose to perform a meta-analysis to determine the association.Twenty-seven eligible articles were identified through electronic databases, providing 5170 CAD cases and 4996 controls. Fixed-effects or random effects summary ORs were calculated to estimate the risk of CAD in relation to A516C and G98T. Forest plots and funnel plots were constructed by Stata software 12.0.A strong association was observed between A516C and susceptibility of CAD among 4757 cases and 4272 controls. The summary OR was greatest in individuals carrying the CC genotype (OR = 1.91, 95% CI, 1.12-3.25). A significantly increased risk was indicated in both Caucasians and Asians. The analyses by disease type showed a significant increase in the risk of AP and MI. We also noted a strong association in population-based studies. In the analyses of G98T, data were available for 1422 cases and 1625 controls. We saw a markedly increased risk of CAD associated with G98T. The highest risk was indicated in individuals with the TT genotype (OR = 2.82, 95% CI, 1.15-6.89). A similar trend was seen in Asians and population-based studies.These findings provide consistent evidence that A516C and G98T polymorphisms of the SELE gene may be associated with increased susceptibility of CAD. PMID- 26937893 TI - Description and Validation of Histological Patterns and Proposal of a Dynamic Model of Inflammatory Infiltration in Giant-cell Arteritis. AB - The extent of inflammatory infiltrates in arteries from patients with giant-cell arteritis (GCA) have been described using different terms and definitions. Studies investigating the relationship between GCA histological features and clinical manifestations have produced controversial results. The aims of this study were to characterize and validate histological patterns in temporal artery biopsies (TABs) from GCA patients, to explore additional histological features, including the coexistence of different patterns, and also to investigate the relationship of the inflammatory patterns with clinical and laboratory features.We performed histological examination of TAB from patients with GCA consecutively diagnosed between 1992 and 2012. Patterns of inflammation were defined according to the extent and distribution of inflammatory infiltrates within the artery. Clinical and laboratory variables were recorded. Two external investigators underwent a focused, one-day training session and then independently scored 77 cases. Quadratic-weighted kappa was calculated.TAB from 285 patients (200 female/85 male) were evaluated. Four histological inflammatory patterns were distinguished: 1 - adventitial (n = 16); 2 - adventitial invasive: adventitial involvement with some extension to the muscular layer (n = 21); 3 - concentric bilayer: adventitial and intimal involvement with media layer preservation (n = 52); and 4 - panarteritic (n = 196). Skip lesions were observed in 10% and coexistence of various patterns in 43%. Raw agreement of each external scorer with the gold-standard was 82% and 77% (55% and 46% agreement expected from chance); kappa = 0.82 (95% confidence interval [CI] 0.70-0.95) and 0.79 (95% CI 0.68-0.91). Although abnormalities on temporal artery palpation and the presence of jaw claudication and scalp tenderness tended to occur more frequently in patients with arteries depicting more extensive inflammation, no statistically significant correlations were found between histological patterns and clinical features or laboratory findings.In conclusion, we have described and validated 4 histological patterns. The presence of different coexisting patterns likely reflects sequential steps in the progression of inflammation and injury. No clear relationship was found between these patterns and clinical or laboratory findings. However, several cranial manifestations tended to occur more often in patients with temporal arteries exhibiting panarteritic inflammation. This validated score system may be useful to standardize stratification of histological severity for immunopathology biomarker studies or correlation with imaging. PMID- 26937894 TI - Systematic Endobronchial Ultrasound-guided Mediastinal Staging Versus Positron Emission Tomography for Comprehensive Mediastinal Staging in NSCLC Before Radical Radiotherapy of Non-small Cell Lung Cancer: A Pilot Study. AB - Despite known limitations of positron emission tomography (PET) for mediastinal staging of non-small cell lung cancer (NSCLC), radiation treatment fields are generally based on PET-identified disease extent. However, no studies have examined the accuracy of FDG-PET/CT on a per-node basis in patients being considered for curative-intent radiotherapy in NSCLC.In a prospective trial, patients with NSCLC being considered for definitive thoracic radiotherapy (+/- systemic chemotherapy) underwent minimally invasive systematic mediastinal evaluation with endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) following noninvasive staging with integrated PET-CT.Thirty patients underwent EBUS-TBNA, with TBNA performed from a mean 2.5 lymph node (LN) stations per patient (median 3, range 1-5). Discordant findings between PET-CT and EBUS TBNA were observed in 10 patients (33%, 95% CI 19%-51%). PET-occult LN metastases were demonstrated by EBUS in 4 patients, whereas a lesser extent of mediastinal involvement, compared with FDG-PET, was demonstrated by EBUS in 6 patients, including 2 patients downstaged from cN3 to pN2. LNs upstaged by EBUS were significantly smaller than nodes downstaged by EBUS, 7.5 mm (range 7-9) versus 12 mm (range 6-21), P = 0.005.A significant proportion of patients considered for definitive radiotherapy (+/-chemotherapy) undergoing systematic mediastinal evaluation with EBUS-TBNA in this study have an extent of mediastinal NSCLC involvement discordant with that indicated by PET-CT. Systematic EBUS-TBNA may aid in defining the extent of mediastinal involvement in NSCLC patients undergoing radiotherapy. Systematic EBUS-TBNA has the potential to contribute significantly to radiotherapy planning and delivery, by either identifying occult nodal metastases, or demonstrating FDG-avid LNs to be disease-free. PMID- 26937895 TI - A Retrospective Study on the Significance of Liver Biopsy and Hepatitis B Surface Antigen in Chronic Hepatitis B Infection. AB - To investigate changes in the HBV replication level along with the natural course of chronic HBV infection and to examine the accuracy of the immune tolerant phase defined by the serological profile.A total of 390 chronic HBV-infected patients were retrospectively recruited for this study. They were classified into immune tolerance (IT), immune-clearance (IC), low-replicative (LR), and HBeAg-negative hepatitis (ENH) phases according to serological profiles (single-standard, SS) or dual-standard (DS) with the inclusion of liver histology. Serum HBV DNA and HBsAg were quantitatively measured, and liver histology was quantitatively analyzed.The accuracy of the SS-defined IT phase was low, and active pathological changes were detected in 56 of 112 SS-defined IT patients. DS-defined IT patients had higher HBsAg levels (P = 0.0002) than the SS-defined patients. The quantitative HBsAg level can help identify SS-defined IT patients with potential liver injury. The area under the received operating characteristic curve for predicting the DS defined IT phase was 0.831 (HBsAg 4.398 log IU/mL; sensitivity 87.5%; specificity 73.2%). HBV DNA was reduced by 4 logs, whereas HBsAg was only decreased by 2 logs with HBeAg positive to negative phase conversion.Approximately half of IT patients defined by SS may have medium or severe liver injury. Quantitative measurement of the HBsAg level can help identify SS-defined IT patients with potential liver injury. PMID- 26937896 TI - Probiotics for Prevention of Atopy and Food Hypersensitivity in Early Childhood: A PRISMA-Compliant Systematic Review and Meta-Analysis of Randomized Controlled Trials. AB - Most studies investigated probiotics on food hypersensitivity, not on oral food challenge confirmed food allergy in children. The authors systematically reviewed the literature to investigate whether probiotic supplementation prenatally and/or postnatally could reduce the risk of atopy and food hypersensitivity in young children.PubMed, Embase, the Cochrane Central Register of Controlled Trials, and 4 main Chinese literature databases (Wan Fang, VIP, China National Knowledge Infrastructure, and SinoMed) were searched for randomized controlled trials regarding the effect of probiotics on the prevention of allergy in children. The last search was conducted on July 11, 2015.Seventeen trials involving 2947 infants were included. The first follow-up studies were analyzed. Pooled analysis indicated that probiotics administered prenatally and postnatally could reduce the risk of atopy (relative risk [RR] 0.78; 95% confidence interval [CI] 0.66 0.92; I = 0%), especially when administered prenatally to pregnant mother and postnatally to child (RR 0.71; 95% CI 0.57-0.89; I = 0%), and the risk of food hypersensitivity (RR 0.77; 95% CI 0.61-0.98; I = 0%). When probiotics were administered either only prenatally or only postnatally, no effects of probiotics on atopy and food hypersensitivity were observed.Probiotics administered prenatally and postnatally appears to be a feasible way to prevent atopy and food hypersensitivity in young children. The long-term effects of probiotics, however, remain to be defined in the follow-up of existing trials. Still, studies on probiotics and confirmed food allergy, rather than surrogate measure of food hypersensitivity, are warranted. PMID- 26937898 TI - Breast-conserving Surgery Rates in Breast Cancer Patients With Different Molecular Subtypes: An Observational Study Based on Surveillance, Epidemiology, and End Results (SEER) Database. AB - This study used the Surveillance, Epidemiology, and End Results database to compare breast-conserving surgery (BCS) rates across patients with different molecular subtypes.We identified female breast cancer patients who were diagnosed between 2010 and 2012 using the Surveillance, Epidemiology, and End Results database. Patients without available critical clinicopathological information were excluded. The chi-square test and logistic regression analysis were used to investigate factors associated with BCS.This study identified 85,415 T1-2N0-3M0 breast cancer patients. Among the patients with HR+/HER2-, HR+/HER2+, HR-/HER2+, and HR-/HER2- diseases, 63.5% (38,823/61,142), 51.2% (4850/9473), 43.2% (1740/4030), and 55.7% (6000/10,770), respectively, received BCS (P < 0.01). Patients with HR-/HER2+ (odds ratio 0.58; 95% confidence interval, 0.54-0.62) disease were significantly less likely to receive BCS than patients with HR+/HER2 disease after adjustment for T-stage, N-stage, age, tumor grade, county type, and race. Differences in BCS rates between the HR+/HER2- and HR-/HER2+ subgroups were 29.1%, 14.0%, 10.1%, 8.5%, and 0.2% in patients with tumor sizes <10 mm, 10 to 20 mm, 20 to 30 mm, 30 to 40 mm, and 40 to 50 mm, respectively. Differences in BCS rates between the HR+/HER2- and HR-/HER2+ subgroups were 20.3% and 5.7% in node-negative and node-positive patients, respectively. BCS rates in patients with grades I, II, and III tumors in the HR+/HER2- and HR-/HER2+ subgroups were 72.2% and 34.6%, 62.7% and 42.3%, and 54.7% and 43.4%, respectively.Our study demonstrated that BCS rates varied significantly across molecular subtypes, especially in patients with lower tumor burden. HR+/HER2- and HR-/HER2+ patients exhibited the highest and lowest BCS rates, respectively. PMID- 26937899 TI - Inverse Relationship Between Helicobacter Pylori Infection and Asthma Among Adults Younger than 40 Years: A Cross-Sectional Study. AB - Recent studies have suggested that Helicobacter pylori could prevent allergic disease, particularly in children. However, whether this is true in adults is controversial. The aim of this study was to investigate whether there is negative association between H. pylori infection and asthma among adults in an area with a high prevalence of H. pylori.This was a cross-sectional study using 2011 health surveillance data. Blood samples were taken from all participants to measure serum H. pylori IgG status. Information on demographics, socioeconomic status, and medical history, including asthma and other allergic conditions were collected by a questionnaire.Of the 15,032 patients, 9492 (63.1%) had a history of H. pylori infection, 359 (2.4%) had asthma, and 3277 (21.8%) had other allergic conditions. H. pylori infection was positively correlated with age (OR, 1.050; 95% CI, 1.047-1.053, P < 0.001). Asthma history was positively correlated with age (OR, 1.022; 95% CI, 1.013-1.032, P < 0.001). H. pylori and age were shown to have interaction on asthma in the total participants (OR, 1.041; 95% CI, 1.021-1.062, P < 0.001). In subgroup analysis, H. pylori infection among those < 40 years old was inversely correlated with asthma (OR, 0.503; 95% CI, 0.280 0.904, P = 0.021). Other allergic conditions were not related with H. pylori infection among the total and those <40 years old.The inverse association between H. pylori infection and asthma among young adults suggests that the underlying immune mechanism induced by H. pylori infection may affect allergic reactions associated with asthma in young adults. PMID- 26937897 TI - Probiotics for Preventing Late-Onset Sepsis in Preterm Neonates: A PRISMA Compliant Systematic Review and Meta-Analysis of Randomized Controlled Trials. AB - The effect of probiotics on late-onset sepsis (LOS) in preterm neonates remains controversial. The authors systematically reviewed the literature to investigate whether enteral probiotic supplementation reduced the risk of LOS in preterm neonates in neonatal intensive care units.PubMed, Embase, and Cochrane Central Register of Controlled Trials were systematically searched for randomized controlled trials (RCTs) regarding the effect of probiotics in preterm neonates. The primary outcome was culture-proven bacterial and/or fungal sepsis. The Mantel Haenszel method with random-effects model was used to calculate pooled relative risks (RRs) and 95% confidence intervals (CIs).Twenty-seven trials were included in our review, and 25 trials involving 6104 preterm neonates were statistically analyzed. Pooled analysis indicated that enteral probiotic supplementation significantly reduced the risk of any sepsis (25 RCTs; RR 0.83, 95% CI 0.73-0.94; I = 26%), bacterial sepsis (11 RCTs; RR 0.82, 95% CI 0.71-0.95; I = 0%), and fungal sepsis (6 RCTs; RR 0.57, 95% CI 0.41-0.78; I = 0%). This beneficial effect remains in very low birth weight infants (<1500 g) (19 RCTs; RR 0.86, 95% CI 0.75 0.97; I = 18%), but not in extremely low birth weight infants (<1000 g) (3 RCTs; RR 0.73, 95% CI 0.45-1.19; I = 53%). All the included trials reported no systemic infection caused by the supplemental probiotic organisms.Current evidence indicates that probiotic supplementation is safe, and effective in reducing the risk of LOS in preterm neonates in neonatal intensive care units. Further studies are needed to address the optimal probiotic organism, dosing, timing, and duration. High-quality and adequately powered RCTs regarding the efficacy and safety of the use of probiotics in extremely low birth weight infants are still warranted. PMID- 26937900 TI - Comparison of the Degree of Exercise Tolerance in Children After Surgical Treatment of Complex Cardiac Defects, Assessed Using Ergospirometry and the Level of Brain Natriuretic Peptide. AB - Children who underwent surgery for complex congenital heart defects present worse exercise capacity than their healthy peers. In adults and adolescents, heart failure is assessed on the basis of clinical symptoms using the New York Heart Association (NYHA) score, while in an infant Ross scale; heart failure can also be evaluated by other parameters. The purpose of this study was to compare the degree of exercise tolerance in children after surgery for complex heart defects, assessed by the ratio of maximum oxygen uptake (VO2max) and the brain natriuretic peptide (N-terminal fragment of the prohormone brain-type natriuretic peptide [NT proBNP]) concentration.The study group consisted of 42 children, ages 9 to 17 years (mean 14.00 +/- 2.72). Among them there were 22 children with tetralogy of Fallot (ToF) after total correction, 18 children with transposition of the great arteries (d-TGA) after the arterial switch operation, and 2 children with single ventricle (SV) after the Fontan operation. All but 1 child were in NYHA class I. The control group consisted of 20 healthy children. Outcomes of interest were the ratio of VO2max, determined during ergospirometry, and the level of NT-proBNP. The statistical analysis was performed and the groups were considered significantly different for P < 0.05.There was no statistically significant correlation between NT-proBNP and maximum oxygen uptake (VO2) kg min in the study group compared with the control group.The VO2max in the test group had a mean value less (34.6 +/- 8.0) than controls (38.4 +/- 7.7), and the differences were statistically significant (P = 0.041). In contrast, the average concentration of NT-proBNP in the study group was higher than controls (117.9 +/- 74.3 vs 18.0 +/- 24.5), and these differences were statistically significant (P < 0.001).After operations for complex heart defects (ToF, TGA, and SV), children have worse heart function parameters and exercise capacity than the healthy population. To control this, we recommend postoperative ergospirometry and determination of NT proBNP concentrations. PMID- 26937901 TI - Malignancy of Cancers and Synthetic Lethal Interactions Associated With Mutations of Cancer Driver Genes. AB - The mutation status of cancer driver genes may correlate with different degrees of malignancy of cancers. The doubling time and multidrug resistance are 2 phenotypes that reflect the degree of malignancy of cancer cells. Because most of cancer driver genes are hard to target, identification of their synthetic lethal partners might be a viable approach to treatment of the cancers with the relevant mutations.The genome-wide screening for synthetic lethal partners is costly and labor intensive. Thus, a computational approach facilitating identification of candidate genes for a focus synthetic lethal RNAi screening will accelerate novel anticancer drug discovery.We used several publicly available cancer cell lines and tumor tissue genomic data in this study.We compared the doubling time and multidrug resistance between the NCI-60 cell lines with mutations in some cancer driver genes and those without the mutations. We identified some candidate synthetic lethal genes to the cancer driver genes APC, KRAS, BRAF, PIK3CA, and TP53 by comparison of their gene phenotype values in cancer cell lines with the relevant mutations and wild-type background. Further, we experimentally validated some of the synthetic lethal relationships we predicted.We reported that mutations in some cancer driver genes mutations in some cancer driver genes such as APC, KRAS, or PIK3CA might correlate with cancer proliferation or drug resistance. We identified 40, 21, 5, 43, and 18 potential synthetic lethal genes to APC, KRAS, BRAF, PIK3CA, and TP53, respectively. We found that some of the potential synthetic lethal genes show significantly higher expression in the cancers with mutations of their synthetic lethal partners and the wild-type counterparts. Further, our experiments confirmed several synthetic lethal relationships that are novel findings by our methods.We experimentally validated a part of the synthetic lethal relationships we predicted. We plan to perform further experiments to validate the other synthetic lethal relationships predicted by this study.Our computational methods achieve to identify candidate synthetic lethal partners to cancer driver genes for further experimental screening with multiple lines of evidences, and therefore contribute to development of anticancer drugs. PMID- 26937902 TI - Evaluation of Intravitreal Ranibizumab on the Surgical Outcome for Diabetic Retinopathy With Tractional Retinal Detachment. AB - This study aims to investigate intravitreal injection of Ranibizumab on the surgical outcome for diabetic patients who had tractional retinal detachment but did not receive any preoperative retinal photocoagulation.Ninety-seven patients (97 eyes) who had diabetic retinopathy with tractional retinal detachment were enrolled to receive 23-G pars plana vitrectomy (PPV). They were assigned to an experimental group (Group I, n = 47 eyes) and a control group (Group II, n = 50 eyes). The patients in Group I were given 1 injection of intravitreal Ranibizumab (Lucentis 0.5 mg/0.05 mL) 1 week before surgery, whereas those in Group II went down to surgery directly. Follow-ups were performed for 6 months to 3 years (16 +/- 6 months), and indicators observed included postoperative best-corrected visual acuity, complications, and retinal thickness in the macula measured by optical coherence tomography.In Group I, BCVA improved from logMAR 1.92 +/- 0.49 to logMAR 0.81 +/- 0.39 following surgery, whereas in Group II, BCVA improved from logMAR 1.91 +/- 0.49 to logMAR 0.85 +/- 0.41. There was significant postoperative gain in vision, but there was no significant difference between the 2 groups at postoperative follow-up visits. The mean duration of vitrectomy in Group I and Group II was (40 +/- 7) minutes and (53 +/- 9) minutes, respectively, with significant difference. Iatrogenic breaks were noted in 5 eyes (11%) in the experimental group and 17 eyes (34%) in the control group; the difference was significant. The retinal thickness in the macula measured by OCT was (256 +/- 44) MUm and (299 +/- 84) MUm in Group I and Group II respectively with significant difference. Besides, there were significantly more eyes in Group II that required silicone oil tamponade and postoperative retinal photocoagulation.23-G PPV combined with intravitreal tamponade and panretinal photocoagulation still remains an effective regimen for the treatment of diabetic retinopathy complicated with tractional retinal detachment. Preoperative intravitreal injection of Ranibizumab could shorten surgical duration, reduce intraoperative complications, and sometimes spare the need for silicone oil tamponade and postoperative retinal photocoagulation, alleviating patients' suffering from surgery. PMID- 26937904 TI - Serum Calcium Increase Correlates With Worsening of Lipid Profile: An Observational Study on a Large Cohort From South Italy. AB - Despite the well-documented role of calcium in cell metabolism, its role in the development of cardiovascular disease is still under heavy debate. Several studies suggest that calcium supplementation might be associated with an increased risk of coronary heart disease, whereas others underline a significant effect on lowering high blood pressure and hyperlipidemia. The purpose of this study was to investigate, in a large nonselected cohort from South Italy, if serum calcium levels correlate with lipid values and can therefore be linked to higher individual cardiovascular risk.Eight-thousand-six-hundred-ten outpatients addressed to the Laboratory of Clinical Biochemistry, University of Magna Graecia, Catanzaro, Italy from January 2012 to December 2013 for routine blood tests, were enrolled in the study. Total HDL-, LDL- and non-HDL colesterol, triglycerides, and calcium were determined with standard methods.We observed a significant association between total cholesterol, LDL-cholesterol, HDL cholesterol, non-HDL cholesterol, triglycerides, and serum calcium in men and postmenopause women. Interestingly, in premenopause women, we only found a direct correlation between serum calcium, total cholesterol, and HDL-cholesterol. Calcium significantly increased while increasing total cholesterol and triglycerides in men and postmenopause women.Our results confirm that progressive increase of serum calcium level correlates with worsening of lipid profile in our study population. Therefore, we suggest that a greater caution should be used in calcium supplement prescription particularly in men and women undergoing menopause, in which an increase of serum lipids is already known to be associated with a higher cardiovascular risk. PMID- 26937903 TI - An Ultra-Deep Targeted Sequencing Gene Panel Improves the Prognostic Stratification of Patients With Advanced Oral Cavity Squamous Cell Carcinoma. AB - An improved prognostic stratification of patients with oral cavity squamous cell carcinoma (OSCC) and pathologically positive (pN+) nodes is urgently needed. Here, we sought to examine whether an ultra-deep targeted sequencing (UDT-Seq) gene panel may improve the prognostic stratification in this patient group.A mutation-based signature affecting 10 genes (including genetic mutations in 6 oncogenes and 4 tumor suppressor genes) was devised to predict disease-free survival (DFS) in 345 primary tumor specimens obtained from pN+ OSCC patients. Of the 345 patients, 144 were extracapsular spread (ECS)-negative and 201 were ECS positive. The 5-year locoregional control, distant metastases, disease-free, disease-specific, and overall survival (OS) rates served as outcome measures.The UDT-Seq panel was an independent risk factor (RF) for 5-year locoregional control (P = 0.0067), distant metastases (P = 0.0001), DFS (P < 0.0001), disease-specific survival (DSS, P < 0.0001), and OS (P = 0.0003) in pN+ OSCC patients. The presence of ECS and pT3-4 disease were also independent RFs for DFS, DSS, and OS. A prognostic scoring system was formulated by summing up the significant covariates (UDT-Seq, ECS, pT3-4) separately for each survival endpoint. The presence of a positive UDT-Seq panel (n = 77) significantly improved risk stratification for all the survival endpoints as compared with traditional AJCC staging (P < 0.0001). Among ECS-negative patients, those with a UDT-Seq-positive panel (n = 31) had significantly worse DFS (P = 0.0005) and DSS (P = 0.0002). Among ECS-positive patients, those with a UDT-Seq-positive panel (n = 46) also had significantly worse DFS (P = 0.0032) and DSS (P = 0.0098).Our UDT-Seq gene panel consisting of clinically actionable genes was significantly associated with patient outcomes and provided better prognostic stratification than traditional AJCC staging. It was also able to predict prognosis in OSCC patients regardless of ECS presence. PMID- 26937905 TI - Disequilibrium of Blood Coagulation and Fibrinolytic System in Patients With Coronary Artery Ectasia. AB - Thrombus formation and myocardial infarction are not uncommon in patients with coronary artery ectasia (CAE). In light of this, the present study aims to systemically evaluate the blood coagulation and fibrinolytic systems in CAE patients. In this study, we enrolled 30 patients with CAE, 30 patients with coronary atherosclerosis disease (CAD), and 29 subjects with normal coronary arteries (control). The coagulation system was evaluated using a routine coagulation function test performed in the hospital laboratory before coronary angiography, and measurements included prothrombin time, international normalized ratio, activated partial thromboplastin time, fibrinogen time, and thrombin time. The evaluation of the fibrinolytic system included measurements of D-dimer, euglobulin lysis time, plasminogen activator inhibitor 1, plasminogen, plasminogen activity assay, alpha1-antitrypsin (alpha1-AT), alpha2 plasmin inhibitor (alpha2-PI), and alpha2-macroglobulin (alpha2-MG). Alpha1-AT, alpha2 PI, and alpha2-MG also inhibit activities of 3 neutrophil serine proteases, namely human neutrophil elastase (HNE), cathepsin G (CG), and proteinase 3 (PR3); therefore, the plasma levels of these 3 proteinases were also evaluated.In CAE patients, the circulating coagulation system was normal. For the fibrinolytic system, a decrease of plasminogen activity was observed (P = 0.029) when compared with CAD patients, and the concentrations of alpha1-AT (both P < 0.001), alpha2 PI (P = 0.002 and P = 0.025), and alpha2-MG (P = 0.034 and P < 0.001) were significantly elevated when compared with CAD patients and normal controls. Moreover, the plasma levels of HNE (both P < 0.001) and CG (P = 0.027 and 0.016) in CAE patients were also significantly higher than those of the CAD and control groups. There was no difference in plasma PR3 concentration among these 3 groups.Disequilibrium of the coagulation/fibrinolytic system may contribute to thrombus formation and clinical coronary events in patients with CAE. The increased plasma concentrations of alpha1-AT, alpha2-PI, and alpha2-MG might provide beneficial effects by inhibiting the proteinases and restraining the ectatic process; on other hand, they led to unfavorable results by inhibiting plasmin and decreasing thrombus degradation in CAE patients. PMID- 26937906 TI - Predicting Mortality in Patients With "Malignant" Middle Cerebral Artery Infarction Using Susceptibility-Weighted Magnetic Resonance Imaging: Preliminary Findings. AB - To evaluate malignant middle cerebral artery (MCA) infarction (defined as space occupying edema in more than 50% to 75% of the MCA territory) on magnetic resonance imaging (MRI) with susceptibility-weighted imaging (SWI) sequence and assess the usefulness of SWI findings, diffusion-weighted imaging (DWI) findings, and apparent diffusion coefficient (ADC) as predictors of clinical outcome.Data from 16 patients with large MCA infarction previously admitted to our institution between December 2009 and October 2012 were retrospectively collected and analyzed. Within 7 days after stroke onset, 1 neurologist and 1 neuroradiologist estimated the area of infarction on DWI/ADC and extent of prominent vessel sign (PVS) on SWI images using the Stroke Program Early MR Score (SPEMRS). The PVS on SWI was defined as a local prominence of hypointense vessels with either increased vessel number or diameter in the target area, when compared with the number or diameter of the contralateral MCA territory vessels.Six patients died and 10 survived. Although the DWI/ADC-SPEMRS and clinical profiles were similar between the nonsurvivor and survivor groups, SWI-SPEMRS was significantly lower in the nonsurvivor group (P < 0.001).The area of deoxygenation on SWI in patients with malignant MCA infarction can predict mortality. Lower SWI-SPEMRS is a potentially better predictor of poor outcome than lower DWI-SPEMRS. A larger prospective study is needed to clarify the role of SWI as a therapeutic guide in malignant MCA. PMID- 26937907 TI - Readmissions in Cancer Patients After Receiving Inpatient Palliative Care in Taiwan: A 9-Year Nationwide Population-Based Cohort Study. AB - Few studies have reported on readmissions among cancer patients receiving inpatient palliative care (IPC). This study investigated readmissions in cancer patients after their first discharge from IPC in Taiwan from 2002 to 2010.This study was a secondary data analysis using information from the National Health Insurance Database in Taiwan from 2002 to 2010. We included subjects >=20 years old diagnosed with malignant neoplasms who were listed in the registry of catastrophic illness. Patients diagnosed with cancer before January 1, 2002 or who had ever been admitted to an inpatient hospice palliative care unit before the study period were excluded. Readmission was defined as hospital readmission at least once after discharge from first admission to IPC until mortality or the end of the study period.A total of 42,022 patients who met the inclusion criteria were identified. The majority of these patients were male (60.4%). The mean age of cancer diagnosis was 64.0 +/- 14.4 years for men and 64.5 +/- 14.7 years for women. The mean age at first hospice ward admission was 65.2 +/- 14.2 years for men and 65.9 +/- 14.9 years for women. During their first admission to IPC, 59.2% patients died, and the median stay of first IPC admission was 8.0 days. Among those discharged alive from their first admission to IPC, 64.9% were readmitted, and 19.4% of these patients were readmitted on the same day of discharge. From first IPC discharge until mortality, 54.8% of patients were readmitted once, 23.9% were readmitted twice, 9.9% were readmitted 3 times, and 11.5% were readmitted 4 or more times. Being male, having a higher insurance premium level, having a longer length of stay during first IPC admission, being admitted to a teaching hospital, or being admitted to a tertiary hospital increased the adjusted hazard ratio for readmission.We found that terminal cancer patients in Taiwan received relatively late referrals for first admission to IPC and experienced a high rate of readmission after first discharge from IPC. Policies to improve hospice palliative care referrals and decrease readmissions should be considered. PMID- 26937908 TI - Doublet Versus Single Agent as Second-Line Treatment for Advanced Gastric Cancer: A Meta-Analysis of 10 Randomized Controlled Trials. AB - The purpose of this study was to perform a meta-analysis of randomized controlled trials (RCTs) to compare the efficacy and safety of doublet versus single agent as second-line treatment for advanced gastric cancer (AGC).A comprehensive literature search was performed to identify relevant RCTs. All clinical studies were independently identified by 2 authors for inclusion. Demographic data, treatment regimens, objective response rate (ORR), and progression-free survival (PFS) and overall survival (OS) were extracted and analyzed using Comprehensive Meta-Analysis software (Version 2.0).Ten RCTs involving 1698 pretreated AGC patients were ultimately identified. The pooled results demonstrated that doublet combination therapy as second-line treatment for AGC significantly improved OS (hazard ratio [HR] 0.87, 95% confidence interval [CI]: 0.78-0.97, P = 0.011), PFS (HR 0.79, 95% CI: 0.72-0.87, P < 0.001), and ORR (relative risk [RR] 1.57, 95% CI: 1.27-1.95, P < 0.001). Sub-group analysis according to treatment regimens also showed that targeted agent plus chemotherapy significantly improve OS, PFS, and ORR. However, no significant survival benefits had been observed in doublet cytotoxic chemotherapy when compared with single cytotoxic agent. Additionally, more incidences of grade 3 or 4 myelosuppression toxicities, diarrhea, and fatigue were observed in doublet combination groups, while equivalent frequencies of grade 3 or 4 thrombocytopenia and nausea were found between the 2 groups.In comparison with single cytotoxic agent alone, the addition of targeted agent to mono-chemotherapy as salvage treatment for pretreated AGC patients provide substantial survival benefits, while no significant survival benefits were observed in doublet cytotoxic chemotherapy regimens. PMID- 26937909 TI - Aldosterone-to-Renin Ratio Is Associated With Reduced 24-Hour Heart Rate Variability and QTc Prolongation in Hypertensive Patients. AB - Aldosterone is considered to exert direct effects on the myocardium and the sympathetic nervous system. Both QT time and heart rate (HR) variability (HRV) are considered to be markers of arrhythmic risk and autonomous dysregulation. In this study, we investigated the associations between aldosterone, QT time, and HRV in patients with arterial hypertension.We recruited 477 hypertensive patients (age: 60.2 +/- 10.2 years; 52.3% females) with a mean systolic/diastolic 24-hour ambulatory blood pressure monitoring (ABPM) value of 128 +/- 12.8/77.1 +/- 9.2 mmHg and with a median of 2 (IQR: 1-3) antihypertensive agents. Patients were recruited from the outpatient clinic at the Department of Internal Medicine of the Medical University of Graz, Austria. Blood samples, 24-hour HRV derived from 24-hour blood pressure monitoring (ABPM) and ECG's were obtained. Plasma aldosterone and plasma renin concentrations were measured by means of a radioimmunoassay. Twenty-four-hour urine specimens were collected in parallel with ABPM.Mean QTc was 423.3 +/- 42.0 milliseconds for males and 434.7 +/- 38.3 milliseconds for females. Mean 24H-HR and 24H-HRV was 71.9 +/- 9.8 and 10.0 +/- 3.6 bpm, respectively. In linear regression analyses adjusted for age, sex, body mass index, ABPM, and current medication, aldosterone to active renin ratio (AARR) was significantly associated with the QTc interval, a marker for cardiac repolarization abnormalities (mean = 426 +/- 42.4 milliseconds; beta-coefficient = 0.121; P = 0.03) as well as with the 24-hour heart rate variability a surrogate for autonomic dysfunction (median = 9.67 [IQR = 7.38-12.22 bpm]; beta-coefficient = -0.133; P = 0.01).In hypertensive patients, AARR is significantly related to QTc prolongation as well as HRV. Further studies investigating the effects of mineralocorticoid receptor blocker and aldosterone synthase inhibitors on QTc and HRV are warranted. PMID- 26937910 TI - Prognostic Value of KIF2A and HER2-Neu Overexpression in Patients With Epithelial Ovarian Cancer. AB - Kinesin family member 2A (KIF2A) is a member of Kinesin-13 family and involved in cell migration and cell signaling. Human epidermal growth factor receptor 2 (HER2 neu) is implicated in the development of many cancers. Both of these 2 proteins are upstream inducer of PI3K/AKT signaling pathway that plays an important role in the regulation of many cellular events including proliferation, survival, and invasion. We hypothesized that aberrant KIF2A and HER2-neu expression might be associated with aggressive behavior of epithelial ovarian cancer (EOC).To address the prognostic implications of KIF2A and HER2-neu in EOC, we assessed protein levels of KIF2A and HER2-neu in 159 ovarian and fallopian tube tissues (111 carcinomas and 48 normal ovary or fallopian tube tissues) by immunohistochemistry (IHC) analysis on tissue microarray and KIF2A mRNA levels in 35 ovarian and fallopian tube tissues (15 carcinomas and 20 normal ovary or fallopian tube tissues) by real-time PCR.We found that significantly higher KIF2A mRNA expression in EOC tumors than that in normal ovary or fallopian tube tissues. The IHC results showed that protein of KIF2A and HER2-neu was overexpressed in EOC tissues compared with normal ovary or fallopian tube tissues, and KIF2A expression level was significantly associated with lymph nodes, metastasis, ascites cells, and FIGO stage. No correlation between KIF2A and HER2-neu expression was observed. Survival analysis showed that patients with KIF2A and HER2-neu overexpression had a worse overall survival (OS) as compared to patients with low or none expression of the 2 proteins. Multivariate analysis of variance revealed that overexpression of KIF2A was an independent prognostic factor for OS.These findings indicate the important role of KIF2A in predicting EOC prognosis. PMID- 26937911 TI - Left Ventricular Diastolic Dysfunction Assessed by Conventional Echocardiography and Spectral Tissue Doppler Imaging in Adolescents With Arterial Hypertension. AB - Compared to conventional echocardiography, spectral tissue Doppler imaging (s TDI) allows more precise evaluation of diastolic cardiac function. The purpose of this study was to conduct s-TDI to analyze the slow movement of the left ventricular (LV) myocardium in adolescents with systemic arterial hypertension (HT) and to determine whether patients with HT suffer from LV diastolic dysfunction. The study group comprised 69 consecutive patients (48 boys and 21 girls aged 14-17 years [mean, 15.5 +/- 1.1 years]) with primary HT, and the control group comprised 48 healthy participants (24 boys and 24 girls aged 14-17 years [mean, 15.8 +/- 1.3 years]). Physical examinations, 24-hour arterial blood pressure monitoring, conventional 2-dimensional and Doppler echocardiography, and s-TDIs were performed. Analysis revealed that study group participants were significantly heavier and had greater LV mass indices than controls (P < 0.001). There were no differences between the velocities of E waves (peak early filling of mitral inflow), but the deceleration times of the mitral E waves were significantly shorter whereas the A waves survived longer in the study group than in the control group. The velocities of A waves (peak late filling of mitral inflow) were elevated (P = 0.041), and the E/A wave pattern (E/A = 1.8 +/- 0.4) was normal. These results suggest pseudonormalization, a type of LV diastolic dysfunction in adolescents with HT.In the study group, when the sample volume was positioned at the septal or lateral insertion site of the mitral leaflet, the e' wave velocity was significantly depressed whereas the a' wave velocity was elevated, compared to those of the control group (P < 0.001).The e'/a' ratios from the septal and lateral insertion sites were lower, whereas the E/e' ratio from the septal insertion site was significantly higher in the study group, similar to that seen in atrial reversal velocity (P < 0.001).These findings indicate that using sTDI to find and measure diastolic LV failure is valuable when the probe is placed at the septal and lateral mitral valve annuli during examination.Changes in the myocardium appear similar to those seen in adults. PMID- 26937912 TI - The Association of Age and Antibiotic Resistance of Helicobacter Pylori: A Study in Jiaxing City, Zhejiang Province, China. AB - The antibiotic resistance of Helicobacter pylori (H pylori) is steadily increasing worldwide, resulting in the low efficiency of the current therapeutic approaches for eradication. In this study, we investigated the relationship between antibiotic resistances, the year of sample collection, and the ages of the infected individuals.A total of 29,034 gastric mucosa biopsy samples were randomly collected from January 1, 2009 to December 9, 2014 in Jiaxing City, Zhejiang Province, China. An antibiotic susceptibility testing was determined using an agar-dilution method. The statistical significance was tested using the chi-squared (chi) test.A total of 9687 strains were isolated. The resistance rate to clarithromycin, levofloxacin, and metronidazole were 17.76%, 19.66%, and 95.5%, respectively. Resistance was rare against amoxicillin, gentamicin, and furazolidone. The metronidazole resistance rate stayed at a consistently high level. In contrast, the resistance rates of clarithromycin and levofloxacin increased rapidly from 2009 to 2011, gradually decreased from 2012 to 2013, and then increased again in 2014. Although patients ages 31 to 50 and 71 to 80 years had lower infection rates of H pylori, they also had higher resistance rates to clarithromycin and levofloxacin. The highest antibiotic resistance rate was observed in patients' ages 71 to 80 years old. Younger patients (below 30 years old) had a lower resistance to levofloxacin. Patients' ages 51 to 60 years old may thus represent an important category for the future study of H pylori infection.Age plays a key element in H pylori resistance to clarithromycin and levofloxacin. It is therefore necessary to consider individualized therapy for the optimized treatment of H pylori-infected patients. PMID- 26937913 TI - Enhanced Recovery Program Versus Traditional Care in Laparoscopic Hepatectomy. AB - Enhanced recovery after surgery (ERAS) has shown effectiveness in terms of reducing the hospital stay and cost associated with open liver resection. However, the benefit of ERAS in patients undergoing laparoscopic liver resection is still unclear, and clinical studies on this topic are limited.The ERAS program for laparoscopic liver resection was used in a group of 80 patients (ERAS group). The results were compared with those in a control group of 107 patients. All patients underwent laparoscopic liver resection. The primary endpoints were the postoperative hospital stay, defined as the number of days from surgery to discharge, and the hospitalization expense. The secondary endpoints were resumption of oral intake, readmissions, and complications.The median postoperative hospital stay was 6.2 +/- 2.6 days in the ERAS group, which was significantly shorter than that in the control group (9.9 +/- 5.9 d; P < 0.001). The hospitalization cost was $6871 +/- 2571 in the ERAS group and $7948 +/- 3630 in the control group (P = 0.020). The morbidity rate was 22.5% (18 of 80 patients) in the ERAS group and 43.9% (47 of 107 patients) in the control group (P = 0.002). There were no significant differences the in rate of readmission between the 2 groups.Enhanced recovery after surgery for laparoscopic liver resection is safe and effective. Patients in the ERPS group had a shorter hospital stay, fewer complications, and lower hospital costs. PMID- 26937914 TI - Tensile Properties of the Deep Transverse Metatarsal Ligament in Hallux Valgus: A CONSORT-Compliant Article. AB - The deep transverse metatarsal ligament (DTML) connects the neighboring2 metatarsal heads and is one of the stabilizers connecting the lateral sesamoid and second metatarsal head. In this study, we aimed to determine the tensile properties of the DTML in normal specimens and to compare these results with hallux valgus specimens. We hypothesized that the tensile properties of the DTML would be different between the 2 groups of specimens.The DTML in the first interspace was dissected from 12 fresh frozen human cadaveric specimens. Six cadavers had bilateral hallux valgus and the other 6 cadavers had normal feet. The initial length (L0) and cross-sectional area (A0) of the DTML were measured using a digital caliper, and tensile tests with load failure were performed using a material testing machine.There were significant between-groups differences in the initial length (L0) P = 0.009 and cross-sectional area (A0) of the DTML P = 0.007. There were also significant between-groups differences for maximum force (N) P = 0.004, maximum distance (mm) P = 0.005, maximum stress (N/mm) P = 0.003, and maximum strain (%) P = 0.006.The DTML is an anatomical structure for which the tensile properties differ in hallux valgus. PMID- 26937915 TI - Association Between Kidney Stones and Risk of Stroke: A Nationwide Population Based Cohort Study. AB - Nephrolithiasis is highly prevalent and has been associated with vascular diseases such as cardiovascular events. Few studies have comprehensively associated renal stones with stroke.This study explored whether patients with renal stones were at a higher stroke risk than those without renal stones. A national insurance claim dataset of 22 million enrollees in Taiwan was used to identify 53,659 patients with renal stones, and 214,107 were selected as age-, sex-, and comorbidity-matched controls for a 13-year follow-up.The relative stroke risk for the RS cohort was 1.06-fold higher than that for the non-RS group (95% confidence interval [CI] = 1.01-1.11). Age-specific analysis revealed that the adjusted stroke risk for the RS cohort increased as age decreased, with the highest risk of 1.47-fold (95% CI = 1.10-1.96) in patients aged 20 to 34 years, followed by a 1.12-fold risk (95% CI = 1.00-1.25) in patients aged 35 to 50 years. Sex-specific analysis clarified that women in the RS group had a 1.12-fold stroke risk compared with women in the non-RS group (95% CI = 1.03-1.21). Patients who had undergone >4 surgeries had up to 42.5-fold higher risk of stroke (95% CI = 33.8-53.4).The study utilized the national database and demonstrated that patients, particularly women and the younger population, with nephrolithiasis have an increased risk of ischemic stroke development. Patients treated with medication or through surgery for RSs showed steady and higher risks of stroke than those without surgical or medical intervention. PMID- 26937916 TI - Campylobacter Fetus Meningitis in Adults: Report of 2 Cases and Review of the Literature. AB - The zoonotic pathogen Campylobacter fetus is a rare cause of bacterial meningitis. Little is known about the clinical characteristics, predisposing factors and outcome of C fetus meningitis in adults.We report cases of C fetus meningitis in a nationwide cohort study of adult bacterial meningitis patients in the Netherlands and performed a review of the literature.Two patients with C fetus meningitis were identified from January 2006 through May 2015. The calculated annual incidence was 0.02 per million adults. Combined with the literature, we identified 22 patients with a median age of 48 years. An immunocompromised state was present in 16 patients (73%), mostly due to alcoholism (41%) and diabetes mellitus (27%). The source of infection was identified in 13 out of 19 patients (68%), consisting of regular contact with domestic animals in 5 and working on a farm in 4. Recurrent fever and illness was reported in 4 patients (18%), requiring prolonged antibiotic treatment. Two patients died (9%) and 3 survivors (15%) had neurological sequelae.C fetus is a rare cause of bacterial meningitis and is associated with an immunocompromised state. Based on the apparent slow clinical response seen in this limited number of cases, the authors of this study recommend a prolonged course of antimicrobial therapy when C fetus is identified as a causative agent of bacterial meningitis. Cases appeared to do best with carbapenem therapy. PMID- 26937917 TI - Body Mass Index and Risk of Rheumatoid Arthritis: A Meta-Analysis of Observational Studies. AB - Although many epidemiological studies have investigated the association between body mass index (BMI) and risk of rheumatoid (RA), the results have been inconsistent. Therefore, we performed a dose-response meta-analysis to quantify the dose-response association between BMI and RA risk.We systematically searched PubMed, Embase, and Web of Science databases and reference lists of articles for relevant studies published before August 2014 using terms related to BMI and RA. Fixed or random-effects models were used to estimate the pooled relative risk (RR) with 95% confidence interval (CI). Several subgroup analyses, sensitivity analyses, and publication bias tests were performed to explore potential study heterogeneity and biasThirteen studies involving 400,609 participants and 13,562 RA cases were included. The RR of RA was 1.21 (95% CI: 1.02-1.44) for obesity, 1.05 (95% CI: 0.97-1.13) for overweight. The risk of RA increased by 13% (RR: 1.13; 95% CI: 1.01-1.26) for every 5 kg/m increase in BMI. The subgroup analyses showed a positive association between BMI and RA risk only in women with an RR of 1.26 (95% CI: 1.12-1.40) for obesity and 1.12(95% CI: 1.07-1.18) for every 5 kg/m increase in BMI. Also, an increased risk of RA was found in sero-negative subgroup with an RR of 1.47 (95% CI: 1.11-1.96) for obesity and 1.21 (95% CI: 1.06-1.39) for every 5 kg/m increase in BMI.There is evidence that obesity is a risk factor for developing of RA. Furthermore, the positive association between BMI and RA risk may be stronger among women than men. PMID- 26937918 TI - Increased Risk of Stroke in Patients With Fibromyalgia: A Population-BASED Cohort Study. AB - Neuropsychiatric diseases might enhance stroke development, possibly through inflammation and atherosclerosis. Approximately 25% to 40% of patients with stroke, largely younger patients, are not associated with any conventional stroke risk factors. In this research, we explored whether fibromyalgia (FM), a neuropsychosomatic disorder, increases stroke risk.From a claims dataset with one million enrollees sourced of the Taiwan National Health Insurance database, we selected 47,279 patients with FM and randomly selected 189,112 age- and sex matched controls within a 3-year period from January 1, 2000 to December 31, 2002. Stroke risk was assessed using Cox proportional hazards regression.Comorbidities associated with increased stroke risk, such as hypertension, diabetes, hyperlipidemia, coronary heart disease, irritable bowel syndrome, and interstitial cystitis, were more prevalent in patients with FM and high stroke risk than in the controls. The overall stroke risk was 1.25-fold (95% confidence interval [CI]: 1.21-1.30) higher in the FM group than in the non-FM group. Even without comorbidities, stroke risk was higher in patients with FM than in the controls (adjusted hazard ratio [aHR] = 1.44, 95% CI: 1.35-1.53, P < 0.001). The relative risk of stroke was 2.26-fold between FM and non-FM groups in younger patients (age <35 years, 95% CI: 1.86-2.75).This is the first investigation associating FM with an increased risk of stroke development. The outcomes imply that FM is a significant risk factor for stroke and that patients with FM, particularly younger patients, require close attention and rigorous measures for preventing stroke. PMID- 26937919 TI - Risk Factors for the Postoperative Transfusion of Allogeneic Blood in Orthopedics Patients With Intraoperative Blood Salvage: A Retrospective Cohort Study. AB - The purpose of this study is to explore the risk factors affecting the postoperative transfusion of allogeneic blood in patients undergoing orthopedics surgery with intraoperative blood salvage (IBS). A retrospective study of 279 patients undergoing orthopedic surgeries with IBS from May 2013 to May 2015 was enrolled. The binary logistic regression was used to find out the risk factors associated with postoperative transfusion of allogeneic blood in orthopedics patients with IBS, and then receiver operating characteristic (ROC) curve was drawn to determine the optimal threshold of the regression model.Single factor analysis showed that age, American Society of Anesthesiologists (ASA) grade, preoperative hemoglobin, operation time, received autologous blood, the laying time of autologous blood, bleeding volume, and postoperative drainage volume had significant effects on postoperative allogeneic blood transfusion.In binary logistic regression analysis, the independent factors predicting orthopedic patients with IBS need to transfuse allogeneic blood after surgeries were age (odds ratio [OR] = 0.415, P = 0.006), ASA grade (OR = 2.393, P = 0.035), preoperative hemoglobin (OR = 0.532, P = 0.022), and postoperative drainage volume (OR = 4.279, P = 0.000). The area under ROC curve was 0.79 and the predicted accuracy rate of the model was 81.58%.After operation, the orthopedic patients with IBS still have a high allogeneic blood transfusion rate, and IBS is not a perfect blood protection method. The logistic regression model of our study provides a reliable prediction for postoperative transfusion of allogeneic blood in orthopedic patients with IBS, which have a certain reference value. PMID- 26937920 TI - Venovenous Extracorporeal Membrane Oxygenation for Acute Respiratory Distress Syndrome in Adults: Prognostic Factors for Outcomes. AB - Despite a therapeutic option for severe acute respiratory distress syndrome (ARDS), the survival benefit of venovenous extracorporeal membrane oxygenation (VV-ECMO) is still controversial in adults. This study was aimed at investigating the prognostic factors for ECMO-treated ARDS in adult patients.From 2012 to 2015, 49 patients (median age: 57 years) received VV-ECMO in our institution and were included in this retrospective study. The indication of VV-ECMO was a severe hypoxemia (PaO2/FiO2 ratio <70 mmHg) under mechanical ventilation (MV) with a peak inspiratory pressure (PIP) >35 cmH2O and a FiO2 >0.8. To decrease the impact of pulmonary injuries associated with the high-pressure ventilation, the settings of MV on VV-ECMO were downgraded according to our protocol. Outcomes of this study were death on VV-ECMO and death in hospital. Important demographic and clinical data during the treatment were collected for outcome analyses.All patients experienced significant improvements in arterial oxygenation on VV-ECMO. Twenty-four hours after initiation of VV-ECMO, the median PaO2/FiO2 ratio increased from 58 to 172 mmHg (P < 0.001) and the median SaO2 increased from 86% to 97% (P < 0.001). In the meantime, the MV settings were also effectively downgraded. The median PIP decreased from 35 to 29 cmH2O (P < 0.001) and the median tidal volume decreased from 7 to 5 ml/kg/min (P < 0.001). Twelve patients died during the treatment of VV-ECMO and 21 patients died before hospital discharge. Among all of the pre-ECMO variables, the pre-ECMO pulmonary dynamic compliance (PCdyn) <20 mL/cmH2O was identified to be the prognostic factor of death on VV-ECMO (odds ratio [OR]: 6, 95% confidence interval [CI]: 1-35, P = 0.03), and the pre-ECMO duration of MV >90 hours was the prognostic factor of death before hospital discharge (OR: 7, 95% CI: 1-29, P = 0.01).VV-ECMO was a useful salvage therapy for severe ARDS in adults. However, the value of PCdyn and the duration of MV before intervention with VV-ECMO may significantly affect the patients' outcomes. PMID- 26937921 TI - Hyperoxia Improves Hemodynamic Status During Head-up Tilt Testing in Healthy Volunteers: A Randomized Study. AB - Head-up tilt test is useful for exploring neurally mediated syncope. Adenosine is an ATP derivative implicated in cardiovascular disturbances that occur during head-up tilt test. The aim of the present study was to investigate the impact of hyperoxia on adenosine plasma level and on hemodynamic changes induced by head-up tilt testing.Seventeen healthy male volunteers (mean age 35 +/- 11 years) were included in the study. The experiment consisted of 2 head-up tilt tests, 1 session with subjects breathing, through a mask, medical air (FiO2 = 21%) and 1 session with administration of pure oxygen (FiO2 = 100%) in double-blind manner. Investigations included continuous monitoring of hemodynamic data and measurement of plasma adenosine levels.No presyncope or syncope was found in 15 of the 17 volunteers. In these subjects, a slight decrease in systolic blood pressure was recorded during orthostatic stress performed under medical air exposure. In contrast, hyperoxia led to increased systolic blood pressure during orthostatic stress when compared with medical air. Furthermore, mean adenosine plasma levels decreased during hyperoxic exposure before (0.31 +/- 0.08 MUM) and during head-up tilt test (0.33 +/- 0.09 MUM) when compared with baseline (0.6 +/- 0.1 MUM). Adenosine plasma level was unchanged during medical air exposure at rest (0.6 +/- 0.1 MUM), and slightly decreased during orthostatic stress. In 2 volunteers, the head-up tilt test induced a loss of consciousness when breathing air. In these subjects, adenosine plasma level increased during orthostatic stress. In contrast, during hyperoxic exposure, the head-up tilt test did not induce presyncope or syncope. In these 2 volunteers, biological study demonstrated a decrease in adenosine plasma level at both baseline and during orthostatic stress for hyperoxic exposure compared with medical air.These results suggest that hyperoxia was able to increase blood pressure during head-up tilt test via a decrease in plasma adenosine concentration. Our results also suggest that adenosine receptor antagonists are worth trying in neurocardiogenic syncope. PMID- 26937923 TI - Clinical Case Report of Expansive Laminoplasty for Cervical Myelopathy Due to Both Disc Herniation and Developmental Cervical Spinal Canal Stenosis in Older Adolescents. AB - Reports on adolescent patients with cervical myelopathy who underwent anterior cervical discectomy and fusion are scarce. However, to our knowledge, no cases of expansive laminoplasty for cervical myelopathy associated with progressive neurological deficit after a series of conservative treatment, caused by both disc herniation and developmental cervical spinal canal stenosis, have been reported.From January 2006 to July 2012, we retrospectively studied 3 patients in late adolescence presenting with cervical myelopathy who underwent expansive unilateral open-door laminoplasty at our hospital. The outcomes after the surgery were evaluated according to the Japanese Orthopedic Association scores.Symptoms presented by these patients were due to both disc herniation and developmental cervical spinal canal stenosis. No major complications occurred after the surgical procedures. The median follow-up time was 66 months (range 36-112 months). The Japanese Orthopedic Association scores after surgery showed a significant increase. Long-term outcomes after surgery were satisfactory according to the evaluation criteria for the Japanese Orthopedic Association scores. However, the ranges of motion of the cervical spine decreased, especially the ranges of motion on flexion after surgery showed a significant decrease.Expansive laminoplasty is helpful for older adolescent patients with cervical myelopathy due to both disc herniation and developmental cervical spinal canal stenosis, presenting with progressive neurological deficit after long conservative treatment. PMID- 26937922 TI - Child-Pugh Versus MELD Score for the Assessment of Prognosis in Liver Cirrhosis: A Systematic Review and Meta-Analysis of Observational Studies. AB - Child-Pugh and MELD scores have been widely used for the assessment of prognosis in liver cirrhosis. A systematic review and meta-analysis aimed to compare the discriminative ability of Child-Pugh versus MELD score to assess the prognosis of cirrhotic patients.PubMed and EMBASE databases were searched. The statistical results were summarized from every individual study. The summary areas under receiver operating characteristic curves, sensitivities, specificities, positive and negative likelihood ratios, and diagnostic odds ratios were also calculated.Of the 1095 papers initially identified, 119 were eligible for the systematic review. Study population was heterogeneous among studies. They included 269 comparisons, of which 44 favored MELD score, 16 favored Child-Pugh score, 99 did not find any significant difference between them, and 110 did not report the statistical significance. Forty-two papers were further included in the meta-analysis. In patients with acute-on-chronic liver failure, Child-Pugh score had a higher sensitivity and a lower specificity than MELD score. In patients admitted to ICU, MELD score had a smaller negative likelihood ratio and a higher sensitivity than Child-Pugh score. In patients undergoing surgery, Child Pugh score had a higher specificity than MELD score. In other subgroup analyses, Child-Pugh and MELD scores had statistically similar discriminative abilities or could not be compared due to the presence of significant diagnostic threshold effects.Although Child-Pugh and MELD scores had similar prognostic values in most of cases, their benefits might be heterogeneous in some specific conditions. The indications for Child-Pugh and MELD scores should be further identified. PMID- 26937924 TI - Intravenous Dexmedetomidine Promotes Spinal Bupivacaine Anesthesia and Postoperative Analgesia in Lower Limb Surgery: A Double-Blind, Randomized Clinical CONSORT Study. AB - Dexmedetomidine (DEX) has been reported to have synergistic action with local anesthetics. This prospective, randomized, double-blind clinical study was designed to observe the efficacy of intravenous DEX without loading dose on spinal blockade duration, postoperative sedation, patient-controlled analgesia and its morphine-sparing effect in lower limb surgeries.Seventy-five patients, scheduled for lower limb surgery under spinal anesthesia, were randomly allocated into 2 groups: group BS (received 15 mg of 0.5% of bupivacaine for subarachnoid anesthesia and continuous intravenous infusion of saline in Ringer solution) and BD group (received 15 mg of 0.5% of bupivacaine for subarachnoid anesthesia and continuous intravenous infusion of DEX in Ringer solution at a rate of 0.25 MUg/kg/h). Intravenous infusion started 15 minutes before spinal anesthesia.The onset time of sensory and motor blockade was shorten, the duration of sensory and motor blockade was significantly prolonged in BD patients when compared to BS patients. The Ramsay sedation score measured immediately after surgery was greater in BD group than BS group. BD patients also shown increased time to the first request of postoperative morphine and decreased total morphine consumption as compared with BS patients.Collectively, intravenous administration of DEX without loading dose promoted the efficacy of spinal bupivacaine anesthesia and postoperative analgesia in patients undergoing lower limb surgery. PMID- 26937925 TI - Association Between Tuberculosis and Parkinson Disease: A Nationwide, Population Based Cohort Study. AB - Few studies have investigated the association between tuberculosis (TB) and Parkinson disease (PD). This nationwide, population-based, retrospective cohort study investigated the risk of PD in patients with TB.We selected patients newly diagnosed with TB (International Classification of Diseases, Ninth Revision, Clinical Modification: 011) from 2000 to 2009 in the Taiwan National Health Insurance Database as the TB cohort. The comparison cohort (the non-TB cohort) was frequency matched to the TB cohort at a ratio of 4:1 by sex, age, and the index date. We analyzed the risks of PD by using Cox proportional hazard regression models.A total of 121,951 patients with TB and 487,800 non-TB controls were enrolled in this study. The TB cohort had a 1.38-fold risk of PD compared with the non-TB cohort after adjustment for age, sex, and comorbidities (aHR, 95% CI: 1.30-1.46). The adjusted risk of PD in the TB and non-TB cohorts increased in subgroups regardless of age, sex, and comorbidities. Combined effect of TB and comorbidities on the risk of PD were significant in patients with TB who had diabetes (aHR: 2.26, 95% CI: 2.02-2.52), hypertension (aHR: 2.23, 95% CI: 2.04 2.44), head injury (aHR: 2.32, 95% CI: 1.95-2.77), chronic kidney disease (aHR: 2.02, 95% CI: 1.49-2.72), chronic obstructive pulmonary disease (aHR: 1.84, 95% CI: 1.66-2.05), depression (aHR: 4.66, 95% CI: 3.59-6.05), dementia (aHR: 3.70, 95% CI: 2.99-4.59), and stroke (aHR: 2.56, 95% CI: 2.28-2.87). The risk of PD was higher in a follow-up within 1 year (aHR: 1.78, 95% CI: 1.58-2.00) and decreased with the follow-up period in the TB cohort.Patients with TB have an independently 1.38-fold risk of PD. The risk of PD decreased with the follow-up period in the TB cohort. Physicians should be aware of the risk of PD in patients with TB when treating such patients. PMID- 26937926 TI - A Retrospective Case-Series of Children With Bone and Joint Infection From Northern Australia. AB - Our clinical workload as infectious diseases pediatricians in northern Australia is dominated by complicated bone and joint infections in indigenous children. We reviewed the clinical presentation, microbiology, management, and outcomes of children presenting to Royal Darwin Hospital with bone and joint infections between 2010 and 2013, and aimed to compare severity and incidence with other populations worldwide.A retrospective audit was performed on children aged 0 to 18 years who were admitted to Royal Darwin Hospital between 1 January 2010 and 31 December 2013 with a bone and joint infection.Seventy-nine patients were identified, of whom 57 (72%) had osteomyelitis +/- associated septic arthritis and 22 (28%) had septic arthritis alone. Sixty (76%) were indigenous Australians. The incidence rate of osteomyelitis for indigenous children was 82 per 100,000 children. Staphylococcus aureus was the confirmed pathogen in 43/79 (54%), of which 17/43 (40%) were methicillin resistant. Median length of stay was 17 days (interquartile range: 10-31 days) and median length of IV antibiotics was 15 days (interquartile range: 6-24 days). Fifty-six (71%) required at least 1 surgical procedure. Relapse within 12 months was documented in 12 (15%) patients.We report 3 key findings: osteomyelitis incidence in indigenous children of northern Australia is amongst the highest reported in the world; methicillin-resistant S aureus accounts for 36% of osteomyelitis with a positive microbiological diagnosis; and the severity of disease requires extended antibiotic therapy. Despite this, 15% of the cohort relapsed within 12 months and required readmission. PMID- 26937927 TI - Cost Minimization Analysis of Precut Cornea Grafts in Descemet Stripping Automated Endothelial Keratoplasty. AB - Descemet stripping automated endothelial keratoplasty (DSAEK) is the most common corneal transplant procedure. A key step in the procedure is preparing the donor cornea for transplantation. This can be accomplished via 1 of 3 alternatives: surgeon cuts the cornea on the day of surgery, the cornea is precut ahead of time in an offsite facility by a trained technician, or a precut cornea is purchased from an eye bank. Currently, there is little evidence on the costs and effectiveness of these 3 strategies to allow healthcare providers decide upon the preferred method to prepare grafts.The aim of this study was to compare the costs and relative effectiveness of each strategy.The Singapore National Eye Centre and Singapore Eye Bank performed both precut cornea and surgeon-cut cornea transplant services between 2009 and 2013.This study included 110 subjects who received precut cornea and 140 who received surgeon-cut cornea. Clinical outcomes and surgical duration were compared across the strategies using the propensity score matching. The cost of each strategy was estimated using the microcosting and consisted of facility costs and procedural costs including surgical duration. One way sensitivity analysis and threshold analysis were performed.The cost for DSAEK was highest for the surgeon-cut approach ($13,965 per procedure), followed by purchasing precut corneas ($12,659) and then setting up precutting ($12,421). The higher procedural cost of the surgeon-cut approach was largely due to the longer duration of the procedure (surgeon-cut = 72.54 minutes, precut = 59.45 minutes, P < 0.001) and the higher surgeon fees. There was no evidence of differences in clinical outcomes between grafts that were precut or surgeon-cut. Threshold analysis demonstrated that if the number of cases was below 31 a year, the strategy that yielded the lowest cost was purchasing precut cornea from eye bank. If there were more than 290 cases annually, the cheapest option would be to setup precutting facility.Our findings suggest that it is more efficient for centers that are performing a large number of cornea transplants (more than 290 cases) to set up their own facility to conduct precutting. PMID- 26937928 TI - Risk Factors of Anastomotic Leakage and Long-Term Survival After Colorectal Surgery. AB - Anastomotic leakage (AL) is one of the most serious complications of colorectal surgery. It can affect long-term oncologic outcomes, but the impact on long-term survival remains uncertain. The aim of this study is to evaluate the operative characteristics of leakage and no leakage groups and to analyze long-term oncologic outcomes.We prospectively enrolled 10,477 patients from 2000 to 2011 and retrospectively reviewed the data.Male sex (odds ratio [OR], 3.90; P < 0.001), intraoperative transfusion (OR, 2.31; P = 0.042), and operative time (OR, 1.73; P = 0.032) were independent risk factors of AL in the colon. In the rectum, male sex (OR, 2.37; P < 0.001), neoadjuvant chemoradiotherapy (OR, 2.26; P < 0.001), and regional lymph node metastasis (OR, 1.43; P = 0.012) were independent risk factors of AL, and diverting stoma (OR, 0.24; P < 0.001) was associated with a deceased risk of AL. AL in the rectum without a diverting stoma was associated with disease-free survival (DFS, OR, 1.47; P = 0.037). Colonic leakage was not associated with 5-year DFS (leakage group vs nonleakage group, 72.4% vs 80.9%, P = 0.084); however, in patients undergoing rectal resection, there was a significant difference in 5-year DFS (67.0% vs 76.6%, P = 0.005, respectively).AL in the rectum is associated with worse long-term DFS and overall survival. A diverting stoma was shown to protect against this effect and was associated with long-term survival in rectal surgery. Therefore, creating a diverting stoma should be considered in high-risk patients undergoing rectal surgery. PMID- 26937929 TI - Three-Dimensional Measurement and Cluster Analysis for Determining the Size Ranges of Chinese Temporomandibular Joint Replacement Prosthesis. AB - The aim of this study was to investigate the osseous characteristics of Chinese temporomandibular joint (TMJ) and detect the size clusters for total joint prostheses design.Computer tomography (CT) data from 448 Chinese adults (226 male and 222 female, aged from 20 to 83 years, mean age 39.3 years) with 896 normal TMJs were chosen from the Department of Radiology in the Shanghai 9th People's Hospital. Proplan CMF 1.4 software was used to reconstruct the skulls. Three dimensional (3D) measurements of the TMJ fossa and condyle-ramus units with 13 parameters were performed. Size clusters for prostheses design were determined by hierarchical cluster analyses, nonhierarchical (K-means) cluster analysis, and discriminant analysis.The glenoid fossa was grouped into 3 clusters, and the condyle-ramus units were grouped into 4 clusters. Discriminant analyses were capable of correctly classifying 97.24% of the glenoid fossa and 94.98% of the condyle-ramus units. The means and standard deviations for the parameter values in each cluster were determined.Fossa depth and angles between the condyle and ramus were important parameters for Chinese TMJ prostheses design. 3D measurements and cluster analysis of the osseous morphology of the TMJ provided an anatomical reference and identified the dimensions of the minimum numbers of prosthesis sizes required for Chinese TMJ replacement. PMID- 26937931 TI - Congenital Giant Right Coronary Artery to Pulmonary Artery Fistula and Congenital Left Main Coronary Artery Atresia: A Case Report. AB - Both of congenital giant RCA, RCA to PA fistula, and CLMCA-A are one of exceedingly rare vascular abnormalities. We present the case of a 34-year-old man with multiple congenital coronary anomalies above, and a successful surgical intervention was proceeded for our patient.This is a case of a 34-year-old man presented with apical systolic murmur and exertional chest pain. Furthermore, a dilated left heart and abnormal pulmonary blood flow was observed in this patient. Coronary CTA and selective CAG showed a 15-mm diameter RCA with a fistula to pulmonary trunk and CLMCA-A. During cardiac surgery, the coronary abnormalities were confirmed and the outlet of the fistula was closed. After surgery, less chest pain, respiratory infection, and left heart failure were observed in this patient.This case illustrates that the surgery of closing the fistula between the giant RCA and pulmonary trunk could improve the symptoms and signs for this patient. It could be predicted that simplified operation could be a promising therapy for patient with giant RCA to PA fistula and CLMCA-A. Moreover, CABG should be taken full account of when myocardial ischemia was found in the blood-supply area of LAD. PMID- 26937930 TI - The Effect and Feasibility Study of Transforaminal Percutaneous Endoscopic Lumbar Discectomy Via Superior Border of Inferior Pedicle Approach for Down-Migrated Intracanal Disc Herniations. AB - Transforaminal percutaneous endoscopic lumbar discectomy (PELD) is gradually regarded as an effective alternative to posterior open surgery. However, migrated herniations bring a great technical challenge even for experienced surgeons due to the absence of the appropriate approaching guideline. We aimed to describe a safe and effective approaching technique for the removal of down-migrations on the basis of the clinical outcomes and complications compared with the conventional approaching method.A total of 45 patients recommended to single level PELD with foraminoplasty were randomly divided into 2 groups, group A received foraminoplasty via upper border of inferior pedicle, group B was approached through the common transforaminal route. The clinical outcomes were evaluated by Visual Analog Scale (VAS) for leg pain and Oswestry Disability Index (ODI) scores. Then participants were classified into 2 types of migrations (high grade and low-grade) based on the extent of migration presented on preoperative magnetic resonance imaging (MRI). The various comparisons between the 2 surgical techniques were analyzed.The postoperative VAS and ODI scores significantly decreased in both of the 2 groups after surgery (P < 0.001). The follow-up continued 1 year. With increasing length of follow-up, the disparities in clinical outcomes between the 2 groups were gradually narrowing and there was no significant difference at the end of follow-up (P = 0.32; P = 0.46). There were no differences in the operation time and duration of hospital stay (P = 0.36; P = 0.08). The highly migration group in group B showed a significant longer operation time (P = 0.02), but the extent of migration did not have a significant influence on the operation time in group A with the modified approach (P = 0.19). There were no apparent approach-related complications in group A during the procedure and follow-up period.Foraminoplastic-PELD via upper border of inferior pedicle can serve as a safe and effective minimally invasive technique for removal of down-migrated herniations. Furthermore, it is essential to identify the radiologic characteristics so as to choose the most appropriate approaching technique. PMID- 26937932 TI - Proton Pump Inhibitor Therapy Is Associated With Reduction of Early Bleeding Risk After Prophylactic Endoscopic Variceal Band Ligation: A Retrospective Cohort Study. AB - Endoscopic variceal band ligation (EVL) is an effective procedure to control and prevent variceal bleeding in patients with liver cirrhosis, but it can be complicated by bleeding from post-EVL ulcers. Several studies have reported that proton pump inhibitors (PPIs) decrease the size of post-EVL ulcers. However, evidence are limited as to whether PPIs actually reduce the risk of bleeding after EVL. This study aimed to analyze the factors associated with bleeding after prophylactic EVL and to assess the effect of PPI therapy.Five hundred and five cirrhotic patients with high risk esophageal varices who received primary prophylactic EVL were included for this retrospective cohort study. Post-EVL bleeding was defined as bleeding after prophylactic EVL within 8 weeks evidenced by the occurrence of melena or hematemesis, or by a decrease of hemoglobin by >2.0 g/dL. If evidence of bleeding from ulceration of the EVL sites was confirmed by endoscopy, we defined it as post-EVL ulcer bleeding.Fourteen patients developed bleeding after prophylactic EVL. Factors associated with post-EVL bleeding included alcohol as etiology, low albumin, high total bilirubin, high Child-Pugh score, high MELD score, coexistence of gastric varices, and not administrating PPI medication by univariate analysis. In multivariate logistic analysis, Co-existing gastric varix (odds ratio [OR] 5.680, P = 0.005] and not administrating PPIs (OR 8.217, P = 0.002) were associated with bleeding after prophylactic EVL. In the subgroup analysis excluding patients whose gastric varices were treated, not administering PPI medication (OR 8.827, P = 0.008) was the sole factor associated with post-EVL bleeding.We suggest that PPI therapy needs to be considered in patients receiving prophylactic EVL to reduce the risk of bleeding after prophylactic EVL. PMID- 26937933 TI - Estrogen Receptor Status Predicts Late-Onset Skeletal Recurrence in Breast Cancer Patients. AB - Estrogen receptor-positive (ER+) breast cancer (BCa) often recurs after long latency, and is known to favor bone as a metastatic site. We hypothesized that skeletal recurrence of ER+ BCa follows a different chronological pattern from that of nonskeletal recurrence.We retrospectively evaluated 434 matched pairs of ER+ and ER- female patients who underwent surgery for clinically localized BCa between 2005 and 2009. Patient age, tumor size, lymph node involvement, and adjuvant treatment biases were adjusted by the propensity score method. We conducted competing risk analysis to determine the prognostic significance of ER expression status on the risk of overall recurrence and late recurrence (after 3 years). We also compared chronological patterns of ER+ and ER- tumor recurrence, stratified by the first metastatic site (skeletal vs nonskeletal).After 3 postoperative years, ER+ tumor had a significantly higher risk of overall distant recurrence than ER- tumor (P = 0.02). When further stratified by first site of metastasis, only late skeletal recurrence was significantly associated with ER status (P = 0.029). In multivariate analysis, ER and lymph node involvement status were significant prognostic factors for late skeletal recurrence, with adjusted hazard ratios of 5.2 (95% CI = 1.2-22.4, P = 0.025) and 5.2 (1.7-16.3, P = 0.005), respectively. For nonskeletal distant recurrence, tumor size (>2 cm) was the only significant risk factor with adjusted hazard ratio of 2.8 (1.4-5.7, P = 0.005). Annual hazard of skeletal recurrence events of ER+ tumors continued to exist up to 10 years, while annual hazard of nonskeletal recurrences decreased after peaking at 5 years. ER- tumor recurrences exhibited similar annual hazard patterns across skeletal and nonskeletal sites.ER expression and lymph node involvement status were strong predictors of BCa late-onset (>3 years) recurrences, especially in skeletal sites. Therefore, skeletal system surveillance is mandatory for long-term follow-up of this subpopulation. PMID- 26937934 TI - Determinants of Quality Care and Mortality for Patients With Locally Advanced Cervical Cancer in Virginia. AB - Outcomes for patients with locally advanced cervical cancer are influenced by receipt of all indicated components of quality care: early diagnosis and receipt of external beam radiation therapy, chemotherapy, and brachytherapy. We performed an observational cohort study to evaluate receipt of quality cancer care and mortality after cancer diagnosis among patients with locally advanced cervical cancer in Virginia.We queried the Virginia state cancer registry to identify patients with International Federation of Gynecology and Obstetrics Stage IB-IVA cervical cancer who were diagnosed during 2002 to 2012. We evaluated the influence of tumor-related, demographic, and geospatial factors on the receipt of indicated therapies and mortality. Treatment quality score of 0 to 3 was defined based upon the extent of receipt of the components of indicated therapy.A total of 1048 patients were identified; 33.1% received all 3 components of treatment and only 54.0% received brachytherapy. Predictors of higher quality score included younger age group versus 66+ years at diagnosis (18-42 odds ratio [OR] = 12.3, 95% confidence interval: 6.6, 23.0; 42-53 OR = 5.6, CI: 3.3, 9.5; 53-66 OR = 5.5, CI: 3.3, 9.1), lower tumor stages versus IVA (IB2 OR = 3.3, CI: 1.8, 6.2; II OR = 2.7, CI: 1.6, 4.5; IIIx OR = 2.1, CI: 1.3, 3.6), and treatment at a high volume facility (OR 2.2, CI: 1.2, 4.2). Predictors of increased mortality included earlier year of diagnosis, higher tumor stage, treatment at a lower volume facility, and lower treatment quality score.In a cohort of locally advanced cervical cancer patients in Virginia, we identified a low rate of receipt of complete quality care for cervical cancer and a strong effect of facility volume on quality treatment and survival. Further research is needed to develop strategies to improve access to quality treatment and outcomes for cervical cancer. PMID- 26937935 TI - The Value of 18F-FDG PET/CT Imaging Combined With Pretherapeutic Ki67 for Early Prediction of Pathologic Response After Neoadjuvant Chemotherapy in Locally Advanced Breast Cancer. AB - To evaluate the value of F-fluorodeoxyglucose-positron emission tomography/computed tomography (F-FDG PET/CT) and pretherapeutic Ki67 in predicting pathologic response in locally advanced breast cancer (LABC) after neoadjuvant chemotherapy (NAC).As a training set, total 301 LABC patients treated with NAC were retrospectively analyzed to evaluate the potential predictive value of pretherapeutic Ki67 for pathologic complete response (pCR) after NAC. Another 60 LABC patients were prospectively included as a validation set to evaluate the value of Ki67 combined PET/CT as pCR predictors. Ki67 was assessed in pretherapy core needle biopsy specimens and PET/CT scans were performed at baseline (before initiating NAC), after the 2nd, and 4th cycle of NAC. Maximum standardized uptake value (SUVmax) and its changes relative to baseline (DeltaSUVmax%) were used as parameters of PEC/CT.In the training set, Ki67 was a predictor of pCR to NAC, with area under the curve (AUC) of 0.624 (P = 0.003) in receiver-operating characteristic (ROC) analysis. In the validation set, Ki67 alone did not show significant value in predicting pCR in the validation set. DeltaSUVmax% after then 2nd or 4th course are predictors of pCR to NAC with the AUC of 0.774 (P = 0.002) and 0.791 (P = 0.002), respectively. When combined with DeltaSUVmax% after the 2nd and 4th course NAC, Ki67 increased the value of DeltaSUVmax% in predicting pCR with the AUC of 0.824 (P = 0.001). Baseline SUVmax and after 2nd, 4th course NAC had no predictive value for pCR, but SUVmax after the 2nd and 4th course showed remarkable predictive value for nonpathologic response (Grade 1 in Miller-Payne Grading System) with the AUC of 0.898 (P = 0.0001) and 0.801 (P = 0.003).Both PET/CT and Ki67 can predict pCR to NAC in LABC patients in the early phases of treatment. PET/CT combined Ki67 is a better pCR predictor for response to NAC. This helps the physician to predict the probability of pCR, and facilitates the optimization of individual treatment plan in case of ineffective and/or excessive chemotherapy. PMID- 26937936 TI - Manual Thrombus Aspiration and the Improved Survival of Patients With Unstable Angina Pectoris Treated With Percutaneous Coronary Intervention (30 Months Follow Up). AB - The clinical effect of intracoronary thrombus aspiration during percutaneous coronary intervention in patients with unstable angina pectoris is unknown. In this study, we aimed to assess how thrombus aspiration during percutaneous coronary intervention affects in-hospital and 30-month mortality and complications in patients with unstable angina pectoris.We undertook an observational cohort study of 645 consecutive unstable angina pectoris patients who had performed percutaneous coronary intervention from February 2011 to March 2013. Before intervention, 159 patients who had culprit lesion with thrombus were randomly assigned to group 1 (thrombus aspiration group) and group 2 (stand-alone percutaneous coronary intervention group). All patients were followed-up 30 months until August 2015.Thrombus aspiration was performed in 64 patients (46%) whose cardiac markers (ie, creatinine kinase [CK-MB] mass and troponin T) were significantly lower after percutaneous coronary intervention than in those of group 2 (CK-MB mass: 3.80 +/- 1.11 vs 4.23 +/- 0.89, P = 0.012; troponin T: 0.012 +/- 0.014 vs 0.018 +/- 0.008, P = 0.002). Left ventricular ejection fraction at 6, 12, and 24 months postintervention was significantly higher in the group 1. During a mean follow-up period of 28.87 +/- 6.28 months, mortality rates were 6.3% in the group 1 versus 12.9% in the group 2. Thrombus aspiration was also associated with significantly less long-term mortality in unstable angina pectoris patients (adjusted HR: 4.61, 95% CI: 1.16-18.21, P = 0.029).Thrombus aspiration in the context of unstable angina pectoris is associated with a limited elevation in cardiac enzymes during intervention that minimises microembolization and significantly improves both of epicardial flow and myocardial perfusion, as shown by angiographic TIMI flow grade and frame count. Thrombus aspiration during percutaneous coronary intervention in unstable angina pectoris patients has better survival over a 30-month follow-up period. PMID- 26937937 TI - Pineal Diffuse Large B-Cell Lymphoma Concomitant With Pituitary Prolactinoma: Possible Correlation Between 2 Distinguished Pathologies: A Case Report. AB - This is the first reported case of pineal lymphoma with concomitant prolactin producing pituitary adenoma.A 51-year-old male experienced worsening headaches accompanied by nausea, diplopia, and memory loss for 1 month. Cranial nerve examination revealed bilateral upward gaze limitation with convergence impairment, which is known as Parinaud syndrome. Magnetic resonance images revealed a mass in the pineal gland with a coexisting mass within the enlarged sella fossa. Hormone analysis revealed hyperprolactinemia. The pineal mass was removed without injuring the hypothalamus, brain stem, or any neighboring vessels. Pathology examination confirmed the diagnosis of diffuse large B-cell lymphoma (DLBCL) involving the pineal gland. After further studies, the pineal lymphoma was determined to be a secondary tumor from a gastric primary tumor. The patient died 6 months after diagnosis due to systemic progression of DLBCL.Although the mechanistic link between hyperprolactinemia and lymphoma progression has not been clarified on a clinical basis, high prolactin levels may contribute to the rapid progression and therapeutic resistance of the lymphoma. PMID- 26937939 TI - Postoperative Complications After Coronary Artery Bypass Grafting in Patients With Chronic Obstructive Pulmonary Disease. AB - Coronary artery disease is common in patients with chronic obstructive pulmonary disease (COPD). Previous studies have shown that patients with COPD have a higher risk of mortality than those without COPD after coronary artery bypass grafting (CABG). However, most of the previous studies were small, single-center studies with limited case numbers (or their only focus was mortality). The aim of our study was to focus on readmission, acute myocardial infarction (AMI), acute respiratory failure (ARF), cerebrovascular accident, and venous thromboembolism rates after CABG in an Asian COPD population.We conducted a nationwide case control study in Taiwan using the claims database of hospitalization between January 1, 2009 and December 31, 2013. Patients with COPD before CABG were defined as the case groups. Each case was propensity score-matched by age, sex, hypertension, diabetes, dyslipidemia, cardiovascular disease, cerebrovascular disease, and chronic kidney disease, with 2 controls selected from CABG patients without COPD. The outcomes of interest were mortality, wound infection, and the readmission rate over 30 days for the following diseases: AMI, pneumonia, ARF, cerebrovascular accident, and venous thromboembolism.There were 14,858 patients without COPD and 758 patients with COPD who underwent CABG. After propensity score matching, the 30-day mortality and 30-day readmission rates and AMI were higher in the non-COPD group. The incidences of pneumonia and ARF after CABG were higher in the COPD group.Chronic obstructive pulmonary disease does not necessarily lead to mortality, readmission, or AMI after CABG, and the major respiratory complications associated with CABG in patients with COPD were pneumonia and ARF. PMID- 26937938 TI - Biological and Prognostic Significance of the Morphological Types and Vascular Patterns in Colorectal Liver Metastases (CRLM): Looking Beyond the Tumor Margin. AB - Patients with encapsulated colorectal liver metastases (CRLM) have a better prognosis than those without a capsule. The reason for the encapsulation is unknown. Hypoxia inducible factor-1alpha (HIF-1alpha) increases tumor angiogenesis and tumor tissue expression is associated with reduced survival. Our aim was to determine whether the good prognosis of encapsulated CRLM is associated with reduced HIF-1alpha expression by the cancer.The study selected only patients who had not undergone neoadjuvant chemotherapy prior to a potentially curative hepatectomy for CRLM. From 30 selected patients, serial sections were cut from a single randomly selected metastasis. Morphology was assessed following H&E staining. Tumor hypoxia, vascular endothelial growth factor (VEGF), proliferation, and microvascular density (MVD) were assessed by immunostaining for HIF-1alpha and carbonic anhydrase-9 (CA-9), VEGF, Ki67, and cluster of differentiation-31, respectively. MVD was calculated in the vascular hot spots. Pathology was reported without clinical outcome information. Actual long-term survival was recorded.Thirteen (43%) of the cancers were encapsulated CRLM containing glands which were large, complex, and cribriform. Thirteen (43%) were infiltrative CRLM and their glands were small, closely packed, and rounded with vessels in the interglandular fibrous tissue with no capsule; 3 (10%) had a mixed picture. Encapsulated CRLM had a higher expression of HIF-1alpha (58% vs 8%, P = 0.03), CA-9 (42% vs 0%, P = 0.04), and VEGF (92% vs 25%, P = 0.02). MVD was lower in the encapsulated CRLM group (37 mm vs 143 mm, P < 0.001). The median follow-up was 115 months. The encapsulated CRLM group had a better overall and 5 year survival (relative hazard: 0.58, P = 0.057 and hazard ratio: 0.52, P = 0.044).There are 2 main morphological appearances of CRLM which have very different long-term survival following liver resection surgery. The morphology is associated with differences in expression of HIF-1alpha, CA-9, VEGF, and angiogenesis. PMID- 26937940 TI - Successful Treatment of Scrub Typhus-Associated Hemophagocytic Lymphohistiocytosis With Chloramphenicol: Report of 3 Pediatric Cases and Literature Review. AB - Scrub typhus is caused by Orientia tsutsugamushi. Any delay in diagnosis can result in delayed treatment and severe complications, including secondary hemophagocytic lymphohistiocytosis, which is rare but potentially fatal.In this paper, the authors present 3 cases of secondary hemophagocytic lymphohistiocytosis associated with scrub typhus, successfully treated with chloramphenicol without additional antineoplastic therapy. All patients cured and achieved complete resolution.This report highlights the effectiveness of chloramphenicol without the need for chemotherapy in the treatment of scrub typhus-associated hemophagocytic lymphohistiocytosis in a pediatric population under the age of 8 years. PMID- 26937941 TI - Endogenous Heparinoids May Cause Bleeding in Mucor Infection and can be Detected by Nonactivated Thromboelastometry and Treated by Recombinant Activated Factor VII: A Case Report. AB - Mucormycosis is an aggressive fungal infection, which invades endothelial cells of blood vessels. This condition might lead to destruction of endothelium and release of heparin-like substances to the bloodstream and cause life-threatening bleeding, which is not well described in the literature.We present a patient with mucormycosis who experienced life-threatening bleeding, although no standard laboratory test could detect any coagulopathy.The cause of bleeding-coagulopathy was detected only by nonactivated thromboelastometry (NATEM), which revealed the presence of heparin-like substances. After treatment with recombinant activated FVII rotational thromboelastometry, results improved and the patient stopped bleeding. Regular application of the drug was necessary during acute phase of infection to prevent further bleeding.In this case report, we show that NATEM can detect the presence of heparin-like substances in bleeding patient with mucormycosis infection and that recombinant activated FVII can be used to stop and prevent bleeding until infection resolves. PMID- 26937942 TI - Nitrous oxide speeds the reduction of distressing intrusive memories in an experimental model of psychological trauma. AB - BACKGROUND: Post-traumatic stress disorder (PTSD) involves maladaptive long-term memory formation which underlies involuntary intrusive thoughts about the trauma. Preventing the development of such maladaptive memory is a key aim in preventing the development of PTSD. We examined whether the N-methyl d-aspartate receptor (NMDAR) antagonist gas nitrous oxide (N2O) could reduce the frequency of intrusive memories by inhibiting NMDAR-dependent memory consolidation in a laboratory analogue of psychological trauma. METHOD: Participants were randomized to inhale N2O (N = 25) or medical air (N = 25) after viewing a negatively valenced emotional film clip ('trauma film'). Participants subsequently completed a daily diary assessing frequency of intrusive thoughts relating to the film clip. A week later, participants completed an explicit memory recall task related to the film. RESULTS: Post-encoding N2O sped the reduction in intrusive memory frequency, with a significant reduction by the next day in the N2O group compared to 4 days later in the air group. N2O also interacted with post-film dissociation, producing increased intrusion frequency in those who were highly dissociated at baseline. Sleep length and quality the night after viewing the film did not differ between the groups. CONCLUSION: N2O speeds the reduction of intrusive analogue trauma memory in a time-dependent manner, consistent with sleep-dependent long-term consolidation disruption. Further research with this drug is warranted to determine its potential to inoculate against enduring effects of psychological trauma; however, caution is also urged in dissociated individuals where N2O may aggravate PTSD-like symptomatology. PMID- 26937943 TI - Both Phosphorus Fertilizers and Indigenous Bacteria Enhance Arsenic Release into Groundwater in Arsenic-Contaminated Aquifers. AB - Arsenic (As) is a human carcinogen, and arsenic contamination in groundwater is a worldwide public health concern. Arsenic-affected areas are found in many places but are reported mostly in agricultural farmlands, yet the interaction of fertilizers, microorganisms, and arsenic mobilization in arsenic-contaminated aquifers remains uncharacterized. This study investigates the effects of fertilizers and bacteria on the mobilization of arsenic in two arsenic contaminated aquifers. We performed microcosm experiments using arsenic contaminated sediments and amended with inorganic nitrogenous or phosphorus fertilizers for 1 and 4 months under aerobic and anaerobic conditions. The results show that microcosms amended with 100 mg/L phosphorus fertilizers (dipotassium phosphate), but not nitrogenous fertilizers (ammonium sulfate), significantly increase aqueous As(III) release in arsenic-contaminated sediments under anaerobic condition. We also show that concentrations of iron, manganese, potassium, sodium, calcium, and magnesium are increased in the aqueous phase and that the addition of dipotassium phosphate causes a further increase in aqueous iron, potassium, and sodium, suggesting that multiple metal elements may take part in the arsenic release process. Furthermore, microbial analysis indicates that the dominant microbial phylum is shifted from alpha-proteobacteria to beta- and gamma-proteobacteria when the As(III) is increased and phosphate is added in the aquifer. Our results provide evidence that both phosphorus fertilizers and microorganisms can mediate the release of arsenic to groundwater in arsenic contaminated sediments under anaerobic condition. Our study suggests that agricultural activity such as the use of fertilizers and monitoring phosphate concentration in groundwater should be taken into consideration for the management of arsenic in groundwater. PMID- 26937945 TI - Overexpression of SULT2B1b Promotes Angiogenesis in Human Gastric Cancer. AB - BACKGROUND/AIMS: Overexpression of cytosolic sulfotransferase 2B1b (SULT2B1b) has been commonly found in colorectal and hepatocellular carcinoma, suggesting that SULT2B1b might act as a potential oncogenic protein. However, its clinical significance and biological role in gastric cancer progression remain largely unknown. METHODS: Expressions of SULT2B1b in clinical gastric cancer (GC) samples were examined using qRT-PCR and Western blot. RESULTS: SULT2B1b was markedly overexpressed in human GC samples, and positively correlated with vessel density and associated with poor clinical features. We also demonstrated that overexpression of SULT2B1b resulted in increased tumor angiogenesis and tumor growth in mouse GC models. In addition, ablation of SULT2B1b in human GC cells lines BGC823 and MKN45 decreased the capability of the cells to recruit endothelial cells. Moreover, depletion of SULT2B1b in GC cells reduced VEGF-A expression by downregulating SP1 and AP2. CONCLUSION: Our results suggested that the SULT2B1b-mediated angiogenic pathway could serve as biomarkers for GC diagnosis and prognosis, and suppressing SULT2B1b-mediated angiogenic signaling might be a promising strategy for developing novel GC treatment. PMID- 26937944 TI - Detection of the Antimicrobial Triclosan in Environmental Samples by Immunoassay. AB - A sensitive, competitive enzyme-linked immunosorbent assay (ELISA) for the detection of the antimicrobial triclosan (TCS; 2,4,4'-trichloro-2' hydroxydiphenyl ether) was developed. Novel immunizing haptens were synthesized by derivatizing at the 4-Cl position of the TCS molecule. Compounds derived from substitutions at 4'-Cl and that replaced the 2'-OH with a Cl atom were designed as unique coating antigen haptens. Polyclonal rabbit antisera were screened against the coating antigen library to identify combinations of immunoreagents resulting in the most sensitive assays. The most sensitive assay identified was one utilizing antiserum no. 1155 and a heterologous competitive hapten, where the 2'-OH group was substituted with a Cl atom. An IC50 value and the detection range for TCS in assay buffer were 1.19 and 0.21-6.71 MUg/L, respectively. The assay was selective for TCS, providing low cross-reactivity (<5%) to the major metabolites of TCS and to brominated diphenyl ether-47. A second assay utilizing a competitive hapten containing Br instead of Cl substitutions was broadly selective for both brominated and chlorinated diphenylethers. Using the most sensitive assay combination, we measured TCS concentrations in water samples following dilution. Biosolid samples were analyzed following the dilution of a simple solvent extract. The immunoassay results were similar to those determined by LC-MS/MS. This immunoassay can be used as a rapid and convenient tool to screen for human and environmental exposure. PMID- 26937946 TI - Survey of Apoptosis After Hypothermic Storage of a Pancreatic beta-Cell Line. AB - Insulin-dependent diabetes mellitus is one of the leading causes of death world wide. Donor-derived pancreas and islet of Langerhans transplantation are potential cures, however, postmortem ischemia impacts islet quality. The murine betat3 cell line was used as a model to study apoptosis after hypothermic storage by comparing UnisolTM with Belzer's machine perfusion solution (BMPS) and the University of Wisconsin (UW) solution. The objective was to determine which of these solutions provided the best support for betat3 cells and which solution demonstrated the least amount of apoptotic activity. Several apoptosis markers were measured that included the translocation of phosphatidylserine, caspase activity, and the formation of DNA laddering. In addition, metabolic activity and membrane integrity were also measured. The results demonstrated that the three solutions behaved similarly during overnight cold storage at 4 degrees C. However, Unisol was consistently better than UW solution and BMPS, demonstrating better cell viability and recovery, and lower levels of apoptotic activity when all three parameters were measured. These results demonstrated that apoptosis plays an important role in the survival of cells and tissues during cold storage. Development of solutions to help prevent or decrease the levels of apoptosis after cold storage will likely improve overall cell and tissue recovery and survival in a clinical setting. PMID- 26937947 TI - Incidence, Risk Factors and Anatomy of Peripersonal Visuospatial Neglect in Acute Stroke. AB - AIM: The study aims to describe the epidemiology and the neural correlates of peripersonal visuospatial neglect (PVN) in patients admitted to the Geneva Stroke Unit for an acute stroke or a transient ischemic attack (TIA). METHODS: Eligible subjects were tested for PVN using both the Ota's discriminative cancellation task and a line bisection task. Brain lesions were identified on diffusion weighted imaging. A multivariate analysis was performed to identify risk factors of PVN. RESULTS: Ninety-eight consecutive patients (40.8% females) were recruited: 64 cases of ischemic stroke, 9 cases of hemorrhagic stroke and 25 cases of TIAs. The mean age was 61.9 +/- 2.86 years. The incidence of PVN was 23.5% (95% CI 15.5-33.1) and was not significantly different between patients with right and left hemisphere stroke. There were 5 cases of ipsilesional neglect. There was no association between PVN and age, sex, stroke severity, handedness, lesion type, lesion volume and time to first examination. Lesions of temporal and parietal lobes were the most frequent in patients with PVN. CONCLUSION: PVN has a low incidence in the acute stroke settings and there is no particular predictor of its presence. It is most often associated with temporo parietal lesions. PMID- 26937948 TI - Use of systemic low-dose unfractionated heparin in microvascular head and neck reconstruction: Influence in free-flap outcomes. AB - BACKGROUND: Intravenous heparin administration is used to prevent thrombosis in free-flap transfer. However, it is unknown whether the use of heparin affects free-flap survival. The purpose of this study is to investigate the effect of heparin in free flap transfer. METHODS: Two hundred and six patients who received ablative surgery for head and neck cancer were classified into three groups. Group A received ablative surgery, neck dissection, and free-flap reconstruction, and postoperatively they were administered continuous intravenous unfractionated heparin (5000-10 000 units/day) until postoperative day 7 (POD7); group B received the same procedures as group A but without heparin; group C received only ablative surgery and neck dissection without heparin. As indicators of coagulation time, the prothrombin time-international normalised ratio (PT-INR) and the activated partial thromboplastin time (APTT) were measured, before surgery and on POD1, 3, and 7. Flap failure, bleeding, haematoma formation, re exploration, and thromboembolic events were recorded. RESULTS: The PT-INR and APTT were 1.3-1.5-times longer in group A (p < 0.01), and 1.3-times longer (p < 0.01) in group B. The PT-INR and APTT were higher in groups A and B than C (p < 0.01). The free-flap success rate was not affected. Only the incidence of haematoma was increased in group A (p = 0.04). CONCLUSION: Heparin increased the haematoma formation, but did not change the incidence of free-flap failure. Thus, the intravenous low-dose heparin use does not affect microvascular flap survival. PMID- 26937949 TI - Triggering of Suicidal Erythrocyte Death by Pazopanib. AB - BACKGROUND/AIMS: The multi-targeted kinase inhibitor pazopanib, a drug employed for the treatment of a wide variety of malignancies, has previously been shown to trigger apoptosis. Similar to apoptosis of nucleated cells, erythrocytes may enter suicidal death or eryptosis, characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Mechanisms involved in the triggering of eryptosis include Ca2+ entry, oxidative stress and ceramide. The present study explored, whether pazopanib induces eryptosis and, if so, whether it is effective by Ca2+ entry, oxidative stress and/or ceramide. METHODS: Phosphatidylserine exposure at the cell surface was estimated from annexin-V-binding, cell volume from forward scatter, reactive oxygen species (ROS) formation from DCF dependent fluorescence, and ceramide abundance utilizing specific antibodies. RESULTS: A 48 hours exposure of human erythrocytes to pazopanib significantly increased the percentage of annexin-V binding (>= 25 ug/ml) and of shrunken erythrocytes (>= 50 ug/ml). Pazopanib treatment further resulted in significant hemolysis (>= 25 ug/ml). The effect of pazopanib on annexin-V-binding was significantly blunted but not abolished by removal of extracellular Ca2+. Pazopanib significantly increased DCF fluorescence (50 ug/ml) and ceramide abundance (50 ug/ml). CONCLUSIONS: Pazopanib triggers eryptosis, an effect involving Ca2+ entry, oxidative stress and ceramide. PMID- 26937953 TI - First-Principles Study of the alpha-beta Phase Transition of Ferroelectric Poly(vinylidene difluoride): Observation of Multiple Transition Pathways. AB - Transition routes from the alpha (nonpolar) phase to the beta (polar) phase of polyvinylidene difluoride (PVDF) are investigated by first-principles simulation methods. Among various possible routes, including complex torsional and rotational motions, we propose two prototypical transition routes and identify important intermediate structures along each transition pathway using the generalized solid-state nudged elastic band (G-SSNEB) method. The effect of the external electric field and mechanical drawing on the transition behavior is investigated by estimating electric enthalpy and stress tensors. Finite temperature ab initio molecular dynamics (AIMD) simulations and stress tensor analysis reveal the possibility of enhancement of the crystallinity under hydrodynamic compression. PMID- 26937952 TI - Age at Transition from Pediatric to Adult Care Has No Relationship with Mortality for Childhood-Onset Type 1 Diabetes in Japan: Diabetes Epidemiology Research International (DERI) Mortality Study. AB - OBJECTIVE: To follow up Japanese patients with type 1 diabetes for a maximum of 40 years to examine when they transitioned from pediatric care to adult care and to explore whether the attending physician, i.e., pediatrician or internist, was associated with prognosis. METHODS: Participants consisted of 1,299 patients who had been diagnosed as having type 1 diabetes at less than 15 years old between 1965 and 1979 identified through two nationwide surveys. Patients were classified as having received either pediatric care or adult care at the age of 15 and 30, and were compared for differences in mortality associated with the attending physician. RESULTS: The attending physicians were confirmed for a total of 1,093 patients at the age of 15. Of these patients, 43.8% and 40.3% received pediatric care and adult care, respectively. Of the 569 patients receiving pediatric care, 74.2%, 56.6%, 53.4%, and 51.3% continued with pediatric care at 20, 30, 40, and 50 years old, respectively. The attending physicians (pediatrician or internist) at the age of 15 and 30 had no significant impact on their survival (P = 0. 892, 0.411, respectively). CONCLUSIONS: More than half of the patients who had received pediatric care at the age of 15 continued to receive pediatric care even after the age of 30, suggesting that their transition was far from smooth, while the attending physician at the age of both 15 and 30 was not a prognostic factor for mortality. Thus, the timing for transition to adult care in these patients has no relationship with mortality in Japan. PMID- 26937954 TI - Steroidal Saponins from the Rhizomes of Aspidistra typica. AB - Eleven new furostanol saponins, typaspidosides B-L (1-11), one new spirostanol saponin, typaspidoside M (12), and five known spirostanol saponins, 25S atropuroside (13), neoaspidistrin (14), (25S)-pratioside D1 (15), 25S-aspidistrin (16) and 25S-neosibiricoside (17) were isolated from the rhizomes of Aspidistra typica Baill. The structures of the new compounds were established using 1D and 2D NMR (1H-1H COSY, HMQC, HMBC and ROESY) spectroscopy, high resolution mass spectrometry, and chemical methods. The aglycones of 1-3 (unusual furostanol saponins with opened E ring type), 9 and 10 (the methoxyl substituent at C-23 position) were found, identified from natural products for the first time. Moreover, the anti-HIV activities of the isolated steroidal glycosides were assessed, and compounds 13, 14, 16 and 17 exhibited high active against HIV-1. PMID- 26937955 TI - Who Are the High-Cost Users? A Method for Person-Centred Attribution of Health Care Spending. AB - OBJECTIVE: To develop person-centered episodes of care (PCE) for community dwelling individuals in the top fifth percentile of Ontario health care expenditures in order to: (1) describe the main clinical groupings for spending; and (2) identify patterns of spending by health sector (e.g. acute care, home care, physician billings) within and across PCE. DATA SOURCES: Data were drawn from population-based administrative databases for all publicly funded health care in Ontario, Canada in 2010/11. STUDY DESIGN: This study is a retrospective cohort study. DATA COLLECTION/EXTRACTION METHODS: A total of 587,982 community dwelling individuals were identified among those accounting for the top 5% of provincial health care expenditures between April 1, 2010 and March 31, 2011. PCE were defined as starting with an acute care admission and persisting through subsequent care settings and providers until individuals were without health system contact for 30 days. PCE were classified according to the clinical grouping for the initial admission. PCE and non-PCE costs were calculated and compared to provide a comprehensive measurement of total health system costs for the year. PRINCIPAL FINDINGS: Among this community cohort, 697,059 PCE accounted for nearly 70% ($11,815.3 million (CAD)) of total annual publicly-funded expenditures on high-cost community-dwelling individuals. The most common clinical groupings to start a PCE were Acute Planned Surgical (35.2%), Acute Unplanned Medical (21.0%) and Post-Admission Events (10.8%). Median PCE costs ranged from $3,865 (IQR = $1,712-$10,919) for Acute Planned Surgical to $20,687 ($12,207-$39,579) for Post-Admission Events. Inpatient acute ($8,194.5 million) and inpatient rehabilitation ($434.6 million) health sectors accounted for the largest proportions of allocated PCE spending over the year. CONCLUSIONS: Our study provides a novel methodological approach to categorize high-cost health system users into meaningful person-centered episodes. This approach helps to explain how costs are attributable within individuals across sectors and has applications in episode-based payment formulas and quality monitoring. PMID- 26937956 TI - Real-World Use of 3rd Line Therapy for Multiple Myeloma in Austria: An Austrian Myeloma Registry (AMR) Analysis of the Therapeutic Landscape and Clinical Outcomes prior to the Use of Next Generation Myeloma Therapeutics. AB - OBJECTIVE: Clinical trials demonstrate improving survival in patients with multiple myeloma (MM) after treatment. However, it is unclear whether increased survival translates to a similar benefit in a real world setting. METHODS: We analyzed the overall survival of 347 multiple myeloma patients in Austria by means of a national registry (AMR), focused on results from 3rd and later lines of therapy. This benchmark was chosen to define a baseline prior to the broad application of upcoming 2nd generation drugs (carfilzomib, pomalidomide). RESULTS: Projected 10 years survival for patients with MM in Austria is estimated to be 56% in patients diagnosed in between the years 2011-2014, 21% in patients with a diagnosis made between 2000-2005, and 39% in those with a diagnosis made between 2006-2010). For the same intervals a significant increase in the use of both bortezomib, lenalidomide and thalidomide-so called IMiDs (from 2005 onwards) and their simultaneous use in combination therapies (from 2010 onwards) could be shown. The use of autologous transplantation (ASCT) remained more or less constant at ~ 35% of patients in the 1st line setting over the whole period, comparing well to international practice patterns, while the use of 2nd line ASCT increased from 5.5% to 18.7% of patients. Patients in 3rd or later line treatment (n = 105), showed that even in relapsed and refractory disease median survival was 27 months with a considerable proportion of long-term survivors (~20%). CONCLUSION & PERSPECTIVE: With the expected emergence of additional active anti myeloma compounds, we aim to assess survival in patients with relapsed and refractory MM. PMID- 26937957 TI - Quantitative Spatiotemporal Chemical Profiling of Individual Lipid Droplets by Hyperspectral CARS Microscopy in Living Human Adipose-Derived Stem Cells. AB - There is increasing evidence showing that cytosolic lipid droplets, present in all eukaryotic cells, play a key role in many cellular functions. Yet their composition at the individual droplet level and how it evolves over time in living cells is essentially unknown due to the lack of suitable quantitative nondestructive measurement techniques. In this work, we demonstrate the ability of label-free hyperspectral coherent anti-Stokes Raman scattering (CARS) microscopy, together with a quantitative image analysis algorithm developed by us, to quantify the lipid type and content in vol/vol concentration units of individual lipid droplets in living human adipose-derived stem cells during differentiation over 9 days in media supplemented with different fatty acids. Specifically, we investigated the addition of the polyunsaturated linoleic and alpha-linolenic fatty acids into the normal differentiation medium (mostly containing monounsaturated fatty acids). We observe a heterogeneous uptake which is droplet-size dependent, time dependent, and lipid dependent. Cells grown in linoleic-acid-supplemented medium show the largest distribution of lipid content across different droplets at all times during differentiation. When analyzing the average lipid content, we find that adding linoleic or alpha-linolenic fatty acids at day 0 results in uptake of the new lipid components with an exponential time constant of 22 +/- 2 h. Conversely, switching lipids at day 3 results in an exponential time constant of 60 +/- 5 h. These are unprecedented findings, exemplifying that the quantitative imaging method demonstrated here could open a radically new way of studying and understanding cytosolic lipid droplets in living cells. PMID- 26937958 TI - Assessment of the Effectiveness of a Seasonal-Long Insecticide-Based Control Strategy against Aedes albopictus Nuisance in an Urban Area. AB - Seasonal-long larvicide treatments and/or outdoor space-spray applications of insecticides are frequently applied to reduce Aedes albopictus nuisance in urban areas of temperate regions, where the species has become a permanent pest affecting people's quality of life and health. However, assessments of the effectiveness of sequential interventions is a difficult task, as it requires to take into account the cumulative and combined effect of multiple treatments, as well as the mosquito seasonal dynamics (rather than mosquito abundance before and after single treatments). We here present the results of the effectiveness assessment of a seasonal-long calendar-based control intervention integrating larvicide treatments of street catch basins and night-time adulticide ground spraying in the main University hospital in Rome (Italy). Cage-experiments and an intensive monitoring of wild mosquito abundance in treated and untreated sites were carried out along an entire season. Sticky traps were used to monitor adult abundance and site-specific eco-climatic variations (by recording water left over in each trap), in order to disentangle the effect of insecticide treatments from eco-climatic drivers on mosquito seasonal dynamics. Despite the apparent limited impact of single adulticide sprayings assessed based on mortality in caged and wild mosquitoes, the results of the temporal analysis showed that mosquito seasonal patterns were initially comparable in the two sites, diverged in the absence of diverging eco-climatic conditions and remained stable afterwards. This allowed to attribute the lack of the expected Ae. albopictus population expansion in the treated site to the combined effect of multiple adulticide sprayings and larvicide treatments carried out during the whole season. The approach proposed was proved to be successful to assess effects of seasonal-long control treatments on adult mosquito population dynamics and could represent a valuable instrument to assess the effectiveness of other control interventions, to evaluate their actual cost-benefits and to possibly minimize space-spraying applications to reduce mosquito nuisance. PMID- 26937959 TI - Objectively Measured Total and Occupational Sedentary Time in Three Work Settings. AB - BACKGROUND: Sedentary behaviour increases the risk for morbidity. Our primary aim is to determine the proportion and factors associated with objectively measured total and occupational sedentary time in three work settings. Secondary aim is to study the proportion of physical activity and prolonged sedentary bouts. METHODS: Data were obtained using ActiGraph accelerometers from employees of: 1) a financial service provider (n = 49 men, 31 women), 2) two research institutes (n = 30 men, 57 women), and 3) a construction company (n = 38 men). Total (over the whole day) and occupational sedentary time, physical activity and prolonged sedentary bouts (lasting >=30 minutes) were calculated by work setting. Linear regression analyses were performed to examine general, health and work-related factors associated with sedentary time. RESULTS: The employees of the financial service provider and the research institutes spent 76-80% of their occupational time in sedentary behaviour, 18-20% in light intensity physical activity and 3-5% in moderate-to-vigorous intensity physical activity. Occupational time in prolonged sedentary bouts was 27-30%. Total time was less sedentary (64-70%), and had more light intensity physical activity (26-33%). The employees of the construction company spent 44% of their occupational time in sedentary behaviour, 49% in light, and 7% in moderate intensity physical activity, and spent 7% in sedentary bouts. Total time spent in sedentary behavior was 56%, 40% in light, and 4% in moderate intensity physical behaviour, and 12% in sedentary bouts. For women, low to intermediate education was the only factor that was negatively associated with occupational sedentary time. CONCLUSIONS: Sedentary behaviour is high among white-collar employees, especially in highly educated women. A relatively small proportion of sedentary time was accrued in sedentary bouts. It is recommended that worksite health promotion efforts should focus on reducing sedentary behaviour through improving light intensity physical activity. PMID- 26937961 TI - Correction: Anterior Lamina Cribrosa Insertion in Primary Open-Angle Glaucoma Patients and Healthy Subjects. PMID- 26937960 TI - Are PECTIN ESTERASE INHIBITOR Genes Involved in Mediating Resistance to Rhynchosporium commune in Barley? AB - A family of putative PECTIN ESTERASE INHIBITOR (PEI) genes, which were detected in the genomic region co-segregating with the resistance gene Rrs2 against scald caused by Rhynchosporium commune in barley, were characterized and tested for their possible involvement in mediating resistance to the pathogen by complementation and overexpression analysis. The sequences of the respective genes were derived from two BAC contigs originating from the susceptible cultivar 'Morex'. For the genes HvPEI2, HvPEI3, HvPEI4 and HvPEI6, specific haplotypes for 18 resistant and 23 susceptible cultivars were detected after PCR-amplification and haplotype-specific CAPS-markers were developed. None of the tested candidate genes HvPEI2, HvPEI3 and HvPEI4 alone conferred a high resistance level in transgenic over-expression plants, though an improvement of the resistance level was observed especially with OE-lines for gene HvPEI4. These results do not confirm but also do not exclude an involvement of the PEI gene family in the response to the pathogen. A candidate for the resistance gene Rrs2 could not be identified yet. It is possible that Rrs2 is a PEI gene or another type of gene which has not been detected in the susceptible cultivar 'Morex' or the full resistance reaction requires the presence of several PEI genes. PMID- 26937962 TI - Genetic Association and Gene-Gene Interaction Reveal Genetic Variations in ADH1B, GSTM1 and MnSOD Independently Confer Risk to Alcoholic Liver Diseases in India. AB - Genetic susceptibility is an important modifier of clinical outcome and natural history of progression in Alcoholic liver disease (ALD). While the significance of ethnicity in this evolution is very clear, subtle inter-individual genetic variant(s) might be important and thus we investigated those in an Indian population. Fourteen markers were genotyped within two alcohol metabolism genes [Alcohol dehydrogenase (ADH) gene clusters (ADH1B and ADH1C) and Aldehyde dehydrogenase (ALDH2)], one microsomal ethanol oxidizing enzyme cytochrome p450 (CYP2E1) and three oxidative stress response (OSR) genes (MnSOD, GSTT1 and GSTM1) among 490 Bengali individuals (322 ALD and 168 control) from Eastern and North Eastern India and validation was performed in a new cohort of 150 Bengali patients including 100 ALD and 50 advanced non-alcoholic steatohepatitis (NASH). Out of 14 genetic variants, carriage of 5 genotypes (rs2066701CC in ADH1B, rs1693425TT in ADH1C, rs4880TT in MnSOD and GSTT1/GSTM1 null, p-value <0.05) were noted significantly higher among ALD patients while inter or intra group gene gene interaction analysis revealed that addition of risk genotype of any OSR gene enhanced the possibility of ALD synergistically. Multiple logistic regression analysis showed independent association of rs2066701CC, rs4880TT and GSTM1 null genotype with ALD while lower frequencies of those genotypes in advanced NASH patients further confirmed their causal relation to ALD. Thus these findings suggest that the three variants of ADH1C, MnSOD and GSTM1 can be used to identify individuals who are at high risk to develop ALD and may be helpful in proper management of Indian alcoholics. PMID- 26937963 TI - Observation of a Flowing Duct in the Abdominal Wall by Using Nanoparticles. AB - The primo vascular system (PVS) is being established as a circulatory system that corresponds to acupuncture meridians. There have been two critical questions in making the PVS accepted as a novel liquid flowing system. The first one was directly to show the flow of liquid in PVS and the second one was to explain why it was not observed in the conventional histological study of animal tissues. Flow in the PVS in the abdominal cavity was previously verified by injecting Alcian blue into a primo node. However, the tracing of the dye to other subsystems of the PVS has not been done. In the current work we injected fluorescent nanoparticles (FNPs) into a primo node and traced them along a primo vessel which was inside a fat tissue in the abdominal wall. Linea alba is a white middle line in the abdominal skin of a mammal and a band of fat tissue is located in parallel to the linea alba in the parietal side of the abdominal wall of a rat. In this fat band a primo vessel runs parallel to the prominent blood vessels in the fat band and is located just inside the parietal peritoneum. About the second question on the reason why the PVS was not in conventional histological study the current work provided the answer. Histological analysis with hematoxyline and eosine, Masson's trichrome, and Toluidine blue could not discriminate the primo vessel even when we knew the location of the PVS by the trace of the FNPs. This clearly explains why the PVS is hard to observe in conventional histology: it is not a matter of resolution but the contrast. The PVS has very similar structure to the connective tissues that surround the PVS. In the current work we propose a method to find the PVS: Observation of mast cell distribution with toluidine blue staining and the PN has a high density of mast cells, while the lymph node has low density. PMID- 26937966 TI - Reproducibility of Fluorescent Expression from Engineered Biological Constructs in E. coli. AB - We present results of the first large-scale interlaboratory study carried out in synthetic biology, as part of the 2014 and 2015 International Genetically Engineered Machine (iGEM) competitions. Participants at 88 institutions around the world measured fluorescence from three engineered constitutive constructs in E. coli. Few participants were able to measure absolute fluorescence, so data was analyzed in terms of ratios. Precision was strongly related to fluorescent strength, ranging from 1.54-fold standard deviation for the ratio between strong promoters to 5.75-fold for the ratio between the strongest and weakest promoter, and while host strain did not affect expression ratios, choice of instrument did. This result shows that high quantitative precision and reproducibility of results is possible, while at the same time indicating areas needing improved laboratory practices. PMID- 26937964 TI - In Vivo Deletion of the Cebpa +37 kb Enhancer Markedly Reduces Cebpa mRNA in Myeloid Progenitors but Not in Non-Hematopoietic Tissues to Impair Granulopoiesis. AB - The murine Cebpa gene contains a +37 kb, evolutionarily conserved 440 bp enhancer that directs high-level expression to myeloid progenitors in transgenic mice. The enhancer is bound and activated by Runx1, Scl, GATA2, C/EBPalpha, c-Myb, Pu.1, and additional Ets factors in myeloid cells. CRISPR/Cas9-mediated replacement of the wild-type enhancer with a variant mutant in its seven Ets sites leads to 20 fold reduction of Cebpa mRNA in the 32Dcl3 myeloid cell line. To determine the effect of deleting the enhancer in vivo, we now characterize C57BL/6 mice in which loxP sites flank a 688 bp DNA segment containing the enhancer. CMV-Cre mediated germline deletion resulted in diminution of the expected number of viable Enh(f/f);CMV-Cre offspring, with 28-fold reduction in marrow Cebpa mRNA but normal levels in liver, lung, adipose, intestine, muscle, and kidney. Cre transduction of lineage-negative marrow cells in vitro reduced Cebpa mRNA 12 fold, with impairment of granulocytic maturation, morphologic blast accumulation, and IL-3 dependent myeloid colony replating for >12 generations. Exposure of Enh(f/f);Mx1-Cre mice to pIpC led to 14-fold reduction of Cebpa mRNA in GMP or CMP, 30-fold reduction in LSK, and <2-fold reduction in the LSK/SLAM subset. FACS analysis of marrow from these mice revealed 10-fold reduced neutrophils, 3-fold decreased GMP, and 3-fold increased LSK cells. Progenitor cell cycle progression was mildly impaired. Granulocyte and B lymphoid colony forming units were reduced while monocytic and erythroid colonies were increased, with reduced Pu.1 and Gfi1 and increased Egr1 and Klf4 in GMP. Finally, competitive transplantation indicated preservation of functional long-term hematopoietic stem cells upon enhancer deletion and confirmed marrow-intrinsic impairment of granulopoiesis and B cell generation with LSK and monocyte lineage expansion. These findings demonstrate a critical role for the +37 kb Cebpa enhancer for hematopoietic specific Cebpa expression, with enhancer deletion leading to impaired myelopoiesis and potentially preleukemic progenitor expansion. PMID- 26937965 TI - Riyadh Mother and Baby Multicenter Cohort Study: The Cohort Profile. AB - OBJECTIVES: To assess the effects of non-communicable diseases, such as diabetes, hypertension and obesity, on the mother and the infant. METHODS: A multicentre cohort study was conducted in three hospitals in the city of Riyadh in Saudi Arabia. All Saudi women and their babies who delivered in participating hospitals were eligible for recruitment. Data on socio-demographic characteristics in addition to the maternal and neonatal outcomes of pregnancy were collected. The cohort demographic profile was recorded and the prevalence of maternal conditions including gestational diabetes, pre-gestational diabetes, hypertensive disorders in pregnancy and obesity were estimated. FINDINGS: The total number of women who delivered in participating hospitals during the study period was 16,012 of which 14,568 women participated in the study. The mean age of the participants was 29 +/- 5.9 years and over 40% were university graduates. Most of the participants were housewives, 70% were high or middle income and 22% were exposed to secondhand smoke. Of the total cohort, 24% were married to a first cousin. More than 68% of the participants were either overweight or obese. The preterm delivery rate was 9%, while 1.5% of the deliveries were postdate. The stillbirth rate was 13/1000 live birth. The prevalence of gestational diabetes was 24% and that of pre-gestational diabetes was 4.3%. The preeclampsia prevalence was 1.1%. The labour induction rate was 15.5% and the cesarean section rate was 25%. CONCLUSION: Pregnant women in Saudi Arabia have a unique demographic profile. The prevalence of obesity and diabetes in pregnancy are among the highest in the world. PMID- 26937967 TI - Power-Law Dynamics of Membrane Conductances Increase Spiking Diversity in a Hodgkin-Huxley Model. AB - We studied the effects of non-Markovian power-law voltage dependent conductances on the generation of action potentials and spiking patterns in a Hodgkin-Huxley model. To implement slow-adapting power-law dynamics of the gating variables of the potassium, n, and sodium, m and h, conductances we used fractional derivatives of order eta<=1. The fractional derivatives were used to solve the kinetic equations of each gate. We systematically classified the properties of each gate as a function of eta. We then tested if the full model could generate action potentials with the different power-law behaving gates. Finally, we studied the patterns of action potential that emerged in each case. Our results show the model produces a wide range of action potential shapes and spiking patterns in response to constant current stimulation as a function of eta. In comparison with the classical model, the action potential shapes for power-law behaving potassium conductance (n gate) showed a longer peak and shallow hyperpolarization; for power-law activation of the sodium conductance (m gate), the action potentials had a sharp rise time; and for power-law inactivation of the sodium conductance (h gate) the spikes had wider peak that for low values of eta replicated pituitary- and cardiac-type action potentials. With all physiological parameters fixed a wide range of spiking patterns emerged as a function of the value of the constant input current and eta, such as square wave bursting, mixed mode oscillations, and pseudo-plateau potentials. Our analyses show that the intrinsic memory trace of the fractional derivative provides a negative feedback mechanism between the voltage trace and the activity of the power-law behaving gate variable. As a consequence, power-law behaving conductances result in an increase in the number of spiking patterns a neuron can generate and, we propose, expand the computational capacity of the neuron. PMID- 26937970 TI - Aplasia Cutis Congenita of the Scalp, Composite Type: The Criticality and Inseparability of Neurosurgical and Plastic Surgical Management. AB - BACKGROUND/AIMS: The object of this report is to review the management of patients having the composite type of aplasia cutis congenita in the context of the relevant literature on this condition. METHODS: Clinical records, neuroimaging and photographic documentation of identified cases of composite type aplasia cutis congenita, with a comprehensive review of the literature, are the material basis of this report. RESULTS: Two neonates with composite type aplasia cutis congenita are described as examples of this disorder, and their management, including complications, is discussed. Both had satisfactory outcomes. CONCLUSIONS: Early aggressive surgical management with scalp rotation flaps has a low rate of complications, provides satisfactory functional and esthetic outcome, minimizes hospital stays, and should provide cost-effective care by reduction of the time to secure wound closure. Most bony defects, even large ones, commonly ossify completely. Optimal case management requires a synchronized neurosurgical and plastic surgical team. Intuitive nonsurgical and surgical approaches by the inexperienced can be hazardous. PMID- 26937968 TI - Oral Bisphosphonates and Upper Gastrointestinal Cancer Risks in Asians with Osteoporosis: A Nested Case-Control Study Using National Retrospective Cohort Sample Data from Korea. AB - BACKGROUND: Bisphosphonate can irritate the gastrointestinal mucosa and increase the risk of esophageal or gastric cancer. The relatively high prevalence of upper gastrointestinal cancers and the widespread use of bisphosphonate in Korea call for further investigation. We conducted a case-control study to evaluate the risk of esophageal or gastric cancer after exposure to oral bisphosphonates in Korean patients with osteoporosis. METHODS: We used the National Health Insurance Service-National Sample Cohort database of Korea from 2002 to 2013. Among osteoporotic patients (>40 years), cases were defined as incident diagnosis of esophageal or gastric cancer between 2006 and 2013. For each case, four controls were matched for age, sex, and income level by type of insurance. We categorized bisphosphonate use as non-user, recent user, past user, and past and recent user, depending on prescription in two periods (1 to 2 years and 2 to 4 years prior to the index date). We also assessed the duration of bisphosphonate use by measuring cumulative duration of exposure (CDE). To examine the association between oral bisphosphonates and esophageal or gastric cancer, we estimated adjusted odds ratios (aORs) and 95% confidence intervals (CIs) using conditional logistic regression analysis, adjusting for concomitant diseases. RESULTS: A total of 1,708 cases and 6,832 controls were identified. The aORs (95% CIs) of recent, past, and continuous bisphosphonate use compared to non-users were 1.18 (0.93 1.51), 1.04 (0.83-1.29), and 1.25 (0.95-1.58)), respectively. In addition, no significant association was observed by CDE, even when different outcome definitions were applied. CONCLUSIONS: This study did not prove an increased risk of esophageal or gastric cancer risk associated with bisphosphonate use, with respect to both risk windows and duration of exposure, in an Asian population based, real-world setting. PMID- 26937969 TI - A Systematic Investigation into Aging Related Genes in Brain and Their Relationship with Alzheimer's Disease. AB - Aging, as a complex biological process, is accompanied by the accumulation of functional loses at different levels, which makes age to be the biggest risk factor to many neurological diseases. Even following decades of investigation, the process of aging is still far from being fully understood, especially at a systematic level. In this study, we identified aging related genes in brain by collecting the ones with sustained and consistent gene expression or DNA methylation changes in the aging process. Functional analysis with Gene Ontology to these genes suggested transcriptional regulators to be the most affected genes in the aging process. Transcription regulation analysis found some transcription factors, especially Specificity Protein 1 (SP1), to play important roles in regulating aging related gene expression. Module-based functional analysis indicated these genes to be associated with many well-known aging related pathways, supporting the validity of our approach to select aging related genes. Finally, we investigated the roles of aging related genes on Alzheimer's Disease (AD). We found that aging and AD related genes both involved some common pathways, which provided a possible explanation why aging made the brain more vulnerable to Alzheimer's Disease. PMID- 26937971 TI - Women's Perceptions and Misperceptions of Male Circumcision: A Mixed Methods Study in Zambia. AB - Women's perceptions of male circumcision (MC) have implications for behavioral risk compensation, demand, and the impact of MC programs on women's health. This mixed methods study combines data from the first two rounds of a longitudinal study (n = 934) and in-depth interviews with a subsample of respondents (n = 45) between rounds. Most women correctly reported that MC reduces men's risk of HIV (64% R1, 82% R2). However, 30% of women at R1, and significantly more (41%) at R2, incorrectly believed MC is fully protective for men against HIV. Women also greatly overestimated the protection MC offers against STIs. The proportion of women who believed MC reduces a woman's HIV risk if she has sex with a man who is circumcised increased significantly (50% to 70%). Qualitative data elaborate women's misperception regarding MC. Programs should address women's informational needs and continue to emphasize that condoms remain critical, regardless of male partner's circumcision status. PMID- 26937972 TI - The Effect of Attentional Cueing and Spatial Uncertainty in Visual Field Testing. AB - PURPOSE: To determine the effect of reducing spatial uncertainty by attentional cueing on contrast sensitivity at a range of spatial locations and with different stimulus sizes. METHODS: Six observers underwent perimetric testing with the Humphrey Visual Field Analyzer (HFA) full threshold paradigm, and the output thresholds were compared to conditions where stimulus location was verbally cued to the observer. We varied the number of points cued, the eccentric and spatial location, and stimulus size (Goldmann size I, III and V). Subsequently, four observers underwent laboratory-based psychophysical testing on a custom computer program using Method of Constant Stimuli to determine the frequency-of-seeing (FOS) curves with similar variables. RESULTS: We found that attentional cueing increased contrast sensitivity when measured using the HFA. We report a difference of approximately 2 dB with size I at peripheral and mid-peripheral testing locations. For size III, cueing had a greater effect for points presented in the periphery than in the mid-periphery. There was an exponential decay of the effect of cueing with increasing number of elements cued. Cueing a size V stimulus led to no change. FOS curves generated from laboratory-based psychophysical testing confirmed an increase in contrast detection sensitivity under the same conditions. We found that the FOS curve steepened when spatial uncertainty was reduced. CONCLUSION: We show that attentional cueing increases contrast sensitivity when using a size I or size III test stimulus on the HFA when up to 8 points are cued but not when a size V stimulus is cued. We show that this cueing also alters the slope of the FOS curve. This suggests that at least 8 points should be used to minimise potential attentional factors that may affect measurement of contrast sensitivity in the visual field. PMID- 26937990 TI - The development and validation of the Contemporary Critical Consciousness Measure. AB - The development of critical consciousness (CC) has been theorized to be an essential prerequisite for individual and collective action toward changing inequitable social conditions. However, empirically supported instruments intended to measure this important construct have only recently been introduced to the literature. The purpose of this project was to create a brief, psychometrically sound measure of CC. Two studies with over 600 observations provide initial reliability and validity data on the Contemporary Critical Consciousness Measure (CCCM). Results from exploratory and confirmatory factor analyses suggest that the final 19-item CCCM assesses CC associated with racism, classism, and heterosexism and provides a general index of CC. Results support the internal consistency and factor structure of the measure. Expected relationships between the CCCM and existing measures of symbolic racism, classism, and homonegativity provide evidence for the validity of the instrument. Limitations, future directions for research, and counseling implications are discussed. PMID- 26937991 TI - Antibody-drug conjugates for non-oncological indications. PMID- 26937992 TI - Hybrid Tip-Enhanced Nanospectroscopy and Nanoimaging of Monolayer WSe2 with Local Strain Control. AB - Many classes of two-dimensional (2D) materials have emerged as potential platforms for novel electronic and optical devices. However, their physical properties are strongly influenced by nanoscale heterogeneities in the form of edges, twin boundaries, and nucleation sites. Using combined tip-enhanced Raman scattering and photoluminescence (PL) nanospectroscopy and nanoimaging, we study the associated effects on the excitonic properties in monolayer WSe2 grown by physical vapor deposition. With ~15 nm spatial resolution, we resolve nanoscale correlations of PL spectral intensity and shifts with crystal edges and internal twin boundaries associated with the expected exciton diffusion length. Through an active atomic force tip interaction we can control the crystal strain on the nanoscale and tune the local bandgap in reversible (up to 24 meV shift) and irreversible (up to 48 meV shift) fashion. This allows us to distinguish the effect of strain from the dominant influence of defects on the PL modification at the different structural heterogeneities. Hybrid nano-optical spectroscopy and imaging with nanomechanical strain control thus enables the systematic study of the coupling of structural and mechanical degrees of freedom to the nanoscale electronic and optical properties in layered 2D materials. PMID- 26937997 TI - Driving the Oxygen Evolution Reaction by Nonlinear Cooperativity in Bimetallic Coordination Catalysts. AB - Developing efficient catalysts for electrolysis, in particular for the oxygen evolution in the anodic half cell reaction, is an important challenge in energy conversion technologies. By taking inspiration from the catalytic properties of single-atom catalysts and metallo-proteins, we exploit the potential of metal organic networks as electrocatalysts in the oxygen evolution reaction (OER). A dramatic enhancement of the catalytic activity toward the production of oxygen by nearly 2 orders of magnitude is demonstrated for novel heterobimetallic organic catalysts compared to metallo-porphyrins. Using a supramolecular approach we deliberately place single iron and cobalt atoms in either of two different coordination environments and observe a highly nonlinear increase in the catalytic activity depending on the coordination spheres of Fe and Co. Catalysis sets in at about 300 mV overpotential with high turnover frequencies that outperform other metal-organic catalysts like the prototypical hangman porphyrins. PMID- 26937998 TI - Building Self-Healing Alloy Architecture for Stable Sodium-Ion Battery Anodes: A Case Study of Tin Anode Materials. AB - The rational design of anode materials is a challenge in developing sodium ion batteries. Alloy anodes provide high gravimetric and volumetric capacities but suffer the short cycle life as a result of the continuous and accumulated pulverization, resulting from a large volume change during the cycling process. Herein, using pure Sn, an irreversible conversion reaction combined with an alloy reaction (SnO), and a reversible conversion reaction combined with an alloy reaction (Sn4P3) as samples, we demonstrate that the pulverization and aggregation of the alloy anode can be partially recovered and the accumulation of pulverization and aggregation during charge/discharge cycles can be terminated using a reversible conversion reaction combined with an alloy reaction. The cycling stability of three Sn-based anodes increases in order of Sn4P3 > SnO > Sn. The enhancement in Sn4P3 can be attributed to a reversible reaction of Sn4P3 + 9Na <-> 4Sn + 3Na3P, which repairs the cracks, damage, and aggregation of Sn particles that occurred in the alloy process of 4Sn + 15Na <-> Na15Sn4 during cycling and, hence, terminates the pulverization. The repair mechanism looks like the self-healing feature in nature, where the damage can be healed by itself. Therefore, the suggested mechanism can be called self-healing, while the repaired anode can be termed as the self-healing anode. The use of self-healing strategies to build an electrode architecture is new and highly desirable because it can increase the cycle life and provide a general approach toward stable electrode materials. PMID- 26937999 TI - Routes of Synthesis of Carbapenems for Optimizing Both the Inactivation of L,D Transpeptidase LdtMt1 of Mycobacterium tuberculosis and the Stability toward Hydrolysis by beta-Lactamase BlaC. AB - Combinations of beta-lactams of the carbapenem class, such as meropenem, with clavulanate, a beta-lactamase inhibitor, are being evaluated for the treatment of drug-resistant tuberculosis. However, carbapenems approved for human use have never been optimized for inactivation of the unusual beta-lactam targets of Mycobacterium tuberculosis or for escaping to hydrolysis by broad-spectrum beta lactamase BlaC. Here, we report three routes of synthesis for modification of the two side chains carried by the beta-lactam and the five-membered rings of the carbapenem core. In particular, we show that the azide-alkyne Huisgen cycloaddition reaction catalyzed by copper(I) is fully compatible with the highly unstable beta-lactam ring of carbapenems and that the triazole ring generated by this reaction is well tolerated for inactivation of the L,D-transpeptidase LdtMt1 target. Several of our new carbapenems are superior to meropenem both with respect to the efficiency of in vitro inactivation of LdtMt1 and reduced hydrolysis by BlaC. PMID- 26938015 TI - From a Phosphaketenyl-Functionalized Germylene to 1,3-Digerma-2,4 diphosphacyclobutadiene. AB - The first 4pi-electron resonance-stabilized 1,3-digerma-2,4 diphosphacyclobutadiene [L(H)2Ge2P2] 4 (L(H)=CH[CHNDipp]2 Dipp=2,6-(i)Pr2C6H3) with four-coordinate germanium supported by a beta-diketiminate ligand and two coordinate phosphorus atoms has been synthesized from the unprecedented phosphaketenyl-functionalized N-heterocyclic germylene [L(H)Ge-P=C=O] 2 a prepared by salt-metathesis reaction of sodium phosphaethynolate (P=C-ONa) with the corresponding chlorogermylene [L(H)GeCl] 1 a. Under UV/Vis light irradiation at ambient temperature, release of CO from the P=C=O group of 2 a leads to the elusive germanium-phosphorus triply bonded species [L(H)Ge=P] 3 a, which dimerizes spontaneously to yield black crystals of 4 as isolable product in 67% yield. Notably, release of CO from the bulkier substituted [L(tBu)Ge-P=C=O] 2 b (L(tBu)=CH[C((t)Bu)N-Dipp]2 ) furnishes, under concomitant extrusion of the diimine [Dipp-NC((t)Bu)]2, the bis-N,P-heterocyclic germylene [DippNC((t)Bu)C(H)PGe]2 5. PMID- 26938016 TI - Lasiolactols A and B Produced by the Grapevine Fungal Pathogen Lasiodiplodia mediterranea. AB - A strain of Lasiodiplodia mediterranea, a fungus associated with grapevine decline in Sicily, produced several metabolites in liquid medium. Two new dimeric gamma-lactols, lasiolactols A and B (1 and 2), were characterized as (2S*,3S*,4R*,5R*,2'S*,3'S*,4'R*,5'R*)- and (2R*,3S*,4R*,5R*,2'R*,3'S*,4'R*,5'R*) (5-(4-hydroxymethyl-3,5-dimethyl-tetrahydro-furan-2-yloxy)-2,4-dimethyl tetrahydro-furan-3-yl]-methanols by IR, 1D- and 2D-NMR, and HR-ESI-MS. Other four metabolites were identified as botryosphaeriodiplodin, (5R)-5 hydroxylasiodiplodin, (-)-(1R,2R)-jasmonic acid, and (-)-(3S,4R,5R)-4 hydroxymethyl-3,5-dimethyldihydro-2-furanone (3 - 6, resp.). The absolute configuration (R) at hydroxylated secondary C-atom C(7) was also established for compound 3. The compounds 1 - 3, 5, and 6, tested for their phytotoxic activities to grapevine cv. Inzolia leaves at different concentrations (0.125, 0.25, 0.5, and 1 mg/ml) were phytotoxic and compound 5 showed the highest toxicity. All metabolites did not show in vitro antifungal activity against four plant pathogens. PMID- 26938018 TI - Bioinspired Omniphobic Coatings with a Thermal Self-Repair Function on Industrial Materials. AB - Inspired by the wax regeneration ability of plant leaves and the slippery surfaces of the Nepenthes pitcher plants, we have developed a new form of cross species bioinspired slippery liquid-infused porous surfaces (X-SLIPS) that can self-repair under thermal stimulation even under large-area physical and chemical damage. The performance and underlying mechanism of the thermal-healing property has been studied and characterized in detail. These thermally self-healing omniphobic coatings can be applied to a broad range of metals, plastics, glass, and ceramics of various shapes and show excellent repellency toward aqueous and organic liquids. PMID- 26938019 TI - Altered mRNP granule dynamics in FTLD pathogenesis. AB - In neurons, RNA-binding proteins (RBPs) play a key role in post-transcriptional gene regulation, for example alternative splicing, mRNA localization in neurites and local translation upon synaptic stimulation. There is increasing evidence that defective or mislocalized RBPs - and consequently altered mRNA processing - lead to neuronal dysfunction and cause neurodegeneration, including frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Cytosolic RBP aggregates containing TAR DNA-binding protein of 43 kDa (TDP-43) or fused in sarcoma (FUS) are a common hallmark of both disorders. There is mounting evidence that translationally silent mRNP granules, such as stress granules or transport granules, play an important role in the formation of these RBP aggregates. These granules are thought to be 'catalytic convertors' of RBP aggregation by providing a high local concentration of RBPs. As recently shown in vitro, RBPs that contain a so-called low-complexity domain start to 'solidify' and eventually aggregate at high protein concentrations. The same may happen in mRNP granules in vivo, leading to 'solidified' granules that lose their dynamic properties and ability to fulfill their physiological functions. This may result in a disturbed stress response, altered mRNA transport and local translation, and formation of pathological TDP-43 or FUS aggregates, all of which may contribute to neuronal dysfunction and neurodegeneration. Here, we discuss the general functional properties of these mRNP granules, how their dynamics may be disrupted in frontotemporal lobar degeneration/amyotrophic lateral sclerosis, for example by loss or gain of function of TDP-43 and FUS, and how this may contribute to the development of RBP aggregates and neurotoxicity. In this review, we discuss how dynamic mRNP granules, such as stress granules or neuronal transport granules, may be converted into pathological aggregates containing misfolded RNA-binding proteins (RBPs), such as TDP-43 and FUS. Abnormal interactions between low complexity domains in RBPs may cause dynamic mRNP granules to solidify and become dysfunctional. This may result in a disturbed stress response, altered mRNA transport and local translation, as well as RBP aggregation, all of which may contribute to neuronal dysfunction and neurodegeneration. PMID- 26938023 TI - Paul Terasaki September 10, 1929--January 26, 2016. PMID- 26938025 TI - Au Nanowire-Striped Cu3P Platelet Photoelectrocatalysts. AB - A stripy pattern of continuous epitaxial growth of thin Au nanowires on plasmonic Cu3P platelets is reported. The obtained Au-Cu3P heterostructures retain their wide area interfacial heterojunction, which is typically not observed in metal semiconductor heterostructures. This is performed by phosphine-mediated in situ reduction of Au ions on specific facets of Cu3P platelets. The intriguing stripy movements of nanowires are regulated by strong surface binding ligands. Because this is a dual plasmon heterostructure with wide visible absorption window, these are further explored as a photoelectrocatalyst for efficient hole transfer and sensing of an important biomolecule, nicotinamide adenine dinucleotide (NADH). The observed anodic photocurrent was 30 times higher in the presence of NADH, and this proves that the heterostructured material is an ideal photosenser and an efficient catalyst for solar energy conversion. PMID- 26938024 TI - Synthesis of the Hemoglobin-Conjugated Polymer Micelles by Thiol Michael Addition Reactions. AB - Amphiphilic triblock copolymers mPEG-b-PMAC-b-PCL are synthesized using methoxyl poly(ethylene glycol), cyclic carbonic ester monomer including acryloyl group, and epsilon-caprolactone. Copolymers are self-assembled into core-shell micelles in aqueous solution. Thiolated hemoglobin (Hb) is conjugated with micelles sufficiently through thiol Michael addition reaction to form hemoglobin nanoparticles (HbNs) with 200 nm in diameter. The conjugation of Hb onto the micelle surface is further confirmed by X-ray photoelectron spectroscopy. Feeding ratio of copolymer micelles to Hb at 1:3 would lead to the highest hemoglobin loading efficiency 36.7 wt%. The UV results demonstrate that the gas transporting capacity of HbNs is well remained after Hb is conjugated with polymeric micelles. Furthermore, the obtained HbNs have no obvious detrimental effects on blood components in vitro. This system may thus have great potential as one of the candidates to be developed as oxygen carriers and provide a reference for the modification of protein drugs. PMID- 26938026 TI - Measurements of Ionization Cross Sections by Molecular Beam Experiments: Information Content on the Imaginary Part of the Optical Potential. AB - In this work, we present and analyze in detail new and recent ionization cross section and mass spectrum determinations, collected in the case of He*, Ne*-H2O, H2S, and -NH3 ionizing collisions. These sets of data, obtained under the same experimental conditions, are relevant to identify differences in the autoionization stereodynamics of the three hydrogenated molecules and on the selective role of the imaginary part of the optical potential. We demonstrate that in these autoionization processes hydrogen and halogen bonds are competing because they are controlling both real and imaginary components of the optical potential that drives the complete reaction dynamics. In particular, we found that both components critically depend on the angular and radial approach between the reagent partners in determining the collision dynamics. PMID- 26938028 TI - Differences in the origins of kinetochore-positive and kinetochore-negative micronuclei: A live cell imaging study. AB - Micronuclei (MNi) are extensively used to evaluate genotoxicity and chromosomal instability. Classification of kinetochore-negative (K-MNi) and kinetochore positive micronuclei (K+MNi) improves the specificity and sensitivity of the micronucleus (MN) test; however, the fundamental differences in the origins of K MNi and K+MNi have not been addressed due to the limitations of traditional methods. In the current study, HeLa CENP B-GFP H2B-mCherry cells were constructed in which histone 2B (H2B) and centromere protein B (CENP B) were expressed as fusion proteins to monomeric Cherry (mCherry) and EGFP, respectively. MNi were identified using H2B-mCherry; K+MN contained CENP B-GFP, while K-MN did not. Long term live cell imaging was conducted to examine MN formation in the dual-color fluorescent HeLa cells. The results suggested that K-MNi were derived from kinetochore-negative displaced chromosomes (K-DCs), kinetochore-negative lagging chromosomes (K-LCs) and fragments of broken chromosome bridges (CBs) during late mitotic stages. The results also indicated that K+MNi are derived from kinetochore-positive displaced chromosomes (K+DCs), kinetochore-positive lagging chromosomes (K+LCs), and fragments of broken CBs. Different aberrant chromosomes emerged during mitosis at different frequencies and developed into K-MNi and/or K+MNi in the daughter cells at different rates. K+LCs formed K+MNi at a higher frequency than K+DCs, and K-LCs formed K-MNi at a higher rate than K-DCs; however, broken CBs transformed into K-MNi and/or K+MNi. In summary, these results show that K-MNi and K+MNi have different origins in HeLa cells and that each mechanism of MN formation contributes differently to the overall number of K MNi and K+MNi. PMID- 26938027 TI - Perception of faces in schizophrenia: Subjective (self-report) vs. objective (psychophysics) assessments. AB - OBJECTIVES: Face perception impairment in schizophrenia has been demonstrated, mostly through experimental studies. How this laboratory-defined behavioral impairment is associated with patients' perceptual experience of various faces in everyday life is however unclear. This question is important because a first person account of face perception has direct consequences on social functioning of patients. In this study, we adapted and administered a self-reported questionnaire on narrative perceptual experience of faces along with psychophysical assessments of face perception in schizophrenia. METHODS: The self reported questionnaire includes six rating items of face-related functioning in everyday life, providing a subjective measure of face perception. The psychophysical assessment determines perceptual threshold for discriminating different facial identities, providing an objective measure of face perception. RESULTS: Compared to controls (n = 25), patients (n = 35) showed significantly lower scores (worse performance) in the subjective assessment and significantly higher thresholds (worse performance) in the objective assessment. The subjective and objective face perception assessments were moderately correlated in controls but not in patients. The subjective face perception assessments were significantly correlated with measurements of a social cognitive ability (Theory of Mind), again in controls but not in patients. CONCLUSION: These results suggest that in schizophrenia the quality of face-related functioning in everyday life is degraded and the role that basic face discrimination capacity plays in face-related everyday functioning is disrupted. PMID- 26938031 TI - Editor's Introduction: Dedication to Doug Green. PMID- 26938032 TI - Comprehensive Imaging Review of Abnormalities of the Placenta. AB - The placenta has a fundamental role in fetal health and functions as an important bridge to normal fetal development throughout pregnancy. A complete fetal ultrasound (US) survey should include full assessment of the placenta for any possible abnormalities. Placental diseases range from abnormal morphology, size, location, extent, and degree of placentation, to abruption and the presence of rare placental neoplasms of benign or malignant nature. Some of these conditions are associated with other diseases including aneuploidies, and their discovery should alert the radiologist to perform a very thorough fetal US examination. At times, a fetal karyotype may be needed to provide additional information. Timely detection of placental abnormalities can alert the clinician regarding the need to make important management decisions to reduce fetal and maternal morbidity and mortality. Familiarity with the normal and abnormal imaging appearance of the placenta is therefore necessary for the radiologist. Ultrasound with Doppler is the initial imaging modality of choice for placental assessment. Magnetic resonance imaging serves as a problem-solving examination in instances where the US findings are equivocal or where additional information is needed. Computed tomography has a limited role in the evaluation of placental disease because of its relatively limited tissue characterization and in particular because of the resultant direct radiation exposure of the fetus. However, in specific instances, particularly after trauma, computed tomography can provide invaluable information for patient management. PMID- 26938033 TI - A Benign Anomalous Umbilical Vein: Not All Umbilical Veins That Wander Are Lost. AB - A rare case of an anomalous umbilical vein with a previously unreported outcome is described. Most reported cases of anomalous umbilical veins are associated with significant concurrent fetal anomalies and poor outcomes. Fetal magnetic resonance imaging was used in this case to confirm normal portal and hepatic venous vasculature. No other fetal anomalies were identified on ultrasound. The infant was delivered at term and is healthy at the age of 8 months. Parental anxiety regarding the diagnosis was the only adverse consequence of this incidental finding. PMID- 26938034 TI - Characterization of Hemodynamics in Great Arteries of Wild-Type Mouse Using Computational Fluid Dynamics Based on Ultrasound Images. AB - Hemodynamic factors in cardiovascular system are hypothesized to play a significant role in causing structural heart development. It is thus important to improve our understanding of velocity characteristics and parameters. We present such a study on wild-type mouse to characterize the vessel geometry, flow pattern, and wall shear stress in great arteries. Microultrasound imaging for small animals was used to measure blood boundary and velocity of the great arteries. Subsequently, specimens' flow boundary conditions were used for 3 dimensional reconstructions of the great artery and aortic arch dimensions, and blood flow velocity data were input into subject-specific computational fluid dynamics for modeling hemodynamics. Measurement by microultrasound imaging showed that blood velocities in the great artery and aortic arch had strong correlations with vascular sizes, whereas blood pressure had a weak trend in relation to vascular size. Wall shear stress magnitude increased when closer to arterial branches and reduced proximally in the aortic root and distally in the descending aorta, and the parameters were related to the fluid mechanics in branches in some degree. We developed a method to investigate fluid mechanics in mouse arteries, using a combination of microultrasound and computational fluid dynamics, and demonstrated its ability to reveal detailed geometric, kinematic, and fluid mechanics parameters. PMID- 26938035 TI - Duplex Doppler Ultrasound of the Hepatic Artery: A Window to Diagnosis of Diffuse Liver Pathology. AB - The use of Doppler sonography for evaluation of the liver is well established, and evaluation of the portal and hepatic veins in native livers, as well as the hepatic artery in transplant livers, is a standard part of the examination. Less well known, however, is that assessment hepatic of artery blood flow velocities and waveforms can permit inferences to be made about liver and system pathophysiology even in native livers. This review will illustrate that hepatic parenchymal abnormalities, as well as primary vascular abnormalities both upstream and downstream of the proper hepatic artery, can be inferred from careful interrogation of its Doppler signature during routine abdominal sonography. PMID- 26938029 TI - Transcatheter intra-arterial infusion of doxorubicin loaded porous magnetic nano clusters with iodinated oil for the treatment of liver cancer. AB - A promising strategy for liver cancer treatment is to deliver chemotherapeutic agents with multifunctional carriers into the tumor tissue via intra-arterial (IA) transcatheter infusion. These carriers should release drugs within the target tissue for prolonged periods and permit intra-procedural multi-modal imaging of selective tumor delivery. This targeted transcatheter delivery approach is enabled via the arterial blood supply to liver tumors and utilized in current clinical practice which is called chemoembolization or radioembolization. During our study, we developed Doxorubicin (Dox) loaded porous magnetic nano clusters (Dox-pMNCs). The porous structure and carboxylic groups on the MNCs achieved high-drug loading efficiency and sustained drug release, along with magnetic properties resulting in high MRI T2-weighted image contrast. Dox-pMNC within iodinated oil, Dox-pMNCs, and Dox within iodinated oil were infused via hepatic arteries to target liver tumors in a rabbit model. MRI and histological evaluations revealed that the long-term drug release and retention of Dox-pMNCs within iodinated oil induced significantly enhanced liver cancer cell death. PMID- 26938036 TI - Redefining the Criteria for Grading Varicoceles Based on Reflux Times: A Clinicoradiological Correlation. AB - The aims of the study were to redefine the criteria used to grade varicoceles, based on reflux times that correlate with Dubin and Amelar clinical grading by overcoming the limitations of clinical grading and to include the less known entity of intratesticular varicoceles in the grading. Prospective correlative study was undertaken at JSS Hospital, Mysore, India during the period from July 2010 to October 2014. All patients with clinical suspicion of varicocele were clinically graded by Dubin and Amelar grading system and were later subjected to duplex ultrasound examination. The duration of the reflux obtained during the Valsalva maneuver was measured in milliseconds. Patients with intratesticular varicocele were noted and they were subgraded. One hundred patients were examined as per the methodology.The mean reflux times obtained as per the clinically graded varicoceles were as follows: subclinical varicocele, 835 ms; grade 1 varicocele, 1907 ms; grade 2 varicocele, 3108 ms; and grade 3 varicocele, 4508 ms.Based on the results obtained, we propose a modified radiological grading of the varicocele that is based on reflux times at Valsalva maneuver for each clinical grade. The presence of an intratesticular varicocele with any of the above grades is to be suffixed with "I." PMID- 26938037 TI - Investigation of the Upper Airway Anatomy With Ultrasound. AB - OBJECTIVE: The aims of this study were to describe the relationship between the scanning planes and appearance of the upper airway on sonography and to demonstrate the reliability and reproducibility of sonographic measurements of the upper airway. METHODS: Airway sonoanatomy was recognized by comparing the airway images and the corresponding cadaver's anatomical specimens. Systemic sonographic examination of 267 healthy volunteers was conducted to obtain the sonographic measurement of airway lumen. The reliability and reproducibility studies were conducted in 40 healthy volunteers. RESULT: The air-filled upper airway appeared as a bright heterogeneous hyperechoic line. During deep inspiration, the upper airway lumen expanded to the highest anterior-posterior dimension, whereas during deep expiration, the lateral dimension tended to increase. The sonographic measurements had good reproducibility, with intraclass correlation coefficient ranging from 0.722 to 0.887 and 0.727 to 0.882 for interobserver and intraobserver reliability, respectively. CONCLUSIONS: Ultrasonography can determine the anatomy of the upper airway and perform the quantitative analysis of the upper airway lumen during respiration. The results were encouraging and support the utility of ultrasonography in future airway disorder studies. PMID- 26938038 TI - Psychiatric side effects of acute high-dose corticosteroid therapy in neurological conditions. AB - It has been implied that high-dose corticosteroids (CSs) commonly cause psychiatric side effects. Here, we examined the rate and risk factors of psychiatric side effects during high-dose CS treatment in patients with neurological disorders. Patients treated with high-dose intravenous CSs for neurological disorders were evaluated for depression, mania, and psychosis using the Beck Depression Inventory, the Geriatric Depression Scale, the Young Mania Rating Scale, and the Brief Psychiatric Rating Scale before CS treatment, immediately after, and 1 month following treatment. Forty-nine consecutive patients were monitored. There was a reduction in the Beck Depression Inventory and Geriatric Depression Scale scores as well as in the Brief Psychiatric Rating Scale scores throughout the study period and a transitory increase in the Young Mania Rating Scale score immediately after CS administration. Thus, a tendency to develop transient mild euphoria during high-dose CS treatment exists, but is reversible at 1 month, whereas a reduction in depressive symptoms tended to persist. Overall, our data indicate that high-dose CS treatment for neurological diseases is relatively safe with respect to psychiatric complications. PMID- 26938039 TI - Genomic Approaches to Phenotype Prediction. PMID- 26938040 TI - Supplementary management of functional, temporary alcoholic hepatic damage with Robuvit(r) (French oak wood extract). AB - : The aim of this registry study was to evaluate Robuvit(r) (quercus robur wood extract) supplementation in the evolution of moderate functional hepatic failure (MTHF) due to alcohol. Recent studies have indicated the protective effect of oak wood (QR) extracts on liver injury. This registry included patients with MTHF characterized by: decreased albumin levels; increased total bilirubin, altered hepatic functions enzymes, increased oxidative stress, negative viral hepatitis markers. RESULTS: The two groups resulted divided into a best management (BM) group and a comparative group (BM+ Robuvit (r) were comparable): 23 Robuvit(r) patients and 21 comparable controls completed the 12-week registry. At inclusion, blood parameters in the two groups were comparable. At the end of the observation period, the increase in albumin levels was significantly (P<0.05 at 12 weeks) faster and higher in the Robuvit(r) group. The decreasee in ALT-SGPT and AST-ASAT were significantly larger in the supplement group (P<0.05 at 6 and 12 weeks). Alkaline phosphatase was reduced more, at 6 and 12 weeks in Robuvit(r) patients; (Robuvit(r) group's values were significantly better; P<0.05). Total bilirubin improved better in Robuvit(r) subjects at 6 and 12 weeks. Results were significantly better in comparison with controls (P<0.05). Also, direct bilirubin values increased more in the Robuvit(r) group at 6 and 12 weeks (P<0.05). Gamma GT values were normalized at 6 and 12 weeks in the Robuvit(r) group. There was a less important decrease in controls (P<0.05) without normalization at 12 weeks. Plasma free radicals, increased at inclusion, showed a more significant decrease in Robuvit(r) subject (at 6 and 12 weeks), with normalization at 12 weeks. Persisting, elevated values in controls were observed even at 12 weeks (P<0.05). ESR decreased in both groups with a more important decrease in the Robuvit(r) group (P<0.05). Hepatitis markers were negative when repeated at 6 and 12 weeks. In conclusion, observations from this pilot, supplement registry study indicate a significant protective activity of the supplementation with Robuvit(r), associated with a very good safety profile, in patients with temporary hepatic failure. The activity of Robuvit (r) seems to be mediated by its anti inflammatory activity associated to its important action on oxidative stress. PMID- 26938041 TI - UVnovo: A de Novo Sequencing Algorithm Using Single Series of Fragment Ions via Chromophore Tagging and 351 nm Ultraviolet Photodissociation Mass Spectrometry. AB - De novo peptide sequencing by mass spectrometry represents an important strategy for characterizing novel peptides and proteins, in which a peptide's amino acid sequence is inferred directly from the precursor peptide mass and tandem mass spectrum (MS/MS or MS(3)) fragment ions, without comparison to a reference proteome. This method is ideal for organisms or samples lacking a complete or well-annotated reference sequence set. One of the major barriers to de novo spectral interpretation arises from confusion of N- and C-terminal ion series due to the symmetry between b and y ion pairs created by collisional activation methods (or c, z ions for electron-based activation methods). This is known as the "antisymmetric path problem" and leads to inverted amino acid subsequences within a de novo reconstruction. Here, we combine several key strategies for de novo peptide sequencing into a single high-throughput pipeline: high-efficiency carbamylation blocks lysine side chains, and subsequent tryptic digestion and N terminal peptide derivatization with the ultraviolet chromophore AMCA yield peptides susceptible to 351 nm ultraviolet photodissociation (UVPD). UVPD-MS/MS of the AMCA-modified peptides then predominantly produces y ions in the MS/MS spectra, specifically addressing the antisymmetric path problem. Finally, the program UVnovo applies a random forest algorithm to automatically learn from and then interpret UVPD mass spectra, passing results to a hidden Markov model for de novo sequence prediction and scoring. We show this combined strategy provides high-performance de novo peptide sequencing, enabling the de novo sequencing of thousands of peptides from an Escherichia coli lysate at high confidence. PMID- 26938042 TI - En bloc endoscopic submucosal dissection for a giant neoplastic lesion in the duodenal bulb. AB - Endoscopic submucosal dissection(ESD) of duodenal neoplasm is technically difficult for the tortuous lumen and thin wall. This letter to editor describes a case with a giant neoplastic lesion in the duodenal bulb, which was en bloc resected by the ESD technique. PMID- 26938043 TI - Do the Threshold Limit Values for Work in Hot Conditions Adequately Protect Workers? AB - PURPOSE: We evaluated core temperature responses and the change in body heat content (DeltaHb) during work performed according to the ACGIH threshold limit values (TLV) for heat stress, which are designed to ensure a stable core temperature that does not exceed 38.0 degrees C. METHODS: Nine young males performed a 120-min work protocol consisting of cycling at a fixed rate of heat production (360 W). On the basis of the TLV, each protocol consisted of a different work-rest (WR) allocation performed in different wet-bulb globe temperatures (WBGT). The first was 120 min of continuous (CON) cycling at 28.0 degrees C WBGT (CON[28.0 degrees C]). The remaining three protocols were intermittent work bouts (15-min duration) performed at various WR and WBGT: (i) WR of 3:1 at 29.0 degrees C (WR3:1[29.0 degrees C]), (ii) WR of 1:1 at 30.0 degrees C (WR1:1[30.0 degrees C]), and (iii) WR of 1:3 at 31.5 degrees C (WR1:3[31.5 degrees C]) (total exercise time: 90, 60, and 30 min, respectively). The change in rectal (DeltaTre) and mean body temperature (DeltaTb) was evaluated with thermometry. DeltaHb was determined via direct calorimetry and also used to calculate DeltaTb. RESULTS: Although average rectal temperature did not exceed 38.0 degrees C, heat balance was not achieved during exercise in any work protocol (i.e., rate of DeltaTre > 0 degrees C.min; all P values <= 0.02). Consequently, it was projected that if work was extended to 4 h, the distribution of participant core temperatures higher and lower than 38.0 degrees C would be statistically similar (all P values >= 0.10). Furthermore, DeltaHb was similar between protocols (P = 0.70). However, a greater DeltaTb was observed with calorimetry relative to thermometry in WR3:1[29.0 degrees C] (P = 0.03), WR1:1[30.0 degrees C] (P = 0.02), and WR1:3[31.5 degrees C] (P < 0.01) but not CON[28.0 degrees C] (P = 0.32). CONCLUSION: The current study demonstrated that heat balance was not achieved and DeltaTb and DeltaHb were inconsistent, suggesting that the TLV may not adequately protect workers during work in hot conditions. PMID- 26938044 TI - Two doses and not three for the human papilloma virus vaccine in Chile. PMID- 26938045 TI - Enantioselective Metabolism of Flufiprole in Rat and Human Liver Microsomes. AB - The enantioselective metabolism of flufiprole in rat and human liver microsomes in vitro was investigated in this study. The separation and determination were performed using a liquid chromatography system equipped with a triple-quadrupole mass spectrometer and a Lux Cellulose-2 chiral column. The enantioselective metabolism of rac-flufiprole was dramatically different in rat and human liver microsomes in the presence of the beta-nicotinamide adenine dinucleotide phosphate regenerating system. The half-lives (t1/2) of flufiprole in rat and human liver microsomes were 7.22 and 21.00 min, respectively, for R-(+) flufiprole, whereas the values were 11.75 and 17.75 min, respectively, for S-(-) flufiprole. In addition, the Vmax of R-(+)-flufiprole was about 3-fold that of S (-)-flufiprole in rat liver microsomes, whereas its value in the case of S-(-) flufiprole was about 2-fold that of R-(+)-flufiprole in human liver microsomes. The CLint of rac-flufiprole also showed opposite enantioselectivy in rat and human liver microsomes. The different compositions and contents of metabolizing enzyme in the two liver microsomes might be the reasons for the difference in the metabolic behavior of the two enantiomers. PMID- 26938046 TI - Rapid Screening for Exposure to "Non-Target" Pharmaceuticals from Wastewater Effluents by Combining HRMS-Based Suspect Screening and Exposure Modeling. AB - Active pharmaceutical ingredients (APIs) have raised considerable concern over the past decade due to their widespread detection in water resources and their potential to affect ecosystem health. This triggered many attempts to prioritize the large number of known APIs to target monitoring efforts and testing of fate and effects. However, so far, a comprehensive approach to screen for their presence in surface waters has been missing. Here, we explore a combination of an automated suspect screening approach based on liquid chromatography coupled to high-resolution mass spectrometry and a model-based prioritization using consumption data, readily predictable fate properties and a generic mass balance model for activated sludge treatment to comprehensively detect APIs with relevant exposure in wastewater treatment plant effluents. The procedure afforded the detection of 27 APIs that had not been covered in our previous target method, which included 119 parent APIs. The newly detected APIs included seven compounds with a high potential for bioaccumulation and persistence, and also three compounds that were suspected to stem from point sources rather than from consumption as medicines. Analytical suspect screening proved to be more selective than model-based prioritization, making it the method of choice for focusing analytical method development or fate and effect testing on those APIs most relevant to the aquatic environment. However, we found that state-of-the practice exposure modeling used to predict potential high-exposure substances can be a useful complement to point toward oversights and known or suspected detection gaps in the analytical method, most of which were related to insufficient ionization. PMID- 26938051 TI - ACE2 Antagonizes VEGFa to Reduce Vascular Permeability During Acute Lung Injury. AB - BACKGROUND/AIMS: Angiotensin converting enzyme 2 (ACE2) treatment suppresses the severity of acute lung injury (ALI), through antagonizing hydrolyzing angiotensin II (AngII) and the ALI-induced apoptosis of pulmonary endothelial cells. Nevertheless, the effects of ACE2 on vessel permeability and its relationship with vascular endothelial growth factor a (VEGFa) remain ill-defined. In the current study, we examined the relationship between ACE2 and VEGFa in ALI model in mice. METHODS: Here, we used a previously published bleomycin method to induce ALI in mice, and treated the mice with ACE2. We analyzed the levels of VEGFa in these mice. The mouse lung vessel permeability was determined by a fluorescence pharmacokinetic assay following i.v. injection of 62.5ug/kg Visudyne. VEGFa pump or SU5416 pump was given to increase or decrease VEGFa effects, respectively. The long-term effects on lung function were determined by measurement of lung resistance using methacholine. RESULTS: ACE2 treatment did not alter VEGFa levels in lung, but antagonized the effects of VEGFa on increases of lung vessel permeability. Ectogenic VEGFa abolished the antagonizing effects of ACE2 on the vessel permeability against VEGFa. On the other hand, suppression of VEGF signaling mimicked the effects of ACE2 on the vessel permeability against VEGFa. The suppression of vessel permeability resulted in improvement of lung function after ALI. CONCLUSION: ACE2 may antagonize the VEGFa-mediated increases in lung vessel permeability during ALI, resulting in improvement of lung function after ALI. PMID- 26938047 TI - Membrane Translocation and Organelle-Selective Delivery Steered by Polymeric Zwitterionic Nanospheres. AB - The majority of nanoparticles designed for cellular delivery of drugs and imaging agents enter the cell via endocytotic pathways leading to their entrapment in endosomes that present a robust barrier to further trafficking of the nanoparticles within the cells. A few materials, such as the cell penetrating peptides (CPPs), are known to enter cells not only via endocytosis, but also via translocation through the cell membrane into the cytoplasm, successfully bypassing the endosomes. We report here that random copolymers of 3 dimethyl(methacryloyloxyethyl)ammonium propanesulfonate and poly(ethylene glycol) methacrylate, p(DMAPS-ran-PEGMA), are internalized in cells primarily via translocation through the cell membrane rather than endocytosis. The properties of the polymers and their modes of uptake were investigated systematically by dynamic light scattering, confocal fluorescence microscopy, and flow cytometry. Using specific inhibitors of the cellular uptake machinery in a human cervical carcinoma cell line (HeLa), we show that these nontoxic synthetic polyzwitterions exist in cell media as self-assembled nanospheres that unravel as they adsorb on the plasma membrane and translocate through it. Conjugates of p(DMAPS-ran-PEGMA) with rhodamine B were delivered selectively to the mitochondria, whereas doxorubicin (Dox)-p(DMAPS-ran-PEGMA) conjugates were accumulated in both the nucleus and the mitochondria, effectively inducing apoptosis in HeLa cells. These findings suggest that the noncytotoxic and readily synthesized p(DMAPS-ran-PEGMA) can find applications as bioimaging tools and drug nanocarriers. PMID- 26938053 TI - The Behavioural Contexts of Red Langur (Presbytis rubicunda) Loud Calls in the Wehea Forest, East Kalimantan, Indonesia. AB - Researchers hypothesize that male loud calls play several roles in primate societies including in the context of intergroup spacing and spatial coordination. Field studies examining the behavioural correlates of vocalizations are essential to evaluate the function of these calls. This preliminary study, from July 2011 to January 2012, explores the behavioural contexts and correlates of male loud calls in a habituated group of red langurs (Presbytis rubicunda) in the Wehea Forest, East Kalimantan, Indonesia. In analysing 418 h of data collection, we find a total of 87 vocal behaviours, including bouts of multiple calls in rapid succession (i.e. calling events) and individual loud calls. In this sample, most vocal behaviour takes place in the morning with 59% of calling events occurring before 8.00 h. The mean rate of calling events is 0.12 events/h, and the mean rate of individual loud calls is 0.20 calls/h. The mean number of calling events per day is 1.31 (range: 0-4), and the mean number of individual loud calls per day is 2.81 (range: 0-13). The rate of calling events is highest in the context of intragroup conflict, followed by intergroup encounters, predator threat, group travel, and the highest number of individual loud calls occurred during intergroup encounters. Although these results are preliminary, they suggest that adult male loud calls among red langurs at Wehea may play a role in both intergroup spacing and social coordination, supporting the hypothesis that these calls can serve different functions. PMID- 26938052 TI - Molecular Dynamics of a Water-Absorbent Nanoscale Material Based on Chitosan. AB - Although hydrogels have been widely investigated for their use in materials science, nanotechnology, and novel pharmaceuticals, mechanistic details explaining their water-absorbent features are not well understood. We performed an all-atom molecular dynamics study of the structural transformation of chitosan nanohydrogels due to water absorption. We analyzed the conformation of dry, nanoscaled chitosan, the structural modifications that emerge during the process of water inclusion, and the dynamics of this biopolymer in the presence of nature's solvent. Two sets of nanoscaled, single-chained chitosan models were simulated: one to study the swelling dependence upon the degree of self-cross linking and other to observe the response with respect to the degree of protonation. We verified that nanohydrogels keep their ability to absorb water and grow, regardless of their degree of cross-linking. Noteworthy, we found that the swelling behavior of nanoscaled chitosan is pH-dependent, and it is considerably more limited than that of larger scale hydrogels. Thus, our study suggests that properties of nanohydrogels are significantly different from those of larger hydrogels. These findings might be important in the design of novel controlled-release and targeted drug-delivery systems based on chitosan. PMID- 26938054 TI - Blood-Based Circulating MicroRNAs are Potential Diagnostic Biomarkers for Leukemia: Result from a Meta-Analysis. AB - AIMS: Circulating microRNAs (miRNAs) as biomarkers for leukemia have been validated by emerging studies. This meta-analysis aims to estimate the overall diagnostic accuracy of blood-based circulating miRNAs for leukemia. METHODS: We searched multiple databases (PubMed, EMBASE, Cochrane Library, CNKI, Wan Fang Data and CQVIP) up to June 18, 2015. RESULTS: 32 studies from 10 publications were included in this meta-analysis. Diagnostic capacity was evaluated by pooled sensitivity, specifIcity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and area under the curve (AUC) through random-effects model. Sensitivity analyses were sequentially performed to find potential sources of heterogeneity. The quality of included studies was assessed by QUADAS (quality assessment for studies of diagnostic accuracy). Meta-Disc 1.4 and Stata 12.0 software were used to perform the meta-analysis. A high diagnostic accuracy was displayed, with a sensitivity of 0.84, a specificity of 0.88, a PLR of 7.20, a NLR of 0.18, a DOR of 52, and an AUC of 0.94. Subgroup analyses revealed better performance for combined miRNAs, acute myeloid leukemia patients and Asian population than other subgroups. CONCLUSION: Our analyses suggested that blood-based circulating miRNAs are promising diagnostic biomarkers for leukemia, especially combined miRNAs. Its clinical application awaits further study. PMID- 26938055 TI - Morphological Variations of Explosive Residue Particles and Implications for Understanding Detonation Mechanisms. AB - The possibility of recovering undetonated explosive residues following detonation events is well-known; however, the morphology and chemical identity of these condensed phase postblast particles remains undetermined. An understanding of the postblast explosive particle morphology would provide vital information during forensic examinations, allowing rapid initial indication of the explosive material to be microscopically determined prior to any chemical analyses and thereby saving time and resources at the crucial stage of an investigation. In this study, condensed phase particles collected from around the detonations of aluminized ammonium nitrate and RDX-based explosive charges were collected in a novel manner utilizing SEM stubs. By incorporating the use of a focused ion beam during analysis, for the first time it is possible to determine that such particles have characteristic shapes, sizes, and internal structures depending on the explosive and the distance from the detonation at which the particles are recovered. Spheroidal particles (10-210 MUm) with microsurface features recovered following inorganic charge detonations were dissimilar to the irregularly shaped particles (5-100 MUm) recovered following organic charge firings. Confirmatory analysis to conclude that the particles were indeed explosive included HPLC-MS, Raman spectroscopy, and mega-electron volt-secondary ionization mass spectrometry. These results may impact not only forensic investigations but also the theoretical constructs that govern detonation theory by indicating the potential mechanisms by which these particles survive and how they vary between the different explosive types. PMID- 26938056 TI - Increasing Disadvantages in Cancer Survival in New Zealand Compared to Australia, between 2000-05 and 2006-10. AB - New Zealand has lower cancer survival compared to its neighbour Australia. If this were due to long established differences between the two patient populations, it might be expected to be either constant in time, or decreasing, as improving health services deals with inequities. In this study we compared trends in relative cancer survival ratios in New Zealand and Australia between 2000-05 and 2006-10, using data from the New Zealand Cancer Registry and the Australian Institute for Health and Welfare. Over this period, Australia showed significant improvements (6.0% in men, 3.0% in women) in overall 5-year cancer survival, with substantial increases in survival from major cancer sites such as lung, bowel, prostate, and breast cancers. New Zealand had only a 1.8% increase in cancer survival in men and 1.3% in women, with non-significant changes in survival from lung and bowel cancers, although there were increases in survival from prostate and breast cancers. For all cancers combined, and for lung and bowel cancer, the improvements in survival and the greater improvements in Australia were mainly in 1-year survival, suggesting factors related to diagnosis and presentation. For breast cancer, the improvements were similar in each country and seen in survival after the first year. The findings underscore the need to accelerate the efforts to improve early diagnosis and optimum treatment for New Zealand cancer patients to catch up with the progress in Australia. PMID- 26938057 TI - Social Experience Is Sufficient to Modulate Sleep Need of Drosophila without Increasing Wakefulness. AB - Organisms quickly learn about their surroundings and display synaptic plasticity which is thought to be critical for their survival. For example, fruit flies Drosophila melanogaster exposed to highly enriched social environment are found to show increased synaptic connections and a corresponding increase in sleep. Here we asked if social environment comprising a pair of same-sex individuals could enhance sleep in the participating individuals. To study this, we maintained individuals of D. melanogaster in same-sex pairs for a period of 1 to 4 days, and after separation, monitored sleep of the previously socialized and solitary individuals under similar conditions. Males maintained in pairs for 3 or more days were found to sleep significantly more during daytime and showed a tendency to fall asleep sooner as compared to solitary controls (both measures together are henceforth referred to as "sleep-enhancement"). This sleep phenotype is not strain-specific as it is observed in males from three different "wild type" strains of D. melanogaster. Previous studies on social interaction mediated sleep-enhancement presumed 'waking experience' during the interaction to be the primary underlying cause; however, we found sleep-enhancement to occur without any significant increase in wakefulness. Furthermore, while sleep-enhancement due to group-wise social interaction requires Pigment Dispersing Factor (PDF) positive neurons; PDF positive and CRYPTOCHROME (CRY) positive circadian clock neurons and the core circadian clock genes are not required for sleep-enhancement to occur when males interact in pairs. Pair-wise social interaction mediated sleep-enhancement requires dopamine and olfactory signaling, while visual and gustatory signaling systems seem to be dispensable. These results suggest that socialization alone (without any change in wakefulness) is sufficient to cause sleep-enhancement in fruit fly D. melanogaster males, and that its neuronal control is context-specific. PMID- 26938058 TI - Enhanced Cutaneous Wound Healing In Vivo by Standardized Crude Extract of Poincianella pluviosa. AB - Wound healing is a complex process that involves several biological events, and a delay in this process may cause economic and social problems for the patient. The search continues for new alternative treatments to aid healing, including the use of herbal medicines. Members of the genus Caesalpinia are used in traditional medicine to treat wounds. The related species Poincianella pluviosa (DC.) L.P. Queiroz increases the cell viability of keratinocytes and fibroblasts and stimulates the proliferation of keratinocytes in vitro. The crude extract (CE) from bark of P. pluviosa was evaluated in the wound-healing process in vivo, to validate the traditional use and the in vitro activity. Standardized CE was incorporated into a gel and applied on cutaneous wounds (TCEG) and compared with the formulation without CE (Control) for 4, 7, 10, or 14 days of treatment. The effects of the CE on wound re-epithelialization; cell proliferation; permeation, using photoacoustic spectroscopy (PAS); and proteins, including vascular endothelial growth factor (VEGF), superoxide dismutase 2 (SOD-2) and cyclooxygenase 2 (COX-2) were evaluated. The TCEG stimulated the migration of keratinocytes at day 4 and proliferation on the following days, with a high concentration of cells in metaphase at 7 days. Type I collagen formed more rapidly in the TCEG. PAS showed that the CE had permeated through the skin. TCEG stimulated VEGF at day 4 and SOD-2 and COX-2 at day 7. The results suggest that the CE promoted the regulation of proteins and helped to accelerate the processes involved in healing, promoting early angiogenesis. This led to an increase in the re-epithelialized surface, with significant mitotic activity. Maturation of collagen fibers was also enhanced, which may affect the resistance of the extracellular matrix. PAS indicated a correlation between the rate of diffusion and biological events during the healing process. The CE from P. pluviosa appears promising as an aid in healing. PMID- 26938059 TI - Beta-Catenin and Plakoglobin Expression during Zebrafish Tooth Development and Replacement. AB - We analyzed the protein distribution of two cadherin-associated molecules, plakoglobin and beta-catenin, during the different stages of tooth development and tooth replacement in zebrafish. Plakoglobin was detected at the plasma membrane already at the onset of tooth development in the epithelial cells of the tooth. This pattern remained unaltered during further tooth development. The mesenchymal cells only showed plakoglobin from cytodifferentiation onwards. Plakoglobin 1a morpholino-injected embryos showed normal tooth development with proper initiation and differentiation. Although plakoglobin is clearly present during normal odontogenesis, the loss of plakoglobin 1a does not influence tooth development. beta-catenin was found at the cell borders of all cells of the successional lamina but also in the nuclei of surrounding mesenchymal cells. Only membranous, not nuclear, beta-catenin, was found during morphogenesis stage. However, during cytodifferentiation stage, both nuclear and membrane-bound beta catenin was detected in the layers of the enamel organ as well as in the differentiating odontoblasts. Nuclear beta-catenin is an indication of an activated Wnt pathway, therefore suggesting a possible role for Wnt signalling during zebrafish tooth development and replacement. PMID- 26938060 TI - Risk of Intestinal Parasitic Infections in People with Different Exposures to Wastewater and Fecal Sludge in Kampala, Uganda: A Cross-Sectional Study. AB - BACKGROUND: There are health risks associated with wastewater and fecal sludge management and use, but little is known about the magnitude, particularly in rapidly growing urban settings of low- and middle-income countries. We assessed the point-prevalence and risk factors of intestinal parasite infections in people with different exposures to wastewater and fecal sludge in Kampala, Uganda. METHODOLOGY: A cross-sectional survey was carried out in September and October 2013, enrolling 915 adults from five distinct population groups: workers maintaining wastewater facilities; workers managing fecal sludge; urban farmers; slum dwellers at risk of flooding; and slum dwellers without risk of flooding. Stool samples were subjected to the Kato-Katz method and a formalin-ether concentration technique for the diagnosis of helminth and intestinal protozoa infections. A questionnaire was administered to determine self-reported signs and symptoms, and risk factors for intestinal parasite infections. Univariate and multivariate analyses, adjusted for sex, age, education, socioeconomic status, water, sanitation, and hygiene behaviors, were conducted to estimate the risk of infection with intestinal parasites and self-reported health outcomes, stratified by population group. PRINCIPAL FINDINGS: The highest point-prevalence of intestinal parasite infections was found in urban farmers (75.9%), whereas lowest point-prevalence was found in workers managing fecal sludge (35.8%). Hookworm was the predominant helminth species (27.8%). In urban farmers, the prevalence of Trichuris trichiura, Schistosoma mansoni, Ascaris lumbricoides, and Entamoeba histolytica/E. dispar was 15% and above. For all investigated parasites, we found significantly higher odds of infection among urban farmers compared to the other groups (adjusted odds ratios ranging between 1.6 and 12.9). In general, female participants had significantly lower odds of infection with soil-transmitted helminths and S. mansoni compared to males. Higher educational attainment was negatively associated with the risk of intestinal protozoa infections, while socioeconomic status did not emerge as a significant risk factor for any tested health outcome. CONCLUSIONS/SIGNIFICANCE: Urban farmers are particularly vulnerable to infections with soil-transmitted helminths, S. mansoni, and intestinal protozoa. Hence, our findings call for public health protection measures for urban farmers and marginalized communities, going hand-in-hand with integrated sanitation safety planning at city level. PMID- 26938063 TI - Correction: Food and Nutrient Intake and Nutritional Status of Finnish Vegans and Non-Vegetarians. PMID- 26938061 TI - Improving the Prognostic Ability through Better Use of Standard Clinical Data - The Nottingham Prognostic Index as an Example. AB - BACKGROUND: Prognostic factors and prognostic models play a key role in medical research and patient management. The Nottingham Prognostic Index (NPI) is a well established prognostic classification scheme for patients with breast cancer. In a very simple way, it combines the information from tumor size, lymph node stage and tumor grade. For the resulting index cutpoints are proposed to classify it into three to six groups with different prognosis. As not all prognostic information from the three and other standard factors is used, we will consider improvement of the prognostic ability using suitable analysis approaches. METHODS AND FINDINGS: Reanalyzing overall survival data of 1560 patients from a clinical database by using multivariable fractional polynomials and further modern statistical methods we illustrate suitable multivariable modelling and methods to derive and assess the prognostic ability of an index. Using a REMARK type profile we summarize relevant steps of the analysis. Adding the information from hormonal receptor status and using the full information from the three NPI components, specifically concerning the number of positive lymph nodes, an extended NPI with improved prognostic ability is derived. CONCLUSIONS: The prognostic ability of even one of the best established prognostic index in medicine can be improved by using suitable statistical methodology to extract the full information from standard clinical data. This extended version of the NPI can serve as a benchmark to assess the added value of new information, ranging from a new single clinical marker to a derived index from omics data. An established benchmark would also help to harmonize the statistical analyses of such studies and protect against the propagation of many false promises concerning the prognostic value of new measurements. Statistical methods used are generally available and can be used for similar analyses in other diseases. PMID- 26938064 TI - Spatiotemporal Rank Filtering Improves Image Quality Compared to Frame Averaging in 2-Photon Laser Scanning Microscopy. AB - Live imaging of biological specimens using optical microscopy is limited by tradeoffs between spatial and temporal resolution, depth into intact samples, and phototoxicity. Two-photon laser scanning microscopy (2P-LSM), the gold standard for imaging turbid samples in vivo, has conventionally constructed images with sufficient signal-to-noise ratio (SNR) generated by sequential raster scans of the focal plane and temporal integration of the collected signals. Here, we describe spatiotemporal rank filtering, a nonlinear alternative to temporal integration, which makes more efficient use of collected photons by selectively reducing noise in 2P-LSM images during acquisition. This results in much higher SNR while preserving image edges and fine details. Practically, this allows for at least a four fold decrease in collection times, a substantial improvement for time-course imaging in biological systems. PMID- 26938065 TI - Global Patterns in the Implementation of Payments for Environmental Services. AB - Assessing global tendencies and impacts of conditional payments for environmental services (PES) programs is challenging because of their heterogeneity, and scarcity of comparative studies. This meta-study systematizes 55 PES schemes worldwide in a quantitative database. Using categorical principal component analysis to highlight clustering patterns, we reconfirm frequently hypothesized differences between public and private PES schemes, but also identify diverging patterns between commercial and non-commercial private PES vis-a-vis their service focus, area size, and market orientation. When do these PES schemes likely achieve significant environmental additionality? Using binary logistical regression, we find additionality to be positively influenced by three theoretically recommended PES 'best design' features: spatial targeting, payment differentiation, and strong conditionality, alongside some contextual controls (activity paid for and implementation time elapsed). Our results thus stress the preeminence of customized design over operational characteristics when assessing what determines the outcomes of PES implementation. PMID- 26938062 TI - Characterization of a Chitosanase from Jelly Fig (Ficus awkeotsang Makino) Latex and Its Application in the Production of Water-Soluble Low Molecular Weight Chitosans. AB - A chitosanase was purified from jelly fig latex by ammonium sulfate fractionation (50-80% saturation) and three successive column chromatography steps. The purified enzyme was almost homogeneous, as determined by SDS-polyacrylamide gel electrophoresis (SDS-PAGE) and gel activity staining. The molecular mass of the enzyme was 20.5 kDa. The isoelectric point (pI) was <3.5, as estimated by isoelectric focusing electrophoresis on PhastGel IEF 3-9. Using chitosan as the substrate, the optimal pH for the enzyme reaction was 4.5; the kinetic parameters Km and Vmax were 0.089 mg mL-1 and 0.69 MUmol min-1 mg-1, respectively. The enzyme showed activity toward chitosan polymers which exhibited various degrees of deacetylation (21-94%). The enzyme hydrolyzed 70-84% deacetylated chitosan polymers most effectively. Substrate specificity analysis indicated that the enzyme catalyzed the hydrolysis of chitin and chitosan polymers and their derivatives. The products of the hydrolysis of chitosan polymer derivatives, ethylene glycol (EG) chitosan, carboxymethyl (CM) chitosan and aminoethyl (AE) chitosan, were low molecular weight chitosans (LMWCs); these products were referred to as EG-LMWC, CM-LMWC and AE-LMWC, respectively. The average molecular weights of EG-LMWC, CM-LMWC and AE-LMWC were 11.2, 11.2 and 8.89 kDa, respectively. All of the LMWC products exhibited free radical scavenging activities toward ABTS*+, superoxide and peroxyl radicals. PMID- 26938079 TI - Aggression-preventive supervisor behavior: Implications for workplace climate and employee outcomes. AB - Workplace aggression remains a serious and costly issue for organizations; thus, it is imperative to understand ways to reduce workplace aggression. To address this need, we used 2 independent samples with varied study designs, one at the employee level and the other at both employee and unit levels, to examine the role of aggression-preventive supervisor behavior (APSB) in aggression-prevention processes. In Sample 1 (237 nurses), we used structural equation modeling to examine the role of individual observations of APSB. First, we found that individual employees' observations of APSB positively related to their individual violence-prevention climate (VPC) perceptions. Further, VPC perceptions mediated the relations between APSB and employees' exposure to coworker aggression, job attitudes, and physical symptoms. In Sample 2 (337 nurses), we used multilevel regression analysis to examine the positive role of APSB in managing the aggression process. First, we established further support for many of the findings in Sample 1. In addition, we found that shared unit-level VPC mediated the relations of unit-level APSB with employees' exposure to aggression from coworkers, their physical symptoms, and turnover intention. Finally, evidence from Sample 2 supported favorable, direct relations of individual- or unit-level APSB with employees' aggression-prevention compliance and turnover intention. Implications for studying context-specific leadership behavior and designing aggression-prevention interventions are discussed. (PsycINFO Database Record PMID- 26938078 TI - Triple Therapy with First Generation Protease Inhibitors for Hepatitis C Markedly Impairs Function of Neutrophil Granulocytes. AB - First-generation HCV protease inhibitors represent a milestone in antiviral therapy for chronic hepatitis C infection (CHC), but substantially increased rates of viral clearance are offset by increased rates of infection and infection associated deaths, especially of patients with advanced liver disease. We aimed to assess whether first generation protease inhibitors interfere with neutrophil function. We included 108 consecutive, retrospective CHC patients and 44 consecutive, prospective CHC patients who were treated with peginterferon and ribavirin with or without protease inhibitors according to the guidelines in the period of November 2012 to June 2015. 33 healthy volunteers served as controls. Infection data were evaluated in all patients. Neutrophil phagocytosis, oxidative burst, elastase and diamine oxidase levels during 12 weeks of triple (n = 23) or dual therapy (n = 21) were studied in the prospective part. In the retro- and prospective cohorts patients experiencing clinically relevant infections were significantly more frequent during protease inhibitor therapy (31% and 26%) than during therapy with peginterferon and ribavirin (13% and 0%). Neutrophil phagocytosis decreased to 40% of baseline with addition of protease inhibitors to P/R but recovered 6 months after end of treatment. Protease inhibitors also seemed to reduce serum elastase levels but did not impact on gut permeability. Impaired neutrophil function during triple therapy with first generation HCV protease inhibitors may explain the high infection rate associated to these treatments and be of relevance for treatment success and patient survival. PMID- 26938080 TI - What about the leader? Crossover of emotional exhaustion and work engagement from followers to leaders. AB - Although a growing body of research links leadership behavior to follower health, comparatively little is known about the health effects of being in the lead. This longitudinal study of 315 team members and 67 leaders examined the crossover of emotional exhaustion and work engagement from followers to leaders. Leader emotional self-efficacy was tested as a moderator in the crossover process. Multiple regression analyses revealed that followers' work engagement was positively related to leaders' work engagement eight months later, controlling for followers' tenure with the leader, leader gender, autonomy, workload, and work engagement at Time 1. Leaders' emotional self-efficacy did not moderate the crossover of work engagement. Followers' emotional exhaustion was not directly related to leaders' emotional exhaustion over time. We did find a significant interaction effect for follower emotional exhaustion and leader emotional self efficacy. This study is the first to show that crossover of emotional exhaustion and work engagement can unfold over time from team members to leaders. Main theoretical implications lie in the finding that-in line with job demands resources theory-followers' psychological states can pose a demand or resource for leaders, and influence their well-being. For practitioners, our results offer valuable insights regarding the design of organizational health interventions as well as leadership development measures. (PsycINFO Database Record PMID- 26938081 TI - 4C-ker: A Method to Reproducibly Identify Genome-Wide Interactions Captured by 4C Seq Experiments. AB - 4C-Seq has proven to be a powerful technique to identify genome-wide interactions with a single locus of interest (or "bait") that can be important for gene regulation. However, analysis of 4C-Seq data is complicated by the many biases inherent to the technique. An important consideration when dealing with 4C-Seq data is the differences in resolution of signal across the genome that result from differences in 3D distance separation from the bait. This leads to the highest signal in the region immediately surrounding the bait and increasingly lower signals in far-cis and trans. Another important aspect of 4C-Seq experiments is the resolution, which is greatly influenced by the choice of restriction enzyme and the frequency at which it can cut the genome. Thus, it is important that a 4C-Seq analysis method is flexible enough to analyze data generated using different enzymes and to identify interactions across the entire genome. Current methods for 4C-Seq analysis only identify interactions in regions near the bait or in regions located in far-cis and trans, but no method comprehensively analyzes 4C signals of different length scales. In addition, some methods also fail in experiments where chromatin fragments are generated using frequent cutter restriction enzymes. Here, we describe 4C-ker, a Hidden-Markov Model based pipeline that identifies regions throughout the genome that interact with the 4C bait locus. In addition, we incorporate methods for the identification of differential interactions in multiple 4C-seq datasets collected from different genotypes or experimental conditions. Adaptive window sizes are used to correct for differences in signal coverage in near-bait regions, far-cis and trans chromosomes. Using several datasets, we demonstrate that 4C-ker outperforms all existing 4C-Seq pipelines in its ability to reproducibly identify interaction domains at all genomic ranges with different resolution enzymes. PMID- 26938083 TI - Prospect and progress of personalized peptide vaccinations for advanced cancers. AB - INTRODUCTION: The field of cancer immunotherapy has made dramatic progress in the past 20 years, in part due to the identification of numerous tumor-associated antigens (TAAs). We have developed a novel immunotherapeutic approach called the personalized peptide vaccine (PPV), in which a maximum of four human leukocyte antigen (HLA)-matched vaccine peptides are selected based on the pre-existing host immunity before vaccination. AREAS COVERED: This review describes recent progress in the use of PPV for various types of advanced cancer. EXPERT OPINION: Although various approaches for therapeutic cancer immunotherapies, including peptide-based vaccines, have been developed and clinically examined, the diverse and heterogeneous characteristics of tumor cells and host immunity seem to limit their therapeutic efficacy. Selection of suitable peptide vaccines for individual patients based on the pre-existing host immunity before vaccination could resolve this limitation and could be a rational approach for developing effective cancer vaccines. PMID- 26938082 TI - Short-Term and Long-Term Biological Effects of Chronic Chemical Contamination on Natural Populations of a Marine Bivalve. AB - Understanding the effects of chronic chemical contamination on natural populations of marine organisms is complex due to the combined effects of different types of pollutants and environmental parameters that can modulate the physiological responses to stress. Here, we present the effects of a chronic contamination in a marine bivalve by combining multiple approaches that provide information on individual and population health. We sampled variegated scallops (Mimachlamys varia) at sites characterized by different contaminants and contamination levels to study the short and long-term (intergenerational) responses of this species to physiological stress. We used biomarkers (SOD, MDA, GST, laccase, citrate synthase and phosphatases) as indicators of oxidative stress, immune system alteration, mitochondrial respiration and general metabolism, and measured population genetic diversity at each site. In parallel, concentration of 14 trace metals and 45 organic contaminants (PAHs, PCBs, pesticides) in tissues were measured. Scallops were collected outside and during their reproductive season to investigate temporal variability in contaminant and biomarker levels. Our analyses revealed that the levels of two biomarkers (Laccase-type phenoloxidase and malondialdehyde) were significantly correlated with Cd concentration. Additionally, we observed significant seasonal differences for four of the five biomarkers, which is likely due to the scallop reproductive status at time of sampling. As a source of concern, a location that was identified as a reference site on the basis of inorganic contaminant levels presented the same level of some persistent organic pollutants (DDT and its metabolites) than more impacted sites. Finally, potential long-term effects of heavy metal contamination were observed for variegated scallops as genetic diversity was depressed in the most polluted sites. PMID- 26938084 TI - Contrasting Partners' Traits of Generalized and Specialized Species in Flower Visitation Networks. AB - Much ecological research has focused on trying to understand why species are generalized or specialized in their interactions and how networks develop in a certain environment. It is now well known that traits such as phenology and abundance of a species are important determinants of its generalization level (i.e., number of different interactions or links to other species). Less information is available, however, on whether generalized and specialized species differ in particular traits of their interacting partners. Such partners might differ, for instance, in abundance and/or in the diversity of functional groups they belong to. Moreover, species might exhibit shifts through time (e.g., flowering season) in their partners' traits, though we know close to nothing on whether these changes do indeed occur. Assessing how such network links in both types of species are established is important for a better understanding of how different types of disturbance can affect community dynamics. Using data from four quantitative flower-visitation networks and independent measures of flower availability obtained when recording interactions, we test for such differences between species which have been previously categorized according to two specialization indexes: (1) number of partners (links), also named linkage level; this is a qualitative index and (2) complementary specialization d', named here selectiveness level; this is a quantitative index. We found that: (1) species with low linkage levels mainly interact with common species in the community whereas generalized species interact with a greater heterogeneity of partner's abundances and functional richness, (2) both selective and opportunistic species (with high and low d', respectively) interact with a similarly high functional richness (number of functional groups or families) of partners, and (3) generalized species are the only ones showing shifts along the season in their partners' traits, driven by changes in community species composition. The risk of extinction in front of a disturbance is generally expected to be highest for specialized species (with few partners) and selective species (which visit non abundant or scarce partners). However, our findings show that by linking to abundant and/or to functionally diverse partners, respectively, these species may be maintained in the community and be less vulnerable to disturbances. PMID- 26938085 TI - How Big Is It Really? Assessing the Efficacy of Indirect Estimates of Body Size in Asian Elephants. AB - Information on an organism's body size is pivotal in understanding its life history and fitness, as well as helping inform conservation measures. However, for many species, particularly large-bodied wild animals, taking accurate body size measurements can be a challenge. Various means to estimate body size have been employed, from more direct methods such as using photogrammetry to obtain height or length measurements, to indirect prediction of weight using other body morphometrics or even the size of dung boli. It is often unclear how accurate these measures are because they cannot be compared to objective measures. Here, we investigate how well existing estimation equations predict the actual body weight of Asian elephants Elephas maximus, using body measurements (height, chest girth, length, foot circumference and neck circumference) taken directly from a large population of semi-captive animals in Myanmar (n = 404). We then define new and better fitting formulas to predict body weight in Myanmar elephants from these readily available measures. We also investigate whether the important parameters height and chest girth can be estimated from photographs (n = 151). Our results show considerable variation in the ability of existing estimation equations to predict weight, and that the equations proposed in this paper predict weight better in almost all circumstances. We also find that measurements from standardised photographs reflect body height and chest girth after applying minor adjustments. Our results have implications for size estimation of large wild animals in the field, as well as for management in captive settings. PMID- 26938102 TI - Characteristics of Patients with Lymphangioleiomyomatosis and Pleural Effusion: A Systematic Review. AB - The characteristics of patients with lymphangioleiomyomatosis (LAM) are poorly defined, as they may present with or without pleural effusion (PE). We performed a systematic review across four electronic databases searching for studies reporting clinical findings, PE characteristics, and the most effective treatment of LAM. Case descriptions and retrospective studies were included, unrestricted by year of publication. The review consisted of 94 studies (199 patients) spanning a period of nearly 55 years. The median age was 38 years (range: 1 month to 69 years), and 79.7% were between 21 and 50 years old. All cases had dyspnea, 95% had a cough, and 87.5% had chest pain. PE was exudative chylothorax, usually unilateral (76%) and right-sided, predominantly lymphocytic, and with proportionately higher levels of proteins than lactate dehydrogenase. Sirolimus was effective in all cases, completely in 87%, and partially in 13%, although the number of patients receiving sirolimus was small. The present study confirmed that LAM and PE mainly occur in women of childbearing age (third to fifth decade of life). PE was usually unilateral and presented as a lymphocyte-predominant chylous exudate. The most effective treatment for PE seems to be sirolimus, although studies with larger series are needed to confirm this. PMID- 26938103 TI - Foxn1 Transcription Factor Regulates Wound Healing of Skin through Promoting Epithelial-Mesenchymal Transition. AB - Transcription factors are key molecules that finely tune gene expression in response to injury. We focused on the role of a transcription factor, Foxn1, whose expression is limited to the skin and thymus epithelium. Our previous studies showed that Foxn1 inactivity in nude mice creates a pro-regenerative environment during skin wound healing. To explore the mechanistic role of Foxn1 in the skin wound healing process, we analyzed post-injured skin tissues from Foxn1::Egfp transgenic and C57BL/6 mice with Western Blotting, qRT-PCR, immunofluorescence and flow cytometric assays. Foxn1 expression in non-injured skin localized to the epidermis and hair follicles. Post-injured skin tissues showed an intense Foxn1-eGFP signal at the wound margin and in leading epithelial tongue, where it co-localized with keratin 16, a marker of activated keratinocytes. This data support the concept that suprabasal keratinocytes, expressing Foxn1, are key cells in the process of re-epithelialization. The occurrence of an epithelial-mesenchymal transition (EMT) was confirmed by high levels of Snail1 and Mmp-9 expression as well as through co-localization of vimentin/E-cadherin-positive cells in dermis tissue at four days post-wounding. Involvement of Foxn1 in the EMT process was verified by co-localization of Foxn1 eGFP cells with Snail1 in histological sections. Flow cytometric analysis showed the increase of double positive E-cadherin/N-cadherin cells within Foxn1-eGFP population of post-wounded skin cells isolates, which corroborated histological and gene expression analyses. Together, our findings indicate that Foxn1 acts as regulator of the skin wound healing process through engagement in re epithelization and possible involvement in scar formation due to Foxn1 activity during the EMT process. PMID- 26938106 TI - Electron Doping of Ultrathin Black Phosphorus with Cu Adatoms. AB - Few-layer black phosphorus is a monatomic two-dimensional crystal with a direct band gap that has high carrier mobility for both holes and electrons. Similarly to other layered atomic crystals, like graphene or layered transition metal dichalcogenides, the transport behavior of few-layer black phosphorus is sensitive to surface impurities, adsorbates, and adatoms. Here we study the effect of Cu adatoms onto few-layer black phosphorus by characterizing few-layer black phosphorus field effect devices and by performing first-principles calculations. We find that the addition of Cu adatoms can be used to controllably n-dope few layer black phosphorus, thereby lowering the threshold voltage for n type conduction without degrading the transport properties. We demonstrate a scalable 2D material-based complementary inverter which utilizes a boron nitride gate dielectric, a graphite gate, and a single bP crystal for both the p- and n channels. The inverter operates at matched input and output voltages, exhibits a gain of 46, and does not require different contact metals or local electrostatic gating. PMID- 26938104 TI - Divergence Times and Phylogenetic Patterns of Sebacinales, a Highly Diverse and Widespread Fungal Lineage. AB - Patterns of geographic distribution and composition of fungal communities are still poorly understood. Widespread occurrence in terrestrial ecosystems and the unique richness of interactions of Sebacinales with plants make them a target group to study evolutionary events in the light of nutritional lifestyle. We inferred diversity patterns, phylogenetic structures and divergence times of Sebacinales with respect to their nutritional lifestyles by integrating data from fossil-calibrated phylogenetic analyses. Relaxed molecular clock analyses indicated that Sebacinales originated late Permian within Basidiomycota, and their split into Sebacinaceae and Serendipitaceae nom. prov. likely occurred during the late Jurassic and the early Cretaceous, coinciding with major diversifications of land plants. In Sebacinaceae, diversification of species with ectomycorrhizal lifestyle presumably started during the Paleocene. Lineage radiations of the core group of ericoid and cavendishioid mycorrhizal Sebacinales started probably in the Eocene, coinciding with diversification events of their hosts. The diversification of Sebacinales with jungermannioid interactions started during the Oligocene, and occurred much later than the diversification of their hosts. Sebacinales communities associated either with ectomycorrhizal plants, achlorophyllous orchids, ericoid and cavendishioid Ericaceae or liverworts were phylogenetically clustered and globally distributed. Major Sebacinales lineage diversifications started after the continents had drifted apart. We also briefly discuss dispersal patterns of extant Sebacinales. PMID- 26938107 TI - An analysis of surface proteomics results reveals novel candidates for intracellular/surface moonlighting proteins in bacteria. AB - Proteins expressed on the bacterial cell surface play important roles in infection and virulence and can be targets for vaccine development or used as biomarkers. Surprisingly, an increasing number of surface proteins are being found to be identical to intracellular enzymes and chaperones, and a few dozen intracellular/surface moonlighting proteins have been found that have different functions inside the cell and on the cell surface. The results of twenty-two published bacterial surface proteomics studies were analyzed using bioinformatics tools to consider how many additional intracellular proteins are also found on the cell surface. More than 1000 out of the 3619 proteins observed on the cell surface lack the transmembrane alpha-helices or transmembrane beta-barrels found in integral membrane proteins and also lack the signal peptides found in proteins secreted through the Sec pathway. Many of the proteins found on the cell surface are intracellular chaperones or enzymes involved in central metabolic pathways, including some that have previously been shown to have a moonlighting function on the cell surface in at least one species, such as Hsp60/GroEL, DnaK, glyceraldehyde 3-phosphate dehydrogenase, enolase, and fructose 1,6-bisphosphate aldolase. The results of the proteomics studies suggest they could also be moonlighting on the surface of many other species. Hundreds of other intracellular proteins are also found on the cell surface, although a second function on the surface has not yet been demonstrated, for example, glutamine synthetase, gamma-glutamyl phosphate reductase, and cysteine desulfurase. The presence of intracellular proteins on the cell surface is more common than previously expected and suggests that many additional proteins might be candidates for being intracellular/surface moonlighting proteins. PMID- 26938105 TI - CHIR99021 enhances Klf4 Expression through beta-Catenin Signaling and miR-7a Regulation in J1 Mouse Embryonic Stem Cells. AB - Understanding the mechanisms that regulate pluripotency of embryonic stem cells (ESCs) is important to ensure their safe clinical use. CHIR99021 (CHIR)-induced activation of Wnt/beta-catenin signaling promotes self-renewal in mouse ESCs (mESCs). beta-catenin functions individually or cooperates with transcription factors to activate stemness factors such as c-Myc, Esrrb, Pou5f1, and Nanog. However the relationship between the core pluripotent factor, Kruppel-like factor 4 (also known as GKLF or EZF) and Wnt/beta-catenin signaling, remains ambiguous in J1 mESCs. DNA microarray analysis revealed that CHIR-treatment promoted pluripotency-maintaining transcription factors and repressed germ layer specification markers. CHIR also promoted genes related to the development of extracellular regions and the plasma membrane to maintain pluripotency of J1 mESCs. Among the CHIR-regulated genes, Klf4 has not been reported previously. We identified a novel cis element in the Klf4 gene that was activated by beta catenin in J1 mESCs. We determined that beta-catenin interacted with this cis element, identifying Klf4 as a beta-catenin target gene in this context. Moreover, several microRNAs that targeted the 3'-UTR of Klf4 mRNA were identified, with miR-7a being down-regulated by CHIR in a beta-catenin independent manner in J1 mESCs. These data collectively suggest that CHIR enhances Klf4 expression by repressing miR-7a expression or canonical Wnt pathway activation. PMID- 26938114 TI - Interferometric scattering microscopy and its combination with single-molecule fluorescence imaging. AB - Interferometric scattering microscopy (iSCAT) is a light scattering-based imaging modality that offers a unique combination of imaging speed and precision for tracking nanoscopic labels and enables label-free optical sensing down to the single-molecule level. In contrast to fluorescence, iSCAT does not suffer from limitations associated with dye photochemistry and photophysics, or the requirement for fluorescent labeling. Here we present a protocol for constructing an iSCAT microscope from commercially available optical components and demonstrate its compatibility with simultaneously operating single-molecule, objective-type, total internal reflection fluorescence microscopy. Given an intermediate level of experience with optics and microscopy, for instance graduate-level familiarity with laser beam steering and optical components, this protocol can be completed in a time frame of 2 weeks. PMID- 26938115 TI - Assembly and operation of the autopatcher for automated intracellular neural recording in vivo. AB - Whole-cell patch clamping in vivo is an important neuroscience technique that uniquely provides access to both suprathreshold spiking and subthreshold synaptic events of single neurons in the brain. This article describes how to set up and use the autopatcher, which is a robot for automatically obtaining high-yield and high-quality whole-cell patch clamp recordings in vivo. By following this protocol, a functional experimental rig for automated whole-cell patch clamping can be set up in 1 week. High-quality surgical preparation of mice takes ~1 h, and each autopatching experiment can be carried out over periods lasting several hours. Autopatching should enable in vivo intracellular investigations to be accessible by a substantial number of neuroscience laboratories, and it enables labs that are already doing in vivo patch clamping to scale up their efforts by reducing training time for new lab members and increasing experimental durations by handling mentally intensive tasks automatically. PMID- 26938116 TI - Monitoring the progression of cell death and the disassembly of dying cells by flow cytometry. AB - The use of annexin A5 (A5) and either propidium iodide or 7-aminoactinomycin D (PI/7-AAD) stains to measure cell death by flow cytometry has been considered the gold standard by most investigators. However, this widely used method often makes the assumption that there are only three types of particles in a sample: viable, apoptotic and necrotic cells. To study the progression of cell death in greater detail, in particular how apoptotic cells undergo fragmentation to generate membrane-bound vesicles known as apoptotic bodies, we established a flow cytometry-based protocol to accurately and rapidly measure the cell death process. This protocol uses a combination of A5 and TO-PRO-3 (a commercially available nucleic acid-binding dye that stains early apoptotic and necrotic cells differentially), and a logical seven-stage analytical approach to distinguish six types of particles in a sample, including apoptotic bodies and cells at three different stages of cell death. The protocol requires 1-5 h for sample preparation (including induction of cell death), 20 min for staining and 5 min for data analysis. PMID- 26938118 TI - Different dosage schedules for reducing cardiotoxicity in people with cancer receiving anthracycline chemotherapy. AB - BACKGROUND: This review update has been managed by both the Childhood Cancer and Cochrane Gynaecological, Neuro-oncology and Orphan Cancer Groups.The use of anthracycline chemotherapy is limited by the occurrence of cardiotoxicity. To prevent this cardiotoxicity, different anthracycline dosage schedules have been studied. OBJECTIVES: To determine the occurrence of cardiotoxicity with the use of different anthracycline dosage schedules (that is peak doses and infusion durations) in people with cancer. SEARCH METHODS: We searched the databases of the Cochrane Register of Controlled Trials (CENTRAL) (the Cochrane Library, Issue 11, 2015), MEDLINE (1966 to December 2015), and EMBASE (1980 to December 2015). We also searched reference lists of relevant articles, conference proceedings, experts in the field, and ongoing trials databases. SELECTION CRITERIA: Randomised controlled trials (RCTs) in which different anthracycline dosage schedules were compared in people with cancer (children and adults). DATA COLLECTION AND ANALYSIS: Two review authors independently performed the study selection, the 'Risk of bias' assessment, and data extraction. We performed analyses according to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions. MAIN RESULTS: We identified 11 studies: 7 evaluated different infusion durations (803 participants), and 4 evaluated different peak doses (5280 participants). Seven studies were RCTs addressing different anthracycline infusion durations; we identified long-term follow-up data for one of the trials in this update. The meta-analysis showed a statistically significant lower rate of clinical heart failure with an infusion duration of six hours or longer as compared to a shorter infusion duration (risk ratio (RR) 0.27; 95% confidence interval 0.09 to 0.81; 5 studies; 557 participants). The majority of participants included in these studies were adults with different solid tumours. For different anthracycline peak doses, we identified two RCTs addressing a doxorubicin peak dose of less than 60 mg/m(2) versus 60 mg/m(2) or more, one RCT addressing a liposomal doxorubicin peak dose of 25 mg/m(2) versus 50 mg/m(2), and one RCT addressing an epirubicin peak dose of 83 mg/m(2) versus 110 mg/m(2). A significant difference in the occurrence of clinical heart failure was identified in none of the studies. The participants included in these studies were adults with different solid tumours. High or unclear 'Risk of bias' issues were present in all studies. AUTHORS' CONCLUSIONS: An anthracycline infusion duration of six hours or longer reduces the risk of clinical heart failure, and it seems to reduce the risk of subclinical cardiac damage. Since there is only a small amount of data for children and data obtained in adults cannot be extrapolated to children, different anthracycline infusion durations should be evaluated further in children.We identified no significant difference in the occurrence of clinical heart failure in participants treated with a doxorubicin peak dose of less than 60 mg/m(2) or 60 mg/m(2) or more. Only one RCT was available for the other identified peak doses, so we can make no definitive conclusions about the occurrence of cardiotoxicity. More high-quality research is needed, both in children and adults and in leukaemias and solid tumours. PMID- 26938117 TI - Real-Time Discrimination and Versatile Profiling of Spontaneous Reactive Oxygen Species in Living Organisms with a Single Fluorescent Probe. AB - Fluorescent probes are powerful tools for the investigations of reactive oxygen species (ROS) in living organisms by visualization and imaging. However, the multiparallel assays of several ROS with multiple probes are often limited by the available number of spectrally nonoverlapping chromophores together with large invasive effects and discrepant biological locations. Meanwhile, the spontaneous ROS profilings in various living organs/tissues are also limited by the penetration capability of probes across different biological barriers and the stability in reactive in vivo environments. Here, we report a single fluorescent probe to achieve the effective discrimination and profiling of hydroxyl radicals (*OH) and hypochlorous acid (HClO) in living organisms. The probe is constructed by chemically grafting an additional five-membered heterocyclic ring and a lateral triethylene glycol chain to a fluorescein mother, which does not only turn off the fluorescence of fluorescein, but also create the dual reactive sites to ROS and the penetration capability in passing through various biological barriers. The reactions of probe with *OH and HClO simultaneously result in cyan and green emissions, respectively, providing the real-time discrimination and quantitative analysis of the two ROS in cellular mitochondria. Surprisingly, the accumulation of probes in the intestine and liver of a normal-state zebrafish and the transfer pathway from intestine-to-blood-to-organ/tissue-to-kidney-to excretion clearly present the profiling of spontaneous *OH and HClO in these metabolic organs. In particular, the stress generation of *OH at the fresh wound of zebrafish is successfully visualized for the first time, in spite of its extremely short lifetime. PMID- 26938119 TI - Effect of Phosphorus-Doping on Electrochemical Performance of Silicon Negative Electrodes in Lithium-Ion Batteries. AB - The effect of phosphorus (P)-doping on the electrochemical performance of Si negative electrodes in lithium-ion batteries was investigated. Field-emission scanning electron microscopy was used to observe changes in surface morphology. Surface crystallinity and the phase transition of Si negative electrodes before and after a charge-discharge cycle were investigated by Raman spectroscopy and X ray diffraction. Li insertion energy into Si was also calculated based on computational chemistry. The results showed that a low P concentration of 124 ppm has a meaningful influence on the electrochemical properties of a Si negative electrode; the cycle performance is improved by P-doping of Si. P-doping suppresses the changes in the surface morphology of a Si negative electrode and the phase transition during a charge-discharge cycle. Li insertion energy increases with an increase in the P concentration; Li insertion into P-doped Si is energetically unfavorable, which indicates that the crystal lattice of Si shrinks as a result of the replacement of some Si atoms with smaller P atoms, and therefore, it is more difficult to insert Li into P-doped Si. These results reveal that suppression of the phase transition reduces the large change in the volume of Si and prevents a Si negative electrode from disintegrating, which helps to improve the otherwise poor cycle performance of a Si electrode. PMID- 26938120 TI - Novel Combretastatin-2-aminoimidazole Analogues as Potent Tubulin Assembly Inhibitors: Exploration of Unique Pharmacophoric Impact of Bridging Skeleton and Aryl Moiety. AB - Combretastatin A-4 (CA-4) in phosphate and serine pro-drug forms is under phase II clinical trials. With our interest of discovering CA-4 inspired new chemical entities, a novel series of 4,5-diaryl-2-aminoimidazole analogues of the compound was designed and synthesized by an efficient and diversity feasible route involving atom economical arene C-H bond arylation. Interestingly, four compounds showed potent cell-based antiproliferative activities in nanomolar concentrations. Among the compounds, compound 12 inhibited the proliferation of several types of cancer cells much more efficiently than CA-4. It depolymerized microtubules, induced spindle defects, and stalled mitosis in cells. Compound 12 bound to tubulin and inhibited the polymerization of tubulin in vitro. In addition, podophyllotoxin and CA-4 inhibited the binding of compound 12 to tubulin. The distinctive pharmacophoric features of the bridging motif as well as quinoline nucleus were explored. We noted also a valuable quality of compound 12 as a potential probe in characterizing new CA-4 analogues. PMID- 26938137 TI - Nickel-Catalyzed Dimerization and Alkylarylation of 1,3-Dienes with Alkyl Fluorides and Aryl Grignard Reagents. AB - In the presence of a nickel catalyst, 1,3-butadiene undergoes selective dimerization and alkylarylation with alkyl fluorides and aryl Grignard reagents to give 1,6-octadienes with alkyl and aryl groups at the 3- and 8-positions, respectively, by the consecutive formation of three carbon-carbon bonds. The formation of an anionic nickel complex plays an important role in forming C-C bonds with alkyl fluorides. PMID- 26938138 TI - Chaephilones A and B, Two New Azaphilone Derivatives Isolated from Chaetomium globosum. AB - Two new azaphilone derivatives, chaephilones A (1) and B (2), were isolated from the fungus Chaetomium globosum, together with four structurally related analogs 3 - 6. The structures of 1 and 2 were elucidated by comprehensive spectroscopic analyses including HR-ESI-MS and NMR. The known compounds were identified as chaetomugilin Q (3), chaetomugilin D (4), 11-epichaetomugilin A (5), and chaetomugilin S (6) by comparing their NMR data and optical rotation values with those reported. Compound 2 represents the first example of azaphilone with an open furan ring. Compounds 1 and 2 were evaluated for cytotoxic activities against five human cancer cell lines (HL-60, SMMC-7721, A-549, MCF-7, and SW480) by the MTS method. PMID- 26938139 TI - Malaria Surveillance - United States, 2013. AB - PROBLEM/CONDITION: Malaria in humans is caused by intraerythrocytic protozoa of the genus Plasmodium. These parasites are transmitted by the bite of an infective female Anopheles mosquito. The majority of malaria infections in the United States occur among persons who have traveled to regions with ongoing malaria transmission. However, malaria is also occasionally acquired by persons who have not traveled out of the country through exposure to infected blood products, congenital transmission, laboratory exposure, or local mosquitoborne transmission. Malaria surveillance in the United States is conducted to identify episodes of local transmission and to guide prevention recommendations for travelers. PERIOD COVERED: This report summarizes cases in persons with onset of illness in 2013 and summarizes trends during previous years. DESCRIPTION OF SYSTEM: Malaria cases diagnosed by blood film, polymerase chain reaction, or rapid diagnostic tests are mandated to be reported to local and state health departments by health care providers or laboratory staff. Case investigations are conducted by local and state health departments, and reports are transmitted to CDC through the National Malaria Surveillance System, National Notifiable Diseases Surveillance System, or direct CDC consultations. CDC conducted antimalarial drug resistance marker testing on blood samples submitted to CDC by health care providers or local/state health departments. Data from these reporting systems serve as the basis for this report. RESULTS: CDC received 1,727 reported cases of malaria, including two congenital cases, with an onset of symptoms in 2013 among persons in the United States. The total number of cases represents a 2% increase from the 1,687 cases reported for 2012. Plasmodium falciparum, P. vivax, P. malariae, and P. ovale were identified in 61%, 14%, 3%, and 4% of cases, respectively. Forty (2%) patients were infected by two species. The infecting species was unreported or undetermined in 17% of cases. Polymerase chain reaction testing determined or corrected the species for 85 of the 137 (62%) samples evaluated for drug resistance marker testing. Of the 904 patients who reported purpose of travel, 635 (70%) were visiting friends or relatives (VFR). Among the 961 cases in U.S. civilians for whom information on chemoprophylaxis use and travel region was known, 42 (4%) patients reported that they had initiated and adhered to a chemoprophylaxis drug regimen recommended by CDC for the regions to which they had traveled. Thirty-six cases were reported in pregnant women, none of whom had adhered to chemoprophylaxis. Among all reported cases, approximately 270 (16%) were classified as severe illnesses in 2013. Of these, 10 persons with malaria died in 2013, the highest number since 2001. In 2013, a total of 137 blood samples submitted to CDC were tested for molecular markers associated with antimalarial drug resistance. Of the 100 P. falciparum positive samples, 95 were tested for pyrimethamine resistance: 88 (93%) had genetic polymorphisms associated with pyrimethamine drug resistance, 74 (76%) with sulfadoxine resistance, 53 (53%) with chloroquine resistance, one (1%) with atovaquone resistance, none with mefloquine drug resistance, and none with artemisinin resistance. INTERPRETATION: The overall trend of malaria cases has been increasing since 1973; the number of cases reported in 2013 is the third highest annual total since then. Despite progress in reducing the global burden of malaria, the disease remains endemic in many regions, and the use of appropriate prevention measures by travelers is still inadequate. PUBLIC HEALTH ACTIONS: Completion of data elements on the malaria case report form increased slightly in 2013 compared with 2012, but still remains unacceptably low. This incomplete reporting compromises efforts to examine trends in malaria cases and prevent infections. VFRs continue to be a difficult population to reach with effective malaria prevention strategies. Evidence-based prevention strategies that effectively target VFRs need to be developed and implemented to have a substantial impact on the numbers of imported malaria cases in the United States. Fewer patients reported taking chemoprophylaxis in 2013 (32%) compared with 2012 (34%), and adherence was poor among those who did take chemoprophylaxis. Proper use of malaria chemoprophylaxis will prevent the majority of malaria illness and reduce the risk for severe disease (http://www.cdc.gov/malaria/travelers/drugs.html). Malaria infections can be fatal if not diagnosed and treated promptly with antimalarial medications appropriate for the patient's age and medical history, the likely country of malaria acquisition, and previous use of antimalarial chemoprophylaxis. Recent molecular laboratory advances have enabled CDC to identify and conduct molecular surveillance of antimalarial drug resistance markers (http://www.cdc.gov/malaria/features/ars.html). These advances will allow CDC to track, guide treatment, and manage drug resistance in malaria parasites both domestically and globally. For this to be successful, specimens should be submitted for all cases diagnosed in the United States. Clinicians should consult the CDC Guidelines for Treatment of Malaria and contact the CDC's Malaria Hotline for case management advice, when needed. Malaria treatment recommendations can be obtained online (http://www.cdc.gov/malaria/diagnosis_treatment) or by calling the Malaria Hotline (770-488-7788 or toll-free at 855-856-4713). PMID- 26938140 TI - Comparison of Intravenous Morphine Versus Paracetamol in Sciatica: A Randomized Placebo Controlled Trial. AB - OBJECTIVE: The objective was to compare intravenous morphine and intravenous acetaminophen (paracetamol) for pain treatment in patients presenting to the emergency department with sciatica. METHODS: Patients, between the ages of 21 and 65 years, suffering from pain in the sciatic nerve distribution and a positive straight leg-raise test composed the study population. Study patients were assigned to one of three intravenous interventions: morphine (0.1 mg/kg), acetaminophen (1 g), or placebo. Physicians, nurses, and patients were blinded to the study drug. Changes in pain intensity were measured at 15 and 30 minutes using a visual analog scale. Rescue drug (fentanyl) use and adverse effects were also recorded. RESULTS: Three-hundred patients were randomized. The median change in pain intensity between treatment arms at 30 minutes were as follows: morphine versus acetaminophen 25 mm (95% confidence interval [CI] = 20 to 29 mm), morphine versus placebo 41 mm (95% CI = 37 to 45 mm), and acetaminophen versus placebo 16 mm (95% CI = 12 to 20 mm). Eighty percent of the patients in the placebo group (95% CI = 63.0% to 99%), 18% of the patients in the acetaminophen group (95% CI = 10.7% to 28.5%), and 6% of those in the morphine group (95% CI = 2.0% to 13.2%) required a rescue drug. Adverse effects were similar between the morphine and acetaminophen groups. CONCLUSION: Morphine and acetaminophen are both effective for treating sciatica at 30 minutes. However, morphine is superior to acetaminophen. PMID- 26938141 TI - Polymeric Colloidal Nanostructures Fabricated via Highly Controlled Convective Assembly and Their Use for Molecular Imprinting. AB - In this work, the formation of various polystyrene (PS) colloidal structures on striped PS patterns is demonstrated based on a simple and novel convective assembly method that controls the electrostatic interactions between the PS colloidal particles and sodium dodecyl sulfate (SDS). Under the optimal conditions (different withdrawal speeds, channel dimensions, suspension concentrations, etc.), highly ordered structures such as highly close-packed, zigzag, and linear colloidal aggregates are observed. In addition, these colloidal arrangements are used for development of molecularly imprinted polymer (MIP) sensors with highly improved sensing properties. Using PDMS replicas, three hemispherical poly(methacrylic acid-ethylene glycol dimethacrylate) (poly(MAA EGDMA)) MIP films, including planar MIP and non-imprinted polymer (NIP) films, are photopolymerized for detection of trace atrazine in an aqueous solution. From gravimetric quartz crystal microbalance (QCM) measurements, a non-close-packed MIP film exhibits highest sensing response (Deltaf = 932 Hz) to atrazine detection among hemispherical MIP films and shows 6.5-fold higher sensing response than the planar MIP film. In addition, the sensitivity of the MIP sensor is equivalent to -119 Hz/(mol L(-1)). From the ratio of slopes of the calibration curves for the hemispherical MIP and NIP films, the imprinting factor (If) is as high as 11.0. The hemispherical MIP film also shows excellent selectivity in comparison with the sensing responses of other analogous herbicides. As a result, this molecular surface imprinting using PS colloidal arrays is highly efficient for herbicide detection. PMID- 26938142 TI - Exocytosis in non-neuronal cells. AB - Exocytosis is the process by which stored neurotransmitters and hormones are released via the fusion of secretory vesicles with the plasma membrane. It is a dynamic, rapid and spatially restricted process involving multiple steps including vesicle trafficking, tethering, docking, priming and fusion. For many years great steps have been undertaken in our understanding of how exocytosis occurs in different cell types, with significant focus being placed on synaptic release and neurotransmission. However, this process of exocytosis is an essential component of cell signalling throughout the body and underpins a diverse array of essential physiological pathways. Many similarities exist between different cell types with regard to key aspects of the exocytosis pathway, such as the need for Ca(2+) to trigger it or the involvement of members of the N-ethyl maleimide-sensitive fusion protein attachment protein receptor protein families. However, it is also equally clear that non-neuronal cells have acquired highly specialized mechanisms to control the release of their own unique chemical messengers. This review will focus on several important non-neuronal cell types and discuss what we know about the mechanisms they use to control exocytosis and how their specialized output is relevant to the physiological role of each individual cell type. These include enteroendocrine cells, pancreatic beta cells, astrocytes, lactotrophs and cytotoxic T lymphocytes. Non-neuronal cells have acquired highly specialized mechanisms to control the release of unique chemical messengers, such as polarised fusion of insulin granules in pancreatic beta cells targeted towards the vasculature (top). This review discusses mechanisms used in several important non-neuronal cell types to control exocytosis, and the relevance of intermediate vesicle fusion pore states (bottom) and their specialized output to the physiological role of each cell type. These include enteroendocrine cells, pancreatic beta cells, astrocytes, lactotrophs and cytotoxic T lymphocytes. This article is part of a mini review series on Chromaffin cells (ISCCB Meeting, 2015). PMID- 26938146 TI - Synthesis, Electrochemistry, and Photophysics of Aza-BODIPY Porphyrin Dyes. AB - The synthesis of dyad and triad aza-BODIPY-porphyrin systems in two steps starting from an aryl-substituted aza-BODIPY chromophore is described. The properties of the resulting aza-BODIPY-porphyrin conjugates have been extensively investigated by means of electrochemistry, spectroelectrochemistry, and absorption/emission spectroscopy. Fluorescence measurements have revealed a dramatic loss of luminescence intensity, mainly due to competitive energy transfer and photoinduced electron transfer involving charge separation followed by recombination. PMID- 26938147 TI - Visible Light and pH Responsive Polymer-Coated Mesoporous Silica Nanohybrids for Controlled Release. AB - A visible light and pH responsive anticancer drug delivery system based on polymer-coated mesoporous silica nanoparticles (MSNs) has been developed. Perylene-functionalized poly(dimethylaminoethyl methacrylates) sensitive to visible light and pH are electrostatically attached on the surface of MSNs to seal the nanopores. Stimulation of visible light and acid can unseal the nanopores to induce controlled drug release from the MSNs. More interestingly, the release can be enhanced under the combined stimulation of the dual-stimuli. The synergistic effect of visible light and acid stimulation on the efficient release of anticancer drugs from the nanohybrids endows the system with great potential for cancer therapy. PMID- 26938148 TI - Extracting the Density of States of Copper Phthalocyanine at the SiO2 Interface with Electronic Sum Frequency Generation. AB - Organic semiconductors (OSCs) constitute an attractive platform for optoelectronics design due to the ease of their processability and chemically tunable properties. Incorporating OSCs into electrical circuits requires forming junctions between them and other materials, yet the change in dielectric properties about these junctions can strongly perturb the electronic structure of the OSC. Here we adapt an interface-selective optical technique, electronic sum frequency generation (ESFG), to the study of a model OSC thin-film system, copper phthalocyanine (CuPc) deposited on SiO2. We find that by modeling the thickness dependence of our measured spectra, we can identify changes in CuPc's electronic density of states at both its buried interface with SiO2 and air-exposed surface. Our work demonstrates that ESFG can be used to noninvasively probe the interfacial electronic structure of optically thick OSC films, indicating that it can be used for the study of OSC-based optoelectronics in situ. PMID- 26938149 TI - Prediction of Kinetic Isotope Effects for Various Hydride Transfer Reactions Using a New Kinetic Model. AB - In this work, kinetic isotope effect (KIEself) values of 68 hydride self-exchange reactions, XH(D) + X(+) -> X(+) + XH(D), in acetonitrile at 298 K were determined using a new experimental method. KIE values of 4556 hydride cross transfer reactions, XH(D) + Y(+) -> X(+) + YH(D), in acetonitrile were estimated from the 68 determined KIEself values of hydride self-exchange reactions using a new KIE relation formula derived from Zhu's kinetic equation and the reliability of the estimations was verified using different experimental methods. A new KIE kinetic model to explain and predict KIE values was developed according to Zhu's kinetic model using two different Morse free energy curves instead of one Morse free energy curve in the traditional KIE theories to describe the free energy changes of X-H bond and X-D bond dissociation in chemical reactions. The most significant contribution of this paper to KIE theory is to build a new KIE kinetic model, which can be used to not only uniformly explain the various (normal, enormous and inverse) KIE values but also safely prodict KIE values of various chemical reactions. PMID- 26938150 TI - Ethical and practical challenges in providing noninvasive prenatal testing for chromosome abnormalities: an update. AB - PURPOSE OF REVIEW: Noninvasive prenatal testing (NIPT) through the analysis of cell-free DNA in maternal plasma has rapidly changed screening for fetal chromosome abnormalities. We review practical and ethical challenges associated with the transition, progress in their resolution, and identify new emerging difficulties. RECENT FINDINGS: NIPT is an advanced screening test for trisomies 21, 18, and 13 that was initially limited to women at high risk for an affected pregnancy. It is now recognized as suitable for all women. The testing has been expanded to include sex chromosome abnormalities and some microdeletion syndromes. Some ethicists are concerned about inclusion of disorders that have less severe phenotypes. SUMMARY: Clinical providers have experienced difficulty in maintaining an up-to-date knowledge about the scope of NIPT, differences between tests, who should be offered the testing, performance of tests, reasons for false-positive results, and optimal patient management following positive results. Some of the practical difficulties associated with the introduction can be attributed to this knowledge gap. There remain some important ethical issues associated with NIPT. We believe that the same ethical and legal principles that were considered in the justification of conventional prenatal screening can be used to assess the appropriateness of additional NIPT applications. PMID- 26938152 TI - Molecular mechanism of endocrine system impairment by 17alpha-methyltestosterone in gynogenic Pengze crucian carp offspring. AB - The effects of synthetic androgen 17alpha-methyltestosterone (MT) on endocrine impairment were examined in crucian carp. Immature 7-month old mono-female Pengze crucian carp (Pcc) F2 offspring were exposed to 50 and 100 MUg/L of MT (week 2, 4, and 8). Gonadosomatic index, hepatosomatic index and intestine weight altered considerably and oocyte development was repressed. In the treatment groups, ovarian 11-ketotestosterone decreased, whereas 17beta-estradiol and testosterone increased, and ovarian aromatase activities increased at week 4. However, in the brain tissue, those values significantly decreased. Quantitative RT-PCR analysis demonstrated changes in steroid receptor genes and upregulation of steroidogenic genes (Pcc-3bhsd, Pcc-11bhsd2 Pcc-cyp11a1), while the other three steroidogenic genes (Pcc-cyp17a1, Pcc-cyp19a1a and Pcc-star) decreased from week 4 to week 8. Ovarian, hepatic Pcc-vtg B and vitellogenin concentration increased in both 50 and 100 MUg/L of MT exposure groups. This study adds further information regarding the effects of androgens on the development of previtellogenic oocytes, which suggests that MT could directly target estrogen signaling pathway, or indirectly affect steroidogenesis and vitellogenesis. PMID- 26938154 TI - Bioaccessibility, sources and health risk assessment of trace metals in urban park dust in Nanjing, Southeast China. AB - Arsenic, Cd, Co, Cr, Cu, Mn, Ni, Pb, V, and Zn total concentrations and bioaccessibilities in 15 urban park dust samples were determined. The oral bioaccessibility measured by the Simple Bioaccessibility Extraction Test (SBET) decreased in the order of Pb>Cd>Zn>Mn>Cu>Co>V>Ni>As>Cr. The Tomlinson pollution load index (PLI) and geoaccumulation index (I(geo)) were calculated to evaluate the pollution extent to which the samples were contaminated. Sources were identified using principal component analysis and Pb isotope compositions. Most elements except Co and V were considered to mainly originate from anthropogenic sources. Non-carcinogenic and carcinogenic risks to humans through urban park dust exposure were assessed using the oral bioaccessibilities of the elements. Ingestion was the main pathway for non-carcinogenic risk. The hazard quotients were below the safe level (=1) for all elements, however, Pb (0.154) and As (0.184) posed potential higher risks to children than adults. The carcinogenic effects occurring were below the acceptable level (10(-4)) for As and <10(-6) for Cd, Co, Cr, and Ni. PMID- 26938153 TI - Characterization of metal kinetics and bioavailability using diffusive gradients in thin films technique in sediments of Taihu Lake, China. AB - For an improved understanding of the metal behavior between the sediment and overlaying water of Taihu Lake, the technique of diffusive gradients in thin films (DGT) was used to characterize the DGT measured concentration in sediments and release kinetics of Cr, Ni, Cu, Zn, Cd and Pb in representative lake parts. Spatially, the DGT-measured concentration of heavy metals showed that Zn, Cu, Ni, Cr, and Pb had higher concentrations in the northern lake than in the eastern Lake Taihu. The order of the release flux for the studied metals from sediments to overlaying water was Zn>Cu>Ni, Cr>Pb>Cd (p<0.05). DGT devices were deployed over a series of time (0.5, 1, 2, 4, 8, 12, 24 and 48 h) in sediment cores from the two typical lake parts (northwest algae dominant area and southeast macrophyte dominant area) to explore the dynamics in the sediment/DGT system, and the best fitted regression model was selected to characterize the release of metals in the two lake parts. The fitted results showed that the equilibration time of the metal release was approximately 24h and Zn had a higher release capacity than other metals. Further analyses indicated that significant correlation existed between the DGT-measured metal concentrations in sediments and metal concentrations in lake organisms (r=0.943 and 0.996 for zoobenthos and coilia ectenes, p<0.05), suggesting that DGT technique is more effective to predict the metal bioavailability in lake sediments. PMID- 26938155 TI - Antithrombotic therapy in patients with non-valvular atrial fibrillation in Southern Sweden: A population-based cohort study. AB - INTRODUCTION: Oral anticoagulants in patients with atrial fibrillation (AF) with moderate-to-high stroke risk are strongly recommended by the current guidelines. MATERIALS AND METHODS: Population-based register study of all 13,837 patients with incident non-valvular AF diagnosed during 2011-2014 in primary and secondary care (including all in- and outpatient visits) in Skane County, Sweden. The outcome was the prescription of direct-acting oral anticoagulants (DOAC), warfarin or acetylsalicylic acid (ASA). RESULTS AND CONCLUSION: Guideline adherence increased from 47.6% in 2011 to 66.1% in 2014, mostly due to decrease in undertreatment. In patients with CHA2DS2-VASc score >= 2, ASA uptake decreased from 29.9% to 14.7% and DOAC uptake increased from 2.1% to 25.1%. The use of ASA was more common among elderly and with increasing stroke- and bleeding risk. Overall, 47.4% of patients with CHA2DS2-VASc score >= 2 did not receive oral anticoagulants. Undertreatment was particularly common in women < 65 years (55.8%) and in patients > 84 years (65.3% in women and 62% in men). Overtreatment of patients at low stroke risk was 35.9% in men and 36.4% in women. Provider speciality affected the choice of treatment only to a minor degree. Despite increasing guideline adherence, there is a suboptimal use of antithrombotic therapy in a large proportion of AF patients diagnosed in different clinical settings. Efforts to further improve guideline adherence should particularly be targeted on women < 65 years, elderly > 84 years and patients at low stroke risk. PMID- 26938156 TI - Non-autoimmune combined factor XIII A and B subunit deficiencies in rheumatoid arthritis patients treated with anti-interleukin-6 receptor monoclonal antibody (tocilizumab). AB - INTRODUCTION: Coagulation factor XIII (FXIII) is a plasma fibrin-stabilizing factor comprising A and B subunits (FXIII-A and FXIII-B, respectively) in the form of a heterotetramer (FXIII-A2B2). A humanized monoclonal antibody to the interleukin-6 receptor (tocilizumab, TCZ) has emerged as an effective treatment for rheumatoid arthritis (RA), because it drastically reduces the inflammation of RA. We previously reported that two TCZ-treated RA patients with acquired FXIII deficiency developed pelvic hemorrhage. METHODS: Because TCZ treatment had been shown to be related to low FXIII ammonia release activity and FXIII antigen in the two RA cases, we further examined FXIII-related parameters in 36 TCZ-treated RA patients and compared to 29 healthy controls by employing functional and immunologic assays for FXIII. RESULTS: FXIII-A antigen and FXIII amine incorporation and ammonia release activities were significantly lower in the TCZ treated group than the control group. The TCZ-treated group also showed mildly low FXIII-A2B2 and FXIII-B levels, and their fibrinogen levels were the lower limit of normal. A significant correlation between FXIII-B and fibrinogen was observed in the control and the TCZ groups, suggesting a common metabolic mechanism(s) for these two hepatic proteins. Because the specific activities of FXIII were normal and neither anti-FXIII-A nor anti-FXIII-B antibody was detected, the overall low FXIII level may have resulted from its impaired synthesis under an unbalanced cytokine milieu caused by TCZ treatment. CONCLUSION: Concomitant deficiencies in multiple hemostatic factors, including FXIII, may lead to an increased risk for hemorrhage in TCZ-treated RA patients. PMID- 26938157 TI - Toll-like receptor 9 gene expression in the post-thrombotic syndrome, residual thrombosis and recurrent deep venous thrombosis: A case-control study. AB - OBJECTIVE: Animal models suggest that toll-like receptor 9 (TLR9) promotes thrombus resolution after acute deep venous thrombosis (DVT). We hypothesized that TLR9 expression is lower in patients with post-thrombotic syndrome (PTS) and investigated the role of TLR9 in residual thrombosis (RT) and recurrence. METHODS: Patients with a history of DVT with PTS (cases, n=30) and without PTS after minimal 24 months follow-up (controls, n=30) were selected. Healthy individuals (HI, n=29) without DVT were included as reference. TLR9 mRNA expression in leukocytes was determined by qPCR and normalized to the housekeeping succinate dehydrogenase subunit A gene using the DeltaCt method. Sub analyses were performed to explore the TLR9 expression in patients with and without RT and multiple DVT episodes. RESULTS: The median TLR9 expression was 0.45 (interquartile range 0.31 to 0.93), 0.39 (0.25 to 0.69) and 0.62 (0.32 to 0.75) in cases, controls and HI respectively (p=0.61). The median TLR9 expression was 0.39 (0.26 to 0.51) in patients with RT compared to 0.55 (0.30 to 0.86, p=0.13) in those without. The median TLR9 expression was significantly lower in patients who had one DVT compared to patients with recurrent DVT, 0.37 (0.23 to 0.63) versus 0.55 (0.43 to 0.96) respectively (p<0.01). CONCLUSION: No significant difference in TLR9 expression was found between cases, controls and HI. However TLR9 expression seems lower in individuals with DVT and RT, albeit not significant. Interestingly, TLR9 might play a role in recurrent DVT, as the TLR9 expression was significantly higher in patients with recurrent DVT. PMID- 26938158 TI - Aspirin has limited ability to modulate shear-mediated platelet activation associated with elevated shear stress of ventricular assist devices. AB - Continuous flow ventricular assist devices (cfVADs) while effective in advanced heart failure, remain plagued by thrombosis related to abnormal flows and elevated shear stress. To limit cfVAD thrombosis, patients utilize complex anti thrombotic regimens built upon a foundation of aspirin (ASA). While much data exists on ASA as a modulator of biochemically-mediated platelet activation, limited data exists as to the efficacy of ASA as a means of limiting shear mediated platelet activation, particularly under elevated shear stress common within cfVADs. We investigated the ability of ASA (20, 25 and 125 MUM) to limit shear-mediated platelet activation under conditions of: 1) constant shear stress (30 dynes/cm(2) and 70 dynes/cm(2)); 2) dynamic shear stress, and 3) initial high shear exposure (70 dynes/cm(2)) followed by low shear exposure - i.e. a platelet sensitization protocol, utilizing a hemodynamic shearing device providing uniform shear stress in vitro. The efficacy of ASA to limit platelet activation mediated via passage through a clinical cfVAD system (DeBakey Micromed) in vitro was also studied. ASA reduced platelet activation only under conditions of low shear stress (38% reduction compared to control, n=10, p<0.004), with minimal protection at higher shear stress and under dynamic conditions (n=10, p>0.5) with no limitation of platelet sensitization. ASA had limited ability (25.6% reduction in platelet activation rate) to modulate shear-mediated platelet activation induced via cfVAD passage. These findings, while performed under "deconstructed" non-clinical conditions by utilizing purified platelets alone in vitro, provide a potential contributory mechanistic explanation for the persistent thrombosis rates experienced clinically in cfVAD patients despite ASA therapy. An opportunity exists to develop enhanced pharmacologic strategies to limit shear mediated platelet activation at elevated shear levels associated with mechanical circulatory support devices. PMID- 26938159 TI - A reference substance free diagnostic fragment ion-based approach for rapid identification of non-target components in Pudilan Xiaoyan oral liquid by high resolution mass spectrometry. AB - Rapid and reliable identification of non-target components in herbal preparations remains a primary challenge, especially when corresponding reference substances are inaccessible. In this work, an efficient post-experiment data processing methodology, named reference substance free diagnostic fragment ion (RSFDFI), was developed based on ultra-high-performance liquid chromatography coupled with linear ion trap-Orbitrap tandem mass spectrometry (UHPLC/LTQ-Orbitrap). The first step of this approach was to cluster the components that share common fragment ions into several groups. After querying the database using a predicted chemical formula, the component with the fewest primary hits was preferentially deduced based on its MS/MS spectrum. Once the structure was characterized, its common fragment ions could be used as the prior structural information to select the possible candidates that would facilitate the subsequent identification for each group. Taking Pudilan Xiaoyan oral liquid (PDL) as a model herbal preparation, which has been extensively used for the treatment of epidemic parotitis and children with hand-foot-mouth diseases, this strategy enables a nearly eight-fold narrowing of the database hits, with fifty-two components, including lignans, flavonoids, alkaloids and steroids, being rapidly identified. In conclusion, our work clearly demonstrates that integrating RSFDFI with high-resolution mass spectrometry is a powerful methodology for rapid identification of non-target components from herbal prescriptions and may open new avenues for chemical analysis in other complex mixtures. PMID- 26938161 TI - Context for Practice: Pressure Ulcer Prevention, Suicide and Urinary Diversion, Continence and Intermittent Catheterization. PMID- 26938160 TI - Rapid analysis of Callicarpa L. using direct spray ionization mass spectrometry. AB - Direct spray such as leaf spray and paper spray ionization mass spectrometry (MS) is a powerful type of ambient MS for phytochemical analysis. In this paper, direct spray MS methods to rapidly distinguish and analyze five species of Callicarpa L. have been developed. To distinguish species, leaf spray MS was employed to directly analyze leaves. A small triangular leaf sample was wetted with 15 MUL of spray solvent and a high DC voltage was then simply applied to the wet leaf sample, which was positioned in front of the inlet of a mass spectrometer to produce electrospray ionization. The MS signals of phenylpropanoid glycosides, i.e. forsythiaside B, poliumoside, verbascoside in leaves could be sensitively detected. The content characteristics of the phenylpropanoid glycosides in five species including Callicarpae kwangtungensis Folium, Callicarpae macrophyllae Folium, Callicarpa nudiflora Folium, Callicarpae formosanae Folium, Callicarpa longissima Folium could be used to distinguish them, then the mass spectra of the Callicarpa L. samples were analyzed using principal component analysis(PCA) or partial least squares-discriminant analysis(PLS-DA). For the rapid semi-quantitative analysis, of phenylpropanoid glycosides in leaves, paper spray MS was employed to determine phenylpropanoid glycosides in the extracts of Callicarpa L. leaves. Ginsenoside Rg1 was selected as an internal standard (I.S.). The calibration curves were constructed through ratios of target ion abundance to I.S. ion abundance vs. concentration of targets. The linearity range was 8-250 MUg/mL (R(2)=0.9947) for forsythiaside B, 9-280 MUg/mL (R(2)=0.9939) for verbascoside, and 9-260 MUg/mL (R(2)=0.9917) for poliumoside, respectively. The limit of detection (LOD) was 1 MUg/mL, 0.5 MUg/mL and 1 MUg/mL for forsythiaside B, verbascoside, and poliumoside, respectively. PMID- 26938162 TI - Distant Origins of Ostomy Rehabilitation. PMID- 26938164 TI - Visual Guide for Accurately Designating the Anatomic Location of Buttocks Lesions. PMID- 26938163 TI - Tap Water Versus Sterile Normal Saline in Wound Swabbing: A Double-Blind Randomized Controlled Trial. AB - PURPOSE: The use of tap water as a wound-cleansing agent is becoming more common in clinical practice, especially in community settings. The aim of this study was to test whether there are differences in wound infection and wound healing rates when wounds are cleansed with tap water or sterile normal saline. DESIGN: Double blinded randomized controlled trial. SUBJECTS AND SETTING: Subjects were recruited from the community nursing service of a local hospital in Hong Kong. The target sample included subjects who were aged 18 years or more, and receiving chronic or acute wound care treatment. METHODS: Subjects were randomly assigned to wound cleansing with tap water (experimental group) or sterile normal saline (control group). Wound assessment was conducted at each home visit, and an assessment of wound size was conducted once a week. The main outcome measures, occurrence of a wound infection and wound healing, were assessed over a period of 6 weeks. RESULTS: Twenty-two subjects (11 subjects in each group) with 30 wounds participated in the study; 16 wounds were managed with tap water cleansing and 14 were randomly allocated to management with the sterile normal saline group. Analysis revealed no significant difference between the experimental and control groups in the proportions of wound infection and wound healing. CONCLUSIONS: Study findings indicate that tap water is a safe alternative to sterile normal saline for wound cleansing in a community setting. PMID- 26938165 TI - Italian Society of Surgery and Association of Stoma Care Nurses Joint Position Statement on Preoperative Stoma Siting. AB - Drawing on the existing position statements approved by the Wound, Ostomy and Continence Nursing Society in collaboration with the American Society of Colon & Rectal Surgeons and the American Urological Association, the Italian Association of Stoma care Nurses and the Italian Society of Surgery jointly developed and approved this document on July 27, 2013. Its purpose was to provide a formal recommendation for preoperative stoma siting and associated counseling for all patients undergoing enterostomy or urostomy surgery, with the goals of preventing complications, enhancing health-related quality of life, improving care, achieving better health outcomes, and reducing health care costs. PMID- 26938166 TI - Suicide Risk in Patients With Bladder Cancer: A Call to Action. PMID- 26938167 TI - Incontinence-Associated Dermatitis: Progress, Promises, and Ongoing Challenges. PMID- 26938168 TI - WOCNCB Providing Certification Exams at All 3 Nursing Education Levels: CWOCN-AP, CWOCN, WTA-C. PMID- 26938169 TI - Topical Therapy As Adjuvant Treatment to Save a Limb With Critical Ischemia From Extensive and Deep Diabetic Foot Infection When Revascularization Is Not Feasible. AB - BACKGROUND: Patients with diabetes mellitus are susceptible to foot ulcerations associated with the complex triad of peripheral sensory neuropathy, vasculopathy, and trauma. Local infection of a diabetic foot ulcer (DFU) acts a significant deterrent to healing because the response to aggressive debridement antimicrobial therapy is limited when peripheral circulation is poor. CASE REPORT: We share an experience of using silver-impregnated hydrofiber wound dressing as an alternative to amputation in an 85-year-old female patient with an infected, ischemic DFU. This patient had a long-standing history of diabetes mellitus and hypertension for more than 30 years; both conditions were managed with oral medications. Penetrative injury caused by toothpicks resulted in 2 ulcers over the right lateral and medial plantar areas of her right foot. The DFUs were present within a period of 6 months. Due to the deep wound and progressively worsening infection, she was admitted for systemic antibiotics, debridement, and plantar fasciotomy. Percutaneous transluminal angioplasty was indicated, but the patient refused due to concerns related to potential nephrotoxicity associated with contrast use. Amputation was proposed as the final resort if the critical ischemia showed no improvement. Before undertaking amputation, silver-impregnated hydrofiber dressings were applied to the DFUs, along with antiplatelet medications. Following 4 months of treatment, the right medial plantar ulcer healed completely and the DFU over the lateral plantar ulcer was 75% smaller in surface area. Both DFUs remained healed when evaluated at 8 months. CONCLUSION: We found that a silver-impregnated hydrofiber dressing, combined with antiplatelet medications, allowed the patient to avoid amputation despite 2 deep and extensively infected DFUs with critical limb ischemia when revascularization was not feasible. PMID- 26938172 TI - The Descending Thoracic Aorta: Forgotten Vascular Access for Endovascular Device Delivery. AB - Vascular access for large endovascular devices has evolved as patients have become more complicated and device indications have expanded. As the benefits of catheter-based treatments for aortic aneurysm repair and aortic valve replacement become mainstream, there is a need to address difficult vascular access by developing not only smaller-diameter devices but also creative options for vascular access. We describe direct descending thoracic aortic access during endovascular aneurysm repair, transcatheter aortic valve replacement, and redo mesenteric revascularization in three patients who did not have traditional access options. PMID- 26938173 TI - Augmented Reality System for Ultrasound Guidance of Transcatheter Aortic Valve Implantation. AB - OBJECTIVE: Transcatheter aortic valve implantation (TAVI) relies on fluoroscopy and nephrotoxic contrast medium for valve deployment. We propose an alternative guidance system using augmented reality (AR) and transesophageal echocardiography (TEE) to guide TAVI deployment. The goals of this study were to determine how consistently the aortic valve annulus is defined from TEE using different aortic valve landmarks and to compare AR guidance with fluoroscopic guidance of TAVI deployment in an aortic root model. METHODS: Magnetic tracking sensors were integrated into the TAVI catheter and TEE probe, allowing these tools to be displayed in an AR environment. Variability in identifying aortic valve commissures and cuspal nadirs was assessed using TEE aortic root images. To compare AR guidance of TAVI deployment with fluoroscopic guidance, a TAVI stent was deployed 10 times in the aortic root model using each of the two guidance systems. RESULTS: Commissures and nadirs were both investigated as features for defining the valve annulus in the AR guidance system. The commissures were identified more consistently than the nadirs, with intraobserver variability of 2.2 and 3.8 mm, respectively, and interobserver variability of 3.3 and 4.7 mm, respectively. The precision of TAVI deployment using fluoroscopic guidance was 3.4 mm, whereas the precision of AR guidance was 2.9 mm, and its overall accuracy was 3.4 mm. This indicates that both have similar performance. CONCLUSIONS: Aortic valve commissures can be identified more reliably than cuspal nadirs from TEE. The AR guidance system achieved similar deployment accuracy to that of fluoroscopy while eliminating the use and consequences of nephrotoxic contrast and radiation. PMID- 26938174 TI - Validation of the Instant Blood Pressure Smartphone App. PMID- 26938175 TI - Correlation between skeletal Class II and temporomandibular joint disorders: a literature review. AB - BACKGROUND: The purpose of this literature review was to evaluate current knowledge about the relationship between Angle class II malocclusion (especially the second division) and temporomandibular dysfunction (TMD). EVIDENCE ACQUISITION: A survey has been conducted through the electronic databases Medline, using specific inclusion and exclusion criteria, the keywords "temporomandibular disorder AND class II malocclusion". Of the 290 articles resulting from research 23 have been selected that met all the inclusion criteria of this review. EVIDENCE SYNTHESIS: The prospective, longitudinal and retrospective analyzed studies do not ultimately support a primary role of occlusion, especially class II malocclusion second division, in the development of joint problems and they also support the hypothesis of a multifactorial origin theory of joint problems. CONCLUSIONS: It is therefore impossible to make any forecast of proper development of TMD on the basis of the presence or absence of a malocclusion although in some studies the class II malocclusion has been associated with a higher prevalence of muscle strains problems. So, while there is a clear lack of association with strictly joint issues (click, lock joint, dislocations) in the literature class II malocclusion can be related only to muscular problems. PMID- 26938177 TI - From the Editor. PMID- 26938176 TI - Pore-Filled Scintillating Membrane as Sensing Matrix for alpha-Emitting Actinides. AB - Pore-filled membranes with scintillating properties have been synthesized for sensing alpha-emitting radionuclides. The membranes have been prepared by in situ UV-initiator-induced polymerization of monomer bis[2-(methacryloxy)ethyl] phosphate in pores of the host membranes, poly(propylene) and poly(ethersulfone). The polymerization has been carried out in the presence of scintillating molecules, 2,5-diphenyloxazole. These scintillating molecules are physically trapped in the thus formed microgel in the membrane. Much higher alpha scintillation efficiency has been obtained for the (241)Am-loaded poly(ethersulfone)-based grafted membrane compared to poly(propylene)-based membrane. This was attributed to the aromatic backbone of the poly(ethersulfone) membrane. The scintillation response of poly(ethersulfone)-based membranes has been found to be linear over the range of (241)Am activity studied. The pore filled scintillating membranes have been found to be selective toward Pu(4+) ions at higher HNO3 concentration compared to Am(3+). The analytical performance of the pore-filled scintillating membranes has been evaluated. The membranes have been found to be stable and reusable. The scintillating membrane with optimized composition has been applied for quantification of Pu in a soil sample. PMID- 26938178 TI - Guest Editorial. Nursing Leadership for the Continuum of Care. PMID- 26938179 TI - NAQ's 40th Birthday: Everything Old Is New Again. PMID- 26938181 TI - Finding Common Ground: Interprofessional Collaborative Practice Competencies in Patient-Centered Medical Homes. AB - The patient-centered medical home model is predicated on interprofessional collaborative practice and team-based care. While information on the roles of various providers is increasingly woven into the literature, the competencies of those providers have been generally profession-specific. In 2011, the Interprofessional Education Collaborative comprising the American Association of Colleges of Nursing, the American Association of Colleges of Osteopathic Medicine, the American Association of Colleges of Pharmacy, the American Dental Education Association, the Association of American Medical Colleges, and the Association of Schools of Public Health sponsored an expert panel of their members to identify and develop 4 domains of core competencies needed for a successful interprofessional collaborative practice: (1) Values/Ethics for Interprofessional Practice; (2) Roles/Responsibilities; (3) Interprofessional Communication; and (4) Teams and Teamwork. Their findings and recommendations were recorded in their Core Competencies for Interprofessional Collaborative Practice: Report of an Expert Panel. This article explores these 4 domains and how they provide common ground for team-based care within the context of the medical home model approach to patient-centered primary care. PMID- 26938180 TI - Nursing Leadership and Care Coordination: Creating Excellence in Coordinating Care Across the Continuum. AB - Continuum Care is different today from in the past. It requires care coordination with an emphasis on relationships and new roles. Nurses and nurse leaders must be located at the epicenter of developing strategies to align resources with patients and family along all points of the continuum. PMID- 26938182 TI - SCI Hospital in Home Program: Bringing Hospital Care Home for Veterans With Spinal Cord Injury. AB - The complex nature of spinal cord injury (SCI) and the level of care required for health maintenance frequently result in repeated hospital admissions for recurrent medical complications. Prolonged hospitalizations of persons with SCI have been linked to the increased risk of hospital-acquired infections and development or worsening pressure ulcers. An evidence-based alternative for providing hospital-level care to patients with specific diagnoses who are willing to receive that level of care in the comfort of their home is being implemented in a Department of Veterans Affairs SCI Home Care Program. The SCI Hospital in Home (HiH) model is similar to a patient-centered interdisciplinary care model that was first introduced in Europe and later tested as part of a National Demonstration and Evaluation Study through Johns Hopkins School of Medicine and School of Public Health. This was funded by the John A. Hartford Foundation and the Department of Veterans Affairs. The objectives of the program are to support veterans' choice and access to patient-centered care, reduce the reliance on inpatient medical care, allow for early discharge, and decrease medical costs. Veterans with SCI who are admitted to the HiH program receive daily oversight by a physician, daily visits by a registered nurse, access to laboratory services, oxygen, intravenous medications, and nursing care in the home setting. In this model, patients may typically access HiH services either as an "early discharge" from the hospital or as a direct admit to the program from the emergency department or SCI clinic. Similar programs providing acute hospital-equivalent care in the home have been previously implemented and are successfully demonstrating decreased length of stay, improved patient access, and increased patient satisfaction. PMID- 26938183 TI - Transitioning the RN to Ambulatory Care: An Investment in Orientation. AB - Registered nurses (RNs) struggle when transitioning from the inpatient setting to the outpatient clinical environment because it results in a diverse skill-set shift. The RN, considered an outpatient revenue source, experiences a decrease in peer-to-peer relationships, changes in leadership responsibilities, and changes in workgroup dynamics (supervision of unlicensed clinical personnel who function under the direction of the physician, not the RN). Ambulatory organizations find themselves implementing clinical orientation programs that may not delineate the attributes of the RN. This diminishes their value while emphasizing the unlicensed technical skill set. Creating a core RN orientation program template is paramount for the transition of the RN to the ambulatory setting. The literature reveals several areas where improving the value of the RN will ultimately enhance recruitment and retention, patient care outcomes, and leverage the RN role within any organization. Eleven 30-minute in-depth telephone interviews were conducted in addition to 4 nurse observations to explore the lived experience of the RN in ambulatory care. The findings disclosed an overarching theme of nurse isolation and offered insightful underpinnings for the nurse leader as ambulatory growth continues and nurse leaders further endorse the RN presence in the ambulatory setting. PMID- 26938184 TI - Coordinating Care: Shifts in Perspective. AB - Effective coordination of care has consistently been a challenge for clinicians, care providers, and systems of health care. The health care system is inherently fraught with unorganized and disparate parts including multiple points of entry. A review of the current issues and the leadership implications is explored in this article with an emphasis on patients becoming more actively engaged in managing their care journey across the continuum. A case study of a primary care clinic in Annapolis, Maryland, is described to illustrate the application of evidence-based leadership skills, knowledge, and a framework to transform health care to more effectively engage patients in their care. As the constant on the continuum of care, the engaged patient is in the unique position to manage coordination, thus ensuring continuity. PMID- 26938185 TI - Transitioning From Volume to Value: A Strategic Approach to Design and Implementation. AB - As the health care delivery system migrates toward a model based on value rather than volume, nursing leaders play a key role in assisting in the design and implementation of new models of care to support this transition. This article provides an overview of one organization's approach to evolve in the direction of value while gaining the experience needed to scope and scale cross-continuum assets to meet this growing demand. This article outlines the development and deployment of an organizational structure, information technology integration, clinical implementation strategies, and tools and metrics utilized to evaluate the outcomes of value-based programs. Experience in Bundled Payments for Care Improvement program is highlighted. The outcomes and lessons learned are incorporated for those interested in advancing value-based endeavors in their own organizations. PMID- 26938186 TI - Caring Across the Continuum: A Call to Nurse Leaders to Manifest Values Through Action With Community Outreach. AB - As health reform continues to advance, there is a need for nurse leaders to broaden their perspective related to possible nursing practice models and potential community partners in order to successfully address caring, accomplish the triple aim mandate, and achieve suitable metrics for maximum reimbursement. Intentional efforts must be made by nurse leaders to maximize caring and ensure that professional nurses are responding to the key drivers shifting health care delivery in the 21st century. Academic-practice collaboration (APC) and community based participatory action research (CBPAR) align well. Together, they provide an ideal mechanism to pursue endeavors that extend evidence for caring services across the health care continuum. One APC/CBPAR model for community outreach that can maximize individual and population health outcomes is highlighted in this article. Furthermore, useful action steps are offered that could be taken by a nurse leader to develop and maintain any form of APC/CBPAR in order to manifest values through caring action across the health care continuum. PMID- 26938187 TI - Decreasing Congestive Heart Failure Readmission Rates Within 30 Days at the Tampa VA. AB - High hospital readmission rates contribute to the problem of escalating costs and fragmented quality in the US health care system. This article describes the implementation of a home telehealth (HT) performance improvement project with subsequent cost-avoidance savings. The HT project was designed to potentiate communication between and among patients, clinicians, and administrative staff, in addition to reducing readmissions for patients with congestive heart failure at the James A. Haley Veterans Hospital in Tampa, Florida. Pre- and post-HT implementation comparisons were made of readmission rates, costs, and veteran satisfaction from the same 4-month periods in 2012 and 2013. The application of telehealth and phone care initiatives reduced the congestive heart failure hospital readmission rate by 5%, decreased costs, and improved veteran satisfaction with overall care experience. PMID- 26938188 TI - Health Care Reform, Care Coordination, and Transformational Leadership. AB - This article is meant to spur debate on the role of the professional nurse in care coordination as well as the role of nursing leaders for defining and leading to a future state. This work highlights the opportunity and benefits associated with transformation of professional nursing practice in response to the mandates of the Affordable Care Act of 2010. An understanding of core concepts and the work of care coordination are used to propose a model of care coordination based on the population health pyramid. This maximizes the roles of nurses across the continuum as transformational leaders in the patient/family and nursing relationship. The author explores the role of the nurse in a transactional versus transformational relationship with patients, leading to actualization of the nurse in care coordination. Focusing on the role of the nurse leader, the challenges and necessary actions for optimization of the professional nurse role are explored, using principles of transformational leadership. PMID- 26938189 TI - Administrative Supervisors: A Qualitative Exploration of Their Perceived Role. AB - The administrative supervisor, who is the nurse manager present on the night and weekend shifts, can be found in hospitals throughout the United States. Yet, very little research has been published about this role on weekend and night shifts in acute care hospitals. The objective of this qualitative research study was to gain a better understanding of the administrative supervisor role. In-depth interviews with administrative supervisors were conducted at acute care hospitals in the mid-Atlantic region of the United States. Thematic analysis was used to reduce the data and identify codes and themes. Administrative supervisors experience and described their role within a "different" hospital world on weekends and at night. The administrative supervisors consistently stated that they oversee and are responsible for staffing and patient flow, crisis management, and management support for the staff. That administrative supervision is a challenging position for nurses is particularly evident as researchers seek to obtain a better understanding of how nurse leaders make a difference. This research delineates these different supervisor role responsibilities to provide a better understanding of management during the "off-shift." Nurse leaders can utilize this information to assist in justifying the need for this shift management role at their institutions. PMID- 26938190 TI - From Caterpillars to Butterflies: Engaging Nurse Leaders in Evidence-Based Practice Reform. AB - Evidence-based practice (EBP) occurs when the integration of best evidence is brought to the bedside to ground patient care decisions. Barriers to EBP have lingered for years and held unabated. The experiences of an academic medical center offer fresh perspectives in devolving the accountability for EBP where care is provided and received by patients. More specifically, the initiative is a focused engagement of nurse leaders in administrative positions for energizing bedside nurses to reform the enculturation of EBP. The goal is not to control but to explore approaches of handling the barriers with a complexity mindset amidst uncertainties. Nurses' collective engagement is envisioned to spark or refine creative ideas that will steer and account for EBP outcomes. The flight of the butterfly is used as a metaphor; hence, the title for the Monarch Moments Initiative. PMID- 26938191 TI - Trends in Nursing Informatics Research and the Importance of the Nurse Administrator. PMID- 26938192 TI - Remembering 'Mrs. Reynolds Needs a Nurse'. PMID- 26938193 TI - Questionnaires for the diagnosis of gastroesophageal reflux disease: are they really useful? AB - Gastroesophageal reflux disease (GERD) is a major medical complaint both in primary care and gastroenterology clinics. This is partly due to the condition's high prevalence, which in developed countries is estimated to be 10-20%. Its initial diagnosis, however, remains controversial. The Montreal definition of GERD is widely accepted, and both heartburn and regurgitation are therein considered the syndrome's typical symptoms. However, in the DIAMOND study only 49% of patients with GERD surprisingly reports these symptoms as major causes of disability (40%) heartburn, 9% regurgitation). PMID- 26938194 TI - Eritadenine from Edible Mushrooms Inhibits Activity of Angiotensin Converting Enzyme in Vitro. AB - The inhibition of angiotensin converting enzyme (ACE) activity was determined in vitro by mushroom-derived eritadenine (EA), which was analyzed in 11 principal Korean edible mushrooms. EA inhibited ACE activity with 0.091 MUM IC50, whereas the IC50 of captopril (CP), which is a reference compound, was 0.025 MUM. Kinetic measurements of ACE reaction in the substrate of hippuryl-l-histidyl-l-leucine (HHL) with or without EA revealed that the Vmax (0.0465 O.D/30 min) was unchanged, but the the Km increased from 2.063 to 3.887 mM, indicating that EA competes with HHL for the active site. When EA was analyzed by HPLC, Lentinus edodes with a soft cap contained the highest amount EA (642.8 mg%); however, Phellinus linteus with a hard cap contained the least amount of EA (9.4 mg%). These results indicate that EA was a strong competitive inhibitor for ACE, and edible mushrooms with soft caps contained a significant amount of EA. PMID- 26938195 TI - Photodemethylation of Methylmercury in Eastern Canadian Arctic Thaw Pond and Lake Ecosystems. AB - Permafrost thaw ponds of the warming Eastern Canadian Arctic are major landscape constituents and often display high levels of methylmercury (MeHg). We examined photodegradation potentials in high-dissolved organic matter (DOC) thaw ponds on Bylot Island (BYL) and a low-DOC oligotrophic lake on Cornwallis Island (Char Lake). In BYL, the ambient MeHg photodemethylation (PD) rate over 48 h of solar exposure was 6.1 * 10(-3) m(2) E(-1), and the rate in MeHg amended samples was 9.3 * 10(-3) m(2) E(-1). In contrast, in low-DOC Char Lake, PD was only observed in the first 12 h, which suggests that PD may not be an important loss process in polar desert lakes. Thioglycolic acid addition slowed PD, while glutathione and chlorides did not impact northern PD rates. During an ecosystem-wide experiment conducted in a covered BYL pond, there was neither net MeHg increase in the dark nor loss attributable to PD following re-exposure to sunlight. We propose that high-DOC Arctic thaw ponds are more prone to MeHg PD than nearby oligotrophic lakes, likely through photoproduction of reactive species rather than via thiol complexation. However, at the ecosystem level, these ponds, which are widespread through the Arctic, remain likely sources of MeHg for neighboring systems. PMID- 26938196 TI - Age-friendly environments and life satisfaction among South Korean elders: person environment fit perspective. AB - OBJECTIVES: Drawing on the person-environment (P-E) fit perspective, this study examined the role of environment on the well-being of vulnerable older adults in a non-western context. Using the indicators from the World Health Organization's (WHO) framework for age friendly cities (ACF), we examined life satisfaction among South Korean older adults, exploring the extent to which multidimensional environmental characteristics are associated with low socioeconomic status (SES). METHOD: Using the regionally representative data from the Seoul City-wide needs assessment of middle- and old-aged adults, an analytic sample (N = 1657) focused on community-living individuals aged 65 and older. Multilevel regression models examined interaction between SES subgroups and varying aspects of the environment (i.e. physical, social, and service environment) as related to life satisfaction. RESULTS: Consistent with the environmental docility hypothesis, members of the most vulnerable subgroup in the Korean context - older adults who are living alone and poor - are more likely to have higher life satisfaction when they have higher levels of support in physical and social environments. Interestingly, a higher level of support in the service environment was related to lower life satisfaction for this subgroup. CONCLUSION: This study provides an empirical foundation for efforts to identify age-friendly environmental characteristics as modifiable environmental resources that can improve older adults' psychological well-being. As the first attempt to use WHO ACF indicators within the P-E fit perspective in a non-Western context, our study provides a foundation for designing support services or programs that effectively meet the needs of vulnerable older adults. PMID- 26938197 TI - pH-Triggered Release of Hydrophobic Molecules from Self-Assembling Hybrid Nanoscaffolds. AB - Self-assembling peptide based hydrogels have a wide range of applications in the field of tissue repair and tissue regeneration. Because of its physicochemical properties, (RADA)4 has been studied as a potential platform for 3D cell culture, drug delivery, and tissue engineering. Despite some small molecule and protein release studies with this system, there is a lack of work investigating the controlled release of hydrophobic compounds (i.e., anti-inflammatory, anticancer, antibacterial drugs, etc.) that are important for many clinical therapies. Attempts to incorporate hydrophobic compounds into self-assembling matrices usually inhibited nanofiber formation, rather resulting in a peptide-drug complex or microcrystal formation. Herein, a self-assembling chitosan/carboxymethyl-beta cyclodextrin nanoparticle system was used to load dexamethasone, which formed within a self-assembling (RADA)4 nanoscaffold matrix. Nanoparticles dispersed within the matrix were stabilized by the nanofibers within. The in vitro release of dexamethasone from the hybrid system was observed to be pH sensitive. At pH 7, release was observed for more than 8 days, with three distinct kinetic domains in the first 6 days. Data suggest that the deprotonation of chitosan at a solution pH > 6.8 leads to nanoparticle dissociation and ultimately the release of dexamethasone from the hybrid system. This system has the potential to form a multifunctional scaffold that can self-assemble with the ability to control the release of hydrophobic drugs for a wide variety of applications. PMID- 26938198 TI - Hereditary angioedema type I: a case report. AB - Hereditary angioedema is a rare disease with great heterogeneity of symptoms such as edema of the skin, gastro-intestinal mucosa and larynx or pharynx. Even though there are three types, the most frequent is type I, which is a result from a deficiency of the complement C1 inhibitor. The severity of its symptoms along with the low prevalence of the disease and the need for appropriate specific treatment make the diagnosis and treatment of the pathology an outstanding subject for the family physician. The present is the case of a male teenager with alpha-1 antitrypsin deficiency since he was six months old, angioedema on arms and legs since 11 years old and diagnosed with hereditary angioedema type I one year after. The definitive diagnosis of the disease enabled an appropriate treatment which consists in preventing outbreaks that may compromise the patient's life and, if they occur, administration of complement C1 inhibitor. PMID- 26938199 TI - Variants in FSHB Are Associated With Polycystic Ovary Syndrome and Luteinizing Hormone Level in Han Chinese Women. AB - CONTEXT: A recent genome-wide association study (GWAS) has identified three susceptibility loci (8p32.1, 11p14.1, and 9q22.32) for polycystic ovary syndrome (PCOS) in women of European ancestry. The 9q22.32 locus was previously found in our Chinese PCOS GWAS. Replication of the other two loci is necessary to determine whether the same variants confer risk to PCOS in Han Chinese women. OBJECTIVE: This study aimed to investigate the effect of the European GWAS loci on PCOS susceptibility in Han Chinese women. DESIGN, SETTING, AND PATIENTS: This was a genetic association study at a university hospital in composed of 1601 PCOS cases and 1238 age-matched controls. Interventions and Main Outcome Measure: After screening of the regions that cover 500 kb upstream and downstream of the two single-nucleotide polymorphisms (SNPs) using our previous Chinese GWAS data, rs11031010, located in the region of follicle-stimulating hormone B polypeptide (FSHB) gene, was selected for further replication. The other SNPs near rs804279 (GATA4/NEIL2) were excluded based on our previous GWAS data. Then, the variant rs11031010 was genotyped in an independent cohort and the associations with PCOS, endocrine and metabolic traits were assessed. RESULTS: In the current replication study, rs11031010 was associated with PCOS in Han Chinese women (P = 2.76 * 10( 3)), even after adjustment for age and body mass index. Meta-analysis with our previous GWAS data showed that the allele frequency difference of rs11031010 between PCOS and controls reached genome-wide significance (P = 4.27 * 10(-8)). PCOS women with AA and AC genotypes had a significantly higher LH level than individuals carrying the CC genotype (P =1.60 * 10(-4)). The genetic risk score based on sixteen total Chinese PCOS-risk SNPs, calculated by total number of risk alleles for each subject, was associated with the diagnosis of PCOS (P < 1.00 * 10(-4)). CONCLUSIONS: Variants in FSHB gene are associated with PCOS and LH levels in Han Chinese women. FSHB is thus likely to play an important role in the etiology of PCOS, regardless of ethnicity. PMID- 26938200 TI - Management of Hypoparathyroidism: Present and Future. AB - CONTEXT: Conventional management of hypoparathyroidism has focused upon maintaining the serum calcium with oral calcium and active vitamin D, often requiring high doses and giving rise to concerns about long-term consequences including renal and brain calcifications. Replacement therapy with PTH has recently become available. This paper summarizes the results of the findings and recommendations of the Working Group on Management of Hypoparathyroidism. EVIDENCE ACQUISITION: Contributing authors reviewed the literature regarding physiology, pathophysiology, and nutritional aspects of hypoparathyroidism, management of acute hypocalcemia, clinical aspects of chronic management, and replacement therapy of hypoparathyroidism with PTH peptides. PubMed and other literature search engines were utilized. EVIDENCE SYNTHESIS: Under normal circumstances, interactions between PTH and active vitamin D along with the dynamics of calcium and phosphorus absorption, renal tubular handing of those ions, and skeletal responsiveness help to maintain calcium homeostasis and skeletal health. In the absence of PTH, the gastrointestinal tract, kidneys, and skeleton are all affected, leading to hypocalcemia, hyperphosphatemia, reduced bone remodeling, and an inability to conserve filtered calcium. Acute hypocalcemia can be a medical emergency presenting with neuromuscular irritability. The recent availability of recombinant human PTH (1-84) has given hope that management of hypoparathyroidism with the missing hormone in this disorder will provide better control and reduced needs for calcium and vitamin D. CONCLUSIONS: Hypoparathyroidism is associated with abnormal calcium and skeletal homeostasis. Control with calcium and active vitamin D can be a challenge. The availability of PTH (1-84) replacement therapy may usher new opportunities for better control with reduced supplementation requirements. PMID- 26938206 TI - Polymer Conjugation as a Strategy for Long-Range Order in Supramolecular Polymers. AB - Supramolecular polymers are polymers in which the individual subunits self assemble via noncovalent and reversible bonds. An important axis of control for systems of mixed subunit composition is the order in which the subunit types assemble. Existing ordering techniques, which rely on pairwise interactions through the inclusion of highly specific chemistry, have the downside that patterns of length n require n specific chemistries, making long-range order complicated to attain. Here we present a simple alternative method: we attach varying numbers of polymers to self-assembling subunits, in our case ring shaped macrocycles, and the polymers' aversion to confinement imposes system order. We evaluate the feasibility of the strategy using coarse-grained molecular dynamics simulations of polymer-conjugated rings designed to model cyclic peptide nanotubes. We discuss the effects of polymer conjugation on the energetics of association and predict the equilibrium orderings for various ratios of ring types. The emergent patterns are associated with a certain stochastic disorder, which we quantify by deriving and employing a formula for the expected statistical weight of any pattern within the ensemble of all possible orderings. PMID- 26938201 TI - Mechanisms Linking the Gut Microbiome and Glucose Metabolism. AB - This review details potential mechanisms linking gut dysbiosis to metabolic dysfunction, including lipopolysaccharide, bile acids, short chain fatty acids, gut hormones, and branched-chain amino acids. PMID- 26938207 TI - Antibody-Free Colorimetric Detection of Total Aflatoxins in Rice Based on a Simple Two-Step Chromogenic Reaction. AB - The prevalently used immunoassays for fast screening of aftatoxins (AFs) usually cannot meet the requirement for simultaneous determination of total AFs (aflatoxin B1 + aflatoxin B2 + aflatoxin G1 + aflatoxin G2) due to the deficiency of highly group-specific antibodies. This paper describes a two-step chromogenic reaction based method to quantitatively detect total AFs in rice using colorimetric measurement without antibody. In the method, colorless AFs transform into green-colored indophenol products through the reaction with sodium hydroxide and 2,6-dibromoquinone-4-chloroimide (DBQC) successively, allowing selectively determining total AFs up to 3.9 MUg/kg over other competitive mycotoxins under optimal conditions by a UV-vis spectrophotometer. In addition, the colorimetric measurement results of the rice samples agree well with that of a standard HPLC method, demonstrating the good reliability and applicability of the method. Uniquely, the method has potential for on-site detection of total AFs in rice when using a nylon membrane-based device. PMID- 26938208 TI - Oxygen-Glucose-Deprivation/Reoxygenation-Induced Autophagic Cell Death Depends on JNK-Mediated Phosphorylation of Bcl-2. AB - BACKGROUND/AIMS: The purpose of this study was to investigate the role of autophagy in oxygen-glucose-deprivation/reoxygenation (OGD/R) injury in rat neurons. METHODS AND RESULTS: Cortical neurons were isolated from Sprague-Dawley rats and identified by immunofluorescence. The cortical neurons were randomly assigned to one of four groups: control group (I), experimental group (OGD/R group, II), JNK inhibitor pretreatment group (III) and JNK inhibitor pretreatment + OGD/R group (IV). Neuronal cell viability significantly decreased after 6h and 12h of reoxygenation in Group IV (P < 0.05). Electron microscopy showed the presence of many autophagic vacuoles and the formation of autolysosomes in the neurons; the number of autophagic vacuoles decreased transiently at 6h, while a new autophagic flux and a large number of empty autophagic vacuoles were observed at 12h. In Group IV, a large number of autophagic vacuoles were present at 0.5h and 2h of reoxygenation, which gradually decreased with increasing reoxygenation time. No significant differences in the expression of the LC3II protein were detected between the Group II and IV prior to 6h of reoxygenation, and LC3II expression showed an overall rise-decline pattern. However, LC3II protein expression increased in Group II at 12h of reoxygenation, whereas a continuous decline was observed in Group IV. The levels of phosphorylated JNK and Bcl-2 and the expression of Beclin-1 increased gradually as the reoxygenation time going in Group II, whereas they increased at 12h of reoxygenation in Group IV (P < 0.05). In addition, progressive dissociation of the Bcl-2/Beclin-1 complex was observed in the Group II, while JNK inhibitor suppressed this dissociation. CONCLUSION: The regulation of the JNK/Bcl-2/Beclin-1 signaling pathway may be one of the mechanisms underlying the OGD/R-induced autophagic cell death of neurons. PMID- 26938202 TI - Subunit vaccines for the prevention of mucosal infection with Chlamydia trachomatis. AB - Chlamydia trachomatis is the most common preventable cause of tubal infertility in women. In high-income countries, despite public health control efforts, C. trachomatis case rates continue to rise. Most medium and low-income countries lack any Chlamydia control program; therefore, a vaccine is essential for the control of Chlamydia infections. A rationally designed Chlamydia vaccine requires understanding of the immunological correlates of protective immunity, pathological responses to this mucosal pathogen, identification of optimal vaccine antigens and selection of suitable adjuvant delivery systems that engender protective immunity. Fortunately, Chlamydia vaccinology is facilitated by genomic knowledge and by murine models that reproduce many of the features of human C. trachomatis infection. This article reviews recent progress in these areas with a focus on subunit vaccine development. PMID- 26938209 TI - Sichuan Snub-Nosed Monkeys (Rhinopithecus roxellana) Consume Cicadas in the Qinling Mountains, China. AB - There is limited information on insectivory in folivorous primates. Here, we report that wild Sichuan snub-nosed monkeys (Rhinopithecus roxellana) consume cicadas (Karenia caelatata) in the Qinling Mountains of China. Our research suggests that snub-nosed monkeys expand their diet and prey on cicadas during summer and early autumn, possibly in response to increased availability of these insects and their relatively high protein and fat content relative to leaves. PMID- 26938210 TI - Association of ADAMTS-7 Levels with Cardiac Function in a Rat Model of Acute Myocardial Infarction. AB - BACKGROUND/AIMS: High ADAMTS-7 levels are associated with acute myocardial infarction (AMI), although its involvement in ventricular remodeling is unclear. In this study, we investigated the association between ADAMTS-7 expression and cardiac function in a rat AMI model. METHODS: Sprague-Dawley rats were randomized into AMI (n = 40) and sham (n = 20) groups. The left anterior descending artery was sutured to model AMI. Before surgery and 7, 14, 28, and 42 days post-surgery, ADAMTS-7 and brain natriuretic peptide (BNP), and cartilage oligomeric matrix protein (COMP) were assessed by ELISA, western blot, real-time RT-PCR, and/or immunohistochemistry. Cardiac functional and structural parameters were assessed by M-mode echocardiography. RESULTS: After AMI, plasma ADAMTS-7 levels increased, peaking on day 28 (AMI: 13.2 +/- 6.3 vs. sham: 3.4 +/- 1.3 ng/ml, P < 0.05). Compared with the sham group, ADAMTS-7 expression was higher in the infarct zone at day 28. COMP present in normal myocardium was degraded by day 28 post-AMI. Plasma ADAMTS-7 correlated positively with BNP (r = 0.642, P = 0.025), left ventricular end-diastolic diameter (r = 0.695, P = 0.041), left ventricular end systolic diameter (r = 0.710, P = 0.039), left ventricular ejection fraction (r = 0.695, P = 0.036), and left ventricular short-axis fractional shortening (r = 0.721, P = 0.024). CONCLUSIONS: ADAMTS-7 levels may reflect the degree of ventricular remodeling after AMI. PMID- 26938211 TI - Barriers and Facilitators to Scaling Up the Non-Pneumatic Anti-Shock Garment for Treating Obstetric Hemorrhage: A Qualitative Study. AB - BACKGROUND: Obstetric hemorrhage (OH), which includes hemorrhage from multiple etiologies during pregnancy, childbirth, or postpartum, is the leading cause of maternal mortality and accounts for one-quarter of global maternal deaths. The Non-pneumatic Anti-Shock Garment (NASG) is a first-aid device for obstetric hemorrhage that can be applied for post-partum/post miscarriage and for ectopic pregnancies to buy time for a woman to reach a health care facility for definitive treatment. Despite successful field trials, and endorsement by safe motherhood organizations and the World Health Organization (WHO), scale-up has been slow in some countries. This qualitative study explores contextual factors affecting uptake. METHODS: From March 2013 to April 2013, we conducted 13 key informant interviews across four countries with a large burden of maternal mortality that had achieved varying success in scaling up the NASG: Ethiopia, India, Nigeria, and Zimbabwe. These key informants were health providers or program specialists working with the NASG. We applied a health policy analysis framework to organize the results. The framework has five domains: attributes of the intervention, attributes of the implementers, delivery strategy, attributes of the adopting community, the socio-political context, and the research context. RESULTS: The interviews from our study found that relevant facilitators for scale up are the simplicity of the device, local and international champions, well developed training sessions, recommendations by WHO and the International Federation of Gynecology and Obstetrics, and dissemination of NASG clinical trial results. Barriers to scaling up the NASG included limited health infrastructure, relatively high upfront cost of the NASG, initial resistance by providers and policy makers, lack of in-country champions or policy makers advocating for NASG implementation, inadequate return and exchange programs, and lack of political will. CONCLUSIONS: There was a continuum of uptake ranging in both speed and scale. Ethiopia while not the first country to use the NASG has the most rapid scale-up, followed by Nigeria, then India, and finally Zimbabwe. Increasing the coverage of the NASG will require collaboration with local NASG champions, greater NASG awareness among clinicians and policymakers, as well as stronger political will and advocacy. PMID- 26938212 TI - Donor Dependent Variations in Hematopoietic Differentiation among Embryonic and Induced Pluripotent Stem Cell Lines. AB - Hematopoiesis generated from human embryonic stem cells (ES) and induced pluripotent stem cells (iPS) are unprecedented resources for cell therapy. We compared hematopoietic differentiation potentials from ES and iPS cell lines originated from various donors and derived them using integrative and non integrative vectors. Significant differences in differentiation toward hematopoietic lineage were observed among ES and iPS. The ability of engraftment of iPS or ES-derived cells in NOG mice varied among the lines with low levels of chimerism. iPS generated from ES cell-derived mesenchymal stem cells (MSC) reproduce a similar hematopoietic outcome compared to their parental ES cell line. We were not able to identify any specific hematopoietic transcription factors that allow to distinguish between good versus poor hematopoiesis in undifferentiated ES or iPS cell lines. There is a relatively unpredictable variation in hematopoietic differentiation between ES and iPS cell lines that could not be predicted based on phenotype or gene expression of the undifferentiated cells. These results demonstrate the influence of genetic background in variation of hematopoietic potential rather than the reprogramming process. PMID- 26938213 TI - Electroacupuncture for Tinnitus: A Systematic Review. AB - BACKGROUND: Treatment effects of electroacupuncture for patients with subjective tinnitus has yet to be clarified. OBJECTIVES: To assess the effect of electroacupuncutre for alleviating the symptoms of subjective tinnitus. METHODS: Extensive literature searches were carried out in three English and four Chinese databases (PubMed, EMBASE, Cochrane Library, CNKI, Wanfang Chinese Digital Periodical and Conference Database, VIP, and ChiCTR).The date of the most recent search was 1 June 2014. Randomized controlled trials (RCTs) or quasi-RCTs were included. The titles, abstracts, and keywords of all records were reviewed by two authors independently. The data were collected and extracted by three authors. The risk of bias in the trials was assessed in accordance with the Cochrane Handbook, version 5.1.0. (http://www.handbook.cochrane.org). Eighty-nine studies were retrieved. After discarding 84 articles, five studies with 322 participants were identified. Assessment of the methodological quality of the studies identified weaknesses in all five studies. All studies were judged as having a high risk of selection and performance bias. The attrition bias was high in four studies. Incompleteness bias was low in all studies. Reporting bias was unclear in all studies. Because of the limited number of trials included and the various types of interventions and outcomes, we were unable to conduct pooled analyses. CONCLUSIONS: Due to the poor methodological quality of the primary studies and the small sample sizes, no convincing evidence that electroacupuncture is beneficial for treating tinnitus could be found. There is an urgent need for more high-quality trials with large sample sizes for the investigation of electroacupuncture treatment for tinnitus. PMID- 26938214 TI - A randomised placebo-controlled trial of oral and topical antibiotics for children with clinically infected eczema in the community: the ChildRen with Eczema, Antibiotic Management (CREAM) study. AB - BACKGROUND: Secondary skin infection is common during eczema exacerbations and many children are treated with antibiotics when this is suspected, although there is little high-quality evidence to justify this practice. OBJECTIVE: To determine the clinical effectiveness of oral and topical antibiotics, in addition to standard treatment with emollients and topical corticosteroids, in children with clinically infected eczema. DESIGN: Multicentre randomised, double-blind, placebo controlled trial. SETTING: General practices and dermatology clinics in England, Wales and Scotland. PARTICIPANTS: Children (aged 3 months to < 8 years) with a diagnosis of eczema (according to U.K. Working Party definition) and clinical suspicion of infection. INTERVENTIONS: (1) Oral flucloxacillin and topical placebo; (2) topical fusidic acid (Fucidin((r)), Leo Laboratories Limited) and oral placebo; and (3) oral and topical placebos, all for 1 week. MAIN OUTCOME MEASURES: Patient-Orientated Eczema Measure (POEM) at 2 weeks (assessing subjective severity in the week following treatment). RESULTS: We randomised 113 children (36 to oral antibiotic, 37 to topical antibiotic and 40 to placebo), which was fewer than our revised target sample size of 282. A total of 103 (92.0%) children had one or more clinical features suggestive of infection and 78 (69.6%) children had Staphylococcus aureus cultured from a skin swab. Oral and topical antibiotics resulted in a 1.52 [95% confidence interval (CI) -1.35 to 4.40] and 1.49 (95% CI -1.55 to 4.53) increase (worse subjective severity) in POEM score at 2 weeks, relative to placebo and controlling for baseline POEM score. Eczema Area and Severity Index (objective severity) scores were also higher (worse) in the intervention groups, at 0.20 (95% CI -0.12 to 0.52) and 0.42 (95% CI 0.09 to 0.75) for oral and topical antibiotics, respectively, at 2 weeks. Analyses of impact on the family, quality of life, daily symptom scores, and longer-term outcomes were all consistent with the finding of no or limited difference and a trend towards worse outcomes in the intervention groups. Sensitivity analyses, including adjusting for compliance and imputation for missing data, were consistent with the main findings. CONCLUSIONS: Our data suggest that oral and topical antibiotics have no effect, or a harmful effect, on subjective eczema severity in children with clinically infected eczema in the community. The CIs around our estimates exclude a meaningful beneficial effect (published minimal clinically important difference for POEM is 3.4). Although most patients in this trial had features suggestive of infection and S. aureus on their skin, participants primarily had mild-moderate eczema and those with signs of more severe infection were often excluded. Clinicians should consider avoiding oral and topical antibiotic use in children with suspected infected eczema in the community who do not have signs of 'severe infection'. Further research should seek to understand how best to encourage the use of topical steroids and limit use of antibiotics in those with eczema flares without signs of severe infection, as well as developing tools to better phenotype eczema flares, in order to better define a population that may benefit from antibiotic treatment. TRIAL REGISTRATION: European Union Drug Regulating Authorities Clinical Trials (EudraCT) number 2011-003591-37 and Current Controlled Trials ISRCTN96705420. FUNDING: The National Institute for Health Research Health Technology Assessment programme. PMID- 26938216 TI - Temporal Uncoupling between Energy Acquisition and Allocation to Reproduction in a Herbivorous-Detritivorous Fish. AB - Although considerable knowledge has been gathered regarding the role of fish in cycling and translocation of nutrients across ecosystem boundaries, little information is available on how the energy obtained from different ecosystems is temporally allocated in fish bodies. Although in theory, limitations on energy budgets promote the existence of a trade-off between energy allocated to reproduction and somatic growth, this trade-off has rarely been found under natural conditions. Combining information on RNA:DNA ratios and carbon and nitrogen stable-isotope analyses we were able to achieve novel insights into the reproductive allocation of diamond mullet (Liza alata), a catadromous, widely distributed herbivorous-detritivorous fish. Although diamond mullet were in better condition during the wet season, most reproductive allocation occurred during the dry season when resources are limited and fish have poorer body condition. We found a strong trade-off between reproductive and somatic investment. Values of delta13C from reproductive and somatic tissues were correlated, probably because delta13C in food resources between dry and wet seasons do not differ markedly. On the other hand, data for delta15N showed that gonads are more correlated to muscle, a slow turnover tissue, suggesting long term synthesis of reproductive tissues. In combination, these lines of evidence suggest that L. alata is a capital breeder which shows temporal uncoupling of resource ingestion, energy storage and later allocation to reproduction. PMID- 26938215 TI - Depression, Stressful Life Events, and the Impact of Variation in the Serotonin Transporter: Findings from the National Longitudinal Study of Adolescent to Adult Health (Add Health). AB - BACKGROUND: The low transcriptionally efficient short-allele of the 5HTTLPR serotonin transporter polymorphism has been implicated to moderate the relationship between the experience of stressful life events (SLEs) and depression. Despite numerous attempts at replicating this observation, results remain inconclusive. METHODS: We examined this relationship in young-adult Non Hispanic white males and females between the ages of 22 and 26 (n = 4724) participating in the National Longitudinal Study of Adolescent to Adult Health (Add Health) with follow-up information every six years since 1995. RESULTS: Linear and logistic regression models, corrected for multiple testing, indicated that carriers of one or more of the S-alleles were more sensitive to stress than those with two L-alleles and at a higher risk for depression. This relationship behaved in a dose-response manner such that the risk for depression was greatest among those who reported experiencing higher numbers of SLEs. In post-hoc analyses we were not able to replicate an interaction effect for suicide ideation but did find suggestive evidence that the effects of SLEs and 5HTTLPR on suicide ideation differed for males and females. There were no effects of childhood maltreatment. DISCUSSION: Our results provide partial support for the original hypothesis that 5-HTTLPR genotype interacts with the experience of stressful life events in the etiology of depression during young adulthood. However, even with this large sample, and a carefully constructed a priori analysis plan, the results were still not definitive. For the purposes of replication, characterizing the 5HTTLPR in other large data sets with extensive environmental and depression measures is needed. PMID- 26938219 TI - Correction: Fitting and Calibrating a Multilevel Mixed-Effects Stem Taper Model for Maritime Pine in NW Spain. PMID- 26938217 TI - A Heterologous Multiepitope DNA Prime/Recombinant Protein Boost Immunisation Strategy for the Development of an Antiserum against Micrurus corallinus (Coral Snake) Venom. AB - BACKGROUND: Envenoming by coral snakes (Elapidae: Micrurus), although not abundant, represent a serious health threat in the Americas, especially because antivenoms are scarce. The development of adequate amounts of antielapidic serum for the treatment of accidents caused by snakes like Micrurus corallinus is a challenging task due to characteristics such as low venom yield, fossorial habit, relatively small sizes and ophiophagous diet. These features make it difficult to capture and keep these snakes in captivity for venom collection. Furthermore, there are reports of antivenom scarcity in USA, leading to an increase in morbidity and mortality, with patients needing to be intubated and ventilated while the toxin wears off. The development of an alternative method for the production of an antielapidic serum, with no need for snake collection and maintenance in captivity, would be a plausible solution for the antielapidic serum shortage. METHODS AND FINDINGS: In this work we describe the mapping, by the SPOT-synthesis technique, of potential B-cell epitopes from five putative toxins from M. corallinus, which were used to design two multiepitope DNA strings for the genetic immunisation of female BALB/c mice. Results demonstrate that sera obtained from animals that were genetically immunised with these multiepitope constructs, followed by booster doses of recombinant proteins lead to a 60% survival in a lethal dose neutralisation assay. CONCLUSION: Here we describe that the genetic immunisation with a synthetic multiepitope gene followed by booster doses with recombinant protein is a promising approach to develop an alternative antielapidic serum against M. corallinus venom without the need of collection and the very challenging maintenance of these snakes in captivity. PMID- 26938218 TI - Network Analysis of Metabolite GWAS Hits: Implication of CPS1 and the Urea Cycle in Weight Maintenance. AB - BACKGROUND AND SCOPE: Weight loss success is dependent on the ability to refrain from regaining the lost weight in time. This feature was shown to be largely variable among individuals, and these differences, with their underlying molecular processes, are diverse and not completely elucidated. Altered plasma metabolites concentration could partly explain weight loss maintenance mechanisms. In the present work, a systems biology approach has been applied to investigate the potential mechanisms involved in weight loss maintenance within the Diogenes weight-loss intervention study. METHODS AND RESULTS: A genome wide association study identified SNPs associated with plasma glycine levels within the CPS1 (Carbamoyl-Phosphate Synthase 1) gene (rs10206976, p-value = 4.709e-11 and rs12613336, p-value = 1.368e-08). Furthermore, gene expression in the adipose tissue showed that CPS1 expression levels were associated with successful weight maintenance and with several SNPs within CPS1 (cis-eQTL). In order to contextualize these results, a gene-metabolite interaction network of CPS1 and glycine has been built and analyzed, showing functional enrichment in genes involved in lipid metabolism and one carbon pool by folate pathways. CONCLUSIONS: CPS1 is the rate-limiting enzyme for the urea cycle, catalyzing carbamoyl phosphate from ammonia and bicarbonate in the mitochondria. Glycine and CPS1 are connected through the one-carbon pool by the folate pathway and the urea cycle. Furthermore, glycine could be linked to metabolic health and insulin sensitivity through the betaine osmolyte. These considerations, and the results from the present study, highlight a possible role of CPS1 and related pathways in weight loss maintenance, suggesting that it might be partly genetically determined in humans. PMID- 26938220 TI - Deformability Assessment of Waterborne Protozoa Using a Microfluidic-Enabled Force Microscopy Probe. AB - Many modern filtration technologies are incapable of the complete removal of Cryptosporidium oocysts from drinking-water. Consequently, Cryptosporidium contaminated drinking-water supplies can severely implicate both water utilities and consumers. Existing methods for the detection of Cryptosporidium in drinking water do not discern between non-pathogenic and pathogenic species, nor between viable and non-viable oocysts. Using FluidFM, a novel force spectroscopy method employing microchannelled cantilevers for single-cell level manipulation, we assessed the size and deformability properties of two species of Cryptosporidium that pose varying levels of risk to human health. A comparison of such characteristics demonstrated the ability of FluidFM to discern between Cryptosporidium muris and Cryptosporidium parvum with 86% efficiency, whilst using a measurement throughput which exceeded 50 discrete oocysts per hour. In addition, we measured the deformability properties for untreated and temperature inactivated oocysts of the highly infective, human pathogenic C. parvum to assess whether deformability may be a marker of viability. Our results indicate that untreated and temperature-inactivated C. parvum oocysts had overlapping but significantly different deformability distributions. PMID- 26938221 TI - Preconditioning 2D Integer Data for Fast Convex Hull Computations. AB - In order to accelerate computing the convex hull on a set of n points, a heuristic procedure is often applied to reduce the number of points to a set of s points, s <= n, which also contains the same hull. We present an algorithm to precondition 2D data with integer coordinates bounded by a box of size p * q before building a 2D convex hull, with three distinct advantages. First, we prove that under the condition min(p, q) <= n the algorithm executes in time within O(n); second, no explicit sorting of data is required; and third, the reduced set of s points forms a simple polygonal chain and thus can be directly pipelined into an O(n) time convex hull algorithm. This paper empirically evaluates and quantifies the speed up gained by preconditioning a set of points by a method based on the proposed algorithm before using common convex hull algorithms to build the final hull. A speedup factor of at least four is consistently found from experiments on various datasets when the condition min(p, q) <= n holds; the smaller the ratio min(p, q)/n is in the dataset, the greater the speedup factor achieved. PMID- 26938222 TI - Coping style and quality of life in Dutch intensive care unit survivors. AB - OBJECTIVE: The purpose of this study was to explore coping styles among intensive care unit (ICU) survivors and investigate the association between coping style and quality of life (QOL). METHOD: In this cross-sectional multicenter study, 150 adult patients who were mechanically ventilated in an ICU for >=2 days and discharged to their homes were invited to visit the post-ICU clinic 3 months after discharge. Before the post-ICU visit, the patients completed questionnaires regarding their QOL, coping style, and psychological distress. Coping style was assessed using the Coping Inventory for Stressful Situations (CISS-21; de Ridder & van Heck, 2004), which measures task-oriented coping, emotion-oriented coping, and avoidance coping styles. QOL was assessed using the Physical Component Score (PCS) and Mental Component Score (MCS) derived from the 36-item Short Form Health Survey (SF-36; Aaronson et al., 1998). Univariate and multivariate linear regressions were performed. RESULTS: One hundred four patients (mean age = 59 years; 71 men, 33 women) completed the questionnaires (response rate = 69%). The highest CISS-21 subscale mean was found in the Task-Oriented subscale (21.3), followed by the Avoidance Coping subscale (18.7) and the Emotion-Oriented subscale (15.2). Emotion-oriented coping style was independently associated with reduced mental health (i.e., SF-36 MCS), but not with physical functioning (i.e., SF-36 PCS). CONCLUSIONS: An emotion-oriented coping style is associated with worse mental health among Dutch ICU survivors. Additional research is needed in order to determine the precise role that coping style plays in the long-term recovery of ICU survivors. (PsycINFO Database Record PMID- 26938239 TI - Oxamate Improves Glycemic Control and Insulin Sensitivity via Inhibition of Tissue Lactate Production in db/db Mice. AB - Oxamate (OXA) is a pyruvate analogue that directly inhibits the lactate dehydrogenase (LDH)-catalyzed conversion process of pyruvate into lactate. Earlier and recent studies have shown elevated blood lactate levels among insulin resistant and type 2 diabetes subjects and that blood lactate levels independently predicted the development of incident diabetes. To explore the potential of OXA in the treatment of diabetes, db/db mice were treated with OXA in vivo. Treatment of OXA (350-750 mg/kg of body weight) for 12 weeks was shown to decrease body weight gain and blood glucose and HbA1c levels and improve insulin secretion, the morphology of pancreatic islets, and insulin sensitivity in db/db mice. Meanwhile, OXA reduced the lactate production of adipose tissue and skeletal muscle and serum lactate levels and decreased serum levels of TG, FFA, CRP, IL-6, and TNF-alpha in db/db mice. The PCR array showed that OXA downregulated the expression of Tnf, Il6, leptin, Cxcr3, Map2k1, and Ikbkb, and upregulated the expression of Irs2, Nfkbia, and Pde3b in the skeletal muscle of db/db mice. Interestingly, LDH-A expression increased in the islet cells of db/db mice, and both treatment of OXA and pioglitazone decreased LDH-A expression, which might be related to the improvement of insulin secretion. Taken together, increased lactate production of adipose tissue and skeletal muscle may be at least partially responsible for insulin resistance and diabetes in db/db mice. OXA improved glycemic control and insulin sensitivity in db/db mice primarily via inhibition of tissue lactate production. Oxamic acid derivatives may be a potential drug for the treatment of type 2 diabetes. PMID- 26938240 TI - Effects of Varying Epoch Lengths, Wear Time Algorithms, and Activity Cut-Points on Estimates of Child Sedentary Behavior and Physical Activity from Accelerometer Data. AB - OBJECTIVE: To examine the effects of accelerometer epoch lengths, wear time (WT) algorithms, and activity cut-points on estimates of WT, sedentary behavior (SB), and physical activity (PA). METHODS: 268 7-11 year-olds with BMI >= 85th percentile for age and sex wore accelerometers on their right hips for 4-7 days. Data were processed and analyzed at epoch lengths of 1-, 5-, 10-, 15-, 30-, and 60-seconds. For each epoch length, WT minutes/day was determined using three common WT algorithms, and minutes/day and percent time spent in SB, light (LPA), moderate (MPA), and vigorous (VPA) PA were determined using five common activity cut-points. ANOVA tested differences in WT, SB, LPA, MPA, VPA, and MVPA when using the different epoch lengths, WT algorithms, and activity cut-points. RESULTS: WT minutes/day varied significantly by epoch length when using the NHANES WT algorithm (p < .0001), but did not vary significantly by epoch length when using the >= 20 minute consecutive zero or Choi WT algorithms. Minutes/day and percent time spent in SB, LPA, MPA, VPA, and MVPA varied significantly by epoch length for all sets of activity cut-points tested with all three WT algorithms (all p < .0001). Across all epoch lengths, minutes/day and percent time spent in SB, LPA, MPA, VPA, and MVPA also varied significantly across all sets of activity cut-points with all three WT algorithms (all p < .0001). CONCLUSIONS: The common practice of converting WT algorithms and activity cut point definitions to match different epoch lengths may introduce significant errors. Estimates of SB and PA from studies that process and analyze data using different epoch lengths, WT algorithms, and/or activity cut-points are not comparable, potentially leading to very different results, interpretations, and conclusions, misleading research and public policy. PMID- 26938242 TI - The Frequency of "Brilliant" and "Genius" in Teaching Evaluations Predicts the Representation of Women and African Americans across Fields. AB - Women and African Americans-groups targeted by negative stereotypes about their intellectual abilities-may be underrepresented in careers that prize brilliance and genius. A recent nationwide survey of academics provided initial support for this possibility. Fields whose practitioners believed that natural talent is crucial for success had fewer female and African American PhDs. The present study seeks to replicate this initial finding with a different, and arguably more naturalistic, measure of the extent to which brilliance and genius are prized within a field. Specifically, we measured field-by-field variability in the emphasis on these intellectual qualities by tallying-with the use of a recently released online tool-the frequency of the words "brilliant" and "genius" in over 14 million reviews on RateMyProfessors.com, a popular website where students can write anonymous evaluations of their instructors. This simple word count predicted both women's and African Americans' representation across the academic spectrum. That is, we found that fields in which the words "brilliant" and "genius" were used more frequently on RateMyProfessors.com also had fewer female and African American PhDs. Looking at an earlier stage in students' educational careers, we found that brilliance-focused fields also had fewer women and African Americans obtaining bachelor's degrees. These relationships held even when accounting for field-specific averages on standardized mathematics assessments, as well as several competing hypotheses concerning group differences in representation. The fact that this naturalistic measure of a field's focus on brilliance predicted the magnitude of its gender and race gaps speaks to the tight link between ability beliefs and diversity. PMID- 26938241 TI - PI-3K Inhibitors Preferentially Target CD15+ Cancer Stem Cell Population in SHH Driven Medulloblastoma. AB - Sonic hedgehog (SHH) medulloblastoma (MB) subtype is driven by a proliferative CD15+ tumor propagating cell (TPC), also considered in the literature as a putative cancer stem cell (CSC). Despite considerable research, much of the biology of this TPC remains unknown. We report evidence that phosphatase and tensin homolog (PTEN) and phosphoinositide 3-kinase (PI-3K) play a crucial role in the propagation, survival and potential response to therapy in this CD15+ CSC/TPC-driven malignant disease. Using the ND2-SmoA1 transgenic mouse model for MB, mouse genetics and patient-derived xenografts (PDXs), we demonstrate that the CD15+TPCs are 1) obligately required for SmoA1Tg-driven tumorigenicity 2) regulated by PTEN and PI-3K signaling 3) selectively sensitive to the cytotoxic effects of pan PI-3K inhibitors in vitro and in vivo but resistant to chemotherapy 4) in the SmoA1Tg mouse model are genomically similar to the SHH human MB subgroup. The results provide the first evidence that PTEN plays a role in MB TPC signaling and biology and that PI-3K inhibitors target and suppress the survival and proliferation of cells within the mouse and human CD15+ cancer stem cell compartment. In contrast, CD15+ TPCs are resistant to cisplatinum, temozolomide and the SHH inhibitor, NVP-LDE-225, agents currently used in treatment of medulloblastoma. These studies validate the therapeutic efficacy of pan PI-3K inhibitors in the treatment of CD15+ TPC dependent medulloblastoma and suggest a sequential combination of PI-3K inhibitors and chemotherapy will have augmented efficacy in the treatment of this disease. PMID- 26938255 TI - Go with the Flow: The Importance of the Assessment of Collateral Ventilation in Endobronchial Valve Treatment. PMID- 26938243 TI - Quantifying and Mitigating the Effect of Preferential Sampling on Phylodynamic Inference. AB - Phylodynamics seeks to estimate effective population size fluctuations from molecular sequences of individuals sampled from a population of interest. One way to accomplish this task formulates an observed sequence data likelihood exploiting a coalescent model for the sampled individuals' genealogy and then integrating over all possible genealogies via Monte Carlo or, less efficiently, by conditioning on one genealogy estimated from the sequence data. However, when analyzing sequences sampled serially through time, current methods implicitly assume either that sampling times are fixed deterministically by the data collection protocol or that their distribution does not depend on the size of the population. Through simulation, we first show that, when sampling times do probabilistically depend on effective population size, estimation methods may be systematically biased. To correct for this deficiency, we propose a new model that explicitly accounts for preferential sampling by modeling the sampling times as an inhomogeneous Poisson process dependent on effective population size. We demonstrate that in the presence of preferential sampling our new model not only reduces bias, but also improves estimation precision. Finally, we compare the performance of the currently used phylodynamic methods with our proposed model through clinically-relevant, seasonal human influenza examples. PMID- 26938256 TI - Dose and Size-Dependent Antiviral Effects of Silver Nanoparticles on Feline Calicivirus, a Human Norovirus Surrogate. AB - OBJECTIVES: Silver nanoparticles (AgNPs) as antibacterial agents are incorporated in many consumer products, while the use as antiviral agents is an ongoing area of research. We evaluated the antiviral properties of AgNPs of variable sizes (10, 75, and 110 nm) and doses (25, 50, and 100 MUg/mL) at different contact time points against feline calicivirus (FCV), a surrogate for norovirus. MATERIALS AND METHODS: Antiviral effects of the AgNPs were determined by comparing the infectivity of FCV, the appearance of cytopathic effects (CPEs), and the integrity of the viral capsid protein in viral suspension treated with AgNPs with the untreated controls. RESULTS: The 10 nm AgNPs at 50 and 100 MUg/mL concentrations inactivated the FCV beyond the limit of detection, resulting in a decrease of up to 6.5 log10 viral titer, prevented development of CPEs, and reduction in the western blot band signal of the viral capsid protein. No significant antiviral effect was observed for the 75 and 110 nm AgNPs. Conclusions and Applications: These results demonstrate that the antiviral effects of AgNPs are both size and dose dependent, thus potential applications of AgNPs as antiviral agents to prevent contamination of foodborne viruses need to consider size and dose effects. PMID- 26938257 TI - Quantifying Migration Behaviour Using Net Squared Displacement Approach: Clarifications and Caveats. AB - Estimating migration parameters of individuals and populations is vital for their conservation and management. Studies on animal movements and migration often depend upon location data from tracked animals and it is important that such data are appropriately analyzed for reliable estimates of migration and effective management of moving animals. The Net Squared Displacement (NSD) approach for modelling animal movement is being increasingly used as it can objectively quantify migration characteristics and separate different types of movements from migration. However, the ability of NSD to properly classify the movement patterns of individuals has been criticized and issues related to study design arise with respect to starting locations of the data/animals, data sampling regime and extent of movement of species. We address the issues raised over NSD using tracking data from 319 moose (Alces alces) in Sweden. Moose is an ideal species to test this approach, as it can be sedentary, nomadic, dispersing or migratory and individuals vary in their extent, timing and duration of migration. We propose a two-step process of using the NSD approach by first classifying movement modes using mean squared displacement (MSD) instead of NSD and then estimating the extent, duration and timing of migration using NSD. We show that the NSD approach is robust to the choice of starting dates except when the start date occurs during the migratory phase. We also show that the starting location of the animal has a marginal influence on the correct quantification of migration characteristics. The number of locations per day (1-48) did not significantly affect the performance of non-linear mixed effects models, which correctly distinguished migration from other movement types, however, high-resolution data had a significant negative influence on estimates for the timing of migrations. The extent of movement, however, had an effect on the classification of movements, and individuals undertaking short- distance migrations can be misclassified as other movements such as sedentary or nomadic. Our study raises important considerations for designing, analysing and interpreting movement ecology studies, and how these should be determined by the biology of the species and the ecological and conservation questions in focus. PMID- 26938258 TI - Quantifying Ecological Literacy in an Adult Western Community: The Development and Application of a New Assessment Tool and Community Standard. AB - Knowledge and understanding about how the Earth functions and supports life create the foundation for ecological literacy. Industrialisation, urbanisation and population growth have resulted in changed relationships between many human communities and the natural world. A potential consequence is a compromised capability to make well-informed decisions about how to live sustainably. To gain a measure of ecological literacy within the South Australian community, we collaborated with senior scientists and educators to develop and apply an instrument with the capacity to determine indicative levels of ecological knowledge and understanding. A formal, variable credit, multiple-choice assessment instrument was distributed online to groups and individuals within diverse community sectors and industries. Quantitative analyses of scores indicated that levels of ecological knowledge and understanding within a self selected sample of over one thousand individuals ranged from very low to extremely high, with the majority of respondents achieving moderate to high scores. This instrument has a demonstrated capacity to determine indicative levels of ecological literacy within and between individuals and groups. It is able to capture mastery of ecological knowledge and understanding achieved through both formal and informal pathways. Using the results, we have been able to establish a range of standards and an aspirational target score for the South Australian community. The value of this work is in its potential to deliver insights into relationships between humans and the rest of the natural world, and into characteristics of eco-literate individuals and communities, that might not otherwise emerge. PMID- 26938259 TI - Toward Optimized Surface delta-Profiles of Nitrogen-Vacancy Centers Activated by Helium Irradiation in Diamond. AB - The negatively charged nitrogen-vacancy (NV) center in diamond has been shown recently as an excellent sensor for external spins. Nevertheless, their optimum engineering in the near-surface region still requires quantitative knowledge in regard to their activation by vacancy capture during thermal annealing. To this aim, we report on the depth profiles of near-surface helium-induced NV centers (and related helium defects) by step-etching with nanometer resolution. This provides insights into the efficiency of vacancy diffusion and recombination paths concurrent to the formation of NV centers. It was found that the range of efficient formation of NV centers is limited only to approximately 10 to 15 nm (radius) around the initial ion track of irradiating helium atoms. Using this information we demonstrate the fabrication of nanometric-thin (delta) profiles of NV centers for sensing external spins at the diamond surface based on a three step approach, which comprises (i) nitrogen-doped epitaxial CVD diamond overgrowth, (ii) activation of NV centers by low-energy helium irradiation and thermal annealing, and (iii) controlled layer thinning by low-damage plasma etching. Spin coherence times (Hahn echo) ranging up to 50 MUs are demonstrated at depths of less than 5 nm in material with 1.1% of (13)C (depth estimated by spin relaxation (T1) measurements). At the end, the limits of the helium irradiation technique at high ion fluences are also experimentally investigated. PMID- 26938265 TI - The mPower study, Parkinson disease mobile data collected using ResearchKit. AB - Current measures of health and disease are often insensitive, episodic, and subjective. Further, these measures generally are not designed to provide meaningful feedback to individuals. The impact of high-resolution activity data collected from mobile phones is only beginning to be explored. Here we present data from mPower, a clinical observational study about Parkinson disease conducted purely through an iPhone app interface. The study interrogated aspects of this movement disorder through surveys and frequent sensor-based recordings from participants with and without Parkinson disease. Benefitting from large enrollment and repeated measurements on many individuals, these data may help establish baseline variability of real-world activity measurement collected via mobile phones, and ultimately may lead to quantification of the ebbs-and-flows of Parkinson symptoms. App source code for these data collection modules are available through an open source license for use in studies of other conditions. We hope that releasing data contributed by engaged research participants will seed a new community of analysts working collaboratively on understanding mobile health data to advance human health. PMID- 26938267 TI - Cancer, biomedical science leaders strive to improve workforce diversity. PMID- 26938268 TI - Early-stage prostate cancer, PSA screening rates decline. PMID- 26938269 TI - FDA launches tobacco use prevention campaign targeting multicultural youth. PMID- 26938266 TI - Trapping of the Enoyl-Acyl Carrier Protein Reductase-Acyl Carrier Protein Interaction. AB - An ideal target for metabolic engineering, fatty acid biosynthesis remains poorly understood on a molecular level. These carrier protein-dependent pathways require fundamental protein-protein interactions to guide reactivity and processivity, and their control has become one of the major hurdles in successfully adapting these biological machines. Our laboratory has developed methods to prepare acyl carrier proteins (ACPs) loaded with substrate mimetics and cross-linkers to visualize and trap interactions with partner enzymes, and we continue to expand the tools for studying these pathways. We now describe application of the slow onset, tight-binding inhibitor triclosan to explore the interactions between the type II fatty acid ACP from Escherichia coli, AcpP, and its corresponding enoyl ACP reductase, FabI. We show that the AcpP-triclosan complex demonstrates nM binding, inhibits in vitro activity, and can be used to isolate FabI in complex proteomes. PMID- 26938270 TI - Preoperative experience for public hospital patients with gynecologic cancer: Do structural barriers widen the gap? AB - BACKGROUND: Widespread disparities in care have been documented in women with gynecologic cancer in the United States. This study was designed to determine whether structural barriers to optimal care were present during the preoperative period for patients with gynecologic cancer. METHODS: A retrospective review was conducted for patients undergoing surgery for a gynecologic malignancy at a public hospital or a private hospital staffed by the same team of gynecologic oncologists between July 1, 2013 and July 1, 2014. RESULTS: Two hundred fifty seven cases were included for analysis (public hospital, 69; private hospital, 188). Patients treated at the private hospital were older (58 vs 52 years; P = .004) and had similar medical comorbidities (median Charlson comorbidity index at both hospitals, 6) but required fewer hospital visits in preparation for surgery (2 vs 4; P < .001). Public hospital patients had a longer wait time from the diagnosis of disease to surgery (63 vs 34 days; P < .001). According to a multiple linear regression model, the public hospital setting was associated with a longer interval from diagnosis to surgery with adjustments for the insurance status, age at diagnosis, cancer stage, and number of preoperative hospital visits (P < .001). CONCLUSIONS: Patients at the public hospital were subject to a greater number of preoperative visits and had to wait longer for surgery than patients at the private hospital. Attempts to reduce health care disparities should focus on improving efficiency in health care delivery systems once contact has been established. PMID- 26938271 TI - Erratum: Long-term quality of life among Dutch prostate cancer survivors. PMID- 26938272 TI - Noble Metal-Free Oxygen Reduction Reaction Catalysts Derived from Prussian Blue Nanocrystals Dispersed in Polyaniline. AB - A highly efficient noble-metal-free catalyst for the oxygen reduction reaction (ORR) is derived from a composite of polyaniline (PANI) and Prussian blue analogue (PBA, Co3[Fe(CN)6]2) by pyrolysis. The composite consists of 2-5 nm PBA nanocrystals homogeneously dispersed in PANI. During the pyrolysis, the PBA nanocrystals serve as both the template for the pore formation and the precursor for the ORR active sites, which results in a nanoporous structure strongly coupled with the ORR active sites. The catalyst exhibits superior ORR performance in both alkaline and acidic electrolyte, comparable to that of the commercial Pt/C with 20 wt % Pt loading. PMID- 26938274 TI - Exploiting the Chromone Scaffold for the Development of Inhibitors of Corticosteroid Biosynthesis. AB - The inhibition of corticosteroid biosynthesis could be considered as an emerging strategy to reduce their abnormally high levels, and in this framework CYP11B1 and CYP11B2 represent the most promising targets. In continuing our studies on flavonoid-like scaffolds as privileged structures in medicinal chemistry, in this paper we describe a small library of pyridyl- and imidazolylmethylchromones as potential inhibitors of these enzymes. Testing results proved that position 3 of the chromone scaffold is the most favorable for the introduction of the heme coordinating heterocycles and, among them, the 4-imidazolyl moiety is the most convenient for the interaction with the heme iron of the selected cytochromes. A low nanomolar inhibitor of CYP11B1 (5c) was obtained, endowed with reasonable selectivity toward CYP11B2 and able to better discriminate with respect to CYP17 and CYP19. PMID- 26938275 TI - A Fluorescent Sensor for Dual-Channel Discrimination between Phosgene and a Nerve Gas Mimic. AB - The ability to analyze highly toxic chemical warfare agents (CWAs) and related chemicals in a rapid and precise manner is essential in order to alleviate serious threats to humankind and public security caused by unexpected terrorist attacks and industrial accidents. In this investigation, we designed a o phenylenediamine-pyronin linked dye that is capable of both fluorogenic and colorimetric discrimination between phosgene and the prototypical nerve-agent mimic, diethyl chlorophosphate (DCP) in the solution or gas phase. Moreover, this dye has been used to construct a portable kit that can be employed for real-time monitoring of DCP and phosgene in the field, both in a discriminatory manner, and in a simple and safe way. PMID- 26938273 TI - Pharmacological Inhibition of Monoacylglycerol O-Acyltransferase 2 Improves Hyperlipidemia, Obesity, and Diabetes by Change in Intestinal Fat Utilization. AB - Monoacylglycerol O-acyltransferase 2 (MGAT2) catalyzes the synthesis of diacylglycerol (DG), a triacylglycerol precursor and potential peripheral target for novel anti-obesity therapeutics. High-throughput screening identified lead compounds with MGAT2 inhibitory activity. Through structural modification, a potent, selective, and orally bioavailable MGAT2 inhibitor, compound A (compA), was discovered. CompA dose-dependently inhibited postprandial increases in plasma triglyceride (TG) levels. Metabolic flux analysis revealed that compA inhibited triglyceride/diacylglycerol resynthesis in the small intestine and increased free fatty acid and acyl-carnitine with shorter acyl chains than originally labelled fatty acid. CompA decreased high-fat diet (HFD) intake in C57BL/6J mice. MGAT2 null mice showed a similar phenotype as compA-treated mice and compA did not suppress a food intake in MGAT2 KO mice, indicating that the anorectic effects were dependent on MGAT2 inhibition. Chronic administration of compA significantly prevented body weight gain and fat accumulation in mice fed HFD. MGAT2 inhibition by CompA under severe diabetes ameliorated hyperglycemia and fatty liver in HFD streptozotocin (STZ)-treated mice. Homeostatic model assessments (HOMA-IR) revealed that compA treatment significantly improved insulin sensitivity. The proximal half of the small intestine displayed weight gain following compA treatment. A similar phenomenon has been observed in Roux-en-Y gastric bypass treated animals and some studies have reported that this intestinal remodeling is essential to the anti-diabetic effects of bariatric surgery. These results clearly demonstrated that MGAT2 inhibition improved dyslipidemia, obesity, and diabetes, suggesting that compA is an effective therapeutic for obesity-related metabolic disorders. PMID- 26938293 TI - Enhanced Upconversion Luminescence of Metal-Capped NaGd0.3 Yb0.7 F4:Er Submicrometer Particles. AB - Metallic nanostructures are often used to enhance photoluminescence of nanomaterials based on local field enhancement with plasmons at metal surfaces. Here upconversion luminescence (UCL) enhancement of submicrometer-size NaGd0.3 Yb0.7 F4 :Er particles in cap-like metal cavities, formed by deposition of a silver film on the particles dispersed on glass substrates, is studied. UCL of the particles is shown to be influenced by not only the plasmon-enhanced local field but also the cavity modes. By varying the cavity size and location of the particles in the cavities, fluctuant variations of the UCL enhancement and electronic depopulation rate are observed in experiments. Typically, a maximum of 12-fold enhancement of the UCL intensity is obtained. Combining the results with numerical simulations, the phenomenon is ascribed to effects of metal quenching, plasmonic field enhancement, and the cavity modes for the excitation and emission photons. Finally it is verified that, for the cap-like submicrometer metal cavities, allocating the particles at the open mouths of the cavities is more advantageous to obtaining stronger enhancements of the particles' UCL. And the demonstrated structure is also convenient to fabricate for applications, e.g., in solar cells. PMID- 26938295 TI - Tumor-suppressive function of long noncoding RNA MALAT1 in glioma cells by downregulation of MMP2 and inactivation of ERK/MAPK signaling. AB - Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a type of long noncoding RNA. It is associated with metastasis and is a favorable prognostic factor for lung cancer. Recent studies have shown that MALAT1 plays an important role in other malignancies. But, little is known about the role of MALAT1 in glioma. In this study, quantitative reverse transcription PCR (qRT-PCR) was used to demonstrate that the expression of MALAT1 was lower than that in normal brain tissues. Stable RNA interference-mediated knockdown of MALAT1 in human glioma cell lines (U87 and U251) significantly promoted the invasion and proliferation of the glioma cells by in vitro assays. Conversely, overexpression of MALAT1 caused significant reduction in cell proliferation and invasion in vitro, and tumorigenicity in both subcutaneous and intracranial human glioma xenograft models. Furthermore, MALAT1-mediated tumor suppression in glioma cells may be via reduction of extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) signaling activity and expression of matrix metalloproteinase 2 (MMP2). In conclusion, overall data demonstrated the tumor-suppressive role of MALAT1 in glioma by attenuating ERK/MAPK-mediated growth and MMP2-mediated invasiveness. PMID- 26938294 TI - Autophagy regulates odontoblast differentiation by suppressing NF-kappaB activation in an inflammatory environment. AB - Odontoblasts are derived from dental papilla mesenchymal cells and have an important role in defense against bacterial infection, whereas autophagy can recycle long-lived proteins and damaged organelles to sustain cellular homeostasis. Thus, this study explores the role of autophagy in odontoblast differentiation with lipopolysaccharide (LPS) stimulation in vitro and the colocalization of p-NF-kappaB and LC3 in caries teeth. The odontoblasts differentiation was enhanced through LPS stimulation, and this outcome was reflected in the increased number of mineralized nodules and alkaline phosphatase (ALP) activity. The expression levels of the autophagy markers LC3, Atg5, Beclin1 and TFE3 increased time dependently, as well along with the amount of autophagosomes and autophagy fluxes. This result suggests that autophagy was enhanced in odontoblasts cultured with mineralized-induced media containing LPS. To confirm the role of autophagy in differentiated odontoblasts with LPS stimulation, chloroquine (CQ) or rapamycin were used to either block or enhance autophagy. The number of mineralized nodules decreased when autophagy was inhibited, but this number increased with rapamycin treatment. Phosphorylated nuclear factor-kappaB (NF-kappaB) expression was negatively related to autophagy and could inhibit odontoblast differentiation. Furthermore, p-NF-kappaB and LC3 colocalization could be detected in cells stimulated with LPS. The nucleus translocation of p-NF-kappaB in odontoblasts was enhanced when autophagy was inhibited by Atg5 small interfering RNA. In addition, the colocalization of p-NF kappaB and LC3 in odontoblasts and sub-odontoblastic layers was observed in caries teeth with reactionary dentin. Therefore, our findings provide a novel insight into the role of autophagy in regulating odontoblast differentiation by suppressing NF-kappaB activation in inflammatory environments. PMID- 26938297 TI - Fat, sex and caspase-2. PMID- 26938296 TI - Alkaline ceramidase 3 deficiency aggravates colitis and colitis-associated tumorigenesis in mice by hyperactivating the innate immune system. AB - Increasing studies suggest that ceramides differing in acyl chain length and/or degree of unsaturation have distinct roles in mediating biological responses. However, still much remains unclear about regulation and role of distinct ceramide species in the immune response. Here, we demonstrate that alkaline ceramidase 3 (Acer3) mediates the immune response by regulating the levels of C18:1-ceramide in cells of the innate immune system and that Acer3 deficiency aggravates colitis in a murine model by augmenting the expression of pro inflammatory cytokines in myeloid and colonic epithelial cells (CECs). According to the NCBI Gene Expression Omnibus (GEO) database, ACER3 is downregulated in immune cells in response to lipopolysaccharides (LPS), a potent inducer of the innate immune response. Consistent with these data, we demonstrated that LPS downregulated both Acer3 mRNA levels and its enzymatic activity while elevating C(18:1)-ceramide, a substrate of Acer3, in murine immune cells or CECs. Knocking out Acer3 enhanced the elevation of C(18:1)-ceramide and the expression of pro inflammatory cytokines in immune cells and CECs in response to LPS challenge. Similar to Acer3 knockout, treatment with C(18:1)-ceramide, but not C18:0 ceramide, potentiated LPS-induced expression of pro-inflammatory cytokines in immune cells. In the mouse model of dextran sulfate sodium-induced colitis, Acer3 deficiency augmented colitis-associated elevation of colonic C(18:1)-ceramide and pro-inflammatory cytokines. Acer3 deficiency aggravated diarrhea, rectal bleeding, weight loss and mortality. Pathological analyses revealed that Acer3 deficiency augmented colonic shortening, immune cell infiltration, colonic epithelial damage and systemic inflammation. Acer3 deficiency also aggravated colonic dysplasia in a mouse model of colitis-associated colorectal cancer. Taken together, these results suggest that Acer3 has an important anti-inflammatory role by suppressing cellular or tissue C(18:1)-ceramide, a potent pro inflammatory bioactive lipid and that dysregulation of ACER3 and C(18:1)-ceramide may contribute to the pathogenesis of inflammatory diseases including cancer. PMID- 26938299 TI - Heat shock protein 90 regulates necroptosis by modulating multiple signaling effectors. PMID- 26938298 TI - Necroptosis in acute kidney injury: a shedding light. AB - Acute kidney injury (AKI) is a common and severe clinical condition with a heavy healthy burden around the world. In spite of supportive therapies, the mortality associated with AKI remains high. Our limited understanding of the complex cell death mechanism in the process of AKI impedes the development of desirable therapeutics. Necroptosis is a recently identified novel form of cell death contributing to numerable diseases and tissue damages. Increasing evidence has suggested that necroptosis has an important role in the pathogenesis of various types of AKI. Therefore, we present here the signaling pathways and main regulators of necroptosis that are potential candidate for therapeutic strategies. Moreover, we emphasize on the potential role and corresponding mechanisms of necroptosis in AKI based on recent advances, and also discuss the possible therapeutic regimens based on manipulating necroptosis. Taken together, the progress in this field sheds new light into the prevention and management of AKI in clinical practice. PMID- 26938300 TI - Knockout of Atg5 delays the maturation and reduces the survival of adult generated neurons in the hippocampus. AB - Autophagy is an evolutionarily conserved lysosomal degradation pathway that plays important roles in cell maintenance, expansion and differentiation. Removal of genes essential for autophagy from embryonic neural stem and precursor cells reduces the survival and inhibits neuronal differentiation of adult-generated neurons. No study has modified autophagy within the adult precursor cells, leaving the cell-autonomous role of autophagy in adult neurogenesis unknown. Here we demonstrate that autophagic flux exists in the adult dividing progenitor cells and their progeny in the dentate gyrus. To investigate the role of autophagy in adult hippocampal neurogenesis, we genetically deleted Autophagy-related gene 5 (Atg5) that reduced autophagic flux and the survival of the progeny of dividing progenitor cells. This significant reduction in survival of adult-generated neurons is accompanied by a delay in neuronal maturation, including a transient reduction in spine density in the absence of a change in differentiation. The delay in cell maturation and loss of progeny of the Atg5-null cells was not present in mice that lacked the essential pro-apoptotic protein Bax (Bcl-2 associated X protein), suggesting that Atg5-deficient cells die through a Bax dependent mechanism. In addition, there was a loss of Atg5-null cells following exposure to running, suggesting that Atg5 is required for running-induced increases in neurogenesis. These findings highlight the cell-autonomous requirement of Atg5 in the survival of adult-generated neurons. PMID- 26938302 TI - The 7th Barossa Meeting--Cell Signalling in Cancer Biology and Therapy in Barossa Valley, Australia. PMID- 26938301 TI - Dengue-induced autophagy, virus replication and protection from cell death require ER stress (PERK) pathway activation. AB - A virus that reproduces in a host without killing cells can easily establish a successful infection. Previously, we showed that dengue-2, a virus that threatens 40% of the world, induces autophagy, enabling dengue to reproduce in cells without triggering cell death. Autophagy further protects the virus-laden cells from further insults. In this study, we evaluate how it does so; we show that dengue upregulates host pathways that increase autophagy, namely endoplasmic reticulum (ER) stress and ataxia telangiectasia mutated (ATM) signaling followed by production of reactive oxygen species (ROS). Inhibition of ER stress or ATM signaling abrogates the dengue-conferred protection against other cell stressors. Direct inhibition of ER stress response in infected cells decreases autophagosome turnover, reduces ROS production and limits reproduction of dengue virus. Blocking ATM activation, which is an early response to infection, decreases transcription of ER stress response proteins, but ATM has limited impact on production of ROS and virus titers. Production of ROS determines only late-onset autophagy in infected cells and is not necessary for dengue-induced protection from stressors. Collectively, these results demonstrate that among the multiple autophagy-inducing pathways during infection, ER stress signaling is more important to viral replication and protection of cells than either ATM or ROS mediated signaling. To limit virus production and survival of dengue-infected cells, one must address the earliest phase of autophagy, induced by ER stress. PMID- 26938305 TI - alpha-Azido Acids in Solid-Phase Peptide Synthesis: Compatibility with Fmoc Chemistry and an Alternative Approach to the Solid Phase Synthesis of Daptomycin Analogs. AB - alpha-Azido acids have been used in solid phase peptide synthesis (SPPS) for almost 20 years. Here we report that peptides bearing an N-terminal alpha azidoaspartate residue undergo elimination of an azide ion when treated with reagents that are commonly used for removing the Fmoc group during SPPS. We also report an alternative solid-phase route to the synthesis of an analog of daptomycin that uses a reduced number of alpha-azido amino acids and without elimination of an azide ion. PMID- 26938304 TI - Cystatin C estimated glomerular filtration rate and all-cause and cardiovascular disease mortality risk in the general population: AusDiab study. AB - AIMS: Uncertainties about the role of cystatin C-based estimated glomerular filtration rate (eGFR) in the prediction of cardiovascular disease (CVD) beyond traditional CVD risk factors remain. We assessed contributions of eGFR to CVD and mortality in the general population. METHODS: Using 14 year follow-up data on 9353 adults without a reported history of CVD from the Australian Diabetes, Obesity and Lifestyle study, we assessed the contributions of eGFR (assessed by cystatin C (eGFRcysC ) and serum creatinine (eGFRcr ) and albuminuria (uACR) to total and CVD mortality. RESULTS: After adjusting for age, sex, CVD risk factors and uACR, compared with an eGFRcysC >90 mL/min per 1.73 m2 , eGFRcysC <60 mL/min per 1.73 m2 was associated with 56% and 73% increases in the risks for all-cause and CVD mortality, respectively. The respective changes for the c-statistic when eGFRcysC was added to a risk prediction model were 0.003 (95% confidence interval: 0.001 to 0.005) and 0.002 (95% confidence interval: -0.001 to 0.006). The net proportion of non-events assigned a lower-risk category significantly improved with the addition of eGFR (non-event net reclassification index eGFRcr : 1.0% and eGFRcysC : 1.5%) for all-cause mortality, but for CVD mortality, improvements were only significant when eGFR was combined with uACR. The net proportion of events assigned a higher-risk category was not significantly improved. CONCLUSION: In our community-based cohort, reduced eGFRcysC was associated with all-cause and CVD mortality. The addition of chronic kidney disease measures to risk prediction models improved overall risk stratification among those at low risk as opposed to those at high baseline risk of mortality. PMID- 26938303 TI - LINC01225 promotes occurrence and metastasis of hepatocellular carcinoma in an epidermal growth factor receptor-dependent pathway. AB - The long noncoding RNAs (lncRNAs) have long been clarified to participate in hepatocellular carcinoma (HCC) as a biomarker. We carried out the present study in order to identify HCC-related lncRNAs and elucidate the functional roles in the development and progression of HCC. Our previous study has provided that LINC01225 may be an HCC-related gene. Here, we verified that LINC01225 was upregulated in HCC. Knockdown of LINC01225 resulted in inhibited cell proliferation and invasion with activated apoptosis and cell cycle arrest in vitro. Overexpression of LINC01225 in LINC01225 knockdown cells presented that attenuated cell proliferation and invasion were restored and enhanced. Subcutaneous and tail vein/intraperitoneal injection xenotransplantation model in vivo validated reduced tumor progression and metastasis. Investigation of mechanism found that LINC01225 could bind to epidermal growth factor receptor (EGFR) and increase the protein level of EGFR, and subsequently fine tune the EGFR/Ras/Raf-1/MEK/MAPK signaling pathway. Analysis with clinicopathological information suggested a high expression of LINC01225 is positively associated with poor prognosis. We also proved that LINC01225 was stably expressed in serum and can act as a novel biomarker in predicting the diagnosis of HCC. As a conclusion, LINC01225 plays a crucial role in HCC and can act as a biomarker for the diagnosis and prognosis of HCC. PMID- 26938306 TI - Acetylene Black Induced Heterogeneous Growth of Macroporous CoV2O6 Nanosheet for High-Rate Pseudocapacitive Lithium-Ion Battery Anode. AB - Metal vanadates suffer from fast capacity fading in lithium-ion batteries especially at a high rate. Pseudocapacitance, which is associated with surface or near-surface redox reactions, can provide fast charge/discharge capacity free from diffusion-controlled intercalation processes and is able to address the above issue. In this work, we report the synthesis of macroporous CoV2O6 nanosheets through a facile one-pot method via acetylene black induced heterogeneous growth. When applied as lithium-ion battery anode, the macroporous CoV2O6 nanosheets show typical features of pseudocapacitive behavior: (1) currents that are mostly linearly dependent on sweep rate and (2) redox peaks whose potentials do not shift significantly with sweep rate. The macroporous CoV2O6 nanosheets display a high reversible capacity of 702 mAh g(-1) at 200 mA g(-1), excellent cyclability with a capacity retention of 89% (against the second cycle) after 500 cycles at 500 mA g(-1), and high rate capability of 453 mAh g( 1) at 5000 mA g(-1). We believe that the introduction of pseudocapacitive properties in lithium battery is a promising direction for developing electrode materials with high-rate capability. PMID- 26938307 TI - "PROPAGANDISTS FOR THE BEHAVIORAL SCIENCES": THE OVERLOOKED PARTNERSHIP BETWEEN THE CARNEGIE CORPORATION AND SSRC IN THE MID-TWENTIETH CENTURY. AB - The Carnegie Corporation's role as a patron of the behavioral sciences has been overlooked; its support for the behavioral sciences not only began earlier than the Ford Foundation's but was also at least equally important to their success. I show how the close postwar collaboration between the Carnegie Corporation and the Social Science Research Council (SSRC) to promote the behavioral sciences emerged after a struggle between Carnegie and the Rockefeller Foundation over the direction and leadership of the SSRC. I then focus on three postwar projects Carnegie helped conceive and fund that were publicized as the work of the SSRC: Chase's The Proper Study of Mankind (1948), Stouffer et al.'s The American Soldier (), and the Michigan's Survey Research Center 1952 election study. In each of these projects, Carnegie deliberately muted its own role and promoted the remade SSRC as a major advocate for the behavioral sciences. PMID- 26938312 TI - Controlling the Growth Modes of Femtoliter Sessile Droplets Nucleating on Chemically Patterned Surfaces. AB - Femtoliter droplet arrays on immersed substrates are essential elements in a broad range of advanced droplet-based technologies, such as light manipulation, sensing, and high throughput diagnosis. Solvent exchange is a bottom-up approach for producing those droplets from a pulse of oil oversaturation when a good solvent of the droplet liquid is displaced by a poor solvent. The position and arrangement of the droplets are regulated by chemical micropatterns on the substrate. Here we show experimentally and theoretically that the growth modes of droplets confined in planar micropatterns on the surface can be manipulated through the laminar flow of the solvent exchange. The control parameters are the area size of the micropatterns and the flow rate, and the observables are the contact angle and the final droplet volume. For a given pattern size, the Peclet number of the flow determines whether the growing droplets switch from an initial constant contact angle mode to a subsequent constant contact radius mode. Good agreement is achieved between the experimental results and our theoretical model that describes the dependence of the final droplet size on Pe. PMID- 26938310 TI - Triple Helix Formation in a Topologically Controlled DNA Nanosystem. AB - In the present study, we demonstrate single-molecule imaging of triple helix formation in DNA nanostructures. The binding of the single-molecule third strand to double-stranded DNA in a DNA origami frame was examined using two different types of triplet base pairs. The target DNA strand and the third strand were incorporated into the DNA frame, and the binding of the third strand was controlled by the formation of Watson-Crick base pairing. Triple helix formation was monitored by observing the structural changes in the incorporated DNA strands. It was also examined using a photocaged third strand wherein the binding of the third strand was directly observed using high-speed atomic force microscopy during photoirradiation. We found that the binding of the third strand could be controlled by regulating duplex formation and the uncaging of the photocaged strands in the designed nanospace. PMID- 26938311 TI - Regenerative strategies for kidney engineering. AB - The kidney is the most important organ for water homeostasis and waste excretion. It performs several important physiological functions for homeostasis: it filters the metabolic waste out of circulation, regulates body fluid balances, and acts as an immune regulator and modulator of cardiovascular physiology. The development of in vitro renal disease models with pluripotent stem cells (both human embryonic stem cells and induced pluripotent stem cells) and the generation of robust protocols for in vitro derivation of renal-specific-like cells from patient induced pluripotent stem cells have just emerged. Here we review major findings in the field of kidney regeneration with a major focus on the development of stepwise protocols for kidney cell production from human pluripotent stem cells and the latest advances in kidney bioengineering (i.e. decellularized kidney scaffolds and bioprinting). The possibility of generating renal-like three-dimensional structures to be recellularized with renal-derived induced pluripotent stem cells may offer new avenues to develop functional kidney grafts on-demand. PMID- 26938313 TI - Interaction of O2 with CH4, CF4, and CCl4 by Molecular Beam Scattering Experiments and Theoretical Calculations. AB - Gas phase collisions of O2 by CH4, CF4, and CCl4 have been investigated with the molecular beam technique by measuring both the integral cross section value, Q, and its dependence on the collision velocity, v. The adopted experimental conditions have been appropriate to resolve the oscillating "glory" pattern, a quantum interference effect controlled by the features of the intermolecular interaction, for all the three case studies. The analysis of the Q(v) data, performed by adopting a suitable representation of the intermolecular potential function, provided the basic features of the anisotropic potential energy surfaces at intermediate and large separation distances and information on the relative role of the physically relevant types of contributions to the global interaction. The present work demonstrates that while O2-CH4 and O2-CF4 are basically bound through the balance between size (Pauli) repulsion and dispersion attraction, an appreaciable intermolecular bond stabilization by charge transfer is operative in O2-CCl4. Ab initio calculations of the strength of the interaction, coupled with detailed analysis of electronic charge displacement promoted by the formation of the dimer, fully rationalizes the experimental findings. This investigation indicates that the interactions of O2, when averaged over its relative orientations, are similar to that of a noble gas (Ng), specifically Ar. We also show that the binding energy in the basic configurations of the prototypical Ng-CF4,CCl4 systems [ Cappelletti , D. ; Chem. Eur. J. 2015 , 21 , 6234 - 6240 ] can be reconstructed by using the interactions in Ng-F and Ng Cl systems, previously characterized by molecular beam scattering experiments of state-selected halogen atom beams. This information is fundamental to approach the modeling of the weak intermolecular halogen bond. On the basis of the electronic polarizability, this also confirms [ Aquilanti , V. ; Angew. Chem., Int. Ed. 2005 , 44 , 2356 - 2360 ] that O2 can be taken as a proper reference partner for simulating the behavior of some basic noncovalent components of the interactions involving water. Present results are of fundamental relevance to build up the force field controlling the hydrophobic behavior of prototypical apolar CX4 (X = H, F, Cl) molecules. PMID- 26938314 TI - Are the drylands in northern China sustainable? A perspective from ecological footprint dynamics from 1990 to 2010. AB - The drylands in northern China (DNC), characterized by water scarcity, high climatic variability, and infertile soil, are crucial for China's sustainable development in the context of rapid urbanization. However, few studies have systematically investigated its sustainability. Our objective was to assess the sustainability of the DNC according to their ecological footprint (EF) dynamics from 1990 to 2010. We analyzed EF in the DNC at multiple scales ranging from the whole, to four dryland subtypes, to the drylands in each province. We found that the total EF in the DNC increased from 3.48 * 10(8) global hectares (gha) in 1990 to 1.26 * 10(9) gha in 2010, with a growth of 2.63 times, resulting in a more than 14 times increase of ecological deficit from 6.26 * 10(7) gha to 9.63 * 10(8)gha. In addition, the water withdrawal increased from 133.29 km(3) to 153.23 km(3) with a growth rate of 14.96%, while the Human Development Index grew from 0.62 to 0.79. We concluded that the DNC has already become unsustainable after the rapid increases of EF and water withdrawal from 1990 to 2010. We argue that effective management is needed to maintain and improve the environmental sustainability of the DNC. PMID- 26938315 TI - The effects of the built environment, traffic patterns, and micrometeorology on street level ultrafine particle concentrations at a block scale: Results from multiple urban sites. AB - This study attempts to explain explicitly the direct and quantitative effects of complicated urban built-environment on near-road dispersion and levels of vehicular emissions at the scale of several city blocks, based on ultrafine particle concentrations ([UFP]). On short timescales, ultrafine particles are an excellent proxy for other roadway emissions. Five measurement sites in the greater Los Angeles with different built environments but similar mesoscale meteorology were explored. After controlling for traffic, for most sampling days and sites, morning [UFP] were higher than those in the afternoon due to limited dispersion capacity combined with a relatively stable surface layer. [UFP] at the intersection corners were also higher than those over the sampling sites, implying that accelerating vehicles around the intersections contributed to [UFP] elevation. In the calm morning, the areal aspect ratio (Ararea), developed in this study for real urban configurations, showed a strong relationship with block scale [UFP]. Ararea includes the building area-weighted building height, the amount of open space, and the building footprint. In the afternoon, however, when wind speeds were generally higher and turbulence was stronger, vertical turbulence intensity sigmaw was the most effective factor controlling [UFP]. The surrounding built environment appears to play an indirect role in observed [UFP], by affecting surface level micrometeorology. The effects are substantial; controlling for traffic, differences in Ararea and building heterogeneity were related to differences in [UFP] of factors of two to three among our five study sites. These results have significant implications for pedestrian exposure as well as transit-oriented urban planning. PMID- 26938316 TI - The influence of tree species composition on the storage and mobility of semivolatile organic compounds in forest soils. AB - Soil contamination with PCBs and PAHs in adjacent forest plots, characterized by a distinct composition in tree species (spruce only, mixed and beech only), was analyzed to investigate the influence of ecosystem type on contaminant mobility in soil under very similar climate and exposure conditions. Physical-chemical properties and contaminant concentrations in litter (L), organic (F, H) and mineral (A, B) soil horizons were analyzed. Contaminant distribution in the soil core varied both in relation to forest type and contaminant group/properties. Contaminant mobility in soil was assessed by examining the ratios of total organic carbon (TOC)-standardized concentrations across soil horizons (Enrichment factors, EFTOC) and the relationship between EFTOC and the octanol-water equilibrium partitioning coefficient (KOW). Contaminant distribution appeared to be highly unsteady, with pedogenic/biogeochemical drivers controlling contaminant mobility in organic layers and leaching controlling accumulation in mineral layers. Lighter PCBs displayed higher mobility in all forest types primarily controlled by leaching and, to a minor extent, diffusion. Pedogenic processes controlling the formation of soil horizons were found to be crucial drivers of PAHs and heavier PCBs distribution. All contaminants appeared to be more mobile in the soil of the broadleaved plot, followed by mixed canopy and spruce forest. Increasing proportion of deciduous broadleaf species in the forest can thus lead to faster degradation or the faster leaching of PAHs and PCBs. The composition of humic substances was found to be a better descriptor of contaminant concentration than TOC. PMID- 26938317 TI - Historical records of mercury in southern latitudes over 1600 years: Lake Futalaufquen, Northern Patagonia. AB - Mercury is released to the environment from natural and anthropogenic sources, and through atmospheric transport is distributed globally. Lake Futalaufquen (42.8 degrees S) is an oligotrophic lake located in Los Alerces National Park (Northern Patagonia), providing a remote and unpolluted study system. A lacustrine sedimentary sequence revealed 1600 years of Hg deposition, identifying natural baselines and marked peaks not correlated with long-range atmospheric transport. Organic matter and catchment erosion were discarded as Hg drivers. Natural background, pre-1300 CE Hg concentrations, ranged between 27 and 47 ng g( 1) (accumulation rates from 8 to 15MUg m(-2) y(-1)). From 1300 CE on, the Hg background profile did not follow the generally increasing Hg pattern observed in both Southern and Northern Hemisphere since pre-industrial times. It was not until the last century that a 1.6-fold increase is observed in the Hg accumulation rate, considered among the lowest increments in southern South America. Noteworthy local/regional sources of Hg for this area, along with global transport, are forest fires and volcanic activity. Between approx. 1340 and 1510 CE, sharp increase in Hg concentration and accumulation rate (up to 204 ng g(-1) and 51 MUg m(-2) y(-1), respectively) were clearly associated with extended fire episodes. Furthermore, high Hg peaks during the last 300 years were associated with volcanic eruptions in northernmost Patagonia together with fairly irregular fire episodes, caused by anthropogenic burning by settling population in the Andes. PMID- 26938318 TI - Environmental life cycle assessment of grain maize production: An analysis of factors causing variability. AB - To meet the growing demand, high yielding, but environmentally sustainable agricultural plant production systems are desired. Today, life cycle assessment (LCA) is increasingly used to assess the environmental impact of these agricultural systems. However, the impact results are very diverse due to management decisions or local natural conditions. The impact of grain maize is often generalized and an average is taken. Therefore, we studied variation in production systems. Four types of drivers for variability are distinguished: policy, farm management, year-to-year weather variation and innovation. For each driver, scenarios are elaborated using ReCiPe and CEENE (Cumulative Exergy Extraction from the Natural Environment) to assess the environmental footprint. Policy limits fertilisation levels in a soil-specific way. The resource consumption is lower for non-sandy soils than for sandy soils, but entails however more eutrophication. Farm management seems to have less influence on the environmental impact when considering the CEENE only. But farm management choices such as fertiliser type have a large effect on emission-related problems (e.g. eutrophication and acidification). In contrast, year-to-year weather variation results in large differences in the environmental footprint. The difference in impact results between favourable and poor environmental conditions amounts to 19% and 17% in terms of resources and emissions respectively, and irrigation clearly is an unfavourable environmental process. The best environmental performance is obtained by innovation as plant breeding results in a steadily increasing yield over 25 years. Finally, a comparison is made between grain maize production in Flanders and a generically applied dataset, based on Swiss practices. These very different results endorse the importance of using local data to conduct LCA of plant production systems. The results of this study show decision makers and farmers how they can improve the environmental performance of agricultural systems, and LCA practitioners are alerted to challenges due to variation. PMID- 26938319 TI - Effect of sulfidation and dissolved organic matters on toxicity of silver nanoparticles in sediment dwelling organism, Chironomus riparius. AB - The properties, fate, and toxicity of silver nanoparticles (AgNPs) are readily modified in the environment. Thus, in order to predict the environmental impact of AgNPs, the toxicity test should be conducted to assess the interactions of AgNPs with environmental matrices. Dissolved organic matter (DOM) is known to mitigate AgNPs toxicity in natural systems, and it is also known that silver binds strongly to sulfur. Little is known, however, about the effect of sulfidation and to what extent it could compete with DOM in the sediment. We therefore investigated the effect of sulfide on a sediment dwelling organism, Chironomus riparius using ecotoxicity endpoints. We then investigated how sulfide and a combination of sulfide and DOM affect the toxicity of AgNPs in C. riparius. We also monitored the concentrations of silver in the water and sediment compartments, as well as in C. riparius tissue, in the presence and absence of sulfide. Finally, in order to investigate how sulfide and DOM affect the release of ions from AgNPs, we also monitored released Ag(+) in each treatment. In the presence of sulfide, AgNPs were found to be less toxic to C. riparius in acute and chronic endpoints than AgNPs alone, whereas DOM treatment did not modulate the toxicity of AgNPs. Sulfide treatment reduced the release of Ag(+) from AgNPs. Water-spiked AgNPs with sulfide were found to be more slowly incorporated into both sediment and larvae as compared to the AgNP alone. Overall, the results suggest that the presence of sulfide in sediment mitigates the ecotoxicity of AgNPs in C. riparius. PMID- 26938320 TI - Carbon dynamics and their link to dissolved organic matter quality across contrasting stream ecosystems. AB - Streams represent active components of the carbon cycle as emitters of carbon dioxide (CO2) and methane to the atmosphere at a global scale. However, the mechanisms and governing factors of these emissions are still largely unknown, especially concerning the effect of land use. We compared dissolved and gaseous carbon dynamics in streams bordered by contrasting types of land use, specifically agriculture and forest. Carbon dioxide and methane partial pressures (pCO2 and pCH4, respectively) in the water body and carbon emissions via both gases were studied for 24h during four field expeditions. pCH4 did not differ between the two system types. pCO2 was constantly oversaturated in all streams and significantly higher in agricultural streams (annual mean 4282 ppm) compared to forest streams (annual mean 2189 ppm) during all seasons. However, emissions of CO2 were not significantly different between the stream types due to significantly higher gas transfer velocity in forest compared to agricultural streams. pCO2 was significantly positively correlated to the concentrations of dissolved organic carbon, dissolved nitrogen and soluble reactive phosphorus in the water. Furthermore, pCO2 was correlated to optical parameters of dissolved organic matter (DOM) quality, e.g., it increased with indicators of molecular size and an allochthonous fluorescent component identified by Parallel Factor Analysis (PARAFAC). This study demonstrates that different forms of land use may trigger a cascade of effects on the carbon production and emission of streams linked to changes in DOM quality. PMID- 26938321 TI - Minimal selective concentrations of tetracycline in complex aquatic bacterial biofilms. AB - Selection pressure generated by antibiotics released into the environment could enrich for antibiotic resistance genes and antibiotic resistant bacteria, thereby increasing the risk for transmission to humans and animals. Tetracyclines comprise an antibiotic class of great importance to both human and animal health. Accordingly, residues of tetracycline are commonly detected in aquatic environments. To assess if tetracycline pollution in aquatic environments promotes development of resistance, we determined minimal selective concentrations (MSCs) in biofilms of complex aquatic bacterial communities using both phenotypic and genotypic assays. Tetracycline significantly increased the relative abundance of resistant bacteria at 10 MUg/L, while specific tet genes (tetA and tetG) increased significantly at the lowest concentration tested (1 MUg/L). Taxonomic composition of the biofilm communities was altered with increasing tetracycline concentrations. Metagenomic analysis revealed a concurrent increase of several tet genes and a range of other genes providing resistance to different classes of antibiotics (e.g. cmlA, floR, sul1, and mphA), indicating potential for co-selection. Consequently, MSCs for the tet genes of <= 1 MUg/L suggests that current exposure levels in e.g. sewage treatment plants could be sufficient to promote resistance. The methodology used here to assess MSCs could be applied in risk assessment of other antibiotics as well. PMID- 26938322 TI - Nutrient release and ammonium sorption by poultry litter and wood biochars in stormwater treatment. AB - The feasibility of using biochar as a filter medium in stormwater treatment facilities was evaluated with a focus on ammonium retention. Successive batch extractions and batch ammonium sorption experiments were conducted in both deionized (DI) water and artificial stormwater using poultry litter (PL) and hardwood (HW) biochars pyrolyzed at 400 degrees C and 500 degrees C. No measureable nitrogen leached from HW biochars except 0.07 MUmol/g of org-N from 400 degrees C HW biochar. PL biochar pyrolyzed at 400 degrees C leached 120-127 MUmol/g of nitrogen but only 7.1-8.6 MUmol/g of nitrogen when pyrolyzed at 500 degrees C. Ammonium sorption was significant for all biochars. At a typical ammonium concentration of 2mg/L in stormwater, the maximum sorption was 150 mg/kg for PL biochar pryolyzed at 400 degrees C. In stormwater, ion competition (e.g. Ca(2+)) suppressed ammonium sorption compared to DI water. Surprisingly, ammonium sorption was negatively correlated to the BET surface area of the tested biochars, but increased linearly with cation exchange capacity. Cation exchange capacity was the primary mechanism controlling ammonium sorption and was enhanced by pyrolysis at 400 degrees C, while BET surface area was enhanced by pyrolysis at 500 degrees C. The optimal properties (BET surface area, CEC, etc.) of biochar as a sorbent are not fixed but depend on the target pollutant. Stormwater infiltration column experiments in sand with 10% biochar removed over 90% of ammonium with influent ammonium concentration of 2mg/L, compared to only 1.7% removal in a sand-only column, indicating that kinetic limitations on sorption were minor for the storm conditions studied. Hardwood and poultry litter biochar pyrolyzed at 500 degrees C and presumably higher temperature may be viable filter media for stormwater treatment facilities, as they showed limited release of organic and inorganic nutrients and acceptable ammonium sorption. PMID- 26938323 TI - Preparation of a paclitaxel-loaded cationic nanoemulsome and its biodistribution via direct intratumoral injection. AB - In this study, a nano-preparation based on nanoemulsome (NES) modified with cetyltrimethylammonium bromide (CTAB) loading paclitaxel (PTX) was designed, and its biodistribution were explored after intratumoral (i.t.) administration on Heps tumor-bearing mice. The PTX-loaded nanoemulsome (PTX-NES) was prepared by using a solvent evaporation method and CTAB, chosen as a cationic material, was absorbed onto the surface of the NES via electrostatic interaction to yield paclitaxel-loaded cationic nanoemulsome (PTX-CTAB-NES). The MTT results exhibited that PTX-CTAB-NES (IC50: 0.50+/-0.035MUg/mL in MCF-7 cells and 0.13+/-0.048MUg/mL in SMMC-7721 cells) had the strongest cytotoxicity compared to Taxol (IC50: 0.88+/-0.054MUg/mL in MCF-7 and 0.15+/-0.011MUg/mL in SMMC-7721) and PTX-NES (IC50: 1.93+/-0.062MUg/mL in MCF-7 and 0.32+/-0.027MUg/mL in SMMC-7721). Body distribution of PTX revealed that the percent of PTX retained in the tumor after i.t. administration of PTX-CTAB-NES (approximately 92.99% at 0.167h and 15.35% at 48h) was higher when compared to that after i.t. injection of Taxol (approximately 58.94% at 0.167h and 0.83% at 48h) or PTX-NES (approximately 83.63% at 0.167h and 6.52% at 48h). Moreover, less PTX accumulated in liver, spleen, kidney, lung and heart after i.t. administration of PTX-CTAB-NES when compared with that after i.v. administration of PTX-CTAB-NES. In conclusion, PTX CTAB-NES was a prospective in-situ delivery system for the therapy of tumor. PMID- 26938324 TI - Redox-sensitive micelles assembled from amphiphilic mPEG-PCL-SS-DTX conjugates for the delivery of docetaxel. AB - Docetaxel (DTX) can produce anti-tumor effects by inhibiting cell growth and inducing apoptosis. However, the poor solubility of DTX restricts its application and its clinical formulation has caused serious adverse reaction due to the use of Tween-80. In the present study, DTX was conjugated to an amphiphilic di-block polymer to solve these problems. Methoxy poly(ethylene glycol)-poly(epsilon caprolactone) (mPEG-PCL) was selected as the polymer skeleton and a redox sensitive disulfide bond was used as the linker between DTX and mPEG-PCL. The synthesized mPEG-PCL-SS-DTX conjugates were characterized by (1)H-nuclear magnetic resonance ((1)H NMR) and Fourier transform infrared spectroscopy (FTIR). Interestingly, the mPEG-PCL-SS-DTX conjugates could self-assemble into micelles in aqueous solution. The critical micelle concentration (CMC) of mPEG-PCL-SS-DTX micelles was about 2.3mgL(-1) determined using pyrene molecule fluorescent probe method while the size of mPEG-PCL-SS-DTX micelles was determined to be ca. 17.6nm and 116.0nm with a bimodal distribution by dynamic light scattering (DLS). The in vitro release results indicated that the as-prepared micelles exhibited a sustained release profile with good redox sensitive properties. In particular, the hemolytic toxicity test indicated the as-prepared mPEG-PCL-SS-DTX micelles had negligible hemolytic activity, demonstrating their safety in drug delivery system. Cytotoxicity assay of the mPEG-PCL-SS-DTX micelles verified their highly enhanced cytotoxicity to MCF-7/A and A549 cells. These results thus demonstrated that the present redox-sensitive mPEG-PCL-SS-DTX micelle was an efficient and safe sustained drug delivery system in the biomedical area. PMID- 26938327 TI - Rhizobium radiobacter: A Recently Recognized Cause of Bacterial Keratitis. AB - PURPOSE: To present the first reported cases of keratitis caused by Rhizobium radiobacter. METHODS: A retrospective review of an observational case series from 2 institutions. RESULTS: There were 4 cases of microbiologically proven R. radiobacter. Three of these patients were contact lens wearers. The patient in case 4 defaulted from follow-up after receipt of the culture result. Keratitis in the other cases resolved with variable clinical courses once culture-directed therapy was instituted. CONCLUSIONS: R. radiobacter is a member of the genus Rhizobium. It is a gram-negative bacillus and was previously identified as an opportunistic pathogen in nonophthalmic infections and in a few cases of endophthalmitis. To our knowledge, we have described the clinical presentation, management, and treatment outcomes of the first reported cases of keratitis caused by R. radiobacter. PMID- 26938325 TI - Protein adsorption on polyanion/polycation layer-by-layer assembled polyelectrolyte films. AB - As layer-by-layer self-assembly deposition (LbL) is a versatile technique for surface modification, protein adsorption on the LbL modified glass is evaluated in this study. At the beginning, glass slides was silanized by 3 aminopropyltriethoxysilane (APTES). Sodium alginate (Alg), poly(gamma-glutamic acid) (PGA) and poly(aspartic acid) (PAsp) were selected as polyanion electrolytes and chitosan (CS) was used as the polycation electrolyte. Both polyanion and polycation electrolytes alternately deposited on the silanized glass slide surface by the LbL technique to get three different polyanion/chitosan series of LbL films ([Alg/CS], [PGA/CS], and [PAsp/CS]). Three kinds of kinetic model including pseudo-first-order, second-order kinetic and intraparticle diffusion model were used to evaluate the adsorption of albumin on the three different polyanion/chitosan series of LbL films. It is found that the adsorption of albumin on the polyanion/chitosan series of LbL films can be described well with the pseudo-second-order kinetic mechanism. To make sure if the pseudo-second-order kinetic mechanism of protein adsorbed on the other polyanion/polycation LbL films is also suitable, poly(allylamine hydrochloride) (PAH) and poly(L-lysine) (PLL) are used as two other polycations. The [polyanion/PAH] and [polyanion/PLL] series of LbL films were prepared with the same LbL technique for albumin, fibrinogen, and fibronectin adsorption. From the results, it is found that albumin, fibrinogen, and fibronectin adsorption on the various polyanion/polycation LbL films can be described well with the pseudo second-order kinetic mechanism. The protein adsorbed at equilibrium and rate constant of protein adsorbed on the various LbL films can be determined. PMID- 26938326 TI - Glass-windowed ultrasound transducers. AB - In research and industrial processes, it is increasingly common practice to combine multiple measurement modalities. Nevertheless, experimental tools that allow the co-linear combination of optical and ultrasonic transmission have rarely been reported. The aim of this study was to develop and characterise a water-matched ultrasound transducer architecture using standard components, with a central optical window larger than 10 mm in diameter allowing for optical transmission. The window can be used to place illumination or imaging apparatus such as light guides, miniature cameras, or microscope objectives, simplifying experimental setups. Four design variations of a basic architecture were fabricated and characterised with the objective to assess whether the variations influence the acoustic output. The basic architecture consisted of a piezoelectric ring and a glass disc, with an aluminium casing. The designs differed in piezoelectric element dimensions: inner diameter, ID=10 mm, outer diameter, OD=25 mm, thickness, TH=4 mm or ID=20 mm, OD=40 mm, TH=5 mm; glass disc dimensions OD=20-50 mm, TH=2-4 mm; and details of assembly. The transducers' frequency responses were characterised using electrical impedance spectroscopy and pulse-echo measurements, the acoustic propagation pattern using acoustic pressure field scans, the acoustic power output using radiation force balance measurements, and the acoustic pressure using a needle hydrophone. Depending on the design and piezoelectric element dimensions, the resonance frequency was in the range 350-630 kHz, the -6 dB bandwidth was in the range 87-97%, acoustic output power exceeded 1 W, and acoustic pressure exceeded 1 MPa peak-to-peak. 3D stress simulations were performed to predict the isostatic pressure required to induce material failure and 4D acoustic simulations. The pressure simulations indicated that specific design variations could sustain isostatic pressures up to 4.8 MPa.The acoustic simulations were able to predict the behaviour of the fabricated devices. A total of 480 simulations, varying material dimensions (piezoelectric ring ID, glass disc diameter, glass thickness) and drive frequency indicated that the emitted acoustic profile varies nonlinearly with these parameters. PMID- 26938328 TI - Development of a Novel Technique to Measure Corneal Nerve Migration Rate. AB - PURPOSE: We have developed a novel technique to measure in vivo corneal nerve migration. METHODS: Wide-field montages of the subbasal corneal nerve plexus were generated at baseline and after 3 weeks. The 2 montages were manually examined side by side to identify a referent landmark in the inferior whorl region and 20 additional nerve landmarks throughout each montage. A software program was developed to measure nerve migration by quantifying the movement of the nerve landmarks relative to the inferior whorl landmark over the 3-week period. To illustrate the utility of this technique, nerve migration was measured in 2 individuals with diabetes (one with and the other without neuropathy) and a healthy control participant. RESULTS: The average nerve migration rate was calculated to be 18.4, 49.9, and 41.5 MUm/wk for the diabetic individuals with and without neuropathy and the control participant, respectively. The number of landmarks for tracking nerve migration in the participants was 26, 21, and 20, and they were at an average distance of 1500, 1940, and 1461 MUm, from the whorl, respectively. The rate of migration depended on the distance from the whorl; hence, linear equations were generated for each subject for comparison. CONCLUSIONS: This novel imaging technique allows rapid measurement of in vivo corneal nerve migration. The results indicate that diabetic neuropathy may be associated with reduced nerve migration; however, because of the high level of manual input required in this technique and the apparent complex characteristics of corneal nerve migration, repeatability and characterization studies are needed. PMID- 26938329 TI - Corynebacterium propinquum Keratitis Identified Using MALDI-TOF. AB - PURPOSE: To report a corneal infection due to Corynebacterium propinquum identified using the matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) method. METHODS: A 94-year-old woman presented with suppurative keratitis. Her ocular history included Fuchs corneal dystrophy, corneal transplantation, and glaucoma. A gram-stained smear revealed coryneforms. Colonies on bacterial culture media were assayed by MALDI-TOF. RESULTS: Identification of C. propinquum was confirmed by RNA polymerase beta subunit (rpoB) gene sequencing. The patient was treated with topical cefazolin, gentamicin, and fluorometholone, and her vision improved to 20/160 unaided when last seen. CONCLUSIONS: MALDI-TOF can correctly identify isolates that are both uncommon and difficult to distinguish from related species. The ease and low running costs of this method will improve the laboratory diagnosis of ocular infections. PMID- 26938330 TI - Adhesion of Acanthamoeba on Silicone Hydrogel Contact Lenses. AB - PURPOSE: To evaluate adhesion of Acanthamoeba trophozoites to different silicone hydrogel contact lens (SHCL) generations with and without multipurpose contact lens care solution (MPS) treatment. METHODS: Acanthamoeba lugdunensis L3a trophozoites were inoculated onto discs trimmed from SHCLs: first generation, Air Optix (Lotrafilcon B) with a plasma surface treatment, second generation, Acuvue Oasys (Senofilcon A), which contains an internal wetting agent (Hydraclear), and third generation, Biofinity (Comfilcon A) with no surface treatment. After 18 hour inoculation, the number of adherent trophozoites on SHCLs was counted as the control under phase contrast microscopy. The effects of the 3 different MPSs, Opti-Free Express, ReNu Fresh, and Biotrue, soaking SHCLs for 6 hours, on Acanthamoeba adhesion were analyzed. Scanning electron microscopic examination was performed for assessment of Acanthamoeba attached on the lens surface. RESULTS: Acanthamoeba trophozoites showed greater adhesion to Air Optix than to Acuvue Oasys and Biofinity (P < 0.05). On Air Optix and Acuvue Oasys, the number of adherent Acanthamoeba was significantly reduced compared with the control after treatment with Opti-Free Express (P < 0.05), but not significantly reduced by treatment with ReNu Fresh and Biotrue (P > 0.05). Acanthamoeba did not adhere to Biofinity regardless of MPSs treatment. Attachment of the acanthopodia of Acanthamoeba on the curved ridge of the Air Optix lens surface was observed. CONCLUSIONS: Acanthamoeba showed greater affinity for the first-generation SHCL and seemed to be more attached on SHCLs with more ridges. MPS with myristamidopropyl dimethylamine reduced the adhesion rate. PMID- 26938331 TI - How to rule the nucleus: divide et impera. AB - Genome-wide molecular studies have provided new insights into the organization of nuclear chromatin by revealing the presence of chromatin domains of differing transcriptional activity, frequency of cis-interactions, proximity to scaffolding structures and replication timing. These studies have not only brought our understanding of genome function to a new level, but also offered functional insight for many phenomena observed in microscopic studies. In this review, we discuss the major principles of nuclear organization based on the spatial segregation of euchromatin and heterochromatin, as well as the dynamic genome rearrangements occurring during cell differentiation and development. We hope to unite the existing molecular and microscopic data on genome organization to get a holistic view of the nucleus, and propose a model, in which repeat repertoire together with scaffolding structures blueprint the functional nuclear architecture. PMID- 26938332 TI - Nanophotonics: a stimulus for light discussion. PMID- 26938333 TI - Cilostazol Can Increase Skin Oxygen Supply Assessed by Transcutaneous Oxygen Pressure Measurement in Type 2 Diabetes With Lower Limb Ischemic Disease: A Randomized Trial. AB - PURPOSE: The purpose of this study was to compare the efficacy and safety of cilostazol versus acetylsalicylic acid (ASA) for amelioration of lower limb ischemia in type 2 diabetes. DESIGN: Prospective, randomized positive-controlled open clinical trial. SUBJECTS AND SETTING: Eighty-nine patients with type 2 diabetes mellitus and symptoms of lower limb ischemia (perceptions of coldness of the lower limbs, numbness, intermittent claudication, or pain at rest) present for 6 months or more that had not significantly changed within the past 3 months participated in the study. All subjects had an initial transcutaneous oxygen pressure (TcpO2) of less than 40 mm Hg in the foot when measured in the supine position. Subjects included 46 males and 43 females; their ages ranged from 35 to 80 years. METHODS: Participants were randomly allocated to 2 groups, one was treated with cilostazol 100 mg taken twice daily (n = 48), and a second group took 100 mg of ASA daily (n = 41) for 8 weeks. Clinical assessment included measurement of transcutaneous oxygenation, and symptoms associated with lower limb ischemia. Blood analyses included a full blood panel, coagulation screen, renal function tests, hepatic function tests, and lipid profiles. All tests were performed at baseline and repeated at 8 weeks. RESULTS: Age, duration of diabetes, diabetic complications, lower limb ischemic symptoms, TcpO2, and smoking status did not differ between the 2 groups. In contrast, TcpO2 significantly improved from 37.1 +/- 11.9 mm Hg to 42.0 +/- 9.7 mm Hg in the cilostazol-treated group (P < .05), whereas no significant change was observed in the ASA-treated group (P > .05). Ischemic symptoms such as intermittent claudication (P = .009), perception of limb coldness (P = .008), and pain at rest (P = .017) showed greater improvement in the cilostazol-treated group when compared to subjects treated with ASA. Approximately 10% of patients treated with cilostazol experienced adverse side effects (palpitations, headache, diarrhea). Cilostazol was not found to have significant detrimental effects in hematologic or biochemical indices, including renal, hepatic, and blood coagulant function tests. CONCLUSIONS: We found that 8 weeks of treatment with cilostazol 100 mg daily was safe and well tolerated for the treatment of type 2 diabetes with lower limb ischemic disease. PMID- 26938334 TI - Management Approaches to Stomal and Peristomal Complications: A Narrative Descriptive Study. AB - PURPOSE: The purpose of this study was to identify optimal interventions for selected complications based on WOC nurse experts' judgment/expertise. METHODS: A cross-sectional quantitative descriptive design with qualitative, narrative-type components was used for this study. Following validation rating of appropriateness of interventions and quantitative rankings of first-, second-, and third-line approaches, participants provided substantive handwritten narrative comments about listed interventions. Comments were organized and prioritized using frequency count. RESULTS: Narrative comments reflected the quantitative rankings of efficacy of approaches. Clinicians offered further specific suggestions regarding product use and progression of care for selected complications. CONCLUSIONS: Narrative analysis using descriptive quantitative frequency count supported the rankings of most preferred treatments of selected stomal and peristomal complications. Findings add to the previous research on prioritized approaches and evidence-based practice in ostomy care. PMID- 26938335 TI - Managing Expectations in Refractive Surgery. PMID- 26938337 TI - Intraoperative LASIK Complications. PMID- 26938338 TI - Femtosecond-assisted LASIK: Complications and Management. AB - FS-assisted LASIK has become the preferred method for LASIK flap creation due to the precision, accuracy, and reproducibility of the flap creation. Thinner, planar flaps may help prevent cases of post-LASIK ectasia and may have a superior refractive outcome. However, FS flap creation has several unique complications that require early recognition and optimal timely management for the best visual outcomes. PMID- 26938339 TI - LASIK Flap: Postoperative Complications. PMID- 26938336 TI - Errors in Treatment of Lower-order Aberrations and Induction of Higher-order Aberrations in Laser Refractive Surgery. PMID- 26938340 TI - Postoperative Pain After Laser Refractive Surgery. PMID- 26938341 TI - Dry Eye Disease After Refractive Surgery. PMID- 26938342 TI - Corneal Haze Following Refractive Surgery: A Review of Pathophysiology, Incidence, Prevention, and Treatment. PMID- 26938343 TI - Complications of Refractive Surgery: Ectasia After Refractive Surgery. PMID- 26938344 TI - Retinal Complications After Refractive Surgery. PMID- 26938345 TI - Complications of Intracorneal Implants in Refractive Surgery. PMID- 26938346 TI - Complications of Phakic Intraocular Lenses. PMID- 26938347 TI - Cataract Surgery After Refractive Surgery. PMID- 26938349 TI - Nutrition for cystectomy with pelvic lymph nodes dissection: perioperative considerations. AB - Assessment of nutritional status by an objective measure such as NRS-2002 or sarcopenia in the preoperative workup of major abdominal surgeries helps identify patients at risk for increased surgical morbidity and mortality. Preoperative and immediate postoperative nutritional supplements have demonstrated to decrease risk of complications and length of stay. Enhancing the immune system with immunonutrition has also been suggested as major player in this setting. In this review on nutritional considerations in the perioperative setting of radical cystectomy, we will describe several tools available to improve the complications rates and mortality surrounding this procedure. PMID- 26938350 TI - Prognosis of node-positive bladder cancer in 2016. AB - INTRODUCTION: Lymph node (LN) positive bladder cancer is a serious disease associated with a poor prognosis. Nevertheless even after radical cystectomy and lymph node dissection alone long-term oncologic control has been reported in a subset of these patients. Efforts have been made to stratify LN-positive patients according to various prognostic factors to make more individualized risk estimations. This review attempts to summarize the existing data on prognostic determinants in node-positive bladder cancer. EVIDENCE ACQUISITION: A literature search of the English literature was performed in October 2015 on PubMed using the search terms "bladder cancer", "node-positive" and "prognosis/outcome". Papers were only selected when separate information on the node-positive subpopulation was available. Data from prospective studies, meta-analysis or multi-institutional were selected primarily. EVIDENCE SYNTHESIS: Current 2010 TNM classification of nodal disease seems to have limited prognostic value. Several other nodal parameters such as number of positive nodes, number of resected nodes, LN density and extracapsular extension have been extensively evaluated and show potential in distinguishing prognostic subgroups. Although node-positive bladder cancer is often seen as systemic disease local tumor characteristics such as T stage and histological variants seem to remain important. Molecular markers are promising in stratifying patients with bladder cancer but need further validation in a specific node-positive subgroup. Neo-adjuvant chemotherapy seems to improve the prognosis of clinical node-positive patients and evaluation of response could help in selecting patients who benefit from consolidating surgery. Although retrospective studies convincingly suggest improved clinical outcome with adjuvant chemotherapy for pathological node-positive patients, these findings are not consistently confirmed in recent prospective studies. CONCLUSIONS: Future research should aim at the incorporation of prognostic variables into clinically applicable nomograms and identification of the subgroup of patients who will benefit from adjuvant treatments. PMID- 26938351 TI - Magnetic impurities in single-walled carbon nanotubes and graphene: a review. AB - Control over magnetism in single-walled carbon nanotubes (SWCNTs) and graphene is of fundamental importance. Creation and manipulation using the unpaired spins without the need for archetypal magnetic elements results in sp(2)-hybridised nanocarbons being at the forefront of applications in both spintronics and nanoelectronics. The crucial limitation for the experimental observation of the intrinsic carbon magnetism stems from the presence of magnetic impurities, from which a magnetic response usually dominates. Thus, the rigorous identification of such magnetic impurities and their efficient removal is of enormous importance. The present review reports on the current state-of-the-art methodology for the detection and quantification of magnetic impurities in SWCNTs and graphene, reflecting both the preparation and subsequent purification procedures. First, the most common techniques for the preparation of SWCNTs (i.e., arc discharge, laser ablation and chemical vapour deposition) and the corresponding magnetic impurities are reviewed. Then, the available volume, surface and local probes for the identification and quantification of the impurities are discussed, and their efficiency and limitations are evaluated for the given cases. A summary of the current understanding of graphene-related magnetism in the context of the identified impurities is also given. Finally, the key knowledge is reviewed with respect to future prospects in the field. PMID- 26938352 TI - Molecularly Imprinted Polymer-Decorated Magnetite Nanoparticles for Selective Sulfonamide Detection. AB - Sulfonamides are known not only to be antimicrobial drugs that lead to antimicrobial resistance but also to be chemotherapeutic agents that may be allergenic and potentially carcinogenic, which represents a potentially hazardous compound once present in soil or water. Herein, a hybrid material based on molecularly imprinted polymer (MIP)-decorated magnetite nanoparticles for specific and label-free sulfonamide detection is reported. The composite has been characterized using different spectroscopic and imaging techniques. The magnetic properties of the composite are used to separate, preconcentrate, and manipulate the analyte which is selectively captured by the MIP onto the surface of the composite. Screen printed electrodes have been employed to monitor the impedance levels of the whole material, which is related to the amount of the captured analyte, via electrochemical impedance spectroscopy. This composite-based sensing system exhibits an extraordinary limit of detection of 1 * 10(-12) mol L(-1) (2.8 * 10(-4) ppb) (S/N = 3), which is close to those obtained with liquid chromatography and mass spectrometry, and it was demonstrated to screen sulfamethoxazole in a complex matrix such as seawater, where according to the literature sulfonamides content is minimum compared with other environmental samples. PMID- 26938353 TI - Individualizing Nursing Care in the Omics Era. PMID- 26938354 TI - Letter to the Editor: Primary Breast Cancer Decision-making Among Chinese American Women, Lee & Knobf (2015). PMID- 26938355 TI - Response to Roe's (2016) Letter to the Editor. PMID- 26938356 TI - Should Faculty Assume First Authorship on Papers When Students Fail to Draft Papers From Work They Conducted During Training? PMID- 26938357 TI - Response to Lindo, LePage, & Beason (2016): "Should Faculty Assume First Authorship on Papers When Students Fail to Draft Papers From Work They Conducted During Training?". PMID- 26938359 TI - Mental Health Disorders in Elderly People Receiving Home Care: Prevalence and Correlates in the National U.S. Population. AB - BACKGROUND: Current evidence on mental health disorders (MHDs) in the U.S. elderly home care population is highly varied and limited to the local level. AIM: The objective of this study was to examine the prevalence and characteristics of U.S. elders with MHDs on the national level. METHODS: This is a primary analysis of secondary use data from a 5% random sample of the 2010 National Outcome and Assessment Information Set (OASIS) data spanning a 60-day home care session. MHDs included depression, anxiety, substance abuse, psychotic disorders, aggression, and socially inappropriate behaviors and were identified by diagnosis, symptoms, or mental health service order in the plan of care. Logistic regression was used to identify correlates of MHD. RESULTS: The final analysis was conducted on records from 28,475 elderly patients with an average age of 79 (range 65-110). Patients were primarily female, White, Medicare beneficiaries, referred from short-stay acute hospitals, and living with others at home. Prevalence of MHDs was approximately 40%; depression (28.0%) and anxiety (18.9%) were common. Factors associated with MHDs were younger age, female, smokers, frail, living alone, referred from psychiatric hospitals, cognitively or sensory impaired, poorer health status, recent history of falls or multiple hospitalizations, and insufficient social support. Only about one third of patients identified with MHD received mental health services during the 60-day home care episode, including psychiatric nursing services and depression interventions. DISCUSSION: MHDs are a national health concern in the older U.S. home care population and are common but largely undermanaged. Future research in the home care sector should be aimed at developing targeted MHD screening and interventional protocols and training the current workforce, as well as expanding the future workforce to improve psychiatric care for the homebound elderly. PMID- 26938358 TI - Testing a Model of Self-Management of Fluid Intake in Community-Residing Long term Indwelling Urinary Catheter Users. AB - BACKGROUND: Urinary tract infection and blockage are serious and recurrent challenges for people with long-term indwelling catheters, and these catheter problems cause worry and anxiety when they disrupt normal daily activities. OBJECTIVE: The goal was to determine whether urinary catheter-related self management behaviors focusing on fluid intake would mediate fluid intake-related self-efficacy toward decreasing catheter-associated urinary tract infection (CAUTI) and/or catheter blockage. METHODS: The sample involved data collected from 180 adult community-living, long-term indwelling urinary catheter users. The authors tested a model of fluid intake self-management related to fluid intake self-efficacy for key outcomes of CAUTI and blockage. To account for the large number of zeros in both outcomes, a zero-inflated negative binomial (ZINB) structural equation model was tested. RESULTS: Structurally, fluid intake self efficacy was positively associated with fluid intake self-management, suggesting that higher fluid intake self-efficacy predicts more (higher) fluid intake self management; however, fluid intake self-management was not associated with either the frequency of CAUTIs or the presence or absence of CAUTI. Fluid intake self efficacy was positively related to fluid intake self-management, and fluid intake self-management predicted less frequency of catheter blockage, but neither fluid intake self-efficacy nor fluid intake self-management predicted the presence or absence of blockage. DISCUSSION: Further research is needed to better understand determinants of CAUTI in long-term catheter users and factors which might influence or prevent its occurrence. Increased confidence (self-efficacy) and self-management behaviors to promote fluid intake could be of value to long-term urinary catheter users to decrease catheter blockage. PMID- 26938361 TI - Attitudes Toward Obese Persons and Weight Locus of Control in Chinese Nurses: A Cross-sectional Survey. AB - BACKGROUND: Obese individuals frequently experience weight-related bias or discrimination-even in healthcare settings. Although obesity bias has been associated with several demographic factors, little is known about the association of weight locus of control with bias against overweight persons or about weight bias among Chinese health professionals. OBJECTIVES: The aim of the study was to examine attitudes toward obese patients in a sample of Chinese registered nurses (RNs) and the relationship between weight bias and nurses' weight locus of control. METHODS: RNs working in nine community health service centers across Shanghai, China, answered three self-report questionnaires: The Attitudes Toward Obese Persons Scale (ATOP), the External Weight Locus of Control Subscale (eWLOC) from the Dieting Belief Scale, and a sociodemographic profile. Hierarchical, stepwise, multiple regression was used to predict ATOP scores. RESULTS: From among 385 invited, a total of 297 RNs took part in the study (77.1% response rate). Participants scored an average of 71.04 on the ATOP, indicating slightly positive attitudes toward obese persons, and 30.08 on the eWLOC, indicating a belief in the uncontrollability of body weight. Using hierarchical, stepwise, multiple regression, two predictors of ATOP scores were statistically significant (eWLOC scores and status as a specialist rather than generalist nurse), but explained variance was low. DISCUSSION: Chinese RNs seemed to have relatively neutral or even slightly positive attitudes toward obese persons. Those nurses who believed that obesity was beyond the individual's control or worked in specialties were more likely to have positive attitudes toward obese people. Improved understanding of the comprehensive etiology of obesity is needed. PMID- 26938360 TI - Chinese Adolescents and Youth With Methamphetamine Dependence: Prevalence and Concurrent Psychological Problems. AB - BACKGROUND: Methamphetamine is a commonly used illicit drug that threatens many adolescents and youth in Asian Pacific countries, contributing to the heavy burden of disease and drug-related death. Little is known about the prevalence of associated psychological problems in methamphetamine-dependent adolescents and youth. PURPOSE: The study sought to estimate the prevalence of psychological problems in adolescents and youth in China with methamphetamine dependence and to identify factors related to co-occurring psychological problems. METHODS: A cross sectional design was used. Methamphetamine-dependent adolescents and youth from two drug rehabilitation centers in Tianjin, China, took part. Each participant was assessed with a sociodemographic questionnaire and Symptom Checklist-90 (SCL 90). RESULTS: A total of 161 adolescents and youth took part. Psychological symptomatology was high, with 59.6% of participants having over 160 points on the SCL-90 total score, indicating significant psychological distress. On the basis of subscale scores, phobic anxiety, depression, and anxiety were common. Male participants, younger adolescents, and those who are addicted to methamphetamine for a longer time with more consumption were more likely to experience psychological problems. DISCUSSION: Nurses should be aware of the type and severity of psychological problems among methamphetamine-dependent adolescents and youth. Nursing care should be designed to relieve psychological problems and improve mental health of the methamphetamine-dependent adolescents and youth. PMID- 26938362 TI - Staff Knowledge, Awareness, Perceptions, and Beliefs About Infection Prevention in Pediatric Long-term Care Facilities. AB - BACKGROUND: The burden of healthcare-associated infection worldwide is considerable, and there is a need to improve surveillance and infection control practices such as hand hygiene. OBJECTIVES: The aims of this study were to explore direct care providers' knowledge about infection prevention and hand hygiene, their attitudes regarding their own and others' hand hygiene practices, and their ideas and advice for improving infection prevention efforts. METHODS: This exploratory study included interviews with direct care providers in three pediatric long-term care facilities. Two trained nurse interviewers conducted semistructured interviews using an interview guide with open-ended questions. Two other nurse researchers independently transcribed the audio recordings and conducted a thematic analysis using a strategy adapted from the systematic text condensation approach. RESULTS: From 31 interviews, four major thematic categories with subthemes emerged from the analysis: (a) hand hygiene products; (b) knowledge, awareness, perceptions, and beliefs; (c) barriers to infection prevention practices; and (d) suggested improvements. There was confusion regarding hand hygiene recommendations, use of soap or sanitizer, and isolation precaution policies. There was a robust "us" and "them" mentality between professionals. DISCUSSION: One essential driver of staff behavior change is having expectations that are meaningful to staff, and many staff members stated that they wanted more in-person staff meetings with education and hands-on, practical advice. Workflow patterns and/or the physical environment need to be carefully evaluated to identify systems and methods to minimize cross contamination. Further studies need to evaluate if personal sized containers of hand sanitizer (e.g., for the pocket, attached to a belt or lanyard) would facilitate improvement of hand hygiene in these facilities. PMID- 26938363 TI - Do You Know My Child? Continuity of Nursing Care in the Pediatric Intensive Care Unit. AB - BACKGROUND: Parents of children with complex, chronic conditions report a desire for continuity of care, but relatively little is known about the ways in which nursing continuity of care occurs and the extent to which it is delivered in the inpatient setting. OBJECTIVES: The objective of this analysis, which arose from a study on best practices in parent/nurse interactions in the pediatric intensive care unit (PICU), was to explore the delivery of continuity of nursing care in the PICU from the perspective of both parents and nurses. METHODS: A qualitative, grounded theory study using situational analysis was conducted with seven parents and 12 nurse participants from a single PICU. Data sources included in-depth interviews, observation, and organizational written materials. Data were coded and analyzed using memoing and situational and positional maps to highlight emerging themes, context, and positions within the data. RESULTS: Parents repeatedly endorsed a desire for continuity of nursing care, wanting to ensure that the bedside nurse valued their child as an individual and understood the complexities of the child's care regimen. Nurses understood this need but faced both contextual and personal challenges to achieving continuity, including fluctuations in staffing needs, training demands, fear of emotional entanglement, and concern for missed learning opportunities. DISCUSSION: Continuity of nursing care is highly valued by parents of children with complex chronic condition in the PICU, but significant barriers to optimal delivery exist within the current critical care environment. Mechanisms for supporting nurses to deliver continuity of care are needed, as are alternative ways to help parents feel that all nurses caring for their child have the knowledge necessary to deliver safe and compassionate care. PMID- 26938366 TI - 28th Annual Scientific Sessions Abstracts. PMID- 26938367 TI - Complementary and Alternative Medicine Use by Normal Weight, Overweight, and Obese Patients with Arthritis or Other Musculoskeletal Diseases. AB - OBJECTIVES: The Centers for Disease Control and Prevention estimates that 50 million Americans have been diagnosed with arthritis and other musculoskeletal diseases. The purpose of the current study was to (1) estimate the prevalence of overall complementary and alternative medicine (CAM) use and (2) examine the role of body mass index (BMI) on CAM use among normal weight, overweight, and obese persons with chronic lower back pain, chronic neck pain, chronic/rheumatoid arthritis, or musculoskeletal diseases, while controlling for other covariates. DESIGN: Cross-sectional design using secondary data for 9724 adults from the 2007 National Health Interview Survey. Data were weighted and analyzed by using Stata 12 for Windows (Stata Corp., College Station, TX). Descriptive, bivariate, and multivariate logistic regression statistics were computed. PARTICIPANTS: The participants were randomly surveyed from U.S. households. OUTCOME MEASURES: CAM use was measured as reported use of any modality within the five National Center for Complementary and Integrative Health domains. RESULTS: CAM use was statistically significantly associated with female sex; race/ethnicity; having chronic neck pain, lower back pain, or chronic/rheumatoid arthritis; having limitations due to chronic disease; and geographic region (p < 0.05). Factors significantly associated with decreased odds of CAM use included age 50-64 years, income categorized as "other/missing," and having musculoskeletal diseases. Stratification by body mass index suggested increased odds of CAM use among normal/underweight persons with chronic neck pain but decreased odds for those with chronic musculoskeletal diseases. For overweight patients, increased odds of CAM use were significant for chronic lower back pain, musculoskeletal diseases, and chronic/rheumatoid arthritis. CONCLUSIONS: Musculoskeletal diseases and arthritis represent important public health problems with economic implications for the well-being of individuals and society. Identifying CAM use trends by patient weight can be used to improve strategies to increase awareness and access to CAM as part of comprehensive and cost-effective approaches for the management and treatment of these conditions. PMID- 26938364 TI - Overall Adiposity, Adipose Tissue Distribution, and Endometriosis: A Systematic Review. AB - BACKGROUND: Endometriosis has been associated with a lean body habitus. However, we do not understand whether endometriosis is also associated with other characteristics of adiposity, including adipose tissue distribution and amount of visceral adipose tissue (VAT; adipose tissue lining inner organs). Having these understandings may provide insights on how endometriosis develops-some of the physiological actions of adipose tissue differ depending on tissue amount and location and are related to proposed mechanisms of endometriosis development. OBJECTIVES: The aim of this study was to review the literature regarding overall adiposity, adipose tissue distribution and/or VAT, and endometriosis. METHODS: We reviewed and synthesized studies indexed in PubMed and/or Web of Science. We included studies that had one or more measures of overall adiposity, adipose tissue distribution, and/or VAT and women with and without endometriosis for comparison. We summarized the findings and commented on the methods used and potential sources of bias. RESULTS: Of 366 identified publications, 19 (5.2%) were eligible. Two additional publications were identified from reference lists. Current research included measures of overall adiposity (e.g., body figure drawings) or adipose tissue distribution (e.g., waist-to-hip ratio), but not VAT. The weight of evidence indicated that endometriosis was associated with low overall adiposity and with a preponderance of adipose tissue distributed below the waist (peripheral). DISCUSSION: Endometriosis may be associated with being lean or having peripherally distributed adipose tissue. Well-designed studies with various sampling frameworks and precise measures of adiposity and endometriosis are needed to confirm associations between adiposity measures and endometriosis and delineate potential etiological mechanisms underlying endometriosis. PMID- 26938370 TI - Correction to "The Effectiveness and Tolerability of Central Nervous System Stimulants in School-Age Children with Attention-Deficit/Hyperactivity Disorder and Disruptive Mood Dysregulation Disorder across Home and School". PMID- 26938369 TI - Quantification of Short-Chain Chlorinated Paraffins by Deuterodechlorination Combined with Gas Chromatography-Mass Spectrometry. AB - Analysis of short-chain chlorinated paraffins (SCCPs) is extremely difficult because of their complex compositions with thousands of isomers and homologues. A novel analytical method, deuterodechlorination combined with high resolution gas chromatography-high resolution mass spectrometry (HRGC-HRMS), was developed. A protocol is applied in the deuterodechlorination of SCCPs with LiAlD4, and the formed deuterated n-alkanes of different alkane chains can be distinguished readily from each other on the basis of their retention time and fragment mass ([M](+)) by HRGC-HRMS. An internal standard quantification of individual SCCP congeners was achieved, in which branched C10-CPs and branched C12-CPs were used as the extraction and reaction internal standards, respectively. A maximum factor of 1.26 of the target SCCP concentrations were determined by this method, and the relative standard deviations for quantification of total SCCPs were within 10%. This method was applied to determine the congener compositions of SCCPs in commercial chlorinated paraffins and environmental and biota samples after method validation. Low-chlorinated SCCP congeners (Cl1-4) were found to account for 32.4%-62.4% of the total SCCPs. The present method provides an attractive perspective for further studies on the toxicological and environmental characteristics of SCCPs. PMID- 26938368 TI - Averaged Solvent Embedding Potential Parameters for Multiscale Modeling of Molecular Properties. AB - We derive and validate averaged solvent parameters for embedding potentials to be used in polarizable embedding quantum mechanics/molecular mechanics (QM/MM) molecular property calculations of solutes in organic solvents. The parameters are solvent-specific atom-centered partial charges and isotropic polarizabilities averaged over a large number of geometries of solvent molecules. The use of averaged parameters reduces the computational cost to obtain the embedding potential, which can otherwise be a rate-limiting step in calculations involving large environments. The parameters are evaluated by analyzing the quality of the resulting molecular electrostatic potentials with respect to full QM potentials. We show that a combination of geometry-specific parameters for solvent molecules close to the QM region and averaged parameters for solvent molecules further away allows for efficient polarizable embedding multiscale modeling without compromising the accuracy. The results are promising for the development of general embedding parameters for biomolecules, where the reduction in computational cost can be considerable. PMID- 26938371 TI - Vancomycin Functionalized Nanoparticles for Bactericidal Biomaterial Surfaces. AB - In this paper, we describe a simple and powerful way to synthesize antibacterial biomaterials with applications as implants in orthopedic surgery. Such implants are obtained by covalently grafting onto the Ti90A16 V4 alloy surface with vancomycin-functionalized nanoparticles. Nanoparticles were produced by ring opening metathesis polymerization of alpha-norbornenyl-omega-vancomycin poly(ethylene oxide) macromonomers. Vancomycin is an interesting candidate because of its use in the field of implant associated infection as it is a glycopeptide which acts on bacterial walls. As a consequence, vancomycin does not need to be released for it to be active. In the first part of this paper, the synthesis and the complete characterization of these materials are described. In a second part, the in vitro antibacterial behavior is analyzed and discussed. PMID- 26938375 TI - Letter to the Editor: Comments on "Sulfonylurea Treatment Before Genetic Testing in Neonatal Diabetes: Pros and Cons" by Carmody D, et al. PMID- 26938372 TI - Pertussis: acellular, whole-cell, new vaccines, what to choose? PMID- 26938376 TI - Response to the Letter to the Editor by Deeb A. PMID- 26938377 TI - Letter to the Editor: Getting to the True Values of Thyroglobulin and Anti Thyroglobulin Antibodies. PMID- 26938379 TI - Rallying call for more action in student bursary battle. PMID- 26938378 TI - Everything changes... and nothing changes. PMID- 26938380 TI - CBE for public health adviser. PMID- 26938382 TI - It is time to tackle staffing crisis, say nurse leaders. PMID- 26938381 TI - Call for 1,000 nursing support roles receives mixed response. PMID- 26938385 TI - Mencap finds little progress made since hospital scandal. PMID- 26938384 TI - New plan puts the spotlight on sepsis. PMID- 26938386 TI - Nurses praised for dedication during Cumbrian floods. PMID- 26938387 TI - Blood pressure lowering drugs 'should be offered to all at risk'. PMID- 26938388 TI - What NHS employers have to do to get you through their doors. PMID- 26938394 TI - Atrial fibrillation. PMID- 26938395 TI - Looking back with pride 1916-2016. PMID- 26938396 TI - A modern take on menopause. PMID- 26938397 TI - Helping remove the shadow of torture. PMID- 26938408 TI - Twelve Steps AA Companion--Alcoholics Anonymous app. PMID- 26938410 TI - This is a time for trailblazing not 'dumbing down' our profession. PMID- 26938411 TI - Work with us, not against us, and we can succeed together. PMID- 26938412 TI - Is education to blame for safeguarding failures? PMID- 26938413 TI - Only a major uprising by nurses can save the NHS. PMID- 26938414 TI - Correction. PMID- 26938418 TI - How to use a self-inflating bag and face mask. PMID- 26938419 TI - Role of environmental cleanliness and decontamination in care homes. AB - While it is widely accepted that the environment has an important role in transmission of healthcare-associated infections, there has been a paucity of empirical investigation in this area to date, and the majority of published literature relates to acute settings. People living in care homes come into contact with a communally used environment and communally used equipment daily. Equipment may include hoists, hoist slings, clinical monitoring equipment, commodes and shower chairs. In care homes, primary responsibility for decontamination lies with the healthcare team, most of whom are not nurses. The challenge for nurses working in care homes is their accountability for the provision of safe and effective care. PMID- 26938420 TI - Implementing culture change in long-term dementia care settings. AB - The approach to nursing in long-term care settings for people living with dementia continues to evolve from a traditional, task-oriented culture to one that is person-centred. Such change can be difficult to manage and may encounter considerable opposition; having an understanding of change management and leadership styles may help to make this transition easier. This article discusses the differences between task-oriented and person-centred care, theories of management, motivation and leadership styles, and focuses on those that are most appropriate for this type of change. An improved understanding of these theories will enable nurses to support others in the delivery of person-centred care. PMID- 26938421 TI - Improving self-management of type 1 and type 2 diabetes. AB - Diabetes is an increasingly common life-long condition, which has significant physical, psychological and behavioural implications for individuals. Self management of type 1 and type 2 diabetes can be complex and challenging. A collaborative approach to care, between healthcare professionals and patients, is essential to promote self-management skills and knowledge to help patients engage in shared decision making and manage any difficulties associated with a diagnosis of diabetes. PMID- 26938422 TI - Limb amputation. PMID- 26938423 TI - Getting back on track. PMID- 26938426 TI - Share skills by teaching. PMID- 26938424 TI - Say never to 'never events'. PMID- 26938427 TI - The Formation and Spatiotemporal Progress of the pH Wave Induced by the Temperature Gradient in the Thin-Layer H2O2-Na2S2O3-H2SO4-CuSO4 Dynamical System. AB - The H2O2-S2O3(2-)-H(+)-Cu(2+) dynamical system exhibits sustained oscillations under flow conditions but reveals only a single initial peak of the indicator electrode potential and pH variation under batch isothermal conditions. Thus, in the latter case, there is no possibility of the coupling of the oscillations and diffusion which could lead to formation of sustained spatiotemporal patterns in this process. However, in the inhomogeneous temperature field, due to dependence of the local reaction kinetics on temperature, spatial inhomogeneities of pH distribution can develop which, in the presence of an appropriate indicator, thymol blue, manifest themselves as the color front traveling along the quasi-one dimensional reactor. In this work, we describe the experimental conditions under which the above-mentioned phenomena can be observed and present their numerical model based on thermokinetic coupling and spatial coordinate introduced to earlier isothermal homogeneous kinetic mechanism. PMID- 26938429 TI - Reply to the comment: With regard to the implementation of the AGREE instrument in Atrial Fibrillation Clinical Guidelines. PMID- 26938428 TI - Matrix-Assisted Ionization on a Portable Mass Spectrometer: Analysis Directly from Biological and Synthetic Materials. AB - Matrix-assisted ionization (MAI)-mass spectrometry (MS) eliminates the need for high voltage, a heat source, lasers, and compressed gases in the ionization process and uses minimal solvents in sample preparation, thus making MAI ideal for field-portable mass spectrometers. The broad applicability of MAI is demonstrated by simple, rapid, and robust positive and negative detection mode analyses of low and high mass compounds including some pesticides, dyes, drugs, lipids, and proteins (186 Da to 8.5 kDa) from various materials including urine, biological tissue sections, paper, and plant material on a low pumping capacity, single-quadrupole mass spectrometer. Different sample introduction methods are applicable, including the use of a pipet tip or glass melting point tube, allowing integration of sample preparation with sample introduction for increased analytical utility and ease of operation, even when sampling directly from surfaces. PMID- 26938430 TI - It's the who not the when: An investigation of safety behavior fading in exposure to contamination. AB - The judicious use of safety behavior may enhance the acceptability of exposure. However, practical questions concerning safety behavior fading remain. The current study compared the efficacy and acceptability of participant- and experimenter-initiated fading of safety behavior during exposure. Undergraduate students (N=100) with subclinical contamination fear were assigned to complete an exposure session under one of three fading conditions: (1) participant-initiated (PI); (2) experimenter-initiated time (ET), in which the timing of safety behavior fading was yoked to the timing observed in PI; or (3) experimenter initiated distress (ED), in which fading was based on subjective distress ratings. Compared to ET, PI demonstrated greater reductions in obsessive beliefs and peak fear, comparable changes in anticipatory fear and behavioral approach, and marginally higher expectancy ratings. PI and ED did not differ in outcome or acceptability. Results are discussed in terms of self-efficacy theory and the potential utility of safety behavior in exposure. PMID- 26938431 TI - Association Studies Between XRCC1, XRCC2, XRCC3 Polymorphisms and Differentiated Thyroid Carcinoma. AB - BACKGROUND/AIMS: DNA HRR pathway and BER pathway play vital roles in differentiated thyroid cancer (DTC) development, thus we supposed that polymorphisms of XRCC1, XRCC2, XRCC3 DNA repair genes are associated with thyroid cancer risk and progression. METHODS: We searched the NCBI database for relevant literatures to determine eight SNPs to be included in our study (XRCC1: rs25487, rs25489, rs1799782; XRCC2: rs3218536; XRCC3: rs1799794, rs56377012, rs1799796, rs861539). RESULTS: SNP of rs25487 was linked with a 53% decrease in DTC risk (OR: 0.47; 95%CI: 0.268-0.82; P = 0.01). For SNP of rs1799782, the homozygous TT genotype indicated a statistically significant 2-fold increased risk of DTC (OR: 2.09; 95%CI: 1.27-3.43; P < 0.001) after multivariate adjustment. For SNP of rs861539, the homozygous TT genotype suggested statistically significant 3-fold increased risk of DTC (OR: 3.02; 95%CI: 1.68-5.42; P < 0.001). No significant association between the other five SNPs and DTC risk. Besides that, female was linked with 47% increase in DTC risk (OR: 1.47; 95%CI: 1.062-2.04; P = 0.02) after multivariate adjustment. Similar results for most of the SNPs were obtained from subgroup analysis by different histological types of DTC. Haplotype analysis revealed that AGC and GGT haplotypes of XRCC1 polymorphisms were associated with DTC. Moreover, results from gene-gene interaction showed that XRCC1-rs25487, XRCC1- rs1799782 and XRCC3- rs861539 variants jointly contributed to a specifically increased risk of DTC, with the combination variant of rs1799782-CT heterozygote and rs861539-TT homozygote exhibiting a higher 3.66-fold risk of DTC (OR: 3.66; 95% CI: 1.476-9.091, P = 0.005). CONCLUSION: Polymorphisms of XRCC1 (rs25487, rs1799782) and XRCC3 (rs861539), may play a critical role in DTC development and progression. Furthermore, XRCC1 variant can interact with XRCC3 variant to significantly increase DTC susceptibility. Identifying these genetic risk markers could provide evidence for exploring the insight pathogenesis and develop novel therapeutic strategies for DTC. PMID- 26938432 TI - Estrogen Accelerates Cutaneous Wound Healing by Promoting Proliferation of Epidermal Keratinocytes via Erk/Akt Signaling Pathway. AB - BACKGROUND: Previous studies have established that estrogen is capable of accelerating cutaneous wound healing through multiple mechanisms, one of which involves affecting keratinocytes biological properties, such as migration, proliferation, etc. This study aims to reveal the underlying molecular mechanisms of estrogen promoting epidermal keratinocytes proliferation. Method & RESULTS: We found that compared with female mice with a normal estrous cycle, female mice with their ovaries removed before puberty exhibited a delayed cutaneous wound healing, thinner epidermis, and significantly fewer proliferating cell nuclear antigen (PCNA)-positive keratinocytes. Moreover, a significant increase in HaCaT proliferation was detected by a CCK8 assay when treated with 17 beta-estradiol compared with those treated with control vehicle. Consistent with the results of the CCK8 assay, flow cytometry indicated a high proportion of 17 beta-estradiol treated HaCaT cells in S phase compared with vehicle-treated cells. Western blot analysis demonstrated the activation of Akt, Erk and upregulation of PCNA in HaCaT cells treated with 17 beta-estradiol. Interestingly, Erk activation occurred prior to Akt activation. Upregulation of PCNA expression, elevated proliferation and high S phase fraction of HaCaT cell by 17 beta-estradiol could be reversed by an Akt or Erk inhibitor. Moreover, Erk inhibition reversed 17 beta estradiol-induced Akt activation, whereas an Akt inhibitor exhibited no effect on Erk, further suggesting that Erk was on the upstream while Akt on the downstream of the signaling pathway. CONCLUSION: This study demonstrates that one of the critical mechanisms underlying 17 beta-estradiol promoting skin wound healing is through regulation of keratinocyte proliferation via Erk/Akt signaling pathway. PMID- 26938435 TI - Inside Out: Core Network of Transcription Factors Drives Axon Regeneration. AB - In this issue, Chandran et al. (2016) pursue a multi-level bioinformatics approach combined with wet bench validation to identify gene networks associated with the regenerative state of injured adult sensory neurons. A small molecular compound, ambroxol, mimics aspects of the identified gene expression patterns and promotes axon regeneration in the injured adult mouse CNS, demonstrating feasibility of in silico-based methods to identify compounds that promote neuronal growth following CNS injury. PMID- 26938434 TI - Evaluating the Phylogenetic Status of the Extinct Japanese Otter on the Basis of Mitochondrial Genome Analysis. AB - The Japanese otter lived throughout four main Japanese islands, but it has not been observed in the wild since 1979 and was declared extinct in 2012. Although recent taxonomic and molecular phylogenetic studies suggest that it should be treated as an independent species, International Union for Conservation of Nature Red List considers it as subspecies of Lutra lutra. Therefore, the taxonomic status of this species needs to be resolved. Here we determined the complete mitochondrial genome of two Japanese otters caught in Kanagawa and Kochi prefectures and five Eurasian otters (L. lutra). We reconstructed a molecular phylogenetic tree to estimate the phylogenetic position of the Japanese otter in Lutrinae using the Japanese otters and the other 11 Lutrinae species on the basis of ND5 (692 bp) and cytochrome b (1,140 bp) sequences. We observed that the two Japanese otters had close relationships with Eurasian otters, forming a monophyletic group (100% bootstrap probability). To elucidate detailed phylogenetic relationships among the Japanese and Eurasian otters, we reconstructed a maximum likelihood tree according to mitochondrial genome sequences (14,740 bp). The Japanese otter (JO1) collected in Kanagawa was deeply nested in the Eurasian otter clade, whereas the Japanese otter (JO2) collected in Kochi formed a distinct independent lineage in the Lutra clade. The estimated molecular divergences time for the ancestral lineages of the Japanese otters was 0.10 Ma (95%: 0.06-0.16 Ma) and 1.27 Ma (95%: 0.98-1.59 Ma) for JO1 and JO2 lineages, respectively. Thus, JO1 was identified as a member of L. lutra; JO2 represented the old Japanese otter lineage, which may be a distinct new species or subspecies of Lutra. We suggest that the ancestral population of the JO2 lineage migrated to Japan via the land bridge that existed between western Japanese islands and Asian continent at 1.27 Ma. PMID- 26938433 TI - Increased Grey Matter Associated with Long-Term Sahaja Yoga Meditation: A Voxel Based Morphometry Study. AB - OBJECTIVES: To investigate regional differences in grey matter volume associated with the practice of Sahaja Yoga Meditation. DESIGN: Twenty three experienced practitioners of Sahaja Yoga Meditation and twenty three non-meditators matched on age, gender and education level, were scanned using structural Magnetic Resonance Imaging and their grey matter volume were compared using Voxel-Based Morphometry. RESULTS: Grey matter volume was larger in meditators relative to non meditators across the whole brain. In addition, grey matter volume was larger in several predominantly right hemispheric regions: in insula, ventromedial orbitofrontal cortex, inferior temporal and parietal cortices as well as in left ventrolateral prefrontal cortex and left insula. No areas with larger grey matter volume were found in non-meditators relative to meditators. CONCLUSIONS: The study shows that long-term practice of Sahaja Yoga Meditation is associated with larger grey matter volume overall, and with regional enlargement in several right hemispheric cortical and subcortical brain regions that are associated with sustained attention, self-control, compassion and interoceptive perception. The increased grey matter volume in these attention and self-control mediating regions suggests use-dependent enlargement with regular practice of this meditation. PMID- 26938436 TI - Novel PAMs Targeting NMDAR GluN2A Subunit. AB - In this issue of Neuron, Hackos et al. (2016) report the discovery of novel positive allosteric modulators that are highly selective for GluN2A-containing NMDA receptors. This novel class of PAMs shows distinct effects on synaptic plasticity. PMID- 26938437 TI - Talk Louder So I Can See You. AB - How does one sense influence the processing of another? In this issue of Neuron, Ibrahim et al. (2016) demonstrate that presence of sound sharpens neural tuning in the primary visual cortex via activation of direct inputs from the primary auditory cortex. PMID- 26938438 TI - The Hyperpolarization-Activated Cation Current Ih: The Missing Link Connecting Cannabinoids to Cognition. AB - In this issue of Neuron, Maroso et al. (2016) describe a novel link between cannabinoids and cognition. They show that CB1Rs bidirectionally modulate HCN mediated Ih in a subset of CA1 pyramidal neurons to influence both short- and long-term circuit dynamics and alter spatial working memory in behaving mice. PMID- 26938439 TI - Paradise Lost: The Neurobiological and Clinical Consequences of Child Abuse and Neglect. AB - In the past two decades, much evidence has accumulated unequivocally demonstrating that child abuse and neglect is associated with a marked increase in risk for major psychiatric disorders (major depression, bipolar disorder, post traumatic stress disorder [PTSD], substance and alcohol abuse, and others) and medical disorders (cardiovascular disease, diabetes, irritable bowel syndrome, asthma, and others). Moreover, the course of psychiatric disorders in individuals exposed to childhood maltreatment is more severe. Recently, the biological substrates underlying this diathesis to medical and psychiatric morbidity have been studied. This Review summarizes many of the persistent biological alterations associated with childhood maltreatment including changes in neuroendocrine and neurotransmitter systems and pro-inflammatory cytokines in addition to specific alterations in brain areas associated with mood regulation. Finally, I discuss several candidate gene polymorphisms that interact with childhood maltreatment to modulate vulnerability to major depression and PTSD and epigenetic mechanisms thought to transduce environmental stressors into disease vulnerability. PMID- 26938440 TI - The Biology of Huntingtin. AB - Huntingtin (HTT) is now a famous protein because an abnormal expansion of a glutamine stretch (polyQ) in its N-terminal sequence leads to the devastating neurodegenerative disorder Huntington's disease (HD). The gene encoding huntingtin, HTT, and its dominantly inherited mutation were identified more than 20 years ago. Subsequently, in the hope of finding a cure for HD, there has been intense research aimed at understanding the molecular mechanisms underlying the deleterious effects of the presence of the abnormal polyQ expansion in HTT. Notwithstanding with the value of this approach, evidence has been emerging of a potential role of context and function of the HTT protein in the specificity and severity of the pathogenicity. HTT is ubiquitous both at the tissue and subcellular levels. It interacts with many partners and has long been considered having no clearly defined cellular function. Based on research over the past 20 years, specifically focused on the function of wild-type HTT, we reconsider the literature describing HTT-regulated molecular and cellular mechanisms that could be dysfunctional in HD and their possible physiological consequences for patients. PMID- 26938441 TI - De Novo Synonymous Mutations in Regulatory Elements Contribute to the Genetic Etiology of Autism and Schizophrenia. AB - We analyze de novo synonymous mutations identified in autism spectrum disorders (ASDs) and schizophrenia (SCZ) with potential impact on regulatory elements using data from whole-exome sequencing (WESs) studies. Focusing on five types of genetic regulatory functions, we found that de novo near-splice site synonymous mutations changing exonic splicing regulators and those within frontal cortex derived DNase I hypersensitivity sites are significantly enriched in ASD and SCZ, respectively. These results remained significant, albeit less so, after incorporating two additional ASD datasets. Among the genes identified, several are hit by multiple functional de novo mutations, with RAB2A and SETD1A showing the highest statistical significance in ASD and SCZ, respectively. The estimated contribution of these synonymous mutations to disease liability is comparable to de novo protein-truncating mutations. These findings expand the repertoire of functional de novo mutations to include "functional" synonymous ones and strengthen the role of rare variants in neuropsychiatric disease risk. PMID- 26938442 TI - PET Imaging of Tau Deposition in the Aging Human Brain. AB - Tau pathology is a hallmark of Alzheimer's disease (AD) but also occurs in normal cognitive aging. Using the tau PET agent (18)F-AV-1451, we examined retention patterns in cognitively normal older people in relation to young controls and AD patients. Age and beta-amyloid (measured using PiB PET) were differentially associated with tau tracer retention in healthy aging. Older age was related to increased tracer retention in regions of the medial temporal lobe, which predicted worse episodic memory performance. PET detection of tau in other isocortical regions required the presence of cortical beta-amyloid and was associated with decline in global cognition. Furthermore, patterns of tracer retention corresponded well with Braak staging of neurofibrillary tau pathology. The present study defined patterns of tau tracer retention in normal aging in relation to age, cognition, and beta-amyloid deposition. PMID- 26938443 TI - NMDA Receptor-Dependent LTD Requires Transient Synaptic Incorporation of Ca2+ Permeable AMPARs Mediated by AKAP150-Anchored PKA and Calcineurin. AB - Information processing in the brain requires multiple forms of synaptic plasticity that converge on regulation of NMDA and AMPA-type glutamate receptors (NMDAR, AMPAR), including long-term potentiation (LTP) and long-term depression (LTD) and homeostatic scaling. In some cases, LTP and homeostatic plasticity regulate synaptic AMPAR subunit composition to increase the contribution of Ca(2+)-permeable receptors (CP-AMPARs) containing GluA1 but lacking GluA2 subunits. Here, we show that PKA anchored to the scaffold protein AKAP150 regulates GluA1 phosphorylation and plays a novel role controlling CP-AMPAR synaptic incorporation during NMDAR-dependent LTD. Using knockin mice that are deficient in AKAP-anchoring of either PKA or the opposing phosphatase calcineurin, we found that CP-AMPARs are recruited to hippocampal synapses by anchored PKA during LTD induction but are then rapidly removed by anchored calcineurin. Importantly, blocking CP-AMPAR recruitment, removal, or activity interferes with LTD. Thus, CP-AMPAR synaptic recruitment is required to transiently augment NMDAR Ca(2+) signaling during LTD induction. PMID- 26938444 TI - Variability of Basal Rate Profiles in Insulin Pump Therapy and Association with Complications in Type 1 Diabetes Mellitus. AB - BACKGROUND: Traditionally, basal rate profiles in continuous subcutaneous insulin infusion therapy are individually adapted to cover expected insulin requirements. However, whether this approach is indeed superior to a more constant BR profile has not been assessed so far. This study analysed the associations between variability of BR profiles and acute and chronic complications in adult type 1 diabetes mellitus. MATERIALS AND METHODS: BR profiles of 3118 female and 2427 male patients from the "Diabetes-Patienten-Verlaufsdokumentation" registry from Germany and Austria were analysed. Acute and chronic complications were recorded 6 months prior and after the most recently documented basal rate. The "variability index" was calculated as variation of basal rate intervals in percent and describes the excursions of the basal rate intervals from the median basal rate. RESULTS: The variability Index correlated positively with severe hypoglycemia (r = .06; p<0.001), hypoglycemic coma (r = .05; p = 0.002), and microalbuminuria (r = 0.05; p = 0.006). In addition, a higher variability index was associated with higher frequency of diabetic ketoacidosis (r = .04; p = 0.029) in male adult patients. Logistic regression analysis adjusted for age, gender, duration of disease and total basal insulin confirmed significant correlations of the variability index with severe hypoglycemia (beta = 0.013; p<0.001) and diabetic ketoacidosis (beta = 0.012; p = 0.017). CONCLUSIONS: Basal rate profiles with higher variability are associated with an increased frequency of acute complications in adults with type 1 diabetes. PMID- 26938445 TI - The influence of wives' and husbands' fertility preferences on progression to a third birth in Nepal, 1997-2009. AB - As couples across the globe increasingly exercise conscious control over their reproduction, both spouses' family-size preferences have the opportunity to influence their fertility. Using couple-level measures of rural Nepalese spouses' family-size preferences and more than a decade of monthly panel data collected subsequently on fertility outcomes, we investigate how both spouses' preferences influence progression to a third birth in a country where the widely professed ideal family size is two children. Contrary to expectations based on women's relative disadvantage, we find that it is wives' preferences that drive couples' progression to a third birth. We find also that the influence of wives' preferences is not explained by contraceptive use but that this influence is moderated by couple communication about family planning. Wives' preferences drive progression to a third birth among couples who had discussed how many children to have. PMID- 26938446 TI - Schoolbook Texts: Behavioral Achievement Priming in Math and Language. AB - Prior research found reliable and considerably strong effects of semantic achievement primes on subsequent performance. In order to simulate a more natural priming condition to better understand the practical relevance of semantic achievement priming effects, running texts of schoolbook excerpts with and without achievement primes were used as priming stimuli. Additionally, we manipulated the achievement context; some subjects received no feedback about their achievement and others received feedback according to a social or individual reference norm. As expected, we found a reliable (albeit small) positive behavioral priming effect of semantic achievement primes on achievement in math (Experiment 1) and language tasks (Experiment 2). Feedback moderated the behavioral priming effect less consistently than we expected. The implication that achievement primes in schoolbooks can foster performance is discussed along with general theoretical implications. PMID- 26938447 TI - Uncertainty of Monetary Valued Ecosystem Services - Value Transfer Functions for Global Mapping. AB - Growing demand of resources increases pressure on ecosystem services (ES) and biodiversity. Monetary valuation of ES is frequently seen as a decision-support tool by providing explicit values for unconsidered, non-market goods and services. Here we present global value transfer functions by using a meta analytic framework for the synthesis of 194 case studies capturing 839 monetary values of ES. For 12 ES the variance of monetary values could be explained with a subset of 93 study- and site-specific variables by utilizing boosted regression trees. This provides the first global quantification of uncertainties and transferability of monetary valuations. Models explain from 18% (water provision) to 44% (food provision) of variance and provide statistically reliable extrapolations for 70% (water provision) to 91% (food provision) of the terrestrial earth surface. Although the application of different valuation methods is a source of uncertainty, we found evidence that assuming homogeneity of ecosystems is a major error in value transfer function models. Food provision is positively correlated with better life domains and variables indicating positive conditions for human well-being. Water provision and recreation service show that weak ownerships affect valuation of other common goods negatively (e.g. non-privately owned forests). Furthermore, we found support for the shifting baseline hypothesis in valuing climate regulation. Ecological conditions and societal vulnerability determine valuation of extreme event prevention. Valuation of habitat services is negatively correlated with indicators characterizing less favorable areas. Our analysis represents a stepping stone to establish a standardized integration of and reporting on uncertainties for reliable and valid benefit transfer as an important component for decision support. PMID- 26938449 TI - The practical and principled problems with educational neuroscience. AB - The core claim of educational neuroscience is that neuroscience can improve teaching in the classroom. Many strong claims are made about the successes and the promise of this new discipline. By contrast, I show that there are no current examples of neuroscience motivating new and effective teaching methods, and argue that neuroscience is unlikely to improve teaching in the future. The reasons are twofold. First, in practice, it is easier to characterize the cognitive capacities of children on the basis of behavioral measures than on the basis of brain measures. As a consequence, neuroscience rarely offers insights into instruction above and beyond psychology. Second, in principle, the theoretical motivations underpinning educational neuroscience are misguided, and this makes it difficult to design or assess new teaching methods on the basis of neuroscience. Regarding the design of instruction, it is widely assumed that remedial instruction should target the underlying deficits associated with learning disorders, and neuroscience is used to characterize the deficit. However, the most effective forms of instruction may often rely on developing compensatory (nonimpaired) skills. Neuroscience cannot determine whether instruction should target impaired or nonimpaired skills. More importantly, regarding the assessment of instruction, the only relevant issue is whether the child learns, as reflected in behavior. Evidence that the brain changed in response to instruction is irrelevant. At the same time, an important goal for neuroscience is to characterize how the brain changes in response to learning, and this includes learning in the classroom. Neuroscientists cannot help educators, but educators can help neuroscientists. (PsycINFO Database Record PMID- 26938448 TI - Treatment of Cutaneous Leishmaniasis Caused by Leishmania aethiopica: A Systematic Review. AB - Leishmania aethiopica is the etiological agent of cutaneous leishmaniasis (CL) in Ethiopia and can cause severe and complicated cases such as diffuse CL (DCL), mucocutaneous leishmaniasis or extensive CL, requiring systemic treatment. Despite the substantial burden, evidence-based treatment guidelines are lacking. We conducted a systematic review of clinical studies reporting on treatment outcomes of CL due to L aethiopica in order to help identify potentially efficacious medications on CL that can be taken forward for clinical trials. We identified a total of 24 records reporting on 506 treatment episodes of CL presumably due to L aethiopica. The most commonly used drugs were antimonials (n = 201), pentamidine (n = 150) and cryotherapy (n = 103). There were 20 case reports/series, with an overall poor study quality. We only identified two small and/or poor quality randomized controlled trials conducted a long time ago. There were two prospective non-randomized studies reporting on cryotherapy, antimonials and pentamidine. With cryotherapy, cure rates were 60-80%, and 69-85% with antimonials. Pentamidine appeared effective against complicated CL, also in cases non-responsive to antimonials. However, all studies suffered from methodological limitations. Data on miltefosine, paromomycin and liposomal amphotericin B are extremely scarce. Only a few studies are available on DCL. The only potentially effective treatment options for DCL seem to be antimonials with paromomycin in combination or pentamidine, but none have been properly evaluated. In conclusion, the evidence-base for treatment of complicated CL due to L aethiopica is extremely limited. While antimonials remain the most available CL treatment in Ethiopia, their efficacy and safety in CL should be better defined. Most importantly, alternative first line treatments (such as miltefosine or paromomycin) should be explored. High quality trials on CL due to L aethiopica are urgently needed, exploring group sequential methods to evaluate several options in parallel. PMID- 26938450 TI - Corneal Transplantation in Disease Affecting Only One Eye: Does It Make a Difference to Habitual Binocular Viewing? AB - BACKGROUND: Clarity of the transplanted tissue and restoration of visual acuity are the two primary metrics for evaluating the success of corneal transplantation. Participation of the transplanted eye in habitual binocular viewing is seldom evaluated post-operatively. In unilateral corneal disease, the transplanted eye may remain functionally inactive during binocular viewing due to its suboptimal visual acuity and poor image quality, vis-a-vis the healthy fellow eye. METHODS AND FINDINGS: This study prospectively quantified the contribution of the transplanted eye towards habitual binocular viewing in 25 cases with unilateral transplants [40 yrs (IQR: 32-42 yrs) and 25 age-matched controls [30 yrs (25-37 yrs)]. Binocular functions including visual field extent, high contrast logMAR acuity, suppression threshold and stereoacuity were assessed using standard psychophysical paradigms. Optical quality of all eyes was determined from wavefront aberrometry measurements. Binocular visual field expanded by a median 21% (IQR: 18-29%) compared to the monocular field of cases and controls (p = 0.63). Binocular logMAR acuity [0.0 (0.0-0.0)] almost always followed the fellow eye's acuity [0.00 (0.00 --0.02)] (r = 0.82), independent of the transplanted eye's acuity [0.34 (0.2-0.5)] (r = 0.04). Suppression threshold and stereoacuity were poorer in cases [30.1% (13.5-44.3%); 620.8 arc sec (370.3 988.2 arc sec)] than in controls [79% (63.5-100%); 16.3 arc sec (10.6-25.5 arc sec)] (p<0.001). Higher-order wavefront aberrations of the transplanted eye [0.34 MU (0.21-0.51 MU)] were higher than the fellow eye [0.07 MU (0.05-0.11 MU)] (p<0.001) and their reduction with RGP contact lenses [0.09 MU (0.08-0.12 MU)] significantly improved the suppression threshold [65% (50-72%)] and stereoacuity [56.6 arc sec (47.7-181.6 arc sec)] (p<0.001). CONCLUSIONS: In unilateral corneal disease, the transplanted eye does participate in gross binocular viewing but offers limited support to fine levels of binocularity. Improvement in the transplanted eye's optics enhances its participation in binocular viewing. Current metrics of this treatment success can expand to include measures of binocularity to assess the functional benefit of the transplantation process in unilateral corneal disease. PMID- 26938451 TI - Beg, Borrow and Steal: Three Aspects of Horizontal Gene Transfer in the Protozoan Parasite, Cryptosporidium parvum. PMID- 26938452 TI - Plasma Glutamine Concentrations in Liver Failure. AB - BACKGROUND: Higher than normal plasma glutamine concentration at admission to an intensive care unit is associated with an unfavorable outcome. Very high plasma glutamine levels are sometimes seen in both acute and chronic liver failure. We aimed to systematically explore the relation between different types of liver failure and plasma glutamine concentrations. METHODS: Four different groups of patients were studies; chronic liver failure (n = 40), acute on chronic liver failure (n = 20), acute fulminant liver failure (n = 20), and post-hepatectomy liver failure (n = 20). Child-Pugh and Model for End-stage Liver Disease (MELD) scores were assessed as indices of liver function. All groups except the chronic liver failure group were followed longitudinally during hospitalisation. Outcomes were recorded up to 48 months after study inclusion. RESULTS: All groups had individuals with very high plasma glutamine concentrations. In the total group of patients (n = 100), severity of liver failure correlated significantly with plasma glutamine concentration, but the correlation was not strong. CONCLUSION: Liver failure, regardless of severity and course of illness, may be associated with a high plasma glutamine concentration. Further studies are needed to understand whether high glutamine levels should be regarded as a biomarker or as a contributor to symptomatology in liver failure. PMID- 26938453 TI - Identification of a Highly Conserved Epitope on Avian Influenza Virus Non Structural Protein 1 Using a Peptide Microarray. AB - Avian influenza virus (AIV) non-structural protein 1 (NS1) is a multifunctional protein. It is present at high levels in infected cells and can be used for AIV detection and diagnosis. In this study, we generated monoclonal antibody (MAb) D7 against AIV NS1 protein by immunization of BALB/c mice with purified recombinant NS1 protein expressed in Escherichia coli. Isotype determination revealed that the MAb was IgG1/kappa-type subclass. To identify the epitope of the MAb D7, the NS1 protein was truncated into a total of 225 15-mer peptides with 14 amino acid overlaps, which were spotted for a peptide microarray. The results revealed that the MAb D7 recognized the consensus DAPF motif. Furthermore, the AIV NS1 protein with the DAPF motif deletion was transiently expressed in 293T cells and failed to react with MAb D7. Subsequently, the DAPF motif was synthesized with an elongated GSGS linker at both the C- and N-termini. The MAb D7 reacted with the synthesized peptide both in enzyme-linked immunosorbent assay (ELISA) and dot blot assays. From these results, we concluded that DAPF motif is the epitope of MAb D7. To our knowledge, this is the first report of a 4-mer epitope on the NS1 protein of AIV that can be recognized by MAb using a peptide microarray, which is able to simplify epitope identification, and that could serve as the basis for immune responses against avian influenza. PMID- 26938454 TI - Light Levels Affect Carbon Utilisation in Tropical Seagrass under Ocean Acidification. AB - Under future ocean acidification (OA), increased availability of dissolved inorganic carbon (DIC) in seawater may enhance seagrass productivity. However, the ability to utilise additional DIC could be regulated by light availability, often reduced through land runoff. To test this, two tropical seagrass species, Cymodocea serrulata and Halodule uninervis were exposed to two DIC concentrations (447 MUatm and 1077 MUatm pCO2), and three light treatments (35, 100, 380 MUmol m(-2) s(-1)) for two weeks. DIC uptake mechanisms were separately examined by measuring net photosynthetic rates while subjecting C. serrulata and H. uninervis to changes in light and addition of bicarbonate (HCO3-) use inhibitors (carbonic anhydrase inhibitor, acetazolamide) and TRIS buffer (pH 8.0). We observed a strong dependence on energy driven H+-HCO3- co-transport (TRIS, which disrupts H+ extrusion) in C. serrulata under all light levels, indicating greater CO2 dependence in low light. This was confirmed when, after two weeks exposure, DIC enrichment stimulated maximum photosynthetic rates (Pmax) and efficiency (alpha) more in C. serrulata grown under lower light levels (36-60% increase) than for those in high light (4% increase). However, C. serrulata growth increased with both DIC enrichment and light levels. Growth, NPP and photosynthetic responses in H. uninervis increased with higher light treatments and were independent of DIC availability. Furthermore, H. uninervis was found to be more flexible in HCO3- uptake pathways. Here, light availability influenced productivity responses to DIC enrichment, via both carbon fixation and acquisition processes, highlighting the role of water quality in future responses to OA. PMID- 26938455 TI - The Effects of 405-nm Visible Light on the Survival of Campylobacter on Chicken Skin and Stainless Steel. AB - Campylobacter spp. are foodborne pathogens responsible for a significant portion of human cases of bacterial-mediated gastrointestinal disease. A primary method for the introduction of Campylobacter into the food supply is through poultry products. Reducing the number of Campylobacter on poultry products may reduce the incidence of human disease. Research has been conducted on the use of light to inactivate Campylobacter on poultry products and processing environments. More recently, the use of high intensity visible 405-nm light has been proposed for the elimination of pathogenic bacteria. This study investigated the ability of 405-nm light to reduce Campylobacter jejuni and Campylobacter coli in poultry products. Campylobacter in chicken exudate were placed onto chicken skin or food grade stainless steel before treatment with 405-nm light. A range of 405-nm light doses were applied to cocktails of six C. jejuni or six C. coli strains in exudate at 10 degrees C to minimize thermal effects. Little difference was observed between inactivation of C. jejuni and C. coli on poultry skin with only minor average reductions of 1.7 logs and 2.1 logs, respectively, at the maximal dose of 184-186 J/cm(2). More noticeable differences were observed when the samples were placed on stainless steel and treated with a dose of 89 J/cm(2), producing an average reduction of 3.0 logs for C. coli but only 1.1 logs for C. jejuni. The maximal dose (181-183 J/cm(2)) applied to Campylobacter on stainless steel produced significant (p <= 0.05) reductions for C. jejuni and C. coli of 4.9 logs and 5.1 logs, respectively. However, significant 405-nm-mediated reductions in Campylobacter numbers required exposure times to achieve necessary dose levels that might be impractical under processing conditions. In addition, the most potent exposure times likely produced secondary thermal effects by raising sample surface temperatures above 48 degrees C. PMID- 26938456 TI - Back Pain Prevalence and Its Associated Factors in Brazilian Athletes from Public High Schools: A Cross-Sectional Study. AB - Most studies on the prevalence of back pain have evaluated it in developed countries (Human Development Index--HDI > 0.808), and their conclusions may not hold for developing countries. The aim of this study was to identify the prevalence of back pain in representative Brazilian athletes from public high schools. This cross-sectional study was performed during the state phase of the 2015 Jogos dos Institutos Federais (JIF), or Federal Institutes Games, in Brazil (HDI = 0.744), and it enrolled 251 athletes, 173 males and 78 females (14-20 years old). The dependent variable was back pain, and the independent variables were demographic, socioeconomic, psychosocial, hereditary, exercise-level, anthropometric, strength, behavioral, and postural factors. The prevalence ratio (PR) was calculated using multivariable analysis according to the Poisson regression model (alpha = 0.05). The prevalence of back pain in the three months prior to the study was 43.7% (n = 104), and 26% of the athletes reported feeling back pain only once. Multivariable analysis showed that back pain was associated with demographic (sex), psychosocial (loneliness and loss of sleep in the previous year), hereditary (ethnicity, parental back pain), strength (lumbar and hand forces), anthropometric (body mass index), behavioral (sleeping time per night, reading and studying in bed, smoking habits in the previous month), and postural (sitting posture while writing, while on a bench, and while using a computer) variables. Participants who recorded higher levels of lumbar and manual forces reported a lower prevalence of back pain (PR < 0.79), whereas feeling lonely in the previous year, obesity, and ethnicity exhibited the highest prevalence ratio (PR > 1.30). In conclusion, there is no association between exercise levels and back pain but there is an association between back pain and non-exercise related variables. PMID- 26938457 TI - Within and Among Patch Variability in Patterns of Insect Herbivory Across a Fragmented Forest Landscape. AB - Fragmentation changes the spatial patterns of landscapes in ways that can alter the flow of materials and species; however, our understanding of the consequences of this fragmentation and flow alteration for ecosystem processes and ecosystem services remains limited. As an ecological process that affects many ecosystem services and is sensitive to fragmentation, insect herbivory is a good model system for exploring the role of fragmentation, and the resulting spatial patterns of landscapes, in the provision of ecosystem services. To refine our knowledge of how changes in landscape pattern affect insect herbivory, we quantified the combined influence of among patch (patch area and patch connectivity) and within patch (location within patch; canopy, edge, interior) factors on amounts of insect herbivory in a fragmented forest landscape. We measured herbivory in 20 forest patches of differing size and connectivity in southern Quebec (Canada). Within each patch, herbivory was quantified at the interior, edge, and canopy of sugar maple trees during the spring and summer of 2011 and 2012. Results show that connectivity affects herbivory differently depending on the location within the patch (edge, interior, canopy), an effect that would have gone unnoticed if samples were pooled across locations. These results suggest considering structure at both the patch and within patch scales may help to elucidate patterns when studying the effects of fragmentation on ecosystem processes, with implications for the services they support. PMID- 26938458 TI - Bending Two-Dimensional Materials To Control Charge Localization and Fermi-Level Shift. AB - High-performance electronics requires the fine control of semiconductor conductivity. In atomically thin two-dimensional (2D) materials, traditional doping technique for controlling carrier concentration and carrier type may cause crystal damage and significant mobility reduction. Contact engineering for tuning carrier injection and extraction and carrier type may suffer from strong Fermi level pinning. Here, using first-principles calculations, we predict that mechanical bending, as a unique attribute of thin 2D materials, can be used to control conductivity and Fermi-level shift. We find that bending can control the charge localization of top valence bands in both MoS2 and phosphorene nanoribbons. The donor-like in-gap edge-states of armchair MoS2 ribbon and their associated Fermi-level pinning can be removed by bending. A bending-controllable new in-gap state and accompanying direct-indirect gap transition are predicted in armchair phosphorene nanoribbon. We demonstrate that such emergent bending effects are realizable. The bending stiffness as well as the effective thickness of 2D materials are also derived from first principles. Our results are of fundamental and technological relevance and open new routes for designing functional 2D materials for applications in which flexuosity is essential. PMID- 26938459 TI - High Prevalence and Putative Lineage Maintenance of Avian Coronaviruses in Scandinavian Waterfowl. AB - Coronaviruses (CoVs) are found in a wide variety of wild and domestic animals, and constitute a risk for zoonotic and emerging infectious disease. In poultry, the genetic diversity, evolution, distribution and taxonomy of some coronaviruses have been well described, but little is known about the features of CoVs in wild birds. In this study we screened 764 samples from 22 avian species of the orders Anseriformes and Charadriiformes in Sweden collected in 2006/2007 for CoV, with an overall CoV prevalence of 18.7%, which is higher than many other wild bird surveys. The highest prevalence was found in the diving ducks--mainly Greater Scaup (Aythya marila; 51.5%)--and the dabbling duck Mallard (Anas platyrhynchos; 19.2%). Sequences from two of the Greater Scaup CoV fell into an infrequently detected lineage, shared only with a Tufted Duck (Aythya fuligula) CoV. Coronavirus sequences from Mallards in this study were highly similar to CoV sequences from the sample species and location in 2011, suggesting long-term maintenance in this population. A single Black-headed Gull represented the only positive sample from the order Charadriiformes. Globally, Anas species represent the largest fraction of avian CoV sequences, and there seems to be no host species, geographical or temporal structure. To better understand the eitiology, epidemiology and ecology of these viruses more systematic surveillance of wild birds and subsequent sequencing of detected CoV is imperative. PMID- 26938460 TI - Extracting Behaviorally Relevant Traits from Natural Stimuli: Benefits of Combinatorial Representations at the Accessory Olfactory Bulb. AB - For many animals, chemosensation is essential for guiding social behavior. However, because multiple factors can modulate levels of individual chemical cues, deriving information about other individuals via natural chemical stimuli involves considerable challenges. How social information is extracted despite these sources of variability is poorly understood. The vomeronasal system provides an excellent opportunity to study this topic due to its role in detecting socially relevant traits. Here, we focus on two such traits: a female mouse's strain and reproductive state. In particular, we measure stimulus-induced neuronal activity in the accessory olfactory bulb (AOB) in response to various dilutions of urine, vaginal secretions, and saliva, from estrus and non-estrus female mice from two different strains. We first show that all tested secretions provide information about a female's receptivity and genotype. Next, we investigate how these traits can be decoded from neuronal activity despite multiple sources of variability. We show that individual neurons are limited in their capacity to allow trait classification across multiple sources of variability. However, simple linear classifiers sampling neuronal activity from small neuronal ensembles can provide a substantial improvement over that attained with individual units. Furthermore, we show that some traits are more efficiently detected than others, and that particular secretions may be optimized for conveying information about specific traits. Across all tested stimulus sources, discrimination between strains is more accurate than discrimination of receptivity, and detection of receptivity is more accurate with vaginal secretions than with urine. Our findings highlight the challenges of chemosensory processing of natural stimuli, and suggest that downstream readout stages decode multiple behaviorally relevant traits by sampling information from distinct but overlapping populations of AOB neurons. PMID- 26938462 TI - Acute Respiratory Events in Connective Tissue Disorders. AB - Subacute-acute, hyperacute, or even catastrophic and fulminant respiratory events occur in almost all classic connective tissue disorders (CTDs); they may share systemic life-threatening manifestations, may precipitously lead to respiratory failure requiring ventilatory support as well as a combination of specific therapeutic measures, and in most affected patients constitute the devastating end-of-life event. In CTDs, acute respiratory events may be related to any respiratory compartment including the airways, lung parenchyma, alveolar capillaries, lung vessels, pleura, and ventilatory muscles. Acute respiratory events may also precipitate disease-specific extrapulmonary organ involvement such as aspiration pneumonia and lead to digestive tract involvement and heart related respiratory events. Finally, antirheumatic drug-related acute respiratory toxicity as well as lung infections related to the rheumatic disease and/or to immunosuppression complete the spectrum of acute respiratory events. Overall, in CTDs the lungs significantly contribute to morbidity and mortality, since they constitute a common site of disease involvement; a major site of infections related to the 'mater' disease; a major site of drug-related toxicity, and a common site of treatment-related infectious complications. The extreme spectrum of the abovementioned events, as well as the 'vicious' coexistence of most of the aforementioned manifestations, requires skills, specific diagnostic and therapeutic means, and most of all a multidisciplinary approach of adequately prepared and expert scientists. Avoiding lung disease might represent a major concern for future advancements in the treatment of autoimmune disorders. PMID- 26938461 TI - Role of Aromatic Interactions in Temperature-Sensitive Amphiphilic Supramolecular Assemblies. AB - Aromatic interactions were found to greatly influence the temperature-dependent dynamic behavior within supramolecular assemblies. Using an amphiphilic dendron, we systematically changed the hydrophobic groups introducing increasing levels of aromaticity while keeping the hydrophilic part constant. We show that the supramolecular assemblies become less sensitive to temperature changes when aromatic interactions in the aggregate are increased. Conversely, the absence of aromaticity in the hydrophobic moieties produces temperature-sensitive aggregates. These results show that subtle molecular-level interactions can be utilized to control temperature-sensitive behavior in the nanoscale. These findings open up new design strategies to rationally tune the behavior of stimuli responsive supramolecular assemblies on multiple spatiotemporal scales. PMID- 26938469 TI - Collagen Fingerprinting: A New Screening Technique for Radiocarbon Dating Ancient Bone. AB - Collagen is the dominant organic component of bone and is intimately locked within the hydroxyapatite structure of this ubiquitous biomaterial that dominates archaeological and palaeontological assemblages. Radiocarbon analysis of extracted collagen is one of the most common approaches to dating bone from late Pleistocene or Holocene deposits, but dating is relatively expensive compared to other biochemical techniques. Numerous analytical methods have previously been investigated for the purpose of screening out samples that are unlikely to yield reliable dates including histological analysis, UV-stimulated fluorescence and, most commonly, the measurement of percentage nitrogen (%N) and ratio of carbon to nitrogen (C:N). Here we propose the use of collagen fingerprinting (also known as Zooarchaeology by Mass Spectrometry, or ZooMS, when applied to species identification) as an alternative screening method for radiocarbon dating, due to its ability to provide information on collagen presence and quality, alongside species identification. The method was tested on a series of sub-fossil bone specimens from cave systems on Cayman Brac (Cayman Islands), chosen due to the observable range in diagenetic alteration, and in particular, the extent of mineralisation. Six (14)C dates, of 18 initial attempts, were obtained from remains of extinct hutia, Capromys sp. (Rodentia; Capromyidae), recovered from five distinct caves on Cayman Brac, and ranging from 393 +/- 25 to 1588 +/- 26 radiocarbon years before present (yr BP). All of the bone samples that yielded radiocarbon dates generated excellent collagen fingerprints, and conversely those that gave poor fingerprints also failed dating. Additionally, two successfully fingerprinted bone samples were screened out from a set of 81. Both subsequently generated (14)C dates, demonstrating successful utilisation of ZooMS as an alternative screening mechanism to identify bone samples that are suitable for 1(4)C analysis. PMID- 26938468 TI - Wireless Cortical Brain-Machine Interface for Whole-Body Navigation in Primates. AB - Several groups have developed brain-machine-interfaces (BMIs) that allow primates to use cortical activity to control artificial limbs. Yet, it remains unknown whether cortical ensembles could represent the kinematics of whole-body navigation and be used to operate a BMI that moves a wheelchair continuously in space. Here we show that rhesus monkeys can learn to navigate a robotic wheelchair, using their cortical activity as the main control signal. Two monkeys were chronically implanted with multichannel microelectrode arrays that allowed wireless recordings from ensembles of premotor and sensorimotor cortical neurons. Initially, while monkeys remained seated in the robotic wheelchair, passive navigation was employed to train a linear decoder to extract 2D wheelchair kinematics from cortical activity. Next, monkeys employed the wireless BMI to translate their cortical activity into the robotic wheelchair's translational and rotational velocities. Over time, monkeys improved their ability to navigate the wheelchair toward the location of a grape reward. The navigation was enacted by populations of cortical neurons tuned to whole-body displacement. During practice with the apparatus, we also noticed the presence of a cortical representation of the distance to reward location. These results demonstrate that intracranial BMIs could restore whole-body mobility to severely paralyzed patients in the future. PMID- 26938470 TI - Molecular Characterization of the Cercosporin Biosynthetic Pathway in the Fungal Plant Pathogen Cercospora nicotianae. AB - Perylenequinones are a class of photoactivated polyketide mycotoxins produced by fungal plant pathogens that notably produce reactive oxygen species with visible light. The best-studied perylenequinone is cercosporin-a product of the Cercospora species. While the cercosporin biosynthetic gene cluster has been described in the tobacco pathogen Cercospora nicotianae, little is known of the metabolite's biosynthesis. Furthermore, in vitro investigations of the polyketide synthase central to cercosporin biosynthesis identified the naphthopyrone nor toralactone as its direct product-an observation in conflict with published biosynthetic proposals. Here, we present an alternative biosynthetic pathway to cercosporin based on metabolites characterized from a series of biosynthetic gene knockouts. We show that nor-toralactone is the key polyketide intermediate and the substrate for the unusual didomain protein CTB3. We demonstrate the unique oxidative cleavage activity of the CTB3 monooxygenase domain in vitro. These data advance our understanding of perylenequinone biosynthesis and expand the biochemical repertoire of flavin-dependent monooxygenases. PMID- 26938473 TI - Small Addition of Boron in Palladium Catalyst, Big Improvement in Fuel Cell's Performance: What May Interfacial Spectroelectrochemistry Tell? AB - Direct formic acid fuel cell (DFAFC) with Pd-based catalyst anode is a promising energy converter to power portable devices. However, its commercialization is entangled with insufficient activity and poor stability of existing anode catalysts. Here we initially report that a DFAFC using facilely synthesized Pd B/C with ca. 6 at. % B doping as the anode catalyst yields a maximum output power density of 316 mW cm(-2) at 30 degrees C, twice that with a same DFAFC using otherwise the state-of-the-art Pd/C. More strikingly, at a constant voltage of 0.3 V, the output power of the former cell is ca. 9 times as high as that of the latter after 4.5 h of continuous operation. In situ attenuated total reflection infrared spectroscopy is applied to probe comparatively the interfacial behaviors at Pd-B/C and Pd/C in conditions mimicking those for the DFAFC anode operation, revealing that the significantly improved cell performance correlates well with a substantially lowered CO accumulation at B-doped Pd surfaces. PMID- 26938472 TI - An unusual case of primary cutaneous Ewing sarcoma in an adult. PMID- 26938471 TI - Sensitive and Specific Biomimetic Lipid Coated Microfluidics to Isolate Viable Circulating Tumor Cells and Microemboli for Cancer Detection. AB - Here we presented a simple and effective membrane mimetic microfluidic device with antibody conjugated supported lipid bilayer (SLB) "smart coating" to capture viable circulating tumor cells (CTCs) and circulating tumor microemboli (CTM) directly from whole blood of all stage clinical cancer patients. The non covalently bound SLB was able to promote dynamic clustering of lipid-tethered antibodies to CTC antigens and minimized non-specific blood cells retention through its non-fouling nature. A gentle flow further flushed away loosely-bound blood cells to achieve high purity of CTCs, and a stream of air foam injected disintegrate the SLB assemblies to release intact and viable CTCs from the chip. Human blood spiked cancer cell line test showed the ~95% overall efficiency to recover both CTCs and CTMs. Live/dead assay showed that at least 86% of recovered cells maintain viability. By using 2 mL of peripheral blood, the CTCs and CTMs counts of 63 healthy and colorectal cancer donors were positively correlated with the cancer progression. In summary, a simple and effective strategy utilizing biomimetic principle was developed to retrieve viable CTCs for enumeration, molecular analysis, as well as ex vivo culture over weeks. Due to the high sensitivity and specificity, it is the first time to show the high detection rates and quantity of CTCs in non-metastatic cancer patients. This work offers the values in both early cancer detection and prognosis of CTC and provides an accurate non-invasive strategy for routine clinical investigation on CTCs. PMID- 26938474 TI - Structurally Diverse Mitochondrial Branched Chain Aminotransferase (BCATm) Leads with Varying Binding Modes Identified by Fragment Screening. AB - Inhibitors of mitochondrial branched chain aminotransferase (BCATm), identified using fragment screening, are described. This was carried out using a combination of STD-NMR, thermal melt (Tm), and biochemical assays to identify compounds that bound to BCATm, which were subsequently progressed to X-ray crystallography, where a number of exemplars showed significant diversity in their binding modes. The hits identified were supplemented by searching and screening of additional analogues, which enabled the gathering of further X-ray data where the original hits had not produced liganded structures. The fragment hits were optimized using structure-based design, with some transfer of information between series, which enabled the identification of ligand efficient lead molecules with micromolar levels of inhibition, cellular activity, and good solubility. PMID- 26938476 TI - Enhanced Optoelectronic Performance of a Passivated Nanowire-Based Device: Key Information from Real-Space Imaging Using 4D Electron Microscopy. AB - Managing trap states and understanding their role in ultrafast charge-carrier dynamics, particularly at surface and interfaces, remains a major bottleneck preventing further advancements and commercial exploitation of nanowire (NW) based devices. A key challenge is to selectively map such ultrafast dynamical processes on the surfaces of NWs, a capability so far out of reach of time resolved laser techniques. Selective mapping of surface dynamics in real space and time can only be achieved by applying four-dimensional scanning ultrafast electron microscopy (4D S-UEM). Charge carrier dynamics are spatially and temporally visualized on the surface of InGaN NW arrays before and after surface passivation with octadecylthiol (ODT). The time-resolved secondary electron images clearly demonstrate that carrier recombination on the NW surface is significantly slowed down after ODT treatment. This observation is fully supported by enhancement of the performance of the light emitting device. Direct observation of surface dynamics provides a profound understanding of the photophysical mechanisms on materials' surfaces and enables the formulation of effective surface trap state management strategies for the next generation of high-performance NW-based optoelectronic devices. PMID- 26938478 TI - Feasibility and Usability Pilot Study of a Novel Irritable Bowel Syndrome Food and Gastrointestinal Symptom Journal Smartphone App. AB - OBJECTIVES: Seventy percent of patients with irritable bowel syndrome (IBS) identify certain foods as triggers for their symptom flare-ups. To help identify potential trigger foods, practitioners often rely on patient food and gastrointestinal (GI) symptom journaling. The aim of the study was to evaluate the feasibility and usability of a novel food and symptom journal app, specifically designed for patients with IBS. Secondary aims were to explore the effect of using the app on GI symptoms and to describe associations between diet and GI symptoms suggested by individual patient data. METHODS: The feasibility and usability of the novel app was studied in 11 IBS patients (8 women), aged 21 65 years. Participants were asked to log GI symptoms (abdominal pain, bloating, diarrhea, constipation) using a 100-point color-graded sliding scale (green=none, red=severe) four times a day and to log every meal/snack they ate (at least three times a day) over a 2-week period. The app's feasibility as a data collection tool was evaluated by daily completion, compliance, data hoarding, and fatigability rates. Usability was evaluated with the System Usability Scale (SUS). To explore potential impact of using the app on bowel distress, we compared before and after intervention IBS-Symptom Severity Scale (IBS-SSS) scores. Meal entries were analyzed for nutrients using the Nutrition Data System for Research. Regression analyses were conducted for each participant journal to explore relationships between meal nutrients and subsequent GI symptoms. RESULTS: Daily average completion rates of the minimum requested entries for meal and GI symptoms were 112+/-47% and 78+/-44%, respectively. Average 24-h compliance rates were 90+/-19% and 94+/-12%, respectively. The SUS score was above average (mean 83, range 65-97.5; n=10). Most participants did not have a clinically significant decrease in IBS-SSS. At least one strong association (P<=0.05) between GI symptoms and a meal nutrient was found in 73% of participants. The mean number of associations was 2 (range 0-7; n=11). Patterns of associations differed between individual participants. CONCLUSIONS: Our app appeared to be a feasible and usable tool for IBS patients. Our findings are in line with anecdotes that most IBS patients have food triggers and that these vary by individual. Future studies can explore whether individualized dietary changes guided by an app can result in IBS symptom improvement. PMID- 26938477 TI - Missed, Not Missing: Phylogenomic Evidence for the Existence of Avian FoxP3. AB - The Forkhead box transcription factor FoxP3 is pivotal to the development and function of regulatory T cells (Tregs), which make a major contribution to peripheral tolerance. FoxP3 is believed to perform a regulatory role in all the vertebrate species in which it has been detected. The prevailing view is that FoxP3 is absent in birds and that avian Tregs rely on alternative developmental and suppressive pathways. Prompted by the automated annotation of foxp3 in the ground tit (Parus humilis) genome, we have questioned this assumption. Our analysis of all available avian genomes has revealed that the foxp3 locus is missing, incomplete or of poor quality in the relevant genomic assemblies for nearly all avian species. Nevertheless, in two species, the peregrine falcon (Falco peregrinus) and the saker falcon (F. cherrug), there is compelling evidence for the existence of exons showing synteny with foxp3 in the ground tit. A broader phylogenomic analysis has shown that FoxP3 sequences from these three species are similar to crocodilian sequences, the closest living relatives of birds. In both birds and crocodilians, we have also identified a highly proline enriched region at the N terminus of FoxP3, a region previously identified only in mammals. PMID- 26938480 TI - Secretion of Alpha-Hemolysin by Escherichia coli Disrupts Tight Junctions in Ulcerative Colitis Patients. AB - OBJECTIVES: The potential of Escherichia coli (E. coli) isolated from inflammatory bowel disease (IBD) patients to damage the integrity of the intestinal epithelium was investigated. METHODS: E. coli strains isolated from patients with ulcerative colitis (UC) and healthy controls were tested for virulence capacity by molecular techniques and cytotoxic assays and transepithelial electric resistance (TER). E. coli isolate p19A was selected, and deletion mutants were created for alpha-hemolysin (alpha-hemolysin) (hly) clusters and cytotoxic necrotizing factor type 1 (cnf1). Probiotic E. coli Nissle and pathogenic E. coli LF82 were used as controls. RESULTS: E. coli strains from patients with active UC completely disrupted epithelial cell tight junctions shortly after inoculation. These strains belong to phylogenetic group B2 and are all alpha-hemolysin positive. In contrast, probiotic E. coli Nissle, pathogenic E. coli LF82, four E. coli from patients with inactive UC and three E. coli strains from healthy controls did not disrupt tight junctions. E. coli p19A WT as well as cnf1, and single loci of hly mutants from cluster I and II were all able to damage Caco-2 (Heterogeneous human epithelial colorectal adenocarcinoma) cell tight junctions. However, this phenotype was lost in a mutant with knockout (Delta) of both hly loci (P<0.001). CONCLUSIONS: UC-associated E. coli producing alpha-hemolysin can cause rapid loss of tight junction integrity in differentiated Caco-2 cell monolayers. This effect was abolished in a mutant unable to express alpha-hemolysin. These results suggest that high Hly expression may be a mechanism by which specific strains of E. coli pathobionts can contribute to epithelial barrier dysfunction and pathophysiology of disease in IBD. PMID- 26938481 TI - Lipotoxicity pathways intersect in hepatocytes: Endoplasmic reticulum stress, c Jun N-terminal kinase-1, and death receptors. AB - Non-alcoholic fatty liver disease (NAFLD) is becoming increasingly more common worldwide. Hepatocyte apoptosis caused by free fatty acids, termed hepatocyte lipoapoptosis, is a feature of non-alcoholic steatohepatitis (NASH), an advanced form of NAFLD. As no salutary treatment for NASH exists, it is important to understand the molecular mechanisms responsible for disease development and progression. This review discusses recent developments in research on hepatocyte lipoapoptosis, focusing on the endoplasmic reticulum stress, c-Jun N-terminal kinase-1, and death receptor-mediated pathway networks and their modulators and interactions. In addition, we describe the emerging importance of the signaling pathways that not only impact the dying hepatocytes themselves, but also influence surrounding cells and possibly promote disease progression through the release of microvesicles. Overall, a more comprehensive understanding of the molecular mediators in lipotoxicity-related pathways would likely benefit the development of mechanism-based therapies of NASH. PMID- 26938479 TI - Anal Neoplasia in Inflammatory Bowel Disease Is Associated With HPV and Perianal Disease. AB - OBJECTIVES: Literature describing the risk factors predisposing inflammatory bowel disease (IBD) patients to anal squamous neoplasia is very scarce. Case reports and small case series have implicated perianal Crohn's disease (CD), long standing IBD, human papillomavirus (HPV) infection, and immunosuppressive treatment. In this study, we retrospectively examined the association between HPV infection and anal squamous neoplastic lesions among IBD patients from our center. METHODS: We reviewed the pathology records and slides of IBD patients diagnosed with anal squamous cell carcinomas (SCCs), high-grade squamous intraepithelial lesions (HSILs), and low-grade squamous intraepithelial lesions (LSILs) who presented at our center between 1 March 1994 and 9 September 2014. The HPV status of the neoplasms was assessed histologically, by immunohistochemical staining for p16 overexpression, and by global and type specific HPV PCR. RESULTS: SCCs, HSILs, LSILs, and small cell carcinoma were identified, respectively, in six, nine, two, and one IBD patients. All six patients with SCC had CD with perianal involvement. HPV-related neoplasia was identified in 3/6 cases of SCC (all HPV-16), 1/1 small cell carcinoma (HPV-18), and 9/9 HSIL (7 HPV-16, 2 not typed); 2/2 LSILs were negative for high-risk HPV. CONCLUSIONS: In our experience, anal squamous neoplastic lesions in IBD are associated with HPV infection and SCC seem to be associated with perianal CD. Prospective studies are needed to confirm these results. PMID- 26938485 TI - A LONGITUDINAL EXAMINATION OF TODDLERS' BEHAVIORAL CUES AS A FUNCTION OF SUBSTANCE-ABUSING MOTHERS' DISENGAGEMENT. AB - As a group, substance-abusing parents are at risk for maladaptive parenting. The association between substance abuse and parenting may result, in part, from parents' emotional disengagement from the parent-child relationship, which makes perceiving and responding to children's cues more challenging. In this study, we examined whether substance-abusing mothers' levels of disengagement from their relationship with their children (ages 2-44 months), operationalized in two different ways using parenting narratives (representational and linguistic disengagement), prospectively predicted children's engagement and disengagement cues during a structured mother-child interaction. Within a sample of 29 mothers, we tested the hypotheses that greater maternal disengagement at Time 1 would predict a decrease in children's engagement and an increase in children's disengagement at Time 2. Results indicated that representational disengagement predicted a decrease in children's engagement cues whereas linguistic disengagement predicted an increase in children's disengagement cues. Results provide partial support for a reciprocal, iterative process in which mothers and children mutually adjust their emotional and behavioral disengagement with one another. PMID- 26938487 TI - 1,3-Alternate Tetraamido-Azacalix[4]arenes as Selective Anion Receptors. AB - Six tetraaza[1.1.1.1]cyclophane derivatives bearing peripheral amide groups were prepared according to two distinct synthetic strategies that depend on the connection pattern between the aryl units. NMR experiments combined with the X ray structures of two tetraamide derivatives 4 b and 10 show that these cavitands adopt a 1,3-alternate conformation both in solution and in the solid state. Consequently, the four amide groups of the aza[1.1.1.1]-m,m,m,m-cyclophane isomer 10 can contribute to the same recognition process towards neutral water molecules or anion guests. NMR experiments, mass spectrometry analyses and single-crystal X ray structures confirm the anion-binding ability of this receptor. Absorption spectrophotometric titrations in nonpolar solvents provided evidence for the selectivity of 10 to chloride anions in the halide series, with a corresponding association constant Ka reaching 2.5 * 10(6) m(-1). PMID- 26938486 TI - Multidimensional Screening Platform for Simultaneously Targeting Oncogenic KRAS and Hypoxia-Inducible Factors Pathways in Colorectal Cancer. AB - Colorectal cancer (CRC) is a genetic disease, due to progressive accumulation of mutations in oncogenes and tumor suppressor genes. Large scale genomic sequencing projects revealed >100 mutations in any individual CRC. Many of these mutations are likely passenger mutations, and fewer are driver mutations. Of these, activating mutations in RAS proteins are essential for cancer initiation, progression, and/or resistance to therapy. There has been significant interest in developing drugs targeting mutated cancer gene products or downstream signaling pathways. Due to the number of mutations involved and inherent redundancy in intracellular signaling, drugs targeting one mutation or pathway have been either ineffective or led to rapid resistance. We have devised a strategy whereby multiple cancer pathways may be simultaneously targeted for drug discovery. For proof-of-concept, we targeted the oncogenic KRAS and HIF pathways, since oncogenic KRAS has been shown to be required for cancer initiation and progression, and HIF-1alpha and HIF-2alpha are induced by the majority of mutated oncogenes and tumor suppressor genes in CRC. We have generated isogenic cell lines defective in either oncogenic KRAS or both HIF-1alpha and HIF-2alpha and subjected them to multiplex genomic, siRNA, and high-throughput small molecule screening. We have identified potential drug targets and compounds for preclinical and clinical development. Screening of our marine natural product library led to the rediscovery of the microtubule agent dolastatin 10 and the class I histone deacetylase (HDAC) inhibitor largazole to inhibit oncogenic KRAS and HIF pathways. Largazole was further validated as an antiangiogenic agent in a HIF-dependent manner in human cells and in vivo in zebrafish using a genetic model with activated HIF. Our general strategy, coupling functional genomics with drug susceptibility or chemical-genetic interaction screens, enables the identification of potential drug targets and candidates with requisite selectivity. Molecules prioritized in this manner can easily be validated in suitable zebrafish models due to the genetic tractability of the system. Our multidimensional platform with cellular and organismal components can be extended to larger scale multiplex screens that include other mutations and pathways. PMID- 26938488 TI - Synthesis and Biological Evaluation of 3, 8-dimethyl-5-isopropylazulene Derivatives as Anti-gastric Ulcer Agent. AB - Recent studies showed that Guaiazulene (GA) and Sodium guaiazulene sulfonate (GAS Na) have good anti-gastric ulcer effect. Here, two series of GA derivatives were synthesized and evaluated for their anti-gastric ulcer activity. The data obtained from in vivo testing of these compounds in a rodent ethanol-induced stomach injury model are discussed. Among the tested compounds, A1, A4, and A9 (ulcer index: 1.125 +/- 1.246**, 1.714 +/- 0.756*, 1.875 +/- 1.126*) exhibited better anti-gastric ulcer activity than the positive control Omeprazole (2.005 +/ 1.011*). The information got from these studies and the results of 3D-SAR investigation may be useful in the design of novel anti-gastric ulcer agents. PMID- 26938489 TI - Randomized, Open-Label, Parallel Group Study to Evaluate the Effect of Internet Based Glucose Management System on Subjects with Diabetes in China. AB - OBJECTIVE: Large amounts of time and effort are needed to implement an Internet based glucose monitoring system (IBGMS) in the clinical setting. This study was designed using research experience that was developed while implementing an IBGMS in Korea, and the research platform was modified to evaluate the efficacy of an IBGMS in controlling blood sugar in the Chinese population. METHODS: A randomized, open-label, parallel group design was used to evaluate the efficacy of an IBGMS among Chinese subjects with type 2 diabetes. Over a 6-month period, 182 subjects were evaluated in the IBGMS (n = 92) or control (n = 90) groups. RESULTS: After 3 months, the control group's HbA1c levels were reduced from 8.0% +/- 0.8% to 7.3% +/- 1.2% (p < 0.001) and the IBGMS group experienced a reduction from 7.9% +/- 0.8% to 6.9% +/- 0.7% (p < 0.001); the IBGMS group's end value was significantly lower (p = 0.014). The intragroup changes in the control and IBGMS groups were significant at the 3-month (p = 0.002) and 6-month (p < 0.01) follow ups. Over this period, the HbA1c levels in the control group increased slightly (7.3% +/- 1.1% to 7.4% +/- 1.3%, p = 0.605), and the HbA1c levels in the IBGMS group decreased slightly (6.9% +/- 0.7% to 6.7% +/- 0.7%, p = 0.081). CONCLUSIONS: The IBGMS was effective in improving blood sugar levels among patients with diabetes. Therefore, IBGMS experience can be effectively transferred between institutions and countries. PMID- 26938491 TI - A highly sensitive aptasensor for OTA detection based on hybridization chain reaction and fluorescent perylene probe. AB - An optical aptasensor was developed for ultrasensitive detection of ochratoxin A (OTA) based on hybridization chain reaction (HCR) amplification strategy and fluorescent perylene probe (PAPDI)/DNA composites. Dendritic DNA concatamers were synthesized by HCR strategy and modified on magnetic nanoparticles through aptamer as medium. A large amount of PAPDI probe aggregated under the induction of DNA concatamers and caused fluorescence quenching. In the presence of OTA, the PAPDI/DNA composites were released from magnetic nanoparticles due to the strong affinity between aptamer and OTA. In ethanol, PAPDI monomers disaggregated and produced strong fluorescence. The present method displays excellent sensitivity and selectivity towards OTA. PMID- 26938492 TI - Grafting of a peptide probe for Prostate-Specific Antigen detection using diazonium electroreduction and click chemistry. AB - The main objective of this work was to validate a label-free electrochemical method of protein detection using peptides as capture probes. As a proof-of concept, we used a 7 amino acids sequence (HSSKLQL) specific for Prostate Specific Antigen. We investigated various electrografting conditions of two anilines (2-[(4-aminophenyl)sulfanyl]-8-hydroxy-1,4-naphthoquinone and 4 azidoaniline) further converted in situ into their corresponding diazonium salts on glassy carbon electrodes. It was demonstrated that the best method to obtain a mixed layer is the simultaneous electroreduction of the two diazonium salts. 4 azidoaniline was used to covalently immobilize the ethynyl-functionalized peptide probe by click coupling, and the hydroxynaphthoquinone derivative plays the role of electrochemical transducer of the peptide-protein recognition. The proteolytic activity of PSA towards a small peptide substrate carrying streptavidin at its distal end was also investigated to design an original sensing architecture leading to a reagentless, label free, and "signal-on" PSA sensor. Without optimization, the limit of quantification can be estimated in the nM to pM range. PMID- 26938490 TI - Sequence Affects the Cyclization of DNA Minicircles. AB - Understanding how the sequence of a DNA molecule affects its dynamic properties is a central problem affecting biochemistry and biotechnology. The process of cyclizing short DNA, as a critical step in molecular cloning, lacks a comprehensive picture of the kinetic process containing sequence information. We have elucidated this process by using coarse-grained simulations, enhanced sampling methods, and recent theoretical advances. We are able to identify the types and positions of structural defects during the looping process at a base pair level. Correlations along a DNA molecule dictate critical sequence positions that can affect the looping rate. Structural defects change the bending elasticity of the DNA molecule from a harmonic to subharmonic potential with respect to bending angles. We explore the subelastic chain as a possible model in loop formation kinetics. A sequence-dependent model is developed to qualitatively predict the relative loop formation time as a function of DNA sequence. PMID- 26938493 TI - Pyrite as a sustainable catalyst in electro-Fenton process for improving oxidation of sulfamethazine. Kinetics, mechanism and toxicity assessment. AB - The degradation of 0.20 mM sulfamethazine (SMT) solutions was investigated by heterogeneous electro-Fenton (EF) process using pyrite as source of Fe(2+) (catalyst) and pH regulator in an undivided electrochemical cell equipped either with a Pt or a BDD anode and carbon-felt as cathode. Effect of pyrite concentration and applied current on the oxidative degradation kinetics and mineralization efficiency has been studied. The higher oxidation power of the process, named "Pyrite-EF" using BDD anode was demonstrated. Pyrite-EF showed a better performance for the oxidation/mineralization of the drug SMT in comparison to the classic EF process: 95% and 87% TOC removal by Pyrite-EF with BDD and Pt anodes, respectively, versus 90% and 83% by classical EF with BDD and Pt anodes, respectively. The rate constant of the oxidation of SMT by OH was determined by the competition kinetics method and found to be 1.87 * 10(9) mol(-1) L s(-1). Based on the identified reaction intermediates by HPLC and GS-MS, as well as released SO4(2-), NH4(+) and NO3(-) ions, a plausible reaction pathway was proposed for the mineralization of SMT during Pyrite-EF process. Toxicity assessment by means of Microtox method revealed the formation of some toxic intermediates during the treatment. However, toxicity of the solution was removed at the end of treatment. PMID- 26938494 TI - The effect of inter-annual variability of consumption, production, trade and climate on crop-related green and blue water footprints and inter-regional virtual water trade: A study for China (1978-2008). AB - Previous studies into the relation between human consumption and indirect water resources use have unveiled the remote connections in virtual water (VW) trade networks, which show how communities externalize their water footprint (WF) to places far beyond their own region, but little has been done to understand variability in time. This study quantifies the effect of inter-annual variability of consumption, production, trade and climate on WF and VW trade, using China over the period 1978-2008 as a case study. Evapotranspiration, crop yields and green and blue WFs of crops are estimated at a 5 * 5 arc-minute resolution for 22 crops, for each year in the study period, thus accounting for climate variability. The results show that crop yield improvements during the study period helped to reduce the national average WF of crop consumption per capita by 23%, with a decreasing contribution to the total from cereals and increasing contribution from oil crops. The total consumptive WFs of national crop consumption and crop production, however, grew by 6% and 7%, respectively. By 2008, 28% of total water consumption in crop fields in China served the production of crops for export to other regions and, on average, 35% of the crop related WF of a Chinese consumer was outside its own province. Historically, the net VW within China was from the water-rich South to the water-scarce North, but intensifying North-to-South crop trade reversed the net VW flow since 2000, which amounted 6% of North's WF of crop production in 2008. South China thus gradually became dependent on food supply from the water-scarce North. Besides, during the whole study period, China's domestic inter-regional VW flows went dominantly from areas with a relatively large to areas with a relatively small blue WF per unit of crop, which in 2008 resulted in a trade-related blue water loss of 7% of the national total blue WF of crop production. The case of China shows that domestic trade, as governed by economics and governmental policies rather than by regional differences in water endowments, determines inter-regional water dependencies and may worsen rather than relieve the water scarcity in a country. PMID- 26938495 TI - Impact of salinity on organic matter and nitrogen removal from a municipal wastewater RO concentrate using biologically activated carbon coupled with UV/H2O2. AB - The concentrate streams generated from reverse osmosis (RO)-based municipal wastewater reclamation processes contain organic substances and nutrients at elevated concentrations, posing environmental and health risks on their disposal to confined receiving environments such as bays. The impact of salinity (TDS at 7, 10 and 16 g/L) of a RO concentrate (ROC) on the treatment efficiency of a biological activated carbon (BAC) system after pre-oxidation with UV/H2O2 was characterised in terms of removal of organic matter and nitrogen species, and the bacterial communities. Organic matter removal was comparable for the ROC over the tested salinity range, with 45-49% of DOC and 70-74% of UVA254 removed by the combined treatment. However, removal in total nitrogen (TN) was considerably higher for the ROC at the high salinity (TDS ~ 16 mg/L) compared with the low (~7 g/L) and medium salinity (~10 g/L). Effective nitrification with high ammonium removal (>90%) was achieved at all salinity levels, whereas greater denitrification (39%) was obtained at high salinity than low (23%) and medium salinity (27%) which might suggest that the bacterial communities contributing to the greater denitrification were more halotolerant. Microbiological characterisation using polymerase chain reaction-denaturing gradient gel electrophoresis (PCR-DGGE) and culture based techniques showed that diversified bacterial communities were present in the BAC system as evident from different 16S rDNA. The major bacterial groups residing on the BAC media belonged to Bacillus (Firmicutes), Pseudomonas (gamma-Proteobacteria), and Rhodococcus (Actinobacteria) for all salinity levels, confirming that these microbial communities could be responsible for carbon and nitrogen removal at the different salinity levels. This has implications in understanding the effectiveness and robustness of the BAC system over the salinity range of the ROC and so would be useful for optimising the treatment efficiency of the BAC system. PMID- 26938496 TI - Enhanced sulfamethoxazole degradation through ammonia oxidizing bacteria co metabolism and fate of transformation products. AB - The occurrence of the widely-used antibiotic sulfamethoxazole (SFX) in wastewaters and surface waters has been reported in a large number of studies. However, the results obtained up-to-date have pointed out disparities in its removal. This manuscript explores the enhanced biodegradation potential of an enriched culture of Ammonia Oxidizing Bacteria (AOB) towards SFX. Several sets of batch tests were conducted to establish a link between SFX degradation and specific ammonia oxidation rate. The occurrence, degradation and generation of SFX and some of its transformation products (4-Nitro SFX, Desamino-SFX and N(4) Acetyl-SFX) was also monitored. A clear link between the degradation of SFX and the nitrification rate was found, resulting in an increased SFX removal at higher specific ammonia oxidation rates. Moreover, experiments conducted under the presence of allylthiourea (ATU) did not present any removal of SFX, suggesting a connection between the AMO enzyme and SFX degradation. Long term experiments (up to 10 weeks) were also conducted adding two different concentrations (10 and 100 MUg/L) of SFX in the influent of a partial nitrification sequencing batch reactor, resulting in up to 98% removal. Finally, the formation of transformation products during SFX degradation represented up to 32%, being 4-Nitro-SFX the most abundant. PMID- 26938497 TI - Temperature change affected groundwater quality in a confined marine aquifer during long-term heating and cooling. AB - Global warming and urbanization together with development of subsurface infrastructures (e.g. subways, shopping complexes, sewage systems, and Ground Source Heat Pump (GSHP) systems) will likely cause a rapid increase in the temperature of relatively shallow groundwater reservoirs (subsurface thermal pollution). However, potential effects of a subsurface temperature change on groundwater quality due to changed physical, chemical, and microbial processes have received little attention. We therefore investigated changes in 34 groundwater quality parameters during a 13-month enhanced-heating period, followed by 14 months of natural or enhanced cooling in a confined marine aquifer at around 17 m depth on the Saitama University campus, Japan. A full-scale GSHP test facility consisting of a 50 m deep U-tube for circulating the heat-carrying fluid and four monitoring wells at 1, 2, 5, and 10 m from the U-tube were installed, and groundwater quality was monitored every 1-2 weeks. Rapid changes in the groundwater level in the area, especially during the summer, prevented accurate analyses of temperature effects using a single-well time series. Instead, Dual-Well Analysis (DWA) was applied, comparing variations in subsurface temperature and groundwater chemical concentrations between the thermally disturbed well and a non-affected reference well. Using the 1 m distant well (temperature increase up to 7 degrees C) and the 10 m distant well (non temperature-affected), the DWA showed an approximately linear relationships for eight components (B, Si, Li, dissolved organic carbon (DOC), Mg(2+), NH4(+), Na(+), and K(+)) during the combined 27 months of heating and cooling, suggesting changes in concentration between 4% and 31% for a temperature change of 7 degrees C. PMID- 26938498 TI - Sulfate-mediated electrooxidation of X-ray contrast media on boron-doped diamond anode. AB - Recently, electrochemical activation of sulfate ions to sulfate radical species and nonradically activated persulfate has been demonstrated at boron-doped diamond (BDD) anode, which enhanced the electrooxidation kinetics of several persistent contaminants. In this study, we investigated the transformation pathways of two X-ray contrast media (ICM), diatrizoate and iopromide, in electrooxidation at BDD anode using sulfate and inert nitrate anolyte. Sulfate anolyte yielded a seven-fold increase in apparent rate constants for ICM oxidation compared to inert nitrate anolyte, and a two-fold increase for the removal of organic carbon. Higher iodine release was observed in electrooxidation of diatrizoate compared to iopromide. In the case of diatrizoate, around 80% of deiodination efficiency was achieved in both anolytes. Deiodination efficiency of iopromide was somewhat lower in nitrate anolyte (<=75%) and significantly reduced in sulfate anolyte (<=46%) due to a larger steric hindrance of alkyl side chains. Moreover, a considerable lag phase of iopromide deiodination was observed in sulfate anolyte, indicating that initial oxidation reactions took place almost exclusively at the alkyl side chains. Several transformation products (TPs) of ICM were identified in electrooxidation in sulfate anolyte, and only three TPs in the case of nitrate anolyte. The main mechanistic steps in the oxidation of iopromide were H-abstraction and bond cleavage in the alkyl side chains. Diatrizoate was mainly transformed through oxidative cleavage of iodine substituent and inter-molecular cyclization. Two hydroxylamine derivatives of iopromide and a nitro-derivative of diatrizoate were observed in sulfate anolyte. These products have not been reported previously for hydroxyl radical-mediated oxidation of ICM. Given that electron-transfer mechanism is more typical for sulfate than for hydroxyl radicals, formation of hydroxylamine and nitro derivatives of ICM was assigned to one-electron charge transfer to sulfate radical species and formation of N-centered radicals. PMID- 26938499 TI - A meta-analysis of public compliance to boil water advisories. AB - Water utilities that generally provide continuous and reliable service to their customers may sometimes issue an advisory notification when service is interrupted or water quality is compromised. When the contamination is biological, utilities or the local public health agencies issue a 'boil water advisory' (BWA). The public health effectiveness of a BWA depends strongly on an implicit public understanding and compliance. In this study, a meta-analysis of 11 articles that investigated public compliance to BWA notifications was conducted. Awareness of BWA was moderately high, except in situations involving extreme weather. Reported rates of compliance were generally high, but when rate of awareness and non-compliant behavior such as brushing teeth were factored in, the median effective compliance rate was found to be around 68 percent. This does not include situations where people forgot to boil water for some part of the duration, or ingested contaminated water after the BWA was issued but before they became aware of the notification. The two-thirds compliance rate is thus an over estimate. Results further suggest that timeliness of receipt, content of the advisory, and number of sources reporting the advisory have a significant impact on public response and compliance. This analysis points to improvements in the phrasing and content of BWA notices that could result in greater compliance, and recommends the use of a standard protocol to limit recall bias and capture the public response accurately. PMID- 26938500 TI - Effect of temperature on selenium removal from wastewater by UASB reactors. AB - The effect of temperature on selenium (Se) removal by upflow anaerobic sludge blanket (UASB) reactors treating selenate and nitrate containing wastewater was investigated by comparing the performance of a thermophilic (55 degrees C) versus a mesophilic (30 degrees C) UASB reactor. When only selenate (50 MUM) was fed to the UASB reactors (pH 7.3; hydraulic retention time 8 h) with excess electron donor (lactate at 1.38 mM corresponding to an organic loading rate of 0.5 g COD L(-1) d(-1)), the thermophilic UASB reactor achieved a higher total Se removal efficiency (94.4 +/- 2.4%) than the mesophilic UASB reactor (82.0 +/- 3.8%). When 5000 MUM nitrate was further added to the influent, total Se removal was again better under thermophilic (70.1 +/- 6.6%) when compared to mesophilic (43.6 +/- 8.8%) conditions. The higher total effluent Se concentration in the mesophilic UASB reactor was due to the higher concentrations of biogenic elemental Se nanoparticles (BioSeNPs). The shape of the BioSeNPs observed in both UASB reactors was different: nanospheres and nanorods, respectively, in the mesophilic and thermophilic UASB reactors. Microbial community analysis showed the presence of selenate respirers as well as denitrifying microorganisms. PMID- 26938501 TI - In-vivo evaluation of apocynin for prevention of Helicobacter pylori-induced gastric carcinogenesis. AB - The emergence of antibiotic-resistant Helicobacter pylori strains impacts the efficacy of eradication therapy and promotes the development of alternative treatment strategies. Apocynin inhibits neutrophil NADPH oxidase and hence may decrease reactive oxygen species-mediated tissue damage in H. pylori-infected stomach tissue. Apocynin was tested in vitro for its cytotoxic and direct antibacterial effects. The therapeutic efficacy of orally administered apocynin (100 mg/kg/day through drinking water or 200 mg/kg/day through combined administration of drinking water and slow-release formulation) was assessed at 9 weeks after infection in the Mongolian gerbil model. Bacterial burdens were quantified by viable plate count and quantitative PCR. Histopathological evaluation of antrum and pylorus provided insight into mucosal inflammation and injury. Apocynin showed no cytotoxic or direct antibacterial effects in vitro or in vivo. Nine weeks of apocynin treatment at 200 mg/kg/day reduced active H. pylori gastritis as neutrophil infiltration in the mucous neck region and pit abscess formation decreased significantly. In our gerbil model, prolonged high dose apocynin treatment significantly improved H. pylori-induced pit abscess formation without indications of drug toxicity and thus further investigation of the dosage regimen and formulation and the long-term impact on neoplastic development should be carried out. PMID- 26938502 TI - A novel CD14(high) CD16(high) subset of peritoneal macrophages from cirrhotic patients is associated to an increased response to LPS. AB - The aim of this study was to characterize monocyte-derived macrophages (M-DM) from blood and ascites of cirrhotic patients comparatively with those obtained from blood of healthy controls. The phenotypic profile based on CD14/CD16 expression was analyzed by flow cytometry. Cells were isolated and stimulated in vitro with LPS and heat killed Candida albicans. Phosphorylation of ERK, c-Jun, p38 MAPK, and PKB/Akt was analyzed by Western blotting. A novel CD14(high)CD16(high) M-DM subpopulation is present in ascites (~33%). The CD14(++)CD16(+) intermediate subset is increased in the blood of cirrhotic patients (~from 4% to 11%) and is predominant in ascites (49%), while the classical CD14(++)CD16(-) subpopulation is notably reduced in ascites (18%). Basal hyperactivation of ERK and JNK/c-Jun pathways observed in ascites M-DM correlates with CD14/CD16 high expressing subsets, while PI3K/PKB does it with the CD16 low expressing cells. In vitro LPS treatment highly increases ERK1/2, PKB/Akt and c-Jun phosphorylation, while that of p38 MAPK is decreased in M-DM from ascites compared to control blood M-DM. Stimulation of healthy blood M-DM with LPS and C. albicans induced higher phosphorylation levels of p38 than those from ascites. Regarding cytokines secretion, in vitro activated M-DM from ascites of cirrhotic patients produced significantly higher amounts of IL-6, IL-10 and TNF-alpha, and lower levels of IL-1beta and IL-12 than control blood M-DM. In conclusion, a new subpopulation of CD14(high)CD16(high) peritoneal M-DM has been identified in ascites of cirrhotic patients, which is very sensitive to LPS stimulation. PMID- 26938503 TI - Complement factor H modulates the activation of human neutrophil granulocytes and the generation of neutrophil extracellular traps. AB - Factor H (FH) is a major inhibitor of the alternative pathway of complement activation in plasma and on certain host surfaces. In addition to being a complement regulator, FH can bind to various cells via specific receptors, including binding to neutrophil granulocytes through complement receptor type 3 (CR3; CD11b/CD18), and modulate their function. The cellular roles of FH are, however, poorly understood. Because neutrophils are important innate immune cells in inflammatory processes and the host defense against pathogens, we aimed at studying the effects of FH on various neutrophil functions, including the generation of extracellular traps. FH co-localized with CD11b on the surface of neutrophils isolated from peripheral blood of healthy individuals, and cell-bound FH retained its cofactor activity and enhanced C3b degradation. Soluble FH supported neutrophil migration and immobilized FH induced cell spreading. In addition, immobilized but not soluble FH enhanced IL-8 release from neutrophils. FH alone did not trigger the cells to produce neutrophil extracellular traps (NETs), but NET formation induced by PMA and by fibronectin plus fungal beta glucan were inhibited by immobilized, but not by soluble, FH. Moreover, in parallel with NET formation, immobilized FH also inhibited the production of reactive oxygen species induced by PMA and by fibronectin plus beta-glucan. Altogether, these data indicate that FH has multiple regulatory roles on neutrophil functions. While it can support the recruitment of neutrophils, FH may also exert anti-inflammatory effects and influence local inflammatory and antimicrobial reactions, and reduce tissue damage by modulating NET formation. PMID- 26938504 TI - Magnetic nanocomposites. AB - Magnetic nanocomposites are multi-component materials, typically containing nanosized magnetic materials to trigger the response to an external stimulus (i.e., an external static or alternating magnetic field). Up to now, the search for novel nanocomposites has lead to the combination of a plethora of different materials (e.g., gels, liquid crystals, renewable polymers, silica, carbon or metal organic frameworks) with various types of magnetic particles, offering exciting perspectives not only for fundamental investigations but also for application in various fields, including medical therapy and diagnosis, separations, actuation, or catalysis. In this review, we have selected a few of the most recent examples to highlight general concepts and advances in the preparation of magnetic nanocomposites and recent advances in the synthesis of magnetic nanoparticles. PMID- 26938505 TI - Characterization of a gate-defined double quantum dot in a Si/SiGe nanomembrane. AB - We report the fabrication and characterization of a gate-defined double quantum dot formed in a Si/SiGe nanomembrane. In the past, all gate-defined quantum dots in Si/SiGe heterostructures were formed on top of strain-graded virtual substrates. The strain grading process necessarily introduces misfit dislocations into a heterostructure, and these defects introduce lateral strain inhomogeneities, mosaic tilt, and threading dislocations. The use of a SiGe nanomembrane as the virtual substrate enables the strain relaxation to be entirely elastic, eliminating the need for misfit dislocations. However, in this approach the formation of the heterostructure is more complicated, involving two separate epitaxial growth procedures separated by a wet-transfer process that results in a buried non-epitaxial interface 625 nm from the quantum dot. We demonstrate that in spite of this buried interface in close proximity to the device, a double quantum dot can be formed that is controllable enough to enable tuning of the inter-dot tunnel coupling, the identification of spin states, and the measurement of a singlet-to-triplet transition as a function of an applied magnetic field. PMID- 26938506 TI - Patterns of Self-care in Adults With Heart Failure and Their Associations With Sociodemographic and Clinical Characteristics, Quality of Life, and Hospitalizations: A Cluster Analysis. AB - BACKGROUND: Self-care is important in heart failure (HF) treatment, but patients may have difficulties and be inconsistent in its performance. Inconsistencies in self-care behaviors may mirror patterns of self-care in HF patients that are worth identifying to provide interventions tailored to patients. OBJECTIVES: The aims of this study are to identify clusters of HF patients in relation to self care behaviors and to examine and compare the profile of each HF patient cluster considering the patient's sociodemographics, clinical variables, quality of life, and hospitalizations. METHODS: This was a secondary analysis of data from a cross sectional study in which we enrolled 1192 HF patients across Italy. A cluster analysis was used to identify clusters of patients based on the European Heart Failure Self-care Behaviour Scale factor scores. Analysis of variance and chi test were used to examine the characteristics of each cluster. RESULTS: Patients were 72.4 years old on average, and 58% were men. Four clusters of patients were identified: (1) high consistent adherence with high consulting behaviors, characterized by younger patients, with higher formal education and higher income, less clinically compromised, with the best physical and mental quality of life (QOL) and lowest hospitalization rates; (2) low consistent adherence with low consulting behaviors, characterized mainly by male patients, with lower formal education and lowest income, more clinically compromised, and worse mental QOL; (3) inconsistent adherence with low consulting behaviors, characterized by patients who were less likely to have a caregiver, with the longest illness duration, the highest number of prescribed medications, and the best mental QOL; (4) and inconsistent adherence with high consulting behaviors, characterized by patients who were mostly female, with lower formal education, worst cognitive impairment, worst physical and mental QOL, and higher hospitalization rates. CONCLUSION: The 4 clusters identified in this study and their associated characteristics could be used to tailor interventions aimed at improving self care behaviors in HF patients. PMID- 26938507 TI - Effects of Stretching Exercise on Heart Rate Variability During Pregnancy. AB - BACKGROUND: Little evidence exists for effects of low-intensity exercises such as stretching on cardiovascular health in pregnant women. AIM: Our aim was to evaluate the effect of a 20-minute stretching exercise on heart rate variability (HRV), blood pressure (BP), and heart rate (HR) in healthy pregnant women. METHODS: In 15 pregnant women with a mean (SD) age of 29.47 (4.07) years and mean (SD) gestational weeks of 26.53 (8.35), HRV, and BP were measured before and after the 20-minute stretching exercise. RESULTS: Compared with before the stretching exercise, standard deviation of the normal-to-normal intervals, total variability of heart rate, increased by 7.40 milliseconds (t = -2.31, P = .04) and root mean square of successive differences, a surrogate measure of parasympathetic outflow, also increased by 11.68 milliseconds (Z = -2.04, P = .04) after the stretching exercise. Diastolic BP and HR decreased by 2.13 mm Hg (t = 1.93, P = .07) and 3.31 bpm (t = 2.17, P = .05), respectively, but they did not reach statistical significance. DISCUSSION: These preliminary data suggest that 20 minutes of stretching exercise may promote cardiovascular health by attenuating the loss of parasympathetic tone associated with pregnancy. PMID- 26938508 TI - Quality and Health Literacy Demand of Online Heart Failure Information. AB - BACKGROUND: The ubiquity of the Internet is changing the way people obtain their health information. Although there is an abundance of heart failure information online, the quality and health literacy demand of these information are still unknown. OBJECTIVE: The purpose of this study is to evaluate the quality and health literacy demand (readability, understandability, and actionability) of the heart failure information found online. METHODS: Google, Yahoo, Bing, Ask.com, and DuckDuckGo were searched for relevant heart failure Web sites. Two independent raters then assessed the quality and health literacy demand of the included Web sites. The quality of the heart failure information was assessed using the DISCERN instrument. Readability was assessed using 7 established readability tests. Finally, understandability and actionability were assessed using the Patient Education Materials Assessment Tool for Print Materials. RESULTS: A total of 46 Web sites were included in this analysis. The overall mean quality rating was 46.0 +/- 8.9 and the mean readability score was 12.6 grade reading level. The overall mean understandability score was 56.3% +/- 16.2%. Finally, the overall mean actionability score was 34.7% +/- 28.7%. CONCLUSIONS: The heart failure information found online was of fair quality but required a relatively high health literacy level. Web content authors need to consider not just the quality but also the health literacy demand of the information found in their Web sites. This is especially important considering that low health literacy is likely prevalent among the usual audience. PMID- 26938510 TI - Incorporation of Amino Acids with Long-Chain Terminal Olefins into Proteins. AB - The increasing need for site-specific protein decorations that mimic natural posttranslational modifications requires access to a variety of noncanonical amino acids with moieties enabling bioorthogonal conjugation chemistry. Here we present the incorporation of long-chain olefinic amino acids into model proteins with rational variants of pyrrolysyl-tRNA synthetase (PylRS). Nepsilon-heptenoyl lysine was incorporated for the first time using the known promiscuous variant PylRS(Y306A/Y384F), and Nepsilon-pentenoyl lysine was incorporated in significant yields with the novel variant PylRS(C348A/Y384F). This is the only example of rational modification at position C348 to enlarge the enzyme's binding pocket. Furthermore, we demonstrate the feasibility of our chosen amino acids in the thiol-ene conjugation reaction with a thiolated polysaccharide. PMID- 26938509 TI - Living Arrangements Modify the Relationship Between Depressive Symptoms and Self care in Patients With Heart Failure. AB - BACKGROUND: Depressive symptoms hinder heart failure patients' engagement in self care. As social support helps improve self-care and decrease depressive symptoms, it is possible that social support buffers the negative impact of depressive symptoms on self-care. OBJECTIVE: The purpose of this study is to examine the effect of living arrangements as an indicator of social support on the relationship between depressive symptoms and self-care in heart failure patients. METHODS: Stable heart failure patients (N = 206) completed the Patient Health Questionnaire-9 to measure depressive symptoms. Self-care (maintenance, management, and confidence) was measured with the Self-Care of Heart Failure Index. Path analyses were used to examine associations among depressive symptoms and the self-care constructs by living arrangements. RESULTS: Depressive symptoms had a direct effect on self-care maintenance and management (standardized beta = 0.362 and -0.351, respectively), but not on self-care confidence in patients living alone. Depressive symptoms had no direct or indirect effect on any of the 3 self-care constructs in patients living with someone. CONCLUSIONS: Depressive symptoms had negative effects on self-care in patients living alone, but were not related to self-care in patients living with someone. Our results suggest that negative effects of depressive symptoms on self-care are buffered by social support. PMID- 26938511 TI - Modified Polyacrylic Acid-Zinc Composites: Synthesis, Characterization and Biological Activity. AB - Polyacrylic acid (PAA) is an important industrial chemical, which has been extensively applied in various fields, including for several biomedical purposes. In this study, we report the synthesis and modification of this polymer with various phenol imides, such as succinimide, phthalimide and 1,8-naphthalimide. The as-synthesized derivatives were used to prepare polymer metal composites by the reaction with Zn(+2). These composites were characterized by using various techniques, including NMR, FT-IR, TGA, SEM and DSC. The as-prepared PAA-based composites were further evaluated for their anti-microbial properties against various pathogens, which include both Gram-positive and Gram-negative bacteria and different fungal strains. The synthesized composites have displayed considerable biocidal properties, ranging from mild to moderate activities against different strains tested. PMID- 26938512 TI - Rapid Authentication of the Herbal Medicine Plant Species Aralia continentalis Kitag. and Angelica biserrata C.Q. Yuan and R.H. Shan Using ITS2 Sequences and Multiplex-SCAR Markers. AB - Accurate identification of the plant species that are present in herbal medicines is important for quality control. Although the dried roots of Aralia continentalis (Araliae Continentalis Radix) and Angelica biserrata (Angelicae Pubescentis Radix) are used in the same traditional medicine, namely Dok-Hwal in Korean and Du-Huo in Chinese, the medicines are described differently in the national pharmacopeia. Further confusion arises from the distribution of dried Levisticum officinale and Heracleum moellendorffii roots as the same medicine. Medicinal ingredients from all four plants are morphologically similar, and discrimination is difficult using conventional methods. Molecular identification methods offer rapidity and accuracy. The internal transcribed spacer 2 (ITS2) region of the nuclear ribosomal RNA gene (rDNA) was sequenced in all four plant species, and the sequences were used to design species-specific primers. Primers for each species were then combined to allow sample analysis in a single PCR reaction. Commercial herbal medicine samples were obtained from Korea and China and analyzed using the multiplex assay. The assay successfully identified authentic medicines and also identified inauthentic or adulterated samples. The multiplex assay will be a useful tool for identification of authentic Araliae Continentalis Radix and/or Angelicae Pubescentis Radix preparations in Korea and China. PMID- 26938513 TI - Silymarin-Loaded Nanoparticles Based on Stearic Acid-Modified Bletilla striata Polysaccharide for Hepatic Targeting. AB - Silymarin has been widely used as a hepatoprotective drug in the treatment of various liver diseases, yet its effectiveness is affected by its poor water solubility and low bioavailability after oral administration, and there is a need for the development of intravenous products, especially for liver-targeting purposes. In this study, silymarin was encapsulated in self-assembled nanoparticles of Bletilla striata polysaccharide (BSP) conjugates modified with stearic acid and the physicochemical properties of the obtained nanoparticles were characterized. The silymarin-loaded micelles appeared as spherical particles with a mean diameter of 200 nm under TEM. The encapsulation of drug molecules was confirmed by DSC thermograms and XRD diffractograms, respectively. The nanoparticles exhibited a sustained-release profile for nearly 1 week with no obvious initial burst. Compared to drug solutions, the drug-loaded nanoparticles showed a lower viability and higher uptake intensity on HepG2 cell lines. After intravenous administration of nanoparticle formulation for 30 min to mice, the liver became the most significant organ enriched with the fluorescent probe. These results suggest that BSP derivative nanoparticles possess hepatic targeting capability and are promising nanocarriers for delivering silymarin to the liver. PMID- 26938514 TI - Biofuels and Their Co-Products as Livestock Feed: Global Economic and Environmental Implications. AB - This review studies biofuel expansion in terms of competition between conventional and advanced biofuels based on bioenergy potential. Production of advanced biofuels is generally more expensive than current biofuels because products are not yet cost competitive. What is overlooked in the discussion about biofuel is the contribution the industry makes to the global animal feed supply and land use for cultivation of feedstocks. The global ethanol industry produces 44 million metric tonnes of high-quality feed, however, the co-products of biodiesel production have a moderate impact on the feed market contributing to just 8-9 million tonnes of protein meal output a year. By economically displacing traditional feed ingredients co-products from biofuel production are an important and valuable component of the biofuels sector and the global feed market. The return of co-products to the feed market has agricultural land use (and GHG emissions) implications as well. The use of co-products generated from grains and oilseeds can reduce net land use by 11% to 40%. The proportion of global cropland used for biofuels is currently some 2% (30-35 million hectares). By adding co products substituted for grains and oilseeds the land required for cultivation of feedstocks declines to 1.5% of the global crop area. PMID- 26938515 TI - On the Traceability of Commercial Saffron Samples Using 1H-NMR and FT-IR Metabolomics. AB - In previous works on authentic samples of saffron of known history (harvest and processing year, storage conditions, and length of time) some biomarkers were proposed using both FT-IR and NMR metabolomics regarding the shelf life of the product. This work addresses the difficulties to trace back the "age" of commercial saffron samples of unknown history, sets a limit value above which these products can be considered substandard, and offers a useful tool to combat saffron mislabeling and fraud with low-quality saffron material. Investigations of authentic and commercial saffron samples of different origin and harvest year, which had been stored under controlled conditions for different lengths of time, allowed a clear-cut clustering of samples in two groups according to the storage period irrespectively of the provenience. In this respect, the four-year cut off point proposed in our previous work assisted to trace back the "age" of unknown samples and to check for possible mislabeling practices. PMID- 26938516 TI - Can Expanded Bacteriochlorins Act as Photosensitizers in Photodynamic Therapy? Good News from Density Functional Theory Computations. AB - The main photophysical properties of a series of expanded bacteriochlorins, recently synthetized, have been investigated by means of DFT and TD-DFT methods. Absorption spectra computed with different exchange-correlation functionals, B3LYP, M06 and omegaB97XD, have been compared with the experimental ones. In good agreement, all the considered systems show a maximum absorption wavelength that falls in the therapeutic window (600-800 nm). The obtained singlet-triplet energy gaps are large enough to ensure the production of cytotoxic singlet molecular oxygen. The computed spin-orbit matrix elements suggest a good probability of intersystem spin-crossing between singlet and triplet excited states, since they result to be higher than those computed for 5,10,15,20-tetrakis-(m hydroxyphenyl)chlorin (Foscan(c)) already used in the photodynamic therapy (PDT) protocol. Because of the investigated properties, these expanded bacteriochlorins can be proposed as PDT agents. PMID- 26938517 TI - Photochemistry of the alpha-Al2O3-PETN Interface. AB - Optical absorption measurements are combined with electronic structure calculations to explore photochemistry of an alpha-Al2O3-PETN interface formed by a nitroester (pentaerythritol tetranitrate, PETN, C5H8N4O12) and a wide band gap aluminum oxide (alpha-Al2O3) substrate. The first principles modeling is used to deconstruct and interpret the alpha-Al2O3-PETN absorption spectrum that has distinct peaks attributed to surface F0-centers and surface-PETN transitions. We predict the low energy alpha-Al2O3 F0-center-PETN transition, producing the excited triplet state, and alpha-Al2O3 F0-center-PETN charge transfer, generating the PETN anion radical. This implies that irradiation by commonly used lasers can easily initiate photodecomposition of both excited and charged PETN at the interface. The feasible mechanism of the photodecomposition is proposed. PMID- 26938518 TI - Recent Advances in Solid Catalysts Obtained by Metalloporphyrins Immobilization on Layered Anionic Exchangers: A Short Review and Some New Catalytic Results. AB - Layered materials are a very interesting class of compounds obtained by stacking of two-dimensional layers along the basal axis. A remarkable property of these materials is their capacity to interact with a variety of chemical species, irrespective of their charge (neutral, cationic or anionic). These species can be grafted onto the surface of the layered materials or intercalated between the layers, to expand or contract the interlayer distance. Metalloporphyrins, which are typically soluble oxidation catalysts, are examples of molecules that can interact with layered materials. This work presents a short review of the studies involving metalloporphyrin immobilization on two different anionic exchangers, Layered Double Hydroxides (LDHs) and Layered Hydroxide Salts (LHSs), published over the past year. After immobilization of anionic porphyrins, the resulting solids behave as reusable catalysts for heterogeneous oxidation processes. Although a large number of publications involving metalloporphyrin immobilization on LDHs exist, only a few papers have dealt with LHSs as supports, so metalloporphyrins immobilized on LHSs represent a new and promising research field. This work also describes new results on an anionic manganese porphyrin (MnP) immobilized on Mg/Al-LDH solids with different nominal Mg/Al molar ratios (2:1, 3:1 and 4:1) and intercalated with different anions (CO3(2-) or NO3(-)). The influence of the support composition on the MnP immobilization rates and the catalytic performance of the resulting solid in cyclooctene oxidation reactions will be reported. PMID- 26938519 TI - Synthesis and Biological Evaluation of Novel Benzothiazole Derivatives as Potential Anticonvulsant Agents. AB - New benztriazoles with a mercapto-triazole and other heterocycle substituents were synthesized and evaluated for their anticonvulsant activity and neurotoxicity by using the maximal electroshock (MES), subcutaneous pentylenetetrazole (scPTZ), and rotarod neurotoxicity (TOX) tests. Among the compounds studied, compound 2-((1H-1,2,4-triazol-3-yl)thio)-N-(6-((3 fluorobenzyl) oxy)benzo[d]thiazol-2-yl)acetamide (5i) and 2-((1H-1,2,4-triazol-3 yl)thio)-N-(6-((4-fluorobenzyl)oxy) benzo[d] thiazol-2-yl)acetmide (5j) were the most potent, with an ED50 value of 50.8 mg/kg and 54.8 mg/kg in the MES test and 76.0 mg/kg and 52.8 mg/kg in the scPTZ seizures test, respectively. They also showed lower neurotoxicity and, therefore a higher protective index. In particular, compound 5j showed high protective index (PI) values of 8.96 in the MES test and 9.30 in the scPTZ test, which were better than those of the standard drugs used as positive controls in this study. PMID- 26938520 TI - Novel Gold Nanoparticles Reduced by Sargassum glaucescens: Preparation, Characterization and Anticancer Activity. AB - The current study investigated the anticancer properties of gold nanoparticles (SG-stabilized AuNPs) synthesized using water extracts of the brown seaweed Sargassum glaucescens (SG). SG-stabilized AuNPs were characterized by ultraviolet visible spectroscopy, transmission and scanning electron microscopy, and energy dispersive X-ray fluorescence spectrometry. The SG-stabilized AuNPs were stable and small at 3.65 +/- 1.69 nm in size. The in vitro anticancer effect of SG stabilized AuNPs was determined on cervical (HeLa), liver (HepG2), breast (MDA-MB 231) and leukemia (CEM-ss) cell lines using fluorescence microscopy, flow cytometry, caspase activity determination, and MTT assays. After 72 h treatment, SG-stabilized AuNPs was shown to be significant (p < 0.05) cytotoxic to the cancer cells in a dose- and time-dependent manner. The IC50 values of SG stabilized AuNPs on the HeLa, HepG2, CEM-ss, MDA-MB-231 cell lines were 4.75 +/- 1.23, 7.14 +/- 1.45, 10.32 +/- 1.5, and 11.82 +/- 0.9 MUg/mL, respectively. On the other hand, SG-stabilized AuNPs showed no cytotoxic effect towards the normal human mammary epithelial cells (MCF-10A). SG-stabilized AuNPs significantly (p < 0.05) arrest HeLa cell cycle at G2/M phase and significantly (p < 0.05) activated caspases-3 and -9 activities. The anticancer effect of SG-stabilized AuNPs is via the intrinsic apoptotic pathway. The study showed that SG-stabilized AuNPs is a good candidate to be developed into a chemotherapeutic compound for the treatment of cancers especially cervical cancer. PMID- 26938521 TI - Methanolic Extract of Pien Tze Huang Induces Apoptosis Signaling in Human Osteosarcoma MG63 Cells via Multiple Pathways. AB - Pien Tze Huang (PZH) is a well-known traditional Chinese formulation and has long been used as an alternative remedy for cancers in China and Southeast Asia. Recently, antitumor activity of PZH on several tumors have been increasingly reported, but its antitumor activity and the possible action mechanism on osteosarcoma remains unclear. After treatment with PZH, cell viability of MG-63 cells was dose-dependently inhibited compared to control cells. Moreover, a DNA ladder characteristic of apoptosis was observed in the cells treated with PZH, especially 500 MUg/mL, 750 MUg/mL. Further investigation showed that PZH treatments led to activation of caspase cascades and changes of apoptotic mediators Bcl2, Bax, and Bcl-xL expression. In addition, our results suggested that PZH activated PI3K/Akt signal pathway, and the phosphorylation of Akt and ERK1/2 were associated with the induction of apoptotic signaling. These results revealed that PZH possesses antitumoral activity on human osteosarcoma MG63 cells by manipulating apoptotic signaling and multiple pathways. It is suggested that PZH alone or combined with regular antitumor drugs may be beneficial as osteosarcoma treatments. PMID- 26938522 TI - Dendrobium moniliforme Exerts Inhibitory Effects on Both Receptor Activator of Nuclear Factor Kappa-B Ligand-Mediated Osteoclast Differentiation in Vitro and Lipopolysaccharide-Induced Bone Erosion in Vivo. AB - Dendrobium moniliforme (DM) is a well-known plant-derived extract that is widely used in Oriental medicine. DM and its chemical constituents have been reported to have a variety of pharmacological effects, including anti-oxidative, anti inflammatory, and anti-tumor activities; however, no reports discuss the beneficial effects of DM on bone diseases such as osteoporosis. Thus, we investigated the relationship between DM and osteoclasts, cells that function in bone resorption. We found that DM significantly reduced receptor activator of nuclear factor kappa-B ligand (RANKL)-induced tartrate-resistant acid phosphatase (TRAP)-positive osteoclast formation; DM directly induced the down-regulation of c-Fos and nuclear factor of activated T cells c1 (NFATc1) without affecting other RANKL-dependent transduction pathways. In the later stages of osteoclast maturation, DM negatively regulated the organization of filamentous actin (F actin), resulting in impaired bone-resorbing activity by the mature osteoclasts. In addition, micro-computed tomography (MU-CT) analysis of the murine model revealed that DM had a beneficial effect on lipopolysaccharide (LPS)-mediated bone erosion. Histological analysis showed that DM attenuated the degradation of trabecular bone matrix and formation of TRAP-positive osteoclasts in bone tissues. These results suggest that DM is a potential candidate for the treatment of metabolic bone disorders such as osteoporosis. PMID- 26938523 TI - The Role of CD44 and ERM Proteins in Expression and Functionality of P glycoprotein in Breast Cancer Cells. AB - Multidrug resistance (MDR) is often attributed to the over-expression of P glycoprotein (P-gp), which prevents the accumulation of anticancer drugs within cells by virtue of its active drug efflux capacity. We have previously described the intercellular transfer of P-gp via extracellular vesicles (EVs) and proposed the involvement of a unique protein complex in regulating this process. In this paper, we investigate the role of these mediators in the regulation of P-gp functionality and hence the acquisition of MDR following cell to cell transfer. By sequentially silencing the FERM domain-binding proteins, Ezrin, Radixin and Moesin (ERM), as well as CD44, which we also report a selective packaging in breast cancer derived EVs, we have established a role for these proteins, in particular Radixin and CD44, in influencing the P-gp-mediated MDR in whole cells. We also report for the first time the role of ERM proteins in the vesicular transfer of functional P-gp. Specifically, we demonstrate that intercellular membrane insertion is dependent on Ezrin and Moesin, whilst P-gp functionality is governed by the integrity of all ERM proteins in the recipient cell. This study identifies these candidate proteins as potential new therapeutic targets in circumventing MDR clinically. PMID- 26938525 TI - Alternatives to Outdoor Daylight Illumination for Photodynamic Therapy--Use of Greenhouses and Artificial Light Sources. AB - Daylight-mediated photodynamic therapy (daylight PDT) is a simple and pain free treatment of actinic keratoses. Weather conditions may not always allow daylight PDT outdoors. We compared the spectrum of five different lamp candidates for indoor "daylight PDT" and investigated their ability to photobleach protoporphyrin IX (PpIX). Furthermore, we measured the amount of PpIX activating daylight available in a glass greenhouse, which can be an alternative when it is uncomfortable for patients to be outdoors. The lamps investigated were: halogen lamps (overhead and slide projector), white light-emitting diode (LED) lamp, red LED panel and lamps used for conventional PDT. Four of the five light sources were able to photobleach PpIX completely. For halogen light and the red LED lamp, 5000 lux could photobleach PpIX whereas 12,000 lux were needed for the white LED lamp. Furthermore, the greenhouse was suitable for daylight PDT since the effect of solar light is lowered only by 25%. In conclusion, we found four of the five light sources and the greenhouse usable for indoor daylight PDT. The greenhouse is beneficial when the weather outside is rainy or windy. Only insignificant ultraviolet B radiation (UVB) radiation passes through the greenhouse glass, so sun protection is not needed. PMID- 26938526 TI - 5-Methoxyl Aesculetin Abrogates Lipopolysaccharide-Induced Inflammation by Suppressing MAPK and AP-1 Pathways in RAW 264.7 Cells. AB - For the first time, a pale amorphous coumarin derivative, 5-methoxyl aesculetin (MOA), was isolated from the dried bark of Fraxinus rhynchophylla Hance (Oleaceae). MOA modulates cytokine expression in lipopolysaccharide (LPS)-treated RAW 264.7 macrophages, but the precise mechanisms are still not fully understood. We determined the effects of MOA on the production of inflammatory mediators and pro-inflammatory cytokines in the LPS-induced inflammatory responses of RAW 264.7 macrophages. MOA significantly inhibited the LPS-induced production of nitric oxide (NO), prostaglandin E2 (PGE2), tumor necrosis factor-alpha (TNF-alpha), interleukin-6, and interleukin-1beta. It also effectively attenuated inducible nitric oxide (NO) synthase, cyclooxygenase-2, and TNF-alpha mRNA expression and significantly decreased the levels of intracellular reactive oxygen species. It inhibited phosphorylation of the extracellular signal-regulated kinase (ERK1/2), thus blocking nuclear translocation of activation protein (AP)-1. In a molecular docking study, MOA was shown to target the binding site of ERK via the formation of three hydrogen bonds with two residues of the kinase, which is sufficient for the inhibition of ERK. These results suggest that the anti-inflammatory effects of MOA in RAW 264.7 macrophages derive from its ability to block both the activation of mitogen-activated protein kinases (MAPKs) and one of their downstream transcription factors, activator protein-1 (AP-1). Our observations support the need for further research into MOA as a promising therapeutic agent in inflammatory diseases. PMID- 26938524 TI - The Latin American DILI Registry Experience: A Successful Ongoing Collaborative Strategic Initiative. AB - Drug induced liver injury (DILI) is a rare but well recognized serious adverse reaction. Pre-marketing studies may not detect liver injury, and DILI becomes very often apparent after the drug is launched to the market. Specific biomarkers for DILI prediction or diagnosis are not available. Toxic liver reactions present with a wide spectrum of phenotypes and severity, and our knowledge on the mechanisms underlying idiosyncratic reactions and individual susceptibility is still limited. To overcome these limitations, country-based registries and multicenter research networks have been created in Europe and North America. Reliable epidemiological data on DILI in Latin America (LA), a region with a large variety of ethnic groups, were however lacking. Fortunately, a LA network of DILI was set up in 2011, with the support of the Spanish DILI Registry from the University of Malaga. The primary aim of the Latin DILI Network (LATINDILIN) Registry was to prospectively identify bona fide DILI cases and to collect biological samples to study genetic biomarkers. Physicians involved in the project must complete a structured report form describing the DILI case presentation and follow-up which is submitted to a Coordinator Center in each country, where it is further assessed for completeness. During the last four years, several LA countries (Argentina, Uruguay, Chile, Mexico, Paraguay, Brazil, Ecuador, Peru, Venezuela and Colombia) have joined the network and committed with this project. At that point, to identify both our strengths and weaknesses was a very important issue. In this review, we will describe how the LATINDILI Registry was created. The aims and methods to achieve these objectives will be discussed in depth. Additionally, both the difficulties we have faced and the strategies to solve them will be also pinpointed. Finally, we will report on our preliminary results, and discuss ideas to expand and to keep running this network. PMID- 26938527 TI - CD86+/CD206+, Diametrically Polarized Tumor-Associated Macrophages, Predict Hepatocellular Carcinoma Patient Prognosis. AB - Tumor-associated macrophages (TAMs), the most abundant infiltrating immune cells in tumor microenvironment, have distinct functions in hepatocellular carcinoma (HCC) progression. CD68+ TAMs represent multiple polarized immune cells mainly containing CD86+ antitumoral M1 macrophages and CD206+ protumoral M2 macrophages. TAMs expression and density were assessed by immunohistochemical staining of CD68, CD86, and CD206 in tissue microarrays from 253 HCC patients. Clinicopathologic features and prognostic value of these markers were evaluated. We found that CD68+ TAMs were not associated with clinicopathologic characteristics and prognosis in HCC. Low presence of CD86+ TAMs and high presence of CD206+ TAMs were markedly correlated with aggressive tumor phenotypes, such as multiple tumor number and advanced tumor-node-metastasis (TNM) stage; and were associated with poor overall survival (OS) (p = 0.027 and p = 0.024, respectively) and increased time to recurrence (TTR) (p = 0.037 and p = 0.031, respectively). In addition, combined analysis of CD86 and CD206 provided a better indicator for OS (p = 0.011) and TTR (p = 0.024) in HCC than individual analysis of CD86 and CD206. Moreover, CD86+/CD206+ TAMs predictive model also had significant prognosis value in alpha-fetoprotein (AFP)-negative patients (OS: p = 0.002, TTR: p = 0.005). Thus, these results suggest that combined analysis of immune biomarkers CD86 and CD206 could be a promising HCC prognostic biomarker. PMID- 26938528 TI - Molecular Recognition of the Catalytic Zinc(II) Ion in MMP-13: Structure-Based Evolution of an Allosteric Inhibitor to Dual Binding Mode Inhibitors with Improved Lipophilic Ligand Efficiencies. AB - Matrix metalloproteinases (MMPs) are a class of zinc dependent endopeptidases which play a crucial role in a multitude of severe diseases such as cancer and osteoarthritis. We employed MMP-13 as the target enzyme for the structure-based design and synthesis of inhibitors able to recognize the catalytic zinc ion in addition to an allosteric binding site in order to increase the affinity of the ligand. Guided by molecular modeling, we optimized an initial allosteric inhibitor by addition of linker fragments and weak zinc binders for recognition of the catalytic center. Furthermore we improved the lipophilic ligand efficiency (LLE) of the initial inhibitor by adding appropriate zinc binding fragments to lower the clogP values of the inhibitors, while maintaining their potency. All synthesized inhibitors showed elevated affinity compared to the initial hit, also most of the novel inhibitors displayed better LLE. Derivatives with carboxylic acids as the zinc binding fragments turned out to be the most potent inhibitors (compound 3 (ZHAWOC5077): IC50 = 134 nM) whereas acyl sulfonamides showed the best lipophilic ligand efficiencies (compound 18 (ZHAWOC5135): LLE = 2.91). PMID- 26938529 TI - Asbestos Induces Oxidative Stress and Activation of Nrf2 Signaling in Murine Macrophages: Chemopreventive Role of the Synthetic Lignan Secoisolariciresinol Diglucoside (LGM2605). AB - The interaction of asbestos fibers with macrophages generates harmful reactive oxygen species (ROS) and subsequent oxidative cell damage that are key processes linked to malignancy. Secoisolariciresinol diglucoside (SDG) is a non-toxic, flaxseed-derived pluripotent compound that has antioxidant properties and may thus function as a chemopreventive agent for asbestos-induced mesothelioma. We thus evaluated synthetic SDG (LGM2605) in asbestos-exposed, elicited murine peritoneal macrophages as an in vitro model of tissue phagocytic response to the presence of asbestos in the pleural space. Murine peritoneal macrophages (MFs) were exposed to crocidolite asbestos fibers (20 ug/cm2) and evaluated at various times post exposure for cytotoxicity, ROS generation, malondialdehyde (MDA), and levels of 8-iso Prostaglandin F2alpha (8-isoP). We then evaluated the ability of LGM2605 to mitigate asbestos-induced oxidative stress by administering LGM2605 (50 uM) 4-h prior to asbestos exposure. We observed a significant (p < 0.0001), time-dependent increase in asbestos-induced cytotoxicity, ROS generation, and the release of MDA and 8-iso Prostaglandin F2alpha, markers of lipid peroxidation, which increased linearly over time. LGM2605 treatment significantly (p < 0.0001) reduced asbestos-induced cytotoxicity and ROS generation, while decreasing levels of MDA and 8-isoP by 71%-88% and 41%-73%, respectively. Importantly, exposure to asbestos fibers induced cell protective defenses, such as cellular Nrf2 activation and the expression of phase II antioxidant enzymes, HO-1 and Nqo1 that were further enhanced by LGM2605 treatment. LGM2605 boosted antioxidant defenses, as well as reduced asbestos-induced ROS generation and markers of oxidative stress in murine peritoneal macrophages, supporting its possible use as a chemoprevention agent in the development of asbestos-induced malignant mesothelioma. PMID- 26938530 TI - Dietary Apigenin Exerts Immune-Regulatory Activity in Vivo by Reducing NF-kappaB Activity, Halting Leukocyte Infiltration and Restoring Normal Metabolic Function. AB - The increasing prevalence of inflammatory diseases and the adverse effects associated with the long-term use of current anti-inflammatory therapies prompt the identification of alternative approaches to reestablish immune balance. Apigenin, an abundant dietary flavonoid, is emerging as a potential regulator of inflammation. Here, we show that apigenin has immune-regulatory activity in vivo. Apigenin conferred survival to mice treated with a lethal dose of Lipopolysaccharide (LPS) restoring normal cardiac function and heart mitochondrial Complex I activity. Despite the adverse effects associated with high levels of splenocyte apoptosis in septic models, apigenin had no effect on reducing cell death. However, we found that apigenin decreased LPS-induced apoptosis in lungs, infiltration of inflammatory cells and chemotactic factors' accumulation, re-establishing normal lung architecture. Using NF-kappaB luciferase transgenic mice, we found that apigenin effectively modulated NF kappaB activity in the lungs, suggesting the ability of dietary compounds to exert immune-regulatory activity in an organ-specific manner. Collectively, these findings provide novel insights into the underlying immune-regulatory mechanisms of dietary nutraceuticals in vivo. PMID- 26938532 TI - Microarray Study of Pathway Analysis Expression Profile Associated with MicroRNA 29a with Regard to Murine Cholestatic Liver Injuries. AB - Accumulating evidence demonstrates that microRNA-29 (miR-29) expression is prominently decreased in patients with hepatic fibrosis, which consequently stimulates hepatic stellate cells' (HSCs) activation. We used a cDNA microarray study to gain a more comprehensive understanding of genome-wide gene expressions by adjusting miR-29a expression in a bile duct-ligation (BDL) animal model. METHODS: Using miR-29a transgenic mice and wild-type littermates and applying the BDL mouse model, we characterized the function of miR-29a with regard to cholestatic liver fibrosis. Pathway enrichment analysis and/or specific validation were performed for differentially expressed genes found within the comparisons. RESULTS: Analysis of the microarray data identified a number of differentially expressed genes due to the miR-29a transgene, BDL, or both. Additional pathway enrichment analysis revealed that TGF-beta signaling had a significantly differential activated pathway depending on the occurrence of miR 29a overexpression or the lack thereof. Furthermore, overexpression was found to elicit changes in Wnt/beta-catenin after BDL. CONCLUSION: This study verified that an elevated miR-29a level could alleviate liver fibrosis caused by cholestasis. Furthermore, the protective effects of miR-29a correlate with the downregulation of TGF-beta and associated with Wnt/beta-catenin signal pathway following BDL. PMID- 26938534 TI - Ground Thermal Diffusivity Calculation by Direct Soil Temperature Measurement. Application to very Low Enthalpy Geothermal Energy Systems. AB - This paper presents a methodology and instrumentation system for the indirect measurement of the thermal diffusivity of a soil at a given depth from measuring its temperature at that depth. The development has been carried out considering its application to the design and sizing of very low enthalpy geothermal energy (VLEGE) systems, but it can has many other applications, for example in construction, agriculture or biology. The methodology is simple and inexpensive because it can take advantage of the prescriptive geotechnical drilling prior to the construction of a house or building, to take at the same time temperature measurements that will allow get the actual temperature and ground thermal diffusivity to the depth of interest. The methodology and developed system have been tested and used in the design of a VLEGE facility for a chalet with basement at the outskirts of Huelva (a city in the southwest of Spain). Experimental results validate the proposed approach. PMID- 26938531 TI - Laminin Receptor-Avid Nanotherapeutic EGCg-AuNPs as a Potential Alternative Therapeutic Approach to Prevent Restenosis. AB - In our efforts to develop new approaches to treat and prevent human vascular diseases, we report herein our results on the proliferation and migration of human smooth muscles cells (SMCs) and endothelial cells (ECs) using epigallocatechin-3-gallate conjugated gold nanoparticles (EGCg-AuNPs) as possible alternatives to drug coated stents. Detailed in vitro stability studies of EGCg AuNPs in various biological fluids, affinity and selectivity towards SMCs and ECs have been investigated. The EGCg-AuNPs showed selective inhibitory efficacy toward the migration of SMCs. However, the endothelial cells remained unaffected under similar experimental conditions. The cellular internalization studies have indicated that EGCg-AuNPs internalize into the SMCs and ECs within short periods of time through laminin receptor mediated endocytosis mode. Favorable toxicity profiles and selective affinity toward SMCs and ECs suggest that EGCg-AuNPs may provide attractive alternatives to drug coated stents and therefore offer new therapeutic approaches in treating cardiovascular diseases. PMID- 26938533 TI - Natural Killer Cells--An Epigenetic Perspective of Development and Regulation. AB - Based on their ability to recognize and eliminate various endo- and exogenous pathogens as well as pathological alterations, Natural Killer (NK) cells represent an important part of the cellular innate immune system. Although the knowledge about their function is growing, little is known about their development and regulation on the molecular level. Research of the past decade suggests that modifications of the chromatin, which do not affect the base sequence of the DNA, also known as epigenetic alterations, are strongly involved in these processes. Here, the impact of epigenetic modifications on the development as well as the expression of important activating and inhibiting NK cell receptors and their effector function is reviewed. Furthermore, external stimuli such as physical activity and their influence on the epigenetic level are discussed. PMID- 26938535 TI - Performance Analysis of Visible Light Communication Using CMOS Sensors. AB - This paper elucidates the fundamentals of visible light communication systems that use the rolling shutter mechanism of CMOS sensors. All related information involving different subjects, such as photometry, camera operation, photography and image processing, are studied in tandem to explain the system. Then, the system performance is analyzed with respect to signal quality and data rate. To this end, a measure of signal quality, the signal to interference plus noise ratio (SINR), is formulated. Finally, a simulation is conducted to verify the analysis. PMID- 26938536 TI - Underwater Imaging Using a 1 * 16 CMUT Linear Array. AB - A 1 * 16 capacitive micro-machined ultrasonic transducer linear array was designed, fabricated, and tested for underwater imaging in the low frequency range. The linear array was fabricated using Si-SOI bonding techniques. Underwater transmission performance was tested in a water tank, and the array has a resonant frequency of 700 kHz, with pressure amplitude 182 dB (MUPa.m/V) at 1 m. The -3 dB main beam width of the designed dense linear array is approximately 5 degrees. Synthetic aperture focusing technique was applied to improve the resolution of reconstructed images, with promising results. Thus, the proposed array was shown to be suitable for underwater imaging applications. PMID- 26938537 TI - Laser Spot Detection Based on Reaction Diffusion. AB - Center-location of a laser spot is a problem of interest when the laser is used for processing and performing measurements. Measurement quality depends on correctly determining the location of the laser spot. Hence, improving and proposing algorithms for the correct location of the spots are fundamental issues in laser-based measurements. In this paper we introduce a Reaction Diffusion (RD) system as the main computational framework for robustly finding laser spot centers. The method presented is compared with a conventional approach for locating laser spots, and the experimental results indicate that RD-based computation generates reliable and precise solutions. These results confirm the flexibility of the new computational paradigm based on RD systems for addressing problems that can be reduced to a set of geometric operations. PMID- 26938538 TI - Fabrication and Evaluation of a Graphene Oxide-Based Capacitive Humidity Sensor. AB - In this study, a CMOS compatible capacitive humidity sensor structure was designed and fabricated on a 200 mm CMOS BEOL Line. A top Al interconnect layer was used as an electrode with a comb/serpent structure, and graphene oxide (GO) was used as sensing material. XRD analysis was done which shows that GO sensing material has a strong and sharp (002) peak at about 10.278 degrees , whereas graphite has (002) peak at about 26 degrees . Device level CV and IV curves were measured in mini-environments at different relative humidity (RH) level, and saturated salt solutions were used to build these mini-environments. To evaluate the potential value of GO material in humidity sensor applications, a prototype humidity sensor was designed and fabricated by integrating the sensor with a dedicated readout ASIC and display/calibration module. Measurements in different mini-environments show that the GO-based humidity sensor has higher sensitivity, faster recovery time and good linearity performance. Compared with a standard humidity sensor, the measured RH data of our prototype humidity sensor can match well that of the standard product. PMID- 26938539 TI - Implementation of Context Aware e-Health Environments Based on Social Sensor Networks. AB - In this work, context aware scenarios applied to e-Health and m-Health in the framework of typical households (urban and rural) by means of deploying Social Sensors will be described. Interaction with end-users and social/medical staff is achieved using a multi-signal input/output device, capable of sensing and transmitting environmental, biomedical or activity signals and information with the aid of a combined Bluetooth and Mobile system platform. The devices, which play the role of Social Sensors, are implemented and tested in order to guarantee adequate service levels in terms of multiple signal processing tasks as well as robustness in relation with the use wireless transceivers and channel variability. Initial tests within a Living Lab environment have been performed in order to validate overall system operation. The results obtained show good acceptance of the proposed system both by end users as well as by medical and social staff, increasing interaction, reducing overall response time and social inclusion levels, with a compact and moderate cost solution that can readily be largely deployed. PMID- 26938540 TI - A Monocular Vision Sensor-Based Obstacle Detection Algorithm for Autonomous Robots. AB - This paper presents a monocular vision sensor-based obstacle detection algorithm for autonomous robots. Each individual image pixel at the bottom region of interest is labeled as belonging either to an obstacle or the floor. While conventional methods depend on point tracking for geometric cues for obstacle detection, the proposed algorithm uses the inverse perspective mapping (IPM) method. This method is much more advantageous when the camera is not high off the floor, which makes point tracking near the floor difficult. Markov random field based obstacle segmentation is then performed using the IPM results and a floor appearance model. Next, the shortest distance between the robot and the obstacle is calculated. The algorithm is tested by applying it to 70 datasets, 20 of which include nonobstacle images where considerable changes in floor appearance occur. The obstacle segmentation accuracies and the distance estimation error are quantitatively analyzed. For obstacle datasets, the segmentation precision and the average distance estimation error of the proposed method are 81.4% and 1.6 cm, respectively, whereas those for a conventional method are 57.5% and 9.9 cm, respectively. For nonobstacle datasets, the proposed method gives 0.0% false positive rates, while the conventional method gives 17.6%. PMID- 26938541 TI - Online Condition Monitoring of Bearings to Support Total Productive Maintenance in the Packaging Materials Industry. AB - The packaging materials industry has already recognized the importance of Total Productive Maintenance as a system of proactive techniques for improving equipment reliability. Bearing faults, which often occur gradually, represent one of the foremost causes of failures in the industry. Therefore, detection of their faults in an early stage is quite important to assure reliable and efficient operation. We present a new automated technique for early fault detection and diagnosis in rolling-element bearings based on vibration signal analysis. Following the wavelet decomposition of vibration signals into a few sub-bands of interest, the standard deviation of obtained wavelet coefficients is extracted as a representative feature. Then, the feature space dimension is optimally reduced to two using scatter matrices. In the reduced two-dimensional feature space the fault detection and diagnosis is carried out by quadratic classifiers. Accuracy of the technique has been tested on four classes of the recorded vibrations signals, i.e., normal, with the fault of inner race, outer race, and ball operation. The overall accuracy of 98.9% has been achieved. The new technique can be used to support maintenance decision-making processes and, thus, to increase reliability and efficiency in the industry by preventing unexpected faulty operation of bearings. PMID- 26938542 TI - A Collaborative Evaluation of LC-MS/MS Based Methods for BMAA Analysis: Soluble Bound BMAA Found to Be an Important Fraction. AB - Exposure to beta-N-methylamino-l-alanine (BMAA) might be linked to the incidence of amyotrophic lateral sclerosis, Alzheimer's disease and Parkinson's disease. Analytical chemistry plays a crucial role in determining human BMAA exposure and the associated health risk, but the performance of various analytical methods currently employed is rarely compared. A CYANOCOST initiated workshop was organized aimed at training scientists in BMAA analysis, creating mutual understanding and paving the way towards interlaboratory comparison exercises. During this workshop, we tested different methods (extraction followed by derivatization and liquid chromatography coupled to tandem mass spectrometry (LC MS/MS) analysis, or directly followed by LC-MS/MS analysis) for trueness and intermediate precision. We adapted three workup methods for the underivatized analysis of animal, brain and cyanobacterial samples. Based on recovery of the internal standard D3BMAA, the underivatized methods were accurate (mean recovery 80%) and precise (mean relative standard deviation 10%), except for the cyanobacterium Leptolyngbya. However, total BMAA concentrations in the positive controls (cycad seeds) showed higher variation (relative standard deviation 21% 32%), implying that D3BMAA was not a good indicator for the release of BMAA from bound forms. Significant losses occurred during workup for the derivatized method, resulting in low recovery (<10%). Most BMAA was found in a trichloroacetic acid soluble, bound form and we recommend including this fraction during analysis. PMID- 26938544 TI - Evaluating the Appropriateness of Downscaled Climate Information for Projecting Risks of Salmonella. AB - Foodborne diseases have large economic and societal impacts worldwide. To evaluate how the risks of foodborne diseases might change in response to climate change, credible and usable climate information tailored to the specific application question is needed. Global Climate Model (GCM) data generally need to, both, be downscaled to the scales of the application to be usable, and represent, well, the key characteristics that inflict health impacts. This study presents an evaluation of temperature-based heat indices for the Washington D.C. area derived from statistically downscaled GCM simulations for 1971-2000--a necessary step in establishing the credibility of these data. The indices approximate high weekly mean temperatures linked previously to occurrences of Salmonella infections. Due to bias-correction, included in the Asynchronous Regional Regression Model (ARRM) and the Bias Correction Constructed Analogs (BCCA) downscaling methods, the observed 30-year means of the heat indices were reproduced reasonably well. In April and May, however, some of the statistically downscaled data misrepresent the increase in the number of hot days towards the summer months. This study demonstrates the dependence of the outcomes to the selection of downscaled climate data and the potential for misinterpretation of future estimates of Salmonella infections. PMID- 26938543 TI - Reduction of Endogenous Melatonin Accelerates Cognitive Decline in Mice in a Simulated Occupational Formaldehyde Exposure Environment. AB - Individuals afflicted with occupational formaldehyde (FA) exposure often suffer from abnormal behaviors such as aggression, depression, anxiety, sleep disorders, and in particular, cognitive impairments. Coincidentally, clinical patients with melatonin (MT) deficiency also complain of cognitive problems associated with the above mental disorders. Whether and how FA affects endogenous MT metabolism and induces cognitive decline need to be elucidated. To mimic occupational FA exposure environment, 16 healthy adult male mice were exposed to gaseous FA (3 mg/m3) for 7 consecutive days. Results showed that FA exposure impaired spatial memory associated with hippocampal neuronal death. Biochemical analysis revealed that FA exposure elicited an intensive oxidative stress by reducing systemic glutathione levels, in particular, decreasing brain MT concentrations. Inversely, intraperitoneal injection of MT markedly attenuated FA-induced hippocampal neuronal death, restored brain MT levels, and reversed memory decline. At tissue levels, injection of FA into the hippocampus distinctly reduced brain MT concentrations. Furthermore, at cellular and molecular levels, we found that FA directly inactivated MT in vitro and in vivo. These findings suggest that MT supplementation contributes to the rescue of cognitive decline, and may alleviate mental disorders in the occupational FA-exposed human populations. PMID- 26938546 TI - Night-Time Noise Index Based on the Integration of Awakening Potential. AB - Sleep disturbance induced by night-time noise is a serious environmental problem that can cause adverse health effects, such as hypertension and ischemic heart disease. Night-time noise indices are used to facilitate the enforcement of permitted noise levels during night-time. However, existing night-time noise indices, such as sound exposure level (SEL), maximum sound level (LA max) and night equivalent level (L night) are selected mainly because of practical reasons. Therefore, this study proposes a noise index based on neurophysiological determinants of the awakening process. These determinants have revealed that the potential on awakening is likely integrated into the brainstem that dominates wakefulness and sleep. From this evidence, a night-time noise index, N awake,year, was redefined based on the integration of the awakening potential unit (p unit) estimated from the existing dose-response relationships of awakening. The newly-defined index considers the total number of awakenings and covers a wide-range and number of noise events. We also presented examples of its applicability to traffic noise. Although further studies are needed, it may reveal a reasonable dose-response relationship between sleep disturbance and adverse health effects and provide a consistent explanation for the risks of different sound sources where the characteristics of noise exposure are quite different. PMID- 26938545 TI - The Effect of Exposure to Persistent Organic Pollutants on Metabolic Health among KOREAN Children during a 1-Year Follow-Up. AB - Previous evidence suggests the potential for adverse effects of persistent organic pollutants (POPs) on metabolic health even at low-dose exposure levels common among the general population, but there is less evidence of these associations among children. Therefore, as part of a prospective cohort study, 214 children were measured for POPs exposure. After the 1-year follow-up, we assessed the effect of circulating POPs exposure among 158 children aged 7-9 years (at baseline) on the change of metabolic components of metabolic syndrome using multiple regression analysis. In addition, we calculated the continuous metabolic syndrome (cMetS) score and assessed the variation among individuals by POPs exposure. The concentrations of marker polychlorinated biphenyls (PCBs) were significantly associated with increased change in diastolic blood pressure (BP) and triglyceride levels during a 1-year follow-up, after controlling for sex, age, household income, and change in body mass index. Total PCBs also showed a marginal association with increasing cMetS score from the baseline. Of the metabolic components, change in diastolic BP over time showed a notable association with specific PCBs, but no association with organochlorine pesticides. Here, we found that low-dose exposures to PCBs among children in the general population could negatively influence metabolic health, particularly diastolic BP. Increased disease sensitivity during childhood can continue to adulthood, thus, these results support the need for continuous assessment of the health impact of POPs. PMID- 26938547 TI - Study of Patients' Willingness to Pay for a Cure of Chronic Obstructive Pulmonary Disease in Taiwan. AB - OBJECTIVES: Chronic Obstructive Pulmonary Disease (COPD) is one of the fastest growing causes of death worldwide. However, few studies, if any, have been conducted that have investigated patient profiles in Asia. This paper analyzes patient willingness to pay (WTP) as a function of patient disease severity, health-related quality of life (HRQL), and smoking behavior in Taiwan. STUDY DESIGN: A cross-sectional survey was conducted using in-person interviews with COPD patients. A hypothetical scenario was designed and presented to ascertain each subject's willingness to pay (WTP) for a cure for COPD. METHODS: A survey of subjects with COPD was performed in Taiwan. The contingent valuation method (CVM) was employed to measure patient financial burden, which was analyzed along with covariates that included various types of health-related quality of life (HRQL), severity level, and demographic background. Multivariate regression and simulation methods were employed for analysis. RESULTS: A total of 142 subjects were interviewed, with an average annual WTP of approximately $1422 USD (or 42,662.37 NTD, New Taiwan Dollars). The annual WTP for patients 55 years of age or younger, $5709.06, was the highest and equivalent to approximately one-third of Taiwan average annual personal income or quadruple the spending amount of the Taiwan National Bureau of Health Insurance (NBHI) for each COPD patient. Current cigarette smokers were willing to pay a substantially higher amount than former smokers and nonsmokers, which reflects a psychological desire for redemption in COPD patients. CONCLUSIONS: The results of this study provide directions for the relevant authorities regarding the alleviation of suffering as a result of COPD. Appropriate health promotion measures, such as measures to reduce tobacco usage, early diagnosis, and active treatment, may be necessary to contain the escalating costs related to COPD and to prevent this epidemic from worsening. PMID- 26938549 TI - Mutation of Glycosylation Sites in BST-2 Leads to Its Accumulation at Intracellular CD63-Positive Vesicles without Affecting Its Antiviral Activity against Multivesicular Body-Targeted HIV-1 and Hepatitis B Virus. AB - BST-2/tetherin blocks the release of various enveloped viruses including HIV-1 with a "physical tethering" model. The detailed contribution of N-linked glycosylation to this model is controversial. Here, we confirmed that mutation of glycosylation sites exerted an effect of post-translational mis-trafficking, leading to an accumulation of BST-2 at intracellular CD63-positive vesicles. BST 2 with this phenotype potently inhibited the release of multivesicular body targeted HIV-1 and hepatitis B virus, without affecting the co-localization of BST-2 with EEA1 and LAMP1. These results suggest that N-linked glycosylation of human BST-2 is dispensable for intracellular virion retention and imply that this recently discovered intracellular tethering function may be evolutionarily distinguished from the canonical antiviral function of BST-2 by tethering nascent virions at the cell surface. PMID- 26938548 TI - Effects of Gold Nanorods on Imprinted Genes Expression in TM-4 Sertoli Cells. AB - Gold nanorods (GNRs) are among the most commonly used nanomaterials. However, thus far, little is known about their harmful effects on male reproduction. Studies from our laboratory have demonstrated that GNRs could decrease glycine synthesis, membrane permeability, mitochondrial membrane potential and disrupt blood-testis barrier factors in TM-4 Sertoli cells. Imprinted genes play important roles in male reproduction and have been identified as susceptible loci to environmental insults by chemicals because they are functionally haploid. In this original study, we investigated the extent to which imprinted genes become deregulated in TM-4 Sertoli cells when treated with low dose of GNRs. The expression levels of 44 imprinted genes were analyzed by quantitative real-time PCR in TM-4 Sertoli cells after a low dose of (10 nM) GNRs treatment for 24 h. We found significantly diminished expression of Kcnq1, Ntm, Peg10, Slc22a2, Pwcr1, Gtl2, Nap1l5, Peg3 and Slc22a2, while Plagl1 was significantly overexpressed. Additionally, four (Kcnq1, Slc22a18, Pwcr1 and Peg3) of 10 abnormally expressed imprinted genes were found to be located on chromosome 7. However, no significant difference of imprinted miRNA genes was observed between the GNRs treated group and controls. Our study suggested that aberrant expression of imprinted genes might be an underlying mechanism for the GNRs-induced reproductive toxicity in TM 4 Sertoli cells. PMID- 26938550 TI - Linking Virus Genomes with Host Taxonomy. AB - Environmental genomics can describe all forms of organisms--cellular and viral- present in a community. The analysis of such eco-systems biology data relies heavily on reference databases, e.g., taxonomy or gene function databases. Reference databases of symbiosis sensu lato, although essential for the analysis of organism interaction networks, are lacking. By mining existing databases and literature, we here provide a comprehensive and manually curated database of taxonomic links between viruses and their cellular hosts. PMID- 26938551 TI - Development of Liposomal Ciprofloxacin to Treat Lung Infections. AB - Except for management of Pseudomonas aeruginosa (PA) in cystic fibrosis, there are no approved inhaled antibiotic treatments for any other diseases or for infections from other pathogenic microorganisms such as tuberculosis, non tuberculous mycobacteria, fungal infections or potential inhaled biowarfare agents including Francisella tularensis, Yersinia pestis and Coxiella burnetii (which cause pneumonic tularemia, plague and Q fever, respectively). Delivery of an antibiotic formulation via the inhalation route has the potential to provide high concentrations at the site of infection with reduced systemic exposure to limit side effects. A liposomal formulation may improve tolerability, increase compliance by reducing the dosing frequency, and enhance penetration of biofilms and treatment of intracellular infections. Two liposomal ciprofloxacin formulations (Lipoquin((r)) and Pulmaquin((r))) that are in development by Aradigm Corporation are described here. PMID- 26938552 TI - Synergistic Antihypertensive Effect of Carthamus tinctorius L. Extract and Captopril in L-NAME-Induced Hypertensive Rats via Restoration of eNOS and AT1R Expression. AB - This study examined the effect of Carthamus tinctorius (CT) extract plus captopril treatment on blood pressure, vascular function, nitric oxide (NO) bioavailability, oxidative stress and renin-angiotensin system (RAS) in N(omega) Nitro-l-arginine methyl ester (l-NAME)-induced hypertension. Rats were treated with l-NAME (40 mg/kg/day) for five weeks and given CT extract (75 or 150 or 300 or 500 mg/kg/day): captopril (5 mg/kg/day) or CT extract (300 mg/kg/day) plus captopril (5 mg/kg/day) for two consecutive weeks. CT extract reduced blood pressure dose-dependently, and the most effective dose was 300 mg/kg/day. l-NAME induced hypertensive rats showed abnormalities including high blood pressure, high vascular resistance, impairment of acetylcholine-induced vasorelaxation in isolated aortic rings and mesenteric vascular beds, increased vascular superoxide production and plasma malondialdehyde levels, downregulation of eNOS, low level of plasma nitric oxide metabolites, upregulation of angiotensin II type 1 receptor and increased plasma angiotensin II. These abnormalities were alleviated by treatment with either CT extract or captopril. Combination treatment of CT extract and captopril normalized all the abnormalities found in hypertensive rats except endothelial dysfunction. These data indicate that there are synergistic antihypertensive effects of CT extract and captopril. These effects are likely mediated by their anti-oxidative properties and their inhibition of RAS. PMID- 26938553 TI - Nutritional Risk, Micronutrient Status and Clinical Outcomes: A Prospective Observational Study in an Infectious Disease Clinic. AB - Malnutrition has been associated with increased morbidity and mortality. The objective of this study was to determine the nutritional status and micronutrient levels of hospitalized patients in an infectious disease clinic and investigate their association with adverse clinical outcomes. The nutritional status of the study participants was assessed using the Nutritional Risk Screening 2002 (NRS 2002) and micronutrient levels and routine biochemical parameters were tested within the first 24 h of the patient's admission. The incidence of zinc, selenium, thiamine, vitamin B6, vitamin B12 deficiency were 66.7% (n = 40), 46.6% (n = 29), 39.7% (n = 27), 35.3% (n = 24), 14.1% (n = 9), respectively. Selenium levels were significantly higher in patients with urinary tract infections, but lower in soft tissue infections. Copper levels were significantly higher in patients with soft tissue infections. In the Cox regression models, lower albumin, higher serum lactate dehydrogenase levels and higher NRS-2002 scores were associated with increased death. Thiamine, selenium, zinc and vitamin B6 deficiencies but not chromium deficiencies are common in infectious disease clinics. New associations were found between micronutrient levels and infection type and their adverse clinical outcomes. Hypoalbuminemia and a high NRS-2002 score had the greatest accuracy in predicting death, systemic inflammatory response syndrome and sepsis on admission. PMID- 26938555 TI - A Pre and Post Survey to Determine Effectiveness of a Dietitian-Based Nutrition Education Strategy on Fruit and Vegetable Intake and Energy Intake among Adults. AB - The purpose of the study was to evaluate the effectiveness of a multicomponent nutrition education program among adults. A pretest-posttest design was used assessing Nutritional Knowledge (NK), BMI, Energy Intake (EI), Physical Activity Level (PAL), Dietary Intake (DI) and attitudes. 353 adults aged 19-55 years (178 control group (CG) and 175 intervention group (IG)) were recruited. IG participants attended nutrition education sessions evaluated through a post-test given at the end of the 12-week program. Statistical tests performed revealed that compared to CG, participants in IG increased fruit intake and decreased intake of snacks high in sugar and fat significantly (p < 0.05). NK and attitudinal scores also increased significantly in the IG (p < 0.05). No intervention effect was found for vegetables intake, EI, BMI and PAL (p > 0.05). Factors influencing NK were age, gender and education level. "Taste" was the main barrier to the application of the nutrition education strategy. Findings are helpful to health practitioners in designing their intervention programs. PMID- 26938556 TI - Particle Size, Surface Area, and Amorphous Content as Predictors of Solubility and Bioavailability for Five Commercial Sources of Ferric Orthophosphate in Ready To-Eat Cereal. AB - Ferric orthophosphate (FePO4) has had limited use as an iron fortificant in ready to-eat (RTE) cereal because of its variable bioavailability, the mechanism of which is poorly understood. Even though FePO4 has desirable sensory properties as compared to other affordable iron fortificants, few published studies have well characterized its physicochemical properties. Semi-crystalline materials such as FePO4 have varying degrees of molecular disorder, referred to as amorphous content, which is hypothesized to be an important factor in bioavailability. The objective of this study was to systematically measure the physicochemical factors of particle size, surface area, amorphous content, and solubility underlying the variation in FePO4 bioavailability. Five commercial FePO4 sources and ferrous sulfate were added to individual batches of RTE cereal. The relative bioavailability value (RBV) of each iron source, determined using the AOAC Rat Hemoglobin Repletion Bioassay, ranged from 51% to 99% (p < 0.05), which is higher than typically reported. Solubility in dilute HCl accurately predicted RBV (R2 = 0.93, p = 0.008). Amorphous content measured by Dynamic Vapor Sorption ranged from 1.7% to 23.8% and was a better determinant of solubility (R2 = 0.91; p = 0.0002) than surface area (R2 = 0.83; p = 0.002) and median particle size (R2 = 0.59; p = 0.12). The results indicate that while solubility of FePO4 is highly predictive of RBV, solubility, in turn, is strongly linked to amorphous content and surface area. This information may prove useful for the production of FePO4 with the desired RBV. PMID- 26938554 TI - Apple-Derived Pectin Modulates Gut Microbiota, Improves Gut Barrier Function, and Attenuates Metabolic Endotoxemia in Rats with Diet-Induced Obesity. AB - This study was aimed at determining potential effects of apple-derived pectin on weight gain, gut microbiota, gut barrier and metabolic endotoxemia in rat models of diet-induced obesity. The rats received a standard diet (control; Chow group; n = 8) or a high-fat diet (HFD; n = 32) for eight weeks to induce obesity. The top 50th percentile of weight-gainers were selected as diet induced obese rats. Thereafter, the Chow group continued on chow, and the diet induced obese rats were randomly divided into two groups and received HFD (HF group; n = 8) or pectin-supplemented HFD (HF-P group; n = 8) for six weeks. Compared to the HF group, the HF-P group showed attenuated weight gain (207.38 +/- 7.96 g vs. 283.63 +/- 10.17 g, p < 0.01) and serum total cholesterol level (1.46 +/- 0.13 mmol/L vs. 2.06 +/- 0.26 mmol/L, p < 0.01). Compared to the Chow group, the HF group showed a decrease in Bacteroidetes phylum and an increase in Firmicutes phylum, as well as subordinate categories (p < 0.01). These changes were restored to the normal levels in the HF-P group. Furthermore, compared to the HF group, the HF-P group displayed improved intestinal alkaline phosphatase (0.57 +/- 0.20 vs. 0.30 +/- 0.19, p < 0.05) and claudin 1 (0.76 +/- 0.14 vs. 0.55 +/- 0.18, p < 0.05) expression, and decreased Toll-like receptor 4 expression in ileal tissue (0.76 +/- 0.58 vs. 2.04 +/- 0.89, p < 0.01). The HF-P group also showed decreased inflammation (TNFalpha: 316.13 +/- 7.62 EU/mL vs. 355.59 +/- 8.10 EU/mL, p < 0.01; IL-6: 51.78 +/- 2.35 EU/mL vs. 58.98 +/- 2.59 EU/mL, p < 0.01) and metabolic endotoxemia (2.83 +/- 0.42 EU/mL vs. 0.68 +/- 0.14 EU/mL, p < 0.01). These results suggest that apple-derived pectin could modulate gut microbiota, attenuate metabolic endotoxemia and inflammation, and consequently suppress weight gain and fat accumulation in diet induced obese rats. PMID- 26938557 TI - Dietary Advanced Glycation End Products and Risk Factors for Chronic Disease: A Systematic Review of Randomised Controlled Trials. AB - Dietary advanced glycation end-products (AGEs) form during heating and processing of food products and are widely prevalent in the modern Western diet. Recent systematic reviews indicate that consumption of dietary AGEs may promote inflammation, oxidative stress and insulin resistance. Experimental evidence indicates that dietary AGEs may also induce renal damage, however, this outcome has not been considered in previous systematic reviews. The purpose of this review was to examine the effect of consumption of a high AGE diet on biomarkers of chronic disease, including chronic kidney disease (CKD), in human randomized controlled trials (RCTs). Six databases (SCOPUS, CINHAL, EMBASE, Medline, Biological abstracts and Web of Science) were searched for randomised controlled dietary trials that compared high AGE intake to low AGE intake in adults with and without obesity, diabetes or CKD. Twelve dietary AGE interventions were identified with a total of 293 participants. A high AGE diet increased circulating tumour necrosis factor-alpha and AGEs in all populations. A high AGE diet increased 8-isoprostanes in healthy adults, and vascular cell adhesion molecule-1 (VCAM-1) in patients with diabetes. Markers of CKD were not widely assessed. The evidence presented indicates that a high AGE diet may contribute to risk factors associated with chronic disease, such as inflammation and oxidative stress, however, due to a lack of high quality randomised trials, more research is required. PMID- 26938558 TI - Isolation and Pharmacological Characterization of alpha-Elapitoxin-Ot1a, a Short Chain Postsynaptic Neurotoxin from the Venom of the Western Desert Taipan, Oxyuranus temporalis. AB - Taipans (Oxyuranus spp.) are elapids with highly potent venoms containing presynaptic (beta) and postsynaptic (alpha) neurotoxins. O. temporalis (Western Desert taipan), a newly discovered member of this genus, has been shown to possess venom which displays marked in vitro neurotoxicity. No components have been isolated from this venom. We describe the characterization of alpha elapitoxin-Ot1a (alpha-EPTX-Ot1a; 6712 Da), a short-chain postsynaptic neurotoxin, which accounts for approximately 30% of O. temporalis venom. alpha Elapitoxin-Ot1a (0.1-1 uM) produced concentration-dependent inhibition of indirect-twitches, and abolished contractile responses to exogenous acetylcholine and carbachol, in the chick biventer cervicis nerve-muscle preparation. The inhibition of indirect twitches by alpha-elapitoxin-Ot1a (1 uM) was not reversed by washing the tissue. Prior addition of taipan antivenom (10 U/mL) delayed the neurotoxic effects of alpha-elapitoxin-Ot1a (1 uM) and markedly attenuated the neurotoxic effects of alpha-elapitoxin-Ot1a (0.1 uM). alpha-Elapitoxin-Ot1a displayed pseudo-irreversible antagonism of concentration-response curves to carbachol with a pA2 value of 8.02 +/- 0.05. De novo sequencing revealed the main sequence of the short-chain postsynaptic neurotoxin (i.e., alpha-elapitoxin-Ot1a) as well as three other isoforms found in O. temporalis venom. alpha-Elapitoxin Ot1a shows high sequence similarity (i.e., >87%) with other taipan short-chain postsynaptic neurotoxins. PMID- 26938559 TI - Botulinum toxin A for the Treatment of Overactive Bladder. AB - The standard treatment for overactive bladder starts with patient education and behavior therapies, followed by antimuscarinic agents. For patients with urgency urinary incontinence refractory to antimuscarinic therapy, currently both American Urological Association (AUA) and European Association of Urology (EAU) guidelines suggested that intravesical injection of botulinum toxin A should be offered. The mechanism of botulinum toxin A includes inhibition of vesicular release of neurotransmitters and the axonal expression of capsaicin and purinergic receptors in the suburothelium, as well as attenuation of central sensitization. Multiple randomized, placebo-controlled trials demonstrated that botulinum toxin A to be an effective treatment for patients with refractory idiopathic or neurogenic detrusor overactivity. The urinary incontinence episodes, maximum cystometric capacity, and maximum detrusor pressure were improved greater by botulinum toxin A compared to placebo. The adverse effects of botulinum toxin A, such as urinary retention and urinary tract infection, were primarily localized to the lower urinary tract. Therefore, botulinum toxin A offers an effective treatment option for patients with refractory overactive bladder. PMID- 26938560 TI - Paulistine--The Functional Duality of a Wasp Venom Peptide Toxin. AB - It has been reported that Paulistine in the venom of the wasp Polybia paulista co exists as two different forms: an oxidized form presenting a compact structure due to the presence of a disulfide bridge, which causes inflammation through an apparent interaction with receptors in the 5-lipoxygenase pathway, and a naturally reduced form (without the disulfide bridge) that exists in a linear conformation and which also causes hyperalgesia and acts in the cyclooxygenase type II pathway. The reduced peptide was acetamidomethylated (Acm-Paulistine) to stabilize this form, and it still maintained its typical inflammatory activity. Oxidized Paulistine docks onto PGHS2 (COX-2) molecules, blocking the access of oxygen to the heme group and inhibiting the inflammatory activity of Acm Paulistine in the cyclooxygenase type II pathway. Docking simulations revealed that the site of the docking of Paulistine within the PGHS2 molecule is unusual among commercial inhibitors of the enzyme, with an affinity potentially much higher than those observed for traditional anti-inflammatory drugs. Therefore, Paulistine causes inflammatory activity at the level of the 5-lipooxygenase pathway and, in parallel, it competes with its reduced form in relation to the activation of the cyclooxygenase pathway. Thus, while the reduced Paulistine causes inflammation, its oxidized form is a potent inhibitor of this activity. PMID- 26938562 TI - Genome-Wide Identification and Characterization of Long Non-Coding RNAs from Mulberry (Morus notabilis) RNA-seq Data. AB - Numerous sources of evidence suggest that most of the eukaryotic genome is transcribed into protein-coding mRNAs and also into a large number of non-coding RNAs (ncRNAs). Long ncRNAs (lncRNAs), a group consisting of ncRNAs longer than 200 nucleotides, have been found to play critical roles in transcriptional, post transcriptional, and epigenetic gene regulation across all kingdoms of life. However, lncRNAs and their regulatory roles remain poorly characterized in plants, especially in woody plants. In this paper, we used a computational approach to identify novel lncRNAs from a published RNA-seq data set and analyzed their sequences and expression patterns. In total, 1133 novel lncRNAs were identified in mulberry, and 106 of these lncRNAs displayed a predominant tissue specific expression in the five major tissues investigated. Additionally, functional predictions revealed that tissue-specific lncRNAs adjacent to protein coding genes might play important regulatory roles in the development of floral organ and root in mulberry. The pipeline used in this study would be useful for the identification of lncRNAs obtained from other deep sequencing data. Furthermore, the predicted lncRNAs would be beneficial towards an understanding of the variations in gene expression in plants. PMID- 26938561 TI - A Review of Bioinsecticidal Activity of Solanaceae Alkaloids. AB - Only a small percentage of insect species are pests. However, pest species cause significant losses in agricultural and forest crops, and many are vectors of diseases. Currently, many scientists are focused on developing new tools to control insect populations, including secondary plant metabolites, e.g., alkaloids, glycoalkaloids, terpenoids, organic acids and alcohols, which show promise for use in plant protection. These compounds can affect insects at all levels of biological organization, but their action generally disturbs cellular and physiological processes, e.g., by altering redox balance, hormonal regulation, neuronal signalization or reproduction in exposed individuals. Secondary plant metabolites cause toxic effects that can be observed at both lethal and sublethal levels, but the most important effect is repellence. Plants from the Solanaceae family, which contains numerous economically and ecologically important species, produce various substances that affect insects belonging to most orders, particularly herbivorous insects and other pests. Many compounds possess insecticidal properties, but they are also classified as molluscides, acaricides, nematocides, fungicides and bactericides. In this paper, we present data on the sublethal and lethal toxicity caused by pure metabolites and crude extracts obtained from Solanaceae plants. Pure substances as well as water and/or alcohol extracts cause lethal and sublethal effects in insects, which is important from the economical point of view. We discuss the results of our study and their relevance to plant protection and management. PMID- 26938563 TI - Effects of Pesticide Treatments on Nutrient Levels in Worker Honey Bees (Apis mellifera). AB - Honey bee colony loss continues to be an issue and no factor has been singled out as to the cause. In this study, we sought to determine whether two beekeeper applied pesticide products, tau-fluvalinate and Fumagilin-B((r)), and one agrochemical, chlorothalonil, impact the nutrient levels in honey bee workers in a natural colony environment. Treatments were performed in-hive and at three different periods (fall, spring, and summer) over the course of one year. Bees were sampled both at pre-treatment and two and four weeks post-treatment, weighed, and their protein and carbohydrate levels were determined using BCA and anthrone based biochemical assays, respectively. We report that, based on the pesticide concentrations tested, no significant negative impact of the pesticide products was observed on wet weight, protein levels, or carbohydrate levels of bees from treated colonies compared with bees from untreated control colonies. PMID- 26938564 TI - A Comparative Analysis of the Mechanism of Toll-Like Receptor-Disruption by TIR Containing Protein C from Uropathogenic Escherichia coli. AB - The TIR-containing protein C (TcpC) of uropathogenic Escherichia coli strains is a powerful virulence factor by impairing the signaling cascade of Toll-like receptors (TLRs). Several other bacterial pathogens like Salmonella, Yersinia, Staphylococcus aureus but also non-pathogens express similar proteins. We discuss here the pathogenic potential of TcpC and its interaction with TLRs and TLR adapter proteins on the molecular level and compare its activity with the activity of other bacterial TIR-containing proteins. Finally, we analyze and compare the structure of bacterial TIR-domains with the TIR-domains of TLRs and TLR-adapters. PMID- 26938565 TI - Correction: Global Occurrence and Emission of Rotaviruses to Surface Waters. Pathogens 2015, 4, 229-255. AB - The authors wish to make the following corrections to their paper [1].[...]. PMID- 26938567 TI - Hybrid and Mixed Matrix Membranes for Separations from Fermentations. AB - Fermentations provide an alternative to fossil fuels for accessing a number of biofuel and chemical products from a variety of renewable and waste substrates. The recovery of these dilute fermentation products from the broth, however, can be incredibly energy intensive as a distillation process is generally involved and creates a barrier to commercialization. Membrane processes can provide a low energy aid/alternative for recovering these dilute fermentation products and reduce production costs. For these types of separations many current polymeric and inorganic membranes suffer from poor selectivity and high cost respectively. This paper reviews work in the production of novel mixed-matrix membranes (MMMs) for fermentative separations and those applicable to these separations. These membranes combine a trade-off of low-cost and processability of polymer membranes with the high selectivity of inorganic membranes. Work within the fields of nanofiltration, reverse osmosis and pervaporation has been discussed. The review shows that MMMs are currently providing some of the most high-performing membranes for these separations, with three areas for improvement identified: Further characterization and optimization of inorganic phase(s), Greater understanding of the compatibility between the polymer and inorganic phase(s), Improved methods for homogeneously dispersing the inorganic phase. PMID- 26938568 TI - Hybrid Processes Combining Photocatalysis and Ceramic Membrane Filtration for Degradation of Humic Acids in Saline Water. AB - This study explored the combined effects of photocatalysis with ceramic membrane filtration for the removal of humic acid in the presence of salt; to simulate saline wastewater conditions. The effects of operating parameters, such as salinity and TiO2 concentration on permeate fluxes, total organic carbon (TOC), and UV absorbance removal, were investigated. The interaction between the humic acids and TiO2 photocatalyst played an important role in the observed flux change during ceramic membrane filtration. The results for this hybrid system showed that the TOC removal was more than 70% for both without NaCl and with the 500 ppm NaCl concentration, and 62% and 66% for 1000 and 2000 ppm NaCl concentrations. The reduction in UV absorbance was more complete in the absence of NaCl compared to the presence of NaCl. The operation of the integrated photoreactor-ceramic membrane filter over five repeat cycles is described. It can be concluded that the overall removal performance of the hybrid system was influenced by the presence of salts, as salt leads to agglomeration of TiO2 particles by suppressing the stabilising effects of electrostatic repulsion and thereby reduces the effective surface contact between the pollutant and the photocatalyst. PMID- 26938566 TI - Integrating Immunologic Signaling Networks: The JAK/STAT Pathway in Colitis and Colitis-Associated Cancer. AB - Cytokines are believed to be crucial mediators of chronic intestinal inflammation in inflammatory bowel diseases (IBD) such as Crohn's disease (CD) and ulcerative colitis (UC). Many of these cytokines trigger cellular effects and functions through signaling via janus kinase (JAK) and signal transducer and activator of transcription (STAT) molecules. In this way, JAK/STAT signaling controls important events like cell differentiation, secretion of cytokines or proliferation and apoptosis in IBD in both adaptive and innate immune cells. Moreover, JAK/STAT signaling, especially via the IL-6/STAT3 axis, is believed to be involved in the transition of inflammatory lesions to tumors leading to colitis-associated cancer (CAC). In this review, we will introduce the main cellular players and cytokines that contribute to pathogenesis of IBD by JAK/STAT signaling, and will highlight the integrative function that JAK/STATs exert in this context as well as their divergent role in different cells and processes. Moreover, we will explain current concepts of the implication of JAK/STAT signaling in CAC and finally discuss present and future therapies for IBD that interfere with JAK/STAT signaling. PMID- 26938569 TI - Culture of Oral Mucosal Epithelial Cells for the Purpose of Treating Limbal Stem Cell Deficiency. AB - The cornea is critical for normal vision as it allows allowing light transmission to the retina. The corneal epithelium is renewed by limbal epithelial cells (LEC), which are located in the periphery of the cornea, the limbus. Damage or disease involving LEC may lead to various clinical presentations of limbal stem cell deficiency (LSCD). Both severe pain and blindness may result. Transplantation of cultured autologous oral mucosal epithelial cell sheet (CAOMECS) represents the first use of a cultured non-limbal autologous cell type to treat this disease. Among non-limbal cell types, CAOMECS and conjunctival epithelial cells are the only laboratory cultured cell sources that have been explored in humans. Thus far, the expression of p63 is the only predictor of clinical outcome following transplantation to correct LSCD. The optimal culture method and substrate for CAOMECS is not established. The present review focuses on cell culture methods, with particular emphasis on substrates. Most culture protocols for CAOMECS used amniotic membrane as a substrate and included the xenogeneic components fetal bovine serum and murine 3T3 fibroblasts. However, it has been demonstrated that tissue-engineered epithelial cell sheet grafts can be successfully fabricated using temperature-responsive culture surfaces and autologous serum. In the studies using different substrates for culture of CAOMECS, the quantitative expression of p63 was generally poorly reported; thus, more research is warranted with quantification of phenotypic data. Further research is required to develop a culture system for CAOMECS that mimics the natural environment of oral/limbal/corneal epithelial cells without the need for undefined foreign materials such as serum and feeder cells. PMID- 26938571 TI - Repeated sprint ability in soccer players: associations with physiological and neuromuscular factors. AB - BACKGROUND: The aim of this study was to examine the relationship between repeated sprint ability (RSA, 6*40 m [20+20 m] with 20-s recovery) and neuromuscular and aerobic fitness variables in male collegiate soccer players. METHODS: Twenty-six players (age 22.5+/-3.6 years) were tested on separate days for countermovement jump (CMJ), squat jump (SJ), and standing long jump (LJ), and for maximal oxygen consumption (VO2max), velocity at onset of blood lactate accumulation (vOBLA), maximal aerobic speed (vVO2max), and peak blood lactate concentration (peak [La]). They were also tested for best and mean times on a repeated shuttle sprint ability test. RESULTS: RSA best time (r=-0.73 and r= 0.54) and RSA mean sprint time (r=-0.69 and r=-0.62) were significantly (P<0.01) correlated with LJ and CMJ, respectively. Significant correlations (P<0.05) were also found between RSA mean sprint time and sprint decrement with vOBLA (r=-0.44) and peak [La] (r=0.47), respectively. CONCLUSIONS: This study showed that RSA performance had a large to very large association with the individual level of jump performance and to a smaller extent to aerobic fitness variables in male collegiate soccer players. Given this finding, lower limbs' explosive-strength performance should be regarded as a relevant factor for male soccer. PMID- 26938570 TI - Comparison of Electrochemical Immunosensors and Aptasensors for Detection of Small Organic Molecules in Environment, Food Safety, Clinical and Public Security. AB - We review here the most frequently reported targets among the electrochemical immunosensors and aptasensors: antibiotics, bisphenol A, cocaine, ochratoxin A and estradiol. In each case, the immobilization procedures are described as well as the transduction schemes and the limits of detection. It is shown that limits of detections are generally two to three orders of magnitude lower for immunosensors than for aptasensors, due to the highest affinities of antibodies. No significant progresses have been made to improve these affinities, but transduction schemes were improved instead, which lead to a regular improvement of the limit of detections corresponding to ca. five orders of magnitude over these last 10 years. These progresses depend on the target, however. PMID- 26938572 TI - Detection of Tumor Invasive Biomarker using a Peptamer of Signal Conversion and Signal Amplification. AB - Inspired by the structural and functional features of proteins in cell signaling, a switchable peptide is designed in this work. This switchable peptide is named a "peptamer," and it can react to ligand binding with conformational change and activation/deactivation of catalytic ability. The peptamer is constructed by elaborately integrating several different peptide motifs with targeting and catalytic abilities. Thus, targeted binding of the peptamer to an integrin can be regulated by a synthetic ligand. Moreover, the conformational rearrangement of the peptamer induced by both integrin and the synthetic ligand can resolve in altered affinity of the peptamer for a catalytic cofactor, cupric ion. This leads to greatly contrasted efficiency of catalysis in the presence/absence of integrin. This distinct switching on/off of catalytic activity also enables a bioassay of tissue integrin expression in clinical samples of thyroid carcinoma. Experimental results reveal that the detected integrin level parallels the state of lymph node metastasis. Therefore, this simple peptide model may help to understand the structural reconfiguration of proteins involved in cellular signal transduction, as well as to provide a new means to assess protein activity under pathological conditions such as cancer. PMID- 26938573 TI - Practice Bulletin No. 162: Prenatal Diagnostic Testing for Genetic Disorders. AB - Prenatal genetic diagnostic testing is intended to determine, with as much certainty as possible, whether a specific genetic disorder or condition is present in the fetus. In contrast, prenatal genetic screening is designed to assess whether a patient is at increased risk of having a fetus affected by a genetic disorder. Originally, prenatal genetic testing focused primarily on Down syndrome (trisomy 21), but now it is able to detect a broad range of genetic disorders. Although it is necessary to perform amniocentesis or chorionic villus sampling (CVS) to definitively diagnose most genetic disorders, in some circumstances, fetal imaging with ultrasonography, echocardiography, or magnetic resonance imaging may be diagnostic of a particular structural fetal abnormality that is suggestive of an underlying genetic condition.The objective of prenatal genetic testing is to detect health problems that could affect the woman, fetus, or newborn and provide the patient and her obstetrician-gynecologist or other obstetric care provider with enough information to allow a fully informed decision about pregnancy management. Prenatal genetic testing cannot identify all abnormalities or problems in a fetus, and any testing should be focused on the individual patient's risks, reproductive goals, and preferences. It is important that patients understand the benefits and limitations of all prenatal screening and diagnostic testing, including the conditions for which tests are available and the conditions that will not be detected by testing. It also is important that patients realize that there is a broad range of clinical presentations, or phenotypes, for many genetic disorders and that results of genetic testing cannot predict all outcomes. Prenatal genetic testing has many benefits, including reassuring patients when results are normal, identifying disorders for which prenatal treatment may provide benefit, optimizing neonatal outcomes by ensuring the appropriate location for delivery and the necessary personnel to care for affected infants, and allowing the opportunity for pregnancy termination.The purpose of this Practice Bulletin is to review the current status of prenatal genetic diagnostic testing and the evidence supporting its use. For information regarding screening for fetal aneuploidy, refer to Practice Bulletin No. 163, Screening for Fetal Aneuploidy. PMID- 26938574 TI - Practice Bulletin No. 163: Screening for Fetal Aneuploidy. AB - Prenatal genetic screening is designed to assess whether a patient is at increased risk of having a fetus affected by a genetic disorder. In contrast, prenatal genetic diagnostic testing is intended to determine, with as much certainty as possible, whether a specific genetic disorder or condition is present in the fetus. The purpose of prenatal screening for aneuploidy is to provide an assessment of the woman's risk of carrying a fetus with one of the more common fetal aneuploidies. This is in contrast to prenatal diagnostic testing for genetic disorders, in which the fetal chromosomes are evaluated for the presence or absence of abnormalities in chromosome number, deletions, and duplications, or the fetal DNA is evaluated for specific genetic disorders. The wide variety of screening test options, each offering varying levels of information and accuracy, has resulted in the need for complex counseling by the health care provider and complex decision making by the patient. No one screening test is superior to other screening tests in all test characteristics. Each test has relative advantages and disadvantages. It is important that obstetrician gynecologists and other obstetric care providers be prepared to discuss not only the risk of aneuploidy but also the benefits, risks, and limitations of available screening tests. Screening for aneuploidy should be an informed patient choice, with an underlying foundation of shared decision making that fits the patient's clinical circumstances, values, interests, and goals.The purpose of this Practice Bulletin is to provide current information regarding the available screening test options for fetal aneuploidy and to review their benefits, accuracy, and limitations. For information regarding prenatal diagnostic testing for genetic disorders, refer to Practice Bulletin No. 162, Prenatal Diagnostic Testing for Genetic Disorders. PMID- 26938575 TI - How Much Can Density Functional Approximations (DFA) Fail? The Extreme Case of the FeO4 Species. AB - A thorough theoretical study of the relative energies of various molecular Fe.4O isomers with different oxidation states of both Fe and O atoms is presented, comparing simple Hartree-Fock through many Kohn-Sham approximations up to extended coupled cluster and DMRG multiconfiguration benchmark methods. The ground state of Fe.4O is a singlet, hexavalent iron(VI) complex (1)C2v [Fe(VI)O2](2+)(O2)(2-), with isomers of oxidation states Fe(II), Fe(III), Fe(IV), Fe(V), and Fe(VIII) all lying slightly higher within the range of 1 eV. The disputed existence of oxidation state Fe(VIII) is discussed for isolated FeO4 molecules. Density functional theory (DFT) at various DF approximation (DFA) levels of local and gradient approaches, Hartree-Fock exchange and meta hybrids, range dependent, DFT-D and DFT+U models do not perform better for the relative stabilities of the geometric and electronic Fe.4O isomers than within 1-5 eV. The Fe.4O isomeric species are an excellent testing and validation ground for the development of density functional and wave function methods for strongly correlated multireference states, which do not seem to always follow chemical intuition. PMID- 26938576 TI - Wrinkles and Folds of Activated Graphene Nanosheets as Fast and Efficient Adsorptive Sites for Hydrophobic Organic Contaminants. AB - To create more wrinkles and folds as available adsorption sites, graphene nanosheets (GNS) were thermally treated with KOH for morphological alteration. The surface structures and properties of the activated graphene nanosheets (AGN) were characterized by BET-N2, SEM, TEM, Raman, XRD, XPS, and FTIR. After KOH etching, the highly crystal structure was altered, self-aggregation of graphene layers were evidently relieved, and more single to few layer graphene nanosheets were created with wrinkles and folds. Also both specific surface area and micropore volume of AGN increased relative to GNS. The adsorption of AGN toward p nitrotoluene, naphthalene and phenanthrene were greatly enhanced in comparison with GNS, and gradually promoted with increasing degree of KOH etching. Adsorption rate of organic contaminants on AGN was very fast and efficient, whereas small molecules showed higher adsorption rates due to the more porous surface of graphene. In addition to pi-pi interaction, the high affinities of p nitrotoluene to AGN are suggested from strong electron charge transfer interactions between nitro groups on p-nitrotoluene and defect sites of AGN. A positively linear correlation between organic molecule uptake and the micropore volume of AGN indicated that pore-filling mechanism may play an important role in adsorption. Morphological wrinkles and folds of graphene nanosheets can be regulated to enhance the adsorption capability and kinetics for efficient pollutant removal and to selectively preconcentrate adsorbates with different sizes for detection. PMID- 26938577 TI - Functional Vomiting Treated Successfully with Aripiprazole in a Child with Autism Spectrum Disorder. PMID- 26938578 TI - Inhaled beclometasone dipropionate/formoterol fumarate extrafine fixed combination for the treatment of asthma. AB - Inhaled therapy is often considered the cornerstone of asthma management and international guidelines recommend combination therapy of inhaled corticosteroids (ICS) and long-acting-beta2-agonists (LABA) in a large proportion of asthmatic patients. The effectiveness of ICS/LABA is dependent on the correct choice of device and proper inhalation technique, this influences drug delivery and distribution along the bronchial tree, including the most peripheral airways. The fixed combination of beclometasone dipropionate/formoterol fumarate (BDP/FF) is the only extrafine formulation available in pressurized metered dose inhaler (pMDI) and in dry powder inhaler (DPI). Here, we focus on the recent significant advances regarding BDP/FF fixed combination for the treatment of asthma. PMID- 26938579 TI - A Prospective Masked Clinical Assessment of Inflammation After Intravitreal Injection of Ranibizumab or Aflibercept. AB - PURPOSE: To compare anterior chamber and vitreous inflammation after intravitreal injection of ranibizumab or aflibercept. METHODS: This was a prospective, open label, nonrandomized phase 4 clinical study. One hundred patients with choroidal neovascularization due to age-related macular degeneration received intravitreal aflibercept (N = 53) or ranibizumab (N = 47). Medication use was balanced by gender, injected eye, and lens status (phakic vs. pseudophakic). An examiner masked to medication graded anterior chamber and vitreous inflammation 1-2 and 5 7 days after injection according to the Standardization of Uveitis Nomenclature grading scheme. RESULTS: Mean patient age was 78.6 years. Maximum anterior chamber reaction of 0.5+ was seen at the first postinjection examination in 2% of eyes receiving ranibizumab and in 19% of eyes receiving aflibercept (Fisher's exact test 2 sided, P = 0.0091); vitreous reaction was minimal and infrequent in both groups and the difference was not statistically significant. At 5-7 days after injection, 1 patient treated with aflibercept had residual anterior chamber inflammation of 0.5+ and no patient treated with ranibizumab had residual inflammation. CONCLUSION: Aflibercept may be associated with more anterior chamber inflammation than ranibizumab, although mild and transient. This should not be mistaken for endophthalmitis. PMID- 26938580 TI - Anterior Loop of the Inferior Alveolar Canal: A Cone-Beam Computerized Tomography Study of 494 Cases. AB - The aim of this study was to use cone-beam computerized tomography (CBCT) images of patients to assess the prevalence of different types, especially anterior loop, of the mental portion of the inferior alveolar canal and to evaluate the anterior loop lengths. CBCT images of 494 patients providing inclusion criteria were examined by 2 oral radiologists. Sagittal, axial, and multiplanar reformatted images were used to detect the type of mental portion of the inferior alveolar canal. The anterior loop length was measured in the respective sections of each CBCT image. Statistical analysis was performed using SPSS v. 15, and t tests were used for statistical analysis. Of the 494 patients, 217 anterior loops were detected in 141 (28.5%) patients. The mean anterior loop lengths for the right side and the left side were 2.19 +/- 1 mm and 2.08 +/- 0.89 mm, respectively. The difference between males and females in the mean anterior loop length was statistically significant for both sides (Right: P < .05; Left: P < .05). A presurgical CBCT image examination is necessary prior to implant insertion to reveal the presence of anterior loop and to detect actual anterior loop length. PMID- 26938581 TI - Nontargeted Screening of Food Matrices: Development of a Chemometric Software Strategy To Identify Unknowns in Liquid Chromatography-Mass Spectrometry Data. AB - The ability to identify contaminants or adulterants in diverse, complex sample matrixes is necessary in food safety. Thus, nontargeted screening approaches must be implemented to detect and identify unexpected, unknown hazardous compounds that may be present. Molecular formulas can be generated for detected compounds from high-resolution mass spectrometry data, but analysis can be lengthy when thousands of compounds are detected in a single sample. Efficient data mining methods to analyze these complex data sets are necessary given the inherent chemical diversity and variability of food matrixes. The aim of this work is to determine necessary requirements to successfully apply data analysis strategies to distinguish suspect and control samples. Infant formula and orange juice samples were analyzed with one lot of each matrix containing varying concentrations of a four compound mixture to represent a suspect sample set. Small molecular differences were parsed from the data, where analytes as low as 10 ppb were revealed. This was accomplished, in part, by analyzing a quality control standard, matrix spiked with an analytical standard mixture, technical replicates, a representative number of sample lots, and blanks within the sample sequence; this enabled the development of a data analysis workflow and ensured that the employed method is sufficient for mining relevant molecular features from the data. PMID- 26938582 TI - Characterization of a small acyl-CoA-binding protein (ACBP) from Helianthus annuus L. and its binding affinities. AB - Acyl-CoA-binding proteins (ACBPs) bind to acyl-CoA esters and promote their interaction with other proteins, lipids and cell structures. Small class I ACBPs have been identified in different plants, such as Arabidopsis thaliana (AtACBP6), Brassica napus (BnACBP) and Oryza sativa (OsACBP1, OsACBP2, OsACBP3), and they are capable of binding to different acyl-CoA esters and phospholipids. Here we characterize HaACBP6, a class I ACBP expressed in sunflower (Helianthus annuus) tissues, studying the specificity of its corresponding recombinant HaACBP6 protein towards various acyl-CoA esters and phospholipids in vitro, particularly using isothermal titration calorimetry and protein phospholipid binding assays. This protein binds with high affinity to de novo synthetized derivatives palmitoly-CoA, stearoyl-CoA and oleoyl-CoA (Kd 0.29, 0.14 and 0.15 MUM respectively). On the contrary, it showed lower affinity towards linoleoyl-CoA (Kd 5.6 MUM). Moreover, rHaACBP6 binds to different phosphatidylcholine species (dipalmitoyl-PC, dioleoyl-PC and dilinoleoyl-PC), yet it displays no affinity towards other phospholipids like lyso-PC, phosphatidic acid and lysophosphatidic acid derivatives. In the light of these results, the possible involvement of this protein in sunflower oil synthesis is considered. PMID- 26938583 TI - RiskSOAP: Introducing and applying a methodology of risk self-awareness in road tunnel safety. AB - Complex socio-technical systems, such as road tunnels, can be designed and developed with more or less elements that can either positively or negatively affect the capability of their agents to recognise imminent threats or vulnerabilities that possibly lead to accidents. This capability is called risk Situation Awareness (SA) provision. Having as a motive the introduction of better tools for designing and developing systems that are self-aware of their vulnerabilities and react to prevent accidents and losses, this paper introduces the Risk Situation Awareness Provision (RiskSOAP) methodology to the field of road tunnel safety, as a means to measure this capability in this kind of systems. The main objective is to test the soundness and the applicability of RiskSOAP to infrastructure, which is advanced in terms of technology, human integration, and minimum number of safety requirements imposed by international bodies. RiskSOAP is applied to a specific road tunnel in Greece and the accompanying indicator is calculated twice, once for the tunnel design as defined by updated European safety standards and once for the 'as-is' tunnel composition, which complies with the necessary safety requirements, but calls for enhancing safety according to what EU and PIARC further suggest. The derived values indicate the extent to which each tunnel version is capable of comprehending its threats and vulnerabilities based on its elements. The former tunnel version seems to be more enhanced both in terms of it risk awareness capability and safety as well. Another interesting finding is that despite the advanced tunnel safety specifications, there is still room for enriching the safe design and maintenance of the road tunnel. PMID- 26938584 TI - Investigating driver injury severity patterns in rollover crashes using support vector machine models. AB - Rollover crash is one of the major types of traffic crashes that induce fatal injuries. It is important to investigate the factors that affect rollover crashes and their influence on driver injury severity outcomes. This study employs support vector machine (SVM) models to investigate driver injury severity patterns in rollover crashes based on two-year crash data gathered in New Mexico. The impacts of various explanatory variables are examined in terms of crash and environmental information, vehicle features, and driver demographics and behavior characteristics. A classification and regression tree (CART) model is utilized to identify significant variables and SVM models with polynomial and Gaussian radius basis function (RBF) kernels are used for model performance evaluation. It is shown that the SVM models produce reasonable prediction performance and the polynomial kernel outperforms the Gaussian RBF kernel. Variable impact analysis reveals that factors including comfortable driving environment conditions, driver alcohol or drug involvement, seatbelt use, number of travel lanes, driver demographic features, maximum vehicle damages in crashes, crash time, and crash location are significantly associated with driver incapacitating injuries and fatalities. These findings provide insights for better understanding rollover crash causes and the impacts of various explanatory factors on driver injury severity patterns. PMID- 26938585 TI - [Neuromyelitis optica spectrum disorders as initial presentation of Sjogren's syndrome: A case report]. AB - Neuromyelitis Optica Spectrum Disorder (NMOSD) is a rare systemic autoimmune disease which is sometimes found in association with other autoimmune disorders including Sjogren's syndrome. Neurological manifestations occur in 20% to 25% of diagnosed cases of Sjogren's syndrome; however, less than 5% of patients with Sjogren's syndrome have neurological manifestations as the initial presenting feature of Sjogren's syndrome. We report the case of an elderly female with longitudinal myelitis as a presenting feature who had positive antibody to aquaporin-4 (NMO-IgG) and Sjogren's syndrome. PMID- 26938586 TI - Characterization of Microvesicles Released from Human Red Blood Cells. AB - BACKGROUND/AIMS: Extracellular vesicles (EVs) are spherical fragments of cell membrane released from various cell types under physiological as well as pathological conditions. Based on their size and origin, EVs are classified as exosome, microvesicles (MVs) and apoptotic bodies. Recently, the release of MVs from human red blood cells (RBCs) under different conditions has been reported. MVs are released by outward budding and fission of the plasma membrane. However, the outward budding process itself, the release of MVs and the physical properties of these MVs have not been well investigated. The aim of this study is to investigate the formation process, isolation and characterization of MVs released from RBCs under conditions of stimulating Ca2+ uptake and activation of protein kinase C. METHODS: Experiments were performed based on single cell fluorescence imaging, fluorescence activated cell sorter/flow cytometer (FACS), scanning electron microscopy (SEM), atomic force microscopy (AFM) and dynamic light scattering (DLS). The released MVs were collected by differential centrifugation and characterized in both their size and zeta potential. RESULTS: Treatment of RBCs with 4-bromo-A23187 (positive control), lysophosphatidic acid (LPA), or phorbol-12 myristate-13 acetate (PMA) in the presence of 2 mM extracellular Ca2+ led to an alteration of cell volume and cell morphology. In stimulated RBCs, exposure of phosphatidylserine (PS) and formation of MVs were observed by using annexin V-FITC. The shedding of MVs was also observed in the case of PMA treatment in the absence of Ca2+, especially under the transmitted bright field illumination. By using SEM, AFM and DLS the morphology and size of stimulated RBCs, MVs were characterized. The sizes of the two populations of MVs were 205.8 +/- 51.4 nm and 125.6 +/- 31.4 nm, respectively. Adhesion of stimulated RBCs and MVs was observed. The zeta potential of MVs was determined in the range from - 40 mV to - 10 mV depended on the solutions and buffers used. CONCLUSION: An increase of intracellular Ca2+ or an activation of protein kinase C leads to the formation and release of MVs in human RBCs. PMID- 26938587 TI - Effect of Dialysis Day on Intradialytic Hypotension Risk. AB - BACKGROUND/AIMS: Intradialytic hypotension (IDH) is a serious and frequent complication of hemodialysis (HD). Thus far, data are scarcely available to assess the impact of first versus subsequent HD sessions of the week in IDH. Therefore, the purpose of this work was to evaluate IDH risk in patients on thrice-weekly HD. METHODS: We conducted an analysis of all blood pressure (BP) measurements obtained during 492 HD treatments given to 41 prevalent adult patients over a one month period. A logistic regression model for repeated binary observations was used to determine the association between hypotension and patient and dialysis factors. RESULTS: The incidence of IDH was 32.5%. First dialysis session of the week was associated with a 9% higher risk of hypotension relatively to the second one. The risk was even higher from the first to the third session of the week (60%) and from the second to the third (50%). A higher hypotension odds ratio was also associated with age (1.03, 90% CI: 1.01-1.06), higher predialysis BP (1.04, 90%CI: 1.03-1.05) and higher phosphorus level (1.38, 90% CI: 1.07-1.76). The risk decreased 24.4% for each additional antihypertensive drug taken by the patient. CONCLUSIONS: The odds of hypotension occurrence decrease throughout dialysis sessions of the week. Minimizing modifiable risk factors may decrease IDH episodes. PMID- 26938588 TI - Achieving the gold standard. PMID- 26938589 TI - College launches initiative to improve the dementia skills of care home nurses. PMID- 26938590 TI - Call for review of health and social care provision. PMID- 26938591 TI - Exhibition of nursing history held to mark RCN's centenary. PMID- 26938592 TI - Patients should be given confidence to make complaints. PMID- 26938594 TI - Are independent care homes heading for the scrap heap? PMID- 26938595 TI - New unit for people with Parkinson's. PMID- 26938599 TI - Appetite for life. PMID- 26938602 TI - Reducing depression and anxiety in visually impaired older people. PMID- 26938603 TI - Botox provides tone reduction and clinical benefit in hemiparesis. PMID- 26938604 TI - Relationship between Alzheimer's disease and heart failure. PMID- 26938605 TI - Practice question. PMID- 26938606 TI - Improving the knowledge base in older people's care. AB - The UK has a rapidly ageing population, and the number of people aged over 75 is projected to double in the next 30 years. In November 2014, King's College London introduced the Older Person's Nurse Fellowship, a pioneering programme designed to give senior nurses the knowledge and skills to optimise quality of life for older people, and lead the way in transforming care and services. This article examines the fellowship programme, its aims and intended effect on practice. It also highlights a series of case study articles by four of the first cohort of fellows beginning in the March issue of Nursing Older People, which will show how the programme is helping senior nurses to improve care in a variety of settings. PMID- 26938607 TI - Arts-based and creative approaches to dementia care. AB - This article presents a review of arts-based and creative approaches to dementia care as an alternative to antipsychotic medications. While use of antipsychotics may be appropriate for some people, the literature highlights the success of creative approaches and the benefits of their lack of negative side effects associated with antipsychotics. The focus is the use of biographical approaches, music, dance and movement to improve wellbeing, enhance social networks, support inclusive practice and enable participation. Staff must be trained to use these approaches. A case study is presented to demonstrate how creative approaches can be implemented in practice and the outcomes that can be expected when used appropriately. PMID- 26938608 TI - Advanced nurse practitioner-led referral for specialist care and rehabilitation. AB - In response to the need for appropriate and timely care of frail older patients admitted to hospital, a dedicated advanced nurse practitioner (ANP)-led referral service was developed. The service has continued to evolve over the 13 years since its implementation in accordance with changing service demands. This article describes the role of the ANP in care of the elderly/rehabilitation medicine and focuses on one area of clinical practice developed by the team: an ANP-led referral service. The aim of developing the service was to ensure that patients who required specialist care and rehabilitation could be identified and assessed as soon as possible after admission, with the premise that they could be transferred to a bed in care of the elderly medical wards. This was perceived by the ANPs to be advantageous for patients, who would receive care from a specialist team, and for care of the elderly staff who could use their knowledge and skills appropriately and safely. PMID- 26938610 TI - Change for good. PMID- 26938609 TI - Associations between alcohol use, polypharmacy and falls in older adults. AB - AIMS: To describe the prevalence of alcohol intake, medication use and falls, evaluate the association between alcohol intake and medication use, and assess the effects of use of alcohol, medication and/or both on the occurrence of falls. METHOD: Trained interviewers collected information on self-reported frequency of alcohol consumption, medication use and falls in a cross-sectional sample of 2,444 community-dwelling older adults in rural US. Polypharmacy was defined as taking five or more medications. RESULTS: Of the sample, 38% consumed alcohol, 83% used medication and 19% had fallen. The ingestion of alcohol was inversely associated with the likelihood of taking medication, but had no statistically significant association with incidence of falls. Analyses with logistic regression indicated that alcohol intake was not a significant predictor of falls. Medication was positively related to, and a significant predictor of, falls. CONCLUSION: Nurses working with older people should be aware of medications that increase the risk of falls. Potentially deleterious falls may be prevented through ongoing risk-benefit assessment of prescribed medicines and, when feasible, use of non-pharmacological interventions. PMID- 26938611 TI - Stimulation of Eryptosis by Combretastatin A4 Phosphate Disodium (CA4P). AB - BACKGROUND/AIMS: Combretastatin A4 phosphate disodium (CA4P) is utilized for the treatment of malignancy. The substance has previously been shown to trigger suicidal cell death or apoptosis. Similar to apoptosis of nucleated cells, erythrocytes may enter suicidal death or eryptosis, characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Stimulators of eryptosis include increase of cytosolic Ca2+ activity ([Ca2+]i), ceramide, oxidative stress and ATP depletion. The present study explored, whether CA4P induces eryptosis and, if so, to gain insight into mechanisms involved. METHODS: Flow cytometry has been employed to estimate phosphatidylserine exposure at the cell surface from annexin-V-binding, cell volume from forward scatter, [Ca2+]i from Fluo3-fluorescence, reactive oxygen species (ROS) abundance from DCF fluorescence, glutathione (GSH) abundance from CMF fluorescence and ceramide abundance from fluorescent antibodies. In addition cytosolic ATP levels were quantified utilizing a luciferin-luciferase based assay and hemolysis was estimated from hemoglobin concentration in the supernatant. RESULTS: A 48 hours exposure of human erythrocytes to CA4P (>= 50 uM) significantly increased the percentage of annexin-V-binding cells and significantly decreased forward scatter. CA4P did not appreciably increase hemolysis. Hundred uM CA4P significantly increased Fluo3-fluorescence. The effect of CA4P (100 uM) on annexin-V-binding was significantly blunted, but not abolished, by removal of extracellular Ca2+. CA4P (>= 50 uM) significantly decreased GSH abundance and ATP levels but did not significantly increase ROS or ceramide. CONCLUSIONS: CA4P triggers cell shrinkage and phospholipid scrambling of the erythrocyte cell membrane, an effect at least in part due to entry of extracellular Ca2+ and energy depletion. PMID- 26938612 TI - Ventilator-Associated Pneumonia in Trauma Patients: Different Criteria, Different Rates. AB - BACKGROUND: No consensus exists regarding the definition of ventilator-associated pneumonia (VAP). Even within a single institution, inconsistent diagnostic criteria result in conflicting rates of VAP. As a Level 1 trauma center participating in the Trauma Quality Improvement Project (TQIP) and the National Healthcare Safety Network (NHSN), our institution showed inconsistencies in VAP rates depending on which criteria was applied. The purpose of this study was to compare VAP definitions, defined by culture-based criteria, National Trauma Data Bank (NTDB) and NHSN, using incidence in trauma patients. METHODS: A retrospective chart review of consecutive trauma patients who were diagnosed with VAP and met pre-determined inclusion and exclusion criteria admitted to our rural, 861-bed, Level 1 trauma and tertiary care center between January 2008 and December 2011 was performed. These patients were identified from the National Trauma Registry of the American College of Surgeons (NTRACS) database and an in house infection control database. Ventilator-associated pneumonia diagnosis criteria defined by the U.S. Center for Disease Control and Prevention (used by the NHSN), the NTDB, and our institutional, culture-based criteria gold standard were compared among patients. RESULTS: Two hundred seventy-nine patients were diagnosed with VAP (25.4% met NHSN criteria, 88.2% met NTDB, and 76.3% met culture-based criteria). Only 58 (20.1%) patients met all three criteria. When NHSN criteria were compared with culture-based criteria, NHSN showed a high specificity (92.5%) and low sensitivity (28.2%). The positive predictive value (PPV) was 84.5%, but the negative predictive value (NPV) was 47.1%. The agreement between the NHSN and the culture-based criteria was poor (kappa = 0.18). Conversely, the NTDB showed a lower specificity (57.8%), but greater sensitivity (86.4%) compared with culture-based criteria. The PPV and NPV were both 74% and the two criteria showed fair agreement (kappa = 0.41). CONCLUSIONS: The lack of standard diagnostic criteria for VAP resulted in variable reporting to different agencies. Emphasis on establishing a consensus VAP definition should be undertaken. PMID- 26938613 TI - Zero-Heat-Flux Thermometry for Non-Invasive Measurement of Core Body Temperature in Pigs. AB - Hypothermia is a severe, unpleasant side effect during general anesthesia. Thus, temperature surveillance is a prerequisite in general anesthesia settings during experimental surgeries. The gold standard to measure the core body temperature (Tcore) is placement of a Swan-Ganz catheter in the pulmonary artery, which is a highly invasive procedure. Therefore, Tcore is commonly examined in the urine bladder and rectum. However, these procedures are known for their inaccuracy and delayed record of temperatures. Zero-heat-flux (ZHF) thermometry is an alternative, non-invasive method quantifying Tcore in human patients by applying a thermosensoric patch to the lateral forehead. Since the porcine cranial anatomy is different to the human's, the optimal location of the patch remains unclear to date. The aim was to compare three different patch locations of ZHF thermometry in a porcine hypothermia model. Hypothermia (33.0 degrees C Tcore) was conducted in 11 anesthetized female pigs (26-30 kg). Tcore was measured continuously by an invasive Swan-Ganz catheter in the pulmonary artery (Tpulm). A ZHF thermometry device was mounted on three different defined locations. The smallest average difference between Tpulm and TZHF during stable temperatures was 0.21 +/- 0.16 degrees C at location A, where the patch was placed directly behind the eye. Also during rapidly changing temperatures location A showed the smallest bias with 0.48 +/- 0.29 degrees C. Location A provided the most reliable data for Tcore. Therefore, the ZHF thermometry patch should be placed directly behind the left temporal corner of the eye to provide a non-invasive method for accurate measurement of Tcore in pigs. PMID- 26938615 TI - Questioning the end effect: Endings are not inherently over-weighted in retrospective evaluations of experiences. AB - The present research re-examines one of the most basic assertions regarding the evaluation of hedonic experiences: the end effect. The end effect suggests that the retrospective evaluation of an experience is disproportionately influenced by the final moments of the experience. The findings in this article indicate that endings are not inherently over-weighted in retrospective evaluations. That is, episodes do not disproportionately affect the evaluation of an experience simply because they occur at the end. We replicate findings that are consistent with the end effect, but provide additional evidence implicating other processes as driving factors of those findings. PMID- 26938616 TI - Heterogeneous Landscapes on Steep Slopes at Low Altitudes as Hotspots of Bird Diversity in a Hilly Region of Nepal in the Central Himalayas. AB - Understanding factors determining the distribution of species is a key requirement for protecting diversity in a specific area. The aim of this study was to explore the factors affecting diversity and distribution of species of birds on different forested hills in central Nepal. The area is rich in species of birds. Because the area is characterized by steep gradients, we were also interested in the importance of altitude in determining the diversity and species composition of the bird communities. We assessed bird diversity and species composition based on point observations along a gradient of increasing altitude in two valleys (Kathmandu and Palung) in central Nepal. Data on environmental variables were also collected in order to identify the main determinants of bird diversity and species composition of the bird communities. We recorded 6522 individual birds belonging to 146 species, 77 genera and 23 families. Resident birds made up 80% (117 species) of the total dataset. The study supported the original expectation that altitude is a major determinant of species richness and composition of bird communities in the area. More diverse bird communities were found also in areas with steeper slopes. This together with the positive effect of greater heterogeneity suggests that forests on steep slopes intermixed with patches of open habitats on shallow soil at large spatial scales are more important for diverse bird communities than more disturbed habitats on shallow slopes. In addition, we demonstrated that while different habitat characteristics such as presence of forests edges and shrubs play an important role in driving species composition, but they do not affect species richness. This indicates that while habitat conditions are important determinants of the distribution of specific species, the number of niches is determined by large scale characteristics, such as landscape level habitat heterogeneity and altitude. Thus, to protect bird diversity in the mid-hills of central Nepal, we should maintain diverse local habitats (viz. forest, shrubs, open land, etc.) but also make sure the natural habitats on steeper slopes with large scale heterogeneity are maintained. PMID- 26938614 TI - GDF15/MIC1 and MMP9 Cerebrospinal Fluid Levels in Parkinson's Disease and Lewy Body Dementia. AB - Based on animal and ex-vivo experiments, Growth/Differentiation Factor-15 (GDF15, also called Macrophage Inhibitory Cytokine-1, MIC1), a member of the transforming growth factor-beta family, and Matrix Metalloproteinase-9 (MMP9), a member of the matrix metalloprotease family may be potential markers for Lewy body disorders, i.e. Parkinson's disease with (PDD) and without dementia (PDND) and Lewy body dementia (DLB). GDF15 has a prominent role in development, cell proliferation, differentiation, and repair, whereas MMP9 degrades, as a proteolytic enzyme, components of the extracellular matrix. In this study, cerebrospinal fluid GDF15 and MMP9 levels of 59 PDND, 17 PDD and 23 DLB patients, as well as of 95 controls were determined, and associated with demographic, clinical and biochemical parameters. Our analysis confirmed the already described association of GDF15 levels with age and gender. Corrected GDF15 levels were significantly higher in PDD than in PDND patients, and intermediate in DLB patients. Within Lewy body disorders, GDF15 levels correlated positively with age at onset of Parkinsonism and dementia, Hoehn & Yahr stage and cerebrospinal fluid t-Tau and p-Tau levels, and negatively with the Mini Mental State Examination. Remarkably, it does not relevantly correlate with disease duration. MMP9 was not relevantly associated with any of these parameters. Cerebrospinal GDF15, but not MMP9, may be a potential marker of and in Lewy body disorders. PMID- 26938617 TI - Noninvasive Mechanical Ventilation Improves Breathing-Swallowing Interaction of Ventilator Dependent Neuromuscular Patients: A Prospective Crossover Study. AB - BACKGROUND: Respiratory involvement in neuromuscular disorders may contribute to impaired breathing-swallowing interactions, swallowing disorders and malnutrition. We investigated whether the use of non-invasive ventilation (NIV) controlled by the patient could improve swallowing performances in a population of neuromuscular patients requiring daytime NIV. METHODS: Ten neuromuscular patients with severe respiratory failure requiring extensive NIV use were studied while swallowing without and with NIV (while ventilated with a modified ventilator allowing the patient to withhold ventilation as desired). Breathing swallowing interactions were investigated by chin electromyography, cervical piezoelectric sensor, nasal flow recording and inductive plethysmography. Two water-bolus sizes (5 and 10ml) and a textured yogurt bolus were tested in a random order. RESULTS: NIV use significantly improved swallowing fragmentation (defined as the number of respiratory interruption of the swallowing of a single bolus) (p = 0.003) and breathing-swallowing synchronization (with a significant increase of swallows followed by an expiration) (p <0.0001). Patient exhibited piecemeal swallowing which was not influenced by NIV use (p = 0.07). NIV use also significantly reduced dyspnea during swallowing (p = 0.04) while preserving swallowing comfort, regardless of bolus type. CONCLUSION: The use of patient controlled NIV improves swallowing parameters in patients with severe neuromuscular respiratory failure requiring daytime NIV, without impairing swallowing comfort. TRIAL REGISTRATION: ClinicalTrials.gov NCT01519388. PMID- 26938618 TI - Longitudinal Analysis of Natural Killer Cells in Dengue Virus-Infected Patients in Comparison to Chikungunya and Chikungunya/Dengue Virus-Infected Patients. AB - BACKGROUND: Dengue virus (DENV) is the most prominent arbovirus worldwide, causing major epidemics in South-East Asia, South America and Africa. In 2010, a major DENV-2 outbreak occurred in Gabon with cases of patients co-infected with chikungunya virus (CHIKV). Although the innate immune response is thought to be of primordial importance in the development and outcome of arbovirus-associated pathologies, our knowledge of the role of natural killer (NK) cells during DENV-2 infection is in its infancy. METHODOLOGY: We performed the first extensive comparative longitudinal characterization of NK cells in patients infected by DENV-2, CHIKV or both viruses. Hierarchical clustering and principal component analyses were performed to discriminate between CHIKV and DENV-2 infected patients. PRINCIPAL FINDINGS: We observed that both activation and differentiation of NK cells are induced during the acute phase of infection by DENV-2 and CHIKV. Combinatorial analysis however, revealed that both arboviruses induced two different signatures of NK-cell responses, with CHIKV more associated with terminal differentiation, and DENV-2 with inhibitory KIRs. We show also that intracellular production of interferon-gamma (IFN-gamma) by NK cells is strongly stimulated in acute DENV-2 infection, compared to CHIKV. CONCLUSIONS/SIGNIFICANCE: Although specific differences were observed between CHIKV and DENV-2 infections, the significant remodeling of NK cell populations observed here suggests their potential roles in the control of both infections. PMID- 26938633 TI - Improving Decision Making about Genetic Testing in the Clinic: An Overview of Effective Knowledge Translation Interventions. AB - BACKGROUND: Knowledge translation (KT) interventions are attempts to change behavior in keeping with scientific evidence. While genetic tests are increasingly available to healthcare consumers in the clinic, evidence about their benefits is unclear and decisions about genetic testing are thus difficult for all parties. OBJECTIVE: We sought to identify KT interventions that involved decisions about genetic testing in the clinical context and to assess their effectiveness for improving decision making in terms of behavior change, increased knowledge and wellbeing. METHODS: We searched for trials assessing KT interventions in the context of genetic testing up to March 2014 in all systematic reviews (n = 153) published by two Cochrane review groups: Effective Practice and Organisation of Care (EPOC) and Consumers and Communication. RESULTS: We retrieved 2473 unique trials of which we retained only 28 (1%). Two EPOC reviews yielded two trials of KT interventions: audit and feedback (n = 1) and educational outreach (n = 1). Both targeted health professionals and the KT intervention they assessed was found to be effective. Four Consumers and Communication reviews yielded 26 trials: decision aids (n = 15), communication of DNA-based disease risk estimates (n = 7), personalized risk communication (n = 3) and mobile phone messaging (n = 1). Among these, 25 trials targeted only health consumers or patients and the KT interventions were found to be effective in four trials, partly effective in seven, and ineffective in four. Lastly, only one trial targeted both physicians and patients and was found to be effective. CONCLUSIONS: More research on the effectiveness of KT interventions regarding genetic testing in the clinical context may contribute to patients making informed value-based decisions and drawing the maximum benefit from clinical applications of genetic and genomic innovations. PMID- 26938635 TI - Real-world evaluation of glycemic control among patients with type 2 diabetes mellitus treated with canagliflozin versus dipeptidyl peptidase-4 inhibitors. AB - Objective To evaluate glycemic control among patients with type 2 diabetes mellitus (T2DM) treated with canagliflozin (CANA) vs. dipeptidyl peptidase-4 (DPP 4) inhibitors. Methods Using integrated claims and lab data from a US health plan of commercial and Medicare Advantage enrollees, this matched-control cohort study assessed adult T2DM patients receiving treatment with CANA or DPP-4 inhibitors (1 April 2013-31 December 2013). Cohorts were chosen hierarchically; the first pharmacy claim for CANA was identified as the index date; then the first pharmacy claim for a DPP-4 inhibitor was identified and index date set. Eligible patients had 6 months of continuous health plan enrollment before the index date (baseline) and 9 months after (follow-up) and no evidence of index drug in baseline. Patients were matched 1:1 using propensity score matching. Changes in glycated hemoglobin (HbA1c) and percentages of patients with HbA1c <8% and <7% during the follow-up were evaluated. Results The matched CANA and DPP-4 inhibitor cohorts (53.2% treated with sitagliptin) included 2766 patients each (mean age: 55.7 years). Among patients with baseline and follow-up HbA1c results, mean baseline HbA1c values were similar, 8.62% and 8.57% (p = 0.615) for the CANA (n = 729) and DPP-4 inhibitor (n = 710) cohorts, respectively. Change in HbA1c was greater among patients in the CANA cohort than for those in the DPP-4 inhibitor cohort (-0.92% vs. -0.63%, p < 0.001), and also among the subset of patients with baseline HbA1c >=7% (-1.07% [n = 624] vs. -0.79% [n = 603], p = 0.004). During follow-up, greater percentages of the CANA cohort relative to the DPP-4 inhibitor cohort achieved HbA1c of <8% (66.0% vs. 58.6%, p = 0.004) and <7% (35.4% vs. 29.9%, p = 0.022). Limitations This study was observational and residual confounding remains a possibility. Conclusions In this real-world study of patients with T2DM, CANA use was associated with greater HbA1c reduction and higher percentages of patients attaining HbA1c goals than those treated with DPP 4 inhibitors. PMID- 26938636 TI - Aspterpenacids A and B, Two Sesterterpenoids from a Mangrove Endophytic Fungus Aspergillus terreus H010. AB - Two new sesterterpenoids, aspterpenacids A (1) and B (2), with an unusual carbon skeleton of a 5/3/7/6/5 ring system were isolated from the mangrove endophytic fungus Aspergillus terreus H010. Their structures were elucidated on the basis of spectroscopic methods, single-crystal X-ray diffraction analysis, and electronic circular dichroism calculations. A biogenetic pathway for 1 and 2 is proposed. Both 1 and 2 showed no significant antibacterial activity or cytotoxicity at 50 MUM. PMID- 26938634 TI - Structural Basis for Recognition of Human Enterovirus 71 by a Bivalent Broadly Neutralizing Monoclonal Antibody. AB - Enterovirus 71 (EV71) is the main pathogen responsible for hand, foot and mouth disease with severe neurological complications and even death in young children. We have recently identified a highly potent anti-EV71 neutralizing monoclonal antibody, termed D5. Here we investigated the structural basis for recognition of EV71 by the antibody D5. Four three-dimensional structures of EV71 particles in complex with IgG or Fab of D5 were reconstructed by cryo-electron microscopy (cryo-EM) single particle analysis all at subnanometer resolutions. The most critical EV71 mature virion-Fab structure was resolved to a resolution of 4.8 A, which is rare in cryo-EM studies of virus-antibody complex so far. The structures reveal a bivalent binding pattern of D5 antibody across the icosahedral 2-fold axis on mature virion, suggesting that D5 binding may rigidify virions to prevent their conformational changes required for subsequent RNA release. Moreover, we also identified that the complementary determining region 3 (CDR3) of D5 heavy chain directly interacts with the extremely conserved VP1 GH-loop of EV71, which was validated by biochemical and virological assays. We further showed that D5 is indeed able to neutralize a variety of EV71 genotypes and strains. Moreover, D5 could potently confer protection in a mouse model of EV71 infection. Since the conserved VP1 GH-loop is involved in EV71 binding with its uncoating receptor, the scavenger receptor class B, member 2 (SCARB2), the broadly neutralizing ability of D5 might attribute to its inhibition of EV71 from binding SCARB2. Altogether, our results elucidate the structural basis for the binding and neutralization of EV71 by the broadly neutralizing antibody D5, thereby enhancing our understanding of antibody-based protection against EV71 infection. PMID- 26938638 TI - Computational Modeling of Open-Irrigated Electrodes for Radiofrequency Cardiac Ablation Including Blood Motion-Saline Flow Interaction. AB - Radiofrequency catheter ablation (RFCA) is a routine treatment for cardiac arrhythmias. During RFCA, the electrode-tissue interface temperature should be kept below 80 degrees C to avoid thrombus formation. Open-irrigated electrodes facilitate power delivery while keeping low temperatures around the catheter. No computational model of an open-irrigated electrode in endocardial RFCA accounting for both the saline irrigation flow and the blood motion in the cardiac chamber has been proposed yet. We present the first computational model including both effects at once. The model has been validated against existing experimental results. Computational results showed that the surface lesion width and blood temperature are affected by both the electrode design and the irrigation flow rate. Smaller surface lesion widths and blood temperatures are obtained with higher irrigation flow rate, while the lesion depth is not affected by changing the irrigation flow rate. Larger lesions are obtained with increasing power and the electrode-tissue contact. Also, larger lesions are obtained when electrode is placed horizontally. Overall, the computational findings are in close agreement with previous experimental results providing an excellent tool for future catheter research. PMID- 26938637 TI - Ginseng and Ginkgo Biloba Effects on Cognition as Modulated by Cardiovascular Reactivity: A Randomised Trial. AB - BACKGROUND: There is some evidence to suggest that ginseng and Ginkgo biloba can improve cognitive performance, however, very little is known about the mechanisms associated with such improvement. Here, we tested whether cardiovascular reactivity to a task is associated with cognitive improvement. METHODOLOGY/PRINCIPAL FINDINGS: Using a double-blind, placebo controlled, crossover design, participants (N = 24) received two doses of Panax Ginseng (500, 1000 mg) or Ginkgo Biloba (120, 240 mg) (N = 24), and underwent a series of cognitive tests while systolic, diastolic, and heart rate readings were taken. Ginkgo Biloba improved aspects of executive functioning (Stroop and Berg tasks) in females but not in males. Ginseng had no effect on cognition. Ginkgo biloba in females reversed the initial (i.e. placebo) increase in cardiovascular reactivity (systolic and diastolic readings increased compared to baseline) to cognitive tasks. This effect (reversal) was most notable after those tasks (Stroop and Iowa) that elicited the greatest cardiovascular reactivity during placebo. In males, although ginkgo also decreased cardiovascular readings, it did so from an initial (placebo) blunted response (i.e. decrease or no change from baseline) to cognitive tasks. Ginseng, on the contrary, increased cardiovascular readings compared to placebo. CONCLUSIONS/SIGNIFICANCE: These results suggest that cardiovascular reactivity may be a mechanism by which ginkgo but not ginseng, in females is associated with certain forms of cognitive improvement. TRIAL REGISTRATION: ClinicalTrials.gov NCT02386852. PMID- 26938640 TI - Mechanism of Spontaneous Blebbing Motion of an Oil-Water Interface: Elastic Stress Generated by a Lamellar-Lamellar Transition. AB - A quaternary system composed of surfactant, cosurfactant, oil, and water showing spontaneous motion of the oil-water interface under far-from-equilibrium condition is studied in order to understand nanometer-scale structures and their roles in spontaneous motion. The interfacial motion is characterized by the repetitive extension and retraction of spherical protrusions at the interface, i.e, blebbing motion. During the blebbing motion, elastic aggregates are accumulated, which were characterized as surfactant lamellar structures with mean repeat distances d of 25 to 40 nm. Still unclear is the relationship between the structure formation and the dynamics of the interfacial motion. In the present study, we find that a new lamellar structure with d larger than 80 nm is formed at the blebbing oil-water interface, while the resultant elastic aggregates, which are the one reported before, have a lamellar structure with smaller d (25 to 40 nm). Such transition of lamellar structures from the larger d to smaller d is induced by a penetration of surfactants from an aqueous phase into the aggregates. We propose a model in which elastic stress generated by the transition drives the blebbing motion at the interface. The present results explain the link between nanometer-scale transition of lamellar structure and millimeter-scale dynamics at an oil-water interface. PMID- 26938639 TI - Adolescent Sexual and Reproductive Health Services and Implications for the Provision of Voluntary Medical Male Circumcision: Results of a Systematic Literature Review. AB - BACKGROUND: Voluntary medical male circumcision (VMMC) is a critical HIV prevention tool. Since 2007, sub-Saharan African countries with the highest prevalence of HIV have been mobilizing resources to make VMMC available. While implementers initially targeted adult men, demand has been highest for boys under age 18. It is important to understand how male adolescents can best be served by quality VMMC services. METHODS AND FINDINGS: A systematic literature review was performed to synthesize the evidence on best practices in adolescent health service delivery specific to males in sub-Saharan Africa. PubMed, Scopus, and JSTOR databases were searched for literature published between January 1990 and March 2014. The review revealed a general absence of health services addressing the specific needs of male adolescents, resulting in knowledge gaps that could diminish the benefits of VMMC programming for this population. Articles focused specifically on VMMC contained little information on the adolescent subgroup. The review revealed barriers to and gaps in sexual and reproductive health and VMMC service provision to adolescents, including structural factors, imposed feelings of shame, endorsement of traditional gender roles, negative interactions with providers, violations of privacy, fear of pain associated with the VMMC procedure, and a desire for elements of traditional non-medical circumcision methods to be integrated into medical procedures. Factors linked to effective adolescent-focused services included the engagement of parents and the community, an adolescent-friendly service environment, and VMMC counseling messages sufficiently understood by young males. CONCLUSIONS: VMMC presents an opportune time for early involvement of male adolescents in HIV prevention and sexual and reproductive health programming. However, more research is needed to determine how to align VMMC services with the unique needs of this population. PMID- 26938642 TI - Soil Quality Indexing Strategies for Evaluating Sugarcane Expansion in Brazil. AB - Increasing demand for biofuel has intensified land-use change (LUC) for sugarcane (Saccharum officinarum) expansion in Brazil. Assessments of soil quality (SQ) response to this LUC are essential for quantifying and monitoring sustainability of sugarcane production over time. Since there is not a universal methodology for assessing SQ, we conducted a field-study at three sites within the largest sugarcane-producing region of Brazil to develop a SQ index (SQI). The most common LUC scenario (i.e., native vegetation to pasture to sugarcane) was evaluated using six SQI strategies with varying complexities. Thirty eight soil indicators were included in the total dataset. Two minimum datasets were selected: one using principal component analysis (7 indicators) and the other based on expert opinion (5 indicators). Non-linear scoring curves were used to interpret the indicator values. Weighted and non-weighted additive methods were used to combine individual indicator scores into an overall SQI. Long-term conversion from native vegetation to extensive pasture significantly decreased overall SQ. In contrast, conversion from pasture to sugarcane had no significant impact on overall SQ at the regional scale, but site-specific responses were found. In general, sugarcane production improved chemical attributes (i.e., higher macronutrient levels and lower soil acidity); however it has negative effects on physical and biological attributes (i.e., higher soil compaction and structural degradation as well as lower soil organic carbon (SOC), abundance and diversity of macrofauna and microbial activity). Overall, we found that simple, user-friendly strategies were as effective as more complex ones for identifying SQ changes. Therefore, as a protocol for SQ assessments in Brazilian sugarcane areas, we recommend using a small number of indicators (e.g., pH, P, K, Visual Evaluation of Soil Structure VESS scores and SOC concentration) and proportional weighting to reflect chemical, physical and biological processes within the soil. Our SQ evaluations also suggest that current approaches for expanding Brazilian sugarcane production by converting degraded pasture land to cropland can be a sustainable strategy for meeting increasing biofuel demand. However, management practices that alleviate negative impacts on soil physical and biological indicators must be prioritized within sugarcane producing areas to prevent unintentional SQ degradation over time. PMID- 26938641 TI - Identifying Likely Transmission Pathways within a 10-Year Community Outbreak of Tuberculosis by High-Depth Whole Genome Sequencing. AB - BACKGROUND: Improved tuberculosis control and the need to contain the spread of drug-resistant strains provide a strong rationale for exploring tuberculosis transmission dynamics at the population level. Whole-genome sequencing provides optimal strain resolution, facilitating detailed mapping of potential transmission pathways. METHODS: We sequenced 22 isolates from a Mycobacterium tuberculosis cluster in New South Wales, Australia, identified during routine 24 locus mycobacterial interspersed repetitive unit typing. Following high-depth paired-end sequencing using the Illumina HiSeq 2000 platform, two independent pipelines were employed for analysis, both employing read mapping onto reference genomes as well as de novo assembly, to control biases in variant detection. In addition to single-nucleotide polymorphisms, the analyses also sought to identify insertions, deletions and structural variants. RESULTS: Isolates were highly similar, with a distance of 13 variants between the most distant members of the cluster. The most sensitive analysis classified the 22 isolates into 18 groups. Four of the isolates did not appear to share a recent common ancestor with the largest clade; another four isolates had an uncertain ancestral relationship with the largest clade. CONCLUSION: Whole genome sequencing, with analysis of single nucleotide polymorphisms, insertions, deletions, structural variants and subpopulations, enabled the highest possible level of discrimination between cluster members, clarifying likely transmission pathways and exposing the complexity of strain origin. The analysis provides a basis for targeted public health intervention and enhanced classification of future isolates linked to the cluster. PMID- 26938643 TI - Occurrence, Management, and Risk Factors for Adverse Drug Reactions in Multidrug Resistant Tuberculosis Patients. AB - Although Pakistan has a high burden of multidrug-resistant tuberculosis (MDR-TB), little is known about prevalence, management, and risk factors for adverse drug reactions (ADRs) in MDR-TB patients in Pakistan. To evaluate occurrence, management, and risk factors for ADRs in MDR-TB patients, and its impact on treatment outcomes, this observational cohort study was conducted at programmatic management unit for drug resistant TB of Lady Reading Hospital Peshawar, Pakistan. A total of 181 MDR-TB patients enrolled at the study site from January 1, 2012 to February 28, 2013 were included. Patients with drug resistant TB other than MDR-TB, transferred out patients and those who were still on treatment at the end of study duration (January 31, 2015) were excluded. Patients were followed until treatment outcomes were reported. ADRs were determined by laboratory data and/or clinical criteria. SPSS 16 was used for data analysis. A total of 131 patients (72.4%) experienced at least 1 ADR. Gastrointestinal disturbance was the most commonly observed adverse event (42%), followed by psychiatric disturbance (29.3%), arthralgia (24.3%), and ototoxicity (21%). Potentially life-threatening ADRs, such as nephrotoxicity (2.7%) and hypokalemia (2.8%) were relatively less prevalent. Owing to ADRs, treatment regimen was modified in 20 (11%) patients. On multivariate analysis, the only risk factor for ADRs was baseline body weight >= 40 kg (OR = 2.321, P-value = 0.013). ADRs neither led to permanent discontinuation of treatment nor adversely affected treatment outcomes. Adverse effects were prevalent in current cohort, but caused minimal modification of treatment regimen, and did not negatively impact treatment outcomes. Patient with baseline body weight >= 40 kg should be closely monitored. PMID- 26938648 TI - Retinal Image Simulation of Subjective Refraction Techniques. AB - Refraction techniques make it possible to determine the most appropriate sphero cylindrical lens prescription to achieve the best possible visual quality. Among these techniques, subjective refraction (i.e., patient's response-guided refraction) is the most commonly used approach. In this context, this paper's main goal is to present a simulation software that implements in a virtual manner various subjective-refraction techniques--including Jackson's Cross-Cylinder test (JCC)--relying all on the observation of computer-generated retinal images. This software has also been used to evaluate visual quality when the JCC test is performed in multifocal-contact-lens wearers. The results reveal this software's usefulness to simulate the retinal image quality that a particular visual compensation provides. Moreover, it can help to gain a deeper insight and to improve existing refraction techniques and it can be used for simulated training. PMID- 26938649 TI - Use of Population-Based Cancer Registry Data to Determine the Effect of Timely Treatment on the Survival of Colorectal Cancer Patients. AB - INTRODUCTION: Colorectal cancer is the third most common cancer in the world. In Singapore, it was the most common cancer in males and second most common cancer in females from 2009 to 2013. The incidence for colorectal cancer is declining, but the mortality remains high. Cancer of the colon is a highly treatable and curable disease when it is localized to the bowel. Timely treatment of cancer, which is defined as the interval between date of diagnosis and starting date of treatment within an assigned time frame, plays an important role for the survival of patients. This is the first study in Southeast Asia looking at multiethnic groups. The study attempts to determine the effect of timely treatment on survival of colorectal cancer patients by using the Singapore cancer registry data. METHODS: Histologically proven colorectal cancer cases of the residents in Singapore diagnosed in 2008-2012 were included. Exclusion criteria for the study were neuroendocrine carcinomas, soft tissue sarcoma, and lymphoma of the bowel. Bivariate analysis was used to describe patient demographic and disease characteristics by survival status of patient as well as by treatment types and stage group. Timely surgery, adjuvant therapy, and neoadjuvant treatment modalities were defined. Cox regression analysis was used to determine the effect of timely treatment on survival of patients by controlling other independent variables of age, sex, the stage of disease, and ethnicity. RESULTS: A total of 7,739 patients were included in this study. Colorectal cancer was more common in males (55.8%) than in females (44.2%), with a median age of 65.5 years for males and 67.1 years for females. It was more common in Chinese ethnicity (87.7%) followed by Malay (7.4%) and Indian (3.2%). About 40% of patients were diagnosed in early stage and 54.3% in late stage. Primary subsites in order of frequency were sigmoid colon (29%) and rectum (24.4%), followed by rectosigmoid colon (11.4%). About 86% of patients had surgery, of which 47% were treated by surgery alone. More than 75% of patients received timely treatment. Cox regression analysis produced a hazard ratio (HR) of 1.18 (95% CI, 1.02-1.36) for patients who did not receive any type of timely first treatment, an HR of 1.35 (95% CI, 1.17-1.57) for patients with no timely surgery, an HR of 1.4 (95% CI, 1.21-1.62) for patients with no timely adjuvant chemotherapy, and an HR of 2.05 (95% CI, 1.23-3.41) for patients with no timely neoadjuvant therapy. CONCLUSION: The study shows that there were significant effects of timely treatment on survival. Information on the timely treatment modalities and its benefits should be included in the public education and emphasized during the treatment planning with patients for better compliance and improved outcomes. Some delays are avoidable and perhaps the causes of these avoidable delays should be identified and resolved to further enhance quality of service in health care. PMID- 26938650 TI - Current Status of Brain Tumor Surveillance in Canada and Why it Matters. AB - The Brain Tumor Foundation of Canada has identified developing a pan-Canadian report on all primary brain tumors as a priority. The objective of this report is to present the history and rationale underlying reporting of brain tumors and to summarize the current status of brain tumor data collection and reporting in Canadian registries. We reviewed the literature on reporting history and rationale, conducted a survey of cancer registries across Canada, and reviewed cancer registry websites and Canadian Cancer Statistics Reports for publicly available descriptive statistics. A brain tumor surveillance system that includes data on both malignant and benign brain tumors is feasible within Canada and will include approximately twice the number of malignant cases currently reported. Once patterns of brain tumors become available, clinicians, researchers, and policy makers will have a clearer understanding of disease burden and how Canadian survival outcomes fare across regions and against other nations. Collaborative efforts on the part of cancer registry and neurooncology stakeholders will serve to enhance the quality and utility of this information for improving the overall patient experience. PMID- 26938651 TI - Analysis of the National Cancer Data Base to Describe Treatment Trends in Stage IV Oral Cavity and Pharyngeal Cancers in the United States, 1998-2012. AB - Treatment recommendations for head and neck cancers have evolved over the last several decades, with a particularly clear shift in 2004 toward use of chemotherapy in late-stage patients. This study examines the national trends in treatment combinations for patients with stage IV oral cavity and pharyngeal cancer between 1998 and 2012 using the National Cancer Data Base (NCDB). Our analysis demonstrates that chemotherapy was widely integrated into the treatment plans for this population following 2004, confirming that recommendations were successfully translated into practice. Stage IV patients treated after this shift in treatment experienced higher 5-year survival rates compared to patients treated prior to the adoption of increased chemotherapy usage. We also examined the patient population for other changes over time and found that smaller primary tumors became more common and that 2 primary sites (base of tongue and tonsil) came to represent a larger percentage of the patient population; these changes may also contribute to a rising survival rate. Patients receiving the recommended trimodal therapy of surgery, radiation, and chemotherapy were found to be more geographically widespread over time, suggesting a penetrance of the recommendations into the medical system across the country. PMID- 26938652 TI - Remote Abstracting: A Home Guide. PMID- 26938653 TI - Quantitative Trait Loci Identify Functional Noncoding Variation in Cancer. AB - The interpretation of noncoding alterations in cancer genomes presents an unresolved problem in cancer studies. While the impact of somatic variations in protein-coding regions is widely accepted, noncoding aberrations are mostly considered as passenger events. However, with the advance of genome-wide profiling strategies, alterations outside the coding context entered the focus, and multiple examples highlight the role of gene deregulation as cancer-driving events. This review describes the implication of noncoding alterations in oncogenesis and provides a theoretical framework for the identification of causal somatic variants using quantitative trait loci (QTL) analysis. Assuming that functional noncoding alterations affect quantifiable regulatory processes, somatic QTL studies constitute a valuable strategy to pinpoint cancer gene deregulation. Eventually, the comprehensive identification and interpretation of coding and noncoding alterations will guide our future understanding of cancer biology. PMID- 26938654 TI - A Protocol for the Comprehensive Flow Cytometric Analysis of Immune Cells in Normal and Inflamed Murine Non-Lymphoid Tissues. AB - Flow cytometry is used extensively to examine immune cells in non-lymphoid tissues. However, a method of flow cytometric analysis that is both comprehensive and widely applicable has not been described. We developed a protocol for the flow cytometric analysis of non-lymphoid tissues, including methods of tissue preparation, a 10-fluorochrome panel for cell staining, and a standardized gating strategy, that allows the simultaneous identification and quantification of all major immune cell types in a variety of normal and inflamed non-lymphoid tissues. We demonstrate that our basic protocol minimizes cell loss, reliably distinguishes macrophages from dendritic cells (DC), and identifies all major granulocytic and mononuclear phagocytic cell types. This protocol is able to accurately quantify 11 distinct immune cell types, including T cells, B cells, NK cells, neutrophils, eosinophils, inflammatory monocytes, resident monocytes, alveolar macrophages, resident/interstitial macrophages, CD11b- DC, and CD11b+ DC, in normal lung, heart, liver, kidney, intestine, skin, eyes, and mammary gland. We also characterized the expression patterns of several commonly used myeloid and macrophage markers. This basic protocol can be expanded to identify additional cell types such as mast cells, basophils, and plasmacytoid DC, or perform detailed phenotyping of specific cell types. In examining models of primary and metastatic mammary tumors, this protocol allowed the identification of several distinct tumor associated macrophage phenotypes, the appearance of which was highly specific to individual tumor cell lines. This protocol provides a valuable tool to examine immune cell repertoires and follow immune responses in a wide variety of tissues and experimental conditions. PMID- 26938656 TI - Two-Photon-Pumped Perovskite Semiconductor Nanocrystal Lasers. AB - Two-photon-pumped lasers have been regarded as a promising strategy to achieve frequency up-conversion for situations where the condition of phase matching required by conventional approaches cannot be fulfilled. However, their practical applications have been hindered by the lack of materials holding both efficient two-photon absorption and ease of achieving population inversion. Here, we show that this challenge can be tackled by employing colloidal nanocrystals of perovskite semiconductors. We observe highly efficient two-photon absorption (with a cross section of 2.7 * 10(6) GM) in toluene solutions of CsPbBr3 nanocrystals that can excite large optical gain (>500 cm(-1)) in thin films. We have succeeded in demonstrating stable two-photon-pumped lasing at a remarkable low threshold by coupling CsPbBr3 nanocrystals with microtubule resonators. Our findings suggest perovskite nanocrystals can be used as excellent gain medium for high-performance frequency-up-conversion lasers toward practical applications. PMID- 26938657 TI - Bifunctional Ag/Fe/N/C Catalysts for Enhancing Oxygen Reduction via Cathodic Biofilm Inhibition in Microbial Fuel Cells. AB - Limitation of the oxygen reduction reaction (ORR) in single-chamber microbial fuel cells (SC-MFCs) is considered an important hurdle in achieving their practical application. The cathodic catalysts faced with a liquid phase are easily primed with the electrolyte, which provides more surface area for bacterial overgrowth, resulting in the difficulty in transporting protons to active sites. Ag/Fe/N/C composites prepared from Ag and Fe-chelated melamine are used as antibacterial ORR catalysts for SC-MFCs. The structure-activity correlations for Ag/Fe/N/C are investigated by tuning the carbonization temperature (600-900 degrees C) to clarify how the active-constituents of Ag/Fe and N-species influence the antibacterial and ORR activities. A maximum power density of 1791 mW m(-2) is obtained by Ag/Fe/N/C (630 degrees C), which is far higher than that of Pt/C (1192 mW m(-2)), only having a decline of 16.14% after 90 days of running. The Fe-bonded N and the cooperation of pyridinic N and pyrrolic N in Ag/Fe/N/C contribute equally to the highly catalytic activity toward ORR. The .OH or O2(-) species originating from the catalysis of O2 can suppress the biofilm growth on Ag/Fe/N/C cathodes. The synergistic effects between the Ag/Fe heterojunction and N-species substantially contribute to the high power output and Coulombic efficiency of Ag/Fe/N/C catalysts. These new antibacterial ORR catalysts show promise for application in MFCs. PMID- 26938655 TI - Sexual Dimorphism in Circadian Physiology Is Altered in LXRalpha Deficient Mice. AB - The mammalian circadian timing system coordinates key molecular, cellular and physiological processes along the 24-h cycle. Accumulating evidence suggests that many clock-controlled processes display a sexual dimorphism. In mammals this is well exemplified by the difference between the male and female circadian patterns of glucocorticoid hormone secretion and clock gene expression. Here we show that the non-circadian nuclear receptor and metabolic sensor Liver X Receptor alpha (LXRalpha) which is known to regulate glucocorticoid production in mice modulates the sex specific circadian pattern of plasma corticosterone. Lxralpha(-/-) males display a blunted corticosterone profile while females show higher amplitude as compared to wild type animals. Wild type males are significantly slower than females to resynchronize their locomotor activity rhythm after an 8 h phase advance but this difference is abrogated in Lxralpha(-/-) males which display a female-like phenotype. We also show that circadian expression patterns of liver 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) and Phosphoenolpyruvate carboxykinase (Pepck) differ between sexes and are differentially altered in Lxralpha(-/-) animals. These changes are associated with a damped profile of plasma glucose oscillation in males but not in females. Sex specific alteration of the insulin and leptin circadian profiles were observed in Lxalpha(-/-) females and could be explained by the change in corticosterone profile. Together this data indicates that LXRalpha is a determinant of sexually dimorphic circadian patterns of key physiological parameters. The discovery of this unanticipated role for LXRalpha in circadian physiology underscores the importance of addressing sex differences in chronobiology studies and future LXRalpha targeted therapies. PMID- 26938660 TI - Integrated Taxonomy and DNA Barcoding of Alpine Midges (Diptera: Chironomidae). AB - Rapid and efficient DNA-based tools are recommended for the evaluation of the insect biodiversity of high-altitude streams. In the present study, focused principally on larvae of the genus Diamesa Meigen 1835 (Diptera: Chironomidae), the congruence between morphological/molecular delimitation of species as well as performances in taxonomic assignments were evaluated. A fragment of the mitochondrial cox1 gene was obtained from 112 larvae, pupae and adults (Diamesinae, Orthocladiinae and Tanypodinae) that were collected in different mountain regions of the Alps and Apennines. On the basis of morphological characters 102 specimens were attributed to 16 species, and the remaining ten specimens were identified to the genus level. Molecular species delimitation was performed using: i) distance-based Automatic Barcode Gap Discovery (ABGD), with no a priori assumptions on species identification; and ii) coalescent tree-based approaches as the Generalized Mixed Yule Coalescent model, its Bayesian implementation and Bayesian Poisson Tree Processes. The ABGD analysis, estimating an optimal intra/interspecific nucleotide distance threshold of 0.7%-1.4%, identified 23 putative species; the tree-based approaches, identified between 25 26 entities, provided nearly identical results. All species belonging to zernyi, steinboecki, latitarsis, bertrami, dampfi and incallida groups, as well as outgroup species, are recovered as separate entities, perfectly matching the identified morphospecies. In contrast, within the cinerella group, cases of discrepancy arose: i) the two morphologically separate species D. cinerella and D. tonsa are neither monophyletic nor diagnosable exhibiting low values of between-taxa nucleotide mean divergence (0.94%); ii) few cases of larvae morphological misidentification were observed. Head capsule color is confirmed to be a valid character able to discriminate larvae of D. zernyi, D. tonsa and D. cinerella, but it is here better defined as a color gradient between the setae submenti and genal setae. DNA barcodes performances were high: average accuracy was ~89% and precision of ~99%. On the basis of the present data, we can thus conclude that molecular identification represents a promising tool that could be effectively adopted in evaluating biodiversity of high-altitude streams. PMID- 26938661 TI - Sudden acquired retinal degeneration in dogs: breed distribution of 495 canines. AB - PURPOSE: The purpose of this study was to describe breed, age, gender, and weight distribution of dogs affected with sudden acquired retinal degeneration (SARD) and to investigate whether SARD is more common in small breed dogs. METHODS: Medical records of dogs diagnosed with SARD confirmed by an electroretinogram were reviewed. Breed, age, gender, and weight were recorded when available. The same data were obtained for dogs with SARD described in the veterinary literature. RESULTS: Three hundred and two dogs were included from the ophthalmology practices and 193 dogs from the veterinary literature. Sixty breeds were present in the study. Mixed-breed dogs were the most common at 108 dogs (21.8%), followed by the Dachshund (68, 13.7%), Chinese Pug (44, 8.9%), Miniature Schnauzer (39, 7.9%), Maltese (23, 4.6%), Cocker Spaniel (22, 4.4%), Bichon Frise (18, 3.6%), Beagle (16, 3.2%), Brittany (15, 3.0%), and Pomeranian (10, 2.0%). Fifty other breeds were represented by 1-9 dogs each. The median age was 9 years (range = 10 months-16 years). The weight was known for 197 dogs. About 60.9% of dogs were less than 25 pounds, 31.5% were between 25 and 50 pounds, and 7.6% were greater than 50 pounds. Gender was recorded in 393 dogs: 217 female dogs and 176 male dogs. CONCLUSIONS: As previously reported, SARD is most common in middle aged to older dogs. Smaller dogs of less than 25 pounds appear overrepresented, while large/giant breed dogs of greater than 50 pounds are infrequently diagnosed. In this study, there was no statistical significance between female and male dogs. PMID- 26938659 TI - Hydrolyzable Tannins of Tamaricaceous Plants. 7.1 Structures and Cytotoxic Properties of Oligomeric Ellagitannins from Leaves of Tamarix nilotica and Cultured Tissues of Tamarix tetrandra. AB - Partially unacylated new oligomeric hydrolyzable tannins, nilotinin T2 (1, trimer) and nilotinin Q1 (2, tetramer), together with four known trimers, nilotinin T1 (3) and hirtellins T1-T3 (4-6), and a dimer, tamarixinin B (7), were isolated from the aqueous acetone extracts of leaves of Tamarix nilotica. Among them, the new trimer 1 and the known trimers 4 and 6, in addition to the partially unacylated new trimer nilotinin T3 (8), the known dimers nilotinin D3 (9) and tamarixinin C (10), and the monomer tellimagrandin I (11), were isolated from the cultured shoots of Tamarix tetrandra. The structures of the new hydrolyzable tannins were established by chromatographic analyses and extensive 1D and 2D NMR, HRESI-TOFMS, and ECD spectroscopic experiments. Among the new oligomeric tannins, the particular unacylated position of a glucose core is attributed to a possible biosynthetic route. Isolation of the same oligomeric tannins from cultured shoots of T. tetrandra emphasizes the unique biogenetic ability of the obtained cultures on production of the structurally and biologically characteristic tamaricaceous tannins commonly produced by the intact Tamarix plants. Additionally, tannins obtained in the present study together with gemin D (12) and 1,3-di-O-galloyl-4,6-O-(aS)-hexahydroxydiphenoyl-beta-d-glucose (13), from our previous investigation of the leaves of T. nilotica, exhibited variable tumor-specific cytotoxic effects. The ellagitannin trimers 4, 6, and 8 and the dimer 9 exerted predominant tumor-selective cytotoxic effects with high specificity toward human promyelocytic leukemia cells. PMID- 26938662 TI - The Pioneer Initiative: A New Era in Chinese Research. AB - A brief description of the background, rational and goals of the Pioneer Initiative (PI), a reform program at the Chinese Academy of Sciences (CAS), is provided. The harmonizing nature and shared missions between this initiative and the CAS 135 Strategy that is concurrently occuring are also discussed. Both initiatives aim to address fundamental challenges and bring CAS to a new high in science excellence and innovation. PMID- 26938663 TI - The MUC1 mucin specifically inhibits activation of the NLRP3 inflammasome. AB - MUC1 is a cell membrane-associated mucin, expressed ubiquitously on the mucosal epithelia as well as by immune cells, that limits the inflammatory response to multiple pathogens. We have recently shown that MUC1 controls inflammation resulting from Helicobacter pylori infection by suppressing interleukin-1beta (IL 1beta) produced via the NLRP3 inflammasome. Here, we demonstrate that MUC1 also regulates IL-1beta secretion induced by the NLRP3-activating bacteria Haemophilus influenzae but not bacteria that activate other inflammasomes. Using purified ligands, we further demonstrate that MUC1 regulation of NLRP3 is specific, as it has no effect on the NLRP1b, NLRC4 and AIM2 inflammasomes. This indicates a unique role for MUC1 in the regulation of NLRP3-activating bacterial infections. PMID- 26938658 TI - Attacking the supply wagons to starve cancer cells to death. AB - The constitutive anabolism of cancer cells not only supports proliferation but also addicts tumor cells to a steady influx of exogenous nutrients. Limiting access to metabolic substrates could be an effective and selective means to block cancer growth. In this review, we define the pathways by which cancer cells acquire the raw materials for anabolism, highlight the actionable proteins in each pathway, and discuss the status of therapeutic interventions that disrupt nutrient acquisition. Critical open questions to be answered before apical metabolic inhibitors can be successfully and safely deployed in the clinic are also outlined. In summary, recent studies provide strong support that substrate limitation is a powerful therapeutic strategy to effectively, and safely, starve cancer cells to death. PMID- 26938664 TI - Interleukin 6 SNP rs1800797 associates with the risk of adult-onset asthma. AB - Interleukin 6 (IL6) is an inflammatory cytokine that has been suggested to have an important role in the pathogenesis of asthma. IL6 single-nucleotide polymorphisms (SNPs) have been associated with levels of IL6, and with childhood and prevalent adult asthma. A recent study also suggested that IL6 SNPs associate especially with atopic asthma. However, association of IL6 SNPs with adult-onset asthma has not been studied. In a population-based study of 467 incident adult onset asthma cases and 613 disease-free controls from South Finland, we analyzed association of 6 tagging SNPs of the IL6 locus with the risk of adult-onset asthma and with atopy. Asthma was clinically diagnosed, and atopy was defined based on Phadiatop test. IL6 SNP rs1800797 associated with the risk of adult onset asthma in a log additive model, with adjusted odds ratio (aOR) 1.31 (95% confidence interval 1.09-1.57), and especially with the risk of atopic adult onset asthma when compared with non-atopic controls, aOR 1.46 (95% CI 1.12-1.90). This is the first study to show an association of IL6 with adult-onset asthma, and especially with atopic adult-onset asthma. PMID- 26938666 TI - Glycosylation of Nucleosides. AB - Nucleoside O-glycosylation represents an archetypal problem in chemical selectivity, inasmuch as the nucleobase (an undesired site of reaction) is usually more nucleophilic than the hydroxyl (the desired site of reaction). Optimized reaction conditions have been developed for the efficient O glycosylation of nucleoside hydroxyls. Both thioglycoside and Schmidt imidate donors (1.5 equiv) have been employed successfully. Interference by the nucleobase is minimized by the use of indium(III) triflate as the donor activating reagent; the In(OTf)3 serves to promote apparent transfer of the donor glycosyl moiety from nucleobase to hydroxyl. Glycosylation of uridine triacetate gives products resulting from O- and N-glycosylation of the pyrimidine ring. PMID- 26938667 TI - Electrode Architecture in Galvanic and Electrolytic Energy Cells. AB - Electrodes in galvanic and electrolytic energy cells are complicated structures comprising redox-active materials, ionic/electronic conductors, and porous pathways for mass transfer of reactants. In contrast to breakthroughs in component development, methods of optimizing whole-system architectural design to draw maximum output have not been well explored. In this Minireview, we introduce generalized types of electrode architecture, discuss fabrication strategies, and characterize already built structures. Systematic efforts to discover optimal electrode configurations will resolve long-standing discrepancies that arise between whole systems and the sums of their parts for a number of electrochemical reactions and technologies. PMID- 26938665 TI - Influence of the polymorphism of the DUSP14 gene on the expression of immune related genes and development of pulmonary tuberculosis. AB - Recently, a genome-wide screening identified a functional single-nucleotide polymorphism in dual-specificity phosphatase 14 gene (DUSP14), which was associated with pulmonary tuberculosis (TB) in a West African study. DUSP14 regulates T-cell proliferation and cytokine production in a negative way via dephosphorylation and inactivation of key signaling molecules. The aim of this study is to further explore the possible significance of the DUSP14 polymorphism. Total RNA was extracted from the whole blood of 109 healthcare workers (HCWs) in Vietnam and subjected to quantitative reverse-transcription PCR for DUSP14 and 20 immune-related genes. DUSP14 rs1051838 was genotyped in 502 new pulmonary TB patients and 506 healthy controls. Among disease-free individuals (HCWs), T helper type-1 (Th1)-related genes, interferon-gamma receptor 2 (IFNGR2) and signal transducer and activator of transcription-1 (STAT1) mRNA levels significantly increased as the number of A alleles of rs1051838 increased, whereas the DUSP14 mRNA level tended to decrease. The AA genotype was associated with protection against active TB in younger patients (?45 years old, OR=0.63, 95% CI 0.44-0.90). Our results suggest that a low-expression genotype of DUSP14 accompanied by high transcript levels of Th1 immune-related genes may confer protection against early TB development. PMID- 26938668 TI - Correction: Correction: Molecular Characterization of Circulating Respiratory Syncytial Virus (RSV) Genotypes in Gilgit Baltistan Province of Pakistan during 2011-2012 Winter Season. PMID- 26938669 TI - A Small Molecule Screen Exposes mTOR Signaling Pathway Involvement in Radiation Induced Apoptosis. AB - Individuals are at risk of exposure to acute ionizing radiation (IR) from a nuclear accident or terrorism, but we lack effective therapies to mitigate the lethal IR effects. In the current study, we exploited an optimized, cell-based, high throughput screening assay to interrogate a small molecule library comprising 3437 known pharmacologically active compounds for mitigation against IR-induced apoptosis. Thirty-three library compounds significantly reduced apoptosis when administered 1 h after 4 Gy IR. Two- or three-dimensional computational structural analyses of the compounds indicated only one or two chemical clusters with most of the compounds being unique structures. The mechanistic target of rapamycin complex 1 (mTORC1) inhibitor, rapamycin, was the most potent compound, and it mitigated apoptosis by 50% at 200 +/- 50 pM. Other mTOR inhibitors, namely everolimus, AZD8055, and torin 1, also suppressed apoptosis, providing additional pharmacological evidence for mTOR pathway involvement in regulating cell death after IR. Everolimus and torin 1 treatment after IR decreased the S phase population and enforced both G1 and G2 phase arrest. This prorogation of cell cycle progression was accompanied by decreased IR-induced DNA damage measured by gammaH2AX phosphorylation at Ser139. RNA interference-mediated knockdown of the respective mTORC1 and mTORC2 subunits, Raptor or Rictor, also mitigated IR-induced apoptosis. Collectively, this study suggests a central role for the mTOR signaling in the cytotoxic response to IR and offers a useful platform to probe for additional agents. PMID- 26938670 TI - 1,2,3-Triazole Bridge as Conformational Constrain in beta-Hairpin Peptides: Analysis of Hydrogen-Bonded Positions. AB - Conformational constrained beta-hairpin peptides are useful tool to modulate protein-protein interactions. A triazole bridge in hydrogen-bonded positions between two antiparallel strands induces a conformational stabilization of the beta-hairpin peptide. The entity of the stability of the beta-hairpin peptide depends on the length of the bridge. PMID- 26938672 TI - Abstracts of the 95th Annual Meeting of the German Physiological Society, 3-5 March 2016. PMID- 26938673 TI - Validation of a New Heart Rate Measurement Algorithm for Fingertip Recording of Video Signals with Smartphones. AB - INTRODUCTION: This study investigates the accuracy of a heart rate (HR) measurement algorithm applied to a pulse wave. This was based on video signals recorded with a smartphone. The results of electrocardiographic HR and standard linear heart rate variability (HRV) analysis were used for reference. MATERIALS AND METHODS: On a total of 68 subjects, an electrocardiogram (ECG) and the pulse curve were simultaneously recorded on an Apple iPhone 4S. The HR was measured using an algorithm developed by the authors that works according to a method combining the detection of the steepest slope of every pulse wave with the correlation to an optimized pulse wave pattern. RESULTS: The results of the HR measured by pulse curves were extremely consistent (R > 0.99) with the HR measured on ECGs. For most standard linear HRV parameters as well, high correlations of R >= 0.90 in the analysis were achieved in the time and frequency domain. CONCLUSION: In conclusion, the overall accuracy of HR and HRV indices of pulse wave analysis, based on video signals of a smartphone, with the developed algorithm was sufficient for preclinical screening applications. PMID- 26938671 TI - MOMENTS OF MEETING: THE RELEVANCE OF LOU SANDER'S AND DAN STERN'S CONCEPTUAL FRAMEWORK FOR UNDERSTANDING THE DEVELOPMENT OF PATHOLOGICAL SOCIAL RELATEDNESS. AB - Lou Sander and Dan Stern made seminal contributions to our understanding of early child development, particularly in regard to the moment-to-moment intersubjective exchanges and mutual sensitivity that are at the core of the caregiver-infant relationship. Although their own studies focused primarily on the ways in which children's intersubjective experiences of mutual attunement lead to adaptive social relatedness and validate a healthy sense of self, this article focuses on the applicability of their theoretical conceptions to the development of pathological social relations. It explores the premise that the emotional validation derived from recurrent intersubjective experiences of mutual attunement involving negative affects can be as emotionally compelling from the child's standpoint as that derived from positive exchanges. Children's needs to recreate unhealthy, but affectively meaningful, moments with their caregivers can lead to ingrained, automatically operating pathological patterns of social behavior and affective expression that can take on a life of their own and strongly shape the child's subsequent socioemotional functioning. Following an overview of Sander's and Stern's conceptual thinking, developmental research and clinical case material will be utilized to illustrate how their work can enrich our understanding of developmental processes that can contribute to a number of emotion-specific, early relational disturbances. PMID- 26938674 TI - Mapping of Defects in Individual Silicon Nanocrystals Using Real-Space Spectroscopy. AB - The photophysical properties of silicon semiconductor nanocrystals (SiNCs) are extremely sensitive to the presence of surface chemical defects, many of which are easily produced by oxidation under ambient conditions. The diversity of chemical structures of such defects and the lack of tools capable of probing individual defects continue to impede understanding of the roles of these defects in SiNC photophysics. We use scanning tunneling spectroscopy to study the impact of surface defects on the electronic structures of hydrogen-passivated SiNCs supported on the Au(111) surface. Spatial maps of the local electronic density of states (LDOS) produced by our measurements allowed us to identify locally enhanced defect-induced states as well as quantum-confined states delocalized throughout the SiNC volume. We use theoretical calculations to show that the LDOS spectra associated with the observed defects are attributable to Si-O-Si bridged oxygen or Si-OH surface defects. PMID- 26938675 TI - CD163(+) M2-type tumor-associated macrophage support the suppression of tumor infiltrating T cells in osteosarcoma. AB - Osteosarcoma is one of the most common childhood cancers with high numbers of cancer-related deaths. Progress in conventional therapies is showing limited improvement. An adaptive T cell-based immunotherapy represents a promising new therapeutic option, but to improve its efficacy, regulatory mechanisms in osteosarcoma need further elucidation. Here, to evaluate the regulatory effect of tumor microenvironment of T cells in osteosarcoma, we examined the peripheral blood (PB) and tumor infiltrating (TI) T cells, and their correlations with PB and tumor immune characteristics. We found that TI T cells contained significantly higher levels of TIM-3(+)PD-1(-) and TIM-3(+)PD-1(+) cells than their PB counterparts. Similar to that in chronic HIV and HCV infections, these TIM-3(+)PD-1(-) and TIM-3(+)PD-1(+) T cells presented reduced proliferation and proinflammatory cytokine secretion in response to stimulation. Presence of M2 type (CD163(+)) macrophages exacerbated T cell immunosuppression, since frequencies of CD163(+) tumor-associated macrophages were directly correlated with the frequencies of suppressed TIM-3(+)PD-1(+) T cells. Moreover, depletion of CD163(+) macrophages significantly improved T cell proliferation and proinflammatory cytokine production. Overall, our data presented an intratumoral T cell-specific immunosuppression that was amplified by M2-type tumor-associated macrophages. PMID- 26938676 TI - Effect of seat positions on discomfort, muscle activation, pressure distribution and pedal force during cycling. AB - The aim of this study was to measure and analyse discomfort and biomechanics of cycling, i.e., muscle activation, centre of pressure of seat pressure profiles and pedal forces as a function of seat position. Twenty-one recreationally active individuals cycled for 10min at 100W on an ergometer cycle using five different seat positions. The neutral position was considered as basic seat position and was compared with upward, downward, forward and backward seat positions. The initial bout was repeated at the end of the recording session. Discomfort increased for upward and backward condition compared with neutral (P<0.05). Normalized surface electromyography from gastrocnemius decreased in the downward and forward position but increased in the upward and backward position. The minimum force became less negative for forward position compared with neutral seat position (P<0.05). The degree of variability of centre of pressure increased in the upward and backward position and the entropy of the centre of pressure of sitting posture for backward position decreased compared with neutral seat position (P<0.05). The present study revealed that consecutive changes of seat position over time lead to increase in discomfort as well as alterations of the biomechanics of cycling. PMID- 26938677 TI - Influence of chronic low back pain and fear of movement on the activation of the transversely oriented abdominal muscles during forward bending. AB - INTRODUCTION: Chronic low back pain (CLBP) and fear of movement (kinesiophobia) are associated with an overactivation of paravertebral muscles during forward bending. This impairs spine motor control and contributes to pain perpetuation. However, the abdominal muscles activation is engaged too in spine stabilization but its modulation with kinesiophobia remains unknown. Our study tested whether CLBP and kinesiophobia affected the activation pattern of abdominal muscles during trunk flexion/extension. METHODS: Surface electromyographical recordings of the internal oblique/transversus abdominis (IO/TrA) and external oblique (EO) muscles were analyzed in 12 people with CLBP and 13 pain-free subjects during low velocity forward bending back and forth from erected posture. Tampa Scale of Kinesiophobia was also administrated. RESULTS: IO/TrA activation, but not EO, was modulated across the phases of movement in both groups, i.e. maximal at onset of flexion and end of extension, and minimal at full flexion. In CLBP group only, IO/TrA activation was increased near to full trunk flexion and in correlation with kinesiophobia. CONCLUSIONS: The phase-dependence of IO/TrA activation during trunk flexion/extension in standing may have a role in spine motor control. The influence of kinesiophobia in CLBP should be further investigated as an important target in CLBP management. PMID- 26938678 TI - Effects of water chemistry on the destabilization and sedimentation of commercial TiO2 nanoparticles: Role of double-layer compression and charge neutralization. AB - Nanomaterials are considered to be emerging contaminants because their release into the environment could cause a threat to our ecosystem and human health. This study aims to evaluate the effects of pH, ions, and humic acid on the destabilization and sedimentation of commercial stabilized TiO2 nanoparticles (NPs) in aquatic environments. The average hydrodynamic size of TiO2 NPs was determined to be 52 +/- 19 nm by dynamic light scattering. The zero point charge (ZPC) of the commercial TiO2 NPs was found to occur at pH 6. The stability of commercial TiO2 NPs is independent of its concentration in the range of 50-200 mg/L. In the absence of NaCl, the commercial TiO2 NPs rapidly settled down near pHzpc when the aggregated nanoparticle size surpassed 1 MUm. However, when the commercial TiO2 NPs aggregated with the increase of NaCl concentrations, the large aggregates (>1 MUm) were found to remain suspended. For example, even at the critical aggregation concentration of NaCl (100 meq/L), TiO2 NP aggregates suspended for 45 min and then slowly deposited. This implies an increase in the exposure risk of NPs. In the presence of Suwannee river humic acid (SRHA), the commercial TiO2 NPs did not settle down until the SRHA concentration increased to 20 mg/L, and were seen to restabilize at SRHA concentrations of 50 mg/L. The uncommon behaviors of the commercial TiO2 NPs we observed may be attributed to the different destabilization mechanisms caused by different species (i.e., NaCl and SRHA) in water. PMID- 26938680 TI - Activated persulfate for organic chemical degradation: A review. AB - Activated persulfate reactions have widespread application for groundwater and environmental remediation, as many of these reactions involve destruction of environmental contaminants. Within the last five years, knowledge of activated persulfate degradation reactions has grown to include novel means of activating persulfate for enhanced removal of organic species. These current studies cover a long list of organic analytes, including pharmaceuticals, pesticides, halogenated compounds and dyes. An extensive review of recently published experimental parameters and results for the destruction of organic compounds via activated persulfate is presented. Focus is placed on emerging methodologies and manipulation of traditional activation techniques. Knowledge gaps are identified and discussed, as despite the number of publications on this subject, more broad reaching guidelines are needed for optimizing applications of activated persulfate in water treatment. PMID- 26938679 TI - Effects of plastic film residues on occurrence of phthalates and microbial activity in soils. AB - Plastic film mulching has played an important role in Chinese agriculture, especially in vegetable production, but large amounts of film residues can accumulate in the soil. The present study investigated the effects of plastic film residues on the occurrence of soil PAEs and microbial activities using a batch pot experiment. PAE concentrations increased with increasing plastic film residues but the soil microbial carbon and nitrogen, enzyme activities and microbial diversity decreased significantly. At the end of the experiment the PAE concentrations were 0-2.02 mg kg(-1) in the different treatments. Soil microbial C and N, enzyme activities, AWCD value, and Shannon-Weaver and Simpson indices declined by about 28.9-76.2%, 14.9-59.0%, 4.9-22.7%, 23.0-42.0% and 1.8-18.7%, respectively. Soil microbial activity was positively correlated with soil PAE concentration, and soil PAE concentrations were impacted by plastic color and residue volume. Correlations among, and molecular mechanisms of, plastic film residues, PAE occurrence and microbial activity require further study. PMID- 26938681 TI - A retrospective analysis of the occurrence of accidents during 20 years of neonatal transport in Liguria region, Italy. AB - Our article focuses on a retrospective analysis of the occurrence of accidents relating to 20 years of activity of Neonatal Emergency Transport Service (NETS) in Liguria region, Italy. The objective of this study is to determine the vehicle accident rate for a specialized emergency medical services-NETS transport system between 1995 and 2015. We reviewed 5035 medical records related to the activity of our NETS from its beginning, in February 1995 to June 2015. We identified the occurrence of three road accidents (rate ~1 : 1600 transports; 1 : 170 000 driven km), no helicopter accidents and only one technical problem during helicopter use; our service was not involved in any crashes resulting in injury. We discussed some reasons possibly explaining these good results. PMID- 26938682 TI - Wound complications and surgical events in de novo heart transplant patients treated with everolimus: Post-hoc analysis of the SCHEDULE trial. AB - OBJECTIVES: The use of mammalian target of rapamycin (mTOR) inhibitors have been limited by adverse events (AE), including delayed wound healing. We retrospectively reviewed all AE and serious AE (SAE) in The Scandinavian heart transplant (HTx) everolimus (EVE) de novo trial with early calcineurin (CNI) avoidance (SCHEDULE). The aim of the study was to compare wound complications between EVE and CNI based regimen. MATERIALS AND METHODS: A total of 115 patients (mean age 51 +/- 13 years, 73% men) were randomized within five days post-HTx to low dose EVE and reduced dose Cyclosporine (CyA) followed by early CyA withdrawal (EVE group; n=56) or standard CyA regimen (CyA group; n=59). All AE/SAEs were prospectively recorded according to the SCHEDULE study protocol, and re-assessed retrospectively by two independent reviewers. Wound complication as primary endpoint was defined as any complication associated with failure of tissue healing. Secondary endpoint was total number of events involving surgical intervention. RESULTS: There were no significant differences between the groups with regards to wound complications (EVE=20, CyA=12)(p=0.08) or total surgical events (EVE=38, CyA=34) (p=0.44). Age>54.5 years (median) was an overall risk factor for surgical wound complications regardless of treatment group (p=0.025). There was no difference in the EVE versus CyA group with regards to other surgical events. Majority of events were in 1/3 of the patients. CONCLUSION: De novo initiation of EVE and early CyA withdrawal in HTx patients did not show any significant differences in wound complications or in total surgical events. Majority of complications were seen in a small number of patients. PMID- 26938683 TI - Use of ACE inhibitors in Fontan: Rational or irrational? AB - BACKGROUND: Despite a lack of evidence supporting the use of angiotensin converting enzyme (ACE) inhibitors in patients with a Fontan circulation, their use is frequent. We decided to identify the rationale for ACE inhibitor therapy in patients within the Australia and New Zealand Fontan Registry. METHODS: All patients in the Registry taking an ACE inhibitor at last follow up were identified, and a review of medical records was undertaken to determine the rationale for treatment initiation and reasons for treatment continuation or dose increase. RESULTS: In 2015, 36% of the surviving patients in the Registry (462/1268) were taking an ACE inhibitor. Indications for initiation of therapy were ventricular systolic or diastolic dysfunction (29%), atrioventricular valve regurgitation (19%), preservation of normal ventricular function (7%), prolonged effusions at Fontan (6%), hypertension (6%), other (6%) and unknown (2%). No indication was stated in the remaining patients (25%). Those with hypoplastic left heart syndrome were more likely to be on an ACE inhibitor than those with an alternative primary morphology (70% vs 32%; p<0.001). Only 36% of the patients treated with an ACE inhibitor at last follow up (166/462) had an indication that would generally justify treatment in a two-ventricle circulation. CONCLUSION: It is likely that the use of ACE inhibitors in patients with a Fontan circulation is excessive within our region. The coordination of prospective, multicentre studies and initiatives such as the Australia and New Zealand Fontan Registry will facilitate further investigations to guide treatment decisions in the growing Fontan population. PMID- 26938684 TI - Cross-linking versus RAGE: How do high molecular weight advanced glycation products induce cardiac dysfunction? AB - BACKGROUND: Several clinical and experimental studies have demonstrated that advanced glycation end products (AGEs) are associated with adverse cardiac outcome. Growing evidence shows that high molecular weight AGEs (HMW-AGEs) might be as important as the characterized low molecular weight AGEs. To date, the role of HMW-AGEs in the pathogenesis of cardiac remodeling remains unknown. In this study, we investigated whether HMW-AGEs are involved in cardiac dysfunction. METHODS: Healthy rats were daily ip injected with 20mg/kg BSA-derived HMW-AGEs or, as a control, unmodified BSA, during 6 weeks. Cardiac function was assessed with echocardiography. Plasma levels of glucose, AGEs and soluble RAGE (sRAGE) were measured. AGEs, RAGE and lysyl oxidase (LOX) expression were determined by western blot. RESULTS: After 6 weeks, animals displayed a sustained increase in circulating total AGEs without hyperglycemia. HMW-AGEs injections induced cardiac dysfunction characterized by wall hypertrophy, increased heart sphericity, reduced strain and strain rate with preserved ejection fraction. Plasma sRAGE levels were significantly higher compared to control and correlated significantly with decreased strain. RAGE expression, TNF-alpha and IL-6 remained unchanged. Finally, HMW-AGEs induced prominent cardiac fibrosis associated with an increased LOX expression. CONCLUSION: Our data demonstrate that rather than via a specific activation of RAGE, the deleterious effects of HMW-AGEs are likely mediated via an increased collagen cross-linking responsible for the observed cardiac stiffness. Additionally, we show that in the setting of elevated HMW-AGEs, increased sRAGE levels are markers of altered cardiac function. PMID- 26938685 TI - Difference in the maintenance mechanism of atrial fibrillation perpetuated after pulmonary vein isolation between paroxysmal and persistent atrial fibrillation: Effects of subsequent stepwise ablation. AB - BACKGROUND: Neither the atrial fibrillation (AF) maintenance mechanism after pulmonary vein isolation (PVI) nor the mechanism of AF termination via stepwise ablation is clearly understood. METHODS: Among 226 consecutive AF patients (154 paroxysmal (P-AF) and 72 persistent AF (Per-AF) patients), left atrial endocardial non-contact mapping was performed after PVI in the initial 10 P-AF and 16 Per-AF patients to define the AF maintenance mechanism. Subsequently, effect of stepwise catheter ablation (linear roof lesion and complex fractionated atrial electrogram (CFAE) following PVI) was evaluated in all patients. RESULTS: After PVI, AF was maintained by the activation around isolated PV/mitral annulus, focal discharge and disorganized activations mostly observed over residual CFAE region (pivoting activation, wave break and fusion). CFAE region in P-AF was smaller than Per-AF after PVI (1.6 +/- 2.1 vs. 7.7 +/- 2.5 cm(2), p<0.0001). The frequency of pivoting activation, wave break and fusion in P-AF were lower than those in Per-AF (1.9 +/- 2.0 vs. 11.8 +/- 5.0 times/s; p<0.0001, 0.1 +/- 0.3 vs. 3.6 +/- 2.5 times/s; p<0.001, 5.8 +/- 3.6 vs. 9.8 +/- 3.2 times/s; p<0.01). AF termination was more frequent in P-AF than Per-AF (94.8% vs 81.9%, p=0.0019). AF termination by PVI alone was more frequent in P-AF than Per-AF (85.6% vs. 18.6%, p<0.0001). However, AF termination via roof line and/or CFAE ablation was less frequent in P-AF than Per-AF (14.4 vs. 81.4%, p<0.0001). CONCLUSIONS: Disorganized activations after PVI, more prominent in Per-AF, were associated with residual CFAE region. Most P-AF was terminated by PVI alone, however additional roof line lesion and CFAE ablation were necessary to terminate Per-AF, consistent with mapping results. PMID- 26938686 TI - Severe stress (takotsubo) cardiomyopathy following subarachnoid haemorrhage. PMID- 26938687 TI - Impact of the physical microenvironment on tumor progression and metastasis. AB - The tumor microenvironment is increasingly understood to contribute to cancer development and progression by affecting the complex interplay of genetic and epigenetic changes within the cells themselves. Moreover, recent research has highlighted that, besides biochemical cues from the microenvironment, physical cues can also greatly alter cellular behavior such as proliferation, cancer stem cell properties, and metastatic potential. Whereas initial assays have focused on basic ECM physical properties, such as stiffness, novel in vitro systems are becoming increasingly sophisticated in differentiating between distinct physical cues-ECM pore size, fiber alignment, and molecular composition-and elucidating the different roles these properties play in driving tumor progression and metastasis. Combined with advances in our understanding of the mechanisms responsible for how cells sense these properties, a new appreciation for the role of mechanics in cancer is emerging. PMID- 26938688 TI - Systematic layer-by-layer characterization of multilayers for three-dimensional data storage and logic. AB - Magnetic kink solitons are used as a probe to experimentally measure the layer-by layer coercivity and interlayer coupling strength of an antiferromagnetically coupled perpendicularly magnetized Co multilayer. The magnetic response is well described by a nearest neighbor Ising macrospin model. By controlling the position of one, two or three solitons in the stack using globally applied magnetic fields, we successfully probe the switching of individual buried layers under different neighboring configurations, allowing us to access individual layer's characteristic parameters. We found the coercivity to increase dramatically up the multilayer, while the interlayer coupling strength decreased slightly. We corroborate these findings with scanning transmission electron microscopy images where a degrading quality of the multilayer is observed. This method provides a very powerful tool to characterize the quality of individual layers in complex multilayers, without the need for depth-sensitive magnetic characterization equipment. PMID- 26938690 TI - Imaging of Rare Primary Malignant Hepatic Tumors in Adults With Histopathological Correlation. AB - Hepatocellular carcinoma and cholangiocarcinoma are the most common primary liver malignancies in adults (comprising >85%); however, liver is also host to some unusual primary malignant tumors. Some of these tumors show distinct demographic, clinicopathologic, and imaging features. Imaging features of these uncommon primary malignant liver tumors are presented with an attempt to correlate them with histopathology. PMID- 26938689 TI - Hepatocellular Carcinoma Histological Grade Prediction: A Quantitative Comparison of Diffusion-Weighted, T2-Weighted, and Hepatobiliary-Phase Magnetic Resonance Imaging. AB - OBJECTIVES: This study aimed to compare quantitative assessments for predicting hepatocellular carcinoma (HCC) histological grades using magnetic resonance imaging. METHODS: We retrospectively reviewed magnetic resonance imaging data from 49 patients with 54 surgically resected HCCs (11 well differentiated, 29 moderately differentiated, and 14 poorly differentiated). We measured the lesion to-liver relative contrast ratio (RCR) on diffusion-weighted (DW), T2-weighted (T2W), and ethoxybenzyl-hepatobiliary images. We also evaluated contrast-to-noise ratio (CNR) on DW images, and the apparent diffusion coefficient. We compared the feasibility of these parameters in predicting HCC histological grade. RESULTS: Areas under the receiver operating characteristic curves of both the DW RCR (97%) and DW CNR (97%) were significantly greater compared with those of the apparent diffusion coefficient (79%), T2W RCR (81%), and ethoxybenzyl-hepatobiliary RCR (80%) (P < 0.05, 0.001, and 0.001, respectively). CONCLUSIONS: The DW RCR and DW CNR might represent accurate predictors of HCC histological grade. PMID- 26938691 TI - Fat Embolism Syndrome: Lung Computed Tomography Findings in 18 Patients. AB - OBJECTIVE: The purpose of this study was to evaluate the lung computed tomography (CT) findings in fat embolism (FE) syndrome. METHODS: We retrospectively evaluated 19 CT examinations of 18 patients with FE syndrome, diagnosed clinically using the Gurd and Wilson criteria. RESULT: Fat embolism syndrome showed 3 patterns: negative examination, bilateral interstitial-alveolar involvement, and adult respiratory distress syndrome like. Frequent findings included consolidations (17 patients), mostly with gravity dependent distribution, and ground-glass opacities (17 patients), mostly with patchy distribution. Fifteen patients showed an overlapping random nodular pattern. Less common findings included lobular ground-glass opacities and lobular consolidations, smooth septal thickening, thickening of the bronchial wall, and areas of crazy paving. The extension of the consolidations correlates with the duration of assisted ventilation. CONCLUSIONS: In FE syndrome, pulmonary CT findings are ground-glass opacities and dependent consolidations, associated with other variably overlapping signs, such as lobular opacities, random nodules, septal thickening, and bronchial wall thickening. PMID- 26938692 TI - Feasibility of Dual Flip Angle-Based Fast 3-Dimensional T1 Mapping for Delayed Gadolinium-Enhanced Magnetic Resonance Imaging of Cartilage of the Knee: A Histologically Controlled Study. AB - OBJECTIVE: The aim of the study was to validate dual-flip angle-based fast 3 dimensional (3D) T1 mapping for delayed gadolinium-enhanced magnetic resonance imaging (MRI) of cartilage (dGEMRIC) by means of histological analyses in the assessment of the cartilage of the knee in a porcine model. METHODS: A total of 15 mini pigs were included in this study. The left knee anterior cruciate ligaments of all mini pigs were transected. The mini pigs were divided into 3 groups postoperatively, with 5 pigs randomly assigned to 1 group. Dual-flip angle based fast T1 mapping for dGEMRIC was obtained in the sagittal planes at 0 week (group 1), 3 weeks (group 2), and 6 weeks (group 3) after operation, using an 8 channel knee coil. Magnetic resonance imaging was performed at 3T with dual-flip angle-based fast 3D T1 mapping sequence for morphological cartilage assessment of dGEMRIC T1 values. After MRI analysis, histological and biochemical composition (water, collagen, and glycosaminoglycan [GAG]) of the knee cartilage in the medial femoral condyle was quantified ex vivo. RESULTS: The T1 values obtained by the dual-flip angle-based fast 3D T1 mapping were positively correlated with the glycosaminoglycan content (r = 0.85; P < 0.05). The values had no significant correlation with the collagen content. The dGEMRIC-T1 values obtained by this method showed the medial femoral condyle cartilage in the anterior cruciate ligament-transected knee after transection decreased with time (P < 0.05). Histological sections of cartilage damage were correlated with MRI data. CONCLUSIONS: This study demonstrated the reliability of using dual-flip angle based fast T1 mapping for dGEMRIC for the biochemical assessment of early cartilage degeneration. This technique is a powerful tool for researchers and clinicians to acquire sufficient resolution data within a reasonable scan time. PMID- 26938693 TI - Computed Tomography Features of Septic Pulmonary Embolism Caused by Klebsiella pneumoniae Liver Abscess Associated With Extrapulmonary Metastatic Infection. AB - OBJECTIVES: The aims of the study were to investigate the computed tomography (CT) features and clinical course of septic pulmonary embolism (SPE) caused by Klebsiella pneumoniae liver abscess (KPLA) and to explore the possible mechanism underlying the spread of infection. METHODS: Twenty-one patients with KPLA induced SPE admitted to our hospital between January 2010 and May 2015 were evaluated. According to the presence or absence of extrapulmonary metastatic infection (EMI), they were divided into EMI and non-EMI groups and clinical and CT features of the 2 groups were compared. Hepatic vein thrombophlebitis was evaluated on liver CT images. Chest CT features included nodules, wedge-shaped lesions, ground-glass opacity, consolidation, cavitation, feeding vessel sign, pleural effusion, and lymphadenopathy. RESULTS: All the vessels within the so called feeding vessel sign were confirmed as pulmonary veins by multiplanar reconstruction, so we used an alternative name draining vessel sign (DVS) instead. Peripheral nodules, DVS, and consolidation were the main CT features of KPLA-induced SPE. Peripheral nodules and DVS were more frequently seen in the EMI group than in the non-EMI group (P = 0.019 and 0.008, respectively). Five of 8 patients with hepatic vein thrombophlebitis had lung consolidation, whereas only 3 of 13 patients without hepatic vein thrombophlebitis had lung consolidation, although the difference was not significant (P = 0.09). CONCLUSIONS: Multiple pulmonary nodules and DVS were associated with EMI. Hepatic and pulmonary vein invasion are possible causes underlying the metastatic spread of infection. PMID- 26938694 TI - Risk Analysis for Pathological Changes in Pulmonary Parenchyma Based on Lung Computed Tomography Images. AB - OBJECTIVE: The purpose of this study is to design a content-based medical image retrieval system, which helps excavate and assess pathological change of pulmonary parenchyma for risks analysis. METHODS: A data set including lung computed tomography images obtained from 115 patients who experienced pathological changes in pulmonary parenchyma is used. Using morphological theory, images are preprocessed and decomposed into groups of pixel blocks (words), which construct vocabulary. A latent Dirichlet allocation (LDA) model is constructed to assess each image for risk analysis with the method of leave-one-out cross validation. The precision and recall rate are used as the performance assessment criteria. RESULTS: The LDA model generates a relevance rank of retrieval results from high to low. From the top 50 images, precision of identical tissue is 0.76 +/- 0.031 and precision of each attribute of pulmonary parenchyma range from 0.776 +/- 0.043 to 0.984 +/- 0.008. CONCLUSIONS: The study results demonstrate that the proposed LDA model is conductive to lung computed tomography image retrieval and has reliable efficacy on risk analysis about pathological changes of pulmonary parenchyma. PMID- 26938695 TI - Diagnostic Usefulness of Low-Dose Nonenhanced Computed Tomography With Coronal Reformations in Patients With Suspected Acute Appendicitis: A Comparison With Standard-Dose Computed Tomography. AB - PURPOSE: The aims of the study were to evaluate the usefulness of low-dose (LD) nonenhanced CT (NECT) with coronal reformation in diagnosing acute appendicitis and to compare LD NECT with standard-dose (SD) NECT and SD contrast-enhanced CT (CECT). METHODS: A total of 452 patients suspected of having acute appendicitis underwent CT using a scan 1 (SD NECT and SD CECT1, n = 182) or a scan 2 protocol (LD NECT and SD CECT2, n = 270). The diagnostic performance and interobserver agreement for diagnosing acute appendicitis were compared. RESULTS: Although the area under the curves of both reviewers of LD NECT were lower than those of SD CECT2, area under the curves of both reviewers for SD NECT were not significantly different for SD CECT1 and LD NECT (all P > 0.05). The interobserver agreements within each scan were excellent (all kappa > 0.8). CONCLUSIONS: Low-dose NECT with coronal reformation showed high diagnostic performance and can be used as the first-line imaging tool in the work-up of patients with suspected acute appendicitis. PMID- 26938696 TI - Standard-b-Value Versus Low-b-Value Diffusion-Weighted Imaging in Hepatic Lesion Discrimination: A Meta-analysis. AB - OBJECTIVE: We sought to determine the comparative diagnostic performance of standard-b-value (500-1000s/mm) versus low-b-value (<=500 s/mm) diffusion weighted imaging (DWI) in the discrimination of hepatic lesions. METHODS: A total of 1775 hepatic malignant lesions and 1120 benign hepatic lesions from 21 studies were included. RESULTS: (1) The global sensitivity was 0.86 (95% confidence interval [CI], 0.847-0.879), the specificity was 0.82 (95% CI, 0.797-0.842), the positive likelihood ratio (PLR) was 6.234 (95% CI, 4.260-9.123), the negative likelihood ratio (NLR) was 0.175 (95% CI, 0.135-0.227), and diagnostic odds ratio (DOR) was 42.836 (95% CI, 24.134-76.031). The area under the curve (AUC) and Q* index were 0.93 and 0.87. Publication bias was not present (P > 0.05). (2)The sensitivity of a subgroup meta-analysis of standard-b-value DWI was 0.858 (95% CI, 0.835-0.880), the specificity was 0.836 (95% CI, 0.807-0.863), the PLR was 6.527 (95% CI, 3.857-11.046), the NLR was 0.168 (95% CI, 0.123-0.239), and the DOR was 49.716 (95% CI, 22.897-107.98). The AUC and Q* index were 0.941 and 0.88. (3)The sensitivity of a subgroup meta-analysis of low-b-value DWI was 0.87 (95% CI, 0.84-0.89), the specificity was 0.80 (95% CI, 0.76-0.83), the PLR was 6.22 (95% CI, 3.29-11.76), the NLR was 0.19 (95% CI, 0.12-0.29), and the DOR was 37.14 (95% CI, 14.80-93.18). The AUC and Q* index were 0.922 and 0.86. CONCLUSIONS: Hepatic DWI is useful in differentiating between malignant and benign hepatic lesions. Standard-b-value DWI displayed an overall superior diagnostic accuracy over low-b-value DWI. Further trials needed to determine whether increasing b values beyond 1000 s/mm affects the diagnostic accuracy of hepatic lesion discrimination. PMID- 26938698 TI - Noninfectious Meningitis Caused by Systemic Lupus Erythematosus: A Case Series of 4 Patients. AB - We report magnetic resonance imaging findings of 4 patients with systemic lupus erythematosus who presented with noninfectious meningitis by lupus itself. Magnetic resonance imaging of the brain demonstrated diffuse or localized high signal intensity in subarachnoid spaces on fluid-attenuated inversion recovery (FLAIR) or postcontrast fluid-attenuated inversion recovery. Cerebrospinal fluid study revealed no abnormalities other than increased level of proteins. Our report is the first description of magnetic resonance findings in context of leptomeningeal involvement in non-infectious meningitis of patients with systemic lupus erythematosus. PMID- 26938697 TI - Implementation and Performance of Automated Software for Computing Right-to-Left Ventricular Diameter Ratio From Computed Tomography Pulmonary Angiography Images. AB - OBJECTIVE: The aim of this study was to prospectively test the performance and potential for clinical integration of software that automatically calculates the right-to-left ventricular (RV/LV) diameter ratio from computed tomography pulmonary angiography images. METHODS: Using 115 computed tomography pulmonary angiography images that were positive for acute pulmonary embolism, we prospectively evaluated RV/LV ratio measurements that were obtained as follows: (1) completely manual measurement (reference standard), (2) completely automated measurement using the software, and (3 and 4) using a customized software interface that allowed 2 independent radiologists to manually adjust the automatically positioned calipers. RESULTS: Automated measurements underestimated (P < 0.001) the reference standard (1.09 [0.25] vs1.03 [0.35]). With manual correction of the automatically positioned calipers, the mean ratio became closer to the reference standard (1.06 [0.29] by read 1 and 1.07 [0.30] by read 2), and the correlation improved (r = 0.675 to 0.872 and 0.887). The mean time required for manual adjustment (37 [20] seconds) was significantly less than the time required to perform measurements entirely manually (100 [23] seconds). CONCLUSIONS: Automated CT RV/LV diameter ratio software shows promise for integration into the clinical workflow for patients with acute pulmonary embolism. PMID- 26938699 TI - Elbasvir/grazoprevir (Zepatier) for hepatitis C. PMID- 26938700 TI - Drugs for tobacco dependence. PMID- 26938701 TI - Sonidegib (Odomzo) for basal cell carcinoma. PMID- 26938702 TI - Olaparib (Lynparza) for advanced ovarian cancer. PMID- 26938703 TI - Zika Virus Infection Among U.S. Pregnant Travelers - August 2015-February 2016. AB - After reports of microcephaly and other adverse pregnancy outcomes in infants of mothers infected with Zika virus during pregnancy, CDC issued a travel alert on January 15, 2016, advising pregnant women to consider postponing travel to areas with active transmission of Zika virus. On January 19, CDC released interim guidelines for U.S. health care providers caring for pregnant women with travel to an affected area, and an update was released on February 5. As of February 17, CDC had received reports of nine pregnant travelers with laboratory-confirmed Zika virus disease; 10 additional reports of Zika virus disease among pregnant women are currently under investigation. No Zika virus-related hospitalizations or deaths among pregnant women were reported. Pregnancy outcomes among the nine confirmed cases included two early pregnancy losses, two elective terminations, and three live births (two apparently healthy infants and one infant with severe microcephaly); two pregnancies (approximately 18 weeks' and 34 weeks' gestation) are continuing without known complications. Confirmed cases of Zika virus infection were reported among women who had traveled to one or more of the following nine areas with ongoing local transmission of Zika virus: American Samoa, Brazil, El Salvador, Guatemala, Haiti, Honduras, Mexico, Puerto Rico, and Samoa. This report summarizes findings from the nine women with confirmed Zika virus infection during pregnancy, including case reports for four women with various clinical outcomes. U.S. health care providers caring for pregnant women with possible Zika virus exposure during pregnancy should follow CDC guidelines for patient evaluation and management. Zika virus disease is a nationally notifiable condition. CDC has developed a voluntary registry to collect information about U.S. pregnant women with confirmed Zika virus infection and their infants. Information about the registry is in preparation and will be available on the CDC website. PMID- 26938704 TI - New AIE-active pyrimidine-based boronfluoride complexes with high solid-state emission and reversible mechanochromism luminescence behavior. AB - A new family of pyrimidine-based BF2 complexes () with aggregation-induced emission (AIE) and mechanochromic luminescence properties were developed. These compounds exhibit intense fluorescence in their aggregation/solid-state resulting from their large Stokes shift and AIE. X-ray crystallographic analysis shows that the weak intermolecular interactions by fixing the molecular conformations of are responsible for the intense fluorescence in solid-state. In addition to their pronounced AIE behaviour, also exhibits a reversible chromic response to grinding, and a distinct red-shift of emission is observed. The high solid-state luminescence and grinding-stimuli response properties of these compounds make them potential candidates for smart materials. PMID- 26938705 TI - A Programmable DNA Origami Platform to Organize SNAREs for Membrane Fusion. AB - Soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complexes are the core molecular machinery of membrane fusion, a fundamental process that drives inter- and intracellular communication and trafficking. One of the questions that remains controversial has been whether and how SNAREs cooperate. Here we show the use of self-assembled DNA-nanostructure rings to template uniform-sized small unilamellar vesicles containing predetermined maximal number of externally facing SNAREs to study the membrane-fusion process. We also incorporated lipid-conjugated complementary ssDNA as tethers into vesicle and target membranes, which enabled bypass of the rate-limiting docking step of fusion reactions and allowed direct observation of individual membrane-fusion events at SNARE densities as low as one pair per vesicle. With this platform, we confirmed at the single event level that, after docking of the templated-SUVs to supported lipid bilayers (SBL), one to two pairs of SNAREs are sufficient to drive fast lipid mixing. Modularity and programmability of this platform makes it readily amenable to studying more complicated systems where auxiliary proteins are involved. PMID- 26938707 TI - Benchmarking Rapid TLES Simulations of Gas Diffusion in Proteins: Mapping O2 Migration and Escape in Myoglobin as a Case Study. AB - Standard molecular dynamics (MD) simulations of gas diffusion consume considerable computational time and resources even for small proteins. To combat this, temperature-controlled locally enhanced sampling (TLES) examines multiple diffusion trajectories per simulation by accommodating multiple noninteracting copies of a gas molecule that diffuse independently, while the protein and water molecules experience an average interaction from all copies. Furthermore, gas migration within a protein matrix can be accelerated without altering protein dynamics by increasing the effective temperature of the TLES copies. These features of TLES enable rapid simulations of gas diffusion within a protein matrix at significantly reduced (~98%) computational cost. However, the results of TLES and standard MD simulations have not been systematically compared, which limits the adoption of the TLES approach. We address this drawback here by benchmarking TLES against standard MD in the simulation of O2 diffusion in myoglobin (Mb) as a case study since this model system has been extensively characterized. We find that 2 ns TLES and 108 ns standard simulations map the same network of diffusion tunnels in Mb and uncover the same docking sites, barriers, and escape portals. We further discuss the influence of simulation time as well as the number of independent simulations on the O2 population density within the diffusion tunnels and on the sampling of Mb's conformational space as revealed by principal component analysis. Overall, our comprehensive benchmarking reveals that TLES is an appropriate and robust tool for the rapid mapping of gas diffusion in proteins when the kinetic data provided by standard MD are not required. Furthermore, TLES provides explicit ligand diffusion pathways, unlike most rapid methods. PMID- 26938708 TI - Bioavailability and Fate of Sediment-Associated Progesterone in Aquatic Systems. AB - The environmental fate and bioavailability of progesterone, a steroid hormone known to cause endocrine-disrupting effects in aquatic organisms, is of growing concern due to its occurrence in the environment in water and sediment influenced by wastewater treatment plant and paper mill effluents, as well as livestock production. The objective of this study was to evaluate the fate of progesterone in two natural sediments and the corresponding alteration of gene expression in three steroid-responsive genes; vitellogenin, androgen receptor and estrogen receptor alpha. When exposed to progesterone-spiked sand, fathead minnows (Pimephales promelas) exhibited significant reductions in the expression of vitellogenin and androgen receptor expression. In contrast, fish exposed to progesterone associated with the silty loam sediment did not show a biological response at 7 days and only realized a significant reduction in vitellogenin. In both sediments, progesterone degradation resulted in the production of androgens including androsteinedione, testosterone, and androstadienedione, as well as the antiestrogen, testolactone. Differences in compound fate resulted in organism exposure to different suites of metabolites either in water or associated with the sediment. Results from this study suggest that environmental progestagens will lead to defeminization at environmentally relevant concentrations, and that exposure is influenced by sediment properties. PMID- 26938710 TI - The role of radioembolization in colorectal cancer treatment. PMID- 26938706 TI - Predictors of Mortality Poorly Predict Common Measures of Disease Progression in Idiopathic Pulmonary Fibrosis. AB - RATIONALE: Mortality prediction is well studied in idiopathic pulmonary fibrosis (IPF), but little is known about predictors of premortality disease progression. Identification of patients at risk for disease progression would be useful for clinical decision-making and designing clinical trials. OBJECTIVES: To develop prediction models for disease progression in IPF. METHODS: In a large clinical trial cohort of patients with IPF (n = 1,113), we comprehensively screened multivariate models of candidate baseline and past-change predictors for disease progression defined by 48-week worsening of FVC, dyspnea (University of California, San Diego Shortness of Breath Questionnaire [UCSD SOBQ]), 6-minute walk distance (6MWD), and occurrence of respiratory hospitalization, or death. Progression outcomes were modeled as appropriate, by slope change using linear regression models and time to binary outcomes using Cox proportional hazards models. MEASUREMENTS AND MAIN RESULTS: The overall cohort experienced considerable disease progression. Top-performing prediction models did not meaningfully predict most measures of disease progression. For example, prediction modeling explained less than or equal to 1% of the observed variation in 48-week slope change in FVC, UCSD SOBQ, and 6MWD. Models performed better for binary measures of time to disease progression but were still largely inaccurate (cross-validated C statistic <=0.63 for >=10% decline in FVC or death, <=0.68 for >=20-U increase in UCSD SOBQ or death, <=0.70 for >=100 m decline in 6MWD or death). Models for time to respiratory hospitalization or death (C statistic <=0.77) or death alone (C statistic <=0.81) demonstrated acceptable discriminative performance. CONCLUSIONS: Clinical prediction models poorly predicted physiologic and functional disease progression in IPF. This is in contrast to respiratory hospitalization and mortality prediction. PMID- 26938712 TI - Comparison of Osteotome and Conventional Drilling Techniques for Primary Implant Stability: An In Vitro Study. AB - It may be difficult to achieve primary stability in the posterior maxilla because of poor quality and quantity of bone. Studies have shown that the osteotome technique immediately increases bone density thereby increasing primary stability. An in vitro study was conducted to compare the stability achieved by the osteotome and conventional drilling techniques in low density bone. Forty endosseous implant fixtures (n = 40) were inserted in a solid rigid polyurethane block simulating low density (D3) bone. The implants were divided into 4 groups to test 2 variables: (1) implant length (10 mm or 13 mm) and (2) preparation of osteotomy (conventional drilling or osteotome technique). Insertion torque (IT) and resonance frequency analysis (RFA) were measured for each implant. Statistical analysis using one-way ANOVA and Tukey post hoc test was done to study IT and RFA data of the 4 groups. Pearson Correlation test was used to determine the correlation between IT and RFA values of the implants. The IT and RFA values were statistically significant higher using the osteotome technique as compared to conventional drilling (P < 0.0001). Statistically significant higher values were also found for IT and RFA of 13 mm implants as compared to 10 mm implants. A significant correlation was found between insertion torque and RFA values in all 4 groups (r = 0.86, P < 0.0001). The conclusion was that the osteotome technique significantly increased primary stability. PMID- 26938713 TI - Tunable Diode Laser Atomic Absorption Spectroscopy for Detection of Potassium under Optically Thick Conditions. AB - Potassium (K) is an important element related to ash and fine-particle formation in biomass combustion processes. In situ measurements of gaseous atomic potassium, K(g), using robust optical absorption techniques can provide valuable insight into the K chemistry. However, for typical parts per billion K(g) concentrations in biomass flames and reactor gases, the product of atomic line strength and absorption path length can give rise to such high absorbance that the sample becomes opaque around the transition line center. We present a tunable diode laser atomic absorption spectroscopy (TDLAAS) methodology that enables accurate, calibration-free species quantification even under optically thick conditions, given that Beer-Lambert's law is valid. Analyte concentration and collisional line shape broadening are simultaneously determined by a least squares fit of simulated to measured absorption profiles. Method validation measurements of K(g) concentrations in saturated potassium hydroxide vapor in the temperature range 950-1200 K showed excellent agreement with equilibrium calculations, and a dynamic range from 40 pptv cm to 40 ppmv cm. The applicability of the compact TDLAAS sensor is demonstrated by real-time detection of K(g) concentrations close to biomass pellets during atmospheric combustion in a laboratory reactor. PMID- 26938715 TI - Novel anti-angiogenic therapeutic strategies in colorectal cancer. AB - INTRODUCTION: Anti-angiogenetic agents are currently the standard of care in metastatic CRC patients. Bevacizumab, aflibercept, regorafenib and recently ramucirumab have significantly improved both progression-free and overall survival in different lines of treatment. Since bevacizumab's approval, a number of novel anti-VEGF agents have been tested in preclinical and clinical models. AREAS COVERED: This review is focused on the most recent clinical results of novel agents targeting VEGF and its receptors with a major focus on those investigated recently in clinical trials. EXPERT OPINION: In the last 15 years, a number of new anti-angiogenetic agents have been tested. Unfortunately, most of them have demonstrated unacceptable toxicities or failed to show activity. When tested as single agents, encouraging preliminary results were reported with fruquintinib, famitinib, and nintedanib. Interesting novel mechanisms of action are also being explored: VGX-100 is a monoclonal antibody (mAb) which binds to VEGF-C, inhibiting activation of VEGFR-2 and VEGFR-3 when combined with bevacizumab; tanibirumab is a mAb which binds to VEGFR-2 and vanucizumab is a bispecific mAb binding both to VEGF-A and Angiopoietin-2. Data about the combination of these agents with chemotherapy are very encouraging, even though preliminary. However, the definition of specific predictive biomarkers remains a priority. PMID- 26938714 TI - The Effects of Interleukin-17 (IL-17)-Related Inflammatory Cytokines and A20 Regulatory Proteins on Astrocytes in Spinal Cord Cultured In Vitro. AB - BACKGROUND/AIMS: This study focused on investigating the expression of several inflammatory cytokines and chemokines, including regulatory proteins in the astrocytes of mice stimulated with IL-17. MATERIALS AND METHODS: The cultured astrocytes from the spinal cords of mice were stimulated with IL-17. The expression of interleukin-6 (IL-6), tumor necrosis factor (TNF), monocyte chemotactic protein-1/5 (MCP-1/5) and macrophage inflammatory protein-2 (MIP-2) stimulated with IL-17 (50 ng/ml) at different time points (3 h, 6 h, 12 h, 24 h and 48 h) were determined using real-time PCR and ELISA. The expressions of A20 (tumor necrosis factor alpha inducible protein 3, TNFAIP3) and NF-x03BA;B were examined using real-time PCR and western blotting. RESULTS: Compared with the control group, the mRNA expression levels of IL-6, TNF, MCP-1/5 and MIP-2 increased significantly at 6 h after IL-17 stimulation, while the protein expression levels also increased significantly and peaked at 12 h. The mRNA expression level of NF-x03BA;B increased and peaked at 6 h before gradually declining, while the expression of A20 decreased. The protein expression level of NF-x03BA;B increased and peaked at 12 h, while the expression A20 had an opposite response. CONCLUSION: The study showed that NF-x03BA;B may have an effect on the cytokines secreted by astrocytes after IL-17 stimulation. Moreover, both A20 and NF-x03BA;B could regulate the expression and secretion of inflammatory mediators. PMID- 26938716 TI - Acute Renal Failure Secondary to Rhabdomyolysis as a Complication of Major Urological Surgery: The Experience of a High-Volume Urological Center. AB - OBJECTIVE: The aim of this study was to determine the incidence of acute renal failure secondary to rhabdomyolysis (ARFSR) as a complication of major urological surgery (MUS), as well as to describe the clinical characteristics and identify possible risk and protective factors. SUBJECTS AND METHODS: Cases of ARFSR due to MUS between January 1997 and August 2011 were identified using the institutional database. The incidence was estimated and the clinical characteristics were analyzed using simple scatterplot graphs to identify possible risk and protective factors. RESULTS: In this period, 14,337 MUS procedures were performed, in which 4 cases suffered from ARFSR (the incidence rate was 0.03%). The incidence rates after radical cystectomy and urethroplasty were 0.26% (3/1,175 cases) and 0.15% (1/651 cases), respectively. No case of rhabdomyolysis was reported among the patients who underwent other major surgical procedures. Two patients required dialysis, and all 4 patients recovered to their baseline renal function at an average of 11 days (7-17) with the appropriate treatment. Male gender, younger age, lower ASA score, prolonged operative time, high body mass index, elevated preoperative serum creatinine and estimated blood loss were possible risk factors for developing ARFSR due to MUS. We found that a higher intraoperative administered volume was a possible protective factor. The operative position and type of surgery seemed to play minor roles. Early diagnosis and treatment possibly leads to an improved outcome. CONCLUSION: In our study, ARFSR due to MUS was a rare entity and had a good prognosis. It was more frequent as a complication of radical cystectomy. Further studies are required to confirm our findings. PMID- 26938717 TI - [Skin reaction to carbamazepine or DRESS syndrome: a case presentation]. AB - Carbamazepine is a frequently used drug that can produce adverse reactions like vertigo, somnolence and severe skin reactions like Drug Rash with Eosinophilia and Systemic Symptoms Syndrome (DRESS Syndrome). This syndrome is characterized by a late-appearing, slow-progressing cutaneous eruption accompanied by atypical lymphocytes, eosinophilia, and systemic symptoms such as fever, lymphadenopathy, hepatic compromise, and renal dysfunction that can be severe enough to cause death. We present a case that aims to highlight the importance of an early diagnosis of DRESS syndrome to adjust therapy and improve survival. The patient is a female patient prescribed carbamazepine for trigeminal neuralgia who presented with skin lesions, which were initially attributed to a hypersensitivity reaction. The lesions worsened in spite of treatment and systemic symptoms ensued. A diagnosis of DRESS syndrome was proposed and steroid treatment was initiated with rapid improvement. PMID- 26938718 TI - Chronic Exposure to Water-Pipe Smoke Induces Alveolar Enlargement, DNA Damage and Impairment of Lung Function. AB - BACKGROUND/AIM: Epidemiological evidence indicates that water-pipe smoking (WPS) adversely affects the respiratory system. However, the mechanisms underlying its effects are not well understood. Recent experimental studies reported the occurrence of lung inflammation and oxidative stress following acute and subacute exposure to WPS. Here, we wanted to verify the extent of inflammation and oxidative stress in mice chronically-exposed to WPS and to evaluate, for the first time, its effect on alveolar injury and DNA damage and their association with impairment of lung function. METHODS: Mice were nose-only exposed to mainstream WPS (30 min/day; 5 days/week for 6 consecutive months). Control mice were exposed using the same protocol to atmospheric air only. At the end of the exposure period, several respiratory parameters were assessed. RESULTS: In bronchoalveolar lavage fluid, WPS increased neutrophil and lymphocyte numbers, lactate dehydrogenase, myeloperoxidase and matrix metallopeptidase 9 activities, as well as several proinflammatory cytokines. In lung tissue, lipid peroxidation, reactive oxygen species, superoxide dismutase activity and reduced glutathione were all increased by WPS exposure. Along with oxidative stress, WPS exposure significantly increased lung DNA damage index. Histologically the lungs of WPS exposed mice had foci of mixed inflammatory cells infiltration in the interalveolar interstitium which consisted of neutrophils, lymphocytes and macrophages. Interestingly, we found dilated alveolar spaces and alveolar ducts with damaged interalveolar septae, and impairment of lung function following WPS exposure. CONCLUSION: We show the persistence of lung inflammation and oxidative stress in mice chronically-exposed to WPS and demonstrate, for the first time, the occurrence of DNA damage and enlargement of alveolar spaces and ducts associated with impairment of lung function. Our findings provide novel mechanistic elucidation for the long-term effects of WPS on the respiratory system. PMID- 26938719 TI - Population Size Predicts Lexical Diversity, but so Does the Mean Sea Level --Why It Is Important to Correctly Account for the Structure of Temporal Data. AB - In order to demonstrate why it is important to correctly account for the (serial dependent) structure of temporal data, we document an apparently spectacular relationship between population size and lexical diversity: for five out of seven investigated languages, there is a strong relationship between population size and lexical diversity of the primary language in this country. We show that this relationship is the result of a misspecified model that does not consider the temporal aspect of the data by presenting a similar but nonsensical relationship between the global annual mean sea level and lexical diversity. Given the fact that in the recent past, several studies were published that present surprising links between different economic, cultural, political and (socio-)demographical variables on the one hand and cultural or linguistic characteristics on the other hand, but seem to suffer from exactly this problem, we explain the cause of the misspecification and show that it has profound consequences. We demonstrate how simple transformation of the time series can often solve problems of this type and argue that the evaluation of the plausibility of a relationship is important in this context. We hope that our paper will help both researchers and reviewers to understand why it is important to use special models for the analysis of data with a natural temporal ordering. PMID- 26938735 TI - Mechanisms responsible for neuromuscular relaxation in the gastrointestinal tract. AB - The enteric nervous system (ENS) is responsible for the genesis of motor patterns ensuring an appropriate intestinal transit. Enteric neurons are classified into afferent, interneuron, and motoneuron types, with the latter two being further categorized as excitatory or inhibitory, which cause smooth muscle contraction or inhibition, respectively. Muscle relaxation mechanisms are key for the understanding of physiological processes such as sphincter relaxation, gastric accommodation, or descending peristaltic reflex. Nitric oxide (NO) and ATP or a related purine represent the primary inhibitory neurotransmitters. Nitrergic neurons synthesize NO through nNOS enzyme activity. NO diffuses across the cell membrane to bind its receptor, namely, guanylyl cyclase, and then activates a number of intracellular mechanisms that ultimately result in muscle relaxation. ATP acts as an inhibitory neurotransmitter together with NO, and the purinergic P2Y1 membrane receptor has been identified as a key item in order to understand how ATP may relax intestinal smooth muscle. Although, probably, no clinician doubts the significance of NO in the pathophysiology of digestive motility, the relevance of purinergic neurotransmission is apparently much lower, as ATP has not been associated with any specific motor dysfunction yet. The goal of this review is to discuss the function of both relaxation mechanisms in order to establish the physiological grounds of potential motor dysfunctions arising from impaired intestinal relaxation. PMID- 26938720 TI - Activation of Bcl-2-Caspase-9 Apoptosis Pathway in the Testis of Asthmatic Mice. AB - BACKGROUND: Apoptosis plays a critical role in controlling the proliferation and differentiation of germ cells during spermatogenesis. Dysregulation of the fine tuned balance may lead to the onset of testicular diseases. In this study, we investigated the activation status of apoptosis pathways in the testicular tissues under the background of an asthmatic mouse model. METHODS: Ten BALB/c mice were divided into two groups: the acute asthma group and the control group. In the acute asthma group, ovalbumin (OVA)-sensitized mice were challenged with aerosolized OVA for 7 days, while the control group was treated with physiological saline. After that, both epididymis and testis were collected to determine the sperm count and motility. Apoptosis in the testis was evaluated by DNA ladder, immunochemistry and further by PCR array of apoptosis-related genes. Finally, the cleavage of caspase-3 and poly ADP-ribose polymerase (PARP) was determined by western blot and the enzymatic activities of caspase-9 and 3/7 were assessed using Caspase-Glo kits. RESULTS: Compared with control mice, significant decreases in the body weight, testis weight, sperm count and motility were seen in the experimental group. DNA ladder and immunochemistry showed significant increase in apoptotic index of the asthmatic testis, whereas a decrease in mRNA expression of Bcl-2 and increases in Bax, BNIP3, caspase-9, and AIF were observed in the asthma group. Furthermore, protein levels of AIF were significantly upregulated, while the translational expression of Bcl-2 was downregulated markedly. Consistently, caspase-9 activity in the testis of asthma mice was significantly higher than that of the control group. CONCLUSION: Collectively, these results showed that Bcl-2-caspase-9 apoptosis pathway was clearly activated in the testis of asthmatic mice with the increased expression of apoptosis related genes and proteins. To our knowledge, this is the first report demonstrating that asthma could lead to the activation of the mitochondrial apoptosis signaling pathway in the mouse testis. PMID- 26938736 TI - The Success of a Universal Hepatitis B Immunization Program as Part of Thailand's EPI after 22 Years' Implementation. AB - Hepatitis B vaccination for newborns was introduced in two provinces in 1988 as part of Thailand's Expanded Program on Immunization (EPI), and extended to the whole country in 1992. Our previous studies showed that children and adolescents who were born after the implementation of this program had a carrier rate of less than 1%, compared with 5-6% before implementation. In 2014 we performed hepatitis B serosurveys among 5964 subjects in the different geographic regions of the country to evaluate the long-term immunogenicity and impact of universal hepatitis B vaccination in newborns as part of the 22-year EPI program, by assessing HBsAg, anti-HBc and anti-HBs seropositivity status. The number of HB virus (HBV) carriers, both children and young adults, who were born after universal HB vaccination was markedly reduced. The carrier rates among the age groups 6 months to 5 years, 5-10, 11-20, 21-30, 31-40, 41-50 and >50 years were respectively 0.1, 0.29, 0.69, 3.12, 3.78, 4.67 and 5.99%. The seropositivity rate for HBsAg in the post-EPI group was 0.6%, whereas in the pre-EPI group it was as high as 4.5% (p<0.001). HBV infection by means of detectable anti-HBc had also drastically declined in the population born after the HB vaccine was integrated into the EPI program. We estimated that the total number of HBV carriers amounted to 2.22 million, or 3.48% of the total population, most of whom are adults. The HB vaccine is the first vaccine shown to be effective in preventing the occurrence of chronic liver disease and hepatocellular carcinoma. Universal vaccination campaign will contribute to the eventual eradication of HBV associated disease. PMID- 26938737 TI - Arousal-But Not Valence-Reduces False Memories at Retrieval. AB - Mood affects both memory accuracy and memory distortions. However, some aspects of this relation are still poorly understood: (1) whether valence and arousal equally affect false memory production, and (2) whether retrieval-related processes matter; the extant literature typically shows that mood influences memory performance when it is induced before encoding, leaving unsolved whether mood induced before retrieval also impacts memory. We examined how negative, positive, and neutral mood induced before retrieval affected inferential false memories and related subjective memory experiences. A recognition-memory paradigm for photographs depicting script-like events was employed. Results showed that individuals in both negative and positive moods-similar in arousal levels correctly recognized more target events and endorsed fewer false memories (and these errors were linked to remember responses less frequently), compared to individuals in neutral mood. This suggests that arousal (but not valence) predicted memory performance; furthermore, we found that arousal ratings provided by participants were more adequate predictors of memory performance than their actual belonging to either positive, negative or neutral mood groups. These findings suggest that arousal has a primary role in affecting memory, and that mood exerts its power on true and false memory even when induced at retrieval. PMID- 26938739 TI - Annulation Reaction of 3-Acylmethylidene Oxindoles with Huisgen Zwitterions and Its Applications in the Syntheses of Pyrrolo[4,3,2-de]quinolinones and Marine Alkaloids Ammosamides. AB - A novel annulation reaction of 3-acylmethylidene oxindoles with Huisgen zwitterions is unveiled that leads to an unprecedented synthetic method for complex pyrrolo[4,3,2-de]quinolinones and marine alkaloids ammosamides A-C. This method features simplicity, high efficiency, and broad substrate scope and is accordingly anticipated to significantly facilitate the preparation and bioassay of the relevant pyrroloquinoline alkaloids and their analogues. PMID- 26938738 TI - Leprosy New Case Detection Trends and the Future Effect of Preventive Interventions in Para State, Brazil: A Modelling Study. AB - BACKGROUND: Leprosy remains a public health problem in Brazil. Although the overall number of new cases is declining, there are still areas with a high disease burden, such as Para State in the north of the country. We aim to predict future trends in new case detection rate (NCDR) and explore the potential impact of contact tracing and chemoprophylaxis on NCDR in Para State. METHODS: We used SIMCOLEP, an existing individual-based model for the transmission and control of M. leprae, in a population structured by households. The model was quantified to simulate the population and observed NCDR of leprosy in Para State for the period 1990 to 2014. The baseline scenario was the current control program, consisting of multidrug therapy, passive case detection, and active case detection from 2003 onwards. Future projections of the NCDR were made until 2050 given the continuation of the current control program (i.e. baseline). We further investigated the potential impact of two scenarios for future control of leprosy: 1) discontinuation of contact tracing; and 2) continuation of current control in combination with chemoprophylaxis. Both scenarios started in 2015 and were projected until 2050. RESULTS: The modelled NCDR in Para State after 2014 shows a continuous downward trend, reaching the official elimination target of 10 cases per 100,000 population by 2030. The cessation of systematic contact tracing would not result in a higher NCDR in the long run. Systematic contact tracing in combination with chemoprophylaxis for contacts would reduce the NCDR by 40% and bring attainment of the elimination target two years forward to 2028. CONCLUSION: The NCDR of leprosy continues to decrease in Para State. Elimination of leprosy as a public health problem could possibly be achieved around 2030, if the current control program is maintained. Providing chemoprophylaxis would decrease the NCDR further and would bring elimination forward by two years. PMID- 26938740 TI - Terbinafine-induced lichenoid drug eruption. AB - Drug-induced lichen planus has been induced by antibiotics, anticonvulsants, antidiabetics, antimalarials, antitubercular drugs, antihypertensives, psychiatric drugs, chemotherapeutic agents, diuretic, heavy metals, NSAIDs, etc. Terbinafine, an antifungal agent, is widely used for dermatophyte infections and onychomycosis. Cutaneous adverse effects of terbinafine are rarely reported. Here, we report a case of terbinafine-induced lichenoid drug eruption in a 22 year-old who presented with generalized lichenoid eruption 2 weeks after terbinafine initiation of. The body and lip cleared completely after 8 weeks of drug withdrawal; nail change cleared after 12 weeks. PMID- 26938741 TI - Chirality Inversion of CdSe and CdS Quantum Dots without Changing the Stereochemistry of the Capping Ligand. AB - L-cysteine derivatives induce and modulate the optical activity of achiral cadmium selenide (CdSe) and cadmium sulfide (CdS) quantum dots (QDs). Remarkably, N-acetyl-L-cysteine-CdSe and L-homocysteine-CdSe as well as N-acetyl-L-cysteine CdS and L-cysteine-CdS showed "mirror-image" circular dichroism (CD) spectra regardless of the diameter of the QDs. This is an example of the inversion of the CD signal of QDs by alteration of the ligand's structure, rather than inversion of the ligand's absolute configuration. Non-empirical quantum chemical simulations of the CD spectra were able to reproduce the experimentally observed sign patterns and demonstrate that the inversion of chirality originated from different binding arrangements of N-acetyl-L-cysteine and L-homocysteine-CdSe to the QD surface. These efforts may allow the prediction of the ligand-induced chiroptical activity of QDs by calculating the specific binding modes of the chiral capping ligands. Combined with the large pool of available chiral ligands, our work opens a robust approach to the rational design of chiral semiconducting nanomaterials. PMID- 26938742 TI - Sibling Competition & Growth Tradeoffs. Biological vs. Statistical Significance. AB - Early childhood growth has many downstream effects on future health and reproduction and is an important measure of offspring quality. While a tradeoff between family size and child growth outcomes is theoretically predicted in high fertility societies, empirical evidence is mixed. This is often attributed to phenotypic variation in parental condition. However, inconsistent study results may also arise because family size confounds the potentially differential effects that older and younger siblings can have on young children's growth. Additionally, inconsistent results might reflect that the biological significance associated with different growth trajectories is poorly understood. This paper addresses these concerns by tracking children's monthly gains in height and weight from weaning to age five in a high fertility Maya community. We predict that: 1) as an aggregate measure family size will not have a major impact on child growth during the post weaning period; 2) competition from young siblings will negatively impact child growth during the post weaning period; 3) however because of their economic value, older siblings will have a negligible effect on young children's growth. Accounting for parental condition, we use linear mixed models to evaluate the effects that family size, younger and older siblings have on children's growth. Congruent with our expectations, it is younger siblings who have the most detrimental effect on children's growth. While we find statistical evidence of a quantity/quality tradeoff effect, the biological significance of these results is negligible in early childhood. Our findings help to resolve why quantity/quality studies have had inconsistent results by showing that sibling competition varies with sibling age composition, not just family size, and that biological significance is distinct from statistical significance. PMID- 26938743 TI - When Parasites Are Good for Health: Cestode Parasitism Increases Resistance to Arsenic in Brine Shrimps. AB - Parasites and pollutants can both affect any living organism, and their interactions can be very important. To date, repeated studies have found that parasites and heavy metals or metalloids both have important negative effects on the health of animals, often in a synergistic manner. Here, we show for the first time that parasites can increase host resistance to metalloid arsenic, focusing on a clonal population of brine shrimp from the contaminated Odiel and Tinto estuary in SW Spain. We studied the effect of cestodes on the response of Artemia to arsenic (acute toxicity tests, 24h LC50) and found that infection consistently reduced mortality across a range of arsenic concentrations. An increase from 25 degrees C to 29 degrees C, simulating the change in mean temperature expected under climate change, increased arsenic toxicity, but the benefits of infection persisted. Infected individuals showed higher levels of catalase and glutathione reductase activity, antioxidant enzymes with a very important role in the protection against oxidative stress. Levels of TBARS were unaffected by parasites, suggesting that infection is not associated with oxidative damage. Moreover, infected Artemia had a higher number of carotenoid-rich lipid droplets which may also protect the host through the "survival of the fattest" principle and the antioxidant potential of carotenoids. This study illustrates the need to consider the multi-stress context (contaminants and temperature increase) in which host-parasite interactions occur. PMID- 26938744 TI - Microfluidic Directed Synthesis of Alginate Nanogels with Tunable Pore Size for Efficient Protein Delivery. AB - Alginate is a biopolymer with favorable pH-sensitive properties for oral delivery of peptides and proteins. However, conventional alginate nanogels have limitations such as low encapsulation efficiency because of drug leaching during bead preparation and burst release in high pH values. These shortcomings originate from large pore size of the nanogels. In this work, we proposed an on chip hydrodynamic flow focusing approach for synthesis of alginate nanogels with adjustable pore size to achieve fine-tunable release profile of the encapsulated bioactive agents. It is demonstrated that the microstructure of nanogels can be controlled through adjusting flow ratio and mixing time directed on microfluidic platforms consisting of cross-junction microchannels. In this study, the average pore size of alginate nanogels (i.e., average molecular weight between cross links, Mc) was related to synthesis parameters. Mc was calculated from equations based on equilibrium swelling theory and proposed methods to modify the theory for pH-sensitive nanogels. In the equations we derived, size and compactness of nanogels are key factors, which can be adjusted by controlling the flow ratio. It was found that increase in flow ratio increases the size of nanogels and decreases their compactness. The size of on-chip generated nanogels for flow ratio of 0.02-0.2 was measured to be in the range of 68-138 nm. Moreover, a method based on the Mie theory was implemented to estimate the aggregation number (Nagg) of polymer chains inside the nanogels as an indicator of compactness. According to the size and compactness results along with equations of modified swelling theory, Mc obtained to be in the range of 0.5-0.8 kDa. The proposed method could be considered as a promising approach for efficient polypeptides encapsulation and their sustained release. PMID- 26938747 TI - Fluconazole-Induced Type 1 Kounis Syndrome. AB - The administration of fluconazole is commonly used in both inpatient and outpatient settings for the management of candidiasis infection. Although it is associated with a relatively safe side effect profile, some patients experience adverse effects associated with increased morbidity. We describe 1 such patient, a 42-year-old woman with a history of severe eczema who developed fluconazole induced type 1 Kounis syndrome. Review of literature indicates that this as the first case reported of fluconazole-induced type 1 Kounis syndrome. PMID- 26938745 TI - Genome Wide Mapping of NR4A Binding Reveals Cooperativity with ETS Factors to Promote Epigenetic Activation of Distal Enhancers in Acute Myeloid Leukemia Cells. AB - Members of the NR4A subfamily of orphan nuclear receptors regulate cell fate decisions via both genomic and non-genomic mechanisms in a cell and tissue selective manner. NR4As play a key role in maintenance of hematopoietic stem cell homeostasis and are critical tumor suppressors of acute myeloid leukemia (AML). Expression of NR4As is broadly silenced in leukemia initiating cell enriched populations from human patients relative to normal hematopoietic stem/progenitor cells. Rescue of NR4A expression in human AML cells inhibits proliferation and reprograms AML gene signatures via transcriptional mechanisms that remain to be elucidated. By intersecting an acutely regulated NR4A1 dependent transcriptional profile with genome wide NR4A binding distribution, we now identify an NR4A targetome of 685 genes that are directly regulated by NR4A1. We show that NR4As regulate gene transcription primarily through interaction with distal enhancers that are co-enriched for NR4A1 and ETS transcription factor motifs. Using a subset of NR4A activated genes, we demonstrate that the ETS factors ERG and FLI-1 are required for activation of NR4A bound enhancers and NR4A target gene induction. NR4A1 dependent recruitment of ERG and FLI-1 promotes binding of p300 histone acetyltransferase to epigenetically activate NR4A bound enhancers via acetylation at histone H3K27. These findings disclose novel epigenetic mechanisms by which NR4As and ETS factors cooperate to drive NR4A dependent gene transcription in human AML cells. PMID- 26938746 TI - Pigmentary Markers in Danes--Associations with Quantitative Skin Colour, Nevi Count, Familial Atypical Multiple-Mole, and Melanoma Syndrome. AB - To investigate whether pigmentation genes involved in the melanogenic pathway (melanogenesis) contributed to melanoma predisposition, we compared pigmentary genetics with quantitative skin pigmentation measurements, the number of atypical nevi, the total nevus count, and the familial atypical multiple mole and melanoma (FAMMM) syndrome. We typed 32 pigmentary SNP markers and sequenced MC1R in 246 healthy individuals and 116 individuals attending periodic control for malignant melanoma development, 50 of which were diagnosed with FAMMM. It was observed that individuals with any two grouped MC1R variants (missense, NM_002386:c. 456C > A (p.TYR152*), or NM_002386:c.83_84insA (p.Asn29Glnfs*14) had significantly (p<0.001) lighter skin pigmentation of the upper-inner arm than those with none or one MC1R variant. We did not observe any significant association of the MC1R variants with constitutive pigmentation measured on the buttock area. We hypothesize that the effect of MC1R variants on arm pigmentation is primarily reflecting the inability to tan when subjected to UVR. A gender specific effect on skin pigmentation was also observed, and it was found that the skin pigmentation of females on average were darker than that of males (p<0.01). We conclude that MC1R variants are associated with quantitative skin colour in a lightly pigmented Danish population. We did not observe any association between any pigmentary marker and the FAMMM syndrome. We suggest that the genetics of FAMMM is not related to the genetics of the pigmentary pathway. PMID- 26938748 TI - Short Stay Unit and Emergency Department: Pharmacotherapeutic Interventions and Its Impact. AB - The incidence of adverse effects in hospitals is very high and a lot of them are related to medication. The most important factor in pharmaceutical interventions to reduce adverse effects is medication reconciliation, and this process is indispensable during hospital care. Reasons for reconciliation errors are numerous but high-rotation care unit, such as emergency department and short stay units (SSUs) are more hazardous areas for patient safety. Prospective observational study was performed for 3 months. Medication reconciliation and pharmacotherapeutic interventions were carried out. Indicators regarding coverage of the program, quality of prescription, and reconciliation were established and a financial analysis was done. A total of 843 patients were studied and pharmacotherapeutic intervention was carried out in 310 patients. A total of 2463 drugs were checked and 452 pharmacotherapeutic interventions were carried out. The most of these interventions belong to cardiovascular system. A total of 149 interventions were according to the pharmacotherapeutical hospital formulary and 303 were drug-related problems (DRPs). The most frequent cause of DRP was drug omission, followed by incomplete prescriptions. Of the DRP, 56.8% were reconciliation errors. The most common recommendation was starting treatment. An overall saving of $49,846.31 is estimated in this study according to the risk of an increased stay for DRP and the cost of avoidable stays. Patient's safety was increased by pharmacist's involvement on emergency department and SSUs. In SSUs, there are many polymedicated patients, so this is the most suitable place to involve the pharmacist. Pharmacist's interventions are equally accepted in both services. PMID- 26938749 TI - Bone Age and Serum Osteocalcin Levels in Children With Obstructive Sleep Apnea Hypopnea Syndrome Before and After Adenotonsillectomy. AB - Our aim was to study the changes in bone age and serum osteocalcin levels before and after adenotonsillectomy (AT) in children with obstructive sleep apnea hypopnea syndrome (OSAHS). A total of 58 OSAHS children (37 males and 21 females) with the mean age of 6.68 +/- 1.11 years were enrolled and assessed by x-ray based bone age estimation and enzyme-linked immunosorbent assay-based measurement of serum osteocalcin levels, before surgery and 6 months after AT. SPSS 19.0 software was used for statistical analysis. Our results revealed that bone age and serum osteocalcin levels in OSAHS patients were significantly lower than normal controls before AT (P < 0.05). Within 6 months after surgery, the bone age and the serum osteocalcin levels were significantly elevated in OSAHS patients (P < 0.05), compared with those before surgery. Serum osteocalcin levels and bone age are negatively correlated with apnea-hypopnea index, oxygen desaturation index, the percentage of the total recorded time spent below 90% oxygen saturation, and Epworth sleepiness scale scores (all P < 0.05). Our findings suggested that bone age and serum osteocalcin levels may be correlated with the development of OSAHS in children. AT may improve bone age and serum osteocalcin levels in OSAHS children. PMID- 26938750 TI - Bioequivalence of 2 Formulations of Sildenafil Oral Soluble Film 100 mg and Sildenafil Citrate (Viagra) 100 mg Oral Tablets in Healthy Male Volunteers. AB - Sildenafil citrate tablets (VIAGRA; Pfizer Inc) have been used since 1998 as an oral therapy for the treatment of erectile dysfunction. However, in some cases, patients may have difficulty in swallowing tablets, and the need to use water to aid in the oral administration of the tablets has the potential to interrupt the sexual encounter, reduce spontaneity, and therefore decrease the quality of the experience. Two oral soluble film (OSF) formulations of sildenafil were developed using MonoSol Rx's proprietary PharmFilm technology. Both films were formulated to dissolve rapidly on the tongue, thereby releasing the drug into the oral cavity, whereupon it is swallowed without the use of water. From a patient perspective, it is anticipated that the film formulations of sildenafil citrate will provide a more compliant and discreet dosage form. The purpose of this clinical study was to compare the bioequivalence of the 2 sildenafil OSF 100 mg formulations (MonoSol Rx, LLC) with the sildenafil citrate 100 mg tablets. The design was a single-dose, randomized, open-label, 3-period, 6-sequence, 3 treatment, single-center, crossover study conducted in 18 healthy, nonsmoking male volunteers under fasting conditions, with each treatment period separated by a 7-day washout period. Plasma sildenafil concentrations were measured predose and then periodically to 24 hours after dosing. The 90% confidence intervals for plasma sildenafil AUC0-t, AUC0-infinity, and Cmax for both sildenafil OSF formulations as compared with sildenafil citrate tablets were all within the 80% 125% range, indicating bioequivalence of both film formulations to sildenafil citrate tablets. Overall, the demonstrated bioequivalence coupled with the performance advantages of an OSF dosage form (ie, rapid dissolution in the mouth, can be taken without water, and can be dosed discreetly) suggest that the sildenafil OSF may provide an attractive alternative to sildenafil citrate oral tablets. PMID- 26938751 TI - Levetiracetam: Probably Associated Diurnal Frequent Urination. AB - Diurnal frequent urination is a common condition in elementary school children who are especially at risk for associated somatic and behavioral problems. Levetiracetam (LEV) is a broad-spectrum antiepileptic drug that has been used in both partial and generalized seizures and less commonly adverse effects including psychiatric and behavioral problems. Diurnal frequent urination is not a well known adverse effect of LEV. Here, we reported 2 pediatric cases with epilepsy that developed diurnal frequent urination after LEV administration. Case 1 was a 6-year-old male patient who presented urinary frequency and urgency in the daytime since the third day after LEV was given as adjunctive therapy. Symptoms increased accompanied by the raised dosage of LEV. Laboratory tests and auxiliary examinations did not found evidence of organic disease. Diurnal frequent urination due to LEV was suspected, and then the drug was discontinued. As expected, his frequency of urination returned to normal levels. Another 13-year old female patient got similar clinical manifestations after oral LEV monotherapy and the symptoms became aggravated while in stress state. Since the most common causes of frequent micturition had been ruled out, the patient was considered to be diagnosed with LEV-associated psychogenic frequent urination. The dosage of LEV was reduced to one-third, and the frequency of urination was reduced by 60%. Both patients got the Naranjo score of 6, which indicated that LEV was a "probable" cause of diurnal frequent urination. Although a definite causal link between LEV and diurnal urinary frequency in the 2 cases remains to be established, we argue that diurnal frequent urination associated with LEV deserves clinician's attention. PMID- 26938752 TI - Effects of Ulinastatin on Perioperative Inflammatory Response and Pulmonary Function in Cardiopulmonary Bypass Patients. AB - The aim of this study was to investigate whether ulinastatin (UTL) has protective effects on perioperative proinflammatory cytokines and lung injury in cardiopulmonary bypass (CPB) patients. The study included 60 patients undergoing CPB who were randomly divided into a UTL group and a control group. Blood routine examination and inflammatory cytokines concentrations were detected after anesthetic induction (T1), immediately after aortic valve opening (T2), and 4 (T3) and 24 (T4) hours after weaning from CPB. Flow cytometry was used to detect TLR4 and HSP70 expressions. Arterial blood gas and respiratory function were analyzed at the same time points. Compared with the control group, the levels of IL-2, IL-8, TNF-alpha, NE, TLR4, PA - aDO2, and RI at T2 were significantly lower, whereas HSP70, PaO2, OI, Cd, and Cs were higher in the UTL group (all P < 0.05). Relative to the control group at T3, white blood cell count, TLR4, IL-2, IL-6, IL-8, TNF-alpha, NE, and RI decreased significantly, whereas IL-10, HSP70, PaO2, OI, and Cs increased in the UTL group (all P < 0.05). At T4, IL-2, IL-6, IL 8, TNF-alpha, TLR4, and PaCO2 in the UTL group were significantly lower, and PaO2, IL-10, HSP70, and Cs were higher than in the control group (all P < 0.05). Our data show strong evidence that UTL suppresses proinflammatory cytokine elevation and upregulates release of anti-inflammatory mediators, reducing pulmonary injury and improving pulmonary function after CPB. PMID- 26938753 TI - Assessment of Depression Prevalence and Its Relation With Interleukin 18 One Year After Renal Transplantation. AB - Renal transplantation is the treatment of choice for many patients with end-stage renal disease. Because there is little information about depression after kidney transplantation, we investigated frequency and determinant factors of depression and also its association with interleukin (IL)-18. Kidney transplant recipients were investigated between January 2011 and February 2013. Depression was assessed using the Beck Depression Inventory (BDI, BDI-II). We investigated the relationship between 1-year posttransplantation depression and all-cause mortality, acute kidney injury, and serum creatinine 1, 3, and 12 months after transplantation. Furthermore, the association of depression with IL-18 biomarker was recorded 1 year after transplantation. A total of 74 patients (age: 37.06 +/- 16.2 years; 59.5% male) were enrolled in this study 1 year after transplantation. Nineteen (25.6%), 2 (2.7%), and 1 (1.3%) of them experienced mild, moderate, and severe depression, respectively. IL-18 biomarker (independent variable) was significantly associated with depression 1 year after transplantation. Our data suggested that IL-18 level increased significantly in renal transplant patients with depression. PMID- 26938754 TI - Comparison of Hybrid Fixation to Dual Plating for Both-Bone Forearm Fractures in Older Children. AB - When operative stabilization of forearm fractures in older children is necessary, the optimal method of fixation is controversial. This study compared the radiographic and functional outcomes of dual plating to a hybrid fixation construct with elastic intramedullary nailing of the radius and plate fixation of the ulna of forearm fractures in children aged between 10 and 16 years. Nineteen patients were treated using a hybrid fixation construct and 13 patients were treated with dual plating fixation. The 2 groups were compared retrospectively according to perioperative data and patient outcome measures. The hybrid fixation construct group had 19, with a mean age of 13.3 years (range, 10-16 years) and the dual plate group had 13 patients, with a mean age of 12.9 years (range, 10-16 years). Groups were similar for sex, arm injured, and fracture location. Duration of surgery and tourniquet use was significantly shorter in the hybrid fixation construct group. There was no significant difference in either time to union or Price scores for function evaluation between the 2 groups. Complication rates were also similar between groups, with 1 ulna delayed unions, 1 superficial infection at entry of nail in hybrid fixation construct group, and 1 ulna delayed unions in the dual plating group. Hybrid fixation, using open reduction and internal fixation with a plate-and-screw construct on the ulna and closed reduction and elastic intramedullary fixation of the ulna, is an acceptable method for treating both-bone diaphyseal forearm fractures in skeletally immature patients aged 10-16 years. PMID- 26938755 TI - Effectiveness of Systemic Fluconazole in Adult Patients With Asymptomatic Candiduria: A Systematic Review and Meta-Analysis. AB - Asymptomatic candiduria is a common finding in hospitalized patients. Its management modalities are still a matter of debate. Urinary catheter should be removed or replaced in all cases. In the current meta-analysis, we aimed to compare 2 different strategies in term of candida clearance from the urinary tract: Systemic fluconazole versus conservative management. A systematic search was performed in Pubmed, Web of science, and Cochrane Library database by 2 investigators. Three studies were included (421 patients). Data were extracted and the quality of each study was assessed. Systemic fluconazole was associated with a significantly higher short-term clearance of the funguria after 14 days of treatment [odds ratio = 0.43; confidence interval (CI) 95% (0.26-0.65)]. No significant heterogeneity was found among the included studies (Q statistic test = 0.38; I = 0). In conclusion, fluconazole significantly hasten short-term candida clearance from the urinary tract. PMID- 26938756 TI - Replacing Alpha-Fetoprotein With Alpha-Fetoprotein-L3 Increases the Sensitivity of Prenatal Screening for Trisomy 21. AB - This study aimed to investigate the serum concentration of alpha-fetoprotein (AFP)-L3 in midterm pregnancies and its potential application in prenatal trisomy screening. The serum samples from 27 women with trisomy 21 fetuses and 800 women with normal fetuses were examined to measure the concentrations of AFP, AFP-L3, human chorionic gonadotropin (hCG), unconjugated estriol (uE3), and inhibin-A. The screening results of various tests consisting of these markers were analyzed. In normal pregnancies within 15-20 weeks of gestation, the medians of serum AFP L3 were 4.63, 5.70, 5.78, 6.58, 7.03, and 7.25 pg/mL. The median of AFP-L3 MoM in the trisomy 21 group was 0.46, which was significantly lower than the value of 1 in the normal group (P < 0.05). When using a cutoff value of 1/270, the sensitivity of the triple marker test (AFP, hCG, uE3) was improved from 74% to 81% by replacing AFP with AFP-L3, with the false-positive rate slightly increased from 5.4% to 6.8%. Similarly, the sensitivity of the quad marker test (AFP, hCG, uE3, inhibin-A) was improved from 81% to 89% by replacing AFP with AFP-L3, with the false-positive rate slightly increased from 4.6% to 5.6%. Serum AFP-L3 concentration increases along with more weeks of gestation in the midterm pregnancies. Trisomy 21 screening tests with AFP replaced by AFP-L3 have higher sensitivities at the expense of slightly increased false-positive rates. This improvement in screening may help to better prepare the parents and caregivers for the special needs of newborns with trisomy 21. PMID- 26938757 TI - Severe Thrombocytopenia Induced by First Infliximab Administration for Rheumatoid Arthritis. AB - Thrombocytopenia due to antitumor necrosis factoralpha agents is very rare. A 68 year-old woman with rheumatoid arthritis on methotorexate received infliximab (IFX). Three days after the first IFX infusion, she developed gingival bleeding, petechia, and gross hematuria. Her platelet count fell to 2000/MUL. We administered a platelet transfusion and intravenous methylprednisolone. Three days after admission, her platelet count was 7000/MUL and her bleeding persisted. After double filtration plasmapheresis, her bleeding stopped and her platelet count recovered over 2 weeks. Thrombocytopenia is a rare but severe complication of IFX. Double filtration plasmapheresis may be useful for removing IFX or possible antibodies against platelets when IFX remaining in the patient's blood interferes with improvement of the patient's condition. PMID- 26938758 TI - The Effect of Antipyretic Temperature Reduction on Heart Rate in Febrile Infants: a Pilot Study. AB - It is generally accepted that fever is associated with tachycardia and that the relationship, of an approximate increase of 10 beats/minute per degrees Celsius rise in temperature, is particularly pronounced in infants. It would be useful to determine how closely pulse and fever are associated during pharmacological temperature reduction, and whether it is influenced by the infectious status of the infant. Infants with fever presenting to the pediatric emergency department were prospectively enrolled in a study to determine temperature, heart rate, and the activity at initial assessment and 1 hour after antipyretic administration. Patients were also grouped into those with and without signs of serious bacterial infection for analysis. During pharmacological antipyresis, the relationship between pulse and fever deviated from the accepted norm, established during the febrile state: there was an average pulse rate reduction of 21.1 beats/minute/ degrees Celsius decrement in fever (P = 0.0027; 95% CI, 14.05-28.15). Pulse reduction/ degrees Celsius may also differ in infants with suspected serious bacterial infection. Our findings suggest caution in ascribing pulse changes to fever alone, especially in sick looking infants, and that this is especially true after the administration of antipyretics, which could be related to the mechanism of action of antipyretic drugs. Further research is needed to ascertain the clinical utility and importance of our observations. PMID- 26938759 TI - Evaluation of the Treatment of Candiduria at an Academic Medical Center. AB - To evaluate the epidemiology, management, and outcomes associated with candiduria in intensive care unit (ICU) and medical ward (MW) patients. This was a retrospective cohort study conducted in a tertiary care academic medical center. Adult patients aged between 18 and 75 years who were admitted for at least 5 days with a urinary culture that grew a Candida species between July 2010 and June 2011 were included. Medical records were retrospectively reviewed. Laboratory data, urinary symptoms, risk factors for urinary and invasive candidiasis, treatment, and patient outcomes were collected and evaluated. Sixty-seven ICU and 65 MW patients met the inclusion criteria. ICU patients were more likely to have risk factors for invasive candidiasis and candiduria. Candida albicans and Candida glabrata were the most frequently identified urinary isolates. Antifungal therapy was commonly initiated despite rapid replacement or removal of urinary drainage devices and a lack of patient reported symptoms. Fluconazole was the most commonly used antifungal agent, followed by micafungin. Hospital length of stay did not vary significantly between the ICU and MW groups (P = 0.0628). All cause mortality was higher in the ICU patients compared with that of the MW patients (22.4% vs. 3.1%, P = 0.0012). Differences exist between ICU and MW patients that develop candiduria with respect to risk factors, and outcomes. Antifungals, including fluconazole and micafungin, were often used inappropriately (ie, asymptomatic patients) in this patient cohort. Efforts to improve healthcare provider awareness of the contemporary recommendations to manage candiduria are necessary to improve patient care and antifungal use. PMID- 26938760 TI - Risk of Gastrointestinal Events During Lapatinib Therapy: A Meta-Analysis From 12,402 Patients With Cancer. AB - Lapatinib, a tyrosine kinase inhibitor used as an anticancer therapeutic agent, has adverse events associated with treatment resulting in noncompliance and withdrawal from the therapy. Here, we performed meta-analysis of published clinical trials to determine relative risk (RR) and incidence of gastrointestinal events during lapatinib therapy in patients with cancer. A comprehensive literature search was performed and summary incidence, RR, and 95% confidence intervals (CI) were calculated using fixed-effects or random-effects models, depending on the heterogeneity of trials. Thirty-six trials with 12,402 patients were included; summary incidences of all-grade gastrointestinal events in patients with cancer were diarrhea 57.8%, nausea 30.8%, and vomiting 19.6%. Lapatinib combination with chemotherapy or any anti-HER2 mAbs were associated with significant risk of all-grade diarrhea [(RR 3.64, 95% CI, 2.96-4.49), (RR 2.89, 95% CI, 2.21-3.79), respectively] and high-grade diarrhea [(RR 11.25, 95% CI, 7.31-17.33), (RR 9.96, 95% CI, 7.23-13.72), respectively], and lapatinib combination with chemotherapy group showed a significantly increased risk of all grade nausea (RR 1.54, 95% CI, 1.25-1.89). Lapatinib combination with chemotherapy or any anti-HER2 mAbs were associated with significant risk of all grade vomiting [(RR 1.47, 95% CI, 1.12-1.93), (RR 1.30, 95% CI, 1.11-1.52), respectively]. Lapatinib combination with any anti-HER2 mAbs was associated with a significant risk of high-grade vomiting (RR 2.25, 95% CI, 1.41-3.61). This study revealed a significantly increased risk of diarrhea, nausea, and vomiting in patients with cancer receiving lapatinib, suggesting that appropriate clinical intervention and gastrointestianal protective agents should be emphasized. PMID- 26938762 TI - Preventive Effects of Different Drugs on Asymptomatic Lower Extremities Deep Venous Thrombosis After Artificial Joint Replacement: A Mixed Treatment Comparison. AB - This network meta-analysis aims to compare the preventive effects of 8 drugs (edoxaban, dabigatran, apixaban, rivaroxaban, warfarin, bemiparin, ximelagatran, and enoxaparin) on asymptomatic deep venous thrombosis (DVT) of lower extremities after artificial joint replacement. PubMed, Cochrane Library, and Embase were searched from their inception through October 2015 for randomized controlled trials comparing 8 drugs for the prevention of asymptomatic DVT of lower extremities after artificial joint replacement. Network meta-analysis combined the direct and indirect evidence to evaluate odd ratios (ORs) and surface under the cumulative ranking curves values. A total of 15 randomized controlled trials satisfying the inclusion criteria were enrolled. Edoxaban, apixaban, and rivaroxaban had poorer preventive effects on asymptomatic DVT of lower extremities after undergoing artificial joint replacement when compared with warfarin [OR = 0.16, 95% confidence interval (CI), 0.04-0.60; OR = 0.22, 95% CI, 0.07-0.64; OR = 0.16, 95% CI, 0.05-0.49, respectively]. When compared with enoxaparin, the preventive effects of edoxaban and rivaroxaban were poorer (OR = 0.37, 95% CI, 0.15-0.85; OR = 0.37, 95% CI, 0.21-0.59, respectively). The preventive effects of edoxaban and rivaroxaban were poorer than dabigatran (OR = 0.38, 95% CI, 0.14-0.99; OR = 0.38, 95% CI, 0.18-0.73, respectively). The surface under the cumulative ranking curves values showed that warfarin had better preventive effects on asymptomatic DVT of lower extremities after undergoing artificial joint replacement. Among the 8 drugs (edoxaban, dabigatran, apixaban, rivaroxaban, warfarin, bemiparin, ximelagatran, and enoxaparin), warfarin had better preventive effects on asymptomatic DVT of lower extremities after undergoing artificial joint replacement. PMID- 26938761 TI - Radiofrequency Thermocoagulation in Relieving Refractory Pain of Knee Osteoarthritis. AB - To investigate the efficacy of radiofrequency thermocoagulation (RFTC) in relieving refractory pain of knee osteoarthritis (OA), we selected 54 patients with chronic knee OA pain, 27 treated with RFTC (case group) and 27 receiving regular treatments (control group). Response evaluations were conducted before treatment, and at the termination of treatment, and 3-month follow-up, applying the visual analog scale, the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36), and American Knee Society Score (AKSS). Data analyses were performed with SPSS 21.0. At the termination of treatments and 3-month follow ups, cases gained significantly increased scores in vitality, bodily pain, general health perceptions, physical functioning, and social role functioning by SF-36 scaling and in pain, range of motion, stability, walking, and stair climbing by AKSS (all P < 0.05). Controls received higher scores by AKSS in pain at the termination of treatments and in pain, range of motion, and walking at the termination of 3-month follow-ups (all P < 0.05). Both cases and controls presented significant difference between visual analog scale scores before treatments and those at the termination of 3-month follow-ups (both P < 0.05). All patients felt less pain after treatments, cases presenting better improvement (P < 0.05). Pain was stronger in females compared with males and in a positive correlation with age while had no obvious relation to disease course. In conclusion, RFTC may have better efficacy in relieving refractory pain and promoting function recovery in patients with knee OA than regular treatment. PMID- 26938763 TI - A Case of Salicylate Intoxication Complicated by Coagulopathy, Pulmonary Edema, and Pancreatitis. AB - The large availability of salicylic acid products makes them an often encountered source of poisoning in the emergency department. Even though in most cases the prognosis is good, with a low incidence of long-term morbidity and mortality, complications do occur, and some of those can be life threatening. We present an unusual case of salicylate intoxication in an adolescent in which several uncommon complications (severe coagulopathy, pulmonary edema, and pancreatitis) conjoined together. We review the literature and discuss the complications pathogenesis and differential diagnosis. We suggest that these potentially life threatening complications be acknowledged, investigated, and rapidly treated. PMID- 26938765 TI - Efficacy and Safety of Zoledronic Acid for Treatment of Postmenopausal Osteoporosis: A Meta-Analysis of Randomized Controlled Trials. AB - We conducted a meta-analysis based on eligible studies to assess the efficacy and safety of zoledronic acid treatment for postmenopausal women with osteoporosis. PubMed, Web of Science, and Embase were searched for eligible studies that assessed the efficacy of zoledronic acid in the prevention of fractures among postmenopausal women with osteoporosis. The primary outcomes were new vertebral fracture, nonvertebral fracture, and hip fracture. Secondary outcomes were bone mineral density (BMD) and safety outcomes. A fixed-effect or random-effect model was used to pool the estimates according to the heterogeneity among the included studies. Eight randomized controlled trials, involving 13,335 patients, were included in this meta-analysis. Pooled results showed that treatment with zoledronic acid significantly reduced the incidences of nonvertebral fractures, vertebral fractures, and hip fractures, as compared with placebo. Zoledronic acid was also associated with significant improvement in BMD at lumbar spine, total hip, femoral neck, and trochanter. However, the incidence of any adverse events was higher in the zoledronic acid group than that in the control group, and serious adverse events were comparable between the 2 groups. This meta-analysis indicated that zoledronic acid could significantly reduce the fracture risk and increase BMD in postmenopausal women with osteoporosis. Furthermore, it would not result in serious adverse events. Zoledronic acid could be used as an effective and well-tolerated treatment for postmenopausal women with osteoporosis. PMID- 26938764 TI - Effect of Perineural Dexamethasone With Bupivacaine in Single Space Paravertebral Block for Postoperative Analgesia in Elective Nephrectomy Cases: A Double-Blind Placebo-Controlled Trial. AB - Various analgesic modalities have been tried to prolong the duration and to improve the quality of postoperative analgesia for the early rehabilitation and discharge from hospital after nephrectomy. Using local anaesthetic along with perineural steroids as adjuvant may prove promising for peripheral nerve block, especially paravertebral block (PVB). This article aims to assess the efficacy of dexamethasone with bupivacaine as adjuvant for single bolus injection of thoracic PVB in patients undergoing elective nephrectomy. Sixty patients of American Society of Anesthesiologists physical status I and II were randomly assigned to 2 groups of 30 patients each. Group D patients received 8 mg (2 mL) of dexamethasone mixed to 18 mL of 0.25% bupivacaine, whereas patients in group B received 18 mL of 0.25% bupivacaine and 2 mL of 0.9% saline as placebo to make a total volume of 20 mL infiltrated in PVB. Degree of analgesia achieved and duration of analgesia were recorded in each group along with total dose requirement of rescue analgesic and side effects in first 24 hours postoperatively. Group D patients with dexamethasone had VAS score of 0-3 after 09 minutes of block up to 610.48 +/- 12.24 minutes and after 16 minutes up to 402.34 +/- 28.12 minutes in another group B patient, respectively. The total dose of intravenous fentanyl in the first 24 hours postoperatively in group D was 98.6 +/- 14.14 MUg as compared with 147.6 +/- 18.22 MUg in group B. No other significant side effects were noted except for nausea and vomiting in 5 patients of placebo group. Dexamethasone, along with bupivacaine as adjunct for thoracic PVB, helps in improving the quality and enhancing the postoperative analgesia duration in patients undergoing nephrectomy. PMID- 26938766 TI - Allele and Genotype Frequencies of Cytochrome P450 2B6 516G>T Single Nucleotide Polymorphism in HIV-Negative and HIV-Infected Adult Nigerian Populations. AB - Polymorphisms in genes have been found in most enzymes involved in drug metabolism, especially in the cytochrome P450 (CYP) family with considerable ethnic differences in their frequencies. Single nucleotide polymorphisms (SNPs) are the major source of these genetic variations. CYP2B6 516G>T SNP found in both CYP2B6*6 and CYP2B6*9 alleles significantly reduces CYP2B6 protein expression and enzyme activity with important implications on the pharmacokinetics and pharmacodynamic outcomes of some clinically relevant drug substrates. This study determined the frequencies of CYP2B6 516G>T SNP in HIV-negative and HIV-infected adult Nigerian populations. Three hundred unrelated subjects (150 each of HIV negative volunteers and HIV-infected patients) of different Nigerian ethnic groups residing in Ilorin and Ile-Ife and its environs, respectively, were recruited and genotyped for their CYP2B6 516G>T genetic status using real-time polymerase chain reaction. Differences in allele and genotype frequencies between both populations were tested using Pearson chi test. Minor allele frequency of 36.4% and genotype frequencies of 38.7% GG, 50.0% GT, 11.3% TT and a minor allele frequency of 37.0% and genotype frequencies of 42.0% GG, 42.0% GT, 16.0% TT were obtained for the HIV-negative volunteers and HIV-infected patients, respectively. chi test indicated a significant relationship between genotype frequencies in both populations (P < 0.001). The minor allele and genotype frequencies obtained in the 2 populations significantly differ and corroborate previous studies, which have reported CYP2B6 516G>T SNP in various other African populations. PMID- 26938767 TI - TCDD-Induced Activation of Aryl Hydrocarbon Receptor Inhibits Th17 Polarization and Regulates Non-Eosinophilic Airway Inflammation in Asthma. AB - The aryl hydrocarbon receptor (AhR), a transcription factor of the bHLH/PAS family, has recently been demonstrated to regulate T cell differentiation. Whether AhR activation participates in allergic airway inflammation remains unknown. In the current study, using a non-eosinophilic asthma model, we demonstrate that 2, 3, 7, 8-tetrachlorodibenzo-P-dioxin (TCDD), a potent AhR ligand, reduced the airway infiltration of neutrophils, airway hyperresponsiveness and Th17 cytokine expression. Furthermore, stimulation with TCDD promoted Treg differentiation and inhibited Th17 differentiation. However, the maturation of dendritic cells may not be inhibited by AhR activation. This study thus indicates a critical role of TCDD-induced AhR activation in the regulation of non-eosinophilic airway inflammation. PMID- 26938769 TI - Digital DC-Reconstruction of AC-Coupled Electrophysiological Signals with a Single Inverting Filter. AB - Since the introduction of digital electrocardiographs, high-pass filters have been necessary for successful analog-to-digital conversion with a reasonable amplitude resolution. On the other hand, such high-pass filters may distort the diagnostically significant ST-segment of the ECG, which can result in a misleading diagnosis. We present an inverting filter that successfully undoes the effects of a 0.05 Hz single pole high-pass filter. The inverting filter has been tested on more than 1600 clinical ECGs with one-minute durations and produces a negligible mean RMS-error of 3.1*10(-8) LSB. Alternative, less strong inverting filters have also been tested, as have different applications of the filters with respect to rounding of the signals after filtering. A design scheme for the alternative inverting filters has been suggested, based on the maximum strength of the filter. With the use of the suggested filters, it is possible to recover the original DC-coupled ECGs from AC-coupled ECGs, at least when a 0.05 Hz first order digital single pole high-pass filter is used for the AC-coupling. PMID- 26938768 TI - Patient-Related Risk Factors for Periprosthetic Joint Infection after Total Joint Arthroplasty: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Periprosthetic joint infections (PJIs) are dreaded complications of total joint arthroplasties. The risk of developing PJIs is likely to be influenced by several patient factors such as sociodemographic characteristics, body mass index (BMI), and medical and surgical histories. However, the nature and magnitude of the long-term longitudinal associations between these patient related factors and risk of developing PJIs are uncertain. OBJECTIVE: To conduct a systematic review and meta-analysis to assess the associations between several patient-related factors and PJI. DATA SOURCES: MEDLINE, EMBASE, Web of Science, Cochrane Library, and reference lists of relevant studies from inception to September 2015. STUDY SELECTION: Longitudinal studies with at least one-year of follow-up for PJIs after total joint arthroplasty. DATA EXTRACTION AND SYNTHESIS: Two investigators extracted data on study characteristics, methods, and outcomes. A consensus was reached with involvement of a third. The relative risk (RR) with 95% confidence intervals was used as the summary measure of association across studies. Study-specific RRs with 95% confidence intervals were meta-analysed using random effect models and were grouped by study-level characteristics. RESULTS: Sixty-six observational (23 prospective cohort and 43 retrospective cohort or case-control) studies with data on 512,508 participants were included. Comparing males to females and smokers to non-smokers, the pooled RRs for PJI were 1.36 (1.18-1.57) and 1.83 (1.24-2.70) respectively. There was no evidence of any significant associations of PJI with age and high alcohol intake. Comparing BMI >= 30 versus < 30 kg/m(2); >= 35 versus < 35 kg/m(2); and >= 40 versus < 40 kg/m(2); the pooled RRs were 1.60 (1.29-1.99); 1.53 (1.22-1.92); and 3.68 (2.25 6.01) respectively. Histories of diabetes, rheumatoid arthritis, depression, steroid use, and previous joint surgery were also associated with increased risk of PJI. The results remained similar when grouped by relevant study level characteristics. CONCLUSIONS: Several potentially modifiable patient-related factors are associated with the risk of developing PJIs. Identifying patients with these risk factors who are due to have arthroplasty surgery and modulating these risk factors might be essential in reducing the incidence of PJI. Further research is however warranted to assess the potential clinical utility of these risk factors as risk assessment tools for PJI. SYSTEMATIC REVIEW REGISTRATION: PROSPERO 2015: CRD42015023485. PMID- 26938770 TI - Microbial pathogenesis revealed by intravital microscopy: pros, cons and cautions. AB - Intravital multiphoton imaging allows visualization of infections and pathogenic mechanisms within intact organs in their physiological context. Today, most organs of mice and rats are applicable to in vivo or ex vivo imaging, opening completely new avenues for many researchers. Advances in fluorescent labeling of pathogens and infected cells, as well as improved small animal models for human pathogens, led to the increased application of in vivo imaging in infectious diseases research in recent years. Here, we review the latest literature on intravital or ex vivo imaging of viral and bacterial infections and critically discuss requirements, benefits and drawbacks of applied animal models, labeling strategies, and imaged organs. PMID- 26938771 TI - Thermal Transport across Surfactant Layers on Gold Nanorods in Aqueous Solution. AB - Ultrafast transient absorption experiments and molecular dynamics simulations are utilized to investigate the thermal transport between aqueous solutions and cetyltrimethylammonium bromide (CTAB)- or polyethylene glycol (PEG) functionalized gold nanorods (GNRs). The transient absorption measurement data are interpreted with a multiscale heat diffusion model, which incorporates the interfacial thermal conductances predicted by molecular dynamics. According to our observations, the effective thermal conductance of the GNR/PEG/water system is higher than that of the GNR/CTAB/water system with a surfactant layer of the same length. We attribute the enhancement of thermal transport to the larger thermal conductance at the GNR/PEG interface as compared with that at the GNR/CTAB interface, in addition to the water penetration into the hydrophilic PEG layer. Our results highlight the role of the GNR/polymer thermal interfaces in designing biological and composite-based heat transfer applications of GNRs, and the importance of multiscale analysis in interpreting transient absorption data in systems consisting of low interfacial thermal conductances. PMID- 26938772 TI - Intermolecular Headgroup Interaction and Hydration as Driving Forces for Lipid Transmembrane Asymmetry. AB - Variations between the inner and outer leaflets of cell membranes are crucial for cell functioning and signaling, drug-membrane interactions, and the formation of lipid domains. Transmembrane asymmetry can in principle be comprised of an asymmetric charge distribution, differences in hydration, specific headgroup/H bonding interactions, or a difference in the number of lipids per leaflet. Here, we characterize the transmembrane asymmetry of small unilamellar liposomes consisting of zwitterionic and charged lipids in aqueous solution using vibrational sum frequency scattering and second harmonic scattering, label-free methods, specifically sensitive to lipid and water asymmetries. For single component liposomes, transmembrane asymmetry is present for the charge distribution and lipid hydration, but the leaflets are not detectably asymmetric in terms of the number of lipids per leaflet, even though geometrical packing arguments would predict so. Such a lipid transmembrane asymmetry can, however, be induced in binary lipid mixtures under conditions that enable H-bonding interactions between phosphate and amine groups. In this case, the measured asymmetry consists of a different number of lipids in the outer and inner leaflet, a difference in transmembrane headgroup hydration, and a different headgroup orientation for the interacting phosphate groups. PMID- 26938773 TI - Investigation of the Differential Contributions of Superficial and Deep Muscles on Cervical Spinal Loads with Changing Head Postures. AB - Cervical spinal loads are predominately influenced by activities of cervical muscles. However, the coordination between deep and superficial muscles and their influence on the spinal loads is not well understood. This study aims to document the changes of cervical spinal loads and the differential contributions of superficial and deep muscles with varying head postures. Electromyography (EMG) of cervical muscles from seventeen healthy adults were measured during maximal isometric exertions for lateral flexion (at 10 degrees , 20 degrees and terminal position) as well as flexion/extension (at 10 degrees , 20 degrees , 30 degrees , and terminal position) neck postures. An EMG-assisted optimization approach was used to estimate the muscle forces and subsequent spinal loads. The results showed that compressive and anterior-posterior shear loads increased significantly with neck flexion. In particular, deep muscle forces increased significantly with increasing flexion. It was also determined that in all different static head postures, the deep muscle forces were greater than those of the superficial muscle forces, however, such pattern was reversed during peak efforts where greater superficial muscle forces were identified with increasing angle of inclination. In summary, the identification of significantly increased spinal loads associated with increased deep muscle activation during flexion postures, implies higher risks in predisposing the neck to occupationally related disorders. The results also explicitly supported that deep muscles play a greater role in maintaining stable head postures where superficial muscles are responsible for peak exertions and reinforcing the spinal stability at terminal head postures. This study provided quantitative data of normal cervical spinal loads and revealed motor control strategies in coordinating the superficial and deep muscles during physical tasks. PMID- 26938774 TI - Drip, Ship, and On-Demand Endovascular Therapy for Acute Ischemic Stroke. AB - BACKGROUND: The "drip and ship" approach can facilitate an early initiation of intravenous thrombolysis (IVT) for acute ischemic stroke (AIS) at community hospitals. New endovascular treatment modalities, such as stent retrieval, have further improved the rate of safe and successful recanalization. We assessed the clinical outcomes of on-demand endovascular therapy in patients with AIS who were transported to a comprehensive stroke center under the "drip and ship" paradigm. METHODS: This retrospective study evaluated prospectively registered patients with acute large vessel occlusions in the anterior circulation who underwent endovascular recanalization after IVT at our regional comprehensive stroke center between January 2011 and April 2014. Clinical outcomes and neuroradiological findings were compared between patients who received IVT at the center (direct visit, DV) and at a community hospital (drip and ship, DS). RESULTS: Baseline characteristics such as age, initial National Institutes of Health Stroke Scale (NIHSS) score, and risk factors for stroke were similar, and most patients underwent endovascular therapy with a Solitaire stent (81.9% vs. 89.3% for DV and DS, respectively, P = 0.55). The average initial NIHSS score was 12.15 +/- 4.1 (12.06 vs. 12.39 for DV and DS, respectively, P = 0.719). The proportions of long term favorable outcomes (modified Rankin Scale score <= 2 at 90 days) and successful recanalization (Thrombolysis in Cerebral Ischemia score >= 2b) were not significantly different (P = 0.828 and 0.158, respectively). The mortality rates and occurrences of symptomatic intracerebral hemorrhage were not significantly different (P = 0.999 and 0.267, respectively). CONCLUSIONS: The "drip and ship" approach with subsequent endovascular therapy is a feasible treatment concept for patients with acute large vessel occlusion in the anterior circulation that could help improve clinical outcomes in patients with AIS. PMID- 26938776 TI - Vestitol Isolated from Brazilian Red Propolis Inhibits Neutrophils Migration in the Inflammatory Process: Elucidation of the Mechanism of Action. AB - Vestitol is an isoflavonoid isolated from Brazilian red propolis with potential anti-inflammatory activity. This study investigated the mechanism of action of vestitol on the modulation of neutrophil migration in the inflammatory process. Pre-treatment with vestitol at 1, 3, or 10 mg/kg reduced LPS- or mBSA-induced neutrophil migration and the release of CXCL1/KC and CXCL2/MIP-2 in vivo. Likewise, pre-treatment with vestitol at 1, 3, or 10 MUM reduced the levels of CXCL1/KC and CXCL2/MIP-2 in macrophage supernatants in vitro. Moreover, the administration of vestitol (10 mg/kg) reduced leukocyte rolling and adherence in the mesenteric microcirculation of mice. The pre-treatment with vestitol (10 mg/kg) in iNOS(-/-) mice did not block its activity concerning neutrophil migration. With regard to the activity of vestitol on neutrophils isolated from the bone marrow of mice, there was a reduction on the chemotaxis of CXCL2/MIP-2 or LTB4-induced neutrophils and on calcium influx after pre-treatment with the compound at 3 or 10 MUM. There was no change in CXCR2 expression by neutrophils treated with vestitol at 10 MUM. These findings demonstrate that vestitol is a promising novel anti-inflammatory agent. PMID- 26938777 TI - MOF-Derived Hollow Co9 S8 Nanoparticles Embedded in Graphitic Carbon Nanocages with Superior Li-Ion Storage. AB - Novel electrode materials consisting of hollow cobalt sulfide nanoparticles embedded in graphitic carbon nanocages (HCSP?GCC) are facilely synthesized by a top-down route applying room-temperature synthesized Co-based zeolitic imidazolate framework (ZIF-67) as the template. Owing to the good mechanical flexibility and pronounced structure stability of carbon nanocages-encapsulated Co9 S8 , the as-obtained HCSP?GCC exhibit superior Li-ion storage. Working in the voltage of 1.0-3.0 V, they display a very high energy density (707 Wh kg(-1) ), superior rate capability (reversible capabilities of 536, 489, 438, 393, 345, and 278 mA h g(-1) at 0.2, 0.5, 1, 2, 5, and 10C, respectively), and stable cycling performance (~26% capacity loss after long 150 cycles at 1C with a capacity retention of 365 mA h g(-1) ). When the work voltage is extended into 0.01-3.0 V, a higher stable capacity of 1600 mA h g(-1) at a current density of 100 mA g(-1) is still achieved. PMID- 26938775 TI - Selection on Coding and Regulatory Variation Maintains Individuality in Major Urinary Protein Scent Marks in Wild Mice. AB - Recognition of individuals by scent is widespread across animal taxa. Though animals can often discriminate chemical blends based on many compounds, recent work shows that specific protein pheromones are necessary and sufficient for individual recognition via scent marks in mice. The genetic nature of individuality in scent marks (e.g. coding versus regulatory variation) and the evolutionary processes that maintain diversity are poorly understood. The individual signatures in scent marks of house mice are the protein products of a group of highly similar paralogs in the major urinary protein (Mup) gene family. Using the offspring of wild-caught mice, we examine individuality in the major urinary protein (MUP) scent marks at the DNA, RNA and protein levels. We show that individuality arises through a combination of variation at amino acid coding sites and differential transcription of central Mup genes across individuals, and we identify eSNPs in promoters. There is no evidence of post-transcriptional processes influencing phenotypic diversity as transcripts accurately predict the relative abundance of proteins in urine samples. The match between transcripts and urine samples taken six months earlier also emphasizes that the proportional relationships across central MUP isoforms in urine is stable. Balancing selection maintains coding variants at moderate frequencies, though pheromone diversity appears limited by interactions with vomeronasal receptors. We find that differential transcription of the central Mup paralogs within and between individuals significantly increases the individuality of pheromone blends. Balancing selection on gene regulation allows for increased individuality via combinatorial diversity in a limited number of pheromones. PMID- 26938779 TI - Use of an ophthalmic formulation of megestrol acetate for the treatment of eosinophilic keratitis in cats. AB - OBJECTIVE: To evaluate a compounded ophthalmic formulation of 0.5% megestrol acetate to treat eosinophilic keratitis in cats. STUDY DESIGN: Prospective study. ANIMALS STUDIED: Seventeen client owned cats with eosinophilic keratitis in one or both eyes. METHODS: Eosinophilic keratitis was confirmed by cytology. At each visit, fluorescein staining and photography were performed. Cats were initially treated q 8-12 h with 0.5% megestrol acetate in an aqueous base. Serum glucose was measured at the first or second reexamination. RESULTS: Fifteen of 17 (88%) cats had a positive response to treatment, with 6 of 17 (35%) having complete resolution at the first reexamination (2-4 weeks). Two of 17 (12%) cats did not respond to treatment. Most cats required a treatment frequency of once daily to once weekly to maintain remission of disease. No ocular irritation or systemic side effects were noted in any cat. CONCLUSIONS AND CLINICAL RELEVANCE: The use of an ophthalmic formulation of 0.5% megestrol acetate is a viable option for treating feline eosinophilic keratitis. PMID- 26938780 TI - An electronic atlas of human malformation syndromes in diverse populations. PMID- 26938778 TI - An Interferon Regulated MicroRNA Provides Broad Cell-Intrinsic Antiviral Immunity through Multihit Host-Directed Targeting of the Sterol Pathway. AB - In invertebrates, small interfering RNAs are at the vanguard of cell-autonomous antiviral immunity. In contrast, antiviral mechanisms initiated by interferon (IFN) signaling predominate in mammals. Whilst mammalian IFN-induced miRNA are known to inhibit specific viruses, it is not known whether host-directed microRNAs, downstream of IFN-signaling, have a role in mediating broad antiviral resistance. By performing an integrative, systematic, global analysis of RNA turnover utilizing 4-thiouridine labeling of newly transcribed RNA and pri/pre miRNA in IFN-activated macrophages, we identify a new post-transcriptional viral defense mechanism mediated by miR-342-5p. On the basis of ChIP and site-directed promoter mutagenesis experiments, we find the synthesis of miR-342-5p is coupled to the antiviral IFN response via the IFN-induced transcription factor, IRF1. Strikingly, we find miR-342-5p targets mevalonate-sterol biosynthesis using a multihit mechanism suppressing the pathway at different functional levels: transcriptionally via SREBF2, post-transcriptionally via miR-33, and enzymatically via IDI1 and SC4MOL. Mass spectrometry-based lipidomics and enzymatic assays demonstrate the targeting mechanisms reduce intermediate sterol pathway metabolites and total cholesterol in macrophages. These results reveal a previously unrecognized mechanism by which IFN regulates the sterol pathway. The sterol pathway is known to be an integral part of the macrophage IFN antiviral response, and we show that miR-342-5p exerts broad antiviral effects against multiple, unrelated pathogenic viruses such Cytomegalovirus and Influenza A (H1N1). Metabolic rescue experiments confirm the specificity of these effects and demonstrate that unrelated viruses have differential mevalonate and sterol pathway requirements for their replication. This study, therefore, advances the general concept of broad antiviral defense through multihit targeting of a single host pathway. PMID- 26938781 TI - Expanded carrier screening in an infertile population: how often is clinical decision making affected? AB - PURPOSE: Options for preconception genetic screening have grown dramatically. Expanded carrier screening (ECS) now allows for determining carrier status for hundreds of genetic mutations by using a single sample, and some recommend ECS prior to in vitro fertilization. This study seeks to evaluate how often ECS alters clinical management when patients present for infertility care. METHODS: All patients tested with ECS at a single infertility care center from 2011 to 2014 were evaluated. The overall rate of positive ECS results and the number of couples who were carriers of the same genetic disorder were evaluated. RESULTS: A total of 6,643 individuals were tested, representing 3,738 couples; 1,666 (25.1%) of the individuals had a positive test result for at least one disorder. In 8 of the 3,738 couples, both members of the couple were positive for the same genetic disorder or had a test result that placed them at risk of having an affected child. Three of eight cases were cystic fibrosis. In this cohort, ECS affected clinical care eight times after 6,643 tests (0.12%, confidence interval: 0.05 0.24%) in 3,738 couples (0.21%, confidence interval: 0.09-0.42%). CONCLUSIONS: ECS is becoming more widespread. In a large case series, ECS affected clinical decision making for patients presenting for infertility care in 0.21% of cases. This information must be weighed when utilizing these tests and may be a helpful part of patient counseling.Genet Med 18 11, 1097-1101. PMID- 26938782 TI - Cost-effectiveness of routine screening for Lynch syndrome in colorectal cancer patients up to 70 years of age. AB - PURPOSE: To assess the cost-effectiveness of routine Lynch syndrome (LS) screening among colorectal cancer (CRC) patients <=70 years of age. METHODS: A population-based series of CRC patients <=70 years of age was routinely screened for LS. We calculated life years gained (LYG) and incremental cost-effectiveness ratios (ICERs) for different age cutoffs and comparing age-targeted screening with the revised Bethesda guidelines. RESULTS: Screening 1,117 CRC patients identified 23 LS patients, of whom 7 were <=50 years of age, 7 were 51-60, and 9 were 61-70. Additionally, 70 LS carriers were identified among relatives (14, 42, and 14 per age category). Screening amounted to 205.9 LYG or 43.6, 118.0, and 44.3 LYG per age category. ICERs were [euro ]4.226/LYG for screening CRC patients <=60 years of age compared with those <=50 years and [euro ]7.051/LYG for screening CRC patients <=70 years compared with those <=60 years. The revised Bethesda guidelines identified 70 of 93 (75%) LS carriers. The ICER for LS screening in CRC patients <=70 years of age compared with the revised Bethesda guidelines was [euro ]7.341/LYG. All ICERs remained less than [euro ]13.000/LYG in one-way sensitivity analyses. CONCLUSION: Routine LS screening by analysis of microsatellite instability, immunohistochemistry, and MLH1 hypermethylation in CRC patients <=70 years of age is a cost-effective strategy with important clinical benefits for CRC patients and their relatives.Genet Med 18 10, 966-973. PMID- 26938783 TI - Clinical utility of a Web-enabled risk-assessment and clinical decision support program. AB - PURPOSE: Risk-stratified guidelines can improve quality of care and cost effectiveness, but their uptake in primary care has been limited. MeTree, a Web based, patient-facing risk-assessment and clinical decision support tool, is designed to facilitate uptake of risk-stratified guidelines. METHODS: A hybrid implementation-effectiveness trial of three clinics (two intervention, one control). PARTICIPANTS: consentable nonadopted adults with upcoming appointments. PRIMARY OUTCOME: agreement between patient risk level and risk management for those meeting evidence-based criteria for increased-risk risk-management strategies (increased risk) and those who do not (average risk) before MeTree and after. MEASURES: chart abstraction was used to identify risk management related to colon, breast, and ovarian cancer, hereditary cancer, and thrombosis. RESULTS: Participants = 488, female = 284 (58.2%), white = 411 (85.7%), mean age = 58.7 (SD = 12.3). Agreement between risk management and risk level for all conditions for each participant, except for colon cancer, which was limited to those <50 years of age, was (i) 1.1% (N = 2/174) for the increased-risk group before MeTree and 16.1% (N = 28/174) after and (ii) 99.2% (N = 2,125/2,142) for the average risk group before MeTree and 99.5% (N = 2,131/2,142) after. Of those receiving increased-risk risk-management strategies at baseline, 10.5% (N = 2/19) met criteria for increased risk. After MeTree, 80.7% (N = 46/57) met criteria. CONCLUSION: MeTree integration into primary care can improve uptake of risk stratified guidelines and potentially reduce "overuse" and "underuse" of increased-risk services.Genet Med 18 10, 1020-1028. PMID- 26938784 TI - A prospective evaluation of whole-exome sequencing as a first-tier molecular test in infants with suspected monogenic disorders. AB - PURPOSE: To prospectively evaluate the diagnostic and clinical utility of singleton whole-exome sequencing (WES) as a first-tier test in infants with suspected monogenic disease. METHODS: Singleton WES was performed as a first-tier sequencing test in infants recruited from a single pediatric tertiary center. This occurred in parallel with standard investigations, including single- or multigene panel sequencing when clinically indicated. The diagnosis rate, clinical utility, and impact on management of singleton WES were evaluated. RESULTS: Of 80 enrolled infants, 46 received a molecular genetic diagnosis through singleton WES (57.5%) compared with 11 (13.75%) who underwent standard investigations in the same patient group. Clinical management changed following exome diagnosis in 15 of 46 diagnosed participants (32.6%). Twelve relatives received a genetic diagnosis following cascade testing, and 28 couples were identified as being at high risk of recurrence in future pregnancies. CONCLUSIONS: This prospective study provides strong evidence for increased diagnostic and clinical utility of singleton WES as a first-tier sequencing test for infants with a suspected monogenic disorder. Singleton WES outperformed standard care in terms of diagnosis rate and the benefits of a diagnosis, namely, impact on management of the child and clarification of reproductive risks for the extended family in a timely manner.Genet Med 18 11, 1090-1096. PMID- 26938786 TI - Oxidative Radical Addition/Cyclization Cascade for the Construction of Carbonyl Containing Quinoline-2,4(1H,3H)-Diones. AB - Oxidative radical addition/cyclization cascade of o-cyanoarylacrylamides with alpha-keto acids as well as aldehydes is reported. This transformation exhibits a wide substrate scope and significant functional group tolerance and provides a convenient and highly efficient access to carbonyl-containing quinoline 2,4(1H,3H)-diones. A possible mechanism for the transformation is proposed. PMID- 26938787 TI - Multifunctional Coating Improves Cell Adhesion on Titanium by using Cooperatively Acting Peptides. AB - Promotion of cell adhesion on biomaterials is crucial for the long-term success of a titanium implant. Herein a novel concept is highlighted combining very stable and affine titanium surface adhesive properties with specific cell binding moieties in one molecule. A peptide containing L-3,4-dihydroxyphenylalanine was synthesized and affinity to titanium was investigated. Modification with a cyclic RGD peptide and a heparin binding peptide (HBP) was realized by an efficient on resin combination of Diels-Alder reaction with inverse electron demand and Cu(I) catalyzed azide-alkyne cycloaddition. The peptide was fluorescently labeled by thiol Michael addition. Conjugating the cyclic RGD and HBP in one peptide gave improved spreading, proliferation, viability, and the formation of well-developed actin cytoskeleton and focal contacts of osteoblast-like cells. PMID- 26938785 TI - The Relationships between Metabolic Disorders (Hypertension, Dyslipidemia, and Impaired Glucose Tolerance) and Computed Tomography-Based Indices of Hepatic Steatosis or Visceral Fat Accumulation in Middle-Aged Japanese Men. AB - BACKGROUND: Most studies on the relationships between metabolic disorders (hypertension, dyslipidemia, and impaired glucose tolerance) and hepatic steatosis (HS) or visceral fat accumulation (VFA) have been cross-sectional, and thus, these relationships remain unclear. We conducted a retrospective cohort study to clarify the relationships between components of metabolic disorders and HS/VFA. METHODS: The participants were 615 middle-aged men who were free from serious liver disorders, diabetes, and HS/VFA and underwent multiple general health check-ups at our institution between 2009 and 2013. The data from the initial and final check-ups were used. HS and VFA were assessed by computed tomography. HS was defined as a liver to spleen attenuation ratio of <=1.0. VFA was defined as a visceral fat cross-sectional area of >=100 cm2 at the level of the navel. Metabolic disorders were defined using Japan's metabolic syndrome diagnostic criteria. The participants were divided into four groups based on the presence (+) or absence (-) of HS/VFA. The onset rates of each metabolic disorder were compared among the four groups. RESULTS: Among the participants, 521, 55, 24, and 15 were classified as HS(-)/VFA(-), HS(-)/VFA(+), HS(+)/VFA(-), and HS(+)/VFA(+), respectively, at the end of the study. Impaired glucose tolerance was more common among the participants that exhibited HS or VFA (p = 0.05). On the other hand, dyslipidemia was more common among the participants that displayed VFA (p = 0.01). CONCLUSIONS: It is likely that VFA is associated with impaired glucose tolerance and dyslipidemia, while HS might be associated with impaired glucose tolerance. Unfortunately, our study failed to detect associations between HS/VFA and metabolic disorders due to the low number of subjects that exhibited fat accumulation. Although our observational study had major limitations, we consider that it obtained some interesting results. HS and VFA might affect different metabolic disorders. Further large-scale longitudinal studies are needed to reveal the relationships between the components of metabolic disorders and HS/VFA. PMID- 26938790 TI - Oxide Nanocrystal Model Catalysts. AB - Model catalysts with uniform and well-defined surface structures have been extensively employed to explore structure-property relationships of powder catalysts. Traditional oxide model catalysts are based on oxide single crystals and single crystal thin films, and the surface chemistry and catalysis are studied under ultrahigh-vacuum conditions. However, the acquired fundamental understandings often suffer from the "materials gap" and "pressure gap" when they are extended to the real world of powder catalysts working at atmospheric or higher pressures. Recent advances in colloidal synthesis have realized controlled synthesis of catalytic oxide nanocrystals with uniform and well-defined morphologies. These oxide nanocrystals consist of a novel type of oxide model catalyst whose surface chemistry and catalysis can be studied under the same conditions as working oxide catalysts. In this Account, the emerging concept of oxide nanocrystal model catalysts is demonstrated using our investigations of surface chemistry and catalysis of uniform and well-defined cuprous oxide nanocrystals and ceria nanocrystals. Cu2O cubes enclosed with the {100} crystal planes, Cu2O octahedra enclosed with the {111} crystal planes, and Cu2O rhombic dodecahedra enclosed with the {110} crystal planes exhibit distinct morphology dependent surface reactivities and catalytic properties that can be well correlated with the surface compositions and structures of exposed crystal planes. Among these types of Cu2O nanocrystals, the octahedra are most reactive and catalytically active due to the presence of coordination-unsaturated (1-fold coordinated) Cu on the exposed {111} crystal planes. The crystal-plane-controlled surface restructuring and catalytic activity of Cu2O nanocrystals were observed in CO oxidation with excess oxygen. In the propylene oxidation reaction with O2, 1-fold-coordinated Cu on Cu2O(111), 3-fold-coordinated O on Cu2O(110), and 2-fold coordinated O on Cu2O(100) were identified as the active sites, respectively, to produce acrolein, propylene oxide, and CO2. Ceria rods enclosed with the {110} and {100} crystal planes, ceria cubes enclosed with the {100} crystal planes, and ceria octahedra enclosed with the {111} crystal planes exhibit distinct morphology-dependent oxygen vacancy concentrations and structures that can be well correlated with the surface compositions and structures of exposed crystal planes. Consequently, the metal-ceria interactions, structures, and catalytic performances of ceria-supported catalysts depend on the CeO2 morphology. Our results comprehensively reveal the morphology-dependent surface chemistry and catalysis of oxide nanocrystals that not only greatly deepen the fundamental understanding of oxide catalysis but also demonstrate a morphology-engineering strategy to optimize the catalytic performance of oxide catalysts. These results adequately exemplify the concept of oxide nanocrystal model catalysts for the fundamental investigations of oxide catalysis without the "materials gap" and "pressure gap". With the structure-catalytic property relationships learned from oxide nanocrystal model catalyst studies and the advancement of controlled synthesis methods, it is promising to realize the structural design and controlled synthesis of novel efficient oxide catalysts in the future. PMID- 26938791 TI - Mechanism of Oxidative Amidation of Nitroalkanes with Oxygen and Amine Nucleophiles by Using Electrophilic Iodine. AB - Recently, we developed a direct method to oxidatively convert primary nitroalkanes into amides that entailed mixing an iodonium source with an amine, base, and oxygen. Herein, we systematically investigated the mechanism and likely intermediates of such methods. We conclude that an amine-iodonium complex first forms through N-halogen bonding. This complex reacts with aci-nitronates to give both alpha-iodo- and alpha,alpha-diiodonitroalkanes, which can act as alternative sources of electrophilic iodine and also generate an extra equimolar amount of I(+) under O2. In particular, evidence supports alpha,alpha-diiodonitroalkane intermediates reacting with molecular oxygen to form a peroxy adduct; alternatively, these tetrahedral intermediates rearrange anaerobically to form a cleavable nitrite ester. In either case, activated esters are proposed to form that eventually reacts with nucleophilic amines in a traditional fashion. PMID- 26938793 TI - Synthesis of C4 and C8 Chemicals from Ethanol on MgO-Incorporated Faujasite Catalysts with Balanced Confinement Effects and Basicity. AB - A new type of catalyst has been designed to adjust the basicity and level of molecular confinement of KNaX faujasites by controlled incorporation of Mg through ion exchange and precipitation of extraframework MgO clusters at varying loadings. The catalytic performance of these catalysts was compared in the conversion of C2 and C4 aldehydes to value-added products. The product distribution depends on both the level of acetaldehyde conversion and the fraction of magnesium as extraframework species. These species form rather uniform and highly dispersed nanostructures that resemble nanopetals. Specifically, the sample containing Mg only in the form of exchangeable Mg(2+) ions has much lower activity than those in which a significant fraction of Mg exists as extraframework MgO. Both the (C6+C8)/C4 and C8/C6 ratios increase with additional extraframework Mg at high acetaldehyde conversion levels. These differences in product distribution can be attributed to 1) higher basicity density on the samples with extraframework species, and 2) enhanced confinement inside the zeolite cages in the presence of these species. Additionally, the formation of linear or aromatic C8 aldehyde compounds depends on the position on the crotonaldehyde molecule from which abstraction of a proton occurs. In addition, catalysts with different confinement effects result in different C8 products. PMID- 26938792 TI - SUPPORTING PRETERM INFANT ATTACHMENT AND SOCIOEMOTIONAL DEVELOPMENT IN THE NEONATAL INTENSIVE CARE UNIT: STAFF PERCEPTIONS. AB - The infant-parent relationship has been shown to be of particular significance to preterm infant socioemotional development. Supporting parents and infants in this process of developing their relationships is an integral part of neonatal intensive care; however, there is limited knowledge of NICU staff perceptions about this aspect of care. To explore NICU staff perceptions about attachment and socioemotional development of preterm infants, experience of training in this area and the emotional impact of their work. A cross-sectional questionnaire survey of staff perceptions of the emotional experiences of parents and the developing parent-infant relationship in an NICU was conducted in a Level III NICU, after pilot testing, revision, and ethical approval. Fifty-seven (68%) of NICU staff responded to the survey. Respondents identified parents' emotional experiences such as "anxiety," "shock," "loss of control," and "lack of feelings of competence as parents" as highly prevalent. Infant cues of "responding to parent's voice" and "quieting-alerting" were ranked most highly; "crying" and "physiological changes" were ranked lowest. Preterm infant medical risk, maternal emotional state, and mental health are perceived to impact most highly on the developing relationship, as compared with infant state or behavior and socioeconomic factors. Fifty-three (93%) respondents felt confident, and 50 (87.8%) felt competent discussing their emotional experiences with parents. Fifty four (95%) responded that attending to these areas was an integral part of their role; however, staff had seldom received education in this area. Respondents also perceived that specific psychological support for parents was lacking both during and after the infant's discharge. While all staff surveyed perceived the nature of their work to be emotionally stressful, there were differences among NICU staff disciplines and with years of experience in the NICU in terms of their perceptions about education in this area, the place of supervision for staff, and in relation to opportunities to discuss the emotional impact of the work on staff. NICU staff perceive their role as integral to supporting the developing parent-infant relationship and preterm infant socioemotional development; however, education in this area and provision of specific psychological support are lacking. Opportunities for staff to discuss and reflect on this aspect of their work should be developed and evaluated given the essential, but emotionally challenging, nature of their work with preterm babies and their parents. PMID- 26938794 TI - Correction: Veterans' Perspectives on Interventions to Improve Retention in HIV Care. PMID- 26938795 TI - The Use of Mn(II) Bound to His-tags as Genetically Encodable Spin-Label for Nanometric Distance Determination in Proteins. AB - A genetically encodable paramagnetic spin-label capable of self-assembly from naturally available components would offer a means for studying the in-cell structure and interactions of a protein by electron paramagnetic resonance (EPR). Here, we demonstrate pulse electron-electron double resonance (DEER) measurements on spin-labels consisting of Mn(II) ions coordinated to a sequence of histidines, so-called His-tags, that are ubiquitously added by genetic engineering to facilitate protein purification. Although the affinity of His-tags for Mn(II) was low (800 MUM), Mn(II)-bound His-tags yielded readily detectable DEER time traces even at concentrations expected in cells. We were able to determine accurately the distance between two His-tag Mn(II) spin-labels at the ends of a rigid helical polyproline peptide of known structure, as well as at the ends of a completely cell-synthesized 3-helix bundle. This approach not only greatly simplifies the labeling procedure but also represents a first step towards using self-assembling metal spin-labels for in-cell distance measurements. PMID- 26938797 TI - Psychotherapy Outcome Research: Issues and Questions. AB - Emphasis on identifying evidence-based therapies (EBTs) has increased markedly. Lists of EBTs are the rationale for recommendations for how psychotherapy provider training programs should be evaluated, professional competence assessed, and licensure and reimbursement policies structured. There are however methodological concerns that limit the external validity of EBTs. Among the most salient is the circularity inherent in randomized control trials (RCTs) of psychotherapy that constrains the manner in which the psychological problems are defined, psychotherapy can be practiced, and change evaluated. RCT studies favor therapies that focus of specific symptoms and can be described in a manual, administered reliably across patients, completed in relatively few sessions, and involve short-term evaluations of outcome. The epistemological assumptions of a natural science approach to psychotherapy research limit how studies are conducted and assessed in ways that that advantage symptom-focused approaches and disadvantage those approaches that seek to bring broad recovery-based changes. Research methods that are not limited to RCTs and include methodology to minimize the effects of "therapist allegiance" are necessary for valid evaluations of therapeutic approaches that seek to facilitate changes that are broader than symptom reduction. Recent proposals to adopt policies that dictate training, credentialing, and reimbursement based on lists of EBTs unduly limit how psychotherapy can be conceptualized and practiced, and are not in the best interests of the profession or of individuals seeking psychotherapy services. PMID- 26938796 TI - Myocardial histopathology in late-repaired and unrepaired adults with tetralogy of Fallot. AB - Survival of patients after repair of tetralogy of Fallot (TOF) is worse than for the general population. We aimed to assess the time-related effects of surgical repair on right (RV) and left ventricle (LV) myocardium by quantifying hypertrophy and fibrosis. Cardiomyocyte transverse diameter and percent of fibrosis were measured in 8 adult heart specimens with late-repaired TOF, 6 with unrepaired TOF, and 11 normal hearts (controls). The RV and LV mean and median cardiomyocyte diameter and percent of fibrosis were significantly greater than controls in both repaired and unrepaired hearts. The mean RV inferior wall myocyte diameter in unrepaired hearts was significantly greater at average age at death than in repaired hearts (24.9+/-2.5 vs. 16.4+/-1.3MUm, P=.015), but not the mean RV anterior wall myocyte diameter (21.5+/-2.2 vs. 17+/-1.2MUm, P=.09) or the mean LV myocyte diameter (19.7+/-1.5 vs. 16.7+/-0.8MUm, P=.10). Of the RV myocyte diameter measurements, only the RV anterior wall myocyte diameter for repaired hearts correlated with age at death, while LV myocyte diameter for both repaired and unrepaired hearts correlated with age at death. None of the measures of myocyte diameter correlated with age at repair. The mean RV anterior wall, inferior wall, and LV percent fibrosis were all significantly greater in unrepaired hearts at average age at death compared with repaired hearts (16.3+/ 1.3 vs. 13.0+/-0.7%, P=.04; 18.1+/-1.9 vs. 12.7+/-1.0%, P=.03; 15.7+/-0.8 vs. 11.6+/-0.4%, P=.004, respectively). There was a significant correlation between RV percent fibrosis (both locations) and age at death for repaired hearts but not for unrepaired hearts, while LV wall percent fibrosis correlated significantly with age at death for both groups. RV percent fibrosis was not significantly correlated with age at repair, while LV percent fibrosis was negatively correlated with age at repair. Hypertrophy and fibrosis in RV and LV of late repaired TOF hearts progress during follow-up despite a good repair. These could be the substrate of ventricular dysfunction and arrhythmia seen clinically late after correction. PMID- 26938798 TI - Evidence-Based Therapies, Evidence-Based Practice, and the Intersection of Nomothetic and Idiographic Foundations of Psychotherapy Research and Application: A Reply to Shean. AB - This article is a commentary on "Psychotherapy Outcome Research: Issues and Questions" by Glenn Shean (this issue). While we agree with a couple of Shean's points, such as over-reliance on diagnoses and lack of attention to global measures of quality of life and functioning, there are several very substantive points of disagreement. We argue that evidence-based therapies and evidence-based practice occupy a central role in developing effective and non-harmful therapies. Shean conflates evidence-based therapies and evidence-based practice in a way that is not representative of how science is intended to advance everyday treatment delivery. We further contest Shean's notion that reliance on empirically based research is limiting to clinicians and instead argue that it offers a helpful and pragmatic starting point for clinical decision making with each unique patient. Further, evidence-based practice, in contrast to evidence based therapies, represents the model ideal for service delivery, rather than a slavish adherence to protocols employed in randomized clinical trials. Finally, we argue that both nomothetic and idiographic approaches are valid and important in the ongoing advancement of modern psychotherapy, a position wholly consistent with the evidence-based practice movement. PMID- 26938799 TI - Varieties of Castration Experience: Relevance to Contemporary Psychoanalysis and Psychodynamic Psychotherapy. AB - Although Freud considered castration to be one of the two major anxieties of human life, the castration complex has been relatively neglected in contemporary psychoanalytic writing and is insufficiently discussed in presentations of clinical cases. This article discusses the relevance of the concept to contemporary psychoanalysis and psychodynamic psychotherapy, in particular the important contributing role of castration conflicts in the pathogenesis of a wide range of clinical symptoms. The author begins by briefly reviewing some classical and contemporary psychoanalytic ideas about castration to show how the concept has broadened and is currently used not only to signify fear of damage to or loss of the genital, but also metaphorically to indicate a threat to or loss of any valued human characteristic or function. He outlines Brenner's distinction between castration anxiety and castration depression, and reviews the role of childhood trauma in intensifying castration conflicts. He then illustrates the clinical application of these ideas by describing aspects of his psychotherapeutic work with three male patients who presented with a variety of symptoms and distressing psychological experiences that were gradually resolved through the analysis of underlying castration anxiety and/or castration depression. Although castration anxiety is frequently intermingled with separation anxiety, the author concludes that with many traumatized patients castration conflicts are in the foreground and the therapist needs to focus on the patient's proneness to humiliation, powerlessness, and shame. PMID- 26938800 TI - Freud's "Project": The Mind-Brain Connection Revisited. AB - Freud's "Project for a Scientific Psychology" (1895) reflected his attempt to explain psychic phenomena in neurobiological terms. The recent discovery of the neuron motivated him to embark on this endeavor. His basic hypothesis was that neurons were vehicles for the conduction of "currents" or "excitations," and that they were connected to one another. Using this model, Freud attempted to describe a number of mental phenomena, including: consciousness, perception, affect, self, cognition, dreaming, memory, and symptom formation. However, he was unable to complete his exploration of these mental processes because he lacked the information and technology that became available over the following century. Subsequent discoveries, including fMRIs, PET scans, EEGs, synapses, neural networks, genetic factors, neurotransmitters, and discrete brain circuits facilitated a significant expansion of our knowledge of mind-brain phenomena. As a result, effective pharmacological treatments have been developed for schizophrenia, mood and anxiety disorders. Moreover, changes in brain function can be measured that reflect successful pharmacologic and psychotherapeutic treatment. Despite these advances, there remain limitations in our understanding of the relationship between mind and brain functions. More than a century after Freud began the "Project," the neurobiology underlying the phenomena of consciousness, unconsciousness, qualities of subjective feelings, thoughts, and memories is still not fully understood. Can we expect to reach a more comprehensive integration of mind and its neurobiological substrate a century from now? The purpose of this article is to update our knowledge of the neurobiology associated with the specific mental functions that Freud examined in the "Project," and to pose questions concerning mind-brain phenomena that will hopefully be answered in the future. PMID- 26938801 TI - Psychodynamic Factors Behind Online Social Networking and its Excessive Use. AB - This article discusses the psychodynamic factors behind the popularity of one form of Internet activity, online social networking (SN). It views online SN as an extension of the social self, organized in a way that is more controllable than real life relating. The SN platforms reward its users with reassuring surfaces and novel self-object experiences while at the same time induces much anxiety. The addictive quality of online SN is understood in the context of collapse of dialectical space and the defensive use of this technology. PMID- 26938803 TI - Letter to the Editor. PMID- 26938802 TI - New Developments of the Therapeutic Alliance (TA): Good News for Psychodynamic Psychiatry. AB - Clinicians have long known that successful psychotherapy, including successful psychodynamic psychotherapy, depends upon the interaction between therapist and patient. In other words, it is important to have a strong therapeutic alliance. This article presents the history of the concept of the therapeutic alliance (TA). It also explores three areas of research that have bearing on the TA. The importance of the TA and the extensive research work that pertains to it hold promise for psychodynamic psychiatry, both in terms of understanding, and in the treatment of mental suffering. PMID- 26938805 TI - Increased risk of colorectal neoplasia in patients with primary sclerosing cholangitis and inflammatory bowel disease: a meta-analysis of 16 observational studies. AB - Ulcerative colitis (UC) patients with concomitant primary sclerosing cholangitis (PSC) carry an increased risk of colorectal neoplasia (dysplasia and cancer), whereas the association between PSC and the development of colorectal neoplasia in Crohn's disease (CD) is controversial. A meta-analysis was carried out to compare the risk of this neoplasia in patients with inflammatory bowel disease (IBD) with and without PSC. A systematic research of MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials was performed to identify studies that compared the risk of colorectal neoplasia (dysplasia and cancer) in patients with IBD with and without PSC. Quality assessment was performed using the Newcastle-Ottawa Scale. Pooled odds ratio (OR) was calculated using the random effects model by STATA 12.0. A total of 16 studies (four cohort studies, 12 case control studies; nine prospective studies and seven retrospective studies) were selected for further study. These studies included 13 379 IBD patients, of whom 1022 also had PSC. Patients with IBD and PSC were at an increased risk of colorectal dysplasia and cancer compared with patients with IBD alone [OR 3.24; 95% confidence interval (CI): 2.14-4.90]. This increased risk was present even when the risk of colorectal cancer alone was analysed (OR 3.41; 95% CI: 2.13 5.48). Data only from patients with UC showed that PSC was associated with an increased risk for the development of colorectal neoplasia and cancer in patients with UC (OR 2.98; 95% CI: 1.54-5.76) (OR 3.01; 95% CI: 1.44-6.29), but there were high heterogeneity among studies (I=76.9 and 62.8%, respectively). Heterogeneity of the studies was affected by the study design (prospective or retrospective). The OR of colorectal neoplasia was 2.32 (95% CI: 0.70-7.70, P=0.133) and that of cancer was 2.91 (95% CI: 0.84-10.16, P=0.388) for patients with CD and concurrent PSC. Patients with IBD and PSC have a markedly higher risk for the development of colorectal neoplasia than patients with IBD, but not PSC. Stratification by IBD type show that the presence of PSC is associated with an increased risk for the development of colorectal neoplasia in patients with UC; however, there is a nonsignificant association in CD patients. When the risk of colorectal cancer alone is analysed, the conclusion does not change. PMID- 26938806 TI - Impact of mulches and growing season on indicator bacteria survival during lettuce cultivation. AB - In fresh produce production, the use of mulches as ground cover to retain moisture and control weeds is a common agricultural practice, but the influence that various mulches have on enteric pathogen survival and dispersal is unknown. The goal of this study was to assess the impact of different mulching methods on the survival of soil and epiphytic fecal indicator bacteria on organically grown lettuce during different growing seasons. Organically managed lettuce, cultivated with various ground covers--polyethylene plastic, corn-based biodegradable plastic, paper and straw mulch--and bare ground as a no-mulch control, was overhead inoculated with manure-contaminated water containing known levels of generic Escherichia coli and Enterococcus spp. Leaves and soil samples were collected at intervals over a two week period on days 0, 1, 3, 5, 7, 10 and 14, and quantitatively assessed for E. coli, fecal coliforms and Enterococcus spp. Data were analyzed using mixed models with repeated measures and an exponential decline with asymptote survival model. Indicator bacterial concentrations in the lettuce phyllosphere decreased over time under all treatments, with more rapid E. coli declines in the fall than in the spring (p<0.01). Persistence of E. coli in spring was correlated with higher maximum and minimum temperatures in this season, and more regular rainfall. The survival model gave very good fits for the progression of E. coli concentrations in the phyllosphere over time (R(2)=0.88 +/ 0.12). In the spring season, decline rates of E. coli counts were faster (2013 p=0.18; 2014 p<0.005) for the bare ground-cultivated lettuce compared to mulches. In fall 2014, the E. coli decline rate on paper mulch-grown lettuce was higher (p<0.005). Bacteria fluctuated more, and persisted longer, in soil compared to lettuce phyllosphere, and mulch type was a factor for fecal coliform levels (p<0.05), with higher counts retrieved under plastic mulches in all trials, and higher enterococci levels under straw in fall 2014 (p<0.05). This study demonstrates that mulches used in lettuce production may impact the fate of enteric bacteria in soil or on lettuce, most likely in relation to soil moisture retention, and other weather-related factors, such as temperature and rainfall. The data suggest that the time between exposure to a source of enteric bacteria and harvesting of the crop is season dependent, which has implications for determining best harvest times. PMID- 26938808 TI - The impact of inocula carryover and inoculum dilution on the methane yields in batch methane potential tests. AB - Batch studies are used to benchmark biohydrogen potential (BHP) and biomethane potential (BMP) yields from feed substrates, digestates residues and different process configurations. This study shows that BMP yields using cellulose can be biased positively by not diluting the initial sewage sludge inoculum and the bias is independent of starting inoculum volatile solids (VS) concentration. The carryover of BHP inoculum also increased the BMP yields when using cellulose as a substrate by up to 18.8%. Furthermore it was also observed that the dilution of BMP inoculum with deionised H2O reduced methane yields from cellulose by up to 132+/-26 N mL-CH4 g-VS(-1). Therefore it is proposed that inoculum and standard substrate controls (as used in this study) should be included in methane batch methodologies, particularly when using a pre-fermentation stage such as dark fermentation. PMID- 26938807 TI - GHG emission factors for bioelectricity, biomethane, and bioethanol quantified for 24 biomass substrates with consequential life-cycle assessment. AB - Greenhouse gas (GHG) emission savings from biofuels dramatically depend upon the source of energy displaced and the effects induced outside the energy sector, for instance land-use changes (LUC). Using consequential life-cycle assessment and including LUC effects, this study provides GHG emission factors (EFs) for bioelectricity, biomethane, and bioethanol produced from twenty-four biomasses (from dedicated crops to residues of different origin) under a fossil and a non fossil energy system. Accounting for numerous variations in the pathways, a total of 554 GHG EFs were quantified. The results showed that, important GHG savings were obtained with residues and seaweed, both under fossil and non-fossil energy systems. For high-yield perennial crops (e.g. willow and Miscanthus), GHG savings were achieved only under fossil energy systems. Biofuels from annual crops and residues that are today used in the feed sector should be discouraged, as LUC GHG emissions exceeded any GHG savings from displacing conventional energy sources. PMID- 26938809 TI - Ceria promoted deoxygenation and denitrogenation of Thalassiosira weissflogii and its model compounds by catalytic in-situ pyrolysis. AB - Pyrolysis of microcrystalline cellulose, egg white powder, palm-jojoba oils mixtures Thalassiosira weissflogii model compounds was performed with CeO2 at 500 degrees C, to evaluate its catalytic upgrading mechanism. Light organics, aromatics and aliphatics were originated from carbohydrates, proteins and lipids, respectively. Dehydration and decarboxylation were the main reactions involved in the algae and model compounds deoxygenation, while nitrogen was removed as NH3 and HCN. CeO2 increased decarbonylation reactions compared to in absence of catalyst, with production of ketones. The results showed that the catalysts had a significant effect on the pyrolysis products composition of T. weissflogii. CeO2, NiCeAl2O3 and MgCe/Al2O3 catalysts increased the aliphatics and decreased the oxygen content in bio-oils to 6-7 wt% of the algae starting O2 content. Ceria catalysts were also able to consistently reduce the N-content in the bio-oil to 20-38% of that in the parent material, with NiCe/Al2O3 being the most effective. PMID- 26938810 TI - Fluorinated ethylene-propylene: a complementary alternative to PDMS for nanoimprint stamps. AB - Polydimethylsiloxane (PDMS) is used by many for nanoimprint applications due to its affordability, ease of preparation, mechanical flexibility, compatibility with imprint resists and transparency to UV light. However PDMS is notoriously flexible, tacky and permeable to air. Here fluorinated ethylene-propylene (FEP) is considered as a viable and versatile alternative material for nanoimprint stamps. FEP possesses many of the desirable nanoimprint attributes associated with PDMS but crucially also features a range of complementary characteristics, including an order of magnitude more mechanical strength allowing it to handle higher loads than PDMS, an intrinsically non-stick surface and is compatible with oxygen sensitive resists. Unlike elastomeric polymers, FEP is glassy so patterning may be realised via hot embossing. Not only is this a facile and rapid means of physical structuring but it also facilitates combinatorial patterning, providing a versatility beyond that of traditional casting materials. Due to the intrinsically slow creep of FEP both micro- and nanopatterning are successfully performed sequentially. Feature sizes from 45 nm were successfully realised via the hot-embossing method. To further demonstrate the potential of the material, a modified computer numerical control machine is used. It is capable of photo-, nanoimprint- and laser lithography in conjunction with patterned FEP foils. The tool is used to perform pattern transfer into a developmental nanoimprint resist from Micro Resist Technology, mr-NIL210 XP, and Nano SU-8 3005 negative tone photo resist from MicroChem. Ultimately three-tier lithography is performed in unison and advantageous step-and-repeat performance is achieved with fabricated FEP imprint stamps as they demould more compliantly and resist pressure and contamination better than PDMS. PMID- 26938811 TI - SBP, DBP, and pulse blood pressure variability are temporally associated with the increase in pulse wave velocity in a model of aortic stiffness. AB - BACKGROUND: Enhanced aortic stiffness and blood pressure variability (BPV) are independent risk factors for cardiovascular disease and all-cause mortality in man. They are also correlated with increased blood pressure (BP) and/or arterial remodeling. However, the interplay between BP and BPV on the stiffening process is still unclear. Our objectives were to determine the temporal evolution of both BPV and pulse wave velocity (PWV), a surrogate measure of arterial stiffness, using an animal model of remodeling-dependent aortic stiffening. METHOD: We thus, developed a new telemetric technique allowing continuous measurement of PWV in conscious, unrestrained rats. Studies were performed in spontaneously hypertensive rats (SHR) treated for 2 weeks with N-nitro-L-arginine methyl ester, a nitric oxide synthase inhibitor (SHR-LN). BPV was evaluated conventionally or with a new device composed of two pressure transducers in two different sets of rats. This allowed a continuous monitoring of telemetered PWV, systolic (SPV), diastolic (DPV), and pulse pressure variability (PPV). Aortic structure was then characterized by immunohistochemical analysis. RESULTS: SPV, DPV, and PPV were increased in SHR-LN, when calculated by 24-h SD or using average real variability a parameter used to assess short-term variability in man. We observed rapid and simultaneous increases in BP, SPV, and PWV. Interestingly, PPV was the most increased parameter resulting mainly from different time course of SPV and DPV. Structural alterations of the aortic wall were observed, with a eutrophic inward remodeling and accumulation of fibronectin and its two main receptors (alpha5 and alphav integrins). CONCLUSION: This offers unequivocal evidence of a significant relationship between PWV, BPV, and arterial structure. PMID- 26938813 TI - Risks associated with permanent discontinuation of blood pressure-lowering medications in patients with type 2 diabetes. AB - OBJECTIVE: The associations of discontinuation of the study medication on major outcomes were assessed in the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation Trial. METHODS: ADVANCE was a factorial randomized controlled trial of blood pressure lowering (a fixed combination of perindopril and indapamide vs. placebo) and intensive glucose control (vs. standard glucose control) in patients with type 2 diabetes. Patients who permanently discontinued the randomized blood pressure-lowering medication during the study period (n = 1557) were compared with others (n = 9583). Cox's proportional hazards models were used to estimate the effects of the discontinuation on the risks of macrovascular events, microvascular events together and separately and all-cause mortality, using discontinuation as a time dependent covariate. RESULTS: In multivariable analyses, discontinuation was associated with increased risks of combined macro and microvascular events (hazard ratio 2.24, 95% CI 1.96-2.57), macrovascular events (3.23, 2.75-3.79), microvascular events (1.38, 1.11-1.71), and all-cause mortality (7.99, 6.92-9.21) compared to continuing administration of randomized medications during the trial period, which were highest in the first year after discontinuation. These associations were similar in active and placebo groups, except in the first year after discontinuation during which event rates were lower in the active group than in the placebo group (P <= 0.01). CONCLUSION: Discontinuation of study medication is a potent risk marker for identifying high-risk patients. Thus it is important that clinicians seek to identify such patients early after discontinuation of treatment. Although some short-term residual effects of previous active treatment can be expected, patients who discontinue require further urgent investigation and management. PMID- 26938812 TI - The association between SBP and mortality risk differs with level of cognitive function in very old individuals. AB - OBJECTIVE: Cognitive impairment and dementia are highly prevalent in very old populations. Cardiovascular disease is a common cause of death in people with dementia.This study investigated whether the association of blood pressure (BP) with mortality differed with respect to mini-mental state examination (MMSE) score in a representative sample of very old individuals. METHODS: The sample consisted of 1115 participants aged 85, 90, and at least 95 years from the Umea85+/GErontological Regional DAtabase cohort study. The main outcome was all cause mortality within 2 years according to BP and MMSE score, using Cox proportional-hazard regression models adjusted for sociodemographic and clinical characteristics associated with death. RESULTS: Mean age, MMSE score, and SBP and DBP were 89.4 +/- 4.6 years, 21.1 +/- 7.6, 146.1 +/- 23.4 mmHg, and 74.1 +/- 11.7 mmHg, respectively. Within 2 years, 293 (26%) participants died. BP was not associated independently with mortality risk, except among participants with MMSE scores of 0-10 among whom mortality risk was increased in association with SBP at least 165 mmHg and 125 mmHg or less, compared with 126-139 mmHg (adjusted hazard ratio 4.54, 95% confidence interval = 1.52-13.60 and hazard ratio 2.23, 95% confidence interval = 1.12-4.45, respectively). In age and sex-adjusted analyses, SBP 125 mmHg or less was associated with increased mortality risk in participants with MMSE scores at least 18. CONCLUSION: In people aged at least 85 years, the association of SBP with mortality appears to differ with respect to MMSE score. Very old individuals with very severe cognitive impairment and low or high BP may have increased mortality risk. PMID- 26938814 TI - Effectiveness of chlorthalidone/amiloride versus losartan in patients with stage I hypertension: results from the PREVER-treatment randomized trial. AB - OBJECTIVES: To compare the blood pressure (BP)-lowering efficacy of a chlorthalidone/amiloride combination pill with losartan, during initial management of stage I hypertension. METHODS: In a randomized, double-blind, controlled trial, 655 participants were followed for 18 months in 21 Brazilian academic centers. Trial participants were adult volunteers aged 30-70 years with stage I hypertension (BP 140-159 or 90-99 mmHg) following 3 months of a lifestyle intervention. Participants were randomized to 12.5/2.5 mg of chlorthalidone/amiloride (N = 333) or 50 mg of losartan (N = 322). If BP remained uncontrolled after 3 months, study medication dose was doubled, and if uncontrolled after 6 months, amlodipine (5 and 10 mg) and propranolol (40 and 80 mg twice daily) were added as open-label drugs in a progressive fashion. At the end of follow-up, 609 (93%) participants were evaluated. RESULTS: The difference in SBP during 18 months of follow-up was 2.3 (95% confidence interval: 1.2 to 3.3) mmHg favoring chlorthalidone/amiloride. Compared with those randomized to diuretic, more participants allocated to losartan had their initial dose doubled and more of them used add-on antihypertensive medication. Levels of blood glucose, glycosilated hemoglobin, and incidence of diabetes were no different between the two treatment groups. Serum potassium was lower and serum cholesterol was higher in the diuretic arm. Microalbuminuria tended to be higher in patients with diabetes allocated to losartan (28.5 +/- 40.4 versus 16.2 +/- 26.7 mg, P = 0.09). CONCLUSION: Treatment with a combination of chlorthalidone and amiloride compared with losartan yielded a greater reduction in BP. CLINICAL TRIALS REGISTRATION NUMBER: NCT00971165. PMID- 26938815 TI - Treatment of Cognitive Deficits in Alzheimer's disease: A psychopharmacological review. AB - The growing and aging population has contributed to the increased prevalence of Alzheimer's disease (AD) and other types of dementia in the world. AD is a progressive and degenerative brain disease with an onset characterized by episodic memory impairments, although progressive deficits can be observed in several domains including language, executive functions, attention and working memory. The relationship between cognitive impairments and the topography and progression of brain neuropathology is well established. The pathophysiologic mechanisms and processes that underline the course of cognitive and clinical decline have been the theoretical support for the development of pharmacological treatments for AD. Cholinesterase inhibitors (ChEIs) and N-methyl-D-aspartate (NMDA) antagonists are the main drugs used in the management of global cognitive impairment and several studies also explore the effects of both in specific cognitive measures. Recent research trends also examine the effects of combination therapy using both compounds. This review aims to update practical recommendations for the treatment of global cognitive functioning and specific neurocognitive deficits in AD using ChEIs, NMDA antagonists and combination therapy with both drugs. PMID- 26938816 TI - Psychotropic medications in older adults: a review. AB - BACKGROUND: Prevalence of prescribing psychotropic medications, particularly inappropriate prescription, is widespread in older adults, both in nursing home residents as well as community-dwelling older adults. This review describes prevalence and prevention of inappropriate prescribing and risk factors associated with psychotropic medications. METHODS: MEDLINE and GOOGLE SCHOLAR data base were searched for the key words "older adults", "psychotropic drugs", "inappropriate prescribing", "nursing home residents", "community-dwelling older adults". The study was limited to the articles published in English in the period from 2007 to 2014. The list of references includes additional articles that were searched manually. RESULTS: The utilization of different psychotropic medications is prevalent among older adults worldwide, regardless of whether they live in nursing homes or in the community. Among older adults, nursing home residents are the most vulnerable individuals for potentially inappropriate drug prescription. The most common potentially inappropriate prescribed medications in the elderly are benzodiazepines, particularly long-acting, antipsychotics and antidepressants, particularly SSRIs. All classes of listed medications have been associated with different adverse events, particularly falls and falls-related fractures and increased risk for mortality. Many different pharmacological and non-pharmacological interventions, such as monitoring polypharmacy, reviewing medications, spending more time in the institution by a physician, reducing the number of prescribers in the institution as well as greater involvement of geriatricians, general practitioners and pharmacists should be implemented to reduce this health issue. CONCLUSION: The prevalence of prescribing psychotropic medications to older adults is high. Inappropriate prescribing of psychotropic drugs and polypharmacy are present in institutionalized and non-institutionalized older adults and can cause adverse health events, and can significantly reduce the quality of life of these vulnerable groups. Multidisciplinary approach is needed in addressing widespread problem of prevalence of psychotropic medications in older adults. PMID- 26938817 TI - State of the art psychopharmacological treatment options in seasonal affective disorder. AB - Seasonal affective disorder (SAD) is defined as a subtype of mood disorders in DSM 5, and it is characterized by a seasonal onset. SAD is proposed to be related to the seasonal changes in naturally occurring light, and the use of bright light therapy for depressive symptoms has been shown to reduce them in placebo controlled trials. Cognitive behavioral therapy has also been demonstrated to be effective in SAD. This review article aims to focus on the psychopharmacological treatment options for SAD. According to clinical trial results, first line treatment options seem to be sertraline and fluoxetine, and are well tolerated by the patients. There is some evidence that other antidepressants (e.g. bupropion) might be effective as well. Although clinical trials have shown that some of these antidepressants may be of benefit, a recent review has concluded that there is not enough evidence to support the use of any of these agents for the treatment of SAD yet. Moreover, more studies are still needed to evaluate the effectiveness of other treatment options, e.g., propranolol, melatonin, hypericum, etc. In addition to the above proposed treatments, patients with seasonal depressive symptoms should thoroughly be evaluated for any cues of bipolarity, and their treatment should be planned accordingly. PMID- 26938818 TI - The role of dehydroepiandrosterone (DHEA) in schizophrenia. AB - Neurosteroid dehydropiandrosterone (DHEA) and its sulphate (DHEAS) are reported to have modulatory effects on neuronal excitabillity and synaptic plasticity. DHEA and DHEAS are synthesized in central and peripheral nervous system from cholesterol or steroidal precursors imported from peripheral sources. There is accumulating evidence that alterations in DHEA(S) levels may be involved in the pathophysiology of schizophrenia. The possible effects of DHEA(S) as augmentation therapy in schizophrenia, related to psychological and somatic aspects of this disease, are discussed. PMID- 26938819 TI - Satisfaction with life and coping skills in the acute and chronic urticaria. AB - BACKGROUND: The purpose of this study was to examine the differences in satisfaction with life and coping strategies between patients with acute and chronic urticaria. SUBJECTS AND METHODS: Sixty patients with urticaria were divided into 2 groups after 6 weeks of standardized dermatology treatment (33 patients with acute and 27 patients with chronic urticaria). At baseline, all patients answered the following questionnaires: Satisfaction with Life Scale (SWLS), Personal Wellbeing Index (PWI-A), The Multidimensional Coping Inventory (COPE) and General questionnaire (age, gender, education, employment, marital status). After six weeks all the participants were re-tested with 2 questionnaires: SWLS and PWI-A. RESULTS: Six weeks after the initial testing there was a statistically significant difference in satisfaction with life between patients with acute and chronic urticaria. Patients with acute urticaria were more satisfied with their lives than patients with chronic urticaria. Also, there was a statistically significant difference in the use of emotion-focused coping, seeking social support for emotional reasons and seeking social support for instrumental reasons. Patients with acute urticaria used emotion-focused coping and sought social support for emotional and instrumental reasons to a greater degree than patients with chronic urticaria. CONCLUSION: Patients with acute urticaria were more satisfied with their lives than patients with chronic urticaria. Patients with acute urticaria used emotion-focused coping and sought social support for emotional and instrumental reasons to a greater degree than patients with chronic urticaria. PMID- 26938820 TI - Test-retest study of the six-minute walk test in people with bipolar disorder. AB - BACKGROUND: The multidisciplinary care for bipolar disorder is highly fragmented with limited opportunities for prevention and treatment of medical co morbidities. We examined the reliability of the 6-minute walk test (6MWT). Secondary aims were to assess minimal detectable changes (MDC(95)), practice effects and the impact of clinical conditions. SUBJECTS AND METHODS: Two 6MWTs were administered within 3 days to 46 (23?) inpatients with a DSM-V diagnosis of bipolar disorder. Physical complaints before and after the 6MWT were recorded. Patients completed the Quick Inventory of Depressive Symptomatology Self Report (QIDS-SR) and Hypomania Check List-32. RESULTS: Patients walked 594.7+/-121.3 meters and 600.0+/-122.9 meters at the first and second test. The intraclass correlation coefficient was 0.98 (95% confidence interval 0.97-0.99). The MDC(95) was 37.8 meters for men and 52.9 meters for women. No practice effect was detected. Longer illness duration, higher QIDS-SR scores and the presence of feet or ankle static problems or pain were independently related to shorter 6MWT distance accounting for 59.8% of the variance. CONCLUSION: The 6MWT is a clinically feasible tool for evaluating the functional exercise capacity in patients with bipolar disorder. Health care professionals should consider depression and physical pain when developing rehabilitation programmes. PMID- 26938821 TI - Increased calcium-independent lipoprotein phospholipase A2 but not protein S100 in patients with schizophrenia. AB - BACKGROUND: The aim of this paper was to investigate serum concentrations of calcium-independent lipoprotein phospholipase A2 (PLA2) and protein S100 in schizophrenia patients in comparison to healthy controls and correlate them with the clinical severity, duration, and number of schizophrenia relapses. SUBJECTS AND METHODS: This study included 65 schizophrenia patients and 70 controls. Schizophrenia was diagnosed according to DSM-IV-TR criteria. Clinical severity was determined by PANSS. PLA2 and protein S100 concentration were assessed by the enzyme-linked immunosorbent assay (ELISA). RESULTS: PLA2 concentrations were higher in patients with schizophrenia, whereas protein S100 concentrations were not. Higher concentrations of PLA2 were positively correlated with the duration of illness and number of episodes, as determined by multivariate analysis. CONCLUSION: PLA2 might be considered a possible biochemical trait marker for schizophrenia. Further research with larger and more homogeneous clinical samples is required. PMID- 26938822 TI - Association of the glucocorticoid receptor gene polymorphisms and their interaction with stressful life events in Polish adolescent girls with anorexia nervosa. AB - BACKGROUND: Disturbances in stress response mechanisms and hypothalamic-pituitary adrenal axis (HPA) functioning are considered important factors involved in the pathophysiology of anorexia nervosa (AN). Thus, genetic variations in the end effector of HPA - glucocorticoid receptor gene and relationships to stressful life events (SLE) may be connected to a higher risk of illness. The aim of the study was examining the association between glucocorticoid receptor gene (NR3C1) polymorphisms and risk factors among stressful life events in AN patients. SUBJECTS AND METHODS: This study comprised 256 patients with AN and 167 control subjects. The questionnaires examining brief history of the mother's pregnancy and long-acting stress factors, as well as life events checklist to assess stressful life events during the 6 months prior to hospitalization were used. The eight common SNPs (rs6198, rs6191, rs6196, rs258813, rs33388, rs41423247, rs56149945 and rs10052957) of NR3C1 gene were genotyped. RESULTS: The association of five polymorphisms (rs6191, rs258813, rs33388, rs41423247 and rs10052957) and one complex allele (TCAGT) of NR3C1 gene with increased risk of AN were found. However, no significant correlations between early, long-acting and predicting hospitalization SLE and any of the analyzed polymorphisms were observed. CONCLUSIONS: The results confirm that the NR3C1 gene is associated with AN risk regardless of the type of stressful triggering factors. PMID- 26938823 TI - Effects of anti-obsessional treatment on pituitary volumes in obsessive compulsive disorder. AB - BACKGROUND: We aimed to examine the effct of anti-obsessional drugs on pituitary gland volumes in the patients with obsessive-compulsive disorder (OCD). SUBJECTS AND METHODS: A group of patients with OCD and of healthy controls were evaluated by using pituitary gland magnetic resonance imaging (MRI) at baseline and after twelve weeks of treatment with selective serotonin re-uptake inhibitors or clomipramine. RESULTS: Pituitary gland volumes were found to be statistically significantly smaller in the patients with OCD compared to healthy control subjects at the beginning of the study. We found that pituitary volumes significantly increased throughout twelve weeks of treatment. CONCLUSIONS: This study provides an evidence of the effect of anti-obsessional treatment on the volumes of pituitary gland in OCD patients. PMID- 26938824 TI - Changes in trait brainwave power and coherence, state and trait anxiety after three-month transcendental meditation (TM) practice. AB - BACKGROUND: The amount of studies showing different benefits of practicing meditation is growing. EEG brainwave patterns objectively reflect both the cognitive processes and objects of meditation. This study aimed to examine the effects of transcendental meditation (TM) practice on baseline EEG brainwave patterns (outside of meditation) and to examine weather TM reduces state and trait anxiety. SUBJECTS AND METHODS: Standard EEG recordings were conducted on volunteer participants (N=12), all students or younger employed people, before and after a three-month meditation training. Artifact-free 100-second epochs were selected and analyzed by Fast Fourier Transformation (FFT) analysis. Endlers Multidimensional Anxiety Scales (EMAS) were used to assess anxiety levels. Power (MUV(2)) and coherence levels were compared in the alpha, beta, theta and delta frequency band. RESULTS: Changes in EEG patterns after meditation practice were found mostly in the theta band. An interaction effect was found on the left hemisphere (p<0.10). Theta power decreased on the left, but not on the right hemisphere. Increased theta coherence was found overall and in the central, temporal and occipital areas (p<0.10). Decrease in alpha power was found on channels T3 (p<0.10), O1 (p<0.05) and O2 (p<0.10). An interaction effect was found in the delta frequency band (p<0.06), too. A trend for power decreasing was found on the left, and a trend for power increasing on the right hemisphere. Also, power decreased on channel O1 (p<0.10). In the beta frequency band, a decrease was found on channel O2 (p<0.10). Trait anxiety did not differ, but a decrease in state anxiety and cognitive worry was found (p<0.05). CONCLUSIONS: Obtained results confirm the effects of TM on some baseline EEG brainwave patterns and state anxiety, suggesting that the left hemisphere is more sensitive to meditation practice. Most of the changes were found in the occipital and temporal areas, less in the central and frontal areas. State anxiety decreased after TM practice. Findings suggest TM practice could be helpful in treating different kinds of disorders, especially anxiety disorders. PMID- 26938825 TI - Myofascial pain of the head and neck among Croatian war veterans treated for depression and posttraumatic stress disorder. AB - BACKGROUND: During the Croatian War of Independence, 1991-1995, Croatian soldiers were exposed to traumatic and stressful events. Certain number of soldiers who took part in the war, developed depression and posttraumatic stress disorder (PTSD). Stress is one of the etiological factors in the development of myofascial pain (MPS), although the mechanism of these processes is not entirely understood. The aims of this study were to determine the frequency of myofascial pain among Croatian war veterans with depression and PTSD, association between MPS and severity of depression, to describe the most common locations of trigger points in the region of head and neck, and to find out if there is any association in frequency between MPS and endotracheal intubation. SUBJECTS AND METHODS: A total of 101 Croatian war veterans suffering from PTSD and depression participated in the current study. Diagnosis of myofascial pain was based on detailed anamnestic history and careful clinical examination. RESULTS: Our findings showed a high rate of myofascial pain among Croatian war veterans, with occipital region and right temporal region as the most common places of trigger points. Higher severity of depression was accompanied by a higher percentage of subjects with MPS. Finally, there was no significant association between endotracheal intubation and development of MPS among the war veterans. CONCLUSIONS: It can be concluded that the rate of myofascial pain among Croatian war veterans is high and therefore it must be considered in patients with depression and PTSD. Moreover, the severity of depressive symptomatology seems to be related to the presence of myofascial pain. PMID- 26938826 TI - Personal space of war veterans with PTSD - some characteristics and comparison with healthy individuals. AB - BACKGROUND: The aim of this study was to determine the size of personal space among war veterans with PTSD, compared to healthy individuals, and to examine its associations with some sociodemographic and clinical characteristics. SUBJECTS AND METHODS: Participants were 83 male war veterans with chronic PTSD and 85 healthy male employees of the medical institutions. Preferred interpersonal distances were assessed by using a stop-distance technique, where male and female research assistants approached the participants from four directions (front, behind, left, right). The patients filled out The Mississippi Scale for Combat Related Posttraumatic Stress Disorder (M-PTSD). RESULTS: War veterans with PTSD preferred significantly larger interpersonal distances compared to healthy participants. Larger personal space size was preferred by those who had children, and the largest preferred distances were observed for the approaches from behind. Both samples preferred larger distances when approached by a male person. CONCLUSION: The findings of this study contribute to increased understanding of the personal space in patients with PTSD, and may be implemented into prevention of aggressive behavior during psychiatric treatment, and into development of more effective therapeutic strategies. PMID- 26938827 TI - Word Use and Content Analysis of the First Verses of Six National Anthems: A Transcultural Aspect of Suicidal Behaviour. AB - BACKGROUND: Suicide is a major health concern worldwide, although suicide rates widely differ among different countries and cultures. Transcultural studies suggest that national anthems reflect national attitudes towards self-harming behaviour as well. Our aim was to analyse the linguistic characteristics of six national anthems, and compare these results with national suicide rates. METHODS: Word use assessment and content analysis of six national anthems were performed. RESULTS: In the anthems of countries with similar historical or cultural background, similar linguistic patterns were found in word use and in content. Anthems of countries with lower suicide rates tend to contain relatively more positive contents, emotions and intentions, while in the anthems of countries with higher suicide rates more ambivalence, denial, loss or even aggressive and self-destructive implications were found. CONCLUSION: This transcultural analysis strengthens previous data that anthems could be indicators for national attitudes toward self-harm. PMID- 26938828 TI - Cigarette smoking has no pro-cognitive effect in subjects with obsessive compulsive disorder: A preliminary study. AB - BACKGROUND: The prevalence of cigarette smoking in patients with different psychiatric disorders is higher than that in the general population, which is partly explained by the pro-cognitive effect of smoking on cognitive functions. In subjects with obsessive-compulsive disorder (OCD), the prevalence of smokers is lower than that in other psychiatric disorders. We hypothesized that cigarette smoking does not provide benefits and even worsen cognitive performance in OCD. SUBJECTS AND METHODS: We compared different executive function subdomains in 20 smoking and 20 non-smoking inpatients with OCD. At the beginning of hospitalization, we assessed visuo-spatial working memory, planning and set shifting abilities (Cambridge Neuropsychological Test Automated Battery), smoking habits (standardized personal interviews), and the severity of obsessive compulsive symptoms (Dimensional Yale-Brown Obsessive-Compulsive Scale). RESULTS: The performance of smokers and non-smokers did not differ significantly in any cognitive subdomain. The smoking duration was significantly associated with poorer visuo-spatial working memory performance (P=0.001). CONCLUSIONS: Our results showed that cigarette smoking did not provide cognitive enhancement across various executive function subdomains in subjects with OCD. The lack of beneficial cognitive effects of smoking may make these subjects less prone to smoking and may partially explain the lower rate of smokers in OCD compared with other psychiatric conditions. PMID- 26938829 TI - Effectiveness of switching from oral ziprasidone to risperidone in a patient with comorbid autistic disorder, profound intellectual disability, Gilbert syndrome, and exacerbation of psychosis. PMID- 26938830 TI - The 26th Danube Symposium of Psychiatry: Psychiatry - ready for the future? PMID- 26938831 TI - Possible Airborne Person-to-Person Transmission of Mycobacterium bovis - Nebraska 2014-2015. AB - Mycobacterium bovis, one of several mycobacteria of the M. tuberculosis complex, is a global zoonotic pathogen that primarily infects cattle. Humans become infected by consuming unpasteurized dairy products from infected cows; possible person-to-person airborne transmission has also been reported. In April 2014, a man in Nebraska who was born in Mexico was determined to have extensive pulmonary tuberculosis (TB) caused by M. bovis after experiencing approximately 3 months of cough and fever. Four months later, a U.S.-born Hispanic girl from a nearby town who had been ill for 4-5 months was also determined to have pulmonary TB caused by M. bovis. The only social connection between the two patients was attendance at the same church, and no common dietary exposure was identified. Both patients had pulmonary cavities on radiography and acid-fast bacilli (AFB) on sputum-smear microscopy, indicators of being contagious. Whole-genome sequencing results of the isolates were nearly indistinguishable. Initial examination of 181 contacts determined that 39 (22%) had latent infection: 10 (42%) of 24 who had close exposure to either patient, 28 (28%) of 100 who were exposed to one or both patients in church, and one (2%) of 57 exposed to the second patient at a school. Latent infection was diagnosed in six contacts on follow-up examination, 2 months after an initial negative test result, for an overall latent infection rate of 25%. No infected contacts recalled consuming unpasteurized dairy products, and none had active TB disease at the initial or secondary examination. Persons who have M. bovis TB should be asked about consumption of unpasteurized dairy products, and contact investigations should follow the same guidance as for M. tuberculosis TB. PMID- 26938832 TI - Sources of organic matter (PAHs and n-alkanes) in PM2.5 of Beijing in haze weather analyzed by combining the C-N isotopic and PCA-MLR analyses. AB - Organic molecular composition and carbon and nitrogen isotope ratios of PM2.5 samples collected in November 2013 were analyzed using gas chromatography/mass spectrometry and isotope ratio mass spectrometry. The samples represented six potential sources and seven sampling sites situated in concentric zones around Beijing under both haze and non-haze conditions. Our results showed that the average concentrations of polycyclic aromatic hydrocarbons (PAHs) and n-alkanes were 258.2 +/- 208.8 ng m(-3) and 499.5 +/- 347.8 ng m(-3), while the delta(13)C and delta(15)N values for PM2.5 varied from -26.29 to -25.260/00 and from 8.68 to 14.500/00 with an average of -25.70 +/- 0.30/00 and 11.97 +/- 1.790/00, respectively. The highest concentrations of PAHs and n-alkanes were recorded in the sixth ring road, with the lowest ones in the third ring road. Concentrations of PAHs during haze were higher than during non-haze conditions, while concentrations of n-alkanes were not markedly different. Principal component analysis/multiple linear regression analyses indicated that the main sources of PAHs were vehicle and coal combustion emissions, while n-alkanes had high contributions from petroleum emissions. These sources were supported by isotopic analyses. Thus, the main sources of organic matter contributing to haze in Beijing were coal combustion and vehicle emissions. Such results provide guidance towards managing haze in Beijing. PMID- 26938833 TI - Antibacterial Peptide Nucleic Acid-Antimicrobial Peptide (PNA-AMP) Conjugates: Antisense Targeting of Fatty Acid Biosynthesis. AB - Antisense peptide nucleic acid (PNA) oligomers constitute a novel class of potential antibiotics that inhibit bacterial growth via specific knockdown of essential gene expression. However, discovery of efficient, nontoxic delivery vehicles for such PNA oligomers has remained a challenge. In the present study we show that antimicrobial peptides (AMPs) with an intracellular mode of action can be efficient vehicles for bacterial delivery of an antibacterial PNA targeting the essential acpP gene. The results demonstrate that buforin 2-A (BF2-A), drosocin, oncocin 10, Pep-1-K, KLW-9,13-a, (P59->W59)-Tat48-60, BF-2A-RXR, and drosocin-RXR are capable of transporting PNA effectively into E. coli (MICs of 1 4 MUM). Importantly, presence of the inner-membrane peptide transporter SbmA was not required for antibacterial activity of PNA-AMP conjugates containing Pep-1-K, KLW-9,13-a, or drosocin-RXR (MICs of 2-4 MUM). PMID- 26938834 TI - Base-Catalyzed Asymmetric alpha-Functionalization of 2-(Cyanomethyl)azaarene N Oxides Leading to Quaternary Stereocenters. AB - A simple, new strategy for the direct asymmetric alpha-functionalization of 2 alkyl azaarenes is described. Specifically, a Bronsted base catalyzed conjugate addition of substituted 2-cyanomethylpyridine (and pyrazine) N-oxides to acrylate equivalents to afford hitherto elusive 2-tert-alkyl azaaryl adducts with high enantioselectivity (up to 94% ee) is realized. Extension of the method to the alpha-amination reaction by using azodicarboxylate esters as electrophiles is also demonstrated. Key for success is the N-oxide functionality of substrates that acts as a removable activating and stereodirecting group. A bifunctional Bronsted base catalyst bearing a squaramide with an attached bulky silyl group is also disclosed. PMID- 26938835 TI - OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY FEATURES OF BRANCH RETINAL VEIN OCCLUSION. AB - PURPOSE: Optical coherence tomography angiography (OCTA) is a novel technology that uses motion contrast instead of dye to generate angiographic images. Using several modalities of OCTA, the authors describe and compare changes observed in branch retinal vein occlusion. METHODS: A case series of three patients with OCTA imaging. RESULTS: Despite presenting at different time frames, the authors found common imaging findings consisting of vascular hypoperfusion, increased tortuosity, and telangiectasia in all their cases. Furthermore, macular edema and intraretinal fluid were noted on the en-face angiograms. The extent of vascular and structural alterations could clearly be delineated in superficial and deep retinal networks. However, fine capillary alterations were better appreciated on smaller-size scans. CONCLUSION: With the ability to noninvasively visualize vascular flow, OCTA could serve as a new diagnostic tool for current ophthalmic research and clinical practice. Such findings can help supplement other imaging modalities in establishing a diagnosis and monitoring disease progression over time. This would potentially be useful in regard to ischemic processes such as branch retinal vein occlusion and diseases affecting different layers of the retinal vasculature. PMID- 26938836 TI - NOVEL RETINAL COMPLICATIONS AFTER ENDOSCOPIC SINUS SURGERY. AB - PURPOSE: To report a novel intraocular complication of endoscopic sinus surgery. METHODS: Retrospective case report. RESULTS: A 44-year-old otherwise-healthy man underwent endoscopic right ethmoid sinus surgery and immediately developed loss of vision in his right eye. Postoperatively, patient had ipsilateral light perception vision, proptosis, periorbital ecchymosis, and large angle exotropia with virtually no adduction. Orbital computed tomography confirmed violation of the right medial rectus muscle and optic nerve. Dilated fundus examination showed a macular fold with edema and hemorrhages, blockage on angiography of the macula, and subretinal hyperfluorescence in the periphery. After 6 months of observation, his central vision had improved to 20/300 with macular atrophy and choroidal atrophy in the periphery. CONCLUSION: Macular edema, nonperfusion and ischemia, choroidal nonperfusion (Amalric sign), and atrophy can be iatrogenic sequelae of endoscopic ethmoid sinus surgery. PMID- 26938837 TI - Automated Prediction of Catalytic Mechanism and Rate Law Using Graph-Based Reaction Path Sampling. AB - In a recent article [ J. Chem. Phys. 2015 , 143 , 094106 ], we introduced a novel graph-based sampling scheme which can be used to generate chemical reaction paths in many-atom systems in an efficient and highly automated manner. The main goal of this work is to demonstrate how this approach, when combined with direct kinetic modeling, can be used to determine the mechanism and phenomenological rate law of a complex catalytic cycle, namely cobalt-catalyzed hydroformylation of ethene. Our graph-based sampling scheme generates 31 unique chemical products and 32 unique chemical reaction pathways; these sampled structures and reaction paths enable automated construction of a kinetic network model of the catalytic system when combined with density functional theory (DFT) calculations of free energies and resultant transition-state theory rate constants. Direct simulations of this kinetic network across a range of initial reactant concentrations enables determination of both the reaction mechanism and the associated rate law in an automated fashion, without the need for either presupposing a mechanism or making steady-state approximations in kinetic analysis. Most importantly, we find that the reaction mechanism which emerges from these simulations is exactly that originally proposed by Heck and Breslow; furthermore, the simulated rate law is also consistent with previous experimental and computational studies, exhibiting a complex dependence on carbon monoxide pressure. While the inherent errors of using DFT simulations to model chemical reactivity limit the quantitative accuracy of our calculated rates, this work confirms that our automated simulation strategy enables direct analysis of catalytic mechanisms from first principles. PMID- 26938838 TI - Luminescent Iridium(III) Cyclometalated Complexes with 1,2,3-Triazole "Click" Ligands. AB - A series of cyclometalated iridium(III) complexes with either 4-(2-pyridyl)-1,2,3 triazole or 1-(2-picolyl)-1,2,3-triazole ancillary ligands to give complexes with either 5- or 6-membered chelate rings were synthesized and characterized by a combination of X-ray crystallography, electron spin ionization-high-resolution mass spectroscopy (ESI-HRMS), and nuclear magnetic resonance (NMR) spectroscopy. The electronic properties of the complexes were probed using absorption and emission spectroscopy, as well as cyclic voltammetry. The relative stability of the complexes formed from each ligand class was measured, and their excited-state properties were compared. The emissive properties are, with the exception of complexes that contain a nitroaromatic substituent, insensitive to functionalization of the ancillary pyridyl-1,2,3-triazole ligand but tuning of the emission maxima was possible by modification of the cyclometalating ligands. It is possible to prepare a wide range of optimally substituted pyridyl-1,2,3 triazoles using copper Cu(I)-catalyzed azide alkyne cycloaddition, which is a commonly used "click" reaction, and this family of ligands represent an useful alternative to bipyridine ligands for the preparation of luminescent iridium(III) complexes. PMID- 26938847 TI - The Teacher. PMID- 26938845 TI - Antagonistic Growth Effects of Mercury and Selenium in Caenorhabditis elegans Are Chemical-Species-Dependent and Do Not Depend on Internal Hg/Se Ratios. AB - The relationship between mercury (Hg) and selenium (Se) toxicity is complex, with coexposure reported to reduce, increase, and have no effect on toxicity. Different interactions may be related to chemical compound, but this has not been systematically examined. Our goal was to assess the interactive effects between the two elements on growth in the nematode Caenorhabditis elegans, focusing on inorganic and organic Hg (HgCl2 and MeHgCl) and Se (selenomethionine, sodium selenite, and sodium selenate) compounds. We utilized aqueous Hg/Se dosing molar ratios that were either above, below, or equal to 1 and measured the internal nematode total Hg and Se concentrations for the highest concentrations of each Se compound. Observed interactions were complicated, differed between Se and Hg compounds, and included greater-than-additive, additive, and less-than-additive growth impacts. Biologically significant interactions were only observed when the dosing Se solution concentration was 100-25,000 times greater than the dosing Hg concentration. Mitigation of growth impacts was not predictable on the basis of internal Hg/Se molar ratio; improved growth was observed at some internal Hg/Se molar ratios both above and below 1. These findings suggest that future assessments of the Hg and Se relationship should incorporate chemical compound into the evaluation. PMID- 26938846 TI - The effects of frequency lowering on speech perception in noise with adult hearing-aid users. AB - OBJECTIVE: Frequency lowering (FL) strategies move high frequency sound into a lower frequency range. This study determined if speech perception differences are observed between some of the different frequency lowering strategies that are available. DESIGN: A cross-sectional, repeated-measures design was used to compare three hearing aids that used wide-dynamic range compression (WDRC) and either non-linear frequency compression (NFC), linear frequency transposition (LFT), or frequency translation (FT). The hearing aids were matched to prescriptive real ear targets for WDRC. The settings for each FL strategy were adjusted to provide audibility for a 6300 Hz filtered speech signal. Sentence recognition in noise, subjective measures of sound quality, and a modified version of the speech intelligibility index (SII) were measured. STUDY SAMPLE: Ten adults between the ages of 63 to 82 years with bilateral, high frequency hearing loss. RESULTS: LFT and FT led to poorer sentence recognition compared to WDRC for most individuals. No difference in sentence recognition occurred with and without NFC. The quality questionnaire and SII showed few differences between conditions. CONCLUSION: Under similar fitting and testing conditions of this study, FL techniques may not provide speech understanding benefit in certain background noise situations. PMID- 26938848 TI - Achieving 100% Efficient Postcolumn Hydride Generation for As Speciation Analysis by Atomic Fluorescence Spectrometry. AB - An experimental setup consisting of a flow injection hydride generator coupled to an atomic fluorescence spectrometer was optimized in order to generate arsanes from tri- and pentavalent inorganic arsenic species (iAs(III), iAs(V)), monomethylarsonic acid (MAs(V)), and dimethylarsinic acid (DMAs(V)) with 100% efficiency with the use of only HCl and NaBH4 as the reagents. The optimal concentration of HCl was 2 mol L(-1); the optimal concentration of NaBH4 was 2.5% (m/v), and the volume of the reaction coil was 8.9 mL. To prevent excessive signal noise due to fluctuations of hydride supply to an atomizer, a new design of a gas-liquid separator was implemented. The optimized experimental setup was subsequently interfaced to HPLC and employed for speciation analysis of arsenic. Two chromatography columns were tested: (i) ion-pair chromatography and (ii) ion exchange chromatography. The latter offered much better results for human urine samples without a need for sample dilution. Due to the equal hydride generation efficiency (and thus the sensitivities) of all As species, a single species standardization by DMAs(V) standard was feasible. The limits of detection for iAs(III), iAs(V), MAs(V), and DMAs(V) were 40, 97, 57, and 55 pg mL(-1), respectively. Accuracy of the method was tested by the analysis of the standard reference material (human urine NIST 2669), and the method was also verified by the comparative analyses of human urine samples collected from five individuals with an independent reference method. PMID- 26938849 TI - Mortality during the 2013 heatwave in England--How did it compare to previous heatwaves? A retrospective observational study. AB - Heatwaves are predicted to increase in frequency and intensity as a result of climate change. The health impacts of these events can be significant, particularly for vulnerable populations when mortality can occur. England experienced a prolonged heatwave in summer 2013. Daily age-group and region specific all-cause excess mortality during summer 2013 and previous heatwave periods back to 2003 was determined using the same linear regression model and heatwave definition to estimate impact and place observations from 2013 in context. Predicted excess mortality due to heat during this period was also independently estimated. Despite a sustained heatwave in England in 2013, the impact on mortality was considerably less than expected; a small cumulative excess of 195 deaths (95% confidence interval -87 to 477) in 65+ year olds and 106 deaths (95% CI -22 to 234) in <65 year olds was seen, nearly a fifth of excess deaths predicted based on observed temperatures. This impact was also less than seen in 2006 (2323 deaths) and 2003 (2234 deaths), despite a similarly prolonged period of high temperatures. The reasons for this are unclear and further work needs to be done to understand this and further clarify the predicted impact of increases in temperature. PMID- 26938853 TI - Investigational drugs for fracture healing: preclinical & clinical data. AB - INTRODUCTION: The need for fracture healing enhancement for the management of fracture complications such as non-union and for the achievement of early function in fracture patients is constantly increasing. Therefore, the development and evaluation of novel pharmaceutical agents is mandatory in order to accelerate the process and increase bone union rates. AREAS COVERED: This review summarizes the most recent knowledge on the pharmacological enhancement of fracture repair. It provides a synopsis of the most important preclinical and clinical studies published over the past five years on long bone fracture healing. EXPERT OPINION: To date, limited drugs seem to have the potential for clinical use in fracture healing enhancement and the field is progressing very slowly. Among anti-osteoporotic drugs, only PTH and anti-sclerostin antibodies have such a potential but further research is needed before clinical use. The same applies also to BMPs, the use of which still carries major drawbacks that should be overcome before their widespread clinical utilization. Other drugs and growth factors, such as statins, VEGF, FGF, EPO, could be future key players in fracture healing but evidence is still lacking. Further in depth understanding of the healing process is essential in order to identify novel effective pharmacological agents. PMID- 26938855 TI - Feasibility, Safety and Long-Term Follow-Up of Transcatheter Closure of Secundum Atrial Septal Defects with Deficient Rims. AB - OBJECTIVE: The aim of this work was to evaluate the feasibility and safety of transcatheter closure procedures for the treatment of atrial septal defects (ASDs) with insufficient rims. METHODS: A total of 507 secondary ASDs were divided into two groups based on whether they had deficient rims or not (152 vs. 355 cases, respectively). Any complications, including residual shunt, heart arrhythmia, occluder translocation, etc., were followed up for 1-3 years. RESULTS: There were no differences in gender, weight, exposure time, ECG states, pulmonary pressure, the intervention success rate, occurrence of residual shunt, the operation time and occurrence of residual shunt during follow-up between the two groups (p > 0.05). However, the occurrence of rhythm disorders was significantly different between the two groups; ASDs with deficient rims were at an elevated risk (p < 0.05). Specifically, there was a significantly higher incidence in the occurrence of arrhythmia in the deficient rims group at 24 h postoperation, but no differences in arrhythmia incidence at any of the other follow-up time points (1, 3, 6, 12 and 36 months; p > 0.05). CONCLUSIONS: Patients with deficient rims experience a high success rate of ASD intervention and low rate of complications when the procedures are performed by experienced operators. PMID- 26938857 TI - Successful management of grade III coronary perforation after percutaneous angioplasty in a high-risk patient: a case report. AB - Coronary perforation is a rare complication in patients undergoing percutaneous coronary angioplasty. The mortality of this complication varies depending on factors related to the patient and the procedure performed, reaching 44% in patients with Ellis type III perforation. We report the case of an 81 year old male with multiple cardiovascular risk factors, who underwent percutaneous angioplasty for unstable angina management. The patient developed grade III coronary perforation in the anterior descending artery, which was successfully managed with balloon inflation to 6 atmospheres for 10 minutes twice in the affected area, with an interval of 5 minutes between each dilatation. The patient improved and was discharged. PMID- 26938856 TI - Liposome Delivery Systems for Inhalation: A Critical Review Highlighting Formulation Issues and Anticancer Applications. AB - This is a critical review on research conducted in the field of pulmonary delivery of liposomes. Issues relating to the mechanism of nebulisation and liposome composition were appraised and correlated with literature reports of liposome formulations used in clinical trials to understand the role of liposome size and composition on therapeutic outcome. A major highlight was liposome inhalation for the treatment of lung cancers. Many in vivo studies that explored the potential of liposomes as anticancer carrier systems were evaluated, including animal studies and clinical trials. Liposomes can entrap anticancer drugs and localise their action in the lung following pulmonary delivery. The safety of inhaled liposomes incorporating anticancer drugs depends on the anticancer agent used and the amount of drug delivered to the target cancer in the lung. The difficulty of efficient targeting of liposomal anticancer aerosols to the cancerous tissues within the lung may result in low doses reaching the target site. Overall, following the success of liposomes as inhalable carriers in the treatment of lung infections, it is expected that more focus from research and development will be given to designing inhalable liposome carriers for the treatment of other lung diseases, including pulmonary cancers. The successful development of anticancer liposomes for inhalation may depend on the future development of effective aerosolisation devices and better targeted liposomes to maximise the benefit of therapy and reduce the potential for local and systemic adverse effects. PMID- 26938858 TI - Function of Deubiquitinating Enzyme USP14 as Oncogene in Different Types of Cancer. AB - BACKGROUND/AIMS: Non-small cell lung cancer (NSCLC) tissues overexpress USP14, which promotes tumor cell proliferation and is associated with shorter overall survival time. METHODS: The expression of USP14 was assayed in many types of cancers. USP14 was up-and down-regulated using appropriate plasmid or lentiviral vector constructs and its effects on proliferation, cell colony number, and apoptosis rate were measured. A human NSCLC cell line was inoculated into nude mice and the survival rates were recorded. RESULTS: We found USP14 amplification and overexpression in many different cancers. The overexpression of USP14 in USP14 low-expression cell lines promoted cell proliferation and migration, whereas USP14 downregulation suppressed tumor cell proliferation, decreased tumor cell colony number, increased apoptosis rate, and decreased cell migration and invasion. CONCLUSION: USP14 plays an oncogenic role in various types of cancer, and may thus represent a new cancer therapy target. PMID- 26938859 TI - Ullmann Reaction of Aryl Chlorides on Various Surfaces and the Application in Stepwise Growth of 2D Covalent Organic Frameworks. AB - On-surface Ullmann coupling reaction of aryl chlorides has been achieved on Cu(111), Ag(111), and Au(111), and the mechanism has been investigated on the single molecule level using scanning tunneling microscopy and density functional theory. The different reactivity of the aryl halides was utilized to design a stepwise on-surface synthesis, which affords a zigzag template and then converts to 2D porous networks. PMID- 26938860 TI - The frequency of hematuria in acne vulgaris patients during isotretinoin treatment. AB - BACKGROUND: Systemic isotretinoin (13-cis-retinoic acid) is effective in the treatment of acne vulgaris. The most common side effects are mucocutaneous ones. Hematuria seen secondary to isotretinoin treatment is thought to be due to mucosal dryness in the urinary system. This study aims to determine the frequency of hematuria in acne vulgaris patients during isotretinoin treatment. MATERIALS AND METHOD: Eighty-eight subjects aged 16-32 years were included in the study group and 52 subjects were in the control group. The subjects were treated for 6 months and were monitored monthly by complete urine analyzes. They were also examined each month in terms of cheilitis, xerosis, epistaxis, rectal bleeding, fatigue, myalgia, weight loss, dry eye, conjunctivitis, headache, dysuria and pollakiuria. RESULTS: In the study group, 15 subjects (17%) had hematuria at least once during the study, and in the control group, four subjects (7.7%) had hematuria. The difference was not statistically significant (p = 0.118). Among the subjects who had hematuria, 11 of them (73.3%) were female and four of them (33.3%) were male in the study group while all the subjects with hematuria in the control group were female. Hematuria and gender did not show a statistically significant correlation. CONCLUSION: Hematuria was observed in 17% of the study group; this frequency rate was not different from that of the normal population. In subjects having isotretinoin treatment, if all the other reasons or disorders are excluded, one must keep in mind that hematuria may be due to isotretinoin use. PMID- 26938861 TI - Evolutionary and Functional Relationships of the dha Regulon by Genomic Context Analysis. AB - 3-hydroxypropionaldehyde (3-HPA) and 1,3-propanediol (1,3-PD) are subproducts of glycerol degradation and of economical interest as they are used for polymers synthesis, such as polyesters and polyurethanes. Some few characterized bacterial species (mostly from Firmicutes and Gamma-proteobacteria groups) are able to catabolize these monomers from glycerol using the gene products from the dha regulon. To expand our knowledge and direct further experimental studies on the regulon and related genes for the anaerobic glycerol metabolism, an extensive genomic screening was performed to identify the presence of the dha genes in fully sequenced prokaryotic genomes. Interestingly, this work shows that although only few bacteria species are known to produce 3-HPA or 1,3-PD, the incomplete regulon is found in more than 100 prokaryotic genomes. However, the complete pathway is found only in a few dozen species belonging to five different taxonomic groups, including one Archaea species, Halalkalicoccus jeotgali. Phylogenetic analysis and conservation of both gene synteny and primary sequence similarity reinforce the idea that these genes have a common origin and were possibly acquired by lateral gene transfer (LGT). Besides the evolutionary aspect, the identification of homologs from several different organisms may predict potential alternative targets for faster or more efficient biological synthesis of 3-HPA or 1,3-PD. PMID- 26938862 TI - Blood Exosomes Endowed with Magnetic and Targeting Properties for Cancer Therapy. AB - Exosomes are a class of naturally occurring nanoparticles that are secreted endogenously by mammalian cells. Clinical applications for exosomes remain a challenge because of their unsuitable donors, low scalability, and insufficient targeting ability. In this study, we developed a dual-functional exosome-based superparamagnetic nanoparticle cluster as a targeted drug delivery vehicle for cancer therapy. The resulting exosome-based drug delivery vehicle exhibits superparamagnetic behavior at room temperature, with a stronger response to an external magnetic field than individual superparamagnetic nanoparticles. These properties enable exosomes to be separated from the blood and to target diseased cells. In vivo studies using murine hepatoma 22 subcutaneous cancer cells showed that drug-loaded exosome-based vehicle delivery enhanced cancer targeting under an external magnetic field and suppressed tumor growth. Our developments overcome major barriers to the utility of exosomes for cancer application. PMID- 26938864 TI - Transanal submucosal endoscopic resection (TASER) by TEO system(r). AB - Given the higher incidence of non-invasive colorectal tumors due to the further implementation of screening techniques, multiple endoscopic techniques have emerged for its resection. Recently described, transanal submucosal endoscopic resection (TASER) pools the concepts of endoscopic resection with the transanal surgery. We report our initial experience and reflections on this new technique. PMID- 26938863 TI - The Full Spectrum of Clinical Ethical Issues in Kidney Failure. Findings of a Systematic Qualitative Review. AB - BACKGROUND: When treating patients with kidney failure, unavoidable ethical issues often arise. Current clinical practice guidelines some of them, but lack comprehensive information about the full range of relevant ethical issues in kidney failure. A systematic literature review of such ethical issues supports medical professionalism in nephrology, and offers a solid evidential base for efforts that aim to improve ethical conduct in health care. AIM: To identify the full spectrum of clinical ethical issues that can arise for patients with kidney failure in a systematic and transparent manner. METHOD: A systematic review in Medline (publications in English or German between 2000 and 2014) and Google Books (with no restrictions) was conducted. Ethical issues were identified by qualitative text analysis and normative analysis. RESULTS: The literature review retrieved 106 references that together mentioned 27 ethical issues in clinical care of kidney failure. This set of ethical issues was structured into a matrix consisting of seven major categories and further first and second-order categories. CONCLUSIONS: The systematically-derived matrix helps raise awareness and understanding of the complexity of ethical issues in kidney failure. It can be used to identify ethical issues that should be addressed in specific training programs for clinicians, clinical practice guidelines, or other types of policies dealing with kidney failure. PMID- 26938865 TI - How Might People Near National Roads Be Affected by Traffic Noise as Electric Vehicles Increase in Number? A Laboratory Study of Subjective Evaluations of Environmental Noise. AB - We face a likely shift to electric vehicles (EVs) but the environmental and human consequences of this are not yet well understood. Simulated auditory traffic scenes were synthesized from recordings of real conventional and EVs. These sounded similar to what might be heard by a person near a major national road. Versions of the simulation had 0%, 20%, 40%, 60%, 80% and 100% EVs. Participants heard the auditory scenes in random order, rating each on five perceptual dimensions such as pleasant-unpleasant and relaxing-stressful. Ratings of traffic noise were, overall, towards the negative end of these scales, but improved significantly when there were high proportions of EVs in the traffic mix, particularly when there were 80% or 100% EVs. This suggests a shift towards a high proportion of EVs is likely to improve the subjective experiences of people exposed to traffic noise from major roads. The effects were not a simple result of EVs being quieter: ratings of bandpass-filtered versions of the recordings suggested that people's perceptions of traffic noise were specifically influenced by energy in the 500-2000 Hz band. Engineering countermeasures to reduce noise in this band might be effective for improving the subjective experience of people living or working near major roads, even for conventional vehicles; energy in the 0-100 Hz band was particularly associated with people identifying sound as 'quiet' and, again, this might feed into engineering to reduce the impact of traffic noise on people. PMID- 26938866 TI - City Level of Income and Urbanization and Availability of Food Stores and Food Service Places in China. AB - OBJECTIVE: The contribution of unhealthy dietary patterns to the epidemic of obesity has been well recognized. Differences in availability of foods may have an important influence on individual eating behaviors and health disparities. This study examined the availability of food stores and food service places by city characteristics on city level of income and urbanization. METHODS: The cross sectional survey was comprised of two parts: (1) an on-site observation to measure availability of food stores and food service places in 12 cities of China; (2) an in-store survey to determine the presence of fresh/frozen vegetables or fruits in all food stores. Trained investigators walked all the streets/roads within study tracts to identify all the food outlets. An observational survey questionnaire was used in all food stores to determine the presence of fresh/frozen vegetables or fruits. Urbanization index was determined for each city using a principal components factor analysis. City level of income and urbanization and numbers of each type of food stores and food service places were examined using negative binomial regression models. RESULTS: Large-sized supermarkets and specialty retailers had higher number of fresh/frozen vegetables or fruits sold compared to small/medium-sized markets. High-income versus low income, high urbanized versus low urbanized areas had significantly more large sized supermarkets and fewer small/medium-sized markets. In terms of restaurants, high urbanized cities had more western fast food restaurants and no statistically significant difference in the relative availability of any type of restaurants was found between high- and low-income areas. CONCLUSIONS: The findings suggested food environment disparities did exist in different cities of China. PMID- 26938867 TI - EXAFS Study of Sr sorption to Illite, Goethite, Chlorite, and Mixed Sediment under Hyperalkaline Conditions. AB - Strontium is an important contaminant radionuclide at many former nuclear sites. This paper investigates the effect of changing pH and ionic strength on the sorption of Sr to a range of common soil minerals. Specifically it focuses on the sorption of Sr onto illite, chlorite, goethite, and a mixed sediment. The interplay between ionic strength and pH was determined by varying the background ionic strength of the system using both NaCl (for a constant pH) and NaOH (to also vary pH). Under conditions of moderate pH, Sr sorption decreased with increasing ionic strength, due to competition between the Na and Sr atoms for the outer-sphere complexes. However, where increasing ionic strength was accompanied by increasing pH, Sr sorption remained high. This suggested that Sr was sorbed to the minerals without competition from background Na ions. Extended X-ray absorption fine structure (EXAFS) spectra confirmed that at highly alkaline pH (>12.5) Sr was forming inner-sphere complexes on the surfaces of all minerals. This specific adsorption of the Sr (as SrOH(+)) explains why it was still adsorbed to the minerals under very high ionic strength conditions and was not out-competed by Na. PMID- 26938868 TI - Differential Susceptibilities of Aedes aegypti and Aedes albopictus from the Americas to Zika Virus. AB - BACKGROUND: Since the major outbreak in 2007 in the Yap Island, Zika virus (ZIKV) causing dengue-like syndromes has affected multiple islands of the South Pacific region. In May 2015, the virus was detected in Brazil and then spread through South and Central America. In December 2015, ZIKV was detected in French Guiana and Martinique. The aim of the study was to evaluate the vector competence of the mosquito spp. Aedes aegypti and Aedes albopictus from the Caribbean (Martinique, Guadeloupe), North America (southern United States), South America (Brazil, French Guiana) for the currently circulating Asian genotype of ZIKV isolated from a patient in April 2014 in New Caledonia. METHODOLOGY/PRINCIPAL FINDINGS: Mosquitoes were orally exposed to an Asian genotype of ZIKV (NC-2014-5132). Upon exposure, engorged mosquitoes were maintained at 28 degrees +/- 1 degrees C, a 16h:8h light:dark cycle and 80% humidity. 25-30 mosquitoes were processed at 4, 7 and 14 days post-infection (dpi). Mosquito bodies (thorax and abdomen), heads and saliva were analyzed to measure infection, dissemination and transmission, respectively. High infection but lower disseminated infection and transmission rates were observed for both Ae. aegypti and Ae. albopictus. Ae. aegypti populations from Guadeloupe and French Guiana exhibited a higher dissemination of ZIKV than the other Ae. aegypti populations examined. Transmission of ZIKV was observed in both mosquito species at 14 dpi but at a low level. CONCLUSIONS/SIGNIFICANCE: This study suggests that although susceptible to infection, Ae. aegypti and Ae. albopictus were unexpectedly low competent vectors for ZIKV. This may suggest that other factors such as the large naive population for ZIKV and the high densities of human-biting mosquitoes contribute to the rapid spread of ZIKV during the current outbreak. PMID- 26938869 TI - Dehydroepiandrosterone Sulfate Stimulates Expression of Blood-Testis-Barrier Proteins Claudin-3 and -5 and Tight Junction Formation via a Gnalpha11-Coupled Receptor in Sertoli Cells. AB - Dehydroepiandrosterone sulfate (DHEAS) is a circulating sulfated steroid considered to be a pro-androgen in mammalian physiology. Here we show that at a physiological concentration (1 MUM), DHEAS induces the phosphorylation of the kinase Erk1/2 and of the transcription factors CREB and ATF-1 in the murine Sertoli cell line TM4. This signaling cascade stimulates the expression of the tight junction (TJ) proteins claudin-3 and claudin-5. As a consequence of the increased expression, tight junction connections between neighboring Sertoli cells are augmented, as demonstrated by measurements of transepithelial resistance. Phosphorylation of Erk1/2, CREB, or ATF-1 is not affected by the presence of the steroid sulfatase inhibitor STX64. Erk1/2 phosphorylation was not observed when dehydroepiandrosterone (DHEA) was used instead of DHEAS. Abrogation of androgen receptor (AR) expression by siRNA did not affect DHEAS-stimulated Erk1/2 phosphorylation, nor did it change DHEAS-induced stimulation of claudin-3 and claudin-5 expression. All of the above indicate that desulfation and conversion of DHEAS into a different steroid hormone is not required to trigger the DHEAS-induced signaling cascade. All activating effects of DHEAS, however, are abolished when the expression of the G-protein Gnalpha11 is suppressed by siRNA, including claudin-3 and -5 expression and TJ formation between neighboring Sertoli cells as indicated by reduced transepithelial resistance. Taken together, these results are consistent with the effects of DHEAS being mediated through a membrane-bound G-protein-coupled receptor interacting with Gnalpha11 in a signaling pathway that resembles the non-classical signaling pathways of steroid hormones. Considering the fact that DHEAS is produced in reproductive organs, these findings also suggest that DHEAS, by acting as an autonomous steroid hormone and influencing the formation and dynamics of the TJ at the blood-testis barrier, might play a crucial role for the regulation and maintenance of male fertility. PMID- 26938871 TI - Rapid and dramatic response to alectinib in an anaplastic lymphoma kinase rearranged non-small-cell lung cancer patient who is critically ill. AB - Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) have shown promising clinical activity in the treatment of non-small-cell lung cancer (NSCLC) that harbors ALK rearrangement. The next-generation ALK-TKI, alectinib, has been reported to have potent efficacy in ALK-positive NSCLC patients including on mutations that confer resistance to crizotinib, which was the first ALK-TKI approved for ALK-positive NSCLC. The efficacy and safety of ALK-TKIs, including crizotinib and alectinib, as the first-line treatment in critically ill patients is unclear. We report one ALK-positive NSCLC patient with poor performance status (PS) and disseminated intravascular coagulation because of respiratory failure and multiple metastases, and experienced the rapid and dramatic response to alectinib without adverse events that can lead to discontinuation and dose reduction of the drug. After a couple of months of treatment with alectinib, radiological review indicated a complete response. The present case is the first reported case of rapid and marked response to alectinib in ALK-positive NSCLC patients who had poor PS and severe organ dysfunction, such as disseminated intravascular coagulation. Further investigation of the safety and efficacy of ALK-TKI for ALK-positive NSCLC patients who are critically ill is warranted. PMID- 26938870 TI - NAD+-Glycohydrolase Promotes Intracellular Survival of Group A Streptococcus. AB - A global increase in invasive infections due to group A Streptococcus (S. pyogenes or GAS) has been observed since the 1980s, associated with emergence of a clonal group of strains of the M1T1 serotype. Among other virulence attributes, the M1T1 clone secretes NAD+-glycohydrolase (NADase). When GAS binds to epithelial cells in vitro, NADase is translocated into the cytosol in a process mediated by streptolysin O (SLO), and expression of these two toxins is associated with enhanced GAS intracellular survival. Because SLO is required for NADase translocation, it has been difficult to distinguish pathogenic effects of NADase from those of SLO. To resolve the effects of the two proteins, we made use of anthrax toxin as an alternative means to deliver NADase to host cells, independently of SLO. We developed a novel method for purification of enzymatically active NADase fused to an amino-terminal fragment of anthrax toxin lethal factor (LFn-NADase) that exploits the avid, reversible binding of NADase to its endogenous inhibitor. LFn-NADase was translocated across a synthetic lipid bilayer in vitro in the presence of anthrax toxin protective antigen in a pH dependent manner. Exposure of human oropharyngeal keratinocytes to LFn-NADase in the presence of protective antigen resulted in cytosolic delivery of NADase activity, inhibition of protein synthesis, and cell death, whereas a similar construct of an enzymatically inactive point mutant had no effect. Anthrax toxin mediated delivery of NADase in an amount comparable to that observed during in vitro infection with live GAS rescued the defective intracellular survival of NADase-deficient GAS and increased the survival of SLO-deficient GAS. Confocal microscopy demonstrated that delivery of LFn-NADase prevented intracellular trafficking of NADase-deficient GAS to lysosomes. We conclude that NADase mediates cytotoxicity and promotes intracellular survival of GAS in host cells. PMID- 26938872 TI - Type 2 Diabetes Management Algorithms? PMID- 26938873 TI - Trichoderma harzianum Produces a New Thermally Stable Acid Phosphatase, with Potential for Biotechnological Application. AB - Acid phosphatases (ACPases) are produced by a variety of fungi and have gained attention due their biotechnological potential in industrial, diagnosis and bioremediation processes. These enzymes play a specific role in scavenging, mobilization and acquisition of phosphate, enhancing soil fertility and plant growth. In this study, a new ACPase from Trichoderma harzianum, named ACPase II, was purified and characterized as a glycoprotein belonging to the acid phosphatase family. ACPase II presents an optimum pH and temperature of 3.8 and 65 degrees C, respectively, and is stable at 55 degrees C for 120 min, retaining 60% of its activity. The enzyme did not require metal divalent ions, but was inhibited by inorganic phosphate and tungstate. Affinity for several phosphate substrates was observed, including phytate, which is the major component of phosphorus in plant foods. The inhibition of ACPase II by tungstate and phosphate at different pH values is consistent with the inability of the substrate to occupy its active site due to electrostatic contacts that promote conformational changes, as indicated by fluorescence spectroscopy. A higher affinity for tungstate rather than phosphate at pH 4.0 was observed, in accordance with its highest inhibitory effect. Results indicate considerable biotechnological potential of the ACPase II in soil environments. PMID- 26938874 TI - Role of CTCF in Regulating SLC45A3-ELK4 Chimeric RNA. AB - The chimeric RNA, SLC45A3-ELK4, was found to be a product of cis-splicing between the two adjacent genes (cis-SAGe). Despite the biological and clinical significance of SLC45A3-ELK4, its generating mechanism has not been elucidated. It was shown in one cell line that the binding of transcription factor CTCF to the insulators located at or near the gene boundaries, inversely correlates with the level of the chimera. To investigate the mechanism of such cis-SAGe events, we sequenced potential regions that may play a role in such transcriptional read through. We could not detect mutations at the transcription termination site, insulator sites, splicing sites, or within CTCF itself in LNCaP cells, thus suggesting a "soft-wired" mechanism in regulating the cis-SAGe event. To investigate the role CTCF plays in regulating the chimeric RNA expression, we compared the levels of CTCF binding to the insulators in different cell lines, as well as clinical samples. Surprisingly, we did not find an inverse correlation between CTCF level, or its bindings to the insulators and SLC45A3-ELK4 expression among different samples. However, in three prostate cancer cell lines, different environmental factors can cause the expression levels of the chimeric RNA to change, and these changes do inversely correlate with CTCF level, and/or its bindings to the insulators. We thus conclude that CTCF and its bindings to the insulators are not the primary reasons for differential SLC45A3-ELK4 expression in different cell lines, or clinical cases. However, they are the likely mechanism for the same cells to respond to different environmental cues, in order to regulate the expression of SLC45A3-ELK4 chimeric RNA. This response to different environmental cues is not general to other cis-SAGe events, as we only found one out of 16 newly identified chimeric RNAs showing a pattern similar to SLC45A3-ELK4. PMID- 26938876 TI - Dechlorination Mechanism of 2,4-Dichlorophenol by Magnetic MWCNTs Supported Pd/Fe Nanohybrids: Rapid Adsorption, Gradual Dechlorination, and Desorption of Phenol. AB - 2,4-dichlorophenol was effectively removed from water using magnetic Pd/Fe nanoparticles supported on multiwalled carbon nanotubes (MWCNTs). The adsorption kinetics, isotherms, and energy for 2,4-dichlorophenol and its partially (4 chlorophenol, 2-chlorophenol) and completely (phenol) dechlorinated products are presented and discussed. The adsorption capacity was 2,4-dichlorophenol > 4 chlorophenol > 2-chlorophenol > phenol for MWCNTs. MWCNTs-Fe3O4-Pd/Fe nanohybrids provided rapid adsorption, gradual dechlorination, and final desorption of phenol, which is attractive as a remediation technology. Over 82.7% of the phenol was desorbed and released to the aqueous phase after 72 h due to its low adsorption capacity, leaving the majority of active sites available on the surface of MWCNTs-Fe3O4-Pd/Fe. The nanohybrids maintained high activity in five consecutive in situ experiments, and they were retrievable using magnetic separation. MWCNTs-Fe3O4-Pd/Fe nanohybrids outperform unsupported Pd/Fe nanoparticles, which were difficult to retrieve, and were easily passivated and aggregated. PMID- 26938877 TI - Characterization of the Fatty Acid Desaturase Genes in Cucumber: Structure, Phylogeny, and Expression Patterns. AB - Fatty acid desaturases (FADs) introduce double bonds into the hydrocarbon chains of fatty acids to produce unsaturated fatty acids, and therefore play a critical role in plant development and acclimation to environmental stresses. In this study, 23 full-length FAD genes in cucumber (Cucumis sativus L.) were identified through database searches, including three CsFAB2 genes, two CsFAD2 genes, fourteen CsFAD5 genes, and one gene each for CsFAD3, CsFAD4, CsFAD6 and CsFAD7. These cucumber FAD genes were distributed on all seven chromosomes and two additional scaffolds. Based on a phylogenetic analysis, the cucumber FAD proteins were clustered into five subfamilies with their counterparts from other plants. Gene structures and protein sequences were considerably conserved in each subfamily. All three CsFAB2 proteins shared conserved structure with the known plant soluble FAD proteins. The other cucumber FADs belonged to the membrane bound FADs and contained three highly conserved histidine boxes. Additionally, the putative endoplasmic reticulum retention signal was found at the C-termini of the CsFAD2 and CsFAD3 proteins, while the N-termini of CsFAD4, CsFAD5, CsFAD6, CsFAD7 and three CsFAB2s contained a predicted chloroplast signal peptide, which was consistent with their associated metabolic pathways. Furthermore, a gene expression analysis showed that CsFAD2 and CsFAD3 were universally expressed in all tested tissues, whereas the other cucumber FAD genes were preferentially expressed in the cotyledons or leaves. The tissue-specific expression patterns of cucumber FAD genes were correlated well with the differences in the fatty acid compositions ofroots and leaves. Finally, the cucumber FAD genes showed a cold induced and heat-repressed expression pattern, although with distinct regulatory time courses among the different CsFAD members, which indicates the potential roles of the FADs in temperature stress resistance in cucumber. PMID- 26938875 TI - Modulation of antigen processing by haem-oxygenase 1. Implications on inflammation and tolerance. AB - Haem-oxygenase-1 (HO-1) is an enzyme responsible for the degradation of haem that can suppress inflammation, through the production of carbon monoxide (CO). It has been shown in several experimental models that genetic and pharmacological induction of HO-1, as well as non-toxic administration of CO, can reduce inflammatory diseases, such as endotoxic shock, type 1 diabetes and graft rejection. Recently, it was shown that the HO-1/CO system can alter the function of antigen-presenting cells (APCs) and reduce T-cell priming, which can be beneficial during immune-driven inflammatory diseases. The molecular mechanisms by which the HO-1 and CO reduce both APC- and T-cell-driven immunity are just beginning to be elucidated. In this article we discuss recent findings related to the immune regulatory capacity of HO-1 and CO at the level of recognition of pathogen-associated molecular patterns and T-cell priming by APCs. Finally, we propose a possible regulatory role for HO-1 and CO over the recently described mitochondria-dependent immunity. These concepts could contribute to the design of new therapeutic tools for inflammation-based diseases. PMID- 26938879 TI - The Completeness of Intervention Descriptions in Randomised Trials of Supervised Exercise Training in Peripheral Arterial Disease. AB - Research supports the use of supervised exercise training as a primary therapy for improving the functional status of people with peripheral arterial disease (PAD). Several reviews have focused on reporting the outcomes of exercise interventions, but none have critically examined the quality of intervention reporting. Adequate reporting of the exercise protocols used in randomised controlled trials (RCTs) is central to interpreting study findings and translating effective interventions into practice. The purpose of this review was to evaluate the completeness of intervention descriptions in RCTs of supervised exercise training in people with PAD. A systematic search strategy was used to identify relevant trials published until June 2015. Intervention description completeness in the main trial publication was assessed using the Template for Intervention Description and Replication checklist. Missing intervention details were then sought from additional published material and by emailing authors. Fifty-eight trials were included, reporting on 76 interventions. Within publications, none of the interventions were sufficiently described for all of the items required for replication; this increased to 24 (32%) after contacting authors. Although programme duration, and session frequency and duration were well-reported in publications, complete descriptions of the equipment used, intervention provider, and number of participants per session were missing for three quarters or more of interventions (missing for 75%, 93% and 80% of interventions, respectively). Furthermore, 20%, 24% and 26% of interventions were not sufficiently described for the mode of exercise, intensity of exercise, and tailoring/progression, respectively. Information on intervention adherence/fidelity was also frequently missing: attendance rates were adequately described for 29 (38%) interventions, whereas sufficient detail about the intensity of exercise performed was presented for only 8 (11%) interventions. Important intervention details are commonly missing for supervised exercise programmes in the PAD trial literature. This has implications for the interpretation of outcome data, the investigation of dose-response effects, and the replication of protocols in future studies and clinical practice. Researchers should be mindful of intervention reporting guidelines when attempting to publish information about supervised exercise programmes, regardless of the population being studied. PMID- 26938878 TI - CmWRKY1 Enhances the Dehydration Tolerance of Chrysanthemum through the Regulation of ABA-Associated Genes. AB - WRKY transcription factors serve as antagonistic or synergistic regulators in a variety of abiotic stress responses in plants. Here, we show that CmWRKY1, a member of the group IIb WRKY family isolated from Chrysanthemum morifolium, exhibits no transcriptional activation in yeast cells. The subcellular localization examination showed that CmWRKY1 localizes to the nucleus in vivo. Furthermore, CmWRKY1-overexpressing transgenic lines exhibit enhanced dehydration tolerance in response to polyethylene glycol (PEG) treatment compared with wild type plants. We further confirmed that the transgenic plants exhibit suppressed expression levels of genes negatively regulated by ABA, such as PP2C, ABI1 and ABI2, and activated expression levels of genes positively regulated by ABA, such as PYL2, SnRK2.2, ABF4, MYB2, RAB18, and DREB1A. Taken together, our results indicate that CmWRKY1 plays an important role in the response to drought in chrysanthemum through an ABA-mediated pathway. PMID- 26938881 TI - Proof of the Structure of the Stemodia chilensis Tetracyclic Diterpenoid (+)-19 Acetoxystemodan-12-ol by Synthesis from (+)-Podocarpic Acid: X-ray Structure Determination of a Key Intermediate. AB - The first synthesis of (+)-19-acetoxystemodan-12-ol (1), a stemodane diterpenoid isolated from Stemodia chilensis, is described. The structure was supported by an X-ray crystallographic analysis of intermediate (+)-9a, which confirmed the proposed structure and excluded the structure of (-)-19-hydroxystemod-12-ene as a possible candidate for the Chilean Calceolaria diterpenoid to which the (-)-19 hydroxystemar-13-ene structure (9b) had been erroneously assigned. PMID- 26938882 TI - Structural Phase Transition Effect on Resistive Switching Behavior of MoS2 Polyvinylpyrrolidone Nanocomposites Films for Flexible Memory Devices. AB - The 2H phase and 1T phase coexisting in the same molybdenum disulfide (MoS2 ) nanosheets can influence the electronic properties of the materials. The 1T phase of MoS2 is introduced into the 2H-MoS2 nanosheets by two-step hydrothermal synthetic methods. Two types of nonvolatile memory effects, namely write-once read-many times memory and rewritable memory effect, are observed in the flexible memory devices with the configuration of Al/1T@2H-MoS2 -polyvinylpyrrolidone (PVP)/indium tin oxide (ITO)/polyethylene terephthalate (PET) and Al/2H-MoS2 PVP/ITO/PET, respectively. It is observed that structural phase transition in MoS2 nanosheets plays an important role on the resistive switching behaviors of the MoS2 -based device. It is hoped that our results can offer a general route for the preparation of various promising nanocomposites based on 2D nanosheets of layered transition metal dichalcogenides for fabricating the high performance and flexible nonvolatile memory devices through regulating the phase structure in the 2D nanosheets. PMID- 26938880 TI - Spatio-Temporal Metabolite Profiling of the Barley Germination Process by MALDI MS Imaging. AB - MALDI mass spectrometry imaging was performed to localize metabolites during the first seven days of the barley germination. Up to 100 mass signals were detected of which 85 signals were identified as 48 different metabolites with highly tissue-specific localizations. Oligosaccharides were observed in the endosperm and in parts of the developed embryo. Lipids in the endosperm co-localized in dependency on their fatty acid compositions with changes in the distributions of diacyl phosphatidylcholines during germination. 26 potentially antifungal hordatines were detected in the embryo with tissue-specific localizations of their glycosylated, hydroxylated, and O-methylated derivates. In order to reveal spatio-temporal patterns in local metabolite compositions, multiple MSI data sets from a time series were analyzed in one batch. This requires a new preprocessing strategy to achieve comparability between data sets as well as a new strategy for unsupervised clustering. The resulting spatial segmentation for each time point sample is visualized in an interactive cluster map and enables simultaneous interactive exploration of all time points. Using this new analysis approach and visualization tool germination-dependent developments of metabolite patterns with single MS position accuracy were discovered. This is the first study that presents metabolite profiling of a cereals' germination process over time by MALDI MSI with the identification of a large number of peaks of agronomically and industrially important compounds such as oligosaccharides, lipids and antifungal agents. Their detailed localization as well as the MS cluster analyses for on tissue metabolite profile mapping revealed important information for the understanding of the germination process, which is of high scientific interest. PMID- 26938883 TI - Endogenous mycotic endophthalmitis in a dog with candiduria and Evans syndrome. AB - This report describes the clinical presentation, diagnosis, histologic lesions, and outcome of endogenous mycotic endophthalmitis secondary to candiduria in a three-year-old female spayed Dachshund. The dog was being treated for Evans syndrome for one month prior to being diagnosed with candiduria and fibrinous uveitis OS. The left eye was enucleated due to secondary glaucoma, and the fungal urinary tract infection was treated successfully. Uveitis developed in the contralateral eye with relapse of the urinary tract infection in the following weeks. The right eye was medically managed until secondary glaucoma developed and was subsequently enucleated. Histopathology of both eyes showed evidence of endophthalmitis with intralesional fungal organisms, consistent with Candida spp. Ocular candidiasis is rare in dogs. To the authors' knowledge, this is the first report of endogenous mycotic endophthalmitis with concurrent candiduria in a dog. PMID- 26938885 TI - Nurses deserve to be rewarded. PMID- 26938886 TI - Foreign nurses need help to adapt to UK hospitals. PMID- 26938887 TI - Mobile learning with RCNi. PMID- 26938884 TI - Ectopic Expression of an Atypical Hydrophobic Group 5 LEA Protein from Wild Peanut, Arachis diogoi Confers Abiotic Stress Tolerance in Tobacco. AB - Late embryogenesis abundant (LEA) proteins are a group of hydrophilic proteins, which accumulate in plants under varied stress conditions like drought, salinity, extreme temperatures and oxidative stress suggesting their role in the protection of plants against these stresses. A transcript derived fragment (TDF) corresponding to LEA gene, which got differentially expressed in wild peanut, Arachis diogoi against the late leaf spot pathogen, Phaeoisariopsis personata was used in this study. We have cloned its full length cDNA by RACE-PCR, which was designated as AdLEA. AdLEA belongs to the atypical Group 5C of LEA protein family as confirmed by sequence analysis. Group 5C LEA protein subfamily contains Pfam LEA_2 domain and is highly hydrophobic. In native conditions, expression of AdLEA was upregulated considerably upon hormonal and abiotic stress treatments emphasizing its role in abiotic stress tolerance. Subcellular localization studies showed that AdLEA protein is distributed in both nucleus and cytosol. Ectopic expression of AdLEA in tobacco resulted in enhanced tolerance of plants to dehydration, salinity and oxidative stress with the transgenic plants showing higher chlorophyll content and reduced lipid peroxidation as compared to wild type plants. Overexpressed AdLEA tobacco plants maintained better photosynthetic efficiency under drought conditions as demonstrated by chlorophyll fluorescence measurements. These plants showed enhanced transcript accumulation of some stress responsive genes. Our study also elucidates that ROS levels were significantly reduced in leaves and stomatal guard cells of transgenic plants upon stress treatments. These results suggest that AdLEA confers multiple stress tolerance to plants, which make it a potential gene for genetic modification in plants. PMID- 26938888 TI - End of life care guidance calls for individualised plans. PMID- 26938889 TI - College to celebrate centenary with picture competition. PMID- 26938890 TI - Government action on agency use cuts NHS staffing bill. PMID- 26938891 TI - Survey results reveal concerns about lack of support. PMID- 26938892 TI - RCN joins march on Downing Street over bursaries. PMID- 26938893 TI - Senior nurse is first national guardian for whistleblowers. PMID- 26938896 TI - RCN launches centenary celebrations. PMID- 26938895 TI - Nursing associates: a return to state enrolled nurses? PMID- 26938894 TI - General practice nurses urged to join professional mainstream. PMID- 26938897 TI - Network your way to success. PMID- 26938904 TI - Vantage point - High standards. PMID- 26938911 TI - Improving patients' sleep: reducing light and noise levels on wards at night. AB - There is much research concerning the psychological and physical effects of sleep deprivation on patients in healthcare systems, yet interrupted sleep on hospital wards at night remains a problem. Staff at Plymouth Hospitals NHS Trust, Devon, wanted to identify the factors that prevent patients from sleeping well at night. Two audits were carried out, between April and August 2015, to assess noise and light levels on wards at night, and to engage nurses in ways of reducing these. A number of recommendations were made based on the audit findings, many of which have been put into practice. PMID- 26938912 TI - Developing a smartphone app to support the nursing community. AB - Healthcare professionals are turning increasingly to the digital sector to access information they need for their work. Mobile technology, such as smartphones and tablets, provides a unique opportunity to place high-quality information directly into users' hands. This article describes the ongoing development of a smartphone app, Preparing for Caring, designed to prepare the future workforce by enabling mentors and nursing students to access supportive material during practice-based learning episodes. The article explores the rationale for designing the app and discusses the challenges and benefits of developing this resource from the perspectives of student, mentor and healthcare manager. PMID- 26938913 TI - Managers' role in maximising investment in continuing professional education. AB - Healthcare organisations face the challenge of delivering care in increasingly complex environments. To do so they depend on competent professionals, and continuing professional education (CPE) plays a major part in ensuring that staff maintain and develop their knowledge and skills. However, there is limited evidence of the effect of CPE on healthcare outcomes, and an emphasis on outcomes has overlooked the contribution of the processes that underlie effective CPE. This article reports the results of a study that explored a range of stakeholders' perceptions of the processes that maximise the positive effects of CPE on practice. Analysis of results shows that CPE can help improve care when supported by positive organisational cultures, effective partnership working between stakeholders and supportive learning environments that enable individuals to maximise their learning. This article discusses how managers play a pivotal role in creating positive cultures in which CPE can flourish by being role models and change agents, ensuring organisational strategic objectives are aligned with personal development plans, and by working collaboratively with education colleagues to ensure that learning from CPE is embedded in practice. PMID- 26938914 TI - Flexible leadership. PMID- 26938915 TI - Combined Use of Gene Expression Modeling and siRNA Screening Identifies Genes and Pathways Which Enhance the Activity of Cisplatin When Added at No Effect Levels to Non-Small Cell Lung Cancer Cells In Vitro. AB - Platinum-based combination chemotherapy is the standard treatment for advanced non-small cell lung cancer (NSCLC). While cisplatin is effective, its use is not curative and resistance often emerges. As a consequence of microenvironmental heterogeneity, many tumour cells are exposed to sub-lethal doses of cisplatin. Further, genomic heterogeneity and unique tumor cell sub-populations with reduced sensitivities to cisplatin play a role in its effectiveness within a site of tumor growth. Being exposed to sub-lethal doses will induce changes in gene expression that contribute to the tumour cell's ability to survive and eventually contribute to the selective pressures leading to cisplatin resistance. Such changes in gene expression, therefore, may contribute to cytoprotective mechanisms. Here, we report on studies designed to uncover how tumour cells respond to sub-lethal doses of cisplatin. A microarray study revealed changes in gene expressions that occurred when A549 cells were exposed to a no-observed effect level (NOEL) of cisplatin (e.g. the IC10). These data were integrated with results from a genome-wide siRNA screen looking for novel therapeutic targets that when inhibited transformed a NOEL of cisplatin into one that induced significant increases in lethality. Pathway analyses were performed to identify pathways that could be targeted to enhance cisplatin activity. We found that over 100 genes were differentially expressed when A549 cells were exposed to a NOEL of cisplatin. Pathways associated with apoptosis and DNA repair were activated. The siRNA screen revealed the importance of the hedgehog, cell cycle regulation, and insulin action pathways in A549 cell survival and response to cisplatin treatment. Results from both datasets suggest that RRM2B, CABYR, ALDH3A1, and FHL2 could be further explored as cisplatin-enhancing gene targets. Finally, pathways involved in repairing double-strand DNA breaks and INO80 chromatin remodeling were enriched in both datasets, warranting further research into combinations of cisplatin and therapeutics targeting these pathways. PMID- 26938917 TI - Risk factors associated with post-hemorrhagic hydrocephalus among very low birth weight infants of 24-28 weeks gestation. AB - OBJECTIVE: Post-hemorrhagic hydrocephalus (PHH) is associated with morbidity and mortality among very low birth weight (VLBW) infants. This study aimed to determine risk factors for PHH among VLBW infants with peri-intraventricular hemorrhage (PIVH). STUDY DESIGN: This is a population-based cohort of VLBW infants of 24 to 28 weeks gestation, born in Israel from 1995 to 2012. Infants in whom a brain ultrasound was not performed before 28 days or with major congenital malformations were excluded. Univariate and multivariable analyses identified risk factors associated with PHH. RESULTS: The final study cohort comprised 2811 infants with grade 2 or higher PIVH, of whom 610 (21.7%) developed PHH. PHH was independently associated with PIVH severity, with bilateral grade 3 PIVH and PIVH grade 3 and contralateral grade 4 having the highest risks (odds ratio (OR) 12.2, 95% confidence interval (CI) 8.56 to 17.4 and OR 13.7, 95% CI 9.4 to 20.1, respectively). Unilateral grade 3 or 4 PIVH's had moderately increased risks of PHH (OR 3.50, 95% CI 2.26 to 5.42 and OR 3.79, 95% CI 2.35 to 6.12, respectively). PHH was independently associated with increasing gestational age (GA) and with neonatal morbidities including patent ductus arteriosus (OR 1.47, 95% CI 1.15 to 1.88 if medically treated and OR 3.01, 95% CI 2.11 to 4.29 if surgically treated), sepsis (OR 1.79, 95% CI 1.44 to 2.22) and necrotizing enterocolitis (OR 1.60, 95% CI 1.18 to 2.17). CONCLUSIONS: Among VLBW infants with PIVH, PHH was independently associated with PIVH severity group, increasing GA and acute neonatal morbidities. Unilateral grade 3 or 4 PIVH was associated with a moderate risk of developing PHH compared with bilateral severe hemorrhages. PMID- 26938918 TI - Clinical trial of tin mesoporphyrin to prevent neonatal hyperbilirubinemia. AB - OBJECTIVE: To assess the efficacy of the heme oxygenase inhibitor, tin mesoporphyrin (SnMP), to reduce total bilirubin (TB) levels. STUDY DESIGN: Masked, SnMP (4.5 mg kg(-1)), placebo-controlled, multicenter trial of single intramuscular injection to newborns ?35 weeks gestational age whose predischarge screening transcutaneous bilirubin (TcB) was >75th percentile. RESULTS: Two hundred and thirteen newborns (median age 30 h) were randomized to treatment with SnMP (n=87) or 'sham' (n=89). We found that the duration of phototherapy was halved. Within 12 h of SnMP administration, the natural TB trajectory was reversed. At age 3 to 5 days, TB in the SnMP-treated group was +8% but sixfold lower than the 47% increase in the sham-treated group (P<0.001). At age 7 to 10 days, mean TB declined 18% (P<0.001) compared with a 7.1% increase among controls. No short-term adverse events from SnMP treatment were noted other than photoreactivity due to inadvertent exposure to white light phototherapy. CONCLUSION: Early, predischarge SnMP administration decreased the duration of phototherapy, reversed TB trajectory and reduced the severity of subsequent hyperbilirubinemia. PMID- 26938916 TI - Role of the BAHD1 Chromatin-Repressive Complex in Placental Development and Regulation of Steroid Metabolism. AB - BAHD1 is a vertebrate protein that promotes heterochromatin formation and gene repression in association with several epigenetic regulators. However, its physiological roles remain unknown. Here, we demonstrate that ablation of the Bahd1 gene results in hypocholesterolemia, hypoglycemia and decreased body fat in mice. It also causes placental growth restriction with a drop of trophoblast glycogen cells, a reduction of fetal weight and a high neonatal mortality rate. By intersecting transcriptome data from murine Bahd1 knockout (KO) placentas at stages E16.5 and E18.5 of gestation, Bahd1-KO embryonic fibroblasts, and human cells stably expressing BAHD1, we also show that changes in BAHD1 levels alter expression of steroid/lipid metabolism genes. Biochemical analysis of the BAHD1 associated multiprotein complex identifies MIER proteins as novel partners of BAHD1 and suggests that BAHD1-MIER interaction forms a hub for histone deacetylases and methyltransferases, chromatin readers and transcription factors. We further show that overexpression of BAHD1 leads to an increase of MIER1 enrichment on the inactive X chromosome (Xi). In addition, BAHD1 and MIER1/3 repress expression of the steroid hormone receptor genes ESR1 and PGR, both playing important roles in placental development and energy metabolism. Moreover, modulation of BAHD1 expression in HEK293 cells triggers epigenetic changes at the ESR1 locus. Together, these results identify BAHD1 as a core component of a chromatin-repressive complex regulating placental morphogenesis and body fat storage and suggest that its dysfunction may contribute to several human diseases. PMID- 26938919 TI - Neonatal-perinatal medicine fellow procedural experience and competency determination: results of a national survey. AB - OBJECTIVE: Ensuring that neonatal-perinatal medicine (NPM) fellows attain competency in performing neonatal procedures is a requirement of training competent neonatologists. STUDY DESIGN: A survey of NPM fellows was performed to determine the procedural experience of current fellows, investigate techniques used to track procedural experience and examine the methods programs use to verify procedural competency. RESULTS: One hundred and sixty-three fellows in 57 accredited training programs responded to the survey. Reported number of procedures provide contemporary normative data on procedural experience during training. The majority of fellows reported using an online reporting system to track experience. The most common technique to verify procedural competency was supervised practice until an arbitrary number of procedures had been performed. CONCLUSIONS: NPM fellow procedural experience increases significantly for most, but not all, procedures duration training. We speculate that supplemental simulation training for rare neonatal procedures would help ensure the competency of graduating NPM fellows. Experience alone is insufficient to verify competency. Further work on the accurate tracking of experience and verification of procedural competency is needed. PMID- 26938920 TI - The Lacuna Trial: a double-blind randomized controlled pilot trial of lactoferrin supplementation in the very preterm infant. AB - OBJECTIVE: To determine tolerability of bovine lactoferrin (bLF) in very preterm infants, and whether the intervention can be adequately masked. STUDY DESIGN: In a single-center masked pilot trial infants under 31 weeks gestation were randomized before 48 h of age to receive milk with 100 mg per day of bLF or control. The primary outcome was feeding tolerance, defined as time to achieve full feeds (140 ml kg(-1) per day). Parents answered a short questionnaire regarding acceptability of the intervention. RESULTS: Seventy-nine infants were enrolled and analyzed according to intention to treat. There was no effect of bLF on the primary outcome. In addition, mortality, late onset sepsis and other complications of prematurity were no different. Equal numbers of parents in both groups believed their infant received bLF. CONCLUSION: We demonstrated that bLF is well tolerated, easy to administer and its presence in prepared milk is not evident. Trial registration number ISRCTN66482337. PMID- 26938923 TI - Decarboxylative Halogenation and Cyanation of Electron-Deficient Aryl Carboxylic Acids via Cu Mediator as Well as Electron-Rich Ones through Pd Catalyst under Aerobic Conditions. AB - Simple strategies for decarboxylative functionalizations of electron-deficient benzoic acids via using Cu(I) as promoter and electron-rich ones by employing Pd(II) as catalyst under aerobic conditions have been established, which lead to smooth synthesis of aryl halides (-I, Br, and Cl) through the decarboxylative functionalization of benzoic acids with readily available halogen sources CuX (X = I, Br, Cl), and easy preparation of benzonitriles from decarboxylative cyanation of aryl carboxylic acids with nontoxic and low-cost K4Fe(CN)6 under an oxygen atmosphere for the first time. PMID- 26938922 TI - Do maternal characteristics influence maternal-fetal medicine physicians' willingness to intervene when managing periviable deliveries? AB - OBJECTIVE: Determine the relative influence of patient characteristics on Maternal-Fetal Medicine (MFM) physicians' willingness to intervene when managing 23-week preterm premature rupture of membranes. STUDY DESIGN: Surveyed 750 randomly sampled US members of the Society of Maternal-Fetal Medicine. Physicians rated their willingness to offer induction, order steroids and perform cesarean across eight vignettes; then completed a questionnaire querying expectations about neonatal outcomes and demographics. RESULTS: Three hundred and twenty-five (43%) MFMs responded. Patient characteristics only influenced ?11% of participants' willingness ratings. Overall, provider characteristics and institutional norms were associated with willingness to perform antenatal interventions, for example, practice region was associated with willingness to offer induction (P<0.001), order steroids (P=0.008) and perform cesarean for distress (P=0.011); while institutional cesarean cutoffs were associated with willingness to order steroids and perform cesarean for labor and distress (all P<0.001). CONCLUSION: Physician-level factors and institutional norms, more so than patient characteristics, may drive periviable care and outcomes. PMID- 26938921 TI - A decision-making tool for exchange transfusions in infants with severe hyperbilirubinemia in resource-limited settings. AB - Late presentation and ineffective phototherapy account for excessive rates of avoidable exchange transfusions (ETs) in many low- and middle-income countries. Several system-based constraints sometimes limit the ability to provide timely ETs for all infants at risk of kernicterus, thus necessitating a treatment triage to optimize available resources. This article proposes a practical priority setting model for term and near-term infants requiring ET after the first 48 h of life. The proposed model combines plasma/serum bilirubin estimation, clinical signs of acute bilirubin encephalopathy and neurotoxicity risk factors for predicting the risk of kernicterus based on available evidence in the literature. PMID- 26938924 TI - Double Deprotonation of Pyridinols Generates Potent Organic Electron-Donor Initiators for Haloarene-Arene Coupling. AB - Transition metal-free couplings of haloarenes with arenes, triggered by the use of alkali metal alkoxides in the presence of an organic additive, are receiving significant attention in the literature. Most of the known organic additives effect coupling of iodoarenes, but not bromoarenes, to arenes. Recently it was reported that 2-pyridinecarbinol (11) extends the reaction to aryl bromides. This paper investigates the mechanism, and reports evidence for dianions derived from 11 as electron donors to initiate the reaction. It also proposes routes by which electron-poor benzoyl derivatives can be transformed into electron donors to initiate these reactions. PMID- 26938925 TI - An Ancient Fingerprint Indicates the Common Ancestry of Rossmann-Fold Enzymes Utilizing Different Ribose-Based Cofactors. AB - Nucleoside-based cofactors are presumed to have preceded proteins. The Rossmann fold is one of the most ancient and functionally diverse protein folds, and most Rossmann enzymes utilize nucleoside-based cofactors. We analyzed an omnipresent Rossmann ribose-binding interaction: a carboxylate side chain at the tip of the second beta-strand (beta2-Asp/Glu). We identified a canonical motif, defined by the beta2-topology and unique geometry. The latter relates to the interaction being bidentate (both ribose hydroxyls interacting with the carboxylate oxygens), to the angle between the carboxylate and the ribose, and to the ribose's ring configuration. We found that this canonical motif exhibits hallmarks of divergence rather than convergence. It is uniquely found in Rossmann enzymes that use different cofactors, primarily SAM (S-adenosyl methionine), NAD (nicotinamide adenine dinucleotide), and FAD (flavin adenine dinucleotide). Ribose-carboxylate bidentate interactions in other folds are not only rare but also have a different topology and geometry. We further show that the canonical geometry is not dictated by a physical constraint--geometries found in noncanonical interactions have similar calculated bond energies. Overall, these data indicate the divergence of several major Rossmann-fold enzyme classes, with different cofactors and catalytic chemistries, from a common pre-LUCA (last universal common ancestor) ancestor that possessed the beta2-Asp/Glu motif. PMID- 26938929 TI - Platinum-Containing Polyoxometalates: syn- and anti-[Pt(II)2(alpha-PW11O39)2](10 ) and Formation of the Metal-Metal-Bonded di-Pt(III) Derivatives. AB - The first examples of dimeric, di-Pt(II) -containing heteropolytungstates are reported. The two isomeric di-platinum(II)-containing 22-tungsto-2-phosphates [anti-Pt(II)2(alpha-PW11O39)2](10-) (1 a) and [syn-Pt(II)2(alpha-PW11O39)2](10-) (2 a) were synthesized in aqueous pH 3.5 medium using one-pot procedures. Polyanions 1 a and 2 a contain a core comprising two face-on PtO4 units, with a Pt???Pt distance of 2.9-3 A. Both polyanions were investigated by single-crystal XRD, IR, TGA, UV/Vis, (31) P NMR, ESI-MS, CID-MS/MS, electrochemistry, and DFT. On the basis of DFT and electrochemistry, we demonstrated that the {Pt2(II)} moiety in 1 a and 2 a can undergo fully reversible two-electron oxidation to {Pt2(III)}, accompanied by formation of a single Pt-Pt bond. Hence we have discovered the novel subclass of Pt(III)-containing heteropolytungstates. PMID- 26938931 TI - Structure-Property Relationships in Atomic-Scale Junctions: Histograms and Beyond. AB - Over the past 10 years, there has been tremendous progress in the measurement, modeling and understanding of structure-function relationships in single molecule junctions. Numerous research groups have addressed significant scientific questions, directed both to conductance phenomena at the single molecule level and to the fundamental chemistry that controls junction functionality. Many different functionalities have been demonstrated, including single-molecule diodes, optically and mechanically activated switches, and, significantly, physical phenomena with no classical analogues, such as those based on quantum interference effects. Experimental techniques for reliable and reproducible single molecule junction formation and characterization have led to this progress. In particular, the scanning tunneling microscope based break-junction (STM-BJ) technique has enabled rapid, sequential measurement of large numbers of nanoscale junctions allowing a statistical analysis to readily distinguish reproducible characteristics. Harnessing fundamental link chemistry has provided the necessary chemical control over junction formation, enabling measurements that revealed clear relationships between molecular structure and conductance characteristics. Such link groups (amines, methylsuflides, pyridines, etc.) maintain a stable lone pair configuration that selectively bonds to specific, undercoordinated transition metal atoms available following rupture of a metal point contact in the STM-BJ experiments. This basic chemical principle rationalizes the observation of highly reproducible conductance signatures. Subsequently, the method has been extended to probe a variety of physical phenomena ranging from basic I-V characteristics to more complex properties such as thermopower and electrochemical response. By adapting the technique to a conducting cantilever atomic force microscope (AFM-BJ), simultaneous measurement of the mechanical characteristics of nanoscale junctions as they are pulled apart has given complementary information such as the stiffness and rupture force of the molecule-metal link bond. Overall, while the BJ technique does not produce a single molecule circuit for practical applications, it has proved remarkably versatile for fundamental studies. Measured data and analysis have been combined with atomic-scale theory and calculations, typically performed for representative junction structures, to provide fundamental physical understanding of structure function relationships. This Account integrates across an extensive series of our specific nanoscale junction studies which were carried out with the STM- and AFM BJ techniques and supported by theoretical analysis and density functional theory based calculations, with emphasis on the physical characteristics of the measurement process and the rich data sets that emerge. Several examples illustrate the impact of measured trends based on the most probable values for key characteristics (obtained from ensembles of order 1000-10 000 individual junctions) to build a solid picture of conductance phenomena as well as attributes of the link bond chemistry. The key forward-looking question posed here is the extent to which the full data sets represented by the individual trajectories can be analyzed to address structure-function questions at the level of individual junctions. Initial progress toward physical modeling of conductance of individual junctions indicates trends consistent with physical junction structures. Analysis of junction mechanics reveals a scaling procedure that collapses existing data onto a universal force-extension curve. This research directed to understanding the distribution of structures and physical characteristics addresses fundamental questions concerning the interplay between chemical control and stochastically driven diversity. PMID- 26938930 TI - Patient choice and clinical outcomes following positive noninvasive prenatal screening for aneuploidy with cell-free DNA (cfDNA). AB - OBJECTIVE: Evaluate patient choices and outcomes following positive cfDNA. METHOD: Retrospective cohort study of women with positive cfDNA through two academic centers between March 2012 and December 2014. Patients were screened based on ACOG indications. Medical records reviewed for counseling, ultrasound findings, diagnostic testing, karyotype and outcome. RESULTS: CfDNA was positive in 114 women; 105 singletons and 9 twin pairs. CfDNA was positive for autosomal trisomy (21, 18, 13) in 96 (84.2%) and sex chromosome aneuploidy in 18 (15.8%). Certified genetic counselors performed 95% of post-cfDNA counseling. Prenatal diagnostic testing was pursued by 71/114 (62%). Karyotype was available in 91/105 (86.7%) singletons and confirmed aneuploidy in 75/91 (82.4%); the PPV of cfDNA with any ultrasound finding was 93.6% versus 58.6% without a finding. An abnormal sonographic finding was seen in 4/16 (25%) singletons with false positive cfDNA. Fetal termination occurred in 53/79 (67%) singletons and 3/5 (60%) twins with prenatal abnormal or unknown karyotype for autosomal trisomy. Eleven fetuses (11/56, 19.6%) were terminated for suspected autosomal trisomy without karyotype confirmation. CONCLUSION: Patient choices following positive cfDNA are varied. Ultrasound modifies the PPV of cfDNA. Termination rates for aneuploidy are not higher than historical controls. Recommendation for karyotype confirmation prior to termination is not universally followed. (c) 2016 John Wiley & Sons, Ltd. PMID- 26938933 TI - Louse-Borne Relapsing Fever with Meningeal Involvement in an Immigrant from Somalia to Italy, October 2015. AB - INTRODUCTION: Borrelia recurrentis, transmitted by Pediculus humanus humanus, is the etiological agent of louse-borne relapsing fever (LBRF). Currently the main focus of endemicity of LBRF is localized in East African countries. From July 2015 to October 2015, 36 cases of LBRF have been diagnosed in Europe in immigrants from the Horn of Africa. Here we report a case of LBRF with meningitis diagnosed in Florence, Italy, in an immigrant arrived from Somalia. CASE STUDY: In October 2015, a 19-year-old Somali male presented to the emergency department of the Azienda Ospedaliero Universitaria Careggi, Florence, Italy, with a 3-day history of high fever. The patient had disembarked in Sicily 10 days before admission after a long migration trip from his country of origin. On clinical examination, neck stiffness was found. Main laboratory findings were thrombocytopenia, increased procalcitonin, and increased polymorphonucleates in the cerebrospinal fluid. Suspecting a possible meningitis, the patient was treated with ceftriaxone, pending results of laboratory testing for malaria, and developed severe hypotension that was treated with fluid resuscitation and hydrocortisone. Hemoscopic testing revealed the presence of spirochetes and no malaria parasites. The patient rapidly improved with doxycycline for 7 days and ceftriaxone for 11 days, then was lost to follow-up. Total DNA from blood was extracted, and amplification and sequencing with universal 16S rDNA primers D88 and E94 revealed a 100% identity with B. recurrentis A1. CONCLUSIONS: LBRF is a rare but emerging infectious disease among vulnerable displaced immigrants from the Horn of Africa. Since immigrants from endemic areas can carry the vector with them, the infection should be suspected even in subjects with compatible clinical features living in the same place where new arrival immigrants are hosted. Healthcare providers should be aware of this condition to implement adequate diagnostic, therapeutic, and public health measures. PMID- 26938932 TI - Evaluation of Intermittent Hemodialysis in Critically Ill Cancer Patients with Acute Kidney Injury Using Single-Pass Batch Equipment. AB - BACKGROUND: Data on renal replacement therapy (RRT) in cancer patients with acute kidney injury (AKI) in the intensive care unit (ICU) is scarce. The aim of this study was to assess the safety and the adequacy of intermittent hemodialysis (IHD) in critically ill cancer patients with AKI. METHODS AND FINDINGS: In this observational prospective cohort study, 149 ICU cancer patients with AKI were treated with 448 single-pass batch IHD procedures and evaluated from June 2010 to June 2012. Primary outcomes were IHD complications (hypotension and clotting) and adequacy. A multiple logistic regression was performed in order to identify factors associated with IHD complications (hypotension and clotting). Patients were 62.2 +/- 14.3 years old, 86.6% had a solid cancer, sepsis was the main AKI cause (51%) and in-hospital mortality was 59.7%. RRT session time was 240 (180 300) min, blood/dialysate flow was 250 (200-300) mL/min and UF was 1000 (0-2000) ml. Hypotension occurred in 25% of the sessions. Independent risk factors (RF) for hypotension were dialysate conductivity (each ms/cm, OR 0.81, CI 0.69-0.95), initial mean arterial pressure (each 10 mmHg, OR 0.49, CI 0.40-0.61) and SOFA score (OR 1.16, CI 1.03-1.30). Clotting and malfunctioning catheters (MC) occurred in 23.8% and 29.2% of the procedures, respectively. Independent RF for clotting were heparin use (OR 0.57, CI 0.33-0.99), MC (OR 3.59, CI 2.24-5.77) and RRT system pressure increase over 25% (OR 2.15, CI 1.61-4.17). Post RRT blood tests were urea 71 (49-104) mg/dL, creatinine 2.71 (2.10-3.8) mg/dL, bicarbonate 24.1 (22.5-25.5) mEq/L and K 3.8 (3.5-4.1) mEq/L. CONCLUSION: IHD for critically ill patients with cancer and AKI offered acceptable hemodynamic stability and provided adequate metabolic control. PMID- 26938935 TI - Relations between language and cognition in native-signing children with autism spectrum disorder. AB - Two populations have been found to exhibit delays in theory of mind (ToM): deaf children of hearing parents and children with autism spectrum disorder (ASD). Deaf children exposed to sign from birth by their deaf parents, however, show no such delay, suggesting that early language exposure is key to ToM development. Sign languages also present frequent opportunities with visual perspective-taking (VPT), leading to the question of whether sign exposure could benefit children with ASD. We present the first study of children with ASD exposed to sign from birth by their deaf parents. Seventeen native-signing children with a confirmed ASD diagnosis and a chronological- and mental age-matched control group of 18 typically developing (TD) native-signing deaf children were tested on American Sign Language (ASL) comprehension, two minimally verbal social cognition tasks (ToM and VPT), and one spatial cognition task (mental rotation). The TD children outperformed the children with ASD on ASL comprehension (p < 0.0001), ToM (p = 0.02), and VPT (p < 0.01), but not mental rotation (p = 0.12). Language strongly correlated with ToM (p < 0.01) and VPT (p < 0.001), but not mental rotation (p = ns). Native exposure to sign is thus insufficient to overcome the language and social impairments implicated in ASD. Contrary to the hypothesis that sign could provide a scaffold for ToM skills, we find that signing children with ASD are unable to access language so as to gain any potential benefit sign might confer. Our results support a strong link between the development of social cognition and language, regardless of modality, for TD and ASD children. Autism Res 2016, 9: 1304-1315. (c) 2016 International Society for Autism Research, Wiley Periodicals, Inc. PMID- 26938934 TI - Cleaning out the Litterbox of Proteomic Scientists' Favorite Pet: Optimized Data Analysis Avoiding Trypsin Artifacts. AB - Chemically modified trypsin is a standard reagent in proteomics experiments but is usually not considered in database searches. Modification of trypsin is supposed to protect the protease against autolysis and the resulting loss of activity. Here, we show that modified trypsin is still subject to self-digestion, and, as a result, modified trypsin-derived peptides are present in standard digests. We depict that these peptides commonly lead to false-positive assignments even if native trypsin is considered in the database. Moreover, we present an easily implementable method to include modified trypsin in the database search with a minimal increase in search time and search space while efficiently avoiding these false-positive hits. PMID- 26938936 TI - No Tryptophan, Tyrosine and Phenylalanine Abnormalities in Children with Attention-Deficit/Hyperactivity Disorder. AB - BACKGROUND: The aim of the current study was to explore the role of aromatic amino acids (AAAs) in blood in relation to attention-deficit/hyperactivity disorder (ADHD). Given their impact on the synthesis of serotonin and dopamine, decreased concentrations of the AAAs tryptophan, tyrosine and phenylalanine in blood may contribute to the expression of ADHD symptoms. Decreased AAA blood concentrations, in turn, may be related to lowered dietary protein intake or to abnormal AAA catabolism, as evidenced by increased urinary AAA concentrations. METHODS: Eighty-three children with ADHD (75% males) and 72 typically developing (TD) children (51% males), aged 6 to 13 years, participated in the study. AAA concentrations were assessed in blood spots and an 18-hour urinary sample. A nutritional diary was filled out by parents to calculate dietary protein intake. Parent and teacher questionnaires assessed symptoms of ADHD, oppositional defiant disorder, conduct disorder, and autism spectrum disorder. RESULTS: Children with ADHD showed normal AAA concentrations in blood spots and urine, as well as normal protein intake compared to controls. No associations between AAA concentrations and symptoms of ADHD or comorbid psychiatric disorders were found. CONCLUSIONS: This study is the first to explore AAA metabolism in children with ADHD using a well-defined and relatively large sample. We found that AAA deficiencies are not related to ADHD. The results do not support treatment with AAA supplements in children with ADHD. Future studies regarding the cause of serotonin and dopamine alterations in ADHD should focus on other explanations, such as effects of altered transport of AAAs. PMID- 26938937 TI - Local Ordering at Mobile Sites in Proteins from Nuclear Magnetic Resonance Relaxation: The Role of Site Symmetry. AB - Restricted motions in proteins (e.g., N-H bond dynamics) are studied effectively with NMR. By analogy with restricted motions in liquid crystals (LC), the local ordering has in the past been primarily represented by potentials comprising the L = 2, |K| = 0, 2 spherical harmonics. However, probes dissolved in LCs experience nonpolar ordering, often referred to as alignment, while protein anchored probes experience polar ordering, often referred to as orientation. In this study we investigate the role of local (site) symmetry in the context of the polarity of the local ordering. We find that potentials comprising the L = 1, |K| = 0, 1 spherical harmonics represent adequately polar ordering. It is useful to characterize potential symmetry in terms of the irreducible representations of D2h point group, which is already implicit in the definition of the rotational diffusion tensor. Thus, the relevant rhombic L = 1 potentials have B1u and B3u symmetry whereas the relevant rhombic L = 2 potentials have Ag symmetry. A comprehensive scheme where local potentials and corresponding probability density functions (PDFs) are represented in Cartesian and spherical coordinates clarifies how they are affected by polar and nonpolar ordering. The Cartesian coordinates are chosen so that the principal axis of polar axial PDF is pointing along the z axis, whereas the principal axis of the nonpolar axial PDF is pointing along +/ z. Two-term axial potentials with 1 <= L <= 3 exhibit substantial diversity; they are expected to be useful in NMR-relaxation-data-fitting. It is shown how potential coefficients are reflected in the experimental order parameters. The comprehensive scheme representing local potentials and PDFs is exemplified for the L = 2 case using experimental data from (15)N-labeled plexin-B1 and thioredoxin, (2)H-, and (13)C-labeled benzenehexa-n-alkanoates, and nitroxide labeled T4 lysozyme. Future prospects for improved ordering analysis based on combined atomistic and mesoscopic approaches are delineated. PMID- 26938938 TI - Soil water availability and capacity of nitrogen accumulation influence variations of intrinsic water use efficiency in rice. AB - Leaf intrinsic water use efficiency (WUEi) coupling maximum assimilation rate (Amax) and transpirable water lost via stomatal conductance (gsc) has been gaining increasing concern in sustainable crop production. Factors that influence leaf Amax and WUEi in rice (Oryza sativa L. cv Unkang) at flooding and rainfed conditions were evaluated. Positive correlations for leaf nitrogen content (Nm) and maximum carboxylation rate (Vcmax), for nitrogen allocation in Rubisco enzymes and mesophyll conductance (gm) were evident independent of cropping cultures. Rainfed rice exhibited enriched canopy leaf average Nm resulting in higher Amax, partially supporting improved leaf WUEi. Maximum WUEi (up to 0.14 MUmol mmol(-1)) recorded in rainfed rice under drought conditions resulted from increasing gm/gsc ratio while at cost of significant decline in Amax due to hydraulically constrained gsc. Amax sensitivity related to gsc which was regulated by plant hydraulic conductance. WUEi was tightly correlated to Vcmax/gsc and gm/gsc ratios across the paddy and rainfed not to light environment, morphological and physiological traits, highlighting enhance capacity of Nm accumulation in rainfed rice with gsc at moderately high level similar to paddy rice facilitate optimization in Amax and WUEi while, is challenged by drought-vulnerable plant hydraulic conductance. PMID- 26938940 TI - Provider practice style and patient health outcomes: The case of heart attacks. AB - When a patient arrives at the Emergency Room with acute myocardial infarction (AMI), the provider on duty must quickly decide how aggressively the patient should be treated. Using Florida data on all such patients from 1992 to 2014, we decompose practice style into two components: The provider's probability of conducting invasive procedures on the average patient (which we characterize as aggressiveness), and the responsiveness of the choice of procedure to the patient's characteristics. We show that within hospitals and years, patients with more aggressive providers have consistently higher costs and better outcomes. Since all patients benefit from higher utilization of invasive procedures, targeting procedure use to the most appropriate patients benefits these patients at the expense of the less appropriate patients. We also find that the most aggressive and responsive physicians are young, male, and trained in top 20 schools. PMID- 26938941 TI - The Iron Triangle: Guidelines, expertise, and patient centered. PMID- 26938942 TI - Wavelength-selective emitters with pyramid nanogratings enhanced by multiple resonance modes. AB - Binary gratings with high or low metal filling ratios in a grating region have been demonstrated as successful candidates in enhancing the emittance of emitters for thermophotovoltaics since they could support surface plasmons (SPs), the Rayleigh-Wood anomaly (RWA), or cavity resonance (CR) within their geometries. This work shows that combining a tungsten binary grating with a low and high filling ratio to form a pyramid grating can significantly increase the emittance, which is nearly perfect in the wavelength region from 0.6 to 1.72 MUm, while being 0.1 at wavelengths longer than 2.5 MUm. Moreover, the emittance spectrum of the hybrid tungsten grating is insensitive to the angle of incidence. The enhancement demonstrated by magnetic field and Poynting vector patterns is due to the interplay between SPs and RWA modes at short wavelengths, and CR at long wavelengths. Furthermore, a combined grating made of nickel is also proposed providing enhanced emittance in a wide angle of incidence. PMID- 26938939 TI - Lung extracellular matrix and redox regulation. AB - Pulmonary fibrosis affects millions worldwide and, even though there has been a significant investment in understanding the processes involved in wound healing and maladaptive repair, a complete understanding of the mechanisms responsible for lung fibrogenesis eludes us, and interventions capable of reversing or halting disease progression are not available. Pulmonary fibrosis is characterized by the excessive expression and uncontrolled deposition of extracellular matrix (ECM) proteins resulting in erosion of the tissue structure. Initially considered an 'end-stage' process elicited after injury, these events are now considered pathogenic and are believed to contribute to the course of the disease. By interacting with integrins capable of signal transduction and by influencing tissue mechanics, ECM proteins modulate processes ranging from cell adhesion and migration to differentiation and growth factor expression. In doing so, ECM proteins help orchestrate complex developmental processes and maintain tissue homeostasis. However, poorly controlled deposition of ECM proteins promotes inflammation, fibroproliferation, and aberrant differentiation of cells, and has been implicated in the pathogenesis of pulmonary fibrosis, atherosclerosis and cancer. Considering their vital functions, ECM proteins are the target of investigation, and oxidation-reduction (redox) reactions have emerged as important regulators of the ECM. Oxidative stress invariably accompanies lung disease and promotes ECM expression directly or through the overproduction of pro-fibrotic growth factors, while affecting integrin binding and activation. In vitro and in vivo investigations point to redox reactions as targets for intervention in pulmonary fibrosis and related disorders, but studies in humans have been disappointing probably due to the narrow impact of the interventions tested, and our poor understanding of the factors that regulate these complex reactions. This review is not meant to provide a comprehensive review of this field, but rather to highlight what has been learned and to raise interest in this area in need of much attention. PMID- 26938943 TI - Automatic Tuning Matching Cycler (ATMC) in situ NMR spectroscopy as a novel approach for real-time investigations of Li- and Na-ion batteries. AB - We have developed and explored the use of a new Automatic Tuning Matching Cycler (ATMC) in situ NMR probe system to track the formation of intermediate phases and investigate electrolyte decomposition during electrochemical cycling of Li- and Na-ion batteries (LIBs and NIBs). The new approach addresses many of the issues arising during in situ NMR, e.g., significantly different shifts of the multi component samples, changing sample conditions (such as the magnetic susceptibility and conductivity) during cycling, signal broadening due to paramagnetism as well as interferences between the NMR and external cycler circuit that might impair the experiments. We provide practical insight into how to conduct ATMC in situ NMR experiments and discuss applications of the methodology to LiFePO4 (LFP) and Na3V2(PO4)2F3 cathodes as well as Na metal anodes. Automatic frequency sweep (7)Li in situ NMR reveals significant changes of the strongly paramagnetic broadened LFP line shape in agreement with the structural changes due to delithiation. Additionally, (31)P in situ NMR shows a full separation of the electrolyte and cathode NMR signals and is a key feature for a deeper understanding of the processes occurring during charge/discharge on the local atomic scale of NMR. (31)P in situ NMR with "on-the-fly" re-calibrated, varying carrier frequencies on Na3V2(PO4)2F3 as a cathode in a NIB enabled the detection of different P signals within a huge frequency range of 4000 ppm. The experiments show a significant shift and changes in the number as well as intensities of (31)P signals during desodiation/sodiation of the cathode. The in situ experiments reveal changes of local P environments that in part have not been seen in ex situ NMR investigations. Furthermore, we applied ATMC (23)Na in situ NMR on symmetrical Na-Na cells during galvanostatic plating. An automatic adjustment of the NMR carrier frequency during the in situ experiment ensured on resonance conditions for the Na metal and electrolyte peak, respectively. Thus, interleaved measurements with different optimal NMR set-ups for the metal and electrolyte, respectively, became possible. This allowed the formation of different Na metal species as well as a quantification of electrolyte consumption during the electrochemical experiment to be monitored. The new approach is likely to benefit a further understanding of Na-ion battery chemistries. PMID- 26938944 TI - A High-avidity WT1-reactive T-Cell Receptor Mediates Recognition of Peptide and Processed Antigen but not Naturally Occurring WT1-positive Tumor Cells. AB - Wilms tumor gene 1 (WT1) is an attractive target antigen for cancer immunotherapy because it is overexpressed in many hematologic malignancies and solid tumors but has limited, low-level expression in normal adult tissues. Multiple HLA class I and class II restricted epitopes have been identified in WT1, and multiple investigators are pursuing the treatment of cancer patients with WT1-based vaccines and adoptively transferred WT1-reactive T cells. Here we isolated an HLA A*0201-restricted WT1-reactive T-cell receptor (TCR) by stimulating peripheral blood lymphocytes of healthy donors with the peptide WT1:126-134 in vitro. This TCR mediated peptide recognition down to a concentration of ~0.1 ng/mL when pulsed onto T2 cells as well as recognition of HLA-A*0201 target cells transfected with full-length WT1 cDNA. However, it did not mediate consistent recognition of many HLA-A*0201 tumor cell lines or freshly isolated leukemia cells that endogeneously expressed WT1. We dissected this pattern of recognition further and observed that WT1:126-134 was more efficiently processed by immunoproteasomes compared with standard proteasomes. However, pretreatment of WT1 tumor cell lines with interferon gamma did not appreciably enhance recognition by our TCR. In addition, we highly overexpressed WT1 in several leukemia cell lines by electroporation with full-length WT1 cDNA. Some of these lines were still not recognized by our TCR suggesting possible antigen processing defects in some leukemias. These results suggest WT1:126-134 may not be a suitable target for T-cell based tumor immunotherapies. PMID- 26938945 TI - Trastuzumab-deBouganin Conjugate Overcomes Multiple Mechanisms of T-DM1 Drug Resistance. AB - The development of antibody drug conjugates has provided enhanced potency to tumor-targeting antibodies by the addition of highly potent payloads. In the case of trastuzumab-DM1 (T-DM1), approved for the treatment of metastatic breast cancer, the addition of mertansine (DM1) to trastuzumab substantially increased progression-free survival. Despite these improvements, most patients eventually relapse due to complex mechanisms of resistance often associated with small molecule chemotherapeutics. Therefore, identifying payloads with different mechanisms of action (MOA) is critical for increasing the efficacy of targeted therapeutics and ultimately improving patient outcomes. To evaluate payloads with different MOA, deBouganin, a deimmunized plant toxin that inhibits protein synthesis, was conjugated to trastuzumab and compared with T-DM1 both in vitro and in vivo. The trastuzumab-deBouganin conjugate (T-deB) demonstrated greater potency in vitro against most cells lines with high levels of Her2 expression. In addition, T-deB, unlike T-DM1, was unaffected by inhibitors of multidrug resistance, Bcl-2-mediated resistance, or Her2-Her3 dimerization. Contrary to T DM1 that showed only minimal cytotoxicity, T-deB was highly potent in vitro against tumor cells with cancer stem cell properties. Overall, the results demonstrate the potency and efficacy of deBouganin and emphasize the importance of using payloads with different MOAs. The data suggest that deBouganin could be a highly effective against tumor cell phenotypes not being addressed by current antibody drug conjugate formats and thereby provide prolonged clinical benefit. PMID- 26938946 TI - An Essential Role of the Avidity of T-Cell Receptor in Differentiation of Self Antigen-reactive CD8+ T Cells. AB - Many studies demonstrated crucial roles of avidity of T-cell receptor (TCR) in T cell fate. However, majority of these findings resulted from analysis of non-self antigen-specific CD8 T cells, and little is known about roles of TCR avidity in the fate of self-antigen-specific CD8 T cells. Wilms tumor gene 1 (WT1) protein is a self-antigen most suitable for addressing this issue because WT1 protein is a highly immunogenic, typical self-antigen. Here, we isolated 2 distinct and functional TCRs, TCR1 and TCR2, from murine WT1 peptide (RMFPNAPYL)-specific cytotoxic T lymphocytes (WT1-CTLs) and generated TCR1-retrogenic (Rg) and TCR2-Rg mice under T and B-cell-deficient and -reconstituted conditions. TCR1-transduced CD8 T (TCR1-T) cells had approximately 2-fold higher avidity to WT1 peptide than TCR2-transduced CD8 T (TCR2-T) cells. Cytokine production profiles and cell surface phenotypes showed that TCR1-T cells were more differentiated than TCR2-T cells under both conditions. Therefore, TCR1-T cells with TCR avidity higher than that of TCR2-T cells are more differentiated compared with TCR2-T cells. Furthermore, TCR1-T cells that developed under T and B-cell-reconstituted conditions displayed cytotoxicity against endogenously WT1-expressing tumor cells, whereas TCR2 T cells that developed under the same conditions did not. Thus, it was demonstrated, for the first time, that TCR avidity played an essential role in differentiation of self-antigen-reactive T cells, through the success of establishment of two distinct WT1-CTLs with a difference in only TCR avidity under the identical genetic background. Present results should provide us with an insight for elucidation of the differentiation mechanisms of self-antigen reactive T cells, including tumor antigen-reactive T cells. PMID- 26938947 TI - Phase I Clinical Trial of 4-1BB-based Adoptive T-Cell Therapy for Epstein-Barr Virus (EBV)-positive Tumors. AB - Although adoptive cell therapy using Ag-specific T cells has been tested successfully in the clinic, the production of these T cells has been challenging. By applying our simple and practical 4-1BB-based method for the generation of Ag specific CD8 T cells, here we determined the maximum tolerated dose, toxicity profile, immunologic responses, and clinical efficacy of autologous Epstein-Barr virus (EBV)/LMP2A-specific CD8 T cells (EBV-induced Natural T cell; EBViNT) in patients with relapsed/refractory EBV-positive tumors. This was a single-center, phase I, dose-escalation trial study evaluating 4 escalating dosing schedules of single injected EBViNT. CD8 T-cell responses against different LMP2A peptides in each patient were determined, and the most effective peptides were used to produce EBViNT. The produced autologous EBViNTs were single infused to patients with EBV-associated malignancy who had failed to standard treatments and were of HLA-A02 or A24 type. Of 11 patients enrolled, 8 patients received a single infusion of EBViNT: 4 with nasopharyngeal carcinomas, 1 with Hodgkin lymphoma, 2 with extranodal NK/T lymphomas, and 1 with diffuse large B-cell lymphoma. Single infusion of EBViNT was well tolerated by all the patients and generated objective antitumor responses in 3 of them. EBViNT infusion induced 2 waves of interferon gamma response: 1 approximately 1 week and the other 4-8 weeks after the treatment. The strength of the second wave was related to the efficacy of the treatment. The current trial shows that EBViNT therapy is safe and may provide a new option for treating EBV-positive recurrent cancer patients resistant to conventional therapy. PMID- 26938948 TI - Toxic Epidermal Necrolysis-like Reaction With Severe Satellite Cell Necrosis Associated With Nivolumab in a Patient With Ipilimumab Refractory Metastatic Melanoma. AB - Nivolumab is a fully humanized monoclonal antibody to PD-1, which has shown improved overall and progression-free survival. Across studies of nivolumab, grade 3 or 4 rash has been noted in <1% of patients. We present a case report of patient with metastatic melanoma treated with nivolumab through expanded access program, who developed toxic epidermal necrolysis. Ours is the first case report, reporting grade 4 skin toxicity associated with nivolumab. A 64-year-old female presented with widespread maculopapular skin rash with bullae and areas of skin detachment after receiving 2 doses of nivolumab for ipilimumab refractory metastatic melanoma (BRAF wild-type). She was initially treated with prednisone, which was soon changed to methyprednisone followed by immunoglobulin with minimal response to the rash. After discussion with Dermatology, she was given cyclosporine and high-dose prednisone with gradual but significant improvement in her rash. Her skin biopsy showed interface dermatitis with a lymphocytic infiltrate in the dermoepidermal junction and apoptotic keratinocytes with focal areas of complete necrosis of the epidermis with minimal infiltrate. PMID- 26938949 TI - Hemodynamic Differences Between Central ECMO and Peripheral ECMO: A Primary CFD Study. AB - BACKGROUND Veno-arterial extracorporeal membrane oxygenation (VAECMO), including central ECMO (cECMO) and peripheral ECMO (pECMO), is widely used in cardiopulmonary surgery. The outcomes and complications of both types of ECMO are quite different from each other. The hemodynamic differences among them are hypothesized as a key factor. Hence, a numerical study was conducted to test this hypothesis. MATERIAL AND METHODS Ideal cardiovascular models with pECMO and cECMO were established. The aortic pressure and flow rate were chosen as boundary conditions. The flow pattern, blood flow distributions, flow junction, harmonic index (HI) of blood flow, wall shear stress (WSS), and the oscillatory shear index (OSI) were calculated to evaluate the hemodynamic states. RESULTS pECMO could achieve better upper limb and brain perfusion (0.05458 vs. 0.05062 kg/s), and worse lower limb perfusion (0.03067 vs. 0.03401 kg/s). There exist low WSS (<0.4 pa) regions at the inner and posterior wall of the aorta, and high WSS (>2 pa) region at the access of the femoral artery. These regions also have relatively high OSI value (reaching 0.45). In contrast, for cECMO, there exist high WSS at the posterior wall of the aortic arch. CONCLUSIONS The hemodynamic performances of various types of ECMO are different from each other, which maybe the key reasons for the differences in the outcomes and complications. Therefore, for pEMCO, the lower-extremity ischemia is a complication that must be considered. The type, support level, and duration of ECMO should also be carefully regulated according to the patients' condition, as they are the important factors related to vascular complications. PMID- 26938950 TI - Cluster of Ebola Virus Disease Linked to a Single Funeral - Moyamba District, Sierra Leone, 2014. AB - As of February 17, 2016, a total of 14,122 cases (62% confirmed) of Ebola Virus Disease (Ebola) and 3,955 Ebola-related deaths had been reported in Sierra Leone since the epidemic in West Africa began in 2014. A key focus of the Ebola response in Sierra Leone was the promotion and implementation of safe, dignified burials to prevent Ebola transmission by limiting contact with potentially infectious corpses. Traditional funeral practices pose a substantial risk for Ebola transmission through contact with infected bodies, body fluids, contaminated clothing, and other personal items at a time when viral load is high; however, the role of funeral practices in the Sierra Leone epidemic and ongoing Ebola transmission has not been fully characterized. In September 2014, a sudden increase in the number of reported Ebola cases occurred in Moyamba, a rural and previously low-incidence district with a population of approximately 260,000. The Sierra Leone Ministry of Health and Sanitation and CDC investigated and implemented public health interventions to control this cluster of Ebola cases, including community engagement, active surveillance, and close follow-up of contacts. A retrospective analysis of cases that occurred during July 11 October 31, 2014, revealed that 28 persons with confirmed Ebola had attended the funeral of a prominent pharmacist during September 5-7, 2014. Among the 28 attendees with Ebola, 21 (75%) reported touching the man's corpse, and 16 (57%) reported having direct contact with the pharmacist before he died. Immediate, safe, dignified burials by trained teams with appropriate protective equipment are critical to interrupt transmission and control Ebola during times of active community transmission; these measures remain important during the current response phase. PMID- 26938951 TI - An investigation of process contaminants' formation during the deep frying of breadcrumbs using a bread coat model. AB - The formation of acrylamide, hydroxymethylfurfural (HMF) and furfural was investigated in a deep fried breadcrumb coat model resembling the coat batter of breaded foods. The influence of the composition of the breadcrumb and the frying conditions on the formation of these contaminants was evaluated. Six wheat-based flour formulations of breadcrumbs were deep fried in sunflower oil at temperatures between 170-200 degrees C and for frying times of 1-5 minutes. Results showed significant differences in the levels of contaminants according to the concentration of the potential precursors in the breadcrumbs. HMF was influenced by the sugar content in the breadcrumbs whereas levels of acrylamide were significantly correlated with the ratio between asparagine and reducing sugars. Acrylamide, HMF and furfural were directly related to the frying time and temperature. The composition of the breadcrumb and the compounds formed during frying contributed to the total antioxidant capacity of the fried samples. The bread coat model is a useful tool in the formulation of breaded foods since it allows the evaluation of the contribution of breadcrumbs in the formation of process contaminants after frying. PMID- 26938952 TI - Hyperoxia Induces Intracellular Acidification in Neonatal Mouse Lung Fibroblasts: Real-Time Investigation Using Plasmonically Enhanced Raman Spectroscopy. AB - It is important to understand the molecular mechanisms underlying oxygen toxicity, which contributes to multiple human disorders. The archetype model of oxygen toxicity is neonatal lung injury induced by hyperoxia exposure. Here, we utilized plasmonically enhanced Raman spectroscopy (PERS) in combination with fluorescence and proteomic analysis to provide comprehensive information on hyperoxia-induced biomolecular modifications in neonatal mouse lung fibroblasts (nMLFs). During this study, we made the novel observation that hyperoxia induces intracellular acidification in nMLF, which we probed in real-time using label free PERS. We found that intracellular acidification induces conformational modifications in proteins followed by significant changes in Raman vibrations corresponding to aromatic amino acids such as phenylalanine and tryptophan as well as cysteine moieties. Hyperoxia-induced intracellular pH changes and subsequent modifications in protein expression and associated post-translational modifications within the cells were further validated by fluorescence and proteomic analysis. These new insights may help identifying unique oxidant stress induced mechanisms in disease processes and may guide the development of more efficient therapeutic strategies. PMID- 26938953 TI - DYNAMIC CHANGES OF THE ANTERIOR CHAMBER ANGLE PRODUCED BY INTRAVITREAL ANTI VASCULAR GROWTH FACTOR INJECTIONS. AB - PURPOSE: To use anterior segment optical coherence tomography (AS-OCT) to evaluate the anterior chamber after intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections. METHODS: Preinjection and immediate postinjection AS-OCT images were taken and measurements were compared including angle opening distance (AOD) and trabeculo-iris space area (TISA) at 500 MUm and 750 MUm from the scleral spur (AOD500, AOD750, TISA500 and TISA750, respectively), and the scleral spur angle. RESULTS: Twenty-one eyes from 21 patients were studied. There was significant narrowing of the temporal AOD500, AOD750, and temporal angle after injection (P = 0.03, 0.01, and 0.02, respectively). The percentage of narrowing of the nasal TISA500 and TISA750 was significantly greater in phakic versus pseudophakic eyes (P = 0.03 and 0.02, respectively). A higher postinjection IOP was correlated with increased narrowing of the nasal AOD500, TISA500, TISA750, and nasal angle (R = 0.22, 0.28, 0.34 and 0.20; P = 0.03, 0.01, 0.005 and 0.04, respectively) and a smaller preinjection anterior chamber depth in phakic eyes (R = 0.53, P = 0.01). CONCLUSION: After an anti-vascular endothelial growth factor injection, there is significant narrowing of the temporal anterior chamber angle in all eyes and increased narrowing of the nasal angle in phakic compared with pseudophakic eyes. Physicians performing intravitreal injections should be aware of these associations as they may contribute to our understanding of prolonged elevation of IOP after injections. PMID- 26938954 TI - The treatment timing of labial inversely impacted maxillary central incisors: A prospective study. AB - OBJECTIVE: To determine the timing of treatment for the labial inversely impacted maxillary central incisors. METHODS: Twenty-eight patients (mean age, 8.2 years) with labial inversely impacted maxillary central incisors were divided into early treated and later-treated groups according to their dental age. All of the patients were treated with a combination of surgery and orthodontic traction using the Guide rod appliance. Cone-beam computed tomography images were taken immediately after treatment for assessing the root morphology, root length, and alveolar bone loss. Sagittal slices were evaluated at the widest labial-lingual width of the tooth in the axial view. All variables were evaluated by Simplant 13.0 software (Materialise Dental NV, Leuven, Belgium). RESULTS: The rank sum test indicated that the root length of two groups showed a statistically significant difference between the impacted and homonym tooth, with a shorter length in the impacted tooth (P < .05). The D-value (difference of root length between the impacted and homonym tooth) and alveolar bone loss on the labial side of the impacted incisor are significantly less in the early-treated groups when compared with the later-treated groups (P < .05). Spearman rank correlation analysis showed a statistically positive association between the treatment timing and D-value (r = .623, P < .05). The chi-square test for morphology of root apex indicated that the incidence of the root-apex-directed labial side is significantly higher in the later-treated groups when compared with the early treated groups. CONCLUSION: The labial inversely impacted maxillary central incisors should be treated early to promote root development by achieving a better morphology of root apex, thus reducing the risk of alveolar bone loss on the labial side. PMID- 26938955 TI - Nonsurgical miniscrew-assisted rapid maxillary expansion results in acceptable stability in young adults. AB - OBJECTIVE: To evaluate the stability of nonsurgical miniscrew-assisted rapid maxillary expansion (MARME) in young adults with a transverse maxillary deficiency. MATERIALS AND METHODS: From a total of 69 adult patients who underwent MARME followed by orthodontic treatment with a straight-wire appliance, 20 patients (mean age, 20.9 +/- 2.9 years) with follow-up records (mean, 30.2 +/- 13.2 months) after debonding were selected. Posteroanterior cephalometric records and dental casts were obtained at the initial examination (T0), immediately after MARME removal (T1), immediately after debonding (T2), and at posttreatment follow up (T3). RESULTS: Suture separation was observed in 86.96% of subjects (60/69). An increase in the maxillary width (J-J; 1.92 mm) accounted for 43.34% of the total expansion with regard to the intermolar width (IMW) increase (4.43 mm; P < .001) at T2. The amounts of J-J and IMW posttreatment changes were -0.07 mm (P > .05) and -0.42 mm (P = .01), respectively, during retention. The postexpansion change in middle alveolus width increased with age (P < .05). The postexpansion change of interpremolar width (IPMW) was positively correlated with the amount of IPMW expansion (P < .05) but not with IMW. The changes of the clinical crown heights in the maxillary canines, first premolars, and first molars were not significant at each time point. CONCLUSIONS: Nonsurgical MARME can be a clinically acceptable and stable treatment modality for young adults with a transverse maxillary deficiency. PMID- 26938956 TI - Remote Control by pi-Conjugation of the Emissive Properties of Fischer Carbene BODIPY Dyads. AB - The synthesis, structure, and complete characterization of mono- and bimetallic dyads joining Fischer carbene complexes and BODIPY chromophores are reported. In these organometallic species, the Fischer carbene complex is attached to the BODIPY moiety through a p-aminophenyl group linked at the C8 carbon atom of the BODIPY core. The photophysical properties, namely the corresponding UV/vis absorption and emission spectra of these new metal-carbene complexes, are analyzed and discussed. It is found that whereas the absorption of the considered dyads strongly resembles that of the parent 4-anilinyl-substituted BODIPY, the fluorescence emission is significantly reduced in these species, very likely as a result of a Forster-type energy transfer mechanism. At variance, the replacement of the pentacarbonyl-metal(0) fragment by a carbonyl group leads to high fluorescence emission intensity. In addition, the emissive properties of the BODIPY core in these organometallic dyads can be tuned by remote groups by means of pi-conjugation, as supported by density functional theory calculations. PMID- 26938964 TI - Optimizing the assessment of suicidal behavior: The application of curtailment techniques. AB - BACKGROUND: Given their length, commonly used scales to assess suicide risk, such as the Beck Scale for Suicide Ideation (SSI) are of limited use as screening tools. In the current study we tested whether deterministic and stochastic curtailment can be applied to shorten the 19-item SSI, without compromising its accuracy. METHODS: Data from 366 patients, who were seen by a liaison psychiatry service in a general hospital in Scotland after a suicide attempt, were used. Within 24h of admission, the SSI was administered; 15 months later, it was determined whether a patient was re-admitted to a hospital as the result of another suicide attempt. We fitted a Receiver Operating Characteristic curve to derive the best cut-off value of the SSI for predicting future suicidal behavior. Using this cut-off, both deterministic and stochastic curtailment were simulated on the item score patterns of the SSI. RESULTS: A cut-off value of SSI>=6 provided the best classification accuracy for future suicidal behavior. Using this cut-off, we found that both deterministic and stochastic curtailment reduce the length of the SSI, without reducing the accuracy of the final classification decision. With stochastic curtailment, on average, less than 8 items are needed to assess whether administration of the full-length test will result in an SSI score below or above the cut-off value of 6. LIMITATIONS: New studies using other datasets should re-validate the optimal cut-off for risk of repeated suicidal behavior after being treated in a hospital following an attempt. CONCLUSIONS: Curtailment can be used to simplify the assessment of suicidal behavior, and should be considered as an alternative to the full scale. PMID- 26938965 TI - Vortioxetine for major depressive disorder: An indirect comparison with duloxetine, escitalopram, levomilnacipran, sertraline, venlafaxine, and vilazodone, using number needed to treat, number needed to harm, and likelihood to be helped or harmed. AB - BACKGROUND: Vortioxetine is approved for the treatment of major depressive disorder and differs from other antidepressants in terms of its pharmacodynamic profile. Given the limited number of head-to-head studies comparing vortioxetine with other antidepressants, indirect comparisons using effect sizes observed in other trials can be helpful to discern potential differences in clinical outcomes. METHODS: Data sources were the clinical trial reports for the pivotal short-term double-blind trials for vortioxetine and from publicly available sources for the pivotal short-term double-blind trials for two commonly used generic serotonin specific reuptake inhibitor antidepressants (sertraline, escitalopram), two commonly used generic serotonin-norepinephrine reuptake inhibitor antidepressants (venlafaxine, duloxetine), and two recently introduced branded antidepressants (vilazodone, levomilnacipran). Response was the efficacy outcome of interest, defined as a>=50% reduction from baseline on the Montgomery Asberg Depression Rating Scale or Hamilton Depression Rating Scale. The tolerability outcome of interest was discontinuation because of an adverse event. Number needed to treat (NNT) and number needed to harm (NNH) for these outcomes vs. placebo were calculated, as well as likelihood to be helped or harmed (LHH) to contrast efficacy vs. tolerability. RESULTS: The analysis included 8 studies for duloxetine, 3 studies for escitalopram, 5 studies for levomilnacipran, 1 study for sertraline, 4 studies for venlafaxine, 2 studies for vilazodone, and 11 studies for vortioxetine. NNTs for response vs. placebo were 6 (95% CI 5-8), 7 (5 11), 10 (8-16), 6 (4-13), 6 (5-9), 8 (6-16), and 9 (7-11), respectively. NNHs for discontinuation because of an adverse event vs. placebo were 25 (17-51), 31 (19 92), 19 (14-27), 7 (5-12), 8 (7-11), 27 (15-104), and 43 (28-91), respectively. LHH values contrasting response vs. discontinuation because of an adverse event were 4.3, 4.6, 1.8, 1.2, 1.4, 3.3, and 5.1 respectively. LIMITATIONS: Subjects were all participants in carefully designed and executed clinical trials and may not necessarily reflect patients in clinical settings who may have complex psychiatric and non-psychiatric comorbidities. The measured outcomes come from different studies and thus comparisons are indirect. CONCLUSIONS: Vortioxetine demonstrates similar efficacy to that observed for duloxetine, escitalopram, levomilnacipran, sertraline, venlafaxine, and vilazodone, however overall tolerability as measured by discontinuation because of an adverse event differs. Vortioxetine is 5.1 times more likely to be associated with response than discontinuation because of an adverse event when compared to placebo. PMID- 26938967 TI - What happens after a single surgical intervention for hidradenitis suppurativa? A retrospective claims-based analysis. AB - Objective Hidradenitis suppurativa (HS) is often treated by surgery. The risk of recurrence after surgery is common and the consequences are substantial, but neither has been quantified using a claims database. This study aimed to estimate the burden associated with non-curative surgery in HS patients. Methods A retrospective analysis was performed of health insurance claims data from Q1 1999 to Q2 2011 in a US claims database. The analysis included 2668 adults with >=1 diagnosis of HS and >=1 claim for skin surgery within 6 months after diagnosis. Healthcare resource utilization and medical costs were compared using multivariate regressions. Results Overall, 46% of HS patients had >=1 indicator of non-curative surgery. The incidences of inpatient, emergency department, and outpatient visits were 88%, 40%, and 30% higher, respectively, for patients with non-curative surgery vs patients without indicator of non-curative surgery (all p < 0.001). Average medical costs were $11,858 and $6427 for patients with and without indicators of non-curative surgery, respectively. The difference of $4185 (p < 0.001) was mainly driven by inpatient costs (difference = $2685; p < 0.001). Limitations Indicators of non-curative HS surgery were defined based on an empirical algorithm. Conclusions Non-curative HS surgery occurred in almost half of all cases and represents a significant burden on patients and payers in terms of resource utilization and costs. PMID- 26938966 TI - Examination of the dynamic interplay between posttraumatic stress symptoms and alcohol misuse among combat-exposed Operation Enduring Freedom (OEF)/Operation Iraqi Freedom (OIF) Veterans. AB - BACKGROUND: Although alcohol misuse co-occurs with PTSD symptoms at a strikingly high rate (i.e., nearly 52% of men and 28% of women with PTSD also meet diagnostic criteria for an Alcohol Use Disorder), the functional associations between these symptom types remain unclear. METHODS: The current study sought to clarify the nature of posttraumatic stress-alcohol misuse relations by employing a prospective longitudinal methodology-the latent difference score approach-to examine dynamic change in posttraumatic stress symptoms and alcohol misuse among 478 combat-exposed Veterans completing a longitudinal survey of post-deployment mental and physical health. This study builds on the existing literature, as most prior research has been limited to cross-sectional studies and has not explored prospective relations between specific PTSD symptom clusters and alcohol misuse. RESULTS: Consistent with the self-medication model, results indicated that PTSD symptoms demonstrate a prospective and proximal association with alcohol misuse during the assessment period; however, alcohol misuse did not appear to be a unique contributor to overall PTSD symptom exacerbation over time. Examination of individual PTSD symptom clusters revealed that more severe symptoms of intrusion and numbing, but not avoidance and hyperarousal, predicted greater alcohol misuse at subsequent time intervals. LIMITATIONS: The constructs examined within this investigation relied on self-report data; diagnostic criteria for PTSD and/or Alcohol Use Disorders were not assessed. Future work may benefit from replicating these findings in clinical populations formally diagnosed with PTSD via clinician administered structured interviews. CONCLUSIONS: Findings underscore the importance of addressing PTSD symptoms in the context of alcohol treatment to facilitate improved drinking outcomes. PMID- 26938968 TI - Maternal Deaths Account for a Small Proportion of the Total Deaths Among Reproductive Age Women. AB - BACKGROUND: For more than 30 years, the focus for women's health in low- and middle-income countries has been on reductions in maternal mortality. This perception was reinforced by the choice of the maternal mortality ratio as the primary indicator for women's health in the Millennium Development Goals. This analysis provides a more objective view by comparing the relative magnitudes of mortality among reproductive age women during pregnancy and the 6-week postpartum period versus other periods during this age range. MATERIALS AND METHODS: Data were aggregated from 38 countries in three regions with Demographic and Health Surveys that contained a maternal mortality module and were conducted in the prior 10 years to derive the proportion of total mortality ascribed to maternal mortality (proportion maternal [PM]) among women 15-49 years of age in 5-year age groups by country, region, and human immunodeficiency virus (HIV) prevalence. Estimates of maternal and nonmaternal deaths were based on the sisterhood method. Age-adjusted PM ranged from 5.7% in Swaziland to 41.7% in Timor-Leste. Regional averages were 14.3% in Latin America and the Caribbean, 24.2% in Asia, and 19.8% in sub-Saharan Africa (SSA). The age-specific pattern of PM showed an increasing trend into the mid-30s followed by a decline. The age-adjusted PM for each country in SSA stratified by HIV prevalence showed an inverse relationship between HIV prevalence and PM with countries with high and low HIV at the lower and upper ends of the PM distribution, respectively. CONCLUSIONS: Maternal deaths account for only 6%-40% of all deaths occurring among reproductive age women in a selection of low- and middle-income countries. Although a continued focus and push to reduce maternal mortality is warranted, attention to other causes of death and health issues for women of reproductive age is clearly needed. Research on the causes of death among women and prevention and treatment policies that provide health, education, and nutrition services to women need to be a priority. PMID- 26938969 TI - "Shoot and Sense" Janus Micromotors-Based Strategy for the Simultaneous Degradation and Detection of Persistent Organic Pollutants in Food and Biological Samples. AB - A novel Janus micromotor-based strategy for the direct determination of diphenyl phthalate (DPP) in food and biological samples is presented. Mg/Au Janus micromotors are employed as novel analytical platforms for the degradation of the non-electroactive DPP into phenol, which is directly measured by difference pulse voltammetry on disposable screen-printed electrodes. The self-movement of the micromotors along the samples result in the generation of hydrogen microbubbles and hydroxyl ions for DPP degradation. The increased fluid transport improves dramatically the analytical signal, increasing the sensitivity while lowering the detection potential. The method has been successfully applied to the direct analysis of DPP in selected food and biological samples, without any sample treatment and avoiding any potential contamination from laboratory equipment. The developed approach is fast (~5 min) and accurate with recoveries of ~100%. In addition, efficient propulsion of multiple Mg/Au micromotors in complex samples has also been demonstrated. The advantages of the micromotors-assisted technology, i.e., disposability, portability, and the possibility to carry out multiple analysis simultaneously, hold considerable promise for its application in food and biological control in analytical applications with high significance. PMID- 26938970 TI - The epilepsy treatment gap in rural Tanzania: A community-based study in adults. AB - PURPOSE: Most people with epilepsy (PWE) in low-income countries are not treated. We identified risk factors for the epilepsy treatment gap in rural Tanzania. METHODS: We identified adult PWE in a community-based prevalence study. Factors associated with failure to access or default from medical care were identified using logistic regression modelling. RESULTS: A total of 291 PWE were included, of whom 253 (86.9%) had presented to medical services. Failure to present was positively associated with using alcohol (odds ratio (OR) 4.20; 95% confidence interval (CI) 1.63 to 10.82) or attending traditional healers (OR 2.62; CI 1.00 to 6.83) and inversely associated with having completed primary education (OR 0.33; CI 0.11 to 0.96). Default from treatment was associated with being male (OR 3.35; CI 1.39 to 8.09), having a seizure-related injury (OR 2.64; CI 1.12 to 6.19), believing in a supernatural cause for epilepsy (OR 5.44; CI 1.48 to 19.94) or having no expressed knowledge of cause (OR 5.29; CI 1.60 to 17.52). Cases less likely to default had a duration of epilepsy greater than 10 years (OR 0.28; CI 0.09 to 0.90) or had previously received a seizure-related diagnosis (OR 0.25; CI 0.09 to 0.65). Of all 291 PWE included, 118 denied taking AEDs; the epilepsy treatment gap in this population was therefore 40.5% (95% CI 34.9 to 46.2). CONCLUSION: Interventions to improve access to education and to support formal diagnoses may promote access to, and retention under, medical care for PWE in rural Tanzania and in other low-income countries. PMID- 26938973 TI - Helix B Surface Peptide Protects against Acute Myocardial Ischemia-Reperfusion Injury via the RISK and SAFE Pathways in a Mouse Model. AB - OBJECTIVE: This study explores the effects of helix B surface peptide (HBSP) on myocardial infarct size (IS), cardiac function, cardiomyocyte apoptosis and oxidative stress damage in mouse hearts subjected to myocardial ischemia reperfusion injury (MIRI) and also the mechanisms underlying the effects. METHOD: Male adult mice were subjected to 45 min of ischemia followed by 2 h of reperfusion; 5 min before the reperfusion, they were treated with HBSP or vehicle. MIRI-induced IS, cardiomyocyte apoptosis and cardiac functional impairment were determined and compared. Western blot analysis was then conducted to elucidate the mechanism of HBSP after treatment. RESULTS: HBSP administration before reperfusion significantly reduced the myocardial IS, decreased cardiomyocyte apoptosis, reduced the activities of superoxide dismutase and malondialdehyde and partially preserved heart function. As demonstrated by the Western blot analysis, HBSP after treatment upregulated Akt/GSK-3beta/ERK and STAT-3 phosphorylation; these inhibitors, in turn, weakened the beneficial effects of HBSP. CONCLUSION: HBSP plays a protective role in MIRI in mice by inhibiting cardiomyocyte apoptosis, reducing the MIRI-induced IS, oxidative stress and improving the heart function after MIRI. The mechanism underlying these effects of HBSP is related to the activation of the RISK (reperfusion injury salvage kinase, Akt/GSK-3beta/ERK) and SAFE (STAT-3) pathways. PMID- 26938974 TI - Is the addition of aminoglycosides to beta-lactams in cancer patients with febrile neutropenia needed? AB - It is still controversial if the combined use of beta-lactam antibiotics and aminoglycosides has advantages over broad-spectrum beta-lactam monotherapy for the empirical treatment of cancer patients with febrile neutropenia. Searching in Epistemonikos database, which is maintained by screening 30 databases, we identified three systematic reviews including 14 pertinent randomized trials. We combined the evidence using meta-analysis and generated a summary of findings table following the GRADE approach. We concluded the combination of beta-lactam antibiotics and aminoglycosides probably does not lead to a reduced mortality in febrile neutropenic cancer patients and it might increase nephrotoxicity. PMID- 26938975 TI - Corrigendum. AB - Levine M, Hoffman RS, Lavergne V, et al. Systematic review of the effect of intravenous lipid emulsion therapy for non-local anesthetics toxicity. Clin Toxicol. 2016. http://dx.doi.org/10.3109/15563650.2015.1126286. When the above article was first published online, the Lipid Emulsion Workgroup was incorrectly listed as the AACT Lipid Emulsion Workgroup in the author list. This has now been corrected in both the print and online versions.The authors apologise for this error. PMID- 26938976 TI - Pleiotropic and Renoprotective Effects of Erythropoietin Beta on Experimental Diabetic Nephropathy Model. AB - BACKGROUND: This study aimed at investigating the possible protective effect of erythropoietin beta on experimental diabetic nephropathy (DN) model in rats. METHODS: Sprague Dawley rats (n = 32) were allocated into 4 equal groups of 8 each, the control (Group C), diabetes (Group D), erythropoietin beta (Group E), and erythropoietin beta treated DN (Group E + D) groups. Streptozocin (65 mg/kg) was used to induce diabetes in 10-week old rats. Erythropoietin beta was given intraperitoneally at a dose of 500 IU/kg/3 days of a week for 12 weeks. Renal function parameters, intrarenal levels and activities of oxidative stress biomarkers, serum inflammatory parameters and kidney histology were determined. RESULTS: Group E + D had lower mean albumin-to-creatinine ratio (p < 0.001) as well as higher creatinine clearance (p = 0.035) than the diabetic rats (Group D). Intrarenal malondialdehyde levels were significantly lower (p = 0.004); glutathione (GSH) levels (p = 0.003), GSH peroxidase (p = 0.004) and superoxide dismutase (p < 0.005) activities of renal tissue were significantly higher in Group E + D than in Group D. The mean serum levels of interleukin-4 (p < 0.005), interleukin 1 beta (p = 0.012), interferon gamma (p = 0.018) and tumor necrosis factor alpha (p < 0.005) were significantly lower; serum levels of monocyte chemoattractant protein 1 (p = 0.018) was significantly higher in Group E + D when compared to Group D. The mean scores of tubulointerstitial inflammation (p = 0.004), tubular injury (p = 0.013) and interstitial fibrosis (p = 0.003) were also lower in Group E + D when compared to Group D. CONCLUSION: Our data seem to suggest a potential role of erythropoietin beta for reducing the progression of DN in an experimental rat model. This protective effect is, in part, attributable to the suppression of the inflammatory response and oxidative damage. PMID- 26938981 TI - A 5-Ureido-Modified Sialyl Donor: A Tool for the Synthesis of alpha-Sialosides. AB - A novel method for the synthesis of alpha-sialosides using a newly developed 5 ureido-modified sialyl donor is reported. The donor was found to be useful for alpha-selective sialidation with various glycosyl acceptors, forming alpha(2,6)Glc, alpha(2,6)Gal, and alpha(2,3)Gal linkages in excellent yield and with stereoselectivity. Furthermore, alpha-sialoside was easily isolated from the reaction mixture by the 1,5-lactamization method under mild conditions. Successful application of the C5-ureido sialyl donor to the synthesis of a sialoside confirmed the usefulness of the present method. PMID- 26938980 TI - Assessing Diabetes Self-Management with the Diabetes Self-Management Questionnaire (DSMQ) Can Help Analyse Behavioural Problems Related to Reduced Glycaemic Control. AB - AIM: To appraise the Diabetes Self-Management Questionnaire (DSMQ)'s measurement of diabetes self-management as a statistical predictor of glycaemic control relative to the widely used SDSCA. METHODS: 248 patients with type 1 diabetes and 182 patients with type 2 diabetes were cross-sectionally assessed using the two self-report measures of diabetes self-management DSMQ and SDSCA; the scales were used as competing predictors of HbA1c. We developed a structural equation model of self-management as measured by the DSMQ and analysed the amount of variation explained in HbA1c; an analogue model was developed for the SDSCA. RESULTS: The structural equation models of self-management and glycaemic control showed very good fit to the data. The DSMQ's measurement of self-management showed associations with HbA1c of -0.53 for type 1 and -0.46 for type 2 diabetes (both P < 0.001), explaining 21% and 28% of variation in glycaemic control, respectively. The SDSCA's measurement showed associations with HbA1c of -0.14 (P = 0.030) for type 1 and -0.31 (P = 0.003) for type 2 diabetes, explaining 2% and 10% of glycaemic variation. Predictive power for glycaemic control was significantly higher for the DSMQ (P < 0.001). CONCLUSIONS: This study supports the DSMQ as the preferred tool when analysing self-reported behavioural problems related to reduced glycaemic control. The scale may be useful for clinical assessments of patients with suboptimal diabetes outcomes or research on factors affecting associations between self-management behaviours and glycaemic control. PMID- 26938982 TI - Comparison Study on the Stability of Copper Nanowires and Their Oxidation Kinetics in Gas and Liquid. AB - The unsaturated "dangling" bonds on the surface of nanomaterials are extremely sensitive to the external environment, which gives nanomaterials a dual nature, i.e., high reactivity and poor stability. However, studies on the long-term effects of stability and reactivity of nanomaterials under practical conditions are rarely found in the literature and lag far behind other research. Furthermore, the long-term effects on the stability and reactivity of a nanomaterial without coating under practical conditions are seriously long neglected. Herein, by choosing copper nanowire as an example, we systematically study the stability of copper nanowires (CuNWs) in the liquid and gas phase by monitoring the change of morphology, phase, and valence state of CuNWs during storage. CuNWs exhibit good dispersibility and durable chemical stability in polar organic solvents, while CuNWs stored in water or nonpolar organic solvents evolve into a mace-like structure. Additionally, fresh CuNWs are oxidized into CuO nanotubes with thin shells by heating in air. The activation energies of oxidation of CuNWs in the gas phase are determined by the Kissinger method. More importantly, the different oxidation pathways have significant effects on the final morphology, surface area, phase, optical absorption, band gap, and vibrational property of the oxidation products. Understanding the stability and reactivity of Cu nanostructures will add value to their storage and applications. This work emphasizes the significant issue on the stability of nanostructures, which should be taken into account from the viewpoint of their practical application. PMID- 26938984 TI - Modulation of Buckling Dynamics in Nanoparticle Laden Droplets Using External Heating. AB - Dynamics of contact free (levitated) drying of nanofluid droplets is ubiquitous in many application domains ranging from spray drying to pharmaceutics. Controlling the final morphology (macro to micro scales) of the dried out sample poses some serious challenges. Evaporation of solvent and agglomeration of particles leads to porous shell formation in acoustically levitated nanosilica droplets. The capillary pressure due to evaporation across the menisci at the nanoscale pores causes buckling of the shell which leads to ring and bowl shaped final structures. Acoustics plays a crucial role in flattening of droplets which is a prerequisite for initiation of buckling in the shell. Introduction of mixed nanocolloids (sodium dodecyl sulfate + nanosilica) reduces evaporation rate, disrupts formation of porous shell, and enhances mechanical strength of the shell, all of which restricts the process of buckling. Although buckling is completely arrested in such surfactant added droplets, controlled external heating using laser enhances evaporation through the pores in the shell due to thermally induced structural changes and rearrangement of SDS aggregates which reinitializes buckling in such droplets. Furthermore, inclusion of anilinium hydrochloride into the nanoparticle laden droplets produces ions which adsorb and modify the morphology of sodium dodecyl sulfate crystals and reinitializes buckling in the shell (irrespective of external heating conditions). The kinetics of buckling is determined by the combined effect of morphology of the colloidal particles, particle/aggregate diffusion rate within the droplet, and the rate of evaporation of water. The buckling dynamics leads to cavity formation which grows subsequently to yield final structures with drastically different morphological features. The cavity growth is controlled by evaporation through the nanoscale pores and exhibits a universal trend irrespective of heating rate and nanoparticle type. PMID- 26938983 TI - An Evidenced-Based Scale of Disease Severity following Human Challenge with Enteroxigenic Escherichia coli. AB - BACKGROUND: Experimental human challenge models have played a major role in enhancing our understanding of infectious diseases. Primary outcomes have typically utilized overly simplistic outcomes that fail to entirely account for complex illness syndromes. We sought to characterize clinical outcomes associated with experimental infection with enterotoxigenic Escherichia coli (ETEC) and to develop a disease score. METHODS: Data were obtained from prior controlled human ETEC infection studies. Correlation and univariate regression across sign and symptom severity was performed. A multiple correspondence analysis was conducted. A 3-parameter disease score with construct validity was developed in an iterative fashion, compared to standard outcome definitions and applied to prior vaccine challenge trials. RESULTS: Data on 264 subjects receiving seven ETEC strains at doses from 1x105 to 1x1010 cfu were used to construct a standardized dataset. The strongest observed correlation was between vomiting and nausea (r = 0.65); however, stool output was poorly correlated with subjective activity-impacting outcomes. Multiple correspondence analyses showed covariability in multiple signs and symptoms, with severity being the strongest factor corresponding across outcomes. The developed disease score performed well compared to standard outcome definitions and differentiated disease in vaccinated and unvaccinated subjects. CONCLUSION: Frequency and volumetric definitions of diarrhea severity poorly characterize ETEC disease. These data support a disease severity score accounting for stool output and other clinical signs and symptoms. Such a score could serve as the basis for better field trial outcomes and gives an additional outcome measure to help select future vaccines that warrant expanded testing in pivotal pre-licensure trials. PMID- 26938986 TI - An unusual etiology of abdominal pain in children. AB - The first case of cholecystitis acalculous by Cryptosporidium in onco-hematology pediatric patient was described in this work. PMID- 26938985 TI - Antiproliferative Effect of Androgen Receptor Inhibition in Mesenchymal Stem-Like Triple-Negative Breast Cancer. AB - BACKGROUND/AIMS: Androgen receptor (AR), a steroid hormone receptor, has recently emerged as prognostic and treatment-predictive marker in breast cancer. Previous studies have shown that AR is widely expressed in up to one-third of triple negative breast cancer (TNBC). However, the role of AR in TNBC is still not fully understood, especially in mesenchymal stem-like (MSL) TNBC cells. METHODS: MSL TNBC MDA-MB-231 and Hs578T breast cancer cells were exposed to various concentration of agonist 5-alpha-dihydrotestosterone (DHT) or nonsteroidal antagonist bicalutamide or untreated. The effects of AR on cell viability and apoptosis were determined by MTT assay, cell counting, flow cytometry analysis and protein expression of p53, p73, p21 and Cyclin D1 were analyzed by western blotting. The bindings of AR to p73 and p21 promoter were detected by ChIP assay. MDA-MB-231 cells were transplanted into nude mice and the tumor growth curves were determined and expression of AR, p73 and p21 were detected by Immunohistochemistry (IHC) staining after treatment of DHT or bicalutamide. RESULTS: We demonstrate that AR agonist DHT induces MSL TNBC breast cancer cells proliferation and inhibits apoptosis in vitro. Similarly, activated AR significantly increases viability of MDA-MB-231 xenografts in vivo. On the contrary, AR antagonist, bicalutamide, causes apoptosis and exerts inhibitory effects on the growth of breast cancer. Moreover, DHT-dependent activation of AR involves regulation in the cell cycle related genes, including p73, p21 and Cyclin D1. Further investigations indicate the modulation of AR on p73 and p21 mediated by direct binding of AR to their promoters, and DHT could make these binding more effectively. CONCLUSIONS: Our study demonstrates the tumorigenesis role of AR and the inhibitory effect of bicalutamide in AR-positive MSL TNBC both in vitro and in vivo, suggesting that AR inhibition could be a potential therapeutic approach for AR-positive TNBC patients. PMID- 26938988 TI - Lipid-free Fluoropolymer-based Propofol Emulsions and Lipid Reversal of Propofol Anesthesia in Rats. AB - BACKGROUND: Propofol, as a lipid-based emulsion, is effective at inducing anesthesia. It does, however, suffer from several drawbacks, including microbial growth, hyperlipidemia, and pain on injection. In this study, the authors examined the ability of four lipid-free propofol nanoemulsions to induce anesthesia in rats and tested whether a subsequent lipid bolus would accelerate emergence from anesthesia. METHODS: The authors administered five formulations of propofol intravenously to six rats, delivering five different doses five times each, in a repeated-measures randomized crossover design and measured time to loss and recovery of righting reflex. The formulations included (1) Diprivan (AstraZeneca, United Kingdom); (2) L3, incorporating a semifluorinated surfactant plus egg lecithin; (3) B8, incorporating a semifluorinated surfactant only; (4) F8, incorporating a semifluorinated surfactant plus perfluorooctyl bromide; and (5) L80, incorporating egg lecithin only. In a second phase of the study, the authors administered a lipid bolus immediately after a dose of B8 or Diprivan. RESULTS: All formulations except L80 impaired the righting reflex without apparent toxic effects. The authors estimated the threshold dose for induction by determining the x-intercept of the linear regression between time to recovery versus log dose. Threshold doses ranged from 5.8 (95% CI, 5.5 to 6.2) to 8.6 (95% CI, 7.2 to 10.2) mg/kg. A 15 ml/kg lipid bolus resulted in an accelerated clearance. CONCLUSIONS: Three of the four novel lipid-free fluoropolymer-based formulations showed efficacy in producing anesthesia, which was comparable to that of Diprivan, and a lipid bolus hastened recovery. These novel propofol formulations have the potential to avoid complications seen with the existing lipid-based formulation. PMID- 26938987 TI - Involvement of Polycomb Repressive Complex 2 in Maturation of Induced Pluripotent Stem Cells during Reprogramming of Mouse and Human Fibroblasts. AB - Induced pluripotent stem cells (iPSCs) provide a reliable source for the study of regenerative medicine, drug discovery, and developmental biology. Despite extensive studies on the reprogramming of mouse and human fibroblasts into iPSCs, the efficiency of reprogramming is still low. Here, we used a bioinformatics and systems biology approach to study the two gene regulatory waves governing the reprogramming of mouse and human fibroblasts into iPSCs. Our results revealed that the maturation phase of reprogramming was regulated by a more complex regulatory network of transcription factors compared to the initiation phase. Interestingly, in addition to pluripotency factors, the polycomb repressive complex 2 (PRC2) members Ezh2, Eed, Jarid2, Mtf2, and Suz12 are crucially recruited during the maturation phase of reprogramming. Moreover, we found that during the maturation phase of reprogramming, pluripotency factors, via the expression and induction of PRC2 complex members, could silence the lineage specific gene expression program and maintain a ground state of pluripotency in human and mouse naive iPSCs. The findings obtained here provide us a better understanding of the gene regulatory network (GRN) that governs reprogramming, and the maintenance of the naive state of iPSCs. PMID- 26938989 TI - Adductor Canal Block Provides Noninferior Analgesia and Superior Quadriceps Strength Compared with Femoral Nerve Block in Anterior Cruciate Ligament Reconstruction. AB - BACKGROUND: By targeting the distal branches of the femoral nerve in the mid thigh, the adductor canal block (ACB) can preserve quadriceps muscle strength while providing analgesia similar to a conventional femoral nerve block (FNB) for inpatients undergoing major knee surgery. In this randomized, double-blind, noninferiority trial, the authors hypothesized that ACB provides postoperative analgesia that is at least as good as FNB while preserving quadriceps strength after outpatient anterior cruciate ligament reconstruction. METHODS: A total of 100 patients were randomized to receive ACB or FNB with 20 ml ropivacaine 0.5% (with epinephrine). The authors sequentially tested the joint hypothesis that ACB is noninferior to FNB for cumulative oral morphine equivalent consumption and area under the curve for pain scores during the first 24 h postoperatively and also superior to FNB for postblock quadriceps maximal voluntary isometric contraction. RESULTS: The authors analyzed 52 and 48 patients who received ACB and FNB, respectively. Compared with preset noninferiority margins, the ACB-FNB difference (95% CI) in morphine consumption and area under the curve for pain scores were -4.8 mg (-12.3 to 2.7) (P = 0.03) and -71 mm h (-148 to 6) (P < 0.00001), respectively, indicating noninferiority of ACB for both outcomes. The maximal voluntary isometric contraction for ACB and FNB at 45 min were 26.6 pound force (24.7-28.6) and 10.6 pound-force (8.3-13.0) (P < 0.00001), respectively, indicating superiority of ACB. CONCLUSION: Compared with FNB, the study findings suggest that ACB preserves quadriceps strength and provides noninferior postoperative analgesia for outpatients undergoing anterior cruciate ligament reconstruction. PMID- 26938990 TI - Construct Validity of the SF-12v2 for the Homeless Population with Mental Illness: An Instrument to Measure Self-Reported Mental and Physical Health. AB - BACKGROUND: Self-reported health measures are important indicators used by clinicians and researchers for the evaluation of health interventions, outcome assessment of clinical studies, and identification of health needs to improve resource allocation. However, the application of self-reported health measures relies on developing reliable and valid instruments that are suitable across diverse populations. The main objective of this study is to evaluate the construct validity of the SF-12v.2, an instrument for measuring self-rated physical and mental health, for homeless adults with mental illness. Various interventions have been aimed at improving the health of homeless people with mental illness, and the development of valid instruments to evaluate these interventions is imperative. STUDY DESIGN: We measured self-rated mental and physical health from a quota sample of 575 homeless people with mental illness using the SF-12v2, EQ-5D, Colorado Symptoms Index, and physical/mental health visual analogue scales. We examined the construct validity of the SF-12v2 through confirmatory factor analyses (CFA), and using ANOVA/correlation analyses to compare the SF-12v2 to the other instruments to ascertain discriminant/convergent validity. RESULTS: Our CFA showed that the measurement properties of the original SF-12v2 model had a mediocre fit with our empirical data (chi2 = 193.6, df = 43, p < .0001, CFI = 0.85, NFI = 0.83, RMSEA = 0.08). We demonstrate that changes based on theoretical rationale and previous studies can significantly improve the model, achieving an excellent fit in our final model (chi2 = 160.6, df = 48, p < .0001, CFI = 0.95, NFI = 0.95, RMSEA = 0.06). Our CFA results suggest that an alternative scoring method based on the new model may optimize health status measurement of a homeless population. Despite these issues, convergent and discriminant validity of the SF-12v2 (scored based on the original model) was supported through multiple comparisons with other instruments. CONCLUSION: Our study demonstrates for the first time that the SF-12v2 is generally appropriate as a measure of physical and mental health status for a homeless population with mental illness. PMID- 26938992 TI - A vision of KIR variation at super resolution. AB - The Ninth Killer Cell Immunoglobulin-Like Receptor (KIR) Workshop was held in Winchester, UK late in the summer of 2015. The extraordinary diversity of KIR and its functional consequences were key themes throughout the meeting. Novel sequencing technologies and new bioinformatics techniques continue to increase our understanding of the genetic diversity and evolution of the KIR; while a deeper understanding of KIR functions, including their specificity for MHC and its peptide ligands, are generating more refined models of their role in disease. Limited to 100 delegates from around the world, this intimate workshop facilitated vigorous discussion, generating new ideas for research in this ever expanding field. PMID- 26938991 TI - Associations of Circulating Oxidized LDL and Conventional Biomarkers of Cardiovascular Disease in a Cross-Sectional Study of the Navajo Population. AB - The prevalences of cardiovascular disease (CVD) and type 2 diabetes (T2D) have increased among the Navajo Native American community in recent decades. Oxidized low-density lipoprotein (oxLDL) is a novel CVD biomarker that has never been assessed in the Navajo population. We examined the relationship of oxLDL to conventional CVD and T2D risk factors and biomarkers in a cross-sectional population of Navajo participants. This cross-sectional study included 252 participants from 20 Navajo communities from the Dine Network for Environmental Health Project. Plasma samples were tested for oxLDL levels by a sandwich enzyme linked immunosorbent assay. Univariate and multivariate analyses were used to determine the relationship of oxLDL and oxidized- to non-oxidized lipoprotein ratios to glycated hemoglobin (HbA1c), C-reactive protein (CRP), interleukin 6 (IL6) and demographic and health variables. Type 2 diabetes, hypertension and obesity are very prevalent in this Navajo population. HbA1c, CRP, body mass index (BMI), high-density lipoprotein, and triglycerides were at levels that may increase risk for CVD and T2D. Median oxLDL level was 47 (36.8-57) U/L. Correlational analysis showed that although oxLDL alone was not associated with HbA1c, oxLDL/HDL, oxLDL/LDL and CRP were significantly associated with HbA1c and glucose. OxLDL, oxLDL/HDL and oxLDL/LDL were significantly associated with CRP. Multivariate analysis showed that triglycerides were a common and strong predictor of oxLDL, oxLDL/HDL and oxLDL/LDL. OxLDL was trended with HbA1c and glucose but did not reach significance, however, HbA1c was an independent predictor of OxLDL/HDL. CRP trended with oxLDL/HDL and was a weak predictor of oxLDL/LDL. This Navajo subset appears to have oxLDL levels comparable to subjects without evidence of CVD reported in other studies. The high prevalence of T2D, hypertension and obesity along with abnormal levels of other biomarkers including HbA1c indicate that the Navajo population has a worsening CVD risk profile. PMID- 26938993 TI - Postnatal Anthropometric and Body Composition Profiles in Infants with Intrauterine Growth Restriction Identified by Prenatal Doppler. AB - INTRODUCTION: Infant anthropometry and body composition have been previously assessed to gauge the impact of intrauterine growth restriction (IUGR) at birth, but the interplay between prenatal Doppler measurements and postnatal development has not been studied in this setting. The present investigation was performed to assess the significance of prenatal Doppler findings relative to postnatal anthropometrics and body composition in IUGR newborns over the first 12 months of life. PATIENTS AND METHODS: Consecutive cases of singleton pregnancies with suspected IUGR were prospectively enrolled over 12 months. Fetal biometry and prenatal Doppler ultrasound examinations were performed. Body composition was assessed by absorptiometry at ages 10 days, and at 4 and 12 months. RESULTS: A total of 48 pregnancies qualifying as IUGR were studied. Doppler parameters were normal in 26 pregnancies. The remaining 22 deviated from normal, marked by an Umbilical Artery Pulsatility Index (UA-PI) >95th centil or Cerebro-placental ratio (CPR) <5th centile. No significant differences emerged when comparing anthropometry and body composition at each time point, in relation to Doppler findings. Specifically, those IUGR newborns with and without abnormal Doppler findings had similar weight, length, body mass index, lean and fat mass, and bone mineral content throughout the first 12 months of life. In a separate analysis, when comparing IUGR newborns by Doppler (abnormal UA-PI vs. abnormal CPR), anthropometry and body composition did not differ significantly. CONCLUSIONS: Infants with IUGR maintain a pattern of body composition during the first year of life that is independent of prenatal Doppler findings. Future studies with larger sample sizes and correlating with hormonal status are warranted to further extend the phenotypic characterization of the various conditions now classified under the common label of IUGR. PMID- 26938994 TI - Dual-Target Electrochemical Biosensing Based on DNA Structural Switching on Gold Nanoparticle-Decorated MoS2 Nanosheets. AB - A MoS2-based electrochemical aptasensor has been developed for the simultaneous detection of thrombin and adenosine triphosphate (ATP) based on gold nanoparticles-decorated MoS2 (AuNPs-MoS2) nanocomposites. Two different aptamer probes labeled with redox tags were simultaneously immobilized on an AuNPs-MoS2 film modified electrode via Au-S bonds. The aptamers presented structural switches with the addition of target molecules (thrombin and ATP), resulting in methylene blue (MB) far from or ferrocene (Fc) close to the electrode surface. Therefore, a dual signaling detection strategy was developed, which featured both "signal-on" and "signal-off" elements in the detection system because of the target-induced structure switching. This proposed aptasensor could simultaneously determine ATP and thrombin as low as 0.74 nM ATP and 0.0012 nM thrombin with high selectivity, respectively. In addition, thrombin and ATP could act as inputs to activate an AND logic gate. PMID- 26938995 TI - Integrated and Total HIV-1 DNA Predict Ex Vivo Viral Outgrowth. AB - The persistence of a reservoir of latently infected CD4 T cells remains one of the major obstacles to cure HIV. Numerous strategies are being explored to eliminate this reservoir. To translate these efforts into clinical trials, there is a strong need for validated biomarkers that can monitor the reservoir over time in vivo. A comprehensive study was designed to evaluate and compare potential HIV-1 reservoir biomarkers. A cohort of 25 patients, treated with suppressive antiretroviral therapy was sampled at three time points, with median of 2.5 years (IQR: 2.4-2.6) between time point 1 and 2; and median of 31 days (IQR: 28-36) between time point 2 and 3. Patients were median of 6 years (IQR: 3 12) on ART, and plasma viral load (<50 copies/ml) was suppressed for median of 4 years (IQR: 2-8). Total HIV-1 DNA, unspliced (us) and multiply spliced HIV-1 RNA, and 2LTR circles were quantified by digital PCR in peripheral blood, at 3 time points. At the second time point, a viral outgrowth assay (VOA) was performed, and integrated HIV-1 DNA and relative mRNA expression levels of HIV-1 restriction factors were quantified. No significant change was found for long- and short-term dynamics of all HIV-1 markers tested in peripheral blood. Integrated HIV-1 DNA was associated with total HIV-1 DNA (p<0.001, R2 = 0.85), us HIV-1 RNA (p = 0.029, R2 = 0.40), and VOA (p = 0.041, R2 = 0.44). Replication-competent virus was detected in 80% of patients by the VOA and it correlated with total HIV-1 DNA (p = 0.039, R2 = 0.54). The mean quantification difference between Alu-PCR and VOA was 2.88 log10, and 2.23 log10 between total HIV-1 DNA and VOA. The levels of usHIV-1 RNA were inversely correlated with mRNA levels of several HIV-1 restriction factors (TRIM5alpha, SAMHD1, MX2, SLFN11, pSIP1). Our study reveals important correlations between the viral outgrowth and total and integrated HIV-1 DNA measures, suggesting that the total pool of HIV-1 DNA may predict the size of the replication-competent virus in ART suppressed patients. PMID- 26938996 TI - Alpha8 Integrin (Itga8) Signalling Attenuates Chronic Renal Interstitial Fibrosis by Reducing Fibroblast Activation, Not by Interfering with Regulation of Cell Turnover. AB - The alpha8 integrin (Itga8) chain contributes to the regulation of cell proliferation and apoptosis in renal glomerular cells. In unilateral ureteral obstruction Itga8 is de novo expressed in the tubulointerstitium and a deficiency of Itga8 results in more severe renal fibrosis after unilateral ureteral obstruction. We hypothesized that the increased tubulointerstitial damage after unilateral ureteral obstruction observed in mice deficient for Itga8 is associated with altered tubulointerstitial cell turnover and apoptotic mechanisms resulting from the lack of Itga8 in cells of the tubulointerstitium. Induction of unilateral ureteral obstruction was achieved by ligation of the right ureter in mice lacking Itga8. Unilateral ureteral obstruction increased proliferation and apoptosis rates of tubuloepithelial and interstitial cells, however, no differences were observed in the tubulointerstitium of mice lacking Itga8 and wild type controls regarding fibroblast or proliferating cell numbers as well as markers of endoplasmic reticulum stress and apoptosis after unilateral ureteral obstruction. In contrast, unilateral ureteral obstruction in mice lacking Itga8 led to more pronounced tubulointerstitial cell activation i.e. to the appearance of more phospho-SMAD2/3-positive cells and more alpha-smooth muscle actin positive cells in the tubulointerstitium. Furthermore, a more severe macrophage and T-cell infiltration was observed in these animals compared to controls. Thus, Itga8 seems to attenuate tubulointerstitial fibrosis in unilateral ureteral obstruction not via regulation of cell turnover, but via regulation of TGF-beta signalling, fibroblast activation and/or immune cell infiltration. PMID- 26938997 TI - Vitamin D Status during Pregnancy: A Longitudinal Study in Swedish Women from Early Pregnancy to Seven Months Postpartum. AB - Low vitamin D levels during pregnancy may have negative consequences for the health of both the mother and child. Cross-sectional studies in childbearing women suggest that vitamin D levels are low during pregnancy, but few studies have followed the same women during pregnancy and postpartum. The aims of this study were to longitudinally assess vitamin D status during pregnancy and postpartum and identify the factors associated with vitamin D status in pregnant women in northern Sweden. Between September 2006 and March 2009, 184 women were consecutively recruited at five antenatal primary care clinics. Blood was sampled, and dietary intake was estimated using a food frequency questionnaire with 66 food items/food aggregates and questions on the intake of vitamin supplements at gestational weeks 12, 21, and 35, as well as at 12 and 29 weeks after birth. Plasma 25(OH) vitamin D levels were analyzed using liquid chromatography tandem-mass spectrometry. At least one-third of the women had 25(OH) vitamin D levels <50 nmol/L on at least one sampling occasion. Plasma levels increased slightly over the gestation period and peaked in late pregnancy. The levels reverted to the baseline levels after birth. Multivariate analysis showed that gestational and postpartum week, season, dietary intake of vitamin D, and vitamin supplementation were significantly related to plasma levels. There was also an influence of season on the longitudinal concentration patterns. In conclusion, more than one-third of the women studied had low 25(OH) vitamin D levels, and gestational and postpartum week was related to 25(OH) vitamin D levels after adjustment for season and vitamin D intake. PMID- 26938998 TI - Antineoplastic Agents. 585. Isolation of Bridelia ferruginea Anticancer Podophyllotoxins and Synthesis of 4-Aza-podophyllotoxin Structural Modifications. AB - Cytotoxic constituents of the terrestrial plant Bridelia ferruginea were isolated using bioactivity-guided fractionation, which revealed the presence of the previously known deoxypodophyllotoxin (1), isopicrodeoxypodophyllotoxin (2), beta peltatin (3), beta-peltatin-5-O-beta-D-glucopyranoside (3a), and the indole neoechinulin (4). As an extension of previous podophyllotoxin research, SAR studies were undertaken focused on 4-aza-podophyllotoxin structural modifications. A number of such derivatives were synthesized following modifications to the A and E rings. Such structural modifications with alkyl and 4-fluorobenzyl substituents at the 4-aza position provided the most potent cancer cell growth inhibitory activity (GI50 0.1 to <0.03 MUg/mL) against a panel of six human cancer cell lines and one murine cancer cell line. Several compounds corresponding to 4'-demethylated modifications were also synthesized and found to be significantly less potent. PMID- 26938999 TI - Ligand-Free Fe3 O4 /CMCS Nanoclusters with Negative Charges for Efficient Structure-Selective Protein Adsorption. AB - The easy and effective capture of a single protein from a complex mixture is of great significance in proteomics and diagnostics. However, adsorbing nanomaterials are commonly decorated with specific ligands through a complicated and arduous process. Fe3 O4 /carboxymethylated chitosan (Fe3 O4 /CMCS) nanoclusters are developed as a new nonligand modified strategy to selectively capture bovine hemoglogin (BHB) and other structurally similar proteins (i.e., lysozyme (LYZ) and chymotrypsin (CTP)). The ligand-free Fe3 O4 /CMCS nanoclusters, in addition to their simple and economical two-step preparation process, possess many merits, including uniform morphology, high negative charges (-27 mV), high saturation magnetization (60 emu g(-1) ), and high magnetic content (85%). Additionally, the ligand-free Fe3 O4 /CMCS nanoclusters are found to selectively capture BHB in a model protein mixture even within biological samples. The reason for selective protein capture is further investigated from nanomaterials and protein structure. In terms of nanomaterials, it is found that high negative charges are conducive to selectively adsorb BHB. In consideration of protein structure, interestingly, the ligand-free magnetic nanoclusters display a structure-selective protein adsorption capacity to efficiently capture other proteins structurally similar to BHB, such as LYZ and CTP, showing great potential of the ligand-free strategy in biomedical field. PMID- 26939001 TI - WHL Note on the Kaiser Permanente Article. PMID- 26939000 TI - How Would Children Register Their Own Births? Insights from a Survey of Students Regarding Birth Registration Knowledge and Policy Suggestions in Kenya. AB - Birth registration and obtaining physical birth certificates impose major challenges in developing countries, with impact on child and community health, education, planning, and all levels of development. However despite initiatives, universal registration is elusive, leading to calls for new approaches to understanding the decisions of parents. In this paper, we report results of a survey of students in grades six to eight (age ~12-16) in an under-registered area of Kenya regarding their own understanding of registration issues and their suggestions for improvement. These students were selected because they themselves were also nearing the age for high school enrollment/entrance examinations, which specifically requires possession of a birth certificate. This assessment was also a companion to our previous representative survey of adults in the same Kenyan region, allowing for parent-child comparison. Results supported previous research, showing that only 43% had birth certificates. At the same time, despite these low totals, students were themselves quite aware of registration factors and purposes. The students also made quite prescient sources for understanding their households' motivations, with many of their suggestions-for focus on communication of pragmatic benefits, or automatic measures shifting responsibility from parents-mirroring our own previous suggestions, and showing a level of pragmatism not witnessed when surveying their parents. This paper therefore adds evidence to the discussion of registration policy planning. More generally, it also builds on an important trend regarding the treatment of children as stakeholders and important sources of information, and raising an intriguing new avenue for future research. PMID- 26939002 TI - Distribution of Voltage-Gated Sodium Channel (Nav) Alleles among the Aedes aegypti Populations In Central Java Province and Its Association with Resistance to Pyrethroid Insecticides. AB - The emergence of insecticide resistant Aedes aegypti mosquitoes has hampered dengue control efforts. WHO susceptibility tests, using several pyrethroid compounds, were conducted on Ae. aegypti larvae that were collected and raised to adulthood from Semarang, Surakarta, Kudus and Jepara in Java. The AaNaV gene fragment encompassing kdr polymorphic sites from both susceptible and resistant mosquitoes was amplified, and polymorphisms were associated with the resistant phenotype. The insecticide susceptibility tests demonstrated Ae, aegypti resistance to the pyrethroids, with mortality rates ranging from 1.6%-15.2%. Three non-synonymous polymorphisms (S989P, V1016G and F1534C) and one synonymous polymorphism (codon 982) were detected in the AaNaV gene. Eight AaNaV alleles were observed in specimens from Central Java. Allele 3 (SGF) and allele 7 (PGF) represent the most common alleles found and demonstrated strong associations with resistance to pyrethroids (OR = 2.75, CI: 0.97-7.8 and OR = 7.37, CI: 2.4-22.5, respectively). This is the first report of 8 Ae. aegypti AaNaV alleles, and it indicates the development of resistance in Ae. aegypti in response to pyrethroid insecticide-based selective pressure. These findings strongly suggest the need for an appropriate integrated use of insecticides in the region. The 989P, 1016G and 1534C polymorphisms in the AaNaV gene are potentially valuable molecular markers for pyrethroid insecticide resistance monitoring. PMID- 26939010 TI - Stereocontrolled Solid-Phase Synthesis of Phosphate/Phosphorothioate (PO/PS) Chimeric Oligodeoxyribonucleotides on an Automated Synthesizer Using an Oxazaphospholidine-Phosphoramidite Method. AB - Stereocontrolled solid-phase synthesis of phosphate/phosphorothioate chimeric oligodeoxyribonucleotides (PO/PS-ODNs) was achieved by integrating the conventional phosphoramidite method into a previously developed oxazaphospholidine method for the stereocontrolled synthesis of P-chiral oligonucleotides. P-Stereodefined PO/PS-ODNs with mixed sequences (up to 12-mers) were obtained in good yields and high stereoselectivities by reacting different combinations of monomers (conventional phosphoramidites/diastereopure nucleoside 3'-O-oxazaphospholidines), activators (ETT/CMPT), capping reagents (Pac2O/CF3COIm), and oxidizing/sulfurizing reagents (TBHP/POS) on an automated synthesizer. A thermal denaturation study examined the resultant diastereopure PO/PS-ODN 12-mers with three consecutive (Rp)- or (Sp)-PS-linkages at the internal or terminal regions of the molecules. We found that (Rp)-PO/PS-ODNs can only moderately destabilize duplexes with complementary oligoribonucleotides (ORNs) compared with their unmodified ODN counterparts (DeltaTm = -0.4 degrees C per modification). In contrast, (Sp)-PO/PS-ODNs have larger destabilizing effects (DeltaTm = -1.2 to -0.8 degrees C per modification). Although smaller destabilizing effects were observed when the (Sp)-PS-linkages were incorporated into the terminal regions of the molecule, there was a weaker correlation between the location of an incorporated (Rp)-PS-linkage and its destabilizing effect. PMID- 26939003 TI - Deletion of Rac1GTPase in the Myeloid Lineage Protects against Inflammation Mediated Kidney Injury in Mice. AB - Macrophage-mediated inflammation has been implicated in various kidney diseases. We previously reported that Rac1, a Rho family small GTP-binding protein, was overactivated in several chronic kidney disease models, and that Rac1 inhibitors ameliorated renal injury, in part via inhibition of inflammation, but the detailed mechanisms have not been clarified. In the present study, we examined whether Rac1 in macrophages effects cytokine production and the inflammatory mechanisms contributing to kidney derangement. Myeloid-selective Rac1 flox control (M-Rac1 FC) and knockout (M-Rac1 KO) mice were generated using the cre loxP system. Renal function under basal conditions did not differ between M-Rac1 FC and KO mice. Accordingly, lipopolysaccharide (LPS)-evoked kidney injury model was created. LPS elevated blood urea nitrogen and serum creatinine, enhanced expressions of kidney injury biomarkers, Kim-1 and Ngal, and promoted tubular injury in M-Rac1 FC mice. By contrast, deletion of myeloid Rac1 almost completely prevented the LPS-mediated renal impairment. LPS triggered a marked induction of macrophage-derived inflammatory cytokines, IL-6 and TNFalpha, in M-Rac1 FC mice, which was accompanied by Rac1 activation, stimulation of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, and reactive oxygen species overproduction. These changes were inhibited in M-Rac1 KO mice. LPS evoked F4/80 positive macrophages accumulation in the kidney, which was not affected by myeloid Rac1 deficiency. We further tested the role of Rac1 signaling in cytokine production using macrophage cell line, RAW264.7. Exposure to LPS increased IL-6 and TNFalpha mRNA expression. The LPS-driven cytokine induction was dose dependently blocked by the Rac1 inhibitor EHT1864, NADPH oxidase inhibitor diphenyleneiodonium, and NF-kappaB inhibitor BAY11-7082. In conclusion, genetic ablation of Rac1 in the myeloid lineage protected against LPS-induced renal inflammation and injury, by suppressing macrophage-derived cytokines, IL-6 and TNFalpha, without blocking recruitment. Our data suggest that Rac1 in macrophage is a novel target for the treatment of kidney disease through inhibition of cytokine production. PMID- 26939004 TI - Microseminoprotein-Beta Expression in Different Stages of Prostate Cancer. AB - Microseminoprotein-beta (MSMB, MSMB) is an abundant secretory protein contributed by the prostate, and is implicated as a prostate cancer (PC) biomarker based on observations of its lower expression in cancerous cells compared with benign prostate epithelium. However, as the current literature on MSMB is inconsistent, we assessed the expression of MSMB at the protein and mRNA levels in a comprehensive set of different clinical stages of PC. Immunohistochemistry using monoclonal and polyclonal antibodies against MSMB was used to study protein expression in tissue specimens representing prostatectomies (n = 261) and in diagnostic needle biopsies from patients treated with androgen deprivation therapy (ADT) (n = 100), and in locally recurrent castration-resistant PC (CRPC) (n = 105) and CRPC metastases (n = 113). The transcript levels of MSMB, nuclear receptor co-activator 4 (NCOA4) and MSMB-NCOA4 fusion were examined by qRT-PCR in prostatectomy samples and by RNA-sequencing in benign prostatic hyperplasia, PC, and CRPC samples. We also measured serum MSMB levels and genotyped the single nucleotide polymorphism rs10993994 using DNA from the blood of 369 PC patients and 903 controls. MSMB expression in PC (29% of prostatectomies and 21% of needle biopsies) was more frequent than in CRPC (9% of locally recurrent CRPCs and 9% of CRPC metastases) (p<0.0001). Detection of MSMB protein was inversely correlated with the Gleason score in prostatectomy specimens (p = 0.024). The read-through MSMB-NCOA4 transcript was detected at very low levels in PC. MSMB levels in serum were similar in cases of PC and controls but were significantly associated with PC risk when adjusted for age at diagnosis and levels of free or total PSA (p<0.001). Serum levels of MSMB in both PC patients and controls were significantly associated with the rs10993994 genotype (p<0.0001). In conclusion, decreased expression of MSMB parallels the clinical progression of PC and adjusted serum MSMB levels are associated with PC risk. PMID- 26939011 TI - First, design for data sharing. PMID- 26939012 TI - Frustrated Lewis Pair-Catalyzed Cycloisomerization of 1,5-Enynes via a 5-endo-dig Cyclization/Protodeborylation Sequence. AB - The first frustrated Lewis pair-catalyzed cycloisomerization of a series of 1,5 enynes was developed. The reaction proceeds via the pi-activation of the alkyne and subsequent 5-endo-dig cyclization with the adjacent alkene. The presence of PPh3 was of utmost importance on the one hand to prevent side reactions (for example, 1,1-carboboration) and on the other hand for the efficient protodeborylation to achieve the catalytic turnover. The mechanism is explained on the basis of quantum-chemical calculations, which are in full agreement with the experimental observations. PMID- 26939017 TI - Amphibian-killing chytrid in Brazil comprises both locally endemic and globally expanding populations. AB - Chytridiomycosis, caused by the fungus Batrachochytrium dendrobatidis (Bd), is the emerging infectious disease implicated in recent population declines and extinctions of amphibian species worldwide. Bd strains from regions of disease associated amphibian decline to date have all belonged to a single, hypervirulent clonal genotype (Bd-GPL). However, earlier studies in the Atlantic Forest of southeastern Brazil detected a novel, putatively enzootic lineage (Bd-Brazil), and indicated hybridization between Bd-GPL and Bd-Brazil. Here, we characterize the spatial distribution and population history of these sympatric lineages in the Brazilian Atlantic Forest. To investigate the genetic structure of Bd in this region, we collected and genotyped Bd strains along a 2400-km transect of the Atlantic Forest. Bd-Brazil genotypes were restricted to a narrow geographic range in the southern Atlantic Forest, while Bd-GPL strains were widespread and largely geographically unstructured. Bd population genetics in this region support the hypothesis that the recently discovered Brazilian lineage is enzootic in the Atlantic Forest of Brazil and that Bd-GPL is a more recently expanded invasive. We collected additional hybrid isolates that demonstrate the recurrence of hybridization between panzootic and enzootic lineages, thereby confirming the existence of a hybrid zone in the Serra da Graciosa mountain range of Parana State. Our field observations suggest that Bd-GPL may be more infective towards native Brazilian amphibians, and potentially more effective at dispersing across a fragmented landscape. We also provide further evidence of pathogen translocations mediated by the Brazilian ranaculture industry with implications for regulations and policies on global amphibian trade. PMID- 26939013 TI - Shaking Takete and Flowing Maluma. Non-Sense Words Are Associated with Motion Patterns. AB - People assign the artificial words takete and kiki to spiky, angular figures and the artificial words maluma and bouba to rounded figures. We examined whether such a cross-modal correspondence could also be found for human body motion. We transferred the body movements of speakers onto two-dimensional coordinates and created animated stick-figures based on this data. Then we invited people to judge these stimuli using the words takete-maluma, bouba-kiki, and several verbal descriptors that served as measures of angularity/smoothness. In addition to this we extracted the quantity of motion, the velocity of motion and the average angle between motion vectors from the coordinate data. Judgments of takete (and kiki) were related to verbal descriptors of angularity, a high quantity of motion, high velocity and sharper angles. Judgments of maluma (or bouba) were related to smooth movements, a low velocity, a lower quantity of motion and blunter angles. A forced-choice experiment during which we presented subsets with low and high rankers on our motion measures revealed that people preferably assigned stimuli displaying fast movements with sharp angles in motion vectors to takete and stimuli displaying slow movements with blunter angles in motion vectors to maluma. Results indicated that body movements share features with information inherent in words such as takete and maluma and that people perceive the body movements of speakers on the level of changes in motion direction (e.g., body moves to the left and then back to the right). Follow-up studies are needed to clarify whether impressions of angularity and smoothness have similar communicative values across different modalities and how this affects social judgments and person perception. PMID- 26939018 TI - Industry is not the dark side, but an essential partner to make progress in reproductive health. AB - For the last 20 years, Thomas D'Hooghe has been coordinator of the Leuven University Fertility Center at Leuven University Hospitals, Belgium, one of the largest teaching hospitals in Europe. Since 1995, he has also been Professor of Reproductive Medicine and Biology at KU Leuven (University of Leuven) and Adjunct Professor at Yale University, USA. Since 1 October 2015, he has been the Vice President and Head of Global Medical Affairs Fertility at Merck's headquarters in Darmstadt, Germany. He has published nearly 300 papers in internationally peer reviewed journals and has contributed to reproductive health serving major international organizations such as the WHO, the European Society of Human Reproduction and Embryology, the Society of Reproductive Investigation and the World Endometriosis Research Foundation. PMID- 26939019 TI - The Association of Childhood Fitness to Proactive and Reactive Action Monitoring. AB - Several studies have claimed that the positive association between childhood fitness and cognitive control is attributable to differences in the child's cognitive control strategy, which can involve either proactive or reactive control. The present study tested this hypothesis by manipulating the probability of trial types during a modified flanker task. Preadolescent children performed mostly congruent and mostly incongruent conditions of the flanker task, with post error task performance and error negativity/error-related negativity (Ne/ERN) being assessed. Results indicated that greater aerobic fitness was related to greater post-error accuracy and larger Ne/ERN amplitudes in the mostly congruent condition. These findings suggest that higher-fit children might be able to transiently upregulate cognitive control by recruiting reactive control in the mostly congruent condition. Further, greater fitness was related to greater modulation of Ne/ERN amplitude between conditions, suggesting that higher-fit children engaged in more proactive control in the mostly incongruent condition. This study supports the hypothesis that greater childhood fitness is associated with a more flexible shift between reactive and proactive modes of cognitive control to adapt to varying task demands. PMID- 26939021 TI - Choice of underwear and male fecundity in a preconception cohort of couples. AB - Our objective was to investigate the relationship between male underwear-type worn during daytime/bedtime and male fecundity as measured by semen quality and time-to-pregnancy. We used data from a prospective preconception cohort conducted in 16 counties in Michigan and Texas, USA. 501 couples were enrolled and followed for 12 months of trying, which facilitated capture of time-to-pregnancy (in cycles), 6-cycle conception delay, and 12-month infertility. Male partners provided semen samples via in-home collection for next-day semen analysis comprised of 35 semen quality endpoints. At enrollment, men provided information on type of underwear worn during daytime and bedtime and were classified into 6 categories by underwear choice (n = 491): (i) briefs day/night, (ii) boxer-briefs day/night, (iii) boxers day/night, (iv) briefs day and boxers/none at night, (v) boxer-briefs day and boxers/none at night, (vi) boxers day and none at night. 473 (96%) men had semen analysis performed. Men switching from their usual daytime underwear to boxers/none for bed (groups 4, 5, 6) had the most evidence of change in semen quality endpoints (10 of 11 differences) relative to men wearing briefs day/night (group 1). Group 4 men had lower percent of sperm with coiled tail (beta = -0.18, 95% CI: -0.35, -0.01), higher percent round (beta = 0.22, 95% CI: 0.01, 0.42), number of immature sperm (beta = 0.44, 95% CI: 0.11, 0.77), and amplitude head displacement (beta = 0.57, 95% CI: 0.10, 1.03). Group 5 men had higher sperm head perimeter (beta=0.17, 95% CI: 0.002, 0.34), amplitude head displacement (beta = 0.47, 95% CI: 0.03, 0.91), percent cytoplasmic droplet (beta = 0.44, 95% CI: 0.11, 0.77) and high DNA stainability (beta=0.39, 95% CI: 0.01, 0.78). After false discovery rate control, no differences remained significant. No significant differences in time-to-pregnancy, conception delay, or infertility were observed. In summary, male underwear choice is associated with few differences in semen parameters; no association with time-to-pregnancy is observed providing reassurance to couples attempting pregnancy. PMID- 26939020 TI - Mariner Transposons Contain a Silencer: Possible Role of the Polycomb Repressive Complex 2. AB - Transposable elements are driving forces for establishing genetic innovations such as transcriptional regulatory networks in eukaryotic genomes. Here, we describe a silencer situated in the last 300 bp of the Mos1 transposase open reading frame (ORF) which functions in vertebrate and arthropod cells. Functional silencers are also found at similar locations within three other animal mariner elements, i.e. IS630-Tc1-mariner (ITm) DD34D elements, Himar1, Hsmar1 and Mcmar1. These silencers are able to impact eukaryotic promoters monitoring strong, moderate or low expression as well as those of mariner elements located upstream of the transposase ORF. We report that the silencing involves at least two transcription factors (TFs) that are conserved within animal species, NFAT-5 and Alx1. These cooperatively act with YY1 to trigger the silencing activity. Four other housekeeping transcription factors (TFs), neuron restrictive silencer factor (NRSF), GAGA factor (GAF) and GTGT factor (GTF), were also found to have binding sites within mariner silencers but their impact in modulating the silencer activity remains to be further specified. Interestingly, an NRSF binding site was found to overlap a 30 bp motif coding a highly conserved PHxxYSPDLAPxD peptide in mariner transposases. We also present experimental evidence that silencing is mainly achieved by co-opting the host Polycomb Repressive Complex 2 pathway. However, we observe that when PRC2 is impaired another host silencing pathway potentially takes over to maintain weak silencer activity. Mariner silencers harbour features of Polycomb Response Elements, which are probably a way for mariner elements to self-repress their transcription and mobility in somatic and germinal cells when the required TFs are expressed. At the evolutionary scale, mariner elements, through their exaptation, might have been a source of silencers playing a role in the chromatin configuration in eukaryotic genomes. PMID- 26939022 TI - Structure-Based Statistical Mechanical Model Accounts for the Causality and Energetics of Allosteric Communication. AB - Allostery is one of the pervasive mechanisms through which proteins in living systems carry out enzymatic activity, cell signaling, and metabolism control. Effective modeling of the protein function regulation requires a synthesis of the thermodynamic and structural views of allostery. We present here a structure based statistical mechanical model of allostery, allowing one to observe causality of communication between regulatory and functional sites, and to estimate per residue free energy changes. Based on the consideration of ligand free and ligand bound systems in the context of a harmonic model, corresponding sets of characteristic normal modes are obtained and used as inputs for an allosteric potential. This potential quantifies the mean work exerted on a residue due to the local motion of its neighbors. Subsequently, in a statistical mechanical framework the entropic contribution to allosteric free energy of a residue is directly calculated from the comparison of conformational ensembles in the ligand free and ligand bound systems. As a result, this method provides a systematic approach for analyzing the energetics of allosteric communication based on a single structure. The feasibility of the approach was tested on a variety of allosteric proteins, heterogeneous in terms of size, topology and degree of oligomerization. The allosteric free energy calculations show the diversity of ways and complexity of scenarios existing in the phenomenology of allosteric causality and communication. The presented model is a step forward in developing the computational techniques aimed at detecting allosteric sites and obtaining the discriminative power between agonistic and antagonistic effectors, which are among the major goals in allosteric drug design. PMID- 26939026 TI - Cardiovascular risk reduction: the future of cholesterol lowering drugs. AB - Atherosclerotic cardiovascular disease is the leading cause of death in developed and developing countries. LDL lowering therapies have a major role in reduction of cardiovascular events. Statins have been the mainstay of LDL lowering therapies with 20-60% reductions in LDL cholesterol. Monoclonal antibodies to proprotein convertase subtilisin kexin type 9 (PCSK9) represent a new therapeutic option, reducing LDL cholesterol by an additional 40-70% on top of other lipid lowering therapies. This is likely to produce significant cardiovascular risk reduction, although clinical cardiovascular outcomes trials are still in progress. HDL cholesterol raising and triglyceride lowering therapies have not yet shown unequivocal benefits for cardiovascular risk reduction. New therapies in these areas are in development, and their future promise remains to be demonstrated. PMID- 26939024 TI - Substrate Dependent Native Luminescence from Cytochromes P450 3A4, 2C9, and P450cam. AB - Metalloporphyrin containing proteins, such as cytochrome P450, play a key role in biological systems. The spectroscopic properties of metalloporphyrins have been a subject of intense interest and intense debate for over 50 years. Iron-porphyrins are usually believed to be nonfluorescent. Herein we report that, contrary to this belief, cytochrome P450 heme groups luminesce with enough intensity to be of use in the characterization of these enzymes. To confirm that the emission is from the heme, we destroyed the heme by titration with cumene hydroperoxide and measured the changes in emission upon titration with compounds known to bind to the distal face of the heme in two human cytochrome P450 enzymes, known as CYP3A4 and CYP2C9. The titration curves gave spectral dissociation constants that were not significantly different from those reported using the Soret UV/vis absorbance changes. We have tentatively assigned the broad luminescence at ~500 nm to a (1)pipi* -> gs fluorescence and the structured luminescence above 600 nm to a (3)pipi* -> gs phosphorescence. These assignments are not associated with the Q band, and are in violation of Kasha's rule. To illustrate the utility of the emission, we measured spectral dissociation constants for testosterone binding to P450 3A4 in bilayers formed on glass coverslips, a measurement that would be very difficult to make using absorption spectroscopy. Complementary experiments were carried out with water-soluble P450cam. PMID- 26939023 TI - BBB-Permeable, Neuroprotective, and Neurotrophic Polysaccharide, Midi-GAGR. AB - An enormous amount of efforts have been poured to find an effective therapeutic agent for the treatment of neurodegenerative diseases including Alzheimer's disease (AD). Among those, neurotrophic peptides that regenerate neuronal structures and increase neuron survival show a promise in slowing neurodegeneration. However, the short plasma half-life and poor blood-brain barrier (BBB)-permeability of neurotrophic peptides limit their in vivo efficacy. Thus, an alternative neurotrophic agent that has longer plasma half-life and better BBB-permeability has been sought for. Based on the recent findings of neuroprotective polysaccharides, we searched for a BBB-permeable neuroprotective polysaccharide among natural polysaccharides that are approved for human use. Then, we discovered midi-GAGR, a BBB-permeable, long plasma half-life, strong neuroprotective and neurotrophic polysaccharide. Midi-GAGR is a 4.7kD cleavage product of low acyl gellan gum that is approved by FDA for human use. Midi-GAGR protected rodent cortical neurons not only from the pathological concentrations of co-/post-treated free reactive radicals and Abeta42 peptide but also from activated microglial cells. Moreover, midi-GAGR showed a good neurotrophic effect; it enhanced neurite outgrowth and increased phosphorylated cAMP responsive element binding protein (pCREB) in the nuclei of primary cortical neurons. Furthermore, intra-nasally administered midi-GAGR penetrated the BBB and exerted its neurotrophic effect inside the brain for 24 h after one-time administration. Midi-GAGR appears to activate fibroblast growth factor receptor 1 (FGFR1) and its downstream neurotrophic signaling pathway for neuroprotection and CREB activation. Additionally, 14-day intranasal administration of midi-GAGR not only increased neuronal activity markers but also decreased hyperphosphorylated tau, a precursor of neurofibrillary tangle, in the brains of the AD mouse model, 3xTg-AD. Taken together, midi-GAGR with good BBB-permeability, long plasma half life, and strong neuroprotective and neurotrophic effects has a great therapeutic potential for the treatment of neurodegenerative diseases, especially AD. PMID- 26939025 TI - 2-Deoxyglucose Reverses the Promoting Effect of Insulin on Colorectal Cancer Cells In Vitro. AB - An increased risk of colorectal cancer is related to the development of metabolic syndromes including hyperglycemia, and hyperinsulinemia. The high circulatory levels of glucose and/or insulin or the application of exogenous insulin may promote carcinogenesis, cancer progression and metastasis, which can be attributed to the Warburg effect or aerobic glycolysis. We attempted to resolve these existing questions by applying the glucose analog 2-deoxyglucose (2DG). According to the in vitro studies we performed, the glycolysis of colorectal cancer cells could be interrupted by 2DG as it decreased the cellular productions of ATP and lactate. In addition, 2DG induced apoptosis and cell cycle arrest, and inhibited proliferation, migration and invasion of these cells. Since insulin can stimulate the cellular uptake of hexose, including 2DG, the combination of 2DG and insulin improved the cytotoxicity of 2DG and meanwhile overcame the cancer promoting effects of insulin. This in vitro study provided a viewpoint of 2DG as a potential therapeutic agent against colorectal cancer, especially for patients with concomitant hyperinsulinemia or treated with exogenous insulin. PMID- 26939028 TI - Reversal of novel oral anticoagulants. AB - The development of a new generation of non-vitamin K oral anticoagulants represents a potential breakthrough in the management of patients with thrombotic diseases, disorders and conditions. While a large and growing body of evidence from large-scale clinical trials and registries supports a favorable safety profile, having a means to rapidly reverse their anticoagulant effects represents an unmet need among practicing clinicians. Several targeted reversal agents are currently in development and the early results are promising. Idarucizumab is a monoclonal antibody that can immediately and specifically reverse dabigatran. Andexanet alfa is a recombinant modified factor Xa that can bind and reverse oral and parenteral factor Xa inhibitors, including rivaroxaban, apixaban and edoxaban, and low molecular weight heparin. Aripazine is a small molecule that can reverse the action of factor Xa inhibitors and possibly dabigatran as well through non-covalent binding and charge-charge interactions. PMID- 26939027 TI - Mineralocorticoid receptor antagonists-pharmacodynamics and pharmacokinetic differences. AB - Mineralocorticoid receptor antagonists (MRAs) are best known as potassium-sparing diuretics due to their blockade of aldosterone action in renal epithelial tissues. They are also beneficial for the treatment of heart failure, primarily due to effects in non-epithelial tissues. Currently there are only two steroidal MRAs that have been approved for use; spironolactone (and its active metabolite canrenone) and eplerenone. However, the search is on for novel generations of MRAs with increased potency and tissue selectivity. A number of novel non steroidal compounds are in preclinical and early development, with one agent moving to phase III trials. The development of these agents and the mechanisms for their pharmacologic superiority compared to earlier generations of MRAs will be discussed in this review. PMID- 26939029 TI - Prospects for electron beam aberration correction using sculpted phase masks. AB - Technological advances in fabrication methods allowed the microscopy community to take incremental steps towards perfecting the electron microscope, and magnetic lens design in particular. Still, state of the art aberration-corrected microscopes are yet 20-30 times shy of the theoretical electron diffraction limit. Moreover, these microscopes consume significant physical space and are very expensive. Here, we show how a thin, sculpted membrane is used as a phase mask to induce specific aberrations into an electron beam probe in a standard high resolution TEM. In particular, we experimentally demonstrate beam splitting, two-fold astigmatism, three-fold astigmatism, and spherical aberration. PMID- 26939030 TI - Assessing strain mapping by electron backscatter diffraction and confocal Raman microscopy using wedge-indented Si. AB - The accuracy of electron backscatter diffraction (EBSD) and confocal Raman microscopy (CRM) for small-scale strain mapping are assessed using the multi axial strain field surrounding a wedge indentation in Si as a test vehicle. The strain field is modeled using finite element analysis (FEA) that is adapted to the near-indentation surface profile measured by atomic force microscopy (AFM). The assessment consists of (1) direct experimental comparisons of strain and deformation and (2) comparisons in which the modeled strain field is used as an intermediate step. Direct experimental methods (1) consist of comparisons of surface elevation and gradient measured by AFM and EBSD and of Raman shifts measured and predicted by CRM and EBSD, respectively. Comparisons that utilize the combined FEA-AFM model (2) consist of predictions of distortion, strain, and rotation for comparison with EBSD measurements and predictions of Raman shift for comparison with CRM measurements. For both EBSD and CRM, convolution of measurements in depth-varying strain fields is considered. The interconnected comparisons suggest that EBSD was able to provide an accurate assessment of the wedge indentation deformation field to within the precision of the measurements, approximately 2*10(-4) in strain. CRM was similarly precise, but was limited in accuracy to several times this value. PMID- 26939031 TI - Implementing the patient-centered medical home in complex adaptive systems: Becoming a relationship-centered patient-centered medical home. AB - BACKGROUND: This study explores the implementation experience of nine primary care practices becoming patient-centered medical homes (PCMH) as part of the New Hampshire Citizens Health Initiative Multi-Stakeholder Medical Home Pilot. PURPOSE: The purpose of this study is to apply complex adaptive systems theory and relationship-centered organizations theory to explore how nine diverse primary care practices in New Hampshire implemented the PCMH model and to offer insights for how primary care practices can move from a structural PCMH to a relationship-centered PCMH. METHODOLOGY/APPROACH: Eighty-three interviews were conducted with administrative and clinical staff at the nine pilot practices, payers, and conveners of the pilot between November and December 2011. The interviews were transcribed, coded, and analyzed using both a priori and emergent themes. FINDINGS: Although there is value in the structural components of the PCMH (e.g., disease registries), these structures are not enough. Becoming a relationship-centered PCMH requires attention to reflection, sensemaking, learning, and collaboration. This can be facilitated by settings aside time for communication and relationship building through structured meetings about PCMH components as well as the implementation process itself. Moreover, team-based care offers a robust opportunity to move beyond the structures to focus on relationships and collaboration. PRACTICE IMPLICATIONS: (a) Recognize that PCMH implementation is not a linear process. (b) Implementing the PCMH from a structural perspective is not enough. Although the National Committee for Quality Assurance or other guidelines can offer guidance on the structural components of PCMH implementation, this should serve only as a starting point. (c) During implementation, set aside structured time for reflection and sensemaking. (d) Use team-based care as a cornerstone of transformation. Reflect on team structures and also interactions of the team members. Taking the time to reflect will facilitate greater sensemaking and learning and will ultimately help foster a relationship-centered PCMH. PMID- 26939032 TI - Acceptance of lean redesigns in primary care: A contextual analysis. AB - BACKGROUND: Lean is a leading change strategy used in health care to achieve short-term efficiency and quality improvement while promising longer-term system transformation. Most research examines Lean intervention to address isolated problems, rather than to achieve broader systemic changes to care delivery. Moreover, no studies examine contextual influences on system-wide Lean implementation efforts in primary care. PURPOSE: The aim of this study was to identify contextual factors most critical to implementing and scaling Lean redesigns across all primary care clinics in a large, ambulatory care delivery system. METHODOLOGY/APPROACH: Over 100 interviews and focus groups were conducted with frontline physicians, clinical staff, and operational leaders. Data analysis was guided by a modified Consolidated Framework for Implementation Research (CFIR), a popular implementation science framework. On the basis of expert recommendations, the modified framework targets factors influencing the implementation of process redesigns. This modified framework, the CFIR-PR, informed our identification of contextual factors that most impacted Lean acceptance among frontline physicians and staff. FINDINGS: Several domains identified by the CFIR-PR were critical to acceptance of Lean redesigns. Regarding the implementation process acceptance was influenced by time and intensity of exposure to changes, "top-down" versus "bottom-up" implementation styles, and degrees of employee engagement in developing new workflows. Important factors in the inner setting were the clinic's culture and style of leadership, along with availability of information about Lean's effectiveness. Last, implementation efforts were impacted by individual and team characteristics regarding changed work roles and related issues of professional identity, authority, and autonomy. PRACTICE IMPLICATIONS: This study underscores the need for change leaders to consider the contextual factors that surround efforts to implement Lean in primary care. As Lean redesigns are scaled across a system, special attention is warranted with respect to the implementation approach, internal clinic setting, and implications for professional roles and identities of physicians and staff. PMID- 26939033 TI - Alteration of natural (37)Ar activity concentration in the subsurface by gas transport and water infiltration. AB - High (37)Ar activity concentration in soil gas is proposed as a key evidence for the detection of underground nuclear explosion by the Comprehensive Nuclear Test Ban Treaty. However, such a detection is challenged by the natural background of (37)Ar in the subsurface, mainly due to Ca activation by cosmic rays. A better understanding and improved capability to predict (37)Ar activity concentration in the subsurface and its spatial and temporal variability is thus required. A numerical model integrating (37)Ar production and transport in the subsurface is developed, including variable soil water content and water infiltration at the surface. A parameterized equation for (37)Ar production in the first 15 m below the surface is studied, taking into account the major production reactions and the moderation effect of soil water content. Using sensitivity analysis and uncertainty quantification, a realistic and comprehensive probability distribution of natural (37)Ar activity concentrations in soil gas is proposed, including the effects of water infiltration. Site location and soil composition are identified as the parameters allowing for a most effective reduction of the possible range of (37)Ar activity concentrations. The influence of soil water content on (37)Ar production is shown to be negligible to first order, while (37)Ar activity concentration in soil gas and its temporal variability appear to be strongly influenced by transient water infiltration events. These results will be used as a basis for practical CTBTO concepts of operation during an OSI. PMID- 26939035 TI - New amide-chloride phases in the Li-Al-N-H-Cl system: formation and hydrogen storage behaviour. AB - New amide-chloride phases were successfully synthesized by mechanical milling of the LiNH2-AlCl3 mixture at a molar ratio of 1 : 0.11 and further heating at 150 degrees C under argon (0.1 MPa) or under hydrogen pressure (0.7 MPa). Powder X ray diffraction measurements as a function of milling time increase revealed that the milling of the LiNH2-0.11AlCl3 mixture results in the formation of a FCC solid solution with an excess of LiNH2. Subsequent heating of the LiNH2-0.11AlCl3 sample ball milled for 5 hours at 150 degrees C under argon or under hydrogen induces the appearance of an amide-chloride phase isostructural with cubic Li4(NH2)3Cl. This Li-Al-N-H-Cl phase transforms progressively into the trigonal phase after prolonged heating at 300 degrees C under hydrogen pressure. The thermal behaviour of the amide-chloride without and with LiH addition displays dissimilar decomposition pathways. The decomposition of amide-chloride alone involves the formation of ammonia and hydrogen from 120 to 300 degrees C. Conversely, the amide-chloride material in the presence of LiH only releases hydrogen avoiding the emission of ammonia. The resultant material is able to be rehydrogenated under moderate conditions (300 degrees C, 0.7 MPa H2), providing a new reversible hydrogen storage system. PMID- 26939036 TI - Current clinical practice guidelines in atrial fibrillation: a review. AB - The aim of this study is the methodological evaluation of Clinical Practice Guidelines (CPG) in atrial fibrillation. This is the second in a series of articles of review, analysis, assessment in methodology and content of clinical practice guidelines in Cardiology. Among all clinical practice guidelines, we selected the American, Canadian and NICE (National Institute for Health and Care Excellence) guidelines. We used the AGREE (Appraisal of Guidelines for Research and Evaluation) II instrument for the assessment. In general, the guidelines obtained the lowest score in the applicability domain (mean 36.1%); while the highest score was for clarity of presentation (mean 93.5%). The lowest percentage was found in the editorial independence domain (Canadian guideline) and the highest of all scores in the applicability domain (NICE guideline). Regarding global quality, the NICE guideline obtained the AGREE II instrument best scores, followed by the American guideline, both recommended for use without modifications. PMID- 26939037 TI - Role of Toll-Like Receptor 3 in Lung Ischemia-Reperfusion Injury. AB - Lung ischemia-reperfusion injury (LIRI) occurs in various clinical situations, such as transplantation, cardio pulmonary bypass, cardiac arrest, and major trauma, leading to significant morbidity and mortality. Despite researchers having spent years of effort to investigate the pathogenesis of pulmonary ischemic injury, the concrete cellular and molecular mechanisms are still unknown. We hypothesized that toll-like receptor (TLR) 3 signaling may play a vital role in inflammation responses, apoptosis, and pulmonary dysfunction during LIRI. Lung ischemia-reperfusion (I/R) mouse model was established by the occlusion of the left pulmonary hilum of adult male C57BL/6J wild-type (WT) and TLR3 deficient (TLR3) mice for 1 h, followed by reperfusion for 2 h. Blood serum and lung tissues of the mice were collected after lung I/R for subsequent experiments. Compared with WT mice, TLR3 mice had better preserved pulmonary function, and significantly attenuated pulmonary cytokines mRNA and protein production after I/R. Pulmonary apoptosis was also inhibited after TLR3 knockout, as indicated by cleaved caspase-3 western blot and terminal deoxynucleotidyl transferase dUTP nick end labeling staining. Levels of serum microRNAs (miRNAs), especially miRNA155, were decreased in the TLR3 I/R group compared with that of the WT I/R group. In conclusion, these data suggest that TLR3 signaling pathway may be a promising target for the treatment of lung I/R injury. PMID- 26939038 TI - Ion-Exchange Resin Anticoagulation (I-ERA): A Novel Extracorporeal Technique for Regional Anticoagulation. AB - BACKGROUND: Extracorporeal treatments always require blood anticoagulation. We tested feasibility and efficacy of a novel technique for regional extracorporeal blood anticoagulation based on calcium removal by ion-exchange resins (i-ER), called ion-exchange resin anticoagulation (i-ERA). METHODS: Eight swine were connected to a veno-venous extracorporeal circuit comprising a hemodiafilter and an i-ER. Blood flow was 150 mL/min. Hemodiafiltrate was generated at 975 mL/min and passed through the i-ER. A fraction of the calcium-free hemodiafiltrate was returned to the hemodiafilter (675 mL/min), while the remaining was recirculated prior the hemodiafilter (300 mL/min) to dilute blood entering the hemodiafilter. A calcium replacement solution was continuously infused. Two hours after i-ERA start, blood was sampled from inlet, before the hemodiafilter (prehemodiafilter blood) and from outlet of the extracorporeal circuit for ionized calcium (iCa) concentration and thromboelastography (TEG). Arterial blood was collected for blood gas analyses, electrolytes concentrations, and plasma free hemoglobin. Hemodynamics and ventilation were monitored. RESULTS: i-ERA reduced iCa from 1.28 +/- 0.05 mmol/L (inlet) to 0.47 +/- 0.03 mmol/L (prehemodiafilter blood) and 0.25 +/- 0.03 mmol/L (outlet). Prehemodiafilter blood and outlet samples showed no sign of clot formation (reaction time (R) >60 min; maximal amplitude (MA) = 0 (0 0) mm), while blood-inlet had normal coagulation (R = 8.5 (5.8-10.2) min; MA = 65.2 (63.2-68.7) mm). Arterial gas analyses and electrolytes concentrations, hemodynamics, and ventilation were unchanged. No hemolysis was recorded. CONCLUSIONS: In a swine model, i-ERA proved feasible and effective in reducing iCa and preventing clot formation with TEG analyses. Further studies are warranted to evaluate the long-term efficacy and safety of i-ERA. LEVEL OF EVIDENCE: V-therapeutic animal experiment. PMID- 26939039 TI - Toll-Like Receptor-9 (TLR9) is Requisite for Acute Inflammatory Response and Injury Following Lung Contusion. AB - Lung contusion (LC) is a significant risk factor for the development of acute respiratory distress syndrome. Toll-like receptor 9 (TLR9) recognizes specific unmethylated CpG motifs, which are prevalent in microbial but not vertebrate genomic DNA, leading to innate and acquired immune responses. TLR9 signaling has recently been implicated as a critical component of the inflammatory response following lung injury. The aim of the present study was to evaluate the contribution of TLR9 signaling to the acute physiologic changes following LC. Nonlethal unilateral closed-chest LC was induced in TLR9 (-/-) and wild-type (WT) mice. The mice were sacrificed at 5, 24, 48, and 72-h time points. The extent of injury was assessed by measuring bronchoalveolar lavage, cells (cytospin), albumin (permeability injury), and cytokines (inflammation). Following LC, only the TLR9 (-/-) mice showed significant reductions in the levels of albumin; release of pro-inflammatory cytokines IL-1beta, IL-6, and Keratinocyte chemoattractant; production of macrophage chemoattractant protein 5; and recruitment of alveolar macrophages and neutrophil infiltration. Histological evaluation demonstrated significantly worse injury at all-time points for WT mice. Macrophages, isolated from TLR9 (-/-) mice, exhibited increased phagocytic activity at 24 h after LC compared with those isolated from WT mice. TLR9, therefore, appears to be functionally important in the development of progressive lung injury and inflammation following LC. Our findings provide a new framework for understanding the pathogenesis of lung injury and suggest blockade of TLR9 as a new therapeutic strategy for the treatment of LC-induced lung injury. PMID- 26939040 TI - Interferon Regulatory Factor-1 Mediates Alveolar Macrophage Pyroptosis During LPS Induced Acute Lung Injury in Mice. AB - Previously, we demonstrated that pyroptosis in alveolar macrophages (AMs) plays an essential role in lipopolysaccharide (LPS)-induced acute lung injury. However, the underlying mechanism remains largely unclear. Here, we show that the absence of interferon regulatory factor 1 (IRF-1) in genetic knock-out mice strongly abrogates pyroptosis in AMs and alleviates the LPS-induced lung injury and systemic inflammation. Our study demonstrates that IRF-1 contributes to caspase-1 activation and apoptosis-associated speck-like protein containing a caspase activation and recruitment domain pyroptosome formation in AMs and leads to downstream inflammatory cytokine release, including that of IL-1beta, IL-18, and HMGB1. The nuclear translocation of IRF-1 is linked to the presence of toll-like receptor 4 (TLR4). Our findings suggest that pyroptosis and the downstream inflammatory response in AMs induced by LPS is a process that is dependent on TLR4-mediated up-regulation of IRF-1. In summary, IRF-1 plays a key role in controlling caspase-1-dependent pyroptosis and inflammation. PMID- 26939041 TI - Aryl Hydrocarbon Receptor Activation in Intestinal Obstruction Ameliorates Intestinal Barrier Dysfunction Via Suppression of MLCK-MLC Phosphorylation Pathway. AB - BACKGROUND: Accumulating evidence suggests that the aryl hydrocarbon receptor (AhR) plays an important role in the maintenance of the function of the intestinal barrier in patients with inflammatory bowel disease and in mouse models. Intestinal obstruction (IO) is a clinical emergency consisting of severe dysfunction of intestinal barrier function, and whether AhR plays a role in the pathogenesis of IO remains unknown but would be highly significant. METHODS: Male C57BL/6 mice were subjected to IO and either treated with AhR endogenous agonist 6-formylindolo [3, 2-b] carbazole (FICZ) or left untreated. Intestinal tissue was harvested after 24 h. Correspondingly, Caco-2 monolayers were treated with FICZ in the absence or presence of hypoxia in vitro or left untreated. The cells were used after 12 h. RESULTS: Damage to the intestinal mucosa was anabatic and intestinal permeability was significantly higher in murine IO and hypoxia-induced Caco-2 models than in controls. Under these conditions the activity of AhR was lower and the fluorescence of zonula occludens-1 (ZO-1) was absent. The increased expression of myosin light chain kinase (MLCK) and phosphorylated MLC (pMLC) indicated that this pathway was open. However, treatment with FICZ caused retention of the tight junction protein ZO-1, alleviated the increase of intestinal permeability, and mitigated epithelial injury. Depletion of AhR by AhR small interfering RNA facilitated the unblocking of the MLCK-pMLC signaling pathway and repressed the protein expression of ZO-1 in vitro. CONCLUSION: AhR activation can ameliorate epithelial barrier dysfunction induced by IO through the suppression of MLCK-pMLC signaling, suggesting that AhR agonist may be a suitable means of addressing this condition. PMID- 26939042 TI - Neonatal SSRI exposure improves mitochondrial function and antioxidant defense in rat heart. AB - Protein restriction during prenatal, postnatal, or in both periods has a close relationship with subsequent development of cardiovascular disease in adulthood. Elevated brain levels of serotonin and its metabolites have been found in malnourished states. The aim in the present study was to investigate whether treatment with fluoxetine (Fx), a selective serotonin reuptake inhibitor, mimics the detrimental effect of low-protein diet during the perinatal period on the male rat heart. Our hypothesis is that increased circulating serotonin as a result of pharmacologic treatment with Fx leads to cardiac dysfunction similar to that observed in protein-restricted rats. Male Wistar rat pups received daily subcutaneous injection of Fx or vehicle from postnatal day 1 to postnatal day 21. Male rats were euthanized at 60 days of age and the following parameters were evaluated in the cardiac tissue: mitochondrial respiratory capacity, respiratory control ratio, reactive oxygen species (ROS) production, mitochondrial membrane potential, and biomarkers of oxidative stress and antioxidant defense. We found that Fx treatment increased mitochondrial respiratory capacity (123%) and membrane potential (212%) and decreased ROS production (55%). In addition we observed an increase in the antioxidant capacity (elevation in catalase activity (5-fold) and glutathione peroxidase (4.6-fold)). Taken together, our results suggest that Fx treatment in the developmental period positively affects the mitochondrial bioenergetics and antioxidant defense in the cardiac tissue. PMID- 26939043 TI - Fish oil supplementation attenuates changes in plasma lipids caused by dexamethasone treatment in rats. AB - Dexamethasone is an anti-inflammatory glucocorticoid that may alter glucose and lipid homeostasis when administered in high doses or for long periods of time. Omega-3 fatty acids, present in fish oil (FO), can be used as potential modulators of intermediary glucose and lipid metabolism. Herein, we evaluate the effects of FO supplementation (1 g.kg(-1) body weight (BW)) on glucose and lipid metabolism in rats treated with dexamethasone (0.5 mg.kg(-1) BW) for 15 days. Adult male Wistar rats were distributed among 4 groups: control (saline, 1 mL.kg( 1) BW and mineral oil, 1 g.kg(-1) BW), DEX (dexamethasone and mineral oil), FO (fish oil and saline), and DFO (fish oil and dexamethasone). Dexamethasone and saline were administered intraperitoneally, and fish oil and mineral oil were administered by gavage. We evaluated functional and molecular parameters of lipid and glycemic profiles at 8 days and at the end of treatment. FO supplementation increased hepatic docosahexaenoic acid (DEX: 5.6% +/- 0.7%; DFO: 10.5% +/- 0.8%) and eicosapentaenoic acid (DEX: 0.3% +/- 0.0%; DFO: 1.3% +/- 0.1%) contents and attenuated the increase of plasma triacylglycerol, total cholesterol, and non high-density lipoprotein cholesterol concentrations in DFO rats compared with DEX rats. These effects seem not to depend on hepatic expression of insulin receptor substrate 1, protein kinase B, peroxisome proliferator-activated receptor gamma coactivator 1-alpha, and peroxisome proliferator-activated receptor gamma. There was no effect of supplementation on body weight loss, fasting glycemia, and glucose tolerance in rats treated with dexamethasone. In conclusion, we show that FO supplementation for 15 days attenuates the dyslipidemia induced by dexamethasone treatment. PMID- 26939044 TI - New design of nucleotide excision repair (NER) inhibitors for combination cancer therapy. AB - Many cancer chemotherapy agents act by targeting the DNA of cancer cells, causing substantial damage within their genome and causing them to undergo apoptosis. An effective DNA repair pathway in cancer cells can act in a reverse way by removing these drug-induced DNA lesions, allowing cancer cells to survive, grow and proliferate. In this context, DNA repair inhibitors opened a new avenue in cancer treatment, by blocking the DNA repair mechanisms from removing the chemotherapy mediated DNA damage. In particular, the nucleotide excision repair (NER) involves more than thirty protein-protein interactions and removes DNA adducts caused by platinum-based chemotherapy. The excision repair cross-complementation group 1 (ERCC1)-xeroderma pigmentosum, complementation group A (XPA) protein (XPA-ERCC1) complex seems to be one of the most promising targets in this pathway. ERCC1 is over expressed in cancer cells and the only known cellular function so far for XPA is to recruit ERCC1 to the damaged point. Here, we build upon our recent advances in identifying inhibitors for this interaction and continue our efforts to rationally design more effective and potent regulators for the NER pathway. We employed in silico drug design techniques to: (1) identify compounds similar to the recently discovered inhibitors, but more effective at inhibiting the XPA ERCC1 interactions, and (2) identify different scaffolds to develop novel lead compounds. Two known inhibitor structures have been used as starting points for two ligand/structure-hybrid virtual screening approaches. The findings described here form a milestone in discovering novel inhibitors for the NER pathway aiming at improving the efficacy of current platinum-based therapy, by modulating the XPA-ERCC1 interaction. PMID- 26939045 TI - "Obesity paradox" in transcatheter aortic valve implantation. AB - BACKGROUND: To determine whether body mass index (BMI) is associated with mortality in transcatheter aortic valve implantation (TAVI), we performed a mete analysis of currently available studies. METHODS: MEDLINE and EMBASE were searched through September 2015 using PubMed and OVID, to identify all studies investigating an association of BMI with early (in-hospital or 30-day) and mid term (mean or median follow-up of approximately >6-month) mortality in patients undergoing TAVI. RESULTS: Our search identified 11 eligible studies including 10,196 patients undergoing TAVI. A pooled analysis of 7 studies (enrolling 4046 patients) reporting a hazard ratio (HR) of BMI as continuous data for mid-term mortality demonstrated that greater BMI was associated with significantly less mid-term mortality (HR per 1-unit increase in BMI, 0.97; 95% confidence interval [CI], 0.94 to 1.00 [0.9982]: P = 0.04). Comparisons of overweight versus normal weight and obesity versus normal weight for mid-term mortality were not statistically significant. A pooled analysis of 3 studies (enrolling 3901 patients) reporting an odds ratio (OR) of BMI as continuous data for 30-day mortality demonstrated that greater BMI was associated with significantly less mortality (OR per 1-unit increase in BMI, 0.95; 95% CI, 0.92 to 0.98: P = 0.001). Comparisons of overweight versus normal weight (P = 0.02) and obesity versus normal weight (P = 0.04) for 30-day mortality were statistically significant. CONCLUSIONS: BMI as continuous data may be associated with better early and mid term post-TAVI survival. Whereas, overweight or obesity as categorized BMI may be associated with early, not mid-term, post-TAVI survival. PMID- 26939046 TI - Current management of aortic arch lesions with hybrid procedures: a tailored approach to a progressive disease. AB - In the current era of cardiac and aortic surgery lines between open and endovascular approaches are becoming blurred. Hybrid techniques emerged with the availability of endovascular devices and the idea that combining open operations with a stent graft might provide a treatment option to those patients deemed too high-risk for conventional surgery. As these procedures evolved, it became clear that they still carried significant risk especially for the "inoperable" or "high risk" patients, but they also offered new options for treating complex pathologies involving multiple segments of the aorta. Hybrid techniques not only provide the potential for less invasive aortic repair, but must be considered as an important complementary treatment option for patients with aortic disease, allowing for a potentially more effective and complete repair. The objective of this article is to review the current options for hybrid arch repair and the indications for choosing the various techniques based on pathologic presentation. PMID- 26939047 TI - Zika Virus and Pregnancy: A Review of the Literature and Clinical Considerations. AB - The latest Zika virus (ZIKV) outbreak has reached epidemic proportions as it spreads throughout South and Central America. In November 2015, the Brazilian Ministry of Health reported a 20-fold increase in the number of cases of neonatal microcephaly, which corresponds geographically and temporally to the ZIKV outbreak. Case reports have provided some evidence of a causal link between maternal ZIKV infection, fetal microcephaly, and intracranial calcifications. The sparse data regarding ZIKV in pregnancy come solely from case reports and personal communications, and recommendations for management of ZIKV exposure during pregnancy are rapidly evolving. Our objective is to review and synthesize the current literature regarding ZIKV as it pertains to pregnancy and provide some assistance to clinicians who may have to manage a pregnant patient with potential exposure to ZIKV. We will also explore certain aspects of related viruses in pregnancy in hopes to shed light on this little-known topic. PMID- 26939048 TI - Protective Effect of Whole and Fat-Free Fluoridated Milk, Applied before or after Acid Challenge, against Dental Erosion. AB - This study analysed in vitro the effect of milk against dental erosion, considering three factors: the type of milk (bovine whole/fat-free), the presence of different fluoride concentrations and the time of application (before/after erosive challenge). Bovine enamel (n = 15/group) and root dentine (n = 12/group) specimens were submitted to the following treatments: after the first erosive challenge - 0.9% NaCl solution (negative control), whole milk with 0, 2.5, 5.0 and 10.0 ppm F, fat-free milk with 0, 2.5, 5.0 and 10.0 ppm F, and 0.05% NaF solution (positive control); before the first erosive challenge - whole milk with 0, 2.5, 5.0 and 10.0 ppm F, fat-free milk with 0, 2.5, 5.0 and 10.0 ppm F, and 0.05% NaF solution (positive control). Specimens were submitted to demineralisation-remineralisation regimes 4 times/day for 5 days. The response variables were enamel and dentine loss (in micrometres). Data were analysed using Kruskal-Wallis/Dunn's test (p < 0.05). For enamel, whole milk containing 10 ppm F, applied before the erosive challenge, was the most protective treatment, but with no significant difference compared with the same treatment carried out after the erosive challenge. For dentine, whole fluoridated milk (all concentrations, after), fat-free 10 ppm F milk (after, before) and whole milk with or without F (except 2.5 ppm F, all before) significantly reduced dentine erosion. It seems that the presence of fluoride, especially at 10 ppm, is the most important factor in reducing dental erosion. PMID- 26939049 TI - The Role of Protein Kinase A in Anxiety Behaviors. AB - This review focuses on the genetic and other evidence supporting the notion that the cyclic AMP (cAMP) signaling pathway and its mediator, the protein kinase A (PKA) enzyme, which respond to environmental stressors and regulate stress responses, are central to the pathogenesis of disorders related to anxiety. We describe the PKA pathway and review in vitro animal studies (mouse) and other evidence that support the importance of PKA in regulating behaviors that lead to anxiety. Since cAMP signaling and PKA have been pharmacologically exploited since the 1940s (even before the identification of cAMP as a second messenger with PKA as its mediator) for a number of disorders from asthma to cardiovascular diseases, there is ample opportunity to develop therapies using this new knowledge about cAMP, PKA, and anxiety disorders. PMID- 26939050 TI - Incidence of AIDS-Defining Opportunistic Infections and Mortality during Antiretroviral Therapy in a Cohort of Adult HIV-Infected Individuals in Hanoi, 2007-2014. AB - BACKGROUND: Although the prognosis for HIV-infected individuals has improved after antiretroviral therapy (ART) scale-up, limited data exist on the incidence of AIDS-defining opportunistic infections (ADIs) and mortality during ART in resource-limited settings. METHODS: HIV-infected adults in two large hospitals in urban Hanoi were enrolled to the prospective cohort, from October 2007 through December 2013. Those who started ART less than one year before enrollment were assigned to the survival analysis. Data on ART history and ADIs were collected retrospectively at enrollment and followed-up prospectively until April 2014. RESULTS: Of 2,070 cohort participants, 1,197 were eligible for analysis and provided 3,446 person-years (PYs) of being on ART. Overall, 161 ADIs episodes were noted at a median of 3.20 months after ART initiation (range 0.03-75.8) with an incidence 46.7/1,000 PYs (95% confidence interval [CI] 39.8-54.5). The most common ADI was tuberculosis with an incidence of 29.9/1,000 PYs. Mortality after ART initiation was 8.68/1,000 PYs and 45% (19/45) died of AIDS-related illnesses. Age over 50 years at ART initiation was significantly associated with shorter survival after controlling for baseline CD4 count, but neither having injection drug use (IDU) history nor previous ADIs were associated with poor survival. Semi competing risks analysis in 951 patients without ADIs history prior to ART showed those who developed ADIs after starting ART were at higher risk of death in the first six months than after six months. CONCLUSION: ADIs were not rare in spite of being on effective ART. Age over 50 years, but not IDU history, was associated with shorter survival in the cohort. This study provides in-depth data on the prognosis of patients on ART in Vietnam during the first decade of ART scale-up. PMID- 26939051 TI - MIRU-VNTR Genotyping of Mycobacterium tuberculosis Strains Using QIAxcel Technology: A Multicentre Evaluation Study. AB - BACKGROUND: Molecular genotyping of M.tuberculosis is an important laboratory tool in the context of emerging drug resistant TB. The standard 24-loci MIRU-VNTR typing includes PCR amplification followed by the detection and sizing of PCR fragments using capillary electrophoresis on automated sequencers or using agarose gels. The QIAxcel Advanced system might offer a cost-effective medium throughput alternative. METHODS: Performance characteristics of the QIAxcel Advanced platform for the standard 24 VNTR loci panel was evaluated at two centres on a total of 140 DNA specimens using automated capillary electrophoresis as a reference method. Additionally 4 hypervariable MIRU-VNTR loci were evaluated on 53 crude DNA extracts. The sizing accuracy, interlaboratory reproducibility and overall instrument's performance were assessed during the study. RESULTS: An overall concordance with the reference method was high reaching 98.5% and 97.6% for diluted genomic and crude DNA extracts respectively. 91.4% of all discrepancies were observed in fragments longer than 700bp. The concordance for hypervariable loci was lower except for locus 4120 (96.2%). The interlaboratory reproducibility agreement rates were 98.9% and 91.3% for standard and hypervariable loci, respectively. Overall performance of the QIAxcel platform for M.tuberculosis genotyping using a panel of standard loci is comparable to that of established methods for PCR fragments up to 700bp. Inaccuracies in sizing of longer fragments could be resolved through using in-house size markers or introduction of offset values. To conclude, the QiaXcel system could be considered an effective alternative to existing methods in smaller reference and regional laboratories offering good performance and shorter turnaround times. PMID- 26939052 TI - Cranial biomechanics, bite force and function of the endocranial sinuses in Diprotodon optatum, the largest known marsupial. AB - The giant extinct marsupial Diprotodon optatum has unusual skull morphology for an animal of its size, consisting of very thin bone and large cranial sinuses that occupy most of the internal cranial space. The function of these sinuses is unknown as there are no living marsupial analogues. The finite element method was applied to identify areas of high and low stress, and estimate the bite force of Diprotodon to test hypotheses on the function of the extensive cranial sinuses. Detailed three-dimensional models of the cranium, mandible and jaw adductor muscles were produced. In addition, manipulations to the Diprotodon cranial model were performed to investigate changes in skull and sinus structure, including a model with no sinuses (sinuses 'filled' with bone) and a model with a midsagittal crest. Results indicate that the cranial sinuses in Diprotodon significantly lighten the skull while still providing structural support, a high bite force and low stress, indicating the cranium may have been able to withstand higher loads than those generated during feeding. Data from this study support the hypothesis that pneumatisation is driven by biomechanical loads and occurs in areas of low stress. The presence of sinuses is likely to be a byproduct of the separation of the outer surface of the skull from the braincase due to the demands of soft tissue including the brain and the large jaw adductor musculature, especially the temporalis. In very large species, such as Diprotodon, this separation is more pronounced, resulting in extensive cranial sinuses due to a relatively small brain compared with the size of the skull. PMID- 26939053 TI - Circulating MiR-19b-3p, MiR-134-5p and MiR-186-5p are Promising Novel Biomarkers for Early Diagnosis of Acute Myocardial Infarction. AB - BACKGROUND/AIMS: Recent studies have shown that circulating microRNAs (miRNAs) are emerging as promising biomarkers for cardiovascular diseases. This study aimed to determine whether miR-19b-3p, miR-134-5p and miR-186-5p can be used as novel indicators for acute myocardial infarction (AMI). METHODS: To investigate the kinetic expression of the three selected miRNAs, we enrolled 18 patients with AMI and 20 matched controls. Plasma samples were collected from each participant, and total RNA was extracted. Quantitative real-time PCR and ELISA assays were used to investigate the expression of circulating miRNAs and cardiac troponin I (cTnI), respectively. Plasma samples from another age- and gender-matched cohort were collected to investigate the impact of medications for AMI on the expression of the selected miRNAs. RESULTS: Levels of plasma miR-19b-3p, miR-134-5p and miR 186-5p were significantly increased in early stage of AMI. Plasma miR-19b-3p and miR-134-5p levels reached peak expression immediately after admission (T0), whereas miR-186-5p achieved peak expression at 4 h after T0. All of these times were earlier than the peak for cTnI (8 h after T0). In addition, all three miRNAs were positively correlated with cTnI. Receiver Operating Characteristic (ROC) analysis indicated that each single miRNA showed considerable diagnostic efficiency for predicting AMI. Furthermore, combining all three miRNAs in a panel increased the efficiency of distinguishing between patients with AMI and controls. Moreover, we found that heparin and medications for AMI did not impact the expression of these circulating miRNAs. CONCLUSION: Circulating miR-19b-3p, miR-134-5p and miR-186-5p could be considered promising novel diagnostic biomarkers for the early phase of AMI. PMID- 26939054 TI - Different Polar Metabolites and Protein Profiles between High- and Low-Quality Japanese Ginjo Sake. AB - Japanese ginjo sake is a premium refined sake characterized by a pleasant fruity apple-like flavor and a sophisticated taste. Because of technical difficulties inherent in brewing ginjo sake, off-flavors sometimes occur. However, the metabolites responsible for off-flavors as well as those present or absent in higher quality ginjo sake remain uncertain. Here, the relationship between 202 polar chemical compounds in sake identified using capillary electrophoresis coupled with time-of-flight mass spectrometry and its organoleptic properties, such as quality and off-flavor, was examined. First, we found that some off flavored sakes contained higher total amounts of metabolites than other sake samples. The results also identified that levels of 2-oxoglutaric acid and fumaric acid, metabolites in the tricarboxylic acid cycle, were highly but oppositely correlated with ginjo sake quality. Similarly, pyridoxine and pyridoxamine, co-enzymes for amino transferase, were also highly but oppositely correlated with ginjo sake quality. Additionally, pyruvic acid levels were associated with good quality as well. Compounds involved in the methionine salvage cycle, oxidative glutathione derivatives, and amino acid catabolites were correlated with low quality. Among off-flavors, an inharmonious bitter taste appeared attributable to polyamines. Furthermore, protein analysis displayed that a diversity of protein components and yeast protein (triosephosphate isomerase, TPI) leakage was linked to the overall metabolite intensity in ginjo sake. This research provides insight into the relationship between sake components and organoleptic properties. PMID- 26939055 TI - Performance of a Predictive Model for Long-Term Hemoglobin Response to Darbepoetin and Iron Administration in a Large Cohort of Hemodialysis Patients. AB - Anemia management, based on erythropoiesis stimulating agents (ESA) and iron supplementation, has become an increasingly challenging problem in hemodialysis patients. Maintaining hemodialysis patients within narrow hemoglobin targets, preventing cycling outside target, and reducing ESA dosing to prevent adverse outcomes requires considerable attention from caregivers. Anticipation of the long-term response (i.e. at 3 months) to the ESA/iron therapy would be of fundamental importance for planning a successful treatment strategy. To this end, we developed a predictive model designed to support decision-making regarding anemia management in hemodialysis (HD) patients treated in center. An Artificial Neural Network (ANN) algorithm for predicting hemoglobin concentrations three months into the future was developed and evaluated in a retrospective study on a sample population of 1558 HD patients treated with intravenous (IV) darbepoetin alfa, and IV iron (sucrose or gluconate). Model inputs were the last 90 days of patients' medical history and the subsequent 90 days of darbepoetin/iron prescription. Our model was able to predict individual variation of hemoglobin concentration 3 months in the future with a Mean Absolute Error (MAE) of 0.75 g/dL. Error analysis showed a narrow Gaussian distribution centered in 0 g/dL; a root cause analysis identified intercurrent and/or unpredictable events associated with hospitalization, blood transfusion, and laboratory error or misreported hemoglobin values as the main reasons for large discrepancy between predicted versus observed hemoglobin values. Our ANN predictive model offers a simple and reliable tool applicable in daily clinical practice for predicting the long-term response to ESA/iron therapy of HD patients. PMID- 26939057 TI - Label-Free Pyrophosphate Recognition with Functionalized Asymmetric Nanopores. AB - The label-free detection of pyrophosphate (PPi) anions with a nanofluidic sensing device based on asymmetric nanopores is demonstrated. The pore surface is functionalized with zinc complexes based on two di(2-picolyl)amine [bis(DPA)] moieties using carbodiimide coupling chemistry. The complexation of zinc (Zn(2+) ) ion is achieved by exposing the modified pore to a solution of zinc chloride to form bis(Zn(2+) -DPA) complexes. The chemical functionalization is demonstrated by recording the changes in the observed current-voltage (I-V) curves before and after pore modification. The bis(Zn(2+) -DPA) complexes on the pore walls serve as recognition sites for pyrophosphate anion. The experimental results show that the proposed nanofluidic sensor has the ability to sense picomolar concentrations of PPi anion in the surrounding environment. On the contrary, it does not respond to other phosphate anions, including monohydrogen phosphate, dihydrogen phosphate, adenosine monophosphate, adenosine diphosphate, and adenosine triphosphate. The experimental results are described theoretically by using a model based on the Poisson-Nernst-Planck equations. PMID- 26939056 TI - Primary Ovarian Insufficiency Induced by Fanconi Anemia E Mutation in a Mouse Model. AB - In most cases of primary ovarian insufficiency (POI), the cause of the depletion of ovarian follicles is unknown. Fanconi anemia (FA) proteins are known to play important roles in follicular development. Using random insertional mutagenesis with a lentiviral transgene, we identified a family with reduced fertility in the homozygous transgenic mice. We identified the integration site and found that the lentivirus had integrated into intron 8 of the Fanconi E gene (Fance). By RT-PCR and in situ hybridization, we found that Fance transcript levels were significantly reduced. The Fance homozygous mutant mice were assayed for changes in ovarian development, follicle numbers and estrous cycle. Ovarian dysplasias and a severe lack of follicles were seen in the mutant mice. In addition, the estrous cycle was disrupted in adult females. Our results suggest that POI has been induced by the Fance mutation in this new mouse model. PMID- 26939058 TI - Quality of Visual Cue Affects Visual Reweighting in Quiet Standing. AB - Sensory reweighting is a characteristic of postural control functioning adopted to accommodate environmental changes. The use of mono or binocular cues induces visual reduction/increment of moving room influences on postural sway, suggesting a visual reweighting due to the quality of available sensory cues. Because in our previous study visual conditions were set before each trial, participants could adjust the weight of the different sensory systems in an anticipatory manner based upon the reduction in quality of the visual information. Nevertheless, in daily situations this adjustment is a dynamical process and occurs during ongoing movement. The purpose of this study was to examine the effect of visual transitions in the coupling between visual information and body sway in two different distances from the front wall of a moving room. Eleven young adults stood upright inside of a moving room in two distances (75 and 150 cm) wearing a liquid crystal lenses goggles, which allow individual lenses transition from opaque to transparent and vice-versa. Participants stood still during five minutes for each trial and the lenses status changed every one minute (no vision to binocular vision, no vision to monocular vision, binocular vision to monocular vision, and vice-versa). Results showed that farther distance and monocular vision reduced the effect of visual manipulation on postural sway. The effect of visual transition was condition dependent, with a stronger effect when transitions involved binocular vision than monocular vision. Based upon these results, we conclude that the increased distance from the front wall of the room reduced the effect of visual manipulation on postural sway and that sensory reweighting is stimulus quality dependent, with binocular vision producing a much stronger down/up-weighting than monocular vision. PMID- 26939059 TI - The Kaiser Permanente Northern California Story: Improving Hypertension Control From 44% to 90% in 13 Years (2000 to 2013). PMID- 26939060 TI - No Evidence for Moral Reward and Punishment in an Anonymous Context. AB - Human social interactions are regulated by moral norms that define individual obligations and rights. These norms are enforced by punishment of transgressors and reward of followers. Yet, the generality and strength of this drive to punish or reward is unclear, especially when people are not personally involved in the situation and when the actual impact of their sanction is only indirect, i.e., when it diminishes or promotes the social status of the punished or rewarded individual. In a real-life study, we investigated if people are inclined to anonymously punish or reward a person for her past deeds in a different social context. Participants from three socio-professional categories voted anonymously for early career violinists in an important violin competition. We found that participants did not punish an immoral violin candidate, nor did they reward another hyper-moral candidate. On the contrary, one socio-professional category sanctioned hyper-morality. Hence, salient moral information about past behavior did not elicit punishment or reward in an impersonal situation where the impact of the sanction was indirect. We conclude that contextual features play an important role in human motivation to enforce moral norms. PMID- 26939063 TI - Strain Rate and Anisotropic Microstructure Dependent Mechanical Behaviors of Silkworm Cocoon Shells. AB - Silkworm cocoons are multi-layered composite structures comprised of high strength silk fiber and sericin, and their mechanical properties have been naturally selected to protect pupas during metamorphosis from various types of external attacks. The present study attempts to gain a comprehensive understanding of the mechanical properties of cocoon shell materials from wild silkworm species Antheraea pernyi under dynamic loading rates. Five dynamic strain rates from 0.00625 s-1 to 12.5 s-1 are tested to show the strain rate sensitivity of the cocoon shell material. In the meantime, the anisotropy of the cocoon shell is considered and the cocoon shell specimens are cut along 0 degrees , 45 degrees and 90 degrees orientation to the short axis of cocoons. Typical mechanical properties including Young's modulus, yield strength, ultimate strength and ultimate strain are extracted and analyzed from the stress-strain curves. Furthermore, the fracture morphologies of the cocoon shell specimens are observed under scanning electron microscopy to help understand the relationship between the mechanical properties and the microstructures of the cocoon material. A discussion on the dynamic strain rate effect on the mechanical properties of cocoon shell material is followed by fitting our experimental results to two previous models, and the effect could be well explained. We also compare natural and dried cocoon materials for the dynamic strain rate effect and interestingly the dried cocoon shells show better overall mechanical properties. This study provides a different perspective on the mechanical properties of cocoon material as a composite material, and provides some insight for bio-inspired engineering materials. PMID- 26939062 TI - Antiplatelet Therapy of Cilostazol or Sarpogrelate with Aspirin and Clopidogrel after Percutaneous Coronary Intervention: A Retrospective Cohort Study Using the Korean National Health Insurance Claim Database. AB - BACKGROUND/OBJECTIVES: Addition of cilostazol or sarpogrelate to the standard dual antiplatelet therapy of aspirin and clopidogrel has been implemented in patients that underwent percutaneous coronary intervention (PCI) with stents in Korea. This study aimed to evaluate the efficacy and safety of triple antiplatelet therapies. METHODS: This retrospective cohort study was performed using the Korean National Insurance Claim Data of the Health Insurance Review and Assessment Service from January 1, 2009 to December 31, 2014. The study cohort population consisted of patients with ischemic heart diseases and a history of PCI. They were treated with antiplatelet therapy of aspirin, clopidogrel (AC); aspirin, clopidogrel, cilostazol (ACCi); or aspirin, clopidogrel, sarpogrelate (ACSa) during the index period from January 1, 2010 to December 31, 2011. During the follow-up period up to December 31, 2014, the major adverse cardiac or cerebral events (MACCE) including death, myocardial infarction, target lesion revascularization, and ischemic stroke were assessed. Bleeding complications were also evaluated as adverse drug events. RESULTS: Out of 93,876 patients with PCI during the index period, 69,491 patients started dual (AC) or triple therapy (ACSa or ACCi). The clinical outcomes of comparing ACSa and ACCi therapy showed beneficial effects in the ACSa group in the prevention of subsequent cardiac or cerebral events. After Propensity score-matching between ACSa and ACCi groups, there were significant differences in MI and revascularization, with corresponding HR of 0.38 (95% CI, 0.20-0.73) and 0.66 (95% CI, 0.53-0.82) in ACSa vs. ACCi at 12 months, respectively. At the 24-month follow-up, the triple therapy groups (ACS or ACC) had a higher incidence of MACCE compared to the dual therapy (AC) group; ACSa vs. AC HR of 1.69 (95% CI, 1.62-1.77); ACC vs. AC HR of 1.22 (95% CI, 1.06-1.41). There was no significant difference in severe or life threatening bleeding risk among three groups; ACSa vs. AC, HR of 0.68 (95% CI, 0.37-1.24), ACCi vs. AC, HR of 0.91 (95% CI, 0.77-1.09). CONCLUSION: Sarpogrelate containing triple antiplatelet therapy demonstrated comparable rates of MACCE prevention to the conventional dual antiplatelet therapy after PCI without significantly increasing bleeding risk during the two-year follow-up period. PMID- 26939064 TI - Combinatorial Low-Volume Synthesis of Well-Defined Polymers by Enzyme Degassing. AB - The synthesis of well-defined polymers in a low-volume, combinatorial fashion has long been a goal in polymer chemistry. Here, we report the preparation of a wide range of highly controlled homo and block co-polymers by Enz-RAFT (enzyme assisted reversible addition-fragmentation chain transfer) polymerization in microtiter plates in the open atmosphere. The addition of 1 MUm glucose oxidase (GOx) to water/solvent mixtures enables polymerization reactions to proceed in extremely low volumes (40 MUL) and low radical concentrations. This procedure provides excellent control and high conversions across a range of monomer families and molecular weights, thus avoiding the need to purify for screening applications. This simple technique enables combinatorial polymer synthesis in microtiter plates on the benchtop without the need of highly specialized synthesizers and at much lower volumes than is currently possible by any other technique. PMID- 26939061 TI - Morphology and Molecular Composition of Purified Bovine Viral Diarrhea Virus Envelope. AB - The family Flaviviridae includes viruses that have different virion structures and morphogenesis mechanisms. Most cellular and molecular studies have been so far performed with viruses of the Hepacivirus and Flavivirus genera. Here, we studied bovine viral diarrhea virus (BVDV), a member of the Pestivirus genus. We set up a method to purify BVDV virions and analyzed their morphology by electron microscopy and their protein and lipid composition by mass spectrometry. Cryo electron microscopy showed near spherical viral particles displaying an electron dense capsid surrounded by a phospholipid bilayer with no visible spikes. Most particles had a diameter of 50 nm and about 2% were larger with a diameter of up to 65 nm, suggesting some size flexibility during BVDV morphogenesis. Morphological and biochemical data suggested a low envelope glycoprotein content of BVDV particles, E1 and E2 being apparently less abundant than Erns. Lipid content of BVDV particles displayed a ~2.3 to 3.5-fold enrichment in cholesterol, sphingomyelin and hexosyl-ceramide, concomitant with a 1.5 to 5-fold reduction of all glycerophospholipid classes, as compared to lipid content of MDBK cells. Although BVDV buds in the endoplasmic reticulum, its lipid content differs from a typical endoplasmic reticulum membrane composition. This suggests that BVDV morphogenesis includes a mechanism of lipid sorting. Functional analyses confirmed the importance of cholesterol and sphingomyelin for BVDV entry. Surprisingly, despite a high cholesterol and sphingolipid content of BVDV envelope, E2 was not found in detergent-resistant membranes. Our results indicate that there are differences between the structure and molecular composition of viral particles of Flaviviruses, Pestiviruses and Hepaciviruses within the Flaviviridae family. PMID- 26939066 TI - How Much Overtesting Is Needed to Safely Exclude a Diagnosis? A Different Perspective on Triage Testing Using Bayes' Theorem. AB - Ruling out disease often requires expensive or potentially harmful confirmation testing. For such testing, a less invasive triage test is often used. Intuitively, few negative confirmatory tests suggest success of this approach. However, if negative confirmation tests become too rare, too many disease cases could have been missed. It is therefore important to know how many negative tests are needed to safely exclude a diagnosis. We quantified this relationship using Bayes' theorem, and applied this to the example of pulmonary embolism (PE), for which triage is done with a Clinical Decision Rule (CDR) and D-dimer testing, and CT-angiography (CTA) is the confirmation test. For a maximum proportion of missed PEs of 1% in triage-negative patients, we calculate a 67% 'mandatory minimum' proportion of negative CTA scans. To achieve this, the proportion of patients with PE undergoing triage testing should be appropriately low, in this case no higher than 24%. Pre-test probability, triage test characteristics, the proportion of negative confirmation tests, and the number of missed diagnoses are mathematically entangled. The proportion of negative confirmation tests--not too high, but definitely not too low either--could be a quality benchmark for diagnostic processes. PMID- 26939065 TI - AtGRP3 Is Implicated in Root Size and Aluminum Response Pathways in Arabidopsis. AB - AtGRP3 is a glycine-rich protein (GRP) from Arabidopsis thaliana shown to interact with the receptor-like kinase AtWAK1 in yeast, in vitro and in planta. In this work, phenotypic analyses using transgenic plants were performed in order to better characterize this GRP. Plants of two independent knockout alleles of AtGRP3 develop longer roots suggesting its involvement in root size determination. Confocal microscopy analysis showed an abnormal cell division and elongation in grp3-1 knockout mutants. Moreover, we also show that grp3-1 exhibits an enhanced Aluminum (Al) tolerance, a feature also described in AtWAK1 overexpressing plants. Together, these results implicate AtGRP3 function root size determination during development and in Al stress. PMID- 26939067 TI - Sorting duplicated loci disentangles complexities of polyploid genomes masked by genotyping by sequencing. AB - Many plants and animals of polyploid origin are currently enjoying a genomics explosion enabled by modern sequencing and genotyping technologies. However, routine filtering of duplicated loci in most studies using genotyping by sequencing introduces an unacceptable, but often overlooked, bias when detecting selection. Retained duplicates from ancient whole-genome duplications (WGDs) may be found throughout genomes, whereas retained duplicates from recent WGDs are concentrated at distal ends of some chromosome arms. Additionally, segmental duplicates can be found at distal ends or nearly anywhere in a genome. Evidence shows that these duplications facilitate adaptation through one of two pathways: neo-functionalization or increased gene expression. Filtering duplicates removes distal ends of some chromosomes, and distal ends are especially known to harbour adaptively important genes. Thus, filtering of duplicated loci impoverishes the interpretation of genomic data as signals from contiguous duplicated genes are ignored. We review existing strategies to genotype and map duplicated loci; we focus in detail on an overlooked strategy of using gynogenetic haploids (1N) as a part of new genotyping by sequencing studies. We provide guidelines on how to use this haploid strategy for studies on polyploid-origin vertebrates including how it can be used to screen duplicated loci in natural populations. We conclude by discussing areas of research that will benefit from better inclusion of polyploid loci; we particularly stress the sometimes overlooked fact that basing genomic studies on dense maps provides value added in the form of locating and annotating outlier loci or colocating outliers into islands of divergence. PMID- 26939068 TI - Stinging Nettle (Urtica dioica L.) Attenuates FFA Induced Ceramide Accumulation in 3T3-L1 Adipocytes in an Adiponectin Dependent Manner. AB - OBJECTIVE: Excess dietary lipids result in the accumulation of lipid metabolites including ceramides that can attenuate insulin signaling. There is evidence that a botanical extract of Urtica dioica L. (stinging nettle) improves insulin action, yet the precise mechanism(s) are not known. Hence, we examined the effects of Urtica dioica L. (UT) on adipocytes. RESEARCH DESIGN: We investigated the effects of an ethanolic extract of UT on free fatty acid (palmitic acid) induced inhibition of insulin-stimulated Akt serine phosphorylation and modulation of ceramidase expression in 3T3-L1 adipocytes. Adipocytes were exposed to excess FFAs in the presence or absence of UT. Effects on adiponectin expression, ceramidase expression, ceramidase activity, ceramide accumulation and insulin signaling were determined. RESULTS: As expected, FFAs reduced adiponectin expression and increased the expression of ceramidase enzymes but not their activity. FFA also induced the accumulation of ceramides and reduced insulin stimulated phosphorylation of Akt in adipocytes. The effects of FFA were partially reversed by UT. UT enhanced adiponectin expression and ceramidase activity in the presence of excess FFAs. UT abated ceramide accumulation and increased insulin sensitivity via enhanced Akt phosphorylation. A siRNA knockdown of adiponectin expression prevented UT from exerting positive effects on ceramidase activity but not Akt phosphorylation. CONCLUSIONS: In adipocytes, the ability of UT to antagonize the negative effects of FFA by modulating ceramidase activity and ceramide accumulation is dependent on the presence of adiponectin. However, the ability of UT to enhance Akt phosphorylation is independent of adiponectin expression. These studies demonstrate direct effects of UT on adipocytes and suggest this botanical extract is metabolically beneficial. PMID- 26939069 TI - Information Needs and Concerns of Patients with Inflammatory Bowel Disease: What Can We Learn from Participants in a Bilingual Clinical Cohort? AB - BACKGROUND: Inflammatory Bowel Disease (IBD) patients are confronted with needs and concerns related to their disease. AIM: To explore information expectations of patients included in a national bilingual IBD cohort in Switzerland (SIBDC). METHODS: This is a mixed-methods study, comprising 1) a semi-narrative survey sent to 1506 patients from the SIBDC and 2) two focus groups conducted with 14 patients to explore and assess the relevance of the survey's findings. Data collected within the framework of the SIBDC was used to characterize survey's responders. RESULTS: 728 patients (48%) replied to the survey: 52.5% females, 56% Crohn's disease (CD), 87% secondary/tertiary level educated, 70% full/part-time employed. On average, 47% of patients sought for information, regardless of the disease stage; 27% of them were dissatisfied with information received at the time of first symptoms. During flares, 43% were concerned about drugs and therapies; in remission, 57% had concerns on research and developments; 27% searched for information linked to daily disease management. Information-seeking increased when active disease, for CD with high levels of perceived stress (OR = 2.47; p = 0.003), and for all with higher posttraumatic stress symptoms. The focus groups confirmed a perceived lack of information about general functioning, disease course, treatments and their risks, extra-intestinal symptoms and manifestations. CONCLUSIONS: Information remains insufficient for IBD patients. Lack of information in specific domains can potentially cause stress and hinder detection of symptoms. Better information should be considered as a potentially important component in improving patients' outcomes in IBD. PMID- 26939070 TI - Metastases and Colon Cancer Tumor Growth Display Divergent Responses to Modulation of Canonical WNT Signaling. AB - Human colon cancers commonly harbor loss of function mutations in APC, a repressor of the canonical WNT pathway, thus leading to hyperactive WNT-TCF signaling. Re-establishment of Apc function in mice, engineered to conditionally repress Apc through RNAi, resolve the intestinal tumors formed due to hyperactivated Wnt-Tcf signaling. These and other results have prompted the search for specific WNT pathway antagonists as therapeutics for clinically problematic human colon cancers and associated metastases, which remain largely incurable. This widely accepted view seems at odds with a number of findings using patient-derived material: Canonical TCF targets are repressed, instead of being hyperactivated, in advanced colon cancers, and repression of TCF function does not generally result in tumor regression in xenografts. The results of a number of genetic mouse studies have also suggested that canonical WNT-TCF signaling drives metastases, but direct in vivo tests are lacking, and, surprisingly, TCF repression can enhance directly seeded metastatic growth. Here we have addressed the abilities of enhanced and blocked WNT-TCF signaling to alter tumor growth and distant metastases using xenografts of advanced human colon cancers in mice. We find that endogenous WNT-TCF signaling is mostly anti metastatic since downregulation of TCF function with dnTCF generally enhances metastatic spread. Consistently, elevating the level of WNT signaling, by increasing the levels of WNT ligands, is not generally pro-metastatic. Our present and previous data reveal a heterogeneous response to modulating WNT-TCF signaling in human cancer cells. Nevertheless, the findings that a fraction of colon cancers tested require WNT-TCF signaling for tumor growth but all respond to repressed signaling by increasing metastases beg for a reevaluation of the goal of blocking WNT-TCF signaling to universally treat colon cancers. Our data suggest that WNT-TCF blockade may be effective in inhibiting tumor growth in only a subset of cases but will generally boost metastases. PMID- 26939072 TI - Fabrication of polyelectrolyte multilayered nano-capsules using a continuous layer-by-layer approach. AB - The layer-by-layer approach is a highly versatile method for the fabrication of multilayered polymeric films and capsules. It has been widely investigated in research for various polyelectrolyte pairs and core template particles. However, the fabrication of nano-sized capsules at the larger scale is difficult and time consuming, due to the necessity of washing and centrifugation steps before the deposition of each polyelectrolyte layer. This results not only in a very long fabrication time, but also in the partial loss of particles during those intermediate steps. In this study, we introduced a continuous approach for the fabrication of multilayer polyelectrolyte based nano-capsules using calcium phosphate core nanoparticles and a tubular flow type reactor with the potential for synthesizing tens of milligrams of capsules per hour. Adsorption of the polyelectrolyte layer occurred in the tubing where particles and polyelectrolyte solution of choice were mixed, creating a layer of polyelectrolyte on the particles. After this, these newly surfaced-modified particles passed into the next segment of tubing, where they were mixed with a second polyelectrolyte of opposite charge. This process can be continuously repeated until the desired number of layers is achieved. One potential problem with this method concerned the presence of any excess polyelectrolyte in the tubing, so careful control of the amount of polymer added was crucial. It was found that slightly under dosing the amount of added polyelectrolyte ensured that negligible unadsorbed polyelectrolyte remained in solution. The particles created at each deposition step were stable, as they all had a zeta potential of greater than +/-25mV. Furthermore the zeta potential measurements showed that charge reversal occurred at each stage. Having achieved the necessary number of polyelectrolyte layers, the calcium phosphate cores were easily removed via dissolution in either hydrochloric or acetic acid. PMID- 26939074 TI - Studies on effect of temperature on synthesis of hierarchical TiO2 nanostructures by surfactant free single step hydrothermal route and its photoelectrochemical characterizations. AB - Exotic hierarchical rutile TiO2 nanostructures are synthesized by surfactant free single step hydrothermal route. The effect of reaction temperature, ranging from 140 degrees C to 200 degrees C on the properties of the synthesized rutile-TiO2 is investigated. The synthesized rutile-TiO2 nanostructures are characterized using X-ray diffraction, X-ray photoelectron spectroscopy, Raman spectroscopy, UV vis spectroscopy and scanning electron microscopy techniques. The deposited TiO2 samples are found to be photoelectrochemically active and the best photoelectrochemical performance (0.95+/-0.05%) is obtained for the sample deposited at 180 degrees C. A possible temperature dependent growth mechanism resulting in photochemically active TiO2 nanostructure thin films is proposed. PMID- 26939071 TI - Genetic Manipulation of Leishmania donovani to Explore the Involvement of Argininosuccinate Synthase in Oxidative Stress Management. AB - Reactive oxygen and nitrogen species (ROS and RNS) produced by the phagocytic cells are the most common arsenals used to kill the intracellular pathogens. However, Leishmania, an intracellular pathogen, has evolved mechanisms to survive by counterbalancing the toxic oxygen metabolites produced during infection. Polyamines, the major contributor in this anti-oxidant machinery, are largely dependent on the availability of L-arginine in the intracellular milieu. Argininosuccinate synthase (ASS) plays an important role as the rate-limiting step required for converting L-citrulline to argininosuccinate to provide arginine for an assortment of metabolic processes. Leishmania produce an active ASS enzyme, yet it has an incomplete urea cycle as it lacks an argininosuccinate lyase (ASL). There is no evidence for endogenous synthesis of L-arginine in Leishmania, which suggests that these parasites salvage L-arginine from extracellular milieu and makes the biological function of ASS and the production of argininosuccinate in Leishmania unclear. Our previous quantitative proteomic analysis of Leishmania promastigotes treated with sub-lethal doses of ROS, RNS, or a combination of both, led to the identification of several differentially expressed proteins which included ASS. To assess the involvement of ASS in stress management, a mutant cell line with greatly reduced ASS activity was created by a double-targeted gene replacement strategy in L. donovani promastigote. Interestingly, LdASS is encoded by three copies of allele, but Western blot analysis showed the third allele did not appear to express ASS. The free thiol levels in the mutant LdASS-/-/+ cell line were decreased. Furthermore, the cell viability in L-arginine depleted medium was greatly attenuated on exposure to different stress environments and was adversely impacted in its ability to infect mice. These findings suggest that ASS is important for Leishmania donovani to counterbalance the stressed environments encountered during infection and can be targeted for chemotherapeutic purpose to treat visceral leishmaniasis. PMID- 26939073 TI - Preparation of biocompatible molecularly imprinted shell on superparamagnetic iron oxide nanoparticles for selective depletion of bovine hemoglobin in biological sample. AB - Bovine hemoglobin (BHb), as one of the high-abundance proteins, could seriously mask and hamper the analysis of low-abundance proteins in serum. To selectively deplete BHb, we design a simple and effective strategy for preparation of biocompatible molecularly imprinted shell on superparamagnetic iron oxide nanoparticles through surface imprinting technique combined with template immobilization strategy. Firstly, template proteins are immobilized on the directly aldehyde-functionalized magnetic nanoparticles through imine bonds. Then, with gelatin as functional monomer, a polymeric network molded around the immobilized template proteins is obtained. Finally, the specific cavities for BHb are fabricated after removing the template proteins. The effects of imprinting conditions were investigated and the optimal imprinting conditions are found to be 40mg of BHb, 150mg of gelatin, and 8h of polymerization time. The resultant materials exhibit good dispersion, high crystallinity, and satisfactory superparamagnetic property with a high saturation magnetization (33.43emug(-1)). The adsorption experiments show that the imprinted nanomaterials have high adsorption capacity of 93.1mgg(-1), fast equilibrium time of 35min, and satisfactory selectivity for target protein. Meanwhile, the obtained polymers could be used without obvious deterioration after six adsorption-desorption cycles. In addition, the resultant polymers are successfully applied in the selective isolation BHb from bovine blood sample, which could provide an alternative solution for the preparatory work of proteomics. PMID- 26939075 TI - Non-enzymatic amperometric detection of hydrogen peroxide in human blood serum samples using a modified silver nanowire electrode. AB - In this paper, we report a highly sensitive amperometric H2O2 sensor based on silver nanowires (AgNWs) modified screen printed carbon electrode. The AgNWs were synthesized using polyol method. The synthesized AgNWs were characterized by scanning electron microscopy, UV-vis spectroscopy and X-ray diffraction techniques. The average diameter and length of the synthesized AgNWs were found as 86+/-5 and 385nm, respectively. Under optimum conditions, the AgNWs modified electrode shows a stable amperometric response for H2O2 and was linear over the concentrations ranging from 0.3 to 704.8MUM. The non-enzymatic sensor showed a high sensitivity of 662.6MUAmM(-1)cm(-2) with a detection limit of 29nM. The response time of the sensor was found as 2s. Furthermore, the AgNWs modified electrode exhibited a good recovery of H2O2 (94.3%) in the human blood serum samples. PMID- 26939076 TI - Rapid carbon nanotubes suspension in organic solvents using organosilicon polymers. AB - A strategy for a simple dispersion of commercial multi-walled carbon nanotubes (MWCNTs) using two organosilicones, polycarbosilane SMP10 and polysilazane Ceraset PSZ20, in organic solvents such as cyclohexane, tetrahydrofuran (THF), m xylene and chloroform is presented. In just a few minutes the combined action of sonication and the presence of Pt(0) catalyst is sufficient to obtain a homogeneous suspension, thanks to the rapid hydrosilylation reaction between SiH groups of the polymer and the CNT sidewall. The as-produced suspensions have a particle size distribution <1MUm and remain unchanged after several months. A maximum of 0.47 and 0.50mg/ml was achieved, respectively, for Ceraset in THF and SMP10 in chloroform. Possible applications as polymeric and ceramic thin films or aerogels are presented. PMID- 26939077 TI - Thermal transformation of bioactive caffeic acid on fumed silica seen by UV-Vis spectroscopy, thermogravimetric analysis, temperature programmed desorption mass spectrometry and quantum chemical methods. AB - Thermochemical studies of hydroxycinnamic acid derivatives and their surface complexes are important for the pharmaceutical industry, medicine and for the development of technologies of heterogeneous biomass pyrolysis. In this study, structural and thermal transformations of caffeic acid complexes on silica surfaces were studied by UV-Vis spectroscopy, thermogravimetric analysis, temperature programmed desorption mass spectrometry (TPD MS) and quantum chemical methods. Two types of caffeic acid surface complexes are found to form through phenolic or carboxyl groups. The kinetic parameters of the chemical reactions of caffeic acid on silica surface are calculated. The mechanisms of thermal transformations of the caffeic chemisorbed surface complexes are proposed. Thermal decomposition of caffeic acid complex chemisorbed through grafted ester group proceeds via three parallel reactions, producing ketene, vinyl and acetylene derivatives of 1,2-dihydroxybenzene. Immobilization of phenolic acids on the silica surface improves greatly their thermal stability. PMID- 26939079 TI - Does As(III) interact with Fe(II), Fe(III) and organic matter through ternary complexes? AB - Up until now, only a small number of studies have been dedicated to the binding processes of As(III) with organic matter (OM) via ionic Fe(III) bridges; none was interested in Fe (II). Complexation isotherms were carried out with As(III), Fe(II) or Fe(III) and Leonardite humic acid (HA). Although PHREEQC/Model VI, implemented with OM thiol groups, reproduced the experimental datasets with Fe(III), the poor fit between the experimental and modeled Fe(II) data suggested another binding mechanism for As(III) to OM. PHREEQC/Model VI was modified to take various possible As(III)-Fe(II)-OM ternary complex conformations into account. The complexation of As(III) as a mononuclear bidentate complex to a bidentate Fe(II)-HA complex was evidenced. However, the model needed to be improved since the distribution of the bidentate sites appeared to be unrealistic with regards to the published XAS data. In the presence of Fe(III), As(III) was bound to thiol groups which are more competitive with regards to the low density of formed Fe(III)-HA complexes. Based on the new data and previously published results, we propose a general scheme describing the various As(III)-Fe-MO complexes that are able to form in Fe and OM-rich waters. PMID- 26939078 TI - Synergistic combination of antioxidants, silver nanoparticles and chitosan in a nanoparticle based formulation: Characterization and cytotoxic effect on MCF-7 breast cancer cell lines. AB - HYPOTHESIS: Chitosan (Cs) is a biocompatible, biodegradable cationic polymer having the ability of targeted drug delivery. Vitamin E and C are not synthesized in our body thus, when encapsulated within a carrier system these vitamins in combination with/alone can be utilized for their anti-cancer potentials. EXPERIMENT: The present investigation was conducted to develop a stable nanoparticle based formulation encapsulating antioxidants (Vitamin E, catechol) and silver nanoparticles synthesized from Hibiscus rosa-sinensis (HRS) petal extracts within a chitosan matrix. The prepared nanoformulations were characterized using Field emission scanning electron microscopy (Fe-SEM), X-ray diffraction (XRD) and Attenuated Total Reflection Fourier Transform Infrared spectroscopy (ATR-FTIR). They were further tested for their antioxidant potentials using DPPH assay, hydrogen peroxide scavenging assay, nitric oxide scavenging assay and ferrous antioxidant reducing potential assay. FINDINGS: The nanoformulations were found to be highly hemocompatible and showed high encapsulation efficiency up to 76%. They also showed higher antioxidant activity than their base materials. Further, their anti-cancer efficacy was observed against MCF-7 breast cancer cells having IC50 values of 53.36+/-0.36MUg/mL (chitosan-ascorbic acid-glucose), 55.28+/-0.85MUg/mL (chitosan-Vitamin E), 63.72+/-0.27MUg/mL (Chitosan-catechol) and 58.53+/-0.55MUg/mL (chitosan-silver nanoparticles). Thus, the prepared formulations can be therapeutically applied for effective and targeted delivery in breast cancer treatment. PMID- 26939080 TI - Stability and Competition in Multi-spike Models of Spike-Timing Dependent Plasticity. AB - Spike-timing dependent plasticity (STDP) is a widespread plasticity mechanism in the nervous system. The simplest description of STDP only takes into account pairs of pre- and postsynaptic spikes, with potentiation of the synapse when a presynaptic spike precedes a postsynaptic spike and depression otherwise. In light of experiments that explored a variety of spike patterns, the pair-based STDP model has been augmented to account for multiple pre- and postsynaptic spike interactions. As a result, a number of different "multi-spike" STDP models have been proposed based on different experimental observations. The behavior of these models at the population level is crucial for understanding mechanisms of learning and memory. The challenging balance between the stability of a population of synapses and their competitive modification is well studied for pair-based models, but it has not yet been fully analyzed for multi-spike models. Here, we address this issue through numerical simulations of an integrate-and fire model neuron with excitatory synapses subject to STDP described by three different proposed multi-spike models. We also analytically calculate average synaptic changes and fluctuations about these averages. Our results indicate that the different multi-spike models behave quite differently at the population level. Although each model can produce synaptic competition in certain parameter regions, none of them induces synaptic competition with its originally fitted parameters. The dichotomy between synaptic stability and Hebbian competition, which is well characterized for pair-based STDP models, persists in multi-spike models. However, anti-Hebbian competition can coexist with synaptic stability in some models. We propose that the collective behavior of synaptic plasticity models at the population level should be used as an additional guideline in applying phenomenological models based on observations of single synapses. PMID- 26939081 TI - Atg7 Knockdown Augments Concanavalin A-Induced Acute Hepatitis through an ROS Mediated p38/MAPK Pathway. AB - Concanavalin A (ConA), a T-cell mitogen that induces acute autoimmune hepatitis, is widely used to model pathophysiological processes of human acute autoimmune liver disease. Although autophagy has been extensively studied in the past decade, little is known about its molecular mechanism underlying the regulation of ConA-induced acute hepatitis. In this study, we used a Cre-conditional atg7 KO mouse to investigate the effects of Atg7-associated autophagy on ConA-induced murine hepatitis. Our results demonstrated that atg7 deficiency in mice enhanced macrophage activation and increased pro-inflammatory cytokines upon ConA stimulation. Atg7 silencing resulted in accumulation of dysfunctional mitochondria, disruption of reactive oxygen species (ROS) degradation, and increase in pro-inflammatory cytokines in Raw264.7 cells. p38/MAPK and NF-kappaB levels were increased upon ConA induction due to Atg7 deficiency. Blocking ROS production inhibited ConA-induced p38/IkappaB phosphorylation and subsequent intracellular inflammatory responses. Hence, this study demonstrated that atg7 knockout in mice or Atg7 knockdown in cell culture augmented ConA-induced acute hepatitis and related cellular malfunction, indicating protective effects of Atg7 on regulating mitochondrial ROS via a p38/MAPK-mediated pathway. Collectively, our findings reveal that autophagy may attenuate macrophage-mediated inflammatory response to ConA and may be the potential therapeutic targets for acute liver injury. PMID- 26939083 TI - Executive function relates to surface area of frontal and temporal cortex in very low-birth-weight late teenagers. AB - BACKGROUND: Being born with very low birth weight (VLBW; birth weight (BW) <=1500 g) is associated with increased risk of maldevelopment of the immature brain which may affect neurological functioning. Deficits in attention and executive function problems have been reported in VLBW survivors compared with healthy subjects. AIMS: The aim of this study was to evaluate attention and executive functions and to relate the clinical test results to cortical morphometry findings in VLBW young adults compared with term-born controls. STUDY DESIGN: Prospective follow-up study of three year cohorts of VLBW and control children from birth to adulthood. OUTCOME MEASURES: A comprehensive neuropsychological test battery was administered to 55 VLBW subjects born preterm (mean BW: 1217 g) and 81 term-born controls (mean BW: 3707 g) at age 19-20. Cerebral MRI was successfully obtained in 46 VLBW subjects and 61 controls. The FreeSurfer software package was applied for the cortical analyses based on T1-weighted MRI images. RESULTS: The VLBW group obtained inferior scores on 15 of the 29 neuropsychological measures assessing attention and executive function and on both the attention and executive function domain scores. We found positive correlations between the executive function domain score and cortical surface area, especially in the antero-medial frontal and the temporal lobes of the brain in the VLBW group. CONCLUSION: Young adults born with VLBW show deficits in attention and executive function compared with controls. The executive problems were related to smaller cortical surface area in brain regions known to be involved in higher order cognitive functioning. PMID- 26939082 TI - Diffusion tensor imaging and behavior in premature infants at 8 years of age, a randomized controlled trial with long-chain polyunsaturated fatty acids. AB - BACKGROUND: Very low birth weight (VLBW, birth weight<1500 g) children have increased risk of behavioral problems. Diffusion tensor imaging (DTI) of the brain shows reduced white matter maturation. Long-chain polyunsaturated fatty acids are hypothesized to improve both myelination and behavioral outcome. AIMS: To test the hypothesis that postnatal supplementation with docosahexaenoic acid (DHA) and arachidonic acid (AA) to very low birth weight infants would influence cerebral white matter measured by DTI and improve behavioral outcome at 8 years of age. STUDY DESIGN: Eight-year follow-up of a randomized, double-blinded, placebo-controlled study of postnatal supplementation with DHA and AA to 129 VLBW infants fed human milk. SUBJECTS: Ninety-eight children (76%) met for follow-up at 8 years. OUTCOME MEASURES: Cerebral white matter measured by DTI. Behavioral outcome measured by Strengths and Difficulties questionnaire and selected scales from the Child Behavior Checklist. RESULTS: No significant differences between the intervention group and the control group were found on white matter microstructure or behavioral data. A non-significant finding of higher fractional anisotropy (FA) in a cluster in the corpus callosum of the intervention group is discussed. CONCLUSIONS: The present study is the first long-term follow-up of a randomized controlled trial with DHA and AA to human milk fed VLBW infants exploring cerebral white matter microstructure measured by DTI and parent reported behavioral problems. No effects on white matter microstructure or behavioral outcome were observed at 8 years of age. PMID- 26939084 TI - Impact of physical fitness on salivary stress markers in sedentary to low-active young to middle-aged men. AB - INTRODUCTION: Salivary cortisol (sCort) and alpha-amylase (sAA) are popular measurement tools for investigating hypothalamic-pituitary-adrenal and autonomic functioning, respectively. Despite their widespread use, only little is known about whether lifestyle factors such as regular exercise and physical fitness impact these two salivary stress markers. The lack of an objectively assessed fitness status is a major drawback of nearly all previous studies in this area. Our main objective was therefore to examine the impact of fitness status on sCort and sAA responses to a validated stressor. METHOD: Sedentary to low-active men (N=115, 45.7+/-10.1 years, 26.7+/-3.4kg/m(2)) were exposed to the Trier Social Stress Test for Groups and provided saliva samples before and repeatedly after the stressor. An ergometer lactate exercise test provided information on physical fitness, that is, power achieved at the individual anaerobic threshold relative to body weight. From age-specific percentiles, a 2- (n=65 low fitness, n=50 high fitness) and a 3-group (n=37 low fitness, n=49 moderate fitness, n=29 high fitness) solution were calculated to elucidate the impact of different fitness levels. RESULTS: Prior to stress testing, sCort and sAA levels were similar in all groups. While both markers increased significantly due to stress exposure, fitness effects appeared rather small. When applying the 3-group solution, we observed attenuated sCort slopes in high- and moderate-fit men. Although sAA response slopes were pronounced in high-fit men, they failed to reach statistical significance. Mean stress reactivity (area under the curve with respect to ground, baseline, and response maximum) did not differ between groups and no association with fitness level was found. DISCUSSION: Our findings suggest only a weak effect of objectively assessed physical fitness on biological stress responses with attenuated hypothalamic-pituitary-adrenal but (non-significantly) higher autonomic responses in fitter men. Physical fitness is a factor that should not be neglected in future studies employing salivary stress markers, especially in studies interested in acute stress responses. PMID- 26939085 TI - Chronic social isolation enhances reproduction in the monogamous prairie vole (Microtus ochrogaster). AB - Chronic stressors are generally considered to disrupt reproduction and inhibit mating. Here we test the hypothesis that a chronic stressor, specifically social isolation, can facilitate adaptive changes that enhance/accelerate reproductive effort. In general, monogamous species display high levels of prosociality, delayed sexual maturation, and greater parental investment in fewer, higher quality offspring compared with closely related polygynous species. We predicted that chronic social isolation would promote behavioral and neurochemical patterns in prairie voles associated with polygyny. Male and female prairie voles were isolated for four weeks and changes in mating behavior, alloparental care, estrogen receptor (ER) alpha expression and tyrosine hydroxylase (TH) expression in brain regions regulating sociosexual behavior were examined. In males, isolation accelerated copulation, increased ERalpha in the medial amygdala (MEApd) and bed nucleus of the stria terminalis (BSTpm), and reduced TH expression in the MEApd and BSTpm, but had no effect on alloparental behavior. In females, isolation resulted in more rapid estrus induction and reduced TH expression in the MEApd and BSTpm, but had no effect on estradiol sensitivity or ERalpha expression. The results support the hypothesis that ERalpha expression in the MEApd and BSTpm is a critical determinant of male copulatory behavior and/or mating system. The lack of change in alloparental behavior suggests that changes in prosocial behavior are selective and regulated by different mechanisms. The results also suggest that TH in the MEApd and BSTpm may play a critical role in determining mating behavior in both sexes. PMID- 26939087 TI - Correction: A Novel Generalized Normal Distribution for Human Longevity and other Negatively Skewed Data. PMID- 26939088 TI - Meiotic recombination and genome evolution in plants. AB - Homologous recombination affects genome evolution through crossover, gene conversion and point mutations. Whole genome sequencing together with a detailed epigenome analysis have shed new light on our understanding of how meiotic recombination shapes plant genes and genome structure. Crossover events are associated with DNA sequence motifs, together with an open chromatin signature (hypomethylated CpGs, low nucleosome occupancy or specific histone modifications). The crossover landscape may differ between male and female meiocytes and between species. At the gene level, crossovers occur preferentially in promoter regions in Arabidopsis. In recent years, there is rising support suggesting that biased mismatch repair during meiotic recombination may increase GC content genome-wide and may be responsible for the GC content gradient found in many plant genes. PMID- 26939086 TI - Sertraline inhibits increases in body fat and carbohydrate dysregulation in adult female cynomolgus monkeys. AB - Selective serotonin reuptake inhibitor (SSRI) antidepressants are widely prescribed for depression and other disorders. SSRIs have become one of the most commonly used drugs in the United States, particularly by women. Acute effects on body composition and carbohydrate metabolism have been reported, but little is known regarding the effects of chronic SSRI use. We evaluated the effects of chronic administration of a commonly prescribed SSRI, sertraline HCl, on body weight and composition, fat distribution, carbohydrate metabolism, as well as activity, in adult female depressed and nondepressed cynomolgus monkeys (Macaca fascicularis; n=42) using a placebo-controlled, longitudinal, randomized study design. Phenotypes were evaluated prior to and after 18 months of oral sertraline (20mg/kg) or placebo. Over the 18 month treatment period, the placebo group experienced increases in body weight, body fat (visceral and subcutaneous) fasting insulin concentrations, and homeostasis model assessment of insulin resistance scores (HOMA-IR). Sertraline treatment prevented increases in body weight, fat, insulin, and HOMA-IR (all p<0.05), without significantly altering activity levels. Sertraline treatment altered adiponectin in an unusual way - reducing circulating adiponectin in depressed monkeys without affecting fat mass or body weight. Deleterious effects on adiponectin, a potentially insulin sensitizing and atheroprotective protein, may result in adverse effects on cardiovascular health despite otherwise beneficial effects on body composition and carbohydrate metabolism. PMID- 26939089 TI - [Gender differences: impact of cardiovascular risk scores]. PMID- 26939090 TI - [Gender differences: impact of cardiovascular risk scores]. PMID- 26939091 TI - [Off-label-drug-use: Scientific evidence counts]. PMID- 26939092 TI - [Imaging procedures for myocarditis and cardiomyopathy]. PMID- 26939093 TI - [Do fluorquinolones support the formation of aortic aneurysms?]. PMID- 26939094 TI - [Lung cysts as incidental findings - harmless or not?]. PMID- 26939096 TI - [Innovation fund: An opportunity not to be missed]. PMID- 26939097 TI - [Primary prevention of sudden cardiac death: Amiodarone is more effective than other antiarrhythmics]. PMID- 26939098 TI - [A married couple suffering from progressive dyspnoea]. PMID- 26939099 TI - [Diagnostic in emergency departments - deciding quickly and confidently]. PMID- 26939101 TI - [Fast diagnostics in the emergency department: Laboratory testing - what we need and what we don't]. AB - Laboratory parameters in emergency medicine can be divided into 3 categories. Urgent obligatory parameters are necessary for immediate therapeutic decisions and must be available within 60 minutes. For these, testing in the emergency department (ED) as point-of-care-testing (POCT) should be considered. The second category are obligatory parameters which require diagnostic / therapeutic consequences in the emergency department, but are not necessary for immediate life-saving actions. Due to international consensus of a 4-hour length of stay target for ED, results should be available within this time. The third category are parameters which do not lead to immediate diagnostic or therapeutic consequences, but are important for process management and patient flow in the ED. They should therefore be available as emergency tests. POC-testing should be used for a limited number of very urgent parameters and should be organized as a satellite laboratory in cooperation with the central laboratory. PMID- 26939100 TI - [Rapid diagnostic in the emergency unit: bedside sonography]. AB - Using bedside ultrasound in the emergency room includes point of care sonography (echoscopy) and several protocols (RUSH, FATE, etc.). The aim of these protocols is to evaluate the life threatening emergency care situation without interrupting the clinical work flow. This article also compares the definition of emergency care echocardiography and focused ultrasound of the heart. In addition this article gives an overview about compression sonography of veins. Examples are presented on how to use bedside ultrasound in clinical settings. PMID- 26939102 TI - [Emergency Triage. An Overview]. AB - In emergency departments, patients present with different severities of diseases and traumatic injuries. However, patients with severe and life-threatening conditions compete for the same resources such as personal and structure. As a general rule, each patient should receive immediate diagnostic and treatment, independent of his or her severity of disease or traumatic injury. However, an unexpected number of patients presenting to the emergency department at the same time may exceed available resources. Thus, waiting times will occur and management of patients may be impeded. As a consequence, patients with diseases or traumatic injuries with a need for time-critical management, have to be detected at the time of presentation. After categorization, patients have to be prioritized and guided to the correct place of treatment ("triage"). Starting in Australia and the United States, nurse-driven triage systems have been introduced in the emergency departments. Aim of triage is to correctly identify at increased risk of death and guide them to rapid and correct treatment. In Germany, two five level triage systems have been introduced: Manchester Triage System (MTS) and Emergency Severity Index (ESI). We give an overview of these risk assessment tools and discuss pros and cons. In addition, new options such as "team triage" and a combination with "Early Warning Scores" are reported. In summary, nurse driven triage is an instrument to improve patient safety in emergency medicine. A structured and systematic triage of patients using validated triage assessment tools are recommended from national and international societies of emergency medicine. Therefore, nurse-driven triage is also a must in Germany. PMID- 26939103 TI - [How to do: central vein catheterization]. AB - The cannulation of a central vein is a standard acces to the vascular system of critically ill patients. It can be used for administration of medication and parenteral nutrition, haemodynamic monitoring as well as hemodialsis via Shaldon catheter.The technique of implantation of a central venous catheter is described step by step in this article. Moreover, advantages and disadvantages of the different techniques and puncture sites as well as indications and contraindications are critically discussed regarding the most recent literature. PMID- 26939104 TI - [Rickettsiosis - Early skin biopsy is essential because of latency in serological findings]. AB - BACKGROUND: Global travel increasis practitioner's confrontation with very special infectious diseases, like hemorrhagic viral diseases that are traditionally rare in European countries. Prompt diagnosis and subsequent induction of therapy are essential to prevent high rates of severe and lethal complications. ANAMNESIS: A 59-year-old man complained deterioration of general health after a 3-week vacation to South Africa. He presented fever and hemorrhagic erythema with pustula surrounded by necrotic margin on the right calf. COURSE AND THERAPY: On the second day of inpatient treatment, a papulovesiculous, partly hemorrhagic exanthema appeared. With a tentative diagnosis of Rickettsiosis, we performed specific diagnostics by serology and biopsy. Therapy was initiated with doxycycline (200 mg/d) for 7 days. Under this regimen clinical symptoms healed without consequences. Rickettsioses are ubiquitious zoonoses that are caused by various Rickettsia subtypes. The stay in endemic regions together with signs of fever, reduced general health, eschar and exanthema are suspicious for this disease. Therapy should be initiated immediately in cases of clinical suspicion with a characteristic case history. The seroconversion, which appears later in course, should not give reason for avoiding early skin biopsy due to the potentially fatal course of the disease. Biopsy enables early histological proof of a dermal vasculitic inflammation pattern and PCR analysis before subsequent serological controls and proofs. PMID- 26939105 TI - [Mechanic valve prosthesis and pregnancy: Is Phenprocoumon replaceable?]. AB - HISTORY AND ADMISSION FINDINGS: We report the case of a 30-year-old pregnant patient with mechanical valve replacement in mitral and aortic position. She had discontinued Phenprocoumon-treatment in the 5+4 week of pregnancy by herself. Because of rheumatic fever she had undergone a mechanical aortic and mitral valve replacement 12 years ago. Due to a thrombosis of the mitral valve, an acute reoperation had to be done 5 years later. 2 years ago, a partially re-thrombosis of the mechanical mitral valve was treated by intravenous thrombolysis. These complications had been probably due to incomplicance. The patient had experienced 3 abortions before. INVESTIGATIONS: The vaginal sonography determined an intact gestation. The laboratory test revealed an INR of 1.2. The transesophageal echocardiography showed a partially thrombosed mechanical mitral valve. The abdominal ultrasonography detected an embolic splenic infarction. DIAGNOSIS, TREATMENT AND CLINICAL COURSE: These findings were consistent with partially thrombosed mechanical mitral valve with thromboembolic splenic infarction among incompetent oral anticoagulation. After initial heparinization with under twice daily control of the partial thromboplastin time the joint decision was made to restart Phenprocoumon (target INR 2.5 to 3.5, and additional ASS 100 mg /day). 9 days later the patient had a missed abortion. An uncomplicated curettage was performed under therapeutic i.v. heparinization. CONCLUSIONS: The use of coumarins in pregnancy carries a fetal risk. But it is the most secure anticoagulation after a mechanical valve replacement, especially in high-risk patients. Alternatives are heparins. They don't cross the placenta but are associated with a slightly elevated risk of thromboembolism. PMID- 26939106 TI - [ASA - from cardiovascular to cancer prevention]. AB - Cardiovascular disease and cancer are the leading causes of morbidity and mortality worldwide. Low-dose ASA has been shown to effectively prevent about one fifth of atherothrombotic vascular complications in patients with previous myocardial infarction, peripheral arterial occlusive disease (PAOD), or stroke 2. In secondary prevention, the benefits of antiplatelet therapy substantially exceed its risk 2. By contrast, recommendations for the use of ASA in primary prevention are still a matter of controversy. The aim of this article is to review the current evidence for the efficacy of low-dose ASA in primary and secondary prevention of cardiovascular diseases as well as to discuss its potential additional chemopreventive action. PMID- 26939107 TI - [An update on glucocorticoid-induced osteoporosis]. AB - Glucocorticoid-induced osteoporosis is the most common cause of secondary osteoporosis. Moreover, it is the most common reason for an osteoporosis among young adults. The clinical use of oral glucocorticoids increases the fracture incidence already within three months after starting the therapy. There does not seem to be a lower threshold: even doses as low as 2,5 mg of prednisone equivalent increase the risk of fractures. Adequate diagnostic and therapy are able to significantly reduce the resulting fracture risk. This article will discuss the pathophysiology of glucocorticoid-induced osteoporosis and give a summary of the current recommendations including the recently updated German guidelines. PMID- 26939108 TI - [Detecting child abuse]. PMID- 26939109 TI - [Pain therapy in in-patients with cancer. Effects of a manual-based approach as guideline for pain-consulting service at a university hospital]. AB - BACKGROUND: Appropriate medication is an important and substantial part in the therapy of tumor-induced pain. OBJECTIVE: The objective of this study was to investigate the efficiency of anaesthesiology-based consultant service characterizing the quality of this type of treatment in daily clinical practice of a university hospital, i. e., in the patient profile of a tertiary center (study design: systematic clinical, unicenter observational study reflecting clinical practice and study-based control of therapeutic care quality). METHODS: In the course of consulting function with regard to pain care on the single wards a considerable portion of cancer patients are recieving drugs. For most patients such care comprises several consultations and subsequently initiated treatment modifications. The consulting function ends if the patients feel free of pain or report a substantial improvement. From 1/1/2010 to 12/31/2012 detailed information on the drug therapy applied prior to, during and after the consultation was prospectively documented.This data was retrospectively evaluated as "pre-vs.-post" comparison (Chi-squared test, Fisher's exact test and McNemar's test), in particular, focussing on the quality of pain medication using the WHO index as well as pain intensity obtained by means of the visual analogue scale (VAS). RESULTS: In total, 375 in-patients were treated. The modified pain medication by the anesthesiological consultant service led to a significant increase (p < 0.001; Wilcoxon's test) in the mean WHO index from 6.37 (SD, 1.83) to 8.43 (SD, 1.47). Furthermore, a reduction of VAS from 5.00 (SD, 2.39) to 2.64 (SD, 1.64) was noted (p < 0.001; Wilcoxon's test). CONCLUSION: The consequent application of established guidelines (according to WHO scheme) and the WHO index leads to a qualitative and measurable improvement of drug therapy for cancer related pain. PMID- 26939110 TI - Inhibition of Notch Signaling Ameliorates Acute Kidney Failure and Downregulates Platelet-Derived Growth Factor Receptor beta in the Mouse Model. AB - Ischemic acute kidney injury (AKI) is associated with high morbidity and frequent complications. Repeated episodes of AKI may lead to end-stage renal failure. The pathobiology of regeneration in AKI is not well understood and there is no effective clinical therapy that improves regeneration. The Notch signaling pathway plays an essential role in kidney development and has been implicated in tissue repair in the adult kidney. Here, we found that kidneys after experimental AKI in mice showed increased expression of Notch receptors, specifically Notch1 3, of the Notch ligands Jagged-1 (Jag1), Jag2 and Delta-like-4 (Dll4) and of the Notch target genes Hes1, Hey2, HeyL, Sox9 and platelet-derived growth factor receptor beta (Pdgfrb). Treatment of ischemic mice with the x03B3;-secretase inhibitor DBZ blocked Notch signaling and specifically downregulated the expression of Notch3 and the Notch target genes Hes1, Hey2, HeyL and Pdgfrb. After DBZ treatment, the mice developed less interstitial edema and displayed altered interstitial inflammation patterns. Furthermore, serum urea and creatinine levels were significantly decreased from 6 h onwards when compared to control mice treated with DMSO only. Our data are consistent with an amelioration of the severity of kidney injury by blocking Notch activation following AKI, and suggest an involvement of Notch-regulated Pdgfrb in AKI pathogenesis. PMID- 26939111 TI - The Global Issue of Vision Loss and What We Can Do About It: Jose Rizal Medal 2015. AB - The prevalence of blindness increases rapidly with increasing age. Globally, there are some 32 million people who are blind and 191 million with poor vision. The leading cause of blindness worldwide is cataract, whereas uncorrected refractive error causes most poor vision. The rates of blindness from diabetes and macular degeneration are rapidly increasing, and age-related macular degeneration is the leading cause of blindness in developed countries. Three quarters of this blindness can be prevented or treated, and although the absolute number of blind people increased slightly between 1990 and 2010, very importantly, the prevalence of blindness has been halved as eye care programs and particularly cataract services have developed. We know how to deliver better eye care, and it works! However, with only 205,000 ophthalmologists worldwide, there is much work to do. The International Council of Ophthalmology has a major focus on education and team building to improve the quality and availability of eye care around the world. Its programs include curricula for all levels, examinations, fellowships, teaching of teachers, continuing professional development, and of course, the World Ophthalmology Congresses. We must work together in partnership to eliminate avoidable blindness worldwide. PMID- 26939113 TI - Regarding "Intravitreal Injection--Technique and Safety". PMID- 26939114 TI - The Rate of Endophthalmitis After Intravitreal Injections. PMID- 26939115 TI - Phacoemulsification Versus Manual Small Incision Cataract Surgery in Patients With Fuchs Heterochromic Iridocyclitis. AB - PURPOSE: To compare the safety and efficacy of phacoemulsification and manual small incision cataract surgery (SICS) to treat cataract in patients with Fuchs heterochromic iridocyclitis (FHI). DESIGN: A randomized, double-masked, prospective, multicenter study. METHODS: Consecutive patients with cataract after FHI were randomly assigned to have phacoemulsification or manual SICS by 1 of 2 surgeons experienced in both techniques. Complications (intraoperatively and postoperatively), operative time, visual acuities, endothelial cell counts, and surgically induced astigmatism were compared. RESULTS: At 6 months, 65 (92.8%) patients in the phacoemulsification group and 70 (92.1%) in the manual SICS group had a corrected distance visual acuity of 20/63 or better (P = 0.974). Surgical time was significantly shorter in the SICS group (11.2 +/- 2.4 minutes) than in the phacoemulsification group (14.2 +/- 3.1 minutes) (P < 0.001). The mean surgically induced astigmatism was 0.8 +/- 0.2 diopters (D) in the phacoemulsification group and 1.16 +/- 0.2 D in the SICS group (P < 0.001). Endothelial cell counts at 1 week and at 6 months did not differ significantly in the phacoemulsification and SICS groups (t test; P = 0.133 and P = 0.032, respectively). Intraoperatively, 2 (3%) eyes randomized to receive phacoemulsification and 4 (5.3%) eyes randomized to receive SICS had posterior capsular rent (P = 0.465). CONCLUSIONS: Both techniques achieved good visual outcomes with low rates of complications. Manual SICS may be a viable alternative for cataract management in patients with FHI in settings with limited access to phacoemulsification. PMID- 26939116 TI - Early Postoperative Nociceptive Threshold and Production of Brain-Derived Neurotrophic Factor Induced by Plantar Incision Are Not Influenced with Minocycline in a Rat: Role of Spinal Microglia. AB - BACKGROUND: Brain-derived neurotrophic factor (BDNF) from spinal microglia is crucial for aberrant nociceptive signaling in several pathological pain conditions, including postoperative pain. We assess the contribution of spinal microglial activation and associated BDNF overexpression to the early post incisional nociceptive threshold. METHODS: Male Sprague-Dawley rats were implanted with an intrathecal catheter. A postoperative pain model was established by plantar incision. Thermal and mechanical nociceptive responses were assessed by infrared radiant heat and von Frey filaments before and after plantar incision. Rats were injected intrathecally the microglial activation inhibitor minocycline before incision, 24 h after incision, or both. Other groups were subjected to the same treatments and the L4-L5 spinal cord segment removed for immunohistochemical analysis of microglia activation and BNDF expression. RESULTS: Plantar incision reduced both thermal latency and mechanical threshold, indicating thermal hypersensitivity and mechanical allodynia. Minocycline temporally reduced thermal withdrawal latency but had no effect on mechanical withdrawal threshold, spinal microglial activity, or dorsal horn BDNF overexpression during the early post-incision period. CONCLUSION: These results suggest that spinal microglia does not contribute substantially to post incisional nociceptive threshold. The BDNF overexpression response that may contribute to postoperative hyperalgesia and allodynia is likely derived from other sources. PMID- 26939117 TI - Evaluation of the Gastrointestinal Tract as Potential Route of Primary Polyomavirus Infection in Mice. AB - BACKGROUND: Detection of Polyomavirus (PyV) DNA in metropolitan rivers worldwide has led to the suggestion that primary viral infection can occur by the oral route. The aim of this study was to test this notion experimentally. METHODS: Mouse PyV (MPyV) was used to infect C57BL/6J mice by the nasal or intragastric route. Viral load kinetics was studied 3, 7, 10, 14, 21 and 28 days post infection (dpi) using quantitative PCR. RESULTS: Following nasal infection, MPyV DNA was readily detected in many organs including lung, heart, aorta, colon, and stool with viral loads in the range of 10(3)-10(6) copies/mg wet weight that peaked 7-10 dpi. Complete viral clearance occurred in the serum and kidney by 28 dpi, while clearance in other organs was partial with a 10-100 fold decrease in viral load. In contrast, following intragastric infection peak detection of PyV was delayed to 21 dpi, and viral loads were up to 3 logs lower. There was no detectable virus in the heart, colon, or stool. CONCLUSIONS: The intragastric route of MPyV infection is successful, not as efficacious as the respiratory route, and associated with delayed viral dissemination as well as a lower peak MPyV load in individual organs. PMID- 26939118 TI - An Allometric Modelling Approach to Identify the Optimal Body Shape Associated with, and Differences between Brazilian and Peruvian Youth Motor Performance. AB - Children from developed and developing countries differ in their body size and shape due to marked differences across their life history caused by social, economic and cultural differences which are also linked to their motor performance (MP). We used allometric models to identify size/shape characteristics associated with MP tests between Brazilian and Peruvian schoolchildren. A total of 4,560 subjects, 2,385 girls and 2,175 boys aged 9-15 years were studied. Height and weight were measured; biological maturation was estimated with the maturity offset technique; MP measures included the 12 minute run (12MR), handgrip strength (HG), standing long jump (SLJ) and the shuttle run speed (SR) tests; physical activity (PA) was assessed using the Baecke questionnaire. A multiplicative allometric model was adopted to adjust for body size differences across countries. Reciprocal ponderal index (RPI) was found to be the most suitable body shape indicator associated with the 12MR, SLJ, HG and SR performance. A positive maturation offset parameter was also associated with a better performance in SLJ, HG and SR tests. Sex differences were found in all motor tests. Brazilian youth showed better scores in MP than their Peruvian peers, even when controlling for their body size differences The current study identified the key body size associated with four body mass-dependent MP tests. Biological maturation and PA were associated with strength and motor performance. Sex differences were found in all motor tests, as well as across countries favoring Brazilian children even when accounting for their body size/shape differences. PMID- 26939120 TI - Correction: Autosomal and mtDNA Markers Affirm the Distinctiveness of Lions in West and Central Africa. PMID- 26939119 TI - Mode of Action of the Sesquiterpene Lactones Psilostachyin and Psilostachyin C on Trypanosoma cruzi. AB - Trypanosoma cruzi is the causative agent of Chagas' disease, which is a major endemic disease in Latin America and is recognized by the WHO as one of the 17 neglected tropical diseases in the world. Psilostachyin and psilostachyin C, two sesquiterpene lactones isolated from Ambrosia spp., have been demonstrated to have trypanocidal activity. Considering both the potential therapeutic targets present in the parasite, and the several mechanisms of action proposed for sesquiterpene lactones, the aim of this work was to characterize the mode of action of psilostachyin and psilostachyin C on Trypanosoma cruzi and to identify the possible targets for these molecules. Psilostachyin and psilostachyin C were isolated from Ambrosia tenuifolia and Ambrosia scabra, respectively. Interaction of sesquiterpene lactones with hemin, the induction of oxidative stress, the inhibition of cruzipain and trypanothione reductase and their ability to inhibit sterol biosynthesis were evaluated. The induction of cell death by apoptosis was also evaluated by analyzing phosphatidylserine exposure detected using annexin V/propidium iodide, decreased mitochondrial membrane potential, assessed with Rhodamine 123 and nuclear DNA fragmentation evaluated by the TUNEL assay. Both STLs were capable of interacting with hemin. Psilostachyin increased about 5 times the generation of reactive oxygen species in Trypanosoma cruzi after a 4h treatment, unlike psilostachyin C which induced an increase in reactive oxygen species levels of only 1.5 times. Only psilostachyin C was able to inhibit the biosynthesis of ergosterol, causing an accumulation of squalene. Both sesquiterpene lactones induced parasite death by apoptosis. Upon evaluating the combination of both compounds, and additive trypanocidal effect was observed. Despite their structural similarity, both sesquiterpene lactones exerted their anti-T. cruzi activity through interaction with different targets. Psilostachyin accomplished its antiparasitic effect by interacting with hemin, while psilostachyin C interfered with sterol synthesis. PMID- 26939121 TI - Assessing the Importance of Intraspecific Variability in Dung Beetle Functional Traits. AB - Functional diversity indices are used to facilitate a mechanistic understanding of many theoretical and applied questions in current ecological research. The use of mean trait values in functional indices assumes that traits are robust, in that greater variability exists between than within species. While the assertion of robust traits has been explored in plants, there exists little information on the source and extent of variability in the functional traits of higher trophic level organisms. Here we investigated variability in two functionally relevant dung beetle traits, measured from individuals collected from three primary forest sites containing distinct beetle communities: body mass and back leg length. In doing so we too addressed the following questions: (i) what is the contribution of intra vs. interspecific differences in trait values; (ii) what sample size is needed to provide representative species mean trait values; and (iii) what impact does omission of intraspecific trait information have on the calculation of functional diversity (FD) indices from naturally assembled communities? At the population level, interspecific differences explained the majority of variability in measured traits (between 94% and 96%). In accordance with this, the error associated with calculating FD without inclusion of intraspecific variability was low, less than 20% in all cases. This suggests that complete sampling to capture intraspecific variance in traits is not necessary even when investigating the FD of small and/or naturally formed communities. To gain an accurate estimation of species mean trait values we encourage the measurement of 30-60 individuals and, where possible, these should be taken from specimens collected from the site of study. PMID- 26939122 TI - Enhancement of DNaseI Salt Tolerance by Mimicking the Domain Structure of DNase from an Extremely Halotolerant Bacterium Thioalkalivibrio sp. K90mix. AB - In our previous work we showed that DNaseI-like protein from an extremely halotolerant bacterium Thioalkalivibrio sp. K90mix retained its activity at salt concentrations as high as 4 M NaCl and the key factor allowing this was the C terminal DNA-binding domain, which comprised two HhH (helix-hairpin-helix) motifs. The further investigations revealed that this domain originated from proteins related to bacterial competence ComEA/ComE proteins. It is likely that in the course of evolution the DNA-binding domain from these proteins was fused to a metallo-beta-lactamase superfamily domain. Very likely such domain organization having proteins subsequently "donated" the DNA-binding domain to bacterial DNases. In this study we have mimicked this evolutionary step by fusing bovine DNaseI and DNA-binding domains. We have created two fusions: one harboring the DNA-binding domain of DNaseI-like protein from Thioalkalivibrio sp. K90mix and the second one harboring the DNA-binding domain of bacterial competence protein ComEA from Bacillus subtilis. Both domains enhanced salt tolerance of DNaseI, albeit to different extent. Molecular modeling revealed the essential differences between their interaction with DNA shedding some light on the differences in salt tolerance. In this study we have enhanced salt tolerance of bovine DNaseI; thus, we successfully mimicked the Nature's evolutionary engineering that created the extremely halotolerant bacterial DNase. We have demonstrated that the newly engineered DNaseI variants can be successfully used in applications where activity of the wild type bovine DNaseI is impeded by buffers used. PMID- 26939123 TI - Quantitative Assessment of Orbital Implant Position--A Proof of Concept. AB - INTRODUCTION: In orbital reconstruction, the optimal location of a predefined implant can be planned preoperatively. Surgical results can be assessed intraoperatively or postoperatively. A novel method for quantifying orbital implant position is introduced. The method measures predictability of implant placement: transformation parameters between planned and resulting implant position are quantified. METHODS: The method was tested on 3 human specimen heads. Computed Tomography scans were acquired at baseline with intact orbits (t0), after creation of the defect (t1) and postoperatively after reconstruction of the defect using a preformed implant (t2). Prior to reconstruction, the optimal implant position was planned on the t0 and t1 scans. Postoperatively, the planned and realized implant position were compared. The t0 and t2 scans were fused using iPlan software and the resulting implant was segmented in the fused t2 scan. An implant reference frame was created (Orbital Implant Positioning Frame); the planned implant was transformed to the reference position using an Iterative Closest Point approach. The segmentation of the resulting implant was also registered on the reference position, yielding rotational (pitch, yaw, roll) as well as translational parameters of implant position. RESULTS: Measurement with the Orbital Implant Positioning Frame proved feasible on all three specimen. The positional outcome provided more thorough and accurate insight in resulting implant position than could be gathered from distance measurements alone. Observer-related errors were abolished from the process, since the method is largely automatic. CONCLUSION: A novel method of quantifying surgical outcome in orbital reconstructive surgery was presented. The presented Orbital Implant Positioning Frame assessed all parameters involved in implant displacement. The method proved to be viable on three human specimen heads. Clinically, the method could provide direct feedback intraoperatively and could improve postoperative evaluation of orbital reconstructive surgery. PMID- 26939124 TI - PKR Transduces MDA5-Dependent Signals for Type I IFN Induction. AB - Sensing invading pathogens early in infection is critical for establishing host defense. Two cytosolic RIG-like RNA helicases, RIG-I and MDA5, are key to type I interferon (IFN) induction in response to viral infection. Mounting evidence suggests that another viral RNA sensor, protein kinase R (PKR), may also be critical for IFN induction during infection, although its exact contribution and mechanism of action are not completely understood. Using PKR-deficient cells, we found that PKR was required for type I IFN induction in response to infection by vaccinia virus lacking the PKR antagonist E3L (VVDeltaE3L), but not by Sendai virus or influenza A virus lacking the IFN-antagonist NS1 (FluDeltaNS1). IFN induction required the catalytic activity of PKR, but not the phosphorylation of its principal substrate, eIF2alpha, or the resulting inhibition of host translation. In the absence of PKR, IRF3 nuclear translocation was impaired in response to MDA5 activators, VVDeltaE3L and encephalomyocarditis virus, but not during infection with a RIG-I-activating virus. Interestingly, PKR interacted with both RIG-I and MDA5; however, PKR was only required for MDA5-mediated, but not RIG-I-mediated, IFN production. Using an artificially activated form of PKR, we showed that PKR activity alone was sufficient for IFN induction. This effect required MAVS and correlated with IRF3 activation, but no longer required MDA5. Nonetheless, PKR activation during viral infection was enhanced by MDA5, as virus stimulated catalytic activity was impaired in MDA5-null cells. Taken together, our data describe a critical and non-redundant role for PKR following MDA5, but not RIG-I, activation to mediate MAVS-dependent induction of type I IFN through a kinase-dependent mechanism. PMID- 26939125 TI - Nuclear Trafficking of the Rabies Virus Interferon Antagonist P-Protein Is Regulated by an Importin-Binding Nuclear Localization Sequence in the C-Terminal Domain. AB - Rabies virus P-protein is expressed as five isoforms (P1-P5) which undergo nucleocytoplasmic trafficking important to roles in immune evasion. Although nuclear import of P3 is known to be mediated by an importin (IMP)-recognised nuclear localization sequence in the N-terminal region (N-NLS), the mechanisms underlying nuclear import of other P isoforms in which the N-NLS is inactive or has been deleted have remained unresolved. Based on the previous observation that mutation of basic residues K214/R260 of the P-protein C-terminal domain (P-CTD) can result in nuclear exclusion of P3, we used live cell imaging, protein interaction analysis and in vitro nuclear transport assays to examine in detail the nuclear trafficking properties of this domain. We find that the effect of mutation of K214/R260 on P3 is largely dependent on nuclear export, suggesting that nuclear exclusion of mutated P3 involves the P-CTD-localized nuclear export sequence (C-NES). However, assays using cells in which nuclear export is pharmacologically inhibited indicate that these mutations significantly inhibit P3 nuclear accumulation and, importantly, prevent nuclear accumulation of P1, suggestive of effects on NLS-mediated import activity in these isoforms. Consistent with this, molecular binding and transport assays indicate that the P CTD mediates IMPalpha2/IMPbeta1-dependent nuclear import by conferring direct binding to the IMPalpha2/IMPbeta1 heterodimer, as well as to a truncated form of IMPalpha2 lacking the IMPbeta-binding autoinhibitory domain (DeltaIBB-IMPalpha2), and IMPbeta1 alone. These properties are all dependent on K214 and R260. This provides the first evidence that P-CTD contains a genuine IMP-binding NLS, and establishes the mechanism by which P-protein isoforms other than P3 can be imported to the nucleus. These data underpin a refined model for P-protein trafficking that involves the concerted action of multiple NESs and IMP-binding NLSs, and highlight the intricate regulation of P-protein subcellular localization, consistent with important roles in infection. PMID- 26939126 TI - Growth in Egg Yolk Enhances Salmonella Enteritidis Colonization and Virulence in a Mouse Model of Human Colitis. AB - Salmonella Enteritidis (SE) is one of the most common causes of bacterial food borne illnesses in the world. Despite the SE's ability to colonize and infect a wide-range of host, the most common source of infection continues to be the consumption of contaminated shell eggs and egg-based products. To date, the role of the source of SE infection has not been studied as it relates to SE pathogenesis and resulting disease. Using a streptomycin-treated mouse model of human colitis, this study examined the virulence of SE grown in egg yolk and Luria Bertani (LB) broth, and mouse feces collected from mice experimentally infected with SEE1 (SEE1 passed through mice). Primary observations revealed that the mice infected with SE grown in egg yolk displayed greater illness and disease markers than those infected with SE passed through mice or grown in LB broth. Furthermore, the SE grown in egg yolk achieved higher rates of colonization in the mouse intestines and extra-intestinal organs of infected mice than the SE from LB broth or mouse feces. Our results here indicate that the source of SE infection may contribute to the overall pathogenesis of SE in a second host. These results also suggest that reservoir-pathogen dynamics may be critical for SE's ability to establish colonization and priming for virulence potential. PMID- 26939127 TI - Transcriptomic Analysis of Differentially Expressed Genes during Flower Organ Development in Genetic Male Sterile and Male Fertile Tagetes erecta by Digital Gene-Expression Profiling. AB - Tagetes erecta is an important commercial plant of Asteraceae family. The male sterile (MS) and male fertile (MF) two-type lines of T. erecta have been utilized in F1 hybrid production for many years, but no report has been made to identify the genes that specify its male sterility that is caused by homeotic conversion of floral organs. In this study, transcriptome assembly and digital gene expression profiling were performed to generate expression profiles of MS and MF plants. A cDNA library was generated from an equal mixture of RNA isolated from MS and MF flower buds (1 mm and 4 mm in diameter). Totally, 87,473,431 clean tags were obtained and assembled into 128,937 transcripts among which 65,857 unigenes were identified with an average length of 1,188 bp. About 52% of unigenes (34,176) were annotated in Nr, Nt, Pfam, KOG/COG, Swiss-Prot, KO (KEGG Ortholog database) and/or GO. Taking the above transcriptome as reference, 125 differentially expressed genes were detected in both developmental stages of MS and MF flower buds. MADS-box genes were presumed to be highly related to male sterility in T. erecta based on histological and cytological observations. Twelve MADS-box genes showed significantly different expression levels in flower buds 4 mm in diameter, whereas only one gene expressed significantly different in flower buds 1 mm in diameter between MS and MF plants. This is the first transcriptome analysis in T. erecta and will provide a valuable resource for future genomic studies, especially in flower organ development and/or differentiation. PMID- 26939128 TI - Reproducing the Hemoglobin Saturation Profile, a Marker of the Blood Oxygenation Level Dependent (BOLD) fMRI Effect, at the Microscopic Level. AB - The advent of functional MRI in the mid-1990s has catalyzed progress pertaining to scientific discoveries in neuroscience. With the prospect of elucidating the physiological aspect of the Blood Oxygenation Level Dependent (BOLD) effect we present a computational capillary-tissue system capable of mapping venous hemoglobin saturation- a marker of the BOLD hemodynamic response. Free and facilitated diffusion and convection for hemoglobin and oxygen are considered in the radial and axial directions. Hemoglobin reaction kinetics are governed by the oxyhemoglobin dissociation curve. Brain activation, mimicked by dynamic transitions in cerebral blood velocity (CBv) and oxidative metabolism (CMRO2), is simulated by normalized changes in m = (DeltaCBv/CBv)/(DeltaCMRO2/CMRO2) of values 2, 3 and 4. Venous hemoglobin saturation profiles and peak oxygenation results, for m = 2, based upon a 50% and a 25% increase in CBv and CMRO2, respectively, lie within physiological limits exhibiting excellent correlation with the BOLD signal, for short-duration stimuli. Our analysis suggests basal CBv and CMRO2 values of 0.6 mm/s and 200 MUmol/100g/min. Coupled CBv and CMRO2 responses, for m = 3 and m = 4, overestimate peak hemoglobin saturation, confirming the system's responsiveness to changes in hematocrit, CBv and CMRO2. Finally, factoring in neurovascular effects, we show that no initial dip will be observed unless there is a time delay in the onset of increased CBv relative to CMRO2. PMID- 26939129 TI - Affective Computing and the Impact of Gender and Age. AB - Affective computing aims at the detection of users' mental states, in particular, emotions and dispositions during human-computer interactions. Detection can be achieved by measuring multimodal signals, namely, speech, facial expressions and/or psychobiology. Over the past years, one major approach was to identify the best features for each signal using different classification methods. Although this is of high priority, other subject-specific variables should not be neglected. In our study, we analyzed the effect of gender, age, personality and gender roles on the extracted psychobiological features (derived from skin conductance level, facial electromyography and heart rate variability) as well as the influence on the classification results. In an experimental human-computer interaction, five different affective states with picture material from the International Affective Picture System and ULM pictures were induced. A total of 127 subjects participated in the study. Among all potentially influencing variables (gender has been reported to be influential), age was the only variable that correlated significantly with psychobiological responses. In summary, the conducted classification processes resulted in 20% classification accuracy differences according to age and gender, especially when comparing the neutral condition with four other affective states. We suggest taking age and gender specifically into account for future studies in affective computing, as these may lead to an improvement of emotion recognition accuracy. PMID- 26939132 TI - Epidemiology of Leprosy in Spain: The Role of the International Migration. AB - BACKGROUND: Although incidence of leprosy in Spain has declined steadily over the years, the fivefold increase in immigration since the turn of the century--much of it from countries where leprosy is still prevalent--has been linked to an uptick in registered cases. OBJECTIVE: To describe the epidemiologic trends of incident leprosy cases detected in Spain among Spanish- and foreign-born population groups. METHODS: Observational, retrospective study of suspected leprosy cases in Spain, as reported through the System of Compulsory Notification of Diseases from 2003 to 2013, with results disaggregated by country of birth. We collected statistical data on leprosy burden for other countries from WHO to estimate the expected number of imported cases. RESULTS: Of the 168 leprosy cases registered during the study period, 40 (24.6%) were in Spanish patients, while 128 (76.2%) were detected in legally resident immigrants. We identified a significantly higher number of imported leprosy cases during the 2008-2010 and 2011-2013 trienniums compared to the reference biennium 2003-2004 (OR 5.38, 95% CI 1.83-14.88 and OR 4.80, 95% CI 1.41-16.33, respectively). Most imported cases were diagnosed in Latin American immigrants (71.9%), especially Brazilians, but also Paraguayans, Bolivians and other nationalities from South and Central America. However, registered incidence was lower than expected for each year. For example, in 2003, the expected new cases in immigrants was 47.12, compared to only four cases that were actually detected (a 91% difference). Likewise, we expected to find 49.6 incident cases among immigrants in 2009, but only 15 new cases were reported (60% fewer than expected). CONCLUSION: Imported cases of leprosy are responsible for most leprosy incidence in Spain, and we cannot rule out some under-diagnosis. Clinicians should be made more aware of the potential for leprosy incidence among patients from countries where the disease is endemic. PMID- 26939131 TI - Beneficial Effect of Covalently Grafted alpha-MSH on Endothelial Release of Inflammatory Mediators for Applications in Implantable Devices. AB - Intravascular devices for continuous glucose monitoring are promising tools for the follow up and treatment of diabetic patients. Limiting the inflammatory response to the implanted devices in order to achieve better biocompatibility is a critical challenge. Herein we report on the production and the characterization of gold surfaces covalently derivatized with the peptide alpha-alpha-melanocyte stimulating hormone (alpha-MSH), with a quantifiable surface density. In vitro study demonstrated that the tethered alpha-MSH is able to decrease the expression of an inflammatory cytokine produced by endothelial cells. PMID- 26939133 TI - Forecasting Large-Scale Habitat Suitability of European Bustards under Climate Change: The Role of Environmental and Geographic Variables. AB - We modelled the distribution of two vulnerable steppe birds, Otis tarda and Tetrax tetrax, in the Western Palearctic and projected their suitability up to the year 2080. We performed two types of models for each species: one that included environmental and geographic variables (space-included model) and a second one that only included environmental variables (space-excluded model). Our assumption was that ignoring geographic variables in the modelling procedure may result in inaccurate forecasting of species distributions. On the other hand, the inclusion of geographic variables may generate an artificial constraint on future projections. Our results show that space-included models performed better than space-excluded models. While distribution of suitable areas for T. tetrax in the future was approximately the same as at present in the space-included model, the space-excluded model predicted a pronounced geographic change of suitable areas for this species. In the case of O. tarda, the space-included model showed that many areas of current presence shifted to low or medium suitability in the future, whereas a northward expansion of intermediate suitable areas was predicted by the space-excluded one. According to the best models, current distribution of these species can restrict future distribution, probably due to dispersal constraints and site fidelity. Species ranges would be expected to shift gradually over the studied time period and, therefore, we consider it unlikely that most of the current distribution of these species in southern Europe will disappear in less than one hundred years. Therefore, populations currently occupying suitable areas should be a priority for conservation policies. Our results also show that climate-only models may have low explanatory power, and could benefit from adjustments using information on other environmental variables and biological traits; if the latter are not available, including the geographic predictor may improve the reliability of predicted results. PMID- 26939130 TI - Associations between Anticholinergic Burden and Adverse Health Outcomes in Parkinson Disease. AB - BACKGROUND: Elderly adults should avoid medications with anticholinergic effects since they may increase the risk of adverse events, including falls, delirium, and cognitive impairment. However, data on anticholinergic burden are limited in subpopulations, such as individuals with Parkinson disease (PD). The objective of this study was to determine whether anticholinergic burden was associated with adverse outcomes in a PD inpatient population. METHODS: Using the Cerner Health Facts(r) database, we retrospectively examined anticholinergic medication use, diagnoses, and hospital revisits within a cohort of 16,302 PD inpatients admitted to a Cerner hospital between 2000 and 2011. Anticholinergic burden was computed using the Anticholinergic Risk Scale (ARS). Primary outcomes were associations between ARS score and diagnosis of fracture and delirium. Secondary outcomes included associations between ARS score and 30-day hospital revisits. RESULTS: Many individuals (57.8%) were prescribed non-PD medications with moderate to very strong anticholinergic potential. Individuals with the greatest ARS score (>= 4) were more likely to be diagnosed with fractures (adjusted odds ratio (AOR): 1.56, 95% CI: 1.29-1.88) and delirium (AOR: 1.61, 95% CI: 1.08-2.40) relative to those with no anticholinergic burden. Similarly, inpatients with the greatest ARS score were more likely to visit the emergency department (adjusted hazard ratio (AHR): 1.32, 95% CI: 1.10-1.58) and be readmitted (AHR: 1.16, 95% CI: 1.01-1.33) within 30-days of discharge. CONCLUSIONS: We found a positive association between increased anticholinergic burden and adverse outcomes among individuals with PD. Additional pharmacovigilance studies are needed to better understand risks associated with anticholinergic medication use in PD. PMID- 26939135 TI - Authors' response. PMID- 26939136 TI - [Importance of statistics in the programme care for patients with diabetes]. PMID- 26939134 TI - Correction: Neural Correlates Associated with Successful Working Memory Performance in Older Adults as Revealed by Spatial ICA. PMID- 26939138 TI - [The National Health Care Information System of the Czech Republic will significantly enhance the information support of diabetology]. PMID- 26939137 TI - [Medicine for the future: clinical foundations firmly anchored through feedback from practice]. PMID- 26939139 TI - [Pulmonary ventilation in patients with silicosis or coal workers' pneumoconiosis -editorial]. PMID- 26939140 TI - [Phosphate homeostasis in cases of kidney failure is attained at the high cost of maladaptive system impacts in the form of extremely high concentration levels of phosphatonin--editorial]. PMID- 26939142 TI - [Carotid stenosis--diagnosis and treatment--editorial]. PMID- 26939143 TI - [Tetralogy of Fallot before and today--editorial]. PMID- 26939141 TI - [ST2 and heart failure: only one more marker or some else?--editorial]. PMID- 26939144 TI - The Top 10 Myths Of Nursing Home Management, Part III: Administration. PMID- 26939145 TI - Communicating Effectively: Success Depends On It. PMID- 26939146 TI - Spiritual Care Poised For Integration In Health Care. PMID- 26939147 TI - Art Enriches Seniors' Lives. PMID- 26939148 TI - Amateur Dentists. PMID- 26939149 TI - Let's Be Proactive. PMID- 26939150 TI - How Secure are Your Patient Records? PMID- 26939151 TI - Final Notice. PMID- 26939152 TI - New York State Dental Establishments and Dentists: 2007-2012. Economic Survey. AB - Every five years a series of studies is carried out by the Census Bureau which provides an opportunity to review the basic economic well-being of the many industries at the national, state and county levels. A comparison of dental economic data from the 2007 and 2012 studies for the period that encompassed the 2007-2009 "Great Recession" details the general economic difficulties faced by the dental profession during this period. PMID- 26939153 TI - Prevention of Alveolar Osteitis. A Case Report and Review of Literature. AB - Alveolar osteitis (aka, "dry socket") is a frustrating complication of exodontia, especially in the posterior mandible. We describe a novel technique for its possible prevention. The method involves administration of doxycycline dispersed in a local anesthetic solution, along with the use of a Gelfoam carrier. The senior author has used this technique as a routine element of care for several decades without complication. PMID- 26939154 TI - A Multidisciplinary Approach for Managing Severely Malaligned Lower Molars. AB - An impacted mandibular molar is a common clinical situation that may damage adjacent teeth and impair periodontal health. Improper treatment brings the risk of damaging adjacent vital tissues. The risk can be reduced by early diagnosis and extraction of the impacted tooth by an experienced clinician. However, in clinical cases of two impacted molars, it may be beneficial for the patient to save at least one molar. This can be achieved by orthodontic alignment of one of the molars, while extracting the other. The decision should be based upon prognosis and risks for each procedure and for both teeth. The case presented here demonstrates a recommended clinical decision-making process before treatment, followed by monitored multidisciplinary treatment with adaptations made as the treatment progresses. PMID- 26939155 TI - The Anterior Double-Tilt Precision Attachment Case for Cleft Palate Patients and Accident Victims. Case Reports. AB - Passively retained precision attachment removable partial dentures have been used successfully since the 1920s. Adult cleft palate patients and accident victims often have endured a lifetime of wearing awkward appliances to replace the missing structures that never formed intraorally or were lost in a traumatic accident. These patients tend to be poor candidates for dental implants, even with repeated grafting surgeries. The anterior double-tilt precision attachment case is a great treatment option for adults to restore the missing dental structures. Anterior precision partial dentures are stable appliances in the mouth that are worn 24 hours a day and only removed for hygiene. They can be custom designed for maximum esthetics. They do not require denture paste, and they extend minimally onto the palate. As a result, they do not interfere with musculature, tongue movements, speech and taste. Cleft palate patients and accident victims with poor or non-existent edentulous ridges will have difficulty retaining a denture, so preservation of the existing dentition is essential for comfort and function. Because these prostheses do not apply destructive forces to the abutment teeth, they can last decades with minimal maintenance. PMID- 26939156 TI - Diagnosing Juvenile Recurrent Parotitis. Case Reports. AB - Diagnosis of juvenile recurrent parotitis is based upon clinical symptomatology, because no positive serologic signs have been identified. Objective confirmation is best obtained from sialographic or ultrasound studies. PMID- 26939157 TI - Management of Traumatized Permanent Incisors. Revascularization and Delayed Replantation. AB - This article reports a clinical case of a 9-year-old boy with a traumatic injury to the maxillary central incisors 24 hours after a fall in his schoolyard. The upper left central incisor was avulsed and was kept in saliva for four hours from the moment of trauma until its replantation. The right one was necrotized after one month. We describe successful revascularization treatment of right necrotic immature upper incisor and delayed replantation of left one. After 18 months, radiolucent lesions in the periapical areas of both maxillary central incisors had healed, and root apex development was noted with thickening of the walls in tooth #8. PMID- 26939158 TI - DOES TREATMENT ALLEVIATE LYMPHEDEMA SYMPTOMS? A CROSS-SECTIONAL STUDY EVALUATING PATIENT PERSPECTIVES. AB - Most studies evaluating lymphedema treatment effect focus on objective reductions in limb volume, with little attention given to subjective treatment outcomes. The objective of this work was to describe the range of lymphedema symptoms experienced by patients and the importance of symptom improvement following treatment. The second aim was to explore lymphedema treatment use and the effect of individual treatments on symptoms, from the patient's perspective. Australian adults with lymphedema (n = 421) completed a self-administered questionnaire. Information was collected about patients' symptoms, the importance of symptom improvement following treatment, as well as treatment types used and perceived effectiveness of each treatment. In addition to swelling, the vast majority of participants experienced heaviness and tightness in the affected region. Overall, symptoms of lymphedema varied between individuals but the majority considered subjective symptom improvement to be an important outcome of treatment. The most commonly used treatments were compression garments, self- massage, prescribed exercises, and manual lymph drainage, and the majority (95%) of participants had used multiple treatments to manage their lymphedema. The impact of treatments on subjective symptoms varies widely between treatments. Consequently, in addition to objective measures of swelling, it is important to include patient-reported outcomes in future prospective lymphedema treatment studies. PMID- 26939159 TI - LYMPHODYSPLASIA AND KRAS MUTATION: A CASE REPORT AND LITERATURE REVIEW. AB - Cardio-facio-cutaneous (CFC) syndrome is a very rare and sporadic disease whose characteristics include dysmorphic facial appearance, ectodermal abnormalities, cardiac abnormalities, growth retardation and neurodevelopmental delay. This syndrome is classified as one of the RAS syndromes which are caused by altered signal transduction of the RAS/MAPK (mitogen activated protein kinase) pathway due to the mutation of genes including BRAF, MEK1/2, HRAS and KRAS. Other RAS syndromes, such as Costello syndrome and Noonan syndrome, share clinical features with CFC. Moreover, patients with the same clinical phenotype may have different molecular diagnoses. Clinical diagnosis is the starting pointfor correct classification. We describe the clinical data of one case of CFC syndrome, genetically determined by KRAS mutation, that involved chylothorax, lymphedema, sinus pericranii, craniosynostosis, and seizures. This is the second case report of the literature. PMID- 26939160 TI - VALIDATION OF THE LYMPHEDEMA LIFE IMPACT SCALE (LLIS): A CONDITION-SPECIFIC MEASUREMENT TOOL FOR PERSONS WITH LYMPHEDEMA. AB - Evidence-based practice supports the use of validated outcome measures to assess the impact of lymphedema; however, condition-specific lymphedema assessment measures are needed. The Lymphedema Life Impact Scale (LLIS) was developed as a comprehensive, lymphedema-specific instrument to assess the effects of lymphedema in any extremity. The LLIS is an 18-item measure of physical, psychosocial, and functional impairments caused by lymphedema. The purpose of this multicenter, cross sectional study was to investigate the reliability and validity of the LLIS. Test-retest reliability was assessed in a subgroup of 17 participants. Internal consistency and validity was assessed in 71 participants with upper (nUE = 37) or lower limb (nLE = 34) lymphedema, and a control group of 31 participants without lymphedema. Intraclass correlation coefficients for test-retest reliability ranged from .965 to .990. Cronbach's alpha coefficients for internal consistency ranged between .841 and .926. Construct validity of the LLIS was upheld with symptoms, but not with edema severity. The LLIS correlated highly with other comparison measures used in this study. Minimal clinically important difference of the LLIS was 7.31; MDC95 = 11.53. Our results showed the LLIS to be a valid and reliable tool for the assessment of severity of impairment among patients with lymphedema. PMID- 26939161 TI - DESCRIBING LYMPHEDEMA IN FEMALES WITH TURNER SYNDROME. AB - Turner syndrome (TS) is a chromosomal condition affecting an estimated 1 in 2,500 girls where the second X chromosome is missing, or partially formed. This abnormality affects multiple body systems and can lead to short stature, cardiac, neural, and renal abnormalities. Due to the chronic, non-life threatening nature of lymphedema in comparison to other symptoms of TS, it is often ignored by girls and women with TS and their physicians. Consequently, little is known about how lymphedema affects girls and women with TS across the lifespan. Therefore, the objective of the study was to deliver an online survey for females with TS and caregivers in the US, UK, and Canada to provide a worldwide perspective on their current experience with lymphedema within the spectrum of TS. There were 219 participants who completed the survey, and we were able to identify incidence and characteristics of lymphedema across the lifespan. In addition, we found that females with 45,X karyotyping were more likely to report lymphedema symptoms. Lymphedema is not the most significant concern of females with TS, but education, physician evaluation, and assistance with referrals for treatment and management would improve the ease of managing lymphedema in girls and women with TS. PMID- 26939162 TI - GENITAL LYMPHEDEMA: A NEW TECHNIQUE OF CORRECTION SURGERY. AB - Genital lymphedema is a common problem seen by lymphology surgeons in India due to filarial infections. We have developed an innovative operative technique to correct this issue using native skin and have found the results in the first fifteen patients to be encouraging. Gross debulking procedures reduced the size and using native skin allowed a better cosmetic appearance. The patients also reported almost normal sensation and good sexualfunction. This technique deserves further testing with more patients and at additional centers. PMID- 26939163 TI - Professor Alfred Bollinger January 23, 1932-April 3, 2015. PMID- 26939164 TI - [When cells go wild, the doctor panics]. PMID- 26939165 TI - [Cancer as a chronic disease: what changes for our practice?]. PMID- 26939166 TI - [Screening: what do we know]. PMID- 26939168 TI - [Patient spirituality: challenges and issues]. PMID- 26939167 TI - [Viral diseases and cancer risk]. PMID- 26939169 TI - [Advance directives]. PMID- 26939170 TI - [Oncological emergencies: they exist!]. PMID- 26939171 TI - [For a practitioner, 40 years of life and death in the rear-view mirror]. PMID- 26939172 TI - [What can a generalist do for me if I am being followed by an oncologist?]. PMID- 26939173 TI - [Until what age do we treat cancer?]. PMID- 26939174 TI - [Localized prostate cancer: detection, check-up and treatment]. PMID- 26939175 TI - [Cancer pain: non-interventional treatment]. PMID- 26939176 TI - [Head and neck cancer: update and innovations]. PMID- 26939177 TI - [Prolonging life: how far?]. PMID- 26939178 TI - [Palliative care: a death sentence or hope? When do you talk about it?]. PMID- 26939179 TI - [Pediatric oncology: update for the practitioner]. PMID- 26939180 TI - [Oral dietary supplements and home enteral nutrition in oncology]. PMID- 26939181 TI - [Occupational exposure and cancer]. PMID- 26939182 TI - [Cancer rehabilitation, 2016]. PMID- 26939183 TI - [Smoking cessation: how do we help the smokers?]. PMID- 26939184 TI - [Radiology update 2016]. PMID- 26939185 TI - [Why do we need molecular medicine in oncology]. PMID- 26939186 TI - [Living will]. PMID- 26939187 TI - [Can traditional Chinese medicine help cancer patients?]. PMID- 26939188 TI - [Differential diagnosis of skin cancer]. PMID- 26939189 TI - [Common gynecological tumors: precautions, diagnosis and treatment]. PMID- 26939190 TI - [Tumors of the musculoskeletal system: what does the family physician need to know?]. PMID- 26939192 TI - [Psychological distress of diagnosis and remission]. PMID- 26939191 TI - [Spiritual Care, what is it and when is it used?]. PMID- 26939194 TI - [Oncological rehabilitation, 2016]. PMID- 26939193 TI - [Paraneoplastic endocrine syndrome]. PMID- 26939195 TI - [Telling bad news in oncology, therapeutic alliance and emotions]. PMID- 26939196 TI - [Epidemiology of hepatitis C and vaccine perspectives]. PMID- 26939197 TI - [The right to not take drugs and be ignorant of sex]. PMID- 26939198 TI - [HIV pre-exposure prophylaxis does not increase the rate of STI]. PMID- 26939199 TI - [The doctor and his "fee" between ingratitude and submission]. PMID- 26939200 TI - [Can we still write that Louis Lambert was suffering from schizophrenia?]. PMID- 26939201 TI - [Second tube at the Gotthard: doctors point out that the health of residents is at stake]. PMID- 26939202 TI - [Clause required: difficult negotiations on a compromise]. PMID- 26939203 TI - [Beyond biology and the human]. PMID- 26939204 TI - Eosinophilia and Hypereosinophilic Disorders - Update on Etiopathogeny, Classification and Clinical Approach. AB - Eosinophils are innate immune leukocytes recruited in large numbers to sites of allergic inflammation and parasitic infections. Recent studies show additional pleiotropic effects of recruited eosinophils impacting immunomodulation, tissue homeostasis and repair. Pathologic conditions accompanied by blood eosinophilia are quite frequent in medical practice and may raise serious differential diagnosis problems in severe cases, that require a multidisciplinary approach. Hypereosinophilia may be reactive to other diseases or primary, representing hypereosinophilic syndromes, that are diagnosed based on clinical and laboratory criteria, according to actual international guidelines. The etiopathogenic diagnosis is difficult and delayed in many cases and clinical evolution may be- severe, with multiorgan involvement and poor prognosis. Some cases remain idiopathic, despite exhaustive investigation.This paper aims to review the most recent data in the literature referring to the role of eosinophils in human pathology, diagnostic criteria and treatment strategies of hypereosinophilic syndromes, actual classification and to draw some useful recommendations in clinical practice. PMID- 26939205 TI - Caspases, Cell Death and Diabetic Nephropathy. AB - Diabetic Nephropathy. In 2014 (according to data published by the World Health Organization) 9% of the global population was affected by Diabetes which was considered to be directly responsible for 1.5 million deaths just two years prior (in 2012). From the entire number of patients suffering from diabetes, approximately a quarter of them develop renal affection. Diabetic nephropathy has similar physiopathology mechanisms and ultrastructural changes in cell injury characteristics in both Type 1 and Type 2 diabetes. Cell Death. Cell Death was less studied in the renal diabetic disease, although it could represent an important pathogenic mechanism in the appearance and progression of nephropathy. At renal level the cellular loss can be explained by several mechanisms; different stimuli with cellular lesion potential can trigger apoptosis signaling with appearance of regulatory proteins having a double role (they participate in the initiation of the apoptosis path and cell death or in the ending of this process). The types of Cell Death and their relative proportion between themselves in the renal tissue have not been completely elucidated. Caspases. Discovered in the middle of the 1990's, Caspases are a part of the cysteine proteases family and play a role in numerous aspects of physiology (having a role in development, aging and apoptosis), but also in aspects of physiopathology of several degenerative affections, autoimmune diseases, oncologic diseases - having an important part in apoptosis, necrosis and also inflammation. PMID- 26939206 TI - Liver Fibrosis: Causes and Methods of Assessment, A Review. AB - Hepatic fibrogenesis is the final result of injury to the liver. Fibrosis could lead to hepatic dysfunction, important in the pathogenesis of other chronic problems. Therefore, understanding the mechanism, accurate diagnosis and staging of it in early stages accelerates the treatment and reduces the prevalence of chirrosis. Treatment strategies of liver problems and detction methods depend on the amount and progression of liver fibrosis and the rate of cirrhosis development. Traditionally the invasive method, liver biopsy, is reference standard to follow progression and stage of fibrosis. However, during the past decade, progressive development of novel non-invasive methodologies has challenged the invasive method. Non-invasive methods have been initially introduced for chronic hepatitis C with increasing use in other chronic liver diseases. The need for liver biopsy has nowadays decreased significantly as a result of these methodologies. Most of the new non-invasive methods depend on either 'biological' or 'physical' approaches. In this review, starting from the mechanism of fibrogenesis, the current knowledge about diagnosis, treatment strategies and different methods for its evaluation is discussed. This is followed by a conclusion on what is expected to be known in this field during the future research. PMID- 26939207 TI - P Wave Signal-Averaged Electrocardiography in Patients with Chronic Obstructive Pulmonary Disease. AB - INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is associated with higher incidence of supraventricular arrhythmias. Atrial late potentials (ALP) detected by P-wave signal-averaged electrocardiography (SAECG) could be useful in detecting the patients at risk for supraventricular arrhythmias. Our objective was to assess the role of P-wave SAECG and ALP detection for arrhythmic risk evaluation of the patients with exacerbated COPD. METHODS: We prospectively included 45 patients with exacerbation of COPD and 58 age- matched patients with no history of pulmonary disease in a control group. We performed pulmonary function tests, arterial blood gases, echocardiography, 24-hour Holter monitoring and P-wave SAECG. We measured filtered P-wave duration (FPD), the root mean square (RMS) voltages in the last 40, 30 and 20 ms of the filtered P-wave (RMS 40, RMS 30 and RMS 20), the root mean square voltage of the filtered P-wave potentials (RMS-p), and the integral of the potentials during the filtered P-wave (Integral-p). ALP was defined as FPD > 132 ms and RMS 20 < 2.3 MUV. RESULTS: Isolated atrial premature beats (APB) and supraventricular tachycardias (SVT) were more frequent in the COPD group. There were no significant differences between groups regarding the P wave SAECG parameters. In the COPD group none of the supraventricular arrhythmias was correlated with ALP or any P-wave SAECG parameters. CONCLUSIONS: The patients with acute exacerbation of COPD but no apparent cardiac disease have a higher incidence of supraventricular arrhythmias. P-wave SAECG analysis and ALP detection have little value in the arrhythmic risk evaluation of these patients. PMID- 26939208 TI - Extended Antiphospholipid Antibodies Screening in Systemic Lupus Erythematosus Patients. AB - BACKGROUND: The antiphospholipid syndrome (APS) is one of the most encountered autoimmunity in systemic lupus erythematosus (SLE) patients and pathogenesis of these two seems to be intricate. AIM: To investigate the association of antiphospholipid antibodies (APLAs) titer with the presence of secondary APS diagnosis in SLE patients. METHODS: 65 patients fulfilling the 2012 Systemic Lupus Collaborating International Clinics (SLICC) SLE's criteria were included. The APS diagnosis was sustained according to the 2006 Sydney APS's criteria. Three groups of patients were defined: SLE patients with secondary APS, SLE with history of positive "criteria" APLAs but without APS clinical features, respectively SLE patients without positive APLAs or clinical APS criteria. An extended APLAs panel was searched in all cases: both IgM and IgG of anticardiolipin antibodies (aCL), anti-P2 glycoprotein I antibodies (abeta2GPI), antiphosphatidylethanolamine antibodies (aPE), antiphosphatidylserine antibodies (aPS), respectively antiprothrombin antibodies (aPT). Results. Only the abeta2GPI, both IgM and IgG serotypes, had significantly higher titers in patients with SLE and secondary APS compared to no APS (with/ without positive APLAs): median (min; max) 7.0 (0.0-300.0) vs. 1.0 (0.0-28.0) vs. 1.0 (0.0-12.0), respectively 3.0 (0.0-79.0) vs. 1.0 (0.0-3.0) vs. 1.0 (0.0-12.0) (p<0.001, Kruskal-Wallis test)]. Also, in regression logistic models, only the abeta2 GPI (IgG and IgM ) were identified as risk factors for secondary APS diagnosis in the SLE patients: OR(95%CI) 5.9 (2.2-15.7), respectively 1.3 (1.1-1.5). In regard with the SLE markers, the IgG serotypes of the "non-criteria" APLAs analyzed (aPS, aPT, aPE) were correlated with the antiDNA titers while the IgM serotypes inversely associated with the complement C3 levels. CONCLUSIONS: IgG abeta2 GPI are accompanied by almost 6-fold increase risk of secondary APS when screening SLE patients. On the contrary, the "non-criteria" APLAs do not seem associated with the APS diagnosis in SLE patients. Some correlates of the "non-criteria" APLAs with the antiDNA and complement C3 levels were also observed. PMID- 26939209 TI - Drug-drug Interactions of Statins Potentially Leading to Muscle-Related Side Effects in Hospitalized Patients. AB - INTRODUCTION: The associations of drugs that may interact with the statins resulting in elevated serum concentration of the statins are an important risk factor for statin induced muscle disorders. We aimed to determine the prevalence of these associations in all hospitalized patients that had been prescribed statins before/during hospitalization and to find out how often they are associated with muscle-related side effects. METHODS: This prospective, non interventional study performed in two internal medicine departments included patients with statin therapy before/during hospitalization. Data on each patient demographic characteristics, co-morbidities and treatment was collected from medical charts and interviews. We evaluated patients' therapy for the targeted associations using Thomson Micromedex Drug Interactions checker and we ranked the identified drug-drug interactions (DDIs) accordingly. Each patient with statin treatment before admission was additionally interviewed in order to identify muscular symptoms. RESULTS: In 109 patients on statin treatment we found 35 potential (p) DDIs of statins in 30 (27.5%) patients, most of which were in the therapy before admission (27 pDDIs). The pDDIs were moderate (20 pDDIs) and major (15 pDDIs). Of the total number of pDDIs, 24 were targeting the muscular system. The drugs most frequently involved in the statins' pDDIs were amiodarone and fenofibrate. Two of the patients with pDDIs reported muscle pain, both having additional risk factors for statin induced muscular effects. CONCLUSION: The prevalence of statins' pDDIs was high in our study, mostly in the therapy before admission, with only a small number of pDDIs resulting in clinical outcome. PMID- 26939210 TI - Homocysteine, trace elements and oxidant/antioxidant status in mild cognitively impaired elderly persons: a cross-sectional study. AB - INTRODUCTION: Mild cognitive impairment (MCI) is the prodromal stage of Alzheimer's disease (AD), so identification of the related risk factors can be helpful. There are controversial data regarding the serum oxidant/antioxidant status, trace elements and homocysteine (Hcy) as effective parameters in this disease, therefore the status of these factors was determined in this study. METHODS: One hundred-twenty elderly persons with cognitive impairment and 120 elderly healthy persons who were differentiated using Mini-mental state examination (MMSE) participated in this study. The patients were divided into mild and moderate-to-severe cognitive impairment group. Serum antioxidant/oxidant, copper (Cu), manganese (Mn), zinc (Zn) and Hcy concentrations were measured using routine methods. RESULTS: Oxidant and antioxidant levels increased and decreased based on the severity of the disease and were higher and lower in patients than in control group, respectively (p<0.001). With adjusting for age, gender and education, significant difference in Hcy levels was not observed. There was no significant difference in trace elements levels among groups. CONCLUSIONS: Results confirmed the association between oxidative damage with increasing the severity of cognitive impairment. These factors may be involved in the etiology of cognitive impairment and AD. Identification of such biomarkers is important to select appropriate treatment goals before the onset of irreversible clinical signs. PMID- 26939211 TI - The Effect of Arterial PaCO2 in COPD Exacerbations with and without Peripheral Edema. AB - INTRODUCTION: Studies often suggest hypoxemia is an important factor for sodium retention in chronic obstructive pulmonary disease (COPD), although hypercapnia is also associated with sodium retention in these patients. Hence, we have presented the major role of PaCO(2) in edema due to COPD. METHOD: COPD patients who were hospitalized due to exacerbation were enrolled in the study and divided into two groups: with and without edema. Exclusion criteria included primary hepatic diseases, nephrotic syndrome and other renal diseases, left heart failure, or using drugs that would interfere with these organs or endocrine function. Data were coded and analyzed by SPSS software. Arterial blood gas variables including bicarbonate, pH, and PaO(2), PaCO(2) and O(2) saturation, and FEV1, FVC, FEV1/FVC were measured and compared between the groups. RESULTS: No significant difference was found between the averages of bicarbonate, pH, PaO(2), 02 saturation, FEV1, FVC and FEV1/FVC in COPD in the two groups. PaCO(2) levels were significantly higher in patients with edema, compared to those without edema (p = 0.05). A reverse and significant correlation between PaCo(2) and FEV1 levels (p = 0.03) (r = -0.501) was observed in patients with edema. CONCLUSION: This study suggests that hypercapnia is a major factor in causing edema in COPD patients compared to hypoxemia. PMID- 26939212 TI - Acute Atherothrombotic Disease and Severe Bleeding: A Difficult Clinical Presentation in Medical Practice. AB - Management of antithrombotic therapy in elderly patients with unstable atherothrombotic disease and increased risk of bleeding is a major clinical challenge. We report the case of a 79 year- old diabetic man with rheumatoid arthritis on both oral corticosteroids and NSAID therapy with mild renal dysfunction, who presented to our hospital because of disabling claudication. Prior to admission he had several episodes of TIA. He also had recurrent small rectal bleeding and mild anemia attributed to his long-standing hemorrhoid disease. Angiography showed a sub-occlusive left internal carotid artery stenosis associated with a significant LAD stenosis and complex peripheral artery disease. Cataclysmic bleeding and hemorrhagic shock occurred in the third day post admission. Withdrawal of all antithrombotic treatment, blood transfusion and emergency sigmoidectomy were performed for bleeding colonic diverticulosis. Subsequently antiplatelet therapy was reinitiated and the patient successfully underwent left carotid artery endarterectomy and LAD stenting. He was discharged from hospital on the 21(st) day post admission and is doing well at 24 months follow-up. PMID- 26939213 TI - Pulmonary Extramedullary Hematopoiesis Mimicking Plasmacytoma in a Patient with Multiple Myeloma. AB - A 42-year-old male patient was admitted to our hospital for planning autologous hematopoietic stem cell transplantation (auto-HSCT). He was diagnosed as multiple mycloma (IgG type Kappa) in 2003. His physical examination was normal with no important abnormality on laboratory evaluation. Chest radiography performed for routine evaluation prior to transplantation revealed a large, well- defined mass, that had obtuse angles with the chest wall consistent with extraparenchymal lesion superposed on second and third ribs. Also, there were multiple bony structures demonstrating changes of destructive effects of multiple myeloma. Computed tomography (CT)-guided biopsy was obtained from the mass by transthoracic fine-needle aspiration (FNAB) method. Biopsy was reported as extramedullary hematopoiesis (EMH) contrary to our expectation of multiple myeloma. PMID- 26939214 TI - Dermatoscopy of Verrucous Pigmented Lesions is Essential for Choosing the Appropriate Treatment. AB - Dermatoscopy, as a noninvasive rapid method, which allows the viewing of melanin in the epidermis and papillary dermis, has an important role in diagnosis of the pigmented lesions localized on skin, mucous membrane, scalp and nails. The term of verrucous pigmented lesions includes a series of non-melanocytic and melanocytic, benign and malignant lesions. Among these, the most frequent is the seborrheic keratosis , a common epidermal tumor, affecting the sun exposed areas of adult. At the other end of the spectrum regarding the frequency is the seborrheic keratosis-like melanoma, whose underdiagnosis has a serious impact on the patient's life. In this work we present the clinical and dermoscopical aspects of three cases of verrucous pigmented lesions (two seborrheic keratoses and one seborrheic keratosis-like melanoma) that determined the diagnostic algorithm as well as the therapeutic approach. The above-presented cases underline the importance of dermatoscopy to determine the malignant potential of the pigmented lesions, the final appropriate treatment being possible after the histopathologic confirmation. PMID- 26939215 TI - Multiple Intracerebral Hemorrhages in an Old Patient with Rheumatoid Arthritis. AB - A 78-year-old Caucasian man was admitted in the Department of Neurology for visual disturbances, started two days before. The next day the patient experienced headache, fever and gait disturbances. He had hypertension, diabetes mellitus, an ischemic stroke 13 years ago, longstanding seronegative rheumatoid arthritis (17 years), polynodular goiter, right ischio-pubian fracture and right femoral vein thrombosis a year ago due to a car accident, since he is treated with oral anticoagulants associated to antiaggregant, hypotensors, statin and oral antidiabetics. The neurologic examination had evidenced nuchal rigidity, left homonymous hemianopsia, left central facial palsy, ataxia of the inferior limbs with wide-based gait, achilean reflexes abolished bilaterally, bilaterally abolished plantar reflexes, ideomotor apraxia, dysarthria, hypoprosexia, and preserved consciousness patient. A non-contrast cerebral CT scan had shown right temporal and parieto-occipital intraparenchymatous hemorrhages, a right frontal sequelar lesion, multiple old lacunar infarets, cortical atrophy. Laboratory findings included an inflammatory syndrome, absence of rheumatoid arthritis positive serology, normal coagulogram, an elevated proteinuria. The cerebral IRM performed on the seventh day of hospitalisation was suggestive for subacute right parietal hemorrhage, old cerebral infarction in the right anterior cerebral artery area, old lacunar infarcts and cerebral atrophy. The anticoagulant and antiaggregant treatment was stopped after a generalized tonic-clonic seizure occurred. Antiedematous, hypotensor, anticonvulsivant, beta-blocker, and symptomatic treatment was started, while the antidiabetic treatment was continued. All symptoms remitted. Arguments for amyloid angiopathy in our patient are previous non-cardioembolic ischemic stroke and a chronic inflammatory disease rheumatoid arthritis in his personal medical history. PMID- 26939216 TI - Association between periodontal disease and pregnancy outcomes. AB - OBJECTIVE: To evaluate the association between periodontal disease and pregnancy outcomes like preterm birth and low birth weight. PATIENTS AND METHOD: Interviewer-administered questionnaires were completed by the subjects who attended the antenatal clinic of the Lagos University Teaching Hospital, Lagos. Information obtained included; maternal age, gestational age, marital status, educational status, occupation and expected date of delivery. After delivery, the questionnaire was completed with baby's weight at birth and the actual date of delivery. Clinical assessment of the periodontium was done using Oral Hygiene Index (OHI) and Community Periodontal Index of Treatment Needs (CPITN). Participants were divided into three groups: Test, Control I and Control II groups. Scaling and polishing were done for all patients with periodontal disease before (Test group) and after delivery (Control I). All Control II participants (those without periodontal disease) were given Oral hygiene instructions. Descriptive and comparative analyses were done using Epi info version 2008. RESULTS: Four hundred and fifty women received the questionnaire but the response rate was 94%, giving an actual sample size of 423 participants. Maternal age range was between 18 and 34 years with mean age of 29.67 (+/- 3.37). Gestational age at the point of recruitment was between 10 weeks and 26 weeks with mean of 23.34 (+/- 4.05). The prevalence of periodontal disease among the study group was 33.38%. About 71% of the participants attained tertiary level of education; only 0.7% had no formal education. There was 9.9% use of alcohol among the participants. The mean oral hygiene score for the participants was 1.94 (+/- 1.31). The prevalences for preterm deliveries, low birth weight and spontaneous abortion were 12.5%, 12.1% and 1.42% respectively. CONCLUSION: This study confirms periodontal disease as a probable risk for adverse pregnancy outcomes such as preterm delivery and low birth weight. Therefore, health workers should be encouraged to promote good oral health among women. PMID- 26939217 TI - [An 18 month evaluation of MM-MTA pulpotomy on primary decayed molars]. AB - Pulpotomy is the most performed and controversial therapeutic in pediatric dentistry. Formocresol is known to have a toxic effect on living tissues, a mutagenic and carcinogenic potential with a systemic uptake of formocresol via pulpotomized teeth, other alternative products have been investigated. 40 molars were pulpotomized using Micro Mega Mineral Trioxide Aggregate (MM-MTA), which eliminates the need for the use of formocresol. The effects of this material were evaluated both clinically and radiographically. Post-operative control examinations were performed at 1, 6, 12, and 18 months trying to detect spontaneous or stimulated pain, pathological tooth mobility, abscesses or fistulas, internal or external pathological tooth resorption, periapical bone destruction, or canal obliteration. Pain was absent at 18 months post operatively. Thirty six molar treated with the MM-MTA didn't show any mobility or pain, one molar presented a pathological resorption and one molar presented an abscess without a fistula at 12 month. The observations were compared to others related to formocresol, ferric sulfate, MTA, and laser pulpotomies, using the Chi square test x2. The abundance of positive result strongly demonstrate that the MM MTA pulpotomy on carious temporary molars is a promising technique. PMID- 26939218 TI - [Gingival displacement techniques in daily practice. Survey among dental surgeons in Abidjan, Ivory Coast]. AB - INTRODUCTION: Access to cervical margins allows the practitioner to record the entire cervical margin in order to provide a true copy to the technician. This requires a gingival displacement obtainable by different techniques. This study aimed to assess the implementation of gingival displacement methods prior to impression taking in fixed prosthodontics. MATERIALS AND METHODS: This is a descriptive and cross-sectional survey of sample of 71 dentists practising in Abidjan, Ivory Coast; which ran from October 2nd, 2010 to November 14th, 2010. A survey form was administered to dentists. The questionnaire was organised around the following headings: identification of dentists and practice of gingival displacement methods. The data processing done using software Epi Info 6 and Excel XP on Window XP, allowed calculation of frequencies, means and proportions and the establishment of connection between variables with the chi2 test. The significance level was set at p < 0.05. RESULTS: The results of the survey indicate that non-surgical methods of gingival displacement, including retraction cords and temporary crowns are those they use most frequently (76.4%) because the vast majority of practitioners (87.22%) believe the most traumatic to the periodontium are surgical methods. CONCLUSION: Our study showed that the gingival displacement methods are frequently carried out in daily practice, regardless of the topography of the abutment teeth and their number, but with a preference for non-surgical methods, particularly those using retraction cords and temporary crowns. The use of injectable gingival displacement paste is not harmful to the periodontal tissues, easy to use and have a very efficient haemostatic action. It should also be known and practiced. PMID- 26939219 TI - Prevalence and unmet treatment need of traumatized incisor among Cameroonian schoolchildren in North West Province. AB - OBJECTIVE: To determine the prevalence and unmet treatment need of traumatized incisor in 12-13 years old among Cameroonian Schoolchildren in the North West Province. MATERIALS AND METHODS: This cross-sectional survey among 12-13 years old children of selected rural and urban secondary schools in North West province of Cameroon was conducted between March and November, 2010. RESULTS: The majority of the 2287 studied children were females (50.2%) and urban dwellers (51.8%). Of the 2287 studied children, 45 of them exhibited evidence of incisor trauma giving a prevalence of 2.0%. This prevalence was higher in males than females (2.3% versus 1.7%) and also higher in urban than rural schools (2.2% versus 1.7%). Upper central incisor was the predominantly traumatized tooth and enamel fracture constituted 62.2% of incisor trauma. Fall and sports were the leading cause of incisor trauma in this study. Some minor variations in the causes of incisor trauma were found among gender and location. The prevalence of unmet treatment need was 91.1% which were mainly acid etch restoration. Males and rural dwellers had more unmet treatment need. CONCLUSION: Data revealed a low prevalence of traumatized incisor with high prevalence of unmet treatment needs among Cameroonian Schoolchildren in North West Province. Findings of this survey provide baseline information on prevalence and unmet treatment need for traumatized incisor among Cameroonian Schoolchildren in the North West Province. PMID- 26939220 TI - [Evaluation of periodontal health of prosthetic abutments. Pilot study about 100 abutments of crowns and bridges]. AB - BACKGROUND: The confection of a fixed prosthesis finds its indication in response to the patient's aesthetic and/or functional whose requirements are stronger in terms of satisfaction. This involves maintaining the stability of prosthetic reconstructions on a sufficiency long time. To achieve this, the preservation of periodontal health of the prosthetic abutments occupies a special choice. PURPOSE: The aim of this study was to evaluate the periodontal health of fixed prosthesis abutment. MATERIALS AND METHODS: Thirty-nine patients having fixed prosthesis in the mouth for more than one year participated in our study. Ultimately, 38 single crowns and 27 seven bridges based on 100 abutments have been recorded. After an interview, clinical and radiographic examination was performed. It was to assess the level of oral hygiene, the health of the superficial and deep periodontal abutment using OHIS index of Green and Vermilion, periodontal index of Russel and mobility index of Muhlemann. RESULTS: On the 100 abutments examined, gingivitis (14%), gingival recession (13%), bone osteolysis (29%) and mobility (5%) were recorded. In addition, about 60% of patients had inadequate oral hygiene and less than 30% of them had a regular prosthetic maintenance. CONCLUSION: From this study, it appears that complications affecting periodontal prosthetic abutments are essentially bone lysed (29%), gingivitis (14%) and gingival recessions (13%). PMID- 26939221 TI - [Tooth decay: epidemiological and therapeutic aspects in dental service of University Teaching Hospital Yalgado Ouedraogo and Municipal Centre of Oral Health]. AB - INTRODUCTION: In order to improve the prevention and treatment of dental caries in Burkina Faso, we conducted a study on the epidemiological and therapeutic aspects of dental caries in the dental services of University Teaching Hospital Yalgado Ouedraogo and in the Municipal Centre of Oral Health of Ouagadougou. MATERIAL AND METHODS: A prospective and descriptive study from October, 15th 2012 to January, 15th 2013 was conducted on a sample of 191 patients. The variables recorded were: patient's identity, age, sex, area of residence, food mode, socioeconomic level, reason for consultation, oral hygiene, DMFT index, degree of tissue damage, the topography of the carious lesions and the applied therapy. RESULTS: Caries prevalence was 93.19% more female consultations, with sex ratio at 0.77. The average age was 31 years for a sample often engaged in trade and the informal sector. Carious lesions were usually limited to less than 4 teeth. The main motivation for the consultation was pain at 82.20%. CONCLUSION: The use of preventive care is quite low in our population. Extractions still occupy an important part of treatment. We need to improve oral hygiene and show to patients the necessity of routine visits to the dentist every year for early treatment. PMID- 26939223 TI - COMPARISON OF A GENUS-SPECIFIC CONVENTIONAL PCR AND A SPECIES-SPECIFIC NESTED-PCR FOR MALARIA DIAGNOSIS USING FTA COLLECTED SAMPLES FROM KINGDOM OF SAUDI ARABIA. AB - Molecular tools are increasingly accepted as the most sensitive and reliable techniques for malaria diagnosis and epidemiological surveys. Also, collection of finger prick blood spots onto filter papers is the most simple and affordable method for samples preservation and posterior molecular analysis, especially in rural endemic regions where malaria remains a major health problem. Two malaria molecular diagnostic tests, a Plasmodium genus-specific conventional PCR and a Plasmodium species-specific Nested PCR, were evaluated using DNA templates prepared from Whatman-FTA cards' dry blood spots using both, Methanol fixation/Heat-extraction and FTA commercial purification kit. A total of 121 blood samples were collected from six Saudi south-western endemic districts both, as thick and thin films for routine microscopic screening and onto FTA cards for molecular studies. Out of the 121 samples, 75 were P. falciparum positive by at least one technique. No other species of Plasmodium were detected. P. falciparum parasites were identified in 69/75 (92%) samples by microscopic screening in health care centers. P. genus-specific PCR was able to amplify P. falciparum DNA in 41/75 (55%) and 59/75 (79%) samples using Methanol-fixation/Heat-extraction and FTA purification kit, respectively. P. species-specific Nested PCR revealed 68/75 (91%) and 75/75 (100%) positive samples using DNA templates were isolated by Methanol-fixation/Heat- extraction and FTA purification methods, respectively. The species-specific Nested PCR applied to Whatman-FTA preserved and processed blood samples represents the best alternative to classical microscopy for malaria diagnosis, particularly in epidemiological screening. PMID- 26939222 TI - [Hyper keratotic oral lichen planus and malignant transformation]. AB - Oral Lichen Planus (OLP) is a chronic inflammatory dermatosis usually benign that can affect skin, integuments and mucosal membranes. It is characterized by a disorder of keratinization and the polymorphism of clinical disease. Some of them correspond to a very intense lichen activity as erythematous, erosive and bullous forms, others concern mostly old forms of lichen planus as atrophic or hyperkeratotic and hypertrophic verrucous forms. In most of the cases, the OLP has a benign evolution but malignant transformation may occur warranting strict monitoring of the disease and effective treatment of exacerbations. PMID- 26939224 TI - PARASITIC INFECTIONS: IS MALE AND FEMALE DIFFERENCE FOR ANEMIA AND GROWTH RETARDATION EVIDENT? AB - Parasitoses are the commonest health problem among school age clildren, which impair children's growth and development and causing anemia. To detect the role of parasitic infections and both anemia and growth affection, on one hand, and if so the common complications among males and females on the other hand, a cross sectional descriptive study was carried out among the outpatient attended the Pediatrics Clinic, Al-Fayoum University's Hospitals. A total of 314 children aged from 1 to 13 years were subjected to clinical examination as well as stool analysis and CBC examination. The detected parasites were Entameba histolytica, Giardia lamblia (Protozoa) and Enterobius vermicularis, Hymenolepis nana, Ascaris lambricoides and Ancylostoma duodenale (Helminthes). There was significance difference (P<0.05) between males and females regarding E. histolytica in females (60%) as to G. lamblia and H. nana in males (16.1%, & 11.5% respecttively). Also, there was significance difference (P<0.05) between males and females regarding to hemoglobin level, and weight percentiles with anemia (92%) and underweight& borderline weight (34.5%) in males. The overall anemia was 89.8%. However, there was no significance difference (P<0.05) regarding to height percentiles. PMID- 26939225 TI - COGNUTUVE AND NEUROLOGICAL COMPLICATIONS OF BACTERIAL MENINGITIS IN ADULT PATIENTS: A HOSPITAL BASED STUDY. AB - Bacterial meningitis is associated with disabling sequelae in a significant proportion of patients. It is associated with high mortality, risk of neuropsychological sequelae and risk of cognitive impairment the purpose of this study is to assess cognitive and neurological complications in adult patients with bacterial meningitis. A total of 45 patients with bacterial meningitis and 16 patients with tuberculous meningitis were enrolled. They were subjected to full medical history taking and clinical examination, full neurological examination on admission and discharge. Mini mental state examination (MMSE) and Wechsler memory scale (WMS) were used to assess cognitive function. The results showed that the ischemic brain insult (87.88%) followed by cranial nerves affection (32.42%) were the commonest neurological complication detected on discharge. Cognitive impairment was detected in 53.66% of patients using MMSE.WMS showed that orientation, information and logical memory were the most common affected. Cognitive and neurological complications were not statistically related to age or etiology (P>0.05). Longer duration until diagnosis (Beta = -.18, p < 0.001), presence of intracranial complications (Beta = -.12, p < 0.005), need for mechanical ventilation (Beta = -.79, p < 0.001) and drug abuse (Beta = -0.11, p < 0.05) were significant predictors of worse outcome assessed by Glasgow outcome score. PMID- 26939226 TI - PLATELET COUNT TO SPLEEN DIAMETER RATIO AND TO SPLEEN AREA RATIO AS PREDICTORS FOR ESOPHA-GEAL VARICES IN CHRONIC HEPATITIS C PATIENTS WITH LIVER CIRRHOSIS. AB - Endoscopic detection of esophageal varices (EV) especially the high risk esophageal varices (HREV) is recommended in cirrhotic patients. There are several studies about non-invasive markers to predict the presence of EV. The aim of this study was to evaluate platelet count to spleen diameter (P/D) ratio and platelet count to spleen area (P/A) ratio as predictors for EV and HREV in patients with liver cirrhosis. This prospective study included 100 cirrhotic patients without previous variceal hemorrhage or endoscopic intervesion. Biochemical, imaging and endoscopic findings were collected in all patients. Several parameters including P/D and P/A ratio were measured and their association with the presence of EV and HREV was tested. The results showed that only P/D and P/A ratios were found to be independent predictors for the presence of EV and HREV in multivariant analysis. For prediction of the EV formation in cirrhotic patients, P/D ratio at value < or =979.9 and P/A ratio of < or =20.6 had area under the curve (AUC) 0.922 and 0.975 respectively with sensitivity 100%, specificity 30% for P/D ratio and sensitivity 100%, specificity 75% for P/A ratio. For prediction of the HREV formation, P/D ratio at value < or = 587.9 and P/A ratio of 513.7 had AUC 0.867 and 0.991 respectively with sensitivity 100%, specificity 50% for P/D ratio and sensitivity 100%, specificity 88% for P/A ratio. PMID- 26939227 TI - HUMAN BABESIOSIS: A GENERAL REVIEW WITH SPECIAL REFERENCE TO EGYPT. AB - Babesiosis is a tick-borne malaria-like illness caused by species of the intra erythrocytic protozoan Babesia. Humans are opportunistic hosts for Babesia when bitten by nymph or adult ticks. Currently, Babesia infection is transmitted by various tick vectors in Europe, Asia, Africa and the northwestern and northeastern United States. Human babesiosis was first described in 1957 but is now known to have worldwide distribution. The increase in reported cases is likely due to increases in actual incidence as well as increased awareness of the disease. Despite the diagnostic and preventive advances resulting from extensive research and a greater understanding of the disease, babesiosis continues to have significant medical impact as a confounding variable in the diagnosis and treatment of Lyme disease and as a potential threat to the blood supply, especially in the United States. Diagnostic advances, like the development of PCR assays, have resulted in increased sensitivity for detection as well as the discovery and characterization of new babesial species. Further studies using the molecular tools now available and those to be developed will lead to a better understanding of the natural history of these organisms, including the transmission cycle and the, potential role of Babesia parasites themselves as immunomodulAtor. Human babesiosis is usually an asymptomatic infection in healthy individuals. Several patients become symptomatic, and, within these subpopulations, significant morbidity and mortality occur, especially in elderly, immunocompromised, or asplenic patients. It is difficult to diagnose. Although the index of suspicion should be high in rural Babesia endemic areas, patients with babesiosis have few, if any, localizing signs to suggest the disease. Diagnosis confirmation depends on the parasitemia degree, the expertise and well trained laboratory personnel. Most patients infected by B microti who are otherwise healthy appear to have a mild illness and typically recover without specific chemotherapy; however, treatment is recommended for all diagnosed cases to prevent sequelae and potential transmission through blood donation. In addition, patients should be advised to take precautions against tick exposure and to refrain from donating blood until completely cured of babesiosis. PMID- 26939228 TI - BLOCKADE OF PGE2, PGD2 RECEPTORS CONFERS PROTECTION AGAINST PREPATENT SCHISTOSOMIASIS MANSONI IN MICE. AB - Schistosomiasis is a chronic disease with considerable social impact. Despite the availability of affordable chemotherapy, drug treatment has not significantly reduced the overall number of disease cases. Among other mechanisms, the parasite produces PGE2 and PGD2 to evade host immune defenses. To investigate the role of PGE2 and PGD2 in schistosomiasis, we evaluated the effects of L-161,982, Ah6809 (PGE2 receptor antagonists alone of combined with each other) and MK-0524 (PGD2 receptor antagonist) during prepatent Schistosoma mansoni infection. Drugs were administered intraperitoneally an hour before and 24 hours after infection of C57BL/6 mice with 100 Schistosoma mansoni cercariae. L-161,982, Ah6809, their combination and MK-0524 caused partial protection against pre-patent S. mansoni infection which was mediated by biasing the immune response towards Th1 phenotype. These results showed that blockade of PGE2 and PGD2 receptors confers partial protection against pre-patent S. mansoni infection in mice and that they may be useful as adjunctive therapy to current anti-schistosomal drugs or vaccines. PMID- 26939229 TI - LABORATORY STUDIES ON THE POSSIBILITY OF CULEX QUINQUEFASCIATUS TO HARBOR HEPATOZOON SP. INFECTING CERASTES CERASTES CERASTES VIPER IN EGYPT. AB - A successful experimental infection of Culex quinquefasciatus with Hepatozoon sp. infecting Cerastes cerastes cerastes viper was carried out under laboratory conditions of 24 +/- 3 degrees C and 60-70% R. H. The period monitored for complete sporogonic cycle was 21 days. The effect of high parasitimic blood meal was nonsignificant (P>0.05) on preoviposition period and hatchability. Meanwhile a highly significant reduction was observed in oviposition rate, number of deposited eggs, number of hatched larvae and longevity (P<0.01). On the contrary moderate infection with Hepatozoon revealed a great significant increase in fecundity (P<0.01) and a nonsignificant decrease in longevity (P>0.05) PMID- 26939230 TI - SAND-FLY PHLEBOTOMUS PAPATASI (PHLEBOTOMINAE): A GENERAL REVIEW WITH SPECIAL REFERENCE TO ZOONOTIC CUTANEOUS LEISHMANIASIS IN EGYPT. AB - Leishmania are digenetic protozoa which inhabit two hosts, the sandfly where they grow as promastigotes in the gut, and the mammalian macrophage where they grow as amastigotes. Sandfly (or sand fly) is a colloquial name for any species or genus of flying, biting, blood-sucking Dipteran encountered in sandy areas. In the United States, sandfly may refer to certain horse flies that are also known as "greenheads" (family Tabanidae), or to members of the family Ceratopogonidae, also known in Florida and elsewhere as a sand gnat, sandflea, no-see-um (no-see em, noseeum), granny nipper, chitra, punkie, or punky. Outside the United States, sandfly may refer to members of the subfamily Phlebotominae within the Psychodidae. Biting midges (Ceratopogonidae) are sometimes called sand flies or no-see-ums (no-see-em, noseeum). New Zealand sandflies are in the Austrosimulium genus, a type of black fly. Of 500 known phlebotomine species, only some 30 of them have been positively identified as vectors of the disease. Cutaneous leishmaniasis (ZCL) is a protozoan disease well documented not only in Egypt, but in nearly all the East Mediterranean Countries. It is prevalent in the Egyptian Sinai Peninsula with at least three identified foci. PMID- 26939231 TI - NON-INVASIVE PREDICTORS OF PORTAL HYPERTENSION IN PATIENTS WITH HEPATITIS C VIRUS RELATED HEPATOCELLULAR CARCINOMA. AB - The reference standard for portal venous pressure measurement which is clinically important for estimating the. feasibility of resection of hepatocellular carcinoma is the hepatic venous pressure gradient, which is, invasive and expqnsive. The present study evaluated the noninvasive parameters for assessment of portal hypertension in Child A patients with hepatocellular carcinoma on top of hepatitis C virus. A total of 112 patients were subjected to clinical assessment, biochemical assay, ultrasonographic Doppler study, triphasic spiral abdominal computed tomography, upper gastrointestinal endoscopy and hepatic venous pressure gradient measurement. According to hepatic venous pressure gradient measurement, they were classified into groups: GI: 58 patients with hepatic venous pressure gradient <10 mmHg and GII: 54 patients with hepatic venous pressure gradient > or = 10 mmHg. Significant variables in univariate analysis were included in a multivariate analysis to establish a model for prediction of clinically significant portal hypertension. Results showed that portal vein diameter > or = 1.3 cm, mono or biphasic pattern of flow in hepatic veins and Giannini index < or = 909 were independent risk factors for the clinically significant portal hypertension as indicated by HVPG > or = 10 mmHg. A model with highest likelihood ratio and good fitness was created. This prediction model was displayed by the receiver operating characteristic curve and under the curve area was 0.969 (0.938-1). PMID- 26939232 TI - EFFECT OF DIFFERENT BLOOD SOURCES ON THE FEEDING TIME OF SAND FLY, PHLEBOTOMUS PAPATASI. AB - The feeding time for sand fly females was determined experimentally by feeding of thirty females (3-5 days-old) sand fly Phlebotomus papatasi on different blood sources (human, pigeon, hamster and blab C mice). Mean feeding time was longest on blab C mice, 8.55 minutes, followed by hamster, 7.05 minutes, then pigeon, 4.84minutes, and finally human, 4.69 minutes. Significant difference was observed in the feeding time between females fed on hamster and balb c mice but there is no significant difference between females fed on human and pigeon. PMID- 26939233 TI - THE EFFICACY OF THREE MEDICINAL PLANTS: GARLIC, GINGER AND MIRAZID AND A CHEMICAL DRUG METRONIDAZOLE AGAINST CRYPTOSPORIDIUM PARVUM. I-IMMUNOLOGICAL RESPONSE. AB - Cryptosporidisis parvum is a zoonotic protozoan parasite infects intestinal epithelial cells causing a major health problem for man and animals. Experimentally the immunologic mediated elimination of C. parvum requires CD4+ T cells and IFN-gamma. But, the innate immune responses also have a significant protective role in both man and animals. the mucosal immune response to C. parvum in C57BL/6 neonatal and GKO mice shows a concomitant Thl and Th2 cytokine mRNA expression, with a crucial role for IFN-gamma in the resolution of the infection. NK cells and IFN-gamma have been shown to be important components in immunity in T and B cell-deficient mice, but IFN-gamma-dependent resistance is demonstrated in alymphocytic mice. Epithelial cells may play a vital role in immunity as once infected these cells have increased expression of inflammatory chemokines and cytokines and demonstrate anti-infection killing mechanisms. C. parvum immunological response was used to evaluate the efficacy of anti-cryptosporidisis agents of Garlic, Ginger, Mirazid and Metronidazole in experimentally infected mice. PMID- 26939234 TI - INCIDENTAL PARASITIC INFECTIONS IN SURGICALLY REMOVED APPENDICES: A RETROSPECTIVE ANALYSIS. AB - Numerous parasitic infections can cause inflammation of the appendix and can mimic appendicitis clinically. The diagnosis is generally achieved only after surgery. However early diagnosis through stool examination may prevent life threatening complications. This study investigated the presence of parasitic infections in surgically removed appendices as an etiology of acute appendicitis. A retrospective study included patients who had undergone surgery for acute appendicitis over a period of three years from Jan 2012 to Dec 2014. Demographic data, laboratory investigations, operative data and pathological findings, presence and type of parasites were retrieved. The results showed that out of 1536 patients with appendectomy done, 938 (61.1%) were males and 598 (38.9%) were females. Parasitic infection was demonstrated only in 0.4% (6 patients). Mean average age of these patients was 12 years. Enterobius vennicularis was present in 4 patients (66% of the parasitic affection) and Schistosoma mansoni in 2 patients (34% of the parasitic affection). Other etiologies were acute suppurative appendicitis (94.1%), chronic appendicitis (3.1%), tumors (0.3%), tuberculosis (0.2%) and actinomycosis (0.1%). Appendix was found normal in 2% of patients underwent appendectomy. PMID- 26939235 TI - DETECTION OF HELICOBACTER ANTIGEN IN STOOL SAMPLES AND ITS RELATION TO H. PYLORI POSITIVE CHOLECYSTITIS IN EGYPTIAN PATIENTS WITH CHRONIC CALCULAR CHOLECYSTITIS. AB - Evidences supporting the association between H. pylori infection and chronic cholecystitis could be found by using direct culture or staining of H. pylori in gallbladder tissues as well as indirect techniques. Stool antigen test has been widely used due to its noninvasive nature. Various stool antigen tests were developed to detect H. pylori using an enzyme immunoassay (EIA) based on monoclonal or polyclonal antibodies This study evaluated the frequency of H. pylori antigen in stool samples of patients with chronic calcular cholecystitis as regard gall bladder histopathological changes. Fifty patients were included presented with symptomatic qholecystolithiasis recruited from the outpatient clinic of National Hepatology and Tropical Medicine Research Institute during 2014-2015. Full history and clinical examination and abdominal ultrasonography were performed. Stool samples were collected, prepared and examined for detection of H. pylori antigen. Cholecystectomy was done for all patients; 45 patients (90%) by laparoscopic Cholecystectomy and 5 patients (10%) by open surgery and removed gallbladders were submitted to pathology department for detection of H. pylori in tissue under microscope using Giemsa stain. The results showed that (82%) were females with mean age (42.6 +/- 1 years). The mean BMI was (29 + 7.2) H. pylori-specific antigen in stool samples was detected in 40% of patients and 38% were detected in patients; tissue, with significant correlation between H. pylori-specific antigen in stool and in tissue. Histopathological pictures infection in tissue were 68.4% mucosal erosions, 63.2% mucosal atrophy, 57.9% mucosal hyperplasia, 26.3% metaplasia, 42.1% musculosa hypertrophy, 26.3% fibrosis, but lymphoid aggregates were in 42.1% of cases. PMID- 26939236 TI - DIRECT GENOTYPING OF TOXOPLASMA GONDII IN BLOOD SAMPLES FROM PREGNANT WOMEN IN JAZAN, SAUDI ARABIA. AB - Toxoplasma gondii (T. gondi) is divided three main clonal lineages designated as type I, II, and III and atypical genotypes were also detected. The distribution of T. gondii genotypes varied from one geographic area to another. This study characterized of T. gondii isolates from pregnant women in Jazan. Genetic analysis of the GRA6-coding fragment was performed for T. gondif genotyping using PCR-RFLP method. The seropositive for Toxoplasma-specific antibodies were determined using ELISA and were 27.9% in pregnant women in Saudi Arabia. Women seropositive for Toxoplasma IgG & IgM (GI=30) or for specific IgG (GII=30) were included. Among pregnant women, 83.3% of GI (women seropositive for IgG and IgM) and 90% of GII (women seropositive for IgG) were asymptomatic and observed clinical symptoms were fever (n=4) and cachexia (n=2) and lymphadenopathy (n=1). GRA6-nested PCR was positive in 8 blood samples (13.3%), 5 of GI & 3 of GII seropositive women. RFLP analysis showed the detention of genotype I in 8 samples with no cases coinciding to pattern of type II or type III. PMID- 26939239 TI - PREVALENCE OF ANISAKID NEMATODE LARVAE INFECTING SOME MARINE FISHES FROM THE LIBYAN COAST. AB - This study examined eight hundred ninety six marine fishes belonging to nine different fish species; Synodus saurus; Merluccius merluccius; Trachurus mediterraneus; Serranus cabrilla; Mullus surmuletus; Diplodus annularis; Spicara maena; Siganus rirulatus and Liza ramada. The fishes were bought from fish markets at five different sites on Libyan coast, from January to December 2013, for study the anisakids larvae among them. The results showed that 344/896 fishes (38.4%) were infected with Anisakids larvae. S. saurus was the highly infected (80.9%), followed by T mediterraneus (77.5%) but, S. cabrilla, S. maena, M merluccius, M surmuletus, and D. annularis were least anisakid infected showed rates of 58.2%, 53.8%, 43.7%, 36.7% & 3.6%, respectively. No parasites were in S. rirulatus and L, ramada. Ten species of Anisakids larvae was detected during the present study. Two Pseudoterranova sp. Larvae, two types of Anisakis larvae, Anisakis simplex larva and Anisakis sp. Larva, two types of Contracaecum sp. Larvae and four Hysterothylacium larvae. Females showed higher prevalence than males. The number of anisakid larvae varied according to body length and weight of infected fish, without significant difference between prevalence and seasons, but, a significant difference was between prevalence and regions. PMID- 26939237 TI - ANTIPARASITIC ACTIVITY OF SILVER AND COPPER OXIDE NANOPARTICLES AGAINST ENTAMOEBA HISTOLYTICA AND CRYPTOSPORIDIUM PARVUM CYSTS. AB - Nanoparticles (NPs) have received more attention as antiparasitic agents. In the present study, silver and copper nanoparticles were synthesized and characterized using scanning electron microscopy (SEM), transmission electron microscope (TEM) and X-ray fluorescence (XRF). The antiparasitic activity of Ag and CuO nanoparticles were tested against two of the most environmentally spread parasites in Egypt (Entamoeba histolytica and Cryptosporidium parvum). The average sizes of synthesized Ag NPs and CuO NPs were 9 & 29 nm respectively and a significant reduction for cysts viability (p > 0.05) was observed for CuO NPs against E. histolytica cysts and Ag NPs against C. parvum oocysts. Moreover, LC50 3h of CuO NPs for E. histolytica and C. parvum were 0.13 and 0.72 mg/l, while Ag NPs recorded 0.34 and 0.54 mg/l respectively. Accordingly, these NPs could be suggested as a new nanoform agent for safe and effective treatment of E. histolytica and C. parvum parasites. PMID- 26939240 TI - REEVALUATION OF MALARIA PARASITES IN EL-FAYOUM GOVERNORATE, EGYPT USING RAPID DIAGNOSTIC TESTS (RDTS). AB - Malaria as a disease has been identified in Egypt since ancient times. Malaria was endemic in almost all parts of the country but prevalence showed a steady decrease by 1990, and regressed in most of the Governorates. Then by the end of 1998 till now Egypt become free from local transmission of malaria. All reported cases were imported mainly from Sudan. However, the outbreak of falciparum (1 case) and vivax (23 cases) that occurred (May 2014) in Aswan Governorate strongly indicated that malaria is reemerging in the country. El-Fayoum should be take special attention, rather than being the last residual focus. The efficient malaria vector A. sergenti, the proven vector A. pharoensis and the suspected vector A. multicolor were encountered. This work reevaluated malaria status by using RDTs in survey and Giemsa stained thick films to confirm positive cases and estimation of parasite rate, formula, densities and species, also to study the ecological and entomological efficacy factors. The result showed that out of 2044 examined persons, 14 (0.68%) were passive cases, i.e., attending themselves to El Fayoum Malaria Units after their return from Sudan. Microscopic examination of their stained thick films obtained from MOH&P shows that 9 (64.2%) out of passive cases were positive 3 of them are P. falciparum (33.3%) and the rest P. vivax 6 (66.7%) The species formulas of P. falciparum and P. vivax were 33.3% and 66.7% respectively. Concerning the density class, only one vivax case was of low density class while the other cases were of high density class. All positive cases were males, imported from Sudan and most of them were merchants having trade activities in Sudan. All examined persons during active case detection ACD (1551) and neighborhood of detected cases NOD (479) were malaria negative by rapid diagnostic tests. The areas recording the highest number of imported cases were Abu Shanap, Aboxa (Ballona) and Kafr Aboud (Abshaway Center) but no Anopheline spp larvae were detected. While in Al Nazla A. sergeni and A. multicolor larvae were detected where there was no any imported case or even traveler to Sudan. If the situation is reversed, i.e., an imported case inhabit Al Nazla, reemergence of local malaria may start. The situation of Kafr Fazara is greatly changed by using fine sand instead of clay in manufacturing red brick after prevention excavation of land. No imported cases or Anopheline spp larvae were recorded. PMID- 26939241 TI - DICROCOELIUM DENDRITICUM INFECTION IN A PATIENT WITH CHRONIC SCHISTOSOMIASIS HAEMATOBIUM. AB - Infection with Dicrocoelium dendriticum in humans is seldom to be reported in Egypt. This liver fluke, which commonly infects ruminants, has a complex life cycle with two intermediate hosts; the land snail and the ant. Human infection occurs by accidental ingestion of the second intermediate host. The present reported a patient suffered from recurrent acute chole-cystitis with chronic urinary schistosomiasis whose Kato stool examination showed Dicroceolium dendriticum eggs. He was successfully treated with Mirazid. PMID- 26939242 TI - RELATIONSHIP BETWEEN ENTEROBIUS VERMICULARIS INFECTION AND PELVIC INFLAMMATORY DISEASES IN CHILDREN AT SOHAG GOVERNORATE, EGYPT. AB - A cohort of children presented with pelvic inflammatory diseases (gastrointestinal and/or genitourinary surgical conditions) and had concomitant infection with E. vermicularis. To find out this relationship, a total of 135 patients suffering from different gastrointestinal and genitourinary surgical conditions were selected from Departments of Surgery and Gynecology. They were subjected to stool analysis, peri-anal swabs and blood examination mainly for eosinophilia. The results showed that 26 patients out of 135 (19.2%) had. E. vermicularis with high eosinophilia in 30 cases (22.2%). Identification of E. vermicularis by peri-anal swab test in the cohort was successful (16.30%). Males were more affected than females with ratio 2.2:1 and age mean 7.13 +/- 1.92. As to residence and housing, rural children with bad housing (73.08% & 88.46% respectively) were more affected than those living in urban areas with healthy housing (26.92% and 11.54% respectively). PMID- 26939243 TI - THE ARTHROPOD-BORNE ONCHOCERCIASIS: IS IT DESERVED TO BE NEGLECTED?. AB - Onchocerciasis a filarial parasitic nematode, also known as river blindness and Robles disease, is a neglected tropical disease infecting more than 18 million people mainly in sub-Saharan of Africa, the Middle East, South and Central America and many other countries. Disease infectivity initiates from Onchocerca volvulus (Filarioidea: Onchocercidae) transmitted by the blackfly, Simulium sp. which introduces the infective stage larva with its saliva into the skin. Within human body, adult females (macrofilaria) produce thousands of larvae (microfilariae) which migrate in skin and eye. Infection results in severe visual impairment or blindness for about 2 million, as being the world's second-leading cause of blindness after trachoma, as well as skin onchocercomata. PMID- 26939244 TI - VALUE OF CEREBROSPINAL FLUID TUMOR NECROSIS FACTOR-ALPHA (TN-ALPHA) FOR RAPID DIAGNOSIS OF BACTERIAL MENINGITIS. AB - Meningitis is common in tropical areas and also in Egypt and has a world-wide distribution. This study evaluated the potential role of CSF TNF alpha in diagnosis and differenfial diagnosis of acute meningitis (bacterial versus asepic meningitis). This case-control study was conducted between Ain Shams University Tropical Medicine Department and Embaba Fever Hospital. Fifty patients with suspected meningitis were recruited during from January 2014 to June 2014. They were divided according to culture results into 2 groups: GI: 40 patients with acute bacteria men ingitis (proved by CSF culture), G2: 10 patients matched according to age and sex with clinical sings of CNS infection but without laboratory evidence of bacterial origin, (Suspected cases, and negative culture). Both groups were subjected to thorough history taking, full clinical examination, and laboratory invistigations including CSF analysis & CS TNF was measured by ELISA. The results showed a highly significantdifference between cases and control reading CSF TNF (P=0.00). The criteria's of diagnostic validity test as 100% for all at cutoff > or = 275 ng/ml and < or = 700 ng/ml with 100% specificity and sensitivity. A significant correlation between CSF-TNF and each of ESR (P=003) & CSF cells (P=0.015), without significant correlation regarding other parameters (P>0.05). PMID- 26939245 TI - DISTRIBUTION AND UTILISATION OF IVERMECTIN (MECTIZAN): A CHEMOTHERAPEUTIC APPROACH TO THE CONTROL OF ONCHOCERCIASIS IN OLD OHAOZARA LGA, EBONYI STATE, EASTERN NIGERIA. AB - Onchocerciasis (river blindness) is a devastating, debilitating Stigmatising and incapacitating parasitic disease that is endemic in tropical and subtropical regions of the world, including Nigeria. Mass distribution of ivermectin (Mectizan) to the endemic parts of the world was initiated by the Onchocerciasis Control Programmes (OCPs). Absolute compliance to the regimen for up to 15 years has been reported to be effective in the control of the disease. The study was carried out in Ohaozara LGA, Onicha LGA and Ivo LGA. The three (3) LGAs made up the defunct Old Ohaozara LGA. A structured questionnaire was used to generate information on knowledge of Onchocerciasis and on the use of ivermectin by the inhabitants of the communities of the study areas. The distribution coverage of ivermectin in the study areas dating from 2010 to 2014 was ascertained with drug distribution charts obtained from Ebonyi State Health Management Board (ESHMB), Abakaliki (the point source of distribution in the state), and from the health centres in communities of old Ohaozara LGA (the service delivery points (SDPs) to inhabitants of the communities. Data was analysed using descriptive statistics. Utilization of the regimen was ascertained by determining the actual number of tablets of mectizan that was administered to the patients at the various health cenrtes (service delivery points (SDPs) in the communities. The percentage utilization of the regimen was determined by dividing the number of mectizan tablets administered to the patients at SDPs with the number of mectizan tablets supplied from state point source of distribution and multiplying by 100. A total of 347, 299 out of 1, 919135 tablets of mectizan supplied to the study areas from 2010 to 2014 were actually utilized, forming an overall percentage utilization of 18.10%. There was adequate supply but very poor utilization of the regimen. The poor utilization resulted from factors including locating of health centres very far from homes of some of the rural villagers, non-yearly compliance with regimen administration, poor health sensitization and education and lack of incentives orpoor incentives to the village-based health workers (VBHWs). Intensification of efforts to cover the lapses in the utilization of the regimen is advocated for a more effective control of the disease. PMID- 26939246 TI - PARASITES TRANSMITTED TO HUMAN BY INGESTION OF DIFFERENT TYPES OF MEAT, EL-MINIA CITY, EL-MINIA GOVERNORATE, EGYPT. AB - Meat-borne parasites are Sarcocystis species, Toxoplasma gondii, Taenia saginata, Taenia solium and Trichinella spiralis. A total of 300 animals including 100 cattle, 100 goat, and 100 pigs, slaughtered in El-Minia governmental slaughterhouses. From each animal, five samples were taken from different muscles (esophageal, tongue and cardiac) and different organs (liver and brain). Meat samples were examined macroscopic and microscopic (direct, homogenization and H&E staining) for detection of the above-mentioned parasites. Serum samples were subjected to IHA for detection of T gondii specific antibodies. This study revealed that Sarcocystis species were the highest parasites that could be detected, with overall prevalence of 80%, which was statistically significant (P < or = 0.001). The digestion method was more sensitive than direct method for detection of Sarcocystis species. On the other hand, T. gondii was only diagnosed by using IHA test as 50.9% serum samples were positive, which was statistically significant (P < or = 0.004). Besides, 20% of examined battle were infected by Cysticercus bovis, and 12% of pigs were infected with C. cellulosae, but without statistical significant (P < or = 0.5). PMID- 26939247 TI - PREVALENCE OF SOME GASTRO-INTESTINAL PARASITES IN DIABETIC PATIENTS IN TANTA CITY, GHARBIA GOVERNORATE, EGYPT. AB - It is well known that diabetes mellitus affects the immune system negatively through various ways. Diabetic patients are also considered as the immunocompromised group of patients. Infections with intestinal parasites are uncommon to cause high morbidity or mortalilty to man, but they are risky to diabetic patients. The study investigated the prevalence of comnion intestinal parasites in diabetic patients in Tanta City. Among the patients who were attending gastrointestinal department (360 patients), complaining of variouse abdominal symptom and discomfort, thirty three (33) patients were known to be diabetic and on current treatment. Fecal samples were collected from diabetic patients and the same number from nondiabetic patients. Samples were examined macroscopically and microscopically by direct smear and different concentration methods then stained with iodine. The study was carried out through six months from March to August 2015 for common intestinal parasites. In diabetic group E histolytica were detected in 13 patients (39.4%), compared to (43%) among controls, G. lamblia was detected in a patient (3%) compared to (3%) in controls, A. lumbricoides was detected in one patient (3%) compared to (5%) in controls, and E. vermicularis was detected in one patient (3%) compared to (3.8%) in controls. The highest level of parasitosis among diabetic patients was E. histolytica (39%), but without significant difference between controls and patients. There for one can assume that E. histolytica could be considered as a monitor for environmental pollution, low stander hygiene and low standard of living. PMID- 26939248 TI - ["My Mirra, my world." Mirra Birens-Eitingon as a key to her husband Max Eitingon's persona]. AB - New reseach in Russia, Germany and Israel has revealed the complex and multifaceted figure of Mirra Eitingon (1877-1947), the wife for 31 years of Dr. Max Eitingon. Her character and her background in the Russian-Jewish intelligentsia and theatrical milieu provided a lifelong inspiration for Max in his many cultural interests as well as in his psychoanalytic activities, in Berlin and later in Jerusalem. His devotion to Mirra as well as to her two sons from previous marriages (one of them was the leading Soviet nuclear physicist Yuli Khariton) also highlight Max's own generosity and kindness. PMID- 26939249 TI - ["... I shall never forget the gift by which you established yourself as friend in my life!" The letters of Lou Andreas-Salome to Max Eitingon (1911-1933)]. AB - The correspondence between Andreas-Salome and the Eitingons draws attention to their long-standing relation. The letters contained among the Eitingon papers in Jerusalem (81 items) were complemented by the much smaller set (5 items) held by the Lou Andreas-Salome Archives in Gottingen. The material highlights for the first time Eitingon's role in securing Andreas-Salome's access to the Berlin psychoanalytic association and for her entering psychoanalytic practice. In the 20s the relation between Andreas-Salome and Mirra Eitingon intensified, based on their common Russian background. Several aspects featured in the letters are discussed in appendixes: the role of Russian language and habits; Max Nachmansohn, an analysand of Andreas-Salome; her literary gift to Freud's 70th birthday; the dealing with fees in psychoanalysis. PMID- 26939250 TI - [Organisation and funding of the Berlin Psychoanalytic Polyclinic. The role of Max Eitingon]. AB - Based on unpublished archival material (Eitingon's yearly reports, account statements), this paper enriches and modifies the hitherto commonly accepted image of the Berlin Polyclinic. It highlights the fact that the indigent patients treated there contributed considerably to the budget by paying fees, albeit relatively low ones. While confirming that Eitingon largely funded the clinic, it also points out (what has hardly been known before) that he reduced his support in 1928 and stopped it altogether in 1931. Among other things, candidates were now required to pay some rent for the rooms where they analyzed their training cases. On the other hand, candidates could get stipends, funded by the course fees of the Berlin Psychoanalytic Institute. Besides a number of employed assistants, candidates did most of the treatments while the members of the psychoanalytic Society had to be repeatedly reminded of their formal obligation to take over one unpaid case from the Polyclinic. At the end, the paper discusses the "spirit" of the institution. PMID- 26939251 TI - [Max Eitingon in Palestine/Eretz Israel (1933-1943)]. AB - In 1933, after the Nazi takeover in Germany, Eitingon decided to settle in Palestine. His ten Jerusalem years highlight a multifaceted personality that does not quite correspond to his usual image as a "grey eminence" of the international psychoanalytic movement: enthusiastic, vivid, highly involved in various- artistic, scientific, academic, social and pedagogic--acitivities of zionism in Palestine. In contrast, his last years were overshadowed by illness, financial ruin und the tragedies of war. Eitingon played a major role in the establishment of psychoanalysis in Palestine. However, the omnipresence of his name, associated with a purely Berlin psychoanalytic tradition, tends to obscure the important contributions of representatives of the Viennese tradition and the significant achievement of Moshe Wulff who was the real pioneer of psychoanalysis in Israel. PMID- 26939252 TI - [Vladimir Zederbaum" (1883-1942): Physician, journalist, contributor to the Russian "Jewish, Encyclopedia". A research report]. AB - Vol. 15 o f the "Jewish Encyclopedia" (St. Petersburg 1908-1913) contains an article on Freud, signed by Vladimir Zederbaum. The data for the article were provided by Max Eitingon. This paper addresses the question of whether Zederbaum himself was Eitingon's contact. Several archives produced a lot of information about Zederbaum's medical and journalistic activities in St. Petersburg. However, to date no connection between the two men could be established. PMID- 26939254 TI - [A "clear reaction formation against death drive hypotheses" (Brun 1953): On one strand of the reception of Freud's death drive concept in German-speaking countries]. AB - If the death drive hypothesis is understood as a possible concept for self destructive clinical phenomena, one can state that before World War II a number of analysts took it up quite naturally, while others raised objections. After the break caused by the Nazi regime the situation suddenly changed. Brun's formulation, quoted in the title of this paper, was a non-intended, but accurate diagnosis of a certain strand in the history of the reception of Freud's death drive concept in the time before, but even more so in the first decades after, 1945. The author takes it as a symptom that for decades there was an uncritical acceptance of Brun's "critical", though in fact biased, study which claimed that the death drive hypothesis was and continued to be refuted in every respect. Taking the example of a few protagonists of the postwar period, she sees hints of an initial lively and positive interest which was then followed by a (relatively) quick distancing. PMID- 26939255 TI - [Freud in Carinthia. A historical search]. AB - This paper sheds some new light on four visits of Freud to Carinthia between 1898 and 1923. New information from contemporary sources is added to already known facts (patient visit in 1898; encounters with Alban Berg in 1900 and 1907). PMID- 26939256 TI - ["Monster with vital hundred-weight voice". An analyst as a fictional character]. PMID- 26939257 TI - Foreword. PMID- 26939258 TI - Ethnobotanical Study. AB - Ethnobotany is the study of interrelationships between human cultures and plants, animals, and other organisms in their environment. It also creates an awareness of the link between biodiversity and cultural diversity. From the beginning of civilization, people have been using plants for various purposes like food, shelter, medicines, etc. Ethnobotanists play a key role in exploring these kinds of information from indigenous people which creates a gateway for formulating a novel drug. The content in this chapter deals with these aspects in an approachable manner. PMID- 26939259 TI - Pharmacognostical Studies. AB - The chapter deals with tools and techniques employed in pharmacognosy. Pharmacognostic evaluation helps to screen the commercial varieties, substitutes, adulterants and any other quality control of the drugs. It is a simple and reliable tool, helps to obtain information about biochemical and physical properties of crude drug. Methods such as macroscopic and microscopic analysis, maceration, histochemical colour reaction, photomicrography, organoleptic character of plant powder and extracts, fluorescence analysis of plant powder with different chemical reagents, determination of pH of plant powder, water solubility index (WSI) and water absorption index (WAI) and acid value are discussed. PMID- 26939260 TI - Extraction of Bioactive Compounds. AB - A bioactive compound influences the health of living organisms and it has extranutritional constituents that typically occur in low quantities in foods, which helps to enhance or boost the immune system. Plants and their products possess bioactive compounds, i.e., secondary metabolites. Here, extraction is an important process to isolate the bioactive compounds. Biological activities of the extract show a significant variation depending on the extraction methods and this also opens a gateway for selecting suitable extraction methods. Hence, different extraction methods have been discussed in this section, which influences the extraction of phytochemicals. PMID- 26939261 TI - Preliminary Phytochemical Studies. AB - Plants are the natural producers of medicinal agents like alkaloids, flavonoids, tannins, and phenolics. These phytocompounds alone or in combination act as a therapeutic agent in various disease complications. Various chemical reagents are used to determine the major phytochemicals present in plant parts. Protocols involved in screening of alkaloids, carbohydrates, glycosides, saponins, phytosterols, fixed oils, and fats are shown in this chapter. PMID- 26939262 TI - Proximate Composition Analysis. AB - The proximate composition of foods includes moisture, ash, lipid, protein and carbohydrate contents. These food components may be of interest in the food industry for product development, quality control (QC) or regulatory purposes. Analyses used may be rapid methods for QC or more accurate but time-consuming official methods. Sample collection and preparation must be considered carefully to ensure analysis of a homogeneous and representative sample, and to obtain accurate results. Estimation methods of moisture content, ash value, crude lipid, total carbohydrates, starch, total free amino acids and total proteins are put together in a lucid manner. PMID- 26939263 TI - Mineral Quantification. AB - Optimal intakes of elements, such as sodium, potassium, magnesium, calcium, manganese, copper, zinc and iodine, can reduce individual risk factors including those related to cardiovascular diseases among humans and animals. In order to meet the need for vitamins, major minerals, trace minerals, fatty acids and amino acids, it is necessary to include a full spectrum programme that can deliver all of the nutrients in the right ratio. Minerals are required for normal growth, activities of muscles, skeletal development (such as calcium), cellular activity, oxygen transport (copper and iron), chemical reactions in the body, intestinal absorption (magnesium), fluid balance and nerve transmission (sodium and potassium), as well as the regulation of the acid base balance (phosphorus). The chapter discusses the chemical and instrumentation techniques used for estimation of minerals such as N, P, Ca, Mg, K, Na, Fe, Cu, Zn, B and Mb. PMID- 26939264 TI - Anti-nutritional Factors. AB - Anti-nutritional factors such as trypsin inhibitor, phytic acid and cyanogen are as important as nutritional content of any edible plant part. The anti nutritional factors can be defined as those substances generated in natural food substances by the normal metabolism of species and by different mechanisms (e.g. inactivation of some nutrients, diminution of the digestive process or metabolic utilization of feed) which exert effects contrary to optimum nutrition. Hence, trypsin inhibitor, phytic acid and cyanogens present in edibles with the methods in the chapter would be helpful. PMID- 26939265 TI - Quantification of Secondary Metabolites. AB - Plants are a rich source of secondary metabolites that have medicinal and aromatic properties. Secondary metabolites such as alkaloids, iridoids and phenolics generally produced by plants for their defence mechanisms have been implicated in the therapeutic properties of most medicinal plants. Hence, quantification of these metabolites will aid to discover new and effective drugs from plant sources and also to scientifically validate the existing traditional practices. Quantification of large group of phytochemicals such as phenolics and flavonoids is quantified in this context. PMID- 26939266 TI - In Vitro Antioxidant Assays. AB - Various chemical in vitro assays have been developed to measure antioxidant capacities of plant products. Despite the recent popularity in the antioxidant research, the lack of standardized assays to compare research results from different research groups has been a major challenge. The examination of various antioxidant assays is required for the development of standard methods that are broadly applicable by researchers and industry. However, due to the complex nature of biological systems, there is no single universal method for measuring antioxidant capacity. Antioxidant methods such as DPPH*, ABTS+, nitric oxide, super oxide, metal chelating confirming the free radical scavenging property of the plants with widely used methods are simplified in this chapter. PMID- 26939267 TI - In Vitro Antihaemolytic Activity. AB - In this assay, the rat erythrocytes are induced with hydroxyl radical damage by the addition of H2O2. This causes the rupture of the RBC and the contents leak out giving the red colour of the haemoglobin to the medium. Hence, anti haemolytic activity has been presented here in a brief and easy manner using the rat erythrocytes. PMID- 26939268 TI - Antimicrobial Activity. AB - Natural products of higher plants may possess a new source of antimicrobial agents with possibly novel mechanisms of action. They are effective in the treatment of infectious diseases while simultaneously mitigating many of the side effects that are often associated with conventional antimicrobials. A method using scanning electron microscope (SEM) to study the morphology of the bacterial and fungal microbes and thus determining antimicrobial activity is presented in the chapter. PMID- 26939269 TI - In Vitro Anthelmintic Assay. AB - Nematodes are believed to have originated 1000 million years ago as free living anaerobic benthic organisms. Modern anthelmintic drugs have been in use but the worms have created resistance to most of the broad spectrum anthelmintics such as benzimidazoles, levamisole, avermectins, etc. However, these drugs cause side effects. More recently, plant extracts have been reported as having developed resistance against anthelmintics. A study using earthworms to determine the activity has been developed and explained in a well-defined manner in this chapter. PMID- 26939270 TI - Toxicity Studies. AB - Toxicity studies in the animal models are done to determine the dose level recommended for the treatment of disease as drug. This guideline enables the characterization of adverse effects following repeated daily inhalation exposure to a test. This chapter includes oral and dermal toxicity studies which are discussed as per OECD guidelines. Both acute and subacute toxicity studies are given special emphasis. PMID- 26939271 TI - In Vivo Antioxidant Assays. AB - Oxidative stress and antioxidant deficiency have been implicated in the pathophysiology of a wide range of diseases and conditions. Consequently, over recent years many different supplementation trials have been implemented, aimed at improving clinical outcomes by boosting antioxidant levels. These trials included supplementation with individual antioxidants, antioxidant combinations, and antioxidant-rich foods such as fruit and vegetable juices and other plant extracts. To ensure that data from these trials are interpreted correctly, it is essential that suitable biomarkers are used to assess changes in in vivo antioxidant activity resulting from supplementation. Therefore, the measurement of antioxidant systems, such as superoxide dismutase, catalase, glutathione reductase, and status of other molecules in biological fluids with their quantification methods are simplified in this chapter. PMID- 26939272 TI - Analgesic Activity. AB - Analgesics are agents which selectively relieve pain by acting in the CNS and peripheral pain mediators without changing consciousness. Analgesics may be narcotic or non-narcotic. The study of pain in animals raises ethical, philosophical, and technical problems. Both peripheral and central pain models are included to make the test more evident for the analgesic property of the plant. This chapter highlights methods such as hot plate and formalin and acetic acid-induced pain models to check the analgesic activity of medicinal plants. PMID- 26939273 TI - Anti-inflammatory Activity. AB - Inflammation is the body's first response to infection or injury and is critical for both innate and adaptive immunity. It can be considered as part of the complex biological response of vascular tissues to harmful stimuli such as pathogens, damaged cells, or irritants. The search for natural compounds and phytoconstituents that are able to interfere with these mechanisms by preventing a prolonged inflammation could be useful for human health. Here, the anti inflammatory properties of plant-based drugs are put together with both in vitro and acute (carrageenan, egg albumin and croton oil) and chronic (cotton pellet) in vivo models. PMID- 26939274 TI - Antipyretic Activity. AB - The concept regarding the pathogenesis of pyrexia is almost exclusively concentrated on humoral mediatory mechanism. As per these views, exogenous pyrogens first persuade the formation of pyrogenic cytokines and these endogenous pyrogens order to increase the synthesis of prostaglandin E in different structures of the central nervous system (CNS). The subsequent alterations of CNS functions are reflected in the modifications of peripheral thermoregulatory effector functions, which hoist body temperature during the development of fever and maintain it during the whole fever course. Brewer's yeast-induced pyrexia model has been furnished in the chapter. PMID- 26939275 TI - Inflammatory Bowel Disease. AB - Inflammation response plays an important role in host survival, and it also leads to acute and chronic inflammatory diseases such as rheumatoid arthritis, bowel diseases, allergic rhinitis, asthma, atopic dermatitis and various neurodegenerative diseases. During the course of inflammation, the ROS level increases. In addition to ROS, several inflammatory mediators produced at the site lead to numerous cell-mediated damages. Inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease, is a chronic intestinal disorder resulting from a dysfunctional epithelial, innate and adaptive immune response to intestinal microorganisms. The methods involving indomethacin-induced enterocolitis in rats with macroscopic changes of IBD, myeloperoxidase assay, microscopic (histologic) characters and biochemical parameters are discussed. PMID- 26939277 TI - Anti-diarrhoeal Activity. AB - Diarrhoea is characterized by an increase in the frequency of bowel movements, wet stool and abdominal pains. It is the world's third highest killer disease, contributing substantially to paediatric morbidity and mortality, especially in the malnourished. Antibiotics used as anti-diarrhoeal drugs sometimes provoke adverse effects and microorganisms tend to develop resistance towards them. Therefore, the search for safe and more effective agents from plant origin using standard protocols of charcoal meal-induced diarrhoea has been defined in this chapter. PMID- 26939276 TI - In Vitro Anti-arthritic Activity. AB - Formaldehyde-induced arthritis and complete Freund's adjuvant (CFA)-induced arthritis in rats are well-known models to determine the anti-arthritic activity. Arthritis is a symptom of chronic inflammation. It is a chronic progressive disorder, developing over months or years and involving essentially the synovial joints of the body. Hence, these two models become the basis of this chapter to analyse the anti-arthritic activity. PMID- 26939278 TI - Anti-ulcer Activity. AB - This chapter explains the procedure of ethanol-induced ulcer to check the protective effect of drugs over induced ulcer in rats. Ulcer is defined as the erosion in the lining of the stomach or duodenum and is caused by the disruptions of the gastric mucosal defence and repair systems. Ulceration of stomach is called gastric ulcer and that of duodenum is called duodenal ulcer and together peptic ulcer. In clinical practice, peptic ulcer is one of the most prevalent gastrointestinal disorders, which commonly occurs in developed countries. PMID- 26939279 TI - Hepatoprotective Activity. AB - The liver performs a vital role in metabolism, secretion, storage, and detoxification of endogenous and exogenous substances. Oxidative stress and free radicals enhance the severity of hepatic damage, which can be overcome by the antioxidant mechanism. Plant extracts can be the best source of such antioxidants and mediate hepatoprotective activity. In this chapter, high-dose paracetamol induced hepatotoxicity in rat model is discussed with explanations of biochemical and histopathological studies. PMID- 26939280 TI - Anti-diabetic Activity. AB - The hyperglycaemia continues to be a major health problem in India and other developing countries. This imbalance of blood glucose causes serious health problems such as damages to the blood vessel, poor healing of wounds, retinal damage, renal damage--kidney failure. The in vitro enzyme models and evaluation of hypoglycaemic effect of sample on normal and glucose-loaded rats has been used as a prediction experiment in this chapter before going for anti-diabetic experiment using animal models. PMID- 26939281 TI - Evaluation of Anti-diabetic Property on Streptozotocin-Induced Diabetic Rats. AB - The diabetes-inducing agent streptozotocin (STZ) is a glucosamine-nitrosourea compound produced by Streptomyces achromogenes, which specifically induces DNA strand breakage in beta-cells causing diabetes mellitus. The destruction of pancreatic beta-cells by STZ is associated with a huge release of insulin in their first phase, and then in the second phase, the destruction has lead to deficiency of insulin causes hyperglycaemia. A detailed method on selection of diabetic animals, investigation of blood glucose levels, body weight, biochemical and histopathological parameters is presented in this chapter. PMID- 26939282 TI - In Vivo Wound Healing Studies. AB - Wound healing has emerged as a major treatment issue which has provoked the development of drugs that can improve the healing process. Studies using plant drugs have revealed many interesting results about existing commercial drugs. Effective wound healing leads to the restoration of tissue integrity and occurs through a highly organized multistage. Use of plant-derived medicines against excision, incision, and dead space models accelerates the wound healing process, which is briefly discussed in a manner to be followed easily during experimental sessions. PMID- 26939283 TI - Determination of Cytotoxicity. AB - Cytotoxicity assays are used for drug screening and cytotoxicity tests of chemicals. Nowadays, various reagents are used for cell viability detection. They are based on various cell functions such as enzyme activity, cell membrane permeability, cell adherence, ATP production, co-enzyme production and nucleotide uptake activity. Many have established methods such as colony formation method, crystal violet method, tritium-labelled thymidine uptake method, MTT and WST methods, which are used for counting the number of live cells. Moreover, trypan blue is a widely used assay for staining dead cells. In this method, cell viability must be determined by counting the unstained cells with a microscope or other instruments. This chapter is a collection of all these methods to be followed by researchers in a sequential manner. PMID- 26939284 TI - Induction of Apoptosis. AB - The apoptotic activity of plants is checked to confirm its anti-tumour and anti cancer activity. Apoptosis is a specific process that leads to intrinsic programmed cell death which is essential in the homeostasis of normal tissues of the body and occurs in various physiological and pathological situations. Method to check apoptosis in EAC cells and DNA analysis are featured in this chapter as a preliminary test manner. PMID- 26939285 TI - Anti-tumour Activity. AB - Experimental tumours have great importance for the purposes of modelling where Dalton's ascites lymphoma (DAL) and Ehrlich ascites carcinoma (EAC) are the commonest. It appeared firstly as a spontaneous breast cancer in a female mouse and then Ehrlich and Apolant (Berlin KlinWshr 28:871-874, 1905) used it as an experimental tumour by transplanting tumour tissues subcutaneously from mouse to mouse. In 1932, Loewenthal and Jahn obtained the liquid form in the peritoneum of the mouse and named it as 'Ehrlich ascites carcinoma' due to the ascites liquid, together with the carcinoma cells. In this chapter, two most common tumour cells (EAC and DAL) are chosen and protocol has been framed to determine the antitumor activity. PMID- 26939286 TI - Protein Bioavailability in Animal Model. AB - All the nutrients in food are not absorbed by our system. The relative amount of nutrition from an administered dosage through which it enters the system of circulation and the rate at which the level of nutrition appears in the systemic circulation is called 'bioavailability'. Although plant foods have high nutrient contents our digestion system cannot absorb it fully. Hence, it becomes necessary to determine the bioavailability of the administered sample to check the overall effect on the living system. Animal food preparation, protein bioavailability in animal model, food efficiency, apparent digestibility, protein digestibility tests, etc., are mentioned in well explained methodologies. PMID- 26939287 TI - Detection of Phenolic and Flavonoid Compounds Using High Performance Thin Layer Chromatography (HPTLC). AB - High performance thin layer chromatography (HPTLC) is a sophisticated instrumental technique based on the full capabilities of thin layerchromatography. The advantages of automation, scanning, full optimization, selective detection principle, minimum sample preparation,hyphenation, etc., enable it to be a powerful analytical tool for chromatographic information of complex mixtures of inorganic, organic andbiomolecules which are characterized in this chapter. PMID- 26939288 TI - Isolation of Compounds. AB - Plants are the storehouse of many chemical compounds that possess various biological activities. Identification of these compounds becomes critical in understanding the exact mechanism behind the therapeutic potential of these plants. Screening and isolation of compounds from plants important to human health involves various methods that need careful handling and attention. A detailed method of isolation using thin layer chromatography (TLC) and column is explained. PMID- 26939289 TI - Molecular Docking of Bioactive Compounds Against BRCA and COX Proteins. AB - The focus of molecular docking is to computationally simulate the molecular recognition process. A binding interaction between a small molecule ligand and protein may result in activation or inhibition of the protein. The docking method using BRCA1 or BRCA2 genes and COX proteins is carefully texted in this chapter to check docking of the best inhibitor molecule. PMID- 26939291 TI - New MRI Equipment at a Rural Hospital. PMID- 26939292 TI - Site Neutral Payment Gaining Traction on Capitol Hill. PMID- 26939293 TI - Streamlining Throughput with the Implementation of a CT Coordinator. AB - Imaging departments today are challenged with streamlining processes to keep up with advancements in healthcare, the increasing complexity of imaging studies and procedures, and bundling of charges for services rendered. Ordering providers are often required to get insurance pre-authorizations for imaging orders, and what is pre-authorized must be the study/procedure performed or reimbursement is not guaranteed. Insurance companies have inhibited radiologists from providing optimal service by placing restrictions on changing orders per radiologist protocol to best meet the individual needs of each patient. Many healthcare systems that are using a central scheduling model are losing money due to scans and procedures being inappropriately ordered and pre-authorized. Implementing a computed tomography (CT) coordinator can streamline throughput of imaging services in radiology departments. The CT improvement project described here used a Lean methodology Plan-Do-Check-Act (PDCA) approach to increase the effectiveness of an organization's ability to maximize process efficiency and revenue. PMID- 26939294 TI - Don't Ever Devalue Your Product. PMID- 26939295 TI - An Onboarding Program for the CT Department. AB - Healthcare organizations compete for employees in the same way television networks compete for new talent. Organizations also compete over experience, knowledge, and skills new employees bring with them. Organizations that can acclimate a new employee into the social and performance aspects of a new job the quickest create a substantial competitive advantage. Onboarding is the term used for orientation or organizational socialization where new employees acquire the necessary knowledge, skills, and behaviors to fit in with a new company. Computed tomography (CT) department specific onboarding programs increase the comfort level of new employees by informing them of the supervisor's and the department's expectations. Although this article discusses CT, specifically, an onboarding program could apply to all of imaging. With the high costs that employee turnover incurs, all departments should have an orientation program that helps retain employees as well as prepare new employees for employment. Current personnel are valuable resources for offering appropriate information for successful employment in specific departments. A structured, department specific onboarding program with the full participation and support of current staff will enhance staff retention. PMID- 26939296 TI - Top Ten List for 2016. AB - These ten items should cover many of the key issues impacting imaging. Every organization should create their own list on an annual basis and update it quarterly. Ensuring compliance with the myriad coding, reimbursement, and regulatory requirements is ongoing. Embrace the challenge, don't get discouraged and know that your efforts make a difference! PMID- 26939297 TI - ICD-10: Bone Density Revisited. PMID- 26939298 TI - Improving HCAHPS Scores with Advances in Digital Radiography. AB - The imaging department can be instrumental in contributing to a healthcare facility's ability to succeed in this new era of competition. Advances in DR technology can improve patient perceptions in the imaging department by improving efficiencies and outcomes which, in turn, can ultimately bolster overall HCAHPS scores. Specific areas for improved scores by utilization of DR include nurse communication, doctor communication, pain management, and communication about medication. Value based purchasing brought with it a mandate for hospitals to track key metrics, which requires an investment in time, tools, and human resources. However, this mandate also presents hospitals and imaging departments, with an opportunity to leverage those very metrics to better market their facilities. PMID- 26939300 TI - Leadership with Love. PMID- 26939299 TI - Changing the Culture. PMID- 26939301 TI - IMPLANTATION OF THE KNEE JOINT ENDOPROSTHESIS. PMID- 26939302 TI - BONE-PATELLAR TENDON-BONE GRAFT PREPARATION TECHNIQUE TO INCREASE CROSS-SECTIONAL AREA OF THE GRAFT IN ANTERIOR CRUCIATE LIGAMENT RECONSTRUCTION. AB - INTRODUCTION: Not much has changed in the way the bone-patellar tendon-bone graft is prepared before implantation. We present a modified bone-patellar tendon-bone graft preparation technique by implying the increased cross-sectional area. MATERIAL AND METHODS: Measurements of bone-patellar tendon-bone graft were made during the reconstruction of the anterior cruciate ligament in 93 male patients. The bone part of bone-patellar tendon-bone graft 10 mm wide and the tendon part 12-14 mm wide was placed on the holder with a handle in a way which allowed sewing the edges of the patellar tendon in a shape of a tube. The circumference of the central part of the graft was measured using a suture tightened around the graft. The diameters of the circle and cross-sectional areas were then calculated using geometrical calculation. RESULTS: After preparation of the bone-patellar tendon-bone graft, the fol- lowing measures were recorded: the circumference of 30 mm, the diameter of 9.55 mm, and the cross-sectional area of 72 mm2 in 9 patients; the circumference of 31mm, the diameter of 9.87 mm, and the cross sectional area of 76 mm2 in 15 patients, and the circumference of 32 mm, the diameter of 10.19 mm, and the cross-sectional area of 82 mm2 in 69 patients. CONCLUSION: For the average thickness (3-5 mm) and width (10 mm) of the patellar tendon graft, the cross-sectional area will be 30-50 mm2. The modified bone patellar tendon-bone graft preparation technique made it possible to increase its cross-sectional area to 71-81 mm2. PMID- 26939303 TI - DIAGNOSTIC ROLE OF FLUORINE-18 (18F) FLUORODEOXYGLUCOSE POSITRON EMISSION TOMOGRAPHY COMPUTED TOMOGRAPHY IN DETECTING RECURRENT DISEASE IN PATIENTS WITH COLORECTAL CANCER AND ELEVATED CARCINOEMBRYONIC ANTIGEN. AB - INTRODUCTION: Early detection of recurrence is an important factor for long term survival of patients with colorectal cancer. Measurement of serum levels of carcinoembryonic antigen has been commonly used in the postoperative surveillance of colorectal cancer. The purpose of this study was to evaluate the ability of positron emission tomography-computed tomography to detect pathological substrate of elevated serum carcinoembryonic antigen in patients with colorectal cancer. MATERIAL AND METHODS: The patients with colorectal cancer who underwent curative surgical resection and/ or chemotherapy, who were found in our database, were analyzed retrospectively. Forty-eight 18F-fluorodeoxyglucose positron emission tomography-computed tomography studies including 45 patients (14 women, 31 men; mean age: 62.93 years) with elevated serum, carcinoembryonic antigen levels, which had been performed between January 2011 and January 2014, were evaluated. Serum levels of carcinoembryonic antigen were measured within 3 months after positron emission tomography-computed tomography examination. Final diagnosis of recurrence was made by histopathological findings, radiology studies or clinical follow-up. RESULTS: Recurrences were diagnosed in 37 patients, the prevalence being 77.1%. Liver metastases were found in 18 patients, abdominal, pelvic and/or mediastinal lymph nodes were positive in 19 patients, 11 patients had loco regional recurrences and 4 patients had pulmonary metastasis, and bone metastases were found in one patient. One patient was diagnosed with metastasis in scar tissue. The overall sensitivity and specificity of positron emission tomography computed tomography was 90.24% and 71.42%, respectively. The positive and negative predictive values were 94.87% and 55.56%, respectively. CONCLUSION: 18F fluorodeoxyglucose positron emission tomography-computed tomography is a powerful tool that could be used in determining colorectal cancer recurrence in patients with elevated carcinoembryonic antigen levels and could have an important clinical impact on the management in patients with suspected recurrent colorectal cancer. PMID- 26939304 TI - KNOWLEDGE AND ATTITUDES OF HEALTH CARE SCIENCE STUDENTS TOWARD OLDER PEOPLE. AB - INTRODUCTION: Education of health science students in geriatrics is important in order to provide optimal care for the growing number of elderly people because it is the attitudes of health professionals toward the elderly that play the key role in the quality of care provided. Therefore, the aim of this study was to assess the knowledge and attitudes of health care science students towards ageing and care for the elderly. MATERIAL AND METHODS: The present cross-sectional study was carried out on a sample of 130 students (medical, nursing and special education and rehabilitation) of the Faculty of Medicine, University of Novi Sad. The students were divided into two groups. The first group (E) included students having been taught geriatrics and nursing older adults and the other group (C) included students who had not been trained in this subject. The authors used Palmore's facts on Ageing Quiz for the knowledge evaluation and Kogan's Attitude toward Older People Scale for the attitude evaluation. RESULTS: The results of Facts on Aging Quiz showed the average level of students' knowledge and statistically significant difference between E and C group. The analysis of Kogan's Attitudes toward Old People Scale showed that both groups had neutral attitudes toward older people. Furthermore, a positive correlation between students' knowledge and attitudes was found. CONCLUSION: There is increasing evidence on the correlation between education, knowledge and attitudes toward older people which suggests that by acquiring better insights into all aspects of ageing through their education the students develop more positive attitudes and interest in working with older adults. PMID- 26939305 TI - THE ROLE OF NUTRITION IN CARIES PREVENTION AND MAINTENANCE OF ORAL HEALTH DURING PREGNANCY. AB - INTRODUCTION: Pregnancy may pose an increased risk for the development of caries and other oral health problems. Continuous screening of oral health status, implementing appropriate preventive measures (particularly oral hygiene, healthy diet plans and education) is of paramount importance not only for oral health but also for the general health status of the future mother and her offspring. EFFECTS OF FOOD ON CARIES DEVELOPMENT: Caries prevention through healthy diet implicates the reduction in frequency and amount of intake of cariogenic food, above all ofrefined carbohydrates, i.e. sugars and sweets. Foods known to have caries-prophylactic effects should predominate in healthy diet plans. They mainly include solid foods, which have mechanical effects on teeth cleaning, as well as foods providing sufficient amounts of vitamins (A, C, D) and a variety of elements and compounds (calcium, phosphates, fluorides) favoring the preservation and remineralization of tooth structures. EDUCATION OF PREGNANT WOMEN ON HEALHY DEIT: In accomplishing these goals, education and direct positive communication between the educator and the pregnant woman play a crucial role. Educative approach is always individual and determined by the patient's specific cultural and socioeconomic features and status, as well as her habits, motivation and willingness to accept relevant recommendations. Accomplishing the aforementioned goals requires the appropriate organization and professional competence within the preventive dental service and its close cooperation with the relevant medical institutions and social support in the framework of public health protection. CONCLUSION: Preserving of oral health during pregnancy is predominantly influenced by the following factors: 1) healthy diet, 2) oral hygiene, 3) patients' education, 4) regular control of oral health, 5) appropriate organization of dental services and 6) community engagement. PMID- 26939306 TI - ENERGY SYSTEMS IN SURGERY. AB - INTRODUCTION: The systems of energy in surgery are applied in order to achieve better and more effective performing of procedures. Whereas various energy sources, including electricity, ultrasound, laser and argon gas, may be used, the fundamental principle involves tissue necrosis and hemostasis by heating. ELECTRO SURGERY: Electro Surgery is a surgical technique by which surgical procedures are performed by focused heating of the tissue using devices based on high-frequency currents. It represents one of the most frequently used energy systems in laparoscopy. ULTRASOUND ENERGY: The basic principle of operation of the ultrasound surgical instruments is the usage of low-frequency mechanic vibrations (ultrasound energy within the range of 20-60 kHz) for cutting and coagulation of tissue. LASER: Laser is the abbreviation for Light Amplification by Stimulated Emission of Radiation, aimed at increasing light by stimulated emission of radiation and it is the name of the instrument which generates coherent beam of light. ARGON PLASMA COAGULATION: It has been in use since 1991 for endoscopic hemostasis. It uses high-frequency electric current and ionized gas argon. The successful application of devices depends on the type of surgical procedure, training of the surgeon and his knowledge about the device. Surgeons do not agree on the choice of device which would be optimal for a certain procedure. CONCLUSION: The whole team in the operating room must have the basic knowledge of the way an energy system works so as to provide a safe and effective treatment of patients. The advantages and shortcomings of different systems of energy have to be taken into account while we use a special mode. PMID- 26939307 TI - CLINICAL CHARACTERISTICS AND TREATMENT OF MELKERSSON-ROSENTHAL SYNDROME--OVERVIEW OF SIX PATIENTS. AB - INTRODUCTION: Melkersson-Rosenthal syndrome is a rare disease of unknown etiology. Histopathologically, it presents as granulomatous cheilitis. From laboratory aspect, it is a nonspecific, differential diagnostically and therapeutically complex condition. CASE REPORT: This is a report of six cases treated at the Department of Allergology and Immunology of the Clinical Center of Serbia, who had presented with the referral diagnosis of recurring or persistent lip edema, and who were diagnosed with Melkersson-Rosenthal syndrome upon detailed evaluation. Three patients had complete triad of symptoms, two had the oligosymptomatic form and one manifested the monosymptomatic form of the disease. Histopathological findings of the oral mucosa specimens verified the presence of non-necrotic epithelioid granulomas in all patients. The patients were treated with the H1 and H2 antihistamines, corticosteroids, followed by anabolic drugs and antibiotics, resulting in transient and unfavorable effects. CONCLUSION: In differential diagnosis, Melkersson-Rosenthal syndrome diagnosis primarily refers to conditions of angioneurotic edema and hereditary angioedema, as well as granulomatous diseases such as sarcoidosis, tuberculosis and Chron's disease. It is necessary to follow-up these patients in view of monitoring the effects of the therapy and possible development of systemic granulomatous diseases. PMID- 26939309 TI - PENTALOGY OF CANTRELL IN TWINS: A CASE REPORT. AB - INTRODUCTION. Pentalogy of Cantrell is a very rare congenital multiple malformation with the poor outcome. Syndrome included the following pentad: abdominal wall defect, a defect of the lower sternum, anterior diaphragm defect, ectopia cordis, as well as a variety of intracardiac anomalies. CASE REPORT: In the fifteenth week of the twin pregnancy, ultrasound examination showed multiple anomalies in one, as well as the absence of the nose apex in the other twin. The autopsy of the fetuses was performed after the abortion had been approved by the Ethics Committee. The external examination of the fetus number one showed ectopic heart and omphalocele. The internal examination revealed the existence of sternum cleft, ectopic heart and part of the left lung outside the thoracic cavity, the presence of diaphragmatic hernia with protrusion of abdominal organs, heart with only one large vessel and the horseshoe kidney. The full expression of the Pentalogy of Cantrell was confirmed. The external and internal examination of the other twin showed just agenesis of the nose apex. CONCLUSION: Recognition and diagnosis of the syndrome is of the exceptional importance. Proper and timely diagnosis should contribute to good outcome of the pregnancy and delivery. PMID- 26939308 TI - MANAGEMENT OF A DISTAL FEMORAL NON-UNION WITH COEXISTING FAILURE OF THE KNEE EXTENSOR MECHANISM USING OSTEOBRIDGE KNEE-ARTHRODESIS SYSTEM--A CASE REPORT. AB - INTRODUCTION: Reconstruction of bone defects is a long, challenging process both for the patient and for the treating surgeon. Bone defects frequently occur as a result of aggressive surgical debridement and bone resection in case of acute trauma, open fractures, chronic bone infections, tumors and non-unions. Early amputation is often superior to prolonged attempts at salvage because they can create serious problems in the patients' lives. There are numerous alternative methods of limb-salvage nowadays. CASE REPORT: We report a case of a fifty-year old man with a distal femoral non-union and a co-existing failure of the knee extensor mechanism, who was treated using an intramedullary segmental defect bridging knee arthrodesis system (Osteobridge). At the final check-up twenty four months later, he had excellent clinical, functional and radiological results. CONCLUSION: Osteobridge is an excellent knee arthrodesis system, which is preferable to other methods in case of resection of the distal femur along with the failure of the knee extensor mechanism. PMID- 26939310 TI - LEIOMYOSARCOMA OF THE COLON. AB - INTRODUCTION: Gastrointestinal stromal tumors are the most common mesenchymal tumors of the digestive tract. Leiomyosarcomas of the gastrointestinal tract are rare mesenchymal neoplasms which grossly and histologically resemble gastrointestinal stromal tumors. They may be differentiated from gastrointestinal stromal tumors by using immunohistochemistry and they are typically positive for a smooth muscle actin and desmin and negative for c-kit, CD34 and DOG1.1. They often express calponin and h-caldesmon. CASE REPORT: We present a case of a 59 year-old male with anemia, weight loss, intermittent abdominal pain and right abdominal mass. Colonoscopy revealed an exophytic ulcerated neoplastic mass in the ascending colon and abdominal computed tomography scan showed an ill-defined heterogeneous tumor mass which surrounded almost the whole ascending colon. The patient underwent right hemicolectomy and partial resection of ileum. Histopathological examination revealed a leiomyosarcoma composed of atypical spindle cells positive for a smooth muscle actin, desmin and vimentin, and negative for c-kit, CD34, S100 and neuron specific enolase. The patient is alive 8 months after the operation, undergoing chemotherapy. CONCLUSION: We have concluded that the multimodal approach comprising chemotherapy and complete surgical resection controls the leiomyosarcomas. PMID- 26939311 TI - COLITIS AND "DIAPHRAGM DISEASE" OF THE COLON IN HEMODIALYSIS PATIENT DUE TO PROLONGED USE OF NON-STEROIDAL ANTI-INFLAMMATORY DRUG. AB - INTRODUCTION: The use of non-steroidal anti-inflammatory drugs may lead to stricture of the small intestine and less frequently of the colon. Colonic strictures have not been described in patients on dialysis and the aim of this report is to show the case of dialysis patient who was followed for recurrent and prolonged diarrhea. CASE REPORT: We present the patient on chronic dialysis for 15 years who used non-steroidal anti-inflammatory drugs due to chronic pain and who developed recurrent diarrhea. Diagnosis was made by endoscopy and confirmed by histology. Specific therapy was applied with a good response. CONCLUSION: Although not described in the literature, non-steroidal anti-inflammatory drug induced colitis and/or diaphragm disease could be a potential reason for recurrent or prolonged diarrhea in dialysis patients. PMID- 26939312 TI - FIXED OR REMOVABLE APPLIANCE FOR EARLY ORTHODONTIC TREATMENT OF FUNCTIONAL ANTERIOR CROSSBITE. AB - Anterior crossbite with functional shift also called pseudo Class III is a malocclusion in which the incisal edges of one or more maxillary incisors occlude with the incisal edges of the mandibular incisors in centric relationship: the mandible and mandibular incisors are then guided anteriorly in central occlusion resulting in an anterior crossbite. Early correction, at the mixed dentition stage, is recommended, in order to avoid a compromising dentofacial condition which could result in the development of a true Class III malocclusion and temporomandibular symptoms. Various treatment options are available. The method of choice for orthodontic correction of this condition should not only be clinically effective, with long-term stability, but also cost-effective and have high patient acceptance, i.e. minimal perceived pain and discomfort. At the mixed dentition stage, the condition may be treated by fixed (FA) or removable appliance (RA). To date there is insufficient evidence to determine the preferred method. The overall aim of this thesis was therefore to compare and evaluate the use of FA and RA for correcting anterior crossbite with functional shift in the mixed dentition, with special reference to clinical effectiveness, stability, cost-effectiveness and patient perceptions. Evidence-based, randomized controlled trial (RCT) methodology was used, in order to generate a high level of evidence. The thesis is based on the following studies: The material comprised 64 patients, consecutively recruited from the Department of Orthodontics, Faculty of Odontology, Malmo University, Sweden and from one Public Dental Health Service Clinic in Malmo, Skane County Council, Sweden. The patients were no syndrome and no cleft patients. The following inclusion criteria were applied: early to late mixed dentition, anterior crossbite affecting one or more incisors with functional shift, moderate space deficiency in the maxilla, no inherent skeletal Class III discrepancy, ANB angle > 0 degrees, and no previous orthodontic treatment. Sixty-two patients agreed to participate and were randomly allocated for treatment either with FA with brackets and wires, or RA, comprising acrylic plates with protruding springs. Paper I compared and evaluated the efficiency of the two different treatment strategies to correct the anterior crossbite with anterior shift in mixed dentition. Paper II compared and evaluated the stability of the results of the two treatment methods two years after the appliances were removed. In Paper III, the cost-effectiveness of the two treatment methods was compared and evaluated by cost-minimization analysis. Paper IV evaluated and compared the patient's perceptions of the two treatment methods, in terms of perceived pain, discomfort and impairment of jaw function. The following conclusions were drawn from the results: Paper I. Anterior crossbite with functional shift in the mixed dentition can be successfully corrected by either fixed or removable appliance therapy in a short-term perspective. Treatment time for correction of anterior crossbite with functional shift was significantly shorter for FA compared to RA but the difference had minor clinical relevance. Paper II. In the mixed dentition, anterior crossbite affecting one or more incisors can be successfully corrected by either fixed or removable appliances, with similarly stable outcomes and equally favourable prognoses. Either type of appliance can be recommended. Paper III. Correction of anterior crossbite with functional shift using fixed appliance offers significant economic benefits over removable appliances, including lower direct costs for materials and lower indirect costs. Even when only successful outcomes are considered, treatment with removable appliance is more expensive. Paper IV. The general levels of pain intensity and discomfort were low to moderate in both groups. The level of pain and discomfort intensity was higher for the first three days in the fixed appliance group, and peaked on day two for both appliances. Adverse effects on school and leisure activities as well as speech difficulties were more pronounced in the removable than in the fixed appliance group, whereas in the fixed appliance group, patients reported more difficulty eating different kinds of hard food. Thus, while there were some statistically significant differences between patients' perceptions of fixed and removable appliances but these differences were only minor and seems to have minor clinical relevance. As fixed and removable appliances were generally well accepted by the patients, both methods of treatment can be recommended. PMID- 26939314 TI - [Case of constipation]. PMID- 26939313 TI - [Impacts on asthma at persistent stage and immune function in the patients treated with acupuncture for warming yang and benefiting qi]. AB - OBJECTIVE: To compare the difference in clinical efficacy on bronchial asthma at chronic persistent stage between acupuncture for warming yang and benefiting qi and seretide. METHODS: One hundred and eighty patients of bronchial asthma at chronic persistent stage were randomized into an acupuncture group and a western medication group, 90 cases in each one. In the acupuncture group, acupuncture for warming yang and benefiting qi was applied at Dazhui (GV 14), Feishu (BL 13), Danzhong (CV 17), Dingchuan (EX-B 1), Jianshi (PC 5), Zhigou (TE 6), Taixi (KI 3) and Zusanli (ST 36), once every two days. In the western medication group, inhalation therapy with seretide was applied, 1 to 2 inhalations each time, twice a day. The treatment for 20 days was as one session in the two groups, at the intervals of 2 days after each session. Four sessions of treatment were required. The immune function indices were observed before and after treatment in the patients of two groups, named immunoglobulin IgG, IgM and IgE; peripheral T lymphocytes (CD3+), helper T lymphocytes (CD4+), inhibitory T lymphocytes (CD8+) and the ratio of CD4+ and CD8+; as well as the pulmonary ventilation function indices, named maximum pulmonary expiratory flow (PEF), forced expiratory volume in one second (FEV1) and forced vital capacity (FVC). The clinical efficacy was compared between the two groups. RESULTS: The total effective rate was 93.3% (84/90) in the acupuncture group, better than 88.9% (80/90) in the western medication group (P < 0.05). After treatment, the immune function indices and pulmonary ventilation function indices were apparently improved as compared with those before treatment in the two groups (all P < 0.05). The improvements in the acupuncture group were much more significant (all P < 0.05). CONCLUSION: Acupuncture for warming yang and benefiting qi effectively controls the symptoms of bronchial asthma at chronic persistent stage and improves immune and pulmonary functions. The efficacy is better than that of seretide. PMID- 26939315 TI - [Constipation predominant irritable bowel syndrome treated with acupuncture for regulating the mind and strengthening the spleen: a randomized controlled trial]. AB - OBJECTIVE: To observe the clinical efficacy on constipation predominant irritable bowel syndrome (IBS-C) treated with acupuncture for regulating the mind and strengthening the spleen and the impacts on the quality of life in the patients. METHODS: Sixty patients of IBS-C were randomized into two groups. In the acupuncture group (30 cases), acupuncture was applied to Tianshu (ST 25), Zusanli (ST 36), Shangjuxu (ST 37), Taichong (LR 3), Sanyinjiao (SP 6), Yintang (GV 29) and Baihui (GV 20), once a day, 5 treatments a week and 4 weeks treatment as one session. In the western medication group (30 cases), lactulose oral solution was prescribed, 15 mL each time, three times a day, 4 weeks treatment as one session. The symptom grade scale and the quality of life scale (IBS-QOL) were adopted to observe the changes in clinical symptoms and quality of life before treatment, after treatment and 2-month follow-up after treatment in the patients of the two groups separately. RESULTS: (1) Clinical symptom score: the difference in the symptom score at each time point was significant statistically in intra-group comparison (P < 0.01). In 1 week, 4 weeks of treatment and 2 months after treatment, the clinical symptom scores in the acupuncture group were lower than those in the western medication group (P < 0.05, P < 0.01). (2) IBS-QOL score after treatment was improved as compared with that before treatment in the two groups (P < 0.01). The improvement of IBS-QOL at 2 months after treatment in the acupuncture group was apparently superior to the western medication group (P < 0.05). (3) The total effective rate was 90.0% (27/30) in the acupuncture group and was 83.3% (25/30) in the western medication group. The overall efficacy in the acupuncture group was better than that in the western medication group (P < 0.01). CONCLUSION: Acupuncture for regulating the mind and strengthening the spleen significantly relieves the clinical symptoms of IBS-C and improves QOL of patients. The total efficacy is superior to lactulose oral solution and presents a certain of long-term efficacy. PMID- 26939316 TI - [Clinical research of post-stroke motor aphasia treated with acupoint application of jieyu plaster combined with acupuncture]. AB - OBJECTIVE: To compare the difference in clinical efficacy on post-stroke motor aphasia among the combined therapy of acupoint application of jieyu plaster and acupuncture, simple acupuncture and simple acupoint application of jieyu plaster. METHODS: Eighty-six patients of post-stroke motor aphasia were randomized into an acupuncture group (28 cases) , an acupoint application gruop (29 cases) and the combined therapy group (29 cases). In the acupuncture group, acupuncture was applied at the Speech No. 1 area and three-tongue needling points, once a day, 6 times a week. In the acupoint application group, jieyue plaster was applied to Yongquan (KI 1) and Laogong (PC 8), once a day, and the bilateral acupoints were selected alternatively. In the combined therapy group, the therapeutic methods of the first two groups were used in combination. The treatment lasted for 4 weeks in the three groups. The speech function score was observed and compared before and after treatment in the three groups and the efficacy was compared among the three groups. RESULTS: The total effective rate was 86.2% (25/29) in the combined therapy group, which was better than 67.9% (19/28) in the acupuncture group and 69.0% (20/29) in the acupoint application group (both P < 0.05). After treatment, the scores of spontaneous conversation, restatement and nomenclature in the speech function were all improved as compared with those before treatment in the three groups (all P < 0.01). The results in the combined therapy group were apparently better than those in the acupuncture group and the acupoint application group (all P < 0.01). CONCLUSION: The combined therapy of acupoint application of jieyu plaster and acupuncture apparently improves the speech function in the treatment of post-stroke motor aphasia and the efficacy is better than that of simple acupuncture or simple acupoint application. PMID- 26939317 TI - [Floating needling reperfusion for 32 cases of periarthritis of shoulder]. PMID- 26939318 TI - [Life quality improvement of spastic hemiplegia of stroke treated with fire needle: a randomized controlled trial]. AB - OBJECTIVE: To observe the life quality improvement of spastic hemiplegia of stroke treated with fire-needle. METHODS: Sixty patients were randomly divided into a fire-needle group and a rehabilitation group, 30 cases in each one. In the two groups, the conventional treatment of neurology and rehabilitation strengthening limbs function were applied. In the fire-needle group, fire-needle was used at Jianyu (LI 15), Binao (LI 14), Quchi (LI 11), Yanglingquan (GB 34), Xuehai (SP 10) and Sanyinjiao (SP 6), etc. , once two days and continuously for 30 days (15 times). In the rehabilitation group, conventional rehabilitation exercises were given five times a week for 4 weeks (20 times). Before treatment, at the end of treating program and one month later after treatment, spasticity of upper and lower limbs was assessed by Ashworth scale and clinic spasticity index (CSI); limbs function was evaluated by Fugl-Meyer (FM) scale; life quality was estimated by patient-reported outcome (PRO). Clinical effects were compared between the two groups. RESULTS: (1) At the end of treating and one month later after treatment, the Ashworth scales were better than those before treatment in the two groups (P < 0.05, P < 0.01), and the scales of the fire-needle group were superior to those at the same time of the rehabilitation group (both P < 0.05). (2) At the end of treating and one month later after treatment, the CSIs were better than those be fore treatment in the fire-needle group (both P < 0.01), but not changed apparently in the rehabilitation group (both P > 0.05). And the indices of the fire-needle group were superior to those at the same time of the rehabilitation group (P < 0.05, P < 0.01). (3) The FM scales of upper and lower limbs at the end of treating and one month later after treatment were better than those before treatment in the two groups (all P 0.01), except the lower limbs at the end of treating in the rehabilitation group (P > 0.05). The FM scales of the fire-needle group were superior to those at the same time of the rehabilitation group (P < 0.05, P < 0.01). (4) At the end of treating and one month later after treatment, the PRO scales were better than those before treatment in the two groups (all P < 0.01), and the scales of the fire-needle group were superior to those at the same time of the rehabilitation group (P < 0.05, P < 0.01). CONCLUSION: Fire-needle can effectively relieve spastic hemiplegia of stroke, and improve limbs motor function and life quality. It is better than rehabilitation. PMID- 26939319 TI - [Case of syncope induced by dysmenorrhea]. PMID- 26939320 TI - [Acupuncture-moxibustion for chronic allograft nephropathy: a randomized controlled trial]. AB - OBJECTIVE: To observe the effects of acupuncture-moxibustion on chronic allograft nephropathy (CAN) and explore the methods of acupoint selection along meridian for transplanted-kidney-related diseases. METHODS: A total of 180 patients of CAN were randomized into a syndrome differentiation group, a spleen-meridian group, a kidney-meridian group and a control group, 45 cases in each one. A total of 33 cases dropped out before the end of the study, including 8 cases in the syndrome differentiation group, 12 cases in the spleen-meridian group, 13 cases in the kidney-meridian group and no case in the control group. Patients in the control group were treated with conventional western medicine; based on this, patients in other three groups were treated with acupuncture-moxibustion. In the syndrome differentiation group, Qihai (CV 6), Hegu (LI 4), Guanyuan (CV 4), Feishu (BL 13), Shenshu (BL 23), etc. were selected for qi deficiency of lung and kidney; Qihai (CV 6), Zusanli (ST 36), Sanyinjiao (SP 6), Taixi (KI 3), Yinlingquan (SP 9), etc. were selected for deficiency of qi and yin; Ganshu (BL 18), Shenshu (BL 23), Sanyinjiao (SP 6), Taixi (KI 3), Yinlingquan (SP 9), Ququan (LR 8), etc. were selected for yin deficiency of liver and kidney; Zhongji (CV 3), Guanyuan (CV 4), Mingmen (GV 4), Guanyuanshu (BL 26), etc. were selected for yang deficiency of spleen and kidney. In addition, Sanyinjiao (SP 6), Diji (SP 8), Yinlingquan (SP 9), Xuehai (SP 10), etc. were added in the spleen-meridian group; Taixi (KI 3), Zhaohai (KI 6), Fuliu (KI 7), Ciliao (BL 32), etc: were added in the kidney-meridian group. Serum creatinine (Scr), creatinine clearance (Ccr) and 24-hour urinary protein before and after the treatment were com- pared among the four groups. RESULTS: After treatment, 24-hour urinary protein in the acupuncture moxibustion groups and control group were all reduced (all P < 0.05); compared before treatment, the Scr in the spleen-meridian group was significantly reduced (P < 0.05); the difference of Ccr before and after treatment was insignificant in all the groups (all P > 0.05). Compared with the control group, 24-hour urinary protein in spleen-meridian group could relieve or recover the damage of transplant kidney induced by CAN. A new interlink may be established between the transplanted kidneys and the spleen meridians, indicating that transplanted kidney-related diseases can be treated by selecting acupoints of spleen meridian. PMID- 26939321 TI - [Electroacupuncture combined with point-injection therapy for 30 cases of hyperprolaceinemia]. PMID- 26939322 TI - [Clinical research of lumbar strain of cold damp pattern treated with acupuncture with the consciousness conduction involved]. AB - OBJECTIVE: To compare the efficacy between the reducing technique with consciousness conduction involved and the reducing technique by needle rotation of acupuncture in the treatment of lunbar strain of cold damp pattern. METHODS: One hundred and eight patients were randomized into group A and group B, 54 cases in each one. Ashi points were the main points in the two groups. In the group A, the reducing technique with consciousness conduction involved was applied to ashi points. In the group B, the reducing technique with needle rotation was adopted. Cupping and the irradiation specific electromagnetic wave apparatus (TDP) were used in the two groups as the adjuvant therapy. The treatment was given once every two days, and 10 treatments made one session. The treatment stopped till pain disappeared. The efficacy was evaluated in 1 session of treatment. The numerical rating scale (NRS) and the Oswestry disability index (ODI) were observed before and at the end of treatment. NRS of acupuncture itself was observed at the end of treatment. The recurrence rate was compared between the two groups. RESULTS: The curative and remarkably effective rate was 87.0% (47/54) in the group A, better than 63.0% (34/54) in the group B (P < 0.01). After treatment, NRS and ODI scores were all reduced as compared with those before treatment in the two groups (both P < 0.01). The results in the group A were better than those in the group B (both P < 0.01). Three months after treatment, the recurrence rate was 3.8% (2/52) in the group A, better than 17.7% (9/51, P < 0.05) in the group B. Pain induced by acupuncture itself was mild in the two groups and NRS score in the group A was lower than that in the group B (P < 0.01). CONCLUSION: Acupuncture with the consciousness conduction involved is superior to the reducing technique with needle rotation in the treatment of lumbar strain of cold damp pattern, in which, pain induced by acupuncture itself is much milder than that induced by the reducing technique with needle rotation. PMID- 26939323 TI - [Impact of huolong moxibustion on TNF-alpha and pain degree in the patients of discogenic low back pain]. AB - OBJECTIVE: To discuss the impact of huolong moxibustion on pain degree in the patients of discogenic low back pain and the effect mechanism. METHODS: Sixty five patients were randomized into an observation group (33 cases) and a control group (32 cases). In the observation group, huolong moxibustion was applied along the distribution of the Governor Vessel, once a day. In the control group, the routine traction combined with massage therapy was adopted, once a day. In the two groups, the treatment was given 6 times a week, at interval of 1 day. In 3 weeks of treatment, pain score and serum tumor necrosis factor alpha (TNF-alpha) level were compared with those before treatment in the two groups. RESULTS: Compared with those before treatment, pain score and TNF-alpha level were reduced significantly after treatment in the two groups (both P < 0.05). The results in the observation group were lower than those in the control group (pain score: 1.95 +/- 0.61 vs 2.11 +/- 0.61; TNF-alpha: (1.33 +/- 0.30) nmol/L vs (1.55 +/- 0.48) nmol/L, (both P < 0.05). CONCLUSION: Huolong moxibustion significantly alleviates pain in the patients of discogenic low back pain and its effect mechanism is possibly relevant with TNF-alpha reducing. PMID- 26939324 TI - [Electro-nape-acupuncture for 33 cases of vocal cord paralysis]. PMID- 26939325 TI - [Moxibustion at Gaohuang (BL 43) for chronic fatigue syndrome: a randomized controlled trial]. AB - OBJECTIVE: To observe the clinical effect of chronic fatigue syndrome (CFS) treated with moxibustion at Gaohuang (BL 43). METHODS: With stratified block randomization, 72 patients accorded with inclusive criteria were divided into a moxibustion at Gaohuang (BL 43) group (moxibustion group) and an acupuncture group, 36 cases in each one. In the moxibustion group, Gaohuang (BL 43) was treated with big moxa cones as the main acupoint, 10 cones a time; Qihai (CV 6) and Zusanli (ST 36) were added with big moxa cones, 7 cones a time. In the acupuncture group, acupoints were the same as those in the moxibustion group, and twirling reinforcing method was used after qi arriving, 60 times one minute and 360 degrees with range. In the two groups, 10-day treatment was made into one course and there were two days between courses. The treatment was given once a day for 3 courses. Changes of fatigue assessment index (FAI) before and after treatment and clinical effects were observed. RESULTS: The total effective rate was 88.9% (32/36) in the moxibustion group, which was better than 72.2% (26/36) in the acupuncture group apparently (P < 0.05). After treatment in the two groups, FAI scores were obviously declined compared with those before treatment (both P < 0.01) and FAI score in the moxibustion group was apparently lower than that in the acupuncture group (P < 0.05). CONCLUSION: Moxibustion at Gaohuang (BL 43) can improve the FAI score of patients with CFS and the clinical efficacy is definite. PMID- 26939326 TI - [Encircling needling combined with physical factor therapy for severe pressure sore]. AB - OBJECTIVE: To compare the clinical efficacy difference between encircling needling combined with physical factor therapy and simple physical factor therapy for severe pressure sore, and to explore the optimal method for severe pressure sores. METHODS: Thirty-four patients with IV-grade pressure sore were randomly divided into an observation group and a control group, 17 cases in each one. Patients in the control group were treated with conventional nursing, ultrasonic wave and short-wave ultraviolet therapy; additionally, the encircling needling was applied in the observation group. All the treatment was given once a day, 5 times a week, and 4-week treatment constituted one session. Totally, two sessions of treatment were performed. Three indices, including the area of pressure sore, 24-h volume of exudates and wound-bed tissue type, were compared between the two groups before and after treatment; the clinical efficacy was evaluated in the two groups. RESULTS: After treatment of one session and two sessions, the area of pressure sore, 24-h volume of exudates and wound-bed tissue type were significantly reduced in the two groups (P < 0.01, P < 0.05), which was more obvious in the observation group (all P < 0.05). The total effective rate in the observation group was 76.5% (13/17) after 1 session and 94.1% (16/17) after 2 sessions, which were superior to 35.3% (6/17) after 1 session and 64.7% (11/17) after 2 sessions in the control group (both P < 0.05). CONCLUSION: Encircling needling combined with physical factor therapy can obviously reduce the pressure sore area and 24-h volume of exudates and improve wound-bed tissue type, which is superior to simple physical factor therapy. PMID- 26939327 TI - [Case of Yang-Huang]. PMID- 26939328 TI - [Characteristics and clinical application of the arrival of qi in suspended moxibustion]. AB - The characteristics and clinical application of the arrival of qi in suspended moxibustion was discussed in this paper. Through literature research and clinical practice, three aspects, including characteristics of arrival of qi in suspended moxibustion, the clinical basis regarding arrival of qi in suspended moxibustion improving therapeutic effects and how to acquire arrival of qi in suspended moxibustion, were discussed to clarify the essential role of arrival of qi in suspended moxibustion as well as its importance to the development of moxibustion medicine. The suspended moxibustion at acupoints could produce arrival of qi similar to acupuncture, which was characterized as non-local or non-superficial heat sensation such as penetrating heat, expanding heat, transmitting heat, even non-hot sensation such as aching, numbing, distending, painful, heavy, cold sensation in the applied region. It is heat-sensitive sensation phenomenon that can improve therapeutic effect in suspended moxibustion. PMID- 26939329 TI - [Discussion on moxibustion with different dose]. AB - Moxibustion dose, closely related to moxibustion methods and sensations, directly influences the efficacy. Moxibustion dose is affected by quantity factors and patients' sensations. Quantity factors are volume and number of moxa cones, and moxibustion time and frequency, etc. The relationship between moxibustion dose and efficacy is discussed from quantity factors and sensations in the paper. PMID- 26939330 TI - [Discussion on sensation along the meridians]. PMID- 26939332 TI - [Effects of acupuncture on morphological changes of photoreceptor cells in rats with retinitis pigmentosa]. AB - OBJECTIVE: To observe the morphological changes of photoreceptor cells in rats with retinitis pigmentosa (RP) induced by N-methyl-N-Nitrosourea (MNU) and the effects of acupuncture against it. METHODS: A total of 16 SD rats were treated with one-time intraperitoneal injection of MNU (50 mg/kg) to induce RP, and randomly divided into an acupuncture group and a model group, 8 rats in each one. In addition, 4 rats were selected as a control group. After model establishment, rats in the acupuncture group were treated with acupuncture at "Xinming-1" (Extra) and "Jingming" (BL 1) for 30 min, once a day for 7 days; rats in the model group and control group received no treatment, and the feeding conditions and fixation were identical as the acupuncture group. 2 h after the end of intervention, rats were sacrificed by cervical dislocation to observe the morphological changes of rhodopsin, rod terminals and rod bipolar cells. RESULTS: Due to the loss of retina photoreceptor cells induced by MNU in rats, in the model group the rhodopsin was stained in residual cell bodies, and there were sporadic rod terminals and little rod bipolar cells; outer segments, inter segments, cell bodies and cell terminals were all affected at different levels. The distribution of rhodopsin was also changed in the acupuncture group, showing more bodies of photoreceptor cells, and the residual rod terminals and rod bipolar cells were more than those in the model group; the injury of retina was less than that in the model group. CONCLUSION: MNU could lead to a comprehensive injury to the morphology of photoreceptor cells, however, acupuncture is capable of inhibiting morphological changes of photoreceptor cells induced by MNU. PMID- 26939331 TI - [Effects of acupuncture-moxibustion on contents of IL-12 and TNF-alpha in spleen of cyclophosphamide- induced cancer-bearing mice]. AB - OBJECTIVE: To explore the molecular biology mechanism of acupuncture on improving immune function damage induced by chemotherapy in cancer-bearing mice. METHODS: Seventy-two mice (36 mice in 3-day treatment and 5-day treatment, respectively) which were successfully made into cancer-bearing model were divided into a blank group, a model group, an acupuncture group and a moxibustion group by stratified randomization method, 9 mice in each one. Except for the mice in the blank group, the remaining mice were treated with intra-peritoneal injection of cyclophosphamide (CTX, 150 mg/kg), to establish the cancer-bearing mice of CTX. The mice in the blank group were treated with intraperitoneal injection of 0.9% NaCl (identical dose as other groups). After 4 h, the mice in the acupuncture group and moxibustion group were treated with acupuncture and moxibustion at "Dazhui" (GV 14), "Geshu" (BL 17), "Shenshu" (BL 23), "Zusanli" (ST 36), once a day. The mice in the blank group and model group were treated with immobilization and fixation during the same time. On the next day of the end of 3-day and 5-day treatment, the sample was collected. The ELISA method was applied to measure the contents of IL-12 and TNF-alpha in spleen of all the mice. RESULTS: After 3-day and 5-day treatment, compared with the blank group, the contents of IL-12 and TNF alpha in spleen in the model group were reduced (all P < 0.05); compared with the model group, the contents of IL-12 and TNF-alpha in spleen in the acupuncture group and moxibustion group were increased (all P < 0.05), but the content of IL 12 and TNF-alpha in the acupuncture group was not different from that in the moxibustion group (both P > 0.05). CONCLUSION: Acupuncture and moxibustion could effectively increase the contents of IL-12 and TNF-alpha in spleen of CTX cancer bearing mice, which could relieve chemotherapy-induced immune function damage to improve immune function. PMID- 26939333 TI - [Case of sleepiness]. PMID- 26939334 TI - [Clinical research of analgesic for labor with acupoint injection and electroacupuncture]. AB - OBJECTIVE: To explore a safe and effective scheme of analgesic for labor. METHODS: Eighty-four primiparas without contraindication of vaginal delivery were divided into an observation group and a control group, 42 cases in each one. In the observation group, the acupoint injection was given at Zusanli (ST 36) combined with electroacupuncture (EA) at Hegu (LI 4) and Sanyinjiao (SP 6) till the cervical opening at the end of first stage labor. In the control group, the routine respiratory instruction was applied. In 5 min, 10 min and 60 min of acupuncture (the same time points in the control group) as well as at the end of the first and second stage labor, the analgesic effect was assessed for the primiparas of the two groups. The labor stages, adverse reactions, postpartum hemorrhage, postpartum urine retention, newborn asphyxia rate and usage rate of oxytocin were compared between the two groups. RESULTS: In the observation group, in 5 min, 10 min and 60 min of acupuncture as well as at the end of the first and second stages, the visual analogue scale (VAS) was lower apparently as compared with the control group at the corresponding time points (all P < 0.05). The differences in the time limit in the active period, the second and third stages were not significant between the two groups (all P > 0.05). The incidence of adverse reactions and the usage rate of oxytocin were lower than those in the control group [2.4% (1/42) vs 31.0% (13/42); 2.4% (1/42) vs 23.8% (10/42), both P < 0.05]. The differences in postpartum hemorrhage, postpartum urine retention and newborn asphyxia rate were not significant between the two groups (all P > 0.05). CONCLUSION: The combination of acupoint injection and EA is the effective analgesic scheme for labor. This scheme effectively alleviates labor pain and has no maternal and child complications. PMID- 26939335 TI - [Experience summary of professor WANG Fuchun's "Zhenjing Anshen" acupuncture method for insomnia]. AB - The experience of "Zhenjing Anshen" acupuncture method originally created by professor WANG Fuchun for treatment of insomnia was introduced in this paper. From aspects of insomnia pathogenesis, theoretical foundation, characteristics of acupoint selection, needing methods, needing time, etc., the experience of Professor WANG Fuchun for treatment of insomnia was explained. The "Zhenjing Anshen" acupuncture method proposed, for the first time, "new three layers" method of acupoint selection, including Sishencong (EX-HN 1), Shenmen (HT 7), Sanyinjiao (SP 6). This method presents the principles of acupoint selection along meridian, acupoint selection based on essence-qi-spirit, harmony of yin and yang. The acupuncture manipulation is emphasized, and treating time (the period of the day from 3 pm to 5 pm) is focused on; acupoint selection is simple but essential, and acupoint combination is scientific, which receives notable therapeutic effect in clinic. PMID- 26939336 TI - [Case of impotence]. PMID- 26939338 TI - [Acupuncture for 58 cases of dry eye syndrome caused by computer]. PMID- 26939337 TI - [Exploration and practice on teaching Meridian, collateral and acupoints to international students in China]. AB - Meridian, collateral and acupoints is the basic course of acupuncture and moxibustion and even is the core for training excellent acupuncture physician. Associated with the characters of international students, the writers had the preliminary exploration and practice on teaching this course. For the acupoint names, the international codes of acupoints and Chinese pinyin were applied in combination and the meanings of acupoint were explained to deepen the understanding of acupoints. For acupoint location, the international standards and classical medical works were combined and the experiences in acupoint location were introduced additionally to open the approach to acupoint location. For acupoint effect, the major functions and ancient medical cases were combined to improve the learning interests. For acupoint location practice, the demonstration by teachers was combined with practice and drawing of acupoints and meridians was supplemented to consolidate the foundational knowledge. PMID- 26939339 TI - [Lower He-sea sequence and indication specificity analysis regarding Zusanli (ST 36), Shangjuxu (ST 37) and Xiajuxu (ST 39)]. AB - Zusanli (ST 36), Shangjuxu (ST 37) and Xiajuxu (ST 39) are considered as the lower He-sea points, which are located along the leg lines of stomach meridian of foot Yangming from top to bottom. According to the corresponding zang-fu of lower He-sea points, the distribution order from top to bottom is stomach, large intestine and small intestine. This is significantly different from digestive physiology function sequence of stomach, small intestine and large intestine in modern medicine. However, it conforms to their anatomical position from top to bottom. In order to make a further confirmation that the indication specificity of Zusanli (ST 36), Shangjuxu (ST 37) and Xiajuxu (ST 39) is closely associated with anatomical location, a great number of ancient and modern literature is reviewed. It is found that the functions of the three acupoints are obviously related to stomach, large intestine and small intestine, respectively, indicating that the sequence of Zusanli (ST 36), Shangjuxu (ST 37) and Xiajuxu (ST 39) is related to anatomical position of corresponding zang-fu. This study conclusion could play an important role for exploring the significance of anatomical location in indication specificity of acupoints. PMID- 26939340 TI - [Case of intractable unilateral sensory disturbance]. PMID- 26939341 TI - [Jingjin acupuncture combined with massage for 62 cases of infrapatellar fat pad injury]. PMID- 26939342 TI - [Analysis on regulating deqi in the ancient works of the late dynasties]. AB - From the time of Neijing (Internal Classic) and Nanjing (Classic of Medical Problems) till the end of Qing dynasty, the medical scholars of each dynasty had taken the recognition of deqi as the subject in the stud- ies. Through the historical analysis, the content of regulating deqi was further understood in relevant ancient liter- ature. By checking the ancient works of acupuncture in each dynasty till the end of Qing dynasty, in reference to the evidences in over 10 works, such as Zhenjiu Dacheng (Great Compendium of Acupuncture and Moxibustion) , Zhenjing Zhinan (Instruction of Acupuncture Canon), Zhenjiu Daquan, and in association with the academic views of acupuncture masters in modern time, it was discovered that the medical scholars after the time of Neijing and Nanjing had enriched the understandings of deqi, such as the connection of cold and heat reaction, radiation to the affected site, reinforcing and reducing purpose in qi regulation. The methods of deqi regulations had, been explored till the end of Qing dynasty since the time of Neijing and Nanjing and the understandings of it were vari- ous among scholars. PMID- 26939343 TI - [Acupoint selection and medication rules analysis for allergic rhinitis treated with acupoint application-based on data mining technology]. AB - To make a systematic study on acupoints selection and medication rules for allergic rhinitis treated with acupoint application, literature regarding clinical researches on acupoint application for allergic rhinitis since 2000 has been retrieved; medication and acupoints involved were preprocessed and cluster analysis technique was applied to classify the data. As a result, a total of 37 pieces of literature were included, involving 27 types of herbs and 33 acupoints. The results showed Baijiezi (Brassica alba Boiss), Xixin (Radix et Rhizoma Asari), Gansui (Radix Kansui), Yanhusuo (Corydalis), Jiangzhi (Ginger juice) and Baizhi (Radix angelicae) constituted the main herb prescription, and the layer was increased along with frequency of use. Feishu (BL 13), Dazhui (GV 14), Shenshu (BL 23), Pishu (BL 20), Gaohuang (BL 43), Fengmen (BL 12) constituted the main acupoint prescription, which were clustered into 4 classes; Feishu (BL 13) and Dazhui (GV 14) constituted the first class; Pishu (BL 20) and Shenshu (BL 23) constituted the second class; the first and second class merged into the third class, Including Feishu (BL 13), Dazhui (GV 14), Shenshu (BL 23) and Pishu (BL 20); Gaohuang (BL 43) and Fengmen (BL 12) constituted the fourth class; the fourth class and the third class constituted the whole acupoint prescription. It was showed that for the allergic rhinitis treated with acupoint application, the medication was mainly epispastic herbs with pungent nature that belonged to the lung, spleen and kidney meridian, which presented the principle of simultaneous treatment of principal and subordinate symptoms; also the medication can be selected from core layer to supporting layer based on clinical needs; for the selection of acupoints, acupoints in lung and bladder meridian were mainly selected to assist exterior and resist the pathogenic qi, which could treat allergic rhinitis fundamentally by joint use with acupoints in soleen and kidney meridian. PMID- 26939345 TI - [The central mechanisms underlying the phenomenon of acupoint sensitization evoked by visceral nociceptive afferent]. AB - The physiological mechanism underlying the acupoint sensitization was evaluated systemically by using the method of electric physiology at spinal cord, medulla, and thalamus levels; the dynamic change of acupoint from the relative "silence" to the relative "activation" function was explained through the study on the dynamic process of acupoint sensitization; the biological process of the therapeutic effect of acupoint stimulation was illuminated through the research of the central mechanism underlining the dose effect relationship between the sensitive acupoint and the related brain area, thus scientific evidence for the functional link between the acupoint and internal organs as well as the nature of the acupoint were provided. PMID- 26939344 TI - [Entity of acupoint: kinetic changes of acupoints in histocytochemistry]. AB - The present study aims to investigate the kinetic histocytochemical changes of acupoints in different condition. The expression of tryptase (+) mast cells, histamine (HA) , serotonin (5-HT) and nociceptive neuropeptides including calcitonin gene-related peptide (CGRP) and substance P (SP) were observed by immunohistochemistry combined with confocal technology. Mast cells were labeled with anti-mast cell tryptase antibody and simultaneously with HA or 5-HT primary antibodies to observe their co-expression. The results showed that: (1) SP and CGRP were expressed more highly on the cutaneous nerve fibers of "Hegu" (LI 4) after acupuncture stimulation than that of the control. Mast cells aggregated in close proximity to the blood vessels in intra-epidermis and dermis, and some of them with degranulation in the lower dermis and subcutaneous tissue of "Hegu" (LI 4). Both mast cells and their granules appeared with HA (+) and 5-HT (+) expression at stimulated LI 4 sites, while a few intact mast cells with a little expression of 5-HT and HA were distributed in areas of non-stimulated Ll 4. (2) The acupoints in different locations such as Baihui (GV 20), Weishu (BL 21), Zhongwan (CV 12) and LI 4 had the same constituent but the contents were different. (3) The histocytochemical responses of acupoints sensitized by the Gastric mucosa injury (GMI) were also investigated. GMI resulted in neurogenic plasma extravasation by Evans Blue (EB) in the skin of the acupoints over the back and abdomen, which mostly occurred in the T9-T11 dermatomere. The EB extravasation dots just like acupoints sensitization appeared after GMI and disappeared gradually during the natural self-recovery of the gastric mucosa. More SP and CGRP positive nerve fibers were distributed in EB dots than in regions beside EB dots and in the control, mostly distributed in the nerve fibers around both the vessels and root of hair follicle. Mast cells also aggregated and degranulated to release algogenic substances of 5-HT and HA around the vessels in areas of the EB dots. Collectively the acupoints displayed the same histocytochemical responses due to either acupuncture stimulation or GMI. This may potentially be the histocytochemical basis in the local acupoints and acupoints displayed kinetic changes in different condition. PMID- 26939347 TI - [Is the location of acupoint unchangeable?]. AB - Acupoint,as the special body surface part where the qi of zang-fu and meridians infuses, arouses the effect of acupuncture and moxibustion. Through the exploration for the origin and the evolution of acupoint, and the integration of the related data about acupuncture-moxibustion theory and modern research, it is believed that acupoint is not fixed and it may be in a state of dynamic change. Also, it is bound up with body function. Acupoint is relatively static and the location is immobile while the body is in normal physiological status. When the body is under pathological condition,however, it is activated and the position is correspondingly changed. PMID- 26939346 TI - [Application of the word Bentai in acupuncture and moxibustion]. AB - By retrieval and analysis of literature, the origin and connotation of the word Bentai were stated. In the early twentieth century, one Japanese scholar introduced the word into acupuncture-moxibustion. It was mostly used to explore the mechanism of acupuncture-moxibustion and acupoints through scientific research. One Chinese scholar introduced the connotation into acupuncture and moxibustion in 1940, and it was mainly expressed the essence. Professor ZHU Bing systematically discussed Bentai of acupoints from a scientific point of view. The knowledge of acupoints, however, is diverse, and there is different cognition due to multiple perspectives. Acupoints may not have unique Bentai. PMID- 26939348 TI - [Discussion on "nearby action", the basic function of acupoints]. AB - Acupoints have "nearby action"and "far action". Only some acupoints own "far action", which is special. The "nearby action", belong to every acupoint, is universal and basic. The research and explanation of "nearby action", however, have been too neglected for a long time. There is a certain relationship between the confusion of some acupuncture-moxibustion theory and the neglect. In this article, the differences between "nearby action" and "far action", the area, the theory and the relevance of "nearby action" are analyzed. It is believed that analyzing and thinking the "nearby action" deeply would improve the understanding of acupoints, meridians and acupuncture-moxibustion therapy. PMID- 26939349 TI - [ZHU Lian's New Acupuncture Academic System and acupuncture science initialization]. AB - Acupuncture scientization was a consensus of most of acupuncture scholars who had long-term perspectives in the 20th century, among them Ms. ZHULian was the important one. Ms. ZHU Lian built a systemic new acupuncture" academic structure in practice and theory aspects. At the same time, as the main architect of Institute of Acupuncture-moxibustion of China Academy of Traditional Chinese Medicine, Ms. ZHU Lian was the first one who began to carry out the acupuncture clinical trail and laboratory experiment in modern way, which meant "acupuncture therapy" was transformed into "acupuncture science" by Ms. ZHULian's endeavor. PMID- 26939350 TI - [The plasticity of acupoint]. AB - Acupoint possesses both diagnosing and treating functions according to the acupuncture theory. Acu point plasticity refers to a patho-physiologically dynamic change which is manifested mainly as a neuronal inflammatory reflection in the special area(s) of the body surface under pathological conditions. These responses of acupoint sensitization could activate simultaneously self-healing system in the body and induce the curative effects. PMID- 26939351 TI - As opioid overdose deaths reach record highs, call for systematic changes grows louder. AB - With deaths from opioid overdoses up sharply, a number of organizations are calling for systematic changes to curb the prescription of opioids while also making it easier for patients with addiction problems to access evidence- based treatment. New data from the National Center for Health Statistics un- derscore the scope of the problem: Deaths related to prescription overdoses reached an all time high in 2014, nearing the 19,000 mark. Deaths linked to heroin reached 10,574, a three-fold increase from 2010. In response to the opioid problem, the CDC has unveiled draft guidelines directing physicians to consider alternative treatments for pain before turning to opioids. When opioids must be used, the guidelines encourage physicians to opt for shorter-acting versions rather than extended-release forms, and they suggest that physicians incorporate strategies to mitigate the risk of overdose, such as offering naloxone to patients in specific high-risk groups. The draft guidelines also call for physicians to ask patients to take urine tests before prescribing opioids, and to continue requiring the urine tests at least once per year if patients continue on the drugs. This is to identify patients who may be supplementing their prescribed dosages. New research reported in JAMA Internal Medicine suggests that the over prescribing of opioids is a problem shared by a broad cross-section of health professionals, not a small subset, as some have suggested. A new report, led by researchers at the Johns Hopkins School of Public Health, recommends significant improvements in the way opioids are prescribed and dispensed as well as in the way patients with addictions or overdoses are identified and managed in the healthcare system. PMID- 26939352 TI - Crowded EDs leaving proven strategies for improving patient flow on the table. AB - While there is a plethora of proven strategies to address crowding, some of the most crowded EDs have failed to take full advantage of these tactics, according to a new study that examined the adoption of a range of both ED-based and hospital-wide interventions at hospitals between 2007 and 2010. The investigators are calling for a national strategy to address crowding as well as the implementation of new measures. They also say that more steps need to be taken so that hospital leaders are held accountable for ED crowding. Researchers found that the average number of interventions adopted to reduce crowding increased during the study period from 5.2% to 6.6%, but that some of the most crowded facilities failed to adopt interventions that have been proven to work well. For instance, 19% of the most crowded EDs did not use bedside registration and 94% did not adopt surgical schedule smoothing, an intervention that can be adopted at little or no cost. Investigators note that the hospitals that have been successful at addressing ED crowding are those that embrace systemic solutions. PMID- 26939353 TI - In wake of terrorist attacks, hospitals scrutinize protection plans and procedures. PMID- 26939355 TI - [Foreword for special column on preparation of separation media with specific selectivity]. PMID- 26939354 TI - [Recent trends and development on liquid chromatography]. PMID- 26939357 TI - [Advances of poly (ionic liquid) materials in separation science]. AB - Ionic liquids, as novel ionization reagents, possess beneficial characteristics including good solubility, conductivity, thermal stability, biocompatibility, low volatility and non-flammability. Ionic liquids are attracting a mass of attention of analytical chemists. Poly (ionic liquid) materials have common performances of ionic liquids and polymers, and have been successfully applied in separation science area. In this paper, we discuss the interaction mechanisms between the poly(ionic liquid) materials and analytes including hydrophobic/hydrophilic interactions, hydrogen bond, ion exchange, pi-pi stacking and electrostatic interactions, and summarize the application advances of the poly(ionic liquid) materials in solid phase extraction, chromatographic separation and capillary electrophoresis. At last, we describe the future prospect of poly(ionic liquid) materials. PMID- 26939356 TI - [Development of preparation of immobilized enzyme reactors in proteomics]. AB - As an important part in "bottom-up" strategy of proteomics, immobilized enzyme reactors have great significance in the development of fast and more efficient protein analytical method, owing to its advantages of high speed and enzymatic efficiency, good stability and activity, easy operation, and the possibility of hyphenating with multiple detection instruments. In this paper, the preparation methods of immobilized enzyme reactors and their applications in proteomic investigation are introduced, focusing on the nature of enzymes, the immobilization methods and the carrier materials used for immobilizing enzyme. In recent years, the investigations are focused on increasing the immobilization amounts of enzyme, keeping enzymatic activity, improving enzymatic efficiency and decreasing nonspecific adsorption. The investigation results showed that by using novel carriers such as nanomaterial and monolith, increasing of hydrophilicity of carrier and tandem hydrolysis with multiple enzymes can greatly improve the performance of immobilized enzyme reactors and increase protein identification efficiencies. PMID- 26939358 TI - [Advances in cucurbituril bonded stationary phases for chromatographic separation]. AB - Cucurbit [n] urils (CB [n]), a kind of host molecules of the fourth generation supramolecule followed crown ethers, cyclodextrins and calixarenes in supramolecular chemistry, are macrocyclic ligands and consist of several glycoluril units. Their special molecular recognition based on unique separation selectivity and stability have gained great interest in supramolecular chemistry and chromatography. Hereby, we give a review of research progresses of cucurbit [n] urils structural features, its homologues and derivatives and their applications in chromatographic stationary phase. PMID- 26939359 TI - [State of the art of mixed-mode stationary phase]. AB - With the development of science and technology, more and more complex samples like peptides and proteins need to be separated. It is difficult to separate them by single mode chromatography. Due to the unique separation character of mixed mode chromatography, the same separation performance can be obtained in mixed mode chromatography in one separation as multidimensional chromatography. And some disadvantages of multidimensional chromatography can be avoided in mixed mode chromatography, such as the complexity of the system, the poor compatibility of mobile phases and the long analytical time. More and more attention is devoted to the mixed-mode chromatography in recent years. The focus on the mixed-mode chromatography is to design new structures of mixed-mode stationary phase. At present, mixed-mode stationary phases included reversed-phase/ion-exchange, reversed-phase/hydrophilic, hydrophilic/ion-exchange, zwitterionic and trimode mixed-mode stationary phases. The kinds of mixed-mode stationary phases are summarized and their features and applications in different fields are discussed in this review. PMID- 26939360 TI - [Advances on the development of detection methods for the phthalate esters in food]. AB - Phthalate esters are most widely used as plasticizers which have toxicity and carcinogenicity. Phthalate esters are found as contaminants in many food products and they are a branch of compounds, homologues and isomers, which present similar structures and properties. And the residue contents vary a lot in different matrices. Efficient sample pretreatment, highly selective separation mode, sensitive detection methods as well as reducing background interference are challenges for their determination in complex samples. In this paper, some sample pretreatment methods such as liquid-liquid extraction, liquid-liquid micro extraction, solid phase extraction, solid phase micro-extraction, matrix solid phase extraction and other traditional and new types of extraction and purification technology applied in the food samples are reviewed. The characteristics of analytical methods including gas chromatography, liquid chromatography, tandem mass spectrometry, high resolution mass spectrometry, enzyme-linked immunoassay, and ion mobility spectrometry are also discussed. PMID- 26939361 TI - [A novel multiple-channel apparatus for packing capillary chromatographic column and its application]. AB - A novel multiple-channel apparatus for packing capillary chromatographic column was designed and manufactured for packing six capillary chromatographic columns with close column efficiency at the same time. Briefly, it consists of a magnetic stirrer, a liquid chromatographic pump and a multiple-channel can. The reagents used for preparing ODS (C18) slurry and stirring condition of the magnetic stirrer were optimized in the study. Two batches of capillary chromatographic columns were packed under the optimum condition, and these packed capillary chromatographic columns were evaluated in the terms of peak capacity, sequence coverage, retention times of three peptide ions and column pressure using the tryptic digest of a bovine serum albumin (BSA) and detected by LC-MS in electrospray ionization (ESI) mode. The experimental results showed that the six capillary chromatographic columns packed at the same time had close column efficiencies, however, the column efficiencies of twelve capillary chromatographic columns packed at two times were significantly different. In addition, there was no significant column efficiency difference when packing one or six capillary chromatographic columns at the same time. The multiple-channel apparatus designed by us is simple, time-saving, and can be applied to pack capillary chromatographic columns with similar column efficiencies, thus it is of evident advantage over traditional one-channel apparatus. PMID- 26939362 TI - [Determination of nine estrogenic steroids in milk using matrix solid phase dispersion-ultra performance liquid chromatography with mass spectrometric detector]. AB - An analytical method for the multiresidue determination of nine estrogenic steroids in milk was developed by modified matrix solid phase dispersion (MSPD) purification and ultra performance liquid chromatography (UPLC) with mass spectrometric detector (MSD). The sensitivity and accuracy of MSD were better than that of ultraviolet detector. In comparison with traditional mass spectrometry, the merits of MSD were simpler in operation and shorter in starting time (5 min). The results showed that the limits of detection of the compounds with nucleophilic substitution were high in positive ion mode of MSD and were easily affected by environmental conditions. The matrix effects of milk samples reduced from 84%-160% to 80%-121% after MSPD purification. The intraday precision and interday precision of the nine estrogenic steroids were 0.87%-1.78% and 1.82% 3.79%, respectively. The average recoveries were 68.7%-94.7%, and the relative standard deviations (RSDs) were less than 10%. The limits of detection (LODs) were 0.5-10 MUg/kg. The limits of quantification (LOQ) were 2-20 MUg/kg. PMID- 26939363 TI - [Determination of amantadine and rimantadine residues in egg and chicken samples by dispersive solid phase extraction purification-ultra high performance liquid chromatography-tandem mass spectrometry]. AB - A method was developed for the determination of residual amantadine and rimantadine in eggs and chickens by dispersive solid phase extraction-ultra high performance liquid chromatography-tandem mass spectrometry. Egg and chicken samples were extracted with ammonia water-acetonitrile (2:98, v/v). The extraction solution was dried to 1 mL under nitrogen, and then purified by dispersive solid phase extraction method with C18 and NH2 sorbents. After purification, the extraction solution was filtered through a filter. The target compounds were analyzed by ultra high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) on a ZORBAX C18 column using a mixture of 1 mmol/L ammonium acetate solution (containing 0.1% (v/v) formic acid) and methanol as mobile phases with gradient elution. The mass spectrometer was operated under multiple reaction monitoring (MRM) mode in positive mode. The good linearities were obtained for amantadine and rimantadine at a concentration range of 0.15 10.0 MUg/L. The limits of detection for amantadine and rimantadine were all 0.05 MUg/kg, and the limits of quantification were 0.20 MUg/kg. The recoveries of amantadine and rimantadine in eggs and chickens at three spiked levels (0.2, 1.0 and 2.0 MUg/kg) age of 89%-108% with the relative standard deviations of 5.0% 8.6%. The results demonstrated that the method is suitable for the determination of amantadine and rimantadine in eggs and chickens. PMID- 26939364 TI - [Determination of 213 pesticide residues in milk and milk power by gas chromatography-triple quadrupole tandem mass spectrometry]. AB - On the basis of the optimization of solid phase extraction adsorbent, eluting solvent types and amounts, a gas chromatography-triple quadrupole tandem mass spectrometry (GC-MS/MS) method was established for the determination of 213 pesticide residues in milk and milk power. The samples were extracted by acetonitrile, cleaned-up with an ENVI-Carb/NH2 solid-phase extractant, and determined by GC-MS/MS using external standard method. The linear ranges were from 10 to 1 000 MUg/L for 197 pesticides, from 50 to 1 000 MUg/L for the other 16 pesticides with the correlation coefficients higher than 0.99. The limits of detection (LODs, S/N = 3) varied over the range of 0.03 to 7.59 MUg/kg, and limits of quantification (LOQs, S/N = 10) ranged from 0.10 to 21.94 MUg/kg. The average recoveries in different matrices were in the range of 66.9% - 120.1% with the relative standard deviations (RSDs) of 1.23% - 17.6%. This method is simple, rapid, sensitive and reliable for meeting the requirements for the simultaneous identification and quantification of the multi-residues in milk and milk power. PMID- 26939365 TI - [Determination of three organophosphate ester flame retardants in baby carriages by gas chromatography-mass spectrometry combined with solid phase extraction]. AB - Organophosphate esters (OPEs) are high-production-volume chemicals used as flame retardants. Some western countries (e. g. America and European Union) have imposed restrictions on OPEs in baby products due to their similar persistent organic-pollutants (POPs) properties. So far, there is no domestic or foreign standard for OPEs flame retardants in baby carriages. Ultrasonic extraction was used to extract three OPEs from baby carriages, and the extracts were purified by a florisil solid phase extraction (SPE) column, and finally detected by gas chromatography-mass spectrometry (GC-MS). The spiked recoveries of the three OPEs were in the range of 89.5% to 107.3%. The limits of detection (3S/N) were 0.01 mg/kg, and the limits of quantification (10S/N) were 0.1 mg/kg. This method could eliminate matrix effects and give accurate qualitative analytical results for the three OPE flame retardants in baby carriages. Thirty-seven samples were analyzed and the tris (2-chloro-1-methylethyl) phosphate (TCPP) detection rate was up to 81.1% with the mass concentration range of 1.0-15 312.8 mg/kg, and 32.4% of the samples exceeded the European Union directive (2014/79/EU) for TCPP (> 5 mg/kg), as well as tris (2-chloroethyl) phosphate (TCEP) and tris [2-chloro-1 (chloromethyl) ethyl] phosphate(TDCP) in two samples, which were in the range of 6.2-44.1 mg/kg. Thus, relatively high OPEs flame retardants risk was presented in baby carriages. PMID- 26939366 TI - Determination of the solubility parameter of ionic liquid 1-butyl-3 methylimidazolium tetrafluoroborate by inverse gas chromatography. AB - Thermodynamic properties of ionic liquid 1-butyl-3-methylimidazolium tetrafluoroborate ([BMIM] BF4) were determined via inverse gas chromatography (IGC). Two groups of solvents with different chemical natures and polarities were used to obtain information about [BMIM] BF4-solvent interactions. The specific retention volume, molar heat of sorption, weight fraction activity coefficient, Flory-Huggins interaction parameter as well as solubility parameter were also determined in a temperature range of 333 - 373 K. The results showed that the selected solvents n-C10 to n-C12, carbon tetrachloride, cyclohexane and toluene were poor solvents for [BMIM] BF4, while dichloromethane, acetone, chloroform, methyl acetate, ethanol and methanol were favorite solvents for [BMIM] BF4. In addition, the solubility parameter of [ BMIM] BF4 was determined as 23.39 (J/cm3)0.5 by the extrapolation at 298 K. The experiment proved that IGC was a simple and accurate method to obtain the thermodynamic properties of ionic liquids. This study could be used as a reference to the application and research of the ionic liquids. PMID- 26939367 TI - [Determination of six anticoccidials in chicken using QuEChERS combined with ultra high liquid chromatography-high resolution mass spectrometry]. AB - An ultra high liquid chromatography-Q Exactive orbitrap mass spectrometry multi residue method has been developed for the determination of six anticoccidials residues (dinitlmide, nicarbazin, diclazuril, toltrazuril, monensin and salinomycin) in chicken tissue. Sample preparation was based on QuEChERS method, using 1% (v/v) trichloroacetic acid/acetonitrile aqueous solution (3:7, v/v) as the extraction solvent and salting-out with sodium chloride followed by clean-up with 50 mg/mL primary secondary amine (PSA) +50 mg/mL neutral alumina (Alumina-N) dispersive solid phase extraction (DSPE). The separation of the compounds in liquid chromatography was carried out using a Waters Acquity UPLC BEH C8 column (100 mm x 2.1 mm, 1.7 MUm) with mobile phases consisting of methanol-5 mmol/L ammonium acetate aqueous solution in gradient elution. The Q Exactive orbitrap mass spectrometric detection was carried out with positive and negative electrospray ionization simultaneously. The results showed the linear ranges of the six target compounds were as follows: dinitolmide, 1.0-30.0 MUg/L; nicarbazin, 0.2-6.0 MUg/L; diclazuril and toltrazuril, 2.0-60.0 [MUg/L; monensin and salinomycin, 4.0-120.0 MUg/L. The external standard method was used for quantification. The spiked recoveries at three levels for the six anticoccidials ranged from 67.7% to 126.8%. The relative standard deviations (RSDs) were <= 10.4%. The limits of quantification (LOQs) were as follows: dinitolmide, 2.50 MUg/kg; nicarbazin, 0.50 MUg/kg; diclazuril and toltrazuril, 5.00 MUg/kg; monensin and salinomycin, 20.00 MUg/kg. The developed method is easy of operation and of high sensitivity. It can meet the requirements of daily inspection. PMID- 26939368 TI - [Determination of imidaclothiz in tea by QuEChERS cleanup and liquid chromatography-tandem mass spectrometry]. AB - The method for the determination of imidaclothiz residue in tea by liquid chromatography-tandem mass spectrometry (LC-MS/MS) has been developed. The imidaclothiz in tea was extracted by acetonitrile and purified by QuEChERS with PSA (primary secondary amine), C18, GCB (graphitized carbon black) as the adsorbents. The purified solution was centrifuged and the supernatant was diluted with water of equal volume. The separation was performed on a C18 column with a gradient elution program of acetonitrile (containing 0.1% (v/v) formic acid) and water at a flow rate of 0.30 mL/min. The mass spectrometer was carried out with electrospray ion source in the positive mode (ESI+) and selective reaction monitoring (SRM), quantified by external standard solution. The results showed that the mass concentration of imidaclothiz in the range of 1 to 500 MUg/L was linearly correlated with the peak area, and the correlation coefficient (r) was 0.999 9. The limit of quantification (LOQ, S/N >= 10) was 0.01 mg/kg. The recoveries in oolong tea and green tea at three spiked levels (0.01, 0.3 and 3 mg/kg) varied from 87.0%-101.0% and the relative standard deviations (RSDs, n = 7) were between 2.1% and 13.1%. The real sample tests showed that the method is simple, cheap, accurate, specific, rapid, and suitable for the qualitative and quantitative confirmation of imidaclothiz residue in tea. PMID- 26939370 TI - [Determination of docosahexaenoic acid in milk powder by gas chromatography using acid hydrolysis]. AB - A method to determine docosahexenoic acid (DHA) in milk powder by gas chromatography was established. The milk powder samples were hydrolyzed with hydrochloric acid, extracted to get total fatty acids by Soxhlet extractor, then esterified with potassium hydroxide methanol solution to form methyl esters, and treated with sodium hydrogen sulfate. The optimal experiment conditions were obtained from orthogonal experiment L9(3(3)) which performed with three factors and three levels, and it requires the reaction performed with 1 mol/L potassium hydroxide solution at 25 degrees C for 5 min. The derivative treated with sodium hydrogen sulfate was separated on a column of SP-2560 (100 m x 0.25 mm x 0.20 MUm), and determined in 55 min by temperature programming-gas chromatography. Good linearity was obtained in the range 5.0-300 mg/L with the correlation coefficient of 0.999 9. The relative standard deviations (RSDs) were 3.4%, 1.2% and 1.1% for the seven repeated experiments of 10, 50 and 100 mg/L of DHA, respectively. The limit of detection was 2 mg/kg, and the recoveries of DHA were in the range of 90.4%-93.5%. The results are satisfactory through the tests of practical samples. PMID- 26939369 TI - [Simultaneous determination of four drugs for kidney diseases in urine by high performance liquid chromatography]. AB - A high performance liquid chromatographic (HPLC) method was proposed for the simultaneous determination of four drugs for kidney disease, enalapril, triamterene, furosemide and valsartan. After proteins being removed by acetone precipitation method, freeze drying and redissolving in mobile phase, the urine samples were analyzed by HPLC. Chromatographic separation was performed on a WondaSil C18-WR (150 mm x 4.6 mm, 5 MUm) in gradient elution mode using 10.0 mmol/L ammonium acetate aqueous solution (pH 3.90) and acetonitrile as mobile phases at a flow rate of 1.0 mL/min. The detection wavelength was set at 254 nm. Under the optimized conditions, good linearities were obtained in the range of 0.15-300 mg/L, 0.05-100 mg/L, 0.75-750 mg/L, 0.05-100 mg/L, and the detection limits were 1.38 x 10(-2), 7. 67x103, 3.69x 10-2, 1. 16x 10-2 mg/L for enalapril, triamterene, furosemide and valsartan, respectively. The recoveries were in the range of 89.49%-99.20% with the relative standard deviations (RSDs) among 4.12% 9.44%. The method is simple, accurate and effective, and the results showed the method is applicable for the analysis of the four drugs for kidney diseases in real urine samples. PMID- 26939372 TI - Cultivating Healthcare Information Governance. HOW TO GROW YOUR PROGRAM INTO MATURITY. PMID- 26939371 TI - House Scanning the HIM Horizon. PMID- 26939373 TI - Adaptive Leadership in Information Governance. PMID- 26939375 TI - The State of Information Governance in 2016. PMID- 26939374 TI - Making the Most of HIM Centralization. PMID- 26939376 TI - Healthcare Privacy Considerations of Body-Worn Cameras. PMID- 26939377 TI - Getting Started with Information Governance: Applying SBAR to IG. PMID- 26939378 TI - HIT Standards for HIM Practices in an Interoperable World. PMID- 26939379 TI - Gauging Stakeholder Response to ICD-10. PMID- 26939380 TI - Why Information Governance Means Real Return on Investment. PMID- 26939381 TI - Exploring the FY 2016 ICD-10-CM/PCS Updates. PMID- 26939382 TI - FY 2016 CPT Updates. PMID- 26939383 TI - To the editorial committee. PMID- 26939384 TI - Nonpharmacologic Neuraxial Interventions for Prophylaxis of Postdural Puncture Headache in the Obstetric Patient. AB - Postdural puncture headache due to accidental dural puncture during epidural catheter placement is a source of morbidity for new mothers. It can interfere with maternal-newborn bonding and increase the length of hospitalization. This evidence-based article examined the question: For obstetric patients experiencing an accidental dural puncture during epidural placement, which nonpharmacologic prophylactic neuraxial interventions safely and effectively decrease the incidence of postdural puncture headache? A search of online databases revealed 4 systematic reviews with meta-analysis and a randomized controlled trial meeting the inclusion criteria. Three of the 4 systematic reviews used rigorous appraisal methods. Two systematic reviews included nonobstetric populations and 3 included additional interventions. Subgroup analyses allowed examination of the interventions of interest. Nonpharmacologic prophylactic neuraxial interventions included prophylactic epidural blood patch, epidural saline administration, and intrathecal catheter placement. There was a lack of standardization of interventions. The evidence suggested there may be value in performing a prophylactic blood patch or placing an intrathecal catheter. The risk of the intervention must be carefully weighed with the benefits. Further rigorous studies are needed to help determine the best methods to decrease the incidence of postdural puncture headache in obstetric patients experiencing an accidental dural puncture during epidural placement. PMID- 26939385 TI - Intrathecal Opioid-Induced Hypothermia Following Subarachnoid Block With Morphine Injection for Elective Cesarean Delivery: A Case Report. AB - Opioids have been administered intrathecally with subarachnoid block for postoperative pain relief in parturients undergoing elective cesarean deliveries. This case report presents the uncommon occurrence of intrathecal opioid-induced hypothermia in the latent phase of recovery following elective cesarean delivery. There are few case reports on the occurrence of latent-phase postanesthesia care hypothermia in patients receiving subarachnoid block with morphine sulfate injection (Duramorph). Hypothermia can occur postoperatively for many reasons and can be life-threatening. In this case, hypothermia developed and progressed throughout the postoperative period. The causes of hypothermia were evaluated and treated without success initially. Thyroid dysfunction and alternative differential diagnoses were ruled out. Further assessment determined that the morphine injection might have been a contributing factor. Naloxone at 40-MUg increments was administered intravenously and corrected the hypothermia. Awareness of hypothermia postoperatively with associated morphine administration through subarachnoid block must be ruled out in cases of progressing hypothermia. PMID- 26939386 TI - A Hypotensive/Bradycardic Episode Leading to Asystole in a Patient Undergoing Shoulder Arthroscopy in the Sitting Position With Interscalene Block and Intravenous Sedation: A Case Report. AB - Anesthesia for shoulder surgery is often accomplished by means of an interscalene block and intravenous sedation, with the patient subsequently placed in the sitting position for surgical access. Despite the advantages of this popular technique, sudden unheralded and severe hypotensive/bradycardic episodes have been reported in this population, with an incidence of 13% to 24%. Although these episodes are usually transient and resolve spontaneously, there are case reports of progression to asystolic cardiac arrest following hypotensive/bradycardic episodes. To raise awareness of the catastrophic potential of these episodes and discuss possible causes and preventive measures, the author presents the case of an ASA class 1 patient undergoing shoulder arthroscopy in the sitting position with an interscalene block and intravenous sedation, who experienced a hypotensive/bradycardic episode that rapidly progressed to intraoperative asystole. PMID- 26939387 TI - Effective Ventilation Strategies for Obese Patients Undergoing Bariatric Surgery: A Literature Review. AB - Obesity causes major alterations in pulmonary mechanics. Obese patients undergoing bariatric surgery present mechanical ventilation-related challenges that may lead to perioperative complications. Databases were systematically searched for clinical trials of ventilation maneuvers for obese patients and bariatric surgery. Thirteen randomized controlled trials were selected. The quality of the studies was evaluated with the Critical Appraisal Skills Programme tool, and a matrix was developed to present the essential components of the studies. Eight strategies of ventilation maneuvers were identified. Recruitment maneuvers followed by positive end-expiratory pressure (PEEP) consistently demonstrated effectiveness in obese patients undergoing bariatric surgery. Pressure-controlled ventilation and volume-controlled ventilation did not differ significantly in their efficacy. Noninvasive positive pressure ventilation (NIPPV) during induction was effective in preventing atelectasis and increasing the duration of safe apnea. Equal ratio ventilation can be a useful ventilation strategy. Recruitment maneuvers followed by PEEP are effective ventilation strategies for obese patients undergoing bariatric surgery. During induction, NIPPV provides further benefit. Future studies are needed to examine the postoperative effects of recruitment maneuvers with PEEP as well as the efficacy and safety of equal ratio ventilation. PMID- 26939388 TI - Effect of a Nontechnical Skills Intervention on First-Year Student Registered Nurse Anesthetists' Skills During Crisis Simulation. AB - Simulation-based education provides a safe place for student registered nurse anesthetists to practice non-technical skills before entering the clinical arena. An anesthetist's lack of nontechnical skills contributes to adverse patient outcomes. The purpose of this study was to determine whether an educational intervention on nontechnical skills could improve the performance of nontechnical skills during anesthesia crisis simulation with a group of first-year student registered nurse anesthetists. Thirty-two first-year students volunteered for this quasi-experimental study. Each subject was videotaped and rated as he or she performed 6 simulated crisis scenarios: 3 scenarios before the intervention and 3 after the intervention. Findings revealed that the nontechnical skills mean posttest score was greater than pretest scores: t (df = 31) = 1.99, P = .028. The mean gain in scores for standardized nontechnical skills were significantly greater than those for standardized technical skills: t (df = 30) = 1.81, P = .04. In conclusion, a 3-hour educational intervention on nontechnical skills resulted in significant improvement. Nontechnical skills therefore are not acquired through experience, but rather through instruction. An educational intervention using the Anaesthetists' Non-Technical Skills system is a valuable tool in the measurement of nontechnical skills assessment of first-year student registered nurse anesthetists. PMID- 26939389 TI - Anesthetic Considerations for the Patient With Cyclic Vomiting Syndrome. AB - Cyclic vomiting syndrome (CVS) is characterized by intense vomiting, recurrent emergency department visits, and return to usual health status between episodes. This syndrome was first described in 1882 in a case series of pediatric patients, but there is growing understanding that CVS may occur in other age groups. This case report describes a 23-year-old with a history of CVS diagnosed in adolescence presenting for revision of a tibial plateau fracture. The patient underwent general anesthesia and had an uneventful perioperative course. Although not much is known about CVS in patients presenting for surgery, this report reviews the pertinent literature and explores anesthetic implications for patients with this challenging syndrome. PMID- 26939390 TI - Residual Neuromuscular Blockade. AB - This article provides an update on residual neuromuscular blockade for nurse anesthetists. The neuromuscular junction, pharmacology for producing and reversing neuromuscular blockade, monitoring sites and methods, and patient implications relating to incomplete reversal of neuromuscular blockade are reviewed. Overall recommendations include using multiple settings when employing a peripheral nerve stimulator for monitoring return of neuromuscular function and administering pharmacologic reversal when the train-of-four ratio is below 0.9. PMID- 26939391 TI - [Phosphodiesterase-5 inhibitors for erectile dysfunction: Adverse reactions and countermeasures]. AB - Phosphodiesterase-5 inhibitors (PDE5i) have been used as the first-line treatment for erectile dysfunction (ED) in recent years. However, with the increased clinical application of PDE5i, the incidence rate of PDE5i-induced adverse reactions is on the rise, which may involve the cardiovascular, digestive, nervous, respiratory, and reproductive systems. Most of the adverse reactions are mild to moderate, occasionally with serious or rare complications. The probability and severity of the adverse reactions are associated with the dosage and frequency of medication as well as with individual differences. Therefore individualized medication is necessitated and, for the patients with cardiovascular disease, epilepsy, psychosis, or anaphylactic conditions, PDE5i should be cautiously given or avoided. This review provides an overview of PDE5i induced adverse reactions and countermeasures in the treatment of ED. PMID- 26939392 TI - [Long-term exposure to PM2.5 from automobile exhaust results in reproductive dysfunction in male rats]. AB - OBJECTIVE: To explore the effects of long-term exposure to particulate matter 2.5 (PM2.5) from automobile exhaust on the reproductive function of Sprague Dawley (SD) rats. METHODS: Forty-five male SD rats, weighing 80 - 94 g and aged 28 days, were randomly assigned to receive intra-tracheal administration of 0.9% normal saline (control group, n = 15), PM2. 5 at 2 MUg per 100 g body weight per day (low-dose PM2.5 group, n = 15), and PM2.5 at 16 MUg per 100 g body weight per day (high-dose PM2.5 group, n = 15), qd, for 60 successive days. After the last 24 hour exposure, 10 rats were taken from each group for copulation with normal female ones, while the others were sacrificed, their testes removed for sperm count and deformity, pathological examination, and determination of the Connexin43 expression. RESULTS: The conception rate was significantly decreased in the low- and high-dose PM2.5 groups as compared with that of the control (70% and 50% vs 100%), and so were the sperm count and quality. The rats in the PM2.5 exposed groups showed significantly disordered histological structure of the seminiferous tubules, reduced sperm count in the testicular lumen, some exfoliated secondary spermatocytes, downregulated Connexin43 expression in the testis, and damaged blood-testis barrier. CONCLUSION: Long-term exposure to PM2.5 from automobile exhaust damages the reproductive function of male SD rats. PMID- 26939393 TI - [Impact of the CFTR chloride channel on the cytoskeleton of mouse Sertoli cells]. AB - OBJECTIVE: To study the impact of the chloride channel dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) on the cytoskeleton of Sertoli cells in the mouse. METHODS: TM4 Sertoli cells were cultured and treated with CFTR(inh)-172 at the concentrations of 1, 5, 10 and 20 MUmol/L for 48 hours. Then the cytotoxicity of CFT(inh)-172 was assessed by CCK-8 assay, the expressions of F-actin and Ac-tub in the TM4 Sertoli cells detected by immunofluorescence assay, and those of N-cadherin, vimentin and vinculin determined by qPCR. RESULTS: CFTR(inh)-172 produced cytotoxicity to the TM4 Sertoli cells at the concentration of 20 MUmol/L. The expressions of F-actin and Ac-tub were decreased gradually in the TM4 Sertoli cells with the prolonging of treatment time and increasing concentration of CFTR(inh)-172 (P < 0.05). The results of qPCR showed that different concentrations of CFTR(inh)-172 worked no significant influence on the mRNA expressions of N-cadherin, vimentin and vinculin in the Sertoli cells. CONCLUSION: The CFTR chloride channel plays an important role in maintaining the normal cytoskeleton of Sertoli cells. The reduced function and expression of the CFTR chloride channel may affect the function of Sertoli cells and consequently spermatogenesis of the testis. PMID- 26939394 TI - [Quinoline derivative PQ1 combined with cisplatin promotes the proliferation and gap junction communication of prostate cancer PC3 cells]. AB - OBJECTIVE: To investigate the effects of the quinoline derivative PQ1 combined with cisplatin on the proliferation and gap junction communication of prostate cancer PC3 cells. METHODS: We cultured in vitro prostate cancer PC3 cells and divided them into DMSO blank control, cisplatin control, and cisplatin (10 mg/ml) plus PQ1 (1, 2, 5, 10, and 15 MUmol/L) groups. We measured the proliferation of the prostate cancer PC3 cells, determined the expressions of the connexin 43 (Cx43) mRNA and protein by RT-PCR and Western blot, and compared the indexes among different groups. RESULTS: Cisplatin combined with PQl at 1 - 10 MUmol/L significantly inhibited the proliferation of the PC3 cells and the inhibition rate rose in a concentration- and time-dependent manner, from (48.72 +/- 0.98)% vs (50.33 +/- 0.62)% at 0 MUmol/L to (77.38 +/- 1.12)% vs (83.50 +/- 1.05)% at 15 MUmol/L at 24 and 48 hours (P < 0.05). Compared with the cisplatin control, cisplatin combined with PQ1 at 1, 2, 5, 10, and 15 MUmol/L increased the expression of Cx43 mRNA from 0.379 +/- 0.113 to 0.669 +/- 0.031, 0.831 +/- 0. 127, 0.769 +/- 0.100, 0.532 +/- 0.086, and 0.475 +/- 0.134, respectively (P < 0.05), and cisplatin combined with PQ1 at 1, 2, 5, and 10 MUmol/L elevated that of Cx43 protein from 0.138 +/- 0.146 to 0.263 +/- 0.111, 0.306 +/- 0.152, 0.415 +/- 0.280, and 0.643 +/- 0.310, respectively (P < 0.05). CONCLUSION: The quinoline derivative PQ1 can promote the gap junction communication of prostate cancer PC3 cells and enhance the killing effect of cisplatin on PC3 cells by upregulating the expressions of Cx43 mRNA and protein. PMID- 26939395 TI - [Regulatory effect of Skp2 on the expression and transactivation of the androgen receptor in the progression of castration-resistant prostate cancer]. AB - OBJECTIVE: To determine the expression of Skp2 in different prostate cancer (PCa) cell lines and tissues, and explore its influence on the androgen receptor (AR) signaling pathway and development of castration-resistant prostate cancer (CRPC). METHODS: The expression levels of Skp2 and AR in different PCa cell lines were detected by Western blot. After knockdown of Skp2 in the C4-2 and 22RV1 cells transfected with shRNA, the expressions of AR and P27 were determined and the activity of ARR3-Luc measured by dual-luciferase reporter gene assay following treatment with dihydrotestosterone (DHT). The expressions of AR and Skp2 in human naive PCa or CRPC specimens were detected by immunohistochemical staining followed by analysis of their differences and correlation. RESULTS: The Skp2 protein expression level was significantly higher in the C4-2 or 22RV1 cells than in the LNCaP cells. DHT treatment increased the expression of Skp2 in the C4-2 cells, but knock-down of Skp2 significantly up-regulated the expression of the well-known downstream protein P27 and down-regulated that of AR. Consistently, DHT treatment increased the activity of ARR3-Luc, while knockdown of Skp2 remarkably decreased it in the C4-2 and 22RV1 cells (P < 0.05). In addition, significantly higher expressions of Skp2 and AR were observed in the CRPC than in the naive specimens (P < 0.05), with a positive correlation between the two proteins (r = 0.658 1, P < 0.05). CONCLUSION: Skp2 can enhance the expression and transcription activity of the AR protein in CRPC cells or tissues and is promising to be a critical molecular therapeutic target. PMID- 26939396 TI - [Role and action mechanisms of FZD5 in prostate cancer bone metastasis in mice]. AB - OBJECTIVE: To investigate the action mechanisms of the FZD5 gene in prostate cancer bone metastasis and search for some new treatments for this disease. METHODS: We determined the expression level of the FZD5 gene in prostate cancer PC3 cells and, after transfection of siRNA into the PC3 cells and silence of the FZD5 gene, observed the changes in the migration and proliferation of the cells. We established the model of prostate cancer bone metastasis by tibial injection of prostate cancer cells in the nude mice. Then we injected control siRNA and FZD5-silenced siRNA into the tibia of the mice followed by evaluation of tumor induced bone destruction by X-ray imaging at 0, 1, and 3 weeks and by HE staining at 3 weeks after injection. RESULTS: After transfection of FZD5-silenced siRNA into the prostate cancer PC3 cells, the expression of the FZD5 gene was decreased about 70%. The rate of cell proliferation was significantly lower in the gene silencing group than in the control (P < 0.05), and that of cell migration dropped by 30% in the former as compared with the latter group at 48 hours after FZD5 silencing (P < 0.05). At 3 weeks after injection of control siRNA or FZD5 silenced siRNA into the tibia of the mice, osteolytic damage was observed in both groups, though less in the FZD5 silencing group, with only a few remaining bone trabeculae visible. CONCLUSION: Silencing the FZD5 gene can reduce the migration and proliferation of prostate cancer cells, help to suppress bone metastasis and destruction, and thereby improve the survival rate and quality of life of the patients. PMID- 26939397 TI - [Rat prostate glandular epithelial cells cultured in vitro and their barrier function]. AB - OBJECTIVE: To culture rat prostate glandular epithelial cells and study their barrier functions in vitro. METHODS: Rat prostate glandular epithelial cells were cultured in vitro. The expression of the tight junction protein claudin-1 was determined by immunohistochemistry, the structure and composition of the epithelial cells observed under the inverted microscope and transmission electron microscope. The transepithelial electrical resistances (TEERs) were monitored with the Millicell system. The permeability of the prostate glandular epithelial cells was assessed by the phenol red leakage test. RESULTS: Compact monolayer cell structures were formed in the prostate glandular epithelial cells cultured in vitro. Immunohistochemistry showed the expression of the tight junction protein claudin-1 and transmission electron microscopy confirmed the formation of tight junctions between the adjacent glandular epithelial cells. The TEERs in the cultured prostate glandular epithelial cells reached the peak of about (201.3 +/- 3.5) Omega/cm2 on the 8th day. The phenol red leakage test manifested a decreased permeability of the cell layers with the increase of TEERs. CONCLUSION: The structure and function of rat prostate glandular epithelial cells are similar to those of brain capillary endothelial cells, retinal capillary endothelial cells, and intestinal epithelial cells. In vitro cultured prostate glandular epithelial cells have the barrier function and can be used as a model for the study of blood prostate barrier in vitro. PMID- 26939398 TI - [Serum homocysteine and metabolic syndrome in middle-aged and elderly men]. AB - OBJECTIVE: To investigate the relationship among serum reproductive hormone levels, serum homocysteine (Hcy) levels, metabolic syndrome (MS), and the components of MS in middle-aged and elderly males. METHODS: Using the cluster and stratified sampling methods and a unified structured questionnaire, we conducted a survey among 948 men aged 40 - 80 years in the rural community, measured their basic physical parameters, and obtained their reproductive hormone levels, serum Hcy concentrations, and metabolism-related indicators. We collected 868 valid questionnaires along with their serum samples, divided the subjects into an MS and a non-MS control group in a 1:1 ratio, and measured their serum Hcy concentrations. RESULTS: Among the subjects included, 132 were diagnosed with MS. Nonparametric tests showed statistically significant differences between the MS and non-MS groups in the waist circumference (WC), waist-hip ratio (WHR), body mass index (BMI), systolic blood pressure (SBP), and diastolic blood pressure (DBP) (P < 0.05), but not in age (P > 0.05). Significant differences were also observed between the two groups in the levels of serum tT, SHBG, LH, and FTI (P < 0.05) , but not in the concentrations of serum Hcy (P > 0.05). The concentration of serum Hcy exhibited no correlation with BMI, SBP, DBP, FBG, TG, and HDL-C (P > 0.05) and had no influence on MS. CONCLUSION: The concentration of serum Hcy is not significantly correlated with MS, nor with its components. The levels of male serum reproductive hormones are associated both with MS and with its components. PMID- 26939399 TI - [The rate of morphologically normal sperm does not affect the clinical outcomes of conventional IVF in patients with one retrieved oocyte]. AB - OBJECTIVE: To investigate the influence of the rate of morphologically normal sperm (MNS) on the clinical outcomes of conventional in vitro fertilization (IVF) in patients with one retrieved oocyte. METHODS: From January 2013 to January 2015, a total of 256 couples with one retrieved oocyte underwent conventional IVF in our center. According to the rate of MNS, the patients were divided into two groups: MNS < 4% (134 cycles) and MNS >= 4% (122 cycles). We compared the rates of no transferrable embryo cycles, fertilization, cleavage, normal fertilization, abnormal fertilization, high-quality embryo and transferrable embryo between the two groups. A total of 75 fresh embryo transfer cycles were performed, 43 in the MNS < 4% group and the other 32 in the MNS >= 4% group. We also compared the rates of implantation, clinical pregnancy and abortion between the two groups. RESULTS: There were no statistically significant differences between the two groups in the rates of no transferrable embryo cycles, fertilization, cleavage, normal fertilization, abnormal fertilization, high-quality embryo and transferrable embryo (P > 0.05). The rates of implantation, clinical pregnancy and abortion exhibited no remarkable differences either in the fresh embryo transfer cycles between the two groups (P > 0.05). CONCLUSION: The rate of MNS does not affect the clinical outcomes of conventional IVF in patients with one retrieved oocyte. PMID- 26939400 TI - [Values of the sperm deformity index, acrosome abnormity rate, and sperm DNA fragmentation index of optimized sperm in predicting IVF fertilization failure]. AB - OBJECTIVE: To investigate the values of the sperm deformity index (SDI), acrosome abnormity rate (AAR), and DNA fragmentation index (DFI) of optimized sperm in the prediction of fertilization failure (fertilization rate < 25%) in conventional in vitro fertilization (IVF). METHODS: We selected 695 cycles of conventional IVF for pure oviductal infertility in this study, including 603 cycles of normal fertilization and 92 cycles of fertilization failure. On the day of oocyte retrieval, we examined sperm morphology, acrosome morphology, and DNA fragmentation using the Diff-Quik, PSA-FITC and SCD methods. We established the joint predictor (JP) by logistic equation and analyzed the values of different parameters in predicting fertilization failure with the receiver operating characteristic (ROC) curve. RESULTS: The fertilization rate was negatively correlated with SDI (r = - 0.07; P = 0.03), AAR (r = -0.49; P < 0.01), and DFI (r = -0. 21; P < 0.01). The SDI, AAR, and DFI in the normal fertilization group were 1.24 +/- 0.20, (7.75 +/- 2.28)%, and (7.87 +/- 3.15)%, and those in the fertilization failure group were 1.42 +/- 0.15, (12.02 +/- 3.06)%, and (13.32 +/- 4.13)%, respectively, all with statistically significant differences between the two groups (P < 0.05). SDI, AAR, and DFI were all risk factors of fertilization failure ( OR = 2.68, 14.11, and 3.85; P = 0.01, < 0.01, and < 0.01). The areas under the ROC curves for SDI, AAR, DFI, and JP were 0.651 +/- 0.033, 0.895 +/- 0.019, 0.789 +/- 0.022, and 0.915 +/- 0.017, respectively. According to the Youden index, the optimal cut-off values of SDI, AAR, and DFI obtained for the prediction of fertilization failure were approximately 1.45, 10%, and 12%. CONCLUSION: The SDI, AAR and DFI of optimized sperm are closely associated with the fertilization rate, and all have the value for predicting fertilization failure in IVF. The AAR is more valuable than the other single predictors, but JP is more effective than the AAR. PMID- 26939401 TI - [Antioxidating and energy metabolism improving effects of Qiangjing Decoction on oligospermia and asthenospermia: An experimental study]. AB - OBJECTIVE: To explore the mechanisms of Qianjing Decoction in the treatment of oligoasthenospermia (OAS). METHODS: We randomly divided 100 SPF male rats into five groups of equal number: normal, model, Huangjingzanyu, levocarnitine, and Qiangjing. OAS models were established in the animals followed by intragastrical administration of normal saline, ornidazole, Huangjingzanyu Capsules (200 mg per kg body weight per day), levocarnitine (100 mg per kg body weight per day), and Qianjing Decoction (10 g per kg body weight per day), respectively, qd, for 4 successive weeks. Then, we detected the concentration and motility of the epididymal sperm, obtained the contents of superoxide dismutase (SOD), malonaldehyde (MDA), glutathione peroxidase (GSH-Px), lactate dehydrogenase (LDH), alpha-glucosidase, and fructose in the epididymis, and determined the mRNA expressions of nuclear factor erythroid 2-related factor 2 (Nrf2) and succinate dehydrogenase (SDH) in the epididymal tissue of the rats by real-time PCR. RESULTS: The concentration and motility of the epididymal sperm in the model, Huangjingzanyu, levocarnitine, and Qianging groups were (35.34 +/- 4.22) x 10(6)/ml and (40.04 +/- 7.05)%, (48.12 +/- 5.56) x 10(6)/ml and (62.46 +/- 7.12)%, (47.14 +/- 4.87) x 10(6)/ml and (63.23 +/- 6.34)%, and (50.25 +/- 5.08) x 10(6)/ml and (66.34 +/- 7.58)%, respectively, all significantly lower than in the normal group ([53.05 +/- 4.55] x 10(6)/ml and [70.20 +/- 8.54]%) (P < 0.05), but remarkably higher in the Huangjingzanyu, levocarnitine, and Qiangjing groups than in the model rats (P < 0.05). Compared with the thinned epididymal lumen walls, decreased sperm count, and disorderly and loose arrangement of the lumens in the OAS models, the rats in the Huangjingzanyu, levocarnitine, and Qiangjing groups showed evidently thicker epididymal lumen walls, with the lumens full of sperm cells and arranged regularly and compactly, similar to those of the normal rats. The levels of SOD and GSH-Px were significantly lower but that of MDA markedly higher in the model rats ([84.12 +/- 23.25], [10.56 +/- 3.02], and [14.04 +/- 2.06] nmol/mg) than in the normal group ([110.04 +/- 19.56], [17.25 +/- 3.56], and [8.87 +/- 1.35] nmol/mg) (P < 0.05), while the former two indexes remarkably higher and the latter one significantly lower in the animals treated with Qiangjing Decoction ([120.56 +/- 23.68], [16.34 +/- 3.12], and [8.45 +/- 1.56] nmol/mg), Huangjingzanyu Capsules ([115.34 +/- 21.35], [15.23 +/- 3.67], and [8.33 +/- 1.54] nmol/mg), and levocarnitine ([116.67 +/- 22.67], [15.35 +/- 3.45], and [8.05 +/- 1.78] nmol/mg) than in the models (P < 0.05). The levels of fructose, LDH and alpha-glucosidase were decreased markedly in the OAS models ([100.22 +/- 12.12] mg/[ ml x g], [322 +/- 46.13] U/[ ml x g], and [10.48 +/- 2.33] U/[ml x g]) as compared with the normal rats ([128.12 +/- 13.45] mg/[ml x g], [428 +/- 35.12] U/[ml x g], and [15.34 +/- 3.12] U/[ ml x g]) (P < 0.05), remarkably higher in the rats treated with Qiangjing ([130.23 +/- 13.67] mg/[ml x g] [455 +/- 51.50] U/[ml x g], and [18.56 +/- 4.67] U/[ml x g]), Huangjingzanyu ([124.16 +/- 14.02] mg/[ml x g], [ 419 +/- 43.14] U/[ml x g], and [17.64 +/- 4.08] U/[ml x g]), and levocarnitine ([123.34 +/- 14.02] mg/[ml x g], [430 +/- 31.80] U/ [ml x g], and [16.85 +/- 5.55] U/[ml x g]) than in the models (P < 0.05). The Nrf2 mRNA expression was significantly reduced in the models as compared with the normal rats (P < 0.05) but remarkably increased in the Huangingzanyu, Qiangjing and levocarnitine groups as compared with the model and normal animals (P < 0.05). The SDH mRNA expression was significantly lower in the model than in the normal rats (P < 0.05) but markedly elevated in the Huangjingzanyu, Qiangjing and levocarnitine groups as compared with the model and normal animals (P < 0.05), remarkably higher in the Qiangjing than in the Huangjingzanyu group (P < 0.05). CONCLUSION: Ornidazole induces OAS in rats, which is closely associated with excessive oxidation and energy metabolism dysfunction. Qiangjing Decoction can improve and even reverse ornidazole-induced OAS in rats as well as improve the ultrastructure of their testicular and epididymal tissues. Antioxidation and improvement of energy metabolism are probably the action mechanisms of Qiangjing Decoction in the treatment of OAS. PMID- 26939402 TI - [Non-coding RNAs and erectile dysfunction: An update]. AB - Erectile dysfunction (ED) is a disease associated with a variety of factors such as age, psychological factors, physical conditions, and lifestyle, and it severely affects the patients quality of life. In the past, some non-coding RNAs (ncRNAs) transcribed by genes but not translated into the protein were regarded as the "waste" in the process of gene expression. But in the recent years, ncRNAs have been found to play a crucial role in regulating gene expression and its products, which may affect penile erectile function. This review focuses on the recent progress in the studies of the relationship between ncRNAs and erectile dysfunction. PMID- 26939403 TI - [Intravaginal ejaculatory latency time: Advances in studies]. AB - Although premature ejaculation (PE) is a common type of male sexual dysfunction, to date we lack a unified definition of PE. The multidimensional definition of PE has been accepted by more and more clinicians. Intravaginal ejaculatory latency time (IELT) is one of the three important dimensions (time to ejaculation, inability to control or delay ejaculation, and negative consequences) for defining PE. Rapid ejaculation is one of the core symptoms of PE and IELT is an objective measurement as well as an important tool for the evaluation of PE. This article reviews estimated IELT, stopwatch-measured IELT, the correlation between estimated and stopwatch-measured IELT, and the factors affecting IELT in the general male population, PE patients, and those complaining of PE. PMID- 26939404 TI - [Relationship of MTHFR gene polymorphisms with infertility]. AB - The folate metabolic pathway plays important roles in cellular physiology by participating in nucleotide synthesis, DNA repair and methylation, and maintenance and stability of the genome. Methylenetetrahydrofolate reductase (MTHFR) is a key regulatory enzyme involved in folate metabolism. Polymorphisms of MTHFR may change the level of homocysteine and affect DNA synthesis and methylation, leading to an increased oxidative stress and disturbed methylation reactions and consequently affecting reproductive function. This article presents an overview on MTHFR gene polymorphisms, proposing that multicentered, large sample and long-term prospective studies are needed to reveal the relationship between MTHFR gene polymorphisms and infertility. PMID- 26939405 TI - [Roles of G protein-coupled estrogen receptor in the male reproductive system]. AB - The G protein-coupled estrogen receptor (GPER), also known as G protein-coupled receptor 30 (GPR30), was identified in the recent years as a functional membrane receptor different from the classical nuclear estrogen receptors. This receptor is widely expressed in the cortex, cerebellum, hippocampus, heart, lung, liver, skeletal muscle, and the urogenital system. It is responsible for the mediation of nongenomic effects associated with estrogen and its derivatives, participating in the physiological activities of the body. The present study reviews the molecular structure, subcellular localization, signaling pathways, distribution, and function of GPER in the male reproductive system. PMID- 26939406 TI - Guest Editorial. PMID- 26939407 TI - Making Sense of Millennials. PMID- 26939408 TI - Thanksgiving in the ER. PMID- 26939409 TI - Opportunity. PMID- 26939410 TI - Thank You for Honoring Mr. Wood. PMID- 26939411 TI - Periodontal Disease and Systemic Diseases: An Update for the Clinician. AB - A link between periodontal disease and various systemic diseases has been investigated for several years. Interest in unearthing such a link has grown as the health care profession is looking for a better understanding of disease processes and their relationships to periodontal and other oral diseases. The article aims to provide recent information on the relationship between periodontal disease and systemic diseases such as; cardiovascular, respiratory, endocrine, musculoskeletal, and reproductive system related abnormalities. PMID- 26939412 TI - Emerging Therapeutic Strategies and Future Challenges in Clinical Periodontics. AB - Currently, the protocol for treating periodontitis follows a standardized and straightforward algorithm: 1) review and reinforce oral hygiene; 2) perform scaling and root planing; 3) proceed to periodontal surgery if the disease process has not been arrested; then 4) enroll the patient in a customized periodontal maintenance recall program to maintain the health of the reduced periodontium. Multiple longitudinal studies have demonstrated that the aforementioned treatment regimen can arrest the progression of periodontitis and can increase the likelihood of tooth retention and periodontal stability. PMID- 26939413 TI - Peri-Implant Disease--A Significant Complication of Dental Implant Supported Restorative Treatment. AB - Over past several decades, oral rehabilitation of fully or partially edentulous patients with dental implants has become a routine procedure in daily practice. Dental implant supported and retained prosthesis can provide a wide variety of treatment options to patients due to their high predictability and survival rate. While many patients treated with dental implants have had high long term success, they are not completely free of complications. Proper patient selection, treatment planning, surgical and prosthodontic procedures, material selection and routine maintenance around the peri-implant tissues are keys to this long term success rate. PMID- 26939414 TI - Hermey Wants to Be a Dentist. AB - I hope you had a festive and enjoyable holiday season. The American Dental Association tried to liven up the holidays with a public service campaign to remind us all to be careful when we are indulging in our sugary snacks. They enlisted the services of Hermey the Elffrom the Rudolf the Red-Nosed Reindeer cartoon. PMID- 26939415 TI - What's the Price of a Helicopter? AB - A while back during the height of the cosmetic dentistry craze, the North Central Dental Society invited a renowned cosmetic dentist from Arizona to present a continuing education program. PMID- 26939416 TI - [SURGICAL TREATMENT OF THE INJURED PERSONS FOR COMBINED CRANIO-ABDOMINAL TRAUMA IN AN ACUTE PERIOD OF TRAUMATIC DISEASE]. AB - The results of surgical treatment of 281 injured persons for combined cranio abdominal trauma in acute period of traumatic disease, were analyzed. Depending on the trauma and internal organs injuries severity, there were applied: conservative therapy, mini-invasive interventions, laparotomy for abdominal element of the trauma, also there were determined the operation volume (complete, reduced, minimal) and expediency of the "damage control" tactics application. It made possible to perform conservative therapy in the main group in 12.6% injured persons, laparoscopic operations--in 35%, and to reduce laparotomy operations duration trustworthy. Indications for craniotomy in acute period of trauma were established in 9 injured persons of a control group and in 15--of the main group. While indications for craniotomy and laparotomy presence, the operation on abdominal organs was performed primarily or both interventions were done simultaneously with minimal or reduced volume. PMID- 26939417 TI - [THE WAYS OF OBJECTIVIZATION OF LIGHT CRANIO-CEREBRAL TRAUMA IN ACUTE PERIOD]. AB - In the analysis 41 injured persons were included, ageing (37.3 +/- 0.5) yrs old at average with light cranio-cerebral trauma. The patients were examined in accordance to actual recommendations of Ukrainian Ministry of Health, using a tonal the threshold audiometry, computeric stabilography (CS). In accordance to data of computeric tomography, concussion of brain (CB) revealed in 32 patients, contusion of brain of light degree--in 9. Using the method of the factor analysis the factors were established, which have determined 55.1% of integral dispersion of the variants values. The changes of basal principles of statokinesiograms (SKG)--enhancement of the oscillations amplitude of common centre of pressure in sagital square and a square of SKG in a modified functional Romberg test with closed eyes--may be applied as objective criteria of a CB diagnosis. PMID- 26939418 TI - [RESULTS OF GASTROPLASTY, USING ILEOCECAL SEGMENT OF INTESTINE AFTER COMBINED GASTRECTOMY]. AB - Results of treatment of 18 patients for locally spread gastric cancer, in whom after combined gastrectomy gastroplasty was accomplished, using ileocecal intestinal segment (the main group), were presented. In a comparison group 20 patients were included, in whom after combined gastrectomy end-to-loop esophagojejunoanastomosis was formated. Early postoperative complications have occurred in the main group--in 7 (38.8%) patients, and in comparison group--in 6 (30%). Postoperatively 2 (11.1%) and 2 (10%) patients died, accordingly. Gastroplasty, using ileo-cecal intestinal segment, have promoted reduction of the remote postgastrectomy syndromes occurrence rate from 58.8 to 11.1%. In a comparison group median survival was 18.6 mo, and in the main--a survival mediana was not achieved, because the investigation still goes on. PMID- 26939419 TI - [ENDOSCOPIC PAPILLECTOMY]. AB - Experience of performance of endoscopic papillectomy in 7 patients, suffering benign tumors of duodenal papilla magna, was adduced. The tumors were revealed while conducting endoscopic retrograde pancreatocholangiography, the diagnosis was verified, basing on morphological investigation data on the biopsy material. Endoscopic ultra-sonographic investigation was conducted with the objective to reveal the process spread. While intestinal extramucosal tumoral spread on a distal part common biliary duct, pancreatic duct the endoscopic papillectomy is contraindicated. In 4 (57.1%) patients endoscopic papillectomy was performed in accordance to method of the loop electroexcision, and in 3 (42.9%)--in accordance to the method, elaborated in the clinic. PMID- 26939420 TI - [SURGICAL TREATMENT OF GASTROESOPHAGEAL REFLUX DISEASE]. AB - Results of operative treatment of 136 patients in 2005-2015 yrs, suffering gastroesophageal reflux disease, are presented. Basing on the deepened comparative analysis of the early postoperative period course peculiarities, the efficacy and lesser traumaticity of miniinvasuve intervention was proved, concerning lesser duration of pulmonary artificial ventilation, lesser doses of preparations for narcosis, a systolic arterial pressure normalization, as well as the respiration rate up to 12 h postoperatively, lesser intensity of pain (in accordance to the visual analogue scale), lesser doses and quantity of application of narcotic analgetics, early restoration of intestinal peristalsis and the patients activity. PMID- 26939422 TI - [MORPHOLOGICAL PECULIARITIES OF MUSCULO-APONEUROTIC TISSUES OF ANTERIOR ABDOMINAL WALL IN PATIENTS, SUFFERING MORBID OBESITY]. AB - Results of morphological investigation of musculo-aponeurotic structures of anterior abdominal wall were presented in the morbid obesity patients. The role of obesity as a primary cause for morphofunctional insufficience of musculo aponeurotic structures was established. PMID- 26939421 TI - [HORMONAL-GENETIC SCREENING IN PATIENTS, SUFFERING GASTRODUODENAL ULCER HEMORRHAGE]. AB - Genetic-hormonal regulation plays a key pathophysiologic role in a blood loss on background of complicated gastroduodenal ulcer disease, but a clinical significance of some genes of compensatory steroidogenesis remains unrevealed. Examination of 63 patients, using a chain reaction with polymerase (CRP); analysis of length of restriction fragments (CRP-RFLP) and immunohistochemical investigation of gastroduodenal mucosa were performed on the base of a Sumsky Rural Clinical Hospital. Trustworthy difference of distribution of polymorphic genes ESR1 and VKORC1 in patients of both gender in presence of the ulcer hemorrhage was not revealed, excluding genotype A/A VKORC1, what trustworthy more frequently was revealed in women (p < 0.05). There was established, that intact zone of gastric fundus owes immunoreactivity towards alpha-receptors of estrogen in nuclei of epitheliocytes and stromocytes. Diagnosis of polymorphic gene VKORC1 and expression of the estrogen receptors may serve the base for pathogenetic therapy in patients with hemorrhage occurrence. PMID- 26939423 TI - [IMPROVEMENT AND CHOICE OF COLOSTOMY METHOD IN THE TREATMENT OF PATIENTS, SUFFERING AN ACUTE OBTURATIVE IMPASSABILITY OF LARGE BOWEL]. AB - Colostomy was done in 49 patients, suffering an acute obturative impassability of large bowel (AOILB). In 28 patients (1st group) colostomy was conducted in accordance to standard method; in 21 (2nd group)--in accordance to the method, proposed by us. Application of the method proposed for surgical treatment of AOILB have guaranteed a reduction of postoperative paracolostomal complications rate in 6.8 times, of postoperative lethality--in 2.2 times, duration of the patient stationary treatment--in 1.4 times, the rate of dressings and the dressing material expanses--in 10 times. PMID- 26939424 TI - [CHANGES OF A TREATMENT PROGRAM FOR AN ACUTE PANCREATITIS]. AB - Pathogenetically substantiated program of complex diagnosis, prophylaxis and treatment of purulent-necrotic complications (PNC) was elaborated for improvement of results of the necrotic pancreatitis treatment. With the objective to study the PNC pathogenesis and a probation of new preparations for local treatment the experimantal simulation of the disease was accomplished. There was proved, that during the disease course the integrity of pancreatic ductal system is disordered . A 42-year experience of treatment of an acute pancreatitis was analyzed. In I period (1970 - 1980) the operative interventions were conducted; in 11 period (1981 - 1991)--a scientifically substantiated conservative therapy; in III period (1992 - 2000)--the diagnostic procedures possibilities were extended, and operative intervention were performed in accordance to severe indications. There was established, that the main cause of PNC is a secondary microbal contamination occurrence on the third-fifth postoperative days, the immediate manipulations on pancreatic gland are forbidden; a one-time surgical processing of the necrosis foci is insufficient; the staged necrsequestrectomy constitutes the optimal operation. PMID- 26939425 TI - [THE PLACE OF PANCREATICODUODENAL RESECTION IN SURGICAL TREATMENT OF COMPLICATED FORMS OF CHRONIC PANCREATITIS]. AB - Results of surgical treatment of 120 patients, suffering complicated forms of chronic pancreatitis, were analyzed. In 5 patients pancreaticoduodenal resection in accordance to Whipple method have constituted the operation of choice. The indications for operation were: impossibility to exclude completely the malignant process inside pancreatic head; enhancement of the pancreatic head, causing duodenal, common biliary duct and the pancreatoduodenal zone vessels compression; cystic changes of pancreatic head with several episodes of hemorrhage inside the cyst and duodenum. The immediate, short-term and intermediate results of the operation were estimated as good and satisfactory. PMID- 26939426 TI - [APOPTOSIS AND NECROSIS OF CIRCULATING NEUTROPHILS IN PATIENTS WHILE HIGH RISK OF POSTOPERAIVE PERITONITIS OCCURRENCE]. AB - Processes of apoptosis and necrosis of peripheral neutrophils were investigated in 43 patients, operated on for an acute abdominal organs diseases on the first and fourth postoperative days. Changes of apoptosis and necrosis processes in peripheral neutrophils in dynamics were established. Unfavorable course of early postoperative period in patients with initial high and average risk of postoperative peritonitis occurrence was accompanied by shift in necrosis/apoptosis ratio towards necrosis of peripheral neutrophils. PMID- 26939427 TI - [PULMONARY COMPLICATIONS IN CHILDREN, OPERATED ON FOR INBORN HEART FAILURES IN THE ARTIFICIAL BLOOD CIRCULATION ENVIRONMENT]. AB - The risk factors of pulmonary complications occurrence were analyzed in children, operated on for inborn heart failures in atrificial blood circulation environment. Pulmonary complications rate and the risk factors of their occurrence were analyzed. PMID- 26939428 TI - [EFFICACY OF ALGORITHM OF SURGICAL HELP PROVISION FOR PATIENTS, SUFFERING MULTIRESISTENT PULMONARY TUBERCULOSIS]. AB - The impact of preoperative patients state in multiresistent pulmonary tuberculosis on results of their surgical treatment was investigated. The actions sequence with determination of optimal kind and volume of surgical intervention, depending on clinico-anatomical peculiarities of pathological process, was regulated. Algorithm of surgical treatment organization in patients, suffering multiresistent pulmonary tuberculosis, was elaborated and introduced, concerning the term and volume of preoperative examination and preparation determination, sequence of actions for determination of kind and technique of the operative intervention performance, as well as postoperative treatment issues. Application of the algorithm elaborated have guaranteed a reconvalescence of 97.6% patients with absent lethality. PMID- 26939429 TI - [AUTOIMMUNE REACTIONS IN PATIENTS WITH DISEASES OF A THYROID GLAND]. AB - A state of autoimmunity was studied in 25 patients, suffering diffuse toxic goiter (DTG), and in 20--in nodular euthyroid goiter (NEG) before and after the operation. The level of circulating immune complexes, quantity of cytotoxic lymphocytes, the subpopulation index, the apoptosis marker were determined. There was established, that in NEG autoimmune disorders have occurred rarer and were less severe, than in DTG. PMID- 26939430 TI - [PROGNOSTICATION OF "HARD" TRACHEAL INTUBATION IN PATIENTS, SUFFERING PURULENT INFLAMMATORY DISEASES OF THE JAW-FACIAL REGION]. AB - Clinical follow-up was conducted in 75 patients, to whom the operation and intensive therapy were performed in 2006-2015 yrs for phlegmon of the neck. Difficulties while providing passability of respiratory ways have occurred in 73.3% patients. It was established, that the predictors of "hard" tracheal intubation in patients, operated on for cervical phlegmon, are follows: the cervical tissues oedema, restriction of the mouth opening lesser than 3 cm, odontogenous phlegmon of oral cavity and the neck, rigid epiglottis, the larynx oedema. Presence of these factors demands application of endoscopic methods for tracheal intubation in such patients. PMID- 26939431 TI - [THE ROLE OF ENDOSCOPIC MAMMODUCTOSCOPY IN COMPLEX DIAGNOSIS OF INTRADUCTAL TUMORS OF MAMMARY GLAND]. AB - First Ukrainian experience in endoscopic mammoductoscopy (EMDS) conduction in 112 patients for revealing of intraductal tumors of mammary gland is presented. In comparison with roentgenological, ultrasonographic and cytological diagnostical methods, EMDS for intraductal tumors of mammary gland differs by highest sensitivity (90.3%) and accuracy (80.2%), but insufficient (47.4%) specificity. To improve the surgical treatment results the authors propose their own method of marking of the mammary gland intraductal tumors under endoscopic and echographic control. PMID- 26939432 TI - [CRITERIA OF ESTIMATION AND RESULTS OF TREATMENT OF IATROGENIC INJURIES OF URETERS IN ONCOLOGICAL PATIENTS]. AB - Clinical analysis was conducted in 74 oncological patients, in whom 103 iatrogenic injuries of ureter (IIU) were revealed and for which they were treated in Scientific-nvestigative Department of Plastic and Reconstructive Oncourology. Restoration of renal and ureteric function were noted in terms up to 6 mo, in these terms were revealed all complications, caused by recurrence of obstruction. Late follow-up results of III were positive in 95.2% patients, unsatisfactory result was revealed in 3 (4.8%) patients, what have demanded conduction of surgical secondary correction of urodynamics. Quality of life after restoration operative treatment have improved in 31.70%patients in comparison of such before the operation. PMID- 26939433 TI - [COMPLEX OF THE TREATMENT MEASURES IN A SYSTEM OF THE MEDICAL CARE DELIVERY TO WOUNDED PERSONS WITH THE GUN-SHOT AND MINE-EXPLOSIVE INJURIES OF THE FOOT]. AB - Complex of the treatment measures, conducted in 302 wounded persons, suffering the gun-shot and mine-explosive injuries of the foot in 2014 - 2015 yrs, was analyzed. Primary surgical processing of the wound was conducted in all injured persons, secondary surgical processing--in 64.6%, the foot bones osteosynthesis- in 13.9%, primary immobilization, using improvised tire--in 77.8%, secondary immobilization, using the plaster splint--in 48.1%, llizarov's spokes--in 35.2%, Ilizarov's apparatus--in 18.5%, the rods apparatuses of external fixation--in 16.7%. For improvement of functioning of a modern system for the treatment evacuation provision it is necessary, to reduce the quantity of levels of the medical help provision maximally. PMID- 26939434 TI - [TECHNIQUE OF EXPERIMENTAL STENTING OF VESSELS FOR INVESTIGATIONS IN VIVO]. AB - Introduction of a new systems for the vessels stenting into clinical practice demands conduction of preclinical investigations in vivo. The method of vascular stents implantation into abdominal aorta of a rabbit, using peripheral vascular catheter, was presented. Successively were presented surgical aspects of the vessels stenting in experiment, estimation of functional state of the heart and aorta, morphometric indices of the stent in 30 days after operation. Introduction of the method depicted permits to simplify a surgical technique, to minimize the expanses for conduction of interventions on vessels in experiment. The method do not demand application of special endovascular equipment and may be successfully realized in environment of the general surgery operation room for conduction of experimental investigations on the stends. PMID- 26939435 TI - [TOTAL PANCREATICODUODENECTOMY WITH RESECTION OF HEPATIC ARTERY AND PORTAL VEIN FOR THE PANCREATIC HEAD CANCER]. PMID- 26939436 TI - [SURGICAL TREATMENT OF AORTO-CAVAL FISTULA ON BACKGROUND OF DISSECTING INFRARENAL ANEURISM OF ABDOMINAL AORTA]. PMID- 26939437 TI - [Advances in CRISPR/Cas9-mediated gene editing]. AB - Clustered regulatory interspaced short palindromic repeats (CRISPR) found in bacteria and archaea genome that contains multiple short repeats loci, provides acquired immunity against invading foreign DNA via RNA-guided DNA cleavage. The first inkling of this hot new genetic engineering tool turned up in 1987, when a research team observed an oddly repetitive sequence at one end of a bacterial gene. Now three types of CRISPR/Cas system have been identified: types I, II and III. In the type II CRISPR/Cas9 system, short segments of foreign DNA termed 'spacers' are integrated within the CRISPR genomic loci, transcribed and processed into short CRISPR RNA (crRNA). These crRNAs anneal to trans-activating crRNA (tracrRNA) and direct sequence-specific cleavage in that a double-strand break (DSB) is generated by Cas proteins. Based on these findings, various genetic methods, including gene targeting (Gene disruption), gene insertion, gene correction etc., are being designed to manipulate the genomes of different species at specific loci. Compared with zinc finger nucleases (ZFN) and transcription activator-like effector nucleases (TALEN), CRISPR/Cas9 is simpler with higher specificity and less toxicity. This review summarizes recent progress, discusses the prospects of CRISPR/Cas9 system, with an emphasis on its structure, principle, applications and potential challenges, and provides a useful reference for researchers who are interested in this new technique. PMID- 26939438 TI - [Sporulation or competence development? A genetic regulatory network model of cell-fate determination in Bacillus subtilis]. AB - Bacillus subtilis is a generally recognized as safe (GRAS) strain that has been widely used in industries including fodder, food, and biological control. In addition, B. subtilis expression system also plays a significant role in the production of industrial enzymes. However, its application is limited by its low sporulation frequency and transformation efficiency. Immense studies have been done on interpreting the molecular mechanisms of sporulation and competence development, whereas only few of them were focused on improving sporulation frequency and transformation efficiency of B. subtilis by genetic modification. The main challenge is that sporulation and competence development, as the two major developmental events in the stationary phase of B. subtilis, are regulated by the complicated intracellular genetic regulatory systems. In addition, mutual regulatory mechanisms also exist in these two developmental events. With the development of genetic and metabolic engineering, constructing genetic regulatory networks is currently one of the most attractive research fields, together with the genetic information of cell growth, metabolism, and development, to guide the industrial application. In this review, the mechanisms of sporulation and competence development of B. subtilis, their interactions, and the genetic regulation of cell growth were interpreted. In addition, the roles of these regulatory networks in guiding basic and applied research of B. subtilis and its related species were discussed. PMID- 26939439 TI - [Pathways of flowering regulation in plants]. AB - Flowering, the floral transition from vegetative growth to reproductive growth, is induced by diverse endogenous and exogenous cues, such as photoperiod, temperature, hormones and age. Precise flowering time is critical to plant growth and evolution of species. The numerous renewal molecular and genetic results have revealed five flowering time pathways, including classical photoperiod pathway, vernalization pathway, autonomous pathway, gibberellins (GA) pathway and newly identified age pathway. These pathways take on relatively independent role, and involve extensive crosstalks and feedback loops. This review describes the complicated regulatory network of this floral transition to understand the molecular mechanism of flowering and provide references for further research in more plants. PMID- 26939440 TI - [Expression of angiopoietin-like proteins for animal breeding: a review]. AB - Angiopoietin-like proteins are a family of proteins that are closely related to lipid, glucose and energy metabolism, as well as angiogenesis. To date, eight Angptls have been discovered, namely Angptl1 to Angptl8 that play key roles in metabolic regulation and marker assisted selection. In this review, we summarized current progress on the structure, signaling pathways, upstream regulatory genes and metabolic network of Angptl1-8. Finally, in combination with our work, the status and problems of animal breeding as well as the future prospects for Angptls were discussed. PMID- 26939441 TI - [Development and evaluation of an inactivated bivalent vaccine against duck viral hepatitis]. AB - The rapid mutation and widely spread of duck hepatitis A virus (DHAV) lead to the vast economic loss of the duck industry. To prepare and evaluate bivalent inactivated vaccine laboratory products of DHAV, 6 strains were screened from 201 DHAV-1 strains and 38 DHAV-3 strains by using serotype epidemiological analysis in most of the duck factory. Vaccine candidate strains were selected by ELD50 and LD50 tests in the 6 strains. Continuously passaged, the 5th passaged duck embryos bodies grinding fluid was selected as vaccine virus seeds. The virus seeds were treated with formaldehyde and water in oil in water (W/O/W) emulsions, making into three batches of two bivalent inactivated vaccine laboratory products. The safety test, antibody neutralization test, challenged protection and cross immune protection experiment suggested that the vaccines possessed good safety, and neutralizing antibodies were detected at 7th day and the challenged protection rate reached 90% to 100% at the 14th and 21st day. Moreover, immune duration of ducklings lasted more than five weeks. However, cross-immunity protection experiments with DHAV-SH and DHAV-FS only had 20%-30%. The two bivalent inactivated vaccine laboratory products of duck viral hepatitis were effective and reliable, providing a new method as well as a new product for DHAV prevention and control. PMID- 26939442 TI - [Overexpressing 3-ketosteroid-Delta1-dehydrogenase for degrading phytosterols into androst-1,4-diene-3,17-dione]. AB - We constructed plasmid pMTac to overexpress 3-ketosteroid-Delta1-dehydrogenase (KSDD) in Mycobacterium neoaurum JC-12 for improving androst-1,4-diene-3,17-dione (ADD) production. To construct pMTac, pACE promoter on pMF41 was replaced by tac promoter, and then four recombinants were constructed, which were M. neoaurum JC 12/pMF41-gfp, M. neoaurum JC-12/pMTac-gfp, M. neoaurum JC-12/pMF41-ksdd and M. neoaurum JC-12/pMTac-ksdd. Fluorescence detection results show that much more green fluorescent protein (GFP) was expressed in M. neoaurum JC-12/pMTac-ksdd than M. neoaurum JC-12/pMF41-ksdd. The activity of KSDD was 2.41 U/mg in M. neoaurum JC-12/pMTac-ksdd, 6.53-fold as that of M. neoaurum JC-12 and 4.36-fold as that of M. neoaurum JC-12/pMF41-ksdd. In shake flask fermentation, ADD production of M. neoaurum JC-12/pMTac-ksdd was 5.94 g/L, increased about 22.2% compared to the original strain M. neoaurum JC-12 and 12.7% to M. neoaurum JC 12/pMF41-ksdd. AD (4-androstene-3,17-dione) production of JC-12/pMTac-ksdd was 0.17 g/L, decreased 81.5% compared to M. neoaurum JC-12 and 71.2% to M neoaurum JC-12/pMF41-ksdd. In the 5 L fermenter, 20 g/L phytosterols was used as substrate, ADD production of M. neoaurum JC-12/pMTac-ksdd was improved to 10.28 g/L. pMTac is favorable for expressing KSDD in M. neoaurum JC-12, and overexpression of KSDD has beneficial effect on ADD producing, and it is the highest level ever reported using fermentation method in M. neoaurum. PMID- 26939443 TI - [Detection of cadmium by a double-promoters based Escherichia coli biosensor]. AB - To detect cadmium ions, we constructed a specific microbial sensor and screened detecting cassettes and different fluorescence proteins. Blue fluorescence protein mTagBFP2 was selected as a reporter and a double-promoters model was used in the construction of the fusion reporter vector Pmer::merR-m-Pmer::mTagBFP2 pMD19-T. The reporter vector was then transformed into Escherichia coli MC4100 wild type strain. The medium, incubation time, initial density for induction, and the optimal detection range were determined. The specificity of the biosensor was also checked. The biosensor responded specifically to cadmium irons with low background, and the linear concentration range detection ranged from 0.1 to 75 MUmol/L at the initial OD600 = 0.1 with 2 h incubation in IHMM medium. Thus we successfully constructed a specific biosensor to detect cadmium irons and provided useful strategies for development and optimization of microbial sensors to detect heavy metals. PMID- 26939444 TI - [Cloning and expression profile of Bmyan in the silkworm (Bombyx mori) and experimental validation as one target of microRNA 7]. AB - microRNAs (miRNAs) are an extensive class of -22-nucleotide (nt) endogenous noncoding RNAs regulating life activities ofmetazoans through binding to 3' untranslated regions (3'-UTRs) of their target genes. This work aimed to identify yan gene in the silkworm, reveal its expression profile and confirm if it is one target of bmo-miR-7 and, as such, have potential for contributing to better understanding of the molecular mechanisms involved in the metamorphosis of silkworm. Based on homolog searching and PCR amplification, we cloned the coding sequence (CDS) of Bmyan, which encodes 476 amino acid residues and contains SAM PNT and ETs domains. Quantitative PCR (q-PCR), RT-PCR and microarray data revealed high expression of Bmyan in the head, body wall and ovary of day-3 fifth instar larval silkworm, low or no expression in other tissues. It was lowly expressed in the early larval stages, but highly expressed from late spinning to day 4 pupa. The 3'-UTR of Bmyan was obtained by rapid-amplification of cDNA ends (3'RACE) and predicted to contain two potential recognition sites of bmo-miR-7. The luciferase reporter vector containing the 3'-UTR of Bmyan was constructed and co-transfected into BmE cell line with the mimic of bmo-miR-7 and the decreased relative activity of luciferase showed that Bmyan is one target of bmo-miR-7. This work helps further functional analysis of bmo-miR-7 and Bmyan in the silkworm. PMID- 26939446 TI - [Expression, purification and characterization of recombinant onconase expressed in Pichia pastoris]. AB - Ranpirnase (onconase, ONC) is a new drug, with weak RNase activity and strong cytotoxicity to various tumor cells in vitro and in vivo. This study is to obtain recombination onconase (rONC) with high bioactivity. Based on the codon preference of Pichia pastoris, we designed and synthesized the gene according to cDNA sequences of ONC and the alpha mating factor's prepeptide. We screened positive clones after transforming the recombination plasmids into P. pastoris X 33, GSS115 and SMD1168. We screened the best combination of seven different vectors and host strains. Moreover, we optimized culture condition in shake flasks and 10 L bioreactor, and purified rONC from the supernatant after inducing it with 0.25% methanol by aqueous two-phase extraction coupling G50 molecular exclusion method. The highest rONC production was 13 mg/L in pPICZalpha-A/X 33/ONC combination under the condition of pH 5.5 and 23 degrees C in shake flasks for 7 d; and that the highest rONC production was 180 mg/L when the induction is performed in the lower basic salt medium with pH 5.5 in the 10 L bioreactor for 7 d. The yield of rONC is more than 90% at a purity of above 95%. rONC can kill various tumor cells in vitro. The expression and purification of rONC would be useful for further investigation of this new drug. PMID- 26939445 TI - [Prokaryotic expression of Staphylococcus aureus Clumping factor B and evaluation of the antiserum-mediated opsonic activity]. AB - Staphylococcus aureus is a major cause of hospital-acquired infection. Because the bacteria are very easy to become resistant to antibiotics, vaccination is a main method against S. aureus infection. Clumping factor B (ClfB) is an adhesion molecule essential for S. aureus to colonize in the host mucosa and is regarded as an important target antigen. In this study, we successfully used Escherichia coli to express a segment encoding the N1-N3 regions of ClfB protein (Truncated ClfB) cloned from S. aureus. The protein was purified by affinity and ion exchange chromatographies and gel filtration. Rabbits were immunized three times with purified Truncated-ClfB. After that, blood was collected to prepare serum which were then used for measurement of antibody level. Phagocytosis of S. aureus opsonized by the serum was determined by a flow cytometry. Results show that the serum IgG titer reached 1:640 000. Phagocytosed S. aureus by polymorphonuclear leukocytes were significantly more when the bacteria were opsonized by the serum from Truncated-ClfB immunized rabbits than those from no immunized group (P < 0.01). Therefore, the results indicated that Truncated-ClfB could be a promising vaccine candidate against S. aureus infection. PMID- 26939447 TI - [Application of reverse phase C18 tip in pretreatment of small amount complex proteomic samples]. AB - To develop a timesaving and easy operating Reverse Phase (RP) chromatography method, we adopted Thermo Pierce RP C18 Tip to separate small amount hippocampus peptide mixtures and to compare with high performance liquid chromatography (HPLC). According to the separation performance of 4 ACN gradient optimization methods, we determined the best ACN concentration gradient. The results showed that, the experiment took only 10 min by separating with eight ACN concentration gradient, which accounted 1/4 for HPLC. But as for the identified proteins, RP C18 Tip accounted 85.5% for HPLC. ACN gradient of 5%, 15%, 20% and 90% had best repeatability (P = 0.429) and result for separating 30 MUg peptides. This method is easy to operate, timesaving and has low cost. It could be used into pretreatment of small amount complex proteomic samples. PMID- 26939448 TI - [Relationship between interferon-alpha conformation and its anti-viral activity determined by circular dichroism and flow cytometry]. AB - The relationship between the conformation of interferon-alpha (IFN-alpha) and its anti-viral activity were analyzed by circular dichroism (CD) and flow cytometry (FCM) techniques. The recombinant human IFN-alpha (rIFN-alpha2b and rIFN-alpha2a) were used. CD spectra from 190 nm to 240 nm indicated that two the IFN-alpha showed stable secondary structure at 65 degrees C, but unstable when the temperature was above 65 degrees C, and the change was irreversible. FCM data of the anti-viral activity of IFN-alpha indicated that the change of its secondary structures partly weakened its anti-viral activity. The rIFN-alpha2b and rIFN alpha2a showed the same phenomenon. These data indicated that the conformation of IFN-alpha is one of the factors to influence its anti-viral activity and the combination of CD and FCM is a good method to analyze the relationship between the conformation of protein drugs and their biological activities in single cell level. PMID- 26939449 TI - [Collagen quantitation by detection of marker peptides with HPLC-MS]. AB - A method for quantitation of collagen was established by detecting marker peptide with high performance liquid chromatography-mass spectrometry (HPLC-MS). Theoretical marker peptides were selected by sequence comparison. Bovine collagen type I was digested with trypsin. Marker peptides typical for collagen type I were identified with HPLC-MS. The relationship between the abundance of marker peptides and collagen concentration was established. The results show that GEAGPSGPAGPTGAR and the other 5 peptides showed high resolution during chromatographic separation and high signal intensity during MS analysis. Peptide signal intensity and collagen concentration showed a good linear relationship in the range from 0.1 to 3 mg/mL. Bovine tendon and collagen sponge were used as actual samples and collagen contents were determined as 90.2% and 93.4% respectively. Quantitation of marker peptides of collagen was a feasible method to identify and quantify collagens in medical device research and development. PMID- 26939451 TI - [Progress in gene regulation mechanisms of Staphylococcus biofilm development--A review]. AB - Bacterial resistance is a threat to public health. Bacterial biofilm formation is one of the main reasons for persistent infection caused by bacteria. Biofilm development is a complex process that involves many factors and genes which play various roles in all stages of the biofilm formation. This review focuses on the gene regulatory mechanisms relate to the biofilm formation of Staphylococcus, the most common pathogen that causes nosocomial infection, as well as the latest developments of pharmacological anti-biofilm therapies. We also address new strategy to treat bacterial infection and the development of drugs and vaccines against biofilm resistance. PMID- 26939450 TI - [Advances in integrase regulations of bacteria--A review]. AB - Because the integrase of class 1 integron in bacteria has been demonstrated closely relative with antimicrobial resistance, we summarize in this review the discussions on some regulation factors with expression of the integrase, such as antibiotics, carbon catabolite repression (cAMP-CRP complex), the promoter of gene cassette variants (Pc-P2 combinations), attC sites, some nucleotide associated proteins, and the length of variable region. Furthermore, we also provide knowledge of the regulation mechanism of integrase, as well as insight into controlling the dissemination of antimicrobial resistance in the environments. PMID- 26939452 TI - [Research advances in the virulence factors of Klebsiella pneumoniae--A review]. AB - Klebsiella pneumoniae is of great attractiveness because it naturally produces a series of bulk chemicals such as 1,3-propanediol, 2,3-butanediol and 3 hydroxypropionic acid. Although this species has been fueled in recent years, its pathogenicity is considered an obstacle hindering industrial applications. Here we portray a picture of the virulence factors, including pili, receptors, capsular polysaccharides, lipopolysaccharides, and newly identified virulence factors. This review covers aspects of virulence genes, proteins, metabolic activities, as well as the mechanisms underlying infection and immune responses. Based on state-of-the-art advances in metabolic engineering and synthetic biology, the strategies for eliminating or attenuating the virulence of K. pneumoniae were proposed, and the feasibilities for these protocols were also briefly discussed. PMID- 26939453 TI - [Identification of soft rot pathogens on Chinese cabbage [Brassica campestris L. ssp. chinensis (L.) Makino var. communis Tsen et Lee] in Beijing]. AB - OBJECTIVE: This study aimed to identify soft rot pathogens of Chinese cabbage [Brassica campestris L. ssp. chinensis (L.) Makino var. communis Tsen et Lee] in Beijing. METHODS: The 40 strains isolated from Tongzhou and Daxing districts in Beijing were characterized by morphological, biological, biochemical and physiological methods, 16S rRNA sequence as well as 16S-23S rRNA intergenic spacer (IGS) region analysis. RESULTS: The strains belonged to two different Pectobacterium carotovorum subspecies: 13 strains of them belonged to Pectobacterium carotovorum subsp. carotovorum (Pcc) and the other 27 strains belonged to Pectobacterium carotovorum subsp. brasiliensis (Pcb). The results of Chinese cabbage (Brassica campestris L. ssp. pekinensis) pathogenicity test showed that the strains in the same subspecies, origins and 16S rRNA gene sequences had significant differences in pathogenicity. CONCLUSION: Pectobacterium carotovorum subsp. carotovorum and Pectobacterium carotovorum subsp. brasiliensis were the soft rot pathogens on Chinese cabbage [ Brassica campestris L. ssp. chinensis(L.) Makino var. communis Tsen et Lee] in Beijing. It was the first report that Pectobacterium carotovorum subsp. brasiliensis (Pcb) caused soft rot disease on cabbage in China. PMID- 26939454 TI - [Identification of a new type III effector XC3176 in Xanthomonas campestris pv. campestris]. AB - OBJECTIVE: Type III secretion system (T3SS) is essential for many phytopathogenic bacteria to cause disease in susceptible host plants and to elicit a hypersensitive response in resistant host and non-host plants. Xanthomonas campestris pv. campestris (Xcc) uses T3SS to deliver T3SS effectors (T3SEs) directly into host cells, where they play important roles in pathogenesis. The aim of this study was to identify a new T3SE in Xcc. METHODS: To validate if XC3176 is a T3S effector translocated into plant cells, the promoter and signal region of XC3176 were fused to the plasmid pLJB of harboring HR-inducing AvrBs1 C terminal domain lack of 58 N-terminal amino acid residues. The recombinant plasmid pLJB3176 was introduced by triparental conjugation into DeltaavrBs1 and DeltahrcV. Hypersensitive response induced by the obtained strains DeltaavrBs1/pLJB3176 and DeltahrcV/pLJB3176 were examined on the pepper ECW-10R. To determine transcription of XC3176, GUS fusion report strains were constructed. The virulence of Xcc strains was investigated on the Chinese radish by the leaf clipping method. RESULTS: Hypersensitive response was elicited on the pepper ECW 10R by the strain DeltaavrBs1/pLJB3176, but not DeltahrcV/pLJB3176. The GUS activities in the mutant strains DeltahrpX and DeltahrpG were significantly lower than that in the wild type Xcc strain. The mutant of XC3176 reduced virulence significantly and the complementary strain C3176 could restore the virulence as the wild-type strain. CONCLUSION: XC3176 is a T3SS-dependent effector of Xanthomonas campestris pv. campestris. The expression of XC3176 is regulated by hrpG and hrpX. XC3176 is required for the full virulence of Xcc 8004. PMID- 26939455 TI - [Cloning, expression, directed evolution in vitro and structural simulation of beta-glycosidase from Bacillus subtilis]. AB - OBJECTIVE: To further study physiological functions and structure of beta glycosidase, we cloned the bglC gene of Bacillus subtilis and expressed it in E. coli BL21 (DE3), followed by the characterization and structural simulation of the enzyme. METHODS: We amplified the bglC gene and transferred it into E. coli BL21 (DE3), then we obtained a mutant with higher hydrolytic activity by directed evolution. After purifying the enzymes through a nickel-nitrilotriacetic acid agarose column, we characterized the wild-type and mutant enzymes. By means of CD spectrum, Native-PAGE and protein 3-D structure modeling, we analyzed the higher structure of the beta-glycosidase. RESULTS: We got one mutant enzyme BS-GLY_M1 (A242T/T385A/S425L) with improved hydrolytic activity by directed evolution and screening. The specific activity of wild-type enzyme was 9.7 U/mg, with optimum temperature at 60 degrees C and optimum pH at 7.0. The specific activity of BS GLY_M1 was 17. 1U/mg, with optimum temperature at 55 degrees C and optimum pH at 7.0. Moreover, the half-life time of the mutant enzyme at 55 degrees C was 3.5 h, 2 h longer than that of wild-type enzyme. Furthermore, the catalytic efficiency (K(m)/K(cat)) of BS-GLY_M1 on the substrates 4-nitrophenyl-beta-galactoside, lactose, and arbutin improved obviously. The polymer forms of the enzyme under the native conditions were of dimer and tetramer, but the dimer was the most probable functional unit. Result of structural simulation also showed slight changes occurred in the tertiary structure of the mutant enzyme, which may be the main reason for the enhanced thermal stability and catalytic efficiency of BS-GLY _M1. [ CONCLUSION: beta-glycosidase from Bacillus subtilis could be expressed in E. coli BL21 (DE3), meanwhile its hydrolysis efficiency could be further improved by directed evolution. PMID- 26939456 TI - [Molecular cloning and characterization of two oxidative stress related genes from medicinal fungus Polyporus umbellatus]. AB - OBJECTIVE: To clone the NADPH gene (PuNOX) and Glyoxal oxidase gene (PuGLOX) from a medicinal fungus Polyporus umbellatus, and to carry out the bioinformatic analysis. METHODS: We used the Rapid Amplification of cDNA ends (RACE) technique to obtain the full length cDNA of these two genes. We used a series of bioinformatic tools to characterize physiochemical properties of the two deduced protein. The analyses of multiple alignment and phylogenetic trees were performed using Bioeditor and MEGA 5.0 softwares. RESULTS: The entire cDNA of PuNOX and PuGLOX were 1674 bp, 1723 bp in length and encoded a 557-amino acid protein and 515-amino acid protein with a molecular weight of 63.845 kDa and 55.891 kDa and the isoelectric point of 5.58 and 4.82, respectively. PuNOX had high identities (74 to 80%) with NADPH peroxidase from other fungus. From the evolutionary tree, PuNOX was closely related to that of Pleurotus ostreatus. PuGLOX had high identities (> 50%) with Glyoxal oxidases from various fungus. Phylogenetic tree analysis suggested that PuGLOX was closely related to that of Phanerochaete chrysosporium. CONCLUSION: Molecular characterization of the two oxidative stress related genes will be useful for further functional determination of the genes involved in the sclerotium development of Polyporus umbellatus. PMID- 26939457 TI - [Effect of lactic acid bacteria isolated from Tibetan Plateau on silage fermentation quality of Elms nutans]. AB - OBJECTIVE: In order to detect the effect of lactic acid bacteria isolated from Tibetan Plateau on silage fermentation quality of Elms nutans. METHODS: We used 3 isolated lactic acid bacteria with better growth at low temperatures of 10 and 15 degrees C at ensiling of Elymus nutans. Subsequently, effects of the selected lactic acid bacteria on fermentation profiles of Elymus nutans silages stored at 15 and 25 degrees C were evaluated by using the same species of commercial inoculants as the control. RESULTS: PP-6 isolated from Tibetan Plateau could ferment raffinose, lactose, sorbitol, melibiose and sucrose, and LS-5 could ferment cottonseed sugar, laetrile, rhamnose, lactose, sorbitol, xylose, arabinose, melibiose and sucrose, but the same species of commercial strains could not use these sugars. Inoculation of these three strains into Elymus nutans at 15 and 25 degrees C ensiled for 50 d, we found that LS-5 significantly reduced silage pH, propionic acid concentration and ratio of ammonia nitrogen/total nitrogen at 15 degrees C (P < 0.05), salvaged more water-soluble carbohydrate and crude protein; Application of LP-2 and PP-6 as a combined inoculant to Elymus nutans significantly improved lactic acid concentration (P < 0.05), resulting in a lower ratio of ammonia nitrogen/total nitrogen, saved more crude protein and significantly reduced neutral detergent fiber content (P < 0.05) as compared with the commercial strains. CONCLUSION: The three isolated strains can improve silage quality of Elymus nutans growing on the Qinghai-Tibetan Plateau at low temperature, but these strains have no obvious advantages at 25 degrees C in comparison with the commercial inoculants. PMID- 26939458 TI - [Biotransformation and safety of cotton stalk alkaline peroxide mechanical pulping waste liquor]. AB - OBJECTIVE: We studied the conditions of culturing Bacillus subtilis SY1 to treat cotton stalk alkaline peroxide mechanical pulping waste water, and evaluated afterwards the safety of its release to plants and animals. METHODS: The culture conditions were optimized through single factor tests, including temperature, initial pH, oxygen, and inoculation size. We used rats and big ear rabbits to test the safety of treated waste water. RESULTS: The optimal condition was as follows: initial pH7.0, hydraulic retention time 30 h, temperature 30 degrees C, filling rate of aeration 16 L/h, the dosage of Bacillus subtilis SY1 0.8 g a liter water, and the stuffing volume accounting for 30% of the effective volume of the reactor. Under these culture conditions, the live spore number of Bacillus subtilis SY1 reached 6.27 x 10(9) CFU/mL. The removal rate of COD reached 70.4%. Results of the acute dermal toxicity test, dermal irritation test, eye irritation test and skin sensitization test after treated by the fermentation showed no clinical signs or changes conditions, and no deaths during the test period of 21 days. Animal body weight had a tendency to increase and had no abnormalities in the major organs, the Lethal Dose 50 (Abbreviated LD50) values was equal or greater than 10.5 g/(kg body weight) in acute dermal toxicity experiments. LD50 values were equal or greater than 2500 mg/(kg body weight) in dermal irritation experiments. No rabbits exhibited chemosis eye at any time during the test period. The results of skin sensitization test showed no erythema or edema. The skin sensitization value was less than 0.5. CONCLUSION: Pulping waste water of APMP cotton stalk fermented by Bacillus subtilis SY1 had reduced COD and no obvious toxicity to animals. PMID- 26939459 TI - [Anchorage of cyclodextrin glycosyltransferase on outer membrane of Saccharomyces cerevisiae to produce 2-O-alpha-D-glucopyranosyl-L-ascorbic acid]. AB - OBJECTIVE: Displaying cyclodextrin glycosyltransferase ( CGTase) from Bacillus circulans 251 on the cell surface of Saccharomyces cerevisiae to improve 2-O alpha-D-glucopyranosyl-L-ascorbic acid (AA-2G) production. METHODS: CGTase encoding gene cgt was inserted into the 3' terminal of Aga2p of vector pYD1 and the obtained recombinant plasmid pYD1-cgt was then transformed into S. cerevisiae EBY100 to produce surface displayed CGTase and culture conditions (culture medium, inductive temperature and concentration of inducer galactose) were optimized. Moreover, resulted CGTase displayed on the yeast cell surface was used for the AA-2G biosynthesis under the optimized condition. RESULTS: CGTase activity on the cell surface of recombinant yeast, S. cerevisiae EBY100-pYD1-cgt, reached 0.5 U/ml in 48 h fermentation using Yeast Peptone Galactose culture medium with 20% galactose as sole carbon source and inducer at 25 degrees C. The displayed CGTase exhibited better thermostability and pH stability than that of free CGTase. The concentration of AA-2G produced by the surface displayed CGTase was 37% higher than that produced by free CGTase at its optimal transformation conditions of 30 degrees C and pH4. 5. CONCLUSION: The cell surface display system based on alpha-agglutinin is an effective system for displaying CGTase. During AA-2G production by surface displayed CGTase, the by-product glucose might be consumed by yeast cell and thus facilitated AA-2G production. The whole cell EBY100-pYD1-cgt will have better prospects for applications. PMID- 26939460 TI - [Diversity of Bdellovibrio-and-like organisms from shrimp mariculture ponds in Zhanjiang]. AB - OBJECTIVE: Bdellovibrio-and-like organisms (BALOs) are small-sized, parasitic bacteria that rely on other Gram-negative bacteria for survival. Our work aimed to characterize the community diversity of BALOs associated with tropical shrimp ponds. METHODS: We collected water samples from eight shrimp ponds culturing Litopenaeus vannamei, in Zhanjiang, China, and extracted total DNA of the samples. Then the 16S rRNA gene clone libraries were constructed following PCR amplification with BALOs family-specific primers. The community composition and structure of BALOs were further analyzed based on phylogenetic analysis. RESULTS: A total of 726 and 664 valid clones were obtained from the 16S rRNA gene libraries of families Halobacteriovoracaceae and Peredibacteraceae, respectively. Subsequently, they were respectively grouped into 68 and 44 OTUs (operational taxonomic units) at 99.5% sequence similarity, and assigned into 37 and 28 clusters at 97% similarity. For the Halobacteriovoracaceae libraries, most clusters were so far uncultured with the exception of 5 members, which accounting for 43.5% clones. And the cultivable cluster IX and the uncultured cluster B28 were the first and second dominant ones respectively. For the Peredibacteraceae libraries, the cluster pa12 and the only cultivable cluster A3.12 were the first and second dominant ones respectively. Notably, the values of Shannon diversity indices of Halobacteriovoracaceae and Peredibacteraceae tend to be reversed with the change of salinity, but the total BALOs diversities among the eight shrimp ponds were similar. CONCLUSION: Shrimp mariculture ponds in Zhanjinag harbor a high diversity of BALOs comprising of Halobacteriovoracaceae and Peredibacteraceae, and salinity affect their community structure and composition greatly. PMID- 26939461 TI - [Diversity of virus-like particles from salt mines in Yunnan, China]. AB - OBJECTIVE: For exploring and characterizing the diversity of virus-like particles from salt mines in Yunnan, China. METHODS: Virus-like particles were identified from enriched brine or saline soil samples by transmission electronic microscopy and double-layer plate, and their morphological properties were further characterized. RESULTS: Three types of virus-like particles, head-tailed virus, linear virus and spherical virus, were observed by using transmission electronic microscopy. Then, two Halomonas viruses and one Chromohalobacter virus were subsequently isolated from Qiaohou salt mine and Yipinglang salt mine. According to the sample sources, their morphological characteristics and the character of host strains, those viruses were named as Qiaohou Halomonas Siphoviridae Virus 1 ( QHHSV-1), Yipinglang Halomonas Siphoviridae Virus 1 (YPHSV-1) and Yipinglang Chromohalobacter Pleomorphic Virus 1 (YPCPV-1). QHHSV-1 was head-tailed virus with a diameter of 47 nm icosahedrons-like head, and an easily broken 75 nm length tail. YPHSV-1 was head-tailed virus with a diameter of 50 nm icosahedrons like head, and a 140 nm length tail. YPCPV-1 was a pleomorphic, variable-sized (20 -50 nm) virus, which possessed protuberances on the virus particles. PMID- 26939462 TI - [Effects of salinity and adhesive materials on the growth and adhesion of Amphora sp. HN08 under static conditions]. AB - OBJECTIVE: To optimize the cultural conditions including adhesive materials and salinity for one tropical benthic diatom (Amphora sp. HN08). METHODS: Two experiments were performed: (1) five adhesive materials including agar, glass, PVC plate, plastic film and nylon net were used to culture Amphora sp. HN08 HN08; (2) Amphora sp. HN08 was cultured under 6 salinity levels from 1 through 6%. The algal cells were harvested after 9 days treatments, and the biomass productivity, adhesive strength and pigments content of cells were examined. RESULTS: For the adhesive materials experiment, cultures with glass and plastic plate showed the highest biomass production and the dry weight of cells reached to 3.64 g/m2. The adhesion strength level of cells on the glass plate was III degree, which means the cells were easy to be separated from the glass and dewatered by centrifugation. Salinity did not contribute significantly to the biomass production, while it significantly influenced the cells adhesion and pigments concentration. The adhesive strength levels of the cells under 3% or 4% salinity was IV degree, which led to an easy harvest process. While the. cells cultured under high salinity (5% and 6%) usually suspended in the medium and were difficult to be dewatered by centrifugation. Both chlorophyll a and carotenoid content of cells cultured with higher salinity (>= 3%) are extremely higher (p < 0.01) than that with lower salinity (1% and 2%). Chlorophyll a and carotenoid content of cells under 5% salinity was 26.27% and 11.11% by dry weight, respectively. CONCLUSION: Taking the harvest and biomass production together, we think the optimal salinity for Amphora sp. HN08 was between 3% and 4%, and the glass plate was suitable for adhesive material. However, considering the cost and safety, the PVC plate is suggested to be used for biomass production. PMID- 26939463 TI - [Characterization of antiserum after co-immunized with adhesins expressing ClfA, FnBPA-A and FnBPA-BCD of Staphylococus aureus]. AB - OBJECTIVE: To compare the antigenicity, adhesion inhibition activity and immune protection of the serum immunized with recombinant adhesins Clumping factor A (CfA), Fibronection binding protein A-A ( FnBPA-A) and Fibronection binding protein A-BCD (FnBPA-BCD) of Staphylococcus aureus. METHODS: ClfA, FnBPA-A and FnBPA-BCD genes were expressed and the resulting recombinant proteins were induced and purified. After immunizing mice with these purified proteins in combination or alone, the serum antibodies of mice were analyzed and compared for their antigenicity, adhesion inhibition activity and immune protection. RESULTS: The recombinant FnBPA-BCD protein had better fibronection (Fn) binding ability than that of fibrinogen (Fg) binding and ClfA. FnBPA-A had better binding capacity to Fg than that of FnBPA-BCD. The antibody titer induced by ClfA and FnBPA-A were better than that of FnBPA-BCD, and three proteins co-immunization group had better antibody titer and adhesion inhibition to Staphylococcus aureus than those of single recombinant protein immunization group (P < 0.05). The immune protection rate for both ClfA and three proteins co-immunization group were 100% and for FnBPA-A and FnBPA-BCD immunization group the immune protection rate were 80% and 50%, respectively. CONCLUSION: Our data suggest that coimmunization with these 3 recombinant proteins helps to achieve better immune effect. PMID- 26939464 TI - [Inflammasome responses in macrophages induced by C-terminal peptides of Escherichia coli EscI protein]. AB - OBJECTIVE: To analyze NLRC4 inflammasome responses in macrophages induced by C terminal of Escherichia coli EscI protein. METHODS: NLRC4 inflammasome responses in mouse peritoneal macrophages were analyzed after delivery of the peptides containing C-terminal amino acid sequences of E. coli EscI protein in vitro. RESULTS: The peptides containing C-terminal 15 amino acids of EscI protein could significantly activate NLRC4 inflammasome responses in macrophages pre-stimulated with lipopolysaccharide. Intracellular caspase-1 was activated and pyroptotic dead cells were found after peptides delivery. The contents of cytokines, IL 1beta and IL-18, in supernatants were elevated significantly compared with that of the control (P < 0.05). Besides, through comparison of IL-1beta contents under different stimulation conditions, 4 h incubation after peptides delivery (peptides: lipofectamine 2000 = 70 MUg/MUL) could obviously promote the secretion of IL-1beta. CONCLUSION: Peptides containing C-terminal 15 amino acids of E. coli EscI protein can significantly induce NLRC4 inflammasome activation in macrophages. PMID- 26939466 TI - What Will Replace the "Private Option?" Formally known as the Health Care Independence Act. PMID- 26939465 TI - Phenotypic analysis of Phytophthora parasitica by using high throughput phenotypic microarray. AB - OBJECTIVE: We studied the phenotypic characterization of Phytophthora parasitica Dastur var. nicotianae. METHODS: Phenotypic characterization of the pathogen was studied to provide information for disease management program by using BIOLOG phenotype MicroArray (PM ). Using PM plates 1 to 10, 950 different phenotypic characterizations were tested. RESULTS: P. parasitica was able to metabolize 74% of tested carbon sources, 96% of nitrogen sources, 100% of sulfur sources, and 98% of phosphorus sources. Most informative utilization patterns for carbon sources of P. parasitica were organic acids and carbohydrates, and for nitrogen were various amino acids. The pathogen presented 285 different nitrogen pathways. It had wide range adaptabilities in osmolytes with up to 1% sodium chloride, up to 3% potassium chloride, up to 5% sodium sulfate, up to 20% ethylene glycol, up to 2% sodium formate, up to 5% urea, and up to 2% sodium lactate. It also exhibited active metabolism under pH values between 3.5 and 10, with optimal pH of around 7.0. The pathogen showed both decarboxylase and deaminase activities in the presence of various amino acids. CONCLUSION: These phenotypic characterizations of P. parasitica provided the theoretical basis for the next study of the pathogen in physiology and metabolism, and provided potential new way for tobacco black shank management. PMID- 26939467 TI - Suggested Principles for Practice in 2016. PMID- 26939468 TI - Prescription Drug Monitoring in Arkansas: An Update. PMID- 26939469 TI - Decreasing Unintended Pregnancy with LARC. PMID- 26939470 TI - Irregular Wide Complex Tachycardia in a Young Man. AB - Wolf Parkinson White syndrome is a pre-excitation syndrome due to an accessory conduction pathway. Electrocardiography demonstrates a short PR interval, long QRS interval and delta waves in normal sinus rhythm. Atrial fibrillation with underlying Wolf Parkinson White syndrome presents with irregular wide complex tachycardia, and can cause sudden cardiac death by precipitating ventricular fibrillation. Irregular wide complex tachycardia may be the first presentation of this underlying conduction abnormality in young patients. Emergency management for irregular wide complex tachycardia in hemodynamically unstable patients involves synchronized cardioversion, while intra-venous Procainamide can be used in hemodynamically stable patients. AV nodal blocking agents should be avoided. Treatment of choice for WPW syndrome is radiofrequency ablation. PMID- 26939471 TI - Acute Eosinophilic Pneumonia in a 16-Year-Old Boy. PMID- 26939472 TI - How I Manage Chronic Lymphocytic Leukemia in 2014. PMID- 26939473 TI - MGMA engages thought leaders to improve healthcare delivery circles. PMID- 26939474 TI - Using data to build your business. PMID- 26939475 TI - Final 2016 Medicare PFS rule includes changes to quality reporting programs, Medicare service updates and more. PMID- 26939476 TI - Negotiate EHR contracts before you sign to ensure success. PMID- 26939477 TI - Embracing innovation at the practice level. PMID- 26939478 TI - What are the best ways to engage staff? PMID- 26939479 TI - Switching to value-based compensation requires data benchmarks. PMID- 26939480 TI - Assessing patient access to care. An MGMA member participates in national study to assess national standards. PMID- 26939481 TI - How do you encourage patient responsibility?. PMID- 26939482 TI - Diminish downtime, waste in your practice. PMID- 26939483 TI - Pre-verifying eligibility and benefits. PMID- 26939484 TI - A reflection on patient education. PMID- 26939486 TI - [Inflammation and cancer - colorectal carcinoma as an example]. AB - Immune system contributes to the pathogenesis of cancer. Immunoediting describes a process in which the immune system can recognize transformed cancer cells and establish an anti-tumor response, potentially leading to the selection of less immunogenic tumor cells. Additionally, inflammation may contribute to cancer progression by activating angiogenesis and oncogenic signaling pathways. In colorectal cancer, dense inflammatory infiltrate in tumor samples is generally associated with improved prognosis but this association is dependent on the type of immune cells and their location. In future, increased knowledge on cancer immunology is expected to benefit the diagnostics, prognostication, follow-up and treatment of cancer. PMID- 26939485 TI - [Antisocial personality disorder]. AB - Antisocial personality disorder (ASP), especially psychopathy as its extreme form, has provoked fear and excitement over thousands of years. Ruthless violence involved in the disorder has inspired scientists, too.The abundance of research results concerning epidemiology, physiology, neuroanatomy, heritability, and treatment interventions has made ASP one of the best documented disorders in psychiatry. Numerous interventions have been tested, but there is no current treatment algorithm. Biological and sociological parameters indicate the importance of early targeted interventions among the high risk children. Otherwise, as adults they cause the greatest harm. The use of medications or psychotherapy for adults needs careful consideration. PMID- 26939488 TI - [Effectiveness of health examinations by occupational health services]. AB - Health examinations are part of the activities of occupational health services in preventing diseases and promoting occupational health. Their aim is to protect workers from health risks on one hand but also to promote the worker's own resources and health in order to maintain their capacity for work. Initiation of preventive, corrective and rehabilitative measures and those directed toward the workplace is attempted at the earliest possible stage. When interpreting the examination data it is in fact important to recognize whether it is the effectiveness of the health examination visit or the subsequent procedures that is being evaluated. PMID- 26939487 TI - [Chronic nonbacterial osteomyelitis]. AB - Chronic nonbacterial osteomyelitis is an autoinflammatory disease occurring mainly in children and adolescents, typically involving recurrent or persistent osteitic foci. The symptom is bone pain, possibly accompanied by soft tissue tenderness. Some patients exhibit symptoms of systemic inflammation. The. precise etiology of the disease is not known, but an imbalance of inflammatory and anti inflammatory cytokines is presumed to play a role in the development of the disease. While an anti-inflammatory analgesic is in most cases sufficient to calm down the osteitis, the use of corticosteroids, anti- TNF-a inhibitors or bisphosphonates is required in some cases. PMID- 26939489 TI - [Somatic examination of a female victim of a sexual offence]. AB - Examination of a female victim of a sexual offence is carried out usually within seven days of the incident. It includes an interview, inspection and documentation of bodily injuries, gynecologic examination and collection of specimens of sexually transmitted diseases and appropriate forensic specimens. Preventive antimicrobial therapy and postcoital contraception will also be provided. The need for anti-HIV medication as well as hepatitis and tetanus vaccines is considered on a case-by-case basis. A tranquil scene of examination, written instructions for follow-up observation and taking care of emotional support are essential for the recovery of the victim. Guidance for the collection of forensic tissue specimens should also be available in gynecology units. PMID- 26939490 TI - [Recurrent epidemics of gastroenteritis caused by norovirus GI.3 in a small hotel]. AB - BACKGROUND: Recurrent cases of gastroenteritis occurred in a small hotel. The causative agent of disease could not be detected. MATERIAL AND METHODS: The cause and the source of the disease were established through epidemiological investigations and laboratory diagnosis. RESULTS: The causative agent of the disease was norovirus GI.3. Norovirus GI was detected in the water from the well and on surfaces at the hotel. CONCLUSIONS: Both epidemiological investigations and laboratory diagnostics are needed in resolving epidemics. Continuous development of laboratory methods is important. PMID- 26939491 TI - [Supraventricular tachycardia during pregnancy]. AB - An increase in cardiac output during pregnancy increases the risk of arrhythmias for the expectant mother. Supraventricular tachycardia (SVT) underlies the sensations of arrhythmia in a pregnant woman in as many as one sixth of the cases. Vagal nerve (n. vagus) stimulation and adenosine serve as first-line treatment, but electrical cardioversion is likely to be a safe alternative as well. We describe a case in which the SVT of a woman in the third trimester of pregnancy was unresponsive to vagal nerve stimulation and pharmacological treatments. Electrical cardioversion was successfully performed after having a cesarean section procedure. PMID- 26939492 TI - [Mortality and cumulative exposure to antipsychotics, antidepressants and benzodiazepines in patients with schizophrenia: an observational follow-up study]. PMID- 26939493 TI - [Update on Current Care Guideline: Headache (children)]. AB - The majority of children with recurrent headaches can be effectively treated in the primary health care. Paracetamol and ibuprofen are the recommended first-line pain medications. Limited evidence is available on the effectiveness of triptans in children and adolescents. However, nasal sumatriptan and possibly oral rizatriptan and nasal zolmitriptan can be considered for children and adolescents, as well as oral almotriptan for adolescents. Propranolol is the first-line prophylactic medication for migraine. PMID- 26939494 TI - COMMERCIAL SURROGACY: WHAT ROLE FOR LAW IN AUSTRALIA? AB - This editorial begins by illuminating current conversations regarding the regulation of commercial surrogacy in Australia. It defines "commercial surrogacy" and explains the interaction between changes in social attitudes and changes to the law before setting out the current Australian law and practice in this area. An examination of current domestic law and practice reveals that surrogacy legislation in Australia is mired in inconsistencies and a lack of uniformity but that the one key common element is the prohibition of commercial surrogacy. The inability of couples to access commercial surrogacy within Australia has led to offshore reproductive tourism and unpredictable, contradictory decision-making as the Family Court attempts to apply legislation which was never intended to apply in this context. The editorial then turns to consider the international arena, discussing the approach of the Hague Conference on Private International Law before delving into a human rights analysis of commercial surrogacy arrangements. The adoption of a rights-based approach requires an analysis of this vexed issue from the perspective of the child, surrogate and intending parents. While questions surrounding the human rights implications of legalising commercial surrogacy continue to be the subject of passionate debate, the authors believe that the human rights of all parties are best protected through appropriate regulation rather than absolute prohibition. PMID- 26939496 TI - THE DANGERS OF DEMENTIA: GETTING THE BALANCE RIGHT. AB - Australia's population is ageing and it is likely that there will be a threefold increase in the number of people living with dementia in the next 30 years. Caring for these individuals will incur a significant burden on our community both fiscal and personal. How we provide this care will say much about our compassion for and commitment to caring for those who are no longer part of the productive workforce. Individuals with dementia are a heterogeneous group with a wide range of function and capacity. Nevertheless, their impairment often requires a high level of formal care in order to reduce the risk of harm to themselves and others in the community. The imposition of such care arrangements can be invasive of their autonomy and in some cases their liberty. These issues are addressed in respect of some of the major risks of harm in a setting of dementia. PMID- 26939495 TI - DEFINING SECLUSION AND RESTRAINT: LEGAL AND POLICY DEFINITIONS VERSUS CONSUMER AND CARER PERSPECTIVES. AB - The practices of seclusion and restraint may be used in a variety of health settings to control behaviour. Laws and policies that seek to regulate these practices define seclusion and restraint in various ways and there are gaps as to which practices are regulated and in what circumstances. This column provides an overview of consumer and carer perspectives as to what is meant by these practices. PMID- 26939497 TI - LECRETIA SEALES AND AID IN DYING IN NEW ZEALAND. AB - The application by Lecretia Seales, in relation to the lawfulness of physician aid in dying in New Zealand, was heard by Collins J, an experienced medical jurisprudentialist. It raised issues re-ignited by the recent Supreme Court of Canada ruling in Carter v Canada and the legislative change in California. Is a continued prohibition in Australasia and the United Kingdom against physician aid in dying causing patients to be subjected to cruel, inhumane and undignified deaths or, in fact, is a legislative change unnecessary given the level of care that patients can receive and the peaceful and harmonious deaths that we often hear about in hospice and other settings. A range of arguments, some traditional and some very contemporary, were canvassed in the case of Lecretia Seales and Collins J considered each of them, commenting in detail both on points of law and matters of ethical substance. A study of his judgment therefore makes fascinating reading for those interested in end-of-life decisions and the way they are dealt with in different developed world jurisdictions, and in particular, how such ethical matters may be considered from the point of view of indigenous and marginalised cultures. PMID- 26939498 TI - THE ROLE OF OBSERVATION AND FEEDBACK IN ENHANCING PERFORMANCE WITH MEDICATION ADMINISTRATION. AB - Legislation in Queensland such as the Health (Drugs and Poisons) Regulation 1996, the national registration competency standards set by the Nursing and Midwifery Board of Australia, and the Continuing Professional Development Registration Standards made pursuant to the Health Practitioner Regulation National Law define expected standards of practice for nurses. The Framework for Assessing Standards for Practice for Registered Nurses, Enrolled Nurses and Midwives, released in July 2015, includes the principles for assessing standards but not the methods. Local policies and procedures offer specific requirements founded on evidence based practice. Observation of clinical practice with the provision of immediate descriptive feedback to individual practitioners has been associated with improved performance. This column describes the role of regular observation and individual feedback on medication administration as a strategy to enhance performance and patient care. PMID- 26939499 TI - MYRIAD VOICES AGAINST GENE PATENTS IN THE HIGH COURT. AB - The Australian High Court's recent landmark decision in D'Arcy v Myriad Genetics Inc overturned the decision by the Federal Court in Cancer Voices Australia v Myriad Genetics Inc regarding patenting of genetic material. The Federal Court had found that isolated DNA and RNA can constitute a patentable invention under s 18(1)(a) of the Patents Act 1990 (Cth). The decision by the High Court unanimously reversed this and declared it was appropriate to look to the policy implications at the heart of the legal question: are genes a category of things that can be patented? This column critically examines the implications of the High Court decision for both research and public health in Australia. PMID- 26939500 TI - Letter to the Editor. PMID- 26939501 TI - Introductory note to Special Issue. PMID- 26939502 TI - The regulation of commercial surrogacy: The wrong answers to the wrong questions. AB - The criminal ban on commercial surrogacy across Australian jurisdictions is the result of the conflation and confusion of two flawed assumptions. The first being that the criminalisation of commercial surrogacy will discourage a surrogacy "industry" and the second that commercial surrogacy and altruistic surrogacy are two distinguishable "types" of surrogacy arrangements. This article argues that the criminalisation of commercial surrogacy has resulted in unforeseen and undesirable consequences, removing opportunity for evidence-based law reform. Moreover, analysis of both the approach of Australian courts and the operation of surrogacy legislation suggests that the binary regulatory approach which distinguishes "commercial" from "altruistic" surrogacy is a legal fiction. In summary, this article argues that the current Australian regulation of surrogacy is both blunt and ineffectual, surrogacy is a nuanced and complex practice which requires a regulatory response which is principled, holistic and evidence based. PMID- 26939503 TI - Responsive regulation of cross-border assisted reproduction. AB - This article considers the question: how might Australian regulators constructively respond to the dynamic and complex challenges posed by cross border assisted reproduction? To begin, the article summarises the available international scholarship and outlines what little we know about Australian cross border reproductive travel. Of the three generally proposed responses to cross border reproductive care (prohibition, harm minimisation and harmonisation), the article summarily rejects the first approach, and instead discusses a mixture of the latter two. The article proposes the beginnings of an immediate policy response aimed not at stopping cross-border practices per se, but rather at understanding and reducing the risks associated with them, as well as flagging the pursuit of more ambitious meta-goals such as developing more equitable and accessible treatment frameworks for assisted reproductive technology and encouraging domestic self-sufficiency in reproduction. PMID- 26939504 TI - Commercial surrogacy and the human right to autonomy. AB - Arguments against commercial surrogacy frequently focus on the rights of the surrogate. For-example, those opposed to commercial surrogacy often argue that surrogacy arrangements amount to the exploitation of women and the commodification of their wombs. Phrased in the language of rights, such arguments draw on the right to be free from degrading treatment and the right to be free from discrimination. In contrast, those who support commercial surrogacy refute the arguments relating to exploitation and commodification and cite the right to work and more commonly the right to privacy/autonomy as the key rights in question. This article focuses on the human right to autonomy and interrogates whether prohibitions on commercial surrogacy violate the right of a woman to choose to be a surrogate. PMID- 26939505 TI - Genes and gestation in Australian regulation of egg donation, surrogacy and mitochondrial donation. AB - This article considers genetic and legal relatedness for the purposes of Australian regulation of egg donation, surrogacy and parentage by examination of that regulation through the lens of mitochondrial (mt) donation. The article addresses whether mt donors would be a child's genetic parents following clinical use in that child's conception should mt donation be legalised for such use in Australia. It then considers how genetic and gestational relatedness are relevant in the discourse around legal parentage following egg donation and surrogacy and argues that the current approach is in need of reform so that intending parents of all children are deemed to be the resulting child's legal parents at birth. PMID- 26939506 TI - The Family Courts and parentage of children conceived through overseas commercial surrogacy arrangements: A child-centred approach. AB - This article adopts a child-centred approach to the vexed issue of commercial surrogacy. These arrangements are prohibited throughout Australia. Nevertheless, Australians are travelling overseas and entering into commercial surrogacy arrangements. This article addresses the dilemma confronting the Family Courts when the commissioning parents and the child return to Australia. Should the Family Courts make parenting orders enabling the commissioning parents to raise the child? Alternatively, should they make parentage orders legally recognising the commissioning parents as the child's parents? After exploring the existing legislative structure and its application, the interest theory of children's rights is utilised to justify changes to the law so that the commissioning parents are regarded as the child's legal parents. PMID- 26939507 TI - Medical and scientific authorship: A conflict between discipline rules and the law. AB - When the results of medical collaborations are to be published, questions of authorship arise. Which members of the research team are to be acknowledged as authors of the paper? In what order are they to be acknowledged? Institutional rules will generally determine the attribution of authorship to members of the research team. However, those rules are most unlikely to be consistent with the legal rules governing authorship and its attribution, most of which will apply regardless of a team's adherence to institutional rules. This article examines the meaning of authorship in the medical community, and in the legal community under the copyright laws. It considers various formulations of the institutional rules governing authorship, as well as editorial practices. Through consideration of a hypothetical scenario, the consequences of the disparity between authorship norms in law and in medicine are elaborated. PMID- 26939508 TI - Foetal Alcohol Spectrum Disorders: A consideration of sentencing and unreliable confessions. AB - While Foetal Alcohol Spectrum Disorders (FASDs) are now a strong focus of policy makers throughout Australia, they have received strikingly little consideration in Australian criminal courts. Many people who have an FASD are highly suggestible, have difficulty linking their actions to consequences, controlling impulses and remembering things, and thus FASD raises particular issues for appropriate sentencing and the admissibility of evidence. This article considers the approach of Australian criminal courts to FASD. It reviews the recent case of AH v Western Australia which exemplifies the difficulties associated with appropriate sentencing in cases where the accused is likely to have an FASD. The article also considers the implications for Australian courts of the New Zealand case of Pora v The Queen, recently heard by the Privy Council. In this case, the Privy Council accepted expert evidence that people with FASD may confabulate evidence, potentially making their testimony unreliable. The article concludes with an overview of developments in criminal policy and legal response in relation to FASD in the United States, Canada and Australia. PMID- 26939509 TI - Cutting the cord: Can society over-invest in extremely premature and critically impaired neonates? AB - This article provides a critical examination of the allocation of scarce public health care funds in relation to extremely premature and sick neonates. Decisions to withdraw or withhold life-sustaining treatment from neonates born extremely premature are generally informed by arbitrary and often subjective considerations of those involved in their care--namely parents and medical practitioners. This article argues for a sharp and immediate focus in decisions to treat such neonates based on the allocation of limited health care resources. Accordingly, decisions to save and preserve the lives of imperilled neonates should not be limited to the immediate financial costs of medical treatment. More explicitly there should be a full appreciation of the cost of disability to the family requirements for long-term care, and the benefits and associated costs of life, not only to the patient, but also to society. PMID- 26939510 TI - Nazi medical experiments on Australian prisoners of war: Commentary on the testimony of an Australian soldier. AB - Archival research reveals that Australian prisoners of war were exposed to non consensual medical experiments during World War II. This article discusses the first known case of an Australian soldier exposed to German medical experiments. PMID- 26939511 TI - A problem of modernity: Dual burial plots, the right to inter, and the interrelationship between the two. AB - Vosnakis v Arfaras directly raises the issue as to how private law will resolve the tensions that can exist between family members in relation to burial licences and the right to inter. In evoking contract, property and statute; the case reveals the complexity associated with this area, specifically in relation to dual burial plots, and how rather simple family disputes can escalate significantly beyond their economic worth. Recommendations to include a registry system to record details of funeral arrangements is encouraged to ensure that the many thousands of dollars spent by the litigants in this case is not repeated by other families. This, along with courts being required to give effect to the wishes of the deceased, will provide a clarity that is currently missing. In a time when the population is increasing, a changed dynamic to family life in Australia, and less land available for internment, the problem of the relationship of a dual burial licence and the right to inter is one of modernity, but one to which the community should expect the application of policy initiatives to complement a coherence within the legal position. This coherency and such policy initiatives are currently lacking but, with simple measures, this position can be rectified. PMID- 26939512 TI - Our Father who art in prison: Conviction and rehabilitation for Australian Catholic clergy who are child sexual offenders. AB - In light of the Royal Commission into Institutional Child Sexual Abuse, this article analyses the custodial sentences of 143 Australian Catholic clergy. The majority of these sentences were for convictions for indecent assault for which the median sentence was two years' imprisonment. It is doubtful whether the Australian community would consider such sentences as adequate, particularly where offences were against children. Current Australian legislation allows for ongoing long-term sanctions, including judicial orders for chemical castration, to be imposed on convicted sex offenders, especially those assessed as being at high risk of re-offending. Clergy on parole are likely to be prohibited from resuming most pastoral responsibilities on the grounds of high actuarial risk of re-offending, but what limited data are available suggests that priests may have low rates of re-offending. If priests do have low rates of recidivism, what then should the Catholic Church do about priests convicted of child sexual abuse offences who want to return to pastoral work and how might they be managed and monitored? Laicisation of offender priests will inevitably produce ostracism and isolation which are conducive to re-offending. PMID- 26939513 TI - Looking forward: HIT in 2016 and beyond Industry experts forecast future trends- no crystal ball required. PMID- 26939514 TI - Correcting critical misperceptions about patient engagement. PMID- 26939515 TI - Not just a buzzword. Engaging your patients has many benefits, including ROI. PMID- 26939516 TI - Is Meaningful Use the most effective way to build an interoperable health system? PMID- 26939517 TI - Look beyond EHRs for MU compliance. PMID- 26939518 TI - Visualization improves workflow, referral numbers. St. John Health System sees big improvements after implementing patient flow software. PMID- 26939519 TI - Making a breakthrough in healthcare interoperability. Good Samaritan anticipates substantial revenue increase while containing integration costs. PMID- 26939521 TI - Women in HIT: Good for women, good for our industry. PMID- 26939520 TI - Increasing mobility to improve patient experience. Better design leads to improved workflow. PMID- 26939522 TI - Efficacy of a Cream Containing Ceramides and Magnesium in the Treatment of Mild to Moderate Atopic Dermatitis: A Randomized, Double-blind, Emollient- and Hydrocortisone-controlled Trial. AB - The aim of this randomized controlled trial was to assess the efficacy of a cream containing ceramides and magnesium (Cer-Mg) in the treatment of mild to moderate atopic dermatitis and to compare it with hydrocortisone and a commonly used emollient (unguentum leniens; cold cream). A total of 100 patients, randomized into 2 groups, were treated for 6 weeks simultaneously (left vs. right side of the body) with either Cer-Mg and hydrocortisone (group I) or Cer-Mg and emollient (group II). The primary outcome was a reduction in severity of lesions as assessed by (local) SCORAD (SCORing Atopic Dermatitis). Levels of trans-epidermal water loss (TEWL), skin hydration, and natural moisturizing factors (NMF) were then measured. After 6 weeks, group I showed comparable significant improvement in SCORAD and TEWL, while in group II, the decrease in SCORAD and TEWL was significantly greater after Cer-Mg compared with emollient. Finally, Cer-Mg cream was more effective in improving skin hydration and maintenance of levels of NMF than hydrocortisone and emollient. PMID- 26939523 TI - Chronic chikungunya virus musculoskeletal disease: what are the underlying mechanisms? PMID- 26939524 TI - In vitro antimicrosporidial activity of gold nanoparticles against Heterosporis saurida. AB - BACKGROUND: Worldwide, there is a need to expand the number of drugs available to treat parasitic infections in aquaculture. One of the new materials being tested is metal nanoparticles, which have unique chemical and physical characteristics owing to their extremely small size and high surface area to volume ratio. We examined the effectiveness of gold nanoparticles against the microsporidian parasite Heterosporis saurida, which causes severe economic losses in lizard fish, Saurida undosquamis aquaculture. RESULTS: We synthesized gold nanoparticles by chemical reduction of tetrachloroauric acid as a metal precursor. We assessed the antimicrosporidial efficacy of the nanoparticles against H. saurida using an in vitro screening approach, which we had developed previously using the eel kidney cell line EK-1. The number of H. saurida spores produced in EK-1 cells was reduced in a proportional manner to the dosage of gold nanoparticles administered. A cell metabolic activity test (MTT) indicated that the gold nanoparticles did not appear to be toxic to the host cells. CONCLUSIONS: Gold nanoparticles can act as an effective antimicrosporidial agent and hold promise to reduce disease in lizardfish aquaculture. Metal nanoparticles should be considered as an alternate choice for development of new antimicrosporidial drugs to combat disease problems in aquaculture. PMID- 26939525 TI - Prognostic implications of mean platelet volume on short- and long-term outcomes among patients with non-ST-segment elevation myocardial infarction treated with percutaneous coronary intervention: A single-center large observational study. AB - BACKGROUND: Mean platelet volume (MPV) is a simple and reliable indicator of platelet size that correlates with platelet activation and their ability to aggregate. We studied the predictive value of MPV in patients with non-ST-segment elevation myocardial infarction (NSTEMI) treated with percutaneous coronary intervention (PCI). METHODS: We analyzed the consecutive records of 1001 patients who were hospitalized due to NSTEMI at our center. The primary end point was a composite end point that included the rates of all-cause death, non-fatal myocardial infarction, and acute coronary syndrome (ACS) driven revascularization at 12 months. The enrolled patients were stratified according to the quartile of the MPV level at admission. RESULTS: Along with the increasing quartile of MPV, the 12-month composite end point increased significantly (p = 0.010), and this association remained significant after the risk-adjusted analyses (per 1 fL higher MPV; adjusted hazard ratio [HR] 1.13; 95% confidence interval [CI] 1.02 1.27; p = 0.026). In the multivariate analysis, the MPV was also an independent factor of all-cause mortality (per 1 fL increase; adjusted HR 1.34; 95% CI 1.12 1.61; p = 0.0014) and death or non-fatal myocardial infarction (per 1 fL increase; adjusted HR 1.16; 95% CI 1.03-1.31; p = 0.017). CONCLUSION: In patients with NSTEMI treated with PCI, a high MPV value was associated with a significantly increased incidence of long-term adverse events, particularly for all-cause mortality. PMID- 26939526 TI - Assessment of contraceptive needs in women undergoing bariatric surgery. AB - OBJECTIVE: To evaluate documentation of contraception and counseling in women planning to undergo bariatric surgery. STUDY DESIGN: Chart review of 1012 women ages 18-45years presenting for bariatric surgery evaluation. Data on socio demographic variables, documented contraceptive method, preconception counseling, gynecology referrals and postoperative pregnancies were collected. RESULTS: The charts of only 272 women (26.9%) contained documentation of a contraceptive method; the most common was oral contraceptives (n=132, 48.5%). Sixteen pregnancies were identified in the first 18months postoperatively. CONCLUSIONS: Currently, the documentation of contraceptive counseling is lacking in clinical practice. Measures to enhance provider and patient awareness of these issues will improve patient care. IMPLICATIONS: Pregnancy planning and documentation of perioperative contraceptive use in women undergoing bariatric surgery are suboptimal, placing these women at risk of unintended pregnancies. Future research should delineate the best practices in contraceptive provision in this high-risk population of women. PMID- 26939527 TI - What influences 11-year-olds to drink? Findings from the Millennium Cohort Study. AB - BACKGROUND: Drinking in youth is linked to other risky behaviours, educational failure and premature death. Prior research has examined drinking in mid and late teenagers, but little is known about the factors that influence drinking at the beginning of adolescence. Objectives were: 1. to assess associations of parental and friends' drinking with reported drinking among 11 year olds; 2. to investigate the roles of perceptions of harm, expectancies towards alcohol, parental supervision and family relationships on reported drinking among 11 year olds. METHODS: Analysis of data from the UK Millennium Cohort Study on 10498 11 year-olds. The outcome measure was having drank an alcoholic drink, self-reported by cohort members. RESULTS: 13.6 % of 11 year olds reported having drank. Estimates reported are odds ratios and 95 % confidence intervals. Cohort members whose mothers drank were more likely to drink (light/moderate = 1.6, 1.3 to 2.0, heavy/binge = 1.8, 1.4 to 2.3). Cohort members whose fathers drank were also more likely to drink but these estimates lost statistical significance when covariates were adjusted for (light/moderate = 1.3, 0.9 to 1.9, heavy/binge = 1.3, 0.9 to 1.9). Having friends who drank was strongly associated with cohort member drinking (4.8, 3.9 to 5.9). Associated with reduced odds of cohort member drinking were: heightened perception of harm from 1-2 drinks daily (some = 0.9, 0.7 to 1.1, great = 0.6, 0.5 to 0.7); and negative expectancies towards alcohol (0.5, 0.4 to 0.7). Associated with increased odds of cohort member drinking were: positive expectancies towards alcohol (1.9, 1.4 to 2.5); not being supervised on weekends and weekdays (often = 1.2, 1.0 to 1.4); frequent battles of will (1.3, 1.1 to 1.5); and not being happy with family (1.2, 1.0 to 1.5). CONCLUSIONS: Examining drinking at this point in the lifecourse has potentially important public health implications as around one in seven 11 year olds have drank, although the vast majority are yet to explore alcohol. Findings support interventions working at multiple levels that incorporate family and peer factors to help shape choices around risky behaviours including drinking. PMID- 26939528 TI - Can providing a morning healthy snack help to reduce hunger during school time? Experimental evidence from an elementary school in Connecticut. AB - While children may be naturally inclined to regulate their hunger, they are also guided by adults and influenced by environmental constraints regarding when and how much to eat. As such, the timing and availability of meals could alter a child's natural eating habits. This could impact the nutritional quality of what they eat as well. We conducted a field experiment with three fourth grade classes at a public elementary school in Eastern Connecticut to analyze if providing a nutritious snack one hour prior to lunch effects a child's level of hunger and consequently their lunch-time consumption. We found students shift their caloric and nutrient intake from lunch to snack time. In addition, we found a significant reduction in student hunger. Our results highlight the importance in considering the timing and quality of meals provided during school time. In our sample, current snack and lunch schedule may not be optimal and changing it can have an impact on the wellbeing of students. Providing healthful options for snack could be an effective way to improve student diets while preserving their ability to make their own choices. PMID- 26939529 TI - Nutritional information and health warnings on wine labels: Exploring consumer interest and preferences. AB - This paper aims to contribute to the current debate on the inclusion of nutritional information and health warnings on wine labels, exploring consumers' interest and preferences. The results of a survey conducted on a sample of Italian wine consumers (N = 300) show the strong interest of respondents in the inclusion of such information on the label. Conjoint analysis reveals that consumers assign greater utility to health warnings, followed by nutritional information. Cluster analysis shows the existence of three different consumer segments. The first cluster, which included mainly female consumers (over 55) and those with high wine involvement, revealed greater awareness of the links between wine and health and better knowledge of wine nutritional properties, preferring a more detailed nutritional label, such as a panel with GDA%. By contrast, the other two clusters, consisting of individuals who generally find it more difficult to understand nutritional labels, preferred the less detailed label of a glass showing calories. The second and largest cluster comprising mainly younger men (under 44), showed the highest interest in health warnings while the third cluster - with a relatively low level of education - preferred the specification of the number of glasses not to exceed. Our results support the idea that the policy maker should consider introducing a mandatory nutritional label in the easier-to-implement and not-too-costly form of a glass with calories, rotating health warnings and the maximum number of glasses not to exceed. PMID- 26939530 TI - Optimizing Salmonella enterica serovar Typhimurium for bacteria-mediated tumor therapy. AB - Bacteria-mediated tumor therapy using Salmonella enterica serovar Typhimurium is a therapeutic option with great potential. Numerous studies explored the potential of Salmonella Typhimurium for therapeutic applications, however reconciling safety with vectorial efficacy remains a major issue. Recently we have described a conditionally attenuated Salmonella vector that is based on genetic lipopolysaccharide modification. This vector combines strong attenuation with appropriate anti-tumor properties by targeting various cancerous tissues in vivo. Therefore, it was promoted as an anti-tumor agent. In this addendum, we summarize these findings and demonstrate additional optimization steps that may further improve the therapeutic efficacy of our vector strain. PMID- 26939531 TI - Characterization of Mycobacterium tuberculosis isolates from Hebei, China: genotypes and drug susceptibility phenotypes. AB - BACKGROUND: Tuberculosis remains a major public health problem in China. The Hebei province is located in the Beijing-Tianjin-Hebei integration region; however little information about the genetic diversity of Mycobacterium tuberculosis was available in this area. This study describes the first attempt to map the molecular epidemiology of MTB strains isolated from Hebei. METHODS: Spoligotyping and 15-locus MIRU-VNTR were performed in combination to yield specific genetic profiles of 1017 MTB strains isolated from ten cities in the Hebei province in China during 2014. Susceptibility testing to first line anti-TB drugs was also conducted for all strains using the L-J proportion method. RESULTS: Based on the SpolDB4.0 database, the predominant spoligotype belonged to the Beijing family (90.5%), followed by T family (6.3%). Using 15-locus MIRU-VNTR clustering analysis, 846 different patterns were identified, including 84 clusters (2-17 strains per cluster) and 764 individual types. Drug susceptibility pattern showed that 347 strains (34.1%) were resistant to at least one of the first line drugs, including 134 (13.2%) multi-drug resistance strains. Statistical analysis indicated that drug resistance was associated with treatment history. The Beijing family was associated with genetic clustering. However, no significant difference was observed between the Beijing and non-Beijing family in gender, age, treatment history and drug resistance. CONCLUSIONS: The Mycobacterium tuberculosis strains in Hebei exhibit high genetic diversity. The Beijing family is the most prevalent lineage in this area. Spoligotyping in combination with 15-locus MIRU-VNTR is a useful tool to study the molecular epidemiology of the MTB strains in Hebei. PMID- 26939532 TI - C-Terminal Charge-Reversal Derivatization and Parallel Use of Multiple Proteases Facilitates Identification of Protein C-Termini by C-Terminomics. AB - The identification of protein C-termini in complex proteomes is challenging due to the poor ionization efficiency of the carboxyl group. Amidating the negatively charged C-termini with ethanolamine (EA) has been suggested to improve the detection of C-terminal peptides and allows for a directed depletion of internal peptides after proteolysis using carboxyl reactive polymers. In the present study, the derivatization with N,N-dimethylethylenediamine (DMEDA) and (4 aminobutyl)guanidine (AG) leading to a positively charged C-terminus was investigated. C-terminal charge-reversed peptides showed improved coverage of b- and y-ion series in the MS/MS spectra compared to their noncharged counterparts. DMEDA-derivatized peptides resulted in many peptides with charge states of 3+, which benefited from ETD fragmentation. This makes the charge-reversal strategy particularly useful for the analysis of protein C-termini, which may also be post translationally modified. The labeling strategy and the indirect enrichment of C termini worked with similar efficiency for both DMEDA and EA, and their applicability was demonstrated on an E. coli proteome. Utilizing two proteases and different MS/MS activation mechanisms allowed for the identification of >400 C-termini, encompassing both canonical and truncated C-termini. PMID- 26939534 TI - Origin of Indium Diffusion in High-k Oxide HfO2. AB - Indium (In) out-diffusion through high-k oxides severely undermines the thermal reliability of the next generation device of III-V/high-k based metal oxide semiconductor (MOS). To date, the microscopic mechanism of In diffusion is not yet fully understood. Here, we utilize angle resolved X-ray photoelectron spectroscopy (ARXPS) and density functional theory (DFT) to explore In diffusion in high-k oxide HfO2. Our ARXPS results confirm the In diffusion through as prepared and annealed HfO2 grown on InP substrate. The theoretical results show that the In diffusion barrier is reduced to ~0.88 eV in the presence of oxygen vacancies (VO), whereas this barrier is as high as ~4.78 eV in pristine HfO2. Fundamentally, we found that the high feasibility of In diffusion is owing to In nonbonding with its neighboring atoms. These findings can be extended to understand the In diffusion in other materials in addition to HfO2. PMID- 26939535 TI - Social media in Ebola outbreak. AB - The West African 2014 Ebola outbreak has highlighted the need for a better information network. Hybrid information networks, an integration of both hierarchical and formalized command control-driven and community-based, or ad hoc emerging networks, could assist in improving public health responses. By filling the missing gaps with social media use, the public health response could be more proactive rather than reactive in responding to such an outbreak of global concern. This article provides a review of the current social media use specifically in this outbreak by systematically collecting data from ProQuest Newsstand, Dow Jones Factiva, Program for Monitoring Emerging Diseases (ProMED) as well as Google Trends. The period studied is from 19 March 2014 (first request for information on ProMED) to 15 October 2014, a total of 31 weeks. The term 'Ebola' was used in the search for media reports. The outcome of the review shows positive results for social media use in effective surveillance response mechanisms - for improving the detection, preparedness and response of the outbreak - as a complement to traditional, filed, work-based surveillance approach. PMID- 26939533 TI - Efficacy and Safety Profile of Diclofenac/Cyclodextrin and Progesterone/Cyclodextrin Formulations: A Review of the Literature Data. AB - BACKGROUND: According to health technology assessment, patients deserve the best medicine. The development of drugs associated with solubility enhancers, such as cyclodextrins, represents a measure taken in order to improve the management of patients. Different drugs, such as estradiol, testosterone, dexamethasone, opioids, non-steroidal anti-inflammatories (NSAIDs; i.e. diclofenac), and progesterone are associated with cyclodextrins. Products containing the association of diclofenac/cyclodextrins are available for subcutaneous, intramuscular, and intravenous administration in doses that range from 25 to 75 mg. Medicinal products containing the association of progesterone/cyclodextrins are indicated for intramuscular and subcutaneous injection at a dose equal to 25 mg. OBJECTIVES AND METHODS: The effects of cyclodextrins have been discussed in the solubility profile and permeability through biological membranes of drug molecules. A literature search was performed in order to give an overview of the pharmacokinetic characteristics, and efficacy and safety profiles of diclofenac/hydroxypropyl-beta-cyclodextrin (HPbetaCD) and progesterone/HPbetaCD associations. RESULTS: The results of more than 20 clinical studies were reviewed. It was suggested that the new diclofenac/HPbetaCD formulation gives a rapid and effective response to acute pain and, furthermore, has pharmacokinetic and efficacy/safety profiles comparable to other medicinal products not containing cyclodextrins. One of the principal aspects of these new diclofenac formulations is that in lowering the dose (lower than 50 mg) the drugs could be more tolerable, especially in patients with comorbid conditions. Moreover, results of studies investigating the characteristics of progesterone and cyclodextrins showed that the new formulation (progesterone/HPbetaCD 25 mg solution) has the same bioavailability as other products containing progesterone. It is more rapidly absorbed and allows the achievement of peak plasma concentrations in a shorter time. Finally, the new formulation of progesterone was shown to be safe and not inferior to other products already on the market, with the exception of progesterone administered vaginally. CONCLUSIONS: As shown by the results of clinical studies presented in this review, the newly approved medicines containing cyclodextrins have been found to be as effective and as well tolerated as other medicinal products that do not contain cyclodextrins. Moreover, the newly approved lower dose of diclofenac associated with cyclodextrins is consistent with the European Medicines Agency recommendations reported in the revision of the Assessment Report for Non-Steroidal Anti Inflammatory Drugs (NSAIDs) and Cardiovascular Risk. Finally, the use of cyclodextrins led to significant increases in solubility and bioavailability of drugs, such as diclofenac and progesterone, and improvement in the efficacy and safety of these drugs. PMID- 26939538 TI - Virological surveillance of influenza and other respiratory viruses during six consecutive seasons from 2006 to 2012 in Catalonia, Spain. AB - Most attention is given to seasonal influenza and respiratory syncytial virus outbreaks, but the cumulative burden caused by other respiratory viruses (RV) is not widely considered. The aim of the present study is to describe the circulation of RV in the general population during six consecutive seasons from 2006 to 2012 in Catalonia, Spain. Cell culture, immunofluorescence and PCR-based assays were used for the RV laboratory-confirmation and influenza subtyping. Phylogenetic and molecular characterizations of viral haemagglutinin, partial neuraminidase and matrix 2 proteins were performed from a representative sampling of influenza viruses. A total of 6315 nasopharyngeal samples were collected, of which 64% were laboratory-confirmed, mainly as influenza A viruses and rhinoviruses. Results show the significant burden of viral aetiological agents in acute respiratory infection, particularly in the youngest cases. The study of influenza strains reveals their continuous evolution through either progressive mutations or by segment reassortments. Moreover, the predominant influenza B lineage was different from that included in the recommended vaccine in half of the studied seasons, supporting the formulation and use of a quadrivalent influenza vaccine. Regarding neuraminidase inhibitors resistance, with the exception of the 2007/08 H275Y seasonal A(H1N1) strains, no other circulating influenza strains carrying known resistance genetic markers were found. Moreover, all circulating A(H1N1)pdm09 and A(H3N2) strains finally became genetically resistant to adamantanes. A wide knowledge of the seasonality patterns of the RV in the general population is well-appreciated, but it is a challenge due to the unpredictable circulation of RV, highlighting the value of local and global RV surveillance. PMID- 26939539 TI - Raman scattering enhanced within the plasmonic gap between an isolated Ag triangular nanoplate and Ag film. AB - Enhanced electromagnetic field in the tiny gaps between metallic nanostructures holds great promise in optical applications. Herein, we report novel out-of-plane nanogaps composed of micrometer-sized Ag triangular nanoplates (AgTN) on Ag films. Notably, the new coupled plasmonic structure can dramatically enhance the surface-enhanced Raman scattering (SERS) by visible laser excitation, although the micrometer-sized AgTN has localized plasmon resonance at infrared wavelength. This enhancement is derived from the gap plasmon polariton between the AgTN and Ag film, which is excited via the antenna effect of the corner and edge of the AgTN. Systematic SERS studies indicated that the plasmon enhancement was on the order of corner > edge > face. These results were further verified by theoretical simulations. Our device paves the way for rational design of sensitive SERS substrates by judiciously choosing appropriate nanoparticles and optimizing the gap distance. PMID- 26939540 TI - Erratum for Euro Surveill. 2016;21(7). PMID- 26939537 TI - Endoplasmic reticulum-plasma membrane junctions: structure, function and dynamics. AB - Endoplasmic reticulum (ER)-plasma membrane (PM) junctions are contact sites between the ER and the PM; the distance between the two organelles in the junctions is below 40 nm and the membranes are connected by protein tethers. A number of molecular tools and technical approaches have been recently developed to visualise, modify and characterise properties of ER-PM junctions. The junctions serve as the platforms for lipid exchange between the organelles and for cell signalling, notably Ca(2+) and cAMP signalling. Vice versa, signalling events regulate the development and properties of the junctions. Two Ca(2+) dependent mechanisms of de novo formation of ER-PM junctions have been recently described and characterised. The junction-forming proteins and lipids are currently the focus of vigorous investigation. Junctions can be relatively short lived and simple structures, forming and dissolving on the time scale of a few minutes. However, complex, sophisticated and multifunctional ER-PM junctions, capable of attracting numerous protein residents and other cellular organelles, have been described in some cell types. The road from simplicity to complexity, i.e. the transformation from simple 'nascent' ER-PM junctions to advanced stable multiorganellar complexes, is likely to become an attractive research avenue for current and future junctologists. Another area of considerable research interest is the downstream cellular processes that can be activated by specific local signalling events in the ER-PM junctions. Studies of the cell physiology and indeed pathophysiology of ER-PM junctions have already produced some surprising discoveries, likely to expand with advances in our understanding of these remarkable organellar contact sites. PMID- 26939541 TI - Lipopolysaccharide-bound structure of the antimicrobial peptide cecropin P1 determined by nuclear magnetic resonance spectroscopy. AB - Antimicrobial peptides (AMPs) are components of the innate immune system and may be potential alternatives to conventional antibiotics because they exhibit broad spectrum antimicrobial activity. The AMP cecropin P1 (CP1), isolated from nematodes found in the stomachs of pigs, is known to exhibit antimicrobial activity against Gram-negative bacteria. In this study, we investigated the interaction between CP1 and lipopolysaccharide (LPS), which is the main component of the outer membrane of Gram-negative bacteria, using circular dichroism (CD) and nuclear magnetic resonance (NMR). CD results showed that CP1 formed an alpha helical structure in a solution containing LPS. For NMR experiments, we expressed (15) N-labeled and (13) C-labeled CP1 in bacterial cells and successfully assigned almost all backbone and side-chain proton resonance peaks of CP1 in water for transferred nuclear Overhauser effect (Tr-NOE) experiments in LPS. We performed (15) N-edited and (13) C-edited Tr-NOE spectroscopy for CP1 bound to LPS. Tr-NOE peaks were observed at the only C-terminal region of CP1 in LPS. The results of structure calculation indicated that the C-terminal region (Lys15 Gly29) formed the well-defined alpha-helical structure in LPS. Finally, the docking study revealed that Lys15/Lys16 interacted with phosphate at glucosamine I via an electrostatic interaction and that Ile22/Ile26 was in close proximity with the acyl chain of lipid A. PMID- 26939542 TI - Moderately lower temperatures greatly extend the lifespan of Brachionus manjavacas (Rotifera): Thermodynamics or gene regulation? AB - Environmental temperature greatly affects lifespan in a wide variety of animals, but the exact mechanisms underlying this effect are still largely unknown. A moderate temperature decrease from 22 degrees C to 16 degrees C extends the lifespan of the monogonont rotifer Brachionus manjavacas by up to 163%. Thermodynamic effects on metabolism contribute to this increase in longevity, but are not the only cause. When rotifers are exposed to 16 degrees C for four days and then transfered to 22 degrees C, they survive until day 13 at nearly identical rates as rotifers maintained at 16 degrees C continuously. This persistence of the higher survival for nine days after transfer to 22 degrees C suggests that low temperature exposure alters the expression of genes that affect the rate of aging. The relative persistence of the gene regulation effect suggests that it may play an even larger role in slowing aging than the thermodynamic effects. The life extending effects of these short-term low temperature treatments are largest when the exposure happens early in the life cycle, demonstrating the importance of early development. There is no advantage to lowering the temperature below 16 degrees C to 11 degrees or 5 degrees C. Rotifers exposed to 16 degrees C also displayed increased resistance to heat, starvation, oxidative and osmotic stress. Reproductive rates at 16 degrees C were lower than those at 22 degrees C, but because they reproduce longer, there is no significant change in the lifetime fecundity of females. To investigate which genes contribute to these effects, the expression of specific temperature sensing genes was knocked down using RNAi. Of 12 genes tested, RNAi knockdown of four eliminated the survival enhancing effects of the four-day cold treatment: TRP7, forkhead box C, Y-box factor, and ribosomal protein S6. This demonstrates that active gene regulation is an important factor in temperature mediated life extension, and that these particular genes play an integral role in these pathways. As a thermoresponsive sensor, TRP7 may be responsible for triggering the signaling cascade contributing to temperature mediated life extension. The TRP genes may also provide especially promising candidates for targeted gene manipulations or pharmacological interventions capable of mimicking the effects of low temperature exposure. These results support recent theories of aging that claim rate of aging is determined by an actively regulated genetic mechanism rather than an accumulation of molecular damage. PMID- 26939543 TI - Preoperative diagnosis and prognosis in 40 Parathyroid Carcinoma Patients. AB - OBJECTIVE: Parathyroid carcinoma (PC) is a rare disease which is difficult to diagnose preoperatively and predict prognosis. The goal of this study was to analyse the preoperative predictive factors and prognostic factors in PC patients and to evaluate the possibility of diagnosing PC preoperatively. DESIGN, SETTING AND PATIENTS: This is a retrospective study from Jan 2000 to Aug 2015 conducted in Shanghai Ruijin Hospital. MEASUREMENTS: Comparisons were made between 40 parathyroid carcinoma patients and 282 patients with benign parathyroid lesions during the same period. All patients underwent parathyroid surgery, and the results were certified by paraffin pathology. Prognostic factors were analysed in the 40 PC patients. RESULTS: Patients with higher levels of intact parathyroid hormone (P < 0.001, OR = 1.001, CI: 1.000-1.002), calcium (P = 0.008, OR = 3.395, CI: 1.382-8.341) and a larger parathyroid volume (P = 0.001, OR = 2.023, CI: 1.333-3.071) were more likely to have PC. Local excision (P = 0.008, OR = 4.992, CI: 1.533-16.252), stage III in the Schulte staging system (P = 0.039, OR = 9.600, CI: 1.12-82.322), high risk in the Schulte Risk Classification (P = 0.012, OR = 5.466, CI: 1.448-20.628) and first surgery by other medical teams (P = 0.008, OR = 4.992, CI: 1.496-15.037) were associated with PC recurrence. Calcium (P = 0.01, OR = 7.270, CI: 1.611-32.812), intact parathyroid hormone (P = 0.037, OR = 1.001, CI: 1.000-1.001), local excision (P = 0.009, OR = 6.875, CI: 1.633 28.936) and recurrence (P = 0.014, OR = 7.762, CI: 1.504-40.055) were associated with death. CONCLUSIONS: A preoperative diagnostic system may provide a new method to distinguish PC from benign parathyroid lesions before surgery. For PC patients who did not undergo en-bloc resection at first operation, timely further surgery may offer a second chance of cure. Early diagnosis and surgery are pivotal to reduce mortality in PC patients. PMID- 26939545 TI - New mechanistic insight into the oxygen reduction reaction on Ruddlesden-Popper cathodes for intermediate-temperature solid oxide fuel cells. AB - Ruddlesden-Popper (R-P) phase materials have been investigated widely as cathode candidates for IT-SOFCs. However, widespread application of R-P phase cathodes demands further improvement in electrode activity whose progress is hindered by the limited information in the oxygen reduction reaction (ORR). The ORR mechanism for the R-P phase is therefore investigated in this paper using (LaSr)2NiO(4+/ delta) as an example. Accurate characterization of the surface oxygen exchange process is realized by developing thin and dense polycrystalline LSNO layers via a versatile spray-modified pressing method we invented before to avoid perceptible bulk diffusion contribution, surface enrichment and geometry complication. The governing factors of the ORR are identified as oxygen adsorption and incorporation based on the findings in reaction orders from electrochemical impedance spectroscopy (EIS), stoichiometry-related chemical capacitance and intrinsic anisotropic properties. The incorporation rate is proven to drastically depend on the amount of interstitial oxygen (O(i)"). Since the unfilled interstitial sites(V(i)(*)) in the R-P phase serve to accommodate the adsorbed oxygen during incorporation, like vacancies in the perovskite structure (V(O)(**)), more O(i)" would seem to suppress the kinetics of this process. In regards to this, for the first time, a physical model is proposed to reconcile the discrepancy between the experimental results and intuitive reasoning. Based on supporting evidence, this model illustrates a possibility of how O(i)" works to regulate the exchange rate, and how the contradiction between V(O)(**) and O(i)" is harmonized so that the latter in the R-P structure also positively promotes the incorporation rate in the ORR. PMID- 26939544 TI - Antarctic skuas recognize individual humans. AB - Recent findings report that wild animals can recognize individual humans. To explain how the animals distinguish humans, two hypotheses are proposed. The high cognitive abilities hypothesis implies that pre-existing high intelligence enabled animals to acquire such abilities. The pre-exposure to stimuli hypothesis suggests that frequent encounters with humans promote the acquisition of discriminatory abilities in these species. Here, we examine individual human recognition abilities in a wild Antarctic species, the brown skua (Stercorarius antarcticus), which lives away from typical human settlements and was only recently exposed to humans due to activities at Antarctic stations. We found that, as nest visits were repeated, the skua parents responded at further distances and were more likely to attack the nest intruder. Also, we demonstrated that seven out of seven breeding pairs of skuas selectively responded to a human nest intruder with aggression and ignored a neutral human who had not previously approached the nest. The results indicate that Antarctic skuas, a species that typically inhabited in human-free areas, are able to recognize individual humans who disturbed their nests. Our findings generally support the high cognitive abilities hypothesis, but this ability can be acquired during a relatively short period in the life of an individual as a result of interactions between individual birds and humans. PMID- 26939546 TI - Sublethal effects of chlorantraniliprole on development, reproduction and vitellogenin gene (CsVg) expression in the rice stem borer, Chilo suppressalis. AB - BACKGROUND: The rice stem borer, Chilo suppressalis (Walker), is one of the most damaging rice pests in the world. The sublethal effects of chlorantraniliprole on development,reproduction and mRNA expression levels of vitellogenin gene (CsVg) in C. suppressalis were investigated. RESULTS: Exposure of third-instar larvae to sublethal concentrations of chlorantraniliprole (LC10 and LC30 ) significantly extended larval duration, lowered the mean weight of male pupae and shortened male adult longevity. Pupal duration was significantly prolonged and the mean weight of female pupae was significantly lowered in the LC30 treatment group. While there were no significant sublethal effects on either the adult emergence rate or the egg hatch, the pupation rates in the LC10 treatment group (41.30%) and in the LC30 treatment group (23.98%) were significantly lower than the pupation rate of the control (71.86%), and LC10 and LC30 chlorantraniliprole significantly reduced fecundity, by 32.18 and 52.94% respectively. Furthermore, the expression levels of CsVg mRNA after exposure to LC10 and LC30 chlorantraniliprole significantly decreased, by 42.52 and 47.84% respectively, in 12-h-old female adults. CONCLUSION: Sublethal concentrations of chlorantraniliprole adversely affect the development and reproduction of C. suppressalis. The downregulation of CsVg by chlorantraniliprole might have negative impacts on the fecundity of C. suppressalis. (c) 2016 Society of Chemical Industry. PMID- 26939548 TI - An Unusual Laryngeal Mass Requiring Unusual Airway Management. PMID- 26939547 TI - Retrospective study of the application of acellular dermis in reconstructing full thickness skin defects. AB - The purpose of the article is to evaluate the acellular dermis' utility in reconstructing full-thickness defects after scar contracture releasing and giant nevus resection. From the year 2012 to 2014, 18 consecutive patients underwent composite graft (thin autograft and alloderma) transplantation. Among these patients, 16 patients suffered from burned scar contracture in the upper extremities, and two young cases were met with giant nevus on the upper extremity. Ten of 13 adult cases with upper extremity scar affection were chosen for a comparative study. Twenty hands were randomly allocated into group A and group B. The thick autograft was used to repair one upper extremity in group B, and the composite grafts were used to cover the other upper extremity in group A. Besides appraisal of the recipient sites' function and aesthetics, donor sites were also estimated after a mean of 12 months' follow-up through the Vancouver Scar Score Scale. After evaluation in the above comparative study through the Vancouver Score Scale, in the recipient evaluation, no statistical difference was found in the pigmentation score between two groups, while statistical difference was achieved in other aspects (vascularity, pliability, height). In the donor site's evaluation, statistical difference was established between the two groups in all facets. One adult patient was dissatisfied with the hypertrophic scar on the donor site, and about almost a half of the area became a hypertrophic scar in the recipient site. No atrophic change occurred; one little girl, suffering from large nevus, was operated on by removing nearly the whole giant nevus on the upper limb. Unfortunately, she presented with finger tip necrosis occurring. The finger tip was not ultimately preserved and was repaired with an abdomen flap. Acellular dermal matrix is an excellent option and a useful tool for reconstructing large full-thickness skin defects after releasing burned scar contracture and removing giant nevus. With thin-skin graft meshed, a donor site's presentation brings courage to patients, while recipient sites can reach nearly the same elasticity and function compared to thick-grafted skin. PMID- 26939549 TI - Nucleic Acid i-Motif Structures in Analytical Chemistry. AB - Under the appropriate experimental conditions of pH and temperature, cytosine rich segments in DNA or RNA sequences may produce a characteristic folded structure known as an i-motif. Besides its potential role in vivo, which is still under investigation, this structure has attracted increasing interest in other fields due to its sharp, fast and reversible pH-driven conformational changes. This "on/off" switch at molecular level is being used in nanotechnology and analytical chemistry to develop nanomachines and sensors, respectively. This paper presents a review of the latest applications of this structure in the field of chemical analysis. PMID- 26939551 TI - Changes in the morphology and protein expression of germ cells and Sertoli cells in plateau pikas testes during non-breeding season. AB - Plateau pikas are seasonally breeding small herbivores that inhabit the meadow ecosystem of the Qinghai-Tibetan Plateau. Testis regression in plateau pikas begins in early June, and the male pikas are completely infertile, with a dramatically reduced testis size, in late July. In this study, a decreased germ cell number in the testes was first noted in early June. By late June, only Sertoli cells and a small number of spermatogonia remained. Interestingly, large gonocyte-like germ cells were observed in early July. In late July, the number of gonocyte-like cells per tubule increased significantly, and most of the Sertoli cell nuclei moved to and clustered in the center of the seminiferous tubules. The gonocyte-like germ cells and Sertoli cells began to express AP-2gamma and anti Mullerian hormone (AMH) proteins, which were detected in the germ cells and Sertoli cells of juvenile pikas but not in adult testes. Simultaneously, LC3 puncta dramatically increased in the seminiferous tubules of the pikas' testes during the non-breeding season. Our study found that spermatogonia and Sertoli cells in non-breeding adult pikas morphologically resembled those in juvenile pikas and expressed specific markers, indicating that de-differentiation-like transitions may occur during this process. PMID- 26939550 TI - Comparative genomic analyses reveal broad diversity in botulinum-toxin-producing Clostridia. AB - BACKGROUND: Clostridium botulinum is a diverse group of bacteria characterized by the production of botulinum neurotoxin. Botulinum neurotoxins are classified into serotypes (BoNT/A-G), which are produced by six species/Groups of Clostridia, but the genetic background of the bacteria remains poorly understood. The purpose of this study was to use comparative genomics to provide insights into the genetic diversity and evolutionary history of bacteria that produce the potent botulinum neurotoxin. RESULTS: Comparative genomic analyses of over 170 Clostridia genomes, including our draft genome assemblies for 59 newly sequenced Clostridia strains from six continents and publicly available genomic data, provided in-depth insights into the diversity and distribution of BoNT-producing bacteria. These newly sequenced strains included Group I and II strains that express BoNT/A,/B,/E, or/F as well as bivalent strains. BoNT-producing Clostridia and closely related Clostridia species were delineated with a variety of methods including 16S rRNA gene, concatenated marker genes, core genome and concatenated multi-locus sequencing typing (MLST) gene phylogenies that related whole genome sequenced strains to publicly available strains and sequence types. These analyses illustrated the phylogenetic diversity in each Group and the diversity of genomic backgrounds that express the same toxin type or subtype. Comparisons of the botulinum neurotoxin genes did not identify novel toxin types or variants. CONCLUSIONS: This study represents one of the most comprehensive analyses of whole genome sequence data for Group I and II BoNT-producing strains. Read data and draft genome assemblies generated for 59 isolates will be a resource to the research community. Core genome phylogenies proved to be a powerful tool for differentiating BoNT-producing strains and can provide a framework for the study of these bacteria. Comparative genomic analyses of Clostridia species illustrate the diversity of botulinum-neurotoxin-producing strains and the plasticity of the genomic backgrounds in which bont genes are found. PMID- 26939552 TI - Total knee arthroplasty for valgus osteoarthritis: the results of a standardized soft-tissue release technique. AB - PURPOSE: The study reports the 2-year follow-up results of patients with valgus osteoarthritis undergoing total knee arthroplasty (TKA) with a standardized soft tissue release. METHODS: Between 2008 and 2013, 222 TKAs were performed for valgus osteoarthritis by a single surgeon. A total of 181 TKAs in 164 patients were available for a minimum 2-year follow-up (range 24-87 months). Preoperative and postoperative range of motion (ROM), mechanical alignment, the postoperative medial proximal tibial angle (MPTA), Western Ontario and McMaster Universities Arthritis Index (WOMAC), VF-12 score, visual analogue pain scale (VAS), and the actual UCLA activity score, desired UCLA score, ligamentous stability (medial collateral ligament) and complications and revision rates were recorded. RESULTS: The ROM increased from a preoperative flexion contracture of 4.7 degrees (range 0-40) and flexion of 110 degrees (range 35-135) to a postoperative mean flexion contracture of 0.1 degrees (range -5 to 10) and flexion of 128 degrees (range 100-140). The mean hip-knee-ankle alignment was changed from 8.4 degrees of mechanical valgus (range 5.3-25.4) to 0.02 degrees of varus alignment (range 2.9 to 4.1). Tibia component angle (MPTA) was 90.4 degrees (range 86.1-93.7). The WOMAC score, VF-12, UCLA and VAS significantly improved after surgery (p < 0.05). Two patients (1.1 %) underwent revision surgery for instability. CONCLUSION: The described standardized soft-tissue release (release of the iliotibial band and posterolateral corner) provided excellent clinical results at a minimum 2-year follow-up and can be used safely for a "cook-book" approach to the valgus knee with up to 25 degrees mechanical valgus alignment. LEVEL OF EVIDENCE: IV. PMID- 26939554 TI - Comment on: 'Effectiveness of a smartphone application for testing near-visual acuity'. PMID- 26939553 TI - Feedback regulation of apical progenitor fate by immature neurons through Wnt7 Celsr3-Fzd3 signalling. AB - Sequential generation of neurons and glial cells during development is critical for the wiring and function of the cerebral cortex. This process requires accurate coordination of neural progenitor cell (NPC) fate decisions, by NPC autonomous mechanisms as well as by negative feedback from neurons. Here, we show that neurogenesis is protracted and gliogenesis decreased in mice with mutations of genes Celsr3 and Fzd3. This phenotype is not due to gene inactivation in progenitors, but rather in immature cortical neurons. Mutant neurons are unable to upregulate expression of Jag1 in response to cortical Wnt7, resulting in blunted activation of Notch signalling in NPC. Thus, Celsr3 and Fzd3 enable immature neurons to respond to Wnt7, upregulate Jag1 and thereby facilitate feedback signals that tune the timing of NPC fate decisions via Notch activation. PMID- 26939555 TI - Intravitreal aflibercept for refractory choroidal neovascularization secondary to angioid streaks. PMID- 26939556 TI - Reply to 'Comment on: Long-term outcomes of neovascular glaucoma treated with and without intravitreal bevacizumab'. PMID- 26939557 TI - Intravitreal aflibercept for choroidal neovascularisation in angioid streaks. PMID- 26939558 TI - Effect of intravitreal dexamethasone implant on retinal and choroidal thickness in refractory diabetic macular oedema after multiple anti-VEGF injections. AB - AimsTo investigate the effect of intravitreal dexamethasone implant (IVD) on central foveal thickness (CFT), choroidal thickness (CT) and its correlation with visual acuity in eyes with refractory diabetic macular oedema (DMO).MethodsThis was a retrospective interventional case-series. Thirty-five eyes of 35 patients were treated with a single injection of IVD because of refractory DMO with CFT over 300 MUm, and persistent intraretinal and subretinal fluid despite of multiple intravitreal bevacizumab injections. Patients were followed-up for 6 months for the evaluation of CFT and subfoveal CT by spectral-domain optical coherence tomography.ResultsAll eyes (mean age: 59.4+/-12.35 years; 18 males, 17 females) had been previously treated with multiple bevacizumab injections and showed persistent DMO (mean number of injections 4.08+/-2.98) The preoperative logMAR BCVA was 0.49+/-0.24, which gradually improved to 0.46+/-0.32 at 6 months (P=0.652) and 26% gained two or more lines of Snellen visual acuity. At baseline, the mean CFT was 526.29+/-123.48 MUm, which significantly improved to 316.15+/ 100.09 MUm at 3 months (P<0.001). However, CFT deteriorated to 457.07+/-136.53 MUm at 6 months (P=0.051). Similarly, the mean preoperative subfoveal CT was 288.91+/-36.47 MUm and it decreased to 266.85+/-30.93 MUm at 3 months (P<0.01), but increased to 278.63+/-32.55 MUm at 6 months (P=0.137). The reduction of CFT from baseline showed significant correlation with that of subfoveal CT at 3 months (P=0.041) and at 6 months (P=0.008).ConclusionsIn DMO refractory to multiple bevacizumab injections, IVD significantly reduced CFT and subfoveal CT, with BCVA improvement in one-fourth of the patients. The reduction of CFT showed significant correlation with reduction of subfoveal CT. PMID- 26939559 TI - Vitrectomy for primary symptomatic vitreous opacities: an evidence-based review. AB - Floaters are a common ocular condition which form as a consequence of aging changes in the vitreous. Although in most patients the symptoms are minimal, they can cause significant impairment in vision-related quality of life in a small population of patients. Recently there has been an increase in awareness of the visual disability caused by floaters, and the evidence-base for treatment of this condition using small-gauge vitrectomy has increased. In this review, we define the term 'floaters' as symptomatic vitreous opacities (SVO). We suggest a classification dependent on the presence or absence of posterior vitreous detachment and discuss their pathogenesis and natural history. We review their impact on patients' quality of life related to visual function. We review the psychological factors that may have a role in some patients who appear to be affected by SVO to the extent that they pursue all options including surgery with all its attendant risks. We summarise the available evidence-base of treatment options available for SVO with special emphasis on the safety and efficacy of vitrectomy for this condition. PMID- 26939560 TI - Retinectomy vs vitrectomy combined with scleral buckling in repair of posterior segment open-globe injuries with retinal incarceration. AB - PurposeTo evaluate the anatomic and functional outcome of pars plana vitrectomy (PPV) combined with scleral buckling (SB) vs retinectomy in treating posterior segment open-globe injuries with retinal incarceration.MethodsPatients (38 eyes) with posterior segment open-globe injuries and retinal incarceration were identified, and they underwent either PPV combined with SB (PPV+SB, n=19) or retinectomy (n=19). The two groups were matched in the following categories: the severity of injury (including wound length), the location of the incarceration site and the presence of retinal detachment. Anatomic reattachment of the retina and best-corrected visual acuity (BCVA) were measured at the time of 12 months after operation.ResultsAt 12 months after operation, the PPV+SB group demonstrated a better anatomic retinal attachment rate (84.2% vs 68.4%, P=0.252) and BCVA (73.7% vs 47.4%, P=0.247) compared with the retinectomy group, however, the differences failed to reach statistical significance. Compared with the PPV+SB group, the rectinectomy group had significantly higher rates of hemorrhage (47.4% vs 15.8%, P=0.036), inflammation (42.1% vs 10.5%, P=0.027), and a lower intraocular pressure (IOP, 9.8+/-3.1 vs 13.6+/-4.1 mmHg, P=0.002) after silicone oil (SO) removal.ConclusionsFor patients with posterior segment open-globe injuries and retinal incarceration, PPV and SB treatments resulted in a better anatomic and functional outcome and less post-operation complications compared with the retinectomy. PMID- 26939561 TI - Occurrence and severity of upper eyelid skin contracture in facial nerve palsy. AB - PurposeTo describe the occurrence and severity of upper eyelid skin contracture in facial nerve palsy (FNP).MethodsWe enroled consecutive patients with unilateral FNP into this study. Patients with previous upper eyelid surgery for either side were excluded. We developed a standardised technique to measure the distance between the upper eyelid margin and the lower border of brow (LMBD). FNP was graded using the Sunnybrook grading scale. Its aetiology, duration, and treatment were noted. Upper and lower marginal reflex distance and lagophthalmos were also noted.ResultsSixty-six patients (mean age 51 years) were included. FNP was owing to a variety of aetiologies. LMBD on the paralytic side was shorter than the normal contralateral side in 47 (71%), equal in 15 (23%), and larger in four (6%) patients. The mean contracture was 3.4 mm (median: 3, range: 1-12) with 11 (17%) patients showing 5 mm or more of skin contracture. The mean LMBD on the paralytic side in all patients was significantly smaller than the contralateral side; 30+/-3.7 (median: 30; 95% CI 29-31) compared with 32+/-3.7 (median: 32; 95% CI 32-33), respectively, P<0.0001, two-tailed paired t-test.ConclusionTo our knowledge, this is the first study that quantitatively demonstrates contraction of the upper eyelid skin in FNP. This finding is valuable in directing optimal early management to minimise skin contracture and to caution surgeons against unnecessary upper eyelid skin excision. PMID- 26939562 TI - Comment on: 'Effectiveness of a smartphone application for testing near visual acuity'. PMID- 26939563 TI - Comment on: 896. PMID- 26939564 TI - 'I Wanted to Come Here Because of My Child': Stories of Migration Told by Turkish Speaking Families Who Have a Son or Daughter with Intellectual Disabilities. AB - BACKGROUND: Despite growing interest in the experiences and social barriers experienced by people with intellectual disabilities from ethnic minorities, the specific challenges associated with migration from abroad faced by these individuals and their families have been overlooked. This research focuses on narratives told by Turkish-speaking families about migrating to the UK with a family member with intellectual disabilities. METHOD: Semi-structured interviews were carried out with five Turkish-speaking families who have a son or daughter with an intellectual disability and had migrated to the UK. Interviews were analysed using narrative analysis. RESULTS: Seeking help for the person with intellectual disabilities in a new country was a central part of migration narratives. The family member with intellectual disabilities was described as being caught up in wider geo-political conflicts. Families continued to face challenges within their own communities and with accessing local services. CONCLUSIONS: Eliciting narratives about families' migration to their new homes can provide professionals with important information about family experiences of trauma and clarify hopes and expectations regarding service provision. PMID- 26939566 TI - Genetic variants associated with rheumatoid arthritis patients and serotypes in European populations. AB - OBJECTIVES: To replicate the association of rheumatoid arthritis (RA) susceptibility loci in an independent European sample and to assess their specificity with anti-citrullinated protein antibodies (ACPA) status. METHODS: A selection of 64 SNP previously associated with RA have been typed in a cohort of 267 RA patients (169 ACPA-positive and 98 ACPA-negative) and 152 controls from the Rheumatology Units of the University Hospital of Pisa (Italy) and the University of Pecs Medical Center (Hungary). Regression analyses were performed first considering overall RA patients and secondly, taking both serotype subgroups as different disease entities. The results have been adjusted for age, gender and origin of individuals. RESULTS: The well-known CD2, REL, TNFAIP3, IRF5, PTPRC, and CCR6 have been confirmed as RA disease associated loci together with recently discovered BACH2, RASGRP1, and IKZF3 loci, taking all RA patients as a unique phenotype. Results from both serological subgroups separately reflect the specificity of these susceptibility loci and show additional ACPA-positive specific associations for variants at IL6R, IL2RA, BLK, DDX6, IL6, and TLE3 genes. CONCLUSIONS: The results from GAPAID project are consistent with previously established RA disease associations for CD2, PTPRC, REL, CCR6, TNFAIP3, IRF5, BLK, IL2RA, and DDX6 loci. In addition, IL6R, BACH2, RASGRP1, TLE3, and IKZF3 are replicated for the first time in an independent European population and IL6 appears to be a suggestive new RA associated locus. The stratified analysis based on ACPA status provides further support for distinct genetic aetiologies of RA subsets, which might have therapeutic implications. PMID- 26939567 TI - Serpentine-like right atrial mass and fulminant bilateral pulmonary embolism during treatment with rivaroxaban. AB - Imaging work-up of a 80-year-old woman with sudden onset of dyspnea during current rivaroxaban therapy: computer tomography angiography revealed fulminant bilateral pulmonary embolism. Furthermore, a serpentine-like huge mass in the right atrium was detected, highly suggestive of thrombus or a giant chiari network, respectively. This case highlights the importance of adequate dose regimen of factor Xa inhibitors, as well as the need of thorough differential diagnostic considerations of net like structures in the right atrium. PMID- 26939568 TI - Hepatitis E virus infection as a direct cause of neuralgic amyotrophy. AB - INTRODUCTION: We describe a patient who developed neuralgic amyotrophy (NA) related to hepatitis E virus (HEV) infection. METHODS: The patient underwent neurological and electrodiagnostic examinations, high-resolution analysis of serological changes, and HEV load profile, and was treated with intravenous immunoglobulin. RESULTS: There was evidence of bilateral, asymmetric acute inflammatory cervical polyradiculopathy and possible brachial plexopathy. Positive serum anti-HEV IgM was followed by seroconversion to anti-HEV IgG positivity. A calculated anti-HEV antibody index was compatible with intrathecal synthesis, and HEV genotype 3 RNA was found in serum and cerebrospinal fluid (CSF). Liver function tests returned to normal within 6 weeks. CONCLUSIONS: Bilateral involvement of cervical nerve roots and/or plexus, elevated liver function tests, and abnormal CSF are typical features of HEV-associated NA. The pathogenesis involves possible immune-mediated mechanisms. However, our findings support the hypothesis that HEV-related NA is associated with direct infection. Muscle Nerve 54: 325-327, 2016. PMID- 26939565 TI - Developmental role of the cell adhesion molecule Contactin-6 in the cerebral cortex and hippocampus. AB - The gene encoding the neural cell adhesion molecule Contactin-6 (Cntn6 a.k.a. NB 3) has been implicated as an autism risk gene, suggesting that its mutation is deleterious to brain development. Due to its GPI-anchor at Cntn6 may exert cell adhesion/receptor functions in complex with other membrane proteins, or serve as a ligand. We aimed to uncover novel phenotypes related to Cntn6 functions during development in the cerebral cortex of adult Cntn6(-/-) mice. We first determined Cntn6 protein and mRNA expression in the cortex, thalamic nuclei and the hippocampus at P14, which decreased specifically in the cortex at adult stages. Neuroanatomical analysis demonstrated a significant decrease of Cux1+ projection neurons in layers II-IV and an increase of FoxP2+ projection neurons in layer VI in the visual cortex of adult Cntn6(-/-) mice compared to wild-type controls. Furthermore, the number of parvalbumin+ (PV) interneurons was decreased in Cntn6( /-) mice, while the amount of NPY+ interneurons remained unchanged. In the hippocampus the delineation and outgrowth of mossy fibers remained largely unchanged, except for the observation of a larger suprapyramidal bundle. The observed abnormalities in the cerebral cortex and hippocampus of Cntn6(-/-) mice suggests that Cntn6 serves developmental functions involving cell survival, migration and fasciculation. Furthermore, these data suggest that Cntn6 engages in both trans- and cis-interactions and may be involved in larger protein interaction networks. PMID- 26939569 TI - Spontaneous intracranial hypotension following epidural anesthesia: a case report. AB - We report a case of refractory spontaneous intracranial hypotension (SIH) following epidural anesthesia. In this case, typical clinical symptoms and concomitant use of regional anesthesia led to the misdiagnosis of SIH as post dural puncture headache (PDPH). A 56-year-old man received a successful appendectomy under epidural anesthesia performed at a T11-T12 intravertebral space. About 20 h later, the patient started complaining about orthostatic headache when getting up from his lying position, then a PDPH was diagnosed. However, the patient did not respond well to conservative treatment. Three months later, the first epidural blood patch was performed at the L3-L4 level, however, the patient still had an orthostatic headache. Five days later, spine magnetic resonance imaging showed multiple meningeal diverticulum in the cervicothoracic junction, and computerized tomography myelography demonstrated a C5-C6 spinal dural tear suggesting cerebrospinal fluid leaks. Finally, the patient was diagnosed as SIH and received a second epidural blood patch at the T2-T3 level and responded with improvements in symptomatology. The patient was then discharged, and at a 2-year follow-up, he had fully recovered except for some remaining neck stiffness. This case illustrates that SIH was misdiagnosed as PDPH because of the common clinical symptoms and potentially confounding events (epidural/spinal anesthesia and assumption that it was a case of PDPH). It is important to carefully observe patients in such conditions and promptly conduct suitable diagnostic tests. For a successful treatment of SIH, a timely epidural blood patch should be considered as soon as the diagnosis is established. PMID- 26939571 TI - Dust Rains Deliver Diverse Assemblages of Microorganisms to the Eastern Mediterranean. AB - Dust rains may be particularly effective at delivering microorganisms, yet their biodiversities have been seldom examined. During 2011 and 2012 in Beirut, Lebanon, 16 of 21 collected rainfalls appeared dusty. Trajectory modelling of air mass origins was consistent with North African sources and at least one Southwest Asian source. As much as ~4 g particulate matter, ~20 MUg DNA, and 50 million colony forming units were found deposited per square meter during rainfalls each lasting less than one day. Sequencing of 93 bacteria and 25 fungi cultured from rain samples revealed diverse bacterial phyla, both Gram positive and negative, and Ascomycota fungi. Denaturing Gradient Gel Electrophoresis of amplified 16S rDNA of 13 rains revealed distinct and diverse assemblages of bacteria. Dust rain 16S libraries yielded 131 sequences matching, in decreasing order of abundance, Betaproteobacteria, Alphaproteobacteria, Firmicutes, Actinobacteria, Bacteroidetes, Cyanobacteria, Epsilonproteobacteria, Gammaproteobacteria, and Deltaproteobacteria. Clean rain 16S libraries yielded 33 sequences matching only Betaproteobacteria family Oxalobacteraceae. Microbial composition varied between dust rains, and more diverse and different microbes were found in dust rains than clean rains. These results show that dust rains deliver diverse communities of microorganisms that may be complex products of revived desert soil species and fertilized cloud species. PMID- 26939572 TI - Glucose and lipid effects of the ileal apical sodium-dependent bile acid transporter inhibitor GSK2330672: double-blind randomized trials with type 2 diabetes subjects taking metformin. AB - AIMS: To investigate the pharmacodynamics, pharmacokinetics and safety/tolerability of blocking reuptake of bile acids using the inhibitor GSK2330672 (GSK672) in patients with type 2 diabetes (T2D). METHODS: Subjects with T2D taking metformin were enrolled in two studies in which they took metformin 850 mg twice daily for 2 weeks prior to and during the randomized treatment periods. In the first crossover study (n = 15), subjects received GSK672 45 mg, escalating to 90 mg, twice daily, or placebo for 7 days. The second parallel-group study (n = 75) investigated GSK672 10-90 mg twice daily, placebo or sitagliptin for 14 days. RESULTS: In both studies, GSK672 reduced circulating bile acids and increased serum 7-alpha-hydroxy-4-cholesten-3-one (C4), an intermediate in the hepatic synthesis of bile acids. Compared with placebo, in the parallel-group study 90 mg GSK672 twice daily reduced fasting plasma glucose [FPG; -1.21 mmol/l; 95% confidence interval (CI) -2.14, -0.28] and weighted-mean glucose area under the curve (AUC)0-24 h (-1.33 mmol/l; 95% CI -2.30, -0.36), as well as fasting and weighted-mean insulin AUC0 -24 h . GSK672 also reduced cholesterol (LDL, non-HDL and total cholesterol) and apolipoprotein B concentrations; the maximum LDL cholesterol reduction was ~40%. There was no change in HDL cholesterol but there was a trend towards increased fasting triglyceride levels in the GSK672 groups compared with placebo. In both studies, the most common adverse events associated with GSK672 were gastrointestinal, mostly diarrhoea (22-100%), which appeared to be independent of dose. CONCLUSIONS: In subjects with T2D on metformin, GSK672 improved glucose and lipids, but there was a high incidence of gastrointestinal adverse events. PMID- 26939570 TI - The blockage of the Nogo/NgR signal pathway in microglia alleviates the formation of Abeta plaques and tau phosphorylation in APP/PS1 transgenic mice. AB - BACKGROUND: Alzheimer's disease (AD) is characterized by extracellular beta amyloid (Abeta) plaques, neurofibrillary tangles (NFTs), and microglia-dominated neuroinflammation. The Nogo/NgR signal pathway is involved in AD pathological features, but the detailed mechanism needs further investigation. Our previous studies have confirmed that the activation of NgR on microglia by Nogo promotes the expression of proinflammatory cytokines and inhibits cell adhesion and migration behaviors. In the present study, we investigated the effects of Nogo/NgR signaling pathway on the pathological features of AD and possible mechanisms. METHODS: After NEP1-40 (a competitive antagonist of Nogo/NgR pathway) was intracerebroventricularly administered via mini-osmotic pumps for 2 months in amyloid precursor protein (APP)/PS1 transgenic mice, plaque load, tau phosphorylation, and inflammatory responses were determined. After primary mouse neurons were exposed to the conditioned medium from BV-2 microglia stimulated by Nogo, the production of Abeta and phosphorylation of tau was quantified by ELISA and western blot. RESULTS: Inhibition of the Nogo/NgR signaling pathway ameliorated pathological features including amyloid plaques and phosphorylated levels of tau in APP/PS1 mice. In addition, after treatment with the conditioned medium from BV-2 microglia stimulated by Nogo, Abeta production and tau phosphorylation in cultured neurons were increased. The conditioned medium also increased the expression of APP, its amyloidogenic processing, and the activity of GSK3beta in neurons. The conditioned medium was also proinflammatory medium, and the blockage of the Nogo/NgR pathway improved the neuroinflammatory environment in APP/PS1 mice. CONCLUSIONS: Taken together, the neuroinflammation mediated by Nogo/NgR pathway in microglia could directly take part in the pathological process of AD by influencing the amyloidogenesis and tau phosphorylation. These results contribute to a better understanding of AD pathogenesis and could offer a new therapeutic option for delaying the progression of AD. PMID- 26939574 TI - Comparison between stimulation with highly purified hMG or recombinant FSH in patients undergoing IVF with GnRH antagonist protocol. AB - PURPOSE: Highly purified Human Menopausal Gonadotropins (hp-hMG) and recombinant FSH (rFSH) are widely used in assisted reproductive technology (ART). The aim of this study was to compare ART results of the two preparations in GnRH antagonist cycles. METHODS: In this retrospective cohort study, IVF antagonist cycles performed from 2011 through 2013 were reviewed. There were 508 antagonist cycles: 320 stimulated with rFSH and 188 with hp-hMG. For every hp-hMG, two rFSH were matched for patient's age and infertility diagnosis. Subgroup analysis of patients younger and older than 35 was done as well. RESULTS: Both treatments were resulted in comparable pregnancy and live birth rates. However, cumulative pregnancy rates were higher for the rFSH group. In the matching analysis, the rFSH group had more mature oocytes and more embryos while using lower doses of gonadotropins. Pregnancy, cumulative pregnancy rates, and live birth rates were comparable. In the subgroup analysis, young patients in the rFSH group had better cycle outcomes compared with those in the hp-hMG group. CONCLUSION: In antagonist protocol, different gonadotropin products are equally effective. The choice of one or the other should depend on the availability, convenience of use, and cost. PMID- 26939573 TI - Oral Immunization of Rabbits with S. enterica Typhimurium Expressing Neisseria gonorrhoeae Filamentous Phage Phi6 Induces Bactericidal Antibodies Against N. gonorrhoeae. AB - All Neisseria gonorrhoeae strains whose DNA sequences have been determined possess filamentous phage DNA sequences. To ascertain if phage encoded proteins could form the basis of a gonococcal vaccine, rabbits were orally infected with S. enterica Typhimurium strain chi3987 harboring phagemid NgoPhi6 fm. The elicited sera contained large quantities of anti-phage IgG and IgA antibodies that bound to the surface of N. gonorrhoeae cells, as shown by indirect fluorescent analysis and flow cytometry. The elicited sera was able to bind to several phage proteins. The sera also had bactericidal activity. These data demonstrate that N. gonorrhoeae filamentous phage can induce antibodies with anti gonococcal activity and that phage proteins may be a candidate for vaccine development. PMID- 26939575 TI - Recombinant human soluble thrombomodulin and mortality in sepsis-induced disseminated intravascular coagulation. A multicentre retrospective study. AB - Recombinant human soluble thrombomodulin (rhTM) is a novel class of anticoagulants for treating disseminated intravascular coagulation (DIC). Although rhTM is widely used in clinical settings throughout Japan, there is limited clinical evidence supporting the use of rhTM in patients with sepsis induced DIC. Furthermore, rhTM is not approved for DIC treatment in other countries. This study aimed to clarify the survival benefits of rhTM administration in critically ill patients. Data from 3,195 consecutive adult patients who were admitted to 42 intensive care units for the treatment of severe sepsis or septic shock between January 2011 and December 2013 were retrospectively analysed, and 1,784 patients were diagnosed with DIC based on the scoring algorithm from the Japanese Association for Acute Medicine DIC (n = 645, rhTM group; n = 1,139, control group). Propensity score matching created 452 matched pairs, and logistic regression analysis revealed a significant association between rhTM administration and lower in-hospital all-cause mortality in the propensity score-matched groups (odds ratio, 0.757; 95 % confidence interval, 0.574-0.999, p = 0.049). Inverse probability of treatment weighted and quintile-stratified analyses also revealed significant associations between rhTM administration and lower in-hospital all-cause mortality. Survival time in the propensity score-matched rhTM group was significantly longer than that in the propensity score-matched control group (hazard ratio, 0.781; 95 % confidence interval, 0.624-0.977, p = 0.03). Bleeding complications were not more frequent in the rhTM groups. In conclusion, this study demonstrated that rhTM administration is associated with reduced in-hospital all-cause mortality among patients with sepsis-induced DIC. PMID- 26939576 TI - Evolutionary dynamics of viral escape under antibodies stress: A biophysical model. AB - Viruses constantly face the selection pressure of antibodies, either from innate immune response of the host or from administered antibodies for treatment. We explore the interplay between the biophysical properties of viral proteins and the population and demographic variables in the viral escape. The demographic and population genetics aspect of the viral escape have been explored before; however one important assumption was the a priori distribution of fitness effects (DFE). Here, we relax this assumption by instead considering a realistic biophysics based genotype-phenotype relationship for RNA viruses escaping antibodies stress. In this model the DFE is itself an evolvable property that depends on the genetic background (epistasis) and the distribution of biophysical effects of mutations, which is informed by biochemical experiments and theoretical calculations in protein engineering. We quantitatively explore in silico the viability of viral populations under antibodies pressure and derive the phase diagram that defines the fate of the virus population (extinction or escape from stress) in a range of viral mutation rates and antibodies concentrations. We find that viruses are most resistant to stress at an optimal mutation rate (OMR) determined by the competition between supply of beneficial mutation to facilitate escape from stressors and lethal mutagenesis caused by excess of destabilizing mutations. We then show the quantitative dependence of the OMR on genome length and viral burst size. We also recapitulate the experimental observation that viruses with longer genomes have smaller mutation rate per nucleotide. PMID- 26939578 TI - A prospective open clinical trial of a proton pump inhibitor, elimination diet and/or budesonide for eosinophilic oesophagitis. AB - BACKGROUND: Elimination diets and high-dose proton pump inhibitors (PPI) are advocated as first-line treatments in patients with eosinophilic oesophagitis (EoE). AIM: To record the treatment outcome for patients with EoE prospectively managed according to a clinical algorithm. METHODS: Patients with oesophageal eosinophilia commenced esomeprazole 40 mg twice daily for 8 weeks. Those in histological remission were re-classified as PPI-responsive oesophageal eosinophilia. Nonresponders were offered the 6-food elimination diet with a PPI, or topical budesonide monotherapy (1 mg orally twice daily as an aqueous gel). Once disease control was achieved remission was reassessed at 3 months (all modalities) and an additional 6 months (diet group). RESULTS: Of 107 patients who completed 8 weeks of PPI, 25 (23%) were PPI-responsive. 56 of 81 (69%) of patients with EoE chose the elimination diet with PPI. 29 (52%) had complete remission, 23 completed dietary reintroduction and food triggers were identified in 20 (36%). 25 chose budesonide with 23/25 (92%) responding. Remission was sustained in >85% of patients at 3 months with all treatment modalities. At 9 months, only 10/18 (55%) of patients who responded to the elimination diet with PPI remained complaint and sustained remission. CONCLUSIONS: Many patients previously diagnosed with EoE will respond to PPI. Initial response >50% is possible with the elimination diet plus PPI, but many will fail to undergo food reintroduction, or will cease the diet and relapse, resulting in only one in four patient sustaining remission at 9 months. Budesonide is very effective short term, but longer term study is needed. PMID- 26939579 TI - Variations of ATP and its metabolites in the hippocampus of rats subjected to pilocarpine-induced temporal lobe epilepsy. AB - Although purinergic receptor activity has lately been associated with epilepsy, little is known about the exact role of purines in epileptogenesis. We have used a rat model of temporal lobe epilepsy induced by pilocarpine to study the dynamics of purine metabolism in the hippocampus during different times of status epilepticus (SE) and the chronic phase. Concentrations of adenosine 5' triphosphate (ATP), adenosine diphosphate (ADP), adenosine monophosphate (AMP), and adenosine in normal and epileptic rat hippocampus were determined by microdialysis in combination with high-performance liquid chromatography (HPLC). Extracellular ATP concentrations did not vary along 4 h of SE onset. However, AMP concentration was elevated during the second hour, whereas ADP and adenosine concentrations augmented during the third and fourth hour following SE. During chronic phase, extracellular ATP, ADP, AMP, and adenosine concentrations decreased, although these levels again increased significantly during spontaneous seizures. These results suggest that the increased turnover of ATP during the acute period is a compensatory mechanism able to reduce the excitatory role of ATP. Increased adenosine levels following 4 h of SE may contribute to block seizures. On the other hand, the reduction of purine levels in the hippocampus of chronic epileptic rats may result from metabolic changes and be part of the mechanisms involved in the onset of spontaneous seizures. This work provides further insights into purinergic signaling during establishment and chronic phase of epilepsy. PMID- 26939580 TI - Chaotic, informational and synchronous behaviour of multiplex networks. AB - The understanding of the relationship between topology and behaviour in interconnected networks would allow to charac- terise and predict behaviour in many real complex networks since both are usually not simultaneously known. Most previous studies have focused on the relationship between topology and synchronisation. In this work, we provide analytical formulas that shows how topology drives complex behaviour: chaos, information, and weak or strong synchronisation; in multiplex net- works with constant Jacobian. We also study this relationship numerically in multiplex networks of Hindmarsh-Rose neurons. Whereas behaviour in the analytically tractable network is a direct but not trivial consequence of the spectra of eigenvalues of the Laplacian matrix, where behaviour may strongly depend on the break of symmetry in the topology of interconnections, in Hindmarsh-Rose neural networks the nonlinear nature of the chemical synapses breaks the elegant mathematical connec- tion between the spectra of eigenvalues of the Laplacian matrix and the behaviour of the network, creating networks whose behaviour strongly depends on the nature (chemical or electrical) of the inter synapses. PMID- 26939581 TI - Genome dynamics of multidrug-resistant Acinetobacter baumannii during infection and treatment. AB - BACKGROUND: Limited treatment options are available for patients infected with multidrug (MDR)- or pan-drug (PDR)-resistant bacterial pathogens, resulting in infections that can persist for weeks or months. In order to better understand transmission and evolutionary dynamics of MDR Acinetobacter baumannii (Ab) during long-term infection, we analyzed genomes from a series of isolates from individual patients at isolate-specific, patient-specific, and population levels. METHODS: Whole genome analysis of longitudinal isolates (range 2-10 isolates per patient spanning 0-829 days) from 40 patients included detection of single nucleotide variants (SNVs), insertion sequence (IS) mapping, and gene content changes. RESULTS: Phylogenetic analysis revealed that a significant fraction of apparently persistent infections are in fact due to re-infection with new strains. SNVs primarily resulted in protein coding changes, and IS events primarily interrupted genes or were in an orientation such that the adjacent gene would be over-expressed. Mutations acquired during infection were over represented in transcriptional regulators, notably pmrAB and adeRS, which can mediate resistance to the last line therapies colistin and tigecycline, respectively, as well as transporters, surface structures, and iron acquisition genes. CONCLUSIONS: Most SNVs and IS events were isolate-specific indicating these mutations did not become fixed on the time scale investigated, yet over representation of independent mutations in some genes or functional categories suggests that they are under selective pressure. Genome analysis at the population-level suggests that gene transfer including recombination also contributes to Ab evolutionary dynamics. These findings provide important insight into the transmission dynamics of Ab and the identification of patients with repeat infections has implications for infection control programs targeted to this pathogen. PMID- 26939582 TI - A Study of Healthy Adults' Oro-lingual Effort During Swallowing Using OroPress, A New Portable Wireless Measurement Tool. AB - OroPress is a new, low profile, portable, wireless tool that enables stable measurement of tongue pressure during isometric ('pushing') tasks and, more importantly, during swallowing. Using this tool, a pressure-time product, the OroPress Absolute (OPA) parameter, has been developed as a representative measure of lingual effort during swallowing. In a sample of 57 adults aged 20-80+ years, of both sexes and without dysphagia, tongue-palate contact pressures generated while swallowing 5 ml, 10 ml of water and 5 ml custard, were recorded using OroPress. Data were examined for effects of gender, age and bolus condition (consistency, volume). OPA was tested for stability of measure and then correlated with the criterion standard, peak pressure recorded when swallowing (PMax(SW)). Swallowing pressures (PMax(SW), OPA) were positively correlated with bolus viscosity. No significant age and gender differences were found. Excellent stability of measure (test, re-test reliability) was demonstrated and OPA was positively correlated with PMax(SW). OroPress produces valid, reliable and reproducible measurements and improved accuracy of oro-lingual pressure measurement during swallowing. With such a tool, interventions/therapy can be proactive and principled as outcomes are better validated. To enhance specificity of intervention, measurement parameters need to reflect the pressure and temporal qualities of swallow function. OPA has the potential to describe differences in effort made, and ability to sustain pressures, in adults without dysphagia. The results of these studies will enable more accurate examination of the oral phase of swallowing as we establish this highly accurate sensor as a criterion standard for oro-lingual pressure measurement in clinical populations. PMID- 26939577 TI - Role of the endothelin system in sexual dimorphism in cardiovascular and renal diseases. AB - Epidemiological studies of blood pressure in men and women and in experimental animal models point to substantial sex differences in the occurrence of arterial hypertension as well as in the various manifestations of arterial hypertension, including myocardial infarction, stroke, retinopathy, chronic kidney failure, as well as hypertension-associated diseases (e.g. diabetes mellitus). Increasing evidence demonstrates that the endothelin (ET) system is a major player in the genesis of sex differences in cardiovascular and renal physiology and diseases. Sex differences in the ET system have been described in the vasculature, heart and kidney of humans and experimental animals. In the current review, we briefly describe the role of the ET system in the cardiovascular and renal systems. We also update information on sex differences at different levels of the ET system including synthesis, circulating and tissue levels, receptors, signaling pathways, ET actions, and responses to antagonists in different organs that contribute to blood pressure regulation. Knowledge of the mechanisms underlying sex differences in arterial hypertension can impact therapeutic strategies. Sex targeted and/or sex-tailored approaches may improve treatment of cardiovascular and renal diseases. PMID- 26939584 TI - Abnormal correlation between phase transformation and cooling rate for pure metals. AB - This work aims to achieve deep insight into the phenomenon of phase transformation upon rapid cooling in metal systems and reveal the physical meaning of scatter in the time taken to reach crystallization. The total number of pure metals considered in this work accounts for 14. Taking pure copper as an example, the correlation between phase selection of crystal or glass and cooling rate was investigated using molecular dynamic simulations. The obtained results demonstrate that there exists a cooling rate region of 6.3 * 10(11)-16.6 * 10(11) K/s, in which crystalline fractions largely fluctuate along with cooling rates. Glass transformation in this cooling rate region is determined by atomic structure fluctuation, which is controlled by thermodynamic factors. According to the feature of bond-orientation order at different cooling rates, we propose two mechanisms of glass formation: (i) kinetic retardation of atom rearrangement or structural relaxation at a high cooling rate; and (ii) competition of icosahedral order against crystal order near the critical cooling rate. PMID- 26939583 TI - Mitochondrial DNA sensing by STING signaling participates in inflammation, cancer and beyond. AB - Recent studies have revealed the diverse pathophysiological functions of mitochondria beyond traditional energetic metabolism in cells. Mitochondria released damage-associated molecular patterns, particularly mitochondrial deoxyribonucleic acid (mtDNA), play a central role in host immune defenses against foreign pathogens. Newly discovered cGAS-STING signaling is responsible for microbial DNA recognition, and potentially participates in mitochondrial DNA sensing. Inappropriate inflammatory signaling mediated by mtDNA is implicated in various human diseases, especially infectious/inflammatory disease and cancer. In addition, mtDNA horizontal transfer between tumor cells and surrounding somatic cells has been recently observed and been associated with tumorigenesis and cancer progression. In this review, we will summarize the molecular signaling of mtDNA recognition (especially STING signaling), and discuss the underlying mechanism by which mtDNA transfer triggers cancer progression in human. Besides, we will highlight the central role of mtDNA in host immunity, with particular emphasis on mtDNA-induced NETs (neutrophil extracellular traps) formation, apoptosis and autophagy. PMID- 26939585 TI - A novel hematopoietic progenitor cell mobilization regimen, utilizing bortezomib and filgrastim, for patients undergoing autologous transplant. AB - Adequate hematopoietic progenitor cell (HPC) collection is critical for patients undergoing autologous HPC transplant (AHPCT). Historically, 15 - 30% of patients failed HPC mobilization with granulocyte-colony stimulating factor (G-CSF) alone. Bortezomib, a proteasome inhibitor, has been shown to down regulate very late antigen-4 (VLA-4), an adhesion molecule expressed on HPCs. In this pilot study, bortezomib was administered on days -11 and -8 at a dose of 1.3 mg/m2 intravenously (IV) or subcutaneously (SQ), followed by G-CSF 10 mcg/kg SQ, on days -4 to -1 prior to HPC collection (Day 1). Nineteen patients, with multiple myeloma (n = 12) or non-Hodgkin lymphoma (n = 7) undergoing AHPCT for the first time, were enrolled. Patients were excluded if they had worse than grade II neuropathy or platelet count less than 100 x 109 /L. Bortezomib was well tolerated and all patients had adequate HPC collections with no mobilization failures. One patient (6%) had a CD34+ cell count of 3.9 cells/uL on Day 1 and received plerixafor per institutional algorithm. Eleven patients completed HPC collection in 1 day and eight in 2 days. All patients underwent AHPCT and had timely neutrophil and platelet engraftment. Comparison with a historical control group of 70 MM and lymphoma patients, who were mobilized with G-CSF, showed significantly higher CD 34+ cells/kg collected in the bortezomib mobilization study group. Bortezomib plus G-CSF is an effective HPC mobilizing regimen worth investigating further in subsequent studies. J. Clin. Apheresis 31:559-563, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26939586 TI - Chronic liquid nutrition intake induces obesity and considerable but reversible metabolic alterations in Wistar rats. AB - We have previously described the development of substantial, but reversible obesity in Wistar rats fed with palatable liquid nutrition (Fresubin). In this study, we investigated changes in serum hormone levels, glycemia, fat mass, adipocyte size, and gene expression of adipokines and inflammatory markers in adipose tissue of Wistar rats fed by Fresubin (i) for 5 months, (ii) up to 90 days of age, or (iii) after 90 days of age to characterize metabolic alterations and their reversibility in rats fed with Fresubin. An intra-peritoneal glucose tolerance test was also performed to determine levels of serum leptin, adiponectin, insulin, and C-peptide in 2- and 4-month-old animals. In addition, mesenteric and epididymal adipose tissue weight, adipocyte diameter, and gene expression of pro- and anti-inflammatory adipokines and other markers were determined at the end of the study. Chronic Fresubin intake significantly increased adipocyte diameter, reduced glucose tolerance, and increased serum leptin, adiponectin, insulin, and C-peptide levels. Moreover, gene expression of leptin, adiponectin, CD68, and nuclear factor kappa B was significantly increased in mesenteric adipose tissue of Fresubin fed rats. Monocyte chemotactic protein 1 messenger RNA (mRNA) levels increased in mesenteric adipose tissue only in the group fed Fresubin during the entire experiment. In epididymal adipose tissue, fatty acid binding protein 4 mRNA levels were significantly increased in rats fed by Fresubin during adulthood. In conclusion, chronic Fresubin intake induced complex metabolic alterations in Wistar rats characteristic of metabolic syndrome. However, transition of rats from Fresubin to standard diet reversed these alterations. PMID- 26939587 TI - Vitamin D deficiency in patients with either rheumatic diseases or inflammatory bowel diseases on biologic therapy. AB - Vitamin D deficiency has been reported in patients with chronic inflammatory conditions, such as rheumatic and inflammatory bowel diseases (IBD). We evaluated the role of biologic therapy on vitamin D, calcium and parathormone (PTH) levels. This cross-sectional study enrolled consecutive patients with either rheumatic diseases or IBD who underwent an ambulatory visit. Patients receiving vitamin D/calcium supplementation were excluded. Vitamin D deficiency or insufficiency was diagnosed when values were <20 ng/mL and 21-29 ng/ml, respectively. Patients were sub-grouped according to biologic therapy. A multivariate analysis was performed. Two-hundred patients, including 136 with a rheumatic disease (M/F 37/99; mean age 60.7 +/- 12.9 years) and 64 with IBD (M/F 41/23; Mean age 49.6 +/ 13.1 years) were enrolled. Vitamin D deficiency/insufficiency was detected in as many as 63.5 % patients, being 61.8 and 67.2 % in patients with either rheumatic diseases or IBD, respectively. The prevalence of vitamin D deficiency/insufficiency was higher in those receiving biologics than other therapies (78.3 vs 43.2 %; p < 0.0001), in either rheumatic diseases (78.7 vs 41 %; p < 0.0001) or IBD (75 vs 50 %; p = 0.03) group. At multivariate analysis, only biologic therapy was independently associated with vitamin D deficit (OR 4.61; p = 0.001). Patients with vitamin D deficiency/insufficiency had hypocalcemia more frequently than controls (22.8 vs 10.9 %; p = 0.03), while PTH values did not differ significantly. This study finds that the prevalence of vitamin D deficiency/insufficiency was very high in patients with either rheumatic diseases or IBD receiving a biologic therapy. PMID- 26939588 TI - ABO Blood Group and Risk of Thromboembolic and Arterial Disease: A Study of 1.5 Million Blood Donors. AB - BACKGROUND: ABO blood groups have been shown to be associated with increased risks of venous thromboembolic and arterial disease. However, the reported magnitude of this association is inconsistent and is based on evidence from small scale studies. METHODS AND RESULTS: We used the SCANDAT2 (Scandinavian Donations and Transfusions) database of blood donors linked with other nationwide health data registers to investigate the association between ABO blood groups and the incidence of first and recurrent venous thromboembolic and arterial events. Blood donors in Denmark and Sweden between 1987 and 2012 were followed up for diagnosis of thromboembolism and arterial events. Poisson regression models were used to estimate incidence rate ratios as measures of relative risk. A total of 9170 venous and 24 653 arterial events occurred in 1 112 072 individuals during 13.6 million person-years of follow-up. Compared with blood group O, non-O blood groups were associated with higher incidence of both venous and arterial thromboembolic events. The highest rate ratios were observed for pregnancy related venous thromboembolism (incidence rate ratio, 2.22; 95% confidence interval, 1.77-2.79), deep vein thrombosis (incidence rate ratio, 1.92; 95% confidence interval, 1.80-2.05), and pulmonary embolism (incidence rate ratio, 1.80; 95% confidence interval, 1.71-1.88). CONCLUSIONS: In this healthy population of blood donors, non-O blood groups explain >30% of venous thromboembolic events. Although ABO blood groups may potentially be used with available prediction systems for identifying at-risk individuals, its clinical utility requires further comparison with other risk markers. PMID- 26939589 TI - Deprescribing Potentially Inappropriate Preventive Cardiovascular Medication: Barriers and Enablers for Patients and General Practitioners. AB - BACKGROUND: The use of preventive cardiovascular medication by patients with low cardiovascular disease (CVD) risk is potentially inappropriate. OBJECTIVE: The aim of this study was to identify barriers to and enablers of deprescribing potentially inappropriate preventive cardiovascular medication experienced by patients and general practitioners (GPs). METHODS: A total of 10 GPs participating in the ECSTATIC trial (Evaluating Cessation of STatins and Antihypertensive Treatment In primary Care) audiotaped deprescribing consultations with low-CVD-risk patients. After initial conventional content analysis, 2 researchers separately coded all barriers to and enablers of deprescribing medication using framework analysis. We performed a within-case and cross-case analysis to explore barriers and enablers among both patients and GPs. RESULTS: Patients (n = 49) and GPs (n = 10) expressed barriers and enablers with regard to the appropriateness of the medication and the deprescribing process. A family history for CVD was identified as a barrier to deprescribing medication for both patients and GPs. Patients feared possible consequences of deprescribing and were influenced by the opinion of their GP. Additionally, a presumed disapproving opinion from specialists influenced the GPs' willingness to deprescribe medication. CONCLUSIONS: Patients appreciated discussing their doubts regarding deprescribing potentially inappropriate preventive cardiovascular medication. Furthermore, they acknowledged their GP's expertise and took their opinion toward deprescribing into consideration. The GPs' decisions to deprescribe were influenced by the low CVD risk of the patients, additional risk factors, and the alleged specialist's opinion toward deprescribing. We recommend deprescribing consultations to be patient centered, with GPs addressing relevant themes and probable consequences of deprescribing preventive cardiovascular medication. PMID- 26939590 TI - Comparing importance and performance from a patient perspective in English general practice: a cross-sectional survey. AB - BACKGROUND: Patient experience and satisfaction are important indicators of quality in health care. Little is known about where to prioritize efforts to improve patient satisfaction. OBJECTIVES: To investigate patient satisfaction with primary care, as part of the Quality and Costs of Primary Care in Europe study in England, identifying areas where improvements could be made from patients' perspectives. METHODS: We conducted a questionnaire survey of general practice patients in three English regions. Patient Values questionnaires assessed what patients thought was important, and Patient Experience questionnaires rated performance of primary care. Fifteen attributes of care were compared using Importance Performance Analysis, a method that simultaneously represents data on importance and performance of a service, enabling identification of its strengths and weaknesses. RESULTS: Patients rated both 'relational' and 'functional' aspects of care as important. Satisfaction with general practice could be improved by concentrating on specific aspects of access (ensuring that patients know how to access out-of-hours services and find it easy to get an appointment), and one aspect of empowerment (after their visit, patients feel able to cope better with their health problem/illness). However, for other attributes (e.g. proximity of the practice to a patient's house or, a short waiting time when contacting the practice), investing additional resources is not likely to increase patient satisfaction. CONCLUSION: Attributes needing most improvement concerned access to primary care and patient empowerment. More research is needed to identify how to improve access without generating unnecessary additional demand or compromising continuity of care. PMID- 26939591 TI - LIFESTAT - Living with statins: An interdisciplinary project on the use of statins as a cholesterol-lowering treatment and for cardiovascular risk reduction. AB - AIM: LIFESTAT is an interdisciplinary project that leverages approaches and knowledge from medicine, the humanities and the social sciences to analyze the impact of statin use on health, lifestyle and well-being in cohorts of Danish citizens. The impetus for the study is the fact that 10% of the population in the Scandinavian countries are treated with statins in order to maintain good health and to avoid cardiovascular disease by counteracting high blood levels of cholesterol. The potential benefit of treatment with statins should be considered in light of evidence that statin use has prevalent and unintended side effects (e.g. myalgia, and glucose and exercise intolerance). METHODS: The LIFESTAT project combines invasive human experiments, biomedical analyses, nationwide surveys, epidemiological studies, qualitative interviews, media content analyses, and ethnographic participant observations. The study investigates the biological consequences of statin treatment; determines the mechanism(s) by which statin use causes muscle and mitochondrial dysfunction; and analyzes achievement of treatment goals, people's perception of disease risk, media influence on people's risk and health perception, and the way people manage to live with the risk (personally, socially and technologically). CONCLUSIONS THE ORIGINALITY AND SUCCESS OF LIFESTAT DEPEND ON AND DERIVE FROM ITS INTERDISCIPLINARY APPROACH, IN WHICH THE DISCIPLINES CONVERGE INTO THOROUGH AND HOLISTIC STUDY AND DESCRIBE THE IMPACT OF STATIN USE ON THE EVERYDAY LIFE OF STATIN USERS THIS HAS THE POTENTIAL FOR MUCH GREATER BENEFIT THAN ANY ONE OF THE DISCIPLINES ALONE INTEGRATING TRADITIONAL DISCIPLINES PROVIDES NOVEL PERSPECTIVES ON POTENTIAL CURRENT AND FUTURE SOCIAL, MEDICAL AND PERSONAL BENEFITS OF STATIN USE. PMID- 26939592 TI - The Unwritten Rules of Mentorship: Facilitators of and Barriers to Effective Mentorship in Pediatric Hospital Medicine. AB - OBJECTIVES: Benefits of effective mentorship include career satisfaction and academic productivity. Given the youth of pediatric hospital medicine (PHM), effective mentorship is a widely acknowledged challenge. This study aimed to characterize successful pediatric hospitalists' past and current mentorship experiences and identify facilitators of and barriers to effective mentorship in PHM. METHODS: Semistructured phone interviews were conducted with peer-nominated pediatric hospitalists, exploring past and current mentorship experiences and approaches perceived to aid or hinder mentorship relationships from both the mentor and mentee perspectives. Interviews were recorded verbatim, professionally transcribed, and analyzed by using a general inductive approach. RESULTS: Sixteen interviews were conducted and transcribed. Participants reported having a median of 3 mentors and 6 mentees. Three themes emerged regarding how mentors can optimize mentorship: (1) comprehensive focus on the mentee, (2) setting of clear expectations, and (3) acknowledgment of mentors' limitations. Five themes emerged regarding how mentees can optimize mentorship: (1) preparation, (2) proactivity, (3) continual reevaluation of relationships, (4) willingness to seek mentorship outside of common venues, and (5) building of a mentorship team. Major barriers to effective mentorship included (1) mismatched expectations between mentor and mentee, (2) lack of available mentors in PHM, (3) lack of time/compensation for PHM mentors, and (4) geographic separation between mentor and mentee. CONCLUSIONS: Several themes emerged regarding facilitators of and barriers to effective mentorship in PHM. These "unwritten rules of mentorship" may serve as a guide to establish and maintain beneficial mentorship relationships and overcome challenges. PMID- 26939594 TI - The BMJ paper and seven day services. PMID- 26939596 TI - Cardiologist shortage prompts NHS trust to ask GPs to cut referrals. PMID- 26939595 TI - Mincle-mediated anti-inflammatory IL-10 response counter-regulates IL-12 in vitro. AB - The role of macrophage-inducible C-type lectin (Mincle) in anti-inflammatory responses has not yet been fully characterized. Herein, we show that engagement of Mincle by trehalose-dimycolate or mycobacteria promotes IL-10 production in macrophages, which causes down-regulation of IL-12p40 secretion. Thus, Mincle mediates both pro- as well as anti-inflammatory responses. PMID- 26939593 TI - 60 YEARS OF POMC: Regulation of feeding and energy homeostasis by alpha-MSH. AB - The melanocortin peptides derived from pro-opiomelanocortin (POMC) were originally understood in terms of the biological actions of alpha-melanocyte stimulating hormone (alpha-MSH) on pigmentation and adrenocorticotrophic hormone on adrenocortical glucocorticoid production. However, the discovery of POMC mRNA and melanocortin peptides in the CNS generated activities directed at understanding the direct biological actions of melanocortins in the brain. Ultimately, discovery of unique melanocortin receptors expressed in the CNS, the melanocortin-3 (MC3R) and melanocortin-4 (MC4R) receptors, led to the development of pharmacological tools and genetic models leading to the demonstration that the central melanocortin system plays a critical role in the regulation of energy homeostasis. Indeed, mutations in MC4R are now known to be the most common cause of early onset syndromic obesity, accounting for 2-5% of all cases. This review discusses the history of these discoveries, as well as the latest work attempting to understand the molecular and cellular basis of regulation of feeding and energy homeostasis by the predominant melanocortin peptide in the CNS, alpha-MSH. PMID- 26939597 TI - Experiences of using mobile phones in everyday life among persons with stroke and their families in Uganda - a qualitative study. AB - Aim The aim of this study was to describe the experiences and meaning of using mobile phones in everyday life after stroke, among persons with stroke and their family members. Methods Qualitative semi-structured interviews were conducted among 11 persons with stroke and 9 family members 2 months to 2 years after the stroke. The interviews were analysed by using constant comparative grounded theory (GT) approach. Results Seven categories were identified from the analysis of the participants' experiences. The mobile phone: (1) as an enabler of communication and connections with other people, (2) a source of inspiration for agency, (3) structuring routine and activities in daily life, (4) as a facilitator of social and economic wellbeing of an individual or family, (5) promoter of belonging and participation in social relationships, (6) facilitator of reintegration to community living and (7) enabler of family members to feel secure. From these categories, a core category emerged: The mobile phone as a "life line" and an extension of the body enabling connection, belonging and agency to act in a complex everyday life situation. Conclusion The study gives support for the possibility of using mobile phones to facilitate change and community integration in the rehabilitation process after stroke. Implications for Rehabilitation Stroke leads to decreased functioning in everyday life due to impairments, activity limitations and participation restrictions as well caregiver burden. Mobile phones seem to be an accessible and affordable technology used in daily life of persons with stroke and family members and connects them to the needed services and social relationships. The mobile phone technology reduces resource and infrastructural challenges and increases accessibility to rehabilitation interventions. The mobile phone was an important instrument that facilitated the quality of life of persons with stroke and their family members and could increase their participation in rehabilitation interventions. PMID- 26939598 TI - Effect of Coronary Slow Flow on the Longitudinal Left Ventricular Function Assessed by 2-Dimensional Speckle-Tracking Echocardiography. AB - OBJECTIVES: The coronary slow flow phenomenon is defined as the slow progression of an angiographic contrast agent to the distal part of the coronary arteries on selective coronary angiography in the absence of stenosis. There are some studies with different results about the effect of this phenomenon on left ventricular (LV) function. The aim of our study was to evaluate the longitudinal LV function in the coronary slow flow phenomenon using 2-dimensional (2D) speckle-tracking echocardiography. METHODS: In a study with a patient-to-patient matched design, 36 patients with the coronary slow flow phenomenon and 36 individuals with normal coronary flow matched for age (+/-5 years), sex, hypertension, and diabetes mellitus were compared in terms of the longitudinal LV systolic and diastolic functions by pulsed wave tissue Doppler echocardiography and 2D speckle-tracking echocardiography-derived indices. RESULTS: Lateral s' and e' waves were lower in the patients with the coronary slow flow phenomenon, but there were no statistically significant differences between the groups regarding the other tissue Doppler echocardiographic indices and longitudinal systolic strain and systolic and diastolic strain rates derived by 2D speckle-tracking echocardiography. CONCLUSIONS: Our results showed that the coronary slow flow phenomenon could not impair the longitudinal LV systolic and diastolic functions. PMID- 26939599 TI - First-Trimester Echocardiographic Features and Perinatal Outcomes in Fetuses With Congenital Absence of the Aortic Valve. AB - OBJECTIVES: The purpose of this study was to describe the echocardiographic features and perinatal outcomes of congenital absence of the aortic valve diagnosed by first-trimester echocardiography. METHODS: This retrospective study assessed the feasibility of first-trimester echocardiography in detecting absence of the aortic valve. All cases of absence of the aortic valve diagnosed by first trimester fetal echocardiography from January 2010 to December 2014 were identified at a single referral center using an established perinatal database. Demographic information, echocardiograms, perinatal outcomes, and autopsy reports were reviewed. Echocardiographic features were described. RESULTS: A total of 50,822 fetuses underwent first-trimester echocardiography during the study period. Ten cases of congenital absence of the aortic valve were diagnosed, for an overall incidence rate of 0.019%. The earliest gestational age at diagnosis was 11 weeks 6 days. The mean crown-lump length was 61.9 mm; mean gestational age was 12 weeks; and mean maternal body mass index +/- SD was 21.2 +/- 3.9 kg/m(2). Nine fetuses had increased nuchal translucency ranging from 2.4 to 12.4 mm (mean +/- SD, 6.4 +/- 3.6 mm). Color Doppler flow imaging revealed biphasic bidirectional flow in the ascending aorta and aortic arch and reversed flow in the ductus venosus during atrial systole in all cases. Reversed diastolic flow was present in the umbilical arteries and thoracic aorta. All cases had complex cardiac malformations as well as extracardiac abnormalities. CONCLUSIONS: Our study confirms that absence of the aortic valve is a rare cardiac defect that can be diagnosed by first-trimester fetal echocardiography. A "to-and-fro" flow pattern or biphasic bidirectional flow in the great arteries is a key echocardiographic feature in fetuses with absence of the aortic valve. PMID- 26939600 TI - An Inexpensive and Easy Ultrasound Phantom: A Novel Use for SPAM. AB - Ultrasound models, commonly referred to as "phantoms," are simulation tools for ultrasound education. Commercially produced phantoms are available, but there are "homemade" alternatives such as raw poultry and gelatin molds. Precooked, processed meat, better known as SPAM (Hormel Foods Corporation, Austin, MN), can be used as an ultrasound phantom to teach several ultrasound applications. It is a versatile, hygienic, and easily manipulated medium that does not require refrigeration or preparatory work and can be easily discarded at the end of use. PMID- 26939602 TI - From Persuasion to Coercion: Responding to the Reluctant Patient in Rehabilitation. AB - Early mobilization of patients while in hospital has been demonstrated to provide better outcomes for patients and use fewer resources. Physical therapy-based rehabilitation is central to achieving those goals. Successful rehabilitation requires that patient's and therapist's goals align, and this is commonly the case. However, occasionally, physical therapists will come across patients who are competent but reluctant to mobilize. This situation leaves the physical therapist in an ethical quandary: either accept the patient's right to refuse proposed treatment or utilize other strategies to encourage the patient to adhere to treatment. Practically, physical therapists will use a range of treatment pressures, including persuasion, offering incentives, inducements, possibly threatening or coercing, and even explicitly overriding the patient's wishes (compulsion). Deciding which treatment pressure is ethically acceptable involves the physical therapist balancing his or her therapeutic view of what is in a patient's best interests against the therapist's ethical responsibility to respect patient autonomy. This article evaluates some common strategies used by physical therapists to influence, persuade, or perhaps pressure patients to adhere to rehabilitation. The work of Szmukler and Appelbaum is utilized in analyzing treatment pressures. The authors conclude that there is a spectrum of treatment pressures, with some (persuasion and incentives) being more acceptable than others (threats and compulsion). As physical therapists balance health system pressures for rapid turnover of beds with obligations to benefit patients within limited reimbursement models, while respecting the patients' autonomy, they must be mindful of the effects of treatment pressure on patient care. PMID- 26939601 TI - Role of Physical Therapists in Reducing Hospital Readmissions: Optimizing Outcomes for Older Adults During Care Transitions From Hospital to Community. AB - Hospital readmissions in older adult populations are an emerging quality indicator for acute care hospitals. Recent evidence has linked functional decline during and after hospitalization with an elevated risk of hospital readmission. However, models of care that have been developed to reduce hospital readmission rates do not adequately address functional deficits. Physical therapists, as experts in optimizing physical function, have a strong opportunity to contribute meaningfully to care transition models and demonstrate the value of physical therapy interventions in reducing readmissions. Thus, the purposes of this perspective article are: (1) to describe the need for physical therapist input during care transitions for older adults and (2) to outline strategies for expanding physical therapy participation in care transitions for older adults, with an overall goal of reducing avoidable 30-day hospital readmissions. PMID- 26939603 TI - Simulated Patients in Physical Therapy Education: Systematic Review and Meta Analysis. AB - BACKGROUND: Traditional models of physical therapy clinical education are experiencing unprecedented pressures. Simulation-based education with simulated (standardized) patients (SPs) is one alternative that has significant potential value, and implementation is increasing globally. However, no review evaluating the effects of SPs on professional (entry-level) physical therapy education is available. PURPOSE: The purpose of this study was to synthesize and critically appraise the findings of empirical studies evaluating the contribution of SPs to entry-level physical therapy education, compared with no SP interaction or an alternative education strategy, on any outcome relevant to learning. DATA SOURCES: A systematic search was conducted of Ovid MEDLINE, PubMed, AMED, ERIC, and CINAHL Plus databases and reference lists of included articles, relevant reviews, and gray literature up to May 2015. STUDY SELECTION: Articles reporting quantitative or qualitative data evaluating the contribution of SPs to entry level physical therapy education were included. DATA EXTRACTION: Two reviewers independently extracted study characteristics, intervention details, and quantitative and qualitative evaluation data from the 14 articles that met the eligibility criteria. DATA SYNTHESIS: Pooled random-effects meta-analysis indicated that replacing up to 25% of authentic patient-based physical therapist practice with SP-based education results in comparable competency (mean difference=1.55/100; 95% confidence interval=-1.08, 4.18; P=.25). Thematic analysis of qualitative data indicated that students value learning with SPs. LIMITATIONS: Assumptions were made to enable pooling of data, and the search strategy was limited to English. CONCLUSION: Simulated patients appear to have an effect comparable to that of alternative educational strategies on development of physical therapy clinical practice competencies and serve a valuable role in entry-level physical therapy education. However, available research lacks the rigor required for confidence in findings. Given the potential advantages for students, high-quality studies that include an economic analysis should be conducted. PMID- 26939604 TI - Expanded Distribution of Pain as a Sign of Central Sensitization in Individuals With Symptomatic Knee Osteoarthritis. AB - BACKGROUND: Expanded distribution of pain is considered a sign of central sensitization (CS). The relationship between recording of symptoms and CS in people with knee osteoarthritis (OA) has been poorly investigated. OBJECTIVE: The aim of this study was to examine whether the area of pain assessed using pain drawings relates to CS and clinical symptoms in people with knee OA. DESIGN: This was a cross-sectional study. METHODS: Fifty-three people with knee OA scheduled to undergo primary total knee arthroplasty were studied. All participants completed pain drawings using a novel digital device, completed self administration questionnaires, and were assessed by quantitative sensory testing. Pain frequency maps were generated separately for women and men. Spearman correlation coefficients were computed to reveal possible correlations between the area of pain and quantitative sensory testing and clinical symptoms. RESULTS: Pain frequency maps revealed enlarged areas of pain, especially in women. Enlarged areas of pain were associated with higher knee pain severity (rs=.325, P<.05) and stiffness (rs=.341, P<.05), lower pressure pain thresholds at the knee (rs=-.306, P<.05) and epicondyle (rs=-.308, P<.05), and higher scores with the Central Sensitization Inventory (rs=.456, P<.01). No significant associations were observed between the area of pain and the remaining clinical symptoms and measures of CS. LIMITATIONS: Firm conclusions about the predictive role of pain drawings cannot be drawn. Further evaluation of the reliability and validity of pain area extracted from pain drawings in people with knee OA is needed. CONCLUSION: Expanded distribution of pain was correlated with some measures of CS in individuals with knee OA. Pain drawings may constitute an easy way for the early identification of CS in people with knee OA, but further research is needed. PMID- 26939605 TI - Development of a Feasible Implementation Fidelity Protocol Within a Complex Physical Therapy-Led Self-Management Intervention. AB - BACKGROUND: Implementation fidelity is poorly addressed within physical therapy interventions, which may be due to limited research on how to develop and implement an implementation fidelity protocol. OBJECTIVE: The purpose of this study was to develop a feasible implementation fidelity protocol within a pilot study of a physical therapy-led intervention to promote self-management for people with chronic low back pain or osteoarthritis. DESIGN: A 2-phase mixed methods design was used. METHODS: Phase 1 involved the development of an initial implementation fidelity protocol using qualitative interviews with potential stakeholders to explore the acceptability of proposed strategies to enhance and assess implementation fidelity. Phase 2 involved testing and refining the initial implementation fidelity protocol to develop a finalized implementation fidelity protocol. Specifically, the feasibility of 3 different strategies (physical therapist self-report checklists, independently rated direct observations, and audio-recorded observations) for assessing implementation fidelity of intervention delivery was tested, followed by additional stakeholder interviews that explored the overall feasibility of the implementation fidelity protocol. RESULTS: Phase 1 interviews determined the proposed implementation fidelity strategies to be acceptable to stakeholders. Phase 2 showed that independently rated audio recordings (n=6) and provider self-report checklists (n=12) were easier to implement than independently rated direct observations (n=12) for assessing implementation fidelity of intervention delivery. Good agreement (79.8% 92.8%) was found among all methods. Qualitative stakeholder interviews confirmed the acceptability, practicality, and implementation of the implementation fidelity protocol. LIMITATIONS: The reliability and validity of assessment checklists used in this study have yet to be fully tested, and blinding of independent raters was not possible. CONCLUSIONS: A feasible implementation fidelity protocol was developed based on a 2-phase development process involving intervention stakeholders. This study provides valuable information on the feasibility of rigorously addressing implementation fidelity within physical therapy interventions and provides recommendations for researchers wanting to address implementation fidelity in similar areas. PMID- 26939606 TI - Reddish Nodule on the Hand: A Quiz. PMID- 26939607 TI - An autochthonous case of Zika due to possible sexual transmission, Florence, Italy, 2014. AB - We report a case of Zika virus infection imported in Florence, Italy ex-Thailand, leading to a secondary autochthonous case, probably through sexual transmission. The two cases occurred in May 2014 but were retrospectively diagnosed in 2016 on the basis of serological tests (plaque reduction neutralisation) performed on stored serum samples. Our report provides further evidence that sexual transmission of Zika virus is possible. PMID- 26939608 TI - ATP citrate lyase mediated cytosolic acetyl-CoA biosynthesis increases mevalonate production in Saccharomyces cerevisiae. AB - BACKGROUND: With increasing concern about the environmental impact of a petroleum based economy, focus has shifted towards greener production strategies including metabolic engineering of microbes for the conversion of plant-based feedstocks to second generation biofuels and industrial chemicals. Saccharomyces cerevisiae is an attractive host for this purpose as it has been extensively engineered for production of various fuels and chemicals. Many of the target molecules are derived from the central metabolite and molecular building block, acetyl-CoA. To date, it has been difficult to engineer S. cerevisiae to continuously convert sugars present in biomass-based feedstocks to acetyl-CoA derived products due to intrinsic physiological constraints-in respiring cells, the precursor pyruvate is directed away from the endogenous cytosolic acetyl-CoA biosynthesis pathway towards the mitochondria, and in fermenting cells pyruvate is directed towards the byproduct ethanol. In this study we incorporated an alternative mode of acetyl-CoA biosynthesis mediated by ATP citrate lyase (ACL) that may obviate such constraints. RESULTS: We characterized the activity of several heterologously expressed ACLs in crude cell lysates, and found that ACL from Aspergillus nidulans demonstrated the highest activity. We employed a push/pull strategy to shunt citrate towards ACL by deletion of the mitochondrial NAD(+)-dependent isocitrate dehydrogenase (IDH1) and engineering higher flux through the upper mevalonate pathway. We demonstrated that combining the two modifications increases accumulation of mevalonate pathway intermediates, and that both modifications are required to substantially increase production. Finally, we incorporated a block strategy by replacing the native ERG12 (mevalonate kinase) promoter with the copper-repressible CTR3 promoter to maximize accumulation of the commercially important molecule mevalonate. CONCLUSION: By combining the push/pull/block strategies, we significantly improved mevalonate production. We anticipate that this strategy can be used to improve the efficiency with which industrial strains of S. cerevisiae convert feedstocks to acetyl-CoA derived fuels and chemicals. PMID- 26939610 TI - Brownian-motion based simulation of stochastic reaction-diffusion systems for affinity based sensors. AB - In this work, we develop a 2D algorithm for stochastic reaction-diffusion systems describing the binding and unbinding of target molecules at the surfaces of affinity-based sensors. In particular, we simulate the detection of DNA oligomers using silicon-nanowire field-effect biosensors. Since these devices are uniform along the nanowire, two dimensions are sufficient to capture the kinetic effects features. The model combines a stochastic ordinary differential equation for the binding and unbinding of target molecules as well as a diffusion equation for their transport in the liquid. A Brownian-motion based algorithm simulates the diffusion process, which is linked to a stochastic-simulation algorithm for association at and dissociation from the surface. The simulation data show that the shape of the cross section of the sensor yields areas with significantly different target-molecule coverage. Different initial conditions are investigated as well in order to aid rational sensor design. A comparison of the association/hybridization behavior for different receptor densities allows optimization of the functionalization setup depending on the target-molecule density. PMID- 26939609 TI - Optimal waist circumference cut-off points and ability of different metabolic syndrome criteria for predicting diabetes in Japanese men and women: Japan Epidemiology Collaboration on Occupational Health Study. AB - BACKGROUND: We sought to establish the optimal waist circumference (WC) cut-off point for predicting diabetes mellitus (DM) and to compare the predictive ability of the metabolic syndrome (MetS) criteria of the Joint Interim Statement (JIS) and the Japanese Committee of the Criteria for MetS (JCCMS) for DM in Japanese. METHODS: Participants of the Japan Epidemiology Collaboration on Occupational Health Study, who were aged 20-69 years and free of DM at baseline (n = 54,980), were followed-up for a maximum of 6 years. Time-dependent receiver operating characteristic analysis was used to determine the optimal cut-off points of WC for predicting DM. Time-dependent sensitivity, specificity, and positive and negative predictive values for the prediction of DM were compared between the JIS and JCCMS MetS criteria. RESULTS: During 234,926 person-years of follow-up, 3180 individuals developed DM. Receiver operating characteristic analysis suggested that the most suitable cut-off point of WC for predicting incident DM was 85 cm for men and 80 cm for women. MetS was associated with 3-4 times increased hazard for developing DM in men and 7-9 times in women. Of the MetS criteria tested, the JIS criteria using our proposed WC cut-off points (85 cm for men and 80 cm for women) had the highest sensitivity (54.5 % for men and 43.5 % for women) for predicting DM. The sensitivity and specificity of the JCCMS MetS criteria were ~37.7 and 98.9 %, respectively. CONCLUSION: Data from the present large cohort of workers suggest that WC cut-offs of 85 cm for men and 80 cm for women may be appropriate for predicting DM for Japanese. The JIS criteria can detect more people who later develop DM than does the JCCMS criteria. PMID- 26939611 TI - Choice of first-line antiretroviral therapy regimen and treatment outcomes for HIV in a middle income compared to a high income country: a cohort study. AB - BACKGROUND: The range of combination antiretroviral therapy (cART) regimens available in many middle-income countries differs from those suggested in international HIV treatment guidelines. We compared first-line cART regimens, timing of initiation and treatment outcomes in a middle income setting (HIV Centre, Belgrade, Serbia - HCB) with a high-income country (Royal Free London Hospital, UK - RFH). METHODS: All antiretroviral-naive HIV-positive individuals from HCB and RFH starting cART between 2003 and 2012 were included. 12-month viral load and CD4 count responses were compared, considering the first available measurement 12-24 months post-cART. The percentage that had made an antiretroviral switch for any reason, or for toxicity and the percentage that had died by 36 months (the latest time at which sufficient numbers remained under follow-up) were investigated using standard survival methods. RESULTS: 361/597 (61 %) of individuals initiating cART at HCB had a prior AIDS diagnosis, compared to 337/1763 (19 %) at RFH. Median pre-ART CD4 counts were 177 and 238 cells/mm(3) respectively (p < 0.0001). The most frequently prescribed antiretrovirals were zidovudine with lamivudine (149; 25 %) and efavirenz [329, 55 %] at HCB and emtricitabine with tenofovir (899; 51 %) and efavirenz [681, 39 %] at RFH. At HCB, a median of 2 CD4 count measurements in the first year of cART were taken, compared to 5 at RFH (p < 0.0001). Median (IQR) CD4 cell increase after 12 months was +211 (+86, +359) and +212 (+105, +318) respectively. 287 (48 %) individuals from HCB and 1452 (82 %) from RFH had an available viral load measurement, of which 271 (94 %) and 1280 (88 %) were <400 copies/mL (p < 0.0001). After 36 months, comparable percentages had made at least one antiretroviral switch (77 % HCB vs. 78 % RFH; p = 0.23). However, switches for toxicity/patient choice were more common at RFH. After 12 and 36 months of cART 3 % and 8 % of individuals died at HCB, versus 2 % and 4 % at RFH (p < 0.0001). CONCLUSION: In middle-income countries, cART is usually started at an advanced stage of HIV disease, resulting in higher mortality rates than in high income countries, supporting improved testing campaigns for early detection of HIV infection and early introduction of newer cART regimens. PMID- 26939612 TI - Sustained moderate-to-high disease activity and higher Charlson score are predictors of incidental serious infection events in RA patients treated with conventional disease-modifying anti-rheumatic drugs: a cohort study in the treat to-target era. AB - OBJECTIVES: Rheumatoid arthritis (RA) guidelines have moved toward intensive treatment aimed at remission. Treatment and disease activity are predictors of infections; patients from developing countries have additional predictors that may further impact the infection spectrum. Our aim was to describe serious infection events (SIEs), predictors and impact on RA outcomes, in a cohort of Mexican Mestizo patients. METHODS: Up to February 2015, charts from 176 early RA patients were reviewed by a single data abstracter. SIEs were defined according to strict criteria. RA patients with >=1 SIE up to last follow-up were considered cases. Descriptive statistics were used; cases and paired controls (no SIE up to last follow-up) were compared by uni-variate analysis and multiple logistic regression. RESULTS: The cohort contributed to 948 patient-years of follow-up. There were 34 SIEs in 15 patients, at a (mean+/-SD) follow-up of 5+/-4 years. Incidence rate of SIE was 8.7 infections per 100 patient-years. Twenty-four isolated SIE were present in 14 patients. The most frequent SIEs were complicated urinary tract infections and pneumonia (each, n=8) and soft-tissue infections (n=7). In the case-control analysis, higher Charlson score (OR: 2.04, 95%CI: 1.001-4.164, p=0.05) and higher cumulative DAS28 (OR: 3.08, 95%CI: 1.91-4.98, p=0.000) were predictors of SIE; in patients with at least moderate disease activity, risk of SIE increased with higher level of cumulative disease activity. However, SIEs did not impact subsequent DAS28, HAQ and SF-36. CONCLUSIONS: Comorbidity and cumulative disease activity increased serious infection risk in early RA patients treated with conventional drugs, but SIEs did not impact disease outcomes. PMID- 26939614 TI - Photochemical fabrication of 3D hierarchical Mn3O4/H-TiO2 composite films with excellent electrochemical capacitance performance. AB - We herein report a novel, energy-saving and environmentally benign photodeposition approach to fabricate a manganese oxide film on hydrogenated TiO2 (H-TiO2) nanotube arrays using a Mn(2+)-containing solution as a precursor. Mn(2+) ions are oxidized to Mn3O4 by the photogenerated holes during the photodeposition. The preferential growth of Mn3O4 on the nucleation sites leads to the formation of Mn3O4 nanorods on each H-TiO2 nanotube, forming a 3D hierarchical Mn3O4/H-TiO2 composite film. The as-fabricated 3D hierarchical Mn3O4/H-TiO2 composite film electrode delivers a high specific capacitance of 508 F g(-1) at a current of 0.7 A g(-1). The composite film electrode still shows a specific capacitance of 228 F g(-1) even at a high rate of 35.7 A g(-1), demonstrating its prominent rate capability. Remarkably, the composite film electrode shows no obvious capacitance decay after 10,000 charge/discharge cycles at a current density of 3.6 A g(-1), revealing its superior electrochemical cycling stability. The prominent pseudocapacitive performance of the composite film electrode can be attributed to its unique structure characteristics. The as constructed energy-saving and environmentally benign photodeposition method can be used as a general and efficient route to prepare other composite materials with controlled morphologies and dimensions. PMID- 26939613 TI - Identification of mRNA isoform switching in breast cancer. AB - BACKGROUND: Alternative splicing provides a major mechanism to generate protein diversity. Increasing evidence suggests a link of dysregulation of splicing associated with cancer. While previous genomic-based studies demonstrated the expression of a handful of tumor-specific isoforms, genome-wide alterations in the balance between isoforms and cancer subtypes is understudied. RESULT: We systematically analyzed the isoform-level expression patterns and isoform switching events of 819 breast tumor and normal samples assayed by mRNA-seq from TCGA project. On average, 2.2 isoforms per gene were detected and 67.5 % of detected genes (i.e. expressed) showed 1-2 isoforms only. While the majority of isoforms for a given gene were positively correlated with each other and the overall gene level, 470 pairs of isoforms displayed an inverse correlation suggesting a switching event. Most of the isoform switching events were associated with molecular subtypes, including a Basal-like-associated switching in CTNND1. 88 genes showed switching independent of subtypes, among which the isoform pattern of PRICKLE1 was associated with a large genomic signature of biological significance. CONCLUSION: Our results reveal that the majority of genes do not undergo complex mRNA splicing within breast cancers, and that there is a general concordance in isoform and gene expression levels in breast tumors. We identified hundreds of isoform switching events across breast tumors, most of which were associated with differences in tumor subtypes. As exemplified by the detailed analysis of CTNND1 and PRICKLE1, these isoform switching events potentially provide new insights into the post-transcriptional regulatory mechanisms of tumor subtypes and cancer biology. PMID- 26939616 TI - Anxiety and depression in patients with advanced ovarian cancer: a prospective study. AB - INTRODUCTION: Survival of ovarian cancer patients is still unsatisfactory despite the introduction of new diagnostic and therapeutic methods. Women with advanced ovarian cancer with long-term survival are at persistent risk of anxiety and reactive depression due to poor prognosis and risk of burdensome symptoms. The aim of the study was to assess changes in anxiety and depression during multimodality ovarian cancer treatment and to identify correlates of anxiety and depression. METHOD: The study included 106 consecutive patients with advanced ovarian cancer. Mean age of the study group was 53.9 years (SD = 10.8, range: 23 79). The participants completed Hospital Anxiety and Depression Scale and State Trait Anxiety Inventory four times: prior to and one week after surgery, and before the second and the fourth course of adjuvant chemotherapy. Multivariate analysis was performed to identify the independent determinants of distress at various stages of treatment. RESULTS: The level of anxiety and the prevalence of pathological anxiety (74%) were the highest prior to surgery and gradually decreased thereafter. Irrespective of the treatment stage, the level of anxiety was higher than the corresponding level of depression. History of abortion, presence of intestinal stoma, poor general status, residual disease and time from the initial diagnosis were the main determinants of distress in ovarian cancer patients. CONCLUSIONS: Significant changes in the level of anxiety and slight fluctuations in the depression level experienced during ovarian cancer treatment are mostly determined by clinical variables. Identification of individuals with psychological comorbidities is a vital component of patient-oriented multidisciplinary care. PMID- 26939615 TI - A physiologically-based flow network model for hepatic drug elimination III: 2D/3D DLA lobule models. AB - BACKGROUND: One of the major issues in current pharmaceutical development is potential hepatotoxicity and drug-induced liver damage. This is due to the unique metabolic processes performed in the liver to prevent accumulation of a wide range of chemicals in the blood. Recently, we developed a physiologically-based lattice model to address the transport and metabolism of drugs in the liver lobule (liver functional unit). METHOD: In this paper, we extend our idealized model to consider structural and spatial variability in two and three dimensions. We introduce a hexagonal-based model with one input (portal vein) and six outputs (hepatic veins) to represent a typical liver lobule. To capture even more realistic structures, we implement a novel sequential diffusion-limited aggregation (DLA) method to construct a morphological sinusoid network in the lobule. A 3D model constructed with stacks of multiple 2D sinusoid realizations is explored to study the effects of 3D structural variations. The role of liver zonation on drug metabolism in the lobule is also addressed, based on flow-based predicted steady-state O2 profiles used as a zonation indicator. RESULTS: With this model, we analyze predicted drug concentration levels observed exiting the lobule with their detailed distribution inside the lobule, and compare with our earlier idealized models. In 2D, due to randomness of the sinusoidal structure, individual hepatic veins respond differently (i.e. at different times) to injected drug. In 3D, however, the variation of response to the injected drug is observed to be less extreme. Also, the production curves show more diffusive behavior in 3D than in 2D. CONCLUSION: Although, the individual producing ports respond differently, the average lobule production summed over all hepatic veins is more diffuse. Thus the net effect of all these variations makes the overall response smoother. We also show that, in 3D, the effect of zonation on drug production characteristics appears quite small. Our new biophysical structural analysis of a physiologically-based 3D lobule can therefore form the basis for a quantitative assessment of liver function and performance both in health and disease. PMID- 26939617 TI - Energy band diagram of device-grade silicon nanocrystals. AB - Device grade silicon nanocrystals (NCs) are synthesized using an atmospheric pressure plasma technique. The Si NCs have a small and well defined size of about 2.3 nm. The synthesis system allows for the direct creation of thin films, enabling a range of measurements to be performed and easy implementation of this material in different devices. The chemical stability of the Si NCs is evaluated, showing relatively long-term durability thanks to hydrogen surface terminations. Optical and electrical characterization techniques, including Kelvin probe, ultraviolet photoemission spectroscopy and Mott-Schottky analysis, are employed to determine the energy band diagram of the Si NCs. PMID- 26939618 TI - A Review for the Analysis of Antidepressant, Antiepileptic and Quinolone Type Drugs in Pharmaceuticals and Environmental Samples. AB - The analysis of drugs in various biological fluids is an important criterion for the determination of the physiological performance of a drug. After sampling of the biological fluid, the next step in the analytical process is sample preparation. Sample preparation is essential for isolation of desired components from complex biological matrices and greatly influences their reliable and accurate determination. The complexity of biological fluids adds to the challenge of direct determination of the drug by chromatographic analysis, therefore demanding a sample preparation step that is often time consuming, tedious and frequently overlooked. However, direct online injection methods offer the advantage of reducing sample preparation steps and enabling effective pre concentration and clean-up of biological fluids. These procedures can be automated and therefore reduce the requirements for handling potentially infectious biomaterial, improve reproducibility, and minimize sample manipulations and potential contamination. This review is focused on the discovery and development of high-performance liquid chromatography (HPLC) and gas chromatography (GC) with different detectors. The drugs covered in this review are antiepileptics, antidepressant (AD), and quinolones. The application of these methods for determination of these drugs in biological, environmental and pharmaceutical samples has also been discussed. PMID- 26939621 TI - Graphene and tricobalt tetraoxide nanoparticles based biosensor for electrochemical glutamate sensing. AB - An amperometric biosensor based on tricobalt tetraoxide nanoparticles (Co3O4), graphene (GR), and chitosan (CS) nanocomposite modified glassy carbon electrode (GCE) for sensitive determination of glutamate was fabricated. Scanning electron microscopy was implemented to characterize morphology of the nanocomposite. The biosensor showed optimum response within 25 s at pH 7.5 and 37 degrees C, at +0.70 V. The linear working range of biosensor for glutamate was from 4.0 * 10-6 to 6.0 * 10-4 M with a detection limit of 2.0 * 10-6 M and sensitivity of 0.73 MUA/mM or 7.37 MUA/mMcm2. The relatively low Michaelis-Menten constant (1.09 mM) suggested enhanced enzyme affinity to glutamate. The glutamate biosensor lost 45% of its initial activity after three weeks. PMID- 26939620 TI - Psychosocial issues in post-treatment cancer survivors: Desire for support and challenges in identifying individuals in need. AB - PURPOSE: The ongoing and late effects of cancer treatment can interfere with quality of life and adoption of healthy behaviors, thus potentially impairing recovery and survival. Developing effective methods to identify individuals in need of support is crucial in providing comprehensive, ongoing care and ensuring optimal use of limited resources. The current study provides an examination of long-term survivors' reports of psychosocial issues, their desire for follow-up, and the role of widely used distress-screening measures for identifying survivors who desire help. METHOD: 317 cancer survivors (M age = 62.98 years, female = 70%, Md years since treatment = 7.5 years, mixed diagnoses) completed measures of psychosocial adjustment and quality of life as well as a checklist of psychosocial issues on which they indicated whether they would like to speak with a health professional regarding each issue. RESULTS: Participants reported an average of 1.7 psychosocial issues. Only a minority desired to speak to a health professional; however, those desiring follow-up reported significant impairments in adjustment and quality of life. Though far from adequate as a stand-alone measure, area under the curve and regression analysis suggested a combination of the distress thermometer and number of psychosocial issues may be the best assessment of those desiring follow-up assistance. CONCLUSION: These results indicate that there is a need for a more sophisticated system of assisting survivors that takes into account issues, symptoms, and motivation for help. The present study is important in guiding the development of effective survivorship care and contributing to the growing literature describing the adjustment and care needs of survivors. PMID- 26939619 TI - Histones as mediators of host defense, inflammation and thrombosis. AB - Histones are known for their ability to bind to and regulate expression of DNA. However, histones are also present in cytoplasm and extracellular fluids where they serve host defense functions and promote inflammatory responses. Histones are a major component of neutrophil extracellular traps that contribute to bacterial killing but also to inflammatory injury. Histones can act as antimicrobial peptides and directly kill bacteria, fungi, parasites and viruses, in vitro and in a variety of animal hosts. In addition, histones can trigger inflammatory responses in some cases acting through Toll-like receptors or inflammasome pathways. Extracellular histones mediate organ injury (lung, liver), sepsis physiology, thrombocytopenia and thrombin generation and some proteins can bind histones and reduce these potentially harmful effects. PMID- 26939624 TI - Cathelicidin regulates myeloid cell accumulation in adipose tissue and promotes insulin resistance during obesity. PMID- 26939622 TI - Step-up fecal microbiota transplantation (FMT) strategy. AB - Gut dysbiosis is a characteristic of inflammatory bowel disease (IBD) and is believed to play a role in the pathogenesis of IBD. Fecal microbiota transplantation (FMT) is an effective strategy to restore intestinal microbial diversity and has been reported to have a potential therapeutic value in IBD. Our recent study reported a holistic integrative therapy called "step-up FMT strategy," which was beneficial in treating steroid-dependent IBD patients. This strategy consists of scheduled FMTs combined with steroids, anti-TNF-alpha antibody treatment or enteral nutrition. Herein, we will elaborate the strategy thoroughly, introducing the concept, potential indication, methodology, and safety of "step-up FMT strategy" in detail. PMID- 26939623 TI - Aliskiren - a promising strategy for ovarian ischemia/reperfusion injury protection in rats via RAAS. AB - The aim of this study was to evaluate the effects of aliskiren, direct renin inhibitor, as an antioxidant and tissue protective agent and evaluate the molecular, biochemical, and histopathological changes in experimental ischemia and ischemia/reperfusion injury in rat ovaries. Forty-eight female rats were randomly divided into eight groups: in Group 1, only sham operation was performed. Group 2 received 100 mg/kg aliskiren and sham operated. In Group 3, 3 h-period of bilateral ovarian ischemia was applied. Group 4 received a 3-h period of ischemia followed by 3 h of reperfusion. Groups 5 and 6 received 50 and 100 mg/kg, respectively, of aliskiren and bilateral ovarian ischemia was applied (after a 3-h period of ischemia, both ovaries were surgically removed). To Groups 7 and 8, 50 and 100 mg/kg of aliskiren were administered, respectively, and the induction of ischemia was performed. At the end of a 3-h period of ischemia, bilateral vascular clips were removed, and 3 h of reperfusion continued. After the experiments, IL-1beta, IL-6, TNF-alpha, and iNOS mRNA expressions and SOD, GSH, MDA, renin, and angiotensin-II levels were determined and histopathological changes were examined in rat ovaries. Aliskiren treatment normalized excessive changes in cytokine and oxidative stress markers in both ischemia and ischemia/reperfusion injury. Histopathologically, treatment with aliskiren ameliorated the development of ischemia and/or ischemia/reperfusion tissue injury. This study concluded that aliskiren treatment is effective in reversing ischemia and/or ischemia/reperfusion induced ovary damage via the improvement of oxidative stress, reduction of inflammation, and suppression of the renin angiotensin aldosterone system. PMID- 26939625 TI - Dietary intake of four artificial sweeteners by Irish pre-school children. AB - In spite of rigorous pre- and post-market reviews of safety, there remains a high level of debate regarding the use of artificial sweeteners in foods. Young children are of particular interest when assessing food chemical exposure as a result of their unique food consumption patterns and comparatively higher exposure to food chemicals on a body weight basis when compared with the general population. The present study examined the intakes of four intense sweeteners (acesulfame K, aspartame, saccharin, sucralose) in the diets of children aged 1-4 years using food consumption and sweetener presence data from the Irish National Pre-school Nutrition Survey (2010-11) and analytical data for sweetener concentration in foods obtained from a national testing programme. Four exposure assessment scenarios were conducted using the available data on sweetener occurrence and concentration. The results demonstrated that the mean daily intakes for all four sweeteners were below the acceptable daily intake (ADI) (17 31%), even considering the most conservative assumptions regarding sweetener presence and concentration. High consumer intakes (P95) were also below the ADI for the four sweeteners when more realistic estimates of exposure were considered. Both sweetener occurrence and concentration data had a considerable effect on reducing the estimated intake values, with a combined reduction in intakes of 95% when expressed as a proportion of the ADI. Flavoured drinks were deemed to be a key contributor to artificial sweetener intakes in this population cohort. It was concluded that there is no health risk to Irish pre-school children at current dietary intake levels of the sweeteners studied. PMID- 26939626 TI - Case-fatality risk of pregnant women with acute viral hepatitis type E: a systematic review and meta-analysis. AB - It is of great concern that pregnant women with acute viral hepatitis (AVH) type E have serious consequences. This study aimed to estimate the case-fatality risk (CFR) and potential risk factors of pregnant women with AVH type E. We searched the PubMed, EMBASE, and Web of Science databases for studies containing data on CFR in pregnancy with AVH type E. A pooled estimate of CFR was calculated using a random-effects model. Potential sources of heterogeneity were explored using subgroup analysis, sensitivity analysis, and meta-regression. We identified 47 eligible studies with a total African and Asian population of 3968 individuals. The pooled CFRs of maternal and fetal outcomes were 20.8% [95% confidence interval (CI) 16.6-25.3] and 34.2% (95% CI 26.0-43.0), respectively. Compared with these, the pooled CFR was highest (61.2%) in women with fulminant hepatic failure (FHF). Community-based surveys had lower pooled CFR (12.2%, 95% CI 9.2 15.6) and heterogeneity (25.8%, 95% CI 20.1-32.0) than hospital-based surveys. Univariate analysis showed that hospital-based surveying (P = 0.007), and patients in the third trimester of pregnancy or with FHF (P < 0.05), were significantly associated with CFR. Intrauterine fetal mortality (27.0%) was statistically higher than neonatal mortality (3.9%). Control measures for HEV infection would reduce feto-maternal mortality in Asia and Africa. PMID- 26939627 TI - Proteomic Profiling Suggests Central Role Of STAT Signaling during Retinal Degeneration in the rd10 Mouse Model. AB - The rd10 mouse is a model of retinitis pigmentosa characterized by the dysfunction of a rod-photoreceptor-specific phosphodiesterase. Compared to the rd1 mouse, retinal degeneration in the rd10 mouse begins later in age with a milder phenotype, making it ideal for investigating cell death and neuroprotective mechanisms. Alterations in the rd10 retina proteome at pre-, peak , and postdegenerative time points were examined using a modified high-recovery filter-aided sample preparation (FASP) method in combination with label-free quantitative mass spectrometry, generating a proteomic data set on almost 3000 proteins. Our data confirmed a period of protein expression similar to age matched wild-type mice predegeneration, with decreases in proteins associated with phototransduction and increases in signaling proteins at peak- and postdegenerative stages. A total of 57 proteins were differentially expressed in the rd10 retinae during peak-degeneration, compared to those in wild-type mice after stringent FDR correction (q < 0.05). Network analysis separated these proteins into one cluster of down-regulated photoreceptor proteins and one of up regulated signaling proteins centered around GFAP, STAT3, and STAT1. This is the first study to identify alterations in STAT1 in the rd10 mouse, which were confirmed with gene expression and immunoblotting experiments, underpinning the efficacy of our approach. This unique proteomic data set on protein dynamics during retinal degeneration could serve as an information source for vision research in the future. PMID- 26939628 TI - Mapping the Orientation of White Matter Fiber Bundles: A Comparative Study of Diffusion Tensor Imaging, Diffusional Kurtosis Imaging, and Diffusion Spectrum Imaging. AB - BACKGROUND AND PURPOSE: White matter fiber tractography relies on fiber bundle orientation estimates from diffusion MR imaging. However, clinically feasible techniques such as DTI and diffusional kurtosis imaging use assumptions, which may introduce error into in vivo orientation estimates. In this study, fiber bundle orientations from DTI and diffusional kurtosis imaging are compared with diffusion spectrum imaging as a criterion standard to assess the performance of each technique. MATERIALS AND METHODS: For each subject, full DTI, diffusional kurtosis imaging, and diffusion spectrum imaging datasets were acquired during 2 independent sessions, and fiber bundle orientations were estimated by using the specific theoretic assumptions of each technique. Angular variability and angular error measures were assessed by comparing the orientation estimates. Tractography generated with each of the 3 reconstructions was also examined and contrasted. RESULTS: Orientation estimates from all 3 techniques had comparable angular reproducibility, but diffusional kurtosis imaging decreased angular error throughout the white matter compared with DTI. Diffusion spectrum imaging and diffusional kurtosis imaging enabled the detection of crossing-fiber bundles, which had pronounced effects on tractography relative to DTI. Diffusion spectrum imaging had the highest sensitivity for detecting crossing fibers; however, the diffusion spectrum imaging and diffusional kurtosis imaging tracts were qualitatively similar. CONCLUSIONS: Fiber bundle orientation estimates from diffusional kurtosis imaging have less systematic error than those from DTI, which can noticeably affect tractography. Moreover, tractography obtained with diffusional kurtosis imaging is qualitatively comparable with that of diffusion spectrum imaging. Because diffusional kurtosis imaging has a shorter typical scan time than diffusion spectrum imaging, diffusional kurtosis imaging is potentially more suitable for a variety of clinical and research applications. PMID- 26939631 TI - Atypical Presentations of Intracranial Hypotension: Comparison with Classic Spontaneous Intracranial Hypotension. AB - BACKGROUND AND PURPOSE: Atypical clinical presentations of spontaneous intracranial hypotension include obtundation, memory deficits, dementia with frontotemporal features, parkinsonism, and ataxia. The purpose of this study was to compare clinical and imaging features of spontaneous intracranial hypotension with typical-versus-atypical presentations. MATERIALS AND METHODS: Clinical records and neuroimaging of patients with spontaneous intracranial hypotension from September 2005 to August 2014 were retrospectively evaluated. Patients with classic spontaneous intracranial hypotension (n = 33; mean age, 41.7 +/- 14.3 years) were compared with those with intracranial hypotension with atypical clinical presentation (n = 8; mean age, 55.9 +/- 14.1 years) and 36 controls (mean age, 41.4 +/- 11.2 years). RESULTS: Patients with atypical spontaneous intracranial hypotension were older than those with classic spontaneous intracranial hypotension (55.9 +/- 14.1 years versus 41.7 +/- 14.3 years; P = .018). Symptom duration was shorter in classic compared with atypical spontaneous intracranial hypotension (3.78 +/- 7.18 months versus 21.93 +/- 18.43 months; P = .015). There was no significant difference in dural enhancement, subdural hematomas, or cerebellar tonsil herniation. Patients with atypical spontaneous intracranial hypotension had significantly more elongated anteroposterior midbrain diameter compared with those with classic spontaneous intracranial hypotension (33.6 +/- 2.9 mm versus 27.3 +/- 2.9 mm; P < .001) and shortened pontomammillary distance (2.8 +/- 1 mm versus 5.15 +/- 1.5 mm; P < .001). Patients with atypical spontaneous intracranial hypotension were less likely to become symptom-free, regardless of treatment, compared with those with classic spontaneous intracranial hypotension (chi(2) = 13.99, P < .001). CONCLUSIONS: In this sample of 8 patients, atypical spontaneous intracranial hypotension was a more chronic syndrome compared with classic spontaneous intracranial hypotension, with more severe brain sagging, lower rates of clinical response, and frequent relapses. Awareness of atypical presentations of spontaneous intracranial hypotension is paramount. PMID- 26939630 TI - Non-Relative Value Unit-Generating Activities Represent One-Fifth of Academic Neuroradiologist Productivity. AB - BACKGROUND AND PURPOSE: A neuroradiologist's activity includes many tasks beyond interpreting relative value unit-generating imaging studies. Our aim was to test a simple method to record and quantify the non-relative value unit-generating clinical activity represented by consults and clinical conferences, including tumor boards. MATERIALS AND METHODS: Four full-time neuroradiologists, working an average of 50% clinical and 50% academic activity, systematically recorded all the non-relative value unit-generating consults and conferences in which they were involved during 3 months by using a simple, Web-based, computer-based application accessible from smartphones, tablets, or computers. The number and type of imaging studies they interpreted during the same period and the associated relative value units were extracted from our billing system. RESULTS: During 3 months, the 4 neuroradiologists working an average of 50% clinical activity interpreted 4241 relative value unit-generating imaging studies, representing 8152 work relative value units. During the same period, they recorded 792 non-relative value unit-generating study reviews as part of consults and conferences (not including reading room consults), representing 19% of the interpreted relative value unit-generating imaging studies. CONCLUSIONS: We propose a simple Web-based smartphone app to record and quantify non-relative value unit-generating activities including consults, clinical conferences, and tumor boards. The quantification of non-relative value unit-generating activities is paramount in this time of a paradigm shift from volume to value. It also represents an important tool for determining staffing levels, which cannot be performed on the basis of relative value unit only, considering the importance of time spent by radiologists on non-relative value unit-generating activities. It may also influence payment models from medical centers to radiology departments or practices. PMID- 26939629 TI - A Novel Methodology for Applying Multivoxel MR Spectroscopy to Evaluate Convection-Enhanced Drug Delivery in Diffuse Intrinsic Pontine Gliomas. AB - BACKGROUND AND PURPOSE: Diffuse intrinsic pontine gliomas are inoperable high grade gliomas with a median survival of less than 1 year. Convection-enhanced delivery is a promising local drug-delivery technique that can bypass the BBB in diffuse intrinsic pontine glioma treatment. Evaluating tumor response is critical in the assessment of convection-enhanced delivery of treatment. We proposed to determine the potential of 3D multivoxel (1)H-MR spectroscopy to evaluate convection-enhanced delivery treatment effect in these tumors. MATERIALS AND METHODS: We prospectively analyzed 3D multivoxel (1)H-MR spectroscopy data for 6 patients with nonprogressive diffuse intrinsic pontine gliomas who received convection-enhanced delivery treatment of a therapeutic antibody (Phase I clinical trial NCT01502917). To compare changes in the metabolite ratios with time, we tracked the metabolite ratios Cho/Cr and Cho/NAA at several ROIs: normal white matter, tumor within the convection-enhanced delivery infusion site, tumor outside of the infused area, and the tumor average. RESULTS: There was a comparative decrease in both Cho/Cr and Cho/NAA metabolite ratios at the tumor convection-enhanced delivery site versus tumor outside the infused area. We used MR spectroscopy voxels with dominant white matter as a reference. The difference between changes in metabolite ratios became more prominent with increasing time after convection-enhanced delivery treatment. CONCLUSIONS: The comparative change in metabolite ratios between the convection-enhanced delivery site and the tumor site outside the infused area suggests that multivoxel (1)H-MR spectroscopy, in combination with other imaging modalities, may provide a clinical tool to accurately evaluate local tumor response after convection-enhanced delivery treatment. PMID- 26939632 TI - The Impact of Middle Turbinate Concha Bullosa on the Severity of Inferior Turbinate Hypertrophy in Patients with a Deviated Nasal Septum. AB - BACKGROUND AND PURPOSE: Inferior turbinate hypertrophy and concha bullosa often occur opposite the direction of nasal septal deviation. The objective of this retrospective study was to determine whether a concha bullosa impacts inferior turbinate hypertrophy in patients who have nasal septal deviation. MATERIALS AND METHODS: The electronic medical record was used to identify sinus CT scans exhibiting nasal septal deviation for 100 adult subjects without and 100 subjects with unilateral middle turbinate concha bullosa. Exclusion criteria included previous sinonasal surgery, tumor, sinusitis, septal perforation, and craniofacial trauma. Nasal septal deviation was characterized in the coronal plane by distance from the midline (severity) and height from the nasal floor. Measurement differences between sides for inferior turbinate width (overall and bone), medial mucosa, and distance to the lateral nasal wall were calculated as inferior turbinate hypertrophy indicators. RESULTS: The cohorts with and without concha bullosa were similarly matched for age, sex, and nasal septal deviation severity, though nasal septal deviation height was greater in the cohort with concha bullosa than in the cohort without concha bullosa (19.1 +/- 4.3 mm versus 13.5 +/- 4.1 mm, P < .001). Compensatory inferior turbinate hypertrophy was significantly greater in the cohort without concha bullosa than in the cohort with it as measured by side-to-side differences in turbinate overall width, bone width, and distance to the lateral nasal wall (P < .01), but not the medial mucosa. Multiple linear regression analyses found nasal septal deviation severity and height to be significant predictors of inferior turbinate hypertrophy with positive and negative relationships, respectively (P < .001). CONCLUSIONS: Inferior turbinate hypertrophy is directly proportional to nasal septal deviation severity and inversely proportional to nasal septal deviation height. The effect of a concha bullosa on inferior turbinate hypertrophy is primarily mediated through influence on septal morphology, because the nasal septal deviation apex tends to be positioned more superior from the nasal floor in these patients. PMID- 26939633 TI - Nonmotor Functions of the Cerebellum: An Introduction. PMID- 26939634 TI - Quantitative Assessment of Circumferential Enhancement along the Wall of Cerebral Aneurysms Using MR Imaging. AB - BACKGROUND AND PURPOSE: The incidence of wall enhancement of cerebral aneurysms on vessel wall MR imaging has been described as higher in ruptured intracranial aneurysms than in unruptured intracranial aneurysms, but the difference in the degree of enhancement between ruptured and unruptured aneurysms is unknown. We compared the degree of enhancement between ruptured and unruptured intracranial aneurysms by using quantitative MR imaging measures. MATERIALS AND METHODS: We performed quantitative analyses of circumferential enhancement along the wall of cerebral aneurysms in 28 ruptured and 76 unruptured consecutive cases by using vessel wall MR imaging. A 3D-T1-weighted fast spin-echo sequence was obtained before and after contrast media injection, and the wall enhancement index was calculated. We then compared characteristics between ruptured and unruptured aneurysms. RESULTS: The wall enhancement index was significantly higher in ruptured than in unruptured aneurysms (1.70 +/- 1.06 versus 0.89 +/- 0.88, respectively; P = .0001). The receiver operating characteristic curve analysis found that the most reliable cutoff value of the wall enhancement index to differentiate ruptured from unruptured aneurysms was 0.53 (sensitivity, 0.96; specificity, 0.47). The wall enhancement index remained significant in the multivariate logistic regression analysis (P < .0001). CONCLUSIONS: Greater circumferential enhancement along the wall of cerebral aneurysms correlates with the ruptured state. A quantitative evaluation of circumferential enhancement by using vessel wall MR imaging could be useful in differentiating ruptured from unruptured intracranial aneurysms. PMID- 26939635 TI - Lesion Heterogeneity on High-Field Susceptibility MRI Is Associated with Multiple Sclerosis Severity. AB - BACKGROUND AND PURPOSE: Susceptibility MR imaging contrast variations reflect alterations in brain iron and myelin content, making this imaging tool relevant to studies of multiple sclerosis lesion heterogeneity. In this study, we aimed to characterize the relationship of high-field, susceptibility contrasts in multiple sclerosis lesions to clinical outcomes. MATERIALS AND METHODS: Twenty-four subjects with multiple sclerosis underwent 7T MR imaging of the brain, disability examinations, and a fatigue inventory. The inverse of T2* relaxation time (R2*), frequency, and relative susceptibility (from quantitative susceptibility mapping) were analyzed in 306 white matter lesions. RESULTS: Most lesions were hypointense on R2* (88% without a rim, 5% with). Lesions that were hyperintense on quantitative susceptibility mapping were more frequent in relapsing-remitting than in progressive multiple sclerosis (54% versus 35%, P = .018). Hyperintense lesion rims on quantitative susceptibility maps were more common in progressive multiple sclerosis and patients with higher levels of disability and fatigue. Mean lesion R2* was inversely related to disability and fatigue and significantly reduced in progressive multiple sclerosis. Relative susceptibility was lower in lesions in progressive multiple sclerosis (median, -0.018 ppm; range, -0.070 to 0.022) than in relapsing-remitting MS (median, -0.010 ppm; range, -0.062 to 0.052; P = .003). CONCLUSIONS: A progressive clinical phenotype and greater disability and fatigue were associated with lower R2* and relative susceptibility values (suggestive of low iron due to oligodendrocyte loss) and rimmed lesions (suggestive of chronic inflammation) in this multiple sclerosis cohort. Lesion heterogeneity on susceptibility MR imaging may help explain disability in multiple sclerosis and provide a window into the processes of demyelination, oligodendrocyte loss, and chronic lesion inflammation. PMID- 26939636 TI - Reduced Myelin Water in the White Matter Tracts of Patients with Niemann-Pick Disease Type C. AB - Previous studies using diffusion tensor imaging to examine white matter in Niemann-Pick disease type C have produced mixed results. However, diffusion tensor imaging does not directly measure myelin and may be affected by other structural changes. We used myelin water imaging to more directly examine demyelination in 2 patients with Niemann-Pick disease type C. The results suggest that this technique may be useful for identifying regional changes in myelination in this condition. PMID- 26939638 TI - Reply. PMID- 26939637 TI - Time-of-Flight MR Angiography for Detection of Cerebral Hyperperfusion Syndrome after Superficial Temporal Artery-Middle Cerebral Artery Anastomosis in Moyamoya Disease. AB - BACKGROUND AND PURPOSE: Cerebral hyperperfusion syndrome is a potential complication of superficial temporal artery-MCA anastomosis for Moyamoya disease. In this study, we evaluated whether TOF-MRA could assess cerebral hyperperfusion syndrome after superficial temporal artery-MCA anastomosis for this disease. MATERIALS AND METHODS: This retrospective study included patients with Moyamoya disease who underwent superficial temporal artery-MCA single anastomosis. TOF-MRA and SPECT were performed before and 1-6 days after anastomosis. Bilateral ROIs on the source image of TOF-MRA were manually placed directly on the parietal branch of the superficial temporal artery just after branching the frontal branch of the superficial temporal artery and on the contralateral superficial temporal artery on the same axial image, respectively. The change ratio of the maximum signal intensity of the superficial temporal artery on TOF-MRA was calculated by using the following formula: (Postoperative Ipsilateral/Postoperative Contralateral)/(Preoperative Ipsilateral/Preoperative Contralateral). RESULTS: Of 23 patients (26 sides) who underwent the operation, 5 sides showed cerebral hyperperfusion syndrome postoperatively. There was a significant difference in the change ratio of signal intensity on TOF-MRA observed between the cerebral hyperperfusion syndrome and non-cerebral hyperperfusion syndrome groups (cerebral hyperperfusion syndrome group: 1.88 +/- 0.32; non-cerebral hyperperfusion syndrome group: 1.03 +/- 0.20; P = .0009). The minimum ratio value for the cerebral hyperperfusion syndrome group was 1.63, and the maximum ratio value for the non-cerebral hyperperfusion syndrome group was 1.30. Thus, no overlap was observed between the 2 groups for the change ratio of signal intensity on TOF MRA. CONCLUSIONS: Diagnosis of cerebral hyperperfusion syndrome is indicated by an increase in the change ratio of signal intensity on TOF-MRA by more than approximately 1.5 times the preoperative levels. PMID- 26939639 TI - Integrative Analysis of 334 Patients with Blister-Like Aneurysms. PMID- 26939640 TI - Experiences among children and adolescents of living with spina bifida and their visions of the future. AB - Purpose Transitioning to independence may be problematic for persons with spina bifida (SB). Experiences of young persons with SB may provide insights into this group's needs for support. Therefore, the aim of this study was to investigate children's and adolescents' experiences of living with SB, their social and emotional adjustment, and their thoughts about becoming independent adults. Method Semi-structured interviews were conducted with young persons with SB (N = 8, age range 10-17 years). Social and emotional problems were assessed using Beck Youth Inventories. The interview transcripts were analyzed using qualitative content analysis. Results Three main themes were found: being a person with SB; everyday living as a person with SB; and preparing for life as an adult with SB. Indications of emotional and social problems were most prominent among participants with milder physical disability. Conclusions The findings indicate that young persons with SB may overestimate their independence. Other potentially problematic areas were lack of motivation, planning and preparedness for becoming independent. Research on transition to independence in this group should consider assistance at an early age in planning and executing strategies for independence. In addition, the potentially difficult situation for young persons with mild SB should be investigated further. Implications for rehabilitation Children and adolescents with spina bifida might lack the motivation and skills for planning their future and health care programmes should therefore include preparations for life as an adult. Clinical assessment of the level of independence should specifically distinguish between the activities they know how to do and what tasks they actually execute independently. Routine follow-ups should include screening for problems with social and emotional adjustment. Be aware of a potential condition-severity paradox whereby those with less severe impairment might have an increased risk of developing symptoms of social and emotional problems. PMID- 26939641 TI - Interface Magnetoelectric Coupling in Co/Pb(Zr,Ti)O3. AB - Magnetoelectric coupling at multiferroic interfaces is a promising route toward the nonvolatile electric-field control of magnetization. Here, we use optical measurements to study the static and dynamic variations of the interface magnetization induced by an electric field in Co/PbZr0.2Ti0.8O3 (Co/PZT) bilayers at room temperature. The measurements allow us to identify different coupling mechanisms. We further investigate the local electronic and magnetic structure of the interface by means of transmission electron microscopy, soft X-ray magnetic circular dichroism, and density functional theory to corroborate the coupling mechanism. The measurements demonstrate a mixed linear and quadratic optical response to the electric field, which results from a magneto-electro-optical effect. We propose a decomposition method of the optical signal to discriminate between different components involved in the electric field-induced polarization rotation of the reflected light. This allows us to extract a signal that we can ascribe to interface magnetoelectric coupling. The associated surface magnetization exhibits a clear hysteretic variation of odd symmetry with respect to the electric field and nonzero remanence. The interface coupling is remarkably stable over a wide frequency range (1-50 kHz), and the application of a bias magnetic field is not necessary for the coupling to occur. These results show the potential of exploiting interface coupling with the prospect of optimizing the performance of magnetoelectric memory devices in terms of stability, as well as fast and dissipationless operation. PMID- 26939642 TI - Influence of Temperature and Humidity on the Stability of Carotenoids in Biofortified Maize (Zea mays L.) Genotypes during Controlled Postharvest Storage. AB - Maize is a staple crop that has been the subject of biofortification efforts to increase the natural content of provitamin A carotenoids. Although significant progress toward increasing provitamin A carotenoid content in maize varieties has been made, postharvest handling factors that influence carotenoid stability during storage have not been fully established. The objectives of this study were to determine carotenoid profiles of six selected provitamin A biofortified maize genotypes at various developmental stages and assess the stability of carotenoids in maize kernels during controlled storage conditions (12 month period), including elevated temperature and relative humidity. There were no significant changes in the content of individual carotenoids within genotypes during kernel development from 45 days after pollination through the time of harvest. Carotenoid losses through traditional grain drying were also minimal (<9%). However, the stability of carotenoids in maize kernels over storage time after harvest was found to be dependent on both temperature and humidity, with variation observed among genotypes. Different forms of provitamin A carotenoids follow similar degradation rates. The genotype C17xDE3 had a degradation rate 2 times faster than those of the other genotypes evaluated (P < 0.001). These differences in carotenoid stability under controlled storage were attributed, in part, to observed differences in the physical properties of the kernels (surface area and porosity). These results support the notion that effective control of moisture content and temperature of the kernels during storage conditions is essential to reduce the speed of degradative reactions. PMID- 26939643 TI - Definition of Sensitive Skin: An Expert Position Paper from the Special Interest Group on Sensitive Skin of the International Forum for the Study of Itch. AB - Sensitive skin is a frequent complaint in the general population, in patients, and among subjects suffering from itch. The International Forum for the Study of Itch (IFSI) decided to initiate a special interest group (SIG) on sensitive skin. Using the Delphi method, sensitive skin was defined as "A syndrome defined by the occurrence of unpleasant sensations (stinging, burning, pain, pruritus, and tingling sensations) in response to stimuli that normally should not provoke such sensations. These unpleasant sensations cannot be explained by lesions attributable to any skin disease. The skin can appear normal or be accompanied by erythema. Sensitive skin can affect all body locations, especially the face". This paper summarizes the background, unresolved aspects of sensitive skin and the process of developing this definition. PMID- 26939645 TI - Strain-Specific Survival of Salmonella enterica in Peanut Oil, Peanut Shell, and Chia Seeds. AB - In North America, outbreaks of Salmonella have been linked to low-water activity (aw) foods, such as nuts and seeds. These outbreaks have implicated an assortment of Salmonella serotypes. Some Salmonella serotypes (e.g., Enteritidis and Typhimurium) cause high proportions of salmonellosis. Nevertheless, there has recently been an emergence of uncommon Salmonella serotypes and strains (e.g., Tennessee, Hartford, and Thompson) in low-aw foods. The aim of this study was to evaluate the survival characteristics of Salmonella serotypes Enteritidis, Typhimurium, Tennessee, Hartford, and Thompson in three low-aw food ingredients with varying aw: peanut oil (aw = 0.521 +/- 0.003), peanut shell (aw = 0.321 +/- 0.20), and chia seeds (aw = 0.585 +/- 0.003). The survival of individual Salmonella strains on each food matrix was monitored for a maximum of 150 days by spreading the bacterial cells onto Luria-Bertani and/or xylose lysine deoxycholate agar. Overall, Salmonella survived for the longest periods of time in peanut oil (96 +/- 8 days), followed by chia seeds (94 +/- 46 days). The survival period was substantially reduced on the surface of peanut shell (42 +/- 49 h), although PCR after 70 days of incubation revealed the presence of Salmonella cells. In addition, Salmonella exhibited a strain-specific response in the three low-aw foods tested. Salmonella Hartford was identified as highly persistent in all low-aw food matrices, whereas Salmonella Typhimurium was the least persistent. The current research emphasizes the adaptable nature of Salmonella to low-aw food ingredients. This may pose additional problems owing to the downstream production of various end products. Additionally, unique survival characteristics among Salmonella strains highlight the need for tailored mitigation strategies regarding high-risk Salmonella strains in the food industry. PMID- 26939644 TI - Prevalence, Level, and Types of Salmonella Isolated from North American In-Shell Pecans over Four Harvest Years. AB - In-shell pecan samples (500 g) were collected over four harvest seasons (2010 to 2014) from seven pecan shelling facilities located in five U.S. states. Four varieties of pecans were analyzed: Mexican Improved, Native Seedlings, Southern Improved, and Western Improved. Pecan samples (100 g) were sent to a third party laboratory for initial Salmonella screening. When a sample was positive for Salmonella, the pathogen level was determined by the most-probable-number (MPN) method (25, 2.5, and 0.25 g). Two sample preparation strategies were used for the MPN analysis, and both strategies were combined for the reported MPN values. Forty-four (0.95%) of 4,641 in-shell pecan samples were positive for Salmonella during initial screening; prevalence by year was 0.47 to 1.4%. Prevalence was not significantly different between varieties: Mexican Improved, 1.2%; Native/Seedling, 0.99%; Southern Improved, 0.97%; and Western Improved, 0.75%. Salmonella was not isolated from 31 of 44 samples upon retesting during MPN analysis (<0.47 MPN/100 g). When Salmonella was detected, the levels were 0.47 to 39 MPN/100 g, with a mean of 2.4 MPN/100 g. Thirty-one Salmonella serotypes were obtained from 42 Salmonella-positive pecan samples; Enteritidis was the most common (12% of samples) followed by Javiana (9%) and Braenderup (7%). All Salmonella Enteritidis isolates were phage type 8. Pulsed-field gel electrophoresis analysis (XbaI) revealed within-serotype diversity, indicating introduction of contamination from a variety of sources. Most (64%) of the isolates were resistant to streptomycin or tetracycline, and 13% were resistant to three or more antibiotics. Salmonella prevalence and level on in-shell pecans is comparable to that on other nuts. PMID- 26939646 TI - Efficacy of Traditional Almond Decontamination Treatments and Electron Beam Irradiation against Heat-Resistant Salmonella Strains. AB - Two outbreaks of salmonellosis were linked to the consumption of raw almonds from California in 2001 and 2004. As a result, federal regulations were developed, which mandate that all almonds grown in California must be treated with a process that results in a 4-log reduction of Salmonella. Because most of the technologies approved to treat almonds rely on the application of heat to control Salmonella, an evaluation of alternative technologies for inactivating heat-resistant Salmonella Enteritidis PT30 and Salmonella Senftenberg 775W was needed. In this study, almonds were inoculated with Salmonella Enteritidis PT30 and Salmonella Senftenberg 775W and then treated with an electron beam (e-beam) or by blanching or oil roasting. The irradiation D10-values for Salmonella Enteritidis PT30 and Salmonella Senftenberg 775W treated with e-beam were 0.90 and 0.72 kGy, respectively. For heat treatments, thermal D10-values for Salmonella Enteritidis PT30 and Salmonella Senftenberg 775W strains were 15.6 and 12.4 s, respectively, when subjected to blanching at 88 degrees C and 13.2 and 10.9 s, respectively, when roasted in oil at 127 +/- 2 degrees C. No significant differences in irradiation and thermal treatment results were observed between Salmonella Enteritidis PT30 and Salmonella Senftenberg 775W (P > 0.05), indicating that e beam irradiation may be a feasible technology for reducing Salmonella in almonds. However, the sensory changes resulting from irradiating at the doses used in this study must be evaluated before e-beam irradiation can be used as a nonthermal alternative for decontamination of almonds. PMID- 26939647 TI - Genome-Scale Screening and Validation of Targets for Identification of Salmonella enterica and Serovar Prediction. AB - Salmonella enterica is the most common foodborne pathogen worldwide, with 2,500 recognized serovars. Detection of S. enterica and its classification into serovars are essential for food safety surveillance and clinical diagnosis. The PCR method is useful for these applications because of its rapidity and high accuracy. We obtained 412 candidate detection targets for S. enterica using a comparative genomics mining approach. Gene ontology (GO) functional enrichment analysis of these candidate targets revealed that the GO term with the largest number of unigenes with known function (38 of 177, 21.5%) was significantly involved in pathogenesis (P < 10(-24)). All the candidate targets were then evaluated by PCR assays. Fifteen targets showed high specificity for the detection of S. enterica by verification with 151 S. enterica strains and 34 non Salmonella strains. The phylogenetic trees of verified targets were highly comparable with those of housekeeping genes, especially for differentiating S. enterica strains into serovars. The serovar prediction ability was validated by sequencing one target (S9) for 39 S. enterica strains belonging to six serovars. Identical mutation sites existed in the same serovar, and different mutation sites were found in diverse serovars. Our findings revealed that 15 verified targets can be potentially used for molecular detection, and some of them can be used for serotyping of S. enterica strains. PMID- 26939648 TI - Spatiotemporal Analysis of Microbiological Contamination in New York State Produce Fields following Extensive Flooding from Hurricane Irene, August 2011. AB - Although flooding introduces microbiological, chemical, and physical hazards onto croplands, few data are available on the spatial extent, patterns, and development of contamination over time postflooding. To address this paucity of information, we conducted a spatially explicit study of Escherichia coli and Salmonella contamination prevalence and genetic diversity in produce fields after the catastrophic flooding that occurred in New England during 2011. Although no significant differences were detected between the two participating farms, both random forest and logistic regression revealed changes in the spatial pattern of E. coli contamination in drag swab samples over time. Analyses also indicated that E. coli detection was associated with changes in farm management to remediate the land after flooding. In particular, E. coli was widespread in drag swab samples at 21 days postflooding, but the spatial pattern changed by 238 days postflooding such that E. coli was then most prevalent in close proximity to surface water features. The combined results of several population genetics analyses indicated that over time postflooding E. coli populations on the farms (i) changed in composition and (ii) declined overall. Salmonella was primarily detected in surface water features, but some Salmonella strains were isolated from soil and drag swab samples at 21 and 44 days postflooding. Although postflood contamination and land management responses should always be evaluated in the context of each unique farm landscape, our results provide quantitative data on the general patterns of contamination after flooding and support the practice of establishing buffer zones between flood-contaminated cropland and harvestable crops in produce fields. PMID- 26939649 TI - Microbiological Food Safety Status of Commercially Produced Tomatoes from Production to Marketing. AB - Tomatoes have been implicated in various microbial disease outbreaks and are considered a potential vehicle for foodborne pathogens. Traceback studies mostly implicate contamination during production and/or processing. The microbiological quality of commercially produced tomatoes was thus investigated from the farm to market, focusing on the impact of contaminated irrigation and washing water, facility sanitation, and personal hygiene. A total of 905 samples were collected from three largescale commercial farms from 2012 through 2014. The farms differed in water sources used (surface versus well) and production methods (open field versus tunnel). Levels of total coliforms and Escherichia coli and prevalence of E. coli O157:H7 and Salmonella Typhimurium were determined. Dominant coliforms were identified using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. No pathogens or E. coli were detected on any of the tomatoes tested throughout the study despite the high levels of coliforms (4.2 to 6.2 log CFU/g) present on the tomatoes at the market. The dominant species associated with tomatoes belonged to the genera Enterobacter, Klebsiella, and Citrobacter. Water used on the farm for irrigation considered not fit for purpose according to national agricultural irrigation standards, with high E. coli levels resulting from either a highly contaminated source water (river water at 3.19 log most probable number [MPN]/100 ml) or improper storage of source water (stored well water at 1.72 log MPN/100 ml). Salmonella Typhimurium was detected on two occasions on a contact surface in the processing facility of the first farm in 2012. Contact surface coliform counts were 2.9 to 4.8 log CFU/cm(2). Risk areas identified in this study were water used for irrigation and poor sanitation practices in the processing facility. Implementation of effective food safety management systems in the fresh produce industry is of the utmost importance to ensure product safety for consumers. PMID- 26939650 TI - Characterization of Salmonella enterica Serovar Typhimurium Isolates from Pigs and Pig Environment-Related Sources and Evidence of New Circulating Monophasic Strains in Spain. AB - A total of 117 Salmonella enterica serovar Typhimurium and 59 monophasic Salmonella Typhimurium (S. enterica serovar 4,[5],12:i:-) strains isolated between 2008 and 2012 from pig, wild bird, rodent, and farm environment samples from the northeast of Spain were characterized by phage typing, antibiotic susceptibility testing, and multiple-locus variable-number tandem repeat analysis in order to evaluate their phenotypic and genetic relatedness. In Salmonella 4,[5],12:i:-, the most prevalent phage types were U311 (40.7%) and DT195 (22%), which did not correspond with the so-called Spanish clone and generally showed a different resistance pattern (ASSuT). Antibiotic resistance was found in 85.8% of the isolates, with 94.1% of them displaying multidrug resistance. Multiple-locus variable-number tandem repeat analysis identified 92 different profiles, six of them shared by both serovars. The minimum spanning tree showed one major cluster that included 95% of the Salmonella 4,[5],12:i:- isolates, which came from different animal sources, geographic locations, and time periods, suggesting high clonality among those Salmonella strains and the ability to spread among pig farms. Overall, isolates of Salmonella 4,[5],12:i:- were more similar to European strains than to the well-characterized Spanish clone. The spread of these new strains of Salmonella 4,[5],12:i:- would likely have been favored by the important pig trade between this Spanish region and other European countries. The overall high prevalence of multidrug resistance observed in these new strains should be noted. PMID- 26939651 TI - Improving the Enrichment and Plating Methods for Rapid Detection of Non-O157 Shiga Toxin-Producing Escherichia coli in Dairy Compost. AB - A culture method to detect non-O157 Shiga toxin-producing Escherichia coli (STEC) was optimized in this study. The finished dairy compost with 30% moisture content was inoculated with a cocktail of six non-O157 STEC serovars at initial concentrations of 1 to 100 CFU/g. Afterward, non-O157 STEC cells in the inoculated dairy compost were enriched by four methods, followed by plating onto cefixime-tellurite sorbitol MacConkey agar supplemented with 5 mg/liter novobiocin (CTNSMAC) and modified Rainbow agar containing 5 mg/liter novobiocin, 0.05 mg/liter cefixime trihydrate, and 0.15 mg/liter potassium tellurite (mRBA). Immunomagnetic bead separation (IMS) was used to compare the cell concentration of individual non-O157 STEC serotypes after enrichment. There was no significant difference (P > 0.05) between CTN-SMAC and mRBA for non-O157 STEC enumeration. The single-step selective enrichment recovered ca. 0.54 log CFU/g more cells (ca. 0.41 log CFU/g for compost-adapted cells) (P < 0.05) compared with the two-step enrichment. Furthermore, the duration of the process to detect non-O157 STEC from dairy compost by selective enrichment, followed by IMS, was optimized. Among six non-O157 STEC serotypes, serotypes O111, O45, and O145 reached the highest cell density after enrichment in dairy compost, and the cell populations reached 7.3, 7.4, and 7.8 log CFU/g within 16 h of incubation, respectively. In contrast, without an enrichment step, the IMS detection limit of individual non-O157 STEC serovars ranged from 3.15 to 4.15 log CFU/g in dairy compost. These results demonstrate that low levels of non-O157 STEC can be detected within 2 days from dairy compost by using a culture method with an optimized enrichment procedure followed by IMS. PMID- 26939652 TI - Prevalence and Level of Enterohemorrhagic Escherichia coli in Culled Dairy Cows at Harvest. AB - The primary objective of this study was to determine the prevalence and level of enterohemorrhagic Escherichia coli (EHEC) O26, O45, O103, O111, O121, and O145 (collectively EHEC-6) plus EHEC O157 in fecal, hide, and preintervention carcass surface samples from culled dairy cows. Matched samples (n = 300) were collected from 100 cows at harvest and tested by a culture-based method and two molecular methods: NeoSEEK STEC (NS) and Atlas STEC EG2 Combo. Both the culture and NS methods can be used to discriminate among the seven EHEC types (EHEC-7), from which the cumulative prevalence was inferred, whereas the Atlas method can discriminate only between EHEC O157 and non-O157 EHEC, without discrimination of the serogroup. The EHEC-7 prevalence in feces, hides, and carcass surfaces was 6.5, 15.6, and 1.0%, respectively, with the culture method and 25.9, 64.9, and 7.0%, respectively, with the NS method. With the Atlas method, the prevalence of non-O157 EHEC was 29.1, 38.3, and 28.0% and that of EHEC O157 was 29.1, 57.0, and 3.0% for feces, hides, and carcasses, respectively. Only two samples (a hide sample and a fecal sample) originating from different cows contained quantifiable EHEC. In both samples, the isolates were identified as EHEC O157, with 4.7 CFU/1,000 cm(2) in the hide sample and 3.9 log CFU/g in the fecal sample. Moderate agreement was found between culture and NS results for detection of EHEC O26 (kappa = 0.58, P < 0.001), EHEC O121 (kappa = 0.50, P < 0.001), and EHEC O157 (kappa = 0.40, P < 0.001). No significant agreement was observed between NS and Atlas results or between culture and Atlas results. Detection of an EHEC serogroup in fecal samples was significantly associated with detection of the same EHEC serogroup in hide samples for EHEC O26 (P = 0.001), EHEC O111 (P = 0.002), EHEC O121 (P < 0.001), and EHEC-6 (P = 0.029) based on NS detection and for EHEC O121 (P < 0.001) based on detection by culture. This study provides evidence that non-O157 EHEC are ubiquitous on hides of culled dairy cattle and that feces are an important source of non-O157 EHEC hide contamination. PMID- 26939653 TI - Multiple-Strain Approach and Probabilistic Modeling of Consumer Habits in Quantitative Microbial Risk Assessment: A Quantitative Assessment of Exposure to Staphylococcal Enterotoxin A in Raw Milk. AB - Quantitative microbial risk assessment (QMRA) models are extensively applied to inform management of a broad range of food safety risks. Inevitably, QMRA modeling involves an element of simplification of the biological process of interest. Two features that are frequently simplified or disregarded are the pathogenicity of multiple strains of a single pathogen and consumer behavior at the household level. In this study, we developed a QMRA model with a multiple strain approach and a consumer phase module (CPM) based on uncertainty distributions fitted from field data. We modeled exposure to staphylococcal enterotoxin A in raw milk in Lombardy; a specific enterotoxin production module was thus included. The model is adaptable and could be used to assess the risk related to other pathogens in raw milk as well as other staphylococcal enterotoxins. The multiplestrain approach, implemented as a multinomial process, allowed the inclusion of variability and uncertainty with regard to pathogenicity at the bacterial level. Data from 301 questionnaires submitted to raw milk consumers were used to obtain uncertainty distributions for the CPM. The distributions were modeled to be easily updatable with further data or evidence. The sources of uncertainty due to the multiple-strain approach and the CPM were identified, and their impact on the output was assessed by comparing specific scenarios to the baseline. When the distributions reflecting the uncertainty in consumer behavior were fixed to the 95th percentile, the risk of exposure increased up to 160 times. This reflects the importance of taking into consideration the diversity of consumers' habits at the household level and the impact that the lack of knowledge about variables in the CPM can have on the final QMRA estimates. The multiple-strain approach lends itself to use in other food matrices besides raw milk and allows the model to better capture the complexity of the real world and to be capable of geographical specificity. PMID- 26939654 TI - Foodborne Outbreaks Reported to the U.S. Food Safety and Inspection Service, Fiscal Years 2007 through 2012. AB - The U.S. Department of Agriculture's Food Safety and Inspection Service (FSIS) works closely with federal, state, and local public health partners to investigate foodborne illness outbreaks associated with its regulated products. To provide insight into outbreaks associated with meat and poultry, outbreaks reported to FSIS during fiscal years 2007 through 2012 were evaluated. Outbreaks were classified according to the strength of evidence linking them to an FSIS regulated product and by their epidemiological, etiological, and vehicle characteristics. Differences in outbreak characteristics between the period 2007 through 2009 and the period 2010 through 2012 were assessed using a chi-square test or Mann-Whitney U test. Of the 163 reported outbreaks eligible for analysis, 89 (55%) were identified as possibly linked to FSIS-regulated products and 74 (45%) were definitively linked to FSIS-regulated products. Overall, these outbreaks were associated with 4,132 illnesses, 772 hospitalizations, and 19 deaths. Shiga toxin-producing Escherichia coli was associated with the greatest proportion of reported outbreaks (55%), followed by Salmonella enterica (34%) and Listeria monocytogenes (7%). Meat and poultry products commercially sold as raw were linked to 125 (77%) outbreaks, and of these, 105 (80%) involved beef. Over the study period, the number of reported outbreaks definitively linked to FSIS regulated products (P = 0.03) declined, while the proportion of culture-confirmed cases (P = 0.0001) increased. Our findings provide insight into the characteristics of outbreaks associated with meat and poultry products. PMID- 26939655 TI - Population Dynamics of Aspergillus Section Nigri Species on Vineyard Samples of Grapes and Raisins. AB - Several species of Aspergillus section Nigri, including potential mycotoxin producers, are common residents of grape vineyards, but the relative population size of individual species throughout the growing season is difficult to determine using traditional isolation and identification methods. Using a quantitative droplet digital PCR (ddPCR) method in combination with dilution plating, total Aspergillus section Nigri populations and relative proportions of A. niger, A. welwitschiae, A. carbonarius, and A. tubingensis were measured from vineyard samples without the need for identifying individual fungal isolates. Grapes were sampled from two raisin vineyards (vineyards A and B) at berry set, veraison, harvest, and raisin stages in two consecutive years. Plate counts showed that the total population of Aspergillus section Nigri present on the fruit increased from berry set to raisin and became a larger component of the total recovered fungal population in both vineyards in both years. Results from ddPCR analysis showed that the relative proportion of A. carbonarius among the four species assayed increased later in the season (harvest and raisin) in comparison to earlier in the season (berry set and veraison). Total fungal and Aspergillus section Nigri plate counts were not significantly different between vineyards in either year. However, vineyard A generally showed higher proportions of A. carbonarius in harvest and raisin samples than vineyard B. This coincided with higher incidence and levels of ochratoxin A in vineyard A harvest and raisin fruit than in vineyard B fruit. This work demonstrates that this ddPCR method is a useful tool for culture-independent monitoring of populations of mycotoxigenic Aspergillus species during grape and raisin production. PMID- 26939656 TI - Effect of Nonthermal, Conventional, and Combined Disinfection Technologies on the Stability of Human Adenoviruses as Fecal Contaminants on Surfaces of Fresh Ready to-Eat Products. AB - Over one-half of foodborne diseases are believed to be of viral origin. The ability of viruses to persist in the environment and fresh produce, as well as their low infectious dose, allows even a small amount of contamination to cause serious foodborne problems. Moreover, the consumer's demands for fresh, convenient, and safe foods have prompted research into alternative food disinfection technologies. Our study focuses on viral inactivation by both conventional and alternative nonthermal disinfection technologies on different fresh ready-to-eat food products. The use of chlorine, as well as that of nonthermal technologies such as UV light and ultrasound (US), was tested for different treatment times. UV nonthermal technology was found to be more effective for the disinfection of human adenoviruses (hAdVs) compared with US, achieving a log reduction of 2.13, 1.25, and 0.92 for lettuce, strawberries, and cherry tomatoes, respectively, when UV treatment was implemented for 30 min. US treatment for the same period achieved a log reduction of 0.85, 0.53, and 0.36, respectively. The sequential use of US and UV was found to be more effective compared with when the treatments were used separately, for the same treatment time, thus indicating a synergistic effect. In addition, human adenoviruses were inactivated sooner, when chlorine treatment was used. Therefore, the effect of each disinfection method was dependent upon the treatment time and the type of food. PMID- 26939657 TI - Inhibition of Morganella morganii Histidine Decarboxylase Activity and Histamine Accumulation in Mackerel Muscle Derived from Filipendula ulumaria Extracts. AB - Filipendula ulmaria, also known as meadowsweet, is an herb; its extract was examined for the prevention of histamine production, primarily that caused by contaminated fish. The efficacy of meadowsweet was assessed using two parameters: inhibition of Morganella morganii histidine decarboxylase (HDC) and inhibition of histamine accumulation in mackerel. Ellagitannins from F. ulmaria (rugosin D, rugosin A methyl ester, tellimagrandin II, and rugosin A) were previously shown to be potent inhibitors of human HDC; and in the present work, these compounds inhibited M. morganii HDC, with half maximal inhibitory concentration values of 1.5, 4.4, 6.1, and 6.8 MUM, respectively. Application of the extracts (at 2 wt%) to mackerel meat yielded significantly decreased histamine accumulation compared with treatment with phosphate-buffered saline as a control. Hence, F. ulmaria exhibits inhibitory activity against bacterial HDC and might be effective for preventing food poisoning caused by histamine. PMID- 26939658 TI - Effect of Sugar on the Changes in Quality of Lightly Salted Grass Carp (Ctenopharyngodon idellus) Fillets under Vacuum Packaging at 4 degrees C. AB - To estimate the effect of a low concentration of sugar on the changes in quality of lightly salted grass carp (Ctenopharyngodon idellus) during storage under vacuum packaging at 4 degrees C, we determined the sensory score, total viable counts, biochemical quality, and physical quality of fish fillets. Fish samples were left untreated, dry cured with 1.3% salt, or dry cured with 1.3% salt plus 1.0% sugar. Compared with untreated samples, curing treatments reduced chemical changes reflected in pH, inosine monophosphate, hypoxanthine riboside, hypoxanthine, and total volatile base nitrogen; decreased the formation of phenylethylamine, putrescine, cadaverine, and histamine; and increased the overall sensory quality of fillets (P < 0.05). Compared to dry cured with 1.3% salt samples, sugar treatment significantly inhibited (P < 0.05) the increase in pH and total volatile base nitrogen value, but it promoted microbial growth and the formation of phenylethylamine and tyramine at later stages of storage. By considering each indicator, the addition of sugar, which can improve the taste of fillets, has no significant effect on the shelf life of vacuum-packaged grass carp fillets. PMID- 26939659 TI - Development and Validation of a Lateral Flow Immunoassay Test Kit for Dual Detection of Casein and beta-Lactoglobulin Residues. AB - Allergies to cow's milk are very common and can present as life-threatening anaphylaxis. Consequently, food labeling legislation mandates that foods containing milk residues, including casein and/or beta-lactoglobulin, provide an indication of such on the product label. Because contamination with either component independent of the other can occur during food manufacturing, effective allergen management measures for containment of milk residues necessitates the use of dual screening methods. To assist the food industry in improving food safety practices, we have developed a rapid lateral flow immunoassay test kit that reliably reports both residues down to 0.01 MUg per swab and 0.1 ppm of protein for foods. The assay utilizes both sandwich and competitive format test lines and is specific for bovine milk residues. Selectivity testing using a panel of matrices with potentially interfering substances, including commonly used sanitizing agents, indicated reduction in the limit of detection by one-to fourfold. With food, residues were easily detected in all cow's milk-based foods tested, but goat and sheep milk residues were not detected. Specificity analysis revealed no cross-reactivity with common commodities, with the exception of kidney beans when present at high concentrations (> 1%). The development of a highly sensitive and rapid test method capable of detecting trace amounts of casein and/or beta-lactoglobulin should aid food manufacturers and regulatory agencies in monitoring for milk allergens in environmental and food samples. PMID- 26939660 TI - Antimicrobial Resistance Profiles in Escherichia coli O157 Isolates from Northern Colorado Dairies. AB - Escherichia coli O157 (EcO157) infections can lead to serious disease and death in humans. Although the ecology of EcO157 is complex, ruminant animals serve as an important reservoir for human infection. Dairy cattle are unique because they may be a source of contamination for milk, meat, and manure-fertilized crops. Foodborne dairy pathogens such as EcO157 are of primary importance to public health. Antimicrobial resistance (AMR) is a complex phenomenon that complicates the treatment of serious bacterial infections and is of increasing concern. In the face of recommended use restrictions for antimicrobial agents in livestock operations, current AMR patterns in known foodborne pathogens should be documented. The objective of this study was to document AMR patterns in EcO157 isolates from dairies in northern Colorado using antimicrobial agents commonly found on dairies and representative of medically important antimicrobial drug classes. Seventy-five EcO157 isolates were recovered from three dairies. Six isolates were resistant to at least 1 of the 10 tested antimicrobial agents: four were resistant to streptomycin, sulfisoxazole, and tetracycline; one was resistant to streptomycin and tetracycline; and one was resistant to only tetracycline. All resistant isolates were from a single dairy. Overall, a low prevalence (8%) of AMR was observed among the 75 EcO157 isolates. No significant effects on AMR profiles due to virulence genes, parity, or previous antimicrobial treatments within the current lactation period were detected. The results of this study provide background information for future comparative studies investigating AMR trends. Future studies should include more participating farms and more samples and should control for potential confounding factors of AMR that may underlie individual farm variation. PMID- 26939661 TI - Development of a Filtration-Based Bioluminescence Assay for Detection of Microorganisms in Tea Beverages. AB - The market for tea drinks as healthy beverages has been steadily expanding, and ready-to-drink beverages in polyethylene terephthalate bottles have been popular. To more rapidly and accurately test tea beverages bottled in polyethylene terephthalate for microbial contamination, a newly developed filtration device and a washing method with a commercial bioluminescence assay were combined to detect low numbers of bacterial spores, fungal conidia, and ascospores. Washing buffers were formulated with nonionic detergents from the Tween series. Commercially available tea beverages were used to evaluate the filtration capacity of the filtration device, the effect of washing buffers, and the performance of the assay. The assay was tested with serially diluted suspensions of colonies of two bacterial strains, spores of three Bacillus strains, conidia of five fungal strains, and ascospores of four fungal strains. The filtration device enabled filtration of a large sample volume (100 to 500 ml), and the washing buffer significantly decreased the background bioluminescence intensity of tea samples when compared with the no-washing method. Low numbers (1 to 10 CFU/100 ml) of the tested strains of bacteria were detected within 8 to 18 h of cultivation, and fungi were detected within 24 to 48 h. Furthermore, a whole bottle (500 ml) of mixed tea was filtered through the filtration device and microbes were detected. This method could be used for quality control of bottled beverages without preincubation. PMID- 26939662 TI - Preservation of Brussels Sprouts by Pullulan Coating Containing Oregano Essential Oil. AB - In this study, the effectiveness of pullulan (a fungal polysaccharide) film containing oregano essential oil (OEO) at 1.0 to 10.0% was evaluated against bacteria, yeasts, and molds. The quality of the sprouts, as determined by weight loss, color, and appearance, was monitored during storage at 2 and 16 degrees C. An organoleptic evaluation of odor preference and odor acceptability of OEO on the Brussels sprouts was also conducted. The antimicrobial activity of pullulan films with OEO increased significantly with the increase in OEO concentration (1 to 10%). Pullulan films with OEO were more effective for inhibiting the growth of yeasts and molds than for inhibiting gram-positive and gram-negative bacteria. Pullulan with 1.0% OEO was an effective combination and was used subsequently as the base coating for maintaining the safety and quality of fresh Brussels sprouts stored at 16 degrees C for 14 days. The pullulan coating containing 1.0% OEO reduced Aspergillus niger populations by 2 log CFU/g. This coating also reduced weight loss in the sprouts. Compared with uncoated Brussels sprouts, the percent weight loss after 14 days was reduced in samples coated with pullulan and with pullulan plus 1% OEO by 3.81 and 6.06%, respectively, after storage at 2 degrees C and by 8.04 and 9.30%, respectively, after storage 16 degrees C. The coating also significantly reduced changes in general appearance and color during storage. Evaluation of the organoleptic properties indicated that pullulan containing OEO had only a slight detrimental effect on odor properties. Incorporating OEO into a delivery system for antimicrobial compounds in pullulan coatings extended the microbiological shelf life of Brussels sprouts. PMID- 26939663 TI - Should Weights and Risk Categories Be Used for Inspection Scores To Evaluate Food Safety in Restaurants? AB - The objective of this study was to verify the characteristics of food safety inspections, considering risk categories and binary scores. A cross-sectional study was performed with 439 restaurants in 43 Brazilian cities. A food safety checklist with 177 items was applied to the food service establishments. These items were classified into four groups (R1 to R4) according to the main factors that can cause outbreaks involving food: R1, time and temperature aspects; R2, direct contamination; R3, water conditions and raw material; and R4, indirect contamination (i.e., structures and buildings). A score adjusted for 100 was calculated for the overall violation score and the violation score for each risk category. The average violation score (standard deviation) was 18.9% (16.0), with an amplitude of 0.0 to 76.7%. Restaurants with a low overall violation score (approximately 20%) presented a high number of violations from the R1 and R2 groups, representing the most risky violations. Practical solutions to minimize this evaluation bias were discussed. Food safety evaluation should use weighted scores and be risk-based. However, some precautions must be taken by researchers, health inspectors, and health surveillance departments to develop an adequate and reliable instrument. PMID- 26939664 TI - Microwave Cooking Practices in Minnesota Food Service Establishments. AB - Uneven cooking due to consumer use of microwave ovens to cook food products that have been prepared but are not ready to eat has been a documented risk factor in several foodborne disease outbreaks. However, the use of microwave ovens in restaurants and other food service establishments has not been well documented. The aim of this study was to describe the types of food service establishments that use microwave ovens, how these ovens are used, types of foods heated or cooked in these ovens, types of microwave ovens used in food service establishments, and the level of compliance with U.S. Food and Drug Administration (FDA) guidelines. From 2008 to 2009, the Minnesota Department of Health collected data from a convenience sample of 60 food establishments within the state. Facility types included fast-food restaurants, sit-down restaurants, school food service, nursing homes, hotels and motels, and daycare centers. Food preparation practices were classified as prep-serve, cookserve, or complex. Minnesota environmental health specialists administered a study questionnaire to managers during routine inspections. Establishments included in this study reported using microwave ovens primarily to warm commercial ready-to-eat products (67%) and to warm foods for palatability (50%). No minimum temperatures are required for these processes because these foods do not require pathogen destruction. However, food establishments using complex preparation practices more often reported using microwave ovens for multiple processes and for processes that require pathogen destruction. For establishments that did report microwave oven use for food requiring pathogen destruction, the majority of managers reported following most FDA recommendations for cooking and reheating for hot-holding potentially hazardous foods, but many did not report letting food stand for 2 min after cooking. Additional training on stand time after microwave cooking could be beneficial because of low reporting of this practice among study participants. PMID- 26939665 TI - Egg Safety Standards in China Need To Be Improved. AB - National and industrial standards used for the certification and inspection of eggs and egg products in the People's Republic of China were reviewed. Although egg production is very high, specific egg and egg product standards are insufficient. Currently, 11 recommended standards and 6 compulsory standards are used to inspect eggs and egg products. Among the related 17 standards, only 6 recommended standards were promulgated for specific egg products even though there are more than 12 kinds of egg products. Egg and egg product standards were formulated and promulgated by six government agencies alone or in cooperation. Communications among agencies should be improved because some of the maximum levels and maximum residue limits for heavy metals, veterinary drugs, and microorganisms are inconsistent among standards, which may confuse producers and customers. The standard for the maximum residue limits of veterinary drugs in eggs and other foods of animal origin need to be revised and updated immediately, which will require the efforts and cooperation of policymakers, researchers, producers, and customers. PMID- 26939666 TI - Zn(2+) -induced Ca(2+) release via ryanodine receptors triggers calcineurin dependent redistribution of cortical neuronal Kv2.1 K(+) channels. AB - KEY POINTS: Increases in intracellular Zn(2+) concentrations are an early, necessary signal for the modulation of Kv2.1 K(+) channel localization and physiological function. Intracellular Zn(2+) -mediated Kv2.1 channel modulation is dependent on calcineurin, a Ca(2+) -activated phosphatase. We show that intracellular Zn(2+) induces a significant increase in ryanodine receptor dependent cytosolic Ca(2+) transients, which leads to a calcineurin-dependent redistribution of Kv2.1 channels from pre-existing membrane clusters to diffuse localization. As such, the link between Zn(2+) and Ca(2+) signalling in this Kv2.1 modulatory pathway is established. We observe that a sublethal ischaemic preconditioning insult also leads to Kv2.1 redistribution in a ryanodine receptor dependent fashion. We suggest that Zn(2+) may be an early and ubiquitous signalling molecule mediating Ca(2+) release from the cortical endoplasmic reticulum via ryanodine receptor activation. ABSTRACT: Sublethal injurious stimuli in neurons induce transient increases in free intracellular Zn(2+) that are associated with regulating adaptive responses to subsequent lethal injury, including alterations in the function and localization of the delayed-rectifier potassium channel, Kv2.1. However, the link between intracellular Zn(2+) signalling and the observed changes in Kv2.1 remain undefined. In the present study, utilizing exogenous Zn(2+) treatment, along with a selective Zn(2+) ionophore, we show that transient elevations in intracellular Zn(2+) concentrations are sufficient to induce calcineurin-dependent Kv2.1 channel dispersal in rat cortical neurons in vitro, which is accompanied by a relatively small but significant hyperpolarizing shift in the voltage-gated activation kinetics of the channel. Critically, using a molecularly encoded calcium sensor, we found that the calcineurin-dependent changes in Kv2.1 probably occur as a result of Zn(2+) -induced cytosolic Ca(2+) release via activation of neuronal ryanodine receptors. Finally, we couple this mechanism with an established model for in vitro ischaemic preconditioning and show that Kv2.1 channel modulation in this process is also ryanodine receptor-sensitive. Our results strongly suggest that intracellular Zn(2+) -initiated signalling may represent an early and possibly widespread component of Ca(2+) -dependent processes in neurons. PMID- 26939668 TI - Early readmissions after liver transplantation and the power of quality improvement. PMID- 26939667 TI - Increased caveolin-1 in intervertebral disc degeneration facilitates repair. AB - BACKGROUND: Preceding intervertebral disc (IVD) degeneration, the cell phenotype in the nucleus pulposus (NP) shifts from notochordal cells (NCs) to chondrocyte like cells (CLCs). Microarray analysis showed a correlation between caveolin-1 expression and the phenotypic transition of NCs to CLCs. With a clinical directive in mind, the aim of this study was to determine the role of caveolin-1 in IVD degeneration. As a scaffolding protein, caveolin-1 influences several signaling pathways, and transforming growth factor (TGF)-beta receptors have been demonstrated to colocalize with caveolin-1. Therefore, the hypothesis of this study was that caveolin-1 facilitates repair by enhancing TGF-beta signaling in the IVD. METHODS: Protein expression (caveolin-1, apoptosis, progenitor cell markers, extracellular matrix, and phosphorylated Smad2 [pSmad2]) was determined in IVDs of wild-type (WT) and caveolin-1-null mice and canine IVDs of different degeneration grades (immunofluorescence, immunohistochemistry, and TUNEL assay). Canine/human CLC microaggregates were treated with chondrogenic medium alone or in combination with caveolin-1 scaffolding domain (CSD) peptide and/or caveolin-1 silencing RNA. After 28 days, gene and protein expression profiles were determined. RESULTS: The NP of WT mice was rich in viable NCs, whereas the NP of caveolin-1-null mice contained more collagen-rich extracellular matrix and fewer cells, together with increased progenitor cell marker expression, pSmad2 TGF-beta signaling, and high apoptotic activity. During canine IVD degeneration, caveolin 1 expression and apoptotic activity increased. In vitro caveolin-1 silencing decreased the CLC microaggregate glycosaminoglycan (GAG) content, which could be rescued by CSD treatment. Furthermore, CSD increased TGF-beta/pSmad2 signaling at gene and protein expression levels and enhanced the anabolic effects of TGF beta1, reflected in increased extracellular matrix deposition by the CLCs. CONCLUSIONS: Caveolin-1 plays a role in preservation of the NC phenotype. Additionally, it may be related to CLC apoptosis, given its increased expression in degenerated IVDs. Nevertheless, CSD enhanced CLC GAG deposition in vitro, and hence the increased caveolin-1 expression during IVD degeneration may also facilitate an ultimate attempt at repair. Further studies are needed to investigate how caveolin-1 modifies other signaling pathways and facilitates IVD repair. PMID- 26939669 TI - Elevated PTH with normal serum calcium level: a structured approach. AB - Normocalcaemic hyperparathyroidism is a common biochemical finding, usually identified during an assessment of bone or renal health. Hypercalcaemia must be considered by calculation of adjusted calcium, and a careful history taken to assess dietary calcium intake and for the possibility of a malabsorption syndrome. 25-hydroxyvitamin D (25OHD) should be measured and replaced if indicated. The management plan for the patient is influenced by the context in which calcium and PTH were measured. In this brief review we describe the assessment of a patient with normocalcaemic hyperparathyroidism. PMID- 26939670 TI - Simple and sensitive electrogenerated chemiluminescence peptide-based biosensor for detection of matrix metalloproteinase 2 released from living cells. AB - A simple and sensitive electrogenerated chemiluminescence biosensor was developed to monitor matrix metalloproteinase 2 (MMP-2) by employing a specific peptide (CGPLGVRGK) as a molecular recognition substrate. Bis(2,2'-bipyridine)-4'-methyl 4-carboxybipyridine-ruthenium N-succinimidyl ester-bis(hexafluorophosphate) (Ru(bpy)2(mcbpy-O-Su-ester)(PF6)2 (Ru1) was used as ECL-emitting species and covalently labeled onto the peptide through NH2-containing lysine on the peptide via acylation reaction to form Ru1-peptide as an ECL probe. An ECL peptide-based biosensor was fabricated by self-assembling the ECL probe onto the surface of gold electrode. MMP-2 can specifically cleave the Ru1-peptide on the electrode surface, which led the partly Ru1-peptide to leave the electrode surface and resulted in the decrease of the ECL intensity obtained from the resulted electrode in 0.1 M phosphate-buffered saline (pH 7.4) containing tri-n propylamine. The decreased ECL intensity was piecewise linear to the concentration of MMP-2 in the range from 1 to 500 ng/mL. Moreover, the ECL biosensor is successfully applied to detection of MMP-2 secreted by living cell, such as HeLa cells. Additionally, the biosensor was also applied to the evaluation of matrix metalloproteinase inhibitors. The strategy presented here is promising for other disease-related matrix metalloproteinase assay and matrix metalloproteinase inhibitor profiling with sensitivity and simplicity. Graphical Abstract Detection of MMP-2 released from living cells by ECL peptide-based biosensor. PMID- 26939671 TI - A miniaturized fiber-optic colorimetric sensor for nitrite determination by coupling with a microfluidic capillary waveguide. AB - A microfluidic-capillary-waveguide-coupled fiber-optic sensor was developed for colorimetric determination of hazardous nitrite based on the Griess-Ilosvay reaction. The sensor was modularly designed by use of a light-emitting diode as the light source, silica fiber as the light transmission element, and a capillary waveguide tube as the light reaction flow cell. With the light interacting with the azo dye generated by the Griess-Ilosvay reaction between nitrite and Griess reagents, nitrite could be determined by a colorimetric method according to Beer's law. By use of the inexpensive and micro-sized elements mentioned above, the sensor provided a new low-cost and portable method for in situ and online measurement of nitrite. The sensor had a wide linear range for nitrite from 0.02 to 1.8 mg L(-1) and a low detection limit of 7 MUg L(-1) (3sigma), with a relative standard deviation of 0.37% (n = 10). With a low reagent demand of 200 MUL, a short response time of 6.24 s, and excellent selectivity, the sensor is environmentally friendly and has been applied to nitrite determination in different water samples. The results were compared with those obtained by conventional spectrophotometry and ion chromatography, indicating the sensor's potential for practical applications. PMID- 26939672 TI - St. Jude Cancer Education for Children Program: The Impact of a Teacher-Led Intervention on Student Knowledge Gains. AB - In 2006, St. Jude Children's Research Hospital (Memphis, Tennessee) began developing a school-based outreach program known as the St. Jude Cancer Education for Children Program (SJCECP). The aim of this program is to teach Memphis-area children about cells, cancer, and healthy habits that can prevent the development of cancer in adulthood. Initial plans for delivery of the program was for St. Jude staff to present the program at local schools. This plan for disseminating instruction was not feasible due to the limited availability of St. Jude staff. As a next step, during the 2012-2014 academic years, we conducted a study entitled SJCECP2, utilizing the SJCECP curriculum, with the objective of evaluating the impact of the educational intervention on knowledge acquisition and retention among fourth-grade students participating in a modified, teacher led version of the program. Eighteen teachers and 426 students from 10 local schools in the greater Memphis area participated in the program evaluation. This study used a single-group, pre-test/post-test design to determine the impact of the SJCECP intervention on changes in knowledge scores among fourth-grade students. Testing was on cells, cancer, and healthy living. The mean scores increased from 6.45 to 8.12, 5.99 to 7.65, and 5.92 to 7.96 on cell, cancer, and health behaviors units, respectively (all p values <.001). Preliminary evidence suggests that the SJCECP2 intervention is a useful tool for teachers to improve student knowledge of knowledge of cells, cancer, and healthy living concepts at the fourth-grade level. PMID- 26939673 TI - Genetic Analysis of Jervel and Lange Nielsen Syndrome with a Novel Mutation in KCNQ1 Gene. PMID- 26939674 TI - Perceived Barriers and Potential Strategies to Improve Self-Management Among Adults with Type 2 Diabetes: A Community-Engaged Research Approach. AB - OBJECTIVE: Type 2 diabetes (T2D) is a leading cause of morbidity and mortality that disproportionately affects adults living in urban areas in the USA. Our goal was to actively engage community members in research to identify strategies to improve T2D self-management in an urban community in Baltimore, MD. METHODS: We partnered with the Johns Hopkins Community Research Advisory Council to establish our stakeholder advisory board-the Diabetes Action Board (DAB). In response to input from DAB members regarding the best approaches for conducting community centered T2D research, we conducted three 90-min focus groups of local adults living with T2D to identify ways to improve self-management. DAB members were involved in each stage of the research, including development of the protocol and materials, participant recruitment, and interpretation and dissemination of findings. RESULTS: In total, 24 adults with self-reported T2D (75 % participation rate; 79 % female) residing in the local area participated in focus groups. Participants reported that barriers within their daily home and work environments, inadequate neighborhood resources, and suboptimal healthcare quality hindered their self-management. Reported strategies that may help to improve self-management included social support from family members, providers, and community members; improved access to healthy food; and wide availability of free or low-cost T2D educational materials and classes within the local area. CONCLUSION: Our study demonstrates a successful mechanism for engaging community members in the design, implementation, and dissemination of T2D research. This research approach was beneficial for building a sustainable partnership to support future work in the local community. PMID- 26939675 TI - The evaluation of vitamin D levels in patients with carpal tunnel syndrome. AB - The aim of this study was to evaluate the relationship between 25-hydroxyvitamin D (25(OH)D) levels and carpal tunnel syndrome (CTS). 25(OH)D levels were checked in 108 consecutive patients with CTS symptoms and 52 healthy controls. All patients underwent nerve conduction studies and completed Boston Carpal Tunnel Questionnaire (BQ) symptom severity and functional status scales to quantify symptom severity, pain status and functional status. There were 57 patients with electrophysiological confirmed CTS (EP+ group) and 51 electrophysiological negative symptomatic patients (EP- group). 25(OH) D deficiency (25(OH)D < 20 ng/ml) was found in 96.1 % of EP- group, in 94.7 % of EP+ group and in 73.8 % of control group. 25(0H) D level was found significantly lower both in EP+ and EP- groups compared to control group (p = 0.006, p < 0.001, respectively). Although mean vitamin D level in EP- group was lower than EP+ group, statistically difference was not significant between EP+ and EP- groups (p = 0.182). BQ symptom severity and functional status scores and BQ pain sum score were not significantly different between EP+ and EP- groups. We found no correlation with 25(OH) D level for BQ symptom severity, functional status and pain sum scores. 25(OH) D deficiency is a common problem in patients with CTS symptoms. As evidenced by the present study, assessment of serum 25(OH)D is recommended in CTS patients even with electrophysiological negative results. PMID- 26939677 TI - The safety and efficacy of bladder cryoablation in a beagle model by using a novel balloon cryoprobe. AB - The poor quality of initial transurethral resection (TUR) would leave residual tumor and compromise the prognosis. The common therapeutic option is to perform re-TUR, which adds burden to patients. We assumed that cryoablation could be applied as adjuvant therapy combined with TUR, thus lead to maxium tumor control. In our study, we investigated the safety and effects of focal bladder wall cryoablation in beagle model using a novel cryoablation balloon probe. Temperature was recorded throughout the freeze process in different parts of the bladder. The bladder was harvested immediately, 2 weeks or 3 months after surgery for histological evaluation. The results demonstrated cryoablation using our newly designed probe is safe and effective. Two-minute cryoablation could induce necrosis within 2-cm range in diameter to superficial muscle layer. The findings provided us reference before cryoablation could be applied in clinical practice. PMID- 26939678 TI - Erratum to: Vitamin D and Evening Primrose Oil Administration Improve Glycemia and Lipid Profiles in Women with Gestational Diabetes. PMID- 26939676 TI - The role of the RTEL1 rs2297440 polymorphism in the risk of glioma development: a meta-analysis. AB - The regulator of the telomere elongation helicase1 (RTEL1) gene plays a crucial role in the DNA double-stand break-repair pathway by maintaining genomic stability. Recent epidemiological studies showed that the rs2297440 polymorphism in the RTEL1 gene was a potential risk locus for glioma development, but the results were inconclusive. To clarify the association between this polymorphism and the risk of glioma, we performed a comprehensive meta-analysis. The PubMed, EMBASE, Web of Science, and China National Knowledge Infrastructure databases were systematically searched to identify all relevant published studies up to 30 August 2015. Four eligible studies were finally included. The pooled results indicated that the RTEL1 rs2297440 polymorphism moderately increased the risk of glioma in all genetic models. A comparison of the dominant model CT + CC versus TT (OR 1.40; 95 % CI 1.24-1.60; p < 0.001) indicated that having the C allele conferred a 40 % increased risk of developing glioma. In a subgroup analysis based on geographic location (Europe, Asia, and America), there was an association between the rs2297440 polymorphism and the risk of glioma in all three areas. The results of the subgroup analysis based on source of control indicated an elevated risk of glioma in population-based control studies. This meta-analysis demonstrates that the RTEL1 rs2297440 polymorphism plays a moderate, but significant role in the risk of glioma. Further studies with larger sample sizes are necessary to confirm this finding. PMID- 26939679 TI - Molecular Mechanisms for the Modulation of Selected Inflammatory Markers by Dietary Rice Bran Oil in Rats Fed Partially Hydrogenated Vegetable Fat. AB - Industrially produced partially hydrogenated vegetable fat (PHVF) contains trans fatty acids (TFA) mostly comprising elaidic acid (EA, 18:1?9t). Though, the harmful effects of TFA on health have been repeatedly publicized, the fat containing TFA have been continued to be used as a cooking medium in many regions of the world. The adverse effects of PHVF on oxidative stress and inflammatory markers and the possible ameliorative action of rice bran oil (RBO) on these markers were evaluated. Weaning rats were fed a AIN-93 purified diet supplemented with the following lipids: groundnut oil (GNO, 10 wt%), PHVF (10 wt%), RBO (10 wt%), PHVF blended with RBO at 2.5, 5.0 and 7.5 wt% levels. The final concentration of the lipids in the diet was maintained at 10 wt%. Rats were fed these diets for 60 days. They were sacrificed and analyzed for oxidative stress and inflammatory markers. The rats fed PHVF showed lower levels of lipid peroxidation and hepatic antioxidant enzymes. The rats fed PHVF-containing diets showed enhanced levels of interleukin-1beta, C-reactive proteins and also showed enhanced levels of paw inflammation when injected with carrageenan as compared to rats given GNO, RBO or PHVF blended with incremental amounts of RBO. The macrophages from rats fed diet containing PHVF showed up-regulation in the expressions of cytosolic phospholipase A2 (cPLA2), nuclear factor-kappaB p65, toll like receptor (TLR)-2, TLR-4 and down-regulation in the expressions of peroxisome proliferator activated receptor gamma (PPAR)gamma, adiponectin receptor (AdipoR)-1 and AdipoR-2 when compared to rats fed diet containing GNO, RBO and PHVF blended with RBO. It was concluded that dietary PHVF enhance pro inflammatory markers which can be reduced by judiciously blending PHVF with RBO. PMID- 26939680 TI - Application of Silver Ion High-Performance Liquid Chromatography for Quantitative Analysis of Selected n-3 and n-6 PUFA in Oil Supplements. AB - The aim of this study was to develop a simple method for simultaneous determination of selected cis/cis PUFA-LNA (18:2), ALA (18:3), GLA (18:3), EPA (20:5), and DHA (22:6) by silver ion high-performance liquid chromatography coupled to a diode array detector (Ag-HPLC-DAD). The separation was performed on three Luna SCX Silver Loaded columns connected in series maintained at 10 degrees C with isocratic elution by 1% acetonitrile in n-hexane. The applied chromatographic system allowed a baseline separation of standard mixture of n-3 and n-6 fatty acid methyl esters containing LNA, DHA, and EPA and partial separation of ALA and GLA positional isomers. The method was validated by means of linearity, precision, stability, and recovery. Limits of detection (LOD) for considered PUFA standard solutions ranged from 0.27 to 0.43 mg L(-1). The developed method was used to evaluate of n-3 and n-6 fatty acids contents in plant and fish softgel oil capsules, results were compared with reference GC-FID based method. PMID- 26939682 TI - Comments on Trachtman et al.: Recurrent focal segmental glomerulosclerosis after kidney transplantation. PMID- 26939681 TI - Recurrent focal segmental glomerulosclerosis after kidney transplantation: response to comments by Straatmann and Vehaskari. PMID- 26939683 TI - Fibroblast growth factor-23 and renin-angiotensin system levels in vitamin-D dependent rickets type I. AB - BACKGROUND: As 1,25(OH)2D3 vitamin D3 induces fibroblast growth factor-23 (FGF 23) production and suppresses the renin-angiotensin-aldosterone system (RAAS), its absence in vitamin-D-dependent rickets type I (VDDR-I) may have adverse health consequences. CASE DESCRIPTION: An infant presented at age 8 months with hypocalcemia and rickets and very low 1,25(OH)2D3 levels. Genetic analysis confirmed VDRR-I, and calcitriol therapy was initiated. During periods of nonadherence to therapy, chemical measurements revealed detectable FGF-23 levels, with undetectable 1,25(OH)2D3, hypophosphatemia, low tubular reabsorption of phosphate, hypocalcemia, and very elevated parathyroid hormone (PTH) levels. These changes, in addition to elevated RAAS levels, normalized during calcitriol therapy despite elevated FGF-23 levels. At age 12 years, all rachitic manifestations were absent, and bone mineral density (BMD) and the echocardiogram were normal. CONCLUSIONS: Whereas 1,25(OH)2D3 is not indispensable for FGF-23 production, PTH in the absence of vitamin D may maintain FGF-23 secretion despite hypocalcemia. Normalization of urinary phosphate losses despite elevated FGF-23 during calcitriol-mediated suppression of secondary hyperparathyroidism points to a cardinal role of PTH as a cause of the phosphaturia in VDRR-I. Normalization of RAAS by calcitriol may conceivably prevent adverse cardiovascular outcomes. PMID- 26939685 TI - Influencing the agricultural sector to embrace adaptation to climate change, for the sake of global food security. PMID- 26939684 TI - A review on bisphenol A occurrences, health effects and treatment process via membrane technology for drinking water. AB - Massive utilization of bisphenol A (BPA) in the industrial production of polycarbonate plastics has led to the occurrence of this compound (at MUg/L to ng/L level) in the water treatment plant. Nowadays, the presence of BPA in drinking water sources is a major concern among society because BPA is one of the endocrine disruption compounds (EDCs) that can cause hazard to human health even at extremely low concentration level. Parallel to these issues, membrane technology has emerged as the most feasible treatment process to eliminate this recalcitrant contaminant via physical separation mechanism. This paper reviews the occurrences and effects of BPA toward living organisms as well as the application of membrane technology for their removal in water treatment plant. The potential applications of using polymeric membranes for BPA removal are also discussed. Literature revealed that modifying membrane surface using blending approach is the simple yet effective method to improve membrane properties with respect to BPA removal without compromising water permeability. The regeneration process helps in maintaining the performances of membrane at desired level. The application of large-scale membrane process in treatment plant shows the feasibility of the technology for removing BPA and possible future prospect in water treatment process. PMID- 26939686 TI - Selected problems with boron determination in water treatment processes. Part I: comparison of the reference methods for ICP-MS and ICP-OES determinations. AB - The aim of the study was to compare the two reference methods for the determination of boron in water samples and further assess the impact of the method of preparation of samples for analysis on the results obtained. Samples were collected during different desalination processes, ultrafiltration and the double reverse osmosis system, connected in series. From each point, samples were prepared in four different ways: the first was filtered (through a membrane filter of 0.45 MUm) and acidified (using 1 mL ultrapure nitric acid for each 100 mL of samples) (FA), the second was unfiltered and not acidified (UFNA), the third was filtered but not acidified (FNA), and finally, the fourth was unfiltered but acidified (UFA). All samples were analysed using two analytical methods: inductively coupled plasma mass spectrometry (ICP-MS) and inductively coupled plasma optical emission spectrometry (ICP-OES). The results obtained were compared and correlated, and the differences between them were studied. The results show that there are statistically significant differences between the concentrations obtained using the ICP-MS and ICP-OES techniques regardless of the methods of sampling preparation (sample filtration and preservation). Finally, both the ICP-MS and ICP-OES methods can be used for determination of the boron concentration in water. The differences in the boron concentrations obtained using these two methods can be caused by several high-level concentrations in selected whole-water digestates and some matrix effects. Higher concentrations of iron (from 1 to 20 mg/L) than chromium (0.02-1 mg/L) in the samples analysed can influence boron determination. When iron concentrations are high, we can observe the emission spectrum as a double joined and overlapping peak. PMID- 26939687 TI - Nanoparticular surface-bound PCBs, PCDDs, and PCDFs-a novel class of potentially higher toxic POPs. AB - In a previous study, Env Sci Poll Res:1-7, 2015 showed that polychlorinated biphenyls (PCBs), polychlorinated dibenzo dioxins (PCDDs), and polychlorinated dibenzo furanes (PCDFs) are found in commercially available (nano) particular titanium dioxide as a result of the fabrication. Here, we give a brief perspective and reason the toxicity of these new classes of persistent organic pollutants (POPs) by reviewing also their nanoparticular properties, such as surface-to-volume ratio, photocatalytic activity, polarity shifts, and stealth effect. These insights point towards a new class of POPs and toxicologic effects, which are related to the size but not a result of nanotechnology itself. We pave the way to the understanding of until now unresolved very complex phenomena, such as the indoor exposure, formation, and transformation of POP and sick-building syndrome. This is a fundamental message for nanotoxicology and kinetics and should be taken into account when determining the toxicity of nanomaterials and POPs separately and as a combination. PMID- 26939688 TI - Facile synthesis of 2D CuO nanoleaves for the catalytic elimination of hazardous and toxic dyes from aqueous phase: a sustainable approach. AB - This article reports for the first time a facile, green synthesis of 2D CuO nanoleaves (NLs) using the amino acid, namely aspartic acid, and NaOH by a microwave heating method. The amino acid acts as a complexing/capping agent in the synthesis of CuO NLs. This method resulted in the formation of self-assembled 2D CuO NLs with an average length and width of ~300-400 and ~50-82 nm, respectively. The as-synthesized 2D CuO NLs were built up from the primary CuO nanoparticles by oriented attachment growth mechanism. The CuO NLs were characterized by an X-ray diffraction (XRD) method, transmission electron microscopy (TEM), selected-area electron diffraction (SAED) pattern, and Fourier transform infrared spectroscopy (FT-IR). The optical properties were investigated using UV-visible spectroscopy. For the first time, rose bengal and eosin Y dyes were degraded photochemically by solar irradiation using CuO NLs as a photocatalyst. The synthesized CuO NLs act as an efficient photocatalyst in the degradation of rose bengal and eosin Y dye under direct sunlight. The degradation of both the dyes, namely rose bengal and eosin Y, took place within 120 and 45 min, respectively, using CuO NLs as a photocatalyst, whereas commercial CuO, SnO2 quantum dots (QDs), and commercial SnO2 took more than 120 and 45 min for the degradation of rose bengal and eosin Y, respectively. The synthesized CuO NLs showed a superior photocatalytic activity as compared to that of commercial CuO, SnO2 QDs, and commercial SnO2. The reusability of the CuO NLs as a photocatalyst in the degradation of dyes was investigated, and it was evident that the catalytic efficiency decreases to a small extent (5-6 %) after the fifth cycle of operation. PMID- 26939689 TI - Dry reforming of methane to syngas: a potential alternative process for value added chemicals-a techno-economic perspective. AB - During the past decade, there has been increasing global concern over the rise of anthropogenic CO2 emission into the Earth's atmosphere (J Air Waste Manage Assoc 53:645-715, 2003). The utilization of CO2 to produce any valuable product is need of the hour. The production of syngas from CO2 and CH4 seems to be one of the promising alternatives in terms of industrial utilization, as it offers several advantages: (a) mitigation of CO2, (b) transformation of natural gas and CO2 into valuable syngas, and (c) producing syngas with H2/CO ratio 1 which may further be used for the production of valuable petrochemicals (J Air Waste Manage Assoc 53:645-715, 2003). A conceptual design for the production of synthesis gas by dry reforming of methane is presented here. An economic assessment of this process with an integrated methanol production section as a case was conceptualized and compared with the conventional steam methane reforming route to produce methanol. The economic study indicated that dry reforming of natural gas/methane is a competitive process with lower operating and capital costs in comparison with steam reforming assuming negligible cost of CO2 import. PMID- 26939690 TI - Geochemistry of the Adige River water from the Eastern Alps to the Adriatic Sea (Italy): evidences for distinct hydrological components and water-rock interactions. AB - The Adige River flows from the Eastern Alps to the Adriatic Sea and the understanding of its fluvial dynamics can be improved by geochemical and O-H isotopic investigation. The most negative isotopic compositions are recorded close to the source (delta(18)O between -14.1 and -13.8 0/00, deltaD between 100.3 and -97.0 0/00), and deltaD and delta(18)O values generally increase downstream through the upper part (UP, the mountainous sector), stabilizing along the lower part (LP, the alluvial plain) of the river with delta(18)O between 12.4 and -11.8 0/00, deltaD between -86.9 and -83.7 0/00. The isotopic variations along the stream path (delta(18)O-deltaD vs distance from the source) depict subparallel distributions for all the investigated periods, with less negative values recorded in winter. Total dissolved solids (TDS) concentration shows the lowest value (<100 mg/l) at the river source, jumping to 310 mg/l at the Rio Ram inflow, then decreasing down to the Isarco River confluence; from here, we observed an increase toward the river mouth, with different values in the distinct sampling periods. The lowest values (140-170 mg/l) were recorded during high discharge in spring, whereas higher TDS values (up to 250 mg/l) were recorded during winter low flow conditions. Extreme TDS values were observed in the estuarine samples (up to 450 mg/l), as result of mixing with seawater. The results allow for the identification of distinct water end-members: glacio-nival component(s) characterized by the most negative isotopic composition and extremely low TDS, a rainfall component characterized by intermediate isotopic and elemental composition and groundwater characterized by the less negative isotopic composition and comparatively higher TDS. An additional component is represented by seawater, which is recorded at the lowest reach of the river during drought periods. These contributions variously mix along the stream path in the distinct hydrological periods, and the presented data are a snapshot of the current hydroclimatic conditions. Future investigations will evaluate possible hydrological variations related to meteo-climatic changes. Monitoring is fundamental for future water management to overcome the vanishing of a significant water end-member of the basin, i.e., the glacio-nival reservoir that is severely affected by the ongoing climatic changes. PMID- 26939691 TI - Organic-inorganic hybrid gels for the selective absorption of oils from water. AB - Organic-inorganic hybrid gels were synthesized by the condensation of a linear aliphatic diol (1,8-octanediol) and altering the chain length of the alkyltriethoxysilanes (from ethyltriethoxysilane to hexadecyltrimethoxysilane) through a bulk polymerization process without using any initiator, activator, catalyst, or solvent for the selective removal of oils from water. Fourier transform infrared spectroscopy (FTIR) and solid-state (13)C and (29)Si cross polarization magic-angle spinning nuclear magnetic resonance (CPMAS NMR) were used for the structural analysis of hybrid gels. Thermal properties of the hybrid gels were determined by thermogravimetric analysis (TGA). Oil absorbency of organic-inorganic hybrid gels was determined by oil absorption tests. The results showed that hybrid gels have high and fast absorption capacities and excellent reusability. Good selectivity, high thermal stability, low density, and excellent recyclability for the oil removal give the material potential applications. PMID- 26939692 TI - Assessment of cryopreserved donor skin viability: the experience of the regional tissue bank of Siena. AB - Skin allografts from cadaver donors are an important resource for treating extensive burns, slow-healing wounds and chronic ulcers. A high level of cell viability of cryopreserved allografts is often required, especially in burn surgery, in Italy. Thus, we aimed to determine which conditions enable procurement of highly viable skin in our Regional Skin Bank of Siena. For this purpose, we assessed cell viability of cryopreserved skin allografts procured between 2011 and 2013 from 127 consecutive skin donors, before and after freezing (at day 15, 180, and 365). For each skin donor, we collected data concerning clinical history (age, sex, smoking, phototype, dyslipidemia, diabetes, cause of death), donation process (multi-tissue or multi-organ) and timing of skin procurement (assessment of intervals such as death-harvesting, harvesting banking, death-banking). All these variables were analysed in the whole case study (127 donors) and in different groups (e.g. multi-organ donors, non refrigerated multi-tissue donors, refrigerated multi-tissue donors) for correlations with cell viability. Our results indicated that cryopreserved skin allografts with higher cell viability were obtained from female, non smoker, heartbeating donors died of cerebral haemorrhage, and were harvested within 2 h of aortic clamping and banked within 12 h of harvesting (13-14 h from clamping). Age, cause of death and dyslipidaemia or diabetes did not appear to influence cell viability. To maintain acceptable cell viability, our skin bank needs to reduce the time interval between harvesting and banking, especially for refrigerated donors. PMID- 26939693 TI - [Does OCT morphology provide indications for prognosis of visual acuity after venous occlusion? : SD-OCT analysis in retinal vein occlusion before and after resolution of initial macular edema]. AB - BACKGROUND: Even though macular edema (ME) in patients with retinal vein occlusion (RVO) is resolved after intravitreal treatment with anti-vascular endothelial growth factor (VEGF), impairment of visual acuity (VA) often persists. OBJECTIVE: A qualitative and quantitative evaluation of spectral domain optical coherence tomography (SD-OCT) images was carried out in patients with RVO and resolved ME to investigate a correlation between retinal morphology and functional results. MATERIAL AND METHODS: Foveal SD-OCT scans of 13 patients with RVO and resolved ME after treatment were retrospectively evaluated. The thickness of inner retinal layers up to the external limiting membrane (ELM) and up to the photoreceptors in the retinal pigment epithelium (RPE) was measured by automatic segmentation software. Foveal continuity of the four outer hyperreflective bands, the ellipsoid zone of the inner segments (ISe), the ELM, the interdigitation zone (IZ), the RPE and the location of the initial ME were evaluated. Patients with good (<= 0.3 logMAR, n = 10) and poor VA (>= 1.0 logMAR, n = 3) were compared. RESULTS: Inner retinal layers up to ELM were thinner in the the poor VA group. In the good VA group the initial ME was significantly more often above the ISe and after resolution of ME the ISe tended to be intact more frequently. CONCLUSION: In patients with poor VA despite resolved ME the inner retinal layers up to the ELM were significantly thinner, which could be a sign of atrophy. Qualitative differences were seen at the photoreceptor level, which could be explained by ischemia or an involvement of the outer retina during initial ME that leads to permanent destruction of the ISe. PMID- 26939695 TI - Community point distribution of insecticide-treated bed nets and community health worker hang-up visits in rural Zambia: a decision-focused evaluation. AB - BACKGROUND: In 2013, the Zambian Ministry of Health through its National Malaria Control Programme distributed over two million insecticide-treated bed nets (ITNs) in four provinces using a door-to-door distribution strategy, and more than 6 million ITNs were allocated to be distributed in 2014. This study was commissioned to measure attendance rates at a community point distribution and to examine the impact of follow-up community health worker (CHW) hang-up visits on short and medium-term ITN retention and usage with a view of informing optimal ITN distribution strategy in Zambia. METHODS: Households received ITNs at community point distributions conducted in three rural communities in Rufunsa District, Zambia. Households were then randomly allocated into five groups to receive CHW visits to hang any unhung ITNs at different intervals: 1-3, 5-7, 10 12, 15-17 days, and no hang-up visit. Follow-up surveys were conducted among all households at 7-11 weeks after distribution and at 5-6 months after distribution to measure short- and medium-term household retention and usage of ITNs. RESULTS: Of the 560 pre-registered households, 540 (96.4 %) attended the community point distribution. Self-installation of ITNs by households increased over the first 10 days after the community point distribution. Retention levels remained high over time with 90.2 % of distributed ITNs still in the household at 7-11 weeks and 85.7 % at 5-6 months. Retention did not differ between households that received a CHW visit and those that did not. At 7-11 weeks, households had an average of 73.8 % of sleeping spaces covered compared to 80.3 % at 5-6 months. On average, 65.6 % of distributed ITNs were hanging at 7-11 weeks compared to 63.1 % at 5-6 months. While a CHW hang-up visit was associated with increased usage at 7-11 weeks, this difference was no longer apparent at 5-6 months. CONCLUSIONS: This evaluation revealed that (1) the community point distributions achieved high attendance rates followed by acceptable rates of short-term and medium-term ITN retention and usage, as compared to reported rates achieved by door-to-door distributions in the recent past, (2) CHW hang-up visits had a modest short-term impact on ITN usage but no medium-term effect, and (3) community point distributions can yield sizeable time savings compared to door-to-door distributions. PMID- 26939694 TI - High veno-arterial carbon dioxide gradient is not predictive of worst outcome after an elective cardiac surgery: a retrospective cohort study. AB - Alteration of tissue perfusion is a main contributor of organ dysfunction. In cardiac surgery, the importance of organ dysfunction is associated with worse outcome. Central venous-arterial difference in CO2 tension (DeltaCO2) has been proposed as a global marker of the adequacy of tissue perfusion in shock states. We hypothesized that DeltaCO2 could be increased in case of postoperative organ failure or worse outcome. In this monocentric retrospective cohort study, we retrieved, from our database, 220 consecutive patients admitted in intensive care after an elective cardiac surgery. Four time points were formed: ICU admission, and 6, 24 and 48 h after. A DeltaCO2 below 6 mmHg defined the normal range values. The SOFA score, intensive care unit and hospital length of stay, hospital and 6-month mortality rate were recorded. We compared patient with low DeltaCO2 (<6 mmHg) and high DeltaCO2 (>=6 mmHg). We included 55 (25 %) and 165 patients in low and high DeltaCO2 groups, respectively. The SOFA score, the hospital and 6 months mortality rate were higher in patients with low DeltaCO2. Surprisingly, we did not find results previously published in other surgical settings. In cardiac surgery, DeltaCO2 has a low predictive value of outcome. PMID- 26939696 TI - Increasing incidence of anogenital warts with an urban-rural divide among males in Manitoba, Canada, 1990-2011. AB - BACKGROUND: Anogenital warts (AGW) are caused by the most common sexually transmitted infection, human papillomavirus. The objective of this study was to examine AGW incidence from 1990 to 2011 by sex, age, income quintile, and residential area category (urban/rural). The study period included the initiation of school-based HPV vaccination for girls in the sixth grade, which began in 2008. The data presented in this paper may also be useful for establishing baseline rates of AGW incidence which may be used to evaluate the success of the school-based HPV immunization program. METHODS: Cases of anogenital warts were identified using Manitoba's administrative databases of Physician Claims and Hospital Discharge Abstracts. Annual age-standardized incidence in Manitoba from 1990 to 2011 was calculated. Incident AGW rates were compared by sex, age group, residential area category (urban/rural), and household income quintile using logistic regression. Joinpoint regression analyses were used to evaluate the time trends of AGW. RESULTS: Prior to 2000, AGW incidence was higher among females than males. However, from 2000 to 2011 the incidence was higher among males and increased steadily over time. AGW incidence tended to peak in younger age groups among females compared to males. Females and males living in urban areas had nearly twice the odds of AGW occurrence compared to those in rural areas. CONCLUSIONS: There is a need for education about AGW in male population. The upcoming initiation of HPV vaccination among boys may reduce the incidence and should be evaluated. PMID- 26939697 TI - Implications of prioritizing HIV cure: new momentum to overcome old challenges in HIV. AB - BACKGROUND: Curing HIV is a new strategic priority for several major AIDS organizations. In step with this new priority, HIV cure research and related programs are advancing in low, middle, and high-income country settings. This HIV cure momentum may influence existing HIV programs and research priorities. DISCUSSION: Despite the early stage of ongoing HIV cure efforts, these changes have directly influenced HIV research funding priorities, pilot programs, and HIV messaging. The building momentum to cure HIV infection may synergize with strategic priorities to better identify adults and infants with very early HIV infection. Although HIV cure represents a new goal, many existing programs and research techniques can be repurposed towards an HIV cure. HIV messages focused on engaging communities towards an HIV cure need to be careful to promote ARV adherence and retention within the HIV continuum of care. An increased emphasis within the AIDS field on finding an HIV cure has several important implications. Strengthening connections between HIV cure research and other areas of HIV research may help to catalyze research and facilitate implementation in the future. PMID- 26939698 TI - Improved Tumor-Specific Drug Accumulation by Polymer Therapeutics with pH Sensitive Drug Release Overcomes Chemotherapy Resistance. AB - The success of chemotherapy is limited by poor selectivity of active drugs combined with occurrence of tumor resistance. New star-like structured N-(2 hydroxypropyl) methacrylamide (HPMA) copolymer-based drug delivery systems containing doxorubicin attached via a pH-sensitive hydrazone bond were designed and investigated for their ability to overcome chemotherapy resistance. These conjugates combine two strategies to achieve a high drug concentration selectively at the tumor site: (I) high accumulation by passive tumor targeting based on enhanced permeability and retention effect and (II) pH-sensitive site specific drug release due to an acidic tumor microenvironment. Mice bearing doxorubicin-resistant xenograft tumors were treated with doxorubicin, PBS, poly HPMA (pHPMA) precursor or pHPMA-doxorubicin conjugate at different equivalent doses of 5 mg/kg bodyweight doxorubicin up to a 7-fold total dose using different treatment schedules. Intratumoral drug accumulation was analyzed by fluorescence imaging utilizing intrinsic fluorescence of doxorubicin. Free doxorubicin induced significant toxicity but hardly any tumor-inhibiting effects. Administering at least a 3-fold dose of pHPMA-doxorubicin conjugate was necessary to induce a transient response, whereas doses of about 5- to 6-fold induced strong regressions. Tumors completely disappeared in some cases. The onset of response was differential delayed depending on the tumor model, which could be ascribed to distinct characteristics of the microenvironment. Further fluorescence imaging based analyses regarding underlying mechanisms of the delayed response revealed a related switch to a more supporting intratumoral microenvironment for effective drug release. In conclusion, the current study demonstrates that the concept of tumor site-restricted high-dose chemotherapy is able to overcome therapy resistance. Mol Cancer Ther; 15(5); 998-1007. (c)2016 AACR. PMID- 26939699 TI - Recombinant Arabidopsis HSP70 Sustains Cell Survival and Metastatic Potential of Breast Cancer Cells. AB - The chaperone HSP70 protein is widely present in many different tumors and its expression correlates with an increased cell survival, low differentiation, and poor therapeutic outcome in human breast cancer. The intracellular protein has prevalently a cytoprotective function, while the extracellular HSP70 mediates immunologic responses. Evolutionarily, HSPs are well conserved from prokaryotes to eukaryotes, and human HSP70 shows a strong similarity to that of plant origin. In the current article, we have tested the potential effect of recombinant HSP70, from Arabidopsis thaliana, on cell survival and metastatic properties of breast cancer cells. Our data show that HSP70 sustains cell viability in MCF-7 and MDA MB-231 breast tumoral cells and increases Cyclin D1 and Survivin expression. The extracellular HSP70 triggers cell migration and the activation of MMPs particularly in MDA-MB-231 cells. Furthermore, under UV-induced stress condition, the low levels of phospho-AKT were increased by exogenous HSP70, together with the upregulation of Cyclin D1, particularly in the tumoral cell phenotype. On the other hand, UV increased TP53 expression, and the coincubation of HSP70 lowers the TP53 levels similar to the control. These findings correlate with the cytoprotective and antiapoptotic role of HSPs, as reported in different cellular contexts. This is the first study on mammary cells that highlights how the heterologous HSP70 from Arabidopsis thaliana sustains cell survival prevalently in breast cancer cell types, thus maintaining their metastatic potential. Therefore, targeting HSP70 would be of clinical importance since HSP70 blocking selectively targets tumor cells, in which it supports cell growth and survival. Mol Cancer Ther; 15(5); 1063-73. (c)2016 AACR. PMID- 26939700 TI - Elevated Translation Initiation Factor eIF4E Is an Attractive Therapeutic Target in Multiple Myeloma. AB - eIF4E is the key regulator of protein translation and critical for translation. The oncogenic potential of tumorigenesis, which is highly contingent on cap dependent eIF4E, also arises from the critical role in the nuclear export and cytosolic translation of oncogenic transcripts. Inhibition of Exportin1 (XPO1), which is the major nuclear export protein for eIF4E-bound oncoprotein mRNAs, results in decreased tumor cell growth in vitro and in vivo, suggesting that eIF4E is critical in multiple myeloma. Indeed, we found that eIF4E is overexpressed in myeloma cell lines and primary myeloma cells compared with normal plasma cells. Although stable overexpression of eIF4E in multiple myeloma cells significantly increases tumorigenesis, knockdown of eIF4E impairs multiple myeloma tumor progression in a human xenograft mouse model. Using a tet-on inducible eIF4E-knockdown system, eIF4E downregulation blocks multiple myeloma tumor growth in vivo, correlating with decreased eIF4E expression. Further overexpression and knockdown of eIF4E revealed that eIF4E regulates translation of mRNAs with highly complex 5'-untranslated regions, such as c-MYC and C/EBPbeta, and subsequently proliferation in multiple myeloma cells, but not in nonmalignant bone marrow stromal cells. Because many transcription factors that are critical for multiple myeloma proliferation exhibit a higher dependency on protein translation, eIF4E is an ideal and selective tool to target multiple myeloma cell growth. Mol Cancer Ther; 15(4); 711-9. (c)2016 AACR. PMID- 26939701 TI - Expression of GRP78, Master Regulator of the Unfolded Protein Response, Increases Chemoresistance in Pancreatic Ductal Adenocarcinoma. AB - The prognosis for patients with pancreatic ductal adenocarcinoma (PDAC) is dismal. Although gemcitabine (GEM) is the standard chemotherapeutic agent for adjuvant therapy of resectable PDAC, recurrent disease is observed in an alarming number of GEM-treated patients. Regardless of the adjuvant therapy, the vast majority of patients treated with chemotherapy after surgical resection show tumor recurrence. A better understanding of the molecular mechanisms that contribute to chemoresistance would aid the development of more effective treatment strategies. GRP78 is an endoplasmic reticulum (ER) chaperone protein that primarily resides in the lumen of the ER and is the master regulator of the unfolded protein response (UPR). Here, we report that expression of GRP78 is significantly higher in GEM-resistant PDAC compared to GEM-sensitive PDAC patient samples. We show that GRP78 induces chemoresistance in PDAC cells. Our results also show that knockdown of GRP78 reduces chemoresistance in PDAC. Finally, we found that IT-139, a ruthenium-based anticancer drug, can overcome GRP78-mediated chemoresistance. In vitro, IT-139 restores sensitivity to cytotoxic drugs in drug resistant PDAC cells and induces twice as much cell death in combination treatment compared with GEM alone. In vivo, a single weekly IT-139 treatment in combination with GEM caused a 35% increase in median survival and a 25% increase in overall survival compared to GEM alone. Collectively, our data show that GRP78 expression promotes chemoresistance in PDAC and therapeutic strategies, blocking the activity of GRP78 increases the efficacy of currently available therapies. Mol Cancer Ther; 15(5); 1043-52. (c)2016 AACR. PMID- 26939702 TI - BRD4 Regulates EZH2 Transcription through Upregulation of C-MYC and Represents a Novel Therapeutic Target in Bladder Cancer. AB - People who develop bladder cancer frequently succumb to the intractable disease. Current treatment strategies are limited presumably due to the underlying molecular complexity and insufficient comprehension. Therefore, exploration of new therapeutic targets in bladder cancer remains necessary. Here, we identify that bromodomain-4 protein (BRD4), an important epigenome reader of bromodomain and extraterminal domain (BET) family member, is a key upstream regulator of enhancer of zeste homologue 2 (EZH2), and represents a novel therapeutic target in bladder cancer. We found that BRD4 was significantly overexpressed in bladder cancer cells and tissues. Inhibition of BRD4 decreased bladder cancer cell proliferation concomitantly with the accumulation of cell apoptosis in vitro and suppressed tumor growth in vivo We further found that suppression of BRD4 decreased the mRNA and protein levels of EZH2, which was reversed by ectopic expression of C-MYC In particular, individual silencing of BRD4 using shRNA or the BET inhibitor JQ1 strikingly diminished the recruitment of C-MYC to EZH2 promoter in bladder cancer. Briefly, our research reveals that BRD4 positively regulates EZH2 transcription through upregulation of C-MYC, and is a novel promising target for pharmacologic treatment in transcriptional program intervention against this intractable disease. Mol Cancer Ther; 15(5); 1029-42. (c)2016 AACR. PMID- 26939703 TI - Targeting Androgen Receptor (AR)->IL12A Signal Enhances Efficacy of Sorafenib plus NK Cells Immunotherapy to Better Suppress HCC Progression. AB - Gender disparity has long been considered as a key to fully understand hepatocellular carcinoma (HCC) development. At the same time, immunotherapy related to IL12 still need more investigation before being applied in clinical settings. The aim of this study is to investigate the influence of the androgen receptor (AR) on natural killer (NK) cell-related innate immune surveillance in liver cancer, and provide a novel therapeutic approach to suppress HCC via altering IL12A. By using in vitro cell cytotoxicity test and in vivo liver orthotopic xenograft mouse model, we identified the role of AR in modulating NK cell cytotoxicity. Luciferase report assay and chromatin immunoprecipitation assay were applied for mechanism dissection. IHC was performed for sample staining. Our results showed AR could suppress IL12A expression at the transcriptional level via direct binding to the IL12A promoter region that resulted in repressing efficacy of NK cell cytotoxicity against HCC, and sorafenib treatment could enhance IL12A signals via suppressing AR signals. These results not only help to explain the AR roles in the gender disparity of HCC but also provide a potential new therapy to better suppress HCC via combining sorafenib with NK cell-related immunotherapy. Mol Cancer Ther; 15(4); 731-42. (c)2016 AACR. PMID- 26939704 TI - Entrectinib, a Pan-TRK, ROS1, and ALK Inhibitor with Activity in Multiple Molecularly Defined Cancer Indications. AB - Activated ALK and ROS1 tyrosine kinases, resulting from chromosomal rearrangements, occur in a subset of non-small cell lung cancers (NSCLC) as well as other tumor types and their oncogenic relevance as actionable targets has been demonstrated by the efficacy of selective kinase inhibitors such as crizotinib, ceritinib, and alectinib. More recently, low-frequency rearrangements of TRK kinases have been described in NSCLC, colorectal carcinoma, glioblastoma, and Spitzoid melanoma. Entrectinib, whose discovery and preclinical characterization are reported herein, is a novel, potent inhibitor of ALK, ROS1, and, importantly, of TRK family kinases, which shows promise for therapy of tumors bearing oncogenic forms of these proteins. Proliferation profiling against over 200 human tumor cell lines revealed that entrectinib is exquisitely potent in vitro against lines that are dependent on the drug's pharmacologic targets. Oral administration of entrectinib to tumor-bearing mice induced regression in relevant human xenograft tumors, including the TRKA-dependent colorectal carcinoma KM12, ROS1 driven tumors, and several ALK-dependent models of different tissue origins, including a model of brain-localized lung cancer metastasis. Entrectinib is currently showing great promise in phase I/II clinical trials, including the first documented objective responses to a TRK inhibitor in colorectal carcinoma and in NSCLC. The drug is, thus, potentially suited to the therapy of several molecularly defined cancer settings, especially that of TRK-dependent tumors, for which no approved drugs are currently available. Mol Cancer Ther; 15(4); 628-39. (c)2016 AACR. PMID- 26939706 TI - Expression Profile of BCL-2, BCL-XL, and MCL-1 Predicts Pharmacological Response to the BCL-2 Selective Antagonist Venetoclax in Multiple Myeloma Models. AB - BCL-2 family proteins dictate survival of human multiple myeloma cells, making them attractive drug targets. Indeed, multiple myeloma cells are sensitive to antagonists that selectively target prosurvival proteins such as BCL-2/BCL-XL (ABT-737 and ABT-263/navitoclax) or BCL-2 only (ABT-199/GDC-0199/venetoclax). Resistance to these three drugs is mediated by expression of MCL-1. However, given the selectivity profile of venetoclax it is unclear whether coexpression of BCL-XL also affects antitumor responses to venetoclax in multiple myeloma. In multiple myeloma cell lines (n = 21), BCL-2 is expressed but sensitivity to venetoclax correlated with high BCL-2 and low BCL-XL or MCL-1 expression. Multiple myeloma cells that coexpress BCL-2 and BCL-XL were resistant to venetoclax but sensitive to a BCL-XL-selective inhibitor (A-1155463). Multiple myeloma xenograft models that coexpressed BCL-XL or MCL-1 with BCL-2 were also resistant to venetoclax. Resistance to venetoclax was mitigated by cotreatment with bortezomib in xenografts that coexpressed BCL-2 and MCL-1 due to upregulation of NOXA, a proapoptotic factor that neutralizes MCL-1. In contrast, xenografts that expressed BCL-XL, MCL-1, and BCL-2 were more sensitive to the combination of bortezomib with a BCL-XL selective inhibitor (A-1331852) but not with venetoclax cotreatment when compared with monotherapies. IHC of multiple myeloma patient bone marrow biopsies and aspirates (n = 95) revealed high levels of BCL-2 and BCL-XL in 62% and 43% of evaluable samples, respectively, while 34% were characterized as BCL-2(High)/BCL-XL (Low) In addition to MCL-1, our data suggest that BCL-XL may also be a potential resistance factor to venetoclax monotherapy and in combination with bortezomib. Mol Cancer Ther; 15(5); 1132-44. (c)2016 AACR. PMID- 26939705 TI - Protein Kinase Inhibitor H89 Enhances the Activity of Pseudomonas Exotoxin A Based Immunotoxins. AB - HA22 (Moxetumomab pasudotox) is a recombinant immunotoxin (RIT), composed of an anti-CD22 Fv fused to a truncated portion of Pseudomonas exotoxin A. HA22 is in clinical trials to treat patients with hairy cell leukemia and acute lymphoblastic leukemia (ALL). LMB-11 is an improved variant of HA22 with reduced immunogenicity, has a longer half-life in the blood and high activity in vitro and in a Burkitt lymphoma model in vivo Searching for RIT enhancing combination therapies, we found the protein kinase A inhibitor H89 to enhance LMB-11 and HA22 activity 5- to 10-fold on ALL cell lines and on patient-derived ALL samples. In addition, H89 increased the activity of mesothelin-targeting RITs SS1P (38-fold) and RG7787 (7-fold) against the cervical cancer cell line KB31. Unexpectedly we found that the enhancement by H89 was not because of inhibition of protein kinase A; it was partially recapitulated by inhibition of S6K1, which led to inactivation of its downstream targets rpS6 and GSK3beta, resulting in a fall in MCL1 levels. H89 increased the rate of ADP-ribosylation of eukaryotic elongation factor 2, enhancing the arrest of protein synthesis and the reduction of MCL1 in synergy with the RIT. In summary, H89 increased RIT activity by enhancing the two key events: ADP-ribosylation of eEF2 and reduction of MCL1 levels. Significant enhancement was seen with both CD22- and mesothelin-targeting RITs, indicating that H89 might be a potent addition to RIT treatment of CD22-positive ALL and mesothelin-expressing solid tumors. Mol Cancer Ther; 15(5); 1053-62. (c)2016 AACR. PMID- 26939707 TI - Novel Anti-CRR9/CLPTM1L Antibodies with Antitumorigenic Activity Inhibit Cell Surface Accumulation, PI3K Interaction, and Survival Signaling. AB - We and others have recently shown cisplatin resistance-related protein 9 (CRR9)/Cleft Lip and Palate Transmembrane 1-Like (CLPTM1L) to affect survival and proliferation in lung and pancreatic tumor cells. Our research has indicated that CLPTM1L affects multiple survival signaling pathways in tumor cells under oncogenic, genotoxic, and microenvironmental stress. We have confirmed the association of CLPTM1L with pancreatic cancer by demonstrating overexpression of CLPTM1L in pancreatic tumors and poor survival in patients with high tumor expression of CLPTM1L. Predicting a transmembrane structure, we determined that CLPTM1L could be targeted at the plasma membrane. Herein, we describe the development of mAbs targeting CLPTM1L. Lead antibodies inhibited surface accumulation of CLPTM1L, Akt phosphorylation, anchorage-independent growth, and chemotherapeutic resistance in lung and pancreatic tumor cells. Gemcitabine promoted a physical interaction between CLPTM1L and p110alpha in pancreatic tumor cells, which was inhibited by anti-CLPTM1L. In vivo treatment with anti-CLPTM1L robustly inhibited the growth of both lung and pancreatic adenocarcinoma xenografts. The efficacy of anti-CLPTM1L correlated with specific epitopes representing important targets in human cancers, particularly those driven by KRas, for which effective targeted therapies have been elusive. This study is the first to report cell-surface exposure of the tumor survival protein CLPTM1L and inhibition of the function of surface CLPTM1L with novel, systematically developed inhibitory mAbs establishing proof of concept of clinically practical agents inhibiting this compelling new tumor survival target in cancer. Mol Cancer Ther; 15(5); 985-97. (c)2016 AACR. PMID- 26939709 TI - An alternative mini buffy coat preparation method for adult patients with extracorporeal photopheresis contraindications. AB - BACKGROUND: Extracorporeal photopheresis (ECP) is an important cell-based therapy for various diseases but is limited to patients eligible for apheresis. We developed an alternative mini buffy coat (BC) preparation method using the Spectra Optia(r) apheresis system and compared its efficacy of white blood cell (WBC) recovery with the standard mini BC preparation method already established for pediatric patients. METHODS: Whole blood (450 +/- 45 mL) samples were collected from 30 randomly selected healthy volunteer blood donors and divided into two groups. In the first group, WBCs were separated with a fully automated separator device (Compomat G4(r) ). In the second group, BCs were separated with the bone marrow processing program of the Spectra Optia apheresis system. RESULTS: There were no significant differences in total leukocyte counts per product between the two groups. In contrast, lymphocyte counts per product were significantly higher (P < 0.001) in BCs separated from apheresis. CONCLUSION: Our novel technique resulted in similar WBC yields but higher lymphocyte yields than the standard mini BC preparation method. This method can serve as an alternative to WBC collection in conventional ECP for adult patients with apheresis contraindications. J. Clin. Apheresis 32:12-15, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 26939708 TI - Circulating miRNA signatures of early pregnancy in cattle. AB - BACKGROUND: Low fertility remains a leading cause of poor productivity in dairy cattle. In this context, there is significant interest in developing novel tools for accurate early diagnosis of pregnancy. MicroRNAs (miRNAs) are short RNA molecules which are critically involved in regulating gene expression during both health and disease. MiRNAs have been shown to regulate ovarian function, uterine receptivity, embryonic development and placental function. Circulating miRNAs can provide useful biomarkers of tissue function and disease; importantly, differential miRNA profiles have been linked to pregnancy and preeclampsia in humans. This study sought to establish the potential of circulating miRNAs as biomarkers of early pregnancy in cattle. RESULTS: We applied Illumina small-RNA sequencing to profile miRNAs in plasma samples collected from eight non-pregnant heifers on Days 0, 8 and 16 of the oestrous cycle and 11 heifers on Days 16 and 24 of pregnancy. We sequenced a total of 46 samples and generated 9.2 million miRNA reads per sample. There were no differences in miRNA read abundance between any of the pregnant and non-pregnant time-points (FDR > 0.1). As a complementary approach, we analysed sample pools (3-4 samples/pool) corresponding to Days 0, 8 and 16 of the oestrous cycle and Day 24 of pregnancy (n = 3 pools/group) using Qiagen PCR arrays. A total of 16 miRNAs were differentially expressed (FDR < 0.1) in plasma between pregnant and non-pregnant animals. RT-qPCR validation using the same plasma samples confirmed that miR-26a was differentially upregulated on Day 16 pregnant relative to non-pregnant heifers (1.7-fold; P = 0.043), whereas miR 1249 tended to be upregulated in Day 16 pregnant heifers (1.6-fold; P = 0.081). Further validation in an independent group of heifers confirmed an increase in plasma miR-26a levels during early pregnancy, which was significant only on Day 24 (2.0-fold; P = 0.027). CONCLUSIONS: Through genome-wide analyses we have successfully profiled plasma miRNA populations associated with early pregnancy in cattle. We have identified miR-26a as a potential circulating biomarker of early pregnancy. PMID- 26939710 TI - Differentiation between early rheumatoid and early psoriatic arthritis by the ultrasonographic study of the synovio-entheseal complex of the small joints of the hands. AB - OBJECTIVES: To determine whether ultrasonographic findings of the synovio entheseal complex of the hand small joints could be used to differentiate between early rheumatoid and early psoriatic arthritis. METHODS: Thirty-four early rheumatoid and 26 early psoriatic arthritis patients with a prevalent involvement of the hands were examined with ultrasound (US). All exams were performed at the first visit by evaluating synovitis, peritendon extensor digitorum tendon oedema, enthesitis of the central slip of extensor tendon, flexor tenosynovitis and soft tissue oedema. In the same patient, the two most clinically involved joints, if possible of the same digit, were evaluated. RESULTS: Sixty-eight clinically involved joints were evaluated in 34 early rheumatoid arthritis patients and 52 joints in 26 early psoriatic arthritis patients.Synovitis was significantly more frequently detected in early rheumatoid arthritis compared to early psoriatic arthritis patients (p=0.0001), in 91.1% joints of the former and in 59.6% joints of the latter. At metacarpohalangeal joint, the presence of peritendon extensor digitorum tendon inflammation was observed in 2.5% of the joints in the early rheumatoid arthritis group and in 54.1% of the joints in the early psoriatic arthritis group (p=0.0001). At PIP joints, central slip enthesitis was exclusively observed in EPsA (p=0.0045). When considering the most clinically involved finger per patient, soft tissue oedema was detected almost exclusively in psoriatic arthritis (p=0.0002). CONCLUSIONS: The US involvement of synovio entheseal complex and US extrasynovial features may be helpful in the differential diagnosis between early rheumatoid and early psoriatic arthritis. PMID- 26939712 TI - Cochlear linear reconstruction with multidetector computed tomography. PMID- 26939713 TI - Effect of Bovine Sperm-Bound Antisperm Antibodies on Oviductal Binding Index. AB - This study was designed to test the hypothesis that sperm-bound IgG and IgA decrease binding of bull spermatozoa to oviductal epithelial cells in vitro. Three ejaculates were cryopreserved from each of four antisperm antibody (ASA) negative satisfactory breeder bulls. Bulls were then immunized with autologous spermatozoa, and three ASA-positive ejaculates were cryopreserved from each bull post-immunization. First, microscopy methods were compared to select the most appropriate assay for evaluation of oviductal binding index (BI). The BI did not differ when the evaluation was performed under fluorescence microscopy (131.1 sperm/mm(2); 62.5-251.1 sperm/mm(2)), phase-contrast microscopy (160.5 sperm/mm(2); 56.8-397.4 mm(2)) or their combination (116.4 sperm/mm(2); 56.8 249.6 sperm/mm(2)) (Median; IQR). The combination of microscopy methods was selected as it allowed better visualization of cells. Then, BI was compared between ASA-negative and ASA-positive ejaculates, and the association between BI and ASA binding was evaluated. The BI was less in ASA-positive (114.9; 0 to 201.8 sperm/0.1 mm(2)) than ASA-negative samples (218.9; 24.7 to 276.8 sperm/0.1 mm(2)) (P = 0.0002). This reduction in BI was significant in three of the four bulls. Regression analysis identified a negative association between BI and the percentage of IgG-bound (p = 0.013) but not IgA-bound spermatozoa. In conclusion, sperm-bound IgG decreased the ability of bovine spermatozoa to bind to oviductal epithelial cells in vitro. PMID- 26939711 TI - Secular trends in antihyperglycaemic medication prescriptions in older adults with diabetes and chronic kidney disease: 2004-2013. AB - AIM: To examine how antihyperglycaemic medications were prescribed to older adults with diabetes and chronic kidney disease over the last decade. METHODS: We conducted a population-based study of 144 252 older adults with diabetes and chronic kidney disease (estimated glomerular filtration rate <60 ml/min/1.73 m(2) or receiving chronic dialysis) in Ontario, Canada. In each study quarter (3-month intervals from 1 April 2004 until 31 March 2013) we studied the proportion of treated and newly treated patients prescribed insulin, sulphonylureas, alpha glucosidase inhibitors, metformin, thiazolidinediones, meglitinides and dipeptidyl peptidase-4 (DPP-4) inhibitors. We further examined prescription trends by stage of chronic kidney disease. RESULTS: The mean age of patients increased slightly (from 76 to 78 years) over the study period and the percentage with comorbidities declined. Metformin was the predominant therapy prescribed (prescribed to a mean of 56.1% of treated patients). Glyburide (glibenclamide) and thiazolidinedione prescriptions decreased (glyburide prescriptions declined from 45.5 to 9.5%, rosiglitazone from 3.6 to 0.2% and pioglitazone from 1.9 to 1.7%), while gliclazide and DPP-4 inhibitor prescriptions increased (gliclazide prescriptions increased from 0.6 to 26.4%, sitagliptin from 0 to 15.3% and saxagliptin from 0 to 2.0%). Up to 48.6% of patients with stage 3a-5 chronic kidney disease or receiving chronic dialysis were prescribed glyburide, and up to 27.6% of patients with stage 4-5 disease or receiving chronic dialysis were prescribed metformin. CONCLUSIONS: In patients with chronic kidney disease, there were trends towards safer antihyperglycaemic medication prescribing. A considerable number of patients, however, continue to receive medications that should be avoided. PMID- 26939714 TI - Evaluation of damage induced by Kwkt and Pikt zymocins against Brettanomyces/Dekkera spoilage yeast, as compared to sulphur dioxide. AB - AIMS: Over the last few decades, the use of zymocins as biological tools to counteract contamination by spoilage yeast in beverages and food has been widely studied. This study examined the damage induced by the Kwkt and Pikt, two zymocins produced by Kluyeromyces wickerhamii and Wickerhanomyces anomalus, respectively, with antimicrobial activity against Brettanomyces/Dekkera wine spoilage yeast. METHODS AND RESULTS: The physiological and biochemical characterization of both of these proteins revealed that only Pikt showed a strict relationship between beta-glucosidase activity and killer activity. The minimum inhibitory concentrations and minimum fungicidal concentrations of Kwkt and Pikt showed inhibitory activities against Brettanomyces/Dekkera yeast. Cytofluorimetric evaluation of cell death was based on both cell membrane permeability and cell metabolism, using fluorescence techniques under increasing zymocin levels over different incubation times. The antimicrobial actions of Kwkt and Pikt were also compared with the mode of action of sulphur dioxide. In this last case, the induction of the viable but noncultivable (VBNC) state was confirmed, with the consequent recovery of Brettanomyces yeast after medium replacement. In contrast, Kwkt and Pikt caused irreversible death of these yeast, without recovery of sensitive cells. CONCLUSIONS: Kwkt and Pikt could be proposed as fungistatic or fungicide biocontrol agents in winemaking to control the colonization and development of Brettanomyces/Dekkera yeasts. SIGNIFICANCE AND IMPACT OF THE STUDY: These data support the potential use of zymocins to reduce wine contamination as an alternative to sulphur dioxide that act on sensitive cells. Differently from sulphur dioxide, that could induce a reversible VBNC state, Kwkt and Pikt determine the irreversible damage on sensitive yeasts, ensuring the complete control of spoilage Brettanomyces yeast. PMID- 26939715 TI - Authors' response, letter concerning DOI: 10.1111/aas.12667. PMID- 26939716 TI - RANDOMIZED CONTROLLED TRIAL OF PARENT-INFANT PSYCHOTHERAPY FOR PARENTS WITH MENTAL HEALTH PROBLEMS AND YOUNG INFANTS. AB - There is a dearth of good-quality research investigating the outcomes of psychoanalytic parent-infant psychotherapy (PIP). This randomized controlled trial investigated the outcomes of PIP for parents with mental health problems who also were experiencing high levels of social adversity and their young infants (<12 months). Dyads were clinically referred and randomly allocated to PIP or a control condition of standard secondary and specialist primary care treatment (n = 38 in each group). Outcomes were assessed at baseline and at 6 month and 12-month follow-ups. The primary outcome was infant development. Secondary outcomes included parent-infant interaction, maternal psychopathology, maternal representations, maternal reflective functioning, and infant attachment. There were no differential effects over time between the groups on measures of infant development, parent-infant interaction, or maternal reflective functioning. Infant attachment classifications, measured only at the 12-month follow-up, did not differ between the groups. There were favorable outcomes over time for the PIP-treated dyads relative to the control group on several measures of maternal mental health, parenting stress, and parental representations of the baby and their relationship. The findings indicate potential benefits of parent infant psychotherapy for improving mothers' psychological well-being and their representations of their baby and the parent-infant relationship. PMID- 26939717 TI - Defensin gamma-thionin from Capsicum chinense has immunomodulatory effects on bovine mammary epithelial cells during Staphylococcus aureus internalization. AB - beta-Defensins are members of the antimicrobial peptide superfamily that are produced in various species from different kingdoms, including plants. Plant defensins exhibit primarily antifungal activities, unlike those from animals that exhibit a broad-spectrum antimicrobial action. Recently, immunomodulatory roles of mammal beta-defensins have been observed to regulate inflammation and activate the immune system. Similar roles for plant beta-defensins remain unknown. In addition, the regulation of the immune system by mammalian beta-defensins has been studied in humans and mice models, particularly in immune cells, but few studies have investigated these peptides in epithelial cells, which are in intimate contact with pathogens. The aim of this work was to evaluate the effect of the chemically synthesized beta-defensin gamma-thionin from Capsicum chinense on the innate immune response of bovine mammary epithelial cells (bMECs) infected with Staphylococcus aureus, the primary pathogen responsible for bovine mastitis, which is capable of living within bMECs. Our results indicate that gamma-thionin at 0.1 MUg/ml was able to reduce the internalization of S. aureus into bMECs (~50%), and it also modulates the innate immune response of these cells by inducing the mRNA expression (~5-fold) and membrane abundance (~3-fold) of Toll like receptor 2 (TLR2), as well as by inducing genes coding for the pro inflammatory cytokines TNF-alpha and IL-1beta (~14 and 8-fold, respectively) before and after the bacterial infection. gamma-Thionin also induces the expression of the mRNA of anti-inflammatory cytokine IL-10 (~12-fold). Interestingly, the reduction in bacterial internalization coincides with the production of other antimicrobial products by bMECs, such as NO before infection, and the secretion into the medium of the endogenous antimicrobial peptide DEFB1 after infection. The results from this work support the potential use of beta defensins from plants as immunomodulators of the mammalian innate immune response. PMID- 26939718 TI - Nuclear expression of Y-box binding protein-1 is associated with poor prognosis in patients with pancreatic cancer and its knockdown inhibits tumor growth and metastasis in mice tumor models. AB - The objective of this study was to examine the implication of Y-box-binding protein-1 (YB-1) for the aggressive phenotypes, prognosis and therapeutic target in pancreatic ductal adenocarcinoma (PDAC). YB-1 expression in PDAC, pancreatic intraepithelial neoplasia (PanIN) and normal pancreas specimens was evaluated by immunohistochemistry, and its correlation with clinicopathological features was assessed in patients with PDAC. The effects of YB-1 on proliferation, invasion and expressions of cell cycle-related proteins and matrix metalloproteinases (MMPs) were analyzed by WST-8, cell cycle and Matrigel invasion assays, Western blotting and quantitative RT-PCR in PDAC cells transfected with YB-1-siRNAs. To verify the significance of YB-1 for tumor progression in vivo, the growth and metastasis were monitored after intrasplenic implantation of ex vivo YB-1 siRNA transfected PDAC cells, and YB-1-targeting antisense oligonucleotides were intravenously administered in nude mice harboring subcutaneous tumor. The intensity of YB-1 expression and positivity of nuclear YB-1 expression were higher in PDAC than PanIN and normal pancreatic tissues. Nuclear YB-1 expression was significantly associated with dedifferentiation, lymphatic/venous invasion and unfavorable prognosis. YB-1 knockdown inhibited cell proliferation via cell cycle arrest by S-phase kinase-associated protein 2 downregulation and consequent p27 accumulation, and decreased the invasion due to downregulated membranous-type 2 MMP expression in PDAC cells. Tumor growth and liver metastasis formation were significantly suppressed in nude mice after implantation of YB-1-silenced PDAC cells, and the YB-1 targeting antisense oligonucleotide significantly inhibited the growth of subcutaneous tumors. In conclusion, YB-1 may be involved in aggressive natures of PDAC and a promising therapeutic target. PMID- 26939720 TI - Correction: The thermodynamics of endosomal escape and DNA release from lipoplexes. AB - Correction for 'The thermodynamics of endosomal escape and DNA release from lipoplexes' by Yotam Y. Avital et al., Phys. Chem. Chem. Phys., 2016, 18, 2591 2596. PMID- 26939719 TI - Alteration of syncytiotrophoblast mitochondria function and endothelial nitric oxide synthase expression in the placenta of rural residents. AB - The impact of environmental organophosphate (OP) pesticide exposure on respiratory complexes, enzymatic antioxidant defense activities, and oxidative damage markers in the syncytiotrophoblast and cytotrophoblast mitochondria was evaluated. Placental progesterone (PG) levels and endothelial nitric oxide synthase (eNOS) expression were studied. Samples from women non-exposed (control group-CG) and women living in a rural area (rural group-RG) were collected during pesticide spraying season (RG-SS) and non-spraying season (RG-NSS). In RG-SS, the exposure biomarker placental carboxylesterase decreased and syncytiotrophoblast cytochrome c oxidase activity increased, while 4-hydroxynonenal levels decreased. PG levels decreased in RG-SS and in the RG. Nitric oxide synthase expression decreased in RG, RG-SS and RG-NSS. No significant changes in mitochondrial antioxidant enzyme activities were found. These results suggest that the alteration of syncytiotrophoblast mitochondrial complex IV activity and steroidogenic function may be associated to pesticide exposure. Reduction in placental PG and eNOS expression may account for low newborn weight in RG. PMID- 26939721 TI - Medication adherence may be more important than other behaviours for optimizing glycaemic control among low-income adults. AB - WHAT IS KNOWN: Patients with type 2 diabetes mellitus (T2DM) are required to perform multiple self-care behaviours to achieve and maintain optimal glycaemic control (HbA1c), which prevents complications and premature mortality. Patients with T2DM and low socioeconomic status (SES) are more likely to have suboptimal HbA1c, often due to being less adherent to recommended self-care activities than their higher-SES counterparts. OBJECTIVE: Although studies support performing certain diabetes self-care behaviours for optimizing glycaemic control, there is limited research on the relative importance of each behaviour for this purpose. Identifying what behaviours are most important for HbA1c among low-SES patients with T2DM would be particularly useful for informing policy and intervention efforts for this high-risk group. METHODS: In a cross-sectional study of 314 adults with T2DM and low SES, we used the Summary of Diabetes Self-Care Activities to assess self-care behaviours and multivariate models to test which behaviours were associated with lower HbA1c. RESULTS AND DISCUSSION: Only medication adherence was significantly associated with lower HbA1c after adjusting for the other self-care behaviours (beta = -0.14, P = 0.028) and further adjusting for demographic and diabetes characteristics (beta = -0.16, P = 0.024). WHAT IS NEW: Medication adherence may be the most important self-care behaviour for glycaemic control among adults with T2DM and low SES. CONCLUSION: Focused efforts to improve medication adherence among low-SES patient populations may improve glycaemic control. PMID- 26939722 TI - New insights about excisable pathogenicity islands in Salmonella and their contribution to virulence. AB - Pathogenicity islands (PAIs) are regions of the chromosome of pathogenic bacteria that harbor virulence genes, which were probably acquired by lateral gene transfer. Several PAIs can excise from the bacterial chromosome by site-specific recombination and in this review have been denominated "excisable PAIs". Here, the characteristic of some of the excisable PAIs from Salmonella enterica and the possible role and impact of the excision process on bacterial virulence is discussed. Understanding the role of PAI excision could provide important insights relative to the emergence, evolution and virulence of pathogenic enterobacteria. PMID- 26939723 TI - Cold-bonding in sub-10 nm indium tin oxide nanorods. AB - Cold-bonding in a typical metal oxide material nanostructure, indium tin oxide nanorods (ITONs), was observed and studied by combining precise in situ nano manipulation, transmission electron microscopy (TEM) observation and on-line electrical properties measurements. Our studies revealed an oriented attachment process caused by enhanced atom mobility or diffusion and rearrangement at the contact, which worked efficiently in reconnecting the ITONs. Electrical measurements exhibited low contact resistance between the re-connectable ITON segments. Our observations indicate that small-sized nanostructures could be cold bonded easily following a similar mechanism with their electrical properties retained. PMID- 26939724 TI - Delay of gratification: a comparison study of children with Down syndrome, moderate intellectual disability and typical development. AB - BACKGROUND: Self-regulation has been found to be an important contributor to a range of outcomes, with delay of gratification (a self-regulatory skill) predicting better academic, social and personal functioning. There is some evidence that individuals with Down syndrome have difficulty with delay of gratification. We investigated the question of whether this difficulty is common to intellectual disability irrespective of aetiology, or whether it presents a particular problem for those with Down syndrome. The latter was considered a possibility because of language difficulties in this group. METHOD: Three groups of children with a mean MA between 36 and 60 months participated in the study: children with Down syndrome (n = 32), children with a moderate intellectual disability from a cause other than Down syndrome (n = 26) and typically developing children (n = 50). Children completed a series of measures of language and cognitive functioning and participated in a delay of gratification task. RESULTS: The group of children with Down syndrome delayed for a significantly shorter time than either of the other two groups that did not differ from each other. Receptive language was associated with delay time for the children with Down syndrome but not for the typically developing group, nor for the group with moderate intellectual disability. CONCLUSIONS: Children with Down syndrome appear to have a particular difficulty with delay of gratification. Language abilities would seem to be implicated in this difficulty, although further examination of this hypothesis is required. PMID- 26939725 TI - Two-step C-H, C-P bond activation at an alpha-diimine iron dinitrogen complex. AB - Reduction of 6-coordinate ((Ph2PPr)DI)FeBr2 under N2 results in formation of the terminal dinitrogen complex, ((Ph2PPr)DI)FeN2. Heating this product to 75 degrees C allows for C-H and C-P activation of the chelate to generate the cisoid and transoid isomers of [(MU-PrPPh-kappa(5)-P,N,N,Cgamma,P (Ph2PPr)DI(PrPPh))Fe]2. Mechanistic possibilities for this transformation are discussed. PMID- 26939726 TI - Sustained housing-type social buffering following social housing in male rats. AB - In social animals, recovery from the adverse effects of distressing stimuli is promoted by subsequent cohousing with a conspecific animal(s). This phenomenon has been termed housing-type social buffering. We previously found that social housing induced housing-type social buffering in fear-conditioned male rats. This buffering took the form of attenuated conditioned hyperthermia in response to an auditory conditioned stimulus (CS). Here, we assessed whether this social buffering is sustained even if the subject is housed alone after a period of social housing. When fear-conditioned subjects were housed alone during a 48-h period between conditioning and re-exposure to the auditory CS, they exhibited conditioned hyperthermia in response to the CS. However, conditioned hyperthermia was not observed when the 12-h period of social housing began 24 and 36h after conditioning during the 48-h period. This was not the case when the 12-h period of social housing began 0 and 12h after the conditioning. These results suggest that housing-type social buffering is sustained for 12h after the 12-h period of social housing. We next considered whether increasing the duration of social housing would extend the period of social buffering. We observed social buffering of conditioned hyperthermia 24 and 48, but not 96h after a 24-h period of social housing. These results suggest that social buffering was extended when the duration of social housing was increased. Taken together, our findings indicate that housing-type social buffering is sustained after a period of social housing. PMID- 26939728 TI - Effect of acute low body temperature on predatory behavior and prey-capture efficiency in a plethodontid salamander. AB - The low-temperature limit for feeding in some salamander species (Desmognathus, Plethodontidae) has been inferred from field studies of seasonal variation in salamander activity and gut contents, which could not determine whether feeding is more dependent on environmental conditions influencing salamander foraging behavior or prey availability and movement. We performed two controlled laboratory experiments to examine the effect of short-term (acute) low body temperature on predatory behavior and prey-capture efficiency in a semiaquatic plethodontid salamander (Desmognathus conanti). In the first experiment, we quantified variation in the feeding responses of cold salamanders (at 1, 3, 5 and 7 degrees C) to a video recording of a walking, warm (15 degrees C) cricket to determine the lower thermal limit for predatory behavior, independent of any temperature effect on movement of prey. Experimental-group salamanders exhibited vigorous feeding responses at 5 and 7 degrees C, large variation in feeding responses both among and within individuals (over time) at 3 degrees C, and little to no feeding response at 1 degrees C. Feeding responses at both 1 and 3 degrees C were significantly less than at each higher temperature, whereas responses of control-group individuals at 15 degrees C did not vary over time. In the second experiment, we quantified feeding by cold salamanders (at 3, 5, 7 and 11 degrees C) on live, warm crickets to examine thermal effects on prey-capture ability. The mean feeding response to live crickets was significantly less at 3 degrees C than at higher temperatures; however, 50% of salamanders captured and ingested prey with high efficiency at this temperature. We conclude that many individuals stalk and capture prey at very low temperatures (down to 3 degrees C). Our results support a growing body of data that indicate many plethodontid salamanders feed at temperatures only a few degrees above freezing. PMID- 26939727 TI - Depressive- and anxiety-like behaviors and stress-related neuronal activation in vasopressin-deficient female Brattleboro rats. AB - Vasopressin can contribute to the development of stress-related psychiatric disorders, anxiety and depression. Although these disturbances are more common in females, most of the preclinical studies have been done in males. We compared female vasopressin-deficient and +/+ Brattleboro rats. To test anxiety we used open-field, elevated plus maze (EPM), marble burying, novelty-induced hypophagia, and social avoidance tests. Object and social recognition were used to assess short term memory. To test depression-like behavior consumption of sweet solutions (sucrose and saccharin) and forced swim test (FST) were studied. The stress-hormone levels were followed by radioimmunoassay and underlying brain areas were studied by c-Fos immunohistochemistry. In the EPM the vasopressin deficient females showed more entries towards the open arms and less stretch attend posture, drank more sweet fluids and struggled more (in FST) than the +/+ rats. The EPM-induced stress-hormone elevations were smaller in vasopressin deficient females without basal as well as open-field and FST-induced genotype differences. On most studied brain areas the resting c-Fos levels were higher in vasopressin-deficient rats, but the FST-induced elevations were smaller than in the +/+ ones. Similarly to males, female vasopressin-deficient animals presented diminished depression- and partly anxiety-like behavior with significant contribution of stress-hormones. In contrast to males, vasopressin deficiency in females had no effect on object and social memory, and stressor-induced c-Fos elevations were diminished only in females. Thus, vasopressin has similar effect on anxiety- and depression-like behavior in males and females, while only in females behavioral alterations are associated with reduced neuronal reactivity in several brain areas. PMID- 26939729 TI - Philippine epidemic calls for urgent action on HIV. PMID- 26939730 TI - Overcoming resistance to HIV testing in sub-Saharan Africa. PMID- 26939731 TI - The tuberculosis emergency in eastern Europe. PMID- 26939732 TI - First-line HIV therapy shall not fail. PMID- 26939733 TI - Let's treat everyone with HIV now: what happens next? PMID- 26939734 TI - A hybrid mobile approach for population-wide HIV testing in rural east Africa: an observational study. AB - BACKGROUND: Despite large investments in HIV testing, only an estimated 45% of HIV-infected people in sub-Saharan Africa know their HIV status. Optimum methods for maximising population-level testing remain unknown. We sought to show the effectiveness of a hybrid mobile HIV testing approach at achieving population wide testing coverage. METHODS: We enumerated adult (>=15 years) residents of 32 communities in Uganda (n=20) and Kenya (n=12) using a door-to-door census. Stable residence was defined as living in the community for at least 6 months in the past year. In each community, we did 2 week multiple-disease community health campaigns (CHCs) that included HIV testing, counselling, and referral to care if HIV infected; people who did not participate in the CHCs were approached for home based testing (HBT) for 1-2 months within the 1-6 months after the CHC. We measured population HIV testing coverage and predictors of testing via HBT rather than CHC and non-testing. FINDINGS: From April 2, 2013, to June 8, 2014, 168,772 adult residents were enumerated in the door-to-door census. HIV testing was achieved in 131,307 (89%) of 146,906 adults with stable residence. 13,043 of 136,033 (9.6%, 95% CI 9.4-9.8) adults with and without stable residence had HIV; median CD4 count was 514 cells per MUL (IQR 355-703). Among 131,307 adults with stable residence tested, 56,106 (43%) reported no previous testing. Among 13,043 HIV-infected adults, 4932 (38%) were unaware of their status. Among 105,170 CHC attendees with stable residence 104,635 (99%) accepted HIV testing. Of 131,307 adults with stable residence tested, 104,635 (80%; range 60-93% across communities) tested via CHCs. In multivariable analyses of adults with stable residence, predictors of non-testing included being male (risk ratio [RR] 1.52, 95% CI 1.48-1.56), single marital status (1.70, 1.66-1.75), age 30-39 years (1.58, 1.52-1.65 vs 15-19 years), residence in Kenya (1.46, 1.41-1.50), and migration out of the community for at least 1 month in the past year (1.60, 1.53 1.68). Compared with unemployed people, testing for HIV was more common among farmers (RR 0.73, 95% CI 0.67-0.79) and students (0.73, 0.69-0.77); and compared with people with no education, testing was more common in those with primary education (0.84, 0.80-0.89). INTERPRETATION: A hybrid, mobile approach of multiple-disease CHCs followed by HBT allowed for flexibility at the community and individual level to help reach testing coverage goals. Men and mobile populations remain challenges for universal testing. FUNDING: National Institutes of Health and President's Emergency Plan for AIDS Relief. PMID- 26939736 TI - The need for second-line antiretroviral therapy in adults in sub-Saharan Africa up to 2030: a mathematical modelling study. AB - BACKGROUND: The number of patients in need of second-line antiretroviral drugs is increasing in sub-Saharan Africa. We aimed to project the need of second-line antiretroviral therapy in adults in sub-Saharan Africa up to 2030. METHODS: We developed a simulation model for HIV and applied it to each sub-Saharan African country. We used the WHO country intelligence database to estimate the number of adult patients receiving antiretroviral therapy from 2005 to 2014. We fitted the number of adult patients receiving antiretroviral therapy to observed estimates, and predicted first-line and second-line needs between 2015 and 2030. We present results for sub-Saharan Africa, and eight selected countries. We present 18 scenarios, combining the availability of viral load monitoring, speed of antiretroviral scale-up, and rates of retention and switching to second-line. HIV transmission was not included. FINDINGS: Depending on the scenario, 8.7-25.6 million people are expected to receive antiretroviral therapy in 2020, of whom 0.5-3.0 million will be receiving second-line antiretroviral therapy. The proportion of patients on treatment receiving second-line therapy was highest (15.6%) in the scenario with perfect retention and immediate switching, no further scale-up, and universal routine viral load monitoring. In 2030, the estimated range of patients receiving antiretroviral therapy will remain constant, but the number of patients receiving second-line antiretroviral therapy will increase to 0.8-4.6 million (6.6-19.6%). The need for second-line antiretroviral therapy was two to three times higher if routine viral load monitoring was implemented throughout the region, compared with a scenario of no further viral load monitoring scale-up. For each monitoring strategy, the future proportion of patients receiving second-line antiretroviral therapy differed only minimally between countries. INTERPRETATION: Donors and countries in sub-Saharan Africa should prepare for a substantial increase in the need for second-line drugs during the next few years as access to viral load monitoring improves. An urgent need exists to decrease the costs of second-line drugs. FUNDING: World Health Organization, Swiss National Science Foundation, National Institutes of Health. PMID- 26939738 TI - Picogram sensing of trinitrophenol in aqueous medium through a water stable nanoscale coordination polymer. AB - A water stable nanoscale coordination polymer (CP) can detect trinitrophenol (TNP) in an aqueous medium at a record-picogram level (~1.66 pg cm(-2)) with a detection limit of 1.66 ppb. This is a simple and low-cost method for the detection of TNP in aqueous media in contact mode, taking advantage of the unique structural arrangement of the as-synthesized CP and the associated photophysical properties. PMID- 26939737 TI - Effect of the US National HIV/AIDS Strategy targets for improved HIV care engagement: a modelling study. AB - BACKGROUND: The recently updated White House National HIV/AIDS Strategy (NHAS) includes specific progress indicators to improve the HIV care continuum in the USA, but the economic and epidemiological effect of achieving those indicators remains unclear. We aimed to project the impact of achieving NHAS goals on HIV incidence, prevalence, mortality, and costs among adults in the USA over 10 years. METHODS: We constructed a dynamic transmission model of HIV progression and care engagement based on literature sources and the most recent published US Centers for Disease Control and Prevention data. We specifically considered achievement of the 2020 targets set forth in NHAS progress indicator 1 (90% awareness of serostatus), indicator 4 (85% linkage within 1 month), and indicator 5 (90% of diagnosed individuals in care). FINDINGS: At current rates of engagement in the HIV care continuum, we project 524,000 (95% uncertainty range 442,000-712,000) new HIV infections and 375,000 deaths (364,000-578,000) between 2016 and 2025. Achievement of NHAS progress indicators 1 and 4 has modest epidemiological effect (new infections reduced by 2.0% and 3.9%, respectively). By contrast, increasing the proportion of diagnosed individuals in care (NHAS indicator 5) averts 52% (95% UR 47-56) of new infections. Achievement of all NHAS targets resulted in a 58% reduction (95% UR 52-61) in new infections and 128 000 lives saved (106,000-223,000) at an incremental health system cost of US$105 billion. INTERPRETATION: Achievement of NHAS progress indicators for screening, linkage, and particularly improving retention in care, can substantially reduce the burden of HIV in the USA, but continued and increased financial investment will be required. FUNDING: The National Institutes of Health, the B Frank and Kathleen Polk Assistant Professorship in Epidemiology, Emory University CFAR, Johns Hopkins University CFAR, and CDC/NCHHSTP Epidemiological and Economic Modeling Agreement (5U38PS004646). PMID- 26939739 TI - Autonomic nervous system activity and anxiety and depressive symptoms in mothers up to 2 years postpartum. AB - INTRODUCTION: We investigated the association between autonomic nervous system (ANS) activity and symptoms of anxiety and depression for the first 2 years postpartum. METHODS: A total of 108 participants within 2 years postpartum underwent physiological measurements of ANS activity using the heart rate variability (HRV) power spectrum and self-reported questionnaires (14-item Hospital Anxiety and Depression Score). The cutoff points for anxiety and depressive symptom scores in this questionnaire were as follows: 7 or less, non cases; 8-10, doubtful cases; 11 or more, definite cases. This study was conducted from 2012 to 2014 at University Hospital in Kyoto Prefectural University of Medicine and a nearby obstetrics and gynecology department clinic in Japan. RESULTS: Anxiety and depression non-cases accounted for 67.6% (n = 73) of subjects, anxiety non-cases and depression doubtful and definite cases 7.4% (n = 8), anxiety doubtful and definite cases and depression non-cases 8.3% (n = 9), and anxiety and depression doubtful and definite cases 16.7% (n = 18). Findings were similar for women with anxiety or depression, with total power (TP), low frequency (LF) and high-frequency (HF) components of HRV among doubtful and definite cases significantly lower than among non-cases for both anxiety (p = 0.006, 0.034, 0.029, respectively) and depression (p = 0.001, 0.004, 0.007). Significant correlations were observed between TP, LF and HF and anxiety and depression scores (respective values for anxiety: rs = -0.331, p <0.001; rs = 0.286, p = 0.003; rs = -0.269, p = 0.005; and depression: rs = -0.389, rs = 0.353, rs = -0.337, all p <0.001). DISCUSSION: The present study demonstrated that mothers with anxiety or depressive symptoms had significantly lower HRV (HF, LF and TP) than those without. PMID- 26939740 TI - Natural attenuation of weathered oil using aquatic plants in a farm in Southeast Mexico. AB - An experiment was conducted in field for three years to assess the sustainability of aquatic plants Leersia hexandra, Cyperus articulatus, and Eleocharis palustris for use in the removal of total hydrocarbons of weathered oil in four areas contaminated with 60916-119373 mg/kg of hydrocarbons. The variables evaluated were coverage of plant, dry matter, density of plant growth-promoting rhizobacteria, and the removal of total weathered oil. The variables showed statistical differences (p = 0.05) due to the effects of time and the amount of oil in the soil. The three aquatic plants survived on the farm during the 36 month evaluation. The grass L. hexandra yielded the greatest coverage of plant but was inhibited by the toxicity of the oil, which, in contrast, stimulated the coverage of C. articulatus. The rhizosphere of L. hexandra in control soil was more densely colonized by N-fixing bacteria, while the density of phosphate and potassium solubilizing rhizobacteria was stimulated by exposure to oil. C. articulatus coverage showed positive relationship with the removal of weathered oil; positive effect between rhizosphere and L. hexandra grass coverage was also identified. These results contributed to the removal of weathered oil in Gleysols flooded and affected by chronic discharges of crude oil. PMID- 26939735 TI - Tuberculosis-related mortality in people living with HIV in Europe and Latin America: an international cohort study. AB - BACKGROUND: Management of tuberculosis in patients with HIV in eastern Europe is complicated by the high prevalence of multidrug-resistant tuberculosis, low rates of drug susceptibility testing, and poor access to antiretroviral therapy (ART). We report 1 year mortality estimates from a multiregional (eastern Europe, western Europe, and Latin America) prospective cohort study: the TB:HIV study. METHODS: Consecutive HIV-positive patients aged 16 years or older with a diagnosis of tuberculosis between Jan 1, 2011, and Dec 31, 2013, were enrolled from 62 HIV and tuberculosis clinics in 19 countries in eastern Europe, western Europe, and Latin America. The primary endpoint was death within 12 months after starting tuberculosis treatment; all deaths were classified according to whether or not they were tuberculosis related. Follow-up was either until death, the final visit, or 12 months after baseline, whichever occurred first. Risk factors for all-cause and tuberculosis-related deaths were assessed using Kaplan-Meier estimates and Cox models. FINDINGS: Of 1406 patients (834 in eastern Europe, 317 in western Europe, and 255 in Latin America), 264 (19%) died within 12 months. 188 (71%) of these deaths were tuberculosis related. The probability of all-cause death was 29% (95% CI 26-32) in eastern Europe, 4% (3-7) in western Europe, and 11% (8-16) in Latin America (p<0.0001) and the corresponding probabilities of tuberculosis-related death were 23% (20-26), 1% (0-3), and 4% (2-8), respectively (p<0.0001). Patients receiving care outside eastern Europe had a 77% decreased risk of death: adjusted hazard ratio (aHR) 0.23 (95% CI 0.16-0.31). In eastern Europe, compared with patients who started a regimen with at least three active antituberculosis drugs, those who started fewer than three active antituberculosis drugs were at a higher risk of tuberculosis-related death (aHR 3.17; 95% CI 1.83-5.49) as were those who did not have baseline drug susceptibility tests (2.24; 1.31-3.83). Other prognostic factors for increased tuberculosis-related mortality were disseminated tuberculosis and a low CD4 cell count. 18% of patients were receiving ART at tuberculosis diagnosis in eastern Europe compared with 44% in western Europe and 39% in Latin America (p<0.0001); 12 months later the proportions were 67% in eastern Europe, 92% in western Europe, and 85% in Latin America (p<0.0001). INTERPRETATION: Patients with HIV and tuberculosis in eastern Europe have a risk of death nearly four-times higher than that in patients from western Europe and Latin America. This increased mortality rate is associated with modifiable risk factors such as lack of drug susceptibility testing and suboptimal initial antituberculosis treatment in settings with a high prevalence of drug resistance. Urgent action is needed to improve tuberculosis care for patients living with HIV in eastern Europe. FUNDING: EU Seventh Framework Programme. PMID- 26939741 TI - Optimizing initial chemotherapy for metastatic pancreatic cancer. AB - The two combination chemotherapy regimens FOLFIRINOX and gemcitabine plus nab paclitaxel represent major breakthroughs in the management of metastatic pancreatic cancer. Both regimens showed unprecedented survival advantage in the setting of front-line therapy. However, their application for treatment of patients in the community is challenging because of significant toxicities, thus limiting potential benefits to a narrow population of patients. Modifications to the dose intensity or schedule of those regimens improve their tolerability, while likely retaining survival advantage over single-agent chemotherapy. Newer strategies to optimize these two active regimens in advanced pancreatic cancer are being explored that can help personalize treatment to individual patients. PMID- 26939742 TI - Outdoor adventure therapy to increase physical activity in young adult cancer survivors. AB - PURPOSE: Despite the health benefits of physical activity (PA), limited research has examined PA interventions in young adult cancer survivors (YACS). This study used a two-group parallel design to examine the effects of a 7-day outdoor adventure camp vs. waitlist control on PA levels among YACS. Secondary aims examined effects on sedentary behavior and PA correlates. METHODS: 50 camp and 66 control participants were assessed at baseline, end of camp, and 3 months. RESULTS: Intent-to-treat analyses indicated that, relative to baseline, camp participants had significantly (p = 0.0001) greater increases in PA than controls during camp (+577 vs. +9 minutes/week) and 3 months post-camp (+133 vs. -75 minutes/week, p = 0.001). Camp participants also reported significantly greater improvements in TV viewing (p = 0.001), hours sitting (p = 0.001), PA variety (p = 0.0001), barriers to PA (p = 0.007), and enjoyment of structured activities (p = 0.04) during camp but not 3 months post-camp. CONCLUSION: A week-long outdoor adventure therapy camp increased PA levels during camp and 3 months after camp termination, although effects were attenuated over time. IMPLICATIONS FOR CANCER SURVIVORS: Outdoor adventure therapy camps may increase PA and its correlates in YACS, but future research should explore methods to promote sustained PA after camp termination. PMID- 26939744 TI - From mutated genes to familial Alzheimer's disease. PMID- 26939743 TI - Diabetes and new-onset atrial fibrillation in a hypertensive population. AB - AIM: The association of diabetes with new-onset atrial fibrillation (AF) remains controversial. Hypertension may partly explain the risk association ascribed to diabetes. We studied the role and characteristics of diabetes in hypertensive patients with no ischemic vascular disease. METHODS: Records of 262,892 persons from the Information System for the Development of Research in Primary Care in Catalonia (Spain) were examined from July 2006 to December 2011. Included participants were >=55-years-old and hypertensive with no ischemic heart disease, stroke, or peripheral artery disease. We used Cox proportional hazards regression to model incidences in the diabetic and non-diabetic subgroups of our population, and among diabetic patients, diabetes duration and pharmacological treatment, hemoglobin A1C, and body mass index. RESULTS: New-onset AF incidence in diabetic patients was 13.3 per 1000 person-years (mean follow-up: 4.3 years). In non diabetic patients, it was 10.4 per 1000 person-years (mean follow-up: 4.1 years). Diabetes hazard ratio (HR) for new-onset AF was 1.11 (95% confidence interval (CI): 1.06-1.16). Diabetic patients also diagnosed with obesity had an HR of 1.41 (95% CI: 1.22-1.64). CONCLUSION: Diabetes was modestly associated with new-onset AF in hypertensive patients with no ischemic vascular disease. Among diabetic patients, only obesity reached significance in its association with this arrhythmia. PMID- 26939745 TI - Do artisanal fishers perceive declining migratory shorebird populations? AB - BACKGROUND: This paper discusses the results of ethno-ornithological research conducted on the local ecological knowledge (LEK) of artisanal fishers in northeast Brazil between August 2013 and October 2014. METHODS: The present study analyzed the LEK of 240 artisanal fishermen in relation to Nearctic shorebirds and the factors that may be affecting their populations. We examined whether differences occurred according to the gender and age of the local population. The research instruments included semi-structured and check-list interviews. RESULTS: We found that greater knowledge of migratory birds and the areas where they occur was retained by the local men compared with the local women. Half of the male respondents stated that the birds are always in the same locations, and most of the respondents believed that changes in certain populations were caused by factors related to habitat disturbance, particularly to increases in housing construction and visitors to the island. The main practices affecting the presence of migratory birds mentioned by the locals were boat traffic and noise from bars and vessels. According to the artisanal fishermen, the population of migratory birds that use the area for foraging and resting has been reduced over time. CONCLUSIONS: Changes in the local landscape related to urbanization and tourism are most likely the primary causes underlying the reduced migratory shorebird populations as reported by local inhabitants. Thus, managing and monitoring urbanization and tourism are fundamental to increasing the success of the migration process and improving the conservation of migratory shorebird species. PMID- 26939746 TI - Elucidating the role of the host genome in shaping microbiome composition. AB - A major goal of microbiome research is to identify the factors that determine bacterial composition within and upon a host. Environmental factors are thought to play a large role, such as diet in determining gut microbiome composition and moisture in determining skin microbiome composition. The role of host genetics, however, has been a source of debate in the literature. Recently, we examined the association of host genetics with human gut microbiome composition in the Hutterites, a population that lives and eats communally. We identified heritable bacterial taxa and host genetic loci associated with their abundances. In this addendum, I put these results into a broader context along with other recent studies of microbiome heritability, and synthesize common themes that appear across organisms and tissues, such as the relatively small extent genetics plays compared to environment and the role of host genetic variation in immune response and barrier integrity. PMID- 26939747 TI - Biologic therapy in familial Mediterranean fever. AB - Familial Mediterranean fever (FMF) is the most common autoinflammatory hereditary disease characterized by self-limited attacks of fever and serositis. Although colchicine is the gold standard treatment for the attacks ~10% of cases of FMF are resistant or intolerant to effective doses of colchicine. In such cases, however, there are increasing numbers of case reports or clinical trials treated by biologic agents which directly target the proinflammatory cytokines. Anti interleukin-1 (IL-1) treatment has proven beneficial in improving the inflammation in terms of clinical manifestations and laboratory findings in clinical trials. Furthermore, anti-tumor necrosis factor treatment has also revealed the efficacy and safety in patients with colchicine-resistant FMF. More recently, cases of successful treatment with IL-6 inhibitor, tocilizumab (TCZ), has been reported from Japan and Turkey. Of note, TCZ may be preferable in the treatment as well as the prevention of secondary amyloidosis of FMF patients since it significantly suppresses acute inflammatory response. In the present review, we summarize the literatures regarding the efficacy of biologic therapy in colchicine-resistant or -intolerant patients with FMF. PMID- 26939748 TI - Supraglottic Mass. PMID- 26939750 TI - Universal synthesis of air stable, phase pure, controllable FeSe2 nanocrystals. AB - Iron diselenium (FeSe2) is a promising semiconductor for thin-film solar cells because it has a suitable band gap (E(g) = 1.0 eV) and high absorption coefficient. Despite these prospects, the controllable synthesis of FeSe2 nanostructures and the diversity of their geometries has hardly been studied previously. Here, we described a successful synthesis of phase-pure, high quality, and stable orthorhombic FeSe2 nanocrystals (NCs) in aqueous solvents. A variety of morphologies of the FeSe2 NCs were achieved by adjusting synthetic methods. FeSe2 nanoparticles with diameters of 30-100 nm were synthesized in the presence of ethylenediamine (en). Moreover, the synthetic approach developed for nanoparticles proved to be quite universal and could be modified to produce nanowires and octahedrons, with which structure the material could display high crystallinity. The diameter of the FeSe2 nanowires was 300-500 nm with a length exceeding 2 MUm. The octahedrons displayed lateral dimensions of 1 MUm. Meanwhile, the probable growth mechanism and fabrication process of the NCs were proposed. Polycrystalline FeSe2 thin films were fabricated by modifying the sedimentation method. The obvious photoconductivity of FeSe2 has already been observed, and it was considered to be one candidate of solar cell for the very first time. PMID- 26939749 TI - Transcatheter stenting of the right ventricular outflow tract augments pulmonary arterial growth in symptomatic infants with right ventricular outflow tract obstruction and hypercyanotic spells. AB - We retrospectively reviewed all the children with right ventricular outflow tract obstruction, hypoplastic pulmonary annulus, and pulmonary arteries who underwent stenting of the right ventricular outflow tract for hypercyanotic spells at our institution between January, 2008 and December, 2013; nine patients who underwent cardiac catheterisation at a median age of 39 days (range 12-60 days) and weight of 3.6 kg (range 2.6-4.3 kg) were identified. The median number of stents placed was one stent (range 1-4). The median oxygen saturation increased from 60% to 96%. The median right pulmonary artery size increased from 3.3 to 5.5 mm (-2.68 to -0.92 Z-score), and the median left pulmonary artery size increased from 3.4 to 5.5 mm (-1.93 to 0 Z-scores). Among all, one patient developed transient pulmonary haemorrhage, and one patient had pericardial tamponade requiring drainage. Complete repair of tetralogy of Fallot +/- atrioventricular septal defect or double-outlet right ventricle was achieved in all nine patients. Transcatheter stent alleviation of the right ventricular outflow tract obstruction resolves hypercyanotic spells and allows reasonable growth of the pulmonary arteries to facilitate successful surgical repair. This represents a viable alternative to placement of a systemic-to-pulmonary artery shunt, particularly in small neonates. PMID- 26939751 TI - Evaluation and Regulation of Oncology Drug Approval: Finding the Right Balance. PMID- 26939752 TI - Long noncoding RNAs (lncRNAs) dynamics evidence immunomodulation during ISAV Infected Atlantic salmon (Salmo salar). AB - Despite evidence for participation in the host response to infection, the roles of many long non-coding RNAs (lncRNAs) remain unknown. Therefore, the aims of this study were to identify lncRNAs in Atlantic salmon (Salmo salar) and evaluate their transcriptomic regulation during ISA virus (ISAV) infection, an Orthomyxoviridae virus associated with high mortalities in salmonid aquaculture. Using next-generation sequencing, whole-transcriptome analysis of the Salmo salar response to ISAV infection was performed, identifying 5,636 putative lncRNAs with a mean length of 695 base pairs. The transcriptional modulation evidenced a similar number of differentially expressed lncRNAs in the gills (3,294), head kidney (3,275), and liver (3,325) over the course of the infection. Moreover, analysis of a subset of these lncRNAs showed the following: (i) Most were similarly regulated in response to ISA virus infection; (ii) The transcript subsets were uniquely modulated in each tissue (gills, liver, and head-kidney); and (iii) A subset of lncRNAs were upregulated for each tissue and time analysed, indicating potential markers for ISAV infection. These findings represent the first discovery of widespread differential expression of lncRNAs in response to virus infection in non-model species, suggesting that lncRNAs could be involved in regulating the host response during ISAV infection. PMID- 26939753 TI - Incidence, epidemiology and clinical features of Kawasaki disease in Catalonia, Spain. AB - OBJECTIVES: To assess the incidence, epidemiology and clinical features of Kawasaki disease (KD) in Catalonia (northeast region of Spain). METHODS: This was an observational population-based study including all Paediatric Units in Catalonia, under both public and private management. Retrospective data retrieval was performed for 10 years (2004-2013). A 12-month (March 2013 to March 2014) prospective collection of new cases of KD was carried out to determine the incidence of KD. RESULTS: Data from 399 patients over the 10-year study period was analysed, revealing that 233 (58.4%) had complete KD, 159 (39.8) incomplete KD and 7 (1.7%) were considered atypical KD. Mean annual incidence was 3.5/105 children <14 years old (yo) and 8/105 children <5 yo (mean age 37+/-33 months, range 1.3-191.3). KD was more frequent in boys (59.6%, p<0.001) and in rural areas (p<0.001). Patients with IVIG non-responsiveness, need of a 2(nd) IVIG dose, delay of treatment >10(th) day of illness, ages <1 yo and >8 yo and the presence of sterile piuria, aseptic meningitis, abdominal pain and uveitis at diagnosis were found to have higher risk of coronary aneurisms (CAA) (p<0.05). CONCLUSIONS: This is the first population-based study on the epidemiology of KD in the western Mediterranean area. Incidence, clinical features and treatment plans in our cohort are similar to those described in other European studies. PMID- 26939754 TI - Image-based quantification of fiber alignment within electrospun tissue engineering scaffolds is related to mechanical anisotropy. AB - It is well documented that electrospun tissue engineering scaffolds can be fabricated with variable degrees of fiber alignment to produce scaffolds with anisotropic mechanical properties. Several attempts have been made to quantify the degree of fiber alignment within an electrospun scaffold using image-based methods. However, these methods are limited by the inability to produce a quantitative measure of alignment that can be used to make comparisons across publications. Therefore, we have developed a new approach to quantifying the alignment present within a scaffold from scanning electron microscopic (SEM) images. The alignment is determined by using the Sobel approximation of the image gradient to determine the distribution of gradient angles with an image. This data was fit to a Von Mises distribution to find the dispersion parameter kappa, which was used as a quantitative measure of fiber alignment. We fabricated four groups of electrospun polycaprolactone (PCL) + Gelatin scaffolds with alignments ranging from kappa = 1.9 (aligned) to kappa = 0.25 (random) and tested our alignment quantification method on these scaffolds. It was found that our alignment quantification method could distinguish between scaffolds of different alignments more accurately than two other published methods. Additionally, the alignment parameter kappa was found to be a good predictor the mechanical anisotropy of our electrospun scaffolds. The ability to quantify fiber alignment within and make direct comparisons of scaffold fiber alignment across publications can reduce ambiguity between published results where cells are cultured on "highly aligned" fibrous scaffolds. This could have important implications for characterizing mechanics and cellular behavior on aligned tissue engineering scaffolds. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 1680-1686, 2016. PMID- 26939755 TI - WNT/beta-catenin and p27/FOXL2 differentially regulate supporting cell proliferation in the developing ovary. AB - Sexual development is initiated through differentiation of testicular Sertoli cells or ovarian granulosa cells. Although these supporting cells are considered to develop from common bipotential precursors, recent evidence suggests that distinct supporting cell populations are present in the ovary, with one providing granulosa cells of the medullary follicles and the other providing granulosa cells of the cortical follicles, the latter of which support lifelong fertility. Here, we demonstrate that XX fetal gonads contain GATA4 expressing supporting cells that either enter mitotic arrest, or remain proliferative. Blocking WNT signalling reduces XX supporting cell proliferation, while stabilising beta catenin signalling promotes proliferation, indicating that the renewal of pre granulosa cells is dependent on WNT/beta-catenin signalling in the proliferative supporting cell population. In contrast, XX supporting cells express p27 and FOXL2 and are maintained in mitotic arrest. Although FOXL2 is required for maintaining high levels of p27 expression, it is dispensable for entry and maintenance of mitotic arrest in XX supporting cells. Combined our data suggest that both medullary and cortical precursors arise from a common GATA4 expressing cell type. In addition, this work indicates that a balance between supporting cell self-renewal and differentiation is maintained in the developing ovary by relative WNT/beta-catenin and p27/FOXL2 activities. This study provides significant new insights into the origin and formation of ovarian follicles and evidence supporting a common fetal origin of medullary and cortical granulosa cells. PMID- 26939756 TI - A case report of inhalation anthrax acquired naturally. AB - BACKGROUND: Anthrax is a zoonotic occupational disease caused by Bacillus anthracis, a rod-shaped immobile aerobic gram-positive bacteria with spore. Anthrax occurs in humans randomly and with low frequency. Most cases of anthrax are acquired through contact with infected animals or contaminated animal products. This old disease became particularly important since 2001 that the biological spores were exploited in America. Depending on the transmission method of the disease, clinical manifestations occur in three classes: Cutaneous, respiratory, and gastrointestinal anthrax. The respiratory form is considered as the most fatal and a rare form of anthrax intending to show complicated and unusual manifestations. CASE PRESENTATION: In this case report a rare case of inhalation anthrax acquired naturally in southeast of Iran is presented. A blind 65-year-old man, living in a rural area, was admitted with respiratory infection, fever, dyspnea, loss of appetite, and myalgia. The patient was treated with outpatient antibiotics a week ago. After admission, the patient was again treated for pneumonia, but there was no improvement despite treatment and the patient was suffering from septicemia symptoms. Radiographic images showed wide mediastinum. Bacillus anthracis was isolated from blood and sputum culture and the results were confirmed by colony morphology, biochemical reactions and PCR. The treatment was changed to ciprofloxacin, clindamycin, and penicillin. On the second day of anthrax treatment, the patient was complicated with jaundice, elevation of liver enzymes, and a significant drop in hemoglobin, hematocrit, and platelet despite lack of obvious bleeding and was complicated with respiratory distress and sepsis and died a week after treatment. CONCLUSIONS: We could discover no specific exposure associated with anthrax infection for this patient. However, due to being located in an endemic and enzootic area, it is proposed that the exposure occurred through contact with infected airborne dust or an unknown contaminated item. Despite many advances in preventing anthrax, still some rare cases of respiratory and complicated anthrax are emerging. With regard to the threat of bioterrorism, medical staff's sensitivity to the clinical syndrome, methods of prophylaxis and treatment of anthrax must be raised. Fast diagnosis and successful treatment the lethal cases of this infection are of utmost important. PMID- 26939758 TI - Challenges in Large-Scale Computational Mass Spectrometry and Multiomics. PMID- 26939757 TI - Sacral nerve stimulation enhances early intestinal mucosal repair following mucosal injury in a pig model. AB - KEY POINTS: Reducing intestinal epithelial barrier (IEB) dysfunctions is recognized as being of major therapeutic interest for various intestinal disorders. Sacral nerve stimulation (SNS) is known to reduce IEB permeability. Here, we report in a pig model that SNS enhances morphological and functional recovery of IEB following mucosal injury induced via 2,4,6 trinitrobenzenesulfonic acid. These effects are associated with an increased expression of tight junction proteins such as ZO-1 and FAK. These results establish that SNS enhances intestinal barrier repair in acute mucosal injury. They further set the scientific basis for future use of SNS as a complementary or alternative therapeutic option for the treatment of gut disorders with IEB dysfunctions such as inflammatory bowel diseases or irritable bowel syndrome. ABSTRACT: Intestinal epithelial barrier (IEB) dysfunctions, such as increased permeability or altered healing, are central to intestinal disorders. Sacral nerve stimulation (SNS) is known to reduce IEB permeability, but its ability to modulate IEB repair remains unknown. This study aimed to characterize the impact of SNS on mucosal repair following 2,4,6-trinitrobenzenesulfonic acid (TNBS) induced lesions. Six pigs were stimulated by SNS 3 h prior to and 3 h after TNBS enema, while sham animals (n = 8) were not stimulated. The impact of SNS on mucosal changes was evaluated by combining in vivo imaging, histological and functional methods. Biochemical and transcriptomic approaches were used to analyse the IEB and mucosal inflammatory response. We observed that SNS enhanced the recovery from TNBS-induced increase in transcellular permeability. At 24 h, TNBS-induced alterations of mucosal morphology were significantly less in SNS compared with sham animals. SNS reduced TNBS-induced changes in ZO-1 expression and its epithelial pericellular distribution, and also increased pFAK/FAK expression compared with sham. Interestingly, SNS increased the mucosal density of neutrophils, which was correlated with an increase in trypsin and TGF-beta1 levels compared with sham. Finally, SNS prevented the TNBS-induced increases in IL-1beta and IL-4 over time that were observed with sham treatment. In conclusion, our results show that SNS enhances mucosal repair following injury. This study highlights novel mechanisms of action of SNS and identifies SNS as a new therapy for diseases with IEB repair disorders. PMID- 26939759 TI - A case of pulmonary adenocarcinoma harboring osteoclast-like giant cells: Its evaluation by immunohistochemical and genetic analyses. AB - Tumors harboring osteoclast-like giant cells (OGCs) at extraosseous site are extremely rare. These rare tumors have been detected most frequently in the pancreas and few pulmonary tumors harboring OGCs have been previously reported. In addition, the genetic profiles of these tumors have remained virtually unknown. Therefore, we report a case of pulmonary adenocarcinoma harboring OGCs in which k-ras mutation and immunohistochemical study of proteins associated with OGCs were examined. The case was a 70-year-old man, who demonstrated a pulmonary mass associated with unusual radiological features. Histopathologically, three different cell types, mucinous adenocarcinoma cell, OGC and mononuclear cell were detected. OGCs were immunohistochemically negative for epithelial markers and positive for histiocytic markers but mononuclear cells were immunopositive for epithelial markers. In addition, both mononuclear and adenocarcinoma cells had the same k-ras mutation profiles and mononuclear cells were immunohistochemically positive for macrophage colony-stimulating factor (M-CSF), one of the factors associated with OGC differentiation. Therefore, mononuclear cells were considered to be derived from neoplastic epithelium and OGCs could represent non-neoplastic cells. In addition, M-CSF locally produced could promote the differentiation of OGCs. PMID- 26939760 TI - FAM3A attenuates ER stress-induced mitochondrial dysfunction and apoptosis via CHOP-Wnt pathway. AB - Endoplasmic reticulum (ER) stress is linked to several neurological disorders, and neuronal injury cascades initiated by excessive ER stress are mediated, in part, via mitochondrial dysfunction. In the present study, we identified FAM3A as an important regulator of ER stress-induced cell death in neuronal HT22 cells. The ER stress inductor tunicamycin (TM) significantly decreased the expression of FAM3A at both mRNA and protein levels, which was shown to be dependent on the induction of reactive oxygen species (ROS). Overexpression of FAM3A attenuated TM induced apoptosis and activation of ER stress factors, but had no effect on ER calcium metabolism in HT22 cells. We also found decreased mitochondrial ROS generation, inhibited cytochrome c release and preserved mitochondrial membrane potential (MMP) in FAM3A overexpressed cells. In addition, the experiments using isolated mitochondria showed that overexpression of FAM3A attenuated mitochondrial swelling and loss of mitochondrial Ca(2+) buffering capacity after TM exposure. By using specific targeted small interfering RNA (siRNA) to knockdown the expression of the C/EBP homologous protein (CHOP), we found that FAM3A-induced protection and inhibition of ER stress was mediated by inverting TM induced decrease of Wnt through the CHOP pathway. Our study demonstrates a pivotal role of FAM3A in protecting against TM-induced cytotoxicity via regulating CHOP-Wnt pathway, and suggests the therapeutic values of FAM3A overexpression against ER stress-associated neuronal injury. PMID- 26939761 TI - Icariside II protects against cerebral ischemia-reperfusion injury in rats via nuclear factor-kappaB inhibition and peroxisome proliferator-activated receptor up-regulation. AB - Icariside II (IRS) is a metabolite of icariin, which is derived from Herba Epimedii. Although the potential therapeutic effects of icariin on ischemic brain injury were well-investigated; the role of IRS in ischemic stroke is still not addressed clearly. Therefore, the current study aimed to evaluate the effects of IRS on cerebral ischemia-reperfusion injury in rats. The rats were pre-treated by IRS (10 or 30 mg kg(-1), twice a day) for 3 days. After pre-treatment, a MCAO (middle cerebral artery occlusion) for 2 h followed by reperfusion for 24 h was applied on the rats to induce the cerebral ischemia injury model. The neurological deficit scores were assessed at 24 h after reperfusion, then animals were sacrificed, infarct volumes were determined by 2,3,5-triphenyltetrazolium chlorid (TTC) staining and protein expression levels of interleukin-1beta (IL 1beta), transforming growth factor-beta1 (TGF-beta1), inhibitory kappaB (IkappaB), nuclear factor kappaB (NF-kappaB) p65, peroxisome proliferator activated receptor alpha (PPARalpha), and peroxisome proliferator-activated receptor gamma (PPARgamma) were assayed by using Western blot. IRS pretreatment markedly improved the neurological dysfunction and decreased infarct volume in MCAO rats. In addition, IRS inhibited IL-1beta and TGF-beta1 protein expression, and resulted in beneficial effects such as inhibition of IkappaB-alpha degradation and NF-kappaB activation induced by MCAO, in a dose-dependent manner. Furthermore, IRS increased the protein expression levels of PPARalpha and PPARgamma in the ischemic brain. In conclusion, pretreatment with IRS protects against cerebral ischemic/reperfusion injury via up-regulation of PPARalpha and PPARgamma and inhibition of NF-kappaB activation. PMID- 26939762 TI - Distinct roles for metalloproteinases during traumatic brain injury. AB - BACKGROUND: Significant protease activations have been reported after traumatic brain injury (TBI). These proteases are responsible for cleavage of transmembrane proteins in neurons, glial, and endothelial cells and this results in the release of their extracellular domains (ectodomains). METHODS: Two TBI models were employed here, representing both closed head injury (CHI) and open head injury (OHI). In situ zymography, immunohistochemistry, bright field and confocal microscopy, quantification of immunopositive cells and statistical analysis were applied. RESULTS: We found, using in situ zymography, that gelatinase activity of matrix metalloproteinases (MMP)-2 and MMP-9 was upregulated in cortex of both injury models. Using immunohistochemistry for several MPPs (Matrix metalloproteinases) and ADAMs (disintegrin and metalloproteinases), including MMP 2, -9, ADAM-10, -17, distinct patterns of induction were observed in the two TBI models. In closed head injury, an early increase in protein expression of MMP-2, 9 and ADAM-17 was found as early as 10 min post injury in cortex and peaked at 1 h for all 4 proteases examined. In contrast, after OHI the maximal expression was observed locally neighboring the impact site, at a later time-point, as long as 24 h after the injury for MMP-2 and MMP-9. Confocal microscopy revealed colocalization of the 4 proteases with the neuronal marker NeuN in CHI, but only MMP2 colocalized with NeuN in OHI. CONCLUSIONS: The findings may lead to a trauma induced therapeutic strategy triggered soon after a primary insult to improve survival and to reduce brain damage following TBI. PMID- 26939763 TI - Fatty acids and their therapeutic potential in neurological disorders. AB - There is little doubt that we are what we eat. Fatty acid supplementation and diets rich in fatty acids are being promoted as ways to a healthier brain. Short chain fatty acids are a product of intestinal microbiota metabolism of dietary fibre; and their derivatives are used as an anti-convulstant. They demonstrated therapeutic potential in neurodegenerative conditions as HDAC inhibitors; and while the mechanism is not well understood, have been shown to lower amyloid beta in Alzheimer's Disease in preclinical studies. Medium chain fatty acids consumed as a mixture in dietary oils can induce ketogenesis without the need for a ketogentic diet. Hence, this has the potential to provide an alternative energy source to prevent neuronal cell death due to lack of glucose. Long chain fatty acids are commonly found in the diet as omega fatty acids. They act as an anti oxidant protecting neuronal cell membranes from oxidative damage and as an anti inflammatory mediator in the brain. We review which agents, from each fatty acid class, have the most therapeutic potential for neurological disorders (primarily Alzheimer's disease, Parkinson's disease, Autism Spectrum Disorder as well as possible applications to traumatic brain injury), by discussing what is known about their biological mechanisms from preclinical studies. PMID- 26939764 TI - Dietary restriction suppresses apoptotic cell death, promotes Bcl-2 and Bcl-xl mRNA expression and increases the Bcl-2/Bax protein ratio in the rat cortex after cortical injury. AB - Traumatic brain injury (TBI) is one of the leading causes of death and disability in humans. Subsequent pathological events occurring in the brain after TBI, referred to as secondary injury, continue to damage surrounding tissue resulting in substantial neuronal loss. Using an animal model of TBI we examined the effect of dietary restriction (DR) on the neuroapoptosis and Bcl-2 family genes as the main regulators of the intrinsic apoptotic pathway. Bcl-2, Bcl-xl and Bax mRNA and protein expression in the ipsilateral cortex of adult Wistar rats exposed to DR before TBI were studied from 2 to 28 days post injury. Our results showed that DR suppressed neuroapoptosis and promoted significant upregulation of antiapoptotic Bcl-2 and Bcl-xl mRNAs in the ipsilateral cortex following injury. Expression of the proapoptotic Bax gene increased in ad libitum (AL) fed rats but remained unchanged in rats exposed to DR. Although the expression of Bcl-2, Bcl xl and Bax proteins was changed in a similar manner in both experimental groups, DR promoted a continuous increase in the Bcl-2:Bax protein ratio throughout the recovery period. Together with our previous finding that DR mediates inhibition of the extrinsic apoptotic pathway the present work reveals that modulation of the intrinsic pathway contributes to the beneficial effect of DR in brain injury. These findings provide new insight into the effects of DR on pro-survival signaling after injury, lending further support to its neuroprotective effect. PMID- 26939766 TI - Comparison between resveratrol and cabergoline in preventing ovarian hyperstimulation syndrome in a rat model. AB - OBJECTIVE: The aim of this study is to investigate the effects of resveratrol in a rat model of ovarian hyperstimulation syndrome (OHSS) and compare with cabergoline. DESIGN: Randomized controlled, animal study. ANIMAL(S): Female Wistar rats. MATERIAL AND METHODS: A rat OHSS model was used to investigate the effects of resveratrol compare with cabergoline administration for preventing OHSS. Body weight, ovary weight, diameter, vascular permeability (VP), vascular endothelial growth factor (VEGF), cyclooxygenase-2 (COX-2) expression (immunohistochemistry), and serum estradiol (E2) levels were then compared. RESULTS: The ovarian VEGF concentration was significantly increased in the OHSS Groups (Groups 3-5) compared with the control groups (1 and 2). But vascular permeability, VEGF, and COX-2 expressions were reduced in animals treated with the resveratrol group compared with the cabergoline group (group 5) and the severe OHSS (group 3) group. Blood E2 levels were decreased in group treated with the resveratrol group compared with the cabergoline group (group 5) and severe the OHSS (group 3) group. CONCLUSION(S): Our results in a rat model suggest that resveratrol has a beneficial effect on OHSS by reducing the increases in ovarian daimeter, VP, and VEGF expression associated with OHSS. These effects may be mediated by the COX-2 inhibitory capacity of resveratrol. PMID- 26939765 TI - Stereological analyses of reward system nuclei in maternally deprived/separated alcohol drinking rats. AB - The experience of early life stress can trigger complex neurochemical cascades that influence emotional and addictive behaviors later in life in both adolescents and adults. Recent evidence suggests that excessive alcohol drinking and drug-seeking behavior, in general, are co-morbid with depressive-like behavior. Both behaviors are reported in humans exposed to early life adversity, and are prominent features recapitulated in animal models of early life stress (ELS) exposure. Currently, little is known about whether or how ELS modulates reward system nuclei. In this study we use operant conditioning of rats to show that the maternal separation stress (MS) model of ELS consumes up to 3-fold greater quantities of 10% vol/vol EtOH in 1-h, consistently over a 3-week period. This was correlated with a significant 22% reduction in the number of dopaminergic-like neurons in the VTA of naive MS rats, similar to genetically alcohol-preferring (P) rats which show a 35% reduction in tyrosine hydroxylase (TH)-positive dopaminergic neurons in the VTA. MS rats had a significantly higher 2-fold immobility time in the forced swim test (FST) and reduced sucrose drinking compared to controls, indicative of depressive-like symptomology and anhedonia. Consistent with this finding, stereological analysis revealed that amygdala neurons were 25% greater in number at P70 following MS exposure. Our previous examination of the dentate gyrus of hippocampus, a region involved in encoding emotional memory, revealed fewer dentate gyrus neurons after MS, but we now report this reduction in neurons occurs without effect on the number of astrocytes or length of astrocytic fibers. These data indicate that MS animals exhibit neuroanatomical changes in reward centers similar to those reported for high alcohol drinking rats, but aspects of astrocyte morphometry remained unchanged. These data are of high relevance to understand the breadth of neuronal pathology that ensues in reward loci following ELS. PMID- 26939767 TI - Janus Kinase Inhibitors against Other Biological Treatments in Alopecia Areata. PMID- 26939768 TI - Monocytic myeloid-derived suppressor cells from females, but not males, alleviate CVB3-induced myocarditis by increasing regulatory and CD4(+)IL-10(+) T cells. AB - Coxsackievirus group B type 3 (CVB3) is a common etiologic agent of viral myocarditis and often causes sexually dimorphic myocarditis with increased incidence and mortality in male. So far, the underlying mechanism for the high male prevalence is not well elucidated. In this study, we deciphered the role of myeloid-derived suppressor cells (MDSCs) in the gender bias in murine CVB3 induced myocarditis by comparing their frequencies, subsets as well as immune suppressive functions. We found that much more myocardial MDSCs were enriched in infected females than males, with dramatically higher percentage ratio of CD11b(+)Ly6G-Ly6C(high) monocytic subset (M-MDSCs) to CD11b(+)Ly6G(+)Ly6C(low) granulocytic subset (G-MDSCs). Interestingly, more potent suppression on T cell proliferation was also evidenced in female-derived M-MDSCs. Consistently, adoptive transfer of female- but not male-derived M-MDSCs efficiently alleviated CVB3-induced myocarditis in male recipient mice, and this protection could be ascribed to the increased induction of regulatory and CD4(+)IL-10(+) T cells. Our study suggested that myocardial MDSCs were distinctively induced not only in quantities but also in phenotypes and immune suppressive functions in CVB3 infected males and females; and female-derived more suppressive M-MDSCs contributed to their insensitivity to CVB3-induced myocarditis. PMID- 26939769 TI - Quantitation of Gingerols in Human Plasma by Newly Developed Stable Isotope Dilution Assays and Assessment of Their Immunomodulatory Potential. AB - In a pilot study with two volunteers, the main pungent and bioactive ginger (Zingiber officinale Roscoe) compounds, the gingerols, were quantitated in human plasma after ginger tea consumption using a newly established HPLC-MS/MS(ESI) method on the basis of stable isotope dilution assays. Limits of quantitation for [6]-, [8]-, and [10]-gingerols were determined as 7.6, 3.1, and 4.0 nmol/L, respectively. The highest plasma concentrations of [6]-, [8]-, and [10]-gingerols (42.0, 5.3, and 4.8 nmol/L, respectively) were reached 30-60 min after ginger tea intake. Incubation of activated human T lymphocytes with gingerols increased the intracellular Ca(2+) concentration as well as the IFN-gamma secretion by about 20 30%. This gingerol-induced increase of IFN-gamma secretion could be blocked by the specific TRPV1 antagonist SB-366791. The results of the present study point to an interaction of gingerols with TRPV1 in activated T lymphocytes leading to an augmentation of IFN-gamma secretion. PMID- 26939771 TI - Corrigendum: Notch signal strength controls cell fate in the haemogenic endothelium. PMID- 26939772 TI - Taking bismuthinite to bismuth sulfide nanorods in two easy steps. AB - The transformation of mineral bismuthinite, to Bi2S3 nanoparticles, via a simple two-step process is described. The reaction of bismuthinite with two aryldithoic acids gave the complexes; [Bi(S2C(C6H4)-4-CH3)3] and [Bi(S2C(C6H4)-4-OCH3)3]. Mild solution decomposition (120 degrees C) of these bismuth aryldithioates produced crystalline Bi2S3 nanorods. PMID- 26939770 TI - Elimination of HIV-1 Genomes from Human T-lymphoid Cells by CRISPR/Cas9 Gene Editing. AB - We employed an RNA-guided CRISPR/Cas9 DNA editing system to precisely remove the entire HIV-1 genome spanning between 5' and 3' LTRs of integrated HIV-1 proviral DNA copies from latently infected human CD4+ T-cells. Comprehensive assessment of whole-genome sequencing of HIV-1 eradicated cells ruled out any off-target effects by our CRISPR/Cas9 technology that might compromise the integrity of the host genome and further showed no effect on several cell health indices including viability, cell cycle and apoptosis. Persistent co-expression of Cas9 and the specific targeting guide RNAs in HIV-1-eradicated T-cells protected them against new infection by HIV-1. Lentivirus-delivered CRISPR/Cas9 significantly diminished HIV-1 replication in infected primary CD4+ T-cell cultures and drastically reduced viral load in ex vivo culture of CD4+ T-cells obtained from HIV-1 infected patients. Thus, gene editing using CRISPR/Cas9 may provide a new therapeutic path for eliminating HIV-1 DNA from CD4+ T-cells and potentially serve as a novel and effective platform toward curing AIDS. PMID- 26939773 TI - Reversible and Nonvolatile Modulations of Magnetization Switching Characteristic and Domain Configuration in L10-FePt Films via Nonelectrically Controlled Strain Engineering. AB - Reversible and nonvolatile modulation of magnetization switching characteristic in ferromagnetic materials is crucial in developing spintronic devices with low power consumption. It is recently discovered that strain engineering can be an active and effective approach in tuning the magnetic/transport properties of thin films. The primary method in strain modulation is via the converse piezoelectric effect of ferroelectrics, which is usually volatile due to the reliance of the required electric field. Also the maximum amount of deformation in ferroelectrics is usually limited to be less than 1%, and the corresponding magnetoelastic strain energy introduced to ferromagnetic films is on the order of 10(4) J/m(3), not enough to overcome magnetocrystalline anisotropy energy (Ku) in many materials. Different from using conventional strain inducing substrates, this paper reports on the significantly large, reversible, and nonvolatile lattice strain in the L10-FePt films (up to 2.18%) using nonelectrically controlled shape memory alloy substrates. Introduced lattice strain can be large enough to effectively affect domain structure and magnetic reversal in FePt. A noticeable decrease of coercivity field by 80% is observed. Moreover, the coercivity field tunability using such substrates is nonvolatile at room temperature and is also reversible due to the characteristics of the shape memory effect. This finding provides an efficient avenue for developing strain assisted spintronic devices such as logic memory device, magnetoresistive random-access memory, and memristor. PMID- 26939774 TI - The current perspective of low-grade myelodysplastic syndrome in children. AB - Myelodysplastic syndrome (MDS) without increased blasts, i.e., low-grade MDS, is the most common subtype of pediatric MDS and has characteristics different from adult form of the disease. Although histological findings of bone marrow (BM) biopsies suggest that low-grade MDS is a morphologically distinctive entity, a subset of pediatric low-grade MDS may clinically overlap with aplastic anemia (AA), such as high likelihood of hypocellular marrow and normal karyotype. In addition, children with low-grade MDS are as likely to respond to immunosuppressive therapy as those with AA, which indicates that a part of these disorders might share a common pathogenesis, that is, T cell-mediated inhibition of hematopoiesis. In contrast, a small part of children with low-grade MDS experience disease progression to advanced MDS. Given that the clinical courses of pediatric low-grade MDS are heterogeneous, assessing prognostic values of clinical, morphological, histological and cytogenetic findings is critical. Thus far, monosomy 7 and multilineage dysplasia have been suggested as prognostic factors that could predict disease progression. Treatment strategy will be optimized based on more precise prognostic factors. In the future, molecular findings may also help prognostification in children with hypoplastic BM disorders. PMID- 26939775 TI - Associations of Sarcopenic Obesity and Dynapenic Obesity with Bone Mineral Density and Incident Fractures Over 5-10 Years in Community-Dwelling Older Adults. AB - The purpose of this study is to determine whether low muscle mass (sarcopenia) or strength (dynapenia), in the presence of obesity, are associated with increased risk for osteoporosis and non-vertebral fracture over 5-10 years in community dwelling older adults. N = 1089 volunteers (mean +/- SD age 62 +/- 7 years; 51 % female) participated at baseline and 761 attended follow-up clinics (mean 5.1 +/- 0.5 years later). Total body, total hip and spine BMD, and appendicular lean and total fat mass were assessed by DXA. Sarcopenic obesity and dynapenic obesity were defined as the lowest sex-specific tertiles for appendicular lean mass or lower-limb strength, respectively, and the highest sex-specific tertile for total fat mass. Fractures were self-reported on three occasions over 10.7 +/- 0.7 years in 563 participants. Obese alone participants had significantly higher BMD at all sites compared with non-sarcopenic non-obese. Sarcopenic obese and dynapenic obese men had lower spine and total body BMD, respectively, and sarcopenic obese women had lower total hip BMD, compared with obese alone (all P < 0.05). Sarcopenic obese men had higher non-vertebral fracture rates compared to non sarcopenic non-obese (incidence rate ratio: 3.0; 95 % CI 1.7-5.5), and obese alone (3.6; 1.7-7.4). Sarcopenic obese women had higher fracture rates compared with obese alone (2.8; 1.4-5.6), but this was non-significant after adjustment for total hip BMD. Sarcopenic and dynapenic obese older adults may have increased risk of osteoporosis and non-vertebral fracture relative to obese alone counterparts. Sarcopenic and dynapenic obese individuals potentially represent a subset of the obese older adult population who require closer monitoring of bone health during ageing. PMID- 26939777 TI - An adaptive technique for multiscale approximate entropy (MAEbin) threshold (r) selection: application to heart rate variability (HRV) and systolic blood pressure variability (SBPV) under postural stress. AB - Multiscale approximate entropy (MAE) is used to quantify the complexity of a time series as a function of time scale tau. Approximate entropy (ApEn) tolerance threshold selection 'r' is based on either: (1) arbitrary selection in the recommended range (0.1-0.25) times standard deviation of time series (2) or finding maximum ApEn (ApEnmax) i.e., the point where self-matches start to prevail over other matches and choosing the corresponding 'r' (rmax) as threshold (3) or computing rchon by empirically finding the relation between rmax, SD1/SD2 ratio and N using curve fitting, where, SD1 and SD2 are short-term and long-term variability of a time series respectively. None of these methods is gold standard for selection of 'r'. In our previous study [1], an adaptive procedure for selection of 'r' is proposed for approximate entropy (ApEn). In this paper, this is extended to multiple time scales using MAEbin and multiscale cross-MAEbin (XMAEbin). We applied this to simulations i.e. 50 realizations (n = 50) of random number series, fractional Brownian motion (fBm) and MIX (P) [1] series of data length of N = 300 and short term recordings of HRV and SBPV performed under postural stress from supine to standing. MAEbin and XMAEbin analysis was performed on laboratory recorded data of 50 healthy young subjects experiencing postural stress from supine to upright. The study showed that (i) ApEnbin of HRV is more than SBPV in supine position but is lower than SBPV in upright position (ii) ApEnbin of HRV decreases from supine i.e. 1.7324 +/- 0.112 (mean +/- SD) to upright 1.4916 +/- 0.108 due to vagal inhibition (iii) ApEnbin of SBPV increases from supine i.e. 1.5535 +/- 0.098 to upright i.e. 1.6241 +/- 0.101 due sympathetic activation (iv) individual and cross complexities of RRi and systolic blood pressure (SBP) series depend on time scale under consideration (v) XMAEbin calculated using ApEnmax is correlated with cross-MAE calculated using ApEn (0.1 0.26) in steps of 0.02 at each time scale in supine and upright position and is concluded that ApEn0.26 has highest correlation at most scales (vi) choice of 'r' is critical in interpreting interactions between RRi and SBP and in ascertaining true complexity of the individual RRi and SBP series. PMID- 26939776 TI - B cell sub-types following acute malaria and associations with clinical immunity. AB - BACKGROUND: Repeated exposure to Plasmodium falciparum is associated with perturbations in B cell sub-set homeostasis, including expansion atypical memory B cells. However, B cell perturbations immediately following acute malaria infection have been poorly characterized, especially with regard to their relationship with immunity to malaria. METHODS: To better understand the kinetics of B cell sub-sets following malaria, the proportions of six B cell sub-sets were assessed at five time points following acute malaria in four to 5 years old children living in a high transmission region of Uganda. B cell sub-set kinetics were compared with measures of clinical immunity to malaria-lower parasite density at the time of malaria diagnosis and recent asymptomatic parasitaemia. RESULTS: Atypical memory B cell and transitional B cell proportions increased following malaria. In contrast, plasmablast proportions were highest at the time of malaria diagnosis and rapidly declined following treatment. Increased proportions of atypical memory B cells were associated with greater immunity to malaria, whereas increased proportions of transitional B cells were associated with evidence of less immunity to malaria. CONCLUSIONS: These findings highlight the dynamic changes in multiple B cell sub-sets following acute, uncomplicated malaria, and how these sub-sets are associated with developing immunity to malaria. PMID- 26939779 TI - Defects in the NC2 repressor affect both canonical and non-coding RNA polymerase II transcription initiation in yeast. AB - BACKGROUND: The formation of the pre-initiation complex in eukaryotic genes is a key step in transcription initiation. The TATA-binding protein (TBP) is a universal component of all pre-initiation complexes for all kinds of RNA polymerase II (RNA pol II) genes, including those with a TATA or a TATA-like element, both those that encode proteins and those that transcribe non-coding RNAs. Mot1 and the negative cofactor 2 (NC2) complex are regulators of TBP, and it has been shown that depletion of these factors in yeast leads to defects in the control of transcription initiation that alter cryptic transcription levels in selected yeast loci. RESULTS: In order to cast light on the molecular functions of NC2, we performed genome-wide studies in conditional mutants in yeast NC2 essential subunits Ydr1 and Bur6. Our analyses show a generally increased level of cryptic transcription in all kinds of genes upon depletion of NC2 subunits, and that each kind of gene (canonical or ncRNAs, TATA or TATA-like) shows some differences in the cryptic transcription pattern for each NC2 mutant. CONCLUSIONS: We conclude that NC2 plays a general role in transcription initiation in RNA polymerase II genes that is related with its known TBP interchange function from free to promoter bound states. Therefore, loss of the NC2 function provokes increases in cryptic transcription throughout the yeast genome. Our results also suggest functional differences between NC2 subunits Ydr1 and Bur6. PMID- 26939780 TI - Outcomes following surgery for fractured neck of femur in dialysis patients: a 5 year review from a district general hospital in the United Kingdom. AB - BACKGROUND: Neck of femur fractures are associated with high mortality and have increased prevalence in dialysis patients. Delays in operating on dialysis patients can occur as a result of logistical or medical issues; it has previously been shown that delays on operating on neck of femur fractures in the general population results in increased mortality. METHODS: Medical records of 27 dialysis patients admitted to a large district general hospital in the UK with a fractured neck of femur between January 2009 and January 2014 were analysed alongside records of 27 age and sex-matched non-dialysis patients. Fisher's exact test and the unpaired t test were applied to data to explore outcomes. Odds ratio was also used to compare mortality between the dialysis and non-dialysis groups. RESULTS: Thirty-day mortality amongst dialysis patients was 22 %, compared to 7 % in the non-dialysis cohort. One-year mortality amongst dialysis patients was 70 %, compared to 15 % in the non-dialysis cohort (odds ratio 13.7 (3.56-52.4, 95 % confidence interval; p = 0.0001)). Average length of survival in dialysis patients overall was 311 days; average length of survival if the patient was operated on within 48 h of admission was 450 days (192-708 days, 95 % confidence interval) and was 224 days (45-402, 95 % confidence interval) if operated on after more than 48 h of admission (p = 0.16). CONCLUSIONS: Dialysis patients had higher post-operative mortality than the non-dialysis cohort. Odds ratio for death was significantly greater at one-year in the cohort of dialysis patients compared to the non-dialysis patients. Delay to operation amongst the dialysis patient cohort did not contribute significantly to mortality in this study. The higher rates of coronary artery disease, diabetes mellitus and malignancy may confound mortality amongst patients on dialysis who sustain a fractured neck of femur. Limitations of this study included small patient numbers, data from only one centre being used, and some missing data for certain patients. PMID- 26939778 TI - Techniques of Human Embryonic Stem Cell and Induced Pluripotent Stem Cell Derivation. AB - Developing procedures for the derivation of human pluripotent stem cells (PSCs) gave rise to novel pathways into regenerative medicine research. For many years, stem cells have attracted attention as a potentially unlimited cell source for cellular therapy in neurodegenerative disorders, cardiovascular diseases, and spinal cord injuries, for example. In these studies, adult stem cells were insufficient; therefore, many attempts were made to obtain PSCs by other means. This review discusses key issues concerning the techniques of pluripotent cell acquisition. Technical and ethical issues hindered the medical use of somatic cell nuclear transfer and embryonic stem cells. Therefore, induced PSCs (iPSCs) emerged as a powerful technique with great potential for clinical applications, patient-specific disease modelling and pharmaceutical studies. The replacement of viral vectors or the administration of analogous proteins or chemical compounds during cell reprogramming are modifications designed to reduce tumorigenesis risk and to augment the procedure efficiency. Intensified analysis of new PSC lines revealed other barriers to overcome, such as epigenetic memory, disparity between human and mouse pluripotency, and variable response to differentiation of some iPSC lines. Thus, multidimensional verification must be conducted to fulfil strict clinical-grade requirements. Nevertheless, the first clinical trials in patients with spinal cord injury and macular dystrophy were recently carried out with differentiated iPSCs, encouraging alternative strategies for potential autologous cellular therapies. PMID- 26939781 TI - Drug Treatment of Heart Failure in Children: Focus on Recent Recommendations from the ISHLT Guidelines for the Management of Pediatric Heart Failure. AB - The International Society of Heart and Lung Transplantation (ISHLT) recently updated consensus pediatric heart failure guidelines from those published in 2004 with an aim to provide a practical evidence-based resource whilst recognizing the influence of adult heart failure practice. The new guidelines were formed from published evidence for heart failure management and used parallels with adult literature where pediatric evidence was lacking. This is a summary of the pharmacological therapies discussed in the new 2014 guidelines, emphasizing changes from the previous recommendations with regards to treatment of chronic heart failure with reduced ejection fraction, chronic heart failure with preserved ejection fraction, and acute decompensated heart failure. Each recommendation is classified according to strength and level of evidence. We also discuss future perspectives in the pharmacological treatment of heart failure. The 2014 ISHLT guidelines have evolved considerably from those published in 2004 with extensive information surrounding the underlying pathophysiology, investigations and recommended treatment. The new guidelines contain a modest amount of new pediatric data on pharmacological therapies and extrapolate adult data when appropriate. It is likely that most new recommendations for pediatric heart failure will continue to be based on therapies of proven benefit in adult heart failure studies. PMID- 26939782 TI - Difficult-To-Treat Juvenile Idiopathic Arthritis: Current and Future Options. AB - Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease in childhood and is usually treated with non-steroidal anti-inflammatory drugs or disease-modifying anti-rheumatic drugs (DMARDs) such as methotrexate or sulfasalazine. However, not all patients respond to these treatments, and toxicities may limit long-term use or diminish compliance. With advances in pharmacotherapy and the development of new therapeutic agents, there have been improvements in treatment of both systemic and non-systemic JIA, particularly with biologic agents such as anti-tumor necrosis factor (TNF)-alpha, anti interleukin (IL)-1, and anti-IL6. Anti-cell therapies, such as co-stimulator blockers or anti-CD20, small molecules, and biosimilars represent new areas of interest, and, while many are not yet currently commercially available for use in children, preliminary studies appear to be promising. In the present article, the authors review therapeutic strategies for the different JIA subtypes, mainly according to guidelines and recommendations. Newer and possible future treatments for arthritis, already approved in adults but currently under study in children, are also discussed. Drugs currently in development plans for rheumatoid arthritis, which hopefully will also be useful for JIA patients in the future, are also mentioned in this paper. PMID- 26939783 TI - Impact of activity outcome and measurement instrument on estimates of youth compliance with physical activity guidelines: a cross-sectional study. AB - BACKGROUND: The national physical activity guidelines (PAG) in many countries recommend that youth accumulate 60 min or more of moderate-to-vigorous physical activity (MVPA) daily (PAG-MVPA). A daily target of >= 11,500 steps/day has been proposed as a step count alternative to this guideline (PAG-Steps). Contemporary activity monitors are capable of estimating both MVPA and steps, but it is not clear how these units compare when used to evaluate compliance with the national PAG. The purpose of this study was to compare prevalence estimates of meeting the PAG-MVPA and PAG-Steps using two commonly used monitors, the ActiGraph (AG) and SenseWear Armband (SWA). METHODS: A sample of 69 children (25 girls and 44 boys) aged 9-16 years each wore a wrist-mounted AG and a SWA over a one-week period. Days with >=10 h of wear time for both monitors were included in the analysis. Estimates of time spent in MVPA were obtained using the Crouter equation for the AG and from proprietary algorithms for the SWA. Step counts for the AG and SWA were directly obtained from the respective software. The prevalence of meeting the PAG-MVPA and PAG-Steps was compared within each monitor, using Cohen's kappa (kappa) statistic. Agreement was similarly assessed between monitors using each guideline individually. RESULTS: When assessed with the AG, the prevalence of meeting PAG was substantially higher for the PAG-MVPA (87.2 %) than for the PAG Steps (54.2 %), with fair classification agreement (kappa = 0.30) between the two guidelines. Higher prevalence rates were also observed for the PAG-MVPA (83.6 %) than for the PAG-Steps (33.8 %) when assessed using the SWA, but the prevalence rates and classification agreement (kappa = 0.18) were lower than the values from the AG. Classification agreement between AG and SWA was lower for the PAG-MVPA (kappa = 0.42) than for the PAG-Steps (kappa = 0.55). CONCLUSIONS: The results show differential patterns of compliance with the PAG-MVPA and PAG-Steps, as assessed by the AG and SWA. Additional research is needed to directly evaluate and compare findings from public health research based on different guidelines and measurement methods. PMID- 26939784 TI - Papular Epidermal Nevus with Skyline Basal Cell Layer (PENS): Three New Cases and Review of the Literature. AB - BACKGROUND/OBJECTIVE: Papular epidermal nevus with skyline basal cell layer (PENS) is a recently described type of epidermal nevus with characteristic histopathologic findings, mainly regular, rectangular acanthosis and a well demarcated basal cell layer with clear palisading and separation between basal cell nuclei and the first row of Malpighian cell nuclei. Although the first reports described randomly distributed lesions appearing sporadically in otherwise healthy patients, cases of Blaschkoid distribution, lesions associated with extracutaneous manifestations, and familial cases have been reported. METHODS: We performed a review of the clinical charts of all patients with histologic diagnosis of PENS in our hospital. We evaluated epidemiologic, clinical, and histologic features. We then reviewed the literature with a particular emphasis on the presence or absence of extra-cutaneous associations. RESULTS: Three patients with PENS are described. One had a single lesion, one had three lesions, and one, a patient with mild developmental delay, a curved penis, and hypospadias, had multiple lesions. CONCLUSION: The probability of having extracutaneous manifestations is 6.3 times as great in individuals with more than four lesions. Therefore these patients may need closer follow-up. PMID- 26939785 TI - The Anti-Mullerian Hormone Profile is Linked with the In Vitro Embryo Production Capacity and Embryo Viability after Transfer but Cannot Predict Pregnancy Outcome. AB - The current study investigated the possibility of using the AMH concentration as a predictor of the ability of Korean Hanwoo cows to produce cumulus-oocyte complexes, embryos that survive after transfer as well as the pregnancy outcome of surrogates. Eight sessions of ovum pick-up (OPU) were performed with 19 donor cows at an interval of 3-4 days. Antral follicle count (AFC), oocyte quality and in vitro embryo development were recorded for each cow. Embryos produced from cows with different AMH profiles were transferred into recipients (n = 96). Cows in the high (>=0.25 ng/ml) and intermediate (0.1>= to <0.25 ng/ml) AMH groups had a significantly higher AFC per OPU session (20.40 +/- 1.36 and 16.91 +/- 1.52, respectively; mean +/- standard deviation) than cows in the low AMH group (<0.1 ng/ml; 12.19 +/- 2.14). In addition, more cumulus-oocyte complexes per donor were recovered in the high (11.46 +/- 1.22) and intermediate (7.38 +/- 0.83) AMH groups than in the low AMH group (4.77 +/- 0.44). The percentage of oocytes reached blastocyst stage was significantly higher in the intermediate (47.0%) and high (38.5%) AMH groups than in the low AMH group (32.3%). The number of embryos produced per cow was higher in the high (3.9 +/- 0.2) and intermediate (6.9 +/- 0.6) AMH groups than in the low AMH group (2.2 +/- 0.3). The percentage of embryos that gave birth to viable calves when transferred into recipients was higher for those derived from cows in the intermediate AMH group (50.7%) than for those derived from cows in the low (35.7%) and high (36.4%) AMH groups. In conclusion, a single measurement of AMH concentration predicted the in vitro embryo production potential of donor Korean native cows before OPU and is linked with embryo viability after transfer into recipients. PMID- 26939786 TI - New insights into the anticancer activity of carnosol: p53 reactivation in the U87MG human glioblastoma cell line. AB - Glioblastoma multiforme (GBM) is an aggressive brain tumour with high resistance to radio- and chemotherapy. As such, increasing attention has focused on developing new therapeutic strategies to improve treatment responses. Recently, attention has been shifted to natural compounds that are able to halt tumour development. Among them, carnosol (CAR), a phenolic diterpene present in rosemary, has become a promising molecule that is able to prevent certain types of solid cancer. However, no data are available on the effects of CAR in GBM. Here, CAR activity decreased the proliferation of different human glioblastoma cell lines, particularly cells that express wild type p53. The p53 pathway is involved in the control of apoptosis and is often impaired in GBM. Notably, CAR, through the dissociation of p53 from its endogenous inhibitor MDM2, was able to increase the intracellular p53 levels in GBM cells. Accordingly, functional reactivation of p53 was demonstrated by the stimulation of p53 target genes' transcription, the induction of apoptosis and cell cycle blockade. Most importantly, CAR produced synergistic effects with temozolomide (TMZ) and reduced the restoration of the tumour cells' proliferation after drug removal. Thus, for the first time, these data highlighted the potential use of the diterpene in the sensitization of GBM cells to chemotherapy through a direct re-activation of p53 pathway. Furthermore, progress has been made in delineating the biochemical mechanisms underlying the pro-apoptotic effects of this molecule. PMID- 26939787 TI - Post-thyroidectomy haemorrhage in a tertiary centre: analysis of 1280 operations and comparison with the BAETS audit 2012. PMID- 26939788 TI - Evolutionary diversification of the BetaM interactome acquired through co-option of the ATP1B4 gene in placental mammals. AB - ATP1B4 genes represent a rare instance of orthologous vertebrate gene co-option that radically changed properties of the encoded BetaM proteins, which function as Na,K-ATPase subunits in lower vertebrates and birds. Eutherian BetaM has lost its ancestral function and became a muscle-specific resident of the inner nuclear membrane. Our earlier work implicated BetaM in regulation of gene expression through direct interaction with the transcriptional co-regulator SKIP. To gain insight into evolution of BetaM interactome we performed expanded screening of eutherian and avian cDNA libraries using yeast-two-hybrid and split-ubiquitin systems. The inventory of identified BetaM interactors includes lamina-associated protein LAP-1, myocyte nuclear envelope protein Syne1, BetaM itself, heme oxidases HMOX1 and HMOX2; transcription factor LZIP/CREB3, ERGIC3, PHF3, reticulocalbin-3, and beta-sarcoglycan. No new interactions were found for chicken BetaM and human Na,K-ATPase beta1, beta2 and beta3 isoforms, indicating the uniqueness of eutherian BetaM interactome. Analysis of truncated forms of BetaM indicates that residues 72-98 adjacent to the membrane in nucleoplasmic domain are important for the interaction with SKIP. These findings demonstrate that evolutionary alterations in structural and functional properties of eutherian BetaM proteins are associated with the increase in its interactome complexity. PMID- 26939789 TI - Prognostic value of platelet to lymphocyte ratio in non-small cell lung cancer: a systematic review and meta-analysis. AB - The prognostic value of the platelet-to-lymphocyte ratio (PLR) in non-small cell lung cancer (NSCLC) remains controversial. We therefore conducted a meta-analysis of published studies to determine the prognostic value of PLR in NSCLC. A systematic search was performed in PubMed, Web of Science and Embase for relevant studies. The data and characteristics of each study were extracted, and the hazard ratio (HR) at a 95% confidence interval (CI) was calculated to estimate the effect. We also performed subgroup and meta-regression analyses. A total of 2,889 patients in 12 studies were enrolled in this meta-analysis, and the pooled HR of 1.492 (95% CI: 1.231-1.807, P < 0.001) indicated that patients with an elevated PLR are expected to have a shorter overall survival (OS) after treatment. This meta-analysis indicates that a high PLR might be a predictive factor of poor prognosis in NSCLC. Further large-cohort studies are needed to confirm these findings. PMID- 26939790 TI - Bias in the reporting of sex and age in biomedical research on mouse models. AB - In animal-based biomedical research, both the sex and the age of the animals studied affect disease phenotypes by modifying their susceptibility, presentation and response to treatment. The accurate reporting of experimental methods and materials, including the sex and age of animals, is essential so that other researchers can build on the results of such studies. Here we use text mining to study 15,311 research papers in which mice were the focus of the study. We find that the percentage of papers reporting the sex and age of mice has increased over the past two decades: however, only about 50% of the papers published in 2014 reported these two variables. We also compared the quality of reporting in six preclinical research areas and found evidence for different levels of sex bias in these areas: the strongest male-bias was observed in cardiovascular disease models and the strongest female-bias was found in infectious disease models. These results demonstrate the ability of text mining to contribute to the ongoing debate about the reproducibility of research, and confirm the need to continue efforts to improve the reporting of experimental methods and materials. PMID- 26939791 TI - Sprouting angiogenesis is regulated by shedding of the C-type lectin family 14, member A (CLEC14A) ectodomain, catalyzed by rhomboid-like 2 protein (RHBDL2). AB - C-type lectin family 14, member A (CLEC14A), is a single-pass transmembrane glycoprotein that is overexpressed in tumor endothelial cells, and it promotes sprouting angiogenesis and modulates endothelial function via interactions with extracellular matrix proteins. Here, we show that CLEC14A is cleaved by rhomboid like protein 2 (RHBDL2), one of 3 catalytic mammalian rhomboid-like (RHBDL) proteases, but that it is not cleaved by RHBDL1 or -3. Site-directed mutagenesis identified the precise site at which RHBDL2 cleaves CLEC14A, and targeted, small interfering RNAs that knockdown endogenous CLEC14A and RHBDL2 in human endothelial cells validated the specificity of CLEC14A shedding by RHBDL2. Loss of endogenous cleaved CLEC14A increased endothelial migration 2-fold, whereas that addition of recombinant cleaved CLEC14A inhibited the sprouting of human and murine endothelial cells 3-fold in several in vitro models. We assessed the in vivo role of cleaved CLEC14A in angiogenesis by using the rodent subcutaneous sponge implant model, and we found that CLEC14A protein inhibited vascular density by >50%. Finally, we show that cleaved CLEC14A binds to sprouting endothelial tip cells. Our data show that the ectodomain of CLEC14A regulates sprouting angiogenesis and suggests a role for RHBDL2 in endothelial function. Noy, P. J., Swain, R. K., Khan, K., Lodhia, P., Bicknell, R. Sprouting angiogenesis is regulated by shedding of the C-type lectin family 14, member A (CLEC14A) ectodomain, catalyzed by rhomboid-like 2 protein (RHBDL2). PMID- 26939792 TI - Surgical resection of hepatic metastases from gastric cancer: outcomes from national series in England. AB - BACKGROUND: The objectives of this national study were to examine the short-term safety and long-term survival benefit associated with surgical resection of hepatic metastases from gastric cancer. METHODS: Patients from the Hospital Episode Statistics database were classified by disease and treatment approach. Gastric cancer: 1. Without liver metastases treated by gastrectomy (GG). 2. With liver metastases treated by gastrectomy and hepatectomy (GGH). 3. With liver metastases treated by gastrectomy without hepatectomy (GGNH). 4. With liver metastases treated with no surgery (GNS). Propensity score matching and multivariable analyses were used to compensate for differences in some baseline characteristics. RESULTS: During the study period, 87,482 were patients diagnosed with gastric cancer, of whom 13,841 underwent partial or total gastrectomy. Of those who underwent gastrectomy, 336 had a diagnosis of liver metastases and 78 of these had a hepatectomy. Propensity-matched analysis showed no significant differences in 30- or 90-day mortality between the GGH and GG groups. The GGH group had significantly improved 1-year mortality (35.9 % vs. 50.0 %, p = 0.049) and 5-year mortality (61.5 % vs. 75.7 %, p = 0.031) compared to the GGNH group, and compared to the GNS group, the GCH group had 1-year mortality (35.9 % vs. 84.6 %, p < 0.001) and 5-year mortality (61.5 % vs. 90.8 %, p < 0.001). CONCLUSIONS: This study showed that hepatectomy for synchronous gastric cancer hepatic metastases may carry survival benefits in selected patients. The data presented should not be a rationale to change current clinical practice but rather a stimulus to prospectively study the role of surgery in a selected group of patients who are currently treated with palliative chemotherapy. PMID- 26939793 TI - Reading prosody in Spanish dyslexics. AB - Reading becomes expressive when word and text reading are quick, accurate and automatic. Recent studies have reported that skilled readers use greater pitch changes and fewer irrelevant pauses than poor readers. Given that developmental dyslexics have difficulty acquiring and automating the alphabetic code and developing orthographic representations of words, it is possible that their use of prosody when reading differs from that of typical readers. The goal of this study was to investigate whether the reading prosody of Spanish-speaking dyslexics differs from that of typical Spanish readers. Two experiments were performed. The first experiment involved 36 children (18 with dyslexia), and the second involved 46 adults (23 with dyslexia). Participants were asked to read aloud a text which included declarative, exclamatory and interrogative sentences. Data on pausing and reading rate (number of pauses, duration of pauses and utterances), pitch changes, intensity changes and syllable lengthening were extracted from the recordings. We found that dyslexic people read more slowly than typical readers and they also made more inappropriate and longer pauses, even as adults with considerable reading experience. We also observed that dyslexics differed from skilled readers in their use of some prosodic features, particularly pitch changes at the end of sentences. This is probably because they have trouble anticipating some structural features of prose, such as sentence ends. PMID- 26939794 TI - Topography and age mediate the growth responses of Smith fir to climate warming in the southeastern Tibetan Plateau. AB - The Tibetan Plateau holds some of the world's highest undisturbed natural treelines and timberlines. Such extreme environments constitute potentially valuable monitoring sites of the effects of climate warming on high-elevation forests. Here, we analyze a network of 21 Smith fir forests situated in the Sygera Mountains, southeastern Tibetan Plateau, using tree-ring width (TRW) and basal area increment (BAI) chronologies. Sampled sites encompassed a wide elevation gradient, from 3600 to 4400 m, including some treeline sites and diverse aspects and tree ages. In comparison with TRW series, BAI series better capture the long-term warming signal. Previous November and current April and summer temperatures are the dominant climatic factors controlling Smith fir radial growth. The mean inter-series correlations of TRW increased upwards, but the forest limit presented the highest potential to reconstruct past temperature variability. Moreover, the growth responses of young trees were less stable than those of trees older than 100 years. Climate warming is accelerating radial growth of Smith fir forest subjected to mesic conditions. Collectively, these findings confirm that the effects of site elevation and tree age should be considered when quantifying climate-growth relationships. The type of tree-ring data (BAI vs. TRW) is also relevant since BAI indices seem to be a better climatic proxy of low-frequency temperature signals than TRW indices. Therefore, site (e.g., elevation) and tree (e.g., age) features should be considered to properly evaluate the effects of climate warming on growth of high-elevation forests. PMID- 26939795 TI - Inducing labour in older women does not increase complications, study finds. PMID- 26939796 TI - A Toolbox for Rapid Quantitative Assessment of Chronological Lifespan and Survival in Saccharomyces cerevisiae. AB - Saccharomyces cerevisiae is a well-established model organism to study the mechanisms of longevity. One of the two aging paradigms studied in yeast is termed chronological lifespan (CLS). CLS is defined by the amount of time non dividing yeast cells can survive at stationary phase. Here, we propose new approaches that allow rapid and efficient quantification of survival rates in aging yeast cultures using either a fluorescent cell counter or microplate imaging. We have generated a software called analysr (Analytical Algorithm for Yeast Survival Rates) that allows automated and highly reproducible analysis of cell survival in aging yeast cultures using fluorescent data. To demonstrate the efficiency of our new experimental tools, we tested the previously characterized ability of caloric restriction to extend lifespan. Interestingly, we found that this process is independent of the expression of three central yeast heat shock proteins (Hsp26, Hsp42, Hsp104). Finally, our new assay is easily adaptable to other types of toxicity studies. Here, we assessed the toxicity of various concentrations of acetic acid, a known contributor of yeast chronological aging. These assays provide researchers with cost-effective, low- and high-content assays that can serve as an efficient complement to the time-consuming colony forming unit assay usually used in CLS studies. PMID- 26939797 TI - Do we need a dedicated hemodynamic control team? PMID- 26939798 TI - Perception of Mattering and Suicide Ideation in the Australian Working Population: Evidence from a Cross-Sectional Survey. AB - Thoughts about suicide are a risk factor for suicide deaths and attempts and are associated with a range of mental health outcomes. While there is considerable knowledge about risk factors for suicide ideation, there is little known about protective factors. The current study sought to understand the role of perceived mattering to others as a protective factor for suicide in a working sample of Australians using a cross-sectional research design. Logistic regression analysis indicated that people with a higher perception that they mattered had lower odds of suicide ideation than those with lower reported mattering, after controlling for psychological distress, demographic and relationship variables. These results indicate the importance of further research and intervention studies on mattering as a lever for reducing suicidality. Understanding more about protective factors for suicide ideation is important as this may prevent future adverse mental health and behavioural outcomes. PMID- 26939799 TI - Psychiatric Mental Health Nursing Workforce Agenda: Optimizing Capabilities and Capacity to Address Workforce Demands. AB - BACKGROUND: The mental health service delivery transformation has created models of care that generate demand for a workforce with particular competencies. OBJECTIVE: This article develops a psychiatric mental health (PMH) nursing workforce agenda in light of demand generated by new models of care and the capacity/capabilities of the PMH RN and advanced practice nurse (APN) workforce. DESIGN: Examine the current capacity of the PMH nursing workforce and how health care reform and related service delivery models create demand for a particular set of behavioral health workforce competencies. RESULTS: PMH RNs and APNs have an educational background that facilitates development of competencies in screening, care coordination, leveling care, and wellness education. PMH RNs are a large workforce but the size of the PMH APN group is inadequate to meet demand. CONCLUSION: The specialty must strategize on how to build requisite PMH RN and APN competencies for the evolving service landscape. PMID- 26939800 TI - Dodging Self-Incriminations: An Examination of Feigned Miranda Abilities on the SAMA. AB - Forensic assessments must always consider whether examinees are putting forth genuine effort or seeking to feign legally relevant incapacities. Miranda abilities are no exception when a putatively invalid Miranda waiver might result in the full suppression of an outright confession. Using a within-subjects simulation design, jail detainees were administered a representative Miranda warning and two Standardized Assessment of Miranda Abilities (SAMA) measures: Miranda Vocabulary Scale and Miranda Quiz. As expected, detainees have no difficulty in feigning severe deficits in their recall of the Miranda warning and portraying markedly impaired abilities on both SAMA measures. However, using floor-effect detection strategies, several feigning indicators proved effective at identifying likely feigned Miranda abilities. As an ancillary issue, the Inventory of Legal Knowledge was found to be very effective using both the traditional and revised scoring. PMID- 26939801 TI - Community-Based Validation of the Social Phobia Screener (SOPHS). AB - There is a need for brief, accurate screening scales for social anxiety disorder to enable better identification of the disorder in research and clinical settings. A five-item social anxiety screener, the Social Phobia Screener (SOPHS), was developed to address this need. The screener was validated in two samples: (a) 12,292 Australian young adults screened for a clinical trial, including 1,687 participants who completed a phone-based clinical interview and (b) 4,214 population-based Australian adults recruited online. The SOPHS (78% sensitivity, 72% specificity) was found to have comparable screening performance to the Social Phobia Inventory (77% sensitivity, 71% specificity) and Mini-Social Phobia Inventory (74% sensitivity, 73% specificity) relative to clinical criteria in the trial sample. In the population-based sample, the SOPHS was also accurate (95% sensitivity, 73% specificity) in identifying Diagnostic and Statistical Manual of Mental Disorders-Fifth edition social anxiety disorder. The SOPHS is a valid and reliable screener for social anxiety that is freely available for use in research and clinical settings. PMID- 26939802 TI - Occurrence and significance of tumor-associated neutrophils in patients with colorectal cancer. AB - Inflammatory cells are an essential component of the tumor microenvironment. Neutrophils have emerged as important players in the orchestration and effector phase of innate and adaptive immunity. The significance of tumor-associated neutrophils (TAN) in colorectal cancer (CRC) has been the subject of conflicting reports and the present study was designed to set up a reliable methodology to assess TAN infiltration in CRC and to evaluate their clinical significance. CD66b and myeloperoxidase (MPO) were assessed as candidate neutrophil markers in CRC using immunohistochemistry. CD66b was found to be a reliable marker to identify TAN in CRC tissues, whereas MPO also identified a subset of CD68(+) macrophages. CRC patients (n = 271) (Stages I-IV) were investigated retrospectively by computer-assisted imaging on whole tumor sections. TAN density dramatically decreases in Stage IV patients as compared to Stage I-III. At Cox analysis, higher TAN density was associated with better prognosis. Importantly, multivariate analysis showed that prognostic significance of TAN can be influenced by clinical stage and 5-fluorouracil(5-FU)-based chemotherapy. On separate analysis of Stage III patients (n = 178), TAN density had a dual clinical significance depending on the use of 5-FU-based chemotherapy. Unexpectedly, higher TAN density was associated with better response to 5-FU based chemotherapy. Thus, TAN are an important component of the immune cell infiltrate in CRC and assessment of TAN infiltration may help identify patients likely to benefit from 5-FU-based chemotherapy. These results call for a reassessment of the role of neutrophils in cancer using rigorous quantitative methodology. PMID- 26939803 TI - NETosis-associated serum biomarkers are reduced in type 1 diabetes in association with neutrophil count. AB - As the immune pathways involved in the pathogenesis of type 1 diabetes (T1D) are not fully understood, biomarkers implicating novel mechanisms of disease are of great interest and call for independent evaluation. Recently, it was reported that individuals with T1D display dramatic elevations in circulating components of neutrophil extracellular traps (NETs), indicating a potential role for NETosis in T1D. Our aim was to evaluate further the potential of NET-associated proteins as novel circulating biomarkers in T1D. We tested serum from subjects with T1D (n = 44) with a median age of 26.5 years and a median duration of 2.2 years, along with 38 age-matched controls. T1D subjects did not show elevations in either neutrophil elastase (NE) or proteinase 3 (PR3), as reported previously. In fact, both NE and PR3 levels were reduced significantly in T1D subjects, particularly in subjects within 3 years of diagnosis, consistent with the known reduction in neutrophil counts in recent-onset T1D. Indeed, levels of both NE and PR3 correlated with absolute neutrophil counts. Therefore, while not ruling out potential local or transient spikes in NETosis activity, the levels of these serum markers do not support a role for systemically elevated NETosis in the T1D population we studied. Rather, a modest reduction in these markers may reflect other important aspects of disease activity associated with reduced neutrophil numbers. PMID- 26939804 TI - Knowledge of staff members of residential care facilities for individuals with intellectual disability on medication administration via enteral feeding tube. AB - BACKGROUND: Guidelines for the safe administration of drugs through enteral feeding tube (EFT) are an important tool to minimise the risk of errors. This study aimed to investigate knowledge of these guidelines among staff of residential care facilities (RCF) for people with ID. METHOD: Knowledge was assessed using a 13-item self-administered questionnaire. Questions reflected key aspects of guidelines on medication administration via EFT. All staff members that administer medication through EFT in Belgian RCFs were invited to participate (n = 553). RESULTS: Nine out of 10 RCFs participated, and 356 questionnaires were collected. Almost all participants were women (96%), and most (82%) had a non-nursing educational background. Mean self-perceived knowledge of medication administration via EFT was 6.7 (on a 0-10 scale). On average, 5.7 (SD 1.9) out of 13 questions were answered correctly. A nursing degree and previous education on medication administration via EFT were associated with significantly higher scores. Guideline recommendations regarding rinsing of used medicine cups (90% correct answers) and preparation of hard gelatin capsules (89%) were known best. Those regarding the use of protective equipment when crushing toxic substances (4% correct answers), crushing of sustained release and enteric-coated dosage forms (6%), elevation of the patient's backrest (14%) and flushing of the EFT (15%) were known the least. CONCLUSION: This study identified a substantial lack of knowledge of guidelines for drug administration through EFT among staff of RCFs for people with ID. Our findings call for tailored educational programmes in order to increase knowledge on this subject. PMID- 26939806 TI - Real-time monitoring of calcification process by Sporosarcina pasteurii biofilm. AB - Sporosarcina pasteurii is known to produce calcite or biocement in the presence of urea and Ca(2+). Herein, we report the use of novel ultramicrosensors such as pH, Ca(2+), and redox sensors, along with a scanning electrochemical microscope (SECM), to monitor a real-time, bacteria-mediated urea hydrolysis process and subsequent changes in morphology due to CaCO3 precipitation. We report that the surface pH of a live biofilm changed rapidly from 7.4 to 9.2 within 2 min, whereas similar fast depletion (10 min) of Ca(2+) was observed from 85 mM to 10 mM in the presence of a high urea (10 g L(-1)) brine solution at 23 degrees C. Both the pH and the Ca(2+) concentration profiles were extended up to 600 MUm from the biofilm surface, whereas the bulk chemical composition of the brine solution remained constant over the entire 4 h of SECM experiments. In addition, we observed a change in biofilm surface morphology and an increase in overall biofilm height of 50 MUm after 4 h of precipitation. Electron microscopy confirmed the changes in surface morphology and formation of CaCO3 crystals. Development of the Ca(2+) profile took 10 min, whereas that of the pH profile took 2 min. This finding indicates that the initial urea hydrolysis process is fast and limited by urease or number of bacteria, whereas later CaCO3 formation and growth of crystals is a slow chemical process. The ultramicrosensors and approaches employed here are capable of accurately characterizing bioremediation on temporal and spatial scales pertinent to the microbial communities and the processes they mediate. PMID- 26939807 TI - The Role of Anticoagulation in a Patient with Atrial Fibrillation and a CHADS2 Score of 1. AB - The CHADS2 score is currently the most widely used stroke risk stratification scheme for identifying patients with atrial fibrillation (AF) at low and high risk of stroke, but there is controversy over how to treat those patients whom it identifies as at intermediate risk. This review summarizes current risk scores and discusses additional markers for risk, including echocardiographic parameters, AF subtype, and AF burden, that may provide further insight into thromboembolism risk in patients with indeterminant risk (CHADS2 1). PMID- 26939808 TI - An Approach to Catheter Ablation of Atrial Fibrillation in the Elderly. AB - Atrial fibrillation (AF) is the most common sustained arrhythmia encountered in clinical practice with a prevalence that is increasing with age. During the past decade, catheter ablation of AF has rapidly evolved from a highly experimental unproved procedure, to its current status as a commonly performed procedure in many major hospitals throughout the world for symptomatic, drug refractory, paroxysmal, and persistent AF. With improved safety and advances in technique, catheter ablation has also been offered to the elderly. This article reviews the most current literature with respect to long-term clinical efficacy, risks, and benefits of catheter ablation of AF in the elderly. PMID- 26939809 TI - The Management of Atrial Fibrillation in a Patient with Unrepaired Atrial Septal Defect. AB - Atrial fibrillation (AF) is a frequent comorbidity in adults with atrial septal defect (ASD), one of the most common congenital heart defects. However, there are currently limited recommendations for the management of AF associated with ASD. This article describes a case using a planned approach of catheter ablation followed by transcatheter device closure and discusses management options. PMID- 26939805 TI - Gastrin-releasing peptide receptor (GRPr) promotes EMT, growth, and invasion in canine prostate cancer. AB - BACKGROUND: The gastrin-releasing peptide receptor (GRPr) is upregulated in early and late-stage human prostate cancer (PCa) and other solid tumors of the mammary gland, lung, head and neck, colon, uterus, ovary, and kidney. However, little is known about its role in prostate cancer. This study examined the effects of a heterologous GRPr agonist, bombesin (BBN), on growth, motility, morphology, gene expression, and tumor phenotype of an osteoblastic canine prostate cancer cell line (Ace-1) in vitro and in vivo. METHODS: The Ace-1 cells were stably transfected with the human GRPr and tumor cells were grown in vitro and as subcutaneous and intratibial tumors in nude mice. The effect of BBN was measured on cell proliferation, cell migration, tumor growth (using bioluminescence), tumor cell morphology, bone tumor phenotype, and epithelial-mesenchymal transition (EMT) and metastasis gene expression (quantitative RT-PCR). GRPr mRNA expression was measured in primary canine prostate cancers and normal prostate glands. RESULTS: Bombesin (BBN) increased tumor cell proliferation and migration in vitro and tumor growth and invasion in vivo. BBN upregulated epithelial-to mesenchymal transition (EMT) markers (TWIST, SNAIL, and SLUG mRNA) and downregulated epithelial markers (E-cadherin and beta-catenin mRNA), and modified tumor cell morphology to a spindle cell phenotype. Blockade of GRPr upregulated E cadherin and downregulated VIMENTIN and SNAIL mRNA. BBN altered the in vivo tumor phenotype in bone from an osteoblastic to osteolytic phenotype. Primary canine prostate cancers had increased GRPr mRNA expression compared to normal prostates. CONCLUSION: These data demonstrated that the GRPr is important in prostate cancer growth and progression and targeting GRPr may be a promising strategy for treatment of prostate cancer. Prostate 76:796-809, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26939810 TI - Defibrillation Threshold Testing: Who Doesn't Get It? AB - Defibrillation testing has been routinely performed as part of the implantable cardioverter-defibrillator (ICD) implantation procedure, and is currently supported by practice guidelines; however, more recently, this practice has been called into question. Such testing is safe, and serious complications are rare. With modern ICD systems, physicians will rarely encounter a patient in whom defibrillation will fail. This article reviews the literature regarding the utility, necessity, complications, and cost of routine operative and follow-up defibrillation testing, and, it is hoped, clarifies the issue of "Who doesn't get it?" PMID- 26939811 TI - A Patient with a 40% Ejection Fraction Undergoes Atrioventricular Nodal Ablation for the Management of Atrial Fibrillation with Rapid Ventricular Rates. What Type of Device Should He Receive? AB - Patients with symptomatic atrial fibrillation not amenable to pharmacologic therapy or catheter ablation may be appropriate candidates for atrioventricular nodal (AVN) ablation and placement of a permanent pacemaker. The question arises as to whether to implant a right ventricular (RV)-only pacing device or a cardiac resynchronization therapy (CRT) device. This article examines 2 similar cases of patients presenting for AVN ablation who received RV-only pacing devices but had different clinical outcomes. This article discusses existing guidelines and studies that can help clinicians address the challenging question of whether an initial implant of a CRT pacing device is warranted in such patients. PMID- 26939812 TI - A Patient Presents with Longstanding, Severe LV Dysfunction. Is There a Role for Additional Risk Stratification Before ICD? AB - Increased longevity of patients with systolic heart failure caused by the use of implantable cardioverter-defibrillators (ICDs) is one of the most successful achievements in contemporary medicine. During the last 2 decades, the scientific community has striven to increase the benefits of ICD usage by specifying indications for primary prevention ICD implantation. Left ventricular ejection fraction is neither highly specific nor is it a highly sensitive risk marker of sudden cardiac death. The authors discuss risk-stratification approaches in different patient populations with structural heart disease and systolic heart failure. PMID- 26939813 TI - Should a Patient with Severe Left Ventricular Dysfunction, Congestive Heart Failure, and Right Bundle Branch Block QRS Receive Cardiac Resynchronization Therapy? AB - Cardiac resynchronization therapy (CRT) is an effective treatment for patients with heart failure and mechanical dyssynchrony. Patients with left bundle branch block and QRS greater than or equal to 150 milliseconds derive the greatest clinical response. Patients with right bundle branch block (RBBB) may not derive the same benefit. The reasons for this disparity are unclear, but may relate to differences in biventricular activation sequence and timing in the presence of left versus RBBB. This article provides a comprehensive review of current understanding of the clinical effectiveness of CRT in patients with left ventricular dysfunction and RBBB. PMID- 26939814 TI - Cardiac Resynchronization Therapy With and Without Defibrillator in a Commercial Truck Driver with Ischemic Cardiomyopathy and New York Heart Association Class III Heart Failure. AB - Commercial drivers warrant tighter restrictions to their driving privileges than private drivers. Patients with cardiac disease who are at risk of consciousness impairing arrhythmias are not allowed to drive commercially. Patients with left ventricular systolic dysfunction and/or heart failure symptoms are permanently disqualified from commercial driving. A biventricular pacemaker without defibrillator can improve symptoms and mortality in selected patients with heart failure. Biventricular pacing may have antiarrhythmic effects that may reduce the added benefit of a defibrillator. Motor vehicle collisions resulting from arrhythmic events are infrequent. The interests of public safety must outweigh individual liberties when driving safety is in question. PMID- 26939815 TI - Preventing Implantable Cardioverter Defibrillator Shocks Improves Survival. AB - Implanted cardioverter defibrillators (ICDs) reduce sudden cardiac death and all cause mortality in patients at an elevated risk of ventricular arrhythmia (VA). Patients with ICDs who receive shocks for VA have an increased mortality primarily due to worsening heart failure. Although VA and ICD shocks are a marker of progression of the underlying cardiomyopathy and disease process, there is evidence suggesting that ICD shocks are directly harmful to the myocardium and may contribute to the increase in mortality. Thus, although ICD shocks are a lifesaving therapy, they are also harmful and should be avoided whenever possible. PMID- 26939816 TI - The Role of Preventive Ablation of Ventricular Tachycardia in the Patient with Coronary Artery Disease, Reduced Left Ventricular Function, and a New Implantable Cardioverter Defibrillator Implant. AB - Most patients referred for ventricular tachycardia (VT) ablation have already suffered multiple therapies for recurrent VT, typically in the form of implantable cardioverter defibrillator (ICD) shocks. Recent landmark trials have looked at these populations and suggest potential usefulness of early, preventive ablation of VT in patients with ischemic cardiomyopathy. In this review the potential role of early VT ablation in patients with ischemic cardiomyopathy, current controversies regarding VT ablation in this population, and ongoing and future research that may further inform clinical decision making regarding optimal timing of ablation in these patients are discussed. PMID- 26939817 TI - Extraction of Sterile Leads: Is it Beneficial? AB - Extraction of sterile leads remains a controversial area. The risks and benefits of abandoning a lead are largely unknown, whereas the risks of lead extraction are better studied. Lead management decisions need to be made on a patient-by patient basis, with important input from the patient and family. This article presents several representative cases and reviews the major considerations in making the decision of whether or not to extract a sterile lead that has become either no longer needed or no longer functional. PMID- 26939818 TI - How Should Implantable Cardioverter-Defibrillator Lead Failures be Managed and What is the Role of Lead Extraction? AB - Despite remarkable advances in design, implantable cardioverter-defibrillator (ICD) leads remain the component most susceptible to failure, which often leads to substantial adverse clinical outcomes. This article focuses on management strategies when ICD lead systems fail. Two cases involving management decisions for ICD lead failures are presented and discussed. One involves a common mode of presentation, inappropriate shocks. The second involves an alert in a patient with a complex system and multiple comorbidities. Although a systematic approach is outlined, management decisions must be balanced by a risk-and-benefit assessment of the individual patient. PMID- 26939819 TI - Diagnostic and Therapeutic Dilemmas with Arrhythmic Right Ventricular Cardiomyopathy. AB - The diagnosis of arrhythmic right ventricular cardiomyopathy (ARVC) can be difficult, particularly in patients who have early manifestations of the disease. Modification of the 1994 Diagnostic Test Task Force criteria has recently been published. The most frequent cause for misdiagnosis is incorrect interpretation of a cardiac imaging test, particularly magnetic resonance imaging. The results of genetic testing must be interpreted with caution. Genetic abnormalities may be absent in 50% of patients with ARVC and penetrance is variable. PMID- 26939820 TI - The Evaluation of a Borderline Long QT Interval in an Asymptomatic Patient. AB - QT prolongation on resting electrocardiography (ECG) is common, and the clinician is often challenged by the dilemma of excluding acquired causes and recognizing potential congenital long QT syndrome (LQTS). The hallmark of LQTS is an abnormally long QT interval. However, a normal or borderline long QT interval may be observed in up to 50% of patients with LQTS because of the intermittent nature of QT prolongation. This review presents an approach to evaluating the asymptomatic patient with a borderline long QT interval, which incorporates a comprehensive clinical assessment, rest and provocative ECG testing, and genetic testing when appropriate. PMID- 26939821 TI - Evaluation of a Patient with a Positive Family History for Long QT Syndrome. AB - The hereditary long QT syndrome (LQTS) is a genetic channelopathy that is associated with increased propensity for polymorphic ventricular tachyarrhythmias and sudden cardiac death in young individuals with normal cardiac morphology. The diagnosis of this genetic disorder relies on a constellation of electrocardiographic, clinical, and genetic factors. Beta-blockers are the mainstay therapy in LQTS, whereas implantation of a cardioverter defibrillator is generally reserved for secondary prevention or for those who remain symptomatic on beta-blocker therapy. Herein we present a case that demonstrates important diagnostic and management dilemmas among patients who have a positive family history of LQTS. PMID- 26939822 TI - Atrial Fibrillation and Brugada Syndrome. AB - Since its first description in 1992, the Brugada syndrome (BrS) has attracted significant attention from the cardiology community because of its association with malignant ventricular arrhythmias and sudden cardiac death. Supraventricular tachyarrhythmias in BrS represent a unique and seemingly higher-risk clinical subgroup of patients with BrS. Atrial fibrillation represents the most common supraventricular arrhythmia in patients with BrS, with average ranges reported in the literature of 20% to 40%. This article summarizes the current literature regarding the patient with BrS with atrial fibrillation and discusses the management of these clinically challenging and potentially higher-risk individuals. PMID- 26939823 TI - The Management of Vasovagal Syncope in a Patient with Brugada Syndrome. AB - Vasovagal syncope is the most common cause of the neurally mediated reflex syncopes. A higher susceptibility to vasovagal syncope has been reported in patients with Brugada syndrome (BrS) and may be caused by associated autonomic dysfunction. It is unclear what risk vasovagal syncope confers to patients with BrS. This article reviews the pathophysiology of vasovagal syncope and autonomic dysfunction in patients with BrS and its association with BrS, treatment options for patients with BrS with vasovagal syncope, specific therapies and those that may be harmful in patients with BrS, and potential therapies and monitoring for patients with BrS with vasovagal syncope. PMID- 26939824 TI - Beyond the Shore of Ignorance. PMID- 26939825 TI - Difficult Decisions in Clinical Electrophysiology-A Case-Based Approach. PMID- 26939827 TI - FRET-based nanoprobes for simultaneous monitoring of multiple mRNAs in living cells using single wavelength excitation. AB - We demonstrate a novel strategy using FRET-based nanoprobes for the simultaneous detection of multiple mRNAs with single wavelength excitation in living cells. PMID- 26939828 TI - The use of Bioptron light (polarized, polychromatic, non-coherent) therapy for the treatment of acute ankle sprains. AB - Purpose The purpose of this study was to investigate the efficacy of Bioptron light therapy for the treatment of acute ankle sprains. Method A parallel group, single-blind, controlled study was carried out in patients with grade II acute ankle sprains. Patients were randomly allocated into two treatment groups (n = 25 for each). Both groups received cryotherapy, and the test group also received Bioptron light therapy. All treatments were performed daily for 5 d. Evaluations included self-reported pain via a visual analogue scale, degree of ankle edema, and ankle range of motion via goniometry carried out before the treatment and at the end of the treatment. Results The test group showed the largest magnitude of improvement for all evaluations at treatment five, and the between-group differences observed were statistically significant (p < 0.0005 for each). Conclusions These data provide preliminary evidence of the efficacy of Bioptron light therapy supplemented with cryotherapy for the treatment of acute ankle sprains; however, larger studies are required to confirm these results. Implications for Rehabilitation Ankle sprains are common acute injuries among professional and recreational sports players but also among people in general. Cryotherapy is the first-standard treatment of acute ankle sprains. Phototherapy such as Bioptron light has been recommended supplement to cryotherapy to reduce the symptoms of ankle sprains. The results of the present trial showed that using BIOPTRON LIGHT and cryotherapy the rehabilitation period of acute ankle sprains can be reduced. PMID- 26939830 TI - Efficacy of Chemical Mimicry by Aphid Predators Depends on Aphid-Learning by Ants. AB - Chemical mimicry is an effective strategy when signal receivers recognize and discriminate models by relying on chemical cues. Some aphid enemies mimic the cuticular chemicals of aphids through various means thus avoiding detection and attack by aphid-tending ants. However, because ants have been reported to learn the chemical signatures of aphids in order to distinguish the aphids, the efficacy of chemical mimicry is predicted to depend on the experience of the ants that had tended aphids. The present study tested this hypothesis using two predator species: larvae of the green lacewing Mallada desjardinsi, and larvae of the ladybeetle Scymnus posticalis. Lacewing larvae carry the carcasses of aphids on which they have preyed upon their backs, and these function via chemical camouflage to reduce the aggressiveness of aphid-tending ants toward the larvae. Ladybeetle larvae reportedly produce a covering of wax structures, and their chemicals appear to attenuate ant aggression. We examined whether the behavior of the ant Tetramorium tsushimae toward these predators changed depending on their aphid-tending experience. Ants moderated their aggressiveness toward both predators when they had previously tended aphids, indicating that chemical mimicry by both aphid predators is dependent on previous experience of the ants in tending aphids. Chemical mimicry by the predators of ant-tended aphids is therefore considered to exploit learning-dependent aphid recognition systems of ants. PMID- 26939826 TI - Rapid estrogen actions on ion channels: A survey in search for mechanisms. AB - A survey of nearly two hundred reports shows that rapid estrogenic actions can be detected across a range of kinds of estrogens, a range of doses, on a wide range of tissue, cell and ion channel types. Striking is the fact that preparations of estrogenic agents that do not permeate the cell membrane almost always mimic the actions of the estrogenic agents that do permeate the membrane. All kinds of estrogens, ranging from natural ones, through receptor modulators, endocrine disruptors, phytoestrogens, agonists, and antagonists to novel G-1 and STX, have been reported to be effective. For actions on specific types of ion channels, the possibility of opposing actions, in different cases, is the rule, not the exception. With this variety there is no single, specific action mechanism for estrogens per se, although in some cases estrogens can act directly or via some signaling pathways to affect ion channels. We infer that estrogens can bind a large number of substrates/receptors at the membrane surface. As against the variety of subsequent routes of action, this initial step of the estrogen's binding action is the key. PMID- 26939829 TI - MATERNAL SELF-REPORTED DEPRESSIVE SYMPTOMS AND MATERNAL CORTISOL LEVELS INTERACT TO PREDICT INFANT CORTISOL LEVELS. AB - Three basic findings have emerged from research on maternal depressive symptoms and offspring hypothalamic-pituitary-adrenal functioning: (a) Mothers' depressive symptoms are positively associated with their offsprings' cortisol stress response, (b) numerous individual and interpersonal maternal characteristics moderate this association, and (c) maternal and infant cortisol levels are highly correlated. In combination, these findings have suggested that maternal cortisol levels may moderate the relation between maternal depressive symptoms and infant cortisol responsivity; the current study assessed this hypothesis. Participants were 297 mother-infant dyads who were recruited from the community. Maternal depressive symptoms were assessed via self-report. Dyads participated in two differentially stressful infant challenges when infants were 16 and 17 months old. Mother and infant salivary cortisol was collected before and after challenges. Results indicate that maternal cortisol levels moderated associations between maternal depressive symptoms and infant cortisol levels across both challenges. Infants showed higher cortisol levels if their mothers had both higher depressive symptoms and higher cortisol levels, as compared to infants of mothers with higher depressive symptoms and lower cortisol, and to infants of mothers with lower depressive symptoms and either higher or lower cortisol levels. We discuss findings in relation to environmental and biological factors that may contribute to the intergenerational transmission of depressive symptoms. PMID- 26939832 TI - Dimethyl trisulfide: A novel cyanide countermeasure. AB - In the present studies, the in vitro and in vivo efficacies of a novel cyanide countermeasure, dimethyl trisulfide (DMTS), were evaluated. DMTS is a sulfur based molecule found in garlic, onion, broccoli, and similar plants. DMTS was studied for effectiveness as a sulfur donor-type cyanide countermeasure. The sulfur donor reactivity of DMTS was determined by measuring the rate of the formation of the cyanide metabolite thiocyanate. In experiments carried out in vitro in the presence of the sulfurtransferase rhodanese (Rh) and at the experimental pH of 7.4, DMTS was observed to convert cyanide to thiocyanate with greater than 40 times higher efficacy than does thiosulfate, the sulfur donor component of the US Food and Drug Administration-approved cyanide countermeasure Nithiodote(r) In the absence of Rh, DMTS was observed to be almost 80 times more efficient than sodium thiosulfate in vitro The fact that DMTS converts cyanide to thiocyanate more efficiently than does thiosulfate both with and without Rh makes it a promising sulfur donor-type cyanide antidote (scavenger) with reduced enzyme dependence in vitro The therapeutic cyanide antidotal efficacies for DMTS versus sodium thiosulfate were measured following intramuscular administration in a mouse model and expressed as antidotal potency ratios (APR = LD50 of cyanide with antidote/LD50 of cyanide without antidote). A dose of 100 mg/kg sodium thiosulfate given intramuscularly showed only slight therapeutic protection (APR = 1.1), whereas the antidotal protection from DMTS given intramuscularly at the same dose was substantial (APR = 3.3). Based on these data, DMTS will be studied further as a promising next-generation countermeasure for cyanide intoxication. PMID- 26939831 TI - Relationship between HRV measurements and demographic and clinical variables in a population of patients with atrial fibrillation. AB - Little is known about the role of HRV in atrial fibrillation (AF) patients. Aim of our study was to assess the relationship between HRV measurements and demographic and clinical variables in a population of 274 AF patients. We selected all consecutive patients with persistent/permanent AF among whom had performed a Holter ECG in our Department from April 2010 to April 2015. Time domain analysis of HRV was evaluated. Demographic and clinical variables were collected for each patient. At multivariable logistic regression, a higher pNN50 was associated with ACE inhibitors/ARBs (p = 0.016) and a lower pNN50 with obesity (p = 0.037) and higher heart rate (HR) (p < 0.0005). A higher RMSSD was associated with ACE inhibitors/ARBs (p = 0.001), digitalis (p < 0.0005) and beta blockers (p = 0.002) and a lower RMSSD with a higher HR (p < 0.0005). A higher SDNNi was associated with ACE inhibitors/ARBs (p < 0.0005), digitalis (p < 0.0005) and beta-blockers (p = 0.002) and a lower SDNNi with dysthyroidism (p = 0.048) and higher HR (p < 0.0005). A higher SDANN was associated with non dihydropyiridine calcium-channel-blockers (p = 0.002) and ACE inhibitors/ARBs (p = 0.002) and a lower SDANN with hypertension (p = 0.034), obesity (p = 0.011), stroke (p = 0.031), pneumonia (p = 0.005) and higher HR (p < 0.0005). A higher SDNN was associated with ACE inhibitors/ARBs (p < 0.0005), digitalis (p < 0.0005) and beta-blockers (p = 0.022) and a lower SDNN with obesity (p = 0.012), pneumonia (p = 0.049) and higher HR (p < 0.0005). Our study showed that, in AF patients, there is a direct relationship between some clinical variables and HRV measurements; as for patients with sinus rhythm, even in AF patients this relationship seemed to reflect the autonomic nervous system activity. PMID- 26939833 TI - Lung toxicity in mice of airborne particulate matter from a modern layer hen facility containing Proposition 2-compliant animal caging. AB - Proposition 2, which requires that egg-laying hens be confined only in ways that allow these animals to lie down, stand up, fully extend their limbs and turn around freely, was passed by the voters of California in 2008. These new housing requirements were introduced in the USA and European Union without considering the potential impact of changes in layer hen housing on the health of poultry workers in the new facilities. Particles were collected from ambient air inside a large layer hen complex featuring separate barns with conventional battery caging, enriched caging, or 'free range' (aviary) housing during winter, spring, and summer seasons over one year. Toxicity of the particles was evaluated by analysis of inflammatory cell influx into lung lavage fluid after intratracheal instillation into mice. Capacity of the particles to elicit oxidative stress was evaluated using a macrophage cell line engineered with a reporter gene sensitive to nuclear factor kappaB activation. We observed similar pro-inflammatory and pro oxidant effects of the particles collected from different types of barns and over different seasons, suggesting that standard industrial hygiene techniques for evaluating respirable particles in ambient air can adequately monitor worker risk. Based on particle concentrations found in ambient air in the barns, we can rank the facilities for worker exposure to particles as conventional caging (now banned) approximately equal to enriched caging (permitted under Proposition 2). Aviary housing is associated with increased exposure of workers to particulate matter and, therefore, to greater risk of allergic reactions and/or decreased respiratory function. PMID- 26939834 TI - Hydrogen sulphide and phosphine interactions with human skin in vitro. AB - Accidental or intentional releases of toxic gases can have significant public health consequences and emergency resource demands. Management of exposed individuals during hazardous material incidents should be risk and evidence based, but there are knowledge gaps in relation to dermal absorption of gases and management advice for potentially exposed individuals. Using a modified Organization for Economic Co-operation and Development (OECD) in vitro toxicology protocol with human donor skin, this article reports on two common and odorous chemicals, hydrogen sulphide and phosphine. Results show that undamaged human skin provides a good barrier to hydrogen sulphide (up to 800 ppm) and phosphine (up to 1000 ppm) penetration for up to 30 min exposures, with little variability in the presence of clothing or in elevated temperature and humidity conditions. A practical guideline template for skin decontamination has been developed, and implications of the research for first responders are outlined. PMID- 26939835 TI - Credible evidence for the passivation effect of remnant PbI2 in CH3NHCH3PbICH3 films in improving the performance of perovskite solar cells. AB - The role of remnant PbI2 in CH3NH3PbI3 films is still controversial, some investigations have revealed that the remnant PbI2 plays a passivation role, reduces the charge recombination in perovskite solar cells (PSCs), and improves the performance of PSCs, but the opposing views state that remnant PbI2 has no passivation effect and it would deteriorate the stability of the devices. In our investigation, the CH3NH3PbI3 films have been prepared by a two-step spin-coating method and the content of the remnant PbI2 in CH3NH3PbI3 films has been tuned by varying the preparation temperature. It has been found that increasing the heating temperature could increase the coverage of spin-coated PbI2 films, which has led to high coverage CH3NH3PbI3 films and more remnant PbI2 in CH3NH3PbI3 films, and as a result, the performance of PSCs was enhanced obviously and the maximum power conversion efficiency of 14.32 +/- 0.28% was achieved by the PSCs prepared at 130/120 degrees C (PbI2 films were heated at 130 degrees C and CH3NH3PbI3 films were heated at 120 degrees C). Furthermore, the dark current, electrochemical impedance spectroscopy and time-resolved fluorescence emission decay measurements revealed that the charge recombination in PSCs has been gradually suppressed and the fluorescence emission lifetime has gradually increased with the content of remnant PbI2 increasing. Thus, the passivation effects of the unreacted and decomposed PbI2 in improving the performance of PSCs have been confirmed unquestionably. PMID- 26939836 TI - Self-Regulatory Skill Among Children with and without Developmental Coordination Disorder: An Exploratory Study. AB - AIM: Children with developmental coordination disorder (DCD) experience difficulty learning and performing everyday motor tasks due to poor motor coordination. Recent research applying a cognitive learning paradigm has argued that children with DCD have less effective cognitive and metacognitive skills with which to effectively acquire motor skills. However, there is currently limited research examining individual differences in children's use of self regulatory and metacognitive skill during motor learning. This exploratory study aimed to compare the self-regulatory performance of children with and without DCD. METHODS: Using a mixed methods approach, this study observed and compared the self-regulatory behavior of 15 children with and without DCD, aged between 7 and 9 years, during socially mediated motor practice. Observation was conducted using a quantitative coding scheme and qualitative analysis of video-recorded sessions. This paper will focus on the results of quantitative analysis, while data arising from the qualitative analysis will be used to support quantitative findings. RESULTS: In general, findings indicate that children with DCD exhibit less independent and more ineffective self-regulatory skill during motor learning than their typically developing peers. In addition, children with DCD rely more heavily on external support for effective regulation and are more likely to exhibit negative patterns of motivational regulation. CONCLUSIONS: These findings provide further support for the notion that children with DCD experience difficulty effectively self-regulating motor learning. Implications for practice and directions for future research are discussed. PMID- 26939837 TI - Introduction: Linkages among traumatic experiences and psychosocial factors and ecological outcomes for children and adolescents. PMID- 26939838 TI - Community-based counselors' interventions for elementary school-age children coping with trauma. AB - Child trauma is a mental health concern and more information is needed about treatment in community mental health settings. This article presents results of a focus group and member checking sessions held with counselors who provided therapy for children experiencing posttraumatic stress disorder in a community based setting. Results indicated that play and art techniques were commonly used during individual child therapy sessions. Sessions were child-directed and allowed children to review trauma experiences in a "safe" setting with an "expert" guide. Several themes were commonly addressed in sessions including opportunities to re-experience, release, and reorganize the trauma, building resilience or self-esteem for the child, promoting safety, and helping the child to regulate emotional reactions and behavior problems. Counselors focused on discussing ways to interact with the child to promote healing and there was a belief that children would return to a positive developmental trajectory after coping with traumatic experiences. Future research needs to address what works for whom, in terms of what interventions are useful in child-directed counseling sessions for children who have experienced specific types of trauma, such as sexual and physical abuse or witnessing domestic violence. Integration of knowledge from evidence-based treatments will also further inform clinical practice with children who have experienced traumatic events. PMID- 26939839 TI - Predictors of child functioning and problem behaviors for children diagnosed with posttraumatic stress disorder and externalizing problems. AB - Posttraumatic stress disorder and behavioral disorders are related to problems in emotional functioning for young children. Factors related to child functioning are important to understand in order to develop interventions and assess their impact. This study examined clinician and parent reports of child functioning and behavior problems and factors related to each of these outcome variables. Results indicated that parental acceptance was inversely related to child behavior problems. Increased parental supervision of the child was related to high total problems scores. Parental acceptance was positively related to child functioning. Future research is needed to examine relations among interventions to improve parental supervision and interactions with the child and child functioning, in terms of both positive and negative behaviors. PMID- 26939840 TI - The influence of potentially traumatic household characteristics on blunt use among Black youth. AB - The residential status of mothers and fathers in the household has been shown to influence drug use and other health outcomes among adolescents. However, no studies have examined if these household characteristics influence blunt use (marijuana mixed with or replacing tobacco in cigar paper), specifically among Black adolescents. Using data from the 2012 National Survey on Drug Use and Health, this study was designed to examine the relationship between household characteristics (non-residential mother vs. residential mother and non residential father vs. residential father) and blunt use among Black male and female adolescents. Findings revealed that Black males with non-residential fathers were more likely to have smoked blunts in their lifetime than Black males with residential fathers, illustrating the importance of fathers in the lives of Black males. PMID- 26939841 TI - Recent alcohol use, episodic heavy drinking, and school violent victimization: Sex and grade level differences among Hispanic youth. AB - Alcohol use and involvement in school violent victimization are two significant public health problems among Hispanic youth. The present study examined alcohol use by involvement in school violent victimization among seventh through twelfth grade Hispanic students in one metropolitan area. The Pride Student National Survey was administered to students in their school classrooms. Results indicated that Hispanic students who were involved in school violent victimization were at increased risk for recent alcohol use and frequent episodic heavy drinking compared to Hispanic students who were not involved. Logistic regression revealed Hispanic males, junior high school, and high school students were at increased odds for recent alcohol use based on involvement in school violent victimization. Regarding frequent episodic heavy drinking, Hispanic males, females, and high school students were at increased odds. These findings can aid professionals in developing effective prevention programs and efforts for this high-risk population. Recommendations for future studies are included. PMID- 26939842 TI - School bullying and student trauma: Fear and avoidance associated with victimization. AB - Bullying is a significant problem in U.S. schools. The purpose of the present study is to examine the impact student bullying has on avoidance behaviors and fear at school among youth nationwide. Data from the School Crime and Safety Survey was analyzed. Participants included 5,784 U.S. students in grades 5 through 12. Almost one-third of students reported being bullied in the past year. Females, junior high school students, and public school students were significantly more likely to report being bullied than their counterparts. Students who were bullied were significantly more likely than students who had not been bullied to report fear and avoidance. Prevention and intervention programs are needed to reduce bullying and negative consequences associated with the behavior. PMID- 26939843 TI - Authoritarian parenting and youth depression: Results from a national study. AB - Depression is a prevalent illness affecting youth across the nation. The study purpose was to examine depression and authoritarian parenting among youth from 12 to 17 years of age. A secondary data analysis of the National Survey on Drug Use and Health was performed in the present study. All participants in the present study were youth (N = 17,399) nationwide. The results revealed that 80.6% of youth participants reported having five or more depressive symptoms. Parenting styles based on depression significantly differed among males, females, 12-13 year-olds, 14-15-year-olds, and 16-17-year-olds. Specifically, those who reported experiencing authoritarian parenting practices were more likely to report depressive symptoms compared to their counterparts who experienced authoritative parenting practices. Emphasizing the role of the parents and teaching positive parenting practices and authoritative parenting styles may increase success of prevention programs. PMID- 26939844 TI - Phosphorus removal coupled to bioenergy production by three cyanobacterial isolates in a biofilm dynamic growth system. AB - In the present study a closed incubator, designed for biofilm growth on artificial substrata, was used to grow three isolates of biofilm-forming heterocytous cyanobacteria using an artificial wastewater secondary effluent as the culture medium. We evaluated biofilm efficiency in removing phosphorus, by simulating biofilm-based tertiary wastewater treatment and coupled this process with biodiesel production from the developed biomass. The three strains were able to grow in the synthetic medium and remove phosphorus in percentages, between 6 and 43%, which varied between strains and also among each strain according to the biofilm growth phase. Calothrix sp. biofilm turned out to be a good candidate for tertiary treatment, showing phosphorus reducing capacity (during the exponential biofilm growth) at the regulatory level for the treated effluent water being discharged into natural water systems. Besides phosphorus removal, the three cyanobacterial biofilms produced high quality lipids, whose profile showed promising chemical stability and combustion behavior. Further integration of the proposed processes could include the integration of oil extracted from these cyanobacterial biofilms with microalgal oil known for high monounsaturated fatty acids content, in order to enhance biodiesel cold flow characteristics. PMID- 26939845 TI - Should clinical trials be approached differently for rare cancers? PMID- 26939846 TI - Insulin and vanadium protect against osteoarthritis development secondary to diabetes mellitus in rats. AB - OBJECTIVE: Diabetic complications such as cardiovascular disease and osteoarthritis (OA) are among the common public health problems. The effect of insulin on OA secondary to diabetes has not been investigated before in animal models. Therefore, we sought to determine whether insulin and the insulin mimicking agent, vanadium can protect from developing OA in diabetic rats. METHODS: Type 1 diabetes mellitus (T1DM) was induced in Sprague-Dawley rats and treated with insulin and/or vanadium. Tissues harvested from the articular cartilage of the knee joint were examined by scanning electron microscopy, and blood samples were assayed for oxidative stress and inflammatory biomarkers. RESULTS: Eight weeks following the induction of diabetes, a profound damage to the knee joint compared to the control non-diabetic group was observed. Treatment of diabetic rats with insulin and/or vanadium differentially protected from diabetes-induced cartilage damage and deteriorated fibrils of collagen fibers. The relative biological potencies were insulin + vanadium >> insulin > vanadium. Furthermore, there was about 2- to 5-fold increase in TNF-alpha (from 31.02 +/- 1.92 to 60.5 +/- 1.18 pg/ml, p < 0.0001) and IL-6 (from 64.67 +/- 8.16 to 338.0 +/- 38.9 pg/ml, p < 0.0001) cytokines and free radicals measured as TBARS (from 3.21 +/- 0.37 to 11.48 +/- 1.5 uM, p < 0.0001) in the diabetic group, which was significantly reduced with insulin and or vanadium. Meanwhile, SOD decreased (from 17.79 +/- 8.9 to 8.250.29, p < 0.0001) and was increased with insulin and vanadium. The relative potencies of the treating agents on inflammatory and oxidative stress biomarkers were insulin + vanadium >> insulin > vanadium. CONCLUSION: The present study demonstrates that co-administration of insulin and vanadium to T1DM rats protect against diabetes-induced OA possibly by lowering biomarkers of inflammation and oxidative stress. PMID- 26939847 TI - Probiotic nomenclature matters. PMID- 26939848 TI - Systems-wide analyses of mucosal immune responses to Helicobacter pylori at the interface between pathogenicity and symbiosis. AB - Helicobacter pylori is the dominant member of the gastric microbiota in over half of the human population of which 5-15% develop gastritis or gastric malignancies. Immune responses to H. pylori are characterized by mixed T helper cell, cytotoxic T cell and NK cell responses. The presence of Tregs is essential for the control of gastritis and together with regulatory CX3CR1+ mononuclear phagocytes and immune-evasion strategies they enable life-long persistence of H. pylori. This H. pylori-induced regulatory environment might contribute to its cross-protective effect in inflammatory bowel disease and obesity. Here we review host-microbe interactions, the development of pro- and anti-inflammatory immune responses and how the latter contribute to H. pylori's role as beneficial member of the gut microbiota. Furthermore, we present the integration of existing and new data into a computational/mathematical model and its use for the investigation of immunological mechanisms underlying initiation, progression and outcomes of H. pylori infection. PMID- 26939850 TI - Gut microbiota amplifies host-intrinsic conversion from the CD8 T cell lineage to CD4 T cells for induction of mucosal immune tolerance. AB - Microbiota has been shown to promote tolerogenic differentiation of T lymphocytes. It remains unclear to what extent microbiota triggers de novo re programming or amplify pre-existing plasticity intrinsic to T cells. In a study with mouse models to track the clonal fate of CD4 and CD8 T cells, we discovered that CD8 T cells converted to MHC class I-restricted CD4 T cells without regard to selfness of their antigen specificity. In mesenteric lymph nodes (MLN), CD8 T cells converted to CD4(+)Foxp3(+) regulatory T (Treg) cells which were enriched in the large intestine lamina propria (LILP) and suppressed chemical- or immune mediated inflammatory damage. In germ-free conditions, the converted CD4 populations were present in MLN, but absent in LILP. Therefore, an intrinsic plasticity in the host was amplified by the gut microbiota, leading to selfless tolerance induction in the intestinal mucosa. The findings may be relevant to HIV infection, cancer and autoimmune disorders. PMID- 26939849 TI - Consequences of bile salt biotransformations by intestinal bacteria. AB - Emerging evidence strongly suggest that the human "microbiome" plays an important role in both health and disease. Bile acids function both as detergents molecules promoting nutrient absorption in the intestines and as hormones regulating nutrient metabolism. Bile acids regulate metabolism via activation of specific nuclear receptors (NR) and G-protein coupled receptors (GPCRs). The circulating bile acid pool composition consists of primary bile acids produced from cholesterol in the liver, and secondary bile acids formed by specific gut bacteria. The various biotransformation of bile acids carried out by gut bacteria appear to regulate the structure of the gut microbiome and host physiology. Increased levels of secondary bile acids are associated with specific diseases of the GI system. Elucidating methods to control the gut microbiome and bile acid pool composition in humans may lead to a reduction in some of the major diseases of the liver, gall bladder and colon. PMID- 26939851 TI - Helicobacter pylori and gut microbiota modulate energy homeostasis prior to inducing histopathological changes in mice. AB - Helicobacter pylori have been shown to influence physiological regulation of metabolic hormones involved in food intake, energy expenditure and body mass. It has been proposed that inducing H. pylori-induced gastric atrophy damages hormone producing endocrine cells localized in gastric mucosal layers and therefore alter their concentrations. In a recent study, we provided additional proof in mice under controlled conditions that H. pylori and gut microbiota indeed affects circulating metabolic gut hormones and energy homeostasis. In this addendum, we presented data from follow-up investigations that demonstrated H. pylori and gut microbiota-associated modulation of metabolic gut hormones was independent and precedes H. pylori-induced histopathological changes in the gut of H. pylori infected mice. Thus, H. pylori-associated argumentation of energy homeostasis is not caused by injury to endocrine cells in gastric mucosa. PMID- 26939852 TI - Do biofilms confer a pro-carcinogenic state? AB - It is now widely recognized that a range of human diseases, including obesity, cancer and inflammatory bowel disease, is strongly linked to the microbiota. For decades, the microbiota has been proposed to contribute to the pathogenesis of colon cancer. Our recent work reveals that the organization of the mucosal microbiota into biofilms marks a subset of human colon cancer. Further, biofilm positive colon mucosa in the colon cancer host yields an infrequently detected polyamine metabolite, N(1), N(12)-diacetylspermine, that deserves further study to determine its utility as a marker for colon neoplasia. PMID- 26939854 TI - Mechanosensing regulates virulence in Escherichia coli O157:H7. AB - Enterohemorrhagic Escherichia coli O157:H7 is a food-borne pathogen transmitted via the fecal-oral route, and can cause bloody diarrhea and hemolytic uremic syndrome (HUS) in the human host. Although a range of colonization factors, Shiga toxins and a type III secretion system (T3SS) all contribute to disease development, the locus of enterocyte effacement (LEE) encoded T3SS is responsible for the formation of lesions in the intestinal tract. While a variety of chemical cues in the host environment are known to up-regulate LEE expression, we recently demonstrated that changes in physical forces at the site of attachment are required for localized, full induction of the system and thus spatial regulation of virulence in the intestinal tract. Here, we discuss our findings in the light of other recent studies describing mechanosensing of the host and force-dependent induction of virulence mechanisms. We discuss potential mechanisms of mechanosensing and mechanotransduction, and the level of conservation across bacterial species. PMID- 26939853 TI - The Intersection of TNF, IBD and the Microbiome. AB - Inflammatory bowel disease (IBD), comprised of Crohn's disease and ulcerative colitis, is a chronic inflammatory condition of multifactorial etiology and risk factors. Currently, one of the most effective treatments for IBD is the use of Tumor Necrosis Factor (TNF) functional inhibitor drugs, however, this treatment can cause adverse reactions and has a relatively large percentage of incomplete or non-responders. This lack of response may be related to differences in patients' gut microbiomes prior to and after disease initiation or treatment. Recent observations in our lab using a rodent model of IBD support the theory that TNF drives acute colitis, but also that the microbiome differs in association with TNF production and colitis severity. Studies such as this and others provide new insights into host-microbiome interactions associated with colitis that can lead to new therapies to prevent or treat the disease. PMID- 26939855 TI - The LT1 and LT2 variants of the enterotoxigenic Escherichia coli (ETEC) heat labile toxin (LT) are associated with major ETEC lineages. AB - The heat-labile toxin (LT) is one of the major virulence factors of enterotoxigenic Escherichia coli (ETEC). We recently described that 20 polymorphic LT variants are present in ETEC strains isolated globally. Two of the variants, LT1 and LT2, are particularly common and we found that they were associated with clonal ETEC lineages that express the colonization factors (CFs), CFA/I, CS1+CS3, CS2+CS3, and CS5+CS6. ETEC expressing these CFs are frequently found among ETEC strains isolated from cases with diarrhea. ETEC expressing the colonization factors CS1+CS3, and CS2+CS3 are found in 2 discrete clonal lineages and express the LT1 variant and heat stable toxin (STh). Although they clearly are virulent they neither produce, nor secrete, high amounts of LT toxin. On the other hand ETEC strains expressing LT, STh, CFA/I and LT, STh, CS5+CS6, carry the LT2 variant and produce and secrete significantly more LT toxin. Despite differences in toxin production, LT1 and LT2 are found in ETEC lineages that have managed to spread globally confirming that these variants are important for ETEC virulence. PMID- 26939856 TI - Different Th17 immunity in gut, liver, and adipose tissues during obesity: the role of diet, genetics, and microbes. AB - Microbes modify immunometabolism responses linking obesity and type 2 diabetes. Immunity helps maintain a host-microbe symbiosis, but inflammation can promote insulin resistance in tissues that control blood glucose. We were interested in compartmentalization of immune responses during obesity and show here that feeding mice an obesity-causing high-fat diet (HFD) decreased a marker of neutrophil activation and cytokines related to Th17 responses in the gut. A HFD decreased IL-17 and IL-21/22 in the ileum and colon, respectively. A HFD increased IL-17, IL-21/22 and other related Th17 responses in the liver. At the whole tissue level, there is divergence in gut and metabolic tissue Th17 cytokines during diet-induced obesity. Deletion of the bacterial peptidoglycan sensor NOD2 had relatively minor effects on these immune responses. We propose a model where diet-induced obesity promotes a permissive gut immune environment and sets the stage for host genetics to contribute to dysbiosis-driven metabolic tissue inflammation. PMID- 26939858 TI - Autophagy gets to the bone. PMID- 26939857 TI - Killing of VRE Enterococcus faecalis by commensal strains: Evidence for evolution and accumulation of mobile elements in the absence of competition. AB - Enterococci are members of the gastrointestinal tract of humans and most animals that, over the past 3 decades, have emerged as leading causes of multidrug resistant hospital acquired infection (HAI). In addition to their general hardiness, many traits have entered enterococcal lineages through horizontal gene transfer, which has led to the evolution of pathogenic hospital-associated lineages uniquely adapted for survival and proliferation in the antibiotic perturbed ecology of the gastrointestinal tract. We recently observed that the accretion of mobile genetic elements in the prototype vancomycin resistant E. faecalis, clinical isolate V583, renders it unable to co-exist with native enterococci in healthy human fecal flora. In this addendum, we discuss how these findings inform our understanding of how multidrug resistant enterococci evolve, and the implications for the development of treatments that limit colonization and spread of highly antibiotic refractory microbes of this type. PMID- 26939859 TI - A preliminary study using virtual touch imaging and quantification for the assessment of skin stiffness in systemic sclerosis. AB - OBJECTIVES: To evaluate ultrasound Virtual Touch Imaging and Quantification (VTIQ) as a method for determining absolute skin stiffness in patients with systemic sclerosis (SSc). METHODS: Skin thickness, assessed by the modified Rodnan Skin Score (mRSS) and absolute skin stiffness, using VTIQ, were measured at all mRSS anatomical sites to quantify the shear wave velocity (in m/s) in 26 SSc patients and in 17 age- and gender-matched controls. Correlations between mRSS and absolute skin stiffness, and comparisons between patients and controls were analysed statistically using Mann-Whitney U tests and correlations between variables using Pearson's. P values <0.05 were considered significant. RESULTS: Shear wave velocity as a measure of skin stiffness was significantly higher in SSc than in controls in 11 out of 16 mRSS sites investigated. Shear-wave velocity was strongly correlated with the local mRSS in the following anatomical sites: forearm, hand, phalanx, and thigh. In the patient group, clinically unaffected skin could also be differentiated from healthy skin using shear-wave velocity. CONCLUSIONS: VTIQ represents an innovative and promising technique that provides, for the first time, a non-invasive, absolute quantification of skin stiffness. Further studies of VTIQ are required, but this early study supports the clinical and scientific potential of this new measure of skin involvement in SSc. PMID- 26939860 TI - Morbidity and Mortality Associated With Robotic Head and Neck Surgery: An Inquiry of the Food and Drug Administration Manufacturer and User Facility Device Experience Database. PMID- 26939861 TI - Positive TTF-1 Expression in Malignant Mesothelioma: A Case Report. AB - BACKGROUND: The histopathological diagnosis of malignant mesothelioma is based mainly on the immunohistological profile of the neoplasia, using different immunohistochemical markers to distinguish between a malignant mesothelioma and a carcinoma. CASE REPORT: A female patient presented with a right paravertebral rapidly growing tumor and severe pain. Based on the immunohistochemical findings, we present the first case of a malignant mesothelioma with immunohistochemical expression of thyroid transcription factor-1. CONCLUSIONS: The detection of a positive reaction for thyroid transcription factor-1 in the tumor cells may not exclude a malignant mesothelioma. PMID- 26939863 TI - Orphan devices: yesterday is history; tomorrow is mystery: towards a European orphan device directive? AB - BACKGROUND: Regulatory and economic frameworks stimulated the research and development of orphan drugs, but very little has been done for devices necessary for the in-vivo diagnosis, prevention and treatment of life-threatening conditions with a low prevalence/incidence. DISCUSSION: A general public consultation in Europe has shown a positive attitude towards an "orphan device" directive. The United States of America have a Humanitarian Use Device exemption, but Europe is still waiting for such a stimulating framework. Post-marketing surveillance ("materio-vigilance") will be necessary for follow-up, patient reported outcome measures (quality of life versus survival) needed and off-label use data available for patient-safety reasons. The marketing period for devices is shorter than for medicinal products. Incentives are necessary to stimulate research and development of such "orphan devices" especially when surgical intervention is the only option. PMID- 26939862 TI - Direct manufacturing of ultrathin graphite on three-dimensional nanoscale features. AB - There have been many successful attempts to grow high-quality large-area graphene on flat substrates. Doing so at the nanoscale has thus far been plagued by significant scalability problems, particularly because of the need for delicate transfer processes onto predefined features, which are necessarily low-yield processes and which can introduce undesirable residues. Herein we describe a highly scalable, clean and effective, in-situ method that uses thin film deposition techniques to directly grow on a continuous basis ultrathin graphite (uG) on uneven nanoscale surfaces. We then demonstrate that this is possible on a model system of atomic force probe tips of various radii. Further, we characterize the growth characteristics of this technique as well as the film's superior conduction and lower adhesion at these scales. This sets the stage for such a process to allow the use of highly functional graphite in high-aspect ratio nanoscale components. PMID- 26939864 TI - Thermo-responsive hydrogels from cellulose-based polyelectrolytes and catanionic vesicles for biomedical application. AB - In this study, negatively charged catanionic vesicles/hydrophobically modified hydroxyethylcellulose polymers thermo-responsive hydrogels have been fabricated. Vesicular aggregates were found to act as multifunctional junctions for networking of modified-cellulose water solutions. The contributions of the electrostatic and hydrophobic interactions were evaluated by changing either vesicles composition or the polymer hydrophobic substitution. Thermal-induced size and lamellarity of hydrogel-enclosed vesicles were detected, with further polygonal shape changes induced by cellulose-based polymer addition. The thermal transition was also found to tune hydrogel mechanical behaviour. The network formation was further assessed through molecular insights, which allow to determine the arrangement of the polymer chains on the vesicles' surface. The examined systems exhibited interesting thermo-responsive characteristics. Thus, vesicularly cross-linked hydrogels herein presented can offer a wide variety of applications, i.e. in biomedical field, as multi-drug delivery systems, thanks to their ability to provide for different environments to guest molecules, comprising bulk water, vesicles' interior and bilayers, sites on polymeric chains. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 1668 1679, 2016. PMID- 26939865 TI - Ablation of ventricular arrhythmia originating from the aortic sinus of Valsalva in an adolescent with anomalous origin of the right coronary artery. AB - A 16-year-old patient underwent successful ablation of ventricular arrhythmia originating from the aortic sinus of Valsalva following surgical unroofing of an anomalous right coronary artery. This case illustrates the complexity of decision making in the management of patients with anomalous coronary arteries and the importance of keeping an open mind when determining ventricular arrhythmia aetiology and origin. PMID- 26939866 TI - Perioperative glycaemic control for preterm infant with transient neonatal hyperglycaemia and gastroschisis. AB - BACKGROUND: Neonatal hyperglycaemia is a rare metabolic disorder. There are no reports of an association between neonatal hyperglycaemia and gastroschisis. CASE PRESENTATION: This report presents preoperative and intraoperative management of blood sugar in a low birth weight Thai preterm neonate with gastroschisis and a diagnosis of neonatal hyperglycaemia. The patient underwent an emergency, multi staged, surgical repair under general anaesthesia. CONCLUSION: Anaesthesiologists should be aware of possible perioperative dysglycaemic conditions in these patients. Proper timing of surgery and appropriate preanaesthetic preparation are necessary to reduce the morbidity and mortality related to hyperglycaemia and gastroschisis. CONSENT: The patient's guardian has given consent for the case report to be published. PMID- 26939867 TI - Glucosensing in the gastrointestinal tract: Impact on glucose metabolism. AB - The gastrointestinal tract is an important interface of exchange between ingested food and the body. Glucose is one of the major dietary sources of energy. All along the gastrointestinal tube, e.g., the oral cavity, small intestine, pancreas, and portal vein, specialized cells referred to as glucosensors detect variations in glucose levels. In response to this glucose detection, these cells send hormonal and neuronal messages to tissues involved in glucose metabolism to regulate glycemia. The gastrointestinal tract continuously communicates with the brain, especially with the hypothalamus, via the gut-brain axis. It is now well established that the cross talk between the gut and the brain is of crucial importance in the control of glucose homeostasis. In addition to receiving glucosensing information from the gut, the hypothalamus may also directly sense glucose. Indeed, the hypothalamus contains glucose-sensitive cells that regulate glucose homeostasis by sending signals to peripheral tissues via the autonomous nervous system. This review summarizes the mechanisms by which glucosensors along the gastrointestinal tract detect glucose, as well as the results of such detection in the whole body, including the hypothalamus. We also highlight how disturbances in the glucosensing process may lead to metabolic disorders such as type 2 diabetes. A better understanding of the pathways regulating glucose homeostasis will further facilitate the development of novel therapeutic strategies for the treatment of metabolic diseases. PMID- 26939868 TI - VEGF-sdf1 recruitment of CXCR7+ bone marrow progenitors of liver sinusoidal endothelial cells promotes rat liver regeneration. AB - In liver injury, recruitment of bone marrow (BM) progenitors of liver sinusoidal endothelial cells (sprocs) is necessary for normal liver regeneration. Hepatic vascular endothelial growth factor (VEGF) is a central regulator of the recruitment process. We examine whether stromal cell-derived factor 1 [sdf1, or CXC ligand 12 (CXCL12)] acts downstream from VEGF to mediate recruitment of BM sprocs, what the sdf1 receptor type [CXC receptor (CXCR)-4 or CXCR7] is on sprocs, and whether sdf1 signaling is required for normal liver regeneration. Studies were performed in the rat partial hepatectomy model. Tracking studies of BM sprocs were performed in wild-type Lewis rats that had undergone BM transplantation from transgenic enhanced green fluorescent protein-positive Lewis rats. Knockdown studies were performed using antisense oligonucleotides (ASOs). Expression of sdf1 doubles in liver and liver sinusoidal endothelial cells (LSECs) after partial hepatectomy. Upregulation of sdf1 expression increases proliferation of sprocs in the BM, mobilization of CXCR7(+) BM sprocs to the circulation, and engraftment of CXCR7(+) BM sprocs in the liver and promotes liver regeneration. Knockdown of hepatic VEGF with ASOs decreases hepatic sdf1 expression and plasma sdf1 levels. When the effect of VEGF knockdown on sdf1 is offset by infusion of sdf1, VEGF knockdown-induced impairment of BM sproc recruitment after partial hepatectomy is completely attenuated and liver regeneration is normalized. These data demonstrate that the VEGF-sdf1 pathway regulates recruitment of CXCR7(+) BM sprocs to the hepatic sinusoid after partial hepatectomy and is required for normal liver regeneration. PMID- 26939869 TI - Distinct miRNA profiles in normal and gastric cancer myofibroblasts and significance in Wnt signaling. AB - Stromal cells influence epithelial function in both health and disease. Myofibroblasts are abundant stromal cells that influence the cellular microenvironment by release of extracellular matrix (ECM) proteins, growth factors, proteases, cytokines, and chemokines. Cancer-associated myofibroblasts (CAMs) differ from adjacent tissue (ATMs) and normal tissue myofibroblasts (NTMs), but the basis of this is incompletely understood. We report now the differential expression of miRNAs in gastric cancer CAMs. MicroRNA arrays identified differences in the miRNA profile in gastric and esophageal NTMs and in CAMs from stomach compared with NTMs. miR-181d was upregulated in gastric CAMs. Analysis of differentially regulated miRNAs indicated an involvement in Wnt signaling. Examination of a microarray data set then identified Wnt5a as the only consistently upregulated Wnt ligand in gastric CAMs. Wnt5a stimulated miR-181d expression, and knockdown of miR-181d inhibited Wnt5a stimulation of CAM proliferation and migration. Analysis of miR-181d targets suggested a role in chemotaxis. Conditioned medium from CAMs stimulated gastric cancer cell (AGS) migration more than that from ATMs, and miR-181d knockdown reduced the effect of CAM-CM on AGS cell migration but had no effect on AGS cell responses to ATM conditioned media. The data suggest that dysregulation of miRNA expression in gastric CAMs, secondary to Wnt5a signaling, accounts at least in part for the effect of CAMs in promoting cancer cell migration. PMID- 26939870 TI - The denominator problem: national hospital quality measures for acute myocardial infarction. AB - BACKGROUND: National Hospital Quality Measures (NHQM) should accurately reflect quality of care, as they increasingly impact reimbursement and reputation. However, similar to risk adjustment of outcomes measures, NHQM process measures pose unique methodological concerns, including lack of representativeness of the final denominator population after exclusions. This study determines population size and characteristics for each acute myocardial infarction (AMI) measure, reasons for exclusion from the measures, and variation in exclusion rates among hospitals. METHODS AND RESULTS: 163 144 discharges from 172 University HealthSystem Consortium hospitals between 2008-Q4 and 2013-Q3 were examined, including characteristics and propensity scores of included and excluded groups. Measure exclusions ranged from 17.8% (discharge aspirin) to 90.1% (percutaneous coronary intervention, PCI, within 90 min), with substantial variation across hospitals. Median annual denominator size (IQR) for PCI within 90 min was 28 (20, 44) at major teaching hospitals, versus 10 (0, 25) at non-teaching hospitals. Patients most likely to be excluded (in the 10th vs 1st propensity decile) were older (mean age (SD) of 78.1 (10.8) vs 50.3 (8.6) years), more likely to have Medicare (90.5% vs 0.9%), had more documented comorbidities (15.6 (4.6) vs 6.2 (2.5) hierarchical clinical condition categories) and higher admission mortality risk (Major or Extreme 80.9% vs 7.3%, respectively), and experienced higher inpatient mortality (10.0% vs 1.6%). CONCLUSIONS: Exclusion from AMI measures varied substantially among hospitals, sample sizes were very small for some measures (PCI and ACE inhibitor measures) and measures often excluded high-risk populations. This has implications for the representativeness and comparability of the measures and provides insight for future measure development. PMID- 26939871 TI - Adherence: the Holy Grail? PMID- 26939873 TI - Comment on 'Ethnography asa methodological descriptor:the editors reply'. PMID- 26939872 TI - Characteristics of hospitals receiving the largest penalties by US pay-for performance programmes. PMID- 26939874 TI - Multilabel immunofluorescence and antigen reprobing on formalin-fixed paraffin embedded sections: novel applications for precision pathology diagnosis. AB - We report new methods for multilabel immunofluorescence (MIF) and reprobing of antigen epitopes on the same formalin-fixed paraffin-embedded (FFPE) sections. The MIF method includes an antigen-retrieval step followed by multilabel immunostaining and examination by confocal microscopy. As examples, we illustrate epitopes localized to the apical and basolateral membranes, and the cytoplasm of enterocytes of normal small intestine and in cases of congenital enteropathies (microvillous inclusion disease and congenital tufting enteropathy). We also demonstrate localization of the bile salt excretion pump protein (BSEP) in bile canalicular membrane of normal hepatocytes and in cases of primary sclerosing cholangitis. To demonstrate colocalization of cytoplasmic and nuclear epitopes we analyzed normal control and hyperplastic pulmonary neuroendocrine cells (PNEC) and neuroepithelial bodies (NEBs), presumed airway sensors in the lungs of infants with bronchopulmonary dysplasia (BPD). As cytoplasmic markers we used anti-bombesin or anti-synaptic vesicle protein 2 (SV2) antibody, respectively, and for nuclear localization, antibodies against neurogenic genes mammalian achaete-scute homolog (Mash1) and prospero homeobox 1 (Prox1), essential for NEB cells differentiation and maturation, hypoxia-inducible factor 1alpha (HIF1alpha) a downstream modulator of hypoxia response and a proliferation marker Ki67. The reprobing method consisted of removal of the previously immunolabeled target and immunostaining with different antibodies, facilitating colocalization of enterocyte brush border epitopes as well as HIF1alpha, Mash1 and Prox1 in PNEC/NEB PNEC and NEBs. As these methods are suitable for routine FFPE pathology samples from various tissues, allowing visualization of multiple epitopes in the same cells/sections with superior contrast and resolution, they are suitable for a wide range of applications in diagnostic pathology and may be particularly well suited for precision medicine diagnostics. PMID- 26939875 TI - Disease-specific survival of patients with invasive cribriform and intraductal prostate cancer at diagnostic biopsy. AB - Invasive cribriform and intraductal carcinoma in radical prostatectomy specimens have been associated with an adverse clinical outcome. Our objective was to determine the prognostic value of invasive cribriform and intraductal carcinoma in pre-treatment biopsies on time to disease-specific death. We pathologically revised the diagnostic biopsies of 1031 patients from the first screening round of the European Randomized Study of Screening for Prostate Cancer (1993-2000). Ninety percent of all patients (n=923) had received active treatment, whereas 10% (n=108) had been followed by watchful waiting. The median follow-up was 13 years. Patients who either had invasive cribriform growth pattern or intraductal carcinoma were categorized as CR/IDC+. The outcome was disease-specific survival. Relationships with outcome were analyzed using multivariable Cox regression and log-rank analysis. In total, 486 patients had Gleason score 6 (47%) and 545 had >=7 (53%). The 15-year disease-specific-survival probabilities were 99% in Gleason score 6 (n=486), 94% in CR/IDC- Gleason score >=7 (n=356) and 67% in CR/IDC+ Gleason score >=7 (n=189). CR/IDC- Gleason score 3+4=7 patients did not have statistically different survival probabilities from those with Gleason score 6 (P=0.30), while CR/IDC+ Gleason score 3+4=7 patients did (P<0.001). In multivariable analysis, CR/IDC+ status was independently associated with a poorer disease-specific survival (HR 2.6, 95% CI 1.4-4.8, P=0.002). We conclude that CR/IDC+ status in prostate cancer biopsies is associated with a worse disease specific survival. Our findings indicate that men with biopsy CR/IDC- Gleason score 3+4=7 prostate cancer could be candidates for active surveillance, as these patients have similar survival probabilities to those with Gleason score 6. PMID- 26939877 TI - Significance of high-normal blood pressure during early second trimester for predicting the onset of hypertensive disorders in pregnancy. AB - OBJECTIVE: The aim of this study was to determine the predictive value of high normal blood pressure (HNBP) during the early second trimester for hypertensive disorders in pregnancy, including gestational hypertension (GH) and preeclampsia (PE). METHODS: This was a retrospective single-center cohort study of 2143 singleton pregnant women. The association of HNBP, ranging from 130/85 to 139/89 mmHg between 14 and 19 weeks of gestation, with the development of hypertensive disorders was assessed by multivariable logistic regression analyses. RESULTS: In a cohort of 2102 pregnant women, 93 (4.4%) pregnancies had HNBP during early second trimester. Pregnant women with HNBP more frequently developed hypertensive disorders than normotensive women (20.4% vs. 8.2%, p < 0.001). HNBP was significantly associated with the development of GH (adjusted odds ratio (aOR): 1.81; 95% confidence interval (CI): 1.16-3.25, p = 0.015) and PE (aOR: 6.05; 95% CI: 3.46-12.6, p = 0.013) after adjustment for confounders. CONCLUSION: HNBP during the early second trimester is an independent risk factor for both GH and PE. PMID- 26939876 TI - Genetic alterations of triple negative breast cancer by targeted next-generation sequencing and correlation with tumor morphology. AB - Triple negative breast cancer represents a heterogeneous group of breast carcinomas, both at the histologic and genetic level. Although recent molecular studies have comprehensively characterized the genetic landscape of these tumors, few have integrated a detailed histologic examination into the analysis. In this study, we defined the genetic alterations in 39 triple negative breast cancers using a high-depth targeted massively parallel sequencing assay and correlated the findings with a detailed morphologic analysis. We obtained representative frozen tissue of primary triple negative breast cancers from patients treated at our institution between 2002 and 2010. We characterized tumors according to their histologic subtype and morphologic features. DNA was extracted from paired frozen primary tumor and normal tissue samples and was subjected to a targeted massively parallel sequencing platform comprising 229 cancer-associated genes common across all experiments. The average number of non-synonymous mutations was 3 (range 0 10) per case. The most frequent somatic alterations were mutations in TP53 (74%) and PIK3CA (10%) and MYC amplifications (26%). Triple negative breast cancers with apocrine differentiation less frequently harbored TP53 mutations (25%) and MYC gains (0%), and displayed a high mutation frequency in PIK3CA and other PI3K signaling pathway-related genes (75%). Using a targeted massively parallel sequencing platform, we identified the key somatic genetic alterations previously reported in triple negative breast cancers. Furthermore, our findings show that triple negative breast cancers with apocrine differentiation constitute a distinct subset, characterized by a high frequency of PI3K pathway alterations similar to luminal subtypes of breast cancer. PMID- 26939879 TI - Oncologic reconstruction: General principles and techniques. AB - Halsted's principle of radical mastectomy influenced cancer treatment for decades. Randomized controlled trials resulted in a paradigm shift to less radical surgery and the use of adjuvant therapies. Oncologic reconstruction performed by plastic surgeons has evolved, ranging from skin grafts and local flaps for smaller defects to pedicled flaps and free flaps for larger and more complex defects. Immediate reconstruction facilitates resection is oncologically safe and contributes to meaningful improvements in quality of life. J. Surg. Oncol. 2016;113:852-864. (c) 2016 Wiley Periodicals, Inc. PMID- 26939878 TI - Impact of weight loss induced by gastric bypass or caloric restriction on oxidative stress and genomic damage in obese Zucker rats. AB - BACKGROUND: Evidence on bariatric surgery induced weight loss and its possible impact on cancer risk is limited, but also controversial. We used obese Zucker(fa/fa) and lean Zucker(fa/+) to investigate the association between obesity, oxidative stress and genomic damage after weight loss induced either by Roux-en-Y gastric bypass surgery (RYGB) or caloric restriction. METHODS: Male Zucker(fa/fa) rats underwent RYGB (n=15) or sham surgery (n=17). Five shams were food restricted and body weight matched (BWM) to RYGB. Twelve Zucker(fa/+) rats served as lean controls. Body weight and food intake were measured daily. An oral glucose tolerance test was performed on day 27. DHE staining and western blots of HSP70 and HO-1 were used to evaluate oxidative stress and anti-3-nitrotyrosine antibody staining for nitrative stress detection in colon and kidney. Lipid peroxidation products in urine were quantified by TBARS assay. LC/MS/MS was applied to measure urinary excretion of 8-oxoGua (oxidized DNA derived base), 8 oxodG (oxidized DNA derived nucleoside) and 8-oxoGuo (oxidized RNA derived nucleoside). DNA double strand breaks (DSBs) and cell proliferation (PCNA) were detected by immunohistochemistry. RESULTS: Sham-operated rats showed impaired glucose tolerance, elevated plasma insulin levels as well as elevated oxidative stress and nitrative stress markers, which were less severe after weight loss by RYGB or caloric restriction. Cell proliferation showed similar trends but no significant alteration. DNA DSBs were more frequent in sham-operated compared to all other groups. DNA damage in Zucker(fa/fa) rats positively correlated with basal plasma insulin values (Spearman's correlation coefficient for colon, 0.634 and for kidney, 0.525). CONCLUSIONS: RYGB and caloric restriction were sufficient to significantly reduce elevated oxidative/nitrative stress and genomic damage in obese Zucker(fa/fa) rats. Further investigations are needed to elucidate the underlying mechanism of these genome protective effects. PMID- 26939880 TI - The evaluation of small-sided games as a talent identification tool in highly trained prepubertal soccer players. AB - The aim of this study was to evaluate physiological and technical attributes of prepubertal soccer players during multiple small-sided games (SSGs), and determine if SSGs can act as a talent identification tool. Sixteen highly trained U10 soccer players participated and separated into two groups of eight. Each group played six small-sided (4 vs. 4) matches of 5-min duration. Each player was awarded total points for the match result and goals scored. A game technical scoring chart was used to rate each player's performance during each game. Time motion characteristics were measured using micromechanical devices. Total points had a very large significant relationship with game technical scoring chart (r = 0.758, P < 0.001). High-speed running distance had a significantly large correlation with game technical scoring chart (r = 0.547, P < 0.05). Total distance covered had a significant and moderate correlation with game technical scoring chart (r = 0.545, P < 0.05) and total points (r = 0.438, P < 0.05). The results demonstrated a large agreement between the highest-rated players and success in multiple SSGs, possibly due to higher-rated players covering larger distances in total and at high speed. Consequently, multiple SSG could be used to identify the more talented prepubertal soccer players. PMID- 26939882 TI - Electrolyte disorders associated with the use of anticancer drugs. AB - The use of anticancer drugs is beneficial for patients with malignancies but is frequently associated with the occurrence of electrolyte disorders, which can be hazardous and in many cases fatal. The review presents the electrolyte abnormalities that can occur with the use of anticancer drugs and provides the related mechanisms. Platinum-containing anticancer drugs induce hypomagnesemia, hypokalemia and hypocalcemia. Moreover, platinum-containing drugs are associated with hyponatremia, especially when combined with large volumes of hypotonic fluids aiming to prevent nephrotoxicity. Alkylating agents have been linked with the occurrence of hyponatremia [due to syndrome of inappropriate antidiuretic hormone secretion (SIADH)] and Fanconi's syndrome (hypophosphatemia, aminoaciduria, hypouricemia and/or glucosuria). Vinca alkaloids are associated with hyponatremia due to SIADH. Epidermal growth factor receptor monoclonal antibody inhibitors induce hypomagnesemia, hypokalemia and hypocalcemia. Other, monoclonal antibodies, such as cixutumumab, cause hyponatremia due to SIADH. Tyrosine kinase inhibitors are linked to hyponatremia and hypophosphatemia. Mammalian target of rapamycin inhibitors induce hyponatremia (due to aldosterone resistance), hypokalemia and hypophosphatemia. Other drugs such as immunomodulators or methotrexate have been also associated with hyponatremia. The administration of estrogens at high doses, streptozocin, azacitidine and suramin may induce hypophosphatemia. Finally, the drug-related tumor lysis syndrome is associated with hyperphosphatemia, hyperkalemia and hypocalcemia. The prevention of electrolyte derangements may lead to reduction of adverse events during the administration of anticancer drugs. PMID- 26939881 TI - In vitro study of histamine and histamine receptor ligands influence on the adhesion of purified human eosinophils to endothelium. AB - It is a well-known fact that histamine is involved in eosinophil-dependent inflammatory responses including cellular chemotaxis and migration. Nevertheless, the relative role of histamine receptors in the mechanisms of eosinophils adhesion to endothelial cells is not known. Therefore the aim of presented study was to examine the effect of selective histamine receptors ligands on eosinophils adhesion to endothelium. For that purpose the highly purified human eosinophils have been isolated from the peripheral blood. The viability and functional integrity of isolated eosinophils have been validated in several tests. Histamine as well as 4-methylhistamine (selective H4 agonist) in concentration-dependent manner significantly increased number of eosinophils that adhere to endothelium. Among the selective histamine receptors antagonist or H1 inverse agonist only JNJ7777120 (histamine H4 antagonist) and thioperamide (dual histamine H3/H4 antagonist) had direct effect on eosinophils adhesion to endothelial cells. Antagonists of H1 (diphenhydramine, mepyramine) H2 (ranitidine and famotidine) and H3 (pitolisant) histamine receptors were ineffective. To the best of our knowledge, this is the first study to demonstrate that histamine receptor H4 plays a dominant role in histamine-induced eosinophils adhesion to endothelium. PMID- 26939883 TI - Aspirin for Cancer Prevention: One Step Closer. PMID- 26939884 TI - Retraction of "Extension to the Charge Fluctuation Model for the Prediction of the Conductivity of Apolar, Reverse Micellar Systems". Langmuir 2012, 28 (45), 15751-5. PMID- 26939886 TI - Engineering a ribozyme cleavage-induced split fluorescent aptamer complementation assay. AB - Hammerhead ribozymes are self-cleaving RNA molecules capable of regulating gene expression in living cells. Their cleavage performance is strongly influenced by intra-molecular loop-loop interactions, a feature not readily accessible through modern prediction algorithms. Ribozyme engineering and efficient implementation of ribozyme-based genetic switches requires detailed knowledge of individual self cleavage performances. By rational design, we devised fluorescent aptamer ribozyme RNA architectures that allow for the real-time measurement of ribozyme self-cleavage activity in vitro The engineered nucleic acid molecules implement a split Spinach aptamer sequence that is made accessible for strand displacement upon ribozyme self-cleavage, thereby complementing the fluorescent Spinach aptamer. This fully RNA-based ribozyme performance assay correlates ribozyme cleavage activity with Spinach fluorescence to provide a rapid and straightforward technology for the validation of loop-loop interactions in hammerhead ribozymes. PMID- 26939885 TI - Structure and decoy-mediated inhibition of the SOX18/Prox1-DNA interaction. AB - The transcription factor (TF) SOX18 drives lymphatic vessel development in both embryogenesis and tumour-induced neo-lymphangiogenesis. Genetic disruption of Sox18 in a mouse model protects from tumour metastasis and established the SOX18 protein as a molecular target. Here, we report the crystal structure of the SOX18 DNA binding high-mobility group (HMG) box bound to a DNA element regulating Prox1 transcription. The crystals diffracted to 1.75A presenting the highest resolution structure of a SOX/DNA complex presently available revealing water structure, structural adjustments at the DNA contact interface and non-canonical conformations of the DNA backbone. To explore alternatives to challenging small molecule approaches for targeting the DNA-binding activity of SOX18, we designed a set of five decoys based on modified Prox1-DNA. Four decoys potently inhibited DNA binding of SOX18 in vitro and did not interact with non-SOX TFs. Serum stability, nuclease resistance and thermal denaturation assays demonstrated that a decoy circularized with a hexaethylene glycol linker and terminal phosphorothioate modifications is most stable. This SOX decoy also interfered with the expression of a luciferase reporter under control of a SOX18-dependent VCAM1 promoter in COS7 cells. Collectively, we propose SOX decoys as potential strategy for inhibiting SOX18 activity to disrupt tumour-induced neo lymphangiogenesis. PMID- 26939888 TI - Chromosome intermingling-the physical basis of chromosome organization in differentiated cells. AB - Chromosome territories (CTs) in higher eukaryotes occupy tissue-specific non random three-dimensional positions in the interphase nucleus. To understand the mechanisms underlying CT organization, we mapped CT position and transcriptional changes in undifferentiated embryonic stem (ES) cells, during early onset of mouse ES cell differentiation and in terminally differentiated NIH3T3 cells. We found chromosome intermingling volume to be a reliable CT surface property, which can be used to define CT organization. Our results show a correlation between the transcriptional activity of chromosomes and heterologous chromosome intermingling volumes during differentiation. Furthermore, these regions were enriched in active RNA polymerase and other histone modifications in the differentiated states. These findings suggest a correlation between the evolution of transcription program in modifying CT architecture in undifferentiated stem cells. This leads to the formation of functional CT surfaces, which then interact to define the three-dimensional CT organization during differentiation. PMID- 26939887 TI - New origin firing is inhibited by APC/CCdh1 activation in S-phase after severe replication stress. AB - Defects in DNA replication and repair are known to promote genomic instability, a hallmark of cancer cells. Thus, eukaryotic cells have developed complex mechanisms to ensure accurate duplication of their genomes. While DNA damage response has been extensively studied in tumour cells, the pathways implicated in the response to replication stress are less well understood especially in non transformed cells. Here we show that in non-transformed cells, APC/C(Cdh1) is activated upon severe replication stress. Activation of APC/C(Cdh1) prevents new origin firing and induces permanent arrest in S-phase. Moreover, Rad51-mediated homologous recombination is also impaired under these conditions. APC/C(Cdh1) activation in S-phase occurs after replication forks have been processed into double strand breaks. Remarkably, this activation, which correlates with decreased Emi1 levels, is not prevented by ATR/ATM inhibition, but it is abrogated in cells depleted of p53 or p21. Importantly, we found that the lack of APC/C(Cdh1) activity correlated with an increase in genomic instability. Taken together, our results define a new APC/C(Cdh1) function that prevents cell cycle resumption after prolonged replication stress by inhibiting origin firing, which may act as an additional mechanism in safeguarding genome integrity. PMID- 26939890 TI - Structural and Electrical Properties of MoTe2 and MoSe2 Grown by Molecular Beam Epitaxy. AB - We demonstrate the growth of thin films of molybdenum ditelluride and molybdenum diselenide on sapphire substrates by molecular beam epitaxy. In situ structural and chemical analyses reveal stoichiometric layered film growth with atomically smooth surface morphologies. Film growth along the (001) direction is confirmed by X-ray diffraction, and the crystalline nature of growth in the 2H phase is evident from Raman spectroscopy. Transmission electron microscopy is used to confirm the layered film structure and hexagonal arrangement of surface atoms. Temperature-dependent electrical measurements show an insulating behavior that agrees well with a two-dimensional variable-range hopping model, suggesting that transport in these films is dominated by localized charge-carrier states. PMID- 26939889 TI - Structures of an all-alpha protein running along the DNA major groove. AB - Despite over 3300 protein-DNA complex structures have been reported in the past decades, there remain some unknown recognition patterns between protein and target DNA. The silkgland-specific transcription factor FMBP-1 from the silkworm Bombyx mori contains a unique DNA-binding domain of four tandem STPRs, namely the score and three amino acid peptide repeats. Here we report three structures of this STPR domain (termed BmSTPR) in complex with DNA of various lengths. In the presence of target DNA, BmSTPR adopts a zig-zag structure of three or four tandem alpha-helices that run along the major groove of DNA. Structural analyses combined with binding assays indicate BmSTPR prefers the AT-rich sequences, with each alpha-helix covering a DNA sequence of 4 bp. The successive AT-rich DNAs adopt a wider major groove, which is in complementary in shape and size to the tandem alpha-helices of BmSTPR. Substitutions of DNA sequences and affinity comparison further prove that BmSTPR recognizes the major groove mainly via shape readout. Multiple-sequence alignment suggests this unique DNA-binding pattern should be highly conserved for the STPR domain containing proteins which are widespread in animals. Together, our findings provide structural insights into the specific interactions between a novel DNA-binding protein and a unique deformed B-DNA. PMID- 26939891 TI - B and T Cell Epitope-Based Peptides Predicted from Evolutionarily Conserved and Whole Protein Sequences of Ebola Virus as Vaccine Targets. AB - Ebola virus (EBV) has become a serious threat to public health. Different approaches were applied to predict continuous and discontinuous B cell epitopes as well as T cell epitopes from the sequence-based and available three dimensional structural analyses of each protein of EBV. Peptides '(79) VPSATKRWGFRSGVPP(94) ' from GP1 and '(515) LHYWTTQDEGAAIGLA(530) ' from GP2 of Ebola were found to be the consensus peptidic sequences predicted as linear B cell epitope of which the latter contains a region (519) TTQDEG(524) that fulfilled all the criteria of accessibility, hydrophilicity, flexibility and beta turn region for becoming an ideal B cell epitope. Different nonamers as T cell epitopes were obtained that interacted with different numbers of MHC class I and class II alleles with a binding affinity of <100 nm. Interestingly, these alleles also bound to the MHC class I alleles mostly prevalent in African and South Asian regions. Of these, 'LANETTQAL' and 'FLYDRLAST' nonamers were predicted to be the most potent T cell epitopes and they, respectively, interacted with eight and twelve class I alleles that covered 63.79% and 54.16% of world population, respectively. These nonamers were found to be the core sequences of 15mer peptides that interacted with the most common class II allele, HLA-DRB1*01:01. They were further validated for their binding to specific class I alleles using docking technique. Thus, these predicted epitopes may be used as vaccine targets against EBV and can be validated in model hosts to verify their efficacy as vaccine. PMID- 26939892 TI - The nucleic acid-binding protein PcCNBP is transcriptionally regulated during the immune response in red swamp crayfish Procambarus clarkii. AB - Gene family encoding cellular nucleic acid binding proteins (CNBP) is well conserved among vertebrates; however, there is limited knowledge in lower organisms. In this study, a CNBP homolog from the red swamp crayfish Procambarus clarkii was characterised. The full-length cDNA of PcCNBP was of 1257 bp with a 5'-untranslated region (UTR) of 63 bp and a 3'-UTR of 331 bp with a poly (A) tail, and an open-reading frame (ORF) of 864 bp encoding a polypeptide of 287 amino acids with the predicted molecular weight of about 33 kDa. The predicted protein possesses 7 tandem repeats of 14 amino acids containing the CCHC zinc finger consensus sequence, two RGG-rich single-stranded RNA-binding domain and a nuclear localization signal, strongly suggesting that PcCNBP was a homolog of vertebrate CNBP. The PcCNBP transcript was constitutively expressed in all tested tissues of unchallenged crayfish, including hepatopancreas, gill, eyestalk, haemocytes, intestine, stomach and cuticle with highest expression in haemocytes, intestine, gills and hepatopancreas. The mRNA expression of PcCNBP in haemocytes was modulated at transcriptional level by different immune challenges, suggesting its involvement in the immune response of P. clarkii during both bacteria and viruses infection. PMID- 26939893 TI - GEM, a member of the GRAM domain family of proteins, is part of the ABA signaling pathway. AB - Abscisic acid (ABA) is fundamental for plant development. Multiple factors have been identified that participate in the ABA signaling network, although a role of many proteins still await to be demonstrated. Here we have investigated the role of GEM (GL2 EXPRESSION MODULATOR), originally annotated as an ABA-responsive protein. GEM contains a GRAM domain, a feature shared with other eight Arabidopsis proteins for which we propose the name of GRE (GEM-RELATED) proteins. We found that (i) GEM expression responds to ABA, (ii) its promoter contains ABRE sites required for ABA response, and (iii) GEM expression depends on members of the ABA signaling pathway. This is consistent with the expression pattern of GEM during development in plant locations were ABA is known to play a direct role. We also found that GEM binds various phospholipids, e.g. mono and diphosphates and phosphatidic acid, suggesting a potential link of GEM with membrane-associated processes. Consistent with this, we found that the phosphoinositol-4-phosphate kinase PIP5K9 binds GEM in vivo. Finally, we demonstrated a role of GEM in seed dormancy. Together, our data led us to propose that GEM is an ABA-responsive protein that may function downstream of ABI5 as part of the ABA signaling pathway. PMID- 26939894 TI - An Evaluation of Active Learning Causal Discovery Methods for Reverse-Engineering Local Causal Pathways of Gene Regulation. AB - Reverse-engineering of causal pathways that implicate diseases and vital cellular functions is a fundamental problem in biomedicine. Discovery of the local causal pathway of a target variable (that consists of its direct causes and direct effects) is essential for effective intervention and can facilitate accurate diagnosis and prognosis. Recent research has provided several active learning methods that can leverage passively observed high-throughput data to draft causal pathways and then refine the inferred relations with a limited number of experiments. The current study provides a comprehensive evaluation of the performance of active learning methods for local causal pathway discovery in real biological data. Specifically, 54 active learning methods/variants from 3 families of algorithms were applied for local causal pathways reconstruction of gene regulation for 5 transcription factors in S. cerevisiae. Four aspects of the methods' performance were assessed, including adjacency discovery quality, edge orientation accuracy, complete pathway discovery quality, and experimental cost. The results of this study show that some methods provide significant performance benefits over others and therefore should be routinely used for local causal pathway discovery tasks. This study also demonstrates the feasibility of local causal pathway reconstruction in real biological systems with significant quality and low experimental cost. PMID- 26939895 TI - Non-enzymatic amperometric sensing of glucose by employing sucrose templated microspheres of copper oxide (CuO). AB - We report a facile hydrothermal synthesis of copper oxide microspheres (CMS) for the enzymeless amperometric detection of glucose in an alkaline medium. The crystallinity, morphology and size were examined by powder X-ray diffraction (PXRD), scanning and transmission electron microscopy (SEM/TEM) and dynamic light scattering (DLS) techniques, respectively. The fabricated CMS were grafted onto the working area of a carbon screen printed electrode (CSPE) and covered with a thin Nafion layer (Nafion/CMS/CSPE), forming a modified carbon screen printed electrode (MCSPE) which acts as a working electrode. Further, the electrochemical behavior of MCSPE was investigated under optimized conditions through cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS), differential pulse voltammetry (DPV) and chronoamperometry (CA) techniques. The CV results showed a drastic enhancement of the current response in the presence of glucose. The amperometry results reveal the catalytic ability of CMS for glucose oxidation with a notable limit of detection (LOD) of 20.6 MUM in a wide linear range of 2-9 mM with a high sensitivity of 26.59 MUA mM(-1) cm(-2). Moreover, the anti interference test confirmed the selectivity of the fabricated sensor towards glucose in the presence of interfering agents such as uric acid (UA), ascorbic acid (AA) and dopamine (DA). PMID- 26939896 TI - [Importance of preoperative and intraoperative imaging for operative strategies]. AB - Recent advances in preoperative and postoperative imaging have an increasing influence on surgical decision-making and make more complex surgical interventions possible. This improves the possibilities for frequently occurring challenges and promoting improved functional and oncological outcome. This manuscript reviews the role of preoperative and intraoperative imaging in surgery. Various techniques are explained based on examples from hepatobiliary surgery and neurosurgery, in particular real-time procedures, such as the online use of augmented reality and in vivo fluorescence, as well as new and promising optical techniques including imaging of intrinsic signals and vibrational spectroscopy. PMID- 26939897 TI - The expanding spectrum of modes of transmission of Zika virus: a global concern. PMID- 26939899 TI - Limited sampling strategies for once daily tacrolimus exposure monitoring. PMID- 26939898 TI - Sub-anesthetic Xenon Increases Erythropoietin Levels in Humans: A Randomized Controlled Trial. AB - BACKGROUND: The licensed anesthetic xenon, which exerts organ protective properties, was recently added by the World Anti-Doping Agency to the list of prohibited substances. Xenon is supposed to trigger the production of hypoxia inducible factor 1alpha (HIF-1alpha) and subsequently erythropoietin, but data are limited to in vivo experimental work. Therefore we evaluated the effect of xenon on erythropoietin levels in healthy persons. METHODS: Twenty-four healthy volunteers were randomly assigned either to a group spontaneously breathing xenon 30 % (Xe/O2 30 %/60 %) or a group breathing control gas (N2/O2 40 %/60 %) for 45 min. Primary outcome parameters were erythropoietin levels at several time-points after exposure. Secondary outcome parameters were serum levels of testosterone, cytokines, and growth factors as well as concentrations of xenon in blood and exhalation samples measured at several time-points after exposure. In addition, hemodynamic safety parameters were monitored during exposure. RESULTS: The administration of xenon significantly increased erythropoietin levels 8 h after exposure (1.34 [+/-0.368]; p = 0.008), peaking at 24 h compared to the baseline values (1.45 [+/-0.498]; p = 0.01) and remained traceable in blood and exhalation probes until 24 h after exposure. In contrast, no significant change was observed in the control group. Measurement of stromal cell-derived factor 1 (SDF-1) revealed a significant increase of SDF-1 levels (p = 0.005), whereas no differences were observed with respect to growth factors, cytokines, or androgens. In an in vitro chemotaxis assay, endothelial progenitor cells (EPCs) showed a trend towards increased migration in serum samples received from participants after xenon exposure (p = 0.080). CONCLUSION: The present study presents first evidence about a xenon-induced effect on increased erythropoietin levels in healthy volunteers. The study was registered at the European Medicines Agency (EudraCT-number: 2014-000973-38) and at ClinicalTrials.gov (NCT number: 02129400). PMID- 26939900 TI - De novo assembly and comparative transcriptome analysis of Euglena gracilis in response to anaerobic conditions. AB - BACKGROUND: The phytoflagellated protozoan, Euglena gracilis, has been proposed as an attractive feedstock for the accumulation of valuable compounds such as beta-1,3-glucan, also known as paramylon, and wax esters. The production of wax esters proceeds under anaerobic conditions, designated as wax ester fermentation. In spite of the importance and usefulness of Euglena, the genome and transcriptome data are currently unavailable, though another research group has recently published E.gracilis transcriptome study during our submission. We herein performed an RNA-Seq analysis to provide a comprehensive sequence resource and some insights into the regulation of genes including wax ester metabolism by comparative transcriptome analysis of E.gracilis under aerobic and anaerobic conditions. RESULTS: The E.gracilis transcriptome analysis was performed using the Illumina platform and yielded 90.3 million reads after the filtering steps. A total of 49,826 components were assembled and identified as a reference sequence of E.gracilis, of which 26,479 sequences were considered to be potentially expressed (having FPKM value of greater than 1). Approximately half of all components were estimated to be regulated in a trans-splicing manner, with the addition of protruding spliced leader sequences. Nearly 40 % of 26,479 sequences were annotated by similarity to Swiss-Prot database using the BLASTX program. A total of 2080 transcripts were identified as differentially expressed genes (DEGs) in response to anaerobic treatment for 24 h. A comprehensive pathway enrichment analysis using the KEGG pathway revealed that the majority of DEGs were involved in photosynthesis, nucleotide metabolism, oxidative phosphorylation, fatty acid metabolism. We successfully identified a candidate gene set of paramylon and wax esters, including novel beta-1,3-glucan and wax ester synthases. A comparative expression analysis of aerobic- and anaerobic treated E.gracilis cells indicated that gene expression changes in these components were not extensive or dynamic during the anaerobic treatment. CONCLUSION: The RNA-Seq analysis provided comprehensive transcriptome information on E.gracilis for the first time, and this information will advance our understanding of this unique organism. The comprehensive analysis indicated that paramylon and wax ester metabolic pathways are regulated at post-transcriptional rather than the transcriptional level in response to anaerobic conditions. PMID- 26939901 TI - Co-expression of ILT4/HLA-G in human non-small cell lung cancer correlates with poor prognosis and ILT4-HLA-G interaction activates ERK signaling. AB - Non-small cell lung cancer (NSCLC) is the most common malignant tumor in the world, of which prognosis is generally poor due to insufficient mechanistic understanding. To explore the molecular pathogenesis of NSCLC, the co-expression of immunoglobulin-like transcript 4 (ILT4) and its ligand human leukocyte antigen G (HLA-G) in NSCLC tissues and cells were investigated. Here, we detected the expression of ILT4 and HLA-G in 81 tumor specimens from primary NSCLC patients, and we found that co-expression of ILT4/HLA-G was significantly associated with regional lymph node involvement, advanced stages, and the overall survival of patients. In NSCLC cell lines, HLA-G expression increased/decreased accordingly when ILT4 was up-/down-regulated, and ILT4 expression increased in a concentration-dependent manner via the stimulation of HLA-G fusion protein. Interestingly, HLA-G fusion protein could also up-regulate the phospho-ERK1/2 expression, which means the activation of extracellular signal-regulated kinase (ERK) signaling. All in all, our results indicate that the ILT4-HLA-G interaction might play an important role in NSCLC progression. Identification of ILT4 and HLA G expression may provide an indicator to predict prognosis and guide prevention and treatment of NSCLC. PMID- 26939903 TI - Immunogenicity and protective efficacy of recombinant Modified Vaccinia virus Ankara candidate vaccines delivering West Nile virus envelope antigens. AB - West Nile virus (WNV) cycles between insects and wild birds, and is transmitted via mosquito vectors to horses and humans, potentially causing severe neuroinvasive disease. Modified Vaccinia virus Ankara (MVA) is an advanced viral vector for developing new recombinant vaccines against infectious diseases and cancer. Here, we generated and evaluated recombinant MVA candidate vaccines that deliver WNV envelope (E) antigens and fulfil all the requirements to proceed to clinical testing in humans. Infections of human and equine cell cultures with recombinant MVA demonstrated efficient synthesis and secretion of WNV envelope proteins in mammalian cells non-permissive for MVA replication. Prime-boost immunizations in BALB/c mice readily induced circulating serum antibodies binding to recombinant WNV E protein and neutralizing WNV in tissue culture infections. Vaccinations in HLA-A2.1-/HLA-DR1-transgenic H-2 class I-/class II-knockout mice elicited WNV E-specific CD8+ T cell responses. Moreover, the MVA-WNV candidate vaccines protected C57BL/6 mice against lineage 1 and lineage 2 WNV infection and induced heterologous neutralizing antibodies. Thus, further studies are warranted to evaluate these recombinant MVA-WNV vaccines in other preclinical models and use them as candidate vaccine in humans. PMID- 26939904 TI - Construction of a novel hierarchical structured NH4-Co-Ni phosphate toward an ultrastable aqueous hybrid capacitor. AB - Aqueous hybrid capacitors (HCs) suffer from sacrificed power density and long cycle life due to the insufficient electric conductivity and poor chemical stability of the battery-type electrode material. Herein, we report a novel NH4 Co-Ni phosphate with a stable hierarchical structure combining ultrathin nanopieces and single crystal microplatelets in one system, which allows for a synergistic integration of two microstructures with different length scales and different energy storage mechanisms. The microplatelets with a stable single crystal structure store charge through the intercalation of hydroxyl ions, while the ultrathin nanopieces store charge through surface redox reaction providing enhanced specific capacitance. Furthermore, the large single crystal can bridge the small nanopieces forming continuous electronic conduction paths as well as ionic conduction channels, and facilitate both electron and ion transportation in the hierarchical structure. The HC cell based on the as prepared material and a 3D hierarchical porous carbon delivers a high energy density of 29.6 Wh kg(-1) at a high power density of 11 kW kg(-1). Particularly, an ultralong cycle life along with 93.5% capacitance retention after 10,000 charge-discharge cycles is achieved, which is outstanding among the state-of-the-art aqueous HC cells. PMID- 26939902 TI - Metformin and AICAR regulate NANOG expression via the JNK pathway in HepG2 cells independently of AMPK. AB - NANOG, a marker of stemness, impacts tumor progression and therapeutic resistance in cancer cells. In human hepatocellular carcinoma (HCC), upregulation of NANOG is associated with metastasis and a low survival rate, while its downregulation results in a lower colony formation rate and enhanced chemosensitivity. Metformin, an agent widely used for diabetes treatment, and AICAR, another AMP activated protein kinase (AMPK) activator, have been reported to inhibit the growth of several types of cancer. Although inhibitory effects of metformin on NANOG in pancreatic cancer cells and of AICAR in mouse embryonic stem cells have been described, the underlying molecular mechanisms remain uncertain in HCC. In this study, we used the HepG2 cell line and found that metformin/AICAR downregulated NANOG expression with decreased cell viability and enhanced chemosensitivity to 5-fluorouracil (5-FU). Moreover, metformin/AICAR inhibited c Jun N-terminal kinase (JNK) activity, and blockade of either the JNK MAPK pathway or knockdown of JNK1 gene expression reduced NANOG levels. The upregulation of NANOG and phospho-JNK by basic fibroblast growth factor (bFGF) was abrogated by metformin/AICAR. Additionally, although transient upregulation of NANOG within 2 h of treatment with metformin/AICAR was concordant with both JNK and AMPK activation, increased NANOG expression with activation of JNK was also observed following AMPK inhibition with compound C. Taken together, our data suggest that metformin/AICAR regulate NANOG expression via the JNK MAPK pathway in HepG2 cells independently of AMPK, and that this JNK/NANOG signaling pathway may offer new therapeutic strategies for the treatment of HCC. PMID- 26939905 TI - Risk factors associated with challenging behaviour in people with profound intellectual and multiple disabilities. AB - BACKGROUND: Several factors that correlate with the onset or continuation of challenging behaviour are mentioned in research. These are factors related to persons with ID, but also to direct support professionals and the context. Although many of these factors seem to affect the onset or continuation of challenging behaviour in people with ID in general, results are often inconclusive and have little focus on people with profound intellectual and multiple disabilities (PIMD). The present study aimed to assess the extent to which known factors related to challenging behaviour are also applicable to a group of 198 people with PIMD. METHOD: To determine which factors were associated with challenging behaviour, univariate analyses on associations between known risk factors and challenging behaviour were conducted. The associated factors were then subject to a regression analysis to determine the extent to which they explain the prevalence of challenging behaviour and can thus be seen as factors associated with challenging behaviour. RESULTS: The results show that, in particular, factors concerning the personal characteristics of people with PIMD, such as sleeping problems and auditory problems, were related to the variance in mean frequency of challenging behaviour. Only one factor related to the direct support professionals was found: when these professionals had been offered training on the subject of challenging behaviour in people with intellectual disabilities in general, they identified significantly more withdrawn behaviour. We found no contextual factors related to challenging behaviour. CONCLUSION: These findings are generally consistent with findings reported in other studies, especially concerning the personal characteristics of people with PIMD. Further research should focus on the effects of providing safe auditory environments and appropriate sleep schedules for people with PIMD on the occurrence of challenging behaviour. PMID- 26939906 TI - Correlates of psychological care strategies for people with diabetes in the second Diabetes Attitudes, Wishes and Needs (DAWN2(TM) ) study. AB - AIMS: To assess the ways in which healthcare professionals address psychological problems of adults with diabetes in the second Diabetes Attitudes, Wishes and Needs (DAWN2(TM) ) study. METHODS: Approximately 120 primary care physicians, 80 diabetes specialists and 80 nurses and dietitians providing diabetes care participated in each of 17 countries (N=4785). Multiple regression analyses were used to evaluate independent statistically significant associations of respondent attributes concerning psychological care strategies, including assessment of diabetes impact on the patient's life, assessment of depression, provision of psychological assessment and support, and coordination with mental health professionals. RESULTS: Psychological care strategies were positively associated with each other but differed by healthcare practice site and discipline; nurses and dietitians were less likely to assess depression than other healthcare professionals, while primary care physicians were less likely to coordinate with mental health specialists or ask patients how diabetes affects their lives. Psychological care was positively associated with healthcare professionals' beliefs that patients need help dealing with emotional issues and that clinical success depends on doing so, and also with level of psychological care training, multidisciplinary team membership and availability of resources for psychological care. There were significant between-country variations in psychological care strategies, before and after adjustment for individual-level factors, and significant country-by-covariate interactions for almost all individual-level factors investigated. CONCLUSIONS: Improvements in training and resources, recognition and assessment of psychological problems, and increased belief in the efficacy of psychological support may enhance healthcare professionals' efforts to address psychological problems in adults with diabetes. PMID- 26939907 TI - Injury prediction in veteran football players using the Functional Movement ScreenTM. AB - The Functional Movement ScreenTM (FMSTM) is aimed at assessing fundamental movements and is often used to identify players' injury risk. The purpose of this study was to determine whether the FMSTM can be used to predict injuries in veteran footballers (aged > 32 years). Eighteen veteran football teams (n = 238) were recruited and prospectively followed for 9 months. The players (44 +/- 7 years; 178 +/- 7 cm, 84 +/- 11 kg) performed the FMSTM at the start of the study period. Players' exposure hours and injuries were recorded. The difference of FMSTM overall score between injured and uninjured players was not significant (11.7 +/- 2.9 vs 12.2 +/- 2.8 points; Mann-Whitney U-test P = 0.17). Players scoring <10 (score < 1 standard deviation [SD]) below the mean) had a significantly higher injury incidence (z-statistics P < 0.05) compared to an intermediate reference group (mean +/- 1 SD; scores of 10-14). No lower injury incidence for players with scores of >14 (score > 1 SD above the mean) was found. Further analyses of potential risk factors suggest higher age, lower body mass and a longer football career to be risk factors for injuries. The findings of this study suggest that the suitability of the FMSTM for injury prediction in veteran footballers is limited. PMID- 26939908 TI - Cross-cultural comparison of political leaders' operational codes. AB - This study aims at comparing operational codes (namely, philosophical and instrumental beliefs about the political universe) of political leaders from different cultures. According to Schwartz (2004), cultures can be categorised into 3 dimensions: autonomy-embeddedness, egalitarianism-hierarchy and mastery harmony. This study draws upon the 1st dimension (akin to the most popular cultural dimension of Hofstede: individualism-collectivism) and focuses on comparing the leaders of autonomous and embedded cultures based on how cooperative/conflictual they are. The main research hypothesis is as follows: the leaders of embedded cultures would be more cooperative than the leaders of autonomous cultures. For this purpose, 3 autonomous cultures (the UK, Canada and Australia) and embedded cultures (Singapore, South Africa and Malaysia) cultures were chosen randomly and the cooperativeness of the correspondent countries' leaders were compared after being profiled by Profiler Plus. The results indicated that the leaders of embedded cultures were significantly more cooperative than autonomous cultures after holding the control variables constant. The findings were discussed in the light of relevant literature. PMID- 26939909 TI - Dietary components and risk of total, cancer and cardiovascular disease mortality in the Linxian Nutrition Intervention Trials cohort in China. AB - Although previous studies have shown that dietary consumption of certain food groups is associated with a lower risk of cancer, heart disease and stroke mortality in western populations, limited prospective data are available from China. We prospectively examined the association between dietary intake of different food groups at baseline and risk of total, cancer, heart disease and stroke mortality outcomes in the Linxian Nutrition Intervention Trials(NIT) cohort. In 1984-1991, 2445 subjects aged 40-69 years from the Linxian NIT cohort completed a food frequency questionnaire. Deaths from esophageal and gastric cancer, heart disease and stroke were identified through up to 26 years of follow up. We used Cox proportional hazard models to calculate hazard ratios and 95% confidence intervals for associations between intake of groups of food items and these mortality endpoints. We concluded that higher intake of certain food groups was associated with lower risk of gastric cancer, heart disease and stroke mortality in a prospective cohort in rural China. Our findings provide additional evidence that increasing intake of grains, vegetables, beans, fruits and nuts may help reduce mortality from these diseases. PMID- 26939911 TI - An interesting case of profound hypoxemia. AB - A 58 year old male with a history of cirrhosis (hepatitis B and C), a long smoking history, and a recently diagnosed high-grade transitional cell carcinoma of the bladder wall presented three days after a biopsy procedure with abdominal pain, nausea, and new hypoxemia on room air. The chest radiograph was clear and the CT angiogram showed only a borderline large pulmonary artery, two small nodules (3mm and 4mm) in the right middle lobe of the lung, and emphysematous changes throughout the lung parenchyma. There was no evidence of pulmonary embolism. A wide range of diagnostic possibilities were entertained, including pneumonia (community or aspiration related to the procedure), COPD exacerbation, pulmonary emboli, porto-pulmonary syndrome, pulmonary hypertension with right to left shunt, tumor emboli, allergic reaction to a medication or chemotherapeutic agent, or lymphangitic/hematogenous spread of tumor to the lungs. The diagnosis was only established on a post mortem examination. The progressive hypoxia was due to diffuse spread of tumor within alveolar capillaries. PMID- 26939912 TI - Octaphlorethol A, a marine algae product, exhibits antidiabetic effects in type 2 diabetic mice by activating AMP-activated protein kinase and upregulating the expression of glucose transporter 4. AB - Octaphlorethol A (OPA), a type of phlorotannin isolated from Ishige foliacea has been shown to have antidiabetic activities. However, the mechanism of action of OPA in type 2 diabetes has not been investigated extensively. Here, we investigated the antidiabetic effects and mechanism of OPA in C57BL/KsJ-db/db mice, a model of type 2 diabetes. Levels of postprandial blood glucose were significantly lower in OPAtreated db/db mice than in control db/db mice. In addition, the OPA supplements significantly improved fasting blood glucose level and impaired glucose tolerance compared to control db/db mice. OPA also significantly decreased the level of serum insulin, augmented the activation of AMP-activated protein kinase (AMPK), and increased the expression of glucose transporter 4 (GLUT4) protein in skeletal muscle. In addition, it significantly suppressed the increases in hepatic mRNA expression level of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase), gluconeogenesis-related enzymes. Therefore, the mechanisms of OPA may involve suppression of gluconeogenesis by inhibiting PEPCK and G6Pase activity in the liver and affecting GLUT4-mediated glucose uptake in skeletal muscle through activation of AMPK. These findings provide a new insight into the antidiabetic clinical applications of OPA and demonstrate the potential of OPA as a new drug candidate for type 2 diabetes. PMID- 26939913 TI - Considering new methodologies in strategies for safety assessment of foods and food ingredients. AB - Toxicology and safety assessment are changing and require new strategies for evaluating risk that are less depending on apical toxicity endpoints in animal models and relying more on knowledge of the mechanism of toxicity. This manuscript describes a number of developments that could contribute to this change and implement this in a stepwise roadmap that can be applied for the evaluation of food and food ingredients. The roadmap was evaluated in four case studies by using literature and existing data. This preliminary evaluation was shown to be useful. However, this experience should be extended by including examples where experimental work needs to be included. To further implement these new insights in toxicology and safety assessment for the area of food and food ingredients, the recommendation is that stakeholders take action in addressing gaps in our knowledge, e.g. with regard to the applicability of the roadmap for mixtures and food matrices. Further development of the threshold of toxicological concern is needed, as well as cooperation with other sectors where similar schemes are under development. Moreover, a more comprehensive evaluation of the roadmap, also including the identification of the need for in vitro experimental work is recommended. PMID- 26939914 TI - Idiopathic basal ganglia calcification (Fahr's disease) and dementia. PMID- 26939916 TI - Factors associated with utilization of motorcycle ambulances by pregnant women in rural eastern Uganda: a cross-sectional study. AB - BACKGROUND: Evidence suggests that use of motorcycle ambulances can help to improve health facility deliveries; however, few studies have explored the motivators for and barriers to their usage. We explored the factors associated with utilization of motorcycle ambulances by pregnant women in eastern Uganda. METHODS: This was a cross-sectional, mixed-methods study conducted among 391 women who delivered at four health facilities supplied with motorcycle ambulances in Mbale district, eastern Uganda, between April and May 2014. Quantitative data were collected on socio-demographic and economic characteristics, pregnancy and delivery history, and community and health facility factors associated with utilization of motorcycle ambulances using semi-structured questionnaires. Qualitative data were collected on the knowledge and attitudes towards using motorcycle ambulances by pregnant women through six focus group discussions. Using STATA v.12, we computed the characteristics of women using motorcycle ambulances and used a logistic regression model to assess the correlates of utilization of motorcycle ambulances. Qualitative data were analyzed manually using a master sheet analysis tool. RESULTS: Of the 391 women, 189 (48.3%) reported that they had ever utilized motorcycle ambulances. Of these, 94.7% were currently married or living together with a partner while 50.8% earned less than 50,000 Uganda shillings (US $20) per month. Factors independently associated with use of motorcycle ambulances were: older age of the mother (>=35 years vs <=24 years; adjusted Odds Ratio (aOR) = 4.3, 95% CI: 2.03, 9.13), sharing a birth plan with the husband (aOR = 2.5, 95% CI: 1.19, 5.26), husband participating in the decision to use the ambulance (aOR =3.22, 95% CI: 1.92, 5.38), and having discussed the use of the ambulance with a traditional birth attendant (TBA) before using it (aOR =3.12, 95% CI: 1.88, 5.19). Qualitative findings indicated that community members were aware of what motorcycle ambulances were meant for and appreciated their role in taking pregnant women to health facilities. CONCLUSION: The use of motorcycle ambulances was associated with older age of the mother, male participation in birth preparedness, and consultations with TBAs. These findings suggest a need for interventions to involve men in reproductive health as well as efforts to reach women younger than 35 years of age. PMID- 26939917 TI - Usefulness of Upper Airway Endoscopy in the Evaluation of Pediatric Pulmonary Aspiration. AB - IMPORTANCE: There is no consensus on the evaluation of pediatric patients with aspiration. OBJECTIVES: To determine the yield of direct laryngoscopy and bronchoscopy (DLB) using general anesthesia in pediatric patients who aspirate and to identify clinical predictors of aspiration-related airway lesions. DESIGN, SETTING, AND PARTICIPANTS: Retrospective review at a tertiary referral children's hospital. A medical record review was performed on all patients with a documented diagnosis of pulmonary aspiration who underwent DLB using general anesthesia during a 5-year period (January 2010 to December 2014). INTERVENTION: Direct laryngoscopy and bronchoscopy using general anesthesia. MAIN OUTCOMES AND MEASURES: Data were collected and analyzed, including age, sex, history of intubation, flexible laryngoscopy results, DLB findings, recurrent pneumonia, and associated diagnoses. RESULTS: Five hundred thirty-two patients met the inclusion criteria. Their mean (SD) age was 2.2 (3.6) years (age range, 0.1-25.0 years), with more than half younger than 1 year. Sixty-two percent (328 of 532) of the participants were male. Flexible laryngoscopy examination alone identified 93 patients with an airway lesion. Direct laryngoscopy and bronchoscopy identified 173 additional diagnoses and had a greater diagnostic yield for airway lesions (45.1% [240 of 532]) than flexible laryngoscopy examination alone (P < .001). Patients with an aspiration-related airway lesion were older (mean [SD] age, 2.7 [3.8] vs 2.2 [3.8] years; P = .02) and more likely to have another aerodigestive disorder than were patients without an airway lesion (21.7% vs 11.6%; P = .004). Older age (adjusted risk ratio [95% CI], 1.37 [1.08-1.73]; P = .01), recurrent pneumonia (1.40 [1.11-1.76]; P = .004), and history of intubation (1.35 [1.07 1.70]; P = .01) were significantly associated with the presence of an aspiration related airway lesion in the multivariable model. Patients with an aspiration related airway lesion were less likely to have neurologic disease than were patients without an airway lesion (0.50 [0.34-0.73]; P < .001). In all, 66.3% of patients (110 of 166) eventually underwent surgical repair of an identified aspiration-related airway lesion. CONCLUSIONS AND RELEVANCE: In children with chronic aspiration who warrant further evaluation, flexible laryngoscopy alone is not sufficient. There is a high incidence of aspiration-related airway lesions identified on DLB and not seen on flexible laryngoscopy, with 66.3% (110 of 166) of those lesions eventually requiring surgical intervention. Patients 1 year or older with a history of recurrent pneumonia or intubation are more likely to have an aspiration-related airway lesion. PMID- 26939910 TI - Altering the course of schizophrenia: progress and perspectives. AB - Despite a lack of recent progress in the treatment of schizophrenia, our understanding of its genetic and environmental causes has considerably improved, and their relationship to aberrant patterns of neurodevelopment has become clearer. This raises the possibility that 'disease-modifying' strategies could alter the course to - and of - this debilitating disorder, rather than simply alleviating symptoms. A promising window for course-altering intervention is around the time of the first episode of psychosis, especially in young people at risk of transition to schizophrenia. Indeed, studies performed in both individuals at risk of developing schizophrenia and rodent models for schizophrenia suggest that pre-diagnostic pharmacotherapy and psychosocial or cognitive-behavioural interventions can delay or moderate the emergence of psychosis. Of particular interest are 'hybrid' strategies that both relieve presenting symptoms and reduce the risk of transition to schizophrenia or another psychiatric disorder. This Review aims to provide a broad-based consideration of the challenges and opportunities inherent in efforts to alter the course of schizophrenia. PMID- 26939918 TI - Fermented Sipjeondaebo-tang Alleviates Memory Deficits and Loss of Hippocampal Neurogenesis in Scopolamine-induced Amnesia in Mice. AB - We investigated the anti-amnesic effects of SJ and fermented SJ (FSJ) on scopolamine (SCO)-induced amnesia mouse model. Mice were orally co-treated with SJ or FSJ (125, 250, and 500 mg/kg) and SCO (1 mg/kg), which was injected intraperitoneally for 14 days. SCO decreased the step-through latency and prolonged latency time to find the hidden platform in the passive avoidance test and Morris water maze test, respectively, and both SCO effects were ameliorated by FSJ treatment. FSJ was discovered to promote hippocampal neurogenesis during SCO treatment by increasing proliferation and survival of BrdU-positive cells, immature/mature neurons. In the hippocampus of SCO, oxidative stress and the activity of acetylcholinesterase were elevated, whereas the levels of acetylcholine and choline acetyltransferase were diminished; however, all of these alterations were attenuated by FSJ-treatment. The alterations in brain derived neurotrophic factor, phosphorylated cAMP response element-binding protein, and phosphorylated Akt that occurred following SCO treatment were protected by FSJ administration. Therefore, our findings are the first to suggest that FSJ may be a promising therapeutic drug for the treatment of amnesia and aging-related or neurodegenerative disease-related memory impairment. Furthermore, the molecular mechanism by which FSJ exerts its effects may involve modulation of the cholinergic system and BDNF/CREB/Akt pathway. PMID- 26939919 TI - Heparin-based self-assembling peptide scaffold reestablish chondrogenic phenotype of expanded de-differentiated human chondrocytes. AB - The use of chondrocytes in cell-based therapies for cartilage lesions are limited by quantity and, therefore, require an in vitro expansion. As monolayer culture leads to de-differentiation, different culture techniques are currently under development to recover chondrocyte phenotype after cell expansion. In the present work, we studied the capacity of the bimolecular heparin-based self-assembling peptide scaffold (RAD16-I) as a three-dimensional (3D) culture system to foster reestablishment of chondrogenic phenotype of de-differentiated human Articular Chondrocytes (AC). The culture was performed in a serum-free medium under control and chondrogenic induction and good viability results were observed after 4 weeks of culture in both conditions. Cells changed their morphology to a more elongated shape and established a cellular network that induced the condensation of the constructs in the case of chondrogenic medium, leading to a compacted structure with improved mechanical properties. Specific extracellular matrix (ECM) proteins of mature cartilage, such as collagen type II and aggrecan were up-regulated under chondrogenic medium and significantly enhanced with the presence of heparin in the scaffold. 3D constructs became highly stained with toluidine blue dye after 4 weeks of culture, indicating the presence of synthetized proteoglycans (PGs) by the cells. Interestingly, the full viscoelastic behavior was closely related to that found in chicken native cartilage. Altogether, the results suggest that the 3D culture model described can help de-differentiated human chondrocytes to recover its cartilage phenotype. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 1694-1706, 2016. PMID- 26939922 TI - Impact of an electronic tool in prescribing primary prophylaxis with ciprofloxacin or granulocyte colony-stimulating factor for breast cancer patients receiving TC chemotherapy. AB - BACKGROUND: The US Oncology Trial 9735 (doxorubicin and cyclophosphamide (AC) versus docetaxel and cyclophosphamide (TC)) reported febrile neutropenia (FN) in 5 % of patients receiving TC chemotherapy, in the absence of routine primary prophylaxis with granulocyte colony-stimulating factor (G-CSF) or antibiotics. In contrast, higher rates of FN have been reported in the 'real world' setting. This retrospective study compares the incidence and severity of FN and other TC related toxicities before and after implementation of a primary prophylaxis computerized prescribing tool. METHODS: Medical records of 207 patients receiving adjuvant TC between May 1, 2006, and November 1, 2011, were reviewed for toxicity. The incidence for each TC adverse event was measured by an incident rate ratio (IRR), and chi-square analysis was used to compare the differences in severity of TC toxicities before and after use of a primary prophylaxis computerized prescribing tool, and to compare G-CSF and ciprofloxacin groups. RESULTS: The implementation of a computerized prescribing tool significantly increased the proportion of patients prescribed primary prophylaxis (18.2 vs. 97.4 %; p < 0.001). Prior to the change in practice, the incidence of FN (incidence rate ratio 3.87; 95 % CI [1.3, 11.5]) and neutropenia (OR 4.8; 95 % CI [2.0, 11.7]) was significantly higher. Primary prophylaxis significantly reduced the rate of febrile neutropenia (20 vs. 5.3 %, p = 0.003). No significant differences were found in incidence and severity of other TC-related toxicities. Patients who did not receive G-CSF were at a greater risk for neutropenia (OR 5.1, 95 % CI [1.06, 24.3]). There were insufficient patients treated with antibiotics alone to compare to those treated with G-CSF. CONCLUSIONS: Implementation of a computerized prescribing tool significantly increased the use of primary prophylaxis by treating physicians in patients receiving TC chemotherapy, which was associated with reduced incidence of febrile neutropenia. Further research efforts should focus on the incorporation and routine use of evidence-based practices using tools such as alerts and prompts, in order to optimize patient care and improve outcomes. PMID- 26939921 TI - The Approach to Acute Lymphoblastic Leukemia in Older Patients: Conventional Treatments and Emerging Therapies. AB - Acute lymphoblastic leukemia (ALL) among older adult patients presents significant clinical challenges. As opposed to pediatric populations, in whom long-term outcomes are markedly superior, those for adults remain grim. Nevertheless, younger adults with ALL have experienced a steady improvement in long-term survival in the last few decades. This is significantly different for older ALL patients, for whom long-term outcomes remain poor. Conventional chemotherapies are associated with sub-optimal outcomes and increased toxicity in this population. However, several emerging therapies, including antibody-drug conjugates, bi-specific engagers, and chimeric antigen receptor (CAR) T cells, have demonstrated much promise and are either incorporated into the existing therapeutic paradigms or being actively investigated to improve outcomes. PMID- 26939924 TI - "Generality of mis-fit"? The real-life difficulty of matching scales in an interconnected world. AB - A clear understanding of processes at multiple scales and levels is of special significance when conceiving strategies for human-environment interactions. However, understanding and application of the scale concept often differ between administrative-political and ecological disciplines. These mirror major differences in potential solutions whether and how scales can, at all, be made congruent. As a result, opportunities of seeking "goodness-of-fit" between different concepts of governance should perhaps be reconsidered in the light of a potential "generality of mis-fit." This article reviews the interdisciplinary considerations inherent in the concept of scale in its ecological, as well as administrative-political, significance and argues that issues of how to manage "mis-fit" should be awarded more emphasis in social-ecological research and management practices. These considerations are exemplified by the case of reindeer husbandry in Fennoscandia. Whilst an indigenous small-scale practice, reindeer husbandry involves multi-level ecological and administrative-political complexities-complexities that we argue may arise in any multi-level system. PMID- 26939925 TI - Metal assisted cyclomerization of benzodipyrrins into expanded norroles, aza heptalene and acyclic dimers. AB - Benzofused dipyrrins react with metal salt copper(II) acetate to predominantly yield a cyclodimer along with a cyclotrimer. N-confused monobenzo-dipyrrin cyclomerized to trioxo-expanded norrole 13a and an acyclic dimer 14 whereas doubly N-confused monobenzo and dibenzo-dipyrrins yielded aza-heptalene 15 and an acyclic dimer 16. PMID- 26939923 TI - Young female cancer survivors' use of fertility care after completing cancer treatment. AB - PURPOSE: The purpose of the present study is to investigate factors associated with female young adult cancer survivors' (YCSs) use of fertility care (FC), including consultation or fertility treatment, after completing their cancer treatment. METHODS: In this cross-sectional study, females between that ages of 18 and 35 years who had been diagnosed with childhood, adolescent, or young adult cancers completed a 20-min web-based survey that included demographics, reproductive history, use of FC, fertility-related informational needs, and reproductive concerns. RESULTS: A total of 204 participants completed the survey. Participants' mean age was 28.3 +/- 4.5 years. Thirty (15 %) participants reported using FC after cancer treatment. The majority of participants recalled not receiving enough information about fertility preservation options at the time of cancer diagnosis (73 %). In multivariable analysis, those with higher concerns about having children because of perceived risk to their personal health (P = 0.003) were less likely to report use of FC after cancer treatment. Those who had used FC before cancer treatment (P = 0.003) and who felt less fertile than age matched women (P = 0.02) were more likely to use FC after their cancer treatment. CONCLUSIONS: While most YCSs in this cohort believed that they did not receive enough information about fertility and most wanted to have children, the vast majority did not seek FC. The findings of this study offer further evidence of the need for improved education and emotional support regarding reproductive options after cancer treatment is completed. Targeted discussions with YCSs about appropriate post-treatment FC options may improve providers' capacity to help YCSs meet their parenthood goals. PMID- 26939926 TI - Assessment of publication bias required improvement in oral health systematic reviews. AB - OBJECTIVES: To examine whether the assessment of publication bias in a broad cross-section of oral health systematic reviews (SRs) is in accordance with established methodology. STUDY DESIGN AND SETTING: The electronic databases of 15 dental journals and the Cochrane Database of Systematic Reviews (Oral Health Group) were searched between January 2008 and December 2014 to identify eligible SRs and meta-analyses. The method of publication bias assessment and a range of study characteristics at the SR and the meta-analysis level were recorded. RESULTS: Four hundred fifty-eight systematic reviews were identified. Quantitative synthesis was undertaken in 162. MEDLINE (N = 454, 99%), Cochrane (N = 343, 75%), and EMBASE (N = 283, 62%) were the most frequently searched databases, whereas search for unpublished literature was used in 40% of the reviews. Publication bias was assessed in 46 meta-analyses with only 46% having appropriately used established methodology, such as funnel plots or statistical tests. Of the 38 meta-analyses including at least 10 studies, only 21 (55%) performed the assessment of publication bias. CONCLUSION: This empirical study highlights the shortcomings related to publication bias assessment in SRs within the field of oral health with publication bias either not assessed or done so inappropriately in more than half of the meta-analyses. PMID- 26939928 TI - We should not be so quick to abandon the use of domain experts and full models (letter commenting: J Clin Epidemiol. 2015;71C:76--85.). PMID- 26939927 TI - PROMIS Fatigue Item Bank had Clinical Validity across Diverse Chronic Conditions. AB - OBJECTIVE: To evaluate the comparability and responsiveness of Patient-Reported Outcomes Measurement Information System (PROMIS) fatigue item bank across six chronic conditions. STUDY DESIGN AND SETTING: Individuals (n = 1,430) with chronic obstructive pulmonary disease (n = 125), chronic heart failure (n = 60), chronic back pain (n = 218), major depressive disorder (n = 196), rheumatoid arthritis (n = 521), and cancer (n = 310) completed assessments from the PROMIS fatigue item bank at baseline and a clinically relevant follow-up. The cancer and arthritis samples were followed in observational studies; the other four groups were enrolled immediately before a planned clinical intervention. All participants completed global ratings of change at follow-up. Linear mixed effects models and standardized response means were estimated to examine clinical validity and responsiveness to change. RESULTS: All patient groups reported more fatigue than the general population (range = 0.2-1.29 standard deviation worse). The four clinical groups with pretreatment baseline data experienced significant improvement in fatigue at follow-up (effect size range = 0.25-0.91). Individuals reporting better overall health usually experienced larger fatigue changes than those reporting worse overall health. CONCLUSION: The results support the PROMIS fatigue measures's responsiveness to change in six different chronic conditions. In addition, these results support the ability of the PROMIS fatigue measures to compare differences in fatigue across a range of chronic conditions, thereby enabling comparative effectiveness research. PMID- 26939929 TI - The rank-heat plot is a novel way to present the results from a network meta analysis including multiple outcomes. AB - OBJECTIVES: To present a novel and simple graphical approach to improve the presentation of the treatment ranking in a network meta-analysis (NMA) including multiple outcomes. STUDY DESIGN AND SETTING: NMA simultaneously compares many relevant interventions for a clinical condition from a network of trials, and allows ranking of the effectiveness and/or safety of each intervention. There are numerous ways to present the NMA results, which can challenge their interpretation by research users. The rank-heat plot is a novel graph that can be used to quickly recognize which interventions are most likely the best or worst interventions with respect to their effectiveness and/or safety for a single or multiple outcome(s) and may increase interpretability. RESULTS: Using empirical NMAs, we show that the need for a concise and informative presentation of results is imperative, particularly as the number of competing treatments and outcomes in an NMA increases. CONCLUSION: The rank-heat plot is an efficient way to present the results of ranking statistics, particularly when a large amount of data is available, and it is targeted to users from various backgrounds. PMID- 26939930 TI - The authors' reply to letter to the editor re: Bagherzadeh-Khiabani et al., J Clin Epi, 2015. PMID- 26939931 TI - How trial results are intended to be used: is PRECIS-2 a step forward? PMID- 26939932 TI - Evidence selection for a prescription drug's benefit-harm assessment: challenges and recommendations. AB - OBJECTIVES: To describe challenges and make recommendations for researchers in how they select evidence to quantitatively assess a prescription drug's benefits and harms. STUDY DESIGN AND SETTING: These challenges and recommendations are based on our recent experience conducting a benefit-harm assessment for the prescription drug roflumilast. We considered the selection of evidence to quantify (1) the drug's treatment effects in patients, (2) the patient population's baseline risks for beneficial and harmful outcomes without treatment, and (3) the patient population's preferences for these beneficial effects and harms. These are fundamental steps for most benefit-harm assessment methods. RESULTS: We identify critical issues in selecting evidence for each of these steps. We justify in particular the need to incorporate (1) clinical trials for the drug's specific treatment effect; (2) observational studies with the most valid, precise, and applicable effect estimates for the baseline risk; and (3) flexible weighting approaches for balancing the drug benefits and harms. CONCLUSION: We identify challenges and make recommendations for selecting evidence at the critical steps in a prescription drug's benefit-harm assessment. Our findings should assist other researchers conducting these assessments for prescription drugs, which could help regulators, medical professionals, and patients make better decisions about prescription drug use. PMID- 26939933 TI - The NLRP3 and NLRP1 inflammasomes are activated in Alzheimer's disease. AB - BACKGROUND: Interleukin-1 beta (IL-1beta) and its key regulator, the inflammasome, are suspected to play a role in the neuroinflammation observed in Alzheimer's disease (AD); no conclusive data are nevertheless available in AD patients. RESULTS: mRNA for inflammasome components (NLRP1, NLRP3, PYCARD, caspase 1, 5 and 8) and downstream effectors (IL-1beta, IL-18) was up-regulated in severe and MILD AD. Monocytes co-expressing NLRP3 with caspase 1 or caspase 8 were significantly increased in severe AD alone, whereas those co-expressing NLRP1 and NLRP3 with PYCARD were augmented in both severe and MILD AD. Activation of the NLRP1 and NLRP3 inflammasomes in AD was confirmed by confocal microscopy proteins co-localization and by the significantly higher amounts of the pro inflammatory cytokines IL-1beta and IL-18 being produced by monocytes. In MCI, the expression of NLRP3, but not the one of PYCARD or caspase 1 was increased, indicating that functional inflammasomes are not assembled in these individuals: this was confirmed by lack of co-localization and of proinflammatory cytokines production. CONCLUSIONS: The activation of at least two different inflammasome complexes explains AD-associated neuroinflammation. Strategies targeting inflammasome activation could be useful in the therapy of AD. PMID- 26939934 TI - Adenovirus-mediated siRNA targeting CXCR2 attenuates titanium particle-induced osteolysis by suppressing osteoclast formation. AB - BACKGROUND Wear particle-induced peri-implant loosening is the most common complication affecting long-term outcomes in patients who undergo total joint arthroplasty. Wear particles and by-products from joint replacements may cause chronic local inflammation and foreign body reactions, which can in turn lead to osteolysis. Thus, inhibiting the formation and activity of osteoclasts may improve the functionality and long-term success of total joint arthroplasty. The aim of this study was to interfere with CXC chemokine receptor type 2 (CXCR2) to explore its role in wear particle-induced osteolysis. MATERIAL AND METHODS Morphological and biochemical assays were used to assess osteoclastogenesis in vivo and in vitro. CXCR2 was upregulated in osteoclast formation. RESULTS Local injection with adenovirus-mediated siRNA targeting CXCR2 inhibited titanium induced osteolysis in a mouse calvarial model in vivo. Furthermore, siCXCR2 suppressed osteoclast formation both directly by acting on osteoclasts themselves and indirectly by altering RANKL and OPG expression in osteoblasts in vitro. CONCLUSIONS CXCR2 plays a critical role in particle-induced osteolysis, and siCXCR2 may be a novel treatment for aseptic loosening. PMID- 26939935 TI - Effect of previous vaccination with pneumococcal conjugate vaccine on pneumococcal polysaccharide vaccine antibody responses. AB - During the past 10 years, pneumococcal conjugate vaccine (PCV) has become part of the standard childhood vaccination programme. This may impact upon the diagnosis of polysaccharide antibody deficiency by measurement of anti-polysaccharide immunoglobulin (Ig)G after immunization with unconjugated pneumococcal polysaccharide vaccine (PPV). Indeed, contrary to PPV, PCV induces a T-dependent, more pronounced memory response. The antibody response to PPV was studied retrospectively in patients referred for suspected humoral immunodeficiency. The study population was divided into four subgroups based on age (2-5 years versus >= 10 years) and time tested (1998-2005 versus 2010-12). Only 2-5-year-old children tested in 2010-12 had been vaccinated with PCV prior to PPV. The PCV primed group showed higher antibody responses for PCV-PPV shared serotypes 4 and 18C than the unprimed groups. To a lesser extent, this was also found for non-PCV serotype 9N, but not for non-PCV serotypes 19A and 8. Furthermore, PCV-priming elicited a higher IgG2 response. In conclusion, previous PCV vaccination affects antibody response to PPV for shared serotypes, but can also influence antibody response to some non-PCV serotypes (9N). With increasing number of serotypes included in PCV, the diagnostic assessment for polysaccharide antibody deficiency requires careful selection of serotypes that are not influenced by prior PCV (e.g. serotype 8). Further research is needed to identify more serotypes that are not influenced. PMID- 26939936 TI - Financial distress during relocation for treatment of a hematological malignancy: Findings for social work. AB - The findings presented in this article are from qualitative research, funded by the Leukaemia Foundation of Queensland, which explored the financial impact of relocation for specialist treatment for hematology patients living in Queensland, Australia. The findings describe the factors that contribute to the lack of, or erosion of, a buffer to the financial distress created by diagnosis and relocation for treatment for a hematological malignancy. Individuals vulnerable to financial distress are those who lose or reduce employment, have restricted or no access to work cover or leave (sick, recreation or long service), have limited savings, and who have major repayments (e.g., home and car repayments). A combination of these factors can facilitate a spiral to acute and irreversible financial distress. The implications of the findings to social work are explored. PMID- 26939937 TI - Toxicokinetics of selenium in the slider turtle, Trachemys scripta. AB - Selenium (Se) is an essential element that can be harmful for wildlife. However, its toxicity in poikilothermic amniotes, including turtles, remains poorly investigated. The present study aims at identifying selenium toxicokinetics and toxicity in juvenile slider turtles (age: 7 months), Trachemys scripta, dietary exposed to selenium, as selenomethionine SeMet, for eight weeks. Non-destructive tissues (i.e. carapace, scutes, skin and blood) were further tested for their suitability to predict selenium levels in target tissues (i.e. kidney, liver and muscle) for conservation perspective. 130 juvenile yellow-bellied slider turtles were assigned in three groups of 42 individuals each (i.e. control, SeMet1 and SeMet2). These groups were subjected to a feeding trial including an eight-week supplementation period SP 8 and a following 4-week elimination period EP 4 . During the SP8, turtles fed on diet containing 1.1 +/- 0.04, 22.1 +/- 1.0 and 45.0 +/- 2.0 ug g(-1) of selenium (control, SeMet1 and SeMet2, respectively). During the EP4, turtles fed on non-supplemented diet. At different time during the trial, six individuals per group were sacrificed and tissues collected (i.e. carapace, scutes, skin, blood, liver, kidney, muscle) for analyses. During the SP8 (Fig. 1), both SeMet1 and SeMet2 turtles efficiently accumulated selenium from a SeMet dietary source. The more selenium was concentrated in the food, the more it was in the turtle body but the less it was removed from their tissues. Moreover, SeMet was found to be the more abundant selenium species in turtles' tissues. Body condition (i.e. growth in mass and size, feeding behaviour and activity) and survival of the SeMet1 and SeMet2 turtles seemed to be unaffected by the selenium exposure. There were clear evidences that reptilian species are differently affected by and sensitive to selenium exposure but the lack of any adverse effects was quite unexpected. Fig. 1 Design of the feeding trial. T, Time of tissues collection in weeks. The feeding trial included a supplementation period of 8 weeks (i.e. SP8) followed by an elimination period of 4 weeks (i.e. EP4). Six turtles from each turtle group (i.e. control, SeMet1 and SeMet2) were sacrifice at each collection time, from T1 to T12. At T0, four turtles were sacrificed. PMID- 26939939 TI - Impact of hydrogenation on physicochemical and biomedical properties of pH sensitive PMAA-b-HTPB-b-PMAA triblock copolymer drug carriers. AB - pH-Sensitive poly(methacrylic acid)-block-hydroxyl-terminated polybutadiene-block poly(methacrylic acid) (PMAA-b-HTPB-b-PMAA) was synthesized and then hydrogenated in this work. The chain structure, phase behavior and thermal properties were characterized by(1)H NMR, FTIR, XRD, DSC, TGA, etc., and the physicochemical and biomedical properties were investigated via fluorescence spectroscopy, TEM, DLS, loading and release of drug and MTT, and so on. The experimental results indicated that the hydrogenation led to the change in the chain aggregate structure of hydrophobic HTPB blocks and the formation of more stable spherical core-shell micelle aggregates, and the critical micelle concentration decreased from 41.8 mg L(-1)before hydrogenation to 4.4 mg L(-1)after hydrogenation. The hydrogenated block copolymer micelle aggregates exhibited pH-triggered response, and could entrap twice as much hydrophobic drug as the unhydrided counterparts and the encapsulation efficiency was significantly improved, which makes them fine to meet the requirements for drug carriers. Therefore, the hydrogenated PMAA b-HTPB-b-PMAA copolymer micelles as drug target release carriers can be well used in the field of prevention and treatment of cancers. PMID- 26939938 TI - Seminal level of clusterin in infertile men as a significant biomarker reflecting spermatogenesis. AB - The objective of this study was to assess the impact of seminal clusterin level on spermatogenesis in infertile men. This study included 89 men who visited our clinic due to infertility, consisting of 28, 33, and 28 diagnosed with normospermia, oligozoospermia and nonobstructive azoospermia (NOA) respectively. The seminal clusterin concentrations measured by enzyme-linked immunosorbent assay were 47.9, 28.2 and 18.4 ng ml-1 in men with normospermia, oligozoospermia and NOA, respectively, with significant differences among these three groups (P < 0.01). Microdissection testicular sperm extraction (MD-TESE) was performed in the 28 men with NOA, and spermatozoon was successfully retrieved from 9. There was a significant correlation between seminal clusterin level and testicular clusterin protein expression evaluated by immunohistochemical staining in these men with NOA (P = 0.026). Of several parameters available before MD-TESE, the univariate analysis identified serum follicle-stimulating hormone (FSH) level <10 IU ml-1 and seminal clusterin level >=18 ng ml-1 as significant predictors of sperm retrieval, and of these, only serum FSH level <10 IU ml-1 was shown to be independently associated with sperm retrieval in the multivariate analysis. Accordingly, it might be worthy to further evaluate the significance of seminal clusterin level as a biomarker for the assessment of spermatogenic status in infertile men. PMID- 26939940 TI - Physiologically induced changes in bound phenolics and antioxidants, DNA/cytoprotective potentials in pectic poly/oligosaccharides of tomato (Solanum lycopersicum). AB - BACKGROUND: Antioxidant, cyto/DNA protective potentials are known to offer significant protection against free radical induced injury to cells or tissues and cellular damages that are envisaged in various diseases including chronic diseases like cancer, diabetes, etc, while galectin-3 inhibitory potentials are known to block or delay the process of metastasis in cancer. Antioxidant, cyto/DNA protection and galectin-3 inhibitory potentials were examined in pectic polysaccharides (PPs) and pectic oligosaccharides (POs) from four types of two varieties of tomatoes such as Sour (Mallika local variety) raw (SrRT-SrRTPP, SrRTPO), Sour ripe (SrRIT-SrRITPP, SrRITPO), Sweet (Rashmi local variety) raw (SwRT-SwRTPP, SwRTPO) and Sweet ripe (SwRIT-SwRITPP and SwRITPO). RESULTS: Results indicate that unripe PPs and POs show approximately four- to five-fold better galectin-3 inhibitory property than ripe ones. An approximately nine- to 10-fold increase in galectin-3 inhibitory activity in sour variety was observed. The IC50 as determined by free radical scavenging (FRS), red blood cell (RBC) and DNA protection assays revealed reduction in FRS and RBC protective potencies in pectic oligosaccharides (POs) than pectic polysaccharides (PPs), supporting the fact that phenolics contribute towards these activities. Loss of activity could be attributed to the hydrolysis of certain phenolics during the ripening process as well as during conversion of PPs to POs. CONCLUSION: This study, for the first time, showed changes in bioactivity profiling in unripened and ripened conditions in tomato. Precise alterations in biomolecular components, such as bound cinnamyl/ferulyl and vanillic acid derivatives, along with alterations in sugar composition that reflect changes in antioxidants, cyto/DNA protective and antimetastatic potentials, have been delineated. (c) 2016 Society of Chemical Industry. PMID- 26939941 TI - Functional analysis of the uL11 protein impact on translational machinery. AB - The ribosomal GTPase associated center constitutes the ribosomal area, which is the landing platform for translational GTPases and stimulates their hydrolytic activity. The ribosomal stalk represents a landmark structure in this center, and in eukaryotes is composed of uL11, uL10 and P1/P2 proteins. The modus operandi of the uL11 protein has not been exhaustively studied in vivo neither in prokaryotic nor in eukaryotic cells. Using a yeast model, we have brought functional insight into the translational apparatus deprived of uL11, filling the gap between structural and biochemical studies. We show that the uL11 is an important element in various aspects of 'ribosomal life'. uL11 is involved in 'birth' (biogenesis and initiation), by taking part in Tif6 release and contributing to ribosomal subunit-joining at the initiation step of translation. uL11 is particularly engaged in the 'active life' of the ribosome, in elongation, being responsible for the interplay with eEF1A and fidelity of translation and contributing to a lesser extent to eEF2-dependent translocation. Our results define the uL11 protein as a critical GAC element universally involved in trGTPase 'productive state' stabilization, being primarily a part of the ribosomal element allosterically contributing to the fidelity of the decoding event. PMID- 26939943 TI - Retrograde double-labeling demonstrates convergent afferent innervation of the prostate and bladder. AB - BACKGROUND: Prostatic inflammation is a common histologic finding in men with lower urinary tract symptoms (LUTS). It has been postulated that prostatic inflammation could sensitize afferent neurons innervating the bladder and thereby produce changes in voiding behavior. In support of this, we demonstrate an anatomic basis for pelvic cross-talk involving the prostate and bladder. METHODS: Retrograde labeling was performed by an application of a neuro-tracer Fast Blue (FB) to one side of either the anterior prostate (AP), dorsal lateral prostate (DLP)/ventral prostate (VP), bladder, or seminal vesicle (SV). RESULTS: Examination of dorsal root ganglion (DRG) neuron labeling revealed shared afferent innervation of the prostate and bladder at spinal segments of T13, L1, L2, L6, and S1. Dual labeling was performed by an application of FB and 1,1' dioctadecyl-3,3,3',3'-tetramethylindocarbocyaine perchlorate (DiI) to the AP and bladder, respectively. We observed double-labeled DRG neurons at T13, L1, L2, L6, and S1--a finding that proves convergent innervation of prostate and bladder. CONCLUSIONS: Our observations demonstrate the potential for neural cross-talk between the prostate and bladder and support a postulated mechanism that prostatic inflammation may induce hyper-sensitization of bladder afferents and produce irritative LUTS. PMID- 26939942 TI - Cryo-soft X-ray tomography as a quantitative three-dimensional tool to model nanoparticle:cell interaction. AB - BACKGROUND: Recent advances in nanoparticle design have generated new possibilities for nano-biotechnology and nano-medicine. Here we used cryo-soft X ray tomography (cryo-SXT) to collect comprehensive three-dimensional (3D) data to characterise the interaction of superparamagnetic iron oxide nanoparticles (SPION) with a breast cancer cell line. RESULTS: We incubated MCF-7 (a human breast cancer cell line) from 0 to 24 h with SPION (15 nm average diameter, coated with dimercaptosuccinic acid), a system that has been studied previously using various microscopy and bulk techniques. This system facilitates the validation and contextualization of the new 3D data acquired using the cryo-SXT based approach. After vitrification, samples tested by correlative cryo epifluorescent microscopy showed SPION accumulation in acidic vesicles related to the endocytic pathway. Microscopy grids bearing MCF-7 cells were then analysed by cryo-SXT to generate whole cell volume 3D maps. Cryo-SXT is an emerging technique that benefits from high X-ray penetration into the biological material to image close-to-native vitrified cells at nanometric resolution with no chemical fixation or staining agents. This unique possibility of obtaining 3D information from whole cells allows quantitative statistical analysis of SPION-containing vesicle (SCV) accumulation inside cells, including vesicle number and size, distances between vesicles, and their distance from the nucleus. CONCLUSIONS: Correlation between fluorescent microscopy, cryo-SXT and transmission electron microscopy allowed us to identify SCV and to generate 3D data for statistical analysis of SPION:cell interaction. This study supports continuous transfer of the internalized SPION from the plasma membrane to an accumulation area near the cell nucleus. Statistical analysis showed SCV increase in number and size concomitant with longer incubation times, and therefore an increase in their accumulated volume within the cell. This cumulative effect expands the accumulation area and cell organelles such as mitochondria are consequently displaced to the periphery. Our 3D cryo-SXT approach demonstrates that a comprehensive quantitative description of SPION:cell interaction is possible, which will serve as a basis for metal-based nanoparticle design and for selection of those best suited for hyperthermia treatment, drug delivery and image diagnosis in nanobiomedicine. PMID- 26939944 TI - Prostate biopsy, targeted prophylaxis and infectious complications: a critique of methods used. PMID- 26939945 TI - Graphene oxide as a p-dopant and an anti-reflection coating layer, in graphene/silicon solar cells. AB - It is shown that coating graphene-silicon (Gr/Si) Schottky junction based solar cells with graphene oxide (GO) improves the power conversion efficiency (PCE) of the cells, while demonstrating unprecedented device stability. The PCE has been shown to be increased to 10.6% (at incident radiation of 100 mW cm(-2)) for the Gr/Si solar cell with an optimal GO coating thickness compared to 3.6% for a bare/uncoated Gr/Si solar cell. The p-doping of graphene by the GO, which also serves as an antireflection coating (ARC) has been shown to be a main contributing factor to the enhanced PCE. A simple spin coating process has been used to apply GO with thickness commensurate with an anti-refection coating (ARC) and indicates the suitability of the developed methodology for large-scale solar cell assembly. PMID- 26939946 TI - Asymptomatic Wolff-Parkinson-White Syndrome: Who Should Be Treated? AB - This article discusses the merits of electrophysiology study (EPS) and/or ablation for asymptomatic preexcitation Wolff-Parkinson-White (WPW) ECG pattern. Sudden deaths in asymptomatic patients are too few to merit broad screening and aggressive intervention. It also discusses the risks of ablation and the low predictive accuracy of EPS. When WPW is an incidental finding, the decision to proceed with investigation and ablation can be made considering patients' situations and preferences. An invasive strategy is targeted at patients concerned about the low risk of life-threatening arrhythmia as a first presentation after a discussion of the risks and benefits. PMID- 26939947 TI - Asymptomatic Wolff-Parkinson-White Syndrome Should be Ablated. AB - Wolff-Parkinson-White syndrome (WPW) is associated with a small but lifetime risk of cardiac arrest and/or sudden cardiac death (SCD). However, the exact risk is not well defined, particularly in asymptomatic persons. Over recent years the authors have collected and reported new follow-up data among a large number of asymptomatic WPW patients, particularly children, intensively followed. These data have significantly contributed to the knowledge and definition of the natural history of WPW from childhood to adulthood. The risk of SCD is higher in asymptomatic children than in adults, and early ablation can be offered only to selected subjects after electrophysiologic testing. PMID- 26939948 TI - Ablation as First-Line Therapy for Atrial Fibrillation: Yes. AB - This article addresses the use of catheter ablation (CA) as first-line therapy for atrial fibrillation (AF). CA increases long-term freedom from AF, reduces hospitalizations, and improves quality of life compared with antiarrhythmic drug (AAD) therapy in patients with symptomatic AF who have already failed one AAD. The role of CA as first-line therapy for AF, however, is still controversial. Evidence from randomized controlled trials shows that CA is definitely superior to AADs as first-line therapy for relatively young patients with paroxysmal AF, with comparable complication rates and results consistently reproducible across different institutions, operators, and types of ablation approaches. PMID- 26939949 TI - Ablation as First-Line Therapy for Atrial Fibrillation: Not Yet for All. AB - Studies have established the superiority of atrial fibrillation ablation in controlling the rhythm compared with medical therapy. The procedure, however, has significant associated risks. Whether ablation therapy would improve the major outcomes of survival and stroke is not yet established. Until this information becomes available, ablation should continue to be used as a second-line option for most patient subgroups when one or more antiarrhythmic medications are ineffective. PMID- 26939950 TI - Atrial Fibrillation Ablation: Do We Really Need Preprocedural Imaging? AB - Atrial fibrillation is the most common human arrhythmia, causing significant mortality and morbidity. Because of the potential for complications, it is important that procedures be made as safe and effective as possible by combining safe procedural planning with effective therapy delivery. To change the current approach, large randomized studies are needed to guide the selection of patients who may safely undergo ablation without transesophageal echocardiography to exclude thrombus. For institutions routinely using computed tomography and magnetic resonance imaging to assess pulmonary vein anatomy before procedures, the possibility of excluding intracardiac thrombi using these imaging modalities should be considered. PMID- 26939951 TI - Postablation Atrial Flutters. AB - Mapping and ablation of post-atrial fibrillation (AF) atrial tachycardia (AT) are challenging electrophysiologic procedures. These tachycardias may be caused by multiple mechanisms and may arise from the left or right atrium, or the coronary sinus. The precise mechanism must be defined before ablation because the procedural end point depends on the correct diagnosis. Postablation ATs can be successfully ablated in approximately 90% of patients. Many patients experience recurrence despite rigorous procedural end points. Efforts should focus on decreasing the incidence of AT after AF ablation and identifying patients who require linear ablation during a procedure for persistent AF. PMID- 26939952 TI - Atrial Fibrillation Ablation in Obese Patients. AB - Despite the increased burden of atrial fibrillation (AF), obese patients have similar, if not slightly improved, mortality, described as the "obesity paradox." Catheter ablation for AF in obese patients is a reasonable option, but patients should be screened for sleep apnea and counseled about the possibility of longer procedure times and repeat procedures to achieve similar success rates. Quality of life will likely improve after successful ablation. Although no statistically significant increases in procedural complications have occurred in obese subjects, patients should be counseled about the increased radiation dose and higher incidence of left atrial thrombus preablation. PMID- 26939953 TI - Ablation of Persistent Atrial Fibrillation: AF Termination is the End Point. AB - This article reviews the literature on various techniques in the ablation of persistent AF, with the aim of highlighting the role of intraprocedural arrhythmia termination, defined as conversion to sinus rhythm or intermediate atrial tachycardia, in the predictability of arrhythmia recurrence. Because arrhythmia termination is not observed universally as a procedural end point, only those studies wherein it has been specifically reported, and its predictive role in arrhythmia recurrence is considered, are described. PMID- 26939954 TI - Ablation for Atrial Fibrillation: Termination of Atrial Fibrillation is Not the End Point. AB - Permanent pulmonary vein isolation constitutes the main procedural goal of current approaches to atrial fibrillation (AF) catheter ablation, with established effectiveness as a stand-alone procedure in most patients with paroxysmal AF. In patients with AF of longer duration, however, the definition of the optimal procedural end point is still controversial. Based on analysis of data from 16 studies that have assessed the value of AF termination in predicting long-term procedural success, it is concluded that AF termination clearly represents an unreliable procedural end point during ablation of nonparoxysmal AF. PMID- 26939955 TI - Atrial Fibrillation Ablation Strategy: "Ready Made" or "Tailored"? AB - Atrial fibrillation (AF) is the most common arrhythmia leading to hospital admissions. Catheter ablation has evolved as an effective treatment strategy; however, ablation strategies continue to evolve due to the complex and multifactorial nature of atrial fibrillation. A standardized and primarily anatomical approach may not be sufficient to eliminate all mechanisms of atrial fibrillation. A tailored ablation strategy can target specific triggers and drivers of atrial fibrillation; however, it is limited by the accuracy and sensitivity of the methods used in identifying specific mechanisms of atrial fibrillation. PMID- 26939956 TI - Anticoagulation Issues in Patients with AF. AB - The evaluation of the risk of stroke for individual patients with atrial fibrillation (AF) is a crucial factor in the decision to provide anticoagulation therapy. Novel oral anticoagulants, as compared with warfarin, are associated with a lower or similar rate of stroke and systemic embolism and a lower rate of hemorrhagic stroke. These drugs are administered at a fixed dose, have a shorter peak action and half-life, and do not require international normalized ratio monitoring. After a successful AF ablation, oral anticoagulation therapy discontinuation seems to be feasible in patients with a CHADS2 score greater than or equal to 2 and normal left atrial (LA) function. However, larger prospective randomized trials are needed to confirm the safety of this strategy. PMID- 26939957 TI - AF Ablation: Do You Need a Mapping System for Ablation? AB - Radiofrequency ablation has become a mainstay in the therapy for atrial fibrillation (AF). Although there are many different techniques for achieving adequate results, the cornerstone of AF remains pulmonary vein isolation. Three dimensional (3D) electroanatomical mapping systems play an important role in the reduction of fluoroscopy and the identification of electrical and anatomic landmarks and are used commonly in AF ablation procedures. In this article, the authors discuss the advantages and limitations of 3D mapping systems and try to answer the question: Are they needed for successful AF ablation? PMID- 26939959 TI - Surgical Atrial Fibrillation Ablation: An Electrophysiologist's Perspective. AB - The experience and insight obtained during surgical ablation of all types of arrhythmias was formative for electrophysiology and catheter ablation. The early surgical ablation experience provided proof of concept as well direct operative observation of anatomy and pathophysiologic mechanisms. For atrial fibrillation (AF), surgical ablation anticipated many of the problems that catheter ablation subsequently encountered, although these lessons were not promptly appreciated. Rather than competition, greater cooperation and communication between surgeons and electrophysiologists in the future would be more likely to enhance understanding of the underlying pathophysiology of AF. PMID- 26939958 TI - Percutaneous Closure of the Left Atrial Appendage. AB - This article reviews the published evidence on stroke prevention with percutaneous closure of the left atrial appendage and provides comparative insight into the various left atrial appendage closure devices currently in development. PMID- 26939960 TI - Ablate and Pace: Is There Still a Role? AB - Despite the development of newer drugs and procedures to improve rhythm control, there is still a place for ablation of the atrioventricular junction (AVJ) in the management of selected patients with AF who are refractory to medical therapy, to improve quality of life, prevent ventricular dysfunction, and to optimize cardiac resynchronization therapy. We review all aspects of the "ablate and pace" strategy, from its history to patient selection, technique, outcomes and applications, and identify the need for randomized clinical trials to address some of the remaining questions regarding its application in some groups of patients. PMID- 26939961 TI - Totally Thoracoscopic Surgical Ablation or Catheter Ablation of Atrial Fibrillation: A Systematic Review and Preliminary Meta-Analysis. AB - This article provides results of a preliminary meta-analysis of the stand-alone atrial fibrillation (AF) surgical publications from 2009 to 2011. In 6 studies with postoperative freedom from AF as primary end point, the meta-analysis indicated an overall success rate of 84% (95% confidence interval [CI], 80.0 88.0). For the 7 studies with the primary end point of postoperative return to normal sinus rhythm, the success rate was 83% (95% CI, 79.0-87.0). These data are compared with 3 comprehensive meta-analyses of catheter ablation. Based on comparison, it is recommended that initial treatment of long-standing persistent atrial fibrillation be minimal access surgery. PMID- 26939963 TI - Premature Ventricular Contraction Ablation: How Aggressive Should We Be? AB - This article explores the prevalence of premature ventricular contractions (PVCs) and their association with underlying heart disease; examines proposed indications for therapy, particularly for catheter ablation; and evaluates the existing data regarding outcomes of ablation in these patients. The aim is to highlight the subset of patients most likely to benefit from catheter ablation targeting PVCs. The article also discusses the implications of symptoms, underlying heart disease, and characteristics of PVCs on clinical management. PMID- 26939962 TI - The Emerging Role of Epicardial Ablation. AB - Sosa and colleagues first described a percutaneous approach (via the subxiphoid area) to access the pericardial space in 1996. Epicardial mapping and ablation is increasingly used for the treatment of supraventricular and ventricular arrhythmias and represents an adjunctive approach for challenging arrhythmias to improve procedural success rates. Epicardial ablation should be considered not only after the failure of an endocardial ablation but often as a first-line approach. Complications may occur during percutaneous access and epicardial ablation, and these might be reduced or avoided by improved operator skills and experience. New tools to access the epicardial space are being evaluated. PMID- 26939964 TI - Renal Denervation: A New Approach to an Old Problem. AB - Renal sympathetic hyperactivity is associated with hypertension. Renal denervation is an interventional approach to selectively denervate the renal sympathetic fibers. The reduction of systolic and diastolic blood pressure in patients with resistant hypertension has been demonstrated in the Symplicity HTN 1 and HTN-2 trials. Before the patient undergoes an interventional procedure, causes of secondary hypertension or pseudoresistance must be excluded. PMID- 26939965 TI - Atrial Tachyarrhythmias After Cardiac Transplantation. AB - Cardiac transplant recipients demonstrate a unique substrate for atrial tachyarrhythmias owing to the surgical techniques involved. Surgical modification of the atria during transplant surgery has both proarrhythmic and antiarrhythmic effects detailed in this paper. Cavotricuspid isthmus-dependent right atrial flutter is the most common arrhythmia identified. Atrial fibrillation is uncommon owing to obligatory surgical pulmonary vein isolation. Donor hearts can also contain pre-existing accessory pathways or dual AV nodal physiology causing supraventricular tachycardia for which adenosine treatment is not recommended, but catheter ablation is curable. PMID- 26939966 TI - "On the Front Lines" Contemporary Debates and Controversies-II. PMID- 26939967 TI - Most melanoma patients have few moles, study finds. PMID- 26939969 TI - (-)-Epicatechin in vitro ameliorates erythrocyte protein carbonyl content in hypertensive patients: comparison with L-ascorbic acid. AB - CONTEXT: Oxidative stress plays a key role in the patho-physiology of hypertension. (-)-Epicatechin has many important biological properties. OBJECTIVE: The present study was undertaken to evaluate effect of (-)-epicatechin on protein carbonyl content in gender-based hypertensive patients and normal subjects. METHODS: The study was carried out on 83 normal (male: 42; female: 41) and 62 hypertensive subjects (male: 32; female: 30). In vitro effect on (-) epicatechin and L-ascorbic acid was estimated on protein carbonyl content. RESULTS: Result showed a significant (p < 0.001) increase in protein carbonyl content in hypertensive patients but no gender-based difference was observed. (-) epicatechin shows significant (p < 0.001) dose-dependent effect as compared to L ascorbic acid, which is manifested as decrease in protein carbonyl content. CONCLUSION: We hypothesizes that a higher intake of (-)-epicatechin may provide protection against hypertension in males and females. PMID- 26939971 TI - The effects of second and third phase duration on defibrillation efficacy of triphasic rectangle waveforms. AB - BACKGROUND: Biphasic waveforms are superior to monophasic waveforms for the termination of ventricular fibrillation (VF). However, whether triphasic waveforms are more effective than biphasic ones is still controversial. In the present study, we investigated the effects of second and third phase duration of triphasic rectangle waveform on defibrillation efficacy in a rabbit model of VF. METHODS: VF was electrically induced and untreated for 30s in 20 New Zealand rabbits. A defibrillatory shock was applied with one of the 7 waveforms: 6 triphasic rectangle waveforms and a biphasic rectangle waveform. The triphasic waveforms had identical first duration but with different second and third phase durations. A 5 step up-and-down protocol was utilized for determining the defibrillation threshold (DFT). After a 5min interval, the procedure was repeated. A total of 35 cardiac arrest events and defibrillations were investigated for each animal. RESULTS: Two triphasic waveforms with identical first and second phase duration but shorter third phase duration had significantly lower DFT energy than biphasic waveform (0.57+/-0.18J vs. 0.80+/ 0.28J, p=0.001; 0.60+/-0.18J vs. 0.80+/-0.28J, p=0.003). However, no statistical difference in DFT energy was observed between the two triaphsic waveforms that had identical phase duration but different voltages (0.57+/-0.18J vs. 0.60+/ 0.18J, p=0.638). CONCLUSIONS: Phase durations played a main role on defibrillation success for triphasic rectangle waveforms. The optimal triphasic rectangle waveforms that composed of identical second and first phase durations but with shorter third pulse were superior to biphasic rectangle waveform for ventricular defibrillation. PMID- 26939970 TI - Hepatic sinusoids in liver injury, inflammation, and fibrosis: new pathophysiological insights. AB - Changes of hepatic sinusoids are crucial in the pathogenesis of liver cirrhosis and portal hypertension. Liver injury leads to distinct morphological abnormalities such as loss of sinusoidal fenestration, vasoconstriction, and angiogenesis as well as molecular changes. Communication between the two key cells in this hepatic microenvironment-hepatic stellate cells (HSC) and sinusoidal endothelial cells (SEC)-has been studied for many years and several canonical pathways have been elucidated, such as decreased eNOS activity or increased PDGF and TGF-beta production leading to activation and migration of HSC. In recent studies, alternative pathways of intercellular communication in liver diseases have been described such as cell-derived extracellular vesicles called exosomes, which deliver cell compounds to their target cells. Moreover, such extracellular vesicles may link injury to inflammation in alcoholic hepatitis. While inflammation leading to liver fibrosis has been studied in detail, in some circumstances pathways other than the known canonical inflammatory pathways may contribute to hepatic fibrogenesis. For example, in congestive hepatopathy, sinusoidal dilatation and fibrosis have been shown to be mediated by non-inflammatory mechanisms and associated with sinusoidal thrombi. A recently developed murine model further enables experimental studies of this disease entity. Increasing knowledge about these alternative disease pathways in liver injury, inflammation, and fibrosis may reveal possible target molecules for future therapies. This article builds upon a seminar given at the recent 3rd JSGE International Topic Conference in Sendai, Japan, and reviews the areas outlined above. PMID- 26939973 TI - Barbara J. Wolfson, MD, FACR (March 2, 1946 - Dec. 15, 2015). PMID- 26939972 TI - Primary hypertrophic osteoarthropathy: ultrasound and MRI findings. AB - Primary hypertrophic osteoarthropathy is a rare genetic disorder related to failures in prostaglandin metabolism. Patients present with joint pain, limb enlargement, skin thickening and finger clubbing. Radiographs show characteristic periosteal reaction and thickening along the long bones. We present MRI and US findings in a child with the condition. Ultrasound showed echogenic tissue surrounding the long bones, presumably reflecting oedema and inflammatory tissue. Doppler sonograms demonstrated increased vascularity on the surface of some superficial bony structures. PMID- 26939974 TI - MR enterography: how to deliver added value. AB - MR enterography (MRE) is increasingly vital to the diagnosis and follow-up of children with Crohn disease. This diagnostic test, which can provide valuable information regarding the presence of intestinal inflammation, intestinal and intra-abdominal complications, and extra-intestinal disease-related manifestations, has the potential to directly impact both medical and surgical decision-making. Consequently, it is imperative that the interpretation and reporting of these examinations provide as much clinical information as possible. This article reviews specific ways radiologists can provide added value when interpreting MRE examinations in the setting of pediatric Crohn disease by (1) establishing the true extent of disease involvement, (2) subjectively and objectively assessing response to medical treatment and (3) accurately characterizing disease-related complications. PMID- 26939975 TI - Acoustic radiation force impulse sonography in assessing children with biliary atresia for liver transplantation. AB - BACKGROUND: Children with biliary atresia are prone to developing progressive hepatic fibrosis and biliary cirrhosis following the Kasai operation. The only treatment is liver transplantation. OBJECTIVE: To assess liver fibrosis by acoustic radiation force impulse elastography (ARFI) in children who had Kasai operation, with the goal of identifying an ARFI value cut-off for children requiring liver transplantation. MATERIALS AND METHODS: Of the 32 post-Kasai children included, 19 were transplanted or listed for transplantation (group A), while 13 were not on the list during their follow-up (group B). We recorded biopsies, blood samples and ARFI values over time, including at Kasai operation and at transplantation. We estimated an association between groups and continuous variables using generalized estimating equations, and we compared categorical variables using the Fisher exact test. RESULTS: Portal hypertension signs were similar in both groups, whereas ARFI values were higher in group A (mean+/ standard deviation=3.3+/-1.2 m/s) than in group B (2.0+/-0.7 m/s; P=.0003). Eighteen of 19 (94.7%) children in group A and 6/13 (46.2%) children in group B presented with two consecutive ARFI values >=2 m/s (sensitivity=7%, specificity=53.8%; P=0.003). CONCLUSION: We found that children who were transplanted had two consecutive ARFI values >=2 m/s during follow-up. ARFI for evaluation of post-Kasai liver fibrosis may assist the long-term assessment of biliary atresia and may even guide treatment decisions. PMID- 26939976 TI - An inactivated whole-virus porcine parvovirus vaccine protects pigs against disease but does not prevent virus shedding even after homologous virus challenge. AB - Inactivated whole-virus vaccines against porcine parvovirus (PPV) can prevent disease but not infection and virus shedding after heterologous virus challenge. Here, we showed that the same is true for a homologous challenge. Pregnant sows were vaccinated with an experimental inactivated vaccine based on PPV strain 27a. They were challenged on day 40 of gestation with the virulent porcine parvovirus PPV-27a from which the vaccine was prepared (homologous challenge). On day 90 of gestation, the fetuses from vaccinated sows were protected against disease, while the fetuses of the non-vaccinated sows (control group) exhibited signs of parvovirus disease. All gilts, whether vaccinated or not vaccinated, showed a boost of PPV-specific antibodies indicative of virus infection and replication. Low DNA copy numbers, but not infectious virus, could be demonstrated in nasal or rectal swabs of immunized sows, but high copy numbers of challenge virus DNA as well as infectious virus could both be demonstrated in non-vaccinated sows. PMID- 26939977 TI - Diabetes: Concerns about long-term use of GLP-1 analogues. PMID- 26939979 TI - Gut microbiota: Growth impairment in undernourished children. PMID- 26939980 TI - Translational medicine: beta cells from stomach-derived organoids. PMID- 26939978 TI - Biological plausibility linking sleep apnoea and metabolic dysfunction. AB - Obstructive sleep apnoea (OSA) is a very common disorder that affects 10-25% of the general population. In the past two decades, OSA has emerged as a cardiometabolic risk factor in both paediatric and adult populations. OSA-induced metabolic perturbations include dyslipidaemia, atherogenesis, liver dysfunction and abnormal glucose metabolism. The mainstay of treatment for OSA is adenotonsillectomy in children and continuous positive airway pressure therapy in adults. Although these therapies are effective at resolving the sleep-disordered breathing component of OSA, they do not always produce beneficial effects on metabolic function. Thus, a deeper understanding of the underlying mechanisms by which OSA influences metabolic dysfunction might yield improved therapeutic approaches and outcomes. In this Review, we summarize the evidence obtained from animal models and studies of patients with OSA of potential mechanistic pathways linking the hallmarks of OSA (intermittent hypoxia and sleep fragmentation) with metabolic dysfunction. Special emphasis is given to adipose tissue dysfunction induced by sleep apnoea, which bears a striking resemblance to adipose dysfunction resulting from obesity. In addition, important gaps in current knowledge and promising lines of future investigation are identified. PMID- 26939982 TI - Morphological and molecular characterization of Thelohanellus macrovacuolaris n. sp. (Myxosporea: Bivalvulida) infecting the palate in the mouth of common carp Cyprinus carpio L. in China. AB - Thelohanellus macrovacuolaris n. sp. is described during a survey on myxozoan diversity of common carp Cyprinus carpio L. in China. It is characterized by the presence of round or ellipsoidal plasmodium in the palate in the mouth of host. Mature spores were pyriform in frontal view, lemon shaped in lateral view, measuring 21.6+/-0.9 (19.3-23.8) long, 12.5+/-0.7 (10.3-13.6) wide, and 10.2+/ 0.4 (9.8-11.8) thick. Most spores were surrounded by the membrane sheath. Single polar capsule was round with an apophysis at its top end presented close to apex of spore, measuring 9.1+/-0.6 (8.0-10.0) in length, 8.6+/-0.5 (7.8-9.6) in width. Polar filaments coiled, with 7 to 8 turns. A large, round iodinophilous vacuole was present, with 5.8-7.5 in diameter. The present species is morphologically distinct from all other Thelohanellus species. The BLAST search indicated that the newly obtained small subunit ribosomal RNA (ssrRNA) gene sequence of T. macrovacuolaris n. sp. did not match any available sequences in GenBank. Phylogenetically, T. macrovacuolaris n. sp. was placed sister to Thelohanellus wangi in the Thelohanellus clade. Both morphology and ssrRNA gene sequence data revealed that the present parasite is a new species of genus Thelohanellus. PMID- 26939983 TI - An in silico, in vitro and in vivo investigation of indole-3-carboxaldehyde identified from the seawater bacterium Marinomonas sp. as an anti-biofilm agent against Vibrio cholerae O1. AB - Biofilm formation is a major contributing factor in the pathogenesis of Vibrio cholerae O1 (VCO1) and therefore preventing biofilm formation could be an effective alternative strategy for controlling cholera. The present study was designed to explore seawater bacteria as a source of anti-biofilm agents against VCO1. Indole-3-carboxaldehyde (I3C) was identified as an active principle component in Marinomonas sp., which efficiently inhibited biofilm formation by VCO1 without any selection pressure. Furthermore, I3C applications also resulted in considerable collapsing of preformed pellicles. Real-time PCR studies revealed the down-regulation of virulence gene expression by modulation of the quorum sensing pathway and enhancement of protease production, which was further confirmed by phenotypic assays. Furthermore, I3C increased the survival rate of Caenorhabditis elegans when infected with VCO1 by significantly reducing in vivo biofilm formation, which was corroborated by a survivability assay. Thus, this study revealed, for the first time, the potential of I3C as an anti-biofilm agent against VCO1. PMID- 26939984 TI - Validity of an Athletic Skills Track among 6- to 12-year-old children. AB - The purpose of this study was to examine the feasibility and validity of an Athletic Skills Track (AST) to assess fundamental movement skills among 6- to 12 year-old children in a physical education setting. Four hundred sixty-three Dutch children (211 girls, 252 boys) completed three tests: the Korperkoordinationstest fur Kinder (KTK) and two Athletic Skills Tracks (AST-1, AST-2). The validity of AST-1 and AST-2 was examined by correlating the time (s) needed to complete the tracks and the KTK Motor Quotient (MQ). Overall, there was a low correlation between AST-1 and the KTK MQ (r = -0.474 (P < 0.01)) and a moderate correlation between AST-2 and the KTK MQ (r = -0.502 (P < 0.01)). When split up by age group the associations were much higher and ranged between r = -0.469 and r = -0.767), with the exception of the low correlation coefficient of the AST-2 in 7-year olds. The results indicate that fundamental movement skills of 6- to 12-year-old children can be assessed with a quick, convenient and low-cost motor competence test in a physical education setting, i.e., an Athletic Skills Track. Future studies should further assess the reliability, discriminative ability and validity of age-specific versions of the AST. PMID- 26939981 TI - Metabolic effects of smoking cessation. AB - Smoking continues to be the leading cause of preventable death in the USA, despite the vast and widely publicized knowledge about the negative health effects of tobacco smoking. Data show that smoking cessation is often accompanied by weight gain and an improvement in insulin sensitivity over time. However, paradoxically, post-cessation-related obesity might contribute to insulin resistance. Furthermore, post-cessation weight gain is reportedly the number one reason why smokers, especially women, fail to initiate smoking cessation or relapse after initiating smoking cessation. In this Review, we discuss the metabolic effects of stopping smoking and highlight future considerations for smoking cessation programs and therapies to be designed with an emphasis on reducing post-cessation weight gain. PMID- 26939985 TI - Radiologic classification of usual interstitial pneumonia in rheumatoid arthritis related interstitial lung disease: correlations with clinical, serological and demographic features of disease. PMID- 26939986 TI - Band-selective excited ultrahigh resolution PSYCHE-TOCSY: fast screening of organic molecules and complex mixtures. AB - Precise assignments of (1) H atomic sites and establishment of their through-bond COSY or TOCSY connectivity are crucial for molecular structural characterization by using (1) H NMR spectroscopy. However, this exercise is often hampered by signal overlap, primarily because of (1) H-(1) H scalar coupling multiplets, even at typical high magnetic fields. The recent developments in homodecoupling strategies for effectively suppressing the coupling multiplets into nice singlets (pure-shift), particularly, Morris's advanced broadband pure-shift yielded by chirp excitation (PSYCHE) decoupling and ultrahigh resolution PSYCHE-TOCSY schemes, have shown new possibilities for unambiguous structural elucidation of complex organic molecules. The superior broadband PSYCHE-TOCSY exhibits enhanced performance over the earlier TOCSY methods, which however warrants prolonged experimental times due to the requirement of large number of dwell increments along the indirect dimension. Herein, we present fast and band-selective analog of the broadband PSYCHE-TOCSY, which is useful for analyzing complex organic molecules that exhibit characteristic yet crowded spectral regions. The simple pulse scheme relies on band-selective excitation (BSE) followed by PSYCHE homodecoupling in the indirect dimension. The BSE-PSYCHE-TOCSY has been exemplified for Estradiol and a complex carbohydrate mixture comprised of six constituents of closely comparable molecular weights. The experimental times are greatly reduced viz., ~20 fold for Estradiol and ~10 fold for carbohydrate mixture, with respect to the broadband PSYCHE-TOCSY. Furthermore, unlike the earlier homonuclear band-selective decoupling, the BSE-PSYCHE-decoupling provides fully decoupled pure-shift spectra for all the individual chemical sites within the excited band. The BSE-PSYCHE-TOCSY is expected to have significant potential for quick screening of complex organic molecules and mixtures at ultrahigh resolution. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26939987 TI - Synthesis of a new 1,2,3,4,5-pentasubstituted cyclohexanol and determining its stereochemistry by NMR spectroscopy and quantum-chemical calculations. AB - The presence of substituents in cyclohexane can influence to the ratio of conformers; for some cases, the boat form is preferable. The new six-membered cyclohexanol derivative 2 has been obtained by the synthesis of (E)-1 (bromophenyl)-3-phenylpropen-2-one (1). The NMR and quantum-chemical conformational analysis for the 2 have carried out, and its possible mechanism of formation was given. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26939988 TI - [New techniques in the operative treatment of calcaneal fractures]. AB - The ideal treatment of displaced intra-articular calcaneal fractures is still controversially discussed. Because of the variable fracture patterns and the vulnerable soft tissue coverage an individual treatment concept is advisable. In order to minimize wound edge necrosis associated with extended lateral approaches, selected fractures may be treated percutaneously or in a less invasive manner while controlling joint reduction via a sinus tarsi approach. Fixation in these cases is achieved with screws, intramedullary locking nails or modified plates that are slid in subcutaneously. A thorough knowledge of the three dimensional calcaneal anatomy and open reduction maneuvers is a prerequisite for good results with less invasive techniques. Early functional follow-up treatment aims at early rehabilitation independent of the kind of fixation. Peripheral fractures of the talus and calcaneus frequently result from subluxation and dislocation at the subtalar and Chopart joints. They are still regularly overlooked and result in painful arthritis if left untreated. If an exact anatomical reduction of these intra-articular fractures is impossible, resection of small fragments is indicated. PMID- 26939989 TI - Effect of myofeedback on the threshold of the stretch reflex response of post stroke spastic patients. AB - Purpose We propose a visual myofeedback protocol as a coadjuvant therapy to standard rehabilitation of post-stroke spastic patients. We also argue in favor of the tonic stretch reflex threshold (TSRT) as a more sensitive unit for quantifying subtle changes in the spastic response that may be induced by biofeedback training. Method Sixteen volunteers with ischaemic stroke were divided into an experimental group (EG), subjected to myofeedback training in parallel with conventional physical therapy and a control group (CG), receiving only conventional physical therapy. The EG subjects underwent a six-week myofeedback training, with two sessions weekly. Both groups followed the same treatment schedule for physical therapy. The TSRTs of the volunteers' spastic muscles were assessed before the beginning of the experimental protocol and 3 weeks after it ended. Results Both groups showed some degree of improvement in the level of spasticity when the final TSRT values were compared to the initial values. However, the percentage of improvement (after-before) of the experimental group (38.59%) was significantly higher than that in the control group (18.58%). Conclusion The myofeedback training provided a significant contribution to conventional treatment, allowing for a better improvement of the spastic condition. Implications for rehabilitation Biofeedback is an effective means of improving motor control of post-stroke spastic patients. The Tonic Stretch Reflex Threshold is a more sensitive quantitative measure to assess upper-limb post stroke spasticity. Spastic patients who participate in myofeedback training along with physical therapy can improve faster then those who participate only in traditional physical therapy rehabilitation protocols. PMID- 26939990 TI - A 20-Year Review of 75 Cases of Salivary Duct Carcinoma. AB - IMPORTANCE: Salivary duct carcinoma is a rare, aggressive malignancy of the salivary glands. Owing to its rare nature, clinical data are limited, and only a few clinical studies comprise more than 50 patients. OBJECTIVE: To review the University of Pittsburgh Medical Center's experience with salivary duct carcinoma over a 20-year period, focusing on demographics, presentation, treatment, and outcome. DESIGN, SETTING, AND PARTICIPANTS: This investigation was a retrospective cohort study in a multihospital institution with tertiary referral. A pathology database was reviewed for all cases of histopathologically diagnosed salivary duct carcinoma from January 1, 1995, to October 20, 2014. Patients who were referrals for pathology review only and were never seen at the institution were excluded. In total, 75 study patients were identified. The electronic medical record was reviewed for details regarding demographics, presentation, treatment, and outcome, including overall survival (OS) and disease-free survival (DFS). This study was supplemented with a review of the institution's Head and Neck Oncology Database for further clinical details. MAIN OUTCOMES AND MEASURES: Primary outcome measures consisted of OS and DFS. RESULTS: The study sample comprised 75 participants with a mean age at diagnosis of 66.0 years (age range, 33-93 years), and 29% (n = 22) were female. Most primary tumors were from the parotid gland (83%), with the next most frequent site being the submandibular gland (12%). Overall, 41% of the cases were carcinoma ex pleomorphic adenoma. Rates of other histologic features included the following: perineural invasion (69%), extracapsular spread (58%), ERBB2 (formerly HER2) positivity (31%) (62% of those who were tested), and vascular invasion (61%). The median OS was 3.1 years, and the median DFS was 2.7 years. Univariate Kaplan-Meier survival analyses demonstrated that facial nerve sacrifice and extracapsular spread were associated with lower OS (2.38 vs 5.11 years and 2.29 vs 6.56 years, respectively) and DFS (2.4 vs 3.88 years and 1.44 vs 4.5 years, respectively). Although underpowered, multivariable analysis demonstrated significantly worse OS in patients with N2 and N3 disease (hazard ratio [HR] 8.42, 95% CI, 1.84-38.5) but did not show significantly worse DFS or OS for facial nerve sacrifice or extracapsular spread. There was no association between ERBB2 positivity and survival and no difference in survival between patients receiving radiation therapy vs radiation therapy plus chemotherapy. No patients had recurrence or distant metastasis after 5 disease-free years. CONCLUSIONS AND RELEVANCE: Salivary duct carcinoma is an aggressive disease. A large number of cases in this review were carcinoma ex pleomorphic adenoma and had classic negative prognostic indicators, such as perineural invasion, vascular invasion, and extracapsular spread. ERBB2 positivity was not associated with any difference in survival. Facial nerve involvement appears to indicate worse prognosis, as does nodal stage higher than N1. Recurrence and metastasis after 5 years are rare. PMID- 26939992 TI - Does overwinter temperature affect maternal body composition and egg traits in yellow perch Perca flavescens? AB - Female yellow perch Perca flavescens exposed to three overwinter temperature regimes (4, 8 and 13 degrees C) for 150 days spawned in markedly different proportions upon spring warming (37% of females in 4 degrees C v. 64 and 91% in 8 and 13 degrees C treatments, respectively), but exhibited no differences in fecundity, egg size or egg lipid content. Females held at 4 degrees C also exhibited less within-clutch egg size variation than females held at 13 degrees C. Moreover, eggs differed among temperature treatments in the overall proportions of 18 fatty acids, with the colder treatments resulting in potentially higher quality eggs containing more of the unsaturated fatty acids C16:1, C22:6-n3 and C18:2 cis. Female somatic condition also varied with temperature. Maternal somatic growth and protein content increased while lipid content decreased in 13 degrees C compared to the colder treatments. There were, however, no differences among treatments in the fatty acid composition of maternal muscle. These results suggest that the temperatures experienced during winter may be less influential to P. flavescens egg size or number, which may exhibit relatively little plasticity in this species, but can alter both the number of females that spawn and the overall composition of eggs and maternal somatic tissues, which may have implications for future reproductive success. PMID- 26939991 TI - The orientation of transcription factor binding site motifs in gene promoter regions: does it matter? AB - BACKGROUND: Gene expression is to large degree regulated by the specific binding of protein transcription factors to cis-regulatory transcription factor binding sites in gene promoter regions. Despite the identification of hundreds of binding site sequence motifs, the question as to whether motif orientation matters with regard to the gene expression regulation of the respective downstream genes appears surprisingly underinvestigated. RESULTS: We pursued a statistical approach by probing 293 reported non-palindromic transcription factor binding site and ten core promoter motifs in Arabidopsis thaliana for evidence of any relevance of motif orientation based on mapping statistics and effects on the co regulation of gene expression of the respective downstream genes. Although positional intervals closer to the transcription start site (TSS) were found with increased frequencies of motifs exhibiting orientation preference, a corresponding effect with regard to gene expression regulation as evidenced by increased co-expression of genes harboring the favored orientation in their upstream sequence could not be established. Furthermore, we identified an intrinsic orientational asymmetry of sequence regions close to the TSS as the likely source of the identified motif orientation preferences. By contrast, motif presence irrespective of orientation was found associated with pronounced effects on gene expression co-regulation validating the pursued approach. Inspecting motif pairs revealed statistically preferred orientational arrangements, but no consistent effect with regard to arrangement-dependent gene expression regulation was evident. CONCLUSIONS: Our results suggest that for the motifs considered here, either no specific orientation rendering them functional across all their instances exists with orientational requirements instead depending on gene-locus specific additional factors, or that the binding orientation of transcription factors may generally not be relevant, but rather the event of binding itself. PMID- 26939995 TI - Multi-layer topological transmissions of spoof surface plasmon polaritons. AB - Spoof surface plasmon polaritons (SPPs) in microwave frequency provide a high field confinement in subwavelength scale and low-loss and flexible transmissions, which have been widely used in novel transmission waveguides and functional devices. To play more important roles in modern integrated circuits and systems, it is necessary and helpful for the SPP modes to propagate among different layers of devices and chips. Owing to the highly confined property and organized near field distribution, we show that the spoof SPPs could be easily transmitted from one layer into another layer via metallic holes and arc-shaped transitions. Such designs are suitable for both the ultrathin and flexible single-strip SPP waveguide and double-strip SPP waveguide for active SPP devices. Numerical simulations and experimental results demonstrate the broadband and high efficiency multi-layer topological transmissions with controllable absorption that is related to the superposition area of corrugated metallic strips. The transmission coefficient of single-strip SPP waveguide is no worse than -0.8 dB within frequency band from 2.67 GHz to 10.2 GHz while the transmission of double strip SPP waveguide keeps above -1 dB within frequency band from 2.26 GHz to 11.8 GHz. The proposed method will enhance the realizations of highly complicated plasmonic integrated circuits. PMID- 26939993 TI - Overview of bladder heating technology: matching capabilities with clinical requirements. AB - Moderate temperature hyperthermia (40-45 degrees C for 1 h) is emerging as an effective treatment to enhance best available chemotherapy strategies for bladder cancer. A rapidly increasing number of clinical trials have investigated the feasibility and efficacy of treating bladder cancer with combined intravesical chemotherapy and moderate temperature hyperthermia. To date, most studies have concerned treatment of non-muscle-invasive bladder cancer (NMIBC) limited to the interior wall of the bladder. Following the promising results of initial clinical trials, investigators are now considering protocols for treatment of muscle invasive bladder cancer (MIBC). This paper provides a brief overview of the devices and techniques used for heating bladder cancer. Systems are described for thermal conduction heating of the bladder wall via circulation of hot fluid, intravesical microwave antenna heating, capacitively coupled radio-frequency current heating, and radiofrequency phased array deep regional heating of the pelvis. Relative heating characteristics of the available technologies are compared based on published feasibility studies, and the systems correlated with clinical requirements for effective treatment of MIBC and NMIBC. PMID- 26939994 TI - Riparian plants on mine runoff in Zimapan, Hidalgo, Mexico: Useful for phytoremediation? AB - Dispersion and runoff of mine tailings have serious implications for human and ecosystem health in the surroundings of mines. Water, soils and plants were sampled in transects perpendicular to the Santiago stream in Zimapan, Hidalgo, which receives runoff sediments from two acidic and one alkaline mine tailing. Concentrations of potentially toxic elements (PTE) were measured in water, soils (rhizosphere and non-rhizosphere) and plants. Using diethylenetriaminepentaacetic acid (DTPA) extractable concentrations of Cu, Zn, Ni, Cd and Pb in rhizosphere soil, the bioconcentration and translocation factors were calculated. Ruderal annuals formed the principal element of the herbaceous vegetation. Accumulation was the most frequent strategy to deal with high concentrations of Zn, Cu, Ni, Cd and Pb. The order of concentration in plant tissue was Zn>Pb>Cu>Ni>Cd. Most plants contained concentrations of PTE considered as phytotoxic and behaved as metal tolerant species. Rorippa nasturtium-aquaticum accumulated particularly high concentrations of Cu. Parietaria pensylvanica and Commelina diffusa, common tropical weeds, behaved as Zn hyperaccumulators and should be studied further. PMID- 26939996 TI - A microfluidic, dual-purpose sensor for in vitro detection of Enterobacteriaceae and biotinylated antibodies. AB - In this paper, we present a versatile, dual-purpose sensor for in vitro detection of Enterobacteriaceae (e.g. Escherichia coli) and biotinylated antibodies (e.g. IgG rabbit polyclonal antibodies), based on different detection principles for each bioanalyte. These bioanalytes are tagged individually with functionalized magnetic microparticles, suspended into a static fluid and injected into a microfluidic channel. Without the need for bulk or complicated pumping systems, the functionalized microparticles are set in motion by a magnetic force exerted on them by integrated microconductors. The fundamental detection principle is the decrease in the velocity of the microparticles that are loaded with the respective bioanalyte, due to factors inhibiting their motion. The velocity of the unloaded, bare microparticles is used as a reference. We discovered a novel mechanism on which the constrained particle motion is based; in the case of E. coli, the inhibiting factor is the enhanced Stokes' drag force due to the greater volume and altered hydrodynamic shape, whereas in the case of biotinylated antibodies, it is the increased friction force at the interface between the modified microparticle and the biosensor's surface. Friction force is for the first time employed in a scheme for resolving biomolecules. Integrated magnetic microsensors are used for the velocity measurements by detecting the microparticles' stray field. Moreover, we developed a biocompatible, easy to implement and reliable surface modification that practically diminishes the problem of bioadhesion on the sensor's surface. PMID- 26939998 TI - The effect of chemically modified alginates on macrophage phenotype and biomolecule transport. AB - Macrophage (MPhi) reprogramming has received significant attention in applications such as cancer therapeutics and tissue engineering where the host immune response to biomaterials is crucial in determining the success or failure of an implanted device. Polymeric systems can potentially be used to redirect infiltrating M1 MPhis toward a proangiogenic phenotype. This work exploits the concept of MPhi reprogramming in the engineering of materials for improving the longevity of tissue engineering scaffolds. We have investigated the effect of 13 different chemical modifications of alginate on MPhi phenotype. Markers of the M1 response-tumor necrosis factor-alpha (TNF-alpha) and inducible nitric oxide synthase-and the M2 response-arginase-were measured and used to determine the ability of the materials to alter MPhi phenotype. It was found that some modifications were able to reduce the pro-inflammatory response of M1 MPhis, others appeared to amplify the M2 phenotype, and the results for two materials suggested they were able to reprogram a MPhi population from M1 to M2. These findings were supplemented by studies done to examine the permselectivity of the materials. Diffusion of TNF-alpha was completely prevented through some of these materials, while up to 84% was found to diffuse through others. The diffusion of insulin through the materials was statistically consistent. These results suggest that the modification of these materials might alter mass transport in beneficial ways. The ability to control polarization of MPhi phenotypes with immunoprotective materials has the potential to augment the success of tissue engineering scaffolds. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 1707-1719, 2016. PMID- 26939997 TI - Developing a novel peer support intervention to promote resilience after stroke. AB - Stroke can lead to physical, mental and social long-term consequences, with the incidence of stroke increasing with age. However, there is a lack of evidence of how to improve long-term outcomes for people with stroke. Resilience, the ability to 'bounce back', flourish or thrive in the face of adversity improves mental health and quality of life in older adults. However, the role of resilience in adjustment after stroke has been little investigated. The purpose of this study is to report on the development and preliminary evaluation of a novel intervention to promote resilience after stroke. We applied the first two phases of the revised UK Medical Research Council (UKMRC) framework for the development and evaluation of complex interventions: intervention development (phase 1) and feasibility testing (phase 2). Methods involved reviewing existing evidence and theory, interviews with 22 older stroke survivors and 5 carers, and focus groups and interviews with 38 professionals to investigate their understandings of resilience and its role in adjustment after stroke. We used stakeholder consultation to co-design the intervention and returned to the literature to develop its theoretical foundations. We developed a 6-week group-based peer support intervention to promote resilience after stroke. Theoretical mechanisms of peer support targeted were social learning, meaning-making, helping others and social comparison. Preliminary evaluation with 11 older stroke survivors in a local community setting found that it was feasible to deliver the intervention, and acceptable to stroke survivors, peer facilitators, and professionals in stroke care and research. This study demonstrates the application of the revised UKMRC framework to systematically develop an empirically and theoretically robust intervention to promote resilience after stroke. A future randomised feasibility study is needed to determine whether a full trial is feasible with a larger sample and wider age range of people with stroke. PMID- 26939999 TI - Aeroallergen sensitivities and development of chronic rhinosinusitis in 13 adults who initially had allergic rhinitis. PMID- 26940000 TI - In Vitro susceptibilities of wild and drug resistant Leishmania donovani amastigotes to piperolactam A loaded hydroxypropyl-beta-cyclodextrin nanoparticles. AB - Leishmaniasis is an epidemic in various countries, and the parasite Leishmania donovani is developing resistance against available drugs. In the present study the antileishmanial action of piperolactam A (PL), isolated after bioactivity guided fractionation from root extracts of Piper betle was accentuated in detail. Activity potentiation was achieved via cyclodextrin complexation. Crude hydro ethanolic extract (PB) and three fractions obtained from PB and fabricated PL hydroxypropyl-beta-cyclodextrin (HPBCD) nanoparticles were evaluated for antileishmanial activity. Tests were performed against L. donovani wild-type, sodium stibogluconate, paromomycin and field isolated (GE1) resistant strains in axenic amastigote and amastigote in macrophage models. PL-HPBCD complex was characterized and FITC loaded HPBCD nanoparticles were assessed for macrophage internalization in confocal microscopic studies. Isolated and purified PL from most potent, alkaloid rich ethyl acetate fraction of PB showed high level of antileishmanial activities in wild-type (IC50=36 MUM), sodium stibogluconate resistant (IC50=103 MUM), paromomycin resistant (IC50=91 MUM) and field isolated resistant (IC50=72 MUM) strains together with cytotoxicity (CC50=900 MUM) in mouse peritoneal macrophage cells. Inclusion of PL in HPBCD nanoparticles resulted in 10-fold and 4-10-fold increase in selectivity indexes (CC50/IC50) for wild-type and drug resistant strains, respectively. Drug-carrier interactions were clearly visualized in FT-IR studies. Complete incorporation of PL in HPBCD cavity was ascertained in DSC and XRD analyses. 180nm size stable nanospheres showed macrophage internalization within 1h of incubation. Piperolactam A (PL), a representative of the inchoate skeleton of aristolactam chassis might be the source of safe and affordable antileishmanial agents for the cure of deadly Leishmania infections. PMID- 26940001 TI - Lepidopteran defence droplets - a composite physical and chemical weapon against potential predators. AB - Insects often release noxious substances for their defence. Larvae of Zygaena filipendulae (Lepidoptera) secrete viscous and cyanogenic glucoside-containing droplets, whose effectiveness was associated with their physical and chemical properties. The droplets glued mandibles and legs of potential predators together and immobilised them. Droplets were characterised by a matrix of an aqueous solution of glycine-rich peptides (H-WG11-NH2) with significant amounts of proteins and glucose. Among the proteins, defensive proteins such as protease inhibitors, proteases and oxidases were abundant. The neurotoxin beta cyanoalanine was also found in the droplets. Despite the presence of cyanogenic glucosides, which release toxic hydrogen cyanide after hydrolysis by a specific beta-glucosidase, the only beta-glucosidase identified in the droplets (ZfBGD1) was inactive against cyanogenic glucosides. Accordingly, droplets did not release hydrogen cyanide, unless they were mixed with specific beta-glucosidases present in the Zygaena haemolymph. Droplets secreted onto the cuticle hardened and formed sharp crystalline-like precipitates that may act as mandible abrasives to chewing predators. Hardening followed water evaporation and formation of antiparallel beta-sheets of the peptide oligomers. Consequently, after mild irritation, Zygaena larvae deter predators by viscous and hardening droplets that contain defence proteins and beta-cyanoalanine. After severe injury, droplets may mix with exuding haemolymph to release hydrogen cyanide. PMID- 26940003 TI - Fast and Simultaneous Determination of the Number and Mass Concentrations of Gold Nanorod Colloid Using an Improved Optical Extinction-Scattering Spectroscopic Method. AB - Accurate determination of the concentrations, including the mass concentration (MC) and number concentration (NC), of metal nanoparticle (NP) colloid is highly demanded in the synthesis, metrology, and application of NPs. The commonly used inductively coupled plasma mass spectrometry (ICP-MS) can only measure the MC of NPs, which is destructive to the NPs and requires advanced operation skills. Here, we present a simple approach based on an improved optical extinction scattering spectroscopic (OESS) method to fast determining the MC and NC of metal nanorod colloids simultaneously. Unlike most existing spectroscopic methods that can only deal with low-concentration NP colloids, the improved OESS method can accurately solve the inverse scattering problem of NP colloids with higher concentrations, so that a two-dimensional joint probability density function of both the width and aspect ratio of nanorods can be retrieved, which makes the basis for the accurate determination of the MC and NC of the colloids in a large range of concentration. The reliability and accuracy of the method are validated by measuring several typical nanorod colloids with different concentrations and comparing the results with those obtained by the standard ICP-MS method. It is shown that the improved OESS method can cover a broad MC measurement range of at least 10-50 ug/mL and a NC measurement range of 10(9)-10(11)/mL. The uncertainty and sources of error in the measurement are also analyzed. Since the improved OESS method is fast, cost-effective, non-destructive, and easy to implement, it provides a simple way to determine the concentrations of metal NPs and has the potential to be extended to other metal NPs. PMID- 26940002 TI - Channel based generating function approach to the stochastic Hodgkin-Huxley neuronal system. AB - Internal and external fluctuations, such as channel noise and synaptic noise, contribute to the generation of spontaneous action potentials in neurons. Many different Langevin approaches have been proposed to speed up the computation but with waning accuracy especially at small channel numbers. We apply a generating function approach to the master equation for the ion channel dynamics and further propose two accelerating algorithms, with an accuracy close to the Gillespie algorithm but with much higher efficiency, opening the door for expedited simulation of noisy action potential propagating along axons or other types of noisy signal transduction. PMID- 26940004 TI - A multi-criteria decision analysis approach to assessing malaria risk in northern South America. AB - BACKGROUND: Malaria control in South America has vastly improved in the past decade, leading to a decrease in the malaria burden. Despite the progress, large parts of the continent continue to be at risk of malaria transmission, especially in northern South America. The objectives of this study were to assess the risk of malaria transmission and vector exposure in northern South America using multi criteria decision analysis. METHODS: The risk of malaria transmission and vector exposure in northern South America was assessed using multi-criteria decision analysis, in which expert opinions were taken on the key environmental and population risk factors. RESULTS: Results from our risk maps indicated areas of moderate-to-high risk along rivers in the Amazon basin, along the coasts of the Guianas, the Pacific coast of Colombia and northern Colombia, in parts of Peru and Bolivia and within the Brazilian Amazon. When validated with occurrence records for malaria, An. darlingi, An. albimanus and An. nuneztovari s.l., t-test results indicated that risk scores at occurrence locations were significantly higher (p < 0.0001) than a control group of geographically random points. CONCLUSION: In this study, we produced risk maps based on expert opinion on the spatial representation of risk of potential vector exposure and malaria transmission. The findings provide information to the public health decision maker/policy makers to give additional attention to the spatial planning of effective vector control measures. Therefore, as the region tackles the challenge of malaria elimination, prioritizing areas for interventions by using spatially accurate, high-resolution (1 km or less) risk maps may guide targeted control and help reduce the disease burden in the region. PMID- 26940005 TI - Forest dynamics and its driving forces of sub-tropical forest in South China. AB - Tree mortality and recruitment are key factors influencing forest dynamics, but the driving mechanisms of these processes remain unclear. To better understand these driving mechanisms, we studied forest dynamics over a 5-year period in a 20 ha sub-tropical forest in the Dinghushan Nature Reserve, South China. The goal was to identify determinants of tree mortality/recruitment at the local scale using neighborhood analyses on some locally dominant tree species. Results show that the study plot was more dynamic than some temperate and tropical forests in a comparison to large, long-term forest dynamics plots. Over the 5-year period, mortality rates ranged from 1.67 to 12.33% per year while recruitment rates ranged from 0 to 20.26% per year. Tree size had the most consistent effect on mortality across species. Recruitment into the >=1-cm size class consistently occurred where local con-specific density was high. This suggests that recruitment may be limited by seed dispersal. Hetero-specific individuals also influenced recruitment significantly for some species. Canopy species had low recruitment into the >=1-cm size class over the 5-year period. In conclusion, tree mortality and recruitment for sixteen species in this plot was likely limited by seed dispersal and density-dependence. PMID- 26940006 TI - Lifetime presence and rates of sleep paralysis in Denmark of ethnic Danes and non ethnic Danes. PMID- 26940007 TI - Full-face motorcycle helmet protection from facial impacts: an investigation using THOR dummy impacts and SIMon finite element head model. AB - OBJECTIVE: Facial impacts are both common and injurious for helmeted motorcyclists who crash; however, there is no facial impact requirement in major motorcycle helmet standards. This study examined the effect of full-face motorcycle helmet protection on brain injury risk in facial impacts using a test device with biofidelic head and neck motion. A preliminary investigation of energy absorbing foam in the helmet chin bar was carried out. METHOD: Flat-faced rigid pendulum impacts were performed on a THOR dummy in an unprotected (no helmet) and protected mode (two full-face helmet conditions). The head responses of the dummy were input into the simulated injury monitor finite element head model to analyse the risk of brain injury in these impacts. RESULTS: Full-face helmet protection provides a significant reduction in brain injury risk in facial impacts at increasing impact speeds compared with an unprotected rider (p<0.05). The effect of low-density crushable foam added to the chin bar could not be distinguished from an unpadded chin bar impact. CONCLUSIONS: Despite the lack of an impact attenuation requirement for the face, full-face helmets do provide a reduction in head injury risk to the wearer in facial impacts. The specific helmet design factors that influence head injury risk in facial impacts need further investigation if improved protection for helmeted motorcyclists is to be achieved. PMID- 26940008 TI - Food-derived immunomodulatory peptides. AB - Food proteins contain specific amino acid sequences within their structures that may positively impact bodily functions and have multiple immunomodulatory effects. The functional properties of these specific sequences, also referred to as bioactive peptides, are revealed only after the degradation of native proteins during digestion processes. Currently, milk proteins have been the most explored source of bioactive peptides, which presents an interesting opportunity for the dairy industry. However, plant- and animal-derived proteins have also been shown to be important sources of bioactive peptides. This review summarizes the in vitro and in vivo evidence of the role of various food proteins as sources of immunomodulatory peptides and discusses the possible pathways involving these properties. (c) 2016 Society of Chemical Industry. PMID- 26940010 TI - Influences of preoperative opioid use on acute pain and analgesic requirement after total knee arthroplasty. PMID- 26940009 TI - Class III-specific HDAC inhibitor Tenovin-6 induces apoptosis, suppresses migration and eliminates cancer stem cells in uveal melanoma. AB - Uveal melanoma (UM) is the most common intraocular malignancy in adults. Despite improvements in surgical, radiation and chemotherapy treatments, the overall survival of UM and prognosis remain poor. In the present study, we hypothesized that Sirtuin 1 and 2 (SIRT1/2), class III histone deacetylases (HDACs), were critical in controlling the destiny of bulk tumor cells and cancer stem cells (CSCs) of UM. We testified this hypothesis in four lines of UM cells (92.1, Mel 270, Omm 1 and Omm 2.3). Our results showed that inhibition of SIRT1/2 by Tenovin 6 induced apoptosis in UM cells by activating the expression of tumor suppressor genes such as p53 and elevating reactive oxygen species (ROS). Tenovin-6 inhibited the growth of UM cells. Tenovin-6 and vinblastine was synergistic in inducing apoptosis of UM cell line 92.1 and Mel 270. Furthermore, Tenovin-6 eliminated cancer stem cells in 92.1 and Mel 270 cells. In conclusion, our findings suggest that Tenovin-6 may be a promising agent to kill UM bulk tumor cells and CSCs. PMID- 26940011 TI - Techniques for aortic arch endovascular repair. AB - This article reviews endovascular strategies for aortic arch repair. Open repair remains the gold standard particularly for good risk patients. Endovascular treatment potentially offers a less invasive repair. Principles, technical considerations, devices and outcomes of each technique are discussed and summarized. Hybrid repair combines less invasive revascularization options, instead of arch replacement while extending stent-graft into the arch. Outcomes vary with regard to extent of repair and aortic arch pathologies treated. Results of arch chimney and other parallel graft techniques perhaps make it a less preferable choice for elective cases. However, they are very appealing options for urgent or bailout situations. Fenestrated stent-grafting is subjected to many technical challenges in aortic arch due to difficulties in stent-graft orientation and fenestration positioning. In situ fenestration techniques emerge to avoid these problems, but durability of stent-grafts after fenestration and ischemic consequences of temporary carotid arteries coverage raises some concern total arch repair using this technique. Arch branched graft is a new technology. Early outcomes did not meet the expectation; however the results have been improving after its learning curve period. Refining stent-graft technologies and implantation techniques positively impact outcomes of endovascular approaches. PMID- 26940012 TI - MAT2B promotes adipogenesis by modulating SAMe levels and activating AKT/ERK pathway during porcine intramuscular preadipocyte differentiation. AB - Intramuscular fat (IMF) has been demonstrated as one of the crucial factors of livestock meat quality. The MAT2B protein with MAT2alpha catalyzes the formation of methyl donor S- adenosylmethionine (SAMe) to mediate cell metabolism including proliferation and apoptosis. However, the regulatory effect of MAT2B on IMF deposition is still unclear. In this study, the effect of MAT2B on adipogenesis and its potential mechanism during porcine intramuscular preadipocyte differentiation was studied. The results showed that overexpression of MAT2B promoted adipogenesis and significantly up-regulated the mRNA and protein levels of adipogenic marker genes including FASN, PPARgamma and aP2, consistently, knockdown of MAT2B inhibited lipid accumulation and down-regulated the mRNA and protein levels of the above genes. Furthermore, flow cytometry and EdU-labeling assay indicated that MAT2B regulate adipogenesis was partly due to influence intracellular SAMe levels and further affect cell clonal expansion. Also, increased expression of MAT2B activated the phosphorylations of AKT and ERK1/2, whereas knockdown of MAT2B blocked AKT signaling and repressed the phosphorylation of ERK1/2. Moreover, the inhibitory effect of LY294002 (a specific PI3K inhibitor) on the activities of AKT and ERK1/2 was partially recovered by overexpression of MAT2B in porcine intramuscular adipocytes. Finally, Co-IP experiments showed that MAT2B can directly interact with AKT. Taken together, our findings suggested that MAT2B acted as a positive regulator through modifying SAMe levels as well as activating AKT/ERK signaling pathway to promote porcine intramuscular adipocyte differentiation. PMID- 26940013 TI - Cardiomyopathy in children: Can we rely on echocardiographic tricuspid regurgitation gradient estimates of right ventricular and pulmonary arterial pressure? AB - Introduction Agreement between echocardiography and right heart catheterisation derived right ventricular systolic pressure is modest in the adult heart failure population, but is unknown in the paediatric cardiomyopathy population. METHODS: All patients at a single centre from 2001 to 2012 with a diagnosis of cardiomyopathy who underwent echocardiography and catheterisation within 30 days were included in this study. The correlation between tricuspid regurgitation gradient and catheterisation-derived right ventricular systolic pressure and mean pulmonary artery pressure was determined. Agreement between echocardiography and catheterisation-derived right ventricular systolic pressure was assessed using Bland-Altman plots. Analysis was repeated for patients who underwent both procedures within 7 days. Haemodynamic data from those with poor agreement and good agreement between echocardiography and catheterisation were compared. RESULTS: A total of 37 patients who underwent 48 catheterisation procedures were included in our study. The median age was 11.8 (0.1-20.6 years) with 22 males (58% total). There was a modest correlation (r=0.65) between echocardiography and catheterisation-derived right ventricular systolic pressure, but agreement was poor. Agreement between tricuspid regurgitation gradient and right ventricular systolic pressure showed wide 95% limits of agreement. There was a modest correlation between the tricuspid regurgitation gradient and mean pulmonary artery pressure (r=0.6). Shorter time interval between the two studies did not improve agreement. Those with poor agreement between echocardiography and catheterisation had higher right heart pressures, but this difference became insignificant after accounting for right atrial pressure. CONCLUSION: Transthoracic echocardiography estimation of right ventricular systolic pressure shows modest correlation with right heart pressures, but has limited agreement and may underestimate the degree of pulmonary hypertension in paediatric cardiomyopathy patients. PMID- 26940015 TI - FOXO3a & haematopoietic stem cells: Goodbye PI3K, hello SIRT1? PMID- 26940014 TI - A human GRPr-transfected Ace-1 canine prostate cancer model in mice. AB - BACKGROUND: A versatile drug screening system was developed to simplify early targeted drug discovery in mice and then translate readily from mice to a dog prostate cancer model that more fully replicates the features of human prostate cancer. METHODS: We stably transfected human cDNA of the GRPr bombesin (BBN) receptor subtype to canine Ace-1 prostate cancer cells (Ace-1(huGRPr) ). Expression was examined by (125) I-Tyr(4) -BBN competition, calcium stimulation assay, and fluorescent microscopy. A dual tumor nude mouse xenograft model was developed from Ace-1(CMV) (vector transfected Ace-1) and Ace-1(huGRPr) cells. The model was used to explore the in vivo behavior of two new IRDye800-labeled GRPr binding optical imaging agents: 800-G-Abz4-t-BBN, from a GRPr agonist peptide, and 800-G-Abz4-STAT, from a GRPr antagonist peptide, by imaging the tumor mice and dissected organs. RESULTS: Both agents bound Ace-1(huGRPr) and PC-3, a known GRPr-expressing human prostate cancer cell line, with 4-13 nM IC50 against (125) I-Tyr(4) -BBN, but did not bind Ace-1(CMV) cells (vector transfected). Binding was blocked by bombesin. Ca(2+) activation assays demonstrated that Ace-1(huGPRr) expressed biologically active GRPr. Both Ace-1 cell lines grew in the flanks of 100% of the nude mice and formed tumors of ~0.5 cm diameter in 1 week. In vivo imaging of the mice at 800 nm emission showed GRPr+: GRPr- tumor signal brighter by a factor of two at 24 h post IV administration of 10 nmol of the imaging agents. Blood retention (4-8% ID at 1 h) was greater by a factor >10 and cumulative urine accumulation (28-30% at 4 h) was less by a factor 2 compared to a radioactive analog of the t-BBN containing agent, (177) LuAMBA, probably due to binding to blood albumin, which we confirmed in a mouse serum assay. CONCLUSIONS: The dual tumor Ace-1(CMV) /Ace-1(huGRPr) model system provides a rapid test of specific to nonspecific binding of new GRPr avid agents in a model that will extend logically to the known Ace-1 orthotopic canine prostate cancer model. Prostate 76:783-795, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26940016 TI - Effects of aerobic training on markers of autophagy in the elderly. AB - Autophagy is a molecular process essential for the maintenance of cellular homeostasis, which appears to (i) decline with age and (ii) respond to physical exercise. In addition, recent evidence suggests a crosstalk between autophagy and toll-like receptor (TLR)-associated inflammatory responses. This study assessed the effects of aerobic exercise training on autophagy and TLR signaling in older subjects. Twenty-nine healthy women and men (age, 69.7 +/- 1.0 year) were randomized to a training (TG) or a control (CG) group. TG performed an 8-week aerobic training program, while CG followed their daily routines. Peripheral blood mononuclear cells were isolated from blood samples obtained before and after the intervention, and protein levels of protein 1 light chain 3 (LC3), sequestosome 1 (p62/SQSTM1), beclin-1, phosphorylated unc-51-like kinase (ULK-1), ubiquitin-like autophagy-related (Atg)12, Atg16, and lysosome-associated membrane protein (LAMP)-2 were measured. TLR2 and TLR4 signaling pathways were also analyzed. Peak oxygen uptake increased in TG after the intervention. Protein expression of beclin-1, Atg12, Atg16, and the LC3II/I ratio increased following the training program (p < 0.05), while expression of p62/SQSTM1 and phosphorylation of ULK-1 at Ser(757) were lower (p < 0.05). Protein content of TLR2, TLR4, myeloid differentiation primary response gen 88 (MyD88), and TIR domain-containing adaptor-inducing interferon (TRIF) were not significantly modified by exercise. The current data indicate that aerobic exercise training induces alterations in multiple markers of autophagy, which seem to be unrelated to changes in TLR2 and TLR4 signaling pathways. These results expand knowledge on exercise-induced autophagy adaptations in humans and suggest that the exercise type employed may be a key factor explaining the potential relationship between autophagy and TLR pathways. PMID- 26940017 TI - Does telomere length predict decline in physical functioning in older twin sisters during an 11-year follow-up? AB - Leukocyte telomere length (LTL) is known to be associated with mortality, but its association with age-related decline in physical functioning and the development of disability is less clear. This study examined the associations between LTL and physical functioning, and investigated whether LTL predicts level of physical functioning over an 11-year follow-up. Older mono- (MZ) and dizygotic (DZ) twin sisters (n = 386) participated in the study. Relative LTL was measured by qPCR at baseline. Physical functioning was measured by 6-min walking distance and level of physical activity (PA). Walking distance was measured at baseline and at 3 year follow-up. PA was assessed by questionnaire at baseline and at 3- and 11 year follow-ups. The baseline analysis was performed with path models, adjusted with age and within-pair dependence of twin pairs. The longitudinal analysis was performed with a repeated measures linear model adjusted for age and longitudinal within-pair dependence. A nonrandom missing data analysis was utilized. At baseline, in all individuals, LTL was associated with PA (est. 0.14, SE 0.06, p = 0.011), but not with walking distance. Over the follow-up, a borderline significant association was observed between LTL and walking distance (est. 0.14, SE 0.07, p = 0.060) and a significant association between LTL and PA (est. 0.19, SE 0.06, p = 0.001). The results suggest that LTL is associated with PA and may, therefore, serve as a biomarker predicting the development of disability. Longitudinal associations between LTL and PA were observed only when nonrandom data missingness was taken into account in the analysis. PMID- 26940019 TI - The non-aqueous synthesis of shape controllable Cu(2-x)S plasmonic nanostructures in a continuous-flow millifluidic chip for the generation of photo-induced heating. AB - In this paper, a new method for synthesizing non-aqueous copper sulfide nanocrystals with different shapes and sizes using a homemade continuous-flow millifluidic chip is presented. Conventionally, the shape control of nanocrystals was accomplished using a surfactant-controlled approach, where directional growth is facilitated by selective passivation of a particular facet of the nanocrystals using surfactants. We demonstrate a "surfactant-free" approach where different sizes and shapes (i.e. spherical, triangular prism and rod) of plasmonic copper sulfide (Cu(2-x)S) nanocrystals can be fabricated by adjusting the flow rate and precursor concentrations. As continuous-flow synthesis enables uniform heating and easy variation of precursors' stoichiometries, it serves as an excellent incubation platform for nanoparticles due to its simplicity and high reproducibility. Transmission electron microscopy (TEM), fast Fourier transform (FFT) and X-ray diffraction (XRD) techniques were used to characterize the as synthesized nanocrystals and revealed structures ranging from copper-deficient covellite (CuS), spionkopite (Cu1.39S), roxbyite (Cu1.75S), to copper-rich djurleite (Cu1.94S). The localized surface plasmon resonance (LSPR) peak of the nanocrystals can be tuned from 1115 to 1644 nm by simply varying the copper to sulfur molar ratio and flow rate. Furthermore, photothermal effects of Cu(2-x)S nanocrystals were also demonstrated to annihilate the RAW264.7 cells upon near infra-red laser irradiation. PMID- 26940018 TI - N-Hydroxyphthalimide exhibits antitumor activity by suppressing mTOR signaling pathway in BT-20 and LoVo cells. AB - BACKGROUND: N-Hydroxyphthalimide (NHPI), an important chemical raw material, was found to have potent and selective anti-proliferative effect on human breast carcinoma BT-20 cells, human colon adenocarcinoma LoVo and HT-29 cells during our screening for anticancer compounds. The purpose of this study is to assess the antitumor efficacy of NHPI in vitro and in vivo and to explore the underlying antitumor mechanism. METHODS: Cell cytotoxicity of NHPI was evaluated using MTS assay and cell morphological analysis. After NHPI treatment, cell cycle, apoptosis and mitochondrial membrane potential were analyzed using flow cytometer. The subcellular localization of eukaryotic initiation factor 4E (eIF4E) was analyzed by immunofluorescence assay. The antitumor efficacy of NHPI in vivo was tested in BT-20 xenografts. The underlying antitumor mechanisms of NHPI in vitro and in vivo were investigated with western blot analysis in NHPI treated cancer cells and tumor tissues. Statistical significance was determined using Student's t-test. RESULTS: In vitro, NHPI selectively inhibited the proliferation and induced G2/M phase arrest in BT-20 and LoVo cells, which was attributed to the inhibition of cyclin B1 and cdc2 expressions. Furthermore, NHPI induced apoptosis via mitochondrial pathway. Of note, NHPI effectively inhibited mammalian target of rapamycin (mTOR) complex 1 (mTORC1) and mTOR complex 2 (mTORC2) signaling, and overcame the feedback activation of Akt and extracellular signal-regulated kinase (ERK) caused by mTORC1 inhibition in BT-20 and LoVo cells. In vivo, NHPI inhibited tumor growth and suppressed mTORC1 and mTORC2 signaling in BT-20 xenografts with no obvious toxicity. CONCLUSIONS: We found for the first time that NHPI displayed antitumor activity which is associated with the inhibition of mTOR signaling pathway. Our findings suggest that NHPI may be developed as a promising candidate for cancer therapeutics by targeting mTOR signaling pathway and as such warrants further exploration. PMID- 26940021 TI - Photoactivatable CO release from engineered protein crystals to modulate NF kappaB activation. AB - Photoactivatable CO releasing protein crystals were developed by immobilization of Mn carbonyl complexes in polyhedral crystals, which are spontaneously formed in insect cells. The photoactivatable CO release from the engineered protein crystals activates nuclear factor kappa B (NF-kappaB) upon stimulation by visible light irradiation with suppression of cytotoxicity of the Mn complex. PMID- 26940020 TI - Origins of oligodendrocytes in the cerebellum, whose development is controlled by the transcription factor, Sox9. AB - Development of oligodendrocytes, myelin-forming glia in the central nervous system (CNS), proceeds on a protracted schedule. Specification of oligodendrocyte progenitor cells (OPCs) begins early in development, whereas their terminal differentiation occurs at late embryonic and postnatal periods. However, for oligodendrocytes in the cerebellum, the developmental origins and the molecular machinery to control these distinct steps remain unclear. By in vivo fate mapping and immunohistochemical analyses, we obtained evidence that the majority of oligodendrocytes in the cerebellum originate from the Olig2-expressing neuroepithelial domain in the ventral rhombomere 1 (r1), while about 6% of cerebellar oligodendrocytes are produced in the cerebellar ventricular zone. Furthermore, to elucidate the molecular determinants that regulate their development, we analyzed mice in which the transcription factor Sox9 was specifically ablated from the cerebellum, ventral r1 and caudal midbrain by means of the Cre/loxP recombination system. This resulted in a delay in the birth of OPCs and subsequent developmental aberrations in these cells in the Sox9 deficient mice. In addition, we observed altered proliferation of OPCs, resulting in a decrease in oligodendrocyte numbers that accompanied an attenuation of the differentiation and an increased rate of apoptosis. Results from in vitro assays using oligodendrocyte-enriched cultures further supported our observations from in vivo experiments. These data suggest that Sox9 participates in the development of oligodendrocytes in the cerebellum, by regulating the timing of their generation, proliferation, differentiation and survival. PMID- 26940022 TI - Sexual dysfunction in men diagnosed as substance use disorder. AB - Illicit drugs are often used as aphrodisiacs to enhance sexual performance and/or pleasure; however, the available data suggest that most illicit drugs have adverse effects on erection, sexual desire and ejaculation latency in males and that these effects are not fully understood. This study aimed to determine the effect of illicit drug abuse on male sexual function, based on the International Index of Erectile Function (IIEF) score. This descriptive study was conducted at the Alcohol and Substance Research Treatment and Education Center, Ankara, Turkey. Males diagnosed as substance use disorder according to DSM-IV (n = 101) were included as the patient group, and age-matched healthy male volunteers (n = 43) were included as the control group. A 30-item sociodemographic interview form developed by researchers and the 15-item IIEF were administered to all the participants. Data were compared between the patient and control groups. Mean IIEF score was 46.7 +/- 3.3 in the patients that used alcohol, 23.7 +/- 3.3 in the opioid users, 34.1 +/- 5.3 in the ecstasy users, 43.5 +/- 4.2 in the cannabis users and 55.3 +/- 1.6 in the control group. There was not a significant difference between the alcohol and cannabis users' mean IIEF scores and that in the control group (P > 0.05 and >0.05 respectively), whereas there was a significant difference between the opioid and ecstasy users' mean IIEF scores and that in the control group (P < 0.001 and <0.001 respectively). All IIEF subscale scores in the opioid users were significantly lower than in the control group (P < 0.001). IIEF erectile function, sexual desire and general satisfaction subscale scores were significantly lower in the ecstasy users than in the control group (P < 0.001, <0.005 and <0.001 respectively). In the alcohol users only, the IIEF general satisfaction subscale score was lower than in the control group (P < 0.005). PMID- 26940023 TI - Probing the binding of two 19-nortestosterone derivatives to human serum albumin: insights into the interactions of steroid hormone drugs with functional biomacromolecule. AB - Norethindrone acetate (NETA) is a fatty acid ester of norethindrone (NET) that can convert to its more active parent compound NET when orally administered. To study the interactions of NETA and NET with human serum albumin (HSA), we applied fluorescence spectroscopy, circular dichroism (CD), and molecular docking. The effects of metal ions on the HSA-NETA/NET system were also explored. Fluorescence data showed that the quenching mechanism of HSA by NETA and NET was consistent with a static model and that the binding constant of NETA was higher than that of NET. Thermodynamic parameters indicated that hydrogen bonds and van der Waals forces were the main forces maintaining the stability of the HSA-NETA/NET complex. Molecular modeling studies revealed that NETA and NET were bound within subdomain IIA of HSA, in accordance with the site probe results. Synchronous fluorescence spectroscopy, CD, and three-dimensional fluorescence spectroscopy further confirmed that the binding of NETA/NET to HSA changed the secondary structure of the protein. All other metal ions, except for Ca(2+) , decreased the K value of the HSA-NETA/NET system with enhancement of the maximum effectiveness of NETA/NET. Three commercially available steroid hormone drugs influenced the binding ability of NETA on HSA to different extents. This study provides novel insights into the interactions between HSA and NETA/NET, as well as a solid foundation for future research on drug pharmacokinetics and pharmacodynamics. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26940024 TI - Atomic Layer Epitaxy of h-BN(0001) Multilayers on Co(0001) and Molecular Beam Epitaxy Growth of Graphene on h-BN(0001)/Co(0001). AB - The direct growth of hexagonal boron nitride (h-BN) by industrially scalable methods is of broad interest for spintronic and nanoelectronic device applications. Such applications often require atomically precise control of film thickness and azimuthal registry between layers and substrate. We report the formation, by atomic layer epitaxy (ALE), of multilayer h-BN(0001) films (up to 7 monolayers) on Co(0001). The ALE process employs BCl3/NH3 cycles at 600 K substrate temperature. X-ray photoelectron spectroscopy (XPS) and low energy electron diffraction (LEED) data show that this process yields an increase in h BN average film thickness linearly proportional to the number of BCl3/NH3 cycles, with BN layers in azimuthal registry with each other and with the Co(0001) substrate. LEED diffraction spot profile data indicate an average BN domain size of at least 1900 A. Optical microscopy data indicate the presence of some domains as large as ~20 MUm. Transmission electron microscopy (TEM) and ambient exposure studies demonstrate macroscopic and microscopic continuity of the h-BN film, with the h-BN film highly conformal to the Co substrate. Photoemission data show that the h-BN(0001) film is p-type, with band bending near the Co/h-BN interface. Growth of graphene by molecular beam epitaxy (MBE) is observed on the surface of multilayer h-BN(0001) at temperatures of 800 K. LEED data indicate azimuthal graphene alignment with the h-BN and Co(0001) lattices, with domain size similar to BN. The evidence of multilayer BN and graphene azimuthal alignment with the lattice of the Co(0001) substrate demonstrates that this procedure is suitable for scalable production of heterojunctions for spintronic applications. PMID- 26940025 TI - Large-Scale Urban Riots and Residential Segregation: A Case Study of the 1960s U.S. Riots. AB - Despite a well-established literature investigating race-related predictors of riot incidence, the racial aftermath of riots remains unexamined. In this study, I use the 1960s U.S. race riots to investigate trends in black residential segregation levels following large-scale riot activity in seven major U.S. cities. I use a novel approach--namely, synthetic control matching--to select a group of cities against which segregation trends can be compared. I find that levels of black segregation rose in 1970 for four of the seven cities, but these increases disappeared in 1980 and 1990 except in Detroit. These results mask differential trends at lower geographic levels: suburban neighborhoods in affected areas experienced larger and longer-term increases in segregation, particularly in traditionally hypersegregated cities in the Midwest and Northeast. PMID- 26940026 TI - Latent cytomegalovirus infection enhances anti-tumour cytotoxicity through accumulation of NKG2C+ NK cells in healthy humans. AB - Cytomegalovirus (CMV) infection markedly expands NKG2C+/NKG2A- NK cells, which are potent killers of infected cells expressing human leucocyte antigen (HLA)-E. As HLA-E is also over-expressed in several haematological malignancies and CMV has been linked to a reduced risk of leukaemic relapse, we determined the impact of latent CMV infection on NK cell cytotoxicity against four tumour target cell lines with varying levels of HLA-E expression. NK cell cytotoxicity against K562 (leukaemia origin) and U266 (multiple myeloma origin) target cells was strikingly greater in healthy CMV-seropositive donors than seronegative donors and was associated strongly with target cell HLA-E and NK cell NKG2C expression. NK cell cytotoxicity against HLA-E transfected lymphoma target cells (221.AEH) was ~threefold higher with CMV, while NK cell cytotoxicity against non-transfected 721.221 cells was identical between the CMV groups. NK cell degranulation (CD107a(+) ) and interferon (IFN)-gamma production to 221.AEH cells was localized almost exclusively to the NKG2C subset, and antibody blocking of NKG2C completely eliminated the effect of CMV on NK cell cytotoxicity against 221.AEH cells. Moreover, 221.AEH feeder cells and interleukin (IL)-15 were found to expand NKG2C(+) /NKG2A(-) NK cells preferentially from CMV-seronegative donors and increase NK cell cytotoxicity against HLA-E(+) tumour cell lines. We conclude that latent CMV infection enhances NK cell cytotoxicity through accumulation of NKG2C(+) NK cells, which may be beneficial in preventing the initiation and progression of haematological malignancies characterized by high HLA-E expression. PMID- 26940027 TI - An analysis of the complementarity of ICECAP-A and EQ-5D-3 L in an adult population of patients with knee pain. AB - BACKGROUND: The ICECAP measures potentially offer a broader assessment of quality of life and well-being, in comparison to measures routinely used in economic evaluation, such as the EQ-5D-3 L. This broader assessment may allow measurement of the full effects of an intervention or treatment. Previous research has indicated that the ICECAP-O (for older people) and EQ-5D-3 L measure provide complementary information. This paper aims to determine similar information for the ICECAP-A (for the entire adult population) in terms of whether the measure is a substitute or complement to the EQ-5D-3 L. METHODS: Data from the BEEP trial - a multi-centre, pragmatic, randomised controlled trial - were used. Spearman rank correlations and exploratory factor analytic methods were used to assess whether ICECAP-A and EQ-5D-3 L are measuring the same, or different, constructs. RESULTS: A correlation of 0.49 (p < 0.01) was found between the ICECAP-A tariff score and the EQ-5D-3 L index. Using the pooled items of the EQ-5D-3 L and the ICECAP-A a two factor solution was optimal, with the majority of EQ-5D-3 L items loading onto one factor and the majority of ICECAP-A items onto another. CONCLUSION: The results presented in this paper indicate that ICECAP-A and EQ-5D-3 L are measuring two different constructs and provide largely different, complementary information. Results showed a similarity to results presented by Davis et al. using the ICECAP-O. TRIAL REGISTRATION: ISRCTN 93634563. PMID- 26940028 TI - Excessive Iron and alpha-Synuclein Oligomer in Brain are Relevant to Pure Apathy in Parkinson Disease. AB - OBJECTIVES: To investigate the demographic features, clinical features, and potential mechanism in patients with Parkinson disease (PD) with pure apathy. METHOD: A total of 145 patients with PD without depression and dementia and 30 age-matched controls were consecutively recruited. Patients with PD were evaluated by Apathy Scale (AS), scales for motor symptoms and quality of life. The levels of iron, oxidative and neuroinflammatory factors, alpha-synuclein oligomer, and dopamine in cerebrospinal fluid (CSF) from patients with PD and controls were detected by enzyme-linked immunosorbent assay, chemical colorimetric method, and high-performance liquid chromatography. Comparisons between PD with pure apathy and with no pure apathy groups and correlation between AS score and the levels of above factors were analyzed. RESULTS: There were 64 (44.14%) cases in PD-apathy group. The PD-apathy group had older age, (97.81 +/- 10.82) years versus (61.86 +/- 10.80) years, and severer quality of life (P < .05). The PD-apathy and PD without apathy groups presented no remarkable differences in motor symptoms (P > .05). The levels of iron, hydroxyl radical (.OH), hydrogen peroxide (H2O2), and alpha-synuclein oligomer in CSF in PD-apathy group were significantly higher than that in PD without the apathy group (P < .05). In patients with PD, the AS score was positively correlated with the levels of iron, .OH, H2O2 and alpha-synuclein oligomer in CSF (r = 19.838, .063, 1.046, and 0.498, respectively, P < .05). In PD-apathy group, iron level was positively correlated with .OH level (r = .011, P < .05), and H2O2 level was positively correlated with alpha-synuclein oligomer level in CSF (r = .045, P < .05). CONCLUSION: Patients with PD had high prevalence of pure apathy. Patients with PD having pure apathy had older age. Pure apathy reduced quality of life for patients without worsening motor function. Excessive iron and alpha-synuclein oligomer in brain commonly contributed to pure apathy of PD through potential mechanism of oxidative stress. PMID- 26940030 TI - Pupil size influences the eye-tracker signal during saccades. AB - While it is known that scleral search coils-measuring the rotation of the eye globe--and modern, video based eye trackers-tracking the center of the pupil and the corneal reflection (CR)--produce signals with different properties, the mechanisms behind the differences are less investigated. We measure how the size of the pupil affects the eye-tracker signal recorded during saccades with a common pupil-CR eye-tracker. Eye movements were collected from four healthy participants and one person with an aphakic eye while performing self-paced, horizontal saccades at different levels of screen luminance and hence pupil size. Results show that pupil-, and gaze-signals, but not the CR-signal, are affected by the size of the pupil; changes in saccade peak velocities in the gaze signal of more than 30% were found. It is important to be aware of this pupil size dependent change when comparing fine grained oculomotor behavior across participants and conditions. PMID- 26940029 TI - No difference in cross-modal attention or sensory discrimination thresholds in autism and matched controls. AB - Autism has been associated with abnormalities in sensory and attentional processing. Here, we assessed these processes independently in the visual and auditory domains using a visual contrast-discrimination task and an auditory modulation-depth discrimination task. To evaluate changes in sensory function by attention, we measured behavioral performance (discrimination accuracy) when subjects were cued to attend and respond to the same stimulus (frequent valid cue) or cued to attend to one stimulus and respond to the non-cued stimulus (infrequent invalid cue). The stimuli were presented at threshold to ensure equal difficulty across participants and groups. Results from fifteen high-functioning adult individuals with autism and fifteen matched controls revealed no significant differences in visual or auditory discrimination thresholds across groups. Furthermore, attention robustly modulated performance accuracy (performance was better for valid than invalid cues) in both sensory modalities and to an equivalent extent in both groups. In conclusion, when using this well controlled method, we found no evidence of atypical sensory function or atypical attentional modulation in a group of high functioning individuals with clear autism symptomatology. PMID- 26940032 TI - Corrigendum: Critical roles for murine Reck in the regulation of vascular patterning and stabilization. PMID- 26940031 TI - Predictors of health care provider anticipatory guidance provision for older drivers. AB - OBJECTIVE: The objective of this study was to determine the frequency of health care provider (HCP) driving safety/cessation-related anticipatory guidance provision and predictors of driving safety-related anticipatory guidance provision by HCPs. METHODS: HCPs in several central/upper Midwest states were surveyed about frequency of anticipatory guidance provision (n = 265). RESULTS: More than half of HCPs stated that they frequently or always provide driving safety/cessation-related anticipatory guidance to patients aged 85 or older, 38.7% provided this guidance to patients aged 75 to 84, and 13.7% to patients aged 65 to 74. Predictors of driving safety/cessation-related anticipatory guidance provision differed by patient age. For patients aged 65-74, HCP personal experience with a motor vehicle crash (either the HCP themselves or a friend/family member) was significant in predicting anticipatory guidance provision. However, for patients aged 75 and older, significant predictors included HCP rural practice, HCP age, and percentage of HCP patients who were older adults. CONCLUSION: HCP counseling provision related to driving issues differs by patient age and several HCP characteristics, including HCP rurality, age, and personal experience with motor vehicle crashes. Because aging results in physical and mental changes that affect driving and can be identified by HCPs, HCPs are in a position to counsel patients on the potential impacts of aging on the act of driving. Future research should examine the reasons for the differences in anticipatory guidance provision found in this study. PMID- 26940033 TI - Bacterial chemotaxis-enabled autonomous sorting of nanoparticles of comparable sizes. AB - High throughput sorting of micro/nanoparticles of similar sizes is of significant interest in many biological and chemical applications. In this work, we report a simple and cost-effective sorting technique for separation of similarly-sized particles of dissimilar surface properties within a diffusion-based microfluidic platform using chemotaxis in Escherichia coli bacteria. Differences in surface chemistry of two groups of similarly-sized nanoparticles in a mixture were exploited to selectively assemble one particle group onto motile E. coli, through either specific or non-specific adhesion, and separate them from the remaining particle group via chemotaxis of the attached bacteria. To enable optimal operation of the sorting platform, the chemotaxis behavior of E. coli bacteria in response to casamino acids, the chemoeffector of choice was first characterized. The chemical concentration gradient range within which the bacteria exhibit a positive chemotactic response was found to be within 0.25 * 10(-7)-1.0 * 10(-3) g ml(-1) mm(-1). We demonstrate that at the optimum concentration gradient of 5.0 * 10(-4) g ml(-1) mm(-1), a sorting efficiency of up to 81% at a throughput of 2.4 * 10(5) particles per min can be achieved. Sensitivity of the sorting efficiency to the adhesion mechanism and particle size in the range of 320-1040 nm was investigated. PMID- 26940034 TI - Feeling like a stranger: negotiations with culture as experienced by Chilean occupational therapists. AB - BACKGROUND: Although occupational therapy has begun to focus on the subject of culture, few studies have examined how occupational therapists outside the English-speaking countries reflect on it. AIM: To explore how Chilean occupational therapists reflect on their personal and professional experiences in regard to the complexity of culture, and its different understandings and expressions. METHODS: This qualitative study uses content analysis to establish common trends in participants' experiences. A validation phase and data triangulation were implemented to ensure trustworthiness. RESULTS: Culture is experienced as a continuous negotiation in personal and professional terms. One central theme, 'negotiating through the dynamism of culture', and three categories, 'dealing with power', 'understanding local and global identities', and 'crossing the boundaries into the client's land', emerged. These experiences are complex, chaotic, and highly context-dependent. DISCUSSION: During therapeutic encounters, practitioners and clients may experience cultural barriers even if their differences are not obvious in cultural terms. As a result of this finding, we recommend the inclusion of culture and cultural issues in professional training. The impact of a multicultural research team is discussed. Future research should explore how the construct of culture is introduced in occupational therapy professional training in Chile. PMID- 26940035 TI - The effect of the patient-physician relationship on health-related quality of life after cardiac rehabilitation. AB - Purpose The patient-physician relationship has effects on adherence and health outcomes in chronic diseases. This prospective study investigates the effect of the patient-physician relationship on patients' health-related quality of life (HRQOL) in the context of cardiac rehabilitation. Methods Three hundred and thirty-eight German patients filled out questionnaires at the start and end of rehabilitation and at 6 months follow-up. Patient-physician relationship variables surveyed were patient involvement (perceived involvement in care scales), trust in the physician, patient satisfaction (PHYSAT) and physician's communicative behaviour (KOVA). After adjusting for multiple confounders, hierarchical regression analyses were conducted to predict the influence of the patient-physician relationship on HRQOL after rehabilitation. We further examined clinical relevance using minimal clinically important differences (MCID). Results In the hierarchical regression analyses, 42.8-54.9% of the variance at the end of rehabilitation and 22.4-40.5% at follow-up were explained. The patient-physician variables patient satisfaction, physician's emotionally supportive communication and effective and open communication accounted for 1.4-2.6% of the variance and proved statistically and clinically significant for HRQOL change. Further predictors for better HRQOL were higher income and less trait anger. Conclusion Aspects of the patient-physician relationship are significant predictors for patients' HRQOL after rehabilitation. Rehabilitation physicians should emotionally support the patients and communicate in an effective and open manner to enhance HRQOL. Implications for rehabilitation Aspects of the patient physician relationship have effects on adherence and clinical outcomes in chronic diseases. In this cardiac sample, the patient-physician relationship had an influence on patients' health-related quality of life (HRQOL) after inpatient rehabilitation. Rehabilitation physicians should emotionally support and encourage the patients and communicate with them in an effective and open manner to enhance patients' HRQOL. PMID- 26940036 TI - Major League Baseball pace-of-play rules and their influence on predicted muscle fatigue during simulated baseball games. AB - Major League Baseball (MLB) has proposed rule changes to speed up baseball games. Reducing the time between pitches may impair recovery from fatigue. Fatigue is a known precursor to injury and may jeopardise joint stability. This study examined how fatigue accumulated during baseball games and how different pace of play initiatives may influence fatigue. Pitcher data were retrieved from a public database. A predictive model of muscle fatigue estimated muscle fatigue in 8 arm muscles. A self-selected pace (22.7 s), 12 s pace (Rule 8.04 from the MLB) and a 20 s rest (a pitch clock examined in the 2014 Arizona Fall League (AFL)) were examined. Significantly more muscle fatigue existed in both the AFL and Rule 8.04 conditions, when compared to the self-selected pace condition (5.01 +/- 1.73%, 3.95 +/- 1.20% and 3.70 +/- 1.10% MVC force lost, respectively). Elevated levels of muscle fatigue are predicted in the flexor-pronator mass, which is responsible for providing elbow stability. Reduced effectiveness of the flexor-pronator mass may reduce the active contributions to joint rotational stiffness, increasing strain on the ulnar collateral ligament (UCL) and possibly increasing injury risk. PMID- 26940037 TI - Selection of a suitable plant for phytoremediation in mining artisanal zones. AB - A study was undertaken with the aim of identifying a suitable plant for the phytoremediation of metal-polluted soil from an artisanal mining area in Ecuador. Three zones including a natural zone (NZ), abandoned zone (AZ) and intensively mined zone (IZ) were selected. Three common native plants grown in the three zones were identified and collected, including Miconia zamorensis, Axonopus compressus and Erato polymnioides. The percentage of arbuscular mycorrhizal colonization that benefits their own survival in polluted soil was analyzed in the root samples of these candidate species. Analysis of the soils and plants collected from the different zones showed that the concentrations of Pb, Zn, Cu and Cd were comparatively lower in the NZ, higher in the AZ and IZ, and highest in the AZ for all the metals. The concentration of all these metals in plant tissues was the highest in E. polymnioides. The data analysis including the metal accumulation index, bioconcentration factor and translocation factor strongly identified E. polymnioides as a hyperaccumulator plant suitable for phytoremediation. PMID- 26940038 TI - Dissecting the structural and functional features of the Luteinizing hormone receptor using receptor specific single chain fragment variables. AB - The Luteinizing hormone receptor (LHR) has a large extracellular domain (amino acid residues, a.a.1-355) and a transmembrane domain (TMD; a.a. 356-699), essential for hormone binding and signaling, respectively. The LHR hinge region (a.a. 256-355) connects the two domains and acts as an activating switch for the receptor by an unknown mechanism. LHR hinge-specific Single chain fragment variables (ScFv) stimulated cAMP production by the stable and transiently transfected cell lines expressing LHR in a hormone-independent manner and the C terminal region of LHR hinge (a.a. 313-349) was identified as the probable epitope for one agonistic ScFv. This epitope attained a helical conformation upon agonistic ScFv binding and the activity of the ScFv was dependent on Y331 sulfation. ScFv was also able to activate TMD mutants, D578Y and A593P, reemphasizing the role of TM helix VI in LHR activation. PMID- 26940039 TI - MiR-185 attenuates androgen receptor function in prostate cancer indirectly by targeting bromodomain containing 8 isoform 2, an androgen receptor co-activator. AB - OBJECTIVES: Aberrant androgen receptor (AR) signaling functions are implicated in prostate cancer (PCa) pathogenesis. Here, we studied interactions between miR-185 and the bromodomain containing 8 isoform 2 (BRD8 ISO2) to investigate indirect mechanisms of miR-185 with respect to AR function through BRD8 ISO2 in PCa. METHODS: Putative miRNA response element (MRE) of miR-185 in 3'-untranslated region (3'-UTR) of BRD8 ISO2 mRNA was predicted by software and confirmed using dual-luciferase assays and Ago2 immunoprecipitation. BRD8 and AR expression were determined by qRT-PCR and Western blot in PCa cells and tissues. MMTV-Fluc reporter plasmids and dual-luciferase assays were used to evaluate AR activity. RESULTS: MRE prediction, dual-luciferase assays and Ago2 immunoprecipitation confirmed that miR-185 is capable of binding the 3'-UTR of BRD8 ISO2 mRNA. QRT PCR and Western blot indicated that BRD8 ISO2 expression is decreased by miR-185 mimic transfection while increased by miR-185 inhibitor transfection. MMTV-Fluc reporter assays revealed that miR-185 can attenuate AR function by suppressing BRD8 ISO2. Additionally, Pearson's correlation analyses confirmed that BRD8 ISO2 mRNA expression is inversely correlated with miR-185 expression in clinical specimens. CONCLUSION: In addition to suppression of AR expression, miR-185 can attenuate AR function indirectly by suppressing BRD8 ISO2. MiR-185 and BRD8 ISO2 may be possible therapeutic targets for PCa treatment. PMID- 26940041 TI - Cancer Communication in the Social Media Age. PMID- 26940040 TI - The association of endothelial nitric oxide synthase (eNOS) G894T gene polymorphism with responsiveness to a selective alpha1 -blocker in men with benign prostatic hyperplasia related lower urinary tract symptoms. AB - OBJECTIVE: To prospectively investigate the association of endothelial nitric oxide synthase (eNOS) G894T gene polymorphism with responsiveness to a selective alpha1 -blocker in men with benign prostatic hyperplasia related lower urinary tract symptoms (BPH/LUTS), as nitric oxide has recently gained increasing recognition as an important neurotransmitter of functions in the lower urinary tract. PATIENTS AND METHODS: In all, 136 men with BPH/LUTS were recruited from urology outpatient clinics in a university hospital. Oral therapy with doxazosin gastrointestinal therapeutic system (GITS) 4 mg once-daily was given for 12 weeks. The drug efficacy was assessed by the changes from baseline in the total International Prostate Symptom Score (IPSS), maximum urinary flow rate (Qmax ) and post-void residual urine volume (PVR) at 12 weeks of treatment. The 'responders' to doxazosin GITS were defined as those who had a total IPSS decrease of >4 points from baseline. eNOS G894T polymorphism was determined using the polymerase chain reaction-restriction fragment length polymorphism method. RESULTS: Patients had statistically significant improvements in total IPSS, quality of life score, and Qmax (P < 0.01) after a 12-week period of treatment. Using multiple logistic regression analysis adjusted for age and IPSS, our results showed that being a eNOS 894T allele carrier was an independent risk factor for being a drug non-responder (P = 0.03, odds ratio 4.19). Moreover, a decreased responder rate (P = 0.01), as well as the lower improvements in IPSS (P = 0.02) and Qmax (P = 0.03) were significantly associated with increment in the T allele number. CONCLUSIONS: The presence of the eNOS 894T allele had a significantly negative impact on responsiveness to a selective alpha1 -blocker in BPH/LUTS treatment, suggesting that eNOS G894T gene polymorphism may be a genetic susceptibility factor for alpha1 -blocker efficacy in men with BPH/LUTS. PMID- 26940042 TI - Association of Caffeine and Hearing Recovery After Acoustic Overstimulation Events in a Guinea Pig Model. AB - IMPORTANCE: Noise-induced hearing loss is an increasingly worrisome problem. Although caffeine intake is common in people involved in noise-related environments, the effect of caffeine on the recovery of hearing after a temporary threshold shift requires further understanding. OBJECTIVES: To determine whether caffeine impairs hearing recovery in a guinea pig model exposed to acoustic overstimulation. DESIGN, SETTING, AND SUBJECTS: This experiment at the McGill University Auditory Sciences Laboratory used 24 female albino guinea pigs (age, 6 months; weight, 500-600 g) divided randomly into 3 groups of 8 animals each. Group 1 was exposed to caffeine; group 2, acoustic overstimulation events (AOSEs); and group 3, both. Data were collected from July 1, 2013, to March 30, 2014, and analyzed from April 1 to August 1, 2014. INTERVENTIONS: Daily caffeine dose for groups 1 and 3 consisted of 25 mg/kg administered intraperitoneally for 15 days. The AOSEs were administered on days 1 and 8 and consisted of 1 hour of 110-dB pure-tone sound. MAIN OUTCOMES AND MEASURES: Serial auditory brainstem response (ABR) tests to determine the audiological threshold shift and recovery were obtained at baseline and on days 1 (1 hour after the first AOSE), 4, 8 (before and 1 hour after the second AOSE), 11, and 15. Scanning electron and light microscopy of the cochleas were performed to determine morphologic changes. RESULTS: The day 1 post-AOSE measurement resulted in a similar threshold shift in all animals in groups 2 and 3 at all frequencies tested (8, 16, 20, and 25 kHz). The maximum threshold shift was at 16 kHz, with a mean of 66.12 dB. By day 8, the threshold shift in group 2 recovered completely at all frequencies except 20 kHz, where a mean threshold shift of 20.63 dB of sound pressure level (SPL) was present. Hearing impairment in group 3 persisted in 8-, 16-, and 25-kHz frequencies with thresholds of 21.88, 28.13, and 26.25 dB SPL, respectively (P = .001). After a second AOSE at day 8, similar threshold shift and outcome were recorded on day 15 compared with day 8, with a mean threshold shift at 20 kHz of 29.38 dB SPL in group 2 and mean threshold shifts at 8, 16, 20, and 25 kHz of 29.38, 35.63, 40.63, and 38.75 dB SPL, respectively, in group 3. The difference in ABR threshold recovery was in concordance with scanning electronic and light microscopy findings for each group. CONCLUSIONS AND RELEVANCE: A daily dose of caffeine was found to impair the recovery of hearing after an AOSE. PMID- 26940043 TI - Potential wrong-level surgery for an intra-dural thoracic spinal tumour: the importance of optimum imaging and consistency in the direction in which the level is determined. AB - The spectre of wrong-level surgery has many a spinal surgeon double-checking the spinal level at which an operation is being carried out especially in the thoracic spine, in the absence of abnormal-looking vertebrae which could help to identify the intended level. Getting the level wrong is easily done if there is an unusual number of vertebrae or if the direction of the count digresses from the imaging available. PMID- 26940044 TI - Anatomy of superior medial genicular artery: A short cadaveric report. PMID- 26940046 TI - Telemetry research on elusive wildlife: A synthesis of studies on giant pandas. AB - Telemetry studies that track animals through space and time can lead to advances in scientific understanding that are vital in conservation efforts. For example, telemetry studies of the giant panda (Ailuropoda melanoleuca) have shed light on many aspects of panda biology, but small sample sizes in each separate study make it difficult to draw broad conclusions. To overcome this problem we conducted the first synthesis of all 5 panda telemetry studies conducted to date. Using these data we investigated patterns in 6 main topics: home range, space-use interactions, core areas, movement patterns, seasonal migration and natal dispersal. We found that panda home range sizes do not vary between 2 main mountain ranges (Qionglai and Qinling), as was previously believed. Our results also suggest that female pandas increase their movement in the mating season: a behavior typically attributed only to males. We found and summarized telemetry and genetic evidence for female natal dispersal in the giant panda. Our synthesis highlights the need for additional research relating panda behavior to human disturbance factors, and can aid future studies on giant pandas as well as other species. PMID- 26940045 TI - A comparison between the Dutch and American-English digits-in-noise (DIN) tests in normal-hearing listeners. AB - OBJECTIVE: The Dutch digits-in-noise test (NL DIN) and the American-English version (US DIN) are speech-in-noise tests for diagnostic and clinical usage. The present study investigated differences between NL DIN and US DIN speech reception thresholds (SRTs) for a group of native Dutch-speaking listeners. DESIGN: In experiment 1, a repeated-measures design was used to compare SRTs for the NL DIN and US DIN in steady-state noise and interrupted noise for monaural, diotic, and dichotic listening conditions. In experiment 2, a subset of these conditions with additional speech material (i.e. US DIN triplets without inter-digit coarticulation/prosody) was used. STUDY SAMPLE: Experiment 1 was conducted with 16 normal-hearing Dutch students. Experiment 2 was conducted with nine different students. RESULTS: No significant differences between SRTs measured with the NL DIN and US DIN were found in steady-state noise. In interrupted noise the US DIN SRTs were significantly better in monaural and diotic listening conditions. Experiment 2 demonstrated that these better SRTs cannot be explained by the combined effect of inter-digit coarticulation and prosody in the American-English triplets. CONCLUSIONS: The NL DIN and US DIN are highly comparable and valuable tests for measuring auditory speech recognition abilities. These tests promote across-language comparisons of results. PMID- 26940047 TI - Genetic diversity and population structure of Lactobacillus delbrueckii subspecies bulgaricus isolated from naturally fermented dairy foods. AB - Lactobacillus delbrueckii subsp. bulgaricus is one of the most widely used starter culture strains in industrial fermented dairy manufacture. It is also common in naturally fermented dairy foods made using traditional methods. The subsp. bulgaricus strains found in naturally fermented foods may be useful for improving current industrial starter cultures; however, little is known regarding its genetic diversity and population structure. Here, a collection of 298 L. delbrueckii strains from naturally fermented products in Mongolia, Russia, and West China was analyzed by multi-locus sequence typing based on eight conserved genes. The 251 confirmed subsp. bulgaricus strains produced 106 unique sequence types, the majority of which were assigned to five clonal complexes (CCs). The geographical distribution of CCs was uneven, with CC1 dominated by Mongolian and Russian isolates, and CC2-CC5 isolates exclusively from Xinjiang, China. Population structure analysis suggested six lineages, L1-L6, with various homologous recombination rates. Although L2-L5 were mainly restricted within specific regions, strains belonging to L1 and L6 were observed in diverse regions, suggesting historical transmission events. These results greatly enhance our knowledge of the population diversity of subsp. bulgaricus strains, and suggest that strains from CC1 and L4 may be useful as starter strains in industrial fermentation. PMID- 26940049 TI - Exposure to low UVA doses increases KatA and KatB catalase activities, and confers cross-protection against subsequent oxidative injuries in Pseudomonas aeruginosa. AB - Solar UVA radiation is one of the main environmental stress factors for Pseudomonas aeruginosa. Exposure to high UVA doses produces lethal effects by the action of the reactive oxygen species (ROS) it generates. P. aeruginosa has several enzymes, including KatA and KatB catalases, which provide detoxification of ROS. We have previously demonstrated that KatA is essential in defending P. aeruginosa against high UVA doses. In order to analyse the mechanisms involved in the adaptation of this micro-organism to UVA, we investigated the effect of exposure to low UVA doses on KatA and KatB activities, and the physiological consequences. Exposure to UVA induced total catalase activity; assays with non denaturing polyacrylamide gels showed that both KatA and KatB activities were increased by radiation. This regulation occurred at the transcriptional level and depended, at least partly, on the increase in H2O2 levels. We demonstrated that exposure to low UVA produced a protective effect against subsequent lethal doses of UVA, sodium hypochlorite and H2O2. Protection against lethal UVA depends on katA, whilst protection against sodium hypochlorite depends on katB, demonstrating that different mechanisms are involved in the defence against these oxidative agents, although both genes can be involved in the global cellular response. Conversely, protection against lethal doses of H2O2 could depend on induction of both genes and/or (an)other defensive factor(s). A better understanding of the adaptive response of P. aeruginosa to UVA is relevant from an ecological standpoint and for improving disinfection strategies that employ UVA or solar irradiation. PMID- 26940048 TI - Three-dimensional scaffold of type II collagen promote the differentiation of adipose-derived stem cells into a nucleus pulposus-like phenotype. AB - Type II collagen is reported to have the capability of guiding adipose-derived stem cells (ADSCs) to differentiate towards a nucleus pulposus (NP)-like phenotype. So this study aimed to establish a three-dimensional (3D) collagen scaffold using N,N-(3-dimethylaminopropyl)-N'-ethyl carbodiimide and N hydroxysuccinimide (EDAC/NHS) to increase the efficiency of ADSC differentiation into NP-like cells. Physical properties, such as porosity, biodegradation, and microstructure, and biological characteristics such as cytotoxicity, cell proliferation, and expression of relevant genes and proteins were measured to evaluate the efficacy of different scaffolds. Collagen scaffolds cross-linked with EDAC/NHS exhibited higher biological stability, better spatial structure, and higher gene and protein expression of functional markers such as aggrecan, SOX9 and COL2 than those of other groups. Based on the results, freeze-dried type II collagen cross-linked with EDAC/NHS formed the best 3D scaffold, for inducing ADSC proliferation and differentiation toward a NP-like phenotype. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 1687-1693, 2016. PMID- 26940050 TI - Archaeal and bacterial community dynamics and bioprocess performance of a bench scale two-stage anaerobic digester. AB - Two-stage technologies have been developed for anaerobic digestion of waste activated sludge. In this study, the archaeal and bacterial community structure dynamics and bioprocess performance of a bench-scale two-stage anaerobic digester treating urban sewage sludge have been studied by the means of high-throughput sequencing techniques and physicochemical parameters such as pH, dried sludge, volatile dried sludge, acid concentration, alkalinity, and biogas generation. The coupled analyses of archaeal and bacterial communities and physicochemical parameters showed a direct relationship between archaeal and bacterial populations and bioprocess performance during start-up and working operation of a two-stage anaerobic digester. Moreover, results demonstrated that archaeal and bacterial community structure was affected by changes in the acid/alkalinity ratio in the bioprocess. Thus, a predominance of the acetoclastic methanogen Methanosaeta was observed in the methanogenic bioreactor at high-value acid/alkaline ratio, while a predominance of Methanomassilicoccaeceae archaea and Methanoculleus genus was observed in the methanogenic bioreactor at low-value acid/alkaline ratio. Biodiversity tag-iTag sequencing studies showed that methanogenic archaea can be also detected in the acidogenic bioreactor, although its biological activity was decreased after 4 months of operation as supported by physicochemical analyses. Also, studies of the VFA producers and VFA consumers microbial populations showed as these microbiota were directly affected by the physicochemical parameters generated in the bioreactors. We suggest that the results obtained in our study could be useful for future implementations of two stage anaerobic digestion processes at both bench- and full-scale. PMID- 26940051 TI - Synthesis and structural characterization of raffinosyl-oligofructosides upon transfructosylation by Lactobacillus gasseri DSM 20604 inulosucrase. AB - A new process based on enzymatic synthesis of a series of raffinose-derived oligosaccharides or raffinosyl-oligofructosides (RFOS) with degree of polymerization (DP) from 4 to 8 was developed in the presence of raffinose. This process involves a transfructosylation reaction catalyzed by an inulosucrase from Lactobacillus gasseri DSM 20604 (IS). The main synthesized RFOS were structurally characterized by nuclear magnetic resonance (NMR). According to the elucidated structures, RFOS consist of beta-2,1-linked fructose unit(s) to raffinose: alpha D-galactopyranosyl-(1 -> 6)-alpha-D-glucopyranosyl-(1<->2)-beta-D-fructofuranosyl ((1 <- 2)-beta-D-fructofuranoside)n (where n refers to the number of transferred fructose moieties). The maximum yield of RFOS was 33.4 % (in weight respect to the initial amount of raffinose) and was obtained at the time interval of 8-24 h of transfructosylation reaction initiated with 50 % (w/v) of raffinose. Results revealed the high acceptor and donor affinity of IS towards raffinose, being fairly comparable with that of sucrose for the production of fructooligosaccharides (FOS), including when both carbohydrates coexisted (sucrose/raffinose mixture, 250 g L(-1) each). The production of RFOS was also attempted in the presence of sucrose/melibiose mixtures; in this case, the predominant acceptor-product formed was raffinose followed by a minor production of a series of oligosaccharides with varying DP. The easiness of RFOS synthesis and the structural similarities with both raffinose and fructan series of oligosaccharides warrant the further study of the potential bioactive properties of these unexplored oligosaccharides. PMID- 26940052 TI - Online analysis of protein inclusion bodies produced in E. coli by monitoring alterations in scattered and reflected light. AB - The online monitoring of recombinant protein aggregate inclusion bodies during microbial cultivation is an immense challenge. Measurement of scattered and reflected light offers a versatile and non-invasive measurement technique. Therefore, we investigated two methods to detect the formation of inclusion bodies and monitor their production: (1) online 180 degrees scattered light measurement (lambda = 625 nm) using a sensor platform during cultivation in shake flask and (2) online measurement of the light reflective interference using a porous Si-based optical biosensor (SiPA). It could be shown that 180 degrees scattered light measurement allows monitoring of alterations in the optical properties of Escherichia coli BL21 cells, associated with the formation of inclusion bodies during cultivation. A reproducible linear correlation between the inclusion body concentration of the non-fluorescent protein human leukemia inhibitory factor (hLIF) carrying a thioredoxin tag and the shift ("Deltaamp") in scattered light signal intensity was observed. This was also observed for the glutathione-S-transferase-tagged green fluorescent protein (GFP-GST). Continuous online monitoring of reflective interference spectra reveals a significant increase in the bacterium refractive index during hLIF production in comparison to a non-induced reference that coincide with the formation of inclusion bodies. These online monitoring techniques could be applied for fast and cost-effective screening of different protein expression systems. PMID- 26940053 TI - Bone pain: current and future treatments. AB - Skeletal conditions are common causes of chronic pain and there is an unmet medical need for improved treatment options. Bone pain is currently managed with disease modifying agents and/or analgesics depending on the condition. Disease modifying agents affect the underlying pathophysiology of the disease and reduce as a secondary effect bone pain. Antiresorptive and anabolic agents, such as bisphosphonates and intermittent parathyroid hormone (1-34), respectively, have proven effective as pain relieving agents. Cathepsin K inhibitors and anti sclerostin antibodies hold, due to their disease modifying effects, promise of a pain relieving effect. NSAIDs and opioids are widely employed in the treatment of bone pain. However, recent preclinical findings demonstrating a unique neuronal innervation of bone tissue and sprouting of sensory nerve fibers open for new treatment possibilities. PMID- 26940054 TI - Influence of lower limbs discrepancy and pelvic coronal rotation on pelvic incidence, pelvic tilt and sacral slope. AB - PURPOSE: Pelvic incidence (PI), pelvic tilt (PT) and sacral slope (SS) are important parameters in sagittal spine alignment evaluation. The measurements are a projection of the three-dimensional pelvis onto a two-dimensional radiograph and they may be influenced by orientation of the pelvis. The aim of this study was to assess the influence of pelvic rotation in the coronal plane (CPR) on radiographic accuracy of PI, PT, and SS measurements. METHODS: Radiological evaluation of the CPR angel was performed on 1 radiological phantom. The radiographs were taken in 5 degrees CPR increments over a range of 0 degrees -45 degrees (evaluated with a digital protractor). On each of the lateral radiograph, PI, PT, and SS were measured three times by three independent researchers. The lowest CPR that changed PI, PT, or SS by >=6 degrees (the highest reported error of measurement of these parameters) was considered as unacceptable. Next, CPR was calculated based on the distance between femoral heads (FHD). The agreement of the calculated and measured CPR was quantified by the intraclass correlation coefficient (ICC) and the median error for a single measurement (SEM), with value 0.75 considered as excellent agreement. RESULTS: PI, PT and SS could be measured with an acceptable error of 6 degrees on radiographs with up to 20 degrees pelvic rotation. From 20 degrees CPR onwards the S1 endplate was distorted, that makes the measurements of PI, PT and SS questionable. There was an excellent agreement between CPR measured with a protractor and calculated based on FHD with ICC of 0.99 and SEM of 1.1 degrees . CONCLUSIONS: Rotation of the pelvis in the coronal plane during acquisition of radiographs influences PI, PT and SS measurements. Substantial error of PI, PT and SS measurements occurs with CPR of more than 20 degrees which is equivalent to a lower limb discrepancy of 5.2 cm. CPR may be calculated while acquiring the radiograph. Further evaluation of the influence of CPR on spinopelvic parameters with a larger sample would be valuable. PMID- 26940055 TI - Management of an unusual sciatica. AB - PURPOSE: Extraforaminal entrapment of the L5 nerve root is uncommon, and its management can sometimes be very challenging. METHODS: We present the case of a 57-year-old female, complaining of a sciatica in her left leg, for 3 years, with no response to any kind of conservative treatment. MRI and CT scan revealed the presence of a large L5S1 strictly lateral osteophyte compressing the left L5 root in its extraforaminal path. RESULTS: The patient underwent a left anterior retroperitoneal approach with assistance from a vascular surgeon given the very close relation between the osteophyte and the left common iliac vein, lying just on top of it, osteophyte was removed in one piece with the use of an osteotome after retraction of the vessels. The patient progressively recovered from her left sciatic pain with a satisfactory clinical result at 1 year. CONCLUSION: Literature is sparse on the treatment of extraforaminal entrapment of the L5 nerve root; the current case shows a successful treatment strategy with the use of an anterior approach for direct vision of the lesion and good control of the vessels. PMID- 26940056 TI - Emotional distress drives health services overuse in patients with acute low back pain: a longitudinal observational study. AB - PURPOSE: To determine whether emotional distress reported at the initial consultation affects subsequent healthcare use either directly or indirectly via moderating the influence of symptoms. METHODS: Longitudinal observational study of 2891 participants consulting primary care for low back pain. Negative binomial regression models were constructed to estimate independent effects of emotional distress on healthcare use. Potential confounders were identified using directed acyclic graphs. RESULTS: After the initial consultation, participants had a mean (SD) of one (1.2) visit for back pain over 3 months, and nine (14) visits for back pain over 12 months. Higher reports of anxiety during the initial consultation led to increased short-term healthcare use (IRR 1.06, 95 % CI 1.01 1.11) and higher reports of depression led to increased long-term healthcare use (IRR 1.04, 95 % CI 1.02-1.07). The effect sizes suggest that a patient with a high anxiety score (8/10) would consult 50 % more frequently over 3 months, and a person with a high depression score (8/10) would consult 30 % more frequently over 12 months, compared to a patient with equivalent pain and disability and no reported anxiety or depression. CONCLUSIONS: Emotional distress in the acute stage of low back pain increased subsequent consultation rates. Interventions that target emotional distress during the initial consultation are likely to reduce costly and potentially inappropriate future healthcare use for patients with non-specific low back pain. PMID- 26940057 TI - Stereoradiography imaging motion artifact: does it affect radiographic measures after spinal instrumentation? AB - PURPOSE: Stereoradiography imaging (SRI) is an accurate and reliable low-dose radiographic method. However, patients must remain motionless during image acquisition. Motion artifacts are frequently noted. The aims of the study were to determine the incidence of the SRI motion artifact and assess if motion during SRI acquisition affects radiographic measurements. METHODS: In this retrospective study, 198 patients with spinal instrumentation had biplanar SRI radiographs performed, of whom 39 had concomitant conventional radiographs. Eight coronal and sagittal spinal parameters were independently measured on SRI and conventional radiographs for the 39 patients by 2 observers. Inclusion criteria were: presence of spinal instrumentation of more than six levels and an SRI motion artifact identified on the coronal and/or the sagittal views on either the spinal rods or on the limbs. Means were compared between both types of radiographs using the Student's t test; intraclass correlation coefficients (ICCs) were used for intraobserver reproducibility and interrater reliability. RESULTS: A motion artifact was identified in 19.7 % (n = 39, mean age 19.5 +/- 1.7 years) of the cases. There were no differences in any of the coronal or sagittal plane measurements between SRI and X-rays. Intraobserver reliability and interrater reproducibility was high (range 0.81-0.98). CONCLUSIONS: Motion artifact during full-spine stereoradiography imaging acquisition is frequent, but does not affect spinal measurements. SRI with a motion artifact can be used to produce reliable measurements of the sagittal and coronal parameters. Some SRI images with a motion artifact may suggest loss of fixation or bending of the rods. However, after becoming familiar with the appearance of the motion artifact, repeat radiographs are rarely indicated. IRB NUMBER: 14-004872. LEVEL OF EVIDENCE: Level IV. PMID- 26940058 TI - Alpha-Synuclein as a Biomarker for Parkinson's Disease. AB - Parkinson's disease (PD) is a common neurodegenerative disorder, characterized pathologically by the presence of alpha-synuclein (alpha-syn)-rich Lewy bodies. As clinical diagnosis of PD is challenging, misdiagnosis is common, highlighting the need for disease-specific and early stage biomarkers. Both early diagnosis of PD and adequate tracking of disease progression could significantly improve outcomes for patients, particularly in regard to existing and future disease modifying treatments. Given its critical roles in PD pathogenesis, alpha-syn may be useful as a biomarker of PD. The aim of this review is, therefore, to summarize the efficacy of tissue and body fluid alpha-syn measurements in the detection of PD as well as monitoring disease progression. In comparison to solid tissue specimens and biopsies, biofluid alpha-syn levels may be the most promising candidates in PD diagnosis and progression based on specificity, sensitivity and availability. Although alpha-syn has been tested most extensively in cerebrospinal fluid (CSF), the relatively invasive procedure for collecting CSF is not suitable in most clinical settings, leading to investigation of plasma, blood and saliva as alternatives. The exploration of combined biomarkers, along with alpha-syn, to improve diagnostic accuracy is also likely required. PMID- 26940059 TI - Brachytherapy in Gynecologic Cancers: Why Is It Underused? AB - Despite its established efficacy, brachytherapy is underused in the management of cervical and vaginal cancers in some parts of the world. Possible reasons for the underutilization of brachytherapy include the adoption of less invasive techniques, such as intensity-modulated radiotherapy; reimbursement policies favoring these techniques over brachytherapy; poor physician or patient access to brachytherapy; inadequate maintenance of brachytherapy skills among practicing radiation oncologists; transitioning to high-dose-rate (HDR) brachytherapy with increased time requirements; and insufficient training of radiation oncology residents. PMID- 26940060 TI - Review of the fossil matamata turtles: earliest well-dated record and hypotheses on the origin of their present geographical distribution. AB - The matamata (Chelus fimbriatus) is a highly aquatic chelid turtle known exclusively from northern South America. Due to its extremely modified morphology, it is well circumscribed among living taxa, but that is not the case of the two extinct species ascribed to the taxon, Chelus colombianus and Chelus lewisi. These were originally described for the Miocene of Colombia and Venezuela, respectively, and are known mostly from post-cranial material. Few traits have been considered diagnostic for these fossil taxa, and their shared geographic and temporal distributions raise doubts about their distinctiveness. Here, we describe new turtle remains from the early Miocene Castillo Formation, at Cerro la Cruz, northwestern Venezuela, assigning them to C. colombianus. We also review the taxonomy and diagnostic features of the fossil species of Chelus, comparing them with the variation recognized within C. fimbriatus. All alleged differences between the fossil Chelus species were found in our sample of the extant species, and may represent intraspecific variation of a single fossil species. Further, we reviewed the fossil record of Chelus spp. and proposed a paleobiogeographic hypothesis to explain its present geographic range. PMID- 26940063 TI - Gerald M. Kidder - bridging the gap in cell and developmental biology. PMID- 26940064 TI - Feedback regulation of biological networks: Examples relevant to signalling pathways and resistance to pharmacological interceptors. PMID- 26940061 TI - Reproductive responses of male Brandt's voles (Lasiopodomys brandtii) to 6 methoxybenzoxazolinone (6-MBOA) under short photoperiod. AB - The plant secondary metabolite 6-methoxybenzoxazolinone (6-MBOA) can stimulate and enhance animal reproduction. This compound has been successfully detected in Leymus chinensis, which is the main diet of Brandt's voles. The aim of this study was to investigate the effect of different 6-MBOA doses on the reproductive physiology of male Brandt's voles under a short photoperiod. The results showed that 6-MBOA administration increased relative testis weight, regardless of the dose, but it had little effect on the body mass. Low and middle doses of 6-MBOA increased the concentrations of luteinizing hormone and testosterone in the serum and the mRNA levels of StAR and CYP11a1 in the testes. However, 6-MBOA did not cause any significant increase in the mRNA levels of KiSS-1, GPR54, and GnRH compared to those in the control group. The mRNA level of KiSS-1 in the arcuate nucleus (ARC) was higher than that in the anteroventral periventricular nucleus (AVPV). Collectively, our results demonstrated that the number of KiSS-1 expressing neurons located in the ARC was the highest, and that 6-MBOA, which might modulate the reproductive activity along the hypothalamic-pituitary-gonadal axis, had a dose-dependent stimulatory effect on the reproductive activity of Brandt's voles under a short photoperiod. Our study provided insights into the mechanism of 6-MBOA action and the factors influencing the onset of reproduction in Brandt's voles. PMID- 26940066 TI - Epidemiologic characteristics of oral cancer: single-center analysis of 4097 patients from the Sun Yat-sen University Cancer Center. AB - BACKGROUND: Oral cancer is a common type of head and neck cancers. Knowing its epidemiologic characteristics is crucial to preventing, diagnosing, and treating this cancer. This study aimed to explore the epidemiologic characteristics of oral cancer in South China. METHODS: We retrospectively analyzed data from 4097 oral cancer patients treated at the Sun Yat-sen University Cancer Center between 1960 and 2013. We compared the age of onset, sex ratio, pathologic type, and primary tumor location among three subcultural areas (Guangfu, Hakka, and Chaoshan) and between an economically developed region and a less-developed one in Guangdong. RESULTS: Overall, oral cancer had a male-to-female ratio of approximately 2:1, and this ratio decreased over time. Oral cancer occurred mostly in patients of 45-64 years old (54.5%), and the percentage of older patients gradually increased over time. The most common tumor location was the tongue. Squamous cell carcinoma was the predominant pathologic type. The percentage of blood type O in oral cancer patients was lower than that in the healthy population. The male-to-female ratio in the Chaoshan area was higher than that in the Guangfu and Hakka areas, whereas the age of disease onset in Guangfu was higher than that in Hakka and Chaoshan. The male-to-female ratio was lower and the age of disease onset was higher in the economically developed region than in the less-developed region. CONCLUSION: The incidence of oral cancer in South China presents typical characteristics to which doctors should pay attention when diagnosing and treating oral cancer patients. PMID- 26940067 TI - Nailfold videocapillaroscopy in healthy children and adolescents: description of normal patterns. AB - OBJECTIVES: to describe normal patterns of nailfold videocapillaroscopy (NVC) in healthy children and adolescents; to quantify the relationship between age and capillary dimensions, intercapillary distance and number of capillaries/mm; to evaluate the inter and intraobserver concordance. METHODS: Cross-sectional study including 100 healthy participants aged 5 to 18 years. Capillary dimensions (capillary loop length, capillary width and intercapillary distance) and number of capillaries/mm were evaluated in 900 capillaries using stereomicroscope under 100x magnification. Intra and inter observer agreements were tested. RESULTS: The capillary dimensions (mean +/- SD) were: capillary loop length 278.6+/-60.3 MUm, intercapillary distance 124.1+/-28.1 MUm, capillary width 15.0+/-2.6 MUm. Teenagers between 15 and 18 years had longer and more enlarged capillaries than the other age groups (p<0.001 and p=0.012 respectively). We also found a significant increase in the number of capillaries/mm with age (p<0.001). There was a positive correlation between age and number of capillaries/mm, capillary length, and capillary width (p<0.001, R=0.796; p<0.001, R=0.368; p=0.004, R=0.285, respectively). There was a good intra and interobserver concordance. Enlarged capillary and avascular areas were present in 11% and 10% of capillaries respectively. A weak negative correlation was found between the intercapillary distance and the number of capillaries/mm (p=0.05; R=-0.20). CONCLUSIONS: There is a wide variability in the capillary morphology among healthy individuals. There was a positive correlation between age and number of capillaries/mm, capillary length, and capillary width. In addition, NVC has been shown to be a reproducible method. PMID- 26940065 TI - Genetic dissection of maize plant architecture with an ultra-high density bin map based on recombinant inbred lines. AB - BACKGROUND: Plant architecture attributes, such as plant height, ear height, and internode number, have played an important role in the historical increases in grain yield, lodging resistance, and biomass in maize (Zea mays L.). Analyzing the genetic basis of variation in plant architecture using high density QTL mapping will be of benefit for the breeding of maize for many traits. However, the low density of molecular markers in existing genetic maps has limited the efficiency and accuracy of QTL mapping. Genotyping by sequencing (GBS) is an improved strategy for addressing a complex genome via next-generation sequencing technology. GBS has been a powerful tool for SNP discovery and high-density genetic map construction. The creation of ultra-high density genetic maps using large populations of advanced recombinant inbred lines (RILs) is an efficient way to identify QTL for complex agronomic traits. RESULTS: A set of 314 RILs derived from inbreds Ye478 and Qi319 were generated and subjected to GBS. A total of 137,699,000 reads with an average of 357,376 reads per individual RIL were generated, which is equivalent to approximately 0.07-fold coverage of the maize B73 RefGen_V3 genome for each individual RIL. A high-density genetic map was constructed using 4183 bin markers (100-Kb intervals with no recombination events). The total genetic distance covered by the linkage map was 1545.65 cM and the average distance between adjacent markers was 0.37 cM with a physical distance of about 0.51 Mb. Our results demonstrated a relatively high degree of collinearity between the genetic map and the B73 reference genome. The quality and accuracy of the bin map for QTL detection was verified by the mapping of a known gene, pericarp color 1 (P1), which controls the color of the cob, with a high LOD value of 80.78 on chromosome 1. Using this high-density bin map, 35 QTL affecting plant architecture, including 14 for plant height, 14 for ear height, and seven for internode number were detected across three environments. Interestingly, pQTL10, which influences all three of these traits, was stably detected in three environments on chromosome 10 within an interval of 14.6 Mb. Two MYB transcription factor genes, GRMZM2G325907 and GRMZM2G108892, which might regulate plant cell wall metabolism are the candidate genes for qPH10. CONCLUSIONS: Here, an ultra-high density accurate linkage map for a set of maize RILs was constructed using a GBS strategy. This map will facilitate identification of genes and exploration of QTL for plant architecture in maize. It will also be helpful for further research into the mechanisms that control plant architecture while also providing a basis for marker-assisted selection. PMID- 26940068 TI - Adaptive major histocompatibility complex (MHC) and neutral genetic variation in two native Baltic Sea fishes (perch Perca fluviatilis and zander Sander lucioperca) with comparisons to an introduced and disease susceptible population in Australia (P. fluviatilis): assessing the risk of disease epidemics. AB - This study assessed the major histocompatibility complex (MHC) and neutral genetic variation and structure in two percid species, perch Perca fluviatilis and zander Sander lucioperca, in a unique brackish ecosystem, the Baltic Sea. In addition, to assess the importance of MHC diversity to disease susceptibility in these populations, comparisons were made to an introduced, disease susceptible, P. fluviatilis population in Australia. Eighty-three MHC class II B exon 2 variants were amplified: 71 variants from 92 P. fluviatilis samples, and 12 variants from 82 S. lucioperca samples. Microsatellite and MHC data revealed strong spatial genetic structure in S. lucioperca, but not P. fluviatilis, across the Baltic Sea. Both microsatellite and MHC data showed higher levels of genetic diversity in P. fluviatilis from the Baltic Sea compared to Australia, which may have facilitated the spread of an endemic virus, EHNV in the Australian population. The relatively high levels of genetic variation in the Baltic Sea populations, together with spatial genetic structure, however, suggest that there currently seems to be little risk of disease epidemics in this system. To ensure this remains the case in the face of ongoing environmental changes, fisheries and habitat disturbance, the conservation of local-scale genetic variation is recommended. PMID- 26940069 TI - Probing the origin of excitonic states in monolayer WSe2. AB - Two-dimensional transition metal dichalcogenides (TMDCs) have spurred excitement for potential applications in optoelectronic and valleytronic devices; however, the origin of the dynamics of excitons, trions, and other localized states in these low dimensional materials is not well-understood. Here, we experimentally probed the dynamics of excitonic states in monolayer WSe2 by investigating the temperature and polarization dependent photoluminescence (PL) spectra. Four pronounced PL peaks were identified below a temperature of 60 K at near-resonant excitation and assigned to exciton, trion and localized states from excitation power dependence measurements. We find that the localized states vanish above 65 K, while exciton and trion emission peaks remain up to room temperature. This can be explained by a multi-level model developed for conventional semiconductors and applied to monolayer TMDCs for the first time here. From this model, we estimated a lower bound of the exciton binding energy of 198 meV for monolayer WSe2 and explained the vanishing of the localized states. Additionally, we observed a rapid decrease in the degree of circular polarization of the PL at increasing temperatures indicating a relatively strong electron-phonon coupling and impurity related scattering. Our results reveal further insight into the excitonic states in monolayer WSe2 which is critical for future practical applications. PMID- 26940070 TI - Helicobacter pylori upregulates Nanog and Oct4 via Wnt/beta-catenin signaling pathway to promote cancer stem cell-like properties in human gastric cancer. AB - Helicobacter pylori (H. pylori) infection is considered a major risk factor for gastric cancer. CagA behaves as a major bacterial oncoprotein playing a key role in H. pylori-induced tumorigenesis. Cancer stem cells (CSCs) are believed to possess the ability to initiate tumorigenesis and promote progression. Although studies have suggested that cancer cells can exhibit CSC-like properties in the tumor microenvironment, it remains unclear whether H. pylori infection could induce the emergence of CSC-like properties in gastric cancer cells and, the underlying mechanism. Here, gastric cancer cells were co-cultured with a CagA positive H. pylori strain or a CagA isogenic mutant strain. We found that H. pylori-infected gastric cancer cells exhibited CSC-like properties, including an increased expression of CSC specific surface markers CD44 and Lgr5, as well as that of Nanog, Oct4 and c-myc, which are known pluripotency genes, and an increased capacity for self-renewal, whereas these properties were not observed in the CagA isogenic mutant strain-infected cells. Further studies revealed that H. pylori activated Wnt/beta-catenin signaling pathway in a CagA-dependent manner and that the activation of this pathway was dependent upon CagA-positive H. pylori-mediated phosphorylation of beta-catenin at the C-terminal Ser675 and Ser552 residues in a c-met- and/or Akt-dependent manner. We further demonstrated that this activation was responsible for H. pylori-induced CSC-like properties. Moreover, we found the promoter activity of Nanog and Oct4 were upregulated, and beta-catenin was observed to bind to these promoters during H. pylori infection, while a Wnt/beta-catenin inhibitor suppressed promoter activity and binding. Taken together, these results suggest that H. pylori upregulates Nanog and Oct4 via Wnt/beta-catenin signaling pathway to promote CSC-like properties in gastric cancer cells. PMID- 26940071 TI - Developing the "Skippu-Mama" program for mothers of children with autism spectrum disorder. AB - The "Skippu-Mama" peer support program was developed to improve quality of life and reduce parental stress in mothers of children with autism spectrum disorders. The program was designed to improve these variables by refreshing and healing participants' minds and bodies. Twenty-four mothers of 26 children diagnosed with ASD in Japan were included in the study and completed measures of quality of life and parental stress before, during, and after participation in the Skippu-Mama program. Our results demonstrated that time was a significant main effect. Further, multiple comparisons with Bonferroni corrections indicated a significant increase in World Health Organization Quality of Life 26 scores three months into the program and at its conclusion six months after commencement. Overall, the Skippu-Mama program improved the quality of life of mothers of children with ASD, and we believe that the intervention's focus on both individual and family variables may be especially effective in this population. PMID- 26940072 TI - Association of Genetic Polymorphisms in the VKORC1 and CYP2C9 Genes with Warfarin Dosage in a Group of Kuwaiti Individuals. AB - BACKGROUND AND OBJECTIVE: Warfarin is the most widely prescribed oral anticoagulant worldwide. The narrow therapeutic index and the large variation in the inter-individual dose of warfarin are problematic, since the side effects can be lethal. Single nucleotide polymorphisms (SNP) in CYP2C9 and VKORC1 have been shown to significantly affect warfarin dosage toleration and this effect varies among different populations. We aimed to investigate the effect of these SNPs on warfarin dosage in a sample of Kuwaiti patients. METHODS: Kuwaiti patients who were taking a maintenance dose of warfarin were genotyped for CYP2C9*1, *2 and *3 and VKORC1 rs9923231, rs9934438, rs7294 and rs2884737. The association of these SNPs with the warfarin dose was evaluated. RESULTS: For CYP2C9, the CYP2C9 *1/*1 genotype required a higher dose (5.5 +/- 3.3 mg/day) compared to non-*1/*1 (3.3 +/- 1.7 mg/day) (p = 0.003). For VKORC1, the daily warfarin dose was significantly different (p = 0.001) among the three genotypes of rs9923231, rs9934438 and rs2884737, with carriers of the wild-type genotype requiring the highest dose compared to variant allele carriers (p <= 0.001-0.002). There was no association found between the daily warfarin dose and the rs7294 polymorphism. CONCLUSIONS: Our data showed that individuals carrying the wild-type allele of CYP2C9 or VKORC1 rs9923231, rs9934438 or rs2884737 are less sensitive than individuals with the variant alleles of these SNPs and therefore required a higher daily maintenance dose of warfarin. Our study confirms the association between SNPs in CYP2C9 and VKORC1 and warfarin dose tolerance in Kuwaiti patients. PMID- 26940074 TI - 'If You Are Not a Liberal When You Are Young, You Have No Heart, and If You Are Not a Conservative When Old, You Have No Brain'. PMID- 26940073 TI - Epithelial to Mesenchymal Transition in Renal Cell Carcinoma: Implications for Cancer Therapy. AB - Epithelial-to-mesenchymal transition (EMT) is a developmentally vital reversible process by which fully differentiated cells lose their epithelial features and acquire a migratory mesenchymal phenotype. EMT contributes to the metastatic potential of tumors. The expression profile and other biological properties of EMT suggest potential targets for cancer therapy, including in renal-cell carcinoma (RCC). The preclinical and clinical results have substantiated the promises that dysregulated elements leading to EMT can be a potential target in RCC patients. In this study, we illustrated the pathogenic and prognostic role of EMT in RCC. In addition, we reconstructed, by literature analysis, the different pathways implicated in the EMT process, thus supporting the rational for future EMT-directed therapeutic approaches for RCC patients. PMID- 26940075 TI - Health challenges of war and peace. PMID- 26940076 TI - Effect of corona discharge plasma jet on surface-borne microorganisms and sprouting of broccoli seeds. AB - BACKGROUND: Different pathogenic microorganisms have been reported to cause sprouts-associated outbreaks. In order to sterilise and enhance the germination of seeds, non-thermal plasma has been increasingly investigated in the field of agricultural science as an alternative to the traditional pre-sowing seed treatments. This work aimed to evaluate the effect of corona discharge plasma jet (CDPJ) on disinfection of the natural bio-contaminants of broccoli seed and also studied the plasma effect on sprout seed germination rate and physico-chemical properties of sprouts. RESULTS: Aerobic bacteria, moulds and yeasts, B. cereus, E. coli, Salmonella spp. were detected on the broccoli seed surface. After 0-3 min treatment using CDPJ, the detected microorganisms were reduced in the range of 1.2-2.3 log units. Inactivation patterns were better explained using pseudo first-order kinetics. The plasma treatment of seeds up to 2 min exhibited a positive effect on germination rate, seedling growth. The physico-chemical and sensory characteristics of sprouts were unaffected due to the CDPJ treatment of their respective seeds. CONCLUSION: Corona discharge plasma jet can potentially be used for microbial decontamination of broccoli seeds. In addition, the plasma treatment of broccoli sprout seeds has enabled a significant enhancement in their germination rate and seedling growth without compromising physico-chemical and sensory characteristics of their corresponding sprouts. (c) 2016 Society of Chemical Industry. PMID- 26940077 TI - Photodynamic killing of cancer cells by a Platinum(II) complex with cyclometallating ligand. AB - Photodynamic therapy that uses photosensitizers which only become toxic upon light-irradiation provides a strong alternative to conventional cancer treatment due to its ability to selectively target tumour material without affecting healthy tissue. Transition metal complexes are highly promising PDT agents due to intense visible light absorption, yet the majority are toxic even without light. This study introduces a small, photostable, charge-neutral platinum-based compound, Pt(II) 2,6-dipyrido-4-methyl-benzenechloride, complex 1, as a photosensitizer, which works under visible light. Activation of the new photosensitizer at low concentrations (0.1-1 MUM) by comparatively low dose of 405 nm light (3.6 J cm(-2)) causes significant cell death of cervical, colorectal and bladder cancer cell lines, and, importantly, a cisplatin resistant cell line EJ-R. The photo-index of the complex is 8. We demonstrate that complex 1 induces irreversible DNA single strand breaks following irradiation, and that oxygen is essential for the photoinduced action. Neither light, nor compound alone led to cell death. The key advantages of the new drug include a remarkably fast accumulation time (diffusion-controlled, minutes), and photostability. This study demonstrates a highly promising new agent for photodynamic therapy, and attracts attention to photostable metal complexes as viable alternatives to conventional chemotherapeutics, such as cisplatin. PMID- 26940078 TI - A mix-and-read drop-based in vitro two-hybrid method for screening high-affinity peptide binders. AB - Drop-based microfluidics have recently become a novel tool by providing a stable linkage between phenotype and genotype for high throughput screening. However, use of drop-based microfluidics for screening high-affinity peptide binders has not been demonstrated due to the lack of a sensitive functional assay that can detect single DNA molecules in drops. To address this sensitivity issue, we introduced in vitro two-hybrid system (IVT2H) into microfluidic drops and developed a streamlined mix-and-read drop-IVT2H method to screen a random DNA library. Drop-IVT2H was based on the correlation between the binding affinity of two interacting protein domains and transcriptional activation of a fluorescent reporter. A DNA library encoding potential peptide binders was encapsulated with IVT2H such that single DNA molecules were distributed in individual drops. We validated drop-IVT2H by screening a three-random-residue library derived from a high-affinity MDM2 inhibitor PMI. The current drop-IVT2H platform is ideally suited for affinity screening of small-to-medium-sized libraries (10(3)-10(6)). It can obtain hits within a single day while consuming minimal amounts of reagents. Drop-IVT2H simplifies and accelerates the drop-based microfluidics workflow for screening random DNA libraries, and represents a novel alternative method for protein engineering and in vitro directed protein evolution. PMID- 26940079 TI - Temporal and geographical clustering of Kawasaki disease in Japan: 2007-2012. AB - BACKGROUND: Since 1987, no study has reported the municipal-level geographical clustering of Kawasaki disease (KD) in Japan. Therefore, the aim of the present study was to identify the temporal and municipal-level geographical clustering of KD. METHODS: The annual incidence rates of KD for each municipality were calculated using nationwide data from 73 758 patients with KD (2007-2012). To determine whether temporal and municipal-level clustering existed, we calculated the correlations of the annual incidence rates for each municipality during the study years, and compared these rates with those of the adjacent municipalities. Spatial scanning analysis was used to identify the geographical clusters for each year, and the incidence rates in those clusters were compared with the rates in the surrounding region. RESULTS: The annual national incidence rate of KD, adjusted for the prefecture-specific response rate, was 322.45 patients per 100 000 children aged 0-4 years. The correlation between the annual incidence rates during 2 consecutive years was significantly positive (coefficients, 0.149 0.428). On spatial scanning analysis, the most likely clusters were in the Tokyo metropolitan area during 2007-2010 and 2012, and in Kumamoto prefecture during 2011. CONCLUSION: Kawasaki disease exhibits temporal and municipal-level clustering. PMID- 26940080 TI - Usability of dexmedetomidine for deep sedation in infants and small children with respiratory morbidities. AB - BACKGROUND: Children with respiratory morbidities are at increased risk of developing adverse respiratory events while undergoing deep sedation. Dexmedetomidine possesses sedative properties with minimal respiratory depression. This report aimed to determine the usability of dexmedetomidine in children with significant respiratory morbidities who require deep sedation. METHODS: Medical records of children with ASA classification III who had at least three characteristics of respiratory morbidities and who received dexmedetomidine sedation for magnetic resonance imaging (MRI) between January 2014 and May 2015 were retrospectively reviewed. Dexmedetomidine was administered as a bolus of 1 MUg/kg over 10 min followed by 1 MUg/kg/h infusion. If necessary, an additional bolus dose was given and the infusion rate was increased to 2 MUg/kg/h. Respiratory morbidities, haemodynamic parameters, total dexmedetomidine dose, adverse cardiorespiratory events and sedation characteristics were analysed. RESULTS: Nineteen out of 642 children who underwent MRI were eligible for evaluation. Seventeen children (89%) had at least four characteristics of respiratory morbidities. The median [IQR] age was 9 months [3.5-14]. All patients completed MRI scans while breathing spontaneously via the native airway. No episodes of adverse respiratory events or haemodynamic instability were observed. Children who were administered a lower dexmedetomidine dose and had a shorter sedation time were more likely to be younger than 1 year of age. CONCLUSION: These data demonstrate that dexmedetomidine deep sedation was well-tolerated in children with significant respiratory morbidities. Moreover, children younger than 1 year of age were administered lower dexmedetomidine dose than children older than 1 year of age for the same sedation level. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02555605. PMID- 26940081 TI - Carbetocin versus oxytocin to reduce additional uterotonic use at non-elective caesarean section: a double-blind, randomised trial (.). AB - OBJECTIVE: We compared the efficacy of Carbetocin (long-acting oxytocin receptor agonist) versus Oxytocin given at non-elective caesarean section. METHOD: We performed a double-blind, randomised, single-centre study. Eligible women were >=37 weeks of gestation undergoing emergency caesarean section. Participants received either carbetocin of 100 MUg or oxytocin 5 international units. The primary outcome was the need to administer additional uterotonics, as determined by the clinician. Secondary outcomes included estimated blood loss, haemoglobin drop pre-post operation and the need for a blood transfusion Results: From August 2012 to February 2013, 114 women were enroled. Two were excluded from analysis as they received a general anaesthetic. Fifty-nine patients received 100-MUg carbetocin; 53 received 5 international units oxytocin. There was no statistically significant difference in the number of women requiring additional uterotonics between the two groups: Carbetocin group 22% and Oxytocin group 13% (p = 0.323). There were no significant differences in the fall in haemoglobin, estimated blood loss, rates of post-partum haemorrhage or blood transfusions. CONCLUSION: Oxytocin and carbetocin have similar requirements for additional uterotonics, estimated blood loss, haemoglobin drop and blood transfusions. There was a trend towards requiring additional uterotonics in patients receiving Carbetocin which was not statistically significant. This study found no benefits in using carbetocin over oxytocin. PMID- 26940082 TI - High-order random Raman lasing in a PM fiber with ultimate efficiency and narrow bandwidth. AB - Random Raman lasers attract now a great deal of attention as they operate in non active turbid or transparent scattering media. In the last case, single mode fibers with feedback via Rayleigh backscattering generate a high-quality unidirectional laser beam. However, such fiber lasers have rather poor spectral and polarization properties, worsening with increasing power and Stokes order. Here we demonstrate a linearly-polarized cascaded random Raman lasing in a polarization-maintaining fiber. The quantum efficiency of converting the pump (1.05 MUm) into the output radiation is almost independent of the Stokes order, amounting to 79%, 83%, and 77% for the 1(st) (1.11 MUm), 2(nd) (1.17 MUm) and 3(rd) (1.23 MUm) order, respectively, at the polarization extinction ratio >22 dB for all orders. The laser bandwidth grows with increasing order, but it is almost independent of power in the 1-10 W range, amounting to ~1, ~2 and ~3 nm for orders 1-3, respectively. So, the random Raman laser exhibits no degradation of output characteristics with increasing Stokes order. A theory adequately describing the unique laser features has been developed. Thus, a full picture of the cascaded random Raman lasing in fibers is shown. PMID- 26940084 TI - Learning to swim, again: Axon regeneration in fish. AB - Damage to the central nervous system (CNS) of fish can often be repaired to restore function, but in mammals recovery from CNS injuries usually fails due to a lack of axon regeneration. The relatively growth-permissive environment of the fish CNS may reflect both the absence of axon inhibitors found in the mammalian CNS and the presence of pro-regenerative environmental factors. Despite their different capacities for axon regeneration, many of the physiological processes, intrinsic molecular pathways, and cellular behaviors that control an axon's ability to regrow are conserved between fish and mammals. Fish models have thus been useful both for identifying factors differing between mammals and fish that may account for differences in CNS regeneration and for characterizing conserved intrinsic pathways that regulate axon regeneration in all vertebrates. The majority of adult axon regeneration studies have focused on the optic nerve or spinal axons of the teleosts goldfish and zebrafish, which have been productive models for identifying genes associated with axon regeneration, cellular mechanisms of circuit reestablishment, and the basis of functional recovery. Lampreys, which are jawless fish lacking myelin, have provided an opportunity to study regeneration of well defined spinal cord circuits. Newer larval zebrafish models offer numerous genetic tools and the ability to monitor the dynamic behaviors of extrinsic cell types regulating axon regeneration in live animals. Recent advances in imaging and gene editing methods are making fish models yet more powerful for investigating the cellular and molecular underpinnings of axon regeneration. PMID- 26940083 TI - Comparison of trophic factors' expression between paralyzed and recovering muscles after facial nerve injury. A quantitative analysis in time course. AB - After peripheral nerve injury, recovery of motor performance negatively correlates with the poly-innervation of neuromuscular junctions (NMJ) due to excessive sprouting of the terminal Schwann cells. Denervated muscles produce short-range diffusible sprouting stimuli, of which some are neurotrophic factors. Based on recent data that vibrissal whisking is restored perfectly during facial nerve regeneration in blind rats from the Sprague Dawley (SD)/RCS strain, we compared the expression of brain derived neurotrophic factor (BDNF), fibroblast growth factor-2 (FGF2), insulin growth factors 1 and 2 (IGF1, IGF2) and nerve growth factor (NGF) between SD/RCS and SD-rats with normal vision but poor recovery of whisking function after facial nerve injury. To establish which trophic factors might be responsible for proper NMJ-reinnervation, the transected facial nerve was surgically repaired (facial-facial anastomosis, FFA) for subsequent analysis of mRNA and proteins expressed in the levator labii superioris muscle. A complicated time course of expression included (1) a late rise in BDNF protein that followed earlier elevated gene expression, (2) an early increase in FGF2 and IGF2 protein after 2 days with sustained gene expression, (3) reduced IGF1 protein at 28 days coincident with decline of raised mRNA levels to baseline, and (4) reduced NGF protein between 2 and 14 days with maintained gene expression found in blind rats but not the rats with normal vision. These findings suggest that recovery of motor function after peripheral nerve injury is due, at least in part, to a complex regulation of lesion-associated neurotrophic factors and cytokines in denervated muscles. The increase of FGF-2 protein and concomittant decrease of NGF (with no significant changes in BDNF or IGF levels) during the first week following FFA in SD/RCS blind rats possibly prevents the distal branching of regenerating axons resulting in reduced poly-innervation of motor endplates. PMID- 26940085 TI - Protistan diversity and activity inferred from RNA and DNA at a coastal ocean site in the eastern North Pacific. AB - Microbial eukaryotes fulfill key ecological positions in marine food webs. Molecular approaches that connect protistan diversity and biogeography to their diverse metabolisms will greatly improve our understanding of marine ecosystem function. The majority of molecular-based studies to date use 18S rRNA gene sequencing to characterize natural microbial assemblages, but this approach does not necessarily discriminate between active and non-active cells. We incorporated RNA sequencing into standard 18S rRNA gene sequence surveys with the purpose of assessing those members of the protistan community contributing to biogeochemical cycling (active organisms), using the ratio of cDNA (reverse transcribed from total RNA) to 18S rRNA gene sequences within major protistan taxonomic groups. Trophically important phytoplankton, such as diatoms and chlorophytes exhibited seasonal trends in relative activity. Additionally, both radiolaria and ciliates displayed previously unreported high relative activities below the euphotic zone. This study sheds new light on the relative metabolic activity of specific protistan groups and how microbial communities respond to changing environmental conditions. PMID- 26940086 TI - Nutrient treatments alter microbial mat colonization in two glacial meltwater streams from the McMurdo Dry Valleys, Antarctica. AB - Microbial mats are abundant in many alpine and polar aquatic ecosystems. With warmer temperatures, new hydrologic pathways are developing in these regions and increasing dissolved nutrient fluxes. In the McMurdo Dry Valleys, thermokarsting may release both nutrients and sediment, and has the potential to influence mats in glacial meltwater streams. To test the role of nutrient inputs on community structure, we created nutrient diffusing substrata (NDS) with agar enriched in N, P and N + P, with controls, and deployed them into two Dry Valley streams. We found N amendments (N and N + P) to have greater chlorophyll-a concentrations, total algal biovolume, more fine filamentous cyanobacteria and a higher proportion of live diatoms than other treatments. Furthermore, N treatments were substantially elevated in Bacteroidetes and the small diatom, Fistulifera pelliculosa. On the other hand, species richness was almost double in P and N + P treatments over others, and coccoid green algae and Proteobacteria were more abundant in both streams. Collectively, these data suggest that nutrients have the potential to stimulate growth and alter community structure in glacial meltwater stream microbial mats, and the recent erosion of permafrost and accelerated glacial melt will likely impact resident biota in polar lotic systems here and elsewhere. PMID- 26940087 TI - Photochemical alteration of dissolved organic matter and the subsequent effects on bacterial carbon cycling and diversity. AB - The impact of solar radiation on dissolved organic matter (DOM) derived from 3 different sources (seawater, eelgrass leaves and river water) and the effect on the bacterial carbon cycling and diversity were investigated. Seawater with DOM from the sources was first either kept in the dark or exposed to sunlight (4 days), after which a bacterial inoculum was added and incubated for 4 additional days. Sunlight exposure reduced the coloured DOM and carbon signals, which was followed by a production of inorganic nutrients. Bacterial carbon cycling was higher in the dark compared with the light treatment in seawater and river samples, while higher levels were found in the sunlight-exposed eelgrass experiment. Sunlight pre-exposure stimulated the bacterial growth efficiency in the seawater experiments, while no impact was found in the other experiments. We suggest that these responses are connected to differences in substrate composition and the production of free radicals. The bacterial community that developed in the dark and sunlight pre-treated samples differed in the seawater and river experiments. Our findings suggest that impact of sunlight exposure on the bacterial carbon transfer and diversity depends on the DOM source and on the sunlight-induced production of inorganic nutrients. PMID- 26940088 TI - Relationships between adverse childhood experiences and adult mental well-being: results from an English national household survey. AB - BACKGROUND: Individuals' childhood experiences can strongly influence their future health and well-being. Adverse childhood experiences (ACEs) such as abuse and dysfunctional home environments show strong cumulative relationships with physical and mental illness yet less is known about their effects on mental well being in the general population. METHODS: A nationally representative household survey of English adults (n = 3,885) measuring current mental well-being (Short Edinburgh-Warwick Mental Well-being Scale SWEMWBS) and life satisfaction and retrospective exposure to nine ACEs. RESULTS: Almost half of participants (46.4 %) had suffered at least one ACE and 8.3 % had suffered four or more. Adjusted odds ratios (AORs) for low life satisfaction and low mental well-being increased with the number of ACEs. AORs for low ratings of all individual SWEMWBS components also increased with ACE count, particularly never or rarely feeling close to others. Of individual ACEs, growing up in a household affected by mental illness and suffering sexual abuse had the most relationships with markers of mental well-being. CONCLUSIONS: Childhood adversity has a strong cumulative relationship with adult mental well-being. Comprehensive mental health strategies should incorporate interventions to prevent ACEs and moderate their impacts from the very earliest stages of life. PMID- 26940089 TI - Fine Mapping Implicates a Deletion of CFHR1 and CFHR3 in Protection from IgA Nephropathy in Han Chinese. AB - An intronic variant at the complement factor H (CFH) gene on chromosome 1q32 (rs6677604) associates with risk of IgA nephropathy (IgAN), but the association signal has not been uniformly replicated in Han Chinese populations. We investigated whether the causal sequence variant resides in the CFH gene or the neighboring complement factor H-related 1 (CFHR1) gene and CFHR3, which harbor an 84-kb combined deletion (CFHR3,1Delta) in linkage disequilibrium with rs6677604. Imputation of 1000 Genomes Project data did not suggest new causal single nucleotide variants within the CFH cluster. We next performed copy number analysis across the CFH locus in two independent Han Chinese case-control cohorts (combined n=3581). The CFHR3,1Delta and rs6677604-A alleles were rare (4.4% in patients and 7.1% in controls) and in strong linkage disequilibrium with each other (r2=0.95); of these alleles, CFHR3,1Delta associated more significantly with decreased risk of IgAN (odds ratio [OR], 0.56; 95% confidence interval [95% CI], 0.46 to 0.70; P=8.5 * 10-8 versus OR, 0.61; 95% CI, 0.50 to 0.75; P=1.6 * 10 6 for rs6677604-A). Moreover, CFHR3,1Delta explained all of the association signal at rs6677604 and remained significant after conditioning on rs6677604 genotype (P=0.01). Exploratory analyses of clinical and histopathologic parameters using the Oxford classification criteria revealed a suggestive association of CFHR3,1Delta with reduced tubulointerstitial injury (OR, 0.46; 95% CI, 0.25 to 0.79). These data indicate that dysregulated activity of the alternative complement pathway contributes to IgAN pathogenesis in both Asians and Europeans and implicate CFHR3,1Delta as the functional allele at this locus. PMID- 26940091 TI - Developmental Origins for Kidney Disease Due to Shroom3 Deficiency. AB - CKD is a significant health concern with an underlying genetic component. Multiple genome-wide association studies (GWASs) strongly associated CKD with the shroom family member 3 (SHROOM3) gene, which encodes an actin-associated protein important in epithelial morphogenesis. However, the role of SHROOM3 in kidney development and function is virtually unknown. Studies in zebrafish and rat showed that alterations in Shroom3 can result in glomerular dysfunction. Furthermore, human SHROOM3 variants can induce impaired kidney function in animal models. Here, we examined the temporal and spatial expression of Shroom3 in the mammalian kidney. We detected Shroom3 expression in the condensing mesenchyme, Bowman's capsule, and developing and mature podocytes in mice. Shroom3 null (Shroom3Gt/Gt) mice showed marked glomerular abnormalities, including cystic and collapsing/degenerating glomeruli, and marked disruptions in podocyte arrangement and morphology. These podocyte-specific abnormalities are associated with altered Rho-kinase/myosin II signaling and loss of apically distributed actin. Additionally, Shroom3 heterozygous (Shroom3Gt/+) mice showed developmental irregularities that manifested as adult-onset glomerulosclerosis and proteinuria. Taken together, our results establish the significance of Shroom3 in mammalian kidney development and progression of kidney disease. Specifically, Shroom3 maintains normal podocyte architecture in mice via modulation of the actomyosin network, which is essential for podocyte function. Furthermore, our findings strongly support the GWASs that suggest a role for SHROOM3 in human kidney disease. PMID- 26940090 TI - Blockade of Orai1 Store-Operated Calcium Entry Protects against Renal Fibrosis. AB - Evidence supports an important role of Ca2+ release-activated Ca2+ channel protein 1 (Orai1)-mediated Ca2+ entry in the development of renal fibrosis, a common pathologic feature of CKDs that lead to ESRD, but the molecular mechanisms remain unclear. We determined the role of Orai1 calcium channel in renal fibrosis induced by high-fat diet and by unilateral ureteral obstruction. Mouse kidneys with fibrosis had higher levels of Orai1 protein expression than did kidneys without fibrosis. In vivo knockdown of Orai1 with adenovirus harboring Orai1 short hairpin RNA or inhibition of Orai1 with SKF96365 dramatically prevented renal fibrosis and significantly decreased protein expression of fibronectin, alpha-smooth muscle actin, and TGF-beta1 in the kidney cortex of ApoE-/- mice on a high-fat diet and in the obstructed kidneys of mice with unilateral ureteral obstruction. Compared with kidney biopsy specimens of patients with glomerular minimal change disease, those of patients with fibrotic nephropathy had higher expression levels of Orai1. In cultured human proximal tubule epithelial cells (HK2), knockdown of Orai1 Ca2+ channel with adenovirus-Orai1-short hairpin RNA markedly inhibited TGF-beta1-induced intracellular Ca2+ influx and phosphorylation of smad2/3. Knockdown or blockade of the Orai1 Ca2+ channel in HK2 cells also prevented epithelial-to-mesenchymal transition induced by TGF beta1. In conclusion, blockade of the Orai1 Ca2+ channel prevented progression of renal fibrosis in mice, likely by suppressing smad2/3 phosphorylation and TGF beta1-induced epithelial-to-mesenchymal transition. These results render the Orai1 Ca2+ channel a potential therapeutic target against renal fibrosis. PMID- 26940092 TI - Mesencephalic Astrocyte-Derived Neurotrophic Factor as a Urine Biomarker for Endoplasmic Reticulum Stress-Related Kidney Diseases. AB - Endoplasmic reticulum (ER) stress and disrupted proteostasis contribute to the pathogenesis of a variety of glomerular and tubular diseases. Thus, it is imperative to develop noninvasive biomarkers for detecting ER stress in podocytes or tubular cells in the incipient stage of disease, when a kidney biopsy is not yet clinically indicated. Mesencephalic astrocyte-derived neurotrophic factor (MANF) localizes to the ER lumen and is secreted in response to ER stress in several cell types. Here, using mouse models of human nephrotic syndrome caused by mutant laminin beta2 protein-induced podocyte ER stress and AKI triggered by tunicamycin- or ischemia-reperfusion-induced tubular ER stress, we examined MANF as a potential urine biomarker for detecting ER stress in podocytes or renal tubular cells. ER stress upregulated MANF expression in podocytes and tubular cells. Notably, urinary MANF excretion concurrent with podocyte or tubular cell ER stress preceded clinical or histologic manifestations of the corresponding disease. Thus, MANF can potentially serve as a urine diagnostic or prognostic biomarker in ER stress-related kidney diseases to help stratify disease risk, predict disease progression, monitor treatment response, and identify subgroups of patients who can be treated with ER stress modulators in a highly targeted manner. PMID- 26940093 TI - Urine of Preterm Neonates as a Novel Source of Kidney Progenitor Cells. AB - In humans, nephrogenesis is completed prenatally, with nephrons formed until 34 weeks of gestational age. We hypothesized that urine of preterm neonates born before the completion of nephrogenesis is a noninvasive source of highly potent stem/progenitor cells. To test this hypothesis, we collected freshly voided urine at day 1 after birth from neonates born at 31-36 weeks of gestational age and characterized isolated cells using a single-cell RT-PCR strategy for gene expression analysis and flow cytometry and immunofluorescence for protein expression analysis. Neonatal stem/progenitor cells expressed markers of nephron progenitors but also, stromal progenitors, with many single cells coexpressing these markers. Furthermore, these cells presented mesenchymal stem cell features and protected cocultured tubule cells from cisplatin-induced apoptosis. Podocytes differentiated from the neonatal stem/progenitor cells showed upregulation of podocyte-specific genes and proteins, albumin endocytosis, and calcium influx via podocyte-specific transient receptor potential cation channel, subfamily C, member 6. Differentiated proximal tubule cells showed upregulation of specific genes and significantly elevated p-glycoprotein activity. We conclude that urine of preterm neonates is a novel noninvasive source of kidney progenitors that are capable of differentiation into mature kidney cells and have high potential for regenerative kidney repair. PMID- 26940094 TI - Urinary Soluble CD163 in Active Renal Vasculitis. AB - A specific biomarker that can separate active renal vasculitis from other causes of renal dysfunction is lacking, with a kidney biopsy often being required. Soluble CD163 (sCD163), shed by monocytes and macrophages, has been reported as a potential biomarker in diseases associated with excessive macrophage activation. Thus, we hypothesized that urinary sCD163 shed by crescent macrophages correlates with active glomerular inflammation. We detected sCD163 in rat urine early in the disease course of experimental vasculitis. Moreover, microdissected glomeruli from patients with small vessel vasculitis (SVV) had markedly higher levels of CD163 mRNA than did those from patients with lupus nephritis, diabetic nephropathy, or nephrotic syndrome. Both glomeruli and interstitium of patients with SVV strongly expressed CD163 protein. In 479 individuals, including patients with SVV, disease controls, and healthy controls, serum levels of sCD163 did not differ between the groups. However, in an inception cohort, including 177 patients with SVV, patients with active renal vasculitis had markedly higher urinary sCD163 levels than did patients in remission, disease controls, or healthy controls. Analyses in both internal and external validation cohorts confirmed these results. Setting a derived optimum cutoff for urinary sCD163 of 0.3 ng/mmol creatinine for detection of active renal vasculitis resulted in a sensitivity of 83%, specificity of 96%, and a positive likelihood ratio of 20.8. These data indicate that urinary sCD163 level associates very tightly with active renal vasculitis, and assessing this level may be a noninvasive method for diagnosing renal flare in the setting of a known diagnosis of SVV. PMID- 26940095 TI - Combined Effects of GSTM1 Null Allele and APOL1 Renal Risk Alleles in CKD Progression in the African American Study of Kidney Disease and Hypertension Trial. AB - Apolipoprotein L-1 (APOL1) high-risk alleles and the glutathione-S-transferase MU1 (GSTM1) null allele have been shown separately to associate with CKD progression in the African American Study of Kidney Disease and Hypertension (AASK) trial participants. Here, we determined combined effects of GSTM1 null and APOL1 high-risk alleles on clinical outcomes in 682 AASK participants who were classified into four groups by GSTM1 null or active genotype and APOL1 high- or low-risk genotype. We assessed survival differences among these groups by log rank test and Cox regression adjusted for important clinical variables for time to GFR event (change in GFR of 50% or 25-ml/min per 1.73 m2 decline), incident ESRD, death, or composite outcomes. The groups differed significantly in event free survival for incident ESRD and composite outcomes (P<=0.001 by log-rank test). Compared with the reference GSTM1 active/APOL1 low-risk group, other groups had these hazard ratios for the composite outcome of incident ESRD and change in GFR: GSTM1 active/APOL1 high-risk hazard ratio, 2.13; 95% confidence interval, 0.76 to 5.90 (P=0.15); GSTM1 null/APOL1 low-risk hazard ratio, 2.05; 95% confidence interval, 1.08 to 3.88 (P=0.03); and GSTM1 null/APOL1 high-risk hazard ratio, 3.0; 95% confidence interval, 1.51 to 5.96 (P=0.002). In conclusion, GSTM1 null and APOL1 high-risk alleles deleteriously affect CKD progression among blacks with hypertension, and subjects with both GSTM1 null and APOL1 high-risk genotypes had highest risk of adverse renal outcomes. Larger cohorts are needed to fully explore interactions of GSTM1 and APOL1 genotypes in other subgroups. PMID- 26940097 TI - MicroRNA-196a/b Mitigate Renal Fibrosis by Targeting TGF-beta Receptor 2. AB - Organ-specific microRNAs have essential roles in maintaining normal organ function. However, the microRNA profile of the kidney and the role of microRNAs in modulating renal function remain undefined. We performed an unbiased assessment of the genome-wide microRNA expression profile in 14 mouse organs using Solexa deep sequencing and found that microRNA-196a (miR-196a) and miR-196b are selectively expressed in kidney, with 74.37% of mouse total miR-196a and 73.19% of mouse total miR-196b distributed in the kidneys. We confirmed the predominant expression of miR-196a/b in mouse and human kidney, particularly in the glomeruli and tubular epithelium, by quantitative RT-PCR and in situ hybridization assays. During unilateral ureteral obstruction (UUO)-induced mouse renal fibrosis, renal miR-196a/b levels rapidly decreased. Elevation of renal miR 196a/b expression by hydrodynamic-based delivery of a miR-196a/b-expressing plasmid before or shortly after UUO significantly downregulated profibrotic proteins, including collagen 1 and alpha-smooth muscle actin, and mitigated UUO induced renal fibrosis. In contrast, depletion of renal miR-196a/b by miR-196a/b antagomirs substantially aggravated UUO-induced renal fibrosis. Mechanistic studies further identified transforming growth factor beta receptor II (TGFbetaR2) as a common target of miR-196a and miR-196b. Decreasing miR-196a/b expression in human HK2 cells strongly activated TGF-beta-Smad signaling and cell fibrosis; whereas increasing miR-196a/b levels in mouse primary cultured tubular epithelial cells inhibited TGF-beta-Smad signaling. In the UUO model, miR-196a/b silenced TGF-beta-Smad signaling, decreased the expression of collagen 1 and alpha-smooth muscle actin, and attenuated renal fibrosis. Our findings suggest that elevating renal miR-196a/b levels may be a novel therapeutic strategy for treating renal fibrosis. PMID- 26940096 TI - Polymorphisms in alpha-Defensin-Encoding DEFA1A3 Associate with Urinary Tract Infection Risk in Children with Vesicoureteral Reflux. AB - The contribution of genetic variation to urinary tract infection (UTI) risk in children with vesicoureteral reflux is largely unknown. The innate immune system, which includes antimicrobial peptides, such as the alpha-defensins, encoded by DEFA1A3, is important in preventing UTIs but has not been investigated in the vesicoureteral reflux population. We used quantitative real-time PCR to determine DEFA1A3 DNA copy numbers in 298 individuals with confirmed UTIs and vesicoureteral reflux from the Randomized Intervention for Children with Vesicoureteral Reflux (RIVUR) Study and 295 controls, and we correlated copy numbers with outcomes. Outcomes studied included reflux grade, UTIs during the study on placebo or antibiotics, bowel and bladder dysfunction, and renal scarring. Overall, 29% of patients and 16% of controls had less than or equal to five copies of DEFA1A3 (odds ratio, 2.09; 95% confidence interval, 1.40 to 3.11; P<0.001). For each additional copy of DEFA1A3, the odds of recurrent UTI in patients receiving antibiotic prophylaxis decreased by 47% when adjusting for vesicoureteral reflux grade and bowel and bladder dysfunction. In patients receiving placebo, DEFA1A3 copy number did not associate with risk of recurrent UTI. Notably, we found that DEFA1A3 is expressed in renal epithelium and not restricted to myeloid-derived cells, such as neutrophils. In conclusion, low DEFA1A3 copy number associated with recurrent UTIs in subjects in the RIVUR Study randomized to prophylactic antibiotics, providing evidence that copy number polymorphisms in an antimicrobial peptide associate with UTI risk. PMID- 26940098 TI - Proteomics of Urinary Vesicles Links Plakins and Complement to Polycystic Kidney Disease. AB - Novel therapies in autosomal dominant polycystic kidney disease (ADPKD) signal the need for markers of disease progression or response to therapy. This study aimed to identify disease-associated proteins in urinary extracellular vesicles (uEVs), which include exosomes, in patients with ADPKD. We performed quantitative proteomics on uEVs from healthy controls and patients with ADPKD using a labeled approach and then used a label-free approach with uEVs of different subjects (healthy controls versus patients with ADPKD versus patients with non-ADPKD CKD). In both experiments, 30 proteins were consistently more abundant (by two-fold or greater) in ADPKD-uEVs than in healthy- and CKD-uEVs. Of these proteins, we selected periplakin, envoplakin, villin-1, and complement C3 and C9 for confirmation because they were also significantly overrepresented in pathway analysis and were previously implicated in ADPKD pathogenesis. Immunoblotting confirmed higher abundances of the selected proteins in uEVs from three independent groups of patients with ADPKD. Whereas uEVs of young patients with ADPKD and preserved kidney function already had higher levels of complement, only uEVs of patients with advanced stages of ADPKD had increased levels of villin-1, periplakin, and envoplakin. Furthermore, all five proteins correlated positively with total kidney volume. Analysis in kidney tissue from mice with kidney specific, tamoxifen-inducible Pkd1 deletion demonstrated higher expression in more severe stages of the disease and correlation with kidney weight for each protein of interest. In summary, proteomic analysis of uEVs identified plakins and complement as disease-associated proteins in ADPKD. These proteins are new candidates for evaluation as biomarkers or targets for therapy in ADPKD. PMID- 26940099 TI - Adjusting the 17beta-Estradiol-to-Androgen Ratio Ameliorates Diabetic Nephropathy. AB - Diabetes is manifested predominantly in males in experimental models, and compelling evidence suggests that 17beta-estradiol (E2) supplementation improves hyperglycemia in humans. We previously generated a severely diabetic transgenic (Tg) mouse model by beta-cell-specific overexpression of inducible cAMP early repressor (ICER) and found that male but not female ICER-Tg mice exhibit sustained hyperglycemia and develop major clinical and pathologic features of human diabetic nephropathy (DN). Thus, we hypothesized that differences in circulating hormone levels have a key role in determining susceptibility to diabetes. Here, we examined whether DN in male ICER-Tg mice is rescued by adjusting the androgen-to-E2 ratio to approximate that in normoglycemic female ICER-Tg mice. We treated hyperglycemic male ICER-Tg mice with orchiectomy (ORX), E2 pellet implantation, or both. E2 pellet implantation at an early stage of DN with or without ORX caused a rapid drop in blood glucose and a dramatic increase in beta-cell number, and it markedly inhibited DN progression [namely, E2 reduced glomerulosclerosis, collagen 4 deposition and albuminuria, and prevented hyperfiltration]. Furthermore, E2 pellet implantation was more effective than ORX alone and induced a remarkable improvement, even when initiated at advanced-stage DN. In contrast, induction of normoglycemia by islet transplant in ICER-Tg mice eliminated albuminuria but was less effective than E2 + ORX in reducing glomerulosclerosis, collagen 4 deposition, and hyperfiltration. These findings indicate that E2 treatment is effective, even after establishment of DN, whereas glucose normalization alone does not improve sclerotic lesions. We propose that E2 intervention is a potential therapeutic option for DN. PMID- 26940100 TI - Molecular determinants of a competent bovine corpus luteum: first- vs final-wave dominant follicles. AB - Reproductive management in cattle requires the synchrony of follicle development and oestrus before insemination. However, ovulation of follicles that have not undergone normal physiological maturation can lead to suboptimal luteal function. Here, we investigated the expression of a targeted set of 47 genes in (a) a first wave vs final-wave dominant follicle (DF; the latter destined to ovulate spontaneously) and (b) 6-day-old corpora lutea (CLs) following either spontaneous ovulation or induced ovulation of a first-wave DF to ascertain their functional significance for competent CL development. Both the mass and progesterone synthesising capacity of a CL formed following induced ovulation of a first-wave DF were impaired. These impaired CLs had reduced expression of steroidogenic enzymes (e.g. STAR and HSD3B1), luteotrophic receptors (LHCGR) and angiogenic regulators (e.g. VEGFA) and increased expression of BMP2 (linked to luteolysis). Relative to final-wave DFs, characteristic features of first-wave DFs included reduced oestradiol concentrations and a reduced oestradiol:progesterone ratio in the face of increased expression of key steroidogenic enzymes (i.e. CYP11A1, HSD3B1 and CYP19A1) in granulosa cells and reduced expression of the HDL receptor SCARB1 in thecal cells. Transcripts for further components of the TGF and IGF systems (e.g. INHA, INHBA, IGF2R and IGFBP2) varied between the first- and final wave DFs. These results highlight the importance of hormones such as progesterone interacting with local components of both the TGF and IGF systems to affect the maturation of the ovulatory follicle and functional competency of the subsequent CL. PMID- 26940101 TI - Regulation of bovine oviductal NO synthesis by follicular steroids and prostaglandins. AB - Nitric oxide (NO) is a regulator of sperm motility, oocyte/embryo survival, and waves of contraction/relaxation in mammalian oviducts. As follicles control oviductal functions by two routes at least, (1) a systemic way via blood vessels before ovulation, (2) a direct way by entering of follicular fluid through fimbria at ovulation, we hypothesized that NO synthesis in the bovine oviduct is regulated by follicular steroids and prostaglandins (PGs). Quantification of mRNA expressions in the ampullary tissues showed that inducible NO synthase (NOS2) mRNA expression was highest on the day of ovulation (day 0). By contrast, NOS2 mRNA expression in the isthmus was highest on days 5-6 and lowest on days 19-21. Endothelial NOS (NOS3) mRNA expressions in either the ampulla or the isthmus did not change during the estrous cycle. PGE2 and PGF2alpha increased NOS2 mRNA expressions in cultured ampullary oviductal epithelial cells after 1-h incubation. These increases were suppressed by an antagonist of E-prostanoid receptor type 2, one of the PGE2 receptor. Estradiol-17beta decreased the expression of NOS2 mRNA expression in cultured isthmic epithelial cells 24h after treatment. This effect was suppressed by an antagonist of estrogen receptoralpha(ESR1). Expression of ESR1 was highest on days 19-21 in the isthmic tissues. The overall findings indicate region-specific difference of NO synthesis in the oviduct. PGs flowed from ruptured follicle may up-regulate NO synthesis in the oviductal epithelium, whereas circulating E2 seems to inhibit NO synthesis via ESR1 in the isthmus at the follicular stage. PMID- 26940102 TI - Identification of specific age groups with a high risk for developing cerebral vasospasm after aneurysmal subarachnoid hemorrhage. AB - The impact of age on the incidence of cerebral vasospasm after aneurysmal subarachnoid hemorrhage (aSAH) is a matter of ongoing discussion. The aim of this study was to identify age groups with a higher risk for developing vasospasm, delayed ischemic neurological deficit (DIND), or delayed infarction (DI) and to identify a cut-off age for a better risk stratification. We defined six age groups (<30, 30-39, 40-49, 50-59, 60-69, and >70 years). ROC analysis was performed to determine a cutoff age with the highest positive predictive value (PPV) for developing vasospasm, defined as a blood-flow-velocity-increase >120 cm/s in transcranial-Doppler-sonography (TCD). Multivariate binary-logistic regression-analysis was then performed to evaluate differences in the incidence of cerebral vasospasm, DIND, and DI among the different age groups. A total of 753 patients were included in the study. The highest incidence (70 %) of TCD vasospasm was found in patients between 30 and 39 years of age. The cutoff age with the highest PPV (65 %) for developing TCD-vasospasm was 38 years. Multivariate analysis revealed that age <38 years (OR 3.6; CI 95 % 2.1-6.1; p < 0.001) best predicted vasospasm, followed by the need for cerebrospinal fluid drainage (OR 1.5; CI 95 % 1.0-2.3; p = 0.04). However, lower age did not correlate with higher rates of DIND or infarcts. The overall vasospasm-incidence after aSAH is age-dependent and highest in the age group <38 years. Surprisingly, the higher incidence in the younger age group does not translate into a higher rate of DIND/DI. This finding may hint towards age-related biological factors influencing the association between arterial narrowing and cerebral ischemia. PMID- 26940103 TI - Salmonella infections modelling in Mississippi using neural network and geographical information system (GIS). AB - OBJECTIVES: Mississippi (MS) is one of the southern states with high rates of foodborne infections. The objectives of this paper are to determine the extent of Salmonella and Escherichia coli infections in MS, and determine the Salmonella infections correlation with socioeconomic status using geographical information system (GIS) and neural network models. METHODS: In this study, the relevant updated data of foodborne illness for southern states, from 2002 to 2011, were collected and used in the GIS and neural networks models. Data were collected from the Centers for Disease Control and Prevention (CDC), MS state Department of Health and the other states department of health. The correlation between low socioeconomic status and Salmonella infections were determined using models created by several software packages, including SAS, ArcGIS @RISK and NeuroShell. RESULTS: Results of this study showed a significant increase in Salmonella outbreaks in MS during the study period, with highest rates in 2011 (47.84 +/- 24.41 cases/100,000; p<0.001). MS had the highest rates of Salmonella outbreaks compared with other states (36 +/- 6.29 cases/100,000; p<0.001). Regional and district variations in the rates were also observed. GIS maps of Salmonella outbreaks in MS in 2010 and 2011 showed the districts with higher rates of Salmonella. Regression analysis and neural network models showed a moderate correlation between cases of Salmonella infections and low socioeconomic factors. Poverty was shown to have a negative correlation with Salmonella outbreaks (R(2)=0.152, p<0.05). CONCLUSIONS: Geographic location besides socioeconomic status may contribute to the high rates of Salmonella outbreaks in MS. Understanding the geographical and economic relationship with infectious diseases will help to determine effective methods to reduce outbreaks within low socioeconomic status communities. PMID- 26940104 TI - Exploring the Current Landscape of Intravenous Infusion Practices and Errors (ECLIPSE): protocol for a mixed-methods observational study. AB - INTRODUCTION: Intravenous medication is essential for many hospital inpatients. However, providing intravenous therapy is complex and errors are common. 'Smart pumps' incorporating dose error reduction software have been widely advocated to reduce error. However, little is known about their effect on patient safety, how they are used or their likely impact. This study will explore the landscape of intravenous medication infusion practices and errors in English hospitals and how smart pumps may relate to the prevalence of medication administration errors. METHODS AND ANALYSIS: This is a mixed-methods study involving an observational quantitative point prevalence study to determine the frequency and types of errors that occur in the infusion of intravenous medication, and qualitative interviews with hospital staff to better understand infusion practices and the contexts in which errors occur. The study will involve 5 clinical areas (critical care, general medicine, general surgery, paediatrics and oncology), across 14 purposively sampled acute hospitals and 2 paediatric hospitals to cover a range of intravenous infusion practices. Data collectors will compare each infusion running at the time of data collection against the patient's medication orders to identify any discrepancies. The potential clinical importance of errors will be assessed. Quantitative data will be analysed descriptively; interviews will be analysed using thematic analysis. ETHICS AND DISSEMINATION: Ethical approval has been obtained from an NHS Research Ethics Committee (14/SC/0290); local approvals will be sought from each participating organisation. Findings will be published in peer-reviewed journals and presented at conferences for academic and health professional audiences. Results will also be fed back to participating organisations to inform local policy, training and procurement. Aggregated findings will inform the debate on costs and benefits of the NHS investing in smart pump technology, and what other changes may need to be made to ensure effectiveness of such an investment. PMID- 26940105 TI - Association of cannabis use with hospital admission and antipsychotic treatment failure in first episode psychosis: an observational study. AB - OBJECTIVE: To investigate whether cannabis use is associated with increased risk of relapse, as indexed by number of hospital admissions, and whether antipsychotic treatment failure, as indexed by number of unique antipsychotics prescribed, may mediate this effect in a large data set of patients with first episode psychosis (FEP). DESIGN: Observational study with exploratory mediation analysis. SETTING: Anonymised electronic mental health record data from the South London and Maudsley NHS Foundation Trust. PARTICIPANTS: 2026 people presenting to early intervention services with FEP. EXPOSURE: Cannabis use at presentation, identified using natural language processing. MAIN OUTCOME MEASURES: admission to psychiatric hospital and clozapine prescription up to 5 years following presentation. MEDIATOR: Number of unique antipsychotics prescribed. RESULTS: Cannabis use was present in 46.3% of the sample at first presentation and was particularly common in patients who were 16-25, male and single. It was associated with increased frequency of hospital admission (incidence rate ratio 1.50, 95% CI 1.25 to 1.80), increased likelihood of compulsory admission (OR 1.55, 1.16 to 2.08) and greater number of days spent in hospital (beta coefficient 35.1 days, 12.1 to 58.1). The number of unique antipsychotics prescribed, mediated increased frequency of hospital admission (natural indirect effect 1.09, 95% CI 1.01 to 1.18; total effect 1.50, 1.21 to 1.87), increased likelihood of compulsory admission (natural indirect effect (NIE) 1.27, 1.03 to 1.58; total effect (TE) 1.76, 0.81 to 3.84) and greater number of days spent in hospital (NIE 17.9, 2.4 to 33.4; TE 34.8, 11.6 to 58.1). CONCLUSIONS: Cannabis use in patients with FEP was associated with an increased likelihood of hospital admission. This was linked to the prescription of several different antipsychotic drugs, indicating clinical judgement of antipsychotic treatment failure. Together, this suggests that cannabis use might be associated with worse clinical outcomes in psychosis by contributing towards failure of antipsychotic treatment. PMID- 26940107 TI - Point-of-care C reactive protein for the diagnosis of lower respiratory tract infection in NHS primary care: a qualitative study of barriers and facilitators to adoption. AB - OBJECTIVES: Point-of-care (POC) C reactive protein (CRP) is incorporated in National Institute of Health and Care Excellence (NICE) guidelines for the diagnosis of pneumonia, reduces antibiotic prescribing and is cost effective. AIM: To determine the barriers and facilitators to adoption of POC CRP testing in National Health Service (NHS) primary care for the diagnosis of lower respiratory tract infection. DESIGN: The study followed a qualitative methodology based on grounded theory. The study was undertaken in 2 stages. Stage 1 consisted of semistructured interviews with 8 clinicians from Europe and the UK who use the test in routine practice, and focused on their subjective experience in the challenges of implementing POC CRP testing. Stage 2 was a multidisciplinary facilitated workshop with NHS stakeholders to discuss barriers to adoption, impact of adoption and potential adoption scenarios. Emergent theme analysis was undertaken. PARTICIPANTS: Participants included general practitioners (including those with commissioning experience), biochemists, pharmacists, clinical laboratory scientists and industry representatives from the UK and abroad. RESULTS: Barriers to the implementation of POC CRP exist, but successful adoption has been demonstrated abroad. Analysis highlighted 7 themes: reimbursement and incentivisation, quality control and training, laboratory services, practitioner attitudes and experiences, effects on clinic flow and workload, use in pharmacy and gaps in evidence. CONCLUSIONS: Successful adoption models from the UK and abroad demonstrate a distinctive pattern and involve collaboration with central laboratory services. Incorporating antimicrobial stewardship into quality improvement frameworks may incentivise adoption. Further research is needed to develop scaling-up strategies to address the resourcing, clinical governance and economic impact of widespread NHS implementation. PMID- 26940106 TI - Prevalence of chronic diseases among physicians in Taiwan: a population-based cross-sectional study. AB - OBJECTIVES: The health of physicians is an important topic which needs to be addressed in order to provide the best quality of patient care. However, there are few studies on the prevalence of chronic diseases among physicians. In this study, we explored the prevalence of chronic diseases among physicians and compared the probability of chronic diseases between physicians and the general population using a population-based data set in Taiwan. STUDY DESIGN: A cross sectional study. SETTING: Taiwan. PARTICIPANTS: Our study consisted of 1426 practising physicians and 5704 general participants. PRIMARY OUTCOME MEASURES: We chose 22 chronic diseases from the Elixhauser Comorbidity index and nine highly prevalent medical conditions in an Asian population for analysis. We used conditional logistic regression analyses to investigate the OR and its corresponding 95% CI of chronic diseases between these two groups. RESULTS: The conditional logistic regression analyses showed that physicians had lower odds of peripheral vascular disorders (OR=0.41, 95% CI=0.19 to 0.90), uncomplicated diabetes (OR=0.76, 95% CI=0.60 to 0.97), complicated diabetes (OR=0.53, 95% CI=0.34 to 0.83), renal failure (OR=0.41, 95% CI=0.19 to 0.90), liver diseases (OR=0.78, 95% CI=0.66 to 0.94), and hepatitis B or C (OR=0.62, 95% CI=0.49 to 0.77) and higher odds of hypertension (OR=1.21, 95% CI=1.03 to 1.41), hyperlipidaemia (OR=1.43, 95% CI=1.23 to 1.67) and asthma (OR=1.59, 95% CI=1.16 to 2.18) than the general population. CONCLUSIONS: We concluded that although physicians had decreased prevalence of some chronic diseases, they had a significantly increased prevalence of hypertension, hyperlipidaemia and asthma. PMID- 26940108 TI - Language spoken at home and the association between ethnicity and doctor-patient communication in primary care: analysis of survey data for South Asian and White British patients. AB - OBJECTIVES: To investigate if language spoken at home mediates the relationship between ethnicity and doctor-patient communication for South Asian and White British patients. METHODS: We conducted secondary analysis of patient experience survey data collected from 5870 patients across 25 English general practices. Mixed effect linear regression estimated the difference in composite general practitioner-patient communication scores between White British and South Asian patients, controlling for practice, patient demographics and patient language. RESULTS: There was strong evidence of an association between doctor-patient communication scores and ethnicity. South Asian patients reported scores averaging 3.0 percentage points lower (scale of 0-100) than White British patients (95% CI -4.9 to -1.1, p=0.002). This difference reduced to 1.4 points (95% CI -3.1 to 0.4) after accounting for speaking a non-English language at home; respondents who spoke a non-English language at home reported lower scores than English-speakers (adjusted difference 3.3 points, 95% CI -6.4 to -0.2). CONCLUSIONS: South Asian patients rate communication lower than White British patients within the same practices and with similar demographics. Our analysis further shows that this disparity is largely mediated by language. PMID- 26940109 TI - Association between secondhand smoke exposure at home and cigarette gifting and sharing in Zhejiang, China: a repeat cross-sectional study. AB - OBJECTIVES: The aims of the current study were to assess the prevalence of household cigarette gifting and sharing, and to evaluate the relationship between secondhand smoke (SHS) exposure, and cigarette gifting and sharing, in Zhejiang, China. DESIGN: A repeat cross-sectional design. SETTING: 10 sites in 5 cities in Zhejiang, China. PARTICIPANTS: Two surveys were conducted with adults in Zhejiang, China, in 2010 (N=2112) and 2012 (N=2279), respectively. At both waves, the same questionnaire was used; respondents were asked questions on residence, number of family smokers, indoor smoking rules, household income and cigarette gifting and sharing. RESULTS: The findings revealed that more than half of respondents' families (54.50% in 2010, 52.79% in 2012) reported exposure to SHS. Many families (54.73% in 2010, 47.04% in 2012) shared cigarettes with others, and a minority (14.91% in 2010, 14.17% in 2012) reported their family giving cigarettes as a gift. There was a significant decrease in cigarette sharing from 2010 to 2012, irrespective of household with SHS exposure status; and the cigarette gifting was significantly decreased in household without SHS exposure. CONCLUSIONS: Compared to households without SHS exposure, the prevalence of cigarette gifting and sharing in households with SHS exposure was more obvious. Encouraging and promoting a smoke-free household environment is necessary to change public smoking customs in Zhejiang, China. PMID- 26940110 TI - Randomised controlled trial of referral to a telephone-based weight management and healthy lifestyle programme for patients with knee osteoarthritis who are overweight or obese: a study protocol. AB - INTRODUCTION: Knee osteoarthritis (OA) is one of the most common chronic diseases worldwide and is associated with significant pain and disability. Clinical practice guidelines consistently recommend weight management as a core aspect of care for overweight and obese patients with knee OA; however, provision of such care is suboptimal. Telephone-based interventions offer a novel approach to delivery of weight management care in these patients. The aim of the proposed study is to assess the effectiveness of referral to a telephone-based weight management and healthy lifestyle programme, previously shown to be effective in changing weight, in improving knee pain intensity in overweight or obese patients with knee OA, compared to usual care. METHODS AND ANALYSIS: A parallel, randomised controlled trial will be undertaken. Patients with OA of the knee who are waiting for an outpatient orthopaedic consultation at a tertiary referral public hospital within New South Wales, Australia, will be allocated to either an intervention or a control group (1:1 ratio). After baseline data collection, patients in the intervention group will receive a 6-month telephone-based intervention, and patients in the control group will continue with usual care. Surveys will be conducted at baseline, 6 and 26 weeks post-randomisation. The study requires 60 participants per group to detect a two-point difference in pain intensity (primary outcome) 26 weeks after baseline. ETHICS AND DISSEMINATION: The study is approved by the Hunter New England Health Human Research Ethics Committee (13/12/11/5.18) and the University of Newcastle Human Research Ethics Committee (H-2015-0043). The results will be disseminated in peer-reviewed journals and at scientific conferences. TRIAL REGISTRATION NUMBER: ACTRN12615000490572, Pre-results. PMID- 26940111 TI - Implementation of tuberculosis infection control measures in designated hospitals in Zhejiang Province, China: are we doing enough to prevent nosocomial tuberculosis infections? AB - OBJECTIVES: Tuberculosis (TB) infection control measures are very important to prevent nosocomial transmission and protect healthcare workers (HCWs) in hospitals. The TB infection control situation in TB treatment institutions in southeastern China has not been studied previously. Therefore, the aim of this study was to investigate the implementation of TB infection control measures in TB-designated hospitals in Zhejiang Province, China. DESIGN: Cross-sectional survey using observation and interviews. SETTING: All TB-designated hospitals (n=88) in Zhejiang Province, China in 2014. PRIMARY AND SECONDARY OUTCOME MEASURES: Managerial, administrative, environmental and personal infection control measures were assessed using descriptive analyses and univariate logistic regression analysis. RESULTS: The TB-designated hospitals treated a median of 3030 outpatients (IQR 764-7094) and 279 patients with confirmed TB (IQR 154-459) annually, and 160 patients with TB (IQR 79-426) were hospitalised in the TB wards. Most infection control measures were performed by the TB-designated hospitals. Measures including regular monitoring of TB infection control in high risk areas (49%), shortening the wait times (42%), and providing a separate waiting area for patients with suspected TB (46%) were sometimes neglected. N95 respirators were available in 85 (97%) hospitals, although only 44 (50%) hospitals checked that they fit. Hospitals with more TB staff and higher admission rates of patients with TB were more likely to set a dedicated sputum collection area and to conduct annual respirator fit testing. CONCLUSIONS: TB infection control measures were generally implemented by the TB-designated hospitals. Measures including separation of suspected patients, regular monitoring of infection control practices, and regular fit testing of respirators should be strengthened. Infection measures for sputum collection and respirator fit testing should be improved in hospitals with lower admission rates of patients with TB. PMID- 26940112 TI - Feasibility randomised controlled trial of Recovery-focused Cognitive Behavioural Therapy for Older Adults with bipolar disorder (RfCBT-OA): study protocol. AB - INTRODUCTION: Bipolar disorder is a severe and chronic mental health problem that persists into older adulthood. The number of people living with this condition is set to rise as the UK experiences a rapid ageing of its population. To date, there has been very little research or service development with respect to psychological therapies for this group of people. METHODS AND ANALYSIS: A parallel two-arm randomised controlled trial comparing a 14-session, 6-month Recovery-focused Cognitive-Behavioural Therapy for Older Adults with bipolar disorder (RfCBT-OA) plus treatment as usual (TAU) versus TAU alone. Participants will be recruited in the North-West of England via primary and secondary mental health services and through self-referral. The primary objective of the study is to evaluate the feasibility and acceptability of RfCBT-OA; therefore, a formal power calculation is not appropriate. It has been estimated that randomising 25 participants per group will be sufficient to be able to reliably determine the primary feasibility outcomes (eg, recruitment and retention rates), in line with recommendations for sample sizes for feasibility/pilot trials. Participants in both arms will complete assessments at baseline and then every 3 months, over the 12-month follow-up period. We will gain an estimate of the likely effect size of RfCBT-OA on a range of clinical outcomes and estimate parameters needed to determine the appropriate sample size for a definitive, larger trial to evaluate the effectiveness and cost-effectiveness of RfCBT-OA. Data analysis is discussed further in the Analysis section in the main paper. ETHICS AND DISSEMINATION: This protocol was approved by the UK National Health Service (NHS) Ethics Committee process (REC ref: 15/NW/0330). The findings of the trial will be disseminated through peer-reviewed journals, national and international conference presentations and local, participating NHS trusts. TRIAL REGISTRATION NUMBER: ISRCTN13875321; Pre-results. PMID- 26940113 TI - Premature adult mortality in urban Zambia: a repeated population-based cross sectional study. AB - OBJECTIVES: To measure the sex-specific and community-specific mortality rates for adults in Lusaka, Zambia, and to identify potential individual-level, household-level and community-level correlates of premature mortality. We conducted 12 survey rounds of a population-based cross-sectional study between 2004 and 2011, and collected data via a structured interview with a household head. SETTING: Households in Lusaka District, Zambia, 2004-2011. PARTICIPANTS: 43,064 household heads (88% female) who enumerated 123,807 adult household members aged between 15 and 60 years. PRIMARY OUTCOME: Premature adult mortality. RESULTS: The overall mortality rate was 16.2/1000 person-years for men and 12.3/1000 person-years for women. The conditional probability of dying between age 15 and 60 (45q15) was 0.626 for men and 0.537 for women. The top three causes of death for men and women were infectious in origin (ie, tuberculosis, HIV and malaria). We observed an over twofold variation of mortality rates between communities. The mortality rate was 1.98 times higher (95% CI 1.57 to 2.51) in households where a family member required nursing care, 1.44 times higher (95% CI 1.22 to 1.71) during the cool dry season, and 1.28 times higher (95% CI 1.06 to 1.54) in communities with low-cost housing. CONCLUSIONS: To meet Zambia's development goals, further investigation is needed into the factors associated with adult mortality. Mortality can potentially be reduced through focus on high need households and communities, and improved infectious disease prevention and treatment services. PMID- 26940114 TI - Impact of universal health coverage on urban-rural inequity in psychiatric service utilisation for patients with first admission for psychosis: a 10-year nationwide population-based study in Taiwan. AB - OBJECTIVE: To examine the disparities in psychiatric service utilisation over a 10-year period for patients with first admission for psychosis in relation to urban-rural residence following the implementation of universal health coverage in Taiwan. DESIGN: Population-based retrospective cohort study. SETTING: Taiwan's National Health Insurance Research Database, which has a population coverage rate of over 99% and contains all medical claim records of a nationwide cohort of patients with at least one psychiatric admission between 1996 and 2007. PARTICIPANTS: 69,690 patients aged 15-59 years with first admission between 1998 and 2007 for any psychotic disorder. MAIN EXPOSURE MEASURE: Patients' urban-rural residence at first admissions. MAIN OUTCOME MEASURES: Absolute and relative inequality indexes of the following quality indicators after discharge from the first admission: all-cause psychiatric readmission at 2 and 4 years, dropout of psychiatric outpatient service at 30 days, and emergency department (ED) treat and-release encounter at 30 days. RESULTS: Between 1998 and 2007, the 4-year readmission rate decreased from 65% to 58%, the 30-day dropout rate decreased from 18% to 15%, and the 30-day ED encounter rate increased from 8% to 10%. Risk of readmission has significantly decreased in rural and urban patients, but at a slower speed for the rural patients (p=0.026). The adjusted HR of readmission in rural versus urban patients has increased from 1.00 (95% CI 0.96 to 1.04) in 1998 2000 to 1.08 (95% CI 1.03 to 1.12) in 2005-2007, indicating a mild widening of the urban-rural gap. Urban-rural differences in 30-day dropout and ED encounter rates have been stationary over time. CONCLUSIONS: The universal health coverage in Taiwan did not narrow urban-rural inequity of psychiatric service utilisation in patients with psychosis. Therefore, other policy interventions on resource allocation, service delivery and quality of care are needed to improve the outcome of rural-dwelling patients with psychosis. PMID- 26940116 TI - Incorporating Transmission Into Causal Models of Infectious Diseases for Improved Understanding of the Effect and Impact of Risk Factors. AB - Conventional measures of causality (which compare risks between exposed and unexposed individuals) do not factor in the population-scale dynamics of infectious disease transmission. We used mathematical models of 2 childhood infections (respiratory syncytial virus and rotavirus) to illustrate this problem. These models incorporated 3 causal pathways whereby malnutrition could act to increase the incidence of severe infection: increasing the proportion of infected children who develop severe infection, increasing the children's susceptibility to infection, and increasing infectiousness. For risk factors that increased the proportion of infected children who developed severe infection, the population attributable fraction (PAF) calculated conventionally was the same as the PAF calculated directly from the models. However, for risk factors that increased transmission (by either increasing susceptibility to infection or increasing infectiousness), the PAF calculated directly from the models was much larger than that predicted by the conventional PAF calculation. The models also showed that even when conventional studies find no association between a risk factor and an outcome, risk factors that increase transmission can still have a large impact on disease burden. For a complete picture of infectious disease causality, transmission effects must be incorporated into causal models. PMID- 26940115 TI - Multiple Healthful Dietary Patterns and Type 2 Diabetes in the Women's Health Initiative. AB - The relationship between various diet quality indices and risk of type 2 diabetes (T2D) remains unsettled. We compared associations of 4 diet quality indices--the Alternate Mediterranean Diet Index, Healthy Eating Index 2010, Alternate Healthy Eating Index 2010, and the Dietary Approaches to Stop Hypertension (DASH) Index- with reported T2D in the Women's Health Initiative, overall, by race/ethnicity, and with/without adjustment for overweight/obesity at enrollment (a potential mediator). This cohort (n = 101,504) included postmenopausal women without T2D who completed a baseline food frequency questionnaire from which the 4 diet quality index scores were derived. Higher scores on the indices indicated a better diet. Cox regression was used to estimate multivariate hazard ratios for T2D. Pearson coefficients for correlation among the indices ranged from 0.55 to 0.74. Follow-up took place from 1993 to 2013. During a median 15 years of follow up, 10,815 incident cases of T2D occurred. For each diet quality index, a 1 standard-deviation higher score was associated with 10%-14% lower T2D risk (P < 0.001). Adjusting for overweight/obesity at enrollment attenuated but did not eliminate associations to 5%-10% lower risk per 1-standard-deviation higher score (P < 0.001). For all 4 dietary indices examined, higher scores were inversely associated with T2D overall and across racial/ethnic groups. Multiple forms of a healthful diet were inversely associated with T2D in these postmenopausal women. PMID- 26940117 TI - Comparison of Self-Reported Sleep Duration With Actigraphy: Results From the Hispanic Community Health Study/Study of Latinos Sueno Ancillary Study. AB - Most studies of sleep and health outcomes rely on self-reported sleep duration, although correlation with objective measures is poor. In this study, we defined sociodemographic and sleep characteristics associated with misreporting and assessed whether accounting for these factors better explains variation in objective sleep duration among 2,086 participants in the Hispanic Community Health Study/Study of Latinos who completed more than 5 nights of wrist actigraphy and reported habitual bed/wake times from 2010 to 2013. Using linear regression, we examined self-report as a predictor of actigraphy-assessed sleep duration. Mean amount of time spent asleep was 7.85 (standard deviation, 1.12) hours by self-report and 6.74 (standard deviation, 1.02) hours by actigraphy; correlation between them was 0.43. For each additional hour of self-reported sleep, actigraphy time spent asleep increased by 20 minutes (95% confidence interval: 19, 22). Correlations between self-reported and actigraphy-assessed time spent asleep were lower with male sex, younger age, sleep efficiency <85%, and night-to-night variability in sleep duration >=1.5 hours. Adding sociodemographic and sleep factors to self-reports increased the proportion of variance explained in actigraphy-assessed sleep slightly (18%-32%). In this large validation study including Hispanics/Latinos, we demonstrated a moderate correlation between self-reported and actigraphy-assessed time spent asleep. The performance of self-reports varied by demographic and sleep measures but not by Hispanic subgroup. PMID- 26940119 TI - The assessment of developmental trauma in children and adolescents: A systematic review. AB - BACKGROUND: The assessment of children and young people with history of complex developmental trauma presents a significant challenge to services. Traditional diagnostic categories such as post-traumatic stress disorder (PTSD) are argued to be of limited value, and while the proposed 'Developmental Trauma Disorder' definition attempts to address this debate, associated assessment tools have yet to be developed. This review builds on a previous review of assessment measures, undertaken in 2005. AIM: To identify trauma assessment tools developed or evaluated since 2004 and determine which are developmentally appropriate for children or adolescents with histories of complex trauma. METHOD: A systematic search of electronic databases was conducted with explicit inclusion and exclusion criteria. RESULTS: A total of 35 papers were identified evaluating 29 measures assessing general functioning and mental health ( N = 10), PTSD ( N = 7) and trauma symptomatology outside, or in addition to, PTSD ( N = 11). Studies were evaluated on sample quality, trauma/adversity type, as well as demographic and psychometric data. Distinction was made between measures validated for children (0-12 years) and adolescents (12-18 years). CONCLUSION: Few instruments could be recommended for immediate use as many required further validation. The Assessment Checklist questionnaires, designed with a developmental and attachment focus, were the most promising tools. PMID- 26940120 TI - The Meaning of the Child Interview: A new procedure for assessing and understanding parent-child relationships of 'at-risk' families. AB - Reder and Duncan's well-known studies of the 1990s on fatal child abuse drew attention to how parental scripts regarding their children could dangerously distort relationships in ways that were sometimes fatal to children. This article reports on a new system for assessing the 'meaning of the child to the parent', called the Meaning of the Child Interview (MotC). Parents are interviewed using the established Parent Development Interview, or equivalent, and the transcript of the interview is then analysed according to parental sensitivity and likely risk to the child. The MotC constructs were developed from those used in observed parent-child interaction (specifically, the CARE-Index) and the form of discourse analysis used in the Dynamic Maturational Model - Adult Attachment Interview, allowing a more systemic and inter-subjective understanding of parenting representations than often put forward. This article discusses the theoretical background to the MotC, gives a brief review of similar measures and then introduces the coding system and patterns of caregiving. The validity of the MotC is addressed elsewhere. PMID- 26940121 TI - Social Communication Anxiety Treatment (S-CAT) for children and families with selective mutism: A pilot study. AB - This research assessed the feasibility of Social Communication Anxiety Treatment (S-CAT) developed by Elisa Shipon-Blum, a brief multimodal approach, to increase social communication in 40 children aged 5-12 years with selective mutism (SM). SM is a disorder in which children consistently fail to speak in specific situations although they have the ability to do so. Key features of this approach are the SM-Social Communication Comfort Scale (SCCS), transfer of control (ToC), a nonchalant therapeutic style, and cognitive-behavioral strategies over a brief time frame. Following 9 weeks of treatment, children showed significant gains in speaking frequency on all 17 items from the Selective Mutism Questionnaire (SMQ), a standardized measure of SM severity. Children also showed decreased levels of anxiety and withdrawal as reported by parents on the Child Behavior Checklist (CBCL). SM initial symptom severity and family therapy compliance, but not duration of SM, contributed to treatment outcomes. PMID- 26940118 TI - Cyclophilin A stabilizes the HIV-1 capsid through a novel non-canonical binding site. AB - The host cell factor cyclophilin A (CypA) interacts directly with the HIV-1 capsid and regulates viral infectivity. Although the crystal structure of CypA in complex with the N-terminal domain of the HIV-1 capsid protein (CA) has been known for nearly two decades, how CypA interacts with the viral capsid and modulates HIV-1 infectivity remains unclear. We determined the cryoEM structure of CypA in complex with the assembled HIV-1 capsid at 8-A resolution. The structure exhibits a distinct CypA-binding pattern in which CypA selectively bridges the two CA hexamers along the direction of highest curvature. EM-guided all-atom molecular dynamics simulations and solid-state NMR further reveal that the CypA-binding pattern is achieved by single-CypA molecules simultaneously interacting with two CA subunits, in different hexamers, through a previously uncharacterized non-canonical interface. These results provide new insights into how CypA stabilizes the HIV-1 capsid and is recruited to facilitate HIV-1 infection. PMID- 26940122 TI - Screening high school students in Italy for sudden cardiac death prevention by using a telecardiology device: a retrospective observational study. AB - BACKGROUND: In 2010, an Italian project was launched aimed at using a telecardiology device in order to perform early diagnosis of young students at risk of sudden cardiac death. METHODS: Our retrospective observational study was conducted on a population of 13,016 students, aged between 16 and 19 years, in different Italian regions. It consisted of analysis of data recorded during a telecardiology pilot study. The recorded data were electrocardiograms and data concerning lifestyle habits and family history of cardiovascular diseases. In total, 14 alterations in the electrocardiogram signal have been considered in this study. Some of these alterations are as follows: ventricular ectopic beats, atrioventricular block, Brugada-like electrocardiogram pattern, left anterior/posterior fascicular block, left/right ventricular hypertrophy, long/short QT interval, left atrial enlargement, right atrial enlargement, short PQ interval, and ventricular pre-excitation Wolff-Parkinson-White syndrome. On the basis of the collected data, we implemented this retrospective observational study. RESULTS: The analysed data showed that 13.60% of students had a family history for cardiovascular diseases, 22.43% reported smoking habits, 26.23% reported alcohol consumption, and 7.24% reported abuse of drugs. A total of 24% of students had at least one of the 14 electrocardiogram pathological alterations considered in our study and 32% had electrocardiogram values within the normal range. CONCLUSIONS: This retrospective observational study analysed data registered during our telecardiology activity. This activity permitted to maximise data collection and minimise the costs for collecting such data. This activity of screening is being continued and in the next few years it will allow us to have a greater mass of data. PMID- 26940123 TI - Treadmill training for patients with Parkinson Disease. An abridged version of a Cochrane Review. AB - INTRODUCTION: Treadmill training is used in rehabilitation might improve gait parameters of patients with Parkinson Disease. Aim of this study was to assess the effectiveness of treadmill training in improving the gait of patients with Parkinson Disease and the acceptability and safety of this type of therapy. EVIDENCE ACQUISITION: We searched the Cochrane Movement Disorders Group Specialized Register (last searched September 2014), Cochrane Central Register of Controlled Trials (The Cochrane Library 2014, Issue 10), MEDLINE (1950 to September 2014), and EMBASE (1980 to September 2014). We also handsearched relevant conference proceedings, searched trials and research registers, and checked reference lists (last searched September 2014). We contacted trialists, experts and researchers in the field and manufacturers of commercial devices. We included all randomized controlled trials comparing treadmill training with no treadmill training in patients with Parkinson Disease. Two review authors independently selected trials for inclusion, assessed trial quality and extracted data. EVIDENCE SYNTHESIS: Treadmill training improved gait speed (MD=0.09 m/s; 95% confidence interval (CI) 0.03 to 0.14; P=0.001; I2=24%; moderate quality of evidence), stride length (MD=0.05 meters; 95% CI 0.01 to 0.09; P=0.01; I2=0%; low quality of evidence), but walking distance (MD=48.9 meters; 95% CI -1.32 to 99.14; P=0.06; I2=91%; very low quality of evidence) and cadence did not improve (MD=2.16 steps/minute; 95% CI -0.13 to 4.46; P=0.07; I2=28%; low quality of evidence) at the end of study. Treadmill training did not increase the risk of patients dropping out from intervention (RD=-0.02; 95% CI -0.06 to 0.02; P=0.32; I2=13%; moderate quality of evidence) and adverse events were not reported. CONCLUSIONS: This systematic review provides evidence from eighteen trials with moderate to low risk of bias that the use of treadmill training in patients with PD may improve clinically relevant gait parameters such as gait speed and stride length. This apparent benefit for patients is, however, not supported by all secondary variables (e.g. cadence and walking distance). The results must be interpreted with caution because the results were heterogeneous and it is not known how long improvements last and differences between the trials in terms of patient characteristics, duration and amount of training and types of treadmill training exists. PMID- 26940124 TI - Plasma microRNA-21 for the early prediction of acute kidney injury in patients undergoing major cardiac surgery. AB - BACKGROUND: Acute kidney injury (AKI) is a complication after major cardiac surgery that is associated with higher rates of morbidity and mortality. MicroRNA 21 (miR-21) has been described as an early biomarker for AKI. We investigated whether miR-21 is predictive of AKI and long-term mortality after cardiac surgery. METHODS: Consecutive patients (n = 115) undergoing major cardiac surgery were included. Serum creatinine was measured prior to, 4 h after, and 1, 4 and 7 days after extracorporeal circulation. Diagnosis of post-operative AKI was made in accordance with the international Kidney Disease: Improving Global Outcomes definition of AKI. Serum cystatin C and miR-21 were measured prior to and 4 h after surgery. miR-21 was determined by quantitative RT-PCR and was normalized to miRNA-39 from Caenorhabditis elegans. The median follow-up time was 2.9 years. RESULTS: AKI occurred in 36.5% (n = 42) of all patients. Baseline miR-21 was significantly lower in patients developing cardiac surgery-associated AKI (CSA AKI) than in patients without CSA-AKI [0.27 (interquartile range, IQR, 0.14-0.30) versus 0.44 (IQR 0.25-0.75); P < 0.01]. Baseline miR-21 predicted CSA-AKI Stage 2/3 with an area under the curve of 0.701 [95% confidence interval (CI) 0.59 0.82; P = 0.007]. Baseline miR-21 <0.31 showed a hazard ratio of 3.11 (95% CI: 1.33-11.26) for CSA-AKI Stage 2/3. Patients with AKI Stage 2/3 had a significantly higher mortality (50 versus 10%; P = 0.0001) and dialysis rate (27 versus 11%; P = 0.038) within the 2.9-year follow-up. CONCLUSIONS: Our results indicate that miR-21 has the potential to identify patients at higher risk for CSA-AKI. This predictive value might be helpful in pre-procedural risk assessment and peri-procedural diagnosis and treatment. PMID- 26940125 TI - Contribution of the TTC21B gene to glomerular and cystic kidney diseases. AB - Background: The TTC21B gene was initially described as causative of nephronophthisis (NPHP). Recently, the homozygous TTC21B p.P209L mutation has been identified in families with focal segmental glomerulosclerosis (FSGS) and tubulointerstitial lesions. Heterozygous TTC21B variants have been proposed as genetic modifiers in ciliopathies. We aimed to study the causative and modifying role of the TTC21B gene in glomerular and cystic kidney diseases. Methods: Mutation analysis of the TTC21B gene was performed by massive parallel sequencing. We studied the causative role of the TTC21B gene in 17 patients with primary diagnosis of FSGS or NPHP and its modifying role in 184 patients with inherited glomerular or cystic kidney diseases. Results: Disease-causing TTC21B mutations were identified in three families presenting nephrotic proteinuria with FSGS and tubulointerstitial lesions in which some family members presented hypertension and myopia. Two families carried the homozygous p.P209L and the third was compound heterozygous for the p.P209L and a novel p.H426D mutation. Rare heterozygous TTC21B variants predicted to be pathogenic were found in five patients. These TTC21B variants were significantly more frequent in renal patients compared with controls (P = 0.0349). Two patients with a heterozygous deleterious TTC21B variant in addition to the disease-causing mutation presented a more severe phenotype than expected. Conclusions: Our results confirm the causal role of the homozygous p.P209L TTC21B mutation in two new families with FSGS and tubulointerstitial disease. We identified a novel TTC21B mutation demonstrating that p.P209L is not the unique causative mutation of this nephropathy. Thus, TTC21B mutation analysis should be considered for the genetic diagnosis of families with FSGS and tubulointerstitial lesions. Finally, we provide evidence that heterozygous deleterious TTC21B variants may act as genetic modifiers of the severity of glomerular and cystic kidney diseases. PMID- 26940126 TI - Magnesium lactate in the treatment of Gitelman syndrome: patient-reported outcomes. AB - Background: Gitelman syndrome (GS) is a rare recessively inherited renal tubulopathy associated with renal potassium (K) and magnesium (Mg) loss. It requires lifelong K and Mg supplementation at high doses that are at best unpalatable and at worst, intolerable. In particular, gastrointestinal side effects often limit full therapeutic usage. Methods: We report here the analysis of a cohort of 28 adult patients with genetically proven GS who attend our specialist tubular disorders clinic, in whom we initiated the use of a modified release Mg preparation (slow-release Mg lactate) and who were surveyed by questionnaire. Results: Twenty-five patients (89%) preferred the new treatment regimen. Of these 25, 17 (68%) regarded their symptom burden as improved and seven reported no worsening. Of the 25 who were not Mg-treatment naive, 13 (59%) patients reported fewer side effects, 7 (32%) described them as the same and only 2 (9%) considered side effects to be worse. Five were able to increase their dose without ill-effect. Overall, biochemistry improved in 91% of the 23 patients switched from therapy with other preparations who chose to continue the modified release Mg preparation. Eleven (48%) improved both their Mg and K mean levels, 3 (13%) improved Mg levels only and in 7 cases (30%), K levels alone rose. Conclusions: Patient-reported and biochemical outcomes using modified-release Mg supplements were very favourable, and patient choice should play a large part in choosing Mg supplements with GS patients. PMID- 26940127 TI - The 26S proteasome: A cell cycle regulator regulated by cell cycle. PMID- 26940128 TI - Corrigendum: ScbR- and ScbR2-mediated signal transduction networks coordinate complex physiological responses in Streptomyces coelicolor. PMID- 26940130 TI - Questions for esophageal stents treatment in acute refractory esophageal variceal bleeding. PMID- 26940131 TI - Structure Evolution and Hydrogenation Performance of IrFe Bimetallic Nanomaterials. AB - By a reverse microemulsion method, a series of IrFe bimetallic nanomaterials of variable morphologies and compositions is synthesized and characterized by (57)Fe Mossbauer spectroscopy, XRD, XPS, and TEM. The structure evolution, such as IrFe alloy nanoparticles to Ir nanoparticles on Fe2O3 flakes, can be simply tuned by changing the molar ratio of Ir to Fe precursors. In terms of Fe, the relative content of IrFe alloy decreased with the increase of Fe species doped, while that of Fe2O3 flakes increased until reached 100%. The as-prepared IrFe bimetallic nanomaterials were served as catalysts for the selective hydrogenation of 3 nitrostyrene to 3-aminostyrene, and it is found that the catalytic performance was related to the morphology and composition of these nanomaterials. Ir1Fe4 was subsequently identified to be a highly active and exceedingly selective catalyst with good stability and recyclability for the hydrogenation of 3-nitrostyrene, underscoring a remarkable "synergistic effect" of the two metals appearing as the form of Ir nanoparticles loaded on Fe2O3 flakes. For Ir nanoparticles, they act as an active species for the hydrogenation; for Fe2O3 flakes, they favor the preferential adsorption of nitro groups, which account for the better chemoselectivity to objective product. PMID- 26940129 TI - Small putative NANOG, SOX2, and SSEA-4-positive stem cells resembling very small embryonic-like stem cells in sections of ovarian tissue in patients with ovarian cancer. AB - BACKGROUND: In previous studies it has been found that in cell cultures of human adult ovaries there is a population of small stem cells with diameters of 2-4 MUm, which are present mainly in the ovarian surface epithelium and are comparable to very small embryonic-like stem cells (VSELs) from bone marrow. These cells are not observed by histopathologists in the ovarian tissue due to their small size and unknown clinical significance. Because these cells express a degree of pluripotency, they might be involved in the manifestation of ovarian cancer. Therefore we studied the ovarian tissue sections in women with borderline ovarian cancer and serous ovarian carcinoma to perhaps identify the small putative stem cells in situ. METHODS: In 27 women with borderline ovarian cancer and 20 women with high-grade serous ovarian carcinoma the ovarian tissue sections were stained, per standard practice, with eosin and hematoxylin staining and on NANOG, SSEA-4 and SOX2 markers, related to pluripotency, using immunohistochemistry. We focused on the presence and localization of small putative stem cells with diameters of up to 5 MUm and with the nuclei spread over nearly the full cell volume. RESULTS: In ovarian sections of both borderline ovarian cancer and serous ovarian carcinoma patients we were able to identify the presence of small round cells complying with the above criteria. Some of these small cells were NANOG-positive, were located among epithelial cells in the ovarian surface epithelium and as a single cell or groups of cells/clusters in typical "chambers", were found only in the presence of ovarian cancer and not in healthy ovaries and are comparable to those in fetal ovaries. We envision that these small cells could be related to NANOG-positive tumor-like structures and oocyte-like cells in similar "chambers" found in sections of cancerous ovaries, which could support their stemness and pluripotency. Further immunohistochemistry revealed a similar population of SSEA-4 and SOX2-positive cells. CONCLUSIONS: We may conclude that putative small stem cells expressing markers, related to pluripotency, are present in the ovarian tissue sections of women with borderline ovarian cancer and high-grade serous ovarian carcinoma thus indicating their potential involvement in ovarian cancer. PMID- 26940133 TI - Roller compaction: Effect of relative humidity of lactose powder. AB - The effect of storage at different relative humidity conditions, for various types of lactose, on roller compaction behaviour was investigated. Three types of lactose were used in this study: anhydrous lactose (SuperTab21AN), spray dried lactose (SuperTab11SD) and alpha-lactose monohydrate 200M. These powders differ in their amorphous contents, due to different manufacturing processes. The powders were stored in a climatic chamber at different relative humidity values ranging from 10% to 80% RH. It was found that the roller compaction behaviour and ribbon properties were different for powders conditioned to different relative humidities. The amount of fines produced, which is undesirable in roller compaction, was found to be different at different relative humidity. The minimum amount of fines produced was found to be for powders conditioned at 20-40% RH. The maximum amount of fines was produced for powders conditioned at 80% RH. This was attributed to the decrease in powder flowability, as indicated by the flow function coefficient ffc and the angle of repose. Particle Image Velocimetry (PIV) was also applied to determine the velocity of primary particles during ribbon production, and it was found that the velocity of the powder during the roller compaction decreased with powders stored at high RH. This resulted in less powder being present in the compaction zone at the edges of the rollers, which resulted in ribbons with a smaller overall width. The relative humidity for the storage of powders has shown to have minimal effect on the ribbon tensile strength at low RH conditions (10-20%). The lowest tensile strength of ribbons produced from lactose 200M and SD was for powders conditioned at 80% RH, whereas, ribbons produced from lactose 21AN at the same condition of 80% RH showed the highest tensile strength. The storage RH range 20-40% was found to be an optimum condition for roll compacting three lactose powders, as it resulted in a minimum amount of fines in the product. PMID- 26940132 TI - Antigen delivery via hydrophilic PEG-b-PAGE-b-PLGA nanoparticles boosts vaccination induced T cell immunity. AB - Here, we evaluate the use of hydrophilic PEG-b-PAGE-b-PLGA (PPP) for the preparation of antigen loaded nanoparticles (NPs) as a platform for prophylactic vaccination. To investigate the suitability of PPP-NPs for antigen delivery, we used the double emulsion evaporation technique to prepare NPs of different sizes, antigen-loading efficiencies and -release kinetics for the model antigen Ovalbumin (OVA). Prior to applying the PPP-NPs in biological in vitro or in vivo models, all materials were tested for absence of cytotoxicity and endotoxins. While the uptake of NPs in antigen presenting cells was size but not polymer dependent, the efficiency of cross presentation of NP-associated antigen on MHC I molecules for CD8 T cell activation depended on the polymer type. T cell activation by antigen-presenting cells was significantly increased in vitro if antigen was delivered via PPP NPs compared to PLGA NPs or soluble OVA, although antigen content was the same in all tested formulations. Subcutaneous application of PPP-OVA-NPs even without adjuvants led to generation of potent CD8 T cell mediated OVA-specific cytotoxicity in vivo that was more pronounced than after application of OVA alone or PLGA-OVA-NPs. Our data suggest that PPP-NPs can serve as platform for antigen-delivery in future vaccination formulations. Although PPP NPs already bear intrinsic adjuvant-function, the complementation with TLR ligands loaded inside NPs may further strengthen the immune response to a point, where it might be possible to use it as a therapeutic vaccine to break immune tolerance in chronic disease states. PMID- 26940134 TI - Anxiety and support resources for Israeli women before gynecological surgery. AB - Gynecologic surgery is a frequent procedure for benign and malignant diseases and may evoke anxiety and a need for support. The purpose of the present study was to examine whether women with suspicion of gynecologic malignancy and those with no suspicion of gynecologic malignancy had different sources of social support and the relationship between this support and their anxiety. A descriptive cross sectional method was used at a large medical center. Data were collected between June and December 2010 from 100 hospitalized women 20-28 hours prior to gynecologic surgery: 50 with suspicion of gynecologic malignancy and 50 with no suspicion of gynecologic malignancy. Social Support and Anxiety Questionnaires were distributed to the participants. The results showed that sources of support differed between the groups: women with suspicion of gynecologic malignancy reported receiving more support from their family and from the nursing staff while women with no suspicion of gynecologic malignancy reported receiving more support from friends or the Internet. Both groups reported similar levels of anxiety. Because women seek support prior to gynecologic surgery, healthcare professionals should play a more active role by offering their support in addition to guiding patients to websites that aim to provide information and support. PMID- 26940136 TI - Surface grafting of octylamine onto poly(ethylene-alt-maleic anhydride) gate insulators for low-voltage DNTT thin-film transistors. AB - This study investigates a spin-coating method for modifying the surface properties of a poly(ethylene-alt-maleic anhydride) (PEMA) gate insulator. The 60 nm-thick PEMA thin film exhibits excellent electrical insulating properties, and its surface properties could be easily modified by surface grafting of octylamine. Due to surface treatment via spin-coating, the surface energy of the PEMA gate insulator decreased, the crystal quality of the organic semiconductor improved, and consequently the performance of low-voltage organic thin-film transistors (TFTs) was enhanced. Our results suggest that the surface treatment of the PEMA gate insulator could be a simple and effective method for enhancing the performance of organic TFTs. PMID- 26940135 TI - Population-wide Impact of Long-term Use of Aspirin and the Risk for Cancer. AB - IMPORTANCE: The US Preventive Services Task Force recently recommended the use of aspirin to prevent colorectal cancer and cardiovascular disease among many US adults. However, the association of aspirin use with the risk for other cancer types and the potential population-wide effect of aspirin use on cancer, particularly within the context of screening, remain uncertain. OBJECTIVES: To examine the potential benefits of aspirin use for overall and subtype-specific cancer prevention at a range of doses and durations of use and to estimate the absolute benefit of aspirin in the context of screening. DESIGN, SETTING, AND PARTICIPANTS: Two large US prospective cohort studies, the Nurses' Health Study (1980-2010) and Health Professionals Follow-up Study (1986-2012), followed up 135 965 health care professionals (88 084 women and 47 881 men, respectively) who reported on aspirin use biennially. The women were aged 30 to 55 years at enrollment in 1976; the men, aged 40 to 75 years in 1986. Final follow-up was completed on June 30, 2012, for the Nurses' Health Study cohort and January 31, 2010, for the Health Professionals Follow-up Study cohort, and data were accessed from September 15, 2014, to December 17, 2015. MAIN OUTCOMES AND MEASURES: Relative risks (RRs) for incident cancers and population-attributable risk (PAR). RESULTS: Among the 88 084 women and 47 881 men who underwent follow-up for as long as 32 years, 20 414 cancers among women and 7571 cancers among men were documented. Compared with nonregular use, regular aspirin use was associated with a lower risk for overall cancer (RR, 0.97; 95% CI, 0.94-0.99), which was primarily owing to a lower incidence of gastrointestinal tract cancers (RR, 0.85; 95% CI, 0.80-0.91), especially colorectal cancers (RR, 0.81; 95% CI, 0.75-0.88). The benefit of aspirin on gastrointestinal tract cancers appeared evident with the use of at least 0.5 to 1.5 standard aspirin tablets per week; the minimum duration of regular use associated with a lower risk was 6 years. Among individuals older than 50 years, regular aspirin use could prevent 33 colorectal cancers per 100 000 person-years (PAR, 17.0%) among those who had not undergone a lower endoscopy and 18 colorectal cancers per 100 000 person-years (PAR, 8.5%) among those who had. Regular aspirin use was not associated with the risk for breast, advanced prostate, or lung cancer. CONCLUSIONS AND RELEVANCE: Long-term aspirin use was associated with a modest but significantly reduced risk for overall cancer, especially gastrointestinal tract tumors. Regular aspirin use may prevent a substantial proportion of colorectal cancers and complement the benefits of screening. PMID- 26940137 TI - A cross-sectional content analysis of Android applications for asthma. AB - Providing patients opportunities for self-management and education about their disease, asthma applications designed for use on an Android operating system can have positive health outcomes across the range of demographics who use mHealth applications. This study provides a content analysis of freely available Google Android Platform Mobile Applications for Asthma. A list of applications was collected on 26 October 2014, using the search feature of the Google Play Android platform and using the words and phrases "Asthma," "Lung Function" and "Peak Flow." Each application was coded for its approach to asthma self-management, based on categories adapted by Huckvale et al., which are based on the Global Initiative for Asthma and the National Asthma Education and Prevention Program. The characteristics of the 15 asthma applications are described. Most of the asthma applications' primary function focused on patient self-monitoring and self assessment. Using the HON Code, we found low health information quality across all asthma applications. Android asthma applications can have positive outcomes in helping patients as they provide opportunities for self-management and education about their disease. Future research should continue to monitor and evaluate the development and use of mHealth Asthma Applications. Based on these findings, and their indication of a gap in existing research, subsequent studies can continue to evaluate the development and use of mHealth Asthma Applications with increasing methodological consistency to improve the quality of in-app health information. PMID- 26940138 TI - GZD856, a novel potent PDGFRalpha/beta inhibitor, suppresses the growth and migration of lung cancer cells in vitro and in vivo. AB - Platelet-derived growth factor receptors (PDGFRalpha/beta) play critical roles in the autocrine-stimulated growth and recruitment of cancer-associated fibroblasts (CAFs) of human lung cancer cells. We have identified GZD856 as a new PDGFR inhibitor that potently inhibits PDGFRalpha/beta kinase activity and blocks this signaling pathway in lung cancer cells both in vitro and in vivo. GZD856 strongly suppresses the proliferation of PDGFRalpha-amplified H1703 (PDGFRbeta(-)) human lung cancer cells and demonstrates significant in vivo antitumor efficacy in a xenograft mouse model. Although GZD856 displays only limited in vitro antiproliferative efficiency against PDGFRalpha(-)/PDGFRbeta(+) A549 lung cancer cells, it efficiently inhibits the in vivo growth and metastasis of A549 cancer cells in xenograft and orthotopic models, respectively. The promising in vivo antitumor activity of GZD856 in A549 models may result from its suppression of PDGFR-related microenvironment factors, such as recruitment of CAFs and collagen content in stromal cells. GZD856 may be considered as a promising new candidate for anti-lung cancer drug development. PMID- 26940139 TI - Multiple cellular origins and molecular evolution of intrahepatic cholangiocarcinoma. AB - Intrahepatic cholangiocarcinoma (ICC) is an aggressive malignancy associated with unfavorable prognosis and for which no effective treatments are available. Its molecular pathogenesis is poorly understood. Genome-wide sequencing and high throughput technologies have provided critical insights into the molecular basis of ICC while sparking a heated debate on the cellular origin. Cancer exhibits variabilities in origin, progression and cell biology. Recent evidence suggests that ICC has multiple cellular origins, including differentiated hepatocytes; intrahepatic biliary epithelial cells (IBECs)/cholangiocytes; pluripotent stem cells, such as hepatic stem/progenitor cells (HPCs) and biliary tree stem/progenitor cells (BTSCs); and peribiliary gland (PBG). However, both somatic mutagenesis and epigenomic features are highly cell type-specific. Multiple cellular origins may have profoundly different genomic landscapes and key signaling pathways, driving phenotypic variation and thereby posing significant challenges to personalized medicine in terms of achieving the optimal drug response and patient outcome. Considering this information, we have summarized the latest experimental evidence and relevant literature to provide an up-to-date view of the cellular origin of ICC, which will contribute to establishment of a hierarchical model of carcinogenesis and allow for improvement of the anatomical based classification of ICC. These new insights have important implications for both the diagnosis and treatment of ICC patients. PMID- 26940140 TI - Epithelial-mesenchymal transition-related genes are linked to aggressive local recurrence of hepatocellular carcinoma after radiofrequency ablation. AB - We reported that poor prognoses of hepatocellular carcinoma (HCC) patients after radiofrequency ablation (RFA) are owing to up-regulation of expression of hypoxia inducible factor-1 and epithelial cell adhesion molecule. We investigated aggressive progression in residual liver tumors (RLTs) after RFA to focus on expression of epithelial-mesenchymal transition (EMT)-related genes and miRNAs. Ten patients with recurrent HCC post-RFA who underwent hepatectomy (RFA group) and 78 patients with HCC without prior RFA (non-RFA group) were enrolled. We examined expression of transforming growth factor (TGF)-beta, Twist, vimentin, and Snail-1 mRNAs in tumor tissues, and expression of miR-34a and miR-200c. Expression of TGF-beta, Twist and Snail-1 in the RFA group was significantly higher than that in the non-RFA group (P < 0.05); vimentin expression in the RFA group was higher than that in the non-RFA group (P = 0.07). Expression of miR 200c and miR-34a in the RFA group was significantly lower than that in the non RFA group (miR-200c: P = 0.04; miR-34a: P < 0.01). Increased expression of EMT markers through down-regulation of miRNA expression in RLTs after RFA may be related to poor prognoses of HCC patients with aggressive local recurrence after RFA. PMID- 26940142 TI - Final robotic frontier: the evolution and current state of robot-assisted radical cystectomy. PMID- 26940144 TI - Post-translational control of protein function with light using a LOV-intein fusion protein. AB - Methods for the post-translational control of protein function with light hold much value as tools in cell biology. To this end, we report a fusion protein that consists of DnaE split-inteins, flanking the light sensitive LOV2 domain of Avena sativa. The resulting chimera combines the activities of these two unrelated proteins to enable controlled formation of a functional protein via upregulation of intein splicing with blue light in bacterial and human cells. PMID- 26940141 TI - Comparative Perspectives on Oxytocin and Vasopressin Receptor Research in Rodents and Primates: Translational Implications. AB - In the last several decades, sophisticated experimental techniques have been used to determine the neurobiology of the oxytocin and vasopressin systems in rodents. Using a suite of methodologies, including electrophysiology, site-specific selective pharmacology, receptor autoradiography, in vivo microdialysis, and genetic and optogenetic manipulations, we have gained unprecedented knowledge about how these neuropeptides engage neural circuits to regulate behaviour, particularly social behaviour. Based on this foundation of information from rodent studies, we have started generating new hypotheses and frameworks about how the oxytocin and vasopressin systems could be acting in humans to influence social cognition. However, despite the recent inundation of publications using intranasal oxytocin in humans, we still know very little about the neurophysiology of the oxytocin system in primates more broadly. Furthermore, the design and analysis of these human studies have remained largely uninformed of the potential neurobiological mechanisms underlying their findings. Although the methods available for studying the oxytocin and vasopressin systems in humans are incredibly limited as a result of practical and ethical considerations, there is great potential to fill the gaps in our knowledge by developing better nonhuman primate models of social functioning. Behavioural pharmacology and receptor autoradiography have been used to study the oxytocin and vasopressin systems in nonhuman primates, and there is now great potential to broaden our understanding of the neurobiology of these systems. In this review, we discuss comparative findings in receptor distributions in rodents and primates, with perspectives on the functionality of conserved regions of expression in these distinct mammalian clades. We also identify specific ways that established technologies can be used to answer basic research questions in primates. Finally, we highlight areas of future research in nonhuman primates that are experimentally poised to yield critical insights into the anatomy, physiology and behavioural effects of the oxytocin system, given its remarkable translational potential. PMID- 26940143 TI - MICA*A4 protects against ulcerative colitis, whereas MICA*A5.1 is associated with abscess formation and age of onset. AB - Ulcerative colitis (UC) is one of the two major forms of inflammatory bowel disease, the aetiology of which remains unknown. Several studies have demonstrated the genetic basis of disease, identifying more than 130 susceptibility loci. The major histocompatibility complex class I chain-related gene A (MICA) is a useful candidate to be involved in UC pathogenesis, because it could be important in recognizing the integrity of the epithelial cell and its response to stress. The aim of this study was to analyse the relationship between polymorphisms in the transmembrane domain of MICA and susceptibility to develop UC. A total of 340 patients with UC and 636 healthy controls were genotyped for MICA transmembrane polymorphism using a polymerase chain reaction (PCR) combined with fluorescent technology. Different MICA alleles were determined depending on the PCR product size. The allele MICA*A4 was less frequent in patients than in controls (P = 0.003; OR = 0.643), and this protective role is higher when it forms haplotype with B*27 (P = 0.002; OR = 0.294). The haplotype HLA-B*52/MICA*A6 was also associated with UC [P = 0.001; odds ratio (OR) = 2.914]. No other alleles, genotypes or haplotypes were related with UC risk. Moreover, MICA*A5.1 is associated independently with abscesses (P = 0.002; OR = 3.096) and its frequency is lower in patients diagnosed between ages 17 and 40 years (P = 0.007; OR = 0.633), meaning an extreme age on onset. No association with location, extra intestinal manifestations or need for surgery was found. PMID- 26940145 TI - Association of single nucleotide polymorphisms in UBR2 gene with idiopathic aspermia or oligospermia in Sichuan, China. AB - The associations between three single nucleotide polymorphisms (SNPs; rs3749897, rs16895863 and rs373341) of UBR2 gene and idiopathic aspermia or oligospermia were investigated in this study by a case-control experiment with 149 fertile and 316 infertile men, including 244 patients with idiopathic aspermia and 72 patients with severe oligospermia. The time-of-flight mass spectrometry (Sequenom MassARRAY(r) system) was used in this study. A significant difference between the oligospermia men (oligospermia group) and the fertile men (control group) was observed in this research (odds ratio [OR]: 2.764; 95% CI: 95% confidence interval [CI]: 1.171-6.525; P = 0.017), which could indicate that the combined AT TC-CC genotype in the UBR2 gene (rs16895863, rs373341, rs3749897 respectively) is a possible risk of idiopathic oligospermia for men in Sichuan, China. PMID- 26940146 TI - "I want a normal life like everyone else": Daily life of asylum seekers in Iceland. AB - AIM: An ever-increasing number of people seek asylum in Iceland. The wait for resolution on application for asylum can take up to three years. During this time participation in daily occupations is disrupted. This study was carried out to gain an understanding of the experience of living as an asylum seeker in Iceland. It explored asylum seekers' opportunities for participation in occupations as well as their overall experiences while waiting for the processing of their application. METHODS: Eleven semi-structured interviews were conducted with nine participants, of whom six were asylum seekers. A constructivist grounded theory approach was applied to categorize and synthesize data. RESULTS: Four major categories emerged that reflected the participants' difficult living conditions, lack of opportunities for participation, lack of belonging, and feelings of powerlessness. The long processing time of their applications was enormously stressful as well as not being in charge of one's life, living conditions, or income. CONCLUSION: The results indicate that the long processing time of application for asylum has deteriorating effects on health. In order to promote asylum seekers' well-being and occupational rights attention needs to be focused on their living conditions and opportunities for participation in meaningful occupations, including work. PMID- 26940147 TI - Canadian women's attitudes toward noninvasive prenatal testing of fetal DNA in maternal plasma (.). AB - OBJECTIVE: To determine the perceptions and attitudes of Canadian women to Noninvasive Prenatal Testing of fetal DNA. STUDY DESIGN: A designed questionnaire was administered to women attending the outpatient antenatal clinic at a tertiary urban hospital. Attitudes to current and new prenatal screening modalities were assessed using a five-point Likert scale. Bowker's test of symmetry was used to compare individual responses regarding the two screening modalities. Changes in women's responses pre- and post-delivery were also compared. RESULTS: One hundred and twenty-nine women were enrolled in this study. 88% of women state that they would perform prenatal screening via fetal DNA in the maternal plasma if available. When compared to conventional screening, significantly less women believe that the NIPT should be available upon request for non-medical traits (36.4% versus 60.4%, p < 0.001). When compared to their answer before delivery, more women agreed that screening with fetal DNA in maternal plasma could be used in a negative way to select for desired non-medical traits such as gender. CONCLUSIONS: The use of fetal DNA in the maternal plasma is widely accepted in our Canadian population as a future method of noninvasive prenatal screening despite recognition of certain ethical concerns. This information can be used when implementing new genetic screening programs. PMID- 26940148 TI - [Not Available]. PMID- 26940149 TI - [Not Available]. PMID- 26940150 TI - Further defining the phenotypic spectrum of B4GALT7 mutations. AB - Proteoglycans are components of the extracellular matrix with diverse biological functions. Defects in proteoglycan synthesis have been linked to several human diseases with common features of short stature, hypermobility, joint dislocations, and skeletal dysplasia. B4GALT7 encodes galactosyltransferase-I that catalyzes the addition of a galactose moiety to a xylosyl group in the tetrasaccharide linker of proteoglycans. Mutations in this gene have been associated with the rare progeroid form of Ehlers Danlos syndrome and in addition more recently found to underlie Larsen of Reunion Island syndrome. Nine individuals have been reported with a diagnosis of the progeroid form of Ehlers Danlos syndrome, four of whom have had molecular characterization showing homozygous or compound heterozygous mutations in B4GALT7. We report two newly described patients with compound heterozygous mutations in B4GALT7, and show that the six individuals with confirmed mutations do not have the progeroid features described in the original five patients with a clinical diagnosis of the progeroid form of Ehlers Danlos syndrome. We suggest that galactosyltransferase-I deficiency does not cause the progeroid form of Ehlers Danlos syndrome, but instead results in a clinically recognizable syndrome comprising short stature, joint hypermobility, radioulnar synostosis, and severe hypermetropia. This group of syndromic patients are on a phenotypic spectrum with individuals who have Larsen of Reunion Island syndrome, although the key features of osteopenia, fractures and hypermetropia have not been reported in patients from Reunion Island. (c) 2016 Wiley Periodicals, Inc. PMID- 26940151 TI - Comparison of the effect of high fruit and soybean products diet and standard diet interventions on serum uric acid in asymptomatic hyperuricemia adults: an open randomized controlled trial. AB - The aim of this study was to compare the effect of high fruit and soybean products diet and standard diet interventions on serum uric acid (SUA) in asymptomatic hyperuricemia adults. A total of 187 Chinese adults (20-59 years old) with asymptomatic hyperuricemia participated in this randomized trial and were assigned to receive the standard diet recommended by guideline (group 1) and high fruit and soybean products diet (group 2) for 3 months. The outcome of SUA was assessed before and at the end of the intervention period. After 3 months, the SUA in group 1 and group 2 was significant reduced, whereas the SUA was not significantly changed in-between groups. These data suggest that over a 3-month period, although the high fruit and soybean products diet and standard diet interventions yield no different effects on SUA, the high fruit and soybean products dietary intervention could be an effective alternative to a standard diet for achieving clinically important reductions in SUA for asymptomatic hyperuricemia patients. PMID- 26940152 TI - Neuroinflammation in Synucleinopathies. AB - The causes of most neurodegenerative diseases are attributed to multiple genetic and environmental factors interacting with one another. Above all, inflammation in the nervous system has been implicated in many neurodegenerative diseases. Still, the roles of neuroinflammation in disease mechanisms and the triggers of inflammatory responses in disease-inflicted brain tissues seem to remain unclear. This review will examine previous studies that had been done from genetic, pathological and epidemiological perspectives. These studies assess the involvement of neuroinflammation in synucleinopathies, a group of neurodegenerative diseases that are characterized by deposition of alpha synuclein aggregates such as Parkinson's disease, dementia with Lewy bodies and multiple system atrophy. The review will also discuss the role of alpha-synuclein aggregates in triggering inflammatory responses from glial cells. It is expected that a precise assessment of the roles and mechanisms of neuroinflammation in neurodegenerative diseases will pave the way for the development of disease modifying drugs. PMID- 26940153 TI - Analysis of National Institutes of Health Funding to Departments of Urology. AB - OBJECTIVE: To elucidate the current portfolio of National Institutes of Health (NIH) funding to departments of urology at U.S. medical schools. MATERIALS AND METHODS: The NIH Research Portfolio Online Reporting Tools Expenditures and Results was used to generate a comprehensive analysis of NIH research grants awarded to urology departments during 2014. Costs, mechanisms, and institutes were summarized with descriptive statistics. Demographic data were obtained for principal investigators and project abstracts were categorized by research type and area. Fiscal totals were calculated for 2005-2014 and compared with other surgical departments during 2014. RESULTS: One hundred one investigators at 36 urology departments received $55,564,952 in NIH funding during 2014. NIH-funded investigators were predominately male (79%) and PhD scientists (52%). Funding totals did not vary by terminal degree or sex, but increased with higher academic rank (P < .001). The National Cancer Institute (54.7%) and National Institute of Diabetes and Digestive and Kidney Diseases (32.2%) supported the majority of NIH funded urologic research. The R01 grant accounted for 41.0% of all costs. The top 3 NIH-funded clinical areas were urologic oncology (62.1%), urinary tract infection (8.8%), and neurourology (7.6%). A minority of costs supported clinical research (12.9%). In 2014, urology had the least number of NIH grants relative to general surgery, ophthalmology, obstetrics & gynecology, otolaryngology, and orthopedic surgery. CONCLUSION: NIH funding to urology departments lags behind awards to departments of other surgical disciplines. Future interventions may be warranted to increase NIH grant procurement in urology. PMID- 26940154 TI - Defying the activity-stability trade-off in enzymes: taking advantage of entropy to enhance activity and thermostability. AB - The biotechnological applications of enzymes are limited due to the activity stability trade-off, which implies that an increase in activity is accompanied by a concomitant decrease in protein stability. This premise is based on thermally adapted homologous enzymes where cold-adapted enzymes show high intrinsic activity linked to enhanced thermolability. In contrast, thermophilic enzymes show low activity around ambient temperatures. Nevertheless, genetically and chemically modified enzymes are beginning to show that the activity-stability trade-off can be overcome. In this review, the origin of the activity-stability trade-off, the thermodynamic basis for enhanced activity and stability, and various approaches for escaping the activity-stability trade-off are discussed. The role of entropy in enhancing both the activity and the stability of enzymes is highlighted with a special emphasis placed on the involvement of solvent water molecules. This review is concluded with suggestions for further research, which underscores the implications of these findings in the context of productivity curves, the Daniel-Danson equilibrium model, catalytic antibodies, and life on cold planets. PMID- 26940156 TI - What influences the implementation of the New Zealand stroke guidelines for physiotherapists and occupational therapists? AB - Purpose To explore perceived barriers and facilitators to the use of the New Zealand (NZ) stroke guidelines by occupational therapists and physiotherapists. Methods A qualitative descriptive methodology was used. Eligible physiotherapists and occupational therapists (NZ registered, working in one of two hospitals, treating at least 10 patients with stroke in the previous year) were invited to participate in semi-structured interviews to elicit their perceptions of the utility and feasibility of the NZ stroke guidelines and identify barriers and facilitators to their implementation. All interviews were audio-recorded and transcribed. Conventional content analysis with constant comparative methods was used for coding and analysis. Results The main themes influencing guideline implementation were resources and characteristics of the guidelines, the organization, the patient and family and the therapist. Insufficient resources were a major barrier that crossed many of the themes. Participants suggested a range of strategies relating to the organization to improve therapists' alignment to the guidelines. Conclusion Alignment to the guidelines in NZ is influenced both positively and negatively by a range of interacting factors, consistent with other studies. Alignment might be improved by the introduction of some relatively simple strategies, such as ring-fencing time for access to resources and training in the use of the guidelines. Many of the barriers and related interventions are likely to be more complex. Implications for rehabilitation Alignment with stroke guidelines has been shown to improve patient outcomes. Therapist alignment with the implementation of the New Zealand stroke guidelines is influenced by guideline characteristics, organizational characteristics, resources, patient and family characteristics and therapist characteristics. Frequently encountered barriers related to limited resources, particularly time. Ring-fencing regular time for access to resources and training in the use of guidelines are examples of simple strategies that may reduce barriers. PMID- 26940155 TI - Psychometric properties of the Albanian version of chewing-function questionnaire CFQ-ALB. AB - BACKGROUND: The new Chewing Function Questionnaire (CFQ) was lately developed in Croatia to measure the chewing ability in prosthodontic patients, as a one dimensional instrument consisting of 10-items. Therefore, the objective of this study was to develop an Albanian version of the CFQ questionnaire and to test its psychometric properties in a new typical environment among the Kosovo population. MATERIALS AND METHODS: The original version of CFQ questionnaire was translated and cross-culturally adapted from the English language into Albanian in accordance with international guidelines. Its validity (construct, convergent and discriminative) and internal consistency (reliability) were tested in 205 participants. Test-retest reliability was evaluated in 61 subjects with natural teeth, and responsiveness was evaluated in 51 prosthodontic patients with treatment needs. RESULTS: Internal consistency of CFQ-ALB indicated excellent agreement, with Cronbach's alpha values of 0.974 and average inter-item correlation of 0.792. Intraclass correlation coeficinets for test-retest were found without significant differences by 95 % of confidence intervals (p > 0.05). Construct validity was supported by a single factor that accounted for 81.711 % of the variance observed. Convergent validity was supported by the association between self-reported general satisfactions with chewing and CFQ summary scores. Discriminat validity was supported as statistically significant differences were observed between pre-defined groups. Responsiveness was confirmed by the significant difference between baseline summary scores and the after treatment scores; the mean change was 15.57 (SD =2.49) (p < 0.001). CONCLUSION: The obtained results suggest excellent psychometric properties of the CFQ-ALB questionnaire for determining chewing function in the Republic of Kosovo. PMID- 26940157 TI - Gastroesophageal junction carcinoma and brachial plexopathy: An anatomic explanation via perineural spread. PMID- 26940158 TI - The Effect of Earplugs in Preventing Hearing Loss From Recreational Noise Exposure: A Systematic Review. AB - IMPORTANCE: The prevalence of hearing loss among children and adolescents is rising dramatically, caused mainly by increased exposure to recreational noise. OBJECTIVE: To present a systematic overview of the effectiveness of wearing earplugs to music venues, such as nightclubs and concert halls, to prevent hearing loss and tinnitus directly after exposure. EVIDENCE ACQUISITION: PubMed, EMBASE, and the Cochrane Library databases were searched for articles from database inception to June 22, 2015, using the keywords music and earplugs and all synonyms. Titles, abstracts, and full text of retrieved articles were screened for eligible articles. The directness of evidence (relevance of the assessed articles) and risk of bias of eligible articles were assessed. For the included articles, the study characteristics and data on our outcomes of interest (hearing loss and tinnitus) were extracted. Data analysis occurred from June 22 to July 3, 2015. FINDINGS: Of 228 articles screened, 4 were eligible for critical appraisal. After critical appraisal, 2 studies with a high directness of evidence and low or moderate risk of bias remained for data extraction. Only 1 of these articles was a randomized clinical trial, which found significantly lower postconcert differences in thresholds and a lower proportion of threshold shifts in the group using earplugs compared with the unprotected group. In the other study, only 3 individuals wore earplugs, and no significant differences were found between the 2 groups. CONCLUSIONS AND RELEVANCE: The available evidence on the effectiveness of earplugs in preventing hearing damage directly after recreational music exposure is scarce. Only 1 well-conducted randomized clinical trial was found, which showed that wearing earplugs to concerts is effective in reducing postconcert threshold shifts. There is a need for further research on this topic to strengthen the level of evidence. Physicians should promote awareness on the risks of recreational noise and recommend the use of earplugs among their patients who visit music venues. PMID- 26940160 TI - Effects of intercropping of oat (Avena sativa L.) with white lupin (Lupinus albus L.) on the mobility of target elements for phytoremediation and phytomining in soil solution. AB - This study aims to investigate how intercropping of oat (Avena sativa L.) with white lupin (Lupinus albus L.) affects the mobile fractions of trace metals (Fe, Mn, Pb, Cd, Th, U, Sc, La, Nd, Ge) in soil solution. Oat and white lupin were cultivated in monocultures and mixed cultures with differing oat/white lupin ratios (11% and 33% lupin, respectively). Temporal variation of soil solution chemistry was compared with the mobilization of elements in the rhizosphere of white lupin and concentrations in plant tissues. Relative to the monocrops, intercropping of oat with 11% white lupin significantly increased the concentrations of Fe, Pb, Th, La and Nd in soil solution as well as the concentrations of Fe, Pb, Th, Sc, La and Nd in tissues of oat. Enhanced mobility of the mentioned elements corresponded to a depletion of elements in the rhizosphere soil of white lupin. In mixed cultures with 33% lupin, concentrations in soil solution only slightly increased. We conclude that intercropping with 11% white lupin might be a promising tool for phytoremediation and phytomining research enhancing mobility of essential trace metals as well as elements with relevance for phytoremediation (Pb, Th) and phytomining (La, Nd, Sc) in soil. PMID- 26940159 TI - Giant Controllable Magnetization Changes Induced by Structural Phase Transitions in a Metamagnetic Artificial Multiferroic. AB - The realization of a controllable metamagnetic transition from AFM to FM ordering would open the door to a plethora of new spintronics based devices that, rather than reorienting spins in a ferromagnet, harness direct control of a materials intrinsic magnetic ordering. In this study FeRh films with drastically reduced transition temperatures and a large magneto-thermal hysteresis were produced for magnetocaloric and spintronics applications. Remarkably, giant controllable magnetization changes (measured to be as high has ~25%) are realized by manipulating the strain transfer from the external lattice when subjected to two structural phase transitions of BaTiO3 (001) single crystal substrate. These magnetization changes are the largest seen to date to be controllably induced in the FeRh system. Using polarized neutron reflectometry we reveal how just a slight in plane surface strain change at ~290C results in a massive magnetic transformation in the bottom half of the film clearly demonstrating a strong lattice-spin coupling in FeRh. By means of these substrate induced strain changes we show a way to reproducibly explore the effects of temperature and strain on the relative stabilities of the FM and AFM phases in multi-domain metamagnetic systems. This study also demonstrates for the first time the depth dependent nature of a controllable magnetic order using strain in an artificial multiferroic heterostructure. PMID- 26940161 TI - A Randomized Trial of Fixed-Dose Combination Brinzolamide 1%/Brimonidine 0.2% as Adjunctive Therapy to Travoprost 0.004. AB - PURPOSE: To evaluate the safety and efficacy of adding fixed-combination brinzolamide 1%/brimonidine 0.2% (BBFC) as adjunctive therapy to travoprost 0.004% (TRAV) in patients with open-angle glaucoma or ocular hypertension. DESIGN: Multicenter, randomized, double-masked, parallel-group phase 4 clinical trial. METHODS: setting: Multicenter; 32 sites in the United States. PATIENT POPULATION: Total of 233 patients with open-angle glaucoma or ocular hypertension and with mean intraocular pressure (IOP) >=21 mm Hg and <32 mm Hg while receiving once-daily TRAV monotherapy. INTERVENTION: Masked BBFC or vehicle (3 times daily) adjunctive to TRAV for 6 weeks. MAIN OUTCOME MEASURE: Mean diurnal IOP averaged over 8 AM, 10 AM, 3 PM, and 5 PM time points at week 6. Superiority of BBFC+TRAV over vehicle+TRAV was based on statistical significance of a treatment difference favoring BBFC+TRAV. RESULTS: Mean diurnal IOP at week 6 (least squares mean +/- standard error) was 17.6 +/- 0.4 mm Hg and 20.7 +/- 0.4 mm Hg in the BBFC+TRAV and vehicle+TRAV groups, respectively (between-group difference, -3.2 +/- 0.5 mm Hg; P < .0001). Superiority of BBFC+TRAV over vehicle+TRAV was established. Mean and percent diurnal IOP change from baseline were significantly greater with BBFC+TRAV compared with vehicle+TRAV (P < .0001 for both). Conjunctival hyperemia was the most common treatment-related adverse event in either group (BBFC+TRAV, 12.8%; vehicle+TRAV, 6.0%). CONCLUSIONS: Adjunctive treatment with BBFC added to TRAV resulted in lower mean diurnal IOP after 6 weeks of treatment compared with vehicle added to TRAV; this difference was both statistically and clinically significant. PMID- 26940162 TI - Potential Predictors of Poor Visual Outcome in Human Leukocyte Antigen-B27 Associated Uveitis. AB - PURPOSE: To identify potential predictors of permanent vision loss in patients with human leukocyte antigen (HLA)-B27-associated uveitis in a tertiary referral center. DESIGN: Retrospective case-control study. METHODS: The charts of 212 patients (338 eyes) with HLA-B27-associated uveitis that visited the University Medical Center Utrecht with a follow-up of at least 6 months were retrospectively studied. Clinical features at presentation and during follow-up were compared to final visual outcome in quiescent state. Eyes with (sub-) normal vision (>20/50) were compared with visually impaired (<=20/50) and blind (<=5/50, or a visual field of <10 degrees) eyes, using survival analysis. A multivariate Cox proportional hazards analysis was performed to analyze potential predictors for permanent vision loss. RESULTS: Median follow-up was 10.4 years (range, 0.5-44.7 years). During follow-up 226 eyes (66%) experienced vision loss up to 20/50, but most recovered. Twenty patients (9%) became permanently visually impaired or blind in at least 1 eye because of uveitis, after a median of 9.7 years (range, 0 20.9 years). The main cause was secondary glaucoma or related to glaucoma surgery (12/22 eyes, 55%). Survival analysis showed, after adjustment for age and sex, an ocular pressure of >21 mm Hg, hypotony, and panuveitis to be potential predictors at presentation, and the development of secondary glaucoma or hypotony to be predictors of blindness or visual impairment during follow-up. CONCLUSIONS: The long-term visual prognosis of HLA-B27-associated uveitis is relatively good, but the true incidence of permanent vision loss is probably still underestimated. Our findings highlight the importance of proper control of intraocular pressure. PMID- 26940163 TI - Relating Retinal Morphology and Function in Aging and Early to Intermediate Age related Macular Degeneration Subjects. AB - PURPOSE: To evaluate relationships between age-related macular degeneration (AMD) morphology on spectral-domain optical coherence tomography (SDOCT) and visual function. DESIGN: Cross-sectional, observational. METHODS: From the Alabama Study on Early AMD baseline visit, visual acuity, cone-mediated sensitivity, rod mediated dark adaptation, and SDOCT were obtained in 1 eye per subject with no apparent retinal aging (n = 15), normal aging (n = 15), early AMD (n = 15), and intermediate AMD (n = 46). The volumes of retinal pigment epithelium (RPE)-drusen complex, RPE-drusen complex abnormal thinning, RPE-drusen complex abnormal thickening, and inner and outer retina were calculated in specified regions using semi-automated SDOCT segmentation. RESULTS: Better cone-mediated sensitivity was associated with greater RPE-drusen complex volume (r = 0.34, P < .001) and less RPE-drusen complex abnormal thinning volume (r = -0.31, P = .003). Longer rod mediated dark adaptation time, the duration for rod-mediated sensitivity to recover from photo-bleach exposure, correlated with lower RPE-drusen complex volume (r = -0.34, P = .005) and greater RPE-drusen complex abnormal thinning volume (r = 0.280, P = .023). In 19 eyes with subretinal drusenoid deposits (SDD) vs 47 eyes without SDD, rod-mediated dark adaptation time was longer (mean +/- SD 13.5 +/- 7.0 vs 10.2 +/- 3.1 minutes, P = .004), RPE-drusen complex abnormal thinning volume was greater (P < .0001), and visual acuity and cone sensitivity did not differ. CONCLUSION: Decreased function relates to structural markers on SDOCT in AMD. Because the RPE-drusen complex includes the interdigitation of outer segments and RPE apical processes and SDD in eyes with AMD, slower dark adaptation might be related to structural abnormalities of the RPE, the RPE photoreceptor interface, or both. PMID- 26940164 TI - Second Primary Neoplasms in Patients With Uveal Melanoma: A SEER Database Analysis. AB - PURPOSE: To determine the risk of second primary neoplasms (SPNs) in subjects previously diagnosed with uveal melanoma (UM), including an analysis on whether radiotherapy is a risk factor to develop these SPNs. DESIGN: Retrospective cohort study. METHODS: Using the Surveillance, Epidemiology, and End Results (SEER) 9 database, we identified patients diagnosed with UM as their first malignancy between 1973 and 2011 (n = 3976). We obtained standardized incidence ratios (SIR) and excess absolute risks of SPNs on patients with UM compared to a reference population. Multivariate Cox regression models were used to evaluate the effect of radiotherapy in SPN risk. RESULTS: Sixteen percent (n = 641) of the patients developed SPNs during a median follow-up of 83 months (range, 1-463 months). This represented an 11% excess risk compared to the reference population, mainly owing to a significantly increased risk of skin melanomas (SIR = 2.93, 95% CI: 2.23 3.78) and kidney tumors (SIR = 1.91, 95% CI: 1.27-2.76), primarily in those diagnosed between 30 and 59 years of age. The occurrence of second UM was also increased (SIR = 16.90, 95% CI: 9.00-28.90), which likely includes recurrences misclassified as a second cancer. Radiotherapy was performed in 39% (n = 1538) of the patients. Multivariate analysis revealed that this treatment was not an independent risk factor for SPNs (hazard ratio = 1.06, 95% CI: 0.88-1.26, P = .54). CONCLUSIONS: Patients with UM presented an 11% higher risk of SPNs compared to the reference population. Radiotherapy does not seem to be a risk factor. SPNs should be considered in the surveillance of UM. PMID- 26940165 TI - Effects of Hormone Therapy on Intraocular Pressure: The Women's Health Initiative Sight Exam Study. AB - PURPOSE: Previous studies suggest that hormone therapy favorably affects intraocular pressure (IOP). Here, we examined the association between hormone therapy use and IOP in the context of a large randomized trial. DESIGN: Secondary data analysis from a randomized controlled trial. METHODS: We used data from the Women's Health Initiative-Sight Exam (WHISE). Women with prior hysterectomy received oral conjugated equine estrogen (0.625 mg/day) or placebo. Women with a uterus received estrogen plus progestin (medroxyprogesterone acetate 2.5 mg/day) or placebo. IOP was measured 5 years after randomization. Adjusted linear regression models were used to assess the association between hormone therapy and IOP. RESULTS: The WHISE included 1668 women in the estrogen-alone trial (aged 63 86, mean 72 years) and 2679 women in the estrogen-plus-progestin trial (aged 63 87, mean 72 years). In multivariate analyses, compared to placebo treatment, treatment with estrogen alone was associated with a 0.5 mm Hg reduction of the IOP in the right eye (95% CI: -0.8, -0.1, P = .005) and a 0.6 mm Hg (95% CI: 0.9, -0.3, P < .001) reduction of the IOP in the left eye. In the estrogen-plus progestin trial, there was no significant difference in IOP between the treatment and placebo groups (P = .30 right eye and P = .43 left eye). CONCLUSIONS: This study represents an IOP analysis in the largest hormone trial available. Estrogen alone therapy in postmenopausal women is associated with a small but significant IOP reduction of 0.5 mm Hg. The clinical significance of this small decrease remains to be determined. PMID- 26940166 TI - Outcomes After Proton Beam Therapy for Large Choroidal Melanomas in 492 Patients. AB - PURPOSE: To evaluate proton beam therapy (PBT) as a means to preserve the eye and spare some vision while not deteriorating survival in patients with large choroidal melanomas. DESIGN: This is a retrospective, consecutive cohort study of patients with T3-4 choroidal melanomas according to the 7th edition of the American Joint Cancer Classification treated with PBT over a 24-year period. RESULTS: A total of 492 patients were included. Mean (range) tumor thickness and diameter were 8.77 (2-15) mm and 14.91 (7-24.1) mm, respectively. Mean macular and optic disc distance were 4.56 (0-19.9) mm and 4.59 (0-22.1) mm, respectively. Mean follow-up was 61.9 months. Rates of neovascular glaucoma (NVG) and enucleation (mainly for local recurrence or NVG) were 27.0% and 19.5%, respectively. Enucleation rates decreased over time. The 5-year local control was 94%. Mean baseline visual acuity was 20/63, and visual acuity >=20/200 was preserved in 20% of patients. At 5 years, 25% of T3 patients presented with metastasis; overall and specific survival rates were 65% and 75%, respectively. CONCLUSION: Local control after PBT remained good with increasingly manageable complications and fewer secondary enucleations over time for these large melanomas. As PBT does not seem to deteriorate survival in these patients having a high risk of metastasis, PBT may be considered as a safe and efficient alternative to enucleation in patients with large choroidal melanoma, and may help to spare some vision. PMID- 26940167 TI - Bupropion Hydrochloride. AB - Bupropion hydrochloride is a norepinephrine-dopamine disinhibitor (NDDI) approved for the treatment of depression and smoking cessation. Bupropion is a trimethylated monocyclic phenylaminoketone second-generation antidepressant, which differs structurally from most antidepressants, and resides in a novel mechanistic class that has no direct action on the serotonin system. Comprehensive chemical, physical, and spectroscopic profiles are presented. This analytical profile provides an extensive spectroscopic investigation utilizing mass spectrometry, one- and two-dimensional NMR, solid-state NMR, IR, NIR, Raman, UV, and X-ray diffraction. The profile also includes significant wet chemistry studies for pH, solubility, solution, and plasma stability. Both HPLC and UPLC methodology are presented for bupropion and its related impurities or major metabolites. The profile concludes with an overview of biological properties that includes toxicity, drug metabolism, and pharmacokinetics. PMID- 26940168 TI - Calcium Carbonate. AB - Calcium carbonate is a chemical compound with the formula CaCO3 formed by three main elements: carbon, oxygen, and calcium. It is a common substance found in rocks in all parts of the world (most notably as limestone), and is the main component of shells of marine organisms, snails, coal balls, pearls, and eggshells. CaCO3 exists in different polymorphs, each with specific stability that depends on a diversity of variables. PMID- 26940169 TI - Carbamazepine. AB - This chapter includes the aspects of carbamazepine. The drug is synthesized by the use of 5H-dibenz[b,f]azepine and phosgene followed by subsequent reaction with ammonia. Carbamazepine is generally used for the treatment of seizure disorders and neuropathic pain, it is also important as off-label for a second line treatment for bipolar disorder and in combination with an antipsychotic in some cases of schizophrenia when treatment with a conventional antipsychotic alone has failed. Other uses may include attention deficit hyperactivity disorder, schizophrenia, phantom limb syndrome, complex regional pain syndrome, borderline personality disorder, and posttraumatic stress disorder. The chapter discusses the drug metabolism and pharmacokinetics and presents various methods of analysis of this drug such electrochemical analysis, spectroscopic analysis, and chromatographic techniques of separation. It also discusses its physical properties such as solubility characteristics, X-ray powder diffraction pattern, and thermal methods of analysis. The chapter is concluded with a discussion on its biological properties such as activity, toxicity, and safety. PMID- 26940170 TI - Dacarbazine. AB - Dacarbazine is a cell cycle nonspecific antineoplastic alkylating agent used in the treatment of metastatic malignant melanoma. This chapter contains the descriptions of the drug: nomenclature, formulae, chemical structure, elemental composition, and appearance. The uses and applications of dacarbazine and the methods that were used for its preparation are reported. The methods which were used for the physical characterization of the drug are ionization constant, solubility, X-ray powder diffraction pattern, crystal structure, melting point, and differential scanning calorimetry. The profile contains the spectra of the drug: ultraviolet spectrum, vibrational spectrum, nuclear magnetic resonance spectra, and mass spectrum. The compendial methods of analysis for dacarbazine include the United States Pharmacopeia methods, British Pharmacopeia methods, and International Pharmacopeia methods. Other reported methods that are used for the analysis of the drug are high-performance liquid chromatography, high-performance liquid chromatography-mass spectrometry, and polarography. Metabolism, pharmacokinetics, and stability studies on dacarbazine are also included. Reviews of some analytical methods and physicochemical properties of the drug as well as the most important enzymes that are involved in the prodrug activation are provided. Sixty-four references are listed at the end of this monograph. PMID- 26940171 TI - Pioglitazone. AB - Pioglitazone is a thiazolidinedione antidiabetic with actions similar to those of rosiglitazone. It is used in the management of type 2 diabetes mellitus and is prepared by reducing 5-[4-[2-(5-ethyl-2-pyridyl)ethoxy]benzilidene]-2,4 thiazolidinedione with sodium borohydride in the presence of a cobalt ion and dimethyl glyoxime. Ultraviolet spectroscopy shows maximum absorption at 270nm. Infrared spectroscopy shows principal peaks at wave numbers 3082, 2964, 1736, 1690, 1472, 1331, 1254, 1040, 841, 728cm(-1) (KBr disk). The determination method by high-performance liquid chromatography was linear over the range of 25 1500ng/mL of pioglitazone in plasma (r(2)>0.999). The within- and between-day precision values were in the range of 2.4-6.8%. The limit of quantitation of the method was 25ng/mL. It is well absorbed with a mean absolute bioavailability of 83% and reaching maximum concentrations in around 1.5h. It is metabolized by the hepatic cytochrome P450 enzyme system. Following oral administration, approximately 15-30% of the pioglitazone dose is recovered in the urine. Renal elimination of pioglitazone is negligible, and the drug is excreted primarily as metabolites and their conjugates. It is presumed that most of the oral dose is excreted into the bile either unchanged or as metabolites and eliminated in the feces. PMID- 26940172 TI - Preface to Volume 41. PMID- 26940173 TI - Implementation and evaluation of a quality improvement project: carepaths for Early Psychosis Intervention Programmes in Northeastern Ontario. AB - AIM: This study aims to describe the implementation and evaluation of a quality improvement project, which aimed to standardize services and documentation across several district Early Psychosis Intervention Programmes in a rural region of Canada (Northeastern Ontario). METHOD: A Carepath for early psychosis intervention (EPI), which outlined best practice EPI care pathways, was implemented across 12 EPI programme sites. It was hypothesized that the proportion of best practice interventions provided across the district programmes would increase after the implementation of the Carepath initiative and that documentation would be standardized. Pre-Carepath and post-Carepath chart audits evaluated the provision and documentation of EPI best practices that were specified in the Carepath. RESULTS: Pre-audits and post-audits were completed on 110 and 108 client files, respectively. Chi-squared tests revealed that the post audit frequencies were significantly higher than the pre-audit frequencies for two of the 12 EPI best practices that were evaluated (i.e. assessed impact on family and assessment of substance use). Standardization of documentation did not improve significantly. CONCLUSIONS: The results are discussed in the context of barriers to implementing and evaluating the Carepaths. Various individual and agency level barriers are identified (e.g. staff resistance, resources and agency documentation parameters), and strategies to overcome them are discussed. It is concluded that, despite barriers to implementation and evaluation, Carepaths can be a useful tool for standardizing services and documentation across a network of EPI programmes and guiding programme evaluation and quality assurance. PMID- 26940174 TI - Structural Basis of Duplex Thermodynamic Stability and Enhanced Nuclease Resistance of 5'-C-Methyl Pyrimidine-Modified Oligonucleotides. AB - Although judicious use of chemical modifications has contributed to the success of nucleic acid therapeutics, poor systemic stability remains a major hurdle. The introduction of functional groups around the phosphate backbone can enhance the nuclease resistance of oligonucleotides (ONs). Here, we report the synthesis of enantiomerically pure (R)- and (S)-5'-C-methyl (C5'-Me) substituted nucleosides and their incorporation into ONs. These modifications generally resulted in a decrease in thermal stability of oligonucleotide (ON) duplexes in a manner dependent on the stereoconfiguration at C5' with greater destabilization characteristic of (R)-epimers. Enhanced stability against snake venom phosphodiesterase resulted from modification of the 3'-end of an ON with either (R)- or (S)-C5'-Me nucleotides. The (S)-isomers with different 2'-substituents provided greater resistance against 3'-exonucleases than the corresponding (R) isomers. Crystal structure analyses of RNA octamers with (R)- or (S)-5'-C-methyl 2'-deoxy-2'-fluorouridine [(R)- or (S)-C5'-Me-2'-FU, respectively] revealed that the stereochemical orientation of the C5'-Me and the steric effects that emanate from the alkyl substitution are the dominant determinants of thermal stability and are likely molecular origins of resistance against nucleases. X-ray and NMR structural analyses showed that the (S)-C5'-Me epimers are spatially and structurally more similar to their natural 5' nonmethylated counterparts than the corresponding (R)-epimers. PMID- 26940176 TI - Sugar-sweetened soft drinks are associated with poorer cognitive function in individuals with type 2 diabetes: the Maine-Syracuse Longitudinal Study. AB - The importance of adequate nutrition on cognitive performance is well recognised. Greater intakes of soft drinks are associated with a higher risk for type 2 diabetes, as well as other cardiometabolic diseases. A few studies have specifically examined whether the intake of soft drinks may be related to cognitive function. The aim of this study was to investigate whether soft drink intakes, including both sugar-sweetened and diet beverages, are associated with cognitive function, with adjustment for cardiovascular, lifestyle and dietary factors, and stratified according to type 2 diabetes status. Cross-sectional analyses were undertaken using 803 community-dwelling participants, aged 23-98 years, from the Maine-Syracuse Longitudinal Study. Cognitive function was measured using an extensive battery of neuropsychological tests. Usual dietary intake of soft drinks was assessed using a FFQ. Stratification by type 2 diabetes indicated that a greater intake of sugar-sweetened soft drinks was significantly associated with poorer performance in visual spatial memory, working memory, scanning and tracking, executive function, the global composite and the Mini Mental State Examination in diabetic individuals. These relations were not attenuated with statistical control for BMI and other cardiovascular, lifestyle and dietary factors. Diet soft drink intake was unrelated to cognitive performance. Frequent sugar-sweetened soft drink intake was associated with poorer cognitive performance, particularly in individuals with type 2 diabetes, but the underlying causal mechanisms are yet to be determined. Longitudinal studies are needed to clarify these findings and the underlying causal mechanisms. PMID- 26940175 TI - The Silk-protein Sericin Induces Rapid Melanization of Cultured Primary Human Retinal Pigment Epithelial Cells by Activating the NF-kappaB Pathway. AB - Restoration of the retinal pigment epithelial (RPE) cells to prevent further loss of vision in patients with age-related macular degeneration represents a promising novel treatment modality. Development of RPE transplants, however, requires up to 3 months of cell differentiation. We explored whether the silk protein sericin can induce maturation of primary human retinal pigment epithelial (hRPE) cells. Microarray analysis demonstrated that sericin up-regulated RPE associated transcripts (RPE65 and CRALBP). Upstream analysis identified the NF kappaB pathway as one of the top sericin-induced regulators. ELISA confirmed that sericin stimulates the main NF-kappaB pathway. Increased levels of RPE-associated proteins (RPE65 and the pigment melanin) in the sericin-supplemented cultures were confirmed by western blot, spectrophotometry and transmission electron microscopy. Sericin also increased cell density and reduced cell death following serum starvation in culture. Inclusion of NF-kappaB agonists and antagonists in the culture medium showed that activation of the NF-kappaB pathway appears to be necessary, but not sufficient, for sericin-induced RPE pigmentation. We conclude that sericin promotes pigmentation of cultured primary hRPE cells by activating the main NF-kappaB pathway. Sericin's potential role in culture protocols for rapid differentiation of hRPE cells derived from embryonic or induced pluripotent stem cells should be investigated. PMID- 26940177 TI - Horses for courses but which horse for which course? PMID- 26940178 TI - The value of assessing post-operative mortality after oesophagectomy. PMID- 26940179 TI - Post-oesophagectomy mortality: the centralization debate revisited. PMID- 26940180 TI - Requesting a magnetic resonance imaging in a patient with a pre-existing implant: a practical surgical guide. PMID- 26940181 TI - Medicine in small doses. PMID- 26940183 TI - Corrigendum. PMID- 26940184 TI - Re: Long-term results of the cutting seton for high anal fistula. PMID- 26940185 TI - Response to Re: Long-term results of the cutting seton for high anal fistula. PMID- 26940186 TI - Re: Nausea, vomiting and return of bowel function after colorectal surgery. PMID- 26940187 TI - Re: Hepatic resection for malignant liver tumours in the elderly: a systematic review and meta-analysis. PMID- 26940188 TI - Response to Re: Nausea, vomiting and return of bowel function after colorectal surgery. PMID- 26940189 TI - Response to Re: Hepatic resection for malignant liver tumours in the elderly: a systematic review and meta-analysis. PMID- 26940190 TI - Localized perianal skin necrosis in neutropenic patients. PMID- 26940191 TI - Verification of nerve decompression using mechanomyography. AB - BACKGROUND CONTEXT: Assessment of nerve root decompression in surgery is largely based on visualization and tactile feedback. Often times, visualization can be limited, such as in minimally invasive surgery, and tactile feedback is a subjective assessment that makes the evaluation of successful nerve decompression difficult. Electromyography (EMG) has been proposed as an assessment tool, but EMG responses are often difficult to quantify. Alternatively, mechanomyography (MMG) provides a quantifiable response with high signal-to-noise ratio compared with EMG. MMG provides a sensitive tool to accurately quantify mechanical responses to motor action potentials generated by electrical stimulus, allowing more reliable assessment of nerve decompression. PURPOSE: The aim of this study was to assess the ability of MMG to quantitatively demonstrate successful nerve root decompression. STUDY DESIGN: Prospective cohort, Therapeutic Level III, Urban Level I Trauma Center. PATIENT SAMPLE: A total of 46 patients (72 affected nerve roots) undergoing decompression procedures for lower extremity radiculopathy caused by nerve root compression were enrolled in the study. The study population included 15 patients with herniated nucleus pulposus (HNP) and 31 with lateral recess stenosis (LRS). OUTCOME MEASURE: Visual analog scale (VAS) score. METHODS: A total of 72 nerves roots in 46 patients undergoing lumbar decompression procedures, for lower extremity radicular symptoms, were tested using MMG. Nerves were stimulated upstream from the compression site, and the lowest threshold current needed to generate a muscle response was determined. Signal response sizes were recorded before and after decompression. VAS scores were collected pre- and postoperatively. RESULTS: Of the patients, 90% (65/72) had elevated stimulation thresholds (>1 milliamp [mA]) before decompression. After decompression, 98% of patients (64/65) with elevated current thresholds exhibited a drop in threshold of >=1 mA (p<.001). A postdecompression increase in response amplitude was recorded in all patients. VAS scores improved postdecompression (6.8 vs. 1.1, p<.001) with a positive correlation between decreased stimulation thresholds and degree of improvement in VAS scores (p<.001). CONCLUSION: MMG is an effective tool that can be used to differentiate normal and compressed nerves by quantifying the mechanomyographic response to a stimulating current. MMG allows one to measure the effect of decompression, judge its effectiveness in real time, and eliminate the subjectivity seen in tactile feedback methods. When the adequacy of decompression is uncertain, MMG can guide the surgeon toward additional or alternative procedures to ensure complete nerve root decompression. PMID- 26940192 TI - Does the duration of symptoms influence outcome in patients with sciatica undergoing micro-discectomy and decompressions? AB - BACKGROUND: Early surgical treatment for back and leg pain secondary to disc herniation has been associated with very good outcomes. However, there are conflicting data on the role of surgical treatment in case of prolonged radicular symptomatology. PURPOSE: We aimed to evaluate whether the duration of symptoms at presentation affects the subjective outcome. STUDY DESIGN/SETTING: This is a retrospective review of prospectively collected data from a single surgeon including micro-discectomies and lateral recess decompressions in patients younger than 60 years old using patient medical notes, radiology imaging, operation notes, and Patient Reported Outcome Measures (PROMS) including Oswestry Disability Index (ODI), visual analogue scale for back pain and leg pain (VAS-BP and VAS-LP). The final follow-up was carried out through postal questionnaire or telephone consultation. METHODS: Demographic information, duration of symptoms, type and incidence of complications, length of hospital stay, and follow-up were analyzed. Data were categorized into four subgroups: symptoms 0>=6 months, 6 months>=1 year, 1 year>=2 years, and >2 years. A clinically significant result was an average improvement of 2 or more points in the VAS and of 20% and over in the ODI. The level of statistical significance was <0.05%. RESULTS: A total number of 107 patients who underwent 109 operations were included. The level of surgery was L5/S1 (50), L4/L5 (43), L3/L4 (3), L2/L3 (2), and two levels (11). The mean improvement was from 0 to <=6 months (VAS-LP 5.21+/-2.81, VAS-BP 3.04+/ 3.15, ODI 35.26+/-19.25), 6 months to <=1 year (VAS-LP 4.73+/-2.61, VAS-BP 3.30+/ 3.05, ODI 26.92+/-19.49), 1 year to <=2 years (VAS-LP 3.78+/-3.68, VAS-BP 3.00+/ 2.78, ODI 19.03+/-20.24), and >2 years (VAS-LP 4.77+/-3.61, VAS-BP 3.54+/-3.43, ODI 28.36+/-20.93). The length of hospital stay and complication rate was comparable between groups. Average follow-up was 15.69 months. CONCLUSIONS: Our study showed significant improvement in patients with symptoms beyond 1 as well as 2 years since onset, and surgery is a viable option in selected patients. PMID- 26940193 TI - Spontaneous epidural hematoma of the thoracic spine. PMID- 26940194 TI - Mechanisation of large-scale agricultural fields in developing countries - a review. AB - Mechanisation of large-scale agricultural fields often requires the application of modern technologies such as mechanical power, automation, control and robotics. These technologies are generally associated with relatively well developed economies. The application of these technologies in some developing countries in Africa and Asia is limited by factors such as technology compatibility with the environment, availability of resources to facilitate the technology adoption, cost of technology purchase, government policies, adequacy of technology and appropriateness in addressing the needs of the population. As a result, many of the available resources have been used inadequately by farmers, who continue to rely mostly on conventional means of agricultural production, using traditional tools and equipment in most cases. This has led to low productivity and high cost of production among others. Therefore this paper attempts to evaluate the application of present day technology and its limitations to the advancement of large-scale mechanisation in developing countries of Africa and Asia. Particular emphasis is given to a general understanding of the various levels of mechanisation, present day technology, its management and application to large-scale agricultural fields. This review also focuses on/gives emphasis to future outlook that will enable a gradual, evolutionary and sustainable technological change. The study concludes that large scale-agricultural farm mechanisation for sustainable food production in Africa and Asia must be anchored on a coherent strategy based on the actual needs and priorities of the large-scale farmers. (c) 2016 Society of Chemical Industry. PMID- 26940195 TI - Food intake rates of inactive fish are positively linked to boldness in three spined sticklebacks Gasterosteus aculeatus. AB - To investigate the link between personality and maximum food intake of inactive individuals, food-deprived three-spined sticklebacks Gasterosteus aculeatus at rest in their home compartments were provided with ad libitum prey items. Bolder individuals ate considerably more than shyer individuals, even after accounting for body size, while sociability did not have an effect. These findings support pace-of-life theory predicting that life-history strategies are linked to boldness. PMID- 26940196 TI - Regulation of sphingomyelin metabolism. AB - Sphingolipids (SFs) represent a large class of lipids playing diverse functions in a vast number of physiological and pathological processes. Sphingomyelin (SM) is the most abundant SF in the cell, with ubiquitous distribution within mammalian tissues, and particularly high levels in the Central Nervous System (CNS). SM is an essential element of plasma membrane (PM) and its levels are crucial for the cell function. SM content in a cell is strictly regulated by the enzymes of SM metabolic pathways, which activities create a balance between SM synthesis and degradation. The de novo synthesis via SM synthases (SMSs) in the last step of the multi-stage process is the most important pathway of SM formation in a cell. The SM hydrolysis by sphingomyelinases (SMases) increases the concentration of ceramide (Cer), a bioactive molecule, which is involved in cellular proliferation, growth and apoptosis. By controlling the levels of SM and Cer, SMSs and SMases maintain cellular homeostasis. Enzymes of SM cycle exhibit unique properties and diverse tissue distribution. Disturbances in their activities were observed in many CNS pathologies. This review characterizes the physiological roles of SM and enzymes controlling SM levels as well as their involvement in selected pathologies of the Central Nervous System, such as ischemia/hypoxia, Alzheimer disease (AD), Parkinson disease (PD), depression, schizophrenia and Niemann Pick disease (NPD). PMID- 26940197 TI - Brain ischemia with Alzheimer phenotype dysregulates Alzheimer's disease-related proteins. AB - There are evidences for the influence of Alzheimer's proteins on postischemic brain injury. We present here an overview of the published evidence underpinning the relationships between beta-amyloid peptide, hyperphosphorylated tau protein, presenilins, apolipoproteins, secretases and neuronal survival/death decisions after ischemia and development of postischemic dementia. The interactions of above molecules and their influence and contribution to final ischemic brain degeneration resulting in dementia of Alzheimer phenotype are reviewed. Generation and deposition of beta-amyloid peptide and tau protein pathology are essential factors involved in Alzheimer's disease development as well as in postischemic brain dementia. Postischemic injuries demonstrate that ischemia may stimulate pathological amyloid precursor protein processing by upregulation of beta- and gamma-secretases and therefore are capable of establishing a vicious cycle. Functional postischemic brain recovery is always delayed and incomplete by an injury-related increase in the amount of the neurotoxic C-terminal of amyloid precursor protein and beta-amyloid peptide. Finally, we present here the concept that Alzheimer's proteins can contribute to and/or precipitate postischemic brain neurodegeneration including dementia with Alzheimer's phenotype. PMID- 26940198 TI - Detection of hydrogen cyanide from oral anaerobes by cavity ring down spectroscopy. AB - Hydrogen cyanide (HCN) has been recognized as a potential biomarker for non invasive diagnosis of Pseudomonas aeruginosa infection in the lung. However, the oral cavity is a dominant production site for exhaled HCN and this contribution can mask the HCN generated in the lung. It is thus important to understand the sources of HCN production in the oral cavity. By screening of oral anaerobes for HCN production, we observed that the genus of Porphyromonas, Prevotella and Fusobacterium generated low levels of HCN in vitro. This is the first study to show that oral anaerobes are capable of producing HCN in vitro. Further investigations were conducted on the species of P. gingivalis and we successfully detected HCN production (0.9-10.9 ppb) in the headspace of three P. gingivalis reference strains (ATCC 33277, W50 and OMG 434) and one clinical isolate. From P. gingivalis ATCC 33277 and W50, a strong correlation between HCN and CO2 concentrations (rs = 0.89, p < 0.001) was observed, indicating that the HCN production of P. gingivalis might be connected with the bacterial metabolic activity. These results indicate that our setup could be widely applied to the screening of in vitro HCN production by both aerobic and anaerobic bacteria. PMID- 26940199 TI - Effects of combined treatments with CTLA4-IG (abatacept), dexamethasone and methotrexate on cultured human macrophages. AB - OBJECTIVES: To evaluate the anti-inflammatory effect of CTLA4-Ig (abatacept) and dexamethasone (DEX) monotreatment versus their combination and adding methotrexate (MTX) on cultured human macrophages. METHODS: THP-1 cells, activated into macrophages (PMA 0.05 MUg/ml), were cultured for 3 and 24 hrs with CTLA4-Ig (500 MUg/ml), DEX (10-8 M), MTX (0.05 MUg/ml), and CTLA4-Ig combined with DEX or CTLA4-Ig combined with DEX plus MTX. CTLA4-Ig/CD86 interaction was evaluated by FACS analysis. Quantitative real time-PCR (qRT-PCR), immunocytochemistry (ICC) and immunoassay (ELISA) analysis for inflammatory cytokine (IL-1beta, TNF-alpha, IL-6) expression were performed. RESULTS: FACS analysis showed in macrophages treated with CTLA4-Ig alone, CTLA4-Ig-DEX and CTLA4-Ig-DEX-MTX a CD86 decrease of almost 35%, versus untreated cells (CNT). After 3 hrs, macrophages treated with DEX alone or with CTLA4-Ig-DEX or CTLA4-Ig-DEX-MTX showed a significant reduction (p<0.05) for all cytokines gene expression, that was still significant for IL 1beta after 24 hrs (p<0.05). After 3 hrs, CTLA4-Ig alone significantly (p<0.05) reduced all cytokine genes; however, after 24 hrs still evident only for TNF alpha (p<0.05). After 24 hrs CTLA4-Ig-DEX induced a significant decrease of gene expression (p<0.05) for TNF-alpha and IL-6, whereas CTLA4-Ig-DEX-MTX induced a decrease (p<0.05) limited to IL-6, versus CNT. Finally, ICC showed, after 24 hrs of CTLA4-Ig-DEX or CTLA4-Ig-DEX-MTX treatment a reduction (p<0.05) of IL-1beta and IL-6 expression, versus CNT; DEX alone reduced only IL-1beta (p<0.05). ELISA analysis confirmed these results. CONCLUSIONS: CTLA4-Ig-DEX and CTLA4-Ig-DEX-MTX combined treatments, decreased at any level the inflammatory cytokine expression more efficiently then monotreatments on activated cultured human macrophages. PMID- 26940201 TI - Anaesthetists stress is induced by patient ASA grade and may impair non-technical skills during intubation. AB - BACKGROUND: The aims of this study were to determine if patient ASA grade was associated with increased stress in anaesthetists with a subsequent effect on non technical skills. METHODS: Stress was measured using a validated objective (heart rate variability or heart rate) and subjective tool. We studied eight consultant anaesthetists at baseline (rest) and during 16 episodes of intubation with an ASA 1 or 2 patient vs. an ASA 3 or 4 patient. The primary outcome for the study was objective and subjective stress between both patient groups. Secondary outcomes were non-technical skill ratings and the association between stress measurements. RESULTS: ASA 3 or 4 patients were associated with increases in objective stress when compared to baseline (mean 4.6 vs. 6.7; P = 0.004). However, ASA 1 or 2 patients were not associated with increases in stress when compared to baseline (mean 4.6 vs. 4.7; P = 1). There was no significant difference in subjective stress between the groups (P = 0.18). Objective stress negatively affected situational awareness (P = 0.03) and decision-making (P = 0.03); however, these did not decline to a clinically significant threshold. Heart rate variability (r = 0.60; P = 0.002) better correlated with subjective stress when compared to heart rate (r = 0.30; P = 0.15). Agreement between raters for Anaesthetic Non Technical Skills (ANTS) scores was acceptable (ICC = 0.51; P = 0.003). CONCLUSION: This study suggests that higher patient ASA grade can increase stress in anaesthetists, which may impair non-technical skills. PMID- 26940202 TI - Use of an appendicitis medical information sheet in the pediatric primary care system. AB - BACKGROUND: Accurate and prompt diagnosis is required for the primary evaluation of pediatric appendicitis. Among pediatricians and surgeons working in Yamanashi Prefecture, the pediatric appendicitis medical information (PAMI) sheet was edited in April 2011 to reflect the diagnostic results of the pediatric primary and emergency medical service and used as a referral document for surgical consultation to secondary hospitals. METHODS: The PAMI sheet consisted of sections for history taking, symptoms, physical signs and laboratory findings without a scoring system. For 32 consecutive months starting in April 2011, 59 patients hospitalized for suspected appendicitis were retrospectively reviewed. In particular, a total of 17 referral patients evaluated with the PAMI sheet were assessed in order to evaluate the utility of the form. RESULTS: The pediatric surgeons were able to easily determine patient condition from the PAMI sheet. In total, 13 of 17 patients had appendicitis. According to the physical findings of the 17 studied patients, the judgment of right lower quadrant tenderness (kappa = 0.63) and guarding (kappa = 1.00) was consistent between the pediatric surgeons and primary attending pediatricians. CONCLUSIONS: The PAMI sheet aids in the collection of detailed history and objective data with a high level of accuracy, and provides useful referral diagnostic information to the secondary-level hospitals. PMID- 26940200 TI - Suppression of the invasive potential of Glioblastoma cells by mTOR inhibitors involves modulation of NFkappaB and PKC-alpha signaling. AB - Glioblastoma (GBM) is the most aggressive type of brain tumors in adults with survival period <1.5 years of patients. The role of mTOR pathway is documented in invasion and migration, the features associated with aggressive phenotype in human GBM. However, most of the preclinical and clinical studies with mTOR inhibitors are focused on antiproliferative and cytotoxic activity in GBM. In this study, we demonstrate that mTOR inhibitors-rapamycin (RAP), temisirolimus (TEM), torin-1 (TOR) and PP242 suppress invasion and migration induced by Tumor Necrosis Factor-alpha (TNFalpha) and tumor promoter, Phorbol 12-myristate 13 acetate (PMA) and also reduce the expression of the TNFalpha and IL1beta suggesting their potential to regulate factors in microenvironment that support tumor progression. The mTOR inhibitors significantly decreased MMP-2 and MMP-9 mRNA, protein and activity that was enhanced by TNFalpha and PMA. The effect was mediated through reduction of Protein kinase C alpha (PKC-alpha) activity and downregulation of NFkappaB. TNFalpha- induced transcripts of NFkappaB targets VEGF, pentraxin-3, cathepsin-B and paxillin, crucial in invasion were restored to basal level by these inhibitors. With limited therapeutic interventions currently available for GBM, our findings are significant and suggest that mTOR inhibitors may be explored as anti-invasive drugs for GBM treatment. PMID- 26940203 TI - SIRT1 alleviates senescence of degenerative human intervertebral disc cartilage endo-plate cells via the p53/p21 pathway. AB - Cartilage end plates (CEP) degeneration plays an integral role in intervertebral disc (IVD) degeneration resulting from nutrient diffusion disorders. Although cell senescence resulting from oxidative stress is known to contribute to degeneration, no studies concerning the role of senescence in CEP degeneration have been conducted. SIRT1 is a longevity gene that plays a pivotal role in many cellular functions, including cell senescence. Therefore, the aim of this study was to investigate whether senescence is more prominent in human degenerative CEP and whether SIRT1-regulated CEP cells senescence in degenerative IVD as well as identify the signaling pathways that control that cell fate decision. In this study, the cell senescence phenotype was found to be more prominent in the CEP cells obtained from disc degenerative disease (DDD) patients than in the CEP cells obtained from age-matched lumbar vertebral fractures (LVF) patients. In addition, the results indicated that p53/p21 pathway plays an important role in the senescence of CEP cells in vivo and vitro. Furthermore, SIRT1 was found to be capable of alleviating the oxidative stress-induced senescence of CEP cells in humans via p53/p21 pathway. Thus, the information presented in this study could be used to further investigate the underlying mechanisms of CEP. PMID- 26940204 TI - The diversity of the structure and genomic integration sites of HTLV-1 provirus in MT-2 cell lines. AB - A human T-lymphotropic virus Type 1 (HTLV-1) positive cell line, MT-2, derived from human cord leukocytes co-culturing with adult T cell leukemia/lymphoma (ATL) cells is commonly used in HTLV-1 research; however, the details of provirus integrated in MT-2 genome have not yet been characterized. In this study, five types of HTLV-1 proviral sequences were detected in 11 different sites of the genome in a reference MT-2 cell line. The five types of HTLV-1 proviral sequences were one complete proviral genome, two types of proviruses with deletion of large internal viral sequences (5.3 and 3.9 kB), one provirus with a large deletion (6.2 kB) from 5'LTR to position 6257, and one provirus of LTR only. The provirus with identical deletion of large internal viral sequence (5.3 kB) was found to be integrated into six different sites (chromosomes). A complete provirus and three of four types of defective provirus were consistently detected in two other MT-2 cell lines cultured in different laboratories. Not only Tax/Rex RNA and HBZ RNA, but also the transcriptional product for a specific defective provirus, were detectable in all three MT-2 cell lines. Because it has been reported that defective provirus is frequently detected in ATL cells, these results may be important in understanding the mechanism of HTLV-1 proviral polymorphism, which may be related to leukemogenesis. In addition, the large variation in integrated HTLV-1 proviruses makes it important for researchers to exercise caution in their assessment and interpretation of results using MT-2 cell lines. PMID- 26940205 TI - Acanthamoeba infection in lungs of mice expressed by toll-like receptors (TLR2 and TLR4). AB - Toll-like receptors (TLRs) play a key role in the innate immune responses to a variety of pathogens including parasites. TLRs are among the most highly conserved in the evolution of the receptor family, localized mainly on cells of the immune system and on other cells such as lung cells. The aim of this study was to determine for the first time the expression of TLR2 and TLR4 in the lung of Acanthamoeba spp. infected mice using quantitative real-time polymerase chain reaction (Q-PCR) and immunohistochemical (IHC) staining. The Acanthamoeba spp. were isolated from a patient with Acanthamoeba keratitis (AK) (strain Ac 55) and from environmental samples of water from Malta Lake (Poznan, Poland - strain Ac 43). We observed a significantly increased level of expression of TLR2 as well as TLR4 mRNA from 2 to 30 days post Acanthamoeba infection (dpi) in the lungs of mice infected with Ac55 (KP120880) and Ac43 (KP120879) strains. According to our observations, increased TLR2 and TLR4 expression in the pneumocytes, interstitial cells and epithelial cells of the bronchial tree may suggest an important role of these receptors in protective immunity against Acanthamoeba infection in the lung. Moreover, increased levels of TLR2 and TLR4 mRNA expression in infected Acanthamoeba mice may suggest the involvement of these TLRs in the recognition of this amoeba pathogen-associated molecular pattern (PAMP). PMID- 26940206 TI - The fungicidal activity of amphotericin B requires autophagy-dependent targeting to the vacuole under a nutrient-starved condition in Saccharomyces cerevisiae. AB - In this study, we demonstrated that in distilled water, a nutrient-starved condition that elicits autophagy in Saccharomyces cerevisiae, an array of autophagy-deficient mutants are resistant to the fungicidal effects of amphotericin B. In addition, we found that a dansyl-labelled derivative of the antibiotic colocalized with disintegrated vacuoles throughout the cytoplasm in the amphotericin B-sensitive parental strain suspended in distilled water. In contrast, the dansyl-labelled derivative was not internalized in the Deltaatg18 strain, which is deficient in the formation of autophagosomes, a key early step in autophagy. However, the derivative accumulated without significant toxicity in structurally intact vacuoles in the Deltavma1 mutant, which is deficient in the degradation of autophagic bodies, the final stage in autophagy. Our data support the idea that amphotericin B can utilize autophagy-dependent trafficking into the intra-vacuolar lumen, where it interacts with the luminal leaf of the membrane to cause structurally catastrophic effects. PMID- 26940207 TI - Care Plans in Community Mental Health: an Audit Focusing on People with Recent Hospital Admissions. PMID- 26940208 TI - Proteomics and transcriptomics analyses of Arabidopsis floral buds uncover important functions of ARABIDOPSIS SKP1-LIKE1. AB - BACKGROUND: The ARABIDOPSIS SKP1-LIKE1 (ASK1) protein functions as a subunit of SKP1-CUL1-F-box (SCF) E3 ubiquitin ligases. Previous genetic studies showed that ASK1 plays important roles in Arabidopsis flower development and male meiosis. However, the molecular impact of ASK1-containing SCF E3 ubiquitin ligases (ASK1 E3s) on the floral proteome and transcriptome is unknown. RESULTS: Here we identified proteins that are potentially regulated by ASK1-E3s by comparing floral bud proteomes of wild-type and the ask1 mutant plants. More than 200 proteins were detected in the ask1 mutant but not in wild-type and >300 were detected at higher levels in the ask1 mutant than in wild-type, but their RNA levels were not significantly different between wild-type and ask1 floral buds as shown by transcriptomics analysis, suggesting that they are likely regulated at the protein level by ASK1-E3s. Integrated analyses of floral proteomics and transcriptomics of ask1 and wild-type uncovered several potential aspects of ASK1 E3 functions, including regulation of transcription regulators, kinases, peptidases, and ribosomal proteins, with implications on possible mechanisms of ASK1-E3 functions in floral development. CONCLUSIONS: Our results suggested that ASK1-E3s play important roles in Arabidopsis protein degradation during flower development. This study opens up new possibilities for further functional studies of these candidate E3 substrates. PMID- 26940210 TI - Total elbow arthroplasty: a radiographic outcome study. AB - OBJECTIVES: Total elbow arthroplasty (TEA) is becoming a popular alternative to arthrodesis for patients with end-stage elbow arthrosis and comminuted distal humeral fractures. Prior outcome studies have primarily focused on surgical findings. Our purpose is to determine the radiographic outcome of TEA and to correlate with clinical symptoms such as pain. MATERIALS AND METHODS: This is an IRB-approved retrospective review from 2005 to 2015 of all patients with semiconstrained TEA. All available elbow radiographs and clinical data were reviewed. Data analysis included descriptive statistics and Kaplan-Meier survival curves for radiographic and clinical survival. RESULTS: A total of 104 total elbow arthroplasties in 102 patients were reviewed; 75 % were in women and the mean patient age was 63.1 years. Mean radiographic follow-up was 826 days with average of four radiographs per patient. Seventy TEAs (67 %) developed radiographic complications, including heterotopic ossification (48 %), perihardware lucency (27 %), periprosthetic fracture (23 %), hardware subluxation/dislocation (7 %), polyethylene wear (3 %), and hardware fracture/dislodgement (3 %); 56 patients (55 %) developed symptoms of elbow pain or instability and 30 patients (30 %) underwent at least one reoperation. In patients with radiographic complications, 66 % developed elbow pain, compared to 19 % of patients with no radiologic complications (p = 0.001). Of the patients with radiographic complications, 39 % had at least one additional surgery compared to 0 % of patients without radiographic complications (p = 0.056). CONCLUSIONS: Radiographic complications are common in patients after total elbow arthroplasty. There is a strong positive association between post-operative radiographic findings and clinical outcome. Knowledge of common postoperative radiographic findings is important for the practicing radiologist. PMID- 26940209 TI - Evaluation and management of ischiofemoral impingement: a pathophysiologic, radiologic, and therapeutic approach to a complex diagnosis. AB - Ischiofemoral impingement syndrome (IFI) is an underrecognized form of atypical, extra-articular hip impingement defined by hip pain related to narrowing of the space between the ischial tuberosity and the femur. The etiology of IFI is multifactorial and potential sources of ischiofemoral engagement include anatomic variants of the proximal femur or pelvis, functional disorders as hip instability, pelvic/spinal instability, or abductor/adductor imbalance, ischial tuberosity enthesopathies, trauma/overuse or extreme hip motion, iatrogenic conditions, tumors and other pathologies. Magnetic resonance imaging (MRI) is the diagnostic procedure of choice for assessing IFI and may substantially influence patient management. The injection test of the ischiofemoral space (IFS) has both a diagnostic and therapeutic function. Endoscopic decompression of the IFS appears useful in improving function and diminishing hip pain in patients with IFI but conservative treatment is always the first step in the treatment algorithm. Because of the ever-increasing use of advanced MRI techniques, the frequent response to conservative treatment, and the excellent outcomes of new endoscopic treatment, radiologists must be aware of factors that predispose or cause IFI. In addition, focused treatment in these conditions is often more important than in secondary impingement. In this article, we briefly describe the anatomy of the IFS, review the clinical examination and symptoms, assess the diagnostic imaging criteria and pathophysiological mechanisms, and develop an understandable classification of IFI, with particular focus on its etiology, predisposing factors, and associated musculoskeletal abnormalities. We also assess the role of the radiologist in the diagnosis, treatment, and preoperative evaluation of both primary and secondary IFI. PMID- 26940211 TI - Future of 34 meniscectomies after bucket-handle meniscus tear: a retrospective study with a follow-up over 22 years. AB - After a bucket-handle meniscus tear, a partial meniscectomy by arthroscopy is recommended, when a meniscal suture is impossible. Short-term results of meniscectomy after bucket-handle meniscus tear, without cartilage or ligament additional injury, are mostly excellent: pain and blocking disappear, return to sports activities is possible. The aim of this retrospective study is to follow a partial meniscectomy evolution with a long follow-up between March 1990 and April 1994, and a senior surgeon operated 34 meniscectomies for bucket-handle meniscus tear by 34 patients (29 male and 5 female) with a mean age of 31.7 years (16-52 years) at time of surgery. The bucket-handle meniscus tear had a traumatic etiology on a knee with no cartilage lesion. The functional results were assessed by IKDC subjective score (International Knee Documentation Committee) and ARPEGE score (Association pour la Recherche et la Promotion de l'Etude du Genou). These scores were obtained by phone call questionnaire in March 2014 with a mean follow up of 22.7 years (20-24 years). In this study, patients were reviewed and got a clinical examination to determine the Lequesne score, a radiological knee assessment according to Ahlback classification and a weight-bearing teleradiography. With an IKDC mean score of 85.8 after surgery, we observed that 29 patients go back to sports activities with the same level as before injury. The level of sports activity, with a regular practice after a mean follow-up of 22.7 years, was the same as immediately after surgery or just the level under for 85.3 % of patients. With ARPEGE score, 48.5 % of patients had a global excellent result and 38.2 % had a global good result after a long follow-up. With a mean Lequesne score of 2.38, osteoarthritis of knee is still clinical minimal after meniscectomy at long term. The score was worse after external meniscectomy (EM) than after an internal meniscectomy (IM). 57.7 % of patients have osteoarthritis on X-rays. In our study, functional results after partial meniscectomy for bucket handle meniscus tear are similar than in the literature. More than half of our patients, reviewed after a long follow-up, had radiological osteoarthritis of knee with a variable clinical result, but often minimal to moderate, intensity modulated by the lower limb axis. PMID- 26940213 TI - Comments on the Italian Society of Endocrinology recommendations on post-surgical thyroid ablation in differentiated thyroid cancer. PMID- 26940212 TI - [Guideline-conform inpatient psychiatric psychotherapeutic treatment of chronic depression: Normative personnel requirements]. AB - BACKGROUND: Chronic depression is a frequent mental disorder representing a significant subjective and economic burden. Effective disorder-specific treatment of chronic depression presupposes sufficient funding of treatment resources. OBJECTIVE: Definition of normative needs of personnel resources for guideline compliant and evidence-based inpatient treatment of chronic depression based on treatment duration and intensity. The personnel resources determined were compared to the resources provided on the basis of the existing reimbursement system (Psych-PV) in Germany. MATERIAL AND METHODS: Resources determined according to national treatment guidelines and empirical evidence were compared to personnel resources dictated by the German Psych-PV reimbursement algorithm. RESULTS: The current funding algorithm greatly underestimates the resources needed for a guideline-compliant and evidence-based treatment program, even if healthcare providers received 100 % reimbursement of the sum determined by the Psych-PV algorithm. DISCUSSION: The results clearly show that even in the case of a full coverage of the current German reimbursement algorithm, funding allocation for evidence-based inpatient treatment of chronic depression is insufficient. In addition, the difficulties of specific coding of chronic depression in the ICD-10 system generates a major problem in the attempt to measure the current resources needed for sufficient treatment. PMID- 26940215 TI - Reply to the Letter to the Editor by Sollini M et al. PMID- 26940214 TI - The analysis of blood pressure profiles and their severity in relation to diabetic cardiovascular autonomic neuropathy in the Chinese population: preliminary analysis. AB - BACKGROUND: The study sought to investigate the associations of blood pressure profiles and its severity with diabetic cardiovascular autonomic neuropathy (DCAN) in a Chinese population. METHODS: We conducted a community-based, cross sectional study for risk factor analysis of DCAN in 455 individuals recruited from a Chinese population. Blood pressure profile risk score (BPRS) was calculated for associations between severity of blood pressure profile and DCAN. Multivariable logistic regression (MLR) was carried out to analyze the associations of blood pressure profiles and its severity with DCAN. RESULTS: In category variable models, participants with high SBP have significantly higher DCAN prevalence as compared to participants with low SBP (25.66 vs. 31.69 %, P = 0.011). MLR demonstrated that there was significant associations between SBP and DCAN controlling for potential confounding factors (P = 0.016). Moreover, MLR assessed significant associations of BPRS-0 or BPRS-2 with DCAN (P value = 0.014 for BPRS-0 and P value = 0.031 for BPRS-2). CONCLUSION: Our findings indicated that SBP and severity of BP profiles were significantly and independently associated with DCAN, respectively. These suggested BP profile may influence the progression of DCAN and also provided insight into biological functions. ClinicalTrials.gov Identifier NCT02461472. PMID- 26940216 TI - Canadian Medical Association dismisses second journal editor in 10 years. PMID- 26940218 TI - Zika Virus Association with Microcephaly: The Power for Population Statistics to Identify Public Health Emergencies. PMID- 26940217 TI - Two-colour live-cell nanoscale imaging of intracellular targets. AB - Stimulated emission depletion (STED) nanoscopy allows observations of subcellular dynamics at the nanoscale. Applications have, however, been severely limited by the lack of a versatile STED-compatible two-colour labelling strategy for intracellular targets in living cells. Here we demonstrate a universal labelling method based on the organic, membrane-permeable dyes SiR and ATTO590 as Halo and SNAP substrates. SiR and ATTO590 constitute the first suitable dye pair for two colour STED imaging in living cells below 50 nm resolution. We show applications with mitochondria, endoplasmic reticulum, plasma membrane and Golgi-localized proteins, and demonstrate continuous acquisition for up to 3 min at 2-s time resolution. PMID- 26940220 TI - Conceptual compression discussion on a multi-linear (FTA) and systematic (FRAM) method in an offshore operation's accident modeling. AB - Risk assessment can be classified into two broad categories: traditional and modern. This paper is aimed at contrasting the functional resonance analysis method (FRAM) as a modern approach with the fault tree analysis (FTA) as a traditional method, regarding assessing the risks of a complex system. Applied methodology by which the risk assessment is carried out, is presented in each approach. Also, FRAM network is executed with regard to nonlinear interaction of human and organizational levels to assess the safety of technological systems. The methodology is implemented for lifting structures deep offshore. The main finding of this paper is that the combined application of FTA and FRAM during risk assessment, could provide complementary perspectives and may contribute to a more comprehensive understanding of an incident. Finally, it is shown that coupling a FRAM network with a suitable quantitative method will result in a plausible outcome for a predefined accident scenario. PMID- 26940219 TI - Pure Natural Orifice Transluminal Endoscopic Surgery (NOTES) with a new elongated, curved Transanal Endoscopic Operation (TEO) device for rectosigmoid resection: a survival study in a porcine model. AB - BACKGROUND: Natural orifice transluminal endoscopic surgery (NOTES) has seen considerable new developments in its evolution to a platform for rectal and sigmoid resection, but to date no true single NOTES procedure has been convincing. This study investigates the safety and feasibility of a further developed transanal NOTES platform for single-access NOTES rectosigmoid resection. METHODS: Ten large female pigs, mean weight 99.3 kg [standard deviation (SD) 7 kg, range 85.1-112.6 kg], underwent transanal rectosigmoid resection. Five animals were included in an acute study group with immediate postoperative euthanization. A second group included five animals in a survival study. Transanal rectosigmoid resections were performed with an elongated and curved transanal endoscopic operation (TEO) device. Coloanal anastomosis was performed using the transanal circular stapler technique. Survival follow-up was at 7 and 28 days via colonoscopy under sedation. RESULTS: Single-access NOTES transanal rectosigmoid resection with coloanal anastomosis was performed in nine out of ten female pigs. Mean length of rectosigmoid specimens exteriorized was 18.7 cm (SD 2.9 cm, range 14-23 cm). Mean operating time was 124 min (SD 35.7 min, range 70-166 min). Within the survival group, no complications occurred during the monitoring phase. In one case, there was ascites and colitis at necropsy as well as fibrosis at the anastomosis site. CONCLUSIONS: Pure transanal rectosigmoid resection is a feasible procedure. The approach via a single transanal access is demanding but viable with the elongated and curved TEO device. The newly developed scope offers an excellent view of the area cephalad to the promontory. PMID- 26940221 TI - Hazardous alcohol use and associated factors in a rural Ethiopian district: a cross-sectional community survey. AB - BACKGROUND: Alcohol related health and social problems are on the rise in sub Saharan Africa. This survey reports the prevalence and associated factors for hazardous drinking in rural Sodo district, southern Ethiopia. The survey was part of a multi-center study, Programme for Improving Mental Health Care (PRIME), which is a consortium of research institutions and ministries of health of five low and middle income countries, namely Ethiopia, India, Nepal, South Africa and Uganda in partnership with UK institutions and World Health Organization (WHO). METHODS: A cross-sectional community survey was conducted involving 1500 adults, age 18 and above, recruited using multi-stage random sampling. Data on alcohol use was collected using the Fast Alcohol Screening Test (FAST). Standardised instruments were used to measure potential associated factors, including a validated adaptation of the Kessler 10 (psychological distress), the List of Threatening Experiences (number of adverse life events). Exploratory multivariable logistic regression was conducted to examine factors associated with hazardous alcohol use. RESULTS: The overall prevalence of hazardous alcohol use was found to be 21 %; 31 % in males and 10.4 % in females, P < 0.05. Factors independently associated with hazardous alcohol use were being male (adjusted OR = 4.0, 95 % CI = 2.44, 6.67), increasing age, having experienced one or more stressful life events (adjusted OR = 1.71, 95 % CI = 1.18, 2.48, and adjusted OR = 2.12, 95 % CI = 1.36, 3.32 for 1-2 and 3 or more adverse life events, respectively) and severe psychological distress (adjusted OR = 2.96, 95 % CI = 1.49, 5.89). High social support was found to be protective from hazardous alcohol use (adjusted OR = 0.41, 95 % CI = 0.23, 0.72). CONCLUSION: High level of hazardous alcohol use was detected in this predominantly rural Ethiopian setting. The finding informed the need to integrate services for hazardous alcohol use such as brief intervention at different levels of primary care services in the district. Public health interventions to reduce hazardous alcohol use also need to be launched. PMID- 26940222 TI - Deep brain stimulation for intractabile epilepsy. AB - INTRODUCTION: Deep brain stimulation (DBS) is currently considered a promising neuromodulation therapy for refractory epilepsy not suitable for resective surgery. Several anatomical targets and different stimulation approaches have been proposed in order to obtain satisfactory seizures reduction. As expected, according with different patterns of neural pathways involvement, the efficacy of each anatomical target stimulation in reducing seizure frequency varies among the different epileptic syndromes. EVIDENCE ACQUISITION: We reviewed the current literature on this topic to provide an overview of the clinical efficacy of the main stimulation targets (anterior nucleus of the thalamus [ANT], hippocampus formation [HF] and centromedian nucleus of the thalamus [CMT]) related to the different epileptic syndromes. We also summarized the available data concerning side effects, neuropsychological outcome, quality of life and future perspective of DBS in intractable epilepsy. EVIDENCE SYNTHESIS: Encouraging results were reported for each target stimulation. However, only in ANT and responsive neurostimulation (RNS) the efficacy and safety were tested on large series of patients and achieving class I evidence level. CONSLUSIONS: We concluded that responsive stimulation could be more appropriate in focal epilepsy, while ANT stimulation could be properly performed also in multifocal seizures with predominant limbic involvement. Despite the small samples size, HF stimulation reduces seizure frequency in (bi) temporal lobe epilepsy, as well as CMT stimulation is able to reduce, seizure frequency, in generalized epilepsy. PMID- 26940224 TI - Microfluidic Diffusion Viscometer for Rapid Analysis of Complex Solutions. AB - The viscosity of complex solutions is a physical property of central relevance for a large number of applications in material, biological, and biotechnological sciences. Here we demonstrate a microfluidic technology to measure the viscosity of solutions by following the advection and diffusion of tracer particles under steady-state flow. We validate our method with standard water-glycerol mixtures, and then we apply this microfluidic diffusion viscometer to measure the viscosity of protein solutions at high concentrations as well as of a crude cell lysate. Our approach exhibits a series of attractive features, including analysis time on the order of seconds and the consumption of a few MUL of sample, as well as the possibility to readily integrate the microfluidic viscometer in other instrument platforms or modular microfluidic devices. These characteristics make microfluidic diffusion viscometry an attractive approach in automated processes in biotechnology and health-care sciences where fast measurements with limited amount of sample consumption are required. PMID- 26940223 TI - E-Cadherin repression increases amount of cancer stem cells in human A549 lung adenocarcinoma and stimulates tumor growth. AB - Here we show that cancer stem cells amount in human lung adenocarcinoma cell line A549 depends on E-cadherin expression. In fact, downregulation of E-cadherin expression enhanced expression of pluripotent genes (c-MYC, NESTIN, OCT3/4 and SOX2) and enriched cell population with the cells possessing the properties of so called 'cancer stem cells' via activation of Wnt/beta-catenin signaling. Repression of E-cadherin also stimulated cell proliferation and migration in vitro, decreased cell amount essential for xenografts formation in nude mice, increased tumors vascularization and growth. On the other hand, E-cadherin upregulation caused opposite effects i.e. diminished the number of cancer stem cells, decreased xenograft vascularization and decelerated tumor growth. Therefore, agents restoring E-cadherin expression may be useful in anticancer therapy. PMID- 26940225 TI - Corrigendum: Tuning the optical response of a dimer nanoantenna using plasmonic nanoring loads. PMID- 26940226 TI - Sex Differences in the Incidence of Anterior Cruciate Ligament, Medial Collateral Ligament, and Meniscal Injuries in Collegiate and High School Sports: 2009-2010 Through 2013-2014. AB - BACKGROUND: Previous research has noted sex-based differences in anterior cruciate ligament (ACL) injury rates in young athletes, while little is known about medial collateral ligament (MCL) and meniscal injury rates in this population. The objective of this study was to compare injury rates for traumatic knee injuries (ie, ACL, MCL, and meniscal injuries) in collegiate and high school (HS) varsity student-athletes across multiple sports. HYPOTHESIS: Knee injury rates vary by sex and across different sports and levels of competition. STUDY DESIGN: Descriptive epidemiology study. METHODS: Injury and athlete-exposure data were utilized from the National Athletic Treatment, Injury and Outcomes Network (NATION) and National Collegiate Athletic Association (NCAA) Injury Surveillance Program (ISP) during the 2009-2010 to 2013-2014 academic years. Analyses focused on ACL, MCL, and meniscal injuries. Injury rates and injury rate ratios (IRRs) with 95% CIs were calculated for basketball, ice hockey, lacrosse, soccer, and baseball/softball. RESULTS: The ACL injury rate was higher for female than male athletes at the collegiate (IRR, 2.49; 95% CI, 1.81-3.41) and HS (IRR, 2.30; 95% CI, 1.67-3.18) levels. At the collegiate level, the highest ACL IRR comparing female to male athletes was reported in softball/baseball (IRR, 6.61; 95% CI, 1.48-29.55). At the HS level, the highest ACL IRR was reported in basketball (IRR, 3.68; 95% CI, 1.91-7.10). The MCL injury rate was higher for female than male athletes at the HS level (IRR, 2.11; 95% CI, 1.25-3.56) but lower for female than male athletes at the collegiate level (IRR, 0.73; 95% CI, 0.59-0.92). The meniscal injury rate was lower for female than male athletes at the HS level (IRR, 0.47; 95% CI, 0.31-0.71), while no differences by sex were seen at the collegiate level (IRR, 1.35; 95% CI, 0.90-2.02). CONCLUSION: Knee injury rates varied by sex across 5 different sports in the HS and collegiate settings. Female athletes sustained ACL injuries at a higher rate than male athletes at both the HS and collegiate levels in these 5 sports; however, there was not a distinct sex disparity in MCL and meniscal injuries. Future studies should examine the rates of concomitant and recurrent injuries to inform injury prevention and rehabilitation programs. PMID- 26940228 TI - Surface Anatomy of the Nail for the Dermatologist. AB - Expert diagnosis of cutaneous pathology requires precise anatomic description. In this brief report the authors review the clinically relevant surface anatomy of the nail and relate it to a case of squamous cell carcinoma. PMID- 26940227 TI - Aspirin use and the risk of cholangiocarcinoma. AB - Whether aspirin use is protective against cholangiocarcinoma (CCA) remains unclear. We determined the association between aspirin use and other risk factors for each CCA subtype individually. In a hospital-based case-control study, 2395 CCA cases (1169 intrahepatic, 995 perihilar, and 231 distal) seen at the Mayo Clinic, Rochester, MN, from 2000 through 2014 were enrolled. Controls selected from the Mayo Clinic Biobank were matched two to one with cases by age, sex, race, and residence (n = 4769). Associations between aspirin use, other risk factors, and CCA risk were determined. Aspirin was used by 591 (24.7%) CCA cases and 2129 (44.6%) controls. There was a significant inverse association of aspirin use with all CCA subtypes, with adjusted odds ratios (AORs) of 0.35 (95% confidence interval [CI], 0.29-0.42), 0.34 (95% CI 0.27-0.42), and 0.29 (95% CI 0.19-0.44) for intrahepatic, perihilar, and distal CCA, respectively (P < 0.001 for all). Primary sclerosing cholangitis was more strongly associated with perihilar (AOR = 453, 95% CI 104-999) than intrahepatic (AOR = 93.4, 95% CI 27.1 322) or distal (AOR = 34.0, 95% CI 3.6-323) CCA, whereas diabetes was more associated with distal (AOR = 4.2, 95% CI 2.5-7.0) than perihilar (AOR = 2.9, 95% CI 2.2-3.8) or intrahepatic (AOR = 2.5, 95% CI 2.0-3.2) CCA. Cirrhosis not related to primary sclerosing cholangitis was associated with both intrahepatic and perihilar CCA, with similar AORs of 14. Isolated inflammatory bowel disease without primary sclerosing cholangitis was not associated with any CCA subtype. CONCLUSIONS: Aspirin use was significantly associated with a 2.7-fold to 3.6-fold decreased risk for the three CCA subtypes; our study demonstrates that individual risk factors confer risk of different CCA subtypes to different extents. (Hepatology 2016;64:785-796). PMID- 26940230 TI - Formation of Periodically Arranged Nanobubbles in Mesopores: Capillary Bridge Formation and Cavitation during Sorption and Solidification in an Hierarchical Porous SBA-15 Matrix. AB - We report synchrotron-based small-angle X-ray scattering experiments on a template-grown porous silica matrix (Santa Barbara Amorphous-15) upon in situ sorption of fluorinated pentane C5F12 along with volumetric gas sorption isotherm measurements. Within the mean-field model of Saam and Cole for vapor condensation in cylindrical pores, a nitrogen and C5F12 sorption isotherm is well described by a bimodal pore radius distribution dominated by meso- and micropores with 3.4 and 1.6 nm mean radius, respectively. In the scattering experiments, two different periodicities become evident. One of them (d1 = 11.5 nm) reflects the next nearest neighbor distance in a 2D-hexagonal lattice of tubular mesopores. A second periodicity (d2 = 11.4 nm) found during in situ sorption and freezing experiments is traced back to a superstructure along the cylindrical mesopores. It is compatible with periodic pore corrugations found in electron tomograms of empty SBA-15 by Gommes et al. ( Chem. Mater. 2009, 21, 1311 - 1317). A Rayleigh Plateau instability occurring at the cylindrical blockcopolymer micelles characteristic of the SBA-15 templating process quantitatively accounts for the superstructure and thus the spatial periodicity of the pore wall corrugation. The consequences of this peculiar morphological feature on the spatial arrangement of C5F12, in particular the formation of periodically arranged nanobubbles (or voids) upon adsorption, desorption, and freezing of liquids, are discussed in terms of capillary bridge formation and cavitation in tubular but periodically corrugated pores. PMID- 26940229 TI - A multistress responsive type I toxin-antitoxin system: bsrE/SR5 from the B. subtilis chromosome. AB - bsrE/SR5 is a type I TA system from prophage-like element P6 of the B. subtilis chromosome. The 256 nt bsrE RNA encodes a 30 aa toxin. The antitoxin SR5 is a 163 nt antisense RNA. Both genes overlap at their 3' ends. Overexpression of bsrE causes cell lysis on agar plates, which can be neutralized by sr5 overexpression, whereas deletion of the chromosomal sr5 copy has no effect. SR5 is short-lived with a half-life of ~7 min, whereas bsrE RNA is stable with a half-life of >80 min. The sr5 promoter is 10-fold stronger than the bsrE promoter. SR5 interacts with the 3' UTR of bsrE RNA, thereby promoting its degradation by recruiting RNase III. RNase J1 is the main RNase responsible for SR5 and bsrE RNA degradation, and PnpA processes an SR5 precursor to the mature RNA. Hfq stabilizes SR5, but is not required for its inhibitory function. While bsrE RNA is affected by temperature shock and alkaline stress, the amount of SR5 is significantly influenced by various stresses, among them pH, anoxia and iron limitation. Only the latter one is dependent on sigB. Both RNAs are extremely unstable upon ethanol stress due to rapid degradation by RNase Y. PMID- 26940232 TI - Is menopausal status related to women's attitudes toward menopause and aging? AB - The objective of this study was to explore the relationship between menopausal status and attitudes toward menopause and aging. We identified 1,400 Bengali Hindu women aged 40-55 years (early perimenopausal n = 445; late perimenopausal n = 240; early postmenopausal n = 285; late postmenopausal n = 430) from West Bengal, India. Information on attitudes toward menopause and aging was collected from March 2009 to July 2012 using ten agree/disagree statements, of which three were positive, four were negative, and the rest were neutral. We used only the positive and negative statements in the analyses. The participants were given three response options for each statement: (1) agreed, (2) disagreed, and (3) felt neutral. Agreement with positive statements and disagreement with negative statements were scored as 3. The converse responses were scored as 1. Neutral responses were not scored. Thus, the total attitude score for each participant ranged from 7 to 21. Additionally, data on sociodemographic and reproductive variables, menopausal symptoms, and perceptions toward menopause were also collected. Multivariable analyses (ANCOVA) showed that postmenopausal women had more positive attitudes toward menopause and aging than perimenopausal women. Providing balanced information about menopause and aging might help to foster positive attitudes toward menopause. PMID- 26940233 TI - Oncologic Drugs Advisory Committee Recommendations and Approval of Cancer Drugs by the US Food and Drug Administration. AB - IMPORTANCE: The US Food and Drug Administration (FDA) advisory committees influence decisions relating to the regulatory approval of drugs in the United States. Outside of the field of oncology, prosponsor voting bias has been observed among members with financial conflicts of interest (FCOIs). OBJECTIVE: To explore factors associated with Oncologic Drugs Advisory Committee (ODAC) recommendations and the influence ODAC members' FCOIs on the drug approval process. DESIGN, SETTING, AND PARTICIPANTS: Retrospective analysis of 82 ODAC meeting transcripts between January 2000 and December 2014. Analysis was restricted to meetings at which votes were cast relating to oncologic drugs. The influence of methodology of trials supporting approval and frequency and type of self-reported FCOIs of voting members was explored using logistic regression. MAIN OUTCOMES AND MEASURES: ODAC recommendation for drug approval and subsequent FDA approval. RESULTS: Eighty-two transcripts of ODAC meetings between January 2000 and December 2014 were available for analysis. During the time period analyzed, ODAC members voted on 68 applications in 79 meetings (the remaining 3 meetings included voting questions regarding postmarketing safety or trial design). There was agreement between ODAC recommendations and final FDA approval; FDA approval was received for all 41 drugs that ODAC recommended approval. Additionally, the FDA approved 7 out of 41 agents that were not recommended for approval by ODAC (kappa = 0.83). In 51 of 79 meetings, more than 1 trial was available to support the indication of a particular drug, and favorable ODAC recommendations were more likely when this was the case (odds ratio [OR], 1.82; 95% CI, 1.19-2.78; P = .01). Availability of randomized data did not appear to be important with selected single-arm phase 2 trials leading to recommendations for approval, especially in rare diseases. There has been a significant reduction in FCOIs over time (31 of 77 voting members [40%] in 2000 vs 0 of 20 voting members in 2014 [0%]; P < .001). Recommendations for approval were made in 28 of 47 meetings with members reporting FCOIs while among meetings with no reported FCOIs, recommendations for approval were made in 13 of 35 meetings (OR, 1.19; 95% CI, 0.97-1.46; P = .10). No significant association between ODAC recommendations and FDA approval was observed for members with FCOIs with the sponsor (OR, 1.79; 95% CI, 0.97-1.46; P = .19 and OR, 3.48; 95% CI, 0.84-14.35; P = .09, respectively) compared with members with FCOIs with competitors (OR, 1.06; 95% CI, 0.78-1.44; P = .72 and OR, 0.94; 95% CI, 0.69-1.28; P = .69, respectively). CONCLUSIONS AND RELEVANCE: Availability of multiple trials is associated with higher odds of ODAC recommendation and drug approval. Availability of randomized data appears less important. Declaration of FCOIs among ODAC members was frequent during the time period of interest but has decreased significantly over time. There is no apparent association between FCOIs and ODAC recommendations and subsequent FDA approval. PMID- 26940234 TI - Self-pairing of 1-methylthymine mediated by two and three Ag(I) ions: a gas phase study using infrared dissociation spectroscopy and density functional theory. AB - Metal base pairs of Ag(I) cations and 1-methylthymine (1MT) or deprotonated 1 methylthymine (1MT-H) are produced and analyzed by electrospray ionization mass spectrometry (ESI-MS). Mass-selected ions of type [Ag2(1MT)(1MT-H)](+) and [Ag3(1MT-H)2](+) are interrogated by infrared multiple-photon dissociation (IRMPD) in an ion trap in the range of 1200-3700 cm(-1). Supporting spectroscopic data were obtained from the investigation of the analogous 2'-deoxy-thymidine complexes which exhibit advantageously high fragment yields. By comparison with calculated linear IR spectra (obtained by density functional theory, DFT) we assign the structures and the possible isomeric forms of these metal base pairs and their dependence on the number of mediating Ag(I) ions. Based on the observed Ag(+)/1MT complexes and related polarizable continuum model DFT calculations we describe the probable formation pathways in aqueous solution. The present findings pave the way for subsequent UV investigations of the multi-metal mediated base pairs. PMID- 26940235 TI - The association between vital signs and mortality in a retrospective cohort study of an unselected emergency department population. AB - BACKGROUND: Vital signs are widely used in emergency departments. Previous studies on the association between vital signs and mortality in emergency departments have been restricted to selected patient populations. We aimed to study the association of vital signs and age with 1-day mortality in patients visiting the emergency department. METHODS: This retrospective cohort included patients visiting the emergency department for adults at Sodersjukhuset, Sweden from 4/1/2012 to 4/30/2013. Exclusion criteria were: age < 18 years, deceased upon arrival, chief complaint circulatory or respiratory arrest, key data missing and patients who were directed to a certain fast track for conditions demanding little resources. Vital sign data was collected through the Rapid Emergency Triage and Treatment System - Adult (RETTS-A). Descriptive analyses and logistic regression models were used. The main outcome measure was 1-day mortality. RESULTS: The 1-day mortality rate was 0.3%. 96,512 patients met the study criteria. After adjustments of differences in the other vital signs, comorbidities, gender and age the following vital signs were independently associated with 1-day mortality: oxygen saturation, systolic blood pressure, temperature, level of consciousness, respiratory rate, pulse rate and age. The highest odds ratios was observed when comparing unresponsive to alert patients (OR 31.0, CI 16.9 to 56.8), patients >= 80 years to <50 years (OR 35.9, CI 10.7 to 120.2) and patients with respiratory rates <8/min to 8-25/min (OR 18.1, CI 2.1 to 155.5). DISCUSSION: Most of the vital signs used in the ED are significantly associated with one-day mortality. The more the vital signs deviate from the normal range, the larger are the odds of mortality. We did not find a suitable way to adjust for the inherent influence the triage system and medical treatment has had on mortality. CONCLUSIONS: Most deviations of vital signs are associated with 1-day mortality. The same triage level is not associated with the same odds for death with respect to the individual vital sign. Patients that were unresponsive or had low respiratory rates or old age had the highest odds of 1 day mortality. PMID- 26940231 TI - Taking cues from the extracellular matrix to design bone-mimetic regenerative scaffolds. AB - There is an ongoing need for effective materials that can replace autologous bone grafts in the clinical treatment of bone injuries and deficiencies. In recent years, research efforts have shifted away from a focus on inert biomaterials to favor scaffolds that mimic the biochemistry and structure of the native bone extracellular matrix (ECM). The expectation is that such scaffolds will integrate with host tissue and actively promote osseous healing. To further enhance the osteoinductivity of bone graft substitutes, ECM-mimetic scaffolds are being engineered with a range of growth factors (GFs). The technologies used to generate GF-modified scaffolds are often inspired by natural processes that regulate the association between endogenous ECMs and GFs. The purpose of this review is to summarize research centered on the development of regenerative scaffolds that replicate the fundamental collagen-hydroxyapatite structure of native bone ECM, and the functionalization of these scaffolds with GFs that stimulate critical events in osteogenesis. PMID- 26940236 TI - Salidroside protects against kainic acid-induced status epilepticus via suppressing oxidative stress. AB - There are numerous mechanisms by which the brain generates seizures. It is well known that oxidative stress plays a pivotal role in status epilepticus (SE). Salidroside (SDS) extracted from Rhodiola rosea L. shows multiple bioactive properties, such as neuroprotection and antioxidant activity in vitro and in vivo. This study explored the role of SDS in kainic acid (KA)-induced SE and investigated the underlying mechanism. Latency to SE increased in the SDS pretreated mice compared to the KA group, while the percentage of incidence of SE was significantly reduced. These results suggested that pretreatment with SDS not only delayed SE, but it also decreased the incidence of SE induced by KA. KA increased MDA level and reduced the production of SOD and GSH at multiple timepoints after KA administration. SDS inhibited the change of MDA, SOD and GSH induced by KA prior to SE onset, indicating that SDS protects against KA-induced SE via suppressing oxidative stress. Based on these results, we investigated the possible molecular mechanism of SDS. Pretreatment with SDS reversed the KA induced decrease in AMP-activated protein kinase (AMPK); increased the sirtuin 1 (SIRT1) deacetylase activity in KA-treated mice, which had no demonstrable effect on SIRT1 mRNA and protein; and suppressed the KA-induced increase in Ace-FoxO1. These results showed that AMPK/SIRT1/FoxO1 signaling is possibly the molecular mechanism of neuroprotection by SDS. PMID- 26940237 TI - Evaluating interhemispheric cortical responses to transcranial magnetic stimulation in chronic stroke: A TMS-EEG investigation. AB - TMS-evoked cortical responses can be measured using simultaneous electroencephalography (TMS-EEG) to directly quantify cortical connectivity in the human brain. The purpose of this study was to evaluate interhemispheric cortical connectivity between the primary motor cortices (M1s) in participants with chronic stroke and controls using TMS-EEG. Ten participants with chronic stroke and four controls were tested. TMS-evoked responses were recorded at rest and during a typical TMS assessment of transcallosal inhibition (TCI). EEG recordings from peri-central gyral electrodes (C3 and C4) were evaluated using imaginary phase coherence (IPC) analyses to quantify levels of effective interhemispheric connectivity. Significantly increased TMS-evoked beta (15-30Hz frequency range) IPC was observed in the stroke group during ipsilesional M1 stimulation compared to controls during TCI assessment but not at rest. TMS evoked beta IPC values were associated with TMS measures of transcallosal inhibition across groups. These results suggest TMS-evoked EEG responses can index abnormal effective interhemispheric connectivity in chronic stroke. PMID- 26940238 TI - Association between CYP17A1 rs3824755 and rs743572 gene polymorphisms and Alzheimer's disease in the Chinese Han population. AB - The CYP17A1 gene encodes cytochrome P450c17alpha, an enzyme that catalyzes the formation of sex hormones, which have been linked to the pathogenesis of Alzheimer's disease (AD). An association between the CYP17A1 rs743572 single nucleotide polymorphism (SNP) and AD has been reported; however, the findings are controversial. In the present study, we investigated the association between rs743572 and another SNP, rs3824755, and AD risk in a Chinese Han population (n=207 patients and 239 controls), and their interaction with the apolipoprotein E (APOE) e4 allele. We found that the C allele and GC+CC genotypes of rs3824755 conferred protection against AD only in APOE e4 carriers. Both rs3824755 and rs743572 polymorphisms showed interactions with APOE e4. The C allele and GC+CC genotypes of rs3824755 acted as protective factors that decreased the risk of APOE e4 in AD. The CYP17A1 rs743572G allele and AG+GG genotypes were found to be potential risk factors that act synergetically with APOE e4. Moreover, the CA and GG haplotypes were protective and conferred a slight risk, respectively, in APOE e4 carriers. These results indicate that CYP17A1 rs3824755 and rs743572 are associated with AD in the Chinese Han population and act in combination with APOE e4. PMID- 26940239 TI - Mechanism of soluble beta-amyloid 25-35 neurotoxicity in primary cultured rat cortical neurons. AB - This study aimed to determine the effects of different concentrations of soluble beta-amyloid 25-35 (Abeta25-35) on cell viability, calcium overload, and PI3K-p85 expression in cultured cortical rat neurons. Primary cultured cerebral cortical neurons of newborn rats were divided randomly into six groups. Five groups were treated with soluble Abeta25-35 at concentrations of 10nmol/L, 100nmol/L, 1MUmol/L, 10MUmol/L, or 30MUmol/L. Cell Counting Kit-8 staining was used to measure cell viability, laser-scanning confocal imaging was used to detect changes in intracellular free calcium concentration, and western blot assay was used to measure neuronal PI3K-p85 expression. Soluble Abeta25-35 was found to reduce cell viability and induce calcium overload in primary cultured rat cerebral cortical neurons, in a concentration-dependent manner. At certain concentrations, soluble Abeta25-35 also increased neuronal PI3K-p85 expression. These findings reveal that soluble Abeta25-35 reduces the viability of cultured cerebral cortical rat neurons. The neurotoxicity mechanism may involve calcium overload and disruption of insulin signal transduction pathways. PMID- 26940240 TI - Depletion of norepinephrine of the central nervous system Down-regulates the blood glucose level in d-glucose-fed and restraint stress models. AB - DSP-4[N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride] is a neurotoxin that depletes norepinephrine. The catecholaminergic system has been implicated in the regulation of blood glucose level. In the present study, the effect of DSP-4 administered intracerebroventricularly (i.c.v.) or intrathecally (i.t.) on blood glucose level was examined in d-glucose-fed and restraint stress mice models. Mice were pretreated once i.c.v. or i.t. with DSP-4 (10-40MUg) for 3days, and d glucose (2g/kg) was fed orally. Blood glucose level was measured 0 (prior to glucose feeding or restraint stress), 30, 60, and 120min after d-glucose feeding or restraint stress. The i.c.v. or i.t. pretreatment with DSP-4 attenuated blood glucose level in the d-glucose-fed model. Plasma corticosterone level was downregulated in the d-glucose-fed model, whereas plasma insulin level increased in the d-glucose-fed group. The i.c.v. or i.t. pretreatment with DSP-4 reversed the downregulation of plasma corticosterone induced by feeding d-glucose. In addition, the d-glucose-induced increase in plasma insulin was attenuated by the DSP-4 pretreatment. Furthermore, i.c.v. or i.t. pretreatment with DSP-4 reduced restraint stress-induced increases in blood glucose levels. Restraint stress increased plasma corticosterone and insulin levels. The i.c.v. pretreatment with DSP-4 attenuated restraint stress-induced plasma corticosterone and insulin levels. Our results suggest that depleting norepinephrine at the supraspinal and spinal levels appears to be responsible for downregulating blood glucose levels in both d-glucose-fed and restraint stress models. PMID- 26940241 TI - Effect of acupuncture stimulation on rats with depression induced by water immersion stress. AB - Depression is a kind of mood disorder. The incidence of depressed patients has demonstrated an upward trend in recent years. Symptoms may improve with treatments such as pharmacotherapy and cognitive-behavioral therapy, but such approaches may exert strong side effects, and therapeutic effects can be slow. We studied how acupuncture stimulation would affect depression as a method to reduce side effects. Mild depression was induced in rats by 1-week water-immersion stress. We treated these mildly depressed rats with either acupuncture stimulation at the "Bai-Hui" (GV 20) and "Yintang" (Ex-HN3) points, or antidepressants. We then measured the immobile time and serum corticosterone level in rats. Immobile time and serum corticosterone level decreased on stimulation with acupuncture or antidepressants. These findings suggest that mild depression in rats was improved by stimulation with acupuncture The mechanisms underlying such improvement may effect HPA system activated by this stress, and inhibit the response to lead to the disorder of the hippocampal nerve cell. PMID- 26940242 TI - Clinical and biomarker profiling of prodromal Alzheimer's disease in workpackage 5 of the Innovative Medicines Initiative PharmaCog project: a 'European ADNI study'. AB - BACKGROUND: In the field of Alzheimer's disease (AD), the validation of biomarkers for early AD diagnosis and for use as a surrogate outcome in AD clinical trials is of considerable research interest. OBJECTIVE: To characterize the clinical profile and genetic, neuroimaging and neurophysiological biomarkers of prodromal AD in amnestic mild cognitive impairment (aMCI) patients enrolled in the IMI WP5 PharmaCog (also referred to as the European ADNI study). METHODS: A total of 147 aMCI patients were enrolled in 13 European memory clinics. Patients underwent clinical and neuropsychological evaluation, magnetic resonance imaging (MRI), electroencephalography (EEG) and lumbar puncture to assess the levels of amyloid beta peptide 1-42 (Abeta42), tau and p-tau, and blood samples were collected. Genetic (APOE), neuroimaging (3T morphometry and diffusion MRI) and EEG (with resting-state and auditory oddball event-related potential (AO-ERP) paradigm) biomarkers were evaluated. RESULTS: Prodromal AD was found in 55 aMCI patients defined by low Abeta42 in the cerebrospinal fluid (Abeta positive). Compared to the aMCI group with high Abeta42 levels (Abeta negative), Abeta positive patients showed poorer visual (P = 0.001), spatial recognition (P < 0.0005) and working (P = 0.024) memory, as well as a higher frequency of APOE4 (P < 0.0005), lower hippocampal volume (P = 0.04), reduced thickness of the parietal cortex (P < 0.009) and structural connectivity of the corpus callosum (P < 0.05), higher amplitude of delta rhythms at rest (P = 0.03) and lower amplitude of posterior cingulate sources of AO-ERP (P = 0.03). CONCLUSION: These results suggest that, in aMCI patients, prodromal AD is characterized by a distinctive cognitive profile and genetic, neuroimaging and neurophysiological biomarkers. Longitudinal assessment will help to identify the role of these biomarkers in AD progression. PMID- 26940246 TI - Proceedings of the 117th meeting of the British Neuropathological Society, Royal College of Physicians, London, UK, 2-4 March 2016. President: Professor Paul Ince. PMID- 26940243 TI - Role of survivin expression in predicting biochemical recurrence after radical prostatectomy: a multi-institutional study. AB - OBJECTIVE: To assess the association of survivin expression with clinicopathological features and biochemical recurrence (BCR) after radical prostatectomy (RP) in a large multi-institutional cohort. METHODS: Survivin expression was evaluated by immunohistochemistry on a tissue microarray of RP cores from 3 117 patients. Survivin expression was considered altered when at least 10% of the tumour cells stained positive. The association of altered survivin expression with BCR was evaluated using Cox proportional hazards regression models. RESULTS: Survivin expression was altered in 1 330 patients (42.6%). Altered expression was associated with higher Gleason score on RP (P = 0.001), extracapsular extension (P = 0.019), seminal vesicle invasion (P < 0.001) and lymph node metastases (P = 0.009). The median (interquartile range) follow-up was 38 (21-66) months. Patients with altered survivin expression had a shorter BCR-free survival time than those with normal expression (5-year BCR-free survival estimates: 74.7 vs 79.0%; P = 0.008). Altered survivin expression did not retain its prognostic value, however, after adjustment for the effect of established clinicopathological factors (P = 0.73). Subgroup analyses also showed no independent prognostic value of survivin. CONCLUSIONS: Survivin expression is commonly altered in patients undergoing RP. Altered survivin expression is associated with the clinicopathological features of biologically and clinically aggressive PCa. Survivin expression was associated with BCR only in univariable analysis, limiting its value in daily clinical decision-making. PMID- 26940245 TI - Expanding the phenotype of RTTN variations: a new family with primary microcephaly, severe growth failure, brain malformations and dermatitis. AB - Primary autosomal recessive microcephaly (MCPH) is a developmental disorder characterized by prenatal onset of abnormal brain growth. MCPH occurs both alone and as part of a broad range of neurodevelopmental syndromes with or without cortical malformations and growth retardation. Here we report a consanguineous Moroccan family with two siblings affected by severe primary microcephaly, failure to thrive, congenital dermatitis and severe developmental delay. Brain magnetic resonance imaging showed lissencephaly of frontal lobes and periventricular heterotopia of the gray matter. We performed both Comparative Genomic Hybridization array and whole exome sequencing (WES) analyses of the kindred. No quantitative defects were detected. However, WES identified a new homozygous missense variation in the penultimate nucleotide of exon 23 of RTTN gene (c.2953A>G;pArg985Gly). cDNA sequencing revealed two abnormal spliced products, one lacking only exon 23 and the other lacking exons 22 and 23 (out-of frame). RTTN is a protein involved in cilia structure and function. Homozygous mutations in RTTN gene have been described in bilateral diffuse isolated polymicrogyria and, more recently, in microcephalic primordial dwarfism (PD). We found a novel homozygous mutation in RTTN associated with microcephalic PD as well as complex brain malformations and congenital dermatitis, thus expanding the phenotypic spectrum of both RTTN-associated diseases and ciliary dysfunction. PMID- 26940247 TI - Crisis and Emergency Risk Messaging in Mass Media News Stories: Is the Public Getting the Information They Need to Protect Their Health? AB - The mass media provide an important channel for delivering crisis and emergency risk information to the public. We conducted a content analysis of 369 newspaper and television broadcast stories covering natural disaster and foodborne outbreak events and coded for seven best practices in crisis and emergency risk messaging. On average, slightly less than two (1.86) of the seven best practices were included in each story. The proportion of stories including individual best practices ranged from 4.6% for "expressing empathy" to 83.7% for "explaining what is known" about the event's impact to human health. Each of the other five best practices appeared in less than 25% of stories. These results suggest much of the risk messaging the public receives via mass media does not follow best practices for effective crisis and emergency communication, potentially compromising public understanding and actions in response to events. PMID- 26940249 TI - Maternal co-morbidities and neonatal outcomes associated with cystic fibrosis. AB - OBJECTIVE: To evaluate maternal co-morbidities and adverse perinatal outcomes associated with cystic fibrosis (CF). METHODS: This is a retrospective cohort study of 2 178 954 singleton pregnancies at >=20 weeks' gestation with and without CF in the state of California during the years 2005-2008. ICD-9 codes and linked hospital discharge and vital statistics data were utilized. Rates of maternal co-morbidities, fetal congenital anomalies and adverse perinatal outcomes were compared in those with CF and those without. Maternal co morbidities included gestational hypertension, preeclampsia, gestational diabetes and primary cesarean delivery. Perinatal outcomes included neonatal demise, preterm birth, intrauterine growth restriction, macrosomia, anomaly, fetal demise, asphyxia, respiratory distress syndrome, jaundice, intraventricular hemorrhage, hypoglycemia and necrotizing enterocolitis. RESULTS: The cohort included 2 178 954 pregnancies of which 77 mothers had CF. Mothers with CF were more likely to have pre-gestational diabetes and had higher rates of primary cesarean delivery. Neonates delivered to mothers with CF were more likely to be born preterm and have congenital anomalies but otherwise were not at increased risk for significant neonatal morbidity or mortality when adjusted for gestational age. CONCLUSION: Mothers with CF are more likely to have pre gestational diabetes, deliver preterm (<37 weeks gestation) and have a primary cesarean delivery. Infants are more likely to have congenital anomalies. In addition to early diabetic screening and genetic counseling, a detailed fetal anatomy ultrasound should be performed in women with CF. PMID- 26940248 TI - Prevalence of malocclusion traits and orthodontic treatment in a Finnish adult population. AB - Objective The aim of the study was to examine the prevalence of malocclusion traits and the extent of orthodontic treatment in a Finnish adult population. Materials and methods The study population comprised subjects (n = 1964) from the Northern Finland Birth Cohort 1966 living in the city of Oulu and within 100 km of it. A clinical oral and dental examination with registration of occlusion was carried out in 2012 in connection with a 46-year follow-up survey. Data on previous orthodontic treatment were collected based on a questionnaire. Results In the clinical examination, 39.5% of the subjects had at least one malocclusion trait. The most common malocclusion traits were lateral crossbite (17.9%), overbite >= 6 mm (11.7%) and overjet >= 6 mm (9.7%). Crossbite on the left premolars, negative overjet and increased overbite were found more frequently in men. The prevalence of malocclusion traits was at the same level in treated and untreated groups. Overall, 18.6% of the subjects had undergone orthodontic treatment. Women showed a significantly higher prevalence of orthodontic treatment. Conclusions The most common malocclusion trait in the present study was lateral crossbite. Significant male dominance in the prevalence of malocclusion was observed, which has not been reported earlier in Finland. Orthodontic treatment of malocclusion traits was more common among females in Northern Finland. This study indicates that orthodontic treatment provided in childhood was, on average, adequate in reducing malocclusion traits to the level observed in the general population. PMID- 26940252 TI - Suppression of superoxide anion generation catalyzed by xanthine oxidase with alkyl caffeates and the scavenging activity. AB - Alkyl caffeates are strong antioxidants and inhibitors of xanthine oxidase. However, it is unclear about the effect of caffeic acid and alkyl caffeates on superoxide anion (O2(-)) generation catalyzed by xanthine oxidase. Effects of caffeic acid and alkyl caffeates on the uric acid formation and O2(-) generation catalyzed by xanthine oxidase were analyzed. The scavenging activities of 1,1 diphenyl-2-picryhydrazyl (DPPH) radical and O2(-) generated with phenazine methosulfate (PMS) and NADH were examined. Caffeic acid derivatives equally suppressed O2(-) generation, and the suppression is stronger than inhibition of xanthine oxidase. Scavenging activity of O2(-) is low compared to the suppression of O2(-) generation. Suppression of O2(-) generation catalyzed by xanthine oxidase with caffeic acid derivatives was not due to enzyme inhibition or O2(-) scavenging but due to the reduction of xanthine oxidase molecules. Alkyl caffeates are effective inhibitors of uric acid and O2(-) catalyzed by xanthine oxidase as well as antioxidants for edible oil. PMID- 26940253 TI - alpha-Synuclein in Neurodegeneration-A Good Protein that may go Bad. PMID- 26940254 TI - Identifying correlates and determinants of physical activity in youth: How can we advance the field? AB - This commentary provides a critical discussion of current research investigating the correlates and determinants of physical activity in young people, with specific focus on conceptual, theoretical and methodological issues. We draw on current child and adolescent literature and our own collective expertise to illustrate our discussion. We conclude with recommendations that will strengthen future research and help to advance the field. PMID- 26940255 TI - Inhibitory effect of Phalaenopsis orchid extract on WNT1-induced immature melanocyte precursor differentiation in a novel in vitro solar lentigo model. AB - Recently, it has been reported that increased expression of WNT1 accelerates the differentiation of melanocyte stem cells (McSCs) in solar lentigines (SLs), hyperpigmented maculae commonly seen on sun-exposed areas of the skin. In this study, to establish an in vitro SL model, human epidermal squamous carcinoma cell line HSC-1, which expresses higher levels of WNT1 than normal human epidermal keratinocytes, was co-cultured with early passage normal human epidermal melanocytes (NHEMs) as an in vitro McSC model. As a result, mRNA expression levels of melanocyte differentiation-related genes MITF and TYR in NHEMs were significantly increased by co-culturing with HSC-1 cells. Furthermore, Phalaenopsis orchid extract (Phex) inhibited McSCs differentiation by suppressing WNT1 expression via down-regulation of DLX2, a transcriptional activator of WNT1, in HSC-1 cells. Therefore, our finding suggested that extracts such as Phex, which suppresses WNT1 expression, may be useful as a novel treatment of SLs. PMID- 26940256 TI - Palaeopathology: Current challenges and medical impact. AB - Palaeopathology is the science which studies ancient human diseases. Throughout its relatively young history it underwent tremendous technological and methodological improvements (from pure morphology and histology to CT scanning) that have constantly reshaped its scientific rationale. Among other achievements, the study of mummies and fossilized hominids has allowed to effectively extract ancient DNA, prove the existence of atherosclerosis in ancient times, demonstrate the presence of disease vectors, better clarify the etiology of infectious diseases otherwise only postulated on the basis of ancient accounts as well as to show the presence of spine pathology in our hominid ancestors. The research levels in this discipline are three: basic research, individual cases, population. The first and the third levels contribute most to the discipline, while the second is the one more appealing to the general public on account of its description of important cases reports. In addition, a recently introduced sub-specialty of palaeopathology, pathography is aiming to use an interdisciplinary approach to find traces of diseases in ancient literary sources and artistic representations. In spite of its discoveries, palaeopathology is not always viewed positively by clinicians because certain old-fashioned techniques are still due to technical restrictions. The authors provide a set of suggestions on how to strengthen the scientific recognition of this subject and explain at length how it could contribute to the progress of medical research. Clin. Anat. 29:816-822, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26940257 TI - Celecoxib for the treatment of atherosclerosis. AB - INTRODUCTION: It is widely accepted that inflammation plays a pivotal role in the progression of atherosclerosis. Anti-inflammatory drugs and especially selective cyclooxygenase-2 (COX-2) inhibitors have attracted a keen interest. AREAS COVERED: In the present drug evaluation article, the authors elucidate the role of celecoxib, a selective COX-2 inhibitor, in the treatment of atherosclerosis. They discuss the atherogenic properties of the COX-2 enzyme. In addition, they address the studies that support an atheroprotective role of celecoxib. Moreover, they provide a review of the literature on the role of COX-2 inhibitors in increasing the rate of major adverse cardiovascular events. Finally, they discuss the emerging evidence that supports celecoxib as an adjuvant or neo-adjuvant therapy to percutaneous coronary intervention (PCI). EXPERT OPINION: Several studies have demonstrated a beneficial effect of celecoxib on the progression of atherosclerosis. Nevertheless, this evidence is mainly derived from preliminary data, while a substantial number of clinical studies have raised concerns regarding the cardiovascular safety of COX-2 inhibitors. Interestingly, recent clinical studies have supported the advantages of short-term celecoxib administration in patients undergoing PCI. However, many more large scale clinical trials are required to assess the long-term safety and efficacy of celecoxib administration in patients with cardiovascular disease. PMID- 26940258 TI - The Future of US Health Care Policy. PMID- 26940259 TI - Many correlates of poor quality of life among substance users entering treatment are not addiction-specific. AB - BACKGROUND: Quality of life (QoL) is an important measure and outcome within chronic disease management and treatment, including substance use disorders (SUD). The aim of this paper was to investigate correlates of poorer QoL of individuals entering SUD treatment in Norway, in order to identify subgroups that may most benefit from different interventions. METHODS: Twenty-one treatment facilities invited all incoming patients to participate. Five hundred forty-nine patients who enrolled between December 2012 and April 2015 are analyzed. QoL, substance use, mental and physical comorbidities, and exercise behaviors were measured. Multinomial regression analysis was used to determine variables significantly associated with poorer QoL. RESULTS: The majority of both genders (75 %) reported "poor" or "very poor" QoL at intake. Depression showed a strong association with poor QoL (relative risk ratio [RRR] 3.3, 95 % confidence interval [CI] 1.0-10.3) and very poor QoL (RRR 3.8, 1.2-11.8) among women. Physical inactivity among men was associated with very poor QoL (RRR 2.0, 1.1 3.7), as was reporting eating most meals alone (RRR 2.6, 1.4-4.8). Evaluating one's weight as too low was also associated with poor QoL (RRR 2.0, 1.0-3.9) and very poor QoL (RRR 2.0, 1.1-3.7) among men. Consuming methadone/buprenorphine was a protective factor for men reporting poor QoL (RRR 0.5, 0.3-0.9) and very poor QoL (RRR 0.4, 0.2-0.9), as well as for women reporting very poor QoL (RRR 0.2, 0.0-0.6). CONCLUSIONS: Factors associated with poorer QoL among other healthy and clinical populations, such as impaired social and physical well-being and psychological distress, were also seen associated in this sample. Treatment should be targeted towards patients with these particular vulnerabilities in addition to focusing on substance-related factors, and interventions proven to improve the QoL of other populations with these vulnerabilities should be explored in a SUD context. PMID- 26940261 TI - Phytoremediation of iron from red soil of tropical region by using Centella asiatica. AB - The accumulation and removal efficiency of Fe by Centella asiatica was carried out at various Fe concentrations in soil treatments (0, 50, 100, 150 and 200 mg Fe/kg soil). Iron accumulation in different parts of C. asiatica (leaf, stem and root) was analyzed by atomic absorption spectrophotometer (AAS). Factorial experiment with a completely randomized design and Duncan's test were used for data analyses. The results revealed that C. asiatica have the ability to uptake and accumulate Fe significantly (p < 0.05; r = 0.977) in the aerial parts. The different soil treatments had significant effect on the total Fe accumulations in C. asiatica (p < 0.05). The potential of C. asiatica as a metal hyperaccumulator plant, harvested for analysis, shows efficient accumulation of Fe at high concentration (p < 0.05; r = 0.977). The root showed the highest accumulation of Fe followed by the leaves (p < 0.05) and the stem (p < 0.05). The Pearson correlation coefficient between leaves and root have showed highly significant correlation (p < 0.01; r = 0.785) as compared to the leaves and stem (p < 0.01; r = 0.780). The efficiency of Fe removal by C. asiatica from the contaminated soil has been evaluated by bioconcentration factor and translocation factor, found to be >1 and <1, respectively, further supporting its metal hyperaccumulator properties. PMID- 26940260 TI - Dislocation-free Ge Nano-crystals via Pattern Independent Selective Ge Heteroepitaxy on Si Nano-Tip Wafers. AB - The integration of dislocation-free Ge nano-islands was realized via selective molecular beam epitaxy on Si nano-tip patterned substrates. The Si-tip wafers feature a rectangular array of nanometer sized Si tips with (001) facet exposed among a SiO2 matrix. These wafers were fabricated by complementary metal-oxide semiconductor (CMOS) compatible nanotechnology. Calculations based on nucleation theory predict that the selective growth occurs close to thermodynamic equilibrium, where condensation of Ge adatoms on SiO2 is disfavored due to the extremely short re-evaporation time and diffusion length. The growth selectivity is ensured by the desorption-limited growth regime leading to the observed pattern independence, i.e. the absence of loading effect commonly encountered in chemical vapor deposition. The growth condition of high temperature and low deposition rate is responsible for the observed high crystalline quality of the Ge islands which is also associated with negligible Si-Ge intermixing owing to geometric hindrance by the Si nano-tip approach. Single island as well as area averaged characterization methods demonstrate that Ge islands are dislocation free and heteroepitaxial strain is fully relaxed. Such well-ordered high quality Ge islands present a step towards the achievement of materials suitable for optical applications. PMID- 26940262 TI - Zinc sensing and regulation in yeast model systems. AB - The Zap1 transcription factor of Saccharomyces cerevisiae and the Loz1 transcription factor of Schizosaccharomyces pombe both play a central role in zinc homeostasis by controlling the expression of genes necessary for zinc metabolism. Zap1 activates gene expression when cells are limited for zinc, while Loz1 is required for gene repression when zinc is in excess. In this review we highlight what is known about the underlying mechanisms by which these factors are regulated by zinc, and how transcriptional activation and repression in eukaryotic cells can be finely tuned according to intracellular zinc availability. PMID- 26940263 TI - Comparative in vitro analyses of recombinant maize starch synthases SSI, SSIIa, and SSIII reveal direct regulatory interactions and thermosensitivity. AB - Starch synthases SSI, SSII, and SSIII function in assembling the amylopectin component of starch, but their specific roles and means of coordination are not fully understood. Genetic analyses indicate regulatory interactions among SS classes, and physical interactions among them are known. The N terminal extension of cereal SSIII, comprising up to 1200 residues beyond the catalytic domain, is responsible at least in part for these interactions. Recombinant maize SSI, SSIIa, and full-length or truncated SSIII, were tested for functional interactions regarding enzymatic activity. Amino-terminal truncated SSIII exhibited reduced activity compared to full-length enzyme, and addition of the N terminus to the truncated protein stimulated catalytic activity. SSIII and SSI displayed a negative interaction that reduced total activity in a reconstituted system. These data demonstrate that SSIII is both a catalytic and regulatory factor. SSIII activity was reduced by approximately 50% after brief incubation at 45 degrees C, suggesting a role in reduced starch accumulation during growth in high temperatures. Buffer effects were tested to address a current debate regarding the SS mechanism. Glucan stimulated the SSIIa and SSIII reaction rate regardless of the buffer system, supporting the accepted mechanism in which glucosyl units are added to exogenous primer substrates. PMID- 26940264 TI - Laboratory Test Utilization Management: General Principles and Applications in Hematopathology. AB - As the cost of health care continues to rise and reimbursement rates decrease, there is a growing demand and need to cut overall costs, enhance quality of services, and maintain as a top priority the needs and safety of the patient. In this article, we provide an introduction to test utilization and outline a general approach to creating an efficient, cost-effective test utilization strategy. We also present and discuss 2 test utilization algorithms that are evidence-based and may be of clinical utility as we move toward the future of doing the necessary tests at the right time. PMID- 26940265 TI - B-cell Non-Hodgkin Lymphomas with Plasmacytic Differentiation. AB - B-cell non-Hodgkin lymphomas with plasmacytic differentiation are a diverse group of entities with extremely variable morphologic features. Diagnostic challenges can arise in differentiating lymphoplasmacytic lymphoma from marginal zone lymphoma and other low-grade B-cell lymphomas. In addition, plasmablastic lymphomas can be difficult to distinguish from diffuse large B-cell lymphoma or other high-grade lymphomas. Judicious use of immunohistochemical studies and molecular testing can assist in appropriate classification. PMID- 26940266 TI - The Expanding Spectrum of Follicular Lymphoma. AB - Follicular lymphoma is a far more heterogeneous entity than originally appreciated. Clinical and biological variants are increasingly more granularly defined, expanding the spectrum of disease. Some variants associate with age, whereas others with anatomic site. Identification of these biologically distinct diseases has real prognostic and predictive value for patients today and likely will be more relevant in the future. Understanding of follicular lymphoma precursors has also made their identification both scientifically and clinically relevant. This review summarizes the features and understanding of follicular lymphoma, variants, and precursor lesions. PMID- 26940267 TI - Comprehensive Assessment and Classification of High-Grade B-cell Lymphomas. AB - High-grade B-cell lymphomas (HGBCLs) are a heterogeneous group of neoplasms that include subsets of diffuse large B-cell lymphoma, Burkitt lymphoma, and lymphomas with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma. Morphologically indistinguishable HGBCLs may demonstrate variable clinical courses and responses to therapy. The morphologic evaluation and classification of these neoplasms must be followed by further genetic and immunophenotypic work-up. These additional diagnostic modalities lead to a comprehensive stratification of HGBCL that determines the prognosis and optimal therapy. This article reviews the well-established and emerging biomarkers that are most relevant to the clinical management of HGBCL. PMID- 26940268 TI - B-cell Lymphoproliferative Disorders Associated with Primary and Acquired Immunodeficiency. AB - The diagnosis of lymphoproliferative disorders associated with immunodeficiency can be challenging because many of these conditions have overlapping clinical and pathologic features and share similarities with their counterparts in the immunocompetent setting. There are subtle but important differences between these conditions that are important to recognize for prognostic and therapeutic purposes. This article provides a clinicopathologic update on how understanding of these B-cell lymphoproliferations in immunodeficiency has evolved over the past decade. PMID- 26940269 TI - Transformation in Low-grade B-cell Neoplasms. AB - Low-grade B-cell leukemias/lymphomas are a diverse group of indolent lymphoproliferative disorders that are typically characterized by good patient outcomes and long life expectancies. A subset of cases, however, undergo histologic transformation to a higher-grade neoplasm, a transition associated with a more aggressive clinical course and poor survival. Transformation of follicular lymphoma to diffuse large B-cell lymphoma and Richter transformation of chronic lymphocytic leukemia/small lymphocytic lymphoma are best characterized in the literature. This article reviews clinical and pathologic characteristics of these most common forms of transformation, with an emphasis on salient histologic, immunophenotypic, and genetic features. PMID- 26940270 TI - Lymphoma Microenvironment and Immunotherapy. AB - Understanding of the lymphoma tumor microenvironment is poised to expand in the era of next-generation sequencing studies of the tumor cells themselves. Successful therapies of the future will rely on deeper appreciation of the interactions between elements of the microenvironment. Although the phenotypic, cytogenetic, and molecular characterization of tumor cells in lymphomas has progressed faster than most other solid organ tumors, concrete advancements in understanding the lymphoma microenvironment have been fewer. This article explores the composition of the lymphoma tumor microenvironment; its role in immune surveillance, evasion, and drug resistance; and its potential role in the development of targeted therapies. PMID- 26940271 TI - Role of Flow Cytometry in the Diagnosis and Prognosis of Plasma Cell Myeloma. AB - This article provides an overview of the role of flow cytometry in the diagnosis and follow-up of plasma cell myeloma. A brief introduction to the general immunophenotypic features of normal and myeloma plasma cells is provided, followed by a discussion of technical issues as they relate to the application of flow cytometry in this entity. The prognostic and therapeutic utility of flow cytometric immunophenotyping in myeloma is also analyzed, with an emphasis on the growing role of minimal residual analysis as potential biomarker for evaluating treatment efficacy and for tailoring risk-adapted treatment, in prospective clinical trials. PMID- 26940272 TI - Immunoglobulin G4-Related Lymphadenopathy. AB - Immunoglobulin G4-related lymphadenopathy (IgG4-RLAD) occurs in the setting of extranodal IgG4-related disease (IgG4-RD), an immune-mediated process described in many organ systems characterized by lymphoplasmacytic infiltrates with abundant IgG4-positive plasma cells and fibrosis. Although the morphologic features in the lymph node sometimes resemble those seen at the extranodal sites, 5 microscopic patterns have been described, most of which resemble reactive lymphoid hyperplasia. This morphologic variability leads to unique diagnostic challenges and a broad differential diagnosis. As IgG4-RD may be exquisitely responsive to steroids or other immunotherapy, histologic recognition and inclusion of IgG4-RLAD in the differential diagnosis is vital. PMID- 26940273 TI - T-cell Lymphomas: Updates in Biology and Diagnosis. AB - Nodal-based peripheral T-cell lymphomas are heterogeneous malignancies with overlapping morphology and clinical features. However, the current World Health Organization classification scheme separates these tumors into prognostically relevant categories. Since its publication, efforts to uncover the gene expression profiles and molecular alterations have subdivided these categories further, and distinct subgroups are emerging with specific profiles that reflect the cell of origin for these tumors and their microenvironment. Identification of the perturbed biologic pathways may prove useful in selecting patients for specific therapies and associating biomarkers with survival and relapse. PMID- 26940274 TI - Genetic Testing in Acute Myeloid Leukemia and Myelodysplastic Syndromes. AB - Cytogenetic analysis of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) is essential for disease diagnosis, classification, prognostic stratification, and treatment guidance. Molecular genetic analysis of CEBPA, NPM1, and FLT3 is already standard of care in patients with AML, and mutations in several additional genes are assuming increasing importance. Mutational analysis of certain genes, such as SF3B1, is also becoming an important tool to distinguish subsets of MDS that have different biologic behaviors. It is still uncertain how to optimally combine karyotype with mutation data in diagnosis and risk-stratification of AML and MDS, particularly in cases with multiple mutations and/or several mutationally distinct subclones. PMID- 26940275 TI - Myeloid Neoplasms with Germline Predisposition: A New Provisional Entity Within the World Health Organization Classification. AB - The forthcoming update of the World Health Organization (WHO) classification of hematopoietic neoplasms will feature "Myeloid Neoplasms with Germline Predisposition" as a new provisional diagnostic entity. This designation will be applied to some cases of acute myeloid leukemia and myelodysplastic syndrome arising in the setting of constitutional mutations that render patients susceptible to the development of myeloid malignancies. For the diagnostic pathologist, recognizing these cases and confirming the diagnosis will demand a sophisticated grasp of clinical genetics and molecular techniques. This article presents a concise review of this new provisional WHO entity, including strategies for clinical practice. PMID- 26940277 TI - Preface. PMID- 26940276 TI - Therapy Effect: Impact on Bone Marrow Morphology. AB - This article highlights the most common morphologic features identified in the bone marrow after chemotherapy for hematologic malignancies, growth-stimulating agents, and specific targeted therapies. The key is to be aware of these changes while reviewing post-therapeutic bone marrow biopsies and to not mistake reactive patterns for neoplastic processes. In addition, given the development and prevalent use of targeted therapy, such as tyrosine kinase inhibitors and immune modulators, knowledge of drug-specific morphologic changes is required for proper bone marrow interpretation and diagnosis. PMID- 26940278 TI - Bone mineral density profile among post-menopausal women in Manipur: a hospital based study. AB - AIM: To study the bone mineral density (BMD) profile in post-menopausal women and to examine the role of various socio-demographic, clinical, laboratory and radiological factors in predicting fracture risk in these patients. METHODS: This cross-sectional study recruited consenting postmenopausal women presenting with some form of pain complaints, such as joint pain, body ache, low back pain and so on. A structured questionnaire was used to collect socio-demographic details. Height and weight were measured and BMI (body mass index) was calculated. Dual energy X-ray absorptiometry was performed in three sites: lumbar spine (LS), femoral neck (FN) and trochanteric region (TR) to assess BMD. Serum levels of calcium, phosphorus and alkaline phosphatase were collected. RESULTS: There were 107 patients. Mean age was 59.70 +/- 9.02 years and mean age at menopause was 46.37 +/- 4.48 years. Fracture history was present in 25/107 (23.36%). Mean BMI observed was 25.34 +/- 3.73. Women with fracture history had statistically significant differences in six factors, namely age, years since menopause, BMI and T-score measurements at LS, FN and TR (P < 0.05). Multivariate logistic regression analysis for these six variables revealed that no factor was independently associated with fracture risk, but those patients who had abnormal T-scores in all three regions had significant history of fracture (P = 0.04). CONCLUSIONS: Age, age since menopause, BMI, and BMD T-score measurements at LS, FN and TR individually predict fracture risk, but none remain significant when all factors are considered together. Patients with abnormal BMD T-scores in all three sites more often gave histories of fractures. Further studies are warranted. PMID- 26940279 TI - Tight-binding approach to penta-graphene. AB - We introduce an effective tight-binding model to discuss penta-graphene and present an analytical solution. This model only involves the pi-orbitals of the sp(2)-hybridized carbon atoms and reproduces the two highest valence bands. By introducing energy-dependent hopping elements, originating from the elimination of the sp(3)-hybridized carbon atoms, also the two lowest conduction bands can be well approximated - but only after the inclusion of a Hubbard onsite interaction as well as of assisted hopping terms. The eigenfunctions can be approximated analytically for the effective model without energy-dependent hopping elements and the optical absorption is discussed. We find large isotropic absorption ranging from 7.5% up to 24% for transitions at the Gamma-point. PMID- 26940280 TI - Morphology of Labronemella major n. sp. (Nematoda: Dorylaimida), a soil-dwelling nematode from China, including a revised key to species of the genus. AB - One new species from Qinghai Province, China, Labronemella major n. sp., is described. The new species is characterized by a body length of 3.03-3.34 mm; lip region wide, offset by a distinct depression, disc-like with six separated inner liplets; amphid fovea funnel-shaped, distinctly bulged on body surface in scanning electron micrographs; odontostyle long (35-39 MUm) with distinct lumen, aperture about 39-47% of its length; odontophore rod-like and long; guiding ring double; pharyngeal basal expansion about half of the total neck length; uterus relatively long and tripartite; vulva transverse and sclerotized; spicules 81-90 MUm long; ventromedial supplements 19-23; tail short, rounded to conoid. It can be differentiated from all other species of the genus by its relatively longer body, odontostyle and spicules, and wider lip region. Due to the lip region being offset by a deep constriction, and the long (three or more times the body diameter at mid-body) tripartite uterus, the new species is close to Labronemella czernowitzensis (Micoletzky, 1922) Andrassy, 2002 and Labronemella labiata Andrassy, 1985. An improved key to the genus including the new species is provided. PMID- 26940281 TI - Realizing a diagnosis of autism spectrum disorder as an adult. AB - Many individuals with autism spectrum disorder are not diagnosed until adulthood, yet little is known about their experiences. This descriptive phenomenological study aimed to explore the experience of realizing a diagnosis of autism spectrum disorder in adulthood. A purposive sample of 77 adults was asked to describe their experiences of realizing a diagnosis as adults via an open-ended online survey. Data were analysed using Colaizzi's method and six themes were derived: feeling different from others, riding an emotional rollercoaster, striving to accept themselves, strategizing to improve their lives, maintaining normalcy, and wandering into the future. Nurses must realize the importance of screening for depression following a new diagnosis. Barriers to reaching a formal diagnosis should also be evaluated. PMID- 26940282 TI - Reply. PMID- 26940283 TI - Changes in volatile profile of soybean residue (okara) upon solid-state fermentation by yeasts. AB - BACKGROUND: Soybean residue (okara), a by-product of soymilk, is produced in large volumes by the soy food industry and is often discarded due to its undesirable flavour. As it contains a considerable amount of protein and fats, biotransformation of okara to improve its flavour presents an opportunity for alternative utilisation. This paper evaluated 10 yeasts in the solid-state fermentation of okara based on their volatile profiles as analysed with HS-SPME GC-MS/FID. Four 'dairy yeasts' (Geotrichum candidum, Yarrowia lipolytica, Debaryomyces hansenii and Kluyveromyces lactis) and six 'wine yeasts' (Saccharomyces cerevisiae, Lachancea thermotolerans, Metschnikowia pulcherrima, Pichia kluyveri, Torulaspora delbrueckii, and Williopsis saturnus) were studied. RESULTS: The main off-odourants in okara, hexanal and trans-2-hexenal, significantly decreased after fermentation due to their bioconversion into methyl ketones and/or esters. The okara fermented by dairy yeasts contained greater proportions of methyl ketones, while that by wine yeasts contained more ethyl and acetyl esters. Notably, the okara fermented by W. saturnus contained 13 esters and the total GC-FID peak area of esters was about 380 times that in fresh okara, leading to a perceptible fruity note. CONCLUSION: Okara can be exploited as an inexpensive substrate for bioflavour extraction and/or a more pleasant food ingredient via yeast fermentation. (c) 2016 Society of Chemical Industry. PMID- 26940284 TI - Domestic violence survivors and their experiences during legal process. AB - BACKGROUND: Many victims of domestic violence do not seek recourse to the needed medical and legal services. The aim of this study was to determine the difficulties faced by and experiences of female survivors of domestic violence during their medical and legal proceedings. METHOD: We designed our study using a qualitative approach to understand the experiences of survivors during the legal process as well as their feelings and attitudes towards domestic violence through in-depth interviews. The data obtained from the participants were analyzed and synthesized using a thematic analysis procedure. RESULTS: Most of our participants reported different types of domestic violence, citing feelings of fear and loneliness during these experiences. They reported feeling dissatisfied with their complaints being ignored by the police and the perpetrators remaining unpunished. They complained of the complex procedures and negligence of staff in health-care centers such as hospitals, and they reported being shifted to several different places. CONCLUSION: We believe that an assessment of such female survivors in terms of specific standards set by specialists will help make improvements to the legal process. Education programs should be organized for professionals dealing with survivors of domestic violence. Special health-care services with fast proceedings must be established in health-care centers. PMID- 26940285 TI - Maternal Cortisol Mediates Hypothalamus-Pituitary-Interrenal Axis Development in Zebrafish. AB - In zebrafish (Danio rerio), de novo synthesis of cortisol in response to stressor exposure commences only after hatch. Maternally deposited cortisol is present during embryogenesis, but a role for this steroid in early development is unclear. We tested the hypothesis that maternal cortisol is essential for the proper development of hypothalamus-pituitary-interrenal (HPI) axis activity and the onset of the stressor-induced cortisol response in larval zebrafish. In this study, zygotic cortisol content was manipulated by microinjecting antibody to sequester this steroid, thereby making it unavailable during embryogenesis. This was compared with embryos containing excess cortisol by microinjection of exogenous steroid. The resulting larval phenotypes revealed distinct treatment effects, including deformed mesoderm structures when maternal cortisol was unavailable and cardiac edema after excess cortisol. Maternal cortisol unavailability heightened the cortisol stress response in post-hatch larvae, whereas excess cortisol abolished the stressor-mediated cortisol elevation. This contrasting hormonal response corresponded with altered expression of key HPI axis genes, including crf, 11B hydroxylase, pomca, and star, which were upregulated in response to reduced cortisol availability and downregulated when embryos had excess cortisol. These findings for the first time underscore a critical role for maternally deposited cortisol in programming HPI axis development and function in zebrafish. PMID- 26940286 TI - Safety profile of anakinra in the management of rheumatologic, metabolic and autoinflammatory disorders. AB - Anakinra is a biologic response modifier that competitively antagonises the biologic effects of interleukin-1, the ancestor pleiotropic proinflammatory cytokine produced by numerous cell types, found in excess in the serum, synovial fluid and any involved tissues of patients with many inflammatory diseases. The magnitude of the risk of different infections, including Mycobacterium tuberculosis (Mtb) infection, associated with the large use of anakinra in many rheumatologic, metabolic or autoinflammatory disorders is still unknown. In addition, it is unclear whether this effect is modified by the concomitant use of antirheumatic drugs and corticosteroids. The rates of development of Mtb disease in patients treated with anakinra due to rheumatoid arthritis, systemic autoinflammatory diseases, Schnitzler's syndrome, Behcet's disease, adult-onset Still disease, systemic juvenile idiopathic arthritis, gout and diabetes mellitus have been usually very low. However, clinicians must carefully weigh the benefits of biological drugs against their risks, particularly in patients prone to infections. Additional data are needed to understand whether this risk of Mtb infection and reactivation are representative of a class effect related to biologics or whether anakinra bears specifically an intrinsic lower risk in comparison with other biologic drugs. PMID- 26940287 TI - Interlimb coordination and academic performance in elementary school children. AB - BACKGROUND: The specific mechanisms linking motor ability and cognitive performance, especially academic achievement, are still unclear. Whereas the literature provides an abundance of information on fine and visual-motor skill and cognitive attributes, much less has been reported on gross motor ability. This study examined interlimb coordination and its relationship to academic performance in children aged 8-11 years. METHODS: Motor and academic skills were examined in 100 Brazilian children using the Bruininks-Oseretsky Test of Motor Proficiency and the Academic Performance Test. Participants were grouped into low (<25%) and high (>75%) academic achievers. RESULTS: There was a significant difference between groups for Total Motor Composite (P < 0.001) favoring the high group. On regression analysis there was a significant association between academic performance and Body Coordination. Of the subtests of Body Coordination (Bilateral Coordination and Balance), Bilateral Coordination accounted for the highest impact on academic performance. Of interest here, that subtest consists primarily of gross motor tasks involving interlimb coordination. CONCLUSION: Overall, there was a positive relationship between motor behavior, in particular activities involving interlimb coordination, and academic performance. Application of these findings in the area of early assessment may be useful in the identification of later academic problems. PMID- 26940288 TI - Suspected antibody negative autoimmune limbic encephalitis: outcome of immunotherapy. AB - OBJECTIVES: Whether and when to immunologically treat epilepsy patients with suggested autoantibody (AB)-negative limbic encephalitis (LE) is clinically challenging. Therefore, we evaluated the clinical outcome and eventual outcome predictors of immunotherapy in a group of AB-negative patients with recent-onset temporal lobe epilepsy (TLE), magnetic resonance imaging (MRI) indicators of LE, subjective cognitive decline, and/or psychiatric symptoms. METHODS: This retrospective, observational, uncontrolled study monitored 28 TLE patients with suggested AB-negative LE along with methylprednisolone immunotherapy. RESULTS: All patients had seizures, amygdala and/or -hippocampal enlargement, subjective cognitive decline and/or behavioral problems. Eighty-six percent (24/28) were impaired in executive or memory functions, 39% (10/25) depressed, 81% were on antiepileptic drugs when pulse therapy started. After a median follow-up of 18 months, 46% (13/28) of the patients were seizure free (>2 months), 48% (13/27) showed MRI improvements (amygdala and/or hippocampal volume reduction), cognition improved in 57% (16/28), worsened in 32% (9/28), mood improved in 14% (4/25), and deteriorated in 11% (3/25). Immunotherapy was discontinued in 75% (21/28). Clinical changes did not correlate to each other. Outcomes could not be predicted. CONCLUSION: Immunological treatment of suggested AB-negative LE showed reasonable seizure control, MRI and cognitive improvements. Treatment success was not predictable from clinical features, nor definitely attributable to immunological treatment. Lacking biomarkers for the reliable diagnosis of AB negative LE, we suggest that in presence of mild manifestations, and after initiating antiepileptic drug therapy, negative dynamics in MRI, seizures, cognition, and behavior should be documented before immunosuppressive treatment is initiated. PMID- 26940290 TI - Massive Open Online Courses: what will be their legacy? AB - Massive Open Online Courses (MOOCs) dominated discussions of online learning and higher education in the news media and in universities between 2012 and 2015. However, fashions pass, needs change and technology evolves. This Commentary looks back, pauses on the present, and then looks forward. Whilst MOOCs are a significant milestone on the road that online teaching and learning is following, open, distance and online learning started long before MOOCs and will continue to grow in importance when MOOCs are just an interesting footnote in its development. PMID- 26940289 TI - Edging into the future: education in microbiology and beyond. AB - State-of-the-art papers from around the globe addressing current topics in education were published in the FEMS Microbiology Letters virtual Thematic Issue 'Education' in November 2015 (http://femsle.oxfordjournals.org/content/thematic issue-education), which was innovative and well received by microbiologists and other educators. Its unique content is reviewed here to facilitate broader access and further discussions in the professional community. Best practice in supporting school teaching and exposing students to concepts from other disciplines is presented in context of inspiring the next generations, where also historical microbiology can be drawn upon. Technology-enhanced education is discussed including its applications (e.g. lecture podcasts for flipped learning, learning from experts via videoconference). Authentic learning is covered with examples of research-led teaching, water and showerhead biofilm analyses and participation in the International Genetically Engineered Machines competition. Enhancing employability is focussed on, including supporting personal development and work-readiness in general and for the changing nature of the microbiology profession. International mobility develops international awareness but challenges teachers. Teaching training, teaching excellence and dissemination of best practice are reviewed. Times of challenge and change in the Higher Education landscape motivate us to improve educational approaches and frameworks, so that we are prepared for new topics to emerge as current topics in education. PMID- 26940291 TI - Photo-catalytic inactivation of an Enterococcus biofilm: the anti-microbial effect of sulphated and europium-doped titanium dioxide nanopowders. AB - The control and prevention of biofilm-related infections is an important public healthcare issue. Given the increasing antibiotic resistance among bacteria and fungi that cause serious infections in humans, promotion of new strategies combating microorganisms has been essential. One attractive approach to inactivate microorganisms is the use of semiconductor photo-catalysis, which has become the subject of extensive research. In this study, the bactericidal properties of four photo-catalysts, TiO2, TiO2-S, TiO2-Eu and TiO2-Eu-S, were investigated against established 24, 48, 72 and 96 h biofilms of Enterococcus The exposure of biofilms to the catalysts induced the production of superoxide radical anions. The best photo-catalytic inactivation was achieved with the TiO2 Eu-S and TiO2-S nanopowders and 24 h biofilms. Transmission electron microscopy images showed significant changes in the structure of the biofilm cells following photo-inactivation. The results suggest that doping with europium and modifying the surface with sulphate groups enhanced the bactericidal activity of the TiO2 nanoparticles against enterococcal biofilms. PMID- 26940292 TI - From CO2 to cell: energetic expense of creating biomass using the Calvin-Benson Bassham and reductive citric acid cycles based on genome data. AB - The factors driving the dominance of the Calvin-Benson-Bassham cycle (CBB) or reductive citric acid cycle (rCAC) in autotrophic microorganisms in different habitats are debated. Based on costs for synthesizing a few metabolic intermediates, it has been suggested that the CBB poses a disadvantage due to higher metabolic cost. The purpose of this study was to extend this estimate of cost from metabolite synthesis to biomass synthesis. For 12 gammaproteobacteria (CBB) and five epsilonproteobacteria (rCAC), the amount of ATP to synthesize a gram of biomass from CO2 was calculated from genome sequences via metabolic maps. The eleven central carbon metabolites needed to synthesize biomass were all less expensive to synthesize via the rCAC (66%-89% of the ATP needed to synthesize them via CBB). Differences in cell compositions did result in differing demands for metabolites among the organisms, but the differences in cost to synthesize biomass were small among organisms that used a particular pathway (e.g. rCAC), compared to the difference between pathways (rCAC versus CBB). The rCAC autotrophs averaged 0.195 moles ATP per g biomass, while their CBB counterparts averaged 0.238. This is the first in silico estimate of the relative expense of both pathways to generate biomass. PMID- 26940293 TI - Identification of a glucose-mannose phosphotransferase system in Clostridium beijerinckii. AB - Effective uptake of fermentable substrates is a fundamentally important aspect of any fermentation process. The solventogenic bacterium Clostridium beijerinckii is noted for its ability to ferment a wide range of carbohydrates, yet few of its sugar transport systems have been characterized. In common with other anaerobes, C. beijerinckii shows a marked dependence on the PEP-dependent phosphotransferase system (PTS) for sugar accumulation. In this study, the gene cbe0751 encoding the sugar-specific domains of a phosphotransferase belonging to the glucose family was cloned into an Escherichia coli strain lacking the ability to take up and phosphorylate glucose. Transformants gained ability to ferment glucose, and also mannose, and further analysis of a selected transformant demonstrated that it could take up and phosphorylate glucose, confirming that cbe0751 encodes a glucose PTS which also recognizes mannose as a substrate. RT-PCR analysis showed that cbe0751 was expressed in cultures grown on both substrates, but also to varying extents during growth on some other carbon sources. Although analogue inhibition studies suggested that Cbe0751 is not the only glucose PTS in C. beijerinckii, this system should nevertheless be regarded as a potential target for metabolic engineering to generate a strain showing improved sugar fermentation properties. PMID- 26940294 TI - Morphology controlling method for amorphous silica nanoparticles and jellyfish like nanowires and their luminescence properties. AB - Uniform silica nanoparticles and jellyfish-like nanowires were synthesized by a chemical vapour deposition method on Si substrates treated without and with Ni(NO3)2, using silicon powder as the source material. Composition and structural characterization using field emission scanning electron microscopy, transmission electron microscopy, energy dispersive X-ray spectroscopy and fourier-transform infrared spectroscopy showed that the as-prepared products were silica nanoparticles and nanowires which have amorphous structures. The form of nanoparticles should be related to gas-phase nucleation procedure. The growth of the nanowires was in accordance with vapour-liquid-solid mechanism, followed by Ostwald ripening to form the jellyfish-like morphology. Photoluminescence and cathodoluminescence measurements showed that the silica products excited by different light sources show different luminescence properties. The emission spectra of both silica nanoparticles and nanowires are due to the neutral oxygen vacancies (=Si-Si=). The as-synthesized silica with controlled morphology can find potential applications in future nanodevices with tailorable photoelectric properties. PMID- 26940295 TI - Expectant management of severe preterm preeclampsia: a comparison of maternal and fetal indications for delivery. AB - OBJECTIVE: To examine the delivery indication (maternal or fetal) for patients with preterm preeclampsia and assess whether disease characteristics at presentation are predictive of delivery indication. METHODS: We conducted a retrospective cohort study at a tertiary hospital in Melbourne, Australia (Mercy Hospital for Women). We assessed indication for delivery for participants presenting with preeclampsia from 23(+0) to 32(+6) weeks gestation. We compared baseline disease characteristics, disease features at delivery and postnatal outcomes between those delivered for maternal or fetal indications, or for both maternal and fetal indications. RESULTS: Two hundred sixty six participants presented with preterm preeclampsia and 108 were eligible for inclusion in our study. More participants were delivered for maternal indications at 65.7% compared to those requiring delivery on fetal grounds at 19.4% or for both indications at 14.8% (p < 0.0001). Maternal disease characteristics at presentation were similar between groups; however, there was a higher proportion of growth restriction and abnormal Dopplers among those delivered on fetal grounds. Participants delivered on maternal grounds gained less gestation, had higher blood pressure and higher incidence of abnormal liver function tests than those delivering for fetal indications at delivery. CONCLUSION: Participants with preterm preeclampsia were predominantly delivered due to maternal disease progression compared to fetal compromise. PMID- 26940297 TI - Erratum, Vol 13, February 4 Release. AB - This corrects the article DOI: 10.5888/pcd13.150228. PMID- 26940296 TI - Screening and surveillance for gastric cancer in the United States: Is it needed? AB - BACKGROUND AND AIMS: Although the incidence of gastric cancer in the United States is relatively low, the incidence of gastric cancer is higher than for esophageal cancer, for which clear guidelines for screening and surveillance exist. With the increasing availability of endoscopic therapy, such as endoscopic submucosal dissection, for treating advanced dysplasia and early gastric cancer, establishing guidelines for screening and surveillance of patients who are at high risk of developing gastric cancer has the potential to diagnose and treat gastric cancer at an earlier stage and improve mortality from gastric cancer. The aims of this article were to review the data regarding the risk factors for developing gastric cancer, methods for gastric cancer screening, and results of national screening programs. METHODS: A review of the existing literature related to the aims was performed. RESULTS: Risk factors for gastric cancer that were identified include race/ethnicity (East Asian, Russian, or South American), first degree relative diagnosed with gastric cancer, positive Helicobacter pylori status, and presence of atrophic gastritis or intestinal metaplasia. Endoscopy has the highest rate of detecting gastric cancer compared with other gastric cancer screening methods. The national screening program in Japan has demonstrated a mortality reduction from gastric cancer based on cohort data. CONCLUSIONS: Gastric cancer screening with endoscopy should be considered in individuals who are immigrants from regions associated with a high risk of gastric cancer (East Asia, Russia, or South America) or who have a family history of gastric cancer. Those with findings of atrophic gastritis or intestinal metaplasia on screening endoscopy should undergo surveillance endoscopy every 1 to 2 years. Large prospective multicenter studies are needed to further identify additional risk factors for developing gastric cancer and to assess whether gastric cancer screening programs for high-risk populations in the United States would result in improved mortality. PMID- 26940298 TI - Erratum, Vol. 12, November 12 Release. AB - This corrects the article DOI: 10.5888/pcd12.150275. PMID- 26940299 TI - Assessment of a Districtwide Policy on Availability of Competitive Beverages in Boston Public Schools, Massachusetts, 2013. AB - INTRODUCTION: Competitive beverages are drinks sold outside of the federally reimbursable school meals program and include beverages sold in vending machines, a la carte lines, school stores, and snack bars. Competitive beverages include sugar-sweetened beverages, which are associated with overweight and obesity. We described competitive beverage availability 9 years after the introduction in 2004 of district-wide nutrition standards for competitive beverages sold in Boston Public Schools. METHODS: In 2013, we documented types of competitive beverages sold in 115 schools. We collected nutrient data to determine compliance with the standards. We evaluated the extent to which schools met the competitive beverage standards and calculated the percentage of students who had access to beverages that met or did not meet the standards. RESULTS: Of 115 schools, 89.6% met the competitive beverage nutrition standards; 88.5% of elementary schools and 61.5% of middle schools did not sell competitive beverages. Nutrition standards were met in 79.2% of high schools; 37.5% did not sell any competitive beverages, and 41.7% sold only beverages meeting the standards. Overall, 85.5% of students attended schools meeting the standards. Only 4.0% of students had access to sugar sweetened beverages. CONCLUSION: A comprehensive, district-wide competitive beverage policy with implementation support can translate into a sustained healthful environment in public schools. PMID- 26940300 TI - Assessment of Factors Contributing to Health Outcomes in the Eight States of the Mississippi Delta Region. AB - INTRODUCTION: The objective of this observational study was to examine the key contributors to health outcomes and to better understand the health disparities between Delta and non-Delta counties in 8 states in the Mississippi River Delta Region. We hypothesized that a unique set of contributors to health outcomes in the Delta counties could explain the disparities between Delta and non-Delta counties. METHODS: Data were from the 2014 County Health Rankings for counties in 8 states (Alabama, Arkansas, Illinois, Kentucky, Louisiana, Mississippi, Missouri, and Tennessee). We used the Delta Regional Authority definition to identify the 252 Delta counties and 468 non-Delta counties or county equivalents. Information on health factors (eg, health behaviors, clinical care) and outcomes (eg, mortality) were derived from 38 measures from the 2014 County Health Rankings. The contributions of health factors to health outcomes in Delta and non Delta counties were examined using path analysis. RESULTS: We found similarities between Delta counties and non-Delta counties in the health factors (eg, tobacco use, diet and exercise) that significantly predicted the health outcomes of self rated health and low birthweight. The most variation was seen in predictors of mortality; however, Delta counties shared 2 of the 3 significant predictors (ie, community safety and income) of mortality with non-Delta counties. On average across all measures, values in the Delta were 16% worse than in the non-Delta and 22% worse than in the rest of the United States. CONCLUSION: The health status of Delta counties is poorer than that of non-Delta counties because the health factors that contribute to health outcomes in the entire region are worse in the Delta counties, not because of a unique set of health predictors. PMID- 26940302 TI - Prevention and treatment of neglected tropical diseases: past, present and future. PMID- 26940301 TI - Self-Locking Optoelectronic Tweezers for Single-Cell and Microparticle Manipulation across a Large Area in High Conductivity Media. AB - Optoelectronic tweezers (OET) has advanced within the past decade to become a promising tool for cell and microparticle manipulation. Its incompatibility with high conductivity media and limited throughput remain two major technical challenges. Here a novel manipulation concept and corresponding platform called Self-Locking Optoelectronic Tweezers (SLOT) are proposed and demonstrated to tackle these challenges concurrently. The SLOT platform comprises a periodic array of optically tunable phototransistor traps above which randomly dispersed single cells and microparticles are self-aligned to and retained without light illumination. Light beam illumination on a phototransistor turns off the trap and releases the trapped cell, which is then transported downstream via a background flow. The cell trapping and releasing functions in SLOT are decoupled, which is a unique feature that enables SLOT's stepper-mode function to overcome the small field-of-view issue that all prior OET technologies encountered in manipulation with single-cell resolution across a large area. Massively parallel trapping of more than 100,000 microparticles has been demonstrated in high conductivity media. Even larger scale trapping and manipulation can be achieved by linearly scaling up the number of phototransistors and device area. Cells after manipulation on the SLOT platform maintain high cell viability and normal multi day divisibility. PMID- 26940304 TI - Leaving no one behind: a neglected tropical disease indicator and tracers for the Sustainable Development Goals. AB - The Sustainable Development Goals (SDGs) have emerged as a global pledge to 'leave no one behind'. Under SDG 3, 'Ensure healthy lives and promote wellbeing for all', target 3.3 extends the Millennium Development Goals (MDGs) beyond HIV, TB and malaria to 'end the epidemic' of neglected tropical diseases (NTDs) by 2030. Other targets are also relevant to NTDs, especially 3.8 (Universal Health Coverage), 6.1 (water) and 6.2 (sanitation). This commentary summarises the proposed NTD indicator (3.3) and tracers (3.8 and 6.1/6.2). These will help ensure that the world's poorest and most marginalized people are prioritized at every step on the path towards SDG targets. PMID- 26940303 TI - RRR for NNN-a rapid research response for the Neglected Tropical Disease NGDO Network: a novel framework to challenges faced by the global programs targeting neglected tropical diseases. AB - While global programs targeting the control or elimination of five of the neglected tropical diseases (NTDs)-lymphatic filariasis, onchocerciasis, soil transmitted helminthiasis, schistosomiasis and trachoma-are well underway, they still face many operational challenges. Because of the urgency of 2020 program targets, the Bill & Melinda Gates Foundation and the U.S. Agency for International Development devised a novel rapid research response (RRR) framework to engage national programs, researchers, implementers and WHO in a Coalition for Operational Research on NTDs. After 2 years, this effort has succeeded as an important basis for the research response to programmatic challenges facing NTD programs. PMID- 26940305 TI - Water, sanitation and hygiene for accelerating and sustaining progress on neglected tropical diseases: a new Global Strategy 2015-20. AB - Neglected tropical diseases (NTDs) affect over 1 billion people. Safe water, sanitation and hygiene (WASH) contribute to prevention and management of most NTDs. Linking WASH and NTD interventions has potential to impact on multiple NTDs and can help secure sustainable and equitable progress towards universal access to WASH. The need to address the determinants of NTDs has been acknowledged. In response, WHO has published a new Global Strategy: 'Water, Sanitation and Hygiene for accelerating and sustaining progress on Neglected Tropical Diseases'. The Strategy focuses on cross-cutting actions that benefit disease control and care efforts, and strengthen health systems. Implementation of the strategy and the accompanying action plan can help ensure that the health and development agenda leaves no one behind. PMID- 26940306 TI - Integration of water, sanitation and hygiene for the control of neglected tropical diseases: a review of progress and the way forward. AB - A WHO roadmap to control, eliminate and eradicate neglected tropical diseases (NTDs) proposes a public health approach integrating diverse prevention and treatment interventions. Water, sanitation and hygiene (WASH) has long been a recognized, yet under-prioritized intervention of global disease control efforts. Through collaboration with the WASH sector, efforts have been made to integrate WASH in NTD control. This article reviews progress made in recent years, explores mechanisms supporting advances, and identifies priorities and next steps for accelerating WASH integration. This paper reveals advances in collaboration between WASH and NTD sectors, resulting in progress made across areas of programming; research; advocacy and policy; training and capacity building; and mapping, data collection and monitoring. Face to face meetings between WASH and NTD sector experts with a clear purpose of informing wider sector discussions, and the development of actionable joint workplans, have been particularly critical in supporting progress. Priority next steps include building capacity for WASH programming among NTD control teams, coordination at the country level, and strengthening the epidemiological evidence and operational learning for joint WASH and NTD interventions. In order to accelerate WASH integration in NTD control through strong collaborations with the WASH sector, the NTD sector could make use of strong data management skills and advocacy opportunities. PMID- 26940307 TI - Neglected tropical diseases in Africa: a new paradigm. AB - Programmes to control onchocerciasis have been ongoing for over 40 years. What was once a devastating blinding and disabling disease, particularly in West Africa, has largely been eliminated at least as a public health problem. Efforts continue to eliminate the transmission of the disease. However, as the elimination agenda has developed so have efforts to control/eliminate other neglected tropical diseases (NTDs). The African Programme for Onchocerciasis Control will close at the end of 2015. There has been considerable discussion as to what should replace it and the World Health Organization Africa Region has been consulting widely during the first part of 2015 and has established a new project framework that will be presented to a wider group of stakeholders to mobilise support with the aim of the coordination of NTD activities in the region. This will be called the Expanded Special Project for Elimination of Neglected Tropical Diseases (ESPEN). This will put the countries in the driving seat but offer technical advice, capacity building and financial support, where needed, to enable countries to implement their NTD Master Plans, and also to implement recommendations of the Regional Programme Review Group. An NTD forum will be held periodically to consult with stakeholders. PMID- 26940308 TI - Ethiopia and its steps to mobilize resources to achieve 2020 elimination and control goals for neglected tropical diseases webs joined can tie a lion. AB - In June 2013, at the launch of its National Neglected Tropical Disease (NTD) Master Plan, the Ethiopian government pledged to achieve WHO NTD elimination and control targets by 2020. With an estimated 80 million people living in areas where one or more NTDs are endemic, this goal presented an enormous challenge for the Federal Ministry of Health. However, as of September 2015, the Federal Ministry of Health has managed to mobilize support to implement mass drug administration in 84% of the trachoma endemic districts and 100% of the endemic districts for onchocerciasis, lymphatic filariasis, soil-transmitted helminthes and schistosomiasis. The national program still is facing large gaps in its podoconiosis and leishmaniasis programs, and it faces significant other challenges to stay on track for 2020 targets. However, this unprecedented scale up in support was achieved through significant government investment in NTD interventions and creative coordination between donors and implementing partners, which may provide valuable lessons for other national NTD programs trying to achieve nationwide coverage. PMID- 26940309 TI - The Neglected Tropical Disease Non-governmental Development Organization Network (NNN): the value and future of a global network aiming to control and eliminate NTDs. PMID- 26940310 TI - Social stigma towards neglected tropical diseases: a systematic review. AB - BACKGROUND: People affected by neglected tropical diseases (NTDs) are frequently the target of social stigmatization. To date not much attention has been given to stigma in relation to NTDs. The objective of this review is to identify the extent of social stigma and the similarities and differences in the causes, manifestations, impact of stigma and interventions used between the NTDs. METHODS: A systematic review was conducted in Pubmed, ScienceDirect, PsycINFO and Web of Knowledge. The search encompassed 17 NTDs, including podoconiosis, but not leprosy as this NTD has recently been reviewed. However, leprosy was included in the discussion. RESULTS: The 52 selected articles provided evidence on stigma related to lymphatic filariasis (LF), podoconiosis, Buruli ulcer, onchocerciasis, schistosomiasis, leishmaniasis, Chagas disease, trachoma, soil-transmitted helminthiasis (STH) and human African trypanosomiasis. The similarities predominated in stigma related to the various NTDs; only minimal differences in stigma reasons and measures were found. CONCLUSION: These similarities suggest that joint approaches to reduce stigmatization may be feasible. Lessons from leprosy and other stigmatized health conditions can be used to plan such joint approaches. Further research will be necessary to study the efficacy of joint interventions and to investigate stigma related to NTDs for which no evidence is available yet. PMID- 26940311 TI - Neglected Tropical Diseases, Cross-Cutting Issues Workshop, 4-6 February 2015, Utrecht, the Netherlands: meeting report. AB - In the last decade, work on neglected tropical diseases (NTDs) has gained momentum. This was accelerated by the London Declaration on NTDs in January 2012. Work on NTDs has expanded worldwide and many countries have set up NTD control and elimination programs. However, the work has focussed disproportionately on preventive treatment. There is an urgent need for more attention and resources to work with people with NTD-related morbidity and disability. A lot can be gained in the fight against NTDs by combining knowledge and experience from cross cutting fields. For this reason a workshop was organized bringing together scientists, experts and practitioners from different NTD backgrounds to explore options for cross-cutting strategies, interventions and research in the field of NTDs, particularly focusing on issues related to morbidity management and disability, in the broadest sense. The workshop produced an inventory of cross cutting issues, an overview of knowledge gaps and research questions, proposals for pilot (research) projects and a list of recommendations. One of the main recommendations is based on the need for baseline data: to review existing indicators used for monitoring and surveillance of NTD-related morbidity and disability in order to identify common indicators that can be shared across NTDs. PMID- 26940312 TI - Towards a toolkit for cross-neglected tropical disease morbidity and disability assessment. AB - BACKGROUND: Neglected tropical diseases (NTDs) are a group of often chronic and disabling infectious conditions, closely related to poverty and inequities. While it is estimated that millions of people are affected, accurate and internationally comparable data about NTD-related morbidity and disability are lacking. Therefore we aimed to develop and pilot a toolkit to assess and monitor morbidity and disability across NTDs. METHODS: A cross-sectional, non-random survey design with a mixed methods approach was used. We conducted a literature review on existing tools to assess and monitor disability, followed by a Delphi study with NTD experts to compile a prototype toolkit. A first-phase validation study was conducted in Northeast Brazil among people with Chagas disease, leishmaniasis, leprosy and schistosomiasis. RESULTS: Instruments included were the clinical profile, WHODAS, P-scale, SRQ, WHOQOL-BREF and WHOQOL-DIS. Most questions in the various instruments were readily understood with the exception of the WHOQOL-BREF, where additional explanations and examples were often needed. The respondents were very appreciative of the instruments and found it valuable to have the opportunity to talk about these aspects of their condition. CONCLUSIONS: Our findings support the acceptability and relevance of five of the six instruments tested and the concept of a cross-NTD toolkit. PMID- 26940313 TI - Statins are not associated with short-term improved aneurysm healing in a rabbit model of unruptured aneurysms. AB - BACKGROUND: Owing to their anti-inflammatory effects and ability to stimulate production of extracellular matrix and chemotactic migration of mesenchymal progenitor cells, statins could potentially improve aneurysm healing after endovascular treatment. OBJECTIVE: To test the hypothesis that systemic administration of simvastatin would improve aneurysm healing in a rabbit model of unruptured intracranial aneurysms. METHODS: Experimental aneurysms were created in female rabbits and were embolized with platinum coils. Six rabbits served as controls and six rabbits received oral administration of simvastatin. Digital subtraction angiography was used to evaluate stability after embolization. Subjects were euthanized 4 weeks after coil embolization. Histologic samples were examined with a grading system (0-12) based on neck and dome features. Aneurysm occlusion data were compared using a Student t test. RESULTS: No significant differences in the mean aneurysm size were found between groups. No coil compaction occurred in either group. All aneurysms in both the statin and control groups showed stable occlusion. There were no significant differences in the histologic grade of occlusion in either group (statin group 2.6+/-0.8 vs control group 2.7+/-3.2, p=0.94). CONCLUSIONS: Systemic statin administration after platinum coil embolization of unruptured aneurysms in a rabbit model does not improve aneurysm occlusion rates at 4 weeks. PMID- 26940314 TI - Impact of immediate post-reperfusion cooling on outcome in patients with acute stroke and substantial ischemic changes. AB - BACKGROUND: In patients with acute stroke and an extensive ischemic burden at baseline, the prognosis is usually poor despite timely reperfusion. OBJECTIVE: To overcome universally poor outcomes in such patients, by applying immediate 'post reperfusion cooling' in order to reduce reperfusion-related complications, and to describe the clinical and imaging characteristics. METHODS: Patients having (1) an acute anterior large vessel occlusive stroke within 4.5 h since last known well, (2) Alberta Stroke Program Early CT Score (ASPECTS) <=5 on baseline imaging, and (3) targeted temperature management with endovascular cooling after confirmed reperfusion were included in this study. RESULTS: Eighteen patients (mean+/-SD age 59.5+/-10.9 years, median National Institutes of Health Stroke Scale score of 17, and median ASPECTS of 3) were analyzed. Median lesion volumes at baseline and after treatment were 130.2 and 110.6 mL, respectively. Median time from onset to the start of hypothermia and hypothermia duration were 213 min and 51 h, respectively. Favorable outcome (modified Rankin Scale <=2) at 3 months was observed in 10 (55.6%) patients. Symptomatic intracranial hemorrhage, malignant brain edema, and pneumonia were observed in 2, 6, and 8 patients, respectively. CONCLUSIONS: The use of post-reperfusion cooling as a rescue treatment in patients with substantial ischemia at baseline might improve clinical outcome. PMID- 26940315 TI - Developing a statewide protocol to ensure patients with suspected emergent large vessel occlusion are directly triaged in the field to a comprehensive stroke center: how we did it. AB - We describe the process by which we developed a statewide field destination protocol to transport patients with suspected emergent large vessel occlusion to a comprehensive stroke center. PMID- 26940317 TI - Infantile intracranial aneurysm of the superior cerebellar artery. AB - Intracranial aneurysms in the pediatric population are rare. We report a case of a 3-month-old infant who presented with inconsolable crying, vomiting, and sunset eye sign. CT revealed a subarachnoid hemorrhage, with CT angiogram revealing a superior cerebellar artery aneurysm. An external ventricular drain was placed for acute management of hydrocephalus, with definitive treatment by endovascular technique with a total of six microcoils to embolize the aneurysm. Serial transcranial Dopplers revealed no subsequent vasospasm. Although aneurysms in the pediatric population are rare, once the diagnosis is established, early treatment results in better outcomes. PMID- 26940316 TI - Lenticulostriate infarctions after successful mechanical thrombectomy in middle cerebral artery occlusion. AB - BACKGROUND: In stroke due to middle cerebral artery (MCA) occlusion, collaterals may sustain tissue in the peripheral MCA territory, extending the time window for recanalizing therapies. However, MCA occlusions often block some or all of the 'lenticulostriate' (LS) arteries originating from the M1 segment, eliminating blood flow to dependent territories in the striatum, which have no collateral supply. This study examines whether mechanical thrombectomy (MTE) can avert imminent striatal infarction in patients with acute MCA occlusion. METHODS: 279 patients with isolated MCA occlusion subjected to MTE were included. Actual LS occlusions and infarctions were assigned to predefined 'LS occlusion' and 'LS infarct' patterns derived from known LS vascular anatomy. The predictive performance of LS occlusion patterns regarding ensuing infarction in striatal subterritories was assessed by standard statistical measures. RESULTS: LS occlusion patterns predicted infarction in associated striatal subterritories with a positive predictive value (PPV) of 91% and a negative predictive value of 81%. In 15 of the 22 patients who did not develop the predicted striatal infarctions, reassessment of angiographies revealed LS vascular supply variants that explained these 'false positive' LS occlusion patterns, raising the PPV to 96%. Symptom onset to recanalization times were relatively short, but this alone could not account for the false positive LS occlusion patterns in the remaining seven of these patients. CONCLUSIONS: With currently achievable symptom onset to recanalization times, striatal infarctions are determined by MCA occlusion sites and individual vascular anatomy, and cannot normally be averted by MTE, but there are exceptions. Further study of such exceptional cases may yield important insights into the determinants of infarct growth in the hyperacute phase of infarct evolution. PMID- 26940318 TI - Concepts from paediatric extracorporeal membrane oxygenation for adult intensivists. AB - Over the last 5 years, there has been a dramatic increase in the use of extracorporeal membrane oxygenation (ECMO) in adult patients with severe respiratory or cardiac failure. This contrasts to the use of the technology in neonatal and paediatric intensive care units, where it has been regarded as a standard of care for a number of conditions for over 25 years. Many innovations in ECMO circuitry or clinical management evolve first in one particular discipline and it may be helpful for individual clinicians to keep abreast of developments in ECMO across the entire age range, from neonatology to older adults. This review addresses nine concepts in ECMO that are better studied or established in paediatric medicine and considers their application in adult patients. PMID- 26940319 TI - Research Misconduct in the Croatian Scientific Community: A Survey Assessing the Forms and Characteristics of Research Misconduct. AB - The prevalence and characteristics of research misconduct have mainly been studied in highly developed countries. In moderately or poorly developed countries such as Croatia, data on research misconduct are scarce. The primary aim of this study was to determine the rates at which scientists report committing or observing the most serious forms of research misconduct, such as falsification , fabrication, plagiarism, and violation of authorship rules in the Croatian scientific community. Additionally, we sought to determine the degree of development and the extent of implementation of the system for defining and regulating research misconduct in a typical scientific community in Croatia. An anonymous questionnaire was distributed among 1232 Croatian scientists at the University of Rijeka in 2012/2013 and 237 (19.2 %) returned the survey. Based on the respondents who admitted having committed research misconduct, 9 (3.8 %) admitted to plagiarism, 22 (9.3 %) to data falsification, 9 (3.8 %) to data fabrication, and 60 (25.3 %) respondents admitted to violation of authorship rules. Based on the respondents who admitted having observed research misconduct of fellow scientists, 72 (30.4 %) observed plagiarism, 69 (29.1 %) observed data falsification, 46 (19.4 %) observed data fabrication, and 132 (55.7 %) respondents admitted having observed violation of authorship rules. The results of our study indicate that the efficacy of the system for managing research misconduct in Croatia is poor. At the University of Rijeka there is no document dedicated exclusively to research integrity, describing the values that should be fostered by a scientist and clarifying the forms of research misconduct and what constitutes a questionable research practice. Scientists do not trust ethical bodies and the system for defining and regulating research misconduct; therefore the observed cases of research misconduct are rarely reported. Finally, Croatian scientists are not formally educated about responsible conduct of research at any level of their formal education. All mentioned indicate possible reasons for higher rates of research misconduct among Croatian scientists in comparison with scientists in highly developed countries. PMID- 26940321 TI - Efficient expression of single chain variable fragment antibody against paclitaxel using the Bombyx mori nucleopolyhedrovirus bacmid DNA system and its characterizations. AB - A single chain variable fragment (scFv), the smallest unit of functional recombinant antibody, is an attractive format of recombinant antibodies for various applications due to its small fragment and possibility of genetic engineering. Hybridoma clone 3A3 secreting anti-paclitaxel monoclonal antibody was used to construct genes encoding its variable domains of heavy (VH) and light (VL) chains. The VH and VL domains were linked to be the PT-scFv3A3 using flexible peptide linker in a format of VH-(GGGGS)5-VL. The PT-scFv3A3 was primarily expressed using the pET28a(+) vector in the Escherichia coli system, and was then further expressed by using the Bombyx mori nucleopolyhedrovirus (BmNPV) bacmid DNA system. Interestingly, the reactivity of PT-scFv3A3 expressed in the hemolymph of B. mori using the BmNPV bacmid DNA system was much higher than that expressed in the E. coli system. Using indirect competitive enzyme linked immunosorbent assay (icELISA), the PT-scFv3A3 (B. mori) reacted not only with immobilized paclitaxel, but also with free paclitaxel in a concentration dependent manner, with the linear range of free paclitaxel between 0.156 and 5.00 ug/ml. The PT-scFv3A3 (B. mori) exhibited less cross-reactivity (%) than its parental MAb clone 3A3 against paclitaxel-related compounds, including docetaxel (31.1 %), 7-xylosyltaxol (22.1 %), baccatin III (<0.68 %), 10-deacetylbaccatin III (<0.68 %), 1-hydroxybaccatin I (<0.68 %), and 1-acetoxy-5-deacetylbaccatin I (<0.68 %). With the exception of cephalomannine, the cross-reactivity was slightly increased to 8.50 %. The BmNPV bacmid DNA system was a highly efficient expression system of active PT-scFv3A3, which is applicable for PT-scFv3A3-based immunoassay of paclitaxel. In addition, the PT-scFv3A3 can be applied to evaluate its neutralizing property of paclitaxel or docetaxel toxicity. PMID- 26940320 TI - Antithrombosis activity of protocatechuic and shikimic acids from functional plant Pinus densiflora Sieb. et Zucc needles. AB - Pine needle extract (PE) and fermented pine needle extract (FPE) have been reported to show various biological and pharmacological activities such as antioxidant, anti-inflammatory, anti-bacterial, anti-cholesterol, gastrointestinal motility control, and fibrinolytic effect. The aims of our research were to isolate fibrinolytic compounds from PE and FPE and evaluate their antithrombotic activity in vitro and in vivo. Protocatechuic (1) and shikimic (2) acids were isolated and identified from FPE. 1 and 2 not only have fibrinolysis activity but also inhibit fibrin formation similar to aspirin. Lysis of fibrin clots by 1 and 2 occurred completely at pH 2-4. Results of SDS-PAGE showed that fibrin polypeptide chains (Aalpha, Bbeta, gamma) lysed by 1 and 2 were intact. The antithrombotic effects of 1 and 2 were confirmed by models of carrageenan-induced tail thrombosis, collagen and epinephrine-induced pulmonary thromboembolism in mice, and FeCl3-induced carotid arterial thrombus. Moreover, 1 and 2 did not induce hemorrhage in the tail veins of mice, unlike common antithrombotic compounds. We also measured changes in the quantities of 1 and 2 obtained from FPE. As fermentation progressed, we demonstrated that the quantity of 1 steadily increased, while the quantity of 2 did not significantly change. We therefore demonstrated that FPE is an excellent resource for 1 and 2 and can be produced inexpensively in sufficient quantities for industrial-scale extraction. PMID- 26940328 TI - UK Groups Plan Cancer Research Hub. AB - Two major cancer research groups in the UK have announced plans to create a global cancer center aimed at accelerating drug development and fostering collaboration with industry. The $1.5 billion campus is expected to house 10,000 scientists and clinicians and deliver two additional drug candidates, an increase of 40%, every 5 years. PMID- 26940322 TI - Exogenous proteinogenic amino acids induce systemic resistance in rice. AB - BACKGROUND: Plant immune responses can be induced by endogenous and exogenous signaling molecules. Recently, amino acids and their metabolites have been reported to affect the plant immune system. However, how amino acids act in plant defense responses has yet to be clarified. Here, we report that treatment of rice roots with amino acids such as glutamate (Glu) induced systemic disease resistance against rice blast in leaves. RESULTS: Treatment of roots with Glu activated the transcription of a large variety of defense-related genes both in roots and leaves. In leaves, salicylic acid (SA)-responsive genes, rather than jasmonic acid (JA) or ethylene (ET)-responsive genes, were induced by this treatment. The Glu-induced blast resistance was partially impaired in rice plants deficient in SA signaling such as NahG plants expressing an SA hydroxylase, WRKY45-knockdown, and OsNPR1-knockdown plants. The JA-deficient mutant cpm2 exhibited full Glu-induced blast resistance. CONCLUSIONS: Our results indicate that the amino acid-induced blast resistance partly depends on the SA pathway but an unknown SA-independent signaling pathway is also involved. PMID- 26940330 TI - Transitioning from peer review to peer learning for abdominal radiologists. PMID- 26940329 TI - Plant-driven removal of heavy metals from soil: uptake, translocation, tolerance mechanism, challenges, and future perspectives. AB - Increasing heavy metal (HM) concentrations in the soil have become a significant problem in the modern industrialized world due to several anthropogenic activities. Heavy metals (HMs) are non-biodegradable and have long biological half lives; thus, once entered in food chain, their concentrations keep on increasing through biomagnification. The increased concentrations of heavy metals ultimately pose threat on human life also. The one captivating solution for this problem is to use green plants for HM removal from soil and render it harmless and reusable. Although this green technology called phytoremediation has many advantages over conventional methods of HM removal from soils, there are also many challenges that need to be addressed before making this technique practically feasible and useful on a large scale. In this review, we discuss the mechanisms of HM uptake, transport, and plant tolerance mechanisms to cope with increased HM concentrations. This review article also comprehensively discusses the advantages, major challenges, and future perspectives of phytoremediation of heavy metals from the soil. PMID- 26940334 TI - [Erratum to: Urology and Sexology in Berlin 1880-1933: Original citations for the establishment of this frontier of urology - protagonists as reflected in their publications]. PMID- 26940332 TI - Commensurate antiferromagnetic excitations as a signature of the pseudogap in the tetragonal high-Tc cuprate HgBa2CuO(4+delta). AB - Antiferromagnetic correlations have been argued to be the cause of the d-wave superconductivity and the pseudogap phenomena exhibited by the cuprates. Although the antiferromagnetic response in the pseudogap state has been reported for a number of compounds, there exists no information for structurally simple HgBa2CuO(4+delta). Here we report neutron-scattering results for HgBa2CuO(4+delta) (superconducting transition temperature Tc~71 K, pseudogap temperature T*~305 K) that demonstrate the absence of the two most prominent features of the magnetic excitation spectrum of the cuprates: the X-shaped 'hourglass' response and the resonance mode in the superconducting state. Instead, the response is Y-shaped, gapped and significantly enhanced below T*, and hence a prominent signature of the pseudogap state. PMID- 26940333 TI - Protective and hypoglycemic effects of celery seed on streptozotocin-induced diabetic rats: experimental and histopathological evaluation. AB - AIMS: Diabetes mellitus is a major manifestation of metabolic disorder which presents with hyperglycemia (high levels of serum blood sugar). In the present study, we aimed to investigate the effects of celery seed extract on different biochemical factors and histopathological changes in normal and streptozotocin (STZ)-induced diabetic rats. METHODS: A total of 35 male Wistar rats were divided into five groups (one normal and four diabetic groups). STZ was injected intraperitoneally to induce diabetes. The effects of hexane extract of celery seed and glibenclamide (as a positive control) were compared. Blood samples were analyzed on days 0, 18, and 33, and histopathological evaluations were performed at the end of the study. RESULTS: Glucose, triglycerides, and cholesterol levels significantly decreased, whereas insulin and high-density lipoprotein (HDL) levels increased in the extract-administered groups, as compared to the negative diabetic control group (P < 0.0001). The concentrations of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in serum of the extract-administered groups were significantly less than the negative control group (P < 0.0001). Histopathological reports revealed significantly less atrophy, necrosis, and inflammation in the rats receiving celery seed extract compared to the negative control group. CONCLUSIONS: The results indicated that celery seed extract can be effective in controlling hyperglycemia and hyperlipidemia in diabetic rats, and demonstrated its protective effects against pancreatic toxicity resulting from STZ-induction. PMID- 26940335 TI - [Radiotherapy vs. radical surgery]. PMID- 26940337 TI - Corrigendum. PMID- 26940331 TI - Magnetic resonance safety. AB - Magnetic resonance imaging (MRI) has a superior soft-tissue contrast compared to other radiological imaging modalities and its physiological and functional applications have led to a significant increase in MRI scans worldwide. A comprehensive MRI safety training to protect patients and other healthcare workers from potential bio-effects and risks of the magnetic fields in an MRI suite is therefore essential. The knowledge of the purpose of safety zones in an MRI suite as well as MRI appropriateness criteria is important for all healthcare professionals who will work in the MRI environment or refer patients for MRI scans. The purpose of this article is to give an overview of current magnetic resonance safety guidelines and discuss the safety risks of magnetic fields in an MRI suite including forces and torque of ferromagnetic objects, tissue heating, peripheral nerve stimulation, and hearing damages. MRI safety and compatibility of implanted devices, MRI scans during pregnancy, and the potential risks of MRI contrast agents will also be discussed, and a comprehensive MRI safety training to avoid fatal accidents in an MRI suite will be presented. PMID- 26940336 TI - The Role of Neuroticism in the Maintenance of Chronic Baseline Stress Perception and Negative Affect. AB - The influence of neuroticism on stress perception and its associated negative affect is explored in a quasi-experimental repeated measure study. The study involves manipulating the stress perception and affect of high N group (n = 24) and low N group (n = 28) three times; first, through exposure to neutral stimuli; second, through exposure to a laboratory stressor; third, through exposure to positive stimuli. The results reveal that after exposure to neutral stimuli, there is a significant difference in the baseline Perceived Stress Scores (PSS) (p = .005) and Negative Affect (NA) scores (p = .001) of the two groups. During the stress task, however, both groups show a non-significant difference in the PSS (p = .200) and NA scores (p = .367). After exposure to positive stimuli, there is a significant difference in the PSS scores (p = .001), but a non significant difference in the NA scores (p = .661) of the two groups. When compared across three conditions, the high N group report significantly higher perceived stress (p = .002), but not significantly higher negative affect (p = .123) than the low N group. Finally for both PSS and NA scores, there is no interaction between neuroticism and any of the three treatment conditions (p = .176; p = .338, respectively). This study shows that the high N group may be at risk for health disparities due to maintaining a chronic higher baseline stress perception and negative affect state under neutral conditions, than the low N group. Implications of the study are discussed. PMID- 26940338 TI - Screening, diagnosis and treatment of hypertension in obese children: an international policy comparison. AB - Hypertension in obese children may require a different diagnostic and treatment approach from that for children with secondary hypertension, yet there is neither consensus nor a clear guideline. The aim of this study was to assess how obese children with hypertension are currently diagnosed and treated by paediatric nephrologists, what obstacles exist and what can be improved. In the period May November 2014, an online questionnaire was sent to all members of the European Society for Paediatric Nephrology (n = 2148). Questions focused on current practices and obstacles regarding screening, diagnosis and treatment of hypertension in obese children. A total of 214 paediatric nephrologists responded. Although nearly 100 % agreed that screening of obese children for hypertension is indicated, it was current practice in only 56 % of participating countries; 88 % of respondents diagnosed hypertension with 24-h ambulatory blood pressure measurement. Diagnostics used to rule out causes or consequences of hypertension varied among the respondents; they included, in particular, the use of serum renin/aldosterone, urine sodium/potassium, and dimercaptosuccinic acid scan. Concerning treatment, 45 % of respondents preferred to start treatment with a lifestyle program, 2 % with antihypertensive medication, and 40 % with both. For 73 % of respondents, angiotensin-converting enzyme-inhibitors or angiotensin receptor blockers were the drugs of first choice. The findings of this study emphasize the urgent need for an international guideline for screening, diagnosis and treatment of hypertension in obese children. PMID- 26940340 TI - How true delivery profile diminution reduces vascular access challenges and complications. AB - Transcatheter aortic valve implantation (TAVI) is the treatment of choice among patients with symptomatic severe aortic stenosis (AS) deemed inoperable and a valuable alternative to surgical aortic valve replacement for high-risk surgical patients. Over the years, this procedure proved to be relatively safe, but despite this complications may occur. When performing TAVI, the most frequent complications are represented by peripheral vascular complications and bleeding involving the access site. Trans-femoral (TF) route is the preferred access site and device evolution has made it possible to reduce in size sheaths and delivery systems from the initial 22- to 24-Fr of the first generation TF devices, progressively down to 18-Fr and then to 16-14-Fr with the latest generations of prostheses, with a required minimal lumen diameter (MLD) of 5.5 mm. The more vascular-friendly TF-TAVI devices, not only have made it possible to patients with small arteries to be treated with this procedure, but also have markedly reduced vascular complications. PMID- 26940339 TI - Kidney-lung connections in acute and chronic diseases: current perspectives. AB - Lung and kidney functions are intimately related in both health and disease. The regulation of acid-base equilibrium, modification of partial pressure of carbon dioxide and bicarbonate concentration, and the control of blood pressure and fluid homeostasis all closely depend on renal and pulmonary activities. These interactions begin in fetal age and are often responsible for the genesis and progression of diseases. In gestational age, urine is a fundamental component of the amniotic fluid, acting on pulmonary maturation and growth. Moreover, in the first trimester of pregnancy, kidney is the main source of proline, contributing to collagen synthesis and lung parenchyma maturation. Pathologically speaking, the kidneys could become damaged by mediators of inflammation or immuno-mediated factors related to a primary lung pathology or, on the contrary, it could be the renal disease that determines a consecutive pulmonary damage. Furthermore, non immunological mechanisms are frequently involved in renal and pulmonary diseases, as observed in chronic pathologies such as sleep apnea syndrome, pulmonary hypertension, progressive renal disease and hemodialysis. Kidney damage has also been related to mechanical ventilation. The aim of this review is to describe pulmonary-renal interactions and their related pathologies, underscoring the need for a close collaboration between intensivists, pneumologists and nephrologists. PMID- 26940342 TI - Evidence of benefit of personal budgets is outdated, says spending watchdog. PMID- 26940343 TI - Comment on "An alternative theory to explain the effects of coalescing oil drops on mouthfeel" by B. Le Reverend and J. Engmann, Soft Matter, 2015, 11, 7077. AB - In a recent paper by B. Le Reverend and J. Engmann, they used a model to explain the change in the perceived viscosity by phase separation. We improved this model by adding the drop in viscosity in the aqueous phase to it and we show how this will significantly change the conclusion in the original paper. The increase in viscosity due to phase separation is highly unlikely to happen because the drop in viscosity due to loss of oil is faster at a high oil concentration. PMID- 26940345 TI - Erratum: How Do the Size, Charge and Shape of Nanoparticles Affect Amyloid beta Aggregation on Brain Lipid Bilayer? PMID- 26940341 TI - T cell proliferation and adaptive immune responses are critically regulated by protein phosphatase 4. AB - The clonal expansion of activated T cells is pivotal for the induction of protective immunity. Protein phosphatase 4 (PP4) is a ubiquitously expressed serine/threonine phosphatase with reported functions in thymocyte development and DNA damage responses. However, the role of PP4 in T cell immunity has not been thoroughly investigated. In this report, our data showed that T cell-specific ablation of PP4 resulted in defective adaptive immunity, impaired T cell homeostatic expansion, and inefficient T cell proliferation. This hypo proliferation was associated with a partial G1-S cell cycle arrest, enhanced transcriptions of CDK inhibitors and elevated activation of AMPK. In addition, resveratrol, a known AMPK activator, induced similar G1-S arrests, while lentivirally-transduced WT or constitutively-active AMPKalpha1 retarded the proliferation of WT T cells. Further investigations showed that PP4 co immunoprecipitated with AMPKalpha1, and the over-expression of PP4 inhibited AMPK phosphorylation, thereby implicating PP4 for the negative regulation of AMPK. In summary, our results indicate that PP4 is an essential modulator for T cell proliferation and immune responses; they further suggest a potential link between PP4 functions, AMPK activation and G1-S arrest in activated T cells. PMID- 26940344 TI - Surgical outcomes of congenital and developmental cataracts in Japan. AB - PURPOSE: To retrospectively analyze the surgical outcomes of congenital/developmental cataracts in Japan. METHODS: A mail questionnaire was sent to facilities engaged in surgical treatment of congenital cataracts. RESULTS: Twenty-nine facilities reported on 809 eyes of 508 patients with congenital/developmental cataracts. Three hundred fifty-nine eyes underwent intraocular lens implantation (pseudophakia group), while 450 eyes were left aphakic (aphakia group). The average age at surgery was significantly higher in the pseudophakia group (70 +/- 53 months) than in the aphakia group (14 +/- 24 months) (P < 0.0001). A significantly larger proportion of patients with unilateral cataract (52.0 %) received IOL implantation than did those with bilateral cataracts (42.6 %) (P = 0.0224). The prevalence of associated ocular disorders, such as nystagmus, microcornea, nanophthalmos, and persistent fetal vasculature, was significantly higher in the aphakia group than in the pseudophakia group. Postoperatively, glaucoma developed more frequently in the aphakia group (5.8 %) than in the pseudophakia group (0.7 %) (P = 0.0003). Posterior capsule opacification developed more frequently in the pseudophakic eyes even when both posterior capsulotomy and anterior vitrectomy were performed, especially in patients aged 1 year or younger. Postoperative visual acuity was significantly better in the pseudophakia group than in the aphakia group, both in the unilateral and in the bilateral cases. CONCLUSIONS: Surgeons tended to select IOL implantation, rather than to leave the eye aphakic, in patients who were older at the time of surgery, had fewer coexisting ocular disorders, and suffered from unilateral cataract. Under such circumstances, pseudophakic eyes obtained significantly better postoperative visual acuity than did aphakic eyes. PMID- 26940347 TI - An Assessment of the Prevalence, Perceived Significance, and Response to Dowry Solicitation and Domestic Violence in Bangladesh. AB - The current study focuses on the prevalence of two pervasive gender-related crimes in Bangladesh: dowry solicitation and domestic violence. We assess victim perceptions of how these two crimes rank in significance compared with other types of crimes experienced and the actions victim households took in response. Our research builds on prior qualitative studies by making use of nation-wide household survey data, collected by the World Bank, to examine dowry and domestic violence in the context of all legal conflicts experienced by households in every administrative region of the country. The analyses show that both dowry solicitation and domestic violence rank in the top five most common crimes, including violent and non-violent crimes. Women report more experiences of dowry solicitation and domestic violence, with urban females most frequently disclosing both. Among the households that experienced multiple types of violent and non violent crimes, 55.9% of dowry and 70.8% of domestic violence victims reported another crime ranked higher in significance. Of the households that considered these two crimes the most serious they experienced, 56.1% of dowry and 32.5% of domestic violence households took no action at all in response. Among the households that took action, most eschewed both police and state judicial institutions. Choosing to act alone or with the help of family members was the most frequent response. The findings illustrate the need for governance reforms in Bangladesh and may inform state and non-state improvement initiatives. PMID- 26940346 TI - The Extent and Risk of Violent Victimization Among International College Students Enrolled in the United States: A Gendered Analysis. AB - Although the risk of being violently victimized in college has been established for college students in the United States in general, this risk has not been explored for international college students. Using data from the Fall 2012 National College Health Assessment Survey, the extent to which international college students experience violent victimization is assessed. In addition, the risk factors for violent victimization for international students are compared with those for domestic students. Finally, in multivariate analyses, whether being an international student influences risk of violent victimization is examined and whether this relationship is moderated by gender is considered. Findings indicate that international students in general have lower risk profiles, in that they reported lower rates of drug use, binge drinking, being a first-year undergraduate student, and having a disability. Multivariate analyses, however, revealed that being an international student reduces the odds of violent victimization among only females. PMID- 26940349 TI - Racial Differences and the Role of Marital Status in the Association Between Intimate Partner Violence and Unintended Pregnancy. AB - More than half of all pregnancies in the U.S. are unintended which may lead to poor health outcomes. Racial and ethnic differences underlying the association between IPV and unintended pregnancy are inconsistent. This study examines the association between IPV and unintended pregnancy across racial/ethnic and marital strata among U.S. women. Data from the national 2009/11 Pregnancy Risk Assessment Monitoring System consisting of women who recently delivered a live birth baby were analyzed (n=108,220). A dichotomous variable was created to indicate whether women experienced IPV in the 12 months leading to their most recent pregnancy (yes; no). The outcome, pregnancy intention, was dichotomized as intended or unintended. Subpopulation analysis was conducted stratified by race/ethnicity and marital status. Adjusted odds ratios and 95% confidence intervals were generated using multiple logistic regression models. The odds of unintended pregnancy were increased for married non-Hispanic White women who reported IPV compared to their non-abused counterparts even after controlling for sociodemographic factors, health care access, and reproductive history. Among unmarried non-Hispanic other women, abused women were significantly less likely to report unintended pregnancy than the non-abused. No significant differences were observed for Hispanic or non Hispanic Black women. There are significant racial and ethnic differences in the association between IPV and unintended pregnancy. Additionally, the association differed by marital status. Public health professionals and health care providers should be aware of these differences. PMID- 26940348 TI - Enhancing Risk Detection Among Homeless Youth: A Randomized Clinical Trial of a Promising Pilot Intervention. AB - Homeless youth frequently experience victimization, and youth with histories of trauma often fail to detect danger risks, making them vulnerable to subsequent victimization. The current study describes a pilot test of a skills-based intervention designed to improve risk detection among homeless youth through focusing attention to internal, interpersonal, and environmental cues. Youth aged 18 to 21 years ( N = 74) were recruited from a shelter and randomly assigned to receive usual case management services or usual services plus a 3-day manualized risk detection intervention. Pretest and posttest interviews assessed youths' risk detection abilities through vignettes describing risky situations and asking youth to identify risk cues present. Separate 2 (intervention vs. control) * 2 (pretest vs. posttest) mixed ANOVAs found significant interaction effects, as intervention youth significantly improved in overall risk detection compared with control youth. Post hoc subgroup analyses found the intervention had a greater effect for youth without previous experiences of indirect victimization than those with previous indirect victimization experiences. PMID- 26940350 TI - Beyond the Situational Model: Bystander Action Consequences to Intervening in Situations Involving Sexual Violence. AB - Sexual violence is a widely reported problem in college communities. To date, research has largely focused on bystander intervention as one way to help prevent this problem. Although perceived consequences of bystander intervention, such as the weighting of costs and benefits, have been examined, little research has explored what happens after a bystander intervenes. The current study investigated what bystanders report as perceived outcomes and actual consequences of their bystander actions in response to risk for sexual assault. Of the 545 surveyed, 150 reported having taking bystander action in the past month and qualitatively described their bystander behavior and the responses of those parties involved. A range of behavioral responses and intervention methods were identified. The most frequent responses reported by participants were victims conveying positive and perpetrators conveying negative responses. Different types of helping were associated with bystanders reporting different types of responses to their actions. Future research should incorporate additional measures of consequences of bystander intervention. Implications for policy and bystander intervention programs are discussed, stressing the need for bystander intervention programs to address a range of bystander behaviors and explain the potential consequences and risks of intervening. PMID- 26940351 TI - Functions of Aggression and Delinquency: The Moderating Role of Parent Criminality and Friends' Gang Membership. AB - This study examined the relationships between two functions of aggression (i.e., reactive and proactive) and delinquency, including the moderating effects of parent criminality and friends' gang membership, in a sample of 1,027 Singaporean adolescents from Grade 7 to Grade 9, with age ranging from 12 to 19 years ( M = 14.10, SD = 1.15). Findings suggested that both reactive aggression and proactive aggression significantly and positively predicted delinquency (after controlling for proactive aggression and reactive aggression, respectively), with proactive aggression being a stronger predictor. Friends' gang membership was found to moderate the relationship between reactive aggression and delinquency, and proactive aggression and delinquency, with stronger moderator effects for the latter. Those who were aggressive proactively and who had friends in a gang appear to be impacted most negatively with respect to delinquency. Parent criminality did not moderate these relationships. These findings highlight the need to effectively address the issues of child and adolescent aggression. Also, developing positive peer relations early is crucial for delinquency prevention. PMID- 26940352 TI - Administration of nintedanib after discontinuation for acute exacerbation of idiopathic pulmonary fibrosis: a case report. AB - BACKGROUND: Nintedanib is a multi-target receptor tyrosine kinase inhibitor. In two recent randomized phase 3 trials (INPULSISTM-1 and -2), it has been shown to slow the disease progression of idiopathic pulmonary fibrosis (IPF) by reducing the decline in the forced vital capacity (FVC). Although the INPULSISTM trials indicate that nintedanib may serve to prevent acute exacerbations or delay the time to the first acute exacerbation, a certain number of IPF patients develop acute exacerbations while receiving nintedanib. However, there has been no report on the readministration of nintedanib in IPF patients who develop acute exacerbations during initial treatment with nintedanib. CASE PRESENTATION: A 64 year-old man with IPF had nintedanib added to his ongoing pirfenidone therapy. He developed dyspnea after 65 days and presented with hypoxemia after 68 days. At presentation, chest computed tomography showed newly developed diffuse ground glass opacities with the pre-existing subpleural reticular shadows. Because of the absence of infection or other potential causative factors, we diagnosed an acute exacerbation of IPF. Nintedanib was temporarily discontinued and the acute exacerbation was successfully managed with intensive treatment. We re-initiated nintedanib 30 days after cessation, which helped stabilize his FVC for 8 months. Nintedanib was safely continued for 28 months until he died of a bacterial infection. CONCLUSION: To the best of our our knowledge, this is the first reported case of an acute exacerbation of IPF during nintedanib treatment, wherein nintedanib was safely and successfully restarted after treatment of the acute exacerbation. Our case indicates that nintedanib can be safely resumed and a desired effect on FVC can be obtained, even in IPF patients who develop acute exacerbations. However, we recommend close monitoring and appropriate measures until the long-term safety profile is clarified. PMID- 26940353 TI - Alcoholic hepatitis: Translational approaches to develop targeted therapies. AB - Alcoholic liver disease is a leading cause of liver-related mortality worldwide. In contrast to recent advances in therapeutic strategies for patients with viral hepatitis, there is a significant lack of novel therapeutic options for patients with alcoholic liver disease. In particular, there is an urgent need to focus our efforts on effective therapeutic interventions for alcoholic hepatitis (AH), the most severe form of alcoholic liver disease. AH is characterized by an abrupt development of jaundice and complications related to liver insufficiency and portal hypertension in patients with heavy alcohol intake. The mortality of patients with AH is very high (20%-50% at 3 months). Available therapies are not effective in many patients, and targeted approaches are imminently needed. The development of such therapies requires translational studies in human samples and suitable animal models that reproduce the clinical and histological features of AH. In recent years, new animal models that simulate some of the features of human AH have been developed, and translational studies using human samples have identified potential pathogenic factors and histological parameters that predict survival. CONCLUSION: This review summarizes the unmet needs for translational studies on the pathogenesis of AH, preclinical translational tools, and emerging drug targets to benefit the AH patient. (Hepatology 2016;64:1343-1355). PMID- 26940355 TI - Determination of serum cholestane-3beta,5alpha,6beta-triol by gas chromatography mass spectrometry for identification of Niemann-Pick type C (NPC) disease. AB - Niemann-Pick type C (NPC) is a neurological disease caused by an intracellular cholesterol accumulation. Cholesterol oxidation product cholestane 3beta,5alpha,6beta-triol (C-triol) serves as diagnostic biomarker for NPC, but its measurement in the routine laboratory remains difficult. We developed an isotope dilution gas chromatography-mass spectrometry (GC-MS) method permitting screening for NPC in plasma. 1440 plasma samples obtained from clinically suspicious patients were subjected to alkaline saponification. C-triol was extracted with carbon tetrachloride, transformed into the trimethylsilylethers, separated on a fused silica capillary column with a nonpolar silicone stationary phase, and analyzed by GC-MS. NPC diagnosis was confirmed by DNA sequencing. The method was linear over a concentration range of 0.03-200ng/mL with a mean recovery rate of 98.6%. The intra- and inter-day variation coefficients assessed at two concentrations were below 15%. Limits of quantification (LOQ) and detection (LOD) were 0.03ng/mL and 0.01ng/mL, respectively. Receiver operating characteristic (ROC) analysis estimated that the area under curve was 0.997 implying a significant discriminatory power to identify subjects with NPC. Nevertheless, 13 NPC patients and 29 control subjects confirmed by sequencing showed false negative or positive results, respectively. Two patients with cerebrotendinous xanthomatosis showed a 5-10-fold increase in C-triol levels. We developed a quick and sensitive GC-MS method for determination of C-triol, which may serve as a simple and inexpensive diagnostic tool aiding NPC diagnosis in a routine hospital laboratory. As C-triol elevation is not limited to NPC, the NPC diagnosis has to be confirmed by DNA sequencing. PMID- 26940354 TI - A fresh look at the function of Rabaptin5 on endosomes. AB - Rab GTPases act as organizers of protein networks defining identities and functions of organelles of the endocytic and secretory pathways. Various modes of coordination between different Rabs drive the timely maturation and conversion of membranes. Endosomal Rab5 has been known as the prime example for self-activation via a feedback loop recruiting Rabaptin5, which is complexed with the Rab5 exchange factor Rabex5, and couples to Rab4-GTP. Among other effectors, Rab5 also recruits the Mon1/SAND1-Ccz1 complex that both activates Rab7 and dissociates Rabex5 for Rab5-to-Rab7 conversion of early-to-late endosomes. A detailed deletion analysis now revealed 2 separate binding sites each for Rab4-GTP and Rab5-GTP and indicates a feedforward mechanism of Rab5 activation. Rabaptin5/Rabex5 is recruited to endosomal membranes positive for Rab4-GTP and ubiquitinated cargo (binding to the ubiquitin binding site of Rabex5). This mechanism also suggests additional criteria for Rab5 inactivation concomitant with increasing Rab7-GTP levels. The disappearance of ubiquitinated cargo upon ESCRT-mediated formation of intraluminal vesicles and inactivation of Rab4 may also contribute to loss of Rab5 activation. Rabaptin5/Rabex5 thus may integrate several cues of maturation to perform Rab conversion. Furthermore Rab5 binding to Rabaptin5 appears to prevent uncontrolled progression to late endosomes. PMID- 26940356 TI - Combined steroidogenic characters of fetal adrenal and Leydig cells in childhood adrenocortical carcinoma. AB - Although childhood adrenocortical carcinomas (c-ACCs) with a TP53 mutation are known to produce androgens, detailed steroidogenic characters have not been clarified. Here, we examined steroid metabolite profiles and expression patterns of steroidogenic genes in a c-ACC removed from the left adrenal position of a 2 year-old Brazilian boy with precocious puberty, using an atrophic left adrenal gland removed at the time of tumorectomy as a control. The c-ACC produced not only abundant dehydroepiandrosterone-sulfate but also a large amount of testosterone via the Delta5 pathway with Delta5-androstenediol rather than Delta4 androstenedione as the primary intermediate metabolite. Furthermore, the c-ACC was associated with elevated expressions of CYP11A1, CYP17A1, POR, HSD17B3, and SULT2A1, a low but similar expression of CYB5A, and reduced expressions of AKR1C3 (HSD17B5) and HSD3B2. Notably, a Leydig cell marker INSL3 was expressed at a low but detectable level in the c-ACC. Furthermore, molecular studies revealed a maternally inherited heterozygous germline TP53 mutation, and several post zygotic genetic aberrations in the c-ACC including loss of paternally derived chromosome 17 with a wildtype TP53 and loss of maternally inherited chromosome 11 and resultant marked hyperexpression of paternally expressed growth promoting gene IGF2 and drastic hypoexpression of maternally expressed growth suppressing gene CDKN1C. These results imply the presence of combined steroidogenic properties of fetal adrenal and Leydig cells in this patient's c-ACC with a germline TP53 mutation and several postzygotic carcinogenic events. PMID- 26940357 TI - Effects of plant stanol ester consumption on fasting plasma oxy(phyto)sterol concentrations as related to fecal microbiota characteristics. AB - Information regarding dietary effects on plasma oxyphytosterol concentrations as well as on the origin of oxyphytosterols is scarce. We hypothesized that plant sterols are oxidized in the intestinal lumen, mediated by microbial activity, followed by uptake into the circulation. To address this hypothesis, we carried out, a randomized, double blind, crossover study in 13 healthy subjects, who consumed for 3 weeks control and plant stanol ester enriched margarines (3.0g/d plant stanols) separated by a 4-week wash-out period. Plasma oxy(phyto)sterols were determined via GC-MS/MS, while microbiota analyses were performed on fecal DNA using a phylogenetic microarray to assess microbial composition and diversity. Plasma plant sterol concentrations did not correlate with plasma oxyphytosterols concentrations at baseline. Plant stanol consumption reduced serum sitosterol and campesterol concentrations (-37% and -38%), respectively (p<0.001), as well as plasma concentrations of 7beta-OH-campesterol (-24%; p<0.05), 7beta-OH-sitosterol (-17%; p<0.05) and 7-keto-sitosterol (-13%; p<0.05). Although the intestinal microbiota composition and diversity of the faecal contents were not different between the two periods, we observed significant correlations between several specific bacterial groups and plasma plant sterol, but not with plasma oxyphytosterol concentrations. In conclusion, plant stanol ester consumption reduced serum plant sterol and plasma oxyphytosterol concentrations, while intestinal microbiota composition and diversity were not changed. To definitely answer the effects of microbiota on oxyphytosterol formation, future studies could examine oxyphytosterol concentrations after changing intestinal microbial composition or by measuring intestinal oxyphytosterol formation after providing labelled non-oxidized plant sterols. PMID- 26940358 TI - Liver X Receptors differentially modulate central myelin gene mRNA levels in a region-, age- and isoform-specific manner. AB - Liver X Receptors (LXRs) alpha and beta are nuclear receptors able to bind oxidative forms of cholesterol. They play important roles in the central nervous system (CNS), through their implication in a large variety of physiological and pathological processes among which modulation of cholesterol homeostasis and inflammation. Besides, we recently revealed their crucial role in myelination and remyelination in the cerebellum. Given the pleiotropic effects of such receptors on CNS functioning, we studied here the influence of LXRs on myelin gene mRNA accumulation in the major myelinated regions of the CNS in vivo. We show that both LXR isoforms differentially affect mRNA amount of myelin genes (PLP and MBP) in highly myelinated structures such as spinal cord, corpus callosum, optic nerve and cerebellum. In the adult, LXR activation by the synthetic agonist TO901317 significantly increases myelin gene mRNA amount in the cerebellum but not in the other regions studied. Invalidation of the sole LXRbeta isoform leads to decreased PLP and MBP mRNA levels in all the structures except the spinal cord, while the knock out of both isoforms (LXR dKO) decreases myelin gene mRNA amounts in all the regions tested except the corpus callosum. Interestingly, during myelination process (post-natal day 21), both cerebellum and optic nerve display a decrease in myelin gene mRNA levels in LXR dKO mice. Concomitantly, PLP and MBP mRNA accumulation in the spinal cord is increased. Relative expression level of LXR isoforms could account for the differential modulation of myelin gene expression in the CNS. Altogether our results suggest that, within the CNS, each LXR isoform differentially influences myelin gene mRNA levels in a region- and age-dependant manner, participating in the fine regulation of myelin gene expression. PMID- 26940360 TI - Practicing Hope. PMID- 26940359 TI - Gender differences in treatment progress of drug-addicted patients. AB - The authors of this study explored the differences in treatment progress between men and women who were addicted to drugs. The differential rate of completion of/dropout from treatment in men and women with substance dependence was established. Moreover, comparisons between completers and dropouts, accounting for gender, were carried out for several variables related to treatment progress and clinical profile. A sample of 183 addicted patients (96 male and 87 female) who sought outpatient treatment between 2002 and 2006 was assessed. Information on socio-demographic, consumption, and associated characteristics was collected. A detailed tracking of each patient's progress was maintained for a minimum period of 8 years to assess treatment progression. The treatment dropout rate in the whole sample was 38.8%, with statistically significant differences between women (47.1%) and men (31.3%). Women who dropped out of treatment presented a more severe profile in most of the psychopathologic variables than women who completed it. Moreover, women who dropped out from treatment presented a more severe profile than men who dropped out. According to these results, drug addicted women showed worse therapeutic progress than men with similar histories. Thus, women must be provided with additional targeted intervention to promote better treatment outcomes. PMID- 26940361 TI - Pediatric Tuberculosis in Nonimmigrants. PMID- 26940362 TI - Reliable vibrational wavenumbers for C=O and N-H stretchings of isolated and hydrogen-bonded nucleic acid bases. AB - The accurate prediction of vibrational wavenumbers for functional groups involved in hydrogen-bonded bridges remains an important challenge for computational spectroscopy. For the specific case of the C=O and N-H stretching modes of nucleobases and their oligomers, the paucity of experimental reference values needs to be compensated by reliable computational data, which require the use of approaches going beyond the standard harmonic oscillator model. Test computations performed for model systems (formamide, acetamide and their cyclic homodimers) in the framework of the second order vibrational perturbation theory (VPT2) confirmed that anharmonic corrections can be safely computed by global hybrid (GHF) or double hybrid (DHF) functionals, whereas the harmonic part is particularly challenging. As a matter of fact, GHFs perform quite poorly and even DHFs, while fully satisfactory for C=O stretchings, face unexpected difficulties when dealing with N-H stretchings. On these grounds, a linear regression for N-H stretchings has been obtained and validated for the heterodimers formed by 4 aminopyrimidine with 6-methyl-4-pyrimidinone (4APM-M4PMN) and by uracil with water. In view of the good performance of this computational model, we have built a training set of B2PLYP-D3/maug-cc-pVTZ harmonic wavenumbers (including linear regression scaling for N-H) for six-different uracil dimers and a validation set including 4APM-M4PMN, one of the most stable hydrogen-bonded adenine homodimers, as well as the adenine-uracil, adenine-thymine, guanine-cytosine and adenine-4 thiouracil heterodimers. Because of the unfavourable scaling of DHF harmonic wavenumbers with the dimensions of the investigated systems, we have optimized a linear regression of B3LYP-D3/N07D harmonic wavenumbers for the training set, which has been next checked against the validation set. This relatively cheap model, which shows very good agreement with experimental data (average errors of about 10 cm(-1)), paves the route toward a reliable analysis of spectroscopic signatures for larger polynucleotides. PMID- 26940363 TI - UniCarbKB: New database features for integrating glycan structure abundance, compositional glycoproteomics data, and disease associations. AB - BACKGROUND: UniCarbKB aims to provide a resource for the representation of mammalian glycobiology knowledge by providing a curated database of structural and experimental data, supported by a web application that allows users to easily find and view richly annotated information. The database comprises two levels of annotation (i) global-specific data of oligosaccharides released and characterised from single purified glycoproteins and (ii) information pertaining to site-specific glycan heterogeneity. Additional, contextual information is provided including structural, bibliographic, and taxonomic information for each entry. METHODS: Since the launch of UniCarbKB in 2012, we have continued to improve the organisation of our data model. Recently, we have extended our pipeline to collate structural and abundance changes of oligosaccharides in different human disease states and experimental models to extend our coverage of the human glycome. RESULTS: In this manuscript, we demonstrate the capability of UniCarbKB to store and query relative glycan abundance data using a set of published colorectal and prostate cancer cell lines as examples. Furthermore, we outline our strategy for managing large-scale glycoproteomics data, site-specific and glycan compositional data, and how this information is adding value to UniCarbKB. Finally, we summarise our efforts to improve the efficient representation of disease terms and associated changes in glycan heterogeneity by integrating the Disease Ontology. CONCLUSIONS: Updates and improvements to UniCarbKB have introduced unique features for storing and displaying glycosylation features of mammalian glycoproteins. The integration of site specific glycosylation data obtained from large-scale glycoproteomics and introduction of cell line studies will improve the analysis of glycoproteins and entire glycomes. GENERAL SIGNIFICANCE: Continuing advancements in analytical technologies and new data types are advancing disease-related glycomics. It is increasingly necessary to ensure all the data are comprehensively annotated. UniCarbKB was established with the mission of providing a resource for human glycobiology by capturing a wide range of data with corresponding annotations. This article is part of a Special Issue entitled "Glycans in personalised medicine" Guest Editor: Professor Gordan Lauc. PMID- 26940364 TI - dbPHCC: a database of prognostic biomarkers for hepatocellular carcinoma that provides online prognostic modeling. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common malignant cancers with a poor prognosis. For decades, more and more biomarkers were found to effect on HCC prognosis, but these studies were scattered and there were no unified identifiers. Therefore, we built the database of prognostic biomarkers and models for hepatocellular carcinoma (dbPHCC). METHODS: dbPHCC focuses on biomarkers which were related to HCC prognosis by traditional experiments rather than high-throughput technology. All of the prognostic biomarkers came from literatures issued during 2002 to 2014 in PubMed and were manually selected. dbPHCC collects comprehensive information of candidate biomarkers and HCC prognosis. RESULTS: dbPHCC mainly contains 567 biomarkers: 323 proteins, 154 genes, and 90 microRNAs. For each biomarker, the reference information, experimental conditions, and prognostic information are shown. Based on two available patient cohort data sets, an exemplified prognostic model was constructed using 15 phosphotransferases in dbPHCC. The web interface does not only provide a full range of browsing and searching, but also provides online analysis tools. dbPHCC is available at http://lifecenter.sgst.cn/dbphcc/ CONCLUSIONS: dbPHCC provides a comprehensive and convenient search and analysis platform for HCC prognosis research. GENERAL SIGNIFICANCE: dbPHCC is the first database to focus on experimentally verified individual biomarkers, which are related to HCC prognosis. Prognostic markers in dbPHCC have the potential to be therapeutic drug targets and may help in designing new treatments to improve survival of HCC patients. This article is part of a Special Issue entitled "System Genetics" Guest Editor: Dr. Yudong Cai and Dr. Tao Huang. PMID- 26940366 TI - TERMINAL FLOWER1 is a breeding target for a novel everbearing trait and tailored flowering responses in cultivated strawberry (Fragaria * ananassa Duch.). AB - The effects of daylength and temperature on flowering of the cultivated octoploid strawberry (Fragaria * ananassa Duch.) have been studied extensively at the physiological level, but information on the molecular pathways controlling flowering in the species is scarce. The flowering pathway has been studied at the molecular level in the diploid short-day woodland strawberry (F. vesca L.), in which the FLOWERING LOCUS T1 (FvFT1)-SUPPRESSOR OF OVEREXPRESSION OF CONSTANS1 (FvSOC1)-TERMINAL FLOWER1 (FvTFL1) pathway is essential for the correct timing of flowering. In this work, we show by transgenic approach that the silencing of the floral repressor FaTFL1 in the octoploid short-day cultivar 'Elsanta' is sufficient to induce perpetual flowering under long days without direct changes in vegetative reproduction. We also demonstrate that although the genes FaFT1 and FaSOC1 show similar expression patterns in different cultivars, the regulation of FaTFL1 varies widely from cultivar to cultivar and is correlated with floral induction, indicating that the transcription of FaTFL1 occurs at least partially independently of the FaFT1-FaSOC1 module. Our results indicate that changing the expression patterns of FaTFL1 through biotechnological or conventional breeding approaches could result in strawberries with specific flowering and runnering characteristics including new types of everbearing cultivars. PMID- 26940367 TI - Oxygen reduction catalyzed by gold nanoclusters supported on carbon nanosheets. AB - Nanocomposites based on p-mercaptobenzoic acid-functionalized gold nanoclusters, Au102(p-MBA)44, and porous carbon nanosheets have been fabricated and employed as highly efficient electrocatalysts for oxygen reduction reaction (ORR). Au102(p MBA)44 clusters were synthesized via a wet chemical approach, and loaded onto carbon nanosheets. Pyrolysis at elevated temperatures led to effective removal of the thiolate ligands and the formation of uniform nanoparticles supported on the carbon scaffolds. The nanocomposite structures were characterized by using a wide range of experimental techniques such as transmission electron microscopy, scanning electron microscopy, X-ray photoelectron spectroscopy, X-ray diffraction, UV-visible absorption spectroscopy, thermogravimetric analysis and BET nitrogen adsorption/desorption. Electrochemical studies showed that the composites demonstrated apparent ORR activity in alkaline media, and the sample with a 30% Au mass loading was identified as the best catalyst among the series, with a performance comparable to that of commercial Pt/C, but superior to those of Au102 nanoclusters and carbon nanosheets alone, within the context of onset potential, kinetic current density, and durability. The results suggest an effective approach to the preparation of high-performance ORR catalysts based on gold nanoclusters supported on carbon nanosheets. PMID- 26940365 TI - Vascular proteomics in metabolic and cardiovascular diseases. AB - The vasculature is essential for proper organ function. Many pathologies are directly and indirectly related to vascular dysfunction, which causes significant morbidity and mortality. A common pathophysiological feature of diseased vessels is extracellular matrix (ECM) remodelling. Analysing the protein composition of the ECM by conventional antibody-based techniques is challenging; alternative splicing or post-translational modifications, such as glycosylation, can mask epitopes required for antibody recognition. By contrast, proteomic analysis by mass spectrometry enables the study of proteins without the constraints of antibodies. Recent advances in proteomic techniques make it feasible to characterize the composition of the vascular ECM and its remodelling in disease. These developments may lead to the discovery of novel prognostic and diagnostic markers. Thus, proteomics holds potential for identifying ECM signatures to monitor vascular disease processes. Furthermore, a better understanding of the ECM remodelling processes in the vasculature might make ECM-associated proteins more attractive targets for drug discovery efforts. In this review, we will summarize the role of the ECM in the vasculature. Then, we will describe the challenges associated with studying the intricate network of ECM proteins and the current proteomic strategies to analyse the vascular ECM in metabolic and cardiovascular diseases. PMID- 26940369 TI - Randomized Trial of a Computerized Touch Screen Decision Aid to Increase Acceptance of Colonoscopy Screening in an African American Population with Limited Literacy. AB - The goal of this study was to assess the effectiveness of a touch screen decision aid to increase acceptance of colonoscopy screening among African American patients with low literacy, developed and tailored using perceptual mapping methods grounded in Illness Self-Regulation and Information-Communication Theories. The pilot randomized controlled trial investigated the effects of a theory-based intervention on patients' acceptance of screening, including their perceptions of educational value, feelings about colonoscopy, likelihood to undergo screening, and decisional conflict about colonoscopy screening. Sixty-one African American patients with low literacy, aged 50-70 years, with no history of colonoscopy, were randomly assigned to receive a computerized touch screen decision aid (CDA; n = 33) or a literacy appropriate print tool (PT; n = 28) immediately before a primary care appointment in an urban, university-affiliated general internal medicine clinic. Patients rated the CDA significantly higher than the PT on all indicators of acceptance, including the helpfulness of the information for making a screening decision, and reported positive feelings about colonoscopy, greater likelihood to be screened, and lower decisional conflict. Results showed that a touch screen decision tool is acceptable to African American patients with low iteracy and, by increasing intent to screen, may increase rates of colonoscopy screening. PMID- 26940368 TI - Pilot PET Study to Assess the Functional Interplay Between ABCB1 and ABCG2 at the Human Blood-Brain Barrier. AB - ABCB1 and ABCG2 work together at the blood-brain barrier (BBB) to limit brain distribution of dual ABCB1/ABCG2 substrates. In this pilot study we used positron emission tomography (PET) to assess brain distribution of two model ABCB1/ABCG2 substrates ([(11) C]elacridar and [(11) C]tariquidar) in healthy subjects without (c.421CC) or with (c.421CA) the ABCG2 single-nucleotide polymorphism (SNP) c.421C>A. Subjects underwent PET scans under conditions when ABCB1 and ABCG2 were functional and during ABCB1 inhibition with high-dose tariquidar. In contrast to the ABCB1-selective substrate (R)-[(11) C]verapamil, [(11) C]elacridar and [(11) C]tariquidar showed only moderate increases in brain distribution during ABCB1 inhibition. This provides evidence for a functional interplay between ABCB1 and ABCG2 at the human BBB and suggests that both ABCB1 and ABCG2 need to be inhibited to achieve substantial increases in brain distribution of dual ABCB1/ABCG2 substrates. During ABCB1 inhibition c.421CA subjects had significantly higher increases in [(11) C]tariquidar brain distribution than c.421CC subjects, pointing to impaired cerebral ABCG2 function. PMID- 26940370 TI - Recessive dystrophic epidermolysis bullosa caused by a de novo interstitial deletion spanning COL7A1 and a hemizygous splicing mutation in trans. AB - BACKGROUND: Recessive dystrophic epidermolysis bullosa (RDEB) is a rare heritable blistering skin condition caused by loss-of-function mutations in the COL7A1 gene. Incongruent gene transmission is occasionally reported in recessive diseases, and its underlying mechanism is often uniparental disomy (UPD). AIM: To understand the genetic basis of incongruent gene transmission in a Chinese family with RDEB, in which a discrepancy of COL7A1 genotyping was encountered during our mutation analysis. METHODS: We used a pCAS2 minigene-based in vitro splicing assay to confirm the pathogenicity of the splicing variant we identified in the proband. Next, a combination of genetic tools, including whole-genome SNP array analysis and multiplex ligation-dependent probe amplification copy number analysis, was used to unravel the cause of the discrepancy in the COL7A1 genotyping. RESULTS: Sanger sequencing identified a novel, single-peak mutation, c.4980+5G>C, in COL7A1 in the proband, which was heterozygous in his father and wild type in his mother. In vitro splicing assay showed that c.4980+5G>C was pathogenic and led to skipping of COL7A1 exon 53. SNP array analysis and multiplex ligation-dependent probe amplification of the proband's DNA revealed a maternally derived, de novo, interstitial deletion on chromosome 3p21.31, which removed COL7A1 and 15 flanking genes, excluding the possibility of UPD. CONCLUSION: Our findings favour an exceptionally rare event, namely a de novo COL7A1 microdeletion in concurrence with an inherited mutation in trans. This study should aid molecular diagnosis and genetic counselling of RDEB and possibly other recessive diseases in which genotyping discrepancy is encountered. PMID- 26940371 TI - A clinical and microbiological study on the enantiomers of delmopinol. AB - Objective The clinical part of this study aimed to investigate whether the racemate of delmopinol [(+/-)-delmopinol] is equivalent to its two enantiomers [(+)-delmopinol and (-)-delmopinol] with respect to efficiency and to determine and compare their pharmacokinetic properties. The purpose of the pre-clinical part was to elucidate possible differences in antimicrobial efficiency. Materials and methods The compounds were tested clinically in a double-blind, randomized, cross-over study comprising three treatment periods of 4 days each. The antimicrobial efficacy of the enantiomers was compared in vitro with respect to planktonic and biofilm bacteria of different species. Results No statistically significant differences in prevention of plaque formation were observed. Except for a somewhat higher systemic exposure in terms of AUC and Cmax indicated for ( )-delmopinol compared to (+)-delmopinol, the pharmacokinetic properties were similar. The most common adverse event was a transient anaesthetic feeling in the mouth. This event was reported with the same frequency for all three test solutions. The enantiomers showed similar antimicrobial effects on planktonic bacteria and their biofilms. Conclusions The enantiomers were found to be equally effective with respect to inhibition of plaque development and only minor differences were observed with respect to their pharmacokinetic properties. No differences could be observed in the adverse events reports. There is, therefore, no reason to use one of the enantiomers of delmopinol instead of the racemate. This was further supported by the antimicrobial tests. It is suggested that the combined action of cationic and neutral delmopinol is important for its effect on biofilms. PMID- 26940372 TI - SisPorto 4.0 - computer analysis following the 2015 FIGO Guidelines for intrapartum fetal monitoring. AB - SisPorto 4.0 is the most recent version of a program for the computer analysis of cardiotocographic (CTG) signals and ST events, which has been adapted to the 2015 International Federation of Gynaecology and Obstetrics (FIGO) guidelines for intrapartum foetal monitoring. This paper provides a detailed description of the analysis performed by the system, including the signal-processing algorithms involved in identification of basic CTG features and the resulting real-time alerts. PMID- 26940373 TI - Scandinavian multicenter study on the treatment of 168 patients with 230 intruded permanent teeth - a retrospective cohort study. AB - BACKGROUND/AIM: The aim of the study was to evaluate the survival of intruded permanent teeth related to treatment in a large number of patients, with special focus on development of pulp necrosis and replacement resorption (ankylosis related resorption). MATERIALS AND METHODS: The material consisted of 168 patients (mean age 9.6 years) with 230 intruded permanent teeth from dental trauma clinics in Copenhagen, Denmark, Stockholm, Sweden, and Oslo, Norway. The degree of intrusion was classified as mild (1-<3 mm), moderate (3-7 mm), and severe (>7 mm). Root development was categorized with respect to root formation and development of the apex into three groups of increasing tooth maturity: very immature, immature, and mature. RESULTS: Awaiting re-eruption was the treatment of choice in 107 teeth (47%), orthodontic repositioning in 28 (12%) and surgical repositioning in 95 (41%) teeth. Pulp necrosis was diagnosed in 173 teeth (75%), infection-related root resorption in 57 (25%) and replacement resorption in 50 teeth (22%). Very immature teeth, teeth diagnosed with mild intrusion, and teeth awaiting re-eruption had significantly (P < 0.05) fewer complications. In a stepwise discriminant function analysis, choice of treatment, root development, and degree of intrusion were significantly (P < 0.05) associated with the development of replacement resorption. Root development and degree of intrusion were significantly (P < 0.05) associated with the development of pulp necrosis. CONCLUSION: This study indicates that root development and degree of intrusion may be important for the development of pulp necrosis as well as replacement resorption, whereas choice of treatment only seems to influence the development of replacement resorption in intruded permanent teeth. Awaiting re-eruption resulted in the lowest risk for developing replacement resorption. PMID- 26940374 TI - Estimated daily intake of phenolics and antioxidants from green tea consumption in the Korean diet. AB - To estimate daily intake of total phenolics and flavonoids from green tea and the contribution of green tea to the antioxidant intake from the Korean diet, 24 commercial brands of green tea were selected and analyzed. Data from the Korea National Health and Nutrition Examination Survey (KNHANES) from 2008 and 2011 indicate that the green tea consumption in these 2 years was 2.8 g/tea drinker/day and 2.9 g/tea drinker/day, respectively. Based on data derived from direct measurements of green tea phenolics and the dataset of the 2008 KNHANES, we estimated the daily per tea drinker phenolics intake to be 172 mg gallic acid equivalents (GAE), the total flavonoids to be 43 mg catechin equivalents (CE) and the total antioxidants to be 267 mg vitamin C equivalents (VCE; 1,1-diphenyl-2 picrylhydrazyl (DPPH) assay) and 401 mg VCE (2,2'-azino-bis(3 ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS) assay). In 2011, we estimated the daily per tea drinker total phenolics intake to be 246 mg GAE, the total flavonoids to be 60 mg CE and the antioxidants to be 448 mg VCE (DPPH assay) and 630 mg VCE (ABTS assay). The daily intake of total phenolics, total flavonoids and antioxidants from green tea consumption increased from 2008 to 2011. PMID- 26940375 TI - Exocytosis and Spreading of Normal and Aberrant alpha-Synuclein. AB - It is now established that alpha-synuclein can be physiologically secreted to the extracellular space. In this sense, mechanisms that govern the secretion of the protein may be of importance in the initiation and progress of synucleinopathies. It is possible that increased secretion may aid the formation of toxic seeds extracellularly. Alternatively, reduced presence of extracellular alpha-synuclein due to impaired secretion may increase the intracellular load and trigger intracellular seeding. Once outside, alpha-synuclein can exert various paracrine actions on neighboring cells again by mechanisms that have not been fully elucidated. It has been demonstrated that, when applied extracellularly, alpha synuclein species can induce multiple neurotoxic and inflammatory responses, and aid the transmission of pathology between neurons. Still, the exact mechanism(s) by which secreted alpha-synuclein affects the homeostasis of other neurons is still not well understood. A portion of alpha-synuclein has been shown to be associated with the surface and lumen of exosomes which can transfer it to the surrounding cells, and potentially trigger seeding. Interestingly, increased exosome release has been linked to pathological situations of lysosomal dysfunction as observed in Parkinson's disease (PD). However, the possibility that the observed alpha-synuclein pathology spread is attributable to the passive diffusion of the initial injected alpha-synuclein strains cannot be excluded. Importantly, most of the studies that have so far addressed the role of extracellular alpha-synuclein have not employed naturally secreted forms of the protein. It is plausible that deregulation in the normal processing of secreted alpha-synuclein may aid the formation of "toxic" species and as such it may also be a causative risk factor for PD. In this capacity, elucidation of the underlying mechanisms that regulate the protein-levels of extracellular alpha synuclein becomes essential. Such mechanisms could involve its proteolytic clearance from the extracellular milieu. PMID- 26940376 TI - A novel alkaline keratinase from Bacillus subtilis DP1 with potential utility in cosmetic formulation. AB - The Bacillus subtilis DP1 was isolated from poultry farm soil at Anand district, India. The highest enzyme production (379.65U/ml) was obtained at pH 10.0, a temperature of 37 degrees C and a growth period of 72h. The extracellular keratinase was purified by gel filtration chromatography with 27.98 purification fold. Purity was also confirmed by High-Performance Liquid Chromatography (HPLC) analysis, where a major peak having retention time of 2.5min was obtained on C18 column using photo diode array detector. Purified keratinase was stable in a broad range of pH (8-12) and temperature (20-50 degrees C) with optimum at pH 10.0 and 37 degrees C. The metallic ions, Ca(2+) and Mg(2+) enhance keratinase activity. Secondary structure from Circular Dichroism (CD) spectra implies that purified keratinase is largely beta-pleated sheet rich protein. For preparation of dehairing cream formulation, compatibility studies of excipients were carried out. Fourier transform infrared spectroscopy (FTIR) spectra of sodium stearate, calcium carbonate and sodium lauryl sulphate shows no reactivity of functional groups and hence mixture was compatible for formulation of keratinase dehairing cream. Prepared biological depilatory was able to remove hair more efficiently compared to marketed formulations. PMID- 26940377 TI - Proteome analysis of Pueraria mirifica tubers collected in different seasons. AB - Pueraria mirifica-derived tuberous powder has been long-term consumed in Thailand as female hormone-replacement traditional remedies. The protein profiles of tubers collected in different seasons were evaluated. Phenol extraction, 2D-PAGE, and mass spectrometry were employed for tuberous proteome analysis. Out of the 322 proteins detected, over 59% were functionally classified as being involved in metabolism. The rest proteins were involved in defense, protein synthesis, cell structure, transportation, stress, storage, and also unidentified function. The proteins were found to be differentially expressed with respect to harvest season. Importantly, chalcone isomerase, isoflavone synthase, cytochrome p450, UDP-glycosyltransferase, and isoflavone reductase, which are all involved in the biosynthesis pathway of bioactive isoflavonoids, were most abundantly expressed in the summer-collected tubers. This is the first report on the proteomic patterns in P. mirifica tubers in relevant with seasonal variation. The study enlights the understanding of variance isoflavonoid production in P. mirifica tubers. PMID- 26940378 TI - The effect of exercise on vastus medialis oblique muscle architecture: An ultrasound investigation. AB - The vastus medialis oblique (VMO) is thought to be implicated in patellofemoral pain (PFP), and weakness in this portion of the vastus medialis muscle may lead to PFP. Management includes physiotherapy to strengthen the VMO. Although this intervention has been shown to be effective, the effects on the architecture of the muscle have not been investigated. This study aims to determine the changes in VMO architecture following a program of strengthening exercises. Twenty-one male participants underwent an initial ultrasound scan to measure the fiber angle and the insertion level of the VMO on the patella. Each subject then undertook a 6-week quadriceps femoris strengthening program; the scan and measurements were then repeated. A significant increase in VMO fiber angle and insertion length was observed. Average fiber angle increased by 5.24 degrees ; average insertion length increased by 2.7 mm. There was found to be a significant negative correlation between the initial values and the degree of change. Pearson's coefficient of correlation for measurements of patella length taken before and after exercise was 0.921, indicating a high degree of reliability. There was a significant positive correlation between fiber angle change and declared level of compliance (R(2) = 0.796). The results reported here indicate that physiotherapy leads to a significant change in VMO morphology. Given the inverse correlation noted between initial architectural parameters and the degree of change, we suggest that patients who would benefit most from physiotherapy can be identified in clinic using a simple ultrasound technique. Clin. Anat. 29:752-758, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26940379 TI - Investigational drugs for bladder pain syndrome (BPS) / interstitial cystitis (IC). AB - INTRODUCTION: Bladder pain syndrome (BPS)/interstitial cystitis (IC) is associated with sensory lower urinary tract symptoms. Unfortunately, many of the existing oral treatments are ineffective in most patients of BPS/IC, which is the motivation for developing new drugs and therapeutic approaches. This review covers the latest drugs that have been investigated in BPS/IC patients. Intravesical treatments offer the opportunity to directly target the painful bladder with less systemic side effects. AREAS COVERED: In this review, the authors analyze the existing literature supporting the treatment of BPS/IC with conventional drugs including heparin, hyaluronic acid, chondroitin sulfate, and dimethylsulfoxide (DMSO). Furthermore, investigational drugs such as tanezumab and adalimumab, capable of sequestering nerve growth factor (NGF), and Tumor necrosis factor-alpha (TNF- alpha) are discussed. Investigational treatments such as liposomes, botulinum toxin (BTX), liposomal BTX, PD-0299685 (a Ca(2+) channel alpha2delta ligand), continuous intravesical lidocaine, and AQX-1125 (a novel SHIP1 activating compound) are also covered. EXPERT OPINION: New investigational drugs offer promising improvements in clinical outcomes for BPS/IC patients; however, BPS/IC is a chronic pain disorder that is very vulnerable to a strong placebo effect. In addition, BPS/IC is a heterogeneous disorder that can be classified into several phenotypes. Since different phenotypes of BPS/IC respond differently to systemic and intravesical treatments, the authors believe that new drugs developed for BPS/IC are more likely to meet their predetermined clinical endpoints if the inclusion/exclusion criterion is tailored to specific phenotype of BPS/IC patients. PMID- 26940380 TI - Replacing the Affordable Care Act and Other Suggested Reforms. PMID- 26940381 TI - Microwave dielectric characterisation of 3D-printed BaTiO3/ABS polymer composites. AB - 3D printing is used extensively in product prototyping and continues to emerge as a viable option for the direct manufacture of final parts. It is known that dielectric materials with relatively high real permittivity-which are required in important technology sectors such as electronics and communications-may be 3D printed using a variety of techniques. Among these, the fused deposition of polymer composites is particularly straightforward but the range of dielectric permittivities available through commercial feedstock materials is limited. Here we report on the fabrication of a series of composites composed of various loadings of BaTiO3 microparticles in the polymer acrylonitrile butadiene styrene (ABS), which may be used with a commercial desktop 3D printer to produce printed parts containing user-defined regions with high permittivity. The microwave dielectric properties of printed parts with BaTiO3 loadings up to 70 wt% were characterised using a 15 GHz split post dielectric resonator and had real relative permittivities in the range 2.6-8.7 and loss tangents in the range 0.005 0.027. Permittivities were reproducible over the entire process, and matched those of bulk unprinted materials, to within ~1%, suggesting that the technique may be employed as a viable manufacturing process for dielectric composites. PMID- 26940382 TI - Effects of co-cropping Bidens pilosa (L.) and Tagetes minuta (L.) on bioaccumulation of Pb in Lactuca sativa (L.) growing in polluted agricultural soils. AB - Polluted agricultural soils are a serious problem for food safety, with phytoremediation being the most favorable alternative from the environmental perspective. However, this methodology is generally time-consuming and requires the cessation of agriculture. Therefore, the purpose of this study was to evaluate two potential phytoextractor plants (the native species Bidens pilosa and Tagetes minuta) co-cropped with lettuce growing on agricultural lead-polluted soils. The concentrations of Pb, as well as of other metals, were investigated in the phytoextractors, crop species, and in soils, with the potential risk to the health of consumers being estimated. The soil parameters pH, EC, organic matter percentage and bioavailable lead showed a direct relationship with the accumulation of Pb in roots. In addition, the concentration of Pb in roots of native species was closely related to Fe (B. pilosa, r = 0.81; T. minuta r = 0.75), Cu (T. minuta, r = 0.93), Mn (B. pilosa, r = 0.89) and Zn (B. pilosa, r = 0.91; T. minuta, r = 0.91). Our results indicate that the interaction between rhizospheres increased the phytoextraction of lead, which was accompanied by an increase in the biomass of the phytoextractor species. However, the consumption of lettuce still revealed a toxicological risk from Pb in all treatments. PMID- 26940383 TI - Safety and Efficacy of an Early Home-Based Walking Program After Receipt of an Initial Implantable Cardioverter-Defibrillator. AB - OBJECTIVE: To assess the safety and efficacy of an early home-based walking program for first-time implantable cardioverter-defibrillator (ICD) recipients. DESIGN: Pre-post intervention trial. SETTING: Institutional and private practice. PARTICIPANTS: Cardiac patients (N=301) with an initial ICD implantation for primary or secondary prevention; able to read, speak, and write English; and having access to telephone. INTERVENTIONS: Early home-based walking protocol implemented 1-month post-ICD implant. Exercise tolerance monitored by study nurses via telephone. MAIN OUTCOME MEASURES: Safety assessment was based on the frequency of ICD therapies and hospitalizations, and efficacy assessment was based on pedometer measures and self-report of ICD self-efficacy and physical activity. RESULTS: ICD recipients were on average 64.1+/-11.9 years old, predominantly men, and white, with an ejection fraction of <35% and a mean Charlson comorbidity score of 2.3+/-1.5. Nineteen individuals (6.3%) received 28 ICD shocks; 15 (53.6%) were appropriate and 13 (46.4%) inappropriate. Antitachycardia pacing therapies were delivered 72 times in 18 individuals (6%), with 61 (84.7%) being appropriate and 11 (15.3%) inappropriate. Five ICD shocks (2 appropriate and 3 inappropriate) and 2 antitachycardia pacing therapies occurred during walking. Five participants (2%) were hospitalized for an ICD shock, none of which was associated with walking. Average steps per day increased by 806 over 3 months. Perceived exercise self-efficacy improved significantly as did weekly exercise. Predictors of receiving any ICD shock were younger age (P<.0001), moderate to severe renal disease (P=.001), and lymphoma (P=.024). CONCLUSIONS: Early ambulation after an initial ICD was safe and effective, with few ICD shocks and improved efficacy. PMID- 26940385 TI - Deconstructing the Growth Hormone Receptor(GHR): Physical and Metabolic Phenotypes of Tissue-Specific GHR Gene-Disrupted Mice. AB - Growth hormone (GH)-induced signaling results in numerous effects in multiple tissues throughout the body. Elucidation of several of these effects has come from studies observing the various phenotypes of the GH receptor (GHR) gene disrupted (GHR-/-) mouse. These mice are dwarf and obese with increased insulin sensitivity, are resistant to cancer and diabetes, and have an extended lifespan. While these mice have proven to be a valuable tool for understanding the pleiotropic effects of GH, we and others have generated novel tissue-specific GHR gene-disrupted mouse lines that are now helping to further dissect the actions of GH on specific cells/tissues. In this chapter, we summarize the various phenotypes observed in these mice. PMID- 26940384 TI - Ghrelin Actions on Somatotropic and Gonadotropic Function in Humans. AB - Ghrelin, a 28 amino-acid octanoylated peptide predominantly produced by the stomach, was discovered to be the natural ligand of the type 1a GH secretagogue receptor (GHS-R1a). It was thus considered as a natural GHS additional to GHRH, although later on ghrelin has mostly been considered a major orexigenic factor. The GH-releasing action of ghrelin takes place both directly on pituitary cells and through modulation of GHRH from the hypothalamus; some functional antisomatostatin action has also been shown. However, ghrelin is much more than a natural GH secretagogue. In fact, it also modulates lactotroph and corticotroph secretion in humans as well as in animals and plays a relevant role in the modulation of the hypothalamic-pituitary-gonadal function. Several studies have indicated that ghrelin plays an inhibitory effect on gonadotropin pulsatility, is involved in the regulation of puberty onset in animals, and may regulate spermatogenesis, follicular development and ovarian cell functions in humans. In this chapter ghrelin actions on the GH/IGF-I and the gonadal axes will be revised. The potential therapeutic role of ghrelin as a treatment of catabolic conditions will also be discussed. PMID- 26940386 TI - Regulation of Growth Hormone by the Splanchnic Area. AB - The regulation of growth hormone (GH) was traditionally thought to be under the control of two main hypothalamic neuropeptides; GH-releasing hormone and somatostatin. In 1999, with the isolation of ghrelin, as a gastric-derived peptide with potent GH-releasing activity, concept of regulation of the somatotropic axis completely changed. In addition to its GH-releasing activity, ghrelin exhibited the capacity to modulate food intake and body weight. The role of this splanchnic factor in regulating GH as a nexus of energy balance control and GH are explored in this chapter. From a physiological standpoint, a novel mechanism of GH regulation mediated by ghrelin exists, implicating the peripheral modulation of the cannabinoid receptor. PMID- 26940387 TI - The Modern Criteria for Medical Management of Acromegaly. AB - Acromegaly is an insidious disorder characterized by excess secretion of growth hormone (GH) and elevated circulating levels of insulin-like growth factor-I (IGF I), generally caused by a pituitary adenoma. It is a rare disease associated with an average 10-year reduction in life expectancy due to metabolic, cardiovascular, and cerebrovascular comorbidities and reduced quality of life caused by paresthesias, fatigue, osteoarthralgia, or bone fractures. In 2000, Cortina Consensus Conference established general criteria for diagnosis and biochemical control of acromegaly, which have been revised in recent years, adapting them to emerging clinical evidences as well as the evolving assay techniques. Authors have proposed a binary definition of cure for acromegaly, where both GH and IGF-I are important determinants: the former is more linked to the presence of residual adenomatous tissue, while the latter to the peripheral activity of the disease. Control of tumor growth and complications is also an essential goal of treatment. Surgical, medical, and radiotherapy approaches are all valid alternatives. The surgical option is, however, unsuccessful in about 50% of patients. Somatostatin analogs (SRLs), octreotide LAR, and lanreotide ATG can inhibit cell growth, besides their beneficial effects on GH hypersecretion and on most comorbidities. Pasireotide is a new multireceptor-targeted SRL with reported superior biochemical efficacy to octreotide, due to higher affinity for SSTR-5, but potentially causing detrimental effects on glucose homeostasis. Pegvisomant could be a valid choice in all patients resistant to SRLs. It is a competitive GH antagonist, which efficaciously blocks IGF-I production, inhibiting the dimerization of GH receptor. Normal IGF-I levels represent, therefore, its only relevant efficacy endpoint, while only few cases of tumor growth on pegvisomant have been reported, so far. PMID- 26940388 TI - Genetic Predictors of Response to Different Medical Therapies in Acromegaly. AB - In the era of predictive medicine, management of diseases is evolving into a more personal and individualized approach, as more data are available regarding clinical, biochemical, radiological, molecular, histopathological, and genetic aspects. In the particular setting of acromegaly, which is a rare, chronic, debilitating, and disfiguring disease, an optimized approach deems even more necessary, especially because of an associated increased morbidity and mortality, the impact on patients' quality of life, and the increased cost of frequently necessary life-long treatments. In this paper, we review the available studies that address potential genetic influences on acromegaly, their role in the outcome, and response to treatments, as well as their contribution to the risk of developing side effects. We focus mainly on pharmacogenetic factors involved during treatment with dopamine agonists, somatostatin analogs, and pegvisomant. Specifically, mutations in dopamine receptors, somatostatin receptors, growth hormone receptors, and metabolic pathways involved in growth hormone action; polymorphisms in the insulin-like growth factor and the insulin-like growth factor binding proteins; and polymorphisms in other genes that may determine differences in the frequency of developing adverse events. PMID- 26940389 TI - Neurosurgical Treatment of Acromegaly. AB - Surgical removal of as much tumor mass as possible is usually considered the first step of treatment in acromegaly, unless the patients are unfit for surgery or refuse an operation. To date, in almost all cases, minimally invasive, transsphenoidal microscopic or endoscopic approaches are used. Whether a curative approach is feasible or a debulking procedure is planned, can be anticipated on the basis of preoperative magnetic resonance imaging. It mostly depends on localization, size, and the invasive character of the lesion. The surgical results depend on tumor-related factors such as size, extension, the presence or absence of invasion, and the magnitude of IGF-1 and growth hormone oversecretion, respectively. However, even surgeon-related factors such as experience and case load of the centers have been shown to strongly affect surgical results and complication rates. A reoperation can be considered at various stages in the treatment algorithm. There are several new technical gadgets which might aid in the surgical procedure: navigation, the Doppler probe, and variants of intraoperative imaging. PMID- 26940390 TI - Burden of Growth Hormone Deficiency and Excess in Children. AB - Longitudinal growth results from multifactorial and complex processes that take place in the context of different genetic traits and environmental influences. Thus, in view of the difficulties in comprehension of the physiological mechanisms involved in the achievement of normal height, our ability to make a definitive diagnosis of GH impairment still remains limited. There is a myriad of controversial aspects in relation to GH deficiency, mainly related to diagnostic controversies and advances in molecular biology. This might explain the diversity in therapeutic responses and may also serve as a rationale for new "nonclassical" treatment indications for GH. It is necessary to acquire more effective tools to reach an adequate evaluation, particularly while considering the long-term implications of a correct diagnosis, the cost, and safety of treatments. On the other hand, overgrowth constitutes a heterogeneous group of different pathophysiological situations including excessive somatic and visceral growth. There are overlaps in clinical and molecular features among overgrowth syndromes, which constitute the real burden for an accurate diagnosis. In conclusion, both GH deficiency and overgrowth are a great dilemma, still not completely solved. In this chapter, we review the most burdensome aspects related to short stature, GH deficiency, and excess in children, avoiding any details about well-known issues that have been extensively discussed in the literature. PMID- 26940391 TI - GH and Pituitary Hormone Alterations After Traumatic Brain Injury. AB - Traumatic brain injury (TBI) is a crucially important public health problem around the world, which gives rise to increased mortality and is the leading cause of physical and psychological disability in young adults, in particular. Pituitary dysfunction due to TBI was first described 95 years ago. However, until recently, only a few papers have been published in the literature and for this reason, TBI-induced hypopituitarism has been neglected for a long time. Recent studies have revealed that TBI is one of the leading causes of hypopituitarism. TBI which causes hypopituitarism may be characterized by a single head injury such as from a traffic accident or by chronic repetitive head trauma as seen in combative sports including boxing, kickboxing, and football. Vascular damage, hypoxic insult, direct trauma, genetic predisposition, autoimmunity, and neuroinflammatory changes may have a role in the development of hypopituitarism after TBI. Because of the exceptional structure of the hypothalamo-pituitary vasculature and the special anatomic location of anterior pituitary cells, GH is the most commonly lost hormone after TBI, and the frequency of isolated GHD is considerably high. TBI-induced pituitary dysfunction remains undiagnosed and therefore untreated in most patients because of the nonspecific and subtle clinical manifestations of hypopituitarism. Treatment of TBI-induced hypopituitarism depends on the deficient anterior pituitary hormones. GH replacement therapy has some beneficial effects on metabolic parameters and neurocognitive dysfunction. Patients with TBI without neuroendocrine changes and those with TBI-induced hypopituitarism share the same clinical manifestations, such as attention deficits, impulsion impairment, depression, sleep abnormalities, and cognitive disorders. For this reason, TBI-induced hypopituitarism may be neglected in TBI victims and it would be expected that underlying hypopituitarism would aggravate the clinical picture of TBI itself. Therefore, the diagnosis and treatment of unrecognized hypopituitarism due to TBI are very important not only to decrease morbidity and mortality due to hypopituitarism but also to alleviate the chronic sequelae caused by TBI. PMID- 26940392 TI - Effects of Growth Hormone on Bone. AB - PURPOSE: Describe the effects of growth hormone (GH) and insulin-like growth factor 1 (IGF-1) on the skeleton. FINDINGS: The GH and IGF-1 axis has pleiotropic effects on the skeleton throughout the lifespan by influencing bone formation and resorption. GH deficiency leads to decreased bone turnover, delayed statural growth in children, low bone mass, and increased fracture risk in adults. GH replacement improves adult stature in GH deficient children, increases bone mineral density (BMD) in adults, and helps to optimize peak bone acquisition in patients, during the transition from adolescence to adulthood, who have persistent GH deficiency. Observational studies suggest that GH replacement may mitigate the excessive fracture risk associated with GH deficiency. Acromegaly, a state of GH and IGF-1 excess, is associated with increased bone turnover and decreased BMD in the lumbar spine observed in some studies, particularly in patients with hypogonadism. In addition, patients with acromegaly appear to be at an increased risk of morphometric-vertebral fractures, especially in the presence of active disease or concurrent hypogonadism. GH therapy also has beneficial effects on statural growth in several conditions characterized by GH insensitivity, including chronic renal failure, Turner syndrome, Prader-Willi syndrome, postnatal growth delay in patients with intrauterine growth retardation who do not demonstrate catchup growth, idiopathic short stature, short stature homeobox-containing (SHOX) gene mutations, and Noonan syndrome. SUMMARY: GH and IGF-1 have important roles in skeletal physiology, and GH has an important therapeutic role in both GH deficiency and insensitivity states. PMID- 26940393 TI - Foreword. PMID- 26940395 TI - Mentoring rheumatology in APLAR countries through quiz. PMID- 26940394 TI - Food insecurity, mental health and quality of life among people living with HIV commencing antiretroviral treatment in Ethiopia: a cross-sectional study. AB - BACKGROUND: Studies from high-income settings show that both food insecurity and common mental disorders (CMDs) are associated with lower quality of life among people living with HIV (PLHIV). However, there is limited research among PLHIV in sub-Saharan Africa. In this study we tested the hypothesis that food insecurity and CMDs would be associated with poorer quality of life of PLHIV in Ethiopia. METHODS: A cross-sectional study was carried out with 348 PLHIV who were initiating antiretroviral therapy recruited from two primary care centers and a tertiary Hospital in southwest Ethiopia. Food insecurity, CMD, and quality of life were measured using instruments adapted and validated in Ethiopia (Household Food Insecurity Access Scale, Kessler-6, and WHOQOL-HIV-BREF-ETH, respectively). Multiple linear regression analysis was used to identify factors associated with quality of life after adjusting for confounders. RESULTS: The prevalence of severe household food insecurity among PLHIV was 38.7 %. After adjusting for confounders, severe food insecurity (beta = -3.24, 95 % CI: -6.19; -0.29) and higher levels of CMD symptoms (beta = -1.72 for each 1 point increase, 95 % CI: 1.94; -1.49) were associated with lower quality of life. Other factors associated with lower quality of life were advanced HIV disease (beta = -3.80, 95 % CI: 6.18; -1.42), and being underweight (BMI = 17.0 - 18.5 kg/m(2)) (beta = -3.45, 95 % CI: -6.18; -0.71). Owning more household assets was associated with higher quality of life (beta = 0.99 for owning one more asset, 95 % CI: 0.09; 1.89). CONCLUSION: Poor mental health and food insecurity are associated with lower quality of life in PLHIV. There is a need for longitudinal studies to elucidate the pathways linking CMD, food insecurity and quality of life. PMID- 26940396 TI - Action-space coding in social contexts. AB - In two behavioural experiments we tested whether performing a spatial task along with another agent changes space representation by rendering some reference frames more/less salient than others. To this end, we used a Simon task in which stimuli were presented in four horizontal locations thus allowing for spatial coding according to multiple frames of reference. In Experiment 1 participants performed a go/no-go Simon task along another agent, each being in charge of one response. In Experiment 2 they performed a two-choice Simon task along another agent, each being in charge of two responses. Results showed that when participants were in charge of only one response, stimulus position was coded only with reference to the centre of the screen hence suggesting that the co actor's response, or the position of the co-actor, was represented and used as a reference for spatial coding. Differently, when participants were in charge of two responses, no effect of the social context emerged and spatial coding relied on multiple frames of reference, similarly to when the Simon task is performed individually. These findings provide insights on the influence played by the interaction between the social context (i.e. the presence of others) and task features on individual performance. PMID- 26940397 TI - Effects of environmental temperature on the gut microbial communities of tadpoles. AB - Numerous studies have investigated the effects of diet, phylogeny and immune status on the gut microbial communities of animals. Most of these studies are conducted on endotherms, especially mammals, which maintain constant body temperature in the face of environmental temperature variability. However, the majority of animals and vertebrates are ectotherms, which often experience fluctuations in body temperature as a result of their environment. While there have been several studies investigating the gut microbial diversity of ectotherms, we lack an understanding of how environmental temperature affects these communities. Here, we used high-throughput sequencing to inventory the gut microbial communities of tadpoles exposed to cool (18 degrees C) or warm (28 degrees C) temperature treatments. We found that temperature significantly impacted the community structure and membership of the tadpole gut. Specifically, tadpoles in the warm treatment exhibited higher abundances of the phylum Planctomycetes and the genus Mycobacterium. These results may be due to the direct effects of temperature, or mediated through changes in host physiology. Given that environmental temperatures are expected to increase due to global climate change, understanding the effects of temperature on the diversity and function of gut microbial communities is critical. PMID- 26940398 TI - In defence of transpalatal, transpalatal-circumaxillary (transpterygopalatine) and transpalatal-circumaxillary-sublabial approaches to lateral extensions of juvenile nasopharyngeal angiofibroma. AB - BACKGROUND: Juvenile nasopharyngeal angiofibroma often presents with lateral extensions. In countries with limited resources, selection of a cost-effective and least morbid surgical approach for complete excision is challenging. METHODS: Sixty-three patients with juvenile nasopharyngeal angiofibroma, with lateral extensions, underwent transpalatal, transpalatal-circumaxillary (transpterygopalatine) or transpalatal-circumaxillary-sublabial approaches for resection. Clinico-radiological characteristics, tumour volume and intra operative bleeding were recorded. RESULTS: The transpalatal approach was suitable for extensions involving medial part of pterygopalatine fossa; transpalatal circumaxillary for extensions involving complete pterygopalatine fossa, with or without partial infratemporal fossa; and transpalatal-circumaxillary-sublabial for extensions involving complete infratemporal fossa, even cheek or temporal fossa up to zygomatic arch. Haemorrhage was greatest with the transpalatal circumaxillary-sublabial approach, followed by transpalatal approach and transpalatal-circumaxillary approach (1212, 950 and 777 ml respectively). Tumour size (volume) was greatest with the transpalatal-circumaxillary approach, followed by transpalatal-circumaxillary-sublabial approach and transpalatal approach (40, 34 and 29 mm3). There was recurrence in three cases and residual disease in two cases. Long-term morbidity included small palatal perforation (n = 1), trismus (n = 1) and atrophic rhinitis (n = 2). CONCLUSION: These modified techniques, performed with endoscopic assistance under hypotensive anaesthesia, without embolisation, offer a superior option over other open procedures with regard to morbidity and recurrences. PMID- 26940399 TI - Occupational contact allergy to components of polyester resin systems. AB - BACKGROUND: Allergic contact dermatitis caused by polyester resin is considered to be rare. OBJECTIVES: To describe 11 new patients diagnosed with occupational contact allergy to components of polyester resin systems in 1994-2009. METHODS: Data on occupations, patch test results, symptoms and exposure to polyester products were retrieved from patient files, covering 1994 to February 2015. RESULTS: Five patients reacted to unsaturated polyester resin putties. In 3 of these cases, putties were considered to be the main cause of the dermatitis. Four patients had cobalt allergy resulting from cobalt salts that were used as accelerators in polyester resins. Three patients were sensitized to triglycidyl isocyanurate (TGIC), a cross-linker in polyester powder paints. CONCLUSIONS: Two product types are of particular importance in contact allergy to polyester resin: powder paints cured by heat with TGIC as the cross-linker, and car putties. Car putties are used not only in repair car painting, but also in some industrial trades to smoothen surfaces before painting. As commercial patch test substances of polyester resin putties are lacking, patients' own products need to be tested. Cobalt salts are used in several types of polyester resin product as accelerators, and these must be considered as a possible cause of cobalt sensitization. PMID- 26940400 TI - A New Hysteroscopic Risk Scoring System for Diagnosing Endometrial Hyperplasia and Adenocarcinoma. AB - STUDY OBJECTIVE: To develop a new hysteroscopic morphologic scoring system that helps physicians, especially those who have less experience, to make a differential diagnosis among normal endometrium (NE), endometrial hyperplasia, and endometrial carcinoma. DESIGN: A retrospective study (Canadian Task Force Classification II). SETTING: An office hysteroscopy service. PATIENTS: A total of 435 endometrial biopsies were included in the study: 201 NE, 160 endometrial hyperplasia without atypia (EH), 30 atypical endometrial hyperplasia (AEH), and 44 endometrial cancer (EC). INTERVENTIONS: The authors retrospectively evaluated all videos of diagnostic hysteroscopies performed before endometrial biopsies to note endometrial morphologic parameters suggestive of pathology. Principal significant variables were selected by means of the chi-square test (p < .05) and integrated into an ordinal multivariate analysis. Through the estimate of the beta coefficient, a score was obtained to be appointed to each of the selected variables, and characteristic intervals of each of the endometrial lesions were created. MEASUREMENTS AND MAIN RESULTS: The scoring system showed a sensitivity and specificity of 71.1% and 80%, 48.7% and 82.5%, 63.3% and 90.4%, and 95.4% and 98.2% regarding NE, EH, AEH, and EC, respectively. The positive predictive values and negative predictive values, respectively, were 76.8% and 80% for NE, 62% and 73.5% for EH, 32.7% and 97% for AEH, and 85.7% and 99.5% for EC. CONCLUSIONS: The proposed scoring system showed good diagnostic performance, especially in relation to endometrial cancer, and may represent a useful diagnostic tool, mainly for operators with less experience. PMID- 26940401 TI - Short-Term Impact of Laparoscopic Cystectomy on Ovarian Reserve Tests in Bilateral and Unilateral Endometriotic and Nonendometriotic Cysts. AB - STUDY OBJECTIVE: To evaluate the short-term changes in ovarian reserve markers after laparoscopic cystectomy performed for endometriotic and nonendometriotic cysts. DESIGN: Prospective case-control study (Canadian Task Force classification II-2). SETTING: The Reproductive Endocrinology Clinic of a training and research hospital. PATIENTS: Thirty-four women with endometrioma >= 4 mm (group 1) and 33 women with nonendometriotic cysts of matched size (group 2) who underwent surgery during the same period. INTERVENTIONS: The follicular phase follicle-stimulating hormone (FSH), estradiol (E2), and antimullerian hormone (AMH) levels and the antral follicle count (AFC) of both groups were analyzed preoperatively and 2 months after laparoscopic cystectomy. The pre- and postoperative values were compared within the same group and between the 2 groups. MEASUREMENT AND MAIN RESULTS: Preoperative FSH and E2 levels were similar in both groups. However, preoperative AMH levels and AFC were significantly lower in group 1 (endometrioma) compared with group 2 (nonendometrioma; p = .004 and p = .025, respectively). In both groups there was a significant decrease in the AMH levels after surgery (3.1 +/- 1.9 ng/mL to 2.5 +/- 1.6 ng/mL, p < .001, and 5.7 +/- 3.7 ng/mL to 4.8 +/- 3.3 ng/mL, p = .04). AMH levels exhibited a significant decrease in the unilateral and bilateral endometrioma groups after cystectomy (p < .001 and p = .025, respectively). However, preoperative and postoperative changes in AMH and AFC were similar in groups 1 and 2 for both unilateral and bilateral cysts (p = .586 and p = .267). CONCLUSION: Preoperative AMH and AFC levels are lower in both unilateral and bilateral endometriomas compared with nonendometriotic cysts. The AMH levels decreased after cystectomy in both endometriotic and nonendometriotic cysts. However, in the short-term period the amount of change in ovarian reserve tests in both unilateral and bilateral cysts was similar for both endometrioma and nonendometriotic cysts. PMID- 26940403 TI - Tougher penalties for animal cruelty in Northern Ireland. PMID- 26940402 TI - Unexpected factors affecting the excitability of human motoneurones in voluntary and stimulated contractions. AB - KEY POINTS: The output of human motoneurone pools decreases with fatiguing exercise, but the mechanisms involved are uncertain. We explored depression of recurrent motoneurone discharges (F-waves) after sustained maximal voluntary contractions (MVCs). MVC depressed the size and frequency of F-waves in a hand muscle but a submaximal contraction (at 50% MVC) did not. Surprisingly, activation of the motoneurones antidromically by stimulation of the ulnar nerve (at 20 or 40 Hz) did not depress F-wave area or persistence. Furthermore, a sustained (3 min) MVC of a hand muscle depressed F-waves in its antagonist but not in a remote hand muscle. Our findings suggest that depression of F-waves after voluntary contractions is not simply due to repetitive activation of the motoneurones but requires descending voluntary drive. Furthermore, this effect may depress nearby, but not distant, spinal motoneurone pools. ABSTRACT: There are major spinal changes induced by repetitive activity and fatigue that could contribute to 'central' fatigue but the mechanisms involved are poorly understood in humans. Here we confirmed that the recurrent motoneuronal discharge (F-wave) is reduced during relaxation immediately after a sustained maximal voluntary contraction (MVC) of an intrinsic hand muscle (abductor digiti minimi, ADM) and explored the relationship between motoneurone firing and the depression of F waves in three ways. First, the depression (in both F-wave area and F-wave persistence) was present after a 10 s MVC (initial decrease 36.4 +/- 19.1%; mean +/- SD) but not after a submaximal voluntary contraction at 50% maximum. Second, to evoke motoneurone discharge without volitional effort, 10 s tetanic contractions were produced by supramaximal ulnar nerve stimulation at the elbow at physiological frequencies of 25 and 40 Hz. Surprisingly, neither produced depression of F-waves in ADM to test supramaximal stimulation of the ulnar nerve at the wrist. Finally, a sustained MVC (3 min) of the antagonist to ADM (4th palmar interosseous) depressed F-waves in the anatomically close ADM (20 +/- 18.2%) but not in the more remote first dorsal interosseous on the radial side of the hand. We argue that depression of F-waves after voluntary contractions may not be due to repetitive activation of the motoneurones but requires descending voluntary drive. Furthermore, this effect may depress nearby, but not distant, spinal motoneurone pools and it reveals potentially novel mechanisms controlling the output of human motoneurones. PMID- 26940404 TI - MEPs seek enhanced measures to tackle the illegal pet trade. PMID- 26940405 TI - VN Futures project launched. PMID- 26940406 TI - Isle of Man achieves OTF status. PMID- 26940408 TI - Animal health law - one vote from approval. PMID- 26940407 TI - MPs call for data on racing greyhound injuries to be made public. PMID- 26940409 TI - Not your usual delivery. PMID- 26940410 TI - 'Open dialogue' needed on potential uptake of bluetongue vaccination. PMID- 26940411 TI - Laboratory twinning to build capacity for rabies diagnosis. AB - In 2009, the UK's OIE Reference Laboratory for rabies, based at the APHA in Weybridge, was awarded a project to twin with the Changchun Veterinary Research Institute in the People's Republic of China to help the institute develop the skills and methods necessary to become an OIE Reference Laboratory itself. Here, Tony Fooks, Trevor Drew and Changchun Tu describe the OIE's twinning project and the success that has since been realised in China. PMID- 26940412 TI - Campaign to eliminate human rabies deaths by 2030. PMID- 26940413 TI - Veterinary medicines update. AB - The following information has been produced for Veterinary Record by the Veterinary Medicines Directorate (VMD) to provide an update for veterinary surgeons on recent changes to marketing authorisations for veterinary medicines in the UK and on other relevant issues. PMID- 26940414 TI - Hypomagnesaemia in suckler cows. AB - Hypomagnesaemia in housed and grazing suckler cows. Coronavirus infection in cows. Suspected nitrite toxicity in lambs associated with feeding broccoli. Maedi visna in ewes. Mycotic pneumonia in a wildcat. These are among matters discussed in the disease surveillance report for November 2015 from SAC Consulting: Veterinary Services (SAC C VS). PMID- 26940415 TI - Treatment of clinical mastitis in dairy cattle. PMID- 26940416 TI - Babesia canis detected in dogs and associated ticks from Essex. PMID- 26940417 TI - Left displaced abomasum correction in three preweaned calves. PMID- 26940426 TI - Making a dream come true. AB - Rachel Wright qualified as a veterinary nurse in England and volunteered extensively in developing countries before setting up an animal hospital in Rajasthan in India. PMID- 26940427 TI - Ten-minute chat. AB - Tim Hutchinson is a managing partner at Larkmead Veterinary Group in Oxfordshire. He is also the Small Animal Director of XLVets, which last year celebrated its 10th anniversary. PMID- 26940429 TI - Anakinra long-term efficacy and safety in the management of Schnitzler's syndrome and latent tuberculosis infection. PMID- 26940428 TI - Metabolite Modulation in Human Plasma in the Early Phase of Acclimatization to Hypobaric Hypoxia. AB - The exposure of healthy subjects to high altitude represents a model to explore the pathophysiology of diseases related to tissue hypoxia. We explored a plasma metabolomics approach to detect alterations induced by the exposure of subjects to high altitude. Plasma samples were collected from 60 subjects both on plain and at high altitude (5300 m). Metabolite profiling was performed by gas chromatography-mass spectrometry (GC-MS) and ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QTOFMS) in conjunction with univariate and multivariate statistical analyses. ELISA assays were further employed to measure the levels of several relevant enzymes together with perturbed metabolic pathways. The results showed that hypobaric hypoxia caused significant and comprehensive metabolic changes, as represented by significant changes of 44 metabolites and 4 relevant enzymes. Using MetaboAnalyst 3.0, it was found that several key metabolic pathways were acutely perturbed. In addition, 5 differentially expressed metabolites in pre-exposure samples from the acute mountain sickness-susceptible (AMS-S) group compared with those from the AMS-resistant (AMS-R) group are identified, which warrant further validation as potential predictive biomarkers for AMS-S individuals. These results provide new insights for further understanding the pathophysiological mechanism of early acclimatization to hypobaric hypoxia and other diseases correlated to tissue hypoxia. PMID- 26940430 TI - Functional neuroimaging studies in functional dyspepsia patients: a systematic review. AB - BACKGROUND: There is increasing evidence in support of the presence of abnormal central changes (compared to healthy controls) in functional dyspepsia (FD) in addition to the peripheral changes in gastrointestinal tract. PURPOSE: This systematic review aims to provide an integrative understanding of the abnormal functional brain activity, visceral sensation, dyspeptic symptoms, and psychological changes of FD. Electronic and hand searches were conducted to identify functional neuroimaging studies involving FD patients. Sixteen studies were selected and divided into three categories: 10 resting state studies, three visceral distention studies, and three acupuncture studies. Changes were reported in several brain areas in FD patients including the frontal cortex, somatosensory cortex, insula, anterior cingulate cortex, thalamus, hippocampus, and amygdala. These brain activity changes were associated with visceral hypersensitivity, dyspeptic symptoms, poorer quality of life, anxiety, and depression. The results show that FD is associated with functional abnormalities in sensory and pain modulation, emotion, saliency, and homeostatic processing regions. The diversity of conditions, heterogeneous results, poorly standardized diagnoses of FD, and various comorbidities may be responsible for the variability in the results. PMID- 26940431 TI - New THAP1 mutation and role of putative modifier in TOR1A. AB - OBJECTIVES: The prevalence of DYT1 (mutation in TOR1A) and DYT6 (mutation in THAP1) may vary in different populations, which can have important implications in clinical investigation. Our goal was to characterize patients with inherited and isolated dystonia and determine the frequency of mutations responsible for DYT1 and DYT6 in Brazilian patients. METHODS: Two movement disorder specialists examined 78 patients with idiopathic isolated dystonia using a standardized questionnaire, before sequencing TOR1A and THAP1 genes. RESULTS: Clinically, our cohort was similar to those described in the international literature. Molecular studies of 68 subjects revealed only one potentially deleterious variant in THAP1 (1/68 patients, 1.47%). This was a novel 10-bp deletion at the end of exon 1, g.5308_5317del (ng_011837.1), which is predicted to create an alternative splicing and the insertion of a premature stop codon. Although we did not observe any potentially deleterious mutations in TOR1A, we found the missense variant rs1801968 (TOR1A p.D216H), previously reported as either a modifier of dystonia phenotype or a predisposing factor for dystonia. However, we did not identify any phenotypic impact related to the missense variant rs1801968 (P = 0.3387). CONCLUSIONS: Although clinically similar to most cohorts with dystonia worldwide, the classical mutation (c.907_909delGAG) in TOR1A (causing DYT1) is absent in our patients. However, we found a potentially deleterious THAP1 mutation not previously reported. In addition, we found no association of rs1801968 with dystonia. PMID- 26940433 TI - Synaptic roles for phosphomannomutase type 2 in a new Drosophila congenital disorder of glycosylation disease model. AB - Congenital disorders of glycosylation (CDGs) constitute a rapidly growing family of human diseases resulting from heritable mutations in genes driving the production and modification of glycoproteins. The resulting symptomatic hypoglycosylation causes multisystemic defects that include severe neurological impairments, revealing a particularly critical requirement for tightly regulated glycosylation in the nervous system. The most common CDG, CDG-Ia (PMM2-CDG), arises from phosphomannomutase type 2 (PMM2) mutations. Here, we report the generation and characterization of the first Drosophila CDG-Ia model. CRISPR generated pmm2-null Drosophila mutants display severely disrupted glycosylation and early lethality, whereas RNAi-targeted knockdown of neuronal PMM2 results in a strong shift in the abundance of pauci-mannose glycan, progressive incoordination and later lethality, closely paralleling human CDG-Ia symptoms of shortened lifespan, movement impairments and defective neural development. Analyses of the well-characterized Drosophila neuromuscular junction (NMJ) reveal synaptic glycosylation loss accompanied by defects in both structural architecture and functional neurotransmission. NMJ synaptogenesis is driven by intercellular signals that traverse an extracellular synaptomatrix and are co regulated by glycosylation and matrix metalloproteinases (MMPs). Specifically, trans-synaptic signaling by the Wnt protein Wingless (Wg) depends on the heparan sulfate proteoglycan (HSPG) co-receptor Dally-like protein (Dlp), which is regulated by synaptic MMP activity. Loss of synaptic MMP2, Wg ligand, Dlp co receptor and downstream trans-synaptic signaling occurs with PMM2 knockdown. Taken together, this Drosophila CDG disease model provides a new avenue for the dissection of cellular and molecular mechanisms underlying neurological impairments and is a means by which to discover and test novel therapeutic treatment strategies. PMID- 26940434 TI - Inheritance of steroid-independent male sexual behavior in male offspring of B6D2F1 mice. AB - The importance of gonadal steroids in modulating male sexual behavior is well established. Individual differences in male sexual behavior, independent of gonadal steroids, are prevalent across a wide range of species, including man. However, the genetic mechanisms underlying steroid-independent male sexual behavior are poorly understood. A high proportion of B6D2F1 hybrid male mice demonstrates steroid-independent male sexual behavior (identified as "maters"), providing a mouse model that opens up avenues of investigation into the mechanisms regulating male sexual behavior in the absence of gonadal hormones. Recent studies have revealed several proteins that play a significant factor in regulating steroid-independent male sexual behavior in B6D2F1 male mice, including amyloid precursor protein (APP), tau, and synaptophysin. The specific goals of our study were to determine whether steroid-independent male sexual behavior was a heritable trait by determining if it was dependent upon the behavioral phenotype of the B6D2F1 sire, and whether the differential expression of APP, tau, and synaptophysin in the medial preoptic area found in the B6D2F1 sires that did and did not mate after gonadectomy was similar to those found in their male offspring. After adult B6D2F1 male mice were bred with C57BL/6J female mice, they and their male offspring (BXB1) were orchidectomized and identified as either maters or "non-maters". A significant proportion of the BXB1 maters was sired only from B6D2F1 maters, indicating that the steroid-independent male sexual behavior behavioral phenotype of the B6D2F1 hybrid males, when crossed with C57BL/6J female mice, is inherited by their male offspring. Additionally, APP, tau, and synaptophysin were elevated in in the medial preoptic area in both the B6D2F1 and BXB1 maters relative to the B6D2F1 and BXB1 non-maters, respectively, suggesting a potential genetic mechanism for the inheritance of steroid-independent male sexual behavior. PMID- 26940436 TI - Capillary electrophoretic focusing of covalently derivatized protein induced by surfactant. AB - In this communication, we present a very simple strategy to focus covalently derivatized proteins for high sensitivity CE analysis by LIF detection. We demonstrated that the covalently tagged protein can be focused just by adding SDS at a concentration above the CMC in the derivatized sample. Under specific injection conditions, SDS concentration below the CMC is also sufficient to induce the focusing of the tagged protein. This method allows the quantification and detection of the covalently tagged protein in a narrow zone with an efficiency approaching 220 000 plates/m. Very good linearity was obtained for the ubiquitin in a concentration range of 2-25 MUM. PMID- 26940437 TI - INVESTIGATION OF PARTIAL VOLUME EFFECT IN DIFFERENT PET/CT SYSTEMS: A COMPARISON OF RESULTS USING THE MADEIRA PHANTOM AND THE NEMA NU-2 2001 PHANTOM. AB - Positron emission tomography combined with computed tomography (PET/CT) is a quantitative technique used for diagnosing various diseases and for monitoring treatment response for different types of tumours. However, the accuracy of the data is limited by the spatial resolution of the system. In addition, the so called partial volume effect (PVE) causes a blurring of image structures, which in turn may cause an underestimation of activity of a structure with high activity content. In this study, a new phantom, MADEIRA (Minimising Activity and Dose with Enhanced Image quality by Radiopharmaceutical Administrations) for activity quantification in PET and single photon emission computed tomography (SPECT) was used to investigate the influence on the PVE by lesion size and tumour-to-background activity concentration ratio (TBR) in four different PET/CT systems. These measurements were compared with data from measurements with the NEMA NU-2 2001 phantom. The results with the MADEIRA phantom showed that the activity concentration (AC) values were closest to the true values at low ratios of TBR (<10) and reduced to 50 % of the actual AC values at high TBR (30-35). For all scanners, recovery of true values became closer to 1 with an increasing diameter of the lesion. The MADEIRA phantom showed good agreement with the results obtained from measurements with the NEMA NU-2 2001 phantom but allows for a wider range of possibilities in measuring image quality parameters. PMID- 26940435 TI - Intratumoral heterogeneity identified at the epigenetic, genetic and transcriptional level in glioblastoma. AB - Heterogeneity is a hallmark of glioblastoma with intratumoral heterogeneity contributing to variability in responses and resistance to standard treatments. Promoter methylation status of the DNA repair enzyme O(6)-methylguanine DNA methyltransferase (MGMT) is the most important clinical biomarker in glioblastoma, predicting for therapeutic response. However, it does not always correlate with response. This may be due to intratumoral heterogeneity, with a single biopsy unlikely to represent the entire lesion. Aberrations in other DNA repair mechanisms may also contribute. This study investigated intratumoral heterogeneity in multiple glioblastoma tumors with a particular focus on the DNA repair pathways. Transcriptional intratumoral heterogeneity was identified in 40% of cases with variability in MGMT methylation status found in 14% of cases. As well as identifying intratumoral heterogeneity at the transcriptional and epigenetic levels, targeted next generation sequencing identified between 1 and 37 unique sequence variants per specimen. In-silico tools were then able to identify deleterious variants in both the base excision repair and the mismatch repair pathways that may contribute to therapeutic response. As these pathways have roles in temozolomide response, these findings may confound patient management and highlight the importance of assessing multiple tumor biopsies. PMID- 26940438 TI - OPERATOR DEPENDENCY OF THE RADIATION EXPOSURE IN CARDIAC INTERVENTIONS: FEASIBILITY OF ULTRA LOW DOSE LEVELS. AB - INTRODUCTION: Mean radiation exposure in invasive cardiology varies greatly between different centres and interventionists. The International Commission on Radiological Protection and the EURATOM Council stipulate that, despite reference values, 'All medical exposure for radiodiagnostic purposes shall be kept as low as reasonably achievable' (ALARA). The purpose of this study is to establish the effects of the routine application of ALARA principles and to determine operator and procedure impact on radiation exposure in interventional cardiology. MATERIALS AND METHODS: A total of 240 consecutive cardiac interventional procedures were analysed. Five operators performed the procedures, two of whom were working in accordance with ALARA principles (Group 1 operators) with the remaining three working in a standard manner (Group 2 operators). Radiation exposure levels of these two groups were compared. RESULTS: Total fluoroscopy time and the number of radiographic runs were similar between groups. However, dose area product and cumulative dose were significantly lower in Group 1 when compared with Group 2. Radiation levels of Group 1 were far below even the reference levels in the literature, thus representing an ultra-low-dose radiation exposure in interventional cardiology. CONCLUSION: By use of simple radiation reducing techniques, ultra-low-dose radiation exposure is feasible in interventional cardiology. Achievability of such levels depends greatly on operator awareness, desire, knowledge and experience of radiation protection. PMID- 26940439 TI - BENCHMARKING OF CT FOR PATIENT EXPOSURE OPTIMISATION. AB - Patient dose optimisation in computed tomography (CT) should be done using clinically relevant tasks when dealing with image quality assessments. In the present work, low-contrast detectability for an average patient morphology was assessed on 56 CT units, using a model observer applied on images acquired with two specific protocols of an anthropomorphic phantom containing spheres. Images were assessed using the channelised Hotelling observer (CHO) with dense difference of Gaussian channels. The results were computed by performing receiver operating characteristics analysis (ROC) and using the area under the ROC curve (AUC) as a figure of merit. The results showed a small disparity at a volume computed tomography dose index (CTDIvol) of 15 mGy depending on the CT units for the chosen image quality criterion. For 8-mm targets, AUCs were 0.999 +/- 0.018 at 20 Hounsfield units (HU) and 0.927 +/- 0.054 at 10 HU. For 5-mm targets, AUCs were 0.947 +/- 0.059 and 0.702 +/- 0.068 at 20 and 10 HU, respectively. The robustness of the CHO opens the way for CT protocol benchmarking and optimisation processes. PMID- 26940440 TI - OCCUPATIONAL EXPOSURE TO RADON IN DIFFERENT KINDS OF NON-URANIUM MINES. AB - For more accurate assessments of the occupational exposure to radon for miners, the individual monitoring was conducted by using an improved passive integrating (222)Rn monitor. A total of 120 miners in 3 different kinds of mines were monitored throughout a year. The results showed that the individual exposure to radon significantly varied with types of mines and work. Compared with the exposure to coal miners, the exposure to copper miners was much higher. Furthermore, it was found that the exposure might be overestimated if the environmental (222)Rn monitored by the passive integrating monitors was used for assessment. The results indicate that the individual monitoring of radon is necessary for an accurate assessment of radon exposure to miners, and radon exposure to non-uranium miners should also be assessed from the viewpoint of radiation protection. PMID- 26940441 TI - EFFICACY OF AN ADDITIONAL MOBILE LEADED SHIELD ON OPERATOR RADIATION DURING PERCUTANEOUS CORONARY ANGIOGRAPHY. AB - Operator radiation protection during percutaneous coronary angiography (CA) is a growing concern in the catheterisation laboratory (cath lab). The purpose of this study was to evaluate the efficacy of an additional mobile leaded shield on operator radiation exposure during diagnostic CA. The study involved two operators from the same cath lab and patients scheduled for diagnostic coronary catheterisation over a period of 2 months. Procedures were performed with standard radiation equipment during the first month. An additional mobile lead shield was added during the second month. Radiation exposure was measured by three dosimeters positioned on the operator's left hand, on their chest under the lead apron and on lead glasses. The intra-operator results were compared. Ninety nine per cent of the procedures were carried out by radial access. For Operators 1 and 2, the mobile shield, respectively, decreased the radiation dose to the eyes by 43 and 33 % and to the hands by 61 and 83 %. Thorax dose was less than the minimum measurable dose (<0.01 mSv) for each operator. There was no significant difference in total procedure duration, fluoroscopy time or contrast dose required between the two groups of patients. Improved operator radiation protection is an important issue in the face of increased occupational doses. Mobile leaded shield, combined with standard preventive measures, seems to be an effective additional option to reduce the radiation exposure during diagnostic CA. PMID- 26940442 TI - HIGH-DOSE 131I-MIBG THERAPIES IN CHILDREN: FEASIBILITY, PATIENT DOSIMETRY AND RADIATION EXPOSURE TO WORKERS AND FAMILY CAREGIVERS. AB - The objective of the present multicentric phase II study (MIITOP) was to determine the response rate, survival and toxicity of tandem infusions of 131I meta-iodobenzylguanidine (mIBG) and topotecan in children with relapsed/refractory neuroblastoma. High-dose 131I-mIBG therapy programme requires a deal of planning, availability of hospital resources and the commitment of individuals with training and expertise in multiple disciplines. Here in the present study, procedures and the results of patient's dosimetry, as well as family and worker's exposures, were reported for the patients treated in Lille. A total of 15 children were treated with 131I-mIBG between 2009 and 2011 according to the MIITOP protocol. High activity of 131I-mIBG (444 MBq kg-1) was administered on Day 0. In vivo dosimetry was used to calculate a second activity, to be given on Day 21, to obtain a total whole body absorbed dose of 4 Gy. Family and worker's exposures were performed too. The injected activity by treatment was from 703 to 11470 MBq. Total whole body absorbed dose by patient ranged from 2.74 to 5.2 Gy. Concerning relatives, whole body exposure ranged from 0.018 to 2.8 mSv. The mean whole body exposure of the radiopharmacist was 4.4 nSv MBq-1, and the mean exposure of fingers ranged from 0.18 to 0.24 uSv MBq-1 according to each finger. The mean whole body exposure was 33.6 and 20.2 uSv d-1 per person, for night nurses and day nurses, respectively. Exposure of doctors was less than 5 uSv d-1. Under strict radiation protection precautions, this study shows the feasibility of high-activity 131I-mIBG therapy in France. PMID- 26940443 TI - A highly selective fluorogenic probe for the detection and in vivo imaging of Cu/Zn superoxide dismutase. AB - Copper/zinc superoxide dismutase (Cu/Zn SOD) is an essential enzyme that protects tissue from oxidative damage. Herein we report the first fluorogenic probe (SODO) for the detection and in vivo imaging of Cu/Zn SOD. SODO represents a unique chemical probe for translational imaging studies of Cu/Zn SOD in inflammatory disorders. PMID- 26940444 TI - Pulsed electromagnetic field (PEMF) prevents pro-oxidant effects of H2O2 in SK-N BE(2) human neuroblastoma cells. AB - Purpose The redox milieu, together with reactive oxygen species (ROS) accumulation, may play a role in mediating some biological effects of extremely low-frequency electromagnetic fields (ELF-EMF). Some of us have recently reported that a pulsed EMF (PEMF) improves the antioxidant response of a drug-sensitive human neuroblastoma SH-SY5Y cell line to pro-oxidants. Since drug resistance may affect cell sensitivity to redox-based treatments, we wanted to verify whether drug-resistant human neuroblastoma SK-N-BE(2) cells respond to a PEMF in a similar fashion. Materials and methods SK-N-BE(2) cells were exposed to repeated 2 mT, 75 Hz PEMF (15 min each, repeated 3 times over 5 days), and ROS production, Mn-dependent superoxide dismutase (MnSOD)-based antioxidant protection and viability were assessed after 10 min or 30 min 1 mM hydrogen peroxide. Sham controls were kept at the same time in identical cell culture incubators. Results The PEMF increased the MnSOD-based antioxidant protection and reduced the ROS production in response to a pro-oxidant challenge. Conclusions Our work might lay foundation for the development of non-invasive PEMF-based approaches aimed at elevating endogenous antioxidant properties in cellular or tissue models. PMID- 26940445 TI - Undifferentiated meningeal sarcoma of childhood presenting as hard mass adhered to major intracranial vessels. PMID- 26940447 TI - Gastrointestinal Motility, Part 1: Esophageal Transit and Gastric Emptying. AB - Although not as well standardized as gastric emptying (GE) scintigraphy, esophageal transit scintigraphy, if performed in a comprehensive manner including both quantitative and qualitative analysis of single- and multiple-swallow studies, is clinically useful when expertise in esophageal manometry is not available or not tolerated and when esophageal manometry or barium videofluoroscopy results are equivocal or nondiagnostic. GE scintigraphy has undergone much-needed standardization. Both solid and liquid GE studies play an important role in assessing patients with upper gastrointestinal symptoms. Because measurement of simple total GE is often not sufficient to explain patient symptoms, there is a need to expand the analysis of GE scintigraphy to include the separate roles of the fundus and antrum and to include the complex interactions the stomach has with other organ systems. PMID- 26940446 TI - "Something Extra on Chromosome 5": Parents' Understanding of Positive Prenatal Chromosomal Microarray Analysis (CMA) Results. AB - This study aims to explore how couples' understanding of the nature and consequences of positive prenatal chromosomal microarray analysis (CMA) results impacts decision-making and concern about pregnancy. We interviewed 28 women and 12 male partners after receiving positive results and analyzed the transcripts to assess their understanding and level of concern about the expected clinical implications of results. Participant descriptions were compared to the original laboratory interpretation. When diagnosed prenatally, couples' understanding of the nature and consequences of copy number variants (CNVs) impacts decision making and concern. Findings suggest women, but less so partners, generally understand the nature and clinical implications of prenatal CMA results. Couples feel reassured, perhaps sometimes falsely so, when a CNV is inherited from a "normal" parent and experience considerable uncertainty when a CNV is de novo, frequently precipitating a search for additional information and guidance. Five factors influenced participants' concern including: the pattern of inheritance, type of possible phenotypic involvement, perceived manageability of outcomes, availability and strength of evidence about outcomes associated with the CNV, and provider messages about continuing the pregnancy. A good understanding of results is vital as couples decide whether or not to continue with their pregnancy and seek additional information to assist in pregnancy decision-making. PMID- 26940448 TI - Gastrointestinal Motility, Part 2: Small-Bowel and Colon Transit. AB - Because of the difficulty often encountered in deciding whether a patient's symptoms originate in the upper or lower gastrointestinal tract, gastrointestinal transit scintigraphy is a uniquely suited noninvasive, quantitative, and physiologic method of determining whether there is a motility disorder affecting the stomach, small bowel, or colon. Small-bowel and colon transit studies can be performed alone or together with gastric emptying studies after oral administration of an appropriately radiolabeled meal. It is hoped that newly published standards for performing these studies and the anticipated arrival of new Current Procedural Terminology codes in the United States for small-bowel and colon transit studies will increase their availability and use. PMID- 26940449 TI - Erratum. PMID- 26940451 TI - Why Is Advocacy Important? PMID- 26940452 TI - Forward Momentum! PMID- 26940454 TI - Dragon kings of the deep sea: marine particles deviate markedly from the common number-size spectrum. AB - Particles are the major vector for the transfer of carbon from the upper ocean to the deep sea. However, little is known about their abundance, composition and role at depths greater than 2000 m. We present the first number-size spectrum of bathy- and abyssopelagic particles to a depth of 5500 m based on surveys performed with a custom-made holographic microscope. The particle spectrum was unusual in that particles of several millimetres in length were almost 100 times more abundant than expected from the number spectrum of smaller particles, thereby meeting the definition of "dragon kings." Marine snow particles overwhelmingly contributed to the total particle volume (95-98%). Approximately 1/3 of the particles in the dragon-king size domain contained large amounts of transparent exopolymers with little ballast, which likely either make them neutrally buoyant or cause them to sink slowly. Dragon-king particles thus provide large volumes of unique microenvironments that may help to explain discrepancies in deep-sea biogeochemical budgets. PMID- 26940456 TI - Rapid acceptability and adherence testing of a lipid-based nutrient supplement and a micronutrient powder among refugee children and pregnant and lactating women in Algeria. AB - OBJECTIVE: To assess the acceptability and adherence to daily doses of lipid based nutrient supplement (LNS) among children and micronutrient powder (MNP) among children and pregnant and lactating women. DESIGN: Household interviews and sachet counting were conducted to measure acceptability and adherence, 15 and 30 d after product distribution. Qualitative information on product acceptability was collected using focus group discussions. SETTING: Saharawi refugee camps, Algeria, August-October 2009. SUBJECTS: LNS was distributed to 123 children aged 6-35 months (LNS-C), and MNP to 112 children aged 36-59 months (MNP-C) and 119 pregnant or lactating women (MNP-W). RESULTS: At the end of the test 98.4 % of LNS-C, 90.4 % of MNP-C and 75.5 % of MNP-W participants reported that they liked the product (P<0.05). Other measures of acceptability did not differ. Median consumption of sachets was highest in the LNS-C group (P<0.001). 'Good' adherence to the daily regimen (consumption of 75-125 % of recommended dose) was 89.1 % in the LNS-C, compared with 57.0 % in the MNP-C and 65.8 % in the MNP-W groups (P<0.001). Qualitative findings supported the quantitative measures and guided selection of local product names, packaging designs, distribution mechanisms, and the design of the information campaign in the subsequent programme scale-up. CONCLUSIONS: Acceptability, consumption and adherence were higher in participants receiving LNS compared with MNP. However, both products were found to be suitable when compared with predefined acceptability criteria. Acceptability studies are feasible and important in emergency nutrition programmes when the use of novel special nutritional products is considered. PMID- 26940455 TI - Melanoma cell lysosome secretory burst neutralizes the CTL-mediated cytotoxicity at the lytic synapse. AB - Human melanoma cells express various tumour antigens that are recognized by CD8(+) cytotoxic T lymphocytes (CTLs) and elicit tumour-specific responses in vivo. However, natural and therapeutically enhanced CTL responses in melanoma patients are of limited efficacy. The mechanisms underlying CTL effector phase failure when facing melanomas are still largely elusive. Here we show that, on conjugation with CTL, human melanoma cells undergo an active late endosome/lysosome trafficking, which is intensified at the lytic synapse and is paralleled by cathepsin-mediated perforin degradation and deficient granzyme B penetration. Abortion of SNAP-23-dependent lysosomal trafficking, pH perturbation or impairment of lysosomal proteolytic activity restores susceptibility to CTL attack. Inside the arsenal of melanoma cell strategies to escape immune surveillance, we identify a self-defence mechanism based on exacerbated lysosome secretion and perforin degradation at the lytic synapse. Interfering with this synaptic self-defence mechanism might be useful in potentiating CTL-mediated therapies in melanoma patients. PMID- 26940457 TI - The role of semaphorin signaling in the etiology of hypogonadotropic hypogonadism. AB - In mammals fertility depends on timely onset and cyclic secretion of gonadotropin releasing hormone (GnRH), secreted by scattered hypothalamic neurons (GnRH neurons). These cells originate in the nasal placode and migrate first in the nasal compartment, then through the cribriform plate and finally across the basal forebrain, before they set in their final position in the hypothalamus. This long journey is regulated by many different factors that could be mutated in neuroendocrine syndromes such as congenital hypogonadotropic hypogonadism (CHH), Kallmann Syndrome (KS) and CHARGE syndrome. Recently, semaphorins, a large family of molecules, previously discovered as axon guidance cues, are emerging as key regulators of the neuroendocrine control of GnRH neurons and are acquiring an increasing role in the etiopathogenesis of CHH and KS. Specifically, semaphorins play a multifaceted action in GnRH neuron biology: on one hand regulating their migration and survival during embryonic development and, on the other, controlling the plasticity of the median eminence (ME) in terms of its response to varying sex steroid hormone levels. In this review we will focus our attention on recent studies describing the roles of different semaphorins in the normal and pathological biology of the GnRH neuronal system. PMID- 26940458 TI - Clinicopathological prognostic and theranostic markers in pituitary tumors. AB - More than just the confirmation of an endocrinological diagnosis, the pathological analysis of pituitary endocrine tumors may contribute to bring crucial information in prognosis as well as useful insights in therapeutic management. Taken individually, parameters such as histopathological subtyping, Ki-67-labelling or P53 immunoexpression cannot accurately predict the outcome of patients affected by such tumors. Conversely, "mixed" classification integrating invasion assessment by imaging to histopathological diagnosis may give critical prognostic information and help the clinician in identifying those aggressive tumors that will require a careful follow-up and a more vigorous postoperative treatment. Analysis of theranostic factors such as O6-methylguanine-DNA methyl transferase or somatostatin receptor expression may guide the choice of postoperative treatment. PMID- 26940460 TI - The Clinical Phenotype of Idiopathic Rapid Eye Movement Sleep Behavior Disorder at Presentation: A Study in 203 Consecutive Patients. AB - OBJECTIVE: To describe the clinical phenotype of idiopathic rapid eye movement (REM) sleep behavior disorder (IRBD) at presentation in a sleep center. METHODS: Clinical history review of 203 consecutive patients with IRBD identified between 1990 and 2014. IRBD was diagnosed by clinical history plus video-polysomnographic demonstration of REM sleep with increased electromyographic activity linked to abnormal behaviors. RESULTS: Patients were 80% men with median age at IRBD diagnosis of 68 y (range, 50-85 y). In addition to the already known clinical picture of IRBD, other important features were apparent: 44% of the patients were not aware of their dream-enactment behaviors and 70% reported good sleep quality. In most of these cases bed partners were essential to convince patients to seek medical help. In 11% IRBD was elicited only after specific questioning when patients consulted for other reasons. Seven percent did not recall unpleasant dreams. Leaving the bed occurred occasionally in 24% of subjects in whom dementia with Lewy bodies often developed eventually. For the correct diagnosis of IRBD, video-polysomnography had to be repeated in 16% because of insufficient REM sleep or electromyographic artifacts from coexistent apneas. Some subjects with comorbid obstructive sleep apnea reported partial improvement of RBD symptoms following continuous positive airway pressure therapy. Lack of therapy with clonazepam resulted in an increased risk of sleep related injuries. Synucleinopathy was frequently diagnosed, even in patients with mild severity or uncommon IRBD presentations (e.g., patients who reported sleeping well, onset triggered by a life event, nocturnal ambulation) indicating that the development of a neurodegenerative disease is independent of the clinical presentation of IRBD. CONCLUSIONS: We report the largest IRBD cohort observed in a single center to date and highlight frequent features that were not reported or not sufficiently emphasized in previous publications. Physicians should be aware of the full clinical expression of IRBD, a sleep disturbance that represents a neurodegenerative disease. COMMENTARY: A commentary on this article appears in this issue on page 7. PMID- 26940461 TI - Calorie restriction-induced SIRT6 activation delays aging by suppressing NF kappaB signaling. AB - Calorie restriction (CR) extends lifespan from yeast to mammals. SIRT6 is a member of the sirtuin family of NAD(+)-dependent histone deacetylases, which is responsible for mediating the effects of CR. The transcription factor NF-kappaB, which is involved in inflammation and aging, has been shown to be regulated by SIRT6. Here we describe the crucial role of SIRT6 in aging and inflammation. We show that CR had improved renal insufficiency and enhanced SIRT6 expression after 6-month treatment in aged mice. Culture cells in low glucose (LG) conditions also showed resistance to cell senescence and enhanced SIRT6 expression compared to normal glucose (NG) group, showing beneficial effects of the CR-mimic cultural conditions. Moreover, SIRT6 overexpression is sufficient to delay the replicative senescence of WI38 by attenuating NF-kappaB signaling, while SIRT6 knockdown results in accelerated cell senescence and overactive NF-kappaB signaling. These findings confirm the key status of CR and disclose the critical role of SIRT6 on aging and inflammation. PMID- 26940462 TI - A fatal case of disseminated chronic Q fever: a case report and brief review of the literature. AB - BACKGROUND: Chronic Q fever is a rare infection, which mainly manifests as endocarditis, infection of vascular prostheses or aortic aneurysms. We present the case of a 74-year-old immunocompromised man with a haematologically disseminated Coxiella burnetii infection, which has never been reported before. CASE REPORT: He was diagnosed with a chronic Q fever infection of an aneurysm with an endovascular prosthesis in 2015, but he died despite optimal treatment. Autopsy revealed a disseminated C. burnetii infection, confirmed by a positive PCR on samples from several organs. Retrospectively, he already had complaints and signs of inflammation since 2012, for which he had already been admitted in February 2014. At that time, Q fever diagnostics using PCR, complement fixation assay, and enzyme-linked immunosorbent assay on serum were all negative. In retrospect however, retesting available samples from February 2014 using immunofluorescence assay (IFA) already revealed serology compatible with chronic Q fever. CONCLUSION: Clinicians should be aware of this silent killer, especially in case of risk factors, and perform an appropriate diagnostic work-up for Q fever including IFA serology and PCR. PMID- 26940463 TI - Corrigendum: Functional identification of SLC43A3 as an equilibrative nucleobase transporter involved in purine salvage in mammals. PMID- 26940464 TI - Reply. PMID- 26940465 TI - The prevalence of functional dyspepsia using Rome III questionnaire among chronic hepatitis C patients. AB - BACKGROUND: Hepatitis C virus (HCV) is a common chronic infection that is widely associated with symptoms of fatigue and abdominal pain. The aim of the present study was to determine the prevalence of functional dyspepsia (FD) among patients with hepatitis C. METHODS: This study included 252 patients with chronic hepatitis C and 150 healthy volunteers. Clinical and laboratory data were recorded for every patient. All patients and controls were administered a questionnaire of FD according to Rome III criteria. RESULTS: The percentage of patients with FD was significantly higher in patients with chronic HCV than normal controls (65.9 % vs 28.7 %, respectively). In chronic HCV patients, post prandial distention syndrome (PDS) subtype was the predominant type (86.1 %). The percentage of patients with a high fibrosis score (F2-3) and raised ALT were significantly higher in patients with FD than in patients without FD (P < 0.001; P < 0.04; respectively). A multivariate regression analysis revealed a significant association between fibrosis score, BMI and FD CONCLUSION: FD is more prevalent in patients with chronic hepatitis C. Obese chronic HCV and those with higher fibrosis scores are more likely to have FD. PMID- 26940467 TI - Sample size determination for fold-increase endpoints defined by paired interval censored data. AB - Medical studies often define binary end-points by comparing the ratio of a pair of measurements at baseline and end-of-study to a clinically meaningful cut-off. For example, vaccine trials may define a response as at least a four-fold increase in antibody titers from baseline to end-of-study. Accordingly, sample size is determined based on comparisons of proportions. Since the pair of measurements is quantitative, modeling the bivariate cumulative distribution function to estimate the proportion gives more precise results than using dichotomization of data. This is known as the distributional approach to the analysis of proportions. However, this can be complicated by interval-censoring. For example, due to the nature of some laboratory measurement methods, antibody titers are interval-censored. We derive a sample size formula based on the distributional approach for paired interval-censored data. We compare the sample size requirement in detecting an intervention effect using the distributional approach to a conventional approach of dichotomization. Some practical guidance on applying the sample size formula is given. PMID- 26940468 TI - Erratum to: Purification of glucose-6-phosphate dehydrogenase and glutathione reductase enzymes from the gill tissue of Lake Van fish and analyzing the effects of some chalcone derivatives on enzyme activities. PMID- 26940466 TI - Cohort Profile: The Flu Watch Study. PMID- 26940469 TI - CORR Insights((r)): The Alpha-defensin Test for Periprosthetic Joint Infection is Not Affected by Prior Antibiotic Administration. PMID- 26940471 TI - Asbestos exposure and the risk of sinonasal cancer. AB - BACKGROUND: While the increased risk of lung cancer and mesothelioma is well established, the relationship between exposure to asbestos dust and sinonasal cancer is less clear. AIMS: To study the risk of sinonasal cancer in relation to asbestos dust exposure. METHODS: A retrospective cohort study of construction workers, linked to the Swedish Cancer Registry. Participants were classified into four exposure groups; heavy, medium, low or very low exposure to asbestos, according to the incidence of pleural mesothelioma in their occupational group. Standardized incidence ratios (SIRs) and relative risks (RRs) were analysed, adjusted for age and smoking habits. The risks of adenocarcinoma and squamous cell carcinoma were investigated separately. RESULTS: Among the 280222 subjects, there was no increased risk of sinonasal cancer compared to the general population [SIR 0.85, 95% confidence interval (CI) 0.68-1.03], or any dose response relationship with exposure to asbestos. The highest RR was found in the low exposure group (RR 1.25, 95% CI 0.69-2.28) and the lowest RR was found in the group with the highest exposure to asbestos (RR 0.71, 95% CI 0.33-1.53). No significantly increased risk or dose-response association could be found for adenocarcinoma or squamous cell carcinoma when analysed separately. CONCLUSIONS: This study did not find an increased risk of developing sinonasal cancer after asbestos exposure. PMID- 26940470 TI - Modular to Monoblock: Difficulties of Detaching the M(2)a-Magnum(TM) Head Are Common in Metal-on-metal Revisions. AB - BACKGROUND: Modern hip implants typically feature modular heads, which allow for easy exchange and removal from the femoral stem at the time of revision. However, owing to fretting, corrosion, or cold welding, the modular head may be difficult or impossible to separate from the underlying trunnion, especially if the implant has titanium interfaces between the head and the stem. We have repeatedly encountered difficulty removing the titanium sleeve adapter in the M(2)a Magnum(TM) implant. Although the manufacturer warns about this complication and cases with these difficulties have been reported to the United States FDA, we believed this topic is important to study, because the frequency of difficulties in head removal is unknown and the complications related to this event have not been characterized. QUESTIONS/PURPOSES: We asked: (1) Do revisions of M(2)a Magnum(TM) implants differ from those of M(2)a-38(TM) implants in terms of ease of removal of the femoral head? (2) In cases where difficulty with M(2)a Magnum(TM) head removal occurred, was the operative time, bleeding, risk of periprosthetic fracture, or joint infection increased compared with cases where the M(2)a-Magnum(TM) head was removed without difficulties? METHODS: Between 2004 and 2014, we revised 296 THAs with metal-on-metal implants that involved M(2)a Magnum(TM) (123) or M(2)a-38(TM) heads (88); of those, 84 were planned to include a femoral stem revision and insufficient data were available for three operations, so they were excluded from this analysis, leaving 124 THAs in the current retrospective study (70 THAs with M(2)a-Magnum(TM) and 54 THAs with M(2)a 38(TM) heads).The method of modular head removal, any difficulties removing the femoral head from the trunnion, operation time, and complications were recorded based on chart review. RESULTS: All the observed problems of detaching the head or taper adapter were among M(2)a-Magnum(TM) heads; there were no problems detaching the head in revisions of the M(2)a-38(TM) implant. In 29% (20 of 70) of revisions of the M(2)a-Magnum(TM) implant, the modular head could not be detached by knocking it with a punch and a mallet. Seventeen percent (12 of 70) of hips needed an unplanned stem revision owing to difficulties with head removal. In revisions of the M(2)a-Magnum(TM) implant that experienced head-removal problems, the median operative time was longer (144 minutes; range, 75-274 minutes) and bleeding was greater (725 mL; range, 300-2200 mL) compared with revisions of the M(2)a-Magnum(TM) implant without head removal problems (77 minutes, range, 33-197 minutes, p < 0.001; 475 mL, range, 50-1500 mL, p = 0.004). With the numbers available, we did not see differences in terms of the proportion of patients experiencing major complications (periprosthetic fracture or postoperative infections) between the groups (difficult versus easy; 25% [five of 20] versus 8% [four of 50]; odds ratio, 3.8 [95% CI, 0.9-16.2], p = 0.067). CONCLUSIONS: The titanium-titanium taper junction can be very difficult to separate during revision THAs, and if not anticipated, this problem can result in larger and more complicated revision procedures in patients who have the M(2)a-Magnum(TM) implant. Although the global use of metal-on-metal implants in THAs has decreased dramatically during the last several years, many thousands remain in service and therefore still might require revision. It is crucial to be prepared with special tools, including a femoral head extraction tool and diamond saw. The patient has to be informed of the possibility of a more extensive operation than preoperatively planned. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 26940472 TI - Outbreak of human astrovirus 1 lineage 1d in a childcare center in China. PMID- 26940473 TI - Comparative proteomic analysis of the saliva of the Rhodnius prolixus, Triatoma lecticularia and Panstrongylus herreri triatomines reveals a high interespecific functional biodiversity. AB - Triatomines are hematophagous arthropods that transmit Trypanosoma cruzi and Trypanosoma rangeli. Feeding behavior and pathogen transmission is known to vary between the different species, and this characteristic is directly or indirectly dependent on the bioactive molecules of the saliva that facilitate the vector host-parasite interaction. Here, we identify, characterize and compare the sialoproteomic (from the Greek sialo: saliva) repertoire of important species of the main triatomine genera in the Americas (Rhodnius prolixus, Triatoma lecticularia and Panstrongylus herreri) to better explain this interaction through two-dimensional electrophoresis and mass spectrometry. We identified 221 proteins, 69 from R. prolixus, 100 from T. lecticularia and 52 from P. herreri. We identified high abundance molecules with a great potential to modulate host defenses and homeostasis, highlighting Nitrophorin-4 (28.7%), Salivary lipocalin 5 (65.2%) and Putative triabin (20.5%) in R. prolixus, T. lecticularia and P. herreri, respectively. We also observed that only a single hypothetical protein is shared among three species, which was not functionally categorized. This study corroborates previous findings with R. prolixus, increasing the knowledge about this species with relevant proteomic information and comparisons with the other two targets of the study, T. lecticularia and P. herreri, for which no studies are available from a proteomics perspective. PMID- 26940475 TI - Understanding super-enhancers. PMID- 26940474 TI - MHC class I chain-related molecule A and B expression is upregulated by cisplatin and associated with good prognosis in patients with non-small cell lung cancer. AB - MHC class I chain-related molecule A and B (MICA/B) are NK group 2 member D (NKG2D) ligands, which are broadly expressed in transformed cells. Both DNA damage-induced ataxia-telangiectasia-mutated (ATM)- and ATM and Rad3-related protein kinases (ATM-ATR) signaling and oncogene-induced PI3K-AKT signaling regulate the expression of NKG2D ligands, which promote NK cell-mediated cytotoxicity via NKG2D-NKG2D ligand interactions. NKG2D ligand overexpression was recently reported to be correlated with good prognosis in several types of cancer. However, the prognostic significance of NKG2D ligands in non-small cell lung cancer (NSCLC) remains unclear. Here, MICA/B expression was evaluated based on immunohistochemistry of 91 NSCLC samples from patients following radical surgery. In addition, expression of MICA/B was assessed in NSCLC cell lines treated with cisplatin in order to evaluate the regulatory mechanisms of MICA/B expression. Overall, 28 out of 91 (30.8%) specimens showed high expression level of MICA/B, which was associated with low (18)F-fluorodeoxyglucose uptake and manifestation of adenocarcinoma. After a median follow-up of 48.2 months, high MICA/B expression was associated with good recurrence-free survival (p = 0.037). In vitro assays using cell lines revealed that MICA/B expression was upregulated by cisplatin via ATM-ATR signaling, resulting in enhanced NK cell-mediated cytotoxicity. Upregulated MICA/B expressions in patients with radically resected NSCLC are predictive of good disease prognosis. Cisplatin-induced MICA/B upregulation is possibly an indirect mechanism by which the innate immune system eliminates tumor cells. NKG2D-NKG2D ligand-targeting therapy is a promising avenue for future immune-chemotherapy development. PMID- 26940476 TI - What have we learned of ablation procedures for atrial fibrillation? AB - Atrial fibrillation is a widespread disease of growing clinical, economic and social importance. Interventional therapy for atrial fibrillation offers encouraging results, with pulmonary vein isolation (PVI) as the established cornerstone. Yet, the challenge to create durable transmural lesions remains, leading to recurrence of atrial fibrillation in long-term follow-up even after multiple ablation procedures in 20% of patients with paroxysmal atrial fibrillation and approximately 50% with persistent atrial fibrillation. To overcome these limitations, innovative tools such as the cryoballoon and contact force catheters have been introduced and have demonstrated their potential for safe and effective PVI. Furthermore, advanced pharmacological and pacing manoeuvres enhance evaluation of conduction block in PVI. PMID- 26940477 TI - Targeting the Cancer Moonshot. PMID- 26940478 TI - Introduction to the special issue: Dynamic and metabolic interactions between astrocytes and neurons. PMID- 26940479 TI - Sporadic Creutzfeldt-Jakob disease diagnostic accuracy is improved by a new CSF ELISA 14-3-3gamma assay. AB - Protein 14-3-3 is a reliable marker of rapid neuronal damage, specifically increased in cerebrospinal fluid (CSF) of sporadic Creutzfeldt-Jakob disease (sCJD) patients. Its detection is usually performed by Western Blot (WB), prone to methodological issues. Our aim was to evaluate the diagnostic performance of a recently developed quantitative enzyme-linked immunosorbent (ELISA) assay for 14 3-3gamma, in comparison with WB and other neurodegeneration markers. CSF samples from 145 patients with suspicion of prion disease, later classified as definite sCJD (n=72) or Non-prion diseases (Non-CJD; n=73) comprised our population. 14-3 3 protein was determined by WB and ELISA. Total Tau (t-Tau) and phosphorylated Tau (p-Tau) were also evaluated. Apolipoprotein E gene (ApoE) and prionic protein gene (PRNP) genotyping was assessed. ELISA 14-3-3gamma levels were significantly increased in sCJD compared to Non-CJD patients (p<0.001), showing very good accuracy (AUC=0.982; sensitivity=97%; specificity=94%), and matching WB results in 81% of all cases. It strongly correlated with t-Tau and p-Tau (p<0.0001), showing slightly higher specificity (14-3-3 WB - 63%; Tau - 90%; p-Tau/t-Tau ratio - 88%). From WB inconclusive results (n=44), ELISA 14-3-3gamma correctly classified 41 patients. Additionally, logistic regression analysis selected ELISA 14-3-3gamma as the best single predictive marker for sCJD (overall accuracy=93%). ApoE and PRNP genotypes did not influence ELISA 14-3-3gamma levels. Despite specificity for 14-3-3gamma isoform, ELISA results not only match WB evaluation but also help discrimination of inconclusive results. Our results therefore reinforce this assay as a single screening test, allowing higher sample throughput and unequivocal results. PMID- 26940480 TI - Correction: Core-shell Zn2GeO4 nanorods and their size-dependent photoluminescence properties. AB - Correction for 'Core-shell Zn2GeO4 nanorods and their size-dependent photoluminescence properties' by Songping Wu et al., Nanoscale, 2013, 5, 12335 12341. PMID- 26940482 TI - Subthalamic nucleus microelectrode recordings (MER) can be reliably detected despite general anaesthesia and dopaminergic treatment. PMID- 26940483 TI - Effects of Framing Health Messages in Terms of Benefits to Loved Ones or Others: An Experimental Study. AB - Many health officials believe the future of public health is in prevention of infectious diseases like pandemic influenza. Vaccine promotion is becoming an increasingly important area for health communication researchers. One strategy health promoters can consider is to emphasize that getting vaccinated protects not only the self, but also loved ones, and unknown others to whom the disease could be spread. The set of experiments described here tested whether such a strategy (called "benefit-target framing") could prove useful in promoting vaccine intentions. In two experiments, subjects from an online panel were randomized to receive a vaccination message focused on the benefits either to the self, to loved ones, or to society as a whole. Outcome measures included intentions to receive the vaccine and intentions to seek more information (n = 495). Results from two virtually identical studies were pooled to maximize power. Results suggest that messages framed in terms of benefits to society were more successful than those focused on the self, but messages focused on loved ones were not different from either of the others. Possible explanations for the findings, and implications for future research, are discussed. PMID- 26940484 TI - Current practice in treatment approach for bullous pemphigoid: comparison between national surveys from the Netherlands and the UK. AB - Treatment approaches for bullous pemphigoid (BP), the most common autoimmune skin blistering disease, are largely based on national and international guidelines. We conducted a national survey among dermatologists in the Netherlands to explore the current treatment of BP, and compared the results with those of a previously published survey from the UK. Almost all responders in the Netherlands (n = 175) used very potent topical corticosteroids, both as monotherapy and as adjunctive therapy. In contrast to UK dermatologists, the majority recommended whole-body application rather than local application to lesions. Systemic antibiotics were used by > 70% of responders. Half of the responders in the Netherlands considered systemic steroids the first-choice treatment, with the majority also using adjunctive therapy as a routine. Despite many similarities in treatment approach between the two countries, these surveys provide an important insight into the gap between actual and recommended practice at a country level in relation to the best external evidence. PMID- 26940481 TI - Complexities of Gut Microbiome Dysbiosis in the Context of HIV Infection and Antiretroviral Therapy. AB - Human immunodeficiency virus (HIV) infection is associated with an altered gut microbiome that is not consistently restored with effective antiretroviral therapy (ART). Interpretation of the specific microbiome changes observed during HIV infection is complicated by factors like population, sample type, and ART each of which may have dramatic effects on gut bacteria. Understanding how these factors shape the microbiome during HIV infection (which we refer to as the HIV associated microbiome) is critical for defining its role in HIV disease, and for developing therapies that restore gut health during infection. PMID- 26940485 TI - Evaluation of C-reactive protein and CC-cytokine ligand 2 polymorphism interaction for age-related macular degeneration. PMID- 26940486 TI - The Italian Supreme Court has dismissed wrongful life claims. PMID- 26940487 TI - Master and servant: Regulation of auxin transporters by FKBPs and cyclophilins. AB - Plant development and architecture are greatly influenced by the polar distribution of the essential hormone auxin. The directional influx and efflux of auxin from plant cells depends primarily on AUX1/LAX, PIN, and ABCB/PGP/MDR families of auxin transport proteins. The functional analysis of these proteins has progressed rapidly within the last decade thanks to the establishment of heterologous auxin transport systems. Heterologous co-expression allowed also for the testing of protein-protein interactions involved in the regulation of transporters and identified relationships with members of the FK506-Binding Protein (FKBP) and cyclophilin protein families, which are best known in non plant systems as cellular receptors for the immunosuppressant drugs, FK506 and cyclosporin A, respectively. Current evidence that such interactions affect membrane trafficking, and potentially the activity of auxin transporters is reviewed. We also propose that FKBPs andcyclophilins might integrate the action of auxin transport inhibitors, such as NPA, on members of the ABCB and PIN family, respectively. Finally, we outline open questions that might be useful for further elucidation of the role of immunophilins as regulators (servants) of auxin transporters (masters). PMID- 26940488 TI - The banana E2 gene family: Genomic identification, characterization, expression profiling analysis. AB - The E2 is at the center of a cascade of Ub1 transfers, and it links activation of the Ub1 by E1 to its eventual E3-catalyzed attachment to substrate. Although the genome-wide analysis of this family has been performed in some species, little is known about analysis of E2 genes in banana. In this study, 74 E2 genes of banana were identified and phylogenetically clustered into thirteen subgroups. The predicted banana E2 genes were distributed across all 11 chromosomes at different densities. Additionally, the E2 domain, gene structure and motif compositions were analyzed. The expression of all of the banana E2 genes was analyzed in the root, stem, leaf, flower organs, five stages of fruit development and under abiotic stresses. All of the banana E2 genes, with the exception of few genes in each group, were expressed in at least one of the organs and fruit developments, which indicated that the E2 genes might involve in various aspects of the physiological and developmental processes of the banana. Quantitative RT-PCR (qRT PCR) analysis identified that 45 E2s under drought and 33 E2s under salt were induced. To the best of our knowledge, this report describes the first genome wide analysis of the banana E2 gene family, and the results should provide valuable information for understanding the classification, cloning and putative functions of this family. PMID- 26940489 TI - Gamma-aminobutyric acid depletion affects stomata closure and drought tolerance of Arabidopsis thaliana. AB - A rapid accumulation of gamma-aminobutyric acid (GABA) during biotic and abiotic stresses is well documented. However, the specificity of the response and the primary role of GABA under such stress conditions are hardly understood. To address these questions, we investigated the response of the GABA-depleted gad1/2 mutant to drought stress. GABA is primarily synthesized from the decarboxylation of glutamate by glutamate decarboxylase (GAD) which exists in five copies in the genome of Arabidopsis thaliana. However, only GAD1 and GAD2 are abundantly expressed, and knockout of these two copies dramatically reduced the GABA content. Phenotypic analysis revealed a reduced shoot growth of the gad1/2 mutant. Furthermore, the gad1/2 mutant was wilted earlier than the wild type following a prolonged drought stress treatment. The early-wilting phenotype was due to an increase in stomata aperture and a defect in stomata closure. The increase in stomata aperture contributed to higher stomatal conductance. The drought oversensitive phenotype of the gad1/2 mutant was reversed by functional complementation that increases GABA level in leaves. The functionally complemented gad1/2 x pop2 triple mutant contained more GABA than the wild type. Our findings suggest that GABA accumulation during drought is a stress-specific response and its accumulation induces the regulation of stomatal opening thereby prevents loss of water. PMID- 26940491 TI - High throughput selection of novel plant growth regulators: Assessing the translatability of small bioactive molecules from Arabidopsis to crops. AB - Plant growth regulators (PGRs) have become an integral part of agricultural and horticultural practices. Accordingly, there is an increased demand for new and cost-effective products. Nevertheless, the market is limited by insufficient innovation. In this context chemical genomics has gained increasing attention as a powerful approach addressing specific traits. Here is described the successful implementation of a highly specific, sensitive and efficient high throughput screening approach using Arabidopsis as a model. Using a combination of techniques, 10,000 diverse compounds were screened and evaluated for several important plant growth traits including root and leaf growth. The phenotype-based selection allowed the compilation of a collection of putative Arabidopsis growth regulators with a broad range of activities and specificities. A subset was selected for evaluating their bioactivity in agronomically valuable plants. Their validation as growth regulators in commercial species such as tomato, lettuce, carrot, maize and turfgrasses reinforced the success of the screening in Arabidopsis and indicated that small molecules activity can be efficiently translated to commercial species. Therefore, the chemical genomics approach in Arabidopsis is a promising field that can be incorporated in PGR discovery programs and has a great potential to develop new products that can be efficiently used in crops. PMID- 26940490 TI - Overexpression of Rosa rugosa anthocyanidin reductase enhances tobacco tolerance to abiotic stress through increased ROS scavenging and modulation of ABA signaling. AB - Anthocyanidin reductase (ANR) is a key enzyme involved in the biosynthesis of proanthocyanidins (PAs) and plays a role in the plant stress response. However, the mechanism by which ANR confers stress tolerance in plants is not understood. Here, we report the isolation of RrANR, the homologous gene from rose, and NtABF, an ABA-response related transcription factor gene from tobacco. These genes were characterized regarding their functions in stress responses through the use of transgenic, transcriptomic and physiological analyses. Over-expression of RrANR in tobacco resulted in an increased accumulation of both PAs and abscisic acid (ABA), and also enhanced stress tolerance. Transcriptomic analysis of these transgenic tobacco lines indicated that RrANR overexpression induced global transcriptomic changes, including these involved in oxidation/reduction, hormone response and secondary metabolism. Genes related to ABA biosynthesis and reactive oxygen species (ROS)-scavenging were up-regulated in RrANR transgenic lines, and these effects were phenocopied by the direct treatment of tobacco plants with PAs and ABA. Transcriptomic data from each of these treatments identified the upregulation of a putative NtABF. Furthermore, the up-regulation of NtABF in RrANR transformants or in PAs- and ABA-treated tobacco plants was associated with enhanced stress tolerance. Overexpression of NtABF in transgenic tobacco mimicked the effects of RrANR-transgenic plants with regard to the up-regulation of ROS scavenging genes and an increase in oxidative tolerance. Taken together, our findings indicate that overexpression of RrANR results in an increase in plant tolerance to oxidative stress via increased scavenging of ROS and modulation of the ABA signaling pathway. PMID- 26940492 TI - Identification of candidate genes for dissecting complex branch number trait in chickpea. AB - The present study exploited integrated genomics-assisted breeding strategy for genetic dissection of complex branch number quantitative trait in chickpea. Candidate gene-based association analysis in a branch number association panel was performed by utilizing the genotyping data of 401 SNP allelic variants mined from 27 known cloned branch number gene orthologs of chickpea. The genome-wide association study (GWAS) integrating both genome-wide GBS- (4556 SNPs) and candidate gene-based genotyping information of 4957 SNPs in a structured population of 60 sequenced desi and kabuli accessions (with 350-400 kb LD decay), detected 11 significant genomic loci (genes) associated (41% combined PVE) with branch number in chickpea. Of these, seven branch number-associated genes were further validated successfully in two inter (ICC 4958 * ICC 17160)- and intra (ICC 12299 * ICC 8261)-specific mapping populations. The axillary meristem and shoot apical meristem-specific expression, including differential up- and down regulation (4-5 fold) of the validated seven branch number-associated genes especially in high branch number as compared to the low branch number-containing parental accessions and homozygous individuals of two aforesaid mapping populations was apparent. Collectively, this combinatorial genomic approach delineated diverse naturally occurring novel functional SNP allelic variants in seven potential known/candidate genes [PIN1 (PIN-FORMED protein 1), TB1 (teosinte branched 1), BA1/LAX1 (BARREN STALK1/LIKE AUXIN1), GRAS8 (gibberellic acid insensitive/GAI, Repressor of ga13/RGA and Scarecrow8/SCR8), ERF (ethylene responsive element-binding factor), MAX2 (more axillary growth 2) and lipase] governing chickpea branch number. The useful information generated from this study have potential to expedite marker-assisted genetic enhancement by developing high-yielding cultivars with more number of productive (pods and seeds) branches in chickpea. PMID- 26940493 TI - RNAi-mediated silencing of the Arabidopsis thaliana ULCS1 gene, encoding a WDR protein, results in cell wall modification impairment and plant infertility. AB - Ubiquitin mediated protein degradation constitutes one of the most complex post translational gene regulation mechanisms in eukaryotes. This fine-tuned proteolytic machinery is based on a vast number of E3 ubiquitin ligase complexes that mark target proteins with ubiquitin. The specificity is accomplished by a number of adaptor proteins that contain functional binding domains, including the WD40 repeat motif (WDRs). To date, only few of these proteins have been identified in plants. An RNAi mediated silencing approach was used here to functionally characterize the Arabidopsis thaliana ULCS1 gene, which encodes for a small molecular weight WDR protein. AtULCS1 interacts with the E3Cullin Ring Ligase subunit DDB1a, regulating most likely the degradation of specific proteins involved in the manifestation of diverse developmental events. Silencing of AtULCS1 results in sterile plants with pleiotropic phenotypes. Detailed analysis revealed that infertility is the outcome of anther indehiscence, which in turn is due to the impairment of the plants to accomplish secondary wall modifications. Furthermore, IREGULAR XYLEM gene expression and lignification is diminished in anther endothecium and the stem vascular tissue of the silenced plants. These data underline the importance of AtULCS1 in plant development and reproduction. PMID- 26940495 TI - Review: Wind impacts on plant growth, mechanics and damage. AB - Land plants have adapted to survive under a range of wind climates and this involve changes in chemical composition, physical structure and morphology at all scales from the cell to the whole plant. Under strong winds plants can re orientate themselves, reconfigure their canopies, or shed needles, leaves and branches in order to reduce the drag. If the wind is too strong the plants oscillate until the roots or stem fail. The mechanisms of root and stem failure are very similar in different plants although the exact details of the failure may be different. Cereals and other herbaceous crops can often recover after wind damage and even woody plants can partially recovery if there is sufficient access to water and nutrients. Wind damage can have major economic impacts on crops, forests and urban trees. This can be reduced by management that is sensitive to the local site and climatic conditions and accounts for the ability of plants to acclimate to their local wind climate. Wind is also a major disturbance in many plant ecosystems and can play a crucial role in plant regeneration and the change of successional stage. PMID- 26940494 TI - Analysis of Block of cell proliferation 1 (BOP1) activity in strawberry and Arabidopsis. AB - Block of cell proliferation (BOP) proteins are conserved among eukaryotes, and studies in mammals and yeast have described their role in ribosome biogenesis and cell cycle regulation. A BOP1 orthologue was identified in plants, and loss-of function analyses in tobacco cells confirmed similar activities. This report characterizes a role for BOP1 activity in planta. Two transgenic plant species were used: the diploid strawberry (Fragaria vesca) and Arabidopsis thaliana. FvBOP1 silencing showed changes in pre-rRNA processing, and demonstrated FvBOP1's role in growth and physiology throughout different stages of plant development. In the strawberry, repression of FvBOP1 activity decreased plant fitness prior to flowering, followed by plant death after the reproductive transition, indicating that BOP1 activity is required for transition back to vegetative growth after flowering. A T-DNA null allele of the AtBOP1 gene is lethal, and a 50% decrease in transcript accumulation is sufficient to cause severe developmental defects linked to defective cell division. The conserved protein BOP1 is essential for viability. Lower transcript levels result in defects in rRNA processing and developmental abnormalities that are consistent with its predicted role in ribosome biogenesis. PMID- 26940496 TI - Strigolactones in the Rhizobium-legume symbiosis: Stimulatory effect on bacterial surface motility and down-regulation of their levels in nodulated plants. AB - Strigolactones (SLs) are multifunctional molecules acting as modulators of plant responses under nutrient deficient conditions. One of the roles of SLs is to promote beneficial association with arbuscular mycorrhizal (AM) fungi belowground under such stress conditions, mainly phosphorus shortage. Recently, a role of SLs in the Rhizobium-legume symbiosis has been also described. While SLs' function in AM symbiosis is well established, their role in the Rhizobium-legume interaction is still emerging. Recently, SLs have been suggested to stimulate surface motility of rhizobia, opening the possibility that they could also act as molecular cues. The possible effect of SLs in the motility in the alfalfa symbiont Sinorhizobium meliloti was investigated, showing that the synthetic SL analogue GR24 stimulates swarming motility in S. meliloti in a dose-dependent manner. On the other hand, it is known that SL production is regulated by nutrient deficient conditions and by AM symbiosis. Using the model alfalfa-S. meliloti, the impact of phosphorus and nitrogen deficiency, as well as of nodulation on SL production was also assessed. The results showed that phosphorus starvation promoted SL biosynthesis, which was abolished by nitrogen deficiency. In addition, a negative effect of nodulation on SL levels was detected, suggesting a conserved mechanism of SL regulation upon symbiosis establishment. PMID- 26940497 TI - Kinetics genetics: Incorporating the concept of genomic balance into an understanding of quantitative traits. AB - While most mutations are recessive, variants that affect quantitative traits are largely semi-dominant in their action making hybrids between divergent genotypes intermediate. In parallel, changes in chromosomal dosage (aneuploidy) for multiple regions of the genome modulate quantitative characters. We have previously argued that these observations are a reflection of a common process, originating from the more or less subtle effects of changes in dosage on the action of multi-subunit regulatory machineries. Kinetic analyses that vary the amount of one subunit of a complex while holding others constant do not always predict a linear response for the production of the whole. Indeed, in many instances, strong non-linear effects are expected. Here, we advocate that these kinetic observations and predictions should be incorporated into quantitative genetics thought. PMID- 26940499 TI - Oxidative metabolism is associated with physiological disorders in fruits stored under multiple environmental stresses. AB - In combination with low temperature, controlled atmosphere storage and 1 methylcyclopropene (ethylene antagonist) application are used to delay senescence of many fruits and vegetables. Controlled atmosphere consists of low O2 and elevated CO2. When sub-optimal partial pressures are used, these practices represent multiple abiotic stresses that can promote the development of physiological disorders in pome fruit, including flesh browning and cavities, although there is some evidence for genetic differences in susceptibility. In the absence of surface disorders, fruit with flesh injuries are not easily distinguished from asymptomatic fruit until these are consumed. Oxidative stress metabolites tend to accumulate (e.g., gamma-aminobutyrate) or rapidly decline (e.g., ascorbate and glutathione) in vegetative tissues exposed to hypoxic and/or elevated CO2 environments. Moreover, these phenomena can be associated with altered energy and redox status. Biochemical investigations of Arabidopsis and tomato plants with genetically-altered levels of enzymes associated with the gamma-aminobutyrate shunt and the ascorbate-glutathione pathway indicate that these metabolic processes are functionally related and critical for dampening the oxidative burst in vegetative and fruit tissues, respectively. Here, we hypothesize that gamma-aminobutyrate accumulation, as well energy and antioxidant depletion are associated with the development of physiological injury in pome fruit under multiple environmental stresses. An improved understanding of this relationship could assist in maintaining the quality of stored fruit. PMID- 26940498 TI - The Arabidopsis KS-type dehydrin recovers lactate dehydrogenase activity inhibited by copper with the contribution of His residues. AB - Dehydrin, which is one of the late embryogenesis abundant (LEA) proteins, is involved in the ability of plants to tolerate the lack of water. Although many reports have indicated that dehydrins bind heavy metals, the physiological role of this metal binding has not been well understood. Here, we report that the Arabidopsis KS-type dehydrin (AtHIRD11) recovered the lactate dehydrogenase (LDH) activity denatured by Cu(2+). The LDH activity was partially inhibited by 0.93 MUM Cu(2+) but totally inactivated by 9.3 MUM Cu(2+). AtHIRD11 recovered the activity of LDH treated with 9.3 MUM Cu(2+) in a dose-dependent manner. The recovery activity of AtHIRD11 was significantly higher than those of serum albumin and lysozyme. The conversion of His residues to Ala in AtHIRD11 resulted in the loss of the Cu(2+) binding of the protein as well as the disappearance of the conformational change induced by Cu(2+) that is observed by circular dichroism spectroscopy. The mutant protein showed lower recovery activity than the original AtHIRD11. These results indicate that AtHIRD11 can reactivate LDH inhibited by Cu(2+) via the His residues. This function may prevent physiological damage to plants due to heavy-metal stress. PMID- 26940501 TI - Mineral composition of some varieties of beans from Mediterranean and Tropical areas. AB - In this study has been evaluated the mineral composition (Cd, Pb, As, Hg, Ba, Cr, Co, Ni, Se, Sb, V, Cu, Fe, Zn, Mo, Na, K, Ca, Mg) of some varieties of bean (Phaseolus vulgaris, Vigna unguiculata and V. angularis) from Mediterranean and Tropical areas of the world (Italy, Mexico, India, Japan, Ghana and Ivory Coast); the correlation between beans mineral composition in micro and macroelements and botanical and/or geographical origin; trace elements dietary intake by beans consumption. The results showed a correlation between beans mineral composition and their geographical origin, with higher values in Ivory Coast samples. Moreover, minerals content found confirmed the importance of these legumes in the diet for the significant content of essential micro and macroelements and a safe consumption of beans for the low residual levels of toxic metals. PMID- 26940500 TI - Effects of fresh frozen plasma, Ringer's acetate and albumin on plasma volume and on circulating glycocalyx components following haemorrhagic shock in rats. AB - BACKGROUND: Early use of fresh frozen plasma (FFP) in haemorrhagic shock is associated with improved outcome. This effect may partly be due to protection of the endothelial glycocalyx and/or secondary to a superior efficacy of FFP as a plasma volume expander compared to crystalloids. The objective of the present study was to investigate if protection of the glycocalyx by FFP can be demonstrated when potential differences in plasma volume (PV) following resuscitation are accounted for. METHODS: Rats were subjected to a volume controlled haemorrhage (30 ml/kg). At 2.5 h after haemorrhage, animals were randomized to resuscitation with FFP (37.5 ml/kg), albumin (30 ml/kg) or Ringer's acetate (RA) (135 ml/kg, 4.5 times the bleed volume). PV was measured 2 h after completion of resuscitation using (125)I-albumin and effects on endothelial glycocalyx were evaluated by measuring circulating heparan sulphate and syndecan 1. Hemodynamic effects of resuscitation were evaluated by measuring lactate and mean arterial pressure (MAP). RESULTS: Resuscitation with FFP or albumin resulted in plasma volume expansion equalling the blood loss (to 55 +/- 5 ml/kg and 54 +/- 4 ml/kg (mean +/- S.D.), respectively), whereas plasma volume expansion in RA group was lower (to 42 +/- 7 ml/kg). Plasma concentration of heparan sulphate was lower in the FFP and albumin groups than in the RA group at 2 h after resuscitation. After correcting for differences in plasma volume, no significant difference in circulating amount of heparan sulphate was detected between the FFP and albumin groups (2879 +/- 1075 MUg/kg and 3318 +/- 1814 MUg/kg, respectively, P = 0.4) and the RA group (3731 +/- 777 MUg/kg). No differences between the groups in plasma concentration or amount of circulating syndecan-1 were detected after resuscitation. After resuscitation, MAP was higher in the FFP and albumin groups than in the RA group. Lactate did not differ between the FFP and RA groups after resuscitation. CONCLUSIONS: Improved outcome in trauma by FFP could in part be explained by better plasma volume expansion compared to crystalloids. The decrease in plasma concentration of markers of glycocalyx degradation after resuscitation with FFP are largely secondary to differences in plasma volume and may not accurately reflect effects of FFP on the glycocalyx. PMID- 26940502 TI - Detection and Quantification of Vibrio cholerae, Vibrio parahaemolyticus, and Vibrio vulnificus in Coastal Waters of Guinea-Bissau (West Africa). AB - V. cholerae, V. parahaemolyticus, and V. vulnificus are recognized human pathogens. Although several studies are available worldwide, both on environmental and clinical contexts, little is known about the ecology of these vibrios in African coastal waters. In this study, their co-occurrence and relationships to key environmental constraints in the coastal waters of Guinea Bissau were examined using the most probable number-polymerase chain reaction (MPN-PCR) approach. All Vibrio species were universally detected showing higher concentrations by the end of the wet season. The abundance of V. cholerae (ISR 16S-23S rRNA) ranged 0-1.2 * 10(4) MPN/L, whereas V. parahaemolyticus (toxR) varied from 47.9 to 1.2 * 10(5) MPN/L. Although the presence of genotypes associated with virulence was found in environmental V. cholerae isolates, ctxA+ V. cholerae was detected, by MPN-PCR, only on two occasions. Enteropathogenic (tdh+ and trh+) V. parahaemolyticus were detected at concentrations up to 1.2 * 10(3) MPN/L. V. vulnificus (vvhA) was detected simultaneously in all surveyed sites only at the end of the wet season, with maximum concentrations of 1.2 * 10(5) MPN/L. Our results suggest that sea surface water temperature and salinity were the major environmental controls to all Vibrio species. This study represents the first detection and quantification of co-occurring Vibrio species in West African coastal waters, highlighting the potential health risk associated with the persistence of human pathogenic Vibrio species. PMID- 26940503 TI - Clinical and epidemiological characteristics of a case of avian influenza A H5N6 virus infection. PMID- 26940504 TI - Zika fever and congenital Zika syndrome: An unexpected emerging arboviral disease. AB - Unlike its mosquito-borne relatives, such as dengue, West Nile, and Japanese encephalitis viruses, which can cause severe human diseases, Zika virus (ZIKV) has emerged from obscurity by its association with a suspected "congenital Zika syndrome", while causing asymptomatic or mild exanthematous febrile infections which are dengue- or rubella-like in infected individuals. Despite having been discovered in Uganda for almost 60 years, <20 human cases were reported before 2007. The massive epidemics in the Pacific islands associated with the ZIKV Asian lineage in 2007 and 2013 were followed by explosive outbreaks in Latin America in 2015. Although increased mosquito breeding associated with the El Nino effect superimposed on global warming is suspected, genetic changes in its RNA virus genome may have led to better adaptation to mosquitoes, other animal reservoirs, and human. We reviewed the epidemiology, clinical manifestation, virology, pathogenesis, laboratory diagnosis, management, and prevention of this emerging infection. Laboratory diagnosis can be confounded by cross-reactivity with other circulating flaviviruses. Besides mosquito bite and transplacental transmission, the risk of other potential routes of transmission by transfusion, transplantation, sexual activity, breastfeeding, respiratory droplet, and animal bite is discussed. Epidemic control requires adequate clearance of mosquito breeding grounds, personal protection against mosquito bite, and hopefully a safe and effective vaccine. PMID- 26940506 TI - The potential lethal consequences of rabies vaccine avoidance and dog smuggling in Europe. PMID- 26940507 TI - Protein Partners of alpha-Synuclein in Health and Disease. AB - alpha-synuclein is normally situated in the nerve terminal but it accumulates and aggregates in axons and cell bodies in synucleinopathies such as Parkinson's disease. The conformational changes occurring during alpha-synucleins aggregation process affects its interactions with other proteins and its subcellular localization. This review focuses on interaction partners of alpha-synuclein within different compartments of the cell with a focus on those preferentially binding aggregated alpha-synuclein. The aggregation state of alpha-synuclein also affects its catabolism and we hypothesize impaired macroautophagy is involved neuronal excretion of alpha-synuclein species responsible for the prion-like spreading of alpha-synuclein pathology. PMID- 26940505 TI - Community-acquired Haemophilus influenzae pneumonia--New insights from the CAPNETZ study. AB - OBJECTIVES: We aimed to identify clinical characteristics and to assess effectiveness of different initial antibiotic regimens in adult patients with community-acquired pneumonia (CAP) caused by Haemophilus influenzae. METHODS: Characteristics were compared between patients with H. influenzae monoinfection versus CAP of other and unknown aetiology enrolled by the German prospective cohort study CAPNETZ. Impact of initial antibiotic treatment on "early clinical response" according to FDA criteria and overall clinical cure were analysed. RESULTS: H. influenzae was found in 176 out of 2790 patients with pathogen detection (6.3%). Characteristics significantly associated with a H. influenzae CAP (p < 0.017) included purulent sputum, prior pneumococcal vaccination and respiratory co-morbidities. Early clinical response rates on day 4 did not differ between patients receiving any mono- versus combination therapy (85.9% versus 88%), but were numerically higher for regimens including any fluoroquinolone (96.7%) and lower under macrolide monotherapy (70%). Initial CURB-65 score and chronic liver disease were identified as negative predictors for "early clinical response". At day 14, overall clinical cure was 91.9%. CONCLUSIONS: H. influenzae was a common CAP pathogen, particularly in patients with previous pneumococcal vaccination and respiratory co-morbidities. Severity of illness and chronic liver disease were associated with a lower rate of "early clinical response". PMID- 26940508 TI - Analysis of the conformation and thermal stability of the high-affinity IgE Fc receptor beta chain polymorphic proteins. AB - The high-affinity IgE Fc receptor (FcepsilonRI) beta chain acts as a signal amplifier through the immunoreceptor tyrosine-based activation motif in its C terminal intracellular region. Polymorphisms in FcepsilonRI beta have been linked to atopy, asthma, and allergies. We investigated the secondary structure, conformation, and thermal stability of FcepsilonRI beta polymorphic (beta-L172I, beta-L174V, and beta-E228G) proteins. Polymorphisms did not affect the secondary structure and conformation of FcepsilonRI beta. However, we calculated Gibbs free energy of unfolding (DeltaGunf) and significant differences were observed in DeltaGunf values between the wild-type FcepsilonRI beta (beta-WT) and beta-E228G. These results suggested that beta-E228G affected the thermal stability of FcepsilonRI beta. The role of beta-E228G in biological functions and its involvement in allergic reactions have not yet been elucidated in detail; therefore, differences in the thermal stability of beta-E228G may affect the function of FcepsilonRI beta. PMID- 26940509 TI - First update of the International Xenotransplantation Association consensus statement on conditions for undertaking clinical trials of porcine islet products in type 1 diabetes--Chapter 1: update on national regulatory frameworks pertinent to clinical islet xenotransplantation. AB - Islet xenotransplantation represents an attractive solution to overcome the shortage of human islets for use in type 1 diabetes. The wide-scale application of clinical islet xenotransplantation, however, requires that such a procedure takes place in a specifically and tightly regulated environment. With a view to promoting the safe application of clinical islet xenotransplantation, a few years ago the International Xenotransplantation Association (IXA) published a Consensus Statement that outlined the key ethical and regulatory requirements to be satisfied before the initiation of xenotransplantation studies in diabetic patients. This earlier IXA Statement also documented a disparate regulatory landscape among different geographical areas. This situation clearly fell short of the 2004 World Health Assembly Resolution WHA57.18 that urged Member States "to cooperate in the formulation of recommendations and guidelines to harmonize global practices" to ensure the highest ethical and regulatory standards on a global scale. In this new IXA report, IXA members who are active in xenotransplantation research in their respective geographic areas herewith briefly describe changes in the regulatory frameworks that have taken place in the intervening period in the various geographic areas or countries. The key reassuring take-home message of the present report is that many countries have embraced the encouragement of the WHO to harmonize the procedures in a more global scale. Indeed, important regulatory changes have taken place or are in progress in several geographic areas that include Europe, Korea, Japan, and China. Such significant regulatory changes encompass the most diverse facets of the clinical application of xenotransplantation and comprise ethical aspects, source animals and product specifications, study supervision, sample archiving, patient follow-up and even insurance coverage in some legislations. All these measures are expected to provide a better care and protection of recipients of xenotransplants but also a higher safety profile to xenotransplantation procedures with an ultimate net gain in terms of international public health. PMID- 26940510 TI - Emerging drugs for the treatment of hepatitis B. AB - INTRODUCTION: Nucleos(t)ide analogs and interferon-based compounds are currently approved for the treatment of chronic hepatitis B (CHB). Although these treatments are effective in suppressing viral replication, it is unable to completely eradicate the virus from the host. Therefore, CHB patients are at a life-long risk of developing complications, including hepatocellular carcinoma. AREAS COVERED: Drugs targeting novel sites of the hepatitis B virus (HBV) replication cycle and the host immune response in development are discussed. As current available drugs only target a small segment of the HBV life cycle, the development of new agents targeting different sites is an important step in eradicating HBV. The host immunological response is also vital in viral clearance. Newer agents in development include immunomodulatory agents and therapeutic vaccines. EXPERT OPINION: For any chance of eradication, a combination of drugs targeting both the host factors and different sites of the viral life cycle will be required. Two key components to achieving this goal include the removal of covalently closed circular DNA (cccDNA) together with restoration of the immune control against HBV. PMID- 26940511 TI - Better Health Care: A Way Forward. PMID- 26940512 TI - Accumulation and partitioning of biomass, nutrients, and trace elements in switchgrass for phytoremediation of municipal biosolids. AB - In situ phytoremediation of municipal biosolids is a promising alternative to the land spreading and landfilling of biosolids from end-of-life municipal lagoons. Accumulation and partitioning of dry matter, nitrogen (N), phosphorus (P), and trace elements were determined in aboveground biomass (AGB) and belowground biomass (BGB) of switchgrass (Panicum virgatum L.) to determine the harvest stage that maximizes phytoextraction of contaminants from municipal biosolids. Seedlings were transplanted into 15-L plastic pails containing 3.9 kg (dry wt.) biosolids. Biomass yield components and contaminant concentrations were assessed every 14 days for up to 161 days. Logistic model fits to biomass yield data indicated no significant differences in asymptotic yield between AGB and BGB. Switchgrass partitioned significantly more N and P to AGB than to BGB. Maximum uptake occurred 86 days after transplanting (DAT) for N and 102 DAT for P. Harvesting at peak aboveground element accumulation removed 5% of N, 1.6% of P, 0.2% of Zn, 0.05% of Cd, and 0.1% of Cr initially present in the biosolids. These results will contribute toward identification of the harvest stage that will optimize contaminant uptake and enhance in situ phytoremediation of biosolids using switchgrass. PMID- 26940514 TI - Reliability and construct validity of the Spanish version of the 6-item CTS symptoms scale for outcomes assessment in carpal tunnel syndrome. AB - BACKGROUND: The purpose of this study was to assess the reliability and construct validity of the Spanish version of the 6-item carpal tunnel syndrome (CTS) symptoms scale (CTS-6). METHODS: In this cross-sectional study 40 patients diagnosed with CTS based on clinical and neurophysiologic criteria, completed the standard Spanish versions of the CTS-6 and the disabilities of the arm, shoulder and hand (QuickDASH) scales on two occasions with a 1-week interval. Internal consistency reliability was assessed with the Cronbach alpha coefficient and test retest reliability with the intraclass correlation coefficient, two way random effect model and absolute agreement definition (ICC2,1). Cross-sectional precision was analyzed with the Standard Error of the Measurement (SEM). Longitudinal precision for test-retest reliability coefficient was assessed with the Standard Error of the Measurement difference (SEMdiff) and the Minimal Detectable Change at 95 % confidence level (MDC95). For assessing construct validity it was hypothesized that the CTS-6 would have a strong positive correlation with the QuickDASH, analyzed with the Pearson correlation coefficient (r). RESULTS: The standard Spanish version of the CTS-6 presented a Cronbach alpha of 0.81 with a SEM of 0.3. Test-retest reliability showed an ICC of 0.85 with a SRMdiff of 0.36 and a MDC95 of 0.7. The correlation between CTS-6 and the QuickDASH was concordant with the a priori formulated construct hypothesis (r 0.69) CONCLUSIONS: The standard Spanish version of the 6-item CTS symptoms scale showed good internal consistency, test-retest reliability and construct validity for outcomes assessment in CTS. The CTS-6 will be useful to clinicians and researchers in Spanish speaking parts of the world. The use of standardized outcome measures across countries also will facilitate comparison of research results in carpal tunnel syndrome. PMID- 26940515 TI - Biodesign for bioenergetics--the design and engineering of electron transfer cofactors, proteins and protein networks. PMID- 26940513 TI - Light-evoked hyperpolarization and silencing of neurons by conjugated polymers. AB - The ability to control and modulate the action potential firing in neurons represents a powerful tool for neuroscience research and clinical applications. While neuronal excitation has been achieved with many tools, including electrical and optical stimulation, hyperpolarization and neuronal inhibition are typically obtained through patch-clamp or optogenetic manipulations. Here we report the use of conjugated polymer films interfaced with neurons for inducing a light-mediated inhibition of their electrical activity. We show that prolonged illumination of the interface triggers a sustained hyperpolarization of the neuronal membrane that significantly reduces both spontaneous and evoked action potential firing. We demonstrate that the polymeric interface can be activated by either visible or infrared light and is capable of modulating neuronal activity in brain slices and explanted retinas. These findings prove the ability of conjugated polymers to tune neuronal firing and suggest their potential application for the in-vivo modulation of neuronal activity. PMID- 26940516 TI - Thermodynamics of proton transport coupled ATP synthesis. AB - The thermodynamic H(+)/ATP ratio of the H(+)-ATP synthase from chloroplasts was measured in proteoliposomes after energization of the membrane by an acid base transition (Turina et al. 2003 [13], 418-422). The method is discussed, and all published data obtained with this system are combined and analyzed as a single dataset. This meta-analysis led to the following results. 1) At equilibrium, the transmembrane DeltapH is energetically equivalent to the transmembrane electric potential difference. 2) The standard free energy for ATP synthesis (reference reaction) is DeltaG degrees (ref)=33.8+/-1.3kJ/mol. 3) The thermodynamic H(+)/ATP ratio, as obtained from the shift of the ATP synthesis equilibrium induced by changing the transmembrane DeltapH (varying either pH(in) or pH(out)) is 4.0+/ 0.1. The structural H(+)/ATP ratio, calculated from the ratio of proton binding sites on the c-subunit-ring in F(0) to the catalytic nucleotide binding sites on the beta-subunits in F(1), is c/beta=14/3=4.7. We infer that the energy of 0.7 protons per ATP that flow through the enzyme, but do not contribute to shifting the ATP/(ADP.Pi) ratio, is used for additional processes within the enzyme, such as activation, and/or energy dissipation, due e.g. to internal uncoupling. The ratio between the thermodynamic and the structural H(+)/ATP values is 0.85, and we conclude that this value represents the efficiency of the chemiosmotic energy conversion within the chloroplast H(+)-ATP synthase. PMID- 26940517 TI - New Insights into Mechanisms and Functions of Nuclear Size Regulation. AB - Nuclear size is generally maintained within a defined range in a given cell type. Changes in cell size that occur during cell growth, development, and differentiation are accompanied by dynamic nuclear size adjustments in order to establish appropriate nuclear-to-cytoplasmic volume relationships. It has long been recognized that aberrations in nuclear size are associated with certain disease states, most notably cancer. Nuclear size and morphology must impact nuclear and cellular functions. Understanding these functional implications requires an understanding of the mechanisms that control nuclear size. In this review, we first provide a general overview of the diverse cellular structures and activities that contribute to nuclear size control, including structural components of the nucleus, effects of DNA amount and chromatin compaction, signaling, and transport pathways that impinge on the nucleus, extranuclear structures, and cell cycle state. We then detail some of the key mechanistic findings about nuclear size regulation that have been gleaned from a variety of model organisms. Lastly, we review studies that have implicated nuclear size in the regulation of cell and nuclear function and speculate on the potential functional significance of nuclear size in chromatin organization, gene expression, nuclear mechanics, and disease. With many fundamental cell biological questions remaining to be answered, the field of nuclear size regulation is still wide open. PMID- 26940518 TI - Rho Signaling in Dictyostelium discoideum. AB - Small GTPases of the Rho family are ubiquitous molecular switches involved in the regulation of most actin cytoskeleton dependent processes and many other processes not directly linked to actin. D. discoideum is a well-established model organism for studies of the actin cytoskeleton and its regulation by signal transduction pathways. D. discoideum is equipped with a complex repertoire of Rho signaling components, with 20 Rho GTPases, more than 100 regulators (including exchange factors, GTPase activating proteins and guanine nucleotide dissociation inhibitors), and nearly 80 effectors or components of effector complexes. In this review we examine the knowledge accumulated to date about proteins involved in Rho-regulated signaling pathways in D. discoideum, with an emphasis on functional studies. We integrate the information about individual components into defined signaling pathways, with a focus on three extensively investigated processes: chemotaxis, vesicle trafficking, and cytokinesis. PMID- 26940521 TI - Leukocytes Crossing the Endothelium: A Matter of Communication. AB - Leukocytes cross the endothelial vessel wall in a process called transendothelial migration (TEM). The purpose of leukocyte TEM is to clear the causing agents of inflammation in underlying tissues, for example, bacteria and viruses. During TEM, endothelial cells initiate signals that attract and guide leukocytes to sites of tissue damage. Leukocytes react by attaching to these sites and signal their readiness to move back to endothelial cells. Endothelial cells in turn respond by facilitating the passage of leukocytes while retaining overall integrity. In this review, we present recent findings in the field and we have endeavored to synthesize a coherent picture of the intricate interplay between endothelial cells and leukocytes during TEM. PMID- 26940522 TI - Membrane Dynamics and Signaling of the Coxsackievirus and Adenovirus Receptor. AB - The coxsackievirus and adenovirus receptor (CAR) belongs to the immunoglobulin superfamily and acts as a receptor for some adenovirus types and group B coxsackieviruses. Its role is best described in epithelia where CAR participates to tight junction integrity and maintenance. Recently, several studies aimed to characterize its potential interaction with intracellular signaling pathways and highlighted several features linking CAR to gene expression. In addition, the molecular mechanisms leading to CAR-specific membrane targeting via the secretory pathway in polarized cells and its internalization are starting to be unraveled. This chapter discusses the interaction between membrane dynamics, intracellular trafficking, and signaling of CAR. PMID- 26940523 TI - Catecholaminergic System of Invertebrates: Comparative and Evolutionary Aspects in Comparison With the Octopaminergic System. AB - In this review we examined the catecholaminergic system of invertebrates, starting from protists and getting to chordates. Different techniques used by numerous researchers revealed, in most examined phyla, the presence of catecholamines dopamine, noradrenaline, and adrenaline or of the enzymes involved in their synthesis. The catecholamines are generally linked to the nervous system and they can act as neurotransmitters, neuromodulators, and hormones; moreover they play a very important role as regards the response to a large number of stress situations. Nevertheless, in some invertebrate phyla belonging to Protostoma, the monoamine octopamine is the main biogenic amine. The presence of catecholamines in some protists suggests a role as intracellular or interorganismal signaling molecules and an ancient origin of their synthetic pathways. The catecholamines appear also involved in the regulation of bioluminescence and in the control of larval development and metamorphosis in some marine invertebrate phyla. PMID- 26940524 TI - Laparoscopic revision of Roux-en-Y gastric bypass to sleeve gastrectomy: A ray of hope for failed Roux-en-Y gastric bypass. AB - INTRODUCTION: Roux-en-Y gastric bypass (RYGB) is the most commonly performed bariatric operation across the world, but sometimes revision is necessary. Inadequate weight loss, weight regain, and complications such as dumping syndrome are common reasons for revision. We report the 1-year outcomes of five patients who underwent laparoscopic conversion of RYGB to sleeve gastrectomy during surgical revision. METHODS: Mean age was 38.8 +/- 9.1 years. Mean BMI at primary surgery was 57.9 +/- 8.1 kg/m(2) . Two patients were diabetic and sleep apneic. One was hypertensive. All patients underwent a RYGB as the primary weight loss procedure. Mean weight loss was 36.8 +/- 8.6 kg (excess weight loss = 39.8 +/- 14.9%) at 2 years. At the end of 5 years, these patients regained 10.9 +/- 4.1 kg (31.5 +/- 13.6% of excess weight loss). Primary indications for revision surgery were failure to lose weight, weight regain, and intractable dumping syndrome. Mean duration between primary and revision surgery was 6.2 +/- 1.1 years. RYGB was converted to sleeve gastrectomy as a first stage in all cases. RESULTS: Mean duration of revision surgery was 120.0 +/- 15.5 min. Mean blood loss was 70 +/- 50 mL. One year after revision surgery, a mean weight loss of 21.5 +/- 10.5 kg was achieved (mean excess weight loss = 35.8 +/- 8.8%). Two patients with type 2 diabetes mellitus and the one with hypertension achieved remission. Dumping was resolved. There were no complications. CONCLUSION: Laparoscopic conversion of RYGB to sleeve gastrectomy as a first stage may be considered as an additional option in the armamentarium of revision procedures after RYGB. PMID- 26940520 TI - Membrane Trafficking in Neuronal Development: Ins and Outs of Neural Connectivity. AB - During development, neurons progress through rapid yet stereotypical shape changes to achieve proper neuronal connectivity. This morphological progression requires carefully orchestrated plasma membrane expansion, insertion of membrane components including receptors for extracellular cues into the plasma membrane and removal and trafficking of membrane materials and proteins to specific locations. This review outlines the cellular machinery of membrane trafficking that play an integral role in neuronal cell shape change and function from initial neurite formation to pathway navigation and synaptogenesis. PMID- 26940525 TI - Experts seek ban on tackling in school rugby to prevent child injuries. PMID- 26940526 TI - Membrane association of SadC enhances its diguanylate cyclase activity to control exopolysaccharides synthesis and biofilm formation in Pseudomonas aeruginosa. AB - Cyclic diguanosine monophosphate (c-di-GMP) is one of the most important bacterial second messengers that controls many bacterial cellular functions including lifestyle switch between plankton and biofilm. Surface attachment defective (SadC) is a diguanylate cyclase (DGC) involved in the biosynthesis of c di-GMP in Pseudomonas aeruginosa, an opportunistic pathogen that can cause diverse infections. Here we report the crystal structure of GGDEF domain from SadC and the critical role of the trans-membrane (TM) domain of SadC with regard to biofilm formation, exopolysaccharide production and motility. We showed that over-expression of SadC in P. aeruginosa PAO1 totally inhibited swimming motility and significantly enhanced the production of exopolysaccharide Psl. SadC lacking TM domains (SadC300-487 ) could not localize on cytoplasmic membrane and form cluster, lost the ability to inhibit the swimming and twitching motility, and showed the attenuated activity to promote Psl production despite that SadC300-487 was able to catalyze the synthesize of c-di-GMP in vitro and in vivo. The GGDEF domain of SadC has a typical GGDEF structure and the alpha-helix connected the TM domains with SadC GGDEF domain is essential for SadC to form DGC oligomers. Our data imply that membrane association of SadC promotes its DGC activity by affecting the formation of active DGC oligomers. PMID- 26940527 TI - The IASLC Lung Cancer Staging Project: Background Data and Proposals for the Application of TNM Staging Rules to Lung Cancer Presenting as Multiple Nodules with Ground Glass or Lepidic Features or a Pneumonic Type of Involvement in the Forthcoming Eighth Edition of the TNM Classification. AB - INTRODUCTION: Application of tumor, node, and metastasis (TNM) classification is difficult in patients with lung cancer presenting as multiple ground glass nodules or with diffuse pneumonic-type involvement. Clarification of how to do this is needed for the forthcoming eighth edition of TNM classification. METHODS: A subcommittee of the International Association for the Study of Lung Cancer Staging and Prognostic Factors Committee conducted a systematic literature review to build an evidence base regarding such tumors. An iterative process that included an extended workgroup was used to develop proposals for TNM classification. RESULTS: Patients with multiple tumors with a prominent ground glass component on imaging or lepidic component on microscopy are being seen with increasing frequency. These tumors are associated with good survival after resection and a decreased propensity for nodal and extrathoracic metastases. Diffuse pneumonic-type involvement in the lung is associated with a worse prognosis, but also with a decreased propensity for nodal and distant metastases. CONCLUSION: For multifocal ground glass/lepidic tumors, we propose that the T category be determined by the highest T lesion, with either the number of tumors or m in parentheses to denote the multifocal nature, and that a single N and M category be used for all the lesions collectively-for example, T1a(3)N0M0 or T1b(m)N0M0. For diffuse pneumonic-type lung cancer we propose that the T category be designated by size (or T3) if in one lobe, as T4 if involving an ipsilateral different lobe, or as M1a if contralateral and that a single N and M category be used for all pulmonary areas of involvement. PMID- 26940519 TI - Building Blocks of Functioning Brain: Cytoskeletal Dynamics in Neuronal Development. AB - Neural connectivity requires proper polarization of neurons, guidance to appropriate target locations, and establishment of synaptic connections. From when neurons are born to when they finally reach their synaptic partners, neurons undergo constant rearrangment of the cytoskeleton to achieve appropriate shape and polarity. Of particular importance to neuronal guidance to target locations is the growth cone at the tip of the axon. Growth-cone steering is also dictated by the underlying cytoskeleton. All these changes require spatiotemporal control of the cytoskeletal machinery. This review summarizes the proteins that are involved in modulating the actin and microtubule cytoskeleton during the various stages of neuronal development. PMID- 26940529 TI - Early Weight Loss during Chemoradiotherapy Has a Detrimental Impact on Outcome in NSCLC. AB - OBJECTIVES: The aim of this study was to assess the effect of early weight loss before the onset of radiation esophagitis on overall survival (OS) in patients with non-small cell lung cancer treated with concurrent chemoradiotherapy. METHODS: Characteristics (e.g., patient weight, radiation esophagitis score, sex, World Health Organization performance status, chemotherapy dose, nodal status, and gross tumor volume) of 151 patients who received concurrent chemoradiotherapy (in 2006-2013) were retrospectively correlated with OS. Early weight loss was defined as weight loss of more than 5% between the start and third week of radiotherapy in patients whose weight was stable before treatment initiation. RESULTS: In 17% of the patients early weight loss was observed. Median OS (95% confidence interval [CI]) was significantly shorter in the early weight loss group (OS = 13.0 months, 95% CI: 2.0-24.0) versus in the non-early weight loss group (OS = 23.0 months, 95% CI: 14.7-31.3) (hazard ratio [HR] = 1.8, 95% CI: 1.12-2.96, p = 0.017). On multivariate analysis sex (HR = 2.1, 95% CI: 1.33-3.29, p = 0.001), World Health Organization performance status (HR = 1.9, 95% CI: 1.20 2.97, p = 0.006), nodal status (HR = 2.9, 95% CI: 1.38-6.01, p = 0.005), and early weight loss (HR = 1.9, 95% CI: 1.10-3.19, p = 0.022) were associated with OS. CONCLUSIONS: Early weight loss in patients with non-small cell lung cancer was found to be associated with worse prognosis. These data warrant further investigation into the efficacy of tailored intervention to prevent early weight loss. PMID- 26940532 TI - A liquid-crystal-based DNA biosensor for pathogen detection. AB - A liquid-crystal (LC)-filled transmission electron microscopy (TEM) grid cell coated with the cationic surfactant dodecyltrimethylammonium bromide (DTAB), to which a single-stranded deoxyribonucleic acid probe (ssDNAprobe) was adsorbed at the LC/aqueous interface (TEMDTAB/DNA), was applied for the highly specific detection of target DNA molecules. The DTAB-coated E7 (used LC mixture) in the TEM grid (TEMDTAB) exhibited a homeotropic orientation, and changed to a planar orientation upon adsorption of the ssDNAprobe. The TEMDTAB/DNA was then exposed to complementary (target) ssDNA, which resulted in a planar-to-homeotropic configurational change of E7 that could be observed through a polarized optical microscope under crossed polarizers. The optimum adsorption density (2 MUM) of ssDNAprobe enabled the detection of >=0.05 nM complementary ssDNA. This TEMDTAB/DNA biosensor could differentiate complementary ssDNA from mismatched ssDNA as well as double-stranded DNA. It also successfully detected the genomic DNAs of the bacterium Erwinia carotovora and the fungi Rhazictonia solani. Owe to the high specificity, sensitivity, and label-free detection, this biosensor may broaden the applications of LC-based biosensors to pathogen detection. PMID- 26940533 TI - Barbershop Prostate Cancer Education: Factors Associated With Client Knowledge. AB - The purpose of this article is to identify characteristics of Black barbershop clients and barbers in an urban Midwestern city participating in a health promotion program called Affecting Cancer Together (ACT) that are associated with client knowledge about prostate cancer. Statistical analyses examined client and barber characteristics for their potential association with client prostate cancer knowledge, while controlling for ACT variables. Study findings suggested clients who are married (beta = 0.99; confidence interval [CI] = 0.38, 1.59; p < .01) and have higher levels of education (beta = 0.34; CI = 0.01, 0.67; p = .04) may be more likely to know more about prostate cancer. Barbers with at least "some college" education may be more effective in increasing client knowledge (beta = 0.85; CI = 0.05, 1.64; p = .04). Trained peer-helper programs may consider prioritizing limited educational resources for barbers with at least some college education and incorporating the social support of spouses for making informed decisions. Considering the potential of barbershop programs to reach Black men about a serious racially disproportionate health issue, ameliorating adoption, implementation, effectiveness, and sustainment are an important public health priority for underserved populations. PMID- 26940534 TI - Geographical distribution of Angiostrongylus vasorum in foxes (Vulpes vulpes) in the Republic of Ireland. AB - The reported incidence of the metastrongylid nematode Angiostrongylus vasorum, that infects dogs and other canids, is increasing worldwide outside recognized endemic foci. This apparent expansion of the parasite's range is causing concern to veterinary clinicians as the disease caused in dogs can be life threatening and its treatment is not straightforward. The red fox is thought to be a reservoir host for dogs. To investigate the spatial distribution of infection in foxes in Ireland, the hearts and lungs of 542 foxes from all over Ireland were examined. The incidence of infection was found to be 39.9% [95% confidence interval (CI) 35.7-44.1] with positive samples occurring in each of the country's 26 counties. This report confirms that the parasite is endemic in Ireland and the overall prevalence is the second highest in Europe. This is the first survey of A. vasorum infection in Irish foxes and highlights the potential exposure of the Irish dog population to high risk of cross-infection. Additionally, Crenosoma vulpis was found in seven of the foxes, a parasite not previously reported in the Irish fox. PMID- 26940528 TI - The IASLC Lung Cancer Staging Project: Summary of Proposals for Revisions of the Classification of Lung Cancers with Multiple Pulmonary Sites of Involvement in the Forthcoming Eighth Edition of the TNM Classification. AB - INTRODUCTION: Patients with lung cancer who harbor multiple pulmonary sites of disease have been challenging to classify; a subcommittee of the International Association for the Study of Lung Cancer Staging and Prognostic Factors Committee was charged with developing proposals for the eighth edition of the tumor, node, and metastasis (TNM) classification to address this issue. METHODS: A systematic literature review and analysis of the International Association for the Study of Lung Cancer database was performed to develop proposals for revision in an iterative process involving multispecialty international input and review. RESULTS: Details of the evidence base are summarized in other articles. Four patterns of disease are recognized; the clinical presentation, pathologic correlates, and biologic behavior of these suggest specific applications of the TNM classification rules. First, it is proposed that second primary lung cancers be designated with a T, N, and M category for each tumor. Second, tumors with a separate tumor nodule of the same histologic type (either suspected or proved) should be classified according to the location of the separate nodule relative to the index tumor-T3 for a same-lobe, T4 for a same-side (different lobe), and M1a for an other-side location-with a single N and M category. Third, multiple tumors with prominent ground glass (imaging) or lepidic (histologic) features should be designated by the T category of the highest T lesion, the number or m in parentheses (#/m) to indicate the multiplicity, and a collective N and M category for all. Finally, it is proposed that diffuse pneumonic-type lung cancers be designated by size (or T3) if in one lobe, T4 if involving multiple same-side lobes, and M1a if involving both lungs with a single N and M category for all areas of involvement. CONCLUSION: We propose to tailor TNM classification of multiple pulmonary sites of lung cancer to reflect the unique aspects of four different patterns of presentation. We hope that this will lead to more consistent classification and clarity in communication and facilitate further research in the nature and optimal treatment of these entities. PMID- 26940530 TI - The IASLC Lung Cancer Staging Project: Background Data and Proposals for the Classification of Lung Cancer with Separate Tumor Nodules in the Forthcoming Eighth Edition of the TNM Classification for Lung Cancer. AB - INTRODUCTION: Separate tumor nodules with the same histologic appearance occur in the lungs in a small proportion of patients with primary lung cancer. This article addresses how such tumors can be classified to inform the eighth edition of the anatomic classification of lung cancer. Separate tumor nodules should be distinguished from second primary lung cancer, multifocal ground glass/lepidic tumors, and pneumonic-type lung cancer, which are addressed in separate analyses. METHODS: Survival of patients with separate tumor nodules in the International Association for the Study of Lung Cancer database were analyzed. This was compared with a systematic literature review. RESULTS: Survival of clinically staged patients decreased according to the location of the separate tumor nodule relative to the index tumor (same lobe > same side > other side) in N0 and N-any cohorts (all M0 except possible other-side nodules). However, there was also a decrease in the proportion of patients resected; among only surgically resected or among nonresected patients no survival differences were noted. There were no survival differences between patients with same-lobe nodules and those with other T3 tumors, between patients with same-side nodules and those with T4 tumors, and patients with other-side nodules and those with other M1a tumors. The data correlated with those identified in a literature review. CONCLUSIONS: Tumors with same-lobe separate tumor nodules (with the same histologic appearance) are recommended to be classified as T3, same-side nodules as T4, and other-side nodules as M1a. Thus, there is no recommended change between the seventh and eighth edition of the TNM classification of lung cancer. PMID- 26940535 TI - Depleted interstitial cells of Cajal and fibrosis in the pylorus: Novel features of gastroparesis. AB - BACKGROUND: Depletion and ultrastructural changes of interstitial cells of Cajal (ICC) in the gastric body and antrum have been observed in gastroparesis. This research was performed to investigate the ICC population in the muscularis propria and fibrosis of the muscular layer of the pylorus in gastroparesis. METHODS: Full thickness pyloric and antral biopsies were obtained from 17 gastroparetic and 6 non-gastroparetic controls. Biopsies were stained with C-Kit for ICC and Trichrome for collagen fibrosis. Interstitial cells of Cajal depletion in the antrum was defined as mean ICC count <10 per 20 high power fields (HPF) based on established data. KEY RESULTS: The average pyloric ICC count was >=10/HPF in the control patients. Twelve (70.5%) gastroparetic patients had pyloric ICC loss. Only five patients (29.4%) had ICC loss in the antrum. Gastric emptying (GE) was not significantly different in patients with depleted vs normal pyloric ICC. However, GE at 2 h was slower in patients with antral ICC <10/HPF compared to those with normal antral ICC populations. Collagen fibrosis was observed in the pylorus of 14 (82.3%) patients. Inclusion bodies in the muscularis propria of the pylorus were identified in four patients, all with diabetic gastroparesis. CONCLUSIONS & INFERENCES: In gastroparetic patients, ICC loss in the pylorus is twice as common as in the antrum and fibrosis in the pyloric smooth muscle is nearly three times more common than the antrum. These findings can provide one explanation for pyloric dysfunction which is a contributing factor to the pathophysiology of gastroparesis. PMID- 26940531 TI - Single cell transcriptome analysis of mouse carotid body glomus cells. AB - KEY POINTS: Carotid body (CB) glomus cells mediate acute oxygen sensing and the initiation of the hypoxic ventilatory response, yet the gene expression profile of these cells is not available. We demonstrate that the single cell RNA-Seq method is a powerful tool for identifying highly expressed genes in CB glomus cells. Our single cell RNA-Seq results characterized novel CB glomus cell genes, including members of the G protein-coupled receptor signalling pathway, ion channels and atypical mitochondrial electron transport chain subunits. A heterologous cell-based screening identified acetate (which is known to affect CB glomus cell activity) as an agonist for the most highly abundant G protein coupled receptor (Olfr78) in CB glomus cells. These data established the first transcriptome profile of CB glomus cells, highlighting genes with potential implications in CB chemosensory function. ABSTRACT: The carotid body (CB) is a major arterial chemoreceptor containing glomus cells whose activities are regulated by changes in arterial blood content, including oxygen. Despite significant advancements in the characterization of their physiological properties, our understanding of the underlying molecular machinery and signalling pathway in CB glomus cells is still limited. To overcome this, we employed the single cell RNA-Seq method by performing next-generation sequencing on single glomus cell-derived cDNAs to eliminate contamination of genes derived from other cell types present in the CB. Using this method, we identified a set of genes abundantly expressed in glomus cells, which contained novel glomus cell specific genes. Transcriptome and subsequent in situ hybridization and immunohistochemistry analyses identified abundant G protein-coupled receptor signalling pathway components and various types of ion channels, as well as members of the hypoxia-inducible factors pathway. A short-chain fatty acid olfactory receptor Olfr78, recently implicated in CB function, was the most abundant G protein-coupled receptor. Two atypical mitochondrial electron transport chain subunits (Ndufa4l2 and Cox4i2) were among the most specifically expressed genes in CB glomus cells, highlighting their potential roles in mitochondria-mediated oxygen sensing. The wealth of information provided by the present study offers a valuable foundation for identifying molecules functioning in the CB. PMID- 26940536 TI - Approximated prediction of genomic selection accuracy when reference and candidate populations are related. AB - BACKGROUND: Genomic selection is still to be evaluated and optimized in many species. Mathematical modeling of selection schemes prior to their implementation is a classical and useful tool for that purpose. These models include formalization of a number of entities including the precision of the estimated breeding value. To model genomic selection schemes, equations that predict this reliability as a function of factors such as the size of the reference population, its diversity, its genetic distance from the group of selection candidates genotyped, number of markers and strength of linkage disequilibrium are needed. The present paper aims at exploring new approximations of this reliability. RESULTS: Two alternative approximations are proposed for the estimation of the reliability of genomic estimated breeding values (GEBV) in the case of non-independence between candidate and reference populations. Both were derived from the Taylor series heuristic approach suggested by Goddard in 2009. A numerical exploration of their properties showed that the series were not equivalent in terms of convergence to the exact reliability, that the approximations may overestimate the precision of GEBV and that they converged towards their theoretical expectations. Formulae derived for these approximations were simple to handle in the case of independent markers. A few parameters that describe the markers' genotypic variability (allele frequencies, linkage disequilibrium) can be estimated from genomic data corresponding to the population of interest or after making assumptions about their distribution. When markers are not in linkage equilibrium, replacing the real number of markers and QTL by the "effective number of independent loci", as proposed earlier is a practical solution. In this paper, we considered an alternative, i.e. an "equivalent number of independent loci" which would give a GEBV reliability for unrelated individuals by considering a sub-set of independent markers that is identical to the reliability obtained by considering the full set of markers. CONCLUSIONS: This paper is a further step towards the development of deterministic models that describe breeding plans based on the use of genomic information. Such deterministic models carry low computational burden, which allows design optimization through intensive numerical exploration. PMID- 26940539 TI - Non-monotonic effect of confinement on the glass transition. AB - The relaxation dynamics of glass forming liquids and their structure are influenced in the vicinity of confining walls. This effect has mostly been observed to be a monotonic function of the slit width. Recently, a qualitatively new behaviour has been uncovered by Mittal and coworkers, who reported that the single particle dynamics in a hard-sphere fluid confined in a planar slit varies in a non-monotonic way as the slit width is decreased from five to roughly two particle diametres (Mittal et al 2008 Phys. Rev. Lett. 100 145901). In view of the great potential of this effect for applications in those fields of science and industry, where liquids occur under strong confinement (e.g. nano technology), the number of researchers studying various aspects and consequences of this non-monotonic behaviour has been rapidly growing. This review aims at providing an overview of the research activity in this newly emerging field. We first briefly discuss how competing mechanisms such as packing effects and short range attraction may lead to a non-monotonic glass transition scenario in the bulk. We then analyse confinement effects on the dynamics of fluids using a thermodynamic route which relates the single particle dynamics to the excess entropy. Moreover, relating the diffusive dynamics to the Widom's insertion probability, the oscillations of the local dynamics with density at moderate densities are fairly well described. At high densities belonging to the supercooled regime, however, this approach breaks down signaling the onset of strongly collective effects. Indeed, confinement introduces a new length scale which in the limit of high densities and small pore sizes competes with the short range local order of the fluid. This gives rise to a non-monotonic dependence of the packing structure on confinement, with a corresponding effect on the dynamics of structural relaxation. This non-monotonic effect occurs also in the case of a cone-plate type channel, where the degree of confinement varies with distance from the apex. This is a very promising issue for future research with the possibility of uncovering the existence of alternating glassy and liquid-like domains. PMID- 26940537 TI - The role of allergen components for the diagnosis of latex-induced occupational asthma. AB - BACKGROUND: Recombinant Hevea brasiliensis (rHev b) natural rubber latex (NRL) allergen components have been developed to assess the patients' allergen sensitization profile and to improve the diagnosis of NRL allergy. OBJECTIVE: To examine whether the determination of specific IgE (sIgE) reactivity to a panel of recombinant allergen components would be helpful for diagnosing NRL-induced occupational asthma (OA) in predicting the outcome of a specific inhalation test. METHODS: sIgE levels to NRL extract and 12 recombinant NRL allergen components were assessed in 82 subjects with OA ascertained by a positive specific inhalation challenge (SIC) with NRL gloves and in 25 symptomatic subjects with a negative challenge. RESULTS: The sensitivity, specificity, positive predictive value, and negative predictive value of a NRL-sIgE level >=0.35 kUA /l as compared to the result of SICs were 94%, 48%, 86%, and 71%, respectively. The positive predictive value increased above 95% when increasing the cutoff value to 5.41 kUA /l. Subjects with a positive SIC showed a significantly higher rate of sIgE reactivity to rHev b 5, 6.01, 6.02, and 11 than those with a negative SIC. A sIgE sum score against rHev b 5 plus 6.01/6.02 >= 1.46 kUA /l provided a positive predictive value >95% with a higher sensitivity (79%) and diagnostic efficiency (Youden index: 0.67) as compared with a NRL-sIgE >=5.41 kUA /l (49% and 0.41, respectively). CONCLUSION: In suspected OA, high levels of sIgE against rHev b 5 combined with rHev b 6.01 or 6.02 are the most efficient predictors of a bronchial response to NRL. PMID- 26940538 TI - Patterns of drug therapy in newly diagnosed Spanish patients with systemic lupus erythematosus. AB - OBJECTIVES: This is the first Spanish multicentric inception lupus cohort, formed by SLE patients attending Spanish Internal Medicine Services since January 2009. We aimed to analyse drug therapy during the first year of follow-up according to disease severity. METHODS: 223 patients who had at least one year of follow-up were enrolled upon diagnosis of SLE. Therapy with prednisone, pulse methyl prednisolone, hydroxychloroquine, immunosuppressives and calcium/vitamin D was analysed. RESULTS: Prednisone was given to 65% patients, at a mean (SD) daily dose of 11 (10) mg/d. 38% patients received average doses >7.5 mg/d during the first year. Patients with nephritis and with a SLEDAI >=6 were treated with higher doses of prednisone. 81% of patients were treated with hydroxychloroquine, with higher frequency among those with a SLEDAI >=6 (88% vs. 68%, p<0.001). The use of immunosuppressive drugs and methyl-prednisolone pulses was higher in patients with a baseline SLEDAI >=6, however, differences were no longer significant when patients with lupus nephritis were excluded. The use of calcium/vitamin D increased with the dose of prednisone, however, 43% of patients on medium-high doses of prednisone did not take any calcium or vitamin D. CONCLUSIONS: This study gives a real-world view of the current therapeutic approach to early lupus in Spain. The generalised use of hydroxychloroquine is well consolidated. There is still a tendency to use prednisone at medium to high doses. Pulse methyl-prednisolone and immunosuppressive drugs were used in more severe cases, but not as steroid sparing agents. Vitamin D use was suboptimal. PMID- 26940541 TI - Decorated self-assembling beta(3)-tripeptide foldamers form cell adhesive scaffolds. AB - A popular strategy to control cellular growth and differentiation is the employment of self-assembling peptides as biomaterials. In this study we decorated ultrashort helical N-acetylated beta-tripeptides with cell adhesion signals IKVAV and RGD, which spontaneously self-assemble to give nanofibres with multiple signals, and form a bioscaffold that supports the growth of cells. PMID- 26940540 TI - Restless legs syndrome in Wilson's disease: frequency, characteristics, and mimics. AB - OBJECTIVE: To determine characteristics, clinical significance, frequency, and mimics of restless legs syndrome (RLS) in a cohort of Wilson's disease (WD, n = 42/f = 18), compared to healthy, matched controls. MATERIALS AND METHODS: Structured clinical interviews (patients and caregiving family members), repeated neurological examinations (afternoon and presleep), comprehensive laboratory tests, WD-, RLS-, and sleep-specific rating scales, and video-polysomnography. RESULTS: Thirteen patients with WD (13/42 = 31.0%) clearly fulfilled the five diagnostic criteria of RLS; in eight patients (19.1%), the burden of RLS was clinically significant. The RLS was of moderate severity, equally distributed among sexes, manifested mainly in the evening and before falling asleep, and had developed mostly after clinical manifestation of WD (time elapsed 10.2 +/- 14.5 years), still at a young mean age (27.5 +/- 11.5 years). The known RLS-associated features were absent (normal iron and kidney parameters) or rare (positive family history, polyneuropathy). Compared to WD patients without RLS, patients with RLS were significantly elder and had suffered longer from WD. WD-specific RLS mimics as well as RLS confounding motor comorbidities (dystonia, tremor, chorea) were frequent and a diagnostic challenge; in difficult cases, the differentiation was reached by clinical observation of the motor behavior in the evening or at nighttime. CONCLUSION: RLS was frequent in this cohort of WD and might be causally related to WD. RLS should be included in the diagnostic work-up of WD. In complex motor disorders, differential diagnosis of RLS might require evening/nighttime examination and video-polysomnography. In WD patients with a clinically significant RLS, treatment with dopaminergic substances may be considered. PMID- 26940542 TI - Development of massive multilevel molecular dynamics simulation program, Platypus (PLATform for dYnamic Protein Unified Simulation), for the elucidation of protein functions. AB - A massively parallel program for quantum mechanical-molecular mechanical (QM/MM) molecular dynamics simulation, called Platypus (PLATform for dYnamic Protein Unified Simulation), was developed to elucidate protein functions. The speedup and the parallelization ratio of Platypus in the QM and QM/MM calculations were assessed for a bacteriochlorophyll dimer in the photosynthetic reaction center (DIMER) on the K computer, a massively parallel computer achieving 10 PetaFLOPs with 705,024 cores. Platypus exhibited the increase in speedup up to 20,000 core processors at the HF/cc-pVDZ and B3LYP/cc-pVDZ, and up to 10,000 core processors by the CASCI(16,16)/6-31G** calculations. We also performed excited QM/MM-MD simulations on the chromophore of Sirius (SIRIUS) in water. Sirius is a pH insensitive and photo-stable ultramarine fluorescent protein. Platypus accelerated on-the-fly excited-state QM/MM-MD simulations for SIRIUS in water, using over 4000 core processors. In addition, it also succeeded in 50-ps (200,000 step) on-the-fly excited-state QM/MM-MD simulations for the SIRIUS in water. PMID- 26940543 TI - Mitochondrial coding genome analysis of tropical root-knot nematodes (Meloidogyne) supports haplotype based diagnostics and reveals evidence of recent reticulate evolution. AB - The polyphagous parthenogenetic root-knot nematodes of the genus Meloidogyne are considered to be the most significant nematode pest in sub-tropical and tropical agriculture. Despite the crucial need for correct diagnosis, identification of these pathogens remains problematic. The traditionally used diagnostic strategies, including morphometrics, host-range tests, biochemical and molecular techniques, now appear to be unreliable due to the recently-suggested hybrid origin of root-knot nematodes. In order to determine a suitable barcode region for these pathogens nine quickly-evolving mitochondrial coding genes were screened. Resulting haplotype networks revealed closely related lineages indicating a recent speciation, an anthropogenic-aided distribution through agricultural practices, and evidence for reticulate evolution within M. arenaria. Nonetheless, nucleotide polymorphisms harbor enough variation to distinguish these closely-related lineages. Furthermore, completeness of lineage sorting was verified by screening 80 populations from widespread geographical origins and variable hosts. Importantly, our results indicate that mitochondrial haplotypes are strongly linked and consistent with traditional esterase isozyme patterns, suggesting that different parthenogenetic lineages can be reliably identified using mitochondrial haplotypes. The study indicates that the barcode region Nad5 can reliably identify the major lineages of tropical root-knot nematodes. PMID- 26940545 TI - Laparoscopic versus traditional peritoneal dialysis catheter insertion: a meta analysis. AB - OBJECTIVE: The objective of this study is to compare the catheter-related complications as well as catheter survival between laparoscopic and traditional surgery in peritoneal dialysis catheter insertion. RESULTS: Five randomized controlled trials and 11 cohort studies were identified. Meta-analysis showed laparoscopic catheter is superior to traditional surgery in terms of controlling catheter migration (OR 0.17, 95% CI 0.08-0.33; p < 0.00001) and catheter survival rate (1-year survival rate: OR 3.05, 95% CI 1.72-5.41, p = 0.0001; 2-year survival rate: OR 2. 07, 95% CI 1.29-3.33, p = 0.0001), but slightly increases the risk of bleeding (OR 2.13, 95% CI 1.07-4.23, p = 0.03). The two groups were not significantly different in other catheter-related complications. As regards the quality of the analysis, only the migration analysis ranked A-level, while the rest fell into Class B or C. The overall research quality was moderate. CONCLUSION: Laparoscopic surgery is superior to traditional surgery on reducing catheter migration and prolonging catheter survival rate according to our analysis. PMID- 26940546 TI - Outstanding supercapacitive properties of Mn-doped TiO2 micro/nanostructure porous film prepared by anodization method. AB - Mn-doped TiO2 micro/nanostructure porous film was prepared by anodizing a Ti-Mn alloy. The film annealed at 300 degrees C yields the highest areal capacitance of 1451.3 mF/cm(2) at a current density of 3 mA/cm(2) when used as a high performance supercapacitor electrode. Areal capacitance retention is 63.7% when the current density increases from 3 to 20 mA/cm(2), and the capacitance retention is 88.1% after 5,000 cycles. The superior areal capacitance of the porous film is derived from the brush-like metal substrate, which could greatly increase the contact area, improve the charge transport ability at the oxide layer/metal substrate interface, and thereby significantly enhance the electrochemical activities toward high performance energy storage. Additionally, the effects of manganese content and specific surface area of the porous film on the supercapacitive performance were also investigated in this work. PMID- 26940544 TI - Macrophage Migration Inhibitory Factor (MIF) Deficiency Exacerbates Aging-Induced Cardiac Remodeling and Dysfunction Despite Improved Inflammation: Role of Autophagy Regulation. AB - Aging leads to unfavorable geometric and functional sequelae in the heart. The proinflammatory cytokine macrophage migration inhibitory factor (MIF) plays a role in the maintenance of cardiac homeostasis under stress conditions although its impact in cardiac aging remains elusive. This study was designed to evaluate the role of MIF in aging-induced cardiac anomalies and the underlying mechanism involved. Cardiac geometry, contractile and intracellular Ca(2+) properties were examined in young (3-4 mo) or old (24 mo) wild type and MIF knockout (MIF(-/-)) mice. Our data revealed that MIF knockout exacerbated aging-induced unfavorable structural and functional changes in the heart. The detrimental effect of MIF knockout was associated with accentuated loss in cardiac autophagy with aging. Aging promoted cardiac inflammation, the effect was attenuated by MIF knockout. Intriguingly, aging-induced unfavorable responses were reversed by treatment with the autophagy inducer rapamycin, with improved myocardial ATP availability in aged WT and MIF(-/-) mice. Using an in vitro model of senescence, MIF knockdown exacerbated doxorubicin-induced premature senescence in H9C2 myoblasts, the effect was ablated by MIF replenishment. Our data indicated that MIF knockout exacerbates aging-induced cardiac remodeling and functional anomalies despite improved inflammation, probably through attenuating loss of autophagy and ATP availability in the heart. PMID- 26940547 TI - Impact of two rounds of praziquantel mass drug administration on Schistosoma mansoni infection prevalence and intensity: a comparison between community wide treatment and school based treatment in western Kenya. AB - This study compared the effectiveness of the community-wide treatment and school based treatment approaches in the control of Schistosoma mansoni infections in villages with ?25% prevalence in western Kenya. Stool samples from first year students, 9-12year olds and adults (20-55years) were analyzed by the Kato-Katz technique for S. mansoni eggs. After two rounds of treatment, S. mansoni prevalence and intensity levels significantly declined in both treatment approaches. Prevalence comparisons between the two approaches did not show any significant differences following treatment. However, infection intensity levels in the 9-12year old school-attending pupils were significantly higher in the community-wide treatment arm than in the school-based treatment arm. Nevertheless, significant reductions in S. mansoni infection prevalence and intensity levels were achieved among school-age children regardless of the treatment approach used. PMID- 26940549 TI - Colonoscopy surveillance: guidelines for polyps and IBD. AB - INTRODUCTION: Evidence on the optimal postpolypectomy surveillance strategies for subjects undergoing colorectal cancer screening as well as among IBD patients, is limited. In the absence of strong evidence, currently adopted guidelines are mainly based on experts' opinion and low quality data and they are often influenced by a safety-first approach and are not consistent. Given the lack of conclusive data from randomized controlled trials and uncertainty about the extent of risk of adenoma patients developing CRC in the future, there is uncertainty regarding cost-effectiveness of surveillance protocols. This may partly explain discrepancies in guidelines recommendations, with regard to definition of risk categories and of the recommended surveillance intervals. Uncertainty persists concerning management of patients with small advanced adenomas (size <10 mm and villous component >20% and/or high-grade dysplasia), high-risk adenomas and serrated polyps. EVIDENCE ACQUISITION: We retrieved the most recent guidelines for postpolypectomy surveillance from Europe and US and we conducted an additional PUBMED search for guidelines, systematic reviews (SR) and primary studies published after the last search update of the most recent review,8 presenting data about predictors of the risk of CRC and adenoma recurrence following polypectomy, and also about surveillance practice and surveillance related workload EVIDENCE SYNTHESIS: The findings of surveys conducted in clinical settings and population screening programs are showing a wide variability in the recommended surveillance protocols. CONCLUSIONS: To be able to adopt evidence bases approach additional information is needed about the risk of CRC and/or advanced adenomas with and without surveillance, as well as about the efficacy of endoscopic surveillance in reducing CRC risk. Indeed, the offer of colonoscopy for surveillance may not be justified if the risk of developing CRC among subjects with removed adenomas is not significantly increased compared to the general population, or, even if the risk is increased, performance of surveillance exams does not result in a reduction of this risk. PMID- 26940550 TI - Microstructural Evolution in 2101 Lean Duplex Stainless Steel During Low- and Intermediate-Temperature Aging. AB - The microstructural evolution of a 2101 lean duplex stainless steel (DSS) during isothermal aging from room temperature to 470 degrees C was investigated using thermoelectric power (TEP) measurements to follow the kinetics, atom probe tomography, and transmission electron microscopy. Despite the low Ni, Cr, and Mo contents, the lean DSS was sensitive to alpha-alpha' phase separation and Ni-Mn Si-Al-Cu clustering at intermediate temperatures. The time-temperature pairs characteristic of the early stages of ferrite decomposition were determined from the TEP kinetics. Considering their composition and locations, the clusters are most likely G phase precursors. PMID- 26940551 TI - Corrigendum: Role of transcription factor-mediated nucleosome disassembly in PHO5 gene expression. PMID- 26940548 TI - Protection from septic peritonitis by rapid neutrophil recruitment through omental high endothelial venules. AB - Acute peritonitis is a frequent medical condition that can trigger severe sepsis as a life-threatening complication. Neutrophils are first-responders in infection but recruitment mechanisms to the abdominal cavity remain poorly defined. Here, we demonstrate that high endothelial venules (HEVs) of the greater omentum constitute a main entry pathway in TNFalpha-, Escherichia coli (E. coli)- and caecal ligation and puncture-induced models of inflammation. Neutrophil transmigration across HEVs is faster than across conventional postcapillary venules and requires a unique set of adhesion receptors including peripheral node addressin, E-, L-selectin and Mac-1 but not P-selectin or LFA-1. Omental milky spots readily concentrate intra-abdominal E. coli where macrophages and recruited neutrophils collaborate in phagocytosis and killing. Inhibition of the omental neutrophil response exacerbates septic progression of peritonitis. This data identifies HEVs as a clinically relevant vascular recruitment site for neutrophils in acute peritonitis that is indispensable for host defence against early systemic bacterial spread and sepsis. PMID- 26940552 TI - Parent-based prevention program for the children of mothers with eating disorders: Feasibility and preliminary outcomes. AB - The children of mothers with eating disorders are at high risk of feeding and eating problems and broader developmental difficulties. The Parent-Based Prevention (PBP) of eating disorders targets risk factors and facilitates behavioral change in parents to mitigate potentially negative outcomes of their children. This pre/post uncontrolled study evaluated the feasibility and preliminary outcomes of PBP. PBP was found to be a feasible intervention for mothers with eating disorders and their spouses, with satisfactory retention rates. A total of 16 intact families were assessed at three measurement points for parents' feeding practices, child outcomes, and maternal functioning. Both parents reported improved feeding practices as well as more positive perceptions of their children in comparison to baseline. These pilot findings suggest that PBP is linked with decreased risk of eating and mental problems among the offspring of mothers with eating disorders. PMID- 26940554 TI - Azacitidine-Induced Pericarditis: A Case Series. AB - STUDY OBJECTIVE: To describe three cases of pericarditis probably related to azacitidine administration in a span of 3 years at our center. DESIGN: Case series. SETTING: Comprehensive cancer center within a large, academic medical center. PATIENTS: Three patients with high-grade myelodysplastic syndrome or acute myeloid leukemia who received azacitidine. INTERVENTION: None. MEASUREMENTS: None. MAIN RESULTS: Patient 1 presented with pericarditis after cycle 2 of azacitidine, patient 3 presented 3 weeks after completing cycle 5, and patient 2 presented during cycle 1. All patients were treated symptomatically and responded to corticosteroids. None of the patients were re-challenged with hypomethylating agents. Use of the Naranjo adverse drug reaction probability scale indicated a probable adverse drug reaction (score of 6) for patients 1 and 3 and a possible adverse drug reaction (score of 3) for patient 2. CONCLUSION: With the exclusion of other common causes of pericarditis, we believe it is likely that azacitidine was responsible for the findings in our patients. Providers caring for patients receiving hypomethylating agents should consider this potential adverse drug reaction in the setting of unexplained chest pain or other clinical signs consistent with cardiotoxicity. PMID- 26940553 TI - Characterization of conserved arginine residues on Cdt1 that affect licensing activity and interaction with Geminin or Mcm complex. AB - All organisms ensure once and only once replication during S phase through a process called replication licensing. Cdt1 is a key component and crucial loading factor of Mcm complex, which is a central component for the eukaryotic replicative helicase. In higher eukaryotes, timely inhibition of Cdt1 by Geminin is essential to prevent rereplication. Here, we address the mechanism of DNA licensing using purified Cdt1, Mcm and Geminin proteins in combination with replication in Xenopus egg extracts. We mutagenized the 223th arginine of mouse Cdt1 (mCdt1) to cysteine or serine (R-S or R-C, respectively) and 342nd and 346th arginines constituting an arginine finger-like structure to alanine (RR-AA). The RR-AA mutant of Cdt1 could not only rescue the DNA replication activity in Cdt1 depleted extracts but also its specific activity for DNA replication and licensing was significantly increased compared to the wild-type protein. In contrast, the R223 mutants were partially defective in rescue of DNA replication and licensing. Biochemical analyses of these mutant Cdt1 proteins indicated that the RR-AA mutation disabled its functional interaction with Geminin, while R223 mutations resulted in ablation in interaction with the Mcm2~7 complex. Intriguingly, the R223 mutants are more susceptible to the phosphorylation induced inactivation or chromatin dissociation. Our results show that conserved arginine residues play critical roles in interaction with Geminin and Mcm that are crucial for proper conformation of the complexes and its licensing activity. PMID- 26940555 TI - Could this be the pioneering case of short-blanket syndrome? Comment on: Development of ultrasound enthesitis score to identify patients with enthesitis having spondyloarthritis: prospective, double-blinded, controlled study. Milutinovic et al. Clin Exp. PMID- 26940556 TI - Relation Between Change in Renal Function and Cardiovascular Outcomes in Atorvastatin-Treated Patients (from the Treating to New Targets [TNT] Study). AB - Statins may have nephroprotective as well as cardioprotective effects in patients with cardiovascular disease. In the Treating to New Targets (TNT) study (NCT00327691), patients with coronary heart disease (CHD) were randomized to atorvastatin 10 or 80 mg/day and followed for 4.9 years. The relation between intrastudy change in estimated glomerular filtration rate (eGFR) from baseline and the risk of major cardiovascular events (MCVEs, defined as CHD death, nonfatal non-procedure-related myocardial infarction, resuscitated cardiac arrest, or fatal or nonfatal stroke) was assessed among 9,500 patients stratified by renal function: improving (change in eGFR more than +2 ml/min/1.73 m(2)), stable (-2 to +2 ml/min/1.73 m(2)), and worsening (less than -2 ml/min/1.73 m(2)). Compared with patients with worsening renal function (1,479 patients, 15.6%), the rate of MCVEs was 28% lower in patients with stable renal function (2,241 patients, 23.6%) (hazard ratio [HR] 0.72; 95% confidence interval [CI] 0.60 to 0.87; p = 0.0005) and 64% lower in patients with improving renal function (5,780 patients, 60.8%; HR 0.36; 95% CI 0.30 to 0.43; p <0.0001). For each 1 ml/min/1.73 m(2) increase in eGFR, the absolute reduction in the rate of MCVEs was 2.7% (HR 0.973; 95% CI 0.967 to 0.980; p <0.0001). An absolute MCVE rate reduction per 1 ml/min/1.73 m(2) increase in eGFR of 2.0% was reported with atorvastatin 10 mg and 3.3% with atorvastatin 80 mg. In conclusion, intrastudy stabilization or increase in eGFR in atorvastatin-treated patients with CHD from the TNT study was associated with a reduced rate of MCVEs. Statin-treated CHD patients with progressive renal impairment are at high risk for future cardiovascular events. PMID- 26940557 TI - Fibromatosis in vertical rectus abdominis myocutaneous flap imitating tumor recurrence after surgery for locally advanced rectal cancer: case report. AB - BACKGROUND: Abdominoperineal excision is performed in patients with locally advanced, low rectal carcinoma. Reconstruction of the dorsal vagina and perineum using the vertical rectus abdominis myocutaneous flap following extensive surgery results in favorable surgical outcome and quality of life. However, the rectus abdominis muscle, as part of the anterior abdominal wall, may develop fibrous lesions also as a transplant. CASE PRESENTATION: A 39-year-old female patient with low rectal cancer and extensive colorectal polyposis was treated with neoadjuvant chemoradiotherapy followed by colectomy and abdominoperineal excision with resection of the dorsal vaginal wall and subsequent reconstruction of the perineum using the vertical rectus abdominis myocutaneous flap. At the 6-month follow-up, a suspected 2 * 2 cm tumor recurrence was detected in the transposed tissue and was subsequently surgically removed. Histologic examination concluded with fibromatosis. Genetic testing revealed a known disease-causing mutation in the adenomatous polyposis coli gene, confirming the diagnosis of familial adenomatous polyposis. CONCLUSIONS: Fibromatosis may affect the anterior abdominal wall, that is the rectus abdominis muscle, at the primary site or may develop in the muscle after its transposition into the perineum at pelvic reconstruction. Fibromatosis in the muscle flap after pelvic reconstruction may present a difficult diagnostic challenge for the multidisciplinary team. PMID- 26940558 TI - [Cornerstones of quality assurance in medicine in Germany. Important impulse for the situation in treatment of rheumatism]. AB - The recently passed German hospital structure act (Krankenhausstrukturgesetz) stresses the immense importance of quality for the medical care of the population. How can inpatient and outpatient treatment in the field of rheumatology be improved and how can this be assessed? A very important basis for such measurement approaches are quality indicators, i.e. parameters that indicate to what degree a certain level of quality has already been reached or is planned to be reached in the future. The work performed by the German Rheumatism Research Center (DRFZ) and the Association of Rheumatological Acute Clinics (VRA) in Germany has already used certain quality indicators and this topic has been recently described elsewhere. International quality indicators have also been published in recent years, all for rheumatoid arthritis (RA), the most prevalent inflammatory rheumatic disease and are the central subject of this article. This overview of proposed instruments for quality assessment in rheumatology is intended to initiate a broad discussion on the subject of quality of rheumatological care in Germany. PMID- 26940561 TI - The entorhinal map of space. AB - How do we know where we are, and how do we remember the places we visited? Since the discovery of place cells in 1971, our understanding of the brain's maps of external space has exploded. Yet the origin of the place-cell signal remained elusive. The discovery of grid cells in the medial entorhinal cortex (MEC) in 2005 put place cells in a context, since the existence of grid cells pointed to circuit mechanisms that might explain the formation of place cells. In this review, I shall review recent experimental and theoretical advances in the understanding of how space is mapped in the medial entorhinal cortex. I will also review recent studies of interactions between hippocampus and the lateral entorhinal cortex (LEC). Research on spatial mapping in the hippocampal entorhinal system provides a fundament for future attempts to decipher some of the neural-circuit codes of the cortex. PMID- 26940562 TI - Testosterone: is it really time to treat his oomph? PMID- 26940563 TI - Right inferior longitudinal fasciculus lesions disrupt visual-emotional integration. AB - The mechanism by which the brain integrates visual and emotional information remains incompletely understood, and can be studied through focal lesions that selectively disrupt this process. To date, three reported cases of visual hypoemotionality, a vision-specific form of derealization, have resulted from lesions of the temporo-occipital junction. We present a fourth case of this rare phenomenon, and investigate the role of the inferior longitudinal fasciculus (ILF) in the underlying pathophysiology. A 50-year-old right-handed male was found to have a right medial temporal lobe tumor following new-onset seizures. Interstitial laser ablation of the lesion was complicated by a right temporo parieto-occipital intraparenchymal hemorrhage. The patient subsequently experienced emotional estrangement from visual stimuli. A lesion overlap analysis was conducted to assess involvement of the ILF by this patient's lesion and those of the three previously described cases, and diffusion tensor imaging was acquired in our case to further investigate ILF disruption. All four lesions specifically overlapped with the expected trajectory of the right ILF, and diminished structural integrity of the right ILF was observed in our case. These findings implicate the ILF in visual hypoemotionality, suggesting that the ILF is critical for integrating visual information with its emotional content. PMID- 26940565 TI - SRJ09, a promising anticancer drug lead: Elucidation of mechanisms of antiproliferative and apoptogenic effects and assessment of in vivo antitumor efficacy. AB - SRJ09 (3,19-(2-bromobenzylidene)andrographolide), a semisynthetic andrographolide (AGP) derivative, was shown to induce G1 cell cycle arrest and eventually apoptosis in breast and colon cancer cell lines. The present investigation was carried out to elucidate the mechanisms cell cycle arrest and apoptosis and evaluate the in vivo antitumor activity of SRJ09. The in vitro growth inhibitory properties of compounds were assessed in colon (HCT-116) and breast (MCF-7) cancer cell lines. Immunoblotting was utilized to quantitate the protein levels in cells. The gene expressions were determined using reverse transcriptase PCR (RT-PCR). Pharmacokinetic investigation was carried out by determining SRJ09 levels in plasma of Balb/C mice using HPLC. In vivo antitumor activity was evaluated in athymic mice carrying HCT-116 colon tumor xenografts. SRJ09 displayed improved in vitro activity when compared with AGP by producing rapid cell killing effect in vitro. Its activity was not compromised in MES-SA/Dx5 multidrug resistant (MDR) cells expressing p-glycoprotein. Cells treated with SRJ09 (0.1-10MUM) displayed increased p21 protein level, which corresponded with gene expression. Whereas CDK4 protein level and gene expression was suppressed. The treatment did not affect cyclin D1. Changes of these proteins paralleled G1 cell cycle arrest in both cell lines as determined by flow cytometry. Induction of apoptosis by SRJ09 in HCT-116 cells which occurred independent of p53 and bcl 2 was inhibited in the presence of caspase 8 inhibitor, implicating the extrinsic apoptotic pathway. A single dose (100mg/kg, i.p) of SRJ09 produced a plasma concentration range of 12-30.4MUM. At 400mg/kg (q4dX3), it significantly retarded growth of tumor xenografts. The antitumor activity of SRJ09 is suggested mediated via the induction of p21 expression and suppression of CDK-4 expression without affecting cyclin D1 to trigger G1 arrest leading to apoptosis. PMID- 26940560 TI - The Different Therapeutic Choices with ARBs. Which One to Give? When? Why? AB - The renin-angiotensin-aldosterone system plays an important role in the pathophysiology of hypertension and is closely related with cardio- and cerebrovascular events and chronic kidney diseases. Each angiotensin receptor blocker (ARB) is important in the treatment of hypertension, according to the results of recent years. This is a practical review of the available evidence on the different benefits of ARBs beyond their blood pressure-lowering effect, with an emphasis on the differences found between the particular compounds and the therapeutic implications of the findings, with specific reference to the co morbidities. PMID- 26940568 TI - Ranavirus in an outbreak of dermatophilosis in captive inland bearded dragons (Pogona vitticeps). AB - BACKGROUND: Various pathogens cause skin diseases in lizards. An outbreak of skin disease occurred in a population of 100 inland bearded dragons at a breeding facility in Japan; 50 developed skin lesions and 15 mortalities were reported. HYPOTHESIS/OBJECTIVES: To identify the pathogens responsible for the skin lesions and to determine the cause of death. ANIMALS: Eight specimens (three dead, two euthanized, three living) were randomly selected from a group of inland bearded dragons with skin lesions consisting of multifocal superficial dermatitis. METHODS: Biopsy samples were taken from skin lesions and healthy skin of the live specimens. Postmortem examinations were performed on the dead and euthanized specimens. Skin samples were processed for microbiological culture, 16S ribosomal DNA (rDNA) sequencing for bacteria, ranavirus major capsid protein (MCP) gene sequencing and histopathological examination. Histopathological examinations were also performed on postmortem tissue samples. RESULTS: Both Austwickia chelonae and ranavirus (DNA) were detected in the skin lesions. Pathological examination revealed no significant visceral lesions caused by A. chelonae or ranavirus infection in dead specimens. CONCLUSIONS AND CLINICAL IMPORTANCE: To the best of the authors' knowledge this is the first report of dermatophilosis due to A. chelonae infection in lizards and the first description of a concurrent infection with a ranavirus. The combined infection associated with the skin lesions may have been the primary cause of death. Co-infection with a ranavirus should be considered as a possible factor in cases of reptilian dermatophilosis. PMID- 26940566 TI - Inoculation with enterococci does not affect colon inflammation in the multi-drug resistance 1a-deficient mouse model of IBD. AB - BACKGROUND: Intestinal bacteria are thought to play a role in the pathogenesis of human inflammatory bowel disease (IBD). We investigated whether oral inoculation with specific intestinal bacteria increased colon inflammation in the multi-drug resistance 1a-deficient (Mdr1a (-/-) ) mouse model of IBD. METHODS: Five-week-old Mdr1a (-/-) mice (FVB background) and FVB mice were randomly assigned to one of two treatment groups (Control or Inoculation, n = 12 per group). All mice were fed AIN-76A rodent diet, and mice in the Inoculation groups also received a single oral bacterial inoculation consisting of twelve cultured Enterococcus species combined with conventional intestinal flora obtained from the gastrointestinal tract of healthy mice (EF.CIF). Body weight, food intake, and disease activity index (DAI) were assessed throughout the study, and at 21 or 24 weeks of age, inflammation was assessed post-mortem by determining colon length and histological injury score (HIS), and plasma serum amyloid A (SAA). RESULTS: Mdr1a (-/-) mice consumed more food than FVB mice at 13 weeks of age (P < 0.05). There was also a significant effect of genotype on body weight, with Mdr1a (-/-) mice weighing less than FVB mice throughout the study (P < 0.05) regardless of treatment, but there was no effect of inoculation on body weight (P > 0.25). Colon HIS of Mdr1a (-/-) mice was significantly higher than that of FVB mice in the Control (9.3 +/- 4.7 (mean +/- SD) vs. 0.58 +/- 0.51; P < 0.001) and Inoculation (6.7 +/- 5.1 vs. 0.92 +/- 0.39; P < 0.001) groups. There was no difference in colon HIS of Mdr1a (-/-) mice in the Control group compared with Mdr1a (-/-) mice in the Inoculation group (P = 0.25), nor was there any difference in within-group variation of colon HIS in these two Mdr1a (-/-) groups. DAI was higher in Mdr1a (-/-) mice than in FVB mice, but there was no effect of treatment in either strain, nor were there any differences in colon length or plasma SAA. CONCLUSIONS: Inoculation of Mdr1a (-/-) mice with the EF.CIF inoculum described here does not increase colon inflammation or reduce the observed variability of inflammation. PMID- 26940567 TI - Allelic variations of alpha-gliadin genes from species of Aegilops section Sitopsis and insights into evolution of alpha-gliadin multigene family among Triticum and Aegilops. AB - The alpha-gliadins account for 15-30 % of the total storage protein in wheat endosperm and play important roles in the dough extensibility and nutritional quality. On the other side, they act as a main source of toxic peptides triggering celiac disease. In this study, 37 alpha-gliadins were isolated from three species of Aegilops section Sitopsis. Sequence similarity and phylogenetic analyses revealed novel allelic variation at Gli-2 loci of species of Sitopsis and regular organization of motifs in their repetitive domain. Based on the comprehensive analyses of a large number of known sequences of bread wheat and its diploid genome progenitors, the distributions of four T cell epitopes and length variations of two polyglutamine domains are analyzed. Additionally, according to the organization of repeat motifs, we classified the alpha-gliadins of Triticum and Aegilops into eight types. Their most recent common ancestor and putative divergence patterns were further considered. This study provides new insights into the allelic variations of alpha-gliadins in Aegilops section Sitopsis, as well as evolution of alpha-gliadin multigene family among Triticum and Aegilops species. PMID- 26940569 TI - Impact of Chronic Nitrate Therapy in Patients With Ischemic Heart Failure. AB - PURPOSE: There is a lack of knowledge on the effects of nitrates alone in heart failure (HF). We aimed to assess the impact of nitrates use in the occurrence of ischemic events in patients with ischemic HF attending an HF clinic. METHODS: We performed a retrospective analysis of a cohort of 632 patients managed in an HF clinic between January 2000 and December 2011. Patients with ischemic etiology were selected (n = 290). Patients were classified according to chronic nitrates use (n = 83 nitrates users vs n = 194) and followed up for 5 years for the occurrence of fatal or nonfatal myocardial infarction or stroke. RESULTS: Nitrates users had more frequently diabetes, dyslipidemia, and higher body mass index but were less frequently treated with statins. Thirty adverse events were recorded (n = 16 in nitrates group). Variables significantly associated with the occurrence of the end point in univariate analysis were arterial hypertension, diabetes, and nitrates use. Male gender, beta-blockers, statin, and clopidogrel use had a protective effect on the occurrence of the end point. In multivariate analysis, nitrates use remained an independent predictor of adverse outcome when adjusted for each of the variables: arterial hypertension, gender, diabetes, beta blocker, and clopidogrel use; however, when adjusted for statin use, nitrates were no longer associated with the outcome. CONCLUSION: Long-term nitrates use in patients with ischemic HF was associated with higher occurrence of ischemic events, defined as fatal or nonfatal myocardial infarction or stroke. Our results, although from a retrospective analysis, do not support a role for chronic nitrate use in HF. PMID- 26940571 TI - Reliable Selection and Holistic Stability Evaluation of Reference Genes for Rice Under 22 Different Experimental Conditions. AB - Stable and uniform expression of reference genes across samples plays a key role in accurate normalization of gene expression by reverse-transcription quantitative polymerase chain reaction (RT-qPCR). For rice study, there is still a lack of validation and recommendation of appropriate reference genes with high stability depending on experimental conditions. Eleven candidate reference genes potentially owning high stability were evaluated by geNorm and NormFinder for their expression stability in 22 various experimental conditions. Best combinations of multiple reference genes were recommended depending on experimental conditions, and the holistic stability of reference genes was also evaluated. Reference genes would become more variable and thus needed to be critically selected in experimental groups of tissues, heat, 6-benzylamino purine, and drought, but they were comparatively stable under cold, wound, and ultraviolet-B stresses. Triosephosphate isomerase (TI), profilin-2 (Profilin-2), ubiquitin-conjugating enzyme E2 (UBC), endothelial differentiation factor (Edf), and ADP-ribosylation factor (ARF) were stable in most of our experimental conditions. No universal reference gene showed good stability in all experimental conditions. To get accurate expression result, suitable combination of multiple reference genes for a specific experimental condition would be a better choice. This study provided an application guideline to select stable reference genes for rice gene expression study. PMID- 26940572 TI - Anaerobic Mesophilic Codigestion of Rice Straw and Chicken Manure: Effects of Organic Loading Rate on Process Stability and Performance. AB - To investigate the effects of organic loading rate (OLR) on performance and stability of mesophilic co-digestion of rice straw (RS) and chicken manure (CM), benchtop experiments (40 L) were carried out at OLRs of 3.0, 3.6, 4.2, 4.8, 6.0, 8.0, and 12.0 kg volatile solid (VS)/(m(3).day) with volatile solid (VS) ratio of 1:1 (RS/CM) which was based on batch tests. Anaerobic co-digestion was slightly and severely inhibited by the accumulation of ammonia when the digester was overloaded at an OLR of 6 and 12 kg VS/(m(3).day), respectively. The recommended OLR for co-digestion is 4.8 kg VS/(m(3).day), which corresponds to average specific biogas production (SBP) of 380 L/kg VS and volumetric biogas production rate (VBPR) of 1.8 m(3)/(m(3).day). An OLR of 6-8 kg VS/(m(3).d) with SBP of 360 440 L/kg VS and VBPR of 2.1-3.5 m(3)/(m(3).day) could be considered, if an Anaerobic digestion (AD) system assisted by in situ removal of ammonia was adopted. PMID- 26940573 TI - Use of Streaming Media (YouTube) as an Educational Tool for Surgeons-A Survey of AAFPRS Members. PMID- 26940570 TI - Nicorandil, a Nitric Oxide Donor and ATP-Sensitive Potassium Channel Opener, Protects Against Dystrophin-Deficient Cardiomyopathy. AB - BACKGROUND: Dystrophin-deficient cardiomyopathy is a growing clinical problem without targeted treatments. We investigated whether nicorandil promotes cardioprotection in human dystrophin-deficient induced pluripotent stem cell (iPSC)-derived cardiomyocytes and the muscular dystrophy mdx mouse heart. METHODS AND RESULTS: Dystrophin-deficient iPSC-derived cardiomyocytes had decreased levels of endothelial nitric oxide synthase and neuronal nitric oxide synthase. The dystrophin-deficient cardiomyocytes had increased cell injury and death after 2 hours of stress and recovery. This was associated with increased levels of reactive oxygen species and dissipation of the mitochondrial membrane potential. Nicorandil pretreatment was able to abolish these stress-induced changes through a mechanism that involved the nitric oxide-cyclic guanosine monophosphate pathway and mitochondrial adenosine triphosphate-sensitive potassium channels. The increased reactive oxygen species levels in the dystrophin-deficient cardiomyocytes were associated with diminished expression of select antioxidant genes and increased activity of xanthine oxidase. Furthermore, nicorandil was found to improve the restoration of cardiac function after ischemia and reperfusion in the isolated mdx mouse heart. CONCLUSION: Nicorandil protects against stress-induced cell death in dystrophin-deficient cardiomyocytes and preserves cardiac function in the mdx mouse heart subjected to ischemia and reperfusion injury. This suggests a potential therapeutic role for nicorandil in dystrophin-deficient cardiomyopathy. PMID- 26940575 TI - Three new sesquiterpene lactone dimers from Carpesium macrocephalum. AB - Three new sesquiterpene lactone dimers (SLDs), carpedilactones E-G (1-3), together with two known monomeric units, ivalin (4) and alantolactone (5), were isolated from the acetonic extract of Carpesium macrocephalum. Their chemical structures were elucidated by IR, UV, HR-ESI-MS, NMR 1D and 2D experiments, and the absolute configuration of 1-3 was resolved according to the (1)H NMR and CD spectrographic features of 1,3-/2,4-linked SLDs. Furthermore, 1 was unambiguously confirmed by Cu-Kalpha X-ray crystallographic analysis. Additionally, compounds 1 and 2 were revealed with potent cytotoxicities against human colon cancer HCT116 cells with IC50 values of 2.27 and 3.30 MUM, respectively. PMID- 26940576 TI - Incidence rates of occupational diseases in the Dutch construction sector, 2010 2014. AB - OBJECTIVE: To estimate incidence and trends in incidence of occupational diseases (ODs) in the Dutch construction sector. METHODS: In a dynamic prospective cohort over a 5-year period (2010-2014), ODs assessed by occupational physicians (OPs) participating in a voluntary construction workers health surveillance (WHS) were reported to the Netherlands Centre for Occupational Diseases (NCOD). ODs were defined as a disease with a specific clinical diagnosis (International Classification of Diseases) that was predominantly caused by work-related factors as assessed by an OP. Annual incidences were determined for the total number of ODs and six frequently occurring OD groups. Trends in incidence were estimated using a multilevel negative binominal regression model. RESULTS: In 2014 the incidence of all OD was 12 964 per 100 000 workers and there was no significant change in incidence between 2010 and 2014 (3%; 95% CI -2% to +9%). Hearing loss (8125 per 100 000 workers) and musculoskeletal disorders (2081 per 100 000 workers) were the most frequently occurring ODs. Noise-induced hearing loss (+7%; 95% CI 1% to 13%) and contact dermatitis (+19%; 95% CI 6% to 33%) showed increasing trends. There was no statistically significant change in the incidence of low back pain, arthrosis, repetitive strain injuries, distress/burnout and chronic obstructive pulmonary disease/asthma. CONCLUSIONS: In total, 13% of workers participating in WHS in the Dutch construction industry during 2014 had an OD diagnosed and reported by an OP. Over a 5-year period the annual incidence of reported ODs showed a statistically non-significant increase. Incidences in noise-induced hearing loss and contact dermatitis showed statistically significant increasing trends, 7% and 19%, respectively. PMID- 26940577 TI - Selective chemical labeling of proteins. AB - Over the years, there have been remarkable efforts in the development of selective protein labeling strategies. In this review, we deliver a comprehensive overview of the currently available bioorthogonal and chemoselective reactions. The ability to introduce bioorthogonal handles to proteins is essential to carry out bioorthogonal reactions for protein labeling in living systems. We therefore summarize the techniques that allow for site-specific "installation" of bioorthogonal handles into proteins. We also highlight the biological applications that have been achieved by selective chemical labeling of proteins. PMID- 26940578 TI - The Case for Oxygen in Global Surgical Care. PMID- 26940574 TI - The prognostic value of non-perfusion variables obtained during vasodilator stress myocardial perfusion imaging. AB - Myocardial perfusion imaging (MPI) is an established diagnostic test that provides useful prognostic data in patients with known or suspected coronary artery disease. In more than half of the patients referred for stress testing, vasodilator stress is used in lieu of exercise. Unlike exercise, vasodilator stress does not provide information on exercise and functional capacity, heart rate recovery, and chronotropy, and ECG changes are less frequent. These non perfusion data provide important prognostic and patient management information. Further, event rates in patients undergoing vasodilator MPI are higher than in those undergoing exercise MPI and even in those with normal images probably due to higher pretest risk. However, there are a number of non-perfusion variables that are obtained during vasodilator stress testing, which have prognostic relevance but their use has not been well emphasized. The purpose of this review is to summarize the prognostic values of these non-perfusion data obtained during vasodilator MPI. PMID- 26940579 TI - Totally Implantable Venous Access Devices: Efforts Are Needed to Standardize Procedures to Avoid Complications. PMID- 26940581 TI - Association Between Cholecystectomy and Nonalcoholic Fatty Liver Disease: A Meta analysis. PMID- 26940580 TI - Impact of Preoperative Exclusive Enteral Nutrition on Postoperative Complications and Recurrence After Bowel Resection in Patients with Active Crohn's Disease. AB - BACKGROUND: The impact of preoperative enteral nutrition (EN) on postoperative complications and recurrence in Crohn's disease (CD) has not been investigated to date. The purpose of the present study was to determine the effect of preoperative exclusive EN on postoperative complications and recurrence after bowel resection in patients with active CD. METHODS: Patient data were obtained from a prospectively maintained database. 81 patients who received bowel resection for ileal or ileocolonic CD were studied. Before operation, 42 CD patients received exclusive EN for 4 weeks, and the other patients had no nutritional therapy. All patients were followed up regularly for 2 years after surgery, and ileocolonoscopy was performed every 6 months after bowel resection. RESULTS: Patients receiving exclusive EN had a dramatic improvement of nutritional (BMI, albumin, pre-albumin, and Hb) and inflammatory (CRP and CDAI) status compared with baseline after the EN therapy for 4 weeks (P < 0.05). Furthermore, significantly lower incidence of both infectious and non-infectious complications was observed in patients receiving exclusive EN compared with those received no nutritional therapy (P < 0.05). Exclusive EN therapy for 4 weeks significantly reduced endoscopic recurrence rates after resection for CD 6 months after operation. However, during the 2-year follow-up, incidence of clinical recurrence was similar in both groups (P > 0.05). CONCLUSIONS: Preoperative exclusive EN therapy for 4 weeks reduced postoperative complications, which may be associated with improvement of nutritional and inflammatory status in patients with active CD. PMID- 26940582 TI - Impact of p53 and PDGFR-beta Expression on Metastasis and Prognosis of Patients with Pancreatic Cancer. AB - BACKGROUND: Identifying novel predictors of hematogenous metastasis is essential to select optimal therapeutic strategies for pancreatic cancer. The goal of this study was to clarify the clinical implications of p53 and platelet-derived growth factor receptor-beta (PDGFR-beta) in pancreatic cancer using immunohistochemistry (IHC). METHODS: Specimens obtained by surgical resection and endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) of the primary tumor were used for IHC. EUS-FNA was performed before any treatment. We analyzed the clinical implications of p53 and PDGFR-beta IHC. We also performed a comparative analysis of the IHC findings between surgical and EUS-FNA specimens. RESULTS: This study involved 149 patients (120 who did not receive and 29 who received preoperative therapy). EUS-FNA specimens were obtained from 20 patients without preoperative therapy and 20 patients with preoperative therapy. Abnormal p53 and high PDGFR beta expression was significantly correlated with a high incidence of hematogenous metastasis (p < 0.001) and poor postoperative survival (p = 0.006). In patients without preoperative therapy, the results for p53 and PDGFR-beta staining were concordant between surgical and EUS-FNA specimens in 95 % of the cases. In patients with preoperative therapy, 80 and 70 % of the patients showed consistent p53 and PDGFR-beta expression between surgical and EUS-FNA specimens, respectively. CONCLUSIONS: Pancreatic cancer patients with simultaneous abnormal p53 and high PDGFR-beta expression have a significantly higher risk of hematogenous metastasis and a poor prognosis after surgery. IHC evaluation using EUS-FNA specimens may be able to identify patients with highly metastatic pancreatic cancer who may benefit from aggressive therapeutic intervention. PMID- 26940583 TI - Severe Hyponatremia and Immune Nephritis Following an Initial Infusion of Nivolumab. AB - Anti-programmed cell death-1 (PD-1) antibodies pembrolizumab and nivolumab are becoming increasingly important in the treatment of melanoma and non-small cell lung cancer. These agents are known to induce many immune-related adverse events, but rapid-onset nephritis and immune-related hyponatremia have not been described to date. We describe the case of an adult patient who developed severe hyponatremia and rapid-onset nephritis following the first infusion of nivolumab for metastatic melanoma. PMID- 26940584 TI - Disease-drug database for pharmacogenomic-based prescribing. AB - Providers have expressed a strong desire to have additional clinical decision support tools to help with interpretation of pharmacogenomic results. We developed and tested a novel disease-drug association tool that enables pharmacogenomic-based prescribing to treat common diseases. First, 324 drugs were mapped to 484 distinct diseases (mean number of drugs treating each disease was 4.9; range 1-37). Then the disease-drug association tool was pharmacogenomically annotated, with an average of 1.8 pharmacogenomically annotated drugs associated/disease. Applying this tool to a prospectively enrolled >1,000 patient cohort from a tertiary medical center showed that 90% of the top ~20 diseases in this population and >=93% of patients could appropriately be treated with >=1 medication with actionable pharmacogenomic information. When combined with clinical patient genotypes, this tool permits delivery of patient-specific pharmacogenomically informed disease treatment recommendations to inform the treatment of many medical conditions of the US population, a key initial step towards implementation of precision medicine. PMID- 26940587 TI - Time to wake up and smell the coffee? Coffee consumption and multiple sclerosis. PMID- 26940586 TI - High consumption of coffee is associated with decreased multiple sclerosis risk; results from two independent studies. AB - OBJECTIVE: Previous studies on consumption of caffeine and risk of multiple sclerosis (MS) have yielded inconclusive results. We aimed to investigate whether consumption of coffee is associated with risk of MS. METHODS: Using two population-representative case-control studies (a Swedish study comprising 1620 cases and 2788 controls, and a US study comprising 1159 cases and 1172 controls), participants with different habits of coffee consumption based on retrospective data collection were compared regarding risk of MS, by calculating ORs with 95% CIs. Logistic regression models were adjusted for a broad range of potential confounding factors. RESULTS: Compared with those who reported no coffee consumption, the risk of MS was substantially reduced among those who reported a high consumption of coffee exceeding 900 mL daily (OR 0.70 (95% CI 0.49 to 0.99) in the Swedish study, and OR 0.69 (95% CI 0.50 to 0.96) in the US study). Lower odds of MS with increasing consumption of coffee were observed, regardless of whether coffee consumption at disease onset or 5 or 10 years prior to disease onset was considered. CONCLUSIONS: In accordance with studies in animal models of MS, high consumption of coffee may decrease the risk of developing MS. Caffeine, one component of coffee, has neuroprotective properties, and has been shown to suppress the production of proinflammatory cytokines, which may be mechanisms underlying the observed association. However, further investigations are needed to determine whether exposure to caffeine underlies the observed association and, if so, to evaluate its mechanisms of action. PMID- 26940585 TI - An Example of How to Supplement Goal Setting to Promote Behavior Change for Families Using Motivational Interviewing. AB - The purpose of this study was to describe the components and use of motivational interviewing (MI) within a behavior change intervention to promote healthful eating and family meals and prevent childhood obesity. The Healthy Home Offerings via the Mealtime Environment (HOME) Plus intervention was part of a two-arm randomized-controlled trial and included 81 families (children 8-12 years old and their parents) in the intervention condition. The intervention included 10 monthly, 2-hour group sessions and 5 bimonthly motivational/goal-setting phone calls. Data were collected for intervention families only at each of the goal setting calls and a behavior change assessment was administered at the 10th/final group session. Descriptive statistics were used to analyze the MI call data and behavior assessment. Overall group attendance was high (68% attending >=7 sessions). Motivational/goal-setting phone calls were well accepted by parents, with an 87% average completion rate. More than 85% of the time, families reported meeting their chosen goal between calls. Families completing the behavioral assessment reported the most change in having family meals more often and improving home food healthfulness. Researchers should use a combination of delivery methods using MI when implementing behavior change programs for families to promote goal setting and healthful eating within pediatric obesity interventions. PMID- 26940588 TI - Mycobacterium fortuitum induces A20 expression that impairs macrophage inflammatory responses. AB - Mycobacterium fortuitum is a rapidly growing mycobacterium that has been regarded as an etiological agent of a variety of human infections. However, little is known about the host inflammatory responses and the molecular mechanisms by which MF-induced inflammation is regulated in macrophages. In this study, we report that MF infection leads to the induction of an anti-inflammatory molecule, A20 (also known as TNFAIP3), which is essential for the regulation of MF-induced inflammatory responses in murine bone marrow-derived macrophages (BMDMs). MF triggered the expression of tumor necrosis factor-alpha and interleukin-6 in BMDMs through signaling of the Toll-like receptor 2 (TLR2)-myeloid differentiation primary response gene 88. Additionally, MF rapidly induced the expression of A20, which inhibited proinflammatory cytokine expression and nuclear factor (NF)-kappaB reporter gene activities in BMDMs. Notably, MF-induced activation of NF-kappaB signaling was required for A20 expression and proinflammatory responses in BMDMs. Furthermore, the rough morphotype of the MF clinical strain induced a higher level of proinflammatory signaling activation, but less A20 induction in BMDMs, compared to the smooth morphotype. Taken together, these results suggest that MF-induced activation of host proinflammatory responses is negatively regulated through TLR2-dependent A20 expression. PMID- 26940589 TI - Biofilm formation by multidrug resistant Escherichia coli ST131 is dependent on type 1 fimbriae and assay conditions. AB - Escherichia coli sequence type 131 (ST131) has emerged as a pandemic lineage of important multidrug resistant pathogens worldwide. Despite many studies examining the epidemiology of ST131, only a few studies to date have investigated the capacity of ST131 strains to form biofilms. Some of these studies have reported contrasting findings, with no specific ST131 biofilm-promoting factors identified. Here, we examined a diverse collection of ST131 isolates for in vitro biofilm formation in different media and assay conditions, including urine from healthy adult women. We found significant differences among strains and assay conditions, which offers an explanation for the contrasting findings reported by previous studies using a single condition. Importantly, we showed that expression of type 1 fimbriae is a critical determinant for biofilm formation by ST131 strains and that inhibition of the FimH adhesin significantly reduces biofilm formation. We also offer direct genetic evidence for the contribution of type 1 fimbriae in biofilm formation by the reference ST131 strain EC958, a representative of the clinically dominant H30-Rx ST131 subgroup. This is the first study of ST131 biofilm formation in biologically relevant conditions and paves the way for the application of FimH inhibitors in treating drug resistant ST131 biofilm infections. PMID- 26940590 TI - Learnt and perceived professional roles of a new type of nurse specialized in Gerontology and Geriatrics, a qualitative study. AB - AIM: To gain insight into a new type of nurse specialized in gerontology and geriatrics, how they find meaning in the care of older persons and how this relates to the seven professional roles derived from the CanMEDS theoretical framework. BACKGROUND: To promote the quality of care for older persons in the Netherlands, one of the measures taken is the training and deployment of Registered Nurses specialized in Gerontology and Geriatrics. We focus on their professional roles in this study, to gain insight into the extent to which they fulfil their professional standards. DESIGN: A qualitative study, consisting of seven focus group interviews. METHODS: The study population included 67 Registered Nurses. Data were collected between October 2011-May 2013. FINDINGS: Nurses work in all seven CanMEDS roles, but not with all competences associated with these seven roles. The more distant the role is from patient activities, the less frequently competences such as social networks; design; research; innovation of care; legal, financial and organizational frameworks; professional ethics and professional innovation are mentioned. CONCLUSION: Nurses engage in activities consistent with nursing care for older people; however, despite their training, they are mainly focused on direct-patient care. Their limited awareness of the complete range of professional competences risks the stagnation of their development in professional roles such as health advocate, scholar and professional, which will not lead to an improvement in the care for older persons. PMID- 26940591 TI - Please exit safely: maternal and twin pair neonatal outcomes according to delivery mode when twin A is vertex. AB - OBJECTIVE: To investigate maternal and infant outcomes associated with delivery mode for twins with a cephalic presenting twin. METHODS: Linked birth certificate and ICD hospital discharge data were analyzed retrospectively for 5573 mothers and their respective twin pairs born live at 34-42 weeks' gestation, with twin A vertex, in Washington State from 1997-2007. Relative risks (RR) and 95% confidence intervals of adverse maternal and twin pair outcomes were calculated for vaginal delivery or cesarean during labor in comparison to cesarean without labor. RESULTS: Vaginal delivery or cesarean during labor was associated with significantly elevated rates of maternal hemorrhage (RR = 2.8 [2.2,3.7]), infection (RR = 2.2 [1.5,3.3]), twin pair birth injury (RR = 2.6 [1.2,5.4]) and low 5-min Apgar scores (RR = 1.4 [1.1,1.8]) and with significantly lower rates of ventilation among preterm twin pairs only (RR = 0.8 [0.7,0.9]). The lowest rate of combined poor short-term outcomes occurred in mothers and twin pairs delivered by cesarean without labor (23%) and the highest rates occurred in those with operative vaginal or cesarean during labor (39% and 34%, respectively). Among women in labor, 35% of nulliparas achieved spontaneous vaginal delivery of both twins compared to 63% of non-nulliparas. CONCLUSION: For nulliparous women who carry twins to term, planned cesarean may improve outcomes. PMID- 26940593 TI - New advanced designation program: Fellow of the Association for Professionals in Infection Control and Epidemiology (FAPIC). PMID- 26940594 TI - Visitor characteristics and alcohol-based hand sanitizer dispenser locations at the hospital entrance: Effect on visitor use rates. AB - BACKGROUND: Hospital visitors' hand hygiene (HH) is an important aspect of preventing health care-associated infections, but little is known about visitors' use of alcohol-based hand sanitizers (AHS). The study aim was to examine if use of AHS is influenced by visitor characteristics and the location of AHS within the lobby of a large hospital. METHODS: An observational study was conducted with AHS placed in 3 different locations. The data included visitor characteristics and if AHS were used. RESULTS: The results suggest that visitors are 5.28 times (95% confidence interval [CI], 3.68-7.82) more likely to use AHS when dispensers are located in the middle of the lobby with limited landmarks or barriers, 1.35 times more likely to use the AHS in the afternoon compared with the morning, or when they are younger visitors (adjusted odds ratio, 1.47; 95% CI, 1.09-1.97). Individuals in a group are more likely (adjusted odds ratio, 1.39; 95% CI, 1.06 1.84) to use AHS. DISCUSSION: In addition to location, time of day, and age, there is a group effect that results in visitors being more likely to use AHS when in a group. The increased use related to groups may serve as a mechanism to encourage visitor HH. CONCLUSIONS: The results suggest future research opportunities to investigate the effect of group dynamics and social pressure on visitor AHS use and to identify strategies for improving visitor HH. PMID- 26940596 TI - Bacterial contamination of computer touch screens. AB - The goal of this study was to determine the occurrence of opportunistic bacterial pathogens on the surfaces of computer touch screens used in hospitals and grocery stores. Opportunistic pathogenic bacteria were isolated on touch screens in hospitals; Clostridium difficile and vancomycin-resistant Enterococcus and in grocery stores; methicillin-resistant Staphylococcus aureus. Enteric bacteria were more common on grocery store touch screens than on hospital computer touch screens. PMID- 26940595 TI - The impact of implementing multifaceted interventions on the prevention of ventilator-associated pneumonia. AB - BACKGROUND: Ventilator-associated pneumonia (VAP) is a frequent hospital acquired infections among intensive care unit patients. The Institute for Healthcare Improvement has suggested a "care bundle" approach for the prevention of VAP. This report describes the effects of implementing this strategy on VAP rates. METHODS: All mechanically ventilated patients admitted to the intensive care unit between 2008 and 2013 were prospectively followed for VAP development according to the National Healthcare Safety Network criteria. In 2011, a 7-element care bundle was implemented, including head-of-bed elevation 30 degrees -45 degrees , daily sedation vacation and assessment for extubation, peptic ulcer disease prophylaxis, deep vein thrombosis prophylaxis, oral care with chlorhexidine, endotracheal intubation with in-line suction and subglottic suctioning, and maintenance of endotracheal tube cuff pressure at 20-30 mmHg. The bundle compliance and VAP rates were then followed. RESULTS: A total of 3665 patients received mechanical ventilation, and there were 9445 monitored observations for bundle compliance. The total bundle compliance before and after initiation of the VAP team was 90.7% and 94.2%, respectively (P < .001). The number of VAP episodes decreased from 144 during 2008-2010 to only 14 during 2011-2013 (P < .0001). The rate of VAP decreased from 8.6 per 1000 ventilator-days to 2.0 per 1000 ventilator-days (P < .0001) after implementation of the care bundle. CONCLUSIONS: This study suggests that systematic implementation of a multidisciplinary team approach can reduce the incidence of VAP. Further sustained improvement requires persistent vigilant inspections. PMID- 26940597 TI - Letter in Response to "Questionable validity of the catheter-associated urinary tract infection metric used for value-based purchasing". PMID- 26940592 TI - Adipose tissue macrophages: going off track during obesity. AB - Inflammation originating from the adipose tissue is considered to be one of the main driving forces for the development of insulin resistance and type 2 diabetes in obese individuals. Although a plethora of different immune cells shapes adipose tissue inflammation, this review is specifically focused on the contribution of macrophages that reside in adipose tissue in lean and obese conditions. Both conventional and tissue-specific functions of adipose tissue macrophages (ATMs) in lean and obese adipose tissue are discussed and linked with metabolic and inflammatory changes that occur during the development of obesity. Furthermore, we will address various circulating and adipose tissue-derived triggers that may be involved in shaping the ATM phenotype and underlie ATM function in lean and obese conditions. Finally, we will highlight how these changes affect adipose tissue inflammation and may be targeted for therapeutic interventions to improve insulin sensitivity in obese individuals. PMID- 26940598 TI - Dysfunction in attentional processing in patients with Parkinson's disease and visual hallucinations. AB - Mechanistic insights into visual hallucinations (VH) in Parkinson's disease (PD) have suggested a role for impaired attentional processes. The current study tested 25 PD patients with and 28 PD patients without VH on the attentional network test. Hallucinators had significantly lower accuracy rates compared to non-hallucinators, but no differences were found in reaction times. This suggests that hallucinators show deficits in attentional processes and conflict monitoring. Our findings provide novel behavioural insights that dovetail with current neurobiological frameworks of VH. PMID- 26940600 TI - A safe place with space for learning: Experiences from an interprofessional training ward. AB - Interprofessional learning in a real ward context effectively increases collaborative and professional competence among students. However, less is known on the processes behind this. The aim of this study was to explore medical, nurse, physiotherapy, and occupational therapy students' perspectives on the process of their own learning at an interprofessional training ward (IPTW). We performed a qualitative content analysis on free-text answers of 333 student questionnaires from the years 2004 to 2011. Two main themes emerged: first, students found that the IPTW provided an enriching learning environment--a safe place with space. It included authentic and relevant patients, well-composed and functioning student teams, competent and supportive supervisors, and adjusted ward structures to support learning. Second, they developed an awareness of their own development with faith in the future--from chaos to clarity. It included personal, professional, and interprofessional development towards a comprehensive view of practice and a faith in their ability to work as professionals in the future. Our findings are discussed with a social constructivist perspective. This study suggests that when an IPTW provides a supportive and permissive learning environment with possibilities to interact with one another--a safe place with space--it enables students to move from insecurity to faith in their abilities- from chaos to clarity. However, if the learning environment is impaired, the students' development could be halted. PMID- 26940599 TI - Erratum to: IkappaBalpha mediates prostate cancer cell death induced by combinatorial targeting of the androgen receptor. PMID- 26940601 TI - Evaluation of sexuality in a Paraguayan mid-aged female urban population using the six-item Female Sexual Function Index. AB - Background There are scant data related to sexuality assessed among mid-aged women from Paraguay. Objective To assess sexual function in a sample of mid-aged Paraguayan women. Methods This was a cross-sectional study in which 265 urban living women from Asuncion (Paraguay) aged 40-65 years were surveyed with the six item version of the Female Sexual Function Index (FSFI-6) and a questionnaire containing personal and partner data. Results The median age of the sample was 48 years, 48.2% were postmenopausal (median/interquartile range age at menopause 46/13 years), 11.3% used hormone therapy, 37.0% used psychotropic drugs, 44.5% had hypertension, 7.2% diabetes, 46.1% abdominal obesity and 89.4% had a partner (n = 237). Overall, 84.1% (223/265) of surveyed women were sexually active, presenting a median total FSFI-6 score of 23.0, and 25.6% obtained a total score of 19 or less, suggestive of sexual dysfunction (lower sexual function). Upon bivariate analysis, several factors were associated with lower total FSFI-6 scores; however, multiple linear regression analysis found that lower total FSFI 6 scores (worse sexual function) were significantly correlated to the postmenopausal status and having an older partner, whereas coital frequency was positively correlated to higher scores (better sexual function). Conclusion In this pilot sample of urban-living, mid-aged Paraguayan women, as determined with the FSFI-6, lower sexual function was related to menopausal status, coital frequency and partner age. There is a need for more research in this regard in this population. PMID- 26940603 TI - A new methodology for automated diagnosis of mild cognitive impairment (MCI) using magnetoencephalography (MEG). AB - Mild cognitive impairment (MCI) is a cognitive disorder characterized by memory impairment, greater than expected by age. A new methodology is presented to identify MCI patients during a working memory task using MEG signals. The methodology consists of four steps: In step 1, the complete ensemble empirical mode decomposition (CEEMD) is used to decompose the MEG signal into a set of adaptive sub-bands according to its contained frequency information. In step 2, a nonlinear dynamics measure based on permutation entropy (PE) analysis is employed to analyze the sub-bands and detect features to be used for MCI detection. In step 3, an analysis of variation (ANOVA) is used for feature selection. In step 4, the enhanced probabilistic neural network (EPNN) classifier is applied to the selected features to distinguish between MCI and healthy patients. The usefulness and effectiveness of the proposed methodology are validated using the sensed MEG data obtained experimentally from 18 MCI and 19 control patients. PMID- 26940602 TI - Ceftriaxone prevents the neurodegeneration and decreased neurogenesis seen in a Parkinson's disease rat model: An immunohistochemical and MRI study. AB - Manganese-enhanced magnetic resonance imaging (MEMRI) is a widely used technique for detecting neuronal activity in the brain of a living animal. Ceftriaxone (CEF) has been shown to have neuroprotective effects in neurodegenerative diseases. The present study was aimed at clarifying whether, in an 1-methyl-4 phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease (PD) rat model, the known CEF-induced neuronal protection was accompanied by neurogenesis and decreased loss of neuronal activity. After MPTP lesioning (day 0), the rats were treated with CEF (100mg/kg/day, i.p.) or saline for 15 days. They were then injected with MnCl2 (40mg/kg, i.p.) on day 13 and underwent a brain MRI scan on day 14, then the brain was taken for histological evaluation on day 15. The results showed that MPTP lesioning resulted in decreased neuronal activity and density in the nigrostriatal dopaminergic (DAergic) system and the hippocampal CA1, CA3, and dentate gyrus (DG) areas and reduced neurogenesis in the DG, but in hyperactivity in the subthalamic nucleus (STN). These neuronal changes were prevented by CEF treatment. Positive correlations between MEMRI R1 values and neuronal density in the hippocampus were evidenced. Neuronal densities in the hippocampus and SNc were positively correlated. In addition, the R1 value of the STN showed a positive correlation with its neuronal activity but showed a negative correlation with the density of DAergic neurons in the SNc. Therefore, MEMRI R1 value may serve as a good indicator for PD severity and the effect of treatment. To our knowledge, this is the first study showing that CEF prevents loss of neuronal activity and neurogenesis in the brain of PD rats. CEF may therefore have clinical potential in the treatment of PD. PMID- 26940604 TI - Protective effect of resveratrol against chronic intermittent hypoxia-induced spatial memory deficits, hippocampal oxidative DNA damage and increased p47Phox NADPH oxidase expression in young rats. AB - Long-term intermittent hypoxia (IH) is a characteristic hallmark of obstructive sleep apnea (OSA) and causes most of the neurological aspects of OSA, such as spatial memory and learning deficits. These deficits are accompanied by an increase in oxidative stress and inflammation in brain areas involved in cognition, such as the hippocampus, particularly in children. Resveratrol is a natural polyphenolic compound with potent antioxidant, anti-inflammatory and neuroprotective properties. AIM: The aim of this work is to study the possible protective effect of resveratrol against IH-induced neurobehavioral deficits and to investigate the possible mechanism of this protective effect in the young rat model of OSA. METHODS: The effect of resveratrol (5 and 10mg/kg, orally) on anxiety, spatial memory and learning deficits in young rats exposed to IH for 6 weeks and the corresponding biochemical changes were studied. RESULTS: Resveratrol attenuated IH-induced anxiety and spatial memory deficits, as indicated by the elevated plus maze and Morris water maze tests, respectively, in a dose-dependent manner. In addition, resveratrol antagonized IH-induced increases in hippocampal glutamate, TBARS and 8-OHdG levels and p47Phox expression and decreases in GSH levels and GSH-Px activity in the hippocampus of IH-exposed young rats. CONCLUSION: Resveratrol ameliorates IH-induced anxiety and spatial learning deficits through multiple beneficial effects on hippocampal oxidative pathways that involve decreased expression of the p47Phox subunit of NADPH oxidase. Hence, the potential therapeutic role of resveratrol in OSA may be utilized in the near future and deserves further exploration. PMID- 26940606 TI - Heterogeneity in the Effect of Common Shocks on Healthcare Expenditure Growth. AB - Healthcare expenditure growth is affected by important unobserved common shocks such as technological innovation, changes in sociological factors, shifts in preferences, and the epidemiology of diseases. While common factors impact in principle all countries, their effect is likely to differ across countries. To allow for unobserved heterogeneity in the effects of common shocks, we estimate a panel data model of healthcare expenditure growth in 34 OECD countries over the years 1980 to 2012, where the usual fixed or random effects are replaced by a multifactor error structure. We address model uncertainty with Bayesian model averaging, to identify a small set of robust expenditure drivers from 43 potential candidates. We establish 16 significant drivers of healthcare expenditure growth, including growth in GDP per capita and in insurance premiums, changes in financing arrangements and some institutional characteristics, expenditures on pharmaceuticals, population ageing, costs of health administration, and inpatient care. Our approach allows us to provide robust evidence to policy makers on the drivers that were most strongly associated with the growth in healthcare expenditures over the past 32 years. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26940605 TI - Comparison of phencyclidine-induced spatial learning and memory deficits and reversal by sertindole and risperidone between Lister Hooded and Wistar rats. AB - Visual learning and memory are one of the key cognitive domains disturbed in schizophrenia. Glutamate NMDA receptors play a crucial role in spatial learning and memory and NMDA receptor antagonists, such as phencyclidine (PCP), impair spatial learning and memory. Pigmented rat strains have superior vision than albino rat strains and are therefore commonly used in visually-demanding cognitive tests. However, all previous water maze experiments using acutely administered PCP to induce schizophrenia-like cognitive deficits have been conducted with albino Wistar rats. This study was designed to assess whether pigmented Lister Hooded (LH) rats would be more suitable in modeling acute PCP induced deficits in Morris water maze (MWM) task than Wistar rats. We also evaluated whether the efficacy of atypical antipsychotics in reversing PCP induced spatial navigation deficits was dependent on the rat strain. First, we compared the PCP dose-response in the range of 1.3-2.0mg/kg (s.c.) at causing deficits in MWM performance. Then, the efficacies of sertindole 1.6mg/kg (s.c.) and risperidone 0.04mg/kg (s.c.) in reversing PCP-induced spatial navigation deficits were investigated. Drug-naive LH rats showed a better spatial memory than Wistar rats. Furthermore, PCP induced deficits in spatial navigation at lower doses in LH than in Wistar rats. In addition, PCP-induced deficits were partly reversed by sertindole in LH but not in Wistar rats. Our results suggest that the deficits in spatial learning and memory that resemble memory deficits found in schizophrenia patients are better modeled by PCP in LH rats than Wistar rats. PMID- 26940607 TI - Phosphorylated testis-specific serine/threonine kinase 4 may phosphorylate Crem at Ser-117. AB - We aimed to investigate the internal existence status of testis-specific serine/threonine kinase 4 (Tssk4) and the interaction of Tssk4 and Cre-responsive element modulator (Crem). The internal existence status of Tssk4 in testis of mice was detected using western blotting and dephosphorylation method. The interaction of Tssk4 and Crem was analyzed by western blotting, immunohistochemistry, immunofluorescence, in vitro co-immunoprecipitation assays, and in vitro kinase assay. The results revealed that Tssk4 existed in testis both in phosphorylation and unphosphorylation status by a temporal manner with the development of testis. Immunofluorescence results showed that Tssk4 had identical distribution pattern with Crem in testis, which was utterly different to the localization of Cre-responsive element binding (Creb). In conclusion, our study demonstrated that phosphorylated Tssk4 might participate in testis genes expressions by phosphorylating Crem at Ser-117. PMID- 26940608 TI - First update of the International Xenotransplantation Association consensus statement on conditions for undertaking clinical trials of porcine islet products in type 1 diabetes--Chapter 2a: source pigs--preventing xenozoonoses. AB - Chapter 2 of the original consensus statement published in 2009 by IXA represents an excellent basis for the production of safe donor pigs and pig-derived materials for porcine islet xenotransplantation. It was intended that the consensus statement was to be reviewed at interval to remain relevant. Indeed, many of the original salient points remain relevant today, especially when porcine islet xenotransplantation is performed in conjunction with immunosuppressants. However, progress in the field including demonstrated safe clinical porcine xenograft studies, increased understanding of risks including those posed by PERV, and advancement of diagnostic capabilities now allow for further consideration. Agents of known and unknown pathogenic significance continue to be identified and should be considered on a geographic, risk-based, dynamic, and product-specific basis, where appropriate using validated, advanced diagnostic techniques. PERV risk can be sufficiently reduced via multicomponent profiling including subtype expression levels in combination with infectivity assays. Barrier facilities built and operated against the AAALAC Ag Guide or suitable alternative criteria should be considered for source animal production as long as cGMPs and SOPs are followed. Bovine material-free feed for source animals should be considered appropriate instead of mammalian free materials to sufficiently reduce TSE risks. Finally, the sponsor retention period for archival samples of donor materials was deemed sufficient until the death of the recipient if conclusively determined to be of unrelated and non-infectious cause or for a reasonable period, that is, five to 10 yrs. In summary, the safe and economical production of suitable pigs and porcine islet xenograft materials, under appropriate guidance and regulatory control, is believed to be a viable means of addressing the unmet need for clinical islet replacement materials. PMID- 26940609 TI - New technologies in drug metabolism and toxicity screening: organ-to-organ interaction. PMID- 26940610 TI - Era 3 for Medicine and Health Care. PMID- 26940612 TI - Using Twitter as a tool for CPD. PMID- 26940611 TI - Cell-Demanded VEGF Release via Nanocapsules Elicits Different Receptor Activation Dynamics and Enhanced Angiogenesis. AB - Although the delivery of vascular endothelial growth factor (VEGF) with extended release profiles has consistently shown beneficial therapeutic effects compared with bolus delivery, [Martino, M. M., F. Tortelli, M. Mochizuki, S. Traub, D. Ben David, G. A. Kuhn, R. Muller, E. Livne, S. A. Eming, and J. A. Hubbell. Sci. Transl. Med. 3(100):100ra189, 2011; Martino, M. M., P. S. Briquez, A. Ranga, M. P. Lutolf, and J. A. Hubbell. Proc. Natl. Acad. Sci. USA. 110(12):4563-4568, 2013; Amiram, M., K. M. Luginbuhl, X. Li, M. N. Feinglos, and A. Chilkoti. Proc. Natl. Acad. Sci. USA. 110(8):2792-2797, 2013] it remains unclear if the reason is solely due to the physical availability and the reduced degradation of the protein. Here we studied the activation of VEGF receptor 2 (VR-2) by sustained released VEGF compared with bolus delivered VEGF to unveil that sustained delivery system alters the dynamics of receptor activation and affects the actions of cells between sprouting and proliferation. We utilized a protein nanocapsule delivery strategy that releases VEGF as mediated by extracellular proteases. These protein nanocapsules were synthesized through an aqueous assembly of a nanogel-peptide shell around the protein, leading to one to two proteins encapsulated per nanocapsule. Receptor activation studies revealed differential dynamics of receptor activation for slowly released VEGF compared with bolus delivered VEGF. As expected sustained released VEGF via nanocapsules resulted in enhanced vascular sprouting in vitro and in vivo. These studies demonstrate the physical presentation of VEGF, in this case of a slow release with time, can affect its molecular mechanism of actions and cause alterations in cellular responses and therapeutic outcomes. PMID- 26940613 TI - Community nursing quality indicators for end-of-life care in England: identification, preparation, and coordination. AB - High-quality community nursing is essential to ensure that end-of-life care can be provided in community settings in line with patient preferences. This article examines the quality priorities commissioners sought to incentivise in end-of life care, by reviewing a survey of Commissioning for Quality and Innovation (CQUIN) indicators for community nursing conducted in England in 2014-2015. Findings from the survey suggest that end-of-life care was not given a high priority with the CQUIN indicators for community nursing. Vigorous quality standards, including training and development, need to be in place to make sure that the potential of community nursing is being used to sensitively engage with people nearing the end of their lives and support them to plan their future care, if they so wish. PMID- 26940614 TI - Advances in infusion sets and insulin pumps in diabetes care. PMID- 26940616 TI - COPD and emotional distress: not always noticed and therefore untreated. AB - There are more than three million people in the UK living with chronic obstructive pulmonary disease (COPD). Focus tends to be on the physical effects of the condition; however, many patients living with COPD develop mental health symptoms that could go unnoticed and therefore untreated. The community nurse's role includes the management of patients with complex long-term conditions, which may include mental health issues. However, training to support patients whose condition includes a mental health component has long been considered inadequate and may lead to under diagnosis. Compared with other patients with long-term conditions, patients with COPD recount worse psychological functioning and greater psychological distress. Health-care workers' lack of mental health knowledge may be a contributory factor to why only a small proportion of patients are diagnosed and receive effective treatment. PMID- 26940617 TI - Exploring the district nurse role in facilitating individualised advance care planning. AB - Health-care policy recognises the importance of engaging people in making decisions related to the management of their health. Advance care planning (ACP) offers a framework for decision making on end-of-life care. There are positive indicators that ACP enables health professionals to meet people's preferences. However, there are reports of insensitive attempts to engage people in end-of life care decision making. District nurses are in the ideal position to facilitate ACP, as they have the opportunity to build relationships with the people they are caring for--an antecedent to sensitive ACP--and in recognising and fulfilling this role, they could ameliorate the risk of insensitive ACP. Distric nurse leaders also have a role to play in ensuring that organisational and environmental factors support appropriate ACP facilitation including: training, fostering a team culture that empowers district nurses to recognise and meet their ACP role, and advocating for appropriate ACP evaluation outcome measures. PMID- 26940615 TI - Nutritional advice for community patients: insights from a panel discussion. AB - This article describes the conclusions of an expert panel that discussed four case studies; these were examples of patients typically encountered by nurses working in the community. The panel considered the nutritional and lifestyle advice that could be given by nurses relating to conditions such as irritable bowel syndrome (IBS), depression, chronic fatigue syndrome, vulnerability to common infections, elderly care, recurrent urinary tract infection, antibiotic use, and risk of type 2 diabetes. A general conclusion was the importance of motivational interviewing techniques in achieving full understanding of patients' concerns and to determine the best health strategy. As well as specific guidance appropriate for each disorder, a range of information sources for both health professionals and patients are listed in the paper. The panel noted that, although general nutritional advice can be given by nurses working at GP surgeries and in the community, patients should always be referred to registered dietitians or nutritionists if significant dietary changes are considered. PMID- 26940618 TI - Community- and hospital-based nurses' implementation of evidence-based practice: are there any differences? AB - The aim of this paper is to discuss the effect of nurses' beliefs, knowledge, and skills on the implementation of evidence-based practice (EBP) in hospital and community settings. EBP refers to the implementation of the most up-to-date robust research into clinical practice. Barriers have been well documented and traditionally include the negative beliefs of nurses as well as a lack of time, knowledge, and skills. However, with degree entry nursing and a focus on community health care provision, what has changed? A comprehensive search of contemporary literature (2010-2015) was completed. The findings of this review show that the traditionally acknowledged barriers of a lack of time, knowledge, and skills remained; however, nurses' beliefs toward EBP were more positive, but positive beliefs did not affect the intentions to implement EBP or the knowledge and skills of EBP. Nurses in hospital and community settings reported similar barriers and facilitators. PMID- 26940619 TI - Repurcussions of negligence in community nursing practice. PMID- 26940620 TI - Spiritual needs in palliative care and the possibility of being nothing. PMID- 26940621 TI - An overview of plantar fasciitis. PMID- 26940622 TI - Productivity in health care. PMID- 26940623 TI - Causal evidence of the involvement of the number form area in the visual detection of numbers and letters. AB - Recent research suggests the existence of a visual area selectively processing numbers in the human inferior temporal cortex (number form area (NFA); Abboud et al., 2015; Grotheer et al., 2016; Shum et al., 2013). The NFA is thought to be involved in the preferential encoding of numbers over false characters, letters and non-number words (Grotheer et al., 2016; Shum et al., 2013), independently of the sensory modality (Abboud et al., 2015). However, it is not yet clear if this area is mandatory for normal number processing. The present study exploited the fact that high-resolution fMRI can be applied to identify the NFA individually (Grotheer et al., 2016) and tested if transcranial magnetic stimulation (TMS) of this area interferes with stimulus processing in a selective manner. Double-pulse TMS targeted at the right NFA significantly impaired the detection of briefly presented and masked Arabic numbers in comparison to vertex stimulation. This suggests the NFA to be necessary for fluent number processing. Surprisingly, TMS of the NFA also impaired the detection of Roman letters. On the other hand, stimulation of the lateral occipital complex (LO) had neither an effect on the detection of numbers nor on letters. Our results show, for the first time, that the NFA is causally involved in the early visual processing of numbers as well as of letters. PMID- 26940624 TI - HoxD expression in the fin-fold compartment of basal gnathostomes and implications for paired appendage evolution. AB - The role of Homeobox transcription factors during fin and limb development have been the focus of recent work investigating the evolutionary origin of limb specific morphologies. Here we characterize the expression of HoxD genes, as well as the cluster-associated genes Evx2 and LNP, in the paddlefish Polyodon spathula, a basal ray-finned fish. Our results demonstrate a collinear pattern of nesting in early fin buds that includes HoxD14, a gene previously thought to be isolated from global Hox regulation. We also show that in both Polyodon and the catshark Scyliorhinus canicula (a representative chondrichthyan) late phase HoxD transcripts are present in cells of the fin-fold and co-localize with And1, a component of the dermal skeleton. These new data support an ancestral role for HoxD genes in patterning the fin-folds of jawed vertebrates, and fuel new hypotheses about the evolution of cluster regulation and the potential downstream differentiation outcomes of distinct HoxD-regulated compartments. PMID- 26940627 TI - Heart Failure Patients Need More Than Heart Failure Care. PMID- 26940628 TI - I Lost a Friend From HFpEF: William Anlyan, MD, Chancellor Emeritus and Duke University Trustee. PMID- 26940625 TI - Current state of theoretical and experimental studies of the voltage-dependent anion channel (VDAC). AB - Voltage-dependent anion channel (VDAC), the major channel of the mitochondrial outer membrane provides a controlled pathway for respiratory metabolites in and out of the mitochondria. In spite of the wealth of experimental data from structural, biochemical, and biophysical investigations, the exact mechanisms governing selective ion and metabolite transport, especially the role of titratable charged residues and interactions with soluble cytosolic proteins, remain hotly debated in the field. The computational advances hold a promise to provide a much sought-after solution to many of the scientific disputes around solute and ion transport through VDAC and hence, across the mitochondrial outer membrane. In this review, we examine how Molecular Dynamics, Free Energy, and Brownian Dynamics simulations of the large beta-barrel channel, VDAC, advanced our understanding. We will provide a short overview of non-conventional techniques and also discuss examples of how the modeling excursions into VDAC biophysics prospectively aid experimental efforts. This article is part of a Special Issue entitled: Membrane Proteins edited by J.C. Gumbart and Sergei Noskov. PMID- 26940629 TI - Reply: Worsening Renal Function in Acute Decompensated Heart Failure: The Puzzle is Still Incomplete. PMID- 26940630 TI - Reply: The "Obesity Paradox" Is Not a Paradox: Time to Focus on Effective Treatments. PMID- 26940626 TI - Atomic-level description of protein-lipid interactions using an accelerated membrane model. AB - Peripheral membrane proteins are structurally diverse proteins that are involved in fundamental cellular processes. Their activity of these proteins is frequently modulated through their interaction with cellular membranes, and as a result techniques to study the interfacial interaction between peripheral proteins and the membrane are in high demand. Due to the fluid nature of the membrane and the reversibility of protein-membrane interactions, the experimental study of these systems remains a challenging task. Molecular dynamics simulations offer a suitable approach to study protein-lipid interactions; however, the slow dynamics of the lipids often prevents sufficient sampling of specific membrane-protein interactions in atomistic simulations. To increase lipid dynamics while preserving the atomistic detail of protein-lipid interactions, in the highly mobile membrane-mimetic (HMMM) model the membrane core is replaced by an organic solvent, while short-tailed lipids provide a nearly complete representation of natural lipids at the organic solvent/water interface. Here, we present a brief introduction and a summary of recent applications of the HMMM to study different membrane proteins, complementing the experimental characterization of the presented systems, and we offer a perspective of future applications of the HMMM to study other classes of membrane proteins. This article is part of a Special Issue entitled: Membrane proteins edited by J.C. Gumbart and Sergei Noskov. PMID- 26940631 TI - Concerning the Role of Gender Difference in Obesity Paradox in Patients With Heart Failure. PMID- 26940632 TI - Reply: Concerning the Role of Gender Difference in Obesity Paradox in Patients With Heart Failure. PMID- 26940634 TI - Plasminogen activator inhibitor-1 concentrations and bone mineral density in postmenopausal women with type 2 diabetes mellitus. AB - BACKGROUND: Women with type 2 diabetes mellitus (T2DM) have a higher risk of fractures despite increased bone mineral density (BMD). In experimental studies a potential role of plasminogen activator inhibitor-1 (PAI-1) in bone remodeling is suggested but studies in humans are lacking. This is a first study in humans investigating whether circulated levels of PAI-1 in postmenopausal women with T2DM are related to BMD and adiposity. METHODS: Anthropometric variables, PAI-1 and insulin levels, serum lipids and bone turnover markers were measured in 127 postmenopausal women with T2DM. A total of 117 female patients were divided according to lumbar spine BMD measurements via dual-energy x-ray absorptiometry in three groups: 47 with osteopenia, 21 with osteoporosis and 49 with normal BMD. RESULTS: Diabetic patients with normal BMD had significantly higher BMI, greater waist circumference and lower bone turnover markers than diabetics with osteopenia and osteoporosis. PAI-1 was lower in diabetics with osteoporosis and osteopenia compared with diabetics with normal BMD. Multiple regression analysis revealed insulin, triglycerides levels, pyrilinks and beta blocker therapy to be the strongest predictors of PAI-1 levels. PAI-1 levels correlated with both L-BMD and hip BMD, but after adjustment for age and BMI association was no longer significant. CONCLUSION: Our findings suggest that elevated PAI-1 levels are associated with higher BMD in obese diabetic patients but the possible implications of this finding and underlying mechanisms still remain unclear. Obviously, metabolic parameters, may affect both BMD and PAI-levels, and association of PAI-1 and BMD could be indirect. However, as pyrilinks is also independently and significantly negatively correlated to PAI-1 its direct involvement in bone metabolism is also plausible. Further investigations are needed to elucidate the nature of interaction of this matrix modulator in relation to energy and bone metabolism in humans. PMID- 26940633 TI - Global transcriptional response of Dickeya dadantii to environmental stimuli relevant to the plant infection. AB - Dickeya species are soft rot disease-causing bacterial plant pathogens and an emerging agricultural threat in Europe. Environmental modulation of gene expression is critical for Dickeya dadantii pathogenesis. While the bacterium uses various environmental cues to distinguish between its habitats, an intricate transcriptional control system coordinating the expression of virulence genes ensures efficient infection. Understanding of this behaviour requires a detailed knowledge of expression patterns under a wide range of environmental conditions, which is currently lacking. To obtain a comprehensive picture of this adaptive response, we devised a strategy to examine the D. dadantii transcriptome in a series of 32 infection-relevant conditions encountered in the hosts. We propose a temporal map of the bacterial response to various stress conditions and show that D. dadantii elicits complex genetic behaviour combining common stress-response genes with distinct sets of genes specifically induced under each particular stress. Comparison of our dataset with an in planta expression profile reveals the combined impact of stress factors and enables us to predict the major stress confronting D. dadantii at a particular stage of infection. We provide a comprehensive catalog of D. dadantii genomic responses to environmentally relevant stimuli, thus facilitating future studies of this important plant pathogen. PMID- 26940635 TI - A Cloud Architecture for Teleradiology-as-a-Service. AB - BACKGROUND: Telemedicine has been promoted by healthcare professionals as an efficient way to obtain remote assistance from specialised centres, to get a second opinion about complex diagnosis or even to share knowledge among practitioners. The current economic restrictions in many countries are increasing the demand for these solutions even more, in order to optimize processes and reduce costs. However, despite some technological solutions already in place, their adoption has been hindered by the lack of usability, especially in the set up process. OBJECTIVES: In this article we propose a telemedicine platform that relies on a cloud computing infrastructure and social media principles to simplify the creation of dynamic user-based groups, opening up opportunities for the establishment of teleradiology trust domains. METHODS: The collaborative platform is provided as a Software-as-a-Service solution, supporting real time and asynchronous collaboration between users. To evaluate the solution, we have deployed the platform in a private cloud infrastructure. The system is made up of three main components - the collaborative framework, the Medical Management Information System (MMIS) and the HTML5 (Hyper Text Markup Language) Web client application - connected by a message-oriented middleware. RESULTS: The solution allows physicians to create easily dynamic network groups for synchronous or asynchronous cooperation. The network created improves dataflow between colleagues and also knowledge sharing and cooperation through social media tools. The platform was implemented and it has already been used in two distinct scenarios: teaching of radiology and tele-reporting. CONCLUSIONS: Collaborative systems can simplify the establishment of telemedicine expert groups with tools that enable physicians to improve their clinical practice. Streamlining the usage of this kind of systems through the adoption of Web technologies that are common in social media will increase the quality of current solutions, facilitating the sharing of clinical information, medical imaging studies and patient diagnostics among collaborators. PMID- 26940636 TI - Molecular detection of bovine Noroviruses in Argentinean dairy calves: Circulation of a tentative new genotype. AB - Bovine noroviruses are enteric pathogens detected in fecal samples of both diarrheic and non-diarrheic calves from several countries worldwide. However, epidemiological information regarding bovine noroviruses is still lacking for many important cattle producing countries from South America. In this study, three bovine norovirus genogroup III sequences were determined by conventional RT PCR and Sanger sequencing in feces from diarrheic dairy calves from Argentina (B4836, B4848, and B4881, all collected in 2012). Phylogenetic studies based on a partial coding region for the RNA-dependent RNA polymerase (RdRp, 503 nucleotides) of these three samples suggested that two of them (B4836 and B4881) belong to genotype 2 (GIII.2) while the third one (B4848) was more closely related to genotype 1 (GIII.1) strains. By deep sequencing, the capsid region from two of these strains could be determined. This confirmed the circulation of genotype 1 (B4848) together with the presence of another sequence (B4881) sharing its highest genetic relatedness with genotype 1, but sufficiently distant to constitute a new genotype. This latter strain was shown in silico to be a recombinant: phylogenetic divergence was detected between its RNA-dependent RNA polymerase coding sequence (genotype GIII.2) and its capsid protein coding sequence (genotype GIII.1 or a potential norovirus genotype). According to this data, this strain could be the second genotype GIII.2_GIII.1 bovine norovirus recombinant described in literature worldwide. Further analysis suggested that this strain could even be a potential norovirus GIII genotype, tentatively named GIII.4. The data provides important epidemiological and evolutionary information on bovine noroviruses circulating in South America. PMID- 26940637 TI - Entertainment or Health? Exploring the Internet Usage Patterns of the Urban Poor: A Secondary Analysis of a Randomized Controlled Trial. AB - BACKGROUND: Important gaps remain in our knowledge of how individuals from low socioeconomic position (SEP) use the Internet for resources and in understanding the full range of activities they perform online. Although self-report data indicate that low SEP individuals use the Internet less than high SEP people for health information and for other beneficial capital-enhancing activities, these results may not provide an accurate overall view of online use. OBJECTIVE: The aim of this study was to determine the ways in which low SEP individuals use the Internet, including for entertainment, social networking, and capital-enhancing functions, and how they are associated with health information seeking. METHODS: Detailed Web tracking data were collected from 118 low SEP individuals who participated in the intervention group of a randomized controlled trial that provided Internet access. Websites were grouped by topic, including categories of capital-enhancing websites that provided access to resources and information. Different types of online activities were summed into an Internet use index. Single and multiple negative binomial regression models were fitted with the Internet use index as the predictor and health information seeking as the outcome. Next, models were fitted with low, medium, and high Web usage in capital enhancing, entertainment, and social network categories to determine their associations with health information seeking. RESULTS: Participants used the Web for diverse purposes, with 63.6% (75/118) accessing the Internet for all defined types of Internet use. Each additional category of Internet use was associated with 2.12 times the rate of health information seeking (95% CI 1.84-2.44, P<.001). Higher use of each type of capital-enhancing information was associated with higher rates of health information seeking, with high uses of government (incident rate ratio [IRR] 8.90, 95% CI 4.82-16.42, P<.001) and news (IRR 11.36, 95% CI 6.21-20.79, P<.001) websites associated with the highest rates of health information seeking compared to their lowest use categories. High entertainment website use (IRR 3.91, 95% CI 2.07-7.37, P<.001) and high social network use (IRR 2.06, 95% CI 1.08-3.92, P=.03) were also associated with higher health information seeking. CONCLUSIONS: These data clearly show that familiarity and skills in using the Internet enhance the capacity to use it for diverse purposes, including health and to increase capital, and that Internet usage for specific activities is not a zero sum game. Using it for one type of topic, such as entertainment, does not detract from using it for other purposes. Findings may inform ways to engage low SEP groups with Internet resources. PMID- 26940638 TI - The gammaH2AX DNA damage assay from a drop of blood. AB - DNA double-strand breaks (DSB) and blocked replication forks activate the DNA damage response (DDR), a signaling pathway marked by phosphorylation of histone 2AX (H2AX). The phosphorylated form, gammaH2AX, accumulates at the site of damage and can be detected as foci by immunocytochemistry. Therefore, gammaH2AX is a sensitive and robust biomarker of DNA damage, notably DSB. Cells from peripheral blood are often used for studies on genotoxic exposure of humans. They are limited, however, by the amount of blood required and the costly blood purification method. Here, we present a method that enables the detection of DNA damage by the analysis of gammaH2AX foci in a drop of blood. The blood drop method (BDM) is simple, fast, inexpensive and allows large series of blood sampling and storage over time. It can be combined with genotoxic treatment of cells in the collected blood sample for experimental purposes on DNA damage induction and repair. The BDM is suitable for rapid and large-scale screenings of genetic damage in human and animal populations. PMID- 26940640 TI - Physician Preferences for Botulinum Toxin Injections in Anticoagulated Patients with Spasticity. AB - To understand physician preferences and bleeding complication rates of intramuscular botulinum neurotoxin type A injections for spasticity management in anticoagulated patients, questionnaires were mailed to 138 physicians across Canada. The international normalized ratio comfort range for injections was <2.0 in 10%, 2.0 to 2.5 in 35%, 2.6 to 3.0 in 25%, and 3.1 to 3.5 in 20% of physicians. Only 23% injected outside their comfort value and 57% did not; 72% did not normalize the international normalized ratio value before injections. Only one injector reported the development of compartment syndrome. As expected, high variability exists in physician preferences in botulinum neurotoxin type A injection in anticoagulated patients. PMID- 26940639 TI - Origins of the vagal drive controlling left ventricular contractility. AB - KEY POINTS: The strength, functional significance and origins of parasympathetic innervation of the left ventricle remain controversial. This study tested the hypothesis that parasympathetic control of left ventricular contractility is provided by vagal preganglionic neurones of the dorsal motor nucleus (DVMN). Under beta-adrenoceptor blockade combined with spinal cord (C1) transection (to remove sympathetic influences), systemic administration of atropine increased left ventricular contractility in rats anaesthetized with urethane, confirming the existence of a tonic inhibitory muscarinic influence on cardiac inotropy. Increased left ventricular contractility in anaesthetized rats was observed when DVMN neurones were silenced. Functional neuroanatomical mapping revealed that vagal preganglionic neurones that have an impact on left ventricular contractility are located in the caudal region of the left DVMN. These neurones provide functionally significant parasympathetic control of left ventricular inotropy. ABSTRACT: The strength, functional significance and origins of direct parasympathetic innervation of the left ventricle (LV) remain controversial. In the present study we used an anaesthetized rat model to first confirm the presence of tonic inhibitory vagal influence on LV inotropy. Using genetic neuronal targeting and functional neuroanatomical mapping we tested the hypothesis that parasympathetic control of LV contractility is provided by vagal preganglionic neurones located in the dorsal motor nucleus (DVMN). It was found that under systemic beta-adrenoceptor blockade (atenolol) combined with spinal cord (C1) transection (to remove sympathetic influences), intravenous administration of atropine increases LV contractility in rats anaesthetized with urethane, but not in animals anaesthetized with pentobarbital. Increased LV contractility in rats anaesthetized with urethane was also observed when DVMN neurones targeted bilaterally to express an inhibitory Drosophila allatostatin receptor were silenced by application of an insect peptide allatostatin. Microinjections of glutamate and muscimol to activate or inhibit neuronal cell bodies in distinct locations along the rostro-caudal extent of the left and right DVMN revealed that vagal preganglionic neurones, which have an impact on LV contractility, are located in the caudal region of the left DVMN. Changes in LV contractility were only observed when this subpopulation of DVMN neurones was activated or inhibited. These data confirm the existence of a tonic inhibitory muscarinic influence on LV contractility. Activity of a subpopulation of DVMN neurones provides functionally significant parasympathetic control of LV contractile function. PMID- 26940641 TI - Expression of inducible nitric oxide synthase in mast cells contributes to the regulation of inflammatory cytokines in irritable bowel syndrome with diarrhea. AB - BACKGROUND: Nitric oxide (NO) and mast cells (MCs) are possibly involved in the development of irritable bowel syndrome (IBS), but details on their role and interactions still remain undetermined. We aimed to investigate the expression of inducible NO synthase (iNOS) in MCs of the colon of IBS with diarrhea (IBS-D), and elucidated a potential role of NO in the differential regulation of cytokines in MCs. METHODS: Colonic mucosal biopsies of 19 IBS-D patients and 16 healthy controls were collected. The expression of tryptase and iNOS was investigated by immunohistochemistry, Western blotting, and real-time PCR. Effects of NO on the expression of cytokines in rat bone marrow MCs (BMMCs) were examined using a cytokine array by NG-nitro-l-arginine methyl ester (L-NAME) treatment. KEY RESULTS: Immunohistochemistry for tryptase revealed an increase in number of MCs with extensive iNOS expression in the colonic mucosa of IBS-D. Tryptase, iNOS and interleukin (IL)-1beta mRNA and protein levels were upregulated in IBS-D compared with healthy controls. Specifically, a positive correlation between tryptase and iNOS protein expression was observed in the colon of IBS-D (r = 0.667, p < 0.05). Supernatant from IBS-D increased iNOS expression in BMMCs. Antibody array showed that agrin, beta-nerve growth factor, fractalkine, granulocyte-macrophage colony stimulating factor, IL-1beta, IL-1R6, IL-13, leptin, tumor necrosis factor alpha were suppressed, and cytokine-induced neutrophil chemoattractant (CINC)-1, CINC 2alpha, CINC-3, monocyte chemotactic protein-1, matrix metalloproteinase-8 were strongly produced in L-NAME treated BMMCs, comparable to levels in the control group. CONCLUSIONS & INFERENCES: Our findings provide new evidence that NO is able to regulate many cytokines in MCs that may be involved in the development of IBS. PMID- 26940642 TI - Zika virus may be linked to several birth defects, expert warns. PMID- 26940643 TI - A new alternative to cosmetics preservation and the effect of the particle size of the emulsion droplets on preservation efficacy. AB - OBJECTIVE: This study describes a new alternative combination preservative containing caprylyl glycol, phenethyl alcohol and glyceryl caprylate and investigates the effects of the particle size of the emulsion droplet on the anti microbial activity of the said blend in the formulation. METHODS: The anti microbial activity of the ingredients and the blend were determined via MIC, MBC, MFC and fractional inhibitory concentration (FIC) determination using the broth microdilution method. The blend inhibited the micro-organism contamination of the oil-in-water emulsion, and its performance was affected by the particle size of the emulsion droplet, as shown by the in vitro microbial challenge test. RESULTS: Results show that the MIC/MBC/MFC values of the blend were lower than those of any of the ingredients used alone. Any two of the ingredients presented no antagonistic activities against all the tested micro-organisms, and synergism or additive effects were also observed. The challenge test also showed that the action of the blend against bacteria and yeast was only 0.3% and 0.2%, respectively, and mould was completely inhibited at 1.4%, meeting the requirements of the PCPC and European Pharmacopoeia. The results showed that anti microbial activity was gradually enhanced when the particle size of the emulsion droplets increased significantly in the range of 100-900 nm. A positive correlation was found between anti-microbial activity and particle size. CONCLUSION: The synergistic performance of caprylyl glycol, phenethyl alcohol and glyceryl caprylate and the anti-microbial activity of their blend suggest that their combination is effective and exhibits broad-spectrum anti-microbial activity. Furthermore, the results show a positive correlation between the anti microbial activity of the preservative and the particle size of the emulsion droplets in the range of 100-900 nm, when the same concentration of the blend is used in the same formulation. The particle size of the emulsion droplets is demonstrated to be a newly discovered factor that influences the preservation of cosmetic products. PMID- 26940644 TI - Young's equation revisited. AB - Young's construction for a contact angle at a three-phase intersection forms the basis of all fields of science that involve wetting and capillary action. We find compelling evidence from recent experimental results on the deformation of a soft solid at the contact line, and displacement of an elastic wire immersed in a liquid, that Young's equation can only be interpreted by surface energies, and not as a balance of surface tensions. It follows that the a priori variable in finding equilibrium is not the position of the contact line, but the contact angle. This finding provides the explanation for the pinning of a contact line. PMID- 26940646 TI - Enhancing the grain size of organic halide perovskites by sulfonate-carbon nanotube incorporation in high performance perovskite solar cells. AB - The grain size of perovskites was enhanced and the grain boundary was filled with sulfonate carbon nanotubes (s-CNTs) during the CH3NH3PbI3 perovskite precursor solution spin-coating process with the incorporation of s-CNTs. The performance of s-CNT incorporated perovskite solar cells remarkably increased from 10.3% to 15.1% (best) compared with pristine CNT incorporated perovskite solar cells. PMID- 26940645 TI - Secondary analysis of outcomes after 11,085 hip fracture operations from the prospective UK Anaesthesia Sprint Audit of Practice (ASAP-2). AB - We re-analysed prospective data collected by anaesthetists in the Anaesthesia Sprint Audit of Practice (ASAP-1) to describe associations with linked outcome data. Mortality was 165/11,085 (1.5%) 5 days and 563/11,085 (5.1%) 30 days after surgery and was not associated with anaesthetic technique (general vs. spinal, with or without peripheral nerve blockade). The risk of death increased as blood pressure fell: the odds ratio (95% CI) for mortality within five days after surgery was 0.983 (0.973-0.994) for each 5 mmHg intra-operative increment in systolic blood pressure, p = 0.0016, and 0.980 (0.967-0.993) for each mmHg increment in mean pressure, p = 0.0039. The equivalent odds ratios (95% CI) for 30-day mortality were 0.968 (0.951-0.985), p = 0.0003 and 0.976 (0.964-0.988), p = 0.0001, respectively. The lowest systolic blood pressure after intrathecal local anaesthetic relative to before induction was weakly correlated with a higher volume of subarachnoid bupivacaine: r(2) -0.10 and -0.16 for hyperbaric and isobaric bupivacaine, respectively. A mean 20% relative fall in systolic blood pressure correlated with an administered volume of 1.44 ml hyperbaric bupivacaine. Future research should focus on refining standardised anaesthesia towards administering lower doses of spinal (and general) anaesthesia and maintaining normotension. PMID- 26940647 TI - Probiotics for the Treatment of Infantile Colic: A Systematic Review. AB - OBJECTIVE: To evaluate whether clinical data support the safety and efficacy of probiotics for the management of infantile colic. BACKGROUND: Probiotics have been suggested as a potential strategy for infantile colic, and the specific species that have been studied in healthy infants are considered to be safe. METHODOLOGY: A systematic review was conducted to identify randomized controlled trials (RCTs) evaluating the use of probiotic supplementation in infants with colic. RCTs with a primary end point assessing crying or fussing time were selected. A meta-analysis comparing "responders" to "nonresponders" in infants receiving probiotic versus control was conducted. The quality of trials selected was assessed. RESULTS: Five RCTs assessing 2 different strains of the probiotic Lactobacillus reuteri in mostly breastfed infants were identified. Analysis of response rates showed that infants receiving probiotics had a 2.3-fold greater chance of having a 50% or greater decrease in crying/fussing time compared to controls ( P = .01). Probiotic supplementation was not associated with any adverse events. CONCLUSION: Supplementation with the probiotic L. reuteri in breastfed infants appears to be safe and effective for the management of infantile colic. Further research is needed to determine the role of probiotics in infants who are formula-fed. PMID- 26940648 TI - A new approach for second-order perturbation theory. AB - A new second-order perturbation theory (MP2) approach is presented for closed shell energy evaluations. The new algorithm has a significantly lower memory footprint, a lower FLOP (floating point operations) count, and a lower time to solution compared to previously implemented parallel MP2 methods in the GAMESS software package. Additionally, this algorithm features an adaptive approach for the disk/distributed memory storage of the MP2 amplitudes. The algorithm works well on a single workstation, small cluster, and large Cray cluster, and it allows one to perform large calculations with thousands of basis functions in a matter of hours on a single workstation. The same algorithm has been adapted for graphical processing unit (GPU) architecture. The performance of the new GPU algorithm is also discussed. PMID- 26940649 TI - Computational methods for ubiquitination site prediction using physicochemical properties of protein sequences. AB - BACKGROUND: Ubiquitination is a very important process in protein post translational modification, which has been widely investigated by biology scientists and researchers. Different experimental and computational methods have been developed to identify the ubiquitination sites in protein sequences. This paper aims at exploring computational machine learning methods for the prediction of ubiquitination sites using the physicochemical properties (PCPs) of amino acids in the protein sequences. RESULTS: We first establish six different ubiquitination data sets, whose records contain both ubiquitination sites and non ubiquitination sites in variant numbers of protein sequence segments. In particular, to establish such data sets, protein sequence segments are extracted from the original protein sequences used in four published papers on ubiquitination, while 531 PCP features of each extracted protein sequence segment are calculated based on PCP values from AAindex (Amino Acid index database) by averaging PCP values of all amino acids on each segment. Various computational machine-learning methods, including four Bayesian network methods (i.e., Naive Bayes (NB), Feature Selection NB (FSNB), Model Averaged NB (MANB), and Efficient Bayesian Multivariate Classifier (EBMC)) and three regression methods (i.e., Support Vector Machine (SVM), Logistic Regression (LR), and Least Absolute Shrinkage and Selection Operator (LASSO)), are then applied to the six established segment-PCP data sets. Five-fold cross-validation and the Area Under Receiver Operating Characteristic Curve (AUROC) are employed to evaluate the ubiquitination prediction performance of each method. Results demonstrate that the PCP data of protein sequences contain information that could be mined by machine learning methods for ubiquitination site prediction. The comparative results show that EBMC, SVM and LR perform better than other methods, and EBMC is the only method that can get AUCs greater than or equal to 0.6 for the six established data sets. Results also show EBMC tends to perform better for larger data. CONCLUSIONS: Machine learning methods have been employed for the ubiquitination site prediction based on physicochemical properties of amino acids on protein sequences. Results demonstrate the effectiveness of using machine learning methodology to mine information from PCP data concerning protein sequences, as well as the superiority of EBMC, SVM and LR (especially EBMC) for the ubiquitination prediction compared to other methods. PMID- 26940650 TI - Intra-epidemic evolutionary dynamics of a Dengue virus type 1 population reveal mutant spectra that correlate with disease transmission. AB - Dengue virus (DENV) is currently the most prevalent mosquito-borne viral pathogen. DENVs naturally exist as highly heterogeneous populations. Even though the descriptions on DENV diversity are plentiful, only a few studies have narrated the dynamics of intra-epidemic virus diversity at a fine scale. Such accounts are important to decipher the reciprocal relationship between viral evolutionary dynamics and disease transmission that shape dengue epidemiology. In the current study, we present a micro-scale genetic analysis of a monophyletic lineage of DENV-1 genotype III (epidemic lineage) detected from November 2012 to May 2014. The lineage was involved in an unprecedented dengue epidemic in Singapore during 2013-2014. Our findings showed that the epidemic lineage was an ensemble of mutants (variants) originated from an initial mixed viral population. The composition of mutant spectrum was dynamic and positively correlated with case load. The close interaction between viral evolution and transmission intensity indicated that tracking genetic diversity through time is potentially a useful tool to infer DENV transmission dynamics and thereby, to assess the epidemic risk in a disease control perspective. Moreover, such information is salient to understand the viral basis of clinical outcome and immune response variations that is imperative to effective vaccine design. PMID- 26940653 TI - Cardiorespiratory fitness estimation using wearable sensors: Laboratory and free living analysis of context-specific submaximal heart rates. AB - In this work, we propose to use pattern recognition methods to determine submaximal heart rate (HR) during specific contexts, such as walking at a certain speed, using wearable sensors in free living, and using context-specific HR to estimate cardiorespiratory fitness (CRF). CRF of 51 participants was assessed by a maximal exertion test (Vo2 max). Participants wore a combined accelerometer and HR monitor during a laboratory-based simulation of activities of daily living and for 2 wk in free living. Anthropometrics, HR while lying down, and walking at predefined speeds in laboratory settings were used to estimate CRF. Explained variance (R(2)) was 0.64 for anthropometrics, and increased up to 0.74 for context-specific HR (0.73-0.78 when including fat-free mass). Next, we developed activity recognition and walking speed estimation algorithms to determine the same contexts (i.e., lying down and walking) in free living. Context-specific HR in free living was highly correlated with laboratory measurements (Pearson's r = 0.71-0.75). R(2) for CRF estimation was 0.65 when anthropometrics were used as predictors, and increased up to 0.77 when including free-living context-specific HR (i.e., HR while walking at 5.5 km/h). R(2) varied between 0.73 and 0.80 when including fat-free mass among the predictors. Root mean-square error was reduced from 354.7 to 281.0 ml/min by the inclusion of context-specific HR parameters (21% error reduction). We conclude that pattern recognition techniques can be used to contextualize HR in free living and estimated CRF with accuracy comparable to what can be obtained with laboratory measurements of HR response to walking. PMID- 26940652 TI - Age-associated metabolic dysregulation in bone marrow-derived macrophages stimulated with lipopolysaccharide. AB - Macrophages are major contributors to age-associated inflammation. Metabolic processes such as oxidative phosphorylation, glycolysis and the urea cycle regulate inflammatory responses by macrophages. Metabolic profiles changes with age; therefore, we hypothesized that dysregulation of metabolic processes could contribute to macrophage hyporesponsiveness to LPS. We examined the intracellular metabolome of bone marrow-derived macrophages from young (6-8 wk) and old (18-22 mo) mice following lipopolysaccharide (LPS) stimulation and tolerance. We discovered known and novel metabolites that were associated with the LPS response of macrophages from young mice, which were not inducible in macrophages from old mice. Macrophages from old mice were largely non-responsive towards LPS stimulation, and we did not observe a shift from oxidative phosphorylation to glycolysis. The critical regulatory metabolites succinate, gamma-aminobutyric acid, arginine, ornithine and adenosine were increased in LPS-stimulated macrophages from young mice, but not macrophages from old mice. A shift between glycolysis and oxidative phosphorylation was not observed during LPS tolerance in macrophages from either young or old mice. Metabolic bottlenecks may be one of the mechanisms that contribute to the dysregulation of LPS responses with age. PMID- 26940651 TI - Metagenomic evidence for taxonomic dysbiosis and functional imbalance in the gastrointestinal tracts of children with cystic fibrosis. AB - Cystic fibrosis (CF) results in inflammation, malabsorption of fats and other nutrients, and obstruction in the gastrointestinal (GI) tract, yet the mechanisms linking these disease manifestations to microbiome composition remain largely unexplored. Here we used metagenomic analysis to systematically characterize fecal microbiomes of children with and without CF, demonstrating marked CF associated taxonomic dysbiosis and functional imbalance. We further showed that these taxonomic and functional shifts were especially pronounced in young children with CF and diminished with age. Importantly, the resulting dysbiotic microbiomes had significantly altered capacities for lipid metabolism, including decreased capacity for overall fatty acid biosynthesis and increased capacity for degrading anti-inflammatory short-chain fatty acids. Notably, these functional differences correlated with fecal measures of fat malabsorption and inflammation. Combined, these results suggest that enteric fat abundance selects for pro inflammatory GI microbiota in young children with CF, offering novel strategies for improving the health of children with CF-associated fat malabsorption. PMID- 26940655 TI - Bronchodilating effect of deep inspirations in asthma and chronic cough. AB - The pathophysiologic processes distinguishing classic asthma (CA), cough-variant asthma (CVA), and methacholine (MCh)-induced cough but normal airway sensitivity (COUGH) are inadequately understood and may be a result of differences in the ability to bronchodilate following a deep inspiration (DI). The purpose of this study was to compare the bronchodilating effect of DIs in individuals with CA, CVA, and COUGH using high-dose MCh. Individuals aged 18-65 yr with CA or suspected CVA completed high-dose MCh testing to a maximum change in forced expiratory volume in 1 s (FEV1) of 50% from baseline (MAX). Impulse oscillometry (IOS) measurements and partial and maximal-flow volume curves (used to calculate a DI index) were recorded at baseline and at each dose of MCh. Body plethysmography was performed at baseline and MAX. Twenty-eight subjects [25 women, 39.8 +/- 11.9 yr (means +/- SD)] were studied (n = 11 CA, n = 10 CVA, and n = 7 COUGH). At MAX, the percent change in FEV1 was greater in subjects with CA compared with those with CVA (P < 0.001) and COUGH (P < 0.001), and the percent change in forced vital capacity was greater in those with CA than with COUGH (P = 0.017). Subjects with CA and CVA developed dynamic hyperinflation and gas trapping. In subjects with CA and CVA, all IOS parameters were significantly increased from baseline to MAX, except for central respiratory resistance (R20). In individuals with COUGH, total respiratory resistance, R20, and resonant frequency were significantly increased from baseline. At MAX, the DI index was positive in all groups, suggesting preserved bronchodilation (CA, 0.67 +/- 0.97; CVA, 0.51 +/- 0.73; COUGH, 0.01 +/- 0.36; P = 0.211). We conclude that the bronchodilating effect of DIs is preserved in individuals with CA, CVA, and borderline with COUGH; however, hyperinflation and gas trapping are avoided in subjects with COUGH alone. PMID- 26940654 TI - Systolic-diastolic functional coupling in healthy children and in those with dilated cardiomyopathy. AB - Systolic and diastolic function affect dilated cardiomyopathy (DCM) outcomes. However, systolic-diastolic coupling, as a distinct characteristic, may itself affect function but is poorly characterized. We hypothesized that echocardiographic left ventricular (LV) longitudinal systolic tissue velocities (S') correlate with diastolic longitudinal velocities (E') and that their relationship is associated with ventricular function and that this relationship is impaired in pediatric DCM. We analyzed data from the Pediatric Heart Network Ventricular Volume Variability study, using linear regression and generalized additive modeling to assess relationships between S' and E' at the lateral and septal mitral annulus. We explored relationships between the systolic:diastolic (S:D) coupling ratio (S':E' relative to age) and ventricular function. Up to 4 echocardiograms from 130 DCM patients (mean age: 9.3 +/- 6.1 yr) and 1 echocardiogram from each of 591 healthy controls were analyzed. S' and E' were linearly related in controls (r = 0.64, P < 0.001) and DCM (r = 0.83, P < 0.001). In DCM, the magnitude of association between S' and E' was reduced with progressive ventricular remodeling. The S:D ratio was more strongly associated with LV function in controls vs. DCM. The septal S:D ratio was higher (presumed worse) in DCM vs. controls (0.69 +/- 0.13 vs. 0.62 +/- 0.12, P = 0.001). A higher septal S:D ratio was associated with worse LV dimensions (parameter estimate: 0.0061, P = 0.004), mass (parameter estimate: 0.0074, P = 0.002), ejection fraction (parameter estimate: -0.0303, P = 0.024), and inflow propagation (parameter estimate: -0.3538, P < .001). S:D coupling becomes weaker in DCM with LV remodeling and dysfunction. The S:D coupling ratio may be useful to assess coupling, warranting study in relation to patient outcomes. PMID- 26940656 TI - A skeleton-tree-based approach to acinar morphometric analysis using microcomputed tomography with comparison of acini in young and old C57BL/6 mice. AB - We seek to establish a method using interior tomographic techniques (Xradia MicroXCT-400) for acinar morphometric analysis using the pathway center lines from micro X-ray computed tomographic (Micro-CT) images as the road map. Through the application of these techniques, we present a method to extend the atlas of murine lungs to acinar levels and present a comparison between two age groups of the C57BL/6 strain. Lungs fixed via vascular perfusion were scanned using high resolution Micro-CT protocols. Individual acini were segmented, and skeletonized paths to alveolar sacs from the entrance to the acinus were formed. Morphometric parameters, including branch lengths, diameters, and branching angles, were generated. Six mice each, at two age groups (~20 and ~90 wk of age), were studied. Additive Gaussian noise (0 mean and SD 1, 2, 5, and 10) was used to test the robustness of the analytical method. Noise-based variations were within +/-6 MUm for branch lengths and +/-5 MUm for diameters. At a noise level of 10, errors increased. Branch diameters were less susceptible to noise than lengths. There was >95% center line overlap across all noise levels. The measurements obtained using the center lines as a road map were not affected by added noise. Acini from younger mice had smaller branch diameters and lengths at all generations without significant differences in branching angles. The relative distribution of volume in the alveolar ducts was similar across both age groups. The method has been demonstrated to be repeatable and robust to image noise and provides a new, nondestructive technique to assess and compare acinar morphometry quantitatively. PMID- 26940658 TI - Age-related differences in plasma BDNF levels after prolonged bed rest. AB - Brain-derived neurotrophic factor (BDNF) is a member of the family of neurotrophins and has been implicated in brain resistance to insults. Murine studies have demonstrated increased hippocampal concentration after acute immobilization and decreased concentration after chronic immobilization. In humans, chronic stress and sedentary lifestyle result in decreased plasma BDNF levels, but there no data exist regarding acute immobilization. The aim of our study was to evaluate age-related responses [comparing 7 younger subjects (age 23 +/- 3 yr) and 8 older subjects (age 60 +/- 4 yr)] of plasma BDNF before (baseline data collection, BDC) and after 14 days (BR14) of horizontal bed rest (BR). At BDC, BDNF levels were not different between the two groups (P = 0.101), although at BR14, BDNF levels were higher in older subjects (62.02 +/- 18.31) than in younger subjects (34.36 +/- 15.24 pg/ml) (P = 0.002). A general linear model for repeated measures showed a significant effect of BR on BDNF (P = 0.002). The BDC BDNF levels correlated with fat-free mass in both populations (ALL) (R = 0.628, P = 0.012), (older, R = 0.753, P = 0.031; younger, R = 0.772, P = 0.042), and with total cholesterol in ALL (R = 0.647, P = 0.009) and older study subjects (R = 0.805, P = 0.016). At BR14, BDNF correlated with total cholesterol (R = 0.579, P = 0.024) and age (R = 0.647, P = 0.009) in ALL. With an increase in age, the brain could become naturally less resistant to acute stressors, including the detrimental effects of prolonged bed rest, and thus the increase in BDNF in the older study group might reflect a protective overshooting of the brain to counteract the negative effects in such conditions. PMID- 26940657 TI - The Hippo signal transduction network for exercise physiologists. AB - The ubiquitous transcriptional coactivators Yap (gene symbol Yap1) and Taz (gene symbol Wwtr1) regulate gene expression mainly by coactivating the Tead transcription factors. Being at the center of the Hippo signaling network, Yap and Taz are regulated by the Hippo kinase cassette and additionally by a plethora of exercise-associated signals and signaling modules. These include mechanotransduction, the AKT-mTORC1 network, the SMAD transcription factors, hypoxia, glucose homeostasis, AMPK, adrenaline/epinephrine and angiotensin II through G protein-coupled receptors, and IL-6. Consequently, exercise should alter Hippo signaling in several organs to mediate at least some aspects of the organ-specific adaptations to exercise. Indeed, Tead1 overexpression in muscle fibers has been shown to promote a fast-to-slow fiber type switch, whereas Yap in muscle fibers and cardiomyocytes promotes skeletal muscle hypertrophy and cardiomyocyte adaptations, respectively. Finally, genome-wide association studies in humans have linked the Hippo pathway members LATS2, TEAD1, YAP1, VGLL2, VGLL3, and VGLL4 to body height, which is a key factor in sports. PMID- 26940660 TI - Mex3B: a coreceptor to present dsRNA to TLR3. AB - Toll-Like Receptors (TLRs) play critical roles in the early innate immune response to invading pathogens by sensing microorganisms; a number of accessory molecules have been shown to assist microbial recognition by TLRs. In a recent paper in Cell Research, Yang et al. demonstrate that Mex3B is associated with TLR3 in the endosomes and promotes dsRNA binding and proteolytic processing of TLR3, suggesting that Mex3B acts as a coreceptor of TLR3 in response to dsRNA. PMID- 26940661 TI - Dimensionality Reduction Based Optimization Algorithm for Sparse 3-D Image Reconstruction in Diffuse Optical Tomography. AB - Diffuse optical tomography (DOT) is a relatively low cost and portable imaging modality for reconstruction of optical properties in a highly scattering medium, such as human tissue. The inverse problem in DOT is highly ill-posed, making reconstruction of high-quality image a critical challenge. Because of the nature of sparsity in DOT, sparsity regularization has been utilized to achieve high quality DOT reconstruction. However, conventional approaches using sparse optimization are computationally expensive and have no selection criteria to optimize the regularization parameter. In this paper, a novel algorithm, Dimensionality Reduction based Optimization for DOT (DRO-DOT), is proposed. It reduces the dimensionality of the inverse DOT problem by reducing the number of unknowns in two steps and thereby makes the overall process fast. First, it constructs a low resolution voxel basis based on the sensing-matrix properties to find an image support. Second, it reconstructs the sparse image inside this support. To compensate for the reduced sensitivity with increasing depth, depth compensation is incorporated in DRO-DOT. An efficient method to optimally select the regularization parameter is proposed for obtaining a high-quality DOT image. DRO-DOT is also able to reconstruct high-resolution images even with a limited number of optodes in a spatially limited imaging set-up. PMID- 26940662 TI - Potential Candidates for a Structured Canadian ECPR Program for Out-of-Hospital Cardiac Arrest. AB - OBJECTIVE: Extracorporeal cardiopulmonary resuscitation (ECPR), while resource intensive, may improve outcomes in selected patients with refractory out-of hospital cardiac arrest (OHCA). We sought to identify patients who fulfilled a set of ECPR criteria in order to estimate: (1) the proportion of patients with refractory cardiac arrest who may have benefited from ECPR; and (2) the outcomes achieved with conventional resuscitation. METHODS: We performed a secondary analysis from a 52-month prospective registry of consecutive adult non-traumatic OHCA cases from a single urban Canadian health region serving one million patients. We developed a hypothetical ECPR-eligible cohort including adult patients <60 years of age with a witnessed OHCA, and either bystander CPR or EMS arrival within five minutes. The primary outcome was the proportion of ECPR eligible patients who had refractory cardiac arrest, defined as termination of resuscitation pre-hospital or in the ED. The secondary outcome was the proportion of EPCR-eligible patients who survived to hospital discharge. RESULTS: Of 1,644 EMS-treated OHCA, 168 (10.2%) fulfilled our ECPR criteria. Overall, 54/1644 (3.3%; 95% CI 2.4%-4.1%) who were ECPR-eligible had refractory cardiac arrest. Of ECPR-eligible patients, 114/168 (68%, 95% CI 61%-75%) survived to hospital admission, and 70/168 (42%; 95% CI 34-49%) survived to hospital discharge. CONCLUSION: In our region, approximately 10% of EMS-treated cases of OHCA fulfilled our ECPR criteria, and approximately one-third of these (an average of 12 patients per year) were refractory to conventional resuscitation. The integration of an ECPR program into an existing high-performing system of care may have a small but clinically important effect on patient outcomes. PMID- 26940659 TI - Nuclear PTEN functions as an essential regulator of SRF-dependent transcription to control smooth muscle differentiation. AB - Vascular disease progression is associated with marked changes in vascular smooth muscle cell (SMC) phenotype and function. SMC contractile gene expression and, thus differentiation, is under direct transcriptional control by the transcription factor, serum response factor (SRF); however, the mechanisms dynamically regulating SMC phenotype are not fully defined. Here we report that the lipid and protein phosphatase, PTEN, has a novel role in the nucleus by functioning as an indispensible regulator with SRF to maintain the differentiated SM phenotype. PTEN interacts with the N-terminal domain of SRF and PTEN-SRF interaction promotes SRF binding to essential promoter elements in SM-specific genes. Factors inducing phenotypic switching promote loss of nuclear PTEN through nucleo-cytoplasmic translocation resulting in reduced myogenically active SRF, but enhanced SRF activity on target genes involved in proliferation. Overall decreased expression of PTEN was observed in intimal SMCs of human atherosclerotic lesions underlying the potential clinical importance of these findings. PMID- 26940663 TI - Application of the Health Belief Model to U.S. Magazine Text and Image Coverage of Skin Cancer and Recreational Tanning (2000-2012). AB - The health belief model (HBM) has been widely used to inform health education, social marketing, and health communication campaigns. Although the HBM can explain and predict an individual's willingness to engage in positive health behaviors, its application to, and penetration of the underlying constructs into, mass media content has not been well characterized. We examined 574 articles and 905 images about skin cancer and tanning risks, behaviors, and screening from 20 U.S. women's and men's magazines (2000-2012) for the presence of HBM constructs: perceived susceptibility, perceived severity, perceived benefits, perceived barriers, self-efficacy, and cues to action. Susceptibility (48.1%) and severity (60.3%) information was common in text. Perceived benefits (36.4%) and barriers (41.5%) to prevention of skin cancer were fairly equally mentioned in articles. Self-efficacy (48.4%) focused on sunscreen use. There was little emphasis on HBM constructs related to early detection. Few explicit cues to action about skin cancer appeared in text (12.0%) or images (0.1%). HBM constructs were present to a significantly greater extent in text versus images (e.g., severity, 60.3% vs. 11.3%, respectively, chi(2) = 399.51, p < .0001; benefits prevention, 36.4% vs. 8.0%, respectively, chi(2) = 184.80, p < .0001), suggesting that readers are not visually messaged in ways that would effectively promote skin cancer prevention and early detection behaviors. PMID- 26940665 TI - Nanofibers of Elastin and Hydrophilic Segmented Polyurethane Solution Blends Show Enhanced Mechanical Properties through Intermolecular Protein-Polymer H Bonding. AB - Combining mechanical properties with enhanced cell interaction is highly desirable in a biomaterial. In this study, a new paradigm for enhancing the mechanical properties of segmented polyurethanes (SPUs) through solution blending with a biopolymer is presented. This noncovalent approach is based on the premise that molecular level blending of SPUs rich in hydrogen bonding (H bonding) domains with a biopolymer capable of H bonding will promote H-bond bridges between the components, leading to molecular annealing and modification of the physicochemical properties of the SPU. We demonstrate that by solution-blending solubilized elastin with a triblock copolymer-derived SPU, a 5-fold increase in tensile modulus of electrospun constructs of the SPU can be achieved, with concomitant enhancement in human endothelial cell attachment. Spectroscopic and calorimetric analysis confirm the role of H bonding in the enhancement, thus providing the impetus to further explore blending with biopolymers as a means of improving the property profiles of synthetic polymeric biomaterials. PMID- 26940666 TI - A multivariate method for meta-analysis and comparison of diagnostic tests. AB - We present here an extension of the classic bivariate random effects meta analysis for the log-transformed sensitivity and specificity that can be applied for two or more diagnostic tests. The advantage of this method is that a closed form expression is derived for the calculation of the within-studies covariances. The method allows the direct calculation of sensitivity and specificity, as well as, the diagnostic odds ratio, the area under curve and the parameters of the summary receiver operator's characteristic curve, along with the means for a formal comparison of these quantities for different tests. There is no need for individual patient data or the simultaneous evaluation of both diagnostic tests in all studies. The method is simple and fast; it can be extended for several diagnostic tests and can be fitted in nearly all statistical packages. The method was evaluated in simulations and applied in a meta-analysis for the comparison of anti-cyclic citrullinated peptide antibody and rheumatoid factor for discriminating patients with rheumatoid arthritis, with encouraging results. Simulations suggest that the method is robust and more powerful compared with the standard bivariate approach that ignores the correlation between tests. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26940664 TI - Aging hair follicles rejuvenated by transplantation to a young subcutaneous environment. AB - We demonstrate in the present study that young host mice rejuvenate aged hair follicles after transplantation. Young mice promote the hair shaft growth of transplanted old hair follicles, as well as young follicles, in contrast to old host mice, which did not support hair-shaft growth from transplanted old or young follicles. Nestin-expressing hair follicle-associated pluripotent (HAP) stem cells of transplanted old and young hair follicles remained active in young host nude mice. In contrast, the nestin-expressing HAP stem cells in young and old hair follicles transplanted to old nude mice were not as active as in young nude host mice. The present study shows that transplanted old hair follicles were rejuvenated by young host mice, suggesting that aging may be reversible. PMID- 26940667 TI - Disease-modifying anti-rheumatic drug use in pregnant women with rheumatic diseases: a systematic review of the risk of congenital malformations. AB - OBJECTIVES: Despite the high incidence of rheumatic diseases during the reproductive years, little is known about the impact of disease-modifying anti rheumatic drug (DMARD) use during pregnancy. Our objective was to systematically review and appraise evidence in women with rheumatic disease on the use of traditional and biologic DMARDs during pregnancy and the risk of congenital malformation outcomes. METHODS: We conducted a systematic search of MEDLINE, EMBASE, and INTERNATIONAL PHARMACEUTICAL ABSTRACTS databases. Inclusion criteria were: 1) study sample including women with rheumatic disease; 2) use of traditional and/or biologic DMARDs during pregnancy; and 3) congenital malformation outcome(s) reported. We extracted information on study design, data source, number of exposed pregnancies, type of DMARD, number of live births, and number of congenital malformations. RESULTS: Altogether, we included 79 studies; the majority were based on designs that did not involve a comparison group, including 26 case reports, 17 case series, 20 cross-sectional studies, and 4 surveys. Studies that had a comparator group included 1 case control, 10 cohort studies, and 1 controlled trial. Hydroxychloroquine and azathioprine represent the most studied traditional DMARD exposures and, among biologics, most of the reports were on infliximab and etanercept. CONCLUSIONS: This is the first systematic review on the use of both traditional and biologic DMARDs during pregnancy among women with rheumatic diseases and congenital malformation outcomes, with a focus on study design and quality. Findings confirm the limited number of studies, as well as the need to improve study designs. PMID- 26940668 TI - (131)I-labeled multifunctional dendrimers modified with BmK CT for targeted SPECT imaging and radiotherapy of gliomas. AB - AIM: The poly(amidoamine) dendrimers modified with Buthus martensii Karsch chlorotoxin (BmK CT) were developed as a (131)I delivery system for glioma targeted imaging and therapy. MATERIALS & METHODS: Dendrimers before and after labeling (131)I were synthetized and their physicochemical properties were tested. The targeting and therapeutic efficacy of (131)I-G5.NHAc-HPAO-(PEG-BmK CT)-(mPEG) dendrimer against glioma was evaluated in vitro and in vivo. RESULTS: All the dendrimers were stable under different conditions. BmK CT modification increased the cellular uptake of dendrimers in C6 glioma cells, but not in the normal RLE-6TN cells. (131)I-G5.NHAc-HPAO-(PEG-BmK CT)-(mPEG) dendrimer was radiochemically pure and could be applied in glioma-targeting single-photon emission CT (SPECT) imaging and radiotherapy. CONCLUSION: (131)I-G5.NHAc-HPAO (PEG-BmK CT)-(mPEG) complex is a promising multifunctional nanoplatform for glioma-specific nuclear imaging and radiotherapy. PMID- 26940669 TI - Hsa-miR-34a mediated repression of corticotrophin releasing hormone receptor 1 regulates pro-opiomelanocortin expression in patients with complex regional pain syndrome. AB - BACKGROUND: Ketamine provides relief for a subset of patients with complex regional pain syndrome (CRPS). The poor responders had a lower body mass index (BMI) relative to responders. Regulation of proopiomelanocortin (POMC) expression is crucial in normal body weight homeostasis. The main objectives of this study were to investigate the mechanisms underlying lower BMI characterizing CRPS patients responding poorly to intravenous ketamine therapy and identify potential biomarkers for predicting response. METHODS: We investigated POMC transcript levels in blood from CRPS patients grouped as responders and poor responders to ketamine therapy. Plasma levels of beta-endorphin, ACTH and alpha-MSH were measured by ELISA. We previously identified differential expression of small noncoding microRNA hsa-miR-34a in blood between responders and poor responders. We investigated whether a 11-fold downregulation of hsa-miR-34a in poor responders relative to responders is contributing to the differences in POMC levels by targeting POMC regulator CRHR1. Binding of miR-34a to CRHR1 was assessed using reporter assay; changes in mRNA and protein levels of CRHR1 were used to determine the regulation of CRHR1 by miR-34a. RNA from blood of CRPS and control subjects were used for quantitative PCR for CRHR1. RESULTS: Though ketamine treatment did not alter POMC expression, poor responders had higher levels of POMC mRNA than responders, both before and after treatment. Corticotropin-releasing hormone (CRH) is a key regulator of POMC expression and the biological effects are mediated through its receptor corticotrophin releasing hormone receptor 1 (CRHR1). We show that hsa-miR-34a is a negative regulator of CRHR1; overexpression of hsa-miR-34a in Jurkat cells resulted in reduction of CRH mediated POMC expression. Poor responders had higher expression of CRHR1 transcripts than responders, indicating a regulatory role for miR-34a. In addition, we found positive correlations between the pretreatment levels of miR 34a to BMI and response to ketamine therapy. CONCLUSIONS: Our findings indicate a mechanism by which hsa-miR-34a can regulate the CRH/CRHR1/POMC axis and may influence BMI. Studies in larger patient cohorts are required to confirm the biomarker utility of circulating hsa-miR-34a levels in predicting treatment response to ketamine therapy. PMID- 26940670 TI - Does hypoxia play a role in infantile hemangioma? AB - Infantile hemangioma (IH), the most common tumor of infancy, is characterized by rapid growth during infancy, followed by spontaneous involution over 5-10 years. Certain clinical observations have led to the suggestion that IH is triggered and maintained by hypoxia. We review the literature on the possible role of hypoxia in the etiology of IH, in particular, (1) the role of hypoxia inducible factor 1alpha (HIF-1alpha) and its downstream targets including GLUT-1 and VEGF; (2) the pathophysiological link between IH and retinopathy of prematurity; (3) hypoxic events in the early life including placental insufficiency, pre-eclampsia and low birthweight that have the potential to promote hypoxic stress; and (4) the evidence supporting the development of IH independent of HIF-1alpha. We also discuss these observations in the context of recent evidence of the crucial role of stem cells and the cytokines niche that governs their proliferation and inevitable differentiation, offering novel insights into the biology of IH. We propose that various triggers may simultaneously up-regulate HIF-1alpha, which is downstream of the renin-angiotensin system, specifically angiotensin II, which promotes production of HIF-1alpha. These developments shed light to the understanding of this enigmatic condition. PMID- 26940671 TI - Societal Preferences for Interventions with the Same Efficiency: Assessment and Application to Decision Making. AB - BACKGROUND AND OBJECTIVES: Although quality-adjusted life-years (QALYs) may not completely reflect the value of a healthcare technology, it remains unclear how to adjust the cost per QALY threshold. First, the present study compares two survey methods of measuring people's preferences for a specific healthcare technology when each choice has the same efficiency. The second objective was to consider how this information regarding preferences could be used in decision making. METHODS: We conducted single-attribute (budget allocation) and multi attribute (discrete-choice) experiments to survey public medical care preferences. Approximately 1000 respondents were sampled for each experiment. Six questions were prepared to address the attributes included in the study: (a) age; (b) objective of care; (c) disease severity; (d) prior medical care; (e) cause of disease; and (f) disease frequency. For the discrete-choice experiment (a) age, (b) objective of care, (c) disease severity, and (d) prior medical care were orthogonally combined. All assumed medical care had the same costs and incremental cost-effectiveness ratio (ICER; cost per life-year or QALY). We also calculated the preference-adjusted threshold (PAT) to reflect people's preferences in a threshold range. RESULTS: The results of both experiments revealed similar preferences: intervention for younger patients was strongly preferred, followed by interventions for treatment and severe disease states being preferred, despite the same cost per life-year or QALY. The single attribute experiment revealed that many people prefer an option in which resources are equally allocated between two interventions. Marginal PATs were calculated for age, objective of care, disease severity, and prior medical care. CONCLUSION: The single- and multi-attribute experiments revealed similar preferences. PAT can reflect people's preferences within the decision-maker's threshold range in a numerical manner. PMID- 26940672 TI - Structure of Leishmania donovani coronin coiled coil domain reveals an antiparallel 4 helix bundle with inherent asymmetry. AB - Coiled coils are ubiquitous structural motifs that serve as a platform for protein-protein interactions and play a central role in myriad physiological processes. Though the formation of a coiled coil requires only the presence of suitably spaced hydrophobic residues, sequence specificities have also been associated with specific oligomeric states. RhXXhE is one such sequence motif, associated with parallel trimers, found in coronins and other proteins. Coronin, present in all eukaryotes, is an actin-associated protein involved in regulating actin turnover. Most eukaryotic coronins possess the RhXXhE trimerization motif. However, a unique feature of parasitic kinetoplastid coronin is that the positions of R and E are swapped within their coiled coil domain, but were still expected to form trimers. To understand the role of swapped motif in oligomeric specificity, we determined the X-ray crystal structure of Leishmania donovani coronin coiled coil domain (LdCoroCC) at 2.2A, which surprisingly, reveals an anti-parallel tetramer assembly. Small angle X-ray scattering studies and chemical crosslinking confirm the tetramer in solution and is consistent with the oligomerization observed in the full length protein. Structural analyses reveal that LdCoroCC possesses an inherent asymmetry, in that one of the helices of the bundle is axially shifted with respect to the other three. The analysis also identifies steric reasons that cause this asymmetry. The bundle adapts an extended a-d-e core packing, the e residue being polar (with an exception) which results in a thermostable bundle with polar and apolar interfaces, unlike the existing a-d-e core antiparallel homotetramers with apolar core. Functional implications of the anti-parallel association in kinetoplastids are discussed. PMID- 26940673 TI - Sepsis Patient Detection and Monitor Based on Auto-BN. AB - Sepsis is a life-threatening condition caused by an inappropriate immune response to infection, and is a leading cause of elderly death globally. Early recognition of patients and timely antibiotic therapy based on guidelines improve survival rate. Unfortunately, for those patients, it is often detected late because it is too expensive and impractical to perform frequent monitoring for all the elderly. In this paper, we present a risk driven sepsis screening and monitoring framework to shorten the time of onset detection without frequent monitoring of all the elderly. Within this framework, the sepsis ultimate risk of onset probability and mortality is calculated based on a novel temporal probabilistic model named Auto BN, which consists of time dependent state, state dependent property, and state dependent inference structures. Then, different stages of a patient are encoded into different states, monitoring frequency is encoded into the state dependent property, and screening content is encoded into different state dependent inference structures. In this way, the screening and monitoring frequency and content can be automatically adjusted when encoding the sepsis ultimate risk into the guard of state transition. This allows for flexible manipulation of the tradeoff between screening accuracy and frequency. We evaluate its effectiveness through empirical study, and incorporate it into existing medical guidance system to improve medical healthcare. PMID- 26940674 TI - Re: Elastic properties of ascending aorta in women with previous pregnancy complicated by early- or late-onset pre-eclampsia. R. Orabona, E. Sciatti, E. Vizzardi, I. Bonadei, A. Valcamonico, M. Metra and T. Frusca. Ultrasound Obstet Gynecol 2016; 47: 316-323. PMID- 26940675 TI - Re: Chorioamniotic membrane separation after fetoscopy in monochorionic twin pregnancy: incidence and impact on perinatal outcome. J. U. Ortiz, E. Eixarch, A. Peguero, S. M. Lobmaier, M. Bennasar, J. M. Martinez and E. Gratacos. Ultrasound Obstet Gynecol 2016; 47: 345-349. PMID- 26940677 TI - Corrigendum. PMID- 26940676 TI - Prediction of small-for-gestational-age at 35-37 weeks of gestation: too late for management? PMID- 26940679 TI - Angiographically Silent Macular Edema. PMID- 26940678 TI - Impact of a transition nurse program on the prevention of thirty-day hospital readmissions of elderly patients discharged from short-stay units: study protocol of the PROUST stepped-wedge cluster randomised trial. AB - BACKGROUND: In France, for patients aged 75 or older, it has been estimated that the hospital readmission rate within 30 days is 14 %, a quarter being avoidable. Some evidence suggests that interventions "bridging" the transition from hospital to home and involving a designated professional (usually nurses) are the most effective in reducing the risk of readmission, but the level of evidence of current studies is low. Our study aims to assess the impact of a care transition program from hospital to home for elderly admitted to short-stay units. METHODS: This is a multicentre, stepped-wedge cluster randomised trial. The program will be implemented at three times of the transition: 1) during the patient's stay in hospital: development of a discharge plan, creation of a transitional care file, and notification of the primary care physician about inpatient care and hospital discharge by the transition nurse; 2) on the day of discharge: meeting between the transition nurse and the patient to review the follow-up recommendations; and 3) for 4 weeks after discharge: follow-up by the transition nurse. The primary outcome is the 30-day unscheduled hospital readmission or emergency visit rate after the index hospital discharge. The patients enrolled will be aged 75 or older, hospitalized in an acute care geriatric unit, and at risk of hospital readmission or an emergency visit after returning home. In all, 630 patients will be included over a 14-month period. Data analysis will be blinded to allocation, but due to the nature of the intervention, physicians and patients will not be blinded. DISCUSSION: Our study makes it possible to evaluate the specific effect of a bridging intervention involving a designated professional intervening before, during, and after hospital discharge. The strengths of the study design are methodological and practical. It permits the estimation of the intervention effect using between- and within-cluster comparisons; the study of the fluctuations in unscheduled hospital readmission or emergency visit rates; the participation of all clusters in the intervention condition; the implementation of the intervention in each cluster successively. TRIAL REGISTRATION: This study has been registered as a cRCT at clinicaltrials.gov (identifier: NCT02421133 ). Registered 9 March 2015. PMID- 26940680 TI - New insights on an old medical emergency: non-portal hypertension related upper gastrointestinal bleeding. AB - Upper gastrointestinal bleeding (UGIB) is a potentially life-threatening condition and is the most common medical emergency managed by gastroenterologists. Despite being one of the most antique medical problems, recent studies have been slowly changing the management of these patients, which should nowadays include not only initial resuscitation, but also risk stratification, pre-endoscopic therapy, endoscopy treatment, and post-procedure care. The aim of this paper is to review the extended approach to the patient with non-portal hypertension related UGIB. PMID- 26940681 TI - Queueing network model for obstetric patient flow in a hospital. AB - A queueing network is used to model the flow of patients in a hospital using the observed admission rate of patients and the histogram for the length of stay for patients in each ward. A complete log of orders for every movement of all patients from room to room covering two years was provided to us by the Medical Information Department of the University of Tsukuba Hospital in Japan. We focused on obstetric patients, who are generally hospitalized at random times throughout the year, and we analyzed the patient flow probabilistically. On admission, each obstetric patient is assigned to a bed in one of the two wards: one for normal delivery and the other for high-risk delivery. Then, the patient may be transferred between the two wards before discharge. We confirm Little's law of queueing theory for the patient flow in each ward. Next, we propose a new network model of M/G/ infinity and M/M/ m queues to represent the flow of these patients, which is used to predict the probability distribution for the number of patients staying in each ward at the nightly census time. Although our model is a very rough and simplistic approximation of the real patient flow, the predicted probability distribution shows good agreement with the observed data. The proposed method can be used for capacity planning of hospital wards to predict future patient load in each ward. PMID- 26940682 TI - DNA adducts induced by food mutagen PhIP in a mouse model expressing human sulfotransferases 1A1 and 1A2. AB - Food processing contaminant 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) has previously been shown to induce formation of DNA adducts in vivo. In a previous study the adduct levels were found to increase in a mouse model expressing human (h) sulfotransferases (SULTs) 1A1 and 1A2 after PhIP exposure, detected by (32)P-postlabelling. Isotope dilution ultra performance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS) is emerging as the method of choice for selective and reproducible detection of known DNA adducts. In the present study we investigated the level and distribution of PhIP induced DNA adducts in male FVB mice 9-11 weeks of age with hSULT mice or wild type mice (wt) using UPLC-MS/MS. Mice received a single administration of 75 mg/kg bw PhIP by oral gavage, and DNA was analysed 3h after exposure. C8-(2-amino 1-methyl-6-phenylimidazo[4,5-b]pyridine- N(2)-yl)-2'-deoxyguanosine (C8-PhIP-dG) adduct levels are significantly higher in PhIP exposed hSULT mice compared with PhIP exposed wt mice. The liver was the least affected organ in wild-type mice, whereas it was the most affected organ in hSULT mice with a 14-fold higher adduct level. PMID- 26940684 TI - Reply to the letter to the editor 'On the tumor risk from dental diagnostic X-ray exposure' by Jargin. PMID- 26940683 TI - Early indicators of survival following exposure to mustard gas: Protective role of 25(OH)D. AB - The use of sulfur mustard (SM) as a chemical weapon for warfare has once again assumed center stage, endangering civilian and the military safety. SM causes rapid local skin vesication and late-onset systemic toxicity. Most studies on SM rely on obtaining tissue and blood for characterizing burn pathogenesis and assessment of systemic pathology, respectively. However the present study focuses on developing a non-invasive method to predict mortality from high dose skin SM exposure. We demonstrate that exposure to SM leads to a dose dependent increase in wound area size on the dorsal surface of mice that is accompanied by a progressive loss in body weight loss, blood cytopenia, bone marrow destruction, and death. Thus our model utilizes local skin destruction and systemic outcome measures as variables to predict mortality in a novel skin-based model of tissue injury. Based on our recent work using vitamin D (25(OH)D) as an intervention to treat toxicity from SM-related compounds, we explored the use of 25(OH)D in mitigating the toxic effects of SM. Here we show that 25(OH)D offers protection against SM and is the first known demonstration of an intervention that prevents SM-induced mortality. Furthermore, 25(OH)D represents a safe, novel, and readily translatable potential countermeasure following mass toxic exposure. PMID- 26940685 TI - Pembrolizumab-induced necrotic myositis in a patient with metastatic melanoma. PMID- 26940686 TI - Single-agent capecitabine as maintenance therapy after induction of XELOX (or FOLFOX) in first-line treatment of metastatic colorectal cancer: randomized clinical trial of efficacy and safety. AB - BACKGROUND: The optimal strategy of maintenance therapy for patients with mCRC is controversial. This study was to evaluate the efficacy and safety of maintenance therapy with capecitabine versus observation following inductive chemotherapy in patients with metastatic colorectal cancer. PATIENTS AND METHODS: In this randomized, open-label, multicenter, phase III trial, patients who received 18-24 weeks of induction chemotherapy with XELOX or FOLFOX and achieved disease control were randomly assigned centrally (1:1) to receive maintenance therapy of capecitabine or only observation until disease progression. The primary end point was progression-free survival (PFS) from randomization; the secondary end points included overall survival (OS), PFS from induction treatment (PFS2) and safety. Analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT02027363. RESULTS: Between 30 July 2010 and 15 September 2013, 274 patients were enrolled in the study from 11 sites in China and randomly assigned to maintenance group (n = 136) or observation group (n = 138). Clinicopathological characteristics were balanced in two groups. The median follow-up time from randomization was 29.0 months [interquartile range (IQR) 21 36 months]. The primary end point of PFS was statistically significantly longer in capecitabine maintenance group than in observation group {6.43 [95% confidence interval (CI) 5.26-7.71] versus 3.43 (2.83-4.16) months, HR 0.54 (0.42-0.70), P < 0.001}. The median OS of capecitabine maintenance group was longer than that of observation group, but not statistically significant [25.63 (22.46-27.80) versus 23.30 (19.68-26.92) months; HR 0.85 (0.64-1.11), P = 0.2247]. Similar safety profiles were observed in both arms. The most common grade 3 or 4 toxicities in capecitabine maintenance group versus observation group were neutropenia, hand foot syndrome, and mucositis. CONCLUSIONS: Maintenance therapy with a single agent of capecitabine can be considered an appropriate option following the induction of XELOX or FOLFOX in mCRC patients with acceptable toxicities. CLINICAL TRIALS NUMBER: NCT02027363. PMID- 26940687 TI - Risk factors, prevalence, and course of severe fatigue after breast cancer treatment: a meta-analysis involving 12 327 breast cancer survivors. AB - BACKGROUND: This meta-analysis aimed to (i) examine demographic, disease-related, and treatment-related risk factors, (ii) estimate the prevalence, and (iii) describe the course of severe fatigue following breast cancer (BC) treatment. METHODS: PubMed, PsycINFO, Cochrane, CINAHL, and Web of Science were systematically searched from inception up to 23 November 2015. Risk factors and prevalence rates were analyzed with inverse variance random-effects analyses. Heterogeneity was studied with sensitivity analyses. RESULTS: Twenty-seven studies were included (N = 12 327). Breast cancer survivors (BCS) with a partner were at lower risk for severe fatigue than survivors without a partner [risk ratio (RR) 0.96, 95% confidence interval (CI) 0.93-0.98]. Survivors with stage II or III cancer, and survivors treated with chemotherapy were at higher risk for severe fatigue than survivors with stage 0 or I cancer and without chemotherapy (RR respectively 1.18, 95% CI 1.08-1.28; 1.12, 95% CI 1.06-1.19). Survivors treated with surgery, radiotherapy, and chemotherapy, and survivors with this combination plus hormone therapy were at higher risk than survivors with other treatment combinations (RR respectively 1.18, 95% CI 1.05-1.33; 1.38, 95% CI 1.15 1.66). Survivors treated with surgery and surgery plus radiotherapy were at lower risk than survivors with additional treatments (RR respectively 0.83, 95% CI 0.70 0.98; 0.87, 95% CI 0.78-0.96). Hormone and targeted therapy were no significant risk factors. The pooled prevalence of severe fatigue was 26.9% (95% CI 23.2 31.0), but this should be interpreted with caution because of high heterogeneity. A relatively large decrease in the prevalence of severe fatigue seemed to occur in the first half year after treatment completion. CONCLUSIONS: Approximately one in four BCS suffer from severe fatigue. Risk factors of severe fatigue were higher disease stages, chemotherapy and receiving the combination of surgery, radiotherapy, and chemotherapy, both with and without hormone therapy. Having a partner, receiving only surgery, and surgery plus radiotherapy decreased the risk. PMID- 26940688 TI - Long-term outcomes after adjuvant treatment of sequential versus combination docetaxel with doxorubicin and cyclophosphamide in node-positive breast cancer: BCIRG-005 randomized trial. AB - BACKGROUND: The optimal regimen for adjuvant breast cancer chemotherapy is undefined. We compared sequential to concurrent combination of doxorubicin and cyclophosphamide with docetaxel chemotherapy in women with node-positive non metastatic breast cancer. We report the final, 10-year analysis of disease-free survival (DFS), overall survival (OS), and long-term safety. PATIENTS AND METHODS: A total of 3298 women with HER2 nonamplified breast cancer were randomized to doxorubicin and cyclophosphamide every 3 weeks for four cycles followed by docetaxel (AC -> T) every 3 weeks for four cycles or docetaxel, doxorubicin, and cyclophosphamide (TAC) every 3 weeks for six cycles. The patients received standard radiotherapy and endocrine therapy and were followed up for 10 years with annual clinical evaluation and mammography. RESULTS: The 10 year DFS rates were 66.5% in the AC -> T arm and 66.3% in the TAC arm (P = 0.749). OS was 79.9% in the AC -> T arm and 78.9% in the TAC arm (P = 0.506). TAC was associated with higher rates of febrile neutropenia, although G-CSF primary prophylaxis greatly reduced this risk. AC -> T was associated with a higher rate of myalgia, hand-foot syndrome, fluid retention, and sensory neuropathy. CONCLUSION: This 10-year analysis of the BCIRG-005 trial confirmed that the efficacy of TAC was not superior to AC -> T in women with node-positive early breast cancer. The toxicity profiles differ between arms and were consistent with previous reports. The TAC regimen with G-CSF support provides shorter adjuvant treatment duration with less toxicity. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT00312208. PMID- 26940690 TI - What is the clinical impact of the LUX-Lung 5 trial? PMID- 26940691 TI - Raman spectroscopy of the N-N bond in rare earth dinitrogen complexes. AB - Raman spectra have been collected on single crystals of over 20 different rare earth complexes containing reduced dinitrogen ligands to determine if these data will correlate with periodic properties or relative stability. Four types of complexes were examined: [(C5Me5)2Ln]2(MU-eta(2):eta(2)-N2), 1-Ln, [(C5Me4H)2(THF)Ln]2(MU-eta(2):eta(2)-N2), 2-Ln, [(C5H4Me)2Ln]2(MU-eta(2):eta(2) N2), 3-Ln, and {[(Me3Si)2N]2(THF)Ln}2(MU-eta(2):eta(2)-N2), 4-Ln. Although each of the complexes contains a side-on bound dinitrogen ligand that is formally (N2)(2-), the N-N bond distances determined by X-ray crystallography range from 1.088(12) to 1.305(6) A. In the 4-Ln series (Ln = Gd, Tb, Dy, Ho, Er and Tm), the 1.26-1.31 A N-N distances do not follow any periodic trends, but the Raman stretching frequencies for Gd-Tm were found to decrease regularly with decreasing atomic number and increasing Lewis acidity of the metal. Similar correlations can be seen with the late metals in complexes of the other series, 1-Ln, 2-Ln and 3 Ln, but exceptions exist, particularly for the larger metals. Comparisons between the several types of complexes as a function of ligand were more complicated and variations in stretching frequency as a function of L in the {[(Me3Si)2N]2Y(L)}2(MU-eta(2):eta(2)-N2) substituted versions of 4-Y did not give trends consistent with bond distances or Gutmann donor numbers. PMID- 26940689 TI - Are strong opioids equally effective and safe in the treatment of chronic cancer pain? A multicenter randomized phase IV 'real life' trial on the variability of response to opioids. AB - BACKGROUND: Guidelines tend to consider morphine and morphine-like opioids comparable and interchangeable in the treatment of chronic cancer pain, but individual responses can vary. This study compared the analgesic efficacy, changes of therapy and safety profile over time of four strong opioids given for cancer pain. PATIENT AND METHODS: In this four-arm multicenter, randomized, comparative, of superiority, phase IV trial, oncological patients with moderate to severe pain requiring WHO step III opioids were randomly assigned to receive oral morphine or oxycodone or transdermal fentanyl or buprenorphine for 28 days. At each visit, pain intensity, modifications of therapy and adverse drug reactions (ADRs) were recorded. The primary efficacy end point was the proportion of nonresponders, meaning patients with worse or unchanged average pain intensity (API) between the first and last visit, measured on a 0-10 numerical rating scale. (NCT01809106). RESULTS: Forty-four centers participated in the trial and recruited 520 patients. Worst pain intensity and API decreased over 4 weeks with no significant differences between drugs. Nonresponders ranged from 11.5% (morphine) to 14.4% (buprenorphine). Appreciable changes were made in the treatment schedules over time. Each group required increases in the daily dose, from 32.7% (morphine) to 121.2% (transdermal fentanyl). Patients requiring adjuvant analgesics ranged from 68.9% (morphine) to 81.6% (oxycodone), switches varied from 22.1% (morphine) to 12% (oxycodone), discontinuation of treatment from 27% ( morphine) to 14.5% (fentanyl). ADRs were similar except for effects on the nervous system, which significantly prevailed with morphine. CONCLUSION: The main findings were the similarity in pain control, response rates and main adverse reactions among opioids. Changes in therapy schedules were notable over time. A considerable proportion of patients were nonresponders or poor responders. CLINICAL TRIAL REGISTRATION: NCT01809106 (https://clinicaltrials.gov/ct2/show/NCT01809106?term=cerp&rank=2). PMID- 26940692 TI - Efficacy and safety of Cinacalcet on secondary hyperparathyroidism in Chinese chronic kidney disease patients receiving hemodialysis. AB - Introduction Secondary hyperparathyroidism (SHPT) develops in patients with chronic renal failure. Cinacalcet hydrochloride has been used successfully in U.S., Europe, and Japan in the treatment of SHPT, while maintaining serum levels of calcium and phosphorus. The efficacy and safety profile of Cinacalcet treatment vs. conventional treatments has been of great interest in clinical practice. In this recent phase III study conducted in China, efficacy and safety of a calcimimetic agent, Cinacalcet (Kyowa Hakko Kirin Co., Ltd.), were assessed for SHPT treatment in stable chronic renal disease patients on hemodialysis. Methods In this double-blind, multicenter, placebo-controlled, randomized phase III study, 238 subjects were enrolled in 12 centers and randomly divided into a Cinacalcet group and a placebo group. The percentage of patients achieving a serum parathyroid hormone (PTH) level <=250 pg/mL was the primary efficacy end point. Serum calcium and phosphorus levels were measured. Adverse events and serious adverse events were recorded, and causal analysis performed. Findings In primary analysis, 25.4% of the Cinacalcet group and 3.5% of the placebo group achieved the primary end point (PTH <=250 pg/mL). Calcium and phosphorus levels and calcium-phosphorus product were lower in the Cinacalcet group compared with the placebo group. Eleven serious adverse events were reported and considered to be not related to study drugs. Mild to moderate hypocalcemia and reduced calcium levels were reported and considered to be Cinacalcet related. Discussion This phase III study demonstrated that Cinacalcet is effective and well tolerated in treating SHPT in Chinese chronic kidney disease patients on hemodialysis, and in a patient population with much higher baseline PTH levels. PMID- 26940694 TI - Heart failure with preserved ejection fraction: current status and challenges for the future. PMID- 26940693 TI - Medical Complications of Tattoos: A Comprehensive Review. AB - Tattoos are defined as the introduction of exogenous pigments into the dermis in order to produce a permanent design. This process may occur unintentional or may be deliberately administered for cosmetic or medical reasons. Tattoos have been around for over 5000 years and over time have evolved to represent a common cosmetic practice worldwide. Currently, adverse reactions are relatively rare and generally unpredictable and predominantly include immune-mediated reactions and skin infections. Along with better healthcare standards and more stringent public health mandates such as the provision of disposable needles, major infectious complications related to hepatitis and human retroviral infections have decreased significantly. When they do occur, skin infections are most frequently associated with Staphylococcus aureus or Streptococcus pyogenes. The aim of this study is to review the types and rates of medical complications of permanent tattoos. PubMed search and search dates were open ended. Acute local inflammation is the most common complication, but infections, allergic contact dermatitis, and other inflammatory or immune responses that are not well-characterized may occur. As many patients with immune reactions to tattoos do not react on skin or patch testing, it is postulated that the antigens contained in dyes or pigments are such small molecules that they need to be haptenized in order to become immunogenic. Red ink is associated more frequently with long-term reactions, including granulomatous and pseudolymphomatous phenomena or morphea-like lesions and vasculitis. Exacerbation of preexisting psoriasis, atopic dermatitis, and pyoderma gangrenosum may occur after tattooing. There is no well-defined association between cancer and tattoos. The treatment of tattoo-related complications may include local destructive measures (cryotherapy, electro surgery, dermabrasion, chemical destruction, ablative laser destruction), surgical excision, and thermolysis of the pigment using Q-switched laser therapy. PMID- 26940695 TI - Patients with heart failure with preserved ejection fraction and low levels of natriuretic peptides. AB - AIMS: Heart failure with preserved ejection fraction (HFpEF) is common and its management remains difficult. B-type natriuretic peptide (BNP) levels are used to diagnose heart failure, and as an entry criterion for inclusion into trials. We investigated a population of HFpEF patients who had been randomised into a study based on clinical parameters, and compared those with low BNP levels to those with elevated BNP levels. METHODS: We examined patients who had been enrolled in the Coordinating study evaluating Outcomes of Advising and Counselling in Heart Failure (COACH), with preserved left ventricular ejection fraction (LVEF >= 40 %), and compared those with low BNP (< 100 pg/ml; n = 30) to those with elevated BNP (>= 100 pg/ml; n = 127). Baseline characteristics, comorbidities, biomarkers, quality of life, and outcome parameters (hospitalisations and death) were compared between the groups. To validate our findings, we repeated all analyses for NT-proBNP (< 300 pg/ml and >= 300 pg/ml). RESULTS: Patients were similar with regard to most clinical characteristics (including age, sex, and LVEF), biomarkers, and comorbidities. In contrast, patients with a low BNP had higher body mass index levels (31 kg/m(2) vs. 27 kg/m(2); p < 0.01) and lower cardiac troponin I (9 pg/ml vs. 15 pg/ml; p = 0.02). In addition, these patients were less frequently prescribed diuretics and beta-blockers. No differences in quality of life, heart failure related symptoms and the primary and secondary outcomes were observed between these groups. These observations were confirmed for NT proBNP. CONCLUSION: Among the patients with clinically diagnosed HFpEF, those with low BNP are strikingly similar to those with elevated BNP levels, except for BMI, which was significantly higher in these patients. PMID- 26940696 TI - Substantial risks associated with few clusters in cluster randomized and stepped wedge designs. AB - Given the growing attention to quality improvement, comparative effectiveness research, and pragmatic trials embedded within learning health systems, the use of the cluster randomization design is bound to increase. The number of clusters available for randomization is often limited in such trials. Designs that incorporate pre-intervention measurements (e.g. cluster cross-over, repeated parallel arm, and stepped wedge designs) can substantially reduce the required numbers of clusters by decreasing between-cluster sources of variation. However, there are substantial risks associated with few clusters, including increased probability of chance imbalances and type I and type II error, limited perceived or actual generalizability, and fewer options for statistical analysis. Furthermore, current sample size methods for the stepped wedge design make a strong underlying assumption with respect to the correlation structure-in particular, that the intracluster and inter-period correlations are equal. This is in contrast with methods for the cluster cross-over design that explicitly allow for a smaller inter-period correlation. Failing to similarly allow for the inter-period correlation in the design of a stepped wedge trial may yield perilously low sample sizes. Further methodological and empirical work is required to inform sample size methods and guidance for the stepped wedge trial and to provide minimum thresholds for this design. PMID- 26940697 TI - Iron-mediated inter- and intramolecular reductive cross-coupling of unactivated alkyl chlorides with aryl bromides. AB - An efficient one-pot intermolecular reductive cross-coupling of unactivated primary and secondary alkyl chlorides bearing beta-hydrogens with aryl bromides is described. A combination of magnesium turnings and a catalytic amount of the commercially available iron(iii) complex Fe(PPh3)2Cl3 was used, and the conditions were also successfully extended to an intramolecular reaction for the first time. Both types of cross-coupling reactions proceed under mild conditions, involving the in situ generation of aryl Grignard reagents, and show good applicability to a variety of readily available unactivated alkyl chlorides, which have previously been challenging substrates in iron-catalyzed reductive cross-coupling reactions. PMID- 26940698 TI - Genetic variation in male attractiveness: It is time to see the forest for the trees. AB - Female choice based on multiple male traits, rather than on any single one, has been reported in many species and may well be a rule rather than an exception. However, the implications this has for selection acting on choosiness itself remain underappreciated. We argue that this constitutes one of the important impediments to our understanding of the evolution of mate choice. We discuss this issue primarily in the context of the Fisherian model of sexual selection. We review theory and empirical data, showing how the crucial parameter of the model genetic variation in male attractiveness-can be estimated when attractiveness is a function of multiple traits. Based on the reviewed theory, we show how relying on individual male traits, instead of overall attractiveness, can produce biased estimates of Fisherian benefits of female choice. This bias can be substantial, especially when many traits contribute to male attractiveness. We discuss a number of methodological issues that, we hope, will stimulate future studies and help resolving the long-standing mystery of mate choice. PMID- 26940700 TI - Disruptions of Sleep/Wake Patterns in the Stable Tubule Only Polypeptide (STOP) Null Mouse Model of Schizophrenia. AB - Disruption of sleep/wake cycles is common in patients with schizophrenia and correlates with cognitive and affective abnormalities. Mice deficient in stable tubule only polypeptide (STOP) show cognitive, behavioral, and neurobiological deficits that resemble those seen in patients with schizophrenia, but little is known about their sleep phenotype. We characterized baseline sleep/wake patterns and recovery sleep following sleep deprivation in STOP null mice. Polysomnography was conducted in adult male STOP null and wild-type (WT) mice under a 12:12 hours light:dark cycle before, during, and after 6 hours of sleep deprivation during the light phase. At baseline, STOP null mice spent more time awake and less time in non-rapid eye movement sleep (NREMS) over a 24-hour period, with more frequent transitions between wake and NREMS, compared to WT mice, especially during the dark phase. The distributions of wake, NREMS and REMS across the light and the dark phases differed by genotype, and so did features of the electroencephalogram (EEG). Following sleep deprivation, both genotypes showed homeostatic increases in sleep duration, with no significant genotype differences in the initial compensatory increase in sleep intensity (EEG delta power). These results indicate that STOP null mice sleep less overall, and their sleep and wake periods are more fragmented than those of WT mice. These features in STOP null mice are consistent with the sleep patterns observed in patients with schizophrenia. PMID- 26940701 TI - Cue-Responding Behaviors During Pharmacy Counseling Sessions With Patients With Asthma About Inhaled Corticosteroids: Potential Relations With Medication Beliefs and Self-Reported Adherence. AB - The aim of this study was to examine cue-responding behavior at the pharmacy while counseling about inhaled corticosteroids (ICS) in relation to medication adherence and medication beliefs. Patients with asthma aged >=18 years using ICS were recruited from 12 pharmacies. Counseling sessions were video-recorded. Patients' emotional and informational cues and pharmacists' and pharmacy technicians' cue-responding behaviors were coded using an expanded version of the Medical Interview Aural Rating Scale. The Beliefs about Medicines Questionnaire assessed patients' ICS concern and necessity beliefs. Self-reported ICS adherence was measured by four questions. During the 86 sessions, patients expressed on average 2.3, mostly informational, cues (70.8%). In 26.7% of the sessions, no cues were expressed. Pharmacists' and technicians' responses to emotional cues (59.3%) were mostly inadequate, and to informational cues mostly appropriate (63.6%). Providing inappropriate information (20.3%) was related to higher concerns post session (p < .05), and cue exploration to higher self-reported adherence at 3 months (p < .05). Apparently, providers' responses to patients' cues might have therapeutic value. In addition, patients might need to be encouraged to ask questions and express their concerns. PMID- 26940702 TI - Postsurgical Biliary Complications: The Increasingly Important Role of Interventional Radiologists. PMID- 26940703 TI - Stent Retriever Thrombectomy in Different Thrombus Locations of Anterior Cerebral Circulation. AB - BACKGROUND: Mechanical thrombectomy (MT) is a safe and efficient treatment for acute ischemic stroke in patients with proximal anterior occlusion and large penumbra. We evaluated the technical and clinical success of MT in relation to the location of the occlusion (internal carotid artery, M1 and M2 segments of the middle cerebral artery). METHODS: We prospectively reviewed 130 patients of whom 105 met the inclusion criteria. Baseline clinical, procedural and imaging variables, technical outcome (TICI, thrombolysis in cerebral infarction), 24 h imaging outcome and three-month clinical outcome (mRS, modified Rankin Scale) were recorded. Differences between the groups were studied with statistical tests according to the type of the variable. RESULTS: There were 37, 46 and 22 patients in the internal carotid artery (ICA), M1 and M2 groups, respectively. TICI 2b or 3 was achieved in 92 cases (88 %) with a non-significant trend towards a better recanalization outcome in the ICA and M1 groups. Overall, 57 of the 105 patients (55 %) experienced favorable clinical outcome (mRS <= 2) with no significant differences between the groups. Excellent outcome (mRS <= 1) was seen in 40 patients (39 %) and there proportionally more patients with excellent outcome in the ICA and M1 groups (ICA: 44 %, M1: 41 %, M2: 23 % of patients, p = 0.22). CONCLUSIONS: There were no statistically significant differences in the technical or clinical outcomes between the different sites of occlusion (ICA, M1 or M2). There was a non-significant trend towards achieving excellent clinical outcome (3 month mRS <= 1) more often and better recanalization results in the two more proximal locations. PMID- 26940699 TI - Differential Patterns of Dysconnectivity in Mirror Neuron and Mentalizing Networks in Schizophrenia. AB - Impairments of social cognition are well documented in patients with schizophrenia (SCZ), but the neural basis remains poorly understood. In light of evidence that suggests that the "mirror neuron system" (MNS) and the "mentalizing network" (MENT) are key substrates of intersubjectivity and joint action, it has been suggested that dysfunction of these neural networks may underlie social difficulties in SCZ patients. Additionally, MNS and MENT might be associated differently with positive vs negative symptoms, given prior social cognitive and symptom associations. We assessed resting state functional connectivity (RSFC) in meta-analytically defined MNS and MENT networks in this patient group. Magnetic resonance imaging (MRI) scans were obtained from 116 patients and 133 age-, gender- and movement-matched healthy controls (HC) at 5 different MRI sites. Network connectivity was analyzed for group differences and correlations with clinical symptoms. Results demonstrated decreased connectivity within the MNS and also the MENT in patients compared to controls. Notably, dysconnectivity of the MNS was related to symptom severity, while no such relationship was observed for the MENT. In sum, these findings demonstrate that differential patterns of dysconnectivity exist in SCZ patients, which may contribute differently to the interpersonal difficulties commonly observed in the disorder. PMID- 26940704 TI - Ameliorative effect of Apodytes dimidiata on cisplatin-induced nephrotoxicity in Wistar rats. AB - Context Nutraceuticals possessing antioxidant potential have been used to alleviate side effects exerted by many chemotherapeutics, including cisplatin. Since Apodytes dimidiata E. Mey. Ex Arn. (Icacinaceae) shows antioxidant potential, it may possess significant chemoprotective effects. Objectives The study investigated whether A. dimidiata could attenuate cisplatin-induced renal damage. Materials and methods Nephrotoxicity was induced by cisplatin (single i.p., 16 mg/kg b wt.) in Wistar rats. Methanolic leaf extract of A. dimidiata (AMF) was administered at a dose of 250 mg/kg b. wt. orally for 5 consecutive days before/after cisplatin administration. Blood and renal parameters were analysed. Total phenolic and flavonoid content in AMF and its NO scavenging effect was determined. Results Significant protective effect of AMF on cisplatin induced nephrotoxicity was observed in pre-treated animals. The reduction of urea, creatinine and lipid peroxidation was 58.31%, 42.19% and 60%, respectively, and the increase in haemoglobin and leucocyte count was 28.25% and 42.91%, respectively. The increase calculated for GSH, GPx, SOD and catalase was 35.64%, 18.14%, 74.42% and 35.46%, respectively. Tissue architecture of kidney was almost normal in AMF treated animals. The results were comparable to the standard drug, silymarin. AMF contained high level of polyphenols and flavonoids and was found to scavenge NO radicals (IC50 121.8 MUg/mL). Discussion and conclusion AMF can effectively counteract cisplatin mediated renal acute toxicity possibly by scavenging reactive oxygen and nitrogen species. Accordingly, the study suggests that AMF can ameliorate free radical-induced damage associated with chemotherapeutic drugs. PMID- 26940706 TI - Foreclosure and Health in Southern Europe: Results from the Platform for People Affected by Mortgages. AB - Housing instability has been shown to be related to poorer health outcomes in various studies, mainly in the USA and UK. Affected individuals are more prone to psychiatric (e.g., major depression, anxiety) and physical disorders (e.g., hypertension). This situation has deteriorated with the onset of the economic crisis. One of the most affected countries is Spain, which has high rates of foreclosure and eviction that continue to rise. In response, a civil movement, The Platform for People Affected by Mortgages (PAH), works to provide solutions to its members affected by foreclosure and advocates for the right to decent housing. The aims of this study ware to describe and compare the health status of PAH members from Catalonia to a sample of the general population and to analyze the association between health status and mortgage status, foreclosure stage, and other socioeconomic variables, among members of the PAH. We conducted a cross sectional study using a self-administered online questionnaire (2014) administered to 905 PAH members in Catalonia (>18 years; 559 women and 346 men). Results were compared with health indicators from The Health Survey of Catalonia 2013 (n = 4830). The dependent variables were poor mental health (GHQ 12 >= 3), and poor self-reported health (fair or poor). All analyses were stratified by sex. We computed age-standardized prevalence and prevalence ratios of poor mental and self-reported health in both samples. We also analyzed health outcomes among PAH members according to mortgage status (mortgage holders or guarantors), stage of foreclosure, and other socioeconomic variables by computing prevalence ratios from robust Poisson regression models. The prevalence of poor mental health among PAH members was 90.6 % in women and 84.4 % in men, and 15.5 and 10.2 % in the general population, respectively. The prevalence of poor self-reported health was 55.6 % in women and 39.4 % in men from the PAH, and 19.2 and 16.1 % in the general population, respectively. These health inequalities were independent of socioeconomic status. The prevalence of poor mental health was higher among individuals in the non-payment stage of foreclosure than among those who were up to date with their payments (e.g., PRc = 1.16 [95 % CI 1.04-1.28]). In contrast, self-reported poor health was more prominent in later stages of foreclosure, such as in post-eviction without dation in payment stage in men (PRc = 2.24 [95 %CI = 1.35-3.72]). We observed a considerably higher prevalence of poor mental and self reported health among male and female PAH members than in the general population. Public policies that tackle housing instability and its consequences are urgently needed in Spain. PMID- 26940705 TI - Social Norms and the Consumption of Fruits and Vegetables across New York City Neighborhoods. AB - Consumption of fruits and vegetables is associated with a lower risk of developing many chronic health conditions such as diabetes and cardiovascular disease. While five or more servings of fruits and vegetables per day are recommended, only 50 % of New York City (NYC) residents consume two or more servings per day. In addition, there is wide variation in dietary behaviors across different neighborhoods in NYC. Using a validated agent-based model and data from 34 NYC neighborhoods, we simulate how a mass media and nutrition education campaign strengthening positive social norms about food consumption may potentially increase the proportion of the population who consume two or more servings of fruits and vegetables per day in NYC. We found that the proposed intervention results in substantial increases in daily fruit and vegetable consumption, but the campaign may be less effective in neighborhoods with relatively low education levels or a relatively high proportion of male residents. A well-designed, validated agent-based model has the potential to provide insights on the impact of an intervention targeting social norms before it is implemented and shed light on the important neighborhood factors that may affect the efficacy of the intervention. PMID- 26940707 TI - Nurse practitioners' focus on health care in terms of cure and care: analysis of graduate theses using the International Classification of Functioning, Disability and Health. AB - AIM: To explore the focus of nurse practitioners on health care in terms of cure and care. BACKGROUND: Nurse practitioners are expected to act on the intersection of cure and care. However, in clinical practice and education, a clear model covering this area is lacking; therefore, it is unknown to what extent nurse practitioners are focused on this specific area. Graduate theses may reflect the focus of nurse practitioners. DESIGN: Sequential exploratory mixed method. METHODS: In total, 413 published abstracts of graduate theses of a Dutch Master of Advanced Nursing Practice (2000-2015) were analysed using the International Classification of Functioning, Disability and Health. Data source included aim, question and outcome of each thesis and graduates' characteristics. A qualitative deductive approach was used for the analyses. Theses were classified as focused on cure, care, or on the intersection of cure and care. RESULTS: A small majority of 53% (N = 219) of the graduate theses addressed patient's health status and could be classified in the International Classification of Functioning, Disability and Health. Of the classified theses, 48% were focused on cure, 39% on the intersection of cure and care and 13% on care. While the percentage of theses addressing health status increased significantly over the 15-year period, the percentage of theses focused on cure, care and on the intersection of cure and care remained the same. CONCLUSION: The graduate theses reflected that nurse practitioners are increasingly oriented towards patients' health status. However, their focus is predominantly on cure rather than on the intersection of cure and care. PMID- 26940708 TI - Posttraumatic stress symptoms, co-morbid psychiatric symptoms and distorted cognitions among flood victims of different ages. AB - BACKGROUND: In literature, the effect of age on posttraumatic stress disorder (PTSD) is inconclusive; the effect on flood-related PTSD is particularly unclear. Little is known on distorted cognitions among flood victims, although cognition distortions and PTSD have been linked among victims of other traumas. AIMS: To investigate: (1) whether flood-related PTSD, psychiatric co-morbidity and cognitive distortions would differ according to age and (2) distinctive patterns of association between the preceding variables for different age groups. METHODS: One hundred and fifty-four flood victims of different ages completed standardized questionnaires measuring PTSD, psychiatric co-morbidity and cognitive distortions. RESULTS: Adolescents and young adults reported significantly fewer PTSD, psychiatric co-morbidity and distorted cognition symptoms than people who were older. Preoccupation with danger and hopelessness were associated with both outcomes for adolescents, people in their thirties and middle-aged/older people. For young adults, helplessness was associated with PTSD; hopelessness and preoccupation with danger with psychiatric co-morbidity. CONCLUSIONS: Adolescents and young adults buffered against flood-related psychological distress better than older people. Distorted cognitions related to distress outcomes differently depending on age. PMID- 26940709 TI - Spatial Eco-Risk Assessment of Heavy Metals in the Surface Soils of Industrial City of Aran-o-Bidgol, Iran. AB - Heavy metals usually accumulate and migrate in soil environment due to human activities and this in return poses potential ecological and health risks. A total of 135 surface soil samples were collected from Aran-o-Bidgol City, Iran and were analyzed for their Cd, Pb, Ni and Cu concentrations to determine these elements' spatial distribution and potential ecological risks. To this end, interpolation mapping was conducted using Ordinary Kriging. The mean concentrations of Cd, Pb, Ni and Cu in the samples were 0.72, 11.41, 29.87 and 14.82 mg kg(-1), respectively, which were all higher than their background values. The spatial variation in the concentration of heavy metals could be attributable to point sources and vehicle emissions. Considering the severity of the potential ecological risks of metals, the descending order of contaminants' concentrations was Cd > Cu > Ni > Pb. The Potential Ecological Risk Index (RI) suggested that approximately 40 % and 59 % of the samples posed high and significantly high potential ecological risks, respectively. Moreover, ecological risk decreased progressively going from southwest to northeast over the under study area. Considering the background values and RI, this area presented a relatively high level of contamination. PMID- 26940710 TI - Antenatal dietary education and/or balanced nutritional supplementation benefits at-risk women and infants. PMID- 26940711 TI - High prevalence of depression in medical residents: the sad reality of medical training. PMID- 26940712 TI - Higher coffee consumption is associated with lower risk of all-cause and cause specific mortality in three large prospective cohorts. PMID- 26940713 TI - Evaluation of Nonacog Beta Pegol Long-term Safety in the Immune-deficient Rowett Nude Rat (Crl:NIH-Foxn1rnu). AB - Nonacog beta pegol is a 40-kDa polyethylene glycosylated (PEGylated) human recombinant coagulation factor IX, intended for the treatment of hemophilia B. Human coagulation factors are immunogenic in animals; therefore, to evaluate the long-term toxicity of nonacog beta pegol, an immune-deficient, athymic rat (Rowett nude; Crl:NIH-Foxn1(rnu)) was used. Rats (n = 216) were given intravenous nonacog beta pegol 0, 40, 150, 600, or 1,200 IU/kg every 5th day for 26 weeks. To avoid infections, the animals were housed in a full-barrier environment with sterilized food and bedding. Standard toxicity end points were unaffected by treatment. All treated animals were exposed to nonacog beta pegol throughout the study, and no animals developed antidrug antibodies. Immunohistochemical staining revealed PEG in choroid plexus epithelial cells in a dose-dependent manner. Transmission electron microscopy showed that PEG was distributed in cytoplasmic vesicles of these cells, with no apparent effect on cellular organelle structures. Fourteen (6.5%) animals were euthanized or died prematurely due to nontreatment-related infections in the urogenital system and skin. In conclusion, the athymic rat is a suitable model for testing chronic toxicity of human proteins that are immunogenic in animals. Nonacog beta pegol was generally well tolerated, with no adverse effect of PEG on choroid plexus epithelial cells. PMID- 26940714 TI - In Vitro Skin Models and Their Predictability in Defining Normal and Disease Biology, Pharmacology, and Toxicity. AB - In vitro skin model systems are increasingly being used both in the early evaluation of therapeutic drug candidates and in confirmatory mechanistic studies. The most commonly used of these in vitro model systems are reconstituted human epidermis (RHE) models. These RHE models consist solely of epidermal keratinocytes, which comes with some limitations but also with the advantage of focusing toxicologic and pharmacologic evaluation on keratinocytes alone. RHE models can generally be implemented more quickly, easily, and reproducibly than in vivo models and can thus be used for high throughput compound screening while potentially reducing the need for animal studies. Histologic evaluation of RHE sections can be done quite easily, and the sections are very amenable to quantification via image analysis, including automated analysis. RHE model systems can provide very valuable early indications of therapeutic candidate biology, pharmacology, and toxicity; and early results have demonstrated that RHE models have been quite predictive for in vivo pharmacologic and toxicologic effects on the skin, including clinical skin toxicity. PMID- 26940715 TI - Normal Anatomy, Histology, and Spontaneous Pathology of the Nasal Cavity of the Cynomolgus Monkey (Macaca fascicularis). AB - The evaluation of inhalation studies in monkeys is often hampered by the scarcity of published information on the relevant nasal anatomy and pathology. We examined nasal cavities of 114 control cynomolgus monkeys from 11 inhalation studies evaluated 2008 to 2013, in order to characterize and document the anatomic features and spontaneous pathology. Compared to other laboratory animals, the cynomolgus monkey has a relatively simple nose with 2 unbranched, dorsoventrally stacked turbinates, large maxillary sinuses, and a nasal septum that continues into the nasopharynx. The vomeronasal organ is absent, but nasopalatine ducts are present. Microscopically, the nasal epithelium is thicker than that in rodents, and the respiratory (RE) and transitional epithelium (TE) rest on a thick basal lamina. Generally, squamous epithelia and TE line the vestibule, RE, the main chamber and nasopharynx, olfactory epithelium, a small caudodorsal region, while TE is observed intermittently along the passages. Relatively high incidences of spontaneous pathology findings, some resembling induced lesions, were observed and included inflammation, luminal exudate, scabs, squamous and respiratory metaplasia or hyperplasia, mucous cell hyperplasia/metaplasia, and olfactory degeneration. Regions of epithelial transition were the most affected. This information is considered helpful in the histopathology evaluation and interpretation of inhalation studies in monkeys. PMID- 26940716 TI - Transparent Data on a Treatment for Discogenic Pain. PMID- 26940718 TI - Sensory and immune genes identification and analysis in a widely used parasitoid wasp Trichogramma dendrolimi (Hymenoptera: Trichogrammatidae). AB - Trichogramma dendrolimi Matsumura (Hymenoptera: Trichogrammatidae) is one of the preponderant egg parasitoids of Dendrolimus spp., which are important defoliators of coniferous forests. This parasitoid wasp has been widely released to control pine caterpillar and other lepidopteran pests, but its control efficiency needs to be improved. Sensory systems are crucial for T. dendrolimi to locate hosts, and immunity is probably involved after egg deposition in the host cavity; however, few reports have focused on the molecular mechanism of olfactory detection and survival of T. dendrolimi. It is necessary to identify these genes before further functional research is conducted. In this study, we assembled and analyzed the transcriptome of T. dendrolimi using next-generation sequencing technology. The sequencing and assembly resulted in 38 565 contigs with N50 of 3422 bp. Sequence comparison indicate that T. dendrolimi sequences are very similar to those of another parasitoid Nasonia vitripennis. Then the olfactory, vision, and immune-related gene families were identified, and phylogenetic analyses were performed with these genes from T. dendrolimi and other model insect species. Furthermore, phylogenetic tree with odorant binding proteins of T. dendrolimi and their host Dendrolimus was constructed to determine whether convergent evolution exists. These genes can be valid targets for further gene function research. The present study may help us to understand host location and survival mechanisms of T. dendrolimi and to use them more efficiently for pest control in the future. PMID- 26940717 TI - Percutaneous Epidural Adhesiolysis with Epidural Steroid Injection: A Non inferiority Test of Non-particulate Steroids Versus Particulate Steroids. AB - OBJECTIVES: To evaluate the efficacy of dexamethasone sodium phosphate (DSP), a non-particulate steroid, during percutaneous epidural adhesiolysis (PEA), as compared with triamcinolone acetate (TA). DESIGN: Retrospective observational study. SETTING: Interventional pain management clinic in a tertiary care center. SUBJECTS: Patients scheduled to receive PEA between March 2011 and January 2014. METHODS: 47 patients underwent the procedure with TA (TA group), and 26 patients underwent the procedure with DSP (DSP group). At the end of the procedure, 20 ml of 0.18% ropivacaine containing 3000 units of hyaluronidase and 80 mg of TA or 10 mg of DSP was injected. Success rates and means of percent decreases in terms of verbal numerical rating scale (VNRS) of pain and Oswestry Disability Index (ODI) at follow-up visits 3 and 6 months after PEA were compared. Non-inferiority test was used for statistical analysis. RESULTS: At 3 months, the success rate in VNRS of TA group and DSP group were 59.6% and 53.8%. The mean percent decreases of VNRS were 42.4% and 46.1% in TA group and DSP group, respectively. At this time point, non-inferiority was not demonstrated. In contrast at 6 months, the success rate in aspect of VNRS was 45.2% in TA group and 62.5% in DSP group. The mean of percent decreases in the VNRS was 34.9% in TA group and 52.8% in DSP group. The non-inferiority was met in two measurements. CONCLUSIONS: DSP presents non inferiority to TA in terms of success rate and percentage decrease of the VNRS 6 months after PEA. PMID- 26940719 TI - Legislating collaborative self-regulation in Canada: A comparative policy analysis. AB - To encourage interprofessional collaboration and to improve the regulation of healthcare providers, Ontario and Nova Scotia, Canada, have each adopted legislation calling for collaboration among the regulators of their self regulating health professions. Ontario's legislation is "top down": it came from government and stresses the obligation of regulators to collaborate. Nova Scotia's legislation is "bottom up": it was proposed and developed by regulators and emphasizes voluntary regulatory collaboration. This article considers the theoretical strengths and weaknesses of both models. It argues that Nova Scotia's approach may be stronger because of its relative consistency with core strengths of self-regulation and interprofessionalism and its grounding in soft law and a governance approach to collaborative self-regulation and to healthcare policy more broadly. PMID- 26940720 TI - Evaluation of efficacy and safety of conjugated estrogens/bazedoxifene in a Latin American population. AB - Introduction Conjugated estrogens/bazedoxifene (CE/BZA) relieves menopausal symptoms and increases bone mineral density (BMD). Objective To evaluate CE/BZA in a Latin American subpopulation from randomized, double-blind, phase-3, multinational trials. Methods Safety data were pooled from three trials from non hysterectomized postmenopausal Latin American women assigned to CE 0.45 mg/BZA 20 mg (n = 227), CE 0.625 mg/BZA 20 mg (n = 222), or placebo (n = 193). Efficacy outcomes from one study included changes in hot flush frequency at week 12 in women with at least seven moderate/severe hot flushes/day or 50/week at baseline (n = 39), and from baseline to month 12 for BMD (n = 381) and genitourinary syndrome of menopause (GSM) (women with baseline GSM; n = 189). Results At week 12, women taking CE/BZA had four to five fewer moderate/severe hot flushes/day vs. placebo. At month 12, percentage changes in BMD with CE 0.45 mg/BZA 20 mg, CE 0.625 mg/BZA 20 mg, and placebo were 1.2%, 1.6%, and -1.1% for lumbar spine and 1.1%, 1.2%, and -0.3% for total hip. GSM improved with treatment (percentage superficial cells: 4.5, 7.4, vs. 2.0; percentage parabasal cells: -9.3, -27.8 vs. 2.8). There were no new/unexpected safety trends. Conclusion CE/BZA improved vasomotor symptoms, GSM, and BMD in Latin American women, with efficacy/safety similar to the global population. PMID- 26940721 TI - The Impact of a Pay-for-Performance Scheme on Prescription Quality in Rural China. AB - In this prospective study, conducted in China where providers have traditionally been paid fee-for-service, and where drug spending is high and irrational drug prescribing common, township health centers in two counties were assigned to two groups: in one fee-for-service was replaced by a capitated global budget (CGB); in the other by a mix of CGB and pay-for-performance. In the latter, 20% of the CGB was withheld each quarter, with the amount returned depending on points deducted for failure to meet performance targets. Outcomes studied included indicators of rational drug prescribing and prescription cost. Impacts were assessed using differences-in-differences, because political interference led to non-random assignment across the two groups. The combination of capitated global budget and pay-for-performance reduced irrational prescribing substantially relative to capitated global budget but only in the county that started above the penalty targets. Endline rates were still appreciable, however, and no effects were found in either county on out-of-pocket spending. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26940722 TI - Pathologic endoplasmic reticulum stress induced by glucotoxic insults inhibits adipocyte differentiation and induces an inflammatory phenotype. AB - Adipocyte differentiation is critical in obesity. By controlling new adipocyte recruitment, adipogenesis contrasts adipocyte hypertrophy and its adverse consequences, such as insulin resistance. Contrasting data are present in literature on the effect of endoplasmic reticulum (ER) stress and subsequent unfolded protein response (UPR) on adipocyte differentiation, being reported to be either necessary or inhibitory. In this study, we sought to clarify the effect of ER stress and UPR on adipocyte differentiation. We have used two different cell lines, the widely used pre-adipocyte 3T3-L1 cells and a murine multipotent mesenchymal cell line, W20-17 cells. A strong ER stress activator, thapsigargin, and a pathologically relevant inducer of ER stress, glucosamine (GlcN), induced ER stress and UPR above those occurring in the absence of perturbation and inhibited adipocyte differentiation. Very low concentrations of 4-phenyl butyric acid (PBA, a chemical chaperone) inhibited only the overactivation of ER stress and UPR elicited by GlcN, leaving unaltered the part physiologically activated during differentiation, and reversed the inhibitory effect of GlcN on differentiation. In addition, GlcN stimulated proinflammatory cytokine release and PBA prevented these effects. An inhibitor of NF-kB also reversed the effects of GlcN on cytokine release. These results indicate that while ER stress and UPR activation is "physiologically" activated during adipocyte differentiation, the "pathologic" part of ER stress activation, secondary to a glucotoxic insult, inhibits differentiation. In addition, such a metabolic insult, causes a shift of the preadipocyte/adipocyte population towards a proinflammatory phenotype. PMID- 26940723 TI - Transcriptomic and metabolic analyses reveal salvage pathways in creatine deficient AGAT(-/-) mice. AB - Skeletal muscles require energy either at constant low (e.g., standing and posture) or immediate high rates (e.g., exercise). To fulfill these requirements, myocytes utilize the phosphocreatine (PCr)/creatine (Cr) system as a fast energy buffer and shuttle. We have generated mice lacking L-arginine:glycine amidino transferase (AGAT), the first enzyme of creatine biosynthesis. These AGAT(-/-) (d/d) mice are devoid of the PCr/Cr system and reveal severely altered oxidative phosphorylation. In addition, they exhibit complete resistance to diet-induced obesity, which is associated with a chronic activation of AMP-activated protein kinase in muscle and white adipose tissue. The underlying metabolic rearrangements have not yet been further analyzed. Here, we performed gene expression analysis in skeletal muscle and a serum amino acid profile of d/d mice revealing transcriptomic and metabolic alterations in pyruvate and glucose pathways. Differential pyruvate tolerance tests demonstrated preferential conversion of pyruvate to alanine, which was supported by increased protein levels of enzymes involved in pyruvate and alanine metabolism. Pyruvate tolerance tests suggested severely impaired hepatic gluconeogenesis despite increased availability of pyruvate and alanine. Furthermore, enzymes of serine production and one-carbon metabolism were significantly up-regulated in d/d mice, indicating increased de novo formation of one-carbon units from carbohydrate metabolism linked to NAD(P)H production. Besides the well-established function of the PCr/Cr system in energy metabolism, our transcriptomic and metabolic analyses suggest that it plays a pivotal role in systemic one-carbon metabolism, oxidation/reduction, and biosynthetic processes. Therefore, the PCr/Cr system is not only an energy buffer and shuttle, but also a crucial component involved in numerous systemic metabolic processes. PMID- 26940724 TI - A neuronal disruption in redox homeostasis elicited by ammonia alters the glycine/glutamate (GABA) cycle and contributes to MMA-induced excitability. AB - Hyperammonemia is a common finding in children with methylmalonic acidemia. However, its contribution to methylmalonate-induced excitotoxicty is poorly understood. The aim of this study was to evaluate the mechanisms by which ammonia influences in the neurotoxicity induced by methylmalonate (MMA) in mice. The effects of ammonium chloride (NH4Cl 3, 6, and 12 mmol/kg; s.c.) on electroencephalographic (EEG) and behavioral convulsions induced by MMA (0.3, 0.66, and 1 umol/2 uL, i.c.v.) were observed in mice. After, ammonia, TNF-alpha, IL1beta, IL-6, nitrite/nitrate (NOx) levels, mitochondrial potential (DeltaPsi), reactive oxygen species (ROS) generation, Methyl-Tetrazolium (MTT) reduction, succinate dehydrogenase (SDH), and Na(+), K(+)-ATPase activity levels were measured in the cerebral cortex. The binding of [(3)H]flunitrazepam, release of glutamate-GABA; glutamate decarboxylase (GAD) and glutamine synthetase (GS) activity and neuronal damage [opening of blood brain barrier (BBB) permeability and cellular death volume] were also measured. EEG recordings showed that an intermediate dose of NH4Cl (6 mmol/kg) increased the duration of convulsive episodes induced by MMA (0.66 MUmol/2 MUL i.c.v). NH4Cl (6 mmol/kg) administration also induced neuronal ammonia and NOx increase, as well as mitochondrial ROS generation throughout oxidation of 2,7-dichlorofluorescein diacetate (DCFH-DA) to DCF-RS, followed by GS and GAD inhibition. The NH4Cl plus MMA administration did not alter cytokine levels, plasma fluorescein extravasation, or neuronal damage. However, it potentiated DCF-RS levels, decreased the DeltaPsi potential, reduced MTT, inhibited SDH activity, and increased Na(+), K(+)-ATPase activity. NH4Cl also altered the GABA cycle characterized by GS and GAD activity inhibition, [(3)H]flunitrazepam binding, and GABA release after MMA injection. On the basis of our findings, the changes in ROS and reactive nitrogen species (RNS) levels elicited by ammonia alter the glycine/glutamate (GABA) cycle and contribute to MMA-induced excitability. PMID- 26940725 TI - First update of the International Xenotransplantation Association consensus statement on conditions for undertaking clinical trials of porcine islet products in type 1 diabetes--Executive summary. AB - The International Xenotransplantation Association has updated its original "Consensus Statement on Conditions for Undertaking Clinical Trials of Porcine Islet Products in Type 1 Diabetes," which was published in Xenotransplantation in 2009. This update is timely and important in light of scientific progress and changes in the regulatory framework pertinent to islet xenotransplantation. Except for the chapter on "informed consent," which has remained relevant in its 2009 version, all other chapters included in the initial consensus statement have been revised for inclusion in this update. These chapters will not provide complete revisions of the original chapters; rather, they restate the key points made in 2009, emphasize new and under-appreciated topics not fully addressed in 2009, suggest relevant revisions, and communicate opinions that complement the consensus opinion. Chapter 1 provides an update on national regulatory frameworks addressing xenotransplantation. Chapter 2 a, previously Chapter 2, suggests several important revisions regarding the generation of suitable source pigs from the perspective of the prevention of xenozoonoses. The newly added Chapter 2b discusses conditions for the use of genetically modified source pigs in clinical islet xenotransplantation. Chapter 3 reviews porcine islet product manufacturing and release testing. Chapter 4 revisits the critically important topic of preclinical efficacy and safety data required to justify a clinical trial. The main achievements in the field of transmission of all porcine microorganisms, the rationale for more proportionate recipient monitoring, and response plans are reviewed in Chapter 5. Patient selection criteria and circumstances where trials of islet xenotransplantation would be both medically and ethically justified are examined in Chapter 6 in the context of recent advances in available and emerging alternative therapies for serious and potentially life-threatening complications of diabetes. It is hoped that this first update of the International Xenotransplantation Association porcine islet transplant consensus statement will assist the islet xenotransplant scientific community, sponsors, regulators, and other stakeholders actively involved in the clinical translation of islet xenotransplantation. PMID- 26940726 TI - 5,6-Dehydrokawain from Alpinia zerumbet promotes osteoblastic MC3T3-E1 cell differentiation. AB - Bone homeostasis is maintained by balancing bone formation and bone resorption, but an imbalance between them is associated with various bone-related diseases such as osteoporosis and rheumatoid arthritis. We found that 5,6-dehydrokawain (DK) and dihydro-5,6-dehydrokawain (DDK), which were isolated as promising compounds from Alpinia zerumbet rhizomes, promote differentiation of osteoblastic MC3T3-E1 cells. DK and DDK increased the alkaline phosphatase activity and matrix mineralization of MC3T3-E1 cells. DK exerts larger effects than DDK. The gene expression of runt-related transcription factor 2 and osterix, which are essential transcription factors in the early period of osteoblast differentiation, was significantly increased by DK treatment. The mRNA level of distal-less homeobox 5 was also enhanced by DK treatment, and DK activated the p38 mitogen-activated protein kinase pathway. Therefore, DK may have clinical potential for preventing osteoporosis, and could be considered as a potential anabolic therapeutic agent. PMID- 26940727 TI - Halfway There? Health Reform Starts Now. PMID- 26940729 TI - Exploring the prevalence and management of wounds in an urban area in Ireland. AB - AIM: This study explores the prevalence and management of wounds within an urban setting in Ireland. METHOD: It employs a cross-sectional survey design, using a predesigned, validated data-collection instrument. FINDINGS: The point prevalence of wounds was 3.7% (n=445), with surgical wounds being the most prevalent (43%; n=189). Wound care was provided across a wide variety of clinical settings, with the majority of patients (60%; n=271) managed in the acute care setting. Most dressings were changed 2-3 times a week (60%; n=271). The mean dressing time was 15 minutes (SD: 12.4 minutes), varying from 2 minutes to 90 minutes. The mean nurse travel time was 3 minutes (SD: 6.5 minutes), varying from 0-60 minutes. Among participants managed using silver and iodine dressings, 53% (n=10, silver) and 78% (n=50, iodine) were prescribed for wounds described as being not infected. Alginate dressings were used incorrectly in 75% of cases, foam dressings in 63% of cases and Hydrofiber dressings in 63% of cases. CONCLUSION: Wound management within the explored geographical area is an important clinical intervention. This study identified areas of practice that need to be addressed, primarily those related to the topical management of the wound and use of offloading. The data has been used to inform practice, education, and further research in this important clinical specialty. PMID- 26940728 TI - A pilot study to compare the detection of HPV-16 biomarkers in salivary oral rinses with tumour p16(INK4a) expression in head and neck squamous cell carcinoma patients. AB - BACKGROUND: Human papilloma virus-16 (HPV-16) infection is a major risk factor for a subset of head and neck squamous cell carcinoma (HNSCC), in particular oropharyngeal squamous cell carcinoma (OPSCC). Current techniques for assessing the HPV-16 status in HNSCC include the detection of HPV-16 DNA and p16(INK4a) expression in tumor tissues. When tumors originate from hidden anatomical sites, this method can be challenging. A non-invasive and cost-effective alternative to biopsy is therefore desirable for HPV-16 detection especially within a community setting to screen at-risk individuals. METHODS: The present study compared detection of HPV-16 DNA and RNA in salivary oral rinses with tumor p16(INK4a) status, in 82 HNSCC patients using end-point and quantitative polymerase chain reaction (PCR). RESULTS: Of 42 patients with p16(INK4a)-positive tumours, 39 (sensitivity = 92.9 %, PPV = 100 % and NPV = 93 %) had oral rinse samples with detectable HPV-16 DNA, using end-point and quantitative PCR. No HPV-16 DNA was detected in oral rinse samples from 40 patients with p16(INK4a) negative tumours, yielding a test specificity of 100 %. For patients with p16(INK4a) positive tumours, HPV-16 mRNA was detected using end-point reverse transcription PCR (RT PCR) in 24/40 (sensitivity = 60 %, PPV = 100 % and NPV = 71 %), and using quantitative RT-PCR in 22/40 (sensitivity = 55 %, PPV = 100 % and NPV = 69 %). No HPV-16 mRNA was detected in oral rinse samples from the p16(INK4a)-negative patients, yielding a specificity of 100 %. CONCLUSIONS: We demonstrate that the detection of HPV-16 DNA in salivary oral rinse is indicative of HPV status in HNSCC patients and can potentially be used as a diagnostic tool in addition to the current methods. PMID- 26940730 TI - Managing wounds in older people: the risk of skin damage from high-exudate levels. PMID- 26940731 TI - An evaluation of a novel alternating mattress and cushion technology. AB - Pressure ulcer prevention and management remain a challenge across all health care settings, and the incidence and prevalence of pressure ulcers in nursing homes and residential homes continues to remain unknown. The use of suitable support surfaces has been found to be beneficial in the prevention and management of pressure ulcers. Carrying out a holistic assessment of the patient and recording the patient's at-risk score would help the clinician to determine the most suitable pressure-relieving surface for the patient. The clinician's clinical experience and judgment are also important. The Domus Auto (by APEX) mattress system and Dynamic Seat Cushion (by APEX) are effective dynamic, support surfaces in the prevention and management of pressure ulceration. They meet the recommendations by both national and international guidelines; they also partly fulfil the SSKIN bundle. From a four-week evaluation carried out in a nursing home, it has been demonstrated that, together with regular assessments and repositioning of the patients, these devices are useful tools in preventing patients' risk of tissue damage and improving the patients' quality of life. PMID- 26940732 TI - Risk of falling for people with venous leg ulcers: a literature review. AB - INTRODUCTION: Little is known about the risk of falling for people with venous leg ulcers (VLUs), and this subject has not been considered in UK populations. Many problems associated with living with VLUs are also known risk factors for sustaining a fall. This literature review considered the question: 'Do community dwelling older adults with VLUs have different outcomes in physical function measures used to assess the risk of falling compared with those without VLUs?' METHOD: A review of quantitative literature relating to measures of physical function in people with and without VLUs was undertaken, the development of which was guided by the PRISMA guidelines. FINDINGS: People with VLUs have poorer scores in measures of physical function than in people without. Reliability of studies included in the review was hampered by small sample sizes and threats to internal validity and generalisability. CONCLUSIONS: People with VLUs may be at a greater risk of falling owing to limitations in balance and mobility. Improving physical function may result in ulcer healing and better quality of life. Reducing falls risk may also lead to improved patient safety and enhanced care outcomes. Further research is needed to better understand the problem. PMID- 26940733 TI - Lindsay Leg Club Foundation. PMID- 26940734 TI - Embedding the ethos of identifying military young carers. PMID- 26940735 TI - Finding the root of wound care expense. PMID- 26940736 TI - Assessment and treatment of fungating, malodorous wounds. PMID- 26940737 TI - Discontinuous nature of the repulsive-to-attractive colloidal glass transition. AB - In purely repulsive colloidal systems a glass transition can be reached by increasing the particle volume fraction beyond a certain threshold. The resulting glassy state is governed by configurational cages which confine particles and restrict their motion. A colloidal glass may also be formed by inducing attractive interactions between the particles. When attraction is turned on in a repulsive colloidal glass a re-entrant solidification ensues. Initially, the repulsive glass melts as free volume in the system increases. As the attraction strength is increased further, this weakened configurational glass gives way to an attractive glass in which motion is hindered by the formation of physical bonds between neighboring particles. In this paper, we study the transition from repulsive-to-attractive glasses using three-dimensional imaging at the single particle level. We show how the onset of cage weakening and bond formation is signalled by subtle changes in local structure. We then demonstrate the discontinuous nature of the solid-solid transition, which is marked by a critical onset at a threshold bonding energy. Finally, we highlight how the interplay between bonding and caging leads to complex and heterogeneous dynamics at the microscale. PMID- 26940738 TI - miR-1271 inhibits migration, invasion and epithelial-mesenchymal transition by targeting ZEB1 and TWIST1 in pancreatic cancer cells. AB - Pancreatic cancer (PC) remains one of the most lethal types of cancer in adults. The purpose of this study was to determine the role of miR-1271 in regulation of epithelial mesenchymal transition (EMT) and metastasis of pancreatic cancer cells. miR-1271 was identified to be significantly down-regulated in PC tissues by miRNA array. Also, an increase of EMT-regulators ZEB1 and TWIST1 expression level is accompanied by a decrease of miR-1271. We showed that expression of miR 1271 was significantly down-regulated in PC tissues as compared with that in normal tissues. In addition, our results showed that miR-1271 expression levels were decreased while ZEB1 and TWIST1 expression levels were increased in detected PC cell lines. Moreover, ectopic expression of miR-1271 suppressed and antagomiR 1271 promoted proliferation, migration, and invasion in SW1990 and PANC-1 cells. Bioinformatics coupled with luciferase and Western blot assays also revealed that miR-1271 inhibited expression of ZEB1 and TWIST1, which are master regulators of tumor metastasis. Our study first indicates that miR-1271 functions as a suppressor in regulating of pancreatic cancer EMT by targeting ZEB1 and TWIST1, and it promise as a therapeutic target and prognostic marker for metastatic pancreatic cancer. PMID- 26940739 TI - Estrogen-dependent expression of sine oculis homeobox 1 in the mouse uterus during the estrous cycle. AB - The sine oculis homeobox 1 (SIX1) is a member of the Six gene family. SIX1 is involved in tissue development by regulating proliferation, apoptosis, and differentiation. However, function of SIX1 in the uterus remains unknown. Here, we found that Six1 expression is regulated along the estrous cycle in mouse uterus. Six1 expression was significantly increased at estrus stage and decreased at the rest of stages. SIX1 is detected in the luminal and glandular epithelium of uterine endometrium at the estrus stage. Estrogen injection increased Six1 expression in the ovariectomized mouse uterus, whereas progesterone had no effect on its expression. Estrogen receptor antagonist inhibited estrogen-induced Six1 expression. Our findings imply that SIX1 may play a role as an important regulator to orchestrate the dynamic of uterine endometrium in response to estrogen level during the estrous cycle. These results will give us a better understanding of uterine biology. PMID- 26940740 TI - Toll-like receptor-6 (TLR6) deficient mice are protected from myocardial fibrosis induced by high fructose feeding through anti-oxidant and inflammatory signaling pathway. AB - Diabetic cardiomyopathy is an essential complication of diabetes and characterized by persistent diastolic dysfunction, leading to myocardial fibrosis. Oxidative stress and inflammation lead to cell damage and are implicated in many disease states. In our study, we evaluated the effects of toll like receptor 6 (TLR6) in cardiac remodeling. We established a mouse model of myocardial fibrosis with diabetes using 30% fructose. In comparison to HF-feeding control mice, TLR6 deficient mice developed less myocardial fibrosis with lower myocardial injury marker enzymes and AngII and aldosterone (ALD). In addition, Collagen type I/III, alpha smooth muscle-actin (alpha-SMA) and FSP-1, as typical markers of myocardial fibrosis formation, were found to be reduced due to TLR6 knockout in HF-induced mice. HF-feeding mice developed myocardial fibrosis with lower SOD activity, high level of MDA, O2(-) and H2O2 and increased serum pro inflammatory cytokines, whereas TLR6 deficient mice after HF-administration were protected from myocardial fibrosis progression significantly. HF-feeding mice also displayed lower Nrf2 and higher XO levels, which was not observed in TLR6 deficient mice after HF-feeding. Furthermore, NF-kappaB pathway was inactivated for TLR6 knockout compared with HF-feeding mice. In vitro, fructose directly up regulated alpha-SMA, TGF-beta1, Collagen type I/III and FSP-1 via ROS production and NF-kappaB phosphorylation as well as pro-inflammatory cytokines releasing, which were inhibited for TLR6 deficiency. Taken together, TLR6 contributed to myocardial fibrosis progression, at least partly, through oxidative stress and inflammatory response, providing a potential therapeutic strategy for myocardial fibrosis treatment. PMID- 26940742 TI - Pyrithione Zn selectively inhibits hypoxia-inducible factor prolyl hydroxylase PHD3. AB - Increasing evidence emphasizes the role of the hypoxia-inducible factor (HIF) prolyl hydroxylase (PHD) isoforms in regulating non-HIF substrates, but isoform selective PHD inhibitors under physiological conditions have not yet been reported. Here we have identified pyrithione Zn (PZ) as a potent, isoform selective PHD3 inhibitor. The IC50 value of PZ was determined as 0.98 MUM for PHD3, while it did not show any inhibitory activity toward full length and truncated PHD2 up to 1 mM. The selective efficacy of PZ was further demonstrated at the cellular level by observing inhibition of the PHD3-dependent DNA damage response pathway without stabilization of HIF-1alpha. PMID- 26940743 TI - Erratum to: Sphingomonas panacis sp. nov., isolated from rhizosphere of rusty ginseng. PMID- 26940741 TI - High glucose suppresses embryonic stem cell differentiation into neural lineage cells. AB - Abnormal neurogenesis occurs during embryonic development in human diabetic pregnancies and in animal models of diabetic embryopathy. Our previous studies in a mouse model of diabetic embryopathy have implicated that high glucose of maternal diabetes delays neurogenesis in the developing neuroepithelium leading to neural tube defects. However, the underlying process in high glucose-impaired neurogenesis is uncharacterized. Neurogenesis from embryonic stem (ES) cells provides a valuable model for understanding the abnormal neural lineage development under high glucose conditions. ES cells are commonly generated and maintained in high glucose (approximately 25 mM glucose). Here, the mouse ES cell line, E14, was gradually adapted to and maintained in low glucose (5 mM), and became a glucose responsive E14 (GR-E14) line. High glucose induced the endoplasmic reticulum stress marker, CHOP, in GR-E14 cells. Under low glucose conditions, the GR-E14 cells retained their pluripotency and capability to differentiate into neural lineage cells. GR-E14 cell differentiation into neural stem cells (Sox1 and nestin positive cells) was inhibited by high glucose. Neuron (Tuj1 positive cells) and glia (GFAP positive cells) differentiation from GR-E14 cells was also suppressed by high glucose. In addition, high glucose delayed GR E14 differentiation into neural crest cells by decreasing neural crest markers, paired box 3 (Pax3) and paired box 7 (Pax7). Thus, high glucose impairs ES cell differentiation into neural lineage cells. The low glucose adapted and high glucose responsive GR-E14 cell line is a useful in vitro model for assessing the adverse effect of high glucose on the development of the central nervous system. PMID- 26940744 TI - Noviherbaspirillum humi sp. nov., isolated from soil. AB - Two novel Gram-stain negative, motile, non-spore forming, facultative aerobic and short rod shaped bacterial strains, designated U15(T) and U32, were isolated from soil obtained from Ukraine. The sequence similarity of the 16S rRNA gene between strains U15(T) and U32 was found to be 99.5 %. Phylogenetic analysis based on 16S rRNA gene sequences confirmed that new bacteria belong to the genus Noviherbaspirillum. The closest member of the genus was found to be Noviherbaspirillum malthae (97.0 %) followed by Noviherbaspirillum suwonensis (96.3 %). The novel isolates was observed to grow optimally at 30 degrees C and pH 7.0. The major fatty acids present in the two strains were identified as summed feature 3 (C16:1 omega7c/C16:1 omega6c), C16:0, and summed feature 8 (C18:1 omega7c/C18:1 omega6c). Ubiquinone 8 was identified as the respiratory quinone component for both the strains. The polar lipid (L) profile contained phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol, aminophospholipid, unidentified aminolipid and unidentified Ls, and putrescine and 2-hydroxyputrescine as major polyamines. The G+C content of the DNA for the strain U15(T) was found to be 61.2 mol%. The DNA-DNA relatedness between U15(T) and U32 and closely related species was less than 40 %. Based on the polyphasic taxonomic analysis, a new species, Noviherbaspirillum humi sp. nov., is proposed. The type strain is strain U15(T) = JCM 19873(T) = KEMB 7305-102(T). PMID- 26940745 TI - An Effectively Activated Hierarchical Nano-/Microspherical Li1.2Ni0.2Mn0.6O2 Cathode for Long-Life and High-Rate Lithium-Ion Batteries. AB - Rechargeable lithium-ion batteries with high energy and high power density are required in the application of electric vehicles and portable electronics. Herein, we introduce a type of spherical Li-rich cathode material, Li1.2Ni0.2Mn0.6O2, assembled from uniform nanocubes by a facile polyvinylpyrrolidone (PVP)-assisted hydrothermal method. The material with a hierarchical nano-/microstructure exhibits stable high-rate performance. Furthermore, the precipitant (i.e., urea) and the structure-directing agent (i.e., PVP) effectively activated the Li2 MnO3 components in the microscale material to achieve a high specific capacity of 298.5 mAh g(-1) in the first cycle. This Li-rich cathode material still delivered 243 mAh g(-1) at 0.1 C after 200 cycles and the capacity retentions at 0.5, 1, 2, and 5 C were 94.4, 78.7, 76.3, and 67.8% after 150 cycles, respectively. The results make this Li-rich nano-/microstructure a promising cathode material for long-life and high performance lithium-ion batteries. PMID- 26940746 TI - Age, introduction of solid feed and weaning are more important determinants of gut bacterial succession in piglets than breed and nursing mother as revealed by a reciprocal cross-fostering model. AB - A reciprocal cross-fostering model with an obese typical Chinese piglet breed and a lean Western breed was used to identify genetic and maternal effects on the acquisition and development gut bacteria from birth until after weaning. Pyrosequencing of 16S rRNA genes results revealed an age- and diet-dependent bacterial succession process in piglets. During the first 3 days after birth, the bacterial community was relatively simple and dominated by Firmicutes with 79% and 65% relative abundance for Meishan and Yorkshire piglets, respectively. During the suckling period until day 14, the piglet breed and the nursing mother lead to increasing differentiation of the fecal bacterial community, with specific bacteria taxa associated with breed, and others with the nursing sow most likely due to its milk composition. Although the effect of nursing mother and the breed were evident through the suckling period, the introduction of solid feed and subsequent weaning were the major events occurring that dominated succession of the gut microbiota in the early life of piglets. This piglet cross fostering model is a useful tool for studying the effects of diet, host genetics and the environment on the development and acquisition of the gut microbiota and over longer studies the subsequent impact on growth, health and performance of pigs. PMID- 26940747 TI - Toxicity of heavy metals and metal-containing nanoparticles on plants. AB - Plants are under the continual threat of changing climatic conditions that are associated with various types of abiotic stresses. In particular, heavy metal contamination is a major environmental concern that restricts plant growth. Plants absorb heavy metals along with essential elements from the soil and have evolved different strategies to cope with the accumulation of heavy metals. The use of proteomic techniques is an effective approach to investigate and identify the biological mechanisms and pathways affected by heavy metals and metal containing nanoparticles. The present review focuses on recent advances and summarizes the results from proteomic studies aimed at understanding the response mechanisms of plants under heavy metal and metal-containing nanoparticle stress. Transport of heavy metal ions is regulated through the cell wall and plasma membrane and then sequestered in the vacuole. In addition, the role of different metal chelators involved in the detoxification and sequestration of heavy metals is critically reviewed, and changes in protein profiles of plants exposed to metal-containing nanoparticles are discussed in detail. Finally, strategies for gaining new insights into plant tolerance mechanisms to heavy metal and metal containing nanoparticle stress are presented. This article is part of a Special Issue entitled: Plant Proteomics--a bridge between fundamental processes and crop production, edited by Dr. Hans-Peter Mock. PMID- 26940748 TI - Valx: A System for Extracting and Structuring Numeric Lab Test Comparison Statements from Text. AB - OBJECTIVES: To develop an automated method for extracting and structuring numeric lab test comparison statements from text and evaluate the method using clinical trial eligibility criteria text. METHODS: Leveraging semantic knowledge from the Unified Medical Language System (UMLS) and domain knowledge acquired from the Internet, Valx takes seven steps to extract and normalize numeric lab test expressions: 1) text preprocessing, 2) numeric, unit, and comparison operator extraction, 3) variable identification using hybrid knowledge, 4) variable - numeric association, 5) context-based association filtering, 6) measurement unit normalization, and 7) heuristic rule-based comparison statements verification. Our reference standard was the consensus-based annotation among three raters for all comparison statements for two variables, i.e., HbA1c and glucose, identified from all of Type 1 and Type 2 diabetes trials in ClinicalTrials.gov. RESULTS: The precision, recall, and F-measure for structuring HbA1c comparison statements were 99.6%, 98.1%, 98.8% for Type 1 diabetes trials, and 98.8%, 96.9%, 97.8% for Type 2 diabetes trials, respectively. The precision, recall, and F-measure for structuring glucose comparison statements were 97.3%, 94.8%, 96.1% for Type 1 diabetes trials, and 92.3%, 92.3%, 92.3% for Type 2 diabetes trials, respectively. CONCLUSIONS: Valx is effective at extracting and structuring free text lab test comparison statements in clinical trial summaries. Future studies are warranted to test its generalizability beyond eligibility criteria text. The open-source Valx enables its further evaluation and continued improvement among the collaborative scientific community. PMID- 26940749 TI - Acetylation mimic of lysine 280 exacerbates human Tau neurotoxicity in vivo. AB - Dysfunction and accumulation of the microtubule-associated human Tau (hTau) protein into intraneuronal aggregates is observed in many neurodegenerative disorders including Alzheimer's disease (AD). Reversible lysine acetylation has recently emerged as a post-translational modification that may play an important role in the modulation of hTau pathology. Acetylated hTau species have been observed within hTau aggregates in human AD brains and multi-acetylation of hTau in vitro regulates its propensity to aggregate. However, whether lysine acetylation at position 280 (K280) modulates hTau-induced toxicity in vivo is unknown. We generated new Drosophila transgenic models of hTau pathology to evaluate the contribution of K280 acetylation to hTau toxicity, by analysing the respective toxicity of pseudo-acetylated (K280Q) and pseudo-de-acetylated (K280R) mutant forms of hTau. We observed that mis-expression of pseudo-acetylated K280Q hTau in the adult fly nervous system potently exacerbated fly locomotion defects and photoreceptor neurodegeneration. In addition, modulation of K280 influenced total hTau levels and phosphorylation without changing hTau solubility. Altogether, our results indicate that pseudo-acetylation of the single K280 residue is sufficient to exacerbate hTau neurotoxicity in vivo, suggesting that acetylated K280-hTau species contribute to the pathological events leading to neurodegeneration in AD. PMID- 26940752 TI - Neuroimaging Findings and Repeat Neuroimaging Value in Pediatric Chronic Ataxia. AB - BACKGROUND: Chronic ataxia, greater than two months in duration, is encountered relatively commonly in clinical pediatric neurology practise and presents with diagnostic challenges. It is caused by multiple and diverse disorders. Our aims were to describe the neuroimaging features and the value of repeat neuroimaging in pediatric chronic ataxia to ascertain their contribution to the diagnosis and management. MATERIALS AND METHODS: A retrospective charts and neuroimaging reports review was undertaken in 177 children with chronic ataxia. Neuroimaging in 130 of 177 patients was also reviewed. RESULTS: Nineteen patients had head computed tomography only, 103 brain magnetic resonance imaging only, and 55 had both. Abnormalities in the cerebellum or other brain regions were associated with ataxia. Neuroimaging was helpful in 73 patients with 30 disorders: It was diagnostic in 9 disorders, narrowed down the diagnostic possibilities in 14 disorders, and revealed important but non-diagnostic abnormalities, e.g. cerebellar atrophy in 7 disorders. Having a normal magnetic resonance imaging scan was mostly seen in genetic diseases or in the early course of ataxia telangiectasia. Repeat neuroimaging, performed in 108 patients, was generally helpful in monitoring disease evolution and in making a diagnosis. Neuroimaging was not directly helpful in 36 patients with 10 disorders or by definition the 55 patients with unknown disease etiology. CONCLUSIONS: Normal or abnormal neuroimaging findings and repeat neuroimaging are very valuable in the diagnosis and management of disorders associated with pediatric chronic ataxia. PMID- 26940750 TI - Health-Related Internet Use by Informal Caregivers of Children and Adolescents: An Integrative Literature Review. AB - BACKGROUND: Internet-based health resources can support informal caregivers who are caring for children or adolescents with health care needs. However, few studies discriminate informal caregivers' needs from those of their care recipients or those of people caring for adults. OBJECTIVE: This study reviews the literature of health-related Internet use among informal caregivers of children and adolescents. METHODS: A total of 17 studies were selected from literature searches conducted in 6 electronic databases: PubMed, Cochrane, CINAHL, PsycINFO, ERIC, and EMBASE. All databases searches were limited to articles published in the years 2004 to 2014 in peer-reviewed publications. Search terms consisted of "health-related Internet use," "eHealth," "Internet use for health-related purpose(s)," "Web-based resource(s)," and "online resources," combined with informal caregiver (or "parents") of "child," "adolescent," "student," "youth," and "teen." The age range of the children receiving care was limited to younger than 22 years. Their informal caregivers were defined as persons (parents) who provided unpaid care or assistance to a child or an adolescent with health problems. RESULTS: Among 17 empirical studies, the majority of informal caregivers of children with medical issues were the parents. Quantitative studies (14/17, 77%) reported prevalence and predictors of health related Internet use, while mixed-methods and qualitative studies (3/17, 24%) investigated informal caregiver perceptions of helpful health-related Internet use and barriers of use. The prevalence of health-related Internet use varied (11%-90%) dependent upon how health-related Internet use was operationalized and measured. Disease-specific information was used for decision making about treatment, while social support via virtual communities and email were used for informal caregiver emotional needs. A digital divide of Internet access was identified in lower educated minorities. Most studies had methodological challenges resulting from convenience sampling, cross-sectional surveys, lack of theoretical frameworks, or no clear definitions of health-related Internet use. CONCLUSIONS: This study provides an important understanding of how family members use Internet-based information and support systems during child caregiving. Healthcare providers and policy makers should integrate family needs into their current practices and policies. Further rigorous research is required to design efficient and effective nursing interventions. PMID- 26940751 TI - Membrane resistance and shunting inhibition: where biophysics meets state dependent human neurophysiology. AB - Activation of neurons not only changes their membrane potential and firing rate but as a secondary action reduces membrane resistance. This loss of resistance, or increase of conductance, may be of central importance in non-invasive magnetic or electric stimulation of the human brain since electrical fields cause larger changes in transmembrane voltage in resting neurons with low membrane conductances than in active neurons with high conductance. This may explain why both the immediate effects and after-effects of brain stimulation are smaller or even reversed during voluntary activity compared with rest. Membrane conductance is also increased during shunting inhibition, which accompanies the classic GABAA IPSP. This short-circuits nearby EPSPs and is suggested here to contribute to the magnitude and time course of short-interval intracortical inhibition and intracortical facilitation. PMID- 26940753 TI - To what degree is palliative care integrated in guidelines and pathways for adult cancer patients in Europe: a systematic literature review. AB - BACKGROUND: Palliative Care (PC) aims to improve the quality of life for patients with cancer and their families and its benefits have been demonstrated by several studies. The objective of this systematic review is to assess the integration of PC in the content of guidelines/pathways of adult cancer patients in Europe. METHODS: We included studies of adult patients with cancer published from 01/01/1995 and 31/12/2013 in Europe in six languages. We searched nine electronic databases, hand-searched six journals and also performed citation tracking. Studies were ranked using Emanuel's Integrated Palliative Care (IPC) criteria, a tool containing 11 domains to assess PC content in guidelines. Two reviewers screened the results and narrative synthesis has been employed. RESULTS: We identified a total of 28,277 potentially relevant articles from which 637 were eligible for full-text screening. The final review included 60 guidelines and 14 pathways. Eighty percent (80%) of the guidelines/pathways emphasize a holistic approach and 66% focus on PC interventions aimed at reducing suffering. Fifty seven percent (57%) did not discuss referral criteria for PC. Of all studies, five fulfilled at least 10/11 IPC criteria. Differences existed with regard to the referral criteria for bereavement care and the continuous adjustment of goals of care. CONCLUSION: Overall, most of the identified guidelines/pathways highlighted the importance of the holistic approach of IPC. The studies that were found to fulfil at least 10/11 Emanuel's IPC criteria could serve as benchmarks of IPC. PMID- 26940754 TI - Discontinuity of care for mothers with chronic hepatitis B diagnosed during pregnancy. AB - Assiduous measures are taken to prevent perinatal transmission of hepatitis B virus (HBV) to infants; it is unclear whether the mothers receive appropriate care for their chronic HBV. We sought to assess the quality of HBV care in hepatitis B surface antigen (HBsAg)-positive mothers following pregnancy. HBsAg positive women (n = 243) who had sought prenatal care at Massachusetts General Hospital were retrospectively identified and charts reviewed. The primary outcome was adherence to the American Association for the Study of Liver Diseases (AASLD) and American College of Obstetricians and Gynecologists guidelines. Over one third (37%) of women were first diagnosed with HBV infection at a prenatal visit. One-third (32%) did not undergo timely liver function test measurements. HBV DNA was never measured in 26% and was untimely in 34% of patients. One-third (34%) of the women were at high-risk for HCC based on AASLD criteria, yet only 33% of these women underwent timely imaging. Nearly half (49%) never saw a liver specialist for their HBV care. In multivariate analysis, women were 3.7 times more likely to have a timely ALT and 8.1 times more likely to have a timely HBV DNA if they were followed by a liver specialist (P = 0.001, <0.001). We demonstrate remarkably inadequate and discontinuous HBV care for chronically infected mothers following pregnancy. As HBV infection is already being identified prenatally, quality improvement measures encompassing obstetricians, primary care providers and hepatologists are needed to ensure that HBV-infected women are linked to care postpregnancy. PMID- 26940755 TI - Evaluation of anti-microbial activities of ZnO, citric acid and a mixture of both against Propionibacterium acnes. AB - OBJECTIVE: In this study, anti-microbial activities of ZnO of three different particle sizes of citric acid (CA) and of mixtures of ZnO and CA were confirmed against Propionibacterium acnes. METHODS: ZnO with the smallest particle size showed relatively high anti-microbial activity by disc diffusion assay and broth macrodilution assay. The mixtures of ZnO and CA also showed relatively high anti microbial activity when the particle size of ZnO was the smallest. Furthermore, anti-microbial activities of ZnO, CA and the mixtures of ZnO and CA were compared through the checkerboard assay. RESULTS: The results indicated that a 1 : 1 ratio of ZnO and CA resulted in the highest anti-microbial activity. The substances were confirmed to have synergic anti-microbial effects. With the time-kill curve assay, the mixture of ZnO-containing CA reduced the surviving microbial content the most after 24 h. CONCLUSION: The results of our study suggest that ZnO may not only be an anti-microbial ingredient for the prevention of and treatment of acne. The results of our study suggest that ZnO may be an anti-microbial ingredient for the prevention of and treatment of acne when mixed with CA. PMID- 26940756 TI - Self-diffusion and structural properties of confined fluids in dynamic coexistence. AB - Self-diffusion and radial distribution functions are studied in a strongly confined Lennard-Jones fluid. Surprisingly, in the solid-liquid phase transition region, where the system exhibits dynamic coexistence, the self-diffusion constants are shown to present up to three-fold variations from solid to liquid phases at fixed temperature, while the radial distribution function corresponding to both the liquid and the solid phases are essentially indistinguishable. PMID- 26940758 TI - Weak backbone CH...O=C and side chain tBu...tBu London interactions help promote helix folding of achiral NtBu peptoids. AB - The synthesis of all-cis amide (NtBu)-glycine oligomers up to 15 residues long by a blockwise coupling approach is reported. The structure and dynamical behavior of these peptoids have been studied by X-ray crystallography, NMR and molecular modeling. Analyses reveal that the folding of these oligomers is driven by weak CH...O=C hydrogen bonding along the peptoid backbone and London interaction between tBu...tBu side-chains. PMID- 26940757 TI - Prediction of 30-day mortality after hip fracture surgery by the Nottingham Hip Fracture Score and the Surgical Outcome Risk Tool. AB - The care of the elderly with hip fractures and their outcomes might be improved with resources targeted by the accurate calculation of risks of mortality and morbidity. We used a multicentre national dataset to evaluate and recalibrate the Nottingham Hip Fracture Score and Surgical Outcome Risk Tool. We split 9,017 hip fracture cases from the Anaesthesia Sprint Audit of Practice into derivation and validation data sets and used logistic regression to derive new model co efficients for death at 30 postoperative days. The area (95% CI) under the receiver operator characteristic curve of 0.71 (0.67-0.75) indicated acceptable discrimination by the Nottingham Hip Fracture Score and acceptable calibration fit (Hosmer-Lemeshow test), p = 0.23, with a similar discrimination by the Surgical Outcome Risk Tool, 0.70 (0.66-0.74), which was miscalibrated to the observed data, p = 0.001. We recommend that studies test these scores for patients with hip fractures in other countries. We also recommend these models are compared with case-mix adjustment tools used in the UK. PMID- 26940760 TI - A simple graphical approach to predict local residue conformation using NMR chemical shifts and density functional theory. AB - The dependency of amino acid chemical shifts on phi and psi torsion angle is, independently, studied using a five-residue fragment of ubiquitin and ONIOM(DFT:HF) approach. The variation of absolute deviation of (13) C(alpha) chemical shifts relative to phi dihedral angle is specifically dependent on secondary structure of protein not on amino acid type and fragment sequence. This dependency is observed neither on any of (13) C(beta) , and (1) H(alpha) chemical shifts nor on the variation of absolute deviation of (13) C(alpha) chemical shifts relative to psi dihedral angle. The (13) C(alpha) absolute deviation chemical shifts (ADCC) plots are found as a suitable and simple tool to predict secondary structure of protein with no requirement of highly accurate calculations, priori knowledge of protein structure and structural refinement. Comparison of Full-DFT and ONIOM(DFT:HF) approaches illustrates that the trend of (13) C(alpha) ADCC plots are independent of computational method but not of basis set valence shell type. PMID- 26940759 TI - Expression of progesterone receptors is significantly impaired in the endometrium of infertile women during the implantation window: a prospective observational study. AB - OBJECTIVE: To compare the expression of progesterone receptors (A + B) and type-B progesterone receptors in the epithelial and stromal cells of fertile and infertile women. METHODS: Women were divided into two groups, the group of fertile controls (group 1) and the group of infertile women (group 2) and were set on regular ultrasound imaging in order to detect ovulation. An endometrial biopsy was obtained on the seventh or eighth post-ovulatory day. Immunohistochemistry was performed to measure percentage of positive nuclei, intensity of staining and h-score for progesterone receptors (PgR) (A + B) as well as type-B progesterone receptors in epithelial and stromal cells. Secondary outcomes included endometrial tissue dating, the rate of tissues being out-of phase and endometrial thickness. RESULTS: Endometrial issue was obtained from 15 fertile and 30 infertile women. Expression of PgR (A + B) and PgR type-B was significantly lower in the epithelial cells of infertile women. PgR (A + B) h score was 220.0 +/- 18.5 for fertile versus 147.3 +/- 18.0 for infertile women (p = 0.02). PgR type-B h-score in epithelial cells was 166.8 +/- 30.7 for fertile versus 90.8 +/- 20.6 for infertile (p = 0.04). No significant difference was observed in stromal cells. CONCLUSIONS: Expression levels of PgR (A + B) as well as type-B receptors are significantly lower in the epithelial cells of infertile women during implantation window. PMID- 26940762 TI - An Unexpected Transient Breakdown of the Blood Brain Barrier Triggers Passage of Large Intravenously Administered Nanoparticles. AB - The highly restrictive blood-brain barrier (BBB) plays a critically important role in maintaining brain homeostasis and is pivotal for proper neuronal function. The BBB is currently considered the main limiting factor restricting the passage of large (up to 200 nm) intravenously administered nanoparticles to the brain. Breakdown of the barrier occurs as a consequence of cerebrovascular diseases and traumatic brain injury. In this article, we report that remote injuries in the CNS are also associated with BBB dysfunction. In particular, we show that a focal partial transection of the optic nerve triggers a previously unknown transient opening of the mammalian BBB that occurs in the visual centres. Importantly, we demonstrate that this transient BBB breakdown results in a dramatic change in the biodistribution of intravenously administered large polymeric nanoparticles which were previously deemed as BBB-impermeable. PMID- 26940764 TI - Prospective Validation of 18F-FDG Brain PET Discriminant Analysis Methods in the Diagnosis of Amyotrophic Lateral Sclerosis. AB - An objective biomarker for early identification and accurate differential diagnosis of amyotrophic lateral sclerosis (ALS) is lacking. (18)F-FDG PET brain imaging with advanced statistical analysis may provide a tool to facilitate this. The objective of this work was to validate volume-of-interest (VOI) and voxel based (using a support vector machine [SVM] approach) (18)F-FDG PET analysis methods to differentiate ALS from controls in an independent prospective large cohort, using a priori-derived classifiers. Furthermore, the prognostic value of (18)F-FDG PET was evaluated. METHODS: A prospective cohort of patients with a suspected diagnosis of a motor neuron disorder (n = 119; mean age +/- SD, 61 +/- 12 y; 81 men and 38 women) was recruited. One hundred five patients were diagnosed with ALS (mean age +/- SD, 61.0 +/- 12 y; 74 men and 31 women) (group 2), 10 patients with primary lateral sclerosis (mean age +/- SD, 55.5 +/- 12 y; 3 men and 7 women), and 4 patients with progressive muscular atrophy (mean age +/- SD, 59.2 +/- 5 y; 4 men). The mean disease duration of all patients was 15.0 +/- 13.4 mo at diagnosis, with PET conducted 15.2 +/- 13.3 mo after the first symptoms. Data were compared with a previously gathered dataset of 20 screened healthy subjects (mean age +/- SD, 62.4 +/- 6.4 y; 12 men and 8 women) and 70 ALS patients (mean age +/- SD, 62.2 +/- 12.5 y; 44 men and 26 women) (group 1). Data were spatially normalized and analyzed on a VOI basis (statistical software (using the Hammers atlas) and voxel basis using statistical parametric mapping. Discriminant analysis and SVM were used to classify new cases based on the classifiers derived from group 1. RESULTS: Compared with controls, ALS patients showed a nearly identical pattern of hypo- and hypermetabolism in groups 1 and 2. VOI-based discriminant analysis resulted in an 88.8% accuracy in predicting the new ALS cases. For the SVM approach, this accuracy was 100%. Brain metabolism between ALS and primary lateral sclerosis patients was nearly identical and not separable on an individual basis. Extensive frontotemporal hypometabolism was predictive for a lower survival using a Kaplan-Meier survival analysis (P < 0.001). CONCLUSION: On the basis of a previously acquired training set, (18)F-FDG PET with advanced discriminant analysis methods is able to accurately distinguish ALS from controls and aids in assessing individual prognosis. Further validation on multicenter datasets and ALS-mimicking disorders is needed to fully assess the general applicability of this approach. PMID- 26940765 TI - Near-Infrared Diffuse Optical Imaging for Early Prediction of Breast Cancer Response to Neoadjuvant Chemotherapy: A Comparative Study Using 18F-FDG PET/CT. AB - Diffuse optical spectroscopic imaging (DOSI) is used as an indicator of tumor blood volume quantified by tissue hemoglobin concentrations. We aimed to determine whether early changes in tumor total hemoglobin (tHb) concentration can predict a pathologic complete response (pCR) to neoadjuvant chemotherapy in patients with operable breast cancer, and we compared the predictive value of pCR between DOSI and (18)F-FDG PET combined with CT. METHODS: Of the 100 patients enrolled, 84 patients were prospectively evaluated for primary objective analysis. Sixty-four of the patients underwent both sequential DOSI scans at baseline after their first and second chemotherapy courses and (18)F-FDG PET/CT at baseline and after their second chemotherapy course. The mean tHb (tHbmean) concentration and SUVmax of the lesion were measured using DOSI and (18)F-FDG PET/CT, respectively, and the percentage change in tHbmean (?tHbmean) and change in SUVmax (?SUVmax) were calculated. We compared the diagnostic performances of DOSI and (18)F-FDG PET/CT for predicting pCR via the analysis of the receiver operating-characteristic curves. RESULTS: pCR was achieved in 16 patients, and neoadjuvant chemotherapy caused a significant reduction of ?tHbmean in pCR compared with non-pCR after the 2 chemotherapy courses. When the tentative ?tHbmean cutoff values after the first and second courses were used, the ability to predict pCR was as follows: 81.2% sensitivity/47.0% specificity and 93.7% sensitivity/47.7% specificity, respectively. Comparison of the diagnostic performances of DOSI and (18)F-FDG PET/CT revealed areas under the curve of 0.69 and 0.75 of ?tHbmean after the first and second courses, respectively, which were lower than those of ?SUVmax (0.90). CONCLUSION: DOSI predicted pCR in patients with breast cancer with moderate accuracy. The diagnostic performance of DOSI was inferior to that of the early metabolic response as monitored by (18)F-FDG PET/CT. PMID- 26940763 TI - TCF/Lef regulates the Gsx ParaHox gene in central nervous system development in chordates. AB - BACKGROUND: The ParaHox genes play an integral role in the anterior-posterior (A P) patterning of the nervous system and gut of most animals. The ParaHox cluster is an ideal system in which to study the evolution and regulation of developmental genes and gene clusters, as it displays similar regulatory phenomena to its sister cluster, the Hox cluster, but offers a much simpler system with only three genes. RESULTS: Using Ciona intestinalis transgenics, we isolated a regulatory element upstream of Branchiostoma floridae Gsx that drives expression within the central nervous system of Ciona embryos. The minimal amphioxus enhancer region required to drive CNS expression has been identified, along with surrounding sequence that increases the efficiency of reporter expression throughout the Ciona CNS. TCF/Lef binding sites were identified and mutagenized and found to be required to drive the CNS expression. Also, individual contributions of TCF/Lef sites varied across the regulatory region, revealing a partial division of function across the Bf-Gsx-Up regulatory element. Finally, when all TCF/Lef binding sites are mutated CNS expression is not only abolished, but a latent repressive function is also unmasked. CONCLUSIONS: We have identified a B. floridae Gsx upstream regulatory element that drives CNS expression within transgenic Ciona intestinalis, and have shown that this CNS expression is dependent upon TCF/Lef binding sites. We examine the evolutionary and developmental implications of these results, and discuss the possibility of TCF/Lef not only as a regulator of chordate Gsx, but as a deeply conserved regulatory factor controlling all three ParaHox genes across the Metazoa. PMID- 26940766 TI - Initial Results of a Prospective Clinical Trial of 18F-Fluciclovine PET/CT in Newly Diagnosed Invasive Ductal and Invasive Lobular Breast Cancers. AB - (18)F-labeled 1-amino-3-fluorocyclobutane-1-carboxylic acid ((18)F-fluciclovine) is a leucine analog PET/CT radiotracer that depicts amino acid transport into cells. Amino acid transport proteins have been shown to be upregulated in breast malignancies by microarray and immunohistochemical analysis, so we hypothesized that (18)F-fluciclovine may provide a novel method of visualizing breast cancer and now report a prospective clinical trial of (18)F-fluciclovine PET/CT in newly diagnosed advanced local invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC). METHODS: Twenty-seven women with a new diagnosis of locally advanced IDC (n = 19) or ILC (n = 8) underwent PET/CT of the chest after intravenous administration of 370 MBq of (18)F-fluciclovine. The SUVmax, SUVmean, metabolic tumor volume, and total lesion avidity were obtained for the primary breast tumor, axillary lymph nodes, and extraaxillary lymph nodes. Sites of previously unsuspected malignancy were recorded and confirmed by pathology. Results of (18)F-fluciclovine PET/CT were compared with those of (18)F-FDG PET/CT, when available, using the concordance correlation coefficient. RESULTS: All locally advanced breast cancers were (18)F-fluciclovine-avid. Of 21 patients with pathologically proven axillary nodal metastases, (18)F-fluciclovine-avid axillary nodes were seen in 20. (18)F-fluciclovine detected pathologically proven extraaxillary nodal metastases in 3 patients, including 2 previously unsuspected internal mammary nodes. Fourteen patients underwent (18)F-FDG PET/CT for comparison with (18)F-fluciclovine. Concordance for metabolic tumor volume between (18)F-fluciclovine and (18)F-FDG was strong (concordance correlation coefficient, 0.89; 95% confidence interval, 0.73-0.96), but concordance for SUVmax was weak (concordance correlation coefficient, 0.04; 95% confidence interval, -0.16-0.24). In patients with both modalities available (n = 14), primary ILCs (n = 4) demonstrated (18)F-fluciclovine avidity (median SUVmax, 6.1; range, 4.5-10.9) greater than (18)F-FDG avidity (median SUVmax, 3.7; range, 1.8 6.0). Primary IDCs (n = 10) had a lower (18)F-fluciclovine avidity (median SUVmax, 6.8; range, 3.6-9.9) than (18)F-FDG avidity (median SUVmax, 10; range, 3.3-43.5). CONCLUSION: (18)F-fluciclovine PET/CT demonstrates potential for imaging of both IDC and ILC, including the detection of unsuspected extraaxillary nodal metastases. The low concordance for SUVmax between (18)F-fluciclovine and (18)F-FDG suggests that these tracers measure different biologic phenomena within the tumor. The apparently higher uptake of (18)F-fluciclovine in ILC requires confirmation in a larger cohort. PMID- 26940767 TI - Comparative Evaluation of the Biodistribution Profiles of a Series of Nonpeptidic Neurotensin Receptor-1 Antagonists Reveals a Promising Candidate for Theranostic Applications. AB - Neurotensin receptor-1 (NTR1) is a promising target for diagnostic imaging and targeted radionuclide therapy. The aim of this study was to evaluate the biodistribution profiles of a series of newly developed diarylpyrazole-based NTR1 antagonists regarding their suitability as diagnostic and potentially radiotherapeutic agents. METHODS: 3BP-227, 3BP-228, and 3BP-483 were labeled with (111)In and injected intravenously into NTR1-positive HT29 xenograft-bearing nude mice. At 3, 6, 12, and 24 h after administration, SPECT/CT images were acquired or mice were sacrificed for ex vivo determination of tissue-associated radioactivity. RESULTS: High-contrast tumor visualization in SPECT/CT images was achieved using the 3 compounds of this study. Ex vivo biodistribution studies confirmed a high and persistent tumor uptake, peaking at 6 h after injection for (111)In-3BP-227 (8.4 +/- 3.1 percentage injected dose per gram [%ID/g]) and at 3 h after injection for (111)In-3BP-228 (10.2 +/- 5.3 %ID/g) and (111)In-3BP-483 (1.9 +/- 0.8 %ID/g). Tumor-to-normal-tissue ratios obtained with (111)In-3BP-227 and (111)In-3BP-228 were consistently greater than 1. CONCLUSION: On the basis of the superior biodistribution profile compared with previously reported radiolabeled NTR1 ligands, (111)In-3BP-227 is an ideal candidate for further development as a theranostic tracer. PMID- 26940768 TI - Molecular Imaging and Quantitation of EphA2 Expression in Xenograft Models with 89Zr-DS-8895a. AB - Subtype A2 of the erythropoietin-producing hepatocellular tyrosine kinase (EphA2) cell surface receptor is expressed in a range of epithelial cancers. This study evaluated the molecular imaging of EphA2 expression in vivo in mouse tumor models using SPECT/MR and PET/MR and a humanized anti-EphA2 antibody, DS-8895a. METHODS: DS-8895a was labeled with (111)In, (125)I, and (89)Zr and assessed for radiochemical purity, immunoreactivity (Lindmo analysis), antigen-binding affinity (Scatchard analysis), and serum stability in vitro. In vivo biodistribution, imaging, and pharmacokinetic studies were performed with SPECT/MR and PET/MR. A dose-escalation study was also performed to determine EphA2 receptor saturability through tissue and imaging quantitative analysis. RESULTS: All conjugates demonstrated good serum stability and specific binding to EphA2-expressing cells in vitro. In vivo biodistribution studies showed high uptake of (111)In-CHX-A"-DTPA-DS-8895a and (89)Zr-Df-Bz-NCS-DS-8895a in EphA2 expressing xenograft models, with no specific uptake in normal tissues. In comparison, retention of (125)I-DS-8895a in tumors was lower because of internalization of the radioconjugate and dehalogenation. These results were confirmed by SPECT/MR and PET/MR. EphA2 receptor saturation was observed at the 30 mg/kg dose. CONCLUSION: Molecular imaging of tumor uptake of DS-8895a allows noninvasive measurement of EphA2 expression in tumors in vivo and determination of receptor saturation. (89)Zr-Df-Bz-NCS-DS-8895a is suited for human bioimaging trials on the basis of superior imaging characteristics and will inform DS-8895a dose assessment and patient response evaluation in clinical trials. PMID- 26940769 TI - The pathway of ligand entry from the membrane bilayer to a lipid G protein coupled receptor. AB - The binding process through the membrane bilayer of lipid-like ligands to a protein target is an important but poorly explored recognition process at the atomic level. In this work we succeeded in resolving the binding of the lipid inhibitor ML056 to the sphingosine-1-phosphate receptor 1 (S1P1R) using unbiased molecular dynamics simulations with an aggregate sampling of over 800 MUs. The binding pathway is a multi-stage process consisting of the ligand diffusing in the bilayer leaflet to contact a "membrane vestibule" at the top of TM 7, subsequently moving from this lipid-facing vestibule to the orthosteric binding cavity through a channel formed by TMs 1 and 7 and the N-terminal of the receptor. Unfolding of the N-terminal alpha-helix increases the volume of the channel upon ligand entry, helping to reach the crystallographic pose that also corresponds to the predicted favorable pose. The relaxation timescales of the binding process show that the binding of the ligand to the "membrane vestibule" is the rate-limiting step in the multi microseconds timescale. We comment on the significance and parallels of the binding process in the context of other binding studies. PMID- 26940771 TI - The relative abundance of hemocyte types in a polyphagous moth larva depends on diet. AB - Hemocytes are crucial cells of the insect immune system because of their involvement in multiple immune responses including coagulation, phagocytosis and encapsulation. There are various types of hemocytes, each having a particular role in immunity, such that variation in their relative abundance affects the outcome of the immune response. This study aims to characterize these various types of hemocytes in larvae of the grapevine pest insect Eupoecilia ambiguella, and to assess variation in their concentration as a function of larval diet and immune challenge. Four types of hemocytes were found in the hemolymph of 5th instar larvae: granulocytes, oenocytoids, plasmatocytes and spherulocytes. We found that the total concentration of hemocytes and the concentration of each hemocyte type varied among diets and in response to the immune challenge. Irrespective of the diet, the concentration of granulocytes increased following a bacterial immune challenge, while the concentration of plasmatocytes and spherulocytes differentially varied between larval diets. The concentration of oenocytoids did not vary among diets before the immune challenge but varied between larval diets in response to the challenge. These results suggest that the resistance of insect larvae to different natural enemies critically depends on the effect of larval diet on the larvae's investment into the different types of hemocytes. PMID- 26940770 TI - BK channel inactivation gates daytime excitability in the circadian clock. AB - Inactivation is an intrinsic property of several voltage-dependent ion channels, closing the conduction pathway during membrane depolarization and dynamically regulating neuronal activity. BK K(+) channels undergo N-type inactivation via their beta2 subunit, but the physiological significance is not clear. Here, we report that inactivating BK currents predominate during the day in the suprachiasmatic nucleus, the brain's intrinsic clock circuit, reducing steady state current levels. At night inactivation is diminished, resulting in larger BK currents. Loss of beta2 eliminates inactivation, abolishing the diurnal variation in both BK current magnitude and SCN firing, and disrupting behavioural rhythmicity. Selective restoration of inactivation via the beta2 N-terminal 'ball and-chain' domain rescues BK current levels and firing rate, unexpectedly contributing to the subthreshold membrane properties that shift SCN neurons into the daytime 'upstate'. Our study reveals the clock employs inactivation gating as a biophysical switch to set the diurnal variation in suprachiasmatic nucleus excitability that underlies circadian rhythm. PMID- 26940772 TI - The History of MDMA as an Underground Drug in the United States, 1960-1979. AB - MDMA (3,4-methylenedioxy-methylamphetamine, a.k.a. "ecstasy") was first synthesized in 1912 and resynthesized more than once for pharmaceutical reasons before it became a popular recreational drug. Partially based on previously overlooked U.S. government documentation, this article reconstructs the early history of MDMA as a recreational drug in the U.S. from 1960 to 1979. According to the literature, MDMA was introduced as a street drug at the end of the 1960s. The first forensic detection of MDMA "on the street" was reported in 1970 in Chicago. It appears that MDMA was first synthesized by underground chemists in search of "legal alternatives" for the closely related and highly sought-after drug MDA, which was scheduled under the Controlled Substances Act (CSA) in 1970. Until 1974, nearly all MDMA street samples seized came from the U.S. Midwest, the first "hot region" of MDMA use. In Canada, MDMA was first detected in 1974 and scheduled in 1976. From 1975 to 1979, MDMA was found in street samples in more than 10 U.S. states, the West Coast becoming the major "hot region" of MDMA use. Recreational use of MDMA spread across the U.S. in the early 1980s, and in 1985 it was scheduled under the CSA. PMID- 26940773 TI - Use of dietary rosemary diterpenes to inhibit rancid volatiles in lamb meat packed under protective atmosphere. AB - The objective of the present study was to determine the inhibitory effect of dietary rosemary diterpenes on the formation of the volatile organic compounds (VOCs) responsible for rancid flavour in raw lamb meat. The lamb diet was supplemented during the fattening stage with two levels (200 and 400 mg/kg feed) of a dietary rosemary extract (DRE) containing carnosic acid and carnosol (1 : 1, w/w). The formation of VOCs (determined by headspace solid-phase microextraction at 40 degrees C and MS) and odour deterioration (assessed by quantitative descriptive analysis) were monitored in meat fillets (longissimus dorsi-lumborum muscle) packed in a 70/30 O2/CO2 protective atmosphere and kept at 2 degrees C for up to 14 days. The raw meat odour deteriorated under pro-oxidizing conditions due to the development of an incipient rancidity caused by the formation of volatiles from lipid oxidation. A total of 46 volatile compounds were determined in lamb headspace: 18 aldehydes, seven alcohols, seven organic acids, six ketones, four furan compounds, two benzene compounds, one ester and one terpenoid. The use of DRE contributed to inhibit VOC formation and rancidity. Heptanal, octanal, nonanal and 2-pentyl-furan were the only VOCs affected (P0.75; P<0.001), although similar values were obtained for the coefficients of a large number of carbonyl, alcohols and furan compounds, among other volatiles, which can be considered molecular markers of rancidity in raw lamb meat. Principal component analysis confirmed that the differences in the VOC profile make it possible to identify whether or not samples have been reinforced with dietary rosemary diterpenes. Thus, VOC profiling can be regarded as a useful tool for assessing the dietary treatments used in sheep to improve the oxidative stability of lamb meat. PMID- 26940774 TI - Bayesian Peer Calibration with Application to Alcohol Use. AB - Peers are often able to provide important additional information to supplement self-reported behavioral measures. The study motivating this work collected data on alcohol in a social network formed by college students living in a freshman dormitory. By using two imperfect sources of information (self-reported and peer reported alcohol consumption), rather than solely self-reports or peer-reports, we are able to gain insight into alcohol consumption on both the population and the individual level, as well as information on the discrepancy of individual peer-reports. We develop a novel Bayesian comparative calibration model for continuous, count, and binary outcomes that uses covariate information to characterize the joint distribution of both self and peer-reports on the network for estimating peer-reporting discrepancies in network surveys, and apply this to the data for fully Bayesian inference. We use this model to understand the effects of covariates on both drinking behavior and peer-reporting discrepancies. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26940776 TI - Erratum: The Biosynthesis of Infrared-Emitting Quantum Dots in Allium Fistulosum. PMID- 26940775 TI - A genetic view of laryngeal cancer heterogeneity. AB - During the recent decades significant improvements in the understanding of laryngeal molecular biology allowed a better characterization of the tumor. However, despite increased molecular knowledge and clinical efforts, survival of patients with laryngeal cancer remains the same as 30 years ago. Although this result may not make major conclusions as preservation approaches were not broadly used until the time of database collection, it seems to be clear that there is still window for improvement. Although the cornerstone for laryngeal cancer eradication is to implement smoking cessation programs, survival progresses will be hopefully seen in the future. Introducing molecular biomarkers as predictive factors to determine which patients will benefit of preservation treatments may become one of the next steps to improve survival. Furthermore, the development of new therapeutic modalities joint to biomarkers to selectively apply such new therapy in these patients may help to define new modalities with improved survival. New inhibitors against Notch pathway, EGFR, VRK1 or DNA damage repair may become gold standard if we are able to identify patients that may benefit from them, either on survival or functional larynx preservation. It is the moment for an inflexion point on the way laryngeal cancer is clinically managed. PMID- 26940777 TI - Declining Bowel Cancer Incidence and Mortality in Germany. AB - BACKGROUND: In October 2002, screening colonoscopy from age 55 onward was introduced as part of the German national statutory cancer screening program. Screening colonoscopy is intended to lower both the mortality and the incidence of bowel cancer by enabling the detection and removal of precursor lesions. METHODS: The authors studied trends in bowel cancer incidence and mortality in Germany from 2003 to 2012 on the basis of data from the epidemiological cancer registries and from cause-of-death statistics. RESULTS: Over the period of investigation, the age-standardized incidence of bowel cancer (with the European population as a standard) fell from 66.1 to 57.0 cases per 100 000 persons per year (-13.8%) in men and from 42.6 to 36.5 per 100 000 persons per year (-14.3%) in women. In parallel with these changes, the age-standardized mortality from bowel cancer fell by 20.8% in men and by 26.5% in women. In the age groups 55-64, 65-74, and 75-84 years, the cumulative risk of receiving a diagnosis of bowel cancer fell by 17-26%; in persons under age 55, this risk fell by only 3% in men, but increased by 14% in women. Long-term data from the cancer registry in the German federal state of Saarland revealed that the incidence of bowel cancer, but not its mortality, had risen over the decades preceding the study; it was only during the period of investigation that the trend reversed itself. CONCLUSION: Within 10 years of the introduction of screening colonoscopy in Germany, the incidence of bowel cancer in persons over age 55 fell by 17-26%, after having risen steadily over the preceding decades. PMID- 26940778 TI - The Prevalence of Sexual Violence. AB - BACKGROUND: Sexual violence can cause severe mental and bodily harm. This is the first study of a population-based sample in Germany to assess both the frequency of the subjects' having experienced sexual violence and the frequency of their having manifested sexually aggressive behavior themselves. METHODS: 2513 persons (of whom 2422 were over age 18 and 91 were aged 14 to 18) were asked about their experiences with sexual violence in the past 12 months, either as the person committing sexual violence or as the victim of sexual violence at the hands of other adults or similarly aged adolescents. RESULTS: 0.6% (n = 6) of the men and 1.2% (n = 16) of the women surveyed, and ca. 5% (n = 4) of the adolescents surveyed, reported having been the victim of some kind of sexual violence. 1.5% (n = 15) of the men and 1.0% (n = 13) of the women reported that they themselves had manifested sexually aggressive behavior. Women were overrepresented and adolescents underrepresented in the sample, in comparison with the overall population. CONCLUSION: These findings suggest that the prevalences of experiences of sexual violence and of sexually aggressive behavior are markedly underestimated in official crime statistics, particularly with respect to events in which women commit sexual violence and men are victims of it. Prevalences were assessed in this study from selfreported information; the findings may thus have been distorted by a tendency on the part of the informants to give answers they thought would be socially acceptable, particularly with respect to their own sexually aggressive behavior. Moreover, the small overall number of events complicates the interpretation of the findings. PMID- 26940779 TI - The Authors' Reasoning Is Impossible to Follow. PMID- 26940780 TI - Added Value Is Still Unclear. PMID- 26940781 TI - In Reply. PMID- 26940782 TI - Disastrous Progression. PMID- 26940783 TI - Helpless Wishful Thinking. PMID- 26940784 TI - In Reply. PMID- 26940785 TI - Evaluating the Quality of Guidelines. PMID- 26940786 TI - In Reply. PMID- 26940787 TI - DHA Suppresses Primary Macrophage Inflammatory Responses via Notch 1/ Jagged 1 Signaling. AB - Persistent macrophages were observed in the lungs of murine offspring exposed to maternal LPS and neonatal hyperoxia. Maternal docosahexaenoic acid (DHA) supplementation prevented the accumulation of macrophages and improved lung development. We hypothesized that these macrophages are responsible for pathologies observed in this model and the effects of DHA supplementation. Primary macrophages were isolated from adult mice fed standard chow, control diets, or DHA supplemented diets. Macrophages were exposed to hyperoxia (O2) for 24 h and LPS for 6 h or 24 h. Our data demonstrate significant attenuation of Notch 1 and Jagged 1 protein levels in response to DHA supplementation in vivo but similar results were not evident in macrophages isolated from mice fed standard chow and supplemented with DHA in vitro. Co-culture of activated macrophages with MLE12 epithelial cells resulted in the release of high mobility group box 1 and leukotriene B4 from the epithelial cells and this release was attenuated by DHA supplementation. Collectively, our data indicate that long term supplementation with DHA as observed in vivo, resulted in deceased Notch 1/Jagged 1 protein expression however, DHA supplementation in vitro was sufficient to suppress release LTB4 and to protect epithelial cells in co-culture. PMID- 26940789 TI - Blastocyst collapse is not an independent predictor of reduced live birth: a time lapse study. AB - OBJECTIVE: To ascertain the rate of blastocyst collapse observed by time-lapse monitoring in a retrospective cohort of unselected infertile patients undergoing single blastocyst transfer and to determine its association with live birth. DESIGN: Blastocyst collapse and morphokinetic variables were scored according to previously published criteria. The association between blastocyst collapse and live birth was evaluated by a multivariate logistic regression analysis including morphokinetic variables and other confounders. SETTING: Private infertility clinic. PATIENT(S): Patients who underwent 277 consecutive single blastocyst transfers (mean age, 38.4 +/- 3.9 years; range, 28-47 years) after minimal ovarian stimulation. INTERVENTION(S): Minimal ovarian stimulation, prolonged embryo culture in time-lapse monitoring incubator, elective vitrification with subsequent vitrified-warmed single blastocyst transfer. MAIN OUTCOME MEASURE(S): Live birth rate per single blastocyst transfer in different blastocyst collapse groups (no, single, multiple collapses). RESULT(S): No, single, or multiple blastocyst collapses occurred in 54% (150/277), 22% (61/277), and 24% (66/277) of the cohort, respectively. In the multiple collapse group on average 2.9 contractions were seen (range, 2-9 contractions). Live birth rate decreased progressively between blastocyst collapse groups (36%, 31%, 14%); significantly lower if multiple collapses occurred. In a multivariate analysis, however, blastocyst collapse was not found to be a significant predictor and was confounded by stronger predictors such as morphokinetic variables t2, texpB2, and female age. CONCLUSION(S): Blastocyst collapse pattern should not be evaluated alone without taking into account morphokinetic variables that are stronger predictors of reproductive outcome. PMID- 26940788 TI - The Italian Observational Study on Severe Osteoporosis (ISSO): 24-month results on incidence of fractures and adherence to treatment. AB - OBJECTIVES: To estimate the proportion of patients with very severe osteoporosis (those covered by the reimbursement criteria of the Italian National Health Service) experiencing new vertebral and non-vertebral fragility fractures in the first 24 months of a new anti-osteoporosis treatment. METHODS: Prospective observational study in men and post-menopausal women (aged > 21 years) initiating anti-osteoporosis treatment for very severe osteoporosis. Eligibility was based on teriparatide (TPD) reimbursement criteria in Italy: incident of vertebral or hip fracture during anti-resorptive treatment (minimum 1 year), or at least three prevalent severe vertebral fractures, or two prevalent severe vertebral fractures and a historical proximal hip fracture. Incidence of new clinical vertebral and non-vertebral fractures was documented by original x-rays and/or radiological reports, and a post-hoc analysis compared data from the TPD monotherapy population versus the total treated group. RESULTS: Overall, 767 patients (mean age 72.8 years, 90.7% women) were enrolled in the study, of whom 628, 538, 419 and 424 attended visits at 6, 12, 18 and 24 months, respectively. The most commonly prescribed therapy was TPD (single-agent; 64.5%), then bisphosphonates and other anti-resorptives (33.3%). A combination of different oral treatments was given to 22.5% of the patients. Overall treatment adherence at 24 months was 65.7%. In a post-hoc analysis, the overall incidence of new clinical vertebral and non-vertebral fractures in the total treated population was, respectively, 4.7% and 2.3% in the first 6 months; 1.8% and 1.6% in the 6-12 month period; 2.9% and 1.4% in the 12-18 month period; and 2.2% and 1.0% in the 18-24 month period. CONCLUSIONS: In patients with very severe osteoporosis, the risk of new vertebral and non-vertebral fractures declined after the first 6 months and remained low throughout the study. PMID- 26940790 TI - Importance of embryo transfer technique in maximizing assisted reproductive outcomes. AB - Embryo transfer is arguably the most critical process in the sequential events that encompass an IVF cycle. Several variables play a role in the success of a transfer, including catheter type, atraumatic technique, and the use of ultrasound guidance. The inclusion of hyaluronan in the ET media also has a benefit for implantation. Because of the adverse effects of controlled ovarian hyperstimulation on the endometrium, frozen embryo transfers have demonstrated improved pregnancy rates as well as better obstetric outcomes. This review will talk about various aspects of ET as it is currently performed, variables affecting its success, and methods of optimization. PMID- 26940791 TI - Both slowly developing embryos and a variable pace of luteal endometrial progression may conspire to prevent normal birth in spite of a capable embryo. AB - Embryonic implantation requires synchrony between the endometrium and the embryo. When analyzed in isolation, competent embryos may be unsuccessful when placed on a nonreceptive endometrium or vice versa, contributing to the "black box" of implantation failure. It is when the two are assessed together that dyssynchrony becomes evident, due to premature progesterone stimulus on the endometrium, physiologic displacement of the window of implantation or late blastulation of the embryo, or all combined. From the embryonic component, detailed assessment of the timing of blastulation is essential. The molecular diagnosis of endometrial receptivity based on its transcriptomic signature could be superior to other techniques used in the past for defining the endometrial window of implantation. PMID- 26940792 TI - Is FMR1 CGG repeat length a predictor of in vitro fertilization stimulation response or outcome? AB - OBJECTIVE: To study a broad range of FMR1 CGG repeat lengths and assisted reproduction technology (ART) outcomes. DESIGN: Retrospective cohort study. SETTING: Private ART practice. PATIENT(S): Fresh autologous ART stimulation cycles. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Oocyte yield, live birth. RESULT(S): We screened 14,088 fresh autologous ART cycles from 2012 to 2015, of which 4,690 cycles in 3,290 patients met the inclusion criteria. The FMR1 repeat length was statistically significantly but weakly associated with oocyte yield and other markers of ovarian response. The receiver operating characteristic curve analysis suggested extremely limited predictive ability. Moreover, the FMR1 repeat length was not statistically significantly associated with outcomes in multivariable models, including other markers of ovarian reserve. The FMR1 repeat length was not associated with embryo quality or live birth. Only patient age had a strong ability to predict live birth. CONCLUSION(S): The FMR1 repeat length is associated with ART response, but only weakly. It provides no incremental predictive ability beyond the conventionally used predictors, including patient age, antimullerian hormone concentration, antral follicle count, and follicle stimulating hormone level. These data suggest a possible role of the FMR1 repeat length within the normal range in ovarian response but demonstrate no clinically relevant indication for testing FMR1 as a predictor of ART outcomes. PMID- 26940793 TI - The relationship between recurrent pregnancy loss and the male contribution. AB - Judge a man by his questions rather than his answers. -Voltaire. PMID- 26940794 TI - Confined Water as Model of Supercooled Water. AB - Water in confined geometries has obvious relevance in biology, geology, and other areas where the material properties are strongly dependent on the amount and behavior of water in these types of materials. Another reason to restrict the size of water domains by different types of geometrical confinements has been the possibility to study the structural and dynamical behavior of water in the deeply supercooled regime (e.g., 150-230 K at ambient pressure), where bulk water immediately crystallizes to ice. In this paper we give a short review of studies with this particular goal. However, from these studies it is also clear that the interpretations of the experimental data are far from evident. Therefore, we present three main interpretations to explain the experimental data, and we discuss their advantages and disadvantages. Unfortunately, none of the proposed scenarios is able to predict all the observations for supercooled and glassy bulk water, indicating that either the structural and dynamical alterations of confined water are too severe to make predictions for bulk water or the differences in how the studied water has been prepared (applied cooling rate, resulting density of the water, etc.) are too large for direct and quantitative comparisons. PMID- 26940796 TI - Can teledermatology be a useful diagnostic tool in dermatology practice in remote areas? An Egyptian experience with 600 patients. AB - Introduction The paucity of studies evaluating teledermatology (TD) in developing countries was the impetus behind conducting this work. We aimed to evaluate the feasibility and reliability of TD in remote areas where medical facilities and consultant dermatologists are not available, through measurement of diagnostic concordance rates between face-to-face diagnosis and store-and-forward (SAF) TD diagnosis. Methods A total of 600 patients with dermatological ailments who attended Abshway Hospital were recruited into the study, examined by an on-site dermatology resident, and offered a diagnosis. The clinical images and patients' history were collected and transferred (through the Dropbox application) to two remote consultant dermatologists. The reliability of the three physicians' agreement rates was assessed. Results Diagnostic agreement rates between the face to-face dermatologist and the two teledermatologists were 86.7% and 87% respectively. Of the cases, 97% had complete or partial agreement and 81.3% of cases showed complete agreement between the three physicians. The reliability of the three physicians' agreement rates was assessed statistically using Cohen's kappa coefficient (kappa) and this showed a range of 0.46-0.52. Conclusion This study might aid in enhancing the utilization of this tool in our country, especially in remote areas with a lack of a proper dermatological service. The simplicity and low cost of the adopted technique might facilitate its use over large sectors. It opens the door for gaining the benefit of this technology in other aspects such as teaching and monitoring health care providers. PMID- 26940795 TI - Antioxidant defenses at transcriptional and enzymatic levels and gene expression of Nrf2-Keap1 signaling molecules in response to acute zinc exposure in the spleen of the large yellow croaker Pseudosciaena crocea. AB - We evaluated the effects of acute Zn exposure (4 and 8 mg L(-1) Zn) on lipid peroxidation, and activities and mRNA levels of antioxidant enzyme genes (Cu/Zn SOD, CAT, GPx, and GR), and gene expression of the Nrf2-Keap1 signaling molecule at different exposure times (0, 6, 12, 24, 48, and 96 h) in the spleen of large yellow croaker. Lipid peroxidation remained relatively constant during 6-48 h and 6-24 h and sharply increased at 96 h and during 48-96 h in fish exposed to 4 and 8 mg L(-1) Zn, respectively. Activities of all tested enzymes increased during the early stage of exposure and decreased towards the end of the exposure in both groups. However, mRNA levels of antioxidant enzyme genes were dramatically up regulated by 4 and 8 mg L(-1) Zn during the late stage of exposure. During the early stage of exposure for 6 h, the 8 mg L(-1) Zn exposure sharply increased mRNA levels of Cu/Zn-SOD, CAT, GPx1b, Nrf2, and Keap1, whereas, the 4 mg L(-1) Zn exposure did not significantly affect the expression of these genes. Our data also showed positive relationships between Nrf2 expression and mRNA levels of its target genes, suggesting that Nrf2 was required for the protracted induction of these genes. Furthermore, a sharp increase in Keap1 expression levels was observed in fish exposed to 4 mg L(-1) at 96 h, and 8 mg L(-1) at 6, 48, and 96 h. In conclusion, the present study demonstrated that Zn-induced antioxidant defenses were involved in modifications at enzymatic and transcriptional levels and the transcriptional regulation of the Nrf2-Keap1 signaling molecule; these results may contribute to the understanding of mechanisms that maintain the correct redox balance in the immune organ of the large yellow croaker. PMID- 26940797 TI - Analysis of an electronic consultation program at an academic medical centre: Primary care provider questions, specialist responses, and primary care provider actions. AB - Introduction Electronic consultations (eConsults) increase access to specialty care, but little is known about the types of questions primary care providers (PCPs) ask through eConsults, and how they respond to specialist recommendations. Methods This is a retrospective descriptive analysis of the first 200 eConsults completed in the UCSF eConsult program. Participating PCPs were from eight adult primary care sites at the University of California, San Francisco (UCSF), USA. Medicine subspecialties participating were Cardiology, Endocrinology, Gastroenterology/hepatology, Hematology, Infectious diseases, Nephrology, Pulmonary medicine, Rheumatology, and Sleep medicine. We categorized eConsult questions into "diagnosis," "treatment," and/or "monitoring." We performed medical record reviews to determine the percentage of specialist recommendations PCPs implemented, and the proportion of patients with a specialist visit in the same specialty as the eConsult, emergency department visit, or hospital admission during the subsequent six months. Results PCP questions related to diagnosis in 71% of cases, treatment in 46%, and monitoring in 21%. Specialist responses related to diagnosis in 76% of cases, treatment in 64%, and monitoring in 40%. PCPs ordered 79% of all recommended laboratory tests, 86% of recommended imaging tests and procedures, 65% of recommended new medications, and 73% of recommended medication changes. In the six months after the eConsult, 14% of patients had a specialist visit within the UCSF system in the same specialty as the eConsult. Discussion eConsults provide guidance to PCPs across the spectrum of patient care. PCPs implement specialists' recommendations in the large majority of cases, and few patients subsequently require in-person specialty care related to the reason for the eConsult. PMID- 26940798 TI - Clinical outcomes of remote asynchronous telerehabilitation are equivalent to traditional therapy following total knee arthroplasty: A randomized control study. AB - Introduction Successful post-operative telerehabilitation following total knee replacement (TKR) has been documented using synchronous (real-time) video. Bandwidth and the need for expensive hardware are cited as barriers to implementation. Web-based asynchronous visual platforms promise to address these problems but have not been evaluated. We performed a randomized control study comparing an asynchronous video-based software platform to in-person outpatient physical therapy visits following TKR. Materials and methods Fifty-one patients were randomized to either the intervention group, using an asynchronous video application on a mobile device, or the traditional group undergoing outpatient physical therapy. Outcome data were collected using validated instruments prior to surgery and at a minimum three-month follow-up. Results Twenty-nine patients completed the study. There were no statistically significant differences in any clinical outcome between groups. The satisfaction with care was equivalent between groups. Overall utilization of hospital-based resources was 60% less than for the traditional group. Discussion We report that clinical outcomes following asynchronous telerehabilitation administered over the web and through a hand-held device were not inferior to those achieved with traditional care. Outpatient resource utilization was lower. Patient satisfaction was high for both groups. The results suggest that asynchronous telerehabilitation may be a more practical alternative to real-time video visits and are clinically equivalent to the in person care model. PMID- 26940799 TI - Remodeling of the conformational ensemble of the repeat domain of tau by an aggregation enhancer. AB - Misfolding of the microtubule-associated protein Tau is a hallmark of Alzheimer disease and several other neurodegenerative disorders. Because of the dynamic nature of the Tau protein, little is known about the changes in Tau structure that occur during misfolding. Here we studied the structural consequences upon binding of the repeat domain of Tau, which plays a key role in pathogenic aggregation, to an aggregation enhancer. By combining NMR experiments with molecular simulations we show that binding of the aggregation enhancer polyglutamic acid remodels the conformational ensemble of Tau. Our study thus provides insight into an early event during misfolding of Tau. PMID- 26940800 TI - Expansive arterial remodeling of the carotid arteries and its effect on atherosclerotic plaque composition and vulnerability: an in-vivo black-blood 3T CMR study in symptomatic stroke patients. AB - BACKGROUND: Based on intravascular ultrasound of the coronary arteries expansive arterial remodeling is supposed to be a feature of the vulnerable atheroslerotic plaque. However, till now little is known regarding the clinical impact of expansive remodeling of carotid lesions. Therefore, we sought to evaluate the correlation of expansive arterial remodeling of the carotid arteries with atherosclerotic plaque composition and vulnerability using in-vivo Cardiovascular Magnetic Resonance (CMR). METHODS: One hundred eleven symptomatic patients (74 male/71.8 +/- 10.3y) with acute unilateral ischemic stroke and carotid plaques of at least 2 mm thickness were included. All patients received a dedicated multi sequence black-blood carotid CMR (3Tesla) of the proximal internal carotid arteries (ICA). Measurements of lumen, wall, outer wall, hemorrhage, calcification and necrotic core were determined. Each vessel-segment was classified according to American Heart Association (AHA) criteria for vulnerable plaque. A modified remodeling index (mRI) was established by dividing the average outer vessel area of the ICA segments by the lumen area measured on TOF images in a not affected reference segment at the distal ipsilateral ICA. Correlations of mRI and clinical symptoms as well as plaque morphology/vessel dimensions were evaluated. RESULTS: Seventy-eight percent (157/202) of all internal carotid arteries showed atherosclerotic disease with AHA Lesion-Type (LT) III or higher. The mRI of the ICA was significantly different in normal artery segments (AHA LT I; mRI 1.9) compared to atherosclerotic segments (AHA LT III-VII; mRI 2.5; p < 0.0001). Between AHA LT III-VII there was no significant difference of mRI. Significant correlations (p < 0.05) of the mRI with lumen-area (LA), wall-area (WA), vessel-area (VA) and wall-thickness (WT), necrotic-core area (NC), and ulcer-area were observed. With respect to clinical presentation (symptomatic/asymptomatic side) and luminal narrowing (stenotic/non-stenotic) no relevant correlations or significant differences regarding the mRI were found. CONCLUSION: Expansive arterial remodeling exists in the ICA. However, no significant association between expansive arterial remodeling, stroke symptoms, complicated AHA VI plaque, and luminal stenosis could be established. Hence, results of our study suggest that expansive arterial remodeling is not a very practical marker for plaque vulnerability in the carotid arteries. PMID- 26940801 TI - Engraftment and regenerative effects of bone marrow stromal cell transplantation on damaged rat olfactory mucosa. AB - To develop a new therapeutic method to treat olfactory deficits, we investigated the engraftment and regenerative effects of transplanted bone marrow stromal cells (BMSCs) on damaged rat olfactory mucosa. To induce olfactory nerve degeneration, one side of the olfactory mucosa of Sprague-Dawley rats was damaged via Triton X-100 irrigation. Phosphate-buffered saline containing syngeneic BMSCs was injected into the olfactory mucosa for transplantation. PKH fluorescent cell dye labeling of BMSCs was used to monitor the transplanted cells. After transplantation of BMSCs, the thickness and regeneration of olfactory mucosa were analyzed using hematoxylin-eosin (H&E) staining. S100 immunohistochemical staining was used to measure nerve sheath regeneration. The increase in NGF (nerve growth factor) level in the olfactory mucosa was measured by Western blot analysis. Transplanted bone marrow stromal cells were engrafted to the lamia propria of damaged mucosa. The mean time for normalization of thickness and morphological recovery of the olfactory mucosa was 4 weeks in the therapeutic group and 9 weeks in the control group. S100 immunoreactivity was higher on the BMSC-treated side than on the control side. During regeneration, the expression of NGF increased in the olfactory mucosa of the experimental group. Based on these results, BMSC transplantation accelerated regeneration of olfactory mucosa damaged by Triton X-100, and NGF may be essential to this regenerative process. PMID- 26940802 TI - Early Treatment in HIV Patients: A Cost-Utility Analysis from the Italian Perspective. AB - BACKGROUND AND OBJECTIVE: Highly active antiretroviral therapy (HAART) has modified the clinical course of human immunodeficiency virus (HIV) infection, reducing the rate of disease progression, the incidence of opportunistic infections and mortality. Several recent studies show early antiretroviral therapy reduces the risk of AIDS and HIV-related disease. The aim of this study was to perform an economic analysis to estimate the cost-utility of early antiretroviral therapy in Italy for managing HIV-infected patients. METHODS: The incremental cost-utility analysis was carried out to quantify the benefits of the early-treatment approach in HIV subjects. A Markov simulation model including direct costs and health outcomes was developed from a third-party (Italian National Healthcare Service) payer's perspective for four CD4 strata. 5000 Monte Carlo simulations were performed on two distinct scenarios: Standard of care (SoC) in which 30% of patients started HAART with a CD4 count >=500 cells/mm(3) versus the early-treatment scenario (ETS), where the number of patients starting HAART with a CD4 count >=500 cells/mm(3) increased to 70%. A systematic literature review was carried out to identify epidemiological and economic data, which were subsequently used to inform the model. In addition, a one-way probabilistic sensitivity analysis was performed in order to measure the relationship between the effectiveness of the treatments and the number of patients to undergo early treatment. RESULTS: The model shows, in terms of the incremental cost-effectiveness ratio (ICER) per quality-adjusted life years (QALY) gained, that early treatment appeared to be the most cost-effective option compared to SoC (ICER = ?13,625) over a time horizon of 10 years. The cost effectiveness of ETS is more sustainable as it extends the time horizon analysis (ICER = ?7526 per QALY to 20 years and ?8382 per QALY to 30 years). The one-way sensitivity analysis on the main variables confirmed the robustness of the model for the early-treatment approach. CONCLUSION: Our model represents a tool for policy makers and health-care professionals to provide information on the cost effectiveness of the early-treatment approach in HIV-infected patients in Italy. Starting HAART earlier keeps HIV-infected patients in better health and reduces the incidence of AIDS- and non-AIDS-related events, generating a gain in terms of both patients' health and correct resource allocation. PMID- 26940803 TI - Long-term Clinical Outcomes and Cataract Formation Rates After Posterior Phakic Lens Implantation for Myopia. PMID- 26940804 TI - All-Cause Mortality in Women With Severe Postpartum Psychiatric Disorders. AB - OBJECTIVE: The postpartum period is associated with a high risk of psychiatric episodes. The authors studied mortality in women with first-onset severe psychiatric disorders following childbirth and compared their mortality rates with those in women from the background population including other female psychiatric patients (mothers and childless women). METHOD: In a register-based cohort study with linked information from Danish population registers, the authors identified women with first psychiatric inpatient or outpatient contacts 0-3 months postpartum. The main outcome measure was mortality rate ratios (MRRs): deaths from natural causes (diseases and medical conditions) or unnatural causes (suicides, accidents, and homicides). The cohort included 1,545,857 women representing 68,473,423 person-years at risk. RESULTS: In total, 2,699 women had first-onset psychiatric disorders 0-3 months postpartum, and 96 of these died during follow-up. Women with postpartum psychiatric disorders had a higher MRR (3.74; 95% CI=3.06-4.57) than non-postpartum-onset mothers (MRR=2.73; 95% CI=2.67 2.79) when compared with mothers with no psychiatric history. However, childless women with psychiatric diagnoses had the highest MRR (6.15; 95% CI=5.94-6.38). Unnatural cause of death represented 40.6% of fatalities among women with postpartum psychiatric disorders, and within the first year after diagnosis, suicide risk was drastically increased (MRR=289.42; 95% CI=144.02-581.62) when compared with mothers with no psychiatric history. CONCLUSIONS: Women with severe postpartum psychiatric disorders had increased MRRs compared with mothers without psychiatric diagnoses, and the first year after diagnosis represents a time of particularly high relative risk for suicide in this vulnerable group. PMID- 26940805 TI - A Randomized Trial to Assess the Efficacy and Safety of ABT-126, a Selective alpha7 Nicotinic Acetylcholine Receptor Agonist, in the Treatment of Cognitive Impairment in Schizophrenia. AB - OBJECTIVE: The authors sought to evaluate the efficacy and safety of ABT-126, a selective alpha7 nicotinic receptor partial agonist, in stable patients with schizophrenia. METHOD: A 12-week, double-blind, placebo-controlled, parallel group phase 2 study was conducted in 22 centers in the United States. Clinically stable patients with schizophrenia were randomly assigned to receive once-daily dosing with 10 mg of ABT-126, 25 mg of ABT-126, or placebo. The primary efficacy measure was change from baseline to week 12 on the MATRICS Consensus Cognitive Battery (MCCB) composite score compared with placebo, tested by a one-sided t test. Secondary measures included MCCB domain scores and UCSD Performance-Based Skills Assessment total score, each tested by two-sided t tests. RESULTS: A total of 207 subjects were randomized, of whom 165 (81%) completed the study. ABT-126 showed an improvement that fell short of significance on the MCCB composite score at week 12 (least squares mean difference from placebo, 1.3 and 1.5 for the 10 mg and 25 mg groups, respectively). A significant treatment-by-smoking status interaction was observed on the mean change from baseline to final MCCB composite score: nonsmokers (N=69) demonstrated a difference from placebo of 2.9 (SE=1.4) in the 10 mg group and 5.2 (SE=1.6) in the 25 mg group, whereas no differences were observed in smokers (N=113). Among the nonsmokers in the ABT-126 25 mg group (N=19), significant improvements compared with placebo occurred at final assessment for verbal learning (least squares mean difference=5.5, SE=1.9), working memory (least squares mean difference=5.4, SE=2.0), and attention/vigilance (least squares mean difference=8.7, SE=2.5). The most frequently reported adverse events for ABT-126 were dizziness, diarrhea, and fatigue (all <8% incidence). CONCLUSIONS: ABT-126 demonstrated a procognitive effect in nonsmoking subjects, particularly in verbal learning, working memory, and attention. PMID- 26940806 TI - Depressive and Anxiety Disorders Showing Robust, but Non-Dynamic, 6-Year Longitudinal Association With Short Leukocyte Telomere Length. AB - OBJECTIVE: Several cross-sectional studies have related depressive and anxiety disorders to shorter leukocyte telomere length (LTL) as an indicator of cellular aging. However, these studies have left many unresolved questions about underlying causality and ordering of associations. The objective of the present large, longitudinal study was to examine the relationship between depressive and anxiety disorders and LTL over a 6-year time period. METHOD: Data are from the Netherlands Study of Depression and Anxiety, including 2,292 patients with remitted and current diagnoses of depressive or anxiety disorders and 644 healthy control subjects. LTL was assessed using quantitative PCR and measured at baseline and after 6 years; depressive and anxiety disorder diagnoses and characteristics (course, duration, and severity) were determined at baseline and after 2, 4, and 6 years. RESULTS: Results showed that persons with remitted (B= 52.6) and current (B=-60.8) depressive or anxiety disorder had consistently shorter LTL compared with healthy control subjects across baseline and at the 6 year follow-up, remaining significant when controlling for lifestyle and somatic health variables. Changes in the course of depressive or anxiety disorder characteristics over 6 years, however, were not associated with different LTL attrition rates. CONCLUSIONS: This study confirmed robust associations of depressive and anxiety disorders with shorter telomeres, but interestingly, it did not demonstrate that depressive and anxiety disorders and LTL change together over time, suggesting the absence of a direct within-person relationship. Short LTL is suggested to be either a long-term consequence or an underlying vulnerability factor for depressive or anxiety disorders. PMID- 26940808 TI - Deeper insights into the drug defense of glioma cells against hydrophobic molecules. AB - By means of fluorescence microscopy the intracellular distribution of fluorescent drugs with different hydrophobicity (quinizarin, emodin and hypericin) was studied. Selective photoactivation of these drugs in precisely defined position (nuclear envelope) allowed moderately hydrophobic emodin enter the nucleus. Highly hydrophobic hypericin was predominantly kept in the membranes with no fluorescence observed in the nucleus. The redistribution of quinizarin, emodin and hypericin between lipids, proteins and DNA was studied in solutions and cells. Based on these results was proposed theoretical model of hydrophobic drugs' nuclear internalization after photo-activation. Molecular docking models showed that hypericin has the strongest affinity to P-glycoprotein involved in the cell detoxification. Presence of 10 MUM quinizarin, emodin or hypericin increased P-glycoprotein function in U87 MG cells. Moreover, emodin pretreatment allowed quinizarin nuclear internalization without photo-activation, which was not the case for hypericin. The synergy of such pretreatment and photo-activation should lessen the drug doses with simultaneous increase of drug efficacy triggering cell apoptosis/necrosis. PMID- 26940807 TI - Prevalence and Correlates of DSM-5 Cannabis Use Disorder, 2012-2013: Findings from the National Epidemiologic Survey on Alcohol and Related Conditions-III. AB - OBJECTIVE: Attitudes toward marijuana are changing, the prevalence of DSM-IV cannabis use disorder has increased, and DSM-5 modified the cannabis use disorder criteria. Therefore, updated information is needed on the prevalence, demographic characteristics, psychiatric comorbidity, disability, and treatment for DSM-5 cannabis use disorder. METHOD: In 2012-2013, 36,309 participants >=18 years old were interviewed in the National Epidemiologic Survey on Alcohol and Related Conditions-III. Psychiatric and substance use disorders were assessed with the Alcohol Use Disorders and Associated Disabilities Interview Schedule-5. RESULTS: The prevalences of 12-month and lifetime cannabis use disorder were 2.5% and 6.3%. Among those with 12-month and lifetime diagnoses, the mean days of marijuana use per year were 225.3 (SE=5.7) and 274.2 (SE=3.8). The odds of 12 month and lifetime cannabis use disorder were higher for men, Native Americans, unmarried individuals, those with low incomes, and young adults (e.g., among those age 18-24 years versus >=45: odds ratio for 12-month disorder, 7.2; 95% confidence interval, 5.5-9.5). Cannabis use disorder was associated with other substance use disorders, affective disorders, anxiety, and personality disorders. Twelve-month cannabis use disorder was associated with disability. As disorder severity increased, virtually all associations became stronger. Only 13.2% with lifetime cannabis use disorder participated in 12-step programs or professional treatment. CONCLUSIONS: DSM-5 cannabis use disorder is prevalent, associated with comorbidity and disability, and largely untreated. Findings suggest the need to improve prevention and educate the public, professionals, and policy makers about possible harms associated with cannabis use disorders and available interventions. PMID- 26940809 TI - The In Vitro Efficacy of Essential Oils and Antifungal Drugs Against Prototheca zopfii. AB - BACKGROUND: The algae of the genus Prototheca are environmental pathogens whose main reservoir is the habitat of cows. They can cause protothecosis in domestic and wild animals, as well as human beings, with the main etiological agents being Prototheca zopfii in animals and Prototheca wickerhamii in humans. AIM: The aim of the study was to evaluate the in vitro activity of selected essential oils and antifungal antibiotics against P. zopfii isolates. MATERIALS AND METHODS: The material consisted of nine P. zopfii strains isolated from the milk of cows suffering from mastitis. Eight essential oils produced by POLLENA-AROMA, Poland, and nine antifungal agents were tested. The effects of essential oils on P. zopfii were evaluated by microdilution with liquid Sabouraud dextrose broth, and susceptibility to antifungal agents was tested using the disk-diffusion method. RESULTS: All used essential oils inhibited the activity of P. zopfii isolates, with MIC values ranging from 0.2 to 10.5 MUl/ml. Cinnamon, clove, and thyme demonstrated the highest activity against the tested P. zopfii strains at concentrations ranging from 0.6 to 1.0 MUl/ml. Of the antifungal agents, the tested strains were the most sensitive to nystatin (100 %). CONCLUSIONS: The tested essential oils can be used to complement protothecosis therapy in animals and human beings. PMID- 26940810 TI - Serum Beta-Trace Protein as a Novel Predictor of Pregnancy-Induced Hypertension. AB - Beta-trace protein (BTP) has emerged as a novel biomarker of cardiovascular risk. However, the level of circulating BTP in pregnancy-induced hypertension (PIH) is still unknown. The aim of this study was to determine the concentration of serum BTP in healthy pregnant women and patients with PIH. No significant difference was found in the serum concentration of BTP in patients with a normal pregnancy. In contrast, serum BTP levels in women with PIH (n=46) were significantly higher than those in women with normal pregnancy (n=57). Receiver operating characteristic analysis revealed that using a serum BTP value of 321.3 ng/mL as a cutoff produced a sensitivity of 91.3% and a specificity of 89.5%. Taken together, these findings suggest that a higher serum BTP concentration in PIH patients compared with those with normal pregnancy and serum BTP might be a novel biomarker in the diagnosis of PIH. PMID- 26940812 TI - Extinction as a driver of avian latitudinal diversity gradients. AB - The role of historical factors in driving latitudinal diversity gradients is poorly understood. Here, we used an updated global phylogeny of terrestrial birds to test the role of three key historical factors-speciation, extinction, and dispersal rates-in generating latitudinal diversity gradients for eight major clades. We fit a model that allows speciation, extinction, and dispersal rates to differ, both with latitude and between the New and Old World. Our results consistently support extinction (all clades had lowest extinction where species richness was highest) as a key driver of species richness gradients across each of eight major clades. In contrast, speciation and dispersal rates showed no consistent latitudinal patterns across replicate bird clades, and thus are unlikely to represent general underlying drivers of latitudinal diversity gradients. PMID- 26940813 TI - Campaigning for Organ Donation at Mosques. AB - There is a trend of recruiting faith leaders at mosques to overcome religious barriers to organ donation, and to increase donor registration among Muslims. Commentators have suggested that Muslims are not given enough information about organ donation in religious sermons or lectures delivered at mosques. Corrective actions have been recommended, such as funding campaigns to promote organ donation, and increasing the availability of organ donation information at mosques. These actions are recommended despite published literature expressing safety concerns (i.e., do no harm) in living and end-of-life organ donation. Living donors require life-long medical follow-up and treatment for complications that can appear years later. Scientific and medical controversies persist regarding the international guidelines for death determination in end-of-life donation. The medical criteria of death lack validation and can harm donors if surgical procurement is performed without general anesthesia and before biological death. In the moral code of Islam, the prevention of harm holds precedence over beneficence. Moral precepts described in the Quran encourage Muslims to be beneficent, but also to seek knowledge prior to making practical decisions. However, the Quran also contains passages that demand honesty and truthfulness when providing information to those who are seeking knowledge. Currently, information is limited to that which encourages donor registration. Campaigning for organ donation to congregations in mosques should adhere to the moral code of complete, rather than selective, disclosure of information. We recommend as a minimal standard the disclosure of risks, uncertainties, and controversies associated with the organ donation process. PMID- 26940811 TI - The geriatric depression scale and the timed up and go test predict fear of falling in community-dwelling elderly women with type 2 diabetes mellitus: a cross-sectional study. AB - BACKGROUND: Fear of falling is a common and potentially disabling problem among older adults. However, little is known about this condition in older adults with diabetes mellitus. The aims of this study were to investigate the impact of the fear of falling on clinical, functional and gait variables in older women with type 2 diabetes and to identify which variables could predict the fear of falling in this population. METHODS: Ninety-nine community-dwelling older women with type 2 diabetes (aged 65 to 89 years) were stratified in two groups based on their Falls Efficacy Scale-International score. Participants with a score < 23 were assigned to the group without the fear of falling (n = 50) and those with a score >= 23 were assigned to the group with the fear of falling (n = 49). Clinical data included demographics, anthropometrics, number of diseases and medications, physical activity level, fall history, frailty level, cognition, depressive symptoms, fasting glucose level and disease duration. Functional measures included the Timed Up and Go test (TUG), the five times sit-to-stand test (5-STS) and handgrip strength. Gait parameters were obtained using the GAITRite(r) system. RESULTS: Participants with a fear of falling were frailer and presented more depressive symptoms and worse performance on the TUG and 5-STS tests compared with those without a fear of falling. The group with the fear of falling also walked with a lower velocity, cadence and step length and increased step time and swing time variability. The multivariate regression analysis showed that the likelihood of having a fear of falling increased 1.34 times (OR 1.34, 95 % CI 1.11-1.61) for a one-point increase in the Geriatric Depression Scale (GDS-15) score and 1.36 times (OR 1.36, 95 % CI 1.07-1.73) for each second of increase in the TUG performance. CONCLUSIONS: The fear of falling in community-dwelling older women with type 2 diabetes mellitus is associated with frailty, depressive symptoms and dynamic balance, functional mobility and gait deficits. Furthermore, both the GDS-15 and the TUG test predict a fear of falling in this population. Therefore, these instruments should be considered during the assessment of diabetic older women with fear of falling. PMID- 26940814 TI - The quality of life of home-ventilated children and their primary caregivers plus the associated social and economic burdens: a prospective study. AB - BACKGROUND: Despite the obvious challenges faced by families caring for children on home ventilation, there is surprisingly little research into the details of their daily lives. In particular, little is known about the quality of life of the child and caregiver plus the associated social and economic burdens of care. METHODS: We prospectively studied 90 families enrolled in a paediatric home ventilation service in British Columbia. In the clinic, we recorded demographic information, patient acuity score and quality of life for patient and caregiver using standardised questionnaires. Parents then monitored social and financial costs of care at home over the subsequent 8 weeks. These data were collected by telephone at 1 and 2 months. RESULTS: Most children led rich active lives. Camping trips, wheelchair sports and foreign travel were the norm, not the exception. Over 90% assessed the burden of care as mild or moderate. Government support covers medical expenses and home nursing (median 32 h/week, IQR 0-62.5 h). Monthly unreimbursed family expenses were low (median $87.7, IQR $15.3-$472). Despite this, nearly 25% of primary caregivers assessed burden of care as severe and over 50% had chronic illnesses requiring daily medication (principally depression, anxiety and arthritis). Quality of life for children or caregivers did not correlate with income or education. INTERPRETATION: Home ventilation of complex children is a successful strategy but it places significant strain on the primary caregiver. Specific attention to the physical and mental health of the caregiver should be an integral part of the management of home-ventilated children. TRIAL REGISTRATION NUMBER: NCT01863992. PMID- 26940815 TI - Irisin modulates the association of interleukin-17A with the presence of non proliferative diabetic retinopathy in patients with type 2 diabetes. AB - The role of inflammation in pathogenesis of diabetic retinopathy (DR) is getting increasingly recognized. However, it is unclear whether and how non-proliferative diabetic retinopathy (NPDR) is affected by Interleukin-17A (IL-17A) and Interleukin-22 (IL-22), two well-known inflammatory factors, and irisin, a novel potential anti-inflammatory factor. Here we recruited 40 type 2 diabetes mellitus (T2DM) patients with NPDR, 60 T2DM patients without DR (no-DR), and 20 normal glucose tolerance (NGT) controls. Serum levels of IL-17A, IL-22, and irisin were examined. Compared with NGT and no-DR subjects, NPDR group had significantly higher IL-17A levels. Irisin levels were significantly lower in T2DM patients, while IL-22 levels were not significantly different across all three groups. Multiple logistic regression analysis revealed that IL-17A significantly increased the risk of NPDR (OR = 1.22, P < 0.05) before adjusting for irisin. When irisin was included in the model, neither irisin nor IL-17A was associated with NPDR. Further partial correlation analysis showed that irisin was intrinsically correlated with IL-17A even after multiple adjustment (r = -0.252; P = 0.018). These findings suggest that IL-17A is an independent risk factor of NPDR, and irisin could protect against DR through potential anti-IL-17A effects. PMID- 26940817 TI - Content Analysis of Diet-Related Mobile Apps: A Self-Regulation Perspective. AB - Diet-related mobile apps hold promise in helping individuals self-regulate their eating behaviors. Nevertheless, little is known about the extent to which diet related mobile apps incorporate the established behavior change theories and evidence-based practices that promote dietary self-regulation. Guided by the self regulation aspect of Bandura's social cognitive theory and the Dietary Guidelines for Americans 2010 of the U.S. Department of Agriculture, this study conducts a content analysis of diet-related mobile apps for iPhone (N = 400). In terms of the adherence to the self-regulation aspect of the social cognitive theory, results show that although 72.5% of the apps incorporate at least one theoretical construct, few apps tap all three processes of self-regulation (i.e., self observation/monitoring, judgment process, and self-reaction). Additionally, outcome expectation is manifested in a majority of the diet-related apps. In terms of the Dietary Guidelines for Americans 2010, while the diet-related apps equally emphasize setting goals for calorie intake or nutrient consumption, more apps feature nutrient tracking than calorie tracking. Implications and limitations are discussed. PMID- 26940818 TI - Impact of the bioresorbable vascular scaffold surface area on on-treatment platelet reactivity. AB - While promising data with the novel bioresorbable vascular scaffold (BVS) are accumulating, signals of scaffold thrombosis (ST) were noted in recent reports. We aimed to assess the relationship between the total surface area (TSA) of implanted everolimus-eluting BVSs and the on-treatment adenosine diphosphate (ADP)-induced platelet reactivity in patients undergoing percutaneous coronary intervention (PCI). 202 consecutive patients undergoing BVS implantation and platelet function testing were included. For investigating the impact of the scaffold surface on platelet reactivity, patients were stratified into two groups regarding the median BVS TSA. The on-treatment ADP-induced platelet reactivity was determined with the Multiplate analyzer and 30-day follow-up was available in 98% of patients. ADP-induced platelet aggregation values (median, [IQR]) did not differ between the two study groups (12.0 [9.0-19.0] U for patients with TSA > 1.39 cm(2) and 13.0 [9.0-19.5] U for patients with TSA <= 1.39 cm(2); p = 0.69). No correlation was observed between the BVS TSA and levels of platelet reactivity (Spearman rank correlation = -0.10, p = 0.16). At 30 days after PCI, two early STs (1%) were documented. Thus, in patients on a dual antiplatelet treatment regimen following BVS implantation, the extent of blood-to-BVS contact surface does not negatively affect levels of on-treatment platelet reactivity. PMID- 26940816 TI - The Prevalence, Attitudes, and Correlates of Waterpipe Smoking Among High School Students in Iran: a Cross-Sectional Study. AB - PURPOSE: The purpose of the present study was to determine the correlates of waterpipe (WP) smoking among 15-17-year-old high school students in Iran. METHOD: Data were collected using the Global Youth Tobacco Survey (GYTS), a self administrated questionnaire distributed to a representative sample of high school students aged 15-17 in the city of Tabriz. Current WP smoking was defined as past 30-day use, and ever WP smoking was defined as at least one or two lifetime puffs. Differences in WP use, knowledge, and attitudes were analyzed using chi square and Fisher exact tests. Binary logistic regression estimated the association between relevant independent variables (e.g., age) and the dependent variables (current/ever WP smoking). RESULTS: Of 1517 students, 21.6 % (95 % confidence interval [CI] = 19.5, 23.8) were ever WP smokers, and 9.7 % (95 % CI = 8.2, 11.2) were current WP smokers. Of current WP smokers, 40.3 % have stated that they want to stop smoking now. Moreover, 14.1 % of non-WP smokers reported that they might enjoy smoking WP. Of current WP smokers, 49.0 % have smoked at cafes. Additionally, 95.3 % of current WP smokers reported that their age did not prevent them from being served a WP. Studying in high school third grade (adjusted odds ratios (AORs) = 1.70; 95 % CI [1.10, 2.63]), experience of cigarette smoking (AORs = 1.57; 95 % CI [1.12, 2.20]), and being prepared to accept a WP offered by close friends (AORs = 3.31; 95 % CI [2.17, 5.04]) were independently associated with ever WP smoking, and accepting a WP offered by close friends (AORs = 4.36; 95 % CI [2.69, 7.07]) and gender (female) (AORs = 0.45; 95 % CI [0.30, 0.70] were independently associated with current WP smoking. CONCLUSION: Prevalence of current and ever WP smoking is high in Tabriz. There is an urgent need to design interventions in order to increase students' and their parents' awareness regarding the harmfulness of WP, and to establish legal measures to restrict adolescents' access to WPs and tobacco in society. PMID- 26940819 TI - Hydrops fetalis in a congenital chagas case in a non-endemic area. PMID- 26940820 TI - The associations of supervisor support and work overload with burnout and depression: a cross-sectional study in two nursing settings. AB - AIMS: To investigate the moderating effects of work overload and supervisor support on the emotional exhaustion-depressive state relationship. BACKGROUND: Burnout and depression are prevalent in human service professionals and have a detrimental impact on clients. Work overload and supervisor support are two key job demands and job resources, whose role and interplay for the development and maintenance of burnout and depression are not fully understood yet. DESIGN: Two consecutive cross-sectional surveys: survey 1 investigated 111 hospital nursing professionals and survey 2 examined 202 day care professionals. Data collection was completed in 2010. RESULTS: After controlling for general well-being and sociodemographic characteristics, nurses' emotional exhaustion was associated with increased depressive state in both samples. We found a meaningful three-way interaction: our results show consistently that the relationship between emotional exhaustion and depressive state was strongest for nurses with high work overload and low supervisor support. Additionally, nurses with low work overload and low supervisor support were also found to have stronger associations between emotional exhaustion and depressive state. CONCLUSION: The findings indicate that nurses' reported supervisor support exerts its buffering effect on the burnout depression link differentially and serves as an important resource for nurses dealing with high self-reported work stress. PMID- 26940821 TI - Review of gestational diabetes mellitus effects on vascular structure and function. AB - Vascular dysfunction has been described in women with a history of gestational diabetes mellitus. Furthermore, previous gestational diabetes mellitus increases the risk of developing Type 2 diabetes mellitus, a risk factor for cardiovascular disease. Factors contributing to vascular changes remain uncertain. The aim of this review was to summarize vascular structure and function changes found to occur in women with previous gestational diabetes mellitus and to identify factors that contribute to vascular dysfunction. A systematic search of electronic databases yielded 15 publications from 1998 to March 2014 that met the inclusion criteria. Our review confirmed that previous gestational diabetes mellitus contributes to vascular dysfunction, and the most consistent risk factor associated with previous gestational diabetes mellitus and vascular dysfunction was elevated body mass index. Heterogeneity existed across studies in determining the relationship of glycaemic levels and insulin resistance to vascular dysfunction. PMID- 26940822 TI - A Fractional Order Recovery SIR Model from a Stochastic Process. AB - Over the past several decades, there has been a proliferation of epidemiological models with ordinary derivatives replaced by fractional derivatives in an ad hoc manner. These models may be mathematically interesting, but their relevance is uncertain. Here we develop an SIR model for an epidemic, including vital dynamics, from an underlying stochastic process. We show how fractional differential operators arise naturally in these models whenever the recovery time from the disease is power-law distributed. This can provide a model for a chronic disease process where individuals who are infected for a long time are unlikely to recover. The fractional order recovery model is shown to be consistent with the Kermack-McKendrick age-structured SIR model, and it reduces to the Hethcote Tudor integral equation SIR model. The derivation from a stochastic process is extended to discrete time, providing a stable numerical method for solving the model equations. We have carried out simulations of the fractional order recovery model showing convergence to equilibrium states. The number of infecteds in the endemic equilibrium state increases as the fractional order of the derivative tends to zero. PMID- 26940823 TI - [Treatment of an osteo-fascio-cutaneous defect of the femur with a serial connected flow-through free-flap]. AB - Covering large osteo-fascio-cutaneous defects after debridement often calls for elaborate soft tissue reconstruction. Large tissue loss or structural damage that requires distinct repair is rarely coverable by a single conventional flap. Here, we report the case of serial flap coverage using sequentially connected fibular and latissimus dorsi free flaps. PMID- 26940824 TI - [Custom-fit kinematic alignment in total knee arthroplasty using PSI. The story of ShapeMatch technology]. AB - BACKGROUND: The story of ShapeMatch(r) custom-fit cutting guides for primary total knee arthroplasty (TKA) is special compared to other available techniques. First, it was the first such patient-specific instrument (PSI) on the market. Second, the underlying philosophy of kinematic alignment is unique compared to other competitors. Finally, it is the only PSI technique that has been withdrawn from the market. OBJECTIVES AND METHODS: The objective of this paper is to summarize the history of the ShapeMatch(r) technology and to review the current literature regarding clinical evidence for kinematically aligned TKA. RESULTS AND CONCLUSIONS: In the recent literature, faster rehabilitation, better knee function and higher patient satisfaction are described for kinematically aligned TKA compared to conventional alignment. However, there is also evidence for inaccuracies by using the PSI technology as a possible cause of treatment failures. Due to those problems, this technology was recalled from the market. As an alternative method to achieve kinematic alignment in TKA, manual as well as computer-assisted techniques are currently under development and are discussed here. PMID- 26940825 TI - Percutaneous kyphoplasty with or without temporary unipedicle screw reduction : A retrospective comparative study of osteoporotic vertebral fractures. AB - BACKGROUND: Temporary unipedicle screw reduction with percutaneous kyphoplasty (TUSR-PKP) is a relatively new method for managing osteoporotic vertebral compression fractures (OVCFs). A clinical retrospective comparative study was conducted to verify whether TUSR-PKP was noninferior to simple PKP regarding the management of OVCFs. METHODS: A total of 38 consecutive patients who sustained OVCFs without neurological deficits and had undergone surgeries in our hospital from June 2012 to January 2014 were included in the study: 24 patients underwent simple PKP (control group) and the other 14 patients underwent TUSR-PKP (treatment group). All 38 patients were asked to participate in a long-term (>1 year) follow-up. Visual analog scale (VAS) pain scores and Oswestry Disability Index (ODI) were recorded, and the Cobb angles and the vertebral body heights were measured on the lateral radiographs before surgery and on day 1, as well as 1, 3, 6, and 12 months after surgery. RESULTS: The patients in the treatment group had better vertebral height gain and greater improvement on ODI compared with the control group (p < 0.05). The VAS scores of the two groups were similar at all points until the end of the 1-year follow-up period. Two patients from the treatment group and 5 patients from the control group had cement leakage. In the control group, 3 patients suffered adjacent or nonadjacent vertebra fractures. CONCLUSION: TUSR-PKP is a safe and effective surgical option for OVCFs. Compared with simple PKP, TUSR-PKP provided at least equal results for OVCFs. Moreover, during the postsurgery observations, TUSR-PKP showed potential advantages including vertebral height gain, ODI improvement, and fewer subsequent refractures. PMID- 26940827 TI - Effect of exercise on the auditory discrimination task in perimenopausal women: a preliminary study. AB - Background The climacteric phase of menopausal transition (perimenopause) is marked by reproductive hormone fluctuations and reduced cognitive capacity. Exercise enhances neurocognitive performance. However, auditory perceptual sensitivity has not been examined. Purpose This study aimed to determine the effect of aerobic exercise on the response speed (reaction time) and error rate during auditory processing among perimenopausal women. Methods Three pitches (500, 1000, and 2000 Hz) were used during a simple auditory discrimination task, which was performed before and after exercise. We included 14 perimenopausal women and 17 right-handed young women (aged 46-54 years and 18-22 years, respectively). To achieve similar exercise intensity in both groups, we proposed two types of physical activities for each group. Mixed models statistics were used to analyze the reaction time and error rate before and after training in the two groups. Results Perimenopausal women exhibited a significantly longer reaction time than young women during the baseline auditory discrimination task (p < 0.05) but not during the second test. The error rate decreased significantly after exercise among perimenopausal women (p < 0.05) but not among young women. Thus, exercise had a stronger beneficial influence on auditory plasticity or sensitivity for perimenopausal women than for young women. Conclusion The ability of aerobic exercise to modulate auditory neurocognitive performance differs between the two groups. Aerobic exercise improves auditory discrimination performance specifically for perimenopausal women. These results provide preliminary evidence concerning the acoustic features of middle-aged women, underscoring the importance of exercise for preventing decline in auditory cognitive function in perimenopausal women. PMID- 26940826 TI - Which sets of elementary flux modes form thermodynamically feasible flux distributions? AB - Elementary flux modes (EFMs) are non-decomposable steady-state fluxes through metabolic networks. Every possible flux through a network can be described as a superposition of EFMs. The definition of EFMs is based on the stoichiometry of the network, and it has been shown previously that not all EFMs are thermodynamically feasible. These infeasible EFMs cannot contribute to a biologically meaningful flux distribution. In this work, we show that a set of thermodynamically feasible EFMs need not be thermodynamically consistent. We use first principles of thermodynamics to define the feasibility of a flux distribution and present a method to compute the largest thermodynamically consistent sets (LTCSs) of EFMs. An LTCS contains the maximum number of EFMs that can be combined to form a thermodynamically feasible flux distribution. As a case study we analyze all LTCSs found in Escherichia coli when grown on glucose and show that only one LTCS shows the required phenotypical properties. Using our method, we find that in our E. coli model < 10% of all EFMs are thermodynamically relevant. PMID- 26940830 TI - [Announcement]. PMID- 26940828 TI - Production of an enzymatically active and immunogenic form of ectodomain of Porcine rubulavirus hemagglutinin-neuraminidase in the yeast Pichia pastoris. AB - Blue-eye disease (BED) of swine is a viral disease endemic in Mexico. The etiological agent is a paramyxovirus classified as Porcine rubulavirus (PoRV LPMV), which exhibits in its envelope the hemagglutinin-neuraminidase (HN) glycoprotein, the most immunogenic and a major target for vaccine development. We report in this study the obtaining of ectodomain of PoRV HN (eHN) through the Pichia pastoris expression system. The expression vector (pPICZalphaB-HN) was integrated by displacement into the yeast chromosome and resulted in a Mut(+) phenotype. Expressed eHN in the P. pastoris X33 strain was recovered from cell free medium, featuring up to 67 nmol/min/mg after 6 days of expression. eHN was recognized by the serum of infected pigs with strains currently circulating in the Mexican Bajio region. eHN induces antibodies in mice after 28 days of immunization with specific recognition in ELISA test. These antibodies were able to inhibit >80% replication by viral neutralization assays in cell culture. These studies show the obtaining of a protein with similar characteristics to the native HN and which may be a candidate to propose a vaccine or to use the antigen in a serologic diagnostic test. PMID- 26940829 TI - Factors associated with self-perceived burden to the primary caregiver in older patients with hematologic malignancies: an exploratory study. AB - OBJECTIVE: Although cancer patients frequently experience self-perceived burden to others, this perception has not been enough studied. The aim of this study was to investigate the prevalence of self-perceived burden to the primary caregiver (SPB-PC) and associated factors in an older patient population with hematologic malignancies at the time of chemotherapy initiation. METHODS: In total, 166 consecutive patients with hematologic malignancies aged >=65 years were recruited at the time of chemotherapy initiation. Patients' SPB-PC was assessed using a 100 mm visual analogue scale (VAS). Characteristics potentially associated with SPB PC, including sociodemographic and medical characteristics, physical functioning status (Karnofsky performance score, activities of daily living (ADL)/instrumental ADL), symptoms (fatigue, pain, nausea, quality of life), psychological distress (Hospital Anxiety and Depression Scale (HADS)), perceived cognitive function (Functional Assessment of Cancer Therapy Cognitive (FACT-Cog) Scale), and patients'/primary caregivers' personal relationship characteristics (family tie, support), were assessed. RESULTS: Thirty-five percent of patients reported moderate to severe SPB-PC (VAS >= 50 mm). Patients' SPB-PC was associated with lower Karnofsky performance (beta = -0.135, p = 0.058) and ADL (beta = -0.148, p = 0.037) scores, and higher HADS (beta = 0.283, p < 0.001) and FACT-Cog perceived cognitive impairments subscale (beta = 0.211, p = 0.004) scores. The proportion of explained variance was 23.5%. CONCLUSIONS: Health care professionals should be aware that about one third of older cancer patients experience moderate to severe SPB-PC at the time of chemotherapy initiation. They should adapt their support of patients who report such a feeling. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26940831 TI - Physiological function and ecological aspects of fatty acid-amino acid conjugates in insects. AB - In tritrophic interactions, plants recognize herbivore-produced elicitors and release a blend of volatile compounds (VOCs), which work as chemical cues for parasitoids or predators to locate their hosts. From detection of elicitors to VOC emissions, plants utilize sophisticated systems that resemble the plant microbe interaction system. Fatty acid-amino acid conjugates (FACs), a class of insect elicitors, resemble compounds synthesized by microbes in nature. Recent evidence suggests that the recognition of insect elicitors by an ancestral microbe-associated defense system may be the origin of tritrophic interactions mediated by FACs. Here we discuss our findings in light of how plants have customized this defense to be effective against insect herbivores, and how some insects have successfully adapted to these defenses. PMID- 26940832 TI - Involvement of EARLY BUD-BREAK, an AP2/ERF Transcription Factor Gene, in Bud Break in Japanese Pear (Pyrus pyrifolia Nakai) Lateral Flower Buds: Expression, Histone Modifications and Possible Target Genes. AB - In the Japanese pear (Pyrus pyrifolia Nakai) 'Kosui', three developmental stages of lateral flower buds have been proposed to occur during ecodormancy to the flowering phase, i.e. rapid enlargement, sprouting and flowering. Here, we report an APETALA2/ethylene-responsive factor (AP2/ERF) transcription factor gene, named pear EARLY BUD-BREAK (PpEBB), which was highly expressed during the rapid enlargement stage occurring prior to the onset of bud break in flower buds. Gene expression analysis revealed that PpEBB expression was dramatically increased during the rapid enlargement stage in three successive growing seasons. PpEBB transcript levels peaked 1 week prior to onset of bud break in 'Kosui' potted plants treated with hydrogen cyanamide or water under forcing conditions. Chromatin immunoprecipitation-quantitative PCR showed that higher levels of active histone modifications (trimethylation of the histone H3 tail at Lys4) in the 5'-upstream and start codon regions of the PpEBB gene were associated with the induced expression level of PpEBB during the rapid enlargement stage. In addition, we provide evidence that PpEBB may interact with and regulate pear four D-type cyclin (PpCYCD3) genes during bud break in 'Kosui' lateral flower buds. PpEBB significantly increased the promoter activities of four PpCYCD3 genes in a dual-luciferase assay using tobacco leaves. Taken together, our findings uncovered aspects of the bud break regulatory mechanism in the Japanese pear and provided further evidence that the EBB family plays an important role in bud break in perennial plants. PMID- 26940833 TI - Lack of improvement at week 2 predicts later antipsychotic non-response in people with acute exacerbations of schizophrenia or schizophrenia-like psychosis. PMID- 26940834 TI - How Well Is the Affordable Care Act Doing?: Reasons for Optimism. PMID- 26940835 TI - Effects of prenatal depressive symptoms on maternal and infant cortisol reactivity. AB - Prenatal depression is associated with adverse offspring outcomes, and the prevailing mechanistic theory to account for mood-associated effects implicates alterations of the maternal and foetal hypothalamic-pituitary adrenal (HPA) axes. Recent research suggests that depression may be associated with a failure to attenuate cortisol reactivity during early pregnancy. The aim of the current study is to investigate whether this effect continues into mid and late gestation. A further aim is to test whether maternal prenatal cortisol reactivity directly predicts infant cortisol reactivity. One hundred three pregnant women were recruited during either the second or third trimester. Depressive symptoms were assessed by self-report, and maternal salivary cortisol responses to a stressor (infant distress film) were measured. Approximately 2 months after birth, mothers (n = 88) reported postnatal depression and infant salivary cortisol responses to inoculation were measured. Prenatal depression was not associated with cortisol reactivity to acute stress in mid and late pregnancy. Similarly, neither prenatal depression nor maternal prenatal cortisol reactivity predicted infant cortisol reactivity to inoculation at 2 months. If the effects of prenatal depression on foetal and infant development are mediated by alterations of the maternal and foetal HPA axes, then early pregnancy may be a particularly vulnerable period. Alternatively, changes to HPA reactivity may not be as central to this association as previously thought. PMID- 26940836 TI - Stroke related to androgen deprivation therapy for prostate cancer: a meta analysis and systematic review. AB - BACKGROUND: Whether androgen deprivation therapy (ADT) leads to stroke morbidity is still unclear because of inconsistent evidence. We performed a systematic review and meta-analysis to evaluate if ADT used in men with prostate cancer (PCa) is associated with stroke. METHODS AND RESULTS: Medline, Embase and Cochrane Library databases up to September 30th 2014 were systematically searched with no date or language restriction, and reports from potentially relevant journals were complementally searched. Both randomized controlled trials and observational studies were included. Two reviewers independently extracted data and assessed study quality. Six observational studies finally met inclusion criteria, with 74,538 ADT users and 85,947 non-ADT users reporting stroke as an endpoint. Although no significant association was observed in pooled estimates, the incidence of stroke in ADT users was 12 % higher than control groups, (HR = 1.12, 95 % confidence interval [CI]: 0.95 to 1.32; P = 0.16). In subgroup analyses of different ADT types, stroke was found to be significantly associated with gonadotropin-releasing hormone (GnRH) alone (HR = 1.20, 95 % CI: 1.12 to 1.28; P < 0.001), GnRH plus oral antiandrogen (AA) (HR = 1.23, 95 % CI: 1.13 to 1.34; P < 0.001) and orchiectomy (HR = 1.37, 95 % CI: 1.33 to 1. 46; P = 0.001), but not with AA alone (HR = 1.06, 95 % CI: 0.71 to 1.57; P = 0.78). CONCLUSIONS: GnRH alone, GnRH plus AA and orchiectomy is significantly associated with stroke in patients with PCa. PMID- 26940837 TI - Pathogenesis of New Strains of Newcastle Disease Virus From Israel and Pakistan. AB - In the past few years, Newcastle disease virus (NDV) strains with epizootic characteristics belonging to subgenotypes VIIi and XIIIb emerged in the Middle East and Asia. In this study, 2 NDV strains-1 representative of subgenotype VIIi isolated in Israel (Kvuzat/13) and 1 representative of subgenotype XIIIb isolated in Pakistan (Karachi/07)-were characterized by intracerebral pathogenicity index and detailed clinicopathologic assessment. The intracerebral pathogenicity index values for Kvuzat/13 and Karachi/07 were 1.89 and 1.85, respectively, classifying these strains as virulent by international standards. In 4-week-old White Leghorn chickens, both strains caused 100% mortality within 4 (Kvuzat/13) and 5 (Karachi/07) days postinfection. Histopathology and immunohistochemistry for NDV nucleoprotein showed that both strains had wide systemic distribution, especially targeting lymphoid organs and mucosa-associated lymphoid tissues in the respiratory and intestinal tracts. Results of the animal experiment confirm that both Kvuzat/13 and Karachi/07 are highly virulent and behaved as velogenic viscerotropic NDV strains. PMID- 26940838 TI - High Numbers of Stromal Cancer-Associated Fibroblasts Are Associated With a Shorter Survival Time in Cats With Oral Squamous Cell Carcinoma. AB - Cancer-associated fibroblasts (CAFs) are fibroblastic cells that express alpha smooth muscle actin and have been identified in the stroma of numerous epithelial tumors. The presence of CAFs within the tumor stroma has been associated with a poorer prognosis in some human cancers, including oral squamous cell carcinomas (SCCs). Cats frequently develop oral SCCs, and although these are generally highly aggressive neoplasms, there is currently a lack of prognostic markers for these tumors. The authors investigated the prognostic value of the presence of CAFs within the stroma of oral SCC biopsy specimens from 47 cats. In addition, several epidemiologic, clinical, and histologic variables were also assessed for prognostic significance. A CAF-positive stroma was identified in 35 of 47 SCCs (74.5%), and the median survival time (ST) of cats with CAF-positive SCCs (35 days) was significantly shorter than that of cats with CAF-negative SCCs (48.5 days) (P = .031). ST was also associated with the location of the primary tumor (P = .0018): the median ST for oropharyngeal SCCs (179 days) was significantly longer than for maxillary (43.5 days; P = .047), mandibular (42 days; P = .022), and sublingual SCCs (22.5 days; P = .0005). The median ST of sublingual SCCs was also shorter compared with maxillary SCCs (P = .0017). Furthermore, a significant association was identified between site and the presence of stromal CAFs (P = .025). On the basis of this retrospective study, evaluating the tumor stroma for CAFs in feline oral SCC biopsy specimens may be of potential prognostic value. PMID- 26940839 TI - MiR-630 Inhibits Endothelial-Mesenchymal Transition by Targeting Slug in Traumatic Heterotopic Ossification. AB - Heterotopic ossification (HO) is the abnormal formation of mature bone in extraskeletal soft tissues that occurs as a result of inflammation caused by traumatic injury or associated with genetic mutation. Despite extensive research to identify the source of osteogenic progenitors, the cellular origins of HO are controversial and the underlying mechanisms, which are important for the early detection of HO, remain unclear. Here, we used in vitro and in vivo models of BMP4 and TGF-beta2-induced HO to identify the cellular origin and the mechanisms mediating the formation of ectopic bone in traumatic HO. Our results suggest an endothelial origin of ectopic bone in early phase of traumatic HO and indicate that the inhibition of endothelial-mesenchymal transition by miR-630 targeting Slug plays a role in the formation of ectopic bone in HO. A matched case-control study showed that miR-630 is specifically downregulated during the early stages of HO and can be used to distinguish HO from other processes leading to bone formation. Our findings suggest a potential mechanism of post-traumatic ectopic bone formation and identify miR-630 as a potential early indicator of HO. PMID- 26940841 TI - Rapidly increased vasopressin promotes acute platelet aggregation and early brain injury after experimental subarachnoid hemorrhage in a rat model. AB - OBJECTIVE: To investigate the dynamic expression of vasopressin and its potential role in rat brain tissue after experimental subarachnoid hemorrhage (SAH). METHODS: Male Sprague-Dawley rats were divided into 10min, 1h, 6h, 24h, 48h and 72h groups. The SAH model was established by endovascular puncture. ELISA and immunohistochemistry were performed to evaluate dynamic expression of vasopressin. Immunohistochemistry of GPIIb/IIIa integrin was used to assess platelet aggregation. Double immunofluorescence labeling was carried out to observe the reaction between vasopressin and platelet. Early brain injury was evaluated by apoptotic cells counting. Neurobehavioral score was performed to assess neuroprotective role of SR 49059 (a selective antagonists of vasopressin receptor). RESULTS: In peripheral blood and hypothalamus, vasopressin increased rapidly at 6h and 24h. Expression of GPIIb/IIIa integrin peaked at 24h in cortex and hippocampus. Immunofluorescence showed that vasopressin and GPIIb/IIIa integrin located at the same site. Administration of SR 49059 significantly decreased platelet aggregation and number of apoptotic cells. The neurobehavioral score was promoted significantly after the intervention. CONCLUSION: The results indicate that rapidly increased vasopressin could induce platelet aggregation and contribute to early brain injury after SAH. PMID- 26940843 TI - MIR376 family and cancer. AB - MicroRNAs (miRNAs) are endogenous non-coding small RNAs that negatively regulate gene expression at the post-transcriptional level. They have been implicated in several fundamental biological processes including development, differentiation, apoptosis and stem cell maintenance. There is increasing evidence that microRNAs also play roles in cellular transformation and carcinogenesis by acting either as tumor suppressors or oncogenes. Recent studies introduced MIR376 as an important microRNA family for cancer formation and progression. The MIR376 family is located on human chromosome 14 and it has several members containing identical or similar seed sequences. Biological roles of family members were studied in different cancer settings, including gliomas, leukemia, breast and ovarian cancers. Furthermore, two MIR376 family members, namely MIR376A and MIR376B were implicated in the regulation of macroautophagy (autophagy herein). Since autophagy dysregulation underlies various diseases including cancer, it is essential to understand the role of the MIR376 family in this context. In this article, we summarize the miRNA-cancer connection, and review accumulating data about the involvement of the MIR376 family in cancer biology. PMID- 26940842 TI - Nutrient pulses driven by internal solitary waves enhance heterotrophic bacterial growth in the South China Sea. AB - This study demonstrated the potential effects of internal waves (IWs) on heterotrophic bacterial activities for the first time. Nine anchored studies were conducted from 2009-2012 in the South China Sea areas with different physical conditions, i.e. areas subjected to elevation IWs, to depression IWs, and to weak/no IWs. The latter two areas were treated as the Control sites. Field survey results indicated that within the euphotic zone, the minima of the depth-averaged bacterial production (IBP; ~1.0 mgC m-3 d-1 ) and growth rate (IBMU; ~0.1 d-1 ) at all sites were similar. Except for one case, the maxima of IBP (6-12 mgC m-3 d 1 ) and IBMU (0.55-1.13 d-1 ) of the elevation IWs areas were ~fivefolds higher than those of the Control sites (IBP 1.7-2.1 mgC m-3 d-1 ; IBMU 0.13-0.24 d-1 ). Replicate surveys conducted at the north-western area of the Dongsha atoll during spring-to-neap (NW1 survey) and neap-to-spring (NW2 survey) tide periods showed a great contrast to each other. Low variation and averages of IBMU in NW1 survey were similar to those of the Control sites, while those in NW2 were similar to the other elevation IWs sites with larger variation and higher averages of IBMU. This finding suggests that bacterial activities may be a function of the lunar fortnightly (14-day) cycle. Enrichment experiments suggested more directly that the limiting inorganic nutrients introduced by the elevation waves (EIWs) may contribute a higher IBMU within the euphotic zone. PMID- 26940840 TI - Urinary bladder hypersensitivity and dysfunction in female mice following early life and adult stress. AB - Early adverse events have been shown to increase the incidence of interstitial cystitis/painful bladder syndrome in adulthood. Despite high clinical relevance and reports of stress-related symptom exacerbation, animal models investigating the contribution of early life stress to female urological pain are lacking. We examined the impact of neonatal maternal separation (NMS) on bladder sensitivity and visceral neuroimmune status both prior-to, and following, water avoidance stress (WAS) in adult female mice. The visceromotor response to urinary bladder distension was increased at baseline and 8d post-WAS in NMS mice, while colorectal sensitivity was transiently increased 1d post-WAS only in naive mice. Bladder micturition rate and output, but not fecal output, were also significantly increased following WAS in NMS mice. Changes in gene expression involved in regulating the stress response system were observed at baseline and following WAS in NMS mice, and WAS reduced serum corticosterone levels. Cytokine and growth factor mRNA levels in the bladder, and to a lesser extent in the colon, were significantly impacted by NMS and WAS. Peripheral mRNA levels of stress-responsive receptors were differentially influenced by early life and adult stress in bladder, but not colon, of naive and NMS mice. Histological evidence of mast cell degranulation was increased in NMS bladder, while protein levels of protease activated receptor 2 (PAR2) and transient receptor potential ankyrin 1 (TRPA1) were increased by WAS. Together, this study provides new insight into mechanisms contributing to stress associated symptom onset or exacerbation in patients exposed to early life stress. PMID- 26940844 TI - An overview on Sardinia's soft ticks (Ixodida: Argasidae). AB - Knowledge about soft ticks (Ixodida: Argasidae) in Sardinia is incomplete and distribution data need to be updated. This work studies soft ticks on the island focusing on two species, Argas reflexus and Ornithodoros maritimus, both recently recorded. A total number of 12 specimens of these species of interest were collected between 2004 and 2015. This study reports for the first time the presence of O. maritimus in a coastal area in Italy, and more generally in a coastal area rather than small islands near the coastline, confirming the presence of this species on the island 20 years after its last recording. Moreover we confirm the presence of A. reflexus on the island, in the town of Cagliari and, for the first time, in the town of Quartu Sant'Elena. At the present state of knowledge, in Sardinia, Ornithodoros erraticus, which was actively looked for within the surveillance for African swine fever, an endemic disease since 1978 on the island, is not present. The presence of another species reported only once in Sardinia, Argas vespertilionis, needs further confirmation. PMID- 26940845 TI - Is There a Consensus when Physicians Evaluate the Relevance of Retrieved Systematic Reviews? AB - BACKGROUND: A significant challenge associated with practicing evidence-based medicine is to provide physicians with relevant clinical information when it is needed. At the same time it appears that the notion of relevance is subjective and its perception is affected by a number of contextual factors. OBJECTIVES: To assess to what extent physicians agree on the relevance of evidence in the form of systematic reviews for a common set of patient cases, and to identify possible contextual factors that influence their perception of relevance. METHODS: A web based survey was used where pediatric emergency physicians from multiple academic centers across Canada were asked to evaluate the relevance of systematic reviews retrieved automatically for 14 written case vignettes (paper patients). The vignettes were derived from prospective data describing pediatric patients with asthma exacerbations presenting at the emergency department. To limit the cognitive burden on respondents, the number of reviews associated with each vignette was limited to three. RESULTS: Twenty-two academic emergency physicians with varying years of clinical practice completed the survey. There was no consensus in their evaluation of relevance of the retrieved reviews and physicians' assessments ranged from very relevant to irrelevant evidence, with the majority of evaluations being somewhere in the middle. This indicates that the study participants did not share a notion of relevance uniformly. Further analysis of commentaries provided by the physicians allowed identifying three possible contextual factors: expected specificity of evidence (acute vs chronic condition), the terminology used in the systematic reviews, and the micro environment of clinical setting. CONCLUSIONS: There is no consensus among physicians with regards to what constitutes relevant clinical evidence for a given patient case. Subsequently, this finding suggests that evidence retrieval systems should allow for deep customization with regards to physician's preferences and contextual factors, including differences in the micro environment of each clinical setting. PMID- 26940846 TI - Lutetium(III) acetate phthalocyanines for photodynamic therapy applications: Synthesis and photophysicochemical properties. AB - BACKGROUND: The development of new water-soluble photosensitizers for photodynamic therapy (PDT) applications is a very active research topic. Efforts have been made to obtain the far-red absorbing phthalocyanine complexes with molecular design that facilitates the uptake and selectivity for a high PDT efficiency. METHODS: The monomolecular lutetium(III) acetate phthalocyanines (LuPcs) substituted with methylpyridyloxy groups at non-peripheral (5) and peripheral (6) positions were synthesized by following the modification of the well-known synthetical routes. The photo-physicochemical properties of the both quaternized LuPcs were evaluated by the steady-state and time-resolved spectroscopy. The photochemical technique was applied to study the generation of the singlet oxygen. RESULTS: Two water-soluble and cationic LuPcs were synthesized and chemically characterized. The photo-physicochemical properties of absorption (675 and 685nm) and the red shifted fluorescence (704 and 721nm) as well as the fluorescence lifetimes (2.24 and 3.27ns) were studied. The promising values of singlet oxygen quantum yields (0.32 for 5 and 0.35 for 6) were determined. CONCLUSIONS: Lutetium(III) acetate phthalocyanine complexes were synthesized and evaluated with physicochemical properties suitable for future photodynamic therapy applications. PMID- 26940847 TI - Reversible control of current across lipid membranes by local heating. AB - Lipid membranes are almost impermeable for charged molecules and ions that can pass the membrane barrier only with the help of specialized transport proteins. Here, we report how temperature manipulation at the nanoscale can be employed to reversibly control the electrical resistance and the amount of current that flows through a bilayer membrane with pA resolution. For this experiment, heating is achieved by irradiating gold nanoparticles that are attached to the bilayer membrane with laser light at their plasmon resonance frequency. We found that controlling the temperature on the nanoscale renders it possible to reproducibly regulate the current across a phospholipid membrane and the membrane of living cells in absence of any ion channels. PMID- 26940849 TI - Variation in the Developmental and Morphological Interaction Between the Nasal Septum and Facial Skeleton. AB - While the nasal septum exerts a morphogenetic influence on the facial skeleton, there is evidence that this relationship is highly variable. To better appreciate the precise role of the septum, it is important understand the variable interaction between the septum and surrounding skeleton during ontogeny. Here we analyzed nasal septal and facial skeletal postnatal phenotypic variation using cross-sectional samples of C3H/HeJ and C57BL/6J mice. Initial observations indicated between-strain variation in the magnitude of septal deviation, suggesting differences in septal and facial skeletal interaction. We examined whether variation in septal deviation is due to ontogenetic differences in septal size, or whether variation in facial skeletal growth imposes spatial constraints on the septum. Using microCT we quantified septal size and deviation, and collected coordinate landmark data, which we analyzed using geometric morphometrics. C3H/HeJ mice were significantly more deviated than C57BL/6J during development. We found no differences in septal size between the two strains. However, while both strains exhibited an ontogenetic increase in snout length, C3H/HeJ mice exhibited a non-allometric reduction in nasal bone length. This appears to be influenced by between-strain variation in the spatial relationship between the nasal septum and nasofrontal suture. Unlike C57BL/6J mice, the C3H/HeJ nasal septum is positioned anterior to the nasofrontal suture potentially limiting an early direct influence of septal growth (e.g., through interstitial expansion) on sutural growth. Ultimately, our results underscore that while the septum is a key facial growth center, its precise influence on facial growth varies even in narrow morphological and taxonomic ranges. Anat Rec, 299:730-740, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26940848 TI - The Impact of Personality Factors and Preceding User Comments on the Processing of Research Findings on Deep Brain Stimulation: A Randomized Controlled Experiment in a Simulated Online Forum. AB - BACKGROUND: Laypeople frequently discuss medical research findings on Web-based platforms, but little is known about whether they grasp the tentativeness that is inherent in these findings. Potential influential factors involved in understanding medical tentativeness have hardly been assessed to date. OBJECTIVE: The research presented here aimed to examine the effects of personality factors and of other users' previous contributions in a Web-based forum on laypeople's understanding of the tentativeness of medical research findings, using the example of research on deep brain stimulation. METHODS: We presented 70 university students with an online news article that reported findings on applying deep brain stimulation as a novel therapeutic method for depression, which participants were unfamiliar with. In a randomized controlled experiment, we manipulated the forum such that the article was either accompanied by user comments that addressed the issue of tentativeness, by comments that did not address this issue, or the article was accompanied by no comments at all. Participants were instructed to write their own individual user comments. Their scientific literacy, epistemological beliefs, and academic self-efficacy were measured. The outcomes measured were perceived tentativeness and tentativeness addressed in the participants' own comments. RESULTS: More sophisticated epistemological beliefs enhanced the perception of tentativeness (standardized beta=.26, P=.034). Greater scientific literacy (stand. beta=.25, P=.025) and greater academic self-efficacy (stand. beta=.31, P=.007) were both predictors of a more extensive discussion of tentativeness in participants' comments. When forum posts presented in the experiment addressed the issue of tentativeness, participants' subsequent behavior tended to be consistent with what they had read in the forum, F2,63=3.66; P=.049, etap(2)=.092. CONCLUSIONS: Students' understanding of the tentativeness of research findings on deep brain stimulation in an online forum is influenced by a number of character traits and by the previous comments that were contributed to the forum by other users. There is potential for targeted modification of traits such as scientific literacy, epistemological beliefs, and academic self-efficacy to foster critical thinking in laypeople who take part in online discussions of medical research findings. PMID- 26940851 TI - Cerebral Venous Thrombosis and Polycythemia: a Potential Pitfall. PMID- 26940852 TI - Communal nesting under climate change: fitness consequences of higher incubation temperatures for a nocturnal lizard. AB - Communal nesting lizards may be vulnerable to climate warming, particularly if air temperatures regulate nest temperatures. In southeastern Australia, velvet geckos Oedura lesueurii lay eggs communally inside rock crevices. We investigated whether increases in air temperatures could elevate nest temperatures, and if so, how this could influence hatching phenotypes, survival, and population dynamics. In natural nests, maximum daily air temperature influenced mean and maximum daily nest temperatures, implying that nest temperatures will increase under climate warming. To determine whether hotter nests influence hatchling phenotypes, we incubated eggs under two fluctuating temperature regimes to mimic current 'cold' nests (mean = 23.2 degrees C, range 10-33 degrees C) and future 'hot' nests (27.0 degrees C, 14-37 degrees C). 'Hot' incubation temperatures produced smaller hatchlings than did cold temperature incubation. We released individually marked hatchlings into the wild in 2014 and 2015, and monitored their survival over 10 months. In 2014 and 2015, hot-incubated hatchlings had higher annual mortality (99%, 97%) than cold-incubated (11%, 58%) or wild-born hatchlings (78%, 22%). To determine future trajectories of velvet gecko populations under climate warming, we ran population viability analyses in Vortex and varied annual rates of hatchling mortality within the range 78- 96%. Hatchling mortality strongly influenced the probability of extinction and the mean time to extinction. When hatchling mortality was >86%, populations had a higher probability of extinction (PE: range 0.52- 1.0) with mean times to extinction of 18-44 years. Whether future changes in hatchling survival translate into reduced population viability will depend on the ability of females to modify their nest-site choices. Over the period 1992-2015, females used the same communal nests annually, suggesting that there may be little plasticity in maternal nest-site selection. The impacts of climate change may therefore be especially severe on communal nesting species, particularly if such species occupy thermally challenging environments. PMID- 26940850 TI - The mechanistic bases of the power-time relationship: muscle metabolic responses and relationships to muscle fibre type. AB - KEY POINTS: The power-asymptote (critical power; CP) of the hyperbolic power-time relationship for high-intensity exercise defines a threshold between steady-state and non-steady-state exercise intensities and the curvature constant (W') indicates a fixed capacity for work >CP that is related to a loss of muscular efficiency. The present study reports novel evidence on the muscle metabolic underpinnings of CP and W' during whole-body exercise and their relationships to muscle fibre type. We show that the W' is not correlated with muscle fibre type distribution and that it represents an elevated energy contribution from both oxidative and glycolytic/glycogenolytic metabolism. We show that there is a positive correlation between CP and highly oxidative type I muscle fibres and that muscle metabolic steady-state is attainable CP. Our findings indicate a mechanistic link between the bioenergetic characteristics of muscle fibre types and the power-time relationship for high-intensity exercise. ABSTRACT: We hypothesized that: (1) the critical power (CP) will represent a boundary separating steady-state from non-steady-state muscle metabolic responses during whole-body exercise and (2) that the CP and the curvature constant (W') of the power-time relationship for high-intensity exercise will be correlated with type I and type IIx muscle fibre distributions, respectively. Four men and four women performed a 3 min all-out cycling test for the estimation of CP and constant work rate (CWR) tests slightly >CP until exhaustion (Tlim ), slightly CP Tlim isotime to test the first hypothesis. Eleven men performed 3 min all-out tests and donated muscle biopsies to test the second hypothesis. Below CP, muscle [PCr] [42.6 +/- 7.1 vs. 49.4 +/- 6.9 mmol (kg d.w.)(-1) ], [La(-) ] [34.8 +/- 12.6 vs. 35.5 +/- 13.2 mmol (kg d.w.)(-1) ] and pH (7.11 +/- 0.08 vs. 7.10 +/- 0.11) remained stable between ~12 and 24 min (P > 0.05 for all), whereas these variables changed with time >CP such that they were greater [[La(-) ] 95.6 +/- 14.1 mmol (kg d.w.)(-1) ] and lower [[PCr] 24.2 +/- 3.9 mmol (kg d.w.)(-1) ; pH 6.84 +/- 0.06] (P < 0.05) at Tlim (740 +/- 186 s) than during the = 0.5 are studied using neutron diffraction with aerodynamic levitation and density functional theory molecular dynamics modelling. Simulated structure factors are found to be in good agreement with experimental structure factors. Local atomic structures from simulations reveal the role of calcium cations as a network modifier, and aluminium cations as a non-tetrahedral network former. Distributions of tetrahedral order show that an increasing concentration of the network former Al increases entropy, while an increasing concentration of the network modifier Ca decreases entropy. This trend is opposite to the conventional understanding that increasing amounts of network former should increase order in the network liquid, and so decrease entropy. The two-body correlation entropy S2 is found to not correlate with the excess entropy values obtained from thermochemical databases, while entropies including higher-order correlations such as tetrahedral order, O-M-O or M-O-M bond angles and Q(N) environments show a clear linear correlation between computed entropy and database excess entropy. The possible relationship between atomic structures and excess entropy is discussed. PMID- 26940853 TI - Relation between sensory analysis and rheology of body lotions. AB - OBJECTIVE: Evaluation of sensory attributes of cosmetic products is traditionally based on sensory panels. However, in some cases, a suitable candidate method that can reduce time and costs is the use of instrumental analysis that can detect relatively very small changes of entry ingredients. Such approach has been already applied for emollients, salt content, stabilizers, etc. The aim of this contribution is to apply the relations between sensory analysis and rheology to a series of body lotions differing in the contents of emulsifiers and viscosity regulators. METHODS: Sensory and rheological analyses are related. Rheological analysis can represent a good alternative to basic orientation in chosen customer's feelings. A rotational rheometer is the only instrumental device required for the measurements. RESULTS: An empirical rheological model was proposed by means of which the selected sensory attributes were evaluated using the numerical values of adjustable model parameters. This approach exhibited a very good agreement with the results obtained by the sensory panel. CONCLUSION: It was shown that a description of chosen sensory attributes can be responsibly carried out by rheological measurements, that is through the attained numerical values of the parameters appearing in a proposed empirical model characterizing shear viscosity of body lotions. PMID- 26940856 TI - Isorefractive high internal phase emulsion organogels for light induced reactions. AB - Isorefractive high internal phase emulsion (HIPE) organogels have been fabricated and investigated for light induced reactions. High transparency facilitates both the UV and visible light induced reactions within HIPE organogels. Transparent HIPE organogels are advantageous for light induced polymerizations, accelerating such polymerizations and enabling the preparation of large polyHIPE monoliths. PMID- 26940855 TI - The frequency of mucosal-associated invariant T cells is selectively increased in dermatitis herpetiformis. AB - BACKGROUND/OBJECTIVES: Mucosal-associated invariant T (MAIT) cells are a novel subset of innate-like T-cells that are enriched in mucosal tissues. Their presence in human skin has only recently been recognised. We describe the expression of skin-tropic molecules on human skin MAIT cells at steady state and investigate their contribution to various dermatoses with known T-cell involvement. METHODS: To examine the expression of skin-tropic molecules by MAIT cells at steady state, we performed a flow cytometric analysis of blood and skin samples from healthy donors. To investigate any potential wider contribution of MAIT cells to skin disease, we examined psoriasis, alopecia areata and dermatitis herpetiformis biopsies using immunofluorescent staining to identify the proportion of T-cells expressing MAIT cell surface markers. RESULTS: We found that MAIT cells constituted a small population of T-cells in normal human skin, similar to the percentage found in peripheral blood. Like other skin T-cells, skin MAIT cells expressed high levels of the skin-associated markers, cutaneous lymphocyte antigen and CD103. In psoriasis and alopecia areata the proportion of MAIT cells was similar to that found in normal skin, but in dermatitis herpetiformis it was significantly elevated. CONCLUSIONS: The expression of skin tropic molecules by skin MAIT cells is consistent with their resident status in normal human skin. Our results suggest that MAIT cells may play a role in the pathogenesis of dermatitis herpetiformis. PMID- 26940857 TI - Regioselective multistep reconstructions of half-saturated zigzag carbon nanotubes. AB - The open edge reconstruction of half-saturated (6,0) zigzag carbon nanotube (CNT) was introduced by density functional calculations. The multistep rearrangement was demonstrated as a regioselective process to generate a defective edge with alternating pentagons and heptagons. Not only the thermal stability was found to be enhanced significantly after reconstruction but also the total spin of CNT was proved to be reduced gradually from high-spin septet to close-shell singlet, revealing the critical role of deformed edge on the geometrical and magnetic properties of open-ended CNTs. Kinetically, the initial transformation was confirmed as the rate-determining step with relatively the largest reaction barrier and the following steps can take place spontaneously. (c) 2016 Wiley Periodicals, Inc. PMID- 26940858 TI - Do commencing nursing and paramedicine students differ in interprofessional learning and practice attitudes: evaluating course, socio-demographic and individual personality effects. AB - BACKGROUND: Interprofessional education (IPE) requires health students to learn with, from and about each other in order to develop a modern workforce with client-centred care at its core. Despite the client centred focus of IPE, training programs often utilize standard approaches across student cohorts without consideration of discipline, sociodemographic and personality variability that attract students to different health disciplines. Knowing the students who engage in IPE to tailor training may prove as beneficial as knowing the client to delivered individualized client centred care in interprofessional practice (IPP). This research investigates whether students commencing undergraduate nursing and paramedicine degrees ener training with existing demographic and personality differences and, if these are associated with different attitudes towards health care teams and interprofessional education. METHOD: This online study recruited 160 nursing and 50 paramedicine students in their first week of their undergraduate course. Students completed questionnaires regarding their background, personality (General Perceived Self Esteem Scale, International Mini Markers) and the attitudes towards health care teams scale (ATHCTS) and interprofessional education perception scale (IEPS). RESULTS: Results show that commencing nursing and paramedicine students are demographically different on education, gender, speaking a language other than English at home (LOTE) and their own experience with healthcare. The results further demonstrate that LOTE, discipline being studied and personality factors play a role in perceptions regarding interprofessional training whilst discipline being studied impacted on attitudes towards health care teams in the workforce. CONCLUSION: These results highlight a number of existing personal and psychological differences between individuals who choose to train in these selected professions. This suggests a need for tertiary education IPE programs to move towards tailoring their education to value this student diversity in the same client centred manner that students are asked to develop clinically. PMID- 26940859 TI - Beyond Neglect: Preliminary Evidence of Retrospective Time Estimation Abnormalities in Non-Neglect Stroke and Transient Ischemic Attack Patients. AB - Perception of the passage of time is essential for safe planning and navigation of everyday activities. Findings from the literature have demonstrated a gross underestimation of time interval in right-hemisphere damaged neglect patients, but not in non-neglect unilaterally-damaged patients, compared to controls. This study aimed to investigate retrospective estimation of the duration of a target detection task over two occasions, in 30 stroke patients (12 left-side stroke 15 right-side stroke, and 3 right-side stroke with neglect) and 10 transient ischemic attack patients, relative to 31 age-matched controls. Performances on visual short-term and working memory tasks were also examined to investigate the associations between timing abilities with residual cognitive functioning. Initial results revealed evidence of perceptual time underestimation, not just in neglect patients, but also in non-neglect unilaterally-damaged stroke patients and transient ischemic attack patients. Three months later, underestimation of time persisted only in left-side stroke and right-side stroke with neglect patients, who also demonstrated reduced short-term and working memory abilities. Findings from this study suggest a predictive role of residual cognitive impairments in determining the prognosis of perceptual timing abnormalities. PMID- 26940861 TI - Field-free magnetization reversal by spin-Hall effect and exchange bias. AB - As the first magnetic random access memories are finding their way onto the market, an important issue remains to be solved: the current density required to write magnetic bits becomes prohibitively high as bit dimensions are reduced. Recently, spin-orbit torques and the spin-Hall effect in particular have attracted significant interest, as they enable magnetization reversal without high current densities running through the tunnel barrier. For perpendicularly magnetized layers, however, the technological implementation of the spin-Hall effect is hampered by the necessity of an in-plane magnetic field for deterministic switching. Here we interface a thin ferromagnetic layer with an anti-ferromagnetic material. An in-plane exchange bias is created and shown to enable field-free S HE-driven magnetization reversal of a perpendicularly magnetized Pt/Co/IrMn structure. Aside from the potential technological implications, our experiment provides additional insight into the local spin structure at the ferromagnetic/anti-ferromagnetic interface. PMID- 26940860 TI - A continuous sirtuin activity assay without any coupling to enzymatic or chemical reactions. AB - Sirtuins are NAD(+) dependent lysine deacylases involved in many regulatory processes such as control of metabolic pathways, DNA repair and stress response. Modulators of sirtuin activity are required as tools for uncovering the biological function of these enzymes and as potential therapeutic agents. Systematic discovery of such modulators is hampered by the lack of direct and continuous activity assays. The present study describes a novel continuous assay based on the increase of a fluorescence signal subsequent to sirtuin mediated removal of a fluorescent acyl chain from a modified TNFalpha-derived peptide. This substrate is well recognized by human sirtuins 1-6 and represents the best sirtuin 2 substrate described so far with a kcat/KM-value of 176 000 M(-1)s(-1). These extraordinary substrate properties allow the first determination of Ki values for the specific Sirt2 inhibitory peptide S2iL5 (600 nM) and for the quasi universal sirtuin inhibitor peptide thioxo myristoyl TNFalpha (80 nM). PMID- 26940863 TI - Complete genome of Staphylococcus aureus Tager 104 provides evidence of its relation to modern systemic hospital-acquired strains. AB - BACKGROUND: Staphylococcus aureus (S. aureus) infections range in severity due to expression of certain virulence factors encoded on mobile genetic elements (MGE). As such, characterization of these MGE, as well as single nucleotide polymorphisms, is of high clinical and microbiological importance. To understand the evolution of these dangerous pathogens, it is paramount to define reference strains that may predate MGE acquisition. One such candidate is S. aureus Tager 104, a previously uncharacterized strain isolated from a patient with impetigo in 1947. RESULTS: We show here that S. aureus Tager 104 can survive in the bloodstream and infect naive organs. We also demonstrate a procedure to construct and validate the assembly of S. aureus genomes, using Tager 104 as a proof-of concept. In so doing, we bridged confounding gap regions that limited our initial attempts to close this 2.82 Mb genome, through integration of data from Illumina Nextera paired-end, PacBio RS, and Lucigen NxSeq mate-pair libraries. Furthermore, we provide independent confirmation of our segmental arrangement of the Tager 104 genome by the sole use of Lucigen NxSeq libraries filled by paired end MiSeq reads and alignment with SPAdes software. Genomic analysis of Tager 104 revealed limited MGE, and a nuSabeta island configuration that is reminiscent of other hospital acquired S. aureus genomes. CONCLUSIONS: Tager 104 represents an early-branching ancestor of certain hospital-acquired strains. Combined with its earlier isolation date and limited content of MGE, Tager 104 can serve as a viable reference for future comparative genome studies. PMID- 26940862 TI - The Notch Intracellular Domain Has an RBPj-Independent Role during Mouse Hair Follicular Development. AB - Ligand-dependent activation, gamma-secretase-processed cleavage, and recombining binding protein Jk (RBPj)-mediated downstream transcriptional activities of Notch receptors constitute the "canonical" Notch signaling pathway, which is essential for skin organogenesis. However, in Msx2-Cre mice, keratinocyte-specific deletion of the Rbpj gene in utero produced a significantly milder phenotype than either global Notch or gamma-secretase loss. Herein, we investigated the underlying mechanisms for this apparent noncanonical signal using mouse genetics. We found no evidence that ligand back-signaling contributed to skin organogenesis. The perdurance of RBPj protein did not establish an epigenetic memory of a canonical signal in the youngest epidermal stem cells, and Notch targets were not derepressed. We provide evidence that gamma-secretase-dependent but RBPj independent Notch intracellular domain activity operating in the first hair follicles is responsible for a delay in follicular destruction, which results in lower serum thymic stromal lymphopoietin levels, milder B-cell lymphoproliferative disease, and improved survival in Msx2-Cre(+/tg);Rbpj(f/f) mice. Minimal amounts of the Notch intracellular domain were sufficient for rescue, which was not mediated by transcription, suggesting that the Notch intracellular domain is acting through a novel mechanism. PMID- 26940864 TI - Liothyronine use in a 17 year observational population-based study - the tears study. AB - OBJECTIVE: To look at adverse outcomes for patients on liothyronine compared to l thyroxine. Some trials have examined the relative merits of liothyronine but none have looked at adverse outcomes in large numbers. STUDY DESIGN: An observational study of all patients prescribed thyroid hormone replacement in Tayside Scotland (population 400 000) from 1997 to 2014. PATIENTS: A study group of patients having ever used liothyronine (n = 400) was compared to those who had only used l thyroxine (n = 33 955). All patients were followed up until end-point, death or leaving Tayside. MEASUREMENTS: Mortality rates and admissions with cardiovascular disease, atrial fibrillation, fractures, breast cancer and mental diseases were compared. Incident use of bisphosphonates, statins, antidepressants and antipsychotics was compared. RESULTS: Compared to patients only taking l thyroxine, those using liothyronine had no increased risk of cardiovascular disease [hazard ratio (HR) 1.04; 95% CI 0.70-1.54], atrial fibrillation (HR 0.91: 0.47-1.75), or fractures (HR 0.79: 0.49-1.27) after adjusting for age. There was no difference in the number of prescriptions for bisphosphonates or statins. There was an increased risk of new prescriptions for antipsychotic medication (HR 2.26: 1.64-3.11 P < 0.0001) which was proportional to the number of liothyronine prescriptions. There was a non-significant trend towards an increase in breast cancer and new use of antidepressant medications. During follow-up, median TSH was higher for patients on l-thyroxine alone (2.08 vs 1.07 mU/L; P < 0.001). CONCLUSION: For patients taking long-term liothyronine we did not identify any additional risk of atrial fibrillation, cardiovascular disease or fractures. There was an increased incident use of antipsychotic medication during follow-up. PMID- 26940865 TI - Evaluating replicability of laboratory experiments in economics. AB - The replicability of some scientific findings has recently been called into question. To contribute data about replicability in economics, we replicated 18 studies published in the American Economic Review and the Quarterly Journal of Economics between 2011 and 2014. All of these replications followed predefined analysis plans that were made publicly available beforehand, and they all have a statistical power of at least 90% to detect the original effect size at the 5% significance level. We found a significant effect in the same direction as in the original study for 11 replications (61%); on average, the replicated effect size is 66% of the original. The replicability rate varies between 67% and 78% for four additional replicability indicators, including a prediction market measure of peer beliefs. PMID- 26940867 TI - Activation of proto-oncogenes by disruption of chromosome neighborhoods. AB - Oncogenes are activated through well-known chromosomal alterations such as gene fusion, translocation, and focal amplification. In light of recent evidence that the control of key genes depends on chromosome structures called insulated neighborhoods, we investigated whether proto-oncogenes occur within these structures and whether oncogene activation can occur via disruption of insulated neighborhood boundaries in cancer cells. We mapped insulated neighborhoods in T cell acute lymphoblastic leukemia (T-ALL) and found that tumor cell genomes contain recurrent microdeletions that eliminate the boundary sites of insulated neighborhoods containing prominent T-ALL proto-oncogenes. Perturbation of such boundaries in nonmalignant cells was sufficient to activate proto-oncogenes. Mutations affecting chromosome neighborhood boundaries were found in many types of cancer. Thus, oncogene activation can occur via genetic alterations that disrupt insulated neighborhoods in malignant cells. PMID- 26940866 TI - Health and population effects of rare gene knockouts in adult humans with related parents. AB - Examining complete gene knockouts within a viable organism can inform on gene function. We sequenced the exomes of 3222 British adults of Pakistani heritage with high parental relatedness, discovering 1111 rare-variant homozygous genotypes with predicted loss of function (knockouts) in 781 genes. We observed 13.7% fewer homozygous knockout genotypes than we expected, implying an average load of 1.6 recessive-lethal-equivalent loss-of-function (LOF) variants per adult. When genetic data were linked to the individuals' lifelong health records, we observed no significant relationship between gene knockouts and clinical consultation or prescription rate. In this data set, we identified a healthy PRDM9-knockout mother and performed phased genome sequencing on her, her child, and control individuals. Our results show that meiotic recombination sites are localized away from PRDM9-dependent hotspots. Thus, natural LOF variants inform on essential genetic loci and demonstrate PRDM9 redundancy in humans. PMID- 26940868 TI - Sequential transcriptional waves direct the differentiation of newborn neurons in the mouse neocortex. AB - During corticogenesis, excitatory neurons are born from progenitors located in the ventricular zone (VZ), from where they migrate to assemble into circuits. How neuronal identity is dynamically specified upon progenitor division is unknown. Here, we study this process using a high-temporal-resolution technology allowing fluorescent tagging of isochronic cohorts of newborn VZ cells. By combining this in vivo approach with single-cell transcriptomics in mice, we identify and functionally characterize neuron-specific primordial transcriptional programs as they dynamically unfold. Our results reveal early transcriptional waves that instruct the sequence and pace of neuronal differentiation events, guiding newborn neurons toward their final fate, and contribute to a road map for the reverse engineering of specific classes of cortical neurons from undifferentiated cells. PMID- 26940870 TI - Two Models of Integrating Buprenorphine Treatment and Medical Staff within Formerly "Drug-Free" Outpatient Programs. AB - "Drug-free" outpatient programs deliver treatment to the largest number of patients of all treatment modalities in the U.S., providing a significant opportunity to expand access to medication treatments for substance use disorders. This analysis examined staff perceptions of organizational dynamics associated with the delivery of buprenorphine maintenance within three formerly "drug-free" outpatient treatment programs. Semi-structured interviews (N = 15) were conducted with counseling and medical staff, and respondents were predominantly African American (n = 11) and female (n = 12). Themes and concepts related to medical staff integration emerged through an inductive and iterative coding process using Atlas.ti qualitative analysis software. Two treatment clinics incorporated buprenorphine maintenance into their programs using a co located model of care. Their staff generally reported greater intra organizational discord regarding the best ways to combine medication and counseling compared to the clinic using an integrated model of care. Co-located program staff reported less communication between medical and clinical staff, which contributed to some uncertainty about proper dosing and concerns about the potential for medication diversion. Clinics that shift from "drug-free" to incorporating buprenorphine maintenance should consider which model of care they wish to adapt and how to train staff and structure staff communication. PMID- 26940871 TI - Disaster Radio for Communication of Vital Messages and Health-Related Information: Experiences From the Haiyan Typhoon, the Philippines. AB - OBJECTIVE: Crisis communication is seen as an integrated and essential part of disaster management measures. After Typhoon Haiyan (Yolanda) in the Philippines 2013, radio was used to broadcast information to the affected community. The aim of this study was to describe how disaster radio was used to communicate vital messages and health-related information to the public in one affected region after Typhoon Haiyan. METHODS: Mixed-methods analysis using qualitative content analysis and descriptive statistics was used to analyze 2587 logged radio log files. RESULTS: Radio was used to give general information and to demonstrate the capability of officials to manage the situation, to encourage, to promote recovery and foster a sense of hope, and to give practical advice and encourage self-activity. The content and focus of the messages changed over time. Encouraging messages were the most frequently broadcast messages. Health-related messages were a minor part of all information broadcast and gaps in the broadcast over time were found. CONCLUSION: Disaster radio can serve as a transmitter of vital messages including health-related information and psychological support in disaster areas. The present study indicated the potential for increased use. The perception, impact, and use of disaster radio need to be further evaluated. (Disaster Med Public Health Preparedness. 2016;10:591-597). PMID- 26940869 TI - Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. AB - As tumors grow, they acquire mutations, some of which create neoantigens that influence the response of patients to immune checkpoint inhibitors. We explored the impact of neoantigen intratumor heterogeneity (ITH) on antitumor immunity. Through integrated analysis of ITH and neoantigen burden, we demonstrate a relationship between clonal neoantigen burden and overall survival in primary lung adenocarcinomas. CD8(+)tumor-infiltrating lymphocytes reactive to clonal neoantigens were identified in early-stage non-small cell lung cancer and expressed high levels of PD-1. Sensitivity to PD-1 and CTLA-4 blockade in patients with advanced NSCLC and melanoma was enhanced in tumors enriched for clonal neoantigens. T cells recognizing clonal neoantigens were detectable in patients with durable clinical benefit. Cytotoxic chemotherapy-induced subclonal neoantigens, contributing to an increased mutational load, were enriched in certain poor responders. These data suggest that neoantigen heterogeneity may influence immune surveillance and support therapeutic developments targeting clonal neoantigens. PMID- 26940872 TI - Structural and Biochemical Characterization of the Early and Late Enzymes in the Lignin beta-Aryl Ether Cleavage Pathway from Sphingobium sp. SYK-6. AB - There has been great progress in the development of technology for the conversion of lignocellulosic biomass to sugars and subsequent fermentation to fuels. However, plant lignin remains an untapped source of materials for production of fuels or high value chemicals. Biological cleavage of lignin has been well characterized in fungi, in which enzymes that create free radical intermediates are used to degrade this material. In contrast, a catabolic pathway for the stereospecific cleavage of beta-aryl ether units that are found in lignin has been identified in Sphingobium sp. SYK-6 bacteria. beta-Aryl ether units are typically abundant in lignin, corresponding to 50-70% of all of the intermonomer linkages. Consequently, a comprehensive understanding of enzymatic beta-aryl ether (beta-ether) cleavage is important for future efforts to biologically process lignin and its breakdown products. The crystal structures and biochemical characterization of the NAD-dependent dehydrogenases (LigD, LigO, and LigL) and the glutathione-dependent lyase LigG provide new insights into the early and late enzymes in the beta-ether degradation pathway. We present detailed information on the cofactor and substrate binding sites and on the catalytic mechanisms of these enzymes, comparing them with other known members of their respective families. Information on the Lig enzymes provides new insight into their catalysis mechanisms and can inform future strategies for using aromatic oligomers derived from plant lignin as a source of valuable aromatic compounds for biofuels and other bioproducts. PMID- 26940873 TI - Analysis of Oligomerization Properties of Heme a Synthase Provides Insights into Its Function in Eukaryotes. AB - Heme a is an essential cofactor for function of cytochrome c oxidase in the mitochondrial electron transport chain. Several evolutionarily conserved enzymes have been implicated in the biosynthesis of heme a, including the heme a synthase Cox15. However, the structure of Cox15 is unknown, its enzymatic mechanism and the role of active site residues remain debated, and recent discoveries suggest additional chaperone-like roles for this enzyme. Here, we investigated Cox15 in the model eukaryote Saccharomyces cerevisiae via several approaches to examine its oligomeric states and determine the effects of active site and human pathogenic mutations. Our results indicate that Cox15 exhibits homotypic interactions, forming highly stable complexes dependent upon hydrophobic interactions. This multimerization is evolutionarily conserved and independent of heme levels and heme a synthase catalytic activity. Four conserved histidine residues are demonstrated to be critical for eukaryotic heme a synthase activity and cannot be substituted with other heme-ligating amino acids. The 20-residue linker region connecting the two conserved domains of Cox15 is also important; removal of this linker impairs both Cox15 multimerization and enzymatic activity. Mutations of COX15 causing single amino acid conversions associated with fatal infantile hypertrophic cardiomyopathy and the neurological disorder Leigh syndrome result in impaired stability (S344P) or catalytic function (R217W), and the latter mutation affects oligomeric properties of the enzyme. Structural modeling of Cox15 suggests these two mutations affect protein folding and heme binding, respectively. We conclude that Cox15 multimerization is important for heme a biosynthesis and/or transfer to maturing cytochrome c oxidase. PMID- 26940874 TI - Crystal Structure and Activity Studies of the C11 Cysteine Peptidase from Parabacteroides merdae in the Human Gut Microbiome. AB - Clan CD cysteine peptidases, a structurally related group of peptidases that include mammalian caspases, exhibit a wide range of important functions, along with a variety of specificities and activation mechanisms. However, for the clostripain family (denoted C11), little is currently known. Here, we describe the first crystal structure of a C11 protein from the human gut bacterium, Parabacteroides merdae (PmC11), determined to 1.7-A resolution. PmC11 is a monomeric cysteine peptidase that comprises an extended caspase-like alpha/beta/alpha sandwich and an unusual C-terminal domain. It shares core structural elements with clan CD cysteine peptidases but otherwise structurally differs from the other families in the clan. These studies also revealed a well ordered break in the polypeptide chain at Lys(147), resulting in a large conformational rearrangement close to the active site. Biochemical and kinetic analysis revealed Lys(147) to be an intramolecular processing site at which cleavage is required for full activation of the enzyme, suggesting an autoinhibitory mechanism for self-preservation. PmC11 has an acidic binding pocket and a preference for basic substrates, and accepts substrates with Arg and Lys in P1 and does not require Ca(2+) for activity. Collectively, these data provide insights into the mechanism and activity of PmC11 and a detailed framework for studies on C11 peptidases from other phylogenetic kingdoms. PMID- 26940875 TI - PNT1 Is a C11 Cysteine Peptidase Essential for Replication of the Trypanosome Kinetoplast. AB - The structure of a C11 peptidase PmC11 from the gut bacterium, Parabacteroides merdae, has recently been determined, enabling the identification and characterization of a C11 orthologue, PNT1, in the parasitic protozoon Trypanosoma brucei. A phylogenetic analysis identified PmC11 orthologues in bacteria, archaea, Chromerids, Coccidia, and Kinetoplastida, the latter being the most divergent. A primary sequence alignment of PNT1 with clostripain and PmC11 revealed the position of the characteristic His-Cys catalytic dyad (His(99) and Cys(136)), and an Asp (Asp(134)) in the potential S1 binding site. Immunofluorescence and cryoelectron microscopy revealed that PNT1 localizes to the kinetoplast, an organelle containing the mitochondrial genome of the parasite (kDNA), with an accumulation of the protein at or near the antipodal sites. Depletion of PNT1 by RNAi in the T. brucei bloodstream form was lethal both in in vitro culture and in vivo in mice and the induced population accumulated cells lacking a kinetoplast. In contrast, overexpression of PNT1 led to cells having mislocated kinetoplasts. RNAi depletion of PNT1 in a kDNA independent cell line resulted in kinetoplast loss but was viable, indicating that PNT1 is required exclusively for kinetoplast maintenance. Expression of a recoded wild-type PNT1 allele, but not of an active site mutant restored parasite viability after induction in vitro and in vivo confirming that the peptidase activity of PNT1 is essential for parasite survival. These data provide evidence that PNT1 is a cysteine peptidase that is required exclusively for maintenance of the trypanosome kinetoplast. PMID- 26940876 TI - Preconditioning c-Kit-positive Human Cardiac Stem Cells with a Nitric Oxide Donor Enhances Cell Survival through Activation of Survival Signaling Pathways. AB - Cardiac stem cell therapy has shown very promising potential to repair the infarcted heart but is severely limited by the poor survival of donor cells. Nitric oxide (NO) has demonstrated cytoprotective properties in various cells, but its benefits are unknown specifically for human cardiac stem cells (hCSCs). Therefore, we investigated whether pretreatment of hCSCs with a widely used NO donor, diethylenetriamine nitric oxide adduct (DETA-NO), promotes cell survival. Results from lactate dehydrogenase release assays showed a dose- and time dependent attenuation of cell death induced by oxidative stress after DETA-NO preconditioning; this cytoprotective effect was abolished by the NO scavenger. Concomitant up-regulation of several cell signaling molecules after DETA-NO preconditioning was observed by Western blotting, including elevated phosphorylation of NRF2, NFkappaB, STAT3, ERK, and AKT, as well as increased protein expression of HO-1 and COX2. Furthermore, pharmaceutical inhibition of ERK, STAT3, and NFkappaB activities significantly diminished NO-induced cytoprotection against oxidative stress, whereas inhibition of AKT or knockdown of NRF2 only produced a minor effect. Blocking PI3K activity or knocking down COX2 expression did not alter the protective effect of DETA-NO on cell survival. The crucial roles of STAT3 and NFkappaB in NO-mediated signaling pathways were further confirmed by stable expression of gene-specific shRNAs in hCSCs. Thus, preconditioning hCSCs with DETA-NO promotes cell survival and resistance to oxidative stress by activating multiple cell survival signaling pathways. These results will potentially provide a simple and effective strategy to enhance survival of hCSCs after transplantation and increase their efficacy in repairing infarcted myocardium. PMID- 26940877 TI - Perchlorate Reductase Is Distinguished by Active Site Aromatic Gate Residues. AB - Perchlorate is an important ion on both Earth and Mars. Perchlorate reductase (PcrAB), a specialized member of the dimethylsulfoxide reductase superfamily, catalyzes the first step of microbial perchlorate respiration, but little is known about the biochemistry, specificity, structure, and mechanism of PcrAB. Here we characterize the biophysics and phylogeny of this enzyme and report the 1.86-A resolution PcrAB complex crystal structure. Biochemical analysis revealed a relatively high perchlorate affinity (Km = 6 MUm) and a characteristic substrate inhibition compared with the highly similar respiratory nitrate reductase NarGHI, which has a relatively much lower affinity for perchlorate (Km = 1.1 mm) and no substrate inhibition. Structural analysis of oxidized and reduced PcrAB with and without the substrate analog SeO3 (2-) bound to the active site identified key residues in the positively charged and funnel-shaped substrate access tunnel that gated substrate entrance and product release while trapping transiently produced chlorate. The structures suggest gating was associated with shifts of a Phe residue between open and closed conformations plus an Asp residue carboxylate shift between monodentate and bidentate coordination to the active site molybdenum atom. Taken together, structural and mutational analyses of gate residues suggest key roles of these gate residues for substrate entrance and product release. Our combined results provide the first detailed structural insight into the mechanism of biological perchlorate reduction, a critical component of the chlorine redox cycle on Earth. PMID- 26940878 TI - ATR Kinase Inhibition Protects Non-cycling Cells from the Lethal Effects of DNA Damage and Transcription Stress. AB - ATR (ataxia telangiectasia and Rad-3-related) is a protein kinase that maintains genome stability and halts cell cycle phase transitions in response to DNA lesions that block DNA polymerase movement. These DNA replication-associated features of ATR function have led to the emergence of ATR kinase inhibitors as potential adjuvants for DNA-damaging cancer chemotherapeutics. However, whether ATR affects the genotoxic stress response in non-replicating, non-cycling cells is currently unknown. We therefore used chemical inhibition of ATR kinase activity to examine the role of ATR in quiescent human cells. Although ATR inhibition had no obvious effects on the viability of non-cycling cells, inhibition of ATR partially protected non-replicating cells from the lethal effects of UV and UV mimetics. Analyses of various DNA damage response signaling pathways demonstrated that ATR inhibition reduced the activation of apoptotic signaling by these agents in non-cycling cells. The pro-apoptosis/cell death function of ATR is likely due to transcription stress because the lethal effects of compounds that block RNA polymerase movement were reduced in the presence of an ATR inhibitor. These results therefore suggest that whereas DNA polymerase stalling at DNA lesions activates ATR to protect cell viability and prevent apoptosis, the stalling of RNA polymerases instead activates ATR to induce an apoptotic form of cell death in non-cycling cells. These results have important implications regarding the use of ATR inhibitors in cancer chemotherapy regimens. PMID- 26940879 TI - Severe mitochondrial damage associated with low-dose radiation sensitivity in ATM and NBS1-deficient cells. AB - Low-dose radiation risks remain unclear owing to a lack of sufficient studies. We previously reported that low-dose, long-term fractionated radiation (FR) with 0.01 or 0.05 Gy/fraction for 31 d inflicts oxidative stress in human fibroblasts due to excess levels of mitochondrial reactive oxygen species (ROS). To identify the small effects of low-dose radiation, we investigated how mitochondria respond to low-dose radiation in radiosensitive human ataxia telangiectasia mutated (ATM) and Nijmegen breakage syndrome (NBS)1-deficient cell lines compared with corresponding cell lines expressing ATM and NBS1. Consistent with previous results in normal fibroblasts, low-dose, long-term FR increased mitochondrial mass and caused accumulation of mitochondrial ROS in ATM- and NBS1-complemented cell lines. Excess mitochondrial ROS resulted in mitochondrial damage that was in turn recognized by Parkin, leading to mitochondrial autophagy (mitophagy). In contrast, ATM- and NBS1-deficient cells showed defective induction of mitophagy after low-dose, long-term FR, leading to accumulation of abnormal mitochondria; this was determined by mitochondrial fragmentation and decreased mitochondrial membrane potential. Consequently, apoptosis was induced in ATM- and NBS1 deficient cells after low-dose, long-term FR. Antioxidant N-acetyl-L-cysteine was effective as a radioprotective agent against mitochondrial damage induced by low dose, long-term FR among all cell lines, including radiosensitive cell lines. In conclusion, we demonstrated that mitochondria are target organelles of low-dose radiation. Mitochondrial response influences radiation sensitivity in human cells. Our findings provide new insights into cancer risk estimation associated with low-dose radiation exposure. PMID- 26940880 TI - Interesting case of lymphocytosis and splenomegaly. PMID- 26940883 TI - Corrigendum: Chimera-like States in Modular Neural Networks. PMID- 26940882 TI - Estrogen-related receptor gamma is upregulated in liver cancer and its inhibition suppresses liver cancer cell proliferation via induction of p21 and p27. AB - Orphan nuclear receptor estrogen-related receptor gamma (ERRgamma) regulates cell growth and tumorigenesis in various cancers. However, the clinical relevance of ERRgamma to hepatocellular carcinoma (HCC) remains unclear. Here we examined the clinical significance of ERRgamma in HCC and its potential as a therapeutic target. ERRgamma levels in tissues from completely resected specimens from 190 HCC patients were examined immunohistochemically and their association with clinical stage and pathological grade was analyzed. Small interfering RNA (siRNA) mediated knockdown of ERRgamma (siRNA-ERRgamma) or an ERRgamma inverse agonist, GSK5182, were also used to examine the effects of ERRgamma inhibition on the proliferation and growth of a human hepatoma cell line, PLC/PRF/5. Immunohistochemical analysis revealed that tumor tissues showed higher levels of ERRgamma-positivity than adjacent non-tumor lesions. Tumors showing high levels of ERRgamma immunoreactivity also had advanced tumor node metastasis (TNM) and Barcelona Clinic Liver Cancer stages and a higher Edmondson-Steiner grade. In addition, high-level expression of ERRgamma in tumors of advanced TNM stage correlated with poorer overall survival. Treatment of PLC/PRF/5 cells with siRNA ERRgamma or GSK5182 inhibited proliferation through G1 arrest, increased expression of p21 and p27 and decreased expression of phosphorylated retinoblastoma protein. GSK5182-induced reactive oxygen species also suppressed the proliferation of PLC/PRF/5 cells. The present study showed that ERRgamma expression is clinically significant in HCC; therefore, it can be considered a biomarker for HCC diagnosis. Moreover, the results provide a rationale for the use of ERRgamma inhibitors such as GSK5182 as potential therapeutic agents. PMID- 26940881 TI - Insight On Colorectal Carcinoma Infiltration by Studying Perilesional Extracellular Matrix. AB - The extracellular matrix (ECM) from perilesional and colorectal carcinoma (CRC), but not healthy colon, sustains proliferation and invasion of tumor cells. We investigated the biochemical and physical diversity of ECM in pair-wised comparisons of healthy, perilesional and CRC specimens. Progressive linearization and degree of organization of fibrils was observed from healthy to perilesional and CRC ECM, and was associated with a steady increase of stiffness and collagen crosslinking. In the perilesional ECM these modifications coincided with increased vascularization, whereas in the neoplastic ECM they were associated with altered modulation of matrisome proteins, increased content of hydroxylated lysine and lysyl oxidase. This study identifies the increased stiffness and crosslinking of the perilesional ECM predisposing an environment suitable for CRC invasion as a phenomenon associated with vascularization. The increased stiffness of colon areas may represent a new predictive marker of desmoplastic region predisposing to invasion, thus offering new potential application for monitoring adenoma with invasive potential. PMID- 26940884 TI - Neurological sequelae of healthcare-associated sepsis in very-low-birthweight infants: Umbrella review and evidence-based outcome tree. AB - Sepsis is a frequent cause of death in very-low-birthweight infants and often results in neurological impairment. Its attributable risk of sequelae has not been systematically assessed. To establish an outcome tree for mapping the burden of neonatal sepsis, we performed systematic literature searches to identify systematic reviews addressing sequelae of neonatal sepsis. We included cohort studies and performed meta-analyses of attributable risks. Evidence quality was assessed using GRADE. Two systematic reviews met inclusion criteria. The first included nine cohort studies with 5,620 participants and five outcomes (neurodevelopmental impairment, cerebral palsy, vision impairment, hearing impairment, death). Pooled risk differences varied between 4% (95% confidence interval (CI):2-10) and 13% (95% CI:5-20). From the second review we analysed four studies with 472 infants. Positive predictive value of neurodevelopmental impairment for later cognitive impairment ranged between 67% (95% CI:22-96) and 83% (95% CI:36-100). Neonatal sepsis increases risk of permanent neurological impairment. Effect size varies by outcome, with evidence quality being low to very low. Data were used to construct an outcome tree for neonatal sepsis. Attributable risk estimates for sequelae following neonatal sepsis are suitable for burden estimation and may serve as outcome parameters in interventional studies. PMID- 26940885 TI - Prevalence and characteristics of fibromyalgia among HIV-positive patients in southern Israel. AB - OBJECTIVES: Fibromyalgia and chronic pain have previously associated with HIV infection for over two decades. We aimed to evaluate the prevalence of FMS symptoms in an ethnically heterogeneous population of HIV-infected individuals in southern Israel, applying the proposed new diagnostic criteria for diagnosis of fibromyalgia symdrome (FMS). METHODS: 156 HIV-positive patients followed at the AIDS clinic of the Soroka University Medical Center (SUMC) who gave written informed consent were recruited in the trial. FMS was diagnosed based on the widespread pain index (WPI) and the Symptom Severity Score (SSS) comprising the modified 2011 diagnostic criteria for FMS. CD4 levels ad viral load were obtained. RESULTS: One hundred and thirty-nine patients (89.1%) were receiving HAART (Highly Active Antiretroviral Therapy). A total of 22 patients (14.1%) were found to fulfill current criteria for diagnosis of FMS. FMS-criteria positive individuals were slightly younger than criteria-negative individuals (40.3+/-9.2 vs. 42.6+/-11.9, p=0.39), but this difference did not reach statistical significance. There was no significant difference between the groups regarding gender, family status, religion, occupation or education. No correlation was found between CD4 and viral load levels and symptoms of FMS. CONCLUSIONS: Despite the dramatic improvement in management of HIV, FMS symptoms remain highly prevalent among these patients and are not directly correlated with indices of active disease. FMS is an important clinical issue to address among patients suffering from HIV infection. PMID- 26940886 TI - Idiopathic Enlargement of the Extraocular Muscles in Young Patients: A Case Series. PMID- 26940888 TI - Use of Endoscopy to Strengthen a Diagnosis. PMID- 26940889 TI - A Picture Worth 250 Million Words (and Counting). PMID- 26940891 TI - A Postmortem Ocular Finding of Tache Noire in a Living Patient. PMID- 26940890 TI - Dynamic behavior of the post-SET loop region of NSD1: Implications for histone binding and drug development. AB - NSD1 is a SET-domain histone methyltransferase that methylates lysine 36 of histone 3. In the crystal structure of NSD1, the post-SET loop is in an autoinhibitory position that blocks binding of the histone peptide as well as the entrance to the lysine-binding channel. The conformational dynamics preceding histone binding and the mechanism by which the post-SET loop moves to accommodate the target lysine is currently unknown, although potential models have been proposed. Using molecular dynamics simulations, we have identified potential conformations of the post-SET loop differing from those of previous studies, as well as proposed a model of peptide-bound NSD1. Our simulations illustrate the dynamic behavior of the post-SET loop and the presence of a few distinct conformations. In every case, the post-SET loop remains in an autoinhibitory position blocking the peptide-binding cleft, suggesting that another interaction is required to optimally position NSD1 in an active conformation. This finding provides initial evidence for a mechanism by which NSD1 preferentially binds nucleosomal substrates. PMID- 26940893 TI - Reflection of the Physiochemical Characteristics of 1-(2-pyridylazo)-2-naphthol on the Pre-concentration of Trace Heavy Metals. AB - 1-(2-pyridylazo)-2-naphthol (PAN) is a heterocyclic azo compound that forms inner, mostly reddish colored, water-insoluble chelates with many transition metal ions with metal ion-ligand ratios of 1:1 or 1:2. PAN is rather unselective but it does not form complexes with the alkali and alkaline earth metals, Ge(IV), As, Se and Te. Numerous reported techniques of pre-concentration have been considered for analyzing the role of PAN on the physiochemical outcome of the procedures. PAN been used as a chelating precipitant, flocculant, auxiliary complexing agent, as a ligand for anchoring on other supports with the purpose of introducing chelating property as well as selectivity. The role of PAN in the different techniques of pre-concentration, namely co-precipitation, membrane filtration, micro-extraction, cloud point extraction and solid phase extraction, has been investigated. PAN influences the optimum experimental parameters, namely pH, temperature, time, amount, tolerance limit, etc. PMID- 26940892 TI - Sequential psychological and pharmacological therapies for comorbid and primary insomnia: study protocol for a randomized controlled trial. AB - BACKGROUND: Chronic insomnia is a prevalent disorder associated with significant psychosocial, health, and economic impacts. Cognitive behavioral therapies (CBTs) and benzodiazepine receptor agonist (BzRA) medications are the most widely supported therapeutic approaches for insomnia management. However, few investigations have directly compared their relative and combined benefits, and even fewer have tested the benefits of sequential treatment for those who do not respond to initial insomnia therapy. Moreover, insomnia treatment studies have been limited by small, highly screened study samples, fixed-dose, and fixed-agent pharmacotherapy strategies that do not represent usual clinical practices. This study will address these limitations. METHODS/DESIGN: This is a two-site randomized controlled trial, which will enroll 224 adults who meet the criteria for a chronic insomnia disorder with or without comorbid psychiatric disorders. Prospective participants will complete clinical assessments and polysomnography and then will be randomly assigned to first-stage therapy involving either behavioral therapy (BT) or zolpidem. Treatment outcomes will be assessed after 6 weeks, and treatment remitters will be followed for the next 12 months on maintenance therapy. Those not achieving remission will be offered randomization to a second, 6-week treatment, again involving either pharmacotherapy (zolpidem or trazodone) or psychological therapy (BT or cognitive therapy (CT)). All participants will be re-evaluated 12 weeks after the protocol initiation and at 3 , 6-, 9-, and 12-month follow-ups. Insomnia remission, defined categorically as a score < 8 on the Insomnia Severity Index, a patient-reported outcome, will serve as the primary endpoint for treatment comparisons. Secondary outcomes will include sleep parameters derived from daily sleep diaries and from polysomnography, subjective measures of fatigue, mood, quality of life, and functional impairments; and measures of adverse events; dropout rates; and treatment acceptability. Centrally trained therapists will administer therapies according to manualized, albeit flexible, treatment algorithms. DISCUSSION: This clinical trial will provide new information about optimal treatment sequencing and will have direct implication for the development of clinical guidelines for managing chronic insomnia with and without comorbid psychiatric conditions. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01651442 , Protocol version 4, 20 April 2011, registered 26 June 2012. PMID- 26940894 TI - Pulmonary artery diameters, cross sectional areas and area changes measured by cine cardiovascular magnetic resonance in healthy volunteers. AB - BACKGROUND: We measured by cine cardiovascular magnetic resonance (CMR) main and branch pulmonary artery diameters and cross sectional areas in diastole and systole in order to establish normal ranges and the effects on them of age, gender and body surface area (BSA). Documentation of normal ranges provides a reference for research and clinical investigation in the fields of congenital heart disease, pulmonary hypertension and connective tissue disorders. METHODS: We recruited 120 healthy volunteers: ten males (M) and ten females (F) in each decile between 20 and 79 years, imaging them in a 1.5 Tesla CMR system. Scout acquisitions guided the placement of steady state free precession cine acquisitions transecting the main, right and left pulmonary arteries (MPA, RPA and LPA). Cross sections were rarely quite circular. RESULTS: From all subjects, the means of the greater and lesser orthogonal diastolic diameters in mm were: MPA, 22.9 +/- 2.4 (M) and 21.2 +/- 2.1 (F), RPA 16.6 +/- 2.8 (M) and 14.7 +/- 2.2 (F), and LPA 17.3 +/- 2.5 (M) and 15.9 +/- 2.0 (F), p < 0.0001 between genders in each case. The diastolic diameters increased with BSA and age, and plots are provided for reference. From measurements of minimum diastolic and maximum systolic cross sectional areas, the % systolic distensions were: MPA 42.7 +/- 17.2 (M) and 41.8 +/- 15.7 (F), RPA 50.6 +/- 16.9 (M) and 48.2 +/- 14.5 (F), LPA 35.6 +/- 10.1 (M) and 35.2 +/- 10.3 (F), and there was a decrease in distension with age (p < 0.0001 for the MPA). CONCLUSIONS: Measurements of MPA, RPA and LPA by cine CMR are provided for reference, with documentation of their changes with age and BSA. PMID- 26940895 TI - Facile fabrication of MIL-103(Eu) porous coordination polymer nanostructures and their sorption and sensing properties. AB - Nano/microscale lanthanide porous coordination polymer MIL-103(Eu) [Eu(BTB)] (H3BTB = 4,4',4''-benzene-1,3,5-triyl-tribenzoic acid) crystals have been fabricated at room temperature by a facile, convenient and environmentally friendly method. The structures of the products were confirmed by powder X-ray diffraction, and the crystal morphologies, including microrods, nanorods and nanospheres, were characterized by scanning electron microscopy. It is found that the addition of sodium acetate and the concentration of the reactants have an important impact on the morphology and size of the MIL-103(Eu) crystals. Gas adsorption measurements reveal that the products show high specific surface areas among the rare earth based coordination polymers and the MIL-103(Eu) nanorods can selectively adsorb CO2 over N2 under ambient conditions. Furthermore, all the products exhibit red emission corresponding to the (5)D0->(7)F2 transition of the Eu(iii) ion, and MIL-103(Eu) nanorods display sensitive and selective sensing for Cu(ii) ions and acetone molecules in solution. PMID- 26940897 TI - Connarus favosus Planch.: An inhibitor of the hemorrhagic activity of Bothrops atrox venom and a potential antioxidant and antibacterial agent. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The plant species Connarus favosus is used in folk medicine in the west of Para state, Brazil, to treat snakebites. AIM OF THE STUDY: To investigate the potential of the aqueous extract of Connarus favosus (AECf) to inhibit hemorrhagic and phospholipase A2 activities induced by Bothrops atrox venom (BaV) and to determine the antioxidant and antimicrobial potentials of the extract. MATERIALS AND METHODS: AECf was analyzed phytochemically for phenolics (condensed tannins and hydrolyzable tannins) by colorimetry. Antioxidant activity was evaluated by quantitative assays using 2,2-diphenyl-1 picrylhydrazyl (DPPH) and Fe(3+)/phenanthroline. Antimicrobial activity was evaluated by the minimal inhibitory concentration test, and cytotoxicity was evaluated using human fibroblast cells (MRC-5). Inhibition of BaV-induced hemorrhagic activity was assessed after oral administration of the extract using pre-treatment, post-treatment and combined (BA plus AECf) treatment protocols. Inhibition of indirect hemolysis caused by phospholipase A2 (PLA2) was investigated in vitro. Interaction between AECf and BaV was investigated by SDS PAGE electrophoresis, Western blot (Wb) and zymography. RESULTS: The phytochemical profile of AECf revealed ten secondary metabolite classes, and colorimetry showed high total phenolic and total (condensed and hydrolyzable) tannin content. AECf exhibited high antioxidant and antimicrobial potentials. The IC50 for the cytotoxic effect was 51.91 (46.86-57.50)ug/mL. Inhibition of BaV induced hemorrhagic activity was significant in all the protocols, and inhibition of PLA2 activity was significant with the two highest concentrations. The BaV/AECf mixture produced the same bands as BaV by itself in SDS-PAGE and Wb although the bands were much fainter. Zymography confirmed the proteolytic activity of BaV, but when the venom was pre-incubated with AECf this activity was blocked. CONCLUSION: AECf was effective in reducing BaV-induced hemorrhagic activity when administered by the same route as that used in folk medicine and exhibited antioxidant and antimicrobial potentials. PMID- 26940896 TI - No evidence of cardiovascular toxicity in workers exposed below 5 ppm carbon disulfide. AB - PURPOSE: Carbon disulfide (CS2), used in the viscose process, is well known for having multiple health effects, including on the cardiovascular system, in workers with long-term exposure higher than 10 ppm. The mechanisms of those effects are, however, not precisely defined, and it remains uncertain whether cardiovascular toxicity may occur at exposure levels lower than 10 ppm. Therefore, the purpose of this study is to explore the health impact of low CS2 exposure levels using an array of preclinical biomarkers of cardiovascular risk. METHODS: Exposure intensity was determined by measuring urinary 2 thiothiazolidine-4-carboxylic acid (TTCA) in 117 workers from two plants using the viscose process, sampled in multiples phases (2003, 2006 and 2013). A cumulative exposure index (CEI) and a recent exposure index (REI) were calculated for each worker, and shiftwork was documented to account for potential confounding. Cardiovascular parameters included blood pressure, total, LDL and HDL cholesterol, triglycerides, C-reactive protein dosed in serum with high sensitivity (HsCRP), N-terminal pro-brain natriuretic peptide, and albuminuria/creatininuria ratio (UACR). Potential biological confounders were fasting blood glucose and serum creatinine. Bivariate and multivariate regression analyses were used to trace relationships between cardiovascular risk biomarkers and other variables, including CEI, REI and shiftwork duration. RESULTS: Median REI and CEI were 0.05 mg TTCA/g creat and 21.5 mg TTCA/g creat*months, respectively. While expected associations, such as between HsCRP and LDL Cholesterol, were found, significant associations between cardiovascular risk markers and CS2 exposure indexes (CEI or REI) were not detected. Shiftwork duration was positively associated with UACR in workers with elevated fasting blood glucose. CONCLUSION: In practice, when CS2 exposure levels are kept below 5 ppm (TTCA < 2.2 mg/g creat), it does not appear useful to perform a systematic monitoring of total serum cholesterol or its subfractions, or of the new biomarkers of cardiovascular risk (NTproBNP, HsCRP, UACR) investigated in the present study. It appears important to carefully monitor the existence of diabetes that may justify avoiding shiftwork. PMID- 26940898 TI - Evaluation of the osteogenic potential of Hancornia speciosa latex in rat calvaria and its phytochemical profile. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Hancornia speciosa Gomes, commonly known as Mangabeira, is a Brazilian native fruit tree belonging to the Apocynaceae family. In folk medicine, the latex obtained from Mangabeira's trunk has been used as an adjunct therapy for bone fractures. Few pharmacological studies on the Hancornia speciosa latex have been developed and despite its popular use for bone healing there is no data about its biological effect on bone. AIM OF THE STUDY: The present study aimed to investigate the osteogenic potential of Hancornia speciosa latex in rat calvaria, as well as its phytochemical profile. MATERIALS AND METHODS: A neutral gel composition containing 5% latex was topical applied to a critical size bone defect and over intact calvaria of rats. Areas of newly formed bone on the borders of the defect and of calvaria periosteum were quantified, as well as the percentage of BrdU-positive cells and total cells in the periosteum at different periods of time after latex application. The cytotoxicity of the latex aqueous phase was evaluated in rat calvarial cells in vitro by MTT assay and its phytochemical profile was investigated by ESI-MS/MS. RESULTS: The area of newly formed bone on the borders of the calvaria defect was larger in rats that received latex at 15 and 30 days of healing. After 3 days of latex application over the intact calvaria, the periosteum area was increased and newly formed bone was observed after 5 and 11 days. There was also an increase in periosteum cell proliferation and population followed latex application on calvaria (p<0.05). The latex aqueous phase limited rat calvarial cell viability in vitro in concentrations larger than 0.6mg/mL. Chlorogenic acid and naringenin-7-O glucoside were identified in the latex aqueous phase, along with catechin and procyanidin compounds. CONCLUSION: There was a stimulus for periosteum cell proliferation and bone formation when Hancornia speciosa latex was topically applied on rat calvaria. In addition, chlorogenic acid and naringenin-7-O glucoside present in Hancornia speciosa latex may contribute to its effects on bone formation. PMID- 26940899 TI - Anti-H1N1 influenza effects and its possible mechanism of Huanglian Xiangru Decoction. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Huangliang Xiangru Decoction (HXD), which is described in a famous TCM monograph "Book of Nanyang for Life Savin", is frequently used for treating cold in summer and summer heat-dampness. AIM OF THE STUDY: To date, no pharmacological study on the anti-H1N1 influenza properties of HXD has been reported. The aim of the present study was to evaluate the therapeutic action of HXD on HIN1-induced acute pulmonary inflammation and its anti-influenza mechanism focus to TLRs signal pathway in a mouse model. MATERIALS AND METHODS: the mice were intranasally infected with influenza virus to induce viral pneumonia, and then treated with different doses of HXD. The Lung index and pathological changes in the lung tissue of mice were investigated to value the anti-influenza virus effect of HXD. The concentrations of cytokines (IL-2, IL-6, TNF-alpha and IFN-gamma) and anti-oxidant factor (NO, SOD and GSH) in serum of mice were determined with ELISA. RT-PCR and Western blot were used to determine the mRNA and protein expression of TLR3, TLR7, MyD88,TRAF3 and NF-kappaB p65 in the lung tissues, which are the key targets of TLRs pathway. RESULTS: Compared with the infection group, the lung index of mice in ribavirin group, HXD high dose group and HXD middle dose group were significantly decreased, the lung indexes of these groups were 10.36+/-1.14mg/g, 9.89+/-0.79mg/g, and 10.97+/ 0.67mg/g. Moreover, pathological changes were remarkable alleviated. HXD can reduce the contents of IL-6, TNF-alpha and IFN-gamma, NO, and increase the contents of IL-2, SOD, GSH in serum of infected-mice significantly. At the same time, HXD can reduce the mRNA and protein expression of TLR3, TLR7, MyD88,TRAF3 and NF-kappaB p65 in the lung tissues of infected-mice significantly. CONCLUSIONS: HXD has significant effects on H1N1 influenza by a quantity-effect relationship, and plays its anti-influenza effect by enhancing the body's antioxidant capacity, regulating the body's immune function and the host's TLRs pathway. PMID- 26940900 TI - Parkinsonia aculeata (Caesalpineaceae) improves high-fat diet-induced insulin resistance in mice through the enhancement of insulin signaling and mitochondrial biogenesis. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The search for natural agents that minimize obesity-associated disorders is receiving special attention. Parkinsonia aculeata L. (Caesalpineaceae) has long been used in Brazil as a hypoglycaemic herbal medicine, without any scientific basis. AIMS OF THE STUDY: In this context, we aimed to use molecular and physiological methods to study the effect of a hydroethanolic extract partitioned with ethyl acetate from the aerial parts of Parkinsonia aculeata (HEPa/EtOAc) on insulin resistance in a mouse model of diet induced obesity (DIO). MATERIAL AND METHODS: Firstly, C57BL/6J mice were fed either with standard rodent chow diet or a high-fat diet (HFD) for 12 consecutive weeks. Then, the animals were treated with HEPa/EtOAc at two doses (125 and 250mg/kg/day) or metformin (200mg/kg/day) for 16 days. At the end of the experiment, body weight, fat pad weight, fasting serum glucose (FSG), insulin (FSI) and leptin were measured. Homeostasis Model Assessment for Insulin Resistance (HOMA-IR) was also calculated. Glucose, insulin and pyruvate tolerance tests were performed. The expression and phosphorylation of IRbeta(tyr), Akt(ser473), AMPKalpha and PGC1alpha in liver, muscle and adipose tissue were determined by Western blot analyses. RESULTS: Herein we demonstrate for the first time an improvement in insulin resistance following HEPa/EtOAc administration in obese mice, as shown by increased glucose, insulin and pyruvate tolerance, as well as an improvement in FSG, FSI, HOMA-IR and circulating leptin levels, which together are in part due to enhancement of the insulin signaling pathway in its main target tissues. Surprisingly, the increase in activation of the AMPKalpha PGC1-alpha axis by HEPa/EtOAc was similar to that produced by metformin treatment in the liver and muscle tissues. CONCLUSION: In conclusion, P. aculeata appears to be a source of therapeutic agent against obesity-related complications. PMID- 26940901 TI - The inhibitory potential of the condensed-tannin-rich fraction of Plathymenia reticulata Benth. (Fabaceae) against Bothrops atrox envenomation. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Ethnobotanical studies have shown that Plathymenia reticulata Benth. (Fabaceae) has been widely used in cases of snake envenomation, particularly in Northern Brazil. In light of this, the aim of this study was to evaluate the inhibitory potential of the condensed-tannin-rich fraction obtained from the bark of P. reticulata against the main biological activities induced by Bothrops atrox venom (BaV). MATERIALS AND METHODS: The chemical composition of the aqueous extract of P. reticulata (AEPr) was first investigated by thin-layer chromatography (TLC) and the extract was then fractionated by column chromatography on Sephadex LH-20. This yielded five main fractions (Pr1, Pr2, Pr3, Pr4 and Pr5), which were analyzed by colorimetry to determine their concentrations of total phenolics, total tannins and condensed tannins and to assess their potential for blocking the phospholipase activity of BaV. The Pr5 fraction was defined as the fraction rich in condensed tannins (CTPr), and its inhibitory potential against the activities of the venom was evaluated. CTPr was evaluated in different in vivo and in vitro experimental protocols. The in vivo protocols consisted of (1) pre-incubation (venom:CTPr, w/w), (2) pre-treatment (orally administered) and (3) post-treatment (orally administered) to evaluate the effect on the hemorrhagic and edematogenic activities of BaV; in the in vitro protocol the effect on phospholipase and coagulant activity using pre-incubation in both tests was evaluated. RESULTS: There was statistically significant inhibition (p<0.05) of hemorrhagic activity by CTPr when the pre-incubation protocol was used [55% (1:5, w/w) and 74% (1:10, w/w)] and when pre-treatment with doses of 50 and 100mg/kg was used (19% and 13%, respectively). However, for the concentrations tested, there was no statistically significant inhibition in the group subjected to post-treatment administered orally. CTPr blocked 100% of phospholipase activity and 63.3% (1:10, w/w) of coagulant activity when it was pre-incubated with BaV. There was a statistically significant reduction (p<0.05) in edema induced by BaV in the oral protocols. Maximum inhibition was 95% (pre-treatment). CONCLUSION: Our findings indicate that CTPr could be a good source of natural inhibitors of the components of snake venom responsible for inducing local inflammation. PMID- 26940902 TI - Simplified strigolactams as potent analogues of strigolactones for the seed germination induction of Orobanche cumana Wallr. AB - BACKGROUND: Strigolactones play an important role in the rhizosphere as signalling molecules stimulating the seed germination of parasitic weed seeds and hyphal branching of arbuscular micorrhiza, and also act as hormones in plant roots and shoots. Strigolactone derivatives, e.g. strigolactams, could be used as suicidal germination inducers in the absence of a host crop for the decontamination of land infested with parasitic weed seeds. RESULTS: We report the stereoselective synthesis of novel strigolactams, together with some of their critical physicochemical properties, such as water solubility, hydrolytic stability, as well as their short soil persistence. In addition, we show that such strigolactams are potent germination stimulants of O. cumana parasitic weed seeds and do not affect the seed germination and the root growth of sunflower. CONCLUSIONS: The novel strigolactam derivatives described here compare favourably with the corresponding GR-28 strigolactones in terms of biological activity and physicochemical properties. However, we believe strigolactone and strigolactam derivatives require further structural optimisation to improve their soil persistence to demonstrate a potential for agronomical applications. (c) 2016 Society of Chemical Industry. PMID- 26940903 TI - Medication Errors: New EU Good Practice Guide on Risk Minimisation and Error Prevention. AB - A medication error is an unintended failure in the drug treatment process that leads to, or has the potential to lead to, harm to the patient. Reducing the risk of medication errors is a shared responsibility between patients, healthcare professionals, regulators and the pharmaceutical industry at all levels of healthcare delivery. In 2015, the EU regulatory network released a two-part good practice guide on medication errors to support both the pharmaceutical industry and regulators in the implementation of the changes introduced with the EU pharmacovigilance legislation. These changes included a modification of the 'adverse reaction' definition to include events associated with medication errors, and the requirement for national competent authorities responsible for pharmacovigilance in EU Member States to collaborate and exchange information on medication errors resulting in harm with national patient safety organisations. To facilitate reporting and learning from medication errors, a clear distinction has been made in the guidance between medication errors resulting in adverse reactions, medication errors without harm, intercepted medication errors and potential errors. This distinction is supported by an enhanced MedDRA((r)) terminology that allows for coding all stages of the medication use process where the error occurred in addition to any clinical consequences. To better understand the causes and contributing factors, individual case safety reports involving an error should be followed-up with the primary reporter to gather information relevant for the conduct of root cause analysis where this may be appropriate. Such reports should also be summarised in periodic safety update reports and addressed in risk management plans. Any risk minimisation and prevention strategy for medication errors should consider all stages of a medicinal product's life cycle, particularly the main sources and types of medication errors during product development. This article describes the key concepts of the EU good practice guidance for defining, classifying, coding, reporting, evaluating and preventing medication errors. This guidance should contribute to the safe and effective use of medicines for the benefit of patients and public health. PMID- 26940904 TI - Antiherbivore defenses alter natural selection on plant reproductive traits. AB - While many studies demonstrate that herbivores alter selection on plant reproductive traits, little is known about whether antiherbivore defenses affect selection on these traits. We hypothesized that antiherbivore defenses could alter selection on reproductive traits by altering trait expression through allocation trade-offs, or by altering interactions with mutualists and/or antagonists. To test our hypothesis, we used white clover, Trifolium repens, which has a Mendelian polymorphism for the production of hydrogen cyanide-a potent antiherbivore defense. We conducted a common garden experiment with 185 clonal families of T. repens that included cyanogenic and acyanogenic genotypes. We quantified resistance to herbivores, and selection on six floral traits and phenology via male and female fitness. Cyanogenesis reduced herbivory but did not alter the expression of reproductive traits through allocation trade-offs. However, the presence of cyanogenic defenses altered natural selection on petal morphology and the number of flowers within inflorescences via female fitness. Herbivory influenced selection on flowers and phenology via female fitness independently of cyanogenesis. Our results demonstrate that both herbivory and antiherbivore defenses alter natural selection on plant reproductive traits. We discuss the significance of these results for understanding how antiherbivore defenses interact with herbivores and pollinators to shape floral evolution. PMID- 26940905 TI - Seeing How Far I've Come: The Impact of the Digital Sexual Life History Calendar on Young Adult Research Participants. AB - The Digital Sexual Life History Calendar (d/SLHC) is a Web-based platform for collecting young adults' sexual histories. In addition to collecting diverse data, the d/SLHC was designed to benefit participants by enabling reflection on their sexual and relationship experiences in the context of other life events and circumstances. In a pilot study of the d/SLHC, survey data were collected to test whether creating a d/SLHC timeline had any impact on sexual well-being. A sample of 18- to 25-year-old participants recruited through Amazon Mechanical Turk (MTurk) completed an online survey about sexuality and relationships. Of those, 113 also completed d/SLHC timelines and 262 served as a comparison group. Six months later, participants from both groups were invited to complete a follow-up survey (total N = 249). Repeated-measures analysis of variance (ANOVA) results indicated that participants who completed d/SLHC timelines exhibited higher sexual esteem immediately following d/SLHC completion and at follow-up. No changes in sexual esteem were observed in the comparison group, and there were no differences between the groups with regard to sexual health behaviors and outcomes. These findings suggest that sexuality studies may have the potential to yield not only rich data for researchers but also rich experiences for participants. PMID- 26940906 TI - Implementation of a more physiological plasma rich in growth factor (PRGF) protocol: Anticoagulant removal and reduction in activator concentration. AB - Plasma rich in growth factors (PRGF) is a biological therapy that uses patient's own growth factors for promoting tissue regeneration. Given the current European regulatory framework in which anticoagulant solution in blood extraction tubes could be considered as a medicinal product, a new PRGF protocol has been developed. The actual protocol (PRGF-A) and the new one (PRGF-B) have been performed and compared under Good Laboratory Practices. PRGF-A protocol uses extraction tubes with 0.9 mL of trisodium citrate as anticoagulant and 50 MUL of calcium chloride/mL PRGF to activate it. The PRGF-B reduces the amount of sodium citrate and calcium chloride to 0.4 mL and to 20 MUL, respectively. Basic hematological parameters, platelet function, the scaffold obtaining process, growth factors content, and the biological effect were compared between both PRGF obtaining protocols. RESULTS: PRGF-B protocol led to a statistically significant higher enrichment and recovery of platelets regarding to the PRGF-A. Hypotonic stress response by platelets was significantly better in the new protocol. A statistically significant decrease in the basal platelet activation status of PRGF-B compared to PRGF-A was also observed. The duration of the lag phase in the platelet aggregation assay was statistically lower for the PRGF-B protocol. Both the clotting and the clot retraction time were significantly reduced in the B protocol. A higher growth factor concentration was detected in the plasma obtained using the PRGF-B protocol. The new PRGF obtaining protocol, with a reduction in the amount of anticoagulant and activator, has even improved the actual one. PMID- 26940907 TI - Spinal meningeal melanocytomas: clinical manifestations, radiological and pathological characteristics, and surgical outcomes. AB - Meningeal melanocytoma is a rare benign tumor, most frequently located in the posterior fossa and spinal canal. The aim of this study was to investigate the clinical manifestations, radiological features, management, and follow-up data of spinal meningeal melanocytomas. We present the clinical data and long-term outcomes from a consecutive surgical series of 16 patients with pathologically diagnosed spinal meningeal melanocytomas. All of the patients underwent surgical resection. Pre and postoperative MRI was performed. Follow-up data and neurological functional assessment is presented and discussed. The mean age at diagnosis was 42.0 years, with a significant male predominance. The primary clinical symptoms were weakness or numbness of the extremities. The appearance of melanocytoma on MRI is typically isointense to hyperintense on T1-weighted images, hypointense on T2-weighted images, and contrast enhancement tends to be remarkable and homogeneous. In most cases, gross total resection is achievable; however, in rare cases with dumbbell-shaped tumors involving the extraspinal region, a staging operation and subtotal resection should be attempted. During a mean follow-up period of 58.1 months, the symptoms were completely relieved in all the patients, and no tumor progression or recurrence was noted. Melanocytic tumors of the central nervous system have a typical appearance on MRI scans, varying with the content and distribution of melanin. However, the differential diagnosis between malignant melanoma and melanocytoma still depends on pathological criteria. Spinal meningeal melanocytoma has a benign course, and it is amenable for gross total resection. The outcome is favorable following complete resection. PMID- 26940909 TI - Uterine arteriovenous malformation: A rising cause of postpartum haemorrhage? PMID- 26940908 TI - Adjuvant chemotherapy in adult medulloblastoma: is it an option for average-risk patients? AB - The standard treatment in children with average-risk medulloblastoma (MB) is reduced-dose radiotherapy (RT) followed by chemotherapy. However, in adults, there is no agreement on the use of adjuvant chemotherapy. We performed a retrospective analysis of adult MB patients with average-risk disease, defined as no postsurgical residual (or <=1.5 cm(2)) and no metastatic disease (M0). Main inclusion criteria were: age >16 years, post-surgical treatment with craniospinal irradiation with or without adjuvant chemotherapy (cisplatin and etoposide +/- cyclophosphamide). From 1988 to 2012 were accrued 43 average-risk MB patients treated with surgery and adjuvant RT. Fifteen (34.9 %) patients received also chemotherapy: 7 before RT, 5 after RT, and 3 before and after RT. Reasons to administer chemotherapy were presence of residual disease (even if <=1.5 cm) and delay in RT. After a median follow up time of 10 years (range: 8-13), median survival was 18 years (95 % CI 9-28) in patients who receive RT alone, and was not reached in patients treated with RT plus chemotherapy. The survival rates at 5, 10 and 15 years were 100 %, 78.6 % (95 % CI 60.0-97.2 %) and 60.2 % (95 % CI 36.9-83.5 %), in patients treated with RT alone, and 100, 100 and 100 %, in patients treated with RT plus chemotherapy (p = 0.079). Our findings suggest a role for adjuvant chemotherapy in the treatment of average-risk MB adult patients. Further improvements might drive to add chemotherapy in average-risk setting with less favourable biological signatures (i.e., non-WNT group). PMID- 26940910 TI - Are current case-finding methods under-diagnosing tuberculosis among women in Myanmar? An analysis of operational data from Yangon and the nationwide prevalence survey. AB - BACKGROUND: Although there is a large increase in investment for tuberculosis control in Myanmar, there are few operational analyses to inform policies. Only 34% of nationally reported cases are from women. In this study, we investigate sex differences in tuberculosis diagnoses in Myanmar in order to identify potential health systems barriers that may be driving lower tuberculosis case finding among women. METHODS: From October 2014 to March 2015, we systematically collected data on all new adult smear positive tuberculosis cases in ten township health centres across Yangon, the largest city in Myanmar, to produce an electronic tuberculosis database. We conducted a descriptive cross-sectional analysis of sex differences in tuberculosis diagnoses at the township health centres. We also analysed national prevalence survey data to calculate additional case finding in men and women by using sputum culture when smear microscopy was negative, and estimated the sex-specific impact of using a more sensitive diagnostic tool at township health centres. RESULTS: Overall, only 514 (30%) out of 1371 new smear positive tuberculosis patients diagnosed at the township health centres were female. The proportion of female patients varied by township (from 21% to 37%, p = 0.0172), month of diagnosis (37% in February 2015 and 23% in March 2015 p = 0.0004) and age group (26% in 25-64 years and 49% in 18-25 years, p < 0.0001). Smear microscopy grading of sputum specimens was not substantially different between sexes. The prevalence survey analysis indicated that the use of a more sensitive diagnostic tool could result in the proportion of females diagnosed at township health centres increasing to 36% from 30%. CONCLUSIONS: Our study, which is the first to systematically compile and analyse routine operational data from tuberculosis diagnostic centres in Myanmar, found that substantially fewer women than men were diagnosed in all study townships. The sex ratio of newly diagnosed cases varied by age group, month of diagnosis and township of diagnosis. Low sensitivity of tuberculosis diagnosis may lead to a potential under-diagnosis of tuberculosis among women. PMID- 26940911 TI - Mitochondrial DNA repair: a novel therapeutic target for heart failure. AB - Mitochondria play a crucial role in a variety of cellular processes ranging from energy metabolism, generation of reactive oxygen species (ROS) and Ca(2+) handling to stress responses, cell survival and death. Malfunction of the organelle may contribute to the pathogenesis of neuromuscular, cancer, premature aging and cardiovascular diseases (CVD), including myocardial ischemia, cardiomyopathy and heart failure (HF). Mitochondria contain their own genome organized into DNA-protein complexes, called "mitochondrial nucleoids," along with multiprotein machineries, which promote mitochondrial DNA (mtDNA) replication, transcription and repair. Although the mammalian organelle possesses almost all known nuclear DNA repair pathways, including base excision repair, mismatch repair and recombinational repair, the proximity of mtDNA to the main sites of ROS production and the lack of protective histones may result in increased susceptibility to various types of mtDNA damage. These include accumulation of mtDNA point mutations and/or deletions and decreased mtDNA copy number, which will impair mitochondrial function and finally, may lead to CVD including HF. PMID- 26940912 TI - Determination of T-2 toxin, HT-2 toxin, and three other type A trichothecenes in layer feed by high-performance liquid chromatography-tandem mass spectrometry (LC MS/MS)--comparison of two sample preparation methods. AB - A sensitive method for the simultaneous determination of T-2 toxin, HT-2 toxin, neosolaniol, T-2 triol, and T-2 tetraol in layer feed using high-performance liquid chromatography coupled to triple quadrupole mass spectrometry in the positive ionization mode (LC-ESI-MS/MS) is described. Two fast and easy clean-up methods-with BondElut Mycotoxin and MycoSep 227 columns, respectively-were tested. The separation of the toxins was conducted on a Pursuit XRs Ultra 2.8 HPLC column using 0.13 mM ammonium acetate as eluent A and methanol as eluent B. Detection of the mycotoxins was carried out in the multiple reaction monitoring (MRM) mode using ammonium adducts as precursor ions. Quantification of all analytes was performed with d3-T-2 toxin as an internal standard. The clean-up method with MycoSep 227 columns gave slightly better results for layer feed compared to the method using BondElut Mycotoxin columns (MycoSep 227: recovery between 50 and 63%, BondElut Mycotoxin: recovery between 32 and 67%) and was therefore chosen as the final method. The limits of detection ranged between 0.9 and 7.5 ng/g depending on the mycotoxin. The method was developed for the analysis of layer feed used at carry-over experiments with T-2 toxin in laying hens. For carry-over experiments, it is necessary that the method includes not only T-2 toxin but also the potential metabolites in animal tissues HT-2 toxin, neosolaniol, T-2 triol, and T-2 tetraol which could naturally occur in cereals used as feed stuff as well. PMID- 26940913 TI - Acute Effect of Intravenous Sildenafil on Cerebral Blood Flow in Patients with Vasospasm After Subarachnoid Hemorrhage. AB - BACKGROUND: The phosphodiesterase-5 inhibitor sildenafil has been shown to attenuate delayed cerebral ischemia (DCI) and improve neurologic function in experimental subarachnoid hemorrhage (SAH). We recently demonstrated that it could improve cerebral vasospasm (CVS) in humans after SAH. However, successful therapies for DCI must also restore cerebral blood flow (CBF) and/or autoregulatory capacity. In this study, we tested the effects of sildenafil on CBF in SAH patients at-risk for DCI. METHODS: Six subjects with angiographically confirmed CVS received 30-mg of intravenous sildenafil (mean 9 +/- 2 days after aneurysmal SAH). Each underwent (15)O-PET imaging to measure global and regional CBF at baseline and post-sildenafil. RESULTS: Mean arterial pressure declined by 10 mm Hg on average post-sildenafil (8 %, p = 0.01), while ICP was unchanged. There was no change in global CBF (mean 34.5 +/- 7 ml/100g/min at baseline vs. 33.9 +/- 8.0 ml/100g/min post-sildenafil, p = 0.84). The proportion of brain regions with low CBF (<25 ml/100g/min) was also unchanged after sildenafil infusion. CONCLUSIONS: Infusion of sildenafil does not lead to a change in global or regional perfusion despite a significant reduction in cerebral perfusion pressure. While this could reflect the ineffectiveness of sildenafil-induced proximal vasodilatation to alter brain perfusion, it also suggests that cerebral autoregulatory function was preserved in this group. Future studies should assess whether sildenafil can restore or enhance autoregulation after SAH. PMID- 26940915 TI - Influenza A virus ribonucleoproteins modulate host recycling by competing with Rab11 effectors. AB - Influenza A virus assembly is an unclear process, whereby individual virion components form an infectious particle. The segmented nature of the influenza A genome imposes a problem to assembly because it requires packaging of eight distinct RNA particles (vRNPs). It also allows genome mixing from distinct parental strains, events associated with influenza pandemic outbreaks. It is important to public health to understand how segmented genomes assemble, a process that is dependent on the transport of components to assembly sites. Previously, it has been shown that vRNPs are carried by recycling endosome vesicles, resulting in a change of Rab11 distribution. Here, we describe that vRNP binding to recycling endosomes impairs recycling endosome function, by competing for Rab11 binding with family-interacting proteins, and that there is a causal relationship between Rab11 ability to recruit family-interacting proteins and Rab11 redistribution. This competition reduces recycling sorting at an unclear step, resulting in clustering of single- and double-membraned vesicles. These morphological changes in Rab11 membranes are indicative of alterations in protein and lipid homeostasis during infection. Vesicular clustering creates hotspots of the vRNPs that need to interact to form an infectious particle. PMID- 26940914 TI - Non-invasive Monitoring of Intracranial Pressure Using Transcranial Doppler Ultrasonography: Is It Possible? AB - Although intracranial pressure (ICP) is essential to guide management of patients suffering from acute brain diseases, this signal is often neglected outside the neurocritical care environment. This is mainly attributed to the intrinsic risks of the available invasive techniques, which have prevented ICP monitoring in many conditions affecting the intracranial homeostasis, from mild traumatic brain injury to liver encephalopathy. In such scenario, methods for non-invasive monitoring of ICP (nICP) could improve clinical management of these conditions. A review of the literature was performed on PUBMED using the search keywords 'Transcranial Doppler non-invasive intracranial pressure.' Transcranial Doppler (TCD) is a technique primarily aimed at assessing the cerebrovascular dynamics through the cerebral blood flow velocity (FV). Its applicability for nICP assessment emerged from observation that some TCD-derived parameters change during increase of ICP, such as the shape of FV pulse waveform or pulsatility index. Methods were grouped as: based on TCD pulsatility index; aimed at non invasive estimation of cerebral perfusion pressure and model-based methods. Published studies present with different accuracies, with prediction abilities (AUCs) for detection of ICP >=20 mmHg ranging from 0.62 to 0.92. This discrepancy could result from inconsistent assessment measures and application in different conditions, from traumatic brain injury to hydrocephalus and stroke. Most of the reports stress a potential advantage of TCD as it provides the possibility to monitor changes of ICP in time. Overall accuracy for TCD-based methods ranges around +/-12 mmHg, with a great potential of tracing dynamical changes of ICP in time, particularly those of vasogenic nature. PMID- 26940916 TI - A novel high-content analysis tool reveals Rab8-driven cytoskeletal reorganization through Rho GTPases, calpain and MT1-MMP. AB - Rab8 is a small Ras-related GTPase that regulates polarized membrane transport to the plasma membrane. Here, we developed a high-content analysis (HCA) tool to dissect Rab8-mediated actin and focal adhesion reorganization that revealed that Rab8 activation significantly induced Rac1 and Tiam1 to mediate cortical actin polymerization and RhoA-dependent stress fibre disassembly. Rab8 activation increased Rac1 activity, whereas its depletion activated RhoA, which led to reorganization of the actin cytoskeleton. Rab8 was also associated with focal adhesions, promoting their disassembly in a microtubule-dependent manner. This Rab8 effect involved calpain, MT1-MMP (also known as MMP14) and Rho GTPases. Moreover, we demonstrate the role of Rab8 in the cell migration process. Indeed, Rab8 is required for EGF-induced cell polarization and chemotaxis, as well as for the directional persistency of intrinsic cell motility. These data reveal that Rab8 drives cell motility by mechanisms both dependent and independent of Rho GTPases, thereby regulating the establishment of cell polarity, turnover of focal adhesions and actin cytoskeleton rearrangements, thus determining the directionality of cell migration. PMID- 26940918 TI - Regulators of actin filament barbed ends at a glance. AB - Cells respond to external stimuli by rapidly remodeling their actin cytoskeleton. At the heart of this function lies the intricately controlled regulation of individual filaments. The barbed end of an actin filament is the hotspot for the majority of the biochemical reactions that control filament assembly. Assays performed in bulk solution and with single filaments have enabled characterization of a plethora of barbed-end-regulating proteins. Interestingly, many of these regulators work in tandem with other proteins, which increase or decrease their affinity for the barbed end in a spatially and temporally controlled manner, often through simultaneous binding of two regulators at the barbed ends, in addition to standard mutually exclusive binding schemes. In this Cell Science at a Glance and the accompanying poster, we discuss key barbed-end interacting proteins and the kinetic mechanisms by which they regulate actin filament assembly. We take F-actin capping protein, gelsolin, profilin and barbed end-tracking polymerases, including formins and WH2-domain-containing proteins, as examples, and illustrate how their activity and competition for the barbed end regulate filament dynamics. PMID- 26940917 TI - The role of myosin 1c and myosin 1b in surfactant exocytosis. AB - Actin and actin-associated proteins have a pivotal effect on regulated exocytosis in secretory cells and influence pre-fusion as well as post-fusion stages of exocytosis. Actin polymerization on secretory granules during the post-fusion phase (formation of an actin coat) is especially important in cells with large secretory vesicles or poorly soluble secretions. Alveolar type II (ATII) cells secrete hydrophobic lipo-protein surfactant, which does not easily diffuse from fused vesicles. Previous work showed that compression of actin coat is necessary for surfactant extrusion. Here, we investigate the role of class 1 myosins as possible linkers between actin and membranes during exocytosis. Live-cell microscopy showed translocation of fluorescently labeled myosin 1b and myosin 1c to the secretory vesicle membrane after fusion. Myosin 1c translocation was dependent on its pleckstrin homology domain. Expression of myosin 1b and myosin 1c constructs influenced vesicle compression rate, whereas only the inhibition of myosin 1c reduced exocytosis. These findings suggest that class 1 myosins participate in several stages of ATII cell exocytosis and link actin coats to the secretory vesicle membrane to influence vesicle compression. PMID- 26940919 TI - Subclinical Cardiovascular Disease and Death, Dementia, and Coronary Heart Disease in Patients 80+ Years. AB - BACKGROUND: The successful prevention and treatment of coronary heart disease (CHD) and stroke has resulted in a substantial increase in longevity, with subsequent growth in the population of older people at risk for dementia. OBJECTIVES: The authors evaluated the relationship of coronary and other peripheral atherosclerosis to risk of death, dementia, and CHD in the very elderly. Because the extent of vascular disease differs substantially between men and women, sex- and race-specific analyses were included, with a specific focus on women with low coronary artery calcium (CAC) Agatston scores. METHODS: We evaluated the relationship between measures of subclinical cardiovascular disease (CAC, carotid intimal medial thickness, stenosis, and ankle brachial index) and risk of dementia, CHD, and total mortality in 532 participants of the Cardiovascular Health Study-Cognition Study from 1998/1999 (mean age, 80 years) to 2012/2013 (mean age, 93 years). RESULTS: Thirty-six percent of participants had CAC scores >400. Women and African-Americans had lower CAC scores. Few men had low CAC scores. CAC score and number of coronary calcifications were directly related to age-adjusted total mortality and CHD. The age-specific incidence of dementia was higher than for CHD. Only about 25% of deaths were caused by CHD and 16% by dementia. Approximately 64% of those who died had a prior diagnosis of dementia. White women with low CAC scores had a significantly decreased incidence of dementia. CONCLUSIONS: In subjects 80+ years of age, there is a greater incidence of dementia than of CHD. CAC, as a marker of atherosclerosis, is a determinant of mortality, and risk of CHD and myocardial infarction. White women with low CAC scores had a significantly decreased risk of dementia. A very important unanswered question, especially in the very elderly, is whether prevention of atherosclerosis and its complications is associated with less Alzheimer disease pathology and dementia. (Cardiovascular Health Study [CHS]; NCT00005133). PMID- 26940920 TI - Coronary Artery Calcification: A Canary in the Cognitive Coalmine. PMID- 26940922 TI - Is There a Subgroup of PE Patients Who Benefit From Inferior Vena Cava Filters? PMID- 26940923 TI - Perioperative Cardiovascular Risk of Prior Coronary Stent Implantation Among Patients Undergoing Noncardiac Surgery. AB - BACKGROUND: Previous studies have observed high rates of perioperative cardiovascular events in patients with coronary stents undergoing noncardiac surgery (NCS). It is uncertain whether this finding reflects an independent association. OBJECTIVES: The goal of this study was to assess the independent relationship between prior coronary stent implantation and the occurrence of perioperative major adverse cardiac and cerebrovascular events (MACCE) and bleeding and its relation with time from stenting to NCS. METHODS: A total of 24,313 NCS cases at the Mayo Clinic (Rochester, Minnesota) from 2006 through 2011 were included in the study; 1,120 (4.6%) cases involved patients with coronary stents. MACCE was defined as death, myocardial infarction, cardiac arrest, or stroke. Age-adjusted odds ratios (aORs) were calculated after propensity adjustment for Revised Cardiac Risk Index factors and other conventional risk factors. RESULTS: The 30-day MACCE rates were 3.7% and 1.5% in stented and unstented patients, respectively (p < 0.001). The risk of MACCE was largely related to the time from stent implantation to NCS, indicating substantially elevated risk in the first year after stenting (aOR: 2.59; 95% confidence interval [CI]: 1.36 to 4.94) but not thereafter (aOR: 0.89; 95% CI: 0.59 to 1.36). Bleeding displayed a similar pattern, indicating elevated risk in the first year after stenting (aOR: 2.23; 95% CI: 1.55 to 3.21) but not thereafter (aOR: 1.07; 95% CI: 0.89 to 1.28). Subgroup analysis in patients with known stent type found that the increased risk of both MACCE and bleeding >1 month after stent implantation was not limited to only those with drug-eluting stents. CONCLUSIONS: This study found that prior coronary stent implantation is an independent risk factor for MACCE and bleeding when time from stenting to NCS is <1 year, both in patients with bare-metal and drug-eluting stents. PMID- 26940921 TI - Vena Caval Filter Utilization and Outcomes in Pulmonary Embolism: Medicare Hospitalizations From 1999 to 2010. AB - BACKGROUND: Inferior vena caval filters (IVCFs) may prevent recurrent pulmonary embolism (PE). Despite uncertainty about their net benefit, patterns of use and outcomes of these devices in contemporary practice are unknown. OBJECTIVES: The authors determined the trends in utilization rates and outcomes of IVCF placement in patients with PE and explored regional variations in use in the United States. METHODS: In a national cohort study of all Medicare fee-for-service beneficiaries >=65 years of age with principal discharge diagnoses of PE between 1999 and 2010, rates of IVCF placement per 100,000 beneficiary-years and per 1,000 patients with PE were determined. The 30-day and 1-year mortality rates after IVCF placement were also investigated. RESULTS: Among 556,658 patients hospitalized with PE, 94,427 underwent IVCF placement. Between 1999 and 2010, the number of PE hospitalizations with IVCF placement increased from 5,003 to 8,928, representing an increase in the rate per 100,000 beneficiary-years from 19.0 to 32.5 (p < 0.001 for both). As the total number of PE hospitalizations increased (from 31,746 in 1999 to 54,392 in 2010), the rate of IVCF placement per 1,000 PE hospitalizations did not change significantly (from 157.6 to 164.1, p = 0.11). Results were consistent across demographic subgroups, although IVCF use was higher in blacks and patients >=85 years of age. IVCF utilization varied widely across regions, with the highest rate in the South Atlantic region and the lowest rate in the Mountain region. CONCLUSIONS: In a period of increasing PE hospitalizations among Medicare fee-for-service beneficiaries, IVCF placement increased as utilization rates in patients with PE remained greater than 15%. Mortality associated with PE hospitalizations is declining, regardless of IVCF use. PMID- 26940924 TI - Coronary Stents and Risk for Noncardiac Surgery: Much Ado About Something, Nothing, or DAPT? PMID- 26940925 TI - Gene-Specific Therapy With Mexiletine Reduces Arrhythmic Events in Patients With Long QT Syndrome Type 3. AB - BACKGROUND: Long QT syndrome type 3 (LQT3) is a lethal disease caused by gain-of function mutations in the SCN5A gene, coding for the alpha-subunit of the sodium channel NaV1.5. Mexiletine is used to block late sodium current and to shorten QT interval in LQT3 patients. OBJECTIVES: The aim of this study was to determine whether mexiletine prevents arrhythmic events (arrhythmic syncope, aborted cardiac arrest, or sudden cardiac death) in LQT3 patients. METHODS: The endpoint of this retrospective cohort study, which studied consecutive LQT3 patients who were referred to our center and treated with mexiletine, was to evaluate the antiarrhythmic efficacy of mexiletine by comparing the number of arrhythmic events per patient and the annual rate of arrhythmic events during observation periods of equal duration before and after the beginning of therapy with mexiletine. RESULTS: The study population comprised 34 LQT3 patients, 19 (56%) of whom were male. The median age at beginning of treatment with mexiletine was 22 years, and median QTc interval before therapy 509 ms. The median duration of oral mexiletine therapy was 36 months, at an average daily dose of 8 +/- 0.5 mg/kg. Mexiletine significantly shortened QTc (by 63 +/- 6 ms; p < 0.0001) and reduced the percentage of patients with arrhythmic events (from 22% to 3%; p = 0.031), the mean number of arrhythmic events per patient (from 0.43 +/- 0.17 to 0.03 +/- 0.03; p = 0.027), and the annual rate of arrhythmic events (from 10.3% to 0.7%; p = 0.0097). CONCLUSIONS: Besides shortening QTc interval, mexiletine caused a major reduction of life-threatening arrhythmic events in LQT3 patients, thus representing an efficacious therapeutic strategy. PMID- 26940926 TI - Gene-Specific Therapy for Congenital Long QT Syndrome: Are We There Yet? PMID- 26940927 TI - Use of Guideline-Directed Medications for Heart Failure Before Cardioverter Defibrillator Implantation. AB - BACKGROUND: Guideline-directed medical therapy (GDMT) for heart failure with reduced ejection fraction (HFrEF) is recommended before primary prevention implantable cardioverter-defibrillator (ICD) placement. Adherence to this recommendation and associated outcomes are unknown. OBJECTIVES: This study examined the use of GDMT (>=1 prescription filled for both a renin-angiotensin inhibitor [RAI] and a heart failure-approved beta-blocker [HFBB]) within 90 days before primary prevention ICD placement in patients with HFrEF. METHODS: Data from the National Cardiovascular Data Registry ICD Registry were merged with a 40% random sample of Medicare administrative data. Prescription fills for recipients of primary prevention ICD between 2007 and 2011 were examined, analyzing GDMT overall and for each U.S. hospital referral region. We identified characteristics associated with GDMT and the association with 1-year mortality. RESULTS: Among 19,733 patients with HFrEF and primary prevention ICD, 61.1% filled any GDMT before implantation. Across hospital referral regions, GDMT was applied in 51% to 71%. The strongest predictors of any GDMT included absence of chronic renal disease or nonsustained ventricular tachycardia, low-income prescription benefits subsidy, and less recent left ventricular ejection fraction evaluation. Patients receiving GDMT versus those without had a lower 1-year mortality rate after ICD implantation (11.1% vs. 16.2%), even after adjustment for comorbidities, left ventricular ejection fraction, and functional heart failure class. CONCLUSIONS: Rates of GDMT for HFrEF before primary prevention ICD implantation were low, and failure to achieve GDMT was associated with significantly decreased 1-year survival. PMID- 26940928 TI - Gaps in Adherence to Guideline-Directed Medical Therapy Before Defibrillator Implantation. PMID- 26940930 TI - Decellularized Scaffold Hydrogel Materials for MI Treatment: Could "The Matrix" Really Be the Future? PMID- 26940929 TI - Evidence for Mechanisms Underlying the Functional Benefits of a Myocardial Matrix Hydrogel for Post-MI Treatment. AB - BACKGROUND: There is increasing need for better therapies to prevent the development of heart failure after myocardial infarction (MI). An injectable hydrogel derived from decellularized porcine ventricular myocardium has been shown to halt the post-infarction progression of negative left ventricular remodeling and decline in cardiac function in both small and large animal models. OBJECTIVES: This study sought to elucidate the tissue-level mechanisms underlying the therapeutic benefits of myocardial matrix injection. METHODS: Myocardial matrix or saline was injected into infarcted myocardium 1 week after ischemia reperfusion in Sprague-Dawley rats. Cardiac function was evaluated by magnetic resonance imaging and hemodynamic measurements at 5 weeks after injection. Whole transcriptome microarrays were performed on RNA isolated from the infarct at 3 days and 1 week after injection. Quantitative polymerase chain reaction and histologic quantification confirmed expression of key genes and their activation in altered pathways. RESULTS: Principal component analysis of the transcriptomes showed that samples collected from myocardial matrix-injected infarcts are distinct and cluster separately from saline-injected control subjects. Pathway analysis indicated that these differences are due to changes in several tissue processes that may contribute to improved cardiac healing after MI. Matrix injected infarcted myocardium exhibits an altered inflammatory response, reduced cardiomyocyte apoptosis, enhanced infarct neovascularization, diminished cardiac hypertrophy and fibrosis, altered metabolic enzyme expression, increased cardiac transcription factor expression, and progenitor cell recruitment, along with improvements in global cardiac function and hemodynamics. CONCLUSIONS: These results indicate that the myocardial matrix alters several key pathways after MI creating a pro-regenerative environment, further demonstrating its promise as a potential post-MI therapy. PMID- 26940932 TI - QRS Duration or QRS Morphology: What Really Matters in Cardiac Resynchronization Therapy? AB - The beneficial effects of cardiac resynchronization therapy (CRT) have been well established in large, randomized trials. Despite the documented success of this treatment strategy, a significant proportion of patients with heart failure do not achieve the desired response. The aim of this review was to delineate factors contributing to a successful CRT response, emphasizing the interrelated roles of QRS morphology and QRS interval duration. More data are available on QRS duration, as this factor has been used as an enrollment criterion in clinical trials. Response to CRT seems to increase as the QRS duration becomes longer, with greatest benefit in QRS duration >=150 ms. Recent data have placed more emphasis on QRS morphology, demonstrating variability in clinical response between patients with left bundle branch block, non-left bundle branch block, and right bundle branch block morphology. Notably, myocardial scarring and cardiac dimensions, among other variables, may alter heterogeneity in ventricular activation. Understanding the electrophysiological underpinnings of the QRS complex has become important not only to predict response but also to facilitate the patient-specific delivery of resynchronization therapy. PMID- 26940933 TI - Tennis and Interventional Cardiology. PMID- 26940931 TI - Leukocytes Link Local and Systemic Inflammation in Ischemic Cardiovascular Disease: An Expanded "Cardiovascular Continuum". AB - Physicians have traditionally viewed ischemic heart disease in a cardiocentric manner: plaques grow in arteries until they block blood flow, causing acute coronary and other ischemic syndromes. Recent research provides new insight into the integrative biology of inflammation as it contributes to ischemic cardiovascular disease. These results have revealed hitherto unsuspected inflammatory signaling networks at work in these disorders that link the brain, autonomic nervous system, bone marrow, and spleen to the atherosclerotic plaque and to the infarcting myocardium. A burgeoning clinical published data indicates that such inflammatory networks-far from a mere laboratory curiosity-operate in our patients and can influence aspects of ischemic cardiovascular disease that determine decisively clinical outcomes. These new findings enlarge the circle of the traditional "cardiovascular continuum" beyond the heart and vessels to include the nervous system, the spleen, and the bone marrow. PMID- 26940934 TI - Pulmonary Valve Replacement After Repair of Pulmonary Stenosis Compared With Tetralogy of Fallot. PMID- 26940935 TI - Blunted Cortisol Stress Response and Depression-Induced Hypocortisolism Is Related to Inflammation in Patients With CAD. PMID- 26940936 TI - Coronary Artery Calcification Testing: A Platonic Certainty. PMID- 26940937 TI - Reply: Coronary Artery Calcification Testing: A Platonic Certainty. PMID- 26940938 TI - Population pharmacokinetics and exposure-response of trametinib, a MEK inhibitor, in patients with BRAF V600 mutation-positive melanoma. AB - PURPOSE: To characterize the pharmacokinetics of oral trametinib, a first in class MEK inhibitor, identify covariates, and describe the relationship between exposure and clinical effects in patients with BRAF V600 metastatic melanoma. EXPERIMENTAL DESIGN: Trametinib concentrations obtained in three clinical studies were included in the population pharmacokinetic analysis. Trametinib 2 mg once daily was administered in the Phase 2 and 3 studies. The impact of exposure [trough (C min) or average concentration] on response rates and progression-free survival (PFS) was examined. RESULTS: Plasma concentrations (n = 3120) obtained in 493 patients were described using a two-compartment model. Trametinib oral clearance was lower in women relative to men (1.26-fold) and increased with body weight. There was no significant effect of age, mild or moderate renal impairment, or mild hepatic impairment on oral clearance. Between-subject variability was low (24 %). The number of responders was consistent across median exposure range, although tended to be lower at trough concentration <10 ng/mL. Disease stage was found to be a significant predictor of response with a lower response rate in patients with disease stage of M1c. Lactate dehydrogenase was significant in the analysis of PFS. Patients with observed C min above the median had longer PFS than those below median based on Phase 2 study (median 10.6 ng/mL), while the effect of exposure was not statistically significant in the Phase 3 study (median 13.6 ng/mL). CONCLUSIONS: No dosage adjustments are required with any of the covariates tested. Clinical efficacy was associated with trametinib trough concentrations greater than 10 ng/mL. PMID- 26940939 TI - Predicting survival of pancreatic cancer patients treated with gemcitabine using longitudinal tumour size data. AB - PURPOSE: Measures derived from longitudinal tumour size data have been increasingly utilised to predict survival of patients with solid tumours. The aim of this study was to examine the prognostic value of such measures for patients with metastatic pancreatic cancer undergoing gemcitabine therapy. METHODS: The control data from two Phase III studies were retrospectively used to develop (271 patients) and validate (398 patients) survival models. Firstly, 31 baseline variables were screened from the training set using penalised Cox regression. Secondly, tumour shrinkage metrics were interpolated for each patient by hierarchical modelling of the tumour size time-series. Subsequently, survival models were built by applying two approaches: the first aimed at incorporating model-derived tumour size metrics in a parametric model, and the second simply aimed at identifying empirical factors using Cox regression. Finally, the performance of the models in predicting patient survival was evaluated on the validation set. RESULTS: Depending on the modelling approach applied, albumin, body surface area, neutrophil, baseline tumour size and tumour shrinkage measures were identified as potential prognostic factors. The distributional assumption on survival times appeared to affect the identification of risk factors but not the ability to describe the training data. The two survival modelling approaches performed similarly in predicting the validation data. CONCLUSIONS: A parametric model that incorporates model-derived tumour shrinkage metrics in addition to other baseline variables could predict reasonably well survival of patients with metastatic pancreatic cancer. However, the predictive performance was not significantly better than a simple Cox model that incorporates only baseline characteristics. PMID- 26940940 TI - Skin grafting for the treatment of chronic leg ulcers - a systematic review in evidence-based medicine. AB - Skin grafting is one of the most common surgical procedures in the area of non healing wounds by which skin or a skin substitute is placed over a wound to replace and regenerate the damaged skin. Chronic leg ulcers are an important problem and a major source of expense for Western countries and for which many different forms of treatment have been used. Skin grafting is a method of treatment that decreases the area of chronic leg ulcers or heals them completely, thus improving a patient's quality of life. Skin grafting is an old technique, rediscovered during the first and second world wars as the main treatment for wound closure. Nowadays, skin grafting has a pivotal role in the context of modern wound healing and tissue regeneration. The aim of this review was to track and to analyse the specific outcomes this technique achieved, especially in the last decade, in relation to venous, arterial, diabetic, rheumatoid and traumatic leg ulcers. Our main findings indicate that autologous split-thickness skin grafting still remains the gold standard in terms of safety and efficacy for chronic leg ulcers; skin grafting procedures have greater success rates in chronic venous leg ulcers compared to other types of chronic leg ulcers; skin tissue engineering, also supported by genetic manipulation, is quickly expanding and, in the near future, may provide even better outcomes in the area of treatments for long-lasting chronic wounds. PMID- 26940941 TI - Effect of gamma-PGA on the formation of collagen fibrils in vitro. AB - The effect of gamma-poly(glutamic acid) (gamma-PGA) on the self-assembly of collagen was studied. Under physiological conditions, the kinetic curves for fibril formation showed that the turbidity of collagen/gamma-PGA blends at 313 nm was increased with the addition of gamma-PGA. Furthermore, it was shown using both field-emission scanning electron microscopy (FESEM) and atomic force microscopy (AFM) that fibrils with a larger diameter were obtained following the addition of gamma-PGA, probably due to the electrostatic and hydrogen bond interactions between collagen and gamma-PGA, which promoted the lateral association of collagen molecules. In addition, both the thermal stability and viscoelastic properties of the hybrid hydrogels, which were evaluated by differential scanning calorimetry and rheological measurements, respectively, were improved by the addition of gamma-PGA. PMID- 26940942 TI - White Paper: SSAT Commitment to Workforce Diversity and Healthcare Disparities. AB - The Society for Surgery of the Alimentary Track (SSAT) is committed to diversity and inclusiveness of its membership, promotion of research related to healthcare disparities, cultural competency of practicing gastrointestinal surgeons, and cultivation of leaders with unique perspectives. The SSAT convened a task force to assess the current state of diversity and inclusion and recommend sustainable initiatives to promote these goals. Working through the current committee structure of the Society, and by establishing a permanent Diversity and Inclusion liaison committee, the SSAT will maintain its commitment and strive towards diversity of thought and inclusiveness on every level to improve the well-being and betterment of its membership and the patients they serve. PMID- 26940943 TI - Colorectal Surgery in Patients with HIV and AIDS: Trends and Outcomes over a 10 Year Period in the USA. AB - BACKGROUND: HIV has become a chronic disease, which may render this population more prone to developing the colorectal pathologies that typically affect older Americans. METHODS: A retrospective review of the Nationwide Inpatient Sample was performed to identify patients who underwent colon and rectal surgery from 2001 to 2010. Multivariate analysis was used to evaluate outcomes among the general population, patients with HIV, and patients with AIDS. RESULTS: Hospital admissions for colon and rectal procedures of patients with HIV/AIDS grew at a faster rate than all-cause admissions of patients with HIV/AIDS, with mean yearly increases of 17.8 and 2.1 %, respectively (p < 0.05). Patients with HIV/AIDS undergoing colon and rectal operations for cancer, polyps, diverticular disease, and Clostridium difficile were younger than the general population (51 vs. 65 years; p < 0.01). AIDS was independently associated with increased odds of mortality (OR 2.11; 95 % CI 1.24, 3.61), wound complications (OR 1.53; 95 % CI 1.09, 2.17), and pneumonia (OR 2.02; 95 % CI 1.33, 3.08). Risk-adjusted outcomes of colorectal surgery in patients with HIV did not differ significantly from the general population. CONCLUSION: Postoperative outcomes in patients with HIV are similar to the general population, while patients with AIDS have a higher risk of mortality and certain complications. PMID- 26940944 TI - The Role of No. 10 Lymphadenectomy for Advanced Proximal Gastric Cancer Patients Without Metastasis to No. 4sa and No. 4sb Lymph Nodes. AB - BACKGROUND: There is no consensus in the impact of No. 10 lymph node dissection (LND) for advanced proximal gastric cancer (APGC) and the status of negative No. 4sa and No. 4sb lymph nodes (No. 4s LNs) is reportedly associated with no metastasis to No. 10 LN. We aimed to evaluate the role of No. 10 LND in APGC patients with negative No. 4s LNs and the diagnostic accuracy of intraoperative pathologic examination. METHODS: We analyzed data on 727 patients with APGC who had undergone D2 lymphadenectomy with No. 10 LND (n = 380) or without No. 10 LND (n = 347) between January 2005 and December 2010. Additionally, from January to July 2014, we prospectively enrolled 48 patients with APGC and examined their No. 4s LNs intraoperatively. RESULTS: The negative predictive efficacy of No. 4s LN status for no metastasis to No. 10 LN was 98.09 %. Operation time, blood loss, time to first solid diet, hospital stay, and postoperative complication rate differed significantly between patients with negative No. 4s LNs who underwent No. 10 LND (n = 260) and those who did not undergo No. 10 LND (n = 243). Differences between the two groups in 5-year overall and disease-free survival were not statistically significant. The sensitivity, specificity, and accuracy of intraoperative pathological examination of LNs were 93.42, 96.56, and 95.86 %, respectively. CONCLUSIONS: The No. 10 lymphadenectomy may not be recommended in patients with APGC who are found by intraoperative pathological examination to have negative No. 4s LNs. PMID- 26940945 TI - What the concept of VILI has taught us about ARDS management. PMID- 26940946 TI - Global analysis of a mathematical model for Hepatitis C virus transmissions. AB - In this paper, a mathematical model is proposed and analyzed for Hepatitis C virus (HCV) infection transmissions. In this model, both of chronic primary infection and possibility of reinfection are considered. Two thresholds of basic reproduction number R0 and control reproduction number Rc are derived. We get the sufficient conditions for the existence of infection-free equilibrium and endemic equilibrium. The sufficient conditions for the local and global stability of the equilibria are also obtained. Some numerical simulations are performed to prove the theoretical results. At last, some discussions are presented. PMID- 26940947 TI - Early gastric cancer with a remarkable morphological change within a short period of time. PMID- 26940948 TI - Sorodiplophrys stercorea: Another Novel Lineage of Sorocarpic Multicellularity. AB - Sorodiplophrys stercorea is a sorocarpic organism that utilizes filose pseudopodia for locomotion and absorptive nutrition. It has traditionally been considered to be a member of the Labyrinthulae based on its morphology. Its closest relatives were thought to be species in the taxon Diplophrys. Since the genus Diplophrys has been shown to be paraphyletic and S. stercorea has pseudopodia similar to some members of Rhizaria, we examined its relationship with other eukaryotes. We obtained four isolates from the dung of cow and horse, brought each into monoeukaryotic culture, and sequenced their SSU rRNA gene for phylogenetic analysis. All our isolates were shown to form a monophyletic group in the Labyrinthulae, nested in the Amphifiloidea clade. Our results demonstrate that Sorodiplophrys is more closely related to species of the genus Amphifila than to Diplophrys and represents an additional independent origin of sorocarpic multicellularity among eukaryotes. This study represents the first confirmed sorocarpic lifestyle in the Stramenopiles. PMID- 26940949 TI - Secondary metabolites in plants: transport and self-tolerance mechanisms. AB - Plants produce a host of secondary metabolites with a wide range of biological activities, including potential toxicity to eukaryotic cells. Plants generally manage these compounds by transport to the apoplast or specific organelles such as the vacuole, or other self-tolerance mechanisms. For efficient production of such bioactive compounds in plants or microbes, transport and self-tolerance mechanisms should function cooperatively with the corresponding biosynthetic enzymes. Intensive studies have identified and characterized the proteins responsible for transport and self-tolerance. In particular, many transporters have been isolated and their physiological functions have been proposed. This review describes recent progress in studies of transport and self-tolerance and provides an updated inventory of transporters according to their substrates. Application of such knowledge to synthetic biology might enable efficient production of valuable secondary metabolites in the future. PMID- 26940950 TI - Detection of HIV-1 p24 antigen in patients with varying degrees of viremia using an ELISA with a photochemical signal amplification system. AB - BACKGROUND: We describe a photochemical signal amplification method (PSAM) for increasing the sensitivity of enzyme-linked immunosorbent assays (ELISAs) for the detection of HIV-1 p24 antigen, and present a preliminary validation study on ELISA+PSAM technology for detection of HIV-1 p24 antigen in clinical samples. METHODS: ELISA+PSAM is compatible with commercially available microtiter plate readers, employs an inexpensive illumination device and the amplification takes around 10 min. RESULTS: The PSAM technology not only increases the analytical sensitivity for detection of HIV-1 p24 antigen by approximately 40 times, but also significantly increases the clinical sensitivity of the ELISA: in instances where viral RNA load is <3000 copies/ml, conventional heat mediated immune complex disruption ELISA (HM-ELISA) cannot detect any HIV positive samples whereas HM-ELISA+PSAM can detect HIV infection in approximately half of the samples (clinical sensitivity is 52.63%). For viral RNA loads between 3000 and 30,000 copies/ml, the clinical sensitivities of the HM-ELISA and HM-ELISA+PSAM are 32.6% and 91.3%, and for that >30,000 copies/ml, clinical sensitivities of HM ELISA and HM-ELISA+PSAM are 52.3% and 100%, respectively. CONCLUSIONS: The HM ELISA+PSAM represents an advancement in monitoring HIV-1 disease progression and treatment in the global healthcare setting. PMID- 26940951 TI - Role of signal peptide-Cub-Egf domain-containing protein-1 in serum as a predictive biomarker of outcome after severe traumatic brain injury. AB - BACKGROUND: Signal peptide-Cub-Epidermal growth factor domain-containing protein 1 (SCUBE1), a marker for coagulation, is secreted under hypoxia and inflammatory conditions from platelet alpha granules. This study was designed to determine the associations of serum SCUBE1 concentrations with trauma severity and prognosis after severe traumatic brain injury. METHODS: Serum SCUBE1 concentrations of 113 patients and 113 controls were measured. An unfavorable outcome was defined as Glasgow Outcome Scale score of 1-3. RESULTS: Serum SCUBE1 concentrations were significantly higher in patients than in controls (15.5 +/- 6.0 vs. 1.1 +/- 0.3 ng/ml, P < 0.001) and were associated with Glasgow coma scale scores (r = -0.439, P < 0.001) and blood platelet count (r = 0.420, P < 0.001). SCUBE1 was identified as an independent prognostic marker of 6-month unfavorable outcome (odds ratio, 1.357; 95% confidence interval, 1.159-1.589; P < 0.001), and had high predictive value according to receiver operating characteristic curve (area under curve, 0.830; 95% confidence interval, 0.748-0.890; P < 0.001). CONCLUSIONS: Increased serum SCUBE1 concentrations are associated highly with trauma severity, platelet activation and poor outcome, suggesting that SCUBE1 might be a novel prognostic biomarker after traumatic brain injury. PMID- 26940952 TI - Original Research: Stable expression of miR-34a mediates fetal hemoglobin induction in K562 cells. AB - Sickle cell anemia is a common genetic disorder caused by a point mutation in the sixth codon of the beta-globin gene affecting people of African descent worldwide. A wide variety of clinical phenotypes ranging from mild to severe symptoms and complications occur due to hemoglobin S polymerization, red blood cell sickling, and vaso-occlusion. Research efforts are ongoing to develop strategies of fetal hemoglobin (HbF; alpha2gamma2) induction to inhibit sickle hemoglobin polymerization and improve clinical outcomes. Insights have been gained from investigating mutations in the beta-globin locus or transcription factors involved in the mechanisms of hemoglobin switching. Recent efforts to expand molecular targets that modulate gamma-globin expression involve microRNAs that work through posttranscriptional gene regulation. Therefore, the goal of our study was to identify novel microRNA genes involved in fetal hemoglobin expression. Using in silico analysis, we identified a miR-34a binding site in the gamma-globin mRNA which was tested for functional relevance. Stable expression of the shMIMIC miR-34a lentivirus vector increased fetal hemoglobin levels in single cell K562 clones consistent with silencing of a gamma-globin gene repressor. Furthermore, miR-34a promoted cell differentiation supported by increased expression of KLF1, glycophorin A, and the erythropoietin receptor. Western blot analysis of known negative regulators of gamma-globin including YY1, histone deacetylase 1, and STAT3, which are regulated by miR-34a showed no change in YY1 and histone deacetylase 1 levels; however, total- and phosphorylated-STAT3 levels were decreased in single cell miR-34a K562 clones. These data support a mechanism of fetal hemoglobin activation by miR-34a involving STAT3 gene silencing. PMID- 26940953 TI - Original Research: Parvovirus B19 infection in children with sickle cell disease in the hydroxyurea era. AB - Parvovirus B19 infection causes transient aplastic crisis in sickle cell disease (SCD) due to a temporary interruption in the red blood cell production. Toxicity from hydroxyurea includes anemia and reticulocytopenia, both of which also occur during a transient aplastic crisis event. Hydroxyurea inhibits proliferation of hematopoietic cells and may be immunosuppressive. We postulated that hydroxyurea could exacerbate parvovirus B19-induced aplastic crisis and inhibit the development of specific immune responses in children with SCD. We conducted a retrospective review of parvovirus B19 infection in 330 children with SCD. Altogether there were 120 known cases of aplastic crisis attributed to parvovirus B19 infection, and 12% of children were on hydroxyurea treatment during the episode. We evaluated hematological and immune responses. Children with HbSS or HbSbeta(0)-thalassemia treated with hydroxyurea, when compared with untreated children, required fewer transfusions and had higher Hb concentration nadir during transient aplastic crisis. Duration of hospital stays was no different between hydroxyurea-treated and untreated groups. Children tested within a week following aplastic crisis were positive for parvovirus-specific IgG. Immune responses lasted for the duration of the observation period, up to 13 years after transient aplastic crisis, and there were no repeat aplastic crisis episodes. The frequencies of parvovirus-specific antibodies in all children with SCD increased with age, as expected due to the increased likelihood of a parvovirus exposure, and were comparable to frequencies reported for healthy children. Approximately one-third of children had a positive parvovirus B19-specific IgG test without a documented history of transient aplastic crisis, and 64% of them were treated with hydroxyurea. Hydroxyurea may reduce requirements for blood transfusions and may attenuate symptoms during transient aplastic crisis episodes caused by parvovirus B19 infections. Children with SCD, whether treated or untreated with hydroxyurea, generate sustained and protective parvovirus B19-specific immune responses. PMID- 26940954 TI - Neonatal pneumococcal colonisation caused by Influenza A infection alters lung function in adult mice. AB - There is emerging epidemiological data to suggest that upper respiratory tract bacterial colonisation in infancy may increase the risk of developing respiratory dysfunction later in life, and respiratory viruses are known to precipitate persistent colonisation. This study utilized a neonatal mouse model of Streptococcus pneumonia (SP) and influenza A virus (IAV) co-infection, where bronchoalveolar leukocyte infiltration had resolved by adulthood. Only co infection resulted in persistent nasopharyngeal colonisation over 40 days and a significant increase in airway resistance in response to in vivo methacholine challenge. A significant increase in hysteresivity was also observed in IAV and co-infected mice, consistent with ventilatory heterogeneity and structural changes in the adult lung. Airway hyper-responsiveness was not associated with a detectable increase in goblet cell transdifferentiation, peribronchial smooth muscle bulk or collagen deposition in regions surrounding the airways. Increased reactivity was not observed in precision cut lung slices challenged with methacholine in vitro. Histologically, the airway epithelium appeared normal and expression of epithelial integrity markers (ZO-1, occludin-1 and E-cadherin) were not altered. In summary, neonatal co-infection led to persistent nasopharyngeal colonisation and increased airway responsiveness that was not associated with detectable smooth muscle or mucosal epithelial abnormalities, however increased hysteresivity may reflect ventilation heterogeneity. PMID- 26940955 TI - TRI6 and TRI10 play different roles in the regulation of deoxynivalenol (DON) production by cAMP signalling in Fusarium graminearum. AB - The biosynthesis of mycotoxin deoxynivalenol (DON) in Fusarium graminearum is regulated by two pathway-specific transcription factors Tri6 and Tri10 and affected by various host and environmental factors. In this study, we showed that cyclic adenosine monophosphate (cAMP) treatment induced DON production by stimulating TRI gene expression and DON-associated cellular differentiation in F. graminearum. Interestingly, exogenous cAMP had no effects on the tri6 mutant but partially recovered the defect of tri10 mutant in DON biosynthesis. Although the two cAMP phosphodiesterase genes PDE1 and PDE2 had overlapping functions in vegetative growth, conidiation, sexual reproduction and plant infection, deletion of PDE2 but not PDE1 activated intracellular PKA activities and increased DON production. Whereas the tri6 pde2 mutant failed to produce DON, the tri10 pde2 double mutant produced a significantly higher level of DON than the tri10 mutant. Cellular differentiation associated with DON production was stimulated by exogenous cAMP or deletion of PDE2 in both tri10 and tri6 mutants. These data indicate that TRI6 is essential for the regulation of DON biosynthesis by cAMP signalling but elevated PKA activities could partially bypass the requirement of TRI10 for TRI gene-expression and DON production, and Pde2 is the major cAMP phosphodiesterase to negatively regulate DON biosynthesis in F. graminearum. PMID- 26940956 TI - The determination of the DNA sequence specificity of bleomycin-induced abasic sites. AB - The DNA sequence specificity of the cancer chemotherapeutic agent, bleomycin, was determined with high precision in purified plasmid DNA using an improved technique. This improved technique involved the labelling of the 5'- and 3'-ends of DNA with different fluorescent tags, followed by simultaneous cleavage by bleomycin and capillary electrophoresis with laser-induced fluorescence. This permitted the determination of bleomycin cleavage specificity with high accuracy since end-label bias was greatly reduced. Bleomycin produces single- and double strand breaks, abasic sites and other base damage in DNA. This high-precision method was utilised to elucidate, for the first time, the DNA sequence specificity of bleomycin-induced DNA damage at abasic sites. This was accomplished using endonuclease IV that cleaves DNA at abasic sites after bleomycin damage. It was found that bleomycin-induced abasic sites formed at 5' GC and 5'-GT sites while bleomycin-induced phosphodiester strand breaks formed mainly at 5'-GT dinucleotides. Since bleomycin-induced abasic sites are produced in the absence of molecular oxygen, this difference in DNA sequence specificity could be important in hypoxic tumour cells. PMID- 26940957 TI - Protonation states of intermediates in the reaction mechanism of [NiFe] hydrogenase studied by computational methods. AB - The [NiFe] hydrogenases catalyse the reversible conversion of H2 to protons and electrons. The active site consists of a Fe ion with one carbon monoxide, two cyanide, and two cysteine (Cys) ligands. The latter two bridge to a Ni ion, which has two additional terminal Cys ligands. It has been suggested that one of the Cys residues is protonated during the reaction mechanism. We have used combined quantum mechanical and molecular mechanics (QM/MM) geometry optimisations, large QM calculations with 817 atoms, and QM/MM free energy simulations, using the TPSS and B3LYP methods with basis sets extrapolated to the quadruple zeta level to determine which of the four Cys residues is more favourable to protonate for four putative states in the reaction mechanism, Ni-SIa, Ni-R, Ni-C, and Ni-L. The calculations show that for all states, the terminal Cys-546 residue is most easily protonated by 14-51 kJ/mol, owing to a more favourable hydrogen-bond pattern around this residue in the protein. PMID- 26940960 TI - Balancing the benefits and detriments among women targeted by the Norwegian Breast Cancer Screening Program. AB - OBJECTIVE: To compute a ratio between the estimated numbers of lives saved from breast cancer death and the number of women diagnosed with a breast cancer that never would have been diagnosed during the woman's lifetime had she not attended screening (epidemiologic over-diagnosis) in the Norwegian Breast Cancer Screening Program. METHODS: The Norwegian Breast Cancer Screening Program invites women aged 50-69 to biennial mammographic screening. Results from published studies using individual level data from the programme for estimating breast cancer mortality and epidemiologic over-diagnosis comprised the basis for the ratio. The mortality reduction varied from 36.8% to 43% among screened women, while estimates on epidemiologic over-diagnosis ranged from 7% to 19.6%. We computed the average estimates for both values. The benefit-detriment ratio, number of lives saved, and number of women over-diagnosed were computed for different scenarios of reduction in breast cancer mortality and epidemiologic over diagnosis. RESULTS: For every 10,000 biennially screened women, followed until age 79, we estimated that 53-61 (average 57) women were saved from breast cancer death, and 45-126 (average 82) were over-diagnosed. The benefit-detriment ratio using average estimates was 1:1.4, indicating that the programme saved about one life per 1-2 women with epidemiologic over-diagnosis. CONCLUSION: The benefit detriment ratio estimates of the Norwegian Breast Cancer Screening Program, expressed as lives saved from breast cancer death and epidemiologic over diagnosis, should be interpreted with care due to substantial uncertainties in the estimates, and the differences in the scale of values of the events compared. PMID- 26940959 TI - Patterns of failure after use of (18)F-FDG PET/CT in integration of extended field chemo-IMRT and 3D-brachytherapy plannings for advanced cervical cancers with extensive lymph node metastases. AB - BACKGROUND: The study is to evaluate the patterns of failure, toxicities and long term outcomes of aggressive treatment using (18)F-FDG PET/CT-guided chemoradiation plannings for advanced cervical cancer with extensive nodal extent that has been regarded as a systemic disease. METHODS: We retrospectively reviewed 72 consecutive patients with (18)F-FDG PET/CT-detected widespread pelvic, para-aortic and/or supraclavicular lymph nodes treated with curative intent PET-guided cisplatin-based extended-field dose-escalating intensity modulated radiotherapy (IMRT) and adaptive high-dose-rate intracavitary 3D brachytherapy between 2002 and 2010. The failure sites were specifically localized by comparing recurrences on fusion of post-therapy recurrent (18)F-FDG PET/CT scans to the initial PET-guided radiation plannings for IMRT and brachytherapy. RESULTS: The median follow-up time for the 72 patients was 66 months (range, 3-142 months). The 5-year disease-free survival rate calculated by the Kaplan-Meier method for the patients with extensive N1 disease with the uppermost PET-positive pelvic-only nodes (26 patients), and the patients with M1 disease with the uppermost PET-positive para-aortic (31 patients) or supraclavicular (15 patients) nodes was 78.5 %, and 41.8-50 %, respectively (N1 vs. M1, p = 0.0465). Eight (11.1 %), 18 (25.0 %), and 3 (4.2 %) of the patients developed in-field recurrence, out-of-field and/or distant metastasis, and combined failure, respectively. The 6 (8.3 %) local failures around the uterine cervix were all at the junction between IMRT and brachytherapy in the parametrium. The rate of late grade 3/4 bladder and bowel toxicities was 4.2 and 9.7 %, respectively. When compared to conventional pelvic chemoradiation/2D brachytherapy during 1990-2001, the adoption of (18)F-FDG PET-guided extended field dose-escalating chemoradiation plannings in IMRT and 3D-brachytherapy after 2002 appeared to provide higher disease-free and overall survival rates with acceptable toxicities in advanced cervical cancer patients. CONCLUSIONS: For AJCC stage M1 cervical cancer with supraclavicular lymph node metastases, curability can be achieved in the era of PET and chemo-IMRT. However, the main pattern of failure is still out-of-field and/or distant metastasis. In addition to improving systemic treatment, how to optimize and integrate the junctional doses between IMRT and 3D-brachytherapy in PET-guided plannings to further decrease local recurrence warrants investigation. PMID- 26940961 TI - Effectiveness of timed and non-timed second appointments in improving uptake in breast cancer screening. AB - OBJECTIVES: To estimate the effect on breast screening uptake of delayed, targeted, second timed appointments in women who did not take up an initial breast cancer screening appointment offer. METHODS: Non-attending women received a four-month delayed second timed appointment following non-response to the initial invitation and the normal open invitation sent to non-attenders. A comparison group was sent a four-month delayed additional open invitation. RESULTS: Response to the second timed appointments (percentage of re-invited women eventually attending in this episode) was 20%, corresponding to an estimated increase on total uptake of 6%. Response was highest in women who had previously attended screens. Response in the women offered an additional delayed open invitation was 7.5%, corresponding to an estimated 2.3% increase in overall uptake. CONCLUSIONS: Second timed appointments were almost three times as effective as additional open invitation. They should be targeted at women most likely to attend. A randomized study of second timed appointments versus open invitations should be conducted. PMID- 26940962 TI - Complications after colonoscopy and surgery in a population-based colorectal cancer screening programme. AB - OBJECTIVES: To report complications after colonoscopy and surgery in patients with neoplasia detected through a population based colorectal cancer (CRC) screening programme in the capital region of Sweden. METHODS: Patients who after a positive FOBT screening result underwent colonoscopy from 1 January 2008 to 30 June 2012 were included. Mortality and complications within 30 days after colonoscopy or subsequent surgery were identified through national registers, and complications were assessed through review of medical charts. Complications were graded using the Clavien-Dindo classification. RESULTS: After 2984 colonoscopies, the complication rate was 1%. The risk of post-polypectomy bleeding was 14/1000. The risk of perforation was 1/1000 after a diagnostic colonoscopy and 2.5/1000 after a colonoscopy with polypectomy. One patient developed a post-polypectomy syndrome. There was one death which was not related to the colonoscopy. After surgery for 37 adenomas and 155 CRCs, the total complication rates were 27% and 50%, respectively. The rate of anastomotic leakage was 13% and 12% after surgery for adenomas and CRC, respectively. There were no deaths after surgery. The overall complication rate after colonoscopy and surgery for adenomas and cancer was 4%. CONCLUSIONS: Overall complication rates were acceptable and mortality low; however, the rate of anastomotic leakage after surgery for both adenomas and CRC was higher than expected. PMID- 26940964 TI - Beyond revascularization--Quality of hemodialysis and its impact on amputation prevention. PMID- 26940963 TI - Estimation of overdiagnosis using short-term trends and lead time estimates uncontaminated by overdiagnosed cases: Results from the Norwegian Breast Screening Programme. AB - BACKGROUND: Estimating overdiagnosis in cancer screening is complicated. Using observational data, estimation of the expected incidence in the screening period and taking account of lead time are two major problems. METHODS: Using data from the Cancer Registry of Norway and the Norwegian Breast Cancer Screening Programme, we estimated incidence trends, using age-specific trends by year in the pre-screening period (1985-95). We also estimated sojourn time and sensitivity using interval cancers only. Thus, lead time estimates were uncontaminated by overdiagnosed cases. Finally, we derived estimates of overdiagnosis separately for all cancers, and for invasive cancers only, correcting for lead time, using two different methods. RESULTS: Our results indicate that overdiagnosis of all cancers, invasive and in situ, constituted 15 17% of all screen-detected cancers in 1996-2009. For invasive cancers only, the corresponding figures were -2 to 7% in the same period, suggesting that a substantial proportion of the overdiagnosis in the Norwegian Programme was due to ductal carcinoma in situ. CONCLUSION: Using short-term trends, instead of long, prior to screening was more effective in predicting incidence in the screening epoch. In addition, sojourn time estimation using symptomatic cancers only avoids over-correction for lead time and consequently underestimation of overdiagnosis. Longer follow-up will provide more precise estimates of overdiagnosis. PMID- 26940965 TI - No Contradictions, But Directions for Further Research: A Reply to Hellmer and Stenson (2016). PMID- 26940966 TI - Number of Sexual Partners and Relationship Status Are Associated With Unprotected Sex Across Emerging Adulthood. AB - Sex with multiple partners, consecutively or concurrently, is a risk factor for contracting sexually transmitted infections (STIs) as multiple partner-partner contacts present increased opportunity for transmission. It is unclear, however, if individuals who tend to have more partners also use protection less reliably than those with sexual histories of fewer partners. Longitudinal data can elucidate whether an individual shows a consistent pattern of sex with multiple partners. We used latent class growth analyses to examine emerging adult survey data (N = 2244) spanning 10 waves of assessment across 6 years. We identified three trajectory classes described with respect to number of partners as (a) Multiple, (b) Single, and (c) Rare. Trajectory group, relationship status, and their interactions were tested as predictors of using protection against STIs and pregnancy at each wave. The Multiple Partners class had the greatest odds ratio of reporting sex without protection against STIs and pregnancy, followed by the Single and Rare classes. Exclusive relationship status was a risk factor for unprotected sex at earlier waves, but a protective factor at most later waves. There was no significant interaction between relationship status and trajectory class in predicting use of protection. The Multiple Partners class reported more permissive values on sex and an elevated proportion of homosexual behavior. This group overlaps with an already identified at-risk population, men who have sex with men. Potential mechanisms explaining the increased risk for sex without protection, including communication, risk assessment, and co-occurring risk behaviors are discussed as targets for intervention. PMID- 26940967 TI - Linking Prenatal Androgens to Gender-Related Attitudes, Identity, and Activities: Evidence From Girls With Congenital Adrenal Hyperplasia. AB - Key questions for developmentalists concern the origins of gender attitudes and their implications for behavior. We examined whether prenatal androgen exposure was related to gender attitudes, and whether and how the links between attitudes and gendered activity interest and participation were mediated by gender identity and moderated by hormones. Gender attitudes (i.e., gender-role attitudes and attitudes about being a girl), gender identity, and gender-typed activities were reported by 54 girls aged 10-13 years varying in degree of prenatal androgen exposure, including 40 girls with classical congenital adrenal hyperplasia (C CAH) exposed to high prenatal androgens and 14 girls with non-classical (NC) CAH exposed to low, female-typical, prenatal androgens. Both girls with C-CAH and NC CAH reported positive attitudes about being a girl and egalitarian gender attitudes, consistent with their female-typical gender identity. In contrast, girls with C-CAH had more male-typed activity interest and participation than girls with NC-CAH. Gender attitudes were linked to activities in both groups, with gender identity mediating the links. Specifically, gender-role attitudes and positive attitudes about being a girl were associated with feminine gender identity, which in turn was associated with decreased male-typed activity interests and participation, and increased female-typed activity interests. Our results are consistent with schema theories, with attitudes more closely associated with gender identity than with prenatal androgens. PMID- 26940968 TI - The Complexity of Multiple Contraceptive Method Use and the Anxiety That Informs It: Implications for Theory and Practice. AB - Despite clinical guidelines and national data describing the use of one contraceptive method as the best and most common way to prevent unintended pregnancy, limited evidence indicates a more complex picture of actual contraceptive practice. Face-to-face in-depth interviews were conducted in November of 2013 with a sample of women from two cities in the United States (n = 52). The interviews explored the ways participants used contraception to protect themselves from unintended pregnancy over the past 12 months. Most respondents reported using multiple methods, many of which are considered to be less effective, within this timeframe. The practice of combining methods in order to increase one's level of protection from pregnancy was prevalent, and was mainly enacted in two ways: by backing up inconsistent method use with other methods and by "buttressing" methods. These practices were found to be more common, and more complex, than previously described in the literature. These behaviors were mainly informed by a deep anxiety about both the efficacy of contraceptive methods, and about respondents' own perceived ability to prevent pregnancy. These findings challenge prevailing assumptions about women's contraceptive method use and have implications for clinical contraceptive counseling practice. PMID- 26940969 TI - Platelet functional and transcriptional changes induced by intralipid infusion. AB - Multiple studies have shown the effects of long-term exposure to high-fat or western diets on the vascular system. There is limited knowledge on the acute effects of high circulating fat levels, specifically on platelets, which have a role in many processes, including thrombosis and inflammation. This study investigated the effects of acute, high-fat exposure on platelet function and transcript profile. Twenty healthy participants were given an intravenous infusion of 20% Intralipid emulsion and heparin over 6 hours. Blood samples were taken prior to and the day after infusion to measure platelet function and transcript expression levels. Platelet aggregation was not significantly affected by Intralipid infusion, but, when mitochondria function was inhibited by carbonyl cyanide 3-chlorophenylhydrazone (CCCP) or oligomycin, platelet aggregation was higher in the post-infusion state compared to baseline. Through RNA sequencing, and verified by RT-qPCR, 902 miRNAs and 617 mRNAs were affected by Intralipid infusion. MicroRNAs increased include miR-4259 and miR-346, while miR-517b and miR-517c are both decreased. Pathway analysis identified two clusters significantly enriched, including cell motility. In conclusion, acute exposure to high fat affects mitochondrial-dependent platelet function, as well as the transcript profile. PMID- 26940970 TI - Multifunctional properties of organic-inorganic hybrid nanocomposites based on chitosan derivatives and layered double hydroxides for ocular drug delivery. AB - To improve the ocular bioavailability of the model drug of pirenoxine sodium (PRN), organic-inorganic hybrid nanocomposites including layered double hydroxides (LDH) and chitosan derivatives (chitosan-glutathione (CG), chitosan glutathione-valine (CG-V) and chitosan-glutathione-valine-valine (CG-VV)) were designed and characterized. In vivo precorneal retention study on rabbits showed that mean residence time (MRT) and area under the curve (AUC0-6h) of CG-PRN-LDH nanocomposite eye drop was up to 2.1-fold and 6.3-fold higher than those of commercial product, respectively. In vitro corneal penetration on rabbits demonstrated that the cumulative permeation of CG-VV-PRN-LDH nanocomposite dispersion was increased by 5.2 folds compared to that of commercial product, which may be due to the active transport effect of the nanocomposites by peptide transporter-1 (PepT-1). In addition, the ex vivo fluorescence imaging showed that fluorescent intensity of crystalline lens in rabbits was increased after the administration of PRN-LDH, CG-PRN-LDH, CG-V-PRN-LDH and CG-VV-PRN-LDH (in increasing order) nanocomposite eye drop. Finally, in vivo distribution evaluation in ocular tissues of rabbits revealed that AUC0-8h and MRT in crystalline lens exhibited 14.7-fold and 2.2-fold increase in CG-VV-PRN-LDH nanocomposite eye drop group than those of commercial group, respectively. In summary, the organic-inorganic hybrid nanocomposites with multifunctional properties may be a promising ocular drug delivery system to achieve prolonged precorneal retention, better corneal permeability and enhanced ocular bioavailability. STATEMENT OF SIGNIFICANCE: Due to several structural and physiological intraocular barriers, drug delivery to the ocular mid-posterior segments still faces great challenges. In this manuscript, organic-inorganic hybrid nanocomposites based on chitosan derivatives and layered double hydroxides (LDH) were designed and constructed. Multifunctional properties of these hybrid nanocomposites were due to the possible active targeting to the peptide transporter-1 on the corneal epithelial cells, the bioadhesive ability and permeation enhancement of chitosan derivatives, and the electrostatic adsorption of LDH. Prolonged precorneal retention, better corneal permeability and enhanced ocular bioavailability of the model drug pirenoxine sodium were observed. Chitosan derivatives-LDH hybrid nanocomposites may be a promising ophthalmic drug system for the treatment of ocular diseases of mid-posterior segments. PMID- 26940971 TI - Stem cells, biomarkers and genetic profiling: approaching future challenges in Urology. AB - Urological research is facing future challenges, the most difficult one is the fast and meaningful transfer of the massive amount of data from research basic to clinical practice. Between the most important issues that research should focus in the next years are targeting of tumor stem cells, clinical application of biomarkers, and wide application of genetic profiling of urological neoplasms. Several clinical implications are expected, from diagnosis to selection of candidates for different treatment modalities, to modulation of sequential treatment plans, to prognosis. A number of clinical trials based on research data from the hottest issues are in the pipeline. In this review, we will focus on new insights from recent work worlwide in urological research, with particular attention to high-risk nonmuscle-invasive and muscle-invasive bladder cancer, prostate cancer, and kidney cancer. Cancer care is moving towards a personalized approach in patient management. The most important issues in urological research point strongly in this direction and show an enormous potential for the rapid landing of Urology in the era of personalized medicine. PMID- 26940973 TI - The evolution of sperm axoneme structure and the dynein heavy chain complement in cecidomid insects. AB - The 9 + 2 axoneme of cilia and flagella is specialized machinery aimed at the production of efficient, finely tuned motility, and it has been evolutionarily conserved from protists to mammals. However, the sperm cells of several insects express unconventional axonemes, which represent unique models for studying the structural-functional relationships underlying axonemal function and evolution. Cecidomids comprise a group of dipterans characterized by an overall tendency to deviate from the standard axonemal pattern. In particular, the subfamily Cecidomyiinae shows a series of progressive modifications of the sperm axoneme. We previously analyzed the unusual sperm axonemes of Asphondylia ruebsaameni (Asphondyliidi) and Monarthropalpus buxi (Cecidomyiidi), which are characterized by the absence of any structure related to the control of motility (that is, the central pair complex, radial spokes and inner dynein arms); however, these sperm are motile, and motility is driven by the outer dynein arms only. This simplification of the motility machinery is accompanied by a parallel reduction in the dynein isoform complement. Here, we complete our survey of the axonemal organization and the parallel evolution of sperm dynein complement in cecidomids with the characterization of both the sperm ultrastructure and the dynein genes in Dryomyia lichtensteini, a representative of Lasiopteridi, the cecidomid taxon with aberrant and immotile sperm cells. On the basis of the whole set of our data, we discuss the potential molecular mechanism(s) underlying the progressive modification of axoneme in cecidomids, leading first to a reduction of dynein genes and eventually to the complete loss of motility. PMID- 26940972 TI - Short-term depression of gap junctional coupling in reticular thalamic neurons of absence epileptic rats. AB - KEY POINTS: Gap junctional electrical coupling between neurons of the reticular thalamic nucleus (RTN) is critical for hypersynchrony in the thalamo-cortical network. This study investigates the role of electrical coupling in pathological rhythmogenesis in RTN neurons in a rat model of absence epilepsy. Rhythmic activation resulted in a Ca(2+) -dependent short-term depression (STD) of electrical coupling between pairs of RTN neurons in epileptic rats, but not in RTN of a non-epileptic control strain. Pharmacological blockade of gap junctions in RTN in vivo induced a depression of seizure activity. The STD of electrical coupling represents a mechanism of Ca(2+) homeostasis in RTN aimed to counteract excessive synchronization. ABSTRACT: Neurons in the reticular thalamic nucleus (RTN) are coupled by electrical synapses, which play a major role in regulating synchronous activity. This study investigates electrical coupling in RTN neurons from a rat model of childhood absence epilepsy, genetic absence epilepsy rats from Strasbourg (GAERS), compared with a non-epileptic control (NEC) strain, to assess the impact on pathophysiological rhythmogenesis. Whole-cell recordings were obtained from pairs of RTN neurons of GAERS and NEC in vitro. Coupling was determined by injection of hyperpolarizing current steps in one cell and monitoring evoked voltage responses in both activated and coupled cell. The coupling coefficient (cc) was compared under resting condition, during pharmacological interventions and repeated activation using a series of current injections. The effect of gap junctional coupling on seizure expression was investigated by application of gap junctional blockers into RTN of GAERS in vivo. At resting conditions, cc did not differ between GAERS and NEC. During repeated activation, cc declined in GAERS but not in NEC. This depression in cc was restored within 25 s and was prevented by intracellular presence of BAPTA in the activated but not in the coupled cell. Local application of gap junctional blockers into RTN of GAERS in vivo resulted in a decrease of spike wave discharge (SWD) activity. Repeated activation results in a short-term depression (STD) of gap junctional coupling in RTN neurons of GAERS, depending on intracellular Ca(2+) mechanisms in the activated cell. As blockage of gap junctions in vivo results in a decrease of SWD activity, the STD observed in GAERS is considered a compensatory mechanism, aimed to dampen SWD activity. PMID- 26940974 TI - High throughput sequencing of small RNAs transcriptomes in two Crassostrea oysters identifies microRNAs involved in osmotic stress response. AB - Increasing evidence suggests that microRNAs post-transcriptionally regulate gene expression and are involved in responses to biotic and abiotic stress. However, the role of miRNAs involved in osmotic plasticity remains largely unknown in marine bivalves. In the present study, we performed low salinity challenge with two Crassostrea species (C. gigas and C. hongkongensis), and conducted high throughput sequencing of four small RNA libraries constructed from the gill tissues. A total of 202 and 87 miRNAs were identified from C. gigas and C. hongkongensis, respectively. Six miRNAs in C. gigas and two in C. hongkongensis were differentially expressed in response to osmotic stress. The expression profiles of these eight miRNAs were validated by qRT-PCR. Based on GO enrichment and KEGG pathway analysis, genes associated with microtubule-based process and cellular component movement were enriched in both species. In addition, five miRNA-mRNA interaction pairs that showed opposite expression patterns were identified in the C. hongkongensis, Differential expression analysis identified the miRNAs that play important regulatory roles in response to low salinity stress, providing insights into molecular mechanisms that are essential for salinity tolerance in marine bivalves. PMID- 26940975 TI - Blood Culture Contamination Definitions Can Obscure the Extent of Blood Culture Contamination: A New Standard for Satisfactory Institution Performance Is Needed. PMID- 26940976 TI - Glucose-regulated protein 78 (GRP78) binds directly to PIP3 phosphatase SKIP and determines its localization. AB - Skeletal muscle and kidney-enriched inositol polyphosphate phosphatase (SKIP), a PIP3 phosphatase, has been implicated in the regulation of insulin signaling in skeletal muscle. SKIP interacts with Pak1 and glucose-regulated protein 78 (GRP78), both of which are necessary for the regulation of insulin signaling. In this study, we showed that GRP78 directly binds to the SKIP C-terminal homology (SKICH) domain of SKIP and that this binding is necessary for the localization of SKIP at the ER. In addition, in vitro binding analysis showed that GRP78 and Pak1 competitively bind to SKIP. Taken together, these findings suggest a model by which GRP78 regulates intracellular localization of SKIP and how SKIP binds to Pak1 on insulin stimulation. PMID- 26940977 TI - A case series of young women with spontaneous regression of vulval intraepithelial neoplasia: Demographics and associated HPV genotypes. AB - OBJECTIVE: To review the clinical features, demography and human papillomavirus (HPV) genotype in a group of young women with usual type vulval intraepithelial neoplasia (VIN) whose lesions regressed spontaneously. MATERIALS AND METHODS: A retrospective case note review was made of the records of women with a diagnosis of usual type VIN whose lesions resolved spontaneously. The clinical features, demography, associated conditions, time to regression and follow-up data were extracted. Stored paraffin-embedded biopsy tissue was tested for the presence and genotype of HPV. RESULTS: Fifty-four women were identified. The median age at diagnosis was 19 years. Forty-four women (81%) were of non-European ethnicity. The median time to regression was 9 months. In 44 (81%) cases, the lesion was an incidental finding during clinical examination. The majority of lesions were multifocal and pigmented (44 (81%) and 48 (89%), respectively). HPV was detected in 40 (87%) of the 46 available biopsy samples, and HPV genotype 16 was identified in 33 (82.5%). Recurrences of usual type VIN occurred in three women, and these all resolved spontaneously. CONCLUSION: Women diagnosed with usual type VIN which resolves spontaneously are very young, mainly non-European, and usually present with multiple, asymptomatic pigmented lesions. HPV genotypes and their frequencies are similar to those detected in older women with usual type VIN. This clinically defined group of women may be managed by observation alone if follow-up is assured. PMID- 26940978 TI - First-principles modeling of 3d-transition-metal-atom adsorption on silicene: a linear-response DFT + U approach. AB - By employing DFT + U calculations with the linear response method, we investigate the interactions between various 3d transition-metal atoms (Cr, Mn, Fe, Co) and silicene. In the cases of two-dimensional (2D) FeSi2 and CoSi2, the metal atoms tend to penetrate into the silicene layer. While CoSi2 is non magnetic, FeSi2 exhibits a total magnetic moment of 2.21 MU(B)/cell. Upon the examination of 2D MSi6, a trend in anti-ferromagnetic (AFM) favorability in the z direction is observed according to our DFT + U calculations. In the ferromagnetic (FM) states (less stable), each primary unit cell of CrSi6, MnSi6, and FeSi6 possesses different levels of total magnetization (4.01, 5.18, and 2.00 MU B/cell, respectively). The absolute magnetization given by AFM MSi6 structures varies in the range of 5.33-5.84 MU(B)/cell. A direct band gap in AFM MnSi6 (0.2 eV) is predicted, while the metastable FM FeSi6 structure has a wider band gap (0.85 eV). Interestingly, there are superexchange interactions between metal atoms in the MSi6 systems, which result in the AFM alignments. PMID- 26940979 TI - Paul A. Levine, M.D. PMID- 26940980 TI - Silver catalyzed domino aza-annulation/Diels-Alder cyclization of 2-ene-yne anilines: a facile one-pot access to carbazole, dihydrocarbazole and tetrahydrocarbazole frameworks. AB - An unprecedented and efficient AgSbF6-catalyzed domino aza-annulation/Diels Alder/aromatization cascade for the construction of carbazoles, dihydrocarbazoles and tetrahydrocarbazoles was achieved using 2-(but-3-en-1-yn-1-yl) anilines in the presence of suitable dienophiles. The reaction proceeds via the in situ generation of 2-vinyl indoles and their subsequent trapping by various dienophiles with concomitant aromatization. A series of symmetrical, unsymmetrical and base sensitive dienophiles provide the corresponding carbazoles under mild conditions in excellent yields with high regioselectivity. PMID- 26940981 TI - Long-term outcome following thulium vaporesection of the prostate. AB - BACKGROUND: The continuous wave 2-MUm Thulium Laser has been introduced as potential technology with both high efficiency and safe practice; although little data have been shown regarding the long-term outcomes. OBJECTIVE: To analyze the long-term outcomes after thulium vaporesection of the prostate (ThuVaRP). METHODS: ThuVaRP was performed using the continuous wave, 2-MUm Thulium: YAG laser at 70 W. The perioperative and post-operative follow-up data were analyzed. RESULTS: The average age at surgery was 71.5 (range 55-94 years). The median prostate size was 60.1 g (range 36.3-109.8 g). A median operation time was noted at 44.8 +/- 6.5 minutes, while the median catheterization time was 3.5 +/- 0.5 days. In regards to hospital stay, most patients had an average duration of 5.5 +/- 1.5 days. Minor complications requiring non-interventional treatment happened in 237 (36.24%) of 654 patients, while major complications requiring re interventions occurred in one patient (0.15%). During a 60-month follow-up, bladder neck fibrosis occurred in 1.22% of the patients. A BPH recurrence happened in 17 (2.60%) patients, of which 14 patients (2.14%) received a second surgery. In comparison to the pre-operative baseline, the patients Qmax, PVR volume, IPSS, and Qol scores all improved significantly (P < 0.01) at time of discharge. This continued into the post-operative follow-up visits (3-6-12-18-14 26-48-60 months). CONCLUSIONS: ThuVaRP is both an effective and safe treatment procedure for symptomatic BPO (with a low occurrence of complications). Lasers Surg. Med. 48:505-510, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26940982 TI - Autologous transplantation of intestine-isolated glia cells improves neuropathology and restores cognitive deficits in beta amyloid-induced neurodegeneration. AB - Alzheimer's disease (AD) is characterized by chronic deposition of beta-amyloid (Abeta) in the brain, progressive neurodegeneration and consequent cognitive and behavioral deficits that typify the disease. Astrocytes are pivotal in this process because they are activated in the attempt to digest Abeta which starts a neuroinflammatory response that further contributes to neurodegeneration. The intestine is a good source of astrocytes-like cells-referred to as enteric glial cells (EGCs). Here we show that the autologous transplantation of EGCs into the brain of Abeta-injected rats arrested the development of the disease after their engraftment. Transplanted EGCs showed anti-amyloidogenic activity, embanked Abeta induced neuroinflammation and neurodegeneration, and released neutrophic factors. The overall result was the amelioration of the pathological hallmarks and the cognitive and behavioral deficits typical of Abeta-associated disease. Our data indicate that autologous EGCs transplantation may provide an efficient alternative for applications in cell-replacement therapies to treat neurodegeneration in AD. PMID- 26940983 TI - A coral-on-a-chip microfluidic platform enabling live-imaging microscopy of reef building corals. AB - Coral reefs, and the unique ecosystems they support, are facing severe threats by human activities and climate change. Our understanding of these threats is hampered by the lack of robust approaches for studying the micro-scale interactions between corals and their environment. Here we present an experimental platform, coral-on-a-chip, combining micropropagation and microfluidics to allow direct microscopic study of live coral polyps. The small and transparent coral micropropagates are ideally suited for live-imaging microscopy, while the microfluidic platform facilitates long-term visualization under controlled environmental conditions. We demonstrate the usefulness of this approach by imaging coral micropropagates at previously unattainable spatio temporal resolutions, providing new insights into several micro-scale processes including coral calcification, coral-pathogen interaction and the loss of algal symbionts (coral bleaching). Coral-on-a-chip thus provides a powerful method for studying coral physiology in vivo at the micro-scale, opening new vistas in coral biology. PMID- 26940985 TI - Predictors of Care Gaps in Adolescents With Complex Chronic Condition Transitioning to Adulthood. AB - CONTEXT: Breaks in the delivery of health care (ie, [health]care gaps) occur in a large proportion of young people transitioning to adulthood. Developing interventions that prevent adolescents from dropping out of the medical system, as they leave pediatric care, requires an understanding of determinants of care gaps. OBJECTIVE: To ascertain determinants of care gaps in young people with chronic conditions as they transition to adulthood by performing a systematic literature search. DATA SOURCES: MEDLINE, CINAHL, and Embase were queried for pertinent peer-reviewed publications. STUDY SELECTION: Primary quantitative or mixed methods studies that aimed to identify determinants of care gaps in young people (aged 10-25 years) diagnosed with complex chronic conditions and written in English, French, or Dutch were selected. Ten publications satisfied these criteria. DATA EXTRACTION: For each publication, determinants of care gaps and quantitative results were extracted. Determinants were categorized into 4 groups using thematic analysis. Quantitative results were standardized, and raw data were converted into odds ratios. RESULTS: Overall, 11 risk factors and 9 protective factors for care gaps were identified. All factors were related to patient characteristics. Demographics, disease-related characteristics, health care services use, and patient health behaviors and beliefs were significant determinants of care gaps in adolescents with chronic conditions. LIMITATIONS: Large variability in study methods, statistical techniques, and study populations resulted in inconsistent study findings. CONCLUSIONS: This systematic review identified patient-related determinants of care gaps. Unfortunately, the internal and external validity of the study findings are limited, warranting future prospective, multilevel studies that address remaining knowledge gaps. PMID- 26940984 TI - H/C atomic ratio as a smart linkage between pyrolytic temperatures, aromatic clusters and sorption properties of biochars derived from diverse precursory materials. AB - Biochar is increasingly gaining attention due to multifunctional roles in soil amelioration, pollution mitigation and carbon sequestration. It is a significant challenge to compare the reported results from world-wide labs regarding the structure and sorption of biochars derived from various precursors under different pyrolytic conditions due to a lack of a simple linkage. By combining the published works on various biochars, we established a quantitative relationship between H/C atomic ratio and pyrolytic temperature (T), aromatic structure, and sorption properties for naphthalene and phenanthrene. A reverse sigmoid shape between T and the H/C ratio was observed, which was independent of the precursors of biochars, including the ash contents. Linear correlations of Freundlich parameters (N, log Kf) and sorption amount (log Qe, log QA) with H/C ratios were found. A rectangle-like model was proposed to predict the aromatic cluster sizes of biochars from their H/C ratios, and then a good structure sorption relationship was derived. These quantitative relationships indicate that the H/C atomic ratio is a universal linkage to predict pyrolytic temperatures, aromatic cluster sizes, and sorption characteristics. This study would guide the global study of biochars toward being comparable, and then the development of the structure-sorption relationships will benefit the structural design and environmental application of biochars. PMID- 26940986 TI - Pediatric Leukemia, Psychosocial Dimensions of Cures, and Implications for HIV. PMID- 26940987 TI - Neurobehavioral Outcomes in Children After Out-of-Hospital Cardiac Arrest. AB - OBJECTIVE: This study examined 12-month neurobehavioral outcomes in children who survived out-of-hospital cardiac arrest (OH-CA), were comatose after resuscitation, and were enrolled in a clinical trial to evaluate targeted temperature management to hypothermia (33.0 degrees C) or normothermia (36.8 degrees C) (Therapeutic Hypothermia after Pediatric Cardiac Arrest, Out-of Hopsital [THAPCA-OH]; NCT00878644). METHODS: Baseline functioning was assessed by caregiver responses on the Vineland Adaptive Behavior Scales-Second Edition (VABS II) soon after OH-CA (based on functioning before OH-CA); children with broadly normal baseline functioning (VABS-II >=70) were included in the THAPCA-OH primary outcome. VABS-II was completed again 12 months later. Then, face-to-face cognitive evaluations were completed. Analyses evaluated changes in VABS-II composite, domain, and subdomain scores and cognitive functioning at follow-up. RESULTS: Ninety-six of 295 enrolled children were alive at 12 months; 87 of 96 had broadly normal baseline functioning (VABS-II >=70). Follow-up was obtained on 85/87. Forty-two of 85 had VABS-II >=70 at 12 months. VABS-II composite, domain, and subdomain scores declined significantly between baseline and 12-month follow up (P < .001). Declines were greatest in older children. Most children displayed well below average cognitive functioning. Older age at cardiac arrest and higher baseline VABS-II scores were predictive of greater decline in neurobehavioral function. Treatment with hypothermia did not influence neurobehavioral outcomes. CONCLUSIONS: This is the largest study exploring long-term neurobehavioral outcomes in children surviving OH-CA who were comatose after resuscitation. Results revealed significant neurobehavioral morbidity across multiple functional domains, based both on caregiver reports and performance on objective cognitive measures, in survivors 1 year later. PMID- 26940989 TI - Survey of Ebola Preparedness in Washington State Emergency Departments. AB - OBJECTIVE: The 2014 Ebola virus disease (EVD) outbreak in West Africa remains the most deadly in history. Emergency departments (EDs) are more likely to come into contact with potential EVD patients. It is important for EDs to be prepared to care for suspected EVD patients. Our objective was to understand the perceived challenges experienced by Washington State ED medical directors in EVD preparedness. METHODS: An anonymous, electronic survey was sent to a convenience sample of ED medical directors across Washington State between November and February of 2014-2015. The perceived challenges of and attitudes toward EVD preparations were assessed and reported as stratified proportions. RESULTS: Of 85 medical directors contacted, 59 responses (69%) were received. This included EDs with annual patient volumes of 60,000 (12 hospitals, 20%). Among the perceived challenges in EVD preparations were spatial modifications (eg, building an anteroom for donning and doffing of personal protective equipment) and waste management planning. Ninety-five percent of respondents moderately or strongly agreed that it is important to have a predesignated hospital to care for EVD patients. CONCLUSIONS: Washington State ED medical directors have faced significant challenges in ensuring their EDs are prepared to safely care for suspected EVD patients. Attitudes toward EVD preparations are mixed. Varying levels of perceived importance may represent an additional barrier to statewide EVD preparedness. (Disaster Med Public Health Preparedness. 2016;10:662-668). PMID- 26940988 TI - Similar and Different? Subjective Effects of Methylphenidate and Cocaine in Opioid-Maintained Patients. AB - Methylphenidate (MPH) is commonly prescribed for attention deficit hyperactivity disorder (ADHD). Recreational nonmedical use has been described and also occurs in patients on opioid maintenance treatment (OMT). MPH has been proposed for use as replacement therapy in cocaine dependence, although evidence for efficacy is inconclusive. We conducted a cross-sectional interview study on patterns of MPH use in a sample of 20 MPH-using patients on OMT with a history of cocaine use. We assessed symptoms of depression, ADHD during childhood, and retrospective subjective-effects profiles of MPH and cocaine. Risky patterns of MPH use were common, in particular illicit acquisition, use of high doses, and parenteral administration. Sixty percent of patients reported having used MPH as a substitute for cocaine. Correspondingly, the subjective-effect profiles of MPH and cocaine showed striking parallels, with overall effects of MPH being rated more positively than those of cocaine. Proportions of patients with elevated scores for depression or childhood ADHD were large, highlighting the importance of treating dual disorders in this population. Clinical studies on MPH substitution in cocaine-dependent patients on opioid maintenance treatment could benefit from consideration of the patterns of application of MPH in this population. Results are preliminary due to small sample size. PMID- 26940990 TI - Correspondence of Drosophila polycomb group proteins with broad H3K27me3 silent domains. PMID- 26940991 TI - Can the follow-up of patients with papillary thyroid carcinoma of low and intermediate risk and excellent response to initial therapy be simplified using second-generation thyroglobulin assays? AB - OBJECTIVE: In view of the low probability of recurrence, the cost-effective follow-up of patients with papillary thyroid carcinoma (PTC) of low or intermediate risk and excellent response to initial therapy represents a challenge. This study evaluated the cases of structural recurrence among these patients. PATIENTS: The sample comprised 578 patients with PTC of low or intermediate risk, who were submitted to total thyroidectomy with or without (131) I therapy and exhibited an excellent response to initial therapy defined based on nonstimulated thyroglobulin (Tg) <=0.2 ng/ml and negative neck ultrasonography (US). RESULTS: Twelve patients (2%) showed structural recurrence. At the time when recurrence was 'confirmed', Tg elevation had not occurred in only two patients, one with lymph node metastases <1 cm detected by US and the other with pulmonary metastases. Antithyroglobulin antibodies (TgAb) were undetectable in both patients. The first alteration observed in patients with recurrence was Tg elevation in six patients, Tg elevation associated with suspicious US in three, and suspicious US in two. An increase in TgAb was not the first alteration in any of the patients. Among the 560 patients who continued to have Tg <= 0.2 ng/ml, US permitted the detection of only one neck recurrence. Measurement of TgAb did not detect any recurrence. CONCLUSION: Our results confirm that in patients with PTC of low or intermediate risk an excellent response to initial therapy can be defined based on nonstimulated Tg <= 0.2 ng/ml. Follow-up consisting only of clinical examination and periodic measurement of Tg with a second-generation assay may be sufficient. PMID- 26940992 TI - A hierarchical method to automatically encode Chinese diagnoses through semantic similarity estimation. AB - BACKGROUND: The accumulation of medical documents in China has rapidly increased in the past years. We focus on developing a method that automatically performs ICD-10 code assignment to Chinese diagnoses from the electronic medical records to support the medical coding process in Chinese hospitals. METHODS: We propose two encoding methods: one that directly determines the desired code (flat method), and one that hierarchically determines the most suitable code until the desired code is obtained (hierarchical method). Both methods are based on instances from the standard diagnostic library, a gold standard dataset in China. For the first time, semantic similarity estimation between Chinese words are applied in the biomedical domain with the successful implementation of knowledge based and distributional approaches. Characteristics of the Chinese language are considered in implementing distributional semantics. We test our methods against 16,330 coding instances from our partner hospital. RESULTS: The hierarchical method outperforms the flat method in terms of accuracy and time complexity. Representing distributional semantics using Chinese characters can achieve comparable performance to the use of Chinese words. The diagnoses in the test set can be encoded automatically with micro-averaged precision of 92.57 %, recall of 89.63 %, and F-score of 91.08 %. A sharp decrease in encoding performance is observed without semantic similarity estimation. CONCLUSION: The hierarchical nature of ICD-10 codes can enhance the performance of the automated code assignment. Semantic similarity estimation is demonstrated indispensable in dealing with Chinese medical text. The proposed method can greatly reduce the workload and improve the efficiency of the code assignment process in Chinese hospitals. PMID- 26940993 TI - RSK3 is required for concentric myocyte hypertrophy in an activated Raf1 model for Noonan syndrome. AB - Noonan syndrome (NS) is a congenital disorder resulting from mutations of the Ras Raf signaling pathway. Hypertrophic cardiomyopathy associated with RAF1 "RASopathy" mutations is a major risk factor for heart failure and death in NS and has been attributed to activation of MEK1/2-ERK1/2 mitogen-activated protein kinases. We recently discovered that type 3 p90 ribosomal S6 kinase (RSK3) is an ERK effector that is required, like ERK1/2, for concentric myocyte hypertrophy in response to pathological stress such as pressure overload. In order to test whether RSK3 also contributes to NS-associated hypertrophic cardiomyopathy, RSK3 knock-out mice were crossed with mice bearing the Raf1(L613V) human NS mutation. We confirmed that Raf1(L613V) knock-in confers a NS-like phenotype, including cardiac hypertrophy. Active RSK3 was increased in Raf1(L613V) mice. Constitutive RSK3 gene deletion prevented the Raf1(L613V)-dependent concentric growth in width of the cardiac myocyte and attenuated cardiac hypertrophy in female mice. These results are consistent with RSK3 being an important mediator of ERK1/2-dependent growth in RASopathy. In conjunction with previously published data showing that RSK3 is important for pathological remodeling of the heart, these data suggest that targeting of this downstream MAP-kinase pathway effector should be considered in the treatment of RASopathy-associated hypertrophic cardiomyopathy. PMID- 26940995 TI - Atlantic SSTs control regime shifts in forest fire activity of Northern Scandinavia. AB - Understanding the drivers of the boreal forest fire activity is challenging due to the complexity of the interactions driving fire regimes. We analyzed drivers of forest fire activity in Northern Scandinavia (above 60 N) by combining modern and proxy data over the Holocene. The results suggest that the cold climate in northern Scandinavia was generally characterized by dry conditions favourable to periods of regionally increased fire activity. We propose that the cold conditions over the northern North Atlantic, associated with low SSTs, expansion of sea ice cover, and the southward shift in the position of the subpolar gyre, redirect southward the precipitation over Scandinavia, associated with the westerlies. This dynamics strengthens high pressure systems over Scandinavia and results in increased regional fire activity. Our study reveals a previously undocumented teleconnection between large scale climate and ocean dynamics over the North Atlantic and regional boreal forest fire activity in Northern Scandinavia. Consistency of the pattern observed annually through millennium scales suggests that a strong link between Atlantic SST and fire activity on multiple temporal scales over the entire Holocene is relevant for understanding future fire activity across the European boreal zone. PMID- 26940994 TI - GWASeq: targeted re-sequencing follow up to GWAS. AB - BACKGROUND: For the last decade the conceptual framework of the Genome-Wide Association Study (GWAS) has dominated the investigation of human disease and other complex traits. While GWAS have been successful in identifying a large number of variants associated with various phenotypes, the overall amount of heritability explained by these variants remains small. This raises the question of how best to follow up on a GWAS, localize causal variants accounting for GWAS hits, and as a consequence explain more of the so-called "missing" heritability. Advances in high throughput sequencing technologies now allow for the efficient and cost-effective collection of vast amounts of fine-scale genomic data to complement GWAS. RESULTS: We investigate these issues using a colon cancer dataset. After QC, our data consisted of 1993 cases, 899 controls. Using marginal tests of associations, we identify 10 variants distributed among six targeted regions that are significantly associated with colorectal cancer, with eight of the variants being novel to this study. Additionally, we perform so-called 'SNP set' tests of association and identify two sets of variants that implicate both common and rare variants in the etiology of colorectal cancer. CONCLUSIONS: Here we present a large-scale targeted re-sequencing resource focusing on genomic regions implicated in colorectal cancer susceptibility previously identified in several GWAS, which aims to 1) provide fine-scale targeted sequencing data for fine-mapping and 2) provide data resources to address methodological questions regarding the design of sequencing-based follow-up studies to GWAS. Additionally, we show that this strategy successfully identifies novel variants associated with colorectal cancer susceptibility and can implicate both common and rare variants. PMID- 26940996 TI - Intermolecular disulfide bond in the dimerization of S-periaxin mediated by Cys88 and Cys139. AB - Periaxin is expressed in mammalian Schwann cells and lens fiber cells, and has been identified in a screen for cytoskeleton-associated proteins. Charcot-Marie Tooth 4F is caused by losses or mutations of theperiaxingene. Theperiaxingene encodes two protein isoforms, namely, L-periaxin and S-periaxin.S-periaxin contains 147 amino acid residues and has an N-terminal PDZ domain. In this paper, S-periaxin was reported to be homodimerized through the formation of intermolecular disulfide bonds with its Cys88 and Cys139 residues under mild oxidation conditions. The covalent dimer of S-periaxin was also observed by western blot analysis and bimolecular fluorescence complementation analyses. S periaxin dimerization formation could be regulated by cellular redox fluctuations. These results offer a possible mechanism to the formation of periaxin complexes, improvement of complex stability, and establishment of a link between the extracellular matrix and the cytoskeleton. PMID- 26940997 TI - Atorvastatin blocks increased l-type Ca2+ current and cell injury elicited by angiotensin II via inhibiting oxide stress. AB - Thel-type Ca(2+)current (ICa,l) plays a crucial role in shaping action potential and is involved in cardiac arrhythmia. Statins have been demonstrated to contribute to anti-apoptotic and anti-arrhythmic effects in the heart. Here, we examined whether atorvastatin regulates theICa,land cell injury induced by angiotensin II (AngII) as well as the putative intracellular cascade responsible for the effects. Cultured neonatal rat ventricular myocytes were incubated with AngII for 24 h, and then cell injury and expression levels of Nox2/gp91(phox), p47(phox) ,and Cav1.2 were analyzed. In addition,ICa,lwas recorded using the whole-cell patch-clamp technique, and mechanisms of atorvastatin actions were also investigated. It was found that the number of apoptotic cardiomyocytes was increased and cell viability was significantly decreased after AngII administration. AngII also augmented the expressions of Nox2/gp91(phox)and p47(phox)compared with control cardiomyocytes. Exposure to AngII evokedICa,lin a voltage-dependent manner without affecting theI-Vrelationship. In addition, AngII enhanced membrane Cav1.2 expression. These effects were abolished in the presence of the reactive oxygen species (ROS) scavenger, manganese (III)-tetrakis 4 benzoic acid porphyrin [Mn(III)TBAP], or the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor, atorvastatin. These results suggested that atorvastatin mediates cardioprotection against arrhythmias and cell injury by controlling the AngII-ROS cascade. PMID- 26940998 TI - Holocene ice marginal fluctuations of the Qassimiut lobe in South Greenland. AB - Knowledge about the Holocene evolution of the Greenland ice sheet (GrIS) is important to put the recent observations of ice loss into a longer-term perspective. In this study, we use six new threshold lake records supplemented with two existing lake records to reconstruct the Holocene ice marginal fluctuations of the Qassimiut lobe (QL) - one of the most dynamic parts of the GrIS in South Greenland. Times when the ice margin was close to present extent are characterized by clastic input from the glacier meltwater, whereas periods when the ice margin was behind its present day extent comprise organic-rich sediments. We find that the overall pattern suggests that the central part of the ice lobe in low-lying areas experienced the most prolonged ice retreat from ~9 0.4 cal. ka BP, whereas the more distal parts of the ice lobe at higher elevation re-advanced and remained close to the present extent during the Neoglacial between ~4.4 and 1.8 cal. ka BP. These results demonstrate that the QL was primarily driven by Holocene climate changes, but also emphasises the role of local topography on the ice marginal fluctuations. PMID- 26940999 TI - Impact of food animal trade on the spread of mcr-1-mediated colistin resistance, Tunisia, July 2015. AB - We report a high prevalence of MCR-1 and CTX-M-1-producing Escherichia coli in three Tunisian chicken farms. Chickens were imported from France or derived from French imported chicks. The same IncHI2-type plasmid reported to carry those genes in cattle in France and in a food sample in Portugal was found in Tunisian chickens of French origin. This suggests a significant impact of food animal trade on the spread of mcr-1-mediated colistin resistance in Europe. PMID- 26941000 TI - Predictors of health-related quality of life in patients with systemic lupus erythematosus associated pulmonary arterial hypertension. AB - OBJECTIVES: Understanding health-related quality of life (HRQoL) is important in the management of patients with systemic lupus erythematosus associated pulmonary arterial hypertension (SLE-APAH), however, little is known about HRQoL and its determinants in these patients. METHODS: A total of 60 female SLE-APAH patients with mean age of 33.5 years were prospectively recruited from May 2013 to November 2014. Right heart catheter, SF-36 generic questionnaire, disease activity and functional status were assessed in all patients. RESULTS: The median duration of SLE was 5 years. Thirty-five participants were with low disease activity (SLEDAI: 0-4). Patients with SLE-APAH reported significant impairment in HRQoL. The mean physical component summary (PCS) and mental component summary (MCS) scores were 46.4 and 56.9, respectively. Among haemodynamic measurements, higher pulmonary vascular resistance and lower cardiac output (CO) were associated with worse HRQoL. Lower body mass index (BMI), lower mean blood pressure and higher disease activity were also associated with poor HRQoL. Multivariate analysis revealed that lower SLEDAI and higher mean blood pressure were predictors for better PCS. However, higher CO (CO>=4L/min) was the only parameter independently associated with both better PCS and MCS. CONCLUSIONS: Self-reported HRQoL was impaired in patients with SLE-APAH. Higher CO was the most important predictor for better HRQoL in these patients. PMID- 26941002 TI - Abdominal compartment syndrome in traumatic hemorrhagic shock: is there a fluid resuscitation inflection point associated with increased risk? AB - BACKGROUND: The volume of fluid administered during trauma resuscitation correlates with the risk of abdominal compartment syndrome (ACS). The exact volume at which this risk rises is uncertain. We established the inflection point for ACS risk during shock resuscitation. METHODS: Using the Glue Grant database, patients aged >=16 years with ACS were compared with those without ACS (no-ACS). Stepwise analysis of the sum or difference of the mean total fluid volume (TV)/kg, TV and/or body weight, (MU) and standard deviations (sigma) vs % ACS at each point was used to determine the fluid inflection point. RESULTS: A total of 1,976 patients were included, of which 122 (6.2%) had ACS. Compared with no-ACS, ACS patients had a higher emergency room lactate (5.8 +/- 3.0 vs 4.5 +/- 2.8, P < .001), international normalized ratio (1.8 +/- 1.5 vs 1.4 +/- .8, P < .001), and mortality (37.7% vs 14.6%, P < .001). ACS group received a higher TV/kg (498 +/- 268 mL/kg vs 293 +/- 171 mL/kg, P < .001) than no-ACS. The % ACS increased exponentially with the sum of MU and incremental sigma, with the sharpest increase occurring at TV and/or body weight = MU + 3sigma or 1,302 mL/kg. CONCLUSIONS: There is a dramatic rise in ACS risk after 1,302 mL/kg of fluid is administered. This plot could serve as a guide in limiting the ACS risk during resuscitation. PMID- 26941001 TI - Architecture of the Yeast Mitochondrial Iron-Sulfur Cluster Assembly Machinery: THE SUB-COMPLEX FORMED BY THE IRON DONOR, Yfh1 PROTEIN, AND THE SCAFFOLD, Isu1 PROTEIN. AB - The biosynthesis of Fe-S clusters is a vital process involving the delivery of elemental iron and sulfur to scaffold proteins via molecular interactions that are still poorly defined. We reconstituted a stable, functional complex consisting of the iron donor, Yfh1 (yeast frataxin homologue 1), and the Fe-S cluster scaffold, Isu1, with 1:1 stoichiometry, [Yfh1]24.[Isu1]24 Using negative staining transmission EM and single particle analysis, we obtained a three dimensional reconstruction of this complex at a resolution of ~17 A. In addition, via chemical cross-linking, limited proteolysis, and mass spectrometry, we identified protein-protein interaction surfaces within the complex. The data together reveal that [Yfh1]24.[Isu1]24 is a roughly cubic macromolecule consisting of one symmetric Isu1 trimer binding on top of one symmetric Yfh1 trimer at each of its eight vertices. Furthermore, molecular modeling suggests that two subunits of the cysteine desulfurase, Nfs1, may bind symmetrically on top of two adjacent Isu1 trimers in a manner that creates two putative [2Fe-2S] cluster assembly centers. In each center, conserved amino acids known to be involved in sulfur and iron donation by Nfs1 and Yfh1, respectively, are in close proximity to the Fe-S cluster-coordinating residues of Isu1. We suggest that this architecture is suitable to ensure concerted and protected transfer of potentially toxic iron and sulfur atoms to Isu1 during Fe-S cluster assembly. PMID- 26941003 TI - Morbid obesity is an independent risk factor for postoperative renal dysfunction in young adults: a review of the American College of Surgeons National Surgical Quality Improvement Program database. AB - BACKGROUND: Little information exists on the acute effects of elective surgery on renal function. Our aim was to determine if obesity was an independent risk factor for postoperative renal complications (RCs). METHODS: A total of 119,142 patients aged 18 to 35 years with body mass index (BMI) >=18 kg/m(2) obtained from American College of Surgeons National Surgical Quality Improvement Project (2005 to 2010) were classified into standard BMI categories. Association between BMI and preoperative estimated glomerular filtration rate (eGFR; calculated using modification of diet in renal disease formula) was analyzed. Postoperative changes in eGFR and RCs were measured. Multivariate regression analysis was performed adjusting for all variables. RESULTS: Postoperatively, there was a reduction in eGFR among the overweight (-3.4 mL/min/1.73 m(2), P < .001), obese class I (-3.9 mL/min/1.73 m(2), P = .001), and obese class II (-5.3 mL/min/1.73 m(2), P < .001). The odds of any postoperative RC was significantly higher in obese class III patients (odds ratio = 2.01 95% confidence interval 1.07 to 3.76, P = .029). CONCLUSIONS: Results seen in patients with BMI greater than 40 indicate that BMI can serve as an independent predictor of RCs. PMID- 26941004 TI - US to require safety warnings for Essure sterilization device. PMID- 26941005 TI - Spontaneous Closure of a Full-Thickness Macular Hole With Conversion to Exudative Age-Related Macular Degeneration. PMID- 26941006 TI - Disruptions in the hypothalamic-pituitary-gonadal axis in rat offspring following prenatal maternal exposure to lipopolysaccharide. AB - Postnatal treatment with bacterial endotoxin lipopolysaccharide (LPS) changes the activity of the hypothalamic-pituitary-gonadal (HPG) axis and the gonadotropin releasing hormone (GnRH) surge in rats. Exposure to an immune challenge in the critical periods of development has profound and long-lasting effects on the stress response, immune, metabolic, and reproductive functions. Prenatal LPS treatment delays the migration of GnRH neurons associated with increased cytokine release in maternal and fetal compartments. We investigated the effects of a single maternal exposure to LPS (18 MUg/kg, i.p.) on day 12 (embryonic day (E)12) of pregnancy on reproductive parameters in rat offspring. Hypothalamic GnRH content, plasma luteinizing hormone (LH), testosterone, and estradiol concentrations were measured in both male and female offsprings at different stages of postnatal development by RIA and ELISA (n = 10 each per group). Body weight and in females day of vaginal opening (VO) were recorded. In offspring exposed to LPS prenatally, compared with controls, body weight was decreased in both sexes at P5 and P30; in females, VO was delayed; hypothalamic GnRH content was decreased at postnatal days 30-60 (P30-P60) in both sexes; plasma LH concentration was decreased at P14-P60 in females; plasma concentrations of testosterone/estradiol were increased at P14 in females, and plasma estradiol was increased at P14 in males. Hence activation of the maternal immune system by LPS treatment at a prenatal critical period leads to decreased GnRH and LH levels in pre- and postpubertal life and sex steroid imbalance in the prepubertal period, and delayed sexual maturation of female offspring. PMID- 26941007 TI - Autoimmunity Against the Heart and Cardiac Myosin in Children With Myocarditis. AB - BACKGROUND: Host autoimmune activity in myocarditis has been proposed to play a role in development of cardiac disease, but evidence of autoimmunity and relationship to outcomes have not been evaluated in pediatric myocarditis. METHODS: We performed a multi-institutional study of children with clinical myocarditis. Newly diagnosed patients were followed for up to 12 months and previously diagnosed patients at a single follow-up for serum levels of autoantibodies to human cardiac myosin, beta-adrenergic receptors 1 and 2, muscarinic-2 receptors, and antibody-mediated protein kinase A (PKA) activation in heart cells in culture. Results were compared with those of healthy control children. RESULTS: Both previously diagnosed patient at follow-up (P = .0061) and newly diagnosed patients at presentation (P = .0127) had elevated cardiac myosin antibodies compared with control subjects. Antibody levels were not associated with recovery status at follow-up in either group. PKA activation was higher at presentation in the newly diagnosed patients who did not recovery normal function (P = .042). CONCLUSIONS: Children with myocarditis have evidence of autoantibodies against human cardiac myosin at diagnosis and follow-up compared with control subjects. Differences in antibody-mediated cell signaling may contribute to differences in patient outcomes, as suggested by elevated antibody mediated PKA activation in heart cells by the serum from nonrecovered patients. PMID- 26941008 TI - Three reasons protein disorder analysis makes more sense in the light of collagen. AB - We have identified that the collagen helix has the potential to be disruptive to analyses of intrinsically disordered proteins. The collagen helix is an extended fibrous structure that is both promiscuous and repetitive. Whilst its sequence is predicted to be disordered, this type of protein structure is not typically considered as intrinsic disorder. Here, we show that collagen-encoding proteins skew the distribution of exon lengths in genes. We find that previous results, demonstrating that exons encoding disordered regions are more likely to be symmetric, are due to the abundance of the collagen helix. Other related results, showing increased levels of alternative splicing in disorder-encoding exons, still hold after considering collagen-containing proteins. Aside from analyses of exons, we find that the set of proteins that contain collagen significantly alters the amino acid composition of regions predicted as disordered. We conclude that research in this area should be conducted in the light of the collagen helix. PMID- 26941009 TI - FTIR Spectroscopy for Carbon Family Study. AB - Fourier transform Infrared (FTIR) spectroscopy is a versatile technique for the characterization of materials belonging to the carbon family. Based on the interaction of the IR radiation with matter this technique may be used for the identification and characterization of chemical structures. Most important features of this method are: non-destructive, real-time measurement and relatively easy to use. Carbon basis for all living systems has found numerous industrial applications from carbon coatings (i.e. amorphous and nanocrystalline carbon films: diamond-like carbon (DLC) films) to nanostructured materials (fullerenes, nanotubes, graphene) and carbon materials at nanoscale or carbon dots (CDots). In this paper, we present the FTIR vibrational spectroscopy for the characterization of diamond, amorphous carbon, graphite, graphene, carbon nanotubes (CNTs), fullerene and carbon quantum dots (CQDs), without claiming to cover entire field. PMID- 26941010 TI - Importance of Integration and Implementation of Emerging and Future Mercury Research into the Minamata Convention. PMID- 26941011 TI - Detection of Zymoseptoria tritici SDHI-insensitive field isolates carrying the SdhC-H152R and SdhD-R47W substitutions. AB - BACKGROUND: Succinate dehydrogenase inhibitor (SDHI) fungicides are important in the management of Zymoseptoria tritici in wheat. New active ingredients from this group of fungicides have been introduced recently and are widely used. Because the fungicides act at a single enzyme site, resistance development in Z. tritici is classified as medium-to-high risk. RESULTS: Isolates from Irish experimental plots in 2015 were tested against the SDHI penthiopyrad during routine monitoring. The median of the population was approximately 2 times less sensitive than the median of the baseline population. Two of the 93 isolates were much less sensitive to penthiopyrad than the least sensitive of the baseline isolates. These isolates were also insensitive to most commercially available SDHIs. Analysis of the succinate dehydrogenase coding genes confirmed the presence of the substitutions SdhC-H152R and SdhD-R47W in the very insensitive isolates. CONCLUSION: This is the first report showing that the SdhC-H152R mutation detected in laboratory mutagenesis studies also exists in the field. The function and relevance of this mutation, combined with SdhD-R47W, still needs to be determined. (c) 2016 Society of Chemical Industry. PMID- 26941012 TI - Anti-N-methyl-D-aspartate receptor encephalitis: the clinical course in light of the chemokine and cytokine levels in cerebrospinal fluid. AB - BACKGROUND: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune disorder of the central nervous system (CNS). Its immunopathogenesis has been proposed to include early cerebrospinal fluid (CSF) lymphocytosis, subsequent CNS disease restriction and B cell mechanism predominance. There are limited data regarding T cell involvement in the disease. To contribute to the current knowledge, we investigated the complex system of chemokines and cytokines related to B and T cell functions in CSF and sera samples from anti-NMDAR encephalitis patients at different time-points of the disease. One patient in our study group had a long-persisting coma and underwent extraordinary immunosuppressive therapy. METHODS: Twenty-seven paired CSF/serum samples were collected from nine patients during the follow-up period (median 12 months, range 1-26 months). The patient samples were stratified into three periods after the onset of the first disease symptom and compared with the controls. Modified Rankin score (mRS) defined the clinical status. The concentrations of the chemokines (C-X-C motif ligand (CXCL)10, CXCL8 and C-C motif ligand 2 (CCL2)) and the cytokines (interferon (IFN)gamma, interleukin (IL)4, IL7, IL15, IL17A and tumour necrosis factor (TNF)alpha) were measured with Luminex multiple bead technology. The B cell-activating factor (BAFF) and CXCL13 concentrations were determined via enzyme-linked immunosorbent assay. We correlated the disease period with the mRS, pleocytosis and the levels of all of the investigated chemokines and cytokines. Non-parametric tests were used, a P value <0.05 was considered to be significant. RESULTS: The increased CXCL10 and CXCL13 CSF levels accompanied early-stage disease progression and pleocytosis. The CSF CXCL10 and CXCL13 levels were the highest in the most complicated patient. The CSF BAFF levels remained unchanged through the periods. In contrast, the CSF levels of T cell-related cytokines (INFgamma, TNFalpha and IL17A) and IL15 were slightly increased at all of the periods examined. No dynamic changes in chemokine and cytokine levels were observed in the peripheral blood. CONCLUSIONS: Our data support the hypothesis that anti-NMDAR encephalitis is restricted to the CNS and that chemoattraction of immune cells dominates at its early stage. Furthermore, our findings raise the question of whether T cells are involved in this disease. PMID- 26941013 TI - A multi-centre open-label randomised non-inferiority trial comparing watchful waiting to antibiotic treatment for acute otitis media without perforation in low risk urban Aboriginal and Torres Strait Islander children (the WATCH trial): study protocol for a randomised controlled trial. AB - BACKGROUND: Treatment guidelines recommend watchful waiting for children older than 2 years with acute otitis media (AOM) without perforation, unless they are at high risk of complications. The high prevalence of chronic suppurative otitis media (CSOM) in remote Aboriginal and Torres Strait Islander communities leads these children to be classified as high risk. Urban Aboriginal and Torres Strait Islander children are at lower risk of complications, but evidence to support the subsequent recommendation for watchful waiting in this population is lacking. METHODS/DESIGN: This non-inferiority multi-centre randomised controlled trial will determine whether watchful waiting is non-inferior to immediate antibiotics for urban Aboriginal and Torres Strait Islander children with AOM without perforation. Children aged 2 - 16 years with AOM who are considered at low risk for complications will be recruited from six participating urban primary health care services across Australia. We will obtain informed consent from each participant or their guardian. The primary outcome is clinical resolution on day 7 (no pain, no fever of at least 38 degrees C, no bulging eardrum and no complications of AOM such as perforation or mastoiditis) as assessed by general practitioners or nurse practitioners. Participants and outcome assessors will not be blinded to treatment. With a sample size of 198 children in each arm, we have 80 % power to detect a non-inferiority margin of up to 10 % at a significance level of 5 %, assuming clinical improvement of at least 80 % in both groups. Allowing for a 20 % dropout rate, we aim to recruit 495 children. We will analyse both by intention-to-treat and per protocol. We will assess the cost- effectiveness of watchful waiting compared to immediate antibiotic prescription. We will also report on the implementation of the trial from the perspectives of parents/carers, health professionals and researchers. DISCUSSION: The trial will provide evidence for the safety and effectiveness of watchful waiting for the management of AOM in Aboriginal and Torres Strait Islander children living in urban settings who are considered to be at low risk of complications. TRIAL REGISTRATION: The trial is registered with Australia New Zealand Clinical Trials Registry ( ACTRN12613001068752 ). Date of registration: 24 September 2013. PMID- 26941014 TI - Sex hormones and the risk of keratinocyte cancers among women in the United States: A population-based case-control study. AB - Men are at a higher risk of developing both squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) than women, but there is emerging evidence that women may be experiencing greater increases in the incidence rates of these malignancies than men. One possible explanation is the expanding use of sex steroids among women, although only a few studies have examined this hypothesis. As part of a population-based, case-control study of women in New Hampshire, USA, we sought to evaluate the risk of SCC, BCC, and early-onset BCC in relation to exogenous and endogenous sex hormones. We found that oral contraceptive (OC) use was associated with an increased risk of SCC (OR = 1.4, 95% CI = 1.1-1.8) and BCC (OR = 1.4, 95% CI = 1.0-1.8), particularly high estrogen dose (>50 mg) OC use. Hormone replacement therapy (HRT) use also related to SCC, with an elevated OR largely for progestin use (OR = 1.4, 95% CI = 1.1-1.8). Additionally, both OC use and combination HRT use were associated with more aggressive BCC subtypes. In contrast, menstrual and reproductive history did not appear to influence keratinocyte cancer risk in our data. Our findings provide evidence that use of sex steroids may enhance risk of keratinocyte cancer. PMID- 26941016 TI - Confirmation of the Intracoronary Near-Infrared Spectroscopy Threshold of Lipid Rich Plaques That Underlie ST-Segment-Elevation Myocardial Infarction. AB - OBJECTIVE: In a previous exploratory analysis, intracoronary near-infrared spectroscopy (NIRS) found the majority of culprit lesions in ST-segment-elevation myocardial infarction (STEMI) to contain a maximum lipid core burden index in 4 mm (maxLCBI4mm) of >400. This initial study was limited by a small sample size, enrollment at a single center, and post hoc selection of the maxLCBI4mm >=400 threshold. This study was designed a priori to substantiate the ability of NIRS to discriminate STEMI culprit from nonculprit segments and to confirm the performance of the maxLCBI4mm >=400 threshold. APPROACH AND RESULTS: At 2 centers in the United States and Sweden, 75 STEMI patients underwent intracoronary NIRS imaging after establishing thrombolysis in myocardial infarction 3 flow, but before stenting. Blinded core laboratory analysis defined the culprit segment as the 10-mm segment distal to the proximal angiographic culprit margin. The remaining vessel was divided into contiguous 10-mm nonculprit segments. The maxLCBI4mm of culprit segments (median [interquartile range]: 543 [273-756]) was 4.4-fold greater than nonculprit segments (median [interquartile range]: 123 [0 307]; P<0.001). Receiver-operating characteristic analysis demonstrated that maxLCBI4mm differentiated culprit from nonculprit segments with high accuracy (c statistic=0.83; P<0.001). A threshold maxLCBI4mm >=400 identified STEMI culprit segments with a sensitivity of 64% and specificity of 85%. CONCLUSIONS: This study substantiates the ability of NIRS to accurately differentiate STEMI culprit from nonculprit segments and confirms that a threshold maxLCBI4mm >=400 is detected by NIRS in the majority of STEMI culprits. PMID- 26941015 TI - Role of Interleukin-1 Signaling in a Mouse Model of Kawasaki Disease-Associated Abdominal Aortic Aneurysm. AB - OBJECTIVE: Kawasaki disease (KD) is the most common cause of acquired cardiac disease in US children. In addition to coronary artery abnormalities and aneurysms, it can be associated with systemic arterial aneurysms. We evaluated the development of systemic arterial dilatation and aneurysms, including abdominal aortic aneurysm (AAA) in the Lactobacillus casei cell-wall extract (LCWE)-induced KD vasculitis mouse model. METHODS AND RESULTS: We discovered that in addition to aortitis, coronary arteritis and myocarditis, the LCWE-induced KD mouse model is also associated with abdominal aorta dilatation and AAA, as well as renal and iliac artery aneurysms. AAA induced in KD mice was exclusively infrarenal, both fusiform and saccular, with intimal proliferation, myofibroblastic proliferation, break in the elastin layer, vascular smooth muscle cell loss, and inflammatory cell accumulation in the media and adventitia. Il1r( /-), Il1a(-/-), and Il1b(-/-) mice were protected from KD associated AAA. Infiltrating CD11c(+) macrophages produced active caspase-1, and caspase-1 or NLRP3 deficiency inhibited AAA formation. Treatment with interleukin (IL)-1R antagonist (Anakinra), anti-IL-1alpha, or anti-IL-1beta mAb blocked LCWE-induced AAA formation. CONCLUSIONS: Similar to clinical KD, the LCWE-induced KD vasculitis mouse model can also be accompanied by AAA formation. Both IL-1alpha and IL-1beta play a key role, and use of an IL-1R blocking agent that inhibits both pathways may be a promising therapeutic target not only for KD coronary arteritis, but also for the other systemic arterial aneurysms including AAA that maybe seen in severe cases of KD. The LCWE-induced vasculitis model may also represent an alternative model for AAA disease. PMID- 26941017 TI - Regulation of Vascular Smooth Muscle Cell Dysfunction Under Diabetic Conditions by miR-504. AB - OBJECTIVE: Diabetes mellitus accelerates proatherogenic and proinflammatory phenotype of vascular smooth muscle cell (VSMC) associated with vascular complications. Evidence shows that microRNAs (miRNAs) play key roles in VSMC functions, but their role under diabetic conditions is unclear. We profiled miRNAs in VSMC from diabetic mice and examined their role in VSMC dysfunction. APPROACH AND RESULTS: High throughput small RNA-sequencing identified 135 differentially expressed miRNAs in VSMC from type 2 diabetic db/db mice (db/dbVSMC) versus nondiabetic db/+ mice. Several of these miRNAs were known to regulate VSMC functions. We further focused on miR-504, because it was highly upregulated in db/dbVSMC, and its function in VSMC is unknown. miR-504 and its host gene Fgf13 were significantly increased in db/dbVSMC and in aortas from db/db mice. Bioinformatics analysis predicted that miR-504 targets including signaling adaptor Grb10 and transcription factor Egr2 could regulate growth factor signaling. We experimentally validated Grb10 and Egr2 as novel targets of miR-504. Overexpression of miR-504 in VSMC inhibited contractile genes and enhanced extracellular signal-regulated kinase 1/2 activation, proliferation, and migration. These effects were blocked by miR-504 inhibitors. Grb10 knockdown mimicked miR-504 functions and increased inflammatory genes. Egr2 knockdown inhibited anti-inflammatory Socs1 and increased proinflammatory genes. Furthermore, high glucose and palmitic acid upregulated miR-504 and inflammatory genes, but downregulated Grb10. CONCLUSIONS: Diabetes mellitus misregulates several miRNAs including miR-504 that can promote VSMC dysfunction. Because changes in many of these miRNAs are sustained in diabetic VSMC even after in vitro culture, they may be involved in metabolic memory of vascular complications. Targeting such mechanisms could offer novel therapeutic strategies for diabetic complications. PMID- 26941018 TI - miRNA Targeting of Oxysterol-Binding Protein-Like 6 Regulates Cholesterol Trafficking and Efflux. AB - OBJECTIVE: Cholesterol homeostasis is fundamental to human health and is, thus, tightly regulated. MicroRNAs exert potent effects on biological pathways, including cholesterol metabolism, by repressing genes with related functions. We reasoned that this mode of pathway regulation could be exploited to identify novel genes involved in cholesterol homeostasis. APPROACH AND RESULTS: Here, we identify oxysterol-binding protein-like 6 (OSBPL6) as a novel target of 2 miRNA hubs regulating cholesterol homeostasis: miR-33 and miR-27b. Characterization of OSBPL6 revealed that it is transcriptionally regulated in macrophages and hepatocytes by liver X receptor and in response to cholesterol loading and in mice and nonhuman primates by Western diet feeding. OSBPL6 encodes the OSBPL related protein 6 (ORP6), which contains dual membrane- and endoplasmic reticulum targeting motifs. Subcellular localization studies showed that ORP6 is associated with the endolysosomal network and endoplasmic reticulum, suggesting a role for ORP6 in cholesterol trafficking between these compartments. Accordingly, knockdown of OSBPL6 results in aberrant clustering of endosomes and promotes the accumulation of free cholesterol in these structures, resulting in reduced cholesterol esterification at the endoplasmic reticulum. Conversely, ORP6 overexpression enhances cholesterol trafficking and efflux in macrophages and hepatocytes. Moreover, we show that hepatic expression of OSBPL6 is positively correlated with plasma levels of high-density lipoprotein cholesterol in a cohort of 200 healthy individuals, whereas its expression is reduced in human atherosclerotic plaques. CONCLUSIONS: These studies identify ORP6 as a novel regulator of cholesterol trafficking that is part of the miR-33 and miR-27b target gene networks that contribute to the maintenance of cholesterol homeostasis. PMID- 26941020 TI - CRISPR-Cas9 Targeting of PCSK9 in Human Hepatocytes In Vivo-Brief Report. AB - OBJECTIVE: Although early proof-of-concept studies of somatic in vivo genome editing of the mouse ortholog of proprotein convertase subtilisin/kexin type 9 (Pcsk9) in mice have established its therapeutic potential for the prevention of cardiovascular disease, the unique nature of genome-editing technology-permanent alteration of genomic DNA sequences-mandates that it be tested in vivo against human genes in normal human cells with human genomes to give reliable preclinical insights into the efficacy (on-target mutagenesis) and safety (lack of off-target mutagenesis) of genome-editing therapy before it can be used in patients. APPROACH AND RESULTS: We used a clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated (Cas) 9 genome-editing system to target the human PCSK9 gene in chimeric liver-humanized mice bearing human hepatocytes. We demonstrated high on-target mutagenesis (approaching 50%), greatly reduced blood levels of human PCSK9 protein, and minimal off-target mutagenesis. CONCLUSIONS: This work yields important information on the efficacy and safety of CRISPR-Cas9 therapy targeting the human PCSK9 gene in human hepatocytes in vivo, and it establishes humanized mice as a useful platform for the preclinical assessment of applications of somatic in vivo genome editing. PMID- 26941021 TI - The Prevalence of Paraphilic Interests and Behaviors in the General Population: A Provincial Survey. AB - Paraphilic sexual interests are defined as unusual or anomalous, but their actual occurrence in nonclinical samples is still unknown. This study looked at desire for and experience of paraphilic behaviors in a sample of adult men and women in the general population. A secondary goal was to compare the results of two survey modes-traditional landline telephone versus online. A total of 1,040 persons classified according to age, gender, education, ethnic background, religious beliefs, area of residency, and corresponding to the norm for the province of Quebec were interviewed. Nearly half of this sample expressed interest in at least one paraphilic category, and approximately one-third had had experience with such a practice at least once. Voyeurism, fetishism, frotteurism, and masochism interested both male and female respondents at levels above what is usually considered to be statistically unusual (15.9%). Interestingly, levels of interest in fetishism and masochism were not significantly different for men and women. Masochism was significantly linked with higher satisfaction with one's own sexual life. As expected, the online mode generated more acknowledgment of paraphilic interest than the telephone mode. These results call into question the current definition of normal (normophilic) versus anomalous (paraphilic) sexual behaviors. PMID- 26941019 TI - Lipoprotein(a) Levels Are Associated With Subclinical Calcific Aortic Valve Disease in White and Black Individuals: The Multi-Ethnic Study of Atherosclerosis. AB - OBJECTIVE: Lipoprotein(a) [Lp(a)] is a risk factor for calcific aortic valve disease (CAVD) but has not been evaluated across multiple races/ethnicities. This study aimed to determine whether Lp(a) cutoff values used in clinical laboratories to assess risk of cardiovascular disease identify subclinical CAVD and its severity and whether significant relations are observed across race/ethnicity. APPROACH AND RESULTS: Lp(a) concentrations were measured using a turbidimetric immunoassay, and subclinical CAVD was measured by quantifying aortic valve calcification (AVC) through computed tomographic scanning in 4678 participants of the Multi-Ethnic Study of Atherosclerosis. Relative risk and ordered logistic regression analysis determined cross-sectional associations of Lp(a) with AVC and its severity, respectively. The conventional 30 mg/dL Lp(a) clinical cutoff was associated with AVC in white (relative risk: 1.56; confidence interval: 1.24-1.96) and was borderline significant (P=0.059) in black study participants (relative risk: 1.55; confidence interval: 0.98-2.44). Whites with levels >=50 mg/dL also showed higher prevalence of AVC (relative risk: 1.72; confidence interval: 1.36-2.17) than those below this level. Significant associations were observed between Lp(a) and degree of AVC in both white and black individuals. The presence of existing coronary artery calcification did not affect these associations of Lp(a) and CAVD. There were no significant findings in Hispanics or Chinese. CONCLUSIONS: Lp(a) cutoff values that are currently used to assess cardiovascular risk seem to be applicable to CAVD, but our results suggest race/ethnicity may be important in cutoff selection. Further studies are warranted to determine whether race/ethnicity influences Lp(a) and risk of CAVD incidence and its progression. PMID- 26941022 TI - Hospitalizations in pediatric patients with immune thrombocytopenia in the United States. AB - To examine utilization and outcomes in pediatric immune thrombocytopenia (ITP) hospitalizations, we used ICD-9 code 287.31 to identify hospitalizations in patients with ITP in the 2009 HCUP KID, an all-payer sample of pediatric hospitalizations from US community hospitals. Diagnosis and procedure codes were used to estimate rates of ITP-related procedures, comorbidity prevalence, costs, length of stay (LOS), and mortality. In 2009, there were an estimated 4499 hospitalizations in children aged 6 months-17 years with ITP; 43% in children aged 1-5 years; and 47% with emergency department encounters. The mean hospitalization cost was $5398, mean LOS 2.0 days, with 0.3% mortality (n = 13). With any bleeding (15.2%, including gastrointestinal 2.0%, hematuria 1.3%, intracranial hemorrhage [ICH] 0.6%), mean hospitalization cost was $7215, LOS 2.5 days, with 1.5% mortality. For ICH (0.6%, n = 27), mean cost was $40 209, LOS 8.5 days, with 21% mortality. With infections (14%, including upper respiratory 5.2%, viral 4.9%, bacterial 1.9%), the mean cost was $6928, LOS 2.9 days, with 0.9% mortality. Septic shock was reported in 0.3% of discharges. Utilization included immunoglobulin administration (37%) and splenectomies (2.3%). Factors associated with higher costs included age >6 years, ICH, hematuria, transfusion, splenectomy, and bone marrow diagnostics (p < 0.05). In conclusion, of the 4499 hospitalizations with ITP, mortality rates of 1.5%, 21%, and 0.9% were seen with any bleeding, ICH, and infection, respectively. Higher costs were associated with clinically significant bleeding and procedures. Future analyses may reveal effects of the implementation of more recent ITP guidelines and use of additional treatments. PMID- 26941025 TI - Biosimilar DMARDs: What Does the Future Hold? AB - Biological medicinal products, albeit fundamental in unresponsive inflammatory rheumatic diseases, represent a significant economic burden to healthcare systems worldwide. A new landmark in the treatment of these conditions was achieved with the European Medicines Agency's endorsement of CT-P13, the first biosimilar of a monoclonal antibody, infliximab. The main driving force behind biosimilar development is to improve accessibility at lower costs, provided the quality, efficacy and safety of the biosimilar is similar to that of the reference drug. Many other biosimilar candidates are currently under development and will probably be approved in the near future, posing complex prescribing decisions for rheumatologists. In this article, biosimilar disease-modifying anti-rheumatic drugs (DMARDs) are put into perspective: what they are, the stepwise manufacturing process and the available mechanisms that regulate the thorough comparability exercise. Non-clinical and clinical data leading to CT-P13 approval are briefly reviewed, and current clinical data on upcoming biosimilars are also addressed. Other matters covered include extrapolation of clinical indications, interchangeability and automatic substitution. As cumulative evidence on the use of biosimilars grows, controversies abate and patients and physicians become reassured. However, adequate answers to the uncertainties still surrounding biosimilar agents are necessary to ensure the trust of rheumatologists and, on a larger scale, to guarantee their widespread use and success. PMID- 26941026 TI - Dichlorphenamide: A Review in Primary Periodic Paralyses. AB - Oral dichlorphenamide (KeveyisTM) is a carbonic anhydrase inhibitor that is approved in the USA for the treatment of primary hyperkalaemic and hypokalaemic periodic paralyses and related variants. The efficacy and safety of dichlorphenamide in patients with primary periodic paralyses have been evaluated in four 9-week, randomized, double-blind, placebo-controlled, phase III trials [two parallel-group trials (HOP and HYP) and two crossover trials]. In two trials in patients with hypokalaemic periodic paralysis, dichlorphenamide was associated with a significantly (eightfold) lower paralytic attack rate and fewer patients with acute intolerable worsening compared with placebo. In two trials in patients with hyperkalaemic periodic paralysis, the attack rate was lower with dichlorphenamide than placebo, with this comparison reaching statistical significance in one trial (crossover) but not the other (HYP), although the attack rate was approximately fivefold lower with dichlorphenamide than placebo in the HYP trial. In 52-week, open-label extensions of the HOP and HYP trials, dichlorphenamide provided sustained efficacy in patients with hypokalaemic or hyperkalaemic periodic paralysis. Dichlorphenamide was generally well tolerated in all four phase III trials and during the extension trials; the most common adverse events were paraesthesia, cognitive disorders and dysgeusia. As the first agent to be approved in the USA for this indication, dichlorphenamide is a valuable treatment option for patients with primary hyperkalaemic or hypokalaemic periodic paralysis. PMID- 26941027 TI - Understanding what influences oncology clinicians' communicating with dying patients: Awareness of one's own mortality may be one key. PMID- 26941024 TI - The effects of resistance exercise training on arterial stiffness in metabolic syndrome. AB - PURPOSE: Arterial stiffness is a strong independent risk factor for cardiovascular disease and is elevated in individuals with metabolic syndrome (MetS). Resistance training is a popular form of exercise that has beneficial effects on muscle mass, strength, balance and glucose control. However, it is unknown whether resistance exercise training (RT) can lower arterial stiffness in patients with MetS. Thus, the aim of this study was to examine whether a progressive RT program would improve arterial stiffness in MetS. METHODS: A total of 57 subjects (28 healthy sedentary subjects; 29 MetS) were evaluated for arterial structure and function, including pulse wave velocity (cfPWV: arterial stiffness), before and after an 8-week period of RT or continuation of sedentary lifestyle. RESULTS: We found that 8 weeks of progressive RT increased skeletal muscle strength in both Con and MetS, but did not change arterial stiffness in either MetS (cfPWV; Pre 7.9 +/- 0.4 m/s vs. Post 7.7 +/- 0.4 m/s) or healthy controls (cfPWV; Pre 6.9 +/- 0.3 m/s vs. Post 7.0 +/- 0.3 m/s). However, when cfPWV is considered as a continuous variable, high baseline measures of cfPWV tended to show a decrease in cfPWV following RT. CONCLUSION: Eight weeks of progressive RT did not decrease the group mean values of arterial stiffness in individuals with MetS or healthy controls. PMID- 26941029 TI - The C-MAC((r)) D-BLADETM: use of the guide rail as a guiding channel for a gum elastic bougie. PMID- 26941023 TI - Rate of force development: physiological and methodological considerations. AB - The evaluation of rate of force development during rapid contractions has recently become quite popular for characterising explosive strength of athletes, elderly individuals and patients. The main aims of this narrative review are to describe the neuromuscular determinants of rate of force development and to discuss various methodological considerations inherent to its evaluation for research and clinical purposes. Rate of force development (1) seems to be mainly determined by the capacity to produce maximal voluntary activation in the early phase of an explosive contraction (first 50-75 ms), particularly as a result of increased motor unit discharge rate; (2) can be improved by both explosive-type and heavy-resistance strength training in different subject populations, mainly through an improvement in rapid muscle activation; (3) is quite difficult to evaluate in a valid and reliable way. Therefore, we provide evidence-based practical recommendations for rational quantification of rate of force development in both laboratory and clinical settings. PMID- 26941028 TI - Antimicrobial resistance in Neisseria gonorrhoeae in China: a meta-analysis. AB - BACKGROUND: Neisseria gonorrhoeae (N. gonorrhoeae) resistance to antimicrobial has been a major concern in China, and epidemiological data on N. gonorrhoeae resistance are not well understood. This meta-analysis was aimed at summarizing the evidence on N. gonorrhoeae resistance to penicillin, tetracycline, ciprofloxacin, ceftriaxone and spectinomycin in China. METHODS: Two researchers independently searched five databases to identify studies on N. gonorrhoeae resistance to antimicrobials from the databases' inception to November 7, 2014. A random-effects model was used to estimate the antimicrobial resistance rates and their corresponding 95% confidence intervals (CIs). Publication bias was assessed with the Begg rank correlation test and the Egger test. RESULTS: We included 127 studies in our synthesis reporting antimicrobial resistance. Our analyses demonstrated that N. gonorrhoeae resistance to penicillin and tetracycline respectively increased from 74.41% (95% CI: 64.1-84.7%) and 68.3% (95% CI: 58.7 78.0%) in 2000 to 84.2% (95% CI: 79.7-88.8%) and 82.4% (95% CI: 79.9-84.7%) in 2012. N. gonorrhoeae resistance to ciprofloxacin experienced a steady increase from 12.7% (95% CI, 8.6-16.7%) in 1995 and reached 93.8% (95% CI: 91.9-95.7%) in 2003. N. gonorrhoeae resistance to ceftriaxone was 1.7% (95% CI: 0.5-5.7%) before 1995 and 0.5% (95% CI: 0.2-1.4%) in 2012, and N. gonorrhoeae resistance to spectinomycin was less than 2% from 1995 to 2012. CONCLUSIONS: N. gonorrhoeae resistance rates to penicillin, tetracycline and ciprofloxacin were high in China. Ceftriaxone and spectinomycin remained effective therapy for the treatment of gonorrhea. It is essential to strengthen N. gonorrhoeae resistance surveillance and update treatment guidelines timely. PMID- 26941030 TI - N-acetylcysteine Ameliorates Prostatitis via miR-141 Regulating Keap1/Nrf2 Signaling. AB - Chronic prostatitis was the most common type of prostatitis and oxidative stress was reported to be highly elevated in prostatitis patients. In this study, we determined the effect of N-acetylcysteine (NAC) on prostatitis and the molecular mechanism involved in it. Male Sprague-Dawley rats were divided into three groups: control group (group A, n = 20), carrageenan-induced chronic nonbacterial prostatitis (CNP) model group (group B, n = 20), and carrageenan-induced CNP model group with NAC injection (group C, n = 20). Eye score, locomotion score, inflammatory cell count, cyclooxygenase 2 (COX2) expression, and Evans blue were compared in these three groups. The expression of miR-141 was determined by quantitative real-time PCR (qRT-PCR). Moreover, protein expressions of Kelch-like ECH-associated protein-1 (Keap1) and nuclear factor erythroid-2 related factor 2 (Nrf2) and its target genes were examined by Western blot. Luciferase reporter assay was performed in RWPE-1 cells transfected miR-141 mimic or inhibitor and the plasmid carrying 3'-UTR of Keap1. The value of eye score, locomotion score, inflammatory cell count, and Evans blue were significantly decreased in group C, as well as the expression of COX2, when comparing to that of group B. These results indicated that NAC relieved the carrageenan-induced CNP. Further, we found that NAC increased the expression of miR-141 and activated the Keap1/Nrf2 signaling. Luciferase reporter assay revealed that miR-141 mimic could suppress the activity of Keap1 and stimulate the downstream target genes of Nrf2. In addition, miR-141 inhibitor could reduce the effect of NAC on prostatitis. NAC ameliorates the carrageenan-induced prostatitis and prostate inflammation pain through miR-141 regulating Keap1/Nrf2 signaling. PMID- 26941031 TI - Prevalence, impact and treatment of spasticity in nursing home patients with central nervous system disorders: a cross-sectional study. AB - Purpose To assess prevalence, impact and treatment of spasticity in nursing home patients with central nervous system (CNS) disorders. Methods The Modified Ashworth Scale was used as the main indicator of spasticity to assess muscle tone of the extremities. Further information was obtained on burden of care, level of independence, sleeping pattern, complaints, restrictions in functions/activities/participation and indication for treatment. Clinical assessments included coordination/sensibility parameters and various tests to assess motor performance. Results Fifty-six out of 77 participants (73%) with CNS disorders had spasticity, of whom 38 subjects also showed pathologically enhanced reflexes and 45 subjects had contractures in various joints. A high burden of care was observed in 71% and cramps/pain, cosmetic problems or other complaints due to spasticity were seen in 46, 20 and 26%, respectively. The vast majority of subjects were dependent for daily living activities and ambulation. Extra treatment of spasticity was indicated for 36% of the patients. Conclusion A high prevalence of spasticity was observed in nursing home residents with CNS disorders associated with substantial impact in terms of caregiving, complaints and compromised clinical outcome measures. To further optimize the treatment of spasticity in this vulnerable population, regional treatment plans should be developed. Implications for Rehabilitation The prevalence of spasticity in nursing home residents with central nervous system disorders is high (73%). The impact of spasticity is substantial in terms of increased dependency in activities of daily living, increased burden of care, sleeping problems and many complaints. Thirty-six percent of patients could be helped by extra specialized treatment, so the challenge for the multidisciplinary rehabilitation team is huge. Regional treatment plans should be developed to further optimize the treatment of spasticity in the vulnerable ageing population of nursing home residents. PMID- 26941033 TI - Exosomes as therapeutics: The implications of molecular composition and exosomal heterogeneity. AB - Harnessing exosomes as therapeutic drug delivery vehicles requires a better understanding of exosomal composition and their mode of action. A full appreciation of all the exosomal components (proteins, lipids, and RNA content) will be important for the design of effective exosome-based or exosome-mimicking drug carriers. In this review we describe the presence of rarely studied, non coding RNAs that exist in high numbers in exosomes. We discuss the implications of the molecular composition and heterogeneity of exosomes on their biological and therapeutic effects. Finally, we highlight outstanding questions with regard to RNA loading into exosomes, analytical methods to sort exosomes and their sub populations, and the effects of exosomal proteins and lipids on recipient cells. Investigations into these facets of exosome biology will further advance the field, could lead to the clinical translation of exosome-based therapeutics, and aid in the reverse-engineering of synthetic exosomes. Although synthetic exosomes are still an underexplored area, they could offer researchers a way to manufacture exosomes with highly defined structure, composition, and function. PMID- 26941032 TI - Lack of Galanin 3 Receptor Aggravates Murine Autoimmune Arthritis. AB - Neurogenic inflammation mediated by peptidergic sensory nerves has a crucial impact on the pathogenesis of various joint diseases. Galanin is a regulatory sensory neuropeptide, which has been shown to attenuate neurogenic inflammation, modulate neutrophil activation, and be involved in the development of adjuvant arthritis, but our current understanding about its targets and physiological importance is incomplete. Among the receptors of galanin (GAL1-3), GAL3 has been found to be the most abundantly expressed in the vasculature and on the surface of some immune cells. However, since there are minimal in vivo data on the role of GAL3 in joint diseases, we analyzed its involvement in different inflammatory mechanisms of the K/BxN serum transfer-model of autoimmune arthritis employing GAL 3 gene-deficient mice. After arthritis induction, GAL3 knockouts demonstrated increased clinical disease severity and earlier hindlimb edema than wild types. Vascular hyperpermeability determined by in vivo fluorescence imaging was also elevated compared to the wild-type controls. However, neutrophil accumulation detected by in vivo luminescence imaging or arthritic mechanical hyperalgesia was not altered by the lack of the GAL3 receptor. Our findings suggest that GAL3 has anti-inflammatory properties in joints by inhibiting vascular hyperpermeability and consequent edema formation. PMID- 26941034 TI - Tobacco mosaic virus-based protein nanoparticles and nanorods for chemotherapy delivery targeting breast cancer. AB - Drug delivery systems are required for drug targeting to avoid adverse effects associated with chemotherapy treatment regimes. Our approach is focused on the study and development of plant virus-based materials as drug delivery systems; specifically, this work focuses on the tobacco mosaic virus (TMV). Native TMV forms a hollow, high aspect-ratio nanotube measuring 300*18nm with a 4nm-wide central channel. Heat-transformation can be applied to TMV yielding spherical nanoparticles (SNPs) measuring ~50nm in size. While bioconjugate chemistries have been established to modify the TMV rod, such methods have not yet been described for the SNP platform. In this work, we probed the reactivity of SNPs toward bioconjugate reactions targeting lysine, glutamine/aspartic acid, and cysteine residues. We demonstrate functionalization of SNPs using these chemistries yielding efficient payload conjugation. In addition to covalent labeling techniques, we developed encapsulation techniques, where the cargo is loaded into the SNP during heat-transition from rod-to-sphere. Finally, we developed TMV and SNP formulations loaded with the chemotherapeutic doxorubicin, and we demonstrate the application of TMV rods and spheres for chemotherapy delivery targeting breast cancer. PMID- 26941035 TI - Enhanced intranasal delivery of mRNA vaccine by overcoming the nasal epithelial barrier via intra- and paracellular pathways. AB - Facing the threat of highly variable virus infection, versatile vaccination systems are urgently needed. Intranasal mRNA vaccination provides a flexible and convenient approach. However, the nasal epithelium remains a major biological barrier to deliver antigens to nasal associated lymphoid tissue (NALT). To address this issue, a potent polymer-based intranasal mRNA vaccination system for HIV-1 treatment was synthesized using cationic cyclodextrin-polyethylenimine 2k conjugate (CP 2k) complexed with anionic mRNA encoding HIV gp120. The delivery vehicle containing CP 2k and mRNA overcame the epithelial barrier by reversibly opening the tight junctions, enhanced the paracellular delivery of mRNA and consequently minimized absorption of toxins in the nasal cavity. Together with the excellent intracellular delivery and prolonged nasal residence time, strong system and mucosal anti-HIV immune responses as well as cytokine productions were achieved with a balanced Th1/Th2/Th17 type. Our study provided the first proof of evidence that cationic polymers can be used as safe and potent intranasal mRNA vaccine carriers to overcome the nasal epithelial barrier. The safe and versatile polymeric delivery system represents a promising vaccination platform for infectious diseases. PMID- 26941036 TI - Sigma receptor-mediated targeted delivery of anti-angiogenic multifunctional nanodrugs for combination tumor therapy. AB - The potential of low molecular weight heparin (LMWH) in anti-angiogenic therapy has been tempered by poor in vivo delivery to the tumor cell and potentially harmful side effects, such as the risk of bleeding due to heparin's anticoagulant activity. In order to overcome these limitations and further improve the therapeutic effect of LMWH, we designed a novel combination nanosystem of LMWH and ursolic acid (UA), which is also an angiogenesis inhibitor for tumor therapy. In this system, an amphiphilic LMWH-UA (LHU) conjugate was synthesized and self assembled into core/shell nanodrugs with combined anti-angiogenic activity and significantly reduced anticoagulant activity. Furthermore, DSPE-PEG-AA-modified LHU nanodrugs (A-LHU) were developed to facilitate the delivery of nanodrugs to the tumor. The anti-angiogenic activity of A-LHU was investigated both in vitro and in vivo. It was found that A-LHU significantly inhibited the tubular formation of human umbilical vein endothelial cells (HUVECs) (p<0.01) and the angiogenesis induced by basic fibroblast growth factor (bFGF) in a Matrigel plug assay (p<0.001). More importantly, A-LHU displayed significant inhibition on the tumor growth in B16F10-bearing mice in vivo. The level of CD31 and p-VEGFR-2 expression has demonstrated that the excellent efficacy of antitumor was associated with a decrease in angiogenesis. In conclusion, A-LHU nanodrugs are a promising multifunctional antitumor drug delivery system. PMID- 26941037 TI - Metformin improves hepatic IRS2/PI3K/Akt signaling in insulin-resistant rats of NASH and cirrhosis. AB - Nonalcoholic fatty liver disease and cirrhosis are strongly associated with insulin resistance and glucose intolerance. To date, the influence of metformin on glycogen synthesis in the liver is controversial. Limited studies have evaluated the effect of metformin on hepatic insulin signaling pathway in vivo In this study, an insulin-resistant rat model of nonalcoholic steatohepatitis and cirrhosis was developed by high-fat and high-sucrose diet feeding in combination with subcutaneous injection of carbon tetrachloride. Liver tissues of the model rats were featured with severe steatosis and cirrhosis, accompanied by impaired liver function and antioxidant capacity. The glucose tolerance was impaired, and the index of insulin resistance was increased significantly compared with the control. The content of hepatic glycogen was dramatically decreased. The expression of insulin receptor beta (IRbeta); phosphorylations of IRbeta, insulin receptor substrate 2 (IRS2), and Akt; and activities of phosphatidylinositol 3 kinase (PI3K) and glycogen synthase (GS) in the liver were significantly decreased, whereas the activities of glycogen synthase kinase 3alpha (GSK3alpha) and glycogen phosphorylase a (GPa) were increased. Metformin treatment remarkably improved liver function, alleviated lipid peroxidation and histological damages of the liver, and ameliorated glucose intolerance and insulin resistance. Metfromin also significantly upregulated the expression of IRbeta; increased the phosphorylations of IRbeta, IRS2, and Akt; increased the activities of PI3K and GS; and decreased GSK3alpha and GPa activities. In conclusion, our study suggests that metformin upregulates IRbeta expression and the downstream IRS2/PI3K/Akt signaling transduction, therefore, to increase hepatic glycogen storage and improve insulin resistance. These actions may be attributed to the improved liver histological alterations by metformin. PMID- 26941038 TI - Feeding different dietary protein to energy ratios to Holstein heifers: effects on growth performance, blood metabolites and rumen fermentation parameters. AB - Eighteen Chinese Holstein heifers average age 230 +/- 14 days were allocated to 1 of 3 dietary crude protein (CP) to metabolizable energy (ME) ratios to examine the effects on growth performance, blood metabolites and rumen fermentation parameters with 90-days experiment. Three different dietary CP:ME ratios were targeted based on the formulation of dietary CP contents of 10.85%, 12.78% and 14.63% on dry matter (DM) basis with similar ME contents (10.42 MJ/kg DM), which were categorized as low, medium and high dietary CP:ME ratios. The actual CP:ME ratios obtained in this study significantly increased from low to high CP:ME ratio groups with a value of 10.59, 11.83 and 13.38 g/MJ respectively. Elevated CP:ME ratios significantly increased CP intake (kg/day) and feed efficiency (FE) which was defined as dry matter intake as a proportion of average daily gain (ADG), whereas little difference was observed in body weight (kg), ADG (kg/day), DM intake (kg/day) and ME intake (MJ/day) among the three different CP:ME ratio groups. Increasing dietary CP to ME ratios significantly increased CP digestibility, whereas digestibility of DM and gross energy remained constant in the current experiment. Blood urea nitrogen and insulin-like growth factor-1 linearly increased with increasing dietary CP:ME ratios. There was significantly dietary treatment effect on rumen fermentation parameters including acetate, propionate, butyrate and total volatile fatty acids. Therefore, this study indicated that increasing dietary CP levels with similar energy content contributed to increased protein intake and its digestibility, as well as FE. Holstein heifers between 200 and 341 kg subjected to 13.38 dietary CP:ME ratio showed improved feed efficiency, nutrient digestibility, some blood metabolites and rumen fermentation characteristics for 0.90 kg/day rate of gain. PMID- 26941040 TI - The Characterization of an Adrenergic Signalling System Involved in the Encystment of the Ocular Pathogen Acanthamoeba spp. AB - The aim of this study was to identify and characterize the receptor system involved in controlling encystment in Acanthamoeba using specific agonists and antagonists and to examine whether endogenous stores of catecholamines are produced by the organism. Acanthamoeba trophozoites suspended in axenic growth medium were exposed to adrenoceptor agonists and antagonists to determine which compounds promoted or prevented encystment. Second, trophozoites were cultured in medium containing a catecholamine synthesis inhibitor to investigate the effect this had on natural encystment. Nonspecific adrenoceptor agonists including epinephrine, isoprotenerol, and the selective beta1 adrenoceptor agonist dobutamine were found to cause > 90% encystment of Acanthamoeba trophozoites compared to < 30% with the controls. The selective beta1 antagonist metoprolol was able to inhibit epinephrine mediated encystment by > 55%. Cultures of Acanthamoeba with the catecholamine synthesis inhibitor alpha-methyl-p-tyrosine significantly reduced the level of amoebic encystment compared to controls. In conclusion, Acanthamoeba appear to contain a functional adrenergic receptor system of unknown structure which is involved in initiating the encystment process that can be activated and blocked by beta1 agonists and antagonists respectively. Furthermore, the presence of this receptor system in Acanthamoeba indicates that topical beta adrenoceptor blockers may be effective adjunct therapy by reducing the transformation of trophozoites into the highly resistant cyst stage. PMID- 26941041 TI - Hospitalization-Associated Disability in Adults Admitted to a Safety-Net Hospital. PMID- 26941042 TI - An Individualized Approach to Cancer Screening Decisions in Older Adults: A Multilevel Framework. AB - Guidelines for optimal cancer screening in older adults remain unclear, particularly for adults over the age of 75. While cancer screening in older adults may benefit some in good health, it may cause unnecessary burdens in others with limited life expectancy. Thus, a systematic approach to enable individualized cancer screening decisions in older adults is needed. We suggest a framework that guides such decisions through evidence-based approaches from multiple interactions, and that involves the patient, clinician, and healthcare system. An individualized approach considers differences in disease risk rather than the chronological age of the patient. This paper presents a comprehensive framework that depicts the independent and converging levels of influences on individualized cancer screening decisions in older adults. This Individualized Decisions for Screening (IDS) framework recognizes the reality of these interrelationships, including the tensions that arise when behaviors and outcomes are valued differently at the patient, clinician, and healthcare organization levels. Person-centered approaches are essential to advancing multilevel research of individualized cancer screening decisions among older adults. PMID- 26941043 TI - Codes and Pheos. PMID- 26941044 TI - Virus infection mediates the effects of elevated CO2 on plants and vectors. AB - Atmospheric carbon dioxide (CO2) concentration has increased significantly and is projected to double by 2100. To increase current food production levels, understanding how pests and diseases respond to future climate driven by increasing CO2 is imperative. We investigated the effects of elevated CO2 (eCO2) on the interactions among wheat (cv. Yitpi), Barley yellow dwarf virus and an important pest and virus vector, the bird cherry-oat aphid (Rhopalosiphum padi), by examining aphid life history, feeding behavior and plant physiology and biochemistry. Our results showed for the first time that virus infection can mediate effects of eCO2 on plants and pathogen vectors. Changes in plant N concentration influenced aphid life history and behavior, and N concentration was affected by virus infection under eCO2. We observed a reduction in aphid population size and increased feeding damage on noninfected plants under eCO2 but no changes to population and feeding on virus-infected plants irrespective of CO2 treatment. We expect potentially lower future aphid populations on noninfected plants but no change or increased aphid populations on virus-infected plants therefore subsequent virus spread. Our findings underscore the complexity of interactions between plants, insects and viruses under future climate with implications for plant disease epidemiology and crop production. PMID- 26941045 TI - Exchange of core chromosomes and horizontal transfer of lineage-specific chromosomes in Fusarium oxysporum. AB - Horizontal transfer of supernumerary or lineage-specific (LS) chromosomes has been described in a number of plant pathogenic filamentous fungi. So far it was not known whether transfer is restricted to chromosomes of certain size or properties, or whether 'core' chromosomes can also undergo horizontal transfer. We combined a directed and a non-biased approach to determine whether such restrictions exist. Selection genes were integrated into the genome of a strain of Fusarium oxysporum pathogenic on tomato, either targeted to specific chromosomes by homologous recombination or integrated randomly into the genome. By testing these strains for transfer of the marker to another strain we could confirm transfer of a previously described mobile pathogenicity chromosome. Surprisingly, we also identified strains in which (parts of) core chromosomes were transferred. Whole genome sequencing revealed that this was accompanied by the loss of the homologous region from the recipient strain. Remarkably, transfer of the mobile pathogenicity chromosome always accompanied this exchange of core chromosomes. PMID- 26941046 TI - MicroRNA-155 is Dysregulated in the Skin of Patients with Vitiligo and Inhibits Melanogenesis-associated Genes in Melanocytes and Keratinocytes. AB - Little is known about the functions of microRNAs (miRNAs) in skin pigmentation disorders. The aim of this study was to investigate the expression and potential role of miRNAs in vitiligo. Of 12 studied miRNAs with proven functions in cell proliferation, differentiation, immune responses and melanogenesis, miR-99b, miR 125b, miR-155 and miR-199a-3p were found to be increased and miR-145 was found to be decreased in the skin of patients with vitiligo. Combined pathway and target analysis revealed melanogenesis-associated targets for miR-99b, miR-125b, miR-155 and miR-199a-3p. In situ hybridization analysis demonstrated increased expression of miR-155 in the epidermis of patients with vitiligo. Correspondingly, miR-155 was induced by vitiligo-associated cytokines in human primary melanocytes and keratinocytes. When overexpressed, miR-155 inhibited the expression of melanogenesis-associated genes and altered interferon-regulated genes in melanocytes and keratinocytes. In conclusion, this study demonstrates that the expression of miRNAs is dysregulated in the skin of patients with vitiligo and suggests that miR-155 contributes to the pathogenesis of vitiligo. PMID- 26941047 TI - [Is the Spanish population aware and capable of acting in response to cardiac arrest?]. PMID- 26941049 TI - Eligibility Criteria and Genetic Testing Results from a High-Risk Cohort for Hereditary Breast and Ovarian Cancer Syndrome in Southeastern Ontario. AB - Germline mutations in breast and ovarian cancer are rare, with approximately 5% to 10% and 13% being hereditary in origin, respectively. In 2001, the Ontario Ministry of Health and Long Term Care, in an effort to contain costs, defined criteria to determine an individual's eligibility for BRCA genetic screening. We studied a cohort of individuals that have undergone genetic testing at Kingston General Hospital between 2001 and late 2013. We focused on determining whether the 13 risk criteria, defined by an expert working group for the Ontario Ministry of Health and Long Term Care, have performed according to expectations in this cohort. Our findings show that all of the criteria perform well by identifying carriers at the expected 10% rate defined by the guidelines. We demonstrate that loose application of the risk criteria does not further enrich for BRCA variant carriers. Our assessment of the established risk criteria that have been in use in Ontario for more than a decade, provide evidence for their effectiveness, and offer insights into how they may be expanded or improved. PMID- 26941048 TI - Elucidating Proteoform Families from Proteoform Intact-Mass and Lysine-Count Measurements. AB - Proteomics is presently dominated by the "bottom-up" strategy, in which proteins are enzymatically digested into peptides for mass spectrometric identification. Although this approach is highly effective at identifying large numbers of proteins present in complex samples, the digestion into peptides renders it impossible to identify the proteoforms from which they were derived. We present here a powerful new strategy for the identification of proteoforms and the elucidation of proteoform families (groups of related proteoforms) from the experimental determination of the accurate proteoform mass and number of lysine residues contained. Accurate proteoform masses are determined by standard LC-MS analysis of undigested protein mixtures in an Orbitrap mass spectrometer, and the lysine count is determined using the NeuCode isotopic tagging method. We demonstrate the approach in analysis of the yeast proteome, revealing 8637 unique proteoforms and 1178 proteoform families. The elucidation of proteoforms and proteoform families afforded here provides an unprecedented new perspective upon proteome complexity and dynamics. PMID- 26941050 TI - A transdisciplinary model to inform randomized clinical trial methods for electronic cigarette evaluation. AB - BACKGROUND: This study is a systematic evaluation of a novel tobacco product, electronic cigarettes (ECIGs) using a two-site, four-arm, 6-month, parallel-group randomized controlled trial (RCT) with a follow-up to 9 months. Virginia Commonwealth University is the primary site and Penn State University is the secondary site. This RCT design is important because it is informed by analytical work, clinical laboratory results, and qualitative/quantitative findings regarding the specific ECIG products used. METHODS: Participants (N = 520) will be randomized across sites and must be healthy smokers of >9 cigarettes for at least one year, who have not had a quit attempt in the prior month, are not planning to quit in the next 6 months, and are interested in reducing cigarette intake. Participants will be randomized into one of four 24-week conditions: a cigarette substitute that does not produce an inhalable aerosol; or one of three ECIG conditions that differ by nicotine concentration 0, 8, or 36 mg/ml. Blocked randomization will be accomplished with a 1:1:1:1 ratio of condition assignments at each site. Specific aims are to: characterize ECIG influence on toxicants, biomarkers, health indicators, and disease risk; determine tobacco abstinence symptom and adverse event profile associated with real-world ECIG use; and examine the influence of ECIG use on conventional tobacco product use. Liquid nicotine concentration-related differences on these study outcomes are predicted. Participants and research staff in contact with participants will be blinded to the nicotine concentration in the ECIG conditions. DISCUSSION: Results from this study will inform knowledge concerning ECIG use as well as demonstrate a model that may be applied to other novel tobacco products. The model of using prior empirical testing of ECIG devices should be considered in other RCT evaluations. TRIAL REGISTRATION: TRN: NCT02342795 , registered December 16, 2014. PMID- 26941052 TI - Use of antipsychotics and risk of venous thromboembolism in postmenopausal women. A population-based nested case-control study. AB - Despite continued uncertainty of venous thromboembolism (VTE) caused from antipsychotic agents, this safety issue has not been examined in postmenopausal women, a population with high usages of antipsychotics and at high risk for VTE. We assessed whether antipsychotic use was associated with an increased VTE risk in women after menopause. We conducted a nested case-control study of all Taiwanese women aged >= 50 years (n = 316,132) using a nationwide healthcare claims database between 2000 and 2011. All newly diagnosed VTE patients treated with an anticoagulant or thrombectomy surgery were identified as cases (n = 2,520) and individually matched to select controls (n = 24,223) by cohort entry date, age, cancer diagnosis and major surgery procedure. The odds ratios (ORs) and 95 % confidence interval (CI) of VTE associated with antipsychotics were estimated by multivariate conditional logistic regressions. Current use of antipsychotics was associated with a 1.90-fold (95 % CI = 1.64-2.19) increased VTE risk compared with nonuse in postmenopausal women. The VTE risk existed in a dose-dependent fashion (test for trend, p<0.001), with a more than quadrupled risk for high-dose antipsychotics (adjusted OR = 4.60; 95 % CI = 2.88-7.33). Current parenteral administration of antipsychotics also led to a 3.46-fold increased risk (95 % CI = 2.39-5.00). Conversely, there was no increased VTE risk when antipsychotics were discontinued for > 30 days. In conclusion, current use of antipsychotics is significantly associated with a dose-dependent increased risk of VTE in postmenopausal women, especially for those currently taking high dose or receiving parenteral antipsychotics. PMID- 26941051 TI - The influence of bone mineral density and bisphosphonate therapy on the determinants of oral health and changes on dental panoramic radiographs in postmenopausal women. AB - OBJECTIVES: The aim of this study was to assess the determinants of oral health including the number of decayed, missing, and filled teeth (DMFT) and periodontal indices in postmenopausal women with osteoporosis, osteoporosis treated with bisphosphonate therapy, and control group and to examine the correlation between dental panoramic indices (Mental Index-MI, Mandibular Cortical Index-MCI) and bone mineral density in these three groups of patients. MATERIALS AND METHODS: The presented non-interventional study involved 120 postmenopausal women: women with osteoporosis (O) (n = 45), women with osteoporosis treated with bisphosphonates (OBP) (n = 45), and control group (C) (n = 30). DMFT, plaque, gingival and papilla bleeding index, pocket depth, clinical attachment loss, and the presence of periodontitis were evaluated for each patient. MI and MCI of all participants were measured on a dental panoramic radiograph. RESULTS: Group OBP showed significantly higher gingival, bleeding index and deeper pocket depth than C and/or O group. No significant differences were found in MI (p = .303) or MCI (p = .06) in all the examined groups. Also, there were no significant differences between the three groups in the presence of periodontitis as well as in the DMFT index. CONCLUSION: BP therapy could have a negative influence on periodontal health. Further, MI and MCI are not precise diagnostic tools for diagnosing low BMD in postmenopausal women. CLINICAL RELEVANCE: BP therapy could have a negative influence on the determinants of oral health in postmenopausal women with osteoporosis. PMID- 26941054 TI - National Athletic Trainers' Association Releases New Guidelines for Exertional Heat Illnesses: What School Nurses Need to Know. AB - Exertional heat illnesses (EHI) occur in various populations and settings. Within a school setting, there are student athletes who take part in physical activity where the risk of EHI is increased. The National Athletic Trainers' Association (NATA) released an updated position statement on EHI in September of 2015. This article is a summary of the position statement. The sports medicine team, including school nurses and athletic trainers, provides quality health care to these physically active individuals. Thus, it is important for school nurses to understand the prevention, recognition, and treatment of EHI. PMID- 26941053 TI - Is bariatric surgery in patients following renal transplantation safe and effective? A best evidence topic. AB - Obesity is common amongst patients with renal transplants (RT). It is associated not only with generic obesity-related complications including diabetes, but also with higher rates of graft rejection and loss. A Best Evidence Topic in surgery was written according to a structured protocol: this is a systematic review of the literature, suitable when the quality of available evidence is low. The question addressed was: is weight-loss surgery (WLS) safe and effective in patients that have had a previous renal transplant? Three prospective case series and one multicentre retrospective study were identified, together reporting on a total of 112 patients who underwent WLS after RT. Eighty-seven patients underwent open WLS and 25 patients underwent laparoscopic operations of which 11 had sleeve gastrectomy and 14 RYGB. Percentage excess weight loss was highly variable between the studies, ranging from an average of 30.8%-75% at 12 months. One graft rejection occurred within 30 days of surgery. All studies were limited by lack of suitable comparison group, short follow-up and heterogeneity in type of bariatric procedure and approach. To date, there is limited evidence to suggest that bariatric surgery is safe and has good short-term outcomes for selected obese patients post-renal transplant. PMID- 26941056 TI - Finding time to make the right decision: using frozen section to inform intra operative management of suspicious ovarian masses. PMID- 26941055 TI - Opsin spectral sensitivity determines the effectiveness of optogenetic termination of ventricular fibrillation in the human heart: a simulation study. AB - KEY POINTS: Optogenetics-based defibrillation, a theoretical alternative to electrotherapy, involves expression of light-sensitive ion channels in the heart (via gene or cell therapy) and illumination of the cardiac surfaces (via implanted LED arrays) to elicit light-induced activations. We used a biophysically detailed human ventricular model to determine whether such a therapy could terminate fibrillation (VF) and identify which combinations of light-sensitive ion channel properties and illumination configurations would be effective. Defibrillation was successful when a large proportion (> 16.6%) of ventricular tissue was directly stimulated by light that was bright enough to induce an action potential in an uncoupled cell. While illumination with blue light never successfully terminated VF, illumination of red light-sensitive ion channels with dense arrays of implanted red light sources resulted in successful defibrillation. Our results suggest that cardiac expression of red light sensitive ion channels is necessary for the development of effective optogenetics based defibrillation therapy using LED arrays. ABSTRACT: Optogenetics-based defibrillation has been proposed as a novel and potentially pain-free approach to enable cardiomyocyte-selective defibrillation in humans, but the feasibility of such a therapy remains unknown. This study aimed to (1) assess the feasibility of terminating sustained ventricular fibrillation (VF) via light-induced excitation of opsins expressed throughout the myocardium and (2) identify the ideal (theoretically possible) opsin properties and light source configurations that would maximise therapeutic efficacy. We conducted electrophysiological simulations in an MRI-based human ventricular model with VF induced by rapid pacing; light sensitisation via systemic, cardiac-specific gene transfer of channelrhodopsin-2 (ChR2) was simulated. In addition to the widely used blue light-sensitive ChR2-H134R, we also modelled theoretical ChR2 variants with augmented light sensitivity (ChR2+), red-shifted spectral sensitivity (ChR2-RED) or both (ChR2-RED+). Light sources were modelled as synchronously activating LED arrays (LED radius: 1 mm; optical power: 10 mW mm-2 ; array density: 1.15-4.61 cm 2 ). For each unique optogenetic configuration, defibrillation was attempted with two different optical pulse durations (25 and 500 ms). VF termination was only successful for configurations involving ChR2-RED and ChR2-RED+ (for LED arrays with density >= 2.30 cm-2 ), suggesting that opsin spectral sensitivity was the most important determinant of optogenetic defibrillation efficacy. This was due to the deeper penetration of red light in cardiac tissue compared with blue light, which resulted in more widespread light-induced propagating wavefronts. Longer pulse duration and higher LED array density were associated with increased optogenetic defibrillation efficacy. In all cases observed, the defibrillation mechanism was light-induced depolarisation of the excitable gap, which led to block of reentrant wavefronts. PMID- 26941057 TI - 9p21 locus rs10757278 is associated with advanced carotid atherosclerosis in a gender-specific manner. AB - Single nucleotide polymorphisms from the chromosome locus 9p21 are reported to carry a risk for various cardiovascular diseases. One of the lead single nucleotide polymorphisms, rs10757278, was mostly investigated in association with coronary artery disease but rarely with carotid atherosclerosis. In this study, we aimed to analyze the association of rs10757278 A/G polymorphism with carotid plaque presence in advanced carotid atherosclerosis. The study included 803 participants, 486 patients with high-grade stenosis (>70%) who were undergoing carotid endarterectomy and 317 controls from Serbian population. Genotypes were determined using the real-time polymerase chain reaction. According to the recessive model of inheritance, GG genotype was significantly and independently associated with carotid plaque in females only (odds ratio 2.42, CI = 1.20-4.90, P = 0.013). Odds ratio was adjusted for age, body mass index, hypertension, TC, LDLC, HDLC and TG, and P value was corrected for multiple comparisons. Our preliminary findings suggest a gender-specific association of rs10757278 polymorphism with carotid plaque. Further studies on larger sample and in genetically and environmentally similar populations are needed. PMID- 26941060 TI - Transmission Clusters of Methicillin-Resistant Staphylococcus Aureus in Long-Term Care Facilities Based on Whole-Genome Sequencing. AB - OBJECTIVE To define how often methicillin-resistant Staphylococcus aureus (MRSA) is spread from resident to resident in long-term care facilities using whole genome sequencing DESIGN Prospective cohort study SETTING A long-term care facility PARTICIPANTS Elderly residents in a long-term care facility METHODS Cultures for MRSA were obtained weekly from multiple body sites from residents with known MRSA colonization over 12-week study periods. Simultaneously, cultures to detect MRSA acquisition were obtained weekly from 2 body sites in residents without known MRSA colonization. During the first 12-week cycle on a single unit, we sequenced 8 MRSA isolates per swab for 2 body sites from each of 6 residents. During the second 12-week cycle, we sequenced 30 MRSA isolates from 13 residents with known MRSA colonization and 3 residents who had acquired MRSA colonization. RESULTS MRSA isolates from the same swab showed little genetic variation between isolates with the exception of isolates from wounds. The genetic variation of isolates between body sites on an individual was greater than that within a single body site with the exception of 1 sample, which had 2 unrelated strains among the 8 isolates. In the second cycle, 10 of 16 residents colonized with MRSA (63%) shared 1 of 3 closely related strains. Of the 3 residents with newly acquired MRSA, 2 residents harbored isolates that were members of these clusters. CONCLUSIONS Point prevalence surveys with whole-genome sequencing of MRSA isolates may detect resident-to-resident transmission more accurately than routine surveillance cultures for MRSA in long-term care facilities. Infect Control Hosp Epidemiol 2016;37:685-691. PMID- 26941058 TI - Effect of silibinin and vitamin E on the ASK1-p38 MAPK pathway in D galactosamine/lipopolysaccharide induced hepatotoxicity. AB - Apoptosis signal-regulating kinase 1 (ASK1), a redox-sensor mitogen-activated protein kinase kinase kinase (MAPKKK) that activates p38 MAPK pathways in oxidative stress-induced hepatotoxicity in D-galactosamine/lipopolysaccharide (D GalN/LPS) model, is a key central pathway in which specific targeting of ASK1 deactivation is of a great therapeutic potential. We tested the effect of silibinin and vitamin E in curative and prophylactic manner of treatment on the negative modulators of ASK1, thioredoxin1 (Trx1), thioredoxin reductase1 (TrxR1), and the protein phosphatase (PP5), whereas they have previously proven to have hepatoprotective effect. Either curative or prophylactic silibinin and vitamin E groups significantly decreased ASK1 and p38 MAPK levels through increasing the gene expression of Trx1, TrxR1, and PP5 to reduce the oxidative stress as demonstrated by decreasing the levels of NADPH oxidase 4 (NOX4), TBARS and conjugated diene with a concomitant increase in the levels of GSH, CAT, and SOD. These results were confirmed by histopathology examination which illustrated progressive degenerative changes of hepatocytes such as hydropic degeneration, vacuolation, pyknosis, karyolysis, and loss of architecture of some cells in D GalN/LPS treatment, and these features were alleviated with silibinin and vitamin E administration. In conclusion, silibinin and vitamin E decreased ASK1-p38 MAPK pathway through deactivating the upstream signalling ASK1 molecule via increasing the levels of Trx1 and TrxR1 as well as the PP5 to alleviate in D-GalN/LPS induced hepatotoxicity. PMID- 26941061 TI - Conductance fluctuations in graphene in the presence of long-range disorder. AB - The fluctuations in the conductance of graphene that arise from a long-range disorder potential induced by random impurities are investigated with an atomic tight-binding lattice. The screened impurities lead to a slow variation of the background potential and this varies the overall potential landscape as the Fermi energy or an applied magnetic field is varied. As a result, the phase interference varies randomly and leads to fluctuations in the conductance. Recently, experiments have shown that an applied magnetic field produces a remarkable reduction in the amplitude of these conductance fluctuations. We find qualitative agreement with these experiments, and it appears that the reduction in magnetic field of the fluctuations arises from a field induced smoothing of the conductance landscape. PMID- 26941059 TI - Fluorescent sperm offer a method for tracking the real-time success of ejaculates when they compete to fertilise eggs. AB - Despite intensive research effort, many uncertainties remain in the field of gamete-level sexual selection, particularly in understanding how sperm from different males interact when competing for fertilisations. Here, we demonstrate the utility of broadcast spawning marine invertebrates for unravelling these mysteries, highlighting their mode of reproduction and, in some species, unusual patterns of mitochondrial inheritance. We present a method utilising both properties in the blue mussel, Mytilus galloprovincialis. In mytilids and many other bivalves, both sperm and egg mitochondria are inherited. We exploit this, using the vital mitochondrial dye MitoTracker, to track the success of sperm from individual males when they compete with those from rivals to fertilise eggs. We confirm that dying mitochondria has no adverse effects on in vitro measures of sperm motility (reflecting mitochondrial energetics) or sperm competitive fertilisation success. Therefore, we propose the technique as a powerful and logistically tractable tool for sperm competition studies. Importantly, our method allows the competitive fertilisation success of sperm from any male to be measured directly and disentangled from confounding effects of post-fertilisation embryo survival. Moreover, the mitochondrial dye has broader applications in taxa without paternal mitochondrial inheritance, for example by tracking the dynamics of competing ejaculates prior to fertilisation. PMID- 26941062 TI - Blood pressure profile in pregnancy: The impact of its duration on results and patients' well-being. AB - BACKGROUND: A blood pressure profile (BPP) is often used to diagnose and manage hypertension in pregnancy. However, there is no consensus on the number and interval of blood pressure (BP) readings required. AIMS: To ascertain whether BP readings at 15-min interval over one hour yields clinically equivalent results to readings at 60-min interval over three hours. MATERIALS AND METHODS: Eighty unique women were recruited to this prospective study. Automated BP machines were used to take readings at 15-min interval over one hour and at 60-min interval over three hours. The mean systolic and diastolic BPs obtained using each regimen were calculated and compared. Women also completed a questionnaire to evaluate the psychosocial and financial impact of a prolonged outpatient investigation. RESULTS: BP readings from 67 patients were included for analysis. Clinical equivalence was assessed using the British Hypertension Society (BHS) validation criteria for comparing nonmercury devices to the gold-standard calibrated mercury device. Mean SBP readings for 54% (36/67), 90% (60/67) and 97% (65/67) and mean DBP readings for 73% (49/67), 94% (63/67) and 100% (67/67) were within 5, 10 and 15 mmHg agreement across the two time regimens which achieved grade B and grade A validation, respectively. A BPP was costly and stressful for women and affected their ability to attend work and look after other children. CONCLUSIONS: A BPP performed over one hour compared to over three hours yields clinically equivalent results, yet has psychosocial and financial advantages. PMID- 26941063 TI - Comparative study of wound healing in rat skin following incision with a novel picosecond infrared laser (PIRL) and different surgical modalities. AB - BACKGROUND AND OBJECTIVE: As a result of wound healing the original tissue is replaced by dysfunctional scar tissue. Reduced tissue damage during surgical procedures beneficially affects the size of the resulting scar and overall healing time. Thus the choice of a particular surgical instrument can have a significant influence on the postoperative wound healing. To overcome these problems of wound healing we applied a novel picosecond infrared laser (PIRL) system to surgical incisions. Previous studies indicated that negligible thermal, acoustic, or ionization stress effects to the surrounding tissue results in a superior wound healing. STUDY DESIGN/MATERIALS AND METHODS: Using the PIRL system as a surgical scalpel, we performed a prospective wound healing study on rat skin and assessed its final impact on scar formation compared to the electrosurgical device and cold steel. As for the incisions, 6 full-thickness, 1-cm long-linear skin wounds were created on the dorsum of four rats using the PIRL, an electrosurgical device, and a conventional surgical scalpel, respectively. Rats were euthanized after 21 days of wound healing. The thickness of the subepithelial fibrosis, the depth and the transverse section of the total scar area of each wound were analyzed histologically. RESULTS: After 21 days of wound healing the incisions made by PIRL showed minor scar tissue formation as compared to the electrosurgical device and the scalpel. Highly significant differences (P < 0.001) were noted by comparing the electrosurgical device with PIRL and scalpel. The transverse section of the scar area also showed significant differences (P = 0.043) when comparing PIRL (mean: 141.46 mm2; 95% CI: 105.8 189.0 mm2) with scalpel incisions (mean: 206.82 mm2; 95% CI: 154.8-276.32 mm2). The subepithelial width of the scars that resulted from using the scalpel were 1.3 times larger than those obtained by using the PIRL (95% CI: 1.0-1.6) though the difference was not significant (P < 0.083). CONCLUSIONS: The hypothesis that PIRL results in minimal scar formation with improved cosmetic outcomes was positively verified. In particular the resection of skin tumors or pathological scars, such as hypertrophic scars or keloids, are promising future fields of PIRL application. PMID- 26941064 TI - TRF2-RAP1 is required to protect telomeres from engaging in homologous recombination-mediated deletions and fusions. AB - Repressor/activator protein 1 (RAP1) is a highly conserved telomere-interacting protein. Yeast Rap1 protects telomeres from non-homologous end joining (NHEJ), plays important roles in telomere length control and is involved in transcriptional gene regulation. However, a role for mammalian RAP1 in telomere end protection remains controversial. Here we present evidence that mammalian RAP1 is essential to protect telomere from homology directed repair (HDR) of telomeres. RAP1 cooperates with the basic domain of TRF2 (TRF2(B)) to repress PARP1 and SLX4 localization to telomeres. Without RAP1 and TRF2(B), PARP1 and SLX4 HR factors promote rapid telomere resection, resulting in catastrophic telomere loss and the generation of telomere-free chromosome fusions in both mouse and human cells. The RAP1 Myb domain is required to repress both telomere loss and formation of telomere-free fusions. Our results highlight the importance of the RAP1-TRF2 heterodimer in protecting telomeres from inappropriate processing by the HDR pathway. PMID- 26941065 TI - Phylogenic analysis of adhesion related genes Mad1 revealed a positive selection for the evolution of trapping devices of nematode-trapping fungi. AB - Adhesions, the major components of the extracellular fibrillar polymers which accumulate on the outer surface of adhesive traps of nematode-trapping fungi, are thought to have played important roles during the evolution of trapping devices. Phylogenetic analyses based on the genes related to adhesive materials can be of great importance for understanding the evolution of trapping devices. Recently, AoMad1, one homologous gene of the entomopathogenic fungus Metarhizium anisopliae cell wall protein MAD1, has been functionally characterized as involved in the production of adhesions in the nematode-trapping fungus Arthrobotrys oligospora. In this study, we cloned Mad1 homologous genes from nematode-trapping fungi with various trapping devices. Phylogenetic analyses suggested that species which formed nonadhesive constricting ring (CR) traps more basally placed and species with adhesive traps evolved along two lineages. Likelihood ratio tests (LRT) revealed that significant positive selective pressure likely acted on the ancestral trapping devices including both adhesive and mechanical traps, indicating that the Mad1 genes likely played important roles during the evolution of nematode-trapping fungi. Our study provides new insights into the evolution of trapping devices of nematode-trapping fungi and also contributes to understanding the importance of adhesions during the evolution of nematode-trapping fungi. PMID- 26941066 TI - Photoactivatable cytotoxic agents derived from mitochondria-targeting luminescent iridium(III) poly(ethylene glycol) complexes modified with a nitrobenzyl linkage. AB - Two novel photoactivatable mitochondria-targeting luminescent iridium(III) poly(ethylene glycol) (PEG) complexes incorporated with a nitrobenzyl group were designed. They showed minimal cytotoxic activity in the dark, but became significantly cytotoxic upon irradiation due to the release of the PEG pendants. PMID- 26941067 TI - CC chemokine receptor 10 cell surface presentation in melanocytes is regulated by the novel interaction partner S100A10. AB - The superfamily of G-protein-coupled receptors (GPCR) conveys signals in response to various endogenous and exogenous stimuli. Consequently, GPCRs are the most important drug targets. CCR10, the receptor for the chemokines CCL27/CTACK and CCL28/MEC, belongs to the chemokine receptor subfamily of GPCRs and is thought to function in immune responses and tumour progression. However, there is only limited information on the intracellular regulation of CCR10. We find that S100A10, a member of the S100 family of Ca(2+) binding proteins, binds directly to the C-terminal cytoplasmic tail of CCR10 and that this interaction regulates the CCR10 cell surface presentation. This identifies S100A10 as a novel interaction partner and regulator of CCR10 that might serve as a target for therapeutic intervention. PMID- 26941068 TI - The Relationship between Antisocial and Borderline Features and Aggression in Young Adult Men in Treatment for Substance Use Disorders. AB - There is a large literature documenting that adult men in treatment for substance use disorders perpetrate more aggression than men without substance use disorders. Unfortunately, there is minimal research on aggression among young adult men (i.e., 18-25 years of age) in treatment for substance use. Moreover, although aggression is more likely to occur when individuals are acutely intoxicated by alcohol or drugs, research also suggests that antisocial (ASPD) and borderline (BPD) personality features increase the chances an individual will use aggression. The current study therefore examined the associations between ASPD and BPD features, including specific features that are reflective of impulsivity, and aggression in young adult men in treatment for substance use disorders (N = 79). Controlling for age, education, alcohol and drug use, ASPD features were positively associated with various indicators of aggression (e.g., physical, verbal, attitudinal), whereas BPD features were only associated with physical aggression. However, ASPD and BPD features that were specific to impulsivity were robustly related to indicators of aggression. Findings suggest that substance use treatment should attempt to target ASPD and BPD features in young adult men, which may help reduce aggression after treatment. PMID- 26941069 TI - The experience of women living with Congenital Adrenal Hyperplasia: impact of the condition and the care given. AB - CONTEXT: Congenital adrenal hyperplasia (CAH) is caused most often by mutations in the CYP21A2 gene, resulting in cortisol and aldosterone deficiency and increased production of androgens. OBJECTIVE: To describe how women with CAH experience their condition and the care given. DESIGN, SETTING AND PARTICIPANTS: Semi-structured interviews with 13 adult Swedish women with CAH were transcribed. Data were analysed by qualitative content analysis to describe the variability in the experiences. MAIN OUTCOME MEASURES: Qualitative evaluation of the participants' life experiences. RESULTS: The participants' experiences of having CAH are described in four different categories. 1. Information comprises the experiences of interaction with healthcare providers, knowledge acquisition and information disclosure. 2. Exposure encompasses the experiences of genital examinations, the medical focus on the genitalia and of being photographed repeatedly. 3. Health covers the self-perceived experiences of having a medical condition that requires pharmacological treatment and sometimes surgery. 4. Research comprises the experiences of having a scientifically well-studied condition. Different experiences of shame reoccur in all categories, thus forming the latent theme. CONCLUSION: The experience of living with congenital adrenal hyperplasia can be facilitated by increased information and by acknowledging that women with CAH are a heterogeneous group with individual needs. Shame may be counterbalanced by increased parental support and increased knowledge among healthcare personnel aimed at providing children with continuous support and coping strategies during their upbringing. Based on the identified themes in this study, there are several research avenues to pursue in the future. PMID- 26941071 TI - Vision-based Nano Robotic System for High-throughput Non-embedded Cell Cutting. AB - Cell cutting is a significant task in biology study, but the highly productive non-embedded cell cutting is still a big challenge for current techniques. This paper proposes a vision-based nano robotic system and then realizes automatic non embedded cell cutting with this system. First, the nano robotic system is developed and integrated with a nanoknife inside an environmental scanning electron microscopy (ESEM). Then, the positions of the nanoknife and the single cell are recognized, and the distance between them is calculated dynamically based on image processing. To guarantee the positioning accuracy and the working efficiency, we propose a distance-regulated speed adapting strategy, in which the moving speed is adjusted intelligently based on the distance between the nanoknife and the target cell. The results indicate that the automatic non embedded cutting is able to be achieved within 1-2 mins with low invasion benefiting from the high precise nanorobot system and the sharp edge of nanoknife. This research paves a way for the high-throughput cell cutting at cell's natural condition, which is expected to make significant impact on the biology studies, especially for the in-situ analysis at cellular and subcellular scale, such as cell interaction investigation, neural signal transduction and low invasive cell surgery. PMID- 26941073 TI - Kallikrein-related peptidases (KLKs) as emerging therapeutic targets: focus on prostate cancer and skin pathologies. AB - INTRODUCTION: Tissue kallikrein and the kallikrein-related peptidases (KLKs) constitute a family of 15 homologous secreted serine proteases with trypsin- or chymotrypsin-like activities, which participate in a broad spectrum of physiological procedures. Deregulated expression and/or activation of the majority of the family members have been reported in several human diseases, thereby making KLKs ideal targets for therapeutic intervention. AREAS COVERED: In the present review, we summarize the role of KLKs in normal human physiology and pathology, focusing on prostate cancer and skin diseases. Furthermore, we discuss the recent advances in the development of KLK-based therapies. A great number of diverse engineered KLKs inhibitors with improved potency, selectivity and immunogenicity have been synthesized by redesigning examples that are endogenous and naturally occurring. Moreover, encouraging results have been documented using KLKs-based vaccines and immunotherapies, as well as KLKs-mediated activation of pro-drugs. Finally, KLKs-targeting aptamers and KLKs-based imaging tools represent novel approaches towards the exploitation of KLKs' therapeutic value. EXPERT OPINION: The central/critical roles of KLK family in several human pathologies highlight KLKs as attractive molecular targets for developing novel therapeutics. PMID- 26941072 TI - High-throughput discovery of post-transcriptional cis-regulatory elements. AB - BACKGROUND: Post-transcriptional gene regulation controls the amount of protein produced from an individual mRNA by altering rates of decay and translation. Many sequence elements that direct post-transcriptional regulation have been found; in mammals, most such elements are located within the 3' untranslated regions (3'UTRs). Comparative genomic studies demonstrate that mammalian 3'UTRs contain extensive conserved sequence tracts, yet only a small fraction corresponds to recognized elements, implying that many additional novel elements exist. Despite a variety of computational, molecular, and biochemical approaches, identifying functional 3'UTRs elements remains difficult. RESULTS: We created a high throughput cell-based screen that enables identification of functional post transcriptional 3'UTR regulatory elements. Our system exploits integrated single copy reporters, which are expressed and processed as endogenous genes. We screened many thousands of short random sequences for their regulatory potential. Control sequences with known effects were captured effectively using our approach, establishing that our methodology was robust. We found hundreds of functional sequences, which we validated in traditional reporter assays, including verifying their regulatory impact in native sequence contexts. Although 3'UTRs are typically considered repressive, most of the functional elements were activating, including ones that were preferentially conserved. Additionally, we adapted our screening approach to examine the effect of elements on RNA abundance, revealing that most elements act by altering mRNA stability. CONCLUSIONS: We developed and used a high-throughput approach to discover hundreds of post-transcriptional cis-regulatory elements. These results imply that most human 3'UTRs contain many previously unrecognized cis-regulatory elements, many of which are activating, and that the post-transcriptional fate of an mRNA is largely due to the actions of many individual cis-regulatory elements within its 3'UTR. PMID- 26941070 TI - Comparative analysis of Wnt expression identifies a highly conserved developmental transition in flatworms. AB - BACKGROUND: Early developmental patterns of flatworms are extremely diverse and difficult to compare between distant groups. In parasitic flatworms, such as tapeworms, this is confounded by highly derived life cycles involving indirect development, and even the true orientation of the tapeworm antero-posterior (AP) axis has been a matter of controversy. In planarians, and metazoans generally, the AP axis is specified by the canonical Wnt pathway, and we hypothesized that it could also underpin axial formation during larval metamorphosis in tapeworms. RESULTS: By comparative gene expression analysis of Wnt components and conserved AP markers in the tapeworms Echinococcus multilocularis and Hymenolepis microstoma, we found remarkable similarities between the early stages of larval metamorphosis in tapeworms and late embryonic and adult development in planarians. We demonstrate posterior expression of specific Wnt factors during larval metamorphosis and show that scolex formation is preceded by localized expression of Wnt inhibitors. In the highly derived larval form of E. multilocularis, which proliferates asexually within the mammalian host, we found ubiquitous expression of posterior Wnt factors combined with localized expression of Wnt inhibitors that correlates with the asexual budding of scoleces. As in planarians, muscle cells are shown to be a source of secreted Wnt ligands, providing an explanation for the retention of a muscle layer in the immotile E. multilocularis larva. CONCLUSIONS: The strong conservation of gene expression between larval metamorphosis in tapeworms and late embryonic development in planarians suggests, for the first time, a homologous developmental period across this diverse phylum. We postulate these to represent the phylotypic stages of these flatworm groups. Our results support the classical notion that the scolex is the true anterior end of tapeworms. Furthermore, the up-regulation of Wnt inhibitors during the specification of multiple anterior poles suggests a mechanism for the unique asexual reproduction of E. multilocularis larvae. PMID- 26941074 TI - Perceived dyscognition reported by patients with fibromyalgia. AB - OBJECTIVES: Patients with fibromyalgia often report dyscognition as a symptom; however, the literature on this symptom is sparse. Our objective for this cross sectional study was to characterize dyscognition among patients with fibromyalgia, identify comorbid symptoms associated with dyscognition, and evaluate its relation with fibromyalgia severity. METHODS: Dyscognition was assessed with the Multiple Abilities Self-report Questionnaire (MASQ) for 681 patients with fibromyalgia. Other assessed comorbid symptoms were pain, fatigue, sleep problems, mood, physical and mental health, and autonomic function. Correlation and regression modeling were used to identify relations between the MASQ subscales and other fibromyalgia symptoms. Mixed analysis of variance was used to examine the profile of dyscognition in different levels of fibromyalgia. MASQ subscale scores from a previously described healthy normal control population were used for comparison. RESULTS: The mean (SD) age of the study patients was 55.8 (12.6) years, and most patients were female (93%) and white (91%). Perceived dyscognition was most related to depression, anxiety, and autonomic function. Across all fibromyalgia severity levels, patients had significantly higher levels of perceived dyscognition than the healthy controls. Significant differences existed for the MASQ total and most MASQ subscales among patients with mild, moderate, and severe fibromyalgia. CONCLUSIONS: Our study results provide further evidence that perceived dyscognition in fibromyalgia is influenced by various comorbid symptoms. In treating patients with fibromyalgia who have dyscognition, clinicians should consider the multiple types of dyscognition and the effects of other fibromyalgia symptoms. PMID- 26941075 TI - Trends in Patient Characteristics and Outcomes of Coronary Artery Bypass Grafting in the 2000 to 2012 Medicare Population. AB - BACKGROUND: The purpose of this analysis was to examine the trends in patient characteristics and outcomes in patients who underwent coronary artery bypass grafting (CABG) over a 12-year period in the Medicare database. METHODS: The study included 1,264,265 isolated CABG procedures in the Medicare population from January 2000 through November 2012. Comorbidities were determined using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnostic codes. Trends in patient characteristics and hospital outcomes were assessed with Cochran-Armitage trend tests. Long-term survival was examined with Kaplan-Meier survival curves. RESULTS: The median age was 74 years. Comorbidity profiles increased significantly over time. The number of patients undergoing CABG decreased from 131,385 in 2000 to 71,086 in 2012. The majority of patients underwent multivessel revascularization (13.5% single-vessel CABG, 35.2% 2-vessel CABG, 32.1% 3-vessel CABG, and 15.7% >=4-vessel CABG). The percentage of patients undergoing 1- and 2-vessel revascularization increased over time, whereas that of >=3-vessel CABG decreased. Single internal mammary artery (IMA) use increased from 75.6% to 88.6%. Median length of stay (LOS) was 8 days. Thirty day mortality decreased from 4.2% to 3.0%. Hospital mortality fell from 4.0% in 2000 to 2.7% in 2012 (odds ratio [OR], 0.73; 95% confidence interval [CI], 0.69 0.77). Survival was 93% at 6 months, 91% at 1 year, 84% at 3 years, and 76% at 5 years. Five-year survival changed little over time (range, 75%-77%). CONCLUSIONS: Despite rising comorbidities in Medicare patients undergoing CABG, hospital mortality fell significantly from 2000 to 2012. When adjusted for comorbidities, this signified a 27% reduction in hospital mortality. IMA use increased during the study period, and there was a trend of decreased use of 3 or more grafts. PMID- 26941076 TI - Clinical Outcomes and Cataract Formation Rates in Eyes 10 Years After Posterior Phakic Lens Implantation for Myopia. AB - Importance: Intraocular collamer lenses (ICLs) are posterior chamber phakic lenses that provide a refractive surgery option for those with high myopia or astigmatism. The short-term and midterm results indicate good refraction stability, efficacy, and safety. Cataract has been suggested to be an important long-term complication of ICL implantation. Objective: To report the rates of cataract development and refractive outcomes 10 years after ICL implantation. Design, Setting, and Participants: The study included 133 eyes of 78 patients undergoing consecutive V4 model ICL implantations, which took place from January 1, 1998, through December 31, 2004, at Jules-Gonin Eye Hospital, Lausanne, Switzerland. Data analysis was performed from January 1, 2014, to May 31, 2014. The lenses implanted were as follows: 53 V4 model ICLs of -15.5 D or greater, 73 V4 model ICLs of less than -15.5 diopter (D), and 7 V4 model toric ICLs for myopia. Main Outcomes and Measures: Rate of cataract surgery, lens opacity, ocular hypertension, refractive safety, predictability, and stability. Results: A total of 133 eyes of 78 patients (34 men and 44 women, with a mean [SD] age of 38.8 [9.2] years at enrollment) met the inclusion criteria. The rate of lens opacity development was 40.9% (95% CI, 32.7%-48.8%) and 54.8% (95% CI, 44.7% 63.0%) at 5 and 10 years, respectively. Phacoemulsification was performed in 5 eyes (4.9%; 95% CI, 1.0%-8.7%) and 18 eyes (18.3%; 95% CI, 10.1%-25.8%) at 5 and 10 years after ICL implantation, respectively. The vault height (distance between the posterior ICL surface and anterior lens surface) measured a mean (SD) of 426 (344) MUm immediately postoperatively, decreasing to 213 (169) MUm at 10 years. A smaller vault height was associated with the development of lens opacity and phacoemulsification (P = .005 and .008, respectively). The intraocular pressure was 15 mm Hg postoperatively, and there was no significant increase in intraocular pressure observed until the 10-year follow-up (16 mm Hg, P = .02). At 10 years, 12 eyes (12.9%; 95% CI, 5.6%-19.6%) had developed ocular hypertension that required topical medication. At 10 years, the mean (SD) safety index was 1.25 (0.57), with a manifest spherical equivalent of -0.5 D at 1-year postoperatively vs -0.7 D at 10 years postoperatively in eyes aimed at emmetropia. Conclusions and Relevance: This retrospective single center study indicates that ICL implantation provides good long-term safety and stability of refraction in patients with high myopia compared with similar short-term studies. However, the rates of cataract formation and ocular hypertension at 10 years have important clinical implications, and as such this information should be part of the available patient information before ICL implantation. PMID- 26941077 TI - Depressive-like immobility behavior and genotype * stress interactions in male mice of selected strains. AB - In this study, we investigated whether basal immobility time of C57BL/6J mice, which are commonly used in transgenesis, interferes with detection of depressive like behavior in the tail suspension test (TST) after chronic restraint stress (CRS). We included in the study mice of the C57BL/6N strain, not previously compared with C57BL/6J for behavior in the TST, and contrasted both strains with NMRI mice which exhibit low basal immobility. NMRI, C57BL/6J, and C57BL/6N male mice (n = 20 per strain) were tested under basal conditions and after CRS (2 h daily for 14 d). NMRI and C57BL/6J mice were differentiated in the TST by low and high basal immobility times, respectively, while the C57BL/6N and NMRI mice showed similar levels of basal immobility. CRS extended the immobility time of NMRI mice in the TST, whereas both C57BL/6J and C57BL/6N mice were unaffected regardless of their initial phenotype. We explored whether detailed analysis of activity microstructure revealed effects of CRS in the TST, which are not apparent in the overall comparison of total immobility time. Interestingly, unlike C57BL/6J and/6N strains which showed no sensitivity to CRS, stressed NRMI mice displayed distinct activity microstructure. In contrast to behavioral differences, all stressed mice showed significant retardation in body weight gain, decreased thymus weight and increased adrenal cortex size. However, after CRS, enlargement of the adrenal medulla was observed in both C57BL/6J and C57BL/6N mice, suggesting similar sympatho-medullary activation and stress coping mechanism in these substrains. PMID- 26941079 TI - One in 10 practices in England faces financial collapse, survey shows. PMID- 26941078 TI - Identification of Kynoxazine, a Novel Fluorescent Product of the Reaction between 3-Hydroxykynurenine and Erythrulose in the Human Lens, and Its Role in Protein Modification. AB - Kynurenine pathway metabolites and ascorbate degradation products are present in human lenses. In this study, we showed that erythrulose, a major ascorbate degradation product, reacts spontaneously with 3-hydroxykynurenine to form a fluorescent product. Structural characterization of the product revealed it to be 2-amino-4-(2-hydroxy-3-(2-hydroxyethyl)-2H-benzo[b][1,4]oxazin-5-yl)-4 oxobutanoic acid, which we named kynoxazine. Unlike 3-hydroxykynurenine, 3 hydroxykynurenine glucoside and kynurenine were unable to form a kynoxazine-like compound, which suggested that the aminophenol moiety in 3-hydroxykynurenine is essential for the formation of kynoxazine. This reasoning was confirmed using a model compound, 1-(2-amino-3-hydroxyphenyl)ethan-1-one, which is an aminophenol lacking the amino acid moiety of 3-hydroxykynurenine. Ultra-performance liquid chromatography-tandem mass spectrometry analyses showed that kynoxazine is present in the human lens at levels ranging from 0 to 64 pmol/mg lens. Kynoxazine as well as erythrulose degraded under physiological conditions to generate 3 deoxythreosone, which modified and cross-linked proteins through the formation of an arginine adduct, 3-deoxythreosone-derived hydroimidazolone, and a lysine arginine cross-linking adduct, 3-deoxythreosone-derived hydroimidazolimine cross link. Ultra-performance liquid chromatography-tandem mass spectrometry quantification showed that 32-169 pmol/mg protein of 3-deoxythreosone-derived hydroimidazolone and 1.1-11.2 pmol/mg protein of 3-deoxythreosone-derived hydroimidazolimine cross-link occurred in aging lenses. Taken together, these results demonstrate a novel biochemical mechanism by which ascorbate oxidation and the kynurenine pathway intertwine, which could promote protein modification and cross-linking in aging human lenses. PMID- 26941080 TI - Dodine as a transparent protein denaturant for circular dichroism and infrared studies. AB - The fungicide dodine combines the cooperative denaturation properties of guanidine with the mM denaturation activity of SDS. It was previously tested only on two small model proteins. Here we show that it can be used as a chemical denaturant for phosphoglycerate kinase (PGK), a much larger two-domain enzyme. In addition to its properties as a chemical denaturant, dodine facilitates thermal denaturation of PGK, and we show for the first time that it also facilitates pressure denaturation of a protein. Much higher quality circular dichroism and amide I' infrared spectra of PGK can be obtained in dodine than in guanidine, opening the possibility for use of dodine as a denaturant when UV or IR detection is desirable. One caution is that dodine denaturation, like other detergent-based denaturants, is less reversible than guanidine denaturation. PMID- 26941081 TI - Colorectal Cancer Screening: Fecal Occult Blood Test Literature Review for Occupational Health Nurses. AB - Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide. It is a potentially preventable disease and ideally suited to a screening program. CRC screening is an early detection strategy for occupational health nurses to offer in the workplace. Education and outreach are key components of this intervention. Many test options are available for CRC screening. This article is an integrative literature review that summarizes evidence to support colorectal screening in the workplace, offers screening recommendations from authoritative agencies, and provides guidance for occupational health nurses who plan to implement a screening program. Current screening limitations using fecal occult blood tests are addressed and an inventory of CRC screening activities in select countries is included. PMID- 26941083 TI - Workers With Irregular Hours During Seasonal Work Surges: Promoting Healthy Sleep. AB - A significant proportion of the labor force works irregular hours during harvest, summer, or holiday work surges. Unfortunately such workers are often uninformed about the importance of sleep and fatigue management. Seasonally timed worker training can improve health and safety outcomes during work surges. PMID- 26941084 TI - Functional imaging of the angiogenic switch in a transgenic mouse model of human breast cancer by dynamic contrast enhanced magnetic resonance imaging. AB - Tumour progression depends on several sequential events that include the microenvironment remodelling processes and the switch to the angiogenic phenotype, leading to new blood vessels recruitment. Non-invasive imaging techniques allow the monitoring of functional alterations in tumour vascularity and cellularity. The aim of this work was to detect functional changes in vascularisation and cellularity through Dynamic Contrast Enhanced (DCE) and Diffusion Weighted (DW) Magnetic Resonance Imaging (MRI) modalities during breast cancer initiation and progression of a transgenic mouse model (BALB-neuT mice). Histological examination showed that BALB-neuT mammary glands undergo a slow neoplastic progression from simple hyperplasia to invasive carcinoma, still preserving normal parts of mammary glands. DCE-MRI results highlighted marked functional changes in terms of vessel permeability (K(trans) , volume transfer constant) and vascularisation (vp , vascular volume fraction) in BALB-neuT hyperplastic mammary glands if compared to BALB/c ones. When breast tissue progressed from simple to atypical hyperplasia, a strong increase in DCE-MRI biomarkers was observed in BALB-neuT in comparison to BALB/c mice (K(trans) = 5.3 +/- 0.7E-4 and 3.1 +/- 0.5E-4; vp = 7.4 +/- 0.8E-2 and 4.7 +/- 0.6E-2 for BALB-neuT and BALB/c, respectively) that remained constant during the successive steps of the neoplastic transformation. Consistent with DCE-MRI observations, microvessel counting revealed a significant increase in tumour vessels. Our study showed that DCE-MRI estimates can accurately detect the angiogenic switch at early step of breast cancer carcinogenesis. These results support the view that this imaging approach is an excellent tool to characterize microvasculature changes, despite only small portions of the mammary glands developed neoplastic lesions in a transgenic mouse model. PMID- 26941085 TI - A historical perspective on the effects of trapping and controlling the muskrat (Ondatra zibethicus) in the Netherlands. AB - BACKGROUND: The muskrat is considered to be a pest species in the Netherlands, and a year-round control programme is in effect. We aimed to evaluate the effectiveness of this programme using historical data on catch and effort collected at a provincial scale. RESULTS: The development of the catch differed between provinces, depending on the year of colonisation by muskrat and the investment of effort (measured as field hours). The catch did not peak in the same year for the various provinces, and provinces that were colonised earlier in time took longer to attain the peak catch. Trapping resulted in declining populations, but only after a certain threshold of annual effort in trapping had been surpassed. On average, populations were observed to decline when the annual effort exceeded 1.4 field hours per km of waterway for several successive years. Having reached a phase of greater control, control organisations tended to reduce effort. CONCLUSION: We conclude that control measures can make muskrat populations decline, provided that the effort is commensurate with the population size. Our study emphasises that experimentation is needed to confirm the causality of the findings, to establish the relation with damage or safety risk and to derive an optimal control strategy. (c) 2016 Society of Chemical Industry. PMID- 26941086 TI - Rectal indomethacin alone versus indomethacin and prophylactic pancreatic stent placement for preventing pancreatitis after ERCP: study protocol for a randomized controlled trial. AB - BACKGROUND: The combination of prophylactic pancreatic stent placement (PSP) - a temporary plastic stent placed in the pancreatic duct - and rectal non-steroidal anti-inflammatory drugs (NSAIDs) is recommended for preventing post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) in high-risk cases. Preliminary data, however, suggest that PSP may be unnecessary if rectal NSAIDs are administered. Given the costs and potential risks of PSP, we aim to determine whether rectal indomethacin obviates the need for pancreatic stent placement in patients undergoing high-risk ERCP. METHODS/DESIGN: The SVI (Stent vs. Indomethacin) trial is a comparative effectiveness, multicenter, randomized, double-blind, non-inferiority study of rectal indomethacin alone versus the combination of rectal indomethacin and PSP for preventing PEP in high-risk cases. One thousand four hundred and thirty subjects undergoing high-risk ERCP, in whom PSP is planned solely for PEP prevention, will be randomized to indomethacin alone or combination therapy. Those who are aware of study group assignment, including the endoscopist, will not be involved in the post-procedure care of the patient for at least 48 hours. Subjects will be assessed for PEP and its severity by a panel of independent and blinded adjudicators. Indomethacin alone will be declared non-inferior to combination therapy if the two-sided 95 % upper confidence bound of the treatment difference is less than 5 % between the two groups. Biological specimens will be obtained from trial participants and centrally banked. DISCUSSION: The SVI trial is designed to determine whether PSP remains necessary in the era of NSAIDs pharmacoprevention. The associated bio repository will establish the groundwork for important scientific breakthrough. TRIAL REGISTRATION: NCT02476279, registered June 2015. PMID- 26941087 TI - Safety of Antithrombotic Agents in Elderly Patients with Acute Coronary Syndromes. AB - There are unique challenges in the treatment and prevention of acute coronary syndromes (ACS) with antithrombotics in elderly patients: elderly patients usually require multiple drugs due to comorbidities, are highly susceptible to adverse drug reactions and drug-drug interactions, may have cognitive problems affecting compliance and complications, are especially exposed to the risk of falls and, most importantly, ageing is an independent risk factor for bleeding. Antithrombotic drugs, alone or in association, further and variously amplify age related bleeding risk. Moreover, age-related changes in primary haemostasis may potentially affect the pharmacodynamics of some antiplatelet drugs. Thus, elderly subjects might be more or less sensitive to standard antiplatelet regimens depending on individual characteristics affecting antiplatelet drug response. Importantly, elderly patients are a rapidly growing population worldwide, have the highest incidence of ACS, but are poorly represented in clinical trials. As a consequence, evidence on antithrombotic drug benefits and risks is limited. Thus, in the real-world setting, older people are often denied antithrombotic drugs because of unjustified concerns, or might be over-treated and exposed to excessive bleeding risk. Personalized antithrombotic therapy in elderly patients is particularly critical, to minimize risks without affecting efficacy. PMID- 26941088 TI - LIGHT-INDUCED RICE1 Regulates Light-Dependent Attachment of LEAF-TYPE FERREDOXIN NADP+ OXIDOREDUCTASE to the Thylakoid Membrane in Rice and Arabidopsis. AB - LIR1 (LIGHT-INDUCED RICE1) encodes a 13-kD, chloroplast-targeted protein containing two nearly identical motifs of unknown function. LIR1 is present in the genomes of vascular plants, mosses, liverworts, and algae, but not in cyanobacteria. Using coimmunoprecipitation assays, pull-down assays, and yeast two-hybrid analyses, we showed that LIR1 interacts with LEAF-TYPE FERREDOXIN NADP(+) OXIDOREDUCTASE (LFNR), an essential chloroplast enzyme functioning in the last step of photosynthetic linear electron transfer. LIR1 and LFNR formed high molecular weight thylakoid protein complexes with the TIC62 and TROL proteins, previously shown to anchor LFNR to the membrane. We further showed that LIR1 increases the affinity of LFNRs for TIC62 and that the rapid light-triggered degradation of the LIR1 coincides with the release of the LFNR from the thylakoid membrane. Loss of LIR1 resulted in a marked decrease in the accumulation of LFNR containing thylakoid protein complexes without a concomitant decrease in total LFNR content. In rice (Oryza sativa), photosynthetic capacity of lir1 plants was slightly impaired, whereas no such effect was observed in Arabidopsis thaliana knockout mutants. The consequences of LIR1 deficiency in different species are discussed. PMID- 26941090 TI - Direct Repression of Evening Genes by CIRCADIAN CLOCK-ASSOCIATED1 in the Arabidopsis Circadian Clock. AB - The circadian clock is a biological timekeeping system that provides organisms with the ability to adapt to day-night cycles. Timing of the expression of four members of the Arabidopsis thaliana PSEUDO-RESPONSE REGULATOR(PRR) family is crucial for proper clock function, and transcriptional control of PRRs remains incompletely defined. Here, we demonstrate that direct regulation of PRR5 by CIRCADIAN CLOCK-ASSOCIATED1 (CCA1) determines the repression state of PRR5 in the morning. Chromatin immunoprecipitation followed by deep sequencing (ChIP-seq) analyses indicated that CCA1 associates with three separate regions upstream of PRR5 CCA1 and its homolog LATE ELONGATED HYPOCOTYL (LHY) suppressed PRR5 promoter activity in a transient assay. The regions bound by CCA1 in the PRR5 promoter gave rhythmic patterns with troughs in the morning, when CCA1 and LHY are at high levels. Furthermore,ChIP-seq revealed that CCA1 associates with at least 449 loci with 863 adjacent genes. Importantly, this gene set contains genes that are repressed but upregulated incca1 lhy double mutants in the morning. This study shows that direct binding by CCA1 in the morning provides strong repression of PRR5, and repression by CCA1 also temporally regulates an evening-expressed gene set that includes PRR5. PMID- 26941089 TI - HLB1 Is a Tetratricopeptide Repeat Domain-Containing Protein That Operates at the Intersection of the Exocytic and Endocytic Pathways at the TGN/EE in Arabidopsis. AB - The endomembrane system plays essential roles in plant development, but the proteome responsible for its function and organization remains largely uncharacterized in plants. Here, we identified and characterized the HYPERSENSITIVE TO LATRUNCULIN B1 (HLB1) protein isolated through a forward genetic screen in Arabidopsis thaliana for mutants with heightened sensitivity to actin-disrupting drugs. HLB1 is a plant-specific tetratricopeptide repeat domain containing protein of unknown function encoded by a single Arabidopsis gene. HLB1 associated with the trans-Golgi network (TGN)/early endosome (EE) and tracked along filamentous actin, indicating that it could link post-Golgi traffic with the actin cytoskeleton in plants. HLB1 was found to interact with the ADP ribosylation-factor guanine nucleotide exchange factor, MIN7/BEN1 (HOPM INTERACTOR7/BREFELDIN A-VISUALIZED ENDOCYTIC TRAFFICKING DEFECTIVE1) by coimmunoprecipitation. The min7/ben1 mutant phenocopied the mild root developmental defects and latrunculin B hypersensitivity of hlb1, and analyses of ahlb1/ min7/ben1 double mutant showed that hlb1 and min7/ben1 operate in common genetic pathways. Based on these data, we propose that HLB1 together with MIN7/BEN1 form a complex with actin to modulate the function of the TGN/EE at the intersection of the exocytic and endocytic pathways in plants. PMID- 26941093 TI - Consumption of medicinal plants by patients with heart diseases at a pharmacist managed anticoagulation clinic in Brazil. AB - BACKGROUND: Medicinal plants (MP) have been used for many years with the purpose of feeding and curing. Several MP may interfere in drug response and are not always considered as potential drug-interactors in clinical practice. OBJECTIVE: To investigate the consumption of MP by outpatients during a one-year follow-up. METHOD: Patients with cardiopathy diagnosis and indication(s) for long-term use of warfarin were recruited at a pharmacist-managed anticoagulation clinic of a Brazilian public hospital. This research employed a descriptive method. The consumption of MP was examined regarding the type, frequency and forms of use. RESULTS: A total of 280 patients were studied. Most patients were female (54.6 %) with an average age of 56.8 +/- 13.1 years. The consumption of MP was reported by 46 (16.4 %) patients, totalizing 59 occurrences. Lemon, lemon balm and plantain were the most common MP. The main pharmacological uses involved the digestive, urinary, and respiratory tracts. Tea was the predominant form of consumption (87 %). Twelve (33.3 %) plants presented potential herb-warfarin interactions according to the literature. CONCLUSION: We described the consumption of MP among outpatients characterized by their complex disease status, propensity for adverse events, and socioeconomic limitations. These results may guide pharmacist interventions and procedures to prevent clinical complications. PMID- 26941091 TI - A Geranylfarnesyl Diphosphate Synthase Provides the Precursor for Sesterterpenoid (C25) Formation in the Glandular Trichomes of the Mint Species Leucosceptrum canum. AB - Plant sesterterpenoids, an important class of terpenoids, are widely distributed in various plants, including food crops. However, little is known about their biosynthesis. Here, we cloned and functionally characterized a plant geranylfarnesyl diphosphate synthase (Lc-GFDPS), the enzyme producing the C25 prenyl diphosphate precursor to all sesterterpenoids, from the glandular trichomes of the woody plant Leucosceptrum canum. GFDPS catalyzed the formation of GFDP after expression in Escherichia coli. Overexpressing GFDPS in Arabidopsis thaliana also gave an extract catalyzing GFDP formation. GFDPS was strongly expressed in glandular trichomes, and its transcript profile was completely in accordance with the sesterterpenoid accumulation pattern. GFDPS is localized to the plastids, and inhibitor studies indicated its use of isoprenyl diphosphate substrates supplied by the 2-C-methyl-D-erythritol 4-phosphate pathway. Application of a jasmonate defense hormone induced GFDPS transcript and sesterterpenoid accumulation, while reducing feeding and growth of the generalist insect Spodoptera exigua, suggesting that these C25 terpenoids play a defensive role. Phylogenetic analysis suggested that GFDPS probably evolved from plant geranylgeranyl diphosphate synthase under the influence of positive selection. The isolation of GFDPS provides a model for investigating sesterterpenoid formation in other species and a tool for manipulating the formation of this group in plants and other organisms. PMID- 26941092 TI - Diatom Phytochromes Reveal the Existence of Far-Red-Light-Based Sensing in the Ocean. AB - The absorption of visible light in aquatic environments has led to the common assumption that aquatic organisms sense and adapt to penetrative blue/green light wavelengths but show little or no response to the more attenuated red/far-red wavelengths. Here, we show that two marine diatom species, Phaeodactylum tricornutum and Thalassiosira pseudonana, possess a bona fide red/far-red light sensing phytochrome (DPH) that uses biliverdin as a chromophore and displays accentuated red-shifted absorbance peaks compared with other characterized plant and algal phytochromes. Exposure to both red and far-red light causes changes in gene expression in P. tricornutum, and the responses to far-red light disappear in DPH knockout cells, demonstrating that P. tricornutum DPH mediates far-red light signaling. The identification of DPH genes in diverse diatom species widely distributed along the water column further emphasizes the ecological significance of far-red light sensing, raising questions about the sources of far-red light. Our analyses indicate that, although far-red wavelengths from sunlight are only detectable at the ocean surface, chlorophyll fluorescence and Raman scattering can generate red/far-red photons in deeper layers. This study opens up novel perspectives on phytochrome-mediated far-red light signaling in the ocean and on the light sensing and adaptive capabilities of marine phototrophs. PMID- 26941094 TI - Anti-Tumoral Effects of Anti-Progestins in a Patient-Derived Breast Cancer Xenograft Model. AB - Breast cancer is a hormone-dependent disease in which estrogen signaling targeting drugs fail in about 10 % due to resistance. Strong evidences highlighted the mitogen role of progesterone, its ligands, and the corresponding progesterone receptor (PR) isoforms in mammary carcinoma. Several PR antagonists have been synthesized; however, some of them are non-selective and led to side or toxic effects. Herein, we evaluated the anti-tumor activity of a commercially available PR modulator, ulipristal acetate (UPA), and a new selective and passive PR antagonist "APR19" in a novel preclinical approach based on patient-derived breast tumor (HBCx-34) xenografted in nude mice. As opposed to P4 that slightly reduces tumor volume, UPA and APR19 treatment for 42 days led to a significant 30 % reduction in tumor weight, accompanied by a significant 40 % retardation in tumor growth upon UPA exposure while a 1.5-fold increase in necrotic areas was observed in APR19-treated tumors. Interestingly, PR expression was upregulated by a 2.5-fold factor in UPA-treated tumors while APR19 significantly reduced expression of both PR and estrogen receptor alpha, indicating a potential distinct molecular mechanism among PR antagonists. Cell proliferation was clearly reduced in UPA group compared to vehicle conditions, as revealed by the significant reduction in Ki-67, Cyclin D1, and proliferating cell nuclear antigen (PCNA) expression. Likewise, an increase in activated, cleaved poly(ADP-ribose) polymerase (PARP) expression was also demonstrated upon UPA exposure. Collectively, our findings provide direct in vivo evidence for anti-progestin mediated control of human breast cancer growth, given their anti-proliferative and pro-apoptotic activities, supporting a potential role in breast cancer therapy. PMID- 26941095 TI - Counter-regulation of rejection activity against human liver grafts by donor PD L1 and recipient PD-1 interaction. AB - BACKGROUND & AIMS: Co-inhibitory receptor-ligand interactions fine-tune immune responses by negatively regulating T cell functions. Our aim is to examine the involvement of co-inhibitory receptor-ligand pair PD-1/PD-L1 in regulating rejection after liver transplantation (LT) in humans. METHODS: PD-L1/PD-1 expression in liver allograft was determined by immunohistochemistry or flow cytometry, and the effect of blockade was studied using graft-infiltrating T cells ex vivo. Five single nucleotide polymorphisms within PD-1 and PD-L1 genes were genotyped in 528 LT recipients and 410 donors, and associations with both early (?6months) and late (>6months) acute rejection were analyzed using Cox proportional-hazards regression model. The effect of PD-L1 rs4143815 on PD-L1 expression was analyzed using donor hepatic leukocytes. RESULTS: PD-L1 was expressed by hepatocytes, cholangiocytes and along the sinusoids in post transplant liver allografts, and PD-1 was abundantly expressed on allograft infiltrating T cells. PD-L1 blockade enhanced allogeneic proliferative responses of graft-infiltrating T cells. In the genetic association analysis, donor PD-L1 rs4143815 (CC/CG vs. GG; HR=0.230; p=0.002) and recipient PD-1 rs11568821 (AA/AG vs. GG; HR=3.739; p=0.004) were associated with acute rejection late after LT in multivariate analysis. Recipients carrying the PD-1 rs11568821 A allele who were transplanted with liver grafts of PD-L1 rs4143815 GG homozygous donors showed the highest risk for late acute rejection. PD-L1 rs4143815 is associated with differential PD-L1 expression on donor hepatic dendritic cells upon IFN-gamma stimulation. CONCLUSION: Our data suggest that interplay between donor PD-L1 and recipient PD-1 counter-regulates rejection activity against liver grafts in humans. PMID- 26941096 TI - Diagnostic application of total antioxidant capacity in seminal plasma to assess oxidative stress in male factor infertility. AB - PURPOSE: This study was undertaken in order to establish a new reference value for the total antioxidant capacity (TAC) in seminal plasma as a predictor of fertility. This study also aims to propose a detailed protocol for the TAC assay including calculation of assay results and assessment of sensitivity and specificity over possible cutoff values in infertile men and controls with proven and unproven fertility. METHODS: Seminal plasma from 279 infertile patients and 46 normal healthy men referred to a male infertility testing laboratory were tested to measure TAC by a colorimetric assay kit. Receiver operating characteristics (ROC) curves were generated to establish cutoff values, sensitivity, and specificity, and the distribution of cutoff values in controls and infertile patients was calculated. RESULTS: Infertile patients showed significantly lower levels (mean +/- SEM) of total antioxidants (micromolar Trolox equivalents) in their seminal plasma (1863.84 +/- 27.16 MUM) compared to those from fertile men (2013 +/- 56.04 MUM, P = 0.019). A preferred cutoff TAC value of 1947 MUM could facilitate better diagnosis of oxidative stress (OS) in men with male factor infertility. At this threshold, the specificity of TAC assay was 63.0 % and the sensitivity 59.5 % with a positive predictive value of 90.7 % and a negative predictive value of 20.4 %. CONCLUSIONS: Our results establish a new diagnostic cutoff TAC value of 1947 MUM in seminal plasma to distinguish prevalence of OS in infertile patients compared to healthy men. This study provides a robust reference value of seminal plasma TAC that may provide an important diagnostic tool to the physicians for managing OS and male factor infertility in such patients. PMID- 26941098 TI - Outcomes of intracytoplasmic sperm injection using the zona pellucida-bound sperm or manually selected sperm. AB - PURPOSE: Zona pellucida (ZP)-bound sperm used for intracytoplasmic sperm injection (ICSI) enhances embryo quality, implantation, and clinical pregnancy rates. This study aimed to assess the pregnancy outcomes and clinical significance of ICSI with ZP-bound sperm. METHOD: A total of 84 infertile couples who underwent cycles of ICSI following failed in vitro fertilization between June 2012 and February 2014 were enrolled and randomized (1:1): in the treatment group, ICSI was performed using ZP-bound sperm; in the control group, ICSI was performed in a standard manner. Rates of fertilization, cleavage, high-quality embryos, and clinical pregnancy were compared between the two groups. RESULTS: There were no significant differences in age, infertile period, gonadotrophin dose, number of metaphase II oocytes, and number of embryo transfers between the two groups (P > 0.05). The clinical pregnancy rate was higher in the treatment group than in the control group, but without statistical significance (60.5 vs. 47.6 %, P > 0.05). No significant differences in the rates of fertilization and cleavage were observed (83.0 vs. 81.6 %, and 96.3 vs. 96.5 %, both P > 0.05), but higher rates of high-quality embryos and useable embryos were observed with ZP bound sperm compared with controls (66.1 vs. 50.8 % and 76.0 vs. 66.3 %, both P < 0.05). CONCLUSIONS: ICSI using ZP-bound sperm might increase the embryo quality and number of useable embryos, possibly improving the clinical pregnancy outcome of ICSI. PMID- 26941097 TI - The role of epigenetics in idiopathic male infertility. AB - Infertility is a complex disorder with multiple genetic and environmental causes. Although some specific mutations have been identified, other factors responsible for sperm defects remain largely unknown. Despite considerable efforts to identify the pathophysiology of the disease, we cannot explain the underlying mechanisms of approximately half of infertility cases. This study reviews current data on epigenetic regulation and idiopathic male infertility. Recent data have shown an association between epigenetic modifications and idiopathic infertility. In this regard, epigenetics has emerged as one of the promising research areas in understanding male infertility. Many studies have indicated that epigenetic modifications, including DNA methylation in imprinted and developmental genes, histone tail modifications and short non-coding RNAs in spermatozoa may have a role in idiopathic male infertility. PMID- 26941100 TI - Microarray Analysis of lncRNA and mRNA Expression Profiles in Patients with Neuromyelitis Optica. AB - For the epigenetic characterization of neuromyelitis optica (NMO), we determined whether messenger RNAs (mRNAs) and long noncoding RNAs (lncRNAs) are expressed differentially in subjects with and without NMO. lncRNA and mRNA expression profiles of NMO patients and healthy controls were generated by using microarray analysis. For comparison, the differentially expressed mRNA functions were annotated by using gene ontology (GO) and pathway analyses. The microarray revealed that 1310 lncRNAs and 743 mRNAs differed in NMO patients from those in healthy controls. Pathway analysis then demonstrated that IL23-mediated signaling events, interferon gamma signaling, natural killer (NK)-kappaB signaling pathway, chemokine receptors that bind chemokines, GPCR ligand binding, and metabolic disorders of biological oxidation enzyme pathways play important roles in NMO. Several GO terms including cytokine stimulus, response to cytokine, immune response, cytokine-mediated signaling pathway, and response to chemical cytokine activity were enriched in gene lists, suggesting a potential correlation with NMO. Co-expression network analysis indicated that 183 lncRNAs and 458 mRNAs were included in the co-expression network. Our present study showed that these differentially expressed mRNAs and lncRNAs may play important roles in NMO and could provide basic information for new biomarkers or treatment targets to alleviate NMO. PMID- 26941099 TI - The Association of SNAP25 Gene Polymorphisms in Attention Deficit/Hyperactivity Disorder: a Systematic Review and Meta-Analysis. AB - Attention deficit/hyperactivity disorder (ADHD) is one of the most highly heritable psychiatric disorders in childhood. The risk gene mutation accounts for about 60 to 90 % cases. Synaptosomal-associated protein of 25 kDa (SNAP-25) is a presynaptic plasma membrane protein which is expressed highly and specifically in the neuronal cells. A number of evidences have suggested the role of SNAP-25 in the etiology of ADHD. Notably, the animal model of coloboma mouse mutant bears a ~2-cM deletion encompassing genes including SNAP25 and displays spontaneous hyperkinetic behavior. Previous investigators have reported association between SNPs in SNAP25 and ADHD, and controversial results were observed. In this study, we analyzed the possible association between six polymorphisms (rs3746544, rs363006, rs1051312, rs8636, rs362549, and rs362998) of SNAP25 and ADHD in a pooled sample of ten family-based studies and four case-control studies by using meta-analysis. The combined analysis results were significant only for rs3746544 (P = 0.010) with mild association (odds ratio (OR) = 1.14). And, the meta analysis data for rs8636, rs362549, and rs362998 are the first time to be reported; however, no positive association was detected. In conclusion, we report some evidence supporting the association of SNAP25 to ADHD. Future research should emphasize genome-wide association studies in more specific subgroups and larger independent samples. PMID- 26941101 TI - MEF2D Mediates the Neuroprotective Effect of Methylene Blue Against Glutamate Induced Oxidative Damage in HT22 Hippocampal Cells. AB - Methylene blue (MB) can ameliorate behavioral, neurochemical, and neuropathological impairments in animal models of acute and chronic neurodegenerative disorders, but the underlying mechanism remains unclear. Myocyte enhancer factor 2 (MEF2D) is known to promote neuronal survival in several models, and several survival and death signals converge on MEF2D and regulate its activity. Here, we investigated the role of MEF2D in the neuroprotective effect of MB against glutamate-induced toxicity in HT22 neuronal cells. Our results showed that MB, event at less than 100 nM, improved the viability of HT22 cells exposed to 2 mM glutamate. MB attenuated the mitochondrial impairment and quenches the reactive oxygen species (ROS) induced by glutamate. Surprisingly, MB at 50-200 nM did not affect the Nrf2/HO-1 pathway, an important endogenous anti-oxidative system. Further study showed that MB increased the transcription and translation of MEF2D. In addition, MB upregulated the expression of mitochondrial NADH dehydrogenase 6 (ND6) in a MEF2D-dependent manner. Knockdown of MEF2D abolished both MB-medicated increase of ND6 and MB induced neuroprotection against glutamate-induced toxicity. Moreover, we showed that MB promoted Akt function activity, suppressed GSK-3beta activity, and increased MEF2D level in hippocampus of mice and HT22 cells. These findings for the first time demonstrate that MB protects HT22 neuronal cells against glutamate induced cell death partially via the regulation of MEF2D-associated survival pathway. PMID- 26941104 TI - The carboxyl terminal mutational hotspot of the ciliary disease protein RPGRORF15 (retinitis pigmentosa GTPase regulator) is glutamylated in vivo. AB - Mutations inRPGR(ORF15)(retinitis pigmentosa GTPase regulator) are a major cause of inherited retinal degenerative diseases. RPGR(ORF15)(1152 residues) is a ciliary protein involved in regulating the composition and function of photoreceptor cilia. The mutational hotspot in RPGR(ORF15)is an unusual C terminal domain encoded by exon ORF15, which is rich in polyglutamates and glycine residues (Glu-Gly domain) followed by a short stretch of basic amino acid residues (RPGR(C2)domain; residues 1072-1152). However, the properties of the ORF15-encoded domain and its involvement in the pathogenesis of the disease are unclear. Here we show that RPGR(ORF15)is glutamylated at the C-terminus, as determined by binding to GT335, which recognizes glutamylated substrates. This reactivity is lost in two mouse mutants ofRpgr, which do not express RPGR(ORF15)due to disease-causing mutations in exon ORF15. Our results indicate that RPGR(ORF15)is posttranslationally glutamylated in the Glu-Gly domain and that the GT335 antibody predominantly recognizes RPGR(ORF15)in photoreceptor cilia. PMID- 26941102 TI - Altered Amygdala Resting-State Functional Connectivity in Maintenance Hemodialysis End-Stage Renal Disease Patients with Depressive Mood. AB - The purpose of this study was to investigate patterns in the amygdala-based emotional processing circuit of hemodialysis patients using resting-state functional MR imaging (rs-fMRI). Fifty hemodialysis patients (25 with depressed mood and 25 without depressed mood) and 26 healthy controls were included. All subjects underwent neuropsychological tests and rs-fMRI, and patients also underwent laboratory tests. Functional connectivity of the bilateral amygdala was compared among the three groups. The relationship between functional connectivity and clinical markers was investigated. Depressed patients showed increased positive functional connectivity of the left amygdala with the left superior temporal gyrus and right parahippocampal gyrus (PHG) but decreased amygdala functional connectivity with the left precuneus, angular gyrus, posterior cingulate cortex (PCC), and left inferior parietal lobule compared with non depressed patients (P < 0.05, AlphaSim corrected). Depressed patients had increased positive functional connectivity of the right amygdala with bilateral supplementary motor areas and PHG but decreased amygdala functional connectivity with the right superior frontal gyrus, superior parietal lobule, bilateral precuneus, and PCC (P < 0.05, AlphaSim corrected). After including anxiety as a covariate, we discovered additional decreased functional connectivity with anterior cingulate cortex (ACC) for bilateral amygdala (P < 0.05, AlphaSim corrected). For the depressed, neuropsychological test scores were correlated with functional connectivity of multiple regions (P < 0.05, AlphaSim corrected). In conclusion, functional connectivity in the amygdala-prefrontal-PCC-limbic circuits was impaired in depressive hemodialysis patients, with a gradual decrease in ACC between controls, non-depressed, and depressed patients for the right amygdala. This indicates that ACC plays a role in amygdala-based emotional regulatory circuits in these patients. PMID- 26941105 TI - Preparation, anti-biofouling and drag-reduction properties of a biomimetic shark skin surface. AB - Shark skin surfaces show non-smoothness characteristics due to the presence of a riblet structure. In this study, biomimetic shark skin was prepared by using the polydimethylsiloxane (PDMS)-embedded elastomeric stamping (PEES) method. Scanning electron microscopy (SEM) was used to examine the surface microstructure and fine structure of shark skin and biomimetic shark skin. To analyse the hydrophobic mechanism of the shark skin surface microstructure, the effect of biomimetic shark skin surface microstructure on surface wettability was evaluated by recording water contact angle. Additionally, protein adhesion experiments and anti-algae adhesion performance testing experiments were used to investigate and evaluate the anti-biofouling properties of the surface microstructure of biomimetic shark skin. The recorded values of the water contact angle of differently microstructured surfaces revealed that specific microstructures have certain effects on surface wettability. The anti-biofouling properties of the biomimetic shark skin surface with microstructures were superior to a smooth surface using the same polymers as substrates. Moreover, the air layer fixed on the surface of the biomimetic shark skin was found to play a key role in their antibiont adhesion property. An experiment into drag reduction was also conducted. Based on the experimental results, the microstructured surface of the prepared biomimetic shark skin played a significant role in reducing drag. The maximum of drag reduction rate is 12.5%, which is higher than the corresponding maximum drag reduction rate of membrane material with a smooth surface. PMID- 26941106 TI - For the New, the Former, and All Those Continuing On: We Offer Our Thanks. PMID- 26941103 TI - RIT2 Polymorphisms: Is There a Differential Association? AB - Neurological disorders include a wide variety of mostly multifactorial diseases related to the development, survival, and function of the neuron cells. Single nucleotide polymorphisms (SNPs) have been extensively studied in neurological disorders, and in a number of instances have been reproducibly linked to disease as risk factors. The RIT2 gene has been recently shown to be associated with a number of neurological disorders, such as Parkinson's disease (PD) and autism. In the study reported here, we investigated the association of the rs12456492 and rs16976358 SNPs of the RIT2 gene with PD, essential tremor (ET), autism, schizophrenia (SCZ), and bipolar disorder (BPD; total of 2290 patients), and 1000 controls, by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Significant association was observed between rs12456492 and two disorders, PD and ET, whereas rs16976358 was found to be associated with autism, SCZ, and BPD. Our findings are indicative of differential association between the RIT2 SNPs and different neurological disorders. PMID- 26941107 TI - Quantitative Proteomic Analysis of the Orbital Frontal Cortex in Rats Following Extended Exposure to Caffeine Reveals Extensive Changes to Protein Expression: Implications for Neurological Disease. AB - Caffeine is a plant-derived psychostimulant and a common additive found in a wide range of foods and pharmaceuticals. The orbitofrontal cortex (OFC) is rapidly activated by flavours, integrates gustatory and olfactory information, and plays a critical role in decision-making, with dysfunction contributing to psychopathologies and neurodegenerative conditions. This study investigated whether long-term consumption of caffeine causes changes to behavior and protein expression in the OFC. Male adult Sprague-Dawley rats (n = 8 per group) were treated for 26 days with either water or a 0.6 g/L caffeine solution. Locomotor behavior was measured on the first and last day of treatment, then again after 9 days treatment free following exposure to a mild stressor. When tested drug free, caffeine-treated animals were hyperactive compared to controls. Two hours following final behavioral testing, brains were rapidly removed and prepared for proteomic analysis of the OFC. Label free shotgun proteomics found 157 proteins differentially expressed in the caffeine-drinking rats compared to control. Major proteomic effects were seen for cell-to-cell communication, cytoskeletal regulation, and mitochondrial function. Similar changes have been observed in neurological disorders including Alzheimer's disease, Parkinson's disease, and schizophrenia. PMID- 26941108 TI - Proteomic identification of gender molecular markers in Bothrops jararaca venom. AB - Variation in the snake venom proteome is a well-documented phenomenon; however, sex-based variation in the venom proteome/peptidome is poorly understood. Bothrops jararaca shows significant sexual size dimorphism and here we report a comparative proteomic/peptidomic analysis of venoms from male and female specimens and correlate it with the evaluation of important venom features. We demonstrate that adult male and female venoms have distinct profiles of proteolytic activity upon fibrinogen and gelatin. These differences were clearly reflected in their different profiles of SDS-PAGE, two-dimensional electrophoresis and glycosylated proteins. Identification of differential protein bands and spots between male or female venoms revealed gender-specific molecular markers. However, the proteome comparison by in-solution trypsin digestion and label-free quantification analysis showed that the overall profiles of male and female venoms are similar at the polypeptide chain level but show striking variation regarding their attached carbohydrate moieties. The analysis of the peptidomes of male and female venoms revealed different contents of peptides, while the bradykinin potentiating peptides (BPPs) showed rather similar profiles. Furthermore we confirmed the ubiquitous presence of four BPPs that lack the C terminal Q-I-P-P sequence only in the female venom as gender molecular markers. As a result of these studies we demonstrate that the sexual size dimorphism is associated with differences in the venom proteome/peptidome in B. jararaca species. Moreover, gender-based variations contributed by different glycosylation levels in toxins impact venom complexity. BIOLOGICAL SIGNIFICANCE: Bothrops jararaca is primarily a nocturnal and generalist snake species, however, it exhibits a notable ontogenetic shift in diet and in venom proteome upon neonate to adult transition. As is common in the Bothrops genus, B. jararaca shows significant sexual dimorphism in snout-vent length and weight, with females being larger than males. This sexual size dimorphism suggests the tendency for female specimens to feed on larger prey, and for male specimens to go on a diet similar to that of juveniles. Variation in the snake venom proteome is a ubiquitous phenomenon occurring at all taxonomic levels. At the intraspecific variation level, the individual contribution to the venom proteome is important but effects contributed by age and feeding habits may also affect the proteome phenotype. Whether sex-based factors play a role in venom variation of a species that shows sexual size dimorphism is poorly known. The use of proteomic strategies supported by transcriptomic data allows a more comprehensive assessment of venom proteomes uncovering components that are gender-specific. PMID- 26941109 TI - Inducible lymphoid clusters, iSALTs, in contact dermatitis: a new concept of acquired cutaneous immune responses. AB - Antigen presentation to peripheral memory T cells is a key step in the prompt elicitation of acquired immune responses. In the mucosa, specific sentinel lymphoid tissues called mucosa-associated lymphoid tissue serve as antigen presentation sites. Correspondingly, the concept of skin-associated lymphoid tissue (SALT) has been proposed in the 1980s. However, the details of SALT have not been clarified so far. Recently, the live imaging analysis using two photon microscopes are developed. Here, we have identified inducible lymphoid clusters in the skin, we called it inducible SALTs (iSALTs), using a murine contact hypersensitivity model. In the elicitation phase, dendritic cells (DCs) formed clusters and interacted for several hours with effector memory T cells in the dermis. This interaction was essential for proliferation and activation of effector memory T cells in situ in an antigen dependent manner. Interestingly, DC clusters were abrogated by depletion of skin macrophages. Furthermore, IL-1 treatment induced CXCL2 production from macrophages and DC clusters were suppressed with the blockade of IL-1R or CXCR2. Taken together, this sustained conjugation between DCs and memory T cells, iSALTs, is essential for establishment of the effector phase in acquired cutaneous immunity. PMID- 26941110 TI - The Troubling Trichotomy 10 Years Later: Where Are We Now? AB - A decade ago, "Nutrition Support and The Troubling Trichotomy: A Call To Action" was published in this journal, identifying existing conflicts among technological, ethical, and legal aspects of nutrition support therapy, particularly in terminal or end-of-life situations. Over the past 10 years, the American Society for Parenteral and Enteral Nutrition and others have responded to the action call. A "state of the trichotomy" reveals that while much has been achieved, differences in all 3 aspects will continue to exist due to their dynamic and ever-changing states. The technology arena has made it possible to increase the delivery of nutrition support in alternative settings with the use of telemedicine and social media. Critical/crucial conversations and earlier declarations of individual wishes for care and treatment while having decision making capacity have been enhanced with the focus on patient-centered and family centered care. The definition of death as brain death has been challenged in at least one instance. Conflicts between the state's interests and the individual's interests have added to recent legal controversies. Notwithstanding the progress made over the past 10 years, several challenges remain. The future challenges presented by the Troubling Trichotomy can be best confronted if we ACT Accountability, Communication, and Teamwork. The focus of teamwork should move from multidisciplinary and interdisciplinary teams to transdisciplinary teams, reflecting the shift to function rather than form presented by the new healthcare environment. The transdisciplinary team will be able address the opportunities of the Troubling Trichotomy in the next decade by incorporating the 12 Cs, as detailed in the article. PMID- 26941111 TI - Multisite silicon neural probes with integrated silicon nitride waveguides and gratings for optogenetic applications. AB - Optimal optogenetic perturbation of brain circuit activity often requires light delivery in a precise spatial pattern that cannot be achieved with conventional optical fibers. We demonstrate an implantable silicon-based probe with a compact light delivery system, consisting of silicon nitride waveguides and grating couplers for out-of-plane light emission with high spatial resolution. 473 nm light is coupled into and guided in cm-long waveguide and emitted at the output grating coupler. Using the direct cut-back and out-scattering measurement techniques, the propagation optical loss of the waveguide is measured to be below 3 dB/cm. The grating couplers provide collimated light emission with sufficient irradiance for neural stimulation. Finally, a probe with multisite light delivery with three output grating emitters from a single laser input is demonstrated. PMID- 26941112 TI - Benefits of oxygen incorporation in atomic laminates. AB - Atomic laminates such as MAX phases benefit from the addition of oxygen in many ways, from the formation of a protective oxide surface layer with self-healing capabilities when cracks form to the tuning of anisotropic conductivity. In this paper oxygen incorporation and vacancy formation in M 2AlC (M = Ti, V, Cr) MAX phases have been studied using first-principles calculations where the focus is on phase stability and electronic structure for different oxygen and/or vacancy configurations. Oxygen prefers different lattice sites depending on M-element and this can be correlated to the number of available non-bonding M d-electrons. In Ti2AlC, oxygen substitutes carbon while in Cr2AlC it is located interstitially within the Al-layer. I predict that oxygen incorporation in Ti2AlC stabilizes the material, which explains the experimentally observed 12.5 at% oxygen (x = 0.5) in Ti2Al(C(1-x)O(x)). In addition, it is also possible to use oxygen to stabilize the hypothetical Zr2AlC and Hf2AlC. Hence, oxygen incorporation may be beneficial in many ways. Not only can it make a material more stable, but it also can act as a reservoir for internal self-healing with shorter diffusion paths. PMID- 26941113 TI - Integrated photonics with programmable non-volatile memory. AB - Silicon photonics integrated circuits (Si-PIC) with well-established active and passive building elements are progressing towards large-scale commercialization in optical communications and high speed optical interconnects applications. However, current Si-PICs do not have memory capabilities, in particular, the non volatile memory functionality for energy efficient data storage. Here, we propose an electrically programmable, multi-level non-volatile photonics memory cell (PMC) fabricated by standard complementary-metal-oxide-semiconductor (CMOS) compatible processes. A micro-ring resonator (MRR) was built using the PMC to optically read the memory states. Switching energy smaller than 20 pJ was achieved. Additionally, a MRR memory array was employed to demonstrate a four-bit memory read capacity. Theoretically, this can be increased up to ~400 times using a 100 nm free spectral range broadband light source. The fundamental concept of this design provides a route to eliminate the von Neumann bottleneck. The energy efficient optical storage can complement on-chip optical interconnects for neutral networking, memory input/output interfaces and other computational intensive applications. PMID- 26941115 TI - Fractional high intensity focused radiofrequency in the treatment of mild to Moderate laxity of the lower face and neck: A pilot study. AB - BACKGROUND AND AIMS: The aging process is commonly associated with skin laxity in the lower face and neck. Conventional surgery can correct this at least to some extent, but is invasive. Fractional high-intensity focused radiofrequency delivered to the dermis with insulated microneedles has recently attracted attention in facial rejuvenation. The present pilot study was designed to assess the efficacy of HiFR for skin laxity of the lower face and neck. METHODS: Thirty three patients (7 males, 26 females, age range 37-74 years) with mild to moderate skin laxity of the lower face/neck participated in the study. Three treatments were given at monthly intervals with protocols developed by the authors, three passes per session, at decreasing dermal depths for each pass. Histologic assessment of skin immediately after treatment was performed to identify the site and area of damage in the dermis. Clinical digital photography was taken at baseline and at 6 months after the final treatment session, based on which standardized computer measurement of improvement in the gnathion and cervicomental angles was the primary objective evaluation. A global assessment of improvement was graded by blinded assessors based on the photography. A telephone survey of patient satisfaction was performed at 12 months post-treatment. RESULTS: A significant post-treatment decrease in the cervicomental and gnathion angles was seen of 28.5 degrees and 16.6 degrees , respectively (P < 0.0001 for both). Histology immediately post-treatment showed a clear demarcated and roughly oval area of coagulation associated with the tip of the needle, confined to the dermis and not involving the epidermis. In the global assessment 81.8% of the patients achieved moderate or higher results, and 87% of patients were very satisfied or better. Downtime was minimal, lasting 3-4 days, and no persistent adverse events were recorded. CONCLUSIONS: Fractional HiFR proved safe and effective in the treatment of neck laxity in a large age range of patients, including the elderly. Lasers Surg. Med. 48:461-470, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26941114 TI - Helicobacter pylori outer membrane protein and virulence marker differences in expatriate patients. AB - We studied the prevalence of Helicobacter pylori virulence markers, e.g. cytotoxin associated gene (cagA), cagA promoter, vacuolating associated cytotoxin A (vacA) alleles induced by contact with epithelium (iceA type), and outer membrane protein Q (hopQ) in expatriates and compared them with those in local residents. Gastric biopsies were obtained at endoscopy for culture, histology and PCR for virulence marker and hopQ. Of 309 patients, 236 (76%) were males with a mean age of 45 years. A total of 102 patients were expatriates. hopQ type 1 was present in 98 (47%) local residents compared to 88 (86%) expatriates (P < 0.001), while hopQ type 2 was present in 176 (85%) local residents, compared to 60 (59%) expatriates (P < 0.001). H. pylori virulence marker cagA was positive in 97 (47%) local residents compared to 86 (84%) expatriates (P < 0.001) while cagA-P was positive in 72 (35%) local residents compared to 87 (85%) expatriates (P < 0.001). iceA type 1 was positive in 157 (76%) local residents compared to 45 (44%) expatriates (P < 0.001), while iceA type 2 was positive in 81 (39%) local residents compared to 86 (84%) expatriates (P < 0.001). Distribution of H. pylori cagA, cagA promoter, iceA and hopQ type in local residents and expatriates was different. H. pylori virulence markers were associated with severe pathology in expatriates. PMID- 26941116 TI - Great variation between ICU physicians in the approach to making end-of-life decisions. AB - INTRODUCTION: End-of-life (EOL) decision-making in the intensive care unit (ICU) is difficult, but is rarely practiced in simulated settings. We wanted to explore different strategies ICU physicians use when making EOL decisions, and whether attitudes towards EOL decisions differ between a small-group simulation setting and a large-group plenary setting. METHODS: The study took place during a Scandinavian anaesthesiology and intensive care conference. The simulated ICU patient had a cancer disease with a grave prognosis, had undergone surgery, suffered from severe co-morbidities and had a son present demanding all possible treatment. The participants were asked to make a decision regarding further ICU care. We presented the same case scenario in a plenary session with voting opportunities. RESULTS: In the simulation group (n = 48), ICU physicians used various strategies to come to an EOL decision: patient-oriented, family-oriented, staff-oriented and regulatory-oriented. The simulation group was more willing than the plenary group (n = 47) to readmit the patient to the ICU if the patient again would need respiratory support (32% vs. 8%, P < 0.001). Still, fewer participants in the simulation group than in the plenary group (21% vs. 38%, P = 0.019) considered the patient's life expectancy of living an independent life to be over 10%. CONCLUSION: There was great variation between ICU physicians in the approach to making EOL decisions, and large variations in their life expectancy estimates. Participants in the simulation group were more willing to admit and readmit the patient to the ICU, despite being more pessimistic towards life expectancies. We believe simulation can be used more extensively in EOL decision making training. PMID- 26941117 TI - Answer to: Dabigatran anticoagulation and Stanford Type A aortic dissection: not a lethal coincidence. PMID- 26941118 TI - The nephrotoxicity of 6% Hydroxyethyl Starch 130/0.4 in surgery. PMID- 26941119 TI - Interleukin-31 receptor and pruritus associated with primary localized cutaneous amyloidosis. PMID- 26941121 TI - Fast and highly efficient SO2 capture by TMG immobilized on hierarchical micro meso-macroporous AlPO-5/cordierite honeycomb ceramic materials. AB - SO2 capacity of the obtained TMG-AlPO-5/cordierite honeycomb ceramic (CHC) adsorbent was measured to be 1.13 mol per mol TMG. More importantly, compared with literature reported supported ionic liquids, it is featured by a significantly improved adsorption rate (t0.9 reduced from >30 min to ~0.1 min) and negligible pressure drop. PMID- 26941122 TI - Lessons learned in andrology: from endocrinology to andrology and backwards: the round trip of a clinician. PMID- 26941120 TI - Genetic suppression reveals DNA repair-independent antagonism between BRCA1 and COBRA1 in mammary gland development. AB - The breast cancer susceptibility gene BRCA1 is well known for its function in double-strand break (DSB) DNA repair. While BRCA1 is also implicated in transcriptional regulation, the physiological significance remains unclear. COBRA1 (also known as NELF-B) is a BRCA1-binding protein that regulates RNA polymerase II (RNAPII) pausing and transcription elongation. Here we interrogate functional interaction between BRCA1 and COBRA1 during mouse mammary gland development. Tissue-specific deletion of Cobra1 reduces mammary epithelial compartments and blocks ductal morphogenesis, alveologenesis and lactogenesis, demonstrating a pivotal role of COBRA1 in adult tissue development. Remarkably, these developmental deficiencies due to Cobra1 knockout are largely rescued by additional loss of full-length Brca1. Furthermore, Brca1/Cobra1 double knockout restores developmental transcription at puberty, alters luminal epithelial homoeostasis, yet remains deficient in homologous recombination-based DSB repair. Thus our genetic suppression analysis uncovers a previously unappreciated, DNA repair-independent function of BRCA1 in antagonizing COBRA1-dependent transcription programme during mammary gland development. PMID- 26941123 TI - Baldness and testicular cancer: the EPSAM case-control study. AB - The etiology of testicular cancer is largely unexplained. Research has mainly focused on prenatal exposures, especially to sex hormones, while less attention has been paid to exposures that may act also postnatally. As baldness has been previously associated with testicular cancer risk we focused on baldness and body hairiness, which are both associated with androgen activity. We used data of the Postnatal Exposures and Male Health (EPSAM) study, a case-control study on testicular cancer conducted in the Province of Turin, Italy, involving cases diagnosed between 1997 and 2008. Information was collected using mailed questionnaires. Analyses included 255 cases and 459 controls. We calculated ORs and 95% CIs to estimate testicular cancer risk among those who developed baldness and among those with body hairiness. We found an inverse association between testicular cancer and baldness (OR: 0.67, 95% CI: 0.46-0.98) and body hairiness (OR: 0.78, 95% CI: 0.53-1.16), although the latter had wider CIs. The inverse association between baldness and testicular cancer is consistent with the results from previous studies. These results suggest that androgens activity may influence testicular cancer risk. PMID- 26941124 TI - A remote-controlled generation of gold@polydopamine (core@shell) nanoparticles via physical-chemical stimuli of polydopamine/gold composites. AB - We present the synthesis of polydopamine particle-gold composites (PdopP-Au) and unique release of Au@Pdop core@shell nanoparticles (NPs) from the PdopP-Au upon external stimuli. The PdopP-Au was prepared by controlled synthesis of AuNPs on the Pdop particles. Upon near infrared (NIR) irradiation or NaBH4 treatment on the PdopP-Au, the synthesized AuNPs within the PdopPs could be burst-released as a form of Au@Pdop NPs. The PdopP-Au composite showed outstanding photothermal conversion ability under NIR irradiation due to the ultrahigh loading of the AuNPs within the PdopPs, leading to a remote-controlled explosion of the PdopP-Au and rapid formation of numerous Au@Pdop NPs. The release of the Au@Pdop NPs could be instantly stopped or re-started by off or reboot of NIR, respectively. The structure of the released Au@Pdop NPs is suitable for a catalyst or adsorbent, thus we demonstrated that the PdopP-Au composite exhibited excellent and sustained performances for environmental remediation due to its capability of the continuous production of fresh catalysts or adsorbents during the reuse. PMID- 26941125 TI - "As Time Went On, I Just Forgot About It": Thematic Analysis of Spontaneous Disclosures of Recovered Memories of Childhood Sexual Abuse. AB - This study was a thematic analysis of transcripts of interviews of child sexual abuse survivors discussing their experiences of recovered memories. This study included 27 English-speaking participants from 3 major Canadian cities: Montreal, Toronto, and Ottawa. Seven participants identified as male and 20 as female. Participants ranged in age from 31 to 69 with a mean age of 47. The educational background of participants ranged from 9th grade to doctoral levels. Out of the sample of 27, 21 participants reported some period of amnesia for their CSA experiences. Three primary global themes emerged in the transcripts of participants describing adult emergent recovered memories: flashbacks, triggers, and denial. Three global themes emerged in the transcripts of participants describing partially discontinuous memories: dreams/nightmares as the "how" of memory recovery, triggers, and active processes of forgetting. PMID- 26941126 TI - Enhancement of artificial magnetism via resonant bianisotropy. AB - All-dielectric "magnetic light" nanophotonics based on high refractive index nanoparticles allows controlling magnetic component of light at nanoscale without having high dissipative losses. The artificial magnetic optical response of such nanoparticles originates from circular displacement currents excited inside those structures and strongly depends on geometry and dispersion of optical materials. Here an approach for enhancing of magnetic response via resonant bianisotropy effect is proposed and analyzed. The key mechanism of enhancement is based on electric-magnetic interaction between two electrically and magnetically resonant nanoparticles of all-dielectric dimer. It was shown that proper geometrical arrangement of the dimer in respect to the incident illumination direction allows flexible control over all vectorial components of the magnetic moment, tailoring the latter in the dynamical range of 100% and delivering enhancement up to 36% relative to performances of standalone spherical particles. The proposed approach provides pathways for designs of all-dielectric metamaterials and metasurfaces with strong magnetic responses. PMID- 26941129 TI - Implementing the extended one-generation reproductive toxicity study (EOGRTS): important points to consider. AB - The hallmark of the extended one-generation reproductive toxicity study (EOGRTS) is that, based on certain criteria or triggers, selected offspring are assigned at weaning to different cohorts for further investigation of sexual maturation, reproductive organ integrity and function, neuropathological and behavioral endpoints, and/or immune function. The triggers allow for a more customizable design based directly on the data, while minimizing animal usage. Compared to the two-generation reproductive toxicity study, the EOGRTS design increases the number, extent, and duration of F1-offspring assessments resulting in more thorough and efficient utilization of the first generation while excluding the second generation of offspring unless triggered. Therefore, the EOGRTS has the potential to reduce the number of rats required by nearly 1200 animals per study. When performing the EOGRTS, the complexity of this study should not be underestimated and experienced flexible testing laboratories with sufficient resources and historical control data for all parameters are essential. The aim of this review is to discuss the important aspects of this challenging study design and to share our knowledge on the implementation of this study in our laboratories. In addition, we elaborate on the type of criteria for expansion of the study and logistical considerations. Altogether, this review can be used as guidance by other labs, study monitors, and registration officers. PMID- 26941127 TI - An La-related protein controls cell cycle arrest by nuclear retrograde transport of tRNAs during diapause formation in Artemia. AB - BACKGROUND: In eukaryotes, tRNA trafficking between the nucleus and cytoplasm is a complex process connected with cell cycle regulation. Such trafficking is therefore of fundamental importance in cell biology, and disruption of this process has grave consequences for cell viability and survival. To cope with harsh habitats, Artemia has evolved a special reproductive mode to release encysted embryos in which cell division can be maintained in a dormancy state for a long period. RESULTS: Using Artemia as a peculiar model of the cell cycle, an La-related protein from Artemia, named Ar-Larp, was found to bind to tRNA and accumulate in the nucleus, leading to cell cycle arrest and controlling the onset of diapause formation in Artemia. Furthermore, exogenous gene expression of Ar Larp could induce cell cycle arrest in cancer cells and suppress tumor growth in a xenograft mouse model, similar to the results obtained in diapause embryos of Artemia. Our study of tRNA trafficking indicated that Ar-Larp controls cell cycle arrest by binding to tRNAs and influencing their retrograde movement from the cytoplasm to the nucleus, which is connected to pathways involved in cell cycle checkpoints. CONCLUSIONS: These findings in Artemia offer new insights into the mechanism underlying cell cycle arrest regulation, as well as providing a potentially novel approach to study tRNA retrograde movement from the cytoplasm to the nucleus. PMID- 26941128 TI - Hepatocyte growth factor and alternative splice variants - expression, regulation and implications in osteogenesis and bone health and repair. AB - INTRODUCTION: Bone marrow-derived mesenchymal stem cells (MSCs) can differentiate into multiple cell types, including osteoblasts, chondrocytes, and adipocytes. These pluripotent cells secrete hepatocyte growth factor (HGF), which regulates cell growth, survival, motility, migration, mitogenesis and is important for tissue development/regeneration. HGF has four splice variants, NK1, NK2, NK3, and NK4 which have varying functions and affinities for the HGF receptor, cMET. HGF promotes osteoblastic differentiation of MSCs into bone forming cells, playing a role in bone development, health and repair. AREAS COVERED: This review will focus on the effects of HGF in osteogenesis, bone repair and bone health, including structural and functional insights into the role of HGF in the body. EXPERT OPINION: Approximately 6.2 million Americans experience a fracture annually, with 5-10% being mal- or non-union fractures. HGF is important in priming MSCs for osteogenic differentiation in vitro and is currently being studied to assess its role during bone repair in vivo. Due to the high turnover rate of systemic HGF, non-classic modes of HGF-treatment, including naked-plasmid HGF delivery and the use of HGF splice variants (NK1 & NK2) are being studied to find safe and efficacious treatments for bone disorders, such as mal- or non union fractures. PMID- 26941130 TI - Glucocorticoid-sparing in patients suffering from rheumatoid arthritis and treated with tocilizumab: the SPARE-1 study. AB - OBJECTIVES: To describe steroid-sparing in rheumatoid arthritis (RA) patients treated with tocilizumab (TCZ). METHODS: To evaluate the proportion of RA patients treated with more than 5 mg of prednisone (or equivalent)/day and starting TCZ who can receive less than 5 mg/day after 12 months without intensification of disease-modifying anti-rheumatic drugs (DMARDs), we conducted a non-interventional, multicentre, prospective study from 2011 to 2013. We included patients with moderate-to-severe RA, >18 years old, starting TCZ and receiving corticosteroids (GCs) at a dose greater than 5 mg/day of prednisone for at least 3 months. RESULTS: Amongst the 307 analysed patients (78% women, median RA duration: 8 years, mean DAS28-ESR: 5.1+/-1.3), 40% (95%CI=[35-46]) reached the targeted daily prednisone dose at M12, without conventional synthetic (cs)DMARD intensification. Predictive factors were RA duration of 5 years or less (OR=2.60, p=0.01), daily prednisone dose of 7.5 mg or less (OR=2.12, p=0.03), and low ESR value before the first TCZ infusion (OR=0.86, p=0.047). The proportion of patients with no more GCs increased up to 20% at M12. Disease activity improved over the 1-year period (DAS28-ESR LDA and remission in 41% and 33% of patients at M12, respectively). Amongst the 314 patients analysed for safety, at least one AE and at least one SAE were reported in 211 patients (67%) and in 48 patients (15%), respectively. No unexplained safety signal arose with TCZ. CONCLUSIONS: A biological DMARD as TCZ allows reducing both GCs dose and disease activity in RA patients. Nevertheless, corticosteroid spare in real life is probably lower. PMID- 26941131 TI - Genome Sequence of a Mycoplasma meleagridis Field Strain. AB - Mycoplasma meleagridis is a major cause of disease and economic loss in turkeys. Here, we report the genome sequence of an M. meleagridis field strain, which enlarges the knowledge about this bacterium and helps the identification of possible coding sequences for drug resistance genes and specific antigens. PMID- 26941132 TI - First High-Quality Draft Genome Sequence of Pasteurella multocida Sequence Type 128 Isolated from Infected Bone. AB - We report here the first high-quality draft genome sequence of Pasteurella multocida sequence type 128, which was isolated from the infected finger bone of an adult female who was bitten by a domestic dog. The draft genome will be a valuable addition to the scarce genomic resources available for P. multocida. PMID- 26941133 TI - Complete Genome Sequence of Pseudomonas syringae pv. lapsa Strain ATCC 10859, Isolated from Infected Wheat. AB - Pseudomonas syringae pv. lapsa is a pathovar of Pseudomonas syringae that can infect wheat. The complete genome of P. syringae pv. lapsa strain ATCC 10859 contains a 5,918,899-bp circular chromosome with 4,973 coding sequences, 16 rRNAs, 69 tRNAs, and an average GC content of 59.13%. The analysis of this genome revealed several gene clusters that are related to pathogenesis and virulence. PMID- 26941134 TI - First Complete Genome Sequence of Zika Virus (Flaviviridae, Flavivirus) from an Autochthonous Transmission in Brazil. AB - We report here the genome sequence of Zika virus, strain ZikaSPH2015, containing all structural and nonstructural proteins flanked by the 5' and 3' untranslated region. It was isolated in Sao Paulo state, Brazil, in 2015, from a patient who received a blood transfusion from an asymptomatic donor at the time of donation. PMID- 26941135 TI - Genome Sequences of the Novel Porcine Parvovirus 3, Identified in Guangxi Province, China. AB - Porcine parvovirus 3 is a novel parvovirus that infects pigs. Here, we report two genome sequences of porcine parvovirus 3 strains GX1 and GX2, which are highly prevalent in Guangxi province. It will help in understanding the epidemiology and molecular characteristics of the porcine parvovirus 3. PMID- 26941137 TI - Draft Genome Sequence of Psychrobacter piscatorii Strain LQ58, a Psychrotolerant Bacterium Isolated from a Deep-Sea Hydrothermal Vent. AB - Here, we report the 3.1-Mb draft genome sequence of Psychrobacter piscatorii strain LQ58, isolated from a deep-sea hydrothermal vent on the East Pacific Rise. The sequence will provide further insight into the environmental adaptation of psychrotolerant bacteria and the development of novel cold-active enzymes for industrial application. PMID- 26941136 TI - Draft Genome Sequence of a Strictly Anaerobic Dichloromethane-Degrading Bacterium. AB - An anaerobic, dichloromethane-degrading bacterium affiliated with novel Peptococcaceae was maintained in a microbial consortium. The organism originated from pristine freshwater sediment collected from Rio Mameyes in Luquillo, Puerto Rico, in October 2009 (latitude 18 degrees 21'43.9", longitude -65 degrees 46'8.4"). The draft genome sequence is 2.1 Mb and has a G+C content of 43.5%. PMID- 26941139 TI - Draft Genome Sequence of the Butyric Acid Producer Clostridium tyrobutyricum Strain CIP I-776 (IFP923). AB - Here, we report the draft genome sequence of Clostridium tyrobutyricum CIP I-776 (IFP923), an efficient producer of butyric acid. The genome consists of a single chromosome of 3.19 Mb and provides useful data concerning the metabolic capacities of the strain. PMID- 26941138 TI - Draft Genome Sequence of Syntrophomonas wolfei subsp. methylbutyratica Strain 4J5T (JCM 14075), a Mesophilic Butyrate- and 2-Methylbutyrate-Degrading Syntroph. AB - Syntrophomonas wolfei subsp. methylbutyratica strain 4J5(T) (=JCM 14075(T)) is a mesophilic bacterium capable of degrading butyrate and 2-methylbutyrate through syntrophic cooperation with a partner methanogen. The draft genome sequence is 3.2 Mb, with a G+C content of 45.5%. PMID- 26941140 TI - Draft Genome Sequence of Shiga Toxin-Negative Escherichia coli O157:H7 Strain C1 057, Isolated from Feedlot Cattle. AB - Escherichia coli O157:H7 is one of the major foodborne pathogens in the United States. We isolated a variant Shiga toxin-negative E. coli O157:H7 strain from feedlot cattle. We report here the draft genome sequence of this isolate, consisting of a chromosome of ~4.8 Mb and two plasmids of ~96 kb and ~14 kb. PMID- 26941142 TI - Draft Genome Sequence of Toluene-Resistant Staphylococcus epidermidis SNUT. AB - Here, we report draft sequence of the Gram-positive toluene-resistant bacterium Staphylococcus epidermidis SNUT. The draft genome sequence is 2,511,658 bases, with 2,346 protein-coding genes, 57 tRNA-coding genes, and 8 rRNA genes. PMID- 26941141 TI - Draft Genome Sequence of Lactobacillus delbrueckii subsp. bulgaricus CFL1, a Lactic Acid Bacterium Isolated from French Handcrafted Fermented Milk. AB - Lactobacillus delbrueckii subsp. bulgaricus (L. bulgaricus) is a lactic acid bacterium widely used for the production of yogurt and cheeses. Here, we report the genome sequence of L. bulgaricus CFL1 to improve our knowledge on its stress induced damages following production and end-use processes. PMID- 26941143 TI - Complete Genome Sequence and Methylome Analysis of Aeromonas hydrophila Strain YL17, Isolated from a Compost Pile. AB - In this report, we announce the complete genome sequence of Aeromonas hydrophila strain YL17. Single-molecule real-time (SMRT) DNA sequencing was used to generate the complete genome sequence and the genome-wide DNA methylation profile of this environmental isolate. A total of five unique DNA methyltransferase recognition motifs were reported here. PMID- 26941144 TI - Draft Genome Sequences of Streptomyces scabiei S58, Streptomyces turgidiscabies T45, and Streptomyces acidiscabies a10, the Pathogens of Potato Common Scab, Isolated in Japan. AB - The draft genome sequences of the three pathogens of potato common scab, Streptomyces scabiei S58, Streptomyces turgidiscabies T45, and Streptomyces acidiscabies a10, isolated in Japan, are presented here. The genome size of each strain is >10 Mb, and the three pathogenic strains share genes located in a pathogenicity island previously described in other pathogenic Streptomyces species. PMID- 26941145 TI - Draft Genome Sequence of Lactobacillus casei DPC6800, an Isolate with the Potential to Diversify Flavor in Cheese. AB - Lactobacillus casei is a nonstarter lactic acid bacterium commonly present in various types of cheeses. It is believed that strains of this species have a significant impact on the development of cheese flavor. The draft genome sequence of L. casei DPC6800, isolated from a semi-hard Dutch cheese, is reported. PMID- 26941146 TI - Draft Genome Sequences of Exfoliative Toxin A-Producing Staphylococcus aureus Strains B-7772 and B-7777 (CC8/ST2993) and B-7774 (CC15/ST2126), Isolated in a Maternity Hospital in the Central Federal District of Russia. AB - Staphylococcus aureus clonal complex 8 (CC8) has not been associated with staphylococcal scalded-skin syndrome (SSSS) in newborns and exfoliative toxin genes. Here, we report the draft genome sequences of exfoliative toxin A producing B-7772, B-7777 (both CC8), and B-7774 (CC15) strains associated with SSSS in newborns. PMID- 26941147 TI - Draft Genome Sequence of Acinetobacter baumannii IITR88, a Bacterium Degrading Indoles and Other Aromatic Compounds. AB - Here, we report the 4.16-Mb draft genome sequence of an indole-degrading bacterium, Acinetobacter baumannii IITR88, isolated from the Bhagirathi river in India. A total of 4,069 coding regions (CDSs), 3 rRNAs, and 52 tRNAs were predicted. Genes for the degradation of indoles, phenylacetaldehyde, anthranilate, and several other aromatic compounds were present. PMID- 26941148 TI - Draft Genome Sequence of Alcaligenes faecalis Strain IITR89, an Indole-Oxidizing Bacterium. AB - We report the draft genome sequence of Alcaligenes faecalis strain IITR89, a bacterium able to form indigo by utilizing indole as the sole carbon source. The Alcaligenes species is increasingly reported for biodegradation of diverse toxicants and thus complete sequencing may provide insight into biodegradation capabilities and other phenotypes. PMID- 26941149 TI - Draft Genome Sequence of Goose Dicistrovirus. AB - We report the draft genome sequence of goose dicistrovirus assembled from the filtered feces of a Canadian goose from South Lake Union in Seattle, Washington. The 9.1-kb dicistronic RNA virus falls within the family Dicistroviridae; however, it shares <33% translated amino acid sequence within the nonstructural open reading frame (ORF) from aparavirus or cripavirus. PMID- 26941150 TI - Genome Sequence of a Virulent Pseudomonas aeruginosa Strain, 12-4-4(59), Isolated from the Blood Culture of a Burn Patient. AB - Pseudomonas aeruginosa is an opportunistic pathogen that frequently infects wounds, significantly impairs wound healing, and causes morbidity and mortality in burn patients. Here, we report the genome sequence of a virulent strain of P. aeruginosa, 12-4-4(59), isolated from the blood culture of a burn patient. PMID- 26941152 TI - Whole-Genome Sequencing Analysis of Chromobacterium piscinae Strain ND17, a Quorum-Sensing Bacterium. AB - Here, we report the draft genome sequence of Chromobacterium piscinae strain ND17. This bacterium was isolated from a fresh water sample in Malaysia and exhibits quorum-sensing activity. This first draft genome of C. piscinae strain ND17 will pave the way to future studies of the quorum-sensing properties of this isolate. PMID- 26941151 TI - Draft Genome Sequence of Chromobacterium violaceum Strain CV017. AB - We announce the draft genome sequence for Chromobacterium violaceum strain CV017, used as a model and tool to understand acyl-homoserine lactone-dependent quorum sensing. The assembly consists of 4,774,638-bp contained in 211 scaffolds. PMID- 26941153 TI - Complete Genome Sequence of PM105, a New Pseudomonas aeruginosa B3-Like Transposable Phage. AB - The complete genome of the Pseudomonas aeruginosa bacteriophage PM105 is 39,593 bp long. The phage belongs to the B3 family of transposable Mu-like phages, as confirmed by the presence of bacterial DNA joined to the phage genome ends. PM105, together with other B3-like phages, form a newly arising species. PMID- 26941155 TI - Draft Genome of Rhodococcus rhodochrous TRN7, Isolated from the Coast of Trindade Island, Brazil. AB - Here, we present a draft genome and annotation of Rhodococcus rhodochrous TRN7, isolated from Trindade Island, Brazil, which will provide genetic data to benefit the understanding of its metabolism. PMID- 26941154 TI - Complete Genome Sequence of Bovine Polyomavirus Type 1 from Aborted Cattle, Isolated in Belgium in 2014. AB - The complete and fully annotated genome sequence of a bovine polyomavirus type 1 (BPyV/BEL/1/2014) from aborted cattle was assembled from a metagenomics data set. The 4,697-bp circular dsDNA genome contains 6 protein-coding genes. Bovine polyomavirus is unlikely to be causally related to the abortion cases. PMID- 26941156 TI - Draft Whole-Genome Sequences of 25 Salmonella enterica Strains Representing 24 Serovars. AB - We report the draft genome sequences of 25 Salmonella enterica strains representing 24 different serotypes, many of which were not available in public repositories during our selection process. These draft genomes will provide useful reference for the genetic variation between serotypes and aid in the development of molecular typing tools. PMID- 26941157 TI - First Complete Coding Sequence of a Spanish Isolate of Swine Vesicular Disease Virus. AB - Swine vesicular disease virus (SVDV) is a porcine pathogen and a member of the Enterovirus genus within the Picornaviridae family. The SVDV genome is composed of a single-stranded RNA molecule of positive polarity. Here, we report the first complete sequence of the coding region of a Spanish SVDV isolate (SPA/1/'93). PMID- 26941158 TI - Draft Genome Sequence of a Chlorinated-Ethene Degrader, Cupriavidus necator Strain PHE3-6 (NBRC 110655). AB - Cupriavidus necator strain PHE3-6 grows on phenol as a sole carbon source and cometabolizes cis- and trans-dichloroethenes and trichloroethene. Here, we report the draft genome sequence of PHE3-6, which provides insights into the degradation system of phenol and chlorinated ethenes. PMID- 26941159 TI - Draft Genome Sequences of Two Extensively Drug-Resistant Strains of Mycobacterium tuberculosis Belonging to the Euro-American S Lineage. AB - We report the whole-genome sequencing of two extensively drug-resistant tuberculosis strains belonging to the Euro-American S lineage. The RSA 114 strain showed single-nucleotide polymorphisms predicted to have drug efflux activity. PMID- 26941161 TI - Government could fire and rehire consultants to introduce new contract, says BMA. PMID- 26941160 TI - Western or Traditional Healers? Understanding Decision Making in the Hmong Population. AB - Research has documented the influence of cultural values, beliefs, and traditional health practices on immigrants' health care utilization in their host countries. We describe our findings of how Hmong immigrants to the United States make decisions about whether and when to use traditional and/or Western health services. We conducted semi-structured interviews with 11 Hmong adults. We found their decisions depended on whether they classified the illness as spiritual or not and how they evaluated the effectiveness of different treatment options for their illness. Hmong participants' expectations for effective treatment in traditional or Western health care encounters combined with physical evidence of an illness influenced their decisions and often led them to shift from one type of care to the other. Understanding cultural differences in perceptions of the causes of illnesses and the link between perceived cause and treatment is important to improving care for the Hmong population. PMID- 26941162 TI - Peroneal Tendon Abnormalities on Routine Magnetic Resonance Imaging of the Foot and Ankle. AB - BACKGROUND: Abnormalities of the peroneal tendons can frequently be identified on routine MRI of the foot and ankle. Previous studies in the orthopedic literature have discussed the prevalence of abnormal MRI findings in asymptomatic patients, most notably with regards to the spine and shoulder. The purpose of this study was to determine the prevalence of abnormal findings of the peroneal tendons on MRI in asymptomatic individuals. METHODS: We retrospectively reviewed all foot and ankle MRIs from 2 independent time periods that were either performed or reviewed at our institution. Studies were excluded if performed on patients with documented inversion injuries, ankle sprains, or lateral ankle trauma. A total of 294 (of 617) MRIs were eligible for inclusion in this study. A single attending musculoskeletal radiologist reviewed each MRI. Pathologies of the peroneal tendons included tendinosis, tenosynovitis, acute tears, chronic tears, and tendon splits. Additionally, the primary pathology encountered on each MRI was noted. The mean age of the MRIs included in this study was 46.8 years (range 9 82) with 155 females and 139 males. RESULTS: The most commonly occurring primary pathology was Achilles tendinosis/tears (86), followed by posterior tibial tendon dysfunction (43). With regards to the peroneal tendons, 103 of the 294 (35%) MRIs demonstrated some pathology. CONCLUSION: The results of this study demonstrated that a sizeable percentage of asymptomatic individuals could have peroneal tendon pathology on MRI of the foot and ankle. This study can have important clinical implications for when patients present with concerning MRI findings that do not correlate clinically. Physicians providing musculoskeletal care can counsel and reassure patients who present with peroneal pathology on MRI but an absence of clinical findings. LEVEL OF EVIDENCE: Level IV, case series. PMID- 26941163 TI - Posteromedial Approach for Open Reduction and Internal Fixation of Talar Process Fractures. AB - Fractures of the posteromedial process of the talus are frequently the result of high-energy trauma to the lower extremity. The treatment of these uncommon injuries may be unfamiliar and challenging to many surgeons. Significant pain and disability can result if these injuries are not recognized or treated appropriately. Open reduction and internal fixation via a posteromedial approach with screws is a mainstay of operative treatment for simple fractures. In cases of fracture impaction and/or comminution, a medial uniplanar external fixator may be used to improve intraoperative fracture visualization and mini-fragment plates and screws can be used to secure areas of comminution. LEVEL OF EVIDENCE: Level V, expert opinion. PMID- 26941166 TI - Missense mutations in the signal peptide of the porcine GH gene affect cellular synthesis and secretion. AB - CONTEXT: In previous investigations, we have demonstrated the mutations in the signal peptide of porcine GH gene were associated with the body size. METHODS: In this study, the fusion gene expression vectors which consisted of eight signal peptide mutants of GH gene and EGFP gene were constructed according to three missense mutations (p.Val9Ala, p.Gln22Arg and p.Asp25Gly), and they were transfected into the GH3 cell line. RESULTS: The inhibition levels of EGFP gene transcriptions with different signal peptide mutants were significantly different. Typically, the allelic variants carrying Val in codon nine showed higher protein synthesis (P < 0.05), and the allelic variants carrying neutral Gln in codon 22 and Gly in codon 25 showed higher secretion proportion (P < 0.05) compared with the other groups as assessed by western blotting. In silico RNA folding prediction indicated that the mutations gave rise to different RNA secondary structures, suggesting that they might affect translation and protein synthesis. CONCLUSION: We conclude that the missense mutations within the signal sequence influence the expression and the secretion of the protein. To the best of our knowledge, this is the first report addressing the functional consequences of the mutations in the signal peptide of porcine GH gene. PMID- 26941165 TI - A role for histone acetylation mechanisms in adolescent alcohol exposure-induced deficits in hippocampal brain-derived neurotrophic factor expression and neurogenesis markers in adulthood. AB - Binge drinking during adolescence is a risk factor for neuropsychiatric disorders that can develop later in life. Histone acetylation is an important epigenetic mechanism that contributes to neurodevelopment. We investigated the effects of adolescent intermittent ethanol (AIE) exposure, as opposed to normal saline (AIS) exposure, on histone acetylation-mediated regulation of brain-derived neurotrophic factor (BDNF) expression and developmental stages of neurogenesis (proliferating and immature neurons) in the hippocampus in adulthood. AIE exposure increased whole hippocampal histone deacetylase (HDAC) activity and decreased binding protein of cyclic adenosine monophosphate response element binding protein (CBP) and histone H3-K9 acetylation levels in the CA1, CA2, and CA3 regions of the hippocampus. BDNF protein and exon IV mRNA levels in the CA1 and CA3 regions of the hippocampus of AIE-exposed adult rats were decreased as compared to AIS-exposed adult rats. AIE-induced anxiety-like behaviors and deficits in histone H3 acetylation at BDNF exon IV promoter in the hippocampus during adulthood, which were reversed by treatment with the HDAC inhibitor, trichostatin A (TSA). Similarly, neurogenesis was inhibited by AIE in adulthood as demonstrated by the decrease in Ki-67 and doublecortin (DCX)-positive cells in the dentate gyrus, which was normalized by TSA treatment. These results indicate that AIE exposure increases HDACs and decreases CBP levels that may be associated with a decrease in histone H3 acetylation in the hippocampus. These epigenetic changes potentially decrease BDNF expression and inhibit neurogenesis in the hippocampus that may be involved in AIE-induced behavioral abnormalities, including anxiety, in adulthood. PMID- 26941167 TI - Erratum to: Defective Leukocyte Adhesion and Chemotaxis Contributes to Combined Immunodeficiency in Humans with Autosomal Recessive MST1 Deficiency. PMID- 26941164 TI - Red blood cells: Supercarriers for drugs, biologicals, and nanoparticles and inspiration for advanced delivery systems. AB - Red blood cells (RBCs) constitute a unique drug delivery system as a biologic or hybrid carrier capable of greatly enhancing pharmacokinetics, altering pharmacodynamics (for example, by changing margination within the intravascular space), and modulating immune responses to appended cargoes. Strategies for RBC drug delivery systems include internal and surface loading, and the latter can be performed both ex vivo and in vivo. A relatively new avenue for RBC drug delivery is their application as a carrier for nanoparticles. Efforts are also being made to incorporate features of RBCs in nanocarriers to mimic their most useful aspects, such as long circulation and stealth features. RBCs have also recently been explored as carriers for the delivery of antigens for modulation of immune response. Therefore, RBC-based drug delivery systems represent supercarriers for a diverse array of biomedical interventions, and this is reflected by several industrial and academic efforts that are poised to enter the clinical realm. PMID- 26941168 TI - Off-Target Vascular Effects of Cholesteryl Ester Transfer Protein Inhibitors Involve Redox-Sensitive and Signal Transducer and Activator of Transcription 3 Dependent Pathways. AB - Elevated blood pressure was an unexpected outcome in some cholesteryl ester transfer protein (CETP) inhibitor trials, possibly due to vascular effects of these drugs. We investigated whether CETP inhibitors (torcetrapib, dalcetrapib, anacetrapib) influence vascular function and explored the putative underlying molecular mechanisms. Resistance arteries and vascular smooth muscle cells (VSMC) from rats, which lack the CETP gene, were studied. CETP inhibitors increased phenylephrine-stimulated vascular contraction (logEC50 (:) 6.6 +/- 0.1; 6.4 +/- 0.06, and 6.2 +/- 0.09 for torcetrapib, dalcetrapib, and anacetrapib, respectively, versus control 5.9 +/- 0.05). Only torcetrapib reduced endothelium dependent vasorelaxation. The CETP inhibitor effects were ameliorated by N acetylcysteine (NAC), a reactive oxygen species (ROS) scavenger, and by S3I-201 [2-hydroxy-4-[[2-(4-methylphenyl)sulfonyloxyacetyl]amino]benzoic acid], a signal transducer and activator of transcription 3 (STAT3) inhibitor. CETP inhibitors increased the phosphorylation (2- to 3-fold) of vascular myosin light chain (MLC) and myosin phosphatase target subunit 1 (MYPT1) (procontractile proteins) and stimulated ROS production. CETP inhibitors increased the phosphorylation of STAT3 (by 3- to 4-fold), a transcription factor important in cell activation. Activation of MLC was reduced by NAC, GKT137831 [2-(2-chlorophenyl)-4-[3 (dimethylamino)phenyl]-5-methyl-1H-pyrazolo[4,3-c]pyridine-3,6-dione] (Nox1/4 inhibitor), and S3I-201. The phosphorylation of STAT3 was unaffected by NAC and GKT137831. CETP inhibitors did not influence activation of mitogen-activated proteins kinases (MAPK) or c-Src. Our data demonstrate that CETP inhibitors influence vascular function and contraction through redox-sensitive, STAT3 dependent, and MAPK-independent processes. These phenomena do not involve CETP because the CETP gene is absent in rodents. Findings from our study indicate that CETP inhibitors have vasoactive properties, which may contribute to the adverse cardiovascular effects of these drugs such as hypertension. PMID- 26941170 TI - Rescue of Synaptic Phenotypes and Spatial Memory in Young Fragile X Mice. AB - Fragile X syndrome (FXS) is characterized by synaptic immaturity, cognitive impairment, and behavioral changes. The disorder is caused by transcriptional shutdown in neurons of thefragile X mental retardation 1gene product, fragile X mental retardation protein. Fragile X mental retardation protein is a repressor of dendritic mRNA translation and its silencing leads to dysregulation of synaptically driven protein synthesis and impairments of intellect, cognition, and behavior, and FXS is a disorder that currently has no effective therapeutics. Here, young fragile X mice were treated with chronic bryostatin-1, a relatively selective protein kinase Cepsilonactivator, which induces synaptogenesis and synaptic maturation/repair. Chronic treatment with bryostatin-1 rescues young fragile X mice from the disorder phenotypes, including normalization of most FXS abnormalities in 1) hippocampal brain-derived neurotrophic factor expression, 2) postsynaptic density-95 levels, 3) transformation of immature dendritic spines to mature synapses, 4) densities of the presynaptic and postsynaptic membranes, and 5) spatial learning and memory. The therapeutic effects were achieved without downregulation of metabotropic glutamate receptor (mGluR) 5 in the hippocampus and are more dramatic than those of a late-onset treatment in adult fragile X mice. mGluR5 expression was in fact lower in fragile X mice and its expression was restored with the bryostatin-1 treatment. Our results show that synaptic and cognitive function of young FXS mice can be normalized through pharmacological treatment without downregulation of mGluR5 and that bryostatin-1-like agents may represent a novel class of drugs to treat fragile X mental retardation at a young age and in adults. PMID- 26941171 TI - Effect of Melatonin and 5-Methoxycarbonylamino-N-Acetyltryptamine on the Intraocular Pressure of Normal and Glaucomatous Mice. AB - Melatonin is a neurohormone that is produced not only by the pineal gland but also by several ocular structures. One of the main physiologic roles of melatonin is the reduction of intraocular pressure (IOP). Using both control C57BL/6J and glaucomatous DBA/2J mice as well as TonoLab tonometry, this study evaluated the effect of melatonin and 5-methoxycarbonylamino-N-acetyltryptamine (5-MCA-NAT) when glaucomatous pathology was fully established and compared pharmacological behavior in treated mice versus control mice. In addition, 5-MCA-NAT was tested to determine its effects on ameliorating increased IOP in a glaucoma model. The results demonstrate that melatonin and 5-MCA-NAT can reduce IOP in a concentration-dependent manner. The EC50values for melatonin in control and glaucomatous animals were 34uM and 50uM, respectively. Interestingly, melatonin decreased IOP in 19.4% +/- 3.7% and 32.6% +/- 6.0% of control and glaucomatous mice, respectively, when the animals were studied at age 12 months. 5-MCA-NAT reduced IOP in the same manner and was able to stop IOP progression in glaucomatous mice. Use of melatonin receptor antagonists showed that hypotensive effects were blocked by the MT2receptor antagonists luzindole and 4-phenyl-2 propionamidotetralin in the case of melatonin and by only 4-phenyl-2 propionamidotetralin in the case of 5-MCA-NAT. In conclusion, melatonin and 5-MCA NAT can effectively reduce IOP in a glaucoma model, and their hypotensive effects are more profound in the glaucoma model than in control animals. PMID- 26941169 TI - Digoxin-Mediated Upregulation of RGS2 Protein Protects against Cardiac Injury. AB - Regulator of G protein signaling (RGS) proteins have emerged as novel drug targets since their discovery almost two decades ago. RGS2 has received particular interest in cardiovascular research due to its role in regulating Gqsignaling in the heart and vascular smooth muscle. RGS2(-/-)mice are hypertensive, prone to heart failure, and display accelerated kidney fibrosis. RGS2 is rapidly degraded through the proteasome, and human mutations leading to accelerated RGS2 protein degradation correlate with hypertension. Hence, stabilizing RGS2 protein expression could be a novel route in treating cardiovascular disease. We previously identified cardiotonic steroids, including digoxin, as selective stabilizers of RGS2 protein in vitro. In the current study we investigated the functional effects of digoxin-mediated RGS2 protein stabilization in vivo. Using freshly isolated myocytes from wild-type and RGS2(-/ )mice treated with vehicle or low-dose digoxin (2ug/kg/day for 7 days) we demonstrated that agonist-induced cAMP levels and cardiomyocyte contractility was inhibited by digoxin in wild-type but not in RGS2(-/-)mice. This inhibition was accompanied by an increase in RGS2 protein levels in cardiomyocytes as well as in whole heart tissue. Furthermore, digoxin had protective effects in a model of cardiac injury in wild-type mice and this protection was lost in RGS2(-/-)mice. Digoxin is the oldest known therapy for heart failure; however, beyond its activity at the Na(+)/K(+)-ATPase, the exact mechanism of action is not known. The current study adds a novel mechanism, whereby through stabilizing RGS2 protein levels digoxin could exert its protective effects in the failing heart. PMID- 26941172 TI - Essential Opposite Roles of ERK and Akt Signaling in Cardiac Steroid-Induced Increase in Heart Contractility. AB - Interaction of cardiac steroids (CS) with the Na(+), K(+)-ATPase elicits, in addition to inhibition of the enzyme's activity, the activation of intracellular signaling such as extracellular signal-regulated (ERK) and protein kinase B (Akt). We hypothesized that the activities of these pathways are involved in CS induced increase in heart contractility. This hypothesis was tested using in vivo and ex vivo wild type (WT) and sarcoplasmic reticulum Ca(2+) atpase1a-deficient zebrafish (accordion, acc mutant) experimental model. Heart contractility was measured in vivo and in primary cardiomyocytes in WT zebrafish larvae and acc mutant. Ca(2+) transients were determined ex vivo in adult zebrafish hearts. CS dose dependently augmented the force of contraction of larvae heart muscle and cardiomyocytes and increased Ca(2+) transients in WT but not in acc mutant. CS in vivo increased the phosphorylation rate of ERK and Akt in the adult zebrafish heart of the two strains. Pretreatment of WT zebrafish larvae or cardiomyocytes with specific MAPK inhibitors completely abolished the CS-induced increase in contractility. On the contrary, pretreatment with Akt inhibitor significantly enhanced the CS-induced increase in heart contractility both in vivo and ex vivo without affecting CS-induced Ca(2+) transients. Furthermore, pretreatment of the acc mutant larvae or cardiomyocytes with Akt inhibitor restored the CS-induced increase in heart contractility also without affecting Ca(2+) transients. These results support the notion that the activity of MAPK pathway is obligatory for CS induced increases in heart muscle contractility. Akt activity, on the other hand, plays a negative role, via Ca(2+) independent mechanisms, in CS action. These findings point to novel potential pharmacological intervention to increase CS efficacy. PMID- 26941175 TI - The determination of dopant ion valence distributions in insulating crystals using XANES measurements. AB - Ytterbium-doped wide-bandgap fluoride crystals CaF2, SrF2 and NaMgF3 have been measured using x-ray absorption near edge structure (XANES) on the L3 edge to determine the ratio of trivalent to divalent Yb ions present in the crystals. This study improves upon previous XANES measurements of dopant ion valency by taking into account the x-ray emission transition probabilities for the divalent and trivalent species instead of simply assuming that the relative concentrations may be determined by the ratio of the x-ray excitation band areas. Trivalent to divalent ratios as high as 5 are inferred even at low total dopant ion concentrations of 0.05 mol% Yb. PMID- 26941173 TI - A Food and Drug Administration-Approved Antiviral Agent that Inhibits Adenylyl Cyclase Type 5 Protects the Ischemic Heart Even When Administered after Reperfusion. AB - A Food and Drug Administration-approved antiviral agent, known as vidarabine or adenine 9-beta-D-arabinofuranoside (AraA), has features of inhibiting adenylyl cyclase type 5 (AC5) and protects against chronic coronary artery occlusion (CAO). The goal of this investigation was to determine whether AraA protects against myocardial ischemia, even when delivered after coronary artery reperfusion (CAR). AraA, delivered after CAR in wild-type mice, reduced infarct size by 55% compared with vehicle-treated controls, whereas an equal dose of adenosine reduced infarct size only when administered before CAR. A 5-fold greater dose of adenosine was required to reduce infarct size when delivered after CAR, which also reduced arterial pressure by 15%, whereas AraA did not affect pressure. The reduction in infarct size with AraA was prevented by a MEK/extracellular signal-regulated kinase blocker, a pathway also involved in the mechanism of protection of the AC5 knockout (KO) model. Infarct size was also reduced in cardiac-specific AC5 KO mice similarly in the presence and absence of AraA, further suggesting that AraA protection involves the AC5 pathway. AraA reduced infarct size in chronically instrumented conscious pigs when delivered after CAR, and in this model, it also reduced post-CAR coronary hyperemia, which could be another mechanism for cardioprotection (i.e., by reducing oxidative stress during CAR). Thus, AraA inhibits AC5 and exhibits unique cardioprotection when delivered after CAR, which is critical for clinical translation. PMID- 26941174 TI - Brain structure in autism: a voxel-based morphometry analysis of the Autism Brain Imaging Database Exchange (ABIDE). AB - Increased brain volume is a consistent finding in young children with autism spectrum disorders (ASD); however, the regional specificity and developmental course of abnormal brain structure are less clear. Small sample sizes, particularly among voxel-based morphometry (VBM) investigations, likely contribute to this difficulty. Recently established large-scale neuroimaging data repositories have helped clarify the neuroanatomy of neuropsychiatric disorders such as schizophrenia and may prove useful in ASD. Structural brain images from the Autism Brain Imaging Database Exchange (ABIDE), which contains over 1100 participants, were analyzing using DARTEL VBM to investigate total brain and tissue volumes, and regional brain structure abnormalities in ASD. Two, overlapping cohorts were analyzed; an 'All Subjects' cohort (n = 833) that included all individuals with usable MRI data, and a 'Matched Samples' cohort (n = 600) comprised of ASD and TD individuals matched, within each site, on age and sex. Total brain and grey matter volumes were enlarged by approximately 1-2 % in ASD; however, the effect reached statistical significance in only the All Subjects cohort. Within the All Subjects cohort, VBM analysis revealed enlargement of the left anterior superior temporal gyrus in ASD. No significant regional changes were detected in the Matched Samples cohort. There was a non significant reduction in the correlation between IQ and TBV in ASD compared to TD. Brain structure abnormalities in ASD individuals age 6 and older consists of a subtle increase in total brain volume due to enlargement of grey matter with little evidence of regionally specific effects. PMID- 26941176 TI - The implications of non-invasive prenatal testing failures: a review of an under discussed phenomenon. AB - INTRODUCTION: Non-invasive prenatal testing (NIPT) using cell-free DNA in maternal blood is a relatively new screening modality for the common trisomies of chromosomes 21, 18 and 13 and sex chromosome aneuploidies. For some patients, however, results are not reported because of laboratory technical issues such as low fetal fraction and sequencing failures. In this review, the clinical implications of NIPT test failures are discussed. METHODS: A Medline search was performed for all studies on NIPT that include >1000 samples. The failure rates were assessed by technology. RESULTS: Methods based on massive parallel sequencing have been found to have the lowest failure rate (1.58%), while tests based on single-nucleotide polymorphism analysis have the highest failure rate (6.39%). CONCLUSIONS: Recent publications suggest that patients who receive a 'no call' result are at increased risk of aneuploidy. Some professional societies have therefore recommended that these patients undergo genetic counseling and be offered invasive diagnostic testing. NIPT technology that has a high failure rate may increase the false positive rates, decrease the positive predictive value, and increase the procedure-related pregnancy loss. (c) 2016 John Wiley & Sons, Ltd. PMID- 26941177 TI - A membrane-based microfluidic device for mechano-chemical cell manipulation. AB - We introduce a microfluidic device for chemical manipulation and mechanical investigation of circulating cells. The device consists of two crossing microfluidic channels separated by a porous membrane. A chemical compound is flown through the upper "stimulus channel", which diffuses through the membrane into the lower "cell analysis channel", in which cells are mechanically deformed in two sequential narrow constrictions, one before and one after crossing the stimulus channel. Thus, this system permits to measure cell deformability before and after chemical cues are delivered to the cells within one single chip. The validity of the device was tested with monocytic cells stimulated with an actin disrupting agent (Cytochalasin-D). Furthermore, as proof of principle of the device application, the effect of an anti-inflammatory drug (Pentoxifylline) was tested on monocytic cells activated with Lipopolysaccharides and on monocytes from patients affected by atherosclerosis. The results show that the system can detect differences in cell mechanical deformation after chemical cues are delivered to the cells through the porous membrane. Diffusion of Cytochalasin-D resulted in a considerable decrease in entry time in the narrow constriction and an evident increase in the velocity within the constriction. Pentoxifylline showed to decrease the entry time but not to affect the transit time within the constriction for monocytic cells. Monocytes from patients affected by atherosclerosis were difficult to test in the device due to increased adhesion to the walls of the microfluidic channel. Overall, this analysis shows that the device has potential applications as a cellular assay for analyzing cell-drug interaction. PMID- 26941178 TI - Elemental superdoping of graphene and carbon nanotubes. AB - Doping of low-dimensional graphitic materials, including graphene, graphene quantum dots and single-wall carbon nanotubes with nitrogen, sulfur or boron can significantly change their properties. We report that simple fluorination followed by annealing in a dopant source can superdope low-dimensional graphitic materials with a high level of N, S or B. The superdoping results in the following doping levels: (i) for graphene, 29.82, 17.55 and 10.79 at% for N-, S- and B-doping, respectively; (ii) for graphene quantum dots, 36.38 at% for N doping; and (iii) for single-wall carbon nanotubes, 7.79 and 10.66 at% for N- and S-doping, respectively. As an example, the N-superdoping of graphene can greatly increase the capacitive energy storage, increase the efficiency of the oxygen reduction reaction and induce ferromagnetism. Furthermore, by changing the degree of fluorination, the doping level can be tuned over a wide range, which is important for optimizing the performance of doped low-dimensional graphitic materials. PMID- 26941179 TI - We Have to Be Willing to Say the World Has Changed and Now We Have to Figure Out How to Deal With That: An Interview With Charles Levenstein, About New Solutions. AB - New Solutions: A Journal of Environmental and Occupational Health Policyhas been published for 25 years. To acknowledge this milestone, Dr. Pia Markkanen interviewed Charles Levenstein, Editor Emeritus of the journal, in August 2015. The purpose of this interview was to review the journal's history: from its earliest roots to the present.New Solutionsbegan in 1990 as a project with the Oil, Chemical and Atomic Workers Union (OCAW). Dr. Charles Levenstein was the founding editor and Tony Mazzocchi was the original publisher. We've tapped Dr. Levenstein's memory to learn the intent of starting the journal and how it developed. The interview presents some of the challenges of sustaining a movement journal with the mission of being a bridge between academics and researchers and workers, environmentalists, as well as advocates and activists. PMID- 26941180 TI - Sensitisation of visible and NIR lanthanide emission by InPZnS quantum dots in bi luminescent hybrids. AB - The synthesis of stable hybrid nanoparticles combining InPZnS@ZnSe/ZnS quantum dots (QDs) and grafted lanthanide complexes has been performed using two different approaches in organic and aqueous media. The final bi-luminescent hybrids exhibit Ln(III) (Ln = Eu and Yb) centred luminescence upon QD excitation, suggesting that an energy transfer occurs from the QD to the lanthanide. PMID- 26941181 TI - Gene of the month: SMARCB1. AB - SMARCB1 is the core subunit of the SWI/sucrose non-fermenting ATP-dependent chromatin remodelling complex located on the long arm of chromosome 22 (22q11.2). Since discovering genetic alterations of the SMARCB1 gene in malignant rhabdoid tumours, the family of tumours harbouring loss of SMARCB1 expression has been steadily expanding. In this review, we give a general overview of SMARCB1, its role in various cancers including germline mutations, association with genetic syndromes and role in future targeted therapies. PMID- 26941182 TI - Molecular interactions of polo-like kinase 1 in human cancers. AB - Polo-like kinase 1 (PLK1) is an essential protein in communicating cell-cycle progression and DNA damage. Overexpression of PLK1 has been validated as a marker for poor prognosis in many cancers. PLK1 knockdown decreases the survival of cancer cells. PLK1 is therefore an attractive target for anticancer treatments. Several inhibitors have been developed, and some have been clinically tested to show additive effects with conventional therapies. Upstream regulation of PLK1 involves multiple interactions of proteins such as FoxM1, E2F and p21. Other cancer-related proteins such as pRB and p53 also indirectly influence PLK1 expression. With the high mutation rates of these genes seen in cancers, they may be associated with PLK1 deregulation. This raises the question of whether PLK1 overexpression is a cause or a consequence of oncogenesis. In addition, hypomethylation of the CpG island of the PLK1 promoter region contributes to its upregulation. PLK1 expression can be affected by many factors; thus, it is possible that PLK1 deregulation in each individual patient tumours could be due to different underlying mechanisms. PMID- 26941183 TI - Genetic mutations in accordance with a low malignant potential tumour are not demonstrated in clear cell papillary renal cell carcinoma. AB - Clear cell papillary renal cell carcinoma (CCPRCC) cases were evaluated for mutations on the following genes: KRAS, NRAS, BRAF, PIK3CA, ALK, ERBB2, DDR2, MAP2K1, RET and EGFR. Four male and three female patients of age 42-74 years were evaluated. All cases were incidentally detected by ultrasound and ranged 1.8-3.5 cm. Microscopic examination showed variably tubulopapillary, tubular acinar, cystic architecture and the characteristic linear arrangement of nuclei. The cells were reactive with CK7 (strong), CA IX (cup-shape) and 34 beta E12. CD10, AMACR/RACEMASE and GATA3 were negative. There were no mutations on any of the investigated genes. This preliminary observation supports the concept that CCPRCC might be indeed an indolent tumour worth it to be named as clear cell papillary neoplasm of low potential. PMID- 26941185 TI - Worldwide withdrawal of medicinal products because of adverse drug reactions: a systematic review and analysis. AB - We have systematically identified medicinal products withdrawn worldwide because of adverse drug reactions, assessed the level of evidence used for making the withdrawal decisions, and explored the patterns of withdrawals over time. We searched PubMed, the WHO database of withdrawn products, and selected texts. We included products that were withdrawn after launch from 1950 onwards, excluding non-human and over-the-counter medicines. We assessed the levels of evidence on which withdrawals were based using the Oxford Center for Evidence Based Medicine Levels of Evidence. Of 353 medicinal products withdrawn from any country, only 40 were withdrawn worldwide. Anecdotal reports were cited as evidence for withdrawal in 30 (75%) and deaths occurred in 27 (68%). Hepatic, cardiac, and nervous system toxicity accounted for over 60% of withdrawals. In 28 cases, the first withdrawal was initiated by the manufacturer. The median interval between the first report of an adverse drug reaction that led to withdrawal and the first withdrawal was 1 year (range 0-43 years). Worldwide withdrawals occurred within 1 year after the first withdrawal in any country. In conclusion, the time it takes for drugs to be withdrawn worldwide after reports of adverse drug reactions has shortened over time. However, there are inconsistencies in current withdrawal procedures when adverse drug reactions are suspected. A uniform method for establishing worldwide withdrawal of approved medicinal products when adverse drug reactions are suspected should be developed, to facilitate global withdrawals. Rapid synthesis of the evidence on harms should be a priority when serious adverse reactions are suspected. PMID- 26941186 TI - Serum cathepsin S and cystatin C: relationship to subclinical carotid atherosclerosis in rheumatoid arthritis. AB - OBJECTIVES: To assess whether serum cathepsin S and cystatin C, two novel markers of cardiovascular disease risk, are associated with subclinical carotid atherosclerosis in patients with rheumatoid arthritis (RA). METHODS: Serum cystatin C and cathepsin S levels, carotid intima-media thickness (cIMT) and carotid plaques were assessed in a cross-sectional study involving 178 RA patients. RESULTS: An association between disease activity scores with higher levels of cystatin C, but not with cathepsin S, was found. Cystatin C levels were also associated with cIMT in the patient subgroup included in the higher quartile of Cimt (OR 1.31, 95%CI [1.00-1.72], p=0.04) after adjusting for traditional cardiovascular risk factors, age and sex. An association between serum cystatin C levels and carotid plaques was also found in the univariate analysis (OR 1.37, 95%CI [1.06-1.76], p=0.02). However, this significant association was lost after adjusting for traditional cardiovascular risk factors and age. Cathepsin S was not associated with cIMT or carotid plaques. CONCLUSIONS: High cystatin C serum levels identify a subgroup of RA patients with a high risk of subclinical atherosclerotic disease. PMID- 26941187 TI - Back pain after trauma. PMID- 26941184 TI - Nav1.7 and other voltage-gated sodium channels as drug targets for pain relief. AB - INTRODUCTION: Chronic pain is a massive clinical problem. We discuss the potential of subtype selective sodium channel blockers that may provide analgesia with limited side effects. AREAS COVERED: Sodium channel subtypes have been linked to human pain syndromes through genetic studies. Gain of function mutations in Nav1.7, 1.8 and 1.9 can cause pain, whilst loss of function Nav1.7 mutations lead to loss of pain in otherwise normal people. Intriguingly, both human and mouse Nav1.7 null mutants have increased opioid drive, because naloxone, an opioid antagonist, can reverse the analgesia associated with the loss of Nav1.7 expression. EXPERT OPINION: We believe there is a great future for sodium channel antagonists, particularly Nav1.7 antagonists in treating most pain syndromes. This review deals with recent attempts to develop specific sodium channel blockers, the mechanisms that underpin the Nav1.7 null pain-free phenotype and new routes to analgesia using, for example, gene therapy or combination therapy with subtype specific sodium channel blockers and opioids. The use of selective Nav1.7 antagonists together with either enkephalinase inhibitors or low dose opioids has the potential for side effect-free analgesia, as well as an important opioid sparing function that may be clinically very significant. PMID- 26941191 TI - Modeling magnetization curves in magnetic thin films with striped patterns. AB - In this work, we study magnetic thin films presenting magnetic stripe patterns. A fingerprint of such domains is a linear behavior of the in-plane magnetization curves below a given saturation field. We present free energy models for the in plane magnetization curves which permit us to extract key geometrical information about the stripe patterns, such as the maximum canted angle of the magnetization and the domain wall width. As an example, we discuss in this work magnetization curves for Fe(1-x)Ga(x) magnetic films which present a stripe pattern with a period of 160 nm and we found a typical maximum canted angle of 85 degrees and a domain wall width around 30 nm. PMID- 26941190 TI - Enhancement of antitumor activity of the oxazaphosphorine cytostatic SUM-IAP by N methylformamide. AB - PURPOSE: SUM-IAP has been developed with the aim to optimize therapeutic response and minimize toxic reactions of oxazaphosphorine cytostatics. In therapy tests in mice, the primary tumor was successfully eradicated, but animals died due to formation of lethal metastases. We supposed that high activities of SUM-IAP detoxifying enzymes caused metastasis formation in the liver. Therefore, therapy tests with SUM-IAP in combination with cisplatin and N-methylformamide (NMF), which were not detoxified in the liver, were carried out. METHOD: Antitumor activity was assayed in female CD2F1 mice with advanced subcutaneously growing P388 mice leukemia cells. RESULT: The results of the therapy tests with SUM-IAP plus cisplatin were as expected: No formation of metastases and long-time survival of more than 100 days were observed; however, the toxicity was increased as measured by decrease in body weight and the number in leukocytes. The results of the tests in combination with NMF were surprising: Applying only half the dose of SUM-IAP used in the experiments with cisplatin, no metastases were found and long-time survivors did not show signs of additional toxicity. CONCLUSION: NMF strongly enhances the antitumor activity of the oxazaphosphorine cytostatic SUM IAP in mice with subcutaneously growing P388 mice leukemia cells by an unknown mechanism of action. PMID- 26941188 TI - Evolutionary origin of Rosaceae-specific active non-autonomous hAT elements and their contribution to gene regulation and genomic structural variation. AB - Transposable elements account for approximately 30 % of the Prunus genome; however, their evolutionary origin and functionality remain largely unclear. In this study, we identified a hAT transposon family, termed Moshan, in Prunus. The Moshan elements consist of three types, aMoshan, tMoshan, and mMoshan. The aMoshan and tMoshan types contain intact or truncated transposase genes, respectively, while the mMoshan type is miniature inverted-repeat transposable element (MITE). The Moshan transposons are unique to Rosaceae, and the copy numbers of different Moshan types are significantly correlated. Sequence homology analysis reveals that the mMoshan MITEs are direct deletion derivatives of the tMoshan progenitors, and one kind of mMoshan containing a MuDR-derived fragment were amplified predominately in the peach genome. The mMoshan sequences contain cis-regulatory elements that can enhance gene expression up to 100-fold. The mMoshan MITEs can serve as potential sources of micro and long noncoding RNAs. Whole-genome re-sequencing analysis indicates that mMoshan elements are highly active, and an insertion into S-haplotype-specific F-box gene was reported to cause the breakdown of self-incompatibility in sour cherry. Taken together, all these results suggest that the mMoshan elements play important roles in regulating gene expression and driving genomic structural variation in Prunus. PMID- 26941189 TI - Chemotherapy with or without autologous cytokine-induced killer cell transfusion as the first-line treatment for stage IV gastrointestinal cancer: a phase II clinical trial. AB - OBJECTIVE: To investigate the efficacy of autologous cytokine-induced killer (CIK) cell therapy combined with chemotherapy versus chemotherapy alone for the treatment of stage IV gastrointestinal (GI) cancer in the first-line setting. METHODS: Thirty-three patients diagnosed with stage IV GI cancer were divided into chemotherapy plus CIK group (chemo-CIK, n = 16) and chemotherapy-alone group (chemo-alone, n = 17). Autologous peripheral blood mononuclear cells were separated by flow cytometry, cultured in vitro to induce CIK cells, and transfused into patients on days 14 and 16 of the first and second chemotherapy cycles. RESULTS: The median progression-free survival (PFS) was 5.6 months for patients in the chemo-CIK group and 3.83 months for those in the chemo-alone group. The difference was borderline significant (P = 0.06), indicating a potential advantage for combined CIK cell transfusion with chemotherapy in improving PFS. A favored objective response rate was also observed in the chemo CIK group than in the chemo-alone group. This study also revealed that CIK cell transfusion restored the cellular immunity in these GI cancer patients. The percentage of natural killer T cells, NK cells, CD3(+) T cells, and T-cell subgroups CD4(+) proportion in the peripheral blood of cancer patients significantly increased after the CIK cell transfusion, while the change in T cell subgroups CD8(+) and CD4(+)/CD8(+) did not differ significantly. CONCLUSIONS: The study showed that the addition of CIK cell transfusion to traditional chemotherapy in the first-line setting was associated with a prolonged PFS and enhanced T-lymphocyte subset activity, supporting a potential treatment choice for advanced GI cancer patients. PMID- 26941192 TI - Copy number variations in multicystic dysplastic kidney: update for prenatal diagnosis and genetic counseling. AB - OBJECTIVE: To assess the clinical implication of chromosomal microarray analysis (CMA) in prenatal diagnosis of MCDK. METHODS: Thirty-seven cases with MCDKs detected by prenatal ultrasound were enrolled in the study; 33 cases were isolated MCDKs and four cases were non-isolated MCDKs. CMA was performed on the Affymetrix CytoScan HD platform. The frequencies of the detected CNVs were compared with 461 cases that underwent CMA for anomalies unrelated to congenital anomalies of kidney and urinary tract (CAKUT) or 124 healthy newborns as controls. All of the annotated CNVs were validated by MLPA or qPCR. RESULTS: Pathogenic CNVs were detected in 13.5% (5/37) of MCDKs. Two 17q12 deletions, one untypical 22q11.2 deletion, and one 22q11.2 duplication were detected in four isolated MCDK cases. Duplication of 1q31.3q44 was identified in a non-isolated MCDK case. Three of the five pathogenic CNVs were inherited. We also validated eight CNVs of uncertain significance only detected in MCDKs and five CNVs with higher frequency in MCDKs. CONCLUSION: A substantial proportion of MCDKs were associated with pathogenic CNVs. Family members with the same CNV were asymptomatic or of different kind of renal malformations. It may be reasonable to perform CMA when MCDKs are identified prenatally. (c) 2016 John Wiley & Sons, Ltd. PMID- 26941194 TI - Activation of the Stt7/STN7 Kinase through Dynamic Interactions with the Cytochrome b6f Complex. AB - Photosynthetic organisms have the ability to adapt to changes in light quality by readjusting the cross sections of the light-harvesting systems of photosystem II (PSII) and photosystem I (PSI). This process, called state transitions, maintains the redox poise of the photosynthetic electron transfer chain and ensures a high photosynthetic yield when light is limiting. It is mediated by the Stt7/STN7 protein kinase, which is activated through the cytochrome b6f complex upon reduction of the plastoquinone pool. Its probable major substrate, the light harvesting complex of PSII, once phosphorylated, dissociates from PSII and docks to PSI, thereby restoring the balance of absorbed light excitation energy between the two photosystems. Although the kinase is known to be inactivated under high light intensities, the molecular mechanisms governing its regulation remain unknown. In this study we monitored the redox state of a conserved and essential Cys pair of the Stt7/STN7 kinase and show that it forms a disulfide bridge. We could not detect any change in the redox state of these Cys during state transitions and high-light treatment. It is only after prolonged anaerobiosis that this disulfide bridge is reduced. It is likely to be mainly intramolecular, although kinase activation may involve a transient covalently linked kinase dimer with two intermolecular disulfide bonds. Using the yeast two-hybrid system, we have mapped one interaction site of the kinase on the Rieske protein of the cytochrome b6f complex. PMID- 26941196 TI - Ecthyma gangrenosum of the scrotum: a case report. AB - A 43-year-old man with pancytopenia from chemotherapy for acute myeloid leukemia developed left scrotal pain, fever, and rigors. Physical exam revealed an ulcerating lesion with central necrosis and eschar surrounded by a halo of erythema on the inferior aspect of the left scrotum. The condition indicated an early necrotizing soft tissue infection. The patient was started on broad spectrum antibiotics and taken to the operating room for a wound debridement. Blood and tissue cultures grew Pseudomonas aeruginosa, which confirmed the diagnosis of ecthyma gangrenosum of the scrotum. The fever resolved, and the wound healed without further progression after wet to dry dressing changes. PMID- 26941197 TI - Mode specificity for the dissociative chemisorption of H2O on Cu(111): a quantum dynamics study on an accurately fitted potential energy surface. AB - The mode-specific dynamics for the dissociative chemisorption of H2O on Cu(111) is first investigated by seven-dimensional quantum dynamics calculations, based on an accurately fitted potential energy surface (PES) recently developed by neural network fitting to DFT energy points. It is indicated that excitations in all three vibrational modes have a significant impact on reactivity, which are more efficacious than increasing the translational energy in promoting the reaction, with the largest enhancement for the excitation in the asymmetric stretching mode. There is large discrepancy between the six-dimensional reactivities with fixed azimuthal angles and seven-dimensional results, revealing that the 6D "flat surface" model cannot accurately characterize the reaction dynamics. The azimuthal angle-averaging approach is validated for vibrational excited states of the reactant, where the 7D mode-specific probability can be well reproduced by averaging the 6D azimuthal angle-fixed probabilities over 18 angles. PMID- 26941195 TI - Defects in Peroxisomal 6-Phosphogluconate Dehydrogenase Isoform PGD2 Prevent Gametophytic Interaction in Arabidopsis thaliana. AB - We studied the localization of 6-phosphogluconate dehydrogenase (PGD) isoforms of Arabidopsis (Arabidopsis thaliana). Similar polypeptide lengths of PGD1, PGD2, and PGD3 obscured which isoform may represent the cytosolic and/or plastidic enzyme plus whether PGD2 with a peroxisomal targeting motif also might target plastids. Reporter-fusion analyses in protoplasts revealed that, with a free N terminus, PGD1 and PGD3 accumulate in the cytosol and chloroplasts, whereas PGD2 remains in the cytosol. Mutagenesis of a conserved second ATG enhanced the plastidic localization of PGD1 and PGD3 but not PGD2. Amino-terminal deletions of PGD2 fusions with a free C terminus resulted in peroxisomal import after dimerization, and PGD2 could be immunodetected in purified peroxisomes. Repeated selfing of pgd2 transfer (T-)DNA alleles yielded no homozygous mutants, although siliques and seeds of heterozygous plants developed normally. Detailed analyses of the C-terminally truncated PGD2-1 protein showed that peroxisomal import and catalytic activity are abolished. Reciprocal backcrosses of pgd2-1 suggested that missing PGD activity in peroxisomes primarily affects the male gametophyte. Tetrad analyses in the quartet1-2 background revealed that pgd2-1 pollen is vital and in vitro germination normal, but pollen tube growth inside stylar tissues appeared less directed. Mutual gametophytic sterility was overcome by complementation with a genomic construct but not with a version lacking the first ATG. These analyses showed that peroxisomal PGD2 activity is required for guided growth of the male gametophytes and pollen tube-ovule interaction. Our report finally demonstrates an essential role of oxidative pentose-phosphate pathway reactions in peroxisomes, likely needed to sustain critical levels of nitric oxide and/or jasmonic acid, whose biosynthesis both depend on NADPH provision. PMID- 26941193 TI - Habitat-Associated Life History and Stress-Tolerance Variation in Arabidopsis arenosa. AB - Weediness in ephemeral plants is commonly characterized by rapid cycling, prolific all-in flowering, and loss of perenniality. Many species made transitions to weediness of this sort, which can be advantageous in high disturbance or human-associated habitats. The molecular basis of this shift, however, remains mostly mysterious. Here, we use transcriptome sequencing, genome resequencing scans for selection, and stress tolerance assays to study a weedy population of the otherwise nonweedy Arabidopsis arenosa, an obligately outbreeding relative of Arabidopsis thaliana Although weedy A. arenosa is widespread, a single genetic lineage colonized railways throughout central and northern Europe. We show that railway plants, in contrast to plants from sheltered outcrops in hill/mountain regions, are rapid cycling, have lost the vernalization requirement, show prolific flowering, and do not return to vegetative growth. Comparing transcriptomes of railway and mountain plants across time courses with and without vernalization, we found that railway plants have sharply abrogated vernalization responsiveness and high constitutive expression of heat- and cold-responsive genes. Railway plants also have strong constitutive heat shock and freezing tolerance compared with mountain plants, where tolerance must be induced. We found 20 genes with good evidence of selection in the railway population. One of these, LATE ELONGATED HYPOCOTYL, is known in A. thaliana to regulate many stress-response genes that we found to be differentially regulated among the distinct habitats. Our data suggest that, beyond life history regulation, other traits like basal stress tolerance also are associated with the evolution of weediness in A. arenosa. PMID- 26941198 TI - Cerebral white matter lesions and silent cerebral infarcts in postmenopausal women with polycystic ovary syndrome. AB - OBJECTIVES: The association between polycystic ovary syndrome (PCOS) and cardiovascular disease remains unclear. Our objective was to examine the relation of PCOS with cerebrovascular disease measured by brain magnetic resonance imaging (MRI) as white matter lesions (WMLs) and silent cerebral infarcts (SCIs). METHODS: Seventy postmenopausal women with PCOS and 140 controls participated in the case-control, cross-sectional study. Clinical, anthropometric, hormonal and metabolic parameters were measured. WMLs and SCIs were evaluated by brain MRI. RESULTS: Compared with controls, postmenopausal women with PCOS had higher mean body mass index, larger waist hip ratio, higher level of low-density lipoprotein cholesterol, free androgen index and lower sex hormone-binding globulin level. The PCOS group had a significantly higher prevalence of WMLs (40% versus 22%, p = 0.009), and SCIs (17% versus 7%, p = 0.032) compared to the control group. CONCLUSIONS: Postmenopausal women with PCOS are associated with WMLs and SCIs. PMID- 26941199 TI - Paclitaxel injection concentrate for nanodispersion versus nab-paclitaxel in women with metastatic breast cancer: a multicenter, randomized, comparative phase II/III study. AB - Paclitaxel is widely used in the treatment of patients with metastatic breast cancer (MBC). Formulations of paclitaxel contain surfactants and solvents or albumin derived from human blood. The use of co-solvents such as polyoxyethylated castor oil is thought to contribute to toxicity profile and hypersensitivity reactions as well as leaching of plasticizers from polyvinyl chloride bags and infusion sets. Currently, nab-paclitaxel, an albumin-bound paclitaxel in nanometer range continues to be the preferred taxane formulation used in clinic. This study (CTRI/2010/091/001116) investigated the efficacy and tolerability of a polyoxyethylated castor oil- and albumin-free formulation of paclitaxel [paclitaxel injection concentrate for nanodispersion (PICN)] compared with nab paclitaxel in women with refractory MBC. The current study was a multicenter, open-label, parallel-group, randomized, comparative phase II/III trial evaluating the efficacy and safety of PICN (260 mg/m(2) [n = 64] and 295 mg/m(2) [n = 58] every 3 weeks) compared with nab-paclitaxel (260 mg/m(2) every 3 weeks [n = 58]) in women 18 and 70 years old with confirmed MBC. Overall response rate (ORR) was assessed with imaging every 2 cycles. An independent analysis of radiologic data was performed for evaluable patients. Progression-free survival (PFS) was a secondary efficacy measure. Independent radiologist-assessed ORRs in the evaluable population of women aged >=70 years were 35, 49, and 43 % in the PICN 260 mg/m(2), PICN 295 mg/m(2), and nab-paclitaxel 260 mg/m(2) arms, respectively. Median PFS in the evaluable population was 23, 35, and 34 weeks in the PICN 260 mg/m(2), PICN 295 mg/m(2), and nab-paclitaxel 260 mg/m(2) arms, respectively. Adverse events occurred in similar proportions of patients across treatment arms. Hypersensitivity reactions were not frequently observed with the clinical use of PICN across the treatment cohorts. In women with metastatic breast cancer, PICN at 260 and 295 mg/m(2) every 3 weeks was effective and well tolerated and showed similar tolerability compared with nab-paclitaxel 260 mg/m(2) every 3 weeks. Statistically, significant differences were not observed in the PICN and nab paclitaxel treatment arms for radiologist-assessed ORR or median PFS. The novel paclitaxel formulation, PICN, offers apart from efficacy, potential safety advantage of decreased use of corticosteroid pretreatment and the absence of the risk of transmission of blood product-borne disease. PMID- 26941200 TI - Greater decreases in cholesterol levels among individuals with high cardiovascular risk than among the general population: the northern Sweden MONICA study 1994 to 2014. AB - AIM: Decreasing cholesterol levels in Western populations is the main reason for decreasing mortality due to coronary heart disease. Our aim was to analyze trends in cholesterol levels in the population during a period of 20 years in relation to previous cardiovascular disease (CVD), other cardiovascular risk factors, and socioeconomic status. METHODS AND RESULTS: A total of 4546 women and 4349 men aged 25-74 years participated in five population-based surveys in the Northern Sweden MONICA Study between 1994 and 2014 (participation rate 76.8-62.5%). Total cholesterol levels decreased from 6.2 mmol/L (95% confidence interval, CI, 6.1 6.2) in 1994 to 5.5 mmol/L (CI 5.4-5.5) in 2014. The decrease was more pronounced in elderly vs. younger participants (1.0 vs. 0.5 mmol/L). In 2014, participants with previous CVD, diabetes, or hypertension had lower cholesterol levels than the general population, whereas their levels were higher or similar to the general population in 1994. The use of lipid-lowering drugs increased markedly and was used by 14.3% in 2014. Previously described differences in cholesterol levels between participants with obesity and normal weight, and between those with and without university education, diminished, or vanished over time. CONCLUSION: Cholesterol levels decreased by 0.7 mmol/L over 20 years with no sign of abating. The improvement occurred in all age and gender groups but more prominently among those at high risk of ischaemic heart disease. PMID- 26941201 TI - Acute decompensated heart failure associated with a heteroplasmic 3243A > G mitochondrial DNA point mutation. PMID- 26941202 TI - FDG-PET/CT images during 5 years before acute aortic dissection. PMID- 26941203 TI - Reprogramming ageing and longevity genes restores paracrine angiogenic properties of early outgrowth cells. AB - AIMS: Impaired tissue vascularization is a major determinant of cardiovascular disease (CVD) in the elderly. Accumulation of reactive oxygen species (ROS) may interfere with vascular repair, but the underlying mechanisms remain unknown. Early outgrowth cells (EOCs) play an important role in endothelial repair. We investigated whether key lifespan genes involved in ROS, i.e. the mitochondrial adaptor p66(Shc) and the AP-1 transcription factor JunD, contribute to age related EOCs dysfunction in humans. METHODS AND RESULTS: Early outgrowth cells were isolated and cultured from peripheral blood mononuclear cells of young and old healthy volunteers. Early outgrowth cells isolated from aged individuals displayed p66(Shc) gene up-regulation and reduced JunD expression. Deregulation of p66(Shc) and JunD in aged EOCs led to up-regulation of NADPH oxidase, reduced expression of manganese superoxide dismutase (MnSOD) and increased O2 (-) generation. This was associated with an impairment of EOCs-induced migration of mature endothelial cells. Secretome profiling revealed that angiogenic chemokines such as stromal-derived factor-1 and monocyte chemoattractant protein-1 were deregulated in conditioned medium collected from aged EOCs. Interestingly, p66(Shc) silencing or JunD overexpression blunted age-related O2 (-) production via the NADPH/MnSOD axis, and restored paracrine angiogenic potential of aged EOCs. CONCLUSION: Reprogramming ageing and longevity genes preserves EOCs functionality by affecting their paracrine properties. These findings set the basis for novel therapeutic strategies to improve for vascular repair after injury and in CVD in the elderly. PMID- 26941204 TI - Comparison of the ATRIA, CHADS2, and CHA2DS2-VASc stroke risk scores in predicting ischaemic stroke in a large Swedish cohort of patients with atrial fibrillation. AB - AIMS: Better stroke risk prediction is needed to optimize the anticoagulation decision in atrial fibrillation (AF). The ATRIA stroke risk score (ATRIA) was developed and validated in two large California community AF cohorts. We compared the performance of the ATRIA, CHADS2, and CHA2DS2-VASc scores in a national Swedish AF (SAF) cohort. METHODS AND RESULTS: We examined all Swedish patients hospitalized, or visiting a hospital-based outpatient clinic, with a diagnosis of AF from July 2005 through December 2010. Variables were determined from comprehensive national databases. Risk scores were assessed via C-index (C) and net reclassification improvement (NRI). The cohort included 152 153 AF patients not receiving warfarin. Overall, 11 053 acute ischaemic strokes were observed with mean rate 3.2%/year, higher than the 2%/year in the California cohorts. Using entire point scores, ATRIA had a good C of 0.708 (0.704-0.713), significantly better than CHADS2 0.690 (0.685-0.695) or CHA2DS2-VASc 0.694 (0.690 0.700). Using published cut-points for low/moderate/high risk, C deteriorated but ATRIA remained superior. Net reclassification improvement favoured ATRIA 0.16 (0.14-0.17) vs. CHADS2 and 0.21 (0.20-0.23) vs. CHA2DS2-VASc. Net reclassification improvement decreased when cut-points were altered to better fit the cohort's stroke rates. CONCLUSION: In this SAF cohort, the ATRIA score predicted ischaemic stroke risk better than CHADS2 or CHA2DS2-VASc. However, relative performance of the categorical scores varied by population stroke rates. Score cut-points may need to be optimized to better fit local population stroke rates. PMID- 26941205 TI - Massive pericardial effusion without cardiac tamponade. PMID- 26941206 TI - Pharmacologic and nonpharmacologic approaches to the prevention and management of delirium. AB - Delirium is a syndrome of neuropsychiatric signs and symptoms that can accompany virtually any serious medical condition. Delirium is characterized by a disturbance of attention and awareness, as well as variety of other aspects of cognition that develops over a short period of time in response to another medical condition. It is an independent risk factor for increased morbidity and mortality and is associated with increased lengths of stay and costs of care. Despite this, it frequently goes unrecognized, and debate continues about the best prevention and treatment strategies. This article will review the current best practices for the prevention and treatment of delirium and how collaborative care can aid in improving outcomes and minimizing adverse events for patients suffering from delirium. PMID- 26941207 TI - Dementia: A complex disease with multiple etiologies and multiple treatments. AB - As the population of the United States ages, the rates of dementia are also likely to increase. Clinicians will, therefore, likely be asked to evaluate and treat an escalating number of patients experiencing a decline in multiple domains of cognitive function, which is the hallmark of neurocognitive disorders. It is also probable that clinicians will be confronted with management dilemmas related to the myriad of psychological and behavioral problems that often occur as a consequence of the neurocognitive impairment. In fact, these behavioral and psychological issues might be the initial symptoms that lead the patient to present to the clinician. Dementia has multiple potential etiologies, and a careful diagnostic assessment is imperative to best characterize the specific type of dementia impacting the patient. This is important, as knowing the type of dementia helps the clinician choose the most effective treatment. Potential treatments should be interdisciplinary in scope, patient/family-centered, and may include both nonpharmacologic and pharmacologic treatments. PMID- 26941209 TI - Recycling and management of waste lead-acid batteries: A mini-review. AB - As a result of the wide application of lead-acid batteries to be the power supplies for vehicles, their demand has rapidly increased owing to their low cost and high availability. Accordingly, the amount of waste lead-acid batteries has increased to new levels; therefore, the pollution caused by the waste lead-acid batteries has also significantly increased. Because lead is toxic to the environment and to humans, recycling and management of waste lead-acid batteries has become a significant challenge and is capturing much public attention. Various innovations have been recently proposed to recycle lead and lead containing compounds from waste lead-acid batteries. In this mini-review article, different recycling techniques for waste lead-acid batteries are highlighted. The present state of such recycling and its future perspectives are also discussed. We hope that this mini-review can provide useful information on recovery and recycling of lead from waste lead-acid batteries in the field of solid waste treatment. PMID- 26941208 TI - Municipal solid waste incineration in China and the issue of acidification: A review. AB - In China, incineration is essential for reducing the volume of municipal solid waste arising in its numerous megacities. The evolution of incinerator capacity has been huge, yet it creates strong opposition from a small, but vocal part of the population. The characteristics of Chinese municipal solid waste are analysed and data presented on its calorific value and composition. These are not so favourable for incineration, since the sustained use of auxiliary fuel is necessary for ensuring adequate combustion temperatures. Also, the emission standard for acid gases is more lenient in China than in the European Union, so special attention should be paid to the issue of acidification arising from flue gas. Next, the techniques used in flue gas cleaning in China are reviewed and the acidification potential by cleaned flue gas is estimated. Still, acidification induced by municipal solid waste incinerators remains marginal compared with the effects of coal-fired power plants. PMID- 26941210 TI - Lobachevsky crystallography made real through carbon pseudospheres. AB - We realize Lobachevsky geometry in a simulation lab, by producing a carbon-based energetically stable molecular structure, arranged in the shape of a Beltrami pseudosphere. We find that this structure: (i) corresponds to a non-Euclidean crystallographic group, namely a loxodromic subgroup of SL(2, Z); (ii) has an unavoidable singular boundary, that we fully take into account. Our approach, substantiated by extensive numerical simulations of Beltrami pseudospheres of different size, might be applied to other surfaces of constant negative Gaussian curvature, and points to a general procedure to generate them. Our results also pave the way to test certain scenarios of the physics of curved spacetimes owing to graphene's unique properties. PMID- 26941211 TI - The framing of two major flood episodes in the Irish print news media: Implications for societal adaptation to living with flood risk. AB - Societal adaptation to flooding is a critical component of contemporary flood policy. Using content analysis, this article identifies how two major flooding episodes (2009 and 2014) are framed in the Irish broadsheet news media. The article considers the extent to which these frames reflect shifts in contemporary flood policy away from protection towards risk management, and the possible implications for adaptation to living with flood risk. Frames help us make sense of the social world, and within the media, framing is an essential tool for communication. Five frames were identified: flood resistance and structural defences, politicisation of flood risk, citizen as risk manager, citizen as victim and emerging trade-offs. These frames suggest that public debates on flood management do not fully reflect shifts in contemporary flood policy, with negative implications for the direction of societal adaptation. Greater discussion is required on the influence of the media on achieving policy objectives. PMID- 26941212 TI - Elucidating the role of methyl viologen as a scavenger of photoactivated electrons from photosystem I under aerobic and anaerobic conditions. AB - We present detailed electrochemical investigations into the role of dissolved O2 in electrolyte solutions in scavenging photoactivated electrons from a uniform photosystem I (PS I) monolayer assembled on alkanethiolate SAM (self-assembled monolayer)/Au surfaces while using methyl viologen (MV(2+)) as the redox mediator. To this end, we report results for direct measurements of light induced photocurrent from uniform monolayer assemblies of PS I on C9 alkanethiolate SAM/Au surfaces. These measurements, apart from demonstrating the ability of dissolved O2 in the electrolyte medium to act as an electron scavenger, also reveal its essential role in driving the solution-phase methyl viologen to initiate light-induced directional electron transfer from an electron donor surface (Au) via surface assembled PS I trimers. Specifically, our systematic electrochemical measurements have revealed that the dissolved O2 in aqueous electrolyte solutions form a complex intermediate species with MV that plays the essential role in mediating redox pathways for unidirectional electron transfer processes. This critical insight into the redox-mediated electron transfer pathways allows for rational design of electron scavengers through systematic tuning of mediator combinations that promote such intermediate formation. Our current findings facilitate the incorporation of PS I-based bio-hybrid constructs as photo-anodes in future photoelectrochemical cells and bio-electronic devices. PMID- 26941214 TI - Bioprocessing of wheat bran for the production of lignocellulolytic enzyme cocktail by Cotylidia pannosa under submerged conditions. AB - Characterization and production of efficient lignocellulytic enzyme cocktails for biomass conversion is the need for biofuel industry. The present investigation reports the modeling and optimization studies of lignocellulolytic enzyme cocktail production by Cotylidia pannosa under submerged conditions. The predominant enzyme activities of cellulase, xylanase and laccase were produced in the cocktail through submerged conditions using wheat bran as a substrate. A central composite design approach was utilized to model the production process using temperature, pH, incubation time and agitation as input variables with the goal of optimizing the output variables namely cellulase, xylanase and laccase activities. The effect of individual, square and interaction terms on cellulase, xylanase and laccase activities were depicted through the non-linear regression equations with significant R(2) and P-values. An optimized value of 20 U/ml, 17 U/ml and 13 U/ml of cellulase, xylanase and laccase activities, respectively, were obtained with a media pH of 5.0 in 77 h at 31C, 140 rpm using wheatbran as a substrate. Overall, the present study introduces a fungal strain, capable of producing lignocellulolytic enzyme cocktail for subsequent applications in biofuel industry. PMID- 26941215 TI - Protein S deficiency complicated pregnancy in women with recurrent pregnancy loss. AB - This prospective study aimed to evaluate pregnancy outcome and complications in women with recurrent pregnancy loss (RPL) and protein S (PS) deficiency, who received low dose aspirin (LDA) or LDA plus heparin (LDA/H) therapies. Clinical characteristics, pregnancy outcome and complications of 38 women with two or more RPL and <60% of plasma free PS antigen were compared among three groups: antiphospholipid antibody (aPL)-negative women who received LDA (group A), aPL negative women who received LDA/H (group B) and aPL-positive women who received LDA/H (group C). Gestational weeks (GW) at delivery in group C (median 32 GW) were earlier than 40 GW in group A and 38.5 GW in group B (p < 0.05). The birth weight in group C (median 1794 g) was less than 2855 g in group B (p < 0.05). The incidences of fetal growth restriction (37.5%), pregnancy-induced hypertension (37.5%), and preterm delivery (62.5%) in group C were higher than those (4.5%, 0%, and 4.5%, respectively) in group B (p<0.05). Women with RPL, PS deficiency, and positive aPL had high risks for adverse pregnancy outcome and complications, even when they received LDA/H therapy. Among women with RPL, PS, and negative aPL, there was no difference in these risks between LDA alone and LDA/H therapies. PMID- 26941216 TI - Considerations for conducting qualitative research with pediatric patients for the purpose of PRO development. AB - PURPOSE: To provide an overview of methodological considerations when conducting qualitative research with pediatric patients for the purpose of patient-reported outcome measure development METHODS: A literature review of qualitative methods in pediatric measure development was completed. Eight clinicians providing care to pediatric patients were interviewed for their expert input. Thematic analysis of the literature and clinician interviews was used to identify themes for consideration. RESULTS: Findings from the literature and expert interviews emphasized the way in which cognitive, linguistic, and social developmental factors affect pediatric patients' understanding of their condition and ability to communicate about their experiences in an interview. There was consensus among the experts that traditional semi-structured interviews with children younger than eight lack characteristics necessary to yield meaningful information about condition and symptom report because they may fail to capture children's understanding and awareness of their condition and may limit their ability to express themselves comfortably. Our findings include recommended strategies to optimize data collected in qualitative interviews with pediatric patients, including modifications to the interview process to establish rapport, construction of interview questions to ensure they are developmentally appropriate, and the use of supplementary techniques to facilitate communication. CONCLUSION: When employing qualitative methods in pediatric measure development, interview guides, methods, and length require careful tailoring to ensure the child's perspectives are captured. This may be best achieved through research performed with narrow age bands that employs flexibility in methods to allow children a comfortable way in which to communicate about their experiences. PMID- 26941213 TI - Differences in the carcinogenic evaluation of glyphosate between the International Agency for Research on Cancer (IARC) and the European Food Safety Authority (EFSA). PMID- 26941217 TI - Change in quality of life and one-year mortality risk in maintenance dialysis patients. AB - BACKGROUND: Quality of life (QOL) is an important metric of high-quality dialysis care. QOL is commonly measured by the Short Form 36 Questionnaire (SF-36), which provides two summary scores: a mental component score (MCS) and a physical component score (PCS). Poor QOL is associated with mortality in dialysis patients. Small studies show that changes in QOL also predicts mortality. We investigated whether changes in QOL over time are associated with mortality in a large cohort of maintenance hemodialysis patients. METHODS: This retrospective study was conducted in 1017 outpatient dialysis facilities. Over 10,000 hemodialysis patients completed two SF-36 surveys. We compared 1-year morality rates in those whose MCS or PCS increased or decreased +/-5 vs. those whose did not. RESULTS: For those who completed two surveys, mean score for PCS was unchanged, whereas MCS increased slightly (48.6 vs. 48.9, p = 0.05). Individual patients, however, showed marked variation. On the second survey, more than half of patients demonstrated a +/- 5 point change in the PCS and/or MCS. After multivariate adjustment, a >= 5 decrease in MCS was associated with an increase in mortality (HR = 1.33, 95 % CI 1.18, 1.50). CONCLUSIONS: Clinicians should be aware that many patients experience a significant change in both the MCS and PCS on dialysis. A MCS decrease of >=5 was associated with increased mortality. More study is needed to determine whether this is a causal relationship. Physicians should evaluate root causes and seek to mitigate declines in QOL whenever possible. PMID- 26941221 TI - Olympus to pay $646m to settle charges over device sales. PMID- 26941220 TI - Functional test measures as risk indicators for low back pain among fixed-wing military pilots. AB - PURPOSE: The purpose of this study was to find out the risk value of functional fitness test (FFT) results for low back pain (LBP) among fixed-wing military pilots. METHODS: A total of 104 male military pilots were recruited for this study. The study was conducted with a self-administered questionnaire and FFT. The functional tests were performed in the beginning of study (baseline). The questionnaire was carried out at the baseline and 5 years later. RESULTS: The isometric low back endurance test result was associated with physical activity related LBP experienced 5 years later. Demographic information was not associated with LBP. The prevalence of overall LBP was 71% and the flight-related LBP prevalence was 31% at the baseline. DISCUSSION: Our findings show that LBP among military pilots is a common problem but it is also associated with tasks other than flying. The functional test results were not associated with flight-related LBP but adequate isometric back endurance may have protective role in LBP caused in physical activities. When trying to find the pilots with increased risk of flight-related LBP, a more sensitive set of tests should be considered. PMID- 26941219 TI - British Military freezing cold injuries: a 13-year review. AB - INTRODUCTION: Cold injuries have been a recurrent feature of warfare for millennia and continue to present during British Military operations today. Those affecting the peripheries are divided into freezing cold injury (FCI) and non FCI. FCI occurs when tissue fluids freeze at around -0.5 degrees C and is commonly referred to as frostnip or frostbite. METHOD: All FMED7 notes held at the Institute of Naval Medicine's Cold Weather Injury Clinic (CIC) from 2002 to 2014 were searched for the terms 'frostbite' and 'frostnip' and then analysed to identify common themes. RESULTS: In total 245 results were found and from these, 149 patients with a positive FCI diagnosis were identified and formed the cohort of this study. Royal Marines (RM) represented over 50% of patients and Arctic training in Norway accounted for over two thirds of the total cases. The extremities were almost always those areas which were affected by FCI. Further analysis of the RM cases showed the majority of those injured were of the most junior rank (Marine/Private or Lance Corporal). CONCLUSIONS: A lack of supporting climatic and activity data meant that it was difficult to draw additional conclusions from the data collected. In future, a greater emphasis should be placed on collection of climatic and additional data when FCIs are diagnosed. These data should be collated at the end of each deployment and published as was regularly done historically. It is hoped that these data could then be used as the starting point for an annual climatic study day, where issues related to FCIs could be discussed in a Tri-Service environment and lessons learned disseminated around all British Forces personnel. PMID- 26941218 TI - Proteomic responses of drought-tolerant and drought-sensitive cotton varieties to drought stress. AB - Drought, one of the most widespread factors reducing agricultural crop productivity, affects biological processes such as development, architecture, flowering and senescence. Although protein analysis techniques and genome sequencing have made facilitated the proteomic study of cotton, information on genetic differences associated with proteomic changes in response to drought between different cotton genotypes is lacking. To determine the effects of drought stress on cotton seedlings, we used two-dimensional polyacrylamide gel electrophoresis (2-DE) and matrix-assisted laser desorption ionization time-of flight (MALDI-TOF) mass spectrometry to comparatively analyze proteome of drought responsive proteins during the seedling stage in two cotton (Gossypium hirsutum L.) cultivars, drought-tolerant KK1543 and drought-sensitive Xinluzao26. A total of 110 protein spots were detected on 2-DE maps, of which 56 were identified by MALDI-TOF and MALDI-TOF/TOF mass spectrometry. The identified proteins were mainly associated with metabolism (46.4 %), antioxidants (14.2 %), and transport and cellular structure (23.2 %). Some key proteins had significantly different expression patterns between the two genotypes. In particular, 5 methyltetrahydropteroyltriglutamate-homocysteine methyltransferase, UDP-D-glucose pyrophosphorylase and ascorbate peroxidase were up-regulated in KK1543 compared with Xinluzao26. Under drought stress conditions, the vacuolar H(+)-ATPase catalytic subunit, a 14-3-3g protein, translation initiation factor 5A and pathogenesis-related protein 10 were up-regulated in KK1543, whereas ribosomal protein S12, actin, cytosolic copper/zinc superoxide dismutase, protein disulfide isomerase, S-adenosylmethionine synthase and cysteine synthase were down regulated in Xinluzao26. This work represents the first characterization of proteomic changes that occur in response to drought in roots of cotton plants. These differentially expressed proteins may be related to biochemical pathways responsible for drought tolerance in KK1543. Although further studies are needed, this proteomic analysis underlines the role of post-translational events. The differentially expressed proteins and their corresponding genes may be used as markers for the breeding of drought tolerance in cotton. PMID- 26941226 TI - Multifunctional reduction-responsive SPIO&DOX-loaded PEGylated polymeric lipid vesicles for magnetic resonance imaging-guided drug delivery. AB - Multifunctional superparamagnetic iron-oxide (SPIO)-based nanoparticles have been emerging as candidate nanosystems for cancer diagnosis and therapy. Here, we report the use of reduction- responsive SPIO/doxorubicin (DOX)-loaded poly(ethylene glycol) monomethyl ether (PEG)ylated polymeric lipid vesicles (SPIO&DOX-PPLVs) as a novel theranostic system for tumor magnetic resonance imaging (MRI) diagnosis and controlled drug delivery. These SPIO&DOX-PPLVs are composed of SPIOs that function as MR contrast agents for tumor enhancement and PPLVs as polymer matrices for encapsulating SPIO and antitumor drugs. The in vitro characterizations show that the SPIO&DOX-PPLVs have nanosized structures (~80 nm), excellent colloidal stability, good biocompatibility, as well as T2 weighted MRI capability with a relatively high T2 relaxivity (r2 = 213.82 mM(-1) s(-1)). In vitro drug release studies reveal that the release rate of DOX from the SPIO&DOX-PPLVs is accelerated in the reduction environment. An in vitro cellular uptake study and an antitumor study show that the SPIO&DOX-PPLVs have magnetic targeting properties and effective antitumor activity. In vivo studies show the SPIO&DOX-PPLVs have excellent T2-weighted tumor targeted MRI capability, image-guided drug delivery capability, and high antitumor effects. These results suggest that the SPIO&DOX-PPLVs are promising nanocarriers for MRI diagnosis and cancer therapy applications. PMID- 26941227 TI - Coordination of cell decisions and promotion of phenotypic diversity in B. subtilis via pulsed behavior of the phosphorelay. AB - The phosphorelay of Bacillus subtilis, a kinase cascade that activates master regulator Spo0A ~ P in response to starvation signals, is the core of a large network controlling the cell's decision to differentiate into sporulation and other phenotypes. This article reviews recent advances in understanding the origins and purposes of the complex dynamical behavior of the phosphorelay, which pulses with peaks of activity coordinated with the cell cycle. The transient imbalance in the expression of two critical genes caused by their strategic placement at opposing ends of the chromosome proved to be the key for this pulsed behavior. Feedback control loops in the phosphorelay use these pulses to implement a timer mechanism, which creates several windows of opportunity for phenotypic transitions over multiple generations. This strategy allows the cell to coordinate multiple differentiation programs in a decision process that fosters phenotypic diversity and adapts to current conditions. PMID- 26941228 TI - The Mycobacterium phlei Genome: Expectations and Surprises. AB - Mycobacterium phlei, a nontuberculosis mycobacterial species, was first described in 1898-1899. We present the complete genome sequence for theM. phlei CCUG21000(T)type strain and the draft genomes for four additional strains. The genome size for all five is 5.3 Mb with 69.4% Guanine-Cytosine content. This is ~0.35 Mbp smaller than the previously reported M. phlei RIVM draft genome. The size difference is attributed partly to large bacteriophage sequence fragments in theM. phlei RIVM genome. Comparative analysis revealed the following: 1) A CRISPR system similar to Type 1E (cas3) in M. phlei RIVM; 2) genes involved in polyamine metabolism and transport (potAD,potF) that are absent in other mycobacteria, and 3) strain-specific variations in the number of sigma-factor genes. Moreover,M. phlei has as many as 82 mce(mammalian cell entry) homologs and many of the horizontally acquired genes in M. phlei are present in other environmental bacteria including mycobacteria that share similar habitat. Phylogenetic analysis based on 693 Mycobacterium core genes present in all complete mycobacterial genomes suggested that its closest neighbor is Mycobacterium smegmatis JS623 and Mycobacterium rhodesiae NBB3, while it is more distant toM. smegmatis mc2 155. PMID- 26941229 TI - Localizing Ashkenazic Jews to Primeval Villages in the Ancient Iranian Lands of Ashkenaz. AB - The Yiddish language is over 1,000 years old and incorporates German, Slavic, and Hebrew elements. The prevalent view claims Yiddish has a German origin, whereas the opposing view posits a Slavic origin with strong Iranian and weak Turkic substrata. One of the major difficulties in deciding between these hypotheses is the unknown geographical origin of Yiddish speaking Ashkenazic Jews (AJs). An analysis of 393 Ashkenazic, Iranian, and mountain Jews and over 600 non-Jewish genomes demonstrated that Greeks, Romans, Iranians, and Turks exhibit the highest genetic similarity with AJs. The Geographic Population Structure analysis localized most AJs along major primeval trade routes in northeastern Turkey adjacent to primeval villages with names that may be derived from "Ashkenaz." Iranian and mountain Jews were localized along trade routes on the Turkey's eastern border. Loss of maternal haplogroups was evident in non-Yiddish speaking AJs. Our results suggest that AJs originated from a Slavo-Iranian confederation, which the Jews call "Ashkenazic" (i.e., "Scythian"), though these Jews probably spoke Persian and/or Ossete. This is compatible with linguistic evidence suggesting that Yiddish is a Slavic language created by Irano-Turko-Slavic Jewish merchants along the Silk Roads as a cryptic trade language, spoken only by its originators to gain an advantage in trade. Later, in the 9th century, Yiddish underwent relexification by adopting a new vocabulary that consists of a minority of German and Hebrew and a majority of newly coined Germanoid and Hebroid elements that replaced most of the original Eastern Slavic and Sorbian vocabularies, while keeping the original grammars intact. PMID- 26941231 TI - Mimics of Mammary Paget Disease: A Rogues' Gallery. PMID- 26941232 TI - Focused-electron-beam-induced-deposited cobalt nanopillars for nanomagnetic logic. AB - Nanomagnetic logic (NML) intends to alleviate problems of continued miniaturization of CMOS-based electronics, such as energy dissipation through heat, through advantages such as low power operation and non-volatile magnetic elements. In line with recent breakthroughs in NML with perpendicularly magnetized elements formed from thin films, we have fabricated NML inverter chains from Co nanopillars by focused electron beam induced deposition (FEBID) that exhibit shape-induced perpendicular magnetization. The flexibility of FEBID allows optimization of NML structures. Simulations reveal that the choice of nanopillar dimensions is critical to obtain the correct antiferromagnetically coupled configuration. Experiments carrying the array through a clocking cycle using the Oersted field from an integrated Cu wire show that the array responds to the clocking cycle. PMID- 26941230 TI - Developmental Progression in the Coral Acropora digitifera Is Controlled by Differential Expression of Distinct Regulatory Gene Networks. AB - Corals belong to the most basal class of the Phylum Cnidaria, which is considered the sister group of bilaterian animals, and thus have become an emerging model to study the evolution of developmental mechanisms. Although cell renewal, differentiation, and maintenance of pluripotency are cellular events shared by multicellular animals, the cellular basis of these fundamental biological processes are still poorly understood. To understand how changes in gene expression regulate morphogenetic transitions at the base of the eumetazoa, we performed quantitative RNA-seq analysis duringAcropora digitifera's development. We collected embryonic, larval, and adult samples to characterize stage-specific transcription profiles, as well as broad expression patterns. Transcription profiles reconstructed development revealing two main expression clusters. The first cluster grouped blastula and gastrula and the second grouped subsequent developmental time points. Consistently, we observed clear differences in gene expression between early and late developmental transitions, with higher numbers of differentially expressed genes and fold changes around gastrulation. Furthermore, we identified three coexpression clusters that represented discrete gene expression patterns. During early transitions, transcriptional networks seemed to regulate cellular fate and morphogenesis of the larval body. In late transitions, these networks seemed to play important roles preparing planulae for switch in lifestyle and regulation of adult processes. Although developmental progression inA. digitiferais regulated to some extent by differential coexpression of well-defined gene networks, stage-specific transcription profiles appear to be independent entities. While negative regulation of transcription is predominant in early development, cell differentiation was upregulated in larval and adult stages. PMID- 26941233 TI - A community survey on knowledge of the impact of environmental and epigenetic factors on health and disease. AB - AIM: An outreach effort was designed to survey breast cancer survivors, supporters and their families and friends with respect to their interest in, and knowledge of, the potential impact of the environment and epigenetics on health. METHODS: Two nearly identical questionnaires (one for adolescents and one for adults) were designed to gauge the perception of this community as to whether the environment impacts health and cancer risk through processes other than genetics. The questionnaires were filled out at casual social gatherings, fundraisers and wellness campaigns as well as in schools (730 participants). The differences among correct (scientific consensus) versus other responses (incorrect and not known) were evaluated. Each answer was first analysed individually and then grouped into one of three categories (diet, inheritance and environment) with age, race and gender. Differences for each response, question or group were compared by repeated measures analysis of variance. RESULTS: Respondents generally acknowledged that many factors could be associated with breast cancer although answers to key questions related to epigenetics based on diet, inheritance and environment were often incorrect or not known. The adult participants tended to answer more questions correctly than adolescents did. The majority of participants preferred the Internet as a major source for obtaining further information. CONCLUSION: The growing awareness and educational needs for adolescents may bring new paradigm-related environmental risk factors, which may minimise negative epigenetic outcome in subsequent generations. There is an educational opportunity, especially using electronic media, for public education concerning the impact of the environment on human health. PMID- 26941234 TI - Complete genome sequence of the cold-active bacteriophage VMY22 from Bacillus cereus. AB - The cold-active bacteriophage VMY22, belonging to the Podoviridae family, was isolated from Mingyong Glacier in China. Sequence analysis revealed that the genome is 18,609 bp long, with an overall G + C content of 36.4 mol%, and 25 open reading frames (ORFs). The sequence contains 46 potential promoters, 6 transcription terminators, and no tRNAs. Most of the ORFs show a high degree of similarity to B103 (NC_004165). Two noteworthy findings were made. First, one of the predicted proteins, ORF 19, shows high sequence similarity to the bacteriocin biosynthesis protein from Bacillus cereus. From this information, we propose that the VMY22 phage is at an intermediate phase in its coevolution with its bacterial host. Second, seven of the hypothetical proteins appear to be unique to this cold active B. cereus phage (i.e., not found in temperate-active B. cereus phages). These observations add to our current knowledge about the coevolution of bacteriophages and their hosts. The identification of a novel group of gene and protein structures and functions will lead to a better understanding of cold adaptation mechanisms in bacteria and their bacteriophages. PMID- 26941235 TI - Identification of UDP-glycosyltransferases involved in the biosynthesis of astringent taste compounds in tea (Camellia sinensis). AB - Galloylated catechins and flavonol 3-O-glycosides are characteristic astringent taste compounds in tea (Camellia sinensis). The mechanism involved in the formation of these metabolites remains unknown in tea plants. In this paper, 178 UGT genes (CsUGTs) were identified inC. sinensis based on an analysis of tea transcriptome data. Phylogenetic analysis revealed that 132 of these genes were clustered into 15 previously established phylogenetic groups (A to M, O and P) and a newly identified group R. Three of the 11 recombinant UGT proteins tested were found to be involved in the in vitro biosynthesis of beta-glucogallin and glycosylated flavonols. CsUGT84A22 exhibited catalytic activity toward phenolic acids, in particular gallic acid, to produce beta-glucogallin, which is the immediate precursor of galloylated catechin biosynthesis in tea plants. CsUGT78A14 and CsUGT78A15 were found to be responsible for the biosynthesis of flavonol 3-O-glucosides and flavonol 3-O-galactosides, respectively. Site directed mutagenesis of the Q373H substitution for CsUGT78A14 indicated that the Q (Gln) residue played a catalytically crucial role for flavonoid 3-O glucosyltransferase activity. The expression profiles of the CsUGT84A22, CsUGT78A14, and CsUGT78A15 genes were correlated with the accumulation patterns of beta-glucogallin and the glycosylated flavonols which indicated that these three CsUGT genes were involved in the biosynthesis of astringent compounds inC. sinensis. PMID- 26941237 TI - A case of a urethral diverticular adenocarcinoma after the fenestration of the anterior vaginal wall for pelvic floor abscess. AB - A 61-year-old woman presented to the gynecology department with complaints of atypical genital bleeding. Magnetic resonance imaging revealed a localized urethral tumor extended to vagina. Histological test of the biopsy tissue of the mass suggested the adenocarcinoma. The patient was performed the fenestration of the anterior vaginal wall 15 years ago. Under the diagnosis of urethral diverticular adenocarcinoma, we performed standard open total cystectomy with lymph node excision and ileal conduit. We could not establish a diagnosis of urethral diverticulum from the histological test; however, we clinically diagnosed as urethral diverticular adenocarcinoma. Because carcinoma arising from urethral diverticula is reported, a close long-term follow-up for the recurrence or generation of malignant tumors by genitourinary examinations or images is necessary, for the patient with urethral diverticula. PMID- 26941236 TI - Super-resolution structured illumination fluorescence microscopy of the lateral wall of the cochlea: the Connexin26/30 proteins are separately expressed in man. AB - Globally 360 million people have disabling hearing loss and, of these, 32 million are children. Human hearing relies on 15,000 hair cells that transduce mechanical vibrations to electrical signals in the auditory nerve. The process is powered by the endo-cochlear potential, which is produced by a vascularized epithelium that actively transports ions in conjunction with a gap junction (GJ) system. This "battery" is located "off-site" in the lateral wall of the cochlea. The GJ syncytium contains the GJ protein genes beta 2 (GJB2/connexin26 (Cx26)) and 6 (GJB6/connexin30 (Cx30)), which are commonly involved in hereditary deafness. Because the molecular arrangement of these proteins is obscure, we analyze GJ protein expression (Cx26/30) in human cochleae by using super-resolution structured illumination microscopy. At this resolution, the Cx26 and Cx30 proteins were visible as separate plaques, rather than being co-localized in heterotypic channels, as previously suggested. The Cx26 and Cx30 proteins thus seem not to be co-expressed but to form closely associated assemblies of GJ plaques. These results could assist in the development of strategies to treat genetic hearing loss in the future. PMID- 26941238 TI - Sialic acid-modified antigens impose tolerance via inhibition of T-cell proliferation and de novo induction of regulatory T cells. AB - Sialic acids are negatively charged nine-carbon carboxylated monosaccharides that often cap glycans on glycosylated proteins and lipids. Because of their strategic location at the cell surface, sialic acids contribute to interactions that are critical for immune homeostasis via interactions with sialic acid-binding Ig-type lectins (siglecs). In particular, these interactions may be of importance in cases where sialic acids may be overexpressed, such as on certain pathogens and tumors. We now demonstrate that modification of antigens with sialic acids (Sia antigens) regulates the generation of antigen-specific regulatory T (Treg) cells via dendritic cells (DCs). Additionally, DCs that take up Sia-antigen prevent formation of effector CD4(+) and CD8(+)T cells. Importantly, the regulatory properties endowed on DCs upon Sia-antigen uptake are antigen-specific: only T cells responsive to the sialylated antigen become tolerized. In vivo, injection of Sia-antigen-loaded DCs increased de novo Treg-cell numbers and dampened effector T-cell expansion and IFN-gamma production. The dual tolerogenic features that Sia-antigen imposed on DCs are Siglec-E-mediated and maintained under inflammatory conditions. Moreover, loading DCs with Sia-antigens not only inhibited the function of in vitro-established Th1 and Th17 effector T cells but also significantly dampened ex vivo myelin-reactive T cells, present in the circulation of mice with experimental autoimmune encephalomyelitis. These data indicate that sialic acid-modified antigens instruct DCs in an antigen-specific tolerogenic programming, enhancing Treg cells and reducing the generation and propagation of inflammatory T cells. Our data suggest that sialylation of antigens provides an attractive way to induce antigen-specific immune tolerance. PMID- 26941241 TI - Photon nanojet lens: design, fabrication and characterization. AB - In this paper, a novel nanolens with super resolution, based on the photon nanojet effect through dielectric nanostructures in visible wavelengths, is proposed. The nanolens is made from plastic SU-8, consisting of parallel semi cylinders in an array. This paper focuses on the lens designed by numerical simulation with the finite-difference time domain method and nanofabrication of the lens by grayscale electron beam lithography combined with a casting/bonding/lift-off transfer process. Monte Carlo simulation for injected charge distribution and development modeling was applied to define the resultant 3D profile in PMMA as the template for the lens shape. After the casting/bonding/lift-off process, the fabricated nanolens in SU-8 has the desired lens shape, very close to that of PMMA, indicating that the pattern transfer process developed in this work can be reliably applied not only for the fabrication of the lens but also for other 3D nanopatterns in general. The light distribution through the lens near its surface was initially characterized by a scanning near-field optical microscope, showing a well defined focusing image of designed grating lines. Such focusing function supports the great prospects of developing a novel nanolithography based on the photon nanojet effect. PMID- 26941240 TI - Accelerated failure time model under general biased sampling scheme. AB - Right-censored time-to-event data are sometimes observed from a (sub)cohort of patients whose survival times can be subject to outcome-dependent sampling schemes. In this paper, we propose a unified estimation method for semiparametric accelerated failure time models under general biased estimating schemes. The proposed estimator of the regression covariates is developed upon a bias offsetting weighting scheme and is proved to be consistent and asymptotically normally distributed. Large sample properties for the estimator are also derived. Using rank-based monotone estimating functions for the regression parameters, we find that the estimating equations can be easily solved via convex optimization. The methods are confirmed through simulations and illustrated by application to real datasets on various sampling schemes including length-bias sampling, the case-cohort design and its variants. PMID- 26941239 TI - Assessing the sensitivity of diffusion MRI to detect neuronal activity directly. AB - Functional MRI (fMRI) is widely used to study brain function in the neurosciences. Unfortunately, conventional fMRI only indirectly assesses neuronal activity via hemodynamic coupling. Diffusion fMRI was proposed as a more direct and accurate fMRI method to detect neuronal activity, yet confirmative findings have proven difficult to obtain. Given that the underlying relation between tissue water diffusion changes and neuronal activity remains unclear, the rationale for using diffusion MRI to monitor neuronal activity has yet to be clearly established. Here, we studied the correlation between water diffusion and neuronal activity in vitro by simultaneous calcium fluorescence imaging and diffusion MR acquisition. We used organotypic cortical cultures from rat brains as a biological model system, in which spontaneous neuronal activity robustly emerges free of hemodynamic and other artifacts. Simultaneous fluorescent calcium images of neuronal activity are then directly correlated with diffusion MR signals now free of confounds typically encountered in vivo. Although a simultaneous increase of diffusion-weighted MR signals was observed together with the prolonged depolarization of neurons induced by pharmacological manipulations (in which cell swelling was demonstrated to play an important role), no evidence was found that diffusion MR signals directly correlate with normal spontaneous neuronal activity. These results suggest that, whereas current diffusion MR methods could monitor pathological conditions such as hyperexcitability, e.g., those seen in epilepsy, they do not appear to be sensitive or specific enough to detect or follow normal neuronal activity. PMID- 26941242 TI - Nonclinical Safety Profile of Etelcalcetide, a Novel Peptide Calcimimetic for the Treatment of Secondary Hyperparathyroidism. AB - Etelcalcetide is a novel d-amino acid peptide that functions as an allosteric activator of the calcium-sensing receptor and is being developed as an intravenous calcimimetic for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease on hemodialysis. To support clinical development and marketing authorization, a comprehensive nonclinical safety package was generated. Primary adverse effects included hypocalcemia, tremoring, and convulsions. Other adverse effects were considered sequelae of stress associated with hypocalcemia. Cardiovascular safety evaluations in the dog revealed an anticipated prolongation of the corrected QT interval that was related to reductions in serum calcium. Etelcalcetide did not affect the human ether-a-go-go gene ion channel current. Etelcalcetide was mutagenic in some strains of Salmonella, however, based on the negative results in 2 in vitro and 2 in vivo mammalian genotoxicity assays, including a 28-day Muta mouse study, etelcalcetide is considered nongenotoxic. Further support for a lack of genotoxicity was provided due to the fact that etelcalcetide was not carcinogenic in a 6-month transgenic rasH2 mouse model or a 2-year study in rats. There were no effects on fertility, embryo-fetal development, and prenatal and postnatal development. All of the adverse effects observed in both rat and dog were considered directly or secondarily related to the pharmacologic activity of etelcalcetide and the expected sequelae associated with dose-related reductions in serum calcium due to suppression of parathyroid hormone secretion. These nonclinical data indicate no safety signal of concern for human risk beyond that associated with hypocalcemia and associated QT prolongation. PMID- 26941244 TI - Interpreting the effect of increasing COD loading rates on the performance of a pre-anoxic MBBR system: implications on the attached and suspended biomass dynamics and nitrification-denitrification activity. AB - A pre-anoxic MBBR system was subjected to increasing organic loading rates up to 18 gCOD/(m(2) day). At 3 gCOD/(m(2) day), most of the incoming organic matter was removed via denitrification. However, at higher loads, anoxic COD removal became limited by the nitrite/nitrate supply from the aerobic reactor, which assumed an important role in this conversion. Despite the application of low dissolved oxygen (DO) levels (<2 mg/L) in this tank, nitrification was observed to be nearly complete until 8 gCOD/(m(2) day). As the organic input was increased, the maximum specific nitrifying activity gradually declined. Activity tests suggested that an oxygen-limited environment was established in the biofilm. At lower loads [3-8 gCOD/(m(2) day)], the nitrification product obtained was affected by the DO concentration, whereas from 16 to 21 gCOD/(m(2) day), nitrite/nitrate profiles were likely associated with microbial stratification in the biofilm. The results also indicated that the role of the suspended biomass in the overall nitrification and denitrification can be very significant in high loaded MBBRs and should not be neglected, even at low HRTs. PMID- 26941245 TI - Enhanced enzymatic hydrolysis of mild alkali pre-treated rice straw at high-solid loadings using in-house cellulases in a bench scale system. AB - In the present study, scale-up systems for cellulase production and enzymatic hydrolysis of pre-treated rice straw at high-solid loadings were designed, fabricated and tested in the laboratory. Cellulase production was carried out using tray fermentation at 45 degrees C by Aspergillus terreus in a temperature controlled humidity chamber. Enzymatic hydrolysis studies were performed in a horizontal rotary drum reactor at 50 degrees C with 25 % (w/v) solid loading and 9 FPU g(-1) substrate enzyme load using in-house as well commercial cellulases. Highly concentrated fermentable sugars up to 20 % were obtained at 40 h with an increased saccharification efficiency of 76 % compared to laboratory findings (69.2 %). These findings demonstrate that we developed a simple and less energy intensive bench scale system for efficient high-solid saccharification. External supplementation of commercial beta-glucosidase and hemicellulase ensured better hydrolysis and further increased the saccharification efficiency by 14.5 and 20 %, respectively. An attempt was also made to recover cellulolytic enzymes using ultrafiltration module and nearly 79-84 % of the cellulases and more than 90 % of the sugars were recovered from the saccharification mixture. PMID- 26941243 TI - Bacteriophage biocontrol in wastewater treatment. AB - Waterborne bacterial pathogens in wastewater remains an important public health concern, not only because of the environmental damage, morbidity and mortality that they cause, but also due to the high cost of disinfecting wastewater by using physical and chemical methods in treatment plants. Bacteriophages are proposed as bacterial pathogen indicators and as an alternative biological method for wastewater treatment. Phage biocontrol in large scale treatment requires adaptive and aggressive phages that are able to overcome the environmental forces that interfere with phage-host interactions while targeting unwanted bacterial pathogens and preventing biofilms and foaming. This review will shed light on aspects of using bacteriophage programming technology in wastewater plants to rapidly target and reduce undesirable bacteria without harming the useful bacteria needed for biodegradation. PMID- 26941246 TI - Novel myokine: irisin may be an independent predictor for subclinic atherosclerosis in Behcet's disease. AB - Behcet's disease (BD) is a vasculitic and inflammatory disease causing endothelial dysfunction. Irisin is a metabolic hormone related to insulin resistance and endothelial functions. In this study, we investigated the relationship between irisin and carotid intima-media thickness (cIMT), which is a marker of atherosclerosis in patients with BD. 48 patients with BD and 50 healthy individuals were enrolled in the study. Disease severity was evaluated by BD current activity form. Irisin, glucose, insulin, C reactive protein, erythrocyte sedimentation rate and lipid panel were examined in all patients. Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) was used to calculate insulin resistance. A simple and inexpensive cIMT test was used as indicator of atherosclerosis. cIMT was 0.62 (0.45-1.05) mm in the patients, while it was 0.38 (0.25-0.65) mm in the control group (p < 0.001). Irisin value was found to be 197.3 (24.8-834.2) ng/mL in the control group, while it was 85.4 (4.7-471.1) ng/mL in the patient group (p = 0.007). There was a negative correlation between irisin level and cIMT (r = -0.511, p < 0.001) and HOMA-IR (r = -0.371, p = 0.009). Decreased irisin levels (OR 0.996, 95% CI 0.992 to 1.000, p = 0.041), male gender (OR 7.634, 95% CI 1.415 to 41.191, p = 0.018), and HOMA-IR (OR 2.596, 95% CI 1.451 to 4.643, p = 0.001) are independent risk factors for cIMT in patients with BD. We detected a very strong relationship between cIMT, which is an indicator of subclinical atherosclerosis, and decreased irisin levels in patients with BD. BD is characterized by chronic inflammation, and low serum irisin levels in BD may be related to atherosclerosis. PMID- 26941247 TI - Bicuspid aortic valve increases risk of permanent pacemaker implant following aortic root replacement. AB - OBJECTIVES: We aimed to assess the incidence and possible differences in postoperative conduction delay after aortic root replacement (ARR) in bicuspid aortic valve (BAV) patients compared with a tricuspid aortic valve (TAV). METHODS: A total of 380 patients undergoing ARR at our institution between 2005 and 2013 were included in the analysis. Patients were stratified by aortic valve anatomy: BAV, n = 191 vs TAV, n = 189. Electrocardiographic and echocardiographic data were retrospectively analysed at different time points (pre-, postoperatively and at follow-up). Primary outcome of interest was permanent pacemaker (PPM) implantation within 30 days, the composite of new PPM or new left fascicular or bundle branch block (PPM or LBBB) was the secondary outcome of interest. Age range was 24-89.5 years and incidence of preoperative moderate to severe aortic stenosis was 9.7%. RESULTS: BAV patients had higher incidence of PPM implantation within 30 days (5.8 vs 1.6% in TAV, P = 0.053); moreover, the composite of PPM or LBBB was also more frequent in BAV (8.4 vs 2.1%, P = 0.010). BAV was independently associated with PPM insertion (OR 4.08, P = 0.047) and also an independent predictor of PPM or LBBB in multiple regression (OR 4.96, P = 0.006). CONCLUSIONS: Significantly higher incidence of PPM implantation or LBBB may exist after ARR in bicuspid patients and BAV was confirmed to be an independent predictor for postoperative conduction disturbances by multivariable regression. PMID- 26941249 TI - The value of video-assisted thoracoscopic surgery: follow the money! PMID- 26941248 TI - Surgical management of aortic root in type A acute aortic dissection: a propensity-score analysis. AB - OBJECTIVES: Surgical management of the aortic root in type A acute aortic dissection (TAAAD) is controversial. This study compares short- and long-term outcomes of root replacement (RR) versus conservative root management (CR). METHODS: Between 1999 and 2014, 296 patients with TAAAD were treated in our department. The mean age was 63.7 years. Of the total, 69% were male. Ten patients (3%) presented with Marfan syndrome or bicuspid aortic valve. RR was performed in 119 (40%) patients, whereas CR in 177 (60%). Pre- and intraoperative data were stratified according to root management, and treatment bias was addressed by propensity-score (PS) analysis. Independent predictors of hospital and long-term mortality and proximal aortic reoperation were identified using multivariable logistic and Cox regression models. RESULTS: Using PS analysis, we obtain two groups of 82 patients. The matched cohort hospital mortality rate was 21% in the CR group and 26% in the RR group (P = 0.45). The unadjusted comparison showed no statistical difference in early and long-term mortality between the groups. This result was confirmed after standard logistic regression and propensity-adjusted logistic regression. Freedom from proximal aortic reintervention was higher in the RR group (at 7 years RR: 96 +/- 3% vs CR: 80 +/- 6%, log-rank P = 0.02) and remained high in the matched cohort of patients (at 7 years RR: 98 +/- 2 vs CR: 86 +/- 6, log-rank P = 0.06). CONCLUSIONS: Conservative and aggressive root management in acute aortic dissection provided similar results for early and late mortality. Nevertheless, a more extensive root intervention appeared to be protective against aortic reintervention. PMID- 26941250 TI - Sister chromatid telomere fusions, but not NHEJ-mediated inter-chromosomal telomere fusions, occur independently of DNA ligases 3 and 4. AB - Telomeres shorten with each cell division and can ultimately become substrates for nonhomologous end-joining repair, leading to large-scale genomic rearrangements of the kind frequently observed in human cancers. We have characterized more than 1400 telomere fusion events at the single-molecule level, using a combination of high-throughput sequence analysis together with experimentally induced telomeric double-stranded DNA breaks. We show that a single chromosomal dysfunctional telomere can fuse with diverse nontelomeric genomic loci, even in the presence of an otherwise stable genome, and that fusion predominates in coding regions. Fusion frequency was markedly increased in the absence of TP53 checkpoint control and significantly modulated by the cellular capacity for classical, versus alternative, nonhomologous end joining (NHEJ). We observed a striking reduction in inter-chromosomal fusion events in cells lacking DNA ligase 4, in contrast to a remarkably consistent profile of intra-chromosomal fusion in the context of multiple genetic knockouts, including DNA ligase 3 and 4 double-knockouts. We reveal distinct mutational signatures associated with classical NHEJ-mediated inter-chromosomal, as opposed to alternative NHEJ mediated intra-chromosomal, telomere fusions and evidence for an unanticipated sufficiency of DNA ligase 1 for these intra-chromosomal events. Our findings have implications for mechanisms driving cancer genome evolution. PMID- 26941251 TI - Human MAF1 targets and represses active RNA polymerase III genes by preventing recruitment rather than inducing long-term transcriptional arrest. AB - RNA polymerase III (Pol III) is tightly controlled in response to environmental cues, yet a genomic-scale picture of Pol III regulation and the role played by its repressor MAF1 is lacking. Here, we describe genome-wide studies in human fibroblasts that reveal a dynamic and gene-specific adaptation of Pol III recruitment to extracellular signals in an mTORC1-dependent manner. Repression of Pol III recruitment and transcription are tightly linked to MAF1, which selectively localizes at Pol III loci, even under serum-replete conditions, and increasingly targets transcribing Pol III in response to serum starvation. Combining Pol III binding profiles with EU-labeling and high-throughput sequencing of newly synthesized small RNAs, we show that Pol III occupancy closely reflects ongoing transcription. Our results exclude the long-term, unproductive arrest of Pol III on the DNA as a major regulatory mechanism and identify previously uncharacterized, differential coordination in Pol III binding and transcription under different growth conditions. PMID- 26941252 TI - Yes, uterus transplants should be publicly funded!'. PMID- 26941253 TI - Lipoprotein (a): a promising target in the treatment of stenotic valvular diseases. PMID- 26941254 TI - Domestic mould exposure and invasive aspergillosis-air sampling of Aspergillus spp. spores in homes of hematological patients, a pilot study. AB - Aspergillus spp.-related morbidity and mortality remains a major challenge in the management of neutropenic patients. Little is known about the impact of domestic Aspergillus spp. EXPOSURE: In this controlled prospective study, fungal spores were collected from homes of neutropenic patients. Cases were defined as patients with probable or proven controls as patients with no invasive pulmonary aspergillosis, while patients with possible disease were evaluated as a third group. Forty patients were enrolled and returned questionnaires on high-risk activities and mould exposure. A. fumigatus was detected in concentrations of 0 to 76 cfu/m(3) in every home. A. terreus was detected in nine (18%) homes. Mean Aspergillus spp. cfu/m(3) according to EORTC criteria were: proven/probable IA (15 patients) - 36; possible IA (12 patients) - 42; no IA (13 patients) - 42. Of the seven patients with self-reported moulded walls at home, four had probable and three had possible aspergillosis; the risk ratio of developing IA was 1.65 (95% CI: 1.25-2.17). In conclusion self-reported domestic mould exposure was associated with a high incidence of IA and may be a feasible tool for identifying high-risk patients. There was no correlation between domestic ambient-air spore counts and IA. PMID- 26941255 TI - Characterizing Cathepsin Activity and Macrophage Subtypes in Excised Human Carotid Plaques. AB - BACKGROUND AND PURPOSE: Atherosclerosis is a leading cause of mortality worldwide, contributing to both strokes and heart attacks. Macrophages are key players in atherogenesis, promoting vascular inflammation and arterial remodeling through cysteine cathepsin proteases. We used a cathepsin-targeted activity-based probe in human carotid plaque to assess its diagnostic potential and evaluate macrophage subtypes ex vivo. METHODS: Carotid plaque specimens surgically removed during endarterectomy from 62 patients (age range, 38% female, 28% symptomatic) were graded pathologically as either stable (Grade 1) or unstable (Grade 2 or 3). A cathepsin activity-based probe was used to quantify individual cathepsins in plaque tissue and macrophage subtypes. RESULTS: Cathepsin B and S activities were increased in unstable carotid plaques. They were quantified using the probe to biochemically investigate individual cathepsins (Cathepsin B and S: 0.97 and 0.90 for grade 3 versus 0.51 and 0.59 for grade 1; P=0.006 and P=0.03 arbitrary units (AU), respectively). Higher cathepsin activity was observed in carotid plaques from symptomatic patients (Cathepsin B and S: 0.65 and 0.77 for asymptomatic, 0.99 and 1.17 for symptomatic; P=0.008 and P=0.005 AU, respectively). Additionally, it was demonstrated that M2 macrophages from unstable plaques express cathepsin activity 5-fold higher than M2 macrophages from stable plaques (25.52 versus 5.22; P=0.008 AU). CONCLUSIONS: Targeting cathepsin activity in human carotid plaques may present a novel diagnostic tool for characterizing high risk plaques. Novel cathepsin activity patterns within plaques and macrophage subpopulations suggest their involvement in the transition to active disease. PMID- 26941256 TI - Response to Letter Regarding Article, "Association of Leukoaraiosis With Convalescent Rehabilitation Outcome in Patients With Ischemic Stroke". PMID- 26941257 TI - Stroke as the Initial Manifestation of the Human Immunodeficiency Virus. PMID- 26941258 TI - Letter by Toscano et al Regarding Article, "Association of Leukoaraiosis With Convalescent Rehabilitation Outcome in Patients With Ischemic Stroke". PMID- 26941259 TI - Shape of the Central Sulcus and Disability After Subcortical Stroke: A Motor Reserve Hypothesis. AB - BACKGROUND AND PURPOSE: Both brain and cognitive reserves modulate the clinical impact of chronic brain diseases. Whether a motor reserve also modulates the relationships between stroke and disability is unknown. We aimed to determine whether the shape of the central sulcus, a marker of the development of underlying motor connections, is independently associated with disability in patients with a positive history of small subcortical ischemic stroke. METHODS: Shapes of central sulci were reconstructed from high-resolution magnetic resonance imaging and ordered without supervision according to a validated algorithm in 166 patients with a positive history of small subcortical ischemic stroke caused by CADASIL (Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy), a severe monogenic cerebral small vessel disease affecting young patients. Ordinal logistic regression modeling was used to test the relationships between modified Rankin scale, a disability scale strongly weighted toward motor disability, and sulcal shape. RESULTS: Modified Rankin scale was strongly associated with sulcal shape, independent of age, sex, and level of education (proportional odds ratio =1.19, 95% confidence interval =1.06-1.35; P=0.002). Results remained significant after further adjustment for brain atrophy, volume of lacunes, and volume of white matter hyperintensities of presumed vascular origin. CONCLUSIONS: The severity of disability in patients with a positive history of small subcortical ischemic stroke caused by a severe cerebral small vessel disease is related to the shape of the central sulcus, independently of the main determinants of disability. These results support the concept of a motor reserve that could modulate the clinical severity in patients with a positive history of small subcortical ischemic stroke. PMID- 26941260 TI - Stroke and Embolic Events in Hypertrophic Cardiomyopathy: Risk Stratification in Patients Without Atrial Fibrillation. AB - BACKGROUND AND PURPOSE: Stroke and systemic embolic events are known to occur as complications of hypertrophic cardiomyopathy (HCM), and these complications are more common in patients with accompanying atrial fibrillation (AF). The diagnosis of AF is sometimes difficult, however, and it is possible that subclinical asymptomatic paroxysmal episodes or a first episode of AF in patients without previously documented AF may lead to embolic events. We investigated the prevalence of embolic events in patients with HCM and evaluated risk factors for these events in patients without documented AF. METHODS: This study enrolled 593 patients with clinically diagnosed HCM (age at diagnosis, 51.0+/-15.6 years) from 1980 to 2010. RESULTS: During a mean follow-up of 10.7+/-7.5 years, 68 (11.5%) experienced stroke and embolic events. AF had been documented before the event in 29 (42.6%) of them. AF was documented for the first time at the time of the event in 5 (7.4%) and after the event in 10 (14.7%). Among the 431 patients without previously documented AF (39 with events and 392 without events), older age at diagnosis and left atrial dimension >=48 mm were identified as the independent determinants of the embolic event after adjusting for sex and classic prognostic markers related to HCM. CONCLUSIONS: The incidence of stroke and embolic events was about 1.0% per year in the HCM cohort. AF had not been previously documented before the event in more than half of patients with events. Older age and enlarged left atrial dimension are possible risk factors for embolic events in patients with HCM without documented AF. PMID- 26941261 TI - Small molecule inhibitors of the Dishevelled-CXXC5 interaction are new drug candidates for bone anabolic osteoporosis therapy. AB - Bone anabolic agents promoting bone formation and rebuilding damaged bones would ideally overcome the limitations of anti-resorptive therapy, the current standard prescription for osteoporosis. However, the currently prescribed parathyroid hormone (PTH)-based anabolic drugs present limitations and adverse effects including osteosarcoma during long-term use. Also, the antibody-based anabolic drugs that are currently being developed present the potential limits in clinical application typical of macromolecule drugs. We previously identified that CXXC5 is a negative feedback regulator of the Wnt/beta-catenin pathway via its interaction with Dishevelled (Dvl) and suggested the Dvl-CXXC5 interaction as a potential target for anabolic therapy of osteoporosis. Here, we screened small molecule inhibitors of the Dvl-CXXC5 interaction via a newly established in vitro assay system. The screened compounds were found to activate the Wnt/beta-catenin pathway and enhance osteoblast differentiation in primary osteoblasts. The bone anabolic effects of the compounds were shown using ex vivo-cultured calvaria. Nuclear magnetic resonance (NMR) titration analysis confirmed interaction between Dvl PDZ domain and KY-02061, a representative of the screened compounds. Oral administration of KY-02327, one of 55 newly synthesized KY-02061 analogs, successfully rescued bone loss in the ovariectomized (OVX) mouse model. In conclusion, small-molecule inhibitors of the Dvl-CXXC5 interaction that block negative feedback regulation of Wnt/beta-catenin signaling are potential candidates for the development of bone anabolic anti-osteoporosis drugs. PMID- 26941263 TI - Reducing excess mortality due to chronic disease in people with severe mental illness: meta-review of health interventions. AB - BACKGROUND: People with severe mental illness (SMI) have high rates of chronic disease and premature death. AIMS: To explore the strength of evidence for interventions to reduce risk of mortality in people with SMI. METHOD: In a meta review of 16 systematic reviews of controlled studies, mortality was the primary outcome (8 reviews). Physiological health measures (body mass index, weight, glucose levels, lipid profiles and blood pressure) were secondary outcomes (14 reviews). RESULTS: Antipsychotic and antidepressant medications had some protective effect on mortality, subject to treatment adherence. Integrative community care programmes may reduce physical morbidity and excess deaths, but the effective ingredients are unknown. Interventions to improve unhealthy lifestyles and risky behaviours can improve risk factor profiles, but longer follow-up is needed. Preventive interventions and improved medical care for comorbid chronic disease may reduce excess mortality, but data are lacking. CONCLUSIONS: Improved adherence to pharmacological and physical health management guidelines is indicated. PMID- 26941262 TI - sTREM2 cerebrospinal fluid levels are a potential biomarker for microglia activity in early-stage Alzheimer's disease and associate with neuronal injury markers. AB - TREM2 is an innate immune receptor expressed on the surface of microglia. Loss-of function mutations of TREM2 are associated with increased risk of Alzheimer's disease (AD). TREM2 is a type-1 protein with an ectodomain that is proteolytically cleaved and released into the extracellular space as a soluble variant (sTREM2), which can be measured in the cerebrospinal fluid (CSF). In this cross-sectional multicenter study, we investigated whether CSF levels of sTREM2 are changed during the clinical course of AD, and in cognitively normal individuals with suspected non-AD pathology (SNAP). CSF sTREM2 levels were higher in mild cognitive impairment due to AD than in all other AD groups and controls. SNAP individuals also had significantly increased CSF sTREM2 compared to controls. Moreover, increased CSF sTREM2 levels were associated with higher CSF total tau and phospho-tau181P, which are markers of neuronal degeneration and tau pathology. Our data demonstrate that CSF sTREM2 levels are increased in the early symptomatic phase of AD, probably reflecting a corresponding change of the microglia activation status in response to neuronal degeneration. PMID- 26941264 TI - VRK2 gene expression in schizophrenia, bipolar disorder and healthy controls. AB - BACKGROUND: Common variants in the Vaccinia-related kinase 2 (VRK2) gene have been associated with schizophrenia, but the relevance of its encoded protein VRK2 in the disorder remains unclear. AIMS: To identify potential differences in VRK2 gene expression levels between schizophrenia, bipolar disorder, psychosis not otherwise specified (PNOS) and healthy controls. METHOD: VRK2 mRNA level was measured in whole blood in 652 individuals (schizophrenia, n = 201; bipolar disorder, n = 167; PNOS, n = 61; healthy controls, n = 223), and compared across diagnostic categories and subcategories. Additionally, we analysed for association between 1566 VRK2 single nucleotide polymorphisms and mRNA levels. RESULTS: We found lower VRK2 mRNA levels in schizophrenia compared with healthy controls (P<10(-12)), bipolar disorder (P<10(-12)) and PNOS (P = 0.0011), and lower levels in PNOS than in healthy controls (P = 0.0042) and bipolar disorder (P = 0.00026). Expression quantitative trait loci in close proximity to the transcription start site of the short isoforms of the VRK2 gene were identified. CONCLUSIONS: Altered VRK2 gene expression seems specific for schizophrenia and PNOS, which is in accordance with findings from genome-wide association studies. These results suggest that reduced VRK2 mRNA levels are involved in the underlying mechanisms in schizophrenia spectrum disorders. PMID- 26941266 TI - Complement factor H and susceptibility to major depressive disorder in Han Chinese. AB - BACKGROUND: Accumulating evidence suggests that altered immunity contributes to the development of major depressive disorder (MDD). AIMS: To examine whether complement factor H (CFH), a regulator of activation of the alternative pathway of the complement cascade, confers susceptibility to MDD. METHOD: Expression analyses were tested in 53 unmedicated people with MDD and 55 healthy controls. A two-stage genetic association analysis was performed in 3323 Han Chinese with or without MDD. Potential associations between CFH single nucleotide polymorphisms and age at MDD onset were evaluated. RESULTS: CFH levels were significantly lower in the MDD group at both protein and mRNA levels (P = 0.009 and P = 0.014 respectively). A regulatory variant in the CFH gene, rs1061170, showed statistically significant genotypic and allelic differences between the MDD and control groups (genotypic P = 0.0005, allelic P = 0.0001). Kaplan-Meier survival analysis showed that age at onset of MDD was significantly associated with the C allele of rs1061170 (log rank statistic chi(2) = 6.82, P = 0.009). The C-allele carriers had a younger age at onset of MDD (22.2 years, s.d. = 4.0) than those without the C allele (23.6 years, s.d. = 4.3). CONCLUSIONS: CFH is likely to play an important role in the development of MDD. rs1061170 has an important effect on age at onset of MDD in Han Chinese and may therefore be related to early pathogenesis of MDD, although further study is needed. PMID- 26941267 TI - A case of severe leg oedema in a patient with Parkinson's disease treated with pramipexole. PMID- 26941265 TI - Parenting style in childhood and mortality risk at older ages: a longitudinal cohort study. AB - BACKGROUND: Parenting style is associated with offspring health, but whether it is associated with offspring mortality at older ages remains unknown. AIMS: We examined whether childhood experiences of suboptimal parenting style are associated with increased risk of death at older ages. METHOD: Longitudinal cohort study of 1964 community-dwelling adults aged 65-79 years. RESULTS: The association between parenting style and mortality was inverse and graded. Participants in the poorest parenting style score quartile had increased risk of death (hazard ratio (HR) = 1.72, 95% CI 1.20-2.48) compared with those in the optimal parenting style score quartile after adjustment for age and gender. Full adjustment for covariates partially explained this association (HR = 1.49, 95% CI 1.02-2.18). Parenting style was inversely associated with cancer and other mortality, but not cardiovascular mortality. Maternal and paternal parenting styles were individually associated with mortality. CONCLUSIONS: Experiences of suboptimal parenting in childhood are associated with increased risk of death at older ages. PMID- 26941268 TI - No teeth, no nails and not enough tears. PMID- 26941269 TI - Impact of socioeconomic deprivation on mortality in people with haemorrhagic stroke: a population-based cohort study. AB - PURPOSE: Socioeconomic deprivation (SED) has an effect on many health outcomes, including ischaemic stroke; however, its impact on mortality after haemorrhagic stroke remains unclear, particularly in the long run. We examined this association in a multiethnic population in the UK. DESIGN: We examined data from 782 patients with first-ever haemorrhagic stroke, collected by the South London Stroke Register from 1995 to 2011. SED was defined as the quartile with the highest Carstairs scores, and was analysed in relation to mortality after stroke in a multivariate-adjusted Cox regression model. RESULTS: In a follow-up of 17 years, 498 patients died. Compared with the first quartile of Carstairs score (the least deprived), the multivariate-adjusted HRs for 17-year mortality in patients in the second, third and fourth quartiles were 0.94 (95% CI 0.72 to 1.23), 1.17 (95% CI 0.90 to 1.52) and 1.36 (95% CI 1.04 to 1.78), overall p=0.04. The SED gradient association remained in patients with intracerebral haemorrhagic stroke, while in patients with subarachnoid haemorrhagic stroke the corresponding HRs were 2.62 (95% CI 1.22 to 5.64), 3.03 (95% CI 1.49 to 6.18) and 1.83 (95% CI 0.87 to 3.83), respectively. Results of 10-year mortality showed similar patterns, although the association of deprivation with 1-year mortality was not significant. CONCLUSIONS: There is a significant impact of SED on long-term mortality after haemorrhagic stroke. The reasons for this survival inequality must be explored to reduce mortality in patients with haemorrhagic stroke. PMID- 26941270 TI - Changes in the prevalence of HBV infection in pregnant women in Turkey between 1995 and 2015: a 20-year evaluation. AB - OBJECTIVE: To determine changes in hepatitis B virus (HBV) prevalence across three different time periods in pregnant women. METHODS: This was a retrospective study of pregnant women attending four healthcare centres between January 1995 and May 2015. Data for serum hepatitis B surface antigen (HBsAg) and anti-HBs levels were collected from routine antenatal screening records. The 20-year study was divided into three periods: 1995-2001, 2002-2008 and 2009-2015. The results are presented by the women's age and gravidity as possible determinants of HBV infection. RESULTS: 7605 pregnant women (56.0% primigravidae) (mean age 23.4+/ 4.8 years) were tested for markers of HBV infection. 3010 pregnant women were screened between 1995 and 2001, 2995 between 2002 and 2008, and 1600 between 2009 and 2015. The overall prevalence of HBsAg and anti-HBs positivity in the 7605 pregnant women was 1.5% (n=114) and 11.5% (n=877), respectively. Regarding temporal change in the prevalence of HBV markers, HBsAg decreased significantly from 2.6% to 0.8% (p<0.01), while anti-HBs increased significantly from 9.5% to 17.5% (p<0.01), between the first and last study periods. Multigravidae and older women had higher HBsAg and anti-HBs positivity compared to primigravidae. CONCLUSIONS: The data suggest that the prevalence of HBsAg positivity is gradually decreasing among pregnant women, while the level of HBsAg antibody seropositivity is lower than expected. HBV carrier rate increases with increasing age and gravidity. In addition to the national HBV immunisation programme, the prevention of perinatal transmission should also be prioritised to decrease the HBV pool of infection. PMID- 26941271 TI - Statin treatment is associated with a decreased risk of active tuberculosis: an analysis of a nationally representative cohort. AB - BACKGROUND: Epidemiological data suggest that statins improve the clinical outcome of respiratory infections. We sought to examine whether statin therapy decreases the risk of active TB. METHODS: We conducted a nested case-control study on data obtained from a national health insurance claims database between 1999 and 2011. The use of statins was classified as current, recent, past or chronic use. Three conditional logistic regression models were used to estimate the incidence rate ratios (RRs). The first assessed the effect of statin use without further adjustment; the second adjusted (individually) for 75 potential confounders; and the third adjusted for the Disease Risk Score (DRS). RESULTS: A total of 8098 new TB cases and 809 800 control patients were examined. All four types of statin users showed a decreased risk of active TB. Chronic use (>90 days in a calendar year) of statins was associated with the lowest unadjusted risk of TB (RR 0.74; 95% CI 0.63 to 0.87). The protective effect of active TB remained after adjusting for individual confounders (RR 0.66; 95% CI 0.56 to 0.78) and after DRS adjustment (RR 0.62; 95% CI 0.53 to 0.72). The effect estimates obtained for chronic and current use of statins were very similar. We also found that the active TB protection increased with increasing length of statin prescription. CONCLUSIONS: We found that statin therapy was associated with a decreased risk of active TB, and the length of statin therapy affected the TB protection. Given the observational nature of this study, the protective effect against active TB must be confirmed in future randomised trials. PMID- 26941272 TI - Unilateral vanishing lung syndrome. PMID- 26941273 TI - Osseous injuries of the foot: an imaging review. Part 3: the hindfoot. AB - Injuries to the foot are a common cause for presentation to the emergency department, and imaging is often used to aid in the diagnosis. The foot can be divided into three distinct anatomic regions: the forefoot, midfoot and hindfoot. Our manuscripts comprise a three-part imaging review in which we address the use of radiography as well as advanced imaging modalities. We provide pearls to radiographic interpretation and discuss prognostic implications and classification systems. Part 1 addresses forefoot injuries, part 2 reviews midfoot injuries and part 3 covers the hindfoot. PMID- 26941274 TI - Osseous injuries of the foot: an imaging review. Part 1: the forefoot. AB - Injuries to the foot are a common cause for presentation to the ED, and imaging is often used to aid in the diagnosis. The foot can be divided into three distinct anatomical regions: the forefoot, midfoot and hindfoot. Our manuscripts comprise a three-part imaging review in which we address the use of radiography as well as advanced imaging modalities. We provide pearls to radiographic interpretation and discuss prognostic implications and classification systems. Part 1 addresses forefoot injuries, part 2 reviews midfoot injuries and part 3 covers the hindfoot. PMID- 26941275 TI - Osseous injuries of the foot: an imaging review. Part 2: the midfoot. AB - Injuries to the foot are a common cause for presentation to the emergency department (ED), and imaging is often used to aid in the diagnosis. The foot can be divided into three distinct anatomic regions: the forefoot, midfoot and hindfoot. Our manuscripts comprise a three-part imaging review in which we address the use of radiography as well as advanced imaging modalities. We provide pearls to radiographic interpretation and discuss prognostic implications and classification systems. Part 1 addressed forefoot injuries, Part 2 reviews midfoot injuries and Part 3 covers the hindfoot. PMID- 26941276 TI - Hypothesised mechanisms of swimming-related death: a systematic review. AB - BACKGROUND: Recent reports from triathlon and competitive open-water swimming indicate that these events have higher rates of death compared with other forms of endurance sport. The potential causal mechanism for swimming-related death is unclear. OBJECTIVE: To examine available studies on the hypothesised mechanisms of swimming-related death to determine the most likely aetiologies. MATERIAL AND METHODS: MEDLINE, EMBASE and the Cochrane Database of Systematic Reviews (1950 to present) were searched, yielding 1950 potential results, which after title and citation reviews were reduced to 83 possible reports. Studies included discussed mechanisms of death during swimming in humans, and were Level 4 evidence or higher. RESULTS: A total of 17 studies (366 total swimmers) were included for further analysis: 5 investigating hyperthermia/hypothermia, 7 examining cardiac mechanisms and responses, and 5 determining the presence of pulmonary edema. The studies provide inconsistent and limited-quality or disease-oriented evidence that make definitive conclusions difficult. CONCLUSIONS: The available evidence is limited but may suggest that cardiac arrhythmias are the most likely aetiology of swimming-related death. While symptoms of pulmonary edema may occur during swimming, current evidence does not support swimming-induced pulmonary edema as a frequent cause of swimming-related death, nor is there evidence to link hypothermia or hyperthermia as a causal mechanism. Further higher level studies are needed. PMID- 26941277 TI - It is time to give concussion an operational definition: a 3-step process to diagnose (or rule out) concussion within 48 h of injury: World Rugby guideline. PMID- 26941278 TI - Training-related and competition-related risk factors for respiratory tract and gastrointestinal infections in elite cross-country skiers. AB - AIM: To examine symptoms indicative of respiratory tract and gastrointestinal infections and determine risk factors for such symptoms in elite cross-country skiers. METHODS: Self-reported training and symptom data for 37 elite cross country skiers from 2007 to 2015 were analysed using multilevel logistic regression equations with symptom incidence and duration as outcome variables, and sex, performance level, season, competition, air travel, altitude exposure and training characteristics as independent variables. RESULTS: Data for 7016 person-weeks were analysed, including 464 self-reported infection events and 110 959 h of training. Athletes reported median (range) 3 (1-7) respiratory tract and/or gastrointestinal events per year, with symptoms lasting 5 (1-24) days. During the winter, symptoms occurred more frequently (OR 2.09, p<0.001) and lasted longer (b=0.043, p<0.001) compared with summer. Competition and air travel increased the risk of symptoms, with ORs of 2.93 (95% CI 2.24 to 3.83) and 4.94 (95% CI 3.74 to 6.53), respectively (p<0.001). Athletes with higher training monotony had lower risk of symptoms (OR 0.87 (95% CI 0.73 to 0.99), p<0.05). Other training variables were not associated with symptoms. Athletes who had won an Olympic/World Championship medal reported shorter symptom duration compared with less successful athletes (b=-0.019, p<0.05) resulting in significantly fewer symptomatic days/year (14 (6-29) vs 22 (8-43) days/year). CONCLUSIONS: Air travel and competition are major risk factors for acute respiratory tract and gastrointestinal symptoms in this population. Athletes who have large fluctuations in training load experience such symptoms more frequently. Shorter duration of symptoms appears to be associated with success in cross-country skiing. PMID- 26941279 TI - Is workload associated with injuries and performance in elite football? A call for action. PMID- 26941280 TI - Ligand binding to the PDZ domains of postsynaptic density protein 95. AB - Cellular scaffolding and signalling is generally governed by multidomain proteins, where each domain has a particular function. Postsynaptic density protein 95 (PSD-95) is involved in synapse formation and is a typical example of such a multidomain protein. Protein-protein interactions of PSD-95 are well studied and include the following three protein ligands: (i)N-methyl-d-aspartate type ionotropic glutamate receptor subunit GluN2B, (ii) neuronal nitric oxide synthase and (iii) cysteine-rich protein (CRIPT), all of which bind to one or more of the three PDZ domains in PSD-95. While interactions for individual PDZ domains of PSD-95 have been well studied, less is known about the influence of neighbouring domains on the function of the respective individual domain. We therefore performed a systematic study on the ligand-binding kinetics of PSD-95 using constructs of different size for PSD-95 and its ligands. Regarding the canonical peptide-binding pocket and relatively short peptides (up to 15-mer), the PDZ domains in PSD-95 by and large work as individual binding modules. However, in agreement with previous studies, residues outside of the canonical binding pocket modulate the affinity of the ligands. In particular, the dissociation of the 101 amino acid CRIPT from PSD-95 is slowed down at least 10 fold for full-length PSD-95 when compared with the individual PDZ3 domain. PMID- 26941281 TI - History of AIDS in HIV-Infected Patients Is Associated With Higher In-Hospital Mortality Following Admission for Acute Myocardial Infarction and Stroke. AB - BACKGROUND: Although human immunodeficiency virus (HIV)-infected persons are at increased risk for major cardiovascular events, short-term prognosis after these events is unclear. METHODS: To determine the association between HIV infection and acute myocardial infarction (AMI) and stroke outcomes, we analyzed hospital discharge data from the Nationwide Inpatient Sample (NIS) between 2002 and 2012. Multivariable logistic regression was used to evaluate the association between HIV infection and in-hospital death after AMI or stroke. RESULTS: Overall, 18 369 785 AMI/stroke hospitalizations were included in the analysis. Patients with a history of AIDS were significantly more likely than uninfected patients to die during hospitalization after admission for AMI or stroke (odds ratio, 3.03 [95% confidence interval {CI}, 1.71-5.38] for AMI and 2.59 [95% CI, 1.97-3.41] for stroke). Additionally, patients with AIDS were more likely than HIV-uninfected patients to be discharged to nonhospital inpatient facilities after admission for AMI (OR, 3.14 [95% CI, 1.72-5.74]) or stroke (OR, 1.45; 95% CI, 1.12-1.87). There was a minimal difference in either outcome between HIV-infected patients without a history of AIDS and uninfected patients. CONCLUSIONS: Patients with a history of AIDS were significantly more likely than uninfected patients to die during hospitalization after admission for AMI or stroke. This disparity was not observed when infected patients without a history of AIDS were compared to uninfected patients, implying that preserving immune function may improve cardiovascular outcomes in HIV-infected persons. PMID- 26941282 TI - Analysis of Mutations in the Gene Encoding Cytomegalovirus DNA Polymerase in a Phase 2 Clinical Trial of Brincidofovir Prophylaxis. AB - Brincidofovir is an oral antiviral in development for prevention of cytomegalovirus disease. Cytomegalovirus genotyping results from a phase 2 trial comparing brincidofovir to placebo for prophylaxis against cytomegalovirus infection in hematopoietic cell transplant recipients provided initial data on the clinical resistance profile for brincidofovir. In this study, no known resistance-associated mutations were detected in brincidofovir-treated subjects; identified genotypic substitutions did not confer resistance to cytomegalovirus antivirals in vitro, suggesting that these changes represent polymorphisms unrelated to brincidofovir resistance. Lack of evidence for genotypic resistance during prophylaxis suggests that first-line use of brincidofovir for prevention of cytomegalovirus infection may preserve downstream options for patients. PMID- 26941283 TI - Prophylaxis With a Middle East Respiratory Syndrome Coronavirus (MERS-CoV) Specific Human Monoclonal Antibody Protects Rabbits From MERS-CoV Infection. AB - With >1600 documented human infections with Middle East respiratory syndrome coronavirus (MERS-CoV) and a case fatality rate of approximately 36%, medical countermeasures are needed to prevent and limit the disease. We examined the in vivo efficacy of the human monoclonal antibody m336, which has high neutralizing activity against MERS-CoV in vitro. m336 was administered to rabbits intravenously or intranasally before infection with MERS-CoV. Prophylaxis with m336 resulted in a reduction of pulmonary viral RNA titers by 40-9000-fold, compared with an irrelevant control antibody with little to no inflammation or viral antigen detected. This protection in rabbits supports further clinical development of m336. PMID- 26941284 TI - Single-Cell Sequencing for Precise Cancer Research: Progress and Prospects. AB - Advances in genomic technology have enabled the faithful detection and measurement of mutations and the gene expression profile of cancer cells at the single-cell level. Recently, several single-cell sequencing methods have been developed that permit the comprehensive and precise analysis of the cancer-cell genome, transcriptome, and epigenome. The use of these methods to analyze cancer cells has led to a series of unanticipated discoveries, such as the high heterogeneity and stochastic changes in cancer-cell populations, the new driver mutations and the complicated clonal evolution mechanisms, and the novel identification of biomarkers of variant tumors. These methods and the knowledge gained from their utilization could potentially improve the early detection and monitoring of rare cancer cells, such as circulating tumor cells and disseminated tumor cells, and promote the development of personalized and highly precise cancer therapy. Here, we discuss the current methods for single cancer-cell sequencing, with a strong focus on those practically used or potentially valuable in cancer research, including single-cell isolation, whole genome and transcriptome amplification, epigenome profiling, multi-dimensional sequencing, and next-generation sequencing and analysis. We also examine the current applications, challenges, and prospects of single cancer-cell sequencing. PMID- 26941285 TI - Genomic Profiling of Pediatric Acute Myeloid Leukemia Reveals a Changing Mutational Landscape from Disease Diagnosis to Relapse. AB - The genomic and clinical information used to develop and implement therapeutic approaches for acute myelogenous leukemia (AML) originated primarily from adult patients and has been generalized to patients with pediatric AML. However, age specific molecular alterations are becoming more evident and may signify the need to age-stratify treatment regimens. The NCI/COG TARGET-AML initiative used whole exome capture sequencing (WXS) to interrogate the genomic landscape of matched trios representing specimens collected upon diagnosis, remission, and relapse from 20 cases of de novo childhood AML. One hundred forty-five somatic variants at diagnosis (median 6 mutations/patient) and 149 variants at relapse (median 6.5 mutations) were identified and verified by orthogonal methodologies. Recurrent somatic variants [in (greater than or equal to) 2 patients] were identified for 10 genes (FLT3, NRAS, PTPN11, WT1, TET2, DHX15, DHX30, KIT, ETV6, KRAS), with variable persistence at relapse. The variant allele fraction (VAF), used to measure the prevalence of somatic mutations, varied widely at diagnosis. Mutations that persisted from diagnosis to relapse had a significantly higher diagnostic VAF compared with those that resolved at relapse (median VAF 0.43 vs. 0.24, P < 0.001). Further analysis revealed that 90% of the diagnostic variants with VAF >0.4 persisted to relapse compared with 28% with VAF <0.2 (P < 0.001). This study demonstrates significant variability in the mutational profile and clonal evolution of pediatric AML from diagnosis to relapse. Furthermore, mutations with high VAF at diagnosis, representing variants shared across a leukemic clonal structure, may constrain the genomic landscape at relapse and help to define key pathways for therapeutic targeting. Cancer Res; 76(8); 2197 205. (c)2016 AACR. PMID- 26941288 TI - Cancer Differentiating Agent Hexamethylene Bisacetamide Inhibits BET Bromodomain Proteins. AB - Agents that trigger cell differentiation are highly efficacious in treating certain cancers, but such approaches are not generally effective in most malignancies. Compounds such as DMSO and hexamethylene bisacetamide (HMBA) have been used to induce differentiation in experimental systems, but their mechanisms of action and potential range of uses on that basis have not been developed. Here, we show that HMBA, a compound first tested in the oncology clinic over 25 years ago, acts as a selective bromodomain inhibitor. Biochemical and structural studies revealed an affinity of HMBA for the second bromodomain of BET proteins. Accordingly, both HMBA and the prototype BET inhibitor JQ1 induced differentiation of mouse erythroleukemia cells. As expected of a BET inhibitor, HMBA displaced BET proteins from chromatin, caused massive transcriptional changes, and triggered cell-cycle arrest and apoptosis in Myc-induced B-cell lymphoma cells. Furthermore, HMBA exerted anticancer effects in vivo in mouse models of Myc-driven B-cell lymphoma. This study illuminates the function of an early anticancer agent and suggests an intersection with ongoing clinical trials of BET inhibitor, with several implications for predicting patient selection and response rates to this therapy and starting points for generating BD2-selective BET inhibitors. Cancer Res; 76(8); 2376-83. (c)2016 AACR. PMID- 26941287 TI - The Proliferative Activity of Mammary Epithelial Cells in Normal Tissue Predicts Breast Cancer Risk in Premenopausal Women. AB - The frequency and proliferative activity of tissue-specific stem and progenitor cells are suggested to correlate with cancer risk. In this study, we investigated the association between breast cancer risk and the frequency of mammary epithelial cells expressing p27, estrogen receptor (ER), and Ki67 in normal breast tissue. We performed a nested case-control study of 302 women (69 breast cancer cases, 233 controls) who had been initially diagnosed with benign breast disease according to the Nurses' Health Studies. Immunofluorescence for p27, ER, and Ki67 was performed on tissue microarrays constructed from benign biopsies containing normal mammary epithelium and scored by computational image analysis. We found that the frequency of Ki67(+) cells was positively associated with breast cancer risk among premenopausal women [OR = 10.1, 95% confidence interval (CI) = 2.12-48.0]. Conversely, the frequency of ER(+) or p27(+) cells was inversely, but not significantly, associated with subsequent breast cancer risk (ER(+): OR = 0.70, 95% CI, 0.33-1.50; p27(+): OR = 0.89, 95% CI, 0.45-1.75). Notably, high Ki67(+)/low p27(+) and high Ki67(+)/low ER(+) cell frequencies were significantly associated with a 5-fold higher risk of breast cancer compared with low Ki67(+)/low p27(+) and low Ki67(+)/low ER(+) cell frequencies, respectively, among premenopausal women (Ki67(hi)/p27(lo): OR = 5.08, 95% CI, 1.43-18.1; Ki67(hi)/ER(lo): OR = 4.68, 95% CI, 1.63-13.5). Taken together, our data suggest that the fraction of actively cycling cells in normal breast tissue may represent a marker for breast cancer risk assessment, which may therefore impact the frequency of screening procedures in at-risk women. Cancer Res; 76(7); 1926-34. (c)2016 AACR. PMID- 26941286 TI - Genomic Loss of DUSP4 Contributes to the Progression of Intraepithelial Neoplasm of Pancreas to Invasive Carcinoma. AB - The progression from precursor lesions of pancreatic cancer, including pancreatic intraepithelial neoplasia and intraductal papillary mucinous neoplasm (IPMN), to invasive disease is characterized by stepwise accumulation of genetic alterations. However, it remains unclear whether additional alterations are required for the progression of high-grade neoplasms to invasive pancreatic carcinoma. We compared the genomic profiles of paired noninvasive and invasive carcinoma tissues collected from patients with IPMN. We demonstrate that the frequency of genomic copy-number aberrations significantly increased during the course of invasion, and the loss of 8p11.22-ter was more often associated with invasive tissues. Expression profiling in pancreatic cancer cell lines with and without 8p11.22-ter revealed that DUSP4, an MAPK phosphatase, was significantly downregulated in cells lacking 8p11.22-ter as well as in invasive carcinomas due to genomic loss. Restoration of DUSP4 expression in pancreatic cancer cells significantly suppressed invasiveness and anoikis resistance via ERK inactivation. Accordingly, we found that blockade of ERK signaling by MEK inhibition was effective in an orthotopic xenograft model and significantly extended survival. Collectively, our findings demonstrate a genetic mechanism by which pancreatic precursor lesions progress to invasive carcinomas and highlight DUSP4 as a novel invasion suppressor that can be therapeutically exploited through manipulation of ERK signaling. Cancer Res; 76(9); 2612-25. (c)2016 AACR. PMID- 26941289 TI - An interdisciplinary approach to better assess global change impacts and drought vulnerability on forest dynamics. PMID- 26941290 TI - Transgenic poplar overexpressing the endogenous transcription factor ERF76 gene improves salinity tolerance. AB - The ethylene response factor (ERF) family is one of the largest plant-specific transcription factor families, playing an important role in plant development and response to stresses. The ERF76 gene is a member of the poplar ERF transcription factor gene family. First, we validated that the ERF76 gene expressed in leaf and root tissues is responsive to salinity stress. We then successfully cloned the ERF76 cDNA fragment containing an open reading frame from di-haploid Populus simonii * Populus nigra and proved that ERF76 protein is targeted to the nucleus. Finally, we transferred the gene into the same poplar clone by the Agrobacterium mediated leaf disc method. Using both RNA-Seq and reverse transcription quantitative polymerase chain reaction, we validated that expression level of ERF76 is significantly higher in transgenic plants than that in the nontransgenic control. Using RNA-Seq data, we have identified 375 genes that are differentially expressed between the transgenic plants and the control under salt treatment. Among the differentially expressed genes, 16 are transcription factor genes and 45 are stress-related genes, both of which are upregulated significantly in transgenic plants, compared with the control. Under salt stress, the transgenic plants showed significant increases in plant height, root length, fresh weight, and abscisic acid (ABA) and gibberellin (GA) concentration compared with the control, suggesting that overexpression of ERF76 in transgenic poplar upregulated the expression of stress-related genes and increased the ability of ABA and GA biosynthesis, which resulted in stronger tolerance to salt stress. PMID- 26941292 TI - #IAmAResearchParasite. PMID- 26941291 TI - Monitoring intra-annual dynamics of wood formation with microcores and dendrometers in Picea abies at two different altitudes. AB - Seasonal analyses of cambial cell production and day-by-day stem radial increment can help to elucidate how climate modulates wood formation in conifers. Intra annual dynamics of wood formation were determined with microcores and dendrometers and related to climatic signals in Norway spruce (Picea abies (L.) Karst.). The seasonal dynamics of these processes were observed at two sites of different altitude, Savignano (650 m a.s.l.) and Lavaze (1800 m a.s.l.) in the Italian Alps. Seasonal dynamics of cambial activity were found to be site specific, indicating that the phenology of cambial cell production is highly variable and plastic with altitude. There was a site-specific trend in the number of cells in the wall thickening phase, with the maximum cell production in early July (DOY 186) at Savignano and in mid-July (DOY 200) at Lavaze. The formation of mature cells showed similar trends at the two sites, although different numbers of cells and timing of cell differentiation were visible in the model shapes; at the end of ring formation in 2010, the number of cells was four times higher at Savignano (106.5 cells) than at Lavaze (26.5 cells). At low altitudes, microcores and dendrometers described the radial growth patterns comparably, though the dendrometer function underlined the higher upper asymptote of maximum growth in comparison with the cell production function. In contrast, at high altitude, these functions exhibited different trends. The best model was obtained by fitting functions of the Gompertz model to the experimental data. By combining radial growth and cambial activity indices we defined a model system able to synchronize these processes. Processes of adaptation of the pattern of xylogenesis occurred, enabling P. abies to occupy sites with contrasting climatic conditions. The use of daily climatic variables in combination with plant functional traits obtained by sensors and/or destructive sampling could provide a suitable tool to better investigate the effect of disturbances on response strategies in trees and, consequently, contribute to improving our prediction of tree growth and species resilience based on climate scenarios. PMID- 26941294 TI - RADIO ASTRONOMY. Fast radio bursts tease astronomers. PMID- 26941295 TI - INFECTIOUS DISEASE. 'Patient Zero' no more. PMID- 26941296 TI - SCIENTIFIC INTEGRITY. Survey fraud test sparks battle. PMID- 26941297 TI - PLANETARY SCIENCE. Scientists to drill into dinosaur-killing blast. PMID- 26941298 TI - SCIENTIFIC WORKFORCE. NSF makes a new bid to boost diversity. PMID- 26941299 TI - Slow burn. PMID- 26941300 TI - Trial by meltdown. PMID- 26941301 TI - Epidemic of fear. PMID- 26941302 TI - RESEARCH INTEGRITY. Liberating field science samples and data. PMID- 26941303 TI - PHYSICS. Electrons go with the flow in exotic material systems. PMID- 26941304 TI - NEUROSCIENCE. Wiring the altruistic brain. PMID- 26941306 TI - CHEMISTRY. Surprised by selectivity. PMID- 26941305 TI - GENETICS. A copy-and-paste gene regulatory network. PMID- 26941307 TI - IMMUNOLOGY. An RNA twist to T(H)17 cells. PMID- 26941308 TI - Seeing the grasslands through the trees. PMID- 26941309 TI - Seeing the grasslands through the trees--Response. PMID- 26941310 TI - Government: Plan for ecosystem services. PMID- 26941311 TI - Comment on "Estimating the reproducibility of psychological science". AB - A paper from the Open Science Collaboration (Research Articles, 28 August 2015, aac4716) attempting to replicate 100 published studies suggests that the reproducibility of psychological science is surprisingly low. We show that this article contains three statistical errors and provides no support for such a conclusion. Indeed, the data are consistent with the opposite conclusion, namely, that the reproducibility of psychological science is quite high. PMID- 26941312 TI - Response to Comment on "Estimating the reproducibility of psychological science". AB - Gilbert et al. conclude that evidence from the Open Science Collaboration's Reproducibility Project: Psychology indicates high reproducibility, given the study methodology. Their very optimistic assessment is limited by statistical misconceptions and by causal inferences from selectively interpreted, correlational data. Using the Reproducibility Project: Psychology data, both optimistic and pessimistic conclusions about reproducibility are possible, and neither are yet warranted. PMID- 26941314 TI - Selective conversion of syngas to light olefins. AB - Although considerable progress has been made in direct synthesis gas (syngas) conversion to light olefins (C2(=)-C4(=)) via Fischer-Tropsch synthesis (FTS), the wide product distribution remains a challenge, with a theoretical limit of only 58% for C2-C4 hydrocarbons. We present a process that reaches C2(=)-C4(=) selectivity as high as 80% and C2-C4 94% at carbon monoxide (CO) conversion of 17%. This is enabled by a bifunctional catalyst affording two types of active sites with complementary properties. The partially reduced oxide surface (ZnCrO(x)) activates CO and H2, and C-C coupling is subsequently manipulated within the confined acidic pores of zeolites. No obvious deactivation is observed within 110 hours. Furthermore, this composite catalyst and the process may allow use of coal- and biomass-derived syngas with a low H2/CO ratio. PMID- 26941313 TI - Cryo-EM structure of a native, fully glycosylated, cleaved HIV-1 envelope trimer. AB - The envelope glycoprotein trimer (Env) on the surface of HIV-1 recognizes CD4(+) T cells and mediates viral entry. During this process, Env undergoes substantial conformational rearrangements, making it difficult to study in its native state. Soluble stabilized trimers have provided valuable insights into the Env structure, but they lack the hydrophobic membrane proximal external region (MPER, an important target of broadly neutralizing antibodies), the transmembrane domain, and the cytoplasmic tail. Here we present (i) a cryogenic electron microscopy (cryo-EM) structure of a clade B virus Env, which lacks only the cytoplasmic tail and is stabilized by the broadly neutralizing antibody PGT151, at a resolution of 4.2 angstroms and (ii) a reconstruction of this form of Env in complex with PGT151 and MPER-targeting antibody 10E8 at a resolution of 8.8 angstroms. These structures provide new insights into the wild-type Env structure. PMID- 26941315 TI - Realization of a scalable Shor algorithm. AB - Certain algorithms for quantum computers are able to outperform their classical counterparts. In 1994, Peter Shor came up with a quantum algorithm that calculates the prime factors of a large number vastly more efficiently than a classical computer. For general scalability of such algorithms, hardware, quantum error correction, and the algorithmic realization itself need to be extensible. Here we present the realization of a scalable Shor algorithm, as proposed by Kitaev. We factor the number 15 by effectively employing and controlling seven qubits and four "cache qubits" and by implementing generalized arithmetic operations, known as modular multipliers. This algorithm has been realized scalably within an ion-trap quantum computer and returns the correct factors with a confidence level exceeding 99%. PMID- 26941316 TI - Highly stretchable electroluminescent skin for optical signaling and tactile sensing. AB - Cephalopods such as octopuses have a combination of a stretchable skin and color tuning organs to control both posture and color for visual communication and disguise. We present an electroluminescent material that is capable of large uniaxial stretching and surface area changes while actively emitting light. Layers of transparent hydrogel electrodes sandwich a ZnS phosphor-doped dielectric elastomer layer, creating thin rubber sheets that change illuminance and capacitance under deformation. Arrays of individually controllable pixels in thin rubber sheets were fabricated using replica molding and were subjected to stretching, folding, and rolling to demonstrate their use as stretchable displays. These sheets were then integrated into the skin of a soft robot, providing it with dynamic coloration and sensory feedback from external and internal stimuli. PMID- 26941317 TI - The brain's functional network architecture reveals human motives. AB - Goal-directed human behaviors are driven by motives. Motives are, however, purely mental constructs that are not directly observable. Here, we show that the brain's functional network architecture captures information that predicts different motives behind the same altruistic act with high accuracy. In contrast, mere activity in these regions contains no information about motives. Empathy based altruism is primarily characterized by a positive connectivity from the anterior cingulate cortex (ACC) to the anterior insula (AI), whereas reciprocity based altruism additionally invokes strong positive connectivity from the AI to the ACC and even stronger positive connectivity from the AI to the ventral striatum. Moreover, predominantly selfish individuals show distinct functional architectures compared to altruists, and they only increase altruistic behavior in response to empathy inductions, but not reciprocity inductions. PMID- 26941318 TI - Regulatory evolution of innate immunity through co-option of endogenous retroviruses. AB - Endogenous retroviruses (ERVs) are abundant in mammalian genomes and contain sequences modulating transcription. The impact of ERV propagation on the evolution of gene regulation remains poorly understood. We found that ERVs have shaped the evolution of a transcriptional network underlying the interferon (IFN) response, a major branch of innate immunity, and that lineage-specific ERVs have dispersed numerous IFN-inducible enhancers independently in diverse mammalian genomes. CRISPR-Cas9 deletion of a subset of these ERV elements in the human genome impaired expression of adjacent IFN-induced genes and revealed their involvement in the regulation of essential immune functions, including activation of the AIM2 inflammasome. Although these regulatory sequences likely arose in ancient viruses, they now constitute a dynamic reservoir of IFN-inducible enhancers fueling genetic innovation in mammalian immune defenses. PMID- 26941319 TI - Expression homeostasis during DNA replication. AB - Genome replication introduces a stepwise increase in the DNA template available for transcription. Genes replicated early in S phase experience this increase before late-replicating genes, raising the question of how expression levels are affected by DNA replication. We show that in budding yeast, messenger RNA (mRNA) synthesis rate is buffered against changes in gene dosage during S phase. This expression homeostasis depends on acetylation of H3 on its internal K56 site by Rtt109/Asf1. Deleting these factors, mutating H3K56 or up-regulating its deacetylation, increases gene expression in S phase in proportion to gene replication timing. Therefore, H3K56 acetylation on newly deposited histones reduces transcription efficiency from replicated DNA, complementing its role in guarding genome stability. Our study provides molecular insight into the mechanism maintaining expression homeostasis during DNA replication. PMID- 26941320 TI - Multiplexed protein-DNA cross-linking: Scrunching in transcription start site selection. AB - In bacterial transcription initiation, RNA polymerase (RNAP) selects a transcription start site (TSS) at variable distances downstream of core promoter elements. Using next-generation sequencing and unnatural amino acid-mediated protein-DNA cross-linking, we have determined, for a library of 4(10) promoter sequences, the TSS, the RNAP leading-edge position, and the RNAP trailing-edge position. We find that a promoter element upstream of the TSS, the "discriminator," participates in TSS selection, and that, as the TSS changes, the RNAP leading-edge position changes, but the RNAP trailing-edge position does not change. Changes in the RNAP leading-edge position, but not the RNAP trailing-edge position, are a defining hallmark of the "DNA scrunching" that occurs concurrent with RNA synthesis in initial transcription. We propose that TSS selection involves DNA scrunching prior to RNA synthesis. PMID- 26941322 TI - Making a game of science. PMID- 26941321 TI - Stochastic activation of a DNA damage response causes cell-to-cell mutation rate variation. AB - Cells rely on the precise action of proteins that detect and repair DNA damage. However, gene expression noise causes fluctuations in protein abundances that may compromise repair. For the Ada protein in Escherichia coli, which induces its own expression upon repairing DNA alkylation damage, we found that undamaged cells on average produce one Ada molecule per generation. Because production is stochastic, many cells have no Ada molecules and cannot induce the damage response until the first expression event occurs, which sometimes delays the response for generations. This creates a subpopulation of cells with increased mutation rates. Nongenetic variation in protein abundances thus leads to genetic heterogeneity in the population. Our results further suggest that cells balance reliable repair against toxic side effects of abundant DNA repair proteins. PMID- 26941325 TI - Erratum for the Review "Somatic mutation in cancer and normal cells" by I. Martincorena and P. J. Campbell. PMID- 26941323 TI - Activation of PKA leads to mesenchymal-to-epithelial transition and loss of tumor initiating ability. AB - The epithelial-to-mesenchymal transition enables carcinoma cells to acquire malignancy-associated traits and the properties of tumor-initiating cells (TICs). TICs have emerged in recent years as important targets for cancer therapy, owing to their ability to drive clinical relapse and enable metastasis. Here, we propose a strategy to eliminate mesenchymal TICs by inducing their conversion to more epithelial counterparts that have lost tumor-initiating ability. We report that increases in intracellular levels of the second messenger, adenosine 3',5' monophosphate, and the subsequent activation of protein kinase A (PKA) induce a mesenchymal-to-epithelial transition (MET) in mesenchymal human mammary epithelial cells. PKA activation triggers epigenetic reprogramming of TICs by the histone demethylase PHF2, which promotes their differentiation and loss of tumor initiating ability. This study provides proof-of-principle for inducing an MET as differentiation therapy for TICs and uncovers a role for PKA in enforcing and maintaining the epithelial state. PMID- 26941324 TI - Spiking neurons can discover predictive features by aggregate-label learning. AB - The brain routinely discovers sensory clues that predict opportunities or dangers. However, it is unclear how neural learning processes can bridge the typically long delays between sensory clues and behavioral outcomes. Here, I introduce a learning concept, aggregate-label learning, that enables biologically plausible model neurons to solve this temporal credit assignment problem. Aggregate-label learning matches a neuron's number of output spikes to a feedback signal that is proportional to the number of clues but carries no information about their timing. Aggregate-label learning outperforms stochastic reinforcement learning at identifying predictive clues and is able to solve unsegmented speech recognition tasks. Furthermore, it allows unsupervised neural networks to discover reoccurring constellations of sensory features even when they are widely dispersed across space and time. PMID- 26941326 TI - The far C-terminus of MCAK regulates its conformation and spindle pole focusing. AB - To ensure proper spindle assembly, microtubule (MT) dynamics needs to be spatially regulated within the cell. The kinesin-13 MCAK is a potent MT depolymerase with a complex subcellular localization, yet how MCAK spatial regulation contributes to spindle assembly is not understood. Here we show that the far C-terminus of MCAK plays a critical role in regulating MCAK conformation, subspindle localization, and spindle assembly in Xenopus egg extracts. Alteration of MCAK conformation by the point mutation E715A/E716A in the far C-terminus increased MCAK targeting to the poles and reduced MT lifetimes, which induced spindles with unfocused poles. These effects were phenocopied by the Aurora A phosphomimetic mutation, S719E. Furthermore, addition of the kinesin-14 XCTK2 to spindle assembly reactions rescued the unfocused-pole phenotype. Collectively our work shows how the regional targeting of MCAK regulates MT dynamics, highlighting the idea that multiple phosphorylation pathways of MCAK cooperate to spatially control MT dynamics to maintain spindle architecture. PMID- 26941327 TI - Unique epigenetic influence of H2AX phosphorylation and H3K56 acetylation on normal stem cell radioresponses. AB - Normal tissue injury resulting from cancer radiotherapy is often associated with diminished regenerative capacity. We examined the relative radiosensitivity of normal stem cell populations compared with non-stem cells within several radiosensitive tissue niches and culture models. We found that these stem cells are highly radiosensitive, in contrast to their isogenic differentiated progeny. Of interest, they also exhibited a uniquely attenuated DNA damage response (DDR) and muted DNA repair. Whereas stem cells exhibit reduced ATM activation and ionizing radiation-induced foci, they display apoptotic pannuclear H2AX-S139 phosphorylation (gammaH2AX), indicating unique radioresponses. We also observed persistent phosphorylation of H2AX-Y142 along the DNA breaks in stem cells, which promotes apoptosis while inhibiting DDR signaling. In addition, down-regulation of constitutively elevated histone-3 lysine-56 acetylation (H3K56ac) in stem cells significantly decreased their radiosensitivity, restored DDR function, and increased survival, signifying its role as a key contributor to stem cell radiosensitivity. These results establish that unique epigenetic landscapes affect cellular heterogeneity in radiosensitivity and demonstrate the nonubiquitous nature of radiation responses. We thus elucidate novel epigenetic rheostats that promote ionizing radiation hypersensitivity in various normal stem cell populations, identifying potential molecular targets for pharmacological radioprotection of stem cells and hopefully improving the efficacy of future cancer treatment. PMID- 26941328 TI - Reciprocal autoregulation by NFI occupancy and ETV1 promotes the developmental expression of dendrite-synapse genes in cerebellar granule neurons. AB - Nuclear Factor One (NFI) transcription factors regulate temporal gene expression required for dendritogenesis and synaptogenesis via delayed occupancy of target promoters in developing cerebellar granule neurons (CGNs). Mechanisms that promote NFI temporal occupancy have not been previously defined. We show here that the transcription factor ETV1 directly binds to and is required for expression and NFI occupancy of a cohort of NFI-dependent genes in CGNs maturing in vivo. Expression of ETV1 is low in early postnatal cerebellum and increases with maturation, mirroring NFI temporal occupancy of coregulated target genes. Precocious expression of ETV1 in mouse CGNs accelerated onset of expression and NFI temporal occupancy of late target genes and enhanced Map2(+) neurite outgrowth. ETV1 also activated expression and NFI occupancy of the Etv1 gene itself, and this autoregulatory loop preceded ETV1 binding and activation of other coregulated target genes in vivo. These findings suggest a potential model in which ETV1 activates NFI temporal binding to a subset of late-expressed genes in a stepwise manner by initial positive feedback regulation of the Etv1 gene itself followed by activation of downstream coregulated targets as ETV1 expression increases. Sequential transcription factor autoregulation and subsequent binding to downstream promoters may provide an intrinsic developmental timer for dendrite/synapse gene expression. PMID- 26941329 TI - Steady-state and dynamic gene expression programs in Saccharomyces cerevisiae in response to variation in environmental nitrogen. AB - Cell growth rate is regulated in response to the abundance and molecular form of essential nutrients. InSaccharomyces cerevisiae(budding yeast), the molecular form of environmental nitrogen is a major determinant of cell growth rate, supporting growth rates that vary at least threefold. Transcriptional control of nitrogen use is mediated in large part by nitrogen catabolite repression (NCR), which results in the repression of specific transcripts in the presence of a preferred nitrogen source that supports a fast growth rate, such as glutamine, that are otherwise expressed in the presence of a nonpreferred nitrogen source, such as proline, which supports a slower growth rate. Differential expression of the NCR regulon and additional nitrogen-responsive genes results in >500 transcripts that are differentially expressed in cells growing in the presence of different nitrogen sources in batch cultures. Here we find that in growth rate controlled cultures using nitrogen-limited chemostats, gene expression programs are strikingly similar regardless of nitrogen source. NCR expression is derepressed in all nitrogen-limiting chemostat conditions regardless of nitrogen source, and in these conditions, only 34 transcripts exhibit nitrogen source specific differential gene expression. Addition of either the preferred nitrogen source, glutamine, or the nonpreferred nitrogen source, proline, to cells growing in nitrogen-limited chemostats results in rapid, dose-dependent repression of the NCR regulon. Using a novel means of computational normalization to compare global gene expression programs in steady-state and dynamic conditions, we find evidence that the addition of nitrogen to nitrogen-limited cells results in the transient overproduction of transcripts required for protein translation. Simultaneously, we find that that accelerated mRNA degradation underlies the rapid clearing of a subset of transcripts, which is most pronounced for the highly expressed NCR regulated permease genesGAP1,MEP2,DAL5,PUT4, andDIP5 Our results reveal novel aspects of nitrogen-regulated gene expression and highlight the need for a quantitative approach to study how the cell coordinates protein translation and nitrogen assimilation to optimize cell growth in different environments. PMID- 26941330 TI - A novel tribasic Golgi export signal directs cargo protein interaction with activated Rab11 and AP-1-dependent Golgi-plasma membrane trafficking. AB - The reovirus fusion-associated small transmembrane (FAST) proteins comprise a unique family of viral membrane fusion proteins dedicated to inducing cell-cell fusion. We recently reported that a polybasic motif (PBM) in the cytosolic tail of reptilian reovirus p14 FAST protein functions as a novel tribasic Golgi export signal. Using coimmunoprecipitation and fluorescence resonance energy transfer (FRET) assays, we now show the PBM directs interaction of p14 with GTP-Rab11. Overexpression of dominant-negative Rab11 and RNA interference knockdown of endogenous Rab11 inhibited p14 plasma membrane trafficking and resulted in p14 accumulation in the Golgi complex. This is the first example of Golgi export to the plasma membrane that is dependent on the interaction of membrane protein cargo with activated Rab11. RNA interference and immunofluorescence microscopy further revealed that p14 Golgi export is dependent on AP-1 (but not AP-3 or AP 4) and that Rab11 and AP-1 both colocalize with p14 at the TGN. Together these results imply the PBM mediates interactions of p14 with activated Rab11 at the TGN, resulting in p14 sorting into AP1-coated vesicles for anterograde TGN-plasma membrane transport. PMID- 26941331 TI - Caenorhabditis elegans paraoxonase-like proteins control the functional expression of DEG/ENaC mechanosensory proteins. AB - Caenorhabditis eleganssenses gentle touch via a mechanotransduction channel formed from the DEG/ENaC proteins MEC-4 and MEC-10. An additional protein, the paraoxonase-like protein MEC-6, is essential for transduction, and previous work suggested that MEC-6 was part of the transduction complex. We found that MEC-6 and a similar protein, POML-1, reside primarily in the endoplasmic reticulum and do not colocalize with MEC-4 on the plasma membrane in vivo. As with MEC-6, POML 1 is needed for touch sensitivity, the neurodegeneration caused by themec 4(d)mutation, and the expression and distribution of MEC-4 in vivo. Both proteins are likely needed for the proper folding or assembly of MEC-4 channels in vivo as measured by FRET. MEC-6 detectably increases the rate of MEC-4 accumulation on theXenopusoocyte plasma membrane. These results suggest that MEC-6 and POML-1 interact with MEC-4 to facilitate expression and localization of MEC-4 on the cell surface. Thus MEC-6 and POML-1 act more like chaperones for MEC-4 than channel components. PMID- 26941333 TI - Structural comparison of the Caenorhabditis elegans and human Ndc80 complexes bound to microtubules reveals distinct binding behavior. AB - During cell division, kinetochores must remain tethered to the plus ends of dynamic microtubule polymers. However, the molecular basis for robust kinetochore microtubule interactions remains poorly understood. The conserved four-subunit Ndc80 complex plays an essential and direct role in generating dynamic kinetochore-microtubule attachments. Here we compare the binding of theCaenorhabditis elegansand human Ndc80 complexes to microtubules at high resolution using cryo-electron microscopy reconstructions. Despite the conserved roles of the Ndc80 complex in diverse organisms, we find that the attachment mode of these complexes for microtubules is distinct. The human Ndc80 complex binds every tubulin monomer along the microtubule protofilament, whereas theC. elegansNdc80 complex binds more tightly to beta-tubulin. In addition, theC. elegansNdc80 complex tilts more toward the adjacent protofilament. These structural differences in the Ndc80 complex between different species may play significant roles in the nature of kinetochore-microtubule interactions. PMID- 26941332 TI - Control of protein trafficking by reversible masking of transport signals. AB - Systems that allow the control of protein traffic between subcellular compartments have been valuable in elucidating trafficking mechanisms. Most current approaches rely on ligand or light-controlled dimerization, which results in either retardation or enhancement of the transport of a reporter. We developed an alternative approach for trafficking regulation that we term "controlled unmasking of targeting elements" (CUTE). Regulated trafficking is achieved by reversible masking of the signal that directs the reporter to its target organelle, relying on the streptavidin-biotin system. The targeting signal is generated within or immediately after a 38-amino acid streptavidin-binding peptide (SBP) that is appended to the reporter. The binding of coexpressed streptavidin to SBP causes signal masking, whereas addition of biotin causes complex dissociation and triggers protein transport to the target organelle. We demonstrate the application of this approach to the control of nuclear and peroxisomal protein import and the generation of biotin-dependent trafficking through the endocytic and COPI systems. By simultaneous masking of COPI and endocytic signals, we were able to generate a synthetic pathway for efficient transport of a reporter from the plasma membrane to the endoplasmic reticulum. PMID- 26941335 TI - PAR3-aPKC regulates Tiam1 by modulating suppressive internal interactions. AB - Tiam1 is one of the most extensively analyzed activators of the small GTPase Rac. However, fundamental aspects of its regulation are poorly understood. Here we demonstrate that Tiam1 is functionally suppressed by internal interactions and that the PAR complex participates in its full activation. The N-terminal region of Tiam1 binds to the protein-binding and catalytic domains to inhibit its localization and activation. Atypical PKCs phosphorylate Tiam1 to relieve its intramolecular interactions, and the subsequent stabilization of its interaction with PAR3 allows it to exert localized activity. By analyzing Tiam1 regulation by PAR3-aPKC within the context of PDGF signaling, we also show that PAR3 directly binds PDGF receptor beta. Thus we provide the first evidence for the negative regulation of Tiam1 by internal interactions, elucidate the nature of Tiam1 regulation by the PAR complex, and reveal a novel role for the PAR complex in PDGF signaling. PMID- 26941337 TI - South Asian ethnicity is associated with a lower prevalence of atrial fibrillation despite greater prevalence of established risk factors: a population based study in Bradford Metropolitan District. AB - Aims: Previous studies indicate that South Asians (SAs) may have a reduced risk of developing atrial fibrillation (AF) despite having a higher prevalence of traditional cardiovascular risk factors. This observational study was designed to explore the relative differences between SAs and Whites in a well-defined, multi ethnic population with careful consideration of traditional cardiovascular risk factors that are thought to contribute to the development of AF. Methods and results: Anonymized data from 417 575 adults were sourced from primary care records within Bradford Metropolitan District, UK. Atrial fibrillation diagnosis was indicated by the presence on the AF Quality Outcomes Framework register. Self reported ethnicity was mapped to census ethnic codes. The age-standardized prevalence rates of AF were calculated for comparison between the White and SA populations; our study sample presented relative proportions of 2.39 and 0.4%. Multivariable logistic regression analysis was performed to estimate the odds of developing AF given SA ethnicity. Adjustment for age, sex, and established risk factors found a 71% reduction in odds of AF in SAs when compared with Whites [odds ratio (OR): 0.29, 95% confidence interval (CI): 0.26-0.32]. When stratified by ethnicity, analyses revealed significantly different odds of AF for patients with diabetes; diabetes was not associated with the development of AF in the SA population (0.81, 95% CI: 0.63-1.05). Conclusion: This study, in a multi-ethnic population, presents ethnicity as a predictor of AF in which prevalence is significantly lower in SAs when compared with Whites. This is despite SAs having a higher frequency of established risk factors for the development of AF, such as ischaemic heart disease, heart failure, hypertension, and type 2 diabetes. These findings are consistent with previous literature and add weight to the need for further investigation, although this is the first study to investigate the differential associations of individual risk factors with development of AF. PMID- 26941334 TI - Unique spatiotemporal activation pattern of Cdc42 by Gef1 and Scd1 promotes different events during cytokinesis. AB - The Rho-family GTPase Cdc42 regulates cell polarity and localizes to the cell division site. Cdc42 is activated by guanine nucleotide exchange factors (GEFs). We report that Cdc42 promotes cytokinesis via a unique spatiotemporal activation pattern due to the distinct action of its GEFs, Gef1 and Scd1, in fission yeast. Before cytokinetic ring constriction, Cdc42 activation, is Gef1 dependent, and after ring constriction, it is Scd1 dependent. Gef1 localizes to the actomyosin ring immediately after ring assembly and promotes timely onset of ring constriction. Gef1 is required for proper actin organization during cytokinesis, distribution of type V myosin Myo52 to the division site, and timely recruitment of septum protein Bgs1. In contrast, Scd1 localizes to the broader region of ingressing membrane during cytokinetic furrowing. Scd1 promotes normal septum formation, andscd1Deltacells display aberrant septa with reduced Bgs1 localization. Thus we define unique roles of the GEFs Gef1 and Scd1 in the regulation of distinct events during cytokinesis. Gef1 localizes first to the cytokinetic ring and promotes timely constriction, whereas Scd1 localizes later to the ingressing membrane and promotes septum formation. Our findings are consistent with reports that complexity in GTPase signaling patterns enables exquisite precision over the control of cellular processes. PMID- 26941336 TI - Subcellular optogenetic activation of Cdc42 controls local and distal signaling to drive immune cell migration. AB - Migratory immune cells use intracellular signaling networks to generate and orient spatially polarized responses to extracellular cues. The monomeric G protein Cdc42 is believed to play an important role in controlling the polarized responses, but it has been difficult to determine directly the consequences of localized Cdc42 activation within an immune cell. Here we used subcellular optogenetics to determine how Cdc42 activation at one side of a cell affects both cell behavior and dynamic molecular responses throughout the cell. We found that localized Cdc42 activation is sufficient to generate polarized signaling and directional cell migration. The optically activated region becomes the leading edge of the cell, with Cdc42 activating Rac and generating membrane protrusions driven by the actin cytoskeleton. Cdc42 also exerts long-range effects that cause myosin accumulation at the opposite side of the cell and actomyosin-mediated retraction of the cell rear. This process requires the RhoA-activated kinase ROCK, suggesting that Cdc42 activation at one side of a cell triggers increased RhoA signaling at the opposite side. Our results demonstrate how dynamic, subcellular perturbation of an individual signaling protein can help to determine its role in controlling polarized cellular responses. PMID- 26941339 TI - Tpeak-Tend interval and Tpeak-Tend/QT ratio in patients with Brugada syndrome. AB - AIMS: Brugada syndrome (BrS) is characterized by a typical electrocardiogram (ECG) pattern in right precordial leads (V1-V3; so-called type 1 ECG) and an increased risk of sudden cardiac death due to ventricular fibrillation. Annual cardiac event rates vary from 0.5% in asymptomatic to 7.7% in high-risk patients. So far, spontaneous occurrence of the type 1 ECG, survived cardiac arrest, and/or documented ventricular arrhythmias are main risk predictors, whereas other factors (e.g. family history or genotype) are not applicable for risk stratification. In this study, we investigated the relationship between Tpeak Tend intervals (TpTe) as a novel ECG parameter for the occurrence of cardiac arrhythmias. METHODS AND RESULTS: Clinical and genetic data of 78 unrelated BrS patients (male: n = 57, age: 45 +/- 14 years) were retrospectively analysed for medical history, gene mutation, and ECG parameters (in particular heart rate, PQ, QRS, QT, and TpTe) as obtained after digital measurements. TpTe in ECG lead V1 (87 +/- 30 vs. 71 +/- 27 ms; P = 0.017) and the TpTe/QT ratio (0.24 vs. 0.19; P = 0.018) were significantly higher in high-risk BrS patients than in other BrS patients. In the other right precordial leads typically indicative for BrS, no significant difference was noted. CONCLUSION: Assessment of the TpTe interval or the TpTe/QT ratio in lead V1 is potentially useful as a non-invasive risk marker for BrS patients with life-threatening arrhythmias. PMID- 26941338 TI - Combined leadless pacemaker and subcutaneous implantable defibrillator therapy: feasibility, safety, and performance. AB - AIMS: The subcutaneous implantable cardioverter-defibrillator (S-ICD) and leadless pacemaker (LP) are evolving technologies that do not require intracardiac leads. However, interactions between these two devices are unexplored. We investigated the feasibility, safety, and performance of combined LP and S-ICD therapy, considering (i) simultaneous device-programmer communication, (ii) S-ICD rhythm discrimination during LP communication and pacing, and (iii) post-shock LP performance. METHODS AND RESULTS: The study consists of two parts. Animal experiments: Two sheep were implanted with both an S-ICD and LP (Nanostim, SJM), and the objectives above were tested. Human experience: Follow-up of one S-ICD patient with bilateral subclavian occlusion who received an LP and two LP (all Nanostim, SJM) patients (without S-ICD) who received electrical cardioversion (ECV) are presented. Animal experiments : Simultaneous device-programmer communication was successful, but LP-programmer communication telemetry was temporarily lost (2 +/- 2 s) during ventricular fibrillation (VF) induction and 4/54 shocks. Leadless pacemaker communication and pacing did not interfere with S-ICD rhythm discrimination. Additionally, all VF episodes (n = 12/12), including during simultaneous LP pacing, were detected and treated by the S-ICD. Post-shock LP performance was unaltered, and no post-shock device resets or dislodgements were observed (24 S-ICD and 30 external shocks). Human experience : The S-ICD/LP patient showed adequate S-ICD sensing during intrinsic rhythm, nominal, and high-output LP pacing. Two LP patients (without S ICD) received ECV during follow-up. No impact on performance or LP dislodgements were observed. CONCLUSION: Combined LP and S-ICD therapy appears feasible in all animal experiments (n = 2) and in one human subject. No interference in sensing and pacing during intrinsic and paced rhythm was noted in both animal and human subjects. However, induced arrhythmia testing was not performed in the patient. Defibrillation therapy did not seem to affect LP function. More data on safety and performance are needed. PMID- 26941340 TI - Effect of fixed-rate vs. rate-RESPONSIve pacing on exercise capacity in patients with permanent, refractory atrial fibrillation and left ventricular dysfunction treated with atrioventricular junction aBLation and bivEntricular pacing (RESPONSIBLE): a prospective, multicentre, randomized, single-blind study. AB - Aims: Atrioventricular junction (AVJ) ablation followed by biventricular pacing is an established strategy for improving symptoms and morbidity in patients with permanent atrial fibrillation (AF), reduced left ventricular ejection fraction (LVEF), and uncontrolled ventricular rate. There is no clear evidence that such patients benefit from rate-responsive (RR) pacing. Methods and results: This prospective, randomized, single-blind, multicentre study was designed as an intra patient comparison and enrolled 60 patients (age 69.5 +/- 11.8 years, males 63.3%, NYHA 3.0 +/- 0.6) with refractory AF and reduced LVEF (mean 32.4 +/- 8.3%) treated with AVJ ablation and biventricular pacing. Two 6-minute walking tests (6MWT) were performed 1 week apart: one during VVI 70/min biventricular pacing and the other during VVIR 70-130/min biventricular pacing; patients were randomly and blindly assigned to Group A (n = 29, first 6MWT in VVIR mode) or B (n = 31, first 6MWT in VVI mode). Rate-responsive activation determined an increase of 18.8 +/- 24.4 m in the distance walked during the 6MWT (P < 0.001). The increase was similar in both groups (P = 0.571). A >5% increase in the distance walked was observed in 76.7% of patients. The increase in the distance walked was linearly correlated with the increase in heart rate recorded during the 6MWT in the VVIR mode (r = 0.54; P < 0.001). Conclusion: In permanent AF patients with uncontrolled rate and reduced LVEF who had undergone AVJ ablation and biventricular pacing, RR pacing yields a significant gain in exercise capacity, which seems to be related to the RR-induced frequency during effort. PMID- 26941341 TI - Can screening for atrial fibrillation be implemented at scale? PMID- 26941342 TI - Longevity of implantable cardioverter-defibrillators: still a long way to go. PMID- 26941343 TI - Ventricular arrhythmia during ajmaline challenge for the Brugada syndrome. AB - The Brugada syndrome is a genetic disease characterized by an abnormal electrocardiogram (ECG) and an elevated risk of sudden cardiac death. Sodium channel blockers (SCBs), such as ajmaline, are used to unmask the characteristic type 1 Brugada electrocardiographic pattern. We review the literature on the incidence of ventricular arrhythmia (VA) during SCB challenge. We evaluate the clinical and electrocardiographic characteristics of these patients as well as their prognosis. All articles published from January 2000 until August 2015, in which the incidence and predictors of VAs during SCB challenge were reported, are reviewed. The occurrence of VA during SCB challenge ranges from 0 to 17.8%. The weighted average for induction of any VA during sodium blocking challenge is 2.4%; for non-sustained ventricular tachycardia (VT), it is 0.34% and for sustained VT 0.59%. No fatal cases were reported. Predictors may be young age, conduction disturbance at baseline ECG, and mutations in the SCN5A gene. All other clinical and electrocardiographic characteristics failed to be consistent predictors. Life-threatening arrhythmias during SCB challenge are not an exceptional event. Therefore, provocation testing must necessarily be performed in an appropriate environment in which advanced life support facilities are present. Patients who have a higher risk for induced arrhythmias might be those who display a conduction disturbance at baseline ECG or have certain SCN5A mutations or are of a younger age. However, survivors of these induced arrhythmias do not seem to suffer from a worse prognosis. PMID- 26941344 TI - Guiding follow-up of paediatric idiopathic intracranial hypertension with optical coherence tomography. AB - Idiopathic intracranial hypertension (IIH) is uncommon in the paediatric population. Papilloedema is the hallmark sign and patients can suffer permanent vision loss as a consequence. We describe the role of optical coherence tomography (OCT) in the follow-up of two paediatric patients with newly diagnosed IIH. Patient A presented with vomiting and examination showed ophthalmoplaegia and papilloedema. She was treated with acetazolamide, furosemide and therapeutic lumbar punctures. Patient B presented with incidental papilloedema and was treated with acetazolamide and she reported intermittent headache during follow up. Fundoscopic examinations for both patients showed persistent blurred disc margins but OCT examinations documented improvement of average retinal nerve fibre layers. OCT may be of value in monitoring for recurrence in paediatric IIH. PMID- 26941345 TI - Air column beside the trachea. AB - A 60-year-old man, a non-smoker, was referred to us for evaluation of an abnormal chest radiograph that had been taken 2 months earlier when the patient had fever and cough. The fever and cough had subsided after treatment with antibiotics. The patient was asymptomatic at the time of presentation to us. Examination was unremarkable. The chest radiograph showed an air pocket in the right paratracheal region. The diagnosis and differential diagnoses are discussed in this case report. PMID- 26941346 TI - Endogenous Candida endophthalmitis and osteomyelitis associated with CARD9 deficiency. AB - A 25-year-old woman presented with unilateral red eye and visual blur, and was found to have panuveitis with an inflammatory white mass at the macula, initially presumed to be Toxoplasma retinitis. After failure to respond, she underwent vitrectomy, which produced Candida albicans. Despite intraocular and systemic antifungal treatment, she lost all vision in that eye. Two years later, she developed unilateral hip osteomyelitis leading to total hip replacement and also revealing Candida infection. By clinical exome sequencing, she was then found to have caspase recruitment domain 9 (CARD9) deficiency, an autosomal recessive disorder that causes a specific susceptibility to candidal infections. She remains otherwise well but on lifelong fluconazole prophylaxis. PMID- 26941348 TI - Orthogeriatric medicine and fracture liaison going from strength to strength. PMID- 26941349 TI - Pharmacists and prevention of inappropriate prescribing in hospital. PMID- 26941350 TI - Intervening to reduce elder abuse: challenges for research. PMID- 26941351 TI - Tilt testing: it may be safe but is it any good? PMID- 26941352 TI - Better teaching in basic gerontology should be seen as both a goal and an opportunity for those shaping undergraduate curricula. PMID- 26941353 TI - New horizons in the implementation and research of comprehensive geriatric assessment: knowing, doing and the 'know-do' gap. AB - In this paper, we outline the relationship between the need to put existing applied health research knowledge into practice (the 'know-do gap') and the need to improve the evidence base (the 'know gap') with respect to the healthcare process used for older people with frailty known as comprehensive geriatric assessment (CGA). We explore the reasons for the know-do gap and the principles of how these barriers to implementation might be overcome. We explore how these principles should affect the conduct of applied health research to close the know gap. We propose that impaired flow of knowledge is an important contributory factor in the failure to implement evidence-based practice in CGA; this could be addressed through specific knowledge mobilisation techniques. We describe that implementation failures are also produced by an inadequate evidence base that requires the co-production of research, addressing not only effectiveness but also the feasibility and acceptability of new services, the educational needs of practitioners, the organisational requirements of services, and the contribution made by policy. Only by tackling these issues in concert and appropriate proportion, will the know and know-do gaps for CGA be closed. PMID- 26941354 TI - Corrigendum to 'Cardiovascular risk profile and use of statins at the age of 70 years: a comparison of two Finnish birth cohorts born 20 years apart'. PMID- 26941355 TI - Corrigendum to 'Analgesic prescribing patterns in Norwegian nursing homes from 2000 to 2011: trend analyses of four data samples'. PMID- 26941357 TI - Australian women's attitudes towards and understandings of the subdermal contraceptive implant: a qualitative study of never-users. AB - OBJECTIVE: Few studies have explored Australian women's understandings of contraception. This study examined the attitudes towards, and understandings of, the subdermal contraceptive implant expressed by women living in New South Wales (NSW), Australia. STUDY DESIGN: As part of a larger qualitative study using in depth, open-ended interviews in 2012-2013 with women aged 16-49 years who had ever used contraception (n=94), 65 interviews from women who discussed or mentioned the subdermal implant, but had not previously used the device, were examined and analysed using thematic analysis. RESULTS: The emergent themes were: satisfaction with current method; weak personal opinions and ambivalence; uncertainty due to specific concerns; and strong negative reactions - fear and dislike. Although there were a few positive perceptions expressed by women who had never used the subdermal implant, for the majority of women the perception was predominantly negative. DISCUSSION AND CONCLUSION: Women tended to form negative impressions from the stories of other women about the subdermal implant. Interventions to enhance evidence-informed awareness of the relative advantages and disadvantages of the implant - for example, improved access to supportive contraceptive counselling - need investigation in the Australian context. Avenues to improve women's perceived control over the device could also be usefully investigated. PMID- 26941358 TI - WNT-C59, a Small-Molecule WNT Inhibitor, Efficiently Induces Anterior Cortex That Includes Cortical Motor Neurons From Human Pluripotent Stem Cells. AB - The recapitulation of human neural development in a controlled, defined manner from pluripotent stem cells (PSCs) has considerable potential for studies of human neural development, circuit formation and function, and the construction of in vitro models of neurological diseases. The inhibition of Wnt signaling, often by the recombinant protein DKK1, is important for the induction of cortical neurons. Here, we report a novel differentiation method using a small-molecule WNT inhibitor, WNT-C59 (C59), to efficiently induce human anterior cortex. We compared two types of small molecules, C59 and XAV939 (XAV), as substitutes for DKK1 to induce cortical neurons from PSCs in serum-free embryoid body-like aggregate culture. DKK1 and XAV inhibited only the canonical pathway of Wnt signaling, whereas C59 inhibited both the canonical and noncanonical pathways. C59 efficiently induced CTIP2+/COUP-TF1- cells, which are characteristic of the cells found in the anterior cortex. In addition, when grafted into the cortex of adult mice, the C59-induced cells showed abundant axonal fiber extension toward the spinal cord. These results raise the possibility of C59 contributing to cell replacement therapy for motor neuron diseases or insults. SIGNIFICANCE: For a cell therapy against damaged corticospinal tract caused by neurodegenerative diseases or insults, cortical motor neurons are needed. Currently, their induction from pluripotent stem cells is considered very promising; however, an efficient protocol to induce motor neurons is not available. For efficient induction of anterior cortex, where motor neurons are located, various WNT inhibitors were investigated. It was found that one of them could induce anterior cortical cells efficiently. In addition, when grafted into the cortex of adult mice, the induced cells showed more abundant axonal fiber extension toward spinal cord. These results raise the possibility that this inhibitor contributes to a cell-replacement therapy for motor neuron diseases or insults. PMID- 26941359 TI - Downregulation of Melanoma Cell Adhesion Molecule (MCAM/CD146) Accelerates Cellular Senescence in Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells. AB - Therapeutic applications of mesenchymal stem cells (MSCs) for treating various diseases have increased in recent years. To ensure that treatment is effective, an adequate MSC dosage should be determined before these cells are used for therapeutic purposes. To obtain a sufficient number of cells for therapeutic applications, MSCs must be expanded in long-term cell culture, which inevitably triggers cellular senescence. In this study, we investigated the surface markers of human umbilical cord blood-derived MSCs (hUCB-MSCs) associated with cellular senescence using fluorescence-activated cell sorting analysis and 242 cell surface-marker antibodies. Among these surface proteins, we selected the melanoma cell adhesion molecule (MCAM/CD146) for further study with the aim of validating observed expression differences and investigating the associated implications in hUCB-MSCs during cellular senescence. We observed that CD146 expression markedly decreased in hUCB-MSCs following prolonged in vitro expansion. Using preparative sorting, we found that hUCB-MSCs with high CD146 expression displayed high growth rates, multilineage differentiation, expression of stemness markers, and telomerase activity, as well as significantly lower expression of the senescence markers p16, p21, p53, and senescence-associated beta-galactosidase, compared with that observed in hUCB-MSCs with low-level CD146 expression. In contrast, CD146 downregulation with small interfering RNAs enhanced the senescence phenotype. In addition, CD146 suppression in hUCB-MSCs caused downregulation of other cellular senescence regulators, including Bmi-1, Id1, and Twist1. Collectively, our results suggest that CD146 regulates cellular senescence; thus, it could be used as a therapeutic marker to identify senescent hUCB-MSCs. SIGNIFICANCE: One of the fundamental requirements for mesenchymal stem cell (MSC) based therapies is the expansion of MSCs during long-term culture because a sufficient number of functional cells is required. However, long-term growth inevitably induces cellular senescence, which potentially causes poor clinical outcomes by inducing growth arrest and the loss of stem cell properties. Thus, the identification of markers for evaluating the status of MSC senescence during long-term culture may enhance the success of MSC-based therapy. This study provides strong evidence that CD146 is a novel and useful marker for predicting senescence in human umbilical cord blood-derived MSCs (hUCB-MSCs), and CD146 can potentially be applied in quality-control assessments of hUCB-MSC-based therapy. PMID- 26941360 TI - Induction of CCAAT/Enhancer-Binding Protein beta Expression With the Phosphodiesterase Inhibitor Isobutylmethylxanthine Improves Myoblast Engraftment Into Dystrophic Muscle. AB - Duchenne muscular dystrophy (DMD), caused by mutations in the dystrophin gene, is the most common muscular dystrophy. Characterized by rounds of muscle degeneration and regeneration, DMD features progressive muscle wasting and is fatal. One approach for treatment is transplantation of muscle progenitor cells to repair and restore dystrophin expression to damaged muscle. However, the success of this approach has been limited by difficulties in isolating large numbers of myogenic progenitors with strong regenerative potential, poor engraftment, poor survival of donor cells, and limited migration in the diseased muscle. We demonstrate that induction of the transcription factor CCAAT/enhancer binding protein beta (C/EBPbeta) using the cyclic adenosine monophosphate phosphodiesterase inhibitor isobutylmethylxanthine (IBMX) results in enhanced myoblast expansion in culture and increased satellite cell marker expression. When equal numbers of IBMX-treated cells were transplanted into dystrophic muscle, they contributed to muscle repair more efficiently than did vehicle treated cells and engrafted into the satellite cell niche in higher numbers, demonstrating improved cell migration from the site of injury and enhanced survival after transplantation. Thus, pharmacologic stimulation of C/EBPbeta expression reprograms myoblasts to a more stem cell-like state, promotes expansion in culture, and improves engraftment such that better transplantation outcomes are achieved. SIGNIFICANCE: Duchenne muscular dystrophy is a genetic disorder for which no cure exists. One therapeutic approach is transplantation of myogenic progenitors to restore dystrophin to damaged muscle, but this approach is limited by poor engraftment of cultured myoblasts. Transient upregulation of CCAAT/enhancer-binding protein beta in primary myoblasts using the phosphodiesterase isobutylmethylxanthine (IBMX) increases satellite cell marker expression in cultured myoblasts, improves their migration, and increases their survival after transplantation. When transplanted into C57BL/10ScSn-mdx/J mice , IBMX-treated myoblasts restored dystrophin expression and were able to occupy the satellite cell niche more efficiently than controls. A myoblast culture approach that reprograms myoblasts to a more primitive state, resulting in improved transplantation outcomes and reinvigorating research into myoblast transplantation as a viable therapeutic approach, is described. PMID- 26941363 TI - Sexual and reproductive health in the European refugee crisis. PMID- 26941362 TI - Saliva use as a lubricant for anal sex is a risk factor for rectal gonorrhoea among men who have sex with men, a new public health message: a cross-sectional survey. AB - BACKGROUND: Apart from penile-anal intercourse, other anal sexual practices (rimming, fingering and saliva use as a lubricant for anal sex) are common among men who have sex with men (MSM). The aim of this study is to evaluate whether these anal sexual practices are risk factors for rectal gonorrhoea in MSM. METHOD: A cross-sectional survey was conducted among MSM attending Melbourne Sexual Health Centre between 31 July 2014 and 30 June 2015. Rectal gonorrhoea cases were identified by culture. RESULTS: Among 1312 MSM, 4.3% (n=56) had rectal gonorrhoea. Other anal sexual practices were common among MSM: receptive rimming (70.5%), receptive fingering or penis dipping (84.3%) and using partner's saliva as a lubricant for anal sex (68.5%). Saliva as a lubricant (adjusted OR 2.17; 95% CI 1.00 to 4.71) was significantly associated with rectal gonorrhoea after adjusting for potential confounding factors. Receptive rimming and fingering or penis dipping were not statistically associated with rectal gonorrhoea. The crude population-attributable fraction of rectal gonorrhoea associated with use of partner's saliva as a lubricant for anal sex was 48.9% (7.9% to 71.7%). CONCLUSIONS: Saliva use as a lubricant for anal sex is a common sexual practice in MSM, and it may play an important role in gonorrhoea transmission. Almost half of rectal gonorrhoea cases may be eliminated if MSM stopped using partner's saliva for anal sex. PMID- 26941361 TI - A Rational Strategy for the Use of Amniotic Epithelial Stem Cell Therapy for Liver Diseases. AB - Stem cell-based therapies hold the potential to alleviate the burden of many serious diseases, including those of the liver. Among the different types of stem cells, human placenta-derived stem cells are potentially one of the most clinically applicable stem cells because of their tissue-specific advantages. They are a readily available cell source that can be procured in a noninvasive manner, and there are few ethical concerns regarding their use. Recent studies have demonstrated that the amniotic epithelium contains stem cells that possess four unique and advantageous properties; human amniotic epithelial cells (hAECs) have low immunogenicity, secrete several immune regulatory molecules, possess the potential to differentiate into all three germ layers, and contain abundant lysosomes allowing them to secrete lysosomal enzymes. This perspective article provides an overview of the beneficial properties of hAECs and proposes a rational strategy for translating placental stem cells toward clinical application for various liver diseases. SIGNIFICANCE: This article provides an overview of the beneficial properties of one type of human placental stem cell and proposes a rational strategy for translating placental stem cells toward clinical application for various liver diseases. PMID- 26941364 TI - Pathway Analysis of Genome-wide Association Study in Childhood Leukemia among Hispanics. AB - BACKGROUND: The incidence of acute lymphoblastic leukemia (ALL) is nearly 20% higher among Hispanics than non-Hispanic Whites. Previous studies have shown evidence for association between risk of ALL and variation within IKZF1, ARID5B, CEBPE, CDKN2A, GATA3, and BM1-PIP4K2A genes. However, variants identified only account for <10% of the genetic risk of ALL. METHODS: We applied pathway-based analyses to genome-wide association study (GWAS) data from the California Childhood Leukemia Study to determine whether different biologic pathways were overrepresented in childhood ALL and major ALL subtypes. Furthermore, we applied causal inference and data reduction methods to prioritize candidate genes within each identified overrepresented pathway, while accounting for correlation among SNPs. RESULTS: Pathway analysis results indicate that different ALL subtypes may involve distinct biologic mechanisms. Focal adhesion is a shared mechanism across the different disease subtypes. For ALL, the top five overrepresented Kyoto Encyclopedia of Genes and Genomes pathways include axon guidance, protein digestion and absorption, melanogenesis, leukocyte transendothelial migration, and focal adhesion (PFDR < 0.05). Notably, these pathways are connected to downstream MAPK or Wnt signaling pathways which have been linked to B-cell malignancies. Several candidate genes for ALL, such as COL6A6 and COL5A1, were identified through targeted maximum likelihood estimation. CONCLUSIONS: This is the first study to show distinct biologic pathways are overrepresented in different ALL subtypes using pathway-based approaches, and identified potential gene candidates using causal inference methods. IMPACT: The findings demonstrate that newly developed bioinformatics tools and causal inference methods can provide insights to furthering our understanding of the pathogenesis of leukemia. Cancer Epidemiol Biomarkers Prev; 25(5); 815-22. (c)2016 AACR. PMID- 26941366 TI - Shift Work, Chronotype, and Melatonin Patterns among Female Hospital Employees on Day and Night Shifts. AB - BACKGROUND: Shift work-related carcinogenesis is hypothesized to be mediated by melatonin; however, few studies have considered the potential effect modification of this underlying pathway by chronotype or specific aspects of shift work such as the number of consecutive nights in a rotation. In this study, we examined melatonin patterns in relation to shift status, stratified by chronotype and number of consecutive night shifts, and cumulative lifetime exposure to shift work. METHODS: Melatonin patterns of 261 female personnel (147 fixed-day and 114 on rotations, including nights) at Kingston General Hospital were analyzed using cosinor analysis. Urine samples were collected from all voids over a 48-hour specimen collection period for measurement of 6-sulfatoxymelatonin concentrations using the Buhlmann ELISA Kit. Chronotypes were assessed using mid-sleep time (MSF) derived from the Munich Chronotype Questionnaire (MCTQ). Sociodemographic, health, and occupational information were collected by questionnaire. RESULTS: Rotational shift nurses working nights had a lower mesor and an earlier time of peak melatonin production compared to day-only workers. More pronounced differences in mesor and acrophase were seen among later chronotypes, and shift workers working >=3 consecutive nights. Among nurses, cumulative shift work was associated with a reduction in mesor. CONCLUSION: These results suggest that evening-types and/or shift workers working >=3 consecutive nights are more susceptible to adverse light-at-night effects, whereas long-term shift work may also chronically reduce melatonin levels. IMPACT: Cumulative and current exposure to shift work, including nights, affects level and timing of melatonin production, which may be related to carcinogenesis and cancer risk. Cancer Epidemiol Biomarkers Prev; 25(5); 830-8. (c)2016 AACR. PMID- 26941365 TI - Association of Prostate Cancer Risk Variants with TMPRSS2:ERG Status: Evidence for Distinct Molecular Subtypes. AB - BACKGROUND: Numerous genetic variants have been confirmed as prostate cancer risk factors. These variants may confer susceptibility to the development of specific molecular alterations during tumor initiation and progression. The TMPRSS2:ERG gene fusion occurs in roughly 50% of prostate cancers. Genetic risk variants may influence the development of this fusion. We sought to determine whether prostate cancer risk variants are differentially associated with TMPRSS2:ERG fusion positive and negative cancer. METHODS: In the Health Professionals Follow-up Study and Physicians' Health Study Tumor Cohort, we evaluated the associations of 39 prostate cancer risk SNPs with TMPRSS2:ERG fusion status, measured by ERG protein expression. Logistic regression was performed to generate OR and 95% confidence intervals. The primary outcome was ERG(+) (n = 227) versus ERG(-) (n = 260) prostate cancer. A secondary outcome was ERG(+) or ERG(-) cancer versus controls without cancer. RESULTS: Six of 39 SNPs were significantly associated (P < 0.05) with ERG(+) versus ERG(-) disease. Three SNPs were exclusively associated with the risk of ERG(+), one with risk of ERG(-), and two with associations trending in opposite directions for ERG(+) and ERG(-) Only two significant SNPs would be expected by chance. CONCLUSIONS: Prostate cancer genetic risk variants are differentially associated with the development of ERG(+) and ERG(-) prostate cancer. IMPACT: Our findings suggest the molecular process of prostate carcinogenesis may be distinct for men with different underlying genetic predisposition. When examining risk factors for prostate cancer, the integration of molecular subtypes may enhance understanding of the etiology of this disease. Cancer Epidemiol Biomarkers Prev; 25(5); 745-9. (c)2016 AACR. PMID- 26941368 TI - Primary leiomyoma of the lung: an exceptional localization. AB - Leiomyoma is a benign smooth muscle tumor usually encountered in the uterus. Primary pulmonary localization is extremely rare in adults and children. However, it must be included in the differential diagnosis of any nodular lung lesion. Its treatment is surgical, with good long-term results. Here, we report a case of leiomyoma of lung parenchyma diagnosed in a 26-year-old man. PMID- 26941369 TI - Accessory orifice on the anterior tricuspid leaflet in Ebstein's anomaly. PMID- 26941367 TI - Impact of Pre-analytic Blood Sample Collection Factors on Metabolomics. AB - BACKGROUND: Many epidemiologic studies are using metabolomics to discover markers of carcinogenesis. However, limited data are available on the influence of pre analytic blood collection factors on metabolite measurement. METHODS: We quantified 166 metabolites in archived plasma from 423 Health Professionals Follow-up Study and Nurses' Health Study participants using liquid chromatography tandem mass spectrometry (LC-MS). We compared multivariable-adjusted geometric mean metabolite LC-MS peak areas across fasting time, season of blood collection, and time of day of blood collection categories. RESULTS: The majority of metabolites (160 of 166 metabolites) had geometric mean peak areas that were within 15% comparing samples donated after fasting 9 to 12 versus >=13 hours; greater differences were observed in samples donated after fasting <=4 hours. Metabolite peak areas generally were similar across season of blood collection, although levels of certain metabolites (e.g., bile acids and purines/pyrimidines) tended to be different in the summer versus winter months. After adjusting for fasting status, geometric mean peak areas for bile acids and vitamins, but not other metabolites, differed by time of day of blood collection. CONCLUSION: Fasting, season of blood collection, and time of day of blood collection were not important sources of variability in measurements of most metabolites in our study. However, considering blood collection variables in the design or analysis of studies may be important for certain specific metabolites, particularly bile acids, purines/pyrimidines, and vitamins. IMPACT: These results may be useful for investigators formulating analysis plans for epidemiologic metabolomics studies, including determining which metabolites to a priori exclude from analyses. Cancer Epidemiol Biomarkers Prev; 25(5); 823-9. (c)2016 AACR. PMID- 26941370 TI - Perspectives of Health-Care Providers Toward Advance Care Planning in Patients With Advanced Cancer and Congestive Heart Failure. AB - BACKGROUND: Advance care planning (ACP) discussions afford patients and physicians a chance to better understand patients' values and wishes regarding end-of-life care; however, these conversations typically take place late in the course of a disease. The goal of this study was to clarify attitudes of oncologists, cardiologists, and primary care physicians (PCPs) toward ACP and to identify persistent barriers to timely ACP discussion following a quality improvement initiative at our health system geared at improvement in ACP implementation. METHODS: A 20-question, cross-sectional online survey was created and distributed to cardiologists, oncologists, PCPs, and cardiology and oncology support staff at the NorthShore University HealthSystem (NorthShore) from February to March 2015. A total of 117 individuals (46% of distributed) completed the surveys. The results were compiled using an online survey analysis tool (SurveyMonkey, Inc., Palo Alto, California, USA). RESULTS: Only 15% of cardiologists felt it was their responsibility to conduct ACP discussions with their patients having congestive heart failure (CHF). In contrast, 68% of oncologists accepted this discussion as their responsibility in patients with terminal cancer ( P < .01). These views were mirrored by PCPs, as 68% of PCPs felt personally responsible for ACP discussion with patients having CHF, while only 34% felt the same about patients with cancer. Reported documentation of these discussions in the electronic health record was inconsistent between specialties. Among all surveyed specialties, lack of time was the major barrier limiting ACP discussion. Perceived patient discomfort and discomfort of the patient's family toward these discussions were also significant reported barriers. CONCLUSION: Attitudes toward ACP implementation vary considerably by medical specialty and medical condition, with oncologists in this study tending to feel more personal responsibility for these discussions with patients having cancer than cardiologists with their patients having heart failure. Robust implementation of ACP across the spectrum of medical diagnoses is likely to require a true collaboration between office-based PCPs and specialists in both the inpatient and the ambulatory settings. PMID- 26941371 TI - Relationship Between the Apolipoprotein E Genotype and LDL Particle Size in Patients With Obstructive Sleep Apnea. AB - Obstructive sleep apnea (OSA) is associated with dyslipidemia and increased cardiovascular risk. We assessed the effects of apolipoprotein E ( APOE) genotype on low-density lipoprotein (LDL) and high-density lipoprotein (HDL) particle size and lipid subclasses (separated by gradient gel electrophoresis) in patients with OSA. Stable patients (n = 181) prospectively recruited underwent full polysomnography. Both LDL particle size and LDL I proportion were reduced from ?3?3 homozygotes to ?2 carriers and to ?4 carriers (analysis of variance: P = .024; P = .040, respectively); carriers of the ?4 allele of the APOE genotype had significantly lower LDL particle size and LDL I proportion compared to ?3?3 homozygotes ( P < .05 for both comparisons). Insulin resistance increased from patients with no OSA to those with mild-moderate and to those with severe OSA ( P < .001). In multivariate analysis, LDL size was independently predicted by APOE genotype, male gender, and the presence of metabolic syndrome (MetS; P = .001, P = .020, P = .027, respectively). The HDL particle size was not affected by APOE genotype. Our data demonstrate that both the ?4 APOE genotype and MetS are independently related to smaller LDL size in patients with OSA. PMID- 26941373 TI - Obituary. Tomoyuki Shirai. PMID- 26941372 TI - Cigarette smoking and bladder cancer risk: an evaluation based on a systematic review of epidemiologic evidence in the Japanese population. AB - OBJECTIVE: Although several epidemiological studies have demonstrated that cigarette smoking is an important risk factor for bladder cancer, no systematic review in the Japanese population has yet been performed. Accurate evaluation of bladder cancer risk in relation to smoking for Japanese populations can provide necessary information for Japanese policy-makers and doctors to enlighten the importance of smoking cessation. We reviewed epidemiologic data to estimate the strength of the association between cigarette smoking and bladder cancer in the Japanese population. METHODS: We identified previous cohort and case-control studies, extracting data from databases in the MEDLINE (PubMed) and Ichushi. The magnitude of association and strength of evidence were evaluated in each study, and a meta-analysis was conducted to obtain summary estimates for the overall magnitude of association. RESULTS: Three cohort and eight case-control studies were identified. Except for one case-control study, all studies showed a strong positive association between cigarette smoking and bladder cancer. The summary relative risk for ever smokers relative to never smokers was 2.14 (95% confidence interval 1.87-2.44) in a fixed-effect model. CONCLUSIONS: We conclude that cigarette smoking is a convincing risk factor for bladder cancer among Japanese. PMID- 26941374 TI - Type distribution of lymphoid leukemia from Cancer Incidence in Five Continents Vol. X. PMID- 26941375 TI - Corrigendum. PMID- 26941376 TI - Corrigendum. PMID- 26941378 TI - Corrigendum. PMID- 26941377 TI - Corrigendum. PMID- 26941379 TI - Restoring Conscious Arousal During Focal Limbic Seizures with Deep Brain Stimulation. AB - Impaired consciousness occurs suddenly and unpredictably in people with epilepsy, markedly worsening quality of life and increasing risk of mortality. Focal seizures with impaired consciousness are the most common form of epilepsy and are refractory to all current medical and surgical therapies in about one-sixth of cases. Restoring consciousness during and following seizures would be potentially transformative for these individuals. Here, we investigate deep brain stimulation to improve level of conscious arousal in a rat model of focal limbic seizures. We found that dual-site stimulation of the central lateral nucleus of the intralaminar thalamus (CL) and the pontine nucleus oralis (PnO) bilaterally during focal limbic seizures restored normal-appearing cortical electrophysiology and markedly improved behavioral arousal. In contrast, single-site bilateral stimulation of CL or PnO alone was insufficient to achieve the same result. These findings support the "network inhibition hypothesis" that focal limbic seizures impair consciousness through widespread inhibition of subcortical arousal. Driving subcortical arousal function would be a novel therapeutic approach to some forms of refractory epilepsy and may be compatible with devices already in use for responsive neurostimulation. Multisite deep brain stimulation of subcortical arousal structures may benefit not only patients with epilepsy but also those with other disorders of consciousness. PMID- 26941381 TI - Motor Learning Induces Plasticity in the Resting Brain-Drumming Up a Connection. AB - Neuroimaging methods have recently been used to investigate plasticity-induced changes in brain structure. However, little is known about the dynamic interactions between different brain regions after extensive coordinated motor learning such as drumming. In this article, we have compared the resting-state functional connectivity (rs-FC) in 15 novice healthy participants before and after a course of drumming (30-min drumming sessions, 3 days a week for 8 weeks) and 16 age-matched novice comparison participants. To identify brain regions showing significant FC differences before and after drumming, without a priori regions of interest, a multivariate pattern analysis was performed. Drum training was associated with an increased FC between the posterior part of bilateral superior temporal gyri (pSTG) and the rest of the brain (i.e., all other voxels). These regions were then used to perform seed-to-voxel analysis. The pSTG presented an increased FC with the premotor and motor regions, the right parietal lobe and a decreased FC with the cerebellum. Perspectives and the potential for rehabilitation treatments with exercise-based intervention to overcome impairments due to brain diseases are also discussed. PMID- 26941380 TI - Early Development of Functional Network Segregation Revealed by Connectomic Analysis of the Preterm Human Brain. AB - Human brain functional networks are topologically organized with nontrivial connectivity characteristics such as small-worldness and densely linked hubs to support highly segregated and integrated information processing. However, how they emerge and change at very early developmental phases remains poorly understood. Here, we used resting-state functional MRI and voxel-based graph theory analysis to systematically investigate the topological organization of whole-brain networks in 40 infants aged around 31 to 42 postmenstrual weeks. The functional connectivity strength and heterogeneity increased significantly in primary motor, somatosensory, visual, and auditory regions, but much less in high order default-mode and executive-control regions. The hub and rich-club structures in primary regions were already present at around 31 postmenstrual weeks and exhibited remarkable expansions with age, accompanied by increased local clustering and shortest path length, indicating a transition from a relatively random to a more organized configuration. Moreover, multivariate pattern analysis using support vector regression revealed that individual brain maturity of preterm babies could be predicted by the network connectivity patterns. Collectively, we highlighted a gradually enhanced functional network segregation manner in the third trimester, which is primarily driven by the rapid increases of functional connectivity of the primary regions, providing crucial insights into the topological development patterns prior to birth. PMID- 26941382 TI - ALDH2 Glu504Lys Confers Susceptibility to Schizophrenia and Impacts Hippocampal Prefrontal Functional Connectivity. AB - Although previous evidence suggested that ALDH2 is a candidate gene for schizophrenia, the association and underlying mechanisms have never been investigated. Therefore, we investigated ALDH2 as a susceptibility gene for schizophrenia and explored the effect of its polymorphisms on brain functions. In the discovery stage, we detected a positive association between a dominant negative mutant, Glu504Lys, and schizophrenia (P= 8.01E-5, OR = 1.34, 95% CI = 1.16-1.55). This association was confirmed in the validation stage (P= 3.48E-6, OR = 1.28, 95% CI = 1.15-1.42). The combined P reached a genome-wide significance (Pcombined= 1.32E-9, OR = 1.30, 95% CI = 1.20-1.42). To investigate the neural mechanism linking Glu504Lys to schizophrenia, we calculated the functional connectivity (FC) and applied an imaging genetics strategy using resting-state fMRI data. The imaging analysis revealed a significant interaction of diagnostic group by genotype for FC between the left hippocampus and the prefrontal cortex. In the Glu homozygotes, hippocampal-prefrontal FC correlated inversely with memory performance in the healthy controls and with the PANSS negative score in the schizophrenia patients. Our results supported a role for ALDH2 in the pathophysiology of schizophrenia. Moreover, variation at Glu504Lys disrupts hippocampal-prefrontal FC, which might be the neural mechanism linking it to the disease. PMID- 26941383 TI - Diverse Synaptic Distributions of G Protein-coupled Estrogen Receptor 1 in Monkey Prefrontal Cortex with Aging and Menopause. AB - Age- and menopause-related impairment in working memory mediated by the dorsolateral prefrontal cortex (dlPFC) occurs in humans and nonhuman primates. Long-term cyclic 17beta-estradiol treatment rescues cognitive deficits in aged ovariectomized rhesus monkeys while restoring highly plastic synapses. Here we tested whether distributions of G protein-coupled estrogen receptor 1 (GPER1) within monkey layer III dlPFC synapses are sensitive to age and estradiol, and coupled to cognitive function. Ovariectomized young and aged monkeys administered vehicle or estradiol were first tested on a delayed response test of working memory. Then, quantitative serial section immunoelectron microscopy was used to determine the distributions of synaptic GPER1. GPER1-containing nonperforated axospinous synapse density was reduced with age, and partially restored with estrogen treatment. The majority of synapses expressed GPER1, which was predominately localized to presynaptic cytoplasm and mitochondria. GPER1 was also abundant at plasmalemmas, and within cytoplasmic and postsynaptic density (PSD) domains of dendritic spines. GPER1 levels did not differ with age or treatment, and none of the variables examined were tightly associated with cognitive function. However, greater representation of GPER1 subjacent to the PSD accompanied higher synapse density. These data suggest that GPER1 is positioned to support diverse functions key to synaptic plasticity in monkey dlPFC. PMID- 26941386 TI - Blood's 70th anniversary: 1988-1992. PMID- 26941385 TI - Mixed Body/Hand Reference Frame for Reaching in 3D Space in Macaque Parietal Area PEc. AB - The neural correlates of coordinate transformations from vision to action are expressed in the activity of posterior parietal cortex (PPC). It has been demonstrated that among the medial-most areas of the PPC, reaching targets are represented mainly in hand-centered coordinates in area PE, and in eye-centered, body-centered, and mixed body/hand-centered coordinates in area V6A. Here, we assessed whether neurons of area PEc, located between V6A and PE in the medial PPC, encode targets in body-centered, hand-centered, or mixed frame of reference during planning and execution of reaching. We studied 104 PEc cells in 3 Macaca fascicularis. The animals performed a reaching task toward foveated targets located at different depths and directions in darkness, starting with the hand from 2 positions located at different depths, one next to the trunk and the other far from it. We show that most PEc neurons encoded targets in a mixed body/hand centered frame of reference. Although the effect of hand position was often rather strong, it was not as strong as reported previously in area PE. Our results suggest that area PEc represents an intermediate node in the gradual transformation from vision to action that takes place in the reaching network of the dorsomedial PPC. PMID- 26941384 TI - Effects of Prior-Knowledge on Brain Activation and Connectivity During Associative Memory Encoding. AB - Forming new associations is a fundamental process of building our knowledge system. At the brain level, how prior-knowledge influences acquisition of novel associations has not been thoroughly investigated. Based on recent cognitive neuroscience literature on multiple-component memory processing, we hypothesize that prior-knowledge triggers additional evaluative, semantic, or episodic binding processes, mainly supported by the ventromedial prefrontal cortex (vmPFC), anterior temporal pole (aTPL), and hippocampus (HPC), to facilitate new memory encoding. To test this hypothesis, we scanned 20 human participants with functional magnetic resonance imaging (fMRI) while they associated novel houses with famous or nonfamous faces. Behaviorally, we found beneficial effects of prior-knowledge on associative memory. At the brain level, we found that the vmPFC and HPC, as well as the parahippocampal place area (PPA) and fusiform face area, showed stronger activation when famous faces were involved. The vmPFC, aTPL, HPC, and PPA also exhibited stronger activation when famous faces elicited stronger emotions and memories, and when associations were later recollected. Connectivity analyses also suggested that HPC connectivity with the vmPFC plays a more important role in the famous than nonfamous condition. Taken together, our results suggest that prior-knowledge facilitates new associative encoding by recruiting additional perceptual, evaluative, or associative binding processes. PMID- 26941387 TI - The clotting action of Russell viper venom. 1954. AB - Samuel I. Rapaport made seminal contributions to our basic understanding of blood coagulation. This paper beautifully illustrates his scientific approach through characterization of the clotting activity of venom from Daboia russelii, distinguishing it from the brain "thromboplastic" activity used in the prothrombin time. Using plasma from patients with deficiencies of proconvertin (factor VII), proaccelerin (factor V), antihemophilic globulin (factor VIII), or Christmas factor (factor IX), Rapaport and colleagues demonstrated that the venom's clotting activity does not require factor VII, but does require factor V and lipid. Thus, by combining the venom clotting test with the quick clotting time (prothrombin time), it was possible to diagnose factor VII deficiency. The venom is now known to act by directly activating factor X, and a form of the clotting test is used in the diagnosis of lupus anticoagulants. PMID- 26941389 TI - Platelets enrich their transcriptome circle. AB - In this issue of Blood, Alhasan et al report the existence of circular RNAs (circRNAs) in circulating human platelets, thereby revealing yet another facet of their already diverse transcriptome. PMID- 26941388 TI - Angry macrophages patrol for fibrin. AB - In this issue of Blood, Motley et al have identified a novel and unexpected mechanism for clearance of extravascular fibrin that is accomplished by a specific proinflammatory macrophage population and is dependent upon active plasmin, yet independent of known fibrinogen receptors. PMID- 26941390 TI - The heads and the tails of malaria and VWF. AB - In this issue of Blood, O'Regan et al have extended our understanding of von Willebrand factor (VWF) in the pathogenesis of malaria. According to the World Health Organization (http://www.who.int/gho/malaria/en/), malaria affects 3.2 billion people in 97 countries with 198 million cases having occurred in 2013, and of those, 584 000 died. Ninety percent of those deaths in 2013 were children under the age of 5. The most devastating form of the disease is cerebral malaria, which occurs most frequently in young children. Although blood coagulation changes such as disseminated intravascular coagulation have been recognized since the 1970s, recent studies have focused on markers of these hemostatic changes as being most prevalent in cerebral malaria caused by Plasmodium falciparum. Cerebral malaria is more lethal in children than adults. Exchange transfusion has been used as an aggressive adjunct therapy for this condition. PMID- 26941391 TI - NK cells pave the road for alloengraftment. AB - In this issue of Blood, Alvarez et al describe a novel inhibitory receptor mediated role for unlicensed natural killer (U-NK) cells in allogeneic graft facilitation. PMID- 26941392 TI - Disgust-Related Personality Traits in Men with Olfactory Dysfunction. AB - Individuals differ in disgust-related personality traits, such as disgust proneness (DP: tendency to experience disgust), disgust sensitivity (DS: tendency to perceive one's own disgust experiences as difficult to control), and self disgust (SD: strong dislike/aversion of yourself). Olfaction is one crucial input for the disgust system. The present study investigated disgust dispositions in individuals with persistent olfactory dysfunction. We studied 16 male patients with anosmia, 20 patients with hyposmia, and 20 normosmic men, and compared DP, DS, and SD scores between the groups. Dysosmic patients reported lowered DP toward spoilage, elevated DP toward poor hygiene, and elevated SD. There were no group differences with regard to DS. We assume that difficulties of perceiving one's own body odor and resulting challenges for personal hygiene are related to domain-specifically elevated trait disgust. Enhanced personal disgust may be related to a general social insecurity in people with olfactory malfunction. Future research should additionally use brain imaging methods to investigate associations between alterations of the disgust system and olfactory dysfunction. PMID- 26941393 TI - Antibody recognition of HIV and dengue glycoproteins. AB - The last 6 years have witnessed an explosion of discoveries at the interface of glycobiology and immunology. Binding of clustered oligosaccharides has turned out to be a very frequent mode by which human antibodies have developed broadly neutralizing activity against HIV. This mini-review will cover many recent developments in the HIV antibody field, as well as emerging data about Dengue broadly neutralizing antibodies. PMID- 26941394 TI - The fucosidase-pool of Emticicia oligotrophica: Biochemical characterization and transfucosylation potential. AB - Three novel bacterial alpha-l-fucosidases, which cleave terminal fucosyl residues from glycoconjugates are reported in this work. Originating from the recently discovered bacterium Emticicia oligotrophica, recombinant fucosidase isoforms designated as Eo0918, Eo3066 and Eo3812 were shown to have the highest activity between pH 6.0 and 7.0 and temperature optima between 30 and 45 degrees C. All enzymes catalyzed the hydrolysis of the model substrate pNP-alpha-l-fucose and revealed significantly different regiospecificities towards fucose-containing oligosaccharides: Eo0918 liberated exclusively alpha1,6-linked fucose and Eo3812 released only alpha1,3-fucosyl residues, whereas Eo3066 showed broader substrate promiscuity. The enzymatic activity of Eo0918 and Eo3812 increased upon the addition of Ca(2+), Mn(2+) and Zn(2+) ions, whereas the activity of Eo3066 was significantly decreased in the presence of these metal ions. In addition, Eo0918 also catalyzed the transfer of fucose from pNP-alpha-l-fucose to the 7-hydroxyl group of 4-methylumbelliferone with up to 15% transglycosylation yield. Facile recombinant expression in E. coli, distinct substrate specificities and the transglycosylation ability of Eo0918 presented herein make these newly discovered fucosidases valuable candidates for bioanalytical and biotechnological applications. PMID- 26941396 TI - Physical activity in the prevention of coronary heart disease: implications for the clinician. AB - Cardiovascular disease (CVD) continues to be a leading cause of death worldwide. Because regular physical activity (PA) independently decreases the risk of coronary heart disease (CHD) while also having a positive, dose-related impact on other cardiovascular (CV) risk factors, it has increasingly become a focus of CHD prevention. Current guidelines recommend 30 min of moderate-intensity PA 5 days a week, but exercise regimens remain underused. PA adherence can be fostered with a multilevel approach that involves active individual participation, physician counselling and health coaching, community involvement, and policy change, with incorporation of cardiac rehabilitation for patients requiring secondary prevention. Viewing exercise quantity as a vital sign, prescribing PA like a medication, and using technology, such as smartphone applications, encourage a global shift in focus from CVD treatment to prevention. Community-wide, home based and internet-based prevention initiatives may also offer a developing pool of resources that can be tapped into to promote education and PA compliance. This review summarises the underlying rationale, current guidelines for and recommendations to cultivate a comprehensive focus in the endorsement of PA in the primary and secondary prevention of CHD. PMID- 26941395 TI - The microtubule-associated protein PRC1 promotes early recurrence of hepatocellular carcinoma in association with the Wnt/beta-catenin signalling pathway. AB - OBJECTIVES: Hepatocellular carcinoma (HCC) is the second leading cause of cancer mortality worldwide. Alterations in microtubule-associated proteins (MAPs) have been observed in HCC. However, the mechanisms underlying these alterations remain poorly understood. Our aim was to study the roles of the MAP protein regulator of cytokinesis 1 (PRC1) in hepatocarcinogenesis and early HCC recurrence. DESIGN: PRC1 expression in HCC samples was evaluated by microarray, immunoblotting and immunohistochemistry analysis. Molecular and cellular techniques including siRNA mediated and lentiviral vector-mediated knockdown were used to elucidate the functions and mechanisms of PRC1. RESULTS: PRC1 expression was associated with early HCC recurrence and poor patient outcome. In HCC, PRC1 exerted an oncogenic effect by promoting cancer proliferation, stemness, metastasis and tumourigenesis. We further demonstrated that the expression and distribution of PRC1 is dynamically regulated by Wnt3a signalling. PRC1 knockdown impaired transcription factor (TCF) transcriptional activity, decreased Wnt target expression and reduced nuclear beta-catenin levels. Mechanistically, PRC1 interacts with the beta-catenin destruction complex, regulates Wnt3a-induced membrane sequestration of this destruction complex, inhibits adenomatous polyposis coli (APC) stability and promotes beta-catenin release from the APC complex. In vivo, high PRC1 expression correlated with nuclear beta-catenin and Wnt target expression. PRC1 acted as a master regulator of a set of 48 previously identified Wnt-regulated recurrence-associated genes (WRRAGs) in HCC. Thus, PRC1 controlled the expression and function of WRRAGs such as FANCI, SPC25, KIF11 and KIF23 via Wnt signalling. CONCLUSIONS: We identified PRC1 as a novel Wnt target that functions in a positive feedback loop that reinforces Wnt signalling to promote early HCC recurrence. PMID- 26941397 TI - Whole exome sequencing identifies lncRNA GAS8-AS1 and LPAR4 as novel papillary thyroid carcinoma driver alternations. AB - Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. However, we know little of mutational spectrum in the Chinese population. Thus, here we report the identification of somatic mutations for Chinese PTC using 402 tumor-normal pairs (Discovery: 91 pairs via exome sequencing; validation: 311 pairs via Sanger sequencing). We observed three distinct mutational signatures, evidently different from the two mutational signatures among Caucasian PTCs. Ten significantly mutated genes were identified, most previously uncharacterized. Notably, we found that long non-coding RNA (lncRNA) GAS8-AS1 is the secondary most frequently altered gene and acts as a novel tumor suppressor in PTC. As a mutation hotspot, the c.713A>G/714T>C dinucleotide substitution was found among 89.1% patients with GAS8-AS1 mutations and associated with advanced PTC disease (P = 0.009). Interestingly, the wild-type lncRNA GAS8-AS1 (A713T714) showed consistently higher capability to inhibit cancer cell growth compared to the mutated lncRNA (G713C714). Further studies also elucidated the oncogene nature of the G protein-coupled receptor LPAR4 and its c.872T>G (p.Ile291Ser) mutation in PTC malignant transformation. The BRAF c.1799T>A (p.Val600Glu) substitution was present in 59.0% Chinese PTCs, more frequently observed in patients with lymph node metastasis (P = 1.6 * 10(-4)). Together our study defines a exome mutational spectrum of PTC in the Chinese population and highlights lncRNA GAS8-AS1 and LPAR4 as potential diagnostics and therapeutic targets. PMID- 26941398 TI - BRAF inhibition in hairy cell leukemia with low-dose vemurafenib. AB - The activating mutation of the BRAF serine/threonine protein kinase (BRAF V600E) is the key driver mutation in hairy cell leukemia (HCL), suggesting opportunities for therapeutic targeting. We analyzed the course of 21 HCL patients treated with vemurafenib outside of trials with individual dosing regimens (240-1920 mg/d; median treatment duration, 90 days). Vemurafenib treatment improved blood counts in all patients, with platelets, neutrophils, and hemoglobin recovering within 28, 43, and 55 days (median), respectively. Complete remission was achieved in 40% (6/15 of evaluable patients) and median event-free survival was 17 months. Response rate and kinetics of response were independent of vemurafenib dosing. Retreatment with vemurafenib led to similar response patterns (n = 6). Pharmacodynamic analysis of BRAF V600E downstream targets showed that vemurafenib (480 mg/d) completely abrogated extracellular signal-regulated kinase phosphorylation of hairy cells in vivo. Typical side effects also occurred at low dosing regimens. We observed the development of acute myeloid lymphoma (AML) subtype M6 in 1 patient, and the course suggested disease acceleration triggered by vemurafenib. The phosphatidylinositol 3-kinase hotspot mutation (E545K) was identified in the AML clone, providing a potential novel mechanism for paradoxical BRAF activation. These data provide proof of dependence of HCL on active BRAF signaling. We provide evidence that antitumor and side effects are observed with 480 mg vemurafenib, suggesting that dosing regimens in BRAF-driven cancers could warrant reassessment in trials with implications for cost of cancer care. PMID- 26941399 TI - miR-181a negatively regulates NF-kappaB signaling and affects activated B-cell like diffuse large B-cell lymphoma pathogenesis. AB - Distinct subgroups of diffuse large B-cell lymphoma (DLBCL) genetically resemble specific mature B-cell populations that are blocked at different stages of the immune response in germinal centers (GCs). The activated B-cell (ABC)-like subgroup resembles post-GC plasmablasts undergoing constitutive survival signaling, yet knowledge of the mechanisms that negatively regulate this oncogenic signaling remains incomplete. In this study, we report that microRNA (miR)-181a is a negative regulator of nuclear factor kappa-light-chain enhancer of activated B-cells (NF-kappaB) signaling. miR-181a overexpression significantly decreases the expression and activity of key NF-kappaB signaling components. Moreover, miR-181a decreases DLBCL tumor cell proliferation and survival, and anti-miR-181a abrogates these effects. Remarkably, these effects are augmented in the NF-kappaB dependent ABC-like subgroup compared with the GC B-cell (GCB)-like DLBCL subgroup. Concordantly, in vivo analyses of miR-181a induction in xenografts results in slower tumor growth rate and prolonged survival in the ABC like DLBCL xenografts compared with the GCB-like DLBCL. We link these outcomes to relatively lower endogenous miR-181a expression and to NF-kappaB signaling dependency in the ABC-like DLBCL subgroup. Our findings indicate that miR-181a inhibits NF-kappaB activity, and that manipulation of miR-181a expression in the ABC-like DLBCL genetic background may result in a significant change in the proliferation and survival phenotype of this malignancy. PMID- 26941400 TI - Silent cerebral infarcts and cerebral aneurysms are prevalent in adults with sickle cell anemia. PMID- 26941402 TI - PLZF mutation alters mouse hematopoietic stem cell function and cell cycle progression. AB - Hematopoietic stem cells (HSCs) give rise to all blood populations due to their long-term self-renewal and multipotent differentiation capacities. Because they have to persist throughout an organism's life span, HSCs tightly regulate the balance between proliferation and quiescence. Here, we investigated the role of the transcription factor promyelocytic leukemia zinc finger (plzf) in HSC fate using the Zbtb16(lu/lu)mouse model, which harbors a natural spontaneous mutation that inactivates plzf. Regenerative stress revealed that Zbtb16(lu/lu)HSCs had a lineage-skewing potential from lymphopoiesis toward myelopoiesis, an increase in the long-term-HSC pool, and a decreased repopulation potential. Furthermore, oldplzf-mutant HSCs present an amplified aging phenotype, suggesting that plzf controls age-related pathway. We found that Zbtb16(lu/lu)HSCs harbor a transcriptional signature associated with a loss of stemness and cell cycle deregulation. Lastly, cell cycle analyses revealed an important role for plzf in the regulation of the G1-S transition of HSCs. Our study reveals a new role for plzf in regulating HSC function that is linked to cell cycle regulation, and positions plzf as a key player in controlling HSC homeostasis. PMID- 26941401 TI - UV-inactivated HSV-1 potently activates NK cell killing of leukemic cells. AB - Herein we demonstrate that oncolytic herpes simplex virus-1 (HSV-1) potently activates human peripheral blood mononuclear cells (PBMCs) to lyse leukemic cell lines and primary acute myeloid leukemia samples, but not healthy allogeneic lymphocytes. Intriguingly, we found that UV light-inactivated HSV-1 (UV-HSV-1) is equally effective in promoting PBMC cytolysis of leukemic cells and is 1000- to 10 000-fold more potent at stimulating innate antileukemic responses than UV inactivated cytomegalovirus, vesicular stomatitis virus, reovirus, or adenovirus. Mechanistically, UV-HSV-1 stimulates PBMC cytolysis of leukemic cells, partly via Toll-like receptor-2/protein kinase C/nuclear factor-kappaB signaling, and potently stimulates expression of CD69, degranulation, migration, and cytokine production in natural killer (NK) cells, suggesting that surface components of UV HSV-1 directly activate NK cells. Importantly, UV-HSV-1 synergizes with interleukin-15 (IL-15) and IL-2 in inducing activation and cytolytic activity of NK cells. Additionally, UV-HSV-1 stimulates glycolysis and fatty acid oxidation dependent oxygen consumption in NK cells, but only glycolysis is required for their enhanced antileukemic activity. Last, we demonstrate that T cell-depleted human PBMCs exposed to UV-HSV-1 provide a survival benefit in a murine xenograft model of human acute myeloid leukemia (AML). Taken together, our results support the preclinical development of UV-HSV-1 as an adjuvant, alone or in combination with IL-15, for allogeneic donor mononuclear cell infusions to treat AML. PMID- 26941413 TI - Study of the Migration of Stabilizer and Plasticizer from Polyethylene Terephthalate into Food Simulants. AB - This study investigates the determination and migration of stabilizers and plasticizers from polyethylene terephthalate (PET). Two methods [ultrasonic extraction with dichloromethane or methanol and total dissolution with phenol/tetrachloroethane (m:m/1:1)] for pre-concentration of additives in PET material were performed. The diffusion of these additives from PET was evaluated by immersing in deionized water, acetic acid 3% (w/v), ethanol 20% (v/v), ethanol 50% (v/v) and isooctane at 20, 40, 55 and 70 degrees C, respectively. The amount of additives in PET and food simulants was quantified by high-performance liquid chromatography-photodiode array detector (HPLC-PDA). The optimized HPLC method showed high correlation coefficients (R >= 0.9993), good precision, accuracy and reproducibility. Experimental diffusion coefficients (DP) were calculated according to a mathematical model based on Fick's second law, and the DP values of considered compounds ranged from 9.8 * 10(-15) to 1.4 * 10(-8) cm(2) s(-1) The experimental DP values were also compared with that predicted by currently used diffusion models. In addition, the effect of temperature on the diffusion rate was assessed. The effect of temperature on the diffusion coefficients followed an Arrhenius-type model with active energies ranged from 40.4 to 113.8 kJ mol(-1) for the target compounds. PMID- 26941412 TI - Surfactant-Assisted Pressurized Liquid Extraction at Room Temperature for Radix glycyrrhizae by a New Class of Surfactants. AB - A laboratory-assembled surfactant-assisted pressurized liquid extraction system at room temperature was used for the extraction of glycyrrhizin (GLY) in Radix glycyrrhizae. Environmentally friendly saccharide fatty acid ester such as glucose oleic acid ester is proposed to replace chemical-based surfactants. As the chemical properties of the surfactant obtained were unknown initially, lipase catalyzed synthesis and liquid chromatography with tandem mass spectrometry were used to ascertain the identity. Surfactant-assisted pressurized liquid extraction (PLE) was carried out dynamically and the extraction efficiencies of the proposed method using different concentration of glucose oleic acid ester were compared with sonication using an organic solvent (ethanol/water, 70:30). The extraction efficiencies of GLY in Radix glycyrrhizae using surfactant-assisted PLE was observed to be higher compared with sonication. The method precision was found to vary from 1.3 to 5.1% (relative standard deviation, RSD, n= 6) on different days. The new method demonstrated the possibility for the extraction to be carried out at room temperature for the production of botanical extracts. PMID- 26941414 TI - Improved Method for the Qualitative Analyses of Palm Oil Carotenes Using UPLC. AB - Palm oil is the richest source of natural carotenes, comprising 500-700 ppm in crude palm oil (CPO). Its concentration is found to be much higher in oil extracted from palm-pressed fiber, a by-product from the milling of oil palm fruits. There are 11 types of carotenes in palm oil, excluding the cis/trans isomers of some of the carotenes. Qualitative separation of these individual carotenes is particularly useful for the identification and confirmation of different types of oil as the carotenes profile is unique to each type of vegetable oil. Previous studies on HPLC separation of the individual palm carotenes reported a total analyses time of up to 100 min using C30 stationary phase. In this study, the separation was completed in <5 min. The qualitative separation was successfully carried out using a commonly used stationary phase, C18. PMID- 26941407 TI - Understanding TERT Promoter Mutations: A Common Path to Immortality. AB - Telomerase (TERT) activation is a fundamental step in tumorigenesis. By maintaining telomere length, telomerase relieves a main barrier on cellular lifespan, enabling limitless proliferation driven by oncogenes. The recently discovered, highly recurrent mutations in the promoter of TERT are found in over 50 cancer types, and are the most common mutation in many cancers. Transcriptional activation of TERT, via promoter mutation or other mechanisms, is the rate-limiting step in production of active telomerase. Although TERT is expressed in stem cells, it is naturally silenced upon differentiation. Thus, the presence of TERT promoter mutations may shed light on whether a particular tumor arose from a stem cell or more differentiated cell type. It is becoming clear that TERT mutations occur early during cellular transformation, and activate the TERT promoter by recruiting transcription factors that do not normally regulate TERT gene expression. This review highlights the fundamental and widespread role of TERT promoter mutations in tumorigenesis, including recent progress on their mechanism of transcriptional activation. These somatic promoter mutations, along with germline variation in the TERT locus also appear to have significant value as biomarkers of patient outcome. Understanding the precise molecular mechanism of TERT activation by promoter mutation and germline variation may inspire novel cancer cell-specific targeted therapies for a large number of cancer patients. PMID- 26941416 TI - Heart Failure With Preserved Ejection Fraction: Do You Know Your Left Atrial Strain? PMID- 26941415 TI - Prognostic Utility and Clinical Significance of Cardiac Mechanics in Heart Failure With Preserved Ejection Fraction: Importance of Left Atrial Strain. AB - BACKGROUND: Left atrial (LA) enlargement is associated with adverse events in heart failure with preserved ejection fraction (HFpEF). However, the role of LA mechanics (ie, LA strain measures) in HFpEF has not been well studied. We hypothesized that in HFpEF, reduced (worse) LA strain is a key pathophysiologic abnormality and is a stronger correlate of adverse events than left ventricular or right ventricular longitudinal strain. METHODS AND RESULTS: We evaluated baseline LA function in 308 patients with HFpEF who were followed up longitudinally for adverse outcomes. All patients underwent speckle-tracking echocardiography for measurement of left ventricular longitudinal strain, right ventricular free wall strain, and LA booster, conduit, and reservoir strains. The clinical and prognostic significance of left ventricular, right ventricular, and LA strain measures was assessed by regression analyses. The mean age was 65+/-13 years, 64% were women, 26% had atrial fibrillation, and LA enlargement was present in the majority of patients (67%). Decreased LA reservoir strain was associated with increased pulmonary vascular resistance (P<0.0001) and decreased peak oxygen consumption (P=0.0001). Of the left ventricular, right ventricular, and LA strain measures, LA reservoir strain was the strongest correlate of adverse events and was independently associated with the composite outcome of cardiovascular hospitalization or death (adjusted hazard ratio per 1-SD decrease in LA strain, 1.54; 95% CI, 1.15-2.07; P=0.006). CONCLUSIONS: Abnormal indices of LA mechanics (particularly LA reservoir strain) are powerful clinical and prognostic factors in HFpEF. Unloading the LA and augmentation of LA function may be important future therapeutic targets in HFpEF. REGISTRATION INFORMATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01030991. PMID- 26941417 TI - Favorable Cardiovascular Risk Profile Is Associated With Lower Healthcare Costs and Resource Utilization: The 2012 Medical Expenditure Panel Survey. AB - BACKGROUND: The American Heart Association's 2020 Strategic Goals emphasize the value of optimizing risk factor status to reduce the burden of morbidity and mortality. In this study, we aimed to quantify the overall and marginal impact of favorable cardiovascular risk factor (CRF) profile on healthcare expenditure and resource utilization in the United States among those with and without cardiovascular disease (CVD). METHODS AND RESULTS: The study population was derived from the 2012 Medical Expenditure Panel Survey (MEPS). Direct and indirect costs were calculated for all-cause healthcare resource utilization. Variables of interest included CVD diagnoses (coronary artery disease, stroke, peripheral artery disease, dysrhythmias, or heart failure), ascertained by International Classification of Diseases, Ninth Edition, Clinical Modification codes, and CRF profile (hypertension, diabetes mellitus, hypercholesterolemia, smoking, physical activity, and obesity). Two-part econometric models were used to study expenditure data. The final study sample consisted of 15 651 MEPS participants (58.5+/-12 years, 54% female). Overall, 5921 (37.8%) had optimal, 7002 (44.7%) had average, and 2728 (17.4%) had poor CRF profile, translating to 54.2, 64.1, and 24.9 million adults in United States, respectively. Significantly lower health expenditures were noted with favorable CRF profile across CVD status. Among study participants with established CVD, overall healthcare expenditures with optimal and average CRF profile were $5946 and $3731 less compared with those with poor CRF profile. The respective differences were $4031 and $2560 in those without CVD. CONCLUSIONS: Favorable CRF profile is associated with significantly lower medical expenditure and healthcare utilization among individuals with and without established CVD. PMID- 26941418 TI - Genetic and Epigenetic Marks Weave Intricate Connections in Cardiac Disease. PMID- 26941419 TI - The Good Neighbor: Coping With Insulin Resistance by Modulating Adipose Tissue Endothelial Cell Function. PMID- 26941420 TI - New Roles for an Old Pore. PMID- 26941421 TI - The Secret Life of Telomerase. PMID- 26941422 TI - c-kit+ Cardiac Stem Cells: Spontaneous Creation or a Perplexing Reality. PMID- 26941424 TI - Cyclic AMP Sensor EPAC Proteins and Their Role in Cardiovascular Function and Disease. AB - cAMP is a universal second messenger that plays central roles in cardiovascular regulation influencing gene expression, cell morphology, and function. A crucial step toward a better understanding of cAMP signaling came 18 years ago with the discovery of the exchange protein directly activated by cAMP (EPAC). The 2 EPAC isoforms, EPAC1 and EPAC2, are guanine-nucleotide exchange factors for the Ras like GTPases, Rap1 and Rap2, which they activate independently of the classical effector of cAMP, protein kinase A. With the development of EPAC pharmacological modulators, many reports in the literature have demonstrated the critical role of EPAC in the regulation of various cAMP-dependent cardiovascular functions, such as calcium handling and vascular tone. EPAC proteins are coupled to a multitude of effectors into distinct subcellular compartments because of their multidomain architecture. These novel cAMP sensors are not only at the crossroads of different physiological processes but also may represent attractive therapeutic targets for the treatment of several cardiovascular disorders, including cardiac arrhythmia and heart failure. PMID- 26941423 TI - Empowering Adult Stem Cells for Myocardial Regeneration V2.0: Success in Small Steps. AB - Much has changed since our survey of the landscape for myocardial regeneration powered by adult stem cells 4 years ago.(1) The intervening years since that first review has witnessed an explosive expansion of studies that advance both understanding and implementation of adult stem cells in promoting myocardial repair. Painstaking research from innumerable laboratories throughout the world is prying open doors that may lead to restoration of myocardial structure and function in the wake of pathological injury. This global effort has produced deeper mechanistic comprehension coupled with an evolving appreciation for the complexity of myocardial regeneration in the adult context. Undaunted by both known and (as yet) unknown challenges, pursuit of myocardial regenerative medicine mediated by adult stem cell therapy has gathered momentum fueled by tantalizing clues and visionary goals. This concise review takes a somewhat different perspective than our initial treatise, taking stock of the business sector that has become an integral part of the field while concurrently updating state of affairs in cutting edge research. Looking retrospectively at advancement over the years as all reviews eventually must, the fundamental lesson to be learned is best explained by Jonatan Martensson: "Success will never be a big step in the future. Success is a small step taken just now." PMID- 26941426 TI - Correction. PMID- 26941427 TI - Health Care Education Must Be More of a Team Sport. PMID- 26941425 TI - Moving Forwards by Blocking Back-Flow: The Yin and Yang of MI Therapy. AB - Mitochondrial reactive oxygen species production has emerged as an important pathological mechanism in myocardial ischemia/reperfusion injury. Attempts at targeting reactive oxygen species by scavenging using antioxidants have, however, been clinically disappointing. This review will provide an overview of the current understanding of mitochondrial reactive oxygen species in ischemia/reperfusion injury. We will outline novel therapeutic approaches designed to directly target the mitochondrial respiratory chain and prevent excessive reactive oxygen species production and its associated pathology. This approach could lead to more effective interventions in an area where there is an urgent need for new treatments. PMID- 26941428 TI - Deliberate Integration of Student Leadership Development in Doctor of Pharmacy Programs. AB - The CAPE 2013 Outcomes answered the call for increased student leadership development (SLD) by identifying leadership as a desired curricular goal. To meet this outcome, colleges and schools of pharmacy are advised to first identify a set of SLD competencies aligned with their institution's mission and goals and then organize these competencies into a SLD framework/model. Student leadership development should be integrated vertically and horizontally within the curriculum in a deliberate and longitudinal manner. It should include all student pharmacists, begin at the point of admission, and extend beyond extracurricular activities. The school's assessment plan should be aligned with the identified SLD competencies so student learning related to leadership is assessed. To accomplish these recommendations, a positive environment for SLD should be cultivated within the school, including administrative backing and resources, as well as support among the broader faculty for integrating SLD into the curriculum. PMID- 26941429 TI - Advancing Pharmacogenomics Education in the Core PharmD Curriculum through Student Personal Genomic Testing. AB - OBJECTIVE: To develop, implement, and evaluate "Test2Learn" a program to enhance pharmacogenomics education through the use of personal genomic testing (PGT) and real genetic data. DESIGN: One hundred twenty-two second-year doctor of pharmacy (PharmD) students in a required course were offered PGT as part of a larger program approach to teach pharmacogenomics within a robust ethical framework. The program added novel learning objectives, lecture materials, analysis tools, and exercises using individual-level and population-level genetic data. Outcomes were assessed with objective measures and pre/post survey instruments. ASSESSMENT: One hundred students (82%) underwent PGT. Knowledge significantly improved on multiple assessments. Genotyped students reported a greater increase in confidence in understanding test results by the end of the course. Similarly, undergoing PGT improved student's self-perceived ability to empathize with patients compared to those not genotyped. Most students (71%) reported feeling PGT was an important part of the course, and 60% reported they had a better understanding of pharmacogenomics specifically because of the opportunity. CONCLUSION: Implementation of PGT in the core pharmacy curriculum was feasible, well-received, and enhanced student learning of pharmacogenomics. PMID- 26941430 TI - Student Pharmacists' Perceptions of a Composite Examination in Their First Professional Year. AB - OBJECTIVE: To assess first-year (P1) pharmacy students' studying behaviors and perceptions after implementation of a new computerized "composite examination" (CE) testing procedure. METHODS: Student surveys were conducted to assess studying behavior and perceptions about the CE before and after its implementation. RESULTS: Surveys were completed by 149 P1 students (92% response rate). Significant changes between survey results before and after the CE included an increase in students' concerns about the limited number of questions per course on each examination and decreased concerns about the time allotted and the inability to write on the CEs. Significant changes in study habits included a decrease in cramming (studying shortly before the test) and an increase in priority studying (spending more time on one course than another). CONCLUSION: The CE positively changed assessment practice at the college. It helped overcome logistic challenges in computerized testing and drove positive changes in study habits. PMID- 26941431 TI - Medical Literature Evaluation Education at US Schools of Pharmacy. AB - OBJECTIVE: To determine how medical literature evaluation (MLE) is being taught across the United States and to summarize methods for teaching and assessing MLE. METHODS: An 18-question survey was administered to faculty members whose primary responsibility was teaching MLE at schools and colleges of pharmacy. RESULTS: Responses were received from 90 (71%) US schools of pharmacy. The most common method of integrating MLE into the curriculum was as a stand-alone course (49%). The most common placement was during the second professional year (43%) or integrated throughout the curriculum (25%). The majority (77%) of schools used a team-based approach. The use of active-learning strategies was common as was the use of multiple methods of evaluation. Responses varied regarding what role the course director played in incorporating MLE into advanced pharmacy practice experiences (APPEs). CONCLUSION: There is a trend toward incorporating MLE education components throughout the pre-APPE curriculum and placement of literature review/evaluation exercises into therapeutics practice skills laboratories to help students see how this skill integrates into other patient care skills. Several pre-APPE educational standards for MLE education exist, including journal club activities, a team-based approach to teaching and evaluation, and use of active-learning techniques. PMID- 26941432 TI - Admissions Criteria as Predictors of Academic Performance in a Three-Year Pharmacy Program at a Historically Black Institution. AB - OBJECTIVE: To determine the ability of University of Maryland Eastern Shore School of Pharmacy's admissions criteria to predict students' academic performance in a 3-year pharmacy program and to analyze transferability to African-American students. METHODS: Statistical analyses were conducted on retrospective data for 174 students. Didactic and experiential scores were used as measures of academic performance. RESULTS: Pharmacy College Admission Test (PCAT), grade point average (GPA), interview, and observational scores combined with previous pharmacy experience and biochemistry coursework predicted the students' academic performance except second-year (P2) experiential performance. For African-American students, didactic performance positively correlated with PCAT writing subtests, while the experiential performance positively correlated with previous pharmacy experience and observational score. For nonAfrican American students, didactic performance positively correlated with PCAT multiple choice subtests, and experiential performance with interview score. The prerequisite GPA positively correlated with both of the student subgroups' didactic performance. CONCLUSION: Both PCAT and GPA were predictors of didactic performance, especially in nonAfrican-Americans. Pharmacy experience and observational scores were predictors of experiential performance, especially in African-Americans. PMID- 26941433 TI - Global Experiential and Didactic Education Opportunities at US Colleges and Schools of Pharmacy. AB - OBJECTIVE: To assess the characteristics of global experiential and didactic education offerings in the pharmacy curricula. METHODS: A 2-stage web-based review of US colleges and schools of pharmacy identified country locations of international advanced pharmacy practice experiences (APPE), globally focused didactic courses, and whether these offerings were interprofessional. Schools were contacted to confirm their offerings and were asked about student participation and demand. RESULTS: Sixty-four percent of responding schools confirmed an international APPE offering in 67 different countries with an average graduating class participation of 6.1%. Forty-seven percent of responding schools confirmed a globally focused course offering with an average graduating class participation of 13.1%. Almost two thirds of international APPEs and a majority of courses were designated as interprofessional. Student demand did not outweigh supply for either. CONCLUSION: Colleges and schools of pharmacy in the United States are continuing to develop global education opportunities for students in the classroom and throughout the world. PMID- 26941434 TI - Racial Differences in Communication Apprehension and Interprofessional Socialization in Fourth-Year Doctor of Pharmacy Students. AB - OBJECTIVE: To examine racial differences in communication apprehension and interprofessional socialization in fourth-year PharmD students and to investigate the relationship between the two constructs. METHODS: Two measures with reliability and validity psychometric evidence were administered to fourth-year pharmacy students at a single historically black university with a large racial minority population. The Personal Report of Communication Apprehension (PRCA-24) measures level of fear or anxiety associated with communication. The Interprofessional Socialization and Valuing Scale (ISVS) measures beliefs, attitudes, and behaviors towards interprofessional collaborative practice. RESULTS: One hundred fourteen students completed the survey. This produced a 77.4% response rate and 45.6% of the participants were African American. There were significant differences between races (ie, White, African-American, and Asian) on both measures. The PCRA-24 and ISVS were significantly correlated in each racial group. CONCLUSION: As pharmacy education moves to more interprofessional collaborations, the racial differences need to be considered and further explored. Pharmacy curricula can be structured to promote students' comfort when communicating interprofessionally across racial groups. Understanding of culture and early education in cultural competence may need to be emphasized to navigate racial or cultural differences. PMID- 26941435 TI - The Validation of a Case-Based, Cumulative Assessment and Progressions Examination. AB - OBJECTIVE: To assess content and criterion validity, as well as reliability of an internally developed, case-based, cumulative, high-stakes third-year Annual Student Assessment and Progression Examination (P3 ASAP Exam). METHODS: Content validity was assessed through the writing-reviewing process. Criterion validity was assessed by comparing student scores on the P3 ASAP Exam with the nationally validated Pharmacy Curriculum Outcomes Assessment (PCOA). Reliability was assessed with psychometric analysis comparing student performance over four years. RESULTS: The P3 ASAP Exam showed content validity through representation of didactic courses and professional outcomes. Similar scores on the P3 ASAP Exam and PCOA with Pearson correlation coefficient established criterion validity. Consistent student performance using Kuder-Richardson coefficient (KR-20) since 2012 reflected reliability of the examination. CONCLUSION: Pharmacy schools can implement internally developed, high-stakes, cumulative progression examinations that are valid and reliable using a robust writing-reviewing process and psychometric analyses. PMID- 26941436 TI - Qualitative Analysis of Written Reflections during a Teaching Certificate Program. AB - OBJECTIVE: To evaluate the success of a teaching certificate program by qualitatively evaluating the content and extent of participants' reflections. METHODS: Two investigators independently identified themes within midpoint and final reflection essays across six program years. Each essay was evaluated to determine the extent of reflection in prompted teaching-related topic areas (strengths, weaknesses, assessment, feedback). RESULTS: Twenty-eight themes were identified within 132 essays. Common themes encompassed content delivery, student assessment, personal successes, and challenges encountered. Deep reflection was exhibited, with 48% of essays achieving the highest level of critical reflection. Extent of reflection trended higher from midpoint to final essays, with significant increases in the strengths and feedback areas. CONCLUSION: The teaching certificate program fostered critical reflection and self-reported positive behavior change in teaching, thus providing a high-quality professional development opportunity. Such programs should strongly consider emphasizing critical reflection through required reflective exercises at multiple points within program curricula. PMID- 26941437 TI - A Simulated Learning Environment for Teaching Medicine Dispensing Skills. AB - OBJECTIVE: To develop an authentic simulation of the professional practice dispensary context for students to develop their dispensing skills in a risk-free environment. DESIGN: A development team used an Agile software development method to create MyDispense, a web-based simulation. Modeled on virtual learning environments elements, the software employed widely available standards-based technologies to create a virtual community pharmacy environment. Assessment. First-year pharmacy students who used the software in their tutorials, were, at the end of the second semester, surveyed on their prior dispensing experience and their perceptions of MyDispense as a tool to learn dispensing skills. CONCLUSION: The dispensary simulation is an effective tool for helping students develop dispensing competency and knowledge in a safe environment. PMID- 26941438 TI - Design Considerations of a Compounded Sterile Preparations Course. AB - OBJECTIVE: To design a comprehensive learning and assessment environment for the practical application of compounded sterile preparations using a constructivist approach. DESIGN: Compounded Sterile Preparations Laboratory is a required 1 credit course that builds upon the themes of training aseptic technique typically used in health system settings and threads application of concepts from other courses in the curriculum. Students used critical-thinking skills to devise appropriate strategies to compound sterile preparations. ASSESSMENT: Aseptic technique skills were assessed with objective, structured, checklist-based rubrics. Most students successfully completed practical assessments using appropriate technique (mean assessment grade=83.2%). Almost all students passed the practical media fill (98%) and gloved fingertip sampling (86%) tests on the first attempt; all passed on the second attempt. CONCLUSION: Employing a constructivist scaffold approach to teaching proper hygiene and aseptic technique prepared students to pass media fill and gloved fingertip tests and to perform well on practical compounding assessments. PMID- 26941439 TI - Using Communication Technology to Enhance Interprofessional Education Simulations. AB - OBJECTIVE: To determine the impact of simulations using an alternative method of communication on students' satisfaction, attitudes, confidence, and performance related to interprofessional communication. DESIGN: One hundred sixty-three pharmacy students participated in a required applications-based capstone course. Students were randomly assigned to one of three interprofessional education (IPE) simulations with other health professions students using communication methods such as telephone, e-mail, and video conferencing. ASSESSMENT: Pharmacy students completed a validated survey instrument, Attitude Toward Healthcare Teams Scale (ATHCTS) prior to and after course participation. Significant positive changes occurred for 5 out of 20 items. Written reflection papers and student satisfaction surveys completed after participation showed positive themes and satisfaction. Course instructors evaluated student performance using rubrics for formative feedback. CONCLUSION: Implementation of IPE simulations using various methods of communication technology is an effective way for pharmacy schools to incorporate IPE into their curriculum. PMID- 26941440 TI - Tracking Patient Encounters and Clinical Skills to Determine Competency in Ambulatory Care Advanced Pharmacy Practice Experiences. AB - OBJECTIVE: To determine if the amount of exposure to patient encounters and clinical skills correlates to student clinical competency on ambulatory care advanced pharmacy practice experiences (APPEs). DESIGN: Students in ambulatory care APPEs tracked the number of patients encountered by medical condition and the number of patient care skills performed. At the end of the APPE, preceptors evaluated students' competency for each medical condition and skill, referencing the Dreyfus model for skill acquisition. ASSESSMENT: Data was collected from September 2012 through August 2014. Forty-six responses from a student tracking tool were matched to preceptor ratings. Students rated as competent saw more patients and performed more skills overall. Preceptors noted minimal impact on workload. CONCLUSIONS: Increased exposure to patient encounters and skills performed had a positive association with higher Dreyfus stage, which may represent a starting point in the conversation for more thoughtful design of ambulatory care APPEs. PMID- 26941441 TI - A Veterinary Comparative Counseling Elective Featuring Web-based, Student created, Client Information Sheets. AB - OBJECTIVE: To design and implement a course in Companion Animal Comparative Counseling that would expose students (N=38) to essential elements of veterinary therapeutics and provide them with the opportunity to apply their knowledge by writing and posting client information sheets (CIS) on an open web site. DESIGN: The elective course was limited to companion animals. Nine different topics were covered over the semester. Class sessions included a didactic component, trivia questions, and field trips. There were 4 major graded assessments: an examination on foundation knowledge, followed by two comparative counseling assessments and evaluation of group-composed CIS. Attendance and participation were also considered. ASSESSMENT: The class learned comparative disease states, how to counsel on common pet prescriptions, where to access informatics about specific veterinary drugs, and how to create their own CIS. CONCLUSION: As pharmacists, these students may have improved their training in veterinary comparative pharmacy. PMID- 26941443 TI - GPU-Accelerated Adjoint Algorithmic Differentiation. AB - Many scientific problems such as classifier training or medical image reconstruction can be expressed as minimization of differentiable real-valued cost functions and solved with iterative gradient-based methods. Adjoint algorithmic differentiation (AAD) enables automated computation of gradients of such cost functions implemented as computer programs. To backpropagate adjoint derivatives, excessive memory is potentially required to store the intermediate partial derivatives on a dedicated data structure, referred to as the "tape". Parallelization is difficult because threads need to synchronize their accesses during taping and backpropagation. This situation is aggravated for many-core architectures, such as Graphics Processing Units (GPUs), because of the large number of light-weight threads and the limited memory size in general as well as per thread. We show how these limitations can be mediated if the cost function is expressed using GPU-accelerated vector and matrix operations which are recognized as intrinsic functions by our AAD software. We compare this approach with naive and vectorized implementations for CPUs. We use four increasingly complex cost functions to evaluate the performance with respect to memory consumption and gradient computation times. Using vectorization, CPU and GPU memory consumption could be substantially reduced compared to the naive reference implementation, in some cases even by an order of complexity. The vectorization allowed usage of optimized parallel libraries during forward and reverse passes which resulted in high speedups for the vectorized CPU version compared to the naive reference implementation. The GPU version achieved an additional speedup of 7.5 +/- 4.4, showing that the processing power of GPUs can be utilized for AAD using this concept. Furthermore, we show how this software can be systematically extended for more complex problems such as nonlinear absorption reconstruction for fluorescence-mediated tomography. PMID- 26941442 TI - Impact of a Paper vs Virtual Simulated Patient Case on Student-Perceived Confidence and Engagement. AB - OBJECTIVE: To evaluate online case simulation vs a paper case on student confidence and engagement. DESIGN: Students enrolled in a pharmacotherapy laboratory course completed a patient case scenario as a component of an osteoarthritis laboratory module. Two laboratory sections used a paper case (n=53); three sections used an online virtual case simulation (n=81). Student module performance was assessed through a submitted subjective objective assessment plan (SOAP) note. Students completed pre/post surveys to measure self perceived confidence in providing medication management. The simulation group completed postmodule questions related to realism and engagement of the online virtual case simulation. Group assessments were performed using chi-square and Mann Whitney tests. ASSESSMENT: A significant increase in all 13 confidence items was seen in both student groups following completion of the laboratory module. The simulation group had an increased change of confidence compared to the paper group in assessing medication efficacy and documenting a thorough assessment. Comparing the online virtual simulation to a paper case, students agreed the learning experience increased interest, enjoyment, relevance, and realism. The simulation group performed better on the subjective SOAP note domain though no differences in total SOAP note scores was found between the two groups. CONCLUSION: Virtual case simulations result in increased student engagement and may lead to improved documentation performance in the subjective domain of SOAP notes. However, virtual patient cases may offer limited benefit over paper cases in improving overall student self-confidence to provide medication management. PMID- 26941445 TI - New Screening Proposals: the Federal Joint Commission Defines the Parameters for Cervical Cancer Screening from 2018: Statement of the Gynecology Oncology Working Group (AGO). AB - The Gynecology Oncology Working Group (AGO e. V.) unequivocally welcomes the decision taken by the German Federal Joint Commission (Gemeinsamer Bundesausschuss, G-BA) on March 19, 2015 regarding screening for cervical cancer. AGO is convinced that, in view of recent medical advances, this evidence-based decision will improve screening for cervical cancer. PMID- 26941446 TI - Statement of the AGO Kommission Ovar, AGO Study Group, NOGGO, AGO Austria and AGO Switzerland Regarding the Use of Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in Ovarian Cancer. AB - The AGO Kommission Ovar already published a statement in 2013, warning about the uncritical use of hyperthermic intraperitoneal chemotherapy (HIPEC) outside controlled studies. This statement has now been updated after the most recent literature was reviewed by AGO Kommission Ovar, the AGO Study Group, NOGGO, AGO Austria and AGO Switzerland. The authors conclude that HIPEC remains experimental. Its use is not recommended and should be rejected outside of prospective controlled trials. PMID- 26941444 TI - Gestational and Non-gestational Trophoblastic Disease. Guideline of the DGGG, OEGGG and SGGG (S2k Level, AWMF Registry No. 032/049, December 2015). AB - Purpose: The aim was to establish an official interdisciplinary guideline, published and coordinated by the German Society of Gynecology and Obstetrics (DGGG). The guideline was developed for use in German-speaking countries. In addition to the Germany Society of Gynecology and Obstetrics, the guideline has also been approved by the Swiss Society of Gynecology and Obstetrics (SGGG) and the Austrian Society of Gynecology and Obstetrics (OEGGG). The aim was to standardize diagnostic procedures and the management of gestational and non gestational trophoblastic disease in accordance with the principles of evidence based medicine, drawing on the current literature and the experience of the colleagues involved in compiling the guideline. Methods: This s2k guideline represents the consensus of a representative panel of experts with a range of different professional backgrounds commissioned by the DGGG. Following a review of the international literature and international guidelines on trophoblastic tumors, a structural consensus was achieved in a formalized, multi-step procedure. This was done using uniform definitions, objective assessments, and standardized management protocols. Recommendations: The recommendations of the guideline cover the epidemiology, classification and staging of trophoblastic tumors; the measurement of human chorionic gonadotropin (hCG) levels in serum, and the diagnosis, management, and follow-up of villous trophoblastic tumors (e.g., partial mole, hydatidiform mole, invasive mole) and non-villous trophoblastic tumors (placental site nodule, exaggerated placental site, placental site tumor, epitheloid trophoblastic tumor, and choriocarcinoma). PMID- 26941448 TI - ABC3 Consensus Commented from the Perspective of the German Guidelines: Third International Consensus Conference for Advanced Breast Cancer (ABC3), Lisbon, 07. 11. 2015. AB - The Third International Consensus Conference for Advanced Breast Cancer ABC3 on the diagnosis and treatment of advanced breast cancer was held in Lisbon from 5 to 7 November 2015. This year the focus was the treatment of metastatic breast cancer (stage IV) - including the patient perspectives. Important topics were questions relating to quality of life, the care for long-term survivors as well as the management of disease-related symptoms and treatment-based side effects. The use of standardised tools to assess individual treatment success and the benefits of new substances were important points for discussion. The diagnosis and treatment of inoperable locally advanced breast cancer were discussed two years ago during the ABC2 consensus 1. A working group of German breast cancer experts commented on the results of the ABC panellists, paying particular attention to the German guidelines (AGO, S3, DGHO) on the diagnosis and treatment of breast cancer 2, 3, 4, 5 in Germany. PMID- 26941449 TI - PARP Inhibitors for Recurrent Ovarian Carcinoma: Current Treatment Options and Future Perspectives. AB - More than simply a promising management option, PARP inhibitors can be regarded as a milestone in the development of personalised treatment of recurrent ovarian carcinoma. Their mechanism of action, known as "synthetic lethality", is dependent on functional differences of the DNA repair mechanisms of healthy cells and tumour cells; cells that repair DNA damage less efficiently are particularly sensitive to PARP inhibitors. Olaparib, licensed for use this year, is the best studied PARP inhibitor used for treatment of high-grade serous ovarian carcinoma (HGSC). The efficacy of PARP inhibitors appears to be increased when used in combination with other treatments. PMID- 26941447 TI - A Review of Integrative Medicine in Gynaecological Oncology. AB - In recent years complementary and alternative medicine (CAM) has increasingly been the focus of international research. Numerous subsidised trials (7903) and systematic reviews (651) have been published, and the evidence is starting to be integrated into treatment guidelines. However, due to insufficient evidence and/or insufficient good quality evidence, this has mostly not translated to practice recommendations in reviews by the Cochrane collaboration gynaecology group. There is nevertheless a not insignificant number of CAM providers and users. The percentage of oncology patients who use CAM varies between 5 and 90 %. Doctors have been identified as the main providers of CAM. Half of gynaecologists offer CAM because of personal conviction or on suggestion from colleagues. This must be viewed in a critical light, since CAM is mostly practiced without appropriate training, often without sufficient evidence for a given method - and where evidence exists, practice guidelines are lacking - and lack of safety or efficacy testing. The combination of patient demand and lucrativeness for doctors/alternative medicine practitioners, both based on supposed effectiveness CAM, often leads to its indiscriminate use with uncertain outcomes and significant cost for patients. On the other hand there is published, positive level I evidence for a number of CAM treatment forms. The aim of this article is therefore to review the available evidence for CAM in gynaecological oncology practice. The continued need for research is highlighted, as is the need to integrate practices supported by good evidence into conventional gynaecological oncology. PMID- 26941450 TI - Current Issues in the Diagnosis and Treatment of Endometrial Carcinoma. AB - Endometrial carcinoma is the most common carcinoma of the female genital tract. Its most important clinical sign is postmenopausal bleeding. An endometrial biopsy is essential for diagnosis. Treatment decisions are governed by tumour risk assessment and patient comorbidity, which is often present. Pelvic and paraaortic lymph node dissection is unnecessary in low risk cases (definition: pT1 a, G1/2) and adjuvant radiotherapy and systemic treatments are usually avoidable. Treatment of high-risk patients (G3 and/or pT1b) and palliative cases is difficult and not well standardised. New molecular-based subtype classification may help treatment decision making in future. PMID- 26941451 TI - Endometriosis-associated Malignancy. AB - Endometriosis is a common condition in women of reproductive age. According to several epidemiological studies endometriosis may be associated with increased risk of various malignancies. However, endometriosis-associated malignancy (EAM) is defined by certain histological criteria. About 80 % of EAM have been found in the ovary, whereas 20 % are localized in extragonadal sites like intestine, rectovaginal septum, abdominal wall, pleura and others. Some authors suggest that EAM arise from atypical endometriosis as an intermediate lesion between endometriosis and cancer. Moreover, a number of genetic alterations, like loss of heterozygosity (LOH), PTEN, ARID1 A and p53 mutations have been found in both endometriosis and EAM. Endometriosis-associated ovarian cancer (EAOC) is mostly a well or intermediately differentiated tumor of endometrioid or clear cell histological sub-type. Women affected by EAOC are on average five to ten years younger than non-EAOC patients; in most of the cases EAOC is a low stage disease with favorable clinical outcome. Since EAM is a rare condition systematic data on EAM are still missing. A systematic retrospective study on endometriosis associated malignancies (EAM study) is currently being conducted by the Endometriosis Research Foundation together with the study groups on ovarian and uterine tumors of the working group for gynecological oncology (AGO) (gyn@mlk berlin.de). PMID- 26941452 TI - Accuracy of Colposcopically Guided Diagnostic Methods for the Detection of Cervical Intraepithelial Neoplasia. AB - Introduction: Many factors can affect the accuracy of colposcopically guided biopsy, endocervical curettage (ECC) and differential cytology, all of which are standard, minimally invasive procedures used to detect cervical intraepithelial neoplasia. Method: All conizations carried out between 2007 and 2013 in the gynecological department of Hannover Medical School were retrospectively reviewed. The agreement between colposcopic diagnosis and histology was evaluated retrospectively. The analysis included 593 complete datasets out of a total of 717 cases treated. Results: The overall agreement was 85.5 %; the accuracy was significantly higher (p = 0.029) when three biopsy specimens were taken rather than just one. The agreement between diagnosis and histological findings from conization was highest for women < 30 years (90.7 %) and lowest for women > 50 years (72.1 %; p = 0.008). The agreement between preoperative differential cytology and histology results after conization was 86.7 % and improved as patient age increased (p = 0.035). The agreement between ECC findings and the results of conization was only 49.1 % irrespective of patient age, transformation zone or the patient's menopausal status. Conclusion: The accuracy of colposcopically guided biopsy appears to increase when three biopsy specimens are taken and is particularly high for younger patients. Differential cytology was also found to be highly accurate and is particularly useful for patients aged more than 50 years. The accuracy of ECC was significantly lower; however ECC can provide important additional information in selected cases. PMID- 26941453 TI - Clinical Characteristics, Surgical Management and Adjuvant Therapy of Patients with Uterine Carcinosarcoma: A Retrospective Case Series. AB - Purpose: To review a single-center experience over a 27-year period of managing uterine carcinosarcoma (UCS), focusing on surgical practice, adjuvant therapy and clinical outcome. Material and Methods: This was a retrospective study of women with histologically proven UCS treated at the Department of Obstetrics and Gynecology, University of Tubingen, Germany, between 1983 and 2010. Inpatient and outpatient records were reviewed; follow-up and survival data were ascertained. Results: The study population comprised 18 patients with UCS. Primary surgical treatment consisted of total abdominal hysterectomy in 12 patients (67 %) and laparoscopic total hysterectomy in 4 patients (22 %). Bilateral salpingo oophorectomy was performed in 94 % of patients (17/18). Lymph nodes were evaluated in 15 patients (83 %). Positive pelvic lymph nodes were present in 2 patients (11 %). A total of 17 patients (94 %) received adjuvant therapy. Disease recurred in 7 (39 %) patients of our study group, with no recurrence noted in the 4 patients who underwent laparoscopic surgical staging. Median disease-free survival (DFS) was 48.7 months (95 % CI: 0.0-157.3) and median overall survival (OS) was 49.9 months (95 % CI: 0.0-108.2). The 5-year survival rate was 40 %. Conclusion: UCS is a rare and aggressive uterine neoplasm with high recurrence rates and metastatic potential. Surgical staging consisting of total hysterectomy with bilateral salpingo-oophorectomy and systematic lymphadenectomy is the most important treatment for patients with UCS. Adjuvant radiation therapy appears to decrease pelvic recurrence, but there is a high incidence of distant recurrence, indicating the need for additional systemic treatment. PMID- 26941454 TI - The effect of lactation educators implementing a telephone-based intervention among low-income Hispanics: A randomised trial. AB - OBJECTIVES: To assess whether a phone-based breastfeeding intervention delivered by lactation educators influenced exclusive breastfeeding rates amongst low income Hispanic women in the USA. DESIGN: Randomised two-group design. SETTING: Pregnant low-income Hispanic women (298) were recruited from community health clinics in Los Angeles County (USA) and randomly assigned to either a control or an intervention group. METHODS: Data relating to the factors associated with breastfeeding were collected during the third trimester. Breastfeeding outcome data was collected at 72 hours, one month, three months, and six months postpartum. RESULTS: There were no differences between the groups in rates of breastfeeding initiation. There was a significant difference in the duration of exclusive breastfeeding among participants during the infant's first week of life. While not significant, after controlling for covariates and intent to breastfeed at third trimester, the duration of exclusive breastfeeding amongst all participants was, on average, longer for intervention group mothers than control group mothers. Additionally, , the intervention group mothers were more likely to report exclusive and only breastfeeding at all data points compared to the control group, and less likely to discontinue breastfeeding. CONCLUSION: Findings from this study suggest that telephone-based breastfeeding interventions delivered by a lactation educator show promise as a cost-effective strategy for improving both the quantity and duration of breastfeeding among low-income Hispanic women in the USA. Intervention group mothers not only sustained breastfeeding for a longer durations, but also provided their infants with greater amounts of breast milk over these longer durations. PMID- 26941455 TI - The Relationship between Temperature and Development in Globodera ellingtonae. AB - A new cyst nematode species, Globodera ellingtonae, was recently described from populations in Oregon and Idaho. This nematode has been shown to reproduce on potato. Because of this nematode's close relationship to the potato cyst nematodes, G. rostochiensis and G. pallida, an understanding of the risk of its potential spread, including prediction of potential geographical distribution, is required. To determine the development of G. ellingtonae under different temperatures, we conducted growth chamber experiments over a range of temperatures (10.0 degrees C to 26.5 degrees C) and tracked length of time to various developmental stages, including adult females bearing the next generation of eggs. Both the time to peak population densities of G. ellingtonae life stages and their duration in roots generally increased with decreasing temperature. Regression of growth rate to second-stage (J2) and third-stage (J3) juveniles on temperature yielded different base temperatures: 6.3 degrees C and 4.4 degrees C for J2 and J3, respectively. Setting a base temperature of 6 degrees C allowed calculation of the degree-days (DD6) over which different life stages occurred. The largest population densities of J2 were found in roots between 50 and 200 DD6. Population densities of J3 peaked between 200 and 300 DD6. Adult males were detected in soil starting at 300 to 400 DD6 and remained detectable for approximately 500 DD6. By 784 to 884 DD6, half of the eggs in adult females contained vermiform juveniles. Given the similarity in temperature ranges for successful development between G. ellingtonae and G. rostochiensis, G. ellingtonae populations likely could survive in the same geographic range in which G. rostochiensis now occurs. PMID- 26941456 TI - Life Cycle of the Golden Cyst Nematode, Globodera rostochiensis, in Quebec, Canada. AB - In 2006, the golden cyst nematode, Globodera rostochiensis, was discovered in the province of Quebec, Canada. We report here the life cycle of G. rostochiensis under the climatic conditions of southwestern Quebec. Only one full generation was completed per year under these latitudes. On susceptible potato cv. Snowden, G. rostochiensis needed a minimum of 579 growing degree units (GDU) (base 5.9 degrees C) to complete its life cycle and the first mature cysts were observed 42 to 63 days after planting (DAP). In soil, second-stage juveniles (J2) were first observed 14 to 21 DAP, whereas both white females on roots and males in soil appeared synchronously after 35 to 42 days. The duration of the life cycle was affected by temperature but not by soil type. A second wave of hatching systematically occurred later in the season and a second generation of males was observed during the 2011 growth season. No complete second cycle was observed before plant senescence. Climate change and later maturing cultivars/crops could allow the development of a full second generation in the future. PMID- 26941457 TI - Plant Roots Increase Bacterivorous Nematode Dispersion through Nonuniform Glass bead Media. AB - Dispersion of bacterivorous nematodes in soil is a crucial ecological process that permits settlement and exploitation of new bacterial-rich patches. Although plant roots, by modifying soil structure, are likely to influence this process, they have so far been neglected. In this study, using an original three compartment microcosm experimental design and polyvinyl chloride (PVC) bars to mimic plant roots, we tested the ability of roots to improve the dispersion of bacterivorous nematode populations through two wet, nonuniform granular (glass bead) media imitating contrasting soil textures. We showed that artificial roots increased migration time of bacterivorous nematode populations in the small-bead medium, suggesting that plant roots may play an important role in nematode dispersion in fine-textured soils or when soil compaction is high. PMID- 26941458 TI - Postinfection Development of Rotylenchulus reniformis on Resistant Gossypium barbadense Accessions. AB - The reniform nematode (Rotylenchulus reniformis) causes significant cotton (Gossypium hirsutum) losses in the southeastern United States. The research objective was to describe the effects of two resistant G. barbadense lines (cultivar TX 110 and accession GB 713) on development and fecundity of reniform nematode. Nematode development and fecundity were evaluated on the resistant lines and susceptible G. hirsutum cultivar Deltapine 16 in three repeated growth chamber experiments. Nematode development on roots early and late in the infection cycle was measured at set intervals from 1 to 25 d after inoculation (DAI) and genotypes were compared based on the number of nematodes in four developmental stages (vermiform, swelling, reniform, and gravid). At 15, 20, and 25 DAI, egg production by individual females parasitizing each genotype was measured. Unique reniform nematode developmental patterns were noted on each of the cotton genotypes. During the early stages of infection, infection and development occurred 1 d faster on susceptible cotton than on the resistant genotypes. Later, progression to the reniform and gravid stages of development occurred first on the susceptible genotype, followed by G. barbadense cultivar TX 110, and finally G. barbadense accession GB 713. Egg production by individual nematodes infecting the three genotypes was similar. This study corroborates delayed development previously reported on G. barbadense cultivar TX 110 and is the first report of delayed infection and development associated with G. barbadense accession GB 713. The different developmental patterns in the resistant genotypes suggest that unique or additional loci may confer resistance in these two lines. PMID- 26941460 TI - Sensitivity of Meloidogyne incognita and Rotylenchulus reniformis to Fluopyram. AB - Fluopyram is a succinate dehydrogenase inhibitor (SDHI) fungicide that is being evaluated as a seed treatment and in-furrow spray at planting on row crops for management of fungal diseases and its effect on plant-parasitic nematodes. Currently, there are no data on nematode toxicity, nematode recovery, or effects on nematode infection for Meloidogyne incognita or Rotylenchulus reniformis after exposure to low concentrations of fluopyram. Nematode toxicity and recovery experiments were conducted in aqueous solutions of fluopyram, while root infection assays were conducted on tomato. Nematode paralysis was observed after 2 hr of exposure at 1.0 ug/ml fluopyram for both nematode species. Using an assay of nematode motility, 2-hr EC50 values of 5.18 and 12.99 ug/ml fluopyram were calculated for M. incognita and R. reniformis, respectively. Nematode recovery in motility was greater than 50% for M. incognita and R. reniformis 24 hr after nematodes were rinsed and removed from a 1-hr treatment of 5.18 and 12.99 ug/ml fluopyram, respectively. Nematode infection of tomato roots was reduced and inversely proportional to 1-hr treatments with water solutions of fluopyram at low concentrations, which ranged from 1.3 to 5.2 ug/ml for M. incognita and 3.3 to 13.0 ug/ml for R. reniformis. Though fluopyram is nematistatic, low concentrations of the fungicide were effective at reducing the ability of both nematode species to infect tomato roots. PMID- 26941459 TI - Efficacy of Fluensulfone in a Tomato-Cucumber Double Cropping System. AB - Vegetable crops in the southeastern United States are commonly grown on plastic mulch with two crop cycles produced on a single mulch application. Field trials were conducted in 2013 and 2014 in two locations to evaluate the efficacy of fluensulfone for controlling Meloidogyne spp. when applied through drip irrigation to cucumber in a tomato-cucumber double-cropping system. In the spring tomato crop, 1,3-dichloropropene (1,3-D), fluensulfone, and a resistant cultivar significantly decreased root galling by 91%, 73%, and 97%, respectively, compared to the untreated control. Tomato plots from the spring were divided into split plots for the fall where the main plots were the spring treatment and the subplots were cucumber either treated with fluensulfone (3.0 kg a.i./ha. via drip irrigation) or left untreated. The fall application of fluensulfone improved cucumber vigor and reduced gall ratings compared to untreated subplots. Fluensulfone reduced damage from root-knot nematodes when applied to the first crop as well as provided additional protection to the second crop when it was applied through a drip system. PMID- 26941461 TI - Effects of Infection by Belonolaimus longicaudatus on Rooting Dynamics among St. Augustinegrass and Bermudagrass Genotypes. AB - Understanding rooting dynamics using the minirhizotron technique is useful for cultivar selection and to quantify nematode damage to roots. A 2-yr microplot study including five bermudagrass ('Tifway', Belonolaimus longicaudatus susceptible; two commercial cultivars [TifSport and Celebration] and two genotypes ['BA132' and 'PI 291590'], which have been reported to be tolerant to B. longicaudatus) and two St. Augustinegrass ('FX 313', susceptible, and 'Floratam' that was reported as tolerant to B. longicaudatus) genotypes in a 5 x 2 and 2 x 2 factorial design with four replications, respectively, was initiated in 2012. Two treatments included were uninoculated and B. longicaudatus inoculated. In situ root images were captured each month using a minirhizotron camera system from April to September of 2013 and 2014. Mixed models analysis and comparison of least squares means indicated significant differences in root parameters studied across the genotypes and soil depths of both grass species. 'Celebration', 'TifSport' and 'PI 291590' bermudagrass, and 'Floratam' St. Augustinegrass had significantly different root parameters compared to the corresponding susceptible genotypes (P <= 0.05). Only 'TifSport' had no significant root loss when infested with B. longicaudatus compared to non infested. 'Celebration' and 'PI 291590' had significant root loss but retained significantly greater root densities than 'Tifway' in B. longicaudatus-infested conditions (P <= 0.05). Root lengths were greater at the 0 to 5 cm depth followed by 5 to 10 and 10 to 15 cm of vertical soil depth for both grass species (P <= 0.05). 'Celebration', 'TifSport', and 'PI 291590' had better root vigor against B. longicaudatus compared to Tifway. PMID- 26941462 TI - Effect of Storage Temperature and Duration on Survival and Infectivity of Steinernema innovationi (Rhabditida: Steinernematidae). AB - Entomopathogenic nematode species differ in their optimum storage temperature; therefore, we conducted a study on the survival and infectivity of the recently described Steinernema innovationi from South Africa at five storage temperatures (5 degrees C, 10 degrees C, 15 degrees C, 20 degrees C, and 25 degrees C) over 84 d using 20,000 infective juveniles (IJ) in 25 ml aqueous suspension containing 0.1% formalin. Our results showed that survival was highest and most stable at 15 degrees C, ranging from 84% to 88% after 84 d. Infectivity of IJ against Galleria mellonella larvae was >90% for all temperatures except for 5 degrees C at which survival decreased to 10% after 84 d. In addition, we stored 2.5 million IJ on a sponge formulation in 15 ml of 0.1% formalin solution for 84 d at the optimum 15 degrees C followed by 2 wk storage at 25 degrees C. Storage of the IJ on a sponge formulation for 14 d at 25 degrees C post 15 degrees C storage for 84 d did not have a detrimental effect on IJ survival (87%) or infectivity to G. mellonella (95%). PMID- 26941464 TI - Description of a New and Two Known Species of the Free-living Nematode Paroigolaimella Paramonov, 1952 (Diplogastridae) from India. AB - This paper describes a new and two known species of Paroigolaimella collected from India. Paroigolaimella helalii n. sp. is characterized by having conspicuous sexual dimorphism in the stoma and pharynx, ovaries with a sphincter separating the mature oocyte from developing ones, a vagina leading to a strong ovijector, a pore-like vulva with cuticular flap; males with slender strongly arcuate spicules with dilated capitula; the gubernaculum slender with expanded plate-like distal end and nine pairs of genital papillae, and four to five pairs of copulatory muscle bands. P. coprophila (Sudhaus and Rehfeld, 1990) Sudhaus and Furst von Lieven, 2003 collected from leaf litter from a farmyard has been redescribed with reassessment of its distinguishing characters from P. bernensis. P. bodamica (Micoletzky, 1922) n. comb. has been described and its status has been discussed with context to P. bernensis. PMID- 26941463 TI - Sensitivity of Ribosomal RNA Character Sampling in the Phylogeny of Rhabditida. AB - Near-full-length 18S and 28S rRNA gene sequences were obtained for 33 nematode species. Datasets were constructed based on secondary structure and progressive multiple alignments, and clades were compared for phylogenies inferred by Bayesian and maximum likelihood methods. Clade comparisons were also made following removal of ambiguously aligned sites as determined using the program ProAlign. Different alignments of these data produced tree topologies that differed, sometimes markedly, when analyzed by the same inference method. With one exception, the same alignment produced an identical tree topology when analyzed by different methods. Removal of ambiguously aligned sites altered the tree topology and also reduced resolution. Nematode clades were sensitive to differences in multiple alignments, and more than doubling the amount of sequence data by addition of 28S rRNA did not fully mitigate this result. Although some individual clades showed substantially higher support when 28S data were combined with 18S data, the combined analysis yielded no statistically significant increases in the number of clades receiving higher support when compared to the 18S data alone. Secondary structure alignment increased accuracy in positional homology assignment and, when used in combination with paired-site substitution models, these structural hypotheses of characters and improved models of character state change yielded high levels of phylogenetic resolution. Phylogenetic results included strong support for inclusion of Daubaylia potomaca within Cephalobidae, whereas the position of Fescia grossa within Tylenchina varied depending on the alignment, and the relationships among Rhabditidae, Diplogastridae, and Bunonematidae were not resolved. PMID- 26941465 TI - Butlerius butleri Goodey, 1929 (Rhabditida) from Iran with the Phylogenetic Position of the Species. AB - A population of Butlerius butleri Goodey, 1929 was isolated from vermicompost in Kerman in the Kerman Province of Iran during a nematode survey that was conducted during 2014. This population of B. butleri is characterized by the presence of a dorsal thorn-like tooth (4 to 5 MUm long), long spicules (44 to 47 MUm long), gubernaculum (33 to 37 MUm or more than half of the spicule length), three pairs of precloacal papillae, five pairs of postcloacal papillae (papillae V3 and V5 comprising three small papillae), and a long filiform tail (304 to 409 MUm in females, 312 to 380 MUm in males). Molecular and phylogenetic analysis of B. butleri individuals from this Iranian population based on 18S ribosomal deoxyribonucleic acid (rDNA) sequence placed this species close to Pseudodiplogasteroides compositus (AB597237) and an unidentified Pseudodiplogasteroides species (AB597238). Measurements, illustrations, and the phylogenetic tree, including the position of B. butleri are provided. PMID- 26941466 TI - Description of Distorhabditis poonchiana n. gen., n. sp. (Nematoda: Rhabditidae) from Jammu and Kashmir, India. AB - Distorhabditis poonchiana n. gen., n. sp. from humus in Jammu and Kashmir, India, is described and illustrated. The new genus is characterized by a small body; slightly setoff labial region; long tubular gymnostom; prominently cuticularized cheilostom; absence of glottoid apparatus; monoprodelphic reproductive system; vulva (V) = 81 to 84; spicules with trifurcated distal ends, simple gubernaculum, peloderan bursa with eight pairs of bursal papillae arranged in 1 + 1 + 1 + 2 + 1 + 2 arrangement. PMID- 26941467 TI - Know the Single-Receptor Sensing Limit? Think Again. AB - How cells reliably infer information about their environment is a fundamentally important question. While sensing and signaling generally start with cell-surface receptors, the degree of accuracy with which a cell can measure external ligand concentration with even the simplest device-a single receptor-is surprisingly hard to pin down. Recent studies provide conflicting results for the fundamental physical limits. Comparison is made difficult as different studies either suggest different readout mechanisms of the ligand-receptor occupancy, or differ on how ligand diffusion is implemented. Here we critically analyse these studies and present a unifying perspective on the limits of sensing, with wide-ranging biological implications. PMID- 26941468 TI - Is Vitamin D Inadequacy in Early Life an Instance of the "Barker Hypothesis"? PMID- 26941470 TI - Qualitative Evaluation of Historical and Relational Factors Influencing Pregnancy and Sexually Transmitted Infection Risks in Foster Youth. AB - PURPOSE: To explore how attitudes, norms, behaviors, responses to early life experiences, and protective factors influence pregnancy and sexually transmitted infection risks from the perspectives of current and former foster youth to inform the development of prevention strategies. METHODS: We conducted semi structured individual qualitative interviews with a diverse sample of 22 current/former foster youth aged 15-21 years (63% female; average age = 18.6 years). We then used Theoretical Thematic Analysis to systematically analyze the data for key themes related to sexual health in four categories: 1) norms and attitudes, 2) responses to early life experiences, 3) protective factors, and 4) youth-driven intervention ideas. RESULTS: Participants reported a range of sexual experience levels, varied sexual orientations, and also reported varied life experiences prior to and during foster care. We detected several norms and attitudes that likely contribute to risks of early pregnancies and sexually transmitted infections. These included that one can tell by looking whether a partner is trustworthy or has a sexually transmitted infection, that condoms aren't necessary with long-term or infrequent partners or if birth control is used, and that teen pregnancy is an inevitable event. With respect to responses to early life experiences, youth frequently described difficulties dealing with strong emotions in the context of romantic and/or sexual relationships; many attributed these difficulties to early experiences with biological family members or in foster care. Participants linked emotion regulation difficulties with struggles in trust appraisal, effective communication, and impulsive behaviors. Youth also described a variety of protective factors that they felt helped them prevent sexual risk behaviors or improved their lives in other respects. Finally, participants endorsed factors likely to improve intervention acceptability and efficacy, including an open, non-judgmental group-based environment, involvement of peer mentors, and inclusion of caregiver and caseworker training components. CONCLUSIONS: Trauma-informed, tailored intervention strategies which address key norms and attitudes and provide broad-based assertiveness and emotion regulation skills are likely to be the most effective strategies to reduce risks of teen pregnancies and sexually transmitted infections among teens in foster care. Group based interventions that involve peer mentors and caregiver and caseworker components may be especially acceptable and effective for teens in foster and/or kinship care. PMID- 26941469 TI - Parallel Simulated Annealing Using an Adaptive Resampling Interval. AB - This paper presents a parallel simulated annealing algorithm that is able to achieve 90% parallel efficiency in iteration on up to 192 processors and up to 40% parallel efficiency in time when applied to a 5000-dimension Rastrigin function. Our algorithm breaks scalability barriers in the method of Chu et al. (1999) by abandoning adaptive cooling based on variance. The resulting gains in parallel efficiency are much larger than the loss of serial efficiency from lack of adaptive cooling. Our algorithm resamples the states across processors periodically. The resampling interval is tuned according to the success rate for each specific number of processors. We further present an adaptive method to determine the resampling interval based on the adoption rate. This adaptive method is able to achieve nearly identical parallel efficiency but higher success rates compared to the fixed interval one using the best interval found. PMID- 26941471 TI - Herbicide options for effective weed management in dry direct-seeded rice under scented rice-wheat rotation of western Indo-Gangetic Plains. AB - Farmers' participatory field trials were conducted at Madhuban, and Taraori, the two participatory experimental sites/locations of the Cereal Systems Initiative for South Asia (CSISA), a collaborative project of IRRI and CIMMYT in Karnal district of Haryana, India, during Kharif (wet season) 2010 and 2011. This research aimed to evaluate preemergence (PRE) and postemergence (POST) herbicides for providing feasible and economically viable weed management options to farmers for predominant scented rice varieties. Treatments with pendimethalin PRE fb bispyribac-sodium + azimsulfuron POST had lower weed biomass at 45 days after sowing (DAS). At Madhuban, highest grain yield of scented basmati rice (3.43 t ha 1) was recorded with the sequential application of pendimethalin PRE fb bispyribac-sodium + azimsulfuron POST. However, at Taraori, yields were similar with pendimethalin or oxadiargyl PRE fb bispyribac-sodium and/or azimsulfuron POST. Applying oxadiargyl by mixing with sand onto flooded field was less effective than spray applications in non-flooded field. The benefit-cost ratio of rice crop was higher with herbicide treatments at both sites as compared with the non-treated weed-free check except single PRE and POST applications and sequential application of oxadiargyl PRE fb oxadiargyl PRE. In a separate experiment conducted at Nagla and Taraori sites, scented rice cultivars' ('CSR 30' and 'Pusa 1121') tolerance to three rates of azimsulfuron (15, 25, and 35 g ai ha-1) was evaluated over two years (2010 and 2011). CSR 30 (superfine, scented) was more sensitive to higher rates (35 g ai ha-1) of azimsulfuron as compared to Pusa 1121 (fine, scented). Crop injuries were 8 and 28% in case of CSR 30; 5 and 15% in Pusa 1121 when applied with azimsulfuron 25 and 35 g ai ha 1, respectively. Azimsulfuron applied at 35 g ai ha-1 reduced yield in both cultivars but in CSR 30 yield reduction was twofold (11.5%) as that of Pusa 1121 (5.2%). PMID- 26941474 TI - Closing system-wide yield gaps to increase food production and mitigate GHGs among mixed crop-livestock smallholders in Sub-Saharan Africa. AB - In this study we estimate yield gaps for mixed crop-livestock smallholder farmers in seven Sub-Saharan African sites covering six countries (Kenya, Tanzania, Uganda, Ethiopia, Senegal and Burkina Faso). We also assess their potential to increase food production and reduce the GHG emission intensity of their products, as a result of closing these yield gaps. We use stochastic frontier analysis to construct separate production frontiers for each site, based on 2012 survey data prepared by the International Livestock Research Institute for the Climate Change, Agriculture and Food Security program. Instead of relying on theoretically optimal yields-a common approach in yield gap assessments-our yield gaps are based on observed differences in technical efficiency among farms within each site. Sizeable yield gaps were estimated to be present in all of the sites. Expressed as potential percentage increases in outputs, the average site-based yield gaps ranged from 28 to 167% for livestock products and from 16 to 209% for crop products. The emission intensities of both livestock and crop products registered substantial falls as a consequence of closing yield gaps. The relationships between farm attributes and technical efficiency were also assessed to help inform policy makers about where best to target capacity building efforts. We found a strong and statistically significant relationship between market participation and performance across most sites. We also identified an efficiency dividend associated with the closer integration of crop and livestock enterprises. Overall, this study reveals that there are large yield gaps and that substantial benefits for food production and environmental performance are possible through closing these gaps, without the need for new technology. PMID- 26941472 TI - Anticardiac Antibodies in Patients with Chronic Pericardial Effusion. AB - OBJECTIVES: Chronic pericardial effusion may be challenging in terms of diagnosis and treatment. Specific laboratory parameters predicting the frequency and severity of recurrences after initial drainage of pericardial effusion are lacking. MATERIALS AND METHODS: Pericardial fluid (PF) and serum (SE) samples from 30 patients with chronic pericardial effusion (PE) who underwent pericardiocentesis and pericardioscopically guided pericardial biopsy were compared with SE and PF samples from 26 control patients. The levels of antimyolemmal (AMLA) and antifibrillary antibodies (AFA) in PE and SE from patients with pericardial effusion as well as PF and SE from controls were determined and compared. RESULTS: AMLAs and AFAs in PF and SE were significantly higher in patients with chronic pericardial effusion than in the control group (AMLAs: p = 0,01 for PF and p = 0,004 for serum; AFAs: p < 0,001 for PF and p = 0,003 for serum). Patients with recurrence of PE within 3 months after pericardiocentesis had significantly higher levels of AMLAs in SE (p = 0,029) than patients without recurrence of PE. CONCLUSIONS: The identification of elevated anticardiac antibodies in PE and SE indicates increased immunological reactivity in chronic pericardial effusion. High titer serum levels of AMLAs also correlate with recurrence of pericardial effusion. PMID- 26941473 TI - Circulating Carbonic Anhydrase IX and Antiangiogenic Therapy in Breast Cancer. AB - INTRODUCTION: Carbonic anhydrase IX (CAIX) is a hypoxia regulated metalloenzyme integral to maintaining cellular pH. Increased CAIX expression is associated with poor prognosis in breast cancer. To explore CAIX as a biomarker for breast cancer therapies, we measured plasma CAIX levels in healthy control subjects and in breast cancer patients. METHODS: In control subjects we evaluated plasma CAIX stability via commercially available ELISA. We then similarly quantified plasma CAIX levels in (1) locally advanced breast cancer (LABC) patients treated with neoadjuvant paclitaxel + sunitinib (T + S) followed by doxorubicin and cyclophosphamide (AC); (2) metastatic breast cancer (MBC) patients treated with systemic chemotherapy. RESULTS: Plasma CAIX levels were stable at room temperature for at least 48 hours in control subjects. Mean baseline plasma CAIX levels were lower in controls compared to patients with LABC or MBC. In LABC, CAIX levels rose significantly in response to administration of antiangiogenic therapy (T + S) (p = 0.02) but not AC (p = 0.37). In patients with MBC treated without an antiangiogenic agent CAIX levels did not change with therapy. CONCLUSIONS: Our results suggest that CAIX may be an easily obtained, stable measure of tumor associated hypoxia as well as a useful pharmacodynamic biomarker for antiangiogenic therapy. PMID- 26941475 TI - A general approach to categorizing a continuous scale according to an ordinal outcome. AB - In practice, disease outcomes are often measured in a continuous scale, and classification of subjects into meaningful disease categories is of substantive interest. To address this problem, we propose a general analytic framework for determining cut-points of the continuous scale. We develop a unified approach to assessing optimal cut-points based on various criteria, including common agreement and association measures. We study the nonparametric estimation of optimal cut-points. Our investigation reveals that the proposed estimator, though it has been ad-hocly used in practice, pertains to nonstandard asymptotic theory and warrants modifications to traditional inferential procedures. The techniques developed in this work are generally adaptable to study other estimators that are maximizers of nonsmooth objective functions while not belonging to the paradigm of M-estimation. We conduct extensive simulations to evaluate the proposed method and confirm the derived theoretical results. The new method is illustrated by an application to a mental health study. PMID- 26941477 TI - Teachers' reported practices for teaching writing in England. AB - To date there have been no systematic studies examining the ways in which teachers in England focus and adapt their teaching of writing. The current study addresses this gap by investigating the nature and frequency of teachers' approaches to the teaching of writing in a sample of English primary schools, using the 'simple view of writing' as a framework to examine the extent to which different aspects of the writing process are addressed. One hundred and eighty eight staff from ten different schools responded to an online questionnaire. Only the data from class teachers (n = 88) who responded to all items on the questionnaire were included in the final analyses. Respondents enjoyed teaching writing and felt prepared to teach it. However, despite feeling that they were effective in identifying approaches to support students' writing, nearly half reported that supporting struggling writers was problematic for them. Overall teachers reported more work at word level, occurring several times a week, than with transcription, sentence or text levels, which were reported to occur weekly. Planning, reviewing and revising occurred least often, only monthly. For these variables no differences were found between teachers of younger (age 4-7) and older students (age 8-11). By contrast, an examination of specific aspects of each component revealed differences between the teachers of the two age groups. Teachers of younger students focused more frequently on phonic activities related to spelling, whereas teachers of older students focussed more on word roots, punctuation, word classes and the grammatical function of words, sentence-level work, and paragraph construction. PMID- 26941476 TI - Effects of a Responsiveness-Focused Intervention in Family Child Care Homes on Children's Executive Function. AB - Caregiver responsiveness has been theorized and found to support children's early executive function (EF) development. This study examined the effects of an intervention that targeted family child care provider responsiveness on children's EF. Family child care providers were randomly assigned to one of two intervention groups or a control group. An intervention group that received a responsiveness-focused online professional development course and another intervention group that received this online course plus weekly mentoring were collapsed into one group because they did not differ on any of the outcome variables. Children (N = 141) ranged in age from 2.5 to 5 years (mean age = 3.58 years; 52% female). At pretest and posttest, children completed delay inhibition tasks (gift delay-wrap, gift delay-bow) and conflict EF tasks (bear/dragon, dimensional change card sort), and parents reported on the children's level of attention problems. Although there were no main effects of the intervention on children's EF, there were significant interactions between intervention status and child age for delay inhibition and attention problems. The youngest children improved in delay inhibition and attention problems if they were in the intervention rather than the control group, whereas older children did not. These results suggest that improving family child care provider responsive behaviors may facilitate the development of certain EF skills in young preschool-age children. PMID- 26941478 TI - Vocabulary does not complicate the simple view of reading. AB - Gough and Tunmer's (1986) simple view of reading (SVR) proposed that reading comprehension (RC) is a function of language comprehension (LC) and word recognition/decoding. Braze et al. (2007) presented data suggesting an extension of the SVR in which knowledge of vocabulary (V) affected RC over and above the effects of LC. Tunmer and Chapman (2012) found a similar independent contribution of V to RC when the data were analyzed by hierarchical regression. However, additional analysis by factor analysis and structural equation modeling indicated that the effect of V on RC was, in fact, completely captured by LC itself and there was no need to posit a separate direct effect of V on RC. In the present study, we present new data from young adults with sub-optimal reading skill (N = 286). Latent variable and regression analyses support Gough and Tunmer's original proposal and the conclusions of Tunmer and Chapman that V can be considered a component of LC and not an independent contributor to RC. PMID- 26941479 TI - The dynamics of narrative writing in primary grade children: writing process factors predict story quality. AB - In this study of third grade school children, we investigated the association between writing process measures recorded with key stroke logging and the final written product. Moreover, we examined the cognitive predictors of writing process and product measures. Analyses of key strokes showed that while most children spontaneously made local online revisions while writing, few revised previously written text. Children with good reading and spelling abilities made more online revisions than their peers. Two process factors, transcription fluency and online revision activity, contributed to explaining variance in narrative macrostructural quality and story length. As for cognitive predictors, spelling was the only factor that gave a unique contribution to explaining variance in writing process factors. Better spelling was associated with more revisions and faster transcription. The results show that developing writers' ability to make online revisions in creative writing tasks is related to both the quality of the final written product and to individual literacy skills. More generally, the findings indicate that investigations of the dynamics of the writing process may provide insights into the factors that contribute to creative writing during early stages of literacy. PMID- 26941480 TI - Sample Shuttling Relaxometry of Contrast Agents: NMRD Profiles above 1 T with a Single Device. AB - Nuclear magnetic relaxation dispersion (NMRD) profiles are essential tools to evaluate the efficiency and investigate the properties of magnetic compounds used as contrast agents for magnetic resonance imaging (MRI), namely gadolinium chelates and superparamagnetic iron oxide particles. These curves represent the evolution of proton relaxation rates with the magnetic field. NMRD profiles are unparalleled to probe extensively the spectral density function involved in the relaxation of water in the presence of the paramagnetic ion or the magnetic nanoparticles. This makes such profiles an excellent test of the adequacy of a theoretical relaxation model and allow for a predictive approach to the development and optimization of contrast agents. From a practical point of view they also allow to evaluate the efficiency of a contrast agent in a certain range of magnetic fields. Nowadays, these curves are recorded with commercial fast field cycling devices, often limited to a maximum Larmor frequency of 40 MHz (0.94 T). In this article, relaxation data were acquired on a wide range of magnetic fields, from 3.5 * 10-4 to 14 T, for a gadolinium-based contrast agent and for PEGylated iron oxide nanoparticles. We show that the low-field NMRD curves can be completed with high-field data obtained on a shuttle apparatus device using the superconductive magnet of a high-field spectrometer. This allows a better characterization of the contrast agents at relevant magnetic fields for clinical and preclinical MRI, but also refines the experimental data that could be used for the validation of relaxation models. PMID- 26941481 TI - 1H, 23Na and 35Cl Imaging in Cementitious Materials with NMR. AB - A set-up especially designed for semi-simultaneous measurements of 1H, 23Na and 35Cl in ordinary cementitious materials using nuclear magnetic resonance was built. This setup makes use of the main field of a whole body magnetic resonance imaging system (Philips Intera), which has allowed us to combine two measurement setups into one, i.e., a 23Na/35Cl and a 1H insert. This 1.5 T field was chosen as a compromise between the signal-to-noise ratio of the spin-echo signal, which increases at higher frequencies, and the line broadening due to the presence of magnetic impurities of these materials, which leads to a decrease of the resolution at higher magnetic fields. The preliminary experiments show that this setup can be used to the study the interaction of different types of ions with cementitious materials. One-dimensional profiles of the moisture and dissolved ions can be measured with a spatial resolution of about 2 mm for 1H, 6 mm for 23Na and 9 mm for 35Cl. PMID- 26941482 TI - Interplay between Cellular and Molecular Inflammatory Mediators in Lung Cancer. AB - Inflammation is a component of the tumor microenvironment and represents the 7th hallmark of cancer. Chronic inflammation plays a critical role in tumorigenesis. Tumor infiltrating inflammatory cells mediate processes associated with progression, immune suppression, promotion of neoangiogenesis and lymphangiogenesis, remodeling of extracellular matrix, invasion and metastasis, and, lastly, the inhibition of vaccine-induced antitumor T cell response. Accumulating evidence indicates a critical role of myeloid cells in the pathophysiology of human cancers. In contrast to the well-characterized tumor associated macrophages (TAMs), the significance of granulocytes in cancer has only recently begun to emerge with the characterization of tumor-associated neutrophils (TANs). Recent studies show the importance of CD47 in the interaction with macrophages inhibiting phagocytosis and promoting the migration of neutrophils, increasing inflammation which can lead to recurrence and progression in lung cancer. Currently, therapies are targeted towards blocking CD47 and enhancing macrophage-mediated phagocytosis. However, antibody-based therapies may have adverse effects that limit its use. PMID- 26941484 TI - Does IL-17 Respond to the Disordered Lung Microbiome and Contribute to the Neutrophilic Phenotype in Asthma? AB - Th17/IL-17 plays an important role in host defense and hyperimmune responses against pathogenic bacteria accompanied by the recruitment of neutrophils. Th17 associated immune response is also involved in the pathogenesis of asthma, which is known as a noninfectious allergic airway disease and has been shown to be heterogeneous. Th17-associated inflammation usually contributes to the neutrophilic phenotype, which is often characterized by greater severity, airflow obstruction, and steroid resistance. Concurrently, advanced culture-independent molecular techniques have increased our understanding of the lung microbiome and demonstrated that disorders of the lung microbiome, including changes of the total burden, diversity, and community composition, may contribute to severe, treatment-resistant neutrophilic asthma, although the precise mechanism is still unclear. Because Th17/IL-17 plays a role in bacteria-mediated immune responses and is involved in neutrophilic asthma, there may be a link between them. We review the effects of Th17/IL-17 on bacteria and asthma, showing the possibility that Th17/IL-17 may be a key player in neutrophilic asthma which may be characterized as severe or treatment-resistant by responding to the disordered lung microbiome. PMID- 26941483 TI - Th17 Cells Pathways in Multiple Sclerosis and Neuromyelitis Optica Spectrum Disorders: Pathophysiological and Therapeutic Implications. AB - Several animal and human studies have implicated CD4+ T helper 17 (Th17) cells and their downstream pathways in the pathogenesis of central nervous system (CNS) autoimmunity in multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD), challenging the traditional Th1-Th2 paradigm. Th17 cells can efficiently cross the blood-brain barrier using alternate ways from Th1 cells, promote its disruption, and induce the activation of other inflammatory cells in the CNS. A number of environmental factors modulate the activity of Th17 pathways, so changes in the diet, exposure to infections, and other environmental factors can potentially change the risk of development of autoimmunity. Currently, new drugs targeting specific points of the Th17 pathways are already being tested in clinical trials and provide basis for the development of biomarkers to monitor disease activity. Herein, we review the key findings supporting the relevance of the Th17 pathways in the pathogenesis of MS and NMOSD, as well as their potential role as therapeutic targets in the treatment of immune-mediated CNS disorders. PMID- 26941486 TI - The revised guidelines of the Medical Council of India for academic promotions: Need for a rethink. PMID- 26941485 TI - Cellular Barriers after Extravasation: Leukocyte Interactions with Polarized Epithelia in the Inflamed Tissue. AB - During the inflammatory response, immune cells egress from the circulation and follow a chemotactic and haptotactic gradient within the tissue, interacting with matrix components in the stroma and with parenchymal cells, which guide them towards the sites of inflammation. Polarized epithelial cells compartmentalize tissue cavities and are often exposed to inflammatory challenges such as toxics or infections in non-lymphoid tissues. Apicobasal polarity is critical to the specialized functions of these epithelia. Indeed, a common feature of epithelial dysfunction is the loss of polarity. Here we review evidence showing that apicobasal polarity regulates the inflammatory response: various polarized epithelia asymmetrically secrete chemotactic mediators and polarize adhesion receptors that dictate the route of leukocyte migration within the parenchyma. We also discuss recent findings showing that the loss of apicobasal polarity increases leukocyte adhesion to epithelial cells and the consequences that this could have for the inflammatory response towards damaged, infected or transformed epithelial cells. PMID- 26941487 TI - Changing paradigm of men's health. PMID- 26941489 TI - Innovations in surgical management of nonobstructive azoospermia. AB - Testicular sperm extraction (TESE) technique and intra-cytoplasmic sperm injection are breakthrough fertility treatments for men with nonobstructive azoospermia (NOA). Newer advances such as the microdissection-TESE (micro-TESE) technique have continued to build upon past success by improving sperm retrieval and minimizing the postoperative complications compared to TESE. However, even with micro-TESE, sperm retrieval success has ranged from 40% to 60% due to the technique's dependence on surgeon and embryologist experience. While postoperative complications are minimal relative to the traditional TESE technique, testicular tissue must still be extracted without the knowledge of whether sperm are present in biopsies. In this review, we discuss the innovations in the surgical management of men with NOA and describe the novel experimental approaches that can improve sperm retrieval success. PMID- 26941488 TI - Peyronie's disease: What's around the bend? AB - INTRODUCTION: Peyronie's disease (PD) is a fibrotic diathesis of the tunica albuginea that results in penile plaque formation and penile deformity, negatively affecting sexual and psychosocial function of both patients and their partners. In this review, we discuss the PD literature and PD treatment options, with special emphasis on potential future therapies. METHODS: The PD literature was reviewed, and articles of interest were identified using keyword search in PubMed. Articles evaluating investigational and novel PD treatments were emphasized. RESULTS: Existing PD treatment modalities are diverse and include oral, topical, intralesional, mechanical, and surgical therapies. Surgical treatment has high success rates and is indicated in men with significant, stable deformity. The United States Food and Drug Administration-approved intralesional collagenase Clostridium histolyticum injection therapy is a minimally invasive option with demonstrated efficacy in PD. Other nonsurgical therapies have been reported, including Botox and stem cell therapy, but these currently have little or equivocal evidence to support their efficacy. CONCLUSIONS: Further research is essential to develop novel, safe, and effective minimally invasive PD treatment options. This work is ongoing, with the promise of specific, targeted, and highly effective therapies on the horizon. PMID- 26941490 TI - Chronic orchialgia: Review of treatments old and new. AB - INTRODUCTION: Chronic orchialgia is historically and currently a challenging disease to treat. It is a diagnostic and therapeutic challenge for physicians. Conservative therapy has served as the first line of treatment. For those who fail conservative therapy, surgical intervention may be required. We aim to provide a review of currently available surgical options and novel surgical treatment options. METHODS: A review of current literature was performed using PubMed. Literature discussing treatment options for chronic orchialgia were identified. The following search terms were used to identify literature that was relevant to this review: Chronic orchialgia, testicular pain, scrotal content pain, and microsurgical denervation of the spermatic cord (MDSC). RESULTS: The incidence of chronic orchialgia has been increasing over time. In the USA, it affects up to 100,000 men per year due to varying etiologies. The etiology of chronic orchialgia can be a confounding problem. Conservative therapy should be viewed as the first line therapy. Studies have reported poor success rates. Current surgical options for those who fail conservative options include varicocelectomy, MDSC, epididymectomy, and orchiectomy. Novel treatment options include microcryoablation of the peri-spermatic cord, botox injection, and amniofix injection. CONCLUSION: Chronic orchialgia has been and will continue to be a challenging disease to treat due to its multiple etiologies and variable treatment outcomes. Further studies are needed to better understand the problem. Treatment options for patients with chronic orchialgia are improving. Additional studies are warranted to better understand the long-term durability of this treatment options. PMID- 26941491 TI - Current management of urethral stricture disease. AB - INTRODUCTION: Broadly defined, urethral strictures are narrowing of the urethral lumen that is surrounded by corpus spongiosum, i.e., urethral meatus through the bulbar urethra. Urethral stenosis is narrowing of the posterior urethra, i.e., membranous urethra through bladder neck/prostate junction, which is not enveloped by corpus spongiosum. The disease has significant quality of life ramifications because many times younger patients are affected by this compared to many other urological diseases. METHODS: A review of the scientific literature concerning urethral stricture, stenosis, treatment, and outcomes was performed using Medline and PubMed (U.S. National Library of Medicine and the National Institutes of Health). Abstracts from scientific meetings were included in this review. RESULTS: There is level 3 evidence regarding the etiology and epidemiology of urethral strictures, stenoses, and pelvic fracture urethral injuries. Outcomes data from literature regarding intervention for urethral stricture are largely limited to level 3 evidence and expert opinion. There is a single level 1 study comparing urethral dilation and direct vision internal urethrotomy. Urethroplasty outcomes data are limited to level 3 case series. CONCLUSIONS: Progress is being made toward consistent terminology, and nomenclature which will, in turn, help to standardize treatment within the field of urology. Treatment for urethral stricture and stenosis remains inconsistent between reconstructive and nonreconstructive urologists due to varying treatment algorithms and approaches to disease management. Tissue engineering appears to be future for reconstructive urethral surgery with reports demonstrating feasibility in the use of different tissue substitutes and grafts. PMID- 26941492 TI - Male chronic pelvic pain: An update. AB - INTRODUCTION: Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) and interstitial cystitis/bladder pain syndrome collectively referred to as urologic CPPS (UCPPS) is defined by the absence of identifiable bacterial infection as a cause for the chronic pain and urinary symptoms. METHODS: A PubMed search of all recent relevant articles using the keywords/phrases: CPPS, CPPS, and male pelvic pain, was conducted. RESULTS: CPPS has a high worldwide prevalence and its negative impact on quality of life compares with or exceeds common chronic morbidities. Triggers include certain comestibles as well as psychosocial factors that promote catastrophizing and illness focused behavior. Several validated tools are currently available to help diagnose and direct targeted therapy. Treatment should begin with the most simple and least invasive based on the presenting clinical phenotype. CONCLUSIONS: Although no gold-standard treatment exists, a multidisciplinary approach with multimodal therapy gives the UCPPS patient the best chance of symptom relief. PMID- 26941493 TI - Outcomes following retroperitoneal lymph node dissection in postchemotherapy residual masses in advanced testicular germ cell tumors. AB - INTRODUCTION: We aimed to study the outcomes of retroperitoneal lymph node dissection (RPLND) in postchemotherapy residual masses in advanced testicular germ cell tumor (GCT) in the Indian population. PATIENTS AND METHODS: We retrospectively analyzed 35 patients who underwent postchemotherapy RPLND at our institute after primary (29 patients) or salvage (6 patients) chemotherapy over a period of 9 years (June 2003 to July 2012). RESULTS: The mean age of our patients was 26.8 years. 18 (51.42%) presented with primary tumor in the right testis and 3 (8.51%) had bilateral tumors. Mixed GCT was the most common histology among 19 (54.3%) patients. 14 (40%) patients had the residual mass in para-aortic location, which was the most common site. 14 (40%) patients required an adjunctive procedure, most commonly nephrectomy which was required in 9 out of 14 (25.7%). We recorded 25 complications, mostly Clavien-Dindo grade II. Histopathology of residual mass was necrosis in 17 (48.57%), teratoma in 12 (34.28%), and viable tumor in 6 (17.14%) patients. CONCLUSION: Nearly half of the patients had either teratoma or viable tumor, thus justifying the surgical resection of postchemotherapy residual mass. Although nearly half of the patients had complications, they were adequately managed and there was no mortality. Thus, postchemotherapy RPLND can be a useful procedure in multimodality approach to GCT in carefully selected patients. PMID- 26941494 TI - Supracostal percutaneous nephrolithotomy: A prospective comparative study. AB - INTRODUCTION: A widely prevalent fear of thoracic complications with the supracostal approach has led to its underutilization in percutaneous nephrolithotomy (PCNL). We frequently use the supracostal approach and compared the efficacy and thoracic complications of infracostal, supra 12(th), and supra 11(th) punctures. MATERIALS AND METHODS: This was a prospective study of patients who underwent PCNL between January 2005 and December 2012. The patients were divided into three groups based on the access: infracostal, supra 12(th) (between the 11(th) and 12(th) ribs) and supra 11(th) (between the 10(th) and 11(th) ribs). Clearance rates, fall in hemoglobin levels, transfusion rates, perioperative analgesic requirements, hospital stay and thoracic complications were compared. RESULTS: Seven hundred patients were included for analysis. There were 179 (25.5%) patients in the supra 11(th) group, 187 (26.7%) patients in the supra 12(th) group and 334 (47.8%) patients in the infracostal group. The overall clearance rate was 78% with no difference in the three groups. The postoperative analgesic requirements were significantly higher in the supracostal groups and showed a graded increase from infracostal to supra 12(th) to supra 11(th). During the study period, only 2 patients required angioembolization (0.3%) and none required open exploration. The number of patients requiring intercostal chest drain insertion was extremely low, at 1.6% and 2.2% in the supra 12(th) and supra 11(th) groups, respectively. CONCLUSIONS: Our results confirm the feasibility of the supracostal approach including punctures above the 11(th) rib, albeit at the cost of an increase in thoracic complications. Staying in the line of the calyx has helped us to minimize the most dreaded complication of bleeding requiring angioembolization. PMID- 26941495 TI - Evaluation of bacteriological profile and antibiotic sensitivity patterns in children with urinary tract infection: A prospective study from a tertiary care center. AB - INTRODUCTION: Development of regional surveillance programs is necessary for the development of community-acquired urinary tract infection (UTI) guidelines, especially for sub-urban and rural areas where empirical treatment is the mainstay in the absence of proper diagnostic modalities. Our aim was to evaluate the bacteriological profile and antibiotic sensitivity patterns in children with UTI prospectively from a tertiary care center. METHODS: A total of 800 children up to 18 years of age with suspected UTI attending our center were included. For all suspected cases urine microscopy, gram staining, and culture were done. Antibiotic sensitivity was performed on selected antimicrobials using disk diffusion method following Clinical Laboratory Standards Institute guidelines. RESULTS: Majority of pathogens were isolated from female (54.2%) patients. Pre teens (52.1%) and teens (27.1%) were most commonly affected age group. The most common presentation in culture-proven UTI was fever with urinary symptoms (33.3%). In a group of 192 patients 26.7% had proven UTI. Escherichia coli (42.3%) was the most common aetiological agent, followed by Enterococcus fecalis (13.5%), Klebsiella spp. (11.5%) and Staphylococcus aureus (11.5%). Most active antibiotics against Gram-negative isolates were nitrofurantoin, cefotaxime, and amikacin. Gram-positive isolates were sensitive to nitrofurantoin, cotrimoxazole, and novobiocin. CONCLUSION: E. coli was the commonest isolate. The organisms grown in significant numbers were E. fecalis, Klebsiella spp. and S. aureus, causing UTI in 0-18 years of age group. Gram-negative isolates were sensitive to nitrofurantoin, amikacin, and cefotaxime. Gram-positive isolates were sensitive to nitrofurantoin, cotrimoxazole, and novobiocin. Prospective, regional studies are ensured periodically to explain bacteriological profile and antibiotic sensitivity patterns to be applicable for children with UTI over that geographic area. PMID- 26941496 TI - Role of dynamic sentinel node biopsy in carcinoma penis with or without palpable nodes. AB - INTRODUCTION: We aimed to evaluate the role of dynamic sentinel node biopsy (DSLNB) in patients diagnosed with carcinoma penis and clinically N0 disease using superficial inguinal dissection as the standard staging modality. MATERIALS AND METHODS: Twenty consecutive men (40 groins) with carcinoma penis having clinically N0 status were enrolled in the study. Patients underwent DSLNB if fine needle aspiration cytology from the groin nodes was negative, followed by injection of radiocolloid and blue dye. The sentinel lymph node(s) were harvested. The inguinal incision was then extended and a modified superficial inguinal dissection was performed and all nodes were labeled separately and sent for frozen section. A completion deep inguinal with pelvic dissection was performed if any of the nodes were reported positive for malignancy. RESULTS: The median age of the patients was 52.5 years. Ten patients were smokers. Phimosis was present in five patients. Lesions were present over the glans penis and shaft in 18 and two patients, respectively. Wide local excision, partial penectomy and total penectomy were performed in one, 15 and four patients, respectively. Clinically palpable nodes were found in 19 groins. Median follow-up was 26 months. Nodes were positive in 10 groins. DSLNB missed the sentinel node in one groin. The accuracy and false-negative rate of DSLNB was 97.5% and 10%, respectively. CONCLUSION: DSLNB is a useful and reliable technique to identify the involved node(s) in patients diagnosed as having carcinoma penis with clinical N0 status (with or without palpable nodes). It helps to avoid the morbidity associated with a staging inguinal dissection in these patients. PMID- 26941497 TI - Variations in renal morphometry: A hospital-based Indian study. AB - INTRODUCTION: The currently available standard renal nomograms for comparison of renal dimensions in India are based on the measurements made in the Western population. The objectives of our study were to identify variations in renal morphometric parameters in subjects with no known renal disease in a hospital based Indian population and to find out any correlation between renal volumes with split renal functions and body mass index (BMI). MATERIALS AND METHODS: One hundred and fifty-one subjects undergoing contrast-enhanced computerized tomography (CT) scan for various purposes, including donor nephrectomy, from June 2012 to August 2014 were included in the study. The renal and ureteral dimensions were assessed from the contrast-enhanced CT scan images of these patients. RESULTS: The mean length, width, thickness and volume of the left kidney were 11.02 +/- 1.13 cm, 5.21 +/- 0.75 cm, 4.65 +/- 0.84 cm and 138.22 +/- 29.81 mL, respectively, and those for the right kidney were 10.86 +/- 1.12 cm, 5.13 +/- 0.77 cm, 4.73 +/- 0.95 cm and 137.54 +/- 34.48 mL, respectively. The mean length of the left ureter was 23.51 +/- 1.48 cm and that of the right ureter was 23.24 +/- 1.93 cm. The mean volume of the kidneys in males and females was also different. The volume of the kidney did not statically correlate with the split glomerular filtration rate ((P = 0.12) and BMI (P = 0.52)). CONCLUSIONS: Our study revealed that there exist differences in various morphometric parameters of the kidney and ureter in different subsets of the Indian population attending our hospital as compared with the standard values quoted in the world literature. PMID- 26941498 TI - Orthotopic genital sparing radical cystectomy in pre-menopausal women with muscle invasive bladder carcinoma: A prospective study. AB - INTRODUCTION: Invasive cancer bladder is a life-threatening disease that is best treated with radical cystectomy and a suitable urinary diversion. The aim of this study was to evaluate the oncological outcome, voiding and sexual functions after genital sparing radical cystectomy with orthotopic bladder reconstruction in pre menopausal women with bladder cancer. MATERIALS AND METHODS: 18 pre-menopausal women who underwent radical cystectomy and orthotopic urinary diversion with preservation of genital organs were included for this study. The patients were followed-up clinically and radiologically to assess their oncological outcome in addition to their voiding and sexual function. RESULTS: Mean age of the patients was 37.8 years, and the median follow-up after surgery was 70 months. One patient was lost to follow-up at 12 months post-operatively. The surgery was completed as planned in all patients, with a mean operative time of 290 min and an average blood loss of 750 mL. 14 patients were able to void satisfactorily, being continent day and night, while four patients needed clean intermittent catheterization. Sexual life remained unchanged in 15 cases, while three patients reported dysparunea. Till the last follow-up, there was no local recurrence while distant metastases were detected in three cases, two of whom died. CONCLUSIONS: Genital sparing cystectomy is a valid option for managing carefully selected women with muscle-invasive bladder cancer with good functional and sexual outcomes. PMID- 26941499 TI - A double J stent misplaced in the inferior vena cava during Boari flap repair. AB - A 30-year-old lady underwent a Boari flap repair for post-hysterectomy mid ureteric stricture. The upper end of the double J stent inserted during the procedure was misplaced in the supra-renal inferior venal cava. Cystoscopic stent removal could be performed uneventfully, while the stricture was managed by endoureterotomy. PMID- 26941500 TI - Can deceased donor with recurrent primary brain tumor donate kidneys for transplantation? AB - Kidney transplantation from deceased donors is in its infancy in India. Cadaver organ donation was accepted legally in 1994 by the "Human Organs Transplantation Act." Marginal donors are now accepted by many centers for kidney transplantation. We report a case of procurement of both kidneys from a young deceased donor having recurrent primary brain tumor, transplanted into two adult recipients with successful outcome. PMID- 26941501 TI - Vesicocutaneous fistula after sliding hernia repair. AB - Sliding inguinal hernias are usually direct inguinal hernias containing various abdominal viscera. The incidence of bladder forming a part of an inguinal hernia, called as "scrotal cystocele," is 1-4%. The risk of bladder injury is as high as 12% when repairing this type of hernia. This case report emphasizes this aspect in a 65-year-old man who presented with urinary leak through the scrotal wound following right inguinal hernia repair. PMID- 26941502 TI - Transitional cell carcinoma: A rare development in congenital ureteropelvic junction obstruction kidney. AB - A 54-year-old male chronic smoker presented with hematuria 13 years after being diagnosed with an asymptomatic left non-functioning kidney secondary to congenital ureteropelvic junction obstruction. On evaluation, he was diagnosed with renal collecting system mass occupying the lower pole region, for which radical nephroureterectomy with bladder cuff excision and nodal dissection was carried out. Histopathology revealed upper tract transitional cell carcinoma. PMID- 26941504 TI - [Not Available]. PMID- 26941503 TI - Giant adrenal cyst displacing the right kidney. AB - Adrenal cysts are rare and should be considered in the differential diagnosis of retroperitoneal cysts. We present a case of a huge adrenal cyst displacing the right kidney anteriorly toward the left side in a young female. PMID- 26941505 TI - We're moving forward...join the momentum! PMID- 26941506 TI - Progressive alliance. PMID- 26941507 TI - Recurrent idiopathic gingival fibromatosis with generalized aggressive periodontitis: A rare case report. PMID- 26941508 TI - Author's Reply: Recurrent idiopathic gingival fibromatosis with generalized aggressive periodontitis: A rare case report. PMID- 26941509 TI - Oral health knowledge and awareness among pregnant women in India: A systematic review. AB - Pregnancy is a unique period during a woman's life and is characterized by complex physiological changes, which may adversely affect oral health. The present systematic review was conducted to assess knowledge and awareness regarding oral health among pregnant women in India. Relevant cross-sectional observational studies were included in the systematic review to assess the level of knowledge and awareness regarding oral health among pregnant women in India. Seven studies out of 255 were finally included in the present review after conducting both electronic and manual search of scientific databases. Potential biases were reported and appropriate data were extracted by the concerned investigators. Almost 67% of the subjects had good knowledge and awareness regarding oral health in one of the study findings. Knowledge regarding effect of decayed teeth on the appearance of the people was significantly related to the parity status of the subjects (P = 0.024) in other study reports. Very few subjects (17.1% and 37.5%) felt the need for visiting a dentist during pregnancy in two studies. The results of the present review showed that pregnant women had poor knowledge and awareness regarding oral health. Therefore, there is an urgent need for education and motivation of expectant mothers regarding oral health through various health promotion interventions. PMID- 26941510 TI - Relationship between interleukin 1alpha levels in the gingival crevicular fluid in health and in inflammatory periodontal disease and periodontal inflamed surface area: A correlative study. AB - BACKGROUND: Periodontitis has been suggested as a source of inflammation for pathological changes in distant sites. Interleukin-1 alpha (IL-1alpha) has shown to have specific roles in inflammation, immunity, tissue breakdown, and tissue homeostasis. This study assessed the correlation of periodontal inflamed surface area (PISA) index with the gingival crevicular fluid (GCF) levels of IL-1alpha, which would be helpful in evaluating the validity of PISA index in terms of reflection of the disease. MATERIALS AND METHODS: A total of 40 subjects were recruited for this study and 20 subjects with healthy gingiva (Group I) served as controls and 20 subjects served as cases with periodontitis (Group II). Samples of GCF were obtained from one site in each patient by placing color-coded, calibrated, volumetric microcapillary pipettes extracrevicularly, and subjected to ELISA test. RESULTS: There was a statistical significance for mean probing depth (PD) and periodontal epithelial surface area (PESA) (P < 0.01), mean bleeding on probing and PISA, IL-1alpha (P < 0.01) and PESA (P < 0.05) in Group I. Statistical significance was found between PISA and IL-1alpha in Group I (P < 0.01). A positive correlation was found in Group II between mean PD and mean attachment loss (P < 0.01), PISA, IL-1alpha and PESA (P < 0.01), PISA and IL 1alpha levels (P < 0.01) which was statistically significant. CONCLUSION: The inflammatory burden index was statistically significant in the periodontitis group correlating with higher IL-1alpha levels, which clearly indicates the validity of PISA index. PMID- 26941511 TI - Evaluation of mRNA expression of the transcription factors of Th1 and Th2 subsets (T-bet and GATA-3) in periodontal health and disease - A pilot study in south Indian population. AB - BACKGROUND: Based on their respective pro- or anti-inflammatory cytokine profiles, the Th1/Th2 paradigm explains pathogenic mechanisms involved in periodontal disease. Establishment of Th1 and Th2 subsets from a naive T-cell precursor depends on transcriptional regulation. The aim of this study was to compare the expression of master transcription factor regulators T-bet and GATA 3, respectively, to indicate the predominance of Th1 and Th2 subsets in the presence and absence of periodontal disease. MATERIALS AND METHODS: A gingival tissue biopsy sample was obtained from each of 10 severe periodontitis patients (>5 mm attachment loss) and 10 periodontally healthy patients (no attachment loss). Biopsies were immediately processed by real-time reverse transcriptase polymerase chain reaction and the difference in mRNA expression of T-bet and GATA 3 was assessed for each group. RESULTS: The mRNA expression of T-bet was marginally increased about 1.31-fold in disease, while the GATA-3 levels showed a significant decrease of 4.39-fold in disease. CONCLUSION: The advanced periodontal lesions lack Th2 cells, which produce anti-inflammatory cytokines. The biopsies were therefore dominated by Th1 cells, which activate macrophages and osteoclasts. PMID- 26941513 TI - A comparative evaluation of the efficacy of probiotic and chlorhexidine mouthrinses on clinical inflammatory parameters of gingivitis: A randomized controlled clinical study. AB - BACKGROUND: The aim of our clinical trial was to assess and compare the antiplaque and anti-inflammatory potential of a probiotic mouthwash with 0.2% chlorhexidine and saline. MATERIALS AND METHODS: A randomized parallel group study was designed for a period of 4 weeks on 45 systemically healthy subjects between 20 and 30 years having chronic gingivitis. The study population was divided into three groups. Group A - 15 subjects were advised experimental (probiotic) mouthwash. Group B - 15 subjects were advised positive control (chlorhexidine) mouthwash and Group C - 15 subjects into a negative control group (normal saline). Oral prophylaxis was done for all groups at baseline. After the proper oral hygiene instructions, all the three groups were instructed to rinse their mouth with 10 ml of their respective mouthrinse, undiluted for 1 min twice daily, 30 min after brushing. Clinical parameters such as plaque index (PI), gingival index (GI), and oral hygiene index simplified (OHI-S) were assessed at baseline, 2 weeks and 4 weeks, respectively. RESULTS: At day 28, the PI, GI, and OHI-S were significantly reduced by all treatment modalities ranking probiotic and chlorhexidine is greater than saline. CONCLUSION: The probiotic mouthrinses tested was effectively used as an adjunct to mechanical plaque control in the prevention of plaque and gingivitis. Thus, the probiotic mouthrinse has a great therapeutic potential. PMID- 26941514 TI - The influence of soft tissue biotype on the marginal bone changes around dental implants: A 1-year prospective clinico-radiological study. AB - BACKGROUND: The peri-implant mucosa undergoes surgical and bacterial assaults in various stages of implant therapy, however, the literature on changes occurring in the peri-implant mucosa is minimal. This study was thus conducted to evaluate the change in the peri-implant mucosal thickness and its effect on the marginal bone levels around dental implants treated in a conventional two-stage implant therapy. MATERIALS AND METHODS: A total of 36 implants were placed in 22 subjects. Two subjects dropped out. Thirty-three implants in 20 subjects were then evaluated. Initial mucosal thickness, marginal bone levels on radiographs, pain, and exudation were evaluated. All these parameters were recorded at the time of implant placement, at the time of cementation of final restoration, 6 months and 12 months post cementation/restoration. RESULTS: The peri-implant mucosal thickness reduced from implant placement to second stage and till restorations and was statistically significant, in both the thick and thin biotypes, however, at 12 months there was a rebound of the tissue thickness, which was more in the thick biotype (P < 0.05). At 1-year follow-up, there was a reduction in the marginal bone levels, which was more in the thick biotype as compared to the thin biotype (P < 0.05). CONCLUSION: The mucosa at implant sites undergoes a reduction in thickness from the time of implant placement till the placement of final restorations. The placement of the final restorations and then end of active therapy leads to a rebound of the tissue thickness. Sites with thicker tissues preoperatively have a lesser bone loss and better rebound as compared to thinner tissues. PMID- 26941512 TI - Association of serum immunoglobulin-G to Porphyromonas gingivalis with acute cerebral infarction in the Chinese population. AB - BACKGROUND/PURPOSE: There is evidence supporting an association between ischemic stroke and periodontitis in western countries. Differing genetic backgrounds and lifestyles among populations may affect this association. The aim of our study was to determine whether antibody titers to Porphyromonas gingivalis are associated with acute cerebral infarction in the Chinese population. MATERIALS AND METHODS: This case-control study was conducted on 88 acute cerebral infarction patients and 40 healthy control subjects. Serum immunoglobulin-G (IgG) antibody to P. gingivalis was analyzed by enzyme-linked immune sorbent assay. Serum lipids were determined with the automatic biochemical analyzer. Fibrinogen was measured using automated coagulation analyzer. High-sensitivity C-reactive protein (hs-CRP) and interleukin-6 (IL-6) were quantified using commercial ELISA kits. The intima-media thickness of the common carotid arteries (IMT-CCA) was measured by ultrasonography. RESULTS: The results showed that P. gingivalis IgG antibody levels were significantly higher in acute cerebral infarction cases than in healthy controls (mean +/- standard deviation, 11.06 +/- 1.49 vs. 9.15 +/- 1.70, P < 0.001). There were significant correlations of P. gingivalis IgG titer with total cholesterol (r = 0.34, P = 0.001), low-density lipoprotein (r = 0.39, P < 0.001), apolipoprotein-B (r = 0.30, P = 0.004), hs-CRP (r = 0.35, P = 0.001), IL-6 (r = 0.27, P = 0.011), and IMT-CCA (left: r = 0.306, P = 0.004; right: r = 0.241, P = 0.024). CONCLUSION: Antibody titers to P. gingivalis are associated with acute cerebral infarction in the Chinese population. PMID- 26941515 TI - A comparative evaluation of freeze-dried bone allograft with and without bioabsorbable guided tissue regeneration membrane Healiguide((r)) in the treatment of Grade II furcation defects: A clinical study. AB - BACKGROUND: Furcation defects represent one of the most demanding therapeutic challenges for periodontal therapy. Various treatment modalities have been tried with different success rates. The present study was undertaken to evaluate the efficacy of freeze-dried bone allograft (FDBA) with and without bioabsorbable guided tissue regeneration (GTR) membrane Healiguide((r)) in the treatment of Grade II furcation defects. MATERIALS AND METHODS: Ten patients with bilateral Grade II furcation defects were selected for the study. After phase I therapy, subjects were divided into two arms and treated in a split-mouth design. Ten defects were treated with FDBA alone in the control arm. Ten defects were treated with FDBA in conjunction with bioabsorbable GTR membrane Healiguide((r)) in test arm. Clinical parameters like plaque index, gingival index, vertical probing depth, horizontal probing depth, and relative attachment level (RAL) were assessed at baseline, 3 months, and 6 months postoperatively. RESULTS: At 6 months, clinical improvement was seen in both the arms with mean pocket depth reduction of 1.2 +/- 1.032 mm and 1.7 +/- 0.948 mm and mean horizontal probing depth reduction being 2.1 +/- 1.969 mm and 1.6 +/- 1.264 mm in control and test arm, respectively. Both surgical procedures resulted in a statistically significant reduction in vertical and horizontal probing depths. CONCLUSION: Both the arms demonstrated a significant improvement in the probing depth, horizontal furcation depth, and RAL at 6 months postsurgery in the treatment of Grade II furcation defects. However, on the intergroup comparison, there was no statistically significant difference in the results achieved between two arms. PMID- 26941516 TI - Evaluation of anorganic bovine-derived hydroxyapatite matrix/cell binding peptide as a bone graft material in the treatment of human periodontal infrabony defects: A clinico-radiographic study. AB - BACKGROUND: Various bone graft materials have been used in the treatment of periodontal defects. A synthetic bone substitute material composed of P-15 with anorganic bone mineral has been scantly studied. Hence, the present study was aimed to evaluate and compare the efficacy of anorganic bovine-derived hydroxyapatite matrix (ABM)/cell binding peptide (P-15) in human periodontal infrabony defects with that of open flap debridement (OFD) alone. MATERIALS AND METHODS: A split-mouth, randomized controlled clinical study was designed to investigate the efficacy of ABM/P-15. In this clinical trial, 10 patients having bilateral periodontal infrabony defects were treated either with ABM/P-15 or OFD and followed for a period of 9 months. At baseline and at 9 months probing pocket depth (PPD), relative attachment level (RAL), depth of a defect, and radiographic bone level were measured; and compared between test and control sites. RESULTS: A statistically significant reduction (P < 0.001) in PPD was observed in test sites compared to control sites. Both sites showed a gain in RAL without any significant difference. Similarly, the radiographic evaluation revealed significantly higher radiographic defect fill in test sites as compared to control sites (P < 0.001). CONCLUSION: ABM/P-15 bone graft material appears to be useful and beneficial in the treatment of human periodontal infrabony defects. PMID- 26941517 TI - Comparative clinical evaluation of laterally positioned pedicle graft and subepithelial connective tissue graft in the treatment of Miller's Class I and II gingival recession: A 6 months study. AB - AIM: The purpose of the study was to compare clinical outcomes of laterally positioned pedicle graft (LPPG) and subepithelial connective tissue graft (SCTG) for treatment of Miller's Class I and II gingival recession defects, at the end of 6 months. MATERIALS AND METHODS: Sixty Miller's Class I or II gingival recession defects (>=3 mm) (n = 30 each) on the labial aspect of anterior teeth were treated by either of the above techniques. Clinical parameters including recession depth (RD), width of keratinized gingiva (WKG), percentage of root coverage (%RC), and complete RC were recorded at baseline and 6 months postoperatively. Data were recorded and statistical analysis was done for both intergroup and intragroup. STATISTICAL ANALYSIS USED: Paired t-test intragroup and Student's t-test intergroup. RESULTS: In LPPG, RD decreased from 4.9 +/- 0.99 mm to 1.1 +/- 0.3 mm and WKG increased from 0.7 +/- 0.87 to 4.5 +/- 0.86 mm at 6 months, while in SCTG, RD decreased from 4.67 +/- 1.12 mm to 0.46 +/- 0.68 mm and WKG increased from 1.1 +/- 0.99 to 5.33 +/- 0.72 mm at 6 months postoperatively. The values of the soft tissue coverage remained stable for 6 months. CONCLUSIONS: Highly significant and effective soft tissue coverage was obtained by both techniques. LPPG resulted in effective soft tissue coverage for isolated deep narrow defects while SCTG in isolated and multiple, deep narrow and wide defects. PMID- 26941518 TI - Platelet Rich Fibrin in double lateral sliding bridge flap procedure for gingival recession coverage: An original study. AB - BACKGROUND: Gingival recession is a common occurrence in periodontal disease leading to an unaesthetic appearance of the gingiva. The effect of platelet-rich fibrin (PRF), when used along with double lateral sliding bridge flap (DLSBF), remains unknown. The aim of this study is to evaluate the effect of PRF in conjunction with DLSBF for multiple gingival recessions. MATERIALS AND METHODS: Twenty systemically healthy individuals exhibiting Grade II gingival recession on their mandibular central incisors were recruited in this study. These patients were randomly assigned into two groups: DLSBF and PRF + DLSBF. The clinical parameters that were evaluated in this study were gingiva recession height, gingiva recession width, width of keratinized gingiva, clinical attachment level, and probing depth. PRF was procured from the patient's blood at the time of the surgery and used for the procedure. The follow-up was performed at 12 and 24 weeks postsurgery. RESULTS: Statistically significant difference was observed between the clinical parameters at baseline and 12 and 24 weeks within the groups. There was no statistically significant difference, between the groups. Mean root coverage (RC) was 80% +/-29.1% in the DLSBF group and 78.8% +/-37.6% in the DLSBF + PRF group with no statistically significant difference. CONCLUSION: From the results obtained in this study, the addition of PRF to DLSBF gives no additional benefits to the clinical parameters measured in RC. PMID- 26941519 TI - Etiology and occurrence of gingival recession - An epidemiological study. AB - OBJECTIVES: Gingival recession is the term used to characterize the apical shift of the marginal gingiva from its normal position on the crown of the tooth. It is frequently observed in adult subjects. The occurrence and severity of the gingival recession present considerable differences between populations. To prevent gingival recession from occurring, it is essential to detect the underlying etiology. The aim of the present study was to determine the occurrence of gingival recession and to identify the most common factor associated with the cause of gingival recession. METHODS: A total of 710 subjects aged between 15 years to 60 years were selected. Data were collected by an interview with the help of a proforma and then the dental examination was carried out. The presence of gingival recession was recorded using Miller's classification of gingival recession. The Silness and Loe Plaque Index, Loe and Silness gingival index, community periodontal index were recorded. The data thus obtained were subjected to statistical analysis using Chi-square test and Student's unpaired t-test. RESULTS: Of 710 subjects examined, 291 (40.98%) subjects exhibited gingival recession. The frequency of gingival recession was found to increase with age. High frequency of gingival recession was seen in males (60.5%) compared to females (39.5%). Gingival recession was commonly seen in mandibular incisors (43.0%). Miller's class I gingival recession was more commonly seen. The most common cause for gingival recession was dental plaque accumulation (44.1%) followed by faulty toothbrushing (42.7%). CONCLUSION: Approximately half of the subjects examined exhibited gingival recession. The etiology of gingival recession is multifactorial, and its appearance is always the result of more than one factor acting together. PMID- 26941520 TI - Periodontal disease status and associated risk factors in patients attending a Dental Teaching Hospital in Rawalpindi, Pakistan. AB - BACKGROUND: Investigators have identified an association of socio-demographic and medical factors with periodontal risk. This study observed status and association of periodontal disease and associated risk factors/indictors. MATERIALS AND METHODS: All patients attending a dental teaching hospital were interviewed for socio-demographic and medical information through a structured questionnaire. Participants were examined for periodontal status using the community periodontal index (CPI), by a single examiner during September to November 2012. An association of age, gender, smoking habit, systemic conditions, and oral hygiene measures with periodontal status ([periodontitis CPI score >=3]/nonperiodontitis [CPI score <=2]) was analyzed by applying Chi-square test and forward selection stepwise regression analysis. RESULTS: One thousand nine hundred and eighteen patients were examined during the study period. The findings revealed that 63.5% of the subjects had CPI score <=2 (nonperiodontitis), while 34.5% were found with CPI score >=3 (periodontitis). Age, gender, occupation, smoking, diabetes, arthritis, cardiovascular disease, kidney disease, stress, medications, and oral hygiene habits of using tooth powder or tooth brushing were significantly (P <= 0.037) associated with periodontal status. Regression analysis showed a significant association of age, occupation, and smoking with periodontitis. CONCLUSION: This study observed prevalence of periodontitis in one-fourth of study sample. The study confirmed various socio-demographic risk factors/indictors associated with increased risk of periodontitis. PMID- 26941521 TI - Evaluation of oral health attitude and behavior among a group of dental students in Puducherry, India: A preliminary cross-sectional study. AB - CONTEXT: Oral behavior reflects individual perception on oral health. Behavior and attitude of oral health providers, especially dentists, towards oral health affect their capacity to deliver oral health care services. This attitude plays a important role in determining the oral health condition of population. AIM: The purpose of this study is to evaluate the oral health attitude and behavior among a group of dental students in India and to find any gender-based differences in terms of oral health attitude and behavior. MATERIALS AND METHODS: A total of 282 dental students of Indira Gandhi Institute of Dental Sciences, SBV University, Puducherry, India participated in the study. A simplified English version of Hiroshima University Dental-Behavioral Inventory (HU-DBI) was adopted. STATISTICAL ANALYSIS USED: SSP version 2.80 software was used to analyze the data. Chi-square test was used to find the differences in the distribution of "yes" among students from the different academic year as well as between male and female students. Statistical significance was set at P <= 0.05. RESULTS: Statistical significance was observed for the responses between the students from different academic years brushing frequency, careful brushing of teeth, using brush with hard bristles, careful self-evaluation of brushing and satisfied appearance of teeth and gums. Male students preferred to use a tooth brush with hard bristles and regular mouth washes than female students. With regards to worrying about bad breath, male students had more "yes" responses than females. CONCLUSIONS: Oral health attitude and behavior increased with the increasing levels of dental education, and no significant differences were observed among male and female dental students. PMID- 26941522 TI - Gingival enlargement in myelodysplastic syndrome. AB - The myelodysplastic syndrome (MDS) is characterized by peripheral blood cytopenias and increased risk of transformation to acute myeloid leukemia. This syndrome affects blood cell production and behavior. MDS is difficult to diagnose because of the absence of symptoms in the early stage of the disease. Often it is accidentally discovered during a routine physical exam/blood test. Till date, only a few cases of gingival enlargement associated with MDS are reported in the literature. Here is a remarkable case of gingival enlargement heralding the presence of MDS. PMID- 26941523 TI - Ankyloglossia with cleft lip: A rare case report. AB - Ankyloglossia or tongue-tie is a congenital anomaly affecting the tongue, which is characterized by thick, short lingual frenulum. This condition causes many difficulties such as limited tongue protrusion, breastfeeding difficulties, speech impairment and lack of self-confidence. It is very rarely associated with any other congenital craniofacial disorders such as cleft lip, X-linked cleft palate, Van der Woude syndrome, Smith-Lemli-Opitz syndrome, Orofacial digital syndrome, Beckwith Weidman syndrome or Simpson-Golabi-Behmel syndrome. This article presents a rare case of ankyloglossia associated with cleft lip treated with diode laser in a 12-year-old Indian boy who had undergone surgical correction of associated cleft lip soon after birth. Correction of ankyloglossia at a young age would lead to enhanced phonetics, improved oral hygiene, and overall personality development. PMID- 26941524 TI - Semilunar vestibular technique: A novel procedure for multiple recession coverage (a report of two cases). AB - The procedures for root coverage have been greatly refined over the past few decades. Still as compared to the other periodontal surgical procedures, predictability of mucogingival procedures remains uncertain which is more in patients who present with multiple recessions or recession complicated with periodontal involvement. Techniques which claim success almost always involve a second surgical site. A novel technique avoiding second surgical site and good predictability for multiple recessions was described by Dr. P.D. Miller in a conference at Pune in 2011. A semilunar vestibular incision technique described by Dr. P.D Miller was performed on two patients who presented with multiple recessions in the maxillary anterior teeth. About 90-100% root coverage was observed when the patients were on a follow-up for 1-year with a significant increase in the vestibular depth. The semilunar vestibular incision technique used in two cases resulted in predictable root coverage with a good color blend, an esthetic marginal morphology and most importantly the avoidance of the second surgical site. PMID- 26941525 TI - Idiopathic gingival fibromatosis. AB - Idiopathic gingival fibromatosis (IGF) is a rare hereditary condition characterized by slowly progressive, nonhemorrhagic, fibrous enlargement of maxillary and mandibular keratinized gingiva caused by increase in submucosal connective tissue elements, mostly associated with some syndrome. This case report describes a case of nonsyndromic generalized IGF in an 18-year-old male patient who presented with generalized gingival enlargement. The enlarged tissue was surgically removed by internal bevel gingivectomy and ledge and wedge procedure. The patient was regularly monitored clinically for improvement in his periodontal condition as well as for any recurrence of gingival overgrowth. PMID- 26941526 TI - Treatment of a large periradicular defect using guided tissue regeneration: A case report of 2 years follow-up and surgical re-entry. AB - Periradicular (PR) bone defects are common sequelae of chronic endodontic lesions. Sometimes, conventional root canal therapy is not adequate for complete resolution of the lesion. PR surgeries may be warranted in such selected cases. PR surgery provides a ready access for the removal of pathologic tissue from the periapical region, assisting in healing. Recently, the regeneration of the destroyed PR tissues has gained more attention rather than repair. In order to promote regeneration after apical surgery, the principle of guided tissue regeneration (GTR) has proved to be useful. This case presents the management of a large PR lesion in a 42-year-old male subject. The PR lesion associated with 21, 11 and 12 was treated using GTR membrane, fixated with titanium minipins. The case was followed up for 2 years radiographically, and a surgical re-entry confirmed the re-establishment of the lost labial plate. Thus, the principle of GTR may immensely improve the clinical outcome and prognosis of an endodontically involved tooth with a large PR defect. PMID- 26941528 TI - Assessment of oral health status among endosulfan victims in endosulfan relief and remediation cell - A cross-sectional survey. AB - BACKGROUND: Endosulfan is a highly toxic agrichemical used in the cashew plantations. The Stockholm Convention held in April 2011 recommended a global ban on the manufacture and use of endosulfan because of its adverse effects on human health and the environment. Its impact on the quality of food, water, and beverages; and its ability to cause neurobehavioral disorders, congenital malformations in female subjects, and abnormalities related to the male reproductive system are studied, but however information regarding the oral health of endosulfan victims is scant. OBJECTIVES: To assess the oral health status of the endosulfan victim in rehabilitation center. METHOD AND METHODOLOGY: A cross sectional study on 18 subjects of 4-50 years of age were interviewed and examined using modified WHO oral health assessment proforma (1997) in Endosulfan Relief and Remediation Cell in Kokkada, Belthangady Taluk, Dakshina Kannada district, Karnataka, India. RESULTS: Among the subjects, 10 (>50%) were found to be in age group <20 years. The overall oral health status of the endosulfan victim's in rehabilitation center considered to be poor, as many of the subjects suffered from major medical problems like mental retardation, physical disabilities etc. CONCLUSION: This study emphasizes the need for special attention from government and voluntary organization to improve overall health status of the victims. PMID- 26941527 TI - Oral telangiectatic granuloma with an intrabony defect. AB - Oral telangiectatic granuloma is a benign hyperplastic lesion occurring in response to trauma or chronic irritation in the oral cavity. The characteristic histological appearance comprises of typical granulation tissue with a proliferation of small thin-walled blood vessels in the loose connective tissue. We describe a case of a 36-year-old female who had a swelling in the left maxillary region which was associated with the intrabony defect. An internal bevel gingivectomy was performed, and the histopathological report was suggestive of telangiectatic granuloma. The intrabony defect was managed with the placement of platelet rich fibrin plug in the defect. A follow-up at 6 months showed no recurrence and no loss in the width of keratinized tissue. The aim of this case is to highlight the rare association of intrabony defect with telangiectatic granuloma and the need for histopathological diagnosis in such lesions. PMID- 26941529 TI - Effect of Beta vulgaris Linn. Leaves Extract on Anxiety- and Depressive-like Behavior and Oxidative Stress in Mice after Acute Restraint Stress. AB - BACKGROUND: Stress plays a significant role in the pathogenesis of neuropsychiatric disorders such as anxiety and depression. Beta vulgaris is commonly known as "beet root" possessing antioxidant, anticancer, hepatoprotective, nephroprotective, wound healing, and anti-inflammatory properties. OBJECTIVE: To study the protective effect of Beta vulgaris Linn. ethanolic extract (BVEE) of leaves against acute restraint stress (ARS)-induced anxiety- and depressive-like behavior and oxidative stress in mice. MATERIALS AND METHODS: Mice (n = 6) were pretreated with BVEE (100 and 200 mg/kg, p. o.) for 7 days and subjected to ARS for 6 h to induce behavioral and biochemical changes. Anxiety- and depressive-like behavior were measured by using different behavioral paradigms such as open field test (OFT), elevated plus maze (EPM), forced swim test (FST), and tail suspension test (TST) 40 min postARS. Brain homogenate was used to analyze oxidative stress parameters, that is, malondialdehyde (MDA) and reduced glutathione (GSH) level. RESULTS: BVEE pretreatment significantly (P < 0.05) reversed the ARS-induced reduction in EPM parameters, that is, percentage entries and time spent in open arms and in OFT parameters, that is, line crossings, and rearings in mice. ARS-induced increase in the immobility time in FST and TST was attenuated significantly (P < 0.05) by BVEE pretreatment at both the dosage. An increase in MDA and depletion of GSH level postARS was prevented significantly (P < 0.05) with BVEE pretreatment at both the dosage (100 and 200 mg/kg). CONCLUSION: BVEE exhibits anxiolytic and antidepressant activity in stressed mice along with good antioxidant property suggesting its therapeutic potential in the treatment of stress-related psychiatric disorders. SUMMARY: Stress plays major role in the pathogenesis of anxiety and depressionARS-induced anxiety- and depressive-like behavior through oxidative damage in miceBVEE pretreatment reversed ARS-induced behavioral changes, that is, anxiety and depressionARS-induced oxidative stress was prevented by BVEE pretreatment in mice. Abbreviations Used: ANOVA: Analysis of variance, ARS: Acute restraint stress, BVEE: Beta vulgaris ethanolic extract, BV: Beta vulgaris, CMC: Carboxymethylcellulose, CNS: Central nervous system, CPCSEA: Committee for the purpose of control and supervision of experiments on animals, cms: Centimeter, DNA: Deoxyribose nucleic acid, EPM: Elevated plus maze, FST: Forced swim test, GSH: Reduced glutathione, g: Gram, h: Hour, IAEC: Institutional Animal Ethics Committee, mg: Milligram, MUM: Microgram, MDA: Malondialdehyde, SEM: Standard error of mean, TST: Tail suspension test, UV: Ultraviolet, w/v: Weight by volume. PMID- 26941530 TI - Crude Extracts of Marine-derived and Soil Fungi of the Genus Neosartorya Exhibit Selective Anticancer Activity by Inducing Cell Death in Colon, Breast and Skin Cancer Cell Lines. AB - BACKGROUND: The crude ethyl acetate extracts of marine-derived fungi Neosartorya tsunodae KUFC 9213 (E1) and N. laciniosa KUFC 7896 (E2), and soil fungus N. fischeri KUFC 6344 (E3) were evaluated for their in vitro anticancer activities on a panel of seven human cancer cell lines. MATERIALS AND METHODS: The 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was performed, after 48 h treatments with different concentrations of extracts, to determine their concentration of the extract or Dox that inhibits cell viability by 50% for each cell line. The effects of the crude extracts on DNA damage, clonogenic potential and their ability to induce cell death were also assessed. RESULTS: E1 was found to the void of anti-proliferative effects. E2 was shown to decrease the clonogenic potential in human colorectal carcinoma cell line (HCT116), human malignant melanoma cell line (A375), human breast adenocarcinoma cell line (MCF7), and human caucasian colon adenocarcinoma Grade II cell line (HT29) cells, whereas E3 showed such effect only in HCT116 and MCF7 cells. Both extracts were found to increase DNA damage in some cell lines. E2 was found to induce cell death in HT29, HCT116, MCF7, and A375 cells while extract E3 increased cell death in MCF7 and HCT116 cell lines. CONCLUSION: The results reveal that E2 and E3 possess anticancer activities in human colon carcinoma, breast adenocarcinoma, and melanoma cells, validating the interest for an identification of molecular targets involved in the anticancer activity. SUMMARY: The crude ethyl acetate extract of N. tsunodae (E1) did not decrease cell viability in any of the tested cell linesThe crude ethyl acetate extracts of N. laciniosa (E2) and N. fischeri (E3) decreased cell proliferation in some human cancer cell lines tested at both short- and long-termN. laciniosa (E2) induced a significant increase in the number of cell death, in part, due to the induction of DNA damageN. fischeri (E3) induce cell death but in some cell lines without induction of DNA damage detected by comet assayCrude ethyl extracts of N. laciniosa (E2) and N. fischeri (E3) exert an anticancer activity in human colon carcinoma, breast adenocarcinoma, and malignant melanoma cells. Abbreviations Used: A375: Human malignant melanoma cell line; A549: Human non-small lung cancer cell line; DAPI: 4,6-diamidino-2 phenylindole; DMEM: Dulbecco's Modified Eagle Medium; DMSO: Dimethylsulfoxide; Dox: Doxorubicin; E1: Neosartorya tsunodae KUFC 9213; E2: Neosartorya laciniosa KUFC 7896; E3: Neosartorya fischeri KUFC 6344; FBS: Fetal bovine serum; HCT116: Human colorectal carcinoma cell line; HEPES: (N-[2-hydroxyethyl] piperazine-N'-[2 ethane-sulfonic acid]); HepG2: Human hepatocellular carcinoma cell line; HT29: Human caucasian colon adenocarcinoma Grade II cell line; IC50: Concentration of the extract or Dox that inhibits cell viability by 50%; MCF7: Human breast adenocarcinoma cell line; MEM: Minimum Essential Medium Eagle; MTT: 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; NCI-H460: Human non-small lung cancer cell line; PBS: Phosphate buffered saline; PE: Plating efficiency; RPMI: Roswell park memorial institute medium; SF: Surviving fraction; U-251: Human malignant glioblastoma cell line. PMID- 26941531 TI - Quantitative and Qualitative Analysis of Phenolic and Flavonoid Content in Moringa oleifera Lam and Ocimum tenuiflorum L. AB - BACKGROUND: Number of secondary compounds is produced by plants as natural antioxidants. Moringa oleifera Lam. and Ocimum tenuiflorum L. are known for their wide applications in food and pharmaceutical industry. OBJECTIVE: To compare phenolic and flavonoid content in M. oleifera Lam and O. tenuiflorum L. by quantitative and qualitative analysis. MATERIALS AND METHODS: Phenolic and flavonoid content were studied spectrophotometrically and by paper chromatography in M. oleifera Lam. and O. tenuiflorum L. RESULTS: Higher phenolic and flavonoid content were observed in Moringa leaf and flower. Ocimum flower showed higher phenolic content and low flavonoid in comparison to Moringa. Flavonoids such as biflavonyl, flavones, glycosylflavones, and kaempferol were identified by paper chromatography. Phytochemical analysis for flavonoid, tannins, saponins, alkaloids, reducing sugars, and anthraquinones were tested positive for Moringa and Ocimum leaf as well as flower. CONCLUSIONS: In the present study higher phenolic and flavonoid content, indicated the natural antioxidant nature of Moringa and Ocimum signifying their medicinal importance. SUMMARY: Moringa oleifera Lam. and Ocimum tenuiflorum L. are widly grown in India and are known for their medicinal properties. Number of secondary metabolites like phenolics and flavonoids are known to be present in both the plants. The present study was conducted with an objective to qualitatively and quantitatively compare the phenolics and flavanoids in these two medicinally important plants.Quantitation of total phenolics and flavanoids was done by spectrophotometrically while qualitative analysis was perfomed by paper chromatography and by phytochemical tests. Our results have shown higher phenolics and flavanoid content in Moringa leaf and flower. However, higher phenolic content was absent in Ocimum flower compared to that of Moringa. Phytochemical analysis of various metabolites such as flavonoids, tanins, sapponins, alkaloids, anthraquinones revealed that both the plant extracts were rich sources of secondary metabolites and thus tested positive for the above tests. Various flavanoids and Phenolics were identified by paper chromatography based on their Rf values and significant colors. From the above study we conclude that Moringa and Ocimum are rich in natural antioxidants hence are potent source in pharmaceutical industry. PMID- 26941532 TI - In vitro and In vivo Antioxidant Evaluation and Estimation of Total Phenolic, Flavonoidal Content of Mimosa pudica L. AB - OBJECTIVE: Mimosa pudica Linn. (Mimosaceae) is traditionally used as a folk medicine to treat various ailments including convulsions, alopecia, diarrhea, dysentery, insomnia, tumor, wound healing, snake bite, etc., Here, the study was aimed to evaluate the antioxidant potential of M. pudica leaves extract against 2, 2-diphenyl-1-picrylhydrazyl (DPPH) (in vitro) and its modulatory effect on rat brain enzymes. MATERIALS AND METHODS: Total phenolic, flavonoid contents, and in vitro antioxidant potential against DPPH radical were evaluated from various extracts of M. pudica leaves. In addition, ethyl acetate extract of Mimosa pudica leaves (EAMP) in doses of 100, 200, and 400 mg/kg/day were administered orally for 7 consecutive days to albino rats and evaluated for the oxidative stress markers as thiobarbituric acid reactive substances (TBARS), superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH) from rat brain homogenate. RESULTS: The ethyl acetate extract showed the highest total phenolic content and total flavonoid content among other extracts of M. pudica leaves. The percentage inhibition and IC50 value of all the extracts were followed dose-dependency and found significant (P < 0.01) as compared to standard (ascorbic acid). The oxidative stress markers as SOD, CAT, and GSH were increased significantly (P < 0.01) at 200 and 400 mg/kg of EAMP treated animals and decreased significantly the TBARS level at 400 mg/kg of EAMP as compared to control group. CONCLUSION: These results revealed that the ethyl acetate extract of M. pudica exhibits both in vitro antioxidant activity against DPPH and in vivo antioxidant activity by modulating brain enzymes in the rat. This could be further correlated with its potential to neuroprotective activity due to the presence of flavonoids and phenolic contents in the extract. SUMMARY: Total phenolic, flavonoid contents and in-vitro antioxidant potential were evaluated from various extracts of M. pudica leaves. Again, in-vivo antioxidant evaluation from brain homogenate on oxidative stress markers as TBARS, SOD, CAT and GSH from rat was investigated. Our findings revealed that M. pudica possesses both in-vitro and in-vivo antioxidant activity due to presence of phenolics and flavonoids. PMID- 26941533 TI - Development, Characterization, and Evaluation of Hepatoprotective Effect of Abutilon indicum and Piper longum Phytosomes. AB - BACKGROUND: Evidences from ethnopharmacological practices have shown that combination of Abutilon indicum and Piper longum are traditionally used to treat symptoms of the liver disorder. The hypothesis is phytosomes of a combination of both crude drug extract will be more effective and safe as hepatoprotective agent. AIM: Present work is aimed at development and characterization of phytosomes containing ethanolic extract of both drugs to meet the need for better effectiveness and safety. MATERIALS AND METHODS: Phytosomes were formulated by using Indena's patented process. Characterization involved following parameters: Particle size determination, percentage yield, entrapment efficiency, differential scanning calorimetry, scanning electron microscope, fourier transform infrared spectroscopy, and high performance thin liquid chromatography. Liver damage was induced in adult Charles foster rats (150 +/- 10 g) with CCl4 in olive oil (1:1 v/v, i.p) 1 ml/kg once daily for 7 days. LIV 52 (1 ml/kg per oral [p.o]), ethanolic extract of A. indicum and P. longum combination (100, 200, and 400 mg/kg p.o) and phytosomes (100 mg/kg p.o.) was given 3 days prior to CCl4 administration. Estimation of liver marker enzymes and histopathological studies were done. Result was analyzed by using (analysis of variance) followed by Student-Newman-Keuls test. RESULT: Combined extract has shown hepatoprotective activity but phytosomal formulation has more potent hepatoprotective effect on CCl4 induced liver toxicity at very low dose comparative to a higher dose of combined extract. CONCLUSION: Novel approach for herbal drug delivery is more prominent than conventional which improves bioavailability of polar extract and also patient compliance. SUMMARY: Standardised ethanolic extract of leaves of abutilon indicum and piper longum fruits by microwave assisted extraction was used for phytosomal complex formation and phytosomal complex was characterised by various parameters and finally the hepatoprotective activity of phytosomes and crude extract was evaluated by different biochemical markers and histopathological study. Abbreviations Used: DSC: Differential scanning calorimetry, SEM: Scanning electron microscope, FTIR: Fourier transform infrared spectroscopy, HPTLC: High performance thin liquid chromatography, p.o: Per oral, A. indicum: Abutilon indicum, P. longum: Piper longum. PMID- 26941534 TI - Quantification of Quercetin and Rutin from Benincasa hispida Seeds and Carissa Congesta Roots by High-performance Thin Layer Chromatography and High-performance Liquid Chromatography. AB - OBJECTIVE: In Indian Ayurvedic system, Benincasa hispida (BH) and Carissa congesta (CC) are well-known plants used for major and minor ailments. BH has been regarded as Kushmanda, whereas CC has been used in immune-related disorders of the human system. Quercetin and rutin identified from the vast plethora of plant extracts have proved to possess ethnopharmacological relevance. MATERIALS AND METHODS: In present studies, we have determined quercetin and rutin in terms of percentage in BH seeds and CC roots by high-performance thin layer chromatography (HPTLC) and high-performance liquid chromatography (HPLC). After extraction and phytochemical screening, the extracts were subjected to quantification for the presence of quercetin and rutin by HPTLC and HPLC. RESULTS: HPTLC showed quercetin as 44.60, 27.13% and rutin as 32.00, 36.31% w/w, whereas HPLC revealed quercetin as 34.00, 35.00% and rutin as 21.99, 45.03% w/v in BH and CC extracts, respectively. CONCLUSION: The BH and CC extracts have elucidated peaks that were corresponding with standard peaks on undertaking chromatographic studies. SUMMARY: Quercetin and rutin are isolated from BH seeds and CC roots by High Performance. Thin Layer Chromatography and High Performance Liquid Chromatography. HPTLC revealed presence of quercetin as 44.60, 27.13 % and rutin as 32.00, 36.31 % w/w. HPLC revealed presence of quercetin as 34.00, 35.00 % and rutin as 21.99, 45.03 % w/v. Abbreviation Used: HPTLC: High Performance Thin Layer Chromatography; HPLC: High Pressure Liquid Chromatography, UV: Ultraviolet, CC: Carissa congesta, BH: Benincasa hispida. PMID- 26941535 TI - Methanolic Extract of Curcuma caesia Roxb. Prevents the Toxicity Caused by Cyclophosphamide to Bone Marrow Cells, Liver and Kidney of Mice. AB - INTRODUCTION: With an ever increasing cause of cancer, it has been recommended to treat with conventional drugs, however because of the side effects caused by the conventional drugs, the research on medicinal plants has been intensified due to their less adverse and toxic effects. OBJECTIVES: The primary objective of the present study was to evaluate the protective effect of the medicinal plant Curcuma caesia Roxb. against free radicals ABTS(+) and O2 (-). Also it was aimed to evaluate the protective effect of C.caesia Roxb. against the chemotherapeutic drug Cyclophosphamide and its side effects in liver and kidney. METHODS: The rhizomes of the plant was extracted with methanol through soxhlet and its antioxidant activity was tested against ABTS(+) and O2 (-). For antigenotoxic studies, animals were divided into eight groups and micronucleus assay was employed and for biochemical analysis serum sample was collected from the blood and SGOT, SGPT analysis was performed. Also the biochemical analysis was performed from both the liver and kidney. RESULTS: The methanolic extract of Curcuma caesia Roxb. was found to scavenge the free radicals ABTS(+) and O2 (-). the micronuclei formation was found to be increased in the positive control group as compared to the negative control group significantly (P<0.002) however increase in the number of micronuclei was found to be decrease with the pretreatment of the extract at different concentrations significantly as compared to the negative control groups (P<0.01, P<0.005, P<0.001). The increased level of serum SGPT and SGOT as well as peroxidation level in both liver and kidney due to treatment of cyclophosphamide was also found to be decreased with the pretreatment of the extract significantly as compared to the positive control groups. There was decreased in the level of endogenous antioxidant such as GSH and GR in the positive control group however decreased level of GSH and GR was found to be increased with the pretreatment of the methanolic extract of C. caesia Roxb. CONCLUSION: The present study suggested that the methanolic extract of C. caesia Roxb has not shown any genotoxicity and reduces the genotoxicity caused by cyclophosphamide. It was also to have the protective effects against the liver and kidney. So it could be provided as one of the herbal supplementation in chemoprevention of CP to ameliorate the side effects of it. SUMMARY: Cancer is characterized by uncontrolled growth of cells and much research has been done for the past several years from various disciplines for the treatment of cancer but till now no therapy has been discovered. Treatment of cancer with chemotherapeutic drugs has been suggested to prevent cancer cells however they are often limited with their toxicity to normal cells. Therefore it has been suggested that the supplementation of medicinal plants which are rich source of antioxidants can decrease the toxic effect caused by chemotherapeutic drugs. Curcuma caesia Roxb is a medicinal plant which has high antioxidant activity, as per present study, methanolic extract of Curcuma caesia Roxb prevents the toxicity caused by cyclophosphosphamide (chemotherapeutic drug) in bone marrow cells by reducing the micronuclei formation; it also prevents the hepatotoxicity and nephrotoxicity caused by cyclophosphamide, so it can be used as a supplement in cancer treatment with cyclophosphamide. PMID- 26941536 TI - Antioxidant and Immunomodulatory Activity of Hydroalcoholic Extract and its Fractions of Leaves of Ficus benghalensis Linn. AB - BACKGROUND: Ficus benghalensis is a folk medicine indigenous plant of India. Several studies on this plant reported and focused on the biological profile of the plant. OBJECTIVES: This study is aimed to evaluate the antioxidant and immunomodulatory activity of F. benghalensis leaf extract using various in vitro screening methods of both parameters. MATERIALS AND METHODS: Hydroalcoholic (FB1) extract and it's four fractions viz. n-hexane (FB2), n-butanol (FB3), chloroform (FB4), and water (FB5) of leaves of F. benghalensis investigated for their free radical scavenging activity using 1-1-diphneyl-2-picrylhydrazyl and 2, 2'-azino bis (3-ethylbenzthiazoline-6-sulfonic acid) radicals. A dose-response curve was plotted and IC50 values were determined to assess antioxidant activity. Nitroblue tetrazolium test, phagocytosis of killed Candida albicans and candidacidal assay were carried out to assess the immunomodulatory activity. Positive non-lymphoid cell number, mean particle number of killed C. albicans, percent value of killed C. albicans by neutrophils were calculated and presented. RESULTS: All extracts showed antioxidant and prominent immunomodulatory activity with compared to standard. CONCLUSIONS: Hydroalcoholic (FB1) extract and its four fractions viz. n hexane (FB2), n-butanol (FB3), chloroform (FB4), and water (FB5) showed promising antioxidant and immunomodulatory activity. SUMMARY: Hydroalcoholic extract and its fractions of F. benghalensis Linn exhibited different DPPH and ABTS scavenging activity in concentration dependent manner.The extract, fractions and reference antioxidants showed DPPH scavenging effect in the order of Vit-C > Quercetin > FB2 > FB1 > FB5 > FB4> FB3 and ABTS scavenging effect in the order of Vit-C > Quercetin > FB1> FB2 > FB5 > FB3> FB4.FB2 and FB3 showed promising immunomodulatory activity at all concentrations. PMID- 26941537 TI - Bio-enhancing Effect of Piperine with Metformin on Lowering Blood Glucose Level in Alloxan Induced Diabetic Mice. AB - BACKGROUND: Diabetes mellitus is the most rampant metabolic pandemic of the 21(st) century. Piperine, the chief alkaloid of Piper nigrum (black pepper) is widely used in alternative and complementary therapies has been extensively studied for its bio-enhancing property. OBJECTIVE: To evaluate the bio-enhancing effect of piperine with metformin in lowering blood glucose levels in alloxan induced diabetic mice. MATERIALS AND METHODS: Piperine was isolated from an extract of fruits of P. nigrum. Alloxan-induced (150 mg/kg intraperitoneal) diabetic mice were divided into four groups. Group I (control 2% gum acacia 2 g/100 mL), Group II (metformin 250 mg/kg), Group III (metformin and piperine 250 mg/kg + 10 mg/kg), and Group IV (metformin and piperine 125 mg/kg + 10 mg/kg). All the drugs were administered orally once daily for 28 days. Blood glucose levels were estimated at day 0, day 14, and end of the study (day 28). RESULTS: The combination of piperine with therapeutic dose of metformin (10 mg/kg + 250 mg/kg) showed significantly more lowering of blood glucose level as compared to metformin alone on both 14(th) and 28(th) day (P < 0.05). Piperine in combination with sub-therapeutic dose of metformin (10 mg/kg + 125 mg/kg) showed significantly more lowering of blood glucose as compared to control group and also showed greater lowering of blood glucose as compared to metformin (250 mg/kg) alone. CONCLUSION: Piperine has the potential to be used as a bio enhancing agent in combination with metformin which can help reduce the dose of metformin and its adverse effects. SUMMARY: Piperine is known for its bioenhancing property. This study evaluates the effect of piperine in combination with oral antidiabetic drug metformin. Drugs were administered for 28 days in alloxan induced diabetic mice and blood glucose lowering effect was seen. Results showed significantly better effect of combination of piperine with therapeutic dose of metformin in comparison to metformin alone. Piperine in combination with subtherapeutic dose of metformin also showed better effect than therapeutic dose of metformin. Piperine, thus shows potential to be used as bioenhancer in combination with metformin. PMID- 26941538 TI - Isolation and Characterization of Chemopreventive Agent from Sphaeranthus amaranthoides Burm F. AB - OBJECTIVE: To investigate the in vitro cytotoxic effect and to isolate and characterize a chemopreventive secondary metabolite from Sphaeranthus amaranthoides Burm F (sivakaranthai). MATERIALS AND METHODS: In vitro cytotoxic effect was carried out by 3 (4,5-dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide assay. Different concentrations of the extracts were tested on three different cell lines namely A549, HT29, and MCF7. The chloroform extract was subjected to column chromatography, and the isolated compound was characterized by various spectral methods and by single crystal X-ray crystallography. RESULTS: The concentration that cause 50% growth inhibition value of chloroform extract was found to be 0.9 and 19 MUg/mL against MCF7 and A549 cell lines, respectively. Chloroform extract was subjected to column chromatography for the isolation of phytoconstituent. The structure of the isolated compound was identified by spectroscopic techniques such as infrared, nuclear magnetic resonance, XRD, and mass spectroscopy. On comparison of complete spectral detail of the compound, the proposed structure was identified as chrysosplenol D (a flavonoid). Chrysosplenol D was isolated for the first time from this plant. CONCLUSION: The chloroform extract had higher cytotoxic effect, and the isolated chrysosplenol D may be responsible for the anti-proliferative effect of the plant. SUMMARY: The plant Sphaeranthus amaranthoides Burm F was extracted with solvents of increasing polarity. The chloroform extract was found to have cell inhibition towards MCF 7 and HT 29 cell lines. This was subjected to fractionation. Chrysosplenol D was isolated from the chloroform extract. PMID- 26941539 TI - Antioxidant and Cytotoxic Effect of Barringtonia racemosa and Hibiscus sabdariffa Fruit Extracts in MCF-7 Human Breast Cancer Cell Line. AB - BACKGROUND: The fruits of Barringtonia racemosa and Hibiscus sabdariffa have been used in the treatment of abscess, ulcer, cough, asthma, and diarrhea as traditional remedy. OBJECTIVE: This study aims to evaluate cytotoxic effect of B. racemosa and H. sabdariffa methanol fruit extracts toward human breast cancer cell lines (MCF-7) and its antioxidant activities. MATERIALS AND METHODS: Total antioxidant activities of extracts were assayed using 2,2'-diphenyl-1 picrylhydrazyl radical (DPPH) and beta-carotene bleaching assay. Content of phytochemicals, total flavonoid content (TFC), and total phenolic content (TPC) were determined using aluminum chloride colorimetric method and Folin-Ciocalteu's reagent, respectively. Cytotoxic activity in vitro was investigated through 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide (MTT) assay. RESULTS: B. racemosa extract exhibited high antioxidant activities compared to H. sabdariffa methanol fruit extracts in DPPH radical scavenging assay (inhibitory concentration [IC50] 15.26 +/- 1.25 MUg/mL) and iota-carotene bleaching assay (I% 98.13 +/- 1.83%). B. racemosa also showed higher TPC (14.70 +/- 1.05 mg gallic acid equivalents [GAE]/g) and TFC (130 +/- 1.18 mg quercetin equivalents [QE]/g) compared to H. sabdariffa (3.80 +/- 2.13 mg GAE/g and 40.75 +/- 1.15 mg QE/g, respectively). In MTT assay, B. racemosa extract also showed a higher cytotoxic activity (IC50 57.61 +/- 2.24 MUg/mL) compared to H. sabdariffa. CONCLUSION: The present study indicated that phenolic and flavonoid compounds known for oxidizing activities indicated an important role among the contents of these plants extract. B. racemosa methanol extract have shown potent cytotoxic activity toward MCF-7. Following these promising results, further fractionation of the plant extract is underway to identify important phytochemical bioactives for the development of potential nutraceutical and pharmaceutical use. SUMMARY: The phenolic and flavonoid compounds were present in B. racemosa and H. sabdariffa methanol extractsB. racemosa methanol extract was found to be potent antioxidant activityB. racemosa methanol extract have shown potent cytotoxic activity (IC50 57.61 +/- 2.24 MUg/mL) toward MCF-7The phenolic and flavonoid compounds may contribute to the antioxidant and cytotoxic activity of B. racemosa. Abbreviations Used: MCF-7: Human breast cancer cell lines, DMEM: Modified eagle medium, DPPH: 2,2'-diphenyl-1-picrylhydrazyl radical, TPC: Total phenolic content, Na2CO3: Sodium carbonate, GAE: Gallic acid equivalents, TFC: Total flavonoid content, NaNO2: Sodium nitrite, AlCl3: Aluminum chloride, NaOH: Sodium hydroxide, QE: Quercetin equivalents, MTT: 3-(4, 5-dimethylthiazol-2-yl)-2, 5 diphenyl tetrazolium bromide, IC50: Inhibitory concentration, ANOVA: Analysis of variance, DLA: Dalton's lymphoma ascitic. PMID- 26941540 TI - The Effect of Ultrafine Process on the Dissolution, Antibacterial Activity, and Cytotoxicity of Coptidis rhizoma. AB - BACKGROUND: The dosage of herb ultrafine particle (UFP) depended on the increased level of its dissolution, toxicity, and efficacy. OBJECTIVE: The dissolution, antibacterial activity, and cytotoxicity of Coptidis rhizoma (CR) UFP were compared with those of traditional decoction (TD). MATERIALS AND METHODS: The dissolution of berberine (BBR) of CR TD and UFP was determined by high performance liquid chromatography. The antibacterial activity of CR extract was assayed by plate-hole diffusion and broth dilution method; the inhibitory effect of rat serums against bacteria growth was evaluated after orally given CR UFP or TD extract. The cytotoxicity of CR extract was evaluated by 3-(4,5 dimethylthiazol-2-Yl)-2,5-diphenyltetrazolium bromide assay. RESULTS: The dissolution amount of BBR from CR UFP increased 6-8-folds in comparison to TD at 2 min, the accumulative amount of BBR in both UFP and TD group increased in a time-dependent manner. The minimal inhibitory concentrations and minimal bactericidal concentrations of CR UFP extract decreased to 1/2~1/4 of those of TD extract. The inhibitory effect of rat serums against bacteria growth decreased time-dependently, and no statistical difference was observed between two groups at each time point. The 50% cytotoxic concentrations of UFP extract increased 1.66~1.97 fold than those of TD. CONCLUSIONS: The antibacterial activity and cytotoxicity of CR UFP increased in a dissolution-effect manner in vitro, the increased level of cytotoxicity was lower than that of antibacterial activity, and the inhibitory effect of rat serums containing drugs of UFP group did not improve. SUMMARY: Ultrafine grinding process caused a rapid increase of BBR dissolution from CR.The antibacterial activity and cytotoxicity of UFP extract in vitro increased in a dissolution-effect manner, but the cytotoxicity increased lower than the antibacterial activity.The antibacterial activity of rat serums of UFP group did not improve in comparison to that of TD group. PMID- 26941541 TI - Anti-Lipoxygenase Activity of Leaf Gall Extracts of Terminalia chebula (Gaertn.) Retz. (Combretaceae). AB - Lipoxygenase (LOX) inhibitors are the promising therapeutic target for treating a wide spectrum of inflammatory-related diseases such as cancer, asthma, lymphoma, leukemia, and autoimmune disorders. In the present study, the photochemical constituents and the anti-LOX potential of leaf galls of Terminalia chebula are evaluated to exemplify its further potential development as medicine. Extracts of T. chebula galls were tested for anti-LOX activity using linoleic acid as substrate and lipoxidase as an enzyme and also the total content of polyphenols with phytochemical analysis of the extract were determined. The presence of highest total phenolic and flavonoid content of 141 +/- 2.2 mg of gallic acid equivalent/g d.w and 125 +/- 1.4 mg of quercetin equivalent/g d.w and maximal LOX inhibitory activity (52.67%) at 800 MUg/mL concentrations were identified in the ethanolic extracts of leaf galls of T.chebula. The higher LOX inhibitory activity was positively correlated to the high content of total polyphenols/flavonoids. The results of this study confirm the folklore use of T. chebula leaves gall extracts as a natural anti-inflammatory agent and justify its ethnobotanical use. Therefore, the results encourage the use of T. chebula leave gall extracts for medicinal health, functional food, and nutraceuticals applications. SUMMARY: The present investigation demonstrated promising anti-LOX proper-ties of T. chebula leaves gall extracts. Presumably, these activities could be attributed in part to the polyphenolic features of the extract, as there was a strong correlation of higher LOX inhibiting activities with that of high total phenolic and flavonoid content in the methanolic leaf gall extracts of T. chebula. The results of this study confirm the folklore use of T. chebula leaves gall extracts as a natural anti-inflammatory agent and justify the ethnobotanical approach in the search for novel bioactive com-pounds. PMID- 26941542 TI - Regularized Quantile Regression and Robust Feature Screening for Single Index Models. AB - We propose both a penalized quantile regression and an independence screening procedure to identify important covariates and to exclude unimportant ones for a general class of ultrahigh dimensional single-index models, in which the conditional distribution of the response depends on the covariates via a single index structure. We observe that the linear quantile regression yields a consistent estimator of the direction of the index parameter in the single-index model. Such an observation dramatically reduces computational complexity in selecting important covariates in the single-index model. We establish an oracle property for the penalized quantile regression estimator when the covariate dimension increases at an exponential rate of the sample size. From a practical perspective, however, when the covariate dimension is extremely large, the penalized quantile regression may suffer from at least two drawbacks: computational expediency and algorithmic stability. To address these issues, we propose an independence screening procedure which is robust to model misspecification, and has reliable performance when the distribution of the response variable is heavily tailed or response realizations contain extreme values. The new independence screening procedure offers a useful complement to the penalized quantile regression since it helps to reduce the covariate dimension from ultrahigh dimensionality to a moderate scale. Based on the reduced model, the penalized linear quantile regression further refines selection of important covariates at different quantile levels. We examine the finite sample performance of the newly proposed procedure by Monte Carlo simulations and demonstrate the proposed methodology by an empirical analysis of a real data set. PMID- 26941543 TI - Homelessness prevention in New York City: On average, it works. AB - This study evaluates the community impact of the first four years of Homebase, a homelessness prevention program in New York City. Family shelter entries decreased on average in the neighborhoods in which Homebase was operating. Homebase effects appear to be heterogeneous, and so different kinds of averages imply different-sized effects. The (geometric) average decrease in shelter entries was about 5% when census tracts are weighted equally, and 11% when community districts (which are much larger) are weighted equally. This study also examines the effect of foreclosures. Foreclosures are associated with more shelter entries in neighborhoods that usually do not send large numbers of families to the shelter system. PMID- 26941544 TI - Outcomes and Use of Laparoscopic Versus Open Gastric Resection. AB - BACKGROUND AND OBJECTIVES: The advantages of laparoscopy over open surgery are well established. Laparoscopic resection for gastric cancer is safe and results in equivalent oncologic outcomes when compared with open resection. The purpose of this study was to assess the use of laparoscopy to treat gastric cancer and the associated outcomes. METHODS: The American College of Surgeons National Surgical Quality Improvement Project (NSQIP) dataset was queried for patients with gastric cancer (ICD-9 Code 151.0-151.9) from January 2005 through December 2012. Logistic regression was used to evaluate the 30-day morbidity and mortality of open gastrectomy (CPT code 43620-2, 43631-4) versus that of the laparoscopic procedure on the stomach (CPT code 43650), while adjusting for preoperative risk factors. RESULTS: A total of 4116 patients with gastric cancer were identified and divided by surgical approach into 2 groups: open gastrectomy (n = 3725; 90.5%) and laparoscopic procedure on the stomach (n = 391; 9.5%). After adjustment for preoperative risk factors, complications were significantly fewer in laparoscopic versus open gastric resection (odds ratio [OR] 0.61, 95% confidence interval [CI] = 0.45-0.82; P = .001). After adjusting for preoperative risk factors, there was no statistically significant difference in mortality with laparoscopic compared to open gastric resection (OR 0.74; 95% CI = 0.32-1.72; P = .481). CONCLUSIONS: Laparoscopy is underused in the treatment of gastric cancer. Given that laparoscopic gastric resection has a lower morbidity in comparison to open resection, steps should be made toward advancing the use of laparoscopy for gastric cancer. PMID- 26941545 TI - Laparoscopic Radical Prostatectomy Alone or With Laparoscopic Herniorrhaphy. AB - BACKGROUND AND OBJECTIVES: Prostate cancer and inguinal hernia are common health issues in men aged more than 50 years. Recently, more data are accumulating that laparoscopic radical prostatectomy (LRP) and laparoscopic inguinal hernia repair (LIHR) can be performed in the same operation. The purpose of this study was to compare patients who underwent simultaneous extraperitoneal LRP (E-LRP) and LIHR with control patients who underwent only E-LRP in a matched-pairs design. METHODS: Medical records of 215 patients were evaluated, and 20 patients who underwent E-LRP+LIHR were compared with 40 patients who underwent only E-LRP in a matched-pairs analysis. Preoperative clinical parameters (age, body mass index, prostate-specific antigen, clinical stage, Gleason score of the prostate biopsy, and prostate volume) and operative data (operation time, duration of catheterization, length of hospital stay, estimated blood loss, time to perform the anastomosis and its quality, and the percentage of patients with bilateral lymphadenectomy) were evaluated, as well as postoperative parameters (pathological stage, Gleason score, specimen weight, follow-up duration, biochemical recurrence, complication rates, and duration of postoperative analgesic treatment). RESULTS: No statistically significant differences were found in the preoperative and operative parameters between the 2 study groups. Pathological parameters and the follow-up period and complication rates were similar between the 2 groups. CONCLUSION: Performing LIHR and E-LRP during the same operation is safe and feasible in the treatment of patients with prostate cancer and inguinal hernia. PMID- 26941547 TI - Robot-Assisted Transabdominal Preperitoneal Ventral Hernia Repair. AB - BACKGROUND AND OBJECTIVES: We believe that complications due to the mesh used in ventral hernia repairs can be reduced by using the natural barrier afforded by the peritoneum. This can be challenging to do laparoscopically, however we felt that the robot-assisted laparoscopic approach reduces the difficulty in placing the mesh in the preperitoneal space, and we want to share our early experiences with this approach. We describe the surgical technique used in robot-assisted laparoscopic transabdominal preperitoneal (TAPP) ventral hernia repair with mesh. In addition, we evaluate its feasibility and present preliminary perioperative results. METHODS: We performed robot-assisted laparoscopic TAPP ventral hernia repairs in 3 patients in the spring of 2015. Demographic information and defect size were measured. Conversion from a laparoscopic to an open procedure was the primary outcome variable. RESULTS: There were 3 cases of robot-assisted TAPP ventral hernia repair with mesh. The mean age of the patients was 49 years, the mean body mass index was 32.6 kg/m(2), and the mean operative time was 163.7 minutes. The mean defect size was 1219.0 mm(2). There were no conversions to open during this early learning phase. All patients were discharged home within the 24 hour postoperative period. No complications were noted during a mean follow-up of 3 months. CONCLUSIONS: We present our early experience with robot-assisted TAPP ventral hernia repair. We note that because of improved ergonomics and wristed instrumentation, the robotic platform enabled creation of peritoneal flaps and complete coverage of mesh with peritoneum after primary closure of the defect. The robotic approach is feasible and may provide a better environment for mesh integration and protection. Further investigations with long-term follow-up are needed to verify that this technique is effective in reducing mesh-related intra abdominal complications. PMID- 26941548 TI - Effects of the Positive Action Program on Indicators of Positive Youth Development Among Urban Youth. AB - This study evaluated effects of Positive Action, a school-based social-emotional and character development (SECD) intervention, on indicators of positive youth development (PYD) among a sample of low-income, ethnic minority youth attending 14 urban schools. The study used a matched-pair, cluster-randomized controlled design at the school level. A multiple-measure self-report protocol assessed four key strengths and resources for PYD: self-concept, peer affiliations, ethics, and social skills. Students (n=1170) were assessed from grades 3 to 8, the duration of the intervention, with drop-outs and late entrants included in analyses. Growth curve analyses revealed evidence of favorable program effects on each of the four types of resources. The study contributes to PYD research by providing evidence for school-based interventions in low-income, urban contexts for ethnic minority youth. PMID- 26941546 TI - Laparoscopic Splenectomy and Azygoportal Disconnection: a Systematic Review. AB - BACKGROUND AND OBJECTIVES: Given the technical difficulty of laparoscopic splenectomy and azygoportal disconnection (LSD), data are limited that compare the laparoscopic to the open procedure. As the technique becomes more widespread, questions regarding its safety, feasibility, and reproducibility must be addressed. This review assesses the current status of LSD. METHODS: We conducted our literature review with a search of the PubMed database. All published series of 5 or more laparoscopic splenectomy and azygoportal disconnection procedures were examined. The demographic, intraoperative, and postoperative data analyzed included number of ports, conversion rate, operative duration, estimated intraoperative blood loss, postoperative hospital stay, and complications. RESULTS: Fifteen articles met the review criteria. Of 412 laparoscopic procedures, traditional laparoscopic splenectomy and azygoportal disconnection (TLSD) was used in 322 patients (78.2%), a modified laparoscopic procedure (MLSD) in 79 (19.2%), and a single-incision laparoscopic procedure (SLSD) in 11 (2.7%). Compared with the traditional and single-incision laparoscopic procedures, the MLSD procedure was associated with shorter operative duration and less blood loss. Furthermore, although the incidence of postoperative portal vein system thrombosis was higher in the laparoscopic than in the open splenectomy with azygoportal disconnection (OSD) procedure, the LSD procedure was associated with less pulmonary infection and pleural effusion and fewer incisional and overall complications than the open procedure. The rate of conversion to an open procedure was 5.4%. CONCLUSIONS: LSD is feasible and safe for selected patients when performed by an expert laparoscopic surgeon. It has perioperative advantages over OSD, but studies with longer follow-up periods and larger samples of patients are needed. PMID- 26941549 TI - Verbal Sexual Coercion Experiences, Sexual Risk, and Substance Use in Women. AB - Research has linked sexual assault, substance use, and sexually transmitted infection (STI) risk in women. Sexual assault by means of verbal sexual coercion (VSC) is more common than sexual assault by means of physical tactics, but VSC is rarely assessed independently. In addition, past work has established global connections among substance use, sexual assault history, and STI risk; however, assessing substance use during sexual behavior is less common. This study examined the relations among VSC, STI risk behavior, and substance use and attitudes. We hypothesized that women with larger numbers of VSC experiences would report more frequent sexual risk behaviors and substance use and attitudes. Participants with larger numbers of VSC experiences reported larger numbers of anal sex partners, more frequent penile-vaginal sex and sexual activity after substance use, and stronger sex-related alcohol expectancies. These findings suggest that VSC is associated with higher levels of STI risk in women. PMID- 26941550 TI - Bridging the gap in paediatric concussion management. PMID- 26941552 TI - Case 2: Zosteriform hypopigmented rash in a 13-year-old girl. PMID- 26941551 TI - Case 1: A newborn with pancytopenia. PMID- 26941553 TI - Case 3: Regression in an adolescent with autism spectrum disorder. PMID- 26941554 TI - Case 4: Vulvitis in a nonsexually active adolescent girl. PMID- 26941555 TI - Factors associated with car seat test failure in late preterm infants: A retrospective chart review. AB - BACKGROUND: Professional organizations recommend car seat testing of preterm infants before discharge from hospital. Late preterm infants (LPIs, 34(0/7) to 36(6/7) weeks' gestational age) are at the greatest risk for failure, despite often being well. OBJECTIVE: To determine the incidence of car seat testing failure in LPIs and associative factors. METHODS: A retrospective chart review was performed of inborn LPIs admitted to all levels of newborn care between July 1, 2012 and June 30, 2013. Data collected included maternal demographics, labour and delivery history, and neonatal course. Data were analyzed using backward logistic regression. RESULTS: A total of 511 charts were reviewed and 367 LPIs were eligible for inclusion. Of the 313 LPIs tested (mean [+/- SD] gestational age 36 weeks +/-6 days and birth weight 2614+/-405 g), 80 (26%) failed (95% CI 21% to 31%). Most failed due to desaturations (>=2) of <88% for >=10 s (n=33 [41%]). Multiple gestation was associated with failure (adjusted OR 2.45 [95% CI 1.44 to 4.18]; P=0.001), and there was a trend toward statistical significance for the variable postnatal age (0.996 [95% CI 0.99 to 1.00]; P=0.05). Infants who passed their car seat test had higher postnatal ages than those who failed (mean difference 39.4 h [95% CI 12.7 h to 66.0 h]; P=0.004). CONCLUSION: Twenty-six percent of LPIs failed car seat testing. Ideally, infants should be tested after an appropriate transitional period. The authors identified factors that may be important in designing future, prospective studies in this area. Future research should evaluate the clinical significance of car seat testing and resource utilization. PMID- 26941556 TI - The Edmonton Obesity Staging System for Pediatrics: A proposed clinical staging system for paediatric obesity. AB - Traditionally, clinical recommendations for assessing and managing paediatric obesity have relied on anthropometric measures, such as body mass index (BMI), BMI percentile and/or BMI z-score, to monitor health risks and determine weight management success. However, anthropometric measures do not always accurately and reliably identify children and youth with obesity-related health risks or comorbidities. The authors propose a new clinical staging system (the Edmonton Obesity Staging System for Pediatrics, EOSS-P), adapted from the adult-oriented EOSS. The EOSS-P is used to stratify patients according to severity of obesity related comorbidities and barriers to weight management into four graded categories (0 to 3) within four main health domains: metabolic, mechanical, mental health and social milieu (the 4Ms). The EOSS-P is based on common clinical assessments that are widely available and routinely completed by clinicians, and has the potential to provide clinical and prognostic information to help evaluate and inform the management of paediatric obesity. PMID- 26941557 TI - Interventions for treating fingertip entrapment injuries in children. PMID- 26941558 TI - Minor injuries... major implications: Watching out for sentinel injuries. PMID- 26941559 TI - Is the medical use of cannabis a therapeutic option for children? AB - Cannabis is a psychoactive compound with a long history of recreational and therapeutic use. Current considerations regarding cannabis use for medical purposes in children have been stimulated by recent case reports describing its beneficial effect with refractory epilepsy. Overall, there are insufficient data to support either the efficacy or safety of cannabis use for any indications in children, and an increasing body of data suggests possible harm, most importantly in specific conditions. The potential for cannabis as a therapeutic agent must be evaluated carefully for both efficacy and safety in treating specific paediatric health conditions. Smoking is not an acceptable mode of drug delivery for children. The use of cannabis for medical purposes in specific cases should not be construed as a justification for recreational cannabis use by adolescents. Recommendations for therapeutic use in exceptional paediatric cases are offered, always providing that this treatment course is carefully evaluated in individuals and in ongoing, well-designed research studies to determine safety and efficacy. PMID- 26941560 TI - Management of acute otitis media in children six months of age and older. AB - Acute otitis media (AOM) continues to be a common infection in young children. Milder disease, usually due to viruses or less virulent bacteria, resolves equally quickly with or without antibiotics. A bulging tympanic membrane, especially if yellow or hemorrhagic, has a high sensitivity for AOM that is likely to be bacterial in origin and is a major diagnostic criterion for AOM. Perforation of the tympanic membrane with purulent discharge similarly indicates a bacterial cause. Immediate antibiotic treatment is recommended for children who are highly febrile (>=39 degrees C), moderately to severely systemically ill or who have very severe otalgia, or have already been significantly ill for 48 h. For all other cases, parents can be provided with a prescription for antibiotics to fill if the child does not improve in 48 h or the child can be reassessed if this occurs. Amoxicillin remains the clear drug of choice. Ten days of therapy is appropriate for children <2 years of age, whereas older children can be treated for five days. PMID- 26941561 TI - We need psychologists! AB - Paediatricians are more likely than ever to encounter patients with mental health problems on a daily basis. There is a need for investment in proven treatments, such as psychology-based interventions, for children identified with mental health disorders. There are four main arguments supporting the engagement of psychologists for children with mental health problems: there is clear evidence that psychological interventions can effectively treat a wide range of mental health disorders; many parents and children are more open to exploring psychological therapies rather than medication for mental health problems; psychologists are trained and licensed to perform psychoeducational assessments, which can provide invaluable information about a child's learning profile, attention problems and overall intelligence; and behaviour problems in children can be prevented or improved through parent-based interventions. The authors' strongly advocate for the public funding of psychology services - both in collaborative primary care models and in the school setting. PMID- 26941562 TI - Evaluation of a practice guideline for the management of respiratory distress syndrome in preterm infants: A quality improvement initiative. AB - BACKGROUND: The use of mechanical ventilation to treat respiratory distress syndrome in preterm infants has been associated with the development of bronchopulmonary dysplasia. As part of a quality improvement initiative to reduce the incidence of bronchopulmonary dysplasia in preterm infants, a new practice guideline for the management of respiratory distress syndrome was developed and adopted into practice in a neonatal intensive care unit in February 2012. OBJECTIVE: To evaluate the effects of implementing the new guideline in regard to the use of mechanical ventilation and surfactant, and the incidence of bronchopulmonary dypslasia. METHODS: An historical cohort of very preterm infants (gestational age 26(0) to 32(6) weeks) born one year before guideline implementation was compared with a similar cohort of infants born one year following guideline implementation. Data were collected retrospectively from the local neonatal intensive care unit database. RESULTS: A total of 272 preterm infants were included in the study: 129 in the preguideline cohort and 143 in the postguideline cohort. Following the implementation of the guideline, the proportion of infants treated with ongoing mechanical ventilation was reduced from 49% to 26% (P<0.001) and there was a trend toward a reduction in bronchopulmonary dysplasia (27% versus 18%; P=0.07). There was no difference in the proportion of infants treated with surfactant (54% versus 50%). CONCLUSION: The implementation of the practice guideline helped to minimize the use of ongoing mechanical ventilation in preterm infants. PMID- 26941563 TI - A high-throughput method for genotyping S-RNase alleles in apple. AB - We present a new efficient screening tool for detection of S-alleles in apple. The protocol using general and multiplexed primers for PCR reaction and fragment detection on an automatized capillary DNA sequencer exposed a higher number of alleles than any previous studies. Analysis of alleles is made on basis of three individual fragment sizes making the allele interpretation highly accurate. The method was employed to genotype 432 Malus accessions and exposed 25 different S alleles in a selection of Malus domestica cultivars of mainly Danish origin (402 accessions) as well as a selection of other Malus species (30 accessions). The allele S3 (28 %) was the most common among the Danish cultivars followed by S1 and S7 (both 27 %). The alleles S36 and S40 not previously reported from M. domestica were found in 6 and 17 cultivars, respectively. Complete allelic composition was found in 91 % of the 369 diploid accessions and in 86 % of the 63 triploids concerned. We further identified a relatively high frequency of S33 and S34, which has not been considered by most previous studies. The protocol presented here is easy to adopt and saves both time and work effort compared to previous methods. The robustness is illustrated by the great accuracy and a high number of S-alleles presented. PMID- 26941564 TI - De-agglomeration and homogenisation of nanoparticles in coal tar pitch-based carbon materials. AB - The aim of the work was to characterise coal tar pitch (CTP) modified with selected nanoparticles as a binder precursor for the manufacture of synthetic carbon materials. Different factors influencing the preliminary preparative steps in the preparation of homogenous nanoparticle/CTP composition were studied. Graphene flakes, carbon black and nano-sized silicon carbide were used to modify CTP. Prior to introducing them into liquid CTP, nanoparticles were subjected to sonication. Various dispersants were used to prepare the suspensions, i.e. water, ethanol, dimethylformamide (DMF) and N-methylpyrrolidone (NMP).The results showed that proper dispersant selection is one of the most important factors influencing the de-agglomeration process of nanoparticles. DMF and NMP were found to be effective dispersants for the preparation of homogenous nanoparticle-containing suspensions. The presence of SiC and carbon black nanoparticles in the liquid pitch during heat treatment up to 2000 degrees C leads to the inhibition of crystallite growth in carbon residue. PMID- 26941565 TI - Preparation and Reinforcement of Dual-Porous Biocompatible Cellulose Scaffolds for Tissue Engineering. AB - 1Biocompatible cellulose-based aerogels composed of nanoporous struts, which embed interconnected voids of controlled micron-size, have been prepared employing temporary templates of fused porogens, reinforcement by interpenetrating PMMA networks and supercritical carbon dioxide drying. Different combinations of cellulose solvent (Ca(SCN)2/H2O/LiCl or [EMIm][OAc]/DMSO) and anti-solvent (EtOH), porogen type (paraffin wax or PMMA spheres) and porogen size (various fractions in the range of 100-500 MUm) as well as intensity of PMMA reinforcement have been investigated to tailor the materials for cell scaffolding applications. All aerogels exhibited an open and dual porosity (micronporosity >100 MUm and nanoporosity extending to the low micrometer range). Mechanical properties of the dual-porous aerogels under compressive stress were considerably improved by introduction of interpenetrating PMMA networks. The effect of the reinforcing polymer on attachment, spreading, and proliferation of NIH 3T3 fibroblast cells, cultivated on selected dual-porous aerogels to pre-evaluate their biocompatibility was similarly positive. PMID- 26941566 TI - Gelsolin and Progression of Aortic Arch Calcification in Chronic Hemodialysis Patients. AB - BACKGROUND: Vascular calcification (VC) is a key process associated with cardiovascular mortality in dialysis patients. Gelsolin is an actin-binding protein that can modulate inflammation, correlated inversely with hemodialysis (HD) mortality and involved in bone calcification homeostasis. In this report, we aim to characterize progression in aortic arch calcification (AAC) and investigate its association with gelsolin. METHODS: 184 HD patients were enrolled and their annual posterior-anterior chest X-ray films (CXR) in 2009 and 2013 were examined. The severity of AAC was classified as grade 0 to 3. Blood levels of gelsolin were measured by ELISA kits. Biographic and biochemical data at baseline were analyzed with status of AAC at baseline and changes after 4 years. RESULTS: At baseline, 60% of the patients had detectable AAC on CXR. After 4 years, 77% had AAC. Patients with grade 1 and 2 AAC had increased risk of progression (Odds ratio [OR] 2~3, P=0.001) compared to those with grade 0 at baseline. Compared to those with no AAC, patients with AAC progression had older age, lower gelsolin, higher waist circumference and prevalence of vascular disease. Regression analysis confirmed baseline gelsolin (odds ratio 0.845, 95% confidence interval [0.734-0.974]) and waist circumference as the independent factors associated with AAC progression. Gelsolin is positively correlated with serum albumin and negatively with tumor necrosis factor-alpha. CONCLUSION: Our study demonstrated that HD patients with grades 1 or 2 baseline AAC are at increased risk of further progression compared to those with grade 0. We also found lower blood levels of gelsolin associated with progressive AAC. Further investigation into the mechanistic roles of gelsolin in vascular calcification may provide new understanding of this key process. PMID- 26941567 TI - Comorbidity Analysis According to Sex and Age in Hypertension Patients in China. AB - BACKGROUND: Hypertension, an important risk factor for the health of human being, is often accompanied by various comorbidities. However, the incidence patterns of those comorbidities have not been widely studied. AIM: Applying big-data techniques on a large collection of electronic medical records, we investigated sex-specific and age-specific detection rates of some important comorbidities of hypertension, and sketched their relationships to reveal the risk for hypertension patients. METHODS: We collected a total of 6,371,963 hypertension related medical records from 106 hospitals in 72 cities throughout China. Those records were reported to a National Center for Disease Control in China between 2011 and 2013. Based on the comprehensive and geographically distributed data set, we identified the top 20 comorbidities of hypertension, and disclosed the sex-specific and age-specific patterns of those comorbidities. A comorbidities network was constructed based on the frequency of co-occurrence relationships among those comorbidities. RESULTS: The top four comorbidities of hypertension were coronary heart disease, diabetes, hyperlipemia, and arteriosclerosis, whose detection rates were 21.71% (21.49% for men vs 21.95% for women), 16.00% (16.24% vs 15.74%), 13.81% (13.86% vs 13.76%), and 12.66% (12.25% vs 13.08%), respectively. The age-specific detection rates of comorbidities showed five unique patterns and also indicated that nephropathy, uremia, and anemia were significant risks for patients under 39 years of age. On the other hand, coronary heart disease, diabetes, arteriosclerosis, hyperlipemia, and cerebral infarction were more likely to occur in older patients. The comorbidity network that we constructed indicated that the top 20 comorbidities of hypertension had strong co occurrence correlations. CONCLUSIONS: Hypertension patients can be aware of their risks of comorbidities based on our sex-specific results, age-specific patterns, and the comorbidity network. Our findings provide useful insights into the comorbidity prevention, risk assessment, and early warning for hypertension patients. PMID- 26941568 TI - Impairment of the Peritoneal Surface as a Decisive Factor for Intestinal Adhesions in Intraperitoneal Onlay Mesh Surgery - Introducing a New Rat Model. AB - BACKGROUND: Meshes implanted intraperitoneally are known to cause adhesions potentially resulting in complications such as chronic pain, enterocutaneous fistula, or mesh infection. This study introduces a model for investigation of intestine-to-mesh adhesions and evaluates as to whether missing of visceral peritoneum is causative. METHODS: In 18 rats, rectangular 1.5 x 2 cm patches of an uncoated polypropylene mesh (Ultrapro((r))) were sewn to the inner abdominal wall next to the cecum. Additionally, a meso-suture ensured contact between cecum and mesh. Rats were assigned to 2 groups: in 8 rats the peritoneum was left intact, in 10 the cecum was depleted from peritoneum with abrasion. Sacrifice was on day 7. Macroscopic evaluation used two adhesion scores. Specimens were evaluated microscopically, statistical analyses employed student's t-test. RESULTS: On day 7, rats with mesh implantation combined with locally de peritonealization by cecal abrasion mostly showed severe cecum-to-mesh agglutination (mean Lauder score 92%, mean total Hoffmann score 90%), whereas meshes of most animals without cecal abrasion only had some coverage with intraabdominal fat (33%, 24%; p = 0.0002). Histological work-up showed adequate wall ingrowth of mesh in all rats. In animals with cecal abrasion, meshes were mostly adhesive with cecal wall. However, when the peritoneum of cecum was unimpaired, abdominal wall above the mesh as well as cecum usually revealed sub peritoneal tissue and a mono-layer cell coverage as seen in normal peritoneum. CONCLUSION: This study introduces a model mimicking a clinical situation of e.g. hernia repair by intraperitoneally implanted meshes when mesh has contact with normal and with de-peritonealized intestine. The model might be useful for testing mesh types and coatings as well as other devices for their efficacy in adhesion prevention. The high adhesion scores of rats with local de peritonealization compared with the low scores of animals with intact peritoneum indicate that the integrity of intestinal peritoneum is a decisive factor for adhesion formation. PMID- 26941569 TI - Exosomes Mediate the Intercellular Communication after Myocardial Infarction. AB - The mechanisms of cardiac repair after myocardial infarction (MI) are complicated and not well-understood currently. It is known that exosomes are released from most cells, recognized as new candidates with important roles in intercellular and tissue-level communication. Cells can package proteins and RNA messages into exosome and secret to recipient cells, which regulate gene expression in recipient cells. The research on exosomes in cardiovascular disease is just emerging. It is well-known that exosomes from cardiomyocyte can transfect endothelial cells, stem cells, fibroblasts and smooth muscle cells to induce cellular changes. After myocardial infarction (MI), the exosomes play important roles in local and distant microcommunication. Nowadays, exosomal microRNAs transportation has been found to deliver signals to mediate cardiac repair after MI. However, the exosomes quality and quantities are variable under different pathological conditions. Therefore, we speculate that the monitoring of the quality and quantity of exosomes may serve as diagnosis and prognosis biomarkers of MI, and the study of exosomes will provide insights for the new therapeutics to cardiac remodeling after MI. PMID- 26941570 TI - Relationship of Genetic Polymorphisms of Aldosterone Synthase Gene Cytochrome P450 11B2 and Mineralocorticoid Receptors with Coronary Artery Disease in Taiwan. AB - The aldosterone synthase gene, cytochrome P450 11B2 (CYP11B2), and mineralocorticoid receptor (MR) genes have been reported to be associated with coronary artery disease (CAD). In this study, we investigated the association of single nucleotide polymorphisms (SNPs) of CYP11B2 (CYP11B2 T-344C) and MR (MR C3514G and MR C4582A) with CAD in Taiwanese. Six hundred and nine unrelated male and female subjects who received elective coronary angiography were recruited from Chung Shan Medical University Hospital. The enrolled subjects were those who had a positive noninvasive test. CYP11B2 T-344C, MR C3514G and MR C4582A were determined by polymerase chain reaction-restriction fragment length polymorphism. We found that women with CYP11B2 C/C had a higher risk of developing CAD. However, there were no significant differences in the genotype distributions of MR C3514G and MR C4582A between the women with and without CAD. In multivariate analysis, CYP11B2 T-344C was most significantly associated with CAD in Taiwanese women. In conclusions, CYP11B2 C/C was more significantly associated with the development of CAD than diabetes mellitus or hypertension. This implies that CYP11B2 C/C plays a more important role than some conventional risk factors in the development of CAD in Taiwanese women. PMID- 26941572 TI - The Association between GWAS-identified BARD1 Gene SNPs and Neuroblastoma Susceptibility in a Southern Chinese Population. AB - A previous genome-wide association study (GWAS) has found that some common variations in the BARD1 gene were associated with neuroblastoma susceptibility especially for high-risk subjects, and the associations have been validated in Caucasians and African-Americans. However, the associations between BARD1 gene polymorphisms and neuroblastoma susceptibility have not been studied among Asians, not to mention Chinese subjects. In the present study, we investigated the association of three BARD1 polymorphisms (rs7585356 G>A, rs6435862 T>G and rs3768716 A>G) with neuroblastoma susceptibility in 201 neuroblastoma patients and 531 controls using TaqMan methodology. Overall, none of these polymorphisms was significantly associated with neuroblastoma susceptibility. However, stratified analysis showed a more profound association between neuroblastoma risk and rs6435862 TG/GG variant genotypes among older children (adjusted OR=1.55, 95% CI=1.04-2.31), and children with adrenal gland-originated disease (adjusted OR=2.94, 95% CI=1.40-6.18), or with ISSN clinical stages III+IV disease (adjusted OR=1.75, 95% CI=1.09-2.84). Similar results were observed for the variant genotypes of rs3768716 A>G polymorphism among these three subgroups. Our results suggest that the BARD1 rs6435862 T>G and rs3768716 A>G polymorphisms may contribute to increased susceptibility to neuroblastoma, especially for the subjects at age >=12 months, with adrenal gland-originated or with late clinical stage neuroblastoma. These findings need further validation by prospective studies with larger sample size with subjects enrolled from multicenter, involving different ethnicities. PMID- 26941571 TI - Ageing/Menopausal Status in Healthy Women and Ageing in Healthy Men Differently Affect Cardiometabolic Parameters. AB - BACKGROUND: Gender medicine requires a global analysis of an individual's life. Menopause and ageing induce variations of some cardiometabolic parameters, but, it is unknown if this occurs in a sex-specific manner. Here, some markers of oxidative stress, systemic inflammation, and endothelial dysfunction are analysed in men younger and older than 45 years and in pre- and postmenopausal women. METHODS: Serum and plasma sample were assayed for TNF-alpha and IL-6, malondialdehyde and protein carbonyls and for methylated arginines using ELISA kits, colorimetric methods and capillary electrophoresis. RESULTS: Before body weight correction, men overall had higher creatinine, red blood cells and haemoglobin and lower triglycerides than women. Men younger than 45 years had lower levels of TNF-alpha and malondialdehyde and higher levels of arginine than age-matched women, while postmenopausal women had higher IL-6 concentrations than men, and higher total cholesterol, triglycerides, creatinine and IL-6 levels than younger women. Men younger than 45 years had lower total cholesterol and malondialdehyde than older men. After correction, some differences remained, others were amplified, others disappeared and some new differences emerged. Moreover, some parameters showed a correlation with age, and some of them correlated with each other as functions of ageing and ageing/menopausal status. CONCLUSIONS: Ageing/menopausal status increased many more cardiovascular risk factors in women than ageing in men, confirming that postmenopausal women had increased vascular vulnerability and indicating the need of early cardiovascular prevention in women. Sex-gender differences are also influenced by body weight, indicating as a matter of debate whether body weight should be seen as a true confounder or as part of the causal pathway. PMID- 26941573 TI - Melissa Officinalis L. Extracts Protect Human Retinal Pigment Epithelial Cells against Oxidative Stress-Induced Apoptosis. AB - BACKGROUND: We evaluated the protective effect of ALS-L1023, an extract of Melissa officinalis L. (Labiatae; lemon balm) against oxidative stress-induced apoptosis in human retinal pigment epithelial cells (ARPE-19 cells). METHODS: ARPE-19 cells were incubated with ALS-L1023 for 24 h and then treated with hydrogen peroxide (H2O2). Oxidative stress-induced apoptosis and intracellular generation of reactive oxygen species (ROS) were assessed by flow cytometry. Caspase-3/7 activation and cleaved poly ADP-ribose polymerase (PARP) were measured to investigate the protective role of ALS-L1023 against apoptosis. The protective effect of ALS-L1023 against oxidative stress through activation of the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) was evaluated by Western blot analysis. RESULTS: ALS-L1023 clearly reduced H2O2-induced cell apoptosis and intracellular production of ROS. H2O2-induced oxidative stress increased caspase-3/7 activity and apoptotic PARP cleavage, which were significantly inhibited by ALS-L1023. Activation of the PI3K/Akt pathway was associated with the protective effect of ALS-L1023 on ARPE-19 cells. CONCLUSIONS: ALS-L1023 protected human RPE cells against oxidative damage. This suggests that ALS-L1023 has therapeutic potential for the prevention of dry age-related macular degeneration. PMID- 26941574 TI - Vitamin D3 Reduces Tissue Damage and Oxidative Stress Caused by Exhaustive Exercise. AB - Exhaustive exercise results in inflammation and oxidative stress, which can damage tissue. Previous studies have shown that vitamin D has both anti inflammatory and antiperoxidative activity. Therefore, we aimed to test if vitamin D could reduce the damage caused by exhaustive exercise. Rats were randomized to one of four groups: control, vitamin D, exercise, and vitamin D+exercise. Exercised rats received an intravenous injection of vitamin D (1 ng/mL) or normal saline after exhaustive exercise. Blood pressure, heart rate, and blood samples were collected for biochemical testing. Histological examination and immunohistochemical (IHC) analyses were performed on lungs and kidneys after the animals were sacrificed. In comparison to the exercise group, blood markers of skeletal muscle damage, creatine kinase and lactate dehydrogenase, were significantly (P < 0.05) lower in the vitamin D+exercise group. The exercise group also had more severe tissue injury scores in the lungs (average of 2.4 +/- 0.71) and kidneys (average of 3.3 +/- 0.6) than the vitamin D treated exercise group did (1.08 +/- 0.57 and 1.16 +/- 0.55). IHC staining showed that vitamin D reduced the oxidative product 4-Hydroxynonenal in exercised animals from 20.6% to 13.8% in the lungs and from 29.4% to 16.7% in the kidneys. In summary, postexercise intravenous injection of vitamin D can reduce the peroxidation induced by exhaustive exercise and ameliorate tissue damage, particularly in the kidneys and lungs. PMID- 26941575 TI - Functional Role of FcgammaRIIB in the Regulation of Mesenchymal Stem Cell Function. AB - Mesenchymal stem cells (MSCs) derived from bone marrow are plural-potent stem cells with immune regulatory functions. We aimed to evaluate role of FcgammaRIIB in the regulation of bone marrow-derived MSC function. MSCs were prepared from mouse bone marrow derived from wild-type (WT) or FcgammaRIIB-deficient (FcgammaRIIB-/-) mice. MSCs were co-cultured with bone marrow-derived dendritic cells (BMDCs), and BMDC maturation and function were evaluated by flow cytometric analysis and carboxyfluorescein succinimidyl ester-labeled OT-II T-cell addition. An acute asthma model was established by aeresol ovalbumin challenge in mice. Mice received WT or FcgammaRIIB-/- MSC therapy. Lung function was evaluated by histological examination and cytokine production measurement. mRNA and protein expression levels of target genes were examined by real-time quantitative polymerase chain reactionor western blotting. We found that MSCs derived from bone marrow exhibit a high level of FcgammaRIIB expression. FcgammaRIIB deficiency impaired the suppressive function of MSCs, as FcgammaRIIB deficiency efficiently reversed the inhibitory effect of MSCs on BMDC maturation and function. Additionally, FcgammaRIIB-/-MSCs were less potent at suppressing asthma in model mice, possibly through reduced expression of Smad2, Smad3, Cox-2, and prostaglandin E2 in FcgammaRIIB-/-MSCs. FcgammaRIIB might play an essential role in regulating the inhibitory effects of MSCs derived from bone marrow. PMID- 26941576 TI - Role of Serum Biomarkers in Early Detection of Diabetic Cardiomyopathy in the West Virginian Population. AB - OBJECTIVES: Diabetic cardiomyopathy (DCM) is an established complication of diabetes mellitus. In West Virginia, the especially high incidence of diabetes and heart failure validate the necessity of developing new strategies for earlier detection of DCM. Since most DCM patients remain asymptomatic until the later stages of the disease when the fibrotic complications become irreversible, we aimed to explore biomarkers that can identify early-stage DCM. METHODS: The patients were grouped into 4 categories based on clinical diabetic and cardiac parameters: Control, Diabetes (DM), Diastolic dysfunction (DD), and Diabetes with diastolic dysfunction (DM+DD), the last group being the preclinical DCM group. RESULTS: Echocardiography images indicated severe diastolic dysfunction in patients with DD+DM and DD compared to DM or control patients. In the DM and DM+DD groups, TNFalpha, isoprostane, and leptin were elevated compared to control (p<0.05), as were clinical markers HDL, glucose and hemoglobin A1C. Fibrotic markers IGFBP7 and TGF-beta followed the same trend. The Control group showed higher beneficial levels of adiponectin and bilirubin, which were reduced in the DM and DM+DD groups (p<0.05). CONCLUSION: The results from our study support the clinical application of biomarkers in diagnosing early stage DCM, which will enable attenuation of disease progression prior to the onset of irreversible complications. PMID- 26941577 TI - Palmitate-induced Regulation of PPARgamma via PGC1alpha: a Mechanism for Lipid Accumulation in the Liver in Nonalcoholic Fatty Liver Disease. AB - The aim was to examine the effect of free fatty acids on the regulation of PPARgamma-PGC1alpha pathway, and the effect of PPARgamma/PGC1alpha in NAFLD. The mRNA and protein expression of PGC1alpha and phospho/total PPARgamma were examined in Huh7 cells after the palmitate/oleate treatment with/without the transfection with siRNA against PGC1a. The palmitate content, mRNA and protein expression of PGC1alpha and PPARgamma in the liver were examined in the control and NAFLD mice. Palmitate (500 MUM), but not oleate, increased protein expression of PGC1alpha and phospho PPARgamma (PGC1alpha, 1.42-fold, P=0.038; phospho PPARgamma, 1.56-fold, P=0.022). The palmitate-induced PPARgamma mRNA expression was reduced after the transfection (0.46-fold), and the protein expressions of PGC1alpha (0.52-fold, P=0.019) and phospho PPARgamma (0.43-fold, P=0.011) were suppressed in siRNA-transfected cells. The palmitate (12325.8 +/- 1758.9 MUg/g vs. 6245.6 +/- 1182.7 MUg/g, p=0.002), and mRNA expression of PGC1alpha (11.0 vs. 5.5, p=0.03) and PPARgamma (4.3 vs. 2.2, p=0.0001) in the liver were higher in high-triglyceride liver mice (>15.2 mg/g) than in low-triglyceride liver mice (<15.2 mg/g). The protein expressions of both PGC1alpha and PPARgamma were higher in the NAFLD group than in the controls (PGC1alpha, 1.41-fold, P=0.035; PPARgamma, 1.39-fold, P=0.042), and were higher in the high-triglyceride liver group (PGC1alpha, 1.52-fold, p=0.03; PPARgamma, 1.22-fold, p=0.05) than in the low-triglyceride liver group. In conclusion, palmitate appear to up-regulate PPARgamma via PGC1alpha in Huh7 cells, and both PGC1alpha and PPARgamma are up regulated in the NAFLD mice liver, suggesting an effect on lipid metabolism leading to intrahepatic triglyceride accumulation. PMID- 26941578 TI - Macrophage Activation Syndrome-Associated Markers in Severe Dengue. AB - Hemophagocytosis, a phenomenon of which activated macrophages phagocytosed hematopoietic elements was reportedly observed in severe dengue patients. In the present study, we investigated whether markers of macrophage activation syndrome (MAS) can be used as differential diagnostic markers of severe dengue. Two hundred and eight confirmed dengue patients were recruited for the study. Sandwich ELISA was used to determine serum ferritin, soluble CD163 (sCD163), and soluble CD25 (sCD25) levels. The population of circulating CD163 (mCD163) monocytes was determined using flow cytometry. Receiver operating characteristic (ROC) analysis was plotted to determine the predictive validity of the biomarkers. Serum ferritin and sCD163 were found significantly increased in severe dengue patients compared to dengue fever patients (P = 0.003). A fair area under ROC curves (AUC) at 0.72 with a significant P value of 0.004 was observed for sCD163. sCD25 and mCD163 levels were not significantly different between severe dengue and dengue fever patients. Our findings suggest that in addition to serum ferritin, sCD163 can differentiate severe dengue from that of dengue fever patients. Hence, sCD163 level can be considered for use as a predictive marker for impending severe dengue. PMID- 26941579 TI - A Prospective Randomized Experimental Study to Investigate the Eradication Rate of Endometriosis after Surgical Resection versus Aerosol Plasma Coagulation in a Rat Model. AB - PURPOSE: To investigate the eradication rate of endometriosis after surgical resection (SR) vs. thermal ablation with aerosol plasma coagulation (AePC) in a rat model. METHODS: In this prospective, randomized, controlled, single-blinded animal study endometriosis was induced on the abdominal wall of 34 female Wistar rats. After 14 days endometriosis was either removed by SR or ablated by AePC. 14 days later the rats were euthanized to evaluate the eradication rate histopathologically. Intervention times were recorded. RESULTS: Eradication rate of endometriosis after 14 days did not significantly differ between AePC and SR (p=0.22). Intervention time per endometrial lesion was 22.1 s for AePC and 51.8 s for SR (p<0.0001). CONCLUSIONS: This study compares the eradication rate of the new aerosol plasma coagulation device versus standard surgical resection of endometriosis in a rat model. Despite being a thermal method, AePC showed equality towards SR regarding eradication rate but with significantly shorter intervention time. PMID- 26941580 TI - Dysregulated Serum MiRNA Profile and Promising Biomarkers in Dengue-infected Patients. AB - OBJECTIVES: Pathological biomarkers and mechanisms of dengue infection are poorly understood. We investigated a new serum biomarker using miRNAs and performed further correlation analysis in dengue-infected patients. METHODS: Expression levels of broad-spectrum miRNAs in serum samples from three patients with dengue virus type 1 (DENV-1) and three healthy volunteers were separately analyzed using miRNA PCR arrays. The expressions of the five selected miRNAs were verified by qRT-PCR in the sera of 40 DENV-1 patients and compared with those from 32 healthy controls. Receiver operating characteristic (ROC) curve and correlation analyses were performed to evaluate the potential of these miRNAs for the diagnosis of dengue infection. RESULTS: MiRNA PCR arrays revealed that 41 miRNAs were upregulated, whereas 12 miRNAs were down-regulated in the sera of DENV-1 patients compared with those in healthy controls. Among these miRNAs, qRT-PCR validation showed that serum hsa-miR-21-5p, hsa-miR-590-5p, hsa-miR-188-5p, and hsa-miR-152 3p were upregulated, whereas hsa-miR-146a-5p was down-regulated in dengue infected patients compared with healthy controls. ROC curves showed serum hsa-miR 21-5p and hsa-miR-146a-5p could distinguish dengue-infected patients with preferable sensitivity and specificity. Correlation analysis indicated that expression levels of serum hsa-miR-21-5p and hsa-miR-146a-5p were negative and positively correlated with the number of white blood cells and neutrophils, respectively. Functional analysis of target proteins of these miRNAs in silico indicated their involvement in inflammation and cell proliferation. CONCLUSION: Dengue-infected patients have a broad "fingerprint" profile with dysregulated serum miRNAs. Among these miRNAs, serum hsa-miR-21-5p, hsa-miR-146a-5p, hsa-miR 590-5p, hsa-miR-188-5p, and hsa-miR-152-3p were identified as promising serum indicators for dengue infection. PMID- 26941582 TI - Pathological Analysis of Cell Differentiation in Cholesterol Granulomas Experimentally Induced in Mice. AB - In this study, cholesterin was implanted in the subcutaneous tissue in mice to induce the formation of cholesterol granuloma. Histological examination was carried out to determine the type and source of cells. The tissue surrounding the embedded cholesterin was examined histologically within the period of 6 months. Cell differentiation in cholesterol granulomas was investigated using ddY mice and GFP bone marrow transplanted mice. Cholesterin was embedded in mice subcutaneously and histopathological examination was carried out in a period of 6 months. Results showed that at 2 weeks, cholesterin was replaced partly by granulation tissues. The majority of cells in the granulation tissues were macrophages and foreign body giant cells and the center consists of small amount of fibroblasts, collagen fibers and capillaries. At 3 months, more granulation tissue was observed compared to 2 weeks. Similar cells were observed, however, there were more fibroblasts, collagen bundles and capillaries present compared to 2 weeks. At 6 months, the cholesterin was mostly substituted by fibrous tissues consisting mainly of fibroblasts and collagen fibers with some macrophages and foreign body giant cells. Specifically, the outer part of the tissue consists of fibroblasts, collagen bundles and capillaries and the inner portion is filled with collagen bundles. Immunohistochemistry revealed that macrophages and foreign body giant cells were positive to GFP and CD68 although the fibroblasts and capillaries in the outer portion of cholesterol granulomas were GFP negative. Some spindle shape fibroblasts were also GFP positive. Immunofluorescent double staining revealed that cells lining the blood vessels were both positive to GFP and CD31 indicating that those were endothelial cells and were actually derived from the transplanted bone marrow cells. The results suggest that macrophages, foreign body giant cells as well as fibroblasts and capillary endothelial cells are bone marrow derived mesenchymal cells. PMID- 26941581 TI - Dietary Flaxseed Mitigates Impaired Skeletal Muscle Regeneration: in Vivo, in Vitro and in Silico Studies. AB - BACKGROUND: Diets enriched with n-3 polyunsaturated fatty acids (n-3 PUFAs) have been shown to exert a positive impact on muscle diseases. Flaxseed is one of the richest sources of n-3 PUFA acid alpha-linolenic acid (ALA). The aim of this study was to assess the effects of flaxseed and ALA in models of skeletal muscle degeneration characterized by high levels of Tumor Necrosis Factor-alpha (TNF). METHODS: The in vivo studies were carried out on dystrophic hamsters affected by muscle damage associated with high TNF plasma levels and fed with a long-term 30% flaxseed-supplemented diet. Differentiating C2C12 myoblasts treated with TNF and challenged with ALA represented the in vitro model. Skeletal muscle morphology was scrutinized by applying the Principal Component Analysis statistical method. Apoptosis, inflammation and myogenesis were analyzed by immunofluorescence. Finally, an in silico analysis was carried out to predict the possible pathways underlying the effects of n-3 PUFAs. RESULTS: The flaxseed-enriched diet protected the dystrophic muscle from apoptosis and preserved muscle myogenesis by increasing the myogenin and alpha myosin heavy chain. Moreover, it restored the normal expression pattern of caveolin-3 thereby allowing protein retention at the sarcolemma. ALA reduced TNF-induced apoptosis in differentiating myoblasts and prevented the TNF-induced inhibition of myogenesis, as demonstrated by the increased expression of myogenin, myosin heavy chain and caveolin-3, while promoting myotube fusion. The in silico investigation revealed that FAK pathways may play a central role in the protective effects of ALA on myogenesis. CONCLUSIONS: These findings indicate that flaxseed may exert potent beneficial effects by preserving skeletal muscle regeneration and homeostasis partly through an ALA-mediated action. Thus, dietary flaxseed and ALA may serve as a useful strategy for treating patients with muscle dystrophies. PMID- 26941583 TI - Dynamic Compression Effects on Immature Nucleus Pulposus: a Study Using a Novel Intelligent and Mechanically Active Bioreactor. AB - BACKGROUND: Previous cell culture and animal in vivo studies indicate the obvious effects of mechanical compression on disc cell biology. However, the effects of dynamic compression magnitude, frequency and duration on the immature nucleus pulposus (NP) from an organ-cultured disc are not well understood. OBJECTIVE: To investigate the effects of a relatively wide range of compressive magnitudes, frequencies and durations on cell apoptosis and matrix composition within the immature NP using an intelligent and mechanically active bioreactor. METHODS: Discs from the immature porcine were cultured in a mechanically active bioreactor for 7 days. The discs in various compressive magnitude groups (0.1, 0.2, 0.4, 0.8 and 1.3 MPa at a frequency of 1.0 Hz for 2 hours), frequency groups (0.1, 0.5, 1.0, 3.0 and 5.0 Hz at a magnitude of 0.4 MPa for 2 hours) and duration groups (1, 2, 4 and 8 hours at a magnitude of 0.4 MPa and frequency of 1.0 Hz) experienced dynamic compression once per day. Discs cultured without compression were used as controls. Immature NP samples were analyzed using the TUNEL assay, histological staining, glycosaminoglycan (GAG) content measurement, real-time PCR and collagen II immunohistochemical staining. RESULTS: In the 1.3 MPa, 5.0 Hz and 8 hour groups, the immature NP showed a significantly increase in apoptotic cells, a catabolic gene expression profile with down-regulated matrix molecules and up-regulated matrix degradation enzymes, and decreased GAG content and collagen II deposition. In the other compressive magnitude, frequency and duration groups, the immature NP showed a healthier status regarding NP cell apoptosis, gene expression profile and matrix production. CONCLUSION: Cell apoptosis and matrix composition within the immature NP were compressive magnitude-, frequency- and duration-dependent. The relatively high compressive magnitude or frequency and long compressive duration are not helpful for maintaining the healthy status of an immature NP. PMID- 26941584 TI - Relationship between Stroke Volume Variation and Blood Transfusion during Liver Transplantation. AB - BACKGROUND: Intraoperative blood transfusion increases the risk for perioperative mortality and morbidity in liver transplant recipients. A high stroke volume variation (SVV) method has been proposed to reduce blood loss during living donor hepatectomy. Herein, we investigated whether maintaining high SVV could reduce the need for blood transfusion and also evaluated the effect of the high SVV method on postoperative outcomes in liver transplant recipients. METHODS: We retrospectively analyzed 332 patients who underwent liver transplantation, divided into control (maintaining <10% of SVV during surgery) and high SVV (maintaining 10-20% of SVV during surgery) groups. We evaluated the blood transfusion requirement and hemodynamic parameters, including SVV, as well as postoperative outcomes, such as incidences of acute kidney injury, durations of postoperative intensive care unit and hospital stay, and rates of 1-year mortality. RESULTS: Mean SVV values were 7.0% +/- 1.3% in the control group (n = 288) and 11.2% +/- 1.8% in the high SVV group (n = 44). The median numbers of transfused packed red blood cells and fresh frozen plasmas in the high SVV group were significantly lower than those in control group (0 vs. 2 units, P = 0.003; and 0 vs. 3 units, P = 0.033, respectively). No significant between-group differences were observed for postoperative outcomes. CONCLUSIONS: Maintaining high SVV can reduce the blood transfusion requirement during liver transplantation without worsening postoperative outcomes. These findings provide insights into improving perioperative management in liver transplant recipients. PMID- 26941585 TI - Endothelial Progenitor Cells Predict Long-Term Mortality in Hemodialysis Patients. AB - BACKGROUND: The endothelial progenitor cells (EPCs) dysfunction is a critical event in the initiation of atherosclerotic plaque development and the level of circulating EPCs can be considered a biomarker of cardiovascular events. The level and functional change in EPCs has been investigated in hemodialysis patients, but the effect of absolute number of EPCs on risk of death has not yet been explored. We hypothesized that the number of EPCs predicted death from cardiovascular and all-cause mortality in hemodialysis patients. METHODS: We evaluate the association between endothelial progenitor cells and clinical outcome in 154 patients on maintenance hemodialysis. The blood sample was drawn at the time of patient enrollment and EPCs were identified by flow cytometry using triple staining for CD34/CD133/KDR. RESULTS: The median duration of follow up was 4.19 years. There were 79 (51.3%) deaths during the follow-up period, 41 of whom died due to a confirmed cardiovascular cause. The cumulative survival was greater in the high-EPC group than the low-EPC group for all-cause and cardiovascular mortality. Decreased EPCs levels were associated with a significant increase in the risk of cardiovascular and all-cause mortality after adjusting for age, gender, current smokers, diabetes mellitus, and hypertension. CONCLUSIONS: The level of circulating EPCs independently predicts the clinical outcome in patients on maintenance hemodialysis. Thus, the EPCs levels may be a useful predictive tool for evaluating the risk of death in maintenance hemodialysis patients. PMID- 26941586 TI - Do we need to worry about eating wheat? AB - Wheat is a staple food throughout the temperate world and an important source of nutrients for many millions of people. However, the last few years have seen increasing concerns about adverse effects of wheat on health, particularly in North America and Europe, with the increasing adoption of wheat-free or gluten free diets. This relates to two concerns: that wheat products are disproportionally responsible for increases in obesity and type 2 diabetes and that wheat gluten proteins cause a range of adverse reactions, including allergies, coeliac disease and 'non-coeliac gluten sensitivity'. The first concern has been refuted in previous publications, and we therefore focus on the second here. Current evidence indicates that allergy to ingested wheat and coeliac disease (and related intolerances) each occur in up to 1% of the population. The extent to which their prevalence has increased is difficult to quantify due to improved diagnosis and increased awareness. However, neither appears to be increasing disproportionally when compared with other immunologically mediated adverse reactions to food. Other adverse reactions to wheat are more difficult to define as their mechanisms are not understood and they are therefore difficult to diagnose. In particular, 'non-coeliac wheat sensitivity' has been reported to occur in 6% or more of the population in the US. However, the application of more rigorous diagnostic criteria is likely to give substantially lower estimates of prevalence. It is therefore unlikely that the health of more than a small proportion of the population will be improved by eliminating wheat or gluten from the diet. In fact, the opposite may occur as wheat is an important source of protein, B vitamins, minerals and bioactive components. PMID- 26941587 TI - Identification of biological targets of therapeutic intervention for clear cell renal cell carcinoma based on bioinformatics approach. AB - BACKGROUND: We aimed to discover the potential microRNA (miRNA) targets and to explore the underlying molecular mechanisms of clear cell renal cell carcinoma (ccRCC). METHODS: Microarray data of GSE16441 was downloaded from Gene Expression Omnibus database. Differentially expressed genes (DEGs) and differentially expressed miRNAs between ccRCC tumors and matched non-tumor samples were analyzed. Target genes of differentially expressed miRNAs were screened. Besides, functional enrichment analysis of DEGs was performed, followed by protein-protein interaction (PPI) network construction and sub-module analysis. Finally, the integrated miRNA-DEGs network was constructed. RESULTS: A total of 1758 up- and 2465 down-regulated DEGs were identified. Moreover, 15 up- and 12 down-regulated differentially expressed miRNAs were screened. The up-regulated DEGs were significantly enriched in pathways such as cell adhesion molecules and focal adhesion. Besides, the down-regulated DEGs were enriched in oxidative phosphorylation, and citrate cycle (TCA cycle). Moreover, eight sub-modules of PPI network were obtained. Totally, eight down-regulated miRNAs were identified to significantly regulate the DEGs and miRNA-200c that could regulate collagen, type V, alpha 2 (COL5A2) as well as COL5A3 was found to be the most significant. Additionally, 10 up-regulated miRNAs were identified to be significantly associated with the DEGs. Thereinto, miRNA-15a that could regulate ATPase, H(+) transporting, lysosomal 21 kDa, V0 subunit b (ATP6V0B) and miRNA-155 were found to be the most significant. CONCLUSIONS: miRNA-200c that could regulate COL5A2 and COL5A3, miRNA-15a that could regulate ATP6V0B and miRNA-155 may play key roles in ccRCC progression. These miRNAs may be potential targets for ccRCC treatment. PMID- 26941588 TI - Building on the Evidence: Guiding Policy and Research on Police Encounters with Persons with Mental Illnesses. PMID- 26941589 TI - Pro-social cognition: helping, practical reasons, and 'theory of mind'. AB - There is converging evidence that over the course of the second year children become good at various fairly sophisticated forms of pro-social activities, such as helping, informing and comforting. Not only are toddlers able to do these things, they appear to do them routinely and almost reliably. A striking feature of these interventions, emphasized in the recent literature, is that they show precocious abilities in two different domains: they reflect complex 'theory of mind' abilities as well as 'altruistic motivation'. Our aim in this paper is to present a theoretical hypothesis that bears on both kinds of developments. The suggestion is that children's 'instrumental helping' reflects their budding understanding of practical reasons (in the standard sense of 'considerations that count in favour of' someone's acting in a certain way). We can put the basic idea in the familiar terminology of common coding: toddlers conceive of the goals of others' actions in the same format as the goals of their own actions: in terms of features of their situation that provide us with reasons to act. PMID- 26941590 TI - Gender-based differences in the antidepressant treatment of patients with depression in German psychiatric practices. AB - BACKGROUND: Depression is recognized as the leading cause of disability in the world. Our goal was to compare treatment initiation in men and women treated in German neuropsychiatric practices after diagnosis of depression. METHODS: Patients aged between 18 and 80 first diagnosed with depression between 2010 and 2013 were identified by 223 psychiatrists in the IMS Disease Analyzer database. Patients who had received antidepressant prescriptions prior to the index date were excluded. The main outcome measure was the initiation of antidepressant drug therapy in men and women within three years after index date in three subgroups of different severity (mild, moderate and severe depression). RESULTS: A total of 35,495 men and 54,467 women were included in this study. After 3 years of follow up, 77.3% of men and 78.5% of women diagnosed with mild depression (p value=0.887), 89.2% of men and 90.7% of women with moderate depression (p value=0.084), and 88.6% of men and 89.5% of women with severe depression (p value=0.769) had been treated. No association was found between the chances of treatment initiation after diagnosis of depression and gender. Finally, patients with moderate and severe depression were more likely to receive therapy than those with mild depression. Selective serotonin reuptake inhibitors and tricyclic antidepressants were the two most commonly prescribed families of drugs in this study (SSRIs: 34.5% to 44.6%, and TCAs: 19.1% to 26.9%). CONCLUSIONS: Gender did not impact therapy initiation in depressed patients. Further studies are needed to identify other potential factors involved. PMID- 26941591 TI - Electrical Brain Responses to Beat Irregularities in Two Cases of Beat Deafness. AB - Beat deafness, a recently documented form of congenital amusia, provides a unique window into functional specialization of neural circuitry for the processing of musical stimuli: Beat-deaf individuals exhibit deficits that are specific to the detection of a regular beat in music and the ability to move along with a beat. Studies on the neural underpinnings of beat processing in the general population suggest that the auditory system is capable of pre-attentively generating a predictive model of upcoming sounds in a rhythmic pattern, subserved largely within auditory cortex and reflected in mismatch negativity (MMN) and P3 event related potential (ERP) components. The current study examined these neural correlates of beat perception in two beat-deaf individuals, Mathieu and Marjorie, and a group of control participants under conditions in which auditory stimuli were either attended or ignored. Compared to control participants, Mathieu demonstrated reduced behavioral sensitivity to beat omissions in metrical patterns, and Marjorie showed a bias to identify irregular patterns as regular. ERP responses to beat omissions reveal an intact pre-attentive system for processing beat irregularities in cases of beat deafness, reflected in the MMN component, and provide partial support for abnormalities in later cognitive stages of beat processing, reflected in an unreliable P3b component exhibited by Mathieu-but not Marjorie-compared to control participants. P3 abnormalities observed in the current study resemble P3 abnormalities exhibited by individuals with pitch-based amusia, and are consistent with attention or auditory-motor coupling accounts of deficits in beat perception. PMID- 26941592 TI - Speed-Dependent Modulation of the Locomotor Behavior in Adult Mice Reveals Attractor and Transitional Gaits. AB - Locomotion results from an interplay between biomechanical constraints of the muscles attached to the skeleton and the neuronal circuits controlling and coordinating muscle activities. Quadrupeds exhibit a wide range of locomotor gaits. Given our advances in the genetic identification of spinal and supraspinal circuits important to locomotion in the mouse, it is now important to get a better understanding of the full repertoire of gaits in the freely walking mouse. To assess this range, young adult C57BL/6J mice were trained to walk and run on a treadmill at different locomotor speeds. Instead of using the classical paradigm defining gaits according to their footfall pattern, we combined the inter-limb coupling and the duty cycle of the stance phase, thus identifying several types of gaits: lateral walk, trot, out-of-phase walk, rotary gallop, transverse gallop, hop, half-bound, and full-bound. Out-of-phase walk, trot, and full-bound were robust and appeared to function as attractor gaits (i.e., a state to which the network flows and stabilizes) at low, intermediate, and high speeds respectively. In contrast, lateral walk, hop, transverse gallop, rotary gallop, and half-bound were more transient and therefore considered transitional gaits (i.e., a labile state of the network from which it flows to the attractor state). Surprisingly, lateral walk was less frequently observed. Using graph analysis, we demonstrated that transitions between gaits were predictable, not random. In summary, the wild-type mouse exhibits a wider repertoire of locomotor gaits than expected. Future locomotor studies should benefit from this paradigm in assessing transgenic mice or wild-type mice with neurotraumatic injury or neurodegenerative disease affecting gait. PMID- 26941595 TI - A Dataset for Visual Navigation with Neuromorphic Methods. AB - Standardized benchmarks in Computer Vision have greatly contributed to the advance of approaches to many problems in the field. If we want to enhance the visibility of event-driven vision and increase its impact, we will need benchmarks that allow comparison among different neuromorphic methods as well as comparison to Computer Vision conventional approaches. We present datasets to evaluate the accuracy of frame-free and frame-based approaches for tasks of visual navigation. Similar to conventional Computer Vision datasets, we provide synthetic and real scenes, with the synthetic data created with graphics packages, and the real data recorded using a mobile robotic platform carrying a dynamic and active pixel vision sensor (DAVIS) and an RGB+Depth sensor. For both datasets the cameras move with a rigid motion in a static scene, and the data includes the images, events, optic flow, 3D camera motion, and the depth of the scene, along with calibration procedures. Finally, we also provide simulated event data generated synthetically from well-known frame-based optical flow datasets. PMID- 26941593 TI - Neurovascular and Immuno-Imaging: From Mechanisms to Therapies. Proceedings of the Inaugural Symposium. AB - Breakthrough advances in intravital imaging have launched a new era for the study of dynamic interactions at the neurovascular interface in health and disease. The first Neurovascular and Immuno-Imaging Symposium was held at the Gladstone Institutes, University of California, San Francisco in March, 2015. This highly interactive symposium brought together a group of leading researchers who discussed how recent studies have unraveled fundamental biological mechanisms in diverse scientific fields such as neuroscience, immunology, and vascular biology, both under physiological and pathological conditions. These Proceedings highlight how advances in imaging technologies and their applications revolutionized our understanding of the communication between brain, immune, and vascular systems and identified novel targets for therapeutic intervention in neurological diseases. PMID- 26941594 TI - Classification of Single Normal and Alzheimer's Disease Individuals from Cortical Sources of Resting State EEG Rhythms. AB - Previous studies have shown abnormal power and functional connectivity of resting state electroencephalographic (EEG) rhythms in groups of Alzheimer's disease (AD) compared to healthy elderly (Nold) subjects. Here we tested the best classification rate of 120 AD patients and 100 matched Nold subjects using EEG markers based on cortical sources of power and functional connectivity of these rhythms. EEG data were recorded during resting state eyes-closed condition. Exact low-resolution brain electromagnetic tomography (eLORETA) estimated the power and functional connectivity of cortical sources in frontal, central, parietal, occipital, temporal, and limbic regions. Delta (2-4 Hz), theta (4-8 Hz), alpha 1 (8-10.5 Hz), alpha 2 (10.5-13 Hz), beta 1 (13-20 Hz), beta 2 (20-30 Hz), and gamma (30-40 Hz) were the frequency bands of interest. The classification rates of interest were those with an area under the receiver operating characteristic curve (AUROC) higher than 0.7 as a threshold for a moderate classification rate (i.e., 70%). Results showed that the following EEG markers overcame this threshold: (i) central, parietal, occipital, temporal, and limbic delta/alpha 1 current density; (ii) central, parietal, occipital temporal, and limbic delta/alpha 2 current density; (iii) frontal theta/alpha 1 current density; (iv) occipital delta/alpha 1 inter-hemispherical connectivity; (v) occipital-temporal theta/alpha 1 right and left intra-hemispherical connectivity; and (vi) parietal limbic alpha 1 right intra-hemispherical connectivity. Occipital delta/alpha 1 current density showed the best classification rate (sensitivity of 73.3%, specificity of 78%, accuracy of 75.5%, and AUROC of 82%). These results suggest that EEG source markers can classify Nold and AD individuals with a moderate classification rate higher than 80%. PMID- 26941598 TI - Emulating the Electrical Activity of the Neuron Using a Silicon Oxide RRAM Cell. AB - In recent years, formidable effort has been devoted to exploring the potential of Resistive RAM (RRAM) devices to model key features of biological synapses. This is done to strengthen the link between neuro-computing architectures and neuroscience, bearing in mind the extremely low power consumption and immense parallelism of biological systems. Here we demonstrate the feasibility of using the RRAM cell to go further and to model aspects of the electrical activity of the neuron. We focus on the specific operational procedures required for the generation of controlled voltage transients, which resemble spike-like responses. Further, we demonstrate that RRAM devices are capable of integrating input current pulses over time to produce thresholded voltage transients. We show that the frequency of the output transients can be controlled by the input signal, and we relate recent models of the redox-based nanoionic resistive memory cell to two common neuronal models, the Hodgkin-Huxley (HH) conductance model and the leaky integrate-and-fire model. We employ a simplified circuit model to phenomenologically describe voltage transient generation. PMID- 26941596 TI - Neuroendocrinal, Neurodevelopmental, and Embryotoxic Effects of Recombinant Tissue Plasminogen Activator Treatment for Pregnant Women with Acute Ischemic Stroke. AB - Thrombolysis with recombinant tissue plasminogen activator (rTPA) was the first evidence-based treatment approved for acute stroke. Ischemic stroke is relatively uncommon in fertile women but treatment is often delayed or not given. In randomized trials, pregnancy has been an exclusion criterion for thrombolysis. Physiologic TPA has been shown to have neuroendocrine effects namely in vasopressin secretion. Important TPA effects in brain function and development include neurite outgrowth, migration of cerebellar granular neurons and promotion of long-term potentiation, among others. Until now, no neuroendocrine side effects have been reported in pregnant women treated with rTPA. The effects of rTPA exposure in the fetus following intravenous thrombolysis in pregnant women are still poorly understood. This depends on low case frequency, short-duration of exposure and the fact that rTPA molecule is too large to pass the placenta. rTPA has a short half-life of 4-5 min, with only 10% of its concentration remaining in circulation after 20 min, which may explain its safety at therapeutically doses. Ischemic stroke during pregnancy occurs most often in the third trimester. Complication rates of rTPA in pregnant women treated for thromboembolic conditions and ischemic stroke were found to be similar when compared to non-pregnant women (7-9% mortality). In embryos of animal models so far, no indications of a teratogenic or mutagenic potential were found. Pregnancy is still considered a relative contraindication when treating acute ischemic stroke with rTPA, however, treatment risk must be balanced against the potential of maternal disability and/or death. PMID- 26941597 TI - IGF-I: A Key Growth Factor that Regulates Neurogenesis and Synaptogenesis from Embryonic to Adult Stages of the Brain. AB - The generation of neurons in the adult mammalian brain requires the activation of quiescent neural stem cells (NSCs). This activation and the sequential steps of neuron formation from NSCs are regulated by a number of stimuli, which include growth factors. Insulin-like growth factor-I (IGF-I) exert pleiotropic effects, regulating multiple cellular processes depending on their concentration, cell type, and the developmental stage of the animal. Although IGF-I expression is relatively high in the embryonic brain its levels drop sharply in the adult brain except in neurogenic regions, i.e., the hippocampus (HP) and the subventricular zone-olfactory bulb (SVZ-OB). By contrast, the expression of IGF-IR remains relatively high in the brain irrespective of the age of the animal. Evidence indicates that IGF-I influences NSC proliferation and differentiation into neurons and glia as well as neuronal maturation including synapse formation. Furthermore, recent studies have shown that IGF-I not only promote adult neurogenesis by regulating NSC number and differentiation but also by influencing neuronal positioning and migration as described during SVZ-OB neurogenesis. In this article we will revise and discuss the actions reported for IGF-I signaling in a variety of in vitro and in vivo models, focusing on the maintenance and proliferation of NSCs/progenitors, neurogenesis, and neuron integration in synaptic circuits. PMID- 26941599 TI - Dual Window Pattern Recognition Classifier for Improved Partial-Hand Prosthesis Control. AB - Although partial-hand amputees largely retain the ability to use their wrist, it is difficult to preserve wrist motion while using a myoelectric partial-hand prosthesis without severely impacting control performance. Electromyogram (EMG) pattern recognition is a well-studied control method; however, EMG from wrist motion can obscure myoelectric finger control signals. Thus, to accommodate wrist motion and to provide high classification accuracy and minimize system latency, we developed a training protocol and a classifier that switches between long and short EMG analysis window lengths. Seventeen non-amputee and two partial-hand amputee subjects participated in a study to determine the effects of including EMG from different arm and hand locations during static and/or dynamic wrist motion in the classifier training data. We evaluated several real-time classification techniques to determine which control scheme yielded the highest performance in virtual real-time tasks using a three-way ANOVA. We found significant interaction between analysis window length and the number of grasps available. Including static and dynamic wrist motion and intrinsic hand muscle EMG with extrinsic muscle EMG significantly reduced pattern recognition classification error by 35%. Classification delay or majority voting techniques significantly improved real-time task completion rates (17%), selection (23%), and completion (11%) times, and selection attempts (15%) for non-amputee subjects, and the dual window classifier significantly reduced the time (8%) and average number of attempts required to complete grasp selections (14%) made in various wrist positions. Amputee subjects demonstrated improved task timeout rates, and made fewer grasp selection attempts, with classification delay or majority voting techniques. Thus, the proposed techniques show promise for improving control of partial-hand prostheses and more effectively restoring function to individuals using these devices. PMID- 26941600 TI - Anti-microRNAs as Novel Therapeutic Agents in the Clinical Management of Alzheimer's Disease. AB - Overview- One hundred and ten years since its first description Alzheimer's disease (AD) still retains its prominent status: (i) as the industrialized world's number one cause of age-related intellectual impairment and cognitive decline; (ii) as this country's most rapidly expanding socioeconomic and healthcare concern; and (iii) as an insidious, progressive and lethal neurological disorder of the human central nervous system (CNS) for which there is currently no adequate treatment or cure (Alzheimer, 1991; Alzheimer et al., 1991, 1995) [https://www.alz.org/facts/downloads/facts_figures_2015.pdf (2015)]. The concept of small non-coding RNAs (ncRNAs) as being involved in the etiopathogenesis of AD and age-related human neurodegenerative disease was first proposed about 25 years ago, however it was not until 2007 that specific microRNA (miRNA) abundance, speciation and localization to the hippocampal CA1 region (an anatomical area of the human CNS specifically targeted by the AD process) was shown to strongly associate with AD-type change when compared to age-matched controls (Lukiw et al., 1992; Lukiw, 2007; Schipper et al., 2007; Cogswell et al., 2008; Guerreiro et al., 2012). Currently about 400 reports address the potential link between disruptions in miRNA signaling and the development of various features associated with AD neuropathology (http://www.ncbi.nlm.nih.gov/pubmed/?term=micro+RNA+alzheimer's+disease). In this "Perspectives" paper we will highlight some of the most recent literature on anti miRNA (AM; antagomir) therapeutic strategies and some very recent technological advances in the analysis and characterization of defective miRNA signaling pathways in AD compared to neurologically normal age-matched controls. PMID- 26941601 TI - Characterization of Artifacts Produced by Gel Displacement on Non-invasive Brain Machine Interfaces during Ambulation. AB - So far, Brain-Machine Interfaces (BMIs) have been mainly used to study brain potentials during movement-free conditions. Recently, due to the emerging concern of improving rehabilitation therapies, these systems are also being used during gait experiments. Under this new condition, the evaluation of motion artifacts has become a critical point to assure the validity of the results obtained. Due to the high signal to noise ratio provided, the use of wet electrodes is a widely accepted technic to acquire electroencephalographic (EEG signals). To perform these recordings it is necessary to apply a conductive gel between the scalp and the electrodes. This work is focused on the study of gel displacements produced during ambulation and how they affect the amplitude of EEG signals. Data recorded during three ambulation conditions (gait training) and one movement-free condition (BMI motor imagery task) are compared to perform this study. Two phenomenons, manifested as unusual increases of the signals' amplitude, have been identified and characterized during this work. Results suggest that they are caused by abrupt changes on the conductivity between the electrode and the scalp due to gel displacement produced during ambulation and head movements. These artifacts significantly increase the Power Spectral Density (PSD) of EEG recordings at all frequencies from 5 to 90 Hz, corresponding to the main bandwidth of electrocortical potentials. They should be taken into consideration before performing EEG recordings in order to asses the correct gel allocation and to avoid the use of electrodes on certain scalp areas depending on the experimental conditions. PMID- 26941602 TI - Differential Modulation of Excitatory and Inhibitory Neurons during Periodic Stimulation. AB - Non-invasive transcranial neuronal stimulation, in addition to deep brain stimulation, is seen as a promising therapeutic and diagnostic approach for an increasing number of neurological diseases such as epilepsy, cluster headaches, depression, specific type of blindness, and other central nervous system disfunctions. Improving its effectiveness and widening its range of use may strongly rely on development of proper stimulation protocols that are tailored to specific brain circuits and that are based on a deep knowledge of different neuron types response to stimulation. To this aim, we have performed a simulation study on the behavior of excitatory and inhibitory neurons subject to sinusoidal stimulation. Due to the intrinsic difference in membrane conductance properties of excitatory and inhibitory neurons, we show that their firing is differentially modulated by the wave parameters. We analyzed the behavior of the two neuronal types for a broad range of stimulus frequency and amplitude and demonstrated that, within a small-world network prototype, parameters tuning allow for a selective enhancement or suppression of the excitation/inhibition ratio. PMID- 26941604 TI - Recombinant Human Myelin-Associated Glycoprotein Promoter Drives Selective AAV Mediated Transgene Expression in Oligodendrocytes. AB - Leukodystrophies are hereditary central white matter disorders caused by oligodendrocyte dysfunction. Recent clinical trials for some of these devastating neurological conditions have employed an ex vivo gene therapy approach that showed improved endpoints because cross-correction of affected myelin-forming cells occurred following secretion of therapeutic proteins by transduced autologous grafts. However, direct gene transfer to oligodendrocytes is required for the majority of leukodystrophies with underlying mutations in genes encoding non-secreted oligodendroglial proteins. Recombinant adeno-associated viral (AAV) vectors are versatile tools for gene transfer to the central nervous system (CNS) and proof-of-concept studies in rodents have shown that the use of cellular promoters is sufficient to target AAV-mediated transgene expression to glia. The potential of this strategy has not been exploited. The major caveat of the AAV system is its limited packaging capacity of ~5 kb, providing the rationale for identifying small yet selective recombinant promoters. Here, we characterize the human myelin associated glycoprotein (MAG) promoter for reliable targeting of AAV mediated transgene expression to oligodendrocytes in vivo. A homology screen revealed highly conserved genomic regions among mammalian species upstream of the transcription start site. Recombinant AAV expression cassettes carrying the cDNA encoding enhanced green fluorescent protein (GFP) driven by truncated versions of the recombinant MAG promoter (2.2, 1.5 and 0.3 kb in size) were packaged as cy5 vectors and delivered into the dorsal striatum of mice. At 3 weeks post injection, oligodendrocytes, neurons and astrocytes expressing the reporter were quantified by immunohistochemical staining. Our results revealed that both 2.2 and 1.5 kb MAG promoters targeted more than 95% of transgene expression to oligodendrocytes. Even the short 0.3 kb fragment conveyed high oligodendroglial specific transgene expression (>90%) in vivo. Moreover, cy5-MAG2.2-GFP delivery to the neonate CNS resulted in selective GFP expression in oligodendrocytes for at least 8 months. Broadly, the characterization of the extremely short yet oligodendrocyte-specific human MAG promoter may facilitate modeling neurological diseases caused by oligodendrocyte pathology and has translational relevance for leukodystrophy gene therapy. PMID- 26941605 TI - D-Serine and Serine Racemase Are Associated with PSD-95 and Glutamatergic Synapse Stability. AB - D-serine is an endogenous coagonist at the glycine site of synaptic NMDA receptors (NMDARs), synthesized by serine racemase (SR) through conversion of L serine. It is crucial for synaptic plasticity and is implicated in schizophrenia. Our previous studies demonstrated specific loss of SR, D-serine-responsive synaptic NMDARs, and glutamatergic synapses in cortical neurons lacking alpha7 nicotinic acetylcholine receptors, which promotes glutamatergic synapse formation and maturation during development. We thus hypothesize that D-serine and SR (D serine/SR) are associated with glutamatergic synaptic development. Using morphological and molecular studies in cortical neuronal cultures, we demonstrate that D-serine/SR are associated with PSD-95 and NMDARs in postsynaptic neurons and with glutamatergic synapse stability during synaptic development. Endogenous D-serine and SR colocalize with PSD-95, but not presynaptic vesicular glutamate transporter 1 (VGLUT1), in glutamatergic synapses of cultured cortical neurons. Low-density astrocytes in cortical neuronal cultures lack SR expression but contain enriched D-serine in large vesicle-like structures, suggesting possible synthesis of D-serine in postsynaptic neurons and storage in astrocytes. More interestingly, endogenous D-serine and SR colocalize with PSD-95 in the postsynaptic terminals of glutamatergic synapses during early and late synaptic development, implicating involvement of D-serine/SR in glutamatergic synaptic development. Exogenous application of D-serine enhances the interactions of SR with PSD-95 and NR1, and increases the number of VGLUT1- and PSD-95-positive glutamatergic synapses, suggesting that exogenous D-serine enhances postsynaptic SR/PSD-95 signaling and stabilizes glutamatergic synapses during cortical synaptic development. This is blocked by NMDAR antagonist 2-amino-5 phosphonopentanoic acid (AP5) and 7-chlorokynurenic acid (7-CK), a specific antagonist at the glycine site of NMDARs, demonstrating that D-serine effects are mediated through postsynaptic NMDARs. Conversely, exogenous application of glycine has no such effects, suggesting D-serine, rather than glycine, modulates postsynaptic events. Taken together, our findings demonstrate that D-serine/SR are associated with PSD-95 and NMDARs in postsynaptic neurons and with glutamatergic synapse stability during synaptic development, implicating D serine/SR as regulators of cortical synaptic and circuit development. PMID- 26941603 TI - Conditional Disabled-1 Deletion in Mice Alters Hippocampal Neurogenesis and Reduces Seizure Threshold. AB - Many animal models of temporal lobe epilepsy (TLE) exhibit altered neurogenesis arising from progenitors within the dentate gyrus subgranular zone (SGZ). Aberrant integration of new neurons into the existing circuit is thought to contribute to epileptogenesis. In particular, adult-born neurons that exhibit ectopic migration and hilar basal dendrites (HBDs) are suggested to be pro epileptogenic. Loss of reelin signaling may contribute to these morphological changes in patients with epilepsy. We previously demonstrated that conditional deletion of the reelin adaptor protein, disabled-1 (Dab1), from postnatal mouse SGZ progenitors generated dentate granule cells (DGCs) with abnormal dendritic development and ectopic placement. To determine whether the early postnatal loss of reelin signaling is epileptogenic, we conditionally deleted Dab1 in neural progenitors and their progeny on postnatal days 7-8 and performed chronic video EEG recordings 8-10 weeks later. Dab1-deficient mice did not have spontaneous seizures but exhibited interictal epileptiform abnormalities and a significantly reduced latency to pilocarpine-induced status epilepticus. After chemoconvulsant treatment, over 90% of mice deficient for Dab1 developed generalized motor convulsions with tonic-clonic movements, rearing, and falling compared to <20% of wild-type mice. Recombination efficiency, measured by Cre reporter expression, inversely correlated with time to the first sustained seizure. These pro epileptogenic changes were associated with decreased neurogenesis and increased numbers of hilar ectopic DGCs. Interestingly, neurons co-expressing the Cre reporter comprised a fraction of these hilar ectopic DGCs cells, suggesting a non cell autonomous effect for the loss of reelin signaling. We also noted a dispersion of the CA1 pyramidal layer, likely due to hypomorphic effects of the conditional Dab1 allele, but this abnormality did not correlate with seizure susceptibility. These findings suggest that the misplacement or reduction of postnatally-generated DGCs contributes to aberrant circuit development and hyperexcitability, but aberrant neurogenesis after conditional Dab1 deletion alone is not sufficient to produce spontaneous seizures. PMID- 26941606 TI - Commentary: Maternal immune activation evoked by polyinosinic: polycytidylic acid does not evoke microglial cell activation in the embryo. PMID- 26941607 TI - Stress-Induced Enhancement of Ethanol Intake in C57BL/6J Mice with a History of Chronic Ethanol Exposure: Involvement of Kappa Opioid Receptors. AB - Our laboratory has previously demonstrated that daily forced swim stress (FSS) prior to ethanol drinking sessions facilitates enhanced ethanol consumption in mice with a history of chronic intermittent ethanol (CIE) vapor exposure without altering ethanol intake in air-exposed controls. Because both stress and chronic ethanol exposure have been shown to activate the dynorphin/kappa opioid receptor (KOR) system, the present study was designed to explore a potential role for KORs in modulating stress effects on ethanol consumption in the CIE model of dependence and relapse drinking. After stable baseline ethanol intake was established in adult male C57BL/6J mice, subjects received chronic intermittent exposure (16 h/day * 4 days/week) to ethanol vapor (CIE group) or air (CTL group). Weekly cycles of inhalation exposure were alternated with 5-day limited access drinking tests (1 h access to 15% ethanol). Experiment 1 compared effects of daily FSS and KOR activation on ethanol consumption. CIE and CTL mice were either exposed to FSS (10 min), the KOR agonist U50,488 (5 mg/kg), or a vehicle injection (non-stressed condition) prior to each daily drinking session during test weeks. FSS selectively increased drinking in CIE mice. U50,488 mimicked this effect in CIE mice, but also increased drinking in CTL mice. Experiment 2 assessed effects of KOR blockade on stress-induced drinking in CIE and CTL mice. Stressed and non-stressed mice were administered the short-acting KOR antagonist LY2444296 (0 or 5 mg/kg) 30 min prior to each drinking session during test weeks. FSS selectively increased ethanol consumption in CIE mice, an effect that was abolished by LY2444296 pretreatment. In Experiment 3, CIE and CTL mice were administered one of four doses of U50,488 (0, 1.25, 2.5, 5.0 mg/kg) 1 h prior to each daily drinking test (in lieu of FSS). All doses of U50,488 increased ethanol consumption in both CIE and CTL mice. The U50,488-induced increase in drinking was blocked by LY2444296. Our results demonstrate that the KOR system contributes to the stress enhancement of ethanol intake in mice with a history of chronic ethanol exposure. PMID- 26941608 TI - Serum S100B Is Related to Illness Duration and Clinical Symptoms in Schizophrenia A Meta-Regression Analysis. AB - S100B has been linked to glial pathology in several psychiatric disorders. Previous studies found higher S100B serum levels in patients with schizophrenia compared to healthy controls, and a number of covariates influencing the size of this effect have been proposed in the literature. Here, we conducted a meta analysis and meta-regression analysis on alterations of serum S100B in schizophrenia in comparison with healthy control subjects. The meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement to guarantee a high quality and reproducibility. With strict inclusion criteria 19 original studies could be included in the quantitative meta analysis, comprising a total of 766 patients and 607 healthy control subjects. The meta-analysis confirmed higher values of the glial serum marker S100B in schizophrenia if compared with control subjects. Meta-regression analyses revealed significant effects of illness duration and clinical symptomatology, in particular the total score of the Positive and Negative Syndrome Scale (PANSS), on serum S100B levels in schizophrenia. In sum, results confirm glial pathology in schizophrenia that is modulated by illness duration and related to clinical symptomatology. Further studies are needed to investigate mechanisms and mediating factors related to these findings. PMID- 26941609 TI - Reelin-Related Disturbances in Depression: Implications for Translational Studies. AB - The finding that reelin expression is significantly decreased in mood and psychotic disorders, together with evidence that reelin can regulate key aspects of hippocampal plasticity in the adult brain, brought our research group and others to study the possible role of reelin in the pathogenesis of depression. This review describes recent progress on this topic using an animal model of depression that makes use of repeated corticosterone (CORT) injections. This methodology produces depression-like symptoms in both rats and mice that are reversed by antidepressant treatment. We have reported that CORT causes a decrease in the number of reelin-immunopositive cells in the dentate gyrus subgranular zone (SGZ), where adult hippocampal neurogenesis takes place; that down-regulation of the number of reelin-positive cells closely parallels the development of a depression-like phenotype during repeated CORT treatment; that reelin downregulation alters the co-expression of reelin with neuronal nitric oxide synthase (nNOS); that deficits in reelin might also create imbalances in glutamatergic and GABAergic circuits within the hippocampus and other limbic structures; and that co-treatment with antidepressant drugs prevents both reelin deficits and the development of a depression-like phenotype. We also observed alterations in the pattern of membrane protein clustering in peripheral lymphocytes in animals with low levels of reelin. Importantly, we found parallel changes in membrane protein clustering in depression patients, which differentiated two subpopulations of naive depression patients that showed a different therapeutic response to antidepressant treatment. Here, we review these findings and develop the hypothesis that restoring reelin-related function could represent a novel approach for antidepressant therapies. PMID- 26941610 TI - Presynaptic Adenosine Receptor-Mediated Regulation of Diverse Thalamocortical Short-Term Plasticity in the Mouse Whisker Pathway. AB - Short-term synaptic plasticity (STP) sets the sensitivity of a synapse to incoming activity and determines the temporal patterns that it best transmits. In "driver" thalamocortical (TC) synaptic populations, STP is dominated by depression during stimulation from rest. However, during ongoing stimulation, lemniscal TC connections onto layer 4 neurons in mouse barrel cortex express variable STP. Each synapse responds to input trains with a distinct pattern of depression or facilitation around its mean steady-state response. As a result, in common with other synaptic populations, lemniscal TC synapses express diverse rather than uniform dynamics, allowing for a rich representation of temporally varying stimuli. Here, we show that this STP diversity is regulated presynaptically. Presynaptic adenosine receptors of the A1R type, but not kainate receptors (KARs), modulate STP behavior. Blocking the receptors does not eliminate diversity, indicating that diversity is related to heterogeneous expression of multiple mechanisms in the pathway from presynaptic calcium influx to neurotransmitter release. PMID- 26941611 TI - Dynamic Analysis of the Conditional Oscillator Underlying Slow Waves in Thalamocortical Neurons. AB - During non-REM sleep the EEG shows characteristics waves that are generated by the dynamic interactions between cortical and thalamic oscillators. In thalamic neurons, low-threshold T-type Ca(2+) channels play a pivotal role in almost every type of neuronal oscillations, including slow (< 1 Hz) waves, sleep spindles and delta waves. The transient opening of T channels gives rise to the low threshold spikes (LTSs), and associated high frequency bursts of action potentials, that are characteristically present during sleep spindles and delta waves, whereas the persistent opening of a small fraction of T channels, (i.e., ITwindow) is responsible for the membrane potential bistability underlying sleep slow oscillations. Surprisingly thalamocortical (TC) neurons express a very high density of T channels that largely exceed the amount required to generate LTSs and therefore, to support certain, if not all, sleep oscillations. Here, to clarify the relationship between T current density and sleep oscillations, we systematically investigated the impact of the T conductance level on the intrinsic rhythmic activities generated in TC neurons, combining in vitro experiments and TC neuron simulation. Using bifurcation analysis, we provide insights into the dynamical processes taking place at the transition between slow and delta oscillations. Our results show that although stable delta oscillations can be evoked with minimal T conductance, the full range of slow oscillation patterns, including groups of delta oscillations separated by Up states ("grouped delta slow waves") requires a high density of T channels. Moreover, high levels of T conductance ensure the robustness of different types of slow oscillations. PMID- 26941612 TI - Quantitative and Qualitative Analysis of Transient Fetal Compartments during Prenatal Human Brain Development. AB - The cerebral wall of the human fetal brain is composed of transient cellular compartments, which show characteristic spatiotemporal relationships with intensity of major neurogenic events (cell proliferation, migration, axonal growth, dendritic differentiation, synaptogenesis, cell death, and myelination). The aim of the present study was to obtain new quantitative data describing volume, surface area, and thickness of transient compartments in the human fetal cerebrum. Forty-four postmortem fetal brains aged 13-40 postconceptional weeks (PCW) were included in this study. High-resolution T1 weighted MR images were acquired on 19 fetal brain hemispheres. MR images were processed using in-house software (MNI-ACE toolbox). Delineation of fetal compartments was performed semi automatically by co-registration of MRI with histological sections of the same brains, or with the age-matched brains from Zagreb Neuroembryological Collection. Growth trajectories of transient fetal compartments were reconstructed. The composition of telencephalic wall was quantitatively assessed. Between 13 and 25 PCW, when the intensity of neuronal proliferation decreases drastically, the relative volume of proliferative (ventricular and subventricular) compartments showed pronounced decline. In contrast, synapse- and extracellular matrix-rich subplate compartment continued to grow during the first two trimesters, occupying up to 45% of telencephalon and reaching its maximum volume and thickness around 30 PCW. This developmental maximum coincides with a period of intensive growth of long cortico-cortical fibers, which enter and wait in subplate before approaching the cortical plate. Although we did not find significant age related changes in mean thickness of the cortical plate, the volume, gyrification index, and surface area of the cortical plate continued to exponentially grow during the last phases of prenatal development. This cortical expansion coincides developmentally with the transformation of embryonic cortical columns, dendritic differentiation, and ingrowth of axons. These results provide a quantitative description of transient human fetal brain compartments observable with MRI. Moreover, they will improve understanding of structural-functional relationships during brain development, will enable correlation between in vitro/in vivo imaging and fine structural histological studies, and will serve as a reference for study of perinatal brain injuries. PMID- 26941613 TI - White Matter Neurons in Young Adult and Aged Rhesus Monkey. AB - In humans and non-human primates (NHP), white matter neurons (WMNs) persist beyond early development. Their functional importance is largely unknown, but they have both corticothalamic and corticocortical connectivity and at least one subpopulation has been implicated in vascular regulation and sleep. Several other studies have reported that the density of WMNs in humans is altered in neuropathological or psychiatric conditions. The present investigation evaluates and compares the density of superficial and deep WMNs in frontal (FR), temporal (TE), and parietal (Par) association regions of four young adult and four aged male rhesus monkeys. A major aim was to determine whether there was age-related neuronal loss, as might be expected given the substantial age-related changes known to occur in the surrounding white matter environment. Neurons were visualized by immunocytochemistry for Neu-N in coronal tissue sections (30 MUm thickness), and neuronal density was assessed by systematic random sampling. Per 0.16 mm(2) sampling box, this yielded about 40 neurons in the superficial WM and 10 in the deep WM. Consistent with multiple studies of cell density in the cortical gray matter of normal brains, neither the superficial nor deep WM populations showed statistically significant age-related neuronal loss, although we observed a moderate decrease with age for the deep WMNs in the frontal region. Morphometric analyses, in contrast, showed significant age effects in soma size and circularity. In specific, superficial WMNs were larger in FR and Par WM regions of the young monkeys; but in the TE, these were larger in the older monkeys. An age effect was also observed for soma circularity: superficial WMNs were more circular in FR and Par of the older monkeys. This second, morphometric result raises the question of whether other age-related morphological, connectivity, or molecular changes occur in the WMNs. These could have multiple impacts, given the wide range of putative WMN functions and their involvement in both corticothalamic and corticocortical circuitry. PMID- 26941614 TI - Claudin-1, -2 and -3 Are Selectively Expressed in the Epithelia of the Choroid Plexus of the Mouse from Early Development and into Adulthood While Claudin-5 is Restricted to Endothelial Cells. AB - A primary function of epithelial and endothelial monolayers is the formation of barriers that separate tissues into functional compartments. Tight junctions (TJs) seal the intercellular space between the single cells of a monolayer. TJs thus contribute importantly to the homeostasis of the cerebrospinal fluid as they help in maintaining the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (CSF). The composition of TJs differs by its localization as well as the stage of development according to its respective function. Claudin-3 is typically present in the epithelia and has been claimed to be a constituent of the BBB. It is, however, notoriously difficult to demonstrate its expression in endothelial cells of the brain vasculature at the morphological level by means of immunohistochemical techniques. Using an improved fixation strategy (4% paraformaldehyde at pH 11, in the presence of EDTA) and the sensitive alkaline phosphatase as a detection system, we show that claudin-3 is present in mouse epithelia from embryonic day 14 onwards. In brain, it is restricted to the anlage of choroid plexus in the ventricles, together with claudin-1 and -2. In adult mice, it is clearly delineating the epithelium of the choroid plexus in the lateral and fourth ventricles. In contrast, in cerebral blood vessels claudin-3 as well as claudin-1 and -2 are absent in cerebral blood vessels during all developmental stages up to adulthood. Rather, the BBB is characterized by the presence of claudin-5, ZO-1 and occludin. Thus, in mice claudin-3 is an important constituent of TJ in the embryonic and in the adult choroid plexus. PMID- 26941615 TI - Microstructural Changes within the Basal Ganglia Differ between Parkinson Disease Subtypes. AB - Diffusion tensor imaging (DTI) of the substantia nigra has shown promise in detecting and quantifying neurodegeneration in Parkinson disease (PD). It remains unknown, however, whether differences in microstructural changes within the basal ganglia underlie PD motor subtypes. We investigated microstructural changes within the basal ganglia of mild to moderately affected PD patients using DTI and sought to determine if microstructural changes differ between the tremor dominant (TD) and postural instability/gait difficulty (PIGD) subtypes. Fractional anisotropy, mean diffusivity, radial, and axial diffusivity were obtained from bilateral caudate, putamen, globus pallidus, and substantia nigra of 21 PD patients (12 TD and 9 PIGD) and 20 age-matched healthy controls. T-tests and ANOVA methods were used to compare PD patients, subtypes, and controls, and Spearman correlations tested for relationships between DTI and clinical measures. We found our cohort of PD patients had reduced fractional anisotropy within the substantia nigra and increased mean and radial diffusivity within the substantia nigra and globus pallidus compared to controls, and that changes within those structures were largely driven by the PIGD subtype. Across all PD patients fractional anisotropy within the substantia nigra correlated with disease stage, while in PIGD patients increased diffusivity within the globus pallidus correlated with disease stage and motor severity. We conclude that PIGD patients have more severely affected microstructural changes within the substantia nigra compared to TD, and that microstructural changes within the globus pallidus may be particularly relevant for the manifestation of the PIGD subtype. PMID- 26941616 TI - From 'Nerve Fiber Regeneration' to 'Functional Changes' in the Human Brain-On the Paradigm-Shifting Work of the Experimental Physiologist Albrecht Bethe (1872 1954) in Frankfurt am Main. AB - Until the beginning 1930's the traditional dogma that the human central nervous system (CNS) did not possess any abilities to adapt functionally to degenerative processes and external injuries loomed large in the field of the brain sciences (Hirnforschung). Cutting-edge neuroanatomists, such as the luminary Wilhelm Waldeyer (1836-1921) in Germany or the Nobel Prize laureate Santiago Ramon y Cajal (1852-1934) in Spain, debated any regenerative and thus "plastic" properties in the human brain. A renewed interest arose in the scientific community to investigate the pathologies and the healing processes in the human CNS after the return of the high number of brain injured war veterans from the fronts during and after the First World War (1914-1918). A leading research center in this area was the "Institute for the Scientific Study of the Effects of Brain Injuries," which the neurologist Ludwig Edinger (1855-1918) had founded shortly before the war. This article specifically deals with the physiological research on nerve fiber plasticity by Albrecht Bethe (1872-1954) at the respective institute of the University of Frankfurt am Main. Bethe conducted here his paradigmatic experimental studies on the pathophysiological and clinical phenomena of peripheral and CNS regeneration. PMID- 26941617 TI - The Dorsal Visual System Predicts Future and Remembers Past Eye Position. AB - Eye movements are essential to primate vision but introduce potentially disruptive displacements of the retinal image. To maintain stable vision, the brain is thought to rely on neurons that carry both visual signals and information about the current direction of gaze in their firing rates. We have shown previously that these neurons provide an accurate representation of eye position during fixation, but whether they are updated fast enough during saccadic eye movements to support real-time vision remains controversial. Here we show that not only do these neurons carry a fast and accurate eye-position signal, but also that they support in parallel a range of time-lagged variants, including predictive and post dictive signals. We recorded extracellular activity in four areas of the macaque dorsal visual cortex during a saccade task, including the lateral and ventral intraparietal areas (LIP, VIP), and the middle temporal (MT) and medial superior temporal (MST) areas. As reported previously, neurons showed tonic eye-position-related activity during fixation. In addition, they showed a variety of transient changes in activity around the time of saccades, including relative suppression, enhancement, and pre-saccadic bursts for one saccade direction over another. We show that a hypothetical neuron that pools this rich population activity through a weighted sum can produce an output that mimics the true spatiotemporal dynamics of the eye. Further, with different pooling weights, this downstream eye position signal (EPS) could be updated long before (<100 ms) or after (<200 ms) an eye movement. The results suggest a flexible coding scheme in which downstream computations have access to past, current, and future eye positions simultaneously, providing a basis for visual stability and delay-free visually-guided behavior. PMID- 26941619 TI - Characterizing Visual Field Deficits in Cerebral/Cortical Visual Impairment (CVI) Using Combined Diffusion Based Imaging and Functional Retinotopic Mapping: A Case Study. PMID- 26941620 TI - Rheotaxis of Larval Zebrafish: Behavioral Study of a Multi-Sensory Process. AB - Awake animals unceasingly perceive sensory inputs with great variability of nature and intensity, and understanding how the nervous system manages this continuous flow of diverse information to get a coherent representation of the environment is arguably a central question in systems neuroscience. Rheotaxis, the ability shared by most aquatic species to orient toward a current and swim to hold position, is an innate and robust multi-sensory behavior that is known to involve the lateral line and visual systems. To facilitate the neuroethological study of rheotaxic behavior in larval zebrafish we developed an assay for freely swimming larvae that allows for high experimental throughtput, large statistic and a fine description of the behavior. We show that there exist a clear transition from exploration to counterflow swim, and by changing the sensory modalities accessible to the fishes (visual only, lateral line only or both) and comparing the swim patterns at different ages we were able to detect and characterize two different mechanisms for position holding, one mediated by the lateral line and one mediated by the visual system. We also found that when both sensory modalities are accessible the visual system overshadows the lateral line, suggesting that at the larval stage the sensory inputs are not merged to finely tune the behavior but that redundant information pathways may be used as functional fallbacks. PMID- 26941618 TI - Beyond the Medial Regions of Prefrontal Cortex in the Regulation of Fear and Anxiety. AB - Fear and anxiety are adaptive responses but if left unregulated, or inappropriately regulated, they become biologically and socially maladaptive. Dysregulated emotions are manifest in a wide variety of psychiatric and neurological conditions but the external expression gives little indication of the underlying causes, which are inevitably multi-determined. To go beyond the overt phenotype and begin to understand the causal mechanisms leading to conditions characterized by anxiety and disorders of mood, it is necessary to identify the base psychological processes that have become dysregulated, and map them on to their associated neural substrates. So far, attention has been focused primarily on the medial regions of prefrontal cortex (PFC) and in particular their contribution to the expression and extinction of conditioned fear. However, functional neuroimaging studies have shown that the sphere of influence within the PFC is not restricted to its medial regions, but extends into dorsal, ventrolateral (vlPFC) and orbitofrontal (OFC) regions too; although the causal role of these other areas in the regulation of fear and anxiety remains to be determined and in the case of the OFC, existing findings are conflicting. Here, we review the evidence for the contribution of these other regions in negative emotion regulation in rodents and old world and new world monkeys. We consider a variety of different contexts, including conditioned and innate fear, learned and unlearned anxiety and cost-benefit decision-making, and a range of physiological and behavioral measures of emotion. It is proposed that both the OFC and vlPFC contribute to emotion regulation via their involvement, respectively, in the prediction of future outcomes and higher-order attentional control. The fractionation of these neurocognitive and neurobehavioral systems that regulate fear and anxiety opens up new opportunities for diagnostic stratification and personalized treatment strategies. PMID- 26941621 TI - Inactivation of Cerebellar Cortical Crus II Disrupts Temporal Processing of Absolute Timing but not Relative Timing in Voluntary Movements. AB - Several recent studies have demonstrated that the cerebellum plays an important role in temporal processing at the scale of milliseconds. However, it is not clear whether intrinsic cerebellar function involves the temporal processing of discrete or continuous events. Temporal processing during discrete events functions by counting absolute time like a stopwatch, while during continuous events it measures events at intervals. During the temporal processing of continuous events, animals might respond to rhythmic timing of sequential responses rather than to the absolute durations of intervals. Here, we tested the contribution of the cerebellar cortex to temporal processing of absolute and relative timings in voluntary movements. We injected muscimol and baclofen to a part of the cerebellar cortex of rats. We then tested the accuracy of their absolute or relative timing prediction using two timing tasks requiring almost identical reaching movements. Inactivation of the cerebellar cortex disrupted accurate temporal prediction in the absolute timing task. The rats formed two groups based on the changes to their timing accuracy following one of two distinct patterns which can be described as longer or shorter declines in the accuracy of learned intervals. However, a part of the cerebellar cortical inactivation did not affect the rats' performance of relative timing tasks. We concluded that a part of the cerebellar cortex, Crus II, contributes to the accurate temporal prediction of absolute timing and that the entire cerebellar cortex may be unnecessary in cases in which accurately knowing the absolute duration of an interval is not required for temporal prediction. PMID- 26941622 TI - When Choice Makes Sense: Menthol Influence on Mating, Oviposition and Fecundity in Drosophila melanogaster. AB - The environment to which insects have been exposed as larvae and adults can affect subsequent behaviors, such as mating, oviposition, food preference or fitness. Experience can change female preference for oviposition, particularly in phytophagous insects. In Drosophila melanogaster, females avoid laying eggs on menthol rich-food when given the choice. Exposure to menthol during larval development reduces this aversion. However, this observation was not reproduced in the following generation. Recently, we have shown that oviposition-site preference (OSP) differs between wild-type D. melanogaster lines freely or forcibly exposed to menthol. After 12 generations, menthol "forced" lines still exhibit a persistent aversion to menthol whereas 'free-choice' lines show a decreased aversion for menthol rich-food. Here, we compare courtship behavior, mating and female fecundity in "forced" and "free-choice" lines, raised either on menthol rich-food (Menthol-lines) or on menthol-free food (Plain-lines). "Forced" males did not discriminate between decapitated virgin females of the two lines. They courted and mated with intact females of both "forced" lines in a comparable rate. However "forced" M-line males did mate significantly more rapidly with "forced" M-line females. In the "free-choice" procedure, P-line males show a similar pattern as "forced" males for discrimination ability and courtship. M line males courted significantly more M-line females. Both 'free-choice' lines males mated significantly more with females of their own line. Female fecundity was assessed during 10 days in 'free-choice' lines. Menthol-line females laid more eggs during the first 4 days than female Plain-lines and parental control line. The total number of eggs laid during the first 10 days of female adult life is comparable in M-line and parental control line. However, Menthol-line females laid eggs earlier than both parental control and Plain-lines. Our findings show that in D. melanogaster, as for OSP, mating and fecundity are more rapidly influenced when flies have a choice between alternative resources compared to flies permanently exposed to menthol. PMID- 26941625 TI - Multi-Modal Homing in Sea Turtles: Modeling Dual Use of Geomagnetic and Chemical Cues in Island-Finding. AB - Sea turtles are capable of navigating across large expanses of ocean to arrive at remote islands for nesting, but how they do so has remained enigmatic. An interesting example involves green turtles (Chelonia mydas) that nest on Ascension Island, a tiny land mass located approximately 2000 km from the turtles' foraging grounds along the coast of Brazil. Sensory cues that turtles are known to detect, and which might hypothetically be used to help locate Ascension Island, include the geomagnetic field, airborne odorants, and waterborne odorants. One possibility is that turtles use magnetic cues to arrive in the vicinity of the island, then use chemical cues to pinpoint its location. As a first step toward investigating this hypothesis, we used oceanic, atmospheric, and geomagnetic models to assess whether magnetic and chemical cues might plausibly be used by turtles to locate Ascension Island. Results suggest that waterborne and airborne odorants alone are insufficient to guide turtles from Brazil to Ascension, but might permit localization of the island once turtles arrive in its vicinity. By contrast, magnetic cues might lead turtles into the vicinity of the island, but would not typically permit its localization because the field shifts gradually over time. Simulations reveal, however, that the sequential use of magnetic and chemical cues can potentially provide a robust navigational strategy for locating Ascension Island. Specifically, one strategy that appears viable is following a magnetic isoline into the vicinity of Ascension Island until an odor plume emanating from the island is encountered, after which turtles might either: (1) initiate a search strategy; or (2) follow the plume to its island source. These findings are consistent with the hypothesis that sea turtles, and perhaps other marine animals, use a multi-modal navigational strategy for locating remote islands. PMID- 26941624 TI - Increased Prevalence of Intermittent Rhythmic Delta or Theta Activity (IRDA/IRTA) in the Electroencephalograms (EEGs) of Patients with Borderline Personality Disorder. AB - INTRODUCTION: An increased prevalence of pathological electroencephalography (EEG) signals has been reported in patients with borderline personality disorder (BPD). In an elaborative case description of such a patient with intermittent rhythmic delta and theta activity (IRDA/IRTA), the BPD symptoms where linked to the frequency of the IRDAs/IRTAs and vanished with the IRDAs/IRTAs following anticonvulsive therapy. This observation raised a question regarding the prevalence of such EEG abnormalities in BPD patients. The aim of this retrospective study was to identify the frequency of EEG abnormalities in a carefully analyzed psychiatric collective. Following earlier reports, we hypothesized an increased prevalence of EEG abnormalities in BPD patients. PARTICIPANTS AND METHODS: We recruited 96 consecutive patients with BPD from the archive of a university clinic for psychiatry and psychotherapy, and compared the prevalence of EEG abnormalities to those of 76 healthy controls subjects. The EEGs were rated by three different blinded clinicians, including a consultant specializing in epilepsy from the local epilepsy center. RESULTS: We found a significant increase in the prevalence of IRDAs and IRTAs in BPD patients (14.6%) compared to the control subjects (3.9%; p = 0.020). DISCUSSION: In this blinded retrospective case-control study, we were able to confirm an increased prevalence of pathological EEG findings (IRDAs/IRTAs only) in BPD patients. The major limitation of this study is that the control group was not matched on age and gender. Therefore, the results should be regarded as preliminary findings of an open uncontrolled, retrospective study. Future research performing prospective, controlled studies is needed to verify our findings and answer the question of whether such EEG findings might predict a positive response to anticonvulsive pharmacological treatment. PMID- 26941623 TI - The Role of Astrocytic Aquaporin-4 in Synaptic Plasticity and Learning and Memory. AB - Aquaporin-4 (AQP4) is the predominant water channel expressed by astrocytes in the central nervous system (CNS). AQP4 is widely expressed throughout the brain, especially at the blood-brain barrier where AQP4 is highly polarized to astrocytic foot processes in contact with blood vessels. The bidirectional water transport function of AQP4 suggests its role in cerebral water balance in the CNS. The regulation of AQP4 has been extensively investigated in various neuropathological conditions such as cerebral edema, epilepsy, and ischemia, however, the functional role of AQP4 in synaptic plasticity, learning, and memory is only beginning to be elucidated. In this review, we explore the current literature on AQP4 and its influence on long term potentiation (LTP) and long term depression (LTD) in the hippocampus as well as the potential relationship between AQP4 and in learning and memory. We begin by discussing recent in vitro and in vivo studies using AQP4-null and wild-type mice, in particular, the impairment of LTP and LTD observed in the hippocampus. Early evidence using AQP4 null mice have suggested that impaired LTP and LTD is brain-derived neurotrophic factor dependent. Others have indicated a possible link between defective LTP and the downregulation of glutamate transporter-1 which is rescued by chronic treatment of beta-lactam antibiotic ceftriaxone. Furthermore, behavioral studies may shed some light into the functional role of AQP4 in learning and memory. AQP4 null mice performances utilizing Morris water maze, object placement tests, and contextual fear conditioning proposed a specific role of AQP4 in memory consolidation. All together, these studies highlight the potential influence AQP4 may have on long term synaptic plasticity and memory. PMID- 26941627 TI - Influence of Ethnicity, Gender and Answering Mode on a Virtual Point-to-Origin Task. AB - In a virtual point-to-origin task, participants seem to show different response patterns and underlying strategies for orientation, such as "turner" and "non turner" response patterns. Turners respond as if succeeding to update simulated heading changes, and non-turners respond as if failing to update their heading, resulting in left-right hemisphere errors. We present two other response patterns, "non-movers" and "spinners," that also appear to result in failures to update heading. We have three specific goals in mind: (1) extend previous findings of higher turner rates with spatial language response mode using a point to-origin task instead of a triangle completion task; (2) replicate the gender effect of males more likely responding as turners; (3) examine ethnicity influence. Designed as a classroom study, we presented participants (N = 498) with four passages through a virtual star field. Participants selected the direction pointing to the origin from four multiple-choice items. Response mode was either pictograms or written language, chosen to compare with similar studies and see if these response modes have an effect on virtual orientation behavior. Results show a majority of participants (48.35%) classified as non-turners, 32.93% turners, 15.57% as non-movers, and 3.14% as spinners. A multinomial regression model reached 49% classification performance. Written spatial language, compared to pictograms, made turner response patterns more likely; this effect was more pronounced for Chinese participants and among females, but not male Caucasians. Moreover, higher turner numbers for written spatial language extends Avraamides findings of higher turner numbers when participants turned their bodies toward the origin but not when they responded verbally. Using pictorial response mode (i.e., top-down picture of a head) may have increased cognitive load because it could be considered more embodied. It remains to be seen how we can reduce the reference frame conflict that might have caused increased cognitive load. Second, our results are inconsistent with previous research in that males overall did not show more turner behavior than females. Future research may look at possible underlying factors, such as cultural norms. Third, individualistic cultures (Caucasians; Greif, 1994) lean toward turner response patterns, whereas collectivist cultures (Asian) lean toward non-turner response patterns. PMID- 26941626 TI - A Novel Heterocyclic Compound CE-104 Enhances Spatial Working Memory in the Radial Arm Maze in Rats and Modulates the Dopaminergic System. AB - Various psychostimulants targeting monoamine neurotransmitter transporters (MATs) have been shown to rescue cognition in patients with neurological disorders and improve cognitive abilities in healthy subjects at low doses. Here, we examined the effects upon cognition of a chemically synthesized novel MAT inhibiting compound 2-(benzhydrylsulfinylmethyl)-4-methylthiazole (named as CE-104). The efficacy of CE-104 in blocking MAT [dopamine transporter (DAT), serotonin transporter (SERT), and norepinephrine transporter] was determined using in vitro neurotransmitter uptake assay. The effect of the drug at low doses (1 and 10 mg/kg) on spatial memory was studied in male rats in the radial arm maze (RAM). Furthermore, the dopamine receptor and transporter complex levels of frontal cortex (FC) tissue of trained and untrained animals treated either with the drug or vehicle were quantified on blue native PAGE (BN-PAGE). The drug inhibited dopamine (IC50: 27.88 MUM) and norepinephrine uptake (IC50: 160.40 MUM), but had a negligible effect on SERT. In the RAM, both drug-dose groups improved spatial working memory during the performance phase of RAM as compared to vehicle. BN PAGE Western blot quantification of dopamine receptor and transporter complexes revealed that D1, D2, D3, and DAT complexes were modulated due to training and by drug effects. The drug's ability to block DAT and its influence on DAT and receptor complex levels in the FC is proposed as a possible mechanism for the observed learning and memory enhancement in the RAM. PMID- 26941631 TI - A New View on an Old Debate: Type of Cue-Conflict Manipulation and Availability of Stars Can Explain the Discrepancies between Cue-Calibration Experiments with Migratory Songbirds. AB - Migratory birds use multiple compass systems for orientation, including a magnetic, star and sun/polarized light compass. To keep these compasses in register, birds have to regularly update them with respect to a common reference. However, cue-conflict studies have revealed contradictory results on the compass hierarchy, favoring either celestial or magnetic compass cues as the primary calibration reference. Both the geomagnetic field and polarized light cues present at sunrise and sunset have been shown to play a role in compass cue integration, and evidence suggests that polarized light cues at sunrise and sunset may provide the primary calibration reference for the other compass systems. We tested whether migratory garden warblers recalibrated their compasses when they were exposed to the natural celestial cues at sunset in a shifted magnetic field, which are conditions that have been shown to be necessary for the use of a compass reference based on polarized light cues. We released the birds on the same evening under a starry sky and followed them by radio tracking. We found no evidence of compass recalibration, even though the birds had a full view of polarized light cues near the horizon at sunset during the cue-conflict exposure. Based on a meta-analysis of the available literature, we propose an extended unifying theory on compass cue hierarchy used by migratory birds to calibrate the different compasses. According to this scheme, birds recalibrate their magnetic compass by sunrise/sunset polarized light cues, provided they have access to the vertically aligned band of maximum polarization near the horizon and a view of landmarks. Once the stars appear in the sky, the birds then recalibrate the star compass with respect of the recalibrated magnetic compass. If sunrise and sunset information can be viewed from the same location, the birds average the information to get a true geographic reference. If polarized light information is not available near the horizon at sunrise or sunset, the birds temporarily transfer the previously calibrated magnetic compass information to the available celestial compasses. We conclude that the type of cue-conflict manipulation and the availability of stars can explain the discrepancies between studies. PMID- 26941629 TI - Resting-State Coupling between Core Regions within the Central-Executive and Salience Networks Contributes to Working Memory Performance. AB - Previous studies investigated the distinct roles played by different cognitive regions and suggested that the patterns of connectivity of these regions are associated with working memory (WM). However, the specific causal mechanism through which the neuronal circuits that involve these brain regions contribute to WM is still unclear. Here, in a large sample of healthy young adults, we first identified the core WM regions by linking WM accuracy to resting-state functional connectivity with the bilateral dorsolateral prefrontal cortex (dLPFC; a principal region in the central-executive network, CEN). Then a spectral dynamic causal modeling (spDCM) analysis was performed to quantify the effective connectivity between these regions. Finally, the effective connectivity was correlated with WM accuracy to characterize the relationship between these connections and WM performance. We found that the functional connections between the bilateral dLPFC and the dorsal anterior cingulate cortex (dACC) and between the right dLPFC and the left orbital fronto-insular cortex (FIC) were correlated with WM accuracy. Furthermore, the effective connectivity from the dACC to the bilateral dLPFC and from the right dLPFC to the left FIC could predict individual differences in WM. Because the dACC and FIC are core regions of the salience network (SN), we inferred that the inter- and causal-connectivity between core regions within the CEN and SN is functionally relevant for WM performance. In summary, the current study identified the dLPFC-related resting-state effective connectivity underlying WM and suggests that individual differences in cognitive ability could be characterized by resting-state effective connectivity. PMID- 26941628 TI - EMOTICOM: A Neuropsychological Test Battery to Evaluate Emotion, Motivation, Impulsivity, and Social Cognition. AB - In mental health practice, both pharmacological and non-pharmacological treatments are aimed at improving neuropsychological symptoms, including cognitive and emotional impairments. However, at present there is no established neuropsychological test battery that comprehensively covers multiple affective domains relevant in a range of disorders. Our objective was to generate a standardized test battery, comprised of existing, adapted and novel tasks, to assess four core domains of affective cognition (emotion processing, motivation, impulsivity and social cognition) in order to facilitate and enhance treatment development and evaluation in a broad range of neuropsychiatric disorders. The battery was administered to 200 participants aged 18-50 years (50% female), 42 of whom were retested in order to assess reliability. An exploratory factor analysis identified 11 factors with eigenvalues greater than 1, which accounted for over 70% of the variance. Tasks showed moderate to excellent test-retest reliability and were not strongly correlated with demographic factors such as age or IQ. The EMOTICOM test battery is therefore a promising tool for the assessment of affective cognitive function in a range of contexts. PMID- 26941630 TI - Two Years Follow up of Domain Specific Cognitive Training in Relapsing Remitting Multiple Sclerosis: A Randomized Clinical Trial. AB - Cognitive rehabilitation in multiple sclerosis (MS) has been reported to induce neuropsychological improvements, but the persistence of these effects has been scarcely investigated over long follow ups. Here, the results of a multicenter randomized clinical trial are reported, in which the efficacy of 15 week domain specific cognitive training was evaluated at 2 years follow up in 41 patients. Included patients were randomly assigned either to domain specific cognitive rehabilitation, or to aspecific psychological intervention. Patients who still resulted to be cognitively impaired at 1 year follow up were resubmitted to the same treatment, whereas the recovered ones were not. Neuropsychological tests and functional scales were administered at 2 years follow up to all the patients. Results revealed that both at 1 and at 2 years follow up more patients in the aspecific group (18/19, 94% and 13/17, 76% respectively) than in the specific group (11/22, 50% and 5/15, 33% respectively) resulted to be cognitively impaired. Furthermore patients belonging to the specific group showed significantly less impaired tests compared with the aspecific group ones (p = 0.02) and a significant amelioration in the majority of the tests. On the contrary patients in the aspecific group did not change. The specific group subjects also perceived a subjective improvement in their cognitive performance, while the aspecific group patients did not. These results showed that short time domain specific cognitive rehabilitation is a useful treatment for patients with MS, shows very long lasting effects, compared to aspecific psychological interventions. Also subjective cognitive amelioration was found in patients submitted to domain specific treatment after 2 years. PMID- 26941632 TI - Neural Basis of Two Kinds of Social Influence: Obedience and Conformity. AB - Event-related potentials (ERPs) were used in this study to explore the neural mechanism of obedience and conformity on the model of online book purchasing. Participants were asked to decide as quickly as possible whether to buy a book based on limited information including its title, keywords and number of positive and negative reviews. Obedience was induced by forcing participants to buy books which received mostly negative reviews. In contrast, conformity was aroused by majority influence (caused by positive and negative comments). P3 and N2, two kinds of ERP components related to social cognitive process, were measured and recorded with electroencephalogram (EEG) test. The results show that compared with conformity decisions, obedience decisions induced greater cognitive conflicts. In ERP measurements, greater amplitudes of N2 component were observed in the context of obedience. However, consistency level did not make a difference on P3 peak latency for both conformity and obedience. This shows that classification process is implicit in both conformity and obedience decision making. In addition, for both conformity and obedience decisions, augmented P3 was observed when the reviews consistency (either negative or positive) was higher. PMID- 26941633 TI - Action Recognition and Movement Direction Discrimination Tasks Are Associated with Different Adaptation Patterns. AB - The ability to discriminate between different actions is essential for action recognition and social interactions. Surprisingly previous research has often probed action recognition mechanisms with tasks that did not require participants to discriminate between actions, e.g., left-right direction discrimination tasks. It is not known to what degree visual processes in direction discrimination tasks are also involved in the discrimination of actions, e.g., when telling apart a handshake from a high-five. Here, we examined whether action discrimination is influenced by movement direction and whether direction discrimination depends on the type of action. We used an action adaptation paradigm to target action and direction discrimination specific visual processes. In separate conditions participants visually adapted to forward and backward moving handshake and high five actions. Participants subsequently categorized either the action or the movement direction of an ambiguous action. The results showed that direction discrimination adaptation effects were modulated by the type of action but action discrimination adaptation effects were unaffected by movement direction. These results suggest that action discrimination and direction categorization rely on partly different visual information. We propose that action discrimination tasks should be considered for the exploration of visual action recognition mechanisms. PMID- 26941634 TI - Spike Pattern Structure Influences Synaptic Efficacy Variability under STDP and Synaptic Homeostasis. I: Spike Generating Models on Converging Motifs. AB - In neural systems, synaptic plasticity is usually driven by spike trains. Due to the inherent noises of neurons and synapses as well as the randomness of connection details, spike trains typically exhibit variability such as spatial randomness and temporal stochasticity, resulting in variability of synaptic changes under plasticity, which we call efficacy variability. How the variability of spike trains influences the efficacy variability of synapses remains unclear. In this paper, we try to understand this influence under pair-wise additive spike timing dependent plasticity (STDP) when the mean strength of plastic synapses into a neuron is bounded (synaptic homeostasis). Specifically, we systematically study, analytically and numerically, how four aspects of statistical features, i.e., synchronous firing, burstiness/regularity, heterogeneity of rates and heterogeneity of cross-correlations, as well as their interactions influence the efficacy variability in converging motifs (simple networks in which one neuron receives from many other neurons). Neurons (including the post-synaptic neuron) in a converging motif generate spikes according to statistical models with tunable parameters. In this way, we can explicitly control the statistics of the spike patterns, and investigate their influence onto the efficacy variability, without worrying about the feedback from synaptic changes onto the dynamics of the post-synaptic neuron. We separate efficacy variability into two parts: the drift part (DriftV) induced by the heterogeneity of change rates of different synapses, and the diffusion part (DiffV) induced by weight diffusion caused by stochasticity of spike trains. Our main findings are: (1) synchronous firing and burstiness tend to increase DiffV, (2) heterogeneity of rates induces DriftV when potentiation and depression in STDP are not balanced, and (3) heterogeneity of cross-correlations induces DriftV together with heterogeneity of rates. We anticipate our work important for understanding functional processes of neuronal networks (such as memory) and neural development. PMID- 26941636 TI - Retraction: Sensing risk, fearing uncertainty: systems science approach to change. AB - [This retracts the article on p. 30 in vol. 8, PMID: 24744723.]. PMID- 26941637 TI - Unsupervised learning of digit recognition using spike-timing-dependent plasticity. AB - In order to understand how the mammalian neocortex is performing computations, two things are necessary; we need to have a good understanding of the available neuronal processing units and mechanisms, and we need to gain a better understanding of how those mechanisms are combined to build functioning systems. Therefore, in recent years there is an increasing interest in how spiking neural networks (SNN) can be used to perform complex computations or solve pattern recognition tasks. However, it remains a challenging task to design SNNs which use biologically plausible mechanisms (especially for learning new patterns), since most such SNN architectures rely on training in a rate-based network and subsequent conversion to a SNN. We present a SNN for digit recognition which is based on mechanisms with increased biological plausibility, i.e., conductance based instead of current-based synapses, spike-timing-dependent plasticity with time-dependent weight change, lateral inhibition, and an adaptive spiking threshold. Unlike most other systems, we do not use a teaching signal and do not present any class labels to the network. Using this unsupervised learning scheme, our architecture achieves 95% accuracy on the MNIST benchmark, which is better than previous SNN implementations without supervision. The fact that we used no domain-specific knowledge points toward the general applicability of our network design. Also, the performance of our network scales well with the number of neurons used and shows similar performance for four different learning rules, indicating robustness of the full combination of mechanisms, which suggests applicability in heterogeneous biological neural networks. PMID- 26941635 TI - On the Complexity of Brain Disorders: A Symptom-Based Approach. AB - Mounting evidence shows that brain disorders involve multiple and different neural dysfunctions, including regional brain damage, change to cell structure, chemical imbalance, and/or connectivity loss among different brain regions. Understanding the complexity of brain disorders can help us map these neural dysfunctions to different symptom clusters as well as understand subcategories of different brain disorders. Here, we discuss data on the mapping of symptom clusters to different neural dysfunctions using examples from brain disorders such as major depressive disorder (MDD), Parkinson's disease (PD), schizophrenia, posttraumatic stress disorder (PTSD) and Alzheimer's disease (AD). In addition, we discuss data on the similarities of symptoms in different disorders. Importantly, computational modeling work may be able to shed light on plausible links between various symptoms and neural damage in brain disorders. PMID- 26941638 TI - Neural Activation During Submaximal Contractions Seems More Reflective of Neuromuscular Ageing than Maximal Voluntary Activation. AB - This study aimed at testing the hypothesis that differences in neural activation strategy during submaximal but not maximal plantarflexions exist between young and older men. Eleven young men (YM, 26 +/- 4 years) and thirteen old men (OM, 76 +/- 3 years) volunteered for the investigation. Maximal voluntary torque (MVT) was 38.2%, lower (p < 0.001) in OM than in YM, while voluntary activation was equivalent (~97%). The relationship between the interpolated twitch-torque and the voluntary torque (IT-VT relationship) was composite (curvilinear + exponential) for both age-groups. However, the OM showed accentuated concavity, as attested by the occurrence of the deviation from linearity at a lower contraction intensity (OM: 54.9 vs. YM: 71.9% MVT). In conclusion, ageing does not affect the capacity to fully activate the plantar flexors during maximal performances, but it alters the activation pattern for submaximal levels of effort. The greater age-related concavity of the IT-VT relationship suggests that, during submaximal contractions, OM need to reach a level of activation higher than YM to develop an equivalent relative torque. PMID- 26941639 TI - Cross-View Neuroimage Pattern Analysis in Alzheimer's Disease Staging. AB - The research on staging of pre-symptomatic and prodromal phase of neurological disorders, e.g., Alzheimer's disease (AD), is essential for prevention of dementia. New strategies for AD staging with a focus on early detection, are demanded to optimize potential efficacy of disease-modifying therapies that can halt or slow the disease progression. Recently, neuroimaging are increasingly used as additional research-based markers to detect AD onset and predict conversion of MCI and normal control (NC) to AD. Researchers have proposed a variety of neuroimaging biomarkers to characterize the patterns of the pathology of AD and MCI, and suggested that multi-view neuroimaging biomarkers could lead to better performance than single-view biomarkers in AD staging. However, it is still unclear what leads to such synergy and how to preserve or maximize. In an attempt to answer these questions, we proposed a cross-view pattern analysis framework for investigating the synergy between different neuroimaging biomarkers. We quantitatively analyzed nine types of biomarkers derived from FDG PET and T1-MRI, and evaluated their performance in a task of classifying AD, MCI, and NC subjects obtained from the ADNI baseline cohort. The experiment results showed that these biomarkers could depict the pathology of AD from different perspectives, and output distinct patterns that are significantly associated with the disease progression. Most importantly, we found that these features could be separated into clusters, each depicting a particular aspect; and the inter cluster features could always achieve better performance than the intra-cluster features in AD staging. PMID- 26941640 TI - Cognitive Benefits of Social Dancing and Walking in Old Age: The Dancing Mind Randomized Controlled Trial. AB - BACKGROUND: A physically active lifestyle has the potential to prevent cognitive decline and dementia, yet the optimal type of physical activity/exercise remains unclear. Dance is of special interest as it complex sensorimotor rhythmic activity with additional cognitive, social, and affective dimensions. OBJECTIVES: To determine whether dance benefits executive function more than walking, an activity that is simple and functional. METHODS: Two-arm randomized controlled trial among community-dwelling older adults. The intervention group received 1 h of ballroom dancing twice weekly over 8 months (~69 sessions) in local community dance studios. The control group received a combination of a home walking program with a pedometer and optional biweekly group-based walking in local community park to facilitate socialization. MAIN OUTCOMES: Executive function tests: processing speed and task shift by the Trail Making Tests, response inhibition by the Stroop Color-Word Test, working memory by the Digit Span Backwards test, immediate and delayed verbal recall by the Rey Auditory Verbal Learning Test, and visuospatial recall by the Brief Visuospatial Memory Test (BVST). RESULTS: One hundred and fifteen adults (mean 69.5 years, SD 6.4) completed baseline and delayed baseline (3 weeks apart) before being randomized to either dance (n = 60) or walking (n = 55). Of those randomized, 79 (68%) completed the follow-up measurements (32 weeks from baseline). In the dance group only, "non-completers" had significantly lower baseline scores on all executive function tests than those who completed the full program. Intention-to-treat analyses showed no group effect. In a random effects model including participants who completed all measurements, adjusted for baseline score and covariates (age, education, estimated verbal intelligence, and community), a between-group effect in favor of dance was noted only for BVST total learning (Cohen's D Effect size 0.29, p = 0.07) and delayed recall (Cohen's D Effect size = 0.34, p = 0.06). CONCLUSION: The superior potential of dance over walking on executive functions of cognitively healthy and active older adults was not supported. Dance improved one of the cognitive domains (spatial memory) important for learning dance. Controlled trials targeting inactive older adults and of a higher dose may produce stronger effects, particularly for novice dancers. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Register (ACTRN12613000782730). PMID- 26941641 TI - The Role of Monocytes in Ischemic Stroke Pathobiology: New Avenues to Explore. AB - Ischemic stroke accounts for the majority of stroke cases and constitutes a major cause of death and disability in the industrialized world. Inflammation has been reported to constitute a major component of ischemic stroke pathobiology. In the acute phase of ischemic stroke, microglia, the resident macrophages of the brain, are activated, followed by several infiltration waves of different circulating immune cells into the brain. Among these circulating immune cells, monocytes have been shown to play a particularly important role. Following their infiltration, monocytes differentiate into potent phagocytic cells, the monocyte-derived macrophages (MDMs), in the ischemic brain. Initially, the presence of these cells was considered as marker of an exacerbated inflammatory response that contributes to brain damage. However, the recent reports are suggesting a more complex and multiphasic roles of these cells in ischemic stroke pathobiology. Monocytes constitute a heterogeneous group of cells, which comprises two major subsets in rodent and three major subsets in human. In both species, two equivalent subsets exist, the pro-inflammatory subset and the anti-inflammatory subset. Recent data have demonstrated that ischemic stroke differentially regulate monocyte subsets, which directly affect ischemic stroke pathobiology and may have direct implications in ischemic stroke therapies. Here, we review the recent findings that addressed the role of different monocyte subsets in ischemic stroke pathobiology, and the implications on therapies. PMID- 26941643 TI - Modulation of Prepulse Inhibition and Startle Reflex by Emotions: A Comparison between Young and Older Adults. AB - This study examined whether or not the acoustic startle response and sensorimotor gating may be modulated by emotions differentially between young and older adults. Two groups of participants (mean age Young: 24 years old; Elderly: 63.6 years old) were presented with three types of auditory stimuli (Startle alone, High or Low frequency Prepulse) while viewing pleasant, neutral, or unpleasant images. Electromyographic activity of the eyeblink response was measured. Results show that older adults displayed diminished eyeblink responses whereas younger adults displayed enhanced eyeblink responses when viewing negative images. Sensorimotor gating also differed between young and older adults, with enhanced sensorimotor gating abilities while viewing positive pictures in older adults and diminished abilities while viewing negative pictures among younger adults. These results argue in favor of a differential emotional influence on the sensorimotor abilities of young and older adults, with a positivity bias among the latter. PMID- 26941642 TI - Implications of GABAergic Neurotransmission in Alzheimer's Disease. AB - Alzheimer's disease (AD) is characterized pathologically by the deposition of beta-amyloid peptides (Abeta) and the accumulation of neurofibrillary tangles (NFTs) composed of hyper-phosphorylated tau. Regardless of the pathological hallmarks, synaptic dysfunction is widely accepted as a causal event in AD. Of the two major types of synapses in the central nervous system (CNS): glutamatergic and GABAergic, which provide excitatory and inhibitory outputs respectively, abundant data implicate an impaired glutamatergic system during disease progression. However, emerging evidence supports the notion that disrupted default neuronal network underlies impaired memory, and that alterations of GABAergic circuits, either plays a primary role or as a compensatory response to excitotoxicity, may also contribute to AD by disrupting the overall network function. The goal of this review is to provide an overview of the involvement of Abeta, tau and apolipoprotein E4 (apoE4), the major genetic risk factor in late-onset AD (LOAD), in GABAergic neurotransmission and the potential of modulating the GABAergic function as AD therapy. PMID- 26941645 TI - Editorial: Today's Nutrition and Tomorrow's Public Health: Challenges and Opportunities. PMID- 26941646 TI - Corrigendum: A PKA activity sensor for quantitative analysis of endogenous GPCR signaling via 2-photon FRET-FLIM imaging. AB - [This corrects the article on p. 56 in vol. 5, PMID: 24765076.]. PMID- 26941644 TI - Pharmacological Intervention in Hepatic Stellate Cell Activation and Hepatic Fibrosis. AB - The activation and transdifferentiation of hepatic stellate cells (HSCs) into contractile, matrix-producing myofibroblasts (MFBs) are central events in hepatic fibrogenesis. These processes are driven by autocrine- and paracrine-acting soluble factors (i.e., cytokines and chemokines). Proof-of-concept studies of the last decades have shown that both the deactivation and removal of hepatic MFBs as well as antagonizing profibrogenic factors are in principle suitable to attenuate ongoing hepatic fibrosis. Although several drugs show potent antifibrotic activities in experimental models of hepatic fibrosis, there is presently no effective pharmaceutical intervention specifically approved for the treatment of liver fibrosis. Pharmaceutical interventions are generally hampered by insufficient supply of drugs to the diseased liver tissue and/or by adverse effects as a result of affecting non-target cells. Therefore, targeted delivery systems that bind specifically to receptors solely expressed on activated HSCs or transdifferentiated MFBs and delivery systems that can improve drug distribution to the liver in general are urgently needed. In this review, we summarize current strategies for targeted delivery of drugs to the liver and in particular to pro fibrogenic liver cells. The applicability and efficacy of sequestering molecules, selective protein carriers, lipid-based drug vehicles, viral vectors, transcriptional targeting approaches, therapeutic liver- and HSC-specific nanoparticles, and miRNA-based strategies are discussed. Some of these delivery systems that had already been successfully tested in experimental animal models of ongoing hepatic fibrogenesis are expected to translate into clinically useful therapeutics specifically targeting HSCs. PMID- 26941648 TI - Long Term Dental Work Force Build-Up and DMFT-12 Improvement in the European Region. PMID- 26941647 TI - Sequential Filtering Processes Shape Feature Detection in Crickets: A Framework for Song Pattern Recognition. AB - Intraspecific acoustic communication requires filtering processes and feature detectors in the auditory pathway of the receiver for the recognition of species specific signals. Insects like acoustically communicating crickets allow describing and analysing the mechanisms underlying auditory processing at the behavioral and neural level. Female crickets approach male calling song, their phonotactic behavior is tuned to the characteristic features of the song, such as the carrier frequency and the temporal pattern of sound pulses. Data from behavioral experiments and from neural recordings at different stages of processing in the auditory pathway lead to a concept of serially arranged filtering mechanisms. These encompass a filter for the carrier frequency at the level of the hearing organ, and the pulse duration through phasic onset responses of afferents and reciprocal inhibition of thoracic interneurons. Further, processing by a delay line and coincidence detector circuit in the brain leads to feature detecting neurons that specifically respond to the species-specific pulse rate, and match the characteristics of the phonotactic response. This same circuit may also control the response to the species-specific chirp pattern. Based on these serial filters and the feature detecting mechanism, female phonotactic behavior is shaped and tuned to the characteristic properties of male calling song. PMID- 26941649 TI - Use of Rat Mature Adipocyte-Derived Dedifferentiated Fat Cells as a Cell Source for Periodontal Tissue Regeneration. AB - Lipid-free fibroblast-like cells, known as dedifferentiated fat (DFAT) cells, can be generated from mature adipocytes with a large single lipid droplet. DFAT cells can re-establish their active proliferation ability and can transdifferentiate into various cell types under appropriate culture conditions. The first objective of this study was to compare the multilineage differentiation potential of DFAT cells with that of adipose-derived stem cells (ASCs) on mesenchymal stem cells. We obtained DFAT cells and ASCs from inbred rats and found that rat DFAT cells possess higher osteogenic differentiation potential than rat ASCs. On the other hand, DFAT cells show similar adipogenic differentiation, and chondrogenic differentiation potential in comparison with ASCs. The second objective of this study was to assess the regenerative potential of DFAT cells combined with novel solid scaffolds composed of PLGA (Poly d, l-lactic-co-glycolic acid) on periodontal tissue, and to compare this with the regenerative potential of ASCs combined with PLGA scaffolds. Cultured DFAT cells and ASCs were seeded onto PLGA scaffolds (DFAT/PLGA and ASCs/PLGA) and transplanted into periodontal fenestration defects in rat mandible. Micro computed tomography analysis revealed a significantly higher amount of bone regeneration in the DFAT/PLGA group compared with that of ASCs/PLGA and PLGA-alone groups at 2, 3, and 5 weeks after transplantation. Similarly, histomorphometric analysis showed that DFAT/PLGA groups had significantly greater width of cementum, periodontal ligament and alveolar bone than ASCs/PLGA and PLGA-alone groups. In addition, transplanted fluorescent-labeled DFAT cells were observed in the periodontal ligament beside the newly formed bone and cementum. These findings suggest that DFAT cells have a greater potential for enhancing periodontal tissue regeneration than ASCs. Therefore, DFAT cells are a promising cell source for periodontium regeneration. PMID- 26941650 TI - Feces Derived Allergens of Tyrophagus putrescentiae Reared on Dried Dog Food and Evidence of the Strong Nutritional Interaction between the Mite and Bacillus cereus Producing Protease Bacillolysins and Exo-chitinases. AB - Tyrophagus putrescentiae (Schrank, 1781) is an emerging source of allergens in stored products and homes. Feces proteases are the major allergens of astigmatid mites (Acari: Acaridida). In addition, the mites are carriers of microorganisms and microbial adjuvant compounds that stimulate innate signaling pathways. We sought to analyze the mite feces proteome, proteolytic activities, and mite bacterial interaction in dry dog food (DDF). Proteomic methods comprising enzymatic and zymographic analysis of proteases and 2D-E-MS/MS were performed. The highest protease activity was assigned to trypsin-like proteases; lower activity was assigned to chymotrypsin-like proteases, and the cysteine protease cathepsin B-like had very low activity. The 2D-E-MS/MS proteomic analysis identified mite trypsin allergen Tyr p3, fatty acid-binding protein Tyr p13 and putative mite allergens ferritin (Grp 30) and (poly)ubiquitins. Tyr p3 was detected at different positions of the 2D-E. It indicates presence of zymogen at basic pI, and mature-enzyme form and enzyme fragment at acidic pI. Bacillolysins (neutral and alkaline proteases) of Bacillus cereus symbiont can contribute to the protease activity of the mite extract. The bacterial exo-chitinases likely contribute to degradation of mite exuviae, mite bodies or food boluses consisting of chitin, including the peritrophic membrane. Thus, the chitinases disrupt the feces and facilitate release of the allergens. B. cereus was isolated and identified based on amplification and sequencing of 16S rRNA and motB genes. B. cereus was added into high-fat, high-protein (DDF) and low-fat, low-protein (flour) diets to 1 and 5% (w/w), and the diets palatability was evaluated in 21 day population growth test. The supplementation of diet with B. cereus significantly suppressed population growth and the suppressive effect was higher in the high-fat, high-protein diet than in the low-fat, low-protein food. Thus, B. cereus has to coexist with the mite in balance to be beneficial for the mite. The mite-B. cereus symbiosis can be beneficial-suppressive at some level. The results increase the veterinary and medical importance of the allergens detected in feces. The B. cereus enzymes/toxins are important components of mite allergens. The strong symbiotic association of T. putrescentiae with B. cereus in DDF was indicated. PMID- 26941651 TI - Impact of Air Pollution on Age and Gender Related Increase in Cough Reflex Sensitivity of Healthy Children in Slovakia. AB - BACKGROUND: Numerous studies show higher cough reflex sensitivity (CRS) and cough outcomes in children compared to adults and in females compared to males. Despite close link that exists between cough and environment the potential influence of environmental air pollution on age- and gender -related differences in cough has not been studied yet. PURPOSE: The purpose of our study was to analyse whether the effects of exposure to environmental tobacco smoke (ETS) from parental smoking and PM10 from living in urban area are implied in age- and gender-related differences in cough outcomes of healthy, non-asthmatic children. Assessment of CRS using capsaicin and incidence of dry and wet cough was performed in 290 children (mean age 13.3 +/- 2.6 years (138 females/152 males). RESULTS: CRS was significantly higher in girls exposed to ETS [22.3 MUmol/l (9.8-50.2 MUmol/l)] compared to not exposed girls [79.9 MUmol/l (56.4-112.2 MUmol/l), p = 0.02] as well as compared to exposed boys [121.4 MUmol/l (58.2-253.1 MUmol/l), p = 0.01]. Incidence of dry cough lasting more than 3 weeks was significantly higher in exposed compared to not exposed girls. CRS was significantly higher in school aged girls living in urban area [22.0 MUmol/l (10.6-45.6 MUmol/l)] compared to school-aged girls living in rural area [215.9 MUmol/l (87.3-533.4 MUmol/l); p = 0.003], as well as compared to teenage girls living in urban area [108.8 MUmol/l (68.7-172.9 MUmol/l); p = 0.007]. No CRS differences were found between urban and rural boys when controlled for age group. No CRS differences were found between school-aged and teenage boys when controlled for living area. CONCLUSIONS: Our results have shown that the effect of ETS on CRS was gender specific, linked to female gender and the effect of PM10 on CRS was both gender and age specific, related to female gender and school-age. We suggest that age and gender related differences in incidence of cough and CRS might be, at least partially, ascribed to the effect of environmental pollutants. The role of age and gender in the effect of air pollution on cough strongly suggest some interplay of development with biological and behavioral factors. PMID- 26941652 TI - The Pathophysiological Hypothesis of Kidney Damage during Intra-Abdominal Hypertension. PMID- 26941653 TI - Genetic Network Inference Using Hierarchical Structure. AB - Many methods for inferring genetic networks have been proposed, but the regulations they infer often include false-positives. Several researchers have attempted to reduce these erroneous regulations by proposing the use of a priori knowledge about the properties of genetic networks such as their sparseness, scale-free structure, and so on. This study focuses on another piece of a priori knowledge, namely, that biochemical networks exhibit hierarchical structures. Based on this idea, we propose an inference approach that uses the hierarchical structure in a target genetic network. To obtain a reasonable hierarchical structure, the first step of the proposed approach is to infer multiple genetic networks from the observed gene expression data. We take this step using an existing method that combines a genetic network inference method with a bootstrap method. The next step is to extract a hierarchical structure from the inferred networks that is consistent with most of the networks. Third, we use the hierarchical structure obtained to assign confidence values to all candidate regulations. Numerical experiments are also performed to demonstrate the effectiveness of using the hierarchical structure in the genetic network inference. The improvement accomplished by the use of the hierarchical structure is small. However, the hierarchical structure could be used to improve the performances of many existing inference methods. PMID- 26941654 TI - Ephrin Ligands and Eph Receptors Show Regionally Restricted Expression in the Developing Palate and Tongue. AB - The Eph family receptor-interacting (ephrin) ligands and erythropoietin-producing hepatocellular carcinoma (Eph) receptors constitute the largest known family of receptor tyrosine kinases. Ephrin ligands and their receptors form an important cell communication system with widespread roles in normal physiology and disease pathogenesis. In order to investigate potential roles of the ephrin-Eph system during palatogenesis and tongue development, we have characterized the cellular mRNA expression of family members EphrinA1-A3, EphA1-A8, and EphrinB2, EphB1, EphB4 during murine embryogenesis between embryonic day 13.5-16.5 using radioactive in situ hybridization. With the exception of EphA6 and ephrinA3, all genes were regionally expressed during the process of palatogenesis, with restricted and often overlapping domains. Transcripts were identified in the palate epithelium, localized at the tip of the palatal shelves, in the mesenchyme and also confined to the medial epithelium seam. Numerous Eph transcripts were also identified during tongue development. In particular, EphA1 and EphA2 demonstrated a highly restricted and specific expression in the tongue epithelium at all stages examined, whereas EphA3 was strongly expressed in the lateral tongue mesenchyme. These results suggest regulatory roles for ephrin-EphA signaling in development of the murine palate and tongue. PMID- 26941655 TI - Role of Bone Marrow-Derived Fibroblasts in Renal Fibrosis. AB - Renal fibrosis represents a common pathway leading to progression of chronic kidney disease. Renal interstitial fibrosis is characterized by extensive fibroblast activation and excessive production and deposition of extracellular matrix (ECM), which leads to progressive loss of kidney function. There is no effective therapy available clinically to halt or even reverse renal fibrosis. Although activated fibroblasts/myofibroblasts are responsible for the excessive production and deposition of ECM, their origin remains controversial. Recent evidence suggests that bone marrow-derived fibroblast precursors contribute significantly to the pathogenesis of renal fibrosis. Understanding the molecular signaling mechanisms underlying the recruitment and activation of the bone marrow derived fibroblast precursors will lead to novel therapy for the treatment of chronic kidney disease. In this review, we summarize recent advances in our understanding of the recruitment and activation of bone marrow-derived fibroblast precursors in the kidney and the development of renal fibrosis and highlights new insights that may lead to novel therapies to prevent or reverse the development of renal fibrosis. PMID- 26941657 TI - Editorial: Exploring Gender and Sex Differences in Behavioral Dyscontrol: From Drug Addiction to Impulse Control Disorders. PMID- 26941658 TI - Cortico-Cerebellar Connectivity in Autism Spectrum Disorder: What Do We Know So Far? AB - Although the Autism Spectrum Disorder (ASD) is renowned to be a connectivity disorder and a condition characterized by cerebellar involvement, the connectivity between the cerebellum and other cortical brain regions is particularly underexamined. Indeed, converging evidence has recently suggested that the cerebellum could play a key role in the etiopathogenesis of ASD, since cerebellar anomalies have been consistently reported in ASD from the molecular to the behavioral level, and damage to the cerebellum early in development has been linked with signs of autistic features. In addition, current data have shown that the cerebellum is a key structure not only for sensory-motor control, but also for "higher functions," such as social cognition and emotion, through its extensive connections with cortical areas. The disruption of these circuits could be implicated in the wide range of autistic symptoms that the term "spectrum" connotes. In this review, we present and discuss the recent findings from imaging studies that investigated cortico-cerebellar connectivity in people with ASD. The literature is still too limited to allow for definitive conclusions; however, this brief review reveals substantial areas for future studies, underlining currently unmet research perspectives. PMID- 26941659 TI - Commentary: Clinical Approach to the Differential Diagnosis between Behavioral Variant Frontotemporal Dementia and Primary Psychiatric Disorders. PMID- 26941656 TI - Changing Paradigms in Cranio-Facial Regeneration: Current and New Strategies for the Activation of Endogenous Stem Cells. AB - Craniofacial area represent a unique district of human body characterized by a very high complexity of tissues, innervation and vascularization, and being deputed to many fundamental function such as eating, speech, expression of emotions, delivery of sensations such as taste, sight, and earing. For this reasons, tissue loss in this area following trauma or for example oncologic resection, have a tremendous impact on patients' quality of life. In the last 20 years regenerative medicine has emerged as one of the most promising approach to solve problem related to trauma, tissue loss, organ failure etc. One of the most powerful tools to be used for tissue regeneration is represented by stem cells, which have been successfully implanted in different tissue/organs with exciting results. Nevertheless, both autologous and allogeneic stem cell transplantation raise many practical and ethical concerns that make this approach very difficult to apply in clinical practice. For this reason different cell free approaches have been developed aiming to the mobilization, recruitment, and activation of endogenous stem cells into the injury site avoiding exogenous cells implant but instead stimulating patients' own stem cells to repair the lesion. To this aim many strategies have been used including functionalized bioscaffold, controlled release of stem cell chemoattractants, growth factors, BMPs, Platelet-Rich Plasma, and other new strategies such as ultrasound wave and laser are just being proposed. Here we review all the current and new strategies used for activation and mobilization of endogenous stem cells in the regeneration of craniofacial tissue. PMID- 26941661 TI - Anxiety as a Risk Factor for Cardiovascular Diseases. PMID- 26941662 TI - Assessing the Moderating Effect of the End User in Consumer Behavior: The Acceptance of Technological Implants to Increase Innate Human Capacities. AB - Today, technological implants are being developed to increase innate human capacities, such as memory or calculation speed, and to endow us with new ones, such as the remote control of machines. This study's aim was two-fold: first, to introduce a Cognitive-Affective-Normative (CAN) model of technology acceptance to explain the intention to use this technology in the field of consumer behavior; and second, to analyze the differences in the intention to use it based on whether the intended implant recipient is oneself or one's child (i.e., the moderating effect of the end user). A multi-group analysis was performed to compare the results between the two groups: implant "for me" (Group 1) and implant "for my child" (Group 2). The model largely explains the intention to use the insideable technology for the specified groups [variance explained (R (2)) of over 0.70 in both cases]. The most important variables were found to be "positive emotions" and (positive) "subjective norm." This underscores the need to broaden the range of factors considered to be decisive in technology acceptance to include variables related to consumers' emotions. Moreover, statistically significant differences were found between the "for me" and "for my child" models for "perceived ease of use (PEU)" and "subjective norm." These findings confirm the moderating effect of the end user on new insideable technology acceptance. PMID- 26941663 TI - Gauging the Impact of Gender Grammaticization in Different Languages: Application of a Linguistic-Visual Paradigm. AB - Employing a linguistic-visual paradigm, we investigated whether the grammaticization of gender information impacts readers' gender representations. French and German were taken as comparative languages, taking into account the male gender bias associated to both languages, as well as the comparative gender biases associated to their plural determiners (French: les [generic] vs. German: die [morphologically feminine]). Bilingual speakers of French and German had to judge whether a pair of facial images representing two men or a man and a woman could represent a gender stereotypical role noun prime (e.g., nurses). The prime was presented in the masculine plural form with or without a plural determiner. Results indicated that the overt grammaticization of the male gender in the masculine form dominated the representation of the role nouns (though interpretable as generic). However, the effect of the determiner was not found, indicating that only gender information associated to a human reference role noun had impacted readers' representations. The results, discussed in the framework of the thinking-for-speaking hypothesis, demonstrated that linguistic-visual paradigms are well-suited to gauge the impact of both stereotype information and grammaticization when processing role nouns. PMID- 26941664 TI - Developmental Dysgraphia as a Reading System and Transfer Problem: A Case Study. AB - This is a case study of an adolescent who had largely overcome his early difficulty in learning to read, but continued to have severe problems with spelling. He had no visual memory impairment, and his letter-sound knowledge and phonemic awareness were at adult levels. Testing revealed that his difficulties in both reading and spelling only manifested when processing unfamiliar words. He was slow and inaccurate when reading non-words, despite a sublexical system dominated by the use of grapheme-phoneme units. It is suggested that limitations in the processing of the reading system were responsible for the lack of an extensive set of induced position-sensitive sublexical representations (ISRs) that are contextually dependent. This would have serious consequences for transfer to spelling. PMID- 26941660 TI - Memory Systems and the Addicted Brain. AB - The view that anatomically distinct memory systems differentially contribute to the development of drug addiction and relapse has received extensive support. The present brief review revisits this hypothesis as it was originally proposed 20 years ago (1) and highlights several recent developments. Extensive research employing a variety of animal learning paradigms indicates that dissociable neural systems mediate distinct types of learning and memory. Each memory system potentially contributes unique components to the learned behavior supporting drug addiction and relapse. In particular, the shift from recreational drug use to compulsive drug abuse may reflect a neuroanatomical shift from cognitive control of behavior mediated by the hippocampus/dorsomedial striatum toward habitual control of behavior mediated by the dorsolateral striatum (DLS). In addition, stress/anxiety may constitute a cofactor that facilitates DLS-dependent memory, and this may serve as a neurobehavioral mechanism underlying the increased drug use and relapse in humans following stressful life events. Evidence supporting the multiple systems view of drug addiction comes predominantly from studies of learning and memory that have employed as reinforcers addictive substances often considered within the context of drug addiction research, including cocaine, alcohol, and amphetamines. In addition, recent evidence suggests that the memory systems approach may also be helpful for understanding topical sources of addiction that reflect emerging health concerns, including marijuana use, high fat diet, and video game playing. PMID- 26941665 TI - Testing Students with Special Educational Needs in Large-Scale Assessments - Psychometric Properties of Test Scores and Associations with Test Taking Behavior. AB - Assessing competencies of students with special educational needs in learning (SEN-L) poses a challenge for large-scale assessments (LSAs). For students with SEN-L, the available competence tests may fail to yield test scores of high psychometric quality, which are-at the same time-measurement invariant to test scores of general education students. We investigated whether we can identify a subgroup of students with SEN-L, for which measurement invariant competence measures of adequate psychometric quality may be obtained with tests available in LSAs. We furthermore investigated whether differences in test-taking behavior may explain dissatisfying psychometric properties and measurement non-invariance of test scores within LSAs. We relied on person fit indices and mixture distribution models to identify students with SEN-L for whom test scores with satisfactory psychometric properties and measurement invariance may be obtained. We also captured differences in test-taking behavior related to guessing and missing responses. As a result we identified a subgroup of students with SEN-L for whom competence scores of adequate psychometric quality that are measurement invariant to those of general education students were obtained. Concerning test taking behavior, there was a small number of students who unsystematically picked response options. Removing these students from the sample slightly improved item fit. Furthermore, two different patterns of missing responses were identified that explain to some extent problems in the assessments of students with SEN-L. PMID- 26941666 TI - Non-Instrumental Movement Inhibition (NIMI) Differentially Suppresses Head and Thigh Movements during Screenic Engagement: Dependence on Interaction. AB - BACKGROUND: Estimating engagement levels from postural micromovements has been summarized by some researchers as: increased proximity to the screen is a marker for engagement, while increased postural movement is a signal for disengagement or negative affect. However, these findings are inconclusive: the movement hypothesis challenges other findings of dyadic interaction in humans, and experiments on the positional hypothesis diverge from it. HYPOTHESES: (1) Under controlled conditions, adding a relevant visual stimulus to an auditory stimulus will preferentially result in Non-Instrumental Movement Inhibition (NIMI) of the head. (2) When instrumental movements are eliminated and computer-interaction rate is held constant, for two identically-structured stimuli, cognitive engagement (i.e., interest) will result in measurable NIMI of the body generally. METHODS: Twenty-seven healthy participants were seated in front of a computer monitor and speakers. Discrete 3-min stimuli were presented with interactions mediated via a handheld trackball without any keyboard, to minimize instrumental movements of the participant's body. Music videos and audio-only music were used to test hypothesis (1). Time-sensitive, highly interactive stimuli were used to test hypothesis (2). Subjective responses were assessed via visual analog scales. The computer users' movements were quantified using video motion tracking from the lateral aspect. Repeated measures ANOVAs with Tukey post hoc comparisons were performed. RESULTS: For two equivalently-engaging music videos, eliminating the visual content elicited significantly increased non-instrumental movements of the head (while also decreasing subjective engagement); a highly engaging user selected piece of favorite music led to further increased non-instrumental movement. For two comparable reading tasks, the more engaging reading significantly inhibited (42%) movement of the head and thigh; however, when a highly engaging video game was compared to the boring reading, even though the reading task and the game had similar levels of interaction (trackball clicks), only thigh movement was significantly inhibited, not head movement. CONCLUSIONS: NIMI can be elicited by adding a relevant visual accompaniment to an audio-only stimulus or by making a stimulus cognitively engaging. However, these results presume that all other factors are held constant, because total movement rates can be affected by cognitive engagement, instrumental movements, visual requirements, and the time-sensitivity of the stimulus. PMID- 26941667 TI - Communicative-Pragmatic Treatment in Schizophrenia: A Pilot Study. AB - This paper aims to verify the efficacy of Cognitive Pragmatic Treatment (CPT), a new remediation training for the improvement of the communicative-pragmatic abilities, in patients with schizophrenia. The CPT program is made up of 20 group sessions, focused on a number of communication modalities, i.e., linguistic, extralinguistic and paralinguistic, theory of mind (ToM) and other cognitive functions able to play a role on the communicative performance, such as awareness and planning. A group of 17 patients with schizophrenia took part in the training program. They were evaluated before and after training, through the equivalent forms of the Assessment Battery for Communication (ABaCo), a tool for testing, both in comprehension and in production, a wide range of pragmatic phenomena such as direct and indirect speech acts, irony and deceit, and a series of neuropsychological and ToM tests. The results showed a significant improvement in patients' performance on both production and comprehension tasks following the program, and in all the communication modalities evaluated through the ABaCo, i.e., linguistic, extralinguistic, paralinguistic, and social appropriateness. This improvement persisted after 3 months from the end of the training program, as shown by the follow-up tests. These preliminary findings provide evidence of the efficacy of the CPT program in improving communicative-pragmatic abilities in schizophrenic individuals. PMID- 26941668 TI - Effects on Inter-Personal Memory of Dancing in Time with Others. AB - We report an experiment investigating whether dancing to the same music enhances recall of person-related memory targets. The experiment used 40 dancers (all of whom were unaware of the experiment's aim), two-channel silent-disco radio headphones, a marked-up dance floor, two types of music, and memory targets (sash colors and symbols). In each trial, 10 dancers wore radio headphones and one of four different colored sashes, half of which carried cat symbols. Using silent disco technology, one type of music was surreptitiously transmitted to half the dancers, while music at a different tempo was transmitted to the remaining dancers. Pre-experiment, the dancers' faces were photographed. Post-experiment, each dancer was presented with the photographs of the other dancers and asked to recall their memory targets. Results showed that same-music dancing significantly enhanced memory for sash color and sash symbol. Our findings are discussed in light of recent eye-movement research that showed significantly increased gaze durations for people observing music-dance synchrony versus music-dance asynchrony, and in relation to current literature on interpersonal entrainment, group cohesion, and social bonding. PMID- 26941669 TI - The Emergence of a Phoneme-Sized Unit in L2 Speech Production: Evidence from Japanese-English Bilinguals. AB - Recent research has revealed that the way phonology is constructed during word production differs across languages. Dutch and English native speakers are suggested to incrementally insert phonemes into a metrical frame, whereas Mandarin Chinese speakers use syllables and Japanese speakers use a unit called the mora (often a CV cluster such as "ka" or "ki"). The present study is concerned with the question how bilinguals construct phonology in their L2 when the phonological unit size differs from the unit in their L1. Japanese-English bilinguals of varying proficiency read aloud English words preceded by masked primes that overlapped in just the onset (e.g., bark-BENCH) or the onset plus vowel corresponding to the mora-sized unit (e.g., bell-BENCH). Low-proficient Japanese-English bilinguals showed CV priming but did not show onset priming, indicating that they use their L1 phonological unit when reading L2 English words. In contrast, high-proficient Japanese-English bilinguals showed significant onset priming. The size of the onset priming effect was correlated with the length of time spent in English-speaking countries, which suggests that extensive exposure to L2 phonology may play a key role in the emergence of a language-specific phonological unit in L2 word production. PMID- 26941670 TI - Editorial: The Variable Mind? How Apparently Inconsistent Effects Might Inform Model Building. PMID- 26941671 TI - Combined Training of One Cognitive and One Metacognitive Strategy Improves Academic Writing Skills. AB - Academic writing is a challenging task. Expert writers apply various writing skills as they anticipate the reader's view of their text while paying attention to structure and content. Research in the high school setting shows that the acquisition of writing skills can be supported by single-strategy training. However, research in higher education is scarce. We tested whether the development of academic writing skills can also be effectively supported by training single strategies or even combined strategies. As metacognition is an important skill for advanced and adult learners, we focused in this study on the benefit of combined cognitive strategies with and without a metacognitive strategy. An experiment including three conditions was conducted (N = 60 German speaking psychology undergraduates, M = 22.8, SD = 4.4), which lasted for three hours. Each group received a modeling intervention of a basic cognitive strategy on the application of text structure knowledge. Two groups received an additional modeling intervention with either a cognitive strategy treatment on text summarization or a metacognitive strategy treatment on self-monitoring the writing process. One group received no further strategy treatment. Prior knowledge and learning outcomes were measured with a specially developed test on academic writing skills. In addition, all participants wrote an abstract of an empirical article. We found that learners who received the additional self monitoring strategy intervention benefited significantly more in terms of acquisition of academic writing skills and the quality of their texts than learners who did not receive this intervention. Thus, the results underline the importance of self-monitoring strategies in academic writing. Implications and further research opportunities are discussed. PMID- 26941672 TI - Using Genetic Algorithms in a Large Nationally Representative American Sample to Abbreviate the Multidimensional Experiential Avoidance Questionnaire. AB - Genetic algorithms (GAs) are robust machine learning approaches for abbreviating a large set of variables into a shorter subset that maximally captures the variance in the original data. We employed a GA-based method to shorten the 62 item Multidimensional Experiential Avoidance Questionnaire (MEAQ) by half without much loss of information. Experiential avoidance or the tendency to avoid negative internal experiences is a key target of many psychological interventions and its measurement is an important issue in psychology. The 62-item MEAQ has been shown to have good psychometric properties, but its length may limit its use in most practical settings. The recently validated 15-item brief version (BEAQ) is one short alternative, but it reduces the multidimensional scale to a single dimension. We sought to shorten the 62-item MEAQ by half while maintaining fidelity to its six dimensions. In a large nationally representative sample of Americans (N = 7884; 52% female; Age: M = 47.9, SD = 16), we employed a GA method of scale abbreviation implemented in the R package, GAabbreviate. The GA-derived short form, MEAQ-30 with five items per subscale, performed virtually identically to the original 62-item MEAQ in terms of inter-subscales correlations, factor structure, factor correlations, and zero-order correlations and unique latent associations of the six subscales with other measures of mental distress, wellbeing and personal strivings. The two measures also showed similar distributions of means across American census regions. The MEAQ-30 provides a multidimensional assessment of experiential avoidance whilst minimizing participant burden. The study adds to the emerging literature on the utility of machine learning methods in psychometrics. PMID- 26941674 TI - Specialized Knowledge Representation and the Parameterization of Context. AB - Though instrumental in numerous disciplines, context has no universally accepted definition. In specialized knowledge resources it is timely and necessary to parameterize context with a view to more effectively facilitating knowledge representation, understanding, and acquisition, the main aims of terminological knowledge bases. This entails distinguishing different types of context as well as how they interact with each other. This is not a simple objective to achieve despite the fact that specialized discourse does not have as many contextual variables as those in general language (i.e., figurative meaning, irony, etc.). Even in specialized text, context is an extremely complex concept. In fact, contextual information can be specified in terms of scope or according to the type of information conveyed. It can be a textual excerpt or a whole document; a pragmatic convention or a whole culture; a concrete situation or a prototypical scenario. Although these versions of context are useful for the users of terminological resources, such resources rarely support context modeling. In this paper, we propose a taxonomy of context primarily based on scope (local and global) and further divided into syntactic, semantic, and pragmatic facets. These facets cover the specification of different types of terminological information, such as predicate-argument structure, collocations, semantic relations, term variants, grammatical and lexical cohesion, communicative situations, subject fields, and cultures. PMID- 26941673 TI - Effectiveness of an Attachment-Based Intervention Program in Promoting Emotion Regulation and Attachment in Adolescent Mothers and their Infants: A Pilot Study. AB - This pilot study examined the effectiveness of an attachment-based intervention program, PRERAYMI, based on video technique, psychological counseling and developmental guidance in improving the style of interaction and emotion regulation of adolescent mothers and their infants after 3 and 6 months of intervention. Analyses revealed that adolescent mothers who participated in the intervention (vs. control group adolescent mothers) increased their Sensitivity and reduced their Controlling style after both 3 and 6 months of treatment. Infants who participated in the intervention (vs. control group infants) increased their Cooperative style and reduced their Passive style from 3 to 9 months. Moreover, the intervention group dyads (vs. control group dyads) increased the amount of time spent in affective positive coordination states (matches), decreased the amount of time spent in affective mismatches, and had a greater ability to repair mismatches from 3 to 9 months. Furthermore, the intervention group dyads (vs. control group dyads) increased the amount of time spent in reciprocal involvement in play with objects from 3 to 9 months. The quality of maternal attachment did not affect the intervention effect. PMID- 26941675 TI - Developmental Abilities to Form Chunks in Immediate Memory and Its Non Relationship to Span Development. AB - Both adults and children -by the time they are 2-3 years old- have a general ability to recode information to increase memory efficiency. This paper aims to evaluate the ability of untrained children aged 6-10 years old to deploy such a recoding process in immediate memory. A large sample of 374 children were given a task of immediate serial report based on SIMON(r), a classic memory game made of four colored buttons (red, green, yellow, blue) requiring players to reproduce a sequence of colors within which repetitions eventually occur. It was hypothesized that a primitive ability across all ages (since theoretically already available in toddlers) to detect redundancies allows the span to increase whenever information can be recoded on the fly. The chunkable condition prompted the formation of chunks based on the perceived structure of color repetition within to-be-recalled sequences of colors. Our result shows a similar linear improvement of memory span with age for both chunkable and non-chunkable conditions. The amount of information retained in immediate memory systematically increased for the groupable sequences across all age groups, independently of the average age group span that was measured on sequences that contained fewer repetitions. This result shows that chunking gives young children an equal benefit as older children. We discuss the role of recoding in the expansion of capacity in immediate memory and the potential role of data compression in the formation of chunks in long-term memory. PMID- 26941677 TI - Multi-Vendor Loyalty Programs: Influencing Customer Behavioral Loyalty? AB - Loyalty programs are a consolidated marketing instrument whose adoption in many sectors has not been associated with appropriate comprehension of either their management elements or their effects. The purpose of this research is to contribute to knowledge about the effect of loyalty programs on repeat purchase behavior. More specifically, it seeks to discover whether joining a program changes the buying behavior of its members, and, if so, to study the profile of those whose behavior changes most. The intention was also to provide new study variables pertaining to multi-vendor loyalty programs, such as where they are joined or purchases in associated outlets as a result of behavioral loyalty. Research was carried out using a sample of 1200 individuals (31,746 purchases) belonging to a multi-vendor loyalty program. The study period was 13 years, 4 months, and split into two phases: before and after the joining the program. Different methodological approaches, such as the use of transactional databases that included pre-program-enrollment data and of the same sampling units throughout the study, were incorporated into the research with the aim of advancing academic knowledge regarding multi-vendor loyalty programs. Moreover, a type of program and market hardly dealt with in the relevant literature was analyzed. The results showed while the loyalty program had managed to reduce the time between purchases, it had not affected purchase volume or average expenditure. They also demonstrated the existence of a differential profile of customers who had changed their buying behavior to a greater extent. Finally, recency was identified as being the decisive variable in behavioral change. PMID- 26941676 TI - Yoga Training in Junior Primary School-Aged Children Has an Impact on Physical Self-Perceptions and Problem-Related Behavior. AB - The present pilot study investigated the effects of yoga training, as compared to physical skill training, on motor and executive function, physical self-concept, and anxiety-related behavior in junior primary school-aged children. Twenty-four participants with a mean age of 8.4 (+/-1.4) years completed either yoga or physical skill training twice a week for 6 weeks outside of regular school class time. Both forms of training were delivered in an individualized and child oriented manner. The type of training did not result in any significant differences in movement and executive function outcomes. In terms of physical self-concept, significant group differences were revealed only for perceived movement speed such that yoga training resulted in perceptions of being slower while physical skill training resulted in perceptions of moving faster. Analysis of anxiety related outcomes revealed significant group effects only for avoidance behavior and coping strategies. Avoidance behavior increased following yoga training, but decreased following physical skill training. In addition, following yoga training, children showed an increased use of divergent coping strategies when facing problematic situations while after physical skill training children demonstrated a decrease in use of divergent coping strategies. Changes in overall physical self-concept scores were not significantly correlated with changes in avoidance behavior following yoga training. In contrast, following physical skill training increased physical self-concept was significantly correlated with decreases in avoidance behavior. In sum, exposure to yoga or physical skill training appears to result in distinct effects for specific domains of physical self-concept and anxiety-related behavior. Further studies with larger samples and more rigorous methodologies are required to further investigate the effects reported here. With respect to future studies, we address potential research questions and specific features associated with the investigation of the effects of yoga in a sample of school-aged children. PMID- 26941678 TI - Discussing the Notion of Decent Work: Senses of Working for a Group of Brazilian Workers without College Education. AB - Despite recent stability and socioeconomic development, Brazil's history is marked by social inequality, informality, precarious work, and psychosocial vulnerability, with little opportunity for decent and meaningful work, as recommended by the International Labour Office (ILO), for people in the country. Nevertheless, based on a social constructionist view, the hypothesis can be raised that there is no substantive definition of decent work, but rather a psychosocial one, constructed based on the discourse, narratives, and practices produced through the relational processes which grant sense and meaning to work. Therefore, the examination of narratives and discourses is an important methodological strategy to understand the socio-occupational reality of Brazil. Thus, this study aims to understand the senses attributed to working through content analysis of the narratives produced by a set of 20 urban workers and contrast them with the ILO definition of decent work, in an effort to analyze the relationships, similarities, and differences between an established collective social discourse and the interviewees' singular narratives. The main results point out that the participants look for working with fair wages, social protection, safety, and personal development opportunities, as the ILO recommends. The main difference is that these characteristics do not derive from the State's actions, as in the employment and formal qualification model, but come from informal sources, such as family and community relationship networks. The informal relationship networks produce job opportunities as well as social protection; qualification takes place through practical learning from more experienced colleagues; the opportunity to be able to keep working (employed or working informally) leads to success and safety; and the possibility to make choices and have control over one's life translates into personal and occupational development. In conclusion, the participants searched for working according to the principles recommended by the ILO. Nevertheless, in contexts of vulnerability and with restricted support from the State, these principles are constructed in the community and not offered by the public power, which generates distinguished forms of decent work. PMID- 26941680 TI - Early Prosodic Acquisition in Bilingual Infants: The Case of the Perceptual Trochaic Bias. AB - Infants start learning the prosodic properties of their native language before 12 months, as shown by the emergence of a trochaic bias in English-learning infants between 6 and 9 months (Jusczyk et al., 1993), and in German-learning infants between 4 and 6 months (Hohle et al., 2009, 2014), while French-learning infants do not show a bias at 6 months (Hohle et al., 2009). This language-specific emergence of a trochaic bias is supported by the fact that English and German are languages with trochaic predominance in their lexicons, while French is a language with phrase-final lengthening but lacking lexical stress. We explored the emergence of a trochaic bias in bilingual French/German infants, to study whether the developmental trajectory would be similar to monolingual infants and whether amount of relative exposure to the two languages has an impact on the emergence of the bias. Accordingly, we replicated Hohle et al. (2009) with 24 bilingual 6-month-olds learning French and German simultaneously. All infants had been exposed to both languages for 30 to 70% of the time from birth. Using the Head Preference Procedure, infants were presented with two lists of stimuli, one made up of several occurrences of the pseudoword /GAba/ with word-initial stress (trochaic pattern), the second one made up of several occurrences of the pseudoword /gaBA/ with word-final stress (iambic pattern). The stimuli were recorded by a native German female speaker. Results revealed that these French/German bilingual 6-month-olds have a trochaic bias (as evidenced by a preference to listen to the trochaic pattern). Hence, their listening preference is comparable to that of monolingual German-learning 6-month-olds, but differs from that of monolingual French-learning 6-month-olds who did not show any preference (Hohle et al., 2009). Moreover, the size of the trochaic bias in the bilingual infants was not correlated with their amount of exposure to German. The present results thus establish that the development of a trochaic bias in simultaneous bilinguals is not delayed compared to monolingual German-learning infants (Hohle et al., 2009) and is rather independent of the amount of exposure to German relative to French. PMID- 26941679 TI - Using a Process Dissociation Approach to Assess Verbal Short-Term Memory for Item and Order Information in a Sample of Individuals with a Self-Reported Diagnosis of Dyslexia. AB - Previous studies have examined whether difficulties in short-term memory for verbal information, that might be associated with dyslexia, are driven by problems in retaining either information about to-be-remembered items or the order in which these items were presented. However, such studies have not used process-pure measures of short-term memory for item or order information. In this work we adapt a process dissociation procedure to properly distinguish the contributions of item and order processes to verbal short-term memory in a group of 28 adults with a self-reported diagnosis of dyslexia and a comparison sample of 29 adults without a dyslexia diagnosis. In contrast to previous work that has suggested that individuals with dyslexia experience item deficits resulting from inefficient phonological representation and language-independent order memory deficits, the results showed no evidence of specific problems in short-term retention of either item or order information among the individuals with a self reported diagnosis of dyslexia, despite this group showing expected difficulties on separate measures of word and non-word reading. However, there was some suggestive evidence of a link between order memory for verbal material and individual differences in non-word reading, consistent with other claims for a role of order memory in phonologically mediated reading. The data from the current study therefore provide empirical evidence to question the extent to which item and order short-term memory are necessarily impaired in dyslexia. PMID- 26941681 TI - Do You Know What I Know? The Impact of Participant Role in Children's Referential Communication. AB - For successful language use, interlocutors must be able to accurately assess their shared knowledge ("common ground"). Such knowledge can be accumulated through linguistic and non-linguistic context, but the same context can be associated with different patterns of knowledge, depending on the interlocutor's participant role (Wilkes-Gibbs and Clark, 1992). Although there is substantial evidence that children's ability to model partners' knowledge develops gradually, most such evidence focuses on non-linguistic context. We investigated the extent to which 8- to 10-year-old children can assess common ground developed through prior linguistic context, and whether this is sensitive to variations in participant role. Children repeatedly described tangram figures to another child, and then described the same figures to a third child who had been a side participant, an overhearer, or absent during the initial conversation. Children showed evidence of partner modeling, producing shorter referential expressions with repeated mention to the same partner. Moreover, they demonstrated sensitivity to differences in common ground with the third child based on participant role on some but not all measures (e.g., description length, but not definiteness). Our results suggest that by ten, children make distinctions about common ground accumulated through prior linguistic context but do not yet consistently deploy this knowledge in an adult-like way. PMID- 26941682 TI - Goal Attribution toward Non-Human Objects during Infancy Predicts Imaginary Companion Status during Preschool Years. AB - It has been shown that there is a significant relationship between children's mentalizing skills and creation of an imaginary companion (IC). Theorists have proposed that interaction with an IC may improve mentalizing skills, but it is also possible that children's mentalizing skills affect their creation of an IC. In this longitudinal study, we examined whether goal attribution in infants younger than 1 years old (Time 1) predicted their creation of ICs at 48 months old (Time 2). At Time 1, infants' goal attribution was measured in an action prediction experiment, where infants anticipated three types of action goals: (1) another person's goal-directed action (GH condition); (2) another person's non goal-directed (BH condition); and (3) a mechanical claw's goal-directed action (MC condition). At Time 2, parents completed questionnaires assessing whether their children had ICs. The path analyses using Bayesian estimation revealed that infants' anticipation in the MC condition, but not in the GH and BH conditions, predicted their later IC status. These results indicate that infants' goal attributions to non-human agents may be a strong predictor of their later IC creation. Early mentalizing skills toward non-human objects may provide children with a basis for their engagement in imaginative play. PMID- 26941683 TI - In Search of Oscillatory Traces of the Internal Clock. PMID- 26941684 TI - Anchoring in Numeric Judgments of Visual Stimuli. AB - This article investigates effects of anchoring in age estimation and estimation of quantities, two tasks which to different extents are based on visual stimuli. The results are compared to anchoring in answers to classic general knowledge questions that rely on semantic knowledge. Cognitive load was manipulated to explore possible differences between domains. Effects of source credibility, manipulated by differing instructions regarding the selection of anchor values (no information regarding anchor selection, information that the anchors are randomly generated or information that the anchors are answers from an expert) on anchoring were also investigated. Effects of anchoring were large for all types of judgments but were not affected by cognitive load or by source credibility in either one of the researched domains. A main effect of cognitive load on quantity estimations and main effects of source credibility in the two visually based domains indicate that the manipulations were efficient. Implications for theoretical explanations of anchoring are discussed. In particular, because anchoring did not interact with cognitive load, the results imply that the process behind anchoring in visual tasks is predominantly automatic and unconscious. PMID- 26941685 TI - The Relationship between Social and Motor Cognition in Primary School Age Children. AB - There is increased interest in the relationship between motor skills and social skills in child development, with evidence that the mechanisms underlying these behaviors may be linked. We took a cognitive approach to this problem, and examined the relationship between four specific cognitive domains: theory of mind, motor skill, action understanding, and imitation. Neuroimaging and adult research suggest that action understanding and imitation are closely linked, but are somewhat independent of theory of mind and low-level motor control. Here, we test if a similar pattern is shown in child development. A sample of 101 primary school aged children with a wide ability range completed tests of IQ (Raven's matrices), theory of mind, motor skill, action understanding, and imitation. Parents reported on their children's social, motor and attention performance as well as developmental concerns. The results showed that action understanding and imitation correlate, with the latter having a weak link to motor control. Theory of mind was independent of the other tasks. These results imply that independent cognitive processes for social interaction (theory of mind) and for motor control can be identified in primary school age children, and challenge approaches that link all these domains together. PMID- 26941686 TI - The Egocentric Nature of Action-Sound Associations. AB - Actions that produce sounds infuse our daily lives. Some of these sounds are a natural consequence of physical interactions (such as a clang resulting from dropping a pan), but others are artificially designed (such as a beep resulting from a keypress). Although the relationship between actions and sounds has previously been examined, the frame of reference of these associations is still unknown, despite it being a fundamental property of a psychological representation. For example, when an association is created between a keypress and a tone, it is unclear whether the frame of reference is egocentric (gesture sound association) or exocentric (key-sound association). This question is especially important for artificially created associations, which occur in technology that pairs sounds with actions, such as gestural interfaces, virtual or augmented reality, and simple buttons that produce tones. The frame of reference could directly influence the learnability, the ease of use, the extent of immersion, and many other factors of the interaction. To explore whether action-sound associations are egocentric or exocentric, an experiment was implemented using a computer keyboard's number pad wherein moving a finger from one key to another produced a sound, thus creating an action-sound association. Half of the participants received egocentric instructions to move their finger with a particular gesture. The other half of the participants received exocentric instructions to move their finger to a particular number on the keypad. All participants were performing the same actions, and only the framing of the action varied between conditions by altering task instructions. Participants in the egocentric condition learned the gesture-sound association, as revealed by a priming paradigm. However, the exocentric condition showed no priming effects. This finding suggests that action-sound associations are egocentric in nature. A second part of the same session further confirmed the egocentric nature of these associations by showing no change in the priming effect after moving to a different starting location. Our findings are consistent with an egocentric representation of action-sound associations, which could have implications for applications that utilize these associations. PMID- 26941687 TI - The Money Buffer Effect in China: A Higher Income Cannot Make You Much Happier but Might Allow You to Worry Less. AB - This study examined the possibility that there is a curvilinear relationship between income and subjective well-being in China. This study also investigated whether this curvilinear relationship is moderated by social class and mediated by respondents' material affluence. The study was conducted in China, and the sample consisted of 900 blue-collar workers and 546 white-collar workers. The results for emotional well-being showed that income significantly predicted negative affect but not positive affect. This finding indicates that in China, high incomes may not make people happier but might allow them to worry less, which we call the "money buffer effect." The results also showed that material affluence mediates the interaction effect between income and social class on subjective well-being. The implications of these results for future research and practice are discussed. PMID- 26941689 TI - Forest, Trees, Dynamics: Results from a Novel Wisconsin Card Sorting Test Variant Protocol for Studying Global-Local Attention and Complex Cognitive Processes. AB - BACKGROUND: Recognition of objects and their context relies heavily on the integrated functioning of global and local visual processing. In a realistic setting such as work, this processing becomes a sustained activity, implying a consequent interaction with executive functions. MOTIVATION: There have been many studies of either global-local attention or executive functions; however it is relatively novel to combine these processes to study a more ecological form of attention. We aim to explore the phenomenon of global-local processing during a task requiring sustained attention and working memory. METHODS: We develop and test a novel protocol for global-local dissociation, with task structure including phases of divided ("rule search") and selective ("rule found") attention, based on the Wisconsin Card Sorting Task (WCST). We test it in a laboratory study with 25 participants, and report on behavior measures (physiological data was also gathered, but not reported here). We develop novel stimuli with more naturalistic levels of information and noise, based primarily on face photographs, with consequently more ecological validity. RESULTS: We report behavioral results indicating that sustained difficulty when participants test their hypotheses impacts matching-task performance, and diminishes the global precedence effect. RESULTS also show a dissociation between subjectively experienced difficulty and objective dimension of performance, and establish the internal validity of the protocol. Contribution: We contribute an advance in the state of the art for testing global-local attention processes in concert with complex cognition. With three results we establish a connection between global local dissociation and aspects of complex cognition. Our protocol also improves ecological validity and opens options for testing additional interactions in future work. PMID- 26941688 TI - A Metaanalysis of Perceptual Organization in Schizophrenia, Schizotypy, and Other High-Risk Groups Based on Variants of the Embedded Figures Task. AB - Current research on perceptual organization in schizophrenia frequently employs shapes with regularly sampled contours (fragmented stimuli), in noise fields composed of similar elements, to elicit visual abnormalities. However, perceptual organization is multi-factorial and, in earlier studies, continuous contours have also been employed in tasks assessing the ability to extract shapes from a background. We conducted a systematic review and meta-analysis of studies using closed-contour stimuli, including the Embedded Figures Test (EFT) and related tasks, both in people with schizophrenia and in healthy schizotypes and relatives, considered at increased risk for psychosis. Eleven studies met the selection criteria for inclusion in the meta-analysis, including six that used a between-groups study design (i.e., perceptual organization abilities of schizophrenia/high-risk groups were compared to healthy or clinical controls), and five that treated schizophrenia symptoms or schizotypy traits and indices of perceptual organization as continuous variables. Effect sizes and heterogeneity statistics were calculated, and the risk of publication bias was explored. A significant, moderate effect for EFT performance was found with studies that compared performance of schizophrenia/high-risk groups to a healthy or patient comparison group (d = -0.523, p < 0.001). However, significant heterogeneity was also found amongst the schizotypy, but not schizophrenia studies, as well as studies using accuracy, but not reaction time as a measure of performance. A non significant correlation was found for the studies that examined schizophrenia symptoms or schizotypy traits as continuous variables (r = 0.012, p = 0.825). These results suggest that deficits in perceptual organization of non-fragmented stimuli are found when differences between schizophrenia/high-risk groups and comparison groups are maximized. These findings should motivate further investigation of perceptual organization abilities with closed-contour stimuli both in schizophrenia and high-risk groups, which is pertinent to current initiatives to improve the assessment and treatment of cognition in schizophrenia. PMID- 26941690 TI - The Elaborated Environmental Stress Hypothesis as a Framework for Understanding the Association Between Motor Skills and Internalizing Problems: A Mini-Review. AB - Poor motor skills have been shown to be associated with a range of psychosocial issues, including internalizing problems (anxiety and depression). While well documented empirically, our understanding of why this relationship occurs remains theoretically underdeveloped. The Elaborated Environmental Stress Hypothesis by Cairney et al. (2013) provides a promising framework that seeks to explain the association between motor skills and internalizing problems, specifically in children with developmental coordination disorder (DCD). The framework posits that poor motor skills predispose the development of internalizing problems via interactions with intermediary environmental stressors. At the time the model was proposed, limited direct evidence was available to support or refute the framework. Several studies and developments related to the framework have since been published. This mini-review seeks to provide an up-to-date overview of recent developments related to the Elaborated Environmental Stress Hypothesis. We briefly discuss the past research that led to its development, before moving to studies that have investigated the framework since it was proposed. While originally developed within the context of DCD in childhood, recent developments have found support for the model in community samples. Through the reviewed literature, this article provides support for the Elaborated Environmental Stress Hypothesis as a promising theoretical framework that explains the psychosocial correlates across the broader spectrum of motor ability. However, given its recent conceptualization, ongoing evaluation of the Elaborated Environmental Stress Hypothesis is recommended. PMID- 26941691 TI - Impressive Words: Linguistic Predictors of Public Approval of the U.S. Congress. AB - What type of language makes the most positive impression within a professional setting? Is competent/agentic language or warm/communal language more effective at eliciting social approval? We examined this basic social cognitive question in a real world context using a "big data" approach-the recent record-low levels of public approval of the U.S. Congress. Using Linguistic Inquiry and Word Count (LIWC), we text analyzed all 123+ million words spoken by members of the U.S. House of Representatives during floor debates between 1996 and 2014 and compared their usage of various classes of words to their public approval ratings over the same time period. We found that neither agentic nor communal language positively predicted public approval. However, this may be because communion combines two disparate social motives (belonging and helping). A follow-up analysis found that the helping form of communion positively predicted public approval, and did so more strongly than did agentic language. Next, we conducted an exploratory analysis, examining which of the 63 standard LIWC categories predict public approval. We found that the public approval of Congress was highest when politicians used tentative language, expressed both positive emotion and anxiety, and used human words, numbers, prepositions, numbers, and avoided conjunctions and the use of second-person pronouns. These results highlight the widespread primacy of warmth over competence as the primary dimensions of social cognition. PMID- 26941693 TI - Undetectable Changes in Image Resolution of Luminance-Contrast Gradients Affect Depth Perception. AB - A great number of studies have suggested a variety of ways to get depth information from two dimensional images such as binocular disparity, shape-from shading, size gradient/foreshortening, aerial perspective, and so on. Are there any other new factors affecting depth perception? A recent psychophysical study has investigated the correlation between image resolution and depth sensation of Cylinder images (A rectangle contains gradual luminance-contrast changes.). It was reported that higher resolution images facilitate depth perception. However, it is still not clear whether or not the finding generalizes to other kinds of visual stimuli, because there are more appropriate visual stimuli for exploration of depth perception of luminance-contrast changes, such as Gabor patch. Here, we further examined the relationship between image resolution and depth perception by conducting a series of psychophysical experiments with not only Cylinders but also Gabor patches having smoother luminance-contrast gradients. As a result, higher resolution images produced stronger depth sensation with both images. This finding suggests that image resolution affects depth perception of simple luminance-contrast differences (Gabor patch) as well as shape-from-shading (Cylinder). In addition, this phenomenon was found even when the resolution difference was undetectable. This indicates the existence of consciously available and unavailable information in our visual system. These findings further support the view that image resolution is a cue for depth perception that was previously ignored. It partially explains the unparalleled viewing experience of novel high resolution displays. PMID- 26941692 TI - 'Syntactic Perturbation' During Production Activates the Right IFG, but not Broca's Area or the ATL. AB - Research on the neural organization of syntax - the core structure-building component of language - has focused on Broca's area and the anterior temporal lobe (ATL) as the chief candidates for syntactic processing. However, these proposals have received considerable challenges. In order to better understand the neural basis of syntactic processing, we performed a functional magnetic resonance imaging experiment using a constrained sentence production task. We examined the BOLD response to sentence production for active and passive sentences, unstructured word lists, and syntactic perturbation. Perturbation involved cued restructuring of the planned syntax of a sentence mid utterance. Perturbation was designed to capture the effects of syntactic violations previously studied in sentence comprehension. Our experiment showed that Broca's area and the ATL did not exhibit response profiles consistent with syntactic operations - we found no increase of activation in these areas for sentences > lists or for perturbation. Syntactic perturbation activated a cortical subcortical network including robust activation of the right inferior frontal gyrus (RIFG). This network is similar to one previously shown to be involved in motor response inhibition. We hypothesize that RIFG activation in our study and in previous studies of sentence comprehension is due to an inhibition mechanism that may facilitate efficient syntactic restructuring. PMID- 26941694 TI - Scientific Content Analysis (SCAN) Cannot Distinguish Between Truthful and Fabricated Accounts of a Negative Event. AB - The Scientific Content Analysis (SCAN) is a verbal veracity assessment method that is currently used worldwide by investigative authorities. Yet, research investigating the accuracy of SCAN is scarce. The present study tested whether SCAN was able to accurately discriminate between true and fabricated statements. To this end, 117 participants were asked to write down one true and one fabricated statement about a recent negative event that happened in their lives. All statements were analyzed using 11 criteria derived from SCAN. Results indicated that SCAN was not able to correctly classify true and fabricated statements. Lacking empirical support, the application of SCAN in its current form should be discouraged. PMID- 26941695 TI - Probing the Cultural Constitution of Causal Cognition - A Research Program. AB - To what extent is the way people perceive, represent, and reason about causal relationships dependent on culture? While there have been sporadic attempts to explore this question, a systematic investigation is still lacking. Here, we propose that human causal cognition is not only superficially affected by cultural background, but that it is co-constituted by the cultural nature of the human species. To this end, we take stock of on-going research, with a particular focus on the methodological approaches taken: cross-species comparisons, archeological accounts, developmental studies, cross-cultural, and cross linguistic experiments, as well as in-depth within-culture analyses of cognitive concepts, processes, and changes over time. We argue that only a combination of these approaches will allow us to integrate different components of cognition, levels of analysis, and points of view-the key requirements for a comprehensive, interdisciplinary research program to advance this field. PMID- 26941696 TI - Cross-Domain Statistical-Sequential Dependencies Are Difficult to Learn. AB - Recent studies have demonstrated participants' ability to learn cross-modal associations during statistical learning tasks. However, these studies are all similar in that the cross-modal associations to be learned occur simultaneously, rather than sequentially. In addition, the majority of these studies focused on learning across sensory modalities but not across perceptual categories. To test both cross-modal and cross-categorical learning of sequential dependencies, we used an artificial grammar learning task consisting of a serial stream of auditory and/or visual stimuli containing both within- and cross-domain dependencies. Experiment 1 examined within-modal and cross-modal learning across two sensory modalities (audition and vision). Experiment 2 investigated within categorical and cross-categorical learning across two perceptual categories within the same sensory modality (e.g., shape and color; tones and non-words). Our results indicated that individuals demonstrated learning of the within-modal and within-categorical but not the cross-modal or cross-categorical dependencies. These results stand in contrast to the previous demonstrations of cross-modal statistical learning, and highlight the presence of modality constraints that limit the effectiveness of learning in a multimodal environment. PMID- 26941697 TI - Temporal Distinctiveness in Task Switching: Assessing the Mixture-Distribution Assumption. AB - In task switching, increasing the response-cue interval has been shown to reduce the switch cost. This has been attributed to a time-based decay process influencing the activation of memory representations of tasks (task-sets). Recently, an alternative account based on interference rather than decay has been successfully applied to this data (Horoufchin et al., 2011a). In this account, variation of the RCI is thought to influence the temporal distinctiveness (TD) of episodic traces in memory, thus affecting their retrieval probability. This can affect performance as retrieval probability influences response time: If retrieval succeeds, responding is fast due to positive priming; if retrieval fails, responding is slow, due to having to perform the task via a slow algorithmic process. This account-and a recent formal model (Grange and Cross, 2015)-makes the strong prediction that all RTs are a mixture of one of two processes: a fast process when retrieval succeeds, and a slow process when retrieval fails. The present paper assesses the evidence for this mixture distribution assumption in TD data. In a first section, statistical evidence for mixture-distributions is found using the fixed-point property test. In a second section, a mathematical process model with mixture-distributions at its core is fitted to the response time distribution data. Both approaches provide good evidence in support of the mixture-distribution assumption, and thus support temporal distinctiveness accounts of the data. PMID- 26941698 TI - Training of Dental Professionals in Motivational Interviewing can Heighten Interdental Cleaning Self-Efficacy in Periodontal Patients. AB - BACKGROUND: The success of periodontal therapy depends on the adherence of patients to professional recommendations. The aim of this study was to investigate the influence of a workshop in motivational interviewing (MI) on non surgical periodontal treatment performed by dental students. MATERIALS AND METHODS: In the experimental group patients with periodontitis were treated by students trained in MI, while in the control group patients were treated by students who had not been trained in MI. Clinical oral parameters were assessed by a blinded periodontist in addition to the evaluation of psychological questionnaires given before and after the non-surgical periodontal treatment (6 months). Conversations between patients and students were recorded and rated with the Motivational Treatment Integrity Code (MITI-d) by a blinded psychologist. RESULTS: There were 73 patients in the MI group and 99 patients in the control group. The MI group showed significantly higher scores in the MITI-d analysis. Regression analysis showed that there were no significant differences between groups with regard to plaque level, gingival bleeding, pocket depth reduction or bleeding upon probing. However, patients in the MI-group showed significantly higher interdental cleaning self-efficacy than patients in the control group (MI = 19.57 +/- 4.7; control = 17.38 +/- 6.01; p = 0.016). CONCLUSION: Teaching MI to dental students resulted in a significant improvement in the self-efficacy of interdental cleaning in patients compared to a control group of non-trained students, but no improvement in other aspects of non-surgical periodontal therapy. The study also showed that an 8-h workshop with supervision significantly improved the MI-compliant conversations of dental students without requiring more conversation time. PMID- 26941699 TI - Investigating the Impact of Item Parameter Drift for Item Response Theory Models with Mixture Distributions. AB - This study investigates the impact of item parameter drift (IPD) on parameter and ability estimation when the underlying measurement model fits a mixture distribution, thereby violating the item invariance property of unidimensional item response theory (IRT) models. An empirical study was conducted to demonstrate the occurrence of both IPD and an underlying mixture distribution using real-world data. Twenty-one trended anchor items from the 1999, 2003, and 2007 administrations of Trends in International Mathematics and Science Study (TIMSS) were analyzed using unidimensional and mixture IRT models. TIMSS treats trended anchor items as invariant over testing administrations and uses pre calibrated item parameters based on unidimensional IRT. However, empirical results showed evidence of two latent subgroups with IPD. Results also showed changes in the distribution of examinee ability between latent classes over the three administrations. A simulation study was conducted to examine the impact of IPD on the estimation of ability and item parameters, when data have underlying mixture distributions. Simulations used data generated from a mixture IRT model and estimated using unidimensional IRT. Results showed that data reflecting IPD using mixture IRT model led to IPD in the unidimensional IRT model. Changes in the distribution of examinee ability also affected item parameters. Moreover, drift with respect to item discrimination and distribution of examinee ability affected estimates of examinee ability. These findings demonstrate the need to caution and evaluate IPD using a mixture IRT framework to understand its effects on item parameters and examinee ability. PMID- 26941701 TI - Sex Differences in Using Spatial and Verbal Abilities Influence Route Learning Performance in a Virtual Environment: A Comparison of 6- to 12-Year Old Boys and Girls. AB - Previous studies have reported sex differences in wayfinding performance among adults. Men are typically better at using Euclidean information and survey strategies while women are better at using landmark information and route strategies. However, relatively few studies have examined sex differences in wayfinding in children. This research investigated relationships between route learning performance and two general abilities: spatial ability and verbal memory in 153 boys and girls between 6- to 12-years-old. Children completed a battery of spatial ability tasks (a two-dimension mental rotation task, a paper folding task, a visuo-spatial working memory task, and a Piagetian water level task) and a verbal memory task. In the route learning task, they had to learn a route through a series of hallways presented via computer. Boys had better overall route learning performance than did girls. In fact, the difference between boys and girls was constant across the age range tested. Structural equation modeling of the children's performance revealed that spatial abilities and verbal memory were significant contributors to route learning performance. However, there were different patterns of correlates for boys and girls. For boys, spatial abilities contributed to route learning while verbal memory did not. In contrast, for girls both spatial abilities and verbal memory contributed to their route learning performance. This difference may reflect the precursor of a strategic difference between boys and girls in wayfinding that is commonly observed in adults. PMID- 26941700 TI - Investigation of the Phenomenological and Psychopathological Features of Trichotillomania in an Italian Sample. AB - Trichotillomania (TTM) is still a scarcely known and often inadequately treated disorder in Italian clinical settings, despite growing evidence about its severe and disabling consequences. The current study investigated the phenomenology of TTM in Italian individuals; in addition, we sought to examine patterns of self esteem, anxiety, depression, and OCD-related symptoms in individuals with TTM compared to healthy participants. The current study represents the first attempt to investigate the phenomenological and psychopathological features of TTM in Italian hair pullers. One hundred and twenty-two individuals with TTM were enrolled: 24 were assessed face-to-face (face-to-face group) and 98 were recruited online (online group). An additional group of 22 face-to-face assessed healthy controls (HC group) was included in the study. The overall female to male ratio was 14:1, which is slightly higher favoring female than findings reported in literature. Main results revealed that a higher percentage of individuals in the online group reported pulling from the pubic region than did face-to-face participants; furthermore, the former engaged in examining the bulb and running the hair across the lips and reported pulling while lying in bed at higher frequencies than the latter. Interestingly, the online TTM group showed greater functional and psychological impairment, as well as more severe psychopathological characteristics (self-esteem, physiological and social anxiety, perfectionism, overestimation of threat, and control of thoughts), than the face-to-face one. Differences between the two TTM groups may be explained by the anonymity nature of the online group, which may have led to successful recruitment of more serious TTM cases, or fostered more open answers to questions. Overall, results revealed that many of the phenomenological features of Italian TTM participants matched those found in U.S. clinical settings, even though some notable differences were observed; therefore, cross-cultural invariance might represent a characteristic of OCD-related disorders. PMID- 26941702 TI - Commentary: Playing the computer game tetris prior to viewing traumatic film material and subsequent intrusive memories: examining proactive interference. PMID- 26941703 TI - Do Political and Economic Choices Rely on Common Neural Substrates? A Systematic Review of the Emerging Neuropolitics Literature. AB - The methods of cognitive neuroscience are beginning to be applied to the study of political behavior. The neural substrates of value-based decision-making have been extensively examined in economic contexts; this might provide a powerful starting point for understanding political decision-making. Here, we asked to what extent the neuropolitics literature to date has used conceptual frameworks and experimental designs that make contact with the reward-related approaches that have dominated decision neuroscience. We then asked whether the studies of political behavior that can be considered in this light implicate the brain regions that have been associated with subjective value related to "economic" reward. We performed a systematic literature review to identify papers addressing the neural substrates of political behavior and extracted the fMRI studies reporting behavioral measures of subjective value as defined in decision neuroscience studies of reward. A minority of neuropolitics studies met these criteria and relatively few brain activation foci from these studies overlapped with regions where activity has been related to subjective value. These findings show modest influence of reward-focused decision neuroscience on neuropolitics research to date. Whether the neural substrates of subjective value identified in economic choice paradigms generalize to political choice thus remains an open question. We argue that systematically addressing the commonalities and differences in these two classes of value-based choice will be important in developing a more comprehensive model of the brain basis of human decision making. PMID- 26941704 TI - The Impact of Bilingualism on Working Memory: A Null Effect on the Whole May Not Be So on the Parts. PMID- 26941705 TI - Mind Invasion: Situated Affectivity and the Corporate Life Hack. AB - In view of the philosophical problems that vex the debate on situated affectivity, it can seem wise to focus on simple cases. Accordingly, theorists often single out scenarios in which an individual employs a device in order to enhance their emotional experience, or to achieve new kinds of experience altogether, such as playing an instrument, going to the movies, or sporting a fancy handbag. I argue that this narrow focus on cases that fit a "user/resource model" tends to channel attention away from more complex and also more problematic instances of situated affectivity. Among these are scenarios in which a social domain draws individuals into certain modes of affective interaction, often by way of attunement and habituation to affective styles and interaction patterns that are normative in the domain in question. This can lead to a phenomenon that is not so much "mind extension" than "mind invasion": affectivity is dynamically framed and modulated from without, often contrary to the prior orientations of the individuals in question. As an example, I discuss affective patterns prevalent in today's corporate workplace. I claim that workplace affect sometimes contributes to what is effectively a "hack" of employees' subjectivity. PMID- 26941706 TI - Editorial: Understanding Social Signals: How Do We Recognize the Intentions of Others? PMID- 26941707 TI - The Effect of Dopaminergic Medication on Beat-Based Auditory Timing in Parkinson's Disease. AB - Parkinson's disease (PD) adversely affects timing abilities. Beat-based timing is a mechanism that times events relative to a regular interval, such as the "beat" in musical rhythm, and is impaired in PD. It is unknown if dopaminergic medication influences beat-based timing in PD. Here, we tested beat-based timing over two sessions in participants with PD (OFF then ON dopaminergic medication) and in unmedicated control participants. People with PD and control participants completed two tasks. The first was a discrimination task in which participants compared two rhythms and determined whether they were the same or different. Rhythms either had a beat structure (metric simple rhythms) or did not (metric complex rhythms), as in previous studies. Discrimination accuracy was analyzed to test for the effects of beat structure, as well as differences between participants with PD and controls, and effects of medication (PD group only). The second task was the Beat Alignment Test (BAT), in which participants listened to music with regular tones superimposed, and responded as to whether the tones were "ON" or "OFF" the beat of the music. Accuracy was analyzed to test for differences between participants with PD and controls, and for an effect of medication in patients. Both patients and controls discriminated metric simple rhythms better than metric complex rhythms. Controls also improved at the discrimination task in the second vs. first session, whereas people with PD did not. For participants with PD, the difference in performance between metric simple and metric complex rhythms was greater (sensitivity to changes in simple rhythms increased and sensitivity to changes in complex rhythms decreased) when ON vs. OFF medication. Performance also worsened with disease severity. For the BAT, no group differences or effects of medication were found. Overall, these findings suggest that timing is impaired in PD, and that dopaminergic medication influences beat-based and non-beat-based timing differently. Judging the beat in music does not appear to be affected by PD or by dopaminergic medication. PMID- 26941708 TI - Opportunities for Guided Multichannel Non-invasive Transcranial Current Stimulation in Poststroke Rehabilitation. AB - Stroke is a leading cause of serious long-term disability worldwide. Functional outcome depends on stroke location, severity, and early intervention. Conventional rehabilitation strategies have limited effectiveness, and new treatments still fail to keep pace, in part due to a lack of understanding of the different stages in brain recovery and the vast heterogeneity in the poststroke population. Innovative methodologies for restorative neurorehabilitation are required to reduce long-term disability and socioeconomic burden. Neuroplasticity is involved in poststroke functional disturbances and also during rehabilitation. Tackling poststroke neuroplasticity by non-invasive brain stimulation is regarded as promising, but efficacy might be limited because of rather uniform application across patients despite individual heterogeneity of lesions, symptoms, and other factors. Transcranial direct current stimulation (tDCS) induces and modulates neuroplasticity, and has been shown to be able to improve motor and cognitive functions. tDCS is suited to improve poststroke rehabilitation outcomes, but effect sizes are often moderate and suffer from variability. Indeed, the location, extent, and pattern of functional network connectivity disruption should be considered when determining the optimal location sites for tDCS therapies. Here, we present potential opportunities for neuroimaging-guided tDCS based rehabilitation strategies after stroke that could be personalized. We introduce innovative multimodal intervention protocols based on multichannel tDCS montages, neuroimaging methods, and real-time closed-loop systems to guide therapy. This might help to overcome current treatment limitations in poststroke rehabilitation and increase our general understanding of adaptive neuroplasticity leading to neural reorganization after stroke. PMID- 26941709 TI - Peptidylarginine Deiminases as Drug Targets in Neonatal Hypoxic-Ischemic Encephalopathy. AB - Oxygen deprivation and infection are major causes of perinatal brain injury leading to cerebral palsy and other neurological disabilities. The identification of novel key factors mediating white and gray matter damage are crucial to allow better understanding of the specific contribution of different cell types to the injury processes and pathways for clinical intervention. Recent studies in the Rice-Vannucci mouse model of neonatal hypoxic ischemia (HI) have highlighted novel roles for calcium-regulated peptidylarginine deiminases (PADs) and demonstrated neuroprotective effects of pharmacological PAD inhibition following HI and synergistic infection mimicked by lipopolysaccharide stimulation. PMID- 26941710 TI - Preliminary Findings Show Maternal Hypothyroidism May Contribute to Abnormal Cortical Morphology in Offspring. AB - In rodents, insufficient thyroid hormone (TH) gestationally has adverse effects on cerebral cortex development. Comparable studies of humans examining how TH insufficiency affects cortical morphology are limited to children with congenital hypothyroidism or offspring of hypothyroxinemic women; effects on cortex of children born to women with clinically diagnosed hypothyroidism are not known. We studied archived MRI scans from 22 children aged 10-12 years born to women treated for preexisting or de novo hypothyroidism in pregnancy (HYPO) and 24 similar age and sex controls from euthyroid women. FreeSurfer Image Analysis Suite software was used to measure cortical thickness (CT) and a vertex-based approach served to compare HYPO versus control groups and Severe versus Mild HYPO subgroups as well as to perform regression analyses examining effects of trimester-specific maternal TSH on CT. Results showed that relative to controls, HYPO had multiple regions of both cortical thinning and thickening, which differed for left and right hemispheres. In HYPO, thinning was confined to medial and mid-lateral regions of each hemisphere and thickening to superior regions (primarily frontal) of the left hemisphere and inferior regions (particularly occipital and temporal) of the right. The Severe HYPO subgroup showed more thinning than Mild in frontal and temporal regions and more thickening in bilateral posterior and frontal regions. Maternal TSH values predicted degree of thinning and thickening within multiple brain regions, with the pattern and direction of correlations differing by trimester. Notably, some correlations remained when cases born to women with severe hypothyroidism were removed from the analyses, suggesting that mild variations of maternal TH may permanently affect offspring cortex. We conclude that maternal hypothyroidism during pregnancy has long-lasting manifestations on the cortical morphology of their offspring with specific effects reflecting both severity and timing of maternal TH insufficiency. PMID- 26941711 TI - Physiological Properties and Genome Structure of the Hyperthermophilic Filamentous Phage phiOH3 Which Infects Thermus thermophilus HB8. AB - A filamentous bacteriophage, phiOH3, was isolated from hot spring sediment in Obama hot spring in Japan with the hyperthermophilic bacterium Thermus thermophilus HB8 as its host. Phage phiOH3, which was classified into the Inoviridae family, consists of a flexible filamentous particle 830 nm long and 8 nm wide. phiOH3 was stable at temperatures ranging from 70 to 90 degrees C and at pHs ranging from 6 to 9. A one-step growth curve of the phage showed a 60-min latent period beginning immediately postinfection, followed by intracellular virus particle production during the subsequent 40 min. The released virion number of phiOH3 was 109. During the latent period, both single stranded DNA (ssDNA) and the replicative form (RF) of phage DNA were multiplied from min 40 onward. During the release period, the copy numbers of both ssDNA and RF DNA increased sharply. The size of the phiOH3 genome is 5688 bp, and eight putative open reading frames (ORFs) were annotated. These ORFs were encoded on the plus strand of RF DNA and showed no significant homology with any known phage genes, except ORF 5, which showed 60% identity with the gene VIII product of the Thermus filamentous phage PH75. All the ORFs were similar to predicted genes annotated in the Thermus aquaticus Y51MC23 and Meiothermus timidus DSM 17022 genomes at the amino acid sequence level. This is the first report of the whole genome structure and DNA multiplication of a filamentous T. thermophilus phage within its host cell. PMID- 26941712 TI - Viral Outbreak in Corals Associated with an In Situ Bleaching Event: Atypical Herpes-Like Viruses and a New Megavirus Infecting Symbiodinium. AB - Previous studies of coral viruses have employed either microscopy or metagenomics, but few have attempted to comprehensively link the presence of a virus-like particle (VLP) to a genomic sequence. We conducted transmission electron microscopy imaging and virome analysis in tandem to characterize the most conspicuous viral types found within the dominant Pacific reef-building coral genus Acropora. Collections for this study inadvertently captured what we interpret as a natural outbreak of viral infection driven by aerial exposure of the reef flat coincident with heavy rainfall and concomitant mass bleaching. All experimental corals in this study had high titers of viral particles. Three of the dominant VLPs identified were observed in all tissue layers and budding out from the epidermis, including viruses that were ~70, ~120, and ~150 nm in diameter; these VLPs all contained electron dense cores. These morphological traits are reminiscent of retroviruses, herpesviruses, and nucleocytoplasmic large DNA viruses (NCLDVs), respectively. Some 300-500 nm megavirus-like VLPs also were observed within and associated with dinoflagellate algal endosymbiont (Symbiodinium) cells. Abundant sequence similarities to a gammaretrovirus, herpesviruses, and members of the NCLDVs, based on a virome generated from five Acropora aspera colonies, corroborated these morphology-based identifications. Additionally sequence similarities to two diagnostic genes, a MutS and (based on re-annotation of sequences from another study) a DNA polymerase B gene, most closely resembled Pyramimonas orientalis virus, demonstrating the association of a cosmopolitan megavirus with Symbiodinium. We also identified several other virus-like particles in host tissues, along with sequences phylogenetically similar to circoviruses, phages, and filamentous viruses. This study suggests that viral outbreaks may be a common but previously undocumented component of natural bleaching events, particularly following repeated episodes of multiple environmental stressors. PMID- 26941713 TI - Hydrogen Production and Enzyme Activities in the Hyperthermophile Thermococcus paralvinellae Grown on Maltose, Tryptone, and Agricultural Waste. AB - Thermococcus may be an important alternative source of H2 in the hot subseafloor in otherwise low H2 environments such as some hydrothermal vents and oil reservoirs. It may also be useful in industry for rapid agricultural waste treatment and concomitant H2 production. Thermococcus paralvinellae grown at 82 degrees C without sulfur produced up to 5 mmol of H2 L(-1) at rates of 5-36 fmol H2 cell(-1) h(-1) on 0.5% (wt vol(-1)) maltose, 0.5% (wt vol(-1)) tryptone, and 0.5% maltose + 0.05% tryptone media. Two potentially inhibiting conditions, the presence of 10 mM acetate and low pH (pH 5) in maltose-only medium, did not significantly affect growth or H2 production. Growth rates, H2 production rates, and cell yields based on H2 production were the same as those for Pyrococcus furiosus grown at 95 degrees C on the same media for comparison. Acetate, butyrate, succinate, isovalerate, and formate were also detected as end products. After 100 h, T. paralvinellae produced up to 5 mmol of H2 L(-1) of medium when grown on up to 70% (vol vol(-1)) waste milk from cows undergoing treatment for mastitis with the bacterial antibiotic Ceftiofur and from untreated cows. The amount of H2 produced by T. paralvinellae increased with increasing waste concentrations, but decreased in P. furiosus cultures supplemented with waste milk above 1% concentration. All mesophilic bacteria from the waste milk that grew on Luria Bertani, Sheep's Blood (selective for Staphylococcus, the typical cause of mastitis), and MacConkey (selective for Gram-negative enteric bacteria) agar plates were killed by heat during incubation at 82 degrees C. Ceftiofur, which is heat labile, was below the detection limit following incubation at 82 degrees C. T. paralvinellae also produced up to 6 mmol of H2 L(-1) of medium when grown on 0.1-10% (wt vol(-1)) spent brewery grain while P. furiosus produced < 1 mmol of H2 L(-1). Twelve of 13 enzyme activities in T. paralvinellae showed significant (p < 0.05) differences across six different growth conditions; however, methyl viologen-dependent membrane hydrogenase activity remained constant across all media types. The results demonstrate the potential of at least some Thermococcus species to produce H2 if protein and alpha-glucosides are present as substrates. PMID- 26941714 TI - New Insights into the Microbiota of the Svalbard Reindeer Rangifer tarandus platyrhynchus. AB - Svalbard reindeer (Rangifer tarandus platyrhynchus) is a non-migratory subspecies of reindeer inhabiting the high-arctic archipelago of Svalbard. In contrast to other Rangifer tarandus subspecies, Svalbard reindeer graze exclusively on natural sources of food and have no chance of ingestion of any crops. We report the use of a non-invasive method for analysis of fecal microbiome by means of sequencing the 16S rDNA extracted from the fecal microbiota of R. tarandus platyrhynchus from a small, isolated population in Hornsund, South Spitsbergen National Park. Analyses of all samples showed that 99% of the total reads were represented by Bacteria. Taxonomy-based analysis showed that fecal bacterial communities consisted of 14 phyla. The most abundant phyla across the population were Firmicutes and Bacteroidetes, and those phyla jointly accounted for more than 95% of total bacterial sequences (ranging between 90.14 and 98.19%). Specifically, Firmicutes comprised 56.53% (42.98-63.64%) and Bacteroidetes comprised 39.17% (34.56-47.16%) of the total reads. The remaining 5% of the population reads comprised of Tenericutes, Cyanobacteria, TM7, Actinobacteria, Proteobacteria, Verrucomicrobia, Elusimicrobia, Planctomycetes, Fibrobacteres, Spirochaetes, Chloroflexi, and Deferribacteres. Differences in the fecal bacteria composition between particular reindeer were not statistically significant which may reflect the restricted location and similar diet of all members of the local population. PMID- 26941715 TI - bla CTX-M-152, a Novel Variant of CTX-M-group-25, Identified in a Study Performed on the Prevalence of Multidrug Resistance among Natural Inhabitants of River Yamuna, India. AB - Natural environment influenced by anthropogenic activities creates selective pressure for acquisition and spread of resistance genes. In this study, we determined the prevalence of Extended Spectrum beta-Lactamases producing gram negative bacteria from the River Yamuna, India, and report the identification and characterization of a novel CTX-M gene variant bla CTX-M-152 . Of the total 230 non-duplicate isolates obtained from collected water samples, 40 isolates were found positive for ESBL production through Inhibitor-Potentiation Disc Diffusion test. Based on their resistance profile, 3% were found exhibiting pandrug resistance (PDR), 47% extensively drug resistance (XDR), and remaining 50% showing multidrug resistant (MDR). Following screening and antimicrobial profiling, characterization of ESBLs (bla TEM and bla CTX-M ), and mercury tolerance determinants (merP, merT, and merB) were performed. In addition to abundance of bla TEM-116 (57.5%) and bla CTX-M-15 (37.5%), bacteria were also found to harbor other variants of ESBLs like bla CTX-M-71 (5%), bla CTX-M-3 (7.5%), bla CTX-M-32 (2.5%), bla CTX-M-152 (7.5%), bla CTX-M-55 (2.5%), along with some non-ESBLs; bla TEM-1 (25%) and bla OXY (5%). Additionally, co occurrence of mercury tolerance genes were observed among 40% of isolates. In silico studies of the new variant, bla CTX-M-152 were conducted through modeling for the generation of structure followed by docking to determine its catalytic profile. CTX-M-152 was found to be an out-member of CTX-M-group-25 due to Q26H, T154A, G89D, P99S, and D146G substitutions. Five residues Ser70, Asn132, Ser237, Gly238, and Arg273 were found responsible for positioning of cefotaxime into the active site through seven H-bonds with binding energy of -7.6 Kcal/mol. Despite small active site, co-operative interactions of Ser237 and Arg276 were found actively contributing to its high catalytic efficiency. To the best of our knowledge, this is the first report of bla CTX-M-152 of CTX-M-group-25 from Indian subcontinent. Taking a note of bacteria harboring such high proportion of multidrug and mercury resistance determinants, their presence in natural water resources employed for human consumption increases the chances of potential risk to human health. Hence, deeper insights into mechanisms pertaining to resistance development are required to frame out strategies to tackle the situation and prevent acquisition and dissemination of resistance determinants so as to combat the escalating burden of infectious diseases. PMID- 26941716 TI - Nitric Oxide and Reactive Oxygen Species Coordinately Regulate the Germination of Puccinia striiformis f. sp. tritici Urediniospores. AB - Nitric oxide (NO) and reactive oxygen species (ROS) function as signaling molecules in a number of critical signal transduction pathways in plants, including plant biotic interactions. In addition to the role of plant-derived NO and ROS in plant resistance, which has been well documented, pathogen-produced NO and ROS have recently emerged as important players in fungal development and pathogenesis. However, the effects of pathogenic fungi-derived NO and ROS on signaling pathways during fungal pre-infection development remain unknown. Here, using a combination of pharmacological approaches and confocal microscopy, we investigated the roles of NO and ROS during the germination of Puccinia striiformis Westend f. sp. tritici (Pst) the wheat stripe rust pathogen. Both NO and ROS have a crucial role in uredinial germination. The scavengers of NO and ROS delayed spore germination and decreased the lengths of germ tubes. A similar phenotype was produced after treatment with the promoter. However, the spores germinated and grew normally when the levels of NO and ROS were simultaneously elevated by the application of a promoter of NO and a donor of ROS. Confocal laser microscopy indicated that both NO and ROS preferentially localized at the germ pores and apexes of growing germ tubes when the ROS/NO ratio in the spores was maintained in a specific range. We concluded that both NO and ROS are critical signaling molecules in the pre-infection development of Pst and that the polar growth of the germ tube is coordinately regulated by NO and ROS. PMID- 26941718 TI - Complete Nucleotide Sequence of pGA45, a 140,698-bp IncFIIY Plasmid Encoding bla IMI-3-Mediated Carbapenem Resistance, from River Sediment. AB - Plasmid pGA45 was isolated from the sediments of Haihe River using Escherichia coli CV601 (gfp-tagged) as recipients and indigenous bacteria from sediment as donors. This plasmid confers reduced susceptibility to imipenem which belongs to carbapenem group. Plasmid pGA45 was fully sequenced on an Illumina HiSeq 2000 sequencing system. The complete sequence of plasmid pGA45 was 140,698 bp in length with an average G + C content of 52.03%. Sequence analysis shows that pGA45 belongs to IncFIIY group and harbors a backbone region which shares high homology and gene synteny to several other IncF plasmids including pNDM1_EC14653, pYDC644, pNDM-Ec1GN574, pRJF866, pKOX_NDM1, and pP10164-NDM. In addition to the backbone region, plasmid pGA45 harbors two notable features including one bla IMI 3-containing region and one type VI secretion system region. The bla IMI-3 containing region is responsible for bacteria carbapenem resistance and the type VI secretion system region is probably involved in bacteria virulence, respectively. Plasmid pGA45 represents the first complete nucleotide sequence of the bla IMI-harboring plasmid from environment sample and the sequencing of this plasmid provided insight into the architecture used for the dissemination of bla IMI carbapenemase genes. PMID- 26941717 TI - The Mitogen-Activated Protein Kinase (MAPK) Pathway: Role in Immune Evasion by Trypanosomatids. AB - Leishmania spp. and Trypanosoma cruzi are the causative agents of leishmaniasis and Chagas disease, respectively, two neglected tropical diseases that affect about 25 million people worldwide. These parasites belong to the family Trypanosomatidae, and are both obligate intracellular parasites that manipulate host signaling pathways and the innate immune system to establish infection. Mitogen-activated protein kinases (MAPKs) are serine and threonine protein kinases that are highly conserved in eukaryotes, and are involved in signal transduction pathways that modulate physiological and pathophysiological cell responses. This mini-review highlights existing knowledge concerning the mechanisms that Leishmania spp. and T. cruzi have evolved to target the host's MAPK signaling pathways and highjack the immune response, and, in this manner, promote parasite maintenance in the host. PMID- 26941719 TI - In silico Analysis Revealed High-risk Single Nucleotide Polymorphisms in Human Pentraxin-3 Gene and their Impact on Innate Immune Response against Microbial Pathogens. AB - Pentraxin-3 (PTX-3) protein is an evolutionary conserved protein that acts as a soluble pattern-recognition receptor for pathogens and plays important role in innate immune response. It recognizes various pathogens by interacting with extracellular moieties such as glactomannan of conidia (Aspergillus fumigatus), lipopolysaccharide of Pseudomonas aeruginosa, Streptococcus pneumonia and Salmonella typhimurium. Thus, PTX-3 protein helps to clear these pathogens by activating downstream innate immune process. In this study, computational methods were used to analyze various non-synonymous single nucleotide polymorphisms (nsSNPs) in PTX-3 gene. Three different databases were used to retrieve SNP data sets followed by seven different in silico algorithms to screen nsSNPs in PTX-3 gene. Sequence homology based approach was used to identify nsSNPs. Conservation profile of PTX-3 protein amino acid residues were predicted by ConSurf web server. In total, 10 high-risk nsSNPs were identified in pentraxin-domain of PTX 3 gene. Out of these 10 high-risk nsSNPs, 4 were present in the conserved structural and functional residues of the pentraxin-domain, hence, selected for structural analyses. The results showed alteration in the putative structure of pentraxin-domain. Prediction of protein-protein interactions analysis showed association of PTX-3 protein with C1q component of complement pathway. Different functional and structural residues along with various putative phosphorylation sites and evolutionary relationship were also predicted for PTX-3 protein. This is the first extensive computational analyses of pentraxin protein family with nsSNPs and will serve as a valuable resource for future population based studies. PMID- 26941720 TI - Temporally Variable Geographical Distance Effects Contribute to the Assembly of Root-Associated Fungal Communities. AB - Root-associated fungi are key contributors to ecosystem functioning, however, the factors which determine community assembly are still relatively poorly understood. This study simultaneously quantified the roles of geographical distance, environmental heterogeneity and time in determining root-associated fungal community composition at the local scale within a short rotation coppice (SRC) willow plantation. Culture independent molecular analyses of the root associated fungal community suggested a strong but temporally variable effect of geographical distance among fungal communities in terms of composition at the local geographical level. Whilst these distance effects were most prevalent on October communities, soil pH had an effect on structuring of the communities throughout the sampling period. Given the temporal variation in the effects of geographical distance and the environment for shaping root-associated fungal communities, there is clearly need for a temporal component to sampling strategies in future investigations of fungal ecology. PMID- 26941721 TI - Are Bacterial Volatile Compounds Poisonous Odors to a Fungal Pathogen Botrytis cinerea, Alarm Signals to Arabidopsis Seedlings for Eliciting Induced Resistance, or Both? AB - Biological control (biocontrol) agents act on plants via numerous mechanisms, and can be used to protect plants from pathogens. Biocontrol agents can act directly as pathogen antagonists or competitors or indirectly to promote plant induced systemic resistance (ISR). Whether a biocontrol agent acts directly or indirectly depends on the specific strain and the pathosystem type. We reported previously that bacterial volatile organic compounds (VOCs) are determinants for eliciting plant ISR. Emerging data suggest that bacterial VOCs also can directly inhibit fungal and plant growth. The aim of the current study was to differentiate direct and indirect mechanisms of bacterial VOC effects against Botrytis cinerea infection of Arabidopsis. Volatile emissions from Bacillus subtilis GB03 successfully protected Arabidopsis seedlings against B. cinerea. First, we investigated the direct effects of bacterial VOCs on symptom development and different phenological stages of B. cinerea including spore germination, mycelial attachment to the leaf surface, mycelial growth, and sporulation in vitro and in planta. Volatile emissions inhibited hyphal growth in a dose-dependent manner in vitro, and interfered with fungal attachment on the hydrophobic leaf surface. Second, the optimized bacterial concentration that did not directly inhibit fungal growth successfully protected Arabidopsis from fungal infection, which indicates that bacterial VOC-elicited plant ISR has a more important role in biocontrol than direct inhibition of fungal growth on Arabidopsis. We performed qRT-PCR to investigate the priming of the defense-related genes PR1, PDF1.2, and ChiB at 0, 12, 24, and 36 h post-infection and 14 days after the start of plant exposure to bacterial VOCs. The results indicate that bacterial VOCs potentiate expression of PR1 and PDF1.2 but not ChiB, which stimulates SA- and JA-dependent signaling pathways in plant ISR and protects plants against pathogen colonization. This study provides new evidence for bacterial VOC-elicited plant ISR that protects Arabidopsis plants from infection by the necrotrophic fungus B. cinerea. Our work reveals that bacterial VOCs primarily act via an indirect mechanism to elicit plant ISR, and have a major role in biocontrol against fungal pathogens. PMID- 26941723 TI - Boromycin Kills Mycobacterial Persisters without Detectable Resistance. AB - Boromycin is a boron-containing polyether macrolide antibiotic isolated from Streptomyces antibioticus. It was shown to be active against Gram positive bacteria and to act as an ionophore for potassium ions. The antibiotic is ineffective against Gram negative bacteria where the outer membrane appears to block access of the molecule to the cytoplasmic membrane. Here we asked whether boromycin is active against Mycobacterium tuberculosis which, similar to Gram negative bacteria, possesses an outer membrane. The results show that boromycin is a potent inhibitor of mycobacterial growth (MIC50 = 80 nM) with strong bactericidal activity against growing and non-growing drug tolerant persister bacilli. Exposure to boromycin resulted in a rapid loss of membrane potential, reduction of the intracellular ATP level and leakage of cytoplasmic protein. Consistent with boromycin acting as a potassium ionophore, addition of KCl to the medium blocked its antimycobacterial activity. In contrast to the potent antimycobacterial activities of the polyether macrolide, its cytotoxicity and haemolytic activity were low (CC50 = 30 MUM, HC50 = 40 MUM) with a selectivity index of more than 300. Spontaneous resistant mutants could not be isolated suggesting a mutation frequency of less than 10(-9)/CFU. Taken together, the results suggests that targeting mycobacterial transmembrane ion gradients may be an attractive chemotherapeutic intervention level to kill otherwise drug tolerant persister bacilli, and to slow down the development of genetic antibiotic resistance. PMID- 26941722 TI - Microbiota Influences Morphology and Reproduction of the Brown Alga Ectocarpus sp. AB - Associated microbiota play crucial roles in health and disease of higher organisms. For macroalgae, some associated bacteria exert beneficial effects on nutrition, morphogenesis and growth. However, current knowledge on macroalgae microbiota interactions is mostly based on studies on green and red seaweeds. In this study, we report that when cultured under axenic conditions, the filamentous brown algal model Ectocarpus sp. loses its branched morphology and grows with a small ball-like appearance. Nine strains of periphytic bacteria isolated from Ectocarpus sp. unialgal cultures were identified by 16S rRNA sequencing, and assessed for their effect on morphology, reproduction and the metabolites secreted by axenic Ectocarpus sp. Six of these isolates restored morphology and reproduction features of axenic Ectocarpus sp. Bacteria-algae co-culture supernatants, but not the supernatant of the corresponding bacterium growing alone, also recovered morphology and reproduction of the alga. Furthermore, colonization of axenic Ectocarpus sp. with a single bacterial isolate impacted significantly the metabolites released by the alga. These results show that the branched typical morphology and the individuals produced by Ectocarpus sp. are strongly dependent on the presence of bacteria, while the bacterial effect on the algal exometabolome profile reflects the impact of bacteria on the whole physiology of this alga. PMID- 26941724 TI - Postoperative Changes in Fecal Bacterial Communities and Fermentation Products in Obese Patients Undergoing Bilio-Intestinal Bypass. AB - We assessed the gut microbial ecology of 11 severely obese patients before and after bilio-intestinal bypass (BIB). Fecal samples were evaluated for microbial communities using 16S rDNA Illumina sequencing, real-time PCR targeting functional genes, and gas chromatography of short chain fatty acids (SCFAs). At 6 months after surgery, subjects exhibited significant improvements in metabolic markers (body weight, glucose, and lipid metabolism) compared with baseline. The fecal microbiota of post-surgery individuals was characterized by an overall decrease of bacterial diversity, with a significant reduction in Lachnospiraceae, Clostridiaceae, Ruminococcaceae, Eubacteriaceae, and Coriobacteriaceae. On the contrary, there were significant increases of genera Lactobacillus, Megasphaera, and Acidaminococcus and the family Enterobacteriaceae. The pH was decreased in fecal samples from patients after BIB and SCFA profiles were altered, with lower percentages of acetate and propionate and higher levels of valerate and hexanoate. Some changes in the bacterial populations were associated with variations in the patients' metabolic health parameters, namely Gemmiger and glucose, Lactobacillus and glucose, and Faecalibacterium and triglycerides. The results from this study of BIB patients furthers our understanding of the composition of gut microbiota and the functional changes that may be involved in improving obesity-related conditions following weight-loss surgery. PMID- 26941725 TI - Bioweathering Potential of Cultivable Fungi Associated with Semi-Arid Surface Microhabitats of Mayan Buildings. AB - Soil and rock surfaces support microbial communities involved in mineral weathering processes. Using selective isolation, fungi were obtained from limestone surfaces of Mayan monuments in the semi-arid climate at Yucatan, Mexico. A total of 101 isolates representing 53 different taxa were studied. Common fungi such as Fusarium, Pestalotiopsis, Trichoderma, and Penicillium were associated with surfaces and were, probably derived from airborne spores. In contrast, unusual fungi such as Rosellinia, Annulohypoxylon, and Xylaria were predominantly identified from mycelium particles of biofilm biomass. Simulating oligotrophic conditions, agar amended with CaCO3 was inoculated with fungi to test for carbonate activity. A substantial proportion of fungi, in particular those isolated from mycelium (59%), were capable of solubilizing calcium by means of organic acid release, notably oxalic acid as evidenced by ion chromatography. Contrary to our hypothesis, nutrient level was not a variable influencing the CaCO3 solubilization ability among isolates. Particularly active fungi (Annulohypoxylon stygium, Penicillium oxalicum, and Rosellinia sp.) were selected as models for bioweathering experiments with limestone-containing mesocosms to identify if other mineral phases, in addition to oxalates, were linked to bioweathering processes. Fungal biofilms were seen heavily covering the stone surface, while a biomineralized front was also observed at the stone-biofilm interface, where network of hyphae and mycogenic crystals was observed. X-ray diffraction analysis (XRD) identified calcite as the main phase, along with whewellite and wedellite. In addition, lower levels of citrate were detected by Attenuated Total Reflectance-Fourier-Transform Infrared Spectroscopy (ATR-FTIR). Overall, our results suggest that a diverse fungal community is associated with limestone surfaces insemi-arid climates. A subset of this community is geochemically active, excreting organic acids under quasi-oligotrophic conditions, suggesting that the high metabolic cost of exuding organic acids beneficial under nutrient limitation. Oxalic acid release may deteriorate or stabilize limestone surfaces, depending on microclimatic dynamics. PMID- 26941726 TI - Development of a High Resolution Virulence Allelic Profiling (HReVAP) Approach Based on the Accessory Genome of Escherichia coli to Characterize Shiga-Toxin Producing E. coli (STEC). AB - Shiga-toxin producing Escherichia coli (STEC) strains possess a large accessory genome composed of virulence genes existing in multiple allelic variants, which sometimes segregate with specific STEC subpopulations. We analyzed the allelic variability of 91 virulence genes of STEC by Real Time PCR followed by melting curves analysis in 713 E. coli strains including 358 STEC. The 91 genes investigated were located on the locus of enterocyte effacement (LEE), OI-57, and OI-122 pathogenicity islands and displayed a total of 476 alleles in the study population. The combinations of the 91 alleles of each strain were termed allelic signatures and used to perform cluster analyses. We termed such an approach High Resolution Virulence Allelic Profiling (HReVAP) and used it to investigate the phylogeny of STEC of multiple serogroups. The dendrograms obtained identified groups of STEC segregating approximately with the serogroups and allowed the identification of subpopulations within the single groups. The study of the allelic signatures provided further evidence of the coevolution of the LEE and OI 122, reflecting the occurrence of their acquisition through a single event. The HReVAP analysis represents a sensitive tool for studying the evolution of LEE positive STEC. PMID- 26941727 TI - Study of Salmonella Typhimurium Infection in Laying Hens. AB - Members of Salmonella enterica are frequently involved in egg and egg product related human food poisoning outbreaks worldwide. In Australia, Salmonella Typhimurium is frequently involved in egg and egg product related foodborne illness and Salmonella Mbandaka has also been found to be a contaminant of the layer farm environment. The ability possessed by Salmonella Enteritidis to colonize reproductive organs and contaminate developing eggs has been well described. However, there are few studies investigating this ability for Salmonella Typhimurium. The hypothesis of this study was that the Salmonella Typhimurium can colonize the gut for a prolonged period of time and that horizontal infection through feces is the main route of egg contamination. At 14 weeks of age hens were orally infected with either S. Typhimurium PT 9 or S. Typhimurium PT 9 and Salmonella Mbandaka. Salmonella shedding in feces and eggs was monitored for 15 weeks post-infection. Egg shell surface and internal contents of eggs laid by infected hens were cultured independently for detection of Salmonella spp. The mean Salmonella load in feces ranged from 1.54 to 63.35 and 0.31 to 98.38 most probable number/g (MPN/g) in the S. Typhimurium and S. Typhimurium + S. Mbandaka group, respectively. No correlation was found between mean fecal Salmonella load and frequency of egg shell contamination. Egg shell contamination was higher in S. Typhimurium + S. Mbandaka infected group (7.2% S. Typhimurium, 14.1% S. Mbandaka) compared to birds infected with S. Typhimurium (5.66%) however, co-infection had no significant impact on egg contamination by S. Typhimurium. Throughout the study Salmonella was not recovered from internal contents of eggs laid by hens. Salmonella was isolated from different segments of oviduct of hens from both the groups, however pathology was not observed on microscopic examination. This study investigated Salmonella shedding for up to 15 weeks p.i which is a longer period of time compared to previously published studies. The findings of current study demonstrated intermittent but persistent fecal shedding of Salmonella after oral infection for up to 15 weeks p.i. Further, egg shell contamination, with lack of internal egg content contamination and the low frequency of reproductive organ infection suggested that horizontal infection through contaminated feces is the main route of egg contamination with S. Typhimurium in laying hens. PMID- 26941728 TI - Potential Molecular Targets for Narrow-Spectrum Agents to Combat Mycoplasma pneumoniae Infection and Disease. AB - As Mycoplasma pneumoniae macrolide resistance grows and spreads worldwide, it is becoming more important to develop new drugs to prevent infection or limit disease. Because other mycoplasma species have acquired resistance to other classes of antibiotics, it is reasonable to presume that M. pneumoniae can do the same, so switching to commonly used antibiotics like fluoroquinolones will not result in forms of therapy with long-term utility. Moreover, broad-spectrum antibiotics can have serious consequences for the patient, as these drugs may have severe impacts on the natural microbiota of the individual, compromising the health of the patient either short-term or long-term. Therefore, developing narrow-spectrum antibiotics that effectively target only M. pneumoniae and no more than a small portion of the microbiota is likely to yield impactful, positive results that can be used perhaps indefinitely to combat M. pneumoniae. Development of these agents requires a deep understanding of the basic biology of M. pneumoniae, in many areas deeper than what is currently known. In this review, we discuss potential targets for new, narrow-spectrum agents and both the positive and negative aspects of selecting these targets, which include toxic molecules, metabolic pathways, and attachment and motility. By gathering this information together, we anticipate that it will be easier for researchers to evaluate topics of priority for study of M. pneumoniae. PMID- 26941729 TI - Differential Expression of miRNA Regulates T Cell Differentiation and Plasticity During Visceral Leishmaniasis Infection. AB - Visceral leishmaniasis (VL) is a tropical neglected disease caused by Leishmania donovani, results in significant mortality in the Indian subcontinent. The plasticity of T cell proliferation and differentiation depends on microRNA mediated gene regulation which leads Th1/Th2 or Th17/Treg type of immune response during human VL. This study depicts the identification of target immune signaling molecule and transcription factors, which play a role in T-cell proliferation and differentiation followed by the identification of miRNA controlling their gene expression using three web servers' viz., TargetScan, miRPath and miRDB. This study provides the bioinformatics evidences that seed region present in the miRNAs miR-29-b, miR-29a, have the putative binding site in the 3'-untranslated region (UTR) of TBX21 transcription factor of CD4(+) T helper (Th1), which may suppress the Th1 specific protective immune response. Development of Th2 type specific immune response can be suppressed by binding of miR-135 and miR-126 miRNAs over the 3'-UTR region of GATA-3 transcription factor of Th2 specific CD4(+) T helper cells. MiRNA identified against Th2/Treg immune cells are important and their over expression or administration can be used for developing the Th1/Th17 type of protective immune response during VL infection. This study indicates that miRNAs have the capacity to regulate immune signaling, cytokine production and immune cell migration to control the VL infection in human. This observation warrants further investigation for the development of miRNA based therapy controlling T cell differentiation in human VL. PMID- 26941730 TI - Biochar Treatment Resulted in a Combined Effect on Soybean Growth Promotion and a Shift in Plant Growth Promoting Rhizobacteria. AB - The application of biochar to soil is considered to have the potential for long term soil carbon sequestration, as well as for improving plant growth and suppressing soil pathogens. In our study we evaluated the effect of biochar on the plant growth of soybeans, as well as on the community composition of root associated bacteria with plant growth promoting traits. Two types of biochar, namely, maize biochar (MBC), wood biochar (WBC), and hydrochar (HTC) were used for pot experiments to monitor plant growth. Soybean plants grown in soil amended with HTC char (2%) showed the best performance and were collected for isolation and further characterization of root-associated bacteria for multiple plant growth promoting traits. Only HTC char amendment resulted in a statistically significant increase in the root and shoot dry weight of soybeans. Interestingly, rhizosphere isolates from HTC char amended soil showed higher diversity than the rhizosphere isolates from the control soil. In addition, a higher proportion of isolates from HTC char amended soil compared with control soil was found to express plant growth promoting properties and showed antagonistic activity against one or more phytopathogenic fungi. Our study provided evidence that improved plant growth by biochar incorporation into soil results from the combination of a direct effect that is dependent on the type of char and a microbiome shift in root-associated beneficial bacteria. PMID- 26941731 TI - Metagenomic Insights into the Uncultured Diversity and Physiology of Microbes in Four Hypersaline Soda Lake Brines. AB - Soda lakes are salt lakes with a naturally alkaline pH due to evaporative concentration of sodium carbonates in the absence of major divalent cations. Hypersaline soda brines harbor microbial communities with a high species- and strain-level archaeal diversity and a large proportion of still uncultured poly extremophiles compared to neutral brines of similar salinities. We present the first "metagenomic snapshots" of microbial communities thriving in the brines of four shallow soda lakes from the Kulunda Steppe (Altai, Russia) covering a salinity range from 170 to 400 g/L. Both amplicon sequencing of 16S rRNA fragments and direct metagenomic sequencing showed that the top-level taxa abundance was linked to the ambient salinity: Bacteroidetes, Alpha-, and Gamma proteobacteria were dominant below a salinity of 250 g/L, Euryarchaeota at higher salinities. Within these taxa, amplicon sequences related to Halorubrum, Natrinema, Gracilimonas, purple non-sulfur bacteria (Rhizobiales, Rhodobacter, and Rhodobaca) and chemolithotrophic sulfur oxidizers (Thioalkalivibrio) were highly abundant. Twenty-four draft population genomes from novel members and ecotypes within the Nanohaloarchaea, Halobacteria, and Bacteroidetes were reconstructed to explore their metabolic features, environmental abundance and strategies for osmotic adaptation. The Halobacteria- and Bacteroidetes-related draft genomes belong to putative aerobic heterotrophs, likely with the capacity to ferment sugars in the absence of oxygen. Members from both taxonomic groups are likely involved in primary organic carbon degradation, since some of the reconstructed genomes encode the ability to hydrolyze recalcitrant substrates, such as cellulose and chitin. Putative sodium-pumping rhodopsins were found in both a Flavobacteriaceae- and a Chitinophagaceae-related draft genome. The predicted proteomes of both the latter and a Rhodothermaceae-related draft genome were indicative of a "salt-in" strategy of osmotic adaptation. The primary catabolic and respiratory pathways shared among all available reference genomes of Nanohaloarchaea and our novel genome reconstructions remain incomplete, but point to a primarily fermentative lifestyle. Encoded xenorhodopsins found in most drafts suggest that light plays an important role in the ecology of Nanohaloarchaea. Putative encoded halolysins and laccase-like oxidases might indicate the potential for extracellular degradation of proteins and peptides, and phenolic or aromatic compounds. PMID- 26941732 TI - Microbes as Engines of Ecosystem Function: When Does Community Structure Enhance Predictions of Ecosystem Processes? AB - Microorganisms are vital in mediating the earth's biogeochemical cycles; yet, despite our rapidly increasing ability to explore complex environmental microbial communities, the relationship between microbial community structure and ecosystem processes remains poorly understood. Here, we address a fundamental and unanswered question in microbial ecology: 'When do we need to understand microbial community structure to accurately predict function?' We present a statistical analysis investigating the value of environmental data and microbial community structure independently and in combination for explaining rates of carbon and nitrogen cycling processes within 82 global datasets. Environmental variables were the strongest predictors of process rates but left 44% of variation unexplained on average, suggesting the potential for microbial data to increase model accuracy. Although only 29% of our datasets were significantly improved by adding information on microbial community structure, we observed improvement in models of processes mediated by narrow phylogenetic guilds via functional gene data, and conversely, improvement in models of facultative microbial processes via community diversity metrics. Our results also suggest that microbial diversity can strengthen predictions of respiration rates beyond microbial biomass parameters, as 53% of models were improved by incorporating both sets of predictors compared to 35% by microbial biomass alone. Our analysis represents the first comprehensive analysis of research examining links between microbial community structure and ecosystem function. Taken together, our results indicate that a greater understanding of microbial communities informed by ecological principles may enhance our ability to predict ecosystem process rates relative to assessments based on environmental variables and microbial physiology. PMID- 26941734 TI - Effects of Megaplasmid Loss on Growth of Neurotoxigenic Clostridium butyricum Strains and Botulinum Neurotoxin Type E Expression. AB - Clostridium butyricum strains that atypically produce the botulinum neurotoxin type E (BoNT/E) possess a megaplasmid of unknown functions in their genome. In this study, we cured two botulinum neurotoxigenic C. butyricum type E strains of their megaplasmids, and compared the obtained megaplasmid-cured strains to their respective wild-type parental strains. Our results showed that the megaplasmids do not confer beta-lactam resistance on the neurotoxigenic C. butyricum type E strains, although they carry several putative beta-lactamase genes. Instead, we found that the megaplasmids are essential for growth of the neurotoxigenic C. butyricum type E strains at the relatively low temperature of 15 degrees C, and are also relevant for growth of strains under limiting pH and salinity conditions, as well as under favorable environmental conditions. Moreover, the presence of the megaplasmids was associated with increased transcript levels of the gene encoding BoNT/E in the C. butyricum type E strains, indicating that the megaplasmids likely contain transcriptional regulators. However, the levels of BoNT/E in the supernatants of the cured and uncured strains were similar after 24 and 48 h culture, suggesting that expression of BoNT/E in the C. butyricum type E strains is not ultimately controlled by the megaplasmids. Together, our results reveal that the C. butyricum type E megaplasmids exert pleiotropic effects on the growth of their microbial hosts under optimal and limiting environmental conditions, and also highlight the possibility of original regulatory mechanisms controlling the expression of BoNT/E. PMID- 26941733 TI - Changes in the Relative Abundance of Two Saccharomyces Species from Oak Forests to Wine Fermentations. AB - Saccharomyces cerevisiae and its sibling species Saccharomyces paradoxus are known to inhabit temperate arboreal habitats across the globe. Despite their sympatric distribution in the wild, S. cerevisiae is predominantly associated with human fermentations. The apparent ecological differentiation of these species is particularly striking in Europe where S. paradoxus is abundant in forests and S. cerevisiae is abundant in vineyards. However, ecological differences may be confounded with geographic differences in species abundance. To compare the distribution and abundance of these two species we isolated Saccharomyces strains from over 1200 samples taken from vineyard and forest habitats in Slovenia. We isolated numerous strains of S. cerevisiae and S. paradoxus, as well as a small number of Saccharomyces kudriavzevii strains, from both vineyard and forest environments. We find S. cerevisiae less abundant than S. paradoxus on oak trees both within and outside the vineyard, but more abundant on grapevines and associated substrates. Analysis of the uncultured microbiome shows, that both S. cerevisiae and S. paradoxus are rare species in soil and bark samples, but can be much more common in grape must. In contrast to S. paradoxus, European strains of S. cerevisiae have acquired multiple traits thought to be important for life in the vineyard and dominance of wine fermentations. We conclude, that S. cerevisiae and S. paradoxus currently share both vineyard and non-vineyard habitats in Slovenia and we discuss factors relevant to their global distribution and relative abundance. PMID- 26941736 TI - The Thanatomicrobiome: A Missing Piece of the Microbial Puzzle of Death. AB - Death is a universal phenomenon; however, is there "life after death?" This topic has been investigated for centuries but still there are gray areas that have yet to be elucidated. Forensic microbiologists are developing new applications to investigate the dynamic and coordinated changes in microbial activity that occur when a human host dies. There is currently a paucity of explorations of the thanatomicrobiome (thanatos-, Greek for death) and epinecrotic communities (microbial communities residing in and/or moving on the surface of decomposing remains). Ongoing studies can help clarify the structure and function of these postmortem microbiomes. Human microbiome studies have revealed that 75-90% of cells in the body prior to death are microbial. Upon death, putrefaction occurs and is a complicated process encompassing chemical degradation and autolysis of cells. Decomposition also involves the release of contents of the intestines due to enzymes under the effects of abiotic and biotic factors. These factors likely have predictable effects on postmortem microbial communities and can be leveraged for forensic studies. This mini review provides a critical examination of emerging research relating to thanatomicrobiome and epinecrotic communities, how each is studied, and possible strategies of stochastic processes. PMID- 26941735 TI - Surface Proteoglycans as Mediators in Bacterial Pathogens Infections. AB - Infectious diseases remain an important global health problem. The interaction of a wide range of pathogen bacteria with host cells from many different tissues is frequently mediated by proteoglycans. These compounds are ubiquitous complex molecules which are not only involved in adherence and colonization, but can also participate in other steps of pathogenesis. To overcome the problem of microbial resistance to antibiotics new therapeutic agents could be developed based on the characteristics of the interaction of pathogens with proteoglycans. PMID- 26941737 TI - Commentary: MARCH8 Inhibits HIV-1 Infection by Reducing Virion Incorporation of Envelope Glycoproteins. PMID- 26941738 TI - T-Cell Immunity to Influenza in Older Adults: A Pathophysiological Framework for Development of More Effective Vaccines. AB - One of the most profound public health consequences of immune senescence is reflected in an increased susceptibility to influenza and other acute respiratory illnesses, as well as a loss of influenza vaccine effectiveness in older people. Common medical conditions and mental and psychosocial health issues as well as degree of frailty and functional dependence accelerate changes associated with immune senescence. All contribute to the increased risk for complications of influenza infection, including pneumonias, heart diseases, and strokes that lead to hospitalization, disability, and death in the over 65 population. Changes in mucosal barrier mechanisms and both innate and adaptive immune functions converge in the reduced response to influenza infection, and lead to a loss of antibody mediated protection against influenza with age. The interactions of immune senescence and reduced adaptive immune responses, persistent cytomegalovirus infection, inflammaging (chronic elevation of inflammatory cytokines), and dysregulated cytokine production, pose major challenges to the development of vaccines designed to improve T-cell-mediated immunity. In older adults, the goal of vaccination is more realistically targeted to providing clinical protection against disease rather than to inducing sterilizing immunity to infection. Standard assays of antibody titers correlate with protection against influenza illness but do not detect important changes in cellular immune mechanisms that correlate with vaccine-mediated protection against influenza in older people. This article will discuss: (i) the burden of influenza in older adults and how this relates to changes in T-cell function, (ii) age-related changes in different T-cell subsets and immunologic targets for improved influenza vaccine efficacy in older, and (iii) the development of correlates of clinical protection against influenza disease to expedite the process of new vaccine development for the 65 and older population. Ultimately, these efforts will address the public health need for improved protection against influenza in older adults and "vaccine preventable disability." PMID- 26941740 TI - Systemic Lupus Erythematosus and Deficiencies of Early Components of the Complement Classical Pathway. AB - The complement system plays an important role in the innate and acquired immune response against pathogens. It consists of more than 30 proteins found in soluble form or attached to cell membranes. Most complement proteins circulate in inactive forms and can be sequentially activated by the classical, alternative, or lectin pathways. Biological functions, such as opsonization, removal of apoptotic cells, adjuvant function, activation of B lymphocytes, degranulation of mast cells and basophils, and solubilization and clearance of immune complex and cell lysis, are dependent on complement activation. Although the activation of the complement system is important to avoid infections, it also can contribute to the inflammatory response triggered by immune complex deposition in tissues in autoimmune diseases. Paradoxically, the deficiency of early complement proteins from the classical pathway (CP) is strongly associated with development of systemic lupus erythematous (SLE) - mainly C1q deficiency (93%) and C4 deficiency (75%). The aim of this review is to focus on the deficiencies of early components of the CP (C1q, C1r, C1s, C4, and C2) proteins in SLE patients. PMID- 26941741 TI - Immunological Landscape and Clinical Management of Rectal Cancer. AB - The clinical management of rectal cancer and colon cancer differs due to increased local relapses in rectal cancer. However, the current molecular classification does not differentiate rectal cancer and colon cancer as two different entities. In recent years, the impact of the specific immune microenvironment in cancer has attracted renewed interest and is currently recognized as one of the major determinants of clinical progression in a wide range of tumors. In colorectal cancer, the density of lymphocytic infiltration is associated with better overall survival. Due to the need for biomarkers of response to conventional treatment with chemoradiotherapy in rectal tumors, the immune status of rectal cancer emerges as a useful tool to improve the management of patients. PMID- 26941739 TI - Vitamin D and Immune Response: Implications for Prostate Cancer in African Americans. AB - Prostate cancer (PCa) is the most common cancer among men in the U.S. African American (AA) men have a higher incidence and mortality rate compared to European American (EA) men, but the cause of PCa disparities is still unclear. Epidemiologic studies have shown that vitamin D deficiency is associated with advanced stage and higher tumor grade and mortality, while its association with overall PCa risk is inconsistent. Vitamin D deficiency is also more common in AAs than EAs, and the difference in serum vitamin D levels may help explain the PCa disparities. However, the role of vitamin D in aggressive PCa in AAs is not well explored. Studies demonstrated that the active form of vitamin D, 1,25 dihydroxyvitamin D, has anti-inflammatory effects by mediating immune-related gene expression in prostate tissue. Inflammation also plays an important role in PCa pathogenesis and progression, and expression of immune-related genes in PCa tissues differs significantly between AAs and EAs. Unfortunately, the evidence linking vitamin D and immune response in relation to PCa is still scarce. This relationship should be further explored at a genomic level in AA populations that are at high risk for vitamin D deficiency and fatal PCa. PMID- 26941742 TI - Antibody Targeting of "Steady-State" Dendritic Cells Induces Tolerance Mediated by Regulatory T Cells. AB - Dendritic cells (DCs) are often defined as pivotal inducers of immunity, but these proinflammatory properties only develop after stimulation or ex vivo manipulation of DCs. Under non-inflammatory conditions in vivo, DCs are embedded into a tissue environment and encounter a plethora of self-antigens derived from apoptotic material. This material is transported to secondary lymphoid organs. As DCs maintain their non-activated phenotype in a sterile tissue environment, interaction with T cells will induce rather regulatory T cells than effector T cells. Thus, DCs are not only inducers of immunity but are also critical for maintenance of peripheral tolerance. Therapeutically, intervention for the induction of long-lasting tolerance in several autoimmune conditions may therefore be possible by manipulating DC activation and/or targeting of DCs in their "natural" tissue environment. PMID- 26941744 TI - Protein Quantity and Quality of Safflower Seed Improved by NP Fertilizer and Rhizobacteria (Azospirillum and Azotobacter spp.). AB - HIGHLIGHTS Rhizobacteria (Azotobacter spp.) have improved the quality and quantity of safflower seed protein.Protein quality was confirmed by SDS-PAGE and new bands were found in response to different combinations of rhizobacteria and lower doses of fertilizers.The PGPR application has reduced the use of fertilizers upto 50%. Protein is an essential part of the human diet. The aim of this present study was to improve the protein quality of safflower seed by the application of plant growth promoting rhizobacteria (PGPR) in combination with conventional nitrogen and phosphate (NP) fertilizers. The seeds of two safflower cultivars Thori and Saif-32, were inoculated with Azospirillum and Azotobacter and grown under field conditions. Protein content and quality was assessed by crude protein, amino acid analysis, and SDS-PAGE. Seed crude protein and amino acids (methionine, phenylalanine, and glutamic acid) showed significant improvements (55-1250%) by Azotobacter supplemented with a quarter dose of fertilizers (BTQ) at P <= 0.05. Additional protein bands were induced in Thori and Saif-32 by BTQ and BTH (Azotobacter supplemented with a half dose of fertilizer) respectively. The Azospirillum in combination with half dose of fertilizer (SPH) and BTQ enhanced both indole acetic acid (IAA) (90%) and gibberellic acid (GA) (23-27%) content in safflower leaf. Taken together, these data suggest that Azospirillum and Azotobacter along with significantly reduced (up to 75%) use of NP fertilizers could improve the quality and quantity of safflower seed protein. PMID- 26941743 TI - Evidence for Resident Memory T Cells in Rasmussen Encephalitis. AB - Rasmussen encephalitis (RE) is a rare pediatric neuroinflammatory disease of unknown etiology characterized by intractable seizures, and progressive atrophy usually confined to one cerebral hemisphere. Surgical removal or disconnection of the affected cerebral hemisphere is currently the only intervention that effectively stops the seizures. Histopathological evaluation of resected brain tissue has shown that activated brain resident macrophages (microglia) and infiltrating T cells are involved in the inflammatory reaction. Here, we report that T cells isolated from seven RE brain surgery specimens express the resident memory T cell (TRM) marker CD103. CD103 was expressed by >50% of CD8(+) alphabeta T cells and gammadelta T cells irrespective of the length of time from seizure onset to surgery, which ranged from 0.3 to 8.4 years. Only ~10% of CD4(+) alphabeta were CD103(+), which was consistent with the observation that few CD4(+) T cells are found in RE brain parenchyma. Clusters of T cells in brain parenchyma, which are a characteristic of RE histopathology, stained for CD103. Less than 10% of T cells isolated from brain specimens from eight surgical cases of focal cortical dysplasia (FCD), a condition that is also characterized by intractable seizures, were CD103(+). In contrast to the RE cases, the percent of CD103(+) T cells increased with the length of time from seizure onset to surgery. In sections of brain tissue from the FCD cases, T cells were predominantly found around blood vessels, and did not stain for CD103. The presence of significant numbers of TRM cells in RE brain irrespective of the length of time between clinical presentation and surgical intervention supports the conclusion that a cellular immune response to an as yet unidentified antigen(s) occurs at an early stage of the disease. Reactivated TRM cells may contribute to disease progression. PMID- 26941745 TI - Long-Term In Vitro System for Maintenance and Amplification of Root-Knot Nematodes in Cucumis sativus Roots. AB - Root-knot nematodes (RKN) are polyphagous plant-parasitic roundworms that produce large crop losses, representing a relevant agricultural pest worldwide. After infection, they induce swollen root structures called galls containing giant cells (GCs) indispensable for nematode development. Among efficient control methods are biotechnology-based strategies that require a deep knowledge of underlying molecular processes during the plant-nematode interaction. Methods of achieving this knowledge include the application of molecular biology techniques such as transcriptomics (as massive sequencing or microarray hybridization), proteomics or metabolomics. These require aseptic experimental conditions, as undetected contamination with other microorganisms could compromise the interpretation of the results. Herein, we present a simple, efficient and long term method for nematode amplification on cucumber roots grown in vitro. Amplification of juveniles (J2) from the starting inoculum is around 40-fold. The method was validated for three Meloidogyne species (Meloidogyne javanica, M. incognita, and M. arenaria), producing viable and robust freshly hatched J2s. These J2s can be used for further in vitro infection of different plant species such as Arabidopsis, tobacco and tomato, as well as to maintain and amplify the population. The method allowed maintenance of around 90 Meloidogyne sp. generations (one every 2 months) from a single initial female over 15 years. PMID- 26941746 TI - Quantitative Proteomic Analysis Provides Novel Insights into Cold Stress Responses in Petunia Seedlings. AB - Low temperature is a major adverse environmental factor that impairs petunia growth and development. To better understand the molecular mechanisms of cold stress adaptation of petunia plants, a quantitative proteomic analysis using iTRAQ technology was performed to detect the effects of cold stress on protein expression profiles in petunia seedlings which had been subjected to 2 degrees C for 5 days. Of the 2430 proteins whose levels were quantitated, a total of 117 proteins were discovered to be differentially expressed under low temperature stress in comparison to unstressed controls. As an initial study, 44 proteins including well known and novel cold-responsive proteins were successfully annotated. By integrating the results of two independent Gene Ontology (GO) enrichment analyses, seven common GO terms were found of which "oxidation reduction process" was the most notable for the cold-responsive proteins. By using the subcellular localization tool Plant-mPLoc predictor, as much as 40.2% of the cold-responsive protein group was found to be located within chloroplasts, suggesting that the chloroplast proteome is particularly affected by cold stress. Gene expression analyses of 11 cold-responsive proteins by real time PCR demonstrated that the mRNA levels were not strongly correlated with the respective protein levels. Further activity assay of anti-oxidative enzymes showed different alterations in cold treated petunia seedlings. Our investigation has highlighted the role of antioxidation mechanisms and also epigenetic factors in the regulation of cold stress responses. Our work has provided novel insights into the plant response to cold stress and should facilitate further studies regarding the molecular mechanisms which determine how plant cells cope with environmental perturbation. The data have been deposited to the ProteomeXchange with identifier PXD002189. PMID- 26941747 TI - Identification of Characteristic Fatty Acids to Quantify Triacylglycerols in Microalgae. AB - The fatty acid profiles of lipids from microalgae are unique. Polyunsaturated fatty acids are generally enriched in polar lipids, whereas saturated and monounsaturated fatty acids constitute the majority of fatty acids in triacylglycerols (TAG). Each species has characteristic fatty acids, and their content is positively or negatively correlated with TAGs. The marine oleaginous diatom Phaeodactylum tricornutum was used as the paradigm to determine the quantitative relationship between TAG and characteristic fatty acid content. Fatty acid profiles and TAG content of Phaeodactylum tricornutum were determined in a time course. C16:0/C16:1 and eicosapentaenoic acid (EPA, C20:5n3) were identified as characteristic fatty acids in TAGs and polar lipids, respectively. The percentage of those characteristic fatty acids in total fatty acids had a significant linear relationship with TAG content, and thus, the correlation coefficient presenting r (2) were 0.96, 0.94, and 0.97, respectively. The fatty acid-based method for TAG quantification could also be applied to other microalgae such as Nannochloropsis oceanica in which the r (2) of C16:0 and EPA were 0.94 and 0.97, respectively, and in Chlorella pyrenoidosa r (2)-values for C18:1 and C18:3 with TAG content were 0.91 and 0.99, repectively. This characteristic fatty acid-based method provided a distinct way to quantify TAGs in microalgae, by which TAGs could be measured precisely by immediate transesterification from wet biomass rather than using conventional methods. This procedure simplified the operation and required smaller samples than conventional methods. PMID- 26941748 TI - Transcriptome Analysis Identifies Candidate Genes Related to Triacylglycerol and Pigment Biosynthesis and Photoperiodic Flowering in the Ornamental and Oil Producing Plant, Camellia reticulata (Theaceae). AB - Camellia reticulata, which is native to Southwest China, is famous for its ornamental flowers and high-quality seed oil. However, the lack of genomic information for this species has largely hampered our understanding of its key pathways related to oil production, photoperiodic flowering process and pigment biosynthesis. Here, we first sequenced and characterized the transcriptome of a diploid C. reticulata in an attempt to identify genes potentially involved in triacylglycerol biosynthesis (TAGBS), photoperiodic flowering, flavonoid biosynthesis (FlaBS), carotenoid biosynthesis (CrtBS) pathways. De novo assembly of the transcriptome provided a catalog of 141,460 unigenes with a total length of ~96.1 million nucleotides (Mnt) and an N50 of 1080 nt. Of them, 22,229 unigenes were defined as differentially expressed genes (DEGs) across five sequenced tissues. A large number of annotated genes in C. reticulata were found to have been duplicated, and differential expression patterns of these duplicated genes were commonly observed across tissues, such as the differential expression of SOC1_a, SOC1_b, and SOC1_c in the photoperiodic flowering pathway. Up regulation of SAD_a and FATA genes and down-regulation of FAD2_a gene in the TAGBS pathway in seeds may be relevant to the ratio of monounsaturated fatty acid (MUFAs) to polyunsaturated fatty acid (PUFAs) in seed oil. MYBF1, a transcription regulator gene of the FlaBS pathway, was found with great sequence variation and alteration of expression patterns, probably resulting in functionally evolutionary differentiation in C. reticulata. MYBA1_a and some anthocyanin specific biosynthetic genes in the FlaBS pathway were highly expressed in both flower buds and flowers, suggesting important roles of anthocyanin biosynthesis in flower development. Besides, a total of 40,823 expressed sequence tag simple sequence repeats (EST-SSRs) were identified in the C. reticulata transcriptome, providing valuable marker resources for further basic and applied researches on this economically important Camellia plant. PMID- 26941749 TI - Multiple Mechanisms Increase Levels of Resistance in Rapistrum rugosum to ALS Herbicides. AB - Rapistrum rugosum (turnip weed) is a common weed of wheat fields in Iran, which is most often controlled by tribenuron-methyl (TM), a sulfonylurea (SU) belonging to the acetolactate synthase (ALS) inhibiting herbicides group. Several cases of unexplained control failure of R. rugosum by TM have been seen, especially in Golestan province-Iran. Hence, there is lack of research in evaluation of the level of resistance of the R. rugosum populations to TM, using whole plant dose response and enzyme assays, then investigating some potential resistance mechanisms Results revealed that the resistance factor (RF) for resistant (R) populations was 2.5-6.6 fold higher than susceptible (S) plant. Neither foliar retention, nor (14)C-TM absorption and translocation were the mechanisms responsible for resistance in turnip weed. Metabolism of TM was the second resistant mechanism in two populations (Ag-R5 and G-1), in which three metabolites were found. The concentration of TM for 50% inhibition of ALS enzyme activity in vitro showed a high level of resistance to the herbicide (RFs were from 28 to 38) and cross-resistance to sulfonyl-aminocarbonyl-triazolinone (SCT), pyrimidinyl-thiobenzoate (PTB) and triazolopyrimidine (TP), with no cross resistance to imidazolinone (IMI). Substitution Pro 197 to Ser 197 provided resistance to four of five ALS-inhibiting herbicides including SU, TP, PTB, and SCT with no resistance to IMI. These results documented the first case of R. rugosum resistant population worldwide and demonstrated that both RST and NRST mechanisms are involved to the resistance level to TM. PMID- 26941750 TI - Promotion of Flowering by Apple Latent Spherical Virus Vector and Virus Elimination at High Temperature Allow Accelerated Breeding of Apple and Pear. AB - Plant viral vectors are superior tools for genetic manipulation, allowing rapid induction or suppression of expression of a target gene in plants. This is a particularly effective technology for use in breeding fruit trees, which are difficult to manipulate using recombinant DNA technologies. We reported previously that if apple seed embryos (cotyledons) are infected with an Apple latent spherical virus (ALSV) vector (ALSV-AtFT/MdTFL1) concurrently expressing the Arabidopsis thaliana florigen (AtFT) gene and suppressing the expression of the apple MdTFL1-1 gene, the period prior to initial flowering (generally lasts 5 12 years) will be reduced to about 2 months. In this study, we examined whether or not ALSV vector technology can be used to promote flowering in pear, which undergoes a very long juvenile period (germination to flowering) similar to that of apple. The MdTFL1 sequence in ALSV-AtFT/MdTFL1 was replaced with a portion of the pear PcTFL1-1 gene. The resulting virus (ALSV-AtFT/PcTFL1) and ALSV AtFT/MdTFL1 were used individually for inoculation to pear cotyledons immediately after germination in two inoculation groups. Those inoculated with ALSV AtFT/MdTFL1 and ALSV-AtFT/PcTFL1 then initiated flower bud formation starting one to 3 months after inoculation, and subsequently exhibited continuous flowering and fruition by pollination. Conversely, Japanese pear exhibited extremely low systemic infection rates when inoculated with ALSV-AtFT/MdTFL1, and failed to exhibit any induction of flowering. We also developed a simple method for eliminating ALSV vectors from infected plants. An evaluation of the method for eliminating the ALSV vectors from infected apple and pear seedlings revealed that a 4-week high-temperature (37 degrees C) incubation of ALSV-infected apples and pears disabled the movement of ALSV to new growing tissues. This demonstrates that only high-temperature treatment can easily eliminate ALSV from infected fruit trees. A method combining the promotion of flowering in apple and pear by ALSV vector with an ALSV elimination technique is expected to see future application as a new plant breeding technique that can significantly shorten the breeding periods of apple and pear. PMID- 26941752 TI - FHY3 and FAR1 Act Downstream of Light Stable Phytochromes. AB - FHY3 and FAR1 are positively acting transcription factors that directly regulate expression of a number of target genes in Arabidopsis thaliana. Here, we looked at the regulation of one specific target gene, ELF4. We demonstrate that the action of FHY3 and FAR1 in upregulation of ELF4 is light dependent. Furthermore, although FHY3 and FAR1 have been exclusively characterized as components of the phytochrome A signaling pathway because of their importance in regulating expression of phyA nuclear importers, we show that, as transcription factors in their own right, FHY3 and FAR1 act downstream of light stable phytochromes, phyB, phyD, and phyE. We demonstrate that light stable phytochrome acts in a red/far red reversible manner to regulate the level of FHY3 protein. We also observed that ELF4 shows specific FHY3 and FAR1-mediated light induction in the evening and we show that regulation by light stable phytochromes at this time is important as it allows the plant to maintain normal ELF4 expression beyond dusk when the day length shortens, something which would not be possible through light labile phytochrome action. Without FHY3 and FAR1, ELF4 expression falls rapidly at dusk and in short days this results in an early drop in ELF4 expression, accompanied by a de-repression of an ELF4 target gene later in the night. Our results, therefore, demonstrate an important role for FHY3 and FAR1 as mediators of light stable phytochrome signaling. PMID- 26941751 TI - Carbon Nanomaterials in Agriculture: A Critical Review. AB - There has been great interest in the use of carbon nano-materials (CNMs) in agriculture. However, the existing literature reveals mixed effects from CNM exposure on plants, ranging from enhanced crop yield to acute cytotoxicity and genetic alteration. These seemingly inconsistent research-outcomes, taken with the current technological limitations for in situ CNM detection, present significant hurdles to the wide scale use of CNMs in agriculture. The objective of this review is to evaluate the current literature, including studies with both positive and negative effects of different CNMs (e.g., carbon nano-tubes, fullerenes, carbon nanoparticles, and carbon nano-horns, among others) on terrestrial plants and associated soil-dwelling microbes. The effects of CNMs on the uptake of various co-contaminants will also be discussed. Last, we highlight critical knowledge gaps, including the need for more soil-based investigations under environmentally relevant conditions. In addition, efforts need to be focused on better understanding of the underlying mechanism of CNM-plant interactions. PMID- 26941753 TI - Tyrosine Phosphorylation Based Homo-dimerization of Arabidopsis RACK1A Proteins Regulates Oxidative Stress Signaling Pathways in Yeast. AB - Scaffold proteins are known as important cellular regulators that can interact with multiple proteins to modulate diverse signal transduction pathways. RACK1 (Receptor for Activated C Kinase 1) is a WD-40 type scaffold protein, conserved in eukaryotes, from Chlamydymonas to plants and humans, plays regulatory roles in diverse signal transduction and stress response pathways. RACK1 in humans has been implicated in myriads of neuropathological diseases including Alzheimer and alcohol addictions. Model plant Arabidopsis thaliana genome maintains three different RACK1 genes termed RACK1A, RACK1B, and RACK1C with a very high (85-93%) sequence identity among them. Loss of function mutation in Arabidopsis indicates that RACK1 proteins regulate diverse environmental stress signaling pathways including drought and salt stress resistance pathway. Recently deduced crystal structure of Arabidopsis RACK1A- very first among all of the RACK1 proteins, indicates that it can potentially be regulated by post-translational modifications, like tyrosine phosphorylations and sumoylation at key residues. Here we show evidence that RACK1A proteins, depending on diverse environmental stresses, are tyrosine phosphorylated. Utilizing site-directed mutagenesis of key tyrosine residues, it is found that tyrosine phosphorylation can potentially dictate the homo-dimerization of RACK1A proteins. The homo-dimerized RACK1A proteins play a role in providing UV-B induced oxidative stress resistance. It is proposed that RACK1A proteins ability to function as scaffold protein may potentially be regulated by the homo-dimerized RACK1A proteins to mediate diverse stress signaling pathways. PMID- 26941755 TI - Moderate Photoinhibition of Photosystem II Protects Photosystem I from Photodamage at Chilling Stress in Tobacco Leaves. AB - It has been indicated that photosystem I (PSI) is susceptible to chilling-light stress in tobacco leaves, but the effect of growth light intensity on chilling induced PSI photoinhibition in tobacco is unclear. We examined the effects of chilling temperature (4 degrees C) associated with moderate light intensity (300 MUmol photons m(-2) s(-1)) on the activities of PSI and photosystem II (PSII) in leaves from sun- and shade-grown plants of tobacco (Nicotiana tabacum cv. k326). The sun leaves had a higher activity of alternative electron flow than the shade leaves. After 4 h chilling treatment, the sun leaves showed significantly a higher PSI photoinhibition than the shade leaves. At chilling temperature the sun leaves showed a greater electron flow from PSII to PSI, accompanying with a lower P700 oxidation ratio. When leaves were pre-treated with lincomycin, PSII activity decreased by 42% (sun leaves) and 47% (shade leaves) after 2 h exposure to the chilling-light stress, but PSI activity remained stable during the chilling-light treatment, because the electron flow from PSII to PSI was remarkably depressed. These results indicated that the stronger chilling-induced PSI photoinhibition in the sun leaves was resulted from a greater electron flow from PSII to PSI. Furthermore, moderate PSII photoinhibition depressed electron flow to PSI and then protected PSI activity against further photodamage in chilled tobacco leaves. PMID- 26941754 TI - Transcriptomic Analysis of Soil-Grown Arabidopsis thaliana Roots and Shoots in Response to a Drought Stress. AB - Drought stress has a negative impact on crop yield. Thus, understanding the molecular mechanisms responsible for plant drought stress tolerance is essential for improving this beneficial trait in crops. In the current study, a transcriptional analysis was conducted of gene regulatory networks in roots of soil-grown Arabidopsis plants in response to a drought stress treatment. A microarray analysis of drought-stressed roots and shoots was performed at 0, 1, 3, 5, 7, and 9 days. Results indicated that the expression of many drought stress responsive genes and abscisic acid biosynthesis-related genes was differentially regulated in roots and shoots from days 3 to 9. The expression of cellular and metabolic process-related genes was up-regulated at an earlier time-point in roots than in shoots. In this regard, the expression of genes involved in oxidative signaling, chromatin structure, and cell wall modification also increased significantly in roots compared to shoots. Moreover, the increased expression of genes involved in the transport of amino acids and other solutes; including malate, iron, and sulfur, was observed in roots during the early time points following the initiation of the drought stress. These data suggest that plants may utilize these signaling channels and metabolic adjustments as adaptive responses in the early stages of a drought stress. Collectively, the results of the present study increases our understanding of the differences pertaining to the molecular mechanisms occurring in roots vs. shoots in response to a drought stress. Furthermore, these findings also aid in the selection of novel genes and promoters that can be used to potentially produce crop plants with increased drought tolerance. PMID- 26941756 TI - Characterizing Croatian Wheat Germplasm Diversity and Structure in a European Context by DArT Markers. AB - Narrowing the genetic base available for future genetic progress is a major concern to plant breeders. In order to avoid this, strategies to characterize and protect genetic diversity in regional breeding pools are required. In this study, 89 winter wheat cultivars released in Croatia between 1936 and 2006 were genotyped using 1,229 DArT (diversity array technology) markers to assess the diversity and population structure. In order to place Croatian breeding pool (CBP) in a European context, Croatian wheat cultivars were compared to 523 European cultivars from seven countries using a total of 166 common DArT markers. The results show higher genetic diversity in the wheat breeding pool from Central Europe (CE) as compared to that from Northern and Western European (NWE) countries. The most of the genetic diversity was attributable to the differences among cultivars within countries. When the geographical criterion (CE vs. NWE) was applied, highly significant difference between regions was obtained that accounted for 16.19% of the total variance, revealing that the CBP represents genetic variation not currently captured in elite European wheat. The current study emphasizes the important contribution made by plant breeders to maintaining wheat genetic diversity and suggests that regional breeding is essential to the maintenance of this diversity. The usefulness of open-access wheat datasets is also highlighted. PMID- 26941758 TI - Projected Dietary Intake of Zinc, Copper, and Cerium from Consumption of Carrot (Daucus carota) Exposed to Metal Oxide Nanoparticles or Metal Ions. AB - The expanding production and use of engineered nanomaterials (ENMs) have raised concerns about the potential risk of those materials to food safety and human health. In a prior study, the accumulation of Zn, Cu, and Ce from ZnO, CuO, or CeO2, respectively, was examined in carrot (Daucus carota L.) grown in sand culture in comparison to accumulation from exposure to equivalent concentrations of ionic Zn(2+), Cu(2+), or Ce(4+). The fresh weight concentration data for peeled and unpeeled carrots were used to project dietary intake of each metal by seven age-mass classes from child to adult based on consumption of a single serving of carrot. Dietary intake was compared to the oral reference dose (oral RfD) for chronic toxicity for Zn or Cu and estimated mean and median oral RfD values for Ce based on nine other rare earth elements. Reverse dietary intake calculations were also conducted to estimate the number of servings of carrot, the mass of carrot consumed, or the tissue concentration of Zn, Cu, or Ce that would cause the oral RfD to be exceeded upon consumption. The projections indicated for Zn and Cu, the oral RfD would be exceeded in only a few highly unrealistic scenarios of exceedingly high Zn or Cu concentrations in the substrate from ZnO or CuO or consumption of excessive amounts of unpeeled carrot. The implications associated with the presence of Ce in the carrot tissues depended upon whether the mean or median oral RfD value from the rare earth elements was used as a basis for comparison. The calculations further indicated that peeling carrots reduced the projected dietary intake by one to two orders of magnitude for both ENM- and ionic-treated carrots. Overall in terms of total metal concentration, the results suggested no specific impact of the ENM form on dietary intake. The effort here provided a conservative view of the potential dietary intake of these three metals that might result from consumption of carrots exposed to nanomaterials (NMs) and how peeling mitigated that dietary intake. The results also demonstrate the potential utility of dietary intake projections for examining potential risks of NM exposure from agricultural foods. PMID- 26941759 TI - Arabidopsis thaliana: A Model Host Plant to Study Plant-Pathogen Interaction Using Rice False Smut Isolates of Ustilaginoidea virens. AB - Rice false smut fungus which is a biotrophic fungal pathogen causes an important rice disease and brings a severe damage where rice is cultivated. We established a new fungal-plant pathosystem where Ustilaginoidea virens was able to interact compatibly with the model plant Arabidopsis thaliana. Disease symptoms were apparent on the leaves of the plants after 6 days of post inoculation in the form of chlorosis. Cytological studies showed that U. virens caused a heavy infestation inside the cells of the chlorotic tissues. Development and colonization of aerial mycelia in association with floral organ, particularly on anther and stigma of the flowers after 3 weeks of post inoculation was evident which finally caused infection on the developing seeds and pod tissues. The fungus adopts a uniquely biotrophic infection strategy in roots and spreads without causing a loss of host cell viability. We have also demonstrated that U. virens isolates infect Arabidopsis and the plant subsequently activates different defense response mechanisms which are witnessed by the expression of pathogenesis related genes, PR-1, PR-2, PR-5, PDF1.1, and PDF1.2. The established A. thaliana U. virens pathosystem will now permit various follow-up molecular genetics and gene expression experiments to be performed to identify the defense signals and responses that restrict fungal hyphae colonization in planta and also provide initial evidence for tissue-adapted fungal infection strategies. PMID- 26941760 TI - Early Summer Drought Stress During the First Growing Year Stimulates Extra Shoot Growth in Oak Seedlings (Quercus petraea). AB - More severe summer droughts are predicted for mid-latitudes in Europe. To evaluate the impact on forest ecosystems and more specifically on forest regeneration, we studied the response to summer drought in oak seedlings (Quercus petraea). Acorns were collected from different mother trees in three stands in Belgium, sown in pots and grown in non-heated greenhouse conditions. We imposed drought on the seedlings in early summer by first watering the pots to saturation and then stopping any watering. Weight of the pots and stomatal conductance were regularly measured. Re-watering followed this drought period of 5 weeks. Height of the seedlings and apical bud development were observed. Stomatal resistance increased toward the end of the experiment in the drought-treated group and was restored after re-watering. The seedlings from the drought treatment displayed a higher probability to produce additional shoot growth after re-watering (p <= 0.05). A higher competition for water (two plants per pot) increased this chance. Although this chance was also higher for smaller seedlings, the actual length of the extra growth after re-watering was higher for larger seedlings (p <= 0.01). Both in the drought-treated and in the control group the autochthonous provenance growing on a xeric site produced less extra shoots compared to the two other provenances. Finally, stressed plants showed less developed apical buds compared to the control group after re-watering, suggesting a phenological effect on the growth cycle of oaks (p <= 0.0001). The higher chance for an extra shoot growth after the drought period can be considered as a compensation for the induced growth arrest during the drought period. PMID- 26941761 TI - Summer Freezing Resistance: A Critical Filter for Plant Community Assemblies in Mediterranean High Mountains. AB - Assessing freezing community response and whether freezing resistance is related to other functional traits is essential for understanding alpine community assemblages, particularly in Mediterranean environments where plants are exposed to freezing temperatures and summer droughts. Thus, we characterized the leaf freezing resistance of 42 plant species in 38 plots at Sierra de Guadarrama (Spain) by measuring their ice nucleation temperature, freezing point (FP), and low-temperature damage (LT50), as well as determining their freezing resistance mechanisms (i.e., tolerance or avoidance). The community response to freezing was estimated for each plot as community weighted means (CWMs) and functional diversity (FD), and we assessed their relative importance with altitude. We established the relationships between freezing resistance, growth forms, and four key plant functional traits (i.e., plant height, specific leaf area, leaf dry matter content (LDMC), and seed mass). There was a wide range of freezing resistance responses and more than in other alpine habitats. At the community level, the CWMs of FP and LT50 responded negatively to altitude, whereas the FD of both traits increased with altitude. The proportion of freezing-tolerant species also increased with altitude. The ranges of FP and LT50 varied among growth forms, and only leaf dry matter content was negatively correlated with freezing-resistance traits. Summer freezing events represent important abiotic filters for assemblies of Mediterranean high mountain communities, as suggested by the CWMs. However, a concomitant summer drought constraint may also explain the high freezing resistance of species that thrive in these areas and the lower FD of freezing resistance traits at lower altitudes. Leaves with high dry matter contents may maintain turgor at lower water potential and enhance drought tolerance in parallel to freezing resistance. This adaptation to drought seems to be a general prerequisite for plants found in xeric mountains. PMID- 26941762 TI - Silicon Enhances Water Stress Tolerance by Improving Root Hydraulic Conductance in Solanum lycopersicum L. AB - Silicon (Si) can improve drought tolerance in plants, but the mechanism is still not fully understood. Previous research has been concentrating on Si's role in leaf water maintenance in Si accumulators, while little information is available on its role in water uptake and in less Si-accumulating plants. Here, we investigated the effects of Si on root water uptake and its role in decreasing oxidative damage in relation to root hydraulic conductance in tomato (Solanum lycopersicum 'Zhongza No.9') under water stress. Tomato seedlings were subjected to water stress induced by 10% (w/v) polyethylene glycol-6000 in the absence or presence of 2.5 mM added silicate. The results showed that Si addition ameliorated the inhibition in tomato growth and photosynthesis, and improved water status under water stress. The root hydraulic conductance of tomato plants was decreased under water stress, and it was significantly increased by added Si. There was no significant contribution of osmotic adjustment in Si-enhanced root water uptake under water stress. The transcriptions of plasma membrane aquaporin genes were not obviously changed by Si under water stress. Water stress increased the production of reactive oxygen species and induced oxidative damage, while added Si reversed these. In addition, Si addition increased the activities of superoxide dismutase and catalase and the levels of ascorbic acid and glutathione in the roots under stress. It is concluded that Si enhances the water stress tolerance via enhancing root hydraulic conductance and water uptake in tomato plants. Si-mediated decrease in membrane oxidative damage may have contributed to the enhanced root hydraulic conductance. PMID- 26941757 TI - Global Plant Stress Signaling: Reactive Oxygen Species at the Cross-Road. AB - Current technologies have changed biology into a data-intensive field and significantly increased our understanding of signal transduction pathways in plants. However, global defense signaling networks in plants have not been established yet. Considering the apparent intricate nature of signaling mechanisms in plants (due to their sessile nature), studying the points at which different signaling pathways converge, rather than the branches, represents a good start to unravel global plant signaling networks. In this regard, growing evidence shows that the generation of reactive oxygen species (ROS) is one of the most common plant responses to different stresses, representing a point at which various signaling pathways come together. In this review, the complex nature of plant stress signaling networks will be discussed. An emphasis on different signaling players with a specific attention to ROS as the primary source of the signaling battery in plants will be presented. The interactions between ROS and other signaling components, e.g., calcium, redox homeostasis, membranes, G proteins, MAPKs, plant hormones, and transcription factors will be assessed. A better understanding of the vital roles ROS are playing in plant signaling would help innovate new strategies to improve plant productivity under the circumstances of the increasing severity of environmental conditions and the high demand of food and energy worldwide. PMID- 26941763 TI - Transcriptome-Wide Identification and Expression Profiling of the DOF Transcription Factor Gene Family in Chrysanthemum morifolium. AB - The family of DNA binding with one finger (DOF) transcription factors is plant specific, and these proteins contain a highly conserved domain (DOF domain) of 50 52 amino acids that includes a C2C2-type zinc finger motif at the N-terminus that is known to function in a number of plant processes. Here, we characterized 20 DOF genes in the important ornamental species chrysanthemum (Chrysanthemum morifolium) based on transcriptomic sequences. Phylogenetic analysis identified one pair of putative orthologous proteins in Arabidopsis and chrysanthemum and six pairs of paralogous proteins in chrysanthemum. Conserved motifs in the DOF proteins shared by Arabidopsis and chrysanthemum were analyzed using MEME. Bioinformatics analysis revealed that 13 CmDOFs could be targeted by 16 miRNA families. Moreover, we used 5' RLM-RACE to map the cleavage sites in CmDOF3, 15, and 21. The expression of these 20 genes in response to phytohormone treatments and abiotic stresses was characterized, and the expression patterns of six pairs of paralogous CmDOF genes were found to completely differ from one another, except for CmDOF6 and CmDOF7. This work will promote our research of the various functions of DOF gene family members in plant hormone and stress responses. PMID- 26941764 TI - 5' and 3' Untranslated Regions Strongly Enhance Performance of Geminiviral Replicons in Nicotiana benthamiana Leaves. AB - We previously reported a recombinant protein production system based on a geminivirus replicon that yields high levels of vaccine antigens and monoclonal antibodies in plants. The bean yellow dwarf virus (BeYDV) replicon generates massive amounts of DNA copies, which engage the plant transcription machinery. However, we noticed a disparity between transcript level and protein production, suggesting that mRNAs could be more efficiently utilized. In this study, we systematically evaluated genetic elements from human, viral, and plant sources for their potential to improve the BeYDV system. The tobacco extensin terminator enhanced transcript accumulation and protein production compared to other commonly used terminators, indicating that efficient transcript processing plays an important role in recombinant protein production. Evaluation of human-derived 5' untranslated regions (UTRs) indicated that many provided high levels of protein production, supporting their cross-kingdom function. Among the viral 5' UTRs tested, we found the greatest enhancement with the tobacco mosaic virus omega leader. An analysis of the 5' UTRs from the Arabidopsis thaliana and Nicotinana benthamiana photosystem I K genes found that they were highly active when truncated to include only the near upstream region, providing a dramatic enhancement of transgene production that exceeded that of the tobacco mosaic virus omega leader. The tobacco Rb7 matrix attachment region inserted downstream from the gene of interest provided significant enhancement, which was correlated with a reduction in plant cell death. Evaluation of Agrobacterium strains found that EHA105 enhanced protein production and reduced cell death compared to LBA4301 and GV3101. We used these improvements to produce Norwalk virus capsid protein at >20% total soluble protein, corresponding to 1.8 mg/g leaf fresh weight, more than twice the highest level ever reported in a plant system. We also produced the monoclonal antibody rituximab at 1 mg/g leaf fresh weight. PMID- 26941766 TI - Changing the Game: Using Integrative Genomics to Probe Virulence Mechanisms of the Stem Rust Pathogen Puccinia graminis f. sp. tritici. AB - The recent resurgence of wheat stem rust caused by new virulent races of Puccinia graminis f. sp. tritici (Pgt) poses a threat to food security. These concerns have catalyzed an extensive global effort toward controlling this disease. Substantial research and breeding programs target the identification and introduction of new stem rust resistance (Sr) genes in cultivars for genetic protection against the disease. Such resistance genes typically encode immune receptor proteins that recognize specific components of the pathogen, known as avirulence (Avr) proteins. A significant drawback to deploying cultivars with single Sr genes is that they are often overcome by evolution of the pathogen to escape recognition through alterations in Avr genes. Thus, a key element in achieving durable rust control is the deployment of multiple effective Sr genes in combination, either through conventional breeding or transgenic approaches, to minimize the risk of resistance breakdown. In this situation, evolution of pathogen virulence would require changes in multiple Avr genes in order to bypass recognition. However, choosing the optimal Sr gene combinations to deploy is a challenge that requires detailed knowledge of the pathogen Avr genes with which they interact and the virulence phenotypes of Pgt existing in nature. Identifying specific Avr genes from Pgt will provide screening tools to enhance pathogen virulence monitoring, assess heterozygosity and propensity for mutation in pathogen populations, and confirm individual Sr gene functions in crop varieties carrying multiple effective resistance genes. Toward this goal, much progress has been made in assembling a high quality reference genome sequence for Pgt, as well as a Pan-genome encompassing variation between multiple field isolates with diverse virulence spectra. In turn this has allowed prediction of Pgt effector gene candidates based on known features of Avr genes in other plant pathogens, including the related flax rust fungus. Upregulation of gene expression in haustoria and evidence for diversifying selection are two useful parameters to identify candidate Avr genes. Recently, we have also applied machine learning approaches to agnostically predict candidate effectors. Here, we review progress in stem rust pathogenomics and approaches currently underway to identify Avr genes recognized by wheat Sr genes. PMID- 26941767 TI - Vernalization Requirement and the Chromosomal VRN1-Region can Affect Freezing Tolerance and Expression of Cold-Regulated Genes in Festuca pratensis. AB - Plants adapted to cold winters go through annual cycles of gain followed by loss of freezing tolerance (cold acclimation and deacclimation). Warm spells during winter and early spring can cause deacclimation, and if temperatures drop, freezing damage may occur. Many plants are vernalized during winter, a process making them competent to flower in the following summer. In winter cereals, a coincidence in the timing of vernalization saturation, deacclimation, downregulation of cold-induced genes, and reduced ability to reacclimate, occurs under long photoperiods and is under control of the main regulator of vernalization requirement in cereals, VRN1, and/or closely linked gene(s). Thus, the probability of freezing damage after a warm spell may depend on both vernalization saturation and photoperiod. We investigated the role of vernalization and the VRN1-region on freezing tolerance of meadow fescue (Festuca pratensis Huds.), a perennial grass species. Two F2 populations, divergently selected for high and low vernalization requirement, were studied. Each genotype was characterized for the copy number of one of the four parental haplotypes of the VRN1-region. Clonal plants were cold acclimated for 2 weeks or vernalized/cold acclimated for a total of 9 weeks, after which the F2 populations reached different levels of vernalization saturation. Vernalized and cold acclimated plants were deacclimated for 1 week and then reacclimated for 2 weeks. All treatments were given at 8 h photoperiod. Flowering response, freezing tolerance and expression of the cold-induced genes VRN1, MADS3, CBF6, COR14B, CR7 (BLT14), LOS2, and IRI1 was measured. We found that some genotypes can lose some freezing tolerance after vernalization and a deacclimation-reacclimation cycle. The relationship between vernalization and freezing tolerance was complex. We found effects of the VRN1-region on freezing tolerance in plants cold acclimated for 2 weeks, timing of heading after 9 weeks of vernalization, expression of COR14B, CBF6, and LOS2 in vernalized and/or deacclimated treatments, and restoration of freezing tolerance during reacclimation. While expression of VRN1, COR14B, CBF6, LOS2, and IRI1 was correlated, CR7 was associated with vernalization requirement by other mechanisms, and appeared to play a role in freezing tolerance in reacclimated plants. PMID- 26941769 TI - The Relative Importance of Genetic Diversity and Phenotypic Plasticity in Determining Invasion Success of a Clonal Weed in the USA and China. AB - Phenotypic plasticity has been proposed as an important adaptive strategy for clonal plants in heterogeneous habitats. Increased phenotypic plasticity can be especially beneficial for invasive clonal plants, allowing them to colonize new environments even when genetic diversity is low. However, the relative importance of genetic diversity and phenotypic plasticity for invasion success remains largely unknown. Here, we performed molecular marker analyses and a common garden experiment to investigate the genetic diversity and phenotypic plasticity of the globally important weed Alternanthera philoxeroides in response to different water availability (terrestrial vs. aquatic habitats). This species relies predominantly on clonal propagation in introduced ranges. We therefore expected genetic diversity to be restricted in the two sampled introduced ranges (the USA and China) when compared to the native range (Argentina), but that phenotypic plasticity may allow the species' full niche range to nonetheless be exploited. We found clones from China had very low genetic diversity in terms of both marker diversity and quantitative variation when compared with those from the USA and Argentina, probably reflecting different introduction histories. In contrast, similar patterns of phenotypic plasticity were found for clones from all three regions. Furthermore, despite the different levels of genetic diversity, bioclimatic modeling suggested that the full potential bioclimatic distribution had been invaded in both China and USA. Phenotypic plasticity, not genetic diversity, was therefore critical in allowing A. philoxeroides to invade diverse habitats across broad geographic areas. PMID- 26941768 TI - Genome-Wide Identification and Expression Analysis of WRKY Gene Family in Capsicum annuum L. AB - The WRKY family of transcription factors is one of the most important families of plant transcriptional regulators with members regulating multiple biological processes, especially in regulating defense against biotic and abiotic stresses. However, little information is available about WRKYs in pepper (Capsicum annuum L.). The recent release of completely assembled genome sequences of pepper allowed us to perform a genome-wide investigation for pepper WRKY proteins. In the present study, a total of 71 WRKY genes were identified in the pepper genome. According to structural features of their encoded proteins, the pepper WRKY genes (CaWRKY) were classified into three main groups, with the second group further divided into five subgroups. Genome mapping analysis revealed that CaWRKY were enriched on four chromosomes, especially on chromosome 1, and 15.5% of the family members were tandemly duplicated genes. A phylogenetic tree was constructed depending on WRKY domain' sequences derived from pepper and Arabidopsis. The expression of 21 selected CaWRKY genes in response to seven different biotic and abiotic stresses (salt, heat shock, drought, Phytophtora capsici, SA, MeJA, and ABA) was evaluated by quantitative RT-PCR; Some CaWRKYs were highly expressed and up-regulated by stress treatment. Our results will provide a platform for functional identification and molecular breeding studies of WRKY genes in pepper. PMID- 26941765 TI - RNA Interference for Functional Genomics and Improvement of Cotton (Gossypium sp.). AB - RNA interference (RNAi), is a powerful new technology in the discovery of genetic sequence functions, and has become a valuable tool for functional genomics of cotton (Gossypium sp.). The rapid adoption of RNAi has replaced previous antisense technology. RNAi has aided in the discovery of function and biological roles of many key cotton genes involved in fiber development, fertility and somatic embryogenesis, resistance to important biotic and abiotic stresses, and oil and seed quality improvements as well as the key agronomic traits including yield and maturity. Here, we have comparatively reviewed seminal research efforts in previously used antisense approaches and currently applied breakthrough RNAi studies in cotton, analyzing developed RNAi methodologies, achievements, limitations, and future needs in functional characterizations of cotton genes. We also highlighted needed efforts in the development of RNAi-based cotton cultivars, and their safety and risk assessment, small and large-scale field trials, and commercialization. PMID- 26941771 TI - Editorial: Genomics Research on Non-model Plant Pathogens: Delivering Novel Insights into Rust Fungus Biology. PMID- 26941770 TI - Identification and Characterization of the Glucose-6-Phosphate Dehydrogenase Gene Family in the Para Rubber Tree, Hevea brasiliensis. AB - As a key enzyme in the pentose phosphate pathway (PPP), glucose-6-phosphate dehydrogenase (G6PDH) provides nicotinamide adenine dinucleotide phosphate (NADPH) and intermediary metabolites for rubber biosynthesis, and plays an important role in plant development and stress responses. In this study, four Hevea brasiliensis (Para rubber tree) G6PDH genes (HbG6PDH1 to 4) were identified and cloned using a genome-wide scanning approach. All four HbG6PDH genes encode functional G6PDH enzymes as shown by heterologous expression in E. coli. Phylogeny analysis and subcellular localization prediction show that HbG6PDH3 is a cytosolic isoform, while the other three genes (HbG6PDH1, 2 and 4) are plastidic isoforms. The subcellular locations of HbG6PDH3 and 4, two latex abundant isoforms were further verified by transient expression in rice protoplasts. Enzyme activity assay and expression analysis showed HbG6PDH3 and 4 were implicated in PPP during latex regeneration, and to influence rubber production positively in rubber tree. The cytosolic HbG6PDH3 is a predominant isoform in latex, implying a principal role for this isoform in controlling carbon flow and NADPH production in the PPP during latex regeneration. The expression pattern of plastidic HbG6PDH4 correlates well with the degree of tapping panel dryness, a physiological disorder that stops the flow of latex from affected rubber trees. In addition, the four HbG6PDHs responded to temperature and drought stresses in root, bark, and leaves, implicating their roles in maintaining redox balance and defending against oxidative stress. PMID- 26941772 TI - Arabidopsis AtDjA3 Null Mutant Shows Increased Sensitivity to Abscisic Acid, Salt, and Osmotic Stress in Germination and Post-germination Stages. AB - DnaJ proteins are essential co-chaperones involved in abiotic and biotic stress responses. Arabidopsis AtDjA3 gene encodes a molecular co-chaperone of 420 amino acids, which belongs to the J-protein family. In this study, we report the functional characterization of the AtDjA3 gene using the Arabidopsis knockout line designated j3 and the 35S::AtDjA3 overexpression lines. Loss of AtDjA3 function was associated with small seed production. In fact, j3 mutant seeds showed a reduction of 24% in seed weight compared to Col-0 seeds. Expression analysis showed that the AtDjA3 gene was modulated in response to NaCl, glucose, and abscisic acid (ABA). The j3 line had increased sensitivity to NaCl and glucose treatments in the germination and cotyledon development in comparison to parental Col-0. Furthermore, the j3 mutant line exhibited higher ABA sensitivity in comparison to parental Col-0 and 35S::AtDjA3 overexpression lines. In addition, we examined the expression of ABI3 gene, which is a central regulator in ABA signaling, in j3 mutant and 35S::AtDjA3 overexpression lines. Under 5 MUM ABA treatment at 24 h, j3 mutant seedlings displayed higher ABI3 expression, whereas in 35S::AtDjA3 overexpression lines, ABI3 gene expression was repressed. Taken together, these results demonstrate that the AtDjA3 gene is involved in seed development and abiotic stress tolerance. PMID- 26941773 TI - CYP96T1 of Narcissus sp. aff. pseudonarcissus Catalyzes Formation of the Para Para' C-C Phenol Couple in the Amaryllidaceae Alkaloids. AB - The Amaryllidaceae alkaloids are a family of amino acid derived alkaloids with many biological activities; examples include haemanthamine, haemanthidine, galanthamine, lycorine, and maritidine. Central to the biosynthesis of the majority of these alkaloids is a C-C phenol-coupling reaction that can have para para', para-ortho', or ortho-para' regiospecificity. Through comparative transcriptomics of Narcissus sp. aff. pseudonarcissus, Galanthus sp., and Galanthus elwesii we have identified a para-para' C-C phenol coupling cytochrome P450, CYP96T1, capable of forming the products (10bR,4aS)-noroxomaritidine and (10bS,4aR)-noroxomaritidine from 4'-O-methylnorbelladine. CYP96T1 was also shown to catalyzed formation of the para-ortho' phenol coupled product, N demethylnarwedine, as less than 1% of the total product. CYP96T1 co-expresses with the previously characterized norbelladine 4'-O-methyltransferase. The discovery of CYP96T1 is of special interest because it catalyzes the first major branch in Amaryllidaceae alkaloid biosynthesis. CYP96T1 is also the first phenol coupling enzyme characterized from a monocot. PMID- 26941774 TI - Corrigendum: Enhancing Heat Tolerance of the Little Dogwood Cornus canadensis L. f. with Introduction of a Superoxide Reductase Gene from the Hyperthermophilic Archaeon Pyrococcus furiosus. AB - [This corrects the article on p. 26 in vol. 7, PMID: 26858741.]. PMID- 26941775 TI - Editorial: Salicylic Acid Signaling Networks. PMID- 26941776 TI - Commentary: Conservation of AtTZF1, AtTZF2, and AtTZF3 homolog gene regulation by salt stress in evolutionarily distant plant species. PMID- 26941777 TI - Family-Based Multi-SNP X Chromosome Analysis Using Parent Information. AB - We propose a method for association analysis of haplotypes on the X chromosome that offers both improved power and robustness to population stratification in studies of affected offspring and their parents if all three have been genotyped. The method makes use of assumed parental haplotype exchangeability (PHE), a weaker assumption than Hardy-Weinberg equilibrium (HWE). PHE requires that in the source population, of the three X chromosome haplotypes carried by the two parents, each is equally likely to be carried by the father. We propose a pseudo sibling approach that exploits that exchangeability assumption. Our method extends the single-SNP PIX-LRT method to multiple SNPs in a high linkage block. We describe methods for testing the PHE assumption and also for determining how apparent violations can be distinguished from true fetal effects or maternally mediated effects. We show results of simulations that demonstrate nominal type I error rate and good power. The methods are then applied to dbGaP data on the birth defect oral cleft, using both Asian and Caucasian families with cleft. PMID- 26941779 TI - Genomic-Based Optimum Contribution in Conservation and Genetic Improvement Programs with Antagonistic Fitness and Productivity Traits. AB - Animal selection for genetic improvement of productivity may lead to an increase in inbreeding through the use of techniques that enhance the reproductive capability of selected animals. Therefore, breeding strategies aim to balance maintaining genetic variability and acceptable fitness levels with increasing productivity. The present study demonstrates the effectiveness of genomic-based optimum contribution strategies at addressing this objective when fitness and productivity are genetically antagonistic traits. Strategies are evaluated in directional selection (increasing productivity) or conservation (maintaining fitness) scenarios. In the former case, substantial rates of genetic gain can be achieved while greatly constraining the rate of increase in inbreeding. Under a conservation approach, inbreeding depression can be effectively halted while also achieving a modest rate of genetic gain for productivity. Furthermore, the use of optimum contribution strategies when combined with a simple non-random mating scheme (minimum kinship method) showed an additional delay in the increase of inbreeding in the short term. In conclusion, genomic-based optimum contribution methods can be effectively used to control inbreeding and inbreeding depression, and still allow genetic gain for productivity traits even when fitness and productivity are antagonistically correlated. PMID- 26941778 TI - Analysis of Genomic Sequence Motifs for Deciphering Transcription Factor Binding and Transcriptional Regulation in Eukaryotic Cells. AB - Eukaryotic genomes contain a variety of structured patterns: repetitive elements, binding sites of DNA and RNA associated proteins, splice sites, and so on. Often, these structured patterns can be formalized as motifs and described using a proper mathematical model such as position weight matrix and IUPAC consensus. Two key tasks are typically carried out for motifs in the context of the analysis of genomic sequences. These are: identification in a set of DNA regions of over represented motifs from a particular motif database, and de novo discovery of over-represented motifs. Here we describe existing methodology to perform these two tasks for motifs characterizing transcription factor binding. When applied to the output of ChIP-seq and ChIP-exo experiments, or to promoter regions of co modulated genes, motif analysis techniques allow for the prediction of transcription factor binding events and enable identification of transcriptional regulators and co-regulators. The usefulness of motif analysis is further exemplified in this review by how motif discovery improves peak calling in ChIP seq and ChIP-exo experiments and, when coupled with information on gene expression, allows insights into physical mechanisms of transcriptional modulation. PMID- 26941781 TI - Hybrid control of the Neimark-Sacker bifurcation in a delayed Nicholson's blowflies equation. AB - In this article, for delayed Nicholson's blowflies equation, we propose a hybrid control nonstandard finite-difference (NSFD) scheme in which state feedback and parameter perturbation are used to control the Neimark-Sacker bifurcation. Firstly, the local stability of the positive equilibria for hybrid control delay differential equation is discussed according to Hopf bifurcation theory. Then, for any step-size, a hybrid control numerical algorithm is introduced to generate the Neimark-Sacker bifurcation at a desired point. Finally, numerical simulation results confirm that the control strategy is efficient in controlling the Neimark Sacker bifurcation. At the same time, the results show that the NSFD control scheme is better than the Euler control method. PMID- 26941780 TI - Commentary: Past, present, and future of epigenetics applied to livestock breeding - Hard versus Soft Lamarckian Inheritance Mechanisms. PMID- 26941782 TI - The stability of a predator-prey system with linear mass-action functional response perturbed by white noise. AB - The present paper deals with the problem of an ecoepidemiological model with linear mass-action functional response perturbed by white noise. The essential mathematical features are analyzed with the help of the stochastic stability, its long time behavior around the equilibrium of deterministic ecoepidemiological model, and the stochastic asymptotic stability by Lyapunov analysis methods. Numerical simulations for a hypothetical set of parameter values are presented to illustrate the analytical findings. PMID- 26941783 TI - shRNA target prediction informed by comprehensive enquiry (SPICE): a supporting system for high-throughput screening of shRNA library. AB - RNA interference (RNAi) screening is extensively used in the field of reverse genetics. RNAi libraries constructed using random oligonucleotides have made this technology affordable. However, the new methodology requires exploration of the RNAi target gene information after screening because the RNAi library includes non-natural sequences that are not found in genes. Here, we developed a web-based tool to support RNAi screening. The system performs short hairpin RNA (shRNA) target prediction that is informed by comprehensive enquiry (SPICE). SPICE automates several tasks that are laborious but indispensable to evaluate the shRNAs obtained by RNAi screening. SPICE has four main functions: (i) sequence identification of shRNA in the input sequence (the sequence might be obtained by sequencing clones in the RNAi library), (ii) searching the target genes in the database, (iii) demonstrating biological information obtained from the database, and (iv) preparation of search result files that can be utilized in a local personal computer (PC). Using this system, we demonstrated that genes targeted by random oligonucleotide-derived shRNAs were not different from those targeted by organism-specific shRNA. The system facilitates RNAi screening, which requires sequence analysis after screening. The SPICE web application is available at http://www.spice.sugysun.org/. PMID- 26941784 TI - Inference of protein-protein interaction networks from multiple heterogeneous data. AB - Protein-protein interaction (PPI) prediction is a central task in achieving a better understanding of cellular and intracellular processes. Because high throughput experimental methods are both expensive and time-consuming, and are also known of suffering from the problems of incompleteness and noise, many computational methods have been developed, with varied degrees of success. However, the inference of PPI network from multiple heterogeneous data sources remains a great challenge. In this work, we developed a novel method based on approximate Bayesian computation and modified differential evolution sampling (ABC-DEP) and regularized laplacian (RL) kernel. The method enables inference of PPI networks from topological properties and multiple heterogeneous features including gene expression and Pfam domain profiles, in forms of weighted kernels. The optimal weights are obtained by ABC-DEP, and the kernel fusion built based on optimal weights serves as input to RL to infer missing or new edges in the PPI network. Detailed comparisons with control methods have been made, and the results show that the accuracy of PPI prediction measured by AUC is increased by up to 23 %, as compared to a baseline without using optimal weights. The method can provide insights into the relations between PPIs and various feature kernels and demonstrates strong capability of predicting faraway interactions that cannot be well detected by traditional RL method. PMID- 26941785 TI - Chaotic Teaching-Learning-Based Optimization with Levy Flight for Global Numerical Optimization. AB - Recently, teaching-learning-based optimization (TLBO), as one of the emerging nature-inspired heuristic algorithms, has attracted increasing attention. In order to enhance its convergence rate and prevent it from getting stuck in local optima, a novel metaheuristic has been developed in this paper, where particular characteristics of the chaos mechanism and Levy flight are introduced to the basic framework of TLBO. The new algorithm is tested on several large-scale nonlinear benchmark functions with different characteristics and compared with other methods. Experimental results show that the proposed algorithm outperforms other algorithms and achieves a satisfactory improvement over TLBO. PMID- 26941786 TI - Trastuzumab in Esophagogastric Cancer: HER2-Testing and Treatment Reality outside Clinical Studies in Germany. AB - We analysed trends over time in palliative first-line chemotherapy in patients with locally advanced or metastatic esophagogastric cancer. Special focus was on frequency and quality of HER2-testing and trends in drug use in combination with trastuzumab. Earlier published data about patients treated outside clinical studies showed a relatively low rate of HER2-testing and insufficient test quality. A total of 2,808 patients retrospectively documented in Therapiemonitor ((r)) from 2006 to 2013 were analysed regarding treatment intensity and trends in used drugs. Data on HER2-testing and therapies were analysed in two cohorts documented in 2010 and 2011 (1) compared to 2012 and 2013 (2). Treatment intensity increased: 49.3% of patients received at least a triplet in 2013 compared to 10.1% in 2006. In cohort 2 HER2 expression was tested in 79.1% of the cases. Still, in 26.9% testing was not done as requested by guidelines. Good performance status, multiple metastases, age <= 65 years, the objective "to prevent progression," good cognitive capabilities, estimated good compliance, and social integration positively influenced the probability of HER2-testing; comorbidities negatively affected it. Usage of the combination of fluoropyrimidines and cisplatin with trastuzumab declined from 67% in cohort 1 to 50% in cohort 2. PMID- 26941787 TI - Current Status and Future Directions of Capsule Endoscopy. PMID- 26941788 TI - Systemic and Splanchnic Lipopolysaccharide and Endothelin-1 Plasma Levels in Liver Cirrhosis before and after Transjugular Intrahepatic Portosystemic Shunt. AB - Lipopolysaccharide (LPS) and endothelin- (ET-) 1 may aggravate portal hypertension by increasing intrahepatic resistance and splanchnic blood flow. In the portal vein, after TIPS shunting, LPS and ET-1 were significantly decreased. Our study suggests that TIPS can benefit cirrhotic patients not only in high hemodynamics related variceal bleeding but also in intestinal bacterial translocation associated complications such as endotoxemia. PMID- 26941789 TI - Pancreatic Cancer Epidemiology, Detection, and Management. AB - PC (pancreatic cancer) is the fourth most common cause of death due to cancer worldwide. The incidence and mortality rates have been increasing year by year worldwide, and this review has analyzed the most recent incidence and mortality data for pancreatic cancer occurrence in China. Several possible risk factors have been discussed here, involving known established risk factors and novel possible risk factors. The development of this cancer is a stepwise progression through intraepithelial neoplasia to carcinoma. Though early and accurate diagnosis is promising based on a combination of recent techniques including tumor markers and imaging modalities, lacking early clinical symptoms makes the diagnosis late. Correct staging is critical because treatment is generally based on this parameter. Treatment options have improved throughout the last decades. However, surgical excision remains the primary therapy and efficacy of conventional chemoradiotherapy for PC is limited. Recently, some novel new therapies have been developed and will be applied in clinics soon. This review will provide an overview of pancreatic cancer, including an understanding of the developments and controversies. PMID- 26941790 TI - Methanolic Extract of Ceplukan Leaf (Physalis minima L.) Attenuates Ventricular Fibrosis through Inhibition of TNF-alpha in Ovariectomized Rats. AB - The increase of heart failure prevalence on menopausal women was correlated with the decrease of estrogen level. The aim of this study is to investigate the effects of ceplukan leaf (Physalis minima L.), which contains phytoestrogen physalin and withanolides, on ventricular TNF-alpha level and fibrosis in ovariectomized rats. Wistar rats were divided into six groups (control (-); OVX 5: 5-week ovariectomy (OVX); OVX 9: 9-week ovariectomy; treatments I, II, and III: 9-weeks OVX + 4-week ceplukan leaf's methanolic extract doses 500, 1500, and 2500 mg/kgBW, resp.). TNF-alpha levels were measured with ELISA. Fibrosis was counted as blue colored tissues percentage using Masson's Trichrome staining. This study showed that prolonged hypoestrogen increases ventricular fibrosis (p < 0.05). Ceplukan leaf treatment also resulted in a decrease of ventricular fibrosis and TNF-alpha level in dose dependent manner compared to without treatment group (p < 0.05). Furthermore, the TNF-alpha level was normalized in 2500 mg/kgBW Physalis minima L. (p < 0.05) treatment. The reduction of fibrosis positively correlated with TNF-alpha level (p < 0.05, r = 0.873). Methanolic extract of ceplukan leaf decreases ventricular fibrosis through the inhibition of ventricular TNF-alpha level in ovariectomized rats. PMID- 26941791 TI - Protective Effect of Diospyros kaki against Glucose-Oxygen-Serum Deprivation Induced PC12 Cells Injury. AB - Ischemic cerebrovascular disease is one of the most common causes of death in the world. Recent interests have been focused on natural antioxidants and anti inflammatory agents as potentially useful neuroprotective agents. Diospyros kaki (persimmon) has been shown to exert anti-inflammatory, antioxidant, and antineoplastic effects. However, its effects on ischemic damage have not been evaluated. Here, we used an in vitro model of cerebral ischemia and studied the effects of hydroalcoholic extract of peel (PeHE) and fruit pulp (PuHE) of persimmon on cell viability and markers of oxidative damage mainly intracellular reactive oxygen species (ROS) induced by glucose-oxygen-serum deprivation (GOSD) in PC12 cells. GOSD for 6 h produced significant cell death which was accompanied by increased levels of ROS. Pretreatment with different concentrations of PeHE and PuHE (0-500 MUg/mL) for 2 and 24 h markedly restored these changes only at high concentrations. However, no significant differences were seen in the protection against ischemic insult between different extracts and the time of exposure. The experimental results suggest that persimmon protects the PC12 cells from GOSD-induced injury via antioxidant mechanisms. Our findings might raise the possibility of potential therapeutic application of persimmon for managing cerebral ischemic and other neurodegenerative disorders. PMID- 26941793 TI - Effect of Reinforcement of Oral Health Education Message through Short Messaging Service in Mobile Phones: A Quasi-Experimental Trial. AB - Objective. This paper aims to assess the effectiveness of reinforcement of oral health education message through short messaging service (SMS) in mobile phones. Material and Methods. 400 subjects from two colleges (200 from each college) belonging to 18-20 years age group possessing mobile phones were randomly selected and baseline examination of oral hygiene and gingival status was carried out using Oral Hygiene Index (OHI) and Gingival Index (GI). Oral health education was provided to all the subjects. Oral health education message was reinforced through short messaging service (SMS) in mobile phones for the subjects belonging to the intervention group. There was no such reinforcement for the control group. Follow-up examinations were done at the end of 1st, 2nd, 3rd, and 6th month. After the 3rd month, subjects of the intervention group did not receive oral health education message through short messaging service (SMS) and were followed up after next three months. Compiled data was analyzed using SPSS version 16 statistical software. Result. Mean OHI and GI scores in intervention group were significantly (p < 0.01) less than those of control group after the 2nd, 3rd, and 6th month. Conclusion. Reinforcement of oral health education message through short messaging service (SMS) is effective media to improve oral health. PMID- 26941792 TI - A Review on Potential Mechanisms of Terminalia chebula in Alzheimer's Disease. AB - The current management of Alzheimer's disease (AD) focuses on acetylcholinesterase inhibitors (AChEIs) and NMDA receptor antagonists, although outcomes are not completely favorable. Hence, novel agents found in herbal plants are gaining attention as possible therapeutic alternatives. The Terminalia chebula (Family: Combretaceae) is a medicinal plant with a wide spectrum of medicinal properties and is reported to contain various biochemicals such as hydrolysable tannins, phenolic compounds, and flavonoids, so it may prove to be a good therapeutic alternative. In this research, we reviewed published scientific literature found in various databases: PubMed, Science Direct, Scopus, Web of Science, Scirus, and Google Scholar, with the keywords: T. chebula, AD, neuroprotection, medicinal plant, antioxidant, ellagitannin, gallotannin, gallic acid, chebulagic acid, and chebulinic acid. This review shows that T. chebula extracts and its constituents have AChEI and antioxidant and anti-inflammatory effects, all of which are currently relevant to the treatment of Alzheimer's disease. PMID- 26941794 TI - A Posterior TAP Block Provides More Effective Analgesia Than a Lateral TAP Block in Patients Undergoing Laparoscopic Gynecologic Surgery: A Retrospective Study. AB - Background. There are a few papers that compared the lateral transversus abdominis plane (TAP) block with the posterior TAP block. Our study aimed to compare retrospectively the quality of analgesia after laparoscopic gynecologic surgery using the lateral TAP block with general anesthesia versus the posterior TAP block with general anesthesia. Method. Sixty-seven adult female patients were included in this retrospective study. Of these patients, thirty-four patients received the lateral TAP block with general anesthesia (lat. TAP group), and the rest of thirty-three patients received the posterior TAP block with general anesthesia (pos. TAP group). Pain scores both at rest and at movement and the use of additional analgesic drugs were recorded in the postoperative care unit within twenty-four hours after the operation. Postoperative complications were noted. Results. Patients who received pos. TAP reported lower visual analog scale (VAS) pain scores in all points, within twenty-four hours after the operation, than patients who received lat. TAP. Moreover, with the use of additional analgesic drugs, the incidence of nausea and vomiting during the first twenty-four hours after surgery was lower in the pos. TAP group than in the lat. TAP group. Conclusion. The posterior TAP block provided more effective analgesia than the lateral TAP block in patients undergoing laparoscopic gynecologic surgery. PMID- 26941795 TI - Caregiver Stigma and Burden in Memory Disorders: An Evaluation of the Effects of Caregiver Type and Gender. AB - Despite considerable gains in public awareness of dementia, dementia patients and their caregivers continue to be stigmatized. Previous work has explored stigma and burden among adult children of persons with dementia in Israel, but no similar data exist for spousal caregivers or caregivers in general in the United States. This study examines the differences in stigma and burden experienced by spousal and adult child caregivers and male and female caregivers of persons with dementia. Eighty-two caregivers were given the Zarit Burden Inventory Short Form (ZBI) and the Caregiver Section of the Family Stigma in Alzheimer's Disease Scale (FS-ADS-C). Scores on the FS-ADS-C and ZBI were positively correlated (r s = .51, p < .001). Female caregivers reported experiencing more stigma on the FS-ADS-C (t(80) = -4.37, p < .001) and more burden on the ZBI (t(80) = -2.68, p = .009) compared to male caregivers, and adult child caregivers reported experiencing more stigma on the FS-ADS-C (t(30.8) = -2.22, p = .034) and more burden on the ZBI (t(80) = -2.65, p = .010) than spousal caregivers. These results reinforce the importance of support for caregivers, particularly adult child and female caregivers who may experience higher levels of stigma and burden. PMID- 26941796 TI - Histopathological Study of Cyclosporine Pulmonary Toxicity in Rats. AB - Cyclosporine is considered one of the common worldwide immunosuppressive drugs that are used for allograft rejection prevention. However, articles that address adverse effects of cyclosporine use on the vital organs such as lung are still few. This study aims to investigate pulmonary toxic effect of cyclosporine in rats by assessment of pulmonary histopathological changes using light and electron microscope examination. Sixty male adult albino rats were divided into three groups; each group consists of twenty rats. The first received physiological saline while the second and third groups received 25 and 40 mg/kg/day of cyclosporine, respectively, by gastric gavage for forty-five days. Cyclosporine reduced the lung and body weight with shrinkage or pyknotic nucleus of pneumocyte type II, degeneration of alveoli and interalveolar septum beside microvilli on the alveolar surface, emphysema, inflammatory cellular infiltration, pulmonary blood vessels congestion, and increase of fibrous tissues in the interstitial tissues and around alveoli with negative Periodic Acid-Schiff staining. Prolonged use of cyclosporine induced pulmonary ultrastructural and histopathological changes with the lung and body weight reduction depending on its dose. PMID- 26941797 TI - Activity of Medicinal Plant Extracts on Multiplication of Mycobacterium tuberculosis under Reduced Oxygen Conditions Using Intracellular and Axenic Assays. AB - Aim. Test the activity of selected medicinal plant extracts on multiplication of Mycobacterium tuberculosis under reduced oxygen concentration which represents nonreplicating conditions. Material and Methods. Acetone, ethanol and aqueous extracts of the plants Acorus calamus L. (rhizome), Ocimum sanctum L. (leaf), Piper nigrum L. (seed), and Pueraria tuberosa DC. (tuber) were tested on Mycobacterium tuberculosis H37Rv intracellularly using an epithelial cell (A549) infection model. The extracts found to be active intracellularly were further studied axenically under reducing oxygen concentrations. Results and Conclusions. Intracellular multiplication was inhibited >=60% by five of the twelve extracts. Amongst these 5 extracts, in axenic culture, P. nigrum (acetone) was active under aerobic, microaerophilic, and anaerobic conditions indicating presence of multiple components acting at different levels and P. tuberosa (aqueous) showed bactericidal activity under microaerophilic and anaerobic conditions implying the influence of anaerobiosis on its efficacy. P. nigrum (aqueous) and A. calamus (aqueous and ethanol) extracts were not active under axenic conditions but only inhibited intracellular growth of Mycobacterium tuberculosis, suggesting activation of host defense mechanisms to mediate bacterial killing rather than direct bactericidal activity. PMID- 26941798 TI - Cronkhite-Canada Syndrome: A Rare Cause of Chronic Diarrhoea in a Young Man. AB - A young Indian man presented with nine-month history of chronic diarrhea, occasionally mixed with blood and intermittent colicky abdominal pain. He also complained of generalized body swelling for the last three months. On examination, he had diffuse hyperpigmentation of the skin and dystrophic nail changes. Upper and lower gastrointestinal endoscopy revealed multiple sessile polyps in the stomach, small bowel, and colon and rectum. Biopsy of polyps showed adenomatous changes with stromal edema and dilated glands. Cronkhite-Canada syndrome (CCS) was diagnosed and treated with glucocorticoids and enteral nutritional supplementation. There was an associated small intestinal bacterial overgrowth (SIBO) and stool was positive for clostridium difficile toxin. After 12 weeks of treatment, the patient achieved remission. Close correlation with clinical findings, including pertinent ectodermal abnormalities, endoscopic studies, and careful examination of biopsies will ensure a timely and correct diagnosis of CCS. PMID- 26941799 TI - DAS181 Treatment of Severe Parainfluenza Virus 3 Pneumonia in Allogeneic Hematopoietic Stem Cell Transplant Recipients Requiring Mechanical Ventilation. AB - Parainfluenza virus (PIV) may cause life-threatening pneumonia in allogeneic hematopoietic stem cell transplant (HSCT) recipients. Currently, there are no proven effective therapies. We report the use of inhaled DAS181, a novel sialidase fusion protein, for treatment of PIV type 3 pneumonia in two allogeneic hematopoietic SCT recipients with respiratory failure. PMID- 26941800 TI - The Influence of Aging on the Regenerative Potential of Human Adipose Derived Mesenchymal Stem Cells. AB - Tissue regeneration using human adipose derived mesenchymal stem cells (hASCs) has significant potential as a novel treatment for many degenerative bone and joint diseases. Previous studies have established that age negatively affects the proliferation status and the osteogenic and chondrogenic differentiation potential of mesenchymal stem cells. The aim of this study was to assess the age related maintenance of physiological function and differentiation potential of hASCs in vitro. hASCs were isolated from patients of four different age groups: (1) >20 years (n = 7), (2) >50 years (n = 7), (3) >60 years (n = 7), and (4) >70 years (n = 7). The hASCs were characterized according to the number of fibroblasts colony forming unit (CFU-F), proliferation rate, population doubling time (PDT), and quantified parameters of adipogenic, chondrogenic, and osteogenic differentiation. Compared to younger cells, aged hASCs had decreased proliferation rates, decreased chondrogenic and osteogenic potential, and increased senescent features. A shift in favor of adipogenic differentiation with increased age was also observed. As many bone and joint diseases increase in prevalence with age, it is important to consider the negative influence of age on hASCs viability, proliferation status, and multilineage differentiation potential when considering the potential therapeutic applications of hASCs. PMID- 26941803 TI - T-cell receptor phenotype pattern in atopic children using commercial fluorescently labeled antibodies against 21 human class-specific v segments for the tcrbeta chain (vbeta) of peripheral blood: a cross sectional study. AB - BACKGROUND: T-cell receptor (TCR) repertoire development is an integral part of the adaptive immune response. T-cell activation requires recognition of appropriately processed antigens by the TCR. Development of a diverse repertoire of TCRs is therefore essential to ensure adequate protection from potential threats. The majority of T-cells in peripheral blood have TCRs composed of an alpha and a beta chain. At the DNA level, the TCR genes are formed through directed recombination from germline sequences-the so-called VDJ recombination [variable (V) joining (J) diversity (D) gene segments] which results in variations in the repertoire. The most variable part of TCRs is the Vbeta region (VbetaTCR), which has multiple V segment families that can be quantitatively measured. However, only sparse data exists on the normal levels of the VbetaTCR repertoire in healthy children. We aimed to establish normal values for the VbetaTCR repertoire in atopic children without immunodeficiency. METHODS: Fifty three children were recruited from food allergy, drug allergy, chronic urticaria and anaphylaxis registries and were divided into groups based on age: >0-2 years, 3-6 years, and 6-18 years. We used commercially available and fluorescently labeled antibodies against 21 human class-specific V segments of the TCRbeta chain (Vbeta) to study in peripheral blood the quantitative pattern of Vbeta variation by flow cytometry. RESULTS: Children of all ages exhibited a similar pattern of TCR Vbeta expression. Vbeta 2 was the most commonly expressed family in all three age groups [9.5 % (95 % CI, 8.9, 10 %), 8.8 % (95 % CI, 7.4, 10.2 %) and 7.6 % (7.0, 8.3 %) respectively]. However, the percentage of Vbeta 2 decreased in older children and the percentage of Vbeta 1 was higher in males. TCR Vbeta expression in our sample of atopic children did not differ substantially from previously published levels in non-atopic cohorts. CONCLUSION: TCR Vbeta diversity follows a predictable and comparable pattern in atopic and healthy non-atopic children. Establishing normal levels for healthy children with and without atopy will contribute to a better definition of Vbeta receptor deviation in children with primary immunodeficiency and/or immunodysregulation conditions. PMID- 26941802 TI - Features of Microsystems for Cultivation and Characterization of Stem Cells with the Aim of Regenerative Therapy. AB - Stem cells have infinite potential for regenerative therapy thanks to their advantageous ability which is differentiable to requisite cell types for recovery and self-renewal. The microsystem has been proved to be more helpful to stem cell studies compared to the traditional methods, relying on its advantageous feature of mimicking in vivo cellular environments as well as other profitable features such as minimum sample consumption for analysis and multiprocedures. A wide variety of microsystems were developed for stem cell studies; however, regenerative therapy-targeted applications of microtechnology should be more emphasized and gain more attractions since the regenerative therapy is one of ultimate goals of biologists and bioengineers. In this review, we introduce stem cell researches harnessing well-known microtechniques (microwell, micropattern, and microfluidic channel) in view point of physical principles and how these systems and principles have been implemented appropriately for characterizing stem cells and finding possible regenerative therapies. Biologists may gain information on the principles of microsystems to apply them to find solutions for their current challenges, and engineers may understand limitations of the conventional microsystems and find new chances for further developing practical microsystems. Through the well combination of engineers and biologists, the regenerative therapy-targeted stem cell researches harnessing microtechnology will find better suitable treatments for human disorders. PMID- 26941801 TI - Molecular Mechanisms Underlying Peritoneal EMT and Fibrosis. AB - Peritoneal dialysis is a form of renal replacement alternative to the hemodialysis. During this treatment, the peritoneal membrane acts as a permeable barrier for exchange of solutes and water. Continual exposure to dialysis solutions, as well as episodes of peritonitis and hemoperitoneum, can cause acute/chronic inflammation and injury to the peritoneal membrane, which undergoes progressive fibrosis, angiogenesis, and vasculopathy, eventually leading to discontinuation of the peritoneal dialysis. Among the different events controlling this pathological process, epithelial to mesenchymal transition of mesothelial cells plays a main role in the induction of fibrosis and in subsequent functional deterioration of the peritoneal membrane. Here, the main extracellular inducers and cellular players are described. Moreover, signaling pathways acting during this process are elucidated, with emphasis on signals delivered by TGF-beta family members and by Toll-like/IL-1beta receptors. The understanding of molecular mechanisms underlying fibrosis of the peritoneal membrane has both a basic and a translational relevance, since it may be useful for setup of therapies aimed at counteracting the deterioration as well as restoring the homeostasis of the peritoneal membrane. PMID- 26941804 TI - Biochemical and molecular evidences on the protection by magnesium oxide nanoparticles of chlorpyrifos-induced apoptosis in human lymphocytes. AB - BACKGROUND: Chlorpyrifos (CP) is one of the most widely used organophosphate (OP) insecticides in agricultural and residential pest control with its attendant adverse health effect. In the present study, it is proposed to investigate the possible modulatory role of magnesium oxide nanoparticles (MgO NPs) against CP induced toxicity in human lymphocytes and determine the mechanisms lying behind this protection by viability and biochemical assays. MATERIALS AND METHODS: Isolated lymphocytes were exposed to 12 MUg/mL CP either alone or in combination with different concentrations of MgO NPs (0.1 MUg/mL, 1 MUg/mL, 10 MUg/mL, and 100 MUg/mL). After a 3-day incubation, the viability and oxidative stress markers including cellular mitochondrial activity, caspase-3 and -9 activities, total antioxidant power, lipid peroxidation, and myeloperoxidase (MPO) activity were measured. Also, the levels of tumor necrosis factor-alpha (TNF-alpha) as inflammatory index, along with acetylcholinesterase (AChE) activity were measured. Statistical differences were determined using one-way analysis of variance (ANOVA) and Dunnett's multiple comparison tests. RESULTS: It is indicated that CP-exposed lymphocytes treated with MgO NPs resulted in a substantial reduction in the pace of mortality as well as the stages of oxidative stress in a dose-dependent manner. Also, MgO NPs (100 MUg/mL) meaningfully restored CP-induced increase of TNF-alpha (P < 0.001) and decrease of AChE activity (P < 0.001) and were capable of preventing CP-treated human lymphocytes from apoptosis (P < 0.001). CONCLUSION: Our results demonstrate that MgO NPs in approximate 100 nm diameter not only make cells resistant to the toxic properties of CP but also attenuate toxic effects of CP, which is demonstrating the potential of MgO NPs to be applied in future immune deficiency therapeutic strategies. PMID- 26941805 TI - Better view on attitudes and perceived parental reactions behind waterpipe smoking among Iranian students. AB - BACKGROUND: Because of the increasing usage of waterpipe globally, we need to know more about the different factors related to waterpipe and cigarette smoking. Therefore, the present study aims at gaining more insight on waterpipe and cigarette smoking based on perceived parental reaction and appeal and repellent of smoking among adolescents. MATERIALS AND METHODS: A cross-sectional survey entitled "Isfahan Tobacco Use Prevention Program" (ITUPP) was conducted among 5,500 adolescents in Isfahan Province, Iran in 2010 using a self-administered anonymous questionnaire. Demographic factors, cigarette and waterpipe smoking status, appeal and repellent of smoking, perceived parental reactions, and the main reasons behind the increase in waterpipe smoking were measured. Chi-square, univariate logistic regression, and multiple logistic regression were used. For all analyses, we defined statistical significance a priori with a two-tailed alpha of 0.05. Statistical analyses were conducted using the Statistical Package for the Social Sciences (SPSS) version 15. RESULTS: 50% of the sample was female and 89% lived in urban areas. The average age of the respondents was 14.37 +/- 1. 70 years. While a majority of cigarette smokers (70.9%) were waterpipe smokers, only 35.7% of waterpipe smokers smoked cigarettes. The incidence of smoking was high in those who expected less extensive parental reaction with odds ratio (OR) = 1.89 [95% confidence interval (CI): 1.35-2.63] (P < 0.001) among cigarette smokers and OR = 2.75 (95% CI: 2.16-3.50) (P < 0.001) among waterpipe smokers. "Taste" was rated the most attractive feature by waterpipe and cigarette smokers 2.83-fold (95% CI: 2.06, 3.90) (P < 0.001). Most waterpipe smokers compared to nonsmokers believed that the main reason behind waterpipe popularity was habit. CONCLUSION: The factors related to waterpipe smoking were different from those in cigarette smoking; so we need to implement different interventions to overcome the surging usage of tobacco use. PMID- 26941806 TI - Apolipoprotein A1 as a novel anti-implantation biomarker in polycystic ovary syndrome: A case-control study. AB - BACKGROUND: Women with polycystic ovary syndrome have lower pregnancy rates, possibly due to the decreased uterine receptivity. Successful implantation depends on protein networks that are essential for cross-talk between the embryo and endometrium. Apolipoprotein A1 has been proposed as a putative anti implantation factor. In this study, we evaluated apolipoprotein A1 expression in human endometrial tissues. MATERIALS AND METHODS: Endometrial apolipoprotein A1 messenger RNA (mRNA) and protein expression were investigated using quantitative real-time polymerase chain reaction (PCR) and Western blot. The distribution of apolipoprotein A1 was also detected by immunostaining. Samples were obtained from 10 patients with polycystic ovary syndrome and 15 healthy fertile women in the proliferative (on day 2 or day 3 before ovulation, n = 7) and secretory (on days 3-5 after ovulation, n = 8) phases. RESULTS: Endometrial apolipoprotein A1 expression was upregulated in patients with polycystic ovary syndrome compared to normal subjects. However, apolipoprotein A1 expression in the proliferative phase was significantly higher than in the luteal phase (P value < 0.05). CONCLUSION: It seems that differentially expressed apolipoprotein A1 negatively affects endometrial receptivity in patients with polycystic ovary syndrome. The results showed that apolipoprotein A1 level significantly changes in the human endometrium during the menstrual cycle with minimum expression in the secretory phase, coincident with the receptive phase (window of implantation). Further studies are required to clarify the clinical application of this protein. PMID- 26941808 TI - Effects of oral vitamin E on treatment of atopic dermatitis: A randomized controlled trial. AB - BACKGROUND: The pathogenesis of atopic dermatitis (AD) remains to be determined; recently a possible change in the immune system with production of immunoglobulins is proposed. As vitamin E is a potent antioxidant, with the ability to decrease the serum levels of immunoglobulin E (IgE) in atopic patients, we aimed to evaluate the effect of oral vitamin E on treatment of AD. MATERIALS AND METHODS: This randomized, double-blind, placebo-controlled trial comprised seventy participants with mild-to-moderate AD, based on the Hanifin and Rajka diagnostic criteria. The patients were randomly selected from teaching skin clinics in Isfahan, Iran. They were randomly assigned to two groups of equal number, receiving vitamin E (400 IU/day) and placebo for four 4 months. Each month, the extent, severity, and subjective symptoms including itch and sleeplessness were measured by SCORAD index. Three months after the end of intervention, the recurrence rate was assessed. RESULTS: The improvement in all symptoms, except sleeplessness, was significantly higher in the group receiving vitamin E than in controls (-1.5 vs. 0.218 in itching, -10.85 vs. -3.54 in extent of lesion, and -11.12 vs. -3.89 in SCORAD index, respectively, P < 0.05). Three months after the end of intervention, the recurrence rate of AD was evaluated. Recurrence rate between all 42 individuals, who remained in the study, was 18.6%. Recurrence ratio of the group receiving vitamin E compared to the placebo group was 1.17, without significant differences between the two groups (P > 0.05). CONCLUSION: This study suggests that vitamin E can improve the symptoms and the quality of life in patients with AD. As vitamin E has no side effects with a dosage of 400 IU/day, it can be recommended for the treatment of AD. PMID- 26941807 TI - Graft survival rate of renal transplantation during a period of 10 years in Iran. AB - BACKGROUND: Kidney transplantation is a preferred treatment for many patients with end-stage renal disease (ESRD) and is far more profitable than hemodialysis. Analyzing renal transplantation data can help to evaluate the effectiveness of transplantation interventions. The aim of this study was to determine the organ survival rate after kidney transplantation during a period of 10 years (March 2001-March 2011) among transplanted patients in Arak, Markazi Province, Iran. MATERIALS AND METHODS: In this historical cohort study, all recipients of kidney transplantation from Arak, Markazi Province, Iran who had medical records in Valiasr Hospital and "charity for kidney patients" of Arak, Markazi Province, Iran during a period of 10 years from March 2001 to March 2011 were included. Data collected by using checklists were completed from patients' hospital records. Kaplan-Meier method was used to determine the graft cumulative survival rate, log-rank test to compare survival curves in subgroups, and Cox regression model to define the hazard ratio and for ruling out the intervening factors. Statistical analysis was conducted by Statistical Package for the Social Sciences (SPSS) 20 and Stata 11. RESULTS: Mean duration of follow-up was 55.43 +/- 42.02 months. By using the Kaplan-Meier method, the cumulative probability of graft survival at 1, 3, 5, 7, and 10 years was 99.1, 97.7, 94.3, 85.7, and 62.1%, respectively. The number of dialysis by controlling the effect of other variables had a significant association with the risk of graft failure [hazard ratios and 95% confidence interval (CI): 1.47 (1.02-2.13)]. CONCLUSION: This study showed that the graft survival rate was satisfactory in this community and was similar to the results of single-center studies in the world. Dialysis time after transplantation was a significant predictor of survival in the recipients of kidney transplantation that should be considered. PMID- 26941809 TI - Effects of mindfulness-based stress reduction on perceived stress and psychological health in patients with tension headache. AB - BACKGROUND: Programs for improving health status of patients with illness related to pain, such as headache, are often still in their infancy. Mindfulness-based stress reduction (MBSR) is a new psychotherapy that appears to be effective in treating chronic pain and stress. This study evaluated efficacy of MBSR in treatment of perceived stress and mental health of client who has tension headache. MATERIALS AND METHODS: This study is a randomized clinical trial. Sixty patients with tension type headache according to the International Headache Classification Subcommittee were randomly assigned to the Treatment As Usual (TAU) group or experimental group (MBSR). The MBSR group received eight weekly classmates with 12-min sessions. The sessions were based on MBSR protocol. The Brief Symptom Inventory (BSI) and Perceived Stress Scale (PSS) were administered in the pre- and posttreatment period and at 3 months follow-up for both the groups. RESULTS: The mean of total score of the BSI (global severity index; GSI) in MBSR group was 1.63 +/- 0.56 before the intervention that was significantly reduced to 0.73 +/- 0.46 and 0.93 +/- 0.34 after the intervention and at the follow-up sessions, respectively (P < 0.001). In addition, the MBSR group showed lower scores in perceived stress in comparison with the control group at posttest evaluation. The mean of perceived stress before the intervention was 16.96 +/- 2.53 and was changed to 12.7 +/- 2.69 and 13.5 +/- 2.33 after the intervention and at the follow-up sessions, respectively (P < 0.001). On the other hand, the mean of GSI in the TAU group was 1.77 +/- 0.50 at pretest that was significantly reduced to 1.59 +/- 0.52 and 1.78 +/- 0.47 at posttest and follow-up, respectively (P < 0.001). Also, the mean of perceived stress in the TAU group at pretest was 15.9 +/- 2.86 and that was changed to 16.13 +/- 2.44 and 15.76 +/- 2.22 at posttest and follow-up, respectively (P < 0.001). CONCLUSION: MBSR could reduce stress and improve general mental health in patients with tension headache. PMID- 26941810 TI - Efficacy of bolus insulin calculation by a mobile-based bolus advisor: An open label clinical trial. AB - BACKGROUND: We investigated the efficacy of a mobile-based bolus advisor app in comparison with the usual multiple daily injections (MDIs) in diabetic patients. MATERIALS AND METHODS: In a nonrandomized, controlled clinical trial, 62 diabetic patients were selected to receive a 12-week intensive glycemic control by either a mobile-based bolus advisor (app) or MDI in the usual manner. We compared mean blood glucose (BG) and HbA1c before and just after the treatment program. The data were analyzed using paired sample t-test and analysis of variance (ANOVA). RESULTS: Fifty-six patients (30 cases and 26 controls) completed the study. The mean [standard deviation (SD)] of BG was 220.57 (43.7) and 231.5 (55) in the app group and control group, respectively. Mean BG decreased 38 mg/dL in the app and 16 mg/dL in the control group (P = 0.001 and 0.049 respectively). Changes of mean BG were different between the two groups significantly (P = 0.039). HbA1c decreased from 8.4% to 7.6% in the case and from 8.4% to 8% in the control group (P = 0.001 and 0.06, respectively). Changes of HbA1c were not different between the two groups (P = 0.141). The mean episodes of hypoglycemia were not different between the groups significantly (P = 0.108). CONCLUSION: In conclusion, this study revealed that mobile-based bolus advisors can reduce mean BG better in patients who are planned to have a tight glycemic control as a feasible and available method and may improve HbA1c in the long term. PMID- 26941811 TI - Thyroid gland volume of schoolchildren in the North of Iran: Comparison with other studies. AB - BACKGROUND: Few studies have shown the limitation of the World Health Organization (WHO)/ International Council for the Control of Iodine Deficiency (ICCIDD)-adopted thyroid gland volume references as universal normative values for thyroid gland volume. So we decided to measure thyroid gland volume by sonography in schoolchildren in Rasht, Gilan Province, Iran - Rasht is a metropolitan city on the Caspian Sea coast - and compare them to WHO normative values. MATERIALS AND METHODS: In a cross-sectional study, 2,522 schoolchildren, aged 6-13 years, in Rasht, Gilan Province, Iran were selected by multistage random sampling. Data were collected on their age, sex, weight, height, body surface area (BSA), and thyroid gland size by palpation and sonography. The terminal phalange of thumb finger volume was calculated with the same formula used in sonography, for the thyroid gland in 1,085 of these cases. RESULTS: Goiter prevalence was 64% (1613 cases) by palpation, 76.1% (1228 subjects) grade I and 23.9% (385 cases) grade II. The mean thyroid gland volume in girls was more than boys (3.67 +/- 1.89 mL vs 3.41 +/- 1.58 mL, P < 0.0001). According to the 1997 WHO thyroid gland volume reference, none of the children had goiter based on BSA and age even in those with grade II goiters (23.9%). In contrast, the median thyroid gland volume in our cases was larger than the 2004 WHO reference. The best single predictor of thyroid gland volume was age (R (2) = 0.391, P < 0.0001) followed by BSA (R (2) = 0.151, P < 0.0001). There was also a significant difference between thyroid gland and finger volume in all grades of goiter and grade II goiters (3 +/- 1.4 mL vs 9.59 +/- 2.4 mL; P < 0.0001. 4.3 +/- 1.4 mL vs 9.3 +/- 2.5 mL; P < 0.0001). CONCLUSION: The WHO standards for thyroid gland volume by sonography may underestimate or overestimate the goiter prevalence in many areas and populations. Finger volume was much larger than thyroid gland volume in even visible goiters. PMID- 26941812 TI - Burden of ischemic heart diseases in Iran, 1990-2010: Findings from the Global Burden of Disease study 2010. AB - BACKGROUND: Cardiovascular diseases are viewed worldwide as one of the main causes of death. This study aims to report the burden of ischemic heart diseases (IHDs) in Iran by using data of the global burden of disease (GBD) study, 1990 2010. MATERIALS AND METHODS: The GBD study 2010 was a systematic effort to provide comprehensive data to calculate disability-adjusted life years (DALYs) for diseases and injuries in the world. Years of life lost (YLLs) due to premature mortality were computed on the basis of cause-of-death estimates, using Cause of Death Ensemble model (CODEm). Years lived with disability (YLDs) were assessed by the multiplication of prevalence, the disability weight for a sequel, and the duration of symptoms. A systematic review of published and unpublished data was performed to evaluate the distribution of diseases, and consequently prevalence estimates were calculated with a Bayesian meta-regression method (DisMod-MR). Data from population-based surveys were used for producing disability weights. Uncertainty from all inputs into the calculations of DALYs was disseminated by Monte Carlo simulation techniques. RESULTS: The age standardized IHDs DALY specified rate decreased 31.25% over 20 years from 1990 to 2010 [from 4720 (95% uncertainty interval (UI): 4,341-5,099) to 3,245 (95% UI: 2,810-3,529) person-years per 100,000]. The decrease were 38.14% among women and 26.87% among men. The age-standardized IHDs death specefied rate decreased by 21.17% [from 222) 95% UI: 207-243 (to 175 (95% UI:152-190) person-years per 100,000] in both the sexes. The age-standardized YLL and YLD rates decreased 32.05% and 4.28%, respectively, in the above period. CONCLUSION: Despite decreasing age-standardized IHD of mortality, YLL, YLD, and DALY rates from 1990 to 2010, population growth and aging increased the global burden of IHD. YLL has decreased more than IHD deaths and YLD since 1990 but IHD mortality remains the greatest contributor to disease burden. PMID- 26941813 TI - In-toeing and out-toeing gait conservative treatment; hip anteversion and retroversion: 10-year follow-up. AB - BACKGROUND: In-toeing and out-toeing rotational deformities are among the most common referrals for consultation with orthopedic specialists. Although a few number of patients need surgical interventions, most of them get better spontaneously without major complications in adult life. In this study, we investigated the prevalence of permanent gait deformities due to hip rotational disorders in a group of patients who underwent conservative treatments. MATERIALS AND METHODS: This retrospective cohort study was conducted in the orthopedic department on patients with rotational deformities of the lower extremities (hip anteversion and hip retroversion). From 2,983 patients, 611 were included in this study and followed up for 10 years. Medial rotation of the hip, lateral rotation of the hip, and tibia fibula angle (TFA) of each patient were measured independently. RESULTS: In this study, 611 patients were assessed and 323 (143 male and 180 female) were followed up in our study. Two hundred and seventy patients had in-toeing gait disorders due to hip anteversion, which 178 of them were corrected conservatively (%). Furthermore, among 53 patients with out-toed gait due to hip retroversion, 44 patients (%) were corrected in the same conditions (P = 0.001). It was determined that gait disorders were corrected conservatively in 102 of 143 males and 120 of 180 females (P = 0.37). CONCLUSION: Our findings showed that rotational deformities are expected to be corrected by conservative management. It is better to consider surgical procedures as the last therapeutic option. PMID- 26941814 TI - Qualitative evaluation of pulmonary CT angiography findings in pregnant and postpartum women with suspected pulmonary thromboembolism. AB - BACKGROUND: Considering the importance of using more appropriate imaging technique for accurate diagnosis of pulmonary thromboembolism (PTE) with less side effects, we aimed to evaluate the quality of pulmonary 64-multidetector computed tomographic (MDCT) angiography in pregnant and postpartum women with suspected PTE in Isfahan. MATERIALS AND METHODS: In this descriptive study, radiological findings of pregnant and postpartum women with suspected PTE who underwent pulmonary 64-MDCT angiography were evaluated. Prevalence of PTE in pregnant and postpartum women, mean of pulmonary arteries density for right and left pulmonary arteries, and their lobar and segmental branches, diagnostic quality of the pulmonary arteries density and their scoring, frequency of diagnostic and nondiagnostic images, mean of radiation dose and mean of bolus time, and the correlation between the quality of the vascular density with the peak density of the pulmonary artery were determined. RESULTS: In this study, 44 pregnant and postpartum women with suspected PTE were selected. The overall prevalence of PTE was 9.1% (4/44). PTE was diagnosed in 1 (3.7%) pregnant and 3 (17.5%) postpartum women (P = 0.14). Mean density of pulmonary trunk was 278.81+/ 108.16 Hounsfield unit (HU) and 308.41 +/- 59.30 HU in pregnant and postpartum women, respectively. Mean of bolus timing, kilovoltage peak (kVp), tube current, and dose length product (DLP) were 12.53 +/- 2.36 s, 105.22+/- 45.71 milliamperage (MA), 382.9 +/- 173.5 MA, and 317.98 +/- 78.92 mGy/cm, respectively. The rate of nondiagnostic images was 4.5%. CONCLUSION: Our findings indicated that pulmonary 64-MDCT angiography is an appropriate imaging method for diagnosing PTE in pregnant and postpartum women with suspected PTE. It seems that, using fast CT systems (64-MDCT), in accordance with high flow rate, high contrast medium concentration and low kVp could explain the obtained appropriate quality of images more efficiently than computed tomographic pulmonary angiography (CTPA). PMID- 26941815 TI - Benzofuran as a promising scaffold for the synthesis of antimicrobial and antibreast cancer agents: A review. AB - Benzofuran as an important heterocyclic compound is extensively found in natural products as well as synthetic materials. Since benzofuran drivatives display a diverse array of pharmacological activities, an interest in developing new biologically active agents from benzofuran is still under consideration. This review highlights recent findings on biological activities of benzofuran derivatives as antimicrobial and antibreast cancer agents and lays emphasis on the importance of benzofurans as a major source for drug design and development. PMID- 26941816 TI - The advantages and barriers in the implementation of a substance dependence treatment information system (SDTIS). AB - Addiction is a phenomenon that causes structural changes in different systems of society. Studies show for planning of addiction prevention and treatment, it is necessary to create an information management system. Substance dependence information systems refer to systems which collect, analyse and report data related to substance dependence information. The aim of this study was to identify advantages and barriers to implement Substance Dependence Treatment Information System (SDTIS). This study was a narrative review. Our review divided into three phases: literature collection, assessing, and selection. We employed the following keywords and their combinations in different areas of articles. In this study, 22 of collected articles and reports were selected based on their relevancy. We found many advantages for a substance dependence treatment information system such as recording sufficient, complete and accurate information and easy and timely access to them and monitoring and enhancing the quality of care received by patients. But we may face some concerns for implementing this information system like taking time and funds from client services, being expensive or even problems regarding the quality of data contained in these information systems. There are some important problems in the way of implementing. In order to overcome these issues, we need to raise community awareness. PMID- 26941818 TI - Questions concerning "Chlorhexidine, octenidine, or povidone-iodine for catheter related infections: A randomized controlled trial". PMID- 26941819 TI - A pediatric case of anesthesia mumps after general anesthesia. PMID- 26941820 TI - Neglected zoonotic diseases: It's now time for action urges WHO. PMID- 26941817 TI - Diabetes mellitus and renal failure: Prevention and management. AB - Nowadays, diabetes mellitus (DM) and hypertension are considered as the most common causes of end-stage renal disease (ESRD). In this paper, other than presenting the role of DM in ESRD, glucose metabolism and the management of hyperglycemia in these patients are reviewed. Although in several large studies there was no significant relationship found between tight glycemic control and the survival of ESRD patients, it is recommended that glycemic control be considered as the main therapeutic goal in the treatment of these patients to prevent damage to other organs. Glycemic control is perfect when fasting blood sugar is less than 140 mg/dL, 1-h postprandial blood glucose is less than 200 mg/dL, and glycosylated hemoglobin (HbA1c) is 6-7 in patients with type 1 diabetes and 7-8 in patients with type 2 diabetes. Administration of metformin should be avoided in chronic renal failure (CRF) because of lactic acidosis, the potentially fatal complication of metformin, but glipizide and repaglinide seem to be good choices. PMID- 26941821 TI - Investigation of Calcium Channel Blockers as Antiprotozoal Agents and Their Interference in the Metabolism of Leishmania (L.) infantum. AB - Leishmaniasis and Chagas disease are neglected parasitic diseases endemic in developing countries; efforts to find new therapies remain a priority. Calcium channel blockers (CCBs) are drugs in clinical use for hypertension and other heart pathologies. Based on previous reports about the antileishmanial activity of dihydropyridine-CCBs, this work aimed to investigate whether the in vitro anti Leishmania infantum and anti-Trypanosoma cruzi activities of this therapeutic class would be shared by other non-dihydropyridine-CCBs. Except for amrinone, our results demonstrated antiprotozoal activity for fendiline, mibefradil, and lidoflazine, with IC50 values in a range between 2 and 16 MUM and Selectivity Index between 4 and 10. Fendiline demonstrated depolarization of mitochondrial membrane potential, with increased reactive oxygen species production in amlodipine and fendiline treated Leishmania, but without plasma membrane disruption. Finally, in vitro combinations of amphotericin B, miltefosine, and pentamidine against L. infantum showed in isobolograms an additive interaction when these drugs were combined with fendiline, resulting in overall mean sum of fractional inhibitory concentrations between 0.99 and 1.10. These data demonstrated that non-dihydropyridine-CCBs present antiprotozoal activity and could be useful candidates for future in vivo efficacy studies against Leishmaniasis and Chagas' disease. PMID- 26941823 TI - Nonsurgical Korean Integrative Treatments for Symptomatic Lumbar Spinal Stenosis: A Three-Armed Randomized Controlled Pilot Trial Protocol. AB - This is a study protocol for a pilot three-armed randomized controlled trial on nonsurgical integrative Korean medicinal treatment for symptomatic lumbar spinal stenosis (LSS). Thirty-six participants who have been diagnosed with (LSS) and recommended for spinal surgery by neurosurgeons or orthopedics and have had spinal symptoms such as severe low back pain and neurological claudication regardless of at least three months of conservative treatments will be recruited. Participants will be randomly assigned to be one of the three intervention groups, including the Mokhuri treatment program group 1 or 2 or usual care group. All treatments will be administered in inpatient units over a period of 4 weeks. The primary outcomes are 0 to 100 Visual Analogue Scales for low back pain and leg pain and the secondary outcomes are Oswestry Disability Index; EQ-5D; Roland Morris Disability Questionnaire; Oxford Claudication Score; physical function test, including treadmill test, walking duration, and distance assessment for free leg pain; radiologic testing; and adverse events which will be assessed during the 4-week treatment period as well as after 3 and 6 months of follow-up. Then, we will assess the feasibility of the clinical trial design as well as a nonsurgical integrative treatment program. This trial is registered with CRIS registration number: KCT0001218. PMID- 26941824 TI - Repeated Electroacupuncture Persistently Elevates Adenosine and Ameliorates Collagen-Induced Arthritis in Rats. AB - The aim of this paper was to investigate the effect of repeated electroacupuncture (EA) over 21 days on the adenosine concentration in peripheral blood of rats with collagen-induced arthritis (CIA). Wistar rats were divided into three groups of 6 animals each: sham-control, CIA-control, and CIA-EA. We determined the adenosine concentration in peripheral blood and assessed pathological changes of ankle joints. Quantitative reverse-transcription polymerase chain reaction was used to determine mRNA levels of ecto-5' nucleotidase (CD73), adenosine deaminase (ADA), and tumor necrosis factor-alpha (TNF-alpha). Immunohistochemical staining was used to detect expression of ADA and CD73 in synovial tissue. Repeated EA treatment on CIA resulted in the persistence of high concentrations of adenosine in peripheral blood, significantly reduced pathological scores, TNF-alpha mRNA concentrations, and synovial hyperplasia. Importantly, EA treatment led to a significant increase in CD73 mRNA levels in peripheral blood but was associated with a decrease of CD73 immunostaining in synovial tissue. In addition, EA treatment resulted in a significant decrease of both ADA mRNA levels in peripheral blood and ADA immunostaining in synovial tissue. Thus, repeated EA treatment exerts an anti inflammatory and immunoregulatory effect on CIA by increasing the concentration of adenosine. The mechanism of EA action may involve the modulation of CD73 and ADA expression levels. PMID- 26941825 TI - Protective Effects of L-Malate against Myocardial Ischemia/Reperfusion Injury in Rats. AB - Objective. To investigate the protective effects of L-malate against myocardial ischemia/reperfusion (I/R) injury in rats. Methods. Male Sprague-Dawley rats were randomly assigned to the following groups: sham (sham), an ischemia/reperfusion (I/R) model group (model), an DMF pretreated group (DMF), and 5 L-malate pretreated groups (15, 60, 120, 240, or 480 mg/kg, gavage) before inducing myocardial ischemia. Plasma LDH, cTn-I, TNF-alpha, hs-CRP, SOD, and GSH-PX were measured 3 h later I/R. Areas of myocardial infarction were measured; hemodynamic parameters during I/R were recorded. Hearts were harvested and Western blot was used to quantify Nrf2, Keap1, HO-1, and NQO-1 expression in the myocardium. Results. L-malate significantly reduced LDH and cTn-I release, reduced myocardial infarct size, inhibited expression of inflammatory cytokines, and partially preserved heart function, as well as increasing antioxidant activity after myocardial I/R injury. Western blot confirmed that L-malate reduced Kelch-like ECH-associated protein 1 in ischemic myocardial tissue, upregulated expression of Nrf2 and Nrf2 nuclear translocation, and increased expression of heme oxygenase-1 and NAD(P)H: quinone oxidoreductase 1, which are major targets of Nrf2. Conclusions. L-malate may protect against myocardial I/R injury in rats and this may be associated with activation of the Nrf2/Keap1 antioxidant pathway. PMID- 26941822 TI - The Therapeutic Potential of Rosemary (Rosmarinus officinalis) Diterpenes for Alzheimer's Disease. AB - Rosemary (Rosmarinus officinalis L.) is one of the most economically important species of the family Lamiaceae. Native to the Mediterranean region, the plant is now widely distributed all over the world mainly due to its culinary, medicinal, and commercial uses including in the fragrance and food industries. Among the most important group of compounds isolated from the plant are the abietane-type phenolic diterpenes that account for most of the antioxidant and many pharmacological activities of the plant. Rosemary diterpenes have also been shown in recent years to inhibit neuronal cell death induced by a variety of agents both in vitro and in vivo. The therapeutic potential of these compounds for Alzheimer's disease (AD) is reviewed in this communication by giving special attention to the chemistry of the compounds along with the various pharmacological targets of the disease. The multifunctional nature of the compounds from the general antioxidant-mediated neuronal protection to other specific mechanisms including brain inflammation and amyloid beta (Abeta) formation, polymerisation, and pathologies is discussed. PMID- 26941827 TI - Effect of Pulsed Electromagnetic Field on Bone Formation and Lipid Metabolism of Glucocorticoid-Induced Osteoporosis Rats through Canonical Wnt Signaling Pathway. AB - Pulsed electromagnetic field (PEMF) has been suggested as a promising method alternative to drug-based therapies for treating osteoporosis (OP), but the role of PEMF in GIOP animal models still remains unknown. This study was performed to investigate the effect of PEMF on bone formation and lipid metabolism and further explored the several important components and targets of canonical Wnt signaling pathway in GIOP rats. After 12 weeks of intervention, bone mineral density (BMD) level of the whole body increased significantly, serum lipid levels decreased significantly, and trabeculae were thicker in GIOP rats of PEMF group. PEMF stimulation upregulated the mRNA and protein expression of Wnt10b, LRP5, beta catenin, OPG, and Runx2 and downregulated Axin2, PPAR-gamma, C/EBPalpha, FABP4, and Dkk-1. The results of this study suggested that PEMF stimulation can prevent bone loss and improve lipid metabolism disorders in GIOP rats. Canonical Wnt signaling pathway plays an important role in bone formation and lipid metabolism during PEMF stimulation. PMID- 26941829 TI - Use of an audience response system to maximise response rates and expedite a modified Delphi process for consensus on occupational health. AB - BACKGROUND: Different methods have attempted to obtain consensus on occupational health issues. The objective of this paper is to describe a modified three-stage Delphi process that uses a wireless audience response system to enable consensus to be attained in a single day and to maximise response rates. The modified Delphi approach required: a) agreeing the topic/s of interest for which consensus is sought, b) identifying key stakeholders whose opinions are required; c) assembling the stakeholders for a one-day event. Participants' opinions were recorded primarily through use of a system of individual wireless audience response devices ('clickers') linked to a computer. Providing immediate feedback enabled the audience to consider the group's views before proceeding to the next stage. From an initial round of responses, participants were asked to narrow their choices to any five preferred options. A third round was conducted, using the 'clickers' to rank 5 of the most popular group options. Through this iterative exercise, stakeholder consensus was achieved after three decision rounds. RESULTS: The use of the modifications and the wireless audience response system described enabled stakeholders to provide a group view on specific occupational health issues e.g. priorities or barriers or resources needed. Completing the three-stage iterative exercise in a day maximised the response rate with advantages for both the participants and the researchers. Careful design of the protocol is essential, with a team familiar with information technology to ensure smooth execution of the various stages. CONCLUSIONS: Modification of the Delphi method with the use of a wireless audience participation system facilitates rapid consensus. PMID- 26941828 TI - Geckos decouple fore- and hind limb kinematics in response to changes in incline. AB - BACKGROUND: Terrestrial animals regularly move up and down surfaces in their natural habitat, and the impacts of moving uphill on locomotion are commonly examined. However, if an animal goes up, it must go down. Many morphological features enhance locomotion on inclined surfaces, including adhesive systems among geckos. Despite this, it is not known whether the employment of the adhesive system results in altered locomotor kinematics due to the stereotyped motions that are necessary to engage and disengage the system. Using a generalist pad-bearing gecko, Chondrodactylus bibronii, we determined whether changes in slope impact body and limb kinematics. RESULTS: Despite the change in demand, geckos did not change speed on any incline. This constant speed was achieved by adjusting stride frequency, step length and swing time. Hind limb, but not forelimb, kinematics were altered on steep downhill conditions, thus resulting in significant de-coupling of the limbs. CONCLUSIONS: Unlike other animals on non level conditions, the geckos in our study only minimally alter the movements of distal limb elements, which is likely due to the constraints associated with the need for rapid attachment and detachment of the adhesive system. This suggests that geckos may experience a trade-off between successful adhesion and the ability to respond dynamically to locomotor perturbations. PMID- 26941830 TI - A rapid phenotyping method for adult plant resistance to leaf rust in wheat. AB - BACKGROUND: Leaf rust (LR), caused by Puccinia triticina and is an important disease of wheat (Triticum aestivum L.). The most sustainable method for controlling rust diseases is deployment of cultivars incorporating adult plant resistance (APR). However, phenotyping breeding populations or germplasm collections for resistance in the field is dependent on weather conditions and limited to once a year. In this study, we explored the ability to phenotype APR to LR under accelerated growth conditions (AGC; i.e. constant light and controlled temperature) using a method that integrates assessment at both seedling and adult growth stages. A panel of 21 spring wheat genotypes, including disease standards carrying known APR genes (i.e. Lr34 and Lr46) were characterised under AGC and in the field. RESULTS: Disease response displayed by adult wheat plants grown under AGC (i.e. flag-2 leaf) was highly correlated with field-based measures (R(2) = 0.77). The integrated method is more efficient requiring less time, space, and labour compared to traditional approaches that perform seedling and adult plant assays separately. Further, this method enables up to seven consecutive adult plant LR assays compared to one in the field. CONCLUSION: The integrated seedling and adult plant phenotyping method reported in this study provides a great tool for identifying APR to LR. Assessing plants at early growth stages can enable selection for desirable gene combinations and crossing of the selected plants in the same plant generation. The method has the potential to be scaled-up for screening large numbers of fixed lines and segregating populations. This strategy would reduce the time required for moving APR genes into adapted germplasm or combining traits in top crosses in breeding programs. This method could accelerate selection for resistance factors effective across diverse climates by conducting successive cycles of screening performed at different temperature regimes. PMID- 26941826 TI - Preclinical Models for Investigation of Herbal Medicines in Liver Diseases: Update and Perspective. AB - Liver disease results from a dynamic pathological process associated with cellular and genetic alterations, which may progress stepwise to liver dysfunction. Commonly, liver disease begins with hepatocyte injury, followed by persistent episodes of cellular regeneration, inflammation, and hepatocyte death that may ultimately lead to nonreversible liver failure. For centuries, herbal remedies have been used for a variety of liver diseases and recent studies have identified the active compounds that may interact with liver disease-associated targets. Further study on the herbal remedies may lead to the formulation of next generation medicines with hepatoprotective, antifibrotic, and anticancer properties. Still, the pharmacological actions of vast majority of herbal remedies remain unknown; thus, extensive preclinical studies are important. In this review, we summarize progress made over the last five years of the most commonly used preclinical models of liver diseases that are used to screen for curative herbal medicines for nonalcoholic fatty liver disease, liver fibrosis/cirrhosis, and liver. We also summarize the proposed mechanisms associated with the observed liver-protective, antifibrotic, and anticancer actions of several promising herbal medicines and discuss the challenges faced in this research field. PMID- 26941831 TI - Drug-Drug Interaction Extraction via Convolutional Neural Networks. AB - Drug-drug interaction (DDI) extraction as a typical relation extraction task in natural language processing (NLP) has always attracted great attention. Most state-of-the-art DDI extraction systems are based on support vector machines (SVM) with a large number of manually defined features. Recently, convolutional neural networks (CNN), a robust machine learning method which almost does not need manually defined features, has exhibited great potential for many NLP tasks. It is worth employing CNN for DDI extraction, which has never been investigated. We proposed a CNN-based method for DDI extraction. Experiments conducted on the 2013 DDIExtraction challenge corpus demonstrate that CNN is a good choice for DDI extraction. The CNN-based DDI extraction method achieves an F-score of 69.75%, which outperforms the existing best performing method by 2.75%. PMID- 26941832 TI - Non-typhoidal Salmonella DNA traces in gallbladder cancer. AB - BACKGROUND: We earlier proposed a genetic model for gallbladder carcinogenesis and its dissemination cascade. However, the association of gallbladder cancer and 'inflammatory stimulus' to drive the initial cascade in the model remained unclear. A recent study suggested infection with Salmonella can lead to changes in the host signalling pathways in gallbladder cancer. FINDINGS: We examined the whole exomes of 26 primary gall bladder tumour and paired normal samples for presence of 143 HPV (Human papilloma virus) types along with 6 common Salmonella serotypes (S. typhi Ty2, S. typhi CT18, S. typhimurium LT2, S. choleraesuis SCB67, S. paratyphi TCC, and S. paratyphi SPB7) using a computational subtraction pipeline based on the HPVDetector, we recently described. Based on our evaluation of 26 whole exome gallbladder primary tumours and matched normal samples: association of typhoidal Salmonella species were found in 11 of 26 gallbladder cancer samples, and non-typhoidal Salmonella species in 12 of 26 gallbladder cancer, with 6 samples were found co-infected with both. CONCLUSIONS: We present the first evidence to support the association of non-typhoidal Salmonella species along with typhoidal strains in gallbladder cancer. Salmonella infection in the chronic carrier state fits the role of the 'inflammatory stimulus' in the genetic model for gallbladder carcinogenesis that may play a role in gallbladder cancer analogous to Helicobacter pylori in gastric cancer. PMID- 26941833 TI - How can psychosomatic physicians contribute to behavioral medicine? AB - In Japan, there is a unique clinical department, "Psychosomatic Medicine", while there is not a department of behavioral science or behavioral medicine in medical schools. Although only eight medical schools have the department, psychosomatic physicians in the department have been involved with behavioral medicine. In the present manuscript, the author would like to introduce the contribution to behavioral medicine made by psychosomatic physicians in three aspects, education, clinical settings, and research, and propose some strategy for psychosomatic physicians to get more involved with behavioral medicine. PMID- 26941834 TI - Erratic electricity supply (Dumsor) and anxiety disorders among university students in Ghana: a cross sectional study. AB - BACKGROUND: Ghana is currently experiencing electricity supply crisis that is believed to have some impact on the mental wellbeing of the population, especially among university students that have become increasingly dependent on uninterrupted electricity supply to fully function academically. There is no known study that explores the link between infrequent electricity supply and generalized anxiety disorders in sub-Saharan Africa. This study aimed to explore that link and determine the proportion of university students whose anxiety levels may be influenced by the electricity supply crisis that the country is experiencing at the moment. METHODS: This exploratory study used the Generalized Anxiety Disorder 7-item scale (GAD-7) to conduct the study on the University of Ghana campus. The likelihood ratio (LR) test and Fisher's Exact tests were used to determine any association between the electricity supply crisis and anxiety levels among students. Unadjusted odds ratio and corresponding confidence intervals were estimated and ordinal logistic regression technique was used for the effect of covariates on anxiety. RESULTS: Overall, nearly 26 % of students interviewed felt nervous, anxious or on edge almost every day due to the erratic power supply. The proportion of students determined to be classified having minimal, mild, moderate and severe anxiety due to the erratic power supply was 24.2, 30.7, 22.1 and 23.1 % respectively. Students were significantly more likely to be anxious if the frequency of power outage increased (OR 1.36; CI 1.23-1.49). CONCLUSIONS: Our finding in this study suggests that although the erratic power supply does not allude to any clinical confirmation of the students having anxiety disorders, it does point to a fact that even in a resource-poor country like Ghana, where constant supply of electricity is not always guaranteed, students may not be entirely immune to the health and well-being implications of failures in some sectors of the economy such as power supply. PMID- 26941835 TI - The mental health and psychosocial impact of the Bougainville Crisis: a synthesis of available information. AB - BACKGROUND: The Bougainville Crisis (1988-1997) was the largest armed conflict in the Pacific since WW-II. Despite this, there has been no assessment of the Mental Health and Psychosocial (MHPS) impact of the war. The aim of this paper is to summarize the available data regarding the longer-term MHPS impact of the Bougainville Crisis. METHODS: A literature review and a sequence of consultations in Bougainville were conducted to identify the MHPS impact of the Bougainville Crisis and the capacity within Bougainville to address these issues. RESULTS: The Bougainville Crisis resulted in violence-related deaths; the displacement of more than half of the population; widespread human rights abuses; far-reaching societal impacts including undermining of the traditional authority of elders and women and damage to cultural values and relationships; property damage; and significant impacts on education and the economy. Conflict-related experiences continue to impact on mental health in the form of trauma-related symptoms, anger, complicated grief, alcohol and substance abuse, domestic violence including sexual assault, excessive alcohol use and a lack of engagement in purposeful activities. Other impacts include an increase in other forms of gender based violence (including sexual assault), population displacement, and adverse trans-generational effects on children exposed to disturbed parental behaviours attributable to conflict exposure. In spite of the evident needs, there is limited capacity within Bougainville to address these pressing MHPS issues. CONCLUSIONS: The Bougainville Crisis has had a significant MHPS impact at multiple levels in the society. There is a strong interest within Bougainville to draw on external expertise to build local capacity to address MHPS issues. Preliminary recommendations are made to assist the process of building the capacity in Bougainville to address MHPS needs. PMID- 26941836 TI - Schizophrenia clinical symptom differences in women vs. men with and without a history of childhood physical abuse. AB - BACKGROUND: Childhood abuse has been implicated as an environmental factor that increases the risk for developing schizophrenia. A recent large population-based case-control study found that abuse may be a risk factor for schizophrenia in women, but not men. Given the sex differences in onset and clinical course of schizophrenia, we hypothesized that childhood abuse may cause phenotypic differences in the disorder between men and women. METHODS: We examined the prevalence of childhood physical abuse in a cohort of men and women with schizophrenia and schizoaffective disorder. Specifically, we examined differences in positive, negative, cognitive and depressive symptoms in men and women who reported a history of childhood physical abuse. We recruited 100 subjects for a single visit and assessed a history of childhood physical abuse using the childhood trauma questionnaire (CTQ) and clinical symptoms and cognition using the brief psychiatric rating scale (BPRS), the calgary depression scale (CDS) and the repeatable battery of the assessment of neuropsychological status (RBANS) for cognition. RESULTS: Ninety-two subjects completed the full CTQ with abuse classified as definitely present, definitely absent or borderline. Twelve subjects who reported borderline abuse scores were excluded. Of the 80 subjects whose data was analyzed, 10 of 24 (41.6 %) women and 11 of 56 (19.6 %) men reported a history of childhood physical abuse (chi(2) = 4.21, df = 1, p = 0.04). Women who reported such trauma had significantly more psychotic (sex by abuse interaction; F = 4.03, df = 1.76, p = 0.048) and depressive (F = 4.23, df = 1.76, p = 0.04) symptoms compared to women who did not have a trauma history and men, regardless of trauma history. There were no differences in negative or cognitive symptoms. CONCLUSIONS: Women with schizophrenia and schizoaffective disorder may represent a distinct phenotype or subgroup with distinct etiologies and may require different, individually tailored treatments. PMID- 26941837 TI - An environmentally friendly and productive process for bioethanol production from potato waste. AB - BACKGROUND: China is the largest sweet potato producer and exporter in the world. Sweet potato residues (SPRs) separated after extracting starch account for more than 10 % of the total dry matter of sweet potatoes. In China, more than 2 million tons of SPRs cannot be utilized, and the unutilized SPRs are perishable and result in environmental pollution. Thus, an environmentally friendly and highly efficient process for bioethanol production from SPRs should be developed. RESULTS: The swelling behaviour of cellulose causes high-gravity sweet potato residues to be recalcitrant to enzymatic hydrolysis. Cellulase plays a major role in viscosity reduction and glucose production. In contrast, pectinase has a minor role in viscosity reduction but acts as a "helper protein" to assist cellulase in liberating glucose, especially at low cellulase activity levels. In total, 153.46 and 168.13 g/L glucose were produced from high-gravity SPRs with cellulase and a mixture of cellulase and pectinase, respectively. These hydrolysates were fermented to form 73.37 and 79.00 g/L ethanol, respectively. Each kilogram of dry SPR was converted to form 209.62 and 225.71 g of ethanol, respectively. CONCLUSION: The processes described in this study have an enormous potential for industrial production of bioethanol because they are environmentally friendly, highly productive, economic with low cost, and can be easily manipulated. PMID- 26941838 TI - Comparative analysis of taxonomic, functional, and metabolic patterns of microbiomes from 14 full-scale biogas reactors by metagenomic sequencing and radioisotopic analysis. AB - BACKGROUND: Biogas production is a very complex process due to the high complexity in diversity and interactions of the microorganisms mediating it, and only limited and diffuse knowledge exists about the variation of taxonomic and functional patterns of microbiomes across different biogas reactors, and their relationships with the metabolic patterns. The present study used metagenomic sequencing and radioisotopic analysis to assess the taxonomic, functional, and metabolic patterns of microbiomes from 14 full-scale biogas reactors operated under various conditions treating either sludge or manure. RESULTS: The results from metagenomic analysis showed that the dominant methanogenic pathway revealed by radioisotopic analysis was not always correlated with the taxonomic and functional compositions. It was found by radioisotopic experiments that the aceticlastic methanogenic pathway was dominant, while metagenomics analysis showed higher relative abundance of hydrogenotrophic methanogens. Principal coordinates analysis showed the sludge-based samples were clearly distinct from the manure-based samples for both taxonomic and functional patterns, and canonical correspondence analysis showed that the both temperature and free ammonia were crucial environmental variables shaping the taxonomic and functional patterns. The study further the overall patterns of functional genes were strongly correlated with overall patterns of taxonomic composition across different biogas reactors. CONCLUSIONS: The discrepancy between the metabolic patterns determined by metagenomic analysis and metabolic pathways determined by radioisotopic analysis was found. Besides, a clear correlation between taxonomic and functional patterns was demonstrated for biogas reactors, and also the environmental factors that shaping both taxonomic and functional genes patterns were identified. PMID- 26941839 TI - Reparable Cell Sonoporation in Suspension: Theranostic Potential of Microbubble. AB - The conjunction of low intensity ultrasound and encapsulated microbubbles can alter the permeability of cell membrane, offering a promising theranostic technique for non-invasive gene/drug delivery. Despite its great potential, the biophysical mechanisms of the delivery at the cellular level remains poorly understood. Here, the first direct high-speed micro-photographic images of human lymphoma cell and microbubble interaction dynamics are provided in a completely free suspension environment without any boundary parameter defect. Our real-time images and theoretical analyses prove that the negative divergence side of the microbubble's dipole microstreaming locally pulls the cell membrane, causing transient local protrusion of 2.5 um in the cell membrane. The linear oscillation of microbubble caused microstreaming well below the inertial cavitation threshold, and imposed 35.3 Pa shear stress on the membrane, promoting an area strain of 0.12%, less than the membrane critical areal strain to cause cell rupture. Positive transfected cells with pEGFP-N1 confirm that the interaction causes membrane poration without cell disruption. The results show that the overstretched cell membrane causes reparable submicron pore formation, providing primary evidence of low amplitude (0.12 MPa at 0.834 MHz) ultrasound sonoporation mechanism. PMID- 26941840 TI - Near-Infrared Light Triggered ROS-activated Theranostic Platform based on Ce6-CPT UCNPs for Simultaneous Fluorescence Imaging and Chemo-Photodynamic Combined Therapy. AB - Many drug controlled release methods have been integrated in multifunctional nanoparticles, such as pH-, redox-, temperature-, enzyme-, and light-responsive release. However, few report is associated with the ROS responsive drug controlled release. Herein, a thioketal linker-based ROS responsive drug (camptothecin conjugated with thioketal linker, abbreviated as TL-CPT) was prepared and the thioketal linker could be cleaved by ROS(reactive oxygen species). To achieve cancer simultaneous optical imaging, photodynamic therapy and chemotherapy, the photosensitizer Chlorin e6(Ce6), TL-CPT and carboxyl-mPEG were loaded on the upconversion nanoparticles (UCNPs), which were named as Ce6 CPT-UCNPs. Under 980 nm laser irradiation, Ce6-CPT-UCNPs emitted a narrow emission band at 645-675 nm which was overlapped with Ce6 absorption peak. Ce6 absorbed the light to produce ROS, which was used for photodynamic therapy and to cleave the thioketal linker in Ce6-CPT-UCNPs to release camptothecin for chemotherapy. Meanwhile, Ce6 absorbed the light, was used for near-infrared fluorescence imaging. The in vivo biodistribution studies showed that the prepared nanoparticles had high orthotopic lung cancer targeting efficiency. The in vivo therapeutic results demonstrated that NCI-H460 lung cancers could be completely eliminated by combining chemo- and photodynamic therapy under 980 nm laser irradiation. The prepared multifunctional Ce6-CPT-UCNPs have great potential in applications such as cancer targeted fluorescent imaging, simultaneous ROS activated chemo- and photodynamic therapy in near future. PMID- 26941842 TI - A Multimodal System with Synergistic Effects of Magneto-Mechanical, Photothermal, Photodynamic and Chemo Therapies of Cancer in Graphene-Quantum Dot-Coated Hollow Magnetic Nanospheres. AB - In this study, a multimodal therapeutic system was shown to be much more lethal in cancer cell killing compared to a single means of nano therapy, be it photothermal or photodynamic. Hollow magnetic nanospheres (HMNSs) were designed and synthesized for the synergistic effects of both magneto-mechanical and photothermal cancer therapy. By these combined stimuli, the cancer cells were structurally and physically destroyed with the morphological characteristics distinctively different from those by other therapeutics. HMNSs were also coated with the silica shells and conjugated with carboxylated graphene quantum dots (GQDs) as a core-shell composite: HMNS/SiO2/GQDs. The composite was further loaded with an anticancer drug doxorubicin (DOX) and stabilized with liposomes. The multimodal system was able to kill cancer cells with four different therapeutic mechanisms in a synergetic and multilateral fashion, namely, the magnetic field-mediated mechanical stimulation, photothermal damage, photodynamic toxicity, and chemotherapy. The unique nanocomposites with combined mechanical, chemo, and physical effects will provide an alternative strategy for highly improved cancer therapy efficiency. PMID- 26941841 TI - Polydopamine-Based Surface Modification of Novel Nanoparticle-Aptamer Bioconjugates for In Vivo Breast Cancer Targeting and Enhanced Therapeutic Effects. AB - In this study, we reported a simple polydopamine (pD)-based surface modification method to prepare novel nanoparticle-aptamer bioconjugates (Apt-pD-DTX/NPs) for in vivo tumor targeting and enhanced therapeutic effects of breast cancer. With simple preparation procedures, the new functionalized Apt-pD-DTX/NPs could maximumly increase the local effective drug concentration on tumor sites, achieving enhanced treatment effectiveness and minimizing side effects. The dopamine polymerization and aptamer conjugation barely changed the characters of NPs. Both in vitro cell experiments (i.e. endocytosis of fluorescent NPs, in vitro cellular targeting and cytotoxicity assays) and in vivo animal studies (i.e. in vivo imaging, biodistribution and antitumor effects of NPs) demonstrated that the Apt-pD-DTX/NPs could achieve significantly high targeting efficiency and enhanced therapeutic effects compared with clinical Taxotere((r)) and NPs without functional modification. Above all, the Apt-pD-DTX/NPs showed great potential as a promising nanoformulation for in vivo breast cancer therapy and the construction of pD-modified NP-aptamer bioconjugates could be of great value in medical use. PMID- 26941843 TI - [(177)Lu-DOTA](0)-D-Phe(1)-Tyr(3)-Octreotide ((177)Lu-DOTATOC) For Peptide Receptor Radiotherapy in Patients with Advanced Neuroendocrine Tumours: A Phase II Study. AB - PURPOSE: To characterise efficacy and safety of (177)Lu-DOTATOC as agent for peptide receptor radiotherapy (PRRT) of advanced neuroendocrine tumours (NET). PATIENTS AND METHODS: Fifty-six subjects with metastasized and progressive NET (50% gastroenteral, 26.8% pancreatic, 23.2% other primary sites) treated consecutively with (177)Lu-DOTATOC were analysed retrospectively. Subjects were administered (177)Lu-DOTATOC (mean 2.1 cycles; range 1-4) as 7.0GBq (median) doses at three-monthly intervals. Efficacy was analysed using CT and/or MRI according to RECIST 1.1 criteria and results were stratified for the number of administered cycles and the primary tumour origin. RESULTS: In the total NET population (A), median progression-free (PFS) and overall survival (OS) were 17.4 and 34.2 months, respectively, assessed in a follow-up time (mean +/- SD) of 16.1 +/- 12.4 months. In patients receiving more than one cycle, mean follow-up time was 22.4 +/- 11.0 months for all NETs (B) and PFS was 32.0 months for all NETs (B), 34.5 months for GEP-NET (C), and 11.9 months for other NETs (D). Objective response rates (Complete/Partial Responses) were 33.9%, 40.6%, 54.2%, and 0% for A, B, C, and D groups, respectively, while disease control rates in the same were 66.1%, 93.8%, 100%, and 75%. Complete responses (16.1%, 18.8% and 25.0% for groups A, B and C) were high, 78% of which were maintained throughout the follow up. There were no serious adverse events. One case of self-limiting grade 3 myelotoxicity was reported. Although 20% of patients had mild renal insufficiency at baseline, there was no evidence of exacerbated or de novo renal toxicity after treatment. CONCLUSION: (177)Lu-DOTATOC is a novel agent for PRRT with major potential to induce objective tumour responses and sustained disease control in progressive neuroendocrine tumours, even when administered in moderate activities. The observed safety profile suggests a particularly favourable therapeutic index, including in patients with impaired bone marrow or renal function, which reflects a uniquely low uptake of (177)Lu-DOTATOC by normal organs. PMID- 26941844 TI - Evaluation of a 3-hydroxypyridin-2-one (2,3-HOPO) Based Macrocyclic Chelator for (89)Zr(4+) and Its Use for ImmunoPET Imaging of HER2 Positive Model of Ovarian Carcinoma in Mice. AB - A novel octadentate 3-hydroxypyridin-2-one (2,3-HOPO) based di-macrocyclic ligand was evaluated for chelation of (89)Zr; subsequently, it was used as a bi functional chelator for preparation of (89)Zr-labeled antibodies. Quantitative chelation of (89)Zr(4+) with the octadentate ligand forming (89)ZrL complex was achieved under mild conditions within 15 minutes. The (89)Zr-complex was stable in vitro in presence of DTPA, but a slow degradation was observed in serum. In vivo, the hydrophilic (89)Zr-complex showed prevalently renal excretion; and an elevated bone uptake of radioactivity suggested a partial release of (89)Zr(4+) from the complex. The 2,3-HOPO based ligand was conjugated to the monoclonal antibodies, HER2-specific trastuzumab and an isotypic anti-gD antibody, using a p phenylene bis-isothiocyanate linker to yield products with an average loading of less than 2 chelates per antibody. Conjugated antibodies were labeled with (89)Zr under mild conditions providing the PET tracers in 60-69% yield. Despite the limited stability in mouse serum; the PET tracers performed very well in vivo. The PET imaging in mouse model of HER2 positive ovarian carcinoma showed tumor uptake of (89)Zr-trastuzumab (29.2 +/- 12.9 %ID/g) indistinguishable (p = 0.488) from the uptake of positive control (89)Zr-DFO-trastuzumab (26.1 +/- 3.3 %ID/g). In conclusion, the newly developed 3-hydroxypyridin-2-one based di-macrocyclic chelator provides a viable alternative to DFO-based heterobifunctional ligands for preparation of (89)Zr-labeled monoclonal antibodies for immunoPET studies. PMID- 26941845 TI - Development of a Loop Mediated Isothermal Amplification (LAMP) - Surface Enhanced Raman spectroscopy (SERS) Assay for the Detection of Salmonella Enterica Serotype Enteritidis. AB - As a major foodborne pathogen, Salmonella enterica serotype Enteritidis is increasingly rising as a global health concern. Here, we developed an integrated assay that combines loop mediated isothermal amplification (LAMP) and surface enhanced Raman spectroscopy (SERS) for DNA detection of S. Enteritidis using specifically designed Raman active Au-nanoprobes. The target DNA was amplified by LAMP and then labeled with Au-nanoprobes comprised of gold nanoparticle-modified with specific cy5/DNA probes to allow the detection by SERS. The sensitivity of the developed LAMP-SERS detection assay (66 CFU/mL) was ~100-fold higher than the conventional polymerase chain reaction (PCR) method. Significantly, this technique allowed highly specific detection of the target DNA of S. Enteritidis and could differentiate it from the DNA of closely related bacterial species or non-specific contamination, making it more accurate and reliable than the standard LAMP technique. The applicability of detection of S. Enteritidis in milk samples using LAMP-SERS assay was validated as well. In sum, the developed LAMP SERS assay is highly specific and sensitive, and has the potential to be applied for rapid detection of different foodborne pathogens and other microbial contaminants. PMID- 26941846 TI - Mifepristone Suppresses Basal Triple-Negative Breast Cancer Stem Cells by Down regulating KLF5 Expression. AB - Triple-negative breast cancer (TNBC) is currently the most malignant subtype of breast cancers without effective targeted therapies. Mifepristone (MIF), a drug regularly used for abortion, has been reported to have anti-tumor activity in multiple hormone-dependent cancers, including luminal type breast cancers. In this study, we showed that MIF suppressed tumor growth of the TNBC cell lines and patient-derived xenografts in NOD-SCID mice. Furthermore, MIF reduced the TNBC cancer stem cell (CSC) population through down-regulating KLF5 expression, a stem cell transcription factor over-expressed in basal type TNBC and promoting cell proliferation, survival and stemness. Interestingly, MIF suppresses the expression of KLF5 through inducing the expression of miR-153. Consistently, miR 153 decreases CSC and miR-153 inhibitor rescued MIF-induced down-regulation of the KLF5 protein level and CSC ratio. Taken together, our findings suggest that MIF inhibits basal TNBC via the miR-153/KLF5 axis and MIF may be used for the treatment of TNBC. PMID- 26941847 TI - EMMPRIN-Targeted Magnetic Nanoparticles for In Vivo Visualization and Regression of Acute Myocardial Infarction. AB - Inhibition of extracellular matrix (ECM) degradation may represent a mechanism for cardiac protection against ischemia. Extracellular matrix metalloproteinase inducer (EMMPRIN) is highly expressed in response to acute myocardial infarction (AMI), and induces activation of several matrix metalloproteinases (MMPs), including gelatinases MMP-2 and MMP-9. We targeted EMMPRIN with paramagnetic/fluorescent micellar nanoparticles conjugated with the EMMPRIN binding peptide AP-9 (NAP9), or an AP-9 scrambled peptide as a negative control (NAPSC). We found that NAP9 binds to endogenous EMMPRIN in cultured HL1 myocytes and in mouse hearts subjected to ischemia/reperfusion (IR). Injection of NAP9 at the time of or one day after IR, was enough to reduce progression of myocardial cell death when compared to CONTROL and NAPSC injected mice (infarct size in NAP9 injected mice: 32%+/-6.59 vs CONTROL: 46%+/-9.04 or NAPSC injected mice: 48%+/ 7.64). In the same way, cardiac parameters were recovered to almost healthy levels (LVEF NAP9 63% +/- 7.24 vs CONTROL 42% +/- 4.74 or NAPSC 39% +/- 6.44), whereas ECM degradation was also reduced as shown by inhibition of MMP-2 and MMP 9 activation. Cardiac magnetic resonance (CMR) scans have shown a signal enhancement in the left ventricle of NAP9 injected mice with respect to non injected, and to mice injected with NAPSC. A positive correlation between CMR enhancement and Evans-Blue/TTC staining of infarct size was calculated (R:0.65). Taken together, these results point to EMMPRIN targeted nanoparticles as a new approach to the mitigation of ischemic/reperfusion injury. PMID- 26941848 TI - A Targetable Molecular Chaperone Hsp27 Confers Aggressiveness in Hepatocellular Carcinoma. AB - Heat shock protein 27 (Hsp27) is an ATP-independent molecular chaperone and confers survival advantages and resistance to cancer cells under stress conditions. The effects and molecular mechanisms of Hsp27 in HCC invasion and metastasis are still unclear. In this study, hepatocellular carcinoma (HCC) tissue array (n = 167) was used to investigate the expression and prognostic relevance of Hsp27 in HCC patients. HCC patients with high expression of Hsp27 exhibited poor prognosis. Overexpression of Hsp27 led to the forced invasion of HCC cells, whereas silencing Hsp27 attenuated invasion and metastasis of HCC cells in vitro and in vivo. We revealed that Hsp27 activated Akt signaling, which in turn promoted MMP2 and ITGA7 expression and HCC metastasis. We further observed that targeting Hsp27 using OGX-427 obviously suppressed HCC metastasis in two metastatic models. These findings indicate that Hsp27 is a useful predictive factor for prognosis of HCC and it facilitates HCC metastasis through Akt signaling. Targeting Hsp27 with OGX-427 may represent an attractive therapeutic option for suppressing HCC metastasis. PMID- 26941850 TI - Novel Bioluminescent Activatable Reporter for Src Tyrosine Kinase Activity in Living Mice. AB - Aberrant activation of the Src kinase is implicated in the development of a variety of human malignancies. However, it is almost impossible to monitor Src activity in an in vivo setting with current biochemical techniques. To facilitate the noninvasive investigation of the activity of Src kinase both in vitro and in vivo, we developed a genetically engineered, activatable bioluminescent reporter using split-luciferase complementation. The bioluminescence of this reporter can be used as a surrogate for Src activity in real time. This hybrid luciferase reporter was constructed by sandwiching a Src-dependent conformationally responsive unit (SH2 domain-Srcpep) between the split luciferase fragments. The complementation bioluminescence of this reporter was dependent on the Src activity status. In our study, Src kinase activity in cultured cells and tumor xenografts was monitored quantitatively and dynamically in response to clinical small-molecular kinase inhibitors, dasatinib and saracatinib. This system was also applied for high-throughput screening of Src inhibitors against a kinase inhibitor library in living cells. These results provide unique insights into drug development and pharmacokinetics/phoarmocodynamics of therapeutic drugs targeting Src signaling pathway enabling the optimization of drug administration schedules for maximum benefit. Using both Firefly and Renilla luciferase imaging, we have successfully monitored Src tyrosine kinase activity and Akt serine/threonine kinase activity concurrently in one tumor xenograft. This dual luciferase reporter imaging system will be helpful in exploring the complex signaling networks in vivo. The strategies reported here can also be extended to study and image other important kinases and the cross-talks among them. PMID- 26941853 TI - Message from the Editor-in-Chief. PMID- 26941851 TI - Anthocyanin accumulation enhanced in Lc-transgenic cotton under light and increased resistance to bollworm. AB - Breeding of naturally colored cotton fiber has been hampered by the limited germplasm, an alternative way is to use transgenic approach to create more germplasm for breeding. Here, we report our effort to engineer anthocyanin production in cotton. The maize Lc gene, under the control of the constitutive 35S promoter, was introduced into cotton through genetic transformation. Our data showed that the expression of the Lc gene alone is sufficient to trigger the accumulation of anthocyanin in a variety of cell types including fiber cells in cotton. However, the accumulation of colored anthocyanin in cotton fibers requires the participation of light signaling. These data indicate that it is feasible to engineer colored fibers through transgenic approach in cotton. Furthermore, we showed that the Lc-transgenic cotton plants are resistant to cotton bollworm. These transgenic plants are, therefore, potentially useful for cotton breeding against cotton bollworm. PMID- 26941849 TI - Glycogen Synthase Kinase-3 (GSK-3)-Targeted Therapy and Imaging. AB - Glycogen synthase kinase-3 (GSK-3) is associated with various key biological processes, including glucose regulation, apoptosis, protein synthesis, cell signaling, cellular transport, gene transcription, proliferation, and intracellular communication. Accordingly, GSK-3 has been implicated in a wide variety of diseases and specifically targeted for both therapeutic and imaging applications by a large number of academic laboratories and pharmaceutical companies. Here, we review the structure, function, expression levels, and ligand binding properties of GSK-3 and its connection to various diseases. A selected list of highly potent GSK-3 inhibitors, with IC50 <20 nM for adenosine triphosphate (ATP)-competitive inhibitors and IC50 <5 MUM for non-ATP-competitive inhibitors, were analyzed for structure activity relationships. Furthermore, ubiquitous expression of GSK-3 and its possible impact on therapy and imaging are also highlighted. Finally, a rational perspective and possible route to selective and effective GSK-3 inhibitors is discussed. PMID- 26941852 TI - Different definitions of CpG island methylator phenotype and outcomes of colorectal cancer: a systematic review. AB - Contradictory results were reported for the prognostic role of CpG island methylator phenotype (CIMP) among colorectal cancer (CRC) patients. Differences in the definitions of CIMP were the most common explanation for these discrepancies. The aim of this systematic review was to give an overview of the published studies on CRC prognosis according to the different definitions of CIMP. A systematic literature search was performed in MEDLINE and ISI Web of Science for articles published until 3 April 2015. Data extraction included information about the study population, the definition of CIMP, and investigated outcomes. Thirty-six studies were included in this systematic review. Among them, 30 studies reported the association of CIMP and CRC prognosis and 11 studies reported the association of CIMP with survival after CRC therapy. Overall, 16 different definitions of CIMP were identified. The majority of studies reported a poorer prognosis for patients with CIMP-positive (CIMP+)/CIMP-high (CIMP-H) CRC than with CIMP-negative (CIMP-)/CIMP-low (CIMP-L) CRC. Inconsistent results or varying effect strengths could not be explained by different CIMP definitions used. No consistent variation in response to specific therapies according to CIMP status was found. Comparative analyses of different CIMP panels in the same large study populations are needed to further clarify the role of CIMP definitions and to find out how methylation information can best be used to predict CRC prognosis and response to specific CRC therapies. PMID- 26941854 TI - PET/MRI: Technical Challenges and Recent Advances. AB - Integrated positron emission tomography (PET)/magnetic resonance imaging (MRI), which can provide complementary functional and anatomical information about a specific organ or body system at the molecular level, has become a powerful imaging modality to understand the molecular biology details, disease mechanisms, and pharmacokinetics in animals and humans. Although the first experiment on the PET/MRI was performed in the early 1990s, its clinical application was accomplished in recent years because there were various technical challenges in integrating PET and MRI in a single system with minimum mutual interference between PET and MRI. This paper presents the technical challenges and recent advances in combining PET and MRI along with several approaches for improving PET image quality of the PET/MRI hybrid imaging system. PMID- 26941856 TI - Correlation between Semi-Quantitative (18)F-FDG PET/CT Parameters and Ki-67 Expression in Small Cell Lung Cancer. AB - PURPOSE: The aim of this study was to evaluate the relationship between semiquantitative parameters on (18)F-FDG PET/CT including maximum standardized uptake value (SUVmax), mean standardized uptake value (SUVmean), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) and the expression level of Ki-67 in small-cell lung cancer (SCLC). METHODS: Ninety-four consecutive patients with SCLC were enrolled in this study. They underwent (18)F-FDG PET/CT for initial evaluation of SCLC, and we measured SUVmax, avgSUVmean, MTVsum, and TLGtotal on (18)F-FDG PET/CT images. The protein expression of Ki-67 was examined by immunohistochemical staining. RESULTS: Significant correlations were found between the MTVsum and Ki-67 labeling index (r = 0.254, p = 0.014) and the TLGtotal and Ki-67 labeling index (r = 0.239, p = 0.020). No correlation was found between the SUVmax and Ki-67 labeling index (r = 0.116, p = 0.264) and the avgSUVmean and Ki-67 labeling index (r = 0.031, p = 0.770). Dividing the Ki-67 expression level into three categories, it was suggested that increasing Ki-67 expression level caused a stepwise increase in the MTVsum and TLGtotal. (p = 0.028 and 0.039, respectively), but not the SUVmax and avgSUVmean (p = 0.526 and 0.729, respectively). CONCLUSION: In conclusion, the volume-based parameters of (18)F-FDG PET/CT correlate with immunohistochemical staining of Ki-67 in SCLC. Measurement of the MTVsum and TLGtotal by (18)F-FDG PET/CT might be a simple, noninvasive, and useful method to determine the proliferative potential of cancer cells. PMID- 26941855 TI - The Use of Anatomical Information for Molecular Image Reconstruction Algorithms: Attenuation/Scatter Correction, Motion Compensation, and Noise Reduction. AB - PET and SPECT are important tools for providing valuable molecular information about patients to clinicians. Advances in nuclear medicine hardware technologies and statistical image reconstruction algorithms enabled significantly improved image quality. Sequentially or simultaneously acquired anatomical images such as CT and MRI from hybrid scanners are also important ingredients for improving the image quality of PET or SPECT further. High-quality anatomical information has been used and investigated for attenuation and scatter corrections, motion compensation, and noise reduction via post-reconstruction filtering and regularization in inverse problems. In this article, we will review works using anatomical information for molecular image reconstruction algorithms for better image quality by describing mathematical models, discussing sources of anatomical information for different cases, and showing some examples. PMID- 26941857 TI - Granulomatous Prostatitis After Intravesical Bacillus Calmette-Guerin Instillation Therapy: A Potential Cause of Incidental F-18 FDG Uptake in the Prostate Gland on F-18 FDG PET/CT in Patients with Bladder Cancer. AB - PURPOSE: This study aimed to evaluate the possibility that Bacillus Calmette Guerin (BCG)-induced granulomatous prostatitis can be a potential cause of benign F-18 FDG uptake. METHODS: A total of 395 bladder cancer patients who underwent F 18 FDG PET/CT (PET/CT) were retrospectively evaluated. Patients were divided into two groups according to BCG therapy status. Elapsed time after BCG therapy, serum PSA level, results of prostate biopsy, and the SUVmax and uptake pattern in the prostate gland were reviewed. For patients who underwent follow-up PET/CT, the changes in SUVmax were calculated. RESULTS: While 35 % of patients showed prostate uptake in the BCG therapy group, only 1 % showed prostate uptake in the non-BCG therapy group (p < 0.001). Among 49 patients with FDG-avid prostate lesions, none had suspected malignancy during the follow-up period (median: 16 months). Five patients revealed granulomatous prostatitis on biopsy. The incidence of FDG-avid prostate lesions was significantly higher if the elapsed time after BCG therapy was less than 1 year compared to more than 1 year (p < 0.001). Serum PSA was normal in 88 % of patients. All patients with incidental F 18 FDG uptake in the prostate gland showed focal or multifocal prostate uptake, and median SUVmax was 4.7. In 16 patients who underwent follow-up PET/CT, SUVmax was decreased in 14 patients (88 %) without treatment, and no patients demonstrated further increased prostate uptake (p < 0.001). CONCLUSIONS: BCG induced granulomatous prostatitis can be a potential cause of benign F-18 FDG uptake, especially in those with a history of bladder cancer treated with BCG. In BCG-induced granulomatous prostatitis, focal or multifocal prostate uptake is frequently seen within 1 year after BCG therapy, and the intensity of prostate uptake is decreased on the follow-up PET/CT without any treatment. PMID- 26941858 TI - Association Between (18)F-FDG Avidity and the BRAF Mutation in Papillary Thyroid Carcinoma. AB - PURPOSE: The BRAF mutation, a potential prognostic factor in papillary thyroid carcinoma (PTC), is associated with a high expression of the glucose transporter gene. We investigated which clinicopathologic factors, including BRAF mutation status, influence (18)F-fluoro-2-deoxyglucose ((18)F-FDG) avidity. METHODS: We retrospectively reviewed 55 patients who underwent BRAF analysis from biopsy confirmed PTC and (18)F-FDG positron emission tomography/computed tomography within 6 months before undergoing thyroid surgery from September 2008 to August 2014. Tumors were considered to be (18)F-FDG avid if the uptake was greater than that of the liver. (18)F-FDG uptake of PTCs was also analyzed semiquantitatively using SUVmax. The association between (18)F-FDG avidity and clinicopathologic variables (age, tumor size, perithyroidal extension, cervical lymph node status, and BRAF mutation status) was investigated. RESULTS: Twenty-nine (52.7 %) of 55 patients had (18)F-FDG-avid PTCs. PTCs with the BRAF mutation showed higher (18)F FDG avidity (24/38, 63.2 %) than those without (5/17, 29.4 %). The BRAF mutation (p = 0.025) and tumor size (p = 0.003) were significantly associated with (18)F FDG avidity in univariate analysis, and the BRAF mutation status remained significant after adjusting for tumor size in multivariate analysis (p = 0.015). In the subgroup of tumor size >= 1 cm, the BRAF mutation was the only factor significantly associated with (18)F-FDG avidity (p = 0.021). The mean SUVmax of PTCs with the BRAF mutation was significantly higher than that of those without (4.89 +/- 6.12 vs. 1.96 +/- 1.10, p = 0.039). CONCLUSIONS: The BRAF mutation must be one of the most important factors influencing (18)F-FDG avidity in PTCs, especially in those with a tumor size >= 1 cm. PMID- 26941859 TI - FDG PET/CT Response Assessment Criteria for Patients with Hodgkin's and Non Hodgkin's Lymphoma at End of Therapy: A Multiparametric Approach. AB - PURPOSE: Based on the International Harmonization Project (IHP) criteria, positron emission tomography (PET) response assessment of residual nodal masses in patients with lymphoma after completion of therapy is performed visually using mediastinal blood pool as the reference. The primary objective of this study was to define the optimal reference for PET response assessment. Secondary aim was to assess if morphological criteria on computed tomography (CT) may improve performance of PET. METHODS: This institutional review board approved retrospective study included 137 patients, with Hodgkin's (n = 43) or non Hodgkin's lymphoma (n = 94) assessed for residual masses (n = 180) after completion of therapy with pathology and clinical and imaging surveillance data (mean, 19 months) as the standard of reference. Two readers independently assessed response by IHP and Deauville criteria. The addition of morphological parameters on CT was assessed in relation to therapy response. RESULTS: Based on the standard of reference, 36 patients (26.3 %) had residual lymphoma. For IHP and Deauville criteria, sensitivity, specificity and accuracy were 97.2 %, 97.2 % (p = 1); 79.2 %, 92.1 % (p < 0.001); and 83.9 %, 93.4 % (p = 0.001), respectively. Of the morphological parameters assessed, only change in size over course of therapy was significant (p < 0.003) and improved specificity for IHP based interpretation to 90.4 % (p = 0.008). CONCLUSIONS: Using liver as the visual reference to determine PET positivity for lymphoma patients being assessed for residual masses at the end of therapy improves specificity, yet maintains the high sensitivity of PET in identifying residual disease. The addition of change in size after therapy improves specificity of PET when using IHP-based but not Deauville-based interpretation. PMID- 26941860 TI - Correlation of Angina Pectoris and Perfusion Decrease by Collateral Circulation in Single-Vessel Coronary Chronic Total Occlusion Using Myocardial Perfusion Single-Photon Emission Computed Tomography. AB - PURPOSE: To evaluate the perfusion decrease in donor myocardium by collateral circulation and its correlation with angina pectoris in patients with chronic total occlusion (CTO) using myocardial perfusion single-photon emission computed tomography (MPS). MATERIALS AND METHODS: Thirty-six patients with single-vessel CTO without any other stenosis were included. All patients underwent MPS and coronary angiography (CAG) within 2 months. Total 72 donor arteries were evaluated for the grades of collaterals to the CTO artery using the Rentrop grading system on CAG. Perfusion defects and perfusion scores in donor and CTO territories were analyzed on MPS. Myocardial perfusion of donor and CTO territories were evaluated according to the presence of angina pectoris and the grades of collateral circulation. RESULTS: When the CTO territory was ischemic, symptomatic patients showed higher summed difference scores in the CTO territory compared to asymptomatic patients (3.5 +/- 2.4 vs. 1.5 +/- 0.8 for symptomatic and asymptomatic groups respectively; p = 0.034). However, when the CTO territory was nonischemic, symptomatic patients showed higher summed stress scores (SSS, 4.3 +/- 2.9 vs. 1.6 +/- 1.2; p = 0.032) and summed rest scores (SRS, 4.2 +/- 2.5 vs. 1.5 +/- 1.1; p = 0.003) in the donor territories. On the per-vessel analysis, perfusion defects in donor territories were more frequent (0 % vs. 53 % vs. 86 % for Rentrop 0, Rentrop 1-2 and Rentrop 3, respectively; p < 0.001) and showed higher SSS (0.0 +/- 0.0, 1.3 +/- 1.6 and 2.1 +/- 1.1 for Rentrop 0, Rentrop 1-2 and Rentrop 3, respectively; p = 0.001) and SRS (0.0 +/- 0.0, 1.0 +/- 1.4 and 1.7 +/- 1.2; p = 0.003) at higher Rentrop grades, but their patterns were variable. CONCLUSION: Angina pectoris was related to either ischemia of the myocardium beyond CTO or a perfusion decrease in the donor myocardium. The perfusion decrease in donor myocardium positively correlated with the collateral grades. PMID- 26941862 TI - Increased Brainstem Serotonergic Transporter Availability in Adult Migraineurs: an [(18)F]FP-CIT PET Imaging Pilot Study. AB - PURPOSE: Recent studies have proposed central serotonergic dysfunction as a major pathophysiology of migraine. We investigated serotonin transporter (SERT) availability in migraineurs using F-18-N-(3-fluoropropyl)-2beta-carbomethoxy 3beta-(4-iodophenyl) nortropane ([(18)F]FP-CIT) positron emission tomography (PET). METHODS: Brain [(18)F]FP-CIT PET images were obtained in eight women with migraine during headache free phase and 12 healthy adult women, 120 min after injection of 185 MBq. Non-displaceable binding potential (BP ND) of [(18)F]FP CIT, which is an estimate of SERT availability, was calculated at the brainstem and compared with clinical parameters. RESULTS: BP ND at the brainstem was significantly higher in adult migraineurs (n = 6, 1.15 +/- 0.17) than healthy subjects (0.95 +/- 0.14) (p = 0.04). Healthy subjects demonstrated negative correlation between brainstem BP ND and age (r = -0.64, p = 0.02), whereas this age-related decline pattern was not found in the migraineurs. Severity of migraine attack was significantly correlated with brainstem BP ND (r = 0.66, p = 0.02), when age and duration of illness were corrected. CONCLUSIONS: Increased SERT availability in the brainstem of adult migraineurs indicates low serotonin neurotransmission during headache-free phase. Patients who experience more painful headaches have lower serotonin neurotransmission. [(18)F]FP-CIT PET is a useful in vivo imaging technique for evaluating brainstem SERT availability in migraineurs. PMID- 26941863 TI - Two Rare Cases of Intrathoracic Splenosis and Subcutaneous Splenosis: Spleen Scintigraphy Avoided the Need for Invasive Procedures. AB - Splenosis is defined as the acquired heterotopic autotransplantation of splenic tissue in other sites of the body after splenic rupture, usually due to either traumatic or iatrogenic causes. It is often found incidentally and is usually asymptomatic. These implants are not limited to the left upper quadrant of the abdomen, however, and splenosis in other locations can mimic various pathologic entities. There are several reports on abdominal splenosis, but intrathoracic and subcutaneous splenosis are rare. We report two cases of intrathoracic and subcutaneous splenosis that were diagnosed using spleen scintigraphy, avoiding the need for an invasive procedure. PMID- 26941861 TI - Semi-Quantitative Analysis of Post-Transarterial Radioembolization (90)Y Microsphere Positron Emission Tomography Combined with Computed Tomography (PET/CT) Images in Advanced Liver Malignancy: Comparison With (99m)Tc Macroaggregated Albumin (MAA) Single Photon Emission Computed Tomography (SPECT). AB - OBJECTIVES: The purpose of this study is to evaluate the correlation between pretreatment planning technetium-99m ((99m)Tc) macroaggregated albumin (MAA) SPECT images and posttreatment transarterial radioembolization (TARE) yttirum-90 ((90)Y) PET/CT images by comparing the ratios of tumor-to-normal liver counts. METHODS: Fifty-two patients with advanced hepatic malignancy who underwent (90)Y microsphere radioembolization from January 2010 to December 2012 were retrospectively reviewed. Patients had undergone (99m)Tc MAA intraarterial injection SPECT for a pretreatment evaluation of microsphere distribution and therapy planning. After the administration of (90)Y microspheres, the patients underwent posttreatment (90)Y PET/CT within 24 h. For semiquantitative analysis, the tumor-to-normal uptake ratios in (90)Y PET/CT (TNR-yp) and (99m)Tc MAA SPECT (TNR-ms) as well as the tumor volumes measured in angiographic CT were obtained and analyzed. The relationship of TNR-yp and TNR-ms was evaluated by Spearman's rank correlation and Wilcoxon's matched pairs test. RESULTS: In a total of 79 lesions of 52 patients, the distribution of microspheres was well demonstrated in both the SPECT and PET/CT images. A good correlation was observed of between TNR ms and TNR-yp (rho value = 0.648, p < 0.001). The TNR-yp (median 2.78, interquartile range 2.43) tend to show significantly higher values than TNR-ms (median 2.49, interquartile range of 1.55) (p = 0.012). The TNR-yp showed weak correlation with tumor volume (rho = 0.230, p = 0.041). CONCLUSIONS: The (99m)Tc MAA SPECT showed a good correlation with (90)Y PET/CT in TNR values, suggesting that (99m)Tc MAA can be used as an adequate pretreatment evaluation method. However, the (99m)Tc MAA SPECT image consistently shows lower TNR values compared to (90)Y PET/CT, which means the possibility of underestimation of tumorous uptake in the partition dosimetry model using (99m)Tc MAA SPECT. Considering that (99m)Tc MAA is the only clinically available surrogate marker for distribution of microsphere, we recommend measurement of tumorous uptake using (90)Y PET/CT should be included routinely in the posttherapeutic evaluation. PMID- 26941864 TI - FDG-PET/CT Brain Findings in a Patient With Macrophagic Myofasciitis. AB - Brain Positron Emission Tomography/Computed Tomography with (18)F fluorodeoxyglucose (FDG PET/CT) was performed in a 44-year-old woman with marked cognitive impairment, diffuse myalgias, sensory, memory and visual disorders, and chronic fatigue, presenting with histopathological features of macrophagic myofasciitis (MMF) at deltoid muscle biopsy. Cerebromedullary Magnetic Resonance Imaging (MRI), electromyography, ophthalmic examination, and cerebrospinal fluid analysis were normal. Visual analysis of FDG PET/CT images showed an atypical pattern of hypometabolism, involving symmetrically the occipital cortex, temporal lobes, and limbic system (including in particular amygdalo-hippocampal complexes), and the cerebellum. Posterior cingulate cortex and parietal areas were preserved. This pattern was confirmed by a voxel-based procedure using Statistical Parametric Mapping (SPM12) that compared a patient's images to normal reference samples from six healthy subjects with adjustment to age obtained using the same PET/CT camera. These results provide a glucose metabolism substrate for cognitive complaints in patients with long-lasting aluminium hydroxide-induced MMF. PMID- 26941866 TI - F-18 Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography Imaging for Diagnosing Ovarian Small Cell Carcinoma of the Hypercalcemic Type. PMID- 26941865 TI - Usefulness of (18)F-FDG PET/CT to Detect Metastatic Mucinous Adenocarcinoma Within an Inguinal Hernia. AB - Metastatic mucinous adenocarcinoma in an inguinal hernia is a rare disease and the image findings of (18)F-fluorodeoxyglucose ((18)F-FDG) positron emission tomography (PET)/computed tomography (CT) are little known. Here, we introduce a 57-year-old man with metastatic mucinous adenocarcinoma in an inguinal hernia. On initial (18)F-FDG PET/CT, hypermetabolism was observed in mucinous adenocarcinoma of the cecum, and adenocarcinomas of the transverse and ascending colon, respectively. Follow-up (18)F-FDG PET/CT revealed newly developed multiple hypermetabolism in peritoneal seeding masses and nodules in the pelvic cavity and scrotum. Peritoneal carcinomatosis in the right pelvic side wall was extended to the incarcerated peritoneum and mesentery in the right inguinoscrotal hernia.(18)F-FDG PET/CT was useful to reveal unexpected peritoneal seeding within the inguinal hernia. Also, this case demonstrated that metastatic mucinous adenocarcinomas had variably intense FDG uptake. PMID- 26941867 TI - Primary Hepatic Actinomycosis Mimicking Hepatic Malignancy with Metastatic Lymph Nodes by F-18 FDG PET/CT. PMID- 26941868 TI - Incidentally Detected Carcinoma Ex Pleomorphic Adenoma of Parotid Gland by F-18 FDG PET/CT. PMID- 26941869 TI - Erratum to: Diagnostic Performance of (68)Ga-DOTATATE PET/CT, (18)F-FDG PET/CT and (131)I-MIBG Scintigraphy in Mapping Metastatic Pheochromocytoma and Paraganglioma. AB - [This corrects the article DOI: 10.1007/s13139-015-0339-z.]. PMID- 26941870 TI - Our ultrasonographic experience in the management of symptomatic hydronephrosis during pregnancy. AB - INTRODUCTION: The aim of the present study was to document the role of ultrasound in the diagnosis and management of symptomatic hydronephrosis during pregnancy. METHODS: In this study, we reviewed 36 consecutive cases of pregnant women whose pregnancy was complicated by symptomatic hydronephrosis. In all patients, management was initially conservative (analgesics and fluids) after hospitalization. The following criteria were used to indicate double-J stent placement under US guidance rather than a conservative treatment: persistent pain with no improvement after conservative treatment, progressive hydronephrosis (>2 cm dilatation of the renal pelvis) or presence of uterine contractions. RESULTS: The mean patient's age was 25 years (17-35) and gestational age at clinical presentation was 24 weeks (13-37). 81 % of cases had a renal pelvis dilatation >2 cm, while in only 19 % of cases there was a hydronephrosis between 1 and 2 cm in diameter; however, calculi were confirmed only in 25 patients. 28 patients required an invasive management with double-J stent insertion under US guidance. The sensitivity and specificity of US in the etiological diagnosis of hydronephrosis during pregnancy was 83 and 91 %, respectively. CONCLUSION: Conservative management with medical therapy and observation should be the first line treatment approach. In our opinion a rapid ureteral decompression with the insertion of a ureteral double-J stent, under US visualization, is the safest method in the treatment of pregnant women with obstructed renal systems. PMID- 26941871 TI - Usefulness of US imaging in overhydrated nephropathic patients. AB - Achievement of a normal hydration status is one of the major targets of hemodialysis. It is based on the estimation of "dry weight", the term used to define normal body fluid content. The concept of dry weight in hemodialysis patients is clinically undisputed, but it is not always easy to achieve in this population. Assessment of hydration status by clinical evaluation is imprecise and often unreliable. Measurement of the inferior vena cava (IVC) diameter has been shown to reflect individual fluid status. The relationship between variation in IVC diameter before and after hemodialysis session and weight loss has been investigated. Ultrasound (US) measurement of the IVC diameter is considered a valid measure of the hydration status and is routinely used in hemodialysis patients. Moreover, a relationship between IVC diameter, respiratory activity and hydration status, evaluated by considering both plasma volume and central venous pressure, has been demonstrated. In conclusion, assessment of hydration status based on blood pressure and central venous pressure can be considered reliable only in patients without signs of heart failure. PMID- 26941872 TI - Intra- and interobserver reliability of transorbital sonographic assessment of the optic nerve sheath diameter and optic nerve diameter in healthy adults. AB - PURPOSE: Transorbital optic nerve sonography (TOS) can measure the optic nerve inclusive the sheath diameter (ONSD) and the optic nerve diameter (OND), which are useful parameters in the diagnosis of several neurological disorders. Data on the reproducibility of TOS are, however, required to use B-mode sonography for clinical purposes. The aim of this study was to assess intra- and interobserver reliability of ultrasound-based evaluations of both OND and ONSD in healthy subjects. METHODS: Using a 4-11-MHz linear array transducer, the OND and ONSD of 20 healthy subjects were independently measured by two expert investigators. RESULTS: Depicting the optic nerve and its sheath was possible in all subjects. The intra- and interobserver reliability was high for both ONSD and OND measurements. Intraobserver agreement, analyzed with Cronbach's Alpha, was higher for ONSD (range: 0.69-0.72) than for OND measurements (range: 0.55-0.65). No differences in interobserver reliability between ONSD and OND measurements were found (p = 0.83 for right and 0.47 for left eye). CONCLUSIONS: Transorbital B mode sonography is a feasible method to assess both ONSD and OND with a high intra- and interobserver reliability. Technical difficulties in differentiating the optic nerve from its sheaths may explain the lower intraobserver agreement for OND than that for ONSD measurements. PMID- 26941873 TI - Could transesophageal echocardiography be useful in selected cases during liver surgery resection? AB - PURPOSE: Although only limited scientific evidence exists promoting the use of transesophageal echocardiography (TEE) in non cardiac surgery, several recent studies have documented its usefulness during liver surgery. METHODS AND RESULTS: In the present case study, through the use of color Doppler TEE, compression of the inferior vena cava and the right hepatic vein was clearly evident, as was their restoration after surgery. CONCLUSION: TEE should be encouraged in patients undergoing liver resection, not only for hemodynamic monitoring, but also for its ability to provide information about the anatomy of the liver, its vessels, and inferior vena cava patency. PMID- 26941874 TI - Giant colon polyp in a child with suspected inflammatory bowel disease: US findings. AB - A 6-year-old boy with a history of diarrhea and rectal bleeding was referred to our department where he underwent ultrasound (US) examination for suspected inflammatory bowel disease. US showed the presence of an echoic oval mass measuring about 30 * 24 mm located at the transition between the transverse and descending colon. It moved with the peristaltic waves and was attached to the intestinal wall through a pedicle. Color Doppler showed intralesional blood flow. On the basis of these findings, the patient was suspected of having a colon polyp. This diagnosis was confirmed at subsequent colonoscopy. The mass was removed using a diathermy snare, and histologic examination revealed hamartomatous polyp measuring 32 mm. PMID- 26941875 TI - Diagnosis of one small bowel tumor: the role of conventional ultrasound and elastography. AB - Neuroendocrine tumors are the most common primary tumors of the small bowel, but diagnosis is usually delayed as the lesions are small and symptoms are mild or nonspecific. Diagnosis of this disease is currently based on radiologic or endoscopic findings. Ultrasound (US) is used as a first-line examination in patients with abdominal symptoms, as this technique permits an overall view of the gastrointestinal tract providing diagnosis of inflammatory and/or neoplastic disorders in a large proportion of patients. The aim of this case report is to describe the feasibility and diagnostic accuracy of elastography in the diagnosis of a tumor of the ileum. The patient underwent conventional gray-scale US and elastography before surgery and these examinations were repeated postoperatively on the surgical specimen confirming preoperative outcome. PMID- 26941876 TI - Contrast-enhanced ultrasound (CEUS) appearance of hepatic myelolipoma. AB - The case report is a description of a single case of hepatic myelolipoma, a very rare benign hepatic tumor, evaluated with contrast sonography, in a 72-year-old female. It was previously reported as hyperechoic lesions at sonography. CEUS features of the lesion were: homogeneous hyperenhancement in the arterial phase and a slight hyperenhancement in the portal venous phase typical of benign tumors. The case report shows CEUS may help in differential diagnosis between benign and malignant lesions, but only the biopsy of the tumor and the pathological evaluation allows the diagnosis. PMID- 26941877 TI - Color-Doppler US features of a pyogenic granuloma of the upper dorsum tongue. AB - The diagnosis of oral lesions is based on clinical history, clinical examination and imaging exams. Different imaging modalities are available for the diagnosis and follow-up of these lesions such as computed tomography, magnetic resonance imaging, color-Doppler ultrasound, angiography and positron emission tomography. To date, color-Doppler ultrasound is considered the first-line imaging approach since it provides a non-invasive, cost-effective, real-time evaluation of oral anomalies. It provides both morphological and vascular information which are useful to determine the best therapeutic options. Differential diagnosis of a bleeding lobular mass of the tongue is, however, not always easy and includes several vascular and non-vascular lesions. We present herein a case of pyogenic granuloma of the tongue that at Color-Doppler US appeared as hypervascular lesion. PMID- 26941878 TI - Focal hepatic lesions characterisation by different sonographic techniques: a prospective analysis. AB - INTRODUCTION: Ultrasound is usually the first diagnostic investigation for the assessment of liver lesions. Apart from conventional sonography (CS), new grey scale sonographic techniques have been developed which have increased the application of ultrasound in liver imaging. The present study was undertaken to compare image quality of CS, real-time compound sonography (RTCS), tissue harmonic sonography (THS) and tissue harmonic compound sonography (THCS) in focal liver lesions. MATERIALS AND METHODS: 100 patients with focal hepatic lesions were enroled. Lesions were divided into solid and cystic group. Solid lesions were evaluated for lesion conspicuity and elimination of artefacts. For cystic lesions, lesion conspicuity, posterior acoustic enhancement and internal echoes within the lesion were evaluated. Grading was done using 3-5-point scales. Overall image quality was assessed depending on the total points. RESULTS: 78 solid and 22 cystic liver lesions were included. THCS showed superior results for lesion conspicuity, elimination of artefacts and overall image quality in solid lesions. RTCS showed similar results as THCS for lesion conspicuity and overall image quality in solid lesions. THS gave better results in cystic lesions for all imaging parameters. Results of THCS though slightly inferior, showed no significant difference from THS, in cystic lesions. CS was found to have least diagnostic value in characterisation. CONCLUSIONS: For evaluation of focal hepatic lesions, a combination of compound and harmonic sonography, i.e. THCS, is the preferred sonographic technique. PMID- 26941879 TI - Detection of small testicular masses in monorchid patients using US, CPDUS, CEUS and US-guided biopsy. AB - PURPOSE: Testis sparing surgery (TSS) is a well-known technique in the treatment of small testicular masses. Grayscale ultrasound (US), color/power Doppler US (CPDUS) and contrast-enhanced ultrasound (CEUS) are considered the best diagnostic imaging tools in those patients. Aim of this study was to assess the role of US imaging in the detection of small testicular masses in monorchid patients after orchiectomy for malignant neoplasm, and in guiding surgery to reach the target and also to differentiate lesions which presented vascular activity within the mass. METHODS: From January 2011 to October 2014, 18 patients were enrolled in this study. They had previously undergone orchiectomy and were investigated for suspected contralateral disease. During routine follow-up, all patients underwent grayscale US. If findings were positive, CPDUS and CEUS were performed and eventually all patients underwent surgery. After exteriorization of the testis, the small mass was identified by intraoperative US, and a needle was placed under US guidance. After excision of the mass, frozen section examination was performed. When malignancy was found, radical orchiectomy was performed; if histological outcome was negative, the healthy testis was conserved. RESULTS: All patients underwent grayscale US examination, which showed small hypoechoic masses. Each mass identified at US imaging was confirmed at surgery. All patients underwent CPDUS; 12/19 lesions showed blood flow while 7/19 showed absence of blood flow. At CEUS, 16/19 lesions showed enhancement and subsequent histological examination revealed that 8 were seminomas and 3 were Leydig cell tumors. In 5/19 cases CEUS showed the presence of lesions (focal inflammatory lesions) and in 3/19 cases CEUS was negative. CONCLUSIONS: TSS in monorchid patients may be a safe procedure leading to excellent results. We therefore consider it a valid alternative to radical orchiectomy, and US imaging is essential to guide the resection of non-palpable neoplasms and to exclude concomitant lesions. PMID- 26941880 TI - Efficacy of ultrasound-guided testicle-sparing surgery for small testicular masses. AB - PURPOSE: The aim of the present study was to evaluate evolution of conservative echo-guided surgery for testicular tumours <=1.5 cm and to assess the safety of this surgical procedure. METHODS: 49 consecutive patients diagnosed with ultrasonography testicular lesions (mono or bilateral) <=1.5 cm and treated with conservative echo-guided testicular surgery were examined. The parameters considered in this retrospective analysis included case history, physical examination, scrotal and abdominal ultrasonography, computed tomography scan, size of the nodule (maximum diameter), tumour markers, chest radiography, frozen section examination, histologic size of the tumour, overall survival (OS) and findings on follow-up. RESULTS: Mean age of patients was 33 years (range 18-62). Patients who presented with a palpable testicular nodule were 32.7 %, gynecomastia 10.2 %, precocious pseudopuberty 4 %, and scrotal pain 12.2 %. Permanent section examination confirmed the FSE data in all cases of certainty malignant lesion and definitive histological types were: 22 seminoma, 13 non seminomatous or mixed germ cell tumours, 4 Leydig tumours, 2 hamartoma, 1 epidermoid cyst, 2 sertoli cell tumours, and 5 fibrous pseudotumour. No complications intra- and postoperative were observed. Overall survival was 100 % and scrotal US showed evidence of local tumour recurrence in 6 patients (12.2 %) after a mean follow-up of 34.7 months. CONCLUSION: The OS, the low rate of local recurrence, and absence of complications, tend to demonstrate the safety of the procedure. The benefits to testicular-sparing surgery include improving the patient's overall quality of life, fertility, endocrine function and negative cosmetic effects of radical orchiectomy. PMID- 26941881 TI - Multiparametric sonographic imaging of a capillary hemangioma of the testis: appearances on gray-scale, color Doppler, contrast-enhanced ultrasound and strain elastography. AB - We report a case of a lobular capillary hemangioma in a 66-year-old man, who presented with left testicular pain, with an asymptomatic incidental right testicular lesion found on ultrasonography. The sonographic examination demonstrated a heterogeneous mainly iso-echoic intratesticular lesion with marked vascularity on the color Doppler examination. Further evaluation with contrast enhanced ultrasound and strain elastography was performed; the multiparametric imaging suggested a benign tumor. The multidisciplinary team decision with patient consent was to perform a radical orchiectomy with subsequent histopathology confirming a benign lobular capillary hemangioma. PMID- 26941882 TI - A variant of type VI choledochal cyst: combined dilatation of cystic duct and common bile duct. PMID- 26941883 TI - Rupture of the sheath of the extensor carpi ulnaris tendon in a patient affected by rheumatoid arthritis. PMID- 26941884 TI - Medical ethics. PMID- 26941885 TI - Bayesian Analysis of Ambulatory Blood Pressure Dynamics with Application to Irregularly Spaced Sparse Data. AB - Ambulatory cardiovascular (CV) measurements provide valuable insights into individuals' health conditions in "real-life," everyday settings. Current methods of modeling ambulatory CV data do not consider the dynamic characteristics of the full data set and their relationships with covariates such as caffeine use and stress. We propose a stochastic differential equation (SDE) in the form of a dual nonlinear Ornstein-Uhlenbeck (OU) model with person-specific covariates to capture the morning surge and nighttime dipping dynamics of ambulatory CV data. To circumvent the data analytic constraint that empirical measurements are typically collected at irregular and much larger time intervals than those evaluated in simulation studies of SDEs, we adopt a Bayesian approach with a regularized Brownian Bridge sampler (RBBS) and an efficient multiresolution (MR) algorithm to fit the proposed SDE. The MR algorithm can produce more efficient MCMC samples that is crucial for valid parameter estimation and inference. Using this model and algorithm to data from the Duke Behavioral Investigation of Hypertension Study, results indicate that age, caffeine intake, gender and race have effects on distinct dynamic characteristics of the participants' CV trajectories. PMID- 26941887 TI - Oxidative Stress to Promote Cell Death or Survival. PMID- 26941886 TI - Coronary Computed Tomography Angiography Derived Fractional Flow Reserve and Plaque Stress. AB - Fractional flow reserve (FFR) measured during invasive coronary angiography is an independent prognosticator in patients with coronary artery disease and the gold standard for decision making in coronary revascularization. The integration of computational fluid dynamics and quantitative anatomic and physiologic modeling now enables simulation of patient-specific hemodynamic parameters including blood velocity, pressure, pressure gradients, and FFR from standard acquired coronary computed tomography (CT) datasets. In this review article, we describe the potential impact on clinical practice and the science behind noninvasive coronary computed tomography (CT) angiography derived fractional flow reserve (FFRCT) as well as future applications of this technology in treatment planning and quantifying forces on atherosclerotic plaques. PMID- 26941888 TI - NADPH Oxidase: A Potential Target for Treatment of Stroke. AB - Stroke is the third leading cause of death in industrialized nations. Oxidative stress is involved in the pathogenesis of stroke, and excessive generation of reactive oxygen species (ROS) by mitochondria is thought to be the main cause of oxidative stress. NADPH oxidase (NOX) enzymes have recently been identified and studied as important producers of ROS in brain tissues after stroke. Several reports have shown that knockout or deletion of NOX exerts a neuroprotective effect in three major experimental stroke models. Recent studies also confirmed that NOX inhibitors ameliorate brain injury and improve neurological outcome after stroke. However, the physiological and pathophysiological roles of NOX enzymes in the central nervous system (CNS) are not known well. In this review, we provide a comprehensive summary of our current understanding about expression and physiological function of NOX enzymes in the CNS and its pathophysiological roles in the three major types of stroke: ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage. PMID- 26941889 TI - Nutrients, Microglia Aging, and Brain Aging. AB - As the life expectancy continues to increase, the cognitive decline associated with Alzheimer's disease (AD) becomes a big major issue in the world. After cellular activation upon systemic inflammation, microglia, the resident immune cells in the brain, start to release proinflammatory mediators to trigger neuroinflammation. We have found that chronic systemic inflammatory challenges induce differential age-dependent microglial responses, which are in line with the impairment of learning and memory, even in middle-aged animals. We thus raise the concept of "microglia aging." This concept is based on the fact that microglia are the key contributor to the acceleration of cognitive decline, which is the major sign of brain aging. On the other hand, inflammation induces oxidative stress and DNA damage, which leads to the overproduction of reactive oxygen species by the numerous types of cells, including macrophages and microglia. Oxidative stress-damaged cells successively produce larger amounts of inflammatory mediators to promote microglia aging. Nutrients are necessary for maintaining general health, including the health of brain. The intake of antioxidant nutrients reduces both systemic inflammation and neuroinflammation and thus reduces cognitive decline during aging. We herein review our microglia aging concept and discuss systemic inflammation and microglia aging. We propose that a nutritional approach to controlling microglia aging will open a new window for healthy brain aging. PMID- 26941890 TI - Bioactive Peptides from Angelica sinensis Protein Hydrolyzate Delay Senescence in Caenorhabditis elegans through Antioxidant Activities. AB - Since excessive reactive oxygen species (ROS) is known to be associated with aging and age-related diseases, strategies modulating ROS level and antioxidant defense systems may contribute to the delay of senescence. Here we show that the protein hydrolyzate from Angelica sinensis was capable of increasing oxidative survival of the model animal Caenorhabditis elegans intoxicated by paraquat. The hydrolyzate was then fractionated by ultrafiltration, and the antioxidant fraction (<3 kDa) was purified by gel filtration to obtain the antioxidant A. sinensis peptides (AsiPeps), which were mostly composed of peptides with <20 amino acid residues. Further studies demonstrate that AsiPeps were able to reduce the endogenous ROS level, increase the activities of the antioxidant enzymes superoxide dismutase and catalase, and decrease the content of the lipid peroxidation product malondialdehyde in nematodes treated with paraquat or undergoing senescence. AsiPeps were also shown to reduce age pigments accumulation and extend lifespan but did not affect the food-intake behavior of the nematodes. Taken together, our results demonstrate that A. sinensis peptides (AsiPeps) are able to delay aging process in C. elegans through antioxidant activities independent of dietary restriction. PMID- 26941891 TI - F360 and F6 Skytaper: SEM evaluation of cleaning efficiency. AB - AIM: Root canal preparation may produce a large quantity of smear layer that covers canal walls. Single-file systems have recently appeared, with the aim of reducing the number of steps and files to reach a correct endodontic treatment. The purpose of this study was to evaluate by SEM the root canal walls after instrumentation with F360 (Komet, Brasseler GmbH & Co., Lemgo, Germany) and F6 Skytaper (Komet, Brasseler GmbH & Co., Lemgo, Germany), in order to evaluate the presence/absence of smear layer and the presence/absence of open tubules on the root canal walls at coronal, middle, and apical third of each sample. METHODS: Twenty single-rooted freshly extracted teeth were selected and divided into 2 groups. For each group root canals were shaped with F360 (Komet, Brasseler GmbH & Co., Lemgo, Germany) and F6 Skytaper (Komet, Brasseler GmbH & Co., Lemgo, Germany) instruments under irrigation with 5,25% NaOCl and 17% EDTA. Specimens were fractured longitudinally and analyzed by SEM at standard magnification of 5000x. The presence/absence of smear layer and the presence/absence of open tubules at the coronal, middle, and apical third of each canal were evaluated using a 5-step scale for scores. Numeric data were analyzed using Kruskall-Wallis and Mann-Whitney U statistical tests and significance was predetermined at P <0.05. RESULTS: This study did not reveal differences among two groups at the coronal and apical third. The apical third showed the highest values of scores for all Ni-Ti systems used. Significant differences in smear layer scores were recorded among the Ni-Ti systems at middle canal level (P < 0.05), where F6 Skytaper showed significantly lower scores than F360. CONCLUSIONS: Within the limitation of this study, F360 and F6 Skytaper rotary instruments seem to be effective in shaping root canals with good debridement from canal walls, without significant differences between the two systems as it regards the coronal third and the apical third, the area where more debris is still visible. Instead, in the middle third F6 Skytaper seems to be more effective than F360, with statistically significative differences between the two systems. PMID- 26941892 TI - Laser-assisted treatment of dentinal hypersensitivity: a literature review. AB - The purpose of this literature review was to evaluate the effectiveness of the laser-assisted treatment of dentinal hypersensitivity. A review with inclusion and exclusion criteria was performed from January 2009 to December 2014 with electronic data-bases: MedLine via PubMed, Science Direct and Cochrane Library. Research of paper magazines by hand was not considered. Forty-three articles were selected between literature reviews, in vitro studies, clinical trials, pilot and preliminary studies. The items were divided into laser-used groups for an accurate description, and then the reading of results into various typologies. Laser-assisted treatment reduces dentinal hypersensitivity-related pain, but also a psychosomatic component must be considered, so further studies and more suitable follow-ups are necessary. PMID- 26941893 TI - Italian recommendations on dental support in the treatment of adult obstructive sleep apnea syndrome (OSAS). AB - BACKGROUND: The aim of the present article is to present a set of proposed clinical recommendations aimed at Italian dentists involved in the management of patients with obstructive sleep apnea syndrome or snoring. METHODS: With the purpose of creating a study group, some of the most important Italian scientific societies operating in fields relevant to the issue of sleep medicine in dentistry were asked to appoint a representative. Each member of the study group was required to answer questions regarding the clinical management of OSAS and snoring. RESULTS: Oral appliances can be used to treat: - simple snoring, in patients who do not respond to, or do not appear to be suitable candidates for behavioral measures such as weight loss or positional therapy; - mild or moderate OSAS, in patients who prefer OAs to continuous positive airway pressure (CPAP) or who are not suitable candidates for CPAP, because of its failure or failure of behavioral approaches like weight loss or positional therapy; - severe OSAS, in patients who do not respond to or do not tolerate CPAP and in whom no indication for either maxillofacial or ENT surgery appears applicable. CONCLUSIONS: The application of oral appliances is highly desirable in cases of simple snoring or mild to moderate OSAS, whereas considerable caution is warranted when treating severe OSAS. It is fundamental to ensure that the patient understands his problem and, at the same time, to present all the various treatment options. PMID- 26941894 TI - Management and treatment of sinonasal inverted papilloma. AB - AIMS: The aim of this paper is to describe the surgical experience of 35 patients with Inverted Papilloma (IP) of paranasal sinuses and its recurrence rate after a year of follow-up. MATERIALS: A retrospective chart review was performed on patients presenting with IP of paranasal sinuses. Thirty-five patients comprised the focus of this study. For all patients was performed a pre-surgery TC, and for more 5 patients it was necessary to perform a Magnetic Resonance (MR) with gadolinium. RESULTS: Among 35 patients selected, 18 patients underwent to open surgery, 4 patients had a combined approach with endoscopy and open surgery, while 13 patients were managed only with an endoscopic approach, with a minimum of 1 year of follow-up. Our results highlighted that the global percentage of success 12 months after the treatment was 93% and it not vary according to the tipology of the approach used if a radical excision of the lesion is achieved. More in depth, among 35 cases, only 2 patients were found to have recurrences and were treated with coronal and endoscopic approach. CONCLUSION: It is fundamental to underline that surgery must be carried on in a radical manner to treat these tend to recur. A complete removal of the lesion and bone peripheral border filing are essential to perform a correct and definitive treatment. Also, endoscopic approach can be taken into account when tumors are localized median to a sagittal plan crossing the orbit median wall and when they did not massively compromised paranasal sinus walls. PMID- 26941896 TI - Preventive strategies in oral health for special needs patients. AB - As regards to the most common oral disease in pediatric patients, intellectual disability is not a risk factor for caries disease itself, but it rather reduces the individual capability to self-care and therefore to his own oral care. Children suffering of systemic pathologies and/or with different stages of disability are to be considered at high risk for dental caries development. According to recent guidelines for oral health prevention in childhood, individual additional strategies for a preventive care should be applied for these patients. All the health providers, family and caregivers should be involved with the aim of being aware, motivated and informed on oral health issues, and a better access system to the dental care structure, both logistic, professional and economical should be assured. PMID- 26941895 TI - A rare case of synovial chondromatosis of the inferior TMJ compartment. Diagnosis and treatment aspect. AB - AIM: Synovial Chondromatosis (SC) is a rare, benign non neoplastic arthopathy characterized by the metaplastic development of cartilaginous nodules within the synovial membrane. In only 3% of all cases does it affect the temporomandibular joint (TMJ) and cases that arise from the lower compartment are rarely found in literature. The aim of this paper is to report a new case of SC of the inferior TMJ compartment with the description of the clinical, therapeutic and histopathological findings. CASE REPORT: This article presents a 68-year-old woman with preauricular swelling on the right side, pain, crepitus and limited joint motion. This patient was evaluated by preoperative clinical manifestation, CT scan and MR images. Both showed multiple, calcified loose bodies in the inferior compartment. Based on these images as well as the patient's signs and symptoms, a surgical intervention was performed. A good functional recovery with no signs of recurrence at 36 months of follow up was obtained. CONCLUSION: Among cases of synovial chondromatosis in literature, only twelve originating in the lower compartment have been reported, this one included. In all the cases treated for SC in the lower compartment, both in literature and in our case report, surgical treatment led to healing. PMID- 26941897 TI - The gingival Stillman's clefts: histopathology and cellular characteristics. AB - AIM OF THE STUDY: Stillman's cleft is a mucogingival triangular-shaped defect on the buccal surface of a root with unknown etiology and pathogenesis. The aim of this study is to examine the Stillman's cleft obtained from excision during root coverage surgical procedures at an histopathological level. MATERIALS AND METHOD: Harvesting of cleft was obtained from two periodontally healthy patients with a scalpel and a bevel incision and then placed in a test tube with buffered solution to be processed for light microscopy. RESULTS: Microscopic analysis has shown that Stillman's cleft presented a lichenoid hand-like inflammatory infiltration, while in the periodontal patient an inflammatory fibrous hyperplasia was identified. CONCLUSION: Stillman's cleft remains to be investigated as for the possible causes of such lesion of the gingival margin, although an inflammatory response seems to be evident and active from a strictly histopathological standpoint. PMID- 26941899 TI - Aesthetic restoration in maxillo-mandibular malformations: the role of genioplasty. AB - AIM: The aim of this study was to determinate how orthognatic surgery aids to cure many skull and face abnormalities and to help re-establishing the correct occlusive relation thanks to the repositioning of the maxillo-mandibular skeleton basis. METHODS: The study included 183 male patients and 338 female patients, with an average age of 23 years. The sample series was divided according to specific pathologies. All patients underwent surgical procedures and the therapeutic strategy was determined based on the anomalies presented. RESULTS: 113 patients had a II class dental skeletal occlusion, 180 patients had a III class dental-skeletal occlusion and 222 patients had skull-facial abnormalities. 5 patients underwent only a genioplasty, 82 patients underwent a genioplasty associated with BSSO, 175 patients underwent a genioplasty associated with Le Fort I osteotomy and the remaining 253 patients underwent a genioplasty associated with BSSO and Le Fort I osteotomy. CONCLUSION: The experience shows that genioplasty has been successfully introduced in orthognathic surgical therapeutic procedures, for dental-skeleton abnormalities and mandibular asymmetries treatment. In recent years, the evolution of computer systems has allowed an accurate assessment and programming, by means of the three-dimensional display, which are of great help in the course of diagnosis and evaluation of the displacements to be carried out, in order to obtain optimal aesthetic results. PMID- 26941898 TI - A tooth preparation technique in fixed prosthodontics for students and neophyte dentists. AB - PURPOSE: The aim of this study was to evaluate a novel technique of tooth preparation in fixed prosthodontics suitable for dental students and neophyte dentists. MATERIALS AND METHODS: Twenty-four dental students of the sixth-year class were recruited to verify the predicibility of this technique. Each student prepared two mandibular second premolars on a typodont for a dental crown with a 90 degrees shoulder finishing line. One tooth was prepared using standard procedures taught in the prosthodontic dental course; the other tooth was prepared with the new technique. Three Professors of Prosthodontics of the same University evaluated the result on the basis of 10 criteria. RESULTS: A statistically significant difference between the two techniques was found in 8 out of 10 criteria. The new technique showed higher values (p<0.05) in 7 criteria, while the conventional technique had better results in just 1 criterion. Moreover, the total sum of values was higher for the new technique (total 41.2+/-3.98, p<0.05) compared to the conventional technique (total 38.12+/ 5.18, p<0.05). CONCLUSIONS: This study showed that the results were less dependent on manual abilities and personal experience with the novel technique. It could helps dental students and neophyte dentists in their learning curve. PMID- 26941900 TI - Endo-restorative treatment of a severly discolored upper incisor: resolution of the "aesthetic" problem through Componeer veneering System. AB - AIM: Re-establishing a patient's lost dental aesthetic appearance is one of the most important topics for contemporary dentistry. New treatment materials and methods have been coming on the scene, day by day, in order to achieve such an aim. Most dentists prefer more conservative and aesthetic approaches, such as direct or indirect veneer restorations, instead of full-ceramic crowns for anteriors where aesthetics is really important. The aim of the study is to evaluate clinically the effectiveness of a direct composite veneering system in resolving aesthetic problem of an upper incisor with a multidisciplinary treatment approach. METHODS: Patient with a severe discolored upper incisor came to our attention; at the X-ray exam there was an evidence of a past not good root canal treatment and also old and incongruent composite obturation. After removing all the material inside the root canal was performed a new correct endodontic filling, then Authors tried to bleach the tooth trough "walking-bleach" technique with a hydrogen peroxide (30 volumes) and sodium perborate solution without excellent results. So it was decided to insert a glass-fiber post and than to perform a direct composite veneer with Componeer System (Coltene). Componeer System is a system of prefabricated composite veneers that are abled to be applied directly in the first appointment: after a conservative preparation of the tooth, it must be used an adhesive agent (for example a "three steps") and then with composite stratification it's possible to apply the componeer veneer (choosing the right measure, modified as necessary) as the last covering aesthetic layer. RESULT: The evaluation of result of this multidisciplinary treatment was essentially clinical and radiological; in fact it's possible to observe, from a clinical point of view, the good aesthetic aspect of the direct composite restoration with componeer veneer that offers also some advantages: conservative preparation with minimal lost of tooth tissue, easy standardized technique, low cost and immediate restoration of the tooth (without provisional passage). From a radiological point of view it's possible to check the good quality of endodontic retreatment on the post-operative periapical X-ray. To verify the long-term result Authors consider follow up at six months and one year. CONCLUSION: A multidisciplinary approach is always necessary to program a treatment plan in dentistry; in the case reported Authors decide to perform an endo-conservative treatment with different steps: - root canal therapy to resolve endodontical problem- glass fiber post to reinforce the conservative restoration- direct composite veneer restoration (after bleaching) to obtain the resolution of anterior aesthetic problems. PMID- 26941901 TI - Breast Cancer: The Perspective of Northern Nigerian Women. AB - BACKGROUND: The rising incidence of breast cancer is complicated by late presentation, which marks breast cancer diagnosis in Nigeria with about 70% of cases presenting at advanced stages of the disease. The aim of this study is to determine the general level of awareness of breast cancer, breast cancer risk factors, signs/symptoms as well as preventive measures nothern Nigerian women. It also aimed at determining their attitudes toward breast cancer cure, prevention and cause. Finally, it aims to determine their practices toward breast cancer and its associated factors. METHODS: A cross-sectional community survey was used to study 230 women aged 15-60 years in Chikun Local Government Area. The subjects were selected based on nonprobability sampling. Data collected using self administered questionnaire were analyzed using Statistical Package for Social Science students (version 16). Test of associations employed Chi-square statistical tool with the level of significance taken at 0.05. RESULTS: About 75.2% knew about breast cancer with health facility (29.13%) being the greatest source of information. An average of 29.35% had knowledge of the risk factors tested. Mean knowledge of the signs and symptoms was 50.1% Average knowledge of breast cancer screening methods was 34.26% with breast self-examination (BSE) (46.1%) being the most recognized. In relation to perception, about 21.7% strongly agreed with the fact that breast cancer is treatable following early detection while 18.3% strongly agreed that screening is effective in detecting breast cancer. Concerning practice, an average of 10.2% practiced any of the screening methods, with BSE (17.4%) being the most practiced. Strongest reasons for nonpractice was ignorance (17.4%). An association was established between knowledge and practice of all the screening methods (P = 0.001 respectively). CONCLUSIONS: There is insufficient knowledge, as well as poor practices in relation to important factors associated with breast cancer prevalence. PMID- 26941902 TI - Ebola-free Liberia: Scrutinizing the Efforts of Public Health Sector and International Agencies. PMID- 26941903 TI - Dairy Consumption and Risk of Stroke: A Case-control Study. AB - BACKGROUND: It remains controversial if dairy product intake is associated with risk of stroke. Limited information is available from Middle East countries in this regard. This case-control study was conducted to assess the relationship between dairy consumption and risk of stroke in Iranian adults. METHODS: In this study, 195 stroke patients (recognized based on clinical findings and computed tomography scan) hospitalized in neurology ward of Alzahra University Hospital were enrolled. Controls (n = 195) were selected with convenience nonrandom sampling procedure from other wards of this hospital. A validated food frequency questionnaire was used to assess participants' usual dietary intakes. Data on other variables were collected by the use of questionnaires. RESULTS: Patients with stroke were older (P < 0.001), had lower weight and body mass index (P < 0.05) and were more likely to be male (P < 0.05) and less likely to be obese (P < 0.001). After adjustment for age, sex and total energy intake, Individuals with the highest consumption of low-fat dairy had a significantly decreased risk of stroke (odds ratio [OR]: 0.58; 95% of confidence interval [CI]: 0.34-0.99), while those with the highest intake of high-fat dairy had a 2-fold increased risk of stroke. The association between high-fat dairy consumption and stroke even persisted after additional adjustments for physical activity, smoking and dietary variables (OR: 2.02; 95% CI: 1.02-4.02); but the association between low-fat dairy intake and stroke disappeared after these adjustments (OR: 0.84; 95% CI: 0.44-1.58). CONCLUSIONS: We found a significant positive association between high fat dairy consumption and risk of stroke. Further prospective studies are required to confirm this finding. PMID- 26941905 TI - Tuberculosis Awareness Program: Need for Longer and More Rigorous Follow-up. PMID- 26941904 TI - Satisfaction and Dissatisfaction Toward Urban Family Physician Program: A Population Based Study in Shiraz, Southern Iran. AB - BACKGROUND: A national project of extending a family physician program to urban areas has been started since May 2013 in Iran. The present study aimed to detect correlates of people's satisfaction and dissatisfaction about urban family physician program. METHODS: This cross-sectional and population-based study was conducted in Shiraz, Southern Iran. Multistage and proportional to size random sampling were used. Different items about satisfaction and dissatisfaction toward urban family physician program were queried. Single variable and then multiple variable analyses of data were done using SPSS software (Chicago, IL. USA). RESULTS: Mean age of 1257 participants in the study was 38.1 +/- 13.2 years. Respondents included men (634; 50.4%), married (882; 70.2%), those who were educated at universities (529; 42%) and self-employed groups (405; 32.2%). One thousand fifty-eight (84.1%) were covered by the family physician program. Mean of referral times to a family physician was 2.2 +/- 2.9 during the year before the study. Satisfaction toward urban family physician program was high in 198 (15.8%), moderate in 394 (31.3%), and low in 391 (31.1%). Dissatisfaction about this program was more among younger than 51-year-old groups (for 31-50 years odds ratio [OR] =2.3, 95% confidence interval [CI] =1.4-3.7, P < 0.001 and for 18-30 years OR = 2, 95% CI = 1.2-3.4, P = 0.005), less knowledgeable ones (OR = 2.2, 95% CI = 1.3-3.6, P = 0.001), singles (OR = 2.1, 95% CI = 1.2-3.4, P = 0.003), and those with more than 4 of family members (OR = 1.3, 95% CI = 1-1.7, P = 0.05). CONCLUSIONS: Overall, the majority of the people are not very satisfied with the urban family physician program. This shows the need for a multi disciplinary approach including training, improvement of infrastructures and referral system, continuous supervision, and frequent monitoring of user's and provider's feedback about this program. According the results, the family physician program should be improved prior to extending this program to other provinces in Iran. PMID- 26941906 TI - Primary Care Physicians Practicing Preventive Medicine in the Outpatient Setting. AB - BACKGROUND: Preventive care is an important part of primary care medicine, yet much variation in its practice exists. The aim of this study is to assess physicians' perspectives of practicing preventive medicine and evaluate which topics are deemed most important. METHODS: All primary care medicine providers at two separate academic medical centers (Mayo Clinic, MN and Mayo Clinic, FL) were surveyed via an E-mail questionnaire assessing physicians' perception of the role of preventive medicine during both acute/routine and yearly visits, physicians' perception of patients' response to preventive medicine topics, and which preventive medicine topics are commonly practiced. RESULTS: Of 445 providers meeting inclusion criteria, a total of 183 (41.1%) responded. Providers were more likely to engage patients in preventive medicine during yearly visits more so than acute visits (3.82 vs. 4.72, range 1-5 Likert Scale), yet providers were very likely to partake in such practices during both visits. Providers perceived that patients received the practice of preventive medicine very well (4.13 on 1-5 Likert Scale). No significant difference between provider practice and patient perception was noted between the two sites, although there was some variation based on clinical experience of the provider. Providers were found to most commonly practice topics recommended by the United States Preventive Services Task Force. CONCLUSIONS: Our study found a high predisposition to practicing preventive medicine. Providers seem to practice according to published evidence based medicine recommendations. PMID- 26941908 TI - Health Promotion Methods for Smoking Prevention and Cessation: A Comprehensive Review of Effectiveness and the Way Forward. AB - Tobacco smoking is one of the greatest causes of mortality in the world, responsible for over 5 million deaths per annum. The prevalence of smoking is over 1 billion people, with the majority coming from low or middle income countries. Yet, the incidence of smoking varies vastly between many countries. Some countries have been able to decline the smoking and tobacco related morbidity and mortality through the introduction of health promotion initiatives and effective policies in order to combat tobacco usage. However, on the other hand, in some countries, the incidence of smoking is increasing still further. With the growing body of evidence of detriment of tobacco to health, many control policies have been implemented as health promotion actions. Such methods include taxation of smoking, mass advertising campaigns in the media, peer education programs, community mobilization, motivational interviewing, health warnings on tobacco products, marketing restrictions, and banning smoking in public places. However, the review of the effectiveness of various health promotion methods used for smoking prevention and cessation is lacking. Therefore, the aim of this review is to identify and critically review the effectiveness of health promotion methods used for smoking prevention and cessation. All available studies and reports published were considered. Searches were conducted using PubMed, MEDLINE, Ovid, Karger, ProQuest, Sage Journals, Science Direct, Springer, Taylor and Francis, EMBASE, CINAHL, and Cochrane and Wiley Online Library. Various relevant search terms and keywords were used. After considering the inclusion and exclusion criteria, we selected 23 articles for the present review. PMID- 26941909 TI - Global Food Safety: Challenges and Recommended Public Health Strategies. PMID- 26941907 TI - The Protective Effect of gamma-aminobutyric Acid on Kidney Injury Induced by Renal Ischemia-reperfusion in Ovariectomized Estradiol-treated Rats. AB - BACKGROUND: Renal ischemia-reperfusion injury (IRI) is one of the most important causes of kidney injury, which is possibly gender-related. This study was designed to investigate the role of gamma-aminobutyric acid (GABA) against IRI in ovariectomized estradiol-treated rats. METHODS: Thirty-five ovariectomized Wistar rats were used in six experimental groups. The first three groups did not subject to estradiol treatment and assigned as sham-operated, control, and GABA-treated groups. GABA (50 MUmol/kg) and saline were injected in the treated and control groups 30 min before the surgery, respectively. The second three groups received the same treatments but received estradiol valerate (500 MUg/kg, intramuscularly) 3 days prior to the surgery. The IRI was induced in the control and treated groups by clamping the renal artery for 45 min and then 24 h of reperfusion. All animals were sacrificed for the measurements. RESULTS: The serum levels of creatinine and blood urea nitrogen, kidney weight, and kidney tissue damage score significantly increased in the IRI rats (P < 0.05). GABA significantly decreased the aforementioned parameters (P < 0.05). The uterus weight increased significantly in rats that received estradiol (P < 0.05). Serum and kidney levels of nitrite (nitric oxide metabolite) did not alter significantly. Serum level of malondialdehyde increased significantly in the ovariectomized rats exposed to IRI (P < 0.05). CONCLUSIONS: It seems that GABA improved IRI in ovariectomized rats. Estradiol was also nephroprotective against IRI. However, co-administration of estradiol and GABA could not protect the kidney against IRI. PMID- 26941910 TI - Comment on: Effect of Pomegranate Flower Extract on Cisplatin-induced Nephrotoxicity in Male Rats. PMID- 26941911 TI - Inequality in Health for Women, Infants, and Children: An Alarming Public Health Concern. PMID- 26941912 TI - 2000 to 2015: How Far Have We Progressed in Achieving the Health Related Millennium Development Goals? PMID- 26941913 TI - Risk Communication: An Integral Element in Public Health Emergencies. PMID- 26941914 TI - How can we Improve the Universal Uptake of HIV Testing Services? World Health Organization. PMID- 26941915 TI - Is There No Solution to Minimize the Aftermaths of Heat Waves? World Health Organization Comes Up with an Answer!!! PMID- 26941916 TI - Palliative Care: An Integral Component of Human Right to Health. PMID- 26941917 TI - World Health Organization Advocates for Expansion in the Role of Health Workforce to Prevent Unsafe Abortions. PMID- 26941918 TI - Recommended Strategies to Move Closer Toward the Global Eradication of Polio: International Health Regulations. PMID- 26941919 TI - The Growing Global Problem of Vaccine Hesitancy: Time to Take Action. PMID- 26941920 TI - Public Health Interventions to Reduce the Incidence of Tobacco Associated Cancers. PMID- 26941921 TI - Tackling the Rising Trends of Noncommunicable Diseases During Public Health Emergencies. PMID- 26941922 TI - A Comparison of the Effect of Nasal bi-level Positive Airway Pressure and Sigh positive Airway Pressure on the Treatment of the Preterm Newborns Weighing Less than 1500 g Affiliated with Respiratory Distress Syndrome. AB - BACKGROUND: Nowadays, administering noninvasive positive airway pressure (PAP) is considered as the building block for the management of respiratory distress syndrome (RDS). Since nasal continuous PAP (n-CPAP) established its roots as an interventional approach to treat RDS, there have always been concerns related to the increased work of breathing in newborns treated with this intervention. Therefore, respiratory support systems such as nasal bi-level PAP (N-BiPAP) and sigh-PAP (SiPAP) have been developed during the last decade. In this study, two respiratory support systems which, unlike n-CPAP, are categorized as cycled noninvasive ventilation, are studied. METHODS: This study was a randomized clinical trial done on 74 newborns weighing 1500 g or less affiliated with RDS hospitalized in NICU at Al-Zahra Hospital from October 2012 to March 2014. Patients were randomly assigned to two respiratory support groups of N-BiPAP and SiPAP. Each group contained 37 newborns who were compared, according to their demographic characteristics, duration of noninvasive ventilation, the need to administer surfactant, apnea incidence, the need for mechanical ventilation, pneumothorax, intraventricular hemorrhage (IVH), patent ductus arteriosus (PDA), the duration of oxygen supplement administration, and chronic lung disease (CLD). RESULTS: The average duration of noninvasive respiratory support, and the average duration of the need for oxygen supplement had no significant difference between the groups. Moreover, apnea incidence, the need for mechanical ventilation, pneumothorax, IVH, PDA, CLD, the need for the second dose of surfactant, and the death rate showed no significant difference in two groups. CONCLUSIONS: In this study, SiPAP showed no significant clinical preference over N-BiPAP in the treatment of the newborns with RDS weighing <1500 g. PMID- 26941923 TI - Race and Ethnic Differences in Additive and Multiplicative Effects of Depression and Anxiety on Cardiovascular Risk. PMID- 26941924 TI - Silymarin for the Prevention of Contrast-Induced Nephropathy: A Placebo Controlled Clinical Trial. AB - BACKGROUND: Silymarin is a flavonoid complex with nephro-protective properties. We evaluated the efficacy of silymarin in the prevention of contrast-induced nephropathy (CIN). METHODS: This placebo-controlled clinical trial was conducted on 143 patients with chronic stable angina referring for elective coronary angiography. Patients with low to moderate risk for CIN were included and were randomized to receive silymarin (280 mg) or placebo 2 h before administration of the contrast material. A nonionic, iso-osmolar contrast material was used. Serum creatinine was measured before and 48 h after injection of the contrast material. CIN was defined as an increase in creatinine of >=0.5 mg/dL or >=25% from the baseline. RESULTS: Serum creatinine was increased by 0.02 +/- 0.07 mg/dL (P = 0.004) with silymarin and by 0.04 +/- 0.15 mg/dL (P = 0.008) with placebo after contrast material injection (between group difference = 0.01 +/- 0.02 mg/dL, P = 0.881). CIN was occurred less frequently, though statistically nonsignificant, with silymarin compared with placebo (2.9% vs. 10.8%, Odds ratio [OR] [95% confidence interval (CI)] = 0.246 [0.050-1.203], P = 0.099). In the logistic regression analysis controlling for patients characteristics and baseline creatinine level, silymarin was nonsignificantly associated with lower frequency of CIN (OR [95% CI] = 0.203 [0.037-1.117], P = 0.067). CONCLUSIONS: We found a trend toward the efficacy of silymarin in preventing contrast-induced renal dysfunction. Further trials with larger sample size and in patients with higher risk of CIN are warranted. PMID- 26941925 TI - First Aid Knowledge Among University Students in Jordan. AB - BACKGROUND: This study has aimed to evaluate the level of knowledge about the first aid process among the university students in Jordan. METHODS: The study population consisted of students of the 14 scientific and unscientific faculties at Yarmouk University, Jordan. Data were obtained via questionnaires from 883 students. RESULTS: The majority of participants were females (65.9%) with mean age (standard deviation) of 19.9 (2.6) years. Only 29.2% of students had previous first aid experience. When asked, only 11% of students knew the normal respiration rate of an adult in 1 min. Results revealed that female students, having previous first aid experience, and being a student of the health sciences and scientific colleges were the only factors had significant statistical associations with better level of first aid knowledge. CONCLUSIONS: The students' knowledge about first aid is not at an adequate level. It would be advisable that first aid course be handled as a separate and practical course at secondary school level. PMID- 26941926 TI - Validity and Reliability of the Persian Version of the PERception de la Scle'rose En Plaques et de ses Pousse'es Questionnaire Evaluating Multiple Sclerosis related Quality of Life. AB - BACKGROUND: Multiple sclerosis (MS) affects all aspects of patients. Recently, the "PERception de la Scle'rose En Plaques et de ses Pousse'es" (PERSEPP) scale was designed to assess MS-related relapse on quality of life (QoL). The aim of this study was to evaluate validity and reliability of Persian version of PERSEPP scale in Iranian patients with MS. METHODS: Two-hundred eleven patients with relapsing-remitting form of the disease asked to fill the PERSEPP scale, MSQOL 54, and SF-36 questionnaires. Fifty cases filed the questionnaire 2 weeks later to assess reliability. The intraclass correlation coefficient (ICC) and Cronbach's alpha analysis were used. RESULTS: Mean age and mean duration of disease were 32.2 +/- 8.4 years and 6.5 +/- 2.5 years, respectively. One hundred sixty-seven (79.1%) were female and 44 (20.9%) were male. Forty-one (19.4%) were in relapse phase of the disease. ICC score of all items was above 0.8. Cronbach's alpha of all items was above 0.8. The results show that the mean scores of four items (relationship difficulties, time perspective, and symptoms) were significantly different between cases in relapse and none relapse. Coping and relationship difficulties scores were significantly different between different expanded disability status scale groups. Pearson correlation score for QoL 54 and PERSEP calculated as r = 0.44, P < 0.001 and r = 0.66, P < 0.001 between SF36 and PERSEP. CONCLUSIONS: Persian version of PERCEPP questionnaire provides valid and reliable instrument to assess MS-related QoL. PMID- 26941927 TI - Can Antidepressant Drug Impact on Blood Pressure Level in Patients with Psychiatric Disorder and Hypertension? A Randomized Trial. AB - BACKGROUND: High blood pressure (BP) has been known as a major risk factor for many chronic diseases. It should be noted, a psychiatric disorder which is common in the people living modern lifestyle may be one of the leading causes of hypertension, and many people are prescribed antidepressant each year. Hence, the purpose of this study was to evaluate the effect of selective serotonin reuptake inhibitors (SSRIs) and alprazolam which defined as antidepressant on the BP levels, and to compare the BP levels between the group of users and nonusers. METHODS: This randomized clinical trial study was conducted at the Nohom Dey Hospital in the Torbat-e Heydarieh, Iran between December 2011 and March 2012. Participants comprised 101 psychiatric patients with hypertension that randomly separated into users and nonusers of antidepressant. The period of intervention lasted for 3 months. The mean of BP calculated by this formula (systolic BP [SBP] +2 diastolic BP [DBP])/3 which was the main outcome of the study. RESULTS: Users of antidepressant drugs did not have any significant changes in BP levels, except in patients who received SSRIs alone, significant improvement was observed in DBP (P = 0.04) and mean of BP (P = 0.03). While, in nonusers of antidepressant, significant development was observed in DBP, and mean of BP. Comparing the users and nonusers did not show any significant differences in SBP, DBP, and Mean of BP; even, when outcomes were adjusted for risk factors and antihypertensive drugs. CONCLUSIONS: Three months treatment with SSRIs and alprazolam did not have any effect on lowering BP level in patients with the psychiatric disorder. PMID- 26941929 TI - Biodiversity conservation: an example of a multidisciplinary approach to marine dispersal. AB - The general aim of this paper is to present a possible multidisciplinary approach to the problem of connectivity among marine protected areas (MPAs) describing some of the mechanisms and vectors that control the dispersal of propagules among spatially distributed marine communities of MPAs in the Southern Adriatic Sea. A joint approach is described that focuses on (a) measurements of surface water current and model data integrated with a dedicated software (LAVA, LAgrangian Variational Analysis), (b) measurements of rafting objects and their evaluation as an alternative way to species dispersal, and (c) a tool to automatically monitor propagules and plankton species in the water column. Studies on the dynamics of water currents demonstrated that the Gargano area has the potential to supply dispersal propagules to the Southern Adriatic both along the Italian coastline and offshore across the basin, thus providing important services to the dispersal processes and the connectivity routes among MPAs. The natural dispersion is however enhanced by floating objects, on which entire marine communities are living and travelling. The number of these objects has greatly increased with the introduction of human litter: in the Adriatic, man-made litter composes nowadays the majority (79 %) of all floating objects, with this corresponding to an almost fourfold increase in the abundance of floating objects since pre-industrial times. Such enhanced dispersion may benefit transmission of propagules from MPAs along biodiversity corridors, but may also enhance the arrival of invasive species. The direct observation of organisms can provide information on the species distribution and mobility. New technology (GUARD-1 system) has been developed to automatically identify spatial or temporal distributions of selected species in the water column by image analysis. The system has so far successfully detected blooms of ctenophores in the water column and is now being tested for identification of other zooplankton groups, such as copepods, as well as marine litter. This low-cost, long-lasting imaging system can be hosted on mobile devices such as drifters, which makes it very suitable for biological dispersal studies. PMID- 26941928 TI - Health-related Quality of Life Among People Participating in a Metabolic Syndrome E-screening Program: A Web-based Study. AB - BACKGROUND: Cardiovascular diseases remain the leading cause of death worldwide. Metabolic syndrome (MetS) is the clustering of risk factors for developing the disease. Strong evidence exists for the efficacy of screening for MetS. However, the potential of novel web-based studies for MetS and online assessing of the quality of life (QOL) for these high-risk participants have not been explored. METHODS: This was a web-based, cross-sectional study. Participants were recruited through online registering on the study website. Then, those who met the study criteria (waist circumference [WC] >=90 and blood pressure [BP] >=130/85) were contacted and invited for the clinical assessments, if they wish. Baseline measurements were MetS risk factors (weight, WC, body mass index and BP, total cholesterol, low-density lipoprotein-cholesterol, high-density lipoprotein cholesterol, triglycerides, and fasting blood glucose) and health-related QOL (HRQOL) that was measured using the short form-36 (SF-36). RESULTS: There were 1436 (male: 928, female: 508) registration data on the study website. Reviewing the data, of 317 eligible participants that were invited to the study, 229 persons were responded to invitation in the screening program. The mean age of participants was 43.8 (standard deviation [SD] = 9.9) years. MetS was more frequent in male and married persons. In addition, participants with MetS had lower mean (SD) scores than participants without MetS for the following subscales of HRQOL as: role-physical (with MetS 51.1+/-35.2; versus without MetS 65.3 +/- SD = 40.1), vitality (with MetS 65+/- 21; versus without MetS 75.3 +/- 21.1), mental health (with MetS 49.5+/-30.1; versus without MetS 34.1+/-17.2)(P < 0.05 for all). CONCLUSIONS: People with MetS experienced lower HRQOL than without MetS. Internet as a powerful medium offers a novel setting for delivery health information. It seems that high BP and abdominal obesity are associated with lower HRQOL in the participants with MetS. A web-based prevention program could make people aware for their vulnerability to MetS and its complications. PMID- 26941931 TI - Genetic susceptibility for cow's milk allergy in Dutch children: the start of the allergic march? AB - BACKGROUND: Cow's milk allergy (CMA) is the most common allergic disease in infancy. It is not clear, whether infants with CMA have an increased risk of developing other allergic diseases later in life, the so-called "allergic march". We aimed to detect genetic associations of CMA using reported single nucleotide polymorphisms (SNP) in other allergic diseases and genetic mutations within the filaggrin (FLG) gene. Both to investigate possible causes of CMA, which also suggests an "allergic march". METHODS: Thirty children from the Dutch EuroPrevall birth cohort study with CMA in infancy and twenty-three healthy controls were studied. Six candidate SNPs were selected (minor allele frequency 10-50 % combined with a large effect) based on the literature. Thirteen FLG candidate mutations were selected spread over repeats 1, 3, 4, 5, 6, 7, 9 and 10 respectively. RESULTS: We found two SNP's, rs17616434 (P = 0.002) and rs2069772 (P = 0.038), significantly associated with CMA. One is located near the toll like receptor 6 (TLR6) gene, which functionally interacts with toll-like receptor 2, and is associated with an increased risk of other allergic diseases. One is located at the Interleukin 2 (IL2) locus. Twelve FLG amplicons were analyzed, but showed no significant enrichment. Nevertheless, we did observe more FLG mutations in the CMA-group compared to controls. CONCLUSION: We significantly associated two SNPs with CMA, suggesting that variation in the TLR6 and IL2 genes contribute to the expression of CMA. In addition, since TLR6 and IL2 were earlier associated with other later onset allergies, this also favours the "allergic march" hypothesis. We observed more FLG mutations in the CMA-group, albeit we found no statistical significant enrichment of FLG mutations. Further studies are necessary to investigate the role of common variants and FLG or other skin barrier gene mutations in CMA. PMID- 26941933 TI - Confronting species distribution model predictions with species functional traits. AB - Species distribution models are valuable tools in studies of biogeography, ecology, and climate change and have been used to inform conservation and ecosystem management. However, species distribution models typically incorporate only climatic variables and species presence data. Model development or validation rarely considers functional components of species traits or other types of biological data. We implemented a species distribution model (Maxent) to predict global climate habitat suitability for Grass Carp (Ctenopharyngodon idella). We then tested the relationship between the degree of climate habitat suitability predicted by Maxent and the individual growth rates of both wild (N = 17) and stocked (N = 51) Grass Carp populations using correlation analysis. The Grass Carp Maxent model accurately reflected the global occurrence data (AUC = 0.904). Observations of Grass Carp growth rate covered six continents and ranged from 0.19 to 20.1 g day(-1). Species distribution model predictions were correlated (r = 0.5, 95% CI (0.03, 0.79)) with observed growth rates for wild Grass Carp populations but were not correlated (r = -0.26, 95% CI (-0.5, 0.012)) with stocked populations. Further, a review of the literature indicates that the few studies for other species that have previously assessed the relationship between the degree of predicted climate habitat suitability and species functional traits have also discovered significant relationships. Thus, species distribution models may provide inferences beyond just where a species may occur, providing a useful tool to understand the linkage between species distributions and underlying biological mechanisms. PMID- 26941930 TI - Targeting the trehalose utilization pathways of Mycobacterium tuberculosis. AB - Tuberculosis (TB) is an epidemic disease and the growing burden of multidrug resistant (MDR) TB world wide underlines the need to discover new drugs to treat the disease. Mycobacterium tuberculosis (Mtb) is the etiological agent of most cases of TB. Mtb is difficult to treat, in part, due to the presence of a sturdy hydrophobic barrier that prevents penetration of drugs through the cell wall. Mtb can also survive in a non-replicative state for long periods of time avoiding the action of common antibiotics. Trehalose is an essential metabolite in mycobacteria since it plays key roles in cell wall synthesis, transport of cell wall glycolipids, and energy storage. It is also known for its stress protective roles such as: protection from desiccation, freezing, starvation and osmotic stress in bacteria. In this review we discuss the drug discovery efforts against enzymes involved in the trehalose utilization pathways (TUPs) and their likelihood of becoming drug targets. PMID- 26941935 TI - Intrinsic and extrinsic drivers of source-sink dynamics. AB - Many factors affect the presence and exchange of individuals among subpopulations and influence not only the emergence, but the strength of ensuing source-sink dynamics within metapopulations. Yet their relative contributions remain largely unexplored. To help identify the characteristics of empirical systems that are likely to exhibit strong versus weak source-sink dynamics and inform their differential management, we compared the relative roles of influential factors in strengthening source-sink dynamics. In a series of controlled experiments within a spatially explicit individual-based model framework, we varied patch quality, patch size, the dispersion of high- and low-quality patches, population growth rates, dispersal distances, and environmental stochasticity in a factorial design. We then recorded source-sink dynamics that emerged from the simulated habitat and population factors. Long-term differences in births and deaths were quantified for sources and sinks in each system and used in a statistical model to rank the influences of key factors. Our results suggest that systems with species capable of rapid growth, occupying habitat patches with more disparate qualities, with interspersed higher- and lower-quality habitats, and that experience relatively stable environments (i.e., fewer negative perturbations) are more likely to exhibit strong source-sink dynamics. Strong source-sink dynamics emerged under diverse combinations of factors, suggesting that simple inferences of process from pattern will likely be inadequate to predict and assess the strength of source-sink dynamics. Our results also suggest that it may be more difficult to detect and accurately measure source-sink dynamics in slow growing populations, highly variable environments, and where a subtle gradient of habitat quality exists. PMID- 26941934 TI - Phenotypic plasticity in life-history traits of Daphnia galeata in response to temperature - a comparison across clonal lineages separated in time. AB - Climatic changes are projected to result in rapid adaptive events with considerable phenotypic shifts. In order to reconstruct the impact of increased mean water temperatures during past decades and to reveal possible thermal micro evolution, we applied a resurrection ecology approach using dormant eggs of the freshwater keystone species Daphnia galeata. To this end, we compared the adaptive response of D. galeata clones from Lake Constance of two different time periods, 1965-1974 ("historical") versus 2000-2009 ("recent"), to experimentally increased temperature regimes. In order to distinguish between genetic versus environmentally induced effects, we performed a common garden experiment in a flow-through system and measured variation in life-history traits. Experimental thermal regimes were chosen according to natural temperature conditions during the reproductive period of D. galeata in Central European lakes, with one additional temperature regime exceeding the currently observable maximum (+2 degrees C). Increased water temperatures were shown to significantly affect measured life-history traits, and significant "temperature * clonal age" interactions were revealed. Compared to historical clones, recent clonal lineages exhibited a shorter time to first reproduction and a higher survival rate, which may suggest temperature-driven micro-evolution over time but does not allow an explicit conclusion on the adaptive nature of such responses. PMID- 26941936 TI - Bacterial characterization of Beijing drinking water by flow cytometry and MiSeq sequencing of the 16S rRNA gene. AB - Flow cytometry (FCM) and 16S rRNA gene sequencing data are commonly used to monitor and characterize microbial differences in drinking water distribution systems. In this study, to assess microbial differences in drinking water distribution systems, 12 water samples from different sources water (groundwater, GW; surface water, SW) were analyzed by FCM, heterotrophic plate count (HPC), and 16S rRNA gene sequencing. FCM intact cell concentrations varied from 2.2 * 10(3) cells/mL to 1.6 * 10(4) cells/mL in the network. Characteristics of each water sample were also observed by FCM fluorescence fingerprint analysis. 16S rRNA gene sequencing showed that Proteobacteria (76.9-42.3%) or Cyanobacteria (42.0-3.1%) was most abundant among samples. Proteobacteria were abundant in samples containing chlorine, indicating resistance to disinfection. Interestingly, Mycobacterium, Corynebacterium, and Pseudomonas, were detected in drinking water distribution systems. There was no evidence that these microorganisms represented a health concern through water consumption by the general population. However, they provided a health risk for special crowd, such as the elderly or infants, patients with burns and immune-compromised people exposed by drinking. The combined use of FCM to detect total bacteria concentrations and sequencing to determine the relative abundance of pathogenic bacteria resulted in the quantitative evaluation of drinking water distribution systems. Knowledge regarding the concentration of opportunistic pathogenic bacteria will be particularly useful for epidemiological studies. PMID- 26941938 TI - Dispersal, niche, and isolation processes jointly explain species turnover patterns of nonvolant small mammals in a large mountainous region of China. AB - Understanding the mechanisms that govern the spatial patterns of species turnover (beta diversity) has been one of the fundamental issues in biogeography. Species turnover is generally recognized as strong in mountainous regions, but the way in which different processes (dispersal, niche, and isolation) have shaped the spatial turnover patterns in mountainous regions remains largely unexplored. Here, we explore the directional and elevational patterns of species turnover for nonvolant small mammals in the Hengduan Mountains of southwest China and distinguish the relative roles of geographic distance, environmental distance, and geographic isolation on the patterns. The spatial turnover was assessed using the halving distance (km), which was the geographic distance that halved the similarity (Jaccard similarity) from its initial value. The halving distance was calculated for the linear, logarithmic, and exponential regression models between Jaccard similarity and geographic distance. We found that the east-west turnover is generally faster than the south-north turnover for high-latitudinal regions in the Hengduan Mountains and that this pattern corresponds to the geographic structure of the major mountain ranges and rivers that mainly extend in a south north direction. There is an increasing trend of turnover toward the higher elevation zones. Most of the variation in the Jaccard similarity could be explained by the pure effect of geographic distance and the joint effects of geographic distance, environmental distance, and average elevation difference. Our study indicates that dispersal, niche, and isolation processes are all important determinants of the spatial turnover patterns of nonvolant small mammals in the Hengduan Mountains. The spatial configuration of the landscape and geographic isolation can strongly influence the rate of species turnover in mountainous regions at multiple spatial scales. PMID- 26941937 TI - Gillespie eco-evolutionary models (GEMs) reveal the role of heritable trait variation in eco-evolutionary dynamics. AB - Heritable trait variation is a central and necessary ingredient of evolution. Trait variation also directly affects ecological processes, generating a clear link between evolutionary and ecological dynamics. Despite the changes in variation that occur through selection, drift, mutation, and recombination, current eco-evolutionary models usually fail to track how variation changes through time. Moreover, eco-evolutionary models assume fitness functions for each trait and each ecological context, which often do not have empirical validation. We introduce a new type of model, Gillespie eco-evolutionary models (GEMs), that resolves these concerns by tracking distributions of traits through time as eco evolutionary dynamics progress. This is done by allowing change to be driven by the direct fitness consequences of model parameters within the context of the underlying ecological model, without having to assume a particular fitness function. GEMs work by adding a trait distribution component to the standard Gillespie algorithm - an approach that models stochastic systems in nature that are typically approximated through ordinary differential equations. We illustrate GEMs with the Rosenzweig-MacArthur consumer-resource model. We show not only how heritable trait variation fuels trait evolution and influences eco-evolutionary dynamics, but also how the erosion of variation through time may hinder eco evolutionary dynamics in the long run. GEMs can be developed for any parameter in any ordinary differential equation model and, furthermore, can enable modeling of multiple interacting traits at the same time. We expect GEMs will open the door to a new direction in eco-evolutionary and evolutionary modeling by removing long standing modeling barriers, simplifying the link between traits, fitness, and dynamics, and expanding eco-evolutionary treatment of a greater diversity of ecological interactions. These factors make GEMs much more than a modeling advance, but an important conceptual advance that bridges ecology and evolution through the central concept of heritable trait variation. PMID- 26941939 TI - The effects of habitat management on the species, phylogenetic and functional diversity of bees are modified by the environmental context. AB - Anthropogenic landscape elements, such as roadsides, hedgerows, field edges, and power line clearings, can be managed to provide important habitats for wild bees. However, the effects of habitat improvement schemes in power line clearings on components of diversity are poorly studied. We conducted a large-scale experiment to test the effects of different management practices on the species, phylogenetic, and functional diversity of wild bees in power line clearings (n = 19 sites across southeastern Norway) and explored whether any treatment effects were modified by the environmental context. At each site, we conducted the following treatments: (1) Cut: all trees cut and left to decay in the clearing; (2) Cut + Remove: all trees cut and removed from the plot; and (3) Uncut: uncleared. The site-specific environmental context (i.e., elevation and floral diversity) influenced the species, phylogenetic, and functional diversity within bee species assemblages. The largest number of species was found in the Cut + Remove treatment in plots with a high forb species richness, indicating that the outcome of management practices depends on the environmental context. Clearing of treatment plots with many forb species also appeared to alter the phylogenetic composition of bee species assemblages, that is, more closely related species were found in the Cut and the Cut + Remove plots than in the Uncut plots. Synthesis and applications: Our experimental simulation of management practices in power line clearings influenced the species, phylogenetic, and functional diversity of bee species assemblages. Frequent clearing and removal of the woody debris at low elevations with a high forb species richness can increase the value of power line clearings for solitary bees. It is therefore important for managers to consider the environmental context when designing habitat improvement schemes for solitary bees. PMID- 26941941 TI - Nested species interactions promote feasibility over stability during the assembly of a pollinator community. AB - The foundational concepts behind the persistence of ecological communities have been based on two ecological properties: dynamical stability and feasibility. The former is typically regarded as the capacity of a community to return to an original equilibrium state after a perturbation in species abundances and is usually linked to the strength of interspecific interactions. The latter is the capacity to sustain positive abundances on all its constituent species and is linked to both interspecific interactions and species demographic characteristics. Over the last 40 years, theoretical research in ecology has emphasized the search for conditions leading to the dynamical stability of ecological communities, while the conditions leading to feasibility have been overlooked. However, thus far, we have no evidence of whether species interactions are more conditioned by the community's need to be stable or feasible. Here, we introduce novel quantitative methods and use empirical data to investigate the consequences of species interactions on the dynamical stability and feasibility of mutualistic communities. First, we demonstrate that the more nested the species interactions in a community are, the lower the mutualistic strength that the community can tolerate without losing dynamical stability. Second, we show that high feasibility in a community can be reached either with high mutualistic strength or with highly nested species interactions. Third, we find that during the assembly process of a seasonal pollinator community located at The Zackenberg Research Station (northeastern Greenland), a high feasibility is reached through the nested species interactions established between newcomer and resident species. Our findings imply that nested mutualistic communities promote feasibility over stability, which may suggest that the former can be key for community persistence. PMID- 26941940 TI - Varying foraging patterns in response to competition? A multicolony approach in a generalist seabird. AB - Reducing resource competition is a crucial requirement for colonial seabirds to ensure adequate self- and chick-provisioning during breeding season. Spatial segregation is a common avoidance strategy among and within species from neighboring breeding colonies. We determined whether the foraging behaviors of incubating lesser black-backed gulls (Larus fuscus) differed between six colonies varying in size and distance to mainland, and whether any differences could be related to the foraging habitats visited. Seventy-nine incubating individuals from six study colonies along the German North Sea coast were equipped with GPS data loggers in multiple years. Dietary information was gained by sampling food pellets, and blood samples were taken for stable isotope analyses. Foraging patterns clearly differed among and within colonies. Foraging range increased with increasing colony size and decreased with increasing colony distance from the mainland, although the latter might be due to the inclusion of the only offshore colony. Gulls from larger colonies with consequently greater density dependent competition were more likely to forage at land instead of at sea. The diets of the gulls from the colonies furthest from each other differed, while the diets from the other colonies overlapped with each other. The spatial segregation and dietary similarities suggest that lesser black-backed gulls foraged at different sites and utilized two main habitat types, although these were similar across foraging areas for all colonies except the single offshore island. The avoidance of intraspecific competition results in colony-specific foraging patterns, potentially causing more intensive utilization of terrestrial foraging sites, which may offer more predictable and easily available foraging compared with the marine environment. PMID- 26941942 TI - Fine root tradeoffs between nitrogen concentration and xylem vessel traits preclude unified whole-plant resource strategies in Helianthus. AB - Recent work suggests variation in plant growth strategies is governed by a tradeoff in resource acquisition and use, ranging from a rapid resource acquisition strategy to a resource-conservative strategy. While evidence for this tradeoff has been found in leaves, knowledge of root trait strategies, and whether they reflect adaptive differentiation across environments, is limited. In the greenhouse, we investigated variation in fine root morphology (specific root length and tissue density), chemistry (nitrogen concentration and carbon:nitrogen), and anatomy (root cross-sectional traits) in populations of 26 Helianthus species and sister Phoebanthus tenuifolius. We also compared root trait variation in this study with leaf trait variation previously reported in a parallel study of these populations. Root traits varied widely and exhibited little phylogenetic signal, suggesting high evolutionary lability. Specific root length and root tissue density were weakly negatively correlated, but neither was associated with root nitrogen, providing little support for a single axis of root trait covariation. Correlations between traits measured in the greenhouse and native site characteristics were generally weak, suggesting a variety of equally viable root trait combinations exist within and across environments. However, high root nitrogen was associated with lower xylem vessel number and cross sectional area, suggesting a tradeoff between nutrient investment and water transport capacity. This led to correlations between root and leaf traits that were not always consistent with an acquisition-conservation tradeoff at the whole plant level. Given that roots must balance acquisition of water and nutrients with functions like anchorage, exudation, and microbial symbioses, the varied evidence for root trait covariation likely reflects the complexity of interacting selection pressures belowground. Similarly, the lack of evidence for a single acquisition-conservation tradeoff at the whole-plant level likely reflects the vastly different selection pressures shaping roots and leaves, and the resources they are optimized to obtain. PMID- 26941943 TI - Accounting for size-specific predation improves our ability to predict the strength of a trophic cascade. AB - Predation can influence the magnitude of herbivory that grazers exert on primary producers by altering both grazer abundance and their per capita consumption rates via changes in behavior, density-dependent effects, and size. Therefore, models based solely on changes in abundance may miss key components of grazing pressure. We estimated shifts in grazing pressure associated with changes in the abundance and per capita consumption rates of sea urchins triggered by size selective predation by sea otters (Enhydra lutris). Field surveys suggest that sea otters dramatically decreased the abundance and median size of sea urchins. Furthermore, laboratory experiments revealed that kelp consumption by sea urchins varied nonlinearly as a function of urchin size such that consumption rates increased to the 0.56 and 0.68 power of biomass for red and green urchins, respectively. This reveals that shifts in urchin size structure due to size selective predation by sea otters alter sea urchin per capita grazing rates. Comparison of two quantitative models estimating total consumptive capacity revealed that a model incorporating shifts in urchin abundance while neglecting urchin size structure overestimated grazing pressure compared to a model that incorporated size. Consequently, incorporating shifts in urchin size better predicted field estimates of kelp abundance compared to equivalent models based on urchin abundance alone. We provide strong evidence that incorporating size specific parameters increases our ability to describe and predict trophic interactions. PMID- 26941944 TI - Genomic population structure of freshwater-resident and anadromous ide (Leuciscus idus) in north-western Europe. AB - Climate change experts largely agree that future climate change and associated rises in oceanic water levels over the upcoming decades, will affect marine salinity levels. The subsequent effects on fish communities in estuarine ecosystems however, are less clear. One species that is likely to become increasingly affected by changes in salinity is the ide (Leuciscus idus). The ide is a stenohaline freshwater fish that primarily inhabits rivers, with frequent anadromous behavior when sea salinity does not exceed 15%. Unlike most other anadromous Baltic Sea fish species, the ide has yet to be subjected to large scale stocking programs, and thus provides an excellent opportunity for studying the natural population structure across the current salinity gradient in the Danish Belts. To explore this, we used Genotyping-by-Sequencing to determine genomic population structure of both freshwater resident and anadromous ide populations in the western Baltic Sea region, and relate the results to the current salinity gradient and the demographic history of ide in the region. The sample sites separate into four clusters, with all anadromous populations in one cluster and the freshwater resident populations in the remaining three. Results demonstrate high level of differentiation between sites hosting freshwater resident populations, but little differentiation among anadromous populations. Thus ide exhibit the genomic population structure of both a typical freshwater species, and a typical anadromous species. In addition to providing a first insight into the population structure of north-western European ide, our data also (1) provide indications of a single illegal introduction by man; (2) suggest limited genetic effects of heavy pollution in the past; and (3) indicate possible historical anadromous behavior in a now isolated freshwater population. PMID- 26941945 TI - Using Africa's protected area network to estimate the global population of a threatened and declining species: a case study of the Critically Endangered White headed Vulture Trigonoceps occipitalis. AB - The White-headed Vulture Trigonoceps occipitalis (WhV) is uncommon and largely restricted to protected areas across its range in sub-Saharan Africa. We used the World Database on Protected Areas to identify protected areas (PAs) likely to contain White-headed Vultures. Vulture occurrence on road transects in Southern, East, and West Africa was adjusted to nests per km(2) using data from areas with known numbers of nests and corresponding road transect data. Nest density was used to calculate the number of WhV nests within identified PAs and from there extrapolated to estimate the global population. Across a fragmented range, 400 PAs are estimated to contain 1893 WhV nests. Eastern Africa is estimated to contain 721 nests, Central Africa 548 nests, Southern Africa 468 nests, and West Africa 156 nests. Including immature and nonbreeding birds, and accounting for data deficient PAs, the estimated global population is 5475 - 5493 birds. The identified distribution highlights are alarming: over 78% (n = 313) of identified PAs contain fewer than five nests. A further 17% (n = 68) of PAs contain 5 - 20 nests and 4% (n = 14) of identified PAs are estimated to contain >20 nests. Just 1% (n = 5) of PAs are estimated to contain >40 nests; none is located in West Africa. Whilst ranging behavior of WhVs is currently unknown, 35% of PAs large enough to hold >20 nests are isolated by more than 100 km from other PAs. Spatially discrete and unpredictable mortality events such as poisoning pose major threats to small localized vulture populations and will accelerate ongoing local extinctions. Apart from reducing the threat of poisoning events, conservation actions promoting linkages between protected areas should be pursued. Identifying potential areas for assisted re-establishment via translocation offers the potential to expand the range of this species and alleviate risk. PMID- 26941946 TI - Testosterone and cortisol concentrations vary with reproductive status in wild female red deer. AB - Although hormones are key regulators of many fitness and life history traits, the causes of individual level variation in hormones, particularly in wild systems, remain understudied. Whilst we know that androgen and glucocorticoid levels vary within and among individuals in mammalian populations, how this relates to key reproductive processes such as gestation and lactation, and their effects on a female's measurable hormone levels are poorly understood in wild systems. Using fecal samples collected from females in a wild red deer population between 2001 and 2013, we explore how fecal androgen (FAM) and cortisol (FCM) metabolite concentrations change with age and season, and how individual differences relate to variation in reproductive state. Both FAM and FCM levels increase toward parturition, although this only affects FCM levels in older females. FCM levels are also higher when females suckle a male rather than a female calf, possibly due to the higher energetic costs of raising a son. This illustrates the importance of accounting for a female's life history and current reproductive status, as well as temporal variation, when examining individual differences in hormone levels. We discuss these findings in relation to other studies of mammalian systems and in particular to the relatively scarce information on variation in natural levels of hormones in wild populations. PMID- 26941947 TI - Context-dependent outcomes in a reproductive mutualism between two freshwater fish species. AB - The development of encompassing general models of ecology is precluded by underrepresentation of certain taxa and systems. Models predicting context dependent outcomes of biotic interactions have been tested using plants and bacteria, but their applicability to higher taxa is largely unknown.We examined context dependency in a reproductive mutualism between two stream fish species: mound nest-building bluehead chub Nocomis leptocephalus and mountain redbelly dace Chrosomus oreas, which often uses N. leptocephalus nests for spawning. We hypothesized that increased predator density and decreased substrate availability would increase the propensity of C. oreas to associate with N. leptocephalus and decrease reproductive success of both species.In a large-scale in situ experiment, we manipulated egg predator density and presence of both symbionts (biotic context), and replicated the experiment in habitats containing high- and low-quality spawning substrate (abiotic context).Contradictory to our first hypothesis, we observed that C. oreas did not spawn without its host. The interaction outcome switched from commensalistic to mutualistic with changing abiotic and biotic contexts, although the net outcome was mutualistic.The results of this study yielded novel insight into how context dependency operates in vertebrate mutualisms. Although the dilution effect provided by C. oreas positively influenced reproductive success of N. leptocephalus, it was not enough to overcome both egg predation and poor spawning habitat quality. Outcomes of the interaction may be ultimately determined by associate density. Studies of context dependency in vertebrate systems require detailed knowledge of species life history traits. PMID- 26941948 TI - Old males reduce melanin-pigmented traits and increase reproductive outcome under worse environmental conditions in common kestrels. AB - Secondary sexual traits displayed by males and females may have evolved as a signal of individual quality. However, both individual quality and investment on producing or maintaining enhanced sexual traits change as individuals age. At the same time, the costs associated to produce sexual traits might be attenuated or increased if environmental conditions are benign or worse respectively. Accordingly, environmental conditions are expected to shape the association between the expression of sexual traits and their reproductive outcome as individuals age. Nonetheless, little is known about the environmental influence on the co-variation between sexual traits and reproductive outcome throughout the life of individuals. We studied the age-dependency of the number and size of back spots, a melanin-based and sexual trait in adults of common kestrels (Falco tinnunculus). We analysed the age-dependence of reproductive traits and the environmental influence, defined as vole abundance, using a 10-year individual based dataset. We broke down age-related changes of reproductive traits into within- and between-individual variation to assess their contribution to population-level patterns. Our results showed a within-individual decrease in the number, but not the size, of back spots in males. The size of back spots was positively correlated with food availability in males. Reproductive performance of males increased as they aged, in agreement with the life-history theory but depending of vole abundance. Remarkably, we found that having fewer back spots was positively associated with clutch size only for old individuals under low food conditions. We suggest that environmental variation may shape the association between the expression of a sexual signal and reproductive outcome. We speculate that the reliability of sexual traits is higher when environmental conditions are poor only for old individuals. Within an evolutionary context, we suggest that the expression of sexual traits might be constrained by environmental conditions at later stages of life. PMID- 26941949 TI - Summer temperature can predict the distribution of wild yeast populations. AB - The wine yeast, Saccharomyces cerevisiae, is the best understood microbial eukaryote at the molecular and cellular level, yet its natural geographic distribution is unknown. Here we report the results of a field survey for S. cerevisiae,S. paradoxus and other budding yeast on oak trees in Europe. We show that yeast species differ in their geographic distributions, and investigated which ecological variables can predict the isolation rate of S. paradoxus, the most abundant species. We find a positive association between trunk girth and S. paradoxus abundance suggesting that older trees harbor more yeast. S. paradoxus isolation frequency is also associated with summer temperature, showing highest isolation rates at intermediate temperatures. Using our statistical model, we estimated a range of summer temperatures at which we expect high S. paradoxus isolation rates, and show that the geographic distribution predicted by this optimum temperature range is consistent with the worldwide distribution of sites where S. paradoxus has been isolated. Using laboratory estimates of optimal growth temperatures for S. cerevisiae relative to S. paradoxus, we also estimated an optimum range of summer temperatures for S. cerevisiae. The geographic distribution of these optimum temperatures is consistent with the locations where wild S. cerevisiae have been reported, and can explain why only human-associated S. cerevisiae strains are isolated at northernmost latitudes. Our results provide a starting point for targeted isolation of S. cerevisiae from natural habitats, which could lead to a better understanding of climate associations and natural history in this important model microbe. PMID- 26941951 TI - Prophylaxis and management of postoperative nausea and vomiting in enhanced recovery protocols: Expert Opinion statement from the American Society for Enhanced Recovery (ASER). AB - International experience and evidence-based practices have shown that reduction in variability through use of protocolized perioperative care improves surgical outcomes and reduces costs to patients and healthcare systems. In this series of Expert Opinions, we provide consensus recommendations for the various components of perioperative care to aid with the development of enhanced recovery after surgery protocols. PMID- 26941950 TI - Hawksbill turtle terra incognita: conservation genetics of eastern Pacific rookeries. AB - Prior to 2008 and the discovery of several important hawksbill turtle (Eretmochelys imbricata) nesting colonies in the EP (Eastern Pacific), the species was considered virtually absent from the region. Research since that time has yielded new insights into EP hawksbills, salient among them being the use of mangrove estuaries for nesting. These recent revelations have raised interest in the genetic characterization of hawksbills in the EP, studies of which have remained lacking to date. Between 2008 and 2014, we collected tissue samples from 269 nesting hawksbills at nine rookeries across the EP and used mitochondrial DNA sequences (766 bp) to generate the first genetic characterization of rookeries in the region. Our results inform genetic diversity, population differentiation, and phylogeography of the species. Hawksbills in the EP demonstrate low genetic diversity: We identified a total of only seven haplotypes across the region, including five new and two previously identified nesting haplotypes (pooled frequencies of 58.4% and 41.6%, respectively), the former only evident in Central American rookeries. Despite low genetic diversity, we found strong stock structure between the four principal rookeries, suggesting the existence of multiple populations and warranting their recognition as distinct management units. Furthermore, haplotypes EiIP106 and EiIP108 are unique to hawksbills that nest in mangrove estuaries, a behavior found only in hawksbills along Pacific Central America. The detected genetic differentiation supports the existence of a novel mangrove estuary "reproductive ecotype" that may warrant additional conservation attention. From a phylogeographic perspective, our research indicates hawksbills colonized the EP via the Indo-Pacific, and do not represent relict populations isolated from the Atlantic by the rising of the Panama Isthmus. Low overall genetic diversity in the EP is likely the combined result of few rookeries, extremely small reproductive populations and evolutionarily recent colonization events. Additional research with larger sample sizes and variable markers will help further genetic understanding of hawksbill turtles in the EP. PMID- 26941952 TI - Anticipated regret in shared decision-making: a randomized experimental study. AB - BACKGROUND: Explicit consideration of anticipated regret is not part of the standard shared decision-making protocols. This pilot study aimed to compare decisions about a hypothetical surgery for breast cancer and examined whether regret is a consideration in treatment decisions. METHODS: In this randomized experimental study, 184 healthy female volunteers were randomized to receive a standard decision aid (control) or one with information on post-surgical regret (experimental). The main outcome measures were the proportion of subjects choosing lumpectomy vs. mastectomy and the proportion reporting that regret played a role in the decision made. We hypothesized that a greater proportion of the experimental group (regret-incorporated decision aid) would make a surgical treatment preference that favored the less regret-inducing option and that they would be more likely to consider regret in their decision-making process as compared to the control group. RESULTS: A significantly greater proportion of the experimental group subjects reported regret played a role in their decision making process compared to the control counterparts (78 vs. 65 %; p = 0.039). Recipients of the regret-incorporated experimental decision aid had a threefold increased odds of choosing the less regret-inducing surgery (OR = 2.97; 95 % CI = 1.25, 7.09; p value = 0.014). CONCLUSIONS: In this hypothetical context, the incorporation of regret in a decision aid for preference-sensitive surgery impacted decision-making. This finding suggests that keying in on anticipated regret may be an important element of shared decision-making strategies. Our results make a strong argument for applying this design and pursuing further research in a surgical patient population. TRIAL REGISTRATION: Clinicaltrials.gov, NCT02563808. PMID- 26941953 TI - New dominant spa type t2741 in livestock-associated MRSA (CC398-MRSA-V) in Finnish fattening pigs at slaughter. AB - BACKGROUND: The emergence of livestock-associated MRSA has become a growing public health concern worldwide. Studies elucidating the population structure, as well as resistance phenotypes and virulence gene profiles of livestock-associated MRSA strains are needed to improve risk assessment and to develop effective control measures. The objective of this study therefore was to determine i) clonal complexes and spa types, as well as ii) resistance phenotypes and iii) virulence and resistance gene profiles of livestock-associated MRSA isolated from Finnish fattening pigs at slaughter. METHODS: Fifty MRSA isolates collected from Finnish fattening pigs at slaughter were characterized by spa typing and DNA microarray profiling. In addition, antimicrobial susceptibility testing was performed using the Kirby Bauer disk diffusion method. RESULTS: MRSA isolates were assigned to clonal complexes CC1 (n = 4) and CC398 (n = 46). One dominant spa type (t2741) was present in 33 out of 50 investigated isolates, originating from 15 out of 18 farms. The remaining isolates were assigned to spa types t034 (n = 7), t108 (n = 5), and t011 (n = 1). Although each herd exhibited isolates assigned to one clonal complex only, five herds harbored MRSA isolates of either two or three different spa types. All tested MRSA isolates were phenotypically resistant to penicillin, oxacillin, cefoxitin, and tetracycline. With the exception of the isolates assigned to t108, all isolates exhibited resistance to clindamycin. On the genomic level, all isolates exhibited mecA, blaZ/I/R, and tetK, and were assigned to SCCmec type V. Many isolates also harbored tetM (46/50 isolates), lnuB (41/50 isolates), ermB (26/50 isolates), and one isolate was positive for aadD. DNA microarray profiling showed that all isolates of the dominant CC398/t2741 MRSA-V type belonged to agr type I, capsule type 5, and were negative for fnbB. Interestingly, one isolate of CC398/t2741 MRSA-V was agr negative and also lacked hld. CONCLUSIONS: A new dominant LA-MRSA clone (CC398/t2741, SCCmec type V) was identified among fattening pigs in Finland. This is the first study identifying t2741 as a common spa type in LA-MRSA in pigs. PMID- 26941954 TI - The BODECOST Index (BCI): a composite index for assessing the impact of COPD in real life. AB - BACKGROUND: Chronic Obstructive Pulmonary Disease (COPD) is a progressive condition which is characterized by a dramatic socio-economic impact. Several indices were extensively investigated in order to asses the mortality risk in COPD, but the utilization of health care resources was never included in calculations. The aim of this study was to assess the predictive value of annual cost of care on COPD mortality at three years, and to develop a comprehensive index for easy calculation of mortality risk in real life. METHODS: COPD patients were anonymously and automatically selected from the local institutional Data Base. Selection criteria were: COPD diagnosis; both genders; age >= 40 years; availability of at least one complete clinical record/year, including history; clinical signs; complete lung function, therapeutic strategy, health BODE index; Charlson Comorbidity Index, and outcomes, collected at the first visit, and over the following 3-years. At the first visit, the health annual cost of care was calculated in each patient for the previous 12 months, and the survival rate was also measured over the following 3 years. The hospitalization and the exacerbation rate were implemented to the BODE index and the novel index thus obtained was called BODECOST index (BCI), ranging from 0 to 10 points. The mean cost for each BCI step was calculated and then compared to the corresponding patients' survival duration. Parametrical, non parametrical tests, and linear regression were used; p < 0.05 was accepted as the lower limit of significance. RESULTS: At the first visit, the selected 275 patients were well matched for all variables by gender. The overall mortality over the 3 year survey was 40.4 % (n = 111/275). When compared to that of BODE index (r = 0.22), the total annual cost of care and the number of exacerbations showed the highest regression value vs the survival time (r = 0.58 and r = 0.44, respectively). BCI score proved strictly proportional to both the cost of care and the survival time in our sample of COPD patients. DISCUSSION: BCI takes origin from the implementation of the BODE index with the two main components of the annual cost of care, such as the number of hospitalizations and of exacerbations occurring yearly in COPD patients, and their corresponding economic impact. In other words, higher the BCI score, shorter the survival and higher the cost, these trends being strictly linked. CONCLUSIONS: BCI is a novel composite index which helps in predicting the impact of COPD at 3 years in real life, both in terms of patients' survival and of COPD economic burden. PMID- 26941955 TI - Pro-eating disorder search patterns: the possible influence of celebrity eating disorder stories in the media. AB - Pro eating disorder websites often contain celebrity-focused content (e.g., images) used as thinspiration to engage in unhealthy eating disorder behaviours. The current study was conducted to examine whether news media stories covering eating disorder disclosures of celebrities corresponded with increases in Internet searches for pro eating disorder material. Results indicated that search volumes for pro eating disorder terms spiked in the month immediately following such news coverage but only for particularly high-profile celebrities. Hence, there may be utility in providing recovery-oriented resources within the search results for pro-eating disorder Internet searches and within news stories of this nature. PMID- 26941956 TI - Equipment, measurement and dose-a survey for therapeutic ultrasound. AB - BACKGROUND: Dosimetry for Ultrasound Therapy (DUTy) is a large international project which addresses the development of a metrological infrastructure for the determination of ultrasound exposure and dose to tissue. METHODS: In order to seek the views of the wider therapy ultrasound community and to review dose and in situ exposure quantities that have been suggested or used previously, a web based questionnaire containing a range of questions covering the type of ultrasound equipment that is used and the range of applications for which it has been developed was created at www.surveymonkey.com. This questionnaire was intended to cover any contemporary therapeutic ultrasound application (including physiotherapy, lithotripsy and drug delivery) and asked specific questions about quantification of in situ exposure and dose, especially as relevant to treatment planning, standardisation and/or regulation. RESULTS: This paper summarises the 123 responses submitted between February and September 2014 to the questions on clinical applications, equipment, quality assurance (QA) and measurement and standards, as well as to those relating to an understanding of "dose" in the context of ultrasound. The full set of anonymous responses is available in an additional Excel file. CONCLUSIONS: The results clearly demonstrate the need not only for further improvements in measuring devices and for measurement guidelines but also for a wider dissemination and higher awareness of existing standards. Whilst it is unlikely that a single definition of dose can be sufficient for all ultrasound treatment modalities, the answers clearly indicate that many aspects would benefit from clear definitions of relevant dose quantities and shed light on the preferred form of such definitions. PMID- 26941958 TI - Hairy cell leukemia followed by polycythemia vera: report of the first case. PMID- 26941959 TI - Understanding inherited genetic risk of adult glioma - a review. AB - During the past six years, researchers have made major progress identifying common inherited genetic variation that increases risk for primary adult glioma. This paper summarizes knowledge about rare familial cancer syndromes that include adult glioma and reviews the available literature on the more recently discovered common inherited variation. Ten independent inherited variants in eight chromosomal regions have been convincingly associated with increased risk for adult glioma. Most of these variants increase relative risk of primary adult glioma by 20% to 40%, but the TP53 variant rs78378222 confers a two-fold relative risk (ie, 200%), and rs557505857 on chromosome 8 confers a six-fold relative risk of IDH-mutated astrocytomas and oligodendroglial tumors (ie, 600%). Even with a six-fold relative risk, the overall risk of developing adult glioma is too low for screening for the high-risk variant on chromosome 8. Future studies will help clarify which inherited adult glioma risk variants are associated with subtypes defined by histology and/or acquired tumor mutations. This review also provides an information sheet for primary adult glioma patients and their families. PMID- 26941960 TI - Formative research to reduce mine worker respirable silica dust exposure: a feasibility study to integrate technology into behavioral interventions. AB - BACKGROUND: The use of formative research as a critical component of intervention planning is highly supported in the literature. However, studies that report such processes in practice are minimal. This paper reports on the formative data collection and analysis that informed the development of a multilevel intervention that utilizes mine assessment technology to bridge health communication between workers and management to reduce mine worker overexposure to respirable silica dust. METHODS: Formative research to assess the feasibility and utility of this intervention design included stakeholder meetings and feedback, mine visits and observations, interviews with mine workers, and a focus group with mine management. Data collection took place at several US industrial mineral mine sites and a southeastern regional safety meeting. Interviews inquired about workers' perceived susceptibility and severity to respirable silica exposure, barriers to preventing overexposure, behaviors that reduce exposure, and perceptions about respirable dust-monitoring technology. A focus group discussed mine stakeholders' uses of various dust assessment technology. RESULTS: The data was qualitatively analyzed and coded using a thematic and theoretical analysis. Researchers found recurring themes for both target audiences that informed the need and subsequent development of a mixed-method multilevel intervention to improve communication quantity and quality around dust control practices. CONCLUSIONS: Results indicate that formative research is critical to: identify and develop an intervention that meets target audience needs; accurately represent the health problem; and develop positive relationships with research partners and stakeholders. PMID- 26941963 TI - Come out of the operating room and see the light! PMID- 26941961 TI - Digital Breast Tomosynthesis guided Near Infrared Spectroscopy: Volumetric estimates of fibroglandular fraction and breast density from tomosynthesis reconstructions. AB - A multimodality system combining a clinical prototype digital breast tomosynthesis with its imaging geometry modified to facilitate near-infrared spectroscopic imaging has been developed. The accuracy of parameters recovered from near-infrared spectroscopy is dependent on fibroglandular tissue content. Hence, in this study, volumetric estimates of fibroglandular tissue from tomosynthesis reconstructions were determined. A kernel-based fuzzy c-means algorithm was implemented to segment tomosynthesis reconstructed slices in order to estimate fibroglandular content and to provide anatomic priors for near infrared spectroscopy. This algorithm was used to determine volumetric breast density (VBD), defined as the ratio of fibroglandular tissue volume to the total breast volume, expressed as percentage, from 62 tomosynthesis reconstructions of 34 study participants. For a subset of study participants who subsequently underwent mammography, VBD from mammography matched for subject, breast laterality and mammographic view was quantified using commercial software and statistically analyzed to determine if it differed from tomosynthesis. Summary statistics of the VBD from all study participants were compared with prior independent studies. The fibroglandular volume from tomosynthesis and mammography were not statistically different (p=0.211, paired t-test). After accounting for the compressed breast thickness, which were different between tomosynthesis and mammography, the VBD from tomosynthesis was correlated with (r =0.809, p<0.001), did not statistically differ from (p>0.99, paired t-test), and was linearly related to, the VBD from mammography. Summary statistics of the VBD from tomosynthesis were not statistically different from prior studies using high resolution dedicated breast computed tomography. The observation of correlation and linear association in VBD between mammography and tomosynthesis suggests that breast density associated risk measures determined for mammography are translatable to tomosynthesis. Accounting for compressed breast thickness is important when it differs between the two modalities. The fibroglandular volume from tomosynthesis reconstructions is similar to mammography indicating suitability for use during near-infrared spectroscopy. PMID- 26941962 TI - Igf1 and Pacap rescue cerebellar granule neurons from apoptosis via a common transcriptional program. AB - A shift of the delicate balance between apoptosis and survival-inducing signals determines the fate of neurons during the development of the central nervous system and its homeostasis throughout adulthood. Both pathways, promoting or protecting from apoptosis, trigger a transcriptional program. We conducted whole genome expression profiling to decipher the transcriptional regulatory elements controlling the apoptotic/survival switch in cerebellar granule neurons following the induction of apoptosis by serum and potassium deprivation or their rescue by either insulin-like growth factor-1 (Igf1) or pituitary adenylyl cyclase activating polypeptide (Pacap). Although depending on different upstream signaling pathways, the survival effects of Igf1 and Pacap converged into common transcriptional cascades, thus suggesting the existence of a general transcriptional program underlying neuronal survival. PMID- 26941964 TI - Physiotherapy for enhanced recovery in thoracic surgery. PMID- 26941965 TI - Clinical pathway for video-assisted thoracic surgery: the Hong Kong story. AB - A clinical pathway provides a scheduled, objective protocol for the multi disciplinary, evidence-based management of patients with a specific condition or undergoing a specific procedure. In implementing a clinical pathway for the care of patients receiving video-assisted thoracic surgery (VATS) in Hong Kong, many insights were gained into what makes a clinical pathway work: meticulous preparation and team-building are keys to success; the pathway must be constantly reviewed and revisions made in response to evolving clinical need; and data collection is a key element to allow auditing and clinical research. If these can be achieved, a clinical pathway delivers not only measurable improvements in patient outcomes, but also fundamentally complements clinical advances such as VATS. This article narrates the story of how the clinical pathway for VATS in Hong Kong was created and evolved, highlighting how the above lessons were learned. PMID- 26941966 TI - Clinical pathway for thoracic surgery in an Italian centre. AB - Clinical care pathways are developed to standardize postoperative patient care and the main impetus is to improve quality of care, decrease variation in care and reduce costs. We report the clinical pathway of care adopted at our centre since the introduction of Uniportal VATS program for major lung resections. PMID- 26941967 TI - Clinical pathway for thoracic surgery in the United States. AB - The paradigm for postoperative care for thoracic surgical patients in the United States has shifted with efforts to reduce hospital length of stay and improve quality of life. The increasing usage of minimally invasive techniques in thoracic surgery has been an important part of this. In this review we will examine our standard practices as well as the evidence behind both general contemporary postoperative care principles and those specific to certain operations. PMID- 26941969 TI - Design and implementation of an enhanced recovery program in thoracic surgery. AB - Despite significant improvements in perioperative care, major surgery is still associated with major complications. Enhanced recovery after surgery was introduced by the National Health Service in the UK with the aim of improving patient outcomes and reducing length of stay in hospital. The degree of applicability differs between surgical specialties, and in thoracic surgery it has not been developed until recently. We have therefore reviewed recent literature specific to thoracic surgery, and will discuss key elements of the design, implementation and monitoring of an enhanced recovery (ER) program based on our recent experience. The program is divided into several high impact intervention measures that involve the preoperative, intraoperative and postoperative periods. Physical activity promotion and educational programs that provide information about the surgery and the surgical pathway are an essential part of the preoperative strategies. During surgery, an optimal pain control strategy, antibiotic prophylaxis and protective ventilation are important. Minimally invasive surgery and well-planned postoperative care including early drain removal and planned discharge are also important. Overall, we have shown that ER in thoracic surgery can facilitate early discharge from hospital and possibly reduce postoperative complications. Further studies are required to understand the extent of ER benefits when applied to thoracic surgery, and to test individual components in a prospective manner. PMID- 26941968 TI - Optimizing postoperative care protocols in thoracic surgery: best evidence and new technology. AB - Postoperative clinical pathways have been shown to improve postoperative care and decrease length of stay in hospital. In thoracic surgery there is a need to develop chest tube management pathways. This paper considers four aspects of chest tube management: (I) appraising the role of chest X-rays in the management of lung resection patients with chest drains; (II) selecting of a fluid output threshold below which chest tubes can be removed safely; (III) deciding whether suction should be applied to chest tubes; (IV) and selecting the safest method for chest tube removal. There is evidence that routine use of chest X-rays does not influence the management of chest tubes. There is a lack of consensus on the highest fluid output threshold below which chest tubes can be safely removed. The optimal use of negative intra-pleural pressure has not yet been established despite multiple randomized controlled trials and meta-analyses. When attempting to improve efficiency in the management of chest tubes, evidence in support of drain removal without a trial of water seal should be considered. Inconsistencies in the interpretation of air leaks and in chest tube management are likely contributors to the conflicting results found in the literature. New digital pleural drainage systems, which provide a more objective air leak assessment and can record air leak trend over time, will likely contribute to the development of new evidence-based guidelines. Technology should be combined with continued efforts to standardize care, create clinical pathways, and analyze their impact on postoperative outcomes. PMID- 26941970 TI - Air leak after lung resection: pathophysiology and patients' implications. AB - Protocols for the management of air leaks are critical aspects in the postoperative course of patients following lung resections. Many investigations in the last decade are focusing on the chest tube modalities or preventative measures, however, little is known about the pathophysiology of air leak and the patient perception of this common complication. This review concentrates on understanding the reasons why a pulmonary parenchyma may start to leak or an air leak may be longer than others. Experimental works support the notion that lung overdistension may favor air leak. These studies may represent the basis of future investigations. Furthermore, the standardization of nomenclature in the field of pleural space management and the creation of novel air leak scoring systems have contributed to improve the knowledge among thoracic surgeons and facilitate the organization of trials on this matter. We tried to summarize available evidences about the patient perception of a prolonged air leak and about what would be useful for them in order to prevent worsening of their quality of life. Future investigations are warranted to better understand the pathophysiologic mechanisms responsible of prolonged air leak in order to define tailored treatments and protocols. Improving the care at home with web-based telemonitoring or real time connected chest drainage may in a future improve the quality of life of the patients experience this complication and also enhance hospital finances. PMID- 26941971 TI - Advances in chest drain management in thoracic disease. AB - An adequate chest drainage system aims to drain fluid and air and restore the negative pleural pressure facilitating lung expansion. In thoracic surgery the post-operative use of the conventional underwater seal chest drainage system fulfills these requirements, however they allow great variability amongst practices. In addition they do not offer accurate data and they are often inconvenient to both patients and hospital staff. This article aims to simplify the myths surrounding the management of chest drains following chest surgery, review current experience and explore the advantages of modern digital chest drain systems and address their disease-specific use. PMID- 26941972 TI - Clinical management IT system for enhanced recovery. AB - Surgical resection has a key role for the treatment of early stage lung cancer along with certain advanced cases, and minimally invasive techniques, representatively video-assisted thoracoscopic surgery (VATS), are becoming standard for lung cancer surgery. Implementation of integrated programs which could manage the whole process of patient treatment including preoperative, intraoperative and postoperative care is thought to be essential partner for successful application of minimally invasive thoracic surgery for lung cancer treatment. Enhanced recovery after surgery (ERAS), so called "fast-track" programs pursue the adequate and efficient delivery of health care services therefore to improve postoperative outcomes and reduce medical cost. Well organized information technology systems would be helpful to achieve the goals of ERAS without increasing the burden of budget or working staffs. Furthermore, it could contribute to create knowledge and translate to the clinical process. PMID- 26941973 TI - Post-operative care to promote recovery for thoracic surgical patients: a nursing perspective. AB - The change in patient population leads to an inevitable transformation among the healthcare system. Over the past decades, thoracic surgical technique has been evolving from conventional open thoracotomy to minimally invasive video assisted thoracoscopic surgery (VATS). Thoracic nursing team of Prince of Wales Hospital (PWH) grows together with the evolution and aims at providing holistic and quality care to patients require thoracic operation. In order to enhance patient post-operative recovery, few strategies have been implemented including early mobilization, staff training and clinical audit. On the other hand, nursing case management approach was proved to be a cost-effective method in managing patients. It is also suitable for thoracic patients, especially for those who are suffering from thoracic neoplasm. It is believed that, the introduction of nursing case management approach would provide a better holistic care to the thoracic patients. PMID- 26941974 TI - Enhanced recovery pathway for thoracic surgery in the UK. AB - BACKGROUND: Enhanced recovery (ER) refers to a combination of perioperative interventions designed to minimise the impact of surgery on patients' recovery in order to reduce postoperative complications and to allow an early discharge reducing hospital costs. METHODS: An ER protocol was established at our institution following a review of the best evidence available. We introduced a multi-disciplinary integrated perioperative pathway by engaging with every person involved, including the patients themselves. The programme was monitored using specifically-designed patients related outcome measures (PROMs). RESULTS: One hundred and fifty-four ER patients were compared with 171 controls from the year before ER was introduced. There was an 80% increase in same-day admissions, with a net gain of more than 300 patient bed-days. The ER group had a significantly higher number of procedures performed by video assisted thoracoscopic surgery (VATS) (ER, 32.9% vs. 9.4%, P=0.0001) and a lower rate of admission to the intensive care unit (ER, 5.8% versus 12.9%, P=0.04). Patients on the ER programme had a significantly reduced postoperative length of stay (mean ER, 5.2 vs. 11.7 days, P<0.0001). Patient satisfaction was higher in the ER group after a patient survey. The project resulted in a net saving of L214,000 for the Trust for the 2013/2014 financial year. We were also able to increase the number of patients who underwent thoracic surgery in 2013/2014 by 30% (159 patients) compared with 2012/2013. CONCLUSIONS: The ER pathway has proven to be a safe perioperative management strategy to improve patient satisfaction and to reduce the length of hospital stay and cost after major thoracic surgery, without increasing morbidity or mortality. PMID- 26941975 TI - From 200 BC to 2015 AD: an integration of robotic surgery and Ayurveda/Yoga. AB - BACKGROUND: Among the traditional systems of medicine practiced all over the world, Ayurveda and Yoga has a documented history dating back to beyond 200 BC. Robotic and video assisted thoracic surgery (VATS) is an invention of the 21(st) century. We aim to quantify the effects of integration of Ayurveda and Yoga on patients undergoing minimally invasive robotic and VATS. METHODS: Four hundred and fifty-four patients undergoing VATS and robotic thoracic surgery were introduced to a pre and postoperative protocol of Yoga therapy, mediation and oil massages. Yoga exercises included Pranayam, Anulom Vilom, and Oil Massages included Urotarpan. Preoperative and postoperative respiratory functions were recorded. Patient satisfaction questionnaire were noted. Statistical comparison was made to control group undergoing minimally invasive thoracic surgery without integrative medicine. Only one patient refused to undergo Ayurveda therapy and was deleted from the group. RESULTS: Acceptability was high among all patients. Preoperative training led to implementation as early as 6 hours post surgery. Pulmonary function test showed significant improvement. All patients suggested an improvement in satisfaction score. Pain score were less in study patients. Quicker mobilization led to early discharge and drain removal. Chronic pain was prevented in patients having oil massages over the healed wound sites. CONCLUSIONS: Integration of Ayurveda, Yoga and minimally invasive robotic and VATS is acceptable to Indian patients and gives better clinical results and higher patient satisfaction. PMID- 26941976 TI - Reduce chest pain using modified silicone fluted drain tube for chest drainage after video-assisted thoracic surgery (VATS) lung resection. AB - BACKGROUND: The aim of this study was to assess the feasibility, efficacy and safety of a modified silicone fluted drain tube after video-assisted thoracic surgery (VATS) lung resection. METHODS: The prospective randomized study included 50 patients who underwent VATS lung resection between March 2015 and June 2015. Eligible patients were randomized into two groups: experimental group (using the silicone fluted drain tubes for chest drainage) and control group (using standard drain tubes for chest drainage). The volume and characteristics of drainage, postoperative (PO) pain scores and hospital stay were recorded. All patients received standard care during hospital admission. RESULTS: In accordance with the exit criteria, three patients were excluded from study. The remaining 47 patients included in the final analysis were divided into two groups: experiment group (N=24) and control group (N=23). There was no significant difference between the two groups in terms of age, sex, height, weight, clinical diagnosis and type of surgical procedure. There was a trend toward less PO pain in experimental group on postoperative day (POD) 1, with a statistically significant difference. Patients in experimental group had a reduced occurrence of fever [temperature (T) >37.4 degrees C] compared to the control group. CONCLUSIONS: The silicone fluted drain tube is feasible and safe and may relieve patient PO pain and reduce occurrence of fever without the added risk of PO complications. PMID- 26941977 TI - The dynamic of nasogastric decompression after esophagectomy and its predictive value of postoperative complications. AB - BACKGROUND: To investigate the regularity and the influence factors of nasogastric decompression volume after esophagectomy, and explore whether the volume of nasogastric decompression can be employed as a predictor for postoperative complications of esophageal carcinoma. METHODS: Consecutive 247 patients with esophageal cancer who underwent esophagectomy were retrospectively evaluated. The volume of postoperative nasogastric decompression was recorded and the regularity based on it was described. The single and multiple factors regression analysis were used to find out relative factors of the nasogastric decompression volume among the patients without postoperative complication. Gender, age, height, weight, tobacco or alcohol exposure, location of the tumor, histological type, pathological staging, operation time, surgical procedures, anastomotic position and gastric conduit reconstruction were considered as the independent variable. Then, verify the former regression models using the data of patients with postoperative complications. RESULTS: In trend analysis, the curve estimation revealed a quadratic trend in the relationship between nasogastric decompression volume and postoperative days (R(2) =0.890, P=0.004). The volume of postoperative nasogastric decompression was described by daily drainage (mL) =82.215 + 69.620 * days - 6.604 * days(2). The results of multiple linear stepwise regression analysis showed that gastric conduit reconstruction (beta=0.410, P=0.000), smoking (beta=-0.231, P=0.000), age (beta=-0.193, P=0.001) and histological type of the tumor (beta=-0.169, P=0.006) were significantly related to the volume of nasogastric decompression. The average drainage in 5 days after surgery =262.287 + 132.873 * X1 - 72.160 * X2 - 27.904 * X3 - 36.368 * X4 (X1, gastric conduit reconstruction; X2, smoking; X3, histological type; X4, age). The nasogastric decompression of the patients with delayed gastric emptying, and lung infection statistically differ from their predictive values respectively according to the former equation (P<0.01), but the data of anastomotic leakage cases had no significance difference (P=0.344). CONCLUSIONS: It is found that the volume of postoperative nasogastric decompression presents a quadratic trend based on the days after esophagectomy. Gastric conduit reconstruction, smoking history, age and histological type were independent factors affecting on the volume of postoperative nasogastric decompression. Also, the volume of nasogastric decompression has validity and application value for predicting postoperative complications. PMID- 26941978 TI - Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for peritoneal surface malignancy. PMID- 26941980 TI - Hyperthermic intraperitoneal chemotherapy for epithelial ovarian cancers: is there a role? AB - BACKGROUND: Hyperthermic intraperitoneal chemotherapy (HIPEC) is often used to treat gastrointestinal malignancies and is of interest in epithelial ovarian cancer (EOC) given the propensity for intraperitoneal spread. The role of HIPEC in the treatment of gynecologic malignancies is not well defined. We sought to describe clinical characteristics and outcomes of our patient population treated with HIPEC. METHODS: IRB approval was obtained. Patients diagnosed with EOC and treated with HIPEC from January 2007 until December 2013 were identified using a prospectively maintained HIPEC database. Patient charts were abstracted to identify patient demographic information, treatment characteristics, and outcome data. Statistical analysis was descriptive. RESULTS: Thirty-four patients were identified. Mean age at diagnosis was 56.5 years. The majority of cases (28, 82%) were of serous histology. The indications for HIPEC administration were as follows: 9% primary treatment, 41% first recurrence, 26% second recurrence, and 24% consolidative therapy in the setting of primary or recurrent disease. The majority of patients (21, 62%) received mitomycin C. The other drugs administered include cisplatin (10, 29%), oxaliplatin (2, 6%), and carboplatin (1, 3%). Mean length of hospital stay was 9 days (range, 3-39 days). The rates of postoperative bacteremia and hematologic toxicity were 6% and 54%, respectively. Seven (21%) patients developed transient renal dysfunction, and this was seen almost exclusively in the patients who received cisplatin. One (3%) additional patient had renal dysfunction that persisted longer than 30 days post-operative but did not go on to require dialysis. There were no perioperative deaths in this cohort. Eleven (32%) patients received additional chemotherapy following HIPEC administration. At a median follow-up of 20 months (range, 3-87 months), eight patients are alive with disease, seven have no evidence of disease, 14 have died of their disease, and five patients have been lost to follow-up. CONCLUSIONS: This data supports a reasonable side effect profile of treatment of EOC with HIPEC. Prospective studies are needed to elucidate the optimal drug and patient population that would derive the most benefit from treatment with HIPEC. PMID- 26941979 TI - Peritoneal dissemination from high-grade appendiceal cancer treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). AB - BACKGROUND: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) have shown variability in survival outcomes when used to treat peritoneal surface disease (PSD) from appendiceal and colorectal cancers. The primary goal of this study was to examine outcomes for high-grade appendiceal (HGA) and high-grade colonic primaries after CRS-HIPEC to determine if a significant difference exists between the two groups. METHODS: A retrospective analysis of patients with peritoneal dissemination from appendiceal and colonic primaries were identified in a prospectively maintained database of 1,223 CRS HIPEC procedures performed between 1991 and 2015. Patient demographics, performance status resection status, tumor grade, nodal status, morbidity, mortality, and survival were reviewed with biopsy-proven PSD being classified according to primary site. Univariate and multivariate analyses were performed, and outcomes compared. RESULTS: The study identified 171 CRS-HIPEC procedures for 165 patients: 110 (66.7%) for HGA and 55 (33.3%) for high-grade colonic lesions. Observed median disease-free survival (DFS) and overall survival (OS) for both groups were the same at14.4 and 18 months, respectively. Median survival according to resection status for R0/R1, R2a, and R2b/c were 36, 15.6, and 8.4 months (P<0.0001). Median OS for those who received preoperative chemotherapy versus those who did not were 14.4 and 20.4 months, respectively (P=0.01). For those who received preoperative chemotherapy, no difference was apparent in the DFS interval (P=0.34). Multivariate predictors of OS included resection status (P<0.0001) and lymph node involvement (P=0.0005). CONCLUSIONS: Preoperative chemotherapy offered no clear DFS or OS benefit, for HGA or high-grade colon cancer patients. Complete cytoreduction offered the greatest survival benefit to both groups with a correlating drop in survival to resection status. Outcomes for high grade appendiceal cancer are remarkably similar to colon cancer. PMID- 26941981 TI - Then and now: cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC), a historical perspective. AB - The management of peritoneal carcinomatosis, once considered a condition with few therapeutic options, has undergone dramatic change with the advancement of surgical techniques and systemic cancer therapy. Cytoreductive surgery (CRS) followed by hyperthermic intraperitoneal chemotherapy (HIPEC) administration, in particular, has significantly impacted the prospect of improving outcomes for this debilitating presentation of malignancy in selected patients. This regional surgical therapy itself has undergone many stages of evolution through its original conception nearly a century ago. Progressive changes in this field have included refinements and ongoing standardization in technique, development of a common language to describe tumor burden and extent of resection, better selection of chemotherapeutics based on tumor histology, reduction of surgical morbidity and mortality, and an improved understanding of factors for appropriate patient selection, to list but a few examples. CRS/HIPEC continues to play an important role in the management of select patients with carcinomatosis of certain tumor histology and its role will no doubt continue to be redefined as new therapies emerge. PMID- 26941982 TI - Surgical technology and pharmacology of hyperthermic perioperative chemotherapy. AB - Although cytoreductive surgery (CRS) and hyperthermic perioperative chemotherapy (HIPEC) have not been shown to be effective by themselves, as a combined treatment they are now standard of care for peritoneal metastases from appendiceal cancer and from colorectal cancer as well as peritoneal mesothelioma. The timing of the HIPEC in relation to the CRS is crucial in that the HIPEC is to destroy minimal residual disease that remains following the CRS and prevent microscopic tumor emboli within the abdomen and pelvis from implanting within the resection site, within fibrinous clot, or within blood clot. Proper selection of chemotherapy agents is crucial to the long-term benefit of CRS and HIPEC. One must consider the response expected with the cancer chemotherapy agent, its area under the curve (AUC) ratio indicating the amount of dose intensity within the peritoneal space, and the drug retention within the peritoneal space for a prolonged exposure. Hyperthermia will augment the cytotoxicity of the cancer chemotherapy agents and improve drug penetration. Irrigation techniques should not be overlooked as an important means of reducing the cancer cell burden within the abdomen and pelvis. Multiple technologies for HIPEC exist and these have advantages and disadvantages. The techniques vary from a totally open technique with a vapor barrier over the open abdominal space to a totally closed technique whereby the HIPEC is administered at the completion of the surgical procedure. The open techniques depend on a table-mounted retractor for suspension of the skin edges allowing a reservoir to occur within the abdomen and pelvis. There are nearly a dozen commercially available hyperthermia pumps, all of which seem to perform adequately for HIPEC although there is a variable degree of convenience and documentation of the HIPEC procedure. As the management of peritoneal metastases has progressed over three decades, early cases are now seen in which a laparoscopic CRS and HIPEC may be appropriate. Also, prophylactic use of laparoscopic HIPEC with perforated appendiceal malignancies and T4 colon cancers may be appropriate. PMID- 26941983 TI - Chemotherapy for intraperitoneal use: a review of hyperthermic intraperitoneal chemotherapy and early post-operative intraperitoneal chemotherapy. AB - Peritoneal spread of tumors is a major problem in cancer management. Patients develop a marked deterioration in quality of life and shortened survival. This is in part due to bowel obstructions, marked ascites, and overall increase debilitation. Standard medical management has shown to be inadequate for the treatment of these problems. Surgery can palliate symptoms, however, it is unable to be complete at the microscopic level by a significant spillage of tumor cells throughout the abdomen. Chemotherapy can have some improvement in symptoms however it is short lived due to poor penetration into the peritoneal cavity. The role of intraperitoneal chemotherapy is to maximize tumor penetration and optimize cell death while minimizing systemic toxicity. Hyperthermic intraperitoneal chemotherapy (HIPEC) and early post-operative intraperitoneal chemotherapy (EPIC) are two treatment methods that serve this role and have been shown to improve survival. This review will discuss different chemotherapies used for both of these treatment options. PMID- 26941984 TI - Preoperative and surveillance MR imaging of patients undergoing cytoreductive surgery and heated intraperitoneal chemotherapy. AB - MR imaging provides considerable advantages for imaging patients with peritoneal tumor. Its inherently superior contrast resolution compared to CT allows MRI to more accurately depict small peritoneal tumors that are often missed on other imaging tests. Combining different contrast mechanisms including diffusion weighted (DW) MRI and gadolinium-enhanced MRI provides a powerful tool for preoperative and surveillance imaging in patients being considered for cytoreductive surgery (CRS) and heated intraperitoneal chemotherapy (HIPEC). PMID- 26941985 TI - Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for colorectal cancer: survival outcomes and patient selection. AB - BACKGROUND: Chemotherapy hyperthermic intraperitoneal chemotherapy (HIPEC) is playing an ever increasing role in the management of colorectal cancer (CRC) with peritoneal metastases (PM) as results approach those of surgical resection of liver metastases. Selection criteria for treatment type, sequence and timing of currently available therapies remain ill-defined. METHODS: We review the current published literature analyzing outcomes by treatments with surgery, systemic chemotherapy, cytoreductive surgery (CRS) and HIPEC, and ongoing clinical trials. A clinical pathway that incorporates all currently available therapies, determining the timing and sequence of such therapies was constructed. RESULTS: Most of the literature on outcome data comes from studies reporting the results of CRS and HIPEC with large series showing a median survival of 32-47 months. Meanwhile, the vast majority of patients, over 90% in the United States, are being treated with palliative systemic therapies following the NCCN guidelines. CONCLUSIONS: Cooperation between medical and surgical oncologists represents an unmet need in oncology when it comes to patients with CRC with PM. The presented clinical pathway constitutes a feasible and much needed first step to start this cooperation. PMID- 26941986 TI - Diagnosis and management of patients with malignant peritoneal mesothelioma. AB - Malignant peritoneal mesothelioma (MPM) is a rare neoplastic condition that arises, usually diffusely, from the serosal membranes of the abdominal cavity. MPM represents about 7% to 10% of all mesothelioma diagnoses and this translates into approximately 800 cases per year in the United States. The disease has variable tumor biology but progression, when it occurs, is almost always within the abdominal cavity. Although many patients can be successfully treated at initial presentation, the disease is almost always fatal in time. It afflicts men and women almost equally and the median age at presentation is 50 years. The diagnosis is made when a diffuse malignant process within the abdominal cavity is observed and a tissue sample reveals the characteristic histopathology and immunohistochemical profile of mesothelioma. Initial staging is usually via a cross sectional imaging study of the abdomen and pelvis making sure that the lower thorax is also assessed. If the disease burden and distribution is favorable then operative exploration, cytoreduction, and hyperthermic intraperitoneal chemotherapy (HIPEC) are considered first line treatment in selected patients. Systemic pemetrexed and cisplatin (or gemcitabine) have modest response rates that are of limited duration. Research advances with novel systemic or intraperitoneal agents hold promise. PMID- 26941987 TI - Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for gastric cancer and other less common disease histologies: is it time? AB - Gastric cancer is the fourth most commonly diagnosed cancer worldwide, and once spread to the peritoneum, has a 5-year survival of less than 5%. Recent years have demonstrated advances in the use of cytoreductive surgery (CRS) in combination with heated intraperitoneal chemotherapy (HIPEC) for the treatment of peritoneal carcinomatosis due to various malignancies. The frequent desmoplastic stroma and poor vascularization impeding drug delivery particularly in the diffuse form of gastric cancer is thought to provide a sound rationale for a regionalized treatment approach in this disease. Here, we seek to review the available data to define the role of CRS and HIPEC in gastric cancer metastatic to the peritoneal surface, and furthermore, analyze the use of CRS and HIPEC in malignancies less commonly treated with the regionalized perfusion approach. PMID- 26941988 TI - Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy: a review of factors contributing to morbidity and mortality. AB - Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is associated with prolonged survival for appropriately selected patients with peritoneal dissemination of abdominal malignancies. CRS and HIPEC has been criticized for perceived high rates of morbidity and mortality. Morbidity and mortality rates of CRS and HIPEC, however, do not appear dissimilar to those of other large abdominal surgeries, particularly when relevant patient and operative factors are accounted for. The risk of morbidity and mortality following this surgery for a given individual can be predicted in part by a variety of patient and operative factors. While strong data are lacking, the limited data that exists on the matter suggests that the independent contribution of the heated intraperitoneal chemotherapy to CRS and HIPEC morbidity is relatively small. A more thorough understanding of the patient and operative factors associated with CRS and HIPEC morbidity and mortality, as well as the specific complications related to the intraperitoneal chemotherapy, can better inform clinicians in multidisciplinary teams and patients alike in the decision-making for this surgery. PMID- 26941989 TI - Palliative cytoreductive surgery and hyperthermic intraperitoneal chemoperfusion: current clinical practice or misnomer? AB - Cytoreductive surgery and hyperthermic intraperitoneal chemoperfusion (CRS/HIPEC) is being used more and more frequently for the management of peritoneal carcinomatosis. Despite significant improvements in oncologic outcomes and the risk of complications and mortality, CRS/HIPEC remains one of the most morbid treatments offered for advanced cancers. Consequently CRS/HIPEC is still considered controversial by many, even in the setting of cancers that are potentially curable. However, as high volume surgical oncologists become more experienced with CRS/HIPEC, the potential role of "palliative CRS/HIPEC" in the management of peritoneal carcinomatosis is being raised. Given the often limited survival benefit expected after CRS/HIPEC, understanding the impact of the treatment on quality of life (QOL) needs to be an essential part of the decision to proceed and is critical to optimizing recovery afterwards. This article reviews the potential definitions of "palliative CRS/HIPEC" in various clinical contexts and describes the current state of the QOL experience after CRS/HIPEC. PMID- 26941990 TI - Impact of surgical volume of centers on post-operative outcomes from cytoreductive surgery and hyperthermic intra-peritoneal chemoperfusion. AB - Complex surgical operations performed at centers of high volume have improved outcomes due to improved surgical proficiency, and betters systems of care including avoidance of errors. Cytoreductive surgery (CRS) and hyperthermic intra peritoneal chemoperfusion (HIPEC), which has been shown to be an oncologically effective strategy for peritoneal carcinomatosis (PC), is one such procedure with significant morbidity and mortality. The learning curve to reach technical proficiency in CRS + HIPEC is about 140-220 cases for a center. Focus on improving surgical proficiency through training, improving systems of care through partnerships and reporting mechanisms for quality could reduce the time to proficiency. PMID- 26941991 TI - Repeat cytoreductive surgery with hyperthermic intraperitoneal chemotherapy: review of indications and outcomes. AB - Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) is an established treatment option in selected patients with peritoneal dissemination from a variety of epithelial primaries. Even though a small proportion will be alive and potentially cured at 10 years, the majority will eventually develop recurrent disease. Repeat CRS/HIPEC is a valid consideration in a selected subpopulation of patients with isolated peritoneal recurrence. This review summarizes the data on patient selection, feasibility, limitations and outcomes of repeat CRS/HIPEC. PMID- 26941992 TI - Cytoreductive surgery and intraperitoneal chemotherapy: an evidence-based review past, present and future. AB - Peritoneal carcinomatosis (PC) has historically been considered a terminal condition with merely palliative treatment achieving a survival rate measured in months. Cytoreductive surgery (CyRS) and intraperitoneal chemotherapy (IPC) have emerged as potentially effective regional treatments with the potential for long term survival in well-selected patients. The fundamentals of CyRS and IPC are patient selection and complete cytoreduction. Since there is now sufficient evidence for the superiority of CyRS and IPC to systemic chemotherapy alone in a highly select group of patients, surgeons and oncologists should be aware of this modality as a potential benefit for patients with PC. The aim of this report is to highlight cancer-specific evidence in the context of ongoing studies regarding the outcome of this treatment. PMID- 26941994 TI - Prevalence of Helminths in Dogs and Owners' Awareness of Zoonotic Diseases in Mampong, Ashanti, Ghana. AB - Dogs are popular pets that live closely with humans. However, this cohabitation allows for the transmission of zoonotic parasites to humans. In Ghana, very little is known about zoonotic parasites in dogs. We examined excrements of 154 dogs for intestinal helminthes using saturated sodium chloride as a floatation medium and further interviewed 100 dog owners regarding knowledge on zoonosis and pet management practices. Thirteen parasite species were identified, with an overall prevalence of 52.6%. Nematodes were more common than cestodes, with Toxocara canis being the most prevalent helminth (18.8%). Age (p = 0.011; chi (2) = 9.034) and location (p = 0.02; chi (2) = 12.323) of dogs were significant risk factors of helminthic infections, while mode of housing, function, and gender of dogs were not. Knowledge on zoonosis and pet management practices were poor, including irregular deworming and feeding of animals off the bare ground. Dogs may play an active role in the transmission of zoonotic diseases in the area, given the cohabitation of infected dogs with humans; irregular deworming pattern of dogs; and rampant excretion of helminth-infested dog excreta into the environment. PMID- 26941993 TI - Ginseng Metabolites on Cancer Chemoprevention: An Angiogenesis Link? AB - Cancer is a leading cause of death in the United States. Angiogenesis inhibitors have been introduced for the treatment of cancer. Based on the fact that many anticancer agents have been developed from botanical sources, there is a significant untapped resource to be found in natural products. American ginseng is a commonly used herbal medicine in the U.S., which possess antioxidant properties. After oral ingestion, natural ginseng saponins are biotransformed to their metabolites by the enteric microbiome before being absorbed. The major metabolites, ginsenoside Rg3 and compound K, showed significant potent anticancer activity compared to that of their parent ginsenosides Rb1, Rc and Rd. In this review, the molecular mechanisms of ginseng metabolites on cancer chemoprevention, especially apoptosis and angiogenic inhibition, are discussed. Ginseng gut microbiome metabolites showed significant anti-angiogenic effects on pulmonary, gastric and ovarian cancers. This review suggests that in addition to the chemopreventive effects of ginseng compounds, as angiogenic inhibitors, ginsenoside metabolites could be used in combination with other cancer chemotherapeutic agents in cancer management. PMID- 26941995 TI - Silent Human Trypanosoma brucei gambiense Infections around the Old Gboko Sleeping Sickness Focus in Nigeria. AB - Trypanosoma brucei gambiense causes Gambian trypanosomosis, a disease ravaging affected rural parts of Sub-Saharan Africa. We screened 1200 human blood samples for T. b. gambiense using the card agglutination test for trypanosomosis, characterized trypanosome isolates with Trypanosoma gambiense serum glycoprotein PCR (TgsGP-PCR), and analyzed our data using Chi square and odds ratio at 95% confidence interval for statistical association. Of the 1200 samples, the CATT revealed an overall infection rate of 1.8% which ranged between 0.0% and 3.5% across study sites. Age and sex based infection rates ranged between 1.2% and 2.3%. We isolated 7 (33.3%) trypanosomes from the 21 seropositive samples using immunosuppressed mice which were identified as T. b. gambiense group 1 by TgsGP PCR. Based on study sites, PCR revealed an overall infection rate of 0.6% which ranged between 0.0% and 1.5%. Females and males revealed PCR based infection rates of 0.3% and 0.8%, respectively. Infection rates in adults (1.3%) and children (0.1%) varied significantly (p < 0.05). We observed silent T. b. gambiense infections among residents of this focus. Risks of disease development into the second fatal stage in these patients who may also serve as reservoirs of infection in the focus exist. PMID- 26941996 TI - Evaluation of the Larvicidal Efficacy of Five Indigenous Weeds against an Indian Strain of Dengue Vector, Aedes aegypti L. (Diptera: Culicidae). AB - Background and Objectives. Aedes aegypti, dengue fever mosquito, is primarily associated with the transmission of dengue and chikungunya in tropical and subtropical regions of the world. The present investigations were carried out to assess the larvicidal efficiency of five indigenous weeds against Ae. aegypti. Methods. The 1,000 ppm hexane and ethanol extracts prepared from the leaves and stem of five plants (Achyranthes aspera, Cassia occidentalis, Catharanthus roseus, Lantana camara, and Xanthium strumarium) were screened for their larvicidal activity against early fourth instars of dengue vector. The extracts which could cause 80-100% mortality were further investigated for their efficacy. Results. The preliminary screening established the efficacy of hexane extracts as compared to the ethanol extracts. Further investigations revealed the highest larvicidal potential of A. aspera extracts exhibiting LC50 value of 82.555 ppm and 68.133 ppm, respectively. Further, their leaf extracts showed 5-85.9% higher larvicidal activity and stem extracts exhibited 0.23- to 0.85-fold more efficiency than the other four extracts. Conclusion. The present investigations suggest the possible use of A. aspera as an ideal ecofriendly, larvicidal agent for the control of dengue vector, Ae. aegypti. Future studies are, however, required to explore and identify the bioactive component involved and its mode of action. PMID- 26941997 TI - Soil-Transmitted Helminth Reinfection and Associated Risk Factors among School Age Children in Chencha District, Southern Ethiopia: A Cross-Sectional Study. AB - Mass drug administration (MDA) to the most risky population including school-age children (SAC) is the central strategy to control soil-transmitted helminth (STH) infection. The present study was aimed at estimating the prevalence of STHs reinfection three months posttreatment and associated risk factors among SAC in Chencha district. A cross-sectional study design was employed from April 20 to May 5, 2015, to enroll 408 SAC. Structured questionnaire and Kato-Katz thick smear technique were used to interview parents or guardians and quantify the number of eggs per gram of stool. Pearson chi-square and logistic regression were used to assess the association between predictor variable and STH reinfection. The prevalence of STHs within three months of mass chemotherapy among SAC was 36.8% which is 93.4% of the prevalence (39.4%) before treatment. The estimated prevalence of reinfection (95%CI) for Ascaris lumbricoides, Trichuris trichiura, and hookworms was 23.8% (21.1-28.2), 16.2% (12.7-20.1), and 1.0% (0.3-2.5), respectively. Children of merchant fathers were more likely to be reinfected by STHs in Chencha district. In conclusion, there is rapid reinfection after mass chemotherapy among SAC in Chencha district. Further studies should be carried out to generate cost efficient methods that can supplement mass drug administration to accelerate the control of STHs. PMID- 26941998 TI - Conjunctival Lymphangiogenesis Was Associated with the Degree of Aggression in Substantial Recurrent Pterygia. AB - Objective. To examine conjunctival lymphatic vessels and to analyze the relationship between lymphangiogenesis and aggressive recurrent pterygia. Methods. Tissues from 60 excised recurrent (including 19 of Grade 1, 28 of Grade 2, and 13 of Grade 3) pterygia were used in the study. Tissues from 9 nasal epibulbar conjunctivae segments were used as controls. Pterygium slices from each patient were immunostained with LYVE-1 monoclonal antibodies to identify lymphatic microvessels in order to calculate the lymphovascular area (LVA), the lymphatic microvessel density (LMD), and the lymphovascular luminal diameter (LVL). The relationship between lymphangiogenesis (LVA, LMD, and LVL) and pterygium aggression (width, extension, and area) was clarified. Results. Few LYVE-1 positive lymphatic vessels were found in the normal epibulbar conjunctiva segments. Lymphatic vessels were slightly increased in Grades 1 and 2 and were dramatically increased in Grade 3 recurrent pterygia. The LMD was correlated with the pterygium area in Grade 1 and 2 pterygia. In Grade 3, both LVA and LMD were significantly correlated with the pterygium area. Conclusions. Lymphangiogenesis was associated with the degree of aggression in recurrent pterygia, particularly in substantial Grade 3 recurrent pterygia. PMID- 26942000 TI - Ocular Surface Disorders in a Group of Egyptian Children with End Stage Renal Failure on Dialysis: A Cross-Sectional Study. AB - Purpose. To investigate tear function, ocular manifestations, and squamous metaplasia of the conjunctival epithelium (SMCE) in children with end stage renal failure (ESRF) on dialysis. Methods. Thirty children with ESRF and 20 age and sex matched controls during the period from January 2014 to May 2015 underwent full ophthalmologic examination and the tear function was investigated by the Schirmer and tear film break-up time (TBUT) tests. SMCE was evaluated by impression cytology and immunocytochemistry. The correlations of tear function status with ESRF-related clinical and biochemical variables were measured statistically. Results. Dry eye symptoms were detected in 26% of children with ESRF, compared with none of the controls (P = 0.05) and SMCE was almost absent. Values of the Schirmer and TBUT tests were significantly lower in children with ESRF for right eye (t = 24.63, P = 0.01, and t = 11.9, P = 0.002, resp.) and left eye (t = 24.7, P = 0.02, and t = 11.4, P = 0.0004, resp.). TBUT and the Schirmer test values were correlated inversely with the duration of ESRF (R = -0.45, P = 0.01, and R = -0.46, P = 0.01, resp.) and with the duration of dialysis (R = -0.39, P = 0.03, and R = -0.45, P = 0.01, resp.). None of the following parameters was associated with distorted tear function including serum creatinine, electrolytes, parathyroid hormone, total protein, albumin, CBC parameters, and systolic or diastolic blood pressure. Conclusion. The basal tear secretion and tear film stability were lower while the dry eye symptoms such as itching and redness were more common among children with ESRF. The duration of ESRF and dialysis duration seem to be related to the disturbances in tear secretion and tear film stability. However, SMCE is very rare. PMID- 26941999 TI - Restoration of the Ellipsoid Zone and Visual Prognosis at 1 Year after Surgical Macular Hole Closure. AB - Purpose. To evaluate the restoration of the ellipsoid zone (EZ) and its influence on visual prognosis 1 year after surgical macular hole (MH) closure. Method. Subjects were patients with stage 2, 3, or 4 idiopathic MH who underwent primary vitrectomy that resulted in successful hole closure. Nineteen eyes with both EZ disruption with foveal detachment and a continuous external limiting membrane on optical coherence tomography during the early postoperative period were included in this study. Result. EZ disruption was restored in 10 eyes (53%, Group A) and remained in 9 eyes (47%, Group B) at 1 year after surgery. In Group B, the diameter of the residual EZ disruption was 54.7 +/- 33.1 MUm. LogMAR visual acuity (VA) 1 year after surgery was significantly better than preoperative VA in each group (Group A: -0.007 +/- 0.102; P < 0.001; Group B: 0.051 +/- 0.148; P < 0.001), but there was no significant difference between the 2 groups (P = 0.332). There was no significant correlation between logMAR VA and EZ disruption diameter at 1 year after surgery. Conclusion. EZ was restored in 53% of eyes at 1 year after surgical closure of idiopathic MH. Mean residual EZ disruption diameter was 54.7 +/- 33.1 MUm. Neither resolved nor residual EZ disruption influenced postoperative VA. PMID- 26942001 TI - Evaluation of LATS1 and LATS2 Promoter Methylation with the Risk of Pterygium Formation. AB - Purpose. Pterygium is a serious eye problem in countries with high exposure to UV. However, despite numerous studies, the molecular etiology of pterygium is unclear. Recent studies have indicated that LATS1 and LATS2 genes are involved in DDR signaling pathways against continuous UV exposure. Our aim was to evaluate the LATS1 and LATS2 promoter methylation with the risk of pterygium formation. Methods. We evaluated the promoter methylation status of LATS1 and LATS2 using methylation-specific PCR technique. Also, mRNA expression of LATS1 and LATS2 was assessed in 14 cases of pterygium and 14 normal specimens by real-time PCR. Results. Promoter methylation of LATS1 and LATS2 was detected significantly between pterygium tissues and normal tissues [LATS1; OR = 4.9; 95% CI: 1.54 to 15.48, P = 0.003; LATS2; OR = 7.1; 95% CI: 1.53 to 33.19, P = 0.004]. The gene expression analysis showed a statistically significant difference between pterygium tissues and healthy controls for both LATS1 and LATS2 (P < 0.05). Conclusions. The data of this study is the first report regarding the effect of promoter methylation of the LATS1 and LATS2 in the pterygium. To confirm these data, doing further studies in various genetic populations with large sample sizes using advanced molecular techniques is proposed. PMID- 26942002 TI - Elevated Transforming Growth Factor-beta2 in the Aqueous Humor: A Possible Explanation for High Rate of Capsular Contraction Syndrome in High Myopia. AB - Purpose. The purpose of the study was to elucidate the role of transforming growth factor-beta 2 (TGF-beta2) in the development of high myopic capsular contraction syndrome. Methods. Nineteen cases of capsular contraction syndrome, including 14 with high myopia, were collected, and their clinical data were reviewed. Aqueous humor and anterior capsular membranes were obtained during capsulotomy. Hematoxylin-eosin and immunohistochemical staining with anti-TGF beta2 antibody were performed on capsular membranes. TGF-beta2 levels in aqueous humor were assayed using ELISA and western blot. Results. High myopia was significantly associated with the incidence of capsular contraction syndrome (odds ratio: 14.74, P < 0.001, 95% CI: 5.29-41.05). Histopathological analysis revealed proliferation of fibroblast-like lens epithelial cells on the shrunken anterior capsule, labeled with TGF-beta2 antibodies. ELISA and Western blot showed higher levels of TGF-beta2 in aqueous humor of patients with capsular contraction syndrome and high myopia. Conclusions. High myopia is a risk factor for capsular contraction syndrome. Elevated TGF-beta2 levels in high myopic cataract patients may play an important role in the pathogenesis of capsular contraction syndrome. PMID- 26942003 TI - Serous Retinal Detachment Associated with Dome-Shaped Macula and Staphyloma Edge in Myopic Patients before and after Treatment with Spironolactone. AB - Objective. Serous retinal detachment (SRD) is a common anatomical complication associated with dome-shaped macula (DSM) and staphyloma margin in myopic patients. Here we described the anatomical and functional outcomes obtained with the use of oral spironolactone, a mineralocorticoid antagonist, in the management of myopic patients with SRD associated with DSM and staphyloma margin. Methods. We evaluated both eyes of twelve myopic patients with long-standing SRD associated with DSM or staphyloma margin. The patients were treated daily for six months with oral spironolactone 50 mg. Best-corrected visual acuity (BCVA) and central retinal thickness (CRT), determined by optical coherence tomography, were evaluated on the first day and on monthly follow-up visits. Results. Pretreatment BCVA (mean +/- standard deviation) was 0.406 +/- 0.324 LogMAR, and posttreatment BCVA was 0.421 +/- 0.354 LogMAR (P = 0.489). Pretreatment CRT was 323.9 +/- 78.6 MUm, and after six months of treatment it was significantly lower, 291.2 +/- 74.5 MUm (P = 0.010). There were no treatment-related complications. Conclusions. We evaluated a novel treatment for SRD associated with DSM and staphyloma margin in myopic patients. After six months of treatment with the mineralocorticoid antagonist spironolactone, the subretinal fluid and CRT were significantly reduced; however, there was no improvement in BCVA. PMID- 26942004 TI - Nonlethal Levels of Zeaxanthin Inhibit Cell Migration, Invasion, and Secretion of MMP-2 via NF-kappaB Pathway in Cultured Human Uveal Melanoma Cells. AB - Zeaxanthin at nonlethal dosages (3-10 MUM) significantly inhibited the cell migration of cultured uveal melanoma cells (C918 cell line) as determined by wound healing assay and Boyden chamber assay. Matrigel invasion assay showed that cell invasion of uveal melanoma cells could be significantly inhibited by zeaxanthin. Secretion of MMP-2 by melanoma cells was significantly inhibited by zeaxanthin in a dose-dependent manner as measured by ELISA kit. Zeaxanthin also significantly inhibited the NF-kappaB levels in nuclear extracts of the UM cells, which is the upstream of the MMP-2 secretion. These results suggest that zeaxanthin might be a potentially therapeutic approach in the prevention of metastasis in uveal melanoma. PMID- 26942005 TI - Overexpression of Soluble Recombinant Human Lysyl Oxidase by Using Solubility Tags: Effects on Activity and Solubility. AB - Lysyl oxidase is an important extracellular matrix enzyme that has not been fully characterized due to its low solubility. In order to circumvent the low solubility of this enzyme, three solubility tags (Nus-A, Thioredoxin (Trx), and Glutathione-S-Transferase (GST)) were engineered on the N-terminus of mature lysyl oxidase. Total enzyme yields were determined to be 1.5 mg for the Nus-A tagged enzyme (0.75 mg/L of media), 7.84 mg for the Trx tagged enzyme (3.92 mg/L of media), and 9.33 mg for the GST tagged enzyme (4.67 mg/L of media). Enzymatic activity was calculated to be 0.11 U/mg for the Nus-A tagged enzyme and 0.032 U/mg for the Trx tagged enzyme, and no enzymatic activity was detected for the GST tagged enzyme. All three solubility-tagged forms of the enzyme incorporated copper; however, the GST tagged enzyme appears to bind adventitious copper with greater affinity than the other two forms. The catalytic cofactor, lysyl tyrosyl quinone (LTQ), was determined to be 92% for the Nus-A and Trx tagged lysyl oxidase using the previously reported extinction coefficient of 15.4 mM(-1 )cm( 1). No LTQ was detected for the GST tagged lysyl oxidase. Given these data, it appears that Nus-A is the most suitable tag for obtaining soluble and active recombinant lysyl oxidase from E. coli culture. PMID- 26942006 TI - Implementation of an Internet Weight Loss Program in a Worksite Setting. AB - BACKGROUND: Worksite wellness programs typically produce modest weight losses. We examined whether an efficacious Internet behavioral weight loss program could be successfully implemented in a worksite setting. METHODS: Participants were 75 overweight or obese employees/dependents of a large healthcare system who were given access to a 12-week Internet-based, multicomponent behavioral weight loss program. Assessments occurred at baseline, Month 3 (end of intervention), and Month 6 (follow-up). RESULTS: Retention was excellent (93% at Month 3 and 89% at Month 6). Intent-to-treat analyses demonstrated that participants lost an average (+/-SE) of -5.8 +/- .60 kg from baseline to Month 3 and regained 1.1 +/- .31 kg from Month 3 to Month 6; overall, weight loss from baseline to Month 6 was -4.7 +/- .71 kg, p < .001. Men lost more weight than women, p = .022, and individuals who had a college degree or higher lost more weight than those with less education, p = .005. Adherence to viewing lessons (8 of 12) and self-monitoring (83% of days) was excellent and significantly associated with weight loss, ps < .05. CONCLUSIONS: An Internet-based behavioral weight management intervention can be successfully implemented in a worksite setting and can lead to clinically significant weight losses. Given the low costs of offering this program, it could easily be widely disseminated. PMID- 26942007 TI - A Novel Structurally Stable Multiepitope Protein for Detection of HCV. AB - Hepatitis C virus (HCV) has emerged as the major pathogen of liver diseases in recent years leading to worldwide blood-transmitted chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. Accurate diagnosis for differentiation of hepatitis C from other viruses is thus of pivotal importance for proper treatment. In this work we developed a recombinant multiepitope protein (rMEHCV) for hepatitis C diagnostic purposes based on conserved and immunodominant epitopes from core, NS3, NS4A, NS4B, and NS5 regions of the virus polyprotein of genotypes 1a, 1b, and 3a, the most prevalent genotypes in South America (especially in Brazil). A synthetic gene was designed to encode eight epitopes in tandem separated by a flexible linker and bearing a his-tag at the C-terminal end. The recombinant protein was produced in Escherichia coli and purified in a single affinity chromatographic step with >95% purity. Purified rMEHCV was used to perform an ELISA which showed that the recombinant protein was recognized by IgG and IgM from human serum samples. The structural data obtained by circular dichroism (CD) spectroscopy showed that rMEHCV is a highly thermal stable protein at neutral and alkaline conditions. Together, these results show that rMEHCV should be considered an alternative antigen for hepatitis C diagnosis. PMID- 26942008 TI - A Review on Platensimycin: A Selective FabF Inhibitor. AB - Emerging resistance to existing antibiotics is an inevitable matter of concern in the treatment of bacterial infection. Naturally occurring unique class of natural antibiotic, platensimycin, a secondary metabolite from Streptomyces platensis, is an excellent breakthrough in recent antibiotic research with unique structural pattern and significant antibacterial activity. beta-Ketoacyl-(acyl-carrier protein (ACP)) synthase (FabF) whose Gram-positive bacteria need to biosynthesize cell membranes is the target of inhibition of platensimycin. So, isolation, retrosynthetic analysis, synthesis of platensimycin, and analogues of platensimycin synthesized till today are the objectives of this review which may be helpful to further investigate and to reveal untouched area on this molecule and to obtain a potential antibacterial lead with enhanced significant antibacterial activity. PMID- 26942009 TI - Lipidomic Modulation in Stressed Albino Rats Is Altered by Yolk and Albumen of Quail (Coturnix japonica) Egg and Poultry Feed. AB - Cold and immobilization stressors can generate oxidative stress as well as skeletal muscle fatigue. Free radicals cause oxidative degradation of lipids, proteins, nucleic acids, and carbohydrates molecules, thereby compromising cell integrity and function. Quail egg had been described as being very functional biochemically, due to the essential biomolecules it contains in very regulated quantity. This study was aimed for evaluating the dietary effect of the egg on lipid profile parameters on selected tissues. The antilipidemic properties of the egg yolk and albumen and poultry (layers) feed were determined in selected tissues in male albino rats assaulted with cold immobilization stress induced on them at 4 degrees C for 2 hours, while diazepam was used as standard antistress drug. Antilipidemic activities were evaluated by lipid profile modulation (HDL, LDL, TRIG., and T-CHOL.). Quantitative and qualitative analyses of fatty acids profile of the yolk hexane-extract were determined by Gas Chromatography and Mass Spectrophotometry (GC-MS). The ameliorative impacts of diazepam (2.5 and 5.0 mg/mL/kg BW), yolk (5 and 10 mL/kg BW), albumen (5 and 10 mL/kg BW), and the feed (5-10 mg/kg BW) were competitively (p < 0.05) specific for each of the tissues. The result of the study suggested yolk and albumen of quail egg and poultry feed as antistress agents as well as lipid modulators. PMID- 26942010 TI - A Comparison of Measures of Endothelial Function in Patients with Peripheral Arterial Disease and Age and Gender Matched Controls. AB - This study compared flow-mediated dilatation (FMD), peripheral artery tonometry (PAT), and serum nitric oxide (NO) measures of endothelial function in patients with peripheral artery disease (PAD) against age/gender matched controls. 25 patients (mean age: 72.4 years, M : F 18 : 7) with established PAD and an age/gender matched group of 25 healthy controls (mean age: 72.4 years, M : F 18 : 7) were studied. Endothelial function was measured using the % FMD, reactive hyperemia index (RHI) using PAT and serum NO (MUmol). Difference for each method between PAD and control patients and correlation between the methods were investigated. FMD and RHI were lower in patients with PAD (median FMD for PAD = 2.16% versus control = 3.77%, p = 0.034 and median RHI in PAD = 1.64 versus control = 1.92, p = 0.005). NO levels were not significantly different between the groups (PAD median = 7.70 MUmol, control median = 13.05 MUmol, p = 0.662). These results were obtained in elderly patients and cannot be extrapolated to younger individuals. FMD and PAT both demonstrated a lower hyperaemic response in patients with PAD; however, FMD results in PAD patients were unequivocally reduced whereas half the PAD patients had RHI values above the established threshold for endothelial dysfunction. This suggests that FMD is a more appropriate method for the measurement of NO-mediated endothelial function. PMID- 26942011 TI - Is There a Relationship between the Stratum Corneum Thickness and That of the Viable Parts of Tumour Cells in Basal Cell Carcinoma? AB - Basal cell carcinoma (BCC) is an invasive epithelial skin tumour. The thickness of the outermost epidermal layer of the skin, the stratum corneum (SC), influences drug uptake and penetration into tumour and may thereby affect the response of BCC to topical treatment. The aim was to investigate a possible relationship between the thickness of the SC and that of the viable part of BCC. Histopathological evaluations of the corresponding SC and viable tumour thickness measurements of individual BCCs of different subtypes were explored. A total of 53 BCCs from 46 patients were studied. The median tumour thickness was 1.7 mm (0.8-3.0 mm), with a significant difference between subtypes (p < 0.001). The SC had a median thickness of 0.3 mm (0.2-0.4 mm), with no difference between tumour subtypes (p = 0.415). Additionally, no significant association between the thickness of the SC and that of the viable part of the tumour was demonstrated (p = 0.381). In conclusion our results indicate that SC thickness is relatively constant in BCC. PMID- 26942012 TI - Comparison of Oil Content and Fatty Acid Profile of Ten New Camellia oleifera Cultivars. AB - The oil contents and fatty acid (FA) compositions of ten new and one wild Camellia oleifera varieties were investigated. Oil contents in camellia seeds from new C. oleifera varied with cultivars from 41.92% to 53.30% and were affected by cultivation place. Average oil content (47.83%) of dry seeds from all ten new cultivars was almost the same as that of wild common C. oleifera seeds (47.06%). New C. oleifera cultivars contained similar FA compositions which included palmitic acid (C16:0, PA), palmitoleic acid (C16:1), stearic acid (C18:0, SA), oleic acid (C18:1, OA), linoleic acid (C18:2, LA), linolenic acid (C18:3), eicosenoic acid (C20:1), and tetracosenoic acid (C24:1). Predominant FAs in mature seeds were OA (75.78%~81.39%), LA (4.85%~10.79%), PA (7.68%~10.01%), and SA (1.46%~2.97%) and OA had the least coefficient of variation among different new cultivars. Average ratio of single FA of ten artificial C. oleifera cultivars was consistent with that of wild common C. oleifera. All cultivars contained the same ratios of saturated FA (SFA) and unsaturated FA (USFA). Oil contents and FA profiles of new cultivars were not significantly affected by breeding and selection. PMID- 26942013 TI - Multidrug Resistant and Extensively Drug Resistant Bacteria: A Study. AB - Background and Objective. Antimicrobial resistance is now a major challenge to clinicians for treating patients. Hence, this short term study was undertaken to detect the incidence of multidrug-resistant (MDR), extensively drug-resistant (XDR), and pandrug-resistant (PDR) bacterial isolates in a tertiary care hospital. Material and Methods. The clinical samples were cultured and bacterial strains were identified in the department of microbiology. The antibiotic susceptibility profile of different bacterial isolates was studied to detect MDR, XDR, and PDR bacteria. Results. The antibiotic susceptibility profile of 1060 bacterial strains was studied. 393 (37.1%) bacterial strains were MDR, 146 (13.8%) strains were XDR, and no PDR was isolated. All (100%) Gram negative bacterial strains were sensitive to colistin whereas all (100%) Gram positive bacterial strains were sensitive to vancomycin. Conclusion. Close monitoring of MDR, XDR, or even PDR must be done by all clinical microbiology laboratories to implement effective measures to reduce the menace of antimicrobial resistance. PMID- 26942014 TI - Utilization of Crude Glycerol as a Substrate for the Production of Rhamnolipid by Pseudomonas aeruginosa. AB - Biosurfactants are produced by bacteria or yeast utilizing different substrates as sugars, glycerol, or oils. They have important applications in the detergent, oil, and pharmaceutical industries. Glycerol is the product of biodiesel industry and the existing glycerol market cannot accommodate the excess amounts generated; consequently, new markets for refined glycerol need to be developed. The aim of present work is to optimize the production of microbial rhamnolipid using waste glycerol. We have developed a process for the production of rhamnolipid biosurfactants using glycerol as the sole carbon source by a local Pseudomonas aeruginosa isolate that was obtained from an extensive screening program. A factorial design was applied with the goal of optimizing the rhamnolipid production. The highest production yield was obtained after 2 days when cells were grown in minimal salt media at pH 6, containing 1% (v/v) glycerol and 2% (w/v) sodium nitrate as nitrogen source, at 37 degrees C and at 180 rpm, and reached 2.164 g/L after 54 hours (0.04 g/L h). Analysis of the produced rhamnolipids by TLC, HPLC, and FTIR confirmed the nature of the biosurfactant as monorhamnolipid. Glycerol can serve as a source for the production of rhamnolipid from microbial isolates providing a cheap and reliable substrate. PMID- 26942015 TI - The Role of Forkhead Box Protein M1 in Breast Cancer Progression and Resistance to Therapy. AB - The Forkhead box M1 (FOXM1) is a transcription factor that has been implicated in normal cell growth and proliferation through control of cell cycle transition and mitotic spindle. It is implicated in carcinogenesis of various malignancies where it is activated by either amplification, increased stability, enhanced transcription, dysfunction of regulatory pathways, or activation of PI3K/AKT, epidermal growth factor receptor, Raf/MEK/MAPK, and Hedgehog pathways. This review describes the role of FOXM1 in breast cancer. This includes how FOXM1 impacts on different subtypes of breast cancer, that is, luminal/estrogen receptor positive (ER+), expressing human epidermal growth factor receptor 2 (HER2), basal-like breast cancer (BBC), and triple negative breast cancer (TNBC). The review also describes different tested preclinical therapeutic strategies targeting FOXM1. Developing clinically applicable therapies that specifically inhibit FOXM1 activity is a logical next step in biomarker-driven approaches against breast cancer but will not be without its challenges due to the unique properties of this transcription factor. PMID- 26942016 TI - Glia and TRPM2 Channels in Plasticity of Central Nervous System and Alzheimer's Diseases. AB - Synaptic plasticity refers to the ability of neurons to strengthen or weaken synaptic efficacy in response to activity and is the basis for learning and memory. Glial cells communicate with neurons and in this way contribute in part to plasticity in the CNS and to the pathology of Alzheimer's disease (AD), a neurodegenerative disease in which impaired synaptic plasticity is causally implicated. The transient receptor potential melastatin member 2 (TRPM2) channel is a nonselective Ca(2+)-permeable channel expressed in both glial cells (microglia and astrocytes) and neurons. Recent studies indicated that TRPM2 regulates synaptic plasticity as well as the activation of glial cells. TRPM2 also modulates oxidative stress and inflammation through interaction with glial cells. As both oxidative stress and inflammation have been implicated in AD pathology, this suggests a possible contribution of TRPM2 to disease processes. Through modulating the homeostasis of glutathione, TRPM2 is involved in the process of aging which is a risk factor of AD. These results potentially point TRPM2 channel to be involved in AD through glial cells. This review summarizes recent advances in studying the contribution of TRPM2 in health and in AD pathology, with a focus on contributions via glia cells. PMID- 26942020 TI - Stenting of Variant Left Carotid Artery Using Brachial Artery Approach in a Patient with Unusual Type of Bovine Aortic Arch. AB - Bovine aortic arch is the most frequently encountered variation in human aortic arch branching. A 63-year-old Asian male presented with symptomatic severe stenosis of left carotid artery originating from the brachiocephalic trunk. Selective engagement to the left carotid artery was unsuccessful using transfemoral approach. We reported on a successful left carotid artery stenting case using right brachial artery approach in a bovine aortic arch. This paper is worthy of reporting in terms of guiding physicians for interventional procedures in these types of challenging cases. PMID- 26942019 TI - Bortezomib-Induced Complete Heart Block and Myocardial Scar: The Potential Role of Cardiac Biomarkers in Monitoring Cardiotoxicity. AB - Bortezomib is a proteasome inhibitor used to treat multiple myeloma and mantle cell lymphoma. Traditionally, bortezomib was thought to have little cardiovascular toxicity; however, there is increasing evidence that bortezomib can lead to cardiac complications including left ventricular dysfunction and atrioventricular block. We present the case of a 66-year-old man with multiple myeloma and persistent asymptomatic elevations of cardiac biomarkers who developed complete heart block and evidence of myocardial scar after his eighth cycle of bortezomib, requiring permanent pacemaker placement. In addition to discussing the cardiovascular complications of bortezomib therapy, we propose a potential role for biomarkers in the prediction and monitoring of bortezomib cardiotoxicity. PMID- 26942021 TI - A Case of Waterhouse-Friderichsen Syndrome Resulting from an Invasive Pneumococcal Infection in a Patient with a Hypoplastic Spleen. AB - A 50-year-old male was brought to our emergency department by ambulance with complaints of pain and numbness in both legs. At arrival, purple spots were evident on his neck and face. Examination of the vital sign indicated septic shock. Laboratory data and blood gas analysis revealed disseminated intravascular coagulation, multiple organ failure, and metabolic acidosis. Peripheral blood smears revealed Howell-Jolly bodies, indicating decreased splenic function. A rapid urinary pneumococcal antigen test was also found to be positive. After admission to the intensive care unit, extensive treatment, including polymyxin-B direct hemoperfusion and administration of methylprednisolone and broad spectrum antibiotics was immediately initiated. Despite of our efforts to save his life, the patient died six hours after the arrival. The following day, blood cultures revealed the presence of Streptococcus pneumoniae. An autopsy revealed a hypoplastic spleen and a bilateral adrenal hemorrhage, indicating acute adrenal insufficiency caused by sepsis. Finally, the patient was diagnosed with Waterhouse-Friderichsen syndrome. Although severe infection may be seen in the splenectomized patients, it should be noted that patients with a hypoplastic spleen may have acute severe infections. We, therefore, report a case of Waterhouse-Friderichsen syndrome resulting from an invasive pneumococcal infection in a patient with a hypoplastic spleen. PMID- 26942017 TI - The Response to Oxidative DNA Damage in Neurons: Mechanisms and Disease. AB - There is a growing body of evidence indicating that the mechanisms that control genome stability are of key importance in the development and function of the nervous system. The major threat for neurons is oxidative DNA damage, which is repaired by the base excision repair (BER) pathway. Functional mutations of enzymes that are involved in the processing of single-strand breaks (SSB) that are generated during BER have been causally associated with syndromes that present important neurological alterations and cognitive decline. In this review, the plasticity of BER during neurogenesis and the importance of an efficient BER for correct brain function will be specifically addressed paying particular attention to the brain region and neuron-selectivity in SSB repair-associated neurological syndromes and age-related neurodegenerative diseases. PMID- 26942018 TI - Developmental Dynamics of Rett Syndrome. AB - Rett Syndrome was long considered to be simply a disorder of postnatal development, with phenotypes that manifest only late in development and into adulthood. A variety of recent evidence demonstrates that the phenotypes of Rett Syndrome are present at the earliest stages of brain development, including developmental stages that define neurogenesis, migration, and patterning in addition to stages of synaptic and circuit development and plasticity. These phenotypes arise from the pleotropic effects of MeCP2, which is expressed very early in neuronal progenitors and continues to be expressed into adulthood. The effects of MeCP2 are mediated by diverse signaling, transcriptional, and epigenetic mechanisms. Attempts to reverse the effects of Rett Syndrome need to take into account the developmental dynamics and temporal impact of MeCP2 loss. PMID- 26942022 TI - Thyroid Swelling and Thyroiditis in the Setting of Recent hCG Injections and Fine Needle Aspiration. AB - A 60-year-old woman presented with a neck mass and underwent fine needle aspiration of a left thyroid nodule. During this time, she had been injected with hCG for weight loss. Soon after, she developed rapid diffuse thyroid growth with pain. She was ultimately diagnosed with thyrotoxicosis due to postaspiration subacute thyroiditis and subsequently became hypothyroid. This condition is rare in the nonpregnant state in noncystic nodules with a smaller needle gauge approach. The incidence of thyroid nodule discovery and evaluation is increasing. As more procedures are undertaken, understanding of potential complications is important. This case highlights potential complications of thyroid fine needle aspiration including diffuse thyroid swelling and thyroiditis. The role of hCG injections is speculated to have potentially stimulated thyroid follicular epithelium via cross-reactivity with the TSH receptor and contributed to the acute inflammatory response after fine needle aspiration. PMID- 26942023 TI - De Novo Trisomy 1q10q23.3 Mosaicism Causes Microcephaly, Severe Developmental Delay, and Facial Dysmorphic Features but No Cardiac Anomalies. AB - Proximal duplications of chromosome 1q are rare chromosomal abnormalities. Most patients with this condition present with neurological, urogenital, and congenital heart disease and short life expectancy. Mosaicism for trisomy 1q10q23.3 has only been reported once in the literature. Here we discuss a second case: a girl with a postnatal diagnosis of a de novo pure mosaic trisomy 1q1023.3 who has no urogenital or cardiac anomalies. PMID- 26942024 TI - Angelman-Like Syndrome: A Genetic Approach to Diagnosis with Illustrative Cases. AB - Epigenetic abnormalities in 15q11-13 imprinted region and UBE3A mutation are the two major mechanisms for molecularly confirmed Angelman Syndrome. However, there is 10% of clinically diagnosed Angelman Syndrome remaining test negative. With the advancement of genomic technology like array comparative genomic hybridization and next generation sequencing methods, it is found that some patients of these test negative Angelman-like Syndromes actually have alternative diagnoses. Accurate molecular diagnosis is paramount for genetic counseling and subsequent management. Despite overlapping phenotypes between Angelman and Angelman-like Syndrome, there are some subtle but distinct features which could differentiate them clinically. It would provide important clue during the diagnostic process for clinicians. PMID- 26942025 TI - Infective Exacerbation of Pasteurella multocida. AB - An 89-year-old lady presented with a one-day history of shortness of breath as well as a cough productive of brown sputum. Her medical history was significant for chronic obstructive pulmonary disease (COPD). She was in severe type one respiratory failure and blood tests revealed markedly raised inflammatory markers; however her chest X-ray was clear. On examination there was bronchial breathing with widespread crepitations and wheeze. She was treated as per an infective exacerbation of COPD. Subsequent blood cultures grew Pasteurella multocida, a common commensal in the oropharynx of domesticated animals. The patient was then asked about any contact with animals, after which she revealed she had a dog and was bitten on her left hand the day before admission. We should not forget to enquire about recent history of injuries or animal bites when patients present acutely unwell. She made a complete recovery after treatment with penicillin. PMID- 26942027 TI - Ganciclovir-Resistant Cytomegalovirus Infection in a Kidney Transplant Recipient Successfully Treated with Foscarnet and Everolimus. AB - Cytomegalovirus (CMV) infection remains a major cause of morbidity, graft failure, and death in kidney transplant recipients. We describe a case of a 53 year-old CMV-seronegative man who underwent renal transplant from a CMV-positive donor and who developed ganciclovir- (GCV-) resistant CMV infection. Foscarnet was started while immunosuppressive therapy was modified with the introduction of everolimus minimizing tacrolimus dosage. Only two weeks after the start of this treatment regimen was the patient's viral load negative. At two-year follow-up the patient has no clinical or laboratory signs of CMV infection and a good and stable renal function or graft survival. In our case, administration of an mTOR inhibitor combined with foscarnet led to rapid and persistent viral clearance without compromising short- and medium-term graft function. This combination therapy supports the need for the kidney transplant community to individualize a target therapy for each type of GCV-resistant CMV infection. PMID- 26942026 TI - Podocyturia: A Clue for the Rational Use of Amiloride in Alport Renal Disease. AB - No specific or efficient treatment exists for Alport syndrome, an X-linked hereditary disease caused by mutations in collagen type IV, a crucial component of the glomerular basement membrane. Kidney failure is usually a major complication of the disease, and patients require renal replacement therapy early in life. Microhematuria and subsequently proteinuria are hallmarks of kidney involvement, which are due to primary basement membrane alterations that mainly cause endothelial thrombosis and podocyte contraction and ulterior irreversible detachment. Commonly drug-based approaches include angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, which are employed to reduce proteinuria and thus retard kidney disease progression and cardiovascular morbidity and mortality. However, as any hereditary disease, it is expressed as early as in the intrauterine life, and usually an index case is helpful to detect family-related cases. As no specific treatment exists, pathophysiologically based approaches are useful. The present case illustrates the reduction rate of urinary podocyte loss and proteinuria after amiloride administration and suggests the molecular pathways involved in Alport renal disease. Finally, podocyturia rather than proteinuria should be considered as an earlier biomarker of kidney involvement and disease progression in Alport disease. PMID- 26942028 TI - Metachronous, Single Metastasis to the Parotid, from Primary Breast Cancer: A Case Report and Review of the Literature. AB - Background. The parotid gland is an unusual site for metastatic disease and when metastasis occurs, it commonly originates from head and neck primaries. Spread from distant infraclavicular sites such as the breast, into the parotid, is even more unusual with very few cases reported in the literature. Case Report. We describe the case of a 65-year-old woman presenting for a rapidly enlarging right parotid mass. She had a history of an invasive ductal carcinoma of the right breast and was disease-free in the past 6 years prior to her presentation. She was thereafter diagnosed as having a solitary parotid metastasis from breast origin. A total parotidectomy was done and she was referred for adjuvant radiotherapy. Conclusion. Any parotid metastasis should be investigated, especially in patients with a prior history of cancer where the possibility of metastasis, even if improbable, should be kept in mind. Fine needle aspiration biopsy (FNAB) is the first diagnostic procedure to be done and immunocytochemistry can provide valuable information even if it is not always needed for diagnosis. Superficial parotidectomy when feasible with adjuvant radiotherapy is the preferred approach for solitary metastasis of the parotid. The prognosis, however, remains poor regardless of the treatment modality used. PMID- 26942029 TI - Postobstructive Pulmonary Edema following Tonsillectomy/Adenoidectomy in a 2-Year Old with Poland-Moebius Syndrome. AB - A 2-year-old male with Poland-Moebius syndrome was transferred from a local hospital to the Pediatric ICU at Children's Hospital of Georgia for suspected postobstructive pulmonary edema (POPE) after tonsillectomy/adenoidectomy (T&A). The patient's respiratory status ultimately declined and he developed respiratory failure. Imaging suggested pulmonary edema as well as a left-sided pneumonia. Echocardiogram showed pulmonary hypertension and airway exam via direct fiberoptic bronchoscopy revealed tracheomalacia and bronchomalacia. He developed acute respiratory distress syndrome (ARDS) and remained intubated for ten days. This case highlights the association between congenital upper body abnormalities with cranial nerve dysfunction and the development of POPE with delayed resolution of symptoms. Patients with upper body abnormalities as above are at great risk of postoperative complications and should therefore be managed in a tertiary-care facility. PMID- 26942031 TI - Dual-Energy CT for Evaluation of Intra- and Extracapsular Silicone Implant Rupture. AB - Silicone implants are commonly used for both breast augmentation and breast reconstruction. With aging of the implant, the silicone envelope may become weak or may rupture. The technique of choice for evaluation of implant integrity is breast MRI; however this may be contraindicated in some patients or the cost may be prohibitive. Dual-energy CT allows determination of density and atomic number of tissue and can provide material composition information. We present a case of extracapsular implant rupture with MRI and dual-energy CT imaging and surgical correlation. PMID- 26942030 TI - Imaging Manifestations of a Subependymal Giant Cell Astrocytoma in Tuberous Sclerosis. AB - Tuberous sclerosis is a rare genetic disorder resulting in benign tumor growth in various organs including the brain, heart, skin, eyes, kidney, and lung as well as systemic manifestations including seizures, cognitive impairment, and dermatologic abnormalities. This report shows the radiological findings and differentiation between a subependymal nodule and subependymal giant cell astrocytoma in a patient with tuberous sclerosis presenting with new onset seizures. PMID- 26942032 TI - A Giant Mature Cystic Teratoma Mimicking a Pleural Effusion. AB - The vast majority of teratomas originating from more than a single germ layer are benign. Often, such teratomas are initially asymptomatic. Later symptoms are caused by the weight per se of the teratoma and include chest pain, cough, dyspnea, and/or recurrent attacks of pneumonia. A mediastinal teratoma is treated by total surgical resection of the mass. Here, we report a case of giant mature cystic teratoma mimicking a pleural effusion in the thorax at the 7-month-old female patient with a symptom of persistent pulmonary infection and tachypnea. PMID- 26942033 TI - Duplicated Renal System with H Shaped Ureter: An Extraordinary Anomaly. AB - Duplex collecting systems are the most commonly encountered anomaly of the urinary system. Complete duplex system with an H shaped ureter is a very rare situation. There are only two reported H ureter cases in the literature. Herein, we aimed to present an H shaped ureter case, which was identified while performing ureterorenoscopy to a 48-year-old female patient due to a right distal ureteral stone. PMID- 26942034 TI - Consistency between Self-Reported and Recorded Values for Clinical Measures. AB - Objectives. This study evaluated consistency between self-reported values for clinical measures and recorded clinical measures. Methods. Self-reported values were collected for the clinical measures: systolic blood pressure, diastolic blood pressure, glucose level, height, weight, and cholesterol from health risk assessments completed by enrollees in a privately insured cohort. Body mass index (BMI) was computed from reported height and weight. Practitioner recorded values for the clinical measures were obtained from health screenings. We used bivariate Pearson correlation analysis and descriptive statistics to evaluate consistency between self-reported data and recorded clinic measurements. Results. There was high correlation between self-reported clinical values and recorded clinical measures for diastolic blood pressure (r = 0.91, P = <0.0001), systolic blood pressure (r = 0.93, P = <0.0001), cholesterol (r = 0.97, P = <0.0001), body mass index (r = 0.96, P = <0.0001), glucose (r = 0.96, P = <0.0001), weight (r = 0.98, P = <0.0001), and height (r = 0.89, P = <0.0001). Conclusions. Self-reported clinical values for each of the eight clinical measures examined had good consistency with practitioner recorded data. PMID- 26942035 TI - The Use of IL-1 Receptor Antagonist (Anakinra) in Idiopathic Recurrent Pericarditis: A Narrative Review. AB - Recurrent pericarditis is a complication of acute pericarditis in 20-30% of the patients and is usually idiopathic in nature. The underlying pathogenesis of this condition remains unclear, although immune-mediated mechanisms seem likely. A subgroup of these patients with refractory symptoms can be challenging to manage, and multiple immunosuppressive medications have been used without consistent benefit. Anakinra, an interleukin-1 receptor antagonist, has been used in treatment of rheumatoid arthritis and autoinflammatory syndromes. Preliminary evidence suggests that anakinra could be a promising therapy for idiopathic recurrent pericarditis. In this narrative review, we summarize the current understanding of the etiopathogenesis of idiopathic recurrent pericarditis, mechanism of action of anakinra, and the preliminary evidence, supporting the use of anakinra in pericarditis. PMID- 26942036 TI - High Prevalence of Plasmodium falciparum Infection in Asymptomatic Individuals from the Democratic Republic of the Congo. AB - Malaria remains a major public health problem in the Democratic Republic of Congo (DRC) with 14 million cases reported by the WHO Malaria Report in 2014. Asymptomatic malaria cases are known to be prevalent in endemic areas and are generally untreated, resulting in a significant source of gametocytes that may serve as reservoir of disease transmission. Considering that microscopy certainly underestimates the prevalence of Plasmodium infections within asymptomatic carriers and that PCR assays are currently recognized as the most sensitive methods for Plasmodium identification, this study was conducted to weigh the asymptomatic carriage in DRC by a molecular method. Six provinces were randomly selected for blood collection in which 80 to 100 individuals were included in the study. Five hundred and eighty blood samples were collected and molecular diagnosis was performed. Globally, almost half of the samples collected from asymptomatic individuals (280/580; 48.2%) had Plasmodium infections and the most species identified was P. falciparum alone in combination with P. malariae. The high prevalence reported here should interpellate the bodies involved in malaria control in DR Congo to take into account asymptomatic carriers in actions taken and consider asymptomatic malaria as a major hurdle for malaria elimination. PMID- 26942039 TI - International Appraisal of Nursing Culture and Curricula: A Qualitative Study of Erasmus Students. AB - Introduction. Globalization of knowledge has emphasized the need to promote the adoption of international exchange programs in nursing. Nevertheless, the differences in cultural, educational, and structural schemes have challenged the mutual appraisal and understanding of the nursing curricula between countries. Research on nursing curricula should allow performing an analysis of different cultural idiosyncrasies in which educational and health institutions are found. These studies would contribute valuable information to the educative and organizational systems and their cultural variability. Objective. To examine the experiences of nursing students on international exchange programs. Methods. Comparative Education was taken as theoretical background. The clinical practice diaries of seven Spanish Nursing Erasmus students (a European international exchange program) were used as field journals. These students undertook their placements in the United Kingdom. A content analysis was carried out to find major themes. Results. Data extracted from the students clinical practice diaries indicated cultural, educational, and structural differences between countries. Most students reflected the hidden curriculum in their diaries, writing about affective, ideological, personal, and social elements and beliefs. Conclusions. The students' experiences on international exchange programs were found to be sources of interest to clarify the ideological and cultural connections that underlie educational and health systems. PMID- 26942038 TI - Biological Evaluation of Pupalia lappacea for Antidiabetic, Antiadipogenic, and Hypolipidemic Activity Both In Vitro and In Vivo. AB - Objective. The present study assesses the effect of Pupalia lappacea (L.) Juss. (Amaranthaceae) (PL) leaves ethanolic extract on adipocytes, blood glucose level, and lipid level in streptozotocin (STZ) induced diabetic rats. Materials and Methods. Male Albino rats were rendered diabetic by a single moderately sized dose of STZ (45 mg/kg, intraperitoneally) at once before starting the treatment. Animals were divided into five groups: normoglycemic control, diabetic control, reference group (glibenclamide, 5.0 mg/kg), AS001 (250 mg/kg extract), and AS002 (500 mg/kg extract) each containing six animals for in vivo study. Antidiabetic and hypolipidemic activity of extract were determined by in vivo method on STZ induced diabetic rats. Antiadipogenic activity was determined by in vitro method on 3T3-L1 cell line in comparison to simvastatin as reference drug. Result. The extract showed significant fall in fasting serum glucose (FSG), that is, 234.68 and 211.61 mg/dL, in STZ induced diabetic animals for dose groups AS001 and AS002, respectively. The PL extract also exhibited noteworthy antiadipogenic activity on 3T3-L1 cell line. The value of inhibitory concentration (IC50) of PL extract to reduce adipocyte cells was found to be 662.14 MUg/mL. Conclusion. The PL extract exhibited significant antiadipogenic, antidiabetic, and hypolipidemic activities. PMID- 26942037 TI - Genetic Profile, Environmental Exposure, and Their Interaction in Parkinson's Disease. AB - The discovery of causative mutations for Parkinson's disease (PD) as well as their functional characterization in cellular and animal models has provided crucial insight into the pathogenesis of this disorder. Today, we know that PD pathogenesis involves multiple related processes including mitochondrial dysfunction, oxidative and nitrative stress, microglial activation and inflammation, and aggregation of alpha-synuclein and impaired autophagy. However, with the exception of a few families with Mendelian inheritance, the cause of PD in most individuals is yet unknown and the identified genetic susceptibility factors have only small effect size. Epidemiologic studies have found increased risk of PD associated with exposure to environmental toxicants such as pesticides, organic solvents, metals, and air pollutants, while reduced risk of PD associated with smoking cigarettes and coffee consumption. The role of environmental exposure, as well as the contribution of single genetic risk factors, is still controversial. In most of PD cases, disease onset is probably triggered by a complex interplay of many genetic and nongenetic factors, each of which conveys a minor increase in the risk of disease. This review summarizes the current knowledge on causal mutation for PD, susceptibility factors increasing disease risk, and the genetic factors that modify the impact of environmental exposure. PMID- 26942040 TI - Association between Perioperative Blood Transfusions and Clinical Outcomes in Patients Undergoing Bladder Cancer Surgery: A Systematic Review and Meta-Analysis Study. AB - Background. Perioperative blood transfusions are associated with poor survival in patients with solid tumors including bladder cancer. Objective. To investigate the impact of perioperative blood transfusions on oncological outcomes after radical cystectomy. Design. Systematic review and meta-analysis. Setting and Participants. Adult patients who underwent radical cystectomy for bladder cancer. Intervention. Packed red blood cells transfusion during or after radical cystectomy for bladder cancer. Outcome Measurements and Statistical Analysis. Recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS). We calculated the pooled hazard ratio (HR) estimates and 95% confidence intervals by random and fixed effects models. Results and Limitation. Eight, seven, and five studies were included in the OS, CSS, and RFS analysis, respectively. Blood transfusions were associated with 27%, 29%, and 12% reduction in OS, CSS, and RFS, respectively. A sensitivity analysis supported the association. This study has several limitations; however the main problem is that it included only retrospective studies. Conclusions. Perioperative BT may be associated with reduced RFS, CSS, and OS in patients undergoing RC for BC. A randomized controlled study is needed to determine the causality between the administration of blood transfusions and bladder cancer recurrence. PMID- 26942042 TI - Piecewise Mixed Effects Model to Compare the Weight-gain Patter ns Before and After Diagnosis of Asthma in Children Younger than 5 Years. AB - Asthma and obesity are two significant public health problems that both originate in early childhood and have shared risk factors and manifestations. Studies suggest a strong association between asthma development and subsequent accelerated weight gain. Children are diagnosed with asthma in early childhood and are often exposed to factors associated with rapid weight gain. This article intends to demonstrate an innovative application of the piecewise mixed effects model to characterize the difference in the temporal rate of change in BMIz, the standardized scores of body mass index and weight-for-length that measure weight status, before and after asthma diagnosis in children younger than 5 years. The data consist of unique sequences from 1194 children's clinic visits during the first 5 years of life. We used a knot at the time of diagnosis and detected a differential weight-gain pattern before and after asthma diagnosis. The pre- and post-asthma-diagnosis weight-gain patterns further differ by sex and race ethnicity. After asthma diagnosis, female children showed a higher increase in the rate of change in BMIz than males. Non-Hispanic African Americans and Hispanics had higher post-diagnosis rates of change in BMIz than Caucasians. The differential weight-gain patterns between male and female children were mainly contributed by Caucasian children. These findings could have important implications in the clinical care of children after asthma diagnosis. PMID- 26942041 TI - Motion Planning for a Three-Stage Multilumen Transoral Lung Access System. AB - Lung cancer is the leading cause of cancer-related death, and early-stage diagnosis is critical to survival. Biopsy is typically required for a definitive diagnosis, but current low-risk clinical options for lung biopsy cannot access all biopsy sites. We introduce a motion planner for a multilumen transoral lung access system, a new system that has the potential to perform safe biopsies anywhere in the lung, which could enable more effective early-stage diagnosis of lung cancer. The system consists of three stages in which a bronchoscope is deployed transorally to the lung, a concentric tube robot pierces through the bronchial tubes into the lung parenchyma, and a steerable needle deploys through a properly oriented concentric tube and steers through the lung parenchyma to the target site while avoiding anatomical obstacles such as significant blood vessels. A sampling-based motion planner computes actions for each stage of the system and considers the coupling of the stages in an efficient manner. We demonstrate the motion planner's fast performance and ability to compute plans with high clearance from obstacles in simulated anatomical scenarios. PMID- 26942043 TI - Alu elements and DNA double-strand break repair. AB - Alu elements represent one of the most common sources of homology and homeology in the human genome. Homeologous recombination between Alu elements represents a major form of genetic instability leading to deletions and duplications. Although these types of events have been studied extensively through genomic sequencing to assess the impact of Alu elements on disease mutations and genome evolution, the overall abundance of Alu elements in the genome often makes it difficult to assess the relevance of the Alu elements to specific recombination events. We recently reported a powerful new reporter gene system that allows the assessment of various cis and trans factors on the contribution of Alu elements to various forms of genetic instability. This allowed a quantitative measurement of the influence of mismatches on Alu elements and instability. It also confirmed that homeologous Alu elements are able to stimulate non-homologous end joining events in their vicinity. This appears to be dependent on portions of the mismatch repair pathway. We are now in a position to begin to unravel the complex influences of Alu density, mismatch and location with alterations of DNA repair processes in various tissues and tumors. PMID- 26942045 TI - LINE retrotransposition and host DNA repair machinery. AB - Long interspersed elements (LINEs), or non-long-terminal repeat (LTR) retrotransposons, are mobile genetic elements that exist in the genomic DNA of most eukaryotes, comprising a considerable portion of the host chromosomes. LINEs constitute endogenous mutagens that cause insertional mutations in host chromosomes and have a large impact on host genome evolution. Despite their importance, however, the molecular mechanism of LINE retrotransposition is not fully understood. Several studies suggest that host proteins that participate in the repair of DNA breaks modulate LINE retrotransposition. Recently, we provided evidence that there are 2 distinct pathways-annealing and direct-that join the 5' end of LINEs to host chromosomal DNA. These pathways appear to be used distinctively by zebrafish LINEs and the human L1 in DT40 cells. In HeLa cells, only the annealing pathway appears to be used. This implies that different characteristics of the 2 LINEs and also host factors dictate which pathway is selected. Here, we discuss the 5'-end-joining pathways of LINE retrotransposition and propose that the pathways of LINE integration adopt certain host repair factors. PMID- 26942044 TI - Selective repression of SINE transcription by RNA polymerase III. AB - A million copies of the Alu short interspersed nuclear element (SINE) are scattered throughout the human genome, providing ~11% of our total DNA. SINEs spread by retrotransposition, using a transcript generated by RNA polymerase (pol) III from an internal promoter. Levels of these pol III-dependent Alu transcripts are far lower than might be expected from the abundance of the template. This was believed to reflect transcriptional suppression through DNA methylation, denying pol III access to most SINEs through chromatin-mediated effects. Contrary to expectations, our recent study found no evidence that methylation of SINE DNA reduces its occupancy or expression by pol III. However, histone H3 associated with SINEs is prominently methylated on lysine 9, a mark that correlates with transcriptional silencing. The SUV39 methyltransferases that deposit this mark can be found at many SINEs. Furthermore, a selective inhibitor of SUV39 stimulates pol III recruitment to these loci, as well as SINE expression. These data suggest that methylation of histone H3 rather than DNA may mediate repression of SINE transcription by pol III, at least under the conditions we studied. PMID- 26942047 TI - Silencing quorum sensing and ICE mobility through antiactivation and ribosomal frameshifting. AB - Mobile genetic elements run an evolutionary gauntlet to maintain their mobility in the face of selection against their selfish dissemination but, paradoxically, they can accelerate the adaptability of bacteria through the gene-transfer events that they facilitate. These temporally conflicting evolutionary forces have shaped exquisite regulation systems that silence mobility and maximize the competitive fitness of the host bacterium, but maintain the ability of the element to deliver itself to a new host should the opportunity arise. Here we review the excision regulation system of the Mesorhizobium loti symbiosis island ICEMlSymR7A, a 502-kb integrative and conjugative element (ICE) capable of converting non-symbiotic mesorhizobia into plant symbionts. ICEMlSymR7A excision is activated by quorum sensing, however, both quorum sensing and excision are strongly repressed in the vast majority of cells by dual-target antiactivation and programmed ribosomal-frameshifting mechanisms. We examine these recently discovered regulatory features under the light of natural selection and discuss common themes that can be drawn from recent developments in ICE biology. PMID- 26942046 TI - The dualistic nature of integrative and conjugative elements. AB - Integrative and conjugative elements (ICEs) are mobile genetic elements that play a key role in bacterial adaptation. Such elements are found in almost every bacterial genera and species, and often code for adaptive traits conferring selective advantages to their host. ICEs maintain by integrating into and replicating along with a replicon of the host genome. ICEs can propagate by conjugative transfer toward a recipient cell following excision from the replicon as a circular covalently-closed molecule. For a long time, the excised form of ICEs was assumed to be non-replicative. This assumption predicts that excised ICEs are sensitive to loss during cell division, unless they carry stabilization systems such as addiction modules or antibiotic resistance genes. Over the past few years, growing evidence have been presented that support conditional replication of the circular intermediate as an intrinsic feature of ICEs. We recently confirmed this feature in the large family of SXT/R391 ICEs, which thrive in several species of Enterobacteriaceae and Vibrionaceae. Furthermore, we demonstrated that SXT/R391 ICEs encode a functional plasmid-like type II partition system that enhances their stability, such systems being probably encoded by other ICEs. The lifecycle of ICEs is therefore much more complex than initially thought as many ICEs may use plasmid-like features to improve their stability and dissemination. PMID- 26942048 TI - New clues on the regulation of the CRISPR-Cas immune system. AB - Research into the CRISPR-Cas immune system of prokaryotes is progressing at a tremendous pace given both its important biological function and its role as a source of new genetic tools. However, a few areas of the field have remained largely unaddressed. A recent report provides information on one such overlooked area: how the cell regulates the CRISPR-Cas immune system. The processes, despite their importance, have remained illusive. In Pectobacterium atrosepticum regulation is, perhaps surprisingly, based on metabolic factors responding to glucose levels in the cell. Regulators include both activators and repressors of cas gene expression. It remains an open question why and how this regulatory system have evolved, and if it is a typical example of how CRISPR-as systems are regulated or not. PMID- 26942049 TI - Cytokine therapy restores antitumor responses of NK cells rendered anergic in MHC I-deficient tumors. AB - Recent extraordinary advances in cancer immunotherapy rely primarily on marshaling T cell responses. Here we discuss how NK cell responses can be amplified. We find that MHC I-deficient tumors induce anergy of NK cells but that cytokine therapy restores NK cell activity and increases the survival of mice bearing MHC I-deficient tumors. PMID- 26942050 TI - The role of NF-kB in modulating antitumor immunity. AB - Recent breakthroughs in therapeutic modulation of immune cells have led to novel exciting treatments for cancers. Moreover, the cytokine milieu in the tumor microenvironment is important for appropriate immune surveillance. Here, we demonstrate that NF-kappaB activity in myeloid cells is essential for cytokine mediated antitumor polarization of immune cells. PMID- 26942051 TI - Effective combination treatment of GD2-expressing neuroblastoma and Ewing's sarcoma using anti-GD2 ch14.18/CHO antibody with Vgamma9Vdelta2+ gammadeltaT cells. AB - Gamma delta T lymphocytes (gammadeltaT cells) have pleiotropic properties including innate cytotoxicity, which make them attractive effectors for cancer immunotherapy. Combination treatment with zoledronic acid and IL-2 can activate and expand the most common subset of blood gammadeltaT, which express the Vgamma9Vdelta2 T cell receptor (TCR) (Vdelta2 T cells). Vgamma9Vdelta2 T cells are equipped for antibody-dependent cell-mediated cytotoxicity (ADCC) through expression of the low-affinity FcgammaR CD16. GD2 is a highly ranked tumor associated antigen for immunotherapy due to bright expression on the cell surface, absent expression on normal tissues and availability of therapeutic antibodies with known efficacy in neuroblastoma. To explore the hypothesis that zoledronic acid, IL-2 and anti-GD2 antibodies will synergize in a therapeutic combination, we evaluated in vitro cytotoxicity and tumor growth inhibition in the GD2 expressing cancers neuroblastoma and Ewing's sarcoma. Vdelta2 T cells exert ADCC against GD2-expressing Ewing's sarcoma and neuroblastoma cell lines, an effect which correlates with the brightness of GD2 expression. In an immunodeficient mouse model of small established GD2-expressing Ewing's sarcoma or neuroblastoma tumors, the combination of adoptively transferred Vdelta2+ T cells, expanded in vitro with zoledronic acid and IL-2, with anti-GD2 antibody ch14.18/CHO, and with systemic zoledronic acid, significantly suppressed tumor growth compared to antibody or gammadeltaT cell-free controls. Combination treatment using ch14.18/CHO, zoledronic acid and IL-2 is more effective than their use in isolation. The already-established safety profiles of these agents make testing of the combination in GD2 positive cancers such as neuroblastoma or Ewing's sarcoma both rational and feasible. PMID- 26942052 TI - Interleukin-1 is required for cancer eradication mediated by tumor-specific Th1 cells. AB - The role of inflammation in cancer is controversial as both tumor-promoting and tumor-suppressive aspects of inflammation have been reported. In particular, it has been shown that pro-inflammatory cytokines, like interleukin-1alpha (IL 1alpha), IL-1beta, IL-6, and tumor necrosis factor alpha (TNFalpha), may either promote or suppress cancer. However, the cellular and molecular basis underlying these opposing outcomes remains enigmatic. Using mouse models for myeloma and lymphoma, we have recently reported that inflammation driven by tumor-specific T helper 1 (Th1) cells conferred protection against B-cell cancer and that interferon-gamma (IFN-gamma) was essential for this process. Here, we have investigated the contribution of several inflammatory mediators. Myeloma eradication by Th1 cells was not affected by inhibition of TNF-alpha, TNF-related weak inducer of apoptosis (TWEAK), or TNF-related apoptosis-inducing ligand (TRAIL). In contrast, cancer elimination by tumor-specific Th1 cells was severely impaired by the in vivo neutralization of both IL-1alpha and IL-1beta (collectively named IL-1) with IL-1 receptor antagonist (IL-1Ra). The antitumor functions of tumor-specific Th1 cells and tumor-infiltrating macrophages were both affected by IL-1 neutralization. Secretion of the Th1-derived cytokines IL-2 and IFN-gamma at the incipient tumor site was severely reduced by IL-1 blockade. Moreover, IL-1 was shown to synergize with IFN-gamma for induction of tumoricidal activity in tumor-infiltrating macrophages. This synergy between IL-1 and IFN gamma may explain how inflammation, when driven by tumor-specific Th1 cells, represses rather than promotes cancer. Collectively, the data reveal a central role of inflammation, and more specifically of the canonical pro-inflammatory cytokine IL-1, in enhancing Th1-mediated immunity against cancer. PMID- 26942053 TI - T cells targeting NY-ESO-1 demonstrate efficacy against disseminated neuroblastoma. AB - The cancer-testis antigen NY-ESO-1 is expressed by many solid tumors and has limited expression by mature somatic tissues, making it a highly attractive target for tumor immunotherapy. Targeting NY-ESO-1 using engineered T cells has demonstrated clinical efficacy in the treatment of some adult tumors. Neuroblastoma is a significant cause of cancer mortality in children, and is a tumor type shown to be responsive to immunotherapies. We evaluated a large panel of primarily resected neuroblastoma samples and demonstrated that 23% express NY ESO-1. After confirming antigen-specific activity of T cells genetically engineered to express an NY-ESO-1 directed high-affinity transgenic T cell receptor in vitro, we performed xenograft mouse studies assessing the efficacy of NY-ESO-1-targeted T cells in both localized and disseminated models of neuroblastoma. Disease responses were monitored by tumor volume measurement and in vivo bioluminescence. After delivery of NY-ESO-1 transgenic TCR T cells, we observed significant delay of tumor progression in mice bearing localized and disseminated neuroblastoma, as well as enhanced animal survival. These data demonstrate that NY-ESO-1 is an antigen target in neuroblastoma and that targeted T cells represent a potential therapeutic option for patients with neuroblastoma. PMID- 26942054 TI - (Compl)Ex-Th17-Treg cell inter-relationship. AB - Codependent development and Th17-to-FoxP3+ T cell inter-conversion account for the enigmatic coexistence of IL17-producing and FoxP3+ cells in tumor-associated inflammation. In addition to Treg cells, exTh17-FoxP3+ cells present a novel subpopulation of FoxP3+ cells. Yin-yang of IL17+ and FoxP3+ cells presents an important principle for improved approaches in cancer immunotherapy. PMID- 26942055 TI - Role of natural killer cell subsets and natural cytotoxicity receptors for the outcome of immunotherapy in acute myeloid leukemia. AB - In a phase IV trial, 84 patients (age 18-79) with acute myeloid leukemia (AML) in first complete remission (CR) received cycles of immunotherapy with histamine dihydrochloride (HDC) and low-dose human recombinant interleukin 2 (IL-2) for 18 months to prevent leukemic relapse. During cycles, the treatment resulted in expansion of CD56(bright) (CD3(-)/16(-)/56(bright)) and CD16(+) (CD3( )/16(+)/56(+)) natural killer (NK) cells in the blood along with increased NK cell expression of the natural cytotoxicity receptors (NCRs) NKp30 and NKp46. Multivariate analyses correcting for age and risk group demonstrated that high CD56(bright) NK cell counts and high expression of NKp30 or NKp46 on CD16(+) NK cells independently predicted leukemia-free survival (LFS) and overall survival (OS). Our results suggest that the dynamics of NK cell subsets and their NCR expression may determine the efficiency of relapse-preventive immunotherapy in AML. PMID- 26942056 TI - Failure recovery of circulating NKG2D+CD56dimNK cells in HBV-associated hepatocellular carcinoma after hepatectomy predicts early recurrence. AB - Dysfunction of natural killer (NK) cells has been implicated in the failure of antitumor immune responses in hepatocellular carcinoma (HCC) patients. However, the changes of NK profile in peripheral blood after surgery and tumor tissues of HCC patients, as well as the underlying reason and the significance are vague. Here, we observed that the frequencies of circulating NKG2D+CD56dimNK cells decreased significantly in HBV-related HCC and were negatively correlated with the levels of serum TGF-beta and soluble MICA (sMICA). In vitro experiments confirmed that the TGF-beta and sMICA in tumor tissue homogenates, as well as sMICA in HCC cells culture supernatants could reduce the frequency of NKG2D+CD56dimNK cells. In addition, in HCC patients the lower frequency of circulating NKG2D+CD56dimNK cells was associated with larger tumor size and/or higher serum GGT. Noticeably, the frequency of NKG2D+CD56dimNK cells at one month after surgery usually failed to restore in early recurrent patients, and that frequency was negatively associated with early recurrence and shorter overall survival. These results suggest that declined frequency of NKG2D+CD56dimNK cells in HCC was associated with higher TGF-beta and sMICA production, and low frequency of circulating NKG2D+CD56dimNK cells at one month after surgery may predict poor prognosis of HBV-related HCC patients accepting hepatectomy. PMID- 26942057 TI - Cryoablation and Meriva have strong therapeutic effect on triple-negative breast cancer. AB - Interleukin-6, a cytokine produced particularly by triple-negative breast cancers, strongly inhibits T cell responses in the tumor microenvironment. Here we tested cryoablation combined with Meriva (a lecithin delivery system of curcumin with improved bioavailability) in mice with metastatic breast cancer (4T1). Cryoablation involves killing of tumor cells through freezing and thawing, resulting in recruitment of tumor-specific T cells, while curcumin stimulates T cells through the reduction of IL-6 in the TME. Cryoablation plus Meriva accumulated and activated CD8+ T cells to multiple tumor-associated antigens such as Mage-b and Survivin (both expressed by 4T1 tumors). This correlated with a nearly complete reduction of 4T1 primary tumors and lung metastases while little effect was observed from saline or Meriva alone (28 d after tumor cell injection). The survival rate in the group of cryoablation plus Meriva was significantly improved compared to all control groups. Using a less aggressive 4T1 model expressing luciferase (4T1.2luc3), we demonstrated that all mice receiving saline or Meriva developed metastases in the lungs and a primary tumor (38 d after tumor cell injection; and died soon after that), but not the mice receiving cryoablation or cryoablation plus Meriva. However, on day 58 the mice receiving cryoablation developed 4T1.2luc3 metastases in the lungs, while mice receiving cryoablation plus Meriva were free of metastases. These results strongly suggest that cryoablation delayed the development of lung metastases on the short-term, but Meriva administered after cryoablation was significantly better in delaying the development of lung metastases and survival on the long term. PMID- 26942059 TI - B7-H4 is a positive regulator of antitumor immunity. AB - B7-H4 (B7x, B7S1, VTCN1, DD-0110) is a member of the B7 superfamily that negatively regulates T cell responses.1 In addition, B7-H4 expression is increased on tumors and has been shown to be a negative prognostic marker for many cancers.2 Unexpectedly our recent study demonstrated that B7-H4 inhibited tumor growth and was required to promote effective antitumor responses.3. PMID- 26942058 TI - T cell receptor mimic antibodies for cancer therapy. AB - The major hurdle to the creation of cancer-specific monoclonal antibodies (mAb) exhibiting limited cross-reactivity with healthy human cells is the paucity of known tumor-specific or mutated protein epitopes expressed on the cancer cell surface. Mutated and overexpressed oncoproteins are typically cytoplasmic or nuclear. Cells can present peptides from these distinguishing proteins on their cell surface in the context of human leukocyte antigen (HLA). T cell receptor mimic (TCRm) mAb can be discovered that react specifically to these complexes, allowing for selective targeting of cancer cells. The state-of-the-art for TCRm and the challenges and opportunities are discussed. Several such TCRm are moving toward clinical trials now. PMID- 26942061 TI - Activation of cytomegalovirus-specific CD8+ T-cell response by antibody-mediated peptide-major histocompatibility class I complexes. AB - Imposing antigenicity on tumor cells is a key step toward successful cancer immunotherapy. A cytomegalovirus-derived peptide recombinantly fused to a major histocompatibility class I complex and a monoclonal antibody can be targeted to tumor cells by antibody-mediated delivery and activate a strong and specific CD8+ T cell response. PMID- 26942060 TI - Non-classical HLA-class I expression in serous ovarian carcinoma: Correlation with the HLA-genotype, tumor infiltrating immune cells and prognosis. AB - In our previous studies, we have shown that patients with serous ovarian carcinoma in advanced surgical stage disease have a particularly poor prognosis if they carry the HLA-A*02 genotype. This represent a stronger prognostic factor than loss or downregulation of the MHC class I heavy chain (HC) on tumor cells. In this study, we investigated the expression of the non-classical, immune tolerogenic HLA -G and -E on the tumor cells along with the infiltration of immune cells in the tumor microenvironment. FFPE primary tumors from 72 patients with advanced stages of serous adenocarcinoma and metastatic cells present in ascites fluid from 8 additional patients were included in this study. Both expression of HLA-G and aberrant expression of HLA-E were correlated to a significant worse prognosis in patients with HLA-A*02, but not with different HLA genotypes. Focal cell expression of HLA-G correlated to a site-specific downregulation of classical MHC class I HC products and aberrant HLA-E expression, showing a poor survival. HLA-G was more frequently expressed in metastatic cells than in primary tumor lesions and the expression of HLA-G inversely correlated with the frequency of tumor infiltrating immune cells. All these parameters can contribute together to identify and discriminate subpopulations of patients with extremely poor prognosis and can give them the opportunity to receive, and benefit of individually tailored treatments. PMID- 26942062 TI - Human ectonucleotidase-expressing CD25high Th17 cells accumulate in breast cancer tumors and exert immunosuppressive functions. AB - Th17 cells contribute to the development of some autoimmune and allergic diseases by driving tissue inflammation. However, the function of Th17 cells during cancer progression remains controversial. Here, we show that human memory CD25high Th17 cells suppress T cell immunity in breast cancer. Ectonucleotidase-expressing Th17 cells accumulated in breast cancer tumors and suppressed CD4+ and CD8+ T cell activation. These cells expressed both Rorgammat and Foxp3 genes and secreted Th17 related cytokines. We further found that CD39 ectonucleotisase expression on tumor-infiltrating Th17 cells was driven by TGF-betaand IL-6. Finally, immunohistochemical analysis of localized breast cancer revealed that high-tumor infiltration by IL-17+ cells was associated with a poor clinical outcome and impeded the favorable effect of high CD8+ infiltration. Altogether, these findings suggest that intratumoral Th17 cells compromise anticancer immune responses in breast cancer patients. PMID- 26942064 TI - Reviving virus based cancer vaccines by using cytomegalovirus vectors expressing modified tumor antigens. AB - Cancer vaccines that have utilized various immunization strategies to induce antitumor immunity have largely failed in clinical settings. We have recently developed a cancer vaccine using a cytomegalovirus (CMV) based vector that expressed a modified melanoma antigen that elicited a robust antitumor CD8+ T cell response and tumor rejection. PMID- 26942063 TI - Hypoxia induces macrophage polarization and re-education toward an M2 phenotype in U87 and U251 glioblastoma models. AB - Hypoxia is a common feature of solid tumors, particularly in glioblastoma (GBM), and known to be a poor prognosis factor in GBM patients. The growth of GBM is also associated with a marked inflammation partially characterized by an accumulation of macrophage (MPhi) of the M2 phenotype. However, the transition between M1 MPhi (antitumoral) and M2 MPhi (protumoral) phenotypes is a dynamic process. We made the assumption that oxygen (O2) availability could be a major regulator of this transition and that the intratumoral O2 gradient is of importance. We evaluated, in vivo, the impact of hypoxia on MPhi tropism and polarization in two models of human GBM, well differentiated by their degree of hypoxia. MPhi migration in the tumor was more pronounced in the more hypoxic tumor of the two GBM models. In the more hypoxic of the models, we have shown that MPhi migrated at the tumor site only when hypoxia takes place. We also demonstrated that the acquisition of the M2 phenotype was clearly an evolving phenomenon with hypoxia as the major trigger for this transition. In support of these in vivo finding, M0 but also M1 MPhi cultured in moderate or severe hypoxia displayed a phenotype close to that of M2 MPhi whose phenotype was further reinforced by severe hypoxia. These results highlight the role of hypoxia in the aggressiveness of GBM, in part, by transforming MPhi such that a protumoral activity is expressed. PMID- 26942065 TI - Ibrutinib enhances IL-17 response by modulating the function of bone marrow derived dendritic cells. AB - Ibrutinib (PCI-32765) is an irreversible dual Btk/Itk inhibitor shown to be effective in treating several B cell malignancies. However, limited studies have been conducted to study the effect of this drug on myeloid cell function. Hence, we studied the effect of ibrutinib treatment on TLR-4 mediated activation of bone marrow derived dendritic cell culture (DCs). Upon ibrutinib treatment, LPS treated DCs displayed lower synthesis of TNF-alpha and nitric oxide (NO) and higher induction of IL-6, TGF-beta, IL-10 and IL-18. While ibrutinib dampened MHC II and CD86 expression on DCs, CD80 expression was upregulated. Further, ibrutinib-treated DCs promoted T cell proliferation and enhanced IL-17 production upon co-culture with nylon wool enriched T cells. Taken together, our results indicate that ibrutinib modulates TLR-4 mediated DC activation to promote an IL 17 response. We describe a novel mode of action for ibrutinib on DCs which should be explored to treat other forms of cancer besides B cell malignancies. PMID- 26942066 TI - Mucin 1-specific B cell immune responses and their impact on overall survival in breast cancer patients. AB - Considering the diverse functions of B cells, responses to tumor-associated antigens (TAA) have been thought to be the main source of B cell-mediated antitumor immunity. Polymorphic epithelial mucin (MUC1) is considered one of the most specific TAA in patients with breast cancer. The present study aims to dissect the level and subclasses of naturally occurring anti-MUC1 antibodies in regard to tumor biologic parameters, clinical characteristics and overall survival. In 288 primary, non-metastatic breast cancer patients, pretreatment serum levels of anti-MUC1 immunoglobulin G (IgG) and its subclasses G1-4 as well as immunoglobulin M (IgM) were analyzed via ELISA. With respect to overall survival (Kaplan-Meier analysis), tumor biologic parameters as hormone receptor status, human epidermal growth factor receptor 2 (Her2), Ki-67 expression and tumor grading have been correlated as well as clinical characteristics as nodal involvement, tumor stage and patients' age at the time of diagnosis. Median follow-up time was 148 mo (IQR: 73.1-158.5 mo). A significant increase in IgG antibody titers was correlated highly significantly with an improved overall survival of patients. In multivariate analysis, total IgG proved to be an independent prognostic marker for overall survival (p = 0.002). IgG subclass analysis did not reveal any correlation of IgG1, IgG3 and IgG4 levels with overall survival, while increased immunoglobulin G2 (IgG2) values, although statistically not significant, tended to correlate with prolonged patient survival. MUC1-specific IgM antibodies were shown not to be predictive of overall survival. Altogether, humoral immune responses appear to play a crucial part in the tumor immunity of breast cancer patients. The present data confirms the positive impact of tumor-specific IgG on prolonged overall survival in breast cancer patients. MUC1-antibody testing might be a useful tool to identify high risk patients who may need adjuvant therapy and potentially might benefit from MUC1-directed immunotherapy. PMID- 26942067 TI - Density of tumor-infiltrating lymphocytes correlates with extent of brain edema and overall survival time in patients with brain metastases. AB - The immune microenvironment of the brain differs from that of other organs and the role of tumor-infiltrating lymphocytes (TILs) in brain metastases (BM), one of the most common and devastating complication of cancer, is unclear. We investigated TIL subsets and their prognostic impact in 116 BM specimens using immunohistochemistry for CD3, CD8, CD45RO, FOXP3, PD1 and PD-L1. The Immunoscore was calculated as published previously. Overall, we found TIL infiltration in 115/116 (99.1%) BM specimens. PD-L1 expression was evident in 19/67 (28.4%) BM specimens and showed no correlation with TIL density (p > 0.05). TIL density was not associated with corticosteroid administration (p > 0.05). A significant difference in infiltration density according to TIL subtype was present (p < 0.001; Chi Square); high infiltration was most frequently observed for CD3+ TILs (95/116; 81.9%) and least frequently for PD1+ TILs (18/116; 15.5%; p < 0.001). Highest TIL density was observed in melanoma, followed by renal cell cancer and lung cancer BM (p < 0.001). The density of CD8+ TILs correlated positively with the extent of peritumoral edema seen on pre-operative magnetic resonance imaging (p = 0.031). The density of CD3+ (15 vs. 6 mo; p = 0.015), CD8+ (15 vs. 11 mo; p = 0.030) and CD45RO+ TILs (18 vs. 8 mo; p = 0.006) showed a positive correlation with favorable median OS times. Immunoscore showed significant correlation with survival prognosis (27 vs. 10 mo; p < 0.001). The prognostic impact of Immunoscore was independent from established prognostic parameters at multivariable analysis (HR 0.612, p < 0.001). In conclusion, our data indicate that dense TILs infiltrates are common in BM and correlate with the amount of peritumoral brain edema and survival prognosis, thus identifying the immune system as potential biomarker for cancer patients with CNS affection. Further studies are needed to substantiate our findings. PMID- 26942068 TI - Favorable overall survival in stage III melanoma patients after adjuvant dendritic cell vaccination. AB - Melanoma patients with regional metastatic disease are at high risk for recurrence and metastatic disease, despite radical lymph node dissection (RLND). We investigated the immunologic response and clinical outcome to adjuvant dendritic cell (DC) vaccination in melanoma patients with regional metastatic disease who underwent RLND with curative intent. In this retrospective study, 78 melanoma patients with regional lymph node metastasis who underwent RLND received autologous DCs loaded with gp100 and tyrosinase and were analyzed for functional tumor-specific T cell responses in skin-test infiltrating lymphocytes. The study shows that adjuvant DC vaccination in melanoma patients with regional lymph node metastasis is safe and induced functional tumor-specific T cell responses in 71% of the patients. The presence of functional tumor-specific T cells was correlated with a better 2-year overall survival (OS) rate. OS was significantly higher after adjuvant DC vaccination compared to 209 matched controls who underwent RLND without adjuvant DC vaccination, 63.6 mo vs. 31.0 mo (p = 0.018; hazard ratio 0.59; 95%CI 0.42-0.84). Five-year survival rate increased from 38% to 53% (p < 0.01). In summary, in melanoma patients with regional metastatic disease, who are at high risk for recurrence and metastatic disease after RLND, adjuvant DC vaccination is well tolerated. It induced functional tumor-specific immune responses in the majority of patients and these were related to clinical outcome. OS was significantly higher compared to matched controls. A randomized clinical trial is needed to prospectively validate the efficacy of DC vaccination in the adjuvant setting. PMID- 26942069 TI - All that glitters is not gold: the need to consider desirable and undesirable immune aspects of oncolytic virus therapy. AB - Oncolytic viruses (OVs), a novel class of anticancer therapeutic agents, can overturn cancer-mediated immunosuppression and initiate antitumor immunity. Contrary to this paradigm, our recent study illustrates that oncolytic reovirus transiently augments cancer-associated immunosuppression immediately following its therapeutic administration. To achieve the optimum efficacy for OV-based anticancer therapies, the pathophysiological as well as clinical implications of this phenomenon need to be considered. PMID- 26942071 TI - Radiotherapy supports tumor-specific immunity by acute inflammation. AB - Local immune stimulation is an integral part of radiotherapy. Production of anaphylatoxins is a crucial initial event in radiotherapy-induced immunity and clinical efficacy. We propose applying radiotherapy in few fractions and include radiation holidays to achieve acute rather than chronic inflammatory responses, which promote protective immunity and therapeutic efficacy. PMID- 26942072 TI - Hyperthermic intra-peritoneal chemotherapy and anticancer immune response. AB - Peritoneal carcinomatosis (PC) is a metastatic disease of primary tumors localized in the abdomen. Although this disease is considered a terminal condition, recent treatments combining surgery with heated intra-peritoneal chemotherapy (HIPEC) significantly increase patient survival. We have determined that the protective effect of HIPEC is partially linked to the induction of an efficient anticancer immune response. PMID- 26942070 TI - Enhancing natural killer cell-mediated lysis of lymphoma cells by combining therapeutic antibodies with CD20-specific immunoligands engaging NKG2D or NKp30. AB - Antibody-dependent cell-mediated cytotoxicity (ADCC) mediated through the IgG Fc receptor FcgammaRIIIa represents a major effector function of many therapeutic antibodies. In an attempt to further enhance natural killer (NK) cell-mediated ADCC, we combined therapeutic antibodies against CD20 and CD38 with recombinant immunoligands against the stimulatory NK cell receptors NKG2D or NKp30. These immunoligands, respectively designated as ULBP2:7D8 and B7-H6:7D8, contained the CD20 scFv 7D8 as a targeting moiety and a cognate ligand for either NKG2D or NKp30 (i.e. ULBP2 and B7-H6, respectively). Both the immunoligands synergistically augmented ADCC in combination with the CD20 antibody rituximab and the CD38 antibody daratumumab. Combinations with ULBP2:7D8 resulted in higher cytotoxicity compared to combinations with B7-H6:7D8, suggesting that coligation of FcgammaRIIIa with NKG2D triggered NK cells more efficiently than with NKp30. Addition of B7-H6:7D8 to ULBP2:7D8 and rituximab in a triple combination did not further increase the extent of tumor cell lysis. Importantly, immunoligand mediated enhancement of ADCC was also observed for tumor cells and autologous NK cells from patients with hematologic malignancies, in which, again, ULBP2:7D8 was particularly active. In summary, co-targeting of NKG2D was more effective in promoting rituximab or daratumumab-mediated ADCC by NK cells than co-ligation of NKp30. The observed increase in the ADCC activity of these therapeutic antibodies suggests promise for a 'dual-dual-targeting' approach in which tumor cell surface antigens are targeted in concert with two distinct activating NK cell receptors (i.e. FcgammaRIIIa and NKG2D or B7-H6). PMID- 26942073 TI - CD11b+Ly6G+ cells inhibit tumor growth by suppressing IL-17 production at early stages of tumorigenesis. AB - Neutrophils are important innate immune cells involved in microbial clearance at the sites of infection. However, their role in cancer development is unclear. We hypothesized that neutrophils mediate antitumor effects in early tumorigenesis. To test this, we first studied the cytotoxic effects of neutrophils in vitro. Neutrophils were cytotoxic against tumor cells, with neutrophils isolated from tumor-bearing mice trending to have increased cytotoxic activities. We then injected an ELR+ CXC chemokine-producing tumor cell line into C57BL/6 and Cxcr2-/ mice, the latter lacking the receptors for neutrophil chemokines. We observed increased tumor growth in Cxcr2-/- mice. As expected, tumors from Cxcr2-/- mice contained fewer neutrophils. Surprisingly, these tumors also contained fewer CD8+ T cells, but more IL-17-producing cells. Replenishment of functional neutrophils was correlated with decreased IL-17-producing cells, increased CD8+ T cells, and decreased tumor size in Cxcr2-/- mice, while depletion of neutrophils in C57BL/6 mice showed the opposite effects. Results from a non-ELR+ CXC chemokine producing tumor further supported that functional neutrophils indirectly mediate tumor control by suppressing IL-17A production. We further studied the correlation of IL-17A and CD8+ T cells in vitro. IL-17A suppressed proliferation and IFNgamma production of CD8+ T cells, while CD11b+Ly6G+ neutrophils did not suppress CD8+ T cell function. Taken together, these data demonstrate that, while neutrophils could control tumor growth by direct cytotoxic effects, the primary mechanism by which neutrophils exert antitumor effects is to regulate IL-17 production, through which they indirectly promote CD8+ T cell responses. PMID- 26942074 TI - Biological network-driven gene selection identifies a stromal immune module as a key determinant of triple-negative breast carcinoma prognosis. AB - Triple-negative breast cancer (TNBC) is a heterogeneous group of aggressive breast cancers for which no targeted treatment is available. Robust tools for TNBC classification are required, to improve the prediction of prognosis and to develop novel therapeutic interventions. We analyzed 3,247 primary human breast cancer samples from 21 publicly available datasets, using a five-step method: (1) selection of TNBC samples by bimodal filtering on ER-HER2 and PR, (2) normalization of the selected TNBC samples, (3) selection of the most variant genes, (4) identification of gene clusters and biological gene selection within gene clusters on the basis of String(c) database connections and gene-expression correlations, (5) summarization of each gene cluster in a metagene. We then assessed the ability of these metagenes to predict prognosis, on an external public dataset (METABRIC). Our analysis of gene expression (GE) in 557 TNBCs from 21 public datasets identified a six-metagene signature (167 genes) in which the metagenes were enriched in different gene ontologies. The gene clusters were named as follows: Immunity1, Immunity2, Proliferation/DNA damage, AR-like, Matrix/Invasion1 and Matrix2 clusters respectively. This signature was particularly robust for the identification of TNBC subtypes across many datasets (n = 1,125 samples), despite technology differences (Affymetrix(c) A, Plus2 and Illumina(c)). Weak Immunity two metagene expression was associated with a poor prognosis (disease-specific survival; HR = 2.68 [1.59-4.52], p = 0.0002). The six metagene signature (167 genes) was validated over 1,125 TNBC samples. The Immunity two metagene had strong prognostic value. These findings open up interesting possibilities for the development of new therapeutic interventions. PMID- 26942075 TI - Cancer cell associated glycans as targets for immunotherapy. AB - Therapeutic anti-glycan antibodies for cancer treatment are limited, in spite of the differential glycophenotype of cancer cells and associated biology. We have generated anti-Le glycan antibodies with clinical potential and multifaceted functionality. Increased understanding of all aspects of glycomic research will ensure the continued development of glycan-targeted immunotherapeutics. PMID- 26942076 TI - Identification of glypican-3-derived long peptides activating both CD8+ and CD4+ T cells; prolonged overall survival in cancer patients with Th cell response. AB - In a recent phase I clinical trial, a vaccine consisting of glypican-3 (GPC3) derived CTL epitopes was found to be safe and induced measurable immune and clinical responses in patients with hepatocellular carcinoma (HCC). The aim of this study was to identify GPC3-derived long peptides (GPC3-LPs) carrying promiscuous HLA class II-restricted T helper (Th) cell epitopes. Using a computer algorithm, we predicted GPC3-LPs that can bind to promiscuous HLA class II molecules. Their antigenicity for induction of specific CD4+ T cells in healthy donors or patients with HCC, before and after vaccination with GPC3-SPs, was proven by IFNgamma enzyme-linked immunospot assays. Natural processing of these epitopes was confirmed by the immune response of helper T cells to dendritic cells (DCs) loaded with GPC3 proteins. Cross-presentation capacity was assessed in vitro using human DCs and LPs encapsulated in liposomes and in vivo in HLA-A2 transgenic mice (Tgm). All five LPs could induce Th1 cells and were presented by several frequently occurring HLA class II molecules in vitro. Four of them were likely to be naturally processed. One of the LPs encapsulated in liposomes was well cross-presented in vitro; it cross-primed CTLs in HLA-A2 Tgm. LP-specific and HLA class II-restricted CD4+ T-cell responses were observed in 14 of 20 HCC patients vaccinated with GPC3-SPs. Repeated vaccinations enhanced GPC3-LP specific responses in 8 of 13 patients with HCC. Moreover, the presence of the specific Th cell was correlated with prolonged overall survival (OS). GPC3-LPs can be useful for cancer immunotherapy. PMID- 26942077 TI - The IL-33/ST2 pathway contributes to intestinal tumorigenesis in humans and mice. AB - Colorectal cancer (CRC) develops through a multistep process and is modulated by inflammation. However, the inflammatory pathways that support intestinal tumors at different stages remain incompletely understood. Interleukin (IL)-33 signaling plays a role in intestinal inflammation, yet its contribution to the pathogenesis of CRC is unknown. Using immunohistochemistry on 713 resected human CRC specimens, we show here that IL-33 and its receptor ST2 are expressed in low grade and early-stage human CRCs, and to a lesser extent in higher-grade and more advanced-stage tumors. In a mouse model of CRC, ST2-deficiency protects from tumor development. Moreover, bone marrow (BM) chimera studies indicate that engagement of the IL-33/ST2 pathway on both the radio-resistant and radio sensitive compartment is essential for CRC development. Mechanistically, activation of IL-33/ST2 signaling compromises the integrity of the intestinal barrier and triggers the production of pro-tumorigenic IL-6 by immune cells. Together, this data reveals a tumor-promoting role of IL-33/ST2 signaling in CRC. PMID- 26942078 TI - Hypoxia-induced soluble CD137 in malignant cells blocks CD137L-costimulation as an immune escape mechanism. AB - Hypoxia is a common feature in solid tumors that has been implicated in immune evasion. Previous studies from our group have shown that hypoxia upregulates the co-stimulatory receptor CD137 on activated T lymphocytes and on vascular endothelial cells. In this study, we show that exposure of mouse and human tumor cell lines to hypoxic conditions (1% O2) promotes CD137 transcription. However, the resulting mRNA is predominantly an alternatively spliced form that encodes for a soluble variant, lacking the transmembrane domain. Accordingly, soluble CD137 (sCD137) is detectable by ELISA in the supernatant of hypoxia-exposed cell lines and in the serum of tumor-bearing mice. sCD137, as secreted by tumor cells, is able to bind to CD137-Ligand (CD137L). Our studies on primed T lymphocytes in co-culture with stable transfectants for CD137L demonstrate that tumor-secreted sCD137 prevents co-stimulation of T lymphocytes. Such an effect results from preventing the interaction of CD137L with the transmembrane forms of CD137 expressed on T lymphocytes undergoing activation. Indeed, silencing CD137 with shRNA renders more immunogenic tumor-cell variants upon inoculation to immunocompetent mice but which readily grafted on immunodeficient or CD8+ T-cell depleted mice. These mechanisms are interpreted as a molecular strategy deployed by tumors to repress lymphocyte co-stimulation via CD137/CD137L. PMID- 26942079 TI - Interleukin 33 in tumor microenvironment is crucial for the accumulation and function of myeloid-derived suppressor cells. AB - Tumor-induced, myeloid-derived suppressor cells (MDSCs)-mediated immune dysfunction is an important mechanism that leads to tumor immune escape and the inefficacy of cancer immunotherapy. Importantly, tumor-infiltrating MDSCs have much stronger ability compared to MDSCs in the periphery. However, the mechanisms that tumor microenvironment induces the accumulation and function of MDSCs are poorly understood. Here, we report that Interleukin-33 (IL-33) - a cytokine which can be abundantly released in tumor tissues both in 4T1-bearing mice and breast cancer patients, is crucial for facilitating the expansion of MDSCs. IL-33 in tumor microenvironment reduces the apoptosis and sustains the survival of MDSCs through induction of autocrine secretion of GM-CSF, which forms a positive amplifying loop for MDSC accumulation. This is in conjunction with IL-33-driven induction of arginase-1 expression and activation of NF-kappaB and MAPK signaling in MDSCs which augments their immunosuppressive ability, and histone modifications were involved in IL-33 signaling in MDSCs. In ST2-/- mice, the defect of IL-33 signaling in MDSCs attenuates the immunosuppressive and pro tumoral capacity of MDSCs. Our results identify IL-33 as a critical mediator that contributes to the abnormal expansion and enhanced immunosuppressive function of MDSCs within tumor microenvironment, which can be potentially targeted to reverse MDSC-mediated tumor immune evasion. PMID- 26942080 TI - PD-L1 expression in metastatic neuroblastoma as an additional mechanism for limiting immune surveillance. AB - The prognosis of high-risk neuroblastoma (NB) remains poor, although immunotherapies with anti-GD2 antibodies have been reported to provide some benefit. Immunotherapies can be associated with an IFNgamma storm that induces in tumor cells the "adaptive immune resistance" characterized by the de-novo expression of Programmed Death Ligands (PD-Ls). Tumor cells can also constitutively express PD-Ls in response to oncogenic signaling. Here, we analyze the constitutive and the inducible surface expression of PD-Ls in NB cells. We show that virtually all HLA class Ipos NB cell lines constitutively express PD L1, whereas PD-L2 is rarely detected. IFNgamma upregulates or induces PD-L1 both in NB cell lines in vitro and in NB engrafted nude/nude mice. Importantly, after IFNgamma stimulation PD-L1 can be acquired by NB cell lines, as well as by metastatic neuroblasts isolated from bone marrow aspirates of high-risk NB patients, characterized by different MYCN amplification status. Interestingly, in one patient NB cells were poorly responsive to IFNgamma stimulation, pointing out that responsiveness to IFNgamma might represent a further element of heterogeneity in metastatic neuroblasts. Finally, we document the presence of lymphocytes expressing the PD-1 receptor in NB-infiltrated bone marrow of patients. PD-1pos cells are mainly represented by alphabeta T cells, but also include small populations of gammadelta T cells and NK cells. Moreover, PD-1pos T cells have a higher expression of activation markers. Overall, our data show that a PD-L1-mediated immune resistance mechanism occurs in metastatic neuroblasts and provide a biological rationale for blocking the PD-1/PD-Ls axis in future combined immunotherapeutic approaches. PMID- 26942081 TI - The thyroid hormone triiodothyronine reinvigorates dendritic cells and potentiates anti-tumor immunity. AB - Dendritic cell (DC) cancer vaccines have shown limited clinical benefit. Thus, the identification of signals and molecular pathways that potentiate the immunogenicity of DCs has become a major challenge in cancer research. Our studies demonstrate that triiodothyronine endows DCs with enhanced ability to stimulate cytotoxic T-cell responses with implications in DC-based immunotherapy. PMID- 26942082 TI - SA-4-1BBL/MPL as a novel immune adjuvant platform to combat cancer. AB - Practical experience with cancer vaccines combined with accumulated knowledge of the complex interactions between cancer and immune system rationalize the combinatorial use of immune adjuvants for better efficacy. We recently described a novel adjuvant system based on the costimulatory SA-4-1BBL and TLR4 agonist MPL that has desired therapeutic and safety profiles. PMID- 26942083 TI - Interferon gamma modulates sensitivity of CML cells to tyrosine kinase inhibitors. AB - Immune effector cells such as T and NK cells can efficiently eliminate tumor cells. However, when activating oncogenic signaling pathways or protective mechanisms against cell death are active, immune cells can also confer therapy resistance. Here, we analyzed the role of activated T and NK cells and released cytokines on tyrosine kinase inhibitors imatinib and nilotinib - mediated apoptosis induction and proliferation of chronic myelogenous leukemia (CML) cells. Incubation of CML cells with activated, but not with resting CD3+ T cells or with activated NK cells significantly inhibited TKI-induced apoptosis induction in CML cells as quantified by nuclear fragmentation assays. Transwell experiments revealed a critical role for T or NK cell-derived cytokines for CML cell protection. Accordingly, CML cells treated with IFNgamma also showed a clearly reduced sensitivity to TKI-mediated cell death induction and inhibition of proliferation. In contrast, IFNalpha or other pro-inflammatory mediators and cytokines, such as TNFalpha and GM-CSF did not impair TKI-induced apoptosis in CML cells. On a molecular level, IFNgamma-exposed CML cells showed a significantly reduced caspase-3 activation and PARP-1 cleavage as well as an increased expression of anti-apoptotic molecule xIAP. Finally, IFNgamma diminished TKI-induced downregulation of Jak-2 and STAT-5 phosphorylation and increased nuclear expression of RUNX-1, which may at least in part contribute to the reduced sensitivity to TKI effects. Our results demonstrate that IFNgamma released by activated T or NK cells may interfere with the therapeutic effects of TKI in CML. Our findings may have important implications for the understanding of inflammation-mediated BCR-ABL independent resistance mechanisms. PMID- 26942085 TI - Oncolytic immunotherapy: The new clinical outbreak. PMID- 26942084 TI - Enhancing tumor-targeting monoclonal antibodies therapy by PARP inhibitors. AB - Monoclonal antibodies (mAbs) have become a successful therapeutic approach in cancer. However, some patients do not achieve long-term clinical benefit and most mAbs only exert modest effects as monotherapies. Therefore, combinations with chemotherapy are currently being investigated. Emerging studies have shown a synergistic therapeutic effect of PARP inhibitors and mAbs in cancer. PARP enzymes catalytically cleave beta-NAD+ and transfer the ADP-ribose moiety to acceptor proteins, modifying their function. In here, we update recent data about the therapeutic effect of the combination of PARP inhibitors with mAbs in cancer treatment and discuss the molecular mechanisms involved in this synergy. PMID- 26942086 TI - Angiotensin converting enzyme inhibitors and angiotensin II receptor antagonist attenuate tumor growth via polarization of neutrophils toward an antitumor phenotype. AB - Tumor microenvironments polarize neutrophils to protumoral phenotypes. Here, we demonstrate that the angiotensin converting enzyme inhibitors (ACEis) and angiotensin II type 1 receptor (AGTR1) antagonist attenuate tumor growth via polarization of neutrophils toward an antitumoral phenotype. The ACEis or AGTR1 antagonist enhanced hypersegmentation of human neutrophils and increased neutrophil cytotoxicity against tumor cells. This neutrophil hypersegmentation was dependent on the mTOR pathway. In a murine tumor model, ACEis and AGTR1 antagonist attenuated tumor growth and enhanced neutrophil hypersegmentation. ACEis inhibited tumor-induced polarization of neutrophils to a protumoral phenotype. Neutrophil depletion reduced the antitumor effect of ACEi. Together, these data suggest that the modulation of Ang II pathway attenuates tumor growth via polarization of neutrophils to an antitumoral phenotype. PMID- 26942087 TI - Long-lasting multifunctional CD8+ T cell responses in end-stage melanoma patients can be induced by dendritic cell vaccination. AB - Cytotoxic T cells are considered crucial for antitumor immunity and their induction is the aim of various immunotherapeutic strategies. High frequencies of tumor-specific CD8+ T cells alone, however, are no guarantee for long-term tumor control. Here, we analyzed the functionality of tumor-specific CD8+ T cells in melanoma patients upon dendritic cell vaccination by measuring multiple T cell effector functions considered crucial for anticancer immunity, including the expression of pro-inflammatory cytokines, chemokines and cytotoxic markers (IFNgamma, TNFalpha, IL-2, CCL4, CD107a). We identified small numbers of multifunctional (polyfunctional) tumor-specific CD8+ T cells in several patients and dendritic cell therapy was able to improve the functionality of these pre existing tumor-specific CD8+ T cells. Generated multifunctional CD8+ T cell responses could persist for up to ten years and within the same patient functionality could vary greatly for the different vaccination antigens. Importantly, after one cycle of DC vaccination highly functional CD8+ T cells were only detected in patients displaying prolonged overall survival. Our results shed light on the dynamics of multifunctional tumor-specific CD8+ T cells during metastatic melanoma and reveal a new feature of dendritic cell vaccination in vivo. PMID- 26942089 TI - Targeting TNF alpha as a novel strategy to enhance CD8+ T cell-dependent immune response in melanoma? AB - Tumor Necrosis Factor alpha (TNF) is a pleiotropic cytokine exhibiting a dual activity in oncoimmunology, either acting as a cytotoxic effector produced by leukocytes or behaving as an immunosuppressive molecule. We have just discovered that TNF signaling impairs the accumulation of tumor-infiltrating CD8+ T lymphocytes in experimental melanoma. PMID- 26942090 TI - The extent to which melanoma alters tissue-resident dendritic cell function correlates with tumorigenicity. AB - We have shown that melanoma-derived factors alter the function of differentiated tissue-resident dendritic cells (DC) in a tumorigenicity-dependent manner. Soluble factors, including TGFbeta1 and VEGF-A, contributed to dendritic cell dysfunction associated with a highly-aggressive melanoma and conferred a phenotype upon DC likely to favor immune escape and tumor outgrowth. PMID- 26942088 TI - Co-delivery of PLGA encapsulated invariant NKT cell agonist with antigenic protein induce strong T cell-mediated antitumor immune responses. AB - Antitumor immunity can be enhanced by the coordinated release and delivery of antigens and immune-stimulating agents to antigen-presenting cells via biodegradable vaccine carriers. So far, encapsulation of TLR ligands and tumor associated antigens augmented cytotoxic T cell (CTLs) responses. Here, we compared the efficacy of the invariant NKT (iNKT) cell agonist alpha galactosylceramide (alpha-GalCer) and TLR ligands (R848 and poly I:C) as an adjuvant for the full length ovalbumin (OVA) in PLGA nanoparticles. We observed that OVA+alpha-GalCer nanoparticles (NP) are superior over OVA+TLR-L NP in generating and stimulating antigen-specific cytotoxic T lymphocytes without the need for CD4+ T cell help. Not only a 4-fold higher induction of antigen-specific T cells was observed, but also a more profound IFN-gamma secretion was obtained by the addition alpha-GalCer. Surprisingly, we observed that mixtures of OVA containing NP with alpha-GalCer were ineffective, demonstrating that co encapsulation of both alpha-GalCer and antigen within the same nanoparticle is essential for the observed T cell responses. Moreover, a single immunization with OVA+alpha-GalCer NP provided substantial protection from tumor formation and even delayed the growth of already established tumors, which coincided with a prominent and enhanced antigen-specific CD8+ T cell infiltration. The provided evidence on the advantage of antigen and alpha-GalCer coencapsulation should be considered in the design of future nanoparticle vaccines for therapeutic purposes. PMID- 26942091 TI - Precise identification of immunotherapeutic targets for solid malignancies using clues within the tumor microenvironment-Evidence to turn on the LIGHT. AB - Targeted immunotherapy for solid gastrointestinal malignancies is challenging due to a lack of identified tumor antigens. Therefore, a strategy that supports and expands tumor infiltrating lymphocytes in the tumor microenvironment may allow these tumor-reactive T-cells to incite an antitumor response. Gene expression analysis of colon metastases has identified specific immunotherapeutic targets for this malignancy. PMID- 26942092 TI - Comparison of naive and central memory derived CD8+ effector cell engraftment fitness and function following adoptive transfer. AB - Human CD8+ effector T cells derived from CD45RO+CD62L+ precursors enriched for central memory (TCM) precursors retain the capacity to engraft and reconstitute functional memory upon adoptive transfer, whereas effectors derived from CD45RO+CD62L- precursors enriched for effector memory precursors do not. Here we sought to compare the engraftment fitness and function of CD8+ effector T cells derived from CD45RA+CD62L+ precursors enriched for naive and stem cell memory precursors (TN/SCM) with that of TCM. We found that cytotoxic T cells (CTLs) derived from TCM transcribed higher levels of CD28, FOS, INFgamma, Eomesodermin (Eomes), and lower levels of BCL2L11, maintained higher levels of phosphorylated AKT, and displayed enhanced sensitivity to the proliferative and anti-apoptotic effects of gamma-chain cytokines compared to CTLs derived from TN/SCM. Higher frequencies of CTLs derived from TCM retained CD28 expression and upon activation secreted higher levels of IL-2. In NOD/Scid IL-2RgammaCnull mice, CD8+ TCM derived CTLs engrafted to higher frequencies in response to human IL-15 and mounted robust proliferative responses to an immunostimulatory vaccine. Similarly, CD8+ TCM derived CD19CAR+ CTLs exhibited superior antitumor potency following adoptive transfer compared to their CD8+ TN/SCM derived counterparts. These studies support the use of TCM enriched cell products for adoptive therapy of cancer. PMID- 26942093 TI - PD-1 expression conditions T cell avidity within an antigen-specific repertoire. AB - Despite its negative regulatory role on tumor-specific T cells, Programmed cell death 1 (PD-1) is also a marker of activated tumor-infiltrating T cells. In cancer, PD-1 blockade partially reverses T cell dysfunction allowing the amplification of tumor reactive T cells. Here, we investigated the role of PD-1 signaling on effector/memory human T cells specific for shared melanoma antigens, derived from blood. We documented for the first time the existence of melanoma specific T cell clones unable to express PD-1. This stable feature was due to the persistent methylation of the PDCD1 promoter. These PD-1neg clones were of lower avidity than their PD-1pos counterparts, suggesting that high-affinity-specific T cell clones unable to express PD-1 are not or rarely present in peripheral blood, as they are probably eliminated by negative selection, due to their high reactivity. We also documented the existence of such PD-1neg T cell clones in melanoma tumor-infiltrating lymphocytes (TIL), which also exhibited a lower functional avidity than PD-1pos TIL clones. This clearly shows that PD-1 expression identifies antigen-specific T cell clonotypes of high functional avidity. Finally, we demonstrated that PD-1 blockade during the in vitro selection process of Melan-A-specific T cells favored the amplification of higher avidity T cell clonotypes. This preferential amplification of high-avidity memory T cells upon PD-1 blockade resonates with the expansion of reactive T cells, including neo-antigen-specific T cells observed in anti-PD-1-treated patients. This feature should also be a useful biomarker of clinical efficiency, while providing new insights for adoptive transfer treatments. PMID- 26942094 TI - Doubling the blockade for melanoma immunotherapy. PMID- 26942095 TI - First oncolytic virus approved for melanoma immunotherapy. AB - On 2015, October 27th, the US Food and Drug Administration (FDA) has officially approved talimogene laherparepvec (T-VEC, also known as OncoVEXGM-CSF) for use in melanoma patients with injectable but non-resectable lesions in the skin and lymph nodes. T-VEC (which is commercialized by Amgen, Inc. under the name of Imlygic(r)) becomes therefore the first oncolytic virus approved for cancer therapy in the US. PMID- 26942096 TI - Corrigendum. AB - [This corrects the article DOI: 10.4161/2162402X.2014.988458.]. PMID- 26942098 TI - Gene therapy for Wiskott-Aldrich Syndrome-Long-term reconstitution and clinical benefits, but increased risk for leukemogenesis. AB - Wiskott-Aldrich-Syndrome (WAS) is a rare X-linked recessive disease caused by mutations of the WAS gene. It is characterized by immunodeficiency, autoimmunity, low numbers of small platelets (microthrombocytopenia) and a high risk of cancer, especially B cell lymphoma and leukemia. PMID- 26942099 TI - Motor neuron degeneration in spinal and Bulbar Muscular Atrophy is a skeletal muscle-driven process: Relevance to therapy development and implications for related motor neuron diseases. AB - Non-cell autonomous degeneration has arisen as an important mechanism in neurodegenerative disorders. Using a novel line of BAC androgen receptor (AR) transgenic mice with a floxed transgene (BAC fxAR121), we uncovered a key role for skeletal muscle in X-linked Spinal and Bulbar Muscular Atrophy (SBMA), a motor neuronopathy caused by a polyglutamine expansion in exon 1 of the AR gene. By excising the mutant AR transgene from muscle only, we achieved complete rescue of neuromuscular phenotypes in these mice, despite retaining strong CNS expression. Furthermore, we delivered an antisense oligonucleotide (ASO) directed against the human AR transgene by peripheral injection, and documented that peripheral ASO delivery could rescue muscle weakness and premature death in BAC fxAR121 mice. Our results reveal a crucial role for skeletal muscle in SBMA disease pathogenesis, and offer an appealing avenue for therapy development for SBMA and perhaps also for related motor neuron diseases. PMID- 26942097 TI - TDP-43-The key to understanding amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that causes motor neuron degeneration leading to progressive muscle atrophy, weakness, paralysis and death. The majority of ALS (>95%) shows intracellular aggregation of transactive response DNA binding protein (TDP-43) as a prominent pathological feature. TDP-43 is normally a nuclear protein. In ALS, TDP-43 accumulates and aggregates in the cytoplasm (thus forming TDP-43 proteinopathy) and is depleted from the nucleus in CNS cells, including motor neurons and glia. While TDP-43 aggregation can harm cells through a gain of toxicity, it can also cause a loss of TDP-43 function in conjunction with its nuclear depletion. TDP-43 regulates its own expression to maintain itself at a constant level. Perturbation of this level by either increasing or decreasing TDP-43 in animal models leads to neurodegeneration and ALS phenotypes. The evidence supports the hypothesis that TDP-43 dysfunction is a critical driver of neurodegeneration in the vast majority of ALS cases. PMID- 26942100 TI - Unraveling the mechanism by which TRPV4 mutations cause skeletal dysplasias. AB - Transient Receptor Potential Vanilloid 4 (TRPV4) is a mechano- and osmosensitive cation channel that is highly expressed in chondrocytes, the cells in cartilage. A large number of mutations in TRPV4 have been linked to skeletal dysplasias, and the goal of this addendum is to shed light on the mechanisms by which mutations in TRPV4 can cause skeletal dysplasias by focusing on 3 recent publications. These papers suggest that skeletal dysplasia-causing TRPV4 mutations reprogram chondrocytes to increase follistatin production, which inhibits BMP signaling, thus slowing the process of endochondral ossification and leading to skeletal dysplasia. In spite of these important advances in our understanding of the disease mechanism, much remains to be elucidated. Nonetheless, these new data suggest that inhibiting aberrant TRPV4 activity in the cartilage may be a promising direction for therapeutic intervention. PMID- 26942102 TI - The methyl binding domain containing protein MBD5 is a transcriptional regulator responsible for 2q23.1 deletion syndrome. AB - 2Iq23.1 microdeletion syndrome is a recently described rare disease that includes intellectual disability, motor delay, autistic-like behaviors, and craniofacial abnormalities. Dosage insufficiency of the methyl-CpG-binding domain protein 5 (MBD5) gene was suggested as the genetic cause, since all the described patients carry a partial or total heterozygous deletion of MBD5. We reported the generation and characterization of a mouse model with haploinsufficiency for Mbd5 that confirmed this hypothesis. As in human 2q23.1 microdeletion syndrome, the MBD5 (+/GT) mouse model exhibited abnormal social behavior, cognitive impairment, and motor and craniofacial abnormalities, supporting a causal role for MBD5 in 2q23.1 microdeletion syndrome. The use of mouse neuronal cultures uncovered a deficiency in neurite outgrowth, suggesting the participation of MBD5 in neuronal processes. The study of the MBD5 (+/GT) mouse advanced our understanding of the abnormal brain development associated with behavioral and cognitive symptoms. PMID- 26942101 TI - Loss of the tumor suppressor SMARCA4 in small cell carcinoma of the ovary, hypercalcemic type (SCCOHT). AB - Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT), is a rare and understudied cancer with a dismal prognosis. SCCOHT's infrequency has hindered empirical study of its biology and clinical management. However, we and others have recently identified inactivating mutations in the SWI/SNF chromatin remodeling gene SMARCA4 with concomitant loss of SMARCA4 protein in the majority of SCCOHT tumors.(1-4) Here we summarize these findings and report SMARCA4 status by targeted sequencing and/or immunohistochemistry (IHC) in an additional 12 SCCOHT tumors, 3 matched germlines, and the cell line SCCOHT-1. We also report the identification of a homozygous inactivating mutation in the gene SMARCB1 in one SCCOHT tumor with wild-type SMARCA4, suggesting that SMARCB1 inactivation may also play a role in the pathogenesis of SCCOHT. To date, SMARCA4 mutations and protein loss have been reported in the majority of 69 SCCOHT cases (including 2 cell lines). These data firmly establish SMARCA4 as a tumor suppressor whose loss promotes the development of SCCOHT, setting the stage for rapid advancement in the biological understanding, diagnosis, and treatment of this rare tumor type. PMID- 26942103 TI - Drosophila as a potential model to ameliorate mutant Huntington-mediated cardiac amyloidosis. AB - Several human diseases, including Huntington's disease (HD), are associated with the expression of mutated, misfolded, and aggregation-prone amyloid proteins. Cardiac disease is the second leading cause of death in HD, which has been mainly studied as a neurodegenerative disease that is caused by expanded polyglutamine repeats in the huntingtin protein. Since the mechanistic basis of mutant HD induced cardiomyopathy is unknown, we established a Drosophila heart model that exhibited amyloid aggregate-induced oxidative stress, resulting in myofibrillar disorganization and physiological defects upon expression of HD-causing PolyQ expression in cardiomyocytes. Using powerful Drosophila genetic techniques, we suppressed mutant HD-induced cardiomyopathy by modulating pathways associated with folding defects and oxidative stress. In this addendum, we describe additional potential molecular players that might be associated with HD cardiac amyloidosis. Drosophila, with its high degree of conservation to the human genome and many techniques to manipulate its gene expression, will be an excellent model for the suppression of cardiac amyloidosis linked to other polyglutamine expansion repeat disorders. PMID- 26942104 TI - Impaired striatal function in Huntington's disease is due to aberrant p75NTR signaling. AB - Huntington's disease (HD) is a rare genetic neurodegenerative disorder for which there is currently no cure. Early hyperkinetic motor symptoms are consistent with reduced activity of indirect pathway striatal projection neurons (iSPNs) responsible for suppression of unwanted actions. Our recent work suggests that one of the factors contributing to this deficit is impaired brain-derived neurotrophic factor (BDNF) signaling that regulates the strength of iSPN excitatory synapses. Specifically, we found that BDNF-dependent corticostriatal synaptic long-term potentiation (LTP) was lost in iSPNs from 2 genetic models of HD, just as they began to robustly manifest motor symptoms. This deficit was not attributable to problems in BDNF production, delivery or receptor binding. Rather, the plasticity deficit stemmed from enhanced signaling through p75 neurotrophin receptors (p75NTRs) and the phosphatase and tensin homolog (PTEN), leading to antagonism of intracellular TrkBR cascades and LTP. This study suggests HD therapeutics should target p75NTR signaling, not TrkBR. PMID- 26942105 TI - Muscle-specific microRNAs as biomarkers of Duchenne Muscular Dystrophy progression and response to therapies. AB - Recent studies have revealed the contribution of fibro-adipogenic progenitors (FAPs) to the pathogenesis and progression of Duchenne Muscular Dystrophy (DMD). While FAPs direct compensatory regeneration at early stages of disease, as the disease progresses they contribute to the progressive replacement of contractile myofibers with fibrotic scars and fatty infiltration. Using the mouse model of DMD - the mdx mice - we have recently reported that FAPs mediate the ability of HDAC inhibitors (HDACi) to promote muscle regeneration and prevent fibro adipogenic degeneration at early stages of disease. This effect is mediated by the induction of myomiRs that, in turn, target the SWI/SNF components BAF60A and B, thereby favoring the formation of BAF60C-based SWI/SNF complex, which directs the switch from the fibro-adipogenic to the myogenic lineage. Here we show direct evidence of induction of miR-206 and BAF60C, and reduction of BAF60A, in FAPs isolated from mdx muscles exposed to the HDACi Trichostatin A (TSA). We also discuss how increased expression of myomiRs in dystrophic muscles can be integrated with circulating myomiRs to provide accurate biomarkers of disease progression and response to treatment. PMID- 26942106 TI - Spondylocheirodysplastic Ehlers-Danlos syndrome (SCD-EDS) and the mutant zinc transporter ZIP13. AB - The zinc transporter protein ZIP13 plays crucial roles in bone, tooth, and connective tissue development, and its dysfunction is responsible for the spondylocheirodysplastic form of Ehlers-Danlos syndrome (SCD-EDS, OMIM 612350). We recently reported that the pathogenic mutations in ZIP13 reduce its functional protein level by accelerating the protein degradation via the VCP-linked ubiquitin proteasome pathway, resulting in the disturbance of intracellular zinc homeostasis that appears to contribute to SCD-EDS pathogenesis. Finally, we implicate that possible therapeutic approaches for SCD-EDS would be based on regulating the degradation of the pathogenic mutant ZIP13 proteins. PMID- 26942107 TI - Transcription Factor HBP1 Enhances Radiosensitivity by Inducing Apoptosis in Prostate Cancer Cell Lines. AB - Radiotherapy for prostate cancer has been gradually carried out in recent years; however, acquired radioresistance often occurred in some patients after radiotherapy. HBP1 (HMG-box transcription factor 1) is a transcriptional inhibitor which could inhibit the expression of dozens of oncogenes. In our previous study, we showed that the expression level of HBP1 was closely related to prostate cancer metastasis and prognosis, but the relationship between HBP1 and radioresistance for prostate cancer is largely unknown. In this study, the clinical data of patients with prostate cancer was compared, and the positive correlation was revealed between prostate cancer brachytherapy efficacy and the expression level of HBP1 gene. Through research on prostate cancer cells in vitro, we found that HBP1 expression levels were negatively correlated with oncogene expression levels. Furthermore, HBP1 overexpression could sensitize prostate cancer cells to radiation and increase apoptosis in prostate cancer cells. In addition, animal model was employed to analyze the relationship between HBP1 gene and prostate cancer radiosensitivity in vivo; the result showed that knockdown of HBP1 gene could decrease the sensitivity to radiation of xenograft. These studies identified a specific molecular mechanism underlying prostate cancer radiosensitivity, which suggested HBP1 as a novel target in prostate cancer radiotherapy. PMID- 26942109 TI - Joining Forces to Overcome Cancer: The Kenya Cancer Research and Control Stakeholder Program. AB - BACKGROUND: Cancer is the third leading cause of mortality in Kenya, accounting for 7% of annual deaths. The Kenyan Ministry of Health (MOH) is committed to reducing cancer mortality, as evidenced by policies such as the National Cancer Control Strategy (2011-2016). There are many Kenyan and international organizations devoted to this task; however, coordination is lacking among stakeholders, resulting in inefficient and overlapping expenditure of resources. METHODS: The MOH and the NCI Center for Global Health collaboratively executed a two day workshop to improve coordination among government, NGO, and private organizations. Over 80 stakeholders participated from leading cancer research and control institutions in Kenya and the international sphere. FINDINGS: Actionable recommendations include: establishment of a nationally representative population based cancer registry; enhanced training for community health workers, nurses, researchers, pathologists, and oncology specialists; a reconfigured referral process, including leveraging of existing resources to improve access to cancer care; and coordinated community outreach and education. The MOH is in the process of forming a Technical Working Group (TWG) and has elected a Board of Directors for the newly established Kenyan National Cancer Institute (KNCI), with both entities committed to advancing the cancer control work of the MOH. INTERPRETATION: This stakeholder meeting enhanced in-country networks, identified priority needs and developed actionable proposals for coordinated improvement of cancer research and control. Active, persistent follow-up by the TWG, KNCI, and other partners will be needed to turn proposals into reality and ensure that partners' investments are integrated into larger cancer control efforts prioritized by MOH. PMID- 26942108 TI - The Predictive Link between Matrix and Metastasis. AB - Cancer spread (metastasis) is responsible for 90% of cancer-related fatalities. Informing patient treatment to prevent metastasis, or kill all cancer cells in a patient's body before it becomes metastatic is extremely powerful. However, aggressive treatment for all non-metastatic patients is detrimental, both for quality of life concerns, and the risk of kidney or liver-related toxicity. Knowing when and where a patient has metastatic risk could revolutionize patient treatment and care. In this review, we attempt to summarize the key work of engineers and quantitative biologists in developing strategies and model systems to predict metastasis, with a particular focus on cell interactions with the extracellular matrix (ECM), as a tool to predict metastatic risk and tropism. PMID- 26942111 TI - The role of serum surfactant protein D as a biomarker of exacerbation of chronic obstructive pulmonary disease. AB - BACKGROUND: The exacerbation of chronic obstructive pulmonary disease (COPD) is a major factor for the high mortality associated with the disease. There is a paucity in the lung-specific biomarkers which diagnose these exacerbations. Surfactant protein D (SP-D) is a promising biomarker in predicting clinical outcomes for patients with COPD, is lung-specific and can be detected in serum. However, the profile in which serum concentrations of SP-D change during acute exacerbation is still unclear. This study aims to estimate and compare the concentrations of serum SP-D in patients with stable disease and during the exacerbation. METHODS: A cross-sectional study was conducted which composed of apparently healthy individuals (n = 28), which included 14 smokers and 14 nonsmokers, patients with stable COPD (n = 28), and patients experiencing acute exacerbations (n = 28). Pulmonary functions were performed for all groups. Serum SP-D concentrations were measured using enzyme-linked immunosorbent assay (ELISA). These concentrations were compared by analysis of variance. RESULTS: Serum SP-D levels were significantly elevated in patients with acute exacerbations (508.733 +/- 102.813 ng/ml) compared to patients with stable COPD (337.916 +/- 86.265 ng/ml) and healthy subjects (177.313 +/- 46.998 ng/ml; p < 0.001). Serum SP-D levels correlated inversely with lung function parameters including FEV1%pred, FVC%pred and FEV1/FVC. CONCLUSION: Serum SP-D levels are raised early on during acute exacerbations of COPD, which could be a potential early diagnostic biomarker for COPD exacerbations. PMID- 26942110 TI - Hypercholesterolemia with consumption of PFOA-laced Western diets is dependent on strain and sex of mice. AB - Perfluorooctanoic acid (PFOA) is a man-made surfactant with a number of industrial applications. It has a long half-life environmentally and biologically. Past studies suggest a direct relationship between plasma cholesterol and PFOA serum concentrations in humans and an inverse one in rodents fed standard rodent chow, making it difficult to examine mechanisms responsible for the potential PFOA-induced hypercholesterolemia and altered sterol metabolism. To examine dietary modification of PFOA-induced effects, C57BL/6 and BALB/c mice were fed PFOA in a fat- and cholesterol-containing diet. When fed these high fat diets, PFOA ingestion resulted in marked hypercholesterolemia in male and female C57BL/6 mice and less robust hypercholesterolemia in male BALB/c mice. The PFOA-induced hypercholesterolemia appeared to be the result of increased liver masses and altered expression of genes associated with hepatic sterol output, specifically bile acid production. mRNA levels of genes associated with sterol input were reduced only in C57BL/6 females, the mice with the greatest increase in plasma cholesterol levels. Strain-specific PFOA-induced changes in cholesterol concentrations in mammary tissues and ovaries paralleled changes in plasma cholesterol levels. mRNA levels of sterol-related genes were reduced in ovaries of C57BL/6 but not in BALB/c mice and not in mammary tissues. Our data suggest that PFOA ingestion leads to hypercholesterolemia in mice fed fat and cholesterol and effects are dependent upon the genetic background and gender of the mice with C57BL/6 female mice being most responsive to PFOA. PMID- 26942112 TI - Dental pain among 10-15 year old children attending oral health promoting schools: A cross-sectional study. AB - INTRODUCTION: Dental pain is a major public health problem and one of the consequences of oral diseases which requires significant adjustments in life management leading to decreased quality of life. OBJECTIVE: To assess prevalence of dental pain and its impact on daily life and to explore its relationship with oral health behavior and clinical oral status among 10-15 year old school children attending oral health promoting schools. METHOD: This cross sectional study was conducted in 6 schools serving low -middle socio economic strata in Bangalore, India. A total of 1237 children were surveyed for history of dental pain during past 3 month. Participants who reported dental pain completed self reported oral health behaviour and Child dental pain questionnaire. Clinical oral examination included assessment of dental caries, periodontal status. Data was analyzed using t - test, Chi-square test, ANOVA and Regression Analysis. RESULTS: Prevalence of dental pain was 15.6% (n = 194). Among children with pain, 17%, 43% and 40% reported mild, moderate and severe pain. Impact on daily activities was reported by 66%. Mean DMFT and DMFS was 1.80 and 2.11 Mean deft and defs was 2.47 and 3.41. Multiple logistic regression revealed that severity and impact of dental pain was associated with gender, frequency of tooth brushing, consumption of sweets and deciduous dental caries experience. CONCLUSION: Prevalence of Dental pain is associated with brushing behavior, consumption of sweets and deciduous dental caries experience, showing need for further attention to these conditions and a need to strengthen preventive and therapeutic dental services. PMID- 26942113 TI - Postural awareness among dental students in Jizan, Saudi Arabia. AB - OBJECTIVE: The study was conducted to assess the postural awareness of dental students in Jizan, Saudi Arabia. MATERIALS AND METHODS: Close-ended, self administered questionnaires were used for data collection in the survey. The questionnaire was prepared by observing the positions of students working in the clinics and the common mistakes they make with regard to their postures. The questionnaires were distributed among the dental students who were present and reported to work in the clinics. Levels of postural awareness and the relationship between postural awareness and the degree of musculoskeletal disorder (MSD) among the students was evaluated. This study was carried out in the College of Dental Sciences and Hospital, Jizan. STATISTICAL ANALYSIS: The level of knowledge of postural awareness was evaluated and correlated with the presence or absence of the MSDs. Categorical variables were compared using Chi square test. P values of less than 0.05 were considered statistically significant. RESULTS: A total of 162 dental students from the age group of 20-25 years were included in the survey, of which 134 dentists responded (83%). When their postural awareness was evaluated, results showed that 89% of the students had poor-to-medium levels of postural awareness. The relation between postural awareness and prevalence of MSDs indicated that 75% of the students with poor awareness, 49% of the students with average awareness, and 40% of the students with good awareness have MSDs. The results were statistically significant (0.002127, which is <0.005) stating that better awareness about proper postures while working helps to minimize the risk of MSDs. CONCLUSION: Evaluation of levels of postural awareness showed that 21% of the students had poor postural awareness, 67% had average awareness, and 11% had good postural awareness. The analysis of results showed that those students with low-to-average postural awareness had significantly greater prevalence of MSDs. PMID- 26942114 TI - Comparing the efficacy of xylitol-containing and conventional chewing gums in reducing salivary counts of Streptococcus mutans: An in vivo study. AB - OBJECTIVE: Dental caries is among the most common chronic diseases in humans. Streptococcus mutans is generally responsible for most cases of dental caries. The present study sought to compare the effects of xylitol-containing and conventional chewing gums on salivary levels of S. mutans. MATERIALS AND METHODS: This study adopted a crossover design. Two type of chewing gums (one containing 70% xylitol and approved by the Iranian Dental Association, and another containing sucrose) were purchased. The participants were 32 individuals aged 18 35 years whose oral hygiene was categorized as moderate or poor based on a caries risk assessment table. Salivary levels of S. mutans were measured at baseline, after the first and second phases of chewing gums, and after the washout period. The measurements were performed on blood agar and mitis salivarius-bacitracin agar (MSBA). Pairwise comparisons were then used to analyze the collected data. RESULTS: Salivary levels of S. mutans in both groups were significantly higher during the two stages of chewing gum than in the washout period or baseline. Moreover, comparisons between the two types of gums suggested that chewing xylitol-containing gums led to greater reductions in S. mutans counts. This effect was more apparent in subjects with poor oral hygiene than in those with moderate oral hygiene. CONCLUSIONS: Xylitol-containing chewing gums are more effective than conventional gums in reducing salivary levels of S. mutans in individuals with poor-moderate oral hygiene. PMID- 26942115 TI - Oral health trends and service utilization at a rural outreach dental clinic, Udo, Southern Nigeria. AB - BACKGROUND: The oral disease burden in Nigerian rural areas is considered high with limited dental services. Normative need assessment to facilitate oral health promotion and interventional activities is essential. Therefore, the aim of this study was to evaluate the dental service utilization and trends of patents attending a rural outreach dental clinic. MATERIALS AND METHODS: A retrospective study was conducted using data from clinical records of patients seen over a period of 54 months at a rural outreach dental clinic of comprehensive health center, Udo, Edo State, and were analyzed for descriptive variables with Chi square test and P value set at <=0.05 significance. RESULTS: One hundred and sixty four (164) patients [males = 74 (45.1%), females = 90 (54.9%)] were seen with a mean age of 36.15 +/- 18.05 years. The major reason for clinic visit was due to dental caries (sequelae) and condition representing 43.3% and 34.8%, respectively. Extractions (41.5%) and scaling and polishing (S and P) (21.3%) accounted for the most frequently provided treatment. Almost 20% patients did not receive any form of treatment. CONCLUSION: The study revealed a low health seeking behavior, low utilization of dental services among the rural dwellers and need for oral health awareness, periodic screening, and preventive approach in the rural population through more frequent outreach visits of dental personnel resident in the community. PMID- 26942116 TI - Knowledge, value, opinion and practice about usage of pit and fissure sealant among dental professionals in Chennai, Tamil Nadu, India. AB - AIM: A study was aimed to assess the knowledge, value, opinion, and practice regarding the use of dental sealants among private dental practitioners in Chennai, Tamil Nadu, India. MATERIALS AND METHODS: A self-administrated questionnaire were distributed to 192 private dental practitioners in Chennai, Tamil Nadu, India by using simple random sampling. A convenience sampling technique was employed. The questionnaire consisted of 28 items, which included information about knowledge, value, opinion, and practice regarding dental sealants. The questionnaire was obtained from the study by San Martin et al. 2013 and Kailash Asawa et al. 2014. Frequency distribution was tabulated. For frequency distribution strongly, strongly agree, and agree were combined as "agree" and strongly disagree and disagree were combined as "disagree." There were no changes in "neutral." RESULTS: Among the 196 study subjects 56.2% were males and 43.8% were females with their clinical experience of 52.1% for <5 years, 35.4% for 5-10 years, and 13.5% for >15 years. The mean scores for knowledge, value, opinion, and practice were 41.8 +/- 3.7, 18.7 +/- 2.8, 18.1 +/- 1.4, and 12.9 +/- 2.3, respectively. CONCLUSION: The results suggest that dental practitioners had satisfactory knowledge about pit and fissure sealant and had neutral attitudes about sealants being effective. Dental practitioners adequately used the pit and fissure sealants but they did not follow the standardized procedures and specific guidelines. PMID- 26942117 TI - A comparative evaluation of oral hygiene using Braille and audio instructions among institutionalized visually impaired children aged between 6 years and 20 years: A 3-monthfollow-up study. AB - AIM: The aim of this study is to compare the oral hygiene status among institutionalized visually impaired children of age between 6 and 20 years given with Braille and audio instructions in Raichur city of Karnataka. MATERIALS AND METHODS: A total of 50 children aged between 6 to 20 years were included in this study from a residential school for visually impaired children. These children were randomly divided into two equal groups. One group was given oral hygiene instructions by audio recordings and another written in Braille and were instructed to practice the same. After three months time the oral hygiene status and dental caries experience was recorded and compared using patient performance index. Statistical analysis was done by student paired t test and multiple comparison by Tukey's HSD (honest significant difference) test. RESULTS: The mean PHP (Patient Hygiene Performance) score of group A at baseline was 3.88 compared to 3.90 of group B. At 7 days PHP score of group A and group B was 3.42 and 3.45 respectively. At 3 month PHP score of group A and group B was 2.47 and 2.86 respectively. Even though over a period of time the mean score of PHP index reduced the score comparison between the 2 groups were statistically non significant. In group A the mean difference of PHP score between baseline and 7 days was 0.46, between baseline and 3 months it was 1.40. The PHP score between 7 days and 3 months was 0.94. All the above values were statistically significant. CONCLUSION: Effective dental health education method has to be instituted for visually impaired children. The present study shows improvement of oral health status in both the study population by decrease in the mean plaque score. Hence continuous motivation and reinforcement in the form of Braille and audio instruction is beneficial to achieve good oral hygiene levels in visually impaired children. PMID- 26942118 TI - Effect of neutral zone technique on marginal bone loss around implant-supported overdentures. AB - AIM: The aim of this study was to compare changes in marginal bone height around immediately loaded implants supporting a mandibular overdenture constructed according to the neutral zone technique with changes around overdentures constructed according to the conventional methods. MATERIALS AND METHODS: Twelve completely edentulous male patients were randomly allocated to two equal groups of patients. Patients in the first group received conventionally constructed complete dentures and patients in the second group received complete dentures constructed using the neutral zone record. All the patients received two single piece titanium implants placed bilaterally in the mandibular canine regions using flapless surgery, which were then immediately loaded by the dentures. Marginal bone height was radiographically evaluated at baseline and 6, 12, and 18 months after implant loading. RESULTS: There was a significant loss in marginal bone height around the supporting implants in each study group. However, no significant differences in marginal bone height were recorded between the study groups over the observation period (P > 0.05). CONCLUSION: Marginal bone height changes induced by overdentures constructed with neutral zone technique on immediately loaded implants are not different from those changes induced by overdentures constructed with a conventional method. PMID- 26942119 TI - Awareness of hepatitis B infection among healthcare students in a private medical college in Odisha. AB - BACKGROUND: The emergence of the blood-borne pathogens and the increasing number of infected patients and the increasing interest in dental health care compel the dental professionals to have thorough knowledge about communicable diseases and the MBBS and nursing students are always at risk because of their profession. As hepatitis B infection is a major health hazard throughout the world, healthcare students should have through knowledge about this disease. Setia et al. had conducted a similar kind of study in Punjab in which the sample size was smaller and it included only the interns, whereas the present study was conducted to assess the level of knowledge, attitude, and behavior about hepatitis B infection among healthcare students of all academic years because they are indulged in clinical work since third year of their curriculum. MATERIALS AND METHODS: A cross-sectional survey was conducted of all the students starting from 1(st) year to final year and the interns of MBBS, BDS, and nursing at KIIT University. The questions were obtained from a study performed in Turkey in 2010 and were modified by an infection control expert. Questions in multiple choice format were in English and it was a self-administered questionnaire consisting of three parts (knowledge, attitude, behavior). Then, ethical clearance for the study was obtained from the institutional ethical committee, KIMS. Subsequently, the students were well informed and explained about the study. Students who voluntarily wanted to participate were included in the study. Questionnaire containing 20 questions to assess the level of knowledge, attitude, and behavior about hepatitis B was distributed among the students. Data were compiled and statistical analysis was done. RESULTS: The response rate was 83% (N = 332). In our study, majority (96.99%) were aware of transmission of HBV infection by blood, body fluid, and secretion. The level of knowledge was higher in MBBS students than BDS and nursing students (MBBS > BDS > nursing). Attitude toward the disease was higher in MBBS students than BDS and nursing students (MBBS > BDS > nursing), whereas behavior was higher in BDS students than MBBS and nursing students (BDS > MBBS > nursing). CONCLUSION: In our study, overall knowledge and attitude toward hepatitis B infection were higher in MBBS students than in dental and nursing students, whereas behavior of dental students toward the disease was quite satisfactory than MBBS and nursing students. PMID- 26942120 TI - Comparison of salivary calcium level in smokers and non-smokers with chronic periodontitis, aggressive periodontitis, and healthy controls. AB - OBJECTIVE: The purpose of this study was to compare salivary calcium (Ca) level in smokers and non-smokers with chronic periodontitis, aggressive periodontitis, and healthy controls. MATERIALS AND METHODS: 56 subjects were included in the study and were grouped as follows: 12 subjects who were periodontally healthy (Group I), 12 subjects having chronic periodontitis who were non-smokers (Group II), 12 non-smokers having aggressive periodontitis (Group III), 12 smokers with chronic periodontitis (Group IV), and 8 smokers with aggressive periodontitis (Group V). Clinical measurements and non-stimulated whole saliva samples were obtained and analyzed for Ca levels by ion-selective electrolyte analyzer. RESULTS: When salivary Ca values were compared between the groups, they showed statistically significant values (P < 0.001) with the highest mean Ca level in Group IV and Group V, which include smokers with chronic periodontitis and smokers with aggressive periodontitis, respectively, than in other groups. Between groups II and III also, the mean salivary Ca level was statistically significant (P < 0.001) with higher mean salivary Ca in non-smokers having chronic periodontitis than in non-smokers having aggressive periodontitis. CONCLUSIONS: The present study showed that smokers having chronic periodontitis as well as smokers having aggressive periodontitis have higher salivary calcium levels. Also, patients with aggressive periodontitis were found to have lesser salivary calcium level than chronic periodontitis patients by ion-selective electrolyte analyzer. PMID- 26942121 TI - Comparative evaluation of shear bond strengths of veneering porcelain to base metal alloy and zirconia substructures before and after aging - An in vitro study. AB - OBJECTIVE: The aim of this study was to evaluate and compare the shear bond strength of veneering porcelain to base metal alloy and zirconia substructures before and after aging. Scanning electron microscopy (SEM) was used to determine the failure pattern. MATERIALS AND METHODS: Twenty rectangular blocks (9 mm length * 4 mm height * 4 mm width) of base metal alloy (Bellabond plus, Bego, Germany) and zirconia (Will ceramZ zirconia K block) were fabricated for shear bond strength test. Surface of the base metal alloy block (4 mm * 4 mm area) was veneered with corresponding veneering porcelain (Ivoclar, IPS classic, vivadent). Similarly, surface of the zirconia rectangular block (4 mm * 4 mm) was veneered with corresponding veneering ceramic (Cercon ceram kiss, Degudent). Out of forty rectangular porcelain veneered core specimen, ten porcelain veneered base metal alloy specimen and ten porcelain veneered zirconia specimen were immersed in water at 37 degrees C for one month to simulate the oral environment. RESULTS: On comparison, the highest shear bond strength value was obtained in porcelain veneered base metal alloy before aging group followed by porcelain veneered base metal alloy after aging group, Porcelain veneered zirconia before aging group, porcelain veneered zirconia after aging group. SEM analysis revealed predominantly cohesive failure of veneering ceramic in all groups. CONCLUSION: Porcelain veneered base metal alloy samples showed highest shear bond strength than porcelain veneered zirconia samples. Study concluded that aging had an influence on shear bond strength. Shear bond strength was found to be decreasing after aging. SEM analysis revealed cohesive failure of veneering ceramic in all groups suggestive of higher bond strength of the interface than cohesive strength of ceramic. Hence, it was concluded that veneering ceramic was the weakest link. PMID- 26942122 TI - Analysis of the greater palatine foramen in a Lebanese population using cone-beam computed tomography technology. AB - OBJECTIVE: The aim of this study was to describe the diameter and the position of the greater palatine foramen (GPF) in relation to adjacent anatomical landmarks in the maxilla in a Lebanese population using cone-beam computed tomography (CBCT) technology. MATERIALS AND METHODS: CBCT images of 58 Lebanese adult patients were included in this study and a total of 116 GPF were evaluated bilaterally. The diameter of the GPF and its position relative to the maxillary molars, and distances to the midline maxillary suture and to the anterior nasal spine were analyzed. RESULTS: Of all foramina assessed, 41.38% were located opposite to the third molar, 29.31% were distal to it, 27.59% were between the second and the third, and only 1.72% were opposite to the second. The average diameter was 5.633 mm on the right and 5.723 mm on the left, and the average distances to midline maxillary suture and anterior nasal spine were 16.228 mm and 48.294 mm on the right and 14.907 mm and 48.122 mm on the left, respectively. CONCLUSION: Within the limits of this study, we conclude that in Lebanese patients, the GPF location is variable, very rarely opposite to the second molar, and more closely related to the third, but may present mesial or distal to it in one-fourth of patients. PMID- 26942123 TI - Antimicrobial activity of herbal medicines (tulsi extract, neem extract) and chlorhexidine against Enterococcus faecalis in Endodontics: An in vitro study. AB - BACKGROUND: Successful endodontic treatment depends on effective disinfection and complete sealing of root canal. Various medicaments are advised for disinfecting root canal, such as herbal and non-herbal medicaments. This study was done to assess the antimicrobial activity of herbal medicines (neem extract, tulsi extract) and chlorhexidine against Enterococcus faecalis in Endodontics. MATERIALS AND METHODS: Agar diffusion method was used to evaluate the antimicrobial action of different medicines. Sixty samples were segregated into four groups with 15 samples in each: Group I: chlorhexidine 2%, Group II: neem extract, Group III: tulsi extract, and Group IV: distilled water. The inhibition zones against E. faecalis were recorded and statistically assessed using one-way analysis of variance (ANOVA) test (P < 0.05). RESULTS: Significant antibacterial effect against E. faecalis was observed with chlorhexidine followed by neem extract and tulsi extract. CONCLUSION: Herbal medicines seemed to be effective against E. faecalis compared to 2% chlorhexidine gluconate. PMID- 26942124 TI - Effectiveness of health education and behavioral intervention for tobacco de addiction among degree students: A clinical trial. AB - BACKGROUND: Objectives of the study were to assess the prevalence of tobacco use among the degree students of Oxford institutions in Bangalore city, offer a tobacco cessation intervention for tobacco users among the degree students, and assess the effectiveness of intervention by comparing with the control group. MATERIALS AND METHODS: A randomized control trial was conducted to assess the prevalence of tobacco use and the effectiveness of tobacco cessation behavioral intervention offered to degree students of Oxford institutions in Bangalore city. Then were randomly selected and divided into 55 students in the study group (group A) and 60 students in the control group (group B). RESULTS: The effect of intervention of tobacco cessation in group A showed an increase of 29.1% students who stopped using tobacco completely after intervention compared to 15% in group B, and the highest reduction of 21.8% change was noticed in the students using one to five tobacco products per day and the least reduction in percentage (1.8%) change was noticed in the students using one tobacco product per day. CONCLUSION: Findings from the present study suggest that the intervention has suggestive significance on tobacco intervention. PMID- 26942125 TI - Differential Superiority of Heavy Charged-Particle Irradiation to X-Rays: Studies on Biological Effectiveness and Side Effect Mechanisms in Multicellular Tumor and Normal Tissue Models. AB - This review is focused on the radiobiology of carbon ions compared to X-rays using multicellular models of tumors and normal mucosa. The first part summarizes basic radiobiological effects, as observed in cancer cells. The second, more clinically oriented part of the review, deals with radiation-induced cell migration and mucositis. Multicellular spheroids from V79 hamster cells were irradiated with X-rays or carbon ions under ambient or restricted oxygen supply conditions. Reliable oxygen enhancement ratios could be derived to be 2.9, 2.8, and 1.4 for irradiation with photons, (12)C(+6) in the plateau region, and (12)C(+6) in the Bragg peak, respectively. Similarly, a relative biological effectiveness of 4.3 and 2.1 for ambient pO2 and hypoxia was obtained, respectively. The high effectiveness of carbon ions was reflected by an enhanced accumulation of cells in G2/M and a dose-dependent massive induction of apoptosis. These data clearly show that heavy charged particles are more efficient in sterilizing tumor cells than conventional irradiation even under hypoxic conditions. Clinically relevant doses (3 Gy) of X-rays induced an increase in migratory activity of U87 but not of LN229 or HCT116 tumor cells. Such an increase in cell motility following irradiation in situ could be the source of recurrence. In contrast, carbon ion treatment was associated with a dose-dependent decrease in migration with all cell lines and under all conditions investigated. The radiation-induced loss of cell motility was correlated, in most cases, with corresponding changes in beta1 integrin expression. The photon induced increase in cell migration was paralleled by an elevated phosphorylation status of the epidermal growth factor receptor and AKT-ERK1/2 pathway. Such a hyperphosphorylation did not occur during (12)C(+6) irradiation under all conditions registered. Comparing the gene toxicity of X-rays with that of particles using the gammaH2AX technique in organotypic cultures of the oral mucosa, the superior effectiveness of heavy ions was confirmed by a twofold higher number of foci per nucleus. However, proinflammatory signs were similar for both treatment modalities, e.g., the activation of NFkappaB and the release of IL6 and IL8. The presence of peripheral blood mononuclear cell increased the radiation-induced release of the proinflammatory cytokines by factors of 2-3. Carbon ions are part of the cosmic radiation. Long-term exposure to such particles during extended space flights, as planned by international space agencies, may thus impose a medical and safety risk on the astronauts by a potential induction of mucositis. In summary, particle irradiation is superior to gamma-rays due to a higher radiobiological effectiveness, a reduced hypoxia induced radioresistance, a multicellular radiosensitization, and the absence of a radiation-induced cell motility. However, the potential of inducing mucositis is similar for both radiation types. PMID- 26942126 TI - Disparities in Gynecological Malignancies. AB - OBJECTIVES: Health disparities and inequalities in access to care among different socioeconomic, ethnic, and racial groups have been well documented in the U.S. healthcare system. In this review, we aimed to provide an overview of barriers to care contributing to health disparities in gynecological oncology management and to describe site-specific disparities in gynecologic care for endometrial, ovarian, and cervical cancer. METHODS: We performed a literature review of peer reviewed academic and governmental publications focusing on disparities in gynecological care in the United States by searching PubMed and Google Scholar electronic databases. RESULTS: There are multiple important underlying issues that may contribute to the disparities in gynecological oncology management in the United States, namely geographic access and hospital-based discrepancies, research-based discrepancies, influence of socioeconomic and health insurance status, and finally the influence of race and biological factors. Despite the reduction in overall cancer-related deaths since the 1990s, the 5-year survival for Black women is significantly lower than for White women for each gynecologic cancer type and each stage of diagnosis. For ovarian and endometrial cancer, black patients are less likely to receive treatment consistent with evidence based guidelines and have worse survival outcomes even after accounting for stage and comorbidities. For cervical and endometrial cancer, the mortality rate for black women remains twice that of White women. CONCLUSION: Health care disparities in the incidence and outcome of gynecologic cancers are complex and involve biologic factors as well as racial, socioeconomic, and geographic barriers that influence treatment and survival. These barriers must be addressed to provide optimal care to women in the U.S. with gynecologic cancer. PMID- 26942127 TI - Personalized Cancer Risk Assessments for Space Radiation Exposures. AB - Individuals differ in their susceptibility to radiogenic cancers, and there is evidence that this inter-individual susceptibility extends to HZE ion-induced carcinogenesis. Three components of individual risk: sex, age at exposure, and prior tobacco use, are already incorporated into the NASA cancer risk model used to determine safe days in space for US astronauts. Here, we examine other risk factors that could potentially be included in risk calculations. These include personal and family medical history, the presence of pre-malignant cells that could undergo malignant transformation as a consequence of radiation exposure, the results from phenotypic assays of radiosensitivity, heritable genetic polymorphisms associated with radiosensitivity, and postflight monitoring. Inclusion of these additional risk or risk reduction factors has the potential to personalize risk estimates for individual astronauts and could influence the determination of safe days in space. We consider how this type of assessment could be used and explore how the provisions of the federal Genetic Information Non-discrimination Act could impact the collection, dissemination and use of this information by NASA. PMID- 26942128 TI - Alterations in Mitochondrial and Endoplasmic Reticulum Signaling by p53 Mutants. AB - The p53 protein is probably the most important tumor suppressor, acting as a nuclear transcription factor primarily through the modulation of cell death. However, currently, it is well accepted that p53 can also exert important transcription-independent pro-cell death actions. Indeed, cytosolic localization of endogenous wild-type or transactivation-deficient p53 is necessary and sufficient for the induction of apoptosis and autophagy. Here, we present the extra-nuclear activities of p53 associated with the mitochondria and the endoplasmic reticulum, highlighting the activities of the p53 mutants on these compartments. These two intracellular organelles play crucial roles in the regulation of cell death, and it is now well established that they also represent sites where p53 can accumulate. PMID- 26942129 TI - Histomolecular Structural Aspects of High Endothelial Vessels in Lymph Node and Its Significance in Oral Cancer and Metastasis. AB - Molecular cancer research studies focus on identifying diagnostic, screening, and metastatic indicators, and monitoring therapeutic responses. Migration of tumor cells and lymphocytes are important aspects in metastasis. High endothelial vessels are specialized histological structures identified in the blood vessels in lymphoid organs, which allow the migration of lymphocytes. In the recent decades, the role of high endothelial vessels is being addressed in cancer metastatic research. This review article is to highlight the histological and molecular structural aspects of high endothelial venules (HEVs) in the lymph node, and to demonstrate the role of HEVs in oral cancer metastasis, specifically oral and pharyngeal squamous cell carcinoma. The literature for the present paper were searched from the data sources such as Medline/PubMed, CINAHL plus, and gray literature sources from inception to May 2015. Searches were conducted using both free texts and medical subject headings related to the title of the present paper. Only the full text manuscripts of the search results that support the objective(s) of the paper and papers written in English were included. HEVs are unique structures that are identified in the lymphocytes and primarily assist in the lymphocytic migration from the blood stream into the lymph node. Understanding the histomolecular characteristics of HEV will allow researchers to develop novel therapeutic approaches in cancer tissues. PMID- 26942130 TI - Clinical Manifestations and Predictors of Thrombocytopenia in Hospitalized Adults with Dengue Fever. AB - BACKGROUND: India is one of the seven identified Southeast Asian countries reporting frequent outbreaks of dengue fever (DF). AIMS: This study was to analyze clinical and laboratory profile and predictive markers of thrombocytopenia and length of hospital stay in DF. MATERIALS AND METHODS: This record-based retrospective study conducted in a coastal district of Karnataka, South India, included all dengue cases in adults aged >18 years, admitted during period of January 2011 to December 2014. Multivariate logistic regression analysis was carried out to compute odds ratio (OR) and 95% confidence interval (CI) to assess independent associations of variables with low platelet count and longer duration of hospital stay. RESULTS: Among 207 dengue immunoglobulin M (IgM) antibody confirmed cases (mean age of 36.94 +/- 14.61 years), 143 (69.1%) were males and 64 were females. The mean duration of illness and hospital stay were 4.94 +/- 3.58 days and 5.98 +/- 2.58 days, respectively. Abdominal symptoms included nausea and vomiting (53.6%), abdominal pain (25.1%), and diarrhea (13.5%). Bleeding manifestations were seen in 24 (11.6%) cases and fluid accumulation was revealed in 18 (8.7%) cases. The mean platelet count was 110,159.42 +/- 68,397.32 (cells/mm(3)). Low platelet count on admission was associated with the presence of rash (OR = 0.43, 95% CI 0.23-0.81), high aspartate aminotransferase (AST) levels (OR = 3.14, 95% CI 1.58-6.23), high alanine aminotransferase (ALT) levels (OR = 2.91, 95% CI 1.55-5.47), and low albumin levels (OR = 4.48, 95% CI 1.02-19.75). The duration of hospital stay was associated with diarrhea (OR = 0.4, 95% CI 0.18-0.9), abdominal pain (OR = 0.52, 95% CI 0.27-1.00), ascites (OR = 0.26, 95% CI 0.09-0.69), and low hemoglobin (OR = 0.46, 95% CI 0.25-0.86) level on admission. CONCLUSIONS: Though thrombocytopenia on admission was associated with the presence of rash, high AST and ALT levels, and low albumin levels, it was not predictive of length of hospitalization. Duration of hospital stay was longer with the presence of diarrhea, abdominal pain, ascites, and low hemoglobin level on admission. PMID- 26942131 TI - A Pilot Study of the Inability to Fit Hands Around Neck as a Predictor of Obstructive Sleep Apnea. AB - BACKGROUND: Considering the high estimates of undiagnosed and untreated obstructive sleep apnea (OSA), there is a need for simple and accurate diagnostic tests. Neck circumference has long been correlated with OSA, but its usefulness as a diagnostic tool has been limited. AIMS: We proposed to evaluate the value of a simple neck grasp test to help identify OSA. We hypothesized that the inability of a patient in a sleep clinic to fit their hands around their neck is predictive of OSA. MATERIALS AND METHODS: A retrospective review of medical records of patients evaluated in a general sleep clinic was performed. Easy sleep apnea predictor (ESAP) positive was defined as the inability to place the hands around the neck with digits touching in the anterior and posterior. ESAP negative was the ability to place hands around the neck. Positive for OSA in this symptomatic sleep clinic population was defined as an apnea-hypopnea index (AHI) of >=5. RESULTS: A total of 47 subjects (36% female) had ESAP data available, which were reviewed. The mean age was 51.6 years (SD 14.4, range 29-81 years). The mean body mass index (BMI) was 38.8 (SD 9.9, range 20.4-69.5). Review showed 87.2% (N = 41) tested positive for OSA by AHI of >=5. The sensitivity and specificity of ESAP were 68.3% and 100%, respectively. The positive predictive power was 100% and the negative predictive power was 31.6%. CONCLUSION: As we hypothesized, ESAP positive (inability to span neck) was predictive of OSA in a population of sleep clinic patients. An ESAP positive test was 100% predictive of the presence of OSA (AHI of >=5). ESAP shows promise for ease of clinical use to predict the presence of OSA in a general sleep clinic population. PMID- 26942132 TI - Metabolic Signatures of Oxidative Stress and Their Relationship with Erythrocyte Membrane Surface Roughness Among Workers of Manual Materials Handling (MMH). AB - BACKGROUND: Brickfield workers in India perform manual materials handling (MMH) and as a result, are at a high risk of developing oxidative stress. This results in an alteration of the various markers of metabolic oxidative stress at the cellular level. Since red blood cell (RBC) is the central point where oxygen, glucose-6-phosphate dehydrogenase (G-6-PD), and glutathione (GSH) are involved, the surface roughness and its alteration and modeling with respect to workers exposed to MMH may be considered as helpful determinants in predicting early damage to the cell and restoring better health to the exposed population, that is, the worker exposed to stress. Hence, nanometric analysis of the surface roughness of the RBC may serve as an early indicator of the stress-related damage in these individuals. AIMS: The purpose of the study was to identify early red blood corpuscular surface damage profile in terms of linear modeling correlating various biochemical parameters. Linear modeling has been aimed to be developed in order to demonstrate how individual oxidative stress markers such as malondialdehyde (MDA), G-6-PD, and reduced GSH are related to the RBC surface roughness [root mean square (RMS)]. MATERIALS AND METHODS: Conventional analysis of these biochemical responses were evaluated in MMH laborers (age varying between 18 years and 21 years) and a comparable control group of the same age group (with sedentary lifestyles). Peak expiratory flow rate (PEFR) and RBC surface analysis by atomic-force microscopy (AFM) and correlated scanning probe microscopy (SPM-analytical software) with corresponding image analysis were performed immediately after completion of standardized exercise (MMH) at the brickfield. RESULTS: A number of correlated significances and regressive linear models were developed among MDA, G-6-PD, GSH, and RBC surface roughness. CONCLUSION: It appears that these linear models might be instrumental in predicting early oxidative damages related to specific occupational hazards. PMID- 26942133 TI - Metabolic Signatures of Oxidative Stress in the Red Blood Cells: Editorial Commentary. PMID- 26942134 TI - New Right Bundle Branch Block as a Criterion for Emergent Coronary Angiography. AB - CONTEXT: ST-segment elevations in two or more contiguous leads or new left bundle branch block (LBBB) on electrocardiography (ECG) in a patient with acute onset chest pain are diagnostic criteria for acute myocardial infarction (AMI) and generally warrant urgent coronary angiography and cardiac catheterization. However, the significance of new right bundle branch block (RBBB) without other acute ECG changes is unclear and is currently not considered a criterion. CASE REPORT: We present a patient with chest pain, positive biomarkers of myocardial necrosis and isolated new right bundle block on ECG. He was diagnosed with AMI but did not undergo urgent reperfusion therapy in the absence of ST-segment elevations or new LBBB. However, angiography ultimately demonstrated complete coronary occlusion. CONCLUSION: The established criteria for emergent catheterization may prove to be more sensitive with the inclusion of the presence of new RBBB on ECG. PMID- 26942135 TI - Cortical Hemiballism: A Case of Hemiballismus Associated with Parietal Lobe Infarct. AB - CONTEXT: Hemiballismus is characterized by involuntary, irregular, large amplitude, and violent flinging movements of limbs. Stroke (middle and posterior cerebral artery) remains the most common etiology with 2/3 being lacunar. Lesions outside the substantia niagra (STN) can cause hemiballism, and only a minority by STN lesions, unlike the classical belief. Compared to those arising from STN, cortical hemiballismus is usually less severe with a good prognosis. CASE REPORT: A 61-year-old man presented with sudden onset involuntary flinging movements of his right upper extremity accompanied by numbness and tingling. Past medical history was significant for stroke 2 years back with no residual deficits. Vitals signs were blood pressure of 165/84 mm Hg, and heart rate - 82 beats/min. Irregular, arrhythmic, jerky flinging movement, and decreased sensation to light touch in right upper extremity was noted. Magnetic resonance imaging of the brain revealed acute posterior left parietal lobe infarction. He was treated with aspirin and atorvastatin. Thrombolytic therapy was offered but declined. The movements resolved spontaneously over the next 2 days. No further episodes occurred at 3-month follow-up. CONCLUSION: Lesions affecting various areas outside the STN can cause hemiballism and usually carries a good prognosis with spontaneous resolution. Acute thrombolytic therapy may be considered on an individual basis. Treatment with antipsychotics can be useful for severe and recurring symptoms. PMID- 26942136 TI - HIV/AIDS Prevention and Control in India: Achievements and Future Challenges. PMID- 26942137 TI - Endometrial Cancer and The Role of Statins. PMID- 26942138 TI - A prospective comparison of perioperative morbidity in advanced epithelial ovarian cancer: Primary versus interval cytoreduction - experience from India. AB - OBJECTIVES: The objective was to compare perioperative morbidity and mortality of patients with advanced epithelial ovarian cancer (EOC) treated with either of the two treatment approaches; neoadjuvant chemotherapy (NACT) followed by interval debulking versus upfront surgery. DESIGN: Prospective comparative observational study. PARTICIPANTS: In total, 51 patients were included in the study. All patients with diagnosed advanced EOC (International Federation of Gynecology and Obstetrics IIIC and IV) presenting for the 1(st) time were included in the study. INTERVENTIONS: Patients were either operated upfront (n = 19) if deemed operable or were subjected to NACT followed by interval debulking (n = 32). PRIMARY AND SECONDARY OUTCOMES: Intra- and postoperative morbidity and mortality were the primary outcome measures. RESULTS: Patients with interval cytoreduction were noted to have significantly lesser operative time, blood loss, and extent of surgery. Their discharge time was also significantly earlier. However, they did not differ from the other group vis. a vis. postoperative complications or mortality. CONCLUSIONS: Neoadjuvant chemotherapy although has a positive impact on various intraoperative adverse events, fails to show any impact on immediate postoperative negative outcomes. PMID- 26942139 TI - Occupation, smoking, opium, and bladder cancer: A case-control study. AB - PURPOSE: The aim of this study was to investigate occupational risk factors associated with bladder cancer. MATERIALS AND METHODS: In this case-control study, control group included patients who referred to a specialized clinic in the same city and hospitals where patients had been registered. Data were entered into SPSS software. Odds ratios (OR) were calculated for occupational variables and other characteristics. Then, using logistic regression, the association between cancer and drugs was studied while smoking was controlled. RESULTS: Cigarette smoking, even after quitting, was also associated with bladder cancer (OR = 2.549). Considering the classification of occupations, the OR of working in metal industry in patients was 10.629. Multivariate analysis showed that use of the drug by itself can be a risk factor for bladder cancer. Drug abuse together with the control of smoking increased the risk of bladder cancer by 4.959. CONCLUSION: According to the findings of this study, contact with metal industries such as welding, and working with tin was found as a risk factor for bladder cancer. In addition, cigarette smoking and opium abuse individually were associated with bladder cancer. PMID- 26942140 TI - Human epidermal growth factor receptor 2/neu overexpression in urothelial carcinoma of the bladder and its prognostic significance: Is it worth hype? AB - AIMS: In urothelial tumors of the urinary bladder, human epidermal growth factor receptor 2 (HER-2)/neu expression has been reported over 10 years, but there is no clear correlation between prognosis and recurrence rate. The present study evaluates prognostic implication of HER-2/neu expression. SUBJECTS AND METHODS: In this study, 100 formalin-fixed paraffin-embedded specimens of primary transitional cell carcinoma of the bladder were processed. HER-2/neu monoclonal antibody immunohistochemistry staining procedure used for the study. RESULTS: A total of 70 (70%) patients were positive for overexpression of HER-2/neu. HER 2/neu was positive in patients with 42 (70%) superficial tumor, 28 (70%) muscle invasive tumor, 41 (75.9%) high-grade tumor, 29 (63%) low grade tumor, 31 (68.9%) recurrent tumor, and 6 (66.6%) had positive lymph nodes. CONCLUSIONS: Human epidermal growth factor receptor 2/neu over expression was not correlated with the tumor stage, lymphnode metastasis or recurrence of the disease. HER-2/neu overexpression was statistically insignificantly correlated with the differentiation grade (P < 0.161) as compared to previous studies. Future studies on HER-2 expression with chemo-sensitivity and efficacy of HER-2-targeted therapies in urothelial carcinomas is needed. PMID- 26942141 TI - Prospective randomized trial to compare the outcome and tolerability of delivering the same total dose of radiation in 61/2 weeks versus 51/2 weeks time in head and neck cancers. AB - BACKGROUND: Concurrent chemoradiation is currently considered to be the standard of care in the treatment of head and neck cancer. In developing countries like ours, a good number of patients cannot tolerate chemoradiation because of the poor general condition and financial constraints. Those patients are treated with radiation alone. The optimum radiotherapy (RT) schedule for best local control and acceptable toxicity is not yet clear. We aimed to find out whether shortening of treatment time using six instead of five RT fractions per week improves the locoregional control in squamous cell carcinoma of head and neck. MATERIALS AND METHODS: We conducted a prospective randomized study for a period of 2 years from September 2007 to August 2009 in 109 untreated patients of squamous cell carcinoma of head and neck with histologically confirmed diagnosis and no evidence of distant metastasis. Study group (55 patients) received accelerated RT with 6 fractions per week (66 Gy/33#/51/2 weeks). Control group (54 patients) received conventional RT with 5 fractions per week (66 Gy/33#/61/2 weeks). Tumor control, survival, acute and late toxicities were assessed. RESULTS: At a median follow-up of 43 months, 29 patients (52.7%) in the 6 fractions group and 24 patients (44.4%) in the 5 fractions group were disease-free (P = 0.852). The benefit of shortening was higher for advanced disease control though it was not statistically significant. Grade 3 and 4 skin toxicity was significantly higher in the accelerated RT (70.9%) arm as compared to conventional (35.1%) arm (P = 0.04). Grade 3 mucositis was significantly higher in the accelerated RT arm (32.7% vs. 16.6%; P = 0.041). Those acute toxicities were managed conservatively. There was no difference in late toxicities between the two arms. CONCLUSION: Use of 6 fractions per week instead of 5 fractions per week is feasible, tolerable, and results in a better outcome in the patients of head and neck cancers. PMID- 26942142 TI - An in vivo cytogenetic analysis of human oral squamous cell carcinoma. AB - BACKGROUND: Oral cancer ranks in the top three of all cancers in India, which accounts for over 30% of all cancers reported in the country. The micronucleus test (MNT) is one of the most widely applied short term tests used in genetic toxicology to evaluate the mutagenicity and carcinogenicity. AIMS: The present study aims at an in vivo cytogenetic analysis of human oral squamous cell carcinoma and to assess the applicability of MNT in diagnosing early detection of oral carcinoma. MATERIALS AND METHODS: Exfoliated scrape smears were collected from the clinically diagnosed 136 patients suffering from oral precancerous and cancerous lesions. The wet fixed smears were stained by adopting Papanicolaou's staining protocol and counter-stained with Giemsa's solution. RESULTS: The frequency of micronucleated cells has been observed to be in increasing order with the increase of the age-groups and from control to precancerous to cancerous cases significantly in both sexes. CONCLUSION: Micronucleus formation in the oral mucosa could be a biomarker of genetic damage and also a potential onco-indicator in the long run of oral carcinogenesis. Therefore, MNT can be applied for the early detection of oral carcinoma in the human being. PMID- 26942143 TI - Surgical management of gastric cancer: Single center experience from a developing country. AB - BACKGROUND: Geographical distributional of gastric cancer (GC), differences in stage at the time of presentation and varying surgical expertise have resulted in different management strategies around the world. The aim of this study is to determine postoperative morbidity/mortality and overall survival in patients with GC treated at a cancer hospital in Pakistan. PATIENTS AND METHODS: A retrospective review of patients who underwent surgical resection with curative intent for GC from June 2006 to July 2012 was performed. Primary end point was overall survival after a minimum follow-up of 15 months. For categorical data, frequencies were calculated, and means were measured for continuous variables. Chi-square test was used to compare categorical data and Kaplan-Meir survival analysis was performed to estimate 5 years survival outcome using SPSS. RESULTS: Majority of the patients were males with median age of 51 years. Perioperative chemotherapy was offered to 75 patients while upfront surgery was performed in 23 patients. In perioperative chemotherapy group 51 patients and 22 in the upfront surgery group ended up having curative resection. The 5 years survival (n = 98) was found to be of 37%. The 5 years survival of patients in perioperative chemotherapy group (n = 75) was 44% while those who had a curative resection (n = 73) had survival of 46%. CONCLUSION: Gastric adenocarcinoma is an aggressive disease. Perioperative chemotherapy works well in Pakistani population as the results at our institution are comparable with international data. PMID- 26942144 TI - Prevalence of oral potentially malignant disorders in workers of Udupi taluk. AB - OBJECTIVE: The objective was to assess the prevalence and risk factors of oral potentially malignant disorders (PMD) among industrial workers of Udupi taluk, Karnataka. MATERIALS AND METHODS: The sample consisted of industrial workers aged >18 years from randomly selected industries in Udupi Taluk. A self-administered questionnaire was given to the participants to assess sociodemographic factors and abusive habits (Tobacco, Alcohol, and Betel quid) followed by clinical oral examination by single trained and calibrated examiner. RESULTS: A total of 396 completed all steps of the survey and were included for analysis. A total of 14, 11.4, and 14.4% were tobacco, alcohol, and betel quid users, respectively. A total of 8.6% (n = 34) have at least one PMD. A significantly higher number of participants with single (11.4%) or combined habits (60.4%) had oral lesions while none of the participants without habits reported any oral lesions (P = 0.001). CONCLUSION: Prevalence of abusive habits and oral premalignant lesions or conditions was substantial among the workers. The cause and effect relationship and dose-response were also shown to be significantly associated. Prevention and early diagnosis through workplace screening are the major cornerstones for the control of oral cancer. PMID- 26942145 TI - Fertility preservation in young patients with cancer. AB - Infertility can arise as a consequence of treatment of oncological conditions. The parallel and continued improvement in both the management of oncology and fertility cases in recent times has brought to the forefront the potential for fertility preservation in patients being treated for cancer. Many survivors will maintain their reproductive potential after the successful completion of treatment for cancer. However total body irradiation, radiation to the gonads, and certain high dose chemotherapy regimens can place women at risk for acute ovarian failure or premature menopause and men at risk for temporary or permanent azoospermia. Providing information about risk of infertility and possible interventions to maintain reproductive potential are critical for the adolescent and young adult population at the time of diagnosis. There are established means of preserving fertility before cancer treatment; specifically, sperm cryopreservation for men and in vitro fertilization and embryo cryopreservation for women. Several innovative techniques are being actively investigated, including oocyte and ovarian follicle cryopreservation, ovarian tissue transplantation, and in vitro follicle maturation, which may expand the number of fertility preservation choices for young cancer patients. Fertility preservation may also require some modification of cancer therapy; thus, patients' wishes regarding future fertility and available fertility preservation alternatives should be discussed before initiation of therapy. PMID- 26942146 TI - Minimal invasive gastric surgery: A systematic review. AB - BACKGROUND: As an alternate to open surgery, laparoscopic gastrectomy (LG) is currently being performed in many centers, and has gained a wide clinical acceptance. The aim of this review article is to compare oncologic adequacy and safety of LG with open surgery for gastric adenocarcinomas with respect to lymphadenectomy, short-term outcomes (postoperative morbidity and mortality) and long-term outcome (5 years overall survival and disease-free survival). MATERIALS AND METHODS: PubMed was searched using query "LG" for literature published in English from January 2000 to April 2014. A total of 875 entries were retrieved. These articles were screened and 59 manuscripts ultimately formed the basis of current review. RESULTS: There is high-quality evidence to support short-term efficacy, safety and feasibility of LG for gastric adenocarcinomas, although accounts on long-term survivals are still infrequent. PMID- 26942147 TI - Complications of chemoport in children with cancer: Experience of 54,100 catheter days from a tertiary cancer center of Southern India. AB - BACKGROUND: Chemoport is an essential part of the management of children with cancer and provides long-term venous access. There are few studies from resource poor countries reporting complications of chemoport. AIMS: This study was aimed at describing the complications of chemoport in patients with cancer. MATERIALS AND METHODS: This retrospective observational study analyzed 200 patients <15 years of age who underwent chemoport insertion. The medical records of these patients were reviewed for the patient characteristics, diagnosis, nature of port use, port-related complications and their management. RESULTS: A total of 209 ports were implanted in 200 patients and 24 ports were removed due to port related complications. There were 122 boys and 78 girls whose ages ranged from 4 months to 13 years (median age 2.5 years). About72% of patients were <2 years old. The cumulative duration of catheterization was 54,100 days. Of 209 ports, there were 36 complications that led to the removal of 21 ports. Port-related infection was the most common infection observed in our study (0.66/1000 catheter days and 11.9%). Mechanical complications were seen in 9 patients. Venous thrombosis and skin necrosis occurred in one patient each. CONCLUSIONS: Use of chemoport is safe and is a boon for children with cancer in developing countries with incidence of complications similar to Western countries. Although use of chemoport is associated with complications, they are easily managed. With stringent catheter care by trained personnel, some complications can be prevented. PMID- 26942148 TI - Demographic and histopathologic profile of pediatric brain tumors: A hospital based study. AB - BACKGROUND: Very few hospital-based or population-based studies are published in the context to the epidemiologic profile of pediatric brain tumors (PBTs) in India and Indian subcontinent. AIM: To study the demographic and histopathologic profile of PBTs according to World Health Organization 2007 classification in a single tertiary health care center in India. MATERIALS AND METHODS: Data regarding age, gender, topography, and histopathology of 76 pediatric patients (0 19 years) with brain tumors operated over a period of 24 months (January-2012 to December-2013) was collected retrospectively and analyzed using EpiInfo 7. Chi square test and test of proportions (Z-test) were used wherever necessary. RESULTS: PBTs were more common in males (55.3%) as compared to females (44.7%) with male to female ratio of 1.23:1. Mean age was 10.69 years. Frequency of tumors was higher in childhood age group (65.8%) when compared to adolescent age group (34.2%). The most common anatomical site was cerebellum (39.5%), followed by hemispheres (22.4%). Supratentorial tumors (52.6%) were predominant than infratentorial tumors (47.4%). Astrocytomas (40.8%) and embryonal tumors (29.0%) were the most common histological types almost contributing more than 2/3(rd) of all tumors. Craniopharyngiomas (11.8%) and ependymomas (6.6%) were the third and fourth most common tumors, respectively. CONCLUSION: Astrocytomas and medulloblastomas are the most common tumors among children and adolescents in our region, which needs special attention from the neurosurgical department of our institute. Demographic and histopathologic profile of cohort in the present study do not differ substantially from that found in other hospital-based and population-based studies except for slight higher frequency of craniopharyngiomas. PMID- 26942149 TI - Two cases of ovarian carcinoma with endobronchial metastases: Rare presentation. PMID- 26942150 TI - Late effects of treatment in breast cancer survivors: A statistical update. PMID- 26942151 TI - Changing trends in clinico-morphological profile of chronic myeloid leukemia-our experience. PMID- 26942152 TI - Study of incidence of malignancy in clinically benign thyroid swelling. PMID- 26942153 TI - Mucosal gastric metastases: A very rare site of metstasis from germ cell tumour. PMID- 26942154 TI - Long-term results of oncoplastic breast surgery with latissimus dorsi flap reconstruction: a pilot study of the objective cosmetic results and patient reported outcome. AB - PURPOSE: The goal of oncoplastic breast surgery is to restore the appearance of the breast and improve patient satisfaction. Thus, the assessment of cosmetic results and patient-reported outcomes (PROs) using appropriately constructed and validated instruments is essential. The aim of the present study was to assess the long-term objective cosmetic results and corresponding PROs after oncoplastic breast surgery. METHODS: Cosmetic results were assessed by the patients, a medical panel, and a computer program (BCCT.core). PROs were assessed using BREAST-Q, a questionnaire that measures the perception of patients having breast surgery. The cosmetic results and PROs were analyzed in patients who underwent quadrantectomy and partial breast reconstruction utilizing the latissimus dorsi flap. RESULTS: The mean duration of the follow-up period was 91.6 months (range, 33.3-171.0 months), and mean age of the patients was 51 years old (range, 33-72 years). The mean tumor size was 2.1 cm (range, 0.9-5.5 cm). There was fair agreement between the medical panel and BCCT.core score (K = 0.32, P < 0.001), and a statistically significant correlation between the BCCT.core score and medical panel cosmetic results was identified (r = 0.606, P < 0.001). A better BCCT.core result was related to a higher PRO of each BREAST-Q domain-satisfaction with breasts (R(2) = 0.070, P = 0.039), satisfaction with outcome (R(2) = 0.087, P = 0.021), psychosocial well-being (R(2) = 0.085, P = 0.023), sexual well-being (R(2) = 0.082, P = 0.029), and satisfaction with information (R(2) = 0.064, P = 0.049). CONCLUSION: Our long-term results of oncoplastic surgery achieved a high level of patient satisfaction with good cosmetic results. The medical panel and BCCT.core results correlated well with the PROs of the patients using valid, reliable, and procedure-specific measures. PMID- 26942155 TI - Validation of international consensus guideline 2012 for intraductal papillary mucinous neoplasm of pancreas. AB - PURPOSE: Intraductal papillary mucinous neoplasm (IPMN) has variable malignant potential ranging from premalignant intraductal lesions to malignant neoplasms with invasive carcinoma. To help physicians managing patients with IPMN, International consensus guidelines was made in 2006 and revised in 2012. This study was designed to evaluate the clinical usefulness of guidelines and to validate. METHODS: From October 1996 to December 2011, we retrospectively reviewed the data of 230 patients who underwent pancreatic resection for IPMN. Univariate and multivariable analyses were used to identify significant predictors of malignancy in IPMN. RESULTS: Of the 230 patients, 62 patients (27%) were diagnosed with invasive carcinoma. Jaundice (P < 0.001; 95% confidence interval [CI], 3.086-40.010) main pancreatic duct diameter equal to or greater than 10 mm (P < 0.001; 95% CI, 1.723-6.673) and also abdominal pain (P < 0.001; 95% CI, 4.363-22.600) show statistical significance in univariate and multivariate analysis. "High-risk stigmata" was statistical powerful predictors of malignancy than "worrisome features". International consensus guidelines 2012 had improvement on specificity but deterioration of sensitivity. CONCLUSION: Revised guidelines seemed to bring about an improvement of weak side of Sendai criteria. Abdominal pain, jaundice, main pancreas duct greater than 10 mm can be clinical variables to predict malignancy. PMID- 26942156 TI - Incidental gallbladder cancer after routine cholecystectomy: when should we suspect it preoperatively and what are predictors of patient survival? AB - PURPOSE: In about 1% of cases, incidental gallbladder cancers (iGBC) are found after routine cholecystectomy. The aim of this study is to compare clinical features of iGBC with benign GB disease and to evaluate factors affecting recurrence and survival. METHODS: Between January 1998 and March 2014, 4,629 patients received cholecystectomy and 73 iGBC patients (1.6%) were identified. We compared clinical features of 4,556 benign GB disease patients with 73 iGBC patients, and evaluated operative outcomes and prognostic factors in 56 eligible patients. RESULTS: The iGBC patients were older and concomitant diseases such as hypertension and anemia were more common than benign ones. And an age of more than 65 years was the only risk factor of iGBC. Adverse prognostic factors affecting patients' survival were age over 65, advanced histology, lymph node metastasis, and lymphovascular invasion on multivariate analysis. Age over 65 years, lymph node involvement, and lymphovascular invasion were identified as unfavorable factors affecting survival in subgroup analysis of extended cholecystectomy with bile duct resection (EC with BDR, n = 22). CONCLUSION: Prior to routine cholecystectomy, incidental GB cancer should be suspected especially in elderly patients. And advanced age, lymph node metastasis, and lymphovascular invasion are important prognostic factors in EC with BDR cohorts. PMID- 26942157 TI - Surgical treatment for hepatocellular carcinoma with bile duct invasion. AB - PURPOSE: There is still some debate on surgical procedures for hepatocellular carcinoma (HCC) patients with bile duct tumor thrombi (BDTT, Ueda type 3 or 4). What is adequate extent of liver resection for curative treatment? Is extrahepatic bile duct resection mandatory for cure? The aim of this study is to answer these questions. METHODS: Between February 1994 and December 2012, 877 consecutive HCC patients underwent hepatic resection at Ajou University Hospital. Thirty HCC patients (3.4%) with BDTT (Ueda type 3 or 4) were retrospective reviewed in this study. RESULTS: In total, 20 patients enrolled in this study were divided into 2 groups: patients who underwent hemihepatectomy with extrahepatic bile duct resection (group 1, n = 10) and with only removal of BDTT (group 2, n = 10). The 1-, 3- and 5-year overall survival rates were 75.0%, 50.0%, and 27.8%, respectively. The 1-, 3-, and 5-year survival rates of group 1 were 100.0%, 80.0%, and 45.7%, and those of group 2 were 50.0%, 20.0%, and 10.0%, respectively (P = 0.014). The 1-, 3-, and 5-year recurrences free survival rates of group 1 were 90.0%, 70.0%, and 42.0%, and those of group 2 were 36.0%, 36.0%, and 0%, respectively (P = 0.014). Thrombectomy and infiltrative growth type (Ig) were found as independent prognostic factors for recurrence free survival by multivariate analysis. Thrombectomy, Ig, and high indocyanine green retention rate at 15 minutes were found as independent prognostic factors for overall survival by multivariate analysis. CONCLUSION: We suggest that the appropriate surgical procedure for icteric HCC patients should be comprised of ipsilateral hemihepatectomy with caudate lobectomy and extrahepatic bile duct resection. PMID- 26942158 TI - Intraoperative radiofrequency ablation for hepatocellular carcinoma in 112 patients with cirrhosis: a surgeon's view. AB - PURPOSE: This retrospective study was an investigation of overall survival (OS), disease-free survival (DFS) and prognostic factors affecting OS and DFS in cirrhotic patients who received intraoperative radiofrequency ablation (IORFA). METHODS: Between April 2009 and November 2013, 112 patients (94 men, 84%; 18 women, 16%) underwent IORFA for 185 cases of hepatocellular carcinomas (HCC). Repeat IORFA was done in 9 patients during the same period (total of 121 treatments). RESULTS: All patients were followed-up for at least 12 months (mean follow-up, 32 months). Surgical resection combined with IORFA was performed in 20 patients. The technical effectiveness at 1 week was 91.78% (111 of 121). Readmission was 9.1% (11 of 121) and the most common cause was ventral hernia. Procedure-related mortality was 2.7% (3 of 112) and continued fatal biliary leakage was 1.8% (2 of 112). Local recurrence developed in 10 patients (8.9%). Most recurrence was intrahepatic. Cumulative survival was assessed in 33 patients who received IORFA as primary treatment (naive patients) and 79 non-naive patients. The cumulative DFS and OS rate at l and 3 years was 54% and 24%, and 87% and 66%, respectively. Moderate ascites (P = 0.001), tumor located segment I (P = 0.001), portal vein thrombosis (P = 0.001) had poor survival were significant factors by multivariate analysis. CONCLUSION: IORFA alone or in combination with surgical resection extends the spectrum of liver surgery. A fundamental understanding of RFA, additional comorbidities, and postablation complication are necessary to maximize the safety and efficacy of IORFA for treating HCC with cirrhosis. PMID- 26942159 TI - Duodenal stump fistula after gastrectomy for gastric cancer: risk factors, prevention, and management. AB - PURPOSE: A duodenal stump fistula is one of the most severe complications after gastrectomy for gastric cancer. We aimed to analyze the risk factors for this problem, and to identify the methods used for its prevention and management. METHODS: We retrospectively reviewed the clinical data of 716 consecutive patients who underwent curative gastrectomy with a duodenal stump for gastric cancer between 2008 and 2013. RESULTS: A duodenal stump fistula occurred in 16 patients (2.2%) and there were 2 deaths in this group. Univariate analysis revealed age >60 years (odds ratio [OR], 3.09; 95% confidence interval [CI], 0.99 9.66), multiple comorbidities (OR, 4.23; 95% CI, 1.50-11.92), clinical T stage (OR, 2.91; 95% CI, 1.045-8.10), and gastric outlet obstruction (OR, 8.64; 95% CI, 2.61-28.61) to be significant factors for developing a duodenal stump fistula. Multivariate analysis identified multiple comorbidities (OR, 3.92; 95% CI, 1.30 11.80) and gastric outlet obstruction (OR, 5.62; 95% CI, 1.45-21.71) as predictors of this complication. CONCLUSION: Multiple comorbidities and gastric outlet obstruction were the main risk factors for a duodenal stump fistula. Therefore, preventive methods and aggressive management should be applied for patients at high risk. PMID- 26942160 TI - The feasibility of single-port laparoscopic appendectomy using a solo approach: a comparative study. AB - PURPOSE: To investigate the feasibility and safety of solo surgery with single port laparoscopic appendectomy, which is termed herein solo-SPLA (solo-single port laparoscopic appendectomy). METHODS: This study prospectively collected and retrospectively analyzed data from patients who had undergone either non-solo SPLA (n = 150) or solo-SPLA (n = 150). Several devices were utilized for complete, skin-to-skin solo-SPSA, including a Lone Star Retractor System and an adjustable mechanical camera holder. RESULTS: Operating times were not significantly different between solo- and non-solo-SPLA (45.0 +/- 21.0 minutes vs. 46.7 +/- 26.1 minutes, P = 0.646). Most postoperative variables were also comparable between groups, including the necessity for intravenous analgesics (0.7 +/- 1.2 ampules [solo-SPLA] vs. 0.9 +/- 1.5 ampules [non-solo-SPLA], P = 0.092), time interval to gas passing (1.3 +/- 1.0 days vs. 1.4 +/- 1.0 days, P = 0.182), and the incidence of postoperative complications (4.0% vs. 8.7%, P = 0.153). Moreover, solo-SPLA effectively lowered the operating cost by reducing surgical personnel expenses. CONCLUSION: Solo-SPLA economized staff numbers and thus lowered hospital costs without lengthening of operating time. Therefore, solo-SPLA could be considered a safe and feasible alternative to non-solo-SPLA. PMID- 26942162 TI - Acute hyperammonemic encephalopathy after 5-fluorouracil based chemotherapy. AB - 5-Fluorouracil (5-FU) based chemotherapy has been commonly used to treat metastatic or advanced colon cancer as an adjuvant chemotherapy. Although the side effects of 5-FU such as gastrointestinal problems and neutropenia and thrombocytopenia are common, not many cases of 5-FU related encephalopathy are reported. Hyperammonemic encephalopathy is a rare central nervous system toxicity following 5-FU chemotherapy manifesting as altered mental status with elevated ammonia levels with no radiologic abnormality. We report one case of 5-FU induced hyperammonemic encephalopathy occurring after Folfox4 (oxaliplatin, folinic acid and 5-fluorouracil) chemotherapy in a colon cancer patient who presented with confused mental status soon after the chemotherapy and review the 5-FU related encephalopathy. PMID- 26942161 TI - Frequency of concomitant ischemic heart disease and risk factor analysis for an early postoperative myocardial infarction after elective abdominal aortic aneurysm repair. AB - PURPOSE: We aimed to see the frequency of concomitant ischemic heart disease (IHD) in Korean patients with abdominal aortic aneurysm (AAA) and to determine risk factors for an early postoperative acute myocardial infarction (PAMI) after elective open or endovascular AAA repair. METHODS: We retrospectively reviewed a database of patients who underwent elective AAA repair over the past 11 years. Patients were classified into 3 groups: control group; group I, medical IHD treatment; group II, invasive IHD treatment. Rates of PAMI and mortality at 30 days were compiled and compared between groups according to the type of AAA repair. RESULTS: Six hundred two elective repairs of infrarenal or juxtarenal AAAs were enrolled in this study. The patients were classified into control group (n = 398, 66.1%), group I (n = 73, 12.1%) and group II (n = 131, 21.8%). PAMI developed more frequently after open surgical repair (OSR) than after endovascular aneurysm repair (EVAR) (5.4% vs. 1.3%, P = 0.012). In OSR patients (n = 373), PAMI developed 2.1% in control group, 18.0% in group I and 7.1% in group II (P < 0.001). In EVAR group (n = 229), PAMI developed 0.6% in control group, 4.3% in group I and 2.2% in group II (P = 0.211). On the multivariable analysis of risk factors of PAMI, PAMI developed more frequently in patients with positive functional stress test. CONCLUSION: The prevalence of concomitant IHD was 34% in Korean AAA patients. The risk of PAMI was significantly higher after OSR compared to EVAR and in patients with IHD compared to control group. Though we found some risk factors for PAMI, these were not applied to postoperative mortality rate. PMID- 26942163 TI - Bilateral congenital alveolar synechiae-a rare cause of trismus. AB - Congenital alveolar synechiae is a rare anomaly mostly presenting in association with cleft palate. Owing to reduced mouth opening, feeding difficulties, and compromised airway in extreme cases along with presentation in early neonatal period, these patients present unique challenges to the surgeon as well as the anesthetist. Here, we discuss the surgical and anesthetic management of this entity in a 12-month-old female child. PMID- 26942164 TI - FEA model analysis of the effects of the stress distribution of saddle-type implants on the alveolar bone and the structural/physical stability of implants. AB - BACKGROUND: As dental implants receive masticatory stress, the distribution of stress is very important to peri-implant bone homeostasis and implant survival. In this report, we created a saddle-type implant and analyzed its stability and ability to distribute stress to the surrounding bone. METHODS: The implants were designed as a saddle-type implant (SI) that wrapped around the alveolar bone, and the sizes of the saddles were 2.5, 3.5, 4.5, and 5.5 mm. The X and Y displacement were compared to clarify the effects of the saddle structures. The control group consisted of dental implants without the saddle design (CI). Using finite element modeling (FEM), the stress distribution around the dental implants was analyzed. RESULTS: With saddle-type implants, saddles longer than 4.5 mm were more effective for stress distribution than CI. Regarding lateral displacement, a SI of 2.5 mm was effective for stress distribution compared to lateral displacement. ASI that was 5.6 mm in length was more effective for stress distribution than a CI that was 10 mm in length. CONCLUSIONS: The saddle-type implant could have a bone-gaining effect. Because it has stress-distributing effects, it might protect the newly formed bone under the implant. PMID- 26942165 TI - Roles of GASP-1 and GDF-11 in Dental and Craniofacial Development. AB - PURPOSE: Growth and differentiation factor-11 (GDF-11) is a TGF-beta family member that plays important regulatory roles in development of multiple tissues which include axial skeletal patterning, palatal closure, and tooth formation. Proteins that have been identified as GDF-11 inhibitors include GDF-associated serum protein-1 (GASP-1) and GASP-2. Recently, we found that mice genetically engineered to lack both Gasp1 and Gdf11 have an increased frequency of cleft palate. The goal of this study was to investigate the roles of GDF-11 and its inhibitors, GASP-1 and GASP-2, during dental and craniofacial development and growth. METHODS: Mouse genetic studies were used in this study. Homozygous knockout mice for Gasp1 (Gasp1-/- ) and Gasp2 (Gasp2-/- ) were viable and fertile, but Gdf11 homozygous knockout (Gdf11-/- ) mice died within 24 hours after birth. The effect of either Gasp1 or Gasp2 deletion in Gdf11-/- mice during embryogenesis was evaluated in Gasp1-/-;Gdf11-/- and Gasp2-/-;Gdf11-/- mouse embryos at 18.5 days post-coitum (E18.5). For the analysis of adult tissues, we used Gasp1-/-;Gdf11+/- and Gasp2-/-;Gdf11+/- mice to evaluate the potential haploinsufficiency of Gdf11 in Gasp1-/- and Gasp2-/- mice. RESULTS: Although Gasp2 expression decreased after E10.5, Gasp1 expression was readily detected in various ectodermal tissues at E17.5, including hair follicles, epithelium in nasal cavity, retina, and developing tooth buds. Interestingly, Gasp1-/- ;Gdf11-/ mice had abnormal formation of lower incisors: tooth buds for lower incisors were under-developed or missing. Although Gdf11+/- mice were viable and had mild transformations of the axial skeleton, no specific defects in the craniofacial development have been observed in Gdf11+/- mice. However, loss of Gasp1 in Gdf11+/- mice occasionally resulted in small and abnormally shaped auricles. CONCLUSIONS: These findings suggest that both GASP-1 and GDF-11 play important roles in dental and craniofacial development both during embryogenesis and in adult tissues. PMID- 26942167 TI - Comparative Analysis of Iron Homeostasis in Sub-Saharan African Children with Sickle Cell Disease and Their Unaffected Siblings. AB - Iron is an essential trace element subject to tight regulation to ensure adequate running of biological processes. In sub-Saharan Africa where hemoglobinopathies are common, iron homeostasis is likely to be impaired by these conditions. Here, we assessed and compared key serum proteins associated with iron metabolism between sub-Saharan African children with sickle cell disease (SCD) and their unaffected siblings. Complete blood counts and serum concentrations of four key proteins involved in iron regulation (ferritin, transferrin, sTfR, and hepcidin) were measured for 73 children with SCD and 68 healthy siblings in Benin, West Africa. We found significant differences in concentration of transferrin, sTfR, and ferritin between the two groups. Hepcidin concentrations were found at unusually high concentrations but did not differ among the two groups. We found a significant negative correlation between hepcidin levels and both MCH and MCV in the SCD group and report that sTfR concentrations show a correlation with MCV and MHC in opposite directions in the two groups. These results highlight the unusually high levels of hepcidin in the Beninese population and the patterns of differential iron homeostasis taking place under SCD status. These results lay the foundation for a systematic evaluation of the underlying mechanisms deregulating iron homeostasis in populations with SCD or high prevalence of iron deficiency. PMID- 26942166 TI - Missed Opportunities for Sedation and Pain Management at a Level III Neonatal Intensive Care Unit, India. AB - BACKGROUND: Neonates in the neonatal intensive care unit (NICU) undergo a multitude of painful and stressful procedures during the first days of life. Stress from this pain can lead to neurodevelopmental problems that manifest in later childhood and should be prevented. OBJECTIVE: To determine the number of painful procedures performed per day for each neonate, to verify documentation of painful procedures performed, and to, subsequently, note missed opportunities for providing pain relief to neonates. METHODS: We conducted a cross-sectional study at a level III NICU located in a rural part of western India. A total of 69 neonates admitted for more than 24 h were included. Twenty-nine neonates were directly observed for a total of 24 h each, and another 40 neonatal records were retrospectively reviewed for the neonate's first 7 days of admission. All stressful and painful procedures performed on the neonate were recorded. Also recorded were any pharmaceutical pain relief agents or central nervous system depressants administered to the neonate before or at the time of the procedures. Average nurse-patient ratio was also calculated. Data were analyzed using descriptive statistics. RESULTS: A documentation deficit of 2.2% was observed. The average nurse-patient ratio was 1.53:1. A total of 13711 procedures were recorded, yielding 44.1 (38.1 stressful, 3.8 mildly painful, and 2.2 moderately painful) procedures per patient day. Common stressful procedures were position changing (2501) and temperature recording (2208). Common mildly and moderately painful procedures were heel prick (757) and endotracheal suctioning (526), respectively. Use of pharmacological agents coincided with 33.48% of the procedures. The choice of drug and time of administration were inappropriate, indicating that the pharmacological agents were intended not for pain relief but rather for a coexisting pathology or as sedation from ventilation with no analgesia. CONCLUSION: Stressful procedures are common in the NICU; mildly and moderately painful procedures fairly common. Almost two-thirds of the times, no pharmaceutical pain relief methods were used, and when administered, the pharmaceutical agents were seldom intended for pain relief; this implies poor pain management practices and emphasizes the imperative need for educating NICU nurses, residents, fellows, and attendings. PMID- 26942169 TI - Resting State EEG Hemispheric Power Asymmetry in Children with Dyslexia. AB - Dyslexia is a neurodevelopmental disorder estimated to affect between 4 and 7% of the population. It is often referred to as a learning disability and is characterized by deficits in the linguistic system. To better understand the neural underpinnings of dyslexia, we examined the electroencephalography (EEG) power spectra between pre-adolescents with dyslexia and neurotypical control children during eyes closed state. We reported the differences in spontaneous oscillatory activity of each major EEG band (delta, theta, alpha, and beta) adopting a global as well as in a region-by-region and hemispheric approach to elucidate whether there are changes in asymmetry in children with dyslexia compared to controls. We also examined the relationship between EEG power spectra and clinical variables. The findings of our study confirm the presence of an atypical linguistic network, evident in children with dyslexia. This abnormal network hallmarked by a dominance of theta activity suggests that these abnormalities are present prior to these children learning to read, thus implicating delayed maturation and abnormal hypoarousal mechanisms. PMID- 26942168 TI - Respiratory Microbiome of New-Born Infants. AB - The respiratory tract, once believed to be sterile, harbors diverse bacterial communities. The role of microorganisms within health and disease is slowly being unraveled. Evidence points to the neonatal period as a critical time for establishing stable bacterial communities and influencing immune responses important for long-term respiratory health. This review summarizes the evidence of early airway and lung bacterial colonization and the role the microbiome has on respiratory health in the short and long term. The challenges of neonatal respiratory microbiome studies and future research directions are also discussed. PMID- 26942170 TI - When the Well is Dry, We Know the Worth of Water. PMID- 26942171 TI - The Hidden Effects of Dairy Farming on Public and Environmental Health in the Netherlands, India, Ethiopia, and Uganda, Considering the Use of Antibiotics and Other Agro-chemicals. AB - The current and expected growth of the world's population warrants an increased production of high-quality animal protein. Dairy farming is regarded as one of the important ways of satisfying this need to meet the growing demand for milk, especially in developing countries. The focus on crossbreeding and increasing the productivity of dairy cattle has, besides enhanced milk production, also resulted in an increased use of agro--chemicals, mainly antibiotics and anti-parasite drugs. The residues of these agro-chemicals, if not managed properly, could leak into the environment, affecting natural processes, biodiversity, and soil life. Public health can also be affected due to residues in milk and meat, especially in countries with insufficient food quality controls. These processes contribute to the growing global threat to human and animal health posed by multi-resistant microbes. This article discusses the differences and similarities of dairy farming, and the effect on public and environmental health, between the Netherlands, India, Ethiopia, and Uganda, emphasizing the strategies that have been developed during the E-Motive exchange project to reduce the use of antibiotics and other chemicals in dairy farming. Proposed solutions include raising consciousness about the risk of antibiotics and their effect on food quality, and implementing the Natural Livestock Farming five-layer approach for reducing the use of antibiotics and other chemicals. This approach is based on improving animal and farm management, revitalizing ethno veterinary knowledge and the use of medicinal plants, genetic improvement through strategic use of local breeds, establishing quality control systems in the dairy chain, and extra payment to farmers for residue-free milk. PMID- 26942172 TI - Caries Experience among Adults Exposed to Low to Moderate Doses of Ionizing Radiation in Childhood - The Tinea Capitis Cohort. AB - While the impact of therapeutic levels of ionizing radiation during childhood on dental defects has been documented, the possible effect of low doses on dental health is unknown. The study aim was to assess the association between childhood exposure to low-moderate doses of therapeutic radiation and caries experience among a cohort of adults 50 years following the exposure. The analysis was based on a sample of 253 irradiated (in the treatment of tinea capitis) and 162 non irradiated subjects. The decayed, missing, and filled teeth (DMFT) index was assessed during a clinical dental examination and questions regarding dental care services utilization, oral hygiene behavior, current self-perceived mouth dryness, socio-demographic parameters, and health behavior variables were obtained through a face-to-face interview. An ordered multivariate logistic regression model was used to assess the association of the main independent variable (irradiation status) and other relevant independent variables on the increase in DMFT. Mean caries experience levels (DMFT) were 18.6 +/- 7.5 for irradiated subjects compared to 16.4 +/- 7.2 for the non-irradiated (p = 0.002). Controlling for gender, age, education, income, smoking, dental visit in the last year, and brushing teeth behavior, irradiation was associated with a 72% increased risk for higher DMFT level (95% CI: 1.19-2.50). A quantification of the risk by dose absorbed in the salivary gland and in the thyroid gland showed adjusted ORs of 2.21 per 1 Gy (95% CI: 1.40-3.50) and 1.05 per 1 cGy (95% CI: 1.01-1.09), respectively. Childhood exposure to ionizing radiation (0.2-0.4 Gy) might be associated with late outcomes of dental health. In line with the guidelines of the American Dental Association, these results call for caution when using dental radiographs. PMID- 26942173 TI - Risk of ARI among Non-exclusively Breastfed Under-Five Passive Smoker Children: A Hospital-Based Cross-sectional Study of Nepal. AB - BACKGROUND: As Nepal witnesses high burden of both acute respiratory infection (ARI) and passive smoking among under-five children, studies on effect modification of exclusive breastfeeding on passive smoking and ARI carry huge significance. With Nepal holding no evidence in this regard, findings would be useful to promote a cost-effective intervention: exclusive breastfeeding. This study was therefore conceived as an effort to bring to light the modifying effect that exclusive breastfeeding may have on the association between household passive smoking and ARI among under-five children. METHODS: One hundred and ninety-eight parents of under-five children from Kanti Children's Hospital, Kathmandu, Nepal, participated in this descriptive, cross-sectional study carried out in October 2012. Data collected from a semi-structured questionnaire were subjected to univariate, bivariate, and multivariable analysis in R version 3.1.2. RESULTS: Non-exclusively breastfed children with presence of anyone smoking at their house [aOR = 4.8, 95% confidence interval (CI): 1.7-13.2] and smoking in presence of children (aOR = 6.4, 95% CI: 1.1-38.3) had higher chances of ARI; nevertheless, this remained insignificant among the exclusively breastfed ones. Having a separate kitchen in the house showed protective effect against ARI among exclusively breastfed children (aOR = 0.2, 95% CI: 0.1-0.6). Children whose mothers spent at least 2 h per day in the kitchen had a higher chance of developing ARI, regardless of being exclusively breastfed (aOR = 4.5, 95% CI: 1.5 13.1) or non-exclusively breastfed (aOR = 4.5, 95% CI: 1.4-14.2) compared to those who spent <2 h per day. CONCLUSION: Non-exclusive breastfeeding may increase the chances of deleterious effects of household passive smoking, such as ARI, among under-five children. As these findings are not conclusive, studies with better design and larger samples are warranted to confirm the effect. PMID- 26942174 TI - Twitter Influence on UK Vaccination and Antiviral Uptake during the 2009 H1N1 Pandemic. AB - OBJECTIVE: Information exchange via Twitter and other forms of social media make public health communication more complex as citizens play an increasingly influential role in shaping acceptable or desired health behaviors. Taking the case of the 2009-2010 H1N1 pandemic, we explore in detail the dissemination of H1N1-related advice in the UK through Twitter to see how it was used to discourage or encourage vaccine and antiviral uptake. METHODS: In three stages we conducted (1) an analysis of general content, retweeting patterns, and URL sharing, (2) a discourse analysis of the public evaluation of press releases and (3) a template analysis of conversations around vaccine and antiviral uptake, using Protection Motivation Theory (PMT) as a way of understanding how the public weighed the costs and benefits. RESULTS: Network analysis of retweets showed that information from official sources predominated. Analysing the spread of significant messages through Twitter showed that most content was descriptive but there was some criticism of health authorities. A detailed analysis of responses to press releases revealed some scepticism over the economic beneficiaries of vaccination, that served to undermine public trust. Finally, the conversational analysis showed the influence of peers when weighing up the risks and benefits of medication. CONCLUSION: Most tweets linked to reliable sources, however Twitter was used to discuss both individual and health authority motivations to vaccinate. The PMT framework describes the ways individuals assessed the threat of the H1N1 pandemic, weighing this against the perceived cost of taking medication. These findings offer some valuable insights for social media communication practices in future pandemics. PMID- 26942175 TI - Project YOURLIFE (What Young People Think and Feel about Relationships, Love, Sexuality, and Related Risk Behavior): Cross-sectional and Longitudinal Protocol. AB - INTRODUCTION: Sexually transmitted infections and unplanned pregnancies affect adolescent sexual health and are serious public health concerns. They result from sexual intercourse in adolescence, which is usually associated with multiple partners, unprotected sex, and condom misuse. This behavior is related to socio ecological factors that influence lifestyles. The YOURLIFE project aims to find out what young people think and feel about relationships, love, and sexuality, and to assess the associations between these thoughts and attitudes, adolescents' social factors, and sexual health. MATERIALS AND EQUIPMENT: An international school-based study with a cross-sectional and optional subsequent longitudinal design. Three online questionnaires designed for adolescents aged 13/14, 15/16, and 17/18, respectively, will be used. A matching coding system will allow longitudinal follow-up when adolescents reply to follow-up surveys. Questionnaires will include questions related to sociodemographic data; information/communication technologies; leisure time; parental supervision; influences of parents/friends; information sources; messages perceived; and sexuality-related knowledge, attitudes, and opinions. The second and third questionnaires for participants aged 15/16 and 17/18 will also contain variables concerning sexual behavior. Schools will be able to use their results to tailor educational approaches targeting the needs of their students. Multivariate analyses will be performed using the larger international dataset. EXPECTED IMPACT OF THE STUDY ON PUBLIC HEALTH: The YOURLIFE project will collect comprehensive information about the socio-ecological determinants of the sexual risk-taking of schooled adolescents worldwide. Effective preventive programs could be subsequently designed and tailored to the specific determinants of adolescents from different schools and settings, and also, when analyzed globally, to public health professionals. PMID- 26942176 TI - Lymphadenopathy: Differentiation between Tuberculosis and Other Non-Tuberculosis Causes like Follicular Lymphoma. PMID- 26942177 TI - The Clusters-in-a-Liquid Approach for Solvation: New Insights from the Conformer Specific Gas Phase Spectroscopy and Vibrational Optical Activity Spectroscopy. AB - Vibrational optical activity spectroscopies, namely vibrational circular dichroism (VCD) and Raman optical activity (ROA), have been emerged in the past decade as powerful spectroscopic tools for stereochemical information of a wide range of chiral compounds in solution directly. More recently, their applications in unveiling solvent effects, especially those associated with water solvent, have been explored. In this review article, we first select a few examples to demonstrate the unique sensitivity of VCD spectral signatures to both bulk solvent effects and explicit hydrogen-bonding interactions in solution. Second, we discuss the induced solvent chirality, or chiral transfer, VCD spectral features observed in the water bending band region in detail. From these chirality transfer spectral data, the related conformer specific gas phase spectroscopic studies of small chiral hydration clusters, and the associated matrix isolation VCD experiments of hydrogen-bonded complexes in cold rare gas matrices, a general picture of solvation in aqueous solution emerges. In such an aqueous solution, some small chiral hydration clusters, rather than the chiral solutes themselves, are the dominant species and are the ones that contribute mainly to the experimentally observed VCD features. We then review a series of VCD studies of amino acids and their derivatives in aqueous solution under different pHs to emphasize the importance of the inclusion of the bulk solvent effects. These experimental data and the associated theoretical analyses are the foundation for the proposed "clusters-in-a-liquid" approach to account for solvent effects effectively. We present several approaches to identify and build such representative chiral hydration clusters. Recent studies which applied molecular dynamics simulations and the subsequent snapshot averaging approach to generate the ROA, VCD, electronic CD, and optical rotatory dispersion spectra are also reviewed. Challenges associated with the molecular dynamics snapshot approach are discussed and the successes of the seemingly random "ad hoc explicit solvation" reported before are also explained. To further test and improve the "clusters-in-a-liquid" model in practice, future work in terms of conformer specific gas phase spectroscopy of sequential solvation of a chiral solute, matrix isolation VCD measurements of small chiral hydration clusters, and more sophisticated models for the bulk solvent effects would be highly valuable. PMID- 26942178 TI - A Novel Device for Grasping Assessment during Functional Tasks: Preliminary Results. AB - This paper presents a methodology and first results obtained in a study with a novel device that allows the analysis of grasping quality. Such a device is able to acquire motion information of upper limbs allowing kinetic of manipulation analysis as well. A pilot experiment was carried out with six groups of typically developing children aged between 5 and 10 years, with seven to eight children in each one. The device, designed to emulate a glass, has an optical system composed by one digital camera and a special convex mirror that together allow image acquisition of grasping hand posture when it is grasped and manipulated. It also carries an Inertial Measurement Unit that captures motion data as acceleration, orientation, and angular velocities. The novel instrumented object is used in our approach to evaluate functional tasks performance in quantitative terms. During tests, each child was invited to grasp the cylindrical part of the device that was placed on the top of a table, simulating the task of drinking a glass of water. In the sequence, the child was oriented to transport the device back to the starting position and release it. The task was repeated three times for each child. A grasping hand posture evaluation is presented as an example to evaluate grasping quality. Additionally, motion patterns obtained with the trials performed with the different groups are presented and discussed. This device is attractive due to its portable characteristics, the small size, and its ability to evaluate grasping form. The results may be also useful to analyze the evolution of the rehabilitation process through reach-to-grasping movement and the grasping images analysis. PMID- 26942180 TI - Response: "Commentary: A Hypothesis for Examining Skeletal Muscle Biopsy-Derived Sarcolemmal nNOSu as Surrogate for Enteric nNOSalpha Function". nNOS(skeletal muscle) may be Evidentiary for Enteric NO-Transmission Despite nNOSu/alpha Differences. PMID- 26942182 TI - Open and Laparo-Endoscopic Repair of Incarcerated Abdominal Wall Hernias by the Use of Biological and Biosynthetic Meshes. AB - INTRODUCTION: Although recently published guidelines recommend against the use of synthetic non-absorbable materials in cases of potentially contaminated or contaminated surgical fields due to the increased risk of infection (1, 2), the use of bio-prosthetic meshes for abdominal wall or ventral hernia repair is still controversially discussed in such cases. Bio-prosthetic meshes have been recommended due to less susceptibility for infection and the decreased risk of subsequent mesh explantation. The purpose of this review is to elucidate if there are any indications for the use of biological and biosynthetic meshes in incarcerated abdominal wall hernias based on the recently published literature. METHODS: A literature search of the Medline database using the PubMed search engine, using the keywords returned 486 articles up to June 2015. The full text of 486 articles was assessed and 13 relevant papers were identified including 5 retrospective case cohort studies, 2 case-controlled studies, and 6 case series. RESULTS: The results of Franklin et al. (3-5) included the highest number of biological mesh repairs (Surgisis((r))) by laparoscopic IPOM in infected fields, which demonstrated a very low incidence of infection and recurrence (0.7 and 5.2%). Han et al. (6) reported in his retrospective study, the highest number of treated patients due to incarcerated hernias by open approach using acellular dermal matrix (ADM((r))) with very low rate of infection as well as recurrences (1.6 and 15.9%). Both studies achieved acceptable outcome in a follow-up of at least 3.5 years compared to the use of synthetic mesh in this high-risk population (7). CONCLUSION: Currently, there is a very limited evidence for the use of biological and biosynthetic meshes in strangulated hernias in either open or laparo-endoscopic repair. Finally, there is an urgent need to start with randomized controlled comparative trials as well as to support registries with data to achieve more knowledge for tailored indication for the use of biological meshes. PMID- 26942179 TI - Hypoxia-Inducible Factors (HIFs) and Phosphorylation: Impact on Stability, Localization, and Transactivity. AB - The hypoxia-inducible factor alpha-subunits (HIFalpha) are key transcription factors in the mammalian response to oxygen deficiency. The HIFalpha regulation in response to hypoxia occurs primarily on the level of protein stability due to posttranslational hydroxylation and proteasomal degradation. However, HIF alpha subunits also respond to various growth factors, hormones, or cytokines under normoxia indicating involvement of different kinase pathways in their regulation. Because these proteins participate in angiogenesis, glycolysis, programmed cell death, cancer, and ischemia, HIFalpha regulating kinases are attractive therapeutic targets. Although numerous kinases were reported to regulate HIFalpha indirectly, direct phosphorylation of HIFalpha affects HIFalpha stability, nuclear localization, and transactivity. Herein, we review the role of phosphorylation-dependent HIFalpha regulation with emphasis on protein stability, subcellular localization, and transactivation. PMID- 26942181 TI - Small Molecule Radiopharmaceuticals - A Review of Current Approaches. AB - Radiopharmaceuticals are an integral component of nuclear medicine and are widely applied in diagnostics and therapy. Though widely applied, the development of an "ideal" radiopharmaceutical can be challenging. Issues such as specificity, selectivity, sensitivity, and feasible chemistry challenge the design and synthesis of radiopharmaceuticals. Over time, strategies to address the issues have evolved by making use of new technological advances in the fields of biology and chemistry. This review presents the application of few advances in design and synthesis of radiopharmaceuticals. The topics covered are bivalent ligand approach and lipidization as part of design modifications for enhanced selectivity and sensitivity and novel synthetic strategies for optimized chemistry and radiolabeling of radiopharmaceuticals. PMID- 26942183 TI - Soft Tissue Sarcomas of the Arm - Oncosurgical and Reconstructive Principles within a Multimodal, Interdisciplinary Setting. AB - Soft tissue sarcomas of the upper extremity represent a severe threat for the patient and a difficult task for the treatment team. Due to the complex anatomy of the arm, most sarcomas involve valuable functional structures. Nonetheless, a large portion of the patients can be treated in a limb-sparing manner, and surgery is the mainstay of local tumor control. This review gives an overview of the disease entities and their epidemiology, on necessary patient work-up, staging, and imaging modalities, as well as the importance of interdisciplinary decision-making. The surgical therapies and principles of tumor excision are outlined, as well as reconstructive options. Furthermore, adjuvant treatments are discussed with a special focus on the various application techniques for radiation therapy. In spite of established treatment algorithms, each case is an individual challenge and individually tailored therapy is required. This aspect is illustrated by presenting three comprehensive cases demonstrating useful strategies. A summary of the relevant literature is given. PMID- 26942184 TI - Timeline of History of Hypertension Treatment. AB - It is surprising that only about 50 years ago hypertension was considered an essential malady and not a treatable condition. Introduction of thiazide diuretics in late 50s made some headway in successful treatment of hypertension and ambitious multicenter VA co-operative study (phase 1 and 2) started in 1964 for diastolic hypertension ranging between 90 and 129 mmHg and completed by 1971 established for the first time that treating diastolic hypertension reduced CV events such as stroke and heart failure and improved mortality. In the following decade, these results were confirmed for the wider US and non-US population, including women and goal-oriented BP treatment to diastolic 90 became the standard therapy recommendation. But isolated systolic hypertension (accounting for two-thirds of the 70 million hypertensive population in USA alone) was not considered treatable until 1991 when SHEP study (systolic hypertension in elderly program) was completed and showed tremendous benefits of treating systolic BP over 160 mmHg using only a simple regimen using small dose chlorthalidone with addition of atenolol if needed. In the next two decades, ALLHAT and other studies examined the comparability of outcomes with use of different classes and combinations of antihypertensive drugs. Although diastolic BP goal was established as 90 in the late 70s and later confirmed by HOT study, the goal BP for systolic hypertension was not settled until very recently with completion of SPRINT study. ACCORD study showed no significant difference in outcome with sys 140 vs. 120 in diabetics. But recently completed SPRINT study with somewhat similar protocol as in ACCORD but in non-diabetic showed almost one-quarter reduction in all-cause mortality and one-third reduction of CV events with systolic BP goal 120. PMID- 26942186 TI - Impacts of Cereal Ergot in Food Animal Production. AB - The negative impacts of ergot contamination of grain on the health of humans and animals were first documented during the fifth century AD. Although ergotism is now rare in humans, cleaning contaminated grain concentrates ergot bodies in screenings which are used as livestock feed. Ergot is found worldwide, with even low concentrations of alkaloids in the diet (<100 ppb total), reducing the growth efficiency of livestock. Extended periods of increased moisture and cold during flowering promote the development of ergot in cereal crops. Furthermore, the unpredictability of climate change may have detrimental impacts to important cereal crops, such as wheat, barley, and rye, favoring ergot production. Allowable limits for ergot in livestock feed are confusing as they may be determined by proportions of ergot bodies or by total levels of alkaloids, measurements that may differ widely in their estimation of toxicity. The proportion of individual alkaloids, including ergotamine, ergocristine, ergosine, ergocornine, and ergocryptine is extremely variable within ergot bodies and the relative toxicity of these alkaloids has yet to be determined. This raises concerns that current recommendations on safe levels of ergot in feeds may be unreliable. Furthermore, the total ergot alkaloid content is greatly dependent on the geographic region, harvest year, cereal species, variety, and genotype. Considerable animal-to-animal variation in the ability of the liver to detoxify ergot alkaloids also exists and the impacts of factors, such as pelleting of feeds or use of binders to reduce bioavailability of alkaloids require study. Accordingly, unknowns greatly outnumber the knowns for cereal ergot and further study to help better define allowable limits for livestock would be welcome. PMID- 26942185 TI - Managing Neuropathic Pain in Dogs. AB - Disorders of the somatosensory system such as neuropathic pain are common in people with chronic neurologic and musculoskeletal diseases, yet these conditions remain an underappreciated morbidity in veterinary patients. This is likely because assessment of neuropathic pain in people relies heavily on self reporting, something our veterinary patients are not able to do. The development of neuropathic pain is a complex phenomenon, and concepts related to it are frequently not addressed in the standard veterinary medical curriculum such that veterinarians may not recognize this as a potential problem in patients. The goals of this review are to discuss basic concepts in the pathophysiology of neuropathic pain, provide definitions for common clinical terms used in association with the condition, and discuss pharmacological treatment options for dogs with neuropathic pain. The development of neuropathic pain involves key mechanisms such as ectopic afferent nerve activity, peripheral sensitization, central sensitization, impaired inhibitory modulation, and pathologic activation of microglia. Treatments aimed at reducing neuropathic pain are targeted at one or more of these mechanisms. Several drugs are commonly used in the veterinary clinical setting to treat neuropathic pain. These include gabapentin, pregabalin, amantadine, and amitriptyline. Proposed mechanisms of action for each drug, and known pharmacokinetic profiles in dogs are discussed. Strong evidence exists in the human literature for the utility of most of these treatments, but clinical veterinary-specific literature is currently limited. Future studies should focus on objective methods to document neuropathic pain and monitor response to therapy in veterinary patients. PMID- 26942187 TI - Rearing Room Affects the Non-dominant Chicken Cecum Microbiota, While Diet Affects the Dominant Microbiota. AB - The combined effect of environment and diet in shaping the gut microbiota remains largely unknown. This knowledge, however, is important for animal welfare and safe food production. For these reasons, we determined the effect of experimental units on the chicken cecum microbiota for a full factorial experiment where we tested the combined effect of room, diet, and antimicrobial treatment. By Illumina Deep sequencing of the 16S rRNA gene, we found that diet mainly affected the dominant microbiota, while the room as a proxy for environment had major effects on the non-dominant microbiota (p = 0.006, Kruskal-Wallis test). We, therefore, propose that the dominant and non-dominant microbiotas are shaped by different experimental units. These findings have implications both for our general understanding of the host-associated microbiota and for setting up experiments related to specific targeting of pathogens. PMID- 26942188 TI - Effects of Ginger Phenylpropanoids and Quercetin on Nrf2-ARE Pathway in Human BJ Fibroblasts and HaCaT Keratinocytes. AB - Quercetin and phenylpropanoids are well known chemoprotective compounds identified in many plants. This study was aimed at determining their effects on activation of Nuclear factor erythroid 2-related factor 2 (Nrf2) antioxidant response element (Nrf2-ARE) signalling pathway and expression of its important downstream effector phase II detoxification enzyme glutathione-S-transferase P1 (GSTP1) in BJ foreskin fibroblasts and skin HaCaT keratinocytes. Cell lines and their corresponding Nrf2-ARE luciferase reporter cells were treated by ginger phenylpropanoids and quercetin for 10 h and the level of Nrf2 activity was subsequently determined. Both, ginger phenylpropanoids and quercetin, significantly increased the level of Nrf2 activity. Subsequent western blot analyses of proteins showed the increased expression level of glutathione-S transferase P1 (GSTP1) in BJ cells but not in HaCaT cells. Such phenomenon of unresponsive downstream target expression in HaCaT cells was consistent with previous studies showing a constitutive expression of their GSTP1. Thus, while both ginger phenylpropanoids and quercetin have the property of increasing the level of Nrf2 both in HaCaT and in BJ cells, their effects on its downstream signalling were mediated only in BJ cells. PMID- 26942189 TI - Potential Diagnostic and Prognostic Biomarkers of Epigenetic Drift within the Cardiovascular Compartment. AB - Biomarkers encompass a wide range of different measurable indicators, representing a tangible link to physiological changes occurring within the body. Accessibility, sensitivity, and specificity are significant factors in biomarker suitability. New biomarkers continue to be discovered, and questions over appropriate selection and assessment of their usefulness remain. If traditional markers of inflammation are not sufficiently robust in their specificity, then perhaps alternative means of detection may provide more information. Epigenetic drift (epigenetic modifications as they occur as a direct function with age), and its ancillary elements, including platelets, secreted microvesicles (MVs), and microRNA (miRNA), may hold enormous predictive potential. The majority of epigenetic drift observed in blood is independent of variations in blood cell composition, addressing concerns affecting traditional blood-based biomarker efficacy. MVs are found in plasma and other biological fluids in healthy individuals. Altered MV/miRNA profiles may also be found in individuals with various diseases. Platelets are also highly reflective of physiological and lifestyle changes, making them extremely sensitive biomarkers of human health. Platelets release increased levels of MVs in response to various stimuli and under a plethora of disease states, which demonstrate a functional effect on other cell types. PMID- 26942190 TI - Do We Pay Enough Attention to Culture Conditions in Context of Perinatal Outcome after In Vitro Fertilization? Up-to-Date Literature Review. AB - Adverse perinatal outcomes in singleton IVF pregnancies have been most often explained by parental underlying diseases and so far laboratory conditions during embryo culture are still not explored well. The following review discusses the current state of knowledge on the influence of IVF laboratory procedures on the possible perinatal outcome. The role of improved media for human embryo culture is unquestionable. Addition of certain components to culture media and their effect on embryo survival and implantation rates have been taken into consideration recently and studied on animal model. Impact of media on perinatal outcome in IVF offspring has also been studied. It has been discovered that epigenetic changes and neonatal birth weight are probably associated with the use of specific culture media, as is the relation between placental size and its influence on perinatal outcome. There are still questions in the discussion about duration of embryo culture (cleavage stage versus blastocyst transfer). Some of the IVF methods, such as in vitro maturation of oocytes and freezing/thawing procedures, also require well-powered randomized controlled trials in order to define their exact impact on perinatal outcome. Constant further research is needed to assess the impact of laboratory environment on fetal and postnatal development. PMID- 26942191 TI - Bioactive Materials for Bone Tissue Engineering. PMID- 26942193 TI - ChemTok: A New Rule Based Tokenizer for Chemical Named Entity Recognition. AB - Named Entity Recognition (NER) from text constitutes the first step in many text mining applications. The most important preliminary step for NER systems using machine learning approaches is tokenization where raw text is segmented into tokens. This study proposes an enhanced rule based tokenizer, ChemTok, which utilizes rules extracted mainly from the train data set. The main novelty of ChemTok is the use of the extracted rules in order to merge the tokens split in the previous steps, thus producing longer and more discriminative tokens. ChemTok is compared to the tokenization methods utilized by ChemSpot and tmChem. Support Vector Machines and Conditional Random Fields are employed as the learning algorithms. The experimental results show that the classifiers trained on the output of ChemTok outperforms all classifiers trained on the output of the other two tokenizers in terms of classification performance, and the number of incorrectly segmented entities. PMID- 26942192 TI - E2A Antagonizes PU.1 Activity through Inhibition of DNA Binding. AB - Antagonistic interactions between transcription factors contribute to cell fate decisions made by multipotent hematopoietic progenitor cells. Concentration of the transcription factor PU.1 affects myeloid/lymphoid development with high levels of PU.1 directing myeloid cell fate acquisition at the expense of B cell differentiation. High levels of PU.1 may be required for myelopoiesis in order to overcome inhibition of its activity by transcription factors that promote B cell development. The B cell transcription factors, E2A and EBF, are necessary for commitment of multipotential progenitors and lymphoid primed multipotential progenitors to lymphocytes. In this report we hypothesized that factors required for early B cell commitment would bind to PU.1 and antagonize its ability to induce myeloid differentiation. We investigated whether E2A and/or EBF associate with PU.1. We observed that the E2A component, E47, but not EBF, directly binds to PU.1. Additionally E47 represses PU.1-dependent transactivation of the MCSFR promoter through antagonizing PU.1's ability to bind to DNA. Exogenous E47 expression in hematopoietic cells inhibits myeloid differentiation. Our data suggest that E2A antagonism of PU.1 activity contributes to its ability to commit multipotential hematopoietic progenitors to the lymphoid lineages. PMID- 26942194 TI - Upscaling Arbuscular Mycorrhizal Symbiosis and Related Agroecosystems Services in Smallholder Farming Systems. AB - Smallholder farming systems form unique ecosystems that can protect beneficial soil biota and form an important source of useful genetic resources. They are characterized by high level of agricultural diversity mainly focused on meeting farmers' needs. Unfortunately, these systems often experience poor crop production mainly associated with poor planning and resource scarcity. Soil fertility is among the primary challenges faced by smallholder farmers, which necessitate the need to come up with affordable and innovative ways of replenishing soils. One such way is the use of microbial symbionts such as arbuscular mycorrhizal fungi (AMF), a beneficial group of soil microbiota that form symbiotic associations with majority of cultivated crops and play a vital role in biological soil fertility, plant nutrition, and protection. AMF can be incorporated in smallholder farming systems to help better exploit chemical fertilizers inputs which are often unaffordable to many smallholder farmers. The present review highlights smallholder farming practices that could be innovatively redesigned to increase AMF symbiosis and related agroecosystem services. Indeed, the future of global food security depends on the success of smallholder farming systems, whose crop productivity depends on the services provided by well-functioning ecosystems, including soil fertility. PMID- 26942195 TI - Behavioral Periodicity Detection from 24 h Wrist Accelerometry and Associations with Cardiometabolic Risk and Health-Related Quality of Life. AB - Periodicities (repeating patterns) are observed in many human behaviors. Their strength may capture untapped patterns that incorporate sleep, sedentary, and active behaviors into a single metric indicative of better health. We present a framework to detect periodicities from longitudinal wrist-worn accelerometry data. GENEActiv accelerometer data were collected from 20 participants (17 men, 3 women, aged 35-65) continuously for 64.4 +/- 26.2 (range: 13.9 to 102.0) consecutive days. Cardiometabolic risk biomarkers and health-related quality of life metrics were assessed at baseline. Periodograms were constructed to determine patterns emergent from the accelerometer data. Periodicity strength was calculated using circular autocorrelations for time-lagged windows. The most notable periodicity was at 24 h, indicating a circadian rest-activity cycle; however, its strength varied significantly across participants. Periodicity strength was most consistently associated with LDL-cholesterol (r's = 0.40-0.79, P's < 0.05) and triglycerides (r's = 0.68-0.86, P's < 0.05) but also associated with hs-CRP and health-related quality of life, even after adjusting for demographics and self-rated physical activity and insomnia symptoms. Our framework demonstrates a new method for characterizing behavior patterns longitudinally which captures relationships between 24 h accelerometry data and health outcomes. PMID- 26942196 TI - Evidence-Based Public Health. PMID- 26942197 TI - Downregulation of Mitofusin 2 in Placenta Is Related to Preeclampsia. AB - Background. Mitofusin 2 (Mfn2) is a novel mitochondrial protein that is implicated in cellular proliferation and metabolism; however, the role of Mfn2 in preeclampsia (PE) remains unknown. This study aimed to explore the relationship between Mfn2 and PE. Method. Preeclamptic and normal pregnancies were enrolled in a comparative study. The expression of Mfn2 in placenta was detected by qRT-PCR. And the mitochondrial function was detected by ATP assay. Then TEV-1 cells were cultured in hypoxic conditions. mRNA and protein expressions of Mfn2 were detected by qRT-PCR and western blot separately. Cells' viability was detected by MTT. And the mitochondrial function was detected by ATP and mitochondrial membrane potential (MMP) assay. We further knocked down the Mfn2 gene in TEV-1 cells and evaluated the cells' viability. Results. Mfn2 and ATP expressions were significantly decreased in preeclamptic placentae compared to normal placentae. Mfn2 expression level and the viability of TEV-1 cells were reduced during hypoxic conditions. TEV-1 cells' viability, ATP, and MMP levels were also significantly decreased after knockdown of the Mfn2 gene. Conclusions. These results suggest that defects in Mfn2 could cause mitochondrial dysfunction and decrease trophoblastic cells' viability. Therefore, Mfn2 may be functionally involved in the pathogenesis of PE. PMID- 26942199 TI - Male Infertility: Genetics, Mechanism, and Therapies. PMID- 26942198 TI - The Impact of Biopsy on Human Embryo Developmental Potential during Preimplantation Genetic Diagnosis. AB - Preimplantation Genetic Diagnosis and Screening (PGD/PGS) for monogenic diseases and/or numerical/structural chromosomal abnormalities is a tool for embryo testing aimed at identifying nonaffected and/or euploid embryos in a cohort produced during an IVF cycle. A critical aspect of this technology is the potential detrimental effect that the biopsy itself can have upon the embryo. Different embryo biopsy strategies have been proposed. Cleavage stage blastomere biopsy still represents the most commonly used method in Europe nowadays, although this approach has been shown to have a negative impact on embryo viability and implantation potential. Polar body biopsy has been proposed as an alternative to embryo biopsy especially for aneuploidy testing. However, to date no sufficiently powered study has clarified the impact of this procedure on embryo reproductive competence. Blastocyst stage biopsy represents nowadays the safest approach not to impact embryo implantation potential. For this reason, as well as for the evidences of a higher consistency of the molecular analysis when performed on trophectoderm cells, blastocyst biopsy implementation is gradually increasing worldwide. The aim of this review is to present the evidences published to date on the impact of the biopsy at different stages of preimplantation development upon human embryos reproductive potential. PMID- 26942200 TI - Mechanical and Histological Effects of Resorbable Blasting Media Surface Treatment on the Initial Stability of Orthodontic Mini-Implants. AB - Introduction. This study aimed to evaluate the effects of resorbable blasting media (RBM) treatment on early stability of orthodontic mini-implants by mechanical, histomorphometric, and histological analyses. Methods. Ninety-six (64 for mechanical study and 32 for histological study and histomorphometric analysis) titanium orthodontic mini-implants (OMIs) with machined (machined group) or RBM-treated (CaP) surface (RBM group) were implanted in the tibiae of 24 rabbits. Maximum initial torque (MIT) was measured during insertion, and maximum removal torque (MRT) and removal angular momentum (RAM) were measured at 2 and 4 weeks after implantation. Bone-to-implant contact (BIC) and bone area (BA) were analyzed at 4 weeks after implantation. Results. RBM group exhibited significantly lower MIT and significantly higher MRT and RAM at 2 weeks than machined group. No significant difference in MRT, RAM, and BIC between the two groups was noted at 4 weeks, although BA was significantly higher in RBM group than in machined group. RBM group showed little bone resorption, whereas machined group showed new bone formation after bone resorption. Conclusions. RBM surface treatment can provide early stability of OMIs around 2 weeks after insertion, whereas stability of machined surface OMIs may decrease in early stages because of bone resorption, although it can subsequently recover by new bone apposition. PMID- 26942201 TI - Advanced Glycation End Products Induce Obesity and Hepatosteatosis in CD-1 Wild Type Mice. AB - AGEs are a heterogeneous group of molecules formed from the nonenzymatic reaction of reducing sugars with free amino groups of proteins, lipids, and/or nucleic acids. AGEs have been shown to play a role in various conditions including cardiovascular disease and diabetes. In this study, we hypothesized that AGEs play a role in the "multiple hit hypothesis" of nonalcoholic fatty liver disease (NAFLD) and contribute to the pathogenesis of hepatosteatosis. We measured the effects of various mouse chows containing high or low AGE in the presence of high or low fat content on mouse weight and epididymal fat pads. We also measured the effects of these chows on the inflammatory response by measuring cytokine levels and myeloperoxidase activity levels on liver supernatants. We observed significant differences in weight gain and epididymal fat pad weights in the high AGE-high fat (HAGE-HF) versus the other groups. Leptin, TNF-alpha, IL-6, and myeloperoxidase (MPO) levels were significantly higher in the HAGE-HF group. We conclude that a diet containing high AGEs in the presence of high fat induces weight gain and hepatosteatosis in CD-1 mice. This may represent a model to study the role of AGEs in the pathogenesis of hepatosteatosis and steatohepatitis. PMID- 26942203 TI - Synergy between Rhizobium phaseoli and Acidithiobacillus ferrooxidans in the Bioleaching Process of Copper. AB - This study investigates the synergy of Rhizobium phaseoli and Acidithiobacillus ferrooxidans in the bioleaching process of copper. The results showed that additional R. phaseoli could increase leaching rate and cell number of A. ferrooxidans. When the initial cell number ratio between A. ferrooxidans and R. phaseoli was 2 : 1, A. ferrooxidans attained the highest final cell number of approximately 2 * 10(8) cells/mL and the highest copper leaching rate of 29%, which is 7% higher than that in the group with A. ferrooxidans only. R. phaseoli may use metabolized polysaccharides from A. ferrooxidans, and organic acids could chelate or precipitate harmful heavy metals to reduce their damage on A. ferrooxidans and promote its growth. Organic acids could also damage the mineral lattice to increase the leaching effect. PMID- 26942202 TI - Two-Dimensional Speckle Tracking Echocardiography Detects Subclinical Left Ventricular Systolic Dysfunction among Adult Survivors of Childhood, Adolescent, and Young Adult Cancer. AB - Two-dimensional speckle tracking echocardiography (2DSTE) provides a sensitive measure of left ventricular (LV) systolic function and may aid in the diagnosis of cardiotoxicity. 2DSTE was performed in a cross-sectional study of 134 patients (mean age: 31.4 +/- 8.8 years; 55% male; mean time since diagnosis: 15.4 +/- 9.4 years) previously treated with anthracyclines (mean cumulative dose: 320 +/- 124 mg/m(2)), with (n = 52) or without (n = 82) mediastinal radiotherapy. The prevalence of LV systolic dysfunction, defined as fractional shortening < 27%, LV ejection fraction (LVEF) < 55%, and global longitudinal strain (GLS) <= 16%, was 5.2%, 6.0%, and 23.1%, respectively. Abnormal GLS was observed in 24 (18%) patients despite a normal LVEF. Indices of LV systolic function were similar regardless of anthracycline dose. However, GLS was worse (18.0 versus 19.0, p = 0.003) and prevalence of abnormal GLS was higher (36.5% versus 14.6%, p = 0.004) in patients treated with mediastinal radiotherapy. Mediastinal radiotherapy was associated with reduced GLS (p = 0.040) after adjusting for sex, age, and cumulative anthracycline dose. In adult survivors of childhood, adolescent, and young adult cancer, 2DSTE frequently detects LV systolic dysfunction despite a normal LVEF and may be useful for the long-term cardiac surveillance of adult cancer survivors. PMID- 26942205 TI - miRNAs in Urine Extracellular Vesicles as Predictors of Early-Stage Diabetic Nephropathy. AB - BACKGROUND: miR-192, miR-194, and miR-215 are enriched in the kidney and play roles in the pathogenesis of diabetic nephropathy (DN). Extracellular vesicles (EVs) can be detected in body fluids and may serve as disease biomarkers. METHODS: Eighty type 2 diabetes patients with normoalbuminuria (n = 30), microalbuminuria (n = 30), or macroalbuminuria (n = 20), as well as 10 healthy controls, were enrolled in this study. Real-time PCR was used to evaluate urinary EV miRNAs expression. RESULTS: The miR-192 levels were significantly higher than the miR-194 and miR-215 levels in urine EVs and all three miRNAs were significantly increased in the microalbuminuric group compared with the normoalbuminuric and control subjects but were decreased in the macroalbuminuric group. In patients with normoalbuminuria and microalbuminuria, miR-192 was positively correlated with albuminuria (r = 0.357, P = 0.005) levels and transforming growth factor- (TGF-) beta1 (r = 0.356, P = 0.005) expression. Receiver operating characteristic (ROC) curve analysis revealed that miR-192 was better than miR-194 and miR-215 in discriminating the normoalbuminuric group from the microalbuminuric group. Exposure of human renal tubular epithelial cells to high glucose increased the expression of both miRNAs in cellular supernatant EVs, indicating a potential source. CONCLUSION: These results suggest the potential use of urinary EV miR-192 as a biomarker of the early stage of DN. PMID- 26942206 TI - Human Macrophages Utilize the Podosome Formin FMNL1 for Adhesion and Migration. AB - Macrophages play a crucial role in detecting, regulating, and resolving immune crises, requiring migration through complex extracellular matrices. Unwarranted macrophage inflammatory activity potentiates kidney disease, rheumatoid arthritis, and transplant rejection. Proper remodeling of the actin cytoskeleton, especially at adhesion structures, is essential to the translocation of macrophages. Macrophages form actin-rich adhesions termed "podosomes", giving them the capacity to make contacts with the substratum for traction through interstitial tissues. Macrophages express multiple formins, including FMNL1, Dia1, and Fhod1, with potential to impact actin remodeling involved in migration. Formins are a family of proteins that are best known for modifying the actin cytoskeleton via nucleation, elongation, bundling, and/or severing actin filaments. In this study we demonstrate that the formin FMNL1 is a key regulator of podosomes and is required for normal macrophage migration. Additionally, this is the first study to demonstrate defects in primary human cell migration resulting from specific formin silencing. Pharmacologic inhibition of all formin activity results in a significant decrease in podosome formation and normal macrophage migration. Furthermore, targeted suppression of FMNL1 results in decreases in macrophage migration similar to inhibition of all expressed macrophage formins. These novel findings suggest FMNL1 as a possible chemotherapeutic target to hinder macrophage migration, which could offer an innovative method for limiting unnecessary macrophage-mediated inflammation. We hypothesize that formins are required in podosome actin dynamics to support macrophage migration. PMID- 26942207 TI - Manufacturing of recombinant adeno-associated viral vectors: new technologies are welcome. PMID- 26942204 TI - An Update on Oxidative Damage to Spermatozoa and Oocytes. AB - On the one hand, reactive oxygen species (ROS) are mandatory mediators for essential cellular functions including the function of germ cells (oocytes and spermatozoa) and thereby the fertilization process. However, the exposure of these cells to excessive levels of oxidative stress by too high levels of ROS or too low levels of antioxidative protection will render these cells dysfunctional thereby failing the fertilization process and causing couples to be infertile. Numerous causes are responsible for the delicate bodily redox system being out of balance and causing disease and infertility. Many of these causes are modifiable such as lifestyle factors like obesity, poor nutrition, heat stress, smoking, or alcohol abuse. Possible correctable measures include foremost lifestyle changes, but also supplementation with antioxidants to scavenge excessive ROS. However, this should only be done after careful examination of the patient and establishment of the individual bodily antioxidant needs. In addition, other corrective measures include sperm separation for assisted reproductive techniques. However, these techniques have to be carried out very carefully as they, if applied wrongly, bear risks of generating ROS damaging the germ cells and preventing fertilization. PMID- 26942208 TI - AAV9-mediated central nervous system-targeted gene delivery via cisterna magna route in mice. AB - Current barriers to the use of adeno-associated virus serotype 9 (AAV9) in clinical trials for treating neurological disorders are its high expression in many off-target tissues such as liver and heart, and lack of cell specificity within the central nervous system (CNS) when using ubiquitous promoters such as human cytomegalovirus (CMV) or chicken-beta-actin hybrid (CAG). To enhance targeting the transgene expression in CNS cells, self-complementary (sc) AAV9 vectors, scAAV9-GFP vectors carrying neuronal Hb9 and synapsin 1, and nonspecific CMV and CAG promoters were constructed. We demonstrate that synapsin 1 and Hb9 promoters exclusively targeted neurons in vitro, although their strengths were up to 10-fold lower than that of CMV. In vivo analyses of mouse tissue after scAAV9 GFP vector delivery via the cisterna magna revealed a significant advantage of synapsin 1 promoter over both Hb9 variants in targeting neurons throughout the brain, since Hb9 promoters were driving gene expression mainly within the motor related areas of the brain stem. In summary, this study demonstrates that cisterna magna administration is a safe alternative to intracranial or intracerebroventricular vector delivery route using scAAV9, and introduces a novel utility of the Hb9 promoter for the targeted gene expression for both in vivo and in vitro applications. PMID- 26942209 TI - Design of a titering assay for lentiviral vectors utilizing direct extraction of DNA from transduced cells in microtiter plates. AB - Using lentiviral vector products in clinical applications requires an accurate method for measuring transduction titer. For vectors lacking a marker gene, quantitative polymerase chain reaction is used to evaluate the number of vector DNA copies in transduced target cells, from which a transduction titer is calculated. Immune Design previously described an integration-deficient lentiviral vector pseudotyped with a modified Sindbis virus envelope for use in cancer immunotherapy (VP02, of the ZVex platform). Standard protocols for titering integration-competent lentiviral vectors employ commercial spin columns to purify vector DNA from transduced cells, but such columns are not optimized for isolation of extrachromosomal (nonintegrated) DNA. Here, we describe a 96 well transduction titer assay in which DNA extraction is performed in situ in the transduction plate, yielding quantitative recovery of extrachromosomal DNA. Vector titers measured by this method were higher than when commercial spin columns were used for DNA isolation. Evaluation of the method's specificity, linear range, and precision demonstrate that it is suitable for use as a lot release assay to support clinical trials with VP02. Finally, the method is compatible with titering both integrating and nonintegrating lentiviral vectors, suggesting that it may be used to evaluate the transduction titer for any lentiviral vector. PMID- 26942210 TI - Eighth Grade Algebra Course Placement and Student Motivation for Mathematics. AB - This study uses student panel data to examine the association between Algebra placement and student motivation for mathematics. Changes in achievement goals, expectancy, and task value for students in eighth grade Algebra are compared with those of peers placed in lower-level mathematics courses (N = 3,306). In our sample, students placed in Algebra reported an increase in performance-avoidance goals as well as decreases in academic self-efficacy and task value. These relations were attenuated for students who had high mathematics achievement prior to Algebra placement. Whereas all students reported an overall decline in performance-approach goals over the course of eighth grade, previously high achieving students reported an increase in these goals. Lastly, previously high achieving students reported an increase in mastery goals. These findings suggest that while previously high-achieving students may benefit motivationally from eighth grade Algebra placement, placing previously average- and low-performing students in Algebra can potentially undermine their motivation for mathematics. PMID- 26942212 TI - Assessment of Newly Proposed Clinical Criteria to Identify HNF1A MODY in Patients with an Initial Diagnosis of Type 1 or Type 2 Diabetes Mellitus. AB - The most common form of maturity-onset diabetes of the young (MODY) is caused by mutations in the hepatocyte nuclear factor 1A (HNF1A) gene. However, most HNF1A mutation-carriers are initially misdiagnosed with type 1 (T1DM) or type 2 (T2DM) diabetes mellitus; hence, they often receive nonoptimal treatment. The aim of our study was to test newly proposed clinical criteria for the identification of HNF1A MODY in patients with a diagnosis of T1DM or T2DM. To achieve this, the following criteria to preselect patients for screening were used: for T1DM: TDIR (total daily insulin requirement) > 0.3 IU of insulin/kg and the percentage of basal insulin > 30% of TDIR; for T2DM: sulphonylurea- (SU-) based oral treatment (monotherapy or combined with Metformin) > 15 years and BMI < 30 kg/m(2). We reviewed the clinical data of 140 patients with T1DM and 524 clinically diagnosed with T2DM. On the basis of these criteria, we found a HNF1A mutation in 1 out of 2 individuals with a diagnosis of T1DM and 1 out of 11 selected individuals with a diagnosis of T2DM. We believe that the simplicity of the proposed criteria might prove useful in clinical practice, as an alternative to more time-consuming classical diagnostic techniques. PMID- 26942211 TI - Predictors of Serum 25-Hydroxyvitamin D Concentrations among a Sample of Egyptian Schoolchildren. AB - OBJECTIVE: To assess the level of 25-hydroxyvitamin D status among a sample of Egyptian schoolchildren and to evaluate predictors of deficiency and insufficiency. SUBJECTS AND METHODS: A cross-sectional study comprising 200 prepubescent schoolchildren aged from 9 to 11 years was performed. A questionnaire including frequency of midday sun exposure, milk intake, physical activity, and level of maternal education was taken. Body mass index (BMI) was calculated; serum 25-hydroxyvitamin D [25(OH)D], serum calcium, phosphorus, and parathyroid hormone were measured. RESULTS: Vitamin D deficiency [serum 25(OH)D < 20 ng/mL] was detected in 11.5% of subjects while its insufficiency (serum 25(OH)D is between 20 and 29.9 ng/mL) was detected in 15%. Results revealed that obesity, low physical activity, low sun exposure, and low maternal education level are significant predictors of insufficiency, though female gender, low maternal education level, and low milk intake are significant predictors of deficiency. Lower serum phosphorus and higher serum parathyroid hormone were significantly associated with both deficiency and insufficiency (p < 0.05). CONCLUSION: Vitamin D deficiency and insufficiency are common among schoolchildren in Egypt. Food fortification, vitamin D supplementation, and increasing maternal awareness about the importance of physical activity and exposure of their children to ultraviolet light may help to overcome this problem. PMID- 26942213 TI - Biophysics Reports: focus on theoretical and technical advances. PMID- 26942215 TI - Detecting peroxiredoxin hyperoxidation by one-dimensional isoelectric focusing. AB - The activity of typical 2-cys peroxiredoxin (Prxs) can be regulated by hyperoxidation with a consequent loss of redox activity. Here we developed a simple assay to monitor the level of hyperoxidation of different typical 2-cys prxs simultaneously. This assay only requires standard equipment and can compare different samples on the same gel. It requires much less time than conventional 2D gels and gives more information than Western blotting with an antibody specific for hyperoxidized peroxiredoxin. This method could also be used to monitor protein modification with a charge difference such as phosphorylation. PMID- 26942214 TI - Physics-based RNA structure prediction. AB - Despite the success of RNA secondary structure prediction for simple, short RNAs, the problem of predicting RNAs with long-range tertiary folds remains. Furthermore, RNA 3D structure prediction is hampered by the lack of the knowledge about the tertiary contacts and their thermodynamic parameters. Low-resolution structural modeling enables us to estimate the conformational entropies for a number of tertiary folds through rigorous statistical mechanical calculations. The models lead to 3D tertiary folds at coarse-grained level. The coarse-grained structures serve as the initial structures for all-atom molecular dynamics refinement to build the final all-atom 3D structures. In this paper, we present an overview of RNA computational models for secondary and tertiary structures' predictions and then focus on a recently developed RNA statistical mechanical model-the Vfold model. The main emphasis is placed on the physics behind the models, including the treatment of the non-canonical interactions in secondary and tertiary structure modelings, and the correlations to RNA functions. PMID- 26942216 TI - Solubilization and purification of recombinant modified C-reactive protein from inclusion bodies using reversible anhydride modification. AB - The precise function of C-reactive protein (CRP) as a regulator of inflammation in health and disease continues to evolve. The true understanding of its role in host defense responses has been hampered by numerous reports of comparable systems with contradictory interpretations of CRP as a stimulator, suppressor, or benign contributor to such processes. These discrepancies may be explained in part by the existence of a naturally occurring CRP isoform, termed modified CRP (i.e., mCRP), that is expressed when CRP subunits are dissociated into monomeric structures. The free mCRP subunit undergoes a non-proteolytic conformational change that has unique solubility, antigenicity, and bioactivity compared to the subunits that remain associated in the native, pentameric CRP molecule (i.e., pCRP). As specific reagents have been developed to identify and quantify mCRP, it has become apparent that this isoform can be formed spontaneously in calcium-free solutions. Furthermore, mCRP can be expressed on perturbed cell membranes with as little as 24-48 h incubation in tissue culture. Because mCRP has the same size as pCRP subunits as evaluated by SDS-PAGE, its presence in a pCRP reagent would not be apparent using this technique to evaluate purity. Finally, because many antibody reagents purported to be specific for "CRP" contains some, or substantial specificity to mCRP, antigen-detection techniques using such reagents may fail to distinguish the specific CRP isoform detected. All these caveats concerning CRP structures and measurements suggest that the aforementioned contradictory studies may reflect to some extent on distinctive bioactivities of mCRP rather than on pCRP. To provide a reliable, abundant supply of mCRP for separate and comparable studies, a recombinant protein was engineered and expressed in E. coli (i.e., recombinant mCRP or rmCRP). Synthesized protein was produced as inclusion bodies which proved difficult to solubilize for purification and characterization. Herein, we describe a method using anhydride reagents to effectively solubilize rmCRP and allow for chromatographic purification in high yield and free of contaminating endotoxin. Furthermore, the purified rmCRP reagent represents an excellent comparable protein to the biologically produced mCRP and as a distinctive reagent from pCRP. Deciphering the true function of CRP in both health and disease requires a knowledge, understanding, and reliable supply of each of its structures so to define the distinctive effects of each on the body's response to tissue damaging events. PMID- 26942217 TI - An efficient two-step subcellular fractionation method for the enrichment of insulin granules from INS-1 cells. AB - Insulin is one of the key regulators for blood glucose homeostasis. More than 99% of insulin is secreted from the pancreatic beta-cells. Within each beta-cell, insulin is packaged and processed in insulin secretary granules (ISGs) before its exocytosis. Insulin secretion is a complicated but well-organized dynamic process that includes the budding of immature ISGs (iISGs) from the trans-Golgi network, iISG maturation, and mature ISG (mISG) fusion with plasma membrane. However, the molecular mechanisms involved in this process are largely unknown. It is therefore crucial to separate and enrich iISGs and mISGs before determining their distinct characteristics and protein contents. Here, we developed an efficient two-step subcellular fractionation method for the enrichment of iISGs and mISGs from INS-1 cells: OptiPrep gradient purification followed by Percoll solution purification. We demonstrated that by using this method, iISGs and mISGs can be successfully distinguished and enriched. This method can be easily adapted to investigate SGs in other cells or tissues, thereby providing a useful tool for elucidating the mechanisms of granule maturation and secretion. PMID- 26942218 TI - Phosphorylation and function of DGAT1 in skeletal muscle cells. AB - Aberrant intramuscular triacylglycerol (TAG) storage in human skeletal muscle is closely related to insulin insensitivity. Excessive lipid storage can induce insulin resistance of skeletal muscle, and under severe conditions, lead to type 2 diabetes. The balance of interconversion between diacylglycerol and TAG greatly influences lipid storage and utilization. Diacylglycerol O-acyltransferase 1 (DGAT1) plays a key role in this process, but its activation and phosphorylation requires further dissection. In this study, 12 putative conserved phosphorylation sites of DGAT1 were identified by examining amino acid conservation of DGAT1 in different species. Another 12 putative phosphorylation sites were also found based on bioinformatics predictions and previous reports. Meanwhile, several phosphorylation sites of DGAT1 were verified by phosphorylation mass spectrometry analysis of purified DGAT1 from mouse myoblast C2C12 cells. Using single point mutations, a regulatory role of 3 putative phosphorylation sites was dissected. Finally, using truncation mutations, a potential domain of DGAT1 that was involved in the regulation of enzymatic activity was revealed. This study provides useful information for further understanding DGAT1 activity regulation. PMID- 26942219 TI - Analysis of chromatin fibers in Hela cells with electron tomography. AB - The presence and folding pattern of chromatin in eukaryotic cells remain elusive and controversial. In this study, we prepared ultra-thin sections of Hela cells with three different fixation and sectioning methods, i.e., chemical fixation, high pressure freezing with freeze substitution, and cryo-ultramicrotomy with SEM FIB (focused ion beam), and analyzed in vivo architecture of chromatin fibers in Hela nuclei with electron tomography technology. The results suggest that the chromatin fibers in eukaryotic Hela cells are likely organized in an architecture with a diameter of about 30 nm. PMID- 26942220 TI - Phenylboronic acid-functionalized magnetic nanoparticles for one-step saccharides enrichment and mass spectrometry analysis. AB - ABSTRACT: In this work, 2-(2-aminoethoxy) ethanol-blocked phenylboronic acid functionalized magnetic nanoparticles (blocked PMNPs) were fabricated for selective enrichment of different types of saccharides. The phenylboronic acid was designed for capturing the cis-diols moieties on saccharides molecules, and the 2-(2-aminoethoxy) ethanol can deplete the nonspecific absorption of peptides and proteins which always coexisted with saccharides. For mass spectrometry analysis, the PMNPs bound saccharides can be directly applied onto the MALDI plate with matrix without removing the PMNPs. By PMNPs, the simple saccharide (glucose) could be detected in pmol level. The complex saccharides can also be reliably purified and analyzed; 16 different N-glycans were successfully identified from ovalbumin, and the high-abundance N-glycans can be detected even when the ovalbumin was in very low concentration (2 MUg). In human milk, ten different oligosaccharides were identified, and the lactose can still be detected when the human milk concentration was low to 0.01 MUL. GRAPHICAL ABSTRACT: PMID- 26942221 TI - A new dimethyl labeling-based SID-MRM-MS method and its application to three proteases involved in insulin maturation. AB - The absolute quantification of target proteins in proteomics involves stable isotope dilution coupled with multiple reactions monitoring mass spectrometry (SID-MRM-MS). The successful preparation of stable isotope-labeled internal standard peptides is an important prerequisite for the SID-MRM absolute quantification methods. Dimethyl labeling has been widely used in relative quantitative proteomics and it is fast, simple, reliable, cost-effective, and applicable to any protein sample, making it an ideal candidate method for the preparation of stable isotope-labeled internal standards. MRM mass spectrometry is of high sensitivity, specificity, and throughput characteristics and can quantify multiple proteins simultaneously, including low-abundance proteins in precious samples such as pancreatic islets. In this study, a new method for the absolute quantification of three proteases involved in insulin maturation, namely PC1/3, PC2 and CPE, was developed by coupling a stable isotope dimethyl labeling strategy for internal standard peptide preparation with SID-MRM-MS quantitative technology. This method offers a new and effective approach for deep understanding of the functional status of pancreatic beta cells and pathogenesis in diabetes. PMID- 26942222 TI - A comprehensive procedure for antiviral inhibitor discovery using EV71 as an example. AB - The prevalence of chronic viral infectious diseases, the emergence and re emergence of new viral infections, and in particular, resistance to currently used antiviral drugs have led to increased demand for new antiviral strategies and reagents. Increased understanding of the molecular mechanisms of viral infection has provided great potential for the discovery of new antiviral agents that target viral proteins or host factors. In this work, we introduce a comprehensive system using enteroviruses 71 (EV71) as an example for leading compound discovery to develop new antiviral. PMID- 26942224 TI - The application of traditional transmission electron microscopy for autophagy research in Caenorhabditis elegans. AB - Traditional ultrastructural characterization of autophagic processes remains an important approach to be used in parallel with molecular genetics, light microscopy, and other methods. The special nature of Caenorhabditis elegans as an object for transmission electron microscopy makes its introduction into autophagy research a challenging task. The basis of the protocol to prepare C. elegans samples for autophagy studies was worked out around the turn of the millennium and has been used since then in my laboratory with some modifications. The method described here enables the user to prepare samples for systematic morphologic as well as morphometric investigations to characterize autophagy with a high but still realistic investment of effort. PMID- 26942223 TI - Skeletal intramyocellular lipid metabolism and insulin resistance. AB - Lipids stored in skeletal muscle cells are known as intramyocellular lipid (IMCL). Disorders involving IMCL and its causative factor, circulatory free fatty acids (FFAs), induce a toxic state and ultimately result in insulin resistance (IR) in muscle tissue. On the other hand, intramuscular triglyceride (IMTG), the most abundant component of IMCL and an essential energy source for active skeletal muscle, is different from other IMCLs, as it is stored in lipid droplets and plays a pivotal role in skeletal muscle energy homeostasis. This review discusses the association of FFA-induced ectopic lipid accumulation and IR, with specific emphasis on the relationship between IMCL/IMTG metabolism and IR. PMID- 26942225 TI - Transcriptomic analysis of human breast cancer cells reveals differentially expressed genes and related cellular functions and pathways in response to gold nanorods. AB - Breast cancer is the leading cause of cancer deaths in women. Recent advances in nanomedicine have shown that gold nanorods (AuNRs), as multifunctional drug delivery and photothermal therapeutic agents, have potential for use in cancer therapy. However, the effect of AuNRs on the transcriptome of breast cancer cells is unknown. In the present study, cells of the triple-negative human breast cancer cell line MDA-MB-231, which has high metastatic activity, were treated with AuNRs for transcriptomic analysis using RNA-seq technology. In total, 3126 genes were found to be up-regulated and 3558 genes were found to be down regulated in AuNR-treated MDA-MB-231 cells. These differentially expressed genes presumably take part in multiple biological pathways, including glycolysis and regulation of the actin cytoskeleton, and impact a variety of cellular functions, including chemoattractant activity. The distinct gene expression profile of MDA MB-231 cells treated with AuNRs provides a foundation for further screening and validation of important genes involved in the interaction between AuNRs and MDA MB-231 cells. PMID- 26942226 TI - Convergence Insufficiency Treatment Trial - Attention and Reading Trial (CITT ART): Design and Methods. AB - OBJECTIVE: To describe the design and methodology of the Convergence Insufficiency Treatment Trial: Attention and Reading Trial (CITT-ART), the first randomized clinical trial evaluating the effect of vision therapy on reading and attention in school-age children with symptomatic convergence insufficiency (CI). METHODS: CITT-ART is a multicenter, placebo-controlled, randomized clinical trial of 324 children ages 9 to 14 years in grades 3 to 8 with symptomatic CI. Participants are randomized to 16 weeks of office-based vergence/accommodative therapy (OBVAT) or placebo therapy (OBPT), both supplemented with home therapy. The primary outcome measure is the change in the Wechsler Individual Achievement Test-Version 3 (WIAT-III) reading comprehension subtest score. Secondary outcome measures are changes in attention as measured by the Strengths and Weaknesses of Attention (SWAN) as reported by parents and teachers, tests of binocular visual function, and other measures of reading and attention. The long-term effects of treatment are assessed 1 year after treatment completion. All analyses will test the null hypothesis of no difference in outcomes between the two treatment groups. The study is entering its second year of recruitment. The final results will contribute to a better understanding of the relationship between the treatment of symptomatic CI and its effect on reading and attention. CONCLUSION: The study will provide an evidence base to help parents, eye professionals, educators, and other health care providers make informed decisions as they care for children with CI and reading and attention problems. Results may also generate additional hypothesis and guide the development of other scientific investigations of the relationships between visual disorders and other developmental disorders in children. PMID- 26942227 TI - Tyrosine phosphorylation of glutamate receptors by non-receptor tyrosine kinases: roles in depression-like behavior. AB - Several key members of the non-receptor tyrosine kinase (nRTK) family are abundantly present within excitatory synapses in the mammalian brain. These neuron-enriched nRTKs interact with glutamate receptors and phosphorylate the receptors at tyrosine sites. The N-methyl-D-aspartate receptor is a direct substrate of nRTKs and has been extensively investigated in its phosphorylation responses to nRTKs. The alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor is the other glutamate receptor subtype that is subject to nRTK-mediated tyrosine phosphorylation. Recently, group I metabotropic glutamate receptors (mGluR1/5) were found to be sensitive to nRTKs. Robust tyrosine phosphorylation may occur in C-terminal tails of mGluR5. Tyrosine phosphorylation of glutamate receptors is either constitutive or induced activity-dependently by changing cellular and/or synaptic input. Through inducing tyrosine phosphorylation, nRTKs regulate trafficking, subcellular distribution, and function of modified receptors. Available data show that nRTK-glutamate receptor interactions and tyrosine phosphorylation of the receptors undergo drastic adaptations in mood disorders such as major depressive disorder. The remodeling of the nRTK-glutamate receptor interplay contributes to the long-lasting pathophysiology and symptomology of depression. This review summarizes the recent progress in tyrosine phosphorylation of glutamate receptors and analyzes the role of nRTKs in regulating glutamate receptors and depression-like behavior. PMID- 26942228 TI - Alternative Splicing in Alzheimer's Disease. AB - Neurodegenerative diseases have a variety of different genes contributing to their underlying pathology. Unfortunately, for many of these diseases it is not clear how changes in gene expression affect pathology. Transcriptome analysis of neurodegenerative diseases using ribonucleic acid sequencing (RNA Seq) and real time quantitative polymerase chain reaction (RT-qPCR) provides for a platform to allow investigators to determine the contribution of various genes to the disease phenotype. In Alzheimer's disease (AD) there are several candidate genes reported that may be associated with the underlying pathology and are, in addition, alternatively spliced. Thus, AD is an ideal disease to examine how alternative splicing may affect pathology. In this context, genes of particular interest to AD pathology include the amyloid precursor protein (APP), TAU, and apolipoprotein E (APOE). Here, we review the evidence of alternative splicing of these genes in normal and AD patients, and recent therapeutic approaches to control splicing. PMID- 26942230 TI - An optical spectrum of a large isolated gas-phase PAH cation: C78H26. AB - A gas-phase optical spectrum of a large polycyclic aromatic hydrocarbon (PAH) cation - C78H26+- in the 410-610 nm range is presented. This large all-benzenoid PAH should be large enough to be stable with respect to photodissociation in the harsh conditions prevailing in the interstellar medium (ISM). The spectrum is obtained via multi-photon dissociation (MPD) spectroscopy of cationic C78H26 stored in the Fourier Transform Ion Cyclotron Resonance (FT-ICR) cell using the radiation from a mid-band optical parametric oscillator (OPO) laser. The experimental spectrum shows two main absorption peaks at 431 nm and 516 nm, in good agreement with a theoretical spectrum computed via time-dependent density functional theory (TD-DFT). DFT calculations indicate that the equilibrium geometry, with the absolute minimum energy, is of lowered, nonplanar C2 symmetry instead of the more symmetric planar D2h symmetry that is usually the minimum for similar PAHs of smaller size. This kind of slightly broken symmetry could produce some of the fine structure observed in some diffuse interstellar bands (DIBs). It can also favor the folding of C78H26+ fragments and ultimately the formation of fullerenes. This study opens up the possibility to identify the most promising candidates for DIBs amongst large cationic PAHs. PMID- 26942229 TI - Network Architecture Predisposes an Enzyme to Either Pharmacologic or Genetic Targeting. AB - Chemical inhibition and genetic knockdown of enzymes are not equivalent in cells, but network-level mechanisms that cause discrepancies between knockdown and inhibitor perturbations are not understood. Here we report that enzymes regulated by negative feedback are robust to knockdown but susceptible to inhibition. Using the Raf-MEK-ERK kinase cascade as a model system, we find that ERK activation is resistant to genetic knockdown of MEK but susceptible to a comparable degree of chemical MEK inhibition. We demonstrate that negative feedback from ERK to Raf causes this knockdown-versus-inhibitor discrepancy in vivo. Exhaustive mathematical modeling of three-tiered enzyme cascades suggests that this result is general: negative autoregulation or feedback favors inhibitor potency, whereas positive autoregulation or feedback favors knockdown potency. Our findings provide a rationale for selecting pharmacologic versus genetic perturbations in vivo and point out the dangers of using knockdown approaches in search of drug targets. PMID- 26942232 TI - MCI Identification by Joint Learning on Multiple MRI Data. AB - The identification of subtle brain changes that are associated with mild cognitive impairment (MCI), the at-risk stage of Alzheimer's disease, is still a challenging task. Different from existing works, which employ multimodal data (e.g., MRI, PET or CSF) to identify MCI subjects from normal elderly controls, we use four MRI sequences, including T1-weighted MRI (T1), Diffusion Tensor Imaging (DTI), Resting-State functional MRI (RS-fMRI) and Arterial Spin Labeling (ASL) perfusion imaging. Since these MRI sequences simultaneously capture various aspects of brain structure and function during clinical routine scan, it simplifies finding the relationship between subjects by incorporating the mutual information among them. To this end, we devise a hypergraph-based semi-supervised learning algorithm. In particular, we first construct a hypergraph for each of MRI sequences separately using a star expansion method with both the training and testing data. A centralized learning is then performed to model the optimal relevance between subjects by incorporating mutual information between different MRI sequences. We then combine all centralized hypergraphs by learning the optimal weight of each hypergraph based on the minimum Laplacian. We apply our proposed method on a cohort of 41 consecutive MCI subjects and 63 age-and-gender matched controls with four MRI sequences. Our method achieves at least a 7.61% improvement in classification accuracy compared to state-of-the-art methods using multiple MRI data. PMID- 26942231 TI - Balance and its Clinical Assessment in Older Adults - A Review. AB - BACKGROUND: Human beings rely on multiple systems to maintain their balance as they perform their activities of daily living. These systems may be undermined functionally by both disease and the normal aging process. Balance impairment is associated with increased fall risk. PURPOSE: This paper examines the dynamic formulation of balance as activity and reviews the biological mechanisms for its control. A "minimal-technology" scheme for its clinical evaluation in the ambulatory care setting is proposed. METHODS: The PubMed, Scopus and CINAHL databases were searched for relevant articles using the following terms in combination with balance: aging, impairment, control mechanisms, clinical assessment. Only articles which describe test procedures, their psychometrics and rely exclusively on equipment found in a regular physician office were reviewed. RESULTS: Human bipedal stance and gait are inherently low in stability. Accordingly, an elaborate sensory apparatus comprising visual, vestibular and proprioceptive elements, constantly monitors the position and movement of the body in its environment and sends signals to the central nervous system. The sensory inputs are processed and motor commands are generated. In response to efferent signals, the musculoskeletal system moves the body as is necessary to maintain or regain balance. The combination of senescent decline in organ function and the higher prevalence of diseases of the balance control systems in older adults predisposes this population subset to balance impairment. Older adults with balance impairment are likely to present with "dizziness". The history should concentrate on the first experience, with an attempt made to categorize it as a Drachman type. Since the symptomatology is often vague, several of the recommended physical tests are provocative maneuvers aimed at reproducing the patient's complaint. Well-validated questionnaires are available for evaluating the impact of "dizziness" on various domains of patient's lives, including their fear of falling. Aspects of a good history and physical examination not otherwise addressed to balance function, such as medications review and cognitive assessment, also yield information that contributes to a better understanding of the patient's complaint. Ordinal scales, which are aggregates of functional performance tests, enable detailed quantitative assessments of balance activity. CONCLUSION: The integrity of balance function is essential for activities of daily living efficacy. Its deterioration with aging and disease places older adults at increased risk of falls and dependency. Balance can be effectively evaluated in the ambulatory care setting, using a combination of scalar questionnaires, dedicated history-taking and physical tests that do not require sophisticated instrumentation. PMID- 26942233 TI - Progressive Label Fusion Framework for Multi-atlas Segmentation by Dictionary Evolution. AB - Accurate segmentation of anatomical structures in medical images is very important in neuroscience studies. Recently, multi-atlas patch-based label fusion methods have achieved many successes, which generally represent each target patch from an atlas patch dictionary in the image domain and then predict the latent label by directly applying the estimated representation coefficients in the label domain. However, due to the large gap between these two domains, the estimated representation coefficients in the image domain may not stay optimal for the label fusion. To overcome this dilemma, we propose a novel label fusion framework to make the weighting coefficients eventually to be optimal for the label fusion by progressively constructing a dynamic dictionary in a layer-by-layer manner, where a sequence of intermediate patch dictionaries gradually encode the transition from the patch representation coefficients in image domain to the optimal weights for label fusion. Our proposed framework is general to augment the label fusion performance of the current state-of-the-art methods. In our experiments, we apply our proposed method to hippocampus segmentation on ADNI dataset and achieve more accurate labeling results, compared to the counterpart methods with single-layer dictionary. PMID- 26942234 TI - Multi-atlas Based Segmentation Editing with Interaction-Guided Constraints. AB - We propose a novel multi-atlas based segmentation method to address the editing scenario, when given an incomplete segmentation along with a set of training label images. Unlike previous multi-atlas based methods, which depend solely on appearance features, we incorporate interaction-guided constraints to find appropriate training labels and derive their voting weights. Specifically, we divide user interactions, provided on erroneous parts, into multiple local interaction combinations, and then locally search for the training label patches well-matched with each interaction combination and also the previous segmentation. Then, we estimate the new segmentation through the label fusion of selected label patches that have their weights defined with respect to their respective distances to the interactions. Since the label patches are found to be from different combinations in our method, various shape changes can be considered even with limited training labels and few user interactions. Since our method does not need image information or expensive learning steps, it can be conveniently used for most editing problems. To demonstrate the positive performance, we apply our method to editing the segmentation of three challenging data sets: prostate CT, brainstem CT, and hippocampus MR. The results show that our method outperforms the existing editing methods in all three data sets. PMID- 26942235 TI - Non-local Atlas-guided Multi-channel Forest Learning for Human Brain Labeling. AB - Labeling MR brain images into anatomically meaningful regions is important in many quantitative brain researches. In many existing label fusion methods, appearance information is widely used. Meanwhile, recent progress in computer vision suggests that the context feature is very useful in identifying an object from a complex scene. In light of this, we propose a novel learning-based label fusion method by using both low-level appearance features (computed from the target image) and high-level context features (computed from warped atlases or tentative labeling maps of the target image). In particular, we employ a multi channel random forest to learn the nonlinear relationship between these hybrid features and the target labels (i.e., corresponding to certain anatomical structures). Moreover, to accommodate the high inter-subject variations, we further extend our learning-based label fusion to a multi-atlas scenario, i.e., we train a random forest for each atlas and then obtain the final labeling result according to the consensus of all atlases. We have comprehensively evaluated our method on both LONI-LBPA40 and IXI datasets, and achieved the highest labeling accuracy, compared to the state-of-the-art methods in the literature. PMID- 26942236 TI - Smoking increases tooth loss risk, research shows. PMID- 26942237 TI - Maternal chronic stress linked with caries level, study reports. PMID- 26942238 TI - Gene responsible for oligodontia found, say researchers. PMID- 26942239 TI - Lab life: Lone-parent scientist. PMID- 26942240 TI - Primary effusion lymphoma. PMID- 26942241 TI - Declines in female CHD now 'stagnating' in USA. PMID- 26942242 TI - More on breast cancer from the WHI. PMID- 26942243 TI - The gender factor in sleep disturbance. PMID- 26942244 TI - Bingo does not cause heart disease. PMID- 26942246 TI - Twenty Contenders Scale New Heights. PMID- 26942245 TI - A Heartfelt Thank You to Reinhold Haux. PMID- 26942247 TI - When major trials mean minor efficacy. PMID- 26942248 TI - liraglutide (SAXENDA0) and obesit. Still no satisfactory weight loss drugs. AB - No existing weight loss drug has an acceptable harm-benefit balance. Liraglutide, a GLP-1 agonist administered by subcutaneous injection and already authorised in type 2 diabetes, is also approved for use in the European Union by obese patients or overweight individuals with other cardiovascular risk factors. The recommended dose in this setting is 3 mg per day, instead of the dose of 1.2 to 1.8 mg per day used in diabetes. In four randomised, double-blind, placebo-controlled trials, each lasting one year, mean weight loss with liraglutide, beyond the placebo effect, was about 5% among patients initially weighing between 100 and 118 kg. These trials were not designed to show an effect of liraglutide on complications of excess weight. Gallstones, one of the complications of obesity, were more frequent in the liraglutide groups. Partial weight regain was reported during the 3 months following liraglutide withdrawal. effects, including pancreatic disorders. Patients should not be exposed to these unjustified risks. The known adverse effect profile of liraglutide, which includes severe pancreatitis and gallstones, was confirmed in the trials in obese patients. Gastrointestinal disorders (nausea, vomiting and diarrhoea) were very frequent. Hypoglycaemic episodes, sometimes severe, have mainly been reported in diabetic patients. Reactions at the injection site can also be serious. In trials in obese patients, liraglutide was associated with an increased risk of miscarriage. In practice, sometimes excessive weight loss is a known adverse effect of GLP-1 agonists used in diabetes. Many patients lose several kilograms with high-dose liraglutide but regain the weight after treatment discontinuation. Liraglutide has no proven impact on complications of obesity and carries a risk of serious adverse. PMID- 26942249 TI - mirabegron (BETMIGA0). Poorly effective in urge urinary incontinence. AB - Mirabegron interacts with many other drugs via cytochrome P450 isoenzymes. It also has additive adverse effects, in particular cardiac disorders, when combined with antimuscarinic drugs. In view of animal data and the lack of clinical data, mirabegron should not be used by women who are or may be pregnant. In practice, drugs have little value in treating urinary urgency attributed to "overactive bladder". The risk of adverse drug reactions is rarely justified, even when the disorder is severe. Antimuscarinic disorders, such as dry mouth, are less frequent with mirabegron than with antimuscarinic drugs. Like antimuscarinic drugs, mirabegron can cause cardiac arrhythmias, especially tachycardia. Mirabegron may also cause a dose-dependent increase in blood pressure. Other adverse effects include rare cases of kidney stones and rare but sometimes serious skin reactions. When a treatable cause of urinary urgency with incontinence has been ruled out and non-drug measures have failed, recourse to an antimuscarinic drug is slightly effective but exposes patients to numerous, potentially severe adverse effects. Mirabegron (Betmiga0, Astellas Pharma), a beta-3 adrenergic receptor agonist, is authorised for use in this setting in the European Union. Clinical evaluation of mirabegron is mainly based on five randomised, double-blind trials versus antimuscarinic drugs, lasting 3 to 12 months and including about 8000 patients with urinary urgency. Mirabegron and the antimuscarinic comparators were similarly effective, even after antimuscarinic drug failure. A meta-analysis of four placebo-controlled trials including about 3500 patients suggested that mirabegron was poorly effective: on average, treatment prevented one episode of urinary incontinence every 2 days. PMID- 26942251 TI - gestodene + ethinvlestradiol (APLEEK0). No place for a patch containing a third generation progestin. PMID- 26942250 TI - Drugs targeting beta-adrenergic receptors: total "selectivity" is elusive. PMID- 26942252 TI - Repackaging. PMID- 26942253 TI - cabozantinib (COMETRIQ0). In medullary thyroid cancer: more harmful than beneficial, as is vandetanib. AB - Surgery is the mainstay of treatment for medullary thyroid cancer. Cytotoxic chemotherapy is generally ineffective in patients with progressive, inoperable, advanced-stage or metastatic tumours. Vandetanib is also authorised in this setting, but it has more harms than benefits. Cabozantinib, like vandetanib, inhibits several tyrosine kinases involved in angiogenesis. Cabozantinib has been authorised in the European Union for use in this setting. In a randomised, placebo-controlled trial in 330 patients, adding cabozantinib to tailored symptomatic treatment did not prolong survival or improve symptoms, despite a favourable effect on tumour imaging and certain laboratory parameters. On the contrary, cabozantinib appeared to undermine quality of life and aggravate diarrhoea. The known adverse effects of cabozantinib are numerous and often severe: diarrhoea, hand-foot syndrome, hypertension, venous and arterial thrombosis, bleeding and fistulae. Deaths unrelated to tumour progression were more frequent with cabozantinib than with placebo. Cabozantinib carries a risk of multiple pharmacokinetic interactions by interfering with cytochrome P450 isoenzyme CYP3A4 and P-glycoprotein. In animals, cabozantinib is teratogenic and also impairs male and female fertility. Contraception is required for women, and also for the partners of treated men, who must use condoms. These precautions must be maintained for at least 4 months after the end of treatment. In practice, in mid-2015, cabozantinib, like vandetanib, has an unfavourable harm-benefit balance in medullary thyroid cancer. The focus should remain on tailored symptomatic care. PMID- 26942255 TI - Postmenopausal hormone replacement therapy: ovarian cancer. AB - About 1 additional ovarian cancer per 1000 women exposed to post- menopausal hormone replacement therapy for 5 years. PMID- 26942254 TI - NSAIDs and serious cardiovascular disorders: especially cox-2 inhibitors and diclofenac. AB - Nonsteroidal anti-inflammatory drugs (NSAIDs) used as analgesics expose patients to cardiovascular risks that can be predicted from their pharmacological properties. As of mid-2015, what is known about the cardiovascular harms of the NSAIDs of choice, ibuprofen and naproxen? Most of the data from comparative trials of NSAIDs concern cox-2 inhibitors, diclofenac, ibuprofen and naproxen. Few studies have addressed the serious cardiovascular effects of other NSAIDs. In 2013, a U.K. team published a large meta-analysis of hundreds of randomised trials comparing NSAIDs with placebo or one NSAID with another NSAID. Compared with placebo, a statistically significant increase in the risk of serious cardiovascular adverse effects was demonstrated with cox-2 inhibitors and with diclofenac (about +40%). This risk is mainly due to an increase in myocardial infarctions and vascular deaths. Another meta-analysis found similar results in terms of cardiovascular deaths. The results of epidemiological studies are consistent with those of randomised clinical trials. According to meta-analyses of randomised trials, high-dose ibuprofen increases cardiovascular risks to the same degree as diclofenac or cox-2 inhibitors. The risk seems to mainly apply to daily doses of 2400 mg, a finding borne out by epidemiological studies that showed no increased risk with ibuprofen 1200 mg. Two meta-analyses of clinical trials showed that all NSAIDs roughly double the risk of heart failure. One meta analysis showed a small, statistically significant increase in the risk of atrial fibrillation. In practice, from a cardiovascular perspective, the NSAIDs of choice are ibuprofen, on condition that the dose does not exceed 1200 mg per day, and naproxen. In contrast, it would appear from the study data that cox-2 inhibitors, diclofenac and high-dose ibuprofen (2400 mg per day) are best avoided. As for other NSAIDs, the clinical data are too sparse to allow a meaningful comparison with the better studied NSAIDs. It is advisable to avoid using these other drugs. PMID- 26942256 TI - Trimethoprim during the 3 months before pregnancy: malformations in children. AB - Malformations linked to folic acid depletion following exposure during the 3 months before pregnancy. PMID- 26942257 TI - Gliptins, exenatide, liraglutide: "intestinal obstruction". AB - Reduced gastrointestinal motility exposes to potentially serious consequences. PMID- 26942258 TI - Helicobacter pylori and gastric or duodenal ulcer. AB - In patients with gastric or duodenal ulcer associated with Helicobacter pylori, treatment of the infection improves healing and prevents complications and recurrences. The drug regimen generally consists of a high-dose proton-pump inhibitor (PPI) such as omeprazole plus antibiotics. Using the standard Prescrire methodology, we conducted a review of the literature in order to determine the standard empirical antibiotic regimen for H. pylori infection in adults with gastric or duodenal ulcer in France. In 2015, due to an increase in H. pylori resistance to clarithromycin, a 7-day course of the PPI + clarithromycin + amoxicillin combination is effective in only about 70% of cases. A Cochrane systematic review and meta-analysis of trials involving thousands of patients suggests that prolonging treatment with a PPI + amoxicillin + clarithromycin or a PPI + amoxicillin + metronidazole to 10 or 14 days improves the rate of H. pylori eradication by 5% to 10%. A metanalysis of seven trials including a total of about 1000 patients showed that combination therapy with a PPI + amoxicillin + clarithromycin + metronidazole for 5 days eradicates H. pylori in about 90% of cases, compared to about 80% of cases with a PPI + amoxicillin + clarithromycin given for 7 days. Sequential treatment with amoxicillin for 5 days, followed by clarithromycin + metronidazole for 5 days, has also been tested in thousands of patients. Efficacy and adverse effects were similar to those observed when the same antibiotics were taken simultaneously for 5 days. In randomised trials, replacing clarithromycin or amoxicillin with a fluoroquinolone yielded conflicting results. In 2009, nearly 20% of H. pylori isolates were resistant to levofloxacin in France. Tetracycline has only been evaluated in combination with bismuth. The few available data on doxycycline suggest that its efficacy is similar to that of tetracycline. A fixed-dose combination of bismuth subcitrate potassium + metronidazole + tetracycline is authorised in the European Union for use in combination with omeprazole for 10 days. It seems effective, even in case of clarithromycin resistance. However, bismuth can cause encephalopathy, and its value when added to antibiotics and a PPI is poorly documented. We found no robust comparative data on second-line empirical treatments. In patients with gastric or duodenal ulcer associated with H. pylori, eradication of the bacterium reduces the risk of complications and recurrence. In mid-2015, the choice of antibiotics is based on trials in which the primary endpoint was a negative urea breath test, which is an acceptable surrogate criterion. In previously untreated patients, the first-choice empirical treatment consists of three antibiotics: amoxicillin (2 g daily), clarithromycin (1 g daily) and metronidazole (1 g daily), plus a PPI (in practice, omeprazole 40 mg daily), with each drug taken in two divided doses per day. The antibiotics may be taken either simultaneously for five days, or sequentially (amoxicillin for 5 days, followed by clarithromycin + metronidazole for 5 days). The adverse effects of these antibiotic combinations correspond to those of their component drugs, which mainly consist of gastrointestinal disorders and the disulfiram-like reaction of metronidazole. Amoxicillin can be replaced by a fluoroquinolone in patients allergic to beta lactam antibiotics, but there is a higher risk of resistance. Tetracycline and doxycycline appear effective, as few H. pylori strains are resistant in vitro. Bismuth can cause encephalopathy and should only be used in special cases. PMID- 26942259 TI - Use a non-invasive test to verify H. pylori eradication. PMID- 26942260 TI - Bronchiolitis in infants: do not use bronchodilators. AB - A Cochrane systematic review of studies including nearly 2000 infants showed that bronchodilators have no proven efficacy in bronchiolitis. PMID- 26942261 TI - Electronic prescribing: the risk of errors and adverse effects. AB - Errors associated with the use of electronic prescribing have been slowly coming to light since the 2000s, as health care has become increasingly computerised. Serious adverse effects and even deaths have resulted from omissions, wrong patient, wrong-drug or wrong-dose errors, and errors in drug administration. The use of order sets has led to duplicate therapy. Compared with handwritten prescriptions, the analysis of electronic prescriptions demands particular efforts on the part of pharmacists and other health professionals in order to detect errors. PMID- 26942262 TI - Ensure ICD-10 claims continue to flow. PMID- 26942263 TI - Using the right chart of accounts contributes to financial success. PMID- 26942264 TI - Ocular Surface Reconstruction in Laryngo-onycho-cutaneous Syndrome. PMID- 26942265 TI - Dystrophin gene replacement and gene repair therapy for Duchenne muscular dystrophy in 2016. AB - After years of relentless efforts, gene therapy has now begun to deliver its therapeutic promise in several diseases. A number of gene therapy products have received regulatory approval in Europe and Asia. Duchenne muscular dystrophy (DMD) is an X-linked inherited lethal muscle disease. It is caused by mutations in the dystrophin gene. Replacing and/or repair the mutated dystrophin gene holds great promises to treated DMD at the genetic level. Last several years have evidenced significant developments in preclinical experimentations in murine and canine models of DMD. There has been a strong interest in moving these promising findings to clinical trials. In light of rapid progress in this field, the Parent Project Muscular Dystrophy (PPMD) recently interviewed me on the current status of DMD gene therapy. Here I summarized the interview with PPMD. PMID- 26942267 TI - Similar head impact acceleration measured using instrumented ear patches in a junior rugby union team during matches in comparison with other sports. AB - OBJECTIVE Direct impact with the head and the inertial loading of the head have been postulated as major mechanisms of head-related injuries, such as concussion. METHODS This descriptive observational study was conducted to quantify the head impact acceleration characteristics in under-9-year-old junior rugby union players in New Zealand. The impact magnitude, frequency, and location were collected with a wireless head impact sensor that was worn by 14 junior rugby players who participated in 4 matches. RESULTS A total of 721 impacts > 10g were recorded. The median (interquartile range [IQR]) number of impacts per player was 46 (IQR 37-58), resulting in 10 (IQR 4-18) impacts to the head per player per match. The median impact magnitudes recorded were 15g (IQR 12g-21g) for linear acceleration and 2296 rad/sec(2) (IQR 1352-4152 rad/sec(2)) for rotational acceleration. CONCLUSIONS There were 121 impacts (16.8%) above the rotational injury risk limit and 1 (0.1%) impact above the linear injury risk limit. The acceleration magnitude and number of head impacts in junior rugby union players were higher than those previously reported in similar age-group sports participants. The median linear acceleration for the under-9-year-old rugby players were similar to 7- to 8-year-old American football players, but lower than 9- to 12-year-old youth American football players. The median rotational accelerations measured were higher than the median and 95th percentiles in youth, high school, and collegiate American football players. PMID- 26942266 TI - Primary pineal rhabdomyosarcoma successfully treated by high-dose chemotherapy followed by autologous peripheral blood stem cell transplantation: case report. AB - Primary intracranial rhabdomyosarcoma is quite rare, and its prognosis is poor compared with that for rhabdomyosarcoma in other organs. The authors present a case of pineal rhabdomyosarcoma successfully managed with multimodal therapy including surgery, chemotherapy, radiation, and high-dose chemotherapy (HDC) followed by autologous peripheral blood stem cell transplantation (HDC/APBSCT). An 8-year-old girl presenting with headache and nausea was referred to the authors' institution. Computed tomography and MRI revealed a pineal tumor associated with obstructive hydrocephalus. Subsequently, an emergent endoscopic tumor biopsy and third ventriculostomy were performed. The patient's symptoms immediately improved. The most likely pathological diagnosis was embryonal rhabdomyosarcoma. Chemotherapy with etoposide, cyclophosphamide, cisplatin, pirarubicin, ifosfamide, actinomycin D, and vincristine was followed by a second look operation and whole-brain and craniospinal radiation. Because the intraoperative findings and pathological examination of the second operation suggested a definitive diagnosis of rhabdomyosarcoma and the presence of viable residual tumor cells, HDC with etoposide and melphalan was followed by APBSCT. The patient was discharged from the hospital without residual tumor or any neurological deficit. No recurrence was observed at 30 months. This is the first case of primary pineal rhabdomyosarcoma treated with HDC/APBSCT. Although the efficacy of HDC/APBSCT for rhabdomyosarcoma has not been established, the prognosis of primary intracranial rhabdomyosarcoma treated with conventional treatment is quite poor. High-dose chemotherapy followed by APBSCT may contribute to a better prognosis for primary intracranial rhabdomyosarcoma. PMID- 26942268 TI - Facet tropism: possible role in the pathology of lumbar disc herniation in adolescents. AB - OBJECTIVE The role of facet tropism (FT) in lumbar disc herniation (LDH) is ambiguous. The present study aimed to investigate the association between FT and LDH in adolescents. METHODS This study included 65 adolescents with LDH with 1- or 2-level LDH, or both. Facet angles were measured with MRI. FT was defined as asymmetry of 10 degrees between the left and right side. The same levels of 30 healthy persons who had no lumbar lesions were used as controls. Statistical analysis was performed using the chi-square test. RESULTS FT was identified in 16 of 39 patients with LDH in L4-5 and in 3 of 30 controls (p = 0.006, OR 6.261, 95% CI 1.619-24.217). It was also identified in 12 of 27 patients with LDH in L5-S1 and in 4 of 30 controls (p = 0.017, OR 5.200, 95% CI 1.420-19.039). One patient had LDH in both L4-5 and L5-S1. CONCLUSIONS FT is associated with LDH in both L4 5 and L5-S1 levels in adolescents. PMID- 26942269 TI - Spinal cord stimulation for recurrent tethered cord syndrome in a pediatric patient: case report. AB - The authors present a patient with a lipomyelomeningocele and worsening back pain due to recurrent tethered cord syndrome. Because of the increased risk and unlikely improvement in symptoms with repeated surgical untethering, she was offered an alternative treatment with a trial of dorsal spinal cord stimulation. She had an excellent response to the percutaneous trial, and a permanent implant was placed, with good initial results. The authors review her case as well as the treatment options, indications, and outcomes for recurrent tethered cord syndrome. PMID- 26942270 TI - Macrocephaly in infancy: benign enlargement of the subarachnoid spaces and subdural collections. AB - OBJECTIVE Benign enlargement of the subarachnoid spaces (BESS) is a common finding on imaging studies indicated by macrocephaly in infancy. This finding has been associated with the presence of subdural fluid collections that are sometimes construed as suggestive of abusive head injury. The prevalence of BESS among infants with macrocephaly and the prevalence of subdural collections among infants with BESS are both poorly defined. The goal of this study was to determine the relative frequencies of BESS, hydrocephalus, and subdural collections in a large consecutive series of imaging studies performed for macrocephaly and to determine the prevalence of subdural fluid collections among patients with BESS. METHODS A text search of radiology requisitions identified studies performed for macrocephaly in patients <= 2 years of age. Studies of patients with hydrocephalus or acute trauma were excluded. Studies that demonstrated hydrocephalus or chronic subdural hematoma not previously recognized but responsible for macrocephaly were noted but not investigated further. The remaining studies were reviewed for the presence of incidental subdural collections and for measurement of the depth of the subarachnoid space. A 3-point scale was used to grade BESS: Grade 0, < 5 mm; Grade 1, 5-9 mm; and Grade 2, >= 10 mm. RESULTS After exclusions, there were 538 studies, including 7 cases of hydrocephalus (1.3%) and 1 large, bilateral chronic subdural hematoma (0.2%). There were incidental subdural collections in 21 cases (3.9%). Two hundred sixty five studies (49.2%) exhibited Grade 1 BESS, and 46 studies (8.6%) exhibited Grade 2 BESS. The prevalence of incidental subdural collections among studies with BESS was 18 of 311 (5.8%). The presence of BESS was associated with a greater prevalence of subdural collections, and higher grades of BESS were associated with increasing prevalence of subdural collections. After controlling for imaging modality, the odds ratio of the association of BESS with subdural collections was 3.68 (95% CI 1.12-12.1, p = 0.0115). There was no association of race, sex, or insurance status with subdural collections. Patients with BESS had larger head circumference Z-scores, but there was no association of head circumference or age with subdural collections. Interrater reliability in the diagnosis and grading of BESS was only fair. CONCLUSIONS The current study confirms the association of BESS with incidental subdural collections and suggests that greater depth of the subarachnoid space is associated with increased prevalence of such collections. These observations support the theory that infants with BESS have a predisposition to subdural collections on an anatomical basis. Incidental subdural collections in the setting of BESS are not necessarily indicative of abusive head injury. PMID- 26942272 TI - To analyse a trace or not? Evaluating the decision-making process in the criminal investigation. AB - In order to broaden our knowledge and understanding of the decision steps in the criminal investigation process, we started by evaluating the decision to analyse a trace and the factors involved in this decision step. This decision step is embedded in the complete criminal investigation process, involving multiple decision and triaging steps. Considering robbery cases occurring in a geographic region during a 2-year-period, we have studied the factors influencing the decision to submit biological traces, directly sampled on the scene of the robbery or on collected objects, for analysis. The factors were categorised into five knowledge dimensions: strategic, immediate, physical, criminal and utility and decision tree analysis was carried out. Factors in each category played a role in the decision to analyse a biological trace. Interestingly, factors involving information available prior to the analysis are of importance, such as the fact that a positive result (a profile suitable for comparison) is already available in the case, or that a suspect has been identified through traditional police work before analysis. One factor that was taken into account, but was not significant, is the matrix of the trace. Hence, the decision to analyse a trace is not influenced by this variable. The decision to analyse a trace first is very complex and many of the tested variables were taken into account. The decisions are often made on a case-by-case basis. PMID- 26942271 TI - p.(L576P) -KIT mutation in GIST: Favorable prognosis and sensitive to imatinib? AB - Exon 11 KIT mutations are found in a majority of gastrointestinal stromal tumors (GIST) and are usually predictive of response to imatinib, a KIT, PDGFRA and ABL inhibitor. Exon 11 mutations with poor sensitivity to imatinib and poor outcome can be observed on rare occasions, including p.(L576P). In silico and in vitro studies suggested a decreased binding affinity for imatinib in p.(L576P) KIT mutations, thereby offering an explanation for their poor outcome and poor response to standard therapy. These observations were further corroborated with anecdotal case reports of refractoriness or non-durable response to imatinib therapy. However, we describe the favorable response to imatinib and outcome in 5 p.(L576P)-KIT mutant GIST patients treated at a tertiary sarcoma referral center. The sensitivity of p.(L576P)-KIT mutations to imatinib, and the prognostic impact of this mutation need to be further evaluated in a larger cohort. Based on our observations, p.(L576P) mutated GISTs should be treated with standard first line imatinib therapy. PMID- 26942273 TI - Febuxostat for the chronic management of hyperuricemia in patients with gout. AB - Febuxostat is a non-purine, selective inhibitor of both isoforms of xanthine oxido-reductase (XOR), and a major alternative to the scarce number of urate lowering medications available in the last decades. Its inhibition of XOR is more potent than allopurinol in a mg to mg comparison, what is associated to achievement of serum urate target more frequently than allopurinol at doses tested in clinical trials, especially in patients with the highest baseline serum urate levels. Its pharmacokinetics is not greatly dependent on renal clearance, contrary to allopurinol, what may be an advantage in patients with chronic kidney disease. Several trials are further evaluating both the cardiovascular safety of febuxostat and its possible beneficial effect on renal function preservation. Still scarce, but clinically interesting, evidence on its use in transplant patients has been recently released. PMID- 26942274 TI - Site-Specific Hydrolysis Reaction C-Terminal of Methionine in Met-His during Metal-Catalyzed Oxidation of IgG-1. AB - The metal-catalyzed oxidation by [Fe(II)(EDTA)](2-)/H2O2 of IgG-1 leads to the site-specific hydrolysis of peptide bonds in the Fc region. The major hydrolytic cleavage occurs between Met428 and His429, consistent with a mechanism reported for the site-specific hydrolysis of parathyroid hormone (1-34) between Met8 and His9 (Mozziconacci, O.; et al. Mol. Pharmaceutics 2013, 10 (2), 739-755). In IgG 1, to a lesser extent, we also observe hydrolysis reactions between Met252 and Ile253. After 2 h of oxidation (at pH 5.8, 37 degrees C) approximately 5% of the protein is cleaved between Met428 and His429. For comparison, after 2 h of oxidation, the amount of tryptic peptides containing a Met sulfoxide residue represents less than 0.1% of the protein. The effect of this site-specific hydrolysis on the conformational stability and aggregation propensity of the antibody was also examined. No noticeable differences in structural integrity and conformational stability were observed between control and oxidized IgG-1 samples as measured by circular dichroism (CD), fluorescence spectroscopy, and static light scattering (SLS). Small amounts of soluble and insoluble aggregates (3-6%) were, however, observed in the oxidized samples by UV-visible absorbance spectroscopy and size exclusion chromatography (SEC). Over the course of metal catalyzed oxidation, increasing amounts of fragments were also observed by SEC. An increase in the concentration of subvisible particles was detected by microflow imaging (MFI). PMID- 26942276 TI - Presidential Address: All in the Family, or "Gee, Our Old LaSalle Ran Great". PMID- 26942280 TI - 2015 Curt Stern Award. PMID- 26942282 TI - 2015 Victor A. McKusick Leadership Award. PMID- 26942278 TI - 2015 William Allan Award. PMID- 26942283 TI - A Clinical Service to Support the Return of Secondary Genomic Findings in Human Research. AB - Human genome and exome sequencing are powerful research tools that can generate secondary findings beyond the scope of the research. Most secondary genomic findings are of low importance, but some (for a current estimate of 1%-3% of individuals) confer high risk of a serious disease that could be mitigated by timely medical intervention. The impact and scope of secondary findings in genome and exome sequencing will only increase in the future. There is considerable agreement that high-impact findings should be returned to participants, but many researchers performing genomic research studies do not have the background, skills, or resources to identify, verify, interpret, and return such variants. Here, we introduce a proposal for the formation of a secondary-genomic-findings service (SGFS) that would support researchers by enabling the return of clinically actionable sequencing results to research participants in a standardized manner. We describe a proposed structure for such a centralized service and evaluate the advantages and challenges of the approach. We suggest that such a service would be of greater benefit to all parties involved than present practice, which is highly variable. We encourage research centers to consider the adoption of a centralized SGFS. PMID- 26942285 TI - A Locus at 5q33.3 Confers Resistance to Tuberculosis in Highly Susceptible Individuals. AB - Immunosuppression resulting from HIV infection increases the risk of progression to active tuberculosis (TB) both in individuals newly exposed to Mycobacterium tuberculosis (MTB) and in those with latent infections. We hypothesized that HIV positive individuals who do not develop TB, despite living in areas where it is hyperendemic, provide a model of natural resistance. We performed a genome-wide association study of TB resistance by using 581 HIV-positive Ugandans and Tanzanians enrolled in prospective cohort studies of TB; 267 of these individuals developed active TB, and 314 did not. A common variant, rs4921437 at 5q33.3, was significantly associated with TB (odds ratio = 0.37, p = 2.11 * 10(-8)). This variant lies within a genomic region that includes IL12B and is embedded in an H3K27Ac histone mark. The locus also displays consistent patterns of linkage disequilibrium across African populations and has signals of strong selection in populations from equatorial Africa. Along with prior studies demonstrating that therapy with IL-12 (the cytokine encoded in part by IL12B, associated with longer survival following MTB infection in mice deficient in CD4 T cells), our results suggest that this pathway might be an excellent target for the development of new modalities for treating TB, especially for HIV-positive individuals. Our results also indicate that studying extreme disease resistance in the face of extensive exposure can increase the power to detect associations in complex infectious disease. PMID- 26942286 TI - A Statistical Approach for Testing Cross-Phenotype Effects of Rare Variants. AB - Increasing empirical evidence suggests that many genetic variants influence multiple distinct phenotypes. When cross-phenotype effects exist, multivariate association methods that consider pleiotropy are often more powerful than univariate methods that model each phenotype separately. Although several statistical approaches exist for testing cross-phenotype effects for common variants, there is a lack of similar tests for gene-based analysis of rare variants. In order to fill this important gap, we introduce a statistical method for cross-phenotype analysis of rare variants using a nonparametric distance covariance approach that compares similarity in multivariate phenotypes to similarity in rare-variant genotypes across a gene. The approach can accommodate both binary and continuous phenotypes and further can adjust for covariates. Our approach yields a closed-form test whose significance can be evaluated analytically, thereby improving computational efficiency and permitting application on a genome-wide scale. We use simulated data to demonstrate that our method, which we refer to as the Gene Association with Multiple Traits (GAMuT) test, provides increased power over competing approaches. We also illustrate our approach using exome-chip data from the Genetic Epidemiology Network of Arteriopathy. PMID- 26942288 TI - Monoallelic and Biallelic Variants in EMC1 Identified in Individuals with Global Developmental Delay, Hypotonia, Scoliosis, and Cerebellar Atrophy. AB - The paradigm of a single gene associated with one specific phenotype and mode of inheritance has been repeatedly challenged. Genotype-phenotype correlations can often be traced to different mutation types, localization of the variants in distinct protein domains, or the trigger of or escape from nonsense-mediated decay. Using whole-exome sequencing, we identified homozygous variants in EMC1 that segregated with a phenotype of developmental delay, hypotonia, scoliosis, and cerebellar atrophy in three families. In addition, a de novo heterozygous EMC1 variant was seen in an individual with a similar clinical and MRI imaging phenotype. EMC1 encodes a member of the endoplasmic reticulum (ER)-membrane protein complex (EMC), an evolutionarily conserved complex that has been proposed to have multiple roles in ER-associated degradation, ER-mitochondria tethering, and proper assembly of multi-pass transmembrane proteins. Perturbations of protein folding and organelle crosstalk have been implicated in neurodegenerative processes including cerebellar atrophy. We propose EMC1 as a gene in which either biallelic or monoallelic variants might lead to a syndrome including intellectual disability and preferential degeneration of the cerebellum. PMID- 26942289 TI - Extensive Hidden Genomic Mosaicism Revealed in Normal Tissue. AB - Genomic mosaicism arising from post-zygotic mutation has recently been demonstrated to occur in normal tissue of individuals ascertained with varied phenotypes, indicating that detectable mosaicism may be less an exception than a rule in the general population. A challenge to comprehensive cataloging of mosaic mutations and their consequences is the presence of heterogeneous mixtures of cells, rendering low-frequency clones difficult to discern. Here we applied a computational method using estimated haplotypes to characterize mosaic megabase scale structural mutations in 31,100 GWA study subjects. We provide in silico validation of 293 previously identified somatic mutations and identify an additional 794 novel mutations, most of which exist at lower aberrant cell fractions than have been demonstrated in previous surveys. These mutations occurred across the genome but in a nonrandom manner, and several chromosomes and loci showed unusual levels of mutation. Our analysis supports recent findings about the relationship between clonal mosaicism and old age. Finally, our results, in which we demonstrate a nearly 3-fold higher rate of clonal mosaicism, suggest that SNP-based population surveys of mosaic structural mutations should be conducted with haplotypes for optimal discovery. PMID- 26942284 TI - Loss of VPS13C Function in Autosomal-Recessive Parkinsonism Causes Mitochondrial Dysfunction and Increases PINK1/Parkin-Dependent Mitophagy. AB - Autosomal-recessive early-onset parkinsonism is clinically and genetically heterogeneous. The genetic causes of approximately 50% of autosomal-recessive early-onset forms of Parkinson disease (PD) remain to be elucidated. Homozygozity mapping and exome sequencing in 62 isolated individuals with early-onset parkinsonism and confirmed consanguinity followed by data mining in the exomes of 1,348 PD-affected individuals identified, in three isolated subjects, homozygous or compound heterozygous truncating mutations in vacuolar protein sorting 13C (VPS13C). VPS13C mutations are associated with a distinct form of early-onset parkinsonism characterized by rapid and severe disease progression and early cognitive decline; the pathological features were striking and reminiscent of diffuse Lewy body disease. In cell models, VPS13C partly localized to the outer membrane of mitochondria. Silencing of VPS13C was associated with lower mitochondrial membrane potential, mitochondrial fragmentation, increased respiration rates, exacerbated PINK1/Parkin-dependent mitophagy, and transcriptional upregulation of PARK2 in response to mitochondrial damage. This work suggests that loss of function of VPS13C is a cause of autosomal-recessive early-onset parkinsonism with a distinctive phenotype of rapid and severe progression. PMID- 26942287 TI - Disruption of POGZ Is Associated with Intellectual Disability and Autism Spectrum Disorders. AB - Intellectual disability (ID) and autism spectrum disorders (ASD) are genetically heterogeneous, and a significant number of genes have been associated with both conditions. A few mutations in POGZ have been reported in recent exome studies; however, these studies do not provide detailed clinical information. We collected the clinical and molecular data of 25 individuals with disruptive mutations in POGZ by diagnostic whole-exome, whole-genome, or targeted sequencing of 5,223 individuals with neurodevelopmental disorders (ID primarily) or by targeted resequencing of this locus in 12,041 individuals with ASD and/or ID. The rarity of disruptive mutations among unaffected individuals (2/49,401) highlights the significance (p = 4.19 * 10(-13); odds ratio = 35.8) and penetrance (65.9%) of this genetic subtype with respect to ASD and ID. By studying the entire cohort, we defined common phenotypic features of POGZ individuals, including variable levels of developmental delay (DD) and more severe speech and language delay in comparison to the severity of motor delay and coordination issues. We also identified significant associations with vision problems, microcephaly, hyperactivity, a tendency to obesity, and feeding difficulties. Some features might be explained by the high expression of POGZ, particularly in the cerebellum and pituitary, early in fetal brain development. We conducted parallel studies in Drosophila by inducing conditional knockdown of the POGZ ortholog row, further confirming that dosage of POGZ, specifically in neurons, is essential for normal learning in a habituation paradigm. Combined, the data underscore the pathogenicity of loss-of-function mutations in POGZ and define a POGZ-related phenotype enriched in specific features. PMID- 26942291 TI - PRICKLE2 Mutations Might Not Be Involved in Epilepsy. PMID- 26942292 TI - Response to Sandford et al.: PRICKLE2 Variants in Epilepsy: A Call for Precision Medicine. PMID- 26942290 TI - Mosaic Activating Mutations in FGFR1 Cause Encephalocraniocutaneous Lipomatosis. AB - Encephalocraniocutaneous lipomatosis (ECCL) is a sporadic condition characterized by ocular, cutaneous, and central nervous system anomalies. Key clinical features include a well-demarcated hairless fatty nevus on the scalp, benign ocular tumors, and central nervous system lipomas. Seizures, spasticity, and intellectual disability can be present, although affected individuals without seizures and with normal intellect have also been reported. Given the patchy and asymmetric nature of the malformations, ECCL has been hypothesized to be due to a post-zygotic, mosaic mutation. Despite phenotypic overlap with several other disorders associated with mutations in the RAS-MAPK and PI3K-AKT pathways, the molecular etiology of ECCL remains unknown. Using exome sequencing of DNA from multiple affected tissues from five unrelated individuals with ECCL, we identified two mosaic mutations, c.1638C>A (p.Asn546Lys) and c.1966A>G (p.Lys656Glu) within the tyrosine kinase domain of FGFR1, in two affected individuals each. These two residues are the most commonly mutated residues in FGFR1 in human cancers and are associated primarily with CNS tumors. Targeted resequencing of FGFR1 in multiple tissues from an independent cohort of individuals with ECCL identified one additional individual with a c.1638C>A (p.Asn546Lys) mutation in FGFR1. Functional studies of ECCL fibroblast cell lines show increased levels of phosphorylated FGFRs and phosphorylated FRS2, a direct substrate of FGFR1, as well as constitutive activation of RAS-MAPK signaling. In addition to identifying the molecular etiology of ECCL, our results support the emerging overlap between mosaic developmental disorders and tumorigenesis. PMID- 26942295 TI - Emergency radiology special feature: editorial. PMID- 26942293 TI - MR phase-contrast imaging in pulmonary hypertension. AB - Pulmonary hypertension (PH) is a life-threatening, multifactorial pathophysiological haemodynamic condition, diagnosed when the mean pulmonary arterial pressure equals or exceeds 25 mmHg at rest during right heart catheterization. Cardiac MRI, in general, and MR phase-contrast (PC) imaging, in particular, have emerged as potential techniques for the standardized assessment of cardiovascular function, morphology and haemodynamics in PH. Allowing the quantification and characterization of macroscopic cardiovascular blood flow, MR PC imaging offers non-invasive evaluation of haemodynamic alterations associated with PH. Techniques used to study the PH include both the routine two-dimensional (2D) approach measuring predominant velocities through an acquisition plane and the rapidly evolving four-dimensional (4D) PC imaging, which enables the assessment of the complete time-resolved, three-directional blood-flow velocity field in a volume. Numerous parameters such as pulmonary arterial mean velocity, vessel distensibility, flow acceleration time and volume and tricuspid regurgitation peak velocity, as well as the duration and onset of vortical blood flow in the main pulmonary artery, have been explored to either diagnose PH or find non-invasive correlates to right heart catheter parameters. Furthermore, PC imaging-based analysis of pulmonary arterial pulse-wave velocities, wall shear stress and kinetic energy losses grants novel insights into cardiopulmonary remodelling in PH. This review aimed to outline the current applications of 2D and 4D PC imaging in PH and show why this technique has the potential to contribute significantly to early diagnosis and characterization of PH. PMID- 26942294 TI - Accurate quantitative assessment of synovitis in rheumatoid arthritis using pixel by-pixel, time-intensity curve shape analysis. AB - OBJECTIVE: To improve on the reproducibility and sensitivity of the assessment of patients with rheumatoid arthritis (RA), two semi-automated measurement methods of the area of enhancing pannus (AEP), based on thresholding (AEP_THRES) and pixel-by-pixel time-intensity curve analysis (AEP_TIC), were evaluated as an alternative for the gold-standard manual contouring method (AEP_MANUAL). METHODS: 8 patients (7 females and 1 male) with RA of the wrist or finger joints participated in the study. A three-dimensional contrast-enhanced dynamic sequence was used at 3 T. After identifying the most relevant time-intensity curve (TIC) shape in terms of synovitis by comparing with the synovitis score using the RA MRI scoring system, three different approaches for measuring the AEP were performed. Spearman's test of rank correlation was used to compare AEPs via two semi-automated methods (AEP_THRES and AEP_TIC) against manual segmentation (AEP_MANUAL) in the entire hand region as well as the wrist and the finger regions. RESULTS: The TIC shape of "washout after fast initial enhancement" had excellent correlation with synovitis score (r = 0.809). The correlation coefficient between AEP_TIC and AEP_MANUAL was evaluated to be better than that of AEP_THRES and AEP_MANUAL in the wrist region (AEP_THRES: r = 0.716, AEP_TIC: r = 0.815), whereas these were of comparable accuracy for the entire hand and the finger regions. CONCLUSION: This study suggests that TIC analysis may be an alternative to manual contouring for pannus quantification and provides important clinical information of the extent of the disease in patients with RA. ADVANCES IN KNOWLEDGE: TIC shape analysis can be applied for new quantitative assessment for RA synovitis in the wrist. PMID- 26942306 TI - Corrigendum: Indirect excitation of ultrafast demagnetization. PMID- 26942307 TI - High-Throughput Fragment Docking into the BAZ2B Bromodomain: Efficient in Silico Screening for X-Ray Crystallography. AB - Bromodomains are protein modules that bind to acetylated lysine side chains in histones and other proteins. The bromodomain adjacent to zinc finger domain protein 2B (BAZ2B) has been reported to be poorly druggable. Here, we screened an in-house library of 350 fragments by automatic docking to the BAZ2B bromodomain. The top 12 fragments according to the predicted binding energy were selected for experiments of soaking into apo crystals of BAZ2B which yielded the structure of the complex for four of them, which is a hit rate of 33%. Additional crystal structures were solved for BAZ2B and two scaffolds identified by analogy. For three topologically similar fragments, the crystal structures reveal binding modes with different penetration, i.e., with zero, one, and two water molecules, respectively, located between the fragment and the side chain of a conserved tyrosine (Tyr1901) in the bottom of the acetyl lysine pocket of BAZ2B. Furthermore, a remarkable stereoselectivity of the acetyl lysine pocket emerges from the crystal structures of the bromodomains of BAZ2B and SMARCA4 in complex with the chiral diol MPD (2-methyl-2,4-pentanediol). PMID- 26942308 TI - Reagent-Controlled Tandem Reactions of Vinyl Epoxides: Access to Functionalized gamma-Butenolides. AB - A new approach to functionalized gamma-butenolides based on reagent-controlled tandem reaction sequences of Morita-Baylis-Hillman-type vinyl epoxides is described. The nucleophilic addition of a tertiary phosphine to the electron deficient alkene led to ring-opening of the epoxide followed by lactonization to produce phosphonium ylides, which could undergo Wittig olefination with aryl trifluoromethyl ketones and aryl aldehydes to give 3-alkenyl gamma-butenolides in moderate to good yields and high E/Z selectivity. Tertiary amine promoted the Michael-type addition of carbon- and nitrogen-based nucleophiles to the vinyl epoxides followed by lactonization to provide diverse 3-substituted gamma butenolides. PMID- 26942309 TI - Immunoglobulin heavy chain variable region gene repertoire and B-cell receptor stereotypes in Indian patients with chronic lymphocytic leukemia. AB - In chronic lymphocytic leukemia (CLL), the geographical bias in immunoglobulin heavy-chain variable (IGHV) gene usage lead us to analyze IGHV gene usage and B cell receptor stereotypy in 195 patients from India. IGHV3, IGHV4, and IGHV1 families were the most frequently used. 20.5% sequences had stereotyped BCR and were clustered in 12 pre-defined and 6 novel subsets. Unmutated IGHV was significantly associated with reduced time to first treatment (p < 0.033) and poor overall survival (OS; p = 0.01). We observed a significant difference in OS between IGHV1, IGHV3, and IGHV4 family cases (p = 0.045) in early stage patients. Regarding subfamily usage, only IGHV1-69 expression was found to have statistically significant poor outcome (p = 0.017). Our results from the analysis of various molecular and clinical features suggest that the expression of specific IGHV gene influences the outcome in early stage CLL, and hence its assessment may be added to the clinical leukemia laboratory armamentarium. PMID- 26942314 TI - Numerical analysis of hemodynamics in spastic middle cerebral arteries. AB - Cerebral vasospasm (CVS) is the most common serious complication of subarachnoid hemorrhage. Among the many factors that are associated with the pathogenesis of CVS, hemodynamics plays an important role in the initiation and development of CVS. Numerical simulation was carried out to obtain the flow patterns and wall shear stress (WSS) distribution in spastic middle cerebral arteries. The blood was assumed to be incompressible, laminar, homogenous, Newtonian, and steady. Our simulations reveal that flow velocity and WSS level increase at the stenosis segment of the spastic vessels, but further downstream of stenosis, the WSS significantly decreases along the inner wall, and flow circulation and stagnation are observed. The hydrodynamic resistance increases with the increase of vessel spasm. Moreover, the change of flow field and hydrodynamic forces are not linearly proportional to the spasm level, and the rapid change of hemodynamic parameters is observed as the spasm is more than 50%. Accordingly, in the view of hemodynamic physiology, vessels with less than 30% stenosis are capable of self restoration towards normal conditions. However, vessels with more than 50% stenosis may eventually lose their capacity to adapt to differing physiologic conditions due to the extreme non-physilogic hemodynamic environment, and the immediate expansion of the vessel lumen might be needed to minimize serious and non-reversible effects. PMID- 26942315 TI - Using Client's Routine Urinalysis Records From Multiple Treatment Systems to Model Five-Year Opioid Substitution Treatment Outcomes. AB - BACKGROUND: At global, national, and local level, the need for ongoing, timely and cost efficient, comprehensive drug treatment monitoring, and evaluation systems have clearly been well recognized. OBJECTIVES: To test the feasibility of linking laboratory data and client intake data and its usefulness for modeling retrospectively, for the first time, 5-year longitudinal drug treatment outcomes in an Irish opiate treatment setting. METHODS: A multisite, retrospective, longitudinal cohort study was implemented to evaluate outcomes for opiate users based on 1.7 million routine urinalysis results collected from 4,518 individuals presenting for opioid substitution treatment in Ireland from January 2006 to December 2010. RESULTS: Analysis of opiates, cocaine, benzodiazepine, and cannabis use at treatment intake, 6 months and at 1-5 year follow-ups revealed differences in urinalysis protocols; significant differences in age of first drug use between those using and not using opiates at 5 years; significant decreases in opiate use; increases in benzodiazepine use and significant increasing effects of concurrent cocaine and benzodiazepine use on the odds of using opiates. Time series analysis of weekly proportions opiate positive predicted 16% (95% confidence interval: 7%-25%) of clients would be opiate positive 5 years postinitial intake. CONCLUSIONS IMPORTANCE: Underutilized urinalysis data can be used to address the need for cost effective, efficient evidence of drug-treatment outcomes across time, place, and systems. Linking and matching the cross sectional data across sites and times also revealed where improvements in electronic records could be made. PMID- 26942316 TI - Validation of a wireless accelerometer network for energy expenditure measurement. AB - The purpose of this study was to validate a wireless network of accelerometers and compare it to a hip-mounted accelerometer for predicting energy expenditure in a semi-structured environment. Adults (n = 25) aged 18-30 engaged in 14 sedentary, ambulatory, exercise, and lifestyle activities over a 60-min protocol while wearing a portable metabolic analyser, hip-mounted accelerometer, and wireless network of three accelerometers worn on the right wrist, thigh, and ankle. Participants chose the order and duration of activities. Artificial neural networks were created separately for the wireless network and hip accelerometer for energy expenditure prediction. The wireless network had higher correlations (r = 0.79 vs. r = 0.72, P < 0.01) but similar root mean square error (2.16 vs. 2.09 METs, P > 0.05) to the hip accelerometer. Measured (from metabolic analyser) and predicted energy expenditure from the hip accelerometer were significantly different for the 3 of the 14 activities (lying down, sweeping, and cycle fast); conversely, measured and predicted energy expenditure from the wireless network were not significantly different for any activity. In conclusion, the wireless network yielded a small improvement over the hip accelerometer, providing evidence that the wireless network can produce accurate estimates of energy expenditure in adults participating in a range of activities. PMID- 26942317 TI - Trial-to-trial Adaptation: Parsing out the Roles of Cerebellum and BG in Predictive Motor Timing. AB - We previously demonstrated that predictive motor timing (i.e., timing requiring visuomotor coordination in anticipation of a future event, such as catching or batting a ball) is impaired in patients with spinocerebellar ataxia (SCA) types 6 and 8 relative to healthy controls. Specifically, SCA patients had difficulties postponing their motor response while estimating the target kinematics. This behavioral difference relied on the activation of both cerebellum and striatum in healthy controls, but not in cerebellar patients, despite both groups activating certain parts of cerebellum during the task. However, the role of these two key structures in the dynamic adaptation of the motor timing to target kinematic properties remained unexplored. In the current paper, we analyzed these data with the aim of characterizing the trial-by-trial changes in brain activation. We found that in healthy controls alone, and in comparison with SCA patients, the activation in bilateral striatum was exclusively associated with past successes and that in the left putamen, with maintaining a successful performance across successive trials. In healthy controls, relative to SCA patients, a larger network was involved in maintaining a successful trial-by-trial strategy; this included cerebellum and fronto-parieto-temporo-occipital regions that are typically part of attentional network and action monitoring. Cerebellum was also part of a network of regions activated when healthy participants postponed their motor response from one trial to the next; SCA patients showed reduced activation relative to healthy controls in both cerebellum and striatum in the same contrast. These findings support the idea that cerebellum and striatum play complementary roles in the trial-by-trial adaptation in predictive motor timing. In addition to expanding our knowledge of brain structures involved in time processing, our results have implications for the understanding of BG disorders, such as Parkinson disease where feedback processing or reward learning is affected. PMID- 26942318 TI - Beta-adrenergic Blockade at Memory Encoding, but Not Retrieval, Decreases the Subjective Sense of Recollection. AB - Humans remember emotional events not only better but also exhibit a qualitatively distinct recollective experience-that is, emotion intensifies the subjective vividness of the memory, the sense of reliving the event, and confidence in the accuracy of the memory [Phelps, E. A., & Sharot, T. How (and why) emotion enhances the subjective sense of recollection. Current Directions in Psychological Science, 17, 147-152, 2008]. Although it has been demonstrated that activation of the beta-adrenergic system, linked to increases in stress hormone levels and physiological arousal, mediates enhanced emotional memory accuracy, the mechanism underlying the increased subjective sense of recollection is unknown. Behavioral evidence suggests that increased arousal associated with emotional events, either at encoding or retrieval, underlies their increased subjective sense of recollection. Using a double-blind, placebo-controlled, within-subject design, we showed that reducing arousal at encoding through oral intake of 80-mg of the beta-adrenergic receptor antagonist propranolol decreases the subjective sense of recollection for both negative and neutral stimuli 24 hr later. In contrast, administration of propranolol before memory retrieval did not alter the subjective sense of recollection. These results suggest that the neurohormonal changes underlying increased arousal at the time of memory formation, rather than the time of memory retrieval, modulate the subjective sense of recollection. PMID- 26942319 TI - Age-related Multiscale Changes in Brain Signal Variability in Pre-task versus Post-task Resting-state EEG. AB - Recent empirical work suggests that, during healthy aging, the variability of network dynamics changes during task performance. Such variability appears to reflect the spontaneous formation and dissolution of different functional networks. We sought to extend these observations into resting-state dynamics. We recorded EEG in young, middle-aged, and older adults during a "rest-task-rest" design and investigated if aging modifies the interaction between resting-state activity and external stimulus-induced activity. Using multiscale entropy as our measure of variability, we found that, with increasing age, resting-state dynamics shifts from distributed to more local neural processing, especially at posterior sources. In the young group, resting-state dynamics also changed from pre- to post-task, where fine-scale entropy increased in task-positive regions and coarse-scale entropy increased in the posterior cingulate, a key region associated with the default mode network. Lastly, pre- and post-task resting state dynamics were linked to performance on the intervening task for all age groups, but this relationship became weaker with increasing age. Our results suggest that age-related changes in resting-state dynamics occur across different spatial and temporal scales and have consequences for information processing capacity. PMID- 26942320 TI - Dopamine Gene Profiling to Predict Impulse Control and Effects of Dopamine Agonist Ropinirole. AB - Dopamine agonists can impair inhibitory control and cause impulse control disorders for those with Parkinson disease (PD), although mechanistically this is not well understood. In this study, we hypothesized that the extent of such drug effects on impulse control is related to specific dopamine gene polymorphisms. This double-blind, placebo-controlled study aimed to examine the effect of single doses of 0.5 and 1.0 mg of the dopamine agonist ropinirole on impulse control in healthy adults of typical age for PD onset. Impulse control was measured by stop signal RT on a response inhibition task and by an index of impulsive decision making on the Balloon Analogue Risk Task. A dopamine genetic risk score quantified basal dopamine neurotransmission from the influence of five genes: catechol-O-methyltransferase, dopamine transporter, and those encoding receptors D1, D2, and D3. With placebo, impulse control was better for the high versus low genetic risk score groups. Ropinirole modulated impulse control in a manner dependent on genetic risk score. For the lower score group, both doses improved response inhibition (decreased stop signal RT) whereas the lower dose reduced impulsiveness in decision-making. Conversely, the higher score group showed a trend for worsened response inhibition on the lower dose whereas both doses increased impulsiveness in decision-making. The implications of the present findings are that genotyping can be used to predict impulse control and whether it will improve or worsen with the administration of dopamine agonists. PMID- 26942321 TI - Don't Think, Just Feel the Music: Individuals with Strong Pavlovian-to Instrumental Transfer Effects Rely Less on Model-based Reinforcement Learning. AB - Behavioral choice can be characterized along two axes. One axis distinguishes reflexive, model-free systems that slowly accumulate values through experience and a model-based system that uses knowledge to reason prospectively. The second axis distinguishes Pavlovian valuation of stimuli from instrumental valuation of actions or stimulus-action pairs. This results in four values and many possible interactions between them, with important consequences for accounts of individual variation. We here explored whether individual variation along one axis was related to individual variation along the other. Specifically, we asked whether individuals' balance between model-based and model-free learning was related to their tendency to show Pavlovian interferences with instrumental decisions. In two independent samples with a total of 243 participants, Pavlovian-instrumental transfer effects were negatively correlated with the strength of model-based reasoning in a two-step task. This suggests a potential common underlying substrate predisposing individuals to both have strong Pavlovian interference and be less model-based and provides a framework within which to interpret the observation of both effects in addiction. PMID- 26942322 TI - Cortical Integration of Contextual Information across Objects. AB - Recognizing objects in the environment and understanding our surroundings often depends on context: the presence of other objects and knowledge about their relations with each other. Such contextual information activates a set of medial lobe brain regions, the parahippocampal cortex and the retrosplenial complex. Both regions are more activated by single objects with a unique contextual association than by objects not associated with any specific context. Similarly they are more activated by spatially coherent arrangements of objects when those are consistent with their known spatial relations. The current study tested how context in multiple-object displays is represented in these regions in the absence of relevant spatial information. Using an fMRI slow-event-related design, we show that the precuneus (a subpart of the retrosplenial complex) is more activated by simultaneously presented contextually related objects than by unrelated objects. This suggests that the representation of context in this region is cumulative, representing integrated information across objects in the display. We discuss these findings in relation to processing of visual information and relate them to previous findings of contextual effects in perception. PMID- 26942323 TI - Dysfunction of the Human Mirror Neuron System in Ideomotor Apraxia: Evidence from Mu Suppression. AB - Stroke patients with ideomotor apraxia (IMA) have difficulties controlling voluntary motor actions, as clearly seen when asked to imitate simple gestures performed by the examiner. Despite extensive research, the neurophysiological mechanisms underlying failure to imitate gestures in IMA remain controversial. The aim of the current study was to explore the relationship between imitation failure in IMA and mirror neuron system (MNS) functioning. Mirror neurons were found to play a crucial role in movement imitation and in imitation-based motor learning. Their recruitment during movement observation and execution is signaled in EEG recordings by suppression of the lower (8-10 Hz) mu range. We examined the modulation of EEG in this range in stroke patients with left (n = 21) and right (n = 15) hemisphere damage during observation of video clips showing different manual movements. IMA severity was assessed by the DeRenzi standardized diagnostic test. Results showed that failure to imitate observed manual movements correlated with diminished mu suppression in patients with damage to the right inferior parietal lobule and in patients with damage to the right inferior frontal gyrus pars opercularis-areas where major components of the human MNS are assumed to reside. Voxel-based lesion symptom mapping revealed a significant impact on imitation capacity for the left inferior and superior parietal lobules and the left post central gyrus. Both left and right hemisphere damages were associated with imitation failure typical of IMA, yet a clear demonstration of relationship to the MNS was obtained only in the right hemisphere damage group. Suppression of the 8-10 Hz range was stronger in central compared with occipital sites, pointing to a dominant implication of mu rather than alpha rhythms. However, the suppression correlated with De Renzi's apraxia test scores not only in central but also in occipital sites, suggesting a multifactorial mechanism for IMA, with a possible impact for deranged visual attention (alpha suppression) beyond the effect of MNS damage (mu suppression). PMID- 26942328 TI - Predictive value of circulating fibroblast growth factor-23 on atrial fibrillation: A meta-analysis. PMID- 26942329 TI - Reduced right ventricular functional reserve: An important end point finding during dobutamine stress echocardiography testing for liver transplant evaluation. PMID- 26942330 TI - A contemporary risk model for predicting 30-day mortality following percutaneous coronary intervention in England and Wales. AB - BACKGROUND: The current risk model for percutaneous coronary intervention (PCI) in the UK is based on outcomes of patients treated in a different era of interventional cardiology. This study aimed to create a new model, based on a contemporary cohort of PCI treated patients, which would: predict 30 day mortality; provide good discrimination; and be well calibrated across a broad risk-spectrum. METHODS AND RESULTS: The model was derived from a training dataset of 336,433 PCI cases carried out between 2007 and 2011 in England and Wales, with 30 day mortality provided by record linkage. Candidate variables were selected on the basis of clinical consensus and data quality. Procedures in 2012 were used to perform temporal validation of the model. The strongest predictors of 30-day mortality were: cardiogenic shock; dialysis; and the indication for PCI and the degree of urgency with which it was performed. The model had an area under the receiver operator characteristic curve of 0.85 on the training data and 0.86 on validation. Calibration plots indicated a good model fit on development which was maintained on validation. CONCLUSION: We have created a contemporary model for PCI that encompasses a range of clinical risk, from stable elective PCI to emergency primary PCI and cardiogenic shock. The model is easy to apply and based on data reported in national registries. It has a high degree of discrimination and is well calibrated across the risk spectrum. The examination of key outcomes in PCI audit can be improved with this risk-adjusted model. PMID- 26942331 TI - Hepatoblastoma in childhood, long term survival achieved: 2 case reports and literature review. AB - INTRODUCTION: Hepatoblastoma is the most common primary liver tumor for children under 5 years of age. It usually presents as an abdominal mass, symptomatic only when large enough to cause mass effect on nearby organs. Symptoms such as early satiety, anorexia, abdominal pain or weight loss are the most common. Diagnosis depends on imaging studies, AFP levels and percutaneous biopsy. Treatment modality is usually surgical with neoadjuvant chemotherapy. CASES: In this article, we present 2 cases of hepatoblastoma treated 15 years ago by neoadjuvant chemotherapy and surgery, and are presenting for long term follow-up with complete disease remission. DISCUSSION: Complete resection and remission can be achieved as demonstrated below by our 2 cases of hepatoblastoma, especially when performing a true anatomical hepatectomy, along with a neoadjuvant chemotherapy regimen. Although one of the cases did not respond to chemotherapy very well a complete resection was achieved and therefore a disease free survival of 15 years. CONCLUSION: Hepatoblastoma are rare tumors of the pediatric age group. Management depends highly on combined surgical and pediatric oncological knowledge. A complete disease remission can be achieved when both modalities are treatment are optimal. Therefore, hepatoblastoma cases should be referred to specialized centers for management. PMID- 26942332 TI - Treatment of ununited femoral neck fractures in young adults using low-intensity pulsed ultrasound: Report of 2 cases. AB - INTRODUCTION: Delayed union and non-union of displaced femoral neck fractures remains a difficult clinical problem for orthopaedic surgeons. In the physiologically young patient, every effort should be made to preserve the native hip joint. We present two cases of ununited femoral neck fractures in young adults who were successfully treated with low-intensity pulsed ultrasound (LIPUS) and showed satisfactory results. PRESENTATION OF CASE 1: A 41-year-old woman was involved in a motor vehicle crash and was diagnosed with displaced femoral neck fracture. Eleven months after internal fixation, a computed tomography (CT) scan revealed the presence of non-union of the femoral neck. LIPUS treatment was therefore initiated. After eight months, the fracture was completely consolidated. PRESENTATION OF CASE 2: A 39-year-old man was involved in a cycling accident and was diagnosed with displaced femoral neck fracture. Thirteen weeks after internal fixation, a CT scan revealed delayed union of the femoral neck. LIPUS treatment was therefore initiated. After six months, the fracture was completely consolidated. CONCLUSION: We suggest use of LIPUS as a possible treatment approach for delayed union and non-union of displaced femoral neck fractures in young patients before considering further surgical intervention. PMID- 26942334 TI - Direct determination of GSK-3beta activity and inhibition by UHPLC-UV-vis diode arrays detector (DAD). AB - Altered GSK-3beta activity can contribute to a number of pathological processes including Alzheimer's disease (AD). Indeed, GSK-3beta catalyzes the hyperphosphorylation of tau protein by transferring a phosphate moiety from ATP to the protein substrate serine residue causing the formation of the toxic insoluble neurofibrillary tangles; for this reason it represents a key target for the development of new therapeutic agents for AD treatment. Herein we describe a new selective UHPLC methodology developed for the direct characterization of GSK 3beta kinase activity and for the determination of its inhibition, which could be crucial in AD drug discovery. The UHPLC-UV (DAD) based method was validated for the very fast determination of ATP as reactant and ADP as product, and applied for the analysis of the enzymatic reaction between a phosphate primed peptide substrate (GSM), resembling tau protein sequence, ATP and GSK-3beta, with/without inhibitors. Analysis time was ten times improved, when compared with previously published chromatographic methods. The method was also validated by determining enzyme reaction kinetic constants (KM and vmax) for GSM and ATP and by analyzing well known GSK-3beta inhibitors. Inhibition potency (IC50) values for SB-415286 (81 +/- 6 nM) and for Tideglusib (251 +/- 17 nM), found by the newly developed UHPLC method, were in good agreement with the luminescence method taken as independent reference method. Further on, the UHPLC method was applied to the elucidation of Tideglusib mechanism of action by determining its inhibition constants (Ki). In agreement with literature data, Tideglusib resulted a GSM competitive inhibitor, whereas SB-415286 was found inhibiting GSK-3beta in an ATP competitive manner. This method was applied to the determination of the potency of a new lead compound and was found potentially scalable to inhibitor screening of large compounds collections. PMID- 26942333 TI - Pseudoaneurysm of the internal maxillary artery: A case report of facial trauma and recurrent bleeding. AB - INTRODUCTION: Pseudoaneurysms occur when there is a partial disruption in the wall of a blood vessel, causing a hematoma that is either contained by the vessel adventitia or the perivascular soft tissue. PRESENTATION OF CASE: A 32-year-old male presented to the emergency department presented with comminuted fractures in the left zygoma, ethmoids, and the right ramus of the mandible following a gunshot wound. The patient underwent open reduction of his fractures and the patient was discharged on the eighth day after the trauma. Thirteen days after the discharge and 21 days after the gunshot wound, the patient returned to the ER due to heavy nasopharyngeal bleeding that compromised the patency of the patient's airways and caused hemodynamic instability. Arteriography of the facial blood vessels revealed a pseudoaneurysm of the maxillary artery. Endovascular embolization with a synthetic embolic agent resulted in adequate hemostasis, and nine days after embolization the patient was discharged. DISCUSSION: The diagnosis of pseudoaneurysm is suggested by history and physical examination, and confirmed by one of several imaging methods, such as CT scan with contrast. Progressive enlargement of the lesion may lead to several complications, including rupture of the aneurysm and hemorrhage, compression of adjacent nerves, or release of embolic thrombi. CONCLUSION: This case reports the long-term follow up and natural history of a patient with a post-traumatic pseudoaneurysm of the internal maxillary artery and the successful use of endovascular embolization to treat the lesion. PMID- 26942335 TI - Determination of the total drug-related chlorine and bromine contents in human blood plasma using high performance liquid chromatography-tandem ICP-mass spectrometry (HPLC-ICP-MS/MS). AB - A fast, accurate and precise method for the separation and determination of the total contents of drug-related Cl and Br in human blood plasma, based on high performance liquid chromatography - inductively coupled plasma - tandem mass spectrometry (HPLC-ICP-MS/MS), has been developed. The novel approach was proved to be a suitable alternative to the presently used standard methodology (i.e. based on a radiolabelled version of the drug molecule and radiodetection), while eliminating the disadvantages of the latter. Interference-free determination of (35)Cl has been accomplished via ICP-MS/MS using H2 as reaction gas and monitoring the (35)ClH2(+) reaction product at mass-to-charge ratio of 37. Br could be measured "on mass" at a mass-to-charge of 79. HPLC was relied on for the separation of the drug-related entities from the substantial amount of inorganic Cl. The method developed was found to be sufficiently precise (repeatability <10% RSD) and accurate (recovery between 95 and 105%) and shows a linear dynamic range (R(2)>0.990) from the limit of quantification (0.05 and 0.01 mg/L for Cl and Br in blood plasma, respectively) to at least 5 and 1mg/L for Cl and Br, respectively. Quantification via either external or internal standard calibration provides reliable results for both elements. As a proof-of-concept, human blood plasma samples from a clinical study involving a newly developed Cl- and Br containing active pharmaceutical ingredient were analysed and the total drug exposure was successfully described. Cross-validation was achieved by comparing the results obtained on Cl- and on Br-basis. PMID- 26942336 TI - A 1H NMR-based metabolomics approach to evaluate the geographical authenticity of herbal medicine and its application in building a model effectively assessing the mixing proportion of intentional admixtures: A case study of Panax ginseng: Metabolomics for the authenticity of herbal medicine. AB - Ginseng, the root of Panax ginseng has long been the subject of adulteration, especially regarding its origins. Here, 60 ginseng samples from Korea and China initially displayed similar genetic makeup when investigated by DNA-based technique with 23 chloroplast intergenic space regions. Hence, (1)H NMR-based metabolomics with orthogonal projections on the latent structure-discrimination analysis (OPLS-DA) were applied and successfully distinguished between samples from two countries using seven primary metabolites as discrimination markers. Furthermore, to recreate adulteration in reality, 21 mixed samples of numerous Korea/China ratios were tested with the newly built OPLS-DA model. The results showed satisfactory separation according to the proportion of mixing. Finally, a procedure for assessing mixing proportion of intentionally blended samples that achieved good predictability (adjusted R(2)=0.8343) was constructed, thus verifying its promising application to quality control of herbal foods by pointing out the possible mixing ratio of falsified samples. PMID- 26942337 TI - Brain Volume, Connectivity, and Neuropsychological Performance in Mild Traumatic Brain Injury: The Impact of Post-Traumatic Stress Disorder Symptoms. AB - Post-traumatic stress disorder (PTSD) is commonly associated with mild traumatic brain injury (mTBI). To better understand their relationship, we examined neuroanatomical structures and neuropsychological performance in a sample of individuals with mTBI, with and without PTSD symptoms. Thirty-nine subjects with mTBI were dichotomized into those with (n = 12) and without (n = 27) significant PTSD symptoms based on scores on the PTSD Checklist. Using a region-of-interest approach, fronto-temporal volumes, fiber bundles obtained by diffusion tensor imaging, and neuropsychological scores were compared between the two groups. After controlling for total intracranial volume and age, subjects with mTBI and PTSD symptoms exhibited volumetric differences in the entorhinal cortex, an area associated with memory networks, relative to mTBI-only patients (F = 4.28; p = 0.046). Additionally, subjects with PTSD symptoms showed reduced white matter integrity in the right cingulum bundle (axial diffusivity, F = 6.04; p = 0.020). Accompanying these structural alterations, mTBI and PTSD subjects also showed impaired performance in encoding (F = 5.98; p = 0.019) and retrieval (F = 7.32; p = 0.010) phases of list learning and in tests of processing speed (Wechsler Adult Intelligence Scale Processing Speed Index, F = 12.23; p = 0.001; Trail Making Test A, F = 5.56; p = 0.024). Increased volume and white matter disruptions in these areas, commonly associated with memory functions, may be related to functional disturbances during cognitively demanding tasks. Differences in brain volume and white matter integrity between mTBI subjects and those with mTBI and co-morbid PTSD symptoms point to neuroanatomical differences that may underlie poorer recovery of mTBI subjects who experience PTSD symptoms. These findings support theoretical models of PTSD and its relationship to learning deficits. PMID- 26942338 TI - Drugs for preventing red blood cell dehydration in people with sickle cell disease. AB - BACKGROUND: Sickle cell disease is an inherited disorder of hemoglobin, resulting in abnormal red blood cells. These are rigid and may block blood vessels leading to acute painful crises and other complications. Recent research has focused on therapies to rehydrate the sickled cells by reducing the loss of water and ions from them. Little is known about the effectiveness and safety of such drugs. This is an updated version of a previously published review. OBJECTIVES: To assess the relative risks and benefits of drugs to rehydrate sickled red blood cells. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register.Last search of the Group's Trials Register: 28 November 2015. SELECTION CRITERIA: Randomized or quasi-randomized controlled trials of drugs to rehydrate sickled red blood cells compared to placebo or an alternative treatment. DATA COLLECTION AND ANALYSIS: Both authors independently selected studies for inclusion, assessed study quality and extracted data. MAIN RESULTS: Of the 51 studies identified, three met the inclusion criteria. The first study tested the effectiveness of zinc sulphate to prevent sickle cell related crises in a total of 145 participants and showed a significant reduction in painful crises over one and a half years, mean difference -2.83 (95% confidence interval -3.51 to -2.15). However, analysis was restricted due to limited statistical data. Changes to red cell parameters and blood counts were inconsistent. No serious adverse events were noted in the study.The second study was a Phase II dose-finding study of senicapoc (a Gardos channel blocker) compared to placebo. Compared to the placebo group the high dose senicapoc showed significant improvement in change in hemoglobin level, number and proportion of dense red blood cells, red blood cell count and indices and hematocrit. The results with low-dose senicapoc were similar to the high-dose senicapoc group but of lesser magnitude. There was no difference in the frequency of painful crises between the three groups. A subsequent Phase III study of senicapoc was terminated early since there was no difference observed between the treatment and control groups in the primary end point of painful crises. AUTHORS' CONCLUSIONS: While the results of zinc for reducing sickle-related crises are encouraging, larger and longer-term multicenter studies are needed to evaluate the effectiveness of this therapy for people with sickle cell disease.While the Phase II and the prematurely terminated phase III studies of senicapoc showed that the drug improved red cell survival (depending on dose), this did not lead to fewer painful crises.We will continue to run searches to identify any potentially relevant trials; however, we do not plan to update other sections of the review until new trials are published. PMID- 26942339 TI - Fighter pilots' heart rate, heart rate variation and performance during instrument approaches. AB - Fighter pilots' heart rate (HR), heart rate variation (HRV) and performance during instrument approaches were examined. The subjects were required to fly instrument approaches in a high-fidelity simulator under various levels of task demand. The task demand was manipulated by increasing the load on the subjects by reducing the range at which they commenced the approach. HR and the time domain components of HRV were used as measures of pilot mental workload (PMWL). The findings of this study indicate that HR and HRV are sensitive to varying task demands. HR and HRV were able to distinguish the level of PMWL after which the subjects were no longer able to cope with the increasing task demands and their instrument landing system performance fell to a sub-standard level. The major finding was the HR/HRV's ability to differentiate the sub-standard performance approaches from the high-performance approaches. Practitioner Summary: This paper examined if HR and HRV were sensitive to varying task demands in a fighter aviation environment and if these measures were related to variations in pilot's performance. PMID- 26942340 TI - Help-seeking patterns and attitudes to treatment amongst men who attempted suicide. AB - BACKGROUND: A high percentage of those who complete suicide are not in contact with the psychiatric services and this is particularly evident among men who are the most at-risk group. AIM: To examine take-up of psychiatric services and attitudes to treatment among a sample of men who made a suicide attempt. METHOD: Fifty-two males, aged between 18 and 30 years, who made a medically serious suicide attempt, were followed up 7 years later using chart information and national mortality records. RESULTS: On discharge from hospital all participants were referred to psychiatric aftercare services but one-third (32.7%) never presented and 20% attended only for a short period. Yet almost half (48%) of the sample made a subsequent attempt and 12% completed suicide. Factors contributing to low take-up of services include lack of awareness of psychiatric symptoms, reluctance to disclose distress and negative attitudes to seeking professional help. CONCLUSION: Young males are reluctant to seek professional help for psychiatric problems even following a serious suicide attempt. Factors influencing this include health behaviours linked to traditional expectations for men as well as the type of services provided. PMID- 26942341 TI - Waiting to Conceive After an Early Pregnancy Loss. PMID- 26942342 TI - Maternal Immunization to Prevent Neonatal Group B Streptococcal Disease: New Progress and Promise. PMID- 26942343 TI - Personalized Therapy in Action: Evolving From a Series of One-Hit Wonders to a Paradigm With Staying Power. PMID- 26942344 TI - Trying to Conceive After an Early Pregnancy Loss: An Assessment on How Long Couples Should Wait. AB - OBJECTIVE: To compare time to pregnancy and live birth among couples with varying intervals of pregnancy loss date to subsequent trying to conceive date. METHODS: In this secondary analysis of the Effects of Aspirin in Gestation and Reproduction trial, 1,083 women aged 18-40 years with one to two prior early losses and whose last pregnancy outcome was a nonectopic or nonmolar loss were included. Participants were actively followed for up to six menstrual cycles and, for women achieving pregnancy, until pregnancy outcome. We calculated intervals as start of trying to conceive date minus pregnancy loss date. Time to pregnancy was defined as start of trying to conceive until subsequent conception. Discrete Cox models, accounting for left truncation and right censoring, estimated fecundability odds ratios (ORs) adjusting for age, race, body mass index, education, and subfertility. Although intervals were assessed prior to randomization and thus reasoned to have no relation with treatment assignment, additional adjustment for treatment was evaluated given that low-dose aspirin was previously shown to be predictive of time to pregnancy. RESULTS: Couples with a 0 3-month interval (n=765 [76.7%]) compared with a greater than 3-month (n=233 [23.4%]) interval were more likely to achieve live birth (53.2% compared with 36.1%) with a significantly shorter time to pregnancy leading to live birth (median [interquartile range] five cycles [three, eight], adjusted fecundability OR 1.71 [95% confidence interval 1.30-2.25]). Additionally adjusting for low-dose aspirin treatment did not appreciably alter estimates. CONCLUSION: Our study supports the hypothesis that there is no physiologic evidence for delaying pregnancy attempt after an early loss. PMID- 26942345 TI - Maternal Immunization With an Investigational Trivalent Group B Streptococcal Vaccine: A Randomized Controlled Trial. AB - OBJECTIVE: To evaluate the safety and immunogenicity of an investigational trivalent group B streptococcal vaccine in pregnant women and antibody transfer to their newborns. METHODS: The primary outcome of this observer-blind, randomized study was to estimate placental antibody transfer rates at birth. Secondary outcomes included measurement of serotype-specific antibodies at screening, 30 days postvaccination, at delivery, and 91 days postpartum, infant antibody levels at 3 months of age, the potential effect on routine infant diphtheria vaccination at 1 month after the third infant series dose, and safety in mother and infant participants through at least 5 months postpartum. Sample size was based on 60 participants in the vaccine group giving a probability of observing at least one adverse event of 90% if the actual rate of the event was 3.8%. RESULTS: From September 2011 to October 2013, 86 pregnant women were allocated in a 3:2 ratio to receive an investigational group B streptococcal vaccine containing glycoconjugates of serotypes Ia, Ib, and III or placebo. Demographics were similar across groups. Transfer ratios were 66-79% and maternal geometric mean concentrations increased 16-, 23-, and 20-fold by delivery against serotypes Ia, Ib, and III, respectively, Women with no detectable antibodies at inclusion had lower responses than those with detectable antibodies. Three months after birth, infant antibody concentrations were 22-25% of birth levels. Antidiphtheria geometric mean concentrations were similar across groups. In the vaccine and placebo groups, 32 of 51 women (63%) and 26 of 35 women (74%) reported adverse effects, respectively. CONCLUSION: The investigational vaccine was well-tolerated without safety signals in recipients and their infants or interference with routine infant diphtheria vaccination, although further studies on safety and effectiveness are needed. The investigational vaccine was immunogenic for all serotypes, particularly among women with detectable antibody levels at baseline. Antibody transfer to neonates was at similar levels to other maternally administered polysaccharide vaccines. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT01446289. PMID- 26942346 TI - Targeted Treatment of a Rare Vaginal Sarcoma With an Anaplastic Lymphoma Kinase Inhibitor. AB - BACKGROUND: Anaplastic lymphoma kinase is a tyrosine kinase receptor that can become oncogenic. Crizotinib is a tyrosine kinase inhibitor that shows activity in patients with anaplastic lymphoma kinase rearrangements that have failed conventional therapies. CASE: A 34-year-old woman presented with a painful 3-cm left vulvar-vaginal mass, which was excised and determined to be a sarcoma with positive surgical margins. Fluorescence in situ hybridization testing of her tumor was conducted and demonstrated anaplastic lymphoma kinase gene rearrangements. A 3-cm mass recurred 1 month later. Treatment with 250 mg crizotinib orally twice daily resulted in complete regression of all visible or palpable tumor within 3 weeks. CONCLUSION: Molecular evaluation techniques can be used to direct targeted therapy for select malignancies. Future technologic advances will expand the number of malignancies for which these treatment approaches can be used. PMID- 26942347 TI - Clinical Characteristics of and Preventative Strategies for Peripartum Group A Streptococcal Infections. AB - OBJECTIVE: To describe clinical characteristics in parturients with group A streptococcal infection and suggest preventive strategies. METHODS: We performed a retrospective review of all group A streptococci cultures from women presenting with peripartum fever or abdominal tenderness between January 2008 and May 2015 in a university hospital. Records and epidemiologic investigations of patients and staff were reviewed. RESULTS: Thirty-seven patients with group A streptococci cultures were identified, with an incidence of one identified postpartum group A streptococcal infection per 2,837 deliveries. Eighty-nine percent of infections occurred postpartum with isolates obtained mainly from the genital tract. Symptoms for group A streptococcal puerperal sepsis were high fever and abdominal tenderness, mostly appearing within 48 hours postpartum. More than one fifth of patients (n=7) developed streptococcal toxic shock syndrome often complicated by multiorgan failure, hysterectomy, and hospitalization in the intensive care unit. There were no uniform risk factors before infection. Epidemiologic investigations suggested that only 23% of infections were nosocomially acquired and that 77% were community-acquired. CONCLUSION: The high morbidity and the scarcity of distinct risk factors related to parturient group A streptococcal infections in the face of often community-acquired group A streptococci call for reassessing preventive strategies. These may include improved microbiological screening during pregnancy in high-prevalence areas or clinical and microbiological risk stratification in the immediate prepartum and peripartum period. PMID- 26942348 TI - Evaluation of Human Papillomavirus as a Risk Factor for Preterm Birth or Pregnancy-Related Hypertension. AB - OBJECTIVE: To compare rates of preterm birth and pregnancy-related hypertension in women with and without human papillomavirus (HPV) infection. METHODS: We performed a retrospective cohort study of all women delivered at our institution in 2013 who had cervical cancer screening test results within 3 years before delivery. Patients were excluded if they had prior procedure(s) for cervical dysplasia other than biopsy. There were two primary outcomes: preterm birth (less than 37 weeks of gestation) and pregnancy-related hypertension (gestational hypertension, preeclampsia, or eclampsia). Multivariable logistic regression was performed to adjust for confounders including demographic variables, diabetes, prior preterm birth, chronic hypertension, and other genital infections. Assuming a 10% prevalence of HPV, a rate of 12% in the HPV-negative group for both preterm birth and pregnancy-related hypertension, alpha of 0.05, and beta of 0.2, we needed 2,207 patients to detect a 60% increase in the rate of either outcome in the HPV-positive group. RESULTS: A total of 3,958 patients delivered in 2013, of whom 2,321 met eligibility criteria, 242 (10.4%) of whom were HPV-positive and 2,079 (89.2%) of whom were HPV-negative. In multivariate analyses, the rate of preterm birth was not significantly different between HPV-positive and HPV negative women (16.5% compared with 12.2%, adjusted odds ratio [OR] 1.3, 95% confidence interval [CI] 0.9-1.9); rates of pregnancy-related hypertension also were not significantly different between HPV-positive and HPV-negative women (17.0% compared with 16.4%, adjusted OR 1.0, 95% CI 0.7-1.5). CONCLUSION: Maternal HPV infection is not an independent risk factor for preterm birth or pregnancy-related hypertension. PMID- 26942349 TI - Extracorporeal Membrane Oxygenation in Pregnant and Postpartum Women With H1N1 Related Acute Respiratory Distress Syndrome: A Systematic Review and Meta analysis. AB - OBJECTIVE: To assess available evidence regarding the use of extracorporeal membrane oxygenation (ECMO) in pregnant and postpartum women with acute respiratory distress syndrome (ARDS) secondary to H1N1 infection. DATA SOURCES: Databases from MEDLINE (U.S. National Library of Medicine, 1946 to April 1, 2015), the Cochrane Library Controlled Trials Register, ClinicalTrials.gov, and Web of Science were queried for studies on ECMO in pregnant or postpartum patients with ARDS. Search terms included: "ARDS," "ECMO," "pregnant," and "postpartum." TABULATION, INTEGRATION, AND RESULTS: All relevant references in any language were reviewed. Literature for inclusion and methodologic quality were reviewed based on the meta-analyses and systematic reviews of observational studies (Meta-analysis Of Observational Studies in Epidemiology) guidelines. Of 266 citations, five retrospective studies (39 patients) fulfilled our inclusion criteria. No randomized controlled trials were found. The pooled estimate of the survival rate among pregnant and postpartum patients who received ECMO for ARDS secondary to H1N1 was 74.6% (95% confidence interval [CI] 60.7-88.6%). Neonatal outcomes were reported in two studies and the rate of live birth was 70% (95% CI 43.7-95.2). Heterogeneity was not significant among studies (I ranged from 0% to 21%; P>.25). CONCLUSION: The role of ECMO in pregnant and postpartum women with ARDS from H1N1 remains unclear and the benefits suggested from our review should be interpreted with caution. PMID- 26942350 TI - Utilization of Clinical Trials Registries in Obstetrics and Gynecology Systematic Reviews. AB - OBJECTIVE: To evaluate the use of clinical trials registries in published obstetrics and gynecologic systematic reviews and meta-analyses. METHODS: We performed a metaepidemiologic study of systematic reviews between January 1, 2007, and December 31, 2015, from six obstetric and gynecologic journals (Obstetrics & Gynecology, Obstetrical & Gynecological Survey, Human Reproduction Update, Gynecologic Oncology, British Journal of Obstetrics and Gynaecology, and American Journal of Obstetrics & Gynecology). All systematic reviews included after exclusions were independently reviewed to determine whether clinical trials registries had been included as part of the search process. Studies that reported using a trials registry were further examined to determine whether trial data were included in the analysis of these systematic reviews. RESULTS: Our initial search resulted in 292 articles, which was narrowed to 256 after exclusions. Of the 256 systematic reviews meeting our selection criteria, 47 (18.4%) used a clinical trials registry. Eleven of the 47 (23.4%) systematic reviews found unpublished data and two included unpublished data in their results. CONCLUSION: A majority of systematic reviews in clinical obstetrics and gynecology journals do not conduct searches of clinical trials registries or do not make use of data obtained from these searches. Failure to make use of such data may lead to an inaccurate summary of available evidence and may contribute to an overrepresentation of published, statistically significant outcomes. PMID- 26942351 TI - Quantitative Fetal Fibronectin at 18 Weeks of Gestation to Predict Preterm Birth in Asymptomatic High-Risk Women. AB - OBJECTIVE: To compare quantitative fetal fibronectin measurement from 18 to 21 weeks of gestation to measurement at 22-27 weeks of gestation for the prediction of spontaneous preterm birth. METHODS: In a prospective cohort study, we studied the accuracy of cervicovaginal fluid quantitative fetal fibronectin concentrations measured between 18 0/7 weeks of gestation and 21 6/7 weeks of gestation in high-risk asymptomatic women to predict spontaneous preterm birth before 34 weeks of gestation. Predefined fibronectin thresholds were 10 or greater, 50 or greater, and 200 ng/mL or greater. Diagnostic accuracy of the early test (n=898) was compared with the standard test performed between 22 0/7 and 27 6/7 weeks of gestation (n=691) in the same cohort. Subgroup analysis was performed according to cervical length measurement. RESULTS: Of 898 women, 8.7% delivered spontaneously before 34 weeks of gestation. Only 3.8% of the women with concentrations less than 10 ng/mL (65% of test results) delivered before 34 weeks of gestation. A concentration threshold of 10 ng/mL measured at 18 and 22 weeks of gestation had comparably high sensitivity (early 0.71, 95% confidence interval 0.60-0.81; standard 0.76, 0.63-0.87) and negative predictive value (early 0.96, 0.94-0.98; standard 0.97, 0.95-0.99) for delivery before 34 weeks of gestation. Specificity was also comparable (early 0.69, 0.65-0.72; standard 0.70, 0.66 0.74). A threshold of 200 ng/mL had high specificity (early 0.96, 0.94-0.98; standard 0.96, 0.94-0.97) with lower sensitivity (early 0.26, 0.17-0.37; standard 0.35, 0.22-0.49). Consideration of cervical length strengthened prediction. CONCLUSION: Quantitative cervicovaginal fetal fibronectin measured from 18 to 21 weeks of gestation has similar predictive value as measurement at 22-27 weeks of gestation for prediction of spontaneous preterm birth. Low fibronectin concentrations are associated with spontaneous preterm birthrates approaching population background levels. PMID- 26942352 TI - The 2015 International Society for the Study of Vulvovaginal Disease (ISSVD) Terminology of Vulvar Squamous Intraepithelial Lesions. AB - OBJECTIVES: The impact of terminology for vulvar intraepithelial lesions has been significant over the years, because it has affected diagnosis, treatment, and research. The introduction of the Lower Anogenital Squamous Terminology (LAST) in 2012 raised 2 concerns in relation to vulvar lesions: firstly, the absence of reference to "differentiated vulvar intraepithelial neoplasia" (differentiated VIN) could lead to its being overlooked by health care providers, despite its malignant potential. Secondly, including the term "low-grade squamous intraepithelial lesion" (LSIL) in LAST recreated the potential for overdiagnosis and overtreatment for benign, self-limiting lesions. MATERIALS AND METHODS: The International Society for the Study of Vulvovaginal Disease (ISSVD) assigned the terminology committee the task of developing a terminology to take these issues into consideration. The committee reviewed the development of terminology for vulvar SILs with the previous 2 concerns in mind and reviewed several new terminology options. RESULTS: The final version accepted by the ISSVD contains the following: 1) Low-grade SIL of the vulva or vulvar LSIL, encompassing flat condyloma or human papillomavirus effect. 2) High-grade SIL or vulvar HSIL (which was termed "vulvar intraepithelial neoplasia usual type" in the 2004 ISSVD terminology). 3) Vulvar intraepithelial neoplasia, differentiated type. CONCLUSION: The advantage of the new terminology is that it includes all types of vulvar SILs, it provides a solution to the concerns in relation to the application of LAST to vulvar lesion, and it is in accordance with the World Health Organization classification as well as the LAST, creating unity among clinicians and pathologists. PMID- 26942353 TI - Resection and Advancement Flap Closure of a Combined Vascular Malformation of the Mons Pubis. AB - BACKGROUND: Vascular malformations are congenital abnormalities that do not spontaneously regress and may require surgical resection for treatment. CASE: A healthy 23-year-old woman presented with a painless, slowly enlarging mass of the mons pubis. Ultrasonography and magnetic resonance imaging demonstrated a cystic mass with minimal Doppler flow. The final pathology showed a combined lymphatic venous vascular malformation. A meshed advancement flap was used to close the skin after surgical resection. These flaps create a lattice of small cutaneous defects that heal rapidly by secondary intention and optimize wound healing. CONCLUSION: Lower genital tract vascular malformations are rare but often become symptomatic in adolescents or young women. Larger lesions may warrant surgical resection. Flap closures may aid in proper wound healing. PMID- 26942354 TI - Alterations in the Genital Microbiota in Women With Spinal Cord Injury. AB - OBJECTIVE: To evaluate the vaginal and cervical microbiota in women with spinal cord injury compared with mobile women. METHODS: Fifty-two women with spinal cord injury (study group) and 57 mobile women (control group) were evaluated in a case control study. All answered a structured questionnaire and were submitted to the following microbiological tests: microscopic examination of vaginal secretions for Trichomonas vaginalis and yeasts, Nugent score by Gram stain, bacterial culture, yeast culture, and endocervical sampling for Chlamydia trachomatis, Neisseria gonorrhoeae, and Mycoplasma species. RESULTS: Candida species detected by direct microscopic examination of vaginal fluid was more common in women with spinal cord injuries than in control women: 17.3% (9/52) compared with 3.5% (2/57), respectively (P=.017). However, the frequency of yeast-positive cultures was similar in both groups (21.2% [10/52] compared with 15.8% [14/57]). Women with spinal cord injury were more likely to have positive vaginal cultures for Escherichia coli (15.4% [8/52] compared with 0% [0/57], P=.002) and Corynebacterium species (25.0% [13/52] compared with 8.8% [5/57], P=.037) and less likely for Lactobacillus species (63.5% [33/52] compared with 94.7% [54/57], P<.001). Women with spinal cord injury were more likely to have intermediate flora by Gram stain (Nugent score 4-6) than did the women in the control group (13.5% [7/52] compared with 1.8% [1/57], P=.033). The frequency of Mycoplasma species detection was similar in both groups (36.9% [18/52] compared with 34.6% [21/57]). No woman in either group was positive for T vaginalis, C trachomatis, or N gonorrhoeae. CONCLUSION: Women with spinal cord injury have an alteration in their vaginal microbiota away from a Lactobacillus species-dominated flora and a higher concentration of vaginal Candida species than do mobile women. PMID- 26942355 TI - Prepregnancy Body Mass Index and Infant Mortality in 38 U.S. States, 2012-2013. AB - OBJECTIVE: To estimate whether prepregnancy body mass index (BMI) is related to infant mortality and whether adherence to weight gain recommendations mitigates the relationship between BMI and infant mortality. METHODS: This was a cohort study using 2012-2013 U.S. national linked birth certificate and infant death files for 38 states and the District of Columbia with the BMI measure, including 6,419,836 singleton births and 36,691 infant deaths (infant mortality rate 5.72/1,000). Prenatal weight gain in three categories was based on adherence to Institute of Medicine recommendations. The outcome measure was infant deaths in the first year of life subdivided into two time periods: neonatal (less than 28 days) and postneonatal (28 days to 1 year). RESULTS: With normal prepregnancy weight as a reference, after adjustment, the odds ratio (OR) for an infant death rose from 1.32 (95% confidence interval [CI] 1.27-1.37) for mothers in the obese I category to 1.73 (95% CI 1.64-1.83) for obese III. Higher BMI was related to higher rates of both neonatal and postneonatal mortality. The adjusted OR for the risk of an infant death among singleton, term, vertex births for those gaining less than the recommended weight was 1.07 (95% CI 1.01-1.12) and 1.04 (95% CI 0.99-1.09) for those gaining more than recommended. CONCLUSION: Even after controlling for multiple risks, prepregnancy BMI was strongly related to infant mortality. Efforts to lower the infant mortality rate may benefit from a focus on reducing obesity among women of reproductive age. PMID- 26942357 TI - Hospital Variation in the Practice of Bilateral Salpingectomy With Ovarian Conservation in 2012. AB - OBJECTIVE: To examine hospital variation in the practice of bilateral salpingectomy with ovarian conservation at the time of benign hysterectomy. METHODS: We conducted a cross-sectional study using data from the 2012 National Inpatient Sample. We identified hospitalizations for benign, nonobstetric hysterectomy in adult women and excluded women who had elevated risk for ovarian cancer or a subsequent operation of the ovary. Of the remaining sample, we calculated the rate of bilateral salpingectomy with ovarian conservation for each hospital and conducted multivariable regression analysis to identify factors associated with a hospital's practice of this procedure. RESULTS: There were 63,306 hospitalizations for hysterectomy, and 20,635 were for adult women at low risk for ovarian cancer or subsequent ovarian surgery. Among these low-risk women, only 5.9% (95% confidence interval 5.4-6.5%) received bilateral salpingectomy with ovarian conservation. The rate varied markedly across 744 hospitals in the United States ranging from 0% to 72.2%. At 376 of the hospitals (50.5%), no low-risk women received bilateral salpingectomy with ovarian conservation. When categorizing hospitals into tertiles based on the proportion of their hysterectomies performed laparoscopically, hospitals in the highest tertile were more likely to have low-risk patients undergoing bilateral salpingectomy with ovarian conservation than those in the lowest tertile (adjusted odds ratio 2.343, P=.02). Geographic region, hysterectomy volume, and proportion of white patients were also significantly associated with a hospital's likelihood of having low-risk patients undergoing this procedure. CONCLUSION: The rate of bilateral salpingectomy with ovarian conservation was low in low-risk women undergoing benign hysterectomies. Hospitals varied widely in their practice. PMID- 26942356 TI - Barriers to Postpartum Contraception in Texas and Pregnancy Within 2 Years of Delivery. AB - OBJECTIVE: To assess pregnancies that could have been averted through improved access to contraceptive methods in the 2 years after delivery. METHODS: In this cohort study, we interviewed 403 postpartum women in a hospital in Austin, Texas, who wanted to delay childbearing for at least 2 years. Follow-up interviews were completed at 3, 6, 9, 12, 18, and 24 months after delivery; retention at 24 months was 83%. At each interview, participants reported their pregnancy status and contraceptive method. At the 3- and 6-month interviews, participants were also asked about their preferred contraceptive method 3 months in the future. We identified types of barriers among women unable to access their preferred method and used Cox models to analyze the risk of pregnancy from 6 to 24 months after delivery. RESULTS: Among women interviewed 6 months postpartum (n=377), two thirds had experienced a barrier to accessing their preferred method of contraception. By 24 months postpartum, 89 women had reported a pregnancy; 71 were unintended. Between 6 and 24 months postpartum, 77 of 377 women became pregnant (20.4%), with 56 (14.9%) lost to follow-up. Women who encountered a barrier to obtaining their preferred method were more likely to become pregnant less than 24 months after delivery. They had a cumulative risk of pregnancy of 34% (95% confidence interval [CI] 0.25-0.43) as compared with 12% (95% CI 0.05 0.18) for women with no barrier. All but three of the women reporting an unintended pregnancy had earlier expressed interest in using long-acting reversible contraception or a permanent method. CONCLUSION: In this study, most unintended pregnancies less than 24 months after delivery could have been prevented or postponed had women been able to access their desired long-acting and permanent methods. PMID- 26942358 TI - Effect of Immediate Compared With Delayed Insertion of Etonogestrel Implants on Medical Abortion Efficacy and Repeat Pregnancy: A Randomized Controlled Trial. AB - OBJECTIVE: To evaluate the effect of insertion of etonogestrel implants with mifepristone compared with after the abortion on the risks of medical abortion failure and repeat pregnancy over the subsequent 6 months. METHODS: In a randomized trial, we assigned patients undergoing medical abortion to receive etonogestrel implants either with the mifepristone (Quickstart group) or after the abortion (Afterstart group). We followed them for 7 months to ascertain abortion outcome, pregnancies, and contraception use. RESULTS: Between September 2013 and August 2014, we enrolled 236 participants in the Quickstart group and 240 in the Afterstart group. To examine abortion failure, we conducted a noninferiority analysis from which we excluded nine participants who had missing outcome data and four with specified protocol violations. Of the rest, 9 of 229 (3.9%) and 9 of 234 (3.8%) in the Quickstart and Afterstart groups, respectively, had surgery to complete the abortion; the difference of 0.08% (90% confidence interval -3.1% to 3.3%) excluded our prestipulated noninferiority margin of 5 percentage points. Among participants with pregnancy follow-up through 6 months, 1 of 213 (0.5%) and 3 of 208 (1.4%) in the Quickstart and Afterstart groups, respectively, became pregnant within that time; 6-month pregnancy rates did not differ significantly by group (exact log-rank test, P=.28). At enrollment, significantly more participants in the Quickstart group than in the Afterstart group were satisfied with their group assignments (187/236 [79%] compared with 129/240 [54%], respectively; P<.001). CONCLUSION: Insertion of etonogestrel implants with mifepristone did not appreciably increase medical abortion failure risk and it enhanced patient satisfaction, but we found no evidence that it decreased repeat pregnancy rates. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT01902485. PMID- 26942359 TI - Medication Abortion Through Telemedicine: Implications of a Ruling by the Iowa Supreme Court. AB - In summer 2015, the Iowa Supreme Court unanimously struck down a restriction that would have prevented physicians from administering a medication abortion remotely through video teleconferencing. In its ruling, the Iowa Supreme Court stated that the restriction would have placed an undue burden on a woman's right to access abortion services. It is crucially important for clinicians--especially primary care clinicians, obstetrician-gynecologists (ob-gyns), and all health care providers of telemedicine services--to understand the implications of this recent ruling, especially in rural settings. The Court's decision has potential ramifications across the country, for both women's access to abortion and the field of telemedicine. Today telemedicine abortion is available only in Iowa and Minnesota; 18 states have adopted bans on it. If telemedicine abortions are indeed being unconstitutionally restricted as the Iowa Supreme Court determined, court decisions reversing these bans could improve access to abortion services for the 21 million reproductive-age women living in these 18 states, which have a limited supply of ob-gyns, mostly concentrated in urban, metropolitan areas. Beyond the potential effects on abortion access, we argue that the Court's decision also has broader implications for telemedicine, by limiting the role of state boards of medicine regarding the restriction of politically controversial medical services when provided through telemedicine. The interplay between telemedicine policy, abortion politics, and the science of medicine is at the heart of the Court's decision and has meaning beyond Iowa's borders for reproductive-age women across the United States. PMID- 26942360 TI - Using Three-Dimensional Printing to Fabricate a Tubing Connector for Dilation and Evacuation. AB - BACKGROUND: This is a proof-of-concept study to show that simple instrumentation problems encountered in surgery can be solved by fabricating devices using a three-dimensional printer. The device used in the study is a simple tubing connector fashioned to connect two segments of suction tubing used in a surgical procedure where no commercially available product for this use is available through our usual suppliers in New Zealand. MATERIALS AND METHODS: A cylindrical tubing connector was designed using three-dimensional printing design software. The tubing connector was fabricated using the Makerbot Replicator 2X three dimensional printer. The connector was used in 15 second-trimester dilation and evacuation procedures. Data forms were completed by the primary operating surgeon. Descriptive statistics were used with the expectation that the device would function as intended in all cases. EXPERIENCE: The three-dimensional printed tubing connector functioned as intended in all 15 instances. CONCLUSION: Commercially available three-dimensional printing technology can be used to overcome simple instrumentation problems encountered during gynecologic surgical procedures. PMID- 26942362 TI - Predicting Risk of Urinary Incontinence and Adverse Events After Midurethral Sling Surgery in Women. AB - OBJECTIVE: To construct and validate models that predict a patient's risk of developing stress and urgency urinary incontinence and adverse events 12 months after sling surgery. METHODS: This was a secondary analysis of four randomized trials. Twenty-five candidate predictors (patient characteristics and urodynamic variables) were identified from the National Institute of Diabetes and Digestive and Kidney Diseases Trial of Mid-Urethral Slings (N=597). Multiple logistic models were fit to predict four different outcomes: 1) bothersome stress urinary incontinence; 2) a positive stress test; 3) bothersome urgency urinary incontinence; and 4) any adverse event up to 12 months after sling surgery. Model discrimination was measured using a concordance index. Each model's concordance index was internally validated using 1,000 bootstrap samples and calibration curves were plotted. Final models were externally validated on a separate data set (n=902) from a combination of three different multicenter randomized trials. RESULTS: Four best models discriminated on internal validation between women with bothersome stress urinary incontinence (concordance index 0.728, 95% confidence interval [CI] 0.683-0.773), a positive stress test (concordance index 0.712, 95% CI 0.669-0.758), bothersome urgency urinary incontinence (concordance index 0.722, 95% CI 0.680-0.764), and any adverse event (concordance index 0.640, 95% CI 0.595-0.681) after sling surgery. Each model's concordance index was reduced as expected when important variables were removed for external validation, but model discrimination remained stable with bothersome stress urinary incontinence (concordance index 0.548), a positive stress test (concordance index 0.656), bothersome urgency urinary incontinence (concordance index 0.621), and any adverse event (concordance index 0.567). Predicted probabilities are closest to actual probabilities when predictions are less than 50%. CONCLUSION: Four best and modified models discriminate between women who will and will not develop urinary incontinence and adverse events 12 months after midurethral sling surgery 64-73% and 55-66% of the time, respectively. PMID- 26942363 TI - Anatomical Cystocele Recurrence: Development and Internal Validation of a Prediction Model. AB - OBJECTIVE: To develop a prediction model that estimates the risk of anatomical cystocele recurrence after surgery. METHODS: The databases of two multicenter prospective cohort studies were combined, and we performed a retrospective secondary analysis of these data. Women undergoing an anterior colporrhaphy without mesh materials and without previous pelvic organ prolapse (POP) surgery filled in a questionnaire, underwent translabial three-dimensional ultrasonography, and underwent staging of POP preoperatively and postoperatively. We developed a prediction model using multivariable logistic regression and internally validated it using standard bootstrapping techniques. The performance of the prediction model was assessed by computing indices of overall performance, discriminative ability, calibration, and its clinical utility by computing test characteristics. RESULTS: Of 287 included women, 149 (51.9%) had anatomical cystocele recurrence. Factors included in the prediction model were assisted delivery, preoperative cystocele stage, number of compartments involved, major levator ani muscle defects, and levator hiatal area during Valsalva. Potential predictors that were excluded after backward elimination because of high P values were age, body mass index, number of vaginal deliveries, and family history of POP. The shrinkage factor resulting from the bootstrap procedure was 0.91. After correction for optimism, Nagelkerke's R and the Brier score were 0.15 and 0.22, respectively. This indicates satisfactory model fit. The area under the receiver operating characteristic curve of the prediction model was 71.6% (95% confidence interval 65.7-77.5). After correction for optimism, the area under the receiver operating characteristic curve was 69.7%. CONCLUSION: This prediction model, including history of assisted delivery, preoperative stage, number of compartments, levator defects, and levator hiatus, estimates the risk of anatomical cystocele recurrence. PMID- 26942361 TI - Prophylactic Antibiotic Choice and Risk of Surgical Site Infection After Hysterectomy. AB - OBJECTIVE: To evaluate associations between prophylactic preoperative antibiotic choice and surgical site infection rates after hysterectomy. METHODS: A retrospective cohort study was performed of patients in the Michigan Surgical Quality Collaborative undergoing hysterectomy from July 2012 to February 2015. The primary outcome was a composite outcome of any surgical site infection (superficial surgical site infections or combined deep organ space surgical site infections). Preoperative antibiotics were categorized based on the recommendations set forth by the American College of Obstetricians and Gynecologists and the Surgical Care Improvement Project. Patients receiving a recommended antibiotic regimen were categorized into those receiving beta-lactam antibiotics and those receiving alternatives to beta-lactam antibiotics. Patients receiving nonrecommended antibiotics were categorized into those receiving overtreatment (excluded from further analysis) and those receiving nonstandard antibiotics. Multivariable logistic regression models were developed to estimate the independent effect of antibiotic choice. Propensity score matching analysis was performed to validate the results. RESULTS: The study included 21,358 hysterectomies. The overall rate of any surgical site infection was 2.06% (n=441). Unadjusted rates of "any surgical site infection" were 1.8%, 3.1%, and 3.7% for beta-lactam, beta-lactam alternatives, and nonstandard groups, respectively. After adjusting for patient and operative factors within clusters of hospitals, compared with the beta-lactam antibiotics (reference group), the risk of "any surgical site infection" was higher for the group receiving beta lactam alternatives (odds ratio [OR] 1.7, confidence interval [CI] 1.27-2.07) or the nonstandard antibiotics (OR 2.0, CI 1.31-3.1). CONCLUSION: Compared with women receiving beta-lactam antibiotic regimens, there is a higher risk of surgical site infection after hysterectomy among those receiving a recommended beta-lactam alternative or nonstandard regimen. PMID- 26942364 TI - Vaginal Swab Test Compared With the Urethral Q-tip Test for Urethral Mobility Measurement: A Randomized Controlled Trial. AB - OBJECTIVE: To assess whether use of a vaginal cotton-tipped swab is equivalent to the standard Q-tip test regarding urethral mobility. Secondarily, to examine whether both tests agree in hypermobility diagnosis, discomfort level, and patients' preference. METHODS: In this randomized crossover trial, women with stress urinary incontinence without prolapse beyond the hymen were randomized to undergo either a vaginal or urethral mobility test first followed by the alternate approach. The primary outcome was the difference in rotation angle, from resting to maximum strain, between tests. The equivalence margin was +/-10 degrees . The secondary outcome was agreement in hypermobility diagnosis using two definitions: 1) maximum straining angle of 30 degrees or greater from the horizontal plane; and 2) rotation angle 30 degrees or greater. Discomfort was assessed using a 0-10 visual analog scale. Using 90% power assuming a standard deviation of 20 degrees , 36 and 139 patients were needed for 10 degrees and 5 degrees equivalence margins, respectively. RESULTS: From January 2014 to March 2015, 140 women were randomized. The mean difference between the two tests was 5.1 degrees (95% confidence interval 3.2-6.9 degrees ), meeting the predefined equivalence criteria. In the hypermobility diagnosis, the urethral and vaginal tests had no disagreement using definition 1 (P=.23), whereas the two tests disagreed using definition 2 (P=.03). The urethral approach had a higher discomfort level (P<.001). The majority preferred the vaginal test (68% preferred vaginal, 32% no preference). CONCLUSION: The vaginal swab test is equivalent to the standard Q-tip test in measuring urethral mobility with less discomfort and is preferred by patients. PMID- 26942365 TI - Short-Term Efficacy of Trichloroacetic Acid in the Treatment of Cervical Intraepithelial Neoplasia. AB - OBJECTIVE: To establish the short-term efficacy and tolerability of a single topical 85% trichloroacetic acid treatment for cervical intraepithelial neoplasia (CIN) 1-3. METHODS: A retrospective case series including all patients with CIN treated with trichloroacetic acid as first-line therapy was performed. Treatment response was evaluated by colposcopy, cervical biopsy, cytology, and type specific human papillomavirus (HPV) testing 8 weeks after a single trichloroacetic acid treatment. Regression was defined as improvement from high grade to low-grade CIN and remission was defined as improvement from any grade of CIN to no CIN. For quantification of treatment-related pain, 107 (44.1%) patients rated their subjective perception on a visual analog scale. RESULTS: A total of 241 women were included in the study with 179 high-grade (CIN 2-3) and 62 low grade (CIN 1) squamous intraepithelial lesions. For high-grade squamous intraepithelial lesions, the histologic regression rate was 87.7% (95% confidence interval [CI] 82.0-92.1) and the remission rate was 80.3% (95% CI 73.3-85.5). For low-grade squamous intraepithelial lesions, the remission rate was 82.3% (95% CI 70.5-90.8). Human papillomavirus types 16 and 18 were found in 53.7% and 7.3% of all women tested, respectively. Clearance rates of HPV type 16 and HPV type 18 were 73.5% (95% CI 62.5-81.3) and 75.0% (95% CI 46.2-95.0), respectively. Median pain score was 3.0 out of 10.0 (25th and 75th percentiles 2.3 and 4.3, respectively). There were no major side effects observed during treatment or follow-up. CONCLUSION: A high regression and remission rate and a high HPV clearance rate were observed 8 weeks after topical 85% trichloroacetic acid treatment for patients with CIN. PMID- 26942368 TI - Industry Payments to Obstetrician-Gynecologists: An Analysis of 2014 Open Payments Data. AB - OBJECTIVE: To evaluate publically available, individually identified data regarding industry payments made to obstetrician-gynecologists (ob-gyns) during 2014 posted on the Centers for Medicare & Medicaid Services' Open Payments website for the purposes of encouraging ob-gyns to partake in disclosure of their fiscal relationships to patients and to take an active role in maintaining accuracy of their payment data. METHODS: In this retrospective study, we reviewed the Centers for Medicare & Medicaid Services' Open Payments website for all 2014 nonresearch payments to ob-gyns. We compared payments to ob-gyns with payments to those in other specialties as well as subspecialties within the field of obstetrics and gynecology. Univariate statistical analyses were performed. RESULTS: Payments to ob-gyns totaled $60,004,472 (3.3% of the total value transferred in 2014) and went to 29,783 physician recipients. Fifty percent of these payments were for royalties and licensing. Obstetrics and gynecology ranked seventh in total number of payments made to a single specialty (n=311,485), and 20th of 35 specialties for highest median payment ($140, interquartile range $50 347). Medtronic USA, Inc. was the leading payer to ob-gyns. CONCLUSION: Ob-gyns are listed as having received substantial payments from industry in 2014. Because this information is publically available, we suggest physicians become familiar with payment data and the correction process, keep independent records, and register for updates to most effectively manage perceived, or real, conflicts of interest. PMID- 26942369 TI - Reproductive Health Management for the Care of Women Veterans. AB - There are more than 2 million women veterans living in the United States. Many women do not identify themselves as veterans. As women's health care providers, it is important to understand and recognize the potentially complex health and social needs of women veterans and the role of military service on their lives. The reproductive health needs of women veterans may be shaped by their military experiences and coexisting medical or mental health conditions. Military sexual trauma and combat exposure are common causes of posttraumatic stress disorder and can affect overall health and well-being. Screening for military service is important in all women, and inclusion of this as a key demographic variable in research and clinical encounters can further inform health care considerations. The following key topics are addressed: who are women veterans, health and social risk factors associated with a history of military service, reproductive health across the life course, military sexual trauma and reproductive health of women veterans, how to take a military history, and the essential role of women's health providers, including obstetrician-gynecologists, in enhancing health systems and providing high-quality care to veterans. PMID- 26942366 TI - Vaginal and Rectal Clostridium sordellii and Clostridium perfringens Presence Among Women in the United States. AB - OBJECTIVE: To characterize the presence of Clostridium sordellii and Clostridium perfringens in the vagina and rectum, identify correlates of presence, and describe strain diversity and presence of key toxins. METHODS: We conducted an observational cohort study in which we screened a diverse cohort of reproductive aged women in the United States up to three times using vaginal and rectal swabs analyzed by molecular and culture methods. We used multivariate regression models to explore predictors of presence. Strains were characterized by pulsed-field gel electrophoresis and tested for known virulence factors by polymerase chain reaction assays. RESULTS: Of 4,152 participants enrolled between 2010 and 2013, 3.4% (95% confidence interval [CI] 2.9-4.0) were positive for C sordellii and 10.4% (95% CI 9.5-11.3) were positive for C perfringens at baseline. Among the 66% with follow-up data, 94.7% (95% CI 88.0-98.3) of those positive for C sordellii and 74.4% (95% CI 69.0-79.3) of those positive for C perfringens at baseline were negative at follow-up. At baseline, recent gynecologic surgery was associated with C sordellii presence, whereas a high body mass index was associated with C perfringens presence in adjusted models. Two of 238 C sordellii isolates contained the lethal toxin gene, and none contained the hemorrhagic toxin gene. Substantial strain diversity was observed in both species with few clusters and no dominant clones identified. CONCLUSION: The relatively rare and transient nature of C sordellii and C perfringens presence in the vagina and rectum makes it inadvisable to use any screening or prophylactic approach to try to prevent clostridial infection. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT01283828. PMID- 26942367 TI - Universal Cystoscopy After Benign Hysterectomy: Examining the Effects of an Institutional Policy. AB - OBJECTIVE: To evaluate the association between a universal cystoscopy policy at the time of benign hysterectomy and the detection of urologic injuries. METHODS: This is a retrospective cohort study at a tertiary care academic center where a policy of universal cystoscopy at the time of benign hysterectomy was instituted on October 1, 2008. Benign hysterectomies performed from March 3, 2006, to September 25, 2013, were included and dichotomized into preuniversal and postuniversal cystoscopy groups. Medical records were reviewed for baseline and perioperative characteristics, cystoscopy use, and urologic injuries related to hysterectomy. Urologic injuries were identified by using a search engine and a departmental quality improvement database. RESULTS: Two thousand nine hundred eighteen hysterectomies were identified during the study time period, 96 of which were excluded for indications of abdominopelvic cancers and peripartum indications. Therefore, 973 women were in the preuniversal cystoscopy group and 1,849 were in the postuniversal cystoscopy group. Thirty-six percent (347/973, 95% confidence interval [CI] 32.8-38.8%) and 86.1% (1,592/1,849, 95% CI 84.5 87.7%) of patients underwent cystoscopy prepolicy and postpolicy, respectively. The urologic injury rates were 2.6% (25/973, 95% CI 1.6-3.6%) and 1.8% (34/1,849, 95% CI 1.2-2.5%) in the prepolicy and postpolicy groups, respectively. Delayed urologic injuries decreased significantly (0.7% [7/973], 95% CI 0.3-1.2% compared with 0.1% [2/1,849], 95% CI 0.0-0.3%). Of the nine patients with delayed injuries, four had normal intraoperative cystoscopy findings and five had no cystoscopy performed. CONCLUSION: The practice of universal cystoscopy at the time of hysterectomy for benign indications is associated with decreased delayed postoperative urologic complications. PMID- 26942370 TI - Definitions of Obstetric and Gynecologic Hospitalists. AB - The obstetric hospitalist and the obstetric and gynecologic hospitalist evolved in response to diverse forces in medicine, including the need for leadership on labor and delivery units, an increasing emphasis on quality and safety in obstetrics and gynecology, the changing demographics of the obstetric and gynecologic workforce, and rising liability costs. Current (although limited) research suggests that obstetric and obstetric and gynecologic hospitalists may improve the quality and safety of obstetric care, including lower cesarean delivery rates and higher vaginal birth after cesarean delivery rates as well as lower liability costs and fewer liability events. This research is currently hampered by the use of varied terminology. The leadership of the Society of Obstetric and Gynecologic Hospitalists proposes standardized definitions of an obstetric hospitalist, an obstetric and gynecologic hospitalist, and obstetric and gynecologic hospital medicine practices to standardize communication and facilitate program implementation and research. Clinical investigations regarding obstetric and gynecologic practices (including hospitalist practices) should define inpatient coverage arrangements using these standardized definitions to allow for fair conclusions and comparisons between practices. PMID- 26942371 TI - What is New in the Management of Acute Preterm Labor?: Best Articles From the Past Year. AB - This month we focus on current research in the management of acute preterm labor. Dr. Malone discusses four recent publications, which are concluded with a "bottom line" that is the take-home message. The complete reference for each can be found in on this page, along with direct links to the abstracts. PMID- 26942373 TI - Connect the Dots--February 2016. PMID- 26942374 TI - Uncontained Compared With Contained Power Morcellation in Total Laparoscopic Hysterectomy. PMID- 26942375 TI - In Reply. PMID- 26942376 TI - College Publications (December 2015): Correction. PMID- 26942380 TI - Practice Bulletin No. 161 Summary: External Cephalic Version. AB - In the United States, there is a widespread belief that the overall cesarean delivery rate is higher than necessary. Efforts are being directed toward decreasing the number of these procedures, in part by encouraging physicians to make changes in their management practices. Because breech presentations are associated with a high rate of cesarean delivery, there is renewed interest in techniques such as external cephalic version (ECV) and vaginal breech delivery. The purpose of this document is to provide information about ECV by summarizing the relevant evidence presented in published studies and to make recommendations regarding its use in obstetric practice. PMID- 26942381 TI - Committee Opinion No 653 Summary: Concerns Regarding Social Media and Health Issues in Adolescents and Young Adults. AB - Although there are many positive aspects of social media for adolescents and young adults, there are also risks. Adolescence is a time of significant developmental changes, during which adolescents exhibit a limited capacity for self-regulation and an increased risk of susceptibility to peer pressure and experimentation. Social media can be harmful, and obstetrician-gynecologists may screen their adolescent and young adult patients for high-risk sexual behaviors, especially if sexualized text communication (sexting), exposure to pornography, online dating, or other risk-taking behaviors are present. Victims of cyberbullying and those who engage in sexting are at increased risk of sexually transmitted infections and pregnancy. The effect of social media may be considered in the differential diagnosis of myriad health problems during adolescence. Referrals to mental health care providers or providing outside resources may be indicated. A multidisciplinary approach to address these issues can include the obstetrician-gynecologist, guardians, and school officials and personnel. Knowledge of resources, including those within the schools and community, allows the obstetrician-gynecologist to provide support to adolescents facing these issues. PMID- 26942382 TI - Committee Opinion No. 654 Summary: Reproductive Life Planning to Reduce Unintended Pregnancy. AB - Approximately one half (51%) of the 6 million pregnancies each year in the United States are unintended. A reproductive life plan is a set of personal goals regarding whether, when, and how to have children based on individual priorities, resources, and values. A lack of reproductive life planning, limited access to contraception, and inconsistent use of contraceptive methods contribute to unintended pregnancy. The American College of Obstetricians and Gynecologists strongly supports women's access to comprehensive and culturally appropriate reproductive life planning and encourages obstetrician-gynecologists and other health care providers to use every patient encounter as an opportunity to talk with patients about their pregnancy intentions and to support initiatives that promote access to and availability of all effective contraceptive methods. PMID- 26942383 TI - Committee Opinion No. 655 Summary: Hepatitis B, Hepatitis C, and Human Immunodeficiency Virus Infections in Obstetrician-Gynecologists. AB - To prevent transmission of bloodborne pathogens, it is important that health care providers adhere to standard precautions, follow fundamental infection-control principles, and use appropriate procedural techniques. All obstetrician gynecologists who provide clinical care should receive the hepatitis B virus vaccine series. The Society for Healthcare Epidemiology of America has established guidelines for the management of health care providers who are infected with hepatitis B virus, hepatitis C virus, or human immunodeficiency virus (HIV). The guidelines categorize representative obstetric and gynecologic procedures according to level of risk of bloodborne pathogen transmission and include recommendations for health care provider clinical activities, based on these categories and viral burden. It is important to note that when no restrictions are recommended, careful supervision should be carried out as highlighted. These recommendations provide a framework within which to consider such cases; however, each case should be independently considered in context by the expert review panel. PMID- 26942384 TI - Committee Opinion No. 656 Summary: Guidelines for Diagnostic Imaging During Pregnancy and Lactation. AB - Imaging studies are important adjuncts in the diagnostic evaluation of acute and chronic conditions. However, confusion about the safety of these modalities for pregnant and lactating women and their infants often results in unnecessary avoidance of useful diagnostic tests or the unnecessary interruption of breastfeeding. Ultrasonography and magnetic resonance imaging are not associated with risk and are the imaging techniques of choice for the pregnant patient, but they should be used prudently and only when use is expected to answer a relevant clinical question or otherwise provide medical benefit to the patient. With few exceptions, radiation exposure through radiography, computed tomography scan, or nuclear medicine imaging techniques is at a dose much lower than the exposure associated with fetal harm. If these techniques are necessary in addition to ultrasonography or magnetic resonance imaging or are more readily available for the diagnosis in question, they should not be withheld from a pregnant patient. Breastfeeding should not be interrupted after gadolinium administration. PMID- 26942385 TI - Committee Opinion No. 657 Summary: The Obstetric and Gynecologic Hospitalist. AB - The term "hospitalist" refers to physicians whose primary professional focus is the general medical care of hospitalized patients. Their activities may include patient care, teaching, research, and inpatient leadership. The American College of Obstetricians and Gynecologists supports the continued development and study of the obstetric and gynecologic (ob-gyn) hospitalist model as one potential approach to improve patient safety and professional satisfaction across delivery settings. Effective patient handoffs, updates on progress, and clear follow-up instructions between ob-gyn hospitalists and patients, nurses, and other health care providers are vital to maintaining patient safety. Hospitals and other health care organizations should ensure that candidates for positions as ob-gyn hospitalists are drawn from those with documented training and experience appropriate for the management of the acute and potentially emergent clinical circumstances that may be encountered in obstetric care. PMID- 26942386 TI - Committee Opinion No. 658 Summary: Optimizing Support For Breastfeeding As Part Of Obstetric Practice. AB - Although most women in the United States initiate breastfeeding, more than one half wean earlier than they desire. As reproductive health experts and advocates for women's health who work in conjunction with other obstetric and pediatric health care providers, obstetrician-gynecologists are uniquely positioned to enable women to achieve their infant feeding goals. The American College of Obstetricians and Gynecologists recommends exclusive breastfeeding for the first 6 months of life, with continued breastfeeding as complementary foods are introduced through the infant's first year of life, or longer as mutually desired by the woman and her infant. Because lactation is an integral part of reproductive physiology, all obstetrician-gynecologists and other obstetric care providers should develop and maintain knowledge and skills in anticipatory guidance, physical assessment and support for normal breastfeeding physiology, and management of common complications of lactation. Obstetrician-gynecologists and other obstetric care providers should support each woman's informed decision about whether to initiate or continue breastfeeding, recognizing that she is uniquely qualified to decide whether exclusive breastfeeding, mixed feeding, or formula feeding is optimal for her and her infant. Obstetrician-gynecologists and other obstetric care providers should support women in integrating breastfeeding into their daily lives in the community and in the workplace. The offices of obstetrician-gynecologists and other obstetric care providers should be a resource for breastfeeding women through the infant's first year of life, and for those who continue beyond the first year. PMID- 26942387 TI - Practice Bulletin No. 161: External Cephalic Version. AB - In the United States, there is a widespread belief that the overall cesarean delivery rate is higher than necessary. Efforts are being directed toward decreasing the number of these procedures, in part by encouraging physicians to make changes in their management practices. Because breech presentations are associated with a high rate of cesarean delivery, there is renewed interest in techniques such as external cephalic version (ECV) and vaginal breech delivery. The purpose of this document is to provide information about ECV by summarizing the relevant evidence presented in published studies and to make recommendations regarding its use in obstetric practice. PMID- 26942388 TI - Committee Opinion No. 653: Concerns Regarding Social Media and Health Issues in Adolescents and Young Adults. AB - Although there are many positive aspects of social media for adolescents and young adults, there are also risks. Adolescence is a time of significant developmental changes, during which adolescents exhibit a limited capacity for self-regulation and an increased risk of susceptibility to peer pressure and experimentation. Social media can be harmful, and obstetrician-gynecologists may screen their adolescent and young adult patients for high-risk sexual behaviors, especially if sexualized text communication (sexting), exposure to pornography, online dating, or other risk-taking behaviors are present. Victims of cyberbullying and those who engage in sexting are at increased risk of sexually transmitted infections and pregnancy. The effect of social media may be considered in the differential diagnosis of myriad health problems during adolescence. Referrals to mental health care providers or providing outside resources may be indicated. A multidisciplinary approach to address these issues can include the obstetrician-gynecologist, guardians, and school officials and personnel. Knowledge of resources, including those within the schools and community, allows the obstetrician-gynecologist to provide support to adolescents facing these issues. PMID- 26942389 TI - Committee Opinion No. 654: Reproductive Life Planning to Reduce Unintended Pregnancy. AB - Approximately one half (51%) of the 6 million pregnancies each year in the United States are unintended. A reproductive life plan is a set of personal goals regarding whether, when, and how to have children based on individual priorities, resources, and values. A lack of reproductive life planning, limited access to contraception, and inconsistent use of contraceptive methods contribute to unintended pregnancy. The American College of Obstetricians and Gynecologists strongly supports women's access to comprehensive and culturally appropriate reproductive life planning and encourages obstetrician-gynecologists and other health care providers to use every patient encounter as an opportunity to talk with patients about their pregnancy intentions and to support initiatives that promote access to and availability of all effective contraceptive methods. PMID- 26942390 TI - Committee Opinion No. 655: Hepatitis B, Hepatitis C, and Human Immunodeficiency Virus Infections in Obstetrician-Gynecologists. AB - To prevent transmission of bloodborne pathogens, it is important that health care providers adhere to standard precautions, follow fundamental infection-control principles, and use appropriate procedural techniques. All obstetrician gynecologists who provide clinical care should receive the hepatitis B virus vaccine series. The Society for Healthcare Epidemiology of America has established guidelines for the management of health care providers who are infected with hepatitis B virus, hepatitis C virus, or human immunodeficiency virus (HIV). The guidelines categorize representative obstetric and gynecologic procedures according to level of risk of bloodborne pathogen transmission and include recommendations for health care provider clinical activities, based on these categories and viral burden. It is important to note that when no restrictions are recommended, careful supervision should be carried out as highlighted. These recommendations provide a framework within which to consider such cases; however, each case should be independently considered in context by the expert review panel. PMID- 26942391 TI - Committee Opinion No. 656: Guidelines for Diagnostic Imaging During Pregnancy and Lactation. AB - Imaging studies are important adjuncts in the diagnostic evaluation of acute and chronic conditions. However, confusion about the safety of these modalities for pregnant and lactating women and their infants often results in unnecessary avoidance of useful diagnostic tests or the unnecessary interruption of breastfeeding. Ultrasonography and magnetic resonance imaging are not associated with risk and are the imaging techniques of choice for the pregnant patient, but they should be used prudently and only when use is expected to answer a relevant clinical question or otherwise provide medical benefit to the patient. With few exceptions, radiation exposure through radiography, computed tomography scan, or nuclear medicine imaging techniques is at a dose much lower than the exposure associated with fetal harm. If these techniques are necessary in addition to ultrasonography or magnetic resonance imaging or are more readily available for the diagnosis in question, they should not be withheld from a pregnant patient. Breastfeeding should not be interrupted after gadolinium administration. PMID- 26942392 TI - Committee Opinion No. 657: The Obstetric and Gynecologic Hospitalist. AB - The term "hospitalist" refers to physicians whose primary professional focus is the general medical care of hospitalized patients. Their activities may include patient care, teaching, research, and inpatient leadership. The American College of Obstetricians and Gynecologists supports the continued development and study of the obstetric and gynecologic (ob-gyn) hospitalist model as one potential approach to improve patient safety and professional satisfaction across delivery settings. Effective patient handoffs, updates on progress, and clear follow-up instructions between ob-gyn hospitalists and patients, nurses, and other health care providers are vital to maintaining patient safety. Hospitals and other health care organizations should ensure that candidates for positions as ob-gyn hospitalists are drawn from those with documented training and experience appropriate for the management of the acute and potentially emergent clinical circumstances that may be encountered in obstetric care. PMID- 26942393 TI - Committee Opinion No. 658: Optimizing Support for Breastfeeding as Part of Obstetric Practice. AB - Although most women in the United States initiate breastfeeding, more than one half wean earlier than they desire. As reproductive health experts and advocates for women's health who work in conjunction with other obstetric and pediatric health care providers, obstetrician-gynecologists are uniquely positioned to enable women to achieve their infant feeding goals. The American College of Obstetricians and Gynecologists recommends exclusive breastfeeding for the first 6 months of life, with continued breastfeeding as complementary foods are introduced through the infant's first year of life, or longer as mutually desired by the woman and her infant. Because lactation is an integral part of reproductive physiology, all obstetrician-gynecologists and other obstetric care providers should develop and maintain knowledge and skills in anticipatory guidance, physical assessment and support for normal breastfeeding physiology, and management of common complications of lactation. Obstetrician-gynecologists and other obstetric care providers should support each woman's informed decision about whether to initiate or continue breastfeeding, recognizing that she is uniquely qualified to decide whether exclusive breastfeeding, mixed feeding, or formula feeding is optimal for her and her infant. Obstetrician-gynecologists and other obstetric care providers should support women in integrating breastfeeding into their daily lives in the community and in the workplace. The offices of obstetrician-gynecologists and other obstetric care providers should be a resource for breastfeeding women through the infant's first year of life, and for those who continue beyond the first year. PMID- 26942394 TI - Real-Time Plasmonic Monitoring of Single Gold Amalgam Nanoalloy Electrochemical Formation and Stripping. AB - Direct electrodeposition of mercury onto gold nanorods on an ITO substrate, without reducing agents, is reported. The growth of single gold amalgam nanoalloy particles and subsequent stripping was monitored in real-time monitoring by plasmonic effects and single-nanoparticle dark-field spectroelectrochemistry techniques. Time-dependent scattering spectral information conferred insight into the growth and stripping mechanism of a single nanoalloy particle. Four critical stages were observed: First, rapid deposition of Hg atoms onto Au nanorods; second, slow diffusion of Hg atoms into Au nanorods; third, prompt stripping of Hg atoms from Au nanorods; fourth, moderate diffusion from the inner core of Au nanorods. Under high Hg(2+) concentrations, homogeneous spherical gold amalgam nanoalloys were obtained. These results demonstrate that the morphology and composition of individual gold amalgam nanoalloys can be precisely regulated electrochemically. Moreover, gold amalgam nanoalloys with intriguing optical properties, such as modulated plasmonic lifetimes and quality factor Q, could be obtained. This may offer opportunities to extend applications in photovoltaic energy conversion and chemical sensing. PMID- 26942407 TI - Benzothienobenzothiophene-Based Molecular Conductors: High Conductivity, Large Thermoelectric Power Factor, and One-Dimensional Instability. AB - On the basis of an excellent transistor material, [1]benzothieno[3,2 b][1]benzothiophene (BTBT), a series of highly conductive organic metals with the composition of (BTBT)2XF6 (X = P, As, Sb, and Ta) are prepared and the structural and physical properties are investigated. The room-temperature conductivity amounts to 4100 S cm(-1) in the AsF6 salt, corresponding to the drift mobility of 16 cm(2) V(-1) s(-1). Owing to the high conductivity, this salt shows a thermoelectric power factor of 55-88 MUW K(-2) m(-1), which is a large value when this compound is regarded as an organic thermoelectric material. The thermoelectric power and the reflectance spectrum indicate a large bandwidth of 1.4 eV. These salts exhibit an abrupt resistivity jump under 200 K, which turns to an insulating state below 60 K. The paramagnetic spin susceptibility, and the Raman and the IR spectra suggest 4kF charge-density waves as an origin of the low temperature insulating state. PMID- 26942408 TI - Consumption of milk and milk products in the population of the Upper Silesian agglomeration inhabitants. AB - BACKGROUND: Providing the appropriate amount of nutrients at every stage of life is a key element determining the proper development and functioning of the body. OBJECTIVE: Because of the nutritional value and resulting position of milk and milk products in the daily diet, this study was undertaken to assess the consumption of milk and milk products among the inhabitants of the Upper Silesian agglomeration. DESIGN: The survey covered 600 people, including 339 women (56.5%) and 261 men (43.5%) aged 18-78 years. To assess the consumption of milk and milk products, as a research tool an original survey with the closed-ended and open ended questions was used. The questions concerned the characteristics of the surveyed group and various aspects of the consumption of milk and milk products. The results obtained were subjected to statistical analysis using the Statistica 10.0 program with a chi-square test for quality features. RESULTS: The level of consumption of milk and milk products among the Upper Silesian agglomeration inhabitants is insufficient in relation to nutrition recommendations. However, despite many controversies surrounding milk, the respondents also claimed that it played an important role in their daily diet. CONCLUSIONS: The most frequently consumed type of milk in the surveyed group is ultra heat treated (UHT) milk with average fat content. PMID- 26942409 TI - Bovine Gamma Delta T Cells Contribute to Exacerbated IL-17 Production in Response to Co-Infection with Bovine RSV and Mannheimia haemolytica. AB - Human respiratory syncytial virus (HRSV) is a leading cause of severe lower respiratory tract infection in children under five years of age. IL-17 and Th17 responses are increased in children infected with HRSV and have been implicated in both protective and pathogenic roles during infection. Bovine RSV (BRSV) is genetically closely related to HRSV and is a leading cause of severe respiratory infections in young cattle. While BRSV infection in the calf parallels many aspects of human infection with HRSV, IL-17 and Th17 responses have not been studied in the bovine. Here we demonstrate that calves infected with BRSV express significant levels of IL-17, IL-21 and IL-22; and both CD4 T cells and gammadelta T cells contribute to this response. In addition to causing significant morbidity from uncomplicated infections, BRSV infection also contributes to the development of bovine respiratory disease complex (BRDC), a leading cause of morbidity in both beef and dairy cattle. BRDC is caused by a primary viral infection, followed by secondary bacterial pneumonia by pathogens such as Mannheimia haemolytica. Here, we demonstrate that in vivo infection with M. haemolytica results in increased expression of IL-17, IL-21 and IL-22. We have also developed an in vitro model of BRDC and show that co-infection of PBMC with BRSV followed by M. haemolytica leads to significantly exacerbated IL-17 production, which is primarily mediated by IL-17-producing gammadelta T cells. Together, our results demonstrate that calves, like humans, mount a robust IL-17 response during RSV infection; and suggest a previously unrecognized role for IL-17 and gammadelta T cells in the pathogenesis of BRDC. PMID- 26942410 TI - Seasonal Dynamics of the Airborne Bacterial Community and Selected Viruses in a Children's Daycare Center. AB - Children's daycare centers appear to be hubs of respiratory infectious disease transmission, yet there is only limited information about the airborne microbial communities that are present in daycare centers. We have investigated the microbial community of the air in a daycare center, including seasonal dynamics in the bacterial community and the presence of specific viral pathogens. We collected filters from the heating, ventilation, and air conditioning (HVAC) system of a daycare center every two weeks over the course of a year. Amplifying and sequencing the 16S rRNA gene revealed that the air was dominated by Proteobacteria, Firmicutes, Actinobacteria, and Bacteroidetes that are commonly associated with the human skin flora. Clear seasonal differences in the microbial community were not evident; however, the community structure differed when the daycare center was closed and unoccupied for a 13-day period. These results suggest that human occupancy, rather than the environment, is the major driver in shaping the microbial community structure in the air of the daycare center. Using PCR for targeted viruses, we detected a seasonal pattern in the presence of respiratory syncytial virus that included the period of typical occurrence of the disease related to the virus; however, we did not detect the presence of adenovirus or rotavirus at any time. PMID- 26942411 TI - Snoo and Dpp Act as Spatial and Temporal Regulators Respectively of Adult Progenitor Cells in the Drosophila Trachea. AB - Clusters of differentiated cells contributing to organ structures retain the potential to re-enter the cell cycle and replace cells lost during development or upon damage. To do so, they must be designated spatially and respond to proper activation cues. Here we show that in the case of Drosophila differentiated larval tracheal cells, progenitor potential is conferred by the spatially restricted activity of the Snoo transcription cofactor. Furthermore, Dpp signalling regulated by endocrine hormonal cues provides the temporal trigger for their activation. Finally, we elucidate the genetic network elicited by Snoo and Dpp activity. These results illustrate a regulatory mechanism that translates intrinsic potential and extrinsic cues into the facultative stem cell features of differentiated progenitors. PMID- 26942412 TI - Plasma tPA-Activity and Progression of Cerebral White Matter Hyperintensities in Lacunar Stroke Patients. AB - INTRODUCTION: Tissue plasminogen activator (tPA)-activity and plasminogen activator inhibitor type 1 (PAI-1) antigen are considered to be haemostasis related markers of endothelial activation and relate to presence of cerebral white matter hyperintensities (WMH) as was earlier shown in a cross-sectional study. We investigated whether tPA-activity and PAI-1 levels are associated with WMH progression in a longitudinal study. METHODS: In 127 first-ever lacunar stroke patients in whom baseline brain MRI and plasma levels of tPA-activity and PAI-1-antigen were available, we obtained a 2-year follow-up MRI. We assessed WMH progression by a visual WMH change scale. We determined the relationship between levels of tPA-activity and PAI-1 and WMH progression, by logistic regression analysis. RESULTS: Plasma tPA-activity was associated with periventricular WMH progression (OR 2.36, 95% CI 1.01-5.49, with correction for age and sex and baseline presence of WMH), but not with deep or any (periventricular and/or deep) WMH progression. PAI-1 levels were lower in patients with WMH progression, but these results were not significant. CONCLUSION: We found a relationship between plasma tPA-activity and progression of periventricular WMH. More research is needed to determine whether there is a (direct) role of tPA in the development and progression of WMH. PMID- 26942413 TI - Effect of Antiglaucoma Medicine on Intraocular Pressure in DBA/2J Mice. AB - BACKGROUND: The DBA/2J mouse strain is known to develop glaucomatous changes. Intraocular pressure (IOP) fluctuations affected by age or antiglaucoma drug administration were compared among three mouse strains, DBA/2J, C57BL/6, and BALB/c. METHODS: IOP was measured using the TonoLab tonometer under systemic anesthesia. For each mouse strain, the effects of age and topical administration of antiglaucoma medications (timolol maleate, dorzolamide, brimonidine tartrate, and travoprost) were assessed, and results were compared among the three strains. RESULTS: IOP started to rise in DBA/2J mice at 21 weeks of age. The highest values of IOP were distributed from 18 to 51 mm Hg. Eighty percent of DBA/2J mice showed maximum IOP at either 35 or 46 weeks. IOP of C57BL/6 ranged from 9 to 14 mm Hg as the mice aged. Treatment with any of the antiglaucoma medications resulted in IOP-lowering effects in all three strains. The difference in levels before and after administration ranged from 6 to 10 mm Hg on average in DBA/2J. CONCLUSION: DBA/2J mice are a useful animal model to study the effects of antiglaucoma therapy. PMID- 26942414 TI - Altered expression of major immune regulatory molecules in peripheral blood immune cells associated with breast cancer. AB - BACKGROUND: The purpose of this study was to clarify the alterations of major immune regulators in peripheral blood mononuclear cells (PBMCs) of cancer patients and to analyze the association with the disease progression in breast cancer patients. METHODS: The study included 6 healthy volunteers (HVs), 12 primary breast cancer (PBC) patients, and 30 metastatic breast cancer (MBC) patients. The expression of immune regulators such as, CCR6, CD4, CD8, CD14, CD40, CD56, CD80, CTLA4, CXCR4, FOXP3, IDO-1, IDO-2, NKG2D, NRP-1, PD-1, and PD L1 mRNA in PBMCs was measured by quantitative RT-PCR. Analysis of variance with contrasts was performed to find expression patterns of the three groups (HVs, PBC, MBC). RESULTS: We clarified the alterations of mRNA of major immune regulators PD-L1, FOXP3, CD80, CD40, and CD14 in PBMCs of cancer patients and the association of these alternations with disease progression. Furthermore, PD-L1 expression was correlated with serum interferon-gamma production. CONCLUSION: Our data suggested that mRNA expressions of PD-L1, FOXP3, CD80, CD40 and CD14 in PBMCs are affected by disease progression. Understanding the roles of these various interactions will be of importance to future studies aiming to uncover biomarkers for predicting response to immune therapy. PMID- 26942415 TI - Diagnostic accuracy of contrast-enhanced spectral mammography in comparison to conventional full-field digital mammography in a population of women with dense breasts. AB - BACKGROUND: Contrast-enhanced spectral mammography to compare clinical efficacy of contrast-enhanced spectral mammography (CESM) and conventional digital mammography (MMG) with histopathology as gold standard in dense breasts. PATIENTS AND METHODS: A total of 143 breasts of 72 women who underwent CESM and MMG between 2011 and 2014 at Showa University Hospital were analyzed. RESULTS: 129 (90.2 %) of 143 breasts revealed dense breasts on MMG. 58 (40.6 %) of 143 breasts were diagnosed with breast cancer at histopathology. The remaining 85 breasts were diagnosed with benign findings after image assessments and/or core needle biopsy. CESM revealed 8 false-negative cases among 58 breast cancer cases (sensitivity 86.2 %) and 5 false-positive cases (specificity 94.1 %). Accuracy was 90.9 %. Conventional MMG was assessed true positive in 31 of 58 breast cancer cases (sensitivity 53.4 %) and false positive in 12 cases (specificity 85.9 %). Accuracy was 72.7 %. Sensitivity (p < 0.001), specificity (p = 0.016) and accuracy (p < 0.001) were significantly higher on CESM compared to MMG. MMG missed malignancy in 27 breasts. Of these, 25 were dense breasts. Of these 25, 20 (80.0 %) breasts were positive on CESM. CONCLUSION: These findings suggest that CESM offers superior clinical performance compared to MMG. Use of CESM may decrease false negatives especially for women with dense breasts. PMID- 26942416 TI - Have You Heard of Schistosomiasis? Knowledge, Attitudes and Practices in Nampula Province, Mozambique. AB - BACKGROUND: Schistosomiasis is a parasitic disease which affects almost 300 million people worldwide each year. It is highly endemic in Mozambique. Prevention and control of schistosomiasis relies mainly on mass drug administration (MDA), as well as adoption of basic sanitation practices. Individual and community perceptions of schistosomiasis are likely to have a significant effect on prevention and control efforts. In order to establish a baseline to evaluate a community engagement intervention with a focus on schistosomiasis, a survey to determine knowledge, attitudes and practices relating to the disease was conducted. METHODOLOGY/PRINCIPAL FINDINGS: A representative cross-sectional household survey was carried out in four districts of Nampula province, Mozambique. Interviews were conducted in a total of 791 households, using a structured questionnaire. While awareness of schistosomiasis was high (91%), correct knowledge of how it is acquired (18%), transmitted (26%) and prevented (13%) was low among those who had heard of the disease. Misconceptions, such as the belief that schistosomiasis is transmitted through sexual contact (27%), were common. Only about a third of those who were aware of the disease stated that they practiced a protective behaviour and only a minority of those (39%) reported an effective behaviour. Despite several rounds of MDA for schistosomiasis in the recent past, only a small minority of households with children reported that at least one of them had received a drug to treat the disease (9%). CONCLUSION/SIGNIFICANCE: Poor knowledge of the causes of schistosomiasis and how to prevent it, coupled with persisting misconceptions, continue to pose barriers to effective disease prevention and control. To achieve high levels of uptake of MDA and adoption of protective behaviours, it will be essential to engage individuals and communities, improving their understanding of the causes and symptoms of schistosomiasis, recommended prevention mechanisms and the rationale behind MDA. PMID- 26942418 TI - Anti-virulence Strategies to Target Bacterial Infections. AB - Resistance of important bacterial pathogens to common antimicrobial therapies and the emergence of multidrug-resistant bacteria are increasing at an alarming rate and constitute one of our greatest challenges in the combat of bacterial infection and accompanied diseases. The current shortage of effective drugs, lack of successful prevention measures and only a few new antibiotics in the clinical pipeline demand the development of novel treatment options and alternative antimicrobial therapies. Our increasing understanding of bacterial virulence strategies and the induced molecular pathways of the infectious disease provides novel opportunities to target and interfere with crucial pathogenicity factors or virulence-associated traits of the bacteria while bypassing the evolutionary pressure on the bacterium to develop resistance. In the past decade, numerous new bacterial targets for anti-virulence therapies have been identified, and structure-based tailoring of intervention strategies and screening assays for small-molecule inhibitors of such pathways were successfully established. In this chapter, we will take a closer look at the bacterial virulence-related factors and processes that present promising targets for anti-virulence therapies, recently discovered inhibitory substances and their promises and discuss the challenges, and problems that have to be faced. PMID- 26942417 TI - The Value of In Vitro Diagnostic Testing in Medical Practice: A Status Report. AB - BACKGROUND: In vitro diagnostic (IVD) investigations are indispensable for routine patient management. Appropriate testing allows early-stage interventions, reducing late-stage healthcare expenditure (HCE). AIM: To investigate HCE on IVDs in two developed markets and to assess the perceived value of IVDs on clinical decision-making. Physician-perceived HCE on IVD was evaluated, as well as desired features of new diagnostic markers. METHODS: Past and current HCE on IVD was calculated for the US and Germany. A total of 79 US/German oncologists and cardiologists were interviewed to assess the number of cases where: physicians ask for IVDs; IVDs are used for initial diagnosis, treatment monitoring, or post treatment; and decision-making is based on an IVD test result. A sample of 201 US and German oncologists and cardiologists was questioned regarding the proportion of HCE they believed to be attributable to IVD testing. After disclosing the actual IVD HCE, the physician's perception of the appropriateness of the amount was captured. Finally, the association between physician-rated impact of IVD on decision-making and perceived contribution of IVD expenditure on overall HCE was assessed. RESULTS: IVD costs account for 2.3% and 1.4% of total HCE in the US and Germany. Most physicians (81%) believed that the actual HCE on IVDs was >5%; 19% rated the spending correctly (0-4%, p<0.001). When informed of the actual amount, 64% of physicians rated this as appropriate (p<0.0001); 66% of decision-making was based on IVD. Significantly, more physicians asked for either additional clinical or combined clinical/health economic data than for the product (test/platform) alone (p<0.0001). CONCLUSIONS: Our results indicate a poor awareness of actual HCE on IVD, but a high attributable value of diagnostic procedures for patient management. New markers should deliver actionable and medically relevant information, to guide decision-making and foster improved patient outcomes. PMID- 26942419 TI - Anti-infectives in Drug Delivery-Overcoming the Gram-Negative Bacterial Cell Envelope. AB - Infectious diseases are becoming a major menace to the state of health worldwide, with difficulties in effective treatment especially of nosocomial infections caused by Gram-negative bacteria being increasingly reported. Inadequate permeation of anti-infectives into or across the Gram-negative bacterial cell envelope, due to its intrinsic barrier function as well as barrier enhancement mediated by resistance mechanisms, can be identified as one of the major reasons for insufficient therapeutic effects. Several in vitro, in silico, and in cellulo models are currently employed to increase the knowledge of anti-infective transport processes into or across the bacterial cell envelope; however, all such models exhibit drawbacks or have limitations with respect to the information they are able to provide. Thus, new approaches which allow for more comprehensive characterization of anti-infective permeation processes (and as such, would be usable as screening methods in early drug discovery and development) are desperately needed. Furthermore, delivery methods or technologies capable of enhancing anti-infective permeation into or across the bacterial cell envelope are required. In this respect, particle-based carrier systems have already been shown to provide the opportunity to overcome compound-related difficulties and allow for targeted delivery. In addition, formulations combining efflux pump inhibitors or antimicrobial peptides with anti-infectives show promise in the restoration of antibiotic activity in resistant bacterial strains. Despite considerable progress in this field however, the design of carriers to specifically enhance transport across the bacterial envelope or to target difficult-to-treat (e.g., intracellular) infections remains an urgently needed area of improvement. What follows is a summary and evaluation of the state of the art of both bacterial permeation models and advanced anti-infective formulation strategies, together with an outlook for future directions in these fields. PMID- 26942420 TI - Adhesive Properties and Acid-Forming Activity of Lactobacilli and Streptococci Under Inhibitory Substances, Such as Nitrates. AB - One of the main requirements for probiotics is their ability to survive during passage through gastrointestinal tract and to maintain their activity at different adverse conditions. The aim of the study was to look for the strains of lactobacilli and streptococci with high adhesive properties even affected by inhibitory substances, such as nitrates (NO3 (-)). To study the adhesion properties hemagglutination reaction of bacterial cells with red blood cells of different animals and humans was used. The acid formation ability of bacteria was determined by the method of titration after 7 days of incubation in the sterile milk. These properties were investigated at different concentrations of NO3 (-). The high concentration (mostly >=2.0 %) NO3 (-) inhibited the growth of both lactobacilli and streptococci, but compared with streptococcal cultures lactobacilli, especially Lactobacillus acidophilus Ep 317/402, have shown more stability and higher adhesive properties. In addition, the concentrations of NO3 (-) of 0.5-2.0 % decreased the acid-forming activity of the strains, but even under these conditions they coagulated milk and, in comparison to control, formed low acidity in milk. Thus, the L. acidophilus Ep 317/402 with high adhesive properties has demonstrated a higher activity of NO3 (-) transformation. PMID- 26942421 TI - Treatment for Vitamin D Deficiency Prior to Bariatric Surgery: a Prospective Cohort Study. AB - BACKGROUND: Since obesity increases vitamin D deficiency (VDD) risk, bariatric surgery candidates are high-risk. Previously, we documented 71.4% VDD at our center. OBJECTIVES: To investigate diagnosis and treatment for VDD in our bariatric candidates. METHODS: 25(OH)D, if pending, and supplementation (form, dosing, frequency) were prospectively documented in 265 candidates. RESULTS: Candidates were 83.0% female, 48.9% white, age 43 +/- 13 years and BMI 46.3 +/- 10.5 kg/m(2). 25(OH)D was available for 18.5%: 35.7% VDD 39.3% insufficiency. VDD history did not differ by demographics or procedure, as with those tested versus not. CONCLUSION: VDD testing was lower than clinically-indicated. Of those tested, 35.7% were deficient and 39.3% insufficient. We previously reported higher rates: 71.4% deficiency, 92.9% insufficiency. Thus, many candidates are untested but high-risk. PMID- 26942422 TI - Confidence limits, error bars and method comparison in molecular modeling. Part 2: comparing methods. AB - The calculation of error bars for quantities of interest in computational chemistry comes in two forms: (1) Determining the confidence of a prediction, for instance of the property of a molecule; (2) Assessing uncertainty in measuring the difference between properties, for instance between performance metrics of two or more computational approaches. While a former paper in this series concentrated on the first of these, this second paper focuses on comparison, i.e. how do we calculate differences in methods in an accurate and statistically valid manner. Described within are classical statistical approaches for comparing widely used metrics such as enrichment, area under the curve and Pearson's product-moment coefficient, as well as generic measures. These are considered of over single and multiple sets of data and for two or more methods that evince either independent or correlated behavior. General issues concerning significance testing and confidence limits from a Bayesian perspective are discussed, along with size-of-effect aspects of evaluation. PMID- 26942423 TI - Neurological Dysfunction in Early Maturity of a Model for Niemann-Pick C1 Carrier Status. AB - Autosomal recessive inheritance of NPC1 with loss-of-function mutations underlies Niemann-Pick disease, type C1 (NP-C1), a lysosomal storage disorder with progressive neurodegeneration. It is uncertain from limited biochemical studies and patient case reports whether NPC1 haploinsufficiency can cause a partial NP C1 phenotype in carriers. In the present study, we examined this possibility in heterozygotes of a natural loss-of-function mutant Npc1 mouse model. We found partial motor dysfunction and increased anxiety-like behavior in Npc1 (+/-) mice by 9 weeks of age. Relative to Npc1 (+/+) mice, Npc1 (+/-) mice failed to show neurodevelopmental improvements in motor coordination and balance on an accelerating Rotarod. In the open-field test, Npc1 (+/-) mice showed an intermediate phenotype in spontaneous locomotor activity compared with Npc1 (+/+) and Npc1 (-/-) mice, as well as decreased center tendency. Together with increased stride length under anxiogenic conditions on the DigiGait treadmill, these findings are consistent with heightened anxiety. Our findings indicate that pathogenic NPC1 allele carriers, who represent about 0.66 % of humans, could be vulnerable to motor and anxiety disorders. PMID- 26942425 TI - The crystal structure and photocatalytic properties of a three-dimensional cadmium(II) metal-organic framework: poly[bis(MU3-benzene-1,2-dicarboxylato)[MU2 1,4-bis(pyridin-3-ylmethoxy)benzene]dicadmium(II)]. AB - Photocatalysis is a green technology for the treatment of all kinds of contaminants and has advantages over other treatment methods. Recently, much effort has been devoted to developing new photocatalytic materials based on metal organic frameworks for use in the degradation of many kinds of organic contaminants. With the aim of searching for more effective photocatalysts, the title three-dimensional coordination polymer, [Cd2(C8H4O4)2(C18H16N2O2)]n, was prepared. The asymmetric unit contains one Cd(II) cation, one benzene-1,2 dicarboxylate anion (denoted L(2-)) and half of a centrosymmetric 1,4-bis(pyridin 3-ylmethoxy)benzene ligand (denoted bpmb). Each Cd(II) centre is five-coordinated by four carboxylate O atoms from two L(2-) ligands and by one N atom from a bpmb ligand, forming a disordered pentagonal pyramidal coordination geometry. The Cd(II) centres are interlinked by L(2-) ligands to form a one-dimensional [Cd2L2]n chain. Adjacent chains are further connected by bpmb linkers, giving rise to a two-dimensional network, and these networks are pillared by bpmb to afford a three-dimensional framework with a 3(3).4(2).6(3).7(1).8(1) topology. Each grid in the framework has large channels which are filled mainly by the two other equivalent frameworks to form a threefold interpenetrating net. The compound exhibits relatively good photocatalytic activity towards the degradation of methylene blue in aqueous solution under UV irradiation. PMID- 26942424 TI - Prediction of Hematopoietic Stem Cell Transplantation Related Mortality- Lessons Learned from the In-Silico Approach: A European Society for Blood and Marrow Transplantation Acute Leukemia Working Party Data Mining Study. AB - Models for prediction of allogeneic hematopoietic stem transplantation (HSCT) related mortality partially account for transplant risk. Improving predictive accuracy requires understating of prediction limiting factors, such as the statistical methodology used, number and quality of features collected, or simply the population size. Using an in-silico approach (i.e., iterative computerized simulations), based on machine learning (ML) algorithms, we set out to analyze these factors. A cohort of 25,923 adult acute leukemia patients from the European Society for Blood and Marrow Transplantation (EBMT) registry was analyzed. Predictive objective was non-relapse mortality (NRM) 100 days following HSCT. Thousands of prediction models were developed under varying conditions: increasing sample size, specific subpopulations and an increasing number of variables, which were selected and ranked by separate feature selection algorithms. Depending on the algorithm, predictive performance plateaued on a population size of 6,611-8,814 patients, reaching a maximal area under the receiver operator characteristic curve (AUC) of 0.67. AUCs' of models developed on specific subpopulation ranged from 0.59 to 0.67 for patients in second complete remission and receiving reduced intensity conditioning, respectively. Only 3-5 variables were necessary to achieve near maximal AUCs. The top 3 ranking variables, shared by all algorithms were disease stage, donor type, and conditioning regimen. Our findings empirically demonstrate that with regards to NRM prediction, few variables "carry the weight" and that traditional HSCT data has been "worn out". "Breaking through" the predictive boundaries will likely require additional types of inputs. PMID- 26942426 TI - Ab initio X-ray structural characterization of an inclusion compound with a compositionally disordered chiral guest: no prior knowledge of the crystal composition. AB - The crystal structure and absolute configuration of a molecular host/guest/impurity inclusion complex were established unequivocally in spite of our having no prior knowledge of its chemical composition. The host (4R,5R)-4,5 bis(hydroxydiphenylmethyl)-2,2-dimethyl-1,3-dioxolane, (I), displays expected conformational features. The crystal-disordered chiral guest 4,4a,5,6,7,8 hexahydronaphthalen-2(3H)-one, (II), is present in the crystal 85.1 (4)% of the time. It shares a common site with 4a-hydroperoxymethyl-4,4a,5,6,7,8 hexahydronaphthalen-2(3H)-one, (III), present 14.9 (4)% of the time, which is the product of autoxidation of (II). This minor peroxide impurity was isolated, and the results of nuclear magnetic resonance, mass spectrometry, and X-ray fluorescence studies are consistent with the proposed structure of (III). The complete structure was therefore determined to be (4R,5R)-4,5 bis(hydroxydiphenylmethyl)-2,2-dimethyl-1,3-dioxolane-4,4a,5,6,7,8 hexahydronaphthalen-2(3H)-one-4a-hydroperoxymethyl-4,4a,5,6,7,8 hexahydronaphthalen-2(3H)-one (1/0.85/0.15), C31H30O4.0.85C10H14O.0.15C10H14O3, (IV). There are host-host, host-guest, and host-impurity hydrogen-bonding interactions of types S and D in the solid state. We believe that the crystals of (IV) were originally prepared to establish the chirality of the guest (II) by means of X-ray diffraction analysis of host/guest crystals obtained in the course of chiral resolution during cocrystallization of (II) with (I). In spite of the absence of 'heavy' elements, the absolute configurations of all anomeric centres in the structure are assigned as R based on resonant scattering effects. PMID- 26942427 TI - Hydrogen versus fluorine: effects on molecular structure and intermolecular interactions in a platinum isocyanate complex. AB - At the molecular level, the enantiomerically pure square-planar organoplatinum complex (SP-4-4)-(R)-[2-(1-aminoethyl)-5-fluorophenyl-kappa(2)C(1),N][(R)-1-(4 fluorophenyl)ethylamine-kappaN](isocyanato-kappaN)platinum(II), [Pt(C8H9FN)(NCO)(C8H10FN)], and its congener without fluorine substituents on the aryl rings adopt the same structure within error. The similarities between the compounds extend to the most relevant intermolecular interactions, i.e. N-H...O and N-H...N hydrogen bonds link neighbouring molecules into chains along the shortest lattice parameter in each structure. Differences between the crystal structures of the fluoro-substituted and parent complex become obvious with respect to secondary interactions perpendicular to the classical hydrogen bonds; the fluorinated compound features short C-H...F contacts with an F...H distance of ca 2.6 A. The fluorine substitution is also reflected in reduced backbonding from the metal cation to the isocyanate ligand. PMID- 26942428 TI - Conformational studies on heteroleptic trifluoromethyl-substituted phenylboranes. AB - Organoboranes carrying electron-withdrawing substituents are commonly used as Lewis acidic catalysts or cocatalysts in a variety of organic processes. These Lewis acids also became popular through their application in 'frustrated Lewis pairs', i.e. combinations of Lewis acids and bases that are unable to fully neutralize each other due to steric or electronic effects. We have determined the crystal and molecular structures of four heteroleptic arylboranes carrying 2 (trifluoromethyl)phenyl, 2,6-bis(trifluoromethyl)phenyl, 3,5 bis(trifluoromethyl)phenyl or mesityl substituents. [3,5 Bis(trifluoromethyl)phenyl]bis[2-(trifluoromethyl)phenyl]borane, C22H11BF12, (I), crystallizes with two molecules in the asymmetric unit which show very similar geometric parameters. In one of the two molecules, both trifluoromethyl groups of the 3,5-bis(trifluoromethyl)phenyl substituent are disordered over two positions. In [3,5-bis(trifluoromethyl)phenyl]bis[2,6-bis(trifluoromethyl)phenyl]borane, C24H9BF18, (II), only one of the two meta-trifluoromethyl groups is disordered. In [2,6-bis(trifluoromethyl)phenyl]bis[3,5-bis(trifluoromethyl)phenyl]borane, C24H9BF18, (III), both meta-trifluoromethyl groups of only one 3,5 bis(trifluoromethyl)phenyl ring are disordered. [3,5 Bis(trifluoromethyl)phenyl]dimesitylborane, C26H25BF6, (IV), carries only one meta-trifluoromethyl-substituted phenyl ring, with one of the two trifluoromethyl groups disordered over two positions. In addition to compounds (I)-(IV), the structure of bis[2,6-bis(trifluoromethyl)phenyl]fluoroborane, C16H6BF13, (V), is presented. None of the ortho-trifluoromethyl groups is disordered in any of the five compounds. In all the structures, the boron centre is in a trigonal planar coordination. Nevertheless, the bond angles around this atom vary according to the bulkiness and mutual repulsion of the substituents of the phenyl rings. Also, the ortho-trifluoromethyl-substituted phenyl rings usually show longer B-C bonds and tend to be tilted out of the BC3 plane by a higher degree than the phenyl rings carrying ortho H atoms. A comparison with related structures corroborates the conclusions regarding the geometric parameters of the boron centre drawn from the five structures in this paper. On the other hand, CF3 groups in meta positions do not seem to have a marked effect on the geometry involving the boron centre. Furthermore, it has been observed for the structures reported here and those reported previously that for CF3 groups in ortho positions of the aromatic ring, disorder of the F atoms is less probable than for CF3 groups in meta or para positions of the ring. PMID- 26942429 TI - The search for formal electrostatic effects on molecular conformation and crystal packing: crystal structure of 2,2''-disubstituted (H versus PPh2) 1,1'-(1,2 phenylene)bis(3-methyl-1H-imidazol-3-ium) bis(trifluoromethanesulfonate). AB - Electrostatic interactions between localized integral charges make the stability and structure of highly charged small and rigid organics intriguing. Can sigma/pi electron delocalization compensate reduced conformational freedom by lowering the repulsion between identical charges? The crystal structure of the title salt, C14H16N4(2+).2CF3SO3(-), (2), is described and compared with that of the 2,2'' bis(diphenylphosphanyl) derivative, (4). The conformations of the dications and their interactions with neighbouring trifluoromethanesulfonate anions are first analyzed from the standpoint of formal electrostatic effects. Neither cation exhibits any geometrical strain induced by the intrinsic repulsion between the positive charges. In contrast, the relative orientation of the imidazolium rings [i.e. anti for (2) and syn for (4)] is controlled by different configurations of the interactions with the closest trifluoromethanesulfonate anions. The long range arrangement is also found to be specific: beyond the formal electrostatic packing, C-H...O and C-H...F contacts have no definite 'hydrogen-bond' character but allow the delineation of layers, which are either pleated or flat in the packing of (2) or (4), respectively. PMID- 26942430 TI - X-ray and neutron powder diffraction analyses of Gly.MgSO4.5H2O and Gly.MgSO4.3H2O, and their deuterated counterparts. AB - We have identified a new compound in the glycine-MgSO4-water ternary system, namely glycine magnesium sulfate trihydrate (or Gly.MgSO4.3H2O) {systematic name: catena-poly[[tetraaquamagnesium(II)]-MU-glycine-kappa(2)O:O'-[diaquabis(sulfato kappaO)magnesium(II)]-MU-glycine-kappa(2)O:O']; [Mg(SO4)(C2D5NO2)(D2O)3]n}, which can be grown from a supersaturated solution at ~350 K and which may also be formed by heating the previously known glycine magnesium sulfate pentahydrate (or Gly.MgSO4.5H2O) {systematic name: hexaaquamagnesium(II) tetraaquadiglycinemagnesium(II) disulfate; [Mg(D2O)6][Mg(C2D5NO2)2(D2O)4](SO4)2} above ~330 K in air. X-ray powder diffraction analysis reveals that the trihydrate phase is monoclinic (space group P21/n), with a unit-cell metric very similar to that of recently identified Gly.CoSO4.3H2O [Tepavitcharova et al. (2012). J. Mol. Struct. 1018, 113-121]. In order to obtain an accurate determination of all structural parameters, including the locations of H atoms, and to better understand the relationship between the pentahydrate and the trihydrate, neutron powder diffraction measurements of both (fully deuterated) phases were carried out at 10 K at the ISIS neutron spallation source, these being complemented with X-ray powder diffraction measurements and Raman spectroscopy. At 10 K, glycine magnesium sulfate pentahydrate, structurally described by the 'double' formula [Gly(d5).MgSO4.5D2O]2, is triclinic (space group P-1, Z = 1), and glycine magnesium sulfate trihydrate, which may be described by the formula Gly(d5).MgSO4.3D2O, is monoclinic (space group P21/n, Z = 4). In the pentahydrate, there are two symmetry-inequivalent MgO6 octahedra on sites of -1 symmetry and two SO4 tetrahedra with site symmetry 1. The octahedra comprise one [tetraaquadiglcyinemagnesium](2+) ion (centred on Mg1) and one [hexaaquamagnesium](2+) ion (centred on Mg2), and the glycine zwitterion, NH3(+)CH2COO(-), adopts a monodentate coordination to Mg2. In the trihydrate, there are two pairs of symmetry-inequivalent MgO6 octahedra on sites of -1 symmetry and two pairs of SO4 tetrahedra with site symmetry 1; the glycine zwitterion adopts a binuclear-bidentate bridging function between Mg1 and Mg2, whilst the Mg2 octahedra form a corner-sharing arrangement with the sulfate tetrahedra. These bridged polyhedra thus constitute infinite polymeric chains extending along the b axis of the crystal. A range of O-H...O, N-H...O and C H...O hydrogen bonds, including some three-centred interactions, complete the three-dimensional framework of each crystal. PMID- 26942431 TI - The challenging case of the theophylline-benzamide cocrystal. AB - Theophylline has been used as an active pharmaceutical ingredient (API) in the treatment of pulmonary diseases, but due to its low water solubility reveals very poor bioavailability. Based on its different hydrogen-bond donor and acceptor groups, theophylline is an ideal candidate for the formation of cocrystals. The crystal structure of the 1:1 benzamide cocrystal of theophylline, C7H8N4O2.C7H7NO, was determined from synchrotron X-ray powder diffraction data. The compound crystallizes in the tetragonal space group P41 with four independent molecules in the asymmetric unit. The molecules form a hunter's fence packing. The crystal structure was confirmed by dispersion-corrected DFT calculations. The possibility of salt formation was excluded by the results of Raman and (1)H solid state NMR spectroscopic analyses. PMID- 26942432 TI - A comparative study of two polymorphs of bis(1-hydroxy-2-methylpropan-2-aminium) carbonate. AB - Alkanolamines have been known for their high CO2 absorption for over 60 years and are used widely in the natural gas industry for reversible CO2 capture. In an attempt to crystallize a salt of (RS)-2-(3-benzoylphenyl)propionic acid with 2 amino-2-methylpropan-1-ol, we obtained instead a polymorph (denoted polymorph II) of bis(1-hydroxy-2-methylpropan-2-aminium) carbonate, 2C4H12NO(+).CO3(2-), (I), suggesting that the amine group of the former compound captured CO2 from the atmosphere forming the aminium carbonate salt. This new polymorph was characterized by single-crystal X-ray diffraction analysis at low temperature (100 K). The salt crystallizes in the monoclinic system (space group C2/c, Z = 4), while a previously reported form of the same salt (denoted polymorph I) crystallizes in the triclinic system (space group P-1, Z = 2) [Barzagli et al. (2012). ChemSusChem, 5, 1724-1731]. The asymmetric unit of polymorph II contains one 1-hydroxy-2-methylpropan-2-aminium cation and half a carbonate anion, located on a twofold axis, while the asymmetric unit of polymorph I contains two cations and one anion. These polymorphs exhibit similar structural features in their three-dimensional packing. Indeed, similar layers of an alternating cation-anion cation neutral structure are observed in their molecular arrangements. Within each layer, carbonate anions and 1-hydroxy-2-methylpropan-2-aminium cations form planes bound to each other through N-H...O and O-H...O hydrogen bonds. In both polymorphs, the layers are linked to each other via van der Waals interactions and C-H...O contacts. In polymorph II, a highly directional C-H...O contact (C H...O = 156 degrees ) shows as a hydrogen-bonding interaction. Periodic theoretical density functional theory (DFT) calculations indicate that both polymorphs present very similar stabilities. PMID- 26942433 TI - The first phosphoramide-mercury(II) complex with a Cl2Hg-OP[N(C)(C)]3 segment. AB - Mercury(II) exhibits a strong preference for linear coordination which has been attributed to relativistic effects splitting the 6p orbitals and promoting sp hybridization. If the two ligands attached to the mercury(II) ion are weak donors, the metal ion can act as a good Lewis acid and expand its coordination number. Moreover, mercury has a special affinity for softer bases, such as S and N atoms, and has much less affinity for hard bases, such as those including an O atom. The asymmetric unit of dichlorido[tris(piperidin-1-yl)phosphane oxide kappaO]mercury(II)-dichloridomercury(II) (2/1), [HgCl2{(C5H10N)3PO}]2.[HgCl2], is composed of one HgCl2{(C5H10N)3PO} complex and one half of a discrete HgCl2 entity located on an inversion centre. The coordination environment around the Hg(II) centre in the complex component is a distorted T-shape. Bond-valence-sum calculations confirm the three-coordination mode of the Hg(II) atom of the complex molecule. The noncovalent nature of the Hg...Cl and Hg...O interactions in the structure are discussed. PMID- 26942434 TI - X-ray and DFT-calculated structures of bis[N-(quinolin-8-yl)benzamidato kappa(2)N,N']copper(II). AB - The application of transition metal chelates as chemotherapeutic agents has the advantage that they can be used as a scaffold around which ligands with DNA recognition elements can be anchored. The facile substitution of these components allows for the DNA recognition and binding properties of the metal chelates to be tuned. Copper is a particularly interesting choice for the development of novel metallodrugs as it is an endogenous metal and is therefore less toxic than other transition metals. The title compound, [Cu(C16H11N2O)2], was synthesized by reacting N-(quinolin-8-yl)benzamide and the metal in a 2:1 ratio. Ligand coordination required deprotonation of the amide N-H group and the isolated complex is therefore neutral. The metal ion adopts a flattened tetrahedral coordination geometry with the ligands in a pseudo-trans configuration. The free rotation afforded by the formal single bond between the amide group and phenyl ring allows the phenyl rings to rotate out-of-plane, thus alleviating nonbonded repulsion between the phenyl rings and the quinolyl groups within the complex. Weak C-H...O interactions stabilize a dimer in the solid state. Density functional theory (DFT) simulations at the PBE/6-311G(dp) level of theory show that the solid-state structure (C1 symmetry) is 79.33 kJ mol(-1) higher in energy than the lowest energy gas-phase structure (C2 symmetry). Natural bond orbital (NBO) analysis offers an explanation for the formation of the C-H...O interactions in electrostatic terms, but the stabilizing effect is insufficient to support the dimer in the gas phase. PMID- 26942436 TI - The new one-dimensional coordination polymer catena-poly[[diaquasodium(I)]-MU oxalato-[diaquairon(III)]-MU-oxalato]. AB - The oxalate dianion is one of the most studied ligands and is capable of bridging two or more metal centres and creating inorganic polymers based on the assembly of metal polyhedra with a wide variety of one-, two- or three-dimensional extended structures. Yellow single crystals of a new mixed-metal oxalate, namely catena-poly[[diaquasodium(I)]-MU-oxalato-kappa(4)O(1),O(2):O(1'),O(2') [diaquairon(III)]-MU-oxalato-kappa(4)O(1),O(2):O(1'),O(2')], [NaFe(C2O4)2(H2O)4]n, have been synthesized and the crystal structure elucidated by X-ray diffraction analysis. The compound crystallizes in the noncentrosymmetric space group I41 (Z = 4). The asymmetric unit contains one Na(I) and one Fe(III) atom lying on a fourfold symmetry axis, one MU2-bridging oxalate ligand and two aqua ligands. Each metal atom is surrounded by two chelating oxalate ligands and two equivalent water molecules. The structure consists of infinite one-dimensional chains of alternating FeO4(H2OW1)2 and NaO4(H2OW2)2 octahedra, bridged by oxalate ligands, parallel to the [100] and [010] directions, respectively. Because of the cis configuration and the MU2 coordination mode of the oxalate ligands, the chains run in a zigzag manner. This arrangement facilitates the formation of hydrogen bonds between neighbouring chains involving the H2O and oxalate ligands, leading to a two-dimensional framework. The structure of this new one-dimensional coordination polymer is shown to be unique among the A(I)M(III)(C2O4)2(H2O)n series. In addition, the absorption bands in the IR and UV-Visible regions and their assignments are in good agreement with the local symmetry of the oxalate ligand and the irregular environment of iron(III). The final product of the thermal decomposition of this precursor is the well-known ternary oxide NaFeO2. PMID- 26942435 TI - Synthesis and crystal structure of the dinuclear copper(II) Schiff base complex MU-hydroxido-MU-chlorido-bis{[bis(trans-2 nitrocinnamaldehyde)ethylenediamine]chloridocopper(II)} dichloromethane sesquisolvate. AB - Transition metal complexes of Schiff base ligands have been shown to have particular application in catalysis and magnetism. The chemistry of copper complexes is of interest owing to their importance in biological and industrial processes. The reaction of copper(I) chloride with the bidentate Schiff base N,N' bis(trans-2-nitrocinnamaldehyde)ethylenediamine {Nca2en, systematic name: (1E,1'E,2E,2'E)-N,N'-(ethane-1,2-diyl)bis[3-(2-nitrophenyl)prop-2-en-1-imine]} in a 1:1 molar ratio in dichloromethane without exclusion of air or moisture resulted in the formation of the title complex MU-chlorido-MU-hydroxido bis(chlorido{(1E,1'E,2E,2'E)-N,N'-(ethane-1,2-diyl)bis[3-(2-nitrophenyl)prop-2-en 1-imine]-kappa(2)N,N'}copper(II)) dichloromethane sesquisolvate, [Cu2Cl3(OH)(C20H18N4O4)2].1.5CH2Cl2. The dinuclear complex has a folded four membered ring in an unsymmetrical Cu2OCl3 core in which the approximate trigonal bipyramidal coordination displays different angular distortions in the equatorial planes of the two Cu(II) atoms; the chloride bridge is asymmetric, but the hydroxide bridge is symmetric. The chelate rings of the two Nca2en ligands have different conformations, leading to a more marked bowing of one of the ligands compared with the other. This is the first reported dinuclear complex, and the first five-coordinate complex, of the Nca2en Schiff base ligand. Molecules of the dimer are associated in pairs by ring-stacking interactions supported by C-H...Cl interactions with solvent molecules; a further ring-stacking interaction exists between the two Schiff base ligands of each molecule. PMID- 26942437 TI - Syntheses and structures of four new mixed-amide phosphoric triamides. AB - Phosphoric triamides have extensive applications in biochemistry and are also used as O-donor ligands. Four new mixed-amide phosphoric triamide structures, namely rac-N-tert-butyl-N',N''-dicyclohexyl-N''-methylphosphoric triamide, C17H36N3OP, (I), rac-N,N'-dicyclohexyl-N'-methyl-N''-(p-tolyl)phosphoric triamide, C20H34N3OP, (II), N,N',N''-tricyclohexyl-N''-methylphosphoric triamide, C19H38N3OP, (III), and 2-[cyclohexyl(methyl)amino]-5,5-dimethyl-1,3,2lambda(5) diazaphosphinan-2-one, C12H26N3OP, (IV), have been synthesized and studied by X ray diffraction and spectroscopic methods. Structures (I) and (II) are the first diffraction studies of acyclic racemic mixed-amide phosphoric triamides. The P-N bonds resulting from the different substituent -N(CH3)(C6H11), (C6H11)NH-, 4-CH3 C6H4NH-, (tert-C4H9)NH- and -NHCH2C(CH3)2CH2NH- groups are compared, along with the different molecular volumes and electron-donor strengths. In all four structures, the molecules form extended chains through N-H...O hydrogen bonds. PMID- 26942439 TI - Longitudinal Treatment Outcomes of Microsurgical Treatment of Neurosensory Deficit after Lower Third Molar Surgery: A Prospective Case Series. AB - OBJECTIVE: To prospectively evaluate the longitudinal subjective and objective outcomes of the microsurgical treatment of lingual nerve (LN) and inferior alveolar nerve (IAN) injury after third molar surgery. MATERIALS AND METHODS: A 1 year longitudinal observational study was conducted on patients who received LN or IAN repair after third molar surgery-induced nerve injury. Subjective assessments ("numbness", "hyperaesthesia", "pain", "taste disturbance", "speech" and "social life impact") and objective assessments (light touch threshold, two point discrimination, pain threshold, and taste discrimination) were recorded. RESULTS: 12 patients (10 females) with 10 LN and 2 IAN repairs were recruited. The subjective outcomes at post-operative 12 months for LN and IAN repair were improved. "Pain" and "hyperaesthesia" were most drastically improved. Light touch threshold improved from 44.7 g to 1.2 g for LN repair and 2 g to 0.5 g for IAN repair. CONCLUSION: Microsurgical treatment of moderate to severe LN injury after lower third molar surgery offered significant subjective and objective sensory improvements. 100% FSR was achieved at post-operative 6 months. PMID- 26942440 TI - Development and psychometric testing of the medication taking behavior tool in Thai patients. AB - BACKGROUND: The previous Thai version of the 8-item Morisky Medication Adherence Scale (8-item MMAS) showed poor sensitivity and unacceptable internal consistency reliability. OBJECTIVES: To develop and test the psychometric properties of a new medication taking behavior measure for Thai patients (MTB-Thai) including practicality, reliability and validity. METHODS: This study was conducted with adult outpatients regularly taking any medicines for at least three months from three university hospitals in Bangkok, Thailand, between July 2014 and March 2015. The study was approved by the Ethical Committees of the three hospitals. Practicality was assessed by administration time and the percentage of missing data. Internal consistency and test-retest reliability were evaluated employing Cronbach's alpha and intraclass correlation coefficients (ICCs), respectively. Validity was evaluated with content, construct, convergent and known-groups validity. RESULTS: Of 1156 patients, the 6-item MTB-Thai had an average administration time of 2 min and no missing data. It showed good Cronbach's alpha value of 0.76 and excellent ICCs of 0.83. The MTB-Thai showed good content validity with the item level and scale level of content validity indexes greater than the acceptable levels of 0.8 and 0.9, respectively. Both exploratory and confirmatory factor analyses showed the MTB-Thai had two domains including unintentional and intentional domains. The MTB-Thai correlated well with the overall medication adherence scale with a Pearson's correlation coefficient of 0.62 (p < 0.001). The sensitivity, specificity, positive predictive value and negative predictive value of the MTB-Thai were 76, 35, 55 and 57 %, respectively. CONCLUSION: The MTB-Thai was practical, reliable and valid in assessing mediation taking behaviors in Thai patients with chronic diseases. PMID- 26942441 TI - Essential and Toxic Metals in Oral Fluid-a Potential Role in the Diagnosis of Periodontal Diseases. AB - Recently, many studies have investigated the relationship between the level of metals in the body and various diseases. The objective of this study was to examine any possible influence of periodontal disease upon the concentration of metals in oral fluid and blood and to explore the usability of applying cluster analysis coupled with the analysis of selected elements in oral fluid, calcium (Ca), copper (Cu), iron (Fe), magnesium (Mg), manganese (Mn), zinc (Zn), cadmium (Cd) and lead (Pb), for effectively distinguishing people affected by periodontitis from healthy individuals. The quantification of eight metals in oral fluid and blood samples was performed by two inductively coupled plasma techniques-inductively coupled plasma mass spectrometry (ICP-MS) and inductively coupled plasma optical emission spectrometry (ICP-OES). Most of the examined elements were detected at elevated concentration in the oral fluid of periodontal patients. However, the differences were statistically significant in the case of three metals: Cu, Mg and Mn (p < 0.05). Approximately, fivefold increase in the concentration of Cu, threefold-elevated levels of Mn and a twofold increase in the concentration of Mg were found in the oral fluid of the periodontal patients compared to the controls. Cluster analysis confirmed the statistical significance of the differences in the level of metals in the oral fluid between the two groups in most cases, plus enabled the correct classification of the subjects into patients and controls. The relationship between concentrations of metals and periodontal disease may in the future serve to prevent the development of such disease. PMID- 26942442 TI - An Evolution-Guided Analysis Reveals a Multi-Signaling Regulation of Fas by Tyrosine Phosphorylation and its Implication in Human Cancers. AB - Demonstrations of both pro-apoptotic and pro-survival abilities of Fas (TNFRSF6/CD95/APO-1) have led to a shift from the exclusive "Fas apoptosis" to "Fas multisignals" paradigm and the acceptance that Fas-related therapies face a major challenge, as it remains unclear what determines the mode of Fas signaling. Through protein evolution analysis, which reveals unconventional substitutions of Fas tyrosine during divergent evolution, evolution-guided tyrosine-phosphorylated Fas proxy, and site-specific phosphorylation detection, we show that the Fas signaling outcome is determined by the tyrosine phosphorylation status of its death domain. The phosphorylation dominantly turns off the Fas-mediated apoptotic signal, while turning on the pro-survival signal. We show that while phosphorylations at Y232 and Y291 share some common functions, their contributions to Fas signaling differ at several levels. The findings that Fas tyrosine phosphorylation is regulated by Src family kinases (SFKs) and the phosphatase SHP-1 and that Y291 phosphorylation primes clathrin-dependent Fas endocytosis, which contributes to Fas pro-survival signaling, reveals for the first time the mechanistic link between SFK/SHP-1-dependent Fas tyrosine phosphorylation, internalization route, and signaling choice. We also demonstrate that levels of phosphorylated Y232 and Y291 differ among human cancer types and differentially respond to anticancer therapy, suggesting context-dependent involvement of Fas phosphorylation in cancer. This report provides a new insight into the control of TNF receptor multisignaling by receptor phosphorylation and its implication in cancer biology, which brings us a step closer to overcoming the challenge in handling Fas signaling in treatments of cancer as well as other pathologies such as autoimmune and degenerative diseases. PMID- 26942443 TI - Visceral Leishmaniasis in Southwestern Iran: A Retrospective Clinico Hematological Analysis of 380 Consecutive Hospitalized Cases (1999-2014). AB - Visceral Leishmaniasis (VL) is an endemic parasitic disease and remains as a major health concern in southwestern Iran. The current study describes clinico hematological, epidemiological and therapeutic features of VL cases, admitted to university-affiliated hospitals, during 1999-2014 in Fars province, southwestern Iran. A total of 380 VL cases were recorded during a 16 years period, giving an average annual admission of 23.75 cases/year in which 217 (57.1%) were male and 163 (42.9%) were female. Mean age of the patients was 3.7 years. The majority of the cases (91.5%) were <= 5 years old. Bone-marrow aspiration detected Leishmania amastigotes only in 26.6% of cases. Fever (98.1%), abdominal protrusion (65.1%) and hepatosplenomegaly (63.7%) were the most common clinical presentations of the patients. Pancytopenia was noted in 43.1, anemia in 87.3 and thrombocytopenia in 64% of cases. Increase in the level of AST (aspartate aminotransferase), ALT (alanine aminotransferase), alkaline phosphatase, LDH (lactate dehydrogenase) and CRP (C-Reactive Proteins) were seen in 84.9, 53.6, 44.4, 72.5 and 83.1% of cases, respectively. Mortality was noted in 5.3% of cases. Deranged haemato-biochemical parameters including total and direct bilirubin, PLT (platelet) and pancytopenia were significantly contributed to mortality from VL. Moreover, clinical features such as severe splenomegaly as well as bacterial infections were meaningfully contributed to death from VL. The majority of patients (74.9%) were treated with meglumine antimoniate. Amphotericin B was administrated in 59 of cases, 11 of them were initially treated with meglumine antimoniate with a shift to amphotericin B, because of treatment failure. Findings of the current study demonstrated that VL is present in southwest of Iran with a fairly continual rate during the last 16 years period. Deranged haemato-biochemical parameters along with severe splenomegaly contributed to mortality from VL. PMID- 26942444 TI - Efficacy of EGFR tyrosine kinase inhibitors for non-adenocarcinoma lung cancer patients harboring EGFR-sensitizing mutations in China. AB - PURPOSE: EGFR tyrosine kinase inhibitors (TKIs) have been established as standard therapy for EGFR-mutated adenocarcinomas; for non-adenocarcinoma non-small cell lung cancer (NSCLC) patients, this therapy remains debatable. METHODS: Stage IIIB/IV patients with non-adenocarcinoma NSCLC who underwent EGFR testing were identified at the Shanghai Chest Hospital from January 2009 to September 2014. RESULTS: A total of 51 patients with EGFR-sensitizing mutations [26 patients with squamous cell carcinoma (SCC), 15 patients with adenosquamous cell carcinoma (ASC), and 10 patients with large cell lung carcinoma (LCLC)] were available for analysis of EGFR TKI treatment efficacy. The progression-free survival (PFS) for the 51 patients harboring EGFR-sensitizing mutations was 4.93 months (95 % CI 3.93-5.93). The PFS for the SCC, ASC, and LCLC patients was 3.98 months (95 % CI 3.32-4.63), 8.08 months (95 % CI 4.17-12.00), and 4.40 months (95 % CI 1.56 7.24), respectively. Among the 51 non-adenocarcinoma NSCLC patients, the PFS of the non-smokers and smokers was 5.49 months (95 % CI 3.28-7.70) and 3.78 months (95 % CI 2.61-4.95), respectively (P = 0.036). The PFS for the patients with a deletion in exon 19 and for those with an exon 21 L858R mutation was 5.16 months (95 % CI 4.21-6.11) and 4.04 months (95 % CI 2.35-5.73), respectively (P = 0.414). CONCLUSIONS: EGFR TKIs could be an option for the treatment of EGFR mutated non-adenocarcinoma NSCLC, especially for patients with adenosquamous histology and non-smokers. PMID- 26942446 TI - Extracorporeal membrane oxygenation: evolving epidemiology and mortality. AB - PURPOSE: The evolution of the epidemiology and mortality of extracorporeal membrane oxygenation (ECMO) remains unclear. The present study investigates the evolving epidemiology and mortality of various ECMO techniques in Germany over time, used for both severe respiratory and cardiac failure. METHODS: Data on all patients receiving venovenous (vv-ECMO) and venoarterial (va-ECMO) ECMO as well as pumpless extracorporeal lung assist/interventional lung assist (PECLA/ILA) outside the operating room in Germany from 1 January 2007 through 31 December 2014 were obtained from the Federal Statistical Office of Germany and analyzed. RESULTS: The incidence of vv-ECMO and va-ECMO in the population increased threefold from 1.0:100,000 inhabitants/year in 2007 to a maximum of 3.0:100,000 in 2012, and from 0.1:100,000 in 2007 to 0.7:100,000 in 2012 and to a maximum of 3.5:100,000 in 2014, respectively. The incidence of arteriovenous PECLA/ILA also increased from 0.4:100,000 to a maximum of 0.6:100,000 in 2011, but decreased thereafter to 0.3:100,000 in 2014. The relative proportion of older patients receiving ECMO is steadily increasing. In-hospital mortality decreased over time and reached 58 and 66 % for vv-ECMO and va-ECMO in 2014, respectively. In addition, mortality steadily increased with age and was especially high in the first 48 h of ECMO use. CONCLUSIONS: In a high-income country like Germany, the use of ECMO has been rapidly increasing since 2007 for both respiratory and cardiac support, with a recent plateau in vv-ECMO use. In-hospital mortality decreased with increasing ECMO utilization, but remains high, especially in older patients and in the first 48 h of use. PMID- 26942447 TI - The definition of ARDS revisited: 20 years later. PMID- 26942445 TI - Mechanisms Regulating Insulin Response to Intragastric Glucose in Lean and Non Diabetic Obese Subjects: A Randomized, Double-Blind, Parallel-Group Trial. AB - BACKGROUND/OBJECTIVES: The changes in blood glucose concentrations that result from an oral glucose challenge are dependent on the rate of gastric emptying, the rate of glucose absorption and the rate of insulin-driven metabolism that include the incretins, glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1). The rate of insulin-driven metabolism is clearly altered in obese subjects, but it is controversial which of these factors is predominant. We aimed to quantify gastric emptying, plasma insulin, C-peptide, glucagon and glucose responses, as well as incretin hormone secretions in obese subjects and healthy controls during increasing glucose loads. SUBJECTS/METHODS: The study was conducted as a randomized, double-blind, parallel-group trial in a hospital research unit. A total of 12 normal weight (6 men and 6 women) and 12 non diabetic obese (BMI > 30, 6 men and 6 women) participants took part in the study. Subjects received intragastric loads of 10 g, 25 g and 75 g glucose dissolved in 300 ml tap water. RESULTS: Main outcome measures were plasma GLP-1 and GIP, plasma glucagon, glucose, insulin, C-peptide and gastric emptying. The primary findings are: i) insulin resistance (P < 0.001) and hyperinsulinemia (P < 0.001); ii) decreased insulin disposal (P < 0.001); iii) trend for reduced GLP-1 responses at 75 g glucose; and iv) increased fasting glucagon levels (P < 0.001) in obese subjects. CONCLUSIONS: It seems that, rather than changes in incretin secretion, fasting hyperglucagonemia and consequent hyperglycemia play a role in reduced disposal of insulin, contributing to hyperinsulinemia and insulin resistance. TRIAL REGISTRATION: ClinicalTrials.gov NCT01875575. PMID- 26942448 TI - Targeted hepatocellular carcinoma therapy: transferrin modified, self-assembled polymeric nanomedicine for co-delivery of cisplatin and doxorubicin. AB - BACKGROUND: Targeted hepatocellular carcinoma (HCC) therapy was carried out to improve the efficacy of liver cancers. The aim of this study was to develop transferrin (Tf) modified, self-assembled polymeric nanoparticles for co-delivery doxorubicin (DOX) and cisplatin (DDP), to achieve combination tumor therapy. METHODS: Tf modified polyethylene glycol (PEG) containing DOX prodrug (Tf-PEG DOX) was synthesized. DDP containing poly(lactic-co-glycolic) acid (PLGA) materials (PLGA-DDP) were prepared. Tf modified DOX and DDP loaded PLGA nanoparticles (Tf-DOX/DDP NPs) were prepared by using nanoprecipitation method. The particles sizes, zeta potentials, drug loading effects were characterized. The cytotoxicity of the NPs was evaluated in human hepatoma carcinoma cell lines (HepG2 cells), and in vivo anti-tumor was observed in mice bearing human HepG2 cells model. RESULTS: Tf-DOX/DDP NPs displayed higher cytotoxicity and enhanced antitumor activity both in vitro and in vivo over their non-modified and single drug loaded counterparts. CONCLUSION: Tf-DOX/DDP NPs can achieve outstanding anti tumor activity due to the combination effect of two drugs and the active targeting ability of Tf ligands. The self-assembled polymeric nanomedicine could act as an efficient therapy method for HCC treatment. PMID- 26942449 TI - pEPito-driven PEDF Expression Ameliorates Diabetic Retinopathy Hallmarks. AB - Diabetic retinopathy (DR) is one of the major complications of diabetes mellitus. It is characterized by retinal microvascular changes caused by chronic exposure to hyperglycemia, leading to low tissue oxygenation and ultimately to neovascularization. Laser photocoagulation and vitrectomy are the most efficient treatments for DR, but display severe side effects such as the destruction of the healthy retina. Another clinical approach uses antiangiogenic agents to prevent and delay progression of neovascularization, but these require recurrent local administrations that increase the possibility of retinal detachment, vitreous hemorrhage, and cataract formation. Studies in human diabetic retinas have revealed an imbalance between proangiogenic factors such as the vascular endothelial growth factor (VEGF) and antiangiogenic factors, such as pigment epithelial-derived factor (PEDF). This imbalance favors pathological angiogenesis contributing to DR, and can constitute a therapeutic target. Gene therapy was recently shown to be an adequate intervention for long-term treatment of several retinal pathologies. We have previously shown the newly engineered episomal vector pEPito to be able of sustained gene expression in the mouse retina. We here show that pEPito was able to overexpress PEDF for up to three months, both in in vitro cultures of human retinal pigment epithelial cells and in the retina of diabetic mice after a single subretinal injection. In vivo, in parallel with the increase in PEDF we observed a decrease in VEGF levels in injected compared with noninjected eyes and a significant effect on two hallmarks of DR: reduction of glucose transport (by glucose transporter GLUT1), and reduction of inflammation by decreased reactivity of microglia. Jointly, these results point to a significant therapeutic potential of gene therapy with pEPito-PEDF for the treatment of DR. PMID- 26942451 TI - Ba2F2Fe(1.5)Se3: An Intergrowth Compound Containing Iron Selenide Layers. AB - The iron selenide compound Ba2F2Fe(1.5)Se3 was synthesized by a high-temperature ceramic method. The single-crystal X-ray structure determination revealed a layered-like structure built on [Ba2F2](2+) layers of the fluorite type and iron selenide layers [Fe(1.5)Se3](2-). These [Fe1.5Se3](2-) layers contain iron in two valence states, namely, Fe(II+) and Fe(III+) located in octahedral and tetrahedral sites, respectively. Magnetic measurements are consistent with a high spin state for Fe(II+) and an intermediate-spin state for Fe(III+). Moreover, susceptibility and resistivity measurements demonstrate that Ba2F2Fe(1.5)Se3 is an antiferromagnetic insulator. PMID- 26942450 TI - The addition of gemtuzumab ozogamicin to chemotherapy in adult patients with acute myeloid leukemia. AB - The treatment of acute myeloid leukaemia has remained largely unchanged for the last 30 years since the advent of combination chemotherapy with cytarabine arabinoside and daunorubicin with remission rates around 70% but with long term survival still only around 40% in young adults. Doses of chemotherapy have been pushed to the limit of toxicity. Gemtuzumab ozogamicin allows additional chemotherapy to be delivered to the leukaemic cells without significantly adding to toxicity since the active agent is coupled to a monoclonal anti-CD33 antibody. It was approved by the FDA in 2000 for the treatment of elderly patients with relapsed CD33 positive AML at a dose of 9mg/m(2) on two days two weeks apart. Almost at once, questions were raised about its safety, with a particular liver signal, and it was voluntarily withdrawn from practice in 2010. Many groups have been examining the role of gemtuzumab ozogamicin in combination with chemotherapy, usually at lower doses than originally recommended, with varying degrees of success and toxicity and gemtuzumab ozogamicin is now entering a period of rehabilitation. Currently it is only commercially available in Japan although it is currently also available in the UK Bloodwise AML18 study. PMID- 26942452 TI - Urban air quality assessment using monitoring data of fractionized aerosol samples, chemometrics and meteorological conditions. AB - The present article deals with assessment of urban air by using monitoring data for 10 different aerosol fractions (0.015-16 MUm) collected at a typical urban site in City of Thessaloniki, Greece. The data set was subject to multivariate statistical analysis (cluster analysis and principal components analysis) and, additionally, to HYSPLIT back trajectory modeling in order to assess in a better way the impact of the weather conditions on the pollution sources identified. A specific element of the study is the effort to clarify the role of outliers in the data set. The reason for the appearance of outliers is strongly related to the atmospheric condition on the particular sampling days leading to enhanced concentration of pollutants (secondary emissions, sea sprays, road and soil dust, combustion processes) especially for ultra fine and coarse particles. It is also shown that three major sources affect the urban air quality of the location studied-sea sprays, mineral dust and anthropogenic influences (agricultural activity, combustion processes, and industrial sources). The level of impact is related to certain extent to the aerosol fraction size. The assessment of the meteorological conditions leads to defining of four downwind patterns affecting the air quality (Pelagic, Western and Central Europe, Eastern and Northeastern Europe and Africa and Southern Europe). Thus, the present study offers a complete urban air assessment taking into account the weather conditions, pollution sources and aerosol fractioning. PMID- 26942453 TI - Impact of Neoadjuvant and Adjuvant Chemotherapy on Immediate Tissue Expander Breast Reconstruction. AB - BACKGROUND: Delayed wound healing or infection leads to premature tissue expander (TE) explantation after immediate postmastectomy breast reconstruction. A large study with sufficient duration of follow-up focusing on the impact of chemotherapy (CT) on premature TE removal after immediate breast reconstruction is lacking. METHODS: A retrospective review of patients undergoing immediate TE reconstruction was conducted. Multivariate analyses identified factors contributing to premature removal of TEs including neoadjuvant and adjuvant CT, specific chemotherapeutic regimens, and other factors like cancer stage, body mass index, smoking, radiation, and age. Kaplan-Meier curves were plotted to study the timing of premature TE removal. RESULTS: Of 899 patients with TEs, 256 received no, 295 neoadjuvant, and 348 adjuvant CT. Premature removal occurred more frequently in the neoadjuvant (17.3 %) and adjuvant (19.9 %) cohorts than the no-CT (12.5 %) cohort (p = 0.056). Premature TE removal occurred earlier (p = 0.005) in patients who received no CT than those with adjuvant CT. Radiation in patients receiving neoadjuvant CT prolonged the mean time to premature removal (p = 0.003). In the absence of radiation, premature removal occurred significantly sooner with neoadjuvant than adjuvant CT (p = 0.035). DISCUSSION: Premature removal of a TE occurs more commonly in patients treated with neoadjuvant or adjuvant CT and is most commonly observed 2-3 months after placement-well after the follow-up period recorded by the American College of Surgeons National Surgery Quality Improvement Program (NSQIP) database. These findings can be used to aid preoperative counseling and guide the timing of follow-up for these patients. PMID- 26942454 TI - An adaptive significance of morning sickness? Trivers-Willard and Hyperemesis Gravidarum. AB - Nausea during pregnancy, with or without vomiting, is a common early indication of pregnancy in humans. The severe form, Hyperemesis Gravidarum (HG), can be fatal. The aetiology of HG is unknown. We propose that HG may be a proximate mechanism for the Trivers-Willard (T-W) evolutionary hypothesis that mothers in poor condition should favor daughters. Using Swedish linked registry data, 1987 2005, we analyze all pregnancies that resulted in an HG admission and/or a live birth, 1.65 million pregnancies in all. Consistent with the T-W hypothesis, we find that: (i) HG is associated with poor maternal condition as proxied by low education; (ii) HG in the first two months of pregnancy is associated with a 7% point increase in live girl births; and (iii) HG affected pregnancies have a 34 percent average rate of inferred pregnancy loss, higher among less educated women. PMID- 26942455 TI - Perceptibility and the "Choice Experience": User Sensory Perceptions and Experiences Inform Vaginal Prevention Product Design. AB - The development of pericoital (on demand) vaginal HIV prevention technologies remains a global health priority. Clinical trials to date have been challenged by nonadherence, leading to an inability to demonstrate product efficacy. The work here provides new methodology and results to begin to address this limitation. We created validated scales that allow users to characterize sensory perceptions and experiences when using vaginal gel formulations. In this study, we sought to understand the user sensory perceptions and experiences (USPEs) that characterize the preferred product experience for each participant. Two hundred four women evaluated four semisolid vaginal formulations using the USPE scales at four randomly ordered formulation evaluation visits. Women were asked to select their preferred formulation experience for HIV prevention among the four formulations evaluated. The scale scores on the Sex-associated USPE scales (e.g., Initial Penetration and Leakage) for each participant's selected formulation were used in a latent class model analysis. Four classes of preferred formulation experiences were identified. Sociodemographic and sexual history variables did not predict class membership; however, four specific scales were significantly related to class: Initial Penetration, Perceived Wetness, Messiness, and Leakage. The range of preferred user experiences represented by the scale scores creates a potential target range for product development, such that products that elicit scale scores that fall within the preferred range may be more acceptable, or tolerable, to the population under study. It is recommended that similar analyses should be conducted with other semisolid vaginal formulations, and in other cultures, to determine product property and development targets. PMID- 26942457 TI - Use of fluorescent proteins and color-coded imaging to visualize cancer cells with different genetic properties. AB - Fluorescent proteins are very bright and available in spectrally-distinct colors, enable the imaging of color-coded cancer cells growing in vivo and therefore the distinction of cancer cells with different genetic properties. Non-invasive and intravital imaging of cancer cells with fluorescent proteins allows the visualization of distinct genetic variants of cancer cells down to the cellular level in vivo. Cancer cells with increased or decreased ability to metastasize can be distinguished in vivo. Gene exchange in vivo which enables low metastatic cancer cells to convert to high metastatic can be color-coded imaged in vivo. Cancer stem-like and non-stem cells can be distinguished in vivo by color-coded imaging. These properties also demonstrate the vast superiority of imaging cancer cells in vivo with fluorescent proteins over photon counting of luciferase labeled cancer cells. PMID- 26942456 TI - The raspberry Gene Is Involved in the Regulation of the Cellular Immune Response in Drosophila melanogaster. AB - Drosophila is an extremely useful model organism for understanding how innate immune mechanisms defend against microbes and parasitoids. Large foreign objects trigger a potent cellular immune response in Drosophila larva. In the case of endoparasitoid wasp eggs, this response includes hemocyte proliferation, lamellocyte differentiation and eventual encapsulation of the egg. The encapsulation reaction involves the attachment and spreading of hemocytes around the egg, which requires cytoskeletal rearrangements, changes in adhesion properties and cell shape, as well as melanization of the capsule. Guanine nucleotide metabolism has an essential role in the regulation of pathways necessary for this encapsulation response. Here, we show that the Drosophila inosine 5'-monophosphate dehydrogenase (IMPDH), encoded by raspberry (ras), is centrally important for a proper cellular immune response against eggs from the parasitoid wasp Leptopilina boulardi. Notably, hemocyte attachment to the egg and subsequent melanization of the capsule are deficient in hypomorphic ras mutant larvae, which results in a compromised cellular immune response and increased survival of the parasitoid. PMID- 26942458 TI - [Acceptance of dementia diagnostics by getriatric hospital patients : Comparison of various investigation methods with emphasis on FDG-PET imaging]. AB - BACKGROUND: The number of people with dementia is continuously rising, in hospitals as well. For the diagnostics novel methods are available but the attitude of the patients to these methods is yet unknown. OBJECTIVE: The aim of the study was to evaluatethe opinion of geriatric hospital patients with suspected dementia on the various possible methods of diagnosing dementia, especially fluorodeoxyglucose positron emission tomography (FDG-PET). Additionally, it was assessed if there are differences in toleration between imaging of the brain and conventional diagnostics by neuropsychological testing and if information on the diagnostic methods and the patient's physical or cognitive status influence their opinion. METHOD: Within the framework of the iDSS001 clinical trial 90 geriatric hospital patients with suspected dementia were interviewed with respect to examinations performed for diagnosing dementia, e.g. anamnesis including physical and neurological examinations, neuropsychological testing, cerebrospinal fluid analysis, magnetic resonance imaging (MRI) and FDG-PET imaging. RESULTS: Imaging of the brain was tolerated less than anamnesis including physical and neurological examinations, neuropsychological testing and cerebrospinal fluid analysis and patients also felt they were less informed about these procedures. The generally well-accepted FDG-PET imaging procedure was received slightly better than MRI. Cognitively impaired and less depressed patients were less willing to allow repeat MRI examinations. CONCLUSION: The results suggest that imaging of the brain is perceived by cognitively impaired hospital patients as being more burdensome than conventional diagnostics, such as neuropsychological testing. Improved care during the investigations as well as physical and organizational adjustments could increase the acceptance. PMID- 26942459 TI - Out of society? Retirement affects perceived social exclusion in Germany. AB - BACKGROUND: Perceived social exclusion (PSE) depends on individual access to resources (e.g. income and social networks) and recognition of a social status. Working provides individuals with both resources and a social status. This situation leaves the non-working population at a severe social disadvantage, which might partly be remedied by retirement. OBJECTIVE: We expected to find differential effects on PSE when individuals retire. For individuals working until retirement the transition might be mostly associated with a loss of resources (leading to an increase in PSE) and for individuals not working before retirement the transition might be more strongly associated with an increase in social status (leading to a decrease in PSE). MATERIAL AND METHODS: We used longitudinal data from the German Panel Study of Labor Market and Social Security (PASS) to estimate fixed effects panel regression models for 790 men and women experiencing the transition to retirement (4110 observations). Models were estimated separately for retired persons who worked or did not work prior to retirement. RESULTS: At retirement those working prior to the transition reported lower levels of PSE than those not working. As expected retirement increased PSE for those previously working and for those not previously working retirement decreased PSE in the short term. Both effects remained stable after compensating for resource changes due to retirement. CONCLUSION: Retirement reduced the differences in PSE between previously working and non-working groups. For those previously working retirement seemed to depict a loss of social acceptance whereas for those previously not working retirement seemed to indicate a reduction of stigmatization. The previous effect of the labor market, however, continued to affect individuals in retirement for a long time. PMID- 26942460 TI - C/EBP homologous protein (CHOP) deficiency ameliorates renal fibrosis in unilateral ureteral obstructive kidney disease. AB - Renal tubulointerstitial fibrosis is an important pathogenic feature in chronic kidney disease and end-stage renal disease, regardless of the initiating insults. A recent study has shown that CCAAT/enhancer binding protein (C/EBP) homologous protein (CHOP) is involved in acute ischemia/reperfusion-related acute kidney injury through oxidative stress induction. However, the influence of CHOP on chronic kidney disease-correlated renal fibrosis remains unclear. Here, we investigated the role of CHOP in unilateral ureteral obstruction (UUO)-induced experimental chronic tubulointerstital fibrosis. The CHOP knockout and wild type mice with or without UUO were used. The results showed that the increased expressions of renal fibrosis markers collagen I, fibronectin, alpha-smooth muscle actin, and plasminogen activator inhibitor-1 in the kidneys of UUO-treated wild type mice were dramatically attenuated in the kidneys of UUO-treated CHOP knockout mice. CHOP deficiency could also ameliorate lipid peroxidation and endogenous antioxidant enzymes depletion, tubular apoptosis, and inflammatory cells infiltration in the UUO kidneys. These results suggest that CHOP deficiency not only attenuates apoptotic death and oxidative stress in experimental renal fibrosis, but also reduces local inflammation, leading to diminish UUO-induced renal fibrosis. Our findings support that CHOP may be an important signaling molecule in the progression of chronic kidney disease. PMID- 26942461 TI - The antihypertensive drug hydralazine activates the intrinsic pathway of apoptosis and causes DNA damage in leukemic T cells. AB - Epigenetic therapies have emerged as promising anticancer approaches, since epigenetic modifications play a major role in tumor initiation and progression. Hydralazine, an approved vasodilator and antihypertensive drug, has been recently shown to act as a DNA methylation inhibitor. Even though hydralazine is already tested in clinical cancer trials, its mechanism of antitumor action remains undefined. Here, we show that hydralazine induced caspase-dependent apoptotic cell death in human p53-mutant leukemic T cells. Moreover, we demonstrate that hydralazine triggered the mitochondrial pathway of apoptosis by inducing Bak activation and loss of the mitochondrial membrane potential. Hydralazine treatment further resulted in the accumulation of reactive oxygen species, whereas a superoxide dismutase mimetic inhibited hydralazine-induced cell death. Interestingly, caspase-9-deficient Jurkat cells or Bcl-2- and Bcl-xL overexpressing cells were strongly resistant to hydralazine treatment, thereby demonstrating the dependence of hydralazine-induced apoptosis on the mitochondrial death pathway. Furthermore, we demonstrate that hydralazine treatment triggered DNA damage which might contribute to its antitumor effect. PMID- 26942462 TI - TIKI2 is upregulated and plays an oncogenic role in renal cell carcinoma. AB - TIKI2 is a negative regulator of the Wnt family. Although many Wnt antagonists play important roles in renal cell carcinoma (RCC), the molecular function of TIKI2 in human RCC has not been fully elucidated. Here, we analyzed TIKI2 mRNA level in RCC specimens, the corresponding non-tumor tissues, RCC cell lines, and human proximal tubule epithelial cell line HK-2 using qPCR. We demonstrated that TIKI2 was highly expressed in RCC tissue (P < 0.05) and most RCC cell lines. In vitro, TIKI2 knockdown significantly inhibited proliferation, invasion, and clone formation ability of 769-P cells compared with controls, while ectopic TIKI2 expression enhanced A498 cell proliferation, invasion, and clone formation ability. In vivo, the average tumor volume was significantly increased in mice injected with A498-Tiki2 cells (P < 0.05). In the 769-P cell TIKI2 knockdown group, the average tumor volume was not significantly different compared to that of the control group (P = 0.08). Moreover, Wnt/beta-catenin signaling was not affected by TIKI2 knockdown or overexpression. Results of the present study indicate that TIKI2 is upregulated in RCC tissues and plays an oncogenic role in RCC. PMID- 26942463 TI - A pharmacokinetic and safety study of a fixed oral dose of enzastaurin HCl in native Chinese patients with refractory solid tumors and lymphoma. AB - PURPOSE: This study was conducted to assess the pharmacokinetics and safety of enzastaurin in native Chinese patients with refractory solid tumors and lymphoma. METHODS: Eligible patients received 500 mg of enzastaurin orally once daily. The pharmacokinetics of enzastaurin and its metabolites were assessed on days 14 to 18. Patients were allowed to continue receiving the agent in a safety extension phase until disease progression or presentation with unacceptable toxicity. RESULTS: Twenty-five patients received at least 1 dose of enzastaurin, and twenty one patients completed the pharmacokinetic phase. Fifteen patients entered the safety extension phase. Except for transient, asymptomatic grade 3 QT interval prolongation in one patient who had baseline grade 2 QT prolongation, other adverse events were of grade 1 to 2. The t(1/2), C(av, ss), and AUC(tau,ss) for enzastaurin and its primary active metabolite LSN326020 were 14 and 42 h, 1,210 and 907 nmol/L, and 29,100 and 21,800 nmol*h/L, respectively. One patient with relapsed diffuse large B-cell lymphoma achieved a partial response that lasted for 8.1 months. CONCLUSIONS: The pharmacokinetics of enzastaurin in Chinese cancer patients were consistent with those observed in previous studies abroad. Enzastaurin 500 mg daily was well tolerated by Chinese patients. We recommend 500 mg daily as the phase II dose in this population. Its efficacy in lymphoma deserves further investigation. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01432951. PMID- 26942465 TI - MicroRNA-432 functions as a tumor suppressor gene through targeting E2F3 and AXL in lung adenocarcinoma. AB - Abnormal proliferation and drug resistance are the hallmarks of lung adenocarcinoma (LAD). Dispite the advances in diagnosis and therapy, the 5-year survival remains low. Increasing studies regarding its pathological mechanism have been focused on microRNA (miRNA) due to its nodal regulatory properties. This study aims to characterize the expression of miR-432 in LAD and investigate its effects on the proliferation and sensitivity of lung cancer cells to cisplatin. Here, we report that downregulation of miR-432 in LAD tissues was correlated with a higher clinical stage (p = 0.03) and poor prognosis (p = 0.036). Additionally, miR-432 expression was negative correlated with high Ki67 labeling index (p = 0.016) in our cohorts. Functionally, over-expression of miR 432 inhibits cell proliferation through arresting cell cycle and sensitizes tumor cells to cisplatin. Mechanistically, miR-432 functions by directly targeting E2F3 and AXL, and they, in turn, mediate the regulation of miR-432 towards cell proliferation and cisplatin sensitivity. Importantly, miR-432 levels are negatively correlated with the levels of E2F3 and AXL in human LAD tissues. These results demonstrated that miR-432 functions as a tumor-suppressive miRNA and may represent a prognostic parameter and therapeutic target for LAD. PMID- 26942464 TI - Prognostic role of lymphocyte to monocyte ratio for patients with cancer: evidence from a systematic review and meta-analysis. AB - Inflammation influences cancer development and progression, and a low lymphocyte to monocyte ratio (LMR) has been reported to be a poor prognostic indicator in several malignancies. Here we quantify the prognostic impact of this biomarker and assess its consistency in various cancers. Eligible studies were retrieved from PubMed, Embase and Web of Science databases. Overall survival (OS) was the primary outcome, cancer-specific survival (CSS), disease-free survival (DFS), recurrence-free survival (RFS), and progression-free survival (PFS) were secondary outcomes. Pooled hazard ratios (HRs), odds ratios (ORs), and 95% confidence intervals (CIs) were calculated. Fifty-six studies comprising 20,248 patients were included in the analysis. Overall, decreased LMR was significantly associated with shorter OS in non-hematological malignancy (HR: 0.59, 95% CI: 0.53-0.66; P < 0.001) and hematological malignancy (HR: 0.44, 95% CI: 0.34-0.56; P < 0.001). Similar results were found in CSS, DFS, RFS and PFS. Moreover, low LMR was significantly associated with some clinicopathological characteristics that are indicative of poor prognosis and disease aggressiveness. By these results, we conclude that a decreased LMR implied poor prognosis in patients with cancer and could serve as a readily available and inexpensive biomarker for clinical decision. PMID- 26942467 TI - Effect of sex steroids on bone formation in an orthopedically expanded suture in rats : An immunohistochemical and computed tomography study. AB - OBJECTIVE: The purpose of this work was to evaluate the effects of sex steroids on bone formation in response to midpalatal suture expansion by means of histological and immunohistochemical examinations and computed tomography (CT). MATERIALS AND METHODS: A total of 32 male and 32 female 12-week-old Wistar rats were divided into four groups per gender. Testosterone was administered to the castrated experimental male rats, estrogen to castrated experimental female rats. Saline solution was given subcutaneously to the male and female control, sham, and castration groups during expansion and retention periods, which lasted 7 and 5 days, respectively. The expansion amount was measured with a digital caliper. The density of the new bone in the expansion area was measured via CT. RESULTS: Histological and CT evaluation revealed that the number of osteoblasts and density of the new bone was higher in male and female experimental groups than in all the other groups. When scores of staining intensity were compared, the experimental groups demonstrated statistically significant greater immunoreactivity in the osteoblasts compared to castrated-only groups. Bone density was higher in the female experimental group than in the others, and higher in the male experimental group than in the others. Expansion amounts in the castrated groups were higher than in the others (p < 0.05). CONCLUSION: Raising the levels of sex steroids in rats revealed positive effects on bone formation in the midpalatal suture in response to expansion. Increased sex steroid levels can reduce the time needed for retention. PMID- 26942466 TI - Sleep-disordered breathing in orthodontic practice: Prevalence of snoring in children and morphological findings. AB - OBJECTIVES: The purpose of this work was to evaluate the prevalence of snoring and its correlation with cranial and upper airway morphology in young individuals with orthodontic treatment need. PATIENTS AND METHODS: Parents of 379 children were consecutively interviewed, using eight questions from a more comprehensive questionnaire about sleep behavior. A total of 100 patients (54 girls, 46 boys, average age 11.3 years) met the inclusion criteria. Based on the parents' interviews, the sample was divided into snorers (n = 53) and nonsnorers (n = 47). Using cephalograms obtained for initial orthodontic diagnostics, airway morphology was measured based on hyoid position and on the posterior airway space (PAS) dimensions at the maxillary, occlusal, and mandibular plane levels (PAS_NL, PAS_OCCL, PAS_ML). Mann-Whitney U testing, ANOVA, and Spearman's rank correlation coefficient were used for statistical analysis. RESULTS: Snoring was reported by 53 % of parents for 63 % (n = 29) of the boys and 44 % (n = 24) of the girls. Significant morphological differences were noted between snorers and nonsnorers. PAS dimensions were significantly reduced in the snorers compared to the nonsnorers at all three anatomical levels tested, which remained statistically significant when adjusted for age and gender. No differences between the two groups emerged for hyoid position or any of the vertical cranial parameters. A significant correlation between sagittal maxillary position (SNA) and PAS_NL was noted, indicating that larger SNA values were mildly associated with larger sagittal PAS dimensions at the maxillary level. CONCLUSION: This random sample of young patients with orthodontic treatment need was found to involve a high prevalence of parent-reported snoring. Characteristic features in cranial and upper airway morphology and thus differences between the snorers and nonsnorers were found. PMID- 26942468 TI - Embedding Physical Activity in the Heart of the NHS: The Need for a Whole-System Approach. AB - Solutions to the global challenge of physical inactivity have tended to focus on interventions at an individual level, when evidence shows that wider factors, including the social and physical environment, play a major part in influencing health-related behaviour. A multidisciplinary perspective is needed to rewrite the research agenda on physical activity if population-level public health benefits are to be demonstrated. This article explores the questions that this raises regarding the particular role that the UK National Health Service (NHS) plays in the system. The National Centre for Sport and Exercise Medicine in Sheffield is put forward as a case study to discuss some of the ways in which health systems can work in collaboration with other partners to develop environments and systems that promote active lives for patients and staff. PMID- 26942469 TI - Bio-inspired 3D microenvironments: a new dimension in tissue engineering. AB - Biomaterial scaffolds have been a foundational element of the tissue engineering paradigm since the inception of the field. Over the years there has been a progressive move toward the rational design and fabrication of bio-inspired materials that mimic the composition as well as the architecture and 3D structure of tissues. In this review, we chronicle advances in the field that address key challenges in tissue engineering as well as some emerging applications. Specifically, a summary of the materials and chemistries used to engineer bio inspired 3D matrices that mimic numerous aspects of the extracellular matrix is provided, along with an overview of bioprinting, an additive manufacturing approach, for the fabrication of engineered tissues with precisely controlled 3D structures and architectures. To emphasize the potential clinical impact of the bio-inspired paradigm in biomaterials engineering, some applications of bio inspired matrices are discussed in the context of translational tissue engineering. However, focus is also given to recent advances in the use of engineered 3D cellular microenvironments for fundamental studies in cell biology, including photoresponsive systems that are shedding new light on how matrix properties influence cell phenotype and function. In an outlook for future work, the need for high-throughput methods both for screening and fabrication is highlighted. Finally, microscale organ-on-a-chip technologies are highlighted as a promising area for future investment in the application of bio-inspired microenvironments. PMID- 26942471 TI - Recidivism Rates After Smoking Cessation Before Spinal Fusion. AB - Tobacco use has documented negative effects on perioperative complications and clinical outcomes. Smoking cessation before spinal surgery may improve clinical outcomes. The goal of this study was to determine the recidivism rate after smoking cessation before spinal fusion. A prospective observational study was performed at the University of Kansas Medical Center between 2006 and 2011. All patients with serum-confirmed nicotine cessation before spinal fusion surgery were eligible. Smoking status was determined with questionnaires at 3 months, 6 months, and 1 year postoperatively. All reported nonsmokers had confirmatory serum nicotine and cotinine tests. Two-tailed Pearson chi-square and independent t tests were conducted, and significance was set at alpha=0.05. A total of 42 subjects (21 women, 21 men) with confirmed preoperative serum-negative test results were prospectively enrolled over a period of 3.9 years. Of these patients, 1 opted out at 6 months and 1 died of unknown cause. The findings showed a recidivism rate (response rate) of 60% (40 of 41) at 3 months, 61% (33 of 41) at 6 months, and 68% (25 of 40) at 1 year. One case of asymptomatic pseudarthrosis occurred 1 year postoperatively in a confirmed nonsmoker. No correlation was found between smoking status at 3 months and sex, primary vs revision surgery, or complications (P>.05). Smokers who relapsed at 3 months were older than nonsmokers (55.2 vs 44.2 years, respectively; P=.03). Some patients are willing to cease smoking before spinal fusion for optimal clinical outcomes; however, the rate of recidivism is high (60%) within the first 3 months post operatively. PMID- 26942470 TI - Evaluation of the Accuracy of T-SPOT.TB for the Diagnosis of Ocular Tuberculosis in a BCG-vaccinated, Non-endemic Population. AB - PURPOSE: To determine the performance of T-SPOT.TB, an interferon gamma release assay test, in patients with ocular tuberculosis (TB) in a BCG-vaccinated, non endemic population. METHODS: We employed a nested case-control design. In total, 45 subjects were enrolled (23 patients with ocular tuberculosis and 22 patients with other causes of uveitis). A blood sample was collected from each subject, and T-SPOT.TB was executed. Laboratory professionals were blinded to the disease status of each subject. RESULTS: Five patients were excluded because of indeterminate results. The calculated sensitivity and specificity were 0.80 and 0.85, respectively. The positive likelihood ratio was 5.33 and the negative likelihood ratio was 0.23. The overall accuracy of the test was 0.83. CONCLUSIONS: T-SPOT.TB adequately diagnosed ocular TB. This technique is particularly useful in populations where BCG vaccinations are still mandatory. PMID- 26942472 TI - Effectiveness of Surgical Safety Checklists in Improving Patient Safety. AB - Wrong-site surgery is all too common. Despite more than a decade of campaigns by major organizations to prevent these events, there are still reports of such mistakes. This article reviews the recent literature on surgical safety checklists and other tools designed to prevent wrong-site surgery and improve patient safety in the operating room. Emphasis is placed on how well institutions comply with these guidelines, the perceptions and attitudes of those who are asked to implement them, and their effectiveness. The literature shows that the implementation of such protocols has improved patient safety. In general, these efforts are viewed favorably by operating room personnel. However, the role of these checklists and other tools in reducing wrong-sided surgeries has not been proven. The goal of the health care profession should be to continue to improve on the advances that have been made in implementing surgical checklists and preventing wrong-site surgery. Practitioners at the authors' institution are continuously searching for ways to improve on the current protocols to prevent wrong-site surgeries. The authors recently employed a protocol in which surgical instruments are kept in the back of the room, away from the patient, until completion of the surgical time-out. This practice helps to ensure that team members are not distracted or preoccupied with setting up equipment during the time-out. This approach also helps to mitigate the hierarchal style in the operating room. PMID- 26942474 TI - Safety, Efficacy, and Cost-effectiveness of Tranexamic Acid in Orthopedic Surgery. AB - Perioperative bleeding and postsurgical hemorrhage are common in invasive surgical procedures, including orthopedic surgery. Tranexamic acid (TXA) is a pharmacologic agent that acts through an antifibrinolytic mechanism to stabilize formed clots and reduce active bleeding. It has been used successfully in orthopedics to reduce perioperative blood loss, particularly in total hip and knee arthroplasty and spine surgery. Numerous research studies have reported favorable safety and efficacy in orthopedic cases, although there is no universal standard on its administration and its use has not yet become the standard of practice. Reported administration methods often depend on the surgeon's preference, with both topical and intravenous routes showing efficacy. The type and anatomic site of the surgery seem to influence the decision making but also result in conflicting opinions. Reported complication rates with TXA use are low. The incidence of both arterial and venous thromboembolic events, particularly deep venous thrombosis and pulmonary embolism, has not been found to be significantly different with TXA use for healthy patients. The route of administration and dosage do not appear to affect complication rates either. However, data on patients with higher-risk conditions are deficient. In addition, TXA has shown potential to reduce blood loss, transfusion rates and volumes, perioperative hemoglobin change, and hospital-related costs at various degrees among the published studies. Conservation of blood products, reduced laboratory costs, and shorter hospital stays are likely the major factors driving the cost savings associated with TXA use. This article reviews current data supporting the safety, efficacy, and cost-effectiveness of TXA in orthopedic surgery. PMID- 26942473 TI - To Beard or Not to Beard? Bacterial Shedding Among Surgeons. AB - Beards in the operating room are controversial because of their potential to retain and transmit pathogenic organisms. Many bearded orthopedic surgeons choose to wear nonsterile hoods in addition to surgical masks to decrease contamination of the operative field. The goal of this study was to determine whether nonsterile surgical hoods reduce the risk of bacterial shedding posed by beards. Bearded (n=10) and clean-shaven (n=10) subjects completed 3 sets of standardized facial motions, each lasting 90 seconds and performed over blood agar plates, while unmasked, masked, and masked and hooded. The plates were cultured for 48 hours under aerobic and anaerobic conditions. Colony-forming units (CFUs) were quantified, expanded, and identified. Overall, the addition of surgical hoods did not decrease the total number of anaerobic and aerobic CFUs isolated per subject, with a mean of 1.1 CFUs while hooded compared with 1.4 CFUs with the mask alone (P=.5). Unmasked subjects shed a mean of 6.5 CFUs, which was significantly higher than the number of CFUs shed while masked (P=.02) or hooded (P=.01). The bearded group did not shed more than the clean-shaven group while unmasked (9.5 vs 3.3 CFUs, P=.1), masked (1.6 vs 1.2 CFUs, P=.9), or hooded (0.9 vs 1.3 CFUs, P=.6). Bearded surgeons did not appear to have an increased likelihood of bacterial shedding compared with their nonbearded counter parts while wearing surgical masks, and the addition of nonsterile surgical hoods did not decrease the amount of bacterial shedding observed. PMID- 26942475 TI - A Biomechanical Analysis of Anchor Placement for Bankart Repair: Effect of Portal Placement. AB - During arthroscopic Bankart repair, penetration of suture anchors through the far cortex can compromise the initial biomechanical characteristics of anchor stability and repair integrity. This study compared the placement of suture anchors through a low anterior-inferior rotator interval portal (AI) vs a trans subscapularis portal to evaluate the rate of anchor perforation as well as biomechanical strength. Ten matched pairs of cadaveric shoulders were randomized to an AI or a trans-subscapularis portal for placement of suture anchors at the 3 o'clock and 5:30 positions. The following measurements were obtained: (1) distance from the portal to the cephalic vein; (2) presence and length of anchor penetration through the inferior glenoid; and (3) ultimate failure strength of the anchors. The distance from the portal to the cephalic vein was significantly greater with the AI vs the trans-subscapularis portal across all specimens (29.9 vs 11.2 mm, P<.05). The rate of anchor penetration was significantly increased in the AI group vs the trans-subscapularis group at the 5:30 position (60% vs 10%, P=.014) but not at the 3 o'clock position (P=.33). Mean pullout strength of the anchors at the 5:30 position trended higher in the trans-subscapularis group, but the difference was not significant (132.8 vs 112.6 N, P=.18). The cephalic vein is closer to the trans-subscapularis portal than to the AI, but is at a safe distance. Both the rate and the degree of glenoid suture anchor penetration were lower with the trans-subscapularis portal compared with the AI at the 5:30 position. Placing anchors through the trans-subscapularis portal provides a safe alternative method, with improved positioning of the inferiormost anchor compared with the traditional AI. PMID- 26942485 TI - The Role of Counterfactual Thinking on Attitudes Toward ADHD Medication Use. AB - OBJECTIVE: Despite serious health risks, attitudes toward Attention-Deficit Hyperactivity Disorder (ADHD) medication use in college students remain favorable. Given the robust link between attitudes and behavior (e.g., the Theory of Planned Behavior), it is important to understand how these attitudes are developed and maintained. The current study examined the role of counterfactual, or "what if'" thinking as a mechanism for the development of attitudes toward ADHD medications. METHOD: All participants (n = 190) were asked to read either a positive or negative scenario regarding ADHD medication misuse and rate their attitudes toward the behavior; half of the participants were also asked to generate counterfactuals prior to rating their attitudes. RESULTS: Results suggest that scenario valence influenced the direction of counterfactual statements. Further, through the generation of upward counterfactuals, the negative scenario elicited more positive attitudes toward ADHD medication misuse. CONCLUSIONS: Based on limited prior research, it is suggested that upward counterfactuals may allow individuals to explain away the misuse of ADHD medication and avoid negative emotions such as guilt and shame related to current or prior ADHD medication misuse. In sum, additional research is needed to confirm preliminary findings that suggest counterfactual thinking could be a precursor to ADHD medication misuse. PMID- 26942476 TI - Disruption of Microtubules Post-Virus Entry Enhances Adeno-Associated Virus Vector Transduction. AB - Perinuclear retention of viral particles is a poorly understood phenomenon observed during many virus infections. In this study, we investigated whether perinuclear accumulation acts as a barrier to limit recombinant adeno-associated virus (rAAV) transduction. After nocodazole treatment to disrupt microtubules at microtubule-organization center (MT-MTOC) after virus entry, we observed higher rAAV transduction. To elucidate the role of MT-MTOC in rAAV infection and study its underlying mechanisms, we demonstrated that rAAV's perinuclear localization was retained by MT-MTOC with fluorescent analysis, and enhanced rAAV transduction from MT-MTOC disruption was dependent on the rAAV capsid's nuclear import signals. Interestingly, after knocking down RhoA or inhibiting its downstream effectors (ROCK and Actin), MT-MTOC disruption failed to increase rAAV transduction or nuclear entry. These data suggest that enhancement of rAAV transduction is the result of increased trafficking to the nucleus via the RhoA ROCK-Actin pathway. Ten-fold higher rAAV transduction was also observed by disrupting MT-MTOC in brain, liver, and tumor in vivo. In summary, this study indicates that virus perinuclear accumulation at MT-MTOC is a barrier-limiting parameter for effective rAAV transduction and defines a novel defense mechanism by which host cells restrain viral invasion. PMID- 26942486 TI - Purification and biochemical properties of SDS-stable low molecular weight alkaline serine protease from Citrullus colocynthis. AB - A low molecular weight serine protease from seeds of Citrullus colocynthis was purified to electrophoretic homogeneity with high level of catalytic efficiency (22,945 M(-1) S(-1)). The enzyme was a monomer with molecular mass of 25 kDa estimated by SDS-PAGE. The enzyme was highly active over a pH range of 6.5-9.0 and temperature range of 20-80 degrees C, with maximum activity at pH 7.5 and at 50 degrees C. The K(m) and K(cat) were 73 MUg/mL and 67/s, respectively. The enzyme was strongly inhibited by PMSF, moderately by soybean trypsin inhibitor, indicating that the enzyme was a serine protease. The enzyme retained 86 and 73% of its activity in the presence of urea and DTT, respectively, and its activity was slightly enhanced in the presence of anionic detergent (SDS). Thus, the enzyme is a novel SDS-stable protease with high catalytic efficiency over wide ranges of pH and temperature which is commercially promising for various industrial applications. PMID- 26942487 TI - Cardiorespiratory fitness in urban adolescent girls: associations with race and pubertal status. AB - Cardiorespiratory fitness affords health benefits to youth. Among females, weight relative fitness declines during puberty and is lower among African American (AA) than Caucasian girls. Data indicate racial differences in pubertal timing and tempo, yet the interactive influence of puberty and race on fitness, and the role of physical activity (PA) in these associations have not been examined. Thus, independent and interactive associations of race and pubertal development with fitness in adolescent girls, controlling for PA were examined. Girls in grades 5 8 (n = 1011; Caucasian = 25.2%, AA = 52.3%, Other Race group = 22.5%) completed the Pubertal Development Scale (pubertal stage assessment) and Fitnessgram(r) Progressive Aerobic Cardiovascular Endurance Run (PACER) test (cardiorespiratory fitness assessment). PA was assessed by accelerometry. Bivariate and multivariate analyses were used to examine associations among race, pubertal stage and fitness, controlling for vigorous PA, AA, and pubertally advanced girls demonstrated lower fitness than Caucasian and less mature counterparts. Puberty and race remained significantly associated with fitness after controlling for vigorous PA. The interaction effect of race and puberty on fitness was non significant. The pubertal influence on fitness is observed among AA adolescents. Associations between fitness and race/puberty appear to be independent of each other and vigorous PA. Pubertally advanced AA girls represent a priority group for fitness interventions. PMID- 26942500 TI - Personal factors influencing the visual reaction time of pedestrians to detect turn indicators in the presence of Daytime Running Lamps. AB - Daytime running lamps (DRL) on vehicles have proven to be an effective measure to prevent accidents during the daytime, particularly when pedestrians and cyclists are involved. However, there are negative interactions of DRL with other functions in automotive lighting, such as delays in pedestrians' visual reaction time (VRT) when turn indicators are activated in the presence of DRL. These negative interactions need to be reduced. This work analyses the influence of variables inherent to pedestrians, such as height, gender and visual defects, on the VRT using a classification and regression tree as an exploratory analysis and a generalized linear model to validate the results. Some pedestrian characteristics, such as gender, alone or combined with the DRL colour, and visual defects, were found to have a statistically significant influence on VRT and, hence, on traffic safety. These results and conclusions concerning the interaction between pedestrians and vehicles are presented and discussed. Practitioner Summary: Visual interactions of vehicle daytime running lamps (DRL) with other functions in automotive lighting, such as turn indicators, have an important impact on a vehicle's conspicuity for pedestrians. Depending on several factors inherent to pedestrians, the visual reaction time (VRT) can be remarkably delayed, which has implications in traffic safety. PMID- 26942501 TI - Family perspectives of how their relatives with mental illness benefit from Clubhouse participation: a qualitative inquiry. AB - BACKGROUND: Although researchers have demonstrated the benefits of psychosocial Clubhouse participation on a number of clinical and psychosocial outcomes, few studies have investigated the consumer's participation from the perspectives of others. AIM: This study aimed to investigate family members' perspectives of how Clubhouse programming has affected consumers' recovery. METHOD: Twenty-four relatives of Clubhouse members were interviewed using a semi-structured protocol. Relatives were nominated by their Clubhouse members as their family member who provided them with the most social support. All interviews were transcribed and underwent content analysis yielding multilevel coding. RESULTS: Four main dimensions emerged from family interviews about how Clubhouses affected their relatives. These dimensions aligned with areas of clinical recovery and personal growth. Family members observed and noted changes in: (1) positive affective changes, (2) improved goal directed and challenging behaviors, (3) positive attitude changes and (4) greater social interactions. CONCLUSION: As one of the first studies to document the perspectives of the relatives of Clubhouse members, this exploratory study indicates that family members recognize positive changes in their Clubhouse family members and these changes align with areas of functional recovery. Implications for practice and future studies are discussed. PMID- 26942517 TI - Good modelling practice in applying computational fluid dynamics for WWTP modelling. AB - Computational fluid dynamics (CFD) modelling in the wastewater treatment (WWT) field is continuing to grow and be used to solve increasingly complex problems. However, the future of CFD models and their value to the wastewater field are a function of their proper application and knowledge of their limits. As has been established for other types of wastewater modelling (i.e. biokinetic models), it is timely to define a good modelling practice (GMP) for wastewater CFD applications. An International Water Association (IWA) working group has been formed to investigate a variety of issues and challenges related to CFD modelling in water and WWT. This paper summarizes the recommendations for GMP of the IWA working group on CFD. The paper provides an overview of GMP and, though it is written for the wastewater application, is based on general CFD procedures. A forthcoming companion paper to provide specific details on modelling of individual wastewater components forms the next step of the working group. PMID- 26942516 TI - Exploring models for the roles of health systems' responsiveness and social determinants in explaining universal health coverage and health outcomes. AB - BACKGROUND: Intersectoral perspectives of health are present in the rhetoric of the sustainable development goals. Yet its descriptions of systematic approaches for an intersectoral monitoring vision, joining determinants of health, and barriers or facilitators to accessing healthcare services are lacking. OBJECTIVE: To explore models of associations between health outcomes and health service coverage, and health determinants and health systems responsiveness, and thereby to contribute to monitoring, analysis, and assessment approaches informed by an intersectoral vision of health. DESIGN: The study is designed as a series of ecological, cross-country regression analyses, covering between 23 and 57 countries with dependent health variables concentrated on the years 2002-2003. Countries cover a range of development contexts. Health outcome and health service coverage dependent variables were derived from World Health Organization (WHO) information sources. Predictor variables representing determinants are derived from the WHO and World Bank databases; variables used for health systems' responsiveness are derived from the WHO World Health Survey. Responsiveness is a measure of acceptability of health services to the population, complementing financial health protection. RESULTS: Health determinants' indicators - access to improved drinking sources, accountability, and average years of schooling - were statistically significant in particular health outcome regressions. Statistically significant coefficients were more common for mortality rate regressions than for coverage rate regressions. Responsiveness was systematically associated with poorer health and health service coverage. With respect to levels of inequality in health, the indicator of responsiveness problems experienced by the unhealthy poor groups in the population was statistically significant for regressions on measles vaccination inequalities between rich and poor. For the broader determinants, the Gini mattered most for inequalities in child mortality; education mattered more for inequalities in births attended by skilled personnel. CONCLUSIONS: This paper adds to the literature on comparative health systems research. National and international health monitoring frameworks need to incorporate indicators on trends in and impacts of other policy sectors on health. This will empower the health sector to carry out public health practices that promote health and health equity. PMID- 26942518 TI - Environmental remediation of heavy metal ions from aqueous solution through hydrogel adsorption: a critical review. AB - Heavy metal ions such as Cd(2+), Pb(2+), Cu(2+), Mg(2+), and Hg(2+) from industrial waste water constitute a major cause of pollution for ground water sources. These ions are toxic to man and aquatic life as well, and should be removed from wastewater before disposal. Various treatment technologies have been reported to remediate the potential toxic elements from aqueous media, such as adsorption, precipitation and coagulation. Most of these technologies are associated with some shortcomings, and challenges in terms of applicability, effectiveness and cost. However, adsorption techniques have the capability of effectively removing heavy metals at very low concentration (1-100 mg/L). Various adsorbents have been reported in the literature for this purpose, including, to a lesser extent, the use of hydrogel adsorbents for heavy metal removal in aqueous phase. Here, we provide an in-depth perspective on the design, application and efficiency of hydrogel systems as adsorbents. PMID- 26942519 TI - Adsorption of Cd, Cu and Zn from aqueous solutions onto ferronickel slag under different potentially toxic metal combination. AB - Adsorption characteristics of potentially toxic metals in single- and multi-metal forms onto ferronickel slag were evaluated. Competitive sorption of metals by ferronickel slag has never been reported previously. The maximum adsorption capacities of toxic metals on ferronickel were in the order of Cd (10.2 mg g(-1)) > Cu (8.4 mg g(-1)) > Zn (4.4 mg g(-1)) in the single-metal adsorption isotherm and Cu (6.1 mg g(-1)) >> Cd (2.3 mg g(-1)) > Zn (0.3 mg g(-1)) in the multi-metal adsorption isotherm. In comparison with single-metal adsorption isotherm, the reduction rates of maximum toxic metal adsorption capacity in the multi-metal adsorption isotherm were in the following order of Zn (93%) > Cd (78%) >> Cu (27%). The Freundlich isotherm provides a slightly better fit than the Langmuir isotherm equation using ferronickel slag for potentially toxic metal adsorption. Multi-metal adsorption behaviors differed from single-metal adsorption due to competition, based on data obtained from Freundlich and Langmuir adsorption models and three-dimensional simulation. Especially, Cd and Zn were easily exchanged and substituted by Cu during multi-metal adsorption. Further competitive adsorption studies are necessary in order to accurately estimate adsorption capacity of ferronickel slag for potentially toxic metals in natural environments. PMID- 26942520 TI - Optimization of the synthesis process of an iron oxide nanocatalyst supported on activated carbon for the inactivation of Ascaris eggs in water using the heterogeneous Fenton-like reaction. AB - An experimental design methodology was used to optimize the synthesis of an iron supported nanocatalyst as well as the inactivation process of Ascaris eggs (Ae) using this material. A factor screening design was used for identifying the significant experimental factors for nanocatalyst support (supported %Fe, (w/w), temperature and time of calcination) and for the inactivation process called the heterogeneous Fenton-like reaction (H2O2 dose, mass ratio Fe/H2O2, pH and reaction time). The optimization of the significant factors was carried out using a face-centered central composite design. The optimal operating conditions for both processes were estimated with a statistical model and implemented experimentally with five replicates. The predicted value of the Ae inactivation rate was close to the laboratory results. At the optimal operating conditions of the nanocatalyst production and Ae inactivation process, the Ascaris ova showed genomic damage to the point that no cell reparation was possible showing that this advanced oxidation process was highly efficient for inactivating this pathogen. PMID- 26942521 TI - On time discretizations for the simulation of the batch settling-compression process in one dimension. AB - The main purpose of the recently introduced Burger-Diehl simulation model for secondary settling tanks was to resolve spatial discretization problems when both hindered settling and the phenomena of compression and dispersion are included. Straightforward time integration unfortunately means long computational times. The next step in the development is to introduce and investigate time-integration methods for more efficient simulations, but where other aspects such as implementation complexity and robustness are equally considered. This is done for batch settling simulations. The key findings are partly a new time-discretization method and partly its comparison with other specially tailored and standard methods. Several advantages and disadvantages for each method are given. One conclusion is that the new linearly implicit method is easier to implement than another one (semi-implicit method), but less efficient based on two types of batch sedimentation tests. PMID- 26942522 TI - Long-term nitrogen compound removal trends of a hybrid subsurface constructed wetland treating milking parlor wastewater throughout its 7 years of operation. AB - This study evaluated the nitrogen compound removal efficiency of a hybrid subsurface constructed wetland, which began treating milking parlor wastewater in Hokkaido, northern Japan, in 2006. The wetland's overall removal rates of total nitrogen (TN) and ammonium (NH4(+)-N) improved after the second year of operation, and its rate of organic nitrogen (Org-N) removal was stable at 90% efficiency. Only nitrate (NO3(-)-N) levels were increased following the treatment. Despite increased NO3(-)-N (maximum of 3 mg-N/L) levels, TN removal rates were only slightly affected. Removal rates of TN and Org-N were highest in the first vertical bed. NH4(+)-N removal rates were highest in the second vertical bed, presumably due to water recirculation and pH adjustment. Concentrations of NO3(-)-N appeared when total carbon (TC) levels were low, which suggests that low TC prevented complete denitrification in the second vertical bed and the final horizontal bed. In practice, the beds removed more nitrogen than the amount theoretically removed by denitrification, as calculated by the amount of carbon removed from the system. This carbon-nitrogen imbalance may be due to other nitrogen transformation mechanisms, which require less carbon. PMID- 26942523 TI - Chloride ions promoted the catalytic wet peroxide oxidation of phenol over clay based catalysts. AB - Catalytic wet peroxide oxidation (CWPO) of phenol over clay-based catalysts in the presence and absence of NaCl was investigated. Changes in the H2O2, Cl(-), and dissolved metal ion concentration, as well as solution pH during phenol oxidation, were also studied. Additionally, the intermediates formed during phenol oxidation were detected by liquid chromatography-mass spectroscopy and the chemical bonding information of the catalyst surfaces was analyzed by X-ray photoelectron spectroscopy (XPS). The results showed that the presence of Cl(-) increased the oxidation rate of phenol to 155%, and this phenomenon was ubiquitous during the oxidation of phenolic compounds by H2O2 over clay-based catalysts. Cl(-)-assisted oxidation of phenol was evidenced by several analytical techniques such as mass spectroscopy (MS) and XPS, and it was hypothesized that the rate-limiting step was accelerated in the presence of Cl(-). Based on the results of this study, the CWPO technology appears to be promising for applications in actual saline phenolic wastewater treatment. PMID- 26942524 TI - The highest inhibition coefficient of phenol biodegradation using an acclimated mixed culture. AB - In this study a membrane biological reactor (MBR) was operated at 25 +/- 1 degrees C and pH = 7.5 +/- 0.5 to treat synthetic wastewater containing high phenol concentrations. Removal efficiencies of phenol and chemical oxygen demand (COD) were evaluated at four various hydraulic retention times (HRTs) of 24, 12, 8, and 4 hours. The removal rate of phenol (5.51 kg-Phenol kg-VSS(-1) d(-1)), observed at HRT of 4 h, was the highest phenol degradation rate in the literature. According to COD tests, there were no significant organic matter in the effluent, and phenol was degraded completely by mixed culture. Substrate inhibition was calculated from experimental growth parameters using the Haldane, Yano, and Edward equations. The results show that the Haldane equation is fitted to the experimental data in an excellent manner. Kinetic parameters were derived by nonlinear regression with a correlation coefficient (R(2)) of 0.974. The values for Haldane constants MUmax, Ks, and Ki were 0.3085 h(-1), 416 mg L(-1) and 1,886 mg L(-1), respectively. The Ki value is the highest value obtained for mixed cultures degrading phenol under batch conditions. PMID- 26942525 TI - Comprehensive scenario management of sustainable spatial planning and urban water services. AB - Adaptations of existing central water supply and wastewater disposal systems to demographic, climatic and socioeconomic changes require a profound knowledge about changing influencing factors. The paper presents a scenario management approach for the identification of future developments of drivers influencing water infrastructures. This method is designed within a research project with the objective of developing an innovative software-based optimisation and decision support system for long-term transformations of existing infrastructures of water supply, wastewater and energy in rural areas. Drivers of water infrastructures comprise engineering and spatial factors and these are predicted by different methods and techniques. The calculated developments of the drivers are illustrated for a model municipality. The developed scenario-manager enables the generation of comprehensive scenarios by combining different drivers. The scenarios are integrated into the optimisation model as input parameters. Furthermore, the result of the optimisation process - an optimal transformation strategy for water infrastructures - can have impacts on the existing fee system. General adaptation possibilities of the present fee system are presented. PMID- 26942526 TI - Evaluation of anaerobic digestion processes for short sludge-age waste activated sludge combined with anammox treatment of digestate liquor. AB - The need to reduce energy input and enhance energy recovery from wastewater is driving renewed interest in high-rate activated sludge treatment (i.e. short hydraulic and solids retention times (HRT and SRT, respectively)). This process generates short SRT activated sludge stream, which should be highly degradable. However, the evaluation of anaerobic digestion of short SRT sludge has been limited. This paper assesses anaerobic digestion of short SRT sludge digestion derived from meat processing wastewater under thermophilic and mesophilic conditions. The thermophilic digestion system (55 degrees C) achieved 60 and 68% volatile solids destruction at 8 day and 10 day HRT, respectively, compared with 50% in the mesophilic digestion system (35 degrees C, 10 day HRT). The digestion effluents from the thermophilic (8-10 day HRT) and mesophilic systems were stable, as assessed by residual methane potentials. The ammonia rich sludge dewatering liquor was effectively treated by a batch anammox process, which exhibited comparable nitrogen removal rate as the tests using a control synthetic ammonia solution, indicating that the dewatering liquor did not have inhibiting/toxic effects on the anammox activity. PMID- 26942527 TI - Potential of nitrous oxide recovery from an aerobic/oxic/anoxic SBR process. AB - A single sequencing batch reactor (SBR) with an operating mode of anaerobic/oxic/anoxic (A/O/A) was developed to determine a simpler process to recover nitrous oxide (N2O) from synthetic wastewater containing ammonia and glucose. This SBR system was initiated in A/O mode to implement nitritation (ammonia to nitrite) and then switched to A/O/A mode. Using measurements of the dissolved N2O concentration and release rate, the total production and conversion rate of N2O were calculated to reveal the potential of producing and recovering N2O in the extended anoxic phase. Results showed that the A/O/A SBR could convert the majority of the nitrite available in the system into N2O by heterotrophic denitritation over longer anoxic periods, and a conversion rate of 77% could be achieved. As a consequence, the A/O/A SBR presents potential ability to produce and recover N2O from wastewater containing ammonia and organic carbon. PMID- 26942528 TI - The kinetics for ammonium and nitrite oxidation under the effect of hydroxylamine. AB - The kinetics for ammonium (NH4(+)) oxidation and nitrite (NO2(-)) oxidation under the effect of hydroxylamine (NH2OH) were studied by respirometry using the nitrifying sludge from a laboratory-scale sequencing batch reactor. Modified models were used to estimate kinetics parameters of ammonia and nitrite oxidation under the effect of hydroxylamine. An inhibition effect of hydroxylamine on the ammonia oxidation was observed under different hydroxylamine concentration levels. The self-inhibition coefficient of hydroxylamine oxidation and noncompetitive inhibition coefficient of hydroxylamine for nitrite oxidation was estimated by simulating exogenous oxygen-uptake rate profiles, respectively. The inhibitive effect of NH2OH on nitrite-oxidizing bacteria was stronger than on ammonia-oxidizing bacteria. This work could provide fundamental data for the kinetic investigation of the nitrification process. PMID- 26942529 TI - Evaluating new processes and concepts for energy and resource recovery from municipal wastewater with life cycle assessment. AB - Energy and resource recovery from municipal wastewater is a pre-requisite for an efficient and sustainable water management in cities of the future. However, a sound evaluation of available processes and pathways is required to identify opportunities and short-comings of the different options and reveal synergies and potentials for optimization. For evaluating environmental impacts in a holistic view, the tool of life cycle assessment (LCA, ISO 14040/44) is suitable to characterize and quantify the direct and indirect effects of new processes and concepts. This paper gives an overview of four new processes and concepts for upgrading existing wastewater treatment plants towards energy positive and resource efficient wastewater treatment, based upon an evaluation of their environmental impacts with LCA using data from pilot and full-scale assessments of the considered processes. PMID- 26942530 TI - Treatment of hydraulic fracturing wastewater by wet air oxidation. AB - Wastewater produced by hydraulic fracturing for oil and gas production is characterized by high salinity and high chemical oxygen demand (COD). We applied a combination of flocculation and wet air oxidation technology to optimize the reduction of COD in the treatment of hydraulic fracturing wastewater. The experiments used different values of flocculant, coagulant, and oxidizing agent added to the wastewater, as well as different reaction times and treatment temperatures. The use of flocculants for the pretreatment of fracturing wastewater was shown to improve treatment efficiency. The addition of 500 mg/L of polyaluminum chloride (PAC) and 20 mg/L of anionic polyacrylamide (APAM) during pretreatment resulted in a COD removal ratio of 8.2% and reduced the suspended solid concentration of fracturing wastewater to 150 mg/L. For a solution of pretreated fracturing wastewater with 12 mL of added H2O2, the COD was reduced to 104 mg/L when reacted at 300 degrees C for 75 min, and reduced to 127 mg/L when reacted at the same temperature for 45 min while using a 1 L autoclave. An optimal combination of these parameters produced treated wastewater that met the GB 8978-1996 'Integrated Wastewater Discharge Standard' level I emission standard. PMID- 26942531 TI - Stabilized chitosan/Fe(0)-nanoparticle beads to remove heavy metals from polluted sediments. AB - Sediment contamination by heavy metals has become a widespread problem that can affect the normal behaviors of rivers and lakes. After chitosan/Fe(0) nanoparticles (CS-NZVI) beads were cross-linked with glutaraldehyde (GLA), their mechanical strength, stability and separation efficiency from the sediment were obviously improved. Moreover, the average aperture size of GLA-CS-NZVI beads was 20.6 MUm and NZVI particles were nearly spherical in shape with a mean diameter of 40.2 nm. In addition, the pH showed an insignificant effect on the removal rates from the sediment. Due to the dissolution of metals species into aqueous solutions as an introduction of the salt, the removal rates of all heavy metals from the sediment were increased with an increase of the salinity. The competitive adsorption of heavy metals between the sediment particles and GLA-CS NZVI beads became stronger as the sediment particles became smaller, leading to decreased removal rates. Therefore, the removal efficiency could be enhanced by optimizing experimental conditions and choosing appropriate materials for the target contaminants. PMID- 26942532 TI - Synthesis of graphene oxide-SiO2 coated mesh film and its properties on oil-water separation and antibacterial activity. AB - Oil-water separation has recently become a worldwide challenge due to the frequent occurrence of oil spill accidents and increasing industrial oily wastewater. In this work, the multifunctional mesh films with underwater oleophobicity and certain bacteriostatic effects are prepared by layer-by-layer assembly of graphene oxide-silica coatings on stainless steel mesh. The mesh film exhibits excellent environmental stability under a series of harsh conditions. The new, facile and reusable separation system is proposed to achieve deep treatment of oily wastewater, and the oil collection rate can reach over 99%. PMID- 26942533 TI - High strength distillery wastewater treatment by a PAC-MBR with low PAC dosage. AB - Augmentation of membrane bioreactors (MBRs) with activated carbon is established to offer several operational advantages. This work investigates the influence of low dosing (2 g/L) of powdered activated carbons (PACs) with different characteristics on the performance of MBR treating high strength molasses distillery wastewater containing difficult-to-biodegrade recalcitrant components. Two MBRs, augmented with different PACs, were operated in parallel over a period of 240 days and their performance monitored in terms of biomass growth, reduction in chemical oxygen demand (COD), sludge properties like extracellular polymeric substances content, filterability, and morphology. Removal of organics and coloring matter by adsorption, biodegradation and membrane filtration was estimated. Although adsorptive removal of color and COD is influenced by the properties of the PAC used, the performance of the PAC-MBRs was independent of PAC properties. Both PACs preferentially adsorbed the low molecular weight components in distillery wastewater. Retention by the membrane filter with the secondary cake layer contributed to reduction in color and COD of treated effluent. The findings indicate that low dosing with PAC adsorbing low molecular weight organics has a limited role in PAC-MBR treating distillery wastewater. PMID- 26942534 TI - Adsorption of Pb(2+) from aqueous solution using spinel ferrite prepared from steel pickling sludge. AB - In this paper, spinel ferrite with high crystallinity and high saturation magnetization was successfully prepared from steel pickling sludge by adding iron source and precipitator in the hydrothermal condition. The obtained spinel ferrite was characterized by X-ray diffraction (XRD), field emission scanning electron microscopy (FE-SEM), vibrating sample magnetometer (VSM), and Zeta potential methods and investigated as an adsorbent for removal of Pb(2+) from aqueous solution. Batch experiments were performed by varying the pH values, contact time, temperature and initial metal concentration. The result of pH impact showed that the adsorption of Pb(2+) was a pH dependent process, and the pH 5.8 +/- 0.2 was found to be the optimum condition. The achieved experimental data were analyzed with various kinetic and isotherm models. The kinetic studies revealed that Pb(2+) adsorption onto spinel ferrite followed a pseudo-second order model, and the Langmuir isotherm model provided the perfect fit to the equilibrium experimental data. At different temperatures, the maximum Pb(2+) adsorption capacities calculated from the Langmuir equation were in the range of 126.5-175.4 mg/g, which can be in competition with other adsorbents. The thermodynamic results showed that the spinel ferrite could spontaneously and endothermically adsorb Pb(2+) from aqueous solution. The regeneration studies showed that spinel ferrite could be used five times (removal efficiency (%) >90%) by desorption with HNO3 reagent. PMID- 26942535 TI - Removal of dyes from aqueous solutions using activated carbon prepared from rice husk residue. AB - The treatment of dye wastewater by activated carbon (AC) prepared from rice husk residue wastes was studied. Batch adsorption studies were conducted to investigate the effects of contact time, initial concentration (50-450 mg/L), pH (3-11) and temperature (30-70 degrees C) on the removal of methylene blue (MB), neutral red, and methyl orange. Kinetic investigation revealed that the adsorption of dyes followed pseudo-second-order kinetics. The results suggested that AC was effective to remove dyes, especially MB, from aqueous solutions. Desorption studies found that chemisorption by the adsorbent might be the major mode of dye removal. Fourier transform infrared results suggested that dye molecules were likely to combine with the O-H and P=OOH groups of AC. PMID- 26942536 TI - Performance of microbial electrolysis cells with bioanodes grown at different external resistances. AB - Bioelectrochemical systems need an anode with a high abundance of exoelectrogenic bacteria for an optimal performance. Among all possible operational parameters for an efficient enrichment, the role of external resistance in microbial fuel cell (MFC) has gained a lot of interest since it indirectly poises an anode potential, a key parameter for biofilm distribution and morphology. Thus, this work aims at investigating and discussing whether bioanodes selected at different external resistances under MFC operation present different responses under both MFC and microbial electrolysis cell (MEC) operation. A better MEC performance (i.e. shorter start-up time, higher current intensity and higher H2 production rate) was obtained with an anode from an MFC developed under low external resistance. Quantitative real-time polymerase chain reaction (qPCR) confirmed that a low external resistance provides an MFC anodic biofilm with the highest content of Geobacter because it allows higher current intensity, which is correlated to exoelectrogenic activity. High external resistances such as 1,000 Omega led to a slower start-up time under MEC operation. PMID- 26942537 TI - Olive mill effluent depuration by ozonation and Fenton processes enhanced by iron wastes. AB - The aim of the present work was to compare the potential of iron industry wastes to enhance ozone and hydrogen peroxide action on the degradation of olive mill wastewaters (OMWs). The results attained show a higher efficiency for ozonation using a lower catalyst load. Nevertheless, Fenton's process led to a larger amount of chemical oxidation demand (COD) removed per mole of oxidant applied. It was concluded that hydroxyl radicals are responsible for the pollutant abatement. High eco-toxicity decay was observed after the treatments. Furthermore, a preliminary analysis of the iron shavings' stability was made by reusing it in two feed-batch trials. It was concluded that while activity was maintained for Fenton's, a decrease of about 20% was verified for catalytic ozonation. Comparing these results with the ones obtained for the same processes applied to an actual OMW, a lower percentage of COD abatement was achieved. However, when reporting the amount of COD removed per mole of oxidant used, the difference between effluents are not so high. This should be taken into account when deciding which process should be implemented at an industrial scale. With the outcomes of this research it was possible to conclude that integrating waste management with wastewater treatment was feasible. PMID- 26942538 TI - Urban vulnerability and resiliency over water-related risks: a case study from Algiers. AB - The ad hoc management of natural environmental features and inappropriate social interventions could cause vulnerability of thriving urban ecosystems. For instance sub-aerial exposure, water-related hazards, urban intrinsic sensitivity, urban adaptation ability or flexibility and urban transformability factors could contribute a potential danger. In spite of seasonal climatic changes, the exposure indicates a significant geographical determinism whereas the other factors express its antithesis. The present paper aims to adapt a vulnerability resilience indicators' multicriteria analysis to show the variability and contribution rate with regard to local water-related risks. The municipality of al-Harrash from Algiers has been selected as a case study. The urban vulnerability-resilience closely tied up with a sum of relevant indicators confirmed by the diagnosis items, which are relevant to the local urban and hydro systems. The cumulative sums are obtained from a classification process referring to several criteria implied in the water-related risks. These were formulated here for the purpose of a multicriteria analysis with the objective of assessing the urban vulnerability-resilience index and subsequently orientating the preventive strategy towards different levels of sustainable measures. With this respect the exposure and sensitivity received a significant score while adaptation ability and transformability scored very low. PMID- 26942539 TI - Electrochemical removal of carbamazepine in water with Ti/PbO2 cylindrical mesh anode. AB - Carbamazepine (CBZ) is one of the most frequently detected organic compounds in the aquatic environment. Due to its bio-persistence and toxicity for humans and the environment its removal has become an important issue. The performance of the electrochemical oxidation process and in situ production of reactive oxygen species (ROS), such as O3 and H2O2, for CBZ removal have been studied using Ti/PbO2 cylindrical mesh anode in the presence of Na2SO4 as supporting electrolyte in a batch electrochemical reactor. In this integrated process, direct oxidation at anode and indirect oxidation by in situ electrogenerated ROS can occur simultaneously. The effect of several factors such as electrolysis time, current intensity, initial pH and oxygen flux was investigated by means of an experimental design methodology, using a 2(4) factorial matrix. CBZ removal of 83.93% was obtained and the most influential parameters turned out to be electrolysis time, current intensity and oxygen flux. Later, the optimal experimental values for CBZ degradation were obtained by means of a central composite design. The best operating conditions, analyzed by Design Expert((r)) software, are the following: 110 min of electrolysis at 3.0 A, pH = 7.05 and 2.8 L O2/min. Under these optimal conditions, the model prediction (82.44%) fits very well with the experimental response (83.90 +/- 0.8%). Furthermore, chemical oxygen demand decrease was quantified. Our results illustrated significant removal efficiency for the CBZ in optimized condition with second order kinetic reaction. PMID- 26942540 TI - Adsorption of reactive blue BF-5G dye by soybean hulls: kinetics, equilibrium and influencing factors. AB - The textile industry is known for the high use of chemicals, such as dyes, and large volumes of effluent that contaminate waters, a fact that has encouraged research and improved treatment techniques. In this study, we used unprocessed soybean hulls for the removal of reactive blue BF-5G dye. The point of zero charge of soybean hulls was 6.76. Regarding the speed of agitation in the adsorption process, the resistance to mass transfer that occurs in the boundary layer was eliminated at 100 rpm. Kinetics showed an experimental amount of dye adsorbed at equilibrium of 57.473 mg g(-1) obtained under the following conditions: dye initial concentration = 400 mg L(-1); diameter of particle = 0.725 mm; dosage = 6 g L(-1); pH 2; 100 rpm; temperature = 30 degrees C; and duration of 24 hours. The pseudo-second order best showed the dye removal kinetics. The adsorption isotherms performed at different temperatures (20, 30, 40 and 50 degrees C) showed little variation in the concentration range assessed, being properly adjusted by the Langmuir isotherm model. The maximum capacity of dye adsorption was 72.427 mg g(-1) at 30 degrees C. Since soybean hull is a low-cost industrial byproduct, it proved to be a potential adsorbent for the removal of the textile dye assessed. PMID- 26942541 TI - Detection of semi-volatile organic compounds (SVOCs) in surface water, soil, and groundwater in a chemical industrial park in Eastern China. AB - China is suffering from serious water and soil pollution, especially in the North China Plain. This work investigated semi-volatile organic compounds (SVOCs) in surface water, groundwater and soil within a chemical industrial park in Eastern China, for which the volatile organic compound (VOC) results have been previously reported. A total of 20 samples were collected from the field, and analyzed in the laboratory. A 100% detection frequency of SVOCs in samples from this chemical industrial park was observed (same as VOCs). Moreover, the detection frequency of 113 SVOCs in each sample reached 15.93, 12.39 and 20.35% for surface water, groundwater and soil, respectively. The most detected SVOCs in the park included N-containing SVOCs, polycyclic aromatic hydrocarbons, phthalates, organic pesticides and polychlorodiphenyls. The elevated detecting frequencies and concentration levels of SVOCs identified in the groundwater were attributed to the intensive chemical production activities in the park. In addition, the agricultural activities in the area might also have contributed to the SVOCs to the groundwater. The results of VOCs and SVOCs from this and previous studies suggest that the groundwater in this industrial park has been severely contaminated, and the contamination likely spreads beyond the park. Imminent hydrogeological assessments and remedial actions are warranted to eliminate the source and mitigate the potential plume expansion beyond the park boundary. PMID- 26942542 TI - Use of anaerobic hydrolysis pretreatment to enhance ultrasonic disintegration of excess sludge. AB - To improve the excess sludge disintegration efficiency, reduce the sludge disintegration cost, and increase sludge biodegradability, a combined pretreatment of anaerobic hydrolysis (AH) and ultrasonic treatment (UT) was proposed for excess sludge. Results showed that AH had an advantage in dissolving flocs, modifying sludge characteristics, and reducing the difficulty of sludge disintegration, whereas UT was advantageous in damaging cell walls, releasing intracellular substances, and decomposing macromolecular material. The combined AH-UT process was an efficient method for excess sludge pretreatment. The optimized solution involved AH for 3 days, followed by UT for 10 min. After treatment, chemical oxygen demand, protein, and peptidoglycan concentrations reached 3,949.5 mg O2/L, 752.5 mg/L and 619.1 mg/L, respectively. This work has great significance for further engineering applications, namely, reducing energy consumption, increasing the sludge disintegration rate, and improving the biochemical properties of sludge. PMID- 26942543 TI - Removal of sodium and chloride ions from aqueous solutions using fique fibers (Furcraea spp.). AB - Fique fibers obtained from the leaves of Furcraea spp., a highly abundant plant in the mountains of South America, may offer an alternative as biosorbents in desalination processes as they exhibit high removal capacities (13.26 meq/g for chloride ions and 15.52 meq/g for sodium ions) up to four times higher than exchange capacities commonly observed in synthetic resins. The ion removal capacity of the fibers was also found to be a function of the pH of the solution with the maximum removal of ions obtained at pH 8. Unlike most commercial ion exchange resins, our results suggest that fique fibers allow simultaneous removal of chloride and sodium ions. PMID- 26942544 TI - The assessment of the coke wastewater treatment efficacy in rotating biological contractor. AB - Coke wastewater is known to be relatively difficult for biological treatment. Nonetheless, biofilm-based systems seem to be promising tool for such treatment. That is why a rotating biological contactor (RBC) system focused on the Anammox process was used in this study. The experiment was divided into two parts with synthetic and then real wastewater. It was proven that it is possible to treat coke wastewater with RBC but such a procedure requires a very long start-up period for the nitritation (190 days), as well as for the Anammox process, where stable nitrogen removal over 70% was achieved after 400 days of experiment. Interestingly, it was possible at a relatively low (20.2 +/- 2.2 degrees C) temperature. The polymerase chain reaction-denaturing gradient gel electrophoresis (PCR-DGGE) based monitoring of the bacterial community showed that its biodiversity decreased when the real wastewater was treated and it was composed mainly of GC-rich genotypes, probably because of the modeling influence of this wastewater and the genotypes specialization. PMID- 26942545 TI - Kinetic studies of nitrate removal from aqueous solution using granular chitosan Fe(III) complex. AB - In the present study, a granular chitosan-Fe(III) complex was prepared as a feasible adsorbent for the removal of nitrate from an aqueous solution. There was no significant change in terms of nitrate removal efficiency over a wide pH range of 3-11. Nitrate adsorption on the chitosan-Fe(III) complex followed the Langmuir Freundlich isotherm model. In order to more accurately reflect adsorption and desorption behaviors at the solid/solution interface, kinetic model I and kinetic model II were proposed to simulate the interfacial process in a batch system. Nitrate adsorption on the chitosan-Fe(III) complex followed the pseudo-first order kinetic model and kinetic model I. The proposed half-time could provide useful information for optimizing process design. Adsorption and desorption rate constants obtained from kinetic model I and kinetic model II were beneficial to understanding the interfacial process and the extent of adsorption reaction. Kinetic model I and kinetic model II implied that nitrate uptake exponentially approaches a limiting value. PMID- 26942546 TI - Mitigation of marine biofouling on tubes of open rack vaporizers using electromagnetic fields. AB - This study quantitatively evaluates the antifouling action of the continuous physical treatment with electromagnetic fields (EMFs) of seawater used as heat exchanger fluid in an open rack vaporizer (ORV) pilot plant to reduce the growth of biofouling on external rib-tube surfaces. The results demonstrate that the biofilm adhered on the treated rib-tubes was reduced by 33% in thickness and by 44% in dissolved solids regarding the biofilm adhered on the untreated control rib-tubes. The lower conductivity and Ca(2+) and Mg(2+) ionic content in the effluent of the treated seawater confirmed that the EMFs accelerated the process of ionic calcium nucleation and precipitation as calcium carbonate. The precipitation of ions dissolved affected the inter-molecular interactions among extracellular polymers, thereby weakening the biofouling film matrix and reducing its adhesion capacity. The drag of small particles by the flow of seawater had an erosive action and decreased the biofouling film thickness. Consequently, the antifouling methods treatment with EMFs allowed reduce the negative effect that the biofouling have for the heat transfer equipment used in the regasification process and keep the highest techno-economic operating conditions. PMID- 26942547 TI - Erratum: Water Science and Technology 72 (12), 2122-2131: Efficient visible-light photocatalytic degradation of sulfadiazine sodium with hierarchical Bi7O9I3 under solar irradiation, MengMeng Xu, YaLei Zhao and QiShe Yan, doi: 10.2166/wst.2015.433. PMID- 26942548 TI - Clinician vs Self-ratings of Hirsutism in Patients With Polycystic Ovarian Syndrome: Associations With Quality of Life and Depression. AB - IMPORTANCE: Qualitative evidence suggests that hirsutism inflicts significant negative impacts on quality of life and may be associated with depression. Quantitative research is essential to determine best practices in caring for hirsute patients. OBJECTIVE: To quantify quality-of-life impact of hirsutism and evaluate how the degree of hirsutism (as assessed by patients and clinicians) is associated with quality of life and depressive symptoms. DESIGN, SETTING, PARTICIPANTS: This study included 229 patients aged 14 to 52 years consecutively recruited from a polycystic ovarian syndrome (PCOS) clinic between May 18, 2006, and October 25, 2012, who met the Rotterdam PCOS criteria. Data analysis was completed July 2015, and alterations were completed in response to reviewer comments in January 2016. MAIN OUTCOMES AND MEASURES: Clinicians and patients rated degree of hirsutism using the modified Ferriman-Gallwey (mFG) instrument, a visual scoring method assessing androgen-dependent hair growth in 9 body areas. Hirsutism-related quality of life was assessed using the Skindex-16, a validated quality of life instrument for skin disorders. Depressive symptoms were assessed using the Beck Depression Inventory-Fast screen. RESULTS: Overall, 229 patients aged 14 to 52 years who met the Rotterdam criteria for polycystic ovarian syndrome rated themselves and were rated by clinicians for hirsutism. Total mean self-rated mFG score for patients was 13.3 out of a total 36 possible points; total mean clinician-rated mFG score for patients was 8.63 (P < .001); self ratings for hirsutism were higher for all body areas except thigh. Hirsutism had a significant negative effect on quality of life; the mean (SD) Skindex-16 score for the emotion domain was 73.9 (29.8) and 44.3 (33.7) for the function domain. Higher degrees of hirsutism (determined by both patients and clinicians) were moderately associated with more negative quality-of-life impact; however, self ratings (r = 0.19-0.46) were more strongly associated than clinician ratings (r = 0.14-0.32)(P < .05 for all). Only self-ratings of hirsutism were significantly associated with risk of depression (r = 0.14; P < .05). CONCLUSIONS AND RELEVANCE: There is notable discordance in the perception of hirsutism between patients and clinicians; patients view their hirsutism as more severe than clinicians do. Quality-of-life impacts of hirsutism are consistent with that reported for other serious skin conditions. This negative impact is only partially associated with the degree of hirsutism, with self-ratings being more highly associated with quality of life impact than clinician ratings. These results support guidelines recommending that treatment be guided largely by patient distress with hair growth and subjective perceptions as opposed to clinician judgment of degree. Patient self-rating is critical information for patient-centered care for hirsute patients. PMID- 26942549 TI - Pharmacological, toxicological and neuronal localization assessment of galantamine/chitosan complex nanoparticles in rats: future potential contribution in Alzheimer's disease management. AB - PURPOSE: Nasal galantamine hydrobromide (GH)/chitosan complex nanoparticles (CX NP2) could have an improved therapeutic potential for managing Alzheimer's disease (AD). The current study aimed to investigate if the complexation reaction between GH and chitosan altered the pharmacological and toxicological profiles of the parent drug; GH. METHODS: The nasal administration of CX-NP2 to male Wistar rats for 12 consecutive days was compared to negative control group, and oral and nasal GH solutions treated groups in 3 mg/kg daily GH dose. Brain acetylcholinesterase (AChE) protein level and activity were assessed. The in vivo toxicity of CX-NP2 was evaluated via monitoring the clinical signs throughout the study. Histopathological examination of brain sections was performed. The intracellular localization of CX-NP2 within brain neurons was investigated using transmission electron microscopy. RESULTS: GH/chitosan complexation did not negatively alter the pharmacological efficiency of GH. Intriguingly, nasal CX-NP2 exhibited a significant decrease of AChE protein level and activity in rat brains compared to the oral and nasal GH solutions. No toxicity signs or histopathological manifestations were noticed. The nanoparticles were found intracellularly in the brain neurons. CONCLUSION: The pharmacological efficacy and in vivo safety of nasal CX-NP2 confirm their promising potential to contribute to the management of AD intranasally. PMID- 26942550 TI - "I Feel Like More of a Man": A Mixed Methods Study of Masculinity, Sexual Performance, and Circumcision for HIV Prevention. AB - Ethnographic studies from numerous societies have documented the central role of male circumcision in conferring masculinity and preparing boys for adult male sexuality. Despite this link between masculinity, sexuality, and circumcision, there has been little research on these dynamics among men who have been circumcised for HIV prevention. We employed a mixed methods approach with data collected from recently circumcised men in the Dominican Republic (DR) to explore this link. We analyzed survey data collected six to 12 months post-circumcision (N = 293) as well as in-depth interviews conducted with a subsample of those men (n = 30). We found that 42% of men felt more masculine post-circumcision. In multivariate analysis, feeling more masculine was associated with greater concern about being perceived as masculine (OR = 1.70, 95% CI: 1.25-2.32), feeling more potent erections post-circumcision (OR = 2.25, 95% CI: 1.26-4.03), and reporting increased ability to satisfy their partners post-circumcision (OR = 2.30, 95% CI: 1.11-4.77). In qualitative interviews, these factors were all related to masculine norms of sexually satisfying one's partner, and men's experiences of circumcision were shaped by social norms of masculinity. This study highlights that circumcision is not simply a biomedical intervention and that circumcision programs need to incorporate considerations of masculine norms and male sexuality into their programming. PMID- 26942552 TI - High-Temperature Continuous-Flow Zincations of Functionalized Arenes and Heteroarenes Using (Cy2N)2Zn.2LiCl. AB - The treatment of sensitive arenes and heteroarenes with the zinc bis-amide (Cy2N)2Zn.2LiCl (0.55 equiv), prepared in quantitative yield by the reaction of Cy2NLi with ZnCl2, leads under flow conditions to a fast zincation within 10 min at temperatures between 25 and 100 degrees C. The resulting organozinc reagents can be trapped with various organic halides (allylic bromides, aryl iodides) in high yields. Moreover, complementary metalation regioselectivities can be obtained for several substituted pyridines compared to commonly used LiCl activated TMP-zinc (TMP = 2,2,6,6-tetramethylpiperidyl) and -magnesium bases. PMID- 26942553 TI - MiRNA 34a: a therapeutic target for castration-resistant prostate cancer. AB - INTRODUCTION: Development of a therapy for bone metastases is of paramount importance for castration-resistant prostate cancer (CRPC). The osteomimetic properties of CRPC confer a propensity to metastasize to osseous sites. Micro ribonucleic acid (miRNA) is non-coding RNA that acts as a post-transcriptional regulator of multiple proteins and associated pathways. Therefore identification of miRNAs could reveal a valid third generation therapy for CRPC. AREAS COVERED: miR34a has been found to play an integral role in the progression of prostate cancer, particularly in the regulation of metastatic genes involved in migration, intravasation, extravasation, bone attachment and bone homeostasis. The correlation between miR34a down-regulation and metastatic progression has generated substantial interest in this field. EXPERT OPINION: Examination of the evidence reveals that miR34a is an ideal target for gene therapy for metastatic CRPC. We also conclude that future studies should focus on the effects of miR34a upregulation in CRPC with respect to migration, translocation to bone micro environment and osteomimetic phenotype development. The success of miR34a as a therapeutic is reliant on the development of appropriate delivery systems and targeting to the bone micro-environment. In tandem with any therapeutic studies, biomarker serum levels should also be ascertained as an indicator of successful miR34a delivery. PMID- 26942551 TI - Ru-Catalyzed C-H Arylation of Fluoroarenes with Aryl Halides. AB - Although the ruthenium-catalyzed C-H arylation of arenes bearing directing groups with haloarenes is well-known, this process has never been achieved in the absence of directing groups. We report the first example of such a process and show that unexpectedly the reaction only takes place in the presence of catalytic amounts of a benzoic acid. Furthermore, contrary to other transition metals, the arylation site selectivity is governed by both electronic and steric factors. Stoichiometric and NMR mechanistic studies support a catalytic cycle that involves a well-defined eta(6)-arene-ligand-free Ru(II) catalyst. Indeed, upon initial pivalate-assisted C-H activation, the aryl-Ru(II) intermediate generated is able to react with an aryl bromide coupling partner only in the presence of a benzoate additive. In contrast, directing-group-containing substrates (such as 2 phenylpyridine) do not require a benzoate additive. Deuterium labeling and kinetic isotope effect experiments indicate that C-H activation is both reversible and kinetically significant. Computational studies support a concerted metalation-deprotonation (CMD)-type ruthenation mode and shed light on the unusual arylation regioselectivity. PMID- 26942554 TI - Ultrasmooth Polydopamine Modified Surfaces for Block Copolymer Nanopatterning on Flexible Substrates. AB - Nature has engineered universal, catechol-containing adhesives which can be synthetically mimicked in the form of polydopamine (PDA). In this study, PDA was exploited to enable the formation of block copolymer (BCP) nanopatterns on a variety of soft material surfaces. While conventional PDA coating times (1 h) produce a layer too rough for most applications of BCP nanopatterning, we found that these substrates could be polished by bath sonication in a weakly basic solution to form a conformal, smooth (root-mean-square roughness ~0.4 nm), and thin (3 nm) layer free of large prominent granules. This chemically functionalized, biomimetic layer served as a reactive platform for subsequently grafting a surface neutral layer of poly(styrene-random-methyl methacrylate random-glycidyl methacrylate) to perpendicularly orient lamellae-forming poly(styrene-block-methyl methacrylate) BCP. Moreover, scanning electron microscopy observations confirmed that a BCP nanopattern on a poly(ethylene terephthalate) substrate was not affected by bending with a radius of ~0.5 cm. This procedure enables nondestructive, plasma-free surface modification of chemically inert, low-surface energy soft materials, thus overcoming many current chemical and physical limitations that may impede high-throughput, roll-to-roll nanomanufacturing. PMID- 26942555 TI - Design and Synthesis of New Transient Receptor Potential Vanilloid Type-1 (TRPV1) Channel Modulators: Identification, Molecular Modeling Analysis, and Pharmacological Characterization of the N-(4-Hydroxy-3-methoxybenzyl)-4-(thiophen 2-yl)butanamide, a Small Molecule Endowed with Agonist TRPV1 Activity and Protective Effects against Oxidative Stress. AB - 4-(Thiophen-2-yl)butanoic acid was identified as a cyclic substitute of the unsaturated alkyl chain of the natural ligand, capsaicin. Accordingly, a new class of amides was synthesized in good yield and high purity and their molecular recognition against the target was investigated by means of docking experiments followed by molecular dynamics simulations, in order to rationalize their geometrical and thermodynamic profiles. The pharmacological properties of these new compounds were expressed as activation (EC50) and desensitization (IC50) potencies. Several compounds were found to activate TRPV1 channels, and in particular, derivatives 1 and 10 behaved as TRPV1 agonists endowed with good efficacy as compared to capsaicin. The most promising compound 1 was also evaluated for its protective role against oxidative stress on keratinocytes and differentiated human neuroblastoma cell lines expressing the TRPV1 receptor as well as for its cytotoxicity and analgesic activity in vivo. PMID- 26942556 TI - Synthesis of 5'-NAD-Capped RNA. AB - In prokaryotic organisms, certain regulatory RNAs have recently been found to be linked to the ubiquitous redox cofactor nicotinamide adenine dinucleotide (NAD) at their 5'-ends. Biochemical and structural investigations of this new caplike RNA modification require synthetic access to pure NAD-RNA. Here we report a chemoenzymatic approach to generate 5'-NAD-capped RNA in high yields and purity under mild conditions. This approach uses unprotected 5'-monophosphate RNA synthesized either chemically or enzymatically, 5',5'-pyrophosphate bond formation by phosphorimidazolide chemistry, and an enzymatic cleanup step. Thus, 5'-NAD-modified RNA can be synthesized independent of length, structure, and nucleotide sequence. PMID- 26942557 TI - Penetrating Peptide-Bioconjugated Persistent Nanophosphors for Long-Term Tracking of Adipose-Derived Stem Cells with Superior Signal-to-Noise Ratio. AB - Reliable long-term in vivo tracking of stem cells is of great importance in stem cell-based therapy and research. Fluorescence imaging with in situ excitation has significant autofluorescence background, which results in poor signal-to-noise ratio (SNR). Here we report TAT penetrating peptide-bioconjugated long persistent luminescence nanoparticles (LPLNP-TAT) for long-term tracking of adipose-derived stem cells (ASC) without constant external excitation. LPLNP-TAT exhibits near infrared emitting, red light renewable capability, and superior in vivo imaging depth and SNR compared with conventional organic dye and quantum dots. Our findings show that LPLNP-TAT can successfully label ASC without impairing their proliferation and differentiation and can effectively track ASC in skin regeneration and tumor-homing models. We believe that LPLNP-TAT represents a new generation of cell tracking probes and will have broad application in diagnosis and therapy. PMID- 26942558 TI - Gold as a 6p-Element in Dense Lithium Aurides. AB - The negative oxidation state of gold (Au) has drawn a great attention due to its unusual valence state that induces exotic properties in its compounds, including ferroelectricity and electronic polarization. Although monatomic anionic gold (Au(-)) has been reported, a higher negative oxidation state of Au has not been observed yet. Here we propose that high pressure becomes a controllable method for preparing high negative oxidation state of Au through its reaction with lithium. First-principles calculations in combination with swarm structural searches disclosed chemical reactions between Au and Li at high pressure, where stable Li-rich aurides with unexpected stoichiometries (e.g., Li4Au and Li5Au) emerge. These compounds exhibit intriguing structural features like Au-centered polyhedrons and a graphene-like Li sublattice, where each Au gains more than one electron donated by Li and acts as a 6p-element. The high negative oxidation state of Au has also been achieved through its reactions with other alkali metals (e.g., Cs) under pressures. Our work provides a useful strategy for achieving diverse Au anions. PMID- 26942560 TI - Metal-Metal Bonding in Uranium-Group 10 Complexes. AB - Heterobimetallic complexes containing short uranium-group 10 metal bonds have been prepared from monometallic IU(IV)(OAr(P)-kappa(2)O,P)3 (2) {[Ar(P)O](-) = 2 tert-butyl-4-methyl-6-(diphenylphosphino)phenolate}. The U-M bond in IU(IV)(MU OAr(P)-1kappa(1)O,2kappa(1)P)3M(0), M = Ni (3-Ni), Pd (3-Pd), and Pt (3-Pt), has been investigated by experimental and DFT computational methods. Comparisons of 3 Ni with two further U-Ni complexes XU(IV)(MU-OAr(P)-1kappa(1)O,2kappa(1)P)3Ni(0), X = Me3SiO (4) and F (5), was also possible via iodide substitution. All complexes were characterized by variable-temperature NMR spectroscopy, electrochemistry, and single crystal X-ray diffraction. The U-M bonds are significantly shorter than any other crystallographically characterized d-f-block bimetallic, even though the ligand flexes to allow a variable U-M separation. Excellent agreement is found between the experimental and computed structures for 3-Ni and 3-Pd. Natural population analysis and natural localized molecular orbital (NLMO) compositions indicate that U employs both 5f and 6d orbitals in covalent bonding to a significant extent. Quantum theory of atoms-in-molecules analysis reveals U-M bond critical point properties typical of metallic bonding and a larger delocalization index (bond order) for the less polar U-Ni bond than U-Pd. Electrochemical studies agree with the computational analyses and the X-ray structural data for the U-X adducts 3-Ni, 4, and 5. The data show a trend in uranium-metal bond strength that decreases from 3-Ni down to 3-Pt and suggest that exchanging the iodide for a fluoride strengthens the metal-metal bond. Despite short U-TM (transition metal) distances, four other computational approaches also suggest low U-TM bond orders, reflecting highly transition metal localized valence NLMOs. These are more so for 3-Pd than 3-Ni, consistent with slightly larger U-TM bond orders in the latter. Computational studies of the model systems (PH3)3MU(OH)3I (M = Ni, Pd) reveal longer and weaker unsupported U TM bonds vs 3. PMID- 26942559 TI - Ultrafast Dynamics of Hole Injection and Recombination in Organometal Halide Perovskite Using Nickel Oxide as p-Type Contact Electrode. AB - There is a mounting effort to use nickel oxide (NiO) as p-type selective electrode for organometal halide perovskite-based solar cells. Recently, an overall power conversion efficiency using this hole acceptor has reached 18%. However, ultrafast spectroscopic investigations on the mechanism of charge injection as well as recombination dynamics have yet to be studied and understood. Using time-resolved terahertz spectroscopy, we show that hole transfer is complete on the subpicosecond time scale, driven by the favorable band alignment between the valence bands of perovskite and NiO nanoparticles (NiO(np)). Recombination time between holes injected into NiO(np) and mobile electrons in the perovskite material is shown to be hundreds of picoseconds to a few nanoseconds. Because of the low conductivity of NiO(np), holes are pinned at the interface, and it is electrons that determine the recombination rate. This recombination competes with charge collection and therefore must be minimized. Doping NiO to promote higher mobility of holes is desirable in order to prevent back recombination. PMID- 26942561 TI - In vitro biocompatibility of nickel-titanium esthetic orthodontic archwires. AB - OBJECTIVE: To investigate the cytotoxicity of nickel-titanium (NiTi) esthetic orthodontic archwires with different surface coatings. MATERIALS AND METHODS: Three fully coated, tooth-colored NiTi wires (BioCosmetic, Titanol Cosmetic, EverWhite), two ion-implanted wires (TMA Purple, Sentalloy High Aesthetic), five uncoated NiTi wires (BioStarter, BioTorque, Titanol Superelastic, Memory Wire Superelastic, and Sentalloy), one beta-titanium wire (TMA), and one stainless steel wire (Stainless Steel) were considered for this study. The wire samples were placed at 37 degrees C in airtight test tubes containing Dulbecco's Modified Eagle's Medium (0.1 mg/mL) for 1, 7, 14, and 30 days. The cell viability of human gingival fibroblasts (HGFs) cultured with this medium was assessed by the 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Data were analyzed by a two-way analysis of variance (alpha = .05). RESULTS: The highest cytotoxic effect was reached on day 30 for all samples. The archwires exhibited a cytotoxicity on HGFs ranging from "none" to "slight," with the exception of the BioTorque, which resulted in moderate cytotoxicity on day 30. Significant differences were found between esthetic archwires and their uncoated pairs only for BioCosmetic (P = .001) and EverWhite (P < .001). CONCLUSIONS: Under the experimental conditions, all of the NiTi esthetic archwires resulted in slight cytotoxicity, as did the respective uncoated wires. For this reason their clinical use may be considered to have similar risks to the uncoated archwires. PMID- 26942562 TI - Optically Transparent Wood from a Nanoporous Cellulosic Template: Combining Functional and Structural Performance. AB - Optically transparent wood (TW) with transmittance as high as 85% and haze of 71% was obtained using a delignified nanoporous wood template. The template was prepared by removing the light-absorbing lignin component, creating nanoporosity in the wood cell wall. Transparent wood was prepared by successful impregnation of lumen and the nanoscale cellulose fiber network in the cell wall with refractive-index-matched prepolymerized methyl methacrylate (MMA). During the process, the hierarchical wood structure was preserved. Optical properties of TW are tunable by changing the cellulose volume fraction. The synergy between wood and PMMA was observed for mechanical properties. Lightweight and strong transparent wood is a potential candidate for lightweight low-cost, light transmitting buildings and transparent solar cell windows. PMID- 26942563 TI - Down-regulation of osteoprotegerin expression as a novel biomarker for colorectal carcinoma. AB - A better understanding of tumor biology is important in the identification of molecules that are down-regulated in malignancy and in determining their role in tumor suppression. The aim of this study was to analyze osteoprotegerin (OPG) expression in colorectal carcinoma (CRC) and to investigate the underlying mechanism for changes in the expression of OPG. OPG expression was assessed in CRC tissue samples and cell lines. The methylation status of the OPG promoter region was determined, and the effects of demethylation on OPG expression were analyzed. The effects of recombinant OPG (rOPG) administration on cellular functions were also investigated. Clinical and prognostic implications of OPG protein expression in CRC patients were analyzed. The CRC tissues and cells showed significantly lower OPG expression. Pyrosequencing of OPG-silenced CRC cells revealed that the OPG gene promoter was highly methylated. Treatment with demethylating agent significantly elevated OPG mRNA and protein expression. rOPG significantly decreased cell viability and MMP-2 and VEGF-A production in CRC cells. Reduced OPG immunoreactivity was associated with aggressive oncogenic behavior in CRC. Also, OPG expression was found to be an independent predictor of recurrent hepatic metastasis and independent prognostic factor for worse survival rates. We demonstrated that OPG silencing in CRC occurs through epigenetic repression, and is involved in the development and progression of CRC. Our data suggest that OPG is a novel prognostic biomarker and a new therapeutic target for the treatment of patients with CRC. PMID- 26942564 TI - Overexpression of RPS27a contributes to enhanced chemoresistance of CML cells to imatinib by the transactivated STAT3. AB - STAT3 plays a pivotal role in the hematopoietic system, which constitutively activated by BCR-ABL via JAK and Erk/MAP-kinase pathways. Phospho-STAT3 was overexpressed in imatinib-resistant CML patients as relative to imatinib responsive ones. By activation of the STAT3 pathway, BCR-ABL can promote cell cycling, and inhibit differentiation and apoptosis. Ribosomal protein S27a (RPS27a) performs extra-ribosomal functions besides imparting a role in ribosome biogenesis and post-translational modifications of proteins. RPS27a can promote proliferation, regulate cell cycle progression and inhibit apoptosis of leukemia cells. However, the relationship between STAT3 and RPS27a has not been reported. In this study, we detected a significantly increased expression of STAT3 and RPS27a in bone marrow samples from CML-AP/BP patients compared with those from CML-CP. In addition, we also demonstrated that it was a positive correlation between the level of STAT3 and that of RPS27a. Imatinib-resistant K562/G01 cells expressed significantly higher levels of STAT3 and RPS27a compared with those of K562 cells. RPS27a could be transactivated by p-STAT3 through the specific p STAT3-binding site located nt -633 to -625 and -486 to -478 of the RPS27a gene promoter in a dose-dependent manner. The transactivated RPS27a could decrease the percentage of apoptotic CML cells induced by imatinib. And the effect of STAT3 overexpression could be counteracted by the p-STAT3 inhibitor WP1066 or RPS27a knockdown. These results suggest that drugs targeting STAT3/p-STAT3/RPS27a combining with TKI might represent a novel therapy strategy in patients with TKI resistant CML. PMID- 26942565 TI - Tumor-selective mitochondrial network collapse induced by atmospheric gas plasma activated medium. AB - Non-thermal atmospheric gas plasma (AGP) exhibits cytotoxicity against malignant cells with minimal cytotoxicity toward normal cells. However, the mechanisms of its tumor-selective cytotoxicity remain unclear. Here we report that AGP activated medium increases caspase-independent cell death and mitochondrial network collapse in a panel of human cancer cells, but not in non-transformed cells. AGP irradiation stimulated reactive oxygen species (ROS) generation in AGP activated medium, and in turn the resulting stable ROS, most likely hydrogen peroxide (H2O2), activated intracellular ROS generation and mitochondrial ROS (mROS) accumulation. Culture in AGP-activated medium resulted in cell death and excessive mitochondrial fragmentation and clustering, and these responses were inhibited by ROS scavengers. AGP-activated medium also increased dynamin-related protein 1-dependent mitochondrial fission in a tumor-specific manner, and H2O2 administration showed similar effects. Moreover, the vulnerability of tumor cells to mitochondrial network collapse appeared to result from their higher sensitivity to mROS accumulation induced by AGP-activated medium or H2O2. The present findings expand our previous observations on death receptor-mediated tumor-selective cell killing and reinforce the importance of mitochondrial network remodeling as a powerful target for tumor-selective cancer treatment. PMID- 26942566 TI - High-throughput drug library screening identifies colchicine as a thyroid cancer inhibitor. AB - We employed a high-throughput drug library screening platform to identify novel agents affecting thyroid cancer cells. We used human thyroid cancer cell lines to screen a collection of approximately 5200 small molecules with biological and/or pharmacologial properties. Parallel primary screens yielded a number of hits differentially active between thyroid and melanoma cells. Amongst compounds specifically targeting thyroid cancer cells, colchicine emerged as an effective candidate. Colchicine inhibited cell growth which correlated with G2 cell cycle arrest and apoptosis. These effects were hampered through inhibition of MEK1/2 and JNK. In contrast, inhibition of p38-MAPK had little effect, and AKT had no impact on colchicine action. Systemic colchicine inhibited thyroid cancer progression in xenografted mice. These findings demonstrate that our screening platform is an effective vehicle for drug reposition and show that colchicine warrants further attention in well-defined clinical niches such as thyroid cancer. PMID- 26942568 TI - Langerhans cell histiocytosis in adults: a case report and review of the literature. AB - BACKGROUND: Langerhans cell histiocytosis (LCH) is a proliferative disease of histiocyte-like cells that generally affects children. Immunohistochemistry is essential to obtain the correct diagnosis, and treatment protocols are controversial. OBJECTIVE: Langerhans cell histiocytosis (LCH) is easy to be misdiagnosed because of its various clinic features and laboratory results. This research focused on the clinicopathological, histopathological, immunohistochemical and other features of LCH and aimed to analyze LCH clinical features for improving diagnosis and decreasing misdiagnosis rate. CASE REPORT: A case of rare adult LCH was reported and the clinicopathological features were summarized by literature review. The multifocal form of this case includes diabetes insipidus, exophthalmos and mucocutaneous lesions in axillae and anogenital regions, such as infiltrated nodules, extensive coalescing, scaling, crusted papules and ulcerated plaques. The Langerhans cells diffusely infiltrated in the dermis and the tumor cells were positive for CD1a and S-100 expression. The diagnosis was Langerhans cell histiocytosis based on the pathological and immunohistochemical changes. CONCLUSION: LCH has high rate of misdiagnosis and definitive diagnosis depends on pathological biopsy and X-ray examination. The prognosis is related to the onset age and the quantity of affected organs. Although specific therapeutic approach hasn't been well established, combined chemotherapy for multisystem lesions and surgical operation or radiotherapy for unifocal lesions may improve the therapy. PMID- 26942567 TI - Expression profile and prognostic value of NNMT in patients with pancreatic cancer. AB - The elevation of Nicotinamide N-methyltransferase (NNMT) has been reported in pancreatic cancer tissues and cell lines, but its clinical and prognostic implications remain controversial. This study aimed at investigating the expression of NNMT in pancreatic benign and malignant tissues and the prognostic value of NNMT in pancreatic cancer. The expression of NNMT in tissue specimens of 28 chronic pancreatitis patients and 178 pancreatic cancer patients were assayed with immunohistochemistry on tissue microarray. The NNMT expression levels of pancreatic patients were correlated with their clinicopathological characteristics. The influences of NNMT expression and patients' clinicopathological characteristics on overall survival (OS) were analyzed. The percentage of NNMT high expression (NNMTh) in pancreatic cancer (55.6%) was significantly higher than those in chronic pancreatitis (21.4%) and paracancerous tissues (14.8%) (p < 0.001). NNMTh tends to significantly correlate with unfavorable clinicopathological features such as age > 60 years old (p = 0.014), tumor diameter > 4 cm (p < 0.001), TNM stage III or IV (p < 0.001) and poor tumor differentiation (p = 0.004). The median OS of patients with NNMTh and NNMTl were 7.0 months (95% CI: 5.275-8.725) and 11.5 months (95% CI: 9.759-13.241) respectively (p = 0.005). On multivariate analysis, NNMTl (hazards ratio [HR]: 0.399; 95% CI: 0.284-0.560; p < 0.001), absence of neurological involvement (HR: 0.651; 95% CI: 0.421-0.947; p = 0.041), TNM stage I or II (HR: 0.506; 95% CI: 0.299-0.719; p = 0.015) and well tumor differentiation (HR: 0.592; 95% CI: 0.319 0.894; p = 0.044) were significant favorable prognostic factors of OS. In conclusion, NNMT is upregulated in pancreatic cancer, correlates with unfavorable clinicopathological features and may serve as an independent prognosticator of patients' survival. PMID- 26942569 TI - The impact of a breast cancer diagnosis on health-related quality of life. A prospective comparison among middle-aged to elderly women with and without breast cancer. AB - Background The improved survival after breast cancer has prompted knowledge on the effect of a breast cancer diagnosis on health-related quality of life (HQoL). This study compared changes in HQoL among women from before to after breast cancer diagnosis with longitudinal changes among women who remained breast cancer free. Material and methods The Danish Diet, Cancer and Health study included 57 053 cancer-free persons aged 50-64 years at baseline (1993-1997). We used data from first follow-up (1999-2002) and second follow-up (2010-2012) on HQoL [Medical Outcomes Survey, short form (SF-36)] obtained from 542 women aged 64-82 years with primary breast cancer (stages I-III) and a randomly matched sample of 729 women who remained breast cancer-free. Linear regression models were used to estimate the differences in changes in HQoL between women with and without breast cancer; the analyses were repeated with stratification according to age, comorbidity, partner support and time since diagnosis. Results Women with breast cancer reported significantly larger decreases in HQoL from before to after diagnosis than those who remained breast cancer-free (physical component summary, -2.0; 95% CI -2.8; -1.2, mental component summary, -1.5, 95% CI -2.3; -0.6). This association was significantly modified by comorbidity and time since diagnosis. Conclusions Women with breast cancer reported significantly larger HQoL declines than breast cancer-free women. Breast cancer diagnosis seems to have the greatest impact on HQoL closest to diagnosis and in women with comorbidity indicating that this group should be offered timely and appropriate follow-up care to prevent HQoL declines. PMID- 26942570 TI - Probing the interaction mechanism of small molecule inhibitors with matriptase based on molecular dynamics simulation and free energy calculations. AB - Matriptase is a serine protease associated with a wide variety of human tumors and carcinoma progression. Up to now, many promising anti-cancer drugs have been developed. However, the detailed structure-function relationship between inhibitors and matriptase remains elusive. In this work, molecular dynamics simulation and binding free energy studies were performed to investigate the biochemistry behaviors of two class inhibitors binding to matriptase. The binding free energies predicted by MM/GBSA methods are in good agreement with the experimental bioactivities, and the analysis of the individual energy terms suggests that the van der Waals interaction is the major driving force for ligand binding. The key residues responsible for achieving strong binding have been identified by the MM/GBSA free energy decomposition analysis. Especially, Trp215 and Phe99 had an important impact on active site architecture and ligand binding. The results clearly identify the two class inhibitors exist different binding modes. Through summarizing the two different modes, we have mastered some important and favorable interaction patterns between matriptase and inhibitors. Our findings would be helpful for understanding the interaction mechanism between the inhibitor and matriptase and afford important guidance for the rational design of potent matriptase inhibitors. PMID- 26942571 TI - News from the Biological Stain Commission, No. 17. AB - In the 17(th) issue of News from the Biological Stain Commission (BSC) under the heading of Regulatory affairs, the Biological Stain Commission's International Affairs Committee presents information from the 20(th) meeting of ISO/TC 212 Clinical laboratory testing and in vitro diagnostic test systems held on October 15 - 17, 2014 in Toronto, Canada, and from the 29(th) meeting of CEN/TC 140 In vitro diagnostic medical devices held on February 3, 2015 in Berlin, Germany. PMID- 26942573 TI - Validation of the Modification of the Prolonged Papanicolaou Stain for the Diagnosis of Cervical Cancer. AB - OBJECTIVES: To validate the modification of the prolonged Papanicolaou stain based on the quality control of time, units and staining stages (micro- and macroscopic), and on the stain reactivation based on the control. STUDY DESIGN: A prospective study was performed on 125,358 cervical smears in Lima (Peru). The microscopic quality control included evaluating the cytological characteristics through the staining quality index (SQI) and the quality criteria for samples described by the Bethesda System (TBS). The macroscopic quality control is based on the interslide staining as a set corresponding to a poststaining vertical angle. The stains were reactivated with the addition of 0.15 and 2 g of phosphotungstic acid for Orange G and EA-50, respectively. RESULTS: Both the nonneoplastic and the neoplastic findings comply with the quality criteria of the TBS (SQI value = 0.94). The yield per battery of staining fluctuated between 5,616 and 17,954 Pap smears, and the reactivation of stains produced a stain yield of up to four times the initial amount of the smears, saving USD 5,598.88 from 2013 to 2014. CONCLUSION: The modification of prolonged Papanicolaou staining is an excellent alternative, with a cost-benefit ratio that generates savings and a higher yield per battery of staining. PMID- 26942572 TI - Estimates and determinants of HPV non-vaccination and vaccine refusal in girls 12 to 14 y of age in Canada: Results from the Childhood National Immunization Coverage Survey, 2013. AB - Since the introduction of HPV vaccination programs in Canada in 2007, coverage has been below public health goals in many provinces and territories. This analysis investigated the determinants of HPV non-vaccination and vaccine refusal. Data from the Childhood National Immunization Coverage Survey (CNICS) 2013 were used to estimate the prevalence of HPV non-vaccination and parental vaccine refusal in girls aged 12-14 years, for Canada and the provinces and territories. Multivariate logistic regression was used to examine factors associated with non-vaccination and vaccine refusal, after adjusting for potential confounders. An estimated 27.7% of 12-14 y old girls had not been vaccinated against HPV, and 14.4% of parents reported refusing the vaccine. The magnitude of non-vaccination and vaccine refusal varied by province or territory and also by responding parent's country of birth. In addition, higher education was associated with a higher risk of refusal of the HPV vaccine. Rates of HPV non vaccination and of refusal of the HPV vaccine differ and are influenced by different variables. These findings warrant further investigation. PMID- 26942575 TI - Eastern Caribbean Circulation and Island Mass Effect on St. Croix, US Virgin Islands: A Mechanism for Relatively Consistent Recruitment Patterns. AB - The northeastern Caribbean Sea is under the seasonal influence of the Trade Winds but also of the Orinoco/Amazon freshwater plume. The latter is responsible for intensification of the Caribbean Current in general and of its eddy activity in the northern part of the Caribbean Sea. More importantly, we show in this study that the front of the freshwater plume drives a northward flow that impinges directly on the island of St. Croix in the United States Virgin Islands. The angle of incidence of the incoming flow controls the nature of the wake on both sides and ends of the island, which changes from cyclonic to anticylonic wake flow, with either attached or shed eddies. Using an off-line bio-physical model, we simulated the dispersal and recruitment of an abundant Caribbean coral reef fish, the bluehead wrasse (Thalassoma bifasciatum) in the context of the wake flow variability around St. Croix. Our results revealed the role played by the consistent seasonal forcing of the wake flow on the recruitment patterns around the island at the interannual scale. The interannual variability of the timing of arrival and northward penetration of the plume instead controls the nature of the wake, hence the regional spatial recruitment patterns. PMID- 26942574 TI - Genome-Wide Association Study to Identify Genes Related to Renal Mercury Concentrations in Mice. AB - BACKGROUND: Following human mercury (Hg) exposure, the metal accumulates in considerable concentrations in kidney, liver, and brain. Although the toxicokinetics of Hg have been studied extensively, factors responsible for interindividual variation in humans are largely unknown. Differences in accumulation of renal Hg between inbred mouse strains suggest a genetic interstrain variation regulating retention or/and excretion of Hg. A.SW, DBA/2 and BALB/C mouse strains accumulate higher amounts of Hg than B10.S. OBJECTIVES: We aimed to find candidate genes associated with regulation of renal Hg concentrations. METHODS: A.SW, B10.S and their F1 and F2 offspring were exposed for 6 weeks to 2.0 mg Hg/L drinking water. Genotyping with microsatellites was conducted on 84 F2 mice for genome-wide scanning with ion pair reverse-phase high performance liquid chromatography (IP RP HPLC). Quantitative trait loci (QTL) were established. Denaturing HPLC was used to detect single nucleotide polymorphisms for haplotyping and fine mapping in 184 and 32 F2 mice, respectively. Candidate genes (Pprc1, Btrc and Nfkb2) verified by fine mapping and QTL were further investigated by real-time polymerase chain reaction. Genes enhanced by Pprc1 (Nrf1 and Nrf2) were included for gene expression analysis. RESULTS: Renal Hg concentrations differed significantly between A.SW and B10.S mice and between males and females within each strain. QTL analysis showed a peak logarithm of odds ratio score 5.78 on chromosome 19 (p = 0.002). Haplotype and fine mapping associated the Hg accumulation with Pprc1, which encodes PGC-1 related coactivator (PRC), a coactivator for proteins involved in detoxification. Pprc1 and two genes coactivated by Pprc1 (Nrf1 and Nrf2) had significantly lower gene expression in the A.SW strain than in the B10.S strain. CONCLUSIONS: This study supports Pprc1 as a key regulator for renal Hg excretion. CITATION: Alkaissi H, Ekstrand J, Jawad A, Nielsen JB, Havarinasab S, Soderkvist P, Hultman P. 2016. Genome-wide association study to identify genes related to renal mercury concentrations in mice. Environ Health Perspect 124:920-926; http://dx.doi.org/10.1289/ehp.1409284. PMID- 26942576 TI - Effects of Methane-Rich Saline on the Capability of One-Time Exhaustive Exercise in Male SD Rats. AB - PURPOSE: To explore the effects of methane-rich saline (CH4 saline) on the capability of one-time exhaustive exercise in male SD rats. METHODS: Thirty rats were equally divided into to three groups at random: control group (C), placebo group (P) and methane saline group (M). Rats in M group underwent intraperitoneal injection of CH4 saline, and the other two groups simultaneously underwent intraperitoneal injection of normal saline. Then, the exercise capability of rats was tested through one-time exhaustive treadmill exercise except C group. Exercise time and body weight were recorded before and after one-time exhaustive exercise. After exhaustive exercise, the blood and gastrocnemius samples were collected from all rats to detect biochemical parameters in different methods. RESULTS: It was found that the treadmill running time was significantly longer in rats treated with CH4 saline. At the same time, CH4 saline reduced the elevation of LD and UN in blood caused by one-time exhaustive exercise. The low level of blood glucose induced by exhaustive exercise was also normalized by CH4 saline. Also CH4 saline lowered the level of CK in plasma. Furthermore, this research indicated that CH4 saline markedly increased the volume of T-AOC in plasma and alleviated the peak of TNF-alpha in both plasma and gastrocnemius. From H&E staining, CH4 saline effectively improved exercise-induced structural damage in gastrocnemius. CONCLUSIONS: CH4 saline could enhance exercise capacity in male SD rats through increase of glucose aerobic oxidation, improvement of metabolic clearance and decrease of exhaustive exercise-induced gastrocnemius injury. PMID- 26942577 TI - Hemophagocytosis in Experimental Visceral Leishmaniasis by Leishmania donovani. AB - Hemophagocytosis is a phenomenon in which macrophages phagocytose blood cells. There are reports on up-regulated hemophagocytosis in patients with infectious diseases including typhoid fever, tuberculosis, influenza and visceral leishmaniasis (VL). However, mechanisms of infection-associated hemophagocytosis remained elusive due to a lack of appropriate animal models. Here, we have established a mouse model of VL with hemophagocytosis. At 24 weeks after infection with 1 x 10(7) Leishmania donovani promastigotes, BALB/cA mice exhibited splenomegaly with an average tissue weight per body weight of 2.96%. In the tissues, 28.6% of macrophages contained phagocytosed erythrocytes. All of the hemophagocytosing macrophages were parasitized by L. donovani, and higher levels of hemophagocytosis was observed in heavily infected cells. Furthermore, more than half of these hemophagocytes had two or more macrophage-derived nuclei, whereas only 15.0% of splenic macrophages were bi- or multi-nuclear. These results suggest that direct infection by L. donovani causes hyper-activation of host macrophages to engulf blood cells. To our knowledge, this is the first report on hemophagocytosis in experimental Leishmania infections and may be useful for further understanding of the pathogenesis. PMID- 26942580 TI - Mucosal Incision and Forceps Biopsy for Reliable Tissue Sampling of Gastric Subepithelial Tumors. AB - BACKGROUND/AIMS: The diagnostic efficacy of current tissue sampling techniques for gastric subepithelial tumors (SETs) is limited. Better tissue sampling techniques are needed to improve pathological diagnosis. The aim of this study was to evaluate the safety and efficacy of a new technique, mucosal incision and forceps biopsy, for reliable tissue sampling of gastric SETs. METHODS: This study enrolled 12 consecutive patients who underwent mucosal incision and forceps biopsy of gastric SETs between November 2011 and September 2014 at Gangneung Asan Hospital. The medical records of patients were reviewed retrospectively. The safety and diagnostic yield of this method were evaluated. RESULTS: By performing mucosal incision and forceps biopsy, we were able to provide a definitive histological diagnosis for 11 out of 12 cases. The pathological diagnoses were leiomyoma (3/11), gastrointestinal stromal tumor (GIST; 2/11), lipoma (2/11), schwannoma (1/11), and ectopic pancreas (3/11). In cases of leiomyoma (n=3) and GIST (n=2), tissue samples were of sufficient size to allow immunohistochemical staining. In addition, the mitotic index was evaluated in two cases of GIST. There were no procedure-related complications. CONCLUSIONS: Mucosal incision and forceps biopsy can be used as one of several methods to obtain adequate tissue samples from gastric SETs. PMID- 26942579 TI - Prefrontal Hemodynamic Functions during a Verbal Fluency Task in Blepharospasm Using Multi-Channel NIRS. AB - Blepharospasm (BSP) has a morbidity of 16 to 133 per million and is characterized by orbicularis oculi spasms. BSP can severely impact daily life. However, to date, its pathophysiology has not been clearly demonstrated. Near-infrared spectroscopy (NIRS) is a portable, non-invasive, and high time resolution apparatus used to measure cerebral blood flow. This study aimed to investigate the hemodynamic response patterns of BSP patients and determine whether BSP alone can be an attributional factor to influence the function of the prefrontal area using a verbal fluency task (VFT) and NIRS. Twenty-three BSP patients (10 males and 13 females) and 13 healthy controls (HC; five males and eight females) matched by gender and education were examined using NIRS. BSP patients were divided into two groups based on the presence or absence of depression and anxiety symptoms. A covariance analysis was conducted to analyze differences between the three groups and reduce the influence of different ages and educational levels. Bonferroni was used to process the post hoc test. The bilateral orbitofrontal area (ch36, 39, and 41; P<0.01) exhibited a lower activation in BSP patients without psychiatric symptoms compared with HC. This study is the first report to identify the prefrontal function in BSP using NIRS. Our findings indicate that BSP alone may cause a hypoactive hemodynamic performance in the prefrontal cortex in the absence of psychiatric symptoms. These findings provide evidence to support novel pathophysiological mechanisms of BSP. PMID- 26942581 TI - Usefulness of the Forrest Classification to Predict Artificial Ulcer Rebleeding during Second-Look Endoscopy after Endoscopic Submucosal Dissection. AB - BACKGROUND/AIMS: Delayed post-endoscopic submucosal dissection (ESD) bleeding (DPEB) is difficult to predict and there is controversy regarding the usefulness of prophylactic hemostasis during second-look endoscopy. This study evaluated the risk factors related to DPEB, the relationship between clinical outcomes and the Forrest classification, and the results of prophylactic hemostasis during second look endoscopy. METHODS: Second-look endoscopy was performed on the day after ESD to check for recent hemorrhage or potential bleeding and the presence of artificial ulcers in all patients. RESULTS: DPEB occurred in 42 of 581 patients (7.2%). Multivariate analysis determined that a specimen size >=40 mm (odds ratio [OR], 3.03; p=0.003), and a high-risk Forrest classification (Forrest Ib+IIa+IIb; OR, 6.88; p<0.001) were risk factors for DPEB. DPEB was significantly more likely in patients classified with Forrest Ib (OR, 24.35; p<0.001), IIa (OR, 12.91; p<0.001), or IIb (OR, 8.31; p<0.001) ulcers compared with Forrest III ulcers. There was no statistically significant difference between the prophylactic hemostasis and non-hemostasis groups (Forrest Ib, p=0.938; IIa, p=0.438; IIb, p=0.397; IIc, p=0.773) during second-look endoscopy. CONCLUSIONS: The Forrest classification of artificial gastric ulcers during second-look endoscopy seems to be a useful tool for predicting delayed bleeding. However, routine prophylactic hemostasis during second-look endoscopy seemed to not be useful for preventing DPEB. PMID- 26942582 TI - Excitation relaxation dynamics and energy transfer in pigment-protein complexes of a dinoflagellate, revealed by ultrafast fluorescence spectroscopy. AB - Photosynthetic light-harvesting complexes, found in aquatic photosynthetic organisms, contain a variety of carotenoids and chlorophylls. Most of the photosynthetic dinoflagellates possess two types of light-harvesting antenna complexes: peridinin (Peri)-chlorophyll (Chl) a/c-protein, as an intrinsic thylakoid membrane complex protein (iPCP), and water-soluble Peri-Chl a-protein, as an extrinsic membrane protein (sPCP) on the inner surface of the thylakoid. Peri is a unique carotenoid that has eight C=C bonds and one C=O bond, which results in a characteristic absorption band in the green wavelength region. In the present study, excitation relaxation dynamics of Peri in solution and excitation energy transfer processes of sPCP and the thylakoid membranes, prepared from the photosynthetic dinoflagellate, Symbiodinium sp., are investigated by ultrafast time-resolved fluorescence spectroscopy. We found that Peri-to-Chl a energy transfer occurs via the Peri S1 state with a time constant of 1.5 ps or 400 fs in sPCP or iPCP, respectively, and that Chl c-to-Chl a energy transfer occurs in the time regions of 350-400 fs and 1.8-2.6 ps. PMID- 26942578 TI - Role of APOBEC3F Gene Variation in HIV-1 Disease Progression and Pneumocystis Pneumonia. AB - Human APOBEC3 cytidine deaminases are intrinsic resistance factors to HIV-1. However, HIV-1 encodes a viral infectivity factor (Vif) that degrades APOBEC3 proteins. In vitro APOBEC3F (A3F) anti-HIV-1 activity is weaker than A3G but is partially resistant to Vif degradation unlike A3G. It is unknown whether A3F protein affects HIV-1 disease in vivo. To assess the effect of A3F gene on host susceptibility to HIV- acquisition and disease progression, we performed a genetic association study in six well-characterized HIV-1 natural cohorts. A common six-Single Nucleotide Polymorphism (SNP) haplotype of A3F tagged by a codon-changing variant (p. I231V, with allele (V) frequency of 48% in European Americans) was associated with significantly lower set-point viral load and slower rate of progression to AIDS (Relative Hazards (RH) = 0.71, 95% CI: 0.56, 0.91) and delayed development of pneumocystis pneumonia (PCP) (RH = 0.53, 95% CI: 0.37-0.76). A validation study in the International Collaboration for the Genomics of HIV (ICGH) showed a consistent association with lower set-point viral load. An in vitro assay revealed that the A3F I231V variant may influence Vif mediated A3F degradation. Our results provide genetic epidemiological evidence that A3F modulates HIV-1/AIDS disease progression. PMID- 26942583 TI - Weak temperature dependence of P (+) H A (-) recombination in mutant Rhodobacter sphaeroides reaction centers. AB - In contrast with findings on the wild-type Rhodobacter sphaeroides reaction center, biexponential P (+) H A (-) -> PH A charge recombination is shown to be weakly dependent on temperature between 78 and 298 K in three variants with single amino acids exchanged in the vicinity of primary electron acceptors. These mutated reaction centers have diverse overall kinetics of charge recombination, spanning an average lifetime from ~2 to ~20 ns. Despite these differences a protein relaxation model applied previously to wild-type reaction centers was successfully used to relate the observed kinetics to the temporal evolution of the free energy level of the state P (+) H A (-) relative to P (+) B A (-) . We conclude that the observed variety in the kinetics of charge recombination, together with their weak temperature dependence, is caused by a combination of factors that are each affected to a different extent by the point mutations in a particular mutant complex. These are as follows: (1) the initial free energy gap between the states P (+) B A (-) and P (+) H A (-) , (2) the intrinsic rate of P (+) B A (-) -> PB A charge recombination, and (3) the rate of protein relaxation in response to the appearance of the charge separated states. In the case of a mutant which displays rapid P (+) H A (-) recombination (ELL), most of this recombination occurs in an unrelaxed protein in which P (+) B A (-) and P (+) H A (-) are almost isoenergetic. In contrast, in a mutant in which P (+) H A (-) recombination is relatively slow (GML), most of the recombination occurs in a relaxed protein in which P (+) H A (-) is much lower in energy than P (+) H A (-) . The weak temperature dependence in the ELL reaction center and a YLH mutant was modeled in two ways: (1) by assuming that the initial P (+) B A (-) and P (+) H A (-) states in an unrelaxed protein are isoenergetic, whereas the final free energy gap between these states following the protein relaxation is large (~250 meV or more), independent of temperature and (2) by assuming that the initial and final free energy gaps between P (+) B A (-) and P (+) H A (-) are moderate and temperature dependent. In the case of the GML mutant, it was concluded that the free energy gap between P (+) B A (-) and P (+) H A (-) is large at all times. PMID- 26942585 TI - Multiscale Approach to Characterize Mechanical Properties of Tissue Engineered Skin. AB - Tissue engineered skin usually consist of a multi-layered visco-elastic material composed of a fibrillar matrix and cells. The complete mechanical characterization of these tissues has not yet been accomplished. The purpose of this study was to develop a multiscale approach to perform this characterization in order to link the development process of a cultured skin to the mechanical properties. As a proof-of-concept, tissue engineered skin samples were characterized at different stages of manufacturing (acellular matrix, reconstructed dermis and reconstructed skin) for two different aging models (using cells from an 18- and a 61-year-old man). To assess structural variations, bi-photonic confocal microscopy was used. To characterize mechanical properties at a macroscopic scale, a light-load micro-mechanical device that performs indentation and relaxation tests was designed. Finally, images of the internal network of the samples under stretching were acquired by combining confocal microscopy with a tensile device. Mechanical properties at microscopic scale were assessed. Results revealed that adding cells during manufacturing induced structural changes, which provided higher elastic modulus and viscosity. Moreover, senescence models exhibited lower elastic modulus and viscosity. This multiscale approach was efficient to characterize and compare skin equivalent samples and permitted the first experimental assessment of the Poisson's ratio for such tissues. PMID- 26942584 TI - Periodic power spectrum with applications in detection of latent periodicities in DNA sequences. AB - Periodic elements play important roles in genomic structures and functions, yet some complex periodic elements in genomes are difficult to detect by conventional methods such as digital signal processing and statistical analysis. We propose a periodic power spectrum (PPS) method for analyzing periodicities of DNA sequences. The PPS method employs periodic nucleotide distributions of DNA sequences and directly calculates power spectra at specific periodicities. The magnitude of a PPS reflects the strength of a signal on periodic positions. In comparison with Fourier transform, the PPS method avoids spectral leakage, and reduces background noise that appears high in Fourier power spectrum. Thus, the PPS method can effectively capture hidden periodicities in DNA sequences. Using a sliding window approach, the PPS method can precisely locate periodic regions in DNA sequences. We apply the PPS method for detection of hidden periodicities in different genome elements, including exons, microsatellite DNA sequences, and whole genomes. The results show that the PPS method can minimize the impact of spectral leakage and thus capture true hidden periodicities in genomes. In addition, performance tests indicate that the PPS method is more effective and efficient than a fast Fourier transform. The computational complexity of the PPS algorithm is [Formula: see text]. Therefore, the PPS method may have a broad range of applications in genomic analysis. The MATLAB programs for implementing the PPS method are available from MATLAB Central ( http://www.mathworks.com/matlabcentral/fileexchange/55298 ). PMID- 26942586 TI - Parametric Modeling of the Mouse Left Ventricular Myocardial Fiber Structure. AB - Magnetic resonance diffusion tensor imaging (DTI) has greatly facilitated detailed quantifications of myocardial structures. However, structural patterns, such as the distinctive transmural rotation of the fibers, remain incompletely described. To investigate the validity and practicality of pattern-based analysis, 3D DTI was performed on 13 fixed mouse hearts and fiber angles in the left ventricle were transformed and fitted to parametric expressions constructed from elementary functions of the prolate spheroidal spatial variables. It was found that, on average, the myocardial fiber helix angle could be represented to 6.5 degrees accuracy by the equivalence of a product of 10th-order polynomials of the radial and longitudinal variables, and 17th-order Fourier series of the circumferential variable. Similarly, the fiber imbrication angle could be described by 10th-order polynomials and 24th-order Fourier series, to 5.6 degrees accuracy. The representations, while relatively concise, did not adversely affect the information commonly derived from DTI datasets including the whole ventricle mean fiber helix angle transmural span and atlases constructed for the group. The unique ability of parametric models for predicting the 3D myocardial fiber structure from finite number of 2D slices was also demonstrated. These findings strongly support the principle of parametric modeling for characterizing myocardial structures in the mouse and beyond. PMID- 26942588 TI - Medical Treatment in Elderly Patients with Non-Small Cell Lung Cancer. AB - OPINION STATEMENT: Lung cancer is the leading cause of cancer-related deaths worldwide. In the USA, ~60 % of lung cancer cases are diagnosed in elderly patients (>=65 years of age). However, elderly patients are underrepresented in clinical studies, leading to a paucity of evidence to guide treatment decisions. Several treatment barriers exist in elderly patients, including comorbidities and poor performance status. In addition, lack of reliable geriatric assessment tools and physician reluctance to treat may contribute to undertreatment in this population. For decades, systemic chemotherapy for elderly patients with advanced non-small cell lung cancer (NSCLC) was either omitted or given as monotherapy, frequently with significant dose reductions, potentially compromising the efficacy of these therapies. Recent analyses of elderly subgroups from multiple clinical trials provide evidence for improved outcomes associated with platinum based doublet chemotherapies vs monotherapy. Moreover, in the new era of precision medicine, molecularly targeted therapies and more recently immune targeting therapies (anti-PD-1 and anti-PD-L1 agents) exhibit relatively milder toxicities but superior clinical outcomes in subgroups of patients compared with conventional cytotoxic chemotherapies. Further clinical trials will be needed to confirm similar safety and efficacy profiles of these therapeutic approaches in the elderly compared with their younger counterparts. In this article, we review available evidence from clinical studies and also present expert consensus on the management of NSCLC in the elderly, including treatment in the adjuvant setting and treatment of advanced disease. Screening tools, such as the Comprehensive Geriatric Assessment, that help to identify the right population of elderly patients suitable for systemic treatment are also discussed. PMID- 26942589 TI - New Approaches for Immune Directed Treatment for Ovarian Cancer. AB - OPINION STATEMENT: The immune system plays an active role in the pathogenesis of ovarian cancer (OC), as well as in the mechanisms of disease progression and overall survival (OS). Immunotherapy in gynecological cancers could help to revert immunosuppression and lymphocyte depletion due to prior treatments. Current immunotherapies for ovarian cancer, like all cancer immunotherapy, are based on either stimulating the immune system or reverting immune suppression. Several approaches have been used, including therapeutic vaccines, monoclonal antibodies; checkpoint inhibitors and adoptive T cell transfer. Most of these therapies are still in early-phase testing (phase I and II) for ovarian cancer, but the initial data in ovarian cancer and successful use in other types of cancers suggests some of these approaches may ultimately prove useful for ovarian cancer as well. Ovarian cancer vaccines have shown only a modest benefit in ovarian cancer when used as monotherapy, but these agents may be able to enhance antitumor activity when combined with chemotherapy, checkpoint inhibitors, or other immunotherapies. Monoclonal antibodies have been explored in ovarian cancer but despite encouraging phase II data, randomized studies failed to demonstrate significant clinical benefit. Check point inhibitors have promising activity in several solid tumors and have demonstrated a favorable toxicity profile. Data from early clinical trials utilizing PD1 and PD-L1 inhibitors showed encouraging results. Ongoing clinical trials are evaluating the role of check point inhibitors in combination with chemotherapy. Adoptive T cell transfer involves the infusion of ex vivo activated and expanded tumor specific T cells, using various sources and types of T cells. While this approach has been explored in several hematologic malignancies, it constitutes early research in ovarian cancer. Immunotherapy remains investigational in ovarian cancer and the benefit of this approach in improving progression-free survival (PFS) or OS is unknown. Previous clinical trials have not selected patients based on biomarkers and this may explain the negative results. We expect to discover that tumor response will relate to the patient's immune features and specific tumor characteristics. We are only beginning to realize the potential of immunotherapy for ovarian cancer patients, and one goal of future clinical trials will be to identify subsets of patient based on histologic, molecular, and immune characteristics. PMID- 26942592 TI - The Retrograde Ventriculosinusal Shunt in an Animal Experimental Model of Hydrocephalus. AB - Currently, hydrocephalus treatment is performed mainly with ventriculoperitoneal shunting. This experimental study aims at assessing whether the experimental model of hydrocephalus in dogs is applicable to the laboratory study of the retrograde ventriculosinusal shunt (RVSS). Four mongrel dogs were assessed. After randomization, the animals were divided into two groups: an experimental group that underwent the induction of hydrocephalus/RVSS and a control group, for the measurement of the mean arterial pressure, intracranial pressure and pressure in the superior sagittal sinus (SSS). The controls presented a mean arterial pressure of 68 mm Hg (71 and 65), an intracranial pressure of 163 mm H2O (149.6 and 176.8) and a pressure at the SSS of 40 mm H2O (40 and 40). The kaolin injection into the cisterna magna at a concentration of 0.3 mg/ml was capable of inducing the clinical and radiological mechanism of hydrocephalus (intracranial pressure = 250 mm H2O, pressure at the SSS = 50 mm H2O). The caliber of the SSS was 2.5 +/- 1.0 mm. The fact that the SSS caliber of the dog was the same size as the external diameter of the catheter used resulted in the complete obstruction of the SSS when the catheter was inserted. We believe we could design and perform an experimental model to test the RVSS. It is applicable and feasible. The model of hydrocephalus, the surgical apparatus and the scenario were adequate, but the shunt system needs to be proportionally made to the canine anatomy. PMID- 26942590 TI - Bladder Sparing Approaches for Muscle-Invasive Bladder Cancers. AB - OPINION STATEMENT: Organ preservation has been increasingly utilised in the management of muscle-invasive bladder cancer. Multiple bladder preservation options exist, although the approach of maximal TURBT performed along with chemoradiation is the most favoured. Phase III trials have shown superiority of chemoradiotherapy compared to radiotherapy alone. Concurrent chemoradiotherapy gives local control outcomes comparable to those of radical surgery, but seemingly more superior when considering quality of life. Bladder-preserving techniques represent an alternative for patients who are unfit for cystectomy or decline major surgical intervention; however, these patients will need lifelong rigorous surveillance. It is important to emphasise to the patients opting for organ preservation the need for lifelong bladder surveillance as risk of recurrence remains even years after radical chemoradiotherapy treatment. No randomised control trials have yet directly compared radical cystectomy with bladder-preserving chemoradiation, leaving the age-old question of superiority of one modality over another unanswered. Radical cystectomy and chemoradiation, however, must be seen as complimentary treatments rather than competing treatments. Meticulous patient selection is vital in treatment modality selection with the success of recent trials within the field of bladder preservation only being possible through this application of meticulous selection criteria compared to previous decades. A multidisciplinary approach with radiation oncologists, medical oncologists, and urologists is needed to closely monitor patients who undergo bladder preservation in order to optimise outcomes. PMID- 26942593 TI - The Social Life of Data. PMID- 26942591 TI - Waldenstrom Macroglobulinemia: Familial Predisposition and the Role of Genomics in Prognosis and Treatment Selection. AB - OPINION STATEMENT: Waldenstrom macroglobulinemia (WM) is a non-Hodgkin lymphoma (NHL) characterized by the presence of a CD20 + lymphoplasmacytic bone marrow (BM) infiltrate and serum immunoglobulin M monoclonal protein. Both sporadic and familial forms exist. A remarkable improvement in outcome of nearly all age groups of WM patients may be primarily a consequence of successful integration of anti-CD20 monoclonal antibody, rituximab, to the conventional chemotherapy. However, the seminal discoveries of MYD88 (L265P) mutation, present in the vast majority (85-100 %), and CXCR4 (WHIM) mutations, identified in nearly a third of patients (who almost exclusively harbor the MYD88 (L265P) variant), have laid a solid foundation for a paradigm shift in our diagnostic and therapeutic approaches towards this rare hematologic malignancy. Given that 20-25 % of patients are asymptomatic at diagnosis and early intervention does not translate into survival benefit, we follow a risk-adapted approach and actively monitor this subset of "smoldering" patients. Those with low-grade cytopenias can generally be managed with an abbreviated course of rituximab monotherapy, while those with B symptoms, bulky lymphadenopathy, or profound disease-related cytopenias require more aggressive strategies, incorporating several courses of chemoimmunotherapy. For symptoms associated with hyperviscosity, prompt plasma exchange is warranted prior to initiation of cytoreductive therapy. Prospective data are unavailable to a support a unique approach in familial WM or initiation of rituximab maintenance post-induction. A multitude of potentially effective therapies targeting cell-survival pathways are in development and offer a more precise approach for WM patients. One such agent, ibrutinib, a Bruton's tyrosine kinase inhibitor, was recently granted approval. Off-study, we limit the use of ibrutinib to relapsed-refractory WM patients who harbor MYD88 mutations. Autologous stem-cell transplantation (ASCT) is another viable option in the relapsed setting for chemosensitive transplant-eligible patients. Unfortunately, despite substantial progress, achieving a minimal residual disease-negative state a prerequisite for cure-is rare in WM. PMID- 26942594 TI - Effects of cannabinoid receptor activation by CP55,940 on normal bladder function and irritation-induced bladder overactivity in non-awake anaesthetised rats. AB - INTRODUCTION AND HYPOTHESIS: This study was designed to evaluate the effects of CP55,940 on normal bladder function in vivo and examine whether it suppresses urinary frequency induced by nociceptive stimuli in the bladder. Cannabinoid receptor (CBR) activity may be involved in the regulation of bladder function. However, the role of CBR subtypes in micturition has yet to be established. CP55,940 is a synthetic analogue of tetrahydrocannabidiol, which is a psychoactive ingredient of the Cannabis plant. METHODS: Cystometry under urethane anaesthesia was performed to evaluate the effect of intravesical delivery of CP55,940 with or without administration of CB1 antagonist AM251 or CB2 antagonist AM630 on bladder function in female rats. The effects of CP55,940 were also examined in rats with urinary irritation induced by intravesical infusion of acetic acid. RESULTS: Infusion of CP55,940 significantly (p < 0.05) increased micturition interval (MI) and bladder capacity (BC) by 52 % and decreased maximal voiding pressure (MP) by 25 %. Pretreatment with AM251 or AM630 before CP55,940 administration prevented CP55,940-induced increases in MI, BC and reduced MP. Acetic acid induced urinary frequency as evidenced by a reduction in MI and was suppressed by CP55,940. CONCLUSIONS: CP55,940 decreases bladder activity and urinary frequency induced by nociceptive stimuli, probably by suppression of bladder afferent activity. Effects of CP55,940 were abolished by both CBR antagonists. This data implicates a role for the endocannabinoid system in bladder mechanoafferent function in rats. In addition, our results show that CP55,940 reverses urinary frequency exemplified in an overactive bladder model, suggesting it could be an effective treatment for patients with lower urinary tract symptoms. PMID- 26942595 TI - A cohort study of interstitial cystitis/bladder pain syndrome and hysterectomy. AB - INTRODUCTION AND HYPOTHESIS: Symptoms of interstitial cystitis/bladder pain syndrome (IC/BPS) are often confused with uterine conditions. Gynecologists may therefore recommend hysterectomy which was inappropriate for these patients. This study investigated whether IC/BPS increases the risk of hysterectomy in a large nationwide retrospective cohort study. METHODS: From the Longitudinal Health Insurance Database 2010 (LHID2010) in Taiwan, we identified women diagnosed with IC/BPS between 2002 and 2013. Those with a history of hysterectomy before IC/BPS diagnosis were excluded. All women were stratified into three subgroups (younger, middle, older age) based on the propensity scores of 15 confounding factors, including age and comorbidities. All were followed until the end of 2013 to detect the event of hysterectomy. The hazard ratio (HR) of hysterectomy in the IC/BPS cohort was compared with the non-IC/BPS cohort among the three subgroups by Cox regression after adjusting for confounding factors. RESULTS: In addition to the representative middle age, subgroup 2 had similar rates of comorbidities as the general population. The study was both externally and internally valid. The risk of hysterectomy in the IC/BPS cohort (n = 536) was significantly higher than in the non-IC/BPS cohort (n = 103846) in subgroup 2 (HR = 1.701, 95 % CI 1.056-2.740). The mean time to hysterectomy after diagnosis of IC/BPS was 2.97 years. CONCLUSIONS: In this nationwide study, we found that IC/BPS has a causal impact on hysterectomy in the middle-age subgroup in LHID 2010. The possibility of a woman having IC/BPS should be evaluated prior to hysterectomy to avoid inappropriate surgery. PMID- 26942596 TI - Basal and stress-activated hypothalamic pituitary adrenal axis function in postmenopausal women with overactive bladder. AB - INTRODUCTION AND HYPOTHESIS: The aim of this study was to measure physiologic and psychologic stress reactivity in women with overactive bladder (OAB). There is growing evidence in preclinical models that central nervous system dysregulation, particularly in response to psychological stress, may contribute to lower urinary tract symptoms in women with OAB. METHODS: Postmenopausal women with OAB and healthy controls underwent Structured Clinical Interview for DSM-IV Axis I disorders (SCID) to identify those without identifiable psychiatric disease. Eligible participants underwent physiologic measures including basal (cortisol awakening response; CAR) and stress-activated salivary cortisol levels, heart rate (HR), urinary metanephrines and neurotrophins, as well as validated symptom assessment for stress, anxiety, depression, and bladder dysfunction at baseline and during, and following an acute laboratory stressor, the Trier Social Stress Test (TSST). RESULTS: Baseline measures of cortisol reactivity measured by CAR showed blunted response among women with OAB (p = 0.015), while cortisol response to the TSST was greater in the OAB group (p = 0.019). Among OAB patients, bladder urgency as measured by visual analog scale (VAS) increased from pre- to post-TSST (p = 0.04). There was a main effect of TSST on HR (p < 0.001), but no group interaction. CONCLUSIONS: Preliminary findings suggest that women with OAB have greater physiologic and psychologic stress reactivity than healthy controls. Importantly for women with OAB, acute stress appears to exacerbate bladder urgency. Evaluation of the markers of stress response may suggest targets for potential diagnostic and therapeutic interventions. PMID- 26942598 TI - Reliability and Validity of the Child and Adolescent Behavior Assessment (CABA): A Brief Structured Scale. AB - Use of valid, affordable, accessible, and brief measures facilitates the assessment of mental health outcomes. The Child and Adolescent Behavior Assessment Scale, a brief, structured scale, assesses problem behavior through patient and/or informant report. The purpose of this paper is to illustrate the scale's psychometric properties. In the cross-sectional study presented, a large national sample of youth (aged 5-18) admitted for psychiatric treatment (N = 32,689) was examined. The two major domains of problem behavior assessed were Internalizing and Externalizing. Reliability was good to excellent with alpha levels ranging from 0.874 to 0.917. Additional items measured Risk Behavior (alpha = 0.648). Subscale total scores correlated well with the Brief Psychiatric Rating Scale for Children, 9-item version (BPRS-C-9). Exploratory and confirmatory factor analyses supported the three-factor, multidimensional model of problem behavior as satisfactory for child and adolescent use, although further research is required to refine some items for clarity and improved model fit. PMID- 26942597 TI - Low-Dose Bisphenol-A Impairs Adipogenesis and Generates Dysfunctional 3T3-L1 Adipocytes. AB - Environmental endocrine disruptors (EDCs), including bisphenol-A (BPA), have been recently involved in obesity and diabetes by dysregulating adipose tissue function. Our aim was to examine whether prolonged exposure to low doses of BPA could affect adipogenesis and adipocyte metabolic functions. Therefore, 3T3-L1 pre-adipocytes were cultured for three weeks with BPA 1 nM to mimic human environmental exposure. We evaluated BPA effect on cell proliferation, differentiation, gene expression and adipocyte metabolic function. BPA significantly increased pre-adipocyte proliferation (p<0.01). In 3T3-L1 adipocytes differentiated in the presence of BPA, the expression of Peroxisome proliferator-activated receptor gamma (PPARgamma), Fatty Acid Binding Protein 4/Adipocyte Protein 2 (FABP4/AP2) and CCAAT/enhancer binding protein (C/EBPalpha) was increased by 3.5, 1.5 and 3 folds, respectively. Mature adipocytes also showed a significant increase in lipid accumulation (p<0.05) and alterations of insulin action, with significant reduction in insulin-stimulated glucose utilization (p<0.001). Moreover, in mature adipocytes, mRNA levels of Leptin, interleukin-6 (IL6) and interferon-gamma (IFNgamma) were significantly increased (p<0.05). In conclusion, BPA prolonged exposure at low doses, consistent with those found in the environment, may affect adipocyte differentiation program, enhancing pre-adipocyte proliferation and anticipating the expression of the master genes involved in lipid/glucose metabolism. The resulting adipocytes are hypertrophic, with impaired insulin signaling, reduced glucose utilization and increased pro-inflammatory cytokine expression. Thus, these data supported the hypothesis that BPA exposure, during critical stages of adipose tissue development, may cause adipocyte metabolic dysfunction and inflammation, thereby increasing the risk of developing obesity-related diseases. PMID- 26942600 TI - Expression and gene doses changes of the p53-regulator PPM1D in meningiomas: a role in meningioma progression? AB - The aim of our study was to clarify the expression and gene copy number levels of protein phosphatase 1D magnesium-dependent, delta isoform (PPM1D), which is thought to be a regulator of the p53 protein in meningiomas of all three different WHO grades. Genomic DNA and mRNA were extracted from frozen tissues of meningiomas (WHO grade I, 20 cases; grade II, 17 cases; grade III, 20 cases). For analysis of the mRNA expression and gene dosage level of PPM1D, semiquantitative duplex RT-PCR, real-time RT-PCR, and semiquantitative duplex PCR were performed. We also analyzed several genes which locate near PPM1D in the genomic locus 17q22 24 using semiquantitative duplex RT-PCR. We found that the mean mRNA expression of PPM1D is higher in WHO grade II and III meningiomas than in grade I tumors. This finding is accompanied by moderate gene dosage increases for PPM1D in meningiomas of higher grades. Other genes located in the vicinity of PPM1D also showed mRNA overexpression in single meningioma cases. For these genes, however, no significant expression differences between meningioma grades could be observed. Thus, PPM1D in the chromosomal location 17q22-24 might be the most relevant candidate gene with respect to a potential functional implication in meningioma progression. PMID- 26942599 TI - Lipomatous ependymoma: report of a rare differentiation pattern with a comprehensive review of literature. AB - We report the case of a 13-year-old girl presenting with left-sided hemiparesis, altered sensorium and episodic headache with bouts of projectile vomiting. Imaging revealed a large heterodense intraventricular mass lesion displaying focal calcification and hyperintensity on T1- and T2- weighted fluid attenuated inversion recovery (FLAIR) magnetic resonance images suggesting the presence of intratumoral fat. Histologically, the tumour showed sheets of glial cells, focal perithelial rosettes and individual cells showing fat vacuoles. The morphological impression was of an ependymoma with lipomatous differentiation. Glial fibrillary acid protein (GFAP) immunohistochemistry revealed positivity in the cytoplasmic processes of the tumour cells as well as in the cytoplasmic rim of the cells having an adipocytic appearance. S100 and vimentin were also immunoreactive. Ultrastructural studies confirmed the ependymal differentiation of the tumour and the presence of an osmiophilic fat component confirming the diagnosis. After 1 year of follow-up, the patient presented with similar complaints and MRI evidence of recurrence of the tumour. A comprehensive literature review revealed that half of the reported cases of this pattern recurred suggesting a possibly tenacious clinical course. PMID- 26942602 TI - Genetic Ablation of Type III Adenylyl Cyclase Exerts Region-Specific Effects on Cilia Architecture in the Mouse Nose. AB - We recently reported that olfactory sensory neurons in the dorsal zone of the mouse olfactory epithelium exhibit drastic location-dependent differences in cilia length. Furthermore, genetic ablation of type III adenylyl cyclase (ACIII), a key olfactory signaling protein and ubiquitous marker for primary cilia, disrupts the cilia length pattern and results in considerably shorter cilia, independent of odor-induced activity. Given the significant impact of ACIII on cilia length in the dorsal zone, we sought to further investigate the relationship between cilia length and ACIII level in various regions throughout the mouse olfactory epithelium. We employed whole-mount immunohistochemical staining to examine olfactory cilia morphology in phosphodiesterase (PDE) 1C-/ ;PDE4A-/- (simplified as PDEs-/- hereafter) and ACIII-/- mice in which ACIII levels are reduced and ablated, respectively. As expected, PDEs-/- animals exhibit dramatically shorter cilia in the dorsal zone (i.e., where the cilia pattern is found), similar to our previous observation in ACIII-/- mice. Remarkably, in a region not included in our previous study, ACIII-/- animals (but not PDEs-/- mice) have dramatically elongated, comet-shaped cilia, as opposed to characteristic star-shaped olfactory cilia. Here, we reveal that genetic ablation of ACIII has drastic, location-dependent effects on cilia architecture in the mouse nose. These results add a new dimension to our current understanding of olfactory cilia structure and regional organization of the olfactory epithelium. Together, these findings have significant implications for both cilia and sensory biology. PMID- 26942604 TI - Hierarchical Bayesian Spatio-Temporal Analysis of Climatic and Socio-Economic Determinants of Rocky Mountain Spotted Fever. AB - This study aims to examine the spatio-temporal dynamics of Rocky Mountain spotted fever (RMSF) prevalence in four contiguous states of Midwestern United States, and to determine the impact of environmental and socio-economic factors associated with this disease. Bayesian hierarchical models were used to quantify space and time only trends and spatio-temporal interaction effect in the case reports submitted to the state health departments in the region. Various socio economic, environmental and climatic covariates screened a priori in a bivariate procedure were added to a main-effects Bayesian model in progressive steps to evaluate important drivers of RMSF space-time patterns in the region. Our results show a steady increase in RMSF incidence over the study period to newer geographic areas, and the posterior probabilities of county-specific trends indicate clustering of high risk counties in the central and southern parts of the study region. At the spatial scale of a county, the prevalence levels of RMSF is influenced by poverty status, average relative humidity, and average land surface temperature (>35 degrees C) in the region, and the relevance of these factors in the context of climate-change impacts on tick-borne diseases are discussed. PMID- 26942603 TI - Genome-wide analysis, expression dynamics and varietal comparison of NAC gene family at various developmental stages in Morus notabilis. AB - NAC genes are important transcription factors and forms a large family in plants. They have shown to play an important role in growth and development and have also been shown to involve in regulation of stress-responsive genes. In the present study, a repertoire of NAC genes in recently published mulberry genome has been identified which consists of a total of 79 members. Structural analysis revealed that most of the NAC genes in mulberry contain two introns. The proteins encoded by them show a wide range of isoelectric points suggestive of their varied roles in varying microcellular environment. Phylogenetic and conserved motif analysis elucidate the presence of 15 sub-groups of these genes along with two novel sub groups having distinct conserved motifs which are not present in Arabidopsis. Gene ontology term enrichment analysis and cis-element identification from their putative 1 K upstream regulatory region indicates their possible role in important biological processes like organ formation, meristem establishment, senescence, and various biotic and abiotic stresses. Expression analysis across various developmental stages led to identification of their preferential expression in diverse tissues. Taken together, this work provides a solid background information related to structure, function, expression and evolution of NAC gene family in mulberry. PMID- 26942606 TI - Annealed Importance Sampling for Neural Mass Models. AB - Neural Mass Models provide a compact description of the dynamical activity of cell populations in neocortical regions. Moreover, models of regional activity can be connected together into networks, and inferences made about the strength of connections, using M/EEG data and Bayesian inference. To date, however, Bayesian methods have been largely restricted to the Variational Laplace (VL) algorithm which assumes that the posterior distribution is Gaussian and finds model parameters that are only locally optimal. This paper explores the use of Annealed Importance Sampling (AIS) to address these restrictions. We implement AIS using proposals derived from Langevin Monte Carlo (LMC) which uses local gradient and curvature information for efficient exploration of parameter space. In terms of the estimation of Bayes factors, VL and AIS agree about which model is best but report different degrees of belief. Additionally, AIS finds better model parameters and we find evidence of non-Gaussianity in their posterior distribution. PMID- 26942605 TI - Effects of the Infusion of 4% or 20% Human Serum Albumin on the Skeletal Muscle Microcirculation in Endotoxemic Rats. AB - BACKGROUND: Sepsis-induced microcirculatory alterations contribute to tissue hypoxia and organ dysfunction. In addition to its plasma volume expanding activity, human serum albumin (HSA) has anti-oxidant and anti-inflammatory properties and may have a protective role in the microcirculation during sepsis. The concentration of HSA infused may influence these effects. We compared the microcirculatory effects of the infusion of 4% and 20% HSA in an experimental model of sepsis. METHODS: Adult male Wistar rats were equipped with arterial and venous catheters and received an intravenous infusion of lipopolysaccharide (LPS, serotype O127:B8, 10 mg/kg over 30 minutes) or vehicle (SHAM, n = 6). Two hours later, endotoxemic animals were randomized to receive 10 mL/kg of either 4% HSA (LPS+4%HSA, n = 6), 20% HSA (LPS+20%HSA, n = 6) or 0.9% NaCl (LPS+0.9%NaCl, n = 6). No fluids were given to an additional 6 animals (LPS). Vessel density and perfusion were assessed in the skeletal muscle microcirculation with sidestream dark field videomicroscopy at baseline (t0), 2 hours after LPS injection (t1), after HSA infusion (t2) and 1 hour later (t3). The mean arterial pressure (MAP) and heart rate were recorded. Serum endothelin-1 was measured at t2. RESULTS: MAP was stable over time in all groups. The microcirculatory parameters were significantly altered in endotoxemic animals at t1. The infusion of both 4% and 20% HSA similarly increased the perfused vessel density and blood flow velocity and decreased the flow heterogeneity to control values. Microvascular perfusion was preserved in the LPS+20%HSA group at t3, whereas alterations reappeared in the LPS+4%HSA group. CONCLUSIONS: In a rat model of normotensive endotoxemia, the infusion of 4% or 20% HSA produced a similar acute improvement in the microvascular perfusion in otherwise unresuscitated animals. PMID- 26942608 TI - Environmental Drivers of Benthic Flux Variation and Ecosystem Functioning in Salish Sea and Northeast Pacific Sediments. AB - The upwelling of deep waters from the oxygen minimum zone in the Northeast Pacific from the continental slope to the shelf and into the Salish Sea during spring and summer offers a unique opportunity to study ecosystem functioning in the form of benthic fluxes along natural gradients. Using the ROV ROPOS we collected sediment cores from 10 sites in May and July 2011, and September 2013 to perform shipboard incubations and flux measurements. Specifically, we measured benthic fluxes of oxygen and nutrients to evaluate potential environmental drivers of benthic flux variation and ecosystem functioning along natural gradients of temperature and bottom water dissolved oxygen concentrations. The range of temperature and dissolved oxygen encountered across our study sites allowed us to apply a suite of multivariate analyses rarely used in flux studies to identify bottom water temperature as the primary environmental driver of benthic flux variation and organic matter remineralization. Redundancy analysis revealed that bottom water characteristics (temperature and dissolved oxygen), quality of organic matter (chl a:phaeo and C:N ratios) and sediment characteristics (mean grain size and porosity) explained 51.5% of benthic flux variation. Multivariate analyses identified significant spatial and temporal variation in benthic fluxes, demonstrating key differences between the Northeast Pacific and Salish Sea. Moreover, Northeast Pacific slope fluxes were generally lower than shelf fluxes. Spatial and temporal variation in benthic fluxes in the Salish Sea were driven primarily by differences in temperature and quality of organic matter on the seafloor following phytoplankton blooms. These results demonstrate the utility of multivariate approaches in differentiating among potential drivers of seafloor ecosystem functioning, and indicate that current and future predictive models of organic matter remineralization and ecosystem functioning of soft-muddy shelf and slope seafloor habitats should consider bottom water temperature variation. Bottom temperature has important implications for estimates of seasonal and spatial benthic flux variation, benthic-pelagic coupling, and impacts of predicted ocean warming at high latitudes. PMID- 26942607 TI - New insights into the roles of the N-terminal region of the ABCC6 transporter. AB - ABCC6 is a human ATP binding cassette (ABC) transporter of the plasma membrane associated with Pseudoxanthoma elasticum (PXE), an autosomal recessive disease characterized by ectopic calcification of elastic fibers in dermal, ocular and vascular tissues. Similar to other ABC transporters, ABCC6 encloses the core structure of four domains: two transmembrane domains (TMDs) and two nucleotide binding domains (NBDs) but also an additional N-terminal extension, including a transmembrane domain (TMD0) and a cytosolic loop (L0), which is only found in some members of ABCC subfamily, and for which the function remains to be established. To investigate the functional roles of this N-terminal region, we generated several domain deletion constructs of ABCC6, expressed in HEK293 and polarized LLC-PK1 cells. ABCC6 lacking TMD0 displayed full transport activity as the wild type protein. Unlike the wild type protein, ABCC6 without L0 was not targeted to the basolateral membrane. Moreover, homology modeling of L0 suggests that it forms an ATPase regulatory domain. Furthermore, we show that the expression of ABCC6 is linked to a cellular influx of Ca(2+). The results suggest that TMD0 is not required for transport function and that L0 maintains ABCC6 in a targeting-competent state for the basolateral membrane and might be involved in regulating the NBDs. These findings shed new light on a possible physiological function of ABCC6 and may explain some of the hallmarks of the clinical features associated with PXE that could contribute to the identification of novel pharmacological targets. PMID- 26942617 TI - Epstein-Barr virus hemorrhagic meningoencephalitis: case report and review of the literature. AB - Neurologic complications related to Epstein-Barr virus (EBV) in immunocompetent adults are rare and most commonly self-limited. However, severe cases have been previously reported in the literature. We describe a case of meningoencephalitis with frontal bilateral hemorrhage in a non-immunocompromised adult following an EBV infection of the central nervous system confirmed by the presence of EBV-DNA in the cerebrospinal fluid. During the patient's hospital stay, there was a favorable clinical and radiologic evolution and the patient was discharged asymptomatic. To our knowledge, this is the fourth case of hemorrhagic meningoencephalitis related to EBV and the first one in an immunocompetent patient with a favorable outcome. PMID- 26942609 TI - Sympathetic Nervous System, Hypertension, Obesity and Metabolic Syndrome. AB - Experimental and clinical studies have clearly shown the role of the sympathetic nervous system in the pathophysiology of several cardiovascular and non cardiovascular diseases. This short review will be aimed at focusing and discussing the new information collected on two specific clinical conditions such as obesity and metabolic syndrome. The paper will briefly describe the four main mechanisms that represent the common link between these two pathophysiological conditions and that through the sympathetic nervous system contribute to increase the cardiovascular risk. PMID- 26942626 TI - Squaraines bearing halogenated moieties as anticancer photosensitizers: Synthesis, characterization and biological evaluation. AB - We report the synthesis and characterization of a series of symmetrical indolenine-based squaraine dyes along with the evaluation of their singlet oxygen generation efficiency. The photodynamic activity of these new photosensitizers has been evaluated on a human tumor fibrosarcoma (HT-1080) cell line. The cytotoxicity increased over time and is induced by the photoactivation of bromo (Br-C4) and iodio (I-C4) long carbon chain squaraine dyes and the consequent increase in reactive oxygen species (ROS) production (p < 0.001), which leads to necrosis 6 h after treatment. Induction of cytochrome c release, DNA damage and up-regulation of GPX1, NQO1 and SOD2 mRNA gene expression after PDT were investigated. PMID- 26942627 TI - Thiazolo[4,5-d]pyrimidines as a privileged scaffold in drug discovery. AB - Thiazolo[4,5-d]pyrimidines are fused heterocyclic ring-systems that can be viewed at the first glance as purine isosteres. They are the 7 thia-analogs of purines via the replacement of the nitrogen at position 7 of the purine ring by a sulfur atom. Because of the structural resemblance to adenine and guanine and their related derivatives as adenosine, guanosine, cAMP, cGMP and similar biomolecules, many thiazolo[4,5-d]pyrimidines scaffold were developed and utilized by medicinal chemists to design novel therapeutics. Many were found to have a broad range of pharmacological activities. The outstanding development of thiazolo[4,5 d]pyrimidines within a short time span shows its magnitude of usefulness for medicinal chemistry research. Despite their importance from pharmacological and synthetic point of views, hardly there is a comprehensive review of thiazolo[4,5 d]pyrimidines applications in medicinal research to date. Thus, this review article describes the structures and medicinal significance of all classes of thiazolo[4,5-d]pyrimidines reported in literature to date. It describe the development of thiazolo[4,5-d]pyrimidines as immune-modulators, Corticotropin Releasing Factor (CRF) receptor antagonists, anti-Parkinson's, antiviral, anticancer, antibacterial, antifungal, analgesic, anti-inflammatory agents including COX inhibitors, chemokines antagonists and Fractlkine receptor antagonists. PMID- 26942628 TI - Reply to Dr. Peter Paradiso. PMID- 26942630 TI - Association between overuse of mobile phones on quality of sleep and general health among occupational health and safety students. AB - Concerns about health problems due to the increasing use of mobile phones are growing. Excessive use of mobile phones can affect the quality of sleep as one of the important issues in the health literature and general health of people. Therefore, this study investigated the relationship between the excessive use of mobile phones and general health and quality of sleep on 450 Occupational Health and Safety (OH&S) students in five universities of medical sciences in the North East of Iran in 2014. To achieve this objective, special questionnaires that included Cell Phone Overuse Scale, Pittsburgh's Sleep Quality Index (PSQI) and General Health Questionnaire (GHQ) were used, respectively. In addition to descriptive statistical methods, independent t-test, Pearson correlation, analysis of variance (ANOVA) and multiple regression tests were performed. The results revealed that half of the students had a poor level of sleep quality and most of them were considered unhealthy. The Pearson correlation co-efficient indicated a significant association between the excessive use of mobile phones and the total score of general health and the quality of sleep. In addition, the results of the multiple regression showed that the excessive use of mobile phones has a significant relationship between each of the four subscales of general health and the quality of sleep. Furthermore, the results of the multivariate regression indicated that the quality of sleep has a simultaneous effect on each of the four scales of the general health. Overall, a simultaneous study of the effects of the mobile phones on the quality of sleep and the general health could be considered as a trigger to employ some intervention programs to improve their general health status, quality of sleep and consequently educational performance. PMID- 26942629 TI - Water-Soluble Cationic Polyphosphazenes Grafted with Cyclic Polyamine and Imidazole as an Effective Gene Delivery Vector. AB - Gene therapy holds immense potential as a future therapeutic strategy for the treatment of numerous genetic diseases which are incurable to date. Nevertheless, safe and efficient gene delivery remains the most challenging aspects of gene therapy. In this study, a series of polyphosphazenes (PPZ) bearing cyclic polyamine and imidazole groups were synthesized and investigated for gene delivery. Agarose gel electrophoresis assays showed that poly(imidazole/1,4,7,10 tetraazyclodocane)phosphazene (Im-PPZ-cyclen) had good binding ability with plasmid DNA (pDNA), yielding positively charged particles with a size around 120 140 nm from a ratio of 10:1 to 5:1 (Im-PPZ-cyclen/pDNA, w/w). The cytotoxicity of Im-PPZ-cyclen assayed by MTT was lower than that of PEI 25 kDa, and was similar to that reported for poly(di-2-dimethylaminoethylamine)phosphazene (poly(di DMAEA)phosphazene) to some degree. The maximum transfection efficiency of Im-PPZ cyclen/pDNA complexes against 293 T cells at the ratio of 5:1 (Im-PPZ cyclen/pDNA, w/w) is close to that of Lipofectamine 2000. The present work may provide a strategy for the design of new cationic polymers with reduced cytotoxicity and be applied to gene delivery as an efficient nonviral vector. PMID- 26942631 TI - Polyurethane foam (PUF) passive samplers for monitoring phenanthrene in stormwater. AB - Pollution from highway stormwater runoff has been an increasing area of concern. Many structural Best Management Practices (BMPs) have been implemented for stormwater treatment and management. One challenge for these BMPs is to sample stormwater and monitor BMP performance. The main objective of this study was to evaluate the feasibility of using polyurethane foam (PUF) passive samplers (PSs) for sampling phenanthrene (PHE) in highway stormwater runoff and BMPs. Tests were conducted using batch reactors, glass-tube columns, and laboratory-scale BMPs (bioretention cells). Results indicate that sorption for PHE by PUF is mainly linearly relative to time, and the high sorption capacity allows the PUF passive sampler to monitor stormwater events for months or years. The PUF passive samplers could be embedded in BMPs for monitoring influent and effluent PHE concentrations. Models developed to link the results of batch and column tests proved to be useful for determining removal or sorption parameters and performance of the PUF-PSs. The predicted removal efficiencies of BMPs were close to the real values obtained from the control columns with errors ranging between 8.46 and 1.52%. This research showed that it is possible to use PUF passive samplers for sampling stormwater and monitoring the performance of stormwater BMPs, which warrants the field-scale feasibility studies in the future. PMID- 26942649 TI - Evaluation of CFH Y402H polymorphism and CFHR3/CFHR1 deletion in age-related macular degeneration patients from Brazil. PMID- 26942650 TI - Perception of social support among family caregivers of vegetative patients: A qualitative study. AB - A vegetative state (VS) is the probable result after brain damage. After VS patients are discharged from the hospital, the responsibility of caring of them is transferred to their families, which impacts a caregiver's physical and psychological health. Social support as a valuable resource reduces the negative effects of stressful events. This study aimed to explore the perception of social support among family caregivers of VS patients. This study is a part of a larger qualitative study which used the descriptive and qualitative method. Purposeful and theoretical sampling was done, and data was gathered through face-to-face, in depth interviews. The four categories of "Family, a supporter in all aspects," "Beautiful emanation of the nurse's role," "Revitalization via empathy and companionship," and "Defects in support," were extracted. The primary concern of participants was receiving social support which can facilitate caregiving and coping with difficulties, but there are many shortcomings in supporting these caregivers. PMID- 26942651 TI - Effective connectivity of brain regions underlying third-party punishment: Functional MRI and Granger causality evidence. AB - Third-party punishment (TPP) for norm violations is an essential deterrent in large-scale human societies, and builds on two essential cognitive functions: evaluating legal responsibility and determining appropriate punishment. Despite converging evidence that TPP is mediated by a specific set of brain regions, little is known about their effective connectivity (direction and strength of connections). Applying parametric event-related functional MRI in conjunction with multivariate Granger causality analysis, we asked healthy participants to estimate how much punishment a hypothetical perpetrator deserves for intentionally committing criminal offenses varying in levels of harm. Our results confirmed that TPP legal decisions are based on two domain-general networks: the mentalizing network for evaluating legal responsibility and the central-executive network for determining appropriate punishment. Further, temporal pole (TP) and dorsomedial prefrontal cortex (PFC) emerged as hubs of the mentalizing network, uniquely generating converging output connections to ventromedial PFC, temporo parietal junction, and posterior cingulate. In particular, dorsomedial PFC received inputs only from TP and both its activation and its connectivity to dorsolateral PFC correlated with degree of punishment. This supports the hypothesis that dorsomedial PFC acts as the driver of the TPP activation pattern, leading to the decision on the appropriate punishment. In conclusion, these results advance our understanding of the organizational elements of the TPP brain networks and provide better insights into the mental states of judges and jurors tasked with blaming and punishing legal wrongs. PMID- 26942652 TI - Environmental lead and childhood blood lead levels in US children: NHANES, 1999 2006. AB - Although blood lead levels in the United States have fallen dramatically since 1980, there remain subgroups of children with high blood lead levels. We assessed the relationship between environmental lead sources and blood lead levels in children ages 1 to 5 years from the National Health and Nutrition Examination Survey (NHANES), 1999-2006. Modeled ambient air lead levels and industrial lead releases at the census-tract level were assigned to each child's residence with adjustment for confounding factors. Of 3,223 children, 272 (8.4%) had blood lead levels >= 5 ug/dL. Industrial releases (2,252 vs 1,696 lbs/mi2) and ambient air lead levels (2.28 vs 1.75 ng/m3) were greater in exposed versus unexposed children. For every 10,000 lb/mi2 increase in inverse distance squared weighted exposure, there was a 1.13% increase (95% CI: 0.45%, 1.81%) in blood lead (p = .001). PMID- 26942654 TI - Domain Configuration and Thermal Stability of (K0.48Na0.52)(Nb0.96Sb0.04)O3 Bi0.50(Na0.82K0.18)0.50ZrO3 Piezoceramics with High d33 Coefficient. AB - The domain configuration of lead-free (K0.48Na0.52)(Nb0.96Sb0.04)O3 Bi0.50(Na0.82K0.18)0.50ZrO3 ceramics with rhombohedral-tetragonal morphotropic phase boundary, accounting for the high piezoelectric property and good thermal stability, were systematically studied. Short domain segments (before poling) and long domain stripes with wedge-shaped or furcated ends (after poling) were found to be typical domain configurations. The reduced elastic energy, lattice distortion, and internal stress, due to the coexistence of rhombohedral and tetragonal phases, result in much easier domain reorientation and domain wall motion, responsible for the high piezoelectric properties, being on the order of 460 pC/N, in which the extrinsic contribution from irreversible domain switching was estimated to be around 50% of the total piezoelectricity. Minor piezoelectric property variations (<6% over a temperature range from -50 to 100 degrees C) were observed as a function of temperature, showing a good thermal stability. In addition, nanodomains (50 +/- 2 nm) were found to be assembled into domain stripes after poling, believed to benefit the high piezoelectric properties but not causing much thermal instability due to the small quantity. PMID- 26942653 TI - Localized rosuvastatin via implantable bioerodible sponge and its potential role in augmenting bone healing and regeneration. AB - OBJECTIVE: Statins proved potential bone healing properties. Rosuvastatin is a synthetic, hydrophilic, potent and highly efficacious statin. In the current work, an attempt was investigated to develop, evaluate various bioerodible composite sponges enclosing rosuvastatin and explore their potential in augmenting bone healing and regeneration. METHOD: Twelve lyophilized sponge formulae were prepared adapting a 41.31 full factorial design. Xanthan gum, polycarbophil, Carbopol(r) and sodium alginate were investigated as anionic polymers, each at three chitosan:anionic polymer ratios (1:3, 1:1, 3:1). The formula of choice was implanted in fractured rat femora. RESULTS: Visual and microscopic examination showed flexible homogenous porous structures with considerable bending ability. Polyelectrolyte complex formation was proved by DSC and FT-IR for all chitosan/anionic combinations except with xanthan gum where chitosan probably bound to the drug rather than xanthan gum. Statistical analysis proved that anionic polymer type and chitosan: polymer ratio, as well as, their interactions, exhibited significant effects on the release parameters at p <= 0.05. The optimum chitosan/anionic polymer complexation ratios were 3:1 for polycarbophil and 1:1 for Carbopol and alginate. The release at these ratios followed Fiction diffusion while other ratios had anomalous diffusion. Imwitor(r) 900K and HPMC K100M were added as release retarardants for further release optimization. The formula of choice was implanted in fractured rat femora. Histopathological examination revealed advanced stages of healing in treated femora compared to control ones. CONCLUSION: Biodegradable sponges for local rosuvastatin delivery proved significantly enhanced wound healing and regeneration properties to fractured bones. PMID- 26942655 TI - Recent developments in the understanding and use of anthrax vaccine adsorbed: achieving more with less. AB - Anthrax Vaccine Adsorbed (AVA, BioThraxTM) is the only Food and Drug Administration (FDA) approved vaccine for the prevention of anthrax in humans. Recent improvements in pre-exposure prophylaxis (PrEP) use of AVA include intramuscular (IM) administration and simplification of the priming series to three doses over 6 months. Administration IM markedly reduced the frequency, severity and duration of injection site reactions. Refinement of animal models for inhalation anthrax, identification of immune correlates of protection and cross-species modeling have created opportunities for reductions in the PrEP booster schedule and were pivotal in FDA approval of a post-exposure prophylaxis (PEP) indication. Clinical and nonclinical studies of accelerated PEP schedules and divided doses may provide prospects for shortening the PEP antimicrobial treatment period. These data may assist in determining feasibility of expanded coverage in a large-scale emergency when vaccine demand may exceed availability. Enhancements to the AVA formulation may broaden the vaccine's PEP application. PMID- 26942656 TI - EMG classification using wavelet functions to determine muscle contraction. AB - Surface electromyogram (SEMG) is a complex signal and is influenced by several external factors/artifacts. The electromyogram signal from the stump of the subject is picked up through surface electrodes. It is amplified and artifacts are removed before digitising it in a controlled manner so that minimum signal loss occurs due to processing. As removing these artifacts is not easy, feature extraction to obtain useful information hidden inside the signal becomes a different process. This paper presents methods of analysing SEMG signals using discrete wavelet Transform (DWT) for extracting accurate patterns of the signals and the performance of the used algorithms is being analysed rigorously. The obtained results suggest a root mean square difference (RMSD) value for the denoising and quality of reconstruction of the SEMG signal. The result shows that the best mother wavelets for tolerance of noise are second order of symmlets and bior6.8. Results inferred that bior6.8 suitable for the classification and analysis of SEMG signals of different arm motions results in a classification accuracy of 88.90%. PMID- 26942657 TI - Physiologic and Perceptual Responses to Cold-Shower Cooling After Exercise Induced Hyperthermia. AB - CONTEXT: Exercise conducted in hot, humid environments increases the risk for exertional heat stroke (EHS). The current recommended treatment of EHS is cold water immersion; however, limitations may require the use of alternative resources such as a cold shower (CS) or dousing with a hose to cool EHS patients. OBJECTIVE: To investigate the cooling effectiveness of a CS after exercise induced hyperthermia. DESIGN: Randomized, crossover controlled study. SETTING: Environmental chamber (temperature = 33.4 degrees C +/- 2.1 degrees C; relative humidity = 27.1% +/- 1.4%). PATIENTS OR OTHER PARTICIPANTS: Seventeen participants (10 male, 7 female; height = 1.75 +/- 0.07 m, body mass = 70.4 +/- 8.7 kg, body surface area = 1.85 +/- 0.13 m(2), age range = 19-35 years) volunteered. INTERVENTION(S): On 2 occasions, participants completed matched intensity volitional exercise on an ergometer or treadmill to elevate rectal temperature to >=39 degrees C or until participant fatigue prevented continuation (reaching at least 38.5 degrees C). They were then either treated with a CS (20.8 degrees C +/- 0.80 degrees C) or seated in the chamber (control [CON] condition) for 15 minutes. MAIN OUTCOME MEASURE(S): Rectal temperature, calculated cooling rate, heart rate, and perceptual measures (thermal sensation and perceived muscle pain). RESULTS: The rectal temperature (P = .98), heart rate (P = .85), thermal sensation (P = .69), and muscle pain (P = .31) were not different during exercise for the CS and CON trials (P > .05). Overall, the cooling rate was faster during CS (0.07 degrees C/min +/- 0.03 degrees C/min) than during CON (0.04 degrees C/min +/- 0.03 degrees C/min; t16 = 2.77, P = .01). Heart-rate changes were greater during CS (45 +/- 20 beats per minute) compared with CON (27 +/- 10 beats per minute; t16 = 3.32, P = .004). Thermal sensation was reduced to a greater extent with CS than with CON (F3,45 = 41.12, P < .001). CONCLUSIONS: Although the CS facilitated cooling rates faster than no treatment, clinicians should continue to advocate for accepted cooling modalities and use CS only if no other validated means of cooling are available. PMID- 26942658 TI - Examining Academic Support After Concussion for the Adolescent Student-Athlete: Perspectives of the Athletic Trainer. AB - CONTEXT: Student-athletes may require cognitive rest and academic support after concussion. Athletic trainers (ATs) in secondary schools are uniquely positioned to provide medical care and to collaborate with school professionals while managing concussions. However, little is known regarding return-to-learn policies and their implementation in secondary schools. OBJECTIVE: To examine ATs' perspectives on return to learn, cognitive rest, and communication with school professionals after concussion. DESIGN: Cross-sectional study. SETTING: Web-based survey. PATIENTS OR OTHER PARTICIPANTS: A total of 1124 secondary school ATs completed the survey (28.5% response rate). The majority of participants were employed full time (752/1114 [67.5%]) in public schools (911/1117 [81.6%]). MAIN OUTCOME MEASURE(S): School and AT employment characteristics, demographics, number of concussions evaluated annually, and perceptions of school professionals' familiarity with ATs' responsibilities were independent variables. RESULTS: Of the ATs, 44% reported having an existing return-to-learn policy. The strongest predictor of a return-to-learn policy was frequent communication with teachers after concussion (odds ratio = 1.5; 95% confidence interval = 1.2, 1.7). Most ATs recommended complete cognitive rest (eg, no reading, television; 492/1087 [45.3%]) or limited cognitive activity based upon symptoms (391/1087 [36.0%]). Common academic accommodations were postponed due dates (789/954 [82.7%]), rest breaks (765/954 [80.2%]), and partial attendance (740/954 [77.6%]). Athletic trainers self-reported as primary monitors of health (764/1037 [73.7%]) and academic progression (359/1011 [35.5%]). The strongest predictor of ATs' communication with school professionals was their perception of school professionals' understanding of ATs' roles. CONCLUSIONS: Overall, ATs followed best practices for cognitive rest and return to learn after concussion. Although ATs are central to the management of student-athletes' physical health after concussion, school professionals may be better suited to monitor academic progress. Increased communication between the AT and school professionals is recommended to monitor recovery and facilitate academic support for symptomatic student-athletes. PMID- 26942659 TI - Clinical Practice Patterns and Beliefs in the Management of Hamstrings Strain Injuries. AB - CONTEXT: Hamstrings strain injuries (HSIs) are among the most commonly occurring injuries in sport and are top causes of missed playing time. Lingering symptoms, prolonged recovery, and a high reinjury rate (12%-34%) make HSI management a frustrating and challenging process for the athletic trainer (AT). The clinical practice patterns and opinions of ATs regarding HSI treatment and rehabilitation are unknown. OBJECTIVE: To examine the frequency of method use and opinions about current HSI management among ATs. DESIGN: Cross-sectional study. SETTING: Survey administered to registrants at the 2013 National Athletic Trainers' Association Clinical Symposia and AT Expo. PATIENTS OR OTHER PARTICIPANTS: A total of 1356 certified ATs (691 men, 665 women; age = 35.4 +/- 10.5 years, time certified = 11.92 +/- 9.75 years). DATA COLLECTION AND ANALYSIS: A survey was distributed electronically to 7272 registrants and on paper to another 700 attendees. Validity and reliability were established before distribution. Participants reported demographic information and rated their frequency of treatment and rehabilitation method use and agreement with questions assessing confidence, satisfaction, and desire for better clinical practice guidelines. Exploratory factor analysis and principal axis factor analysis were used. We also calculated descriptive statistics and chi(2) tests to assess practice patterns. RESULTS: The response rate was 17% (n = 1356). A 2-factor solution was accepted for factor analysis (r = 0.76, r = 0.70), indicating that ATs follow either a contemporary or traditional management style. Various practice patterns were evident across employment settings and years of clinical experience. Satisfaction with the current HSI management plan was high (73.6%), whereas confidence in returning an athlete to play was lower (62.0%). Rates of use were associated with belief in effectiveness for all methods assessed (P < .001). Higher confidence levels were associated with high use of several methods; we observed increased satisfaction (chi(2)2 = 22.5, P = .002) but not increased confidence levels in more experienced ATs. CONCLUSIONS: Our study demonstrated the lack of consensus in HSI treatment and rehabilitation and the ATs' desire for better clinical practice guidelines. Future research in which multimodal strategies, including both traditional and contemporary methods, are studied is warranted for effective management of HSI. PMID- 26942660 TI - Using Pre-Exercise Photobiomodulation Therapy Combining Super-Pulsed Lasers and Light-Emitting Diodes to Improve Performance in Progressive Cardiopulmonary Exercise Tests. AB - CONTEXT: Skeletal muscle fatigue and exercise performance are novel areas of research and clinical application in the photobiomodulation field, and positive outcomes have been reported in several studies; however, the optimal measures have not been fully established. OBJECTIVE: To assess the acute effect of photobiomodulation therapy (PBMT) combining superpulsed lasers (low-level laser therapy) and light-emitting diodes (LEDs) on muscle performance during a progressive cardiopulmonary treadmill exercise test. DESIGN: Crossover study. SETTING: Laboratory. PATIENTS OR OTHER PARTICIPANTS: Twenty untrained male volunteers (age = 26.0 +/- 6.0 years, height = 175.0 +/- 10.0 cm, mass = 74.8 +/- 10.9 kg). INTERVENTION(S): Participants received PBMT with either combined superpulsed lasers and LED (active PBMT) or placebo at session 1 and the other treatment at session 2. All participants completed a cardiopulmonary test on a treadmill after each treatment. For active PBMT, we performed the irradiation at 17 sites on each lower limb (9 on the quadriceps, 6 on the hamstrings, and 2 on the gastrocnemius muscles), using a cluster with 12 diodes (four 905-nm superpulsed laser diodes with an average power of 0.3125 mW, peak power of 12.5 W for each diode, and frequency of 250 Hz; four 875-nm infrared LED diodes with an average power of 17.5 mW; and four 640-nm red LED diodes with an average power of 15 mW) and delivering a dose of 30 J per site. MAIN OUTCOME MEASURE(S): Distance covered, time until exhaustion, pulmonary ventilation, and dyspnea score. RESULTS: The distance covered (1.96 +/- 0.30 versus 1.84 +/- 0.40 km, t19 = 2.119, P < .001) and time until exhaustion on the cardiopulmonary test (780.2 +/- 91.0 versus 742.1 +/- 94.0 seconds, t19 = 3.028, P < .001) was greater after active PBMT than after placebo. Pulmonary ventilation was greater (76.4 +/- 21.9 versus 74.3 +/- 19.8 L/min, t19 = 0.180, P = .004) and the score for dyspnea was lower (3.0 [interquartile range = 0.5-9.0] versus 4.0 [0.0-9.0], U = 184.000, P < .001) after active PBMT than after placebo. CONCLUSIONS: The combination of lasers and LEDs increased the time, distance, and pulmonary ventilation and decreased the score of dyspnea during a cardiopulmonary test. PMID- 26942661 TI - Factors Associated With Concurrent Tobacco Smoking and Heavy Alcohol Consumption Within a Socioeconomically Disadvantaged Australian Sample. AB - BACKGROUND: Tobacco use and heavy alcohol consumption occur more frequently in socioeconomically disadvantaged groups. Little is known about the sociodemographic and psychosocial factors associated with use of alcohol and tobacco in disadvantaged groups in comparison to low-risk users. OBJECTIVES: This study aimed to compare the characteristics of low-risk users with: disadvantaged smokers only; disadvantaged heavy drinkers only; and disadvantaged concurrent smokers and heavy drinkers. METHODS: A cross-sectional survey of socioeconomically disadvantaged adult clients attending a community welfare agency assessed tobacco use, alcohol use, demographic, and psychosocial variables. Multivariable analysis using multinomial logistic regression was carried out. RESULTS: The sample consisted of 835 participants; 40% (n = 331) were concurrent users, 31% were smokers only (n = 252), 11% were heavy drinkers only (n = 93), and 18% were low-risk users (n = 149). Compared with those who neither smoked nor consumed alcohol heavily, concurrent users were more likely to be younger, have only some contact with family, have more friends and family who were smokers, have no fixed home address, live alone, and have higher levels of financial stress. Most of these factors were shared by individuals who were smokers only. Factors associated with heavy drinkers only were frequent contact with family and having more friends and family who were smokers. CONCLUSION: Among those Australians who suffer severe economic hardship, being a concurrent smoker and heavy drinker appears to be associated with more isolated living conditions and financial stress but some contact with family. PMID- 26942662 TI - Engineering the Structure and Properties of DNA-Nanoparticle Superstructures Using Polyvalent Counterions. AB - DNA assembly of nanoparticles is a powerful approach to control their properties and prototype new materials. However, the structure and properties of DNA assembled nanoparticles are labile and sensitive to interactions with counterions, which vary with processing and application environment. Here we show that substituting polyamines in place of elemental counterions significantly enhanced the structural rigidity and plasmonic properties of DNA-assembled metal nanoparticles. These effects arose from the ability of polyamines to condense DNA and cross-link DNA-coated nanoparticles. We further used polyamine wrapped DNA nanostructures as structural templates to seed the growth of polymer multilayers via layer-by-layer assembly, and controlled the degree of DNA condensation, plasmon coupling efficiency, and material responsiveness to environmental stimuli by varying polyelectrolyte composition. These results highlight counterion engineering as a versatile strategy to tailor the properties of DNA-nanoparticle assemblies for various applications, and should be applicable to other classes of DNA nanostructures. PMID- 26942663 TI - Corrigendum: Cultural traditions across a migratory network shape the genetic structure of southern right whales around Australia and New Zealand. PMID- 26942664 TI - Highly Selective Fluorescence Determination of the Hematin Level in Human Erythrocytes with No Need for Separation from Bulk Hemoglobin. AB - Hematin-induced fluorescence quenching of boron-doped graphene quantum dots (BGQDs) allows for determination of hematin concentration in human erythrocytes with no need for separating hematin from hemoglobin before performing the assay. The BGQDs are made by oxidizing a graphite anode by holding the voltage between a graphite rod and a Pt cathode at 3 V for 2 h in an aqueous borax solution at pH 7; then, the borate solution was filtered with BGQDs, and the borate was dialyzed from the filtrate, leaving a solution of BGQDs in water. The fluorescence intensity of BGQDs is measurable in real time, and its quenching is very sensitive to the concentration of hematin in the system but not to other coexisting biological substances. The analytical signal is defined as DeltaF = 1 F/F0, where F0 and F are the fluorescence intensities of the BGQDs before and after interaction with hematin, respectively. There is a good linear relationship between DeltaF and hematin concentration, ranging from 0.01 to 0.92 MUM, with the limit of detection (LOD) being ~0.005 +/- 0.001 MUM at a signal-to-noise ratio of 3. This new method is sensitive, label-free, simple, and inexpensive, and many tedious procedures related to sample separation and preparation can be omitted, implying that this method has potential for applications in clinical examinations and disease diagnoses. For example, the determination of the hematin levels in two kind of red blood cell samples, healthy human and sickle cell erythrocytes, gives average concentrations of hematin of ~(23.1 +/- 4.9) MUM (average of five samples) for healthy red cell cytosols and ~(52.5 +/- 9.5) MUM (average of two samples) for sickle red cell cytosols. PMID- 26942665 TI - The Mighty Mitochondria. PMID- 26942666 TI - Exploiting Mitochondria In Vivo as Chemical Reaction Chambers Dependent on Membrane Potential. AB - Recently in Cell Metabolism, Logan et al. (2016) exploit membrane potential dependent mitochondrial accumulation of charged precursors, causing them to combine by "click" chemistry 1,000,000 times faster than without accumulation to generate an ultrasensitive indicator for membrane potentials and foreshadow targeted drug synthesis in vivo. PMID- 26942667 TI - Clean Up after Yourself. AB - NLRP3 inflammasome activation is accompanied by induction of mitochondrial damage. In the current issue of Cell, Zhong et al. describe an intracellular mechanism orchestrated by NF-kappaB to remove inflammasome-activating damaged mitochondria and prevent pathologic inflammation. PMID- 26942668 TI - Intramitochondrial Ca(2+) Sensing by EMRE: The Matrix Outlook on Stimulus Metabolism Coupling. AB - Mitochondrial Ca(2+) entry is an important process regulating cellular bioenergetics, redox responses, and apoptosis. The study by Vais and colleagues (Vais et al., 2016), recently published in Cell Reports, describes a novel mechanism of modulating Ca(2+) entry that involves mitochondrial matrix Ca(2+). PMID- 26942669 TI - The Emerging Network of Mitochondria-Organelle Contacts. AB - Membrane contact sites between mitochondria and other organelles are important for lipid and ion exchange, membrane dynamics, and signaling. Recent advances are revealing their molecular features and how different types of mitochondria contacts are coordinated with each other for cell function. PMID- 26942670 TI - The Mitochondrial Basis of Aging. AB - A decline in mitochondrial quality and activity has been associated with normal aging and correlated with the development of a wide range of age-related diseases. Here, we review the evidence that a decline in mitochondria function contributes to aging. In particular, we discuss how mitochondria contribute to specific aspects of the aging process, including cellular senescence, chronic inflammation, and the age-dependent decline in stem cell activity. Signaling pathways regulating the mitochondrial unfolded protein response and mitophagy are also reviewed, with particular emphasis placed on how these pathways might, in turn, regulate longevity. Taken together, these observations suggest that mitochondria influence or regulate a number of key aspects of aging and suggest that strategies directed at improving mitochondrial quality and function might have far-reaching beneficial effects. PMID- 26942672 TI - Metabolism and the UPR(mt). AB - During mitochondrial dysfunction or the accumulation of unfolded proteins within mitochondria, cells employ a transcriptional response known as the mitochondrial unfolded protein response (UPR(mt)) to promote cell survival along with the repair and recovery of defective mitochondria. Considerable progress has been made in understanding how cells monitor mitochondrial function and activate the response, as well as in identifying scenarios where the UPR(mt) plays a protective role, such as during bacterial infection, hematopoietic stem cell maintenance, or general aging. To date, much of the focus has been on the role of the UPR(mt) in maintaining or re-establishing protein homeostasis within mitochondria by transcriptionally inducing mitochondrial molecular chaperone and protease genes. In this review, we focus on the metabolic adaptations or rewiring mediated by the UPR(mt) and how this may contribute to the resolution of mitochondrial unfolded protein stress and cell-type-specific physiology. PMID- 26942673 TI - Mitofusins, from Mitochondria to Metabolism. AB - Mitochondrial architecture is involved in several functions crucial for cell viability, proliferation, senescence, and signaling. In particular, mitochondrial dynamics, through the balance between fusion and fission events, represents a central mechanism for bioenergetic adaptation to metabolic needs of the cell. As key regulators of mitochondrial dynamics, the fusogenic mitofusins have recently been linked to mitochondrial biogenesis and respiratory functions, impacting on cell fate and organism homeostasis. Here we review the implication of mitofusins in the regulation of mitochondrial metabolism, and their consequence on energy homeostasis at the cellular and physiological level, highlighting their crucial role in metabolic disorders, cancer, and aging. PMID- 26942671 TI - Mitochondria and Cancer. AB - Decades ago, Otto Warburg observed that cancers ferment glucose in the presence of oxygen, suggesting that defects in mitochondrial respiration may be the underlying cause of cancer. We now know that the genetic events that drive aberrant cancer cell proliferation also alter biochemical metabolism, including promoting aerobic glycolysis, but do not typically impair mitochondrial function. Mitochondria supply energy; provide building blocks for new cells; and control redox homeostasis, oncogenic signaling, innate immunity, and apoptosis. Indeed, mitochondrial biogenesis and quality control are often upregulated in cancers. While some cancers have mutations in nuclear-encoded mitochondrial tricarboxylic acid (TCA) cycle enzymes that produce oncogenic metabolites, there is negative selection for pathogenic mitochondrial genome mutations. Eliminating mtDNA limits tumorigenesis, and rare human tumors with mutant mitochondrial genomes are relatively benign. Thus, mitochondria play a central and multifunctional role in malignant tumor progression, and targeting mitochondria provides therapeutic opportunities. PMID- 26942674 TI - Mitochondria-Judges and Executioners of Cell Death Sentences. AB - Apoptosis is a form of programmed cell death that is critical for basic human development and physiology. One of the more important surprises in cell biology in the last two decades is the extent to which mitochondria represent a physical point of convergence for many apoptosis-inducing signals in mammalian cells. Mitochondria not only adjudicate the decision of whether or not to commit to cell death, but also release toxic proteins culminating in widespread proteolysis, nucleolysis, and cell engulfment. Interactions among BCL-2 family proteins at the mitochondrial outer membrane control the release of these toxic proteins and, by extension, control cellular commitment to apoptosis. This pathway is particularly relevant to cancer treatment, as most cancer chemotherapies trigger mitochondrial mediated apoptosis. In this Review, we discuss recent advances in the BCL-2 family interactions, their control by upstream factors, and how the mitochondria itself alters these interactions. We also highlight recent clinical insights into mitochondrial-mediated apoptosis and novel cancer therapies that exploit this pathway. PMID- 26942675 TI - Mitochondria-Translocated PGK1 Functions as a Protein Kinase to Coordinate Glycolysis and the TCA Cycle in Tumorigenesis. AB - It is unclear how the Warburg effect that exemplifies enhanced glycolysis in the cytosol is coordinated with suppressed mitochondrial pyruvate metabolism. We demonstrate here that hypoxia, EGFR activation, and expression of K-Ras G12V and B-Raf V600E induce mitochondrial translocation of phosphoglycerate kinase 1 (PGK1); this is mediated by ERK-dependent PGK1 S203 phosphorylation and subsequent PIN1-mediated cis-trans isomerization. Mitochondrial PGK1 acts as a protein kinase to phosphorylate pyruvate dehydrogenase kinase 1 (PDHK1) at T338, which activates PDHK1 to phosphorylate and inhibit the pyruvate dehydrogenase (PDH) complex. This reduces mitochondrial pyruvate utilization, suppresses reactive oxygen species production, increases lactate production, and promotes brain tumorigenesis. Furthermore, PGK1 S203 and PDHK1 T338 phosphorylation levels correlate with PDH S293 inactivating phosphorylation levels and poor prognosis in glioblastoma patients. This work highlights that PGK1 acts as a protein kinase in coordinating glycolysis and the tricarboxylic acid (TCA) cycle, which is instrumental in cancer metabolism and tumorigenesis. PMID- 26942677 TI - CDK1-Cyclin B1 Activates RNMT, Coordinating mRNA Cap Methylation with G1 Phase Transcription. AB - The creation of translation-competent mRNA is dependent on RNA polymerase II transcripts being modified by addition of the 7-methylguanosine (m7G) cap. The factors that mediate splicing, nuclear export, and translation initiation are recruited to the transcript via the cap. The cap structure is formed by several activities and completed by RNMT (RNA guanine-7 methyltransferase), which catalyzes N7 methylation of the cap guanosine. We report that CDK1-cyclin B1 phosphorylates the RNMT regulatory domain on T77 during G2/M phase of the cell cycle. RNMT T77 phosphorylation activates the enzyme both directly and indirectly by inhibiting interaction with KPNA2, an RNMT inhibitor. RNMT T77 phosphorylation results in elevated m7G cap methyltransferase activity at the beginning of G1 phase, coordinating mRNA capping with the burst of transcription that occurs following nuclear envelope reformation. RNMT T77 phosphorylation is required for the production of cohort of proteins, and inhibiting T77 phosphorylation reduces the cell proliferation rate. PMID- 26942676 TI - TRIM21 Ubiquitylates SQSTM1/p62 and Suppresses Protein Sequestration to Regulate Redox Homeostasis. AB - TRIM21 is a RING finger domain-containing ubiquitin E3 ligase whose expression is elevated in autoimmune disease. While TRIM21 plays an important role in immune activation during pathogen infection, little is known about its inherent cellular function. Here we show that TRIM21 plays an essential role in redox regulation by directly interacting with SQSTM1/p62 and ubiquitylating p62 at lysine 7 (K7) via K63-linkage. As p62 oligomerizes and sequesters client proteins in inclusions, the TRIM21-mediated p62 ubiquitylation abrogates p62 oligomerization and sequestration of proteins including Keap1, a negative regulator of antioxidant response. TRIM21-deficient cells display an enhanced antioxidant response and reduced cell death in response to oxidative stress. Genetic ablation of TRIM21 in mice confers protection from oxidative damages caused by arsenic-induced liver insult and pressure overload heart injury. Therefore, TRIM21 plays an essential role in p62-regulated redox homeostasis and may be a viable target for treating pathological conditions resulting from oxidative damage. PMID- 26942678 TI - Enhancer of Rudimentary Cooperates with Conserved RNA-Processing Factors to Promote Meiotic mRNA Decay and Facultative Heterochromatin Assembly. AB - Erh1, the fission yeast homolog of Enhancer of rudimentary, is implicated in meiotic mRNA elimination during vegetative growth, but its function is poorly understood. We show that Erh1 and the RNA-binding protein Mmi1 form a stoichiometric complex, called the Erh1-Mmi1 complex (EMC), to promote meiotic mRNA decay and facultative heterochromatin assembly. To perform these functions, EMC associates with two distinct complexes, Mtl1-Red1 core (MTREC) and CCR4-NOT. Whereas MTREC facilitates assembly of heterochromatin islands coating meiotic genes silenced by the nuclear exosome, CCR4-NOT promotes RNAi-dependent heterochromatin domain (HOOD) formation at EMC-target loci. CCR4-NOT also assembles HOODs at retrotransposons and regulated genes containing cryptic introns. We find that CCR4-NOT facilitates HOOD assembly through its association with the conserved Pir2/ARS2 protein, and also maintains rDNA integrity and silencing by promoting heterochromatin formation. Our results reveal connections among Erh1, CCR4-NOT, Pir2/ARS2, and RNAi, which target heterochromatin to regulate gene expression and protect genome integrity. PMID- 26942681 TI - Timeline: Mitochondria. AB - Mitochondria perform diverse yet interconnected cellular functions and are dynamically regulated by complex signaling pathways. Interest in this fascinating organelle has recently undergone a renaissance due to a series of discoveries revealing that mitochondrial function goes beyond the generation of molecular fuel. This Timeline highlights some of the groundbreaking events over the last 30 years in our understanding of how mitochondria are made and turned over, and how they integrate and signal within the cell and organism. To view this Timeline, open or download the PDF. PMID- 26942679 TI - A Specialized Mechanism of Translation Mediated by FXR1a-Associated MicroRNP in Cellular Quiescence. AB - MicroRNAs predominantly decrease gene expression; however, specific mRNAs are translationally upregulated in quiescent (G0) mammalian cells and immature Xenopus laevis oocytes by an FXR1a-associated microRNA-protein complex (microRNP) that lacks the microRNP repressor, GW182. Their mechanism in these conditions of decreased mTOR signaling, and therefore reduced canonical (cap-and-poly(A)-tail mediated) translation, remains undiscovered. Our data reveal that mTOR inhibition in human THP1 cells enables microRNA-mediated activation. Activation requires shortened/no poly(A)-tail targets; polyadenylated mRNAs are partially activated upon PAIP2 overexpression, which interferes with poly(A)-bound PABP, precluding PABP-enhanced microRNA-mediated inhibition and canonical translation. Consistently, inhibition of PARN deadenylase prevents activation. P97/DAP5, a homolog of canonical translation factor, eIF4G, which lacks PABP- and cap binding complex-interacting domains, is required for activation, and thereby for the oocyte immature state. P97 interacts with 3' UTR-binding FXR1a-associated microRNPs and with PARN, which binds mRNA 5' caps, forming a specialized complex to translate recruited mRNAs in these altered canonical translation conditions. PMID- 26942682 TI - Assessing practice-based influences on adolescent psychosocial development in sport: the activity context in youth sport questionnaire. AB - The aim of this study was to provide initial evidence of validity and reliability of scores derived from the Activity Context in Youth Sport Questionnaire (ACYSQ), an instrument designed to offer a comprehensive assessment of the activities adolescents take part in during sport practices. Two studies were designed for the purposes of item development and selection, and to provide evidence of structural and criterion validity of ACYSQ scores, respectively (N = 334; M age = 14.93, SD = 1.76 years). Confirmatory factor analysis (CFA) supported the adequacy of a 20-item ACYSQ measurement model, which was invariant across gender, and comprised the following dimensions: (1) stimulation; (2) usefulness-value; (3) authenticity; (4) repetition-boredom; and (5) ineffectiveness. Internal consistency reliability estimates and composite reliability estimates for ACYSQ subscale scores ranged from 0.72 to 0.91. In regression analyses, stimulation predicted enjoyment and perceived competence, ineffectiveness was significantly associated with perceived competence and authenticity emerged as a predictor of commitment in sport. These findings indicate that the ACYSQ displays adequate psychometric properties and the use of the instrument may be useful for studying selected activity-based features of the practice environment and their motivational consequences in youth sport. PMID- 26942680 TI - Licensing of Centromeric Chromatin Assembly through the Mis18alpha-Mis18beta Heterotetramer. AB - Centromeres are specialized chromatin domains specified by the centromere specific CENP-A nucleosome. The stable inheritance of vertebrate centromeres is an epigenetic process requiring deposition of new CENP-A nucleosomes by HJURP. We show HJURP is recruited to centromeres through a direct interaction between the HJURP centromere targeting domain and the Mis18alpha-beta C-terminal coiled-coil domains. We demonstrate Mis18alpha and Mis18beta form a heterotetramer through their C-terminal coiled-coil domains. Mis18alpha-beta heterotetramer formation is required for Mis18BP1 binding and centromere recognition. S. pombe contains a single Mis18 isoform that forms a homotetramer, showing tetrameric Mis18 is conserved from fission yeast to humans. HJURP binding disrupts the Mis18alpha beta heterotetramer and removes Mis18alpha from centromeres. We propose stable binding of Mis18 to centromeres in telophase licenses them for CENP-A deposition. Binding of HJURP deposits CENP-A at centromeres and facilitates the removal of Mis18, restricting CENP-A deposition to a single event per cell cycle. PMID- 26942683 TI - The effects of urban particulate matter on the nasal epithelium by gender: An experimental study in mice. AB - Nose is the first portion of the respiratory system into contact with air pollution particles, including organic compounds that could act as endocrine releasers. The objective was to identify and quantify estrogenic receptor-beta (ERbeta), aryl hydrocarbon receptor (AhR), the cytochrome P450 enzymes CYP1A1, 1A2, 1B1, and mucus profile in the nasal epithelium of mice. BALB/c mice male (n = 32) and female (n = 82) in proestrus, estrus and diestrus were divided into two groups: 1) exposed to ambient air; 2) concentrated ambient particles (CAPs) to achieve an accumulated dose (concentration vs. time product) of 600 MUg/m(3), the time of the exposure was controlled to ensure the same concentration for all groups (5 days per week for 40-51 days). RT-PCR (Erbeta-1, Erbeta-2, Ahr, Cyp1a1, Cyp1a2, Cyp1b1), immunohistochemistry and morphometry (ERbeta, AhR) were used to analyze. The mucus profiles were examined using acid (Alcian Blue) and neutral (periodic acid Schiff's) stains. Exposed females had significantly lower levels of Erbeta-2 mRNA than exposed males (p = 0.036). Cyp1b1 mRNA in diestrus females was significantly lower in the CAP-exposed group compared with the ambient air group (p <= 0.05). ERbeta expression in the epithelium and submucosa nucleus was lower in estrus exposed to CAPs compared with ambient air. CAPs increases AhR in the epithelium (p = 0.044) and submucosa (p = 0.001) nucleus of female when compared with male mice. Exposure to CAPs, also led to relatively increased acidic content in the mucus of males (p = 0.048), but decreased acidic content in that of females (p = 0.04). This study revealed sex-dependent responses to air pollution in the nasal epithelium that may partially explain the predisposition of females to airway respiratory diseases. PMID- 26942684 TI - Genotoxic effects of starvation and dimethoate in haemocytes and midgut gland cells of wolf spider Xerolycosa nemoralis (Lycosidae). AB - The aim of this study was to assess the genotoxic effects of starvation and dimethoate (organophosphate insecticide) in female and male wolf spiders Xerolycosa nemoralis (Lycosidae) exposed to the stressors under laboratory conditions. DNA damage was measured in haemocytes and midgut gland cells using the comet assay. In response to the two stressing factors, both cell types showed %TDNA, tail length (TL) and OTM values higher in males than in females. Level of DNA damage in haemocytes was greater than in midgut gland cells. In both sexes, the strongest genotoxicity was recorded at single application of dimethoate. After five-time exposure to the pesticide, genotoxic effects of a single dose were sustained in males and reduced to the control level in females. Starvation stress was well tolerated by the females, in which neither cell type was affected by DNA damage. However, in male haemocytes food deprivation induced severe DNA damage, what suggests suppression of the defence potential at prolonged starvation periods. PMID- 26942685 TI - Trophic magnification of polybrominated diphenyl ethers in the marine food web from coastal area of Bohai Bay, North China. AB - Trophic transfer of polybrominated diphenyl ethers (PBDEs) in aquatic ecosystems is an important criterion for assessing their environmental risk. This study analyzed 13 PBDEs in marine organisms collected from coastal area of Bohai Bay, China. The concentrations of total PBDEs (Sigma13PBDEs) ranged from 12 +/- 1.1 ng/g wet weight (ww) to 230 +/- 54 ng/g ww depending on species. BDE-47 was the predominant compound, with a mean abundance of 20.21 +/- 12.97% of total PBDEs. Stable isotopic ratios of carbon (delta(13)C) and nitrogen (delta(15)N) were analyzed to determine the food web structure and trophic level respectively. Trophic magnification factors (TMFs) of PBDEs were assessed as the slope of lipid equivalent concentrations regressed against trophic levels. Significant positive relationships were found for Sigma13PBDEs and eight PBDE congeners (BDE-28, BDE 47, BDE-49, BDE-66, BDE-85, BDE-99, BDE-100 and BDE-154). Monte-Carlo simulations showed that the probabilities of TMF >1 were 100% for Sigma13PBDEs, BDE-47, BDE 85, BDE-99 and BDE-100, 99% for DE-28, BDE-49, BDE-66 and BDE-154, 94% for BDE 153, and 35% for BDE-17. PMID- 26942686 TI - Polybrominated diphenyl ethers (PBDEs) and alternative brominated flame retardants (aBFRs) in sediments from four bays of the Yellow Sea, North China. AB - The distribution characteristics and potential sources of polybrominated diphenyl ethers (PBDEs) and alternative brominated flame retardants (aBFRs) were investigated in 54 surface sediment samples from four bays (Taozi Bay, Sishili Bay, Dalian Bay, and Jiaozhou Bay) of North China's Yellow Sea. Of the 54 samples studied, 51 were collected from within the four bays and 3 were from rivers emptying into Jiaozhou Bay. Decabromodiphenylethane (DBDPE) was the predominant flame retardant found, and concentration ranged from 0.16 to 39.7 ng g(-1) dw and 1.13-49.9 ng g(-1) dw in coastal and riverine sediments, respectively; these levels were followed by those of BDE 209, and its concentrations ranged from n.d. to 10.2 ng g(-1) dw and 0.05-7.82 ng g(-1) dw in coastal and riverine sediments, respectively. The levels of DBDPE exceeded those of decabromodiphenyl ether (BDE 209) in most of the samples in the study region, whereas the ratio of DBDPE/BDE 209 varied among the four bays. This is indicative of different usage patterns of brominated flame retardants (BFRs) and also different hydrodynamic conditions among these bay areas. The spatial distribution and composition profile analysis indicated that BFRs in Jiaozhou Bay and Dalian Bay were mainly from local sources, whereas transport from Laizhou Bay by coastal currents was the major source of BFRs in Taozi Bay and Sishili Bay. Both the ?PBDEs and ?aBFRs (sum of pentabromotoluene (PBT), 2,3-diphenylpropyl-2,4,6-tribromophenyl ether (DPTE), pentabromoethylbenzene (PBEB), and hexabromobenzene (HBB)) were at low concentrations in all the sediments. This is probably attributable to a combination of factors such as low regional usage of these products, atmospheric deposition patterns, coastal currents transportation patterns, and degradation processes for higher BDE congeners. This paper is the first study that has investigated the levels of DBDPE in the coastal sediments of China's Yellow Sea. PMID- 26942687 TI - Occurrence of illicit drugs in surface waters in China. AB - Illicit drugs have been recognized as a group of emerging contaminants. In this work, occurrence of common illicit drugs and their metabolites in Chinese surface waters was examined by collecting samples from 49 lakes and 4 major rivers across the country. Among the drugs examined, methamphetamine and ketamine were detected with highest frequencies and concentration levels, consistent with the fact that these are primary drugs of abuse in China. Detection frequencies and concentrations of other drugs were much lower than in European lakes and rivers reported in the literature. In most Chinese surface waters methamphetamine and ketamine were detected at concentrations of several ng L(-1) or less, but in some southern lakes and rivers, these two drugs were detected at much higher concentrations (up to several tens ng L(-1)). Greater occurrence of methamphetamine and ketamine in southern surface waters was attributed to greater abuse and more clandestine production of the two drugs in southern China. PMID- 26942688 TI - Bacterial chromatin: converging views at different scales. AB - Bacterial genomes are functionally organized and compactly folded into a structure referred to as bacterial chromatin or the nucleoid. An important role in genome folding is attributed to Nucleoid-Associated Proteins, also referred to as bacterial chromatin proteins. Although a lot of molecular insight in the mechanisms of operation of these proteins has been generated in the test tube, knowledge on genome organization in the cellular context is still lagging behind severely. Here, we discuss important advances in the understanding of three dimensional genome organization due to the application of Chromosome Conformation Capture and super-resolution microscopy techniques. We focus on bacterial chromatin proteins whose proposed role in genome organization is supported by these approaches. Moreover, we discuss recent insights into the interrelationship between genome organization and genome activity/stability in bacteria. PMID- 26942689 TI - Lipoxygenase directed anti-inflammatory and anti-cancerous secondary metabolites: ADMET-based screening, molecular docking and dynamics simulation. AB - Lipoxygenases (LOXs), key enzymes involved in the biosynthesis of leukotrienes, are well known to participate in the inflammatory and immune responses. With the recent reports of involvement of 5-LOX (one of the isozymes of LOX in human) in cancer, there is a need to find out selective inhibitors of 5-LOX for their therapeutic application. In the present study, plant-derived 300 anti inflammatory and anti-cancerous secondary metabolites (100 each of alkaloids, flavonoids and terpenoids) have been screened for their pharmacokinetic properties and subsequently docked for identification of potent inhibitors of 5 LOX. Pharmacokinetic analyses revealed that only 18 alkaloids, 26 flavonoids, and 9 terpenoids were found to fulfill all the absorption, distribution, metabolism, excretion, and toxicity descriptors as well as those of Lipinski's Rule of Five. Docking analyses of pharmacokinetically screened metabolites and their comparison with a known inhibitor (drug), namely zileuton revealed that only three alkaloids, six flavonoids and three terpenoids were found to dock successfully with 5-LOX with the flavonoid, velutin being the most potent inhibitor among all. The results of the docking analyses were further validated by performing molecular dynamics simulation and binding energy calculations for the complexes of 5-LOX with velutin, galangin, chrysin (in order of LibDock scores), and zileuton. The data revealed stabilization of all the complexes within 15 ns of simulation with velutin complex exhibiting least root-mean-square deviation value (.285 +/- .007 nm) as well as least binding energy (DeltaGbind = -203.169 kJ/mol) as compared to others during the stabilization phase of simulation. PMID- 26942691 TI - A pilot trial of acceptance and commitment therapy for symptoms of depression and anxiety in older adults residing in long-term care facilities. AB - OBJECTIVES: The aim of this study was to evaluate the efficacy and acceptability of a psychological intervention based on acceptance and commitment therapy (ACT) to improve symptoms of depression and anxiety among older adults living in long term care. METHOD: Forty one residents aged between 63 and 97 years (M = 85.3 years) participated in this study. Residents were allocated to receive either a 12 session ACT intervention implemented by trainee psychology therapists or a wait-list control group. Measures of depression and anxiety were collected at baseline and 8 week post-intervention, and residents who received the intervention were tracked for three months. A treatment satisfaction questionnaire was administered to residents who received the intervention and a sample of 10 facility staff members. RESULTS: Using an intention to treat approach and controlling for baseline scores, scores on depression measures were significantly lower after the ACT intervention than after the wait-list control. These outcomes were maintained at three-month follow-up. Treatment satisfaction was rated highly by both residents and their care staff. CONCLUSION: This preliminary trial suggests that ACT shows promise as a therapeutic approach to address symptoms of depression in long-term care. PMID- 26942692 TI - Please Welcome John Yates, III as Editor of the Journal of Proteome Research. PMID- 26942690 TI - Design of Asymmetric Peptide Bilayer Membranes. AB - Energetic insights emerging from the structural characterization of peptide cross beta assemblies have enabled the design and construction of robust asymmetric bilayer peptide membranes. Two peptides differing only in their N-terminal residue, phosphotyrosine vs lysine, coassemble as stacks of antiparallel beta sheets with precisely patterned charged lattices stabilizing the bilayer leaflet interface. Either homogeneous or mixed leaflet composition is possible, and both create nanotubes with dense negative external and positive internal solvent exposed surfaces. Cross-seeding peptide solutions with a preassembled peptide nanotube seed leads to domains of different leaflet architecture within single nanotubes. Architectural control over these cross-beta assemblies, both across the bilayer membrane and along the nanotube length, provides access to highly ordered asymmetric membranes for the further construction of functional mesoscale assemblies. PMID- 26942693 TI - Protein-surface interactions on stimuli-responsive polymeric biomaterials. AB - Responsive surfaces: a review of the dependence of protein adsorption on the reversible volume phase transition in stimuli-responsive polymers. Specifically addressed are a widely studied subset: thermoresponsive polymers. Findings are also generalizable to other materials which undergo a similarly reversible volume phase transition. As of 2015, over 100,000 articles have been published on stimuli-responsive polymers and many more on protein-biomaterial interactions. Significantly, fewer than 100 of these have focused specifically on protein interactions with stimuli-responsive polymers. These report a clear trend of increased protein adsorption in the collapsed state compared to the swollen state. This control over protein interactions makes stimuli-responsive polymers highly useful in biomedical applications such as wound repair scaffolds, on demand drug delivery, and antifouling surfaces. Outstanding questions are whether the protein adsorption is reversible with the volume phase transition and whether there is a time-dependence. A clear understanding of protein interactions with stimuli-responsive polymers will advance theoretical models, experimental results, and biomedical applications. PMID- 26942695 TI - Authors' Correction Letter. PMID- 26942694 TI - Target Cultivation and Financing Parameters for Sustainable Production of Fuel and Feed from Microalgae. AB - Production of economically competitive and environmentally sustainable algal biofuel faces technical challenges that are subject to high uncertainties. Here we identify target values for algal productivity and financing conditions required to achieve a biocrude selling price of $5 per gallon and beneficial environmental impacts. A modeling framework--combining process design, techno economic analysis, life cycle assessment, and uncertainty analysis--was applied to two conversion pathways: (1) "fuel only (HTL)", using hydrothermal liquefaction to produce biocrude, heat and power, and (2) "fuel and feed", using wet extraction to produce biocrude and lipid-extracted algae, which can substitute components of animal and aqua feeds. Our results suggest that with supporting policy incentives, the "fuel and feed" scenario will likely achieve a biocrude selling price of less than $5 per gallon at a productivity of 39 g/m(2)/day, versus 47 g/m(2)/day for the "fuel only (HTL)" scenario. Furthermore, if lipid-extracted algae are used to substitute fishmeal, the process has a 50% probability of reaching $5 per gallon with a base case productivity of 23 g/m(2)/day. Scenarios with improved economics were associated with beneficial environmental impacts for climate change, ecosystem quality, and resource depletion, but not for human health. PMID- 26942696 TI - Signal transducer and activator of transcription 3 (STAT3) inhibitor, S3I-201, acts as a potent and non-selective alkylating agent. AB - The Signal Transducer and Activator of Transcription 3 (STAT3) oncogene is a master regulator of many human cancers, and a well-recognized target for therapeutic intervention. A well known STAT3 inhibitor, S3I-201 (NSC 74859), is hypothesized to block STAT3 function in cancer cells by binding the STAT3 SH2 domain and disrupt STAT3 protein complexation events. In this study, liquid chromatography tandem mass spectrometry analysis revealed that STAT3, in the presence of S3I-201, showed a minimum of five specific sites of modification, cysteine's 108, 259, 367, 542, and 687. Moreover, a prepared fluorescently labeled chemical probe of S3I-201 (DB-6-055) revealed that S3I-201 non specifically and globally alkylated intracellular proteins at concentrations consistent with S3I-201's reported IC50. These data are consistent with the hypothesis that S3I-201 is a sub-optimal probe for interrogating STAT3-related cell biology. PMID- 26942697 TI - Repeated PM2.5 exposure inhibits BEAS-2B cell P53 expression through ROS-Akt DNMT3B pathway-mediated promoter hypermethylation. AB - Long-term exposure to fine particulate matter (PM2.5) has been reported to be closely associated with the increased lung cancer risk in populations, but the mechanisms underlying PM-associated carcinogenesis are not yet clear. Previous studies have indicated that aberrant epigenetic alterations, such as genome-wide DNA hypomethylation and gene-specific DNA hypermethylation contribute to lung carcinogenesis. And silence or mutation of P53 tumor suppressor gene is the most prevalent oncogenic driver in lung cancer development. To explore the effects of PM2.5 on global and P53 promoter methylation changes and the mechanisms involved, we exposed human bronchial epithelial cells (BEAS-2B) to low concentrations of PM2.5 for 10 days. Our results indicated that PM2.5-induced global DNA hypomethylation was accompanied by reduced DNMT1 expression. PM2.5 also induced hypermethylation of P53 promoter and inhibited its expression by increasing DNMT3B protein level. Furthermore, ROS-induced activation of Akt was involved in PM2.5-induced increase in DNMT3B. In conclusion, our results strongly suggest that repeated exposure to PM2.5 induces epigenetic silencing of P53 through ROS Akt-DNMT3B pathway-mediated promoter hypermethylation, which not only provides a possible explanation for PM-induced lung cancer, but also may help to identify specific interventions to prevent PM-induced lung carcinogenesis. PMID- 26942698 TI - Multiparametric monitoring of chemotherapy treatment response in locally advanced breast cancer using quantitative ultrasound and diffuse optical spectroscopy. AB - PURPOSE: This study evaluated pathological response to neoadjuvant chemotherapy using quantitative ultrasound (QUS) and diffuse optical spectroscopy imaging (DOSI) biomarkers in locally advanced breast cancer (LABC). MATERIALS AND METHODS: The institution's ethics review board approved this study. Subjects (n = 22) gave written informed consent prior to participating. US and DOSI data were acquired, relative to the start of neoadjuvant chemotherapy, at weeks 0, 1, 4, 8 and preoperatively. QUS parameters including the mid-band fit (MBF), 0-MHz intercept (SI), and the spectral slope (SS) were determined from tumor ultrasound data using spectral analysis. In the same patients, DOSI was used to measure parameters relating to tumor hemoglobin and composition. Discriminant analysis and receiver-operating characteristic (ROC) analysis was used to classify clinical and pathological response during treatment and to estimate the area under the curve (AUC). Additionally, multivariate analysis was carried out for pairwise QUS/DOSI parameter combinations using a logistic regression model. RESULTS: Individual QUS and DOSI parameters, including the (SI), oxy-hemoglobin (HbO2), and total hemoglobin (HbT) were significant markers for response after one week of treatment (p < 0.01). Multivariate (pairwise) combinations increased the sensitivity, specificity and AUC at this time; the SI + HbO2 showed a sensitivity/specificity of 100%, and an AUC of 1.0. CONCLUSIONS: QUS and DOSI demonstrated potential as coincident markers for treatment response and may potentially facilitate response-guided therapies. Multivariate QUS and DOSI parameters increased the sensitivity and specificity of classifying LABC patients as early as one week after treatment. PMID- 26942699 TI - DDA1 promotes stage IIB-IIC colon cancer progression by activating NFkappaB/CSN2/GSK-3beta signaling. AB - Conventional high-recurrence risk factors are not sufficient to predict post operative risk of tumor recurrence or sensitivity to 5-fluorouracil (5-FU)-based chemotherapy for stage II colon cancer. DDA1, an evolutionarily conserved gene located at 19p13.11, may be involved in the activation of nuclear factor kappaB (NFkappaB). This study aimed to investigate whether DDA1 contributes to tumorigenesis and progression of stage II colon cancer via activation of the NFkappaB pathway. We found that positive expression of DDA1 alone or in combination with p65 nuclear translocation correlated with increased risk of tumor recurrence in patients with stage IIB-IIC colon cancer. DDA1 overexpression in colon cancer lines promoted cell proliferation, facilitated cell cycle progression, inhibited 5-FU-induced apoptosis, enhanced invasion, and induced the epithelial-mesenchymal transition. Suppression of DDA1 inhibited tumor progression, and reduced tumor growth in vivo. We also demonstrated that DDA1 mediated tumor progression is associated with the activation of the NFkappaB/COP9 signalosome 2(CSN2)/glycogen synthase kinase3beta (GSK3beta) pathway. These results indicate that DDA1 promotes colon cancer progression through activation of NFkappaB/CSN2/GSK3beta signaling. DDA1, together with NFkappaB activation status, may serve as a sensitive biomarker for tumor recurrence risk and prognosis in patients with stage IIB-IIC colon cancers. PMID- 26942700 TI - The role of adjuvant chemotherapy in nasopharyngeal carcinoma with bulky neck lymph nodes in the era of IMRT. AB - Nasopharyngeal carcinoma (NPC) patients with N2-3 diseases are prone to develop distant metastasis even treated with standard concurrent chemoradiotherapy (CCRT). Our study is aim to determine the optimal treatment strategy of these patients. Patients with histologically proven NPC were retrospectively analyzed according to the AJCC 2002 stage classification system. A total of 547 patients who had N2-3 diseases were enrolled. They were all treated with Intensity modulated radiation therapy (IMRT) combined with systemic treatments, including radiotherapy alone (RT alone), neoadjuvant chemotherapy followed by radiotherapy (NACT+RT), CCRT, NACT+CCRT, NACT followed by radiotherapy and adjuvant chemotherapy (NACT+RT+AC), CCRT+AC and NACT+CCRT+AC. A subgroup analysis was also conducted. With a median follow-up time of 53.8 months, adjuvant chemotherapy significantly decreased the risk of distant metastasis (HR 0.413, 95% CI 0.194 0.881, p = 0.022) as well as significantly increased the OS (HR 0.398, 95% CI 0.187-0.848, p = 0.017) in patients with N3 disease. The addition of adjuvant chemotherapy seemed to provide benefits to patients with N3 stage NPC and the current study may indicate the need for further randomized investigation. PMID- 26942702 TI - IL-17A promotes migration and tumor killing capability of B cells in esophageal squamous cell carcinoma. AB - We have previously reported that the accumulation of IL-17-producing cells could mediate tumor protective immunity by promoting the migration of NK cells, T cells and dendritic cells in esophageal squamous cell carcinoma (ESCC) patients. However, there were no reports concerning the effect of IL-17A on tumor infiltrating B cells. In this study, we investigated the accumulation of CD20+ B cells in the ESCC tumor nests and further addressed the effect of IL-17A on the migration and cytotoxicity of B cells. There was positive correlation between the levels of CD20+ B cells and IL-17+ cells. IL-17A could promote the ESCC tumor cells to produce more chemokines CCL2, CCL20 and CXCL13, which were associated with the migration of B cells. In addition, IL-17A enhanced the IgG-mediated antibody and complement mediated cytotoxicity of B cells against tumor cells. IL 17A-stimulated B cells gained more effective direct killing capability through enhanced expression of Granzyme B and FasL. The effect of IL-17A on the migration and cytotoxicity of B cells was IL-17A pathway dependent, which could be inhibited by IL-17A inhibitor. This study provides further understanding of the roles of IL-17A in humoral response, which may contribute to the development of novel tumor immunotherapy strategy. PMID- 26942703 TI - Use of urine alarms in toilet training children with intellectual and developmental disabilities: A review. AB - The purpose of this review is to describe and evaluate the existing research on the use of urine alarms in the daytime toilet training of children with intellectual and developmental disabilities (IDD). A systematic literature search yielded 12 studies, many of which were published over a decade ago. The findings suggest that interventions that incorporate the use of urine alarms are promising in the treatment of daytime enuresis for children with IDD; however, more carefully controlled research is needed to confirm these findings and elucidate the precise role urine alarms may play in toileting interventions. Methodological strengths and limitations of the body of research are discussed. PMID- 26942701 TI - The preclinical study of predicting radiosensitivity in human nasopharyngeal carcinoma xenografts by 18F-ML-10 animal- PET/CT imaging. AB - Previous studies have reported that the radiosensitivity is associated with apoptosis. Hereby, we aimed to investigate the value of 18F-ML-10 PET/CT, which selectively targeted cells undergoing apoptosis, in predicting radiosensitivity of human nasopharyngeal carcinoma (NPC) xenografts. We used CNE1 (highly differentiated) and CNE2 (poorly differentiated) NPC cell lines to construct tumor models, which had very different radiosensitivities. After irradiation, the volumes of CNE2 tumors decreased significantly while those of CNE1 tumors increased. In 18F-ML-10 imaging, the values of tumor/muscle (T/M) between CNE1 and CNE2 mice were statistically different at both 24 h and 48 h after irradiation. Besides, DeltaT/M1-0 and DeltaT/M2-0 of CNE2 mice were higher than those of CNE1 mice, demonstrating obvious discrepancy. Furthermore, we observed obvious changes of radioactive distribution in CNE2 group. On the contrary, T/M of 18F-FDG in irradiation group revealed no obvious change in both CNE1 and CNE2 groups. In conclusion, 18F-ML-10 animal PET/CT showed its potential to predict radiosensitivity in NPC. PMID- 26942704 TI - Cognitive phenotype and psychiatric disorder in 22q11.2 deletion syndrome: A review. AB - The behavioural phenotype of 22q11.2 deletion syndrome syndrome (22q11DS), one of the most common human multiple anomaly syndromes, frequently includes intellectual disability (ID) together with high risk of diagnosis of psychotic disorders including schizophrenia. Candidate cognitive endophenotypes include problems with retrieval of contextual information from memory and in executive control and focussing of attention. 22q11DS may offer a model of the relationship between ID and risk of psychiatric disorder. This paper reviews research on the relationship between the cognitive phenotype and the development of psychiatric disorders in 22q11DS. Aspects of cognitive function including verbal I.Q., visual memory, and executive function, are associated with mental health outcome in people with 22q11DS. This relationship may result from a common neurobiological basis for the cognitive difficulties and psychiatric disorders. Some of the cognitive difficulties experienced by people with 22q11DS, especially in attention, memory retrieval, and face processing, may, however, in themselves constitute risk factors for development of hallucinations and paranoid delusions. Future research into factors leading to psychiatric disorder in people with 22q11DS should include assessment of social and psychological factors including life events, symptoms associated with trauma, attachment, and self-esteem, which together with cognitive risk factors may mediate mental health outcome. PMID- 26942712 TI - Synthesis of N-Doped Hollow-Structured Mesoporous Carbon Nanospheres for High Performance Supercapacitors. AB - We have demonstrated a facile and controllable synthesis of monodispersed N-doped hollow mesoporous carbon nanospheres (N-HMCSs) and yolk-shell hollow mesoporous carbon nanospheres (N-YSHMCSs) by a modified "silica-assisted" route. The synthesis process can be carried out by using resorcinol-formaldehyde resin as a carbon precursor, melamine as a nitrogen source, hexadecyl trimethylammonium chloride as a template, and silicate oligomers as structure-supporter. The morphological (i.e., particle size, shell thickness, cavity size, and core diameter) and textural features of the carbon nanospheres are easily controlled by varying the amount of ammonium. The resultant carbon nanospheres possess high surface areas (up to 2464 m(2) g(-1)), large pore volumes (up to 2.36 cm(3) g( 1)), and uniform mesopore size (~2.4 nm for N-HMCSs, ~ 4.5 nm for N-YSHMCSs). Through combining the hollow mesoporous structure, high porosity, large surface area, and N heteroatomic functionality, the as-synthesized N-doped hollow structured carbon nanospheres manifest excellent supercapacitor performance with high capacitance (up to 240 F/g), favorable capacitance retention (97.0% capacitive retention after 5000 cycles), and high energy density (up to 11.1 Wh kg(-1)). PMID- 26942713 TI - Important Update for the Readers of Our Article. PMID- 26942715 TI - Inhibitors of mTOR in aging and cancer. PMID- 26942714 TI - Identification of a Short Cell-Penetrating Peptide from Bovine Lactoferricin for Intracellular Delivery of DNA in Human A549 Cells. AB - Cell-penetrating peptides (CPPs) have been shown to deliver cargos, including protein, DNA, RNA, and nanomaterials, in fully active forms into live cells. Most of the CPP sequences in use today are based on non-native proteins that may be immunogenic. Here we demonstrate that the L5a CPP (RRWQW) from bovine lactoferricin (LFcin), stably and noncovalently complexed with plasmid DNA and prepared at an optimal nitrogen/phosphate ratio of 12, is able to efficiently enter into human lung cancer A549 cells. The L5a CPP delivered a plasmid containing the enhanced green fluorescent protein (EGFP) coding sequence that was subsequently expressed in cells, as revealed by real-time PCR and fluorescent microscopy at the mRNA and protein levels, respectively. Treatment with calcium chloride increased the level of gene expression, without affecting CPP-mediated transfection efficiency. Zeta-potential analysis revealed that positively electrostatic interactions of CPP/DNA complexes correlated with CPP-mediated transport. The L5a and L5a/DNA complexes were not cytotoxic. This biomimetic LFcin L5a represents one of the shortest effective CPPs and could be a promising lead peptide with less immunogenic for DNA delivery in gene therapy. PMID- 26942717 TI - Enantioselective Synthesis of Dihydrospiro[indoline-3,4'-pyrano[2,3-c]pyrazole] Derivatives via Michael/Hemiketalization Reaction. AB - A new bifunctional squaramide organocatalyst derived from L-proline mediated the first enantioselective synthesis of dihydrospiro[indoline-3,4'-pyrano[2,3 c]pyrazole] derivatives in excellent enantioselectivity by reacting pyrazolones with isatylidine beta,gamma-unsaturated alpha-ketoester. This new catalyst outperformed widely used thioureas and squaramides in inducing enantioselectivity. PMID- 26942716 TI - Ingested Nitrate and Breast Cancer in the Spanish Multicase-Control Study on Cancer (MCC-Spain). AB - BACKGROUND: Ingested nitrate leads to endogenous formation of N-nitroso compounds that are breast carcinogens in animals, but human evidence is limited. OBJECTIVE: We evaluated ingested nitrate as a risk factor for breast cancer (BC) in a multicase-control study. METHODS: Hospital-based incident BC cases and population based controls were recruited in eight Spanish regions in 2008-2013; participants provided residential and water consumption from 18 years of age and information on known BC risk factors. Long-term nitrate levels (1940-2010) were estimated and linked with residential histories and water consumption to calculate waterborne ingested nitrate (milligrams/day). Dietary ingested nitrate (milligrams/day) was calculated using food frequency questionnaires and published dietary nitrate contents. Interactions with endogenous nitrosation factors and other variables were evaluated. A total of 1,245 cases and 1,520 controls were included in the statistical analysis. RESULTS: Among the study regions, average +/- SD waterborne ingested nitrate ranged from 2.9 +/- 1.9 to 13.5 +/- 7.5 mg/day, and dietary ingested nitrate ranged from 88.5 +/- 48.7 to 154 +/- 87.8 mg/day. Waterborne ingested nitrate was not associated with BC overall, but among postmenopausal women, those with both high nitrate (> 6 vs. < 2.6 mg/day) and high red meat intake (>= 20 vs. < 20 g/day) were more likely to be cases than women with low nitrate and low red meat intake (adjusted odds ratio = 1.64; 95% confidence interval: 1.08, 2.49; overall interaction p-value = 0.17). No association was found with dietary nitrate. CONCLUSIONS: Waterborne ingested nitrate was associated with BC only among postmenopausal women with high red meat consumption. Dietary nitrate was not associated with BC regardless of the animal or vegetable source or of menopausal status. CITATION: Espejo-Herrera N, Gracia Lavedan E, Pollan M, Aragones N, Boldo E, Perez-Gomez B, Altzibar JM, Amiano P, Zabala AJ, Ardanaz E, Guevara M, Molina AJ, Barrio JP, Gomez-Acebo I, Tardon A, Peiro R, Chirlaque MD, Palau M, Munoz M, Font-Ribera L, Castano-Vinyals G, Kogevinas M, Villanueva CM. 2016. Ingested nitrate and breast cancer in the Spanish Multicase-Control Study on Cancer (MCC-Spain). Environ Health Perspect 124:1042-1049; http://dx.doi.org/10.1289/ehp.1510334. PMID- 26942719 TI - Chromosome 15q25 (CHRNA3-CHRNB4) Variation Indirectly Impacts Lung Cancer Risk in Chinese Males. AB - INTRODUCTION: Recently, genome-wide association studies (GWAS) in Caucasian populations have identified an association between single nucleotide polymorphisms (SNPs) in the CHRNA5-A3-B4 nicotinic acetylcholine receptor subunit gene cluster on chromosome 15q25, lung cancer risk and smoking behaviors. However, these SNPs are rare in Asians, and there is currently no consensus on whether SNPs in CHRNA5-A3-B4 have a direct or indirect carcinogenic effect through smoking behaviors on lung cancer risk. Though some studies confirmed rs6495308 polymorphisms to be associated with smoking behaviors and lung cancer, no research was conducted in China. Using a case-control study, we decided to investigate the associations between CHRNA3 rs6495308, CHRNB4 rs11072768, smoking behaviors and lung cancer risk, as well as explore whether the two SNPs have a direct or indirect carcinogenic effect on lung cancer. METHODS: A total of 1025 males were interviewed using a structured questionnaire (204 male lung cancer patients and 821 healthy men) to acquire socio-demographic status and smoking behaviors. Venous blood samples were collected to measure rs6495308 and rs11072768 gene polymorphisms. All subjects were divided into 3 groups: non smokers, light smokers (1-15 cigarettes per day) and heavy smokers (>15 cigarettes per day). RESULTS: Compared to wild genotype, rs6495308 and rs11072768 variant genotypes reported smoking more cigarettes per day and a higher pack years of smoking (P<0.05). More importantly, among smokers, both rs6495308 CT/TT and rs11072768 GT/GG had a higher risk of lung cancer compared to wild genotype without adjusting for potential confounding factors (OR = 1.36, 95%CI = 1.09 1.95; OR = 1.11, 95%CI = 1.07-1.58 respectively). Furthermore, heavy smokers with rs6495308 or rs11072768 variant genotypes have a positive interactive effect on lung cancer after adjustment for potential confounding factors (OR = 1.13, 95%CI = 1.01-3.09; OR = 1.09, 95%CI = 1.01-3.41 respectively). However, No significant associations were found between lung cancer risk and both rs6495308 and rs11072768 genotypes among non-smokers and smokers after adjusting for age, occupation, and education. CONCLUSION: This study confirmed both rs6495308 and rs11072768 gene polymorphisms association with smoking behaviors and had an indirect link between gene polymorphisms and lung cancer risk. PMID- 26942720 TI - A Four-Point Screening Method for Assessing Molecular Mechanism of Action (MMOA) Identifies Tideglusib as a Time-Dependent Inhibitor of Trypanosoma brucei GSK3beta. AB - BACKGROUND: New therapeutics are needed for neglected tropical diseases including Human African trypanosomiasis (HAT), a progressive and fatal disease caused by the protozoan parasites Trypanosoma brucei gambiense and T. b. rhodesiense. There is a need for simple, efficient, cost effective methods to identify new molecules with unique molecular mechanisms of action (MMOAs). The mechanistic features of a binding mode, such as competition with endogenous substrates and time-dependence can affect the observed inhibitory IC50, and differentiate molecules and their therapeutic usefulness. Simple screening methods to determine time-dependence and competition can be used to differentiate compounds with different MMOAs in order to identify new therapeutic opportunities. METHODOLOGY/PRINCIPAL FINDINGS: In this work we report a four point screening methodology to evaluate the time dependence and competition for inhibition of GSK3beta protein kinase isolated from T. brucei. Using this method, we identified tideglusib as a time-dependent inhibitor whose mechanism of action is time-dependent, ATP competitive upon initial binding, which transitions to ATP non-competitive with time. The enzyme activity was not recovered following 100-fold dilution of the buffer consistent with an irreversible mechanism of action. This is in contrast to the T. brucei GSK3beta inhibitor GW8510, whose inhibition was competitive with ATP, not time dependent at all measured time points and reversible in dilution experiments. The activity of tideglusib against T. brucei parasites was confirmed by inhibition of parasite proliferation (GI50 of 2.3 MUM). CONCLUSIONS/SIGNIFICANCE: Altogether this work demonstrates a straightforward method for determining molecular mechanisms of action and its application for mechanistic differentiation of two potent TbGSK3beta inhibitors. The four point MMOA method identified tideglusib as a mechanistically differentiated TbGSK3beta inhibitor. Tideglusib was shown to inhibit parasite growth in this work, and has been reported to be well tolerated in one year of dosing in human clinical studies. Consequently, further supportive studies on the potential therapeutic usefulness of tideglusib for HAT are justified. PMID- 26942721 TI - Cost-effectiveness of screening for anal cancer using regular digital ano-rectal examinations in men who have sex with men living with HIV. AB - INTRODUCTION: Anal cancer in men who have sex with men (MSM) living with HIV is an important issue but there are no consistent guidelines for how to screen for this cancer. In settings where screening with anal cytology is unavailable, regular anal examinations have been proposed in some guidelines but their cost effectiveness is unknown. METHODS: Our objective was to estimate the cost effectiveness of regular anal examinations to screen for anal cancer in HIV positive MSM living in Australia using a probabilistic Markov model. Data sources were based on the medical literature and a clinical trial of HIV-positive MSM receiving an annual anal examination in Australia. The main outcome measures for calculating effectiveness were undiscounted and discounted (at 3%) lifetime costs, life years gained, quality-adjusted life years (QALY) gained and incremental cost-effectiveness ratio (ICER). RESULTS: Base-case analysis estimated the average cost of screening for and management of anal cancer ranged from $195 for no screening to $1,915 for lifetime annual screening of men aged >= 50. Screening of men aged >= 50 generated ICERs of $29,760 per QALY gained (for screening every four years), $32,222 (every three years) and $45,484 (every two years). Uncertainty for ICERs was mostly influenced by the cost (financially and decrease in quality of life) from a false-positive result, progression rate of anal cancer, specificity of the anal examination, the probability of detection outside a screening program and the discount rate. CONCLUSIONS: Screening for anal cancer by incorporating regular anal examinations into routine HIV care for MSM aged >= 50 is most likely to be cost-effective by conventional standards. Given that anal pap smears are not widely available yet in many clinical settings, regular anal exams for MSM living with HIV to detect anal cancer earlier should be implemented. PMID- 26942722 TI - NCP1/AtMOB1A Plays Key Roles in Auxin-Mediated Arabidopsis Development. AB - MOB1 protein is a core component of the Hippo signaling pathway in animals where it is involved in controlling tissue growth and tumor suppression. Plant MOB1 proteins display high sequence homology to animal MOB1 proteins, but little is known regarding their role in plant growth and development. Herein we report the critical roles of Arabidopsis MOB1 (AtMOB1A) in auxin-mediated development in Arabidopsis. We found that loss-of-function mutations in AtMOB1A completely eliminated the formation of cotyledons when combined with mutations in PINOID (PID), which encodes a Ser/Thr protein kinase that participates in auxin signaling and transport. We showed that atmob1a was fully rescued by its Drosophila counterpart, suggesting functional conservation. The atmob1a pid double mutants phenocopied several well-characterized mutant combinations that are defective in auxin biosynthesis or transport. Moreover, we demonstrated that atmob1a greatly enhanced several other known auxin mutants, suggesting that AtMOB1A plays a key role in auxin-mediated plant development. The atmob1a single mutant displayed defects in early embryogenesis and had shorter root and smaller flowers than wild type plants. AtMOB1A is uniformly expressed in embryos and suspensor cells during embryogenesis, consistent with its role in embryo development. AtMOB1A protein is localized to nucleus, cytoplasm, and associated to plasma membrane, suggesting that it plays roles in these subcellular localizations. Furthermore, we showed that disruption of AtMOB1A led to a reduced sensitivity to exogenous auxin. Our results demonstrated that AtMOB1A plays an important role in Arabidopsis development by promoting auxin signaling. PMID- 26942724 TI - 'Pregnancy Has Its Advantages': The Voices of Street Connected Children and Youth in Eldoret, Kenya. AB - OBJECTIVE: Little is known about the reproductive health or family planning needs of street-connected children and youth in resource-constrained countries. The study objective was to describe how street-connected children and youth (SCCY) in Eldoret, Kenya, perceive pregnancy. METHODS: This qualitative study was conducted between August 2013 and February 2014. A total of 65 SCCY aged 11-24 years were purposively sampled from the three referral points: 1) A dedicated study clinic for vulnerable children and youth at Moi Teaching and Referral Hospital (MTRH); 2) Primary locations in which street children reside known as "bases/barracks"; and 3) Street youth community-based organizations. In-depth interviews and focus group discussions were audio recorded, transcribed, and translated into English. Content analysis was performed after thematic coding by 4 independent coders. RESULTS: The majority of SCCY interviewed were male (69%) and sexually active (81.5%). None had gone beyond primary level of education. The strong desire for SCCY to go through conventional life experiences including marriage and child bearing was evident. Sub-themes around desired pregnancies included: sense of identity with other SCCY, sense of hope, male ego, lineage, source of income, and avoiding stigmatization. The desire for children was highly gendered with male SCCY more focused on their social status in the street community, while for females it was primarily for survival on the street. Female SCCY generally lacked agency around reproductive health issues and faced gender-based violence. Abortions (either assisted or self-induced), infanticide, and child abandonment were reported. Respondents described a lucrative market for babies born to SCCY and alleged that healthcare workers were known to abduct these babies following hospital deliveries. CONCLUSION: Our findings indicate gender differences in the reasons why SCCY become pregnant and have children. We also noted gender inequalities in reproductive health decisions. SCCY friendly interventions that provide tailored reproductive health services are needed. PMID- 26942725 TI - Healthcare Cost of Over-Diagnosis of Low-Grade Dysplasia in Barrett's Esophagus. AB - INTRODUCTION: Published reports have demonstrated that many Barrett's esophagus patients are over-diagnosed as low-grade dysplasia (BE-LGD). We performed an analysis of the surveillance and treatment costs associated with the over diagnosis of BE-LGD. METHODS: As the principal cost variables, we used endoscopic and histologic procedures performed during the recommended surveillance intervals for patients with BE-LGD, the national average Medicare reimbursement for the Current Procedural Terminology codes of the procedures performed, and a spreadsheet-based tool we created to determine the overall healthcare cost associated with the over-diagnosis of BE-LGD in the US population. RESULTS: The average excess cost (range) for every patient in the US who is over-diagnosed with BE-LGD is estimated to be $5557 ($3115 to $8072). The principal contributors to the excess cost of over-diagnosis of BE-LGD in these patients are: endoscopy ($2626 to $4639), pathologist biopsy review ($275 to $2185), and esophagogastroduodenoscopy-guided endoscopic ablation ($214 to $1249). CONCLUSIONS: The healthcare cost of over-diagnosis of BE-LGD is significant. To reduce the overall healthcare cost impact of over-diagnosis of BE-LGD, strict adherence to the recommendations of the American Gastroenterological Association, American College of Gastroenterology, and American Society for Gastrointestinal Endoscopy that pathology review of all BE biopsy specimens be performed by a gastrointestinal pathologist is warranted. PMID- 26942723 TI - Transgenic Drosophila for Investigating DUX4 and FRG1, Two Genes Associated with Facioscapulohumeral Muscular Dystrophy (FSHD). AB - Facioscapulohumeral muscular dystrophy (FSHD) is typically an adult onset dominant myopathy. Epigenetic changes in the chromosome 4q35 region linked to both forms of FSHD lead to a relaxation of repression and increased somatic expression of DUX4-fl (DUX4-full length), the pathogenic alternative splicing isoform of the DUX4 gene. DUX4-fl encodes a transcription factor expressed in healthy testis and pluripotent stem cells; however, in FSHD, increased levels of DUX4-fl in myogenic cells lead to aberrant regulation of target genes. DUX4-fl has proven difficult to study in vivo; thus, little is known about its normal and pathogenic roles. The endogenous expression of DUX4-fl in FSHD-derived human muscle and myogenic cells is extremely low, exogenous expression of DUX4-fl in somatic cells rapidly induces cytotoxicity, and, due in part to the lack of conservation beyond primate lineages, viable animal models based on DUX4-fl have been difficult to generate. By contrast, the FRG1 (FSHD region gene 1), which is linked to FSHD, is evolutionarily conserved from invertebrates to humans, and has been studied in several model organisms. FRG1 expression is critical for the development of musculature and vasculature, and overexpression of FRG1 produces a myopathic phenotype, yet the normal and pathological functions of FRG1 are not well understood. Interestingly, DUX4 and FRG1 were recently linked when the latter was identified as a direct transcriptional target of DUX4-FL. To better understand the pathways affected in FSHD by DUX4-fl and FRG1, we generated transgenic lines of Drosophila expressing either gene under control of the UAS/GAL4 binary system. Utilizing these lines, we generated screenable phenotypes recapitulating certain known consequences of DUX4-fl or FRG1 overexpression. These transgenic Drosophila lines provide resources to dissect the pathways affected by DUX4-fl or FRG1 in a genetically tractable organism and may provide insight into both muscle development and pathogenic mechanisms in FSHD. PMID- 26942727 TI - Iron deficiency: a novel risk factor of recurrence in patients after unprovoked venous thromboembolism. AB - INTRODUCTION: Patients with unprovoked venous thromboembolism (VTE) are at high risk of recurrence; however, its predictors remain largely unknown. There is evidence that iron is implicated in the pathophysiology of thrombosis. OBJECTIVES: We aimed to investigate whether iron deficiency (ID) affects the risk of recurrence in patients after unprovoked VTE. PATIENTS AND METHODS: In this prospective cohort study, we examined 229 consecutive patients aged 65 years or younger with the first-ever episode of unprovoked VTE within 6 to 12 months prior to enrollment. The exclusion criteria were as follows: hemoglobin levels of less than 11 g/dl, heart failure, diabetes, cancer, serum creatinine levels exceeding 120 MUM, and previous or current use of iron or erythropoiesisstimulating agents, or both. ID was defined as serum ferritin levels below 30 MUg/l. Recurrent VTE was recorded during a 24-month follow-up. RESULTS: ID was observed in 47 patients (21%). In a multivariate regression model, the presence of ID was associated with female sex, elevated C-reactive protein (CRP), anemia and reduced hemoglobin levels (all P <0.05). In a multivariate model, the presence of ID (or low serum ferritin levels) and elevated CRP levels, but not anemia, predicted VTE recurrence during 24 months. The hazard ratio adjusted for CRP and the presence of anemia was 3.17 for ID (95% confidence interval [CI], 1.20-8.38; P = 0.02) and 0.64 for serum ferritin levels (95% CI, 0.43-0.94; P = 0.02). CONCLUSIONS: ID may represent a novel risk factor for VTE recurrence in young and middle-aged patients following an unprovoked episode. PMID- 26942726 TI - Laboratory assessment of anti-thrombotic therapy in heart failure, atrial fibrillation and coronary artery disease: insights using thrombelastography and a micro-titre plate assay of thrombogenesis and fibrinolysis. AB - As heart failure, coronary artery disease and atrial fibrillation all bring a risk of thrombosis, anti-thrombotic therapy is recommended. Despite such treatment, major cardiovascular events such as myocardial infarction and stroke still occur, implying inadequate suppression of thrombus formation. Accordingly, identification of patients whose haemostasis remains unimpaired by treatment is valuable. We compared indices for assessing thrombogenesis and fibrinolysis by two different techniques in patients on different anti-thrombotic agents, i.e. aspirin or warfarin. We determined fibrin clot formation and fibrinolysis by a microplate assay and thromboelastography, and platelet marker soluble P selectin in 181 patients with acute or chronic heart failure, coronary artery disease who were taking either aspirin or warfarin. Five thromboelastograph indices and four microplate assay indices were different on aspirin versus warfarin (p < 0.05). In multivariate regression analysis, only microplate assay indices rate of clot formation and rate of clot dissolution were independently related to aspirin or warfarin use (p <= 0.001). Five microplate assay indices, but no thrombelastograph index, were different (p < 0.001) in aspirin users. Three microplate assay indices were different (p <= 0.002) in warfarin users. The microplate assay indices of lag time and rate of clot formation were abnormal in chronic heart failure patients on aspirin, suggesting increased risk of thrombosis despite anti-platelet use. Soluble P selectin was lower in patients on aspirin (p = 0.0175) but failed to correlate with any other index of haemostasis. The microplate assay shows promise as a tool for dissecting thrombogenesis and fibrinolysis in cardiovascular disease, and the impact of antithrombotic therapy. Prospective studies are required to determine a role in predicting thrombotic risk. PMID- 26942729 TI - [Nephroblastomas: Almost exclusively in clinical trials!]. AB - Nephroblastomas are the most commonly occurring renal neoplasms in childhood and are treated almost exclusively in clinical trials. An important factor for further therapeutic management is the pathological evaluation of the nephrectomy specimen. Tumor stage and risk group classification are the most crucial parameters. An independent assessment of the tumor by a reference pathology center is an essential standard procedure. Although many molecular genetic discoveries have been made in nephroblastomas over recent years, molecular parameters do not (yet) play a role in treatment stratification. PMID- 26942730 TI - Taking into Account the Quality of the Relationship in HIV Disclosure. AB - Despite growing interest in HIV disclosure, most theoretical frameworks and empirical studies focus on individual and social factors affecting the process, leaving the contribution of interpersonal factors relatively unexplored. HIV transmission and disclosure often occur within a couple however, and this is where disclosure has the most scope as a HIV transmission intervention. With this in mind, this study explores whether perceived relationship quality influences HIV disclosure outcomes. Ninety-five UK individuals with HIV participated in a cross-sectional survey. Retrospective data were collected on their perceived relationship quality prior to disclosing their HIV positive status, and on disclosure outcomes. Perceived relationship quality was found to significantly affect disclosure outcomes. Positive qualities in the relationship were associated with positive outcomes, whereas negative qualities were associated with negative outcomes. Results further confirmed that this association was not merely correlational, but demonstrated predictive power. Relationship quality might act as either a risk or a resilience factor in the disclosure process, and thus warrants greater attention in future research. PMID- 26942728 TI - [WHO classification 2016 and first S3 guidelines on renal cell cancer: What is important for the practice?]. AB - The first S3 guidelines on renal cell cancer cover the practical aspects of imaging, diagnostics and therapy as well as the clinical relevance of pathology reporting. This review summarizes the changes in renal tumor classification and the new recommendations for reporting renal cell tumors. The S3 guidelines recommend the 2016 World Health Organization (WHO) classification of renal cell tumors. Novel renal cell tumor entities and provisional or emerging renal cell tumor entities of the 2016 WHO classification of renal tumors are discussed. The S3 guidelines for renal cell cancer also recommend the use of the WHO/International Society of Urologic Pathology (ISUP) grading system for clear cell and for papillary renal cell carcinomas, which replaces the previously used Fuhrman grading system. PMID- 26942733 TI - Safety of Drugs during Pregnancy and Breastfeeding in Cystic Fibrosis Patients. AB - Health management of cystic fibrosis (CF) patients should be maximized during pregnancy and breastfeeding because of its significant impact on the maternal and newborn outcomes. Thus, numerous drugs will have to be continued during pregnancy and lactation. Most of the drugs representing CF treatment lines cross the placenta or are excreted into human milk. Research addressing the risks and benefits of drugs used in CF patients during pregnancy and lactation is often incomplete or challenged by limited methodology, which often leads to conflicting or inconclusive results. Yet, potential treatment benefits for CF pregnant patients most often outbalance potential risks for the unborn child. PMID- 26942731 TI - Current and Emerging Therapies for IgE-Mediated Food Allergy. AB - Food allergies are a growing clinical problem leading to increased health care utilization and decreases in patient quality of life. Current treatment recommendations include strict dietary avoidance of the offending food as well as use of self-injectable epinephrine in case of accidental exposure with allergic reaction. Although many individuals will eventually outgrow their food allergies, a substantial number will not. Significant effort has been made to find novel treatments that protect patients from food-triggered reactions as well as to develop immune-modulating therapies that could lead to tolerance. In this review, three therapies that have shown the most promise for the treatment of food allergies are highlighted: oral immunotherapy, sublingual immunotherapy, and epicutaneous immunotherapy. PMID- 26942732 TI - Vancomycin Pharmacokinetic Parameters in Patients with Hemorrhagic Stroke. AB - BACKGROUND: Infections are a common medical complication in hemorrhagic stroke patients, with vancomycin commonly used as empiric therapy. The purpose of this study was to evaluate the pharmacokinetic parameters of vancomycin in hemorrhagic stroke patients. METHODS: This was a retrospective study of adult patients with aneurysmal subarachnoid hemorrhage (aSAH) or intracerebral hemorrhage (ICH) admitted between May 2010 and February 2015 who received vancomycin. Predicted pharmacokinetic parameters based on population data were compared with calculated pharmacokinetic parameters based on serum trough concentrations. RESULTS: Eighty aSAH patients and 66 ICH patients met inclusion criteria. In the aSAH group, the mean dosing regimen was 17.6 +/- 4 mg/kg every 12 (8-12) h. The mean measured trough concentration was lower than the predicted trough concentration (9.9 +/- 4.1 vs. 19 +/- 8.7 MUg/mL; p < 0.001). The mean calculated elimination rate constant was higher than the predicted value (0.135 +/- 0.04 vs. 0.092 +/- 0.03 h(-1); p < 0.001), and the mean calculated half-life was lower than predicted (5.7 +/- 1.8 vs. 8.3 +/- 2.9 h; p < 0.001). In the ICH group, the mean dosing regimen was 15.9 +/- 4.3 mg/kg every 12 (8-12) h. Similarly, the mean measured trough concentration was lower than the predicted trough concentration (10.7 +/- 4.6 vs. 17.5 +/- 8.5 MUg/mL; p < 0.001). The mean calculated elimination rate constant was higher than the predicted value (0.106 +/- 0.03 vs. 0.079 +/- 0.02 h(-1); p < 0.001), and the mean calculated half-life was lower than predicted (7.2 +/- 2.3 vs. 9.6 +/- 3.2 h; p < 0.001). CONCLUSIONS: Patients with hemorrhagic stroke exhibited pharmacokinetic alterations favoring increased elimination of vancomycin when compared to predicted pharmacokinetic parameters based on population data. This may result in underexposure to vancomycin, leading to treatment failure and other medical complications. PMID- 26942736 TI - Electrogenerated chemiluminescence of tris(2,2'-bipyridine)ruthenium(II) using N (3-aminopropyl)diethanolamine as coreactant. AB - Coreactant plays a critical role for the application of electrochemiluminescence (ECL). Herein, N-(3-aminopropyl)diethanolamine (APDEA) has been explored as a potential coreactant for enhancing tris(2,2'-bipyridyl)ruthenium(II) ECL. It is much more effective than tripropylamine at gold and platinum electrodes although it has one primary amine group besides a tertiary amine group. The presence of primary amine group and hydroxyl groups in APDEA promotes the oxidation rates of amine and thus remarkably increases ECL intensity. The ECL intensities of the Ru(bpy)3 (2+)/APDEA system are approximately 10 and 36 times stronger than that of Ru(bpy)3 (2+)/tripropylamine system and about 1.6 and 1.14 times stronger than that of Ru(bpy)3 (2+)/N-butyldiethanolamine system at Au and Pt electrodes, respectively. The ECL intensity of the Ru(bpy)3 (2+)/APDEA system is 2.42 times stronger than that of Ru(bpy)3 (2+)/N-butyldiethanolamine at glassy carbon electrodes. PMID- 26942734 TI - Medical and Surgical Treatment Options for Nonalcoholic Steatohepatitis. AB - Nonalcoholic fatty liver disease (NAFLD) is the most common cause of liver disease in the USA with a growing prevalence worldwide. Nonalcoholic steatohepatitis (NASH), progressive form of NAFLD, can lead to the development of cirrhosis, hepatocellular carcinoma, and the need for liver transplantation. Treatment of NASH may decrease the risk of progressive disease. Treatment for NAFLD should center around weight loss and exercise. Pharmacotherapy with vitamin E and pioglitazone should be considered for those with NASH, especially those with fibrosis. Weight loss surgery is also an effective treatment for NASH in individuals with other indications for surgery. In this review, we will discuss the currently available therapies for NASH including lifestyle, pharmacologic, and surgical options. PMID- 26942737 TI - A universal SI-traceable isotope dilution mass spectrometry method for protein quantitation in a matrix by tandem mass tag technology. AB - Isotope dilution mass spectrometry (IDMS), an important metrological method, is widely used for absolute quantification of peptides and proteins. IDMS employs an isotope-labeled peptide or protein as an internal standard although the use of a protein provides improved accuracy. Generally, the isotope-labeled protein is obtained by stable isotope labeling by amino acids in cell culture (SILAC) technology. However, SILAC is expensive, laborious, and time-consuming. To overcome these drawbacks, a novel universal SI-traceable IDMS method for absolute quantification of proteins in a matrix is described with human transferrin (hTRF). The hTRF and a human serum sample were labeled with different tandem mass tags (TMTs). After mixing the TMT-labeled hTRF and serum sample together followed by digestion, the peptides were separated by nano-liquid chromatography and analyzed by matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS). Using the signature peptides, we calculated the ratios of reporter ions from the TMT-labeled peptides which, in turn, allowed determination of the mass fraction of hTRF. The recovery ranged from 97% to 105% with a CV of 3.9%. The LOD and LOQ were 1.71 * 10(-5) g/g and 5.69 * 10(-5) g/g of hTRF in human serum, respectively, and the relative expanded uncertainty was 4.7% with a mass fraction of 2.08 mg/g. For comparison, an enzyme-linked immunosorbent assay (ELISA) method for hTRF yielded a mass fraction of 2.03 mg/g. This method provides a starting point for establishing IDMS technology to accurately determine the mass fractions of protein biomarkers in a matrix with traceability to SI units. This technology should support the development of a metrological method useful for quantification of a wide variety of proteins. PMID- 26942739 TI - A self-assembling RNA aptamer-based nanoparticle sensor for fluorometric detection of Neomycin B in milk. AB - To date, there are few reports regarding the development of RNA aptamer-based biosensors for the detection of small molecules. The possible reason is attributed to the weak nuclease resistance of RNA in biological environments. In this study, we have developed an RNA aptamer-based gold nanoparticle (AuNP) sensor for fluorometric detection of Neomycin B in milk. This aptasensor depends on the self-assembly of the RNA aptamer/Neomycin B complex and fluorescence quenching by AuNPs. This biosensor exhibited a low detection limit of 0.01 MUM, with a linear dynamic range from 0.1 to 10 MUM in milk, and a good selectivity toward Neomycin B. Specifically, because of the shorter RNA fragments and the nuclease inhibition ability of the RNA-modified AuNPs, the RNA sequences remained stable during the experiments. This work will serve as an example for the development of novel biosensors based on RNA aptamers. Graphical Abstract An RNA aptamer-based nanoparticle sensor, developed for the detection of Neomycin B in milk, shows high binding affinity and selectivity. This aptasensor depends on the self-assembly of the aptamer/ligand complex and fluorescence quenching by gold nanoparticles (AuNPs). Because of the shorter RNA fragments and the nuclease inhibition ability of RNA-modified AuNPs, RNA sequences remain stable during the detection. PMID- 26942740 TI - Morphological and Molecular Characterization of Reared Parasitoid Wasps of the Genus Glyptapanteles Ashmead 1904 (Insecta: Hymenoptera: Braconidae: Microgastrinae) Associated with Lepidoptera in India. AB - Glyptapanteles Ashmead (Hymenoptera: Braconidae: Microgastrinae) is a cosmopolitan group of hyperdiverse parasitic wasps. The genus remains taxonomically challenging in India due to its highly speciose nature, morphological similarity amongst species and negligible host records. The Indian fauna is one of the most diverse and also the least studied. The present study is based on 60 populations reared from 35 host species, 100+ individual caterpillar rearings (1100 wasp specimens pinned and 2000 in alcohol) and from 12 different geographical locations of the country (11 states and one Union territory) that represent 26 provisional Glyptapanteles species within 8 species-groups. Out of 60 populations, phylogenetic analyses were performed on 38 based on mitochondrial cytochrome oxidase subunit I (COI) nucleotide sequences. Maximum likelihood and Bayesian inference methods displayed three and four major discrete Glyptapanteles clades, respectively. In clade A very few Indian species were grouped along with Neotropical and Thailand species. The other clades B and C grouped the majority of the Indian species and showed considerable host specificity in both the trees. All parasitic wasp species were gregarious in nature, except for two populations. Three different sets of data (morphology, host records, and COI) were integrated in order to generate accurate boundaries between species/species-groups. Illustrations of all parasitized caterpillars/cocoons and 42 habitus views of Glyptapanteles spp., distributional information, and GenBank accession numbers, are presented. The present study, perhaps the most comprehensive done to date in India, suggests the presence of several additional Glyptapanteles species, which were previously unrecognized. PMID- 26942738 TI - TransOmic analysis of forebrain sections in Sp2 conditional knockout embryonic mice using IR-MALDESI imaging of lipids and LC-MS/MS label-free proteomics. AB - Quantitative methods for detection of biological molecules are needed more than ever before in the emerging age of "omics" and "big data." Here, we provide an integrated approach for systematic analysis of the "lipidome" in tissue. To test our approach in a biological context, we utilized brain tissue selectively deficient for the transcription factor Specificity Protein 2 (Sp2). Conditional deletion of Sp2 in the mouse cerebral cortex results in developmental deficiencies including disruption of lipid metabolism. Silver (Ag) cationization was implemented for infrared matrix-assisted laser desorption electrospray ionization (IR-MALDESI) to enhance the ion abundances for olefinic lipids, as these have been linked to regulation by Sp2. Combining Ag-doped and conventional IR-MALDESI imaging, this approach was extended to IR-MALDESI imaging of embryonic mouse brains. Further, our imaging technique was combined with bottom-up shotgun proteomic LC-MS/MS analysis and western blot for comparing Sp2 conditional knockout (Sp2-cKO) and wild-type (WT) cortices of tissue sections. This provided an integrated omics dataset which revealed many specific changes to fundamental cellular processes and biosynthetic pathways. In particular, step-specific altered abundances of nucleotides, lipids, and associated proteins were observed in the cerebral cortices of Sp2-cKO embryos. PMID- 26942741 TI - Abstracts : 20th Annual Congress of Euroacademia Multidisciplinaria Neurotraumatologica (EMN). PMID- 26942742 TI - Advancing clinician-performed sonography in the twenty-first century: building on the rich legacy of the twentieth century pioneers. PMID- 26942745 TI - Robust Clustering Method in the Presence of Scattered Observations. AB - Contamination of scattered observations, which are either featureless or unlike the other observations, frequently degrades the performance of standard methods such as K-means and model-based clustering. In this letter, we propose a robust clustering method in the presence of scattered observations called Gamma-clust. Gamma-clust is based on a robust estimation for cluster centers using gamma divergence. It provides a proper solution for clustering in which the distributions for clustered data are nonnormal, such as t-distributions with different variance-covariance matrices and degrees of freedom. As demonstrated in a simulation study and data analysis, Gamma-clust is more flexible and provides superior results compared to the robustified K-means and model-based clustering. PMID- 26942743 TI - Peritonsillar abscess (PTA): clinical characteristics, microbiology, drug exposures and outcomes of a large multicenter cohort survey of 412 patients hospitalized in 13 French university hospitals. AB - The aim of this study was to describe the epidemiology of hospitalized patients with peritonsillar abscess (PTA). We conducted a multicenter survey in 13 French university hospitals in 2009-2012 describing 412 patients. Median age was 29 year (range, 2-84) and current smoking habit was reported by 177 (43 %) patients. Most of the patients (92 %) had consulted a physician for sore throat within 10 days before admission for PTA diagnosis. Additional symptoms such as visible tonsil abnormalities (83 %), tender cervical adenopathy (57 %) and fever >= 38.5 degrees C (53 %) were also reported. A total of 65 % patients (269/412) reported recent systemic anti-inflammatory agents (AIAs) exposure by medical prescription (70 %), self-medication (22 %), or both (8 %); 61 % and 27 % reported recent exposure to antibiotic and topical treatments for sore throat, respectively. Non steroidal AIAs were used most often (45 %), particularly arylpropionic derivatives. A rapid diagnosis antigen test (RDT) for Streptococcus pyogenes was performed in 70 (17 %) patients and was positive in 17 (24 %), of whom 9 (53 %) were exposed to AIAs and 14 (82 %) to antibiotics. To treat PTA, antibiotic therapy was given to 392 (95 %) patients. Of 333 antibiotic prescriptions, amoxicillin-clavulanic acid and metronidazole were the most prescribed antibiotics (42 and 17 %, respectively). Surgical drainage of the abscess was performed in 119 (29 %) cases and tonsillectomy in 75 (18 %) cases. The clinical outcome was favorable during the hospital stay in 404 (98 %) patients. In conclusion, patients with sore throat are often exposed to AIAs before PTA diagnosis, and antibiotic prescription was not often based on the RDT positivity. PMID- 26942744 TI - MALDI-TOF MS performance compared to direct examination, culture, and 16S rDNA PCR for the rapid diagnosis of bone and joint infections. AB - The rapid identification of bacterial species involved in bone and joint infections (BJI) is an important element to optimize the diagnosis and care of patients. The aim of this study was to evaluate the usefulness of matrix-assisted laser desorption ionization mass spectrometry (MALDI-TOF MS) for the rapid diagnosis of bone infections, directly on synovial fluid (SF) or on crushed osteoarticular samples (CS). From January to October 2013, we prospectively analyzed 111 osteoarticular samples (bone and joint samples, BJS) from 78 patients in care at the University Hospital of Rennes, France. The diagnosis procedure leading to the sample collection was linked to a suspicion of infection, inflammatory disease, arthritis, or for any bone or joint abnormalities. Standard bacteriological diagnosis and molecular biology analysis [16S rRNA polymerase chain reaction (PCR) and sequencing] were conducted. In addition, analysis by MALDI-TOF MS was performed directly on the osteoarticular samples, as soon as the amount allowed. Culture, which remains the gold standard for the diagnosis of BJI, has the highest sensitivity (85.9 %) and remains necessary to test antimicrobial susceptibility. The 16S rDNA PCR results were positive in the group with positive BJI (28.6 %) and negative in the group without infection. Direct examination remains insensitive (31.7 %) but more effective than MALDI-TOF MS directly on the sample (6.3 %). The specificity was 100 % in all cases, except for culture (74.5 %). Bacterial culture remains the gold standard, especially enrichment in blood bottles. Direct analysis of bone samples with MALDI-TOF MS is not useful, possibly due to the low inoculum of BJS. PMID- 26942747 TI - Feature-Linking Model for Image Enhancement. AB - Inspired by gamma-band oscillations and other neurobiological discoveries, neural networks research shifts the emphasis toward temporal coding, which uses explicit times at which spikes occur as an essential dimension in neural representations. We present a feature-linking model (FLM) that uses the timing of spikes to encode information. The first spiking time of FLM is applied to image enhancement, and the processing mechanisms are consistent with the human visual system. The enhancement algorithm achieves boosting the details while preserving the information of the input image. Experiments are conducted to demonstrate the effectiveness of the proposed method. Results show that the proposed method is effective. PMID- 26942746 TI - Separating Spike Count Correlation from Firing Rate Correlation. AB - Populations of cortical neurons exhibit shared fluctuations in spiking activity over time. When measured for a pair of neurons over multiple repetitions of an identical stimulus, this phenomenon emerges as correlated trial-to-trial response variability via spike count correlation (SCC). However, spike counts can be viewed as noisy versions of firing rates, which can vary from trial to trial. From this perspective, the SCC for a pair of neurons becomes a noisy version of the corresponding firing rate correlation (FRC). Furthermore, the magnitude of the SCC is generally smaller than that of the FRC and is likely to be less sensitive to experimental manipulation. We provide statistical methods for disambiguating time-averaged drive from within-trial noise, thereby separating FRC from SCC. We study these methods to document their reliability, and we apply them to neurons recorded in vivo from area V4 in an alert animal. We show how the various effects we describe are reflected in the data: within-trial effects are largely negligible, while attenuation due to trial-to-trial variation dominates and frequently produces comparisons in SCC that, because of noise, do not accurately reflect those based on the underlying FRC. PMID- 26942748 TI - Effect of Reference Scheme on Power and Phase of the Local Field Potential. AB - Brain signals are often analyzed in the spectral domain, where the power spectral density (PSD) and phase differences and consistency can reveal important information about the network. However, for proper interpretation, it is important to know whether these measures depend on stimulus/behavioral conditions or the reference scheme used to analyze data. We recorded local field potential (LFP) from an array of microelectrodes chronically implanted in area V1 of monkeys under different stimulus/behavioral conditions and computed PSD slopes, coherence, and phase difference between LFPs as a function of frequency and interelectrode distance while using four reference schemes: single wire, average, bipolar, and current source density. PSD slopes were dependent on reference scheme at low frequencies (below 200 Hz) but became invariant at higher frequencies. Average phase differences between sites also depended critically on referencing, switching from 0 degrees for single-wire to 180 degrees for average reference. Results were consistent across different stimulus/behavioral conditions. We were able to account for these results based on the coherence profile across sites and properties of the spectral estimator. Our results show that using different reference schemes can have drastic effects on phase differences and PSD slopes and therefore must be interpreted carefully to gain insights about network properties. PMID- 26942750 TI - Learning Precise Spike Train-to-Spike Train Transformations in Multilayer Feedforward Neuronal Networks. AB - We derive a synaptic weight update rule for learning temporally precise spike train-to-spike train transformations in multilayer feedforward networks of spiking neurons. The framework, aimed at seamlessly generalizing error backpropagation to the deterministic spiking neuron setting, is based strictly on spike timing and avoids invoking concepts pertaining to spike rates or probabilistic models of spiking. The derivation is founded on two innovations. First, an error functional is proposed that compares the spike train emitted by the output neuron of the network to the desired spike train by way of their putative impact on a virtual postsynaptic neuron. This formulation sidesteps the need for spike alignment and leads to closed-form solutions for all quantities of interest. Second, virtual assignment of weights to spikes rather than synapses enables a perturbation analysis of individual spike times and synaptic weights of the output, as well as all intermediate neurons in the network, which yields the gradients of the error functional with respect to the said entities. Learning proceeds via a gradient descent mechanism that leverages these quantities. Simulation experiments demonstrate the efficacy of the proposed learning framework. The experiments also highlight asymmetries between synapses on excitatory and inhibitory neurons. PMID- 26942749 TI - State-Space Analysis of Granger-Geweke Causality Measures with Application to fMRI. AB - The recent interest in the dynamics of networks and the advent, across a range of applications, of measuring modalities that operate on different temporal scales have put the spotlight on some significant gaps in the theory of multivariate time series. Fundamental to the description of network dynamics is the direction of interaction between nodes, accompanied by a measure of the strength of such interactions. Granger causality and its associated frequency domain strength measures (GEMs) (due to Geweke) provide a framework for the formulation and analysis of these issues. In pursuing this setup, three significant unresolved issues emerge. First, computing GEMs involves computing submodels of vector time series models, for which reliable methods do not exist. Second, the impact of filtering on GEMs has never been definitively established. Third, the impact of downsampling on GEMs has never been established. In this work, using state-space methods, we resolve all these issues and illustrate the results with some simulations. Our analysis is motivated by some problems in (fMRI) brain imaging, to which we apply it, but it is of general applicability. PMID- 26942751 TI - Whole-Body Reaching Movements Formulated by Minimum Muscle-Tension Change Criterion. AB - It is well known that planar reaching movements of the human shoulder and elbow joints have invariant features: roughly straight hand paths and bell-shaped velocity profiles. The optimal control models with the criteria of smoothness or precision, which determine a unique movement pattern, predict such features of hand trajectories. In this letter on expanding the research on simple arm reaching movements, we examine whether the smoothness criteria can be applied to whole-body reaching movements with many degrees of freedom. Determining a suitable joint trajectory in the whole-body reaching movement corresponds to the optimization problem with constraints, since body balance must be maintained during a motion task. First, we measured human joint trajectories and ground reaction forces during whole-body reaching movements, and confirmed that subjects formed similar movements with common characteristics in the trajectories of the hand position and body center of mass. Second, we calculated the optimal trajectories according to the criteria of torque and muscle-tension smoothness. While the minimum torque change trajectories were not consistent with the experimental data, the minimum muscle-tension change model was able to predict the stereotyped features of the measured trajectories. To explore the dominant effects of the extension from the torque change to the muscle-tension change, we introduced a weighted torque change cost function. Considering the maximum voluntary contraction (MVC) force of the muscle as the weighting factor of each joint torque, we formulated the weighted torque change cost as a simplified version of the minimum muscle-tension change cost. The trajectories owing to the minimum weighted torque change criterion also showed qualitative agreement with the common features of the measured data. Proper estimation of the MVC forces in the body joints is essential to reproduce human whole-body movements according to the minimum muscle-tension change criterion. PMID- 26942752 TI - Maternal Serum C-Reactive Protein in Women with Preterm Prelabor Rupture of Membranes. AB - OBJECTIVE: This study evaluated maternal C-reactive protein (CRP) as a predictor of microbial invasion of the amniotic cavity (MIAC) and histological chorioamnionitis (HCA) in women with preterm prelabor rupture of the membranes (PPROM) before and after 32 weeks of gestation. METHODS: This study was a prospective observational cohort study of 386 women. Maternal serum CRP concentrations were evaluated, and amniotic fluid samples were obtained via transabdominal amniocentesis at the time of admission. Placentas underwent histopathological examination after delivery. MIAC was defined based on a positive PCR for Ureaplasma species, Mycoplasma hominis and Chlamydia trachomatis and/or positive 16S rRNA gene amplification. HCA was defined based on the Salafia classification. RESULTS: Maternal CRP was significantly higher in women with MIAC and HCA (median 9.0 mg/l) than in women with HCA alone (median 6.9 mg/l), MIAC alone (median 7.4 mg/l) and without MIAC or HCA (median 4.5 mg/l) (p<0.0001). CRP was a weak predictor of the occurrence of MIAC and HCA before and after 32 weeks of gestation. Only the 95th percentile of CRP and PPROM before 32 weeks exhibited a false-positive rate of 1%, a positive predictive value of 90% and a positive likelihood ratio of 13.2 to predict MIAC and HCA. However, the low sensitivity of 15% limits the clinical utility of this detection. CONCLUSION: CRP is a poor predictor of the occurrence of MIAC and HCA, even at early gestational ages. PMID- 26942753 TI - Pronephric tubule formation in zebrafish: morphogenesis and migration. AB - The nephron is the functional subunit of the vertebrate kidney and plays important osmoregulatory and excretory roles during embryonic development and in adulthood. Despite its central role in kidney function, surprisingly little is known about the molecular and cellular processes that control nephrogenesis. The zebrafish pronephric kidney, comprising two nephrons, provides a visually accessible and genetically tractable model system for a better understanding of nephron formation. Using this system, various developmental processes, including the commitment of mesoderm to a kidney fate, renal tubule proliferation, and migration, can be studied during nephrogenesis. Here, we discuss some of these processes in zebrafish with a focus on the pathways that influence renal tubule cell morphogenesis. PMID- 26942764 TI - Association between Electronic Cigarette Use and Asthma among High School Students in South Korea. AB - OBJECTIVES: Little is known about health outcomes related to electronic cigarette (EC) use, despite its growing popularity. The aim of this study is to investigate the association between EC use and asthma. METHODS: The study design is a cross sectional study. A total of 35,904 high school students were included as the final study population. The presence of asthma was based on a student's self reported doctor diagnosis of asthma in the past 12 months. RESULTS: Prevalence rates of asthmatics in 'current EC users' (n = 2,513), 'former EC users' (n = 2,078), and 'never EC users' (n = 31,313), were 3.9% (n = 98), 2.2% (n = 46) and 1.7% (n = 530), respectively. Comparing 'current EC' users with 'never EC' users, the unadjusted OR for asthma was 2.36 (95% CI: 1.89-2.94). In order to control for the effect of conventional cigarette (CC) smoking, after stratifying the subjects by the three CC smoking categories (never CC, former CC, and current CC), within the 'never CC' category, the unadjusted OR for asthma for 'current EC' users was 3.41 (95% CI: 1.79-6.49), and the adjusted OR was 2.74 (95% CI: 1.30-5.78). Severe asthma was reflected by the number of days absent from school due to asthma symptoms; current EC users had the highest adjusted OR for severe asthma compared to 'never EC' users. CONCLUSIONS: When compared to a reference population of high school students in South Korea, EC users have an increased association with asthma and are more likely to have had days absent from school due to severe asthma symptoms. In conclusion, the results indicate that EC use may be a risk factor for asthma. The results may be useful in developing a scientific basis for the evaluation of a potential health hazard by EC. PMID- 26942763 TI - Microstructure and Cerebral Blood Flow within White Matter of the Human Brain: A TBSS Analysis. AB - BACKGROUND: White matter (WM) fibers connect different brain regions and are critical for proper brain function. However, little is known about the cerebral blood flow in WM and its relation to WM microstructure. Recent improvements in measuring cerebral blood flow (CBF) by means of arterial spin labeling (ASL) suggest that the signal in white matter may be detected. Its implications for physiology needs to be extensively explored. For this purpose, CBF and its relation to anisotropic diffusion was analyzed across subjects on a voxel-wise basis with tract-based spatial statistics (TBSS) and also across white matter tracts within subjects. METHODS: Diffusion tensor imaging and ASL were acquired in 43 healthy subjects (mean age = 26.3 years). RESULTS: CBF in WM was observed to correlate positively with fractional anisotropy across subjects in parts of the splenium of corpus callosum, the right posterior thalamic radiation (including the optic radiation), the forceps major, the right inferior fronto occipital fasciculus, the right inferior longitudinal fasciculus and the right superior longitudinal fasciculus. Furthermore, radial diffusivity correlated negatively with CBF across subjects in similar regions. Moreover, CBF and FA correlated positively across white matter tracts within subjects. CONCLUSION: The currently observed findings on a macroscopic level might reflect the metabolic demand of white matter on a microscopic level involving myelination processes or axonal function. However, the exact underlying physiological mechanism of this relationship needs further evaluation. PMID- 26942766 TI - Screening for Antepartum Depression Through Community Health Outreach in Swaziland. AB - Maternal depression, including antepartum and postpartum depression, is a neglected public health issue with potentially far-reaching effects on maternal and child health. We aimed to measure the burden of antepartum depression and identify risk factors among women in a peri-urban community in Swaziland. We conducted a cross-sectional study within the context of a community outreach peer support project involving "Mentor Mothers". We used of the Edinburgh Postnatal Depression Scale (EPDS) to screen women for depression during the third trimester of pregnancy, using a cut-off score of >=13 to indicate depression. We also collected demographic and socioeconomic factors, and assessed the association of these factors with EPDS score using logistic regression models. A total of 1038 pregnant women were screened over a period of 9 months. Almost a quarter (22.7 %) had EPDS scores >=13 and 41.2 % were HIV positive. A fifth, 17.5 % were teenagers and 73.7 % were unemployed. Depression was not associated with HIV status, age or employment status. However, women with multiple socioeconomic stressors were found to be more likely to score highly on the EPDS. Depression was common among pregnant women in the peri-urban areas of Swaziland. Screening for depression using the EPDS is feasible and can be included in the community health worker standard tool box as a way to improve early detection of depression and to highlight the importance of maternal mental health as a core public health concern. PMID- 26942765 TI - Reconstruction of Tissue-Specific Metabolic Networks Using CORDA. AB - Human metabolism involves thousands of reactions and metabolites. To interpret this complexity, computational modeling becomes an essential experimental tool. One of the most popular techniques to study human metabolism as a whole is genome scale modeling. A key challenge to applying genome scale modeling is identifying critical metabolic reactions across diverse human tissues. Here we introduce a novel algorithm called Cost Optimization Reaction Dependency Assessment (CORDA) to build genome scale models in a tissue-specific manner. CORDA performs more efficiently computationally, shows better agreement to experimental data, and displays better model functionality and capacity when compared to previous algorithms. CORDA also returns reaction associations that can greatly assist in any manual curation to be performed following the automated reconstruction process. Using CORDA, we developed a library of 76 healthy and 20 cancer tissue specific reconstructions. These reconstructions identified which metabolic pathways are shared across diverse human tissues. Moreover, we identified changes in reactions and pathways that are differentially included and present different capacity profiles in cancer compared to healthy tissues, including up-regulation of folate metabolism, the down-regulation of thiamine metabolism, and tight regulation of oxidative phosphorylation. PMID- 26942767 TI - Acute Effects of Particulate Air Pollution on the Incidence of Coronary Heart Disease in Shanghai, China. AB - INTRODUCTION: Evidence based on ecological studies in China suggests that short term exposure to particulate matter (PM) is associated with cardiovascular mortality. However, there is less evidence of PM-related morbidity for coronary heart disease (CHD) in China. This study aims to investigate the relationship between acute PM exposure and CHD incidence in people aged above 40 in Shanghai. METHODS: Daily CHD events during 2005-2012 were identified from outpatient and emergency department visits. Daily average concentrations for particulate matter with aerodynamic diameter less than 10 microns (PM10) were collected over the 8 year period. Particulate matter with aerodynamic diameter less than 2.5 microns (PM2.5) were measured from 2009 to 2012. Analyses were performed using quasi poisson regression models adjusting for confounders, including long-term trend, seasonality, day of the week, public holiday and meteorological factors. The effects were also examined by gender and age group (41-65 years, and >65 years). RESULTS: There were 619928 CHD outpatient and emergency department visits. The average concentrations of PM10 and PM2.5 were 81.7 MUg/m3 and 38.6 MUg/m3, respectively. Elevated exposure to PM10 and PM2.5 was related with increased risk of CHD outpatients and emergency department visits in a short time course. A 10 MUg/m3 increase in the 2-day PM10 and PM2.5 was associated with increase of 0.23% (95% CI: 0.12%, 0.34%) and 0.74% (95% CI: 0.44%, 1.04%) in CHD morbidity, respectively. The associations appeared to be more evident in the male and the elderly. CONCLUSION: Short-term exposure to high levels of PM10 and PM2.5 was associated with increased risk of CHD outpatient and emergency department visits. Season, gender and age were effect modifiers of their association. PMID- 26942769 TI - Protease-Activated Fluorescent Probe Shows Promise as a Cancer Imaging Device. PMID- 26942770 TI - Detecting single-target changes in multiple object tracking: The case of peripheral vision. AB - In the present study, we investigated whether peripheral vision can be used to monitor multiple moving objects and to detect single-target changes. For this purpose, in Experiment 1, a modified multiple object tracking (MOT) setup with a large projection screen and a constant-position centroid phase had to be checked first. Classical findings regarding the use of a virtual centroid to track multiple objects and the dependency of tracking accuracy on target speed could be successfully replicated. Thereafter, the main experimental variations regarding the manipulation of to-be-detected target changes could be introduced in Experiment 2. In addition to a button press used for the detection task, gaze behavior was assessed using an integrated eyetracking system. The analysis of saccadic reaction times in relation to the motor response showed that peripheral vision is naturally used to detect motion and form changes in MOT, because saccades to the target often occurred after target-change offset. Furthermore, for changes of comparable task difficulties, motion changes are detected better by peripheral vision than are form changes. These findings indicate that the capabilities of the visual system (e.g., visual acuity) affect change detection rates and that covert-attention processes may be affected by vision-related aspects such as spatial uncertainty. Moreover, we argue that a centroid-MOT strategy might reduce saccade-related costs and that eyetracking seems to be generally valuable to test the predictions derived from theories of MOT. Finally, we propose implications for testing covert attention in applied settings. PMID- 26942771 TI - Development of Solid-Phase Site-Specific Conjugation and Its Application toward Generation of Dual Labeled Antibody and Fab Drug Conjugates. AB - The focus of the antibody-drug conjugate (ADC) field is shifting toward development of site-specific, next-generation ADCs to address the issue of heterogeneity, metabolic instability, conjugatability, and less than ideal therapeutic index associated with the conventional (heterogeneous) ADCs. It is evident from the recent literature that the site of conjugation, the structure of the linker, and the physicochemical properties of the linker-payload all have a significant impact on the safety and efficacy of the resulting ADCs. Screening multiple linker-payloads on multiple sites of an antibody presents a combinatorial problem that necessitates high-throughput conjugation and purification methodology to identify ADCs with the best combination of site and payload. Toward this end, we developed a protein A/L-based solid-phase, site specific conjugation and purification method that can be used to generate site specific ADCs in a 96-well plate format. This solid-phase method has been shown to be versatile because of its compatibility with various conjugation functional handles such as maleimides, haloacetamides, copper free click substrates, and transglutaminase substrates. The application of this methodology was further expanded to generate dual labeled, site-specific antibody and Fab conjugates. PMID- 26942768 TI - A systematic review of the health-related quality of life and economic burdens of anorexia nervosa, bulimia nervosa, and binge eating disorder. AB - PURPOSE: To perform a systematic review of the health-related quality of life (HRQoL) and economic burdens of anorexia nervosa (AN), bulimia nervosa (BN), and binge eating disorder (BED). METHODS: A systematic literature search of English language studies was performed in Medline, Embase, PsycINFO, PsycARTICLES, Academic Search Complete, CINAHL Plus, Business Source Premier, and Cochrane Library. Cost data were converted to 2014 Euro. RESULTS: Sixty-nine studies were included. Data on HRQoL were reported in 41 studies (18 for AN, 17 for BN, and 18 for BED), on healthcare utilization in 20 studies (14 for AN, 12 for BN, and 8 for BED), and on healthcare costs in 17 studies (9 for AN, 11 for BN, and only 2 for BED). Patients' HRQoL was significantly worse with AN, BN, and BED compared with healthy populations. AN, BN, and BED were associated with a high rate of hospitalization, outpatient care, and emergency department visits. However, patients rarely received specific treatment for their eating disorder. The annual healthcare costs for AN, BN, and BED were ?2993 to ?55,270, ?888 to ?18,823, and ?1762 to ?2902, respectively. CONCLUSIONS: AN, BN, and BED have a serious impact on patient's HRQoL and are also associated with increased healthcare utilization and healthcare costs. The burden of BED should be examined separately from that of BN. The limited evidence suggests that further research is warranted to better understand the differences in long-term HRQoL and economic burdens of AN, BN, and BED. PMID- 26942772 TI - Ionic and biochemical characterization of bovine intervertebral disk. AB - INTRODUCTION: Intervertebral disks have been associated with low back pain, and many therapies have been proposed for its treatment. The cellular and molecular knowledge of intervertebral disks composition and precise methods to quantify disk components are important for any type of proposed therapy. Thus, the aim of this study was to correlate glycosaminoglycans presence with the quantitation of cells, ions and collagen fiber distributions in different intervertebral disk sections. METHODS: In total, 14 intervertebral disks were used from cattle. All of the disks were dehydrated, separated in seven sections and digested in sodium free papain buffer. Glycosaminoglycan measurements were performed in the samples according to agarose electrophoresis method; total cells were measured using the PicoGreen(r) technique, ions were quantified, and collagen fiber birefringence was analyzed with polarized light. RESULTS: Cations Na+ and K+ are more concentrate in the nucleus (Na(+) = 1688.50 +/- 110 mmol/L; K(+) = 111.9 +/- 28 mmol/L) of intervertebral disks than the annulus (Na(+) = 652.80 +/- 75 mmol/L; K(+) = 55.6 +/- 8 mmol/L). A negative correlation between cells number and sodium/potassium was observed (p < 0.001) Additionally, thin collagen fibers were largest in the nucleus, similar to hyaluronate distribution. CONCLUSIONS: The results suggest that annulus fibrosus cells are also sensitive to changes in ionic concentrations such as nucleus pulposus cells. Additionally, hyaluronate is related to thin collagen fibers type II. PMID- 26942773 TI - Rapid identification of antibiotic resistance using droplet microfluidics. AB - Culturing bacteria and monitoring bacterial cell growth is a critical issue when dealing with patients who present with bacterial infections. One of the main challenges that arises is the time taken to identify the particular strain of bacteria and consequently, decide the correct treatment. In the majority of cases, broad spectrum antibiotics are used to target infections when a narrow spectrum drug would be more appropriate. The efficient monitoring of bacterial growth and potential antibiotic resistance is necessary to identify the best treatment options for patients. Minturising the reactions into microfluidic droplets offers a novel method to rapidy analyze bacteria. Microfluidics facilitates low volume reactions that provide a unique system where each droplet reaction acts as an individual bioreactor. Here, we designed and built a novel platform that allowed us to create and monitor E.coli microfluidic droplet cultures. Optical capacity was built in and measurements of bacterial cultures were captured facilitating the continuous monitoring of individual reactions. The capacity of the instrument was demonstrated by the application of treatments to both bacteria and drug resistant strains of bacteria. We were able to detect responses within one hour in the droplet cultures, demonstrating the capacity of this workflow to the culture and rapid characterization of bacterial strains. PMID- 26942778 TI - Endometrial thickness significantly affects clinical pregnancy and live birth rates in frozen-thawed embryo transfer cycles. AB - In order to explore the relationship between endometrial thickness on the day of embryo transfer and pregnancy outcomes in frozen-thawed embryo transfer (FET) cycles, we retrospectively analyzed data from 2997 patients undergoing their first FET cycles from January 2010 to December 2012. All patients were divided into three groups (Group A, <=8 mm; Group B, 9-13 mm; Group C, >=14 mm) according to the endometrial thickness on embryo transfer day. Compared with patients in the other two groups, patients with thin endometrial thickness in Group A had significantly lower clinical pregnancy rate (33.4%, 41.3% and 45.4%, p < 0.01) and live birth rate (23.8%, 32.2% and 34.0%, p < 0.01). After adjusting for age, body mass index (BMI), baseline follicle stimulating hormone (FSH) FET protocol and number of embryos transferred, the associations between medium endometrial thickness (Group B) and clinical pregnancy rate [adjusted odds ratio (aOR): 1.39; 95% confidence interval (CI): 1.10-1.77, p < 0.01] and live birth rate (aOR: 1.50; 95% CI: 1.16-1.95, p < 0.01) were significant. We conclude that for patients undergoing FET, endometrial thickness on the embryo transfer day significantly affects IVF outcomes in cleavage embryo transfer cycles independent of other factors. PMID- 26942825 TI - The epidemiology of hearing problems: how should we investigate it? AB - Within published reports, the prevalence of reported hearing difficulties is quite variable. In the present study, we have considered factors that could influence the apparent prevalence of hearing difficulties in the Welsh population, surveyed in a number of different studies. The first important factor to emerge was whether the questions were asked in the context of a general health approach (together with questions about other aspects of health), in which case the prevalence was usually less than 15%. When the same questions were posed in conjunction with a number of other questions on auditory function the prevalence was 20% or greater. Secondly, when a household survey approach is used, with one person being asked to respond on behalf of all members of the household, the prevalence among those reporting is markedly higher than among the other members of the household whose problems they are reporting. PMID- 26942826 TI - The role of antioxidants in protection from ototoxic drugs. AB - A number of studies have shown that cisplatin and gentamicin ototoxic effects may result from free radical-mediated damage due to the reduction of antioxidant substances and an increased lipid peroxidation. The authors summarize the results obtained evaluating the auditory and vestibular functions and the inner ear hair cell morphology and survival after administration of antioxidant agents against cisplatin and gentamicin. In the first experiment, albino guinea pigs were treated with gentamicin (100 mg/kg per day, i.m.) alone or gentamicin (100 mg/kg per day, i.m.) plus alpha-tocopherol (100 mg/kg per day, i.m.) for 2 weeks. In a second experiment, albino guinea pigs were injected with cisplatin (2.5 mg/kg per day) or cisplatin (2.5 mg/kg per day) plus tiopronin (300 mg/kg) for 6 days. Electrocochleographic recordings were made from an implanted round window electrode. In all experiments compound action potentials (CAPs) were measured at 2-16 kHz. Changes in cochlear function were characterized as CAP threshold shifts. To evaluate vestibular function, the animals underwent sinusoidal oscillations in the dark about their vertical and longitudinal axes to evoke horizontal and vertical vestibulo-ocular reflexes (VOR). Frequency stimulation parameters ranged from 0.02 to 0.4 Hz and peak-to-peak amplitude was 20 degrees . Morphological changes were analysed by light microscopy and scanning electron microscopy. Both hearing loss and vestibular dysfunction induced by gentamicin were significantly attenuated by alpha-tocopherol. However, tiopronin co-therapy slowed the progression of hearing loss in cisplatin-treated animals and significantly attenuated the final threshold shifts. Cisplatin had little effect on the hair cells of cristae ampullares and maculae. Vestibular function was completely preserved in tiopronin co-treated animals. In conclusion, antioxidants such as alpha-tocopherol or tiopronin interfere with gentamicin and cisplatin damage and this suggests that they may be useful in preventing oto vestibulotoxicity. Therefore, it is important to develop protective strategies that permit the avoidance of the toxic side effects of these drugs without interfering with their therapeutic effects. PMID- 26942827 TI - Imaging procedures in cochlear implant patients - evaluation of different radiological techniques. AB - The purpose of this study was to evaluate the feasibility and usability of different radiologic methods (single-slice computed tomography (CT), multi-slice CT and rotational tomography (RT)) for assessment of the position of cochlear implant electrodes. Cochlear implants in an isolated human temporal bone and in a complete formalin-fixed cadaver head were examined and the electrode position was determined. Subsequently, the labyrinth bone was isolated out of the cadaver head and histologically examined to compare the results of histology with imaging. Single-slice CT reliably identifies the electrode inside the human cochlea; however, due to the technically based large electrode artifact its position inside the cochlear spaces (e.g. electrode position in scala tympani or scala vestibuli) cannot be detected. Multi-slice CT of the cadaver head also showed artifacts that complicate the assessment of electrode position. Using RT the electrode artifact is small and therefore the electrode position within the cochlear spaces, scala tympani versus scala vestibuli, can be assessed. This technique was also applicable in a complete cadaver head, which is in contrast with former studies. In conclusion, CT allows the identification of electrode arrays inside the human cochlea. Multi-slice CT permits a much more precise depiction of the electrode inside the cochlea. RT alone has minimized electrode artifacts to a high extent and permits the assessment of the electrode position within the scala tympani or scala vestibuli. As RT was performed successfully in a complete cadaver head, further studies for evaluation of the intracochlear electrode position can now be performed in patients. PMID- 26942828 TI - Cochlear Implants in Elderly People: Preliminary Results. AB - The objective of this study was to evaluate the benefit of cochlear implantation in adults aged 60 years and over. Twenty-eight patients, older than 60 years and with profound bilateral sensorineural hearing loss, received a cochlear implant between 1991 and 2001. The mean age was 66 years and the median follow-up was 22.5 months. Speech perception scores before and after implantation were analyzed retrospectively in order to evaluate the benefit of cochlear implantation. There was a significant improvement of the disyllabic words and sentences scores after implantation. The patients who were over 70 years performed as well as those who were younger. The surgical procedure was well tolerated in all patients. One patient developed a postoperative vertigo due to a perilymphatic fistula. In conclusion, cochlear implantation offers improvement in speech perception to the elderly population, as in the younger population. A careful assessment of the physical status of these patients remains essential in order to evaluate the risk benefit of this procedure. PMID- 26942829 TI - Cochlear implants: indications in groups of patients with borderline indications. A review. AB - Cochlear implants (CI) represent the current treatment for patients affected by profound sensorineural hearing loss (SNHL). Initially only deaf adult patients were considered to be candidates for a CI; however, the development of technology and matured experience have expanded the indications for cochlear implantation. Today, CIs are implanted in adults and children and broader indications are followed. There are, however, a number of patients who do not completely fulfill the current indications and who are potential candidates for CI. The duration of deafness and residual hearing represent prognostic indicators for CI performance; however, the candidacy of children with residual hearing and prelingually deafened adults are still under debate. Anatomical variants such as cochlear ossification, cochlear malformation and chronic otitis media represented and still represent for some surgeons a contraindication to CI. The otological experience of CI surgeons and the advent of auditory brainstem implants have changed the approach to these patients, who may still benefit from hearing rehabilitation. This paper briefly analyses and reviews the results obtained in these groups of patients, who were not, at least initially, considered to be candidates for cochlear implantation. PMID- 26942830 TI - Cochlear Implants in Special Cases: Deafness in the Presence of Disabilities and/or Associated Problems. AB - The aim of the present study is to construct a reference model with the indication for the attitude, the requirements and the resources needed in order to be able to deal with deafness in the presence of disabilities or associated problems. The study group consisted of 13 adults and 18 children affected by profound deafness, with associated problems and disabilities, who were implanted with Clarion(r) and Med-El(r) devices. Selection criteria for candidacy to cochlear implantation and counselling, hospitalization, fitting and speech therapy/rehabilitation are described. Findings were assessed evaluating: (i) use of acoustic feedback, on the ground of Erber's model; (ii) self-sufficiency: assessed by a questionnaire; and (iii) social and family relationships: qualitative judgment based on direct observation, analysis of drawings and structured interviews with family teachers and therapists. The whole group showed benefit from cochlear implantation, with particular satisfaction for post-lingual deaf-blind adults, as well as for subjects with associated psychopathologies and mental retardation. In conclusion, cochlear implants can improve life quality in profoundly deaf subjects with associated disabilities, increasing both listening and communication skills as well as self-sufficiency while family and social relationships tend to remain stable. PMID- 26942831 TI - Cytomegalovirus appendicitis in an immunocompetent host. AB - Cytomegalovirus (CMV) is a common viral pathogen. Asymptomatic infection or a mononucleosis syndrome are the most common manifestations in otherwise healthy individuals. End-organ disease is rare in immunocompetent individuals. Here, we describe a case of CMV appendicitis in a patient without an immune-compromising condition. PMID- 26942833 TI - Older Workers and Federal Work Programs: The Korean Senior Employment Program (KSEP). AB - Federal older worker programs are attracting attention due to the growing number of older workers across the world. They are uniquely situated to provide out-of market work opportunities to older job seekers, who often find their age a barrier to securing desirable jobs. In 2004, the Korean government established its own program, the Korean Senior Employment Program (KSEP); however, literature for international readers on this innovative program is lacking. Thus, this article aims to provide an in-depth description of KSEP and a brief comparison between the Senior Community Service Employment Program in the U.S. and KSEP. The unique characteristics of KSEP include having the dual program foci on supplemental income and social participation; expanding work opportunities in the private sector beyond community-based jobs; accepting participants who are financially disadvantaged as well as those with a high desire for social participation regardless of their income; and broadening work opportunities for those with professional skills beyond repetitive, simple, and temporary jobs. This article may offer helpful insights to older worker advocates from various countries in creating or modifying their programs. PMID- 26942832 TI - Increasing generosity by disrupting prefrontal cortex. AB - Recent research suggests that prosocial outcomes in sharing games arise from prefrontal control of self-maximizing impulses. We used continuous theta burst stimulation (cTBS) to disrupt the functioning of two prefrontal areas, the right dorsolateral prefrontal cortex (DLPFC) and the dorsomedial prefrontal cortex (DMPFC). We used cTBS in the right MT/V5, as a control area. We then tested subjects' prosocial inclinations with an unsupervised Dictator Game in which they allocated real money anonymously between themselves and low and high socioeconomic status (SES) players. cTBS over the two prefrontal sites made subjects more generous compared to MT/V5. More specifically, cTBS over DLPFC increased offers to high-SES players, while cTBS over DMPFC caused increased offers to low-SES players. These data, the first to demonstrate an effect of disruptive neuromodulation on costly sharing, suggest that DLPFC and MPFC exert inhibitory control over prosocial inclinations during costly sharing, though they may do so in different ways. DLPFC may implement contextual control, while DMPFC may implement a tonic form of control. This study demonstrates that humans' prepotent inclination is toward prosocial outcomes when cognitive control is reduced, even when prosocial decisions carry no strategic benefit and concerns for reputation are minimized. PMID- 26942834 TI - Upper limb function and activity in people with facioscapulohumeral muscular dystrophy: a web-based survey. AB - Purpose To investigate the upper extremity (UE) at the level of impairments and related activity limitations and participation restrictions in people with facioscapulohumeral muscular dystrophy (FSHD). Methods The study was conducted using web-based questionnaires that were distributed amongst people with FSHD in the Netherlands. Eighty-eight respondents started the survey, and 71 completed it. The questionnaires covered the following dimensions: Function, Activity and Participation of the International Classification of Functioning Disability and Health. Results More than 40% of the respondents experienced pain in one arm or both the arms. Increased pain and stiffness scores and longer disease duration were associated with increased limitation scores. For basic activities, lifting the arm above shoulder-level was most frequently reported as most limited, coherent with the clinical picture of FSHD. Among the respondents, 50% indicated restrictions at school, 78% indicated restrictions at work and more than 80% indicated restrictions whilst participating in sports, hobbies, household activities and romantic relationships. Conclusions This study has shown that alongside the well-known problem of lifting the arms above shoulder-level, UE activities below shoulder height during vocational and occupational activities are also problematic in patients with FSHD. Alongside disease duration, pain and stiffness are associated with UE activity limitations. Implications for Rehabilitation Attention is needed for pain and experienced stiffness in the upper extremity as it is frequently present in patients with FSHD. Rehabilitation professionals need to be aware that patients with FSHD not only experience problems with activities above shoulder height, but also with activities below shoulder height. At least 50% of the patients with FSHD experience restrictions in participation as a result of limitations in their UE. PMID- 26942835 TI - Directed Self-Assembly of Block Copolymers for High Breakdown Strength Polymer Film Capacitors. AB - Emerging needs for fast charge/discharge yet high-power, lightweight, and flexible electronics requires the use of polymer-film-based solid-state capacitors with high energy densities. Fast charge/discharge rates of film capacitors on the order of microseconds are not achievable with slower charging conventional batteries, supercapacitors and related hybrid technologies. However, the current energy densities of polymer film capacitors fall short of rising demand, and could be significantly enhanced by increasing the breakdown strength (EBD) and dielectric permittivity (epsilonr) of the polymer films. Co-extruded two-homopolymer component multilayered films have demonstrated much promise in this regard showing higher EBD over that of component polymers. Multilayered films can also help incorporate functional features besides energy storage, such as enhanced optical, mechanical, thermal and barrier properties. In this work, we report accomplishing multilayer, multicomponent block copolymer dielectric films (BCDF) with soft-shear driven highly oriented self-assembled lamellar diblock copolymers (BCP) as a novel application of this important class of self assembling materials. Results of a model PS-b-PMMA system show ~50% enhancement in EBD of self-assembled multilayer lamellar BCP films compared to unordered as cast films, indicating that the breakdown is highly sensitive to the nanostructure of the BCP. The enhancement in EBD is attributed to the "barrier effect", where the multiple interfaces between the lamellae block components act as barriers to the dielectric breakdown through the film. The increase in EBD corresponds to more than doubling the energy storage capacity using a straightforward directed self-assembly strategy. This approach opens a new nanomaterial paradigm for designing high energy density dielectric materials. PMID- 26942836 TI - Leiomyoma mimicking a pelvic tumour in Mayer-Rokitansky-Kuster-Hauser syndrome: A case report. PMID- 26942837 TI - Targeted agents and combinations in ovarian cancer: where are we now? AB - Epithelial ovarian cancer is a heterogeneous disease with distinct histological subtypes characterized by different patterns of clinical behaviour. The identification of molecular pathways associated with individual subtypes has fuelled enthusiasm for the development of targeted therapies directed at specific subtypes of ovarian cancer. To date, the most successful targeted therapies in ovarian cancer to have undergone clinical development include anti-angiogenic agents and PARP inhibitors. Other promising areas of development include folate receptor antagonists, MEK and BRAF inhibitors in low-grade serous carcinoma, and immunotherapy. These novel therapeutic agents have the potential to maximize tumor efficacy, minimize toxicity and improve outcomes for women with epithelial ovarian cancer. PMID- 26942838 TI - Occurrence of vancomycin-resistant and -susceptible Enterococcus spp. in reclaimed water used for spray irrigation. AB - Reclaiming municipal wastewater for agricultural, environmental, and industrial purposes is increasing in the United States to combat dwindling freshwater supplies. However, there is a lack of data regarding the microbial quality of reclaimed water. In particular, no previous studies have evaluated the occurrence of vancomycin-resistant enterococci (VRE) in reclaimed water used at spray irrigation sites in the United States. To address this knowledge gap, we investigated the occurrence, concentration, and antimicrobial resistance patterns of VRE and vancomycin-susceptible enterococci at three U.S. spray irrigation sites that use reclaimed water. We collected 48 reclaimed water samples from one Mid-Atlantic and two Midwest spray irrigation sites, as well as their respective wastewater treatment plants, in 2009 and 2010. Samples were analyzed for total enterococci and VRE using standard membrane filtration. Isolates were purified and then confirmed using biochemical tests and PCR. Antimicrobial susceptibility testing was conducted using the Sensititre(r) microbroth dilution system. Data were analyzed by two-sample proportion tests and one-way analysis of variance. We detected total enterococci and VRE in 71% (34/48) and 4% (2/48) of reclaimed water samples, respectively. Enterococcus faecalis was the most common species identified. At the Mid-Atlantic spray irrigation site, UV radiation decreased total enterococci to undetectable levels; however, subsequent storage in an open air pond at this site resulted in increased concentrations of enterococci. E. faecalis isolates recovered from the Mid-Atlantic spray irrigation site expressed intrinsic resistance to quinupristin/dalfopristin; however, non-E. faecalis isolates expressed resistance to quinupristin/dalfopristin (52% of isolates), vancomycin (4%), tetracycline (13%), penicillin (4%) and ciprofloxacin (17%). Our findings show that VRE are present in low numbers in reclaimed water at point-of use at the sampled spray irrigation sites; however, resistance to other antimicrobial classes is more prevalent, particularly among non-E. faecalis isolates. PMID- 26942839 TI - Single-energy metal artefact reduction with CT for carbon-ion radiation therapy treatment planning. AB - OBJECTIVE: One approach to improving image quality of CT is to use metal artefact reduction image processing, such as single-energy metal artefact reduction (SEMAR). To quantify the impact of image correction on the quality of carbon-ion dose distribution, treatment planning using SEMAR was evaluated. METHODS: Using a head phantom into which metal screws could be inserted, we acquired standard planning CT images. We calculated dose distributions using phantom images with and without metal added, and with and without SEMAR. Hounsfield unit (HU) and dose distribution variation of these images with and without SEMAR were measured using metal-free image subtraction. We similarly analysed the image data sets of two patients with head and neck cancer who had dental implants. RESULTS: HU difference between metal-containing images and metal-free images without and with SEMAR were -79.5 +/- 97.2 HU and -1.4 +/- 19.5 HU on severe artefact area, respectively. The range of dose distribution difference from the prescribed dose between uncorrected and SEMAR-corrected images varied from -19.5% to -3.4% within planning target volume (PTV). PTV-D95 (%) for uncorrected and SEMAR-corrected image data were 82.4% and 95.4%, respectively. For data in patients with metal dental work, PTV-D95 (%) for uncorrected and SEMAR-corrected data were 92.2% and 92.5% (Patient 1), and 90.9% and 95.7% (Patient 2), respectively. CONCLUSION: SEMAR algorithm shows promise in improving CT image quality and in ensuring an accurate representation of dose distribution. ADVANCES IN KNOWLEDGE: SEMAR may improve treatment accuracy without the need for dental implant extraction in patients with head and neck cancer. PMID- 26942840 TI - Body fluid status and physical demand during the Giro d'Italia. AB - The aim of the study was to investigate changes in hydration status by means of bioelectrical impedance vector analyses (BIVA) and to assess its influence on power output and rating of perceived exertion (RPE) during the Giro d'Italia 2014. Daily bioelectrical impedance analysis were performed on 9 professional road cyclists (age: 28.2 +/- 4.7 yr, height: 176.0 +/- 5.5 cm, weight: 64.7 +/- 3.4 kg) during the race. Additionally, body weight, RPE, and power output were recorded throughout the race. Impedance vectors shortened during the race, whereas body weight remained unchanged at the end of the tour when compared to pre-tour. Vector changes were not related to power output or RPE. The shortening of the BIVA vector indicates that fluid gain occurred during the Giro d'Italia. This fluid gain was not reflected by body weight measurements and might be mainly attributed to muscle edema and/or haemodilution. Furthermore, power output and RPE, mostly depending on team tactic, were not affected by the body water increases. PMID- 26942841 TI - Treatment Professionals' Basic Beliefs About Alcohol Use Disorders: The Impact of Different Cultural Contexts. AB - BACKGROUND: The treatment of alcohol abusers in different cultural contexts does not depend only on the methods used but also on the ways in which treatment providers perceive the problem and relate to their clients. OBJECTIVES: This study compares treatment professionals' basic beliefs about alcohol use disorders in two culturally different European countries to find out to what extent these ideas are shaped by the respondents' socio-cultural context, profession, and other background variables. METHODS: Similar postal surveys were conducted among professionals working in specialized addiction treatment units in Finland (n = 520) and France (n = 472). The data were analyzed by descriptive statistical methods and logistic regression analysis. RESULTS: Consistent cultural differences were found in almost all the questions asked and they remained significant even after controlling for the other background factors. The French professionals emphasized the addictiveness of alcohol more than their Finnish colleagues. They also believed less in the chances of recovery and attributed more responsibility for the problem to external factors, while the Finns emphasized individual responsibility. Profession, gender and some other background variables also modified beliefs about specific questions. CONCLUSIONS: Cultural factors shape the ways in which alcohol use disorders are perceived more pervasively than the other background variables. The French professionals' low trust in treatment and the Finnish professionals' lack of concern for the addiction potential of alcohol and stronger tendency to regard the person as responsible for the problem could be seen as potential impediments to effective ways of helping alcohol abusers in these countries. PMID- 26942842 TI - Radioactivity of cigarettes and the importance of (210)Po and thorium isotopes for radiation dose assessment due to smoking. AB - Tobacco and tobacco smoke are very complex mixtures. In addition to various chemical and organic compounds they also contain natural radioactive elements (radionuclides). In this work, the natural radionuclide activity concentrations ((234)U, (238)U, (228)Th, (230)Th, (232)Th, (226)Ra, (210)Pb and (210)Po) of nine different cigarette samples available on the Slovenian market are reported. In addition to (210)Po, the transfer of thorium isotopes from a cigarette to a smoker's body and lungs have been determined for the first time. Cigarette smoke and exhaled air from smokers' lungs were collected from volunteer smokers (C-4 brand) to determinate what quantity of (210)Po and thorium isotopes is transferred from the tobacco to the smoker's lungs. Cigarette ash and smoked filters were also collected and analysed. Among the determined isotopes, (210)Pb and (210)Po showed the highest activity concentrations. During the smoking of one cigarette approximately 22% of (210)Po (and presumably its predecessor (210)Pb), 0.6% of (228)Th, 24% of (230)Th, and 31% of (232)Th are transferred from the cigarette and retained in the smoker's body. The estimated annual effective dose for smokers is 61 MUSv/year from (210)Po; 9 MUSv/year from (210)Pb; 6 MUSv/year from (228)Th; 47 MUSv/year from (230)Th, and 37 MUSv/year from (232)Th. These results show the importance of thorium isotopes in contributing to the annual effective dose for smoking. PMID- 26942843 TI - Naturally occurring radioactivity in some Swedish concretes and their constituents - Assessment by using I-index and dose-model. AB - The reference level for effective dose due to gamma radiation from building materials and construction products used for dwellings is set to 1 mSv per year (EC, 1996, 1999), (CE, 2014). Given the specific conditions presented by the EC in report 112 (1999) considering building and construction materials, an I-index of 1 may generate an effective dose of 1 mSv per year. This paper presents a comparison of the activity concentrations of (4)(0)K, (226)Ra and (232)Th of aggregates and when these aggregates constitute a part of concrete. The activity concentration assessment tool for building and construction materials, the I index, introduced by the EC in 1996, is used in the comparison. A comparison of the I-indices values are also made with a recently presented dose model by Hoffman (2014), where density variations of the construction material and thickness of the construction walls within the building are considered. There was a ~16-19% lower activity index in concretes than in the corresponding aggregates. The model by Hoffman further implies that the differences between the I-indices of aggregates and the concretes' final effective doses are even larger. The difference is due, mainly to a dilution effect of the added cement with low levels of natural radioisotopes, but also to a different and slightly higher subtracted background value (terrestrial value) used in the modeled calculation of the revised I-index by Hoffman (2014). Only very minimal contributions to the annual dose could be related to the water and additives used, due to their very low content of radionuclides reported. PMID- 26942844 TI - Sweet Relief: Reprogramming Gastric Endocrine Cells to Make Insulin. AB - Two promising approaches toward a cell-based cure for diabetes are the directed differentiation of pluripotent stem cells or lineage reprogramming of other cell types to generate beta cells. In this issue of Cell Stem Cell, Ariyachet et al. (2016) reprogrammed gastric endocrine cells to generate a renewable source of insulin-producing cells. PMID- 26942845 TI - Stressed out? Healing Tips for Newly Reprogrammed Neurons. AB - How do astrocyte-derived neurons deal with the sudden loss of their glial identity? Exciting new findings from Gascon et al. (2016) single out metabolic conversion as a critical checkpoint for direct neuronal reprogramming. PMID- 26942846 TI - Expanding Reprogramming to Cardiovascular Progenitors. AB - Methods to generate expandable cardiac progenitor populations are desirable for developing cellular therapies for heart failure and for studying cardiac specification. Now in Cell Stem Cell, Lalit et al. (2016) and Zhang et al. (2016) report two different strategies for reprogramming adult mouse fibroblasts into highly expandable cardiovascular progenitor cells. PMID- 26942847 TI - Human Naive Embryonic Stem Cells: How Full Is the Glass? AB - Human naive embryonic stem cells in the ground state of pluripotency provide a new opportunity to study human developmental biology and potential clinical applications. Two studies now report related work in human naive stem cell derivation and DNA methylation analysis, with one reporting some differences from oocyte and blastocyst profiles. PMID- 26942848 TI - HSC Fate Is Tethered to Mitochondria. AB - Mitochondria play important roles in homeostasis of hematopoietic stem cells (HSCs), which exhibit clonal heterogeneity in their lymphoid and myeloid production. Recently in Nature, Luchsinger et al. (2016) showed that mitochondria ER tethering maintains lymphoid-biased HSCs through calcium-dependent NFAT signaling, providing molecular insights into the basis of HSC heterogeneity. PMID- 26942849 TI - Finding Shangri-La: Limiting the Impact of Senescence on Aging. AB - Senescence plays an important role in the age-associated decline of tissue functions. Recent studies now show that targeting senescent cells can enhance the functions of stem/progenitor cells in aged mice and extend lifespan. PMID- 26942850 TI - An Interactive Multimedia Approach to Improving Informed Consent for Induced Pluripotent Stem Cell Research. PMID- 26942851 TI - Complex Tissue and Disease Modeling using hiPSCs. AB - Defined genetic models based on human pluripotent stem cells have opened new avenues for understanding disease mechanisms and drug screening. Many of these models assume cell-autonomous mechanisms of disease but it is possible that disease phenotypes or drug responses will only be evident if all cellular and extracellular components of a tissue are present and functionally mature. To derive optimal benefit from such models, complex multicellular structures with vascular components that mimic tissue niches will thus likely be necessary. Here we consider emerging research creating human tissue mimics and provide some recommendations for moving the field forward. PMID- 26942852 TI - Expandable Cardiovascular Progenitor Cells Reprogrammed from Fibroblasts. AB - Stem cell-based approaches to cardiac regeneration are increasingly viable strategies for treating heart failure. Generating abundant and functional autologous cells for transplantation in such a setting, however, remains a significant challenge. Here, we isolated a cell population with extensive proliferation capacity and restricted cardiovascular differentiation potentials during cardiac transdifferentiation of mouse fibroblasts. These induced expandable cardiovascular progenitor cells (ieCPCs) proliferated extensively for more than 18 passages in chemically defined conditions, with 10(5) starting fibroblasts robustly producing 10(16) ieCPCs. ieCPCs expressed cardiac signature genes and readily differentiated into functional cardiomyocytes (CMs), endothelial cells (ECs), and smooth muscle cells (SMCs) in vitro, even after long term expansion. When transplanted into mouse hearts following myocardial infarction, ieCPCs spontaneously differentiated into CMs, ECs, and SMCs and improved cardiac function for up to 12 weeks after transplantation. Thus, ieCPCs are a powerful system to study cardiovascular specification and provide strategies for regenerative medicine in the heart. PMID- 26942854 TI - SnapShot: Key Advances in hiPSC Disease Modeling. AB - This SnapShot presents a timeline of key advances in directed differentiation and disease modeling using human pluripotent stem cells. The selected papers are color-coded for different systems and show progress in the field, from making disease- and tissue-specific hiPSC derivatives to the development of disease models for drug screening and therapeutics and the generation of complex systems that mimic tissue architecture and self-organized structures. To view this SnapShot, open or download the PDF. PMID- 26942855 TI - Erratum: Conformational dynamics is key to understanding loss-of-function of NQO1 cancer-associated polymorphisms and its correction by pharmacological ligands. PMID- 26942856 TI - Electrochemical Detection and Distribution Analysis of beta-Catenin for the Evaluation of Invasion and Metastasis in Hepatocellular Carcinoma. AB - Pro-metastatic cell signaling controls the switch to distant metastasis and the final cancer death. In hepatocellular carcinoma (HCC), this death switch is turned on by the multiprotein interactions of beta-catenin with many transcription factors, so a method to assay the bioactivity of beta-catenin to participate in these pro-metastatic protein/protein interactions has been proposed in this work. This method employs cost-effective peptide-based protein targeting ligands, while the electrochemical catalytic cross-linking in this method also "finalize" the noncovalent molecular recognition, so that the robustness can be improved to enable detection of relatively more complex biosamples. In studying clinical samples with the proposed method, the cellular distribution and overall expression of beta-catenin show a parallel with the pathological grade of the sample, particularly, nuclear translocation. The pro metastatic activation of beta-catenin can also be observed as evidently correlated with higher-grade cases, suggesting the active role of beta-catenin in promoting metastasis. According to these results, the proposed method may have the prospective use as a prognostic tool for evaluating the potential of invasion and metastasis in cancer. PMID- 26942853 TI - Bmi1 Is a Key Epigenetic Barrier to Direct Cardiac Reprogramming. AB - Direct reprogramming of induced cardiomyocytes (iCMs) suffers from low efficiency and requires extensive epigenetic repatterning, although the underlying mechanisms are largely unknown. To address these issues, we screened for epigenetic regulators of iCM reprogramming and found that reducing levels of the polycomb complex gene Bmi1 significantly enhanced induction of beating iCMs from neonatal and adult mouse fibroblasts. The inhibitory role of Bmi1 in iCM reprogramming is mediated through direct interactions with regulatory regions of cardiogenic genes, rather than regulation of cell proliferation. Reduced Bmi1 expression corresponded with increased levels of the active histone mark H3K4me3 and reduced levels of repressive H2AK119ub at cardiogenic loci, and de-repression of cardiogenic gene expression during iCM conversion. Furthermore, Bmi1 deletion could substitute for Gata4 during iCM reprogramming. Thus, Bmi1 acts as a critical epigenetic barrier to iCM production. Bypassing this barrier simplifies iCM generation and increases yield, potentially streamlining iCM production for therapeutic purposes. PMID- 26942857 TI - Anti-RNA polymerase III antibody-associated scleroderma renal crisis in a patient with limited cutaneous systemic sclerosis: A case report. AB - A 69-year-old Japanese man was presented with hypertensive crisis. Renal histology revealed malignant nephrosclerosis, including an onion skin pattern with fibrinoid necrosis of the small arteries from arterioles up to interlobular arteries. Immunological investigation clarified positive anti-RNA polymerase (RNAP) III antibody, and limited cutaneous systemic sclerosis (Lc SSc) was diagnosed by skin biopsy as the underlying disease causing scleroderma renal crisis (SRC). Angiotensin covering enzyme (ACE) inhibitor therapy and calcium antagonist were effective for his renal condition. Although an association between SRC and anti-RNAP III antibody has already been reported in patients with diffuse cutaneous SSc (Dc SSc), this case indicates that SRC with hypetensive emergency with malignant nephrosclerosis can also be diagnosed on patients with Lc SSc patients by the examination of anti-RNAP III antibody. PMID- 26942858 TI - Dominant vs. non-dominant shoulder morphology in volleyball players and associations with shoulder pain and spike speed. AB - The aims of our study were to compare the dominant (DOM) and non-dominant (NDOM) shoulders of high-level volleyball athletes and identify possible associations of shoulder adaptations with spike speed (SS) and shoulder pathology. A total of 22 male volleyball players from two teams participating in the first division of the Cypriot championship underwent clinical shoulder tests and simple measurements around their shoulder girdle joints bilaterally. SS was measured with the use of a sports speed radar. Compared with the NDOM side, the DOM scapula was more lateralised, the DOM dorsal capsule demonstrated greater laxity, the DOM dorsal muscles stretching ability was compromised, and the DOM pectoralis muscle was more lengthened. Players with present or past DOM shoulder pain demonstrated greater laxity in their DOM dorsal capsule, tightening of their DOM inferior capsule, and lower SS compared with those without shoulder pain. Dorsal capsule measurements bilaterally were significant predictors of SS. None of the shoulder measurements was associated with team roles or infraspinatus atrophy, while scapular lateralisation was more pronounced with increasing years of experience, and scapular antetilting was greater with increasing age. Adaptations of the DOM shoulder may be linked to pathology and performance. We describe simple shoulder measurements that may have the potential to predict chronic shoulder injury and become part of injury prevention programmes. Detailed biomechanical and large prospective studies are warranted to assess the validity of our findings and reach more definitive conclusions. PMID- 26942859 TI - Interactions of the metal tolerant heterotrophic microorganisms and iron oxidizing autotrophic bacteria from sulphidic mine environment during bioleaching experiments. AB - Iron and sulfur oxidizing chemolithoautotrophic acidophilic bacteria, such as Acidithiobacillus species, hold the dominant role in mine environments characterized by low pH values and high concentrations of reduced sulfur and iron compounds, such as ores, rocks and acid drainage waters from mines. On the other hand, heterotrophic microorganisms, especially their biofilms, from these specific niches are receiving increased attention, but their potential eco physiological roles have not been fully understood. Biofilms are considered a threat to human health, but biofilms also have beneficial properties as they are deployed in waste recycling and bioremediation systems. We have analyzed interactions of the metal tolerant heterotrophic microorganisms in biofilms with iron oxidizing autotrophic bacteria both from the sulphidic mine environment (copper mine Bor, Serbia). High tolerance to Cu(2+), Cd(2+) and Cr(6+) and the presence of genetic determinants for the respective metal tolerance and biofilm forming ability was shown for indigenous heterotrophic bacteria that included strains of Staphylococcus and Rhodococcus. Two well characterized bacteria- Pseudomonas aeruginosa PAO1 (known biofilm former) and Cupriavidus metallidurans CH34 (known metal resistant representative) were also included in the study. The interaction and survivability of autotrophic iron oxidizing Acidithiobacillus bacteria and biofilms of heterotrophic bacteria during co-cultivation was revealed. Finally, the effect of heterotrophic biofilms on bioleaching process with indigenous iron oxidizing Acidithiobacillus species was shown not to be inhibitory under in vitro conditions. PMID- 26942860 TI - Optimization of a Novel Quinazolinone-Based Series of Transient Receptor Potential A1 (TRPA1) Antagonists Demonstrating Potent in Vivo Activity. AB - There has been significant interest in developing a transient receptor potential A1 (TRPA1) antagonist for the treatment of pain due to a wealth of data implicating its role in pain pathways. Despite this, identification of a potent small molecule tool possessing pharmacokinetic properties allowing for robust in vivo target coverage has been challenging. Here we describe the optimization of a potent, selective series of quinazolinone-based TRPA1 antagonists. High throughput screening identified 4, which possessed promising potency and selectivity. A strategy focused on optimizing potency while increasing polarity in order to improve intrinsic clearance culminated with the discovery of purinone 27 (AM-0902), which is a potent, selective antagonist of TRPA1 with pharmacokinetic properties allowing for >30-fold coverage of the rat TRPA1 IC50 in vivo. Compound 27 demonstrated dose-dependent inhibition of AITC-induced flinching in rats, validating its utility as a tool for interrogating the role of TRPA1 in in vivo pain models. PMID- 26942861 TI - Recent progress in therapeutic natural product biosynthesis using Escherichia coli. AB - E. coli has become a common host for the heterologous biosynthesis of natural products that demonstrate therapeutic value but suffer from access challenges posed by native production hosts. This review will highlight recent examples of heterologous products produced using E. coli. An emphasis will be placed on tools at the cellular and process levels to enable, improve, and alter production efforts. At the cellular scale, summaries of the process to enable heterologous biosynthesis will be supplemented with strategies (synthetic biology and metabolic engineering) to improve production levels. Process engineering strategies such as precursor-directed biosynthesis will also be highlighted in analog formation cases. In summary, the article will provide a recent overview of heterologous production efforts using E. coli and the relationship of the products produced to therapeutic applications. PMID- 26942862 TI - Understanding the effects of two bound glucose in Sudlow site I on structure and function of human serum albumin: theoretical studies. AB - Human serum albumin (HSA) is the most abundant protein found in blood serum. It carries essential metabolites and many drugs. The glycation of HSA causes abnormal biological effects. Importantly, glycated HSA (GHSA) is of interest as a biomarker for diabetes. Recently, the first HSA structure with bound pyranose (GLC) and open-chain (GLO) glucose at Sudlow site I has been crystallised. We therefore employed molecular dynamics (MD) simulations and ONIOM calculations to study the dynamic nature of two bound glucose in a pre-glycated HSA (pGHSA) and observe how those sugars alter a protein structure comparing to wild type (Apo) and fatty acid-bound HSA (FA). Our analyses show that the overall structural stability of pGHSA is similar to Apo and FA, except Sudlow site II. Having glucose induces large protein flexibility at Sudlow site II. Besides, the presence of glucose causes W214 to reorient resulting in a change in W214 microenvironment. Considering sugars, both sugars are exposed to water, but GLO is more solvent-accessible. ONIOM results show that glucose binding is favoured for HSA (-115.04 kcal/mol) and GLO (-85.10 kcal/mol) is more preferable for Sudlow site I over GLC (-29.94 kcal/mol). GLO can strongly react with K195 and K199, whereas K195 and K199 provide slightly repulsive forces for GLC. This can confirm that an open-chain GLO is more favourable inside a pocket. PMID- 26942864 TI - Silica sol assisted chromatographic NMR spectroscopy for resolution of trans- and cis-isomers. AB - Chromatographic NMR spectroscopy can separate the mixtures of species with significantly different molecular size, but generally fails for isomeric species. Herein, we reported the resolution of trans- and cis-isomers and their structural analogue, which are different in molecular shapes, but similar in mass, were greatly enhanced in the presence of silica sol. The mixtures of maleic acid, fumaric acid and succinic acid, and the mixtures of trans- and cis-1,2 cyclohexanedicarboxylic acids, were distinguished by virtue of their different degrees of interaction with silica sol. Moreover, we found mixed solvents could improve the spectral resolution of DOSY spectra of mixtures. PMID- 26942865 TI - Comparing the immune responses of two genetically B-complex disparate Fayoumi chicken lines to Eimeria tenella. AB - The present study was conducted to compare the susceptibility of congenic Fayoumi lines to Eimeria tenella infection and to assess genetic differences in Eimeria egression. Chickens were orally inoculated with 5 * 10(4) sporulated E. tenella oocysts and challenged with 5 * 10(6) oocysts on the 10th day after the primary infection. The Fayoumi M5.1 line exhibited higher levels of body weight gain, less oocyst shedding and higher percentages of B and CD4(+)/CD8(+) T cells than the M15.2 chickens. These results demonstrate that M5.1 line is more resistant to E. tenella infection than M15.2 line. Furthermore, the percentage of sporozoite egress from peripheral blood mononuclear cells (PBMCs) was higher in the M5.1 line. The results of this study suggest that enhanced resistance of Fayoumi M5.1 to E. tenella infection may involve heightened cell-mediated and adaptive immunity, resulting in reduced intracellular development of Eimeria parasites. PMID- 26942863 TI - TEMPOL increases NAD(+) and improves redox imbalance in obese mice. AB - Continuous energy conversion is controlled by reduction-oxidation (redox) processes. NAD(+) and NADH represent an important redox couple in energy metabolism. 4-Hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPOL) is a redox cycling nitroxide that promotes the scavenging of several reactive oxygen species (ROS) and is reduced to hydroxylamine by NADH. TEMPOL is also involved in NAD(+) production in the ascorbic acid-glutathione redox cycle. We utilized the chemical properties of TEMPOL to investigate the effects of antioxidants and NAD(+)/NADH modulators on the metabolic imbalance in obese mice. Increases in the NAD(+)/NADH ratio by TEMPOL ameliorated the metabolic imbalance when combined with a dietary intervention, changing from a high-fat diet to a normal diet. Plasma levels of the superoxide marker dihydroethidium were higher in mice receiving the dietary intervention compared with a control diet, but were normalized with TEMPOL consumption. These findings provide novel insights into redox regulation in obesity. PMID- 26942866 TI - Magnetic correlations in the magnetocaloric materials Mn3GaC and Mn3GaC0.85N0.15 studied by neutron polarization analysis and neutron depolarization. AB - Partially substituting carbon by nitrogen in the antiperovskite compound Mn3GaC increases the first order antiferromagnetic/ferromagnetic transition temperature and at the same time causes the high-temperature long-range ferromagnetism to weaken. To show that the weakening is related to the diminishing of ferromagnetic domain formation, we undertake neutron depolarization and neutron polarization analysis experiments on Mn3GaC and Mn3GaC0.85N0.15. Polarization analysis experiments show that strong ferromagnetic correlations are present at high temperatures in the paramagnetic states of both Mn3GaC and Mn3GaC0.85N0.15 and that these correlations vanish in the antiferromagnetic state. Neutron depolarization studies show that above the first order transition temperature, ferromagnetic domain formation is present in Mn3GaC but is absent in Mn3GaC0.85N0.15. The relationship between ferromagnetic domain formation and transitional hysteresis is brought forward for these two important magnetocaloric materials. PMID- 26942868 TI - Docosahexaenoic Acid Induces Growth Suppression on Epithelial Ovarian Cancer Cells More Effectively than Eicosapentaenoic Acid. AB - Omega-3 fatty acids, especially eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have been shown to possess definitively suppressive effects on the growth of epithelial ovarian cancer cells. This study investigated the differential effects of pure EPA and DHA on the growth of epithelial ovarian cancer cells and the potential molecular mechanisms that may be involved. There were significant time- and dose-dependent inhibitory effects of both EPA and DHA on cellular proliferation of the epithelial ovarian cancer cell line TOV-21G (P < 0.05). TOV-21G cells pretreated with peroxisome proliferator receptor activator gamma (PPARgamma) antagonist, GW9662, markedly suppressed EPA/DHA-induced apoptosis as determined by TUNEL assay, Annexin V-FITC/PI staining, and caspase-3 activity. EPA/DHA significantly induced PPARgamma and p53 overexpression as observed in immunoblotting assay and the induction of p53 by EPA/DHA was abolished by GW9662. In all cases, the effect of DHA was significantly more potent than that of EPA (P < 0.05). Our findings suggested that DHA may be more effective than EPA in growth suppression of TOV-21G cells and the biologic effects may be partly mediated by PPARgamma and p53 activation. Further research is required to elucidate additional divergent mechanisms to account for apparent differences between EPA and DHA. PMID- 26942867 TI - Photoreactivity of Metal-Organic Frameworks in Aqueous Solutions: Metal Dependence of Reactive Oxygen Species Production. AB - Promising applications of metal-organic frameworks (MOFs) in various fields have raised concern over their environmental fate and safety upon inevitable discharge into aqueous environments. Currently, no information regarding the transformation processes of MOFs is available. Due to the presence of repetitive pi-bond structure and semiconductive property, photochemical transformations are an important fate process that affects the performance of MOFs in practical applications. In the current study, the generation of reactive oxygen species (ROS) in isoreticular MIL-53s was studied. Scavengers were employed to probe the production of (1)O2, O2(*-), and *OH, respectively. In general, MIL-53(Cr) and MIL-53(Fe) are dominated by type I and II photosensitization reactions, respectively, and MIL-53(Al) appears to be less photoreactive. The generation of ROS in MIL-53(Fe) may be underestimated due to dismutation. Further investigation of MIL-53(Fe) encapsulated diclofenac transformation revealed that diclofenac can be easily transformed by MIL-53(Fe) generated ROS. However, the cytotoxicity results implied that the ROS generated from MIL-53s have little effect on the viability of the human hepatocyte (HepG2) cell line. These results suggest that the photogeneration of ROS by MOFs may be metal-node dependent, and the application of MIL-53s as drug carriers needs to be carefully considered due to their high photoreactivity. PMID- 26942869 TI - Deletion of the gamma-secretase subunits Aph1B/C impairs memory and worsens the deficits of knock-in mice modeling the Alzheimer-like familial Danish dementia. AB - Mutations in BRI2/ITM2b genes cause Familial British and Danish Dementias (FBD and FDD), which are pathogenically similar to Familial Alzheimer Disease (FAD). BRI2 inhibits processing of Amyloid precursor protein (APP), a protein involved in FAD pathogenesis. Accumulation of a carboxyl-terminal APP metabolite -beta-CTF causes memory deficits in a knock-in mouse model of FDD, called FDDKI.We have investigated further the pathogenic function of beta-CTF studying the effect of Aph1B/C deletion on FDDKI mice. This strategy is based on the evidence that deletion of Aph1B/C proteins, which are components of the gamma-secretase that cleaves beta-CTF, results in stabilization of beta-CTF and a reduction of Abeta. We found that both the FDD mutation and the Aph1B/C deficiency mildly interfered with spatial long term memory, spatial working/short-term memory and long-term contextual fear memory. In addition, the Aph1BC deficiency induced deficits in long-term cued fear memory. Moreover, the two mutations have additive adverse effects as they compromise the accuracy of spatial long-term memory and induce spatial memory retention deficits in young mice. Overall, the data are consistent with a role for beta-CTF in the genesis of memory deficits. PMID- 26942870 TI - Prognostic value of wait time in nasopharyngeal carcinoma treated with intensity modulated radiotherapy: a propensity matched analysis. AB - The aim of this study was to determine the prognostic value of wait time from histological diagnosis to primary treatmen for nasopharyngeal carcinoma (NPC) treated with intensity-modulated radiotherapy (IMRT). Between October 2009 and February 2012, a total of 1672 NPC patients were retrospectively analyzed. A cutoff value of > 4 weeks was used to define prolonged wait time. Matched patients according to the wait time were identified using propensity score matching (PSM), which was also used to identify matched patients for subsequent stratified analyses. Differences in progression-free survival (PFS), overall survival (OS), distant metastasis-free survival (DMFS), and locoregional relapse free survival (LRFS) were estimated using the Kaplan-Meier method and Cox proportional hazards models. In total, 407 pairs of NPC patients were selected by PSM. The 3-year PFS rate was significantly lower for patients with a prolonged wait time (> 4 weeks) than for those with an acceptable wait time (P = 0.035). Stratified analyses revealed that the negative effects of a prolonged wait time occurred primarily in patients with advanced NPC without neoadjuvant chemotherapy (NACT; PFS:P = 0.040; DMFS:P = 0.028). In multivariate analysis, a prolonged wait time was found to be an independent unfavorable prognostic factor for PFS and DMFS in advanced-staged patients without NACT. These results suggest that a prolonged time (> 4 weeks) between diagnosis and primary radical radiotherapy is a disadvantage for NPC patients, particularly those with advanced disease receiving no NACT. Thus, it is necessary to optimize resources for decreasing this wait time, although additional studies are warranted to further clarify our findings. PMID- 26942871 TI - Age-related alterations in blood and colonic dendritic cell properties. AB - BACKGROUND: Dendritic cells (DC) determine initiation, type and location of immune responses and, in adults, show decreased Toll-like receptors and some increased cytokine levels on ageing. Few studies in children have characterised DC or explored DC-related mechanisms producing age-related immune changes. RESULTS: The pDC marker BDCA2 (but not CD123) was absent in pre-pubertal children and numbers of pDC decreased with age. Blood and colonic DC were more mature and activated in adults. Decrease in pDC numbers correlated with reduced GM-CSF levels with aging, but increasing IL-4 and IL-8 levels correlated with a more activated DC profile in blood. CXCL16 levels decreased with age. METHODS: Blood and colonic DC phenotypes were determined in healthy adults and children by flow cytometry and correlated with aging. Blood DC were divided into plasmacytoid (pDC) and myeloid (mDC) while only mDC were identified in colon. Serum cytokine levels were determined by multiplex cytokine assays and correlated with DC properties. CONCLUSIONS: In children, lack of BDCA2, a receptor mediating antigen capture and inhibiting interferon induction, may be immunologically beneficial during immune development. Conversely, reduced pDC numbers, probably secondary to decreasing GM-CSF and increasing cytokine-induced maturation of DC are likely to determine deteriorating immunity with ageing. PMID- 26942872 TI - APIP, an ERBB3-binding partner, stimulates erbB2-3 heterodimer formation to promote tumorigenesis. AB - Despite the fact that the epidermal growth factor (EGF) family member ERBB3 (HER3) is deregulated in many cancers, the list of ERBB3-interacting partners remains limited. Here, we report that the Apaf-1-interacting protein (APIP) stimulates heregulin-beta1 (HRG-beta1)/ERBB3-driven cell proliferation and tumorigenesis. APIP levels are frequently increased in human gastric cancers and gastric cancer-derived cells. Cell proliferation and tumor formation are repressed by APIP downregulation and stimulated by its overexpression. APIP's role in the ERBB3 pathway is not associated with its functions within the methionine salvage pathway. In response to HRG-beta1, APIP binds to the ERBB3 receptor, leading to an enhanced binding of ERBB3 and ERBB2 that results in sustained activations of ERK1/2 and AKT protein kinases. Furthermore, HRG beta1/ERBB3-dependent signaling is gained in APIP transgenic mouse embryonic fibroblasts (MEFs), but not lost in Apip-/- MEFs. Our findings offer compelling evidence that APIP plays an essential role in ERBB3 signaling as a positive regulator for tumorigenesis, warranting future development of therapeutic strategies for ERBB3-driven gastric cancer. PMID- 26942874 TI - Exceptional antineoplastic activity of a dendritic-cell-targeted vaccine loaded with a Listeria peptide proposed against metastatic melanoma. AB - Vaccination with dendritic cells (DCs) is proposed to induce lasting responses against melanoma but its survival benefit in patients needs to be demonstrated. We propose a DC-targeted vaccine loaded with a Listeria peptide with exceptional anti-tumour activity to prevent metastasis of melanoma. Mice vaccinated with vaccines based on DCs loaded with listeriolysin O peptide (91-99) (LLO91-99) showed clear reduction of metastatic B16OVA melanoma size and adhesion, prevention of lung metastasis, enhanced survival, and reversion of immune tolerance. Robust innate and specific immune responses explained the efficiency of DC-LLO91-99 vaccines against B16OVA melanoma. The noTable features of this vaccine related to melanoma reduction were: expansion of immune-dominant LLO91-99 specific CD8 T cells that helped to expand melanoma-specific CD8+ T cells; high numbers of tumour-infiltrating lymphocytes with a cytotoxic phenotype; and a decrease in CD4+CD25high regulatory T cells. This vaccine might be a useful alternative treatment for advanced melanoma, alone or in combination with other therapies. PMID- 26942873 TI - Hepatic cancer stem cell marker granulin-epithelin precursor and beta-catenin expression associate with recurrence in hepatocellular carcinoma. AB - Granulin-epithelin precursor (GEP) has been demonstrated to confer enhanced cancer stem-like cell properties in hepatocellular carcinoma (HCC) cell line models in our previous studies. Here, we aimed to examine the GEP-expressing cells in relation to the stem cell related molecules and stem-like cell properties in the prospective HCC clinical cohort. GEP protein levels were significantly higher in HCCs than the paralleled non-tumor liver tissues, and associated with venous infiltration. GEPhigh cells isolated from clinical HCC samples exhibited higher levels of stem cell marker CD133, pluripotency associated signaling molecules beta-catenin, Oct4, SOX2, Nanog, and chemodrug transporter ABCB5. In addition, GEPhigh cells possessed preferential ability to form colonies and spheroids, and enhanced in vivo tumor-initiating ability while their xenografts were able to be serially subpassaged into secondary mouse recipients. Expression levels of GEP and pluripotency-associated genes were further examined in the retrospective HCC cohort and demonstrated significant correlation of GEP with beta-catenin. Notably, HCC patients with high GEP and beta-catenin levels demonstrated poor recurrence-free survival. In summary, GEP positive HCC cells directly isolated from clinical specimens showed beta-catenin elevation and cancer stem-like cell properties. PMID- 26942875 TI - Screening of candidate G-quadruplex ligands for the human c-KIT promotorial region and their effects in multiple in-vitro models. AB - Stabilization of G-quadruplex (G4) structures in promoters is a novel promising strategy to regulate gene expression at transcriptional and translational levels. c-KIT proto-oncogene encodes for a tyrosine kinase receptor. It is involved in several physiological processes, but it is also dysregulated in many diseases, including cancer. Two G-rich sequences able to fold into G4, have been identified in c-KIT proximal promoter, thus representing suitable targets for anticancer intervention. Herein, we screened an "in house" library of compounds for the recognition of these G4 elements and we identified three promising ligands. Their G4-binding properties were analyzed and related to their antiproliferative, transcriptional and post-transcriptional effects in MCF7 and HGC27 cell lines. Besides c-KIT, the transcriptional analysis covered a panel of oncogenes known to possess G4 in their promoters.From these studies, an anthraquinone derivative (AQ1) was found to efficiently downregulate c-KIT mRNA and protein in both cell lines. The targeted activity of AQ1 was confirmed using c-KIT-dependent cell lines that present either c-KIT mutations or promoter engineered (i.e., alpha155, HMC1.2 and ROSA cells).Present results indicate AQ1 as a promising compound for the target therapy of c-KIT-dependent tumors, worth of further and in depth molecular investigations. PMID- 26942876 TI - Smoking-promoted oxidative DNA damage response is highly correlated to lung carcinogenesis. AB - Oxidative stress induced by tobacco smoking is one of the main causes of DNA damage and is known to be involved in various cancers. Smoking is the leading cause of lung cancer, while the role of cigarette smoke-induced oxidative DNA damage response during lung carcinogenesis is largely unknown. In this study, we investigated oxidative DNA damage response levels in smoking and nonsmoking patients with lung cancer, and evaluated the potential diagnostic value of 8-OHdG for lung cancer. We observed a higher level of 8-OHdG expression and secretion in airways of lung cancer patients than that of noncancer controls. 8-OHdG expression was associated with the TNM stages. Additionally, cigarette smoke induced oxidative DNA damage response was observed in bronchial epithelial cells in vitro and in vivo. A statistical significance correlation was found between the levels of 8-OHdG and smoking index. With a cut-off value of 2.86 ng/ml, 8 OHdG showed a sensitivity and specificity of 70.0% and 73.7%, respectively, to identify a patient with lung cancer. These findings not only underscore the importance of smoking in oxidative DNA damage response of lung cancer patients, but also suggest 8-OHdG as a potential diagnostic biomarker for lung cancer. PMID- 26942878 TI - SIRT2 inhibits non-small cell lung cancer cell growth through impairing Skp2 mediated p27 degradation. AB - Skp2 is a component of the E3 ubiquitin ligase which promotes the ubiquitination associated degradation of a cyclin-dependent kinase inhibitor, p27, resulting in increases in non-small cell lung cancer (NSCLC) cell growth. We recently showed that down-regulation of Sirtuin deacetylases 2 (SIRT2) in NSCLC increased cancer cell growth through suppressing p27. However, the underlying mechanisms remain unknown. Here, we examined the relationship between SIRT2 and Skp2 in regulation of NSCLC cell growth through p27. We found that the levels of SIRT2 significantly decreased, while the levels of Skp2 significantly increased in NSCLC specimens, compared to the paired non-tumor lung tissue. The levels of SIRT2 and Skp2 inversely correlated. Low SIRT2 levels were associated with poor patients' survival. Moreover, in several lung cancer cell lines, the SIRT2 levels significantly decreased and the Skp2 levels significantly increased. Overexpression of SIRT2 promoted Skp2 deacetylation and degradation, resulting in increases in p27 and suppression of NSCLC cell growth, whereas knockdown of Skp2 inhibited Skp2 deacetylation and degradation, resulting in decreases in p27 and increases in NSCLC cell growth. The deacetylation of Skp2 by SIRT2 and degradation of p27 by Skp2 were significantly inhibited by histone deacetylase inhibitor and proteasome inhibitor, respectively. Finally, SIRT2 and Skp2 co immunoprecipitated in NSCLC cells. Together, our data suggest that SIRT2 may induce Skp2 deacetylation and subsequent degradation to abolish the effects of Skp2 on p27 to affect NSCLC cell growth. Thus, re-expression of SIRT2 may be a promising strategy for treating NSCLC. PMID- 26942877 TI - iACP: a sequence-based tool for identifying anticancer peptides. AB - Cancer remains a major killer worldwide. Traditional methods of cancer treatment are expensive and have some deleterious side effects on normal cells. Fortunately, the discovery of anticancer peptides (ACPs) has paved a new way for cancer treatment. With the explosive growth of peptide sequences generated in the post genomic age, it is highly desired to develop computational methods for rapidly and effectively identifying ACPs, so as to speed up their application in treating cancer. Here we report a sequence-based predictor called iACP developed by the approach of optimizing the g-gap dipeptide components. It was demonstrated by rigorous cross-validations that the new predictor remarkably outperformed the existing predictors for the same purpose in both overall accuracy and stability. For the convenience of most experimental scientists, a publicly accessible web server for iACP has been established at http://lin.uestc.edu.cn/server/iACP, by which users can easily obtain their desired results. PMID- 26942879 TI - Lnc-SGK1 induced by Helicobacter pylori infection and highsalt diet promote Th2 and Th17 differentiation in human gastric cancer by SGK1/Jun B signaling. AB - Serum and glucocorticoid-inducible kinase (SGK) 1can be triggered in several malignancies. Most research on SGK1has focused on its role in cancer cells, and we sought to investigate its potential upstream non-coding RNA nominated as Lnc SGK1, and their expression and diagnostic value in T cells in human gastric cancer (GC). Excessive expression of Lnc-SGK1 and SGK1 were observed in T cell either within the tumor or peripheral T cells, and furthermore associated with Helicobacter pylori infection and high-salt diet (HSD). Within T cells, Helicobacter pylori (Hp) infection and high-salt dietcan up-regulated SGK1 expression and in turn enhance expression of Lnc-SGK1 through JunB activation. And expression of Lnc-SGK1 can further enhance transcription of SGK1 through cis regulatory mode. Lnc-SGK1 can induce Th2 and Th17 and reduce Th1 differentiation via SGK1/JunB signaling. Serum Lnc-SGK1 expression in combination with H. pylori infection and/or HSD in T cells was associated with poor prognosis of GC patients, and could be an ideal diagnostic index in human GC. PMID- 26942881 TI - A prospective study on radiation doses to organs at risk (OARs) during intensity modulated radiotherapy for nasopharyngeal carcinoma patients. AB - This study is to investigate the dose distribution of organs at risk (OARs) in cases of nasopharyngeal carcinoma (NPC). From July 2013 to October 2014, a prospective cohort study involving 148 patients was carried out at our center. OARs surrounding the nasopharynx were contoured on axial CT planning images in all patients. Dose-volume histograms of OARs and gross tumor volumes (GTV) were calculated. Multivariate analysis showed that radiation dose to OARs was associated with T stage and, especially, GTV. Seven OARs, including the spinal cord, eye and mandible, easily tolerated radiation doses in all patients; six OARs including the brain stem, chiasm and temporal lobe easily tolerated radiation doses in patients with a small GTV, but with difficulty when GTV was large; and other nine OARs including the parotid gland, cochlea and tympanic cavity met tolerance doses with difficulty in all patients. According to the patterns of radiation doses to OARs, it may help us to further reduce subsequent complications by improving the efficiency of plan optimization and evaluation. PMID- 26942880 TI - 4EGI-1 induces apoptosis and enhances radiotherapy sensitivity in nasopharyngeal carcinoma cells via DR5 induction on 4E-BP1 dephosphorylation. AB - The eIF4F complex regulated by a various group of eIF4E-binding proteins (4E-BPs) can initial the protein synthesis. Small molecule compound 4EGI-1, an inhibitor of the cap-dependent translation initiation through disturbing the interaction between eIF4E and eIF4G which are main elements of the eIF4E complex, has been reported to suppress cell proliferation by inducing apoptosis in many types of cancer. And death receptor 5 (DR5) is a major component in the extrinsic apoptotic pathway. However, the correlation among 4EGI-1, DR5 and 4E-BPs have not been discovered in NPC now. Therefore, we intend to find out the effect of 4EGI-1 on the apoptosis process of NPC and the relationship among 4EGI-1, DR5 and 4E BPs. Our results revealed a significant down regulation of DR5 expression in NPC tissues, which inversely correlated with lymph node metastasis status and clinical stages. Depressed DR5 expression was an independent biomarker for poor prognosis in NPC, and elevated DR5 expression showed longer overall survival time in 174 NPC patients. Besides, 4EGI-1 induced apoptosis in NPC cells through the DR5-caspase-8 axis on 4E-BP1 and eIF4E dephosphorylation exerting positive influence on their anti-tumor activities. The induction of DR5 also sensitized NPC cells to radiotherapy, and the SER was 1.195. These results establish the death receptor pathway as a novel anticancer mechanism of eIF4E/eIF4G interaction inhibitor in NPC. PMID- 26942882 TI - Long non-coding RNAs as prognostic markers in human breast cancer. AB - Long non-coding RNAs (lncRNAs) have been recently shown to play an important role in gene regulation and normal cellular functions, and disease processes. However, despite the overwhelming number of lncRNAs identified to date, little is known about their role in cancer for vast majority of them. The present study aims to determine whether lncRNAs can serve as prognostic markers in human breast cancer. We interrogated the breast invasive carcinoma dataset of the Cancer Genome Atlas (TCGA) at the cBioPortal consisting of ~ 1,000 cases. Among 2,730 lncRNAs analyzed, 577 lncRNAs had alterations ranging from 1% to 32% frequency, which include mutations, alterations of copy number and RNA expression. We found that deregulation of 11 lncRNAs, primarily due to copy number alteration, is associated with poor overall survival. At RNA expression level, upregulation of 4 lncRNAs (LINC00657, LINC00346, LINC00654 and HCG11) was associated with poor overall survival. A third signature consists of 9 lncRNAs (LINC00705, LINC00310, LINC00704, LINC00574, FAM74A3, UMODL1-AS1, ARRDC1-AS1, HAR1A, and LINC00323) and their upregulation can predict recurrence. Finally, we selected LINC00657 to determine their role in breast cancer, and found that LINC00657 knockout significantly suppresses tumor cell growth and proliferation, suggesting that it plays an oncogenic role. Together, these results highlight the clinical significance of lncRNAs, and thus, these lncRNAs may serve as prognostic markers for breast cancer. PMID- 26942883 TI - Increased PTP1B expression and phosphatase activity in colorectal cancer results in a more invasive phenotype and worse patient outcome. AB - Cell signaling is dependent on the balance between phosphorylation of proteins by kinases and dephosphorylation by phosphatases. This balance if often disrupted in colorectal cancer (CRC), leading to increased cell proliferation and invasion. For many years research has focused on the role of kinases as potential oncogenes in cancer, while phosphatases were commonly assumed to be tumor suppressive. However, this dogma is currently changing as phosphatases have also been shown to induce cancer growth. One of these phosphatases is protein tyrosine phosphatase 1B (PTP1B). Here we report that the expression of PTP1B is increased in colorectal cancer as compared to normal tissue, and that the intrinsic enzymatic activity of the protein is also enhanced. This suggests a role for PTP1B phosphatase activity in CRC formation and progression. Furthermore, we found that increased PTP1B expression is correlated to a worse patient survival and is an independent prognostic marker for overall survival and disease free survival. Knocking down PTP1B in CRC cell lines results in a less invasive phenotype with lower adhesion, migration and proliferation capabilities. Together, these results suggest that inhibition of PTP1B activity is a promising new target in the treatment of colorectal cancer and the prevention of metastasis. PMID- 26942884 TI - Activation of hERG3 channel stimulates autophagy and promotes cellular senescence in melanoma. AB - Ion channels play a major factor in maintaining cellular homeostasis but very little is known about the role of these proteins in cancer biology. In this work we have discovered that, the Kv11.3 (hERG3) a plasma-membrane potassium channel plays a critical role in the regulation of autophagy in a cancer cell model. We have found that pharmacologic stimulation of the Kv11.3 channel with a small molecule activator, NS1643 induced autophagy via activation of an AMPK-dependent signaling pathway in melanoma cell line. In addition, we have found that NS1643 produced a strong inhibition of cell proliferation by activating a cellular senescence program. Furthermore, inhibition of autophagy via siRNA targeting AMPK or treatment with hydroxychloroquine an autophagy inhibitor activates apoptosis in NS1643-treated cells. Thus, we propose that, Kv11.3 is a novel mediator of autophagy, autophagy can be a survival mechanism contributing to cellular senescence, and that use of a combinatorial pharmacologic approach of Kv11.3 activator with inhibitors of autophagy represents a novel therapeutic approach against melanoma. PMID- 26942885 TI - CD226 ligation protects against EAE by promoting IL-10 expression via regulation of CD4+ T cell differentiation. AB - Treatment targeting CD226 can ameliorate experimental autoimmune encephalomyelitis (EAE), the widely accepted model of MS. However, the mechanisms still need to be elucidated. Here we showed that CD226 blockage by anti-CD226 blocking mAb LeoA1 efficiently promoted IL-10 production in human peripheral blood monocytes (PBMC) or in mixed lymphocyte culture (MLC) system, significantly induced the CD4+IL-10+ T cell differentiation while suppressing the generation of Th1 and Th17. Furthermore, CD226 pAb administration in vivo reduced the onset of EAE in mice by promoting IL-10 production and regulating T cell differentiation. Concomitantly, the onset and severity of EAE were reduced and the serum IL-10 expression levels were increased in CD226 knockout mice than that in control mice when both received EAE induction. These novel findings confirmed that CD226 played a pivotal role in mediating autoimmune diseases such as EAE. Furthermore, to our knowledge, we show for the first time that IL-10 is an important contributor in the inhibitory effects of CD226 ligation on EAE. PMID- 26942886 TI - Impact of molecular profiling on overall survival of patients with advanced ovarian cancer. AB - OBJECTIVE: Patients with recurrent epithelial ovarian cancer (EOC) have limited treatment options. Studies have reported that biomarker profiling may help predict patient response to available treatments. This study sought to determine the value of biomarker profiling in recurrent EOC. RESULTS: Patients in the Matched cohort had a median OS of 36 months compared to 27 months for patients in the Unmatched cohort (HR 0.62, 95% CI 0.41-0.96; p < 0.03). Individual biomarkers were analyzed, with TUBB3, and PGP prognostic for survival. Biomarker analysis also identified a molecular subtype (positive for at least two of the following markers: ERCC1, RRM1, TUBB3, PGP) with particularly poor overall survival. METHODS: 224 patients from a commercial registry (NCT02678754) with stage IIIC/IV EOC at diagnosis, or restaged to IIIC/IV EOC at the time of molecular profiling, were retrospectively divided into two cohorts based on whether or not the drugs they received matched their profile recommendations. The Matched cohort received no drugs predicted to be lack-of-benefit while the Unmatched cohort received at least one drug predicted to be lack-of-benefit. Profile biomarker/drug associations were based on multiple test platforms including immunohistochemistry, fluorescent in situ hybridization and DNA sequencing. CONCLUSIONS: This report demonstrates the ability of multi-platform molecular profiling to identify EOC patients at risk of inferior survival. It also suggests a potential beneficial role of avoidance of lack-of-benefit therapies which, when administered, resulted in decreased survival relative to patients who received only therapies predicted to be of benefit. PMID- 26942895 TI - How To Improve Capacity and Cycling Stability for Next Generation Li-O2 Batteries: Approach with a Solid Electrolyte and Elevated Redox Mediator Concentrations. AB - Because of their exceptionally high specific energy, aprotic lithium oxygen (Li O2) batteries are considered as potential future energy stores. Their practical application is, however, still hindered by the high charging overvoltages and detrimental side reactions. Recently, the use of redox mediators dissolved in the electrolyte emerged as a promising tool to enable charging at moderate voltages. The presented work advances this concept and distinctly improves capacity and cycling stability of Li-O2 batteries by combining high redox mediator concentrations with a solid electrolyte (SE). The use of high redox mediator concentrations significantly increases the discharge capacity by including the oxidation and reduction of the redox mediator into charge cycling. Highly efficient cycling is achieved by protecting the lithium anode with a solid electrolyte, which completely inhibits unfavored deactivation of oxidized species at the anode. Surprisingly, the SE also suppresses detrimental side reactions at the carbon electrode to a large extent and enables stable charging completely below 4.0 V over a prolonged period. It is demonstrated that anode and cathode communicate deleteriously via the liquid electrolyte, which induces degradation reactions at the carbon electrode. The separation of cathode and anode with a SE is therefore considered as a key step toward stable Li-O2 batteries, in conjunction with a concentrated redox mediator electrolyte. PMID- 26942887 TI - A disintegrin and metalloprotease 10 (ADAM10) is a central regulator of murine liver tissue homeostasis. AB - A Disintegrin And Metalloprotease (ADAM) 10 exerts essential roles during organ development and tissue integrity in different organs, mainly through activation of the Notch pathway. However, only little is known about its implication in liver tissue physiology. Here we show that in contrast to its role in other tissues, ADAM10 is dispensable for the Notch2-dependent biliary tree formation. However, we demonstrate that expression of bile acid transporters is dependent on ADAM10. Consequently, mice deficient for Adam10 in hepatocytes, cholangiocytes and liver progenitor cells develop spontaneous hepatocyte necrosis and concomitant liver fibrosis. We furthermore observed a strongly augmented ductular reaction in 15-week old ADAM10(Deltahep/Deltach) mice and demonstrate that c-Met dependent liver progenitor cell activation is enhanced. Additionally, liver progenitor cells are primed to hepatocyte differentiation in the absence of ADAM10. These findings show that ADAM10 is a novel central node controlling liver tissue homeostasis. HIGHLIGHTS: Loss of ADAM10 in murine liver results in hepatocyte necrosis and concomitant liver fibrosis. ADAM10 directly regulates expression of bile acid transporters but is dispensable for Notch2-dependent formation of the biliary system. Activation of liver progenitor cells is enhanced through increased c-Met signalling, in the absence of ADAM10. Differentiation of liver progenitor cells to hepatocytes is augmented in the absence of ADAM10. PMID- 26942904 TI - [Mosquito]. PMID- 26942903 TI - [Dengue, Zika and Chikungunya]. AB - Arboviruses are transmitted by arthropods, including those responsible for the current pandemic: alphavirus (Chikungunya) and flaviviruses (dengue and Zika). Its importance increased in the Americas over the past 20 years. The main vectors are Aedes aegypti and A. albopictus. Dengue infection provides long lasting immunity against the specific serotype and temporary to the other three. Subsequent infection by another serotype determines more serious disease. There is a registered vaccine for dengue, Dengvaxia (Sanofi Pasteur). Other two (Butantan and Takeda) are in Phase III in 2016. Zika infection is usually asymptomatic or occurs with rash, conjunctivitis and not very high fever. There is no vaccine or specific treatment. It can be transmitted by parental, sexual and via blood transfusion. It has been associated with microcephaly. Chikungunya causes prolonged joint pain and persistent immune response. Two candidate vaccines are in Phase II. Dengue direct diagnosis is performed by virus isolation, RT-PCR and ELISA for NS1 antigen detection; indirect methods are ELISA IgM (cross-reacting with other flavivirus), MAC-ELISA, and plaque neutralization. Zika is diagnosed by RT-PCR and virus isolation. Serological diagnosis cross reacts with other flavivirus. For CHIKV culture, RT-PCR, MAC-ELISA and plaque neutralization are used. Against Aedes organophosphate larvicides (temephos), organophosphorus insecticides (malathion and fenitrothion) and pyrethroids (permethrin and deltamethrin) are usually employed. Resistance has been described to all these products. Vegetable derivatives are less expensive and biodegradable, including citronella oil, which microencapsulated can be preserved from evaporation. PMID- 26942906 TI - Prediction of Small for Gestational Age: Accuracy of Different Sonographic Fetal Weight Estimation Formulas. AB - OBJECTIVE: To compare the accuracy of various sonographic estimated fetal weight (sEFW) formulas for the prediction of small for gestational age (SGA) neonates. METHODS: A retrospective analysis of 6,126 fetal biometrical measurements performed within 3 days of delivery. SGA prediction was evaluated for various sEFW formulas by calculating the sensitivity, specificity, positive/negative predictive value (PPV/NPV), likelihood ratio (+LR/-LR), overall accuracy and area under the receiver operating characteristic curve (AUC). Systematic error, random error, proportion of estimates >10% of birth weights, actual and absolute weight differences were compared between SGA and non-SGA neonates. RESULTS: Overall, 638 (10.4%) neonates were SGA. There was considerable variation among formulas in sensitivity (mean +/- SD, 62 +/- 14.4%; range, 32.4-91.2), PPV (72.5 +/- 10.7%; 45.8-95.6) and +LR (24.2 +/- 10.9; 7.2-57.3), mild variation in specificity (96.6 +/- 2.7%; 87.4-99.4), NPV (94.6 +/- 5.3%; 72.2-98.9) and -LR (0.4 +/- 0.1; 0.1 0.7) and minimal variation in AUC (mean, 0.93; range, 0.91-0.93). The majority of formulas had a lower accuracy for the SGA neonates, with systematic error and random error ranging from -4.2 to 14.3% and from 8.4 to 12.9% for SGA, and from 8.7 to 16.1% and from 7.2 to 10.5% for non-SGA, respectively. CONCLUSION: sEFW formulas differ in their accuracy for SGA prediction. In our population, the most accurate formula for SGA prediction was Hadlock's formula utilizing femur length, abdominal and head circumference. PMID- 26942905 TI - Synaptosomal Mitochondrial Dysfunction in 5xFAD Mouse Model of Alzheimer's Disease. AB - Brain mitochondrial dysfunction is hallmark pathology of Alzheimer's disease (AD). Recently, the role of synaptosomal mitochondrial dysfunction in the development of synaptic injury in AD has received increasing attention. Synaptosomal mitochondria are a subgroup of neuronal mitochondria specifically locating at synapses. They play an essential role in fueling synaptic functions by providing energy on the site; and their defects may lead to synaptic failure, which is an early and pronounced pathology in AD. In our previous studies we have determined early synaptosomal mitochondrial dysfunction in an AD animal model (J20 line) overexpressing human Amyloid beta (Abeta), the key mediator of AD. In view of the limitations of J20 line mice in representing the full aspects of amyloidopathy in AD cases, we employed 5xFAD mice which are thought to be a desirable paradigm of amyloidopathy as seen in AD subjects. In addition, we have also examined the status of synaptosomal mitochondrial dynamics as well as Parkin mediated mitophagy which have not been previously investigated in this mouse model. In comparison to nontransgenic (nonTg mice), 5xFAD mice demonstrated prominent synaptosomal mitochondrial dysfunction. Moreover, synaptosomal mitochondria from the AD mouse model displayed imbalanced mitochondrial dynamics towards fission along with activated Parkin and LC3BII recruitment correlating to spatial learning & memory impairments in 5xFAD mice in an age-dependent manner. These results suggest that synaptosomal mitochondrial deficits are primary pathology in Abeta-rich environments and further confirm the relevance of synaptosomal mitochondrial deficits to the development of AD. PMID- 26942907 TI - Deprescribing in Frail Older People: A Randomised Controlled Trial. AB - OBJECTIVES: Deprescribing has been proposed as a way to reduce polypharmacy in frail older people. We aimed to reduce the number of medicines consumed by people living in residential aged care facilities (RACF). Secondary objectives were to explore the effect of deprescribing on survival, falls, fractures, hospital admissions, cognitive, physical, and bowel function, quality of life, and sleep. METHODS: Ninety-five people aged over 65 years living in four RACF in rural mid west Western Australia were randomised in an open study. The intervention group (n = 47) received a deprescribing intervention, the planned cessation of non beneficial medicines. The control group (n = 48) received usual care. Participants were monitored for twelve months from randomisation. Primary outcome was change in the mean number of unique regular medicines. All outcomes were assessed at baseline, six, and twelve months. RESULTS: Study participants had a mean age of 84.3 +/- 6.9 years and 52% were female. Intervention group participants consumed 9.6 +/- 5.0 and control group participants consumed 9.5 +/- 3.6 unique regular medicines at baseline. Of the 348 medicines targeted for deprescribing (7.4 +/- 3.8 per person, 78% of regular medicines), 207 medicines (4.4 +/- 3.4 per person, 59% of targeted medicines) were successfully discontinued. The mean change in number of regular medicines at 12 months was 1.9 +/- 4.1 in intervention group participants and +0.1 +/- 3.5 in control group participants (estimated difference 2.0 +/- 0.9, 95%CI 0.08, 3.8, p = 0.04). Twelve intervention participants and 19 control participants died within 12 months of randomisation (26% versus 40% mortality, p = 0.16, HR 0.60, 95%CI 0.30 to 1.22) There were no significant differences between groups in other secondary outcomes. The main limitations of this study were the open design and small participant numbers. CONCLUSIONS: Deprescribing reduced the number of regular medicines consumed by frail older people living in residential care with no significant adverse effects on survival or other clinical outcomes. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12611000370909. PMID- 26942908 TI - Bringing Antonovsky's salutogenic theory to life: A qualitative inquiry into the experiences of young people with congenital heart disease. AB - OBJECTIVE: Antonovsky coined sense of coherence (SOC) as the central concept of his salutogenic theory focusing on the origins of well-being. SOC captures the degree to which one perceives the world as comprehensible, manageable, and meaningful. Life events and resources are considered to be the building blocks of a person's SOC. However, mainly quantitative studies have looked into the role of life events and resources. Therefore, the present study aims to gain a deeper insight into the experiences of patients with congenital heart disease (CHD) regarding resources and life events. METHOD: For this qualitative study, patients were selected from the sample of a preceding study on development of SOC (n = 429). In total, 12 young individuals with CHD who had either a weak (n = 6) or strong SOC (n = 6) over time were interviewed (8 women, median age of 20 years). Data analysis was based on the constant comparative method as detailed in the Qualitative Analysis Guide of Leuven. Commonalities and differences between patients from both groups were explored. RESULTS: The following themes emerged: (1) self-concept; (2) social environment; (3) daytime activities; (4) life events and disease-related turning points; (5) stress and coping; and (6) illness integration. Additionally, the degree of personal control was identified as an overarching topic that transcended the other themes when comparing both groups of patients. CONCLUSION: These results may have implications for the structure and content of interventions improving well-being in young people with CHD. PMID- 26942909 TI - The lived experiences of resilience in Iranian adolescents living in residential care facilities: A hermeneutic phenomenological study. AB - BACKGROUND: Resilience is one of the main factors affecting human health, and perceiving its meaning for high-risk adolescents is of particular importance in initiating preventive measures and providing resilience care. OBJECTIVES: This qualitative study was conducted to explain the meaning of resilience in the lived experiences of Iranian adolescents living in governmental residential care facilities. MATERIALS AND METHODS: This study was conducted using the hermeneutic phenomenological method. Semi-structured interviews were conducted with eight adolescents aged 13-17 living in governmental residential care facilities of Tehran province affiliated to the Welfare Organization of Iran who articulated their experiences of resilience. Sampling lasted from May 2014 to July 2015 and continued until new themes were no longer emerging. The researchers analyzed the verbatim transcripts using Van Manen's six-step method of phenomenology. RESULTS: The themes obtained in this study included "going through life's hardships," "aspiring for achievement," "self-protection," "self-reliance," and "spirituality." CONCLUSION: Our study indicates that the meaning of resilience coexists with self-reliance in adolescents' lived experiences. Adolescents look forward to a better future. They always trust God in the face of difficulties and experience resilience by keeping themselves physically and mentally away from difficulties. Adverse and bitter experiences of the past positively affected their positive view on life and its difficulties and also their resilience. The five themes that emerged from the findings describe the results in detail. The findings of this study enable nurses, health administrators, and healthcare providers working with adolescents to help this vulnerable group cope better with their stressful life conditions and improve their health through increasing their capacity for resilience. PMID- 26942910 TI - Impact of Six Years Community Directed Treatment with Ivermectin in the Control of Onchocerciasis, Western Ethiopia. AB - BACKGROUND: The African Program for Onchocerciais Control (APOC) with a main strategy of community directed treatment with ivermectin (CDTI) was established with the aim of eliminating Onchocerciasis as a disease of public health and socio-economic importance. The study area was a hyper endemic area just before the implementation of CDTI. It has been implemented for six years in this district but yet not been evaluated. So, the objective of this study was to evaluate the impact of six years CDTI on parasitological and clinical indices of Onchocerciasis. METHODS: This study employed a pre-post impact evaluation design. The minimum sample size for this study was 1318; the respondents were selected by multi-stage sampling technique. Data on socio-demographic characteristics using a semi-structured questionnaire, clinical examination for skin signs and symptoms of Onchocerciasis and two bloodless skin snips from each side of the gluteal fold were taken from the entire study participants. SPSS version 16.0 and Medcalc version 12.2.1.0 were used for analysis. RESULT: The microfilaridermia reduced from the pre-intervention value of 74.8% to 40.7%, indicating a 45.6% reduction, mean intensity from 32.1(SD = 61.5) mf/mg skin snip to 18.7(SD = 28.7)indicating 41.75% reduction, CMFL from 19.6 mf/mg skin snip to 4.7 indicating 76% reduction. The result also showed that microfilaridermia and mean intensity decreased as the number of treatment taken increased. Pruritis, leopard skin, onchocercomata and hanging groin reduced by 54.4%, 61.3%, 77.7% and 88.5% respectively. CONCLUSIONS: The implementation of CDTI significantly reduced the parasitological and clinical indices of Onchocerciasis, so, efforts should be made to improve the annual treatment coverage and sustainability of CDTI to drastically reduce the micro filarial load to the level the disease would no longer be a public health problem. PMID- 26942911 TI - Utility of MRI Diffusion Tensor Imaging in Carpal Tunnel Syndrome: A Meta Analysis. AB - BACKGROUND After successful utilization of diffusion tensor imaging (DTI) in detecting brain pathologies, it is now being examined for use in the detection of peripheral neuropathies. The aim of this meta-analysis was to evaluate the diagnostic potentials of DTI in carpal tunnel syndrome (CTS). MATERIAL AND METHODS The literature search was performed in multiple electronic databases using a keyword search and final selection of the studies was based on predetermined inclusion and exclusion criteria. We performed a meta-analyses of mean differences in fractional anisotropy (FA) and apparent diffusion coefficient (ADC) between CTS patient and healthy subjects. Publication bias detection was done with Begg's test and sensitivity analyses were performed to explore the source/s of higher heterogeneity and the authenticity of results. RESULTS FA was significantly lower in CTS patients in comparison with healthy subjects (mean and the difference [95% confidence interval] was -0.06 [-0.10, -0.02] (p=0.003). The ADC was significantly higher in CTS patients (mean difference [95% CI] was 0.10 [0.02, 0.18], p=0.02). Overall sensitivity of FA-based diagnosis was 82.82%, with 77.83% specificity. CONCLUSIONS DTI can be a valuable tool in diagnosing CTS. PMID- 26942912 TI - Exposure versus Susceptibility as Alternative Bases for New Approaches to Surveillance for Schistosoma japonicum in Low Transmission Environments. AB - Currently, schistosomiasis in China provides an excellent example of many of the challenges of moving from low transmission to the elimination of transmission for infectious diseases generally. In response to the surveillance dimension of these challenges, we here explore two strategic approaches to inform priorities for the development of improved methods addressed specifically to schistosomiasis in the low transmission environment. We utilize an individually-based model and the exposure data used earlier to explore surveillance strategies, one focused on exposure assessment and the second on our estimates of variability in individual susceptibility in the practical context of the current situation in China and the theoretical context of the behavior of transmission dynamics near the zero state. Our findings suggest that individual susceptibility is the major single determinant of infection intensity in both the low and medium risk environments. We conclude that there is considerable motivation to search for a biomarker of susceptibility to infection in humans, but that there would also be value in a method for monitoring surface waters for the free-swimming forms of the parasite in endemic or formerly endemic environments as an early warning of infection risk. PMID- 26942913 TI - T-Lymphocytes Traffic into the Brain across the Blood-CSF Barrier: Evidence Using a Reconstituted Choroid Plexus Epithelium. AB - An emerging concept of normal brain immune surveillance proposes that recently and moderately activated central memory T lymphocytes enter the central nervous system (CNS) directly into the cerebrospinal fluid (CSF) via the choroid plexus. Within the CSF space, T cells inspect the CNS environment for cognate antigens. This gate of entry into the CNS could also prevail at the initial stage of neuroinflammatory processes. To actually demonstrate T cell migration across the choroidal epithelium forming the blood-CSF barrier, an in vitro model of the rat blood-CSF barrier was established in an "inverse" configuration that enables cell transmigration studies in the basolateral to apical, i.e. blood/stroma to CSF direction. Structural barrier features were evaluated by immunocytochemical analysis of tight junction proteins, functional barrier properties were assessed by measuring the monolayer permeability to sucrose and the active efflux transport of organic anions. The migratory behaviour of activated T cells across the choroidal epithelium was analysed in the presence and absence of chemokines. The migration pathway was examined by confocal microscopy. The inverse rat BCSFB model reproduces the continuous distribution of tight junction proteins at cell margins, the restricted paracellular permeability, and polarized active transport mechanisms, which all contribute to the barrier phenotype in vivo. Using this model, we present experimental evidence of T cell migration across the choroidal epithelium. Cell migration appears to occur via a paracellular route without disrupting the restrictive barrier properties of the epithelial interface. Apical chemokine addition strongly stimulates T cell migration across the choroidal epithelium. The present data provide evidence for the controlled migration of T cells across the blood-CSF barrier into brain. They further indicate that this recruitment route is sensitive to CSF-borne chemokines, extending the relevance of this migration pathway to neuroinflammatory and neuroinfectious disorders which are typified by elevated chemokine levels in CSF. PMID- 26942915 TI - Growth performance and carcass characteristics of feedlot Thai native * Lowline Angus crossbred steer fed with fermented cassava starch residue. AB - Ten Thai native * Lowline Angus crossbred (50:50) steers were used in a completely randomized design to receive two treatments including concentrate containing cassava chips (Control) and fermented cassava starch residue (FCSR) as major carbohydrate sources. FCSR was prepared as yeast (Saccharomyces cerevisiae) inoculates with exogenous enzyme addition. All steers received ad libitum rice straw and concentrate in equal proportions (1:1). Replacement of cassava chip with FCSR increased neutral detergent fiber and acid detergent fiber intakes but decreased non-protein nitrogen intake of steers. Digestibility of dry matter, organic matter, and crude protein were decreased with replacement of cassava chip by FCSR; however, digested nutrients were similar between groups. Replacement of cassava chip in the concentrate with FCSR resulted in comparable growth performance and feed efficiency of the feedlot steers. Moreover, carcass characteristics in terms of yield and meat quality of the steers were not affected by cassava chips replaced by FCSR as a major carbohydrate source in the concentrate. In conclusion, replacement of cassava chip in the concentrate with FCSR decreased feed digestibility; however, it did not impact negatively on growth performance and carcass traits of feedlot Thai native * Lowline Angus crossbred steers. PMID- 26942914 TI - Combination of Eight Alleles at Four Quantitative Trait Loci Determines Grain Length in Rice. AB - Grain length is an important quantitative trait in rice (Oryza sativa L.) that influences both grain yield and exterior quality. Although many quantitative trait loci (QTLs) for grain length have been identified, it is still unclear how different alleles from different QTLs regulate grain length coordinately. To explore the mechanisms of QTL combination in the determination of grain length, five mapping populations, including two F2 populations, an F3 population, an F7 recombinant inbred line (RIL) population, and an F8 RIL population, were developed from the cross between the U.S. tropical japonica variety 'Lemont' and the Chinese indica variety 'Yangdao 4' and grown under different environmental conditions. Four QTLs (qGL-3-1, qGL-3-2, qGL-4, and qGL-7) for grain length were detected using both composite interval mapping and multiple interval mapping methods in the mapping populations. In each locus, there was an allele from one parent that increased grain length and another allele from another parent that decreased it. The eight alleles in the four QTLs were analyzed to determine whether these alleles act additively across loci, and lead to a linear relationship between the predicted breeding value of QTLs and phenotype. Linear regression analysis suggested that the combination of eight alleles determined grain length. Plants carrying more grain length-increasing alleles had longer grain length than those carrying more grain length-decreasing alleles. This trend was consistent in all five mapping populations and demonstrated the regulation of grain length by the four QTLs. Thus, these QTLs are ideal resources for modifying grain length in rice. PMID- 26942916 TI - Biomarkers in heart failure with preserved ejection fraction. AB - Biomarkers are widely used and studied in heart failure. Most studies have described the utility and performance of biomarkers in sub-studies of randomised clinical trials, where the vast majority of the patients suffered from heart failure with reduced ejection fraction (HFrEF), and not with preserved ejection fraction (HFpEF). As a result, there is a scarcity of data describing the levels, dynamics, clinical and biochemical correlates, and biology of biomarkers in patients suffering from HFpEF, whereas HFpEF is in fact a very frequent clinical entity. This article discusses the value of different biomarkers in HFpEF. We describe various aspects of natriuretic peptide measurements in HFpEF patients, with a focus on diagnosis, prognosis and the risk prediction of developing heart failure. Further, we will discuss several emerging biomarkers such as galectin-3 and suppression of tumorigenicity 2, and recently discovered ones such as growth differentiation factor-15 and syndecan-1. PMID- 26942917 TI - Unique gene expression profile in osteoarthritis synovium compared with cartilage: analysis of publicly accessible microarray datasets. AB - The purpose of this study was to identify a gene expression signature in osteoarthritis (OA) synovium and genomic pathways likely to be involved in the pathogenesis of OA. Four publicly accessible microarray studies from synovium of OA patients were integrated, and a transcriptomic and network-based meta-analysis was performed. Based on pathways according to the Kyoto Encyclopedia of Genes and Genomes, functional enrichment analysis was performed. Meta-analysis results of OA synovium were compared to two previously published studies of OA cartilage to determine the relative number of common and specific DEGs of the cartilage and synovium. According to our meta-analysis, a total of 1350 genes were found to be differentially expressed in the synovium of OA patients as compared to that of healthy controls. Pathway analysis found 41 significant pathways in the total DEGs, and 22 and 16 pathways in the upregulated and downregulated DEGs, respectively. Cell adhesion molecules and cytokine-cytokine receptor interaction were the most significant pathway in the upregulated and downregulated DEGs, respectively. Comparison of meta-analysis results of OA synovium with results of two previous studies of OA cartilage identified 85 common genes and 1632 cartilage-specific DEGs and 1265 synovium-specific DEGs in the first study; and 142 common genes, and 856 cartilage-specific DEGs and 1208 synovium-specific DEGs in the second study. Our results show a small overlap between the DEGs of the synovium compared to DEGs of the cartilage, suggesting different pathogenic mechanisms that are specific to the synovium. PMID- 26942918 TI - Halobacillus salicampi sp. nov., a moderately halophilic bacterium isolated from a solar saltern sediment. AB - A Gram-positive, moderately halophilic bacterium, designated strain TGS-15(T), was isolated from the sediment of a solar saltern pond located in Shinan, Korea. Strain TGS-15(T) was found to be a strictly aerobic, non-motile rod which can grow at pH 6.0-10.0 (optimum, pH 9.0), at 20-35 degrees C (optimum, 28 degrees C) and at salinities of 1-20 % (w/v) NaCl (optimum, 9 % NaCl). Phylogenetic analyses based on 16S rRNA gene sequences indicated that strain TGS-15(T) belongs to the genus Halobacillus, with sequence similarity of 98.5-96.0 % to known type strains, showing high sequence similarity to Halobacillus locisalis MSS-155(T) (98.5 %), Halobacillus faecis IGA7-4(T) (98.2 %) and Halobacillus alkaliphilus FP5(T) (98.0 %), and less than 98.0 % sequence similarity to other currently recognised type strains of the genus. The major polar lipids were phosphatidylglycerol, diphosphatidylglycerol, phosphatidylethanolamine, an unidentified glycolipid and an unidentified lipid. The cell wall peptidoglycan was found to be based on L-Orn-D-Asp, the predominant isoprenoid quinone was identified as menaquinone-7 (MK-7) and the major fatty acids were identified as anteiso-C15:0, iso-C15:0, anteiso-C17:0 and C16:1 omega7c alcohol. The DNA G+C content of this novel isolate was determined to be 45.3 mol %. Levels of DNA:DNA relatedness between strain TGS-15(T) and the type strains of 13 other species of the genus ranged from 52 to 9 %. On the basis of the polyphasic analysis conducted in this study, strain TGS-15(T) is concluded to represent a novel species of the genus Halobacillus, for which the name Halobacillus salicampi sp. nov. is proposed. The type strain is TGS-15(T) (=KACC 18264(T) = NBRC 110640(T)). PMID- 26942919 TI - Micromonospora mangrovi sp. nov., isolated from mangrove soil. AB - A novel actinomycete strain 2803GPT1-18(T) was isolated from a composite mangrove soil sample collected from Beihai, Guangxi province, China. Phylogenetic analysis of the 16S rRNA gene sequence of strain 2803GPT1-18(T) indicated high similarity with 'Micromonospora harpali' NEAU-JC6(T) (99.2 %), Micromonospora haikouensis 232617(T) (99.1 %), Micromonospora wenchangensis 2602GPT1-05(T) (99.1 %), Micromonospora schwarzwaldensis HKI0641(T) (99.1 %). The gyrB gene sequence analysis also indicated that strain 2803GPT1-18(T) should be assigned to the genus Micromonospora but different from any established Micromonospora species. The strain harbored meso-DAP and glycine as major cell wall amino acids, MK 10(H6) (53.5 %), MK-9(H6) (25.1 %) and MK-9(H4) (13.4 %) as predominant menaquinones. The characteristic whole cell sugars are arabinose, xylose, glucose, galactose and mannose. The polar lipid profile comprises phosphatidylethanolamine, diphosphatidylglycerol, phosphatidylinositol and unidentified polar lipids. The major cellular fatty acids present are iso-C16:0 (44.2 %) and iso-C15:0 (12.4 %). The DNA G+C content is 71.2 mol%. Furthermore, a combination of DNA-DNA relatedness and some physiological and biochemical properties indicated that the novel strain could be readily distinguished from the closely related species. On the basis of these phenotypic and genotypic data, strain 2803GPT1-18(T) represents a novel species of the genus Micromonospora, for which the name Micromonospora mangrovi sp. nov. is proposed. The type strain is 2803GPT1-18(T) (=CCTCC AA2012012(T) = DSM45761(T)). PMID- 26942920 TI - Late onset and high-frequency dominant hearing loss in a family with MYH9 disorder. AB - MYH9 disorder is a rare autosomal-dominant disorder. We previously reported that it is caused by mutations in the gene for nonmuscle myosin heavy chain IIA (NMMHC IIA). MYH9 disorder causes congenital macrothrombocytopenia accompanied by progressive sensorineural hearing loss, nephropathy, and cataract. However, there are few reports that describe the audiological features of MYH9 disorder. The objective of this study was to characterize auditory and other phenotypes of patients with MYH9 disorder. We examined nine subjects from one Japanese family. Audiological, ophthalmological, hematological, and imaging examinations were used to assess clinical features. We carried out genetic analysis of the causative gene, MYH9. Five subjects exhibited macrothrombocytopenia and neutrophil cytoplasmic inclusion bodies. Immunofluorescence analysis of neutrophil NMMHC-IIA revealed abnormal type II localization. Two subjects had high-frequency dominant hearing loss, which was adult onset and progressive. Only one subject had cataract. MYH9 sequencing analysis of all thrombocytopenic subjects revealed a heterozygous c.4270G>A mutation in exon 30 (p.D1424N). We identified five patients with MYH9 disorder from the family. The hearing impairment associated with MYH9 disorder in this family was characterized as adult onset, progressive, and high-frequency dominant. Hematological manifestations of MYH9 disorder show complete penetrance, whereas extra-hematological manifestations show incomplete penetrance and variable expressivity in this family. PMID- 26942921 TI - Valproic acid inhibits the angiogenic potential of cervical cancer cells via HIF 1alpha/VEGF signals. AB - PURPOSE: Cervical cancer is one of the most prevalent malignancies in women worldwide. Therefore, the investigation about the molecular pathogenesis and related therapy targets of cervical cancer is an emergency. The objective of the present study is to investigate the effects of valproic acid (VPA), a histone deacetylase inhibitor, on the angiogenesis of cervical cancer. METHODS: The effects and mechanisms of VPA on in vitro angiogenesis and vascular endothelial growth factor (VEGF) expression of human cervical cancer HeLa and SiHa cells were investigated. RESULTS: Our present study reveals that 1 mM VPA can significantly inhibit the in vitro angiogenic potential and VEGF expression of human cervical cancer HeLa and SiHa cells. Further, the transcription and protein levels of hypoxia inducible factor-1alpha (HIF-1alpha), and not HIF-1beta, are significantly inhibited in VPA-treated cervical cancer cells. Over expression of HIF-1alpha can obviously reverse VPA-induced VEGF down regulation. VPA-treatment decreases the activation of Akt and ERK1/2 in both HeLa and SiHa cells in a time dependent manner. The inhibitor of Akt (LY 294002) or ERK1/2 (PD98059) can inhibit VEGF alone and cooperatively reinforce the suppression effects of VPA on HIF-1alpha and VEGF expression. CONCLUSION: Collectively, our data reveal that the inhibition of PI3K/Akt and ERK1/2 signals are involved in VPA-induced HIF 1alpha and VEGF suppression of cervical cancer cells. PMID- 26942923 TI - Fetal Development of the Bovine Uterus: A Light Microscopy and Immunohistochemical Study. AB - Important steps during the prenatal development of the bovine uterus are described using conventional hematoxylin-eosin staining of fetuses from different developmental stages [crown-rump length (CRL) 9.2-94.0 cm]. Additionally, a number of intermediate filaments (keratin 7, 8, 14, 18, 19; and vimentin), the basement membrane protein laminin, smooth-muscle marker (SMA), and S100 were studied to further characterize certain differentiation processes. During early development, the uterine epithelium is simple or (pseudo)stratified with bud-like protrusions. Developing caruncles can be observed in the corpus uteri at a CRL of 15.8 cm onwards, showing a simple, keratin-positive epithelium. In contrast, the intercaruncular areas are characterized by a (pseudo)stratified epithelium, which also shows positive staining in a different manner for the investigated keratins. A differentiation of smooth muscle cell layers can be observed from a CRL of 24.4 cm onwards. Intense SMA-positive cells/fibers, arranged perpendicularly to the developing circular SMA-positive muscle cell layer, can be found preferentially located in the developing caruncles. Lymphocytes occur in the uterine epithelium and stroma in the corpora and cornua of fetuses with a CLR of 15.8 cm and higher. PMID- 26942922 TI - Effect of Avoidance on Peanut Allergy after Early Peanut Consumption. AB - BACKGROUND: In a randomized trial, the early introduction of peanuts in infants at high risk for allergy was shown to prevent peanut allergy. In this follow-up study, we investigated whether the rate of peanut allergy remained low after 12 months of peanut avoidance among participants who had consumed peanuts during the primary trial (peanut-consumption group), as compared with those who had avoided peanuts (peanut-avoidance group). METHODS: At the end of the primary trial, we instructed all the participants to avoid peanuts for 12 months. The primary outcome was the percentage of participants with peanut allergy at the end of the 12-month period, when the participants were 72 months of age. RESULTS: We enrolled 556 of 628 eligible participants (88.5%) from the primary trial; 550 participants (98.9%) had complete primary-outcome data. The rate of adherence to avoidance in the follow-up study was high (90.4% in the peanut-avoidance group and 69.3% in the peanut-consumption group). Peanut allergy at 72 months was significantly more prevalent among participants in the peanut-avoidance group than among those in the peanut-consumption group (18.6% [52 of 280 participants] vs. 4.8% [13 of 270], P<0.001). Three new cases of allergy developed in each group, but after 12 months of avoidance there was no significant increase in the prevalence of allergy among participants in the consumption group (3.6% [10 of 274 participants] at 60 months and 4.8% [13 of 270] at 72 months, P=0.25). Fewer participants in the peanut-consumption group than in the peanut-avoidance group had high levels of Ara h2 (a component of peanut protein)-specific IgE and peanut specific IgE; in addition, participants in the peanut-consumption group continued to have a higher level of peanut-specific IgG4 and a higher peanut-specific IgG4:IgE ratio. CONCLUSIONS: Among children at high risk for allergy in whom peanuts had been introduced in the first year of life and continued until 5 years of age, a 12-month period of peanut avoidance was not associated with an increase in the prevalence of peanut allergy. Longer-term effects are not known. (Funded by the National Institute of Allergy and Infectious Diseases and others; LEAP-On ClinicalTrials.gov number, NCT01366846.). PMID- 26942927 TI - Gene expression profile changes in Eisenia fetida chronically exposed to PFOA. AB - Eisenia fetida is a terrestrial organism, which can be used to diagnose sub lethal concentrations of PFOA by using molecular biomarkers. In order to identify potential molecular biomarkers, we have exposed E. fetida to 10 mg/kg of PFOA in soil for 8 months. The mRNA isolation, sequencing, transcriptome assembly followed by differential gene expression studies have revealed that genes that are involved in apoptotic process, reproduction, calcium signalling, neuronal development and lipid metabolism are predominantly affected. Highly specific genes that are altered by PFOA can be further validated and used as biomarker to detect sub-lethal concentrations of PFOA in the soil. PMID- 26942928 TI - The difficulty of the postural control task affects multi-muscle control during quiet standing. AB - The aim of this study was to compare the electromyographic (EMG) coherence between the lower limb and the core muscles when carrying out two postural tasks at different difficulty levels. EMG was recorded in 20 healthy male subjects while performing two independent quiet standing tasks. The first one involved a bipedal stance with the eyes open, while the second consisted of a dominant unipedal stance also with the eyes open. The obtained EMG signals were analysed by computing estimations of EMG-EMG coherence between muscle pairs, both singly (single-pair estimations) and combined (pooled estimations). Pooled and single coherence of anterior, posterior, core, antagonist and mixed pairs of muscles were significant in the 0-5 Hz frequency band. The results indicate that core and antagonist muscle groups, such as the anterior and posterior muscles, share low frequency neural inputs (0-5 Hz) which could be responsible of the M-modes assembly. The core muscles could therefore provide the necessary synergy to maintain spine stability during the balancing exercise. Finally, differences in EMG-EMG coherence suggest that the muscle synergies formed during unipedal stance tasks are different from those established during bipedal stance. PMID- 26942929 TI - High Throughput Sequencing Identifies Misregulated Genes in the Drosophila Polypyrimidine Tract-Binding Protein (hephaestus) Mutant Defective in Spermatogenesis. AB - The Drosophila polypyrimidine tract-binding protein (dmPTB or hephaestus) plays an important role during spermatogenesis. The heph2 mutation in this gene results in a specific defect in spermatogenesis, causing aberrant spermatid individualization and male sterility. However, the array of molecular defects in the mutant remains uncharacterized. Using an unbiased high throughput sequencing approach, we have identified transcripts that are misregulated in this mutant. Aberrant transcripts show altered expression levels, exon skipping, and alternative 5' ends. We independently verified these findings by reverse transcription and polymerase chain reaction (RT-PCR) analysis. Our analysis shows misregulation of transcripts that have been connected to spermatogenesis, including components of the actomyosin cytoskeletal apparatus. We show, for example, that the Myosin light chain 1 (Mlc1) transcript is aberrantly spliced. Furthermore, bioinformatics analysis reveals that Mlc1 contains a high affinity binding site(s) for dmPTB and that the site is conserved in many Drosophila species. We discuss that Mlc1 and other components of the actomyosin cytoskeletal apparatus offer important molecular links between the loss of dmPTB function and the observed developmental defect in spermatogenesis. This study provides the first comprehensive list of genes misregulated in vivo in the heph2 mutant in Drosophila and offers insight into the role of dmPTB during spermatogenesis. PMID- 26942931 TI - [From the national competence network for viral hepatitis (HepNet) emerged the German Liver Foundation (Deutsche Leberstiftung)]. AB - The competence network for viral hepatitis (HepNet) was founded in 2002 with funding from the German government and has influenced the research on viral hepatitis in Germany. HepNet collaborator sites have been involved in numerous national and international investigator-initiated, as well as industry-sponsored, phase 1-3 studies. Within the HepNet Study-House, many groundbreaking investor initiated trials have been completed and are still ongoing. For example, the acute hepatitis C trials and trials on chronic hepatitis D (delta), which led to therapy optimization. Continuation of the competence network on viral hepatitis has been achieved by the foundation of the German Liver Foundation, which has been an external cooperation partner of the German Center for Infection Research (DZIF) for two years. The well-established HepNet Study-House acts here as the clinical trial platform for all DZIF hepatitis trials. PMID- 26942932 TI - [Competence Network Stroke. A successful model for stroke research]. AB - In 1999 the German Ministry of Education and Research initiated a funding initiative for competence networks in health research in order to improve research and health care for major diseases with high morbidity and relevance to public health. All major players in a given field were invited to cooperate. The aims were to improve horizontal as well as vertical networking in order to improve research quality and the transfer of new results into general clinical practice. Another aim was to establish sustainable structures for lasting cooperation. After a highly competitive application round, the Competence Network Stroke was among the very first to be funded. The incidence of stroke in Germany is about 250,000 new patients per year, it is the leading cause of adult impairment and its societal impact is dramatic.This article describes how the Competence Network Stroke managed to meet the above-mentioned goals and how cooperation among stroke researchers and caregivers in Germany has improved. Furthermore it provides examples of researcher achievements in the network, which have advanced research and benefited patients. PMID- 26942934 TI - Assessment of incident intensity on laser speckle contrast imaging using a nematic liquid crystal spatial light modulator. AB - Before laser speckle contrast imaging (LSCI) can be used reliably and quantitatively in a clinical setting, there are several theoretical and practical issues that still must be addressed. In order to address some of these issues, an electro-optical system that utilizes a nematic liquid crystal spatial light modulator (SLM) to mimic LSCI experiments was assembled. The focus of this paper is to address the issue of how incident intensity affects LSCI results. Using the SLM-based system, we systematically adjusted incident intensity on the SLM and assessed the resulting first- and second-order statistics of the imaged speckle to explain the corresponding spatial contrast values in both frozen and time integrated speckle patterns. The SLM-based system was used to generate speckle patterns with a controlled minimum speckle size, probability intensity distribution, and temporal decorrelation behavior. By eliminating many experimental parameters, this system is capable of serving as a useful intermediary tool between computer simulation and physical experimentation for further developing LSCI as a quantitative imaging modality. PMID- 26942933 TI - Can we detect a nonlinear response to temperature in European plant phenology? AB - Over a large temperature range, the statistical association between spring phenology and temperature is often regarded and treated as a linear function. There are suggestions that a sigmoidal relationship with definite upper and lower limits to leaf unfolding and flowering onset dates might be more realistic. We utilised European plant phenological records provided by the European phenology database PEP725 and gridded monthly mean temperature data for 1951-2012 calculated from the ENSEMBLES data set E-OBS (version 7.0). We analysed 568,456 observations of ten spring flowering or leafing phenophases derived from 3657 stations in 22 European countries in order to detect possible nonlinear responses to temperature. Linear response rates averaged for all stations ranged between 7.7 (flowering of hazel) and -2.7 days degrees C-1 (leaf unfolding of beech and oak). A lower sensitivity at the cooler end of the temperature range was detected for most phenophases. However, a similar lower sensitivity at the warmer end was not that evident. For only ~14 % of the station time series (where a comparison between linear and nonlinear model was possible), nonlinear models described the relationship significantly better than linear models. Although in most cases simple linear models might be still sufficient to predict future changes, this linear relationship between phenology and temperature might not be appropriate when incorporating phenological data of very cold (and possibly very warm) environments. For these cases, extrapolations on the basis of linear models would introduce uncertainty in expected ecosystem changes. PMID- 26942935 TI - Symbolic Numerical Magnitude Processing Is as Important to Arithmetic as Phonological Awareness Is to Reading. AB - In this article, we tested, using a 1-year longitudinal design, whether symbolic numerical magnitude processing or children's numerical representation of Arabic digits, is as important to arithmetic as phonological awareness is to reading. Children completed measures of symbolic comparison, phonological awareness, arithmetic, reading at the start of third grade and the latter two were retested at the start of fourth grade. Cross-sectional and longitudinal correlations indicated that symbolic comparison was a powerful domain-specific predictor of arithmetic and that phonological awareness was a unique predictor of reading. Crucially, the strength of these independent associations was not significantly different. This indicates that symbolic numerical magnitude processing is as important to arithmetic development as phonological awareness is to reading and suggests that symbolic numerical magnitude processing is a good candidate for screening children at risk for developing mathematical difficulties. PMID- 26942930 TI - Maternal BMI Associations with Maternal and Cord Blood Vitamin D Levels in a North American Subset of Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study Participants. AB - OBJECTIVE: Obesity in pregnancy may be associated with reduced placental transfer of 25-hydroxyvitamin D (25-OHD). The objective of this study was to examine associations between maternal BMI and maternal and cord blood levels of 25-OHD in full term neonates born to a single racial cohort residing at similar latitude. Secondary objectives were to examine associations between maternal glucose tolerance with maternal levels of 25-OHD and the relationship between cord blood 25-OHD levels and neonatal size. METHODS: This study was conducted among participants of the Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) Study meeting the following criteria: residing at latitudes 41-43 degrees , maternal white race, and gestational age 39-41 weeks. Healthy pregnant women underwent measures of height, weight, and a 75-g fasting oral glucose tolerance test (OGTT) at approximately 28 weeks gestation. Maternal and cord blood sera were analyzed for total 25-OHD by HPLC tandem mass spectrometry. Statistical analyses included ANOVA and linear regression models. RESULTS: Maternal and cord blood (N = 360) mean levels (sd) of 25-OHD were 37.2 (11.2) and 23.4 (9.2) ng/ml, respectively, and these levels were significantly different among the 3 field centers (ANOVA p< 0.001). Maternal serum 25-OHD was lower by 0.40 ng/ml for BMI higher by 1 kg/m2 (p<0.001) in an adjusted model. Maternal fasting plasma glucose, insulin sensitivity, and presence of GDM were not associated with maternal serum 25-OHD level when adjusted for maternal BMI. Cord blood 25-OHD was lower by 0.26 ng/ml for maternal BMI higher by 1 kg/m2 (p<0.004). With adjustment for maternal age, field center, birth season and maternal serum 25-OHD, the association of cord blood 25-OHD with maternal BMI was attenuated. Neither birth weight nor neonatal adiposity was significantly associated with cord blood 25-OHD levels. CONCLUSION: These results suggest that maternal levels of 25-OHD are associated with maternal BMI. The results also suggest that interpretation of neonatal 25-OHD levels may need to incorporate specific maternal factors in addition to season of birth and latitude. PMID- 26942936 TI - Artisanal Fisheries Research: A Need for Globalization? AB - Given limited funds for research and widespread degradation of ecosystems, environmental scientists should geographically target their studies where they will be most effective. However, in academic areas such as conservation and natural resource management there is often a mismatch between the geographic foci of research effort/funding and research needs. The former frequently being focused in the developed world while the latter is greater in the biodiverse countries of the Global South. Here, we adopt a bibliometric approach to test this hypothesis using research on artisanal fisheries. Such fisheries occur throughout the world, but are especially prominent in developing countries where they are important for supporting local livelihoods, food security and poverty alleviation. Moreover, most artisanal fisheries in the Global South are unregulated and unmonitored and are in urgent need of science-based management to ensure future sustainability. Our results indicate that, as predicted, global research networks and centres of knowledge production are predominantly located in developed countries, indicating a global mismatch between research needs and capacity. PMID- 26942937 TI - Correction: Plasticity-Driven Self-Organization under Topological Constraints Accounts for Non-random Features of Cortical Synaptic Wiring. PMID- 26942938 TI - In Vitro Evaluation of Doxorubicin Conjugates Based on Sugar Core Nonlinear Polymethacrylates toward Anticancer Drug Delivery. AB - V-shaped and star-shaped hydroxylamine-functionalized polymethacrylates designed as nanosized conjugates (<120 nm) with anticancer agent, namely, doxorubicin (DOX), were evaluated in vitro toward their potential usage as drug delivery systems in breast cancer (MCF-7) treatment. Statistical analysis of MTS assay results showed that the 4-arm conjugate (n(DOX) = 16) was the most effective polymeric system against MCF-7/W (wild type) and MCF-7/R (DOX resistant) cell lines. Apoptosis assay analysis showed that MCF-7/R cells cultured with nonlinear copolymers died due to necrosis and late apoptotis, whereas MCF-7/W cells were in early and late apoptosis. Among all tested conjugates, the most promising results with induction of apoptosis without inducing necrosis in both MCF-7 cell lines were obtained for conjugate based on 4-arm stars with low content of DOX. The cell cycle assay revealed that increase of MMA units in 4-arm copolymers induced MCF-7/R cell arrest in the SubG1 phase. In the same cell line, the corresponding conjugates triggered S and G2/M arrest. Gradual internalization of the chosen conjugate by MCF-7/R cells was monitored via fluorescence microscopy showing its main localization in the cytoplasm. PMID- 26942939 TI - Does CenteringPregnancy Group Prenatal Care Affect the Birth Experience of Underserved Women? A Mixed Methods Analysis. AB - We examined the birth experience of immigrant and minority women and how CenteringPregnancy (Centering), a model of group prenatal care and childbirth education, influenced that experience. In-depth interviews and surveys were conducted with a sample of racially diverse Centering participants about their birth experiences. Interview transcripts were analyzed thematically. Study participants (n = 34) were primarily low-income, Spanish-speaking immigrants with an average age of 29.7. On a scale from 1 (not satisfied) to 10 (very satisfied), women reported high satisfaction with birth (9.0) and care (9.3). In interviews, they expressed appreciation for the choice to labor with minimal medical intervention. Difficulties with communication arose from fragmented labor and delivery care by multiple providers. Centering provided women with pain coping skills, a familiar birth attendant, and knowledge to advocate for themselves. High reported satisfaction may obscure challenges to providing high quality childbirth care for marginalized women. Further study should examine the potential of Centering to positively impact underserved women's birth experiences. PMID- 26942940 TI - Carbamazepine and carbamazepine-10,11-epoxide clearance measurements during continuous venovenous hemofiltration in a massive overdose. AB - INTRODUCTION: Carbamazepine (CBZ) overdose can result in significant neurologic and cardiovascular toxicity, and is compounded by the presence of an active metabolite, carbamazepine-10,11-epoxide (CBZE). Existing publications describing continuous venovenous hemofiltration (CVVH) in CBZ overdose are limited in their ability to calculate accurate clearances. We report a case of CBZ overdose treated with CVVH with detailed measurement of CBZ, CBZE and their respective clearances calculated utilizing serial effluent measurements. This was coupled with serum level determinations comparing two analytical methodologies, time-of flight mass spectroscopy and an immunoassay. CASE DETAILS: A 41-year-old woman presented unresponsive after an overdose of CBZ. Initial CBZ serum levels were markedly elevated (57.8 MUg/mL) and continued to rise. Due to continued hemodynamic instability, extracorporeal removal was initiated using CVVH. MATERIALS AND METHODS: During the first 30 h of CVVH, interval serum samples and all ultrafiltrate bags were collected and analyzed. Serum and effluent levels of CBZ and CBZE were measured using an Agilent 6230 time-of-flight high-resolution mass spectrometer (TOF-MS). CBZ levels were also obtained utilizing the Microgenics CEDIA Carbamazepine Immunoassay (Thermo Fisher, Waltham, MA) for serum and effluent samples. Immunoassay analysis was performed using Siemens ADVIA 1800 instrument. RESULTS: The clearances achieved for CBZE (mean = 25.2, range 17.7-42.6 mL/min) exceeded that for CBZ (mean = 18.1, range 12.7-28.7 mL/min). CVVH removed a total of 1293 and 1261 mg of CBZ and CBZE, respectively. Serum levels of CBZ measured by immunoassay when compared with TOF-MS indicated cross reactivity of CBZE with the immunoassay. CONCLUSIONS: CVVH removed CBZE with higher clearances than CBZ. However, CVVH clearance rates for both CBZ and CBZE were lower than published clearances of CBZ and CBZE by intermittent hemodialysis. Our methodology allowed for a precise pharmacokinetic assessment of clearance based on total quantity of parent drug and active metabolite removed. Use of an immunoassay to determine CBZ serum levels reflects both parent compound and active metabolite due to cross-reactivity with CBZE. PMID- 26942941 TI - The Influence of Matrix Size on Statistical Properties of Co-Occurrence and Limiting Similarity Null Models. AB - Null models exploring species co-occurrence and trait-based limiting similarity are increasingly used to explore the influence of competition on community assembly; however, assessments of common models have not thoroughly explored the influence of variation in matrix size on error rates, in spite of the fact that studies have explored community matrices that vary considerably in size. To determine how smaller matrices, which are of greatest concern, perform statistically, we generated biologically realistic presence-absence matrices ranging in size from 3-50 species and sites, as well as associated trait matrices. We examined co-occurrence tests using the C-Score statistic and independent swap algorithm. For trait-based limiting similarity null models, we used the mean nearest neighbour trait distance (NN) and the standard deviation of nearest neighbour distances (SDNN) as test statistics, and considered two common randomization algorithms: abundance independent trait shuffling (AITS), and abundance weighted trait shuffling (AWTS). Matrices as small as three * three resulted in acceptable type I error rates (p < 0.05) for both the co-occurrence and trait-based limiting similarity null models when exclusive p-values were used. The commonly used inclusive p-value (<= or >=, as opposed to exclusive p values; < or >) was associated with increased type I error rates, particularly for matrices with fewer than eight species. Type I error rates increased for limiting similarity tests using the AWTS randomization scheme when community matrices contained more than 35 sites; a similar randomization used in null models of phylogenetic dispersion has previously been viewed as robust. Notwithstanding other potential deficiencies related to the use of small matrices to represent communities, the application of both classes of null model should be restricted to matrices with 10 or more species to avoid the possibility of type II errors. Additionally, researchers should restrict the use of the AWTS randomization to matrices with fewer than 35 sites to avoid type I errors when testing for trait-based limiting similarity. The AITS randomization scheme performed better in terms of type I error rates, and therefore may be more appropriate when considering systems for which traits are not clustered by abundance. PMID- 26942945 TI - Trends in Income Insecurity Among U.S. Children, 1984-2010. AB - Has income insecurity increased among U.S. children with the emergence of an employment-based safety net and the polarization of labor markets and family structure? We study the trend in insecurity from 1984-2010 by analyzing fluctuations in children's monthly family incomes in the Survey of Income and Program Participation. Going beyond earlier research on income volatility, we examine income insecurity more directly by analyzing income gains and losses separately and by relating them to changes in family composition and employment. The analysis provides new evidence of increased income insecurity by showing that large income losses increased more than large income gains for low-income children. Nearly one-half the increase in extreme income losses is related to trends in single parenthood and parental employment. Large income losses proliferated with the increased incidence of very low incomes (less than $150 per month). Extreme income losses and very low monthly incomes became more common particularly for U.S. children of nonworking single parents from the mid-1990s. PMID- 26942946 TI - Pregnancy after oocyte donation in 45, X Turner syndrome women, complicated by gestational diabetes and polyhydramnios. Case report and mini-review of literature. AB - Patients suffering from Turner syndrome (TS) demonstrate characteristic clinical features, with a short stature and gonadal dysgenesis causing infertility in most patients. Spontaneous pregnancies in women with TS are quite rare and pregnancy outcomes involving an increased risk of miscarriage and stillbirths are observed. In this case report, we present a 28 years old pregnant woman with the diagnosis of TS. Due to hypergonadotrophic hypogonadism, she was proposed an in vitro fertilization (IVF) program with an oocyte donor from unrelated anonymous women. After the second transfer, implantation occurred. In the 24th week of gestation, gestational diabetes class 1 was diagnosed. In the 31st week of gestation, polyhydramnios was diagnosed, although other parameters were reassuring. Considering the polyhydramnios, along with the diagnosis of Turner syndrome in the mother, we decided to perform an elective cesarean section. Subsequently, a healthy term male was born. For most women with the diagnosis of TS, the only way to become pregnant is through oocyte donation. The aim of this work was to characterize the course of pregnancy in TS patient and review literature addressing this issue. PMID- 26942995 TI - Retrospective Evaluation of Children with Congenital Pulmonary Airway Malformation: A Single Center Experience of 20 Years. AB - OBJECTIVES: Congenital pulmonary airway malformation (CPAM) is an uncommon congenital abnormality of the lungs that generally presents during prenatal period or early childhood. In this study, we aimed to evaluate clinical and pathologic findings of the children with CPAMs who were referred to our center between 1992 and 2011. MATERIAL AND METHODS: We reviewed 19 children with CPAM, who were diagnosed and treated at the Izmir Dr. Behcet Uz Children's Hospital between 1992 and 2011. All of them are alive and have been still followed up by our center. RESULTS: The study population consisted of 9 boys (47.4%) and 10 girls (52.6%) with a mean age of 3.26 (1 month - 13 years). Most newborns had respiratory distress, while recurrent pulmonary infections were detected in older children. Surgical treatment was performed on patients with subtypes I (n = 4; 21.1%), II (n = 8; 42.1%), III (n = 5; 26.3%), and IV (n = 2; 10.5%). In 13 cases (63.4%), lesions were located in the right lung and in almost all cases lesions were confined to one lobe. A one-month- old child with type I CPAM had multiple lesions involving two lobes and in only a newborn with type II CPAM, lesions were located bilaterally. There was no type 0 cases in this series. All cases were treated with lobectomy without any complication. CONCLUSION: In the present study, a realistic comprehensive picture of CPAM in a central children's hospital has been provided. In addition, we want to emphasize that complications and unnecessary medical treatment could be reduced with early surgery. PMID- 26942996 TI - Beliefs about human agency influence the neural processing of gaze during joint attention. AB - The current study measured adults' P350 and N170 ERPs while they interacted with a character in a virtual reality paradigm. Some participants believed the character was controlled by a human ("avatar" condition, n = 19); others believed it was controlled by a computer program ("agent" condition, n = 19). In each trial, participants initiated joint attention in order to direct the character's gaze toward a target. In 50% of trials, the character gazed toward the target (congruent responses), and in 50% of trials the character gazed to a different location (incongruent response). In the avatar condition, the character's incongruent gaze responses generated significantly larger P350 peaks at centro parietal sites than congruent gaze responses. In the agent condition, the P350 effect was strikingly absent. Left occipitotemporal N170 responses were significantly smaller in the agent condition compared to the avatar condition for both congruent and incongruent gaze shifts. These data suggest that beliefs about human agency may recruit mechanisms that discriminate the social outcome of a gaze shift after approximately 350 ms, and that these mechanisms may modulate the early perceptual processing of gaze. These findings also suggest that the ecologically valid measurement of social cognition may depend upon paradigms that simulate genuine social interactions. PMID- 26942997 TI - Oral bioavailability of curcumin: problems and advancements. AB - Curcumin is a natural compound of Curcuma longa L. and has shown many pharmacological activities such as anti-inflammatory, anti-oxidant in both preclinical and clinical studies. Moreover, curcumin has hepatoprotective, neuroprotective activities and protects against myocardial infarction. Particularly, curcumin has also demonstrated favorite anticancer efficacy. But limiting factors such as its extremely low oral bioavailability hampers its application as therapeutic agent. Therefore, many technologies have been developed and applied to overcome this limitation. This review described the main physicochemical properties of curcumin and summarized the recent studies in the design and development of oral delivery systems for curcumin to enhance the solubility and oral bioavailability, including liposomes, nanoparticles and polymeric micelles, phospholipid complexes, and microemulsions. PMID- 26942998 TI - FRET Characterization of Complex Conformational Changes in a Large 16S Ribosomal RNA Fragment Site-Specifically Labeled Using Unnatural Base Pairs. AB - Ribosome assembly has been studied intensively using Forster resonance energy transfer (FRET) with fluorophore-labeled fragments of RNA produced by chemical synthesis. However, these studies are limited by the size of the accessible RNA fragments. We have developed a replicable unnatural base pair (UBP) formed between (d)5SICS and (d)MMO2 or (d)NaM, which efficiently directs the transcription of RNA containing unnatural nucleotides. We now report the synthesis and evaluation of several of the corresponding ribotriphosphates bearing linkers that enable the chemoselective attachment of different functionalities. We found that the RNA polymerase from T7 bacteriophage does not incorporate NaM derivatives but does efficiently incorporate 5SICS(CO), whose linker enables functional group conjugation via Click chemistry, and when combined with the previously identified MMO2(A), whose amine side chains permits conjugation via NHS coupling chemistry, enables site-specific double labeling of transcribed RNA. To study ribosome assembly, we transcribed RNA corresponding to a 243-nt fragment of the central domain of Thermus thermophilus 16S rRNA containing 5SICS(CO) and MMO2(A) at defined locations and then site-specifically attached the fluorophores Cy3 and Cy5. FRET was characterized using single molecule total internal reflection fluorescence (smTIRF) microscopy in the presence of various combinations of added ribosomal proteins. We demonstrate that each of the fragment's two three-helix junctions exist in open and closed states, with the latter favored by sequential protein binding. These results elucidate early and previously uncharacterized folding events underlying ribosome assembly and demonstrate the applicability of UBPs for biochemical, structural, and functional studies of RNAs. PMID- 26942999 TI - Atypical BCR-ABL1 fusion transcripts in adult B-acute lymphoblastic leukemia, including a novel fusion transcript-e8a1. PMID- 26943000 TI - A catalogue of treatment and technologies for malignant pleural mesothelioma. AB - Malignant pleural mesothelioma is an aggressive fatal malignancy with a prognosis that has not significantly improved in the last decades. This review summarizes the current state of treatment and the various attempts that are made to improve overall survival for patients with malignant pleural mesothelioma. It also discusses technologies and protocols to test new and hopefully more effective compounds in a more individualized manner. These developments are expected to improve the prognosis for this group of patients. PMID- 26943001 TI - Synthesis of higher alcohols over highly dispersed Cu-Fe based catalysts derived from layered double hydroxides. AB - Highly dispersed Cu-Fe based catalysts with Fe/Cu molar ratios ranging from 0.2 to 1 were prepared via thermal decomposition of layered double hydroxides (LDHs) precursors and tested for higher alcohol synthesis (HAS) via CO hydrogenation. The catalysts were characterized using different techniques such as XRD, TEM, XPS, and H2-TPR. It was demonstrated that the Cu and Fe ions were highly dispersed in the brucite-like layers of the LDHs. With increased Fe/Cu atomic ratio, the tetrahedrally coordinated Cu ion content, Cu reduction temperatures, and the spacing of layers initially increase until the Fe/Cu ratio reaches 0.5 and then decrease. In addition to the catalytic evaluation for CO hydrogenation and catalyst characterization, the relationships between the physical-chemical properties of the catalysts and their catalytic performances were also investigated. It was also found that the alcohols/hydrocarbons ratios correlate linearly with the tetrahedrally coordinated Cu ion content. Moreover, higher reduction temperatures of Cu species as well as larger spacing between the layers in the catalyst are favorable for the synthesis of alcohols. The incorporation of a suitable amount of Fe is beneficial for the production of higher alcohols, with the best catalytic performance (alcohol selectivity of 20.77% and C2+ alcohol selectivity of 48.06%) obtained from a Fe/Cu atomic ratio of 0.5. PMID- 26943002 TI - Bimodal porous silica microspheres decorated with polydopamine nano-particles for the adsorption of methylene blue in fixed-bed columns. AB - Bimodal meso/macro-porous silica microspheres (MSM) were synthesized by a modified sol-emulsion-gel method and then the surface was coated with polydopamine (PDA) nano-particles of 39nm in size. Focusing on the encouraging properties of the synthesized adsorbent, such as high specific surface area (612.3m(2)g(-1), because of mesopores), fast mass transfer (0.9-2.67*10(-3)mLmin( 1)mg, because of macropores), and abundant "adhesive" functional groups of PDA, it was used for the removal of methylene blue (MB) from aqueous solution in a fixed-bed column. The effect of different parameters such as pH, initial concentration, and flow rate was studied. The results revealed that an appropriate sorption condition is an alkaline solution of MB (e.g., pH 10) at low flow rate (less than 5mLmin(-1)). Furthermore, the compatibility of the experimental data with mathematical models such as Thomas and Adams-Bohart was investigated. Both of the models showed a good agreement with the experimental data (R(2)=0.9954-0.9994), and could be applied for the prediction of the column properties and breakthrough curves. Regeneration of the column was performed by using HCl solution with a concentration of 0.1M as an eluent. PMID- 26943003 TI - Vasovagal-related stress immediately before FDG injection may increase bilateral adrenal FDG uptake. AB - OBJECTIVE: To evaluate the relationship between vasovagal-related stress on positron emission tomography (PET)/CT and adrenal fludeoxyglucose (FDG) uptake. METHODS: We reviewed the medical records of 1358 consecutive patients who underwent FDG PET/CT examinations and selected those who presented with vasovagal related symptoms and acute hypotension immediately before FDG injection (vasovagal reflex group). Patients who underwent FDG PET/CT examinations on the same days as the vasovagal reflex group without new complaints or any adrenal lesion were used as controls. We evaluated adrenal FDG uptake visually and by means of adrenal maximum standardized uptake value (SUV(max)) and adrenal/liver (A/L) SUV(max) ratio. Next, we reviewed the FDG PET/CT images of the same 1358 patients and selected the cases presenting with bilateral avid FDG uptake. RESULTS: 4 patients were included in the vasovagal reflex group, and all of them showed bilateral avid adrenal FDG uptake visually, while 19 patients in the control group did not. The mean adrenal SUV(max) and the mean A/L SUV(max) ratio were significantly higher in the vasovagal reflex group than in the control group (p < 0.001). 10 (0.74%) patients, including 4 patients from the vasovagal reflex group, showed bilateral avid FDG uptake with normal adrenal configuration on CT. CONCLUSION: Vasovagal-related stress immediately before FDG injection may increase bilateral adrenal FDG uptake. ADVANCES IN KNOWLEDGE: Vasovagal-related stress may be included in the differential diagnosis of the cause of bilateral avid adrenal FDG uptake. PMID- 26943004 TI - An introduction to the Ruthven Impairment Assessment (RIA): A stability study. AB - The Ruthven Impairment Assessment (RIA) is introduced as a new neurocognitive test for the evaluation of complex attentional, reasoning, and working-memory abilities. It contains 5 subtests and is administered by computer within 15 min. The subtests include measures of simple and complex attention, working memory, sequential reasoning, and problem-solving abilities. A clock is presented on the computer screen and the participant is instructed to use the space bar or a mouse to respond to the test items. Scores include reaction time and accuracy measures. The present study evaluates the stability of the RIA in healthy, normal individuals by repeating the procedure 3 times and comparing performance with analyses of variance (ANOVAs). The ANOVA results with 1 exception were nonsignificant, indicating that the RIA scores are stable in normal individuals and do not fluctuate significantly across testing. PMID- 26943005 TI - Free-Radical-Induced Grafting from Plasma Polymer Surfaces. AB - With the advances in science and engineering in the second part of the 20th century, emerging plasma-based technologies continuously find increasing applications in the domain of polymer chemistry, among others. Plasma technologies are predominantly used in two different ways: for the treatment of polymer substrates by a reactive or inert gas aiming at a specific surface functionalization or for the synthesis of a plasma polymer with a unique set of properties from an organic or mixed organic-inorganic precursor. Plasma polymer films (PPFs), often deposited by plasma-enhanced chemical vapor deposition (PECVD), currently attract a great deal of attention. Such films are widely used in various fields for the coating of solid substrates, including membranes, semiconductors, metals, textiles, and polymers, because of a combination of interesting properties such as excellent adhesion, highly cross-linked structures, and the possibility of tuning properties by simply varying the precursor and/or the synthesis parameters. Among the many appealing features of plasma-synthesized and -treated polymers, a highly reactive surface, rich in free radicals arising from deposition/treatment specifics, offers a particular advantage. When handled carefully, these reactive free radicals open doors to the controllable surface functionalization of materials without affecting their bulk properties. The goal of this review is to illustrate the increasing application of plasma-based technologies for tuning the surface properties of polymers, principally through free-radical chemistry. PMID- 26943006 TI - Hybrid Co3O4/SnO2 Core-Shell Nanospheres as Real-Time Rapid-Response Sensors for Ammonia Gas. AB - Novel hybrid Co3O4/SnO2 core-shell nanospheres have been effectively realized by a one-step hydrothermal, template-free preparation method. Our strategy involves a simple fabrication scheme that entails the coating of natural cross-link agents followed by electrostatic interaction between the positive charges of Sn and Co ions and the negative charge of glutamic acid. The core-shell architecture enables novel flexibility of gas sensor surfaces compared to commonly used bulk materials. The highly efficient charge transfer and unique structure are key to ensuring the availability of high response and rapid-response speed. It demonstrates how hybrid core-shell nanospheres can be used as an advance function material to fabricate electrical sensing devices that may be useful as gas sensors. PMID- 26943007 TI - Alcohol Drinking Among Kosovar Adolescents: An Examination of Gender-Specific Sociodemographic, Sport, and Familial Factors Associated With Harmful Drinking. AB - BACKGROUND: Adolescent alcohol consumption is a significant public-health problem, although there is a lack of studies investigating this issue in Kosovo. OBJECTIVES: The aim of this investigation was to examine the prevalence of alcohol drinking, and the factors associated with harmful drinking (HD) in Kosovar 17-18 years old adolescents. METHODS: The sample comprised 636 girls and 366 boys (17-18 years old) from Pristina, Kosovo. The independent variables included sociodemographic factors, variables examining familial-monitoring and conflict (familial-variables), and sport-factors. Alcohol-drinking (dependent variable) was measured by means of the alcohol use disorders identification test scale. RESULTS: 39% of the girls and 43% of the boys reported HD (odds ratio (OR) = 1.17; 95% confidence interval = 0.90-1.55). A higher likelihood of HD is found for those girls whose mothers have an advanced education (OR = 1.59), who reported a higher level of conflict with their parents (OR = 1.95), whose parents are frequently absent from home (OR = 1.93), and who reported lower religiosity (OR = 0.90). HD is more frequent among boys who have participated longer in sports (OR = 1.49), whose fathers have an advanced education (OR = 1.80), and who reported higher level of familial conflict (OR = 2.87). CONCLUSIONS/IMPORTANCE: The prevalence of HD is high. Knowing the problems related to alcohol drinking in girls (violence, trafficking, etc.), public-health authorities should urgently develop a specific preventive programme (SPP) to combat the misuse of alcohol. In preparing SPP, special attention should be paid to the varying influences of the studied factors on HD in boys and girls. PMID- 26943008 TI - Socio-economic divergence in public opinions about preventive obesity regulations: Is the purpose to 'make some things cheaper, more affordable' or to 'help them get over their own ignorance'? AB - The potential for regulatory measures to address escalating rates of obesity is widely acknowledged in public health circles. Many advocates support regulations for their potential to reduce health inequalities, in light of the well documented social gradient in obesity. This paper examines how different social groups understand the role of regulations and other public health interventions in addressing obesity. Drawing upon focus group data from a metropolitan city in southern Australia, we argue that implementing obesity regulations without attention to the ways in which disadvantaged communities problematise obesity may lead to further stigmatisation of this key target population. Tuana's work on the politics of ignorance, and broader literature on classed asymmetries of power, provides a theoretical framework to demonstrate how middle class understandings of obesity align with dominant 'obesity epidemic' discourses. These position obese people as lacking knowledge; underpinning support for food labelling and mandatory nutrition education for welfare recipients as well as food taxes. In contrast, disadvantaged groups emphasised the potential for a different set of interventions to improve material circumstances that constrain their ability to act upon existing health promotion messages, while also describing priorities of everyday living that are not oriented to improving health status. Findings demonstrate how ignorance is produced as an explanation for obesity, widely replicated in political settings and mainstream public health agendas. This politics of ignorance and its logical reparation serve to reproduce power relations in which particular groups are constructed as lacking capacity to act on knowledge, whilst maintaining others in privileged positions of knowing. PMID- 26943010 TI - An education gradient in health, a health gradient in education, or a confounded gradient in both? AB - There is a positive gradient associating educational attainment with health, yet the explanation for this gradient is not clear. Does higher education improve health (causation)? Do the healthy become highly educated (selection)? Or do good health and high educational attainment both result from advantages established early in the life course (confounding)? This study evaluates these competing explanations by tracking changes in educational attainment and Self-rated Health (SRH) from age 15 to age 31 in the National Longitudinal Study of Youth, 1997 cohort. Ordinal logistic regression confirms that high-SRH adolescents are more likely to become highly educated. This is partly because adolescent SRH is associated with early advantages including adolescents' academic performance, college plans, and family background (confounding); however, net of these confounders adolescent SRH still predicts adult educational attainment (selection). Fixed-effects longitudinal regression shows that educational attainment has little causal effect on SRH at age 31. Completion of a high school diploma or associate's degree has no effect on SRH, while completion of a bachelor's or graduate degree have effects that, though significant, are quite small (less than 0.1 points on a 5-point scale). While it is possible that educational attainment would have greater effect on health at older ages, at age 31 what we see is a health gradient in education, shaped primarily by selection and confounding rather than by a causal effect of education on health. PMID- 26943009 TI - Gender balance and its impact on male and female smoking rates in Chinese cities. AB - OBJECTIVE: Although gender differences in smoking have received much attention, few studies have explored the importance of contextual effects on male and female smoking rates. The aim of this study is to examine the association between variations in city-level sex ratios and gender differences in smoking in China. METHODS: Participants included 16,866 urban residents, who were identified through multi-stage sampling conducted in 21 Chinese cities. RESULTS: The study found that, independent of personal characteristics, cities with more males had higher male smoking rates and lower female rates. CONCLUSIONS: Our research underscores the importance of city-level contextual effects in understanding gender differences in smoking in China. PMID- 26943011 TI - A question of balance: Explaining differences between parental and grandparental perspectives on preschoolers' feeding and physical activity. AB - RATIONALE: Although one quarter of US and UK families rely on grandparents as the main providers of informal childcare, grandparental perspectives on the feeding and physical activity of young children remain understudied. OBJECTIVE: The study's aim was to elucidate parents' and grandparents' perspectives on young children's feeding and physical activity, and identify how they negotiate potential differences between these perspectives. METHODS: We interviewed 22 parents and 27 grandparents from 16 families of children aged 3-5 years in the Pacific Northwest, US. Using familial homeostasis as a novel theoretical framework, the interviews were analyzed to assess differences between parental and grandparental perspectives on feeding and physical activity. RESULTS: The analysis yielded six thematic categories: (1) disagreements about feeding stem from parents' and grandparents' differing definitions of healthy feeding; (2) differences between parents' and grandparents' feeding practices reflect differences in perceived caretaking roles; (3) parents and grandparents negotiate differences in feeding practices through grandparental compliance and parental compromise; (4) differences in preschoolers' physical activity are influenced by parents' and grandparents' own access to and engagement in physical activity; (5) parents and grandparents express few disagreements about preschoolers' screen time; (6) parents and grandparents rarely discuss preschoolers' physical activity. The findings suggest that parental and grandparental decision-making about feeding and exercise is informed by ideas of what constitutes familial balance and a balanced lifestyle for a preschool aged child, rather than by the child's weight status. CONCLUSIONS: Parents and grandparents appear to engage in practices designed to preserve familial homeostasis, which may provide a compelling explanation for the persistent difficulties in implementing family based childhood obesity interventions. PMID- 26943012 TI - Educational mismatch and health status among foreign-born workers in Sweden. AB - Foreign-born workers have been shown to experience poorer working conditions than native-born workers. Yet relationships between health and educational mismatch have been largely overlooked among foreign-born workers. This study uses objective and self-reported measures of educational mismatch to compare the prevalence of educational mismatch among native (n = 2359) and foreign-born (n = 1789) workers in Sweden and to examine associations between educational mismatch and poor self-rated health. Findings from weighted multivariate logistic regression which controlled for social position and individual-level demographic characteristics suggested that over-educated foreign-born workers had greater odds ratios for poor-self rated health compared to native-born matched workers. This association was particularly evident among men (OR = 2.14, 95% CI: 1.04 4.39) and women (OR = 2.13, 95% CI: 1.12-4.03) from countries outside of Western Europe, North America, and Australia/New Zealand. Associations between under education and poor-self rated health were also found among women from countries outside of Western Europe, North America, and Australia/New Zealand (OR = 2.02, 95% CI: 1.27-3.18). These findings suggest that educational mismatch may be an important work-related social determinant of health among foreign-born workers. Future studies are needed to examine the effects of long-term versus short-term states of educational mismatch on health and to study relationships over time. PMID- 26943013 TI - Deciding to tell: Qualitative configurational analysis of decisions to disclose experience of intimate partner violence in antenatal care. AB - RATIONALE: Intimate partner violence (IPV) is a significant global public health risk causing premature death and morbidity that largely remains hidden. Understanding decisions about whether or not to disclose abuse when asked about it in health settings is important to ensuring that those experiencing violence are provided with access to services to support their safety and wellbeing. OBJECTIVE: This study tested a model for women's decisions to disclose IPV in response to routine inquiry as part of antenatal assessment. METHODS: Qualitative configurational analysis, suited to the study of causal pathways in complex social phenomena, was used to analyse interviews with 32 women who had experienced IPV in the past 12 months and who elected, when asked, to either disclose this to the midwife (n = 24) or not to do so (n = 8). FINDINGS: Multiple pathways to disclosure were identified. While no single factor was necessary or sufficient for a decision to disclose, direct asking and care, defined as showing interest and a non-judgemental attitude, were found to be key conditions. The absence of care was also central to decisions not to disclose, as were perceptions of relevance of the abuse at the time of assessment. CONCLUSION: Confirming key elements of the original model, these findings highlight the importance of being asked about abuse in women's decisions to disclose, as well as the relational nature of this process. Trauma-informed practices for identifying and responding to intimate partner violence are needed. PMID- 26943014 TI - Biofidelity evaluation of WorldSID and ES-2re under side impact conditions with and without airbag. AB - This study evaluated the biofidelity of the WorldSID and the ES-2re under whole body side impact conditions with and without a side airbag using the biomechanical cadaveric response data generated from 4.3m/s whole-body side impact tests. Impact forces, spinal kinematics, and chest deflections were considered in the biofidelity evaluation. Average responses and response corridors of PMHS were created using a time-alignment technique to reduce variability of the PMHS responses while maintaining the sum of the time shifts to be zero for each response. Biofidelity of the two dummies was compared using a correlation and analysis (CORA) method. The WorldSID demonstrated better biofidelity than the ES-2re in terms of CORA ratings in the conditions with airbag (0.53 vs. 0.46) and without an airbag (0.57 vs. 0.49). Lastly, the kinematic analysis of the two dummies indicated an overly compliant shoulder response of the WorldSID and excessive forward rotation of the ES-2re relative to the PMHS. PMID- 26943015 TI - Corrigendum: Targeting miR-155 to Treat Experimental Scleroderma. PMID- 26943016 TI - High-Sensitivity and High-Efficiency Detection of DNA Hydroxymethylation in Genomic DNA by Multiplexing Electrochemical Biosensing. AB - DNA hydroxymethylation (5-hmC) is a kind of new epigenetic modification, which plays key roles in DNA demethylation, genomic reprogramming, and the gene expression in mammals. For further exploring the functions of 5-hmC, it is necessary to develop sensitive and selective methods for detecting 5-hmC. Herein, we developed a novel multiplexing electrochemical (MEC) biosensor for 5-hmC detection based on the glycosylation modification of 5-hmC and enzymatic signal amplification. The 5-hmC was first glycosylated by T4 beta-glucosyltransferase and then oxidated by sodium periodate. The resulting glucosyl-modified 5-hmC (5 ghmC) was incubated with ARP-biotin and was bound to avidin-HRP. The 5-hmC can be detected at the subnanogram level. Finally, we performed 5-hmC detection for mouse tissue samples and cancer cell lines. The limit of detection of the MEC biosensor is 20 times lower than that of commercial kits based on optical meaurement. Also, the biosensor presented high detection specificity because the chemical reaction for 5-hmC modification can not happen at any other unhydroxymethylated nucleic acid bases. Importantly, benefited by its multiplexing capacity, the developed MEC biosensor showed excellent high efficiency, which was time-saving and cost less. PMID- 26943018 TI - Concentration-dependent conformational changes in GQ-forming ODNs. AB - Guanine-rich oligodeoxyribonucleotides (ODNs) can form non-canonical DNA structures known as G-quadruplexes, which are four stranded structures stabilized by sodium or potassium cations. The topologies of G-quadruplexes are highly polymorphic. H-Tel, an ODN with four consecutive repeats of the human telomeric sequence, [d(AGGGTTAGGGTTAGGGTTAGGG)], can assume different monomolecular G quadruplex topologies depending on the type of cation present in solution. Our previous work demonstrated that at high concentrations of H-Tel, the monomolecular G-quadruplexes formed by H-Tel self-associate to form higher order structures. The aggregates display circular dichroism (CD) spectra similar to that of an all-parallel structure. In the current work, we present data for 19 ODNs for which we have modified the loop sequences of H-Tel in order to learn if concentration-dependent self-aggregation is a general phenomenon and to probe the contribution of the loops to the self-association of these ODNs. Our studies use CD spectroscopy and spectroscopically monitored heat denaturation. Our data show that the concentration-dependent formation of parallel G-quadruplex aggregates is a general phenomenon. We propose that one of the factors that might affect this process is the association of partially unfolded antiparallel structures. PMID- 26943017 TI - Modulation of Hematopoietic Chemokine Effects In Vitro and In Vivo by DPP-4/CD26. AB - Dipeptidyl peptidase 4 (DPP4)/CD26 truncates certain proteins, and this posttranslational modification can influence their activity. Truncated (T) colony stimulating factors (CSFs) are decreased in potency for stimulating proliferation of hematopoietic progenitor cells (HPCs). T-CXCL12, a modified chemokine, is inactive as an HPC chemotactic, survival, and enhancing factor for replating or ex-vivo expansion of HPCs. Moreover, T-CSFs and T-CXCL12 specifically downmodulates the positively acting effects of their own full-length molecule. Other chemokines have DPP4 truncation sites. In the present study, we evaluated effects of DPP4 inhibition (by Diprotin A) or gene deletion of HPC on chemokine inhibition of multicytokine-stimulated HPC, and on chemokine-enhancing effects on single CSF-stimulated HPC proliferation, as well as effects of DPP4 treatment of a number of chemokines. Myelosuppressive effects of chemokines with, but not without, a DPP4 truncation site were greatly enhanced in inhibitory potency by pretreating target bone marrow (BM) cells with Diprotin A, or by assaying their activity on dpp4/cd26(-/-) BM cells. DPP4 treatment of myelosuppressive chemokines containing a DPP4 truncation site produced a nonmyelosuppressive molecule, but one which had the capacity to block suppression by that unmodified chemokine both in vitro and in vivo. Additionally, DPP4 treatment ablated the single cytokine-stimulated HPC-enhancing activity of CCL3/MIP-1alpha and CCL4/MIP 1beta, and blocked the enhancing activity of each unmodified molecule, in vitro and in vivo. These results highlight the functional posttranslational modulating effects of DPP4 on chemokine activities, and information offering additional biological insight into chemokine regulation of hematopoiesis. PMID- 26943019 TI - Complete reaction mechanisms of mercury oxidation on halogenated activated carbon. AB - The reaction mechanisms of mercury (Hg) adsorption and oxidation on halogenated activated carbon (AC) have been completely studied for the first time using density functional theory (DFT) method. Two different halogenated AC models, namely X-AC and X-AC-X (X=Cl, Br, I), were adopted. The results revealed that HgX is found to be stable-state on the AC edge since its further desorption from the AC as HgX, or further oxidation to HgX2, are energetically unfavorable. Remarkably, the halide type does not significantly affect the Hg adsorption energy but it strongly affects the activation energy barrier of HgX formation, which obviously increases in the order HgIBr-AC>Cl-AC. Thus, the study of the complete reaction mechanism is essential because the adsorption energy can not be used as a guideline for the rational material design in the halide impregnated AC systems. The activation energy is an important descriptor for the predictions of sorbent reactivity to the Hg oxidation process. PMID- 26943020 TI - Pyrrolopyrimidine Derivatives as Novel Inhibitors of Multidrug Resistance Associated Protein 1 (MRP1, ABCC1). AB - Five series of pyrrolo[3,2-d]pyrimidines were synthesized and evaluated with respect to potency and selectivity toward multidrug resistance-associated protein 1 (MRP1, ABCC1). This transport protein is a major target to overcome multidrug resistance in cancer patients. We investigated differently substituted pyrrolopyrimidines using the doxorubicin selected and MRP1 overexpressing small cell lung cancer cell line H69 AR in a calcein AM and daunorubicin cell accumulation assay. New compounds with high potency and selectivity were identified. Piperazine residues at position 4 bearing large phenylalkyl side chains proved to be beneficial for MRP1 inhibition. Its replacement by an amino group led to decreased activity. Aliphatic and aliphatic-aromatic variations at position 5 and 6 revealed compounds with IC50 values in high nanomolar range. All investigated compounds had low affinity toward P-glycoprotein (P-gp, ABCB1). Pyrrolopyrimidines with small substituents showed moderate inhibition against breast cancer resistance protein (BCRP, ABCG2). PMID- 26943021 TI - Piriformospora indica requires kaurene synthase activity for successful plant colonization. AB - Ent-kaurene (KS) synthases and ent-kaurene-like (KSL) synthases are involved in the biosynthesis of phytoalexins and/or gibberellins which play a role in plant immunity and development. The relationship between expression of five synthase genes (HvKSL1, HvKS2, HvKS4, HvKS5, HvKSL4) and plant colonization by the endophytic fungus Piriformospora indica was assessed in barley (Hordeum vulgare). The KS gene family is differently up-regulated at 1, 3 and 7 day after P. indica inoculation. By comparison, the HvKSL4 gene expression pattern is more significantly affected by UV irradiation and P. indica colonization. The characterizations of two silencing lines (HvKSL1-RNAi, HvKSL4-RNAi) also were analyzed. HvKSL1-RNAi and HvKSL4-RNAi lines in the first generation lead to less dark green leaves and slower plant development. Further, reduced spikelet fertility in progenies of RNAi plants heterozygous for HvKSL1 were observed, but not for HvKSL4. T2 generation of HvKSL1-RNAi line showed semi-dwarf phenotype while the wild type phenotype could be restored by applying GA3. Silencing of HvKSL4 and HvKSL1 resulted in reduced colonization by P. indica especially in the HvKSL1-RNAi line. These results probably suggest the presence of two ent-KS synthase in barley, one (HvKSL1) that participates in the biosynthesis of GAs and another (HvKSL4) that is involved in the biosynthesis of phytoalexins. PMID- 26943022 TI - Correction to "A Dual-Ion Battery Cathode via Oxidative Insertion of Anions in a Metal-Organic Framework". PMID- 26943023 TI - Establishment of safety paradigms and trust in emerging adult relationships. AB - There is a critical need to understand the interplay between relationship trust and public health outcomes. The purpose of this study was to develop an understanding of emerging adult women's processes of establishing trust in sexual relationships. Twenty-five women aged 18-24 years participated in semi-structured interviews. Throughout the interviews, women compared and contrasted experiences in which they felt comfortable engaging in sexual intercourse with a partner versus times in which they did not feel comfortable. Analysis was based on a critical qualitative research orientation. When asked to speak to instances when they felt comfortable having sex, most women spoke about relationship trust. Many participants conceptualised trust based on past experiences with bad relationships or sexual violence. Based on their previous experiences of feeling unsafe or undervalued, emotional and physical security became prioritised in relationship development. Trust was developed through friendship, communication over time, and through shared life experiences. This research is among the first to qualitatively investigate trust formation and other impersonal dynamics related to sexual health decision-making. Insights from this study should be translated into future action by public health practitioners to promote healthy sexual relationships and communication about sexual health topics as a form of trust building. PMID- 26943024 TI - New-Structure-Type Fe-Based Superconductors: CaAFe4As4 (A = K, Rb, Cs) and SrAFe4As4 (A = Rb, Cs). AB - Fe-based superconductors have attracted research interest because of their rich structural variety, which is due to their layered crystal structures. Here we report the new-structure-type Fe-based superconductors CaAFe4As4 (A = K, Rb, Cs) and SrAFe4As4 (A = Rb, Cs), which can be regarded as hybrid phases between AeFe2As2 (Ae = Ca, Sr) and AFe2As2. Unlike solid solutions such as (Ba(1 x)K(x))Fe2As2 and (Sr(1-x)Na(x))Fe2As2, Ae and A do not occupy crystallographically equivalent sites because of the large differences between their ionic radii. Rather, the Ae and A layers are inserted alternately between the Fe2As2 layers in the c-axis direction in AeAFe4As4 (AeA1144). The ordering of the Ae and A layers causes a change in the space group from I4/mmm to P4/mmm, which is clearly apparent in powder X-ray diffraction patterns. AeA1144 is the first known structure of this type among not only Fe-based superconductors but also other materials. AeA1144 is formed as a line compound, and therefore, each AeA1144 has its own superconducting transition temperature of approximately 31-36 K. PMID- 26943025 TI - Cloning of the growth hormone receptor and its muscle-specific mRNA expression in black Muscovy duck (Cairina moschata). AB - The cDNA sequence of the growth hormone receptor (GHR) from the black Muscovy duck was obtained and compared to the mRNA expression of growth hormone (GH) in the breast and leg muscles during 2-13 weeks of age using quantitative RT-PCR. The cDNA sequence of the Muscovy duck GHR gene is 1903 bp in length, with an 1830 bp coding region that encodes 609 amino acids. It exhibits > 92.9% homology with the poultry GHR cDNA and amino acid sequences. Overall, GHR mRNA expression was the highest at 2 weeks and the lowest at 13 weeks of age, exhibiting different profiles in different muscles. In the breast muscles, the GHR mRNA level declined sharply at 2-4 weeks, maintained at a plateau at 4-10 weeks and decreased slightly at 10-13 weeks. In the leg muscles, a gradual and slow decrease was observed during the whole period of 2-13 weeks. Robust extra-pituitary GH mRNA expression was detected in the muscles and the expression profile was highly correlated with that of GHR mRNA, in contrast to the inverse correlation between the pituitary GH and tissue GHR levels shown previously. These data suggest that the locally synthesised GH in the muscles, rather than the pituitary GH, is more closely associated with GHR and may be more critical for the regulation of muscle growth and contribute to the tissue-specific effects of GH. PMID- 26943026 TI - Dependence of ultrasound echo decorrelation on local tissue temperature during ex vivo radiofrequency ablation. AB - This study investigates echo decorrelation imaging, an ultrasound method for thermal ablation monitoring. The effect of tissue temperature on the mapped echo decorrelation parameter was assessed in radiofrequency ablation experiments performed on ex vivo bovine liver tissue. Echo decorrelation maps were compared with corresponding tissue temperatures simulated using the finite element method. For both echo decorrelation imaging and integrated backscatter imaging, the mapped tissue parameters correlated significantly but weakly with local tissue temperature. Receiver operating characteristic (ROC) curves were used to assess the ability of echo decorrelation and integrated backscatter to predict tissue temperature greater than 40, 60, and 80 degrees C. Significantly higher area under the ROC curve (AUROC) values were obtained for prediction of tissue temperatures greater than 40, 60, and 80 degrees C using echo decorrelation imaging (AUROC = 0.871, 0.948 and 0.966) compared to integrated backscatter imaging (AUROC = 0.865, 0.877 and 0.832). PMID- 26943027 TI - Bioavailability of Fullerene under Environmentally Relevant Conditions: Effects of Humic Acid and Fetal Bovine Serum on Accumulation in Lipid Bilayers and Cellular Uptake. AB - Carbon fullerene (C60) has emerged at the forefront of nanoscale research and application due to its unique properties. As the production of this nanoparticle rapidly increases, it can be released into natural aquatic environments and can accumulate in biological systems. This research examined the effects of humic acid and fetal bovine serum (FBS), which are ubiquitous in aquatic environments and representative of blood plasma in living organisms, respectively, on bioavailability of fullerene. Bioavailability was investigated using in vitro methods for lipid membrane accumulation and cellular uptake studies. Humic acid and FBS significantly changed the characteristics of fullerene including its particle size and surface charge. The effects of humic acid on lipid accumulation of fullerene depended on the lipid head charge. FBS also significantly decreased the lipid accumulation when positively charged and zwitterionic head groups were present on the lipids, possibly due to the higher steric repulsion of the protein coated nanoparticles. In addition, both humic acid and FBS protein effectively lowered the amounts of fullerene taken up by Caco-2 cells, which are derived from a human colorectal adenocarcinoma and have similar functions to the small intestinal epithelium. Results of this study suggest that surface modification of fullerene by environmentally relevant matrices can significantly affect the biological transport, as well as the possible toxicity of this nanomaterial. PMID- 26943028 TI - Macranthoside B Induces Apoptosis and Autophagy Via Reactive Oxygen Species Accumulation in Human Ovarian Cancer A2780 Cells. AB - Macranthoside B (MB), a saponin compound in Lonicera macranthoides, can block cell proliferation and induce cell death in several types of cancer cells; however, the precise mechanisms by which MB exerts its anticancer effects remain poorly understood. MB blocked A2780 human ovarian carcinoma cell proliferation both dose- and time-dependently. MB induced apoptosis, with increased poly (ADP ribose) polymerase (PARP) and caspase-3/9 cleavage. MB also caused autophagy in A2780 cells, with light chain 3 (LC3)-II elevation. Inhibiting MB-induced autophagy with the autophagy inhibitor 3-methyladenine (3-MA) significantly decreased apoptosis, with a reduction of growth inhibition; inhibiting MB-induced apoptosis with the pan-caspase inhibitor Z-VAD-FMK did not decrease autophagy but elevated LC3-II levels, indicating that MB-induced autophagy is cytotoxic and may be upstream of apoptosis. Furthermore, MB increased intracellular reactive oxygen species (ROS) levels, with activated 5' adenosine monophosphate-activated protein kinase (AMPK), decreased mammalian target of rapamycin (mTOR) and P70S6 kinase phosphorylation, and increased PARP and caspase-3/9 cleavage, and LC3-II elevation; treatment with the ROS scavenger N-acetyl cysteine and the AMPK inhibitor Compound C diminished this effect. Therefore, the ROS/AMPK/mTOR pathway mediates the effect of MB on induction of apoptosis via autophagy in human ovarian carcinoma cells. PMID- 26943029 TI - Renal cell carcinoma alters endothelial receptor expression responsible for leukocyte adhesion. AB - Renal cell carcinoma (RCC) escapes immune recognition. To elaborate the escape strategy the influence of RCC cells on endothelial receptor expression and endothelial leukocyte adhesion was evaluated. Human umbilical vein endothelial cells (HUVEC) were co-cultured with the RCC cell line, Caki-1, with and without tumor necrosis factor (TNF)-alpha. Intercellular cell adhesion molecule-1 (ICAM 1), vascular cell adhesion molecule-1 (VCAM-1), endothelial (E)-selectin, standard and variants (V) of CD44 were then analysed in HUVEC, using flow cytometry and Western blot analysis. To determine which components are responsible for HUVEC-Caki-1 interaction causing receptor alteration, Caki-1 membrane fragments versus cell culture supernatant were applied to HUVECS. Adhesion of peripheral blood lymphocytes (PBL) and polymorphonuclear neutrophils (PMN) to endothelium was evaluated by co-culture adhesion assays. Relevance of endothelial receptor expression for adhesion to endothelium was determined by receptor blockage. Co-culture of RCC and HUVECs resulted in a significant increase in endothelial ICAM-1, VCAM-1, E-selectin, CD44 V3 and V7 expression. Previous stimulation of HUVECs with TNF-alpha and co-cultivation with Caki-1 resulted in further elevation of endothelial CD44 V3 and V7 expression, whereas ICAM-1, VCAM-1 and E-selectin expression were significantly diminished. Since Caki-1 membrane fragments also caused these alterations, but cell culture supernatant did not, cell-cell contact may be responsible for this process. Blocking ICAM-1, VCAM-1, E-selectin or CD44 with respective antibodies led to a significant decrease in PBL and PMN adhesion to endothelium. Thus, exposing HUVEC to Caki-1 results in significant alteration of endothelial receptor expression and subsequent endothelial attachment of PBL and PMN. PMID- 26943030 TI - UBE2T promotes nasopharyngeal carcinoma cell proliferation, invasion, and metastasis by activating the AKT/GSK3beta/beta-catenin pathway. AB - Increasing evidence has shown that UBE2T plays an important role in genomic integrity and carcinogenesis; however, its role in nasopharyngeal carcinoma (NPC) has not been investigated. Here, we evaluated the clinicopathological significance of UBE2T in NPC and its underlying mechanisms. Using immunohistochemical analysis of UBE2T expression in NPC samples, we demonstrated that UBE2T is highly expressed in NPC tissues, which correlated with the T/M classification, skull invasion, and poor prognosis. The in vitro assay showed that UBE2T overexpression promoted proliferation, migration, and invasion of NPC cells, while UBE2T knockdown inhibited these processes. Consistent with our in vitro results, in vivo studies indicated that UBE2T overexpression promoted the growth of NPC xenografts and NPC cell metastasis. We found that UBE2T overexpression activated, whereas UBE2T knockdown inhibited, the AKT/GSK3beta/beta-catenin pathway. Moreover, the pathway-activation and in vitro pro-metastasis effects of UBE2T were blocked by the AKT inhibitor, MK-2206 2HCl. Additionally, UBE2T and p-GSK3 beta co-expressed in NPC samples by serial section, and their expressions are correlated. Collectively, our findings demonstrated that UBE2T is a possible diagnostic/prognostic biomarker for NPC and may promote the development and progression of NPC by activating the AKT/GSK3beta/beta-catenin pathway. Thus, UBE2T could serve as an alternative target for the treatment of NPC. PMID- 26943031 TI - Evidence of intermetastatic heterogeneity for pathological response and genetic mutations within colorectal liver metastases following preoperative chemotherapy. AB - BACKGROUND: In patients receiving preoperative chemotherapy, colorectal liver metastases (CLM) are expected to demonstrate a similar behaviour because of similar organ microenvironment and tumour cell chemosensitivity. We focused on the occurrence of pathological and genetic heterogeneity within CLM. METHODS: Patients resected for multiple CLM between 2004 and 2011 after > three cycles of chemotherapy were included. Pathological heterogeneity was arbitrarily defined as a > 50% difference in the percentage of remaining tumour cells between individual CLM. In patients with pathological heterogeneity, the mutational genotyping (KRAS, NRAS, BRAF and PIK3CA) was determined from the most heterogeneous CLM. RESULTS: Pathological heterogeneity was observed in 31 of 157 patients with multiple CLM (median = 4, range, 2-32) (19.7%). In 72.4% of them, we found a concordance of the mutation status between the paired CLM: both wild-type in 55%, and both mutated in 17.2%. We observed a discordance of the mutation status of 27.6% between CLM: one mutated and the other wild-type. The mutated CLM was the less florid one in 75% of patients with genetic heterogeneity. CONCLUSIONS: Pathological heterogeneity is present in 19.7% of patients with multiple CLM. Genetic heterogeneity is present in 27.6% of patients with pathological heterogeneity. Heterogeneity could refine guide management for tissue sampling. PMID- 26943032 TI - BRAF and TERT promoter mutations in the aggressiveness of papillary thyroid carcinoma: a study of 653 patients. AB - The role of telomerase reverse transcriptase (TERT) gene promoter mutations in the aggressiveness of papillary thyroid cancer (PTC) remains to be further investigated. Here we examined the relationship of TERT promoter mutations and BRAF V600E with the clinicopathological features of PTC in 653 patients. Sanger sequencing of genomic DNA from primary PTC tumors was performed for mutation detection and genotype-clinicopathological correlation of the tumor was analyzed. BRAF V600E and TERT promoter mutations were found in 63.7% (416 of 653) and 4.1% (27 of 653) of patients, respectively; the latter became 9.8% when only tumors >= 1.5 cm were analyzed. TERT promoter mutations occurred more frequently in BRAF mutation-positive cases compared to wild-type cases, being 5.3% in the former versus 2.1% in the latter (P = 0.050). BRAF and TERT promoter mutations were each significantly associated with high-risk clinicopathological features of PTC, such as old patient age, large tumor size, extrathyroidal invasion, capsular invasion, and advanced disease stages. Coexistence of BRAF V600E and TERT promoter mutations was particularly associated with high-risk clinicopathological features, as exemplified by extrathyroidal invasion seen in 54.5% (12/22) of patients harboring both mutations versus 9.9% (23/232) of patients harboring neither mutation (P < 0.001). Thus, this study, the largest on TERT mutation so far, demonstrates a significant role of BRAF V600E and TERT promoter mutations in the aggressiveness of PTC, which is particularly robust and cooperative when the two mutations coexist. These results, together with previous studies, establish a significant role of these mutations in the aggressiveness of PTC. PMID- 26943033 TI - Glutamate dependent NMDA receptor 2D is a novel angiogenic tumour endothelial marker in colorectal cancer. AB - Current vascular-targeted therapies in colorectal cancer (CRC) have shown limited benefit. The lack of novel, specific treatment in CRC has been hampered by a dearth of specific endothelial markers. Microarray comparison of endothelial gene expression in patient-matched CRC and normal colon identified a panel of putative colorectal tumour endothelial markers. Of these the glutamate dependent NMDA receptor GRIN2D emerged as the most interesting target. GRIN2D expression was shown to be specific to colorectal cancer vessels by RTqPCR and IHC analysis. Its expression was additionally shown be predictive of improved survival in CRC. Targeted knockdown studies in vitro demonstrated a role for GRIN2D in endothelial function and angiogenesis. This effect was also shown in vivo as vaccination against the extracellular region of GRIN2D resulted in reduced vascularisation in the subcutaneous sponge angiogenesis assay. The utility of immunologically targeting GRIN2D in CRC was demonstrated by the vaccination approach inhibiting murine CRC tumour growth and vascularisation. GRIN2D represents a promising target for the future treatment of CRC. PMID- 26943034 TI - Ran Binding Protein 9 (RanBP9) is a novel mediator of cellular DNA damage response in lung cancer cells. AB - Ran Binding Protein 9 (RanBP9, also known as RanBPM) is an evolutionary conserved scaffold protein present both in the nucleus and the cytoplasm of cells whose biological functions remain elusive. We show that active ATM phosphorylates RanBP9 on at least two different residues (S181 and S603). In response to IR, RanBP9 rapidly accumulates into the nucleus of lung cancer cells, but this nuclear accumulation is prevented by ATM inhibition. RanBP9 stable silencing in three different lung cancer cell lines significantly affects the DNA Damage Response (DDR), resulting in delayed activation of key components of the cellular response to IR such as ATM itself, Chk2, gammaH2AX, and p53. Accordingly, abrogation of RanBP9 expression reduces homologous recombination-dependent DNA repair efficiency, causing an abnormal activation of IR-induced senescence and apoptosis. In summary, here we report that RanBP9 is a novel mediator of the cellular DDR, whose accumulation into the nucleus upon IR is dependent on ATM kinase activity. RanBP9 absence hampers the molecular mechanisms leading to efficient repair of damaged DNA, resulting in enhanced sensitivity to genotoxic stress. These findings suggest that targeting RanBP9 might enhance lung cancer cell sensitivity to genotoxic anti-neoplastic treatment. PMID- 26943035 TI - Overexpression of pig selenoprotein S blocks OTA-induced promotion of PCV2 replication by inhibiting oxidative stress and p38 phosphorylation in PK15 cells. AB - Porcine circovirus type 2 (PCV2) is the primary cause of porcine circovirus disease, and ochratoxin A (OTA)-induced oxidative stress promotes PCV2 replication. In humans, selenoprotein S (SelS) has antioxidant ability, but it is unclear whether SelS affects viral infection. Here, we stably transfected PK15 cells with pig pCDNA3.1-SelS to overexpress SelS. Selenium (Se) at 2 or 4 MUM and SelS overexpression blocked the OTA-induced increases of PCV2 DNA copy number and infected cell numbers. SelS overexpression also increased glutathione (GSH), NF E2-related factor 2 (Nrf2) mRNA, and gamma-glutamyl-cysteine synthetase mRNA levels; decreased reactive oxygen species (ROS) levels; and inhibited p38 phosphorylation in PCV2-infected PK15 cells, regardless of OTA treatment. Buthionine sulfoximine reversed all of the above SelS-induced changes. siRNA mediated SelS knockdown decreased Nrf2 mRNA and GSH levels, increased ROS levels, and promoted PCV2 replication in OTA-treated PK15 cells. These data indicate that pig SelS blocks OTA-induced promotion of PCV2 replication by inhibiting the oxidative stress and p38 phosphorylation in PK15 cells. PMID- 26943036 TI - Depletion of FAP+ cells reduces immunosuppressive cells and improves metabolism and functions CD8+T cells within tumors. AB - The tumor stroma, which is essential to support growth and metastasis of malignant cells, provides targets for active immunotherapy of cancer. Previous studies have shown that depleting fibroblast activation protein (FAP)-expressing stromal cells reduces tumor progression and concomitantly increases tumor antigen (TA)-specific T cell responses. However the underlying pathways remain ill defined. Here we identify that immunosuppressive cells (ISCs) from tumor-bearing mice impose metabolic stress on CD8+T cells, which is associated with increased expression of the co-inhibitor PD-1. In two mouse melanoma models, depleting FAP+ stroma cells from the tumor microenvironment (TME) upon vaccination with an adenoviral-vector reduces frequencies and functions of ISCs. This is associated with changes in the cytokine/chemokine milieu in the TME and decreased activity of STAT6 signaling within ISCs. Decreases in ISCs upon FAP+stromal cell depletion is associated with reduced metabolic stress of vaccine-induced tumor infiltrating CD8+T cells and their delayed progression towards functional exhaustion, resulting in prolonged survival of tumor-bearing mice. PMID- 26943037 TI - Immunoglobulin gene rearrangements in Chinese and Italian patients with chronic lymphocytic leukemia. AB - Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in the Western world, whereas in Asia the incidence is about 10 times lower. The basis for this ethnic and geographic variation is currently unknown. The aim of this study was to characterize IGHVDJ rearrangements and stereotype of the HCDR3 region in a series of 623 Chinese CLL, in order to identify possible differences in immunoglobulin gene usage and their potential pathogenetic implications. Chinese CLL were compared to 789 Italian CLL. Chinese patients showed a higher proportion of mutated IGHV and a more frequent usage of IGHV3-7, IGHV3-74, IGHV4 39 and IGHV4-59 genes. A significantly lower usage of IGHV1-69 and IGHV1-2 was documented, with comparable IGHV3-21 frequency (3% Chinese vs 3.8% Italian CLL). The proportion of known stereotyped receptors was significantly lower in Chinese (19.7%) than in Italian CLL (25.8%), despite a significantly higher frequency of subset #8 (p= 0.0001). Moreover, new paired clusters were identified among Chinese cases. Overall, these data support a potential different antigenic exposure between Eastern and Western CLL. PMID- 26943038 TI - The epigenetic modifier CHD5 functions as a novel tumor suppressor for renal cell carcinoma and is predominantly inactivated by promoter CpG methylation. AB - Renal cell carcinoma (RCC) is the most common urological cancer with steadily increasing incidence. A series of tumor suppressor genes (TSGs) have been identified methylated in RCC as potential epigenetic biomarkers. We identified a 1p36.3 TSG candidate CHD5 as a methylated target in RCC through epigenome study. As the role of CHD5 in RCC pathogenesis remains elusive, we further studied its expression and molecular functions in RCC cells. We found that CHD5 was broadly expressed in most normal genitourinary tissues including kidney, but frequently silenced or downregulated by promoter CpG methylation in 78% of RCC cell lines and 44% (24/55) of primary tumors. In addition, CHD5 mutations appear to be rare in RCC tumors through genome database mining. In methylated/silenced RCC cell lines, CHD5 expression could be restored with azacytidine demethylation treatment. Ectopic expression of CHD5 in RCC cells significantly inhibited their clonogenicity, migration and invasion. Moreover, we found that CHD5, as a chromatin remodeling factor, suppressed the expression of multiple targets including oncogenes (MYC, MDM2, STAT3, CCND1, YAP1), epigenetic master genes (Bmi 1, EZH2, JMJD2C), as well as epithelial-mesenchymal transition and stem cell markers (SNAI1, FN1, OCT4). Further chromatin immunoprecipitation (ChIP) assays confirmed the binding of CHD5 to target gene promoters. Thus, we demonstrate that CHD5 functions as a novel TSG for RCC, but is predominantly inactivated by promoter methylation in primary tumors. PMID- 26943040 TI - The clock gene PER1 suppresses expression of tumor-related genes in human oral squamous cell carcinoma. AB - Abnormal expression of the clock gene PER1 is highly correlated with carcinogenesis and the development of malignant tumors. Here, we designed short hairpin RNAs (shRNAs) to effectively knock down PER1 in SCC15 human oral squamous cell carcinoma cells. shRNA-mediated PER1 knockdown promoted SCC15 cell growth, proliferation, apoptosis resistance, migration and invasion in vitro. PER1 knockdown also increased the cells' expression of KI-67, MDM2, BCL-2, MMP2 and MMP9 mRNA, and decreased expression of C-MYC, p53, BAX and TIMP-2. In BALB/c nu/nu nude mice subcutaneously injected with SCC15 cells, PER1 knockdown in the cells enhanced tumor development, leading to increased tumor weights and volumes. These results suggest that PER1 is an important tumor suppressor gene and may be a useful molecular target for the treatment of cancer. PMID- 26943039 TI - Alkaline ceramidase 2 and its bioactive product sphingosine are novel regulators of the DNA damage response. AB - Human cells respond to DNA damage by elevating sphingosine, a bioactive sphingolipid that induces programmed cell death (PCD) in response to various forms of stress, but its regulation and role in the DNA damage response remain obscure. Herein we demonstrate that DNA damage increases sphingosine levels in tumor cells by upregulating alkaline ceramidase 2 (ACER2) and that the upregulation of the ACER2/sphingosine pathway induces PCD in response to DNA damage by increasing the production of reactive oxygen species (ROS). Treatment with the DNA damaging agent doxorubicin increased both ACER2 expression and sphingosine levels in HCT116 cells in a dose-dependent manner. ACER2 overexpression increased sphingosine in HeLa cells whereas knocking down ACER2 inhibited the doxorubicin-induced increase in sphingosine in HCT116 cells, suggesting that DNA damage elevates sphingosine by upregulating ACER2. Knocking down ACER2 inhibited an increase in the apoptotic and necrotic cell population and the cleavage of poly ADP ribose polymerase (PARP) in HCT116 cells in response to doxorubicin as well as doxorubicin-induced release of lactate dehydrogenase (LDH) from these cells. Similar to treatment with doxorubicin, ACER2 overexpression induced an increase in the apoptotic and necrotic cell population and PARP cleavage in HeLa cells and LDH release from cells, suggesting that ACER2 upregulation mediates PCD in response to DNA damage through sphingosine. Mechanistic studies demonstrated that the upregulation of the ACER2/sphingosine pathway induces PCD by increasing ROS levels. Taken together, these results suggest that the ACER2/sphingosine pathway mediates PCD in response to DNA damage through ROS production. PMID- 26943041 TI - Systematic review with network meta-analysis: statins and risk of hepatocellular carcinoma. AB - OBJECTIVES: Usage of statins is suggested to decrease the incidence of HCC. When it comes to different statin subtypes, the chemopreventive action remains controversial. We aim to compare the usage of different statins and reduction of HCC risk. METHODS: We searched PubMed, Embase.com and Cochrane Library database up to August 10, 2015. Duplicated or overlapping reports were eliminated. We performed a traditional pair-wise meta-analysis and a Bayesian network meta analysis to compare different treatments with a random-effects model. RESULTS: We reviewed five observational studies enrolling a total of 87127 patients who received at least two different treatment strategies including rosuvastatin, atorvastatin, simvastatin, pravastatin, fluvastatin, cerivastatin, and lovastatin or observation alone. Direct comparisons showed that usage of atorvastatin (OR 0.63, 95%CI 0.45-0.89) and fluvastatin (OR 0.58, 95%CI 0.40-0.85) could significantly cut the risk of liver cancer. The difference of indirect comparisons between the included regimens is not statistically significant. However, usage of all types of statins, such as fluvastatin (RR 0.55, 95%CI 0.26 1.11), atorvastatin (RR 0.59, 95%CI 0.30-1.16), simvastatin (RR 0.69, 95%CI 0.38 1.25), cerivastatin (RR 0.71, 95%CI 0.19-2.70), pravastatin (RR 0.72, 95%CI 0.37 1.45), lovastatin (RR 0.81, 95%CI 0.34-1.96) and rosuvastatin (RR 0.92, 95%CI 0.44-1.80), appeared to be superior to observation alone. Notably, fluvastatin was hierarchically the best when compared with the six other statins. CONCLUSIONS: Our analyses indicate the superiority of usage of statins in reduction of liver cancer. Available evidence supports that fluvastatin is the most effective strategy for reducing HCC risk compared with other statin interventions. PMID- 26943042 TI - Long non-coding RNA containing ultraconserved genomic region 8 promotes bladder cancer tumorigenesis. AB - Ultraconserved regions (UCRs) have been shown to originate non-coding RNA transcripts (T-UCRs) that have different expression profiles and play functional roles in the pathophysiology of multiple cancers. The relevance of these functions to the pathogenesis of bladder cancer (BlCa) is speculative. To elucidate this relevance, we first used genome-wide profiling to evaluate the expression of T-UCRs in BlCa tissues. Analysis of two datasets comprising normal bladder tissues and BlCa specimens with a custom T-UCR microarray identified ultraconserved RNA (uc.) 8+ as the most upregulated T-UCR in BlCa tissues, although its expression was lower than in pericancerous bladder tissues. These results were confirmed on BlCa tissues by real-time PCR and by in situ hybridization. Although uc.8+ is located within intron 1 of CASZ1, a zinc-finger transcription factor, the transcribed non-coding RNA encoding uc.8+ is expressed independently of CASZ1. In vitro experiments evaluating the effects of uc.8+ silencing, showed significantly decreased capacities for cancer cell invasion, migration, and proliferation. From this, we proposed and validated a model of interaction in which uc.8+ shuttles from the nucleus to the cytoplasm of BlCa cells, interacts with microRNA (miR)-596, and cooperates in the promotion and development of BlCa. Using computational analysis, we investigated the miR binding domain accessibility, as determined by base-pairing interactions within the uc.8+ predicted secondary structure, RNA binding affinity, and RNA species abundance in bladder tissues and showed that uc.8+ is a natural decoy for miR 596. Thus uc.8+ upregulation results in increased expression of MMP9, increasing the invasive potential of BlCa cells. These interactions between evolutionarily conserved regions of DNA suggest that natural selection has preserved this potentially regulatory layer that uses RNA to modulate miR levels, opening up the possibility for development of useful markers for early diagnosis and prognosis as well as for development of new RNA-based cancer therapies. PMID- 26943043 TI - Dietary pterostilbene is a novel MTA1-targeted chemopreventive and therapeutic agent in prostate cancer. AB - Overexpression of the epigenetic modifier metastasis-associated protein 1 (MTA1) is associated with aggressive human prostate cancer. The purpose of this study was to determine MTA1- targeted chemopreventive and therapeutic efficacy of pterostilbene, a natural potent analog of resveratrol, in pre-clinical models of prostate cancer. Here, we show that high levels of MTA1 expression in Pten-loss prostate cooperate with key oncogenes, including c-Myc and Akt among others, to promote prostate cancer progression. Loss-of-function studies using human prostate cancer cells indicated direct involvement of MTA1 in inducing inflammation and epithelial-to-mesenchymal transition. Importantly, pharmacological inhibition of MTA1 by pterostilbene resulted in decreased proliferation and angiogenesis and increased apoptosis. This restrained prostatic intraepithelial neoplasia (PIN) formation in prostate-specific Pten heterozygous mice and reduced tumor development and progression in prostate-specific Pten-null mice. Our findings highlight MTA1 as a key upstream regulator of prostate tumorigenesis and cancer progression. More significantly, it offers pre-clinical proof for pterostilbene as a promising lead natural agent for MTA1-targeted chemopreventive and therapeutic strategy to curb prostate cancer. PMID- 26943044 TI - Tau accumulation impairs mitophagy via increasing mitochondrial membrane potential and reducing mitochondrial Parkin. AB - Intracellular accumulation of wild type tau is a hallmark of sporadic Alzheimer's disease (AD). However, the molecular mechanisms underlying tau toxicity is not fully understood. Here, we detected mitophagy deficits evidenced by the increased levels of mitophagy markers, including COX IV, TOMM20, and the ratio of mtDNA to genomic DNA indexed as mt-Atp6/Rpl13, in the AD brains and in the human wild type full-length tau (htau) transgenic mice. More interestingly, the mitophagy deficit was only shown in the AD patients who had an increased total tau level. Further studies demonstrated that overexpression of htau induced mitophagy deficits in HEK293 cells, the primary hippocampal neurons and in the brains of C57 mice. Upon overexpression of htau, the mitochondrial membrane potential was increased and the levels of PTEN-induced kinase 1 (PINK1) and Parkin decreased in the mitochondrial fraction, while upregulation of Parkin attenuated the htau-induced mitophagy deficits. Finally, we detected a dose-dependent allocation of tau proteins into the mitochondrial outer membrane fraction along with its cytoplasmic accumulation. These data suggest that intracellular accumulation of htau induces mitophagy deficits by direct inserting into the mitochondrial membrane and thus increasing the membrane potential, which impairs the mitochondrial residence of PINK1/Parkin. Our findings reveal a novel mechanism underlying the htau-induced neuronal toxicities in AD and other tauopathies. PMID- 26943045 TI - Common DNA methylation alterations of Alzheimer's disease and aging in peripheral whole blood. AB - Alzheimer's disease (AD) is a common aging-related neurodegenerative illness. Recently, many studies have tried to identify AD- or aging-related DNA methylation (DNAm) biomarkers from peripheral whole blood (PWB). However, the origin of PWB biomarkers is still controversial. In this study, by analyzing 2565 DNAm profiles for PWB and brain tissue, we showed that aging-related DNAm CpGs (Age-CpGs) and AD-related DNAm CpGs (AD-CpGs) observable in PWB both mainly reflected DNAm alterations intrinsic in leukocyte subtypes rather than methylation differences introduced by the increased ratio of myeloid to lymphoid cells during aging or AD progression. The PWB Age-CpGs and AD-CpGs significantly overlapped 107 sites (P-value = 2.61*10-12) and 97 had significantly concordant methylation alterations in AD and aging (P-value < 2.2*10-16), which were significantly enriched in nervous system development, neuron differentiation and neurogenesis. More than 60.8% of these 97 concordant sites were found to be significantly correlated with age in normal peripheral CD4+ T cells and CD14+ monocytes as well as in four brain regions, and 44 sites were also significantly differentially methylated in different regions of AD brain tissue. Taken together, the PWB DNAm alterations related to both aging and AD could be exploited for identification of AD biomarkers. PMID- 26943047 TI - CLEC4C p.K210del variant causes impaired cell surface transport in plasmacytoid dendritic cells of amyotrophic lateral sclerosis. AB - The type II C-type lectin CLEC4C is a transmembrane protein selectively expressed on plasmacytoid dendritic cells (PDCs). Although its mechanism of action remains unclear, triggering of the extracellular C-terminal C-type carbohydrate recognition region of CLEC4C regulates the secretion of proinflammatory cytokines and type I IFNs in PDCs. Applying whole-exome sequencing in a patient with juvenile amyotrophic lateral sclerosis (ALS) and both healthy parents, we identified a de novo CLEC4C variant (c.629_631delAGA; p.Lys210del). In this study, we report that the deletion of a lysine residue at the extracellular region of CLEC4C yields a C-terminal dilysine motif that results in endoplasmic reticulum (ER) retention of the protein in transfected HeLa and Jurkat T lymphoma cell models. As a consequence, a decrease in the surface expression of CLEC4C and the ER localization of the mutant construct were observed. Furthermore, depletion of the cell surface CLEC4C level was also observed in the patient PDCs, further suggesting that the variant p.Lys210del CLEC4C may contribute to juvenile ALS susceptibility. PMID- 26943048 TI - Appropriate density of PCL nano-fiber sheath promoted muscular remodeling of PGS/PCL grafts in arterial circulation. AB - Cell-free approach represents a philosophical shift from the prevailing focus on cells in vascular tissue engineering. Porous elastomeric grafts made of poly(glycerol sebacate) (PGS) enforced with polycaprolactone (PCL) nano-fibers degrade rapidly and yield neoarteries nearly free of foreign materials in rat abdominal aorta. However, considering the larger variation of blood pressure and slower host remodeling in human body than in rat, it is important to investigate the in vivo performance of PGS-PCL graft with enhanced mechanical properties, so that optimized arterial grafts could be developed for clinical translation. We acquired increasingly compacted sheath by prolonging the electrospinning period of PCL appropriately, which significantly enforced whole grafts. The rational design of sheath density significantly decreased the risk of dilation, rupture as well as enabling the long-term muscular remodeling. Since 3-12 months after implantation, the PGS grafts with rationally strengthened sheath were remodeled into neoarteries resembled native arteries in the following aspects: high patency rate and even vessel wall thickness; a confluent endothelium and contractile smooth muscle layers; expression of elastin, collagen and glycosaminoglycan; tough and compliant mechanical properties. Although loose sheath may result in rupture of vessel wall, adequate porosity was proved to be essential for sheath structure and directly determined muscular remodeling through M2 macrophage involved constructive remodeling. Therefore, this study confirmed that adequate density of PCL sheath in PGS grafts could initiate stable and high-quality muscular remodeling, which contributes to long-term success in arterial circulation before clinical translation. PMID- 26943046 TI - Morphofunctional and signaling molecules overlap of the pineal gland and thymus: role and significance in aging. AB - Deficits in neuroendocrine-immune system functioning, including alterations in pineal and thymic glands, contribute to aging-associated diseases. This study looks at ageing-associated alterations in pineal and thymic gland functioning evaluating common signaling molecules present in both human and animal pinealocytes and thymocytes: endocrine cell markers (melatonin, serotonin, pCREB, AANAT, CGRP, VIP, chromogranin D?); cell renovation markers (p53, AIF, Ki67), matrix metalloproteinases (MMP2, MMP9) and lymphocytes markers (CD4, CD5, CD8, CD20). Pineal melatonin is decreased, as is one of the melatonin pathway synthesis enzymes in the thymic gland. A further similarity is the increased MMPs levels evident over age in both glands. Significant differences are evident in cell renovation processes, which deteriorate more quickly in the aged thymus versus the pineal gland. Decreases in the number of pineal B-cells and thymic T cells were also observed over aging. Collected data indicate that cellular involution of the pineal gland and thymus show many commonalities, but also significant changes in aging-associated proteins. It is proposed that such ageing associated alterations in these two glands provide novel pharmaceutical targets for the wide array of medical conditions that are more likely to emerge over the course of ageing. PMID- 26943057 TI - High-Fidelity Replica Molding of Glassy Liquid Crystalline Polymer Microstructures. AB - Liquid crystalline polymers have recently been engineered to exhibit complex macroscopic shape adaptivity, including optically- and thermally driven bending, self-sustaining oscillation, torsional motion, and three-dimensional folding. Miniaturization of these novel materials is of great interest for both fundamental study of processing conditions and for the development of shape changing microdevices. Here, we present a scalable method for high-fidelity replica molding of glassy liquid crystalline polymer networks (LCNs), by vacuum assisted replica molding, along with magnetic field-induced control of the molecular alignment. We find that an oxygen-free environment is essential to establish high-fidelity molding with low surface roughness. Identical arrays of homeotropic and polydomain LCN microstructures are fabricated to assess the influence of molecular alignment on the elastic modulus (E = 1.48 GPa compared to E = 0.54 GPa), and side-view imaging is used to quantify the reversible thermal actuation of individual LCN micropillars by high-resolution tracking of edge motion. The methods and results from this study will be synergistic with future advances in liquid crystalline polymer chemistry, and could enable the scalable manufacturing of stimuli-responsive surfaces for applications including microfluidics, tunable optics, and surfaces with switchable wetting and adhesion. PMID- 26943056 TI - Effectiveness and side-effects of peptide receptor radionuclide therapy for neuroendocrine neoplasms in Germany: A multi-institutional registry study with prospective follow-up. AB - BACKGROUND: Monocentric and retrospective studies indicate effectiveness of peptide receptor radionuclide therapy targeting somatostatin receptors of neuroendocrine neoplasms. We assessed overall and progression-free survival and adverse events of peptide receptor radionuclide therapy by a multi-institutional, board certified registry with prospective follow-up in five centres in Germany. METHODS: A total of 450 patients were included and followed for a mean of 24.4 months. Most patients had progressive low- or intermediate grade neuroendocrine neoplasms and 73% were pretreated with at least one therapy. Primary neuroendocrine neoplasms were mainly derived of pancreas (38%), small bowel (30%), unknown primary (19%) or bronchial system (4%). Patients were treated with Lutetium-177 in 54%, with Yttrium-90 in 17% and with both radionuclides in 29%. Overall and progression-free survival was determined with Kaplan-Meier curves and uni-variate log rank test Cox models. FINDINGS: Median overall survival of all patients was 59 (95% confidence interval [CI] 49-68.9) months. Overall survival was significantly inferior in the patients treated with Yttrium-90 solely (hazard ratio, 3.22; 95% CI, 1.83-5.64) compared to any peptide receptor radionuclide therapy with Lutetium-177. Grade II (hazard ratio, 2.06; 95% CI, 0.79-5.32) and grade III (hazard ratio, 4.22; 95% CI, 1.41-12.06) neuroendocrine neoplasms had significantly worse overall survival than grade I neuroendocrine neoplasms. Patients with small neuroendocrine neoplasms of small bowel had significantly increased survival (hazard ratio, 0.39; 95% CI, 0.18-0.87) compared to neuroendocrine neoplasms of other locations. Median progression-free survival was 41 (35.9-46.1) months and significantly inferior in patients treated with Yttrium solely (hazard ratio, 2.7; 95% CI, 1.71-4.55). Complete remission was observed in 5.6% of patients, 22.4% had a partial remission, 47.3% were stable and 4% were progressive as best response. Adverse events of bone marrow and kidney function higher than grade III occurred in 0.2-1.5% of patients. INTERPRETATION: These results indicate that peptide receptor radionuclide therapy is a highly effective therapy for patients with low to intermediate grade neuroendocrine neoplasms with minor adverse events. PMID- 26943071 TI - Enantioselective Approach to (-)-Hamigeran B and (-)-4-Bromohamigeran B via Catalytic Asymmetric Hydrogenation of Racemic Ketone To Assemble the Chiral Core Framework. AB - A new strategy featuring an iridium-catalyzed asymmetric hydrogenation of a racemic ketone via dynamic kinetic resolution to generate a cyclopentanol with three contiguous stereocenters and a SmI2-promoted pinacol coupling to install the six-membered ring with correct stereochemistry has been described for the enantioselective total synthesis of (-)-hamigeran B (19 steps, 10.6% overall yield) and (-)-4-bromohamigeran B (19 steps, 12.3% overall yield). PMID- 26943080 TI - Learners. PMID- 26943081 TI - Rapid maxillary expansion in a pediatric patient with exocrine pancreatic insufficiency. AB - Exocrine pancreatic insufficiency is a condition capable of promoting changes in craniofacial growth and development. This case report describes treatment of a 9 year-old patient with chronic pancreatic insufficiency, highlighting the diagnostic aspects involved and clinical implications of this condition with respect to dental treatment. The treatment plan involved oral hygiene recommendations and correction of bilateral posterior crossbite and anterior open bite. Just 2 weeks after orthodontic treatment, the corrected dentition relapsed completely, confirming the difficulty of promoting ossification in the median palatine suture. Orthodontists should be careful to develop an individualized treatment plan for each patient with this abnormality, because these determinations could mean the difference between success and failure of the treatment approach. PMID- 26943082 TI - Doxycycline as a matrix metalloproteinase inhibitor to prevent bond degradation: the effect of acid and neutral solutions on dentin bond strength. AB - The aim of this in vitro study was to evaluate the pH effect of doxycycline solutions on the immediate dentin bond strength of a total-etch adhesive system. Twenty human molars were divided into 4 groups (n = 5) after acid etching according to surface treatment: 10% acidic doxycycline, 10% neutral doxycycline, 2% chlorhexidine, and control. Composite resin blocks were made and subjected to microtensile testing. Mean bond strength values were submitted to a 1-way analysis of variance and a Tukey test (alpha = 0.05). No statistically significant differences between the experimental groups were found (P = 0.093). The chlorhexidine group showed the highest number of pretesting failures. The application of either acidic or neutral doxycycline solution prior to the dentin adhesive did not influence the bond strength of the total-etch adhesive system evaluated. PMID- 26943083 TI - A 12-month clinical trial examining the effects of a surface sealant on Class I composite resin restorations. AB - A split-mouth, double-blind trial evaluated the effects of a surface sealant on the clinical performance of Class I composite resin restorations. In 16 patients, 27 pairs of maxillary and mandibular molars or premolars with Class I carious lesions or unsatisfactory restorations were restored with composite resin. For each pair, 1 surface was sealed with surface sealant. Clinical evaluations of marginal integrity, marginal discoloration, anatomical form, and secondary caries were performed by 2 experienced operators using modified US Public Health Service criteria 1-2 weeks and 6 and 12 months after treatment. Data were analyzed with the McNemar test (P < 0.05). After 6 months, only 1 (4%) sealed restoration presented a Bravo rating for marginal integrity. After 12 months, the Bravo ratings for marginal integrity were 2 (7%) for sealed restorations and 1 (4%) for nonsealed restorations. Restorations received a score of Alfa for all other parameters at all time periods. There were no statistically significant differences within or between the sealed and nonsealed groups (P = 1.0). The use of a surface sealant did not improve the clinical performance of posterior composite resin Class I restorations. PMID- 26943084 TI - Florid osseous dysplasia associated with multiple simple bone cysts: a patient with 22 years of follow-up. AB - Florid osseous dysplasia (FOD) has been described as a condition that typically affects the jaws of middle-aged women of African descent and usually presents as multiple radiopaque masses distributed throughout the jaws. The diagnosis is generally based on clinical and radiographic presentation, often involving various regions of the jaws without evident bone expansion. This article describes the course of FOD in a 27-year-old African-American woman during 22 years of follow-up, emphasizing the dynamic radiographic characteristics of this entity and unusual co-occurrence with multiple simple bone cysts. These data reinforce the importance of long-term follow-up in patients diagnosed with FOD. PMID- 26943085 TI - Influence of irradiance on Knoop hardness, degree of conversion, and polymerization shrinkage of nanofilled and microhybrid composite resins. AB - The purpose of this study was to investigate the influence of the irradiance emitted by a light-curing unit on microhardness, degree of conversion (DC), and gaps resulting from shrinkage of 2 dental composite resins. Cylinders of nanofilled and microhybrid composites were fabricated and light cured. After 24 hours, the tops and bottoms of the specimens were evaluated via indentation testing and Fourier transform infrared spectroscopy to determine Knoop hardness number (KHN) and DC, respectively. Gap width (representing polymerization shrinkage) was measured under a scanning electron microscope. The nanofilled composite specimens presented significantly greater KHNs than did the microhybrid specimens (P < 0.05). The microhybrid composite resin exhibited significantly greater DC and gap width than the nanofilled material (P < 0.05). Irradiance had a mostly material-dependent influence on the hardness and DC, but not the polymerization shrinkage, of composite resins. PMID- 26943086 TI - Fracture strength of the remaining dental structure after different cavity preparation designs. AB - The aim of this in vitro study was to evaluate the loss of tooth structure after cavity preparation for direct (retentive) and indirect (nonretentive) restorations and its relationship to the fracture strength of the prepared tooth. Sound human third molars (60 maxillary and 60 mandibular) were randomly assigned into 12 groups (n = 10) according to the type of cavity preparation and the respective buccolingual width. Class II mesio-occlusodistal cavity preparations, for both indirect inlay and direct resin restorations, were prepared with standardized dimensions of one-half, one-third, or one-quarter of the occlusal intercuspal distance. Fracture resistance was lower and weight loss was greater for all nonretentive preparations. Greater losses in weight and fracture resistance occurred when the buccolingual width for both types of cavities increased, except for the weight loss of the one-quarter and one-third indirect cavity preparations in the mandibular molars, and the fracture resistance of the one-half and one-third direct cavity preparations in maxillary molars. Higher tooth structure loss and lower fracture strength were recorded after preparation of the inlay cavities. PMID- 26943087 TI - Progression of gingival squamous cell carcinoma from early to late stage after invasive dental procedure. AB - Early presentation of gingival squamous cell carcinoma (GSCC) is at times misdiagnosed as a benign inflammatory or reactive oral condition. Some misdiagnosed patients undergo unnecessary, invasive dental procedures, resulting in delayed cancer diagnosis and an increased risk of accelerated disease progression due to disruption of the periosteum and cortical bone. The records of 58 patients with biopsy-proven GSCC were retrospectively reviewed. The sample included 32 patients who underwent an invasive dental procedure (IDP) prior to cancer diagnosis and 26 patients who did not undergo an IDP (non-case group). Patients from both groups initially presented with similar symptoms. The median duration of symptoms at initial clinical presentation was 6 months for the IDP group and 2 months for the non-case group. In IDP patients, symptoms worsened after the IDP was rendered, with 37.5% presenting with a severe-grade symptom. In both groups, the majority of lesions were found on the posterior mandible and had a histologic grading of moderately differentiated GSCC. The odds of the IDP group having late-stage disease were 2.94 times greater than the odds for the control group. Stage T3/T4 malignancy was diagnosed in 77.4% of the IDP patients versus 53.8% of non-case patients. Disease-specific mortality was comparable; however, surgical treatment was significantly more extensive in the IDP group than in the non-case group. The disruption of alveolar periosteum in undiagnosed oral cancer patients results in significant delay in diagnosis, necessitating more complicated treatment regimens because of local tumor progression. PMID- 26943088 TI - Psychosocial impact of anterior dental esthetics on periodontal health, dental caries, and oral hygiene practices in young adults. AB - This study sought to determine whether the self-perceived image of a young adult's anterior dental esthetics is linked with periodontal health, dental caries, and oral hygiene practices. Two hundred subjects were assessed via a clinical examination, including intraoral photographs. The subjects were questioned about their demographics and oral hygiene practices and given the Psychosocial Impact of Dental Aesthetics Questionnaire (PIDAQ) to measure their self-perceived variables related to dental esthetics. A high PIDAQ score indicates a negative image of one's own dental esthetics, while a low PIDAQ score indicates a positive outlook. A self-perceived negative psychosocial impact of anterior dental esthetics was detected in subjects with higher levels of dental caries and visible gingival inflammation in the anterior region of the mouth. PMID- 26943089 TI - Photogrammetric analysis of facial profile in Persian adults. AB - When facial photographs are analyzed for the purpose of identifying esthetics norms, differences in dentofacial relationships among ethnic and racial groups must be taken into consideration. Therefore, it is necessary to establish standards for various populations. The purpose of this study was to establish norms of photogrammetric soft tissue profile analysis for Persian adults. Pretreatment lateral photographs of 147 subjects (66 men and 81 women aged 18-35 years) with a Class I skeletal pattern were collected. Twelve angular parameters were evaluated in the subjects. Values for men and women were compared with a t test. Statistically significant sexual dimorphism was found for nasofrontal (P < 0.059), nasal (P < 0.059), nasal dorsum (P < 0.001), cervicomental (P < 0.001), facial convexity (P < 0.004), and total facial convexity (P < 0.002) angles. The mean values obtained from this study can assist in orthodontic diagnosis and treatment planning for Persian adults. PMID- 26943090 TI - Mechanical properties of silorane-based and methacrylate-based composite resins after artificial aging. AB - The aim of this study was to compare the compressive strength of a silorane-based composite resin (Filtek P90) to that of conventional composite resins (Charisma, Filtek Z250, Fill Magic, and NT Premium) before and after accelerated artificial aging (AAA). For each composite resin, 16 cylindrical specimens were prepared and divided into 2 groups. One group underwent analysis of compressive strength in a universal testing machine 24 hours after preparation, and the other was subjected first to 192 hours of AAA and then the compressive strength test. Data were analyzed by analysis of variance, followed by the Tukey HSD post hoc test (alpha = 0.05). Some statistically significant differences in compressive strength were found among the commercial brands (P < 0.001). The conventional composite resin Fill Magic presented the best performance before (P < 0.05) and after AAA (P < 0.05). Values for compressive strength of the silorane-based composite were among the lowest obtained, both before and after aging. Comparison of each material before and after AAA revealed that the aging process did not influence the compressive strength of the tested resins (P = 0.785). PMID- 26943091 TI - Esthetic rehabilitation with tooth bleaching, enamel microabrasion, and direct adhesive restorations. AB - The aim of this case report is to report esthetic rehabilitation with combined tooth bleaching, enamel microabrasion, and anterior restoration replacement in a 26-year-old man. Clinical examination showed deficient restorations in the maxillary anterior teeth, significant discoloration of the maxillary left central incisor, and hypoplastic stains affecting the maxillary right lateral incisor. A radiograph of the left central incisor showed satisfactory endodontic treatment, allowing preparation for the walking bleach technique. For 3 weeks, 37% carbamide peroxide in the pulp chamber was renewed every week. In-office bleaching with 35% hydrogen peroxide was also performed on the maxillary teeth. After 21 days, all teeth had been bleached to shade A1. After bleaching was completed, enamel microabrasion of the maxillary right lateral incisor was conducted with 6% hydrochloric acid. In later sessions, microhybrid composite resin restorations were placed in all 4 maxillary incisors. A combination of dental bleaching techniques, enamel microabrasion, and resin restorations was a successful and conservative choice for reestablishing the natural appearance of discolored teeth, improving the self-esteem of the patient. PMID- 26943092 TI - Congenital labial mucocele: rare presentation of a common disease. AB - Oral mucoceles are common lesions characterized by accumulation of mucus following rupture of a minor salivary gland duct. However, congenital mucoceles are a rare and distinctive oral condition observed in newborns. This case report details the features of a congenital labial nodule diagnosed as congenital mucocele. These lesions are rare in the oral cavity and should be diagnosed in the delivery room, but many cases are referred for further evaluation. Management is simple, and recurrence is not expected. PMID- 26943093 TI - Properties of dual-cure, bulk-fill composite resin restorative materials. AB - The purpose of this study was to compare the properties of 2 new dual-cure, bulk fill restorative composite resins to those of a hybrid composite resin material. Depth of cure, fracture toughness, porosity, microleakage, and volumetric shrinkage properties were examined. With the exception of fracture toughness, significant differences were found among materials. Compared to the incrementally placed hybrid composite, the dual-cure, bulk-fill restorative composites in self cured mode had unlimited depth of cure, similar fracture toughness and porosity formation, and greater polymerization shrinkage and microleakage. PMID- 26943094 TI - A minimally invasive approach for a compromised treatment plan. AB - A primary goal in dentistry is the execution of appropriate treatment plans that are minimally invasive and maintainable. However, it is sometimes necessary to repair existing dental restorations or revise treatment plans to accommodate changes in a patient's condition. In the present case, a patient who was satisfied with a removable partial overdenture lost a critical abutment tooth. A creative, minimally invasive approach enabled the patient to keep his existing partial prosthesis and avoid the need for a full reconstruction or complete denture. PMID- 26943095 TI - Effect of artificial aging on the surface roughness and microhardness of resin based materials. AB - This study sought to verify the effects of aging on the surface roughness (Ra) and microhardness (Knoop hardness number [KHN]) of resin-based restorative materials protected with a surface sealer. Disc specimens of 2 resin-modified glass ionomers (RMGIs) and 1 composite resin (CR) were fabricated in a metal mold. Specimens of each material were divided into 1 group that was covered with surface sealer and 1 group that was not. Both groups of each material were then subdivided according to whether they were stored (aged) in cola or distilled water. Surface roughness and KHN values were obtained from each specimen before and after storage. After aging of the specimens, significantly higher Ra values were observed in the 2 RMGIs when they were not covered with a surface sealer, while the CR was not affected. The KHN values varied by materials and storage conditions (with and without a surface sealer). All the groups with a surface sealer exhibited increased Ra values after aging. PMID- 26943096 TI - Persistent infection by Staphylococcus epidermidis in endodontic flare-up: a case report. AB - Endodontic flare-ups are challenging situations and may result from selective growth of specific bacterial species; microbial cultures and antibiograms should be used to allow faster, successful management of refractory lesions. A 47-year old man reported pain on percussion after uncomplicated retreatment of the maxillary left canine for prosthetic purposes. In the following days, pain dramatically increased, leading to removal of the filling and use of intracanal medication. After many unsuccessful attempts to resolve the problem, a microbial culture of the root canal detected the presence of Staphylococcus epidermidis. An antibiogram determined the best drug combination to control this infection: tetracycline (oxytetracycline hydrochloride, 500 mg orally) plus third-generation cephalosporin (ceftriaxone, 1 g intramuscularly). Once the infection was controlled, the root canal was obturated. There was a reduction in the area of radiolucency, and the patient reported no pain at a 2-year follow-up. PMID- 26943097 TI - Effect of a surface sealant on the color stability of composite resins after immersion in staining solution. AB - This study evaluated the influence of surface sealants on the color stability of 2 different composite resins after immersion in coffee. Four groups were created (n = 10): microhybrid composite, microhybrid with surface sealant, nanofilled composite, and nanofilled composite with surface sealant. Half of the specimens of each group were immersed in distilled water and half were immersed in coffee for 48 hours. Color was measured before and after immersion. Groups with surface sealants presented less color variation when compared with the groups without surface sealants. The nanofilled resin specimens presented the greatest color variation within the groups without sealant. The surface sealant positively influenced the color stability of composite resin specimens immersed in coffee. When surface sealant was not applied, the microhybrid specimens had better color stability than the nanofilled. PMID- 26943098 TI - Influence of alveolar bone level on the pull-out bond strength of fiber reinforced composite posts to root dentin. AB - This in vitro study evaluated the influence of alveolar bone level and type of cement on pull-out bond strength between different fiber-reinforced composite (FRC) posts and root dentin. Sixty bovine teeth were sectioned, and their root canals were prepared. The specimens were divided into 6 groups (n = 10) according to 2 factors: alveolar bone level and type of cement. Each root was embedded in acrylic resin to the depth of 7, 10, or 14 mm, simulating different alveolar bone levels. After the FRC posts were treated with 37% phosphoric acid and silane was applied, they were cemented with either a conventional resin cement or a self adhesive resin cement and subjected to mechanical cycling. The results indicated that neither the alveolar bone level nor the type of cement played a significant role in the pull-out bond strength of the FRC posts to root dentin. Therefore, it is concluded that conventional and self-adhesive resin cements can be used to lute FRC posts to tooth roots, even in the presence of significant alveolar bone resorption. PMID- 26943100 TI - Erratum. PMID- 26943102 TI - Role of Occupational Therapy in Case Management and Care Coordination for Clients With Complex Conditions. AB - Specific aspects of the profession of occupational therapy support a distinct value for its practitioners participating fully in the development of case management and care coordination systems. The expectation in the 21st century is that the U.S. health care system must be transformed from one that promotes volume of service to one that promotes value of care. Case management and care coordination will be critical components of that transformation. Occupational therapy's principles, education, practice, approach, and perspective offer much to benefit this increased attention to case management and care coordination. Occupational therapy practitioners should promote themselves and their profession as these system changes develop. PMID- 26943099 TI - Efficacy of different techniques for removal of calcium hydroxide-chlorhexidine paste from root canals. AB - The purpose of this study was to evaluate the efficacy of different techniques for removal of combined calcium hydroxide [Ca(OH)2] and chlorhexidine paste from root canals. Fifty single-rooted human teeth were prepared by oscillatory and rotary systems and filled with a paste of Ca(OH)2 and 2% chlorhexidine gel. After incubation for 14 days, the specimens were divided into 5 groups (n = 10), and the medication was removed by 1 of 5 different procedures. In group 1 (control), removal procedures involved a master apical file, foraminal debridement, and 5 mL of saline solution applied with the NaviTip irrigation needle. Group 2 was treated the same as group 1, but in addition 0.5 mL of 17% ethylenediaminetetraacetic acid was used for 3 minutes. In group 3, ultrasonic agitation was performed for 1 minute. Group 4 was treated as group 2, but the NaviTip FX needle was used for irrigation. In group 5, a master apical file, foraminal debridement, and 3-minute application of 5 mL of citric acid were used. After the root-cleaning procedures, the crowns were removed at the cementoenamel junction, and the roots were split longitudinally into halves. The success of intracanal medicament removal was observed under stereoscopic microscope and scanning electron microscope. Remnants of Ca(OH)2 were found in all experimental groups, regardless of the removal technique used. There was no statistically significant difference in cleanliness in the apical third of the root canal among groups 1, 2, and 3. Group 4 showed the best and group 5 the worst results with statistically significant differences. Overall, the NaviTip FX irrigation needle technique was more efficient in removing a Ca(OH)2-chlorhexidine paste from the root canal. PMID- 26943103 TI - Elementary Students' Physical Activity Levels and Behavior When Using Stability Balls. AB - OBJECTIVE: Physical activity is positively related to improved student behaviors. Stability balls have been used as interventions to affect student behavior. The objective of this study was to determine whether the use of stability balls elicits more physical activity than the use of regular chairs and whether stability balls positively influence behavior. METHOD: Participants (n = 43 fourth graders) sat on stability balls during class and wore accelerometers. Eight were randomly selected for behavioral observations using momentary time sampling. RESULTS: Significant decreases in accelerometer counts were found. No obvious difference for on-task behaviors was found between students using stability balls and those using chairs. CONCLUSION: Stability balls do not necessarily elicit more physical activity than do chairs; however, students accumulate light-intensity physical activity when using them. Classroom behavior was not detrimentally affected by stability ball use; thus, stability balls do not appear to detract from the classroom instructional atmosphere. PMID- 26943104 TI - Effect of Occupational Therapy-Led Playgroups in Early Intervention on Child Playfulness and Caregiver Responsiveness: A Repeated-Measures Design. AB - OBJECTIVE: This study's objective was to investigate the effects of a community playgroup on the playfulness of children with special needs ages 15 mo to 3 yr and the responsiveness of their caregivers. METHOD: Using a pretest-posttest, repeated-measures design, we evaluated 8 child-caregiver dyads participating in an 8-wk occupational therapist-led community playgroup recruited from a purposive sample enrolled in early intervention. Video recordings from four time points over 4 mo were used to determine playfulness (Test of Playfulness) of the child and the responsiveness of the caregiver. RESULTS: Blinded raters assessed playfulness and responsiveness outcomes. A repeated-measures analysis of variance demonstrated that participation in the playgroup significantly increased child playfulness (etap2 = .89, p < .01). Analysis did not detect a change in caregiver responsiveness. CONCLUSION: The results of this study have implications for the use of playgroups in comprehensive occupational therapy practice in early intervention. PMID- 26943105 TI - Single-Case-Design Study of Finger-to-Axilla Compression Bandaging for Edema of the Hemiplegic Upper Limb. AB - OBJECTIVE: This single-case study investigated the effectiveness of compression bandaging from the finger to the axilla in reducing poststroke edema in the upper limb. METHOD: Repeated circumferential measurements were recorded at five points along the participants' hand and forearm. Analysis of the data included the generation of graphs, celeration lines, and visual analysis. RESULTS: Five participants with edema (mean 38 days poststroke) were recruited to the study. Fluctuations in edema were observed in all three study phases, with an increasing to decreasing trend in edema between the baseline and intervention phases. There was no clear trend from the intervention to second baseline phase. CONCLUSION: Bandaging from the fingers to the axilla appears to be effective in reducing edema in the hand and forearm. However, return of edema after removal of the bandaging suggest that a greater understanding of underlying mechanisms and the appropriate intervention protocols is warranted. PMID- 26943106 TI - Comparing and Exploring the Sensory Processing Patterns of Higher Education Students With Attention Deficit Hyperactivity Disorder and Autism Spectrum Disorder. AB - OBJECTIVE: Research regarding sensory processing and adults with attention deficit hyperactivity disorder (ADHD) or autism spectrum disorder (ASD) is limited. This study aimed to compare sensory processing patterns of groups of higher education students with ADHD or ASD and to explore the implications of these disorders for their college life. METHOD: The Adolescent/Adult Sensory Profile was administered to 28 students with ADHD and 27 students with ASD. Students and professionals were interviewed. RESULTS: The majority of students received scores that differed from those of the general population. Students with ADHD received significantly higher scores than students with ASD in relation to sensation seeking; however, there were no other major differences. CONCLUSION: Few differences exist between the sensory processing patterns of students with ADHD and ASD; however, both groups differ significantly from the general population. Occupational therapists should consider sensory processing patterns when designing supports for these groups. PMID- 26943108 TI - Survey of College Personnel: Preparedness to Serve Students With Autism Spectrum Disorder. AB - OBJECTIVE: This study explored the perceptions, preparedness, and practices of college personnel regarding support for students with autism spectrum disorder (ASD). METHOD: Members of the Association on Higher Education and Disability were invited to complete an online survey in 2012. The survey gathered data on training level, understanding of student needs, and supports provided to students with ASD in the areas of academic transitional situations, social activities, sensory needs, attention and organization, self-advocacy and self-disclosure, and emotional regulation. RESULTS: Of the 315 respondents who completed the survey, 94% were involved in designing needed supports for students with ASD. Of those involved in designing needed supports, 55% indicated the need for additional information and 63% indicated that their institution struggled with outlining the supports needed and would have liked to know more about how to support these students. CONCLUSION: Opportunities exist for occupational therapy collaboration, consultation, case management, and direct intervention to support college students with ASD. PMID- 26943107 TI - Systematic Review of Mindfulness Practice for Reducing Job Burnout. AB - OBJECTIVE: A systematic search and critical appraisal of interdisciplinary literature was conducted to evaluate the evidence for practicing mindfulness to treat job burnout and to explore implications for occupational therapy practitioners. METHOD: Eight articles met inclusion criteria. Each study was assessed for quality using the Physiotherapy Evidence Database scale. We used the U.S. Agency for Health Care Policy and Research guidelines to determine strength of evidence. RESULTS: Of the studies reviewed, participants included health care professionals and teachers; no studies included occupational therapy practitioners. Six of the 8 studies demonstrated statistically significant decreases in job burnout after mindfulness training. Seven of the studies were of fair to good quality. CONCLUSION: There is strong evidence for the use of mindfulness practice to reduce job burnout among health care professionals and teachers. Research is needed to fill the gap on whether mindfulness is effective for treating burnout in occupational therapy practitioners. PMID- 26943109 TI - Driving Rehabilitation Specialists' Perspectives on Older Driver Evaluations. AB - OBJECTIVE: We explored driving rehabilitation specialists' (DRSs') perspectives on older driver evaluations. METHOD: We conducted interviews with 26 DRSs across the United States who evaluate older drivers. Transcript analysis followed general inductive techniques to identify themes related to current systems and barriers to use. RESULTS: Themes, by Social-Ecological Model level, were as follows: (1) individual occupational therapists' commitment to mobility and safety, perceived responsibilities, and experience; (2) DRSs' relationships with drivers, medical providers, and licensing bureaus; (3) the community surrounding the DRSs, including the health care system and transportation resources; and (4) societal factors, including DRS reimbursement, reporting requirements and liability coverage, and role of national organizations. CONCLUSIONS: This qualitative study identified barriers to the development of an effective system for older driver evaluations. Future work should verify, refine, and expand these findings by targeting other stakeholder groups. PMID- 26943110 TI - Community Relocation in Very Old Age: Changes in Housing Accessibility. AB - OBJECTIVE: The objective of this study was to compare environmental barriers, housing accessibility, and usability before and after relocation of very old, single-living people in the community. It also examined whether accessibility improved after relocation compared with a simulated scenario in which participants would have remained in their former dwellings. METHOD: Data from the Swedish part of the longitudinal Enabling Autonomy, Participation, and Well-Being in Old Age: The Home Environment as a Determinant for Healthy Ageing database were analyzed with a before-and-after design (N = 29). Mean time from before to after data collection was 2.6 yr. RESULTS: The number of environmental barriers was significantly reduced after relocation, especially barriers at entrances and in bathrooms. In addition, usability was stable and accessibility improved compared with the simulated scenario of remaining in the former dwelling. CONCLUSION: Community-based moves to new dwellings may lead to fewer environmental barriers and stable levels of usability and accessibility. This relocation is a positive outcome, considering the expected functional decline in old age. PMID- 26943111 TI - Simulator Measures and Identification of Older Drivers With Mild Cognitive Impairment. AB - This study examined whether a sign recall task on a driving simulator, self report of driving ability, or age predicted differences in performance between drivers with mild cognitive impairment (MCI) and control participants. For the dependent measure, gathered using a driving simulator, working memory was subjected to interference at varying levels of driving task demands. Reliable between-groups differences in sign recall accuracy were demonstrated; recall declined under higher task demands. Recall scores, self-reported frequency of avoiding driving, and driver age did not predict MCI; only self-reported decline in global driving ability was significant. Findings support the use of driving simulators in practice and suggest that screening for age-related cognitive impairment should incorporate self-reported changes in driving proficiency for early identification of drivers who merit medical review. The results, although exploratory, have implications for practitioners. PMID- 26943112 TI - Validation of the Evidence-Based Practice Confidence (EPIC) Scale With Occupational Therapists. AB - OBJECTIVE: This study evaluated the reliability, minimal detectable change (MDC), and construct validity of the Evidence-Based Practice Confidence (EPIC) scale among occupational therapists. METHOD: In a cross-sectional mail survey, 126 occupational therapists completed the EPIC scale and a questionnaire to provide data for validity testing. Seventy-nine occupational therapists (63%) completed a second EPIC scale a median of 24 days later. RESULTS: Test-retest reliability was .92 (95% confidence interval [.88, .95]). The MDC values at the 90% and 95% confidence levels were 3.9 percentage points and 4.6 percentage points, respectively. The total EPIC score was significantly associated with holding a master's or doctoral degree; education in evidence-based practice (EBP); higher EBP knowledge and skill; and frequently searching, reading, and using research findings in clinical decision making (p < .05). CONCLUSION: The EPIC scale has excellent reliability and acceptable construct validity for use in evaluating EBP self-efficacy among occupational therapists. PMID- 26943115 TI - Efficacy of Compression Gloves in Maintaining Edema Reductions After Application of Compression Bandaging to the Stroke-Affected Upper Limb. AB - OBJECTIVE: We explored the efficacy of compression gloves in maintaining the benefits gained from compression bandaging of the stroke-affected upper limb. METHOD: Four participants completed a single-case (ABC) design study consisting of a baseline period (Phase A) and compression bandaging of the hand and upper limb (Phase B), followed by the application of a compression glove (Phase C). Edema was measured with circumferential tape at five specified points from the phalanx to the midforearm. All measurements were represented graphically for visual analysis, and celeration lines were calculated to indicate the degree of slope within each phase. RESULTS: Visual analysis indicated fluctuating edema volume during Phase A, decreasing edema volume during Phase B, and a mixed trend during Phase C. CONCLUSION: Compression gloves had mixed benefits in managing reductions in edema volume poststroke. Further research may consider the material, sizing, and style of glove in the development of a maintenance strategy. PMID- 26943114 TI - Cognitive Assessment Trends in Home Health Care for Adults With Mild Stroke. AB - OBJECTIVE: This article describes current trends in cognitive assessment use for adults with mild stroke by home health practitioners in the United States. METHOD: Participants were 56 home health occupational therapists and occupational therapy assistants. A self-administered survey about use of cognitive assessment tools in home health care and influences on their use was conducted. RESULTS: Ninety-six percent of participants assessed cognition in adults with mild stroke. Nonstandardized assessments were the most widely used method for evaluating cognition in the home health setting. Influences such as specialized training in specific assessments, confidence, and productivity requirements may have affected the practitioners' cognitive assessment decisions in home health care. CONCLUSION: Although cognitive assessments are widely used in home health care, occupational therapy practitioners are selecting nonstandardized assessments most frequently to assess cognition. PMID- 26943113 TI - Combined Cognitive-Strategy and Task-Specific Training Affects Cognition and Upper-Extremity Function in Subacute Stroke: An Exploratory Randomized Controlled Trial. AB - The purpose of this study was to estimate the effect of Cognitive Orientation to Daily Occupational Performance (CO-OP) compared with usual occupational therapy on upper-extremity movement, cognitive flexibility, and stroke impact in people less than 3 mo after stroke. An exploratory, single-blind randomized controlled trial was conducted with people referred to outpatient occupational therapy services at two rehabilitation centers. Arm movement was measured with the Action Research Arm Test, cognitive flexibility with the Delis-Kaplan Executive Function System Trail Making subtest, and stroke impact with subscales of the Stroke Impact Scale. A total of 35 participants were randomized, and 26 completed the intervention. CO-OP demonstrated measurable effects over usual care on all measures. These data provide early support for the use of CO-OP to improve performance and remediate cognitive and arm movement impairments after stroke over usual care; however, future study is warranted to confirm the effects observed in this trial. PMID- 26943116 TI - Validity and Responsiveness of the Revised Nottingham Sensation Assessment for Outcome Evaluation in Stroke Rehabilitation. AB - OBJECTIVE: This study establishes the concurrent validity, predictive validity, and responsiveness of the Revised Nottingham Sensation Assessment (rNSA) during rehabilitation for people with stroke. METHOD: The study recruited 147 patients with stroke. The main assessment used was the rNSA, and outcome measures were the Fugl-Meyer Assessment sensory subscale (FMA-S) and motor subscale (FMA-M) and the Nottingham Extended Activities of Daily Living (NEADL) scale. RESULTS: Correlation coefficients were good to excellent between the rNSA and the FMA-S. The rNSA proprioception measure was a predictor for the FMA-S. The rNSA stereognosis and tactile-pinprick measures for the proximal upper limb were predictors for the FMA-M and the NEADL scale, respectively. Responsiveness was moderate to large for three subscales of the rNSA (standardized response mean = .51-.83). CONCLUSION: This study may support the concurrent validity, predictive validity, and responsiveness of the rNSA for people with stroke. PMID- 26943117 TI - Reliability and Validity of the Brazilian Version of the Late-Life Function and Disability Instrument. AB - OBJECTIVE: We evaluated the test-retest reliability, internal consistency, and construct validity of the Brazilian version of the Late-Life Function and Disability Instrument. METHOD: A sample of 118 older adults provided data for testing construct validity and internal consistency, and 14 provided data for testing test-retest reliability. Factor analysis with varimax rotation was used to assess construct validity. RESULTS: The Function component had excellent test retest and total internal consistency reliability. Factor analysis revealed that the Upper Extremity Function and Advanced Lower Extremity Function domains were similar to the original analysis. The Disability component showed adequate to excellent test-retest reliability, except in the Management role; total internal consistency was excellent. Factor analysis revealed that its domains were similar to the original analysis, except for some items. CONCLUSION: The Late-Life Function and Disability Instrument is recommended for assessment of Brazilian community-dwelling older adults who are functionally independent and who do not require mobility assistance. PMID- 26943118 TI - Innovative Power Wheelchair Control Interface: A Proof-of-Concept Study. AB - Some people without independent mobility are candidates for powered mobility but are unable to use a traditional power wheelchair joystick. This proof-of-concept study tested and further developed an innovative method of driving power wheelchairs for people whose impairments prevent them from operating commercial wheelchair controls. Our concept, Self-referenced Personal Orthotic Omni-purpose Control Interface (SPOOCI), is distinguished by referencing the control sensor not to the wheelchair frame but instead to the adjacent proximal lower-extremity segment via a custom-formed orthosis. Using a descriptive case-series design, we compared the pre-post functional power wheelchair driving skill data of 4 participants, measured by the Power Mobility Program, using descriptive analyses. The intervention consisted of standard-care power wheelchair training during 12 outpatient occupational or physical therapy sessions. All 4 participants who completed the 12-wk intervention improved their functional power wheelchair driving skills using SPOOCI, but only 3 were deemed safe to continue with power wheelchair driving. PMID- 26943119 TI - Evidence-Based Approach to Treating Lateral Epicondylitis Using the Occupational Adaptation Model. AB - The occupational therapy Centennial Vision reinforces the importance of informing consumers about the benefit of occupational therapy and continuing to advocate for the unique client-centered role of occupational therapy. Occupational therapy practitioners working in hand therapy have traditionally found it difficult to combine the biomechanical foundations of hand therapy with the fundamental client centered tenets of occupational therapy. Embracing our historical roots will become more important as health care evolves and third-party payers continue to scrutinize the need for the profession of occupational therapy. This article outlines a client-centered approach for hand therapists for the treatment of lateral epicondylitis using the Occupational Adaptation Model. PMID- 26943121 TI - Novel Perspectives on the Characterization of Species-Dependent Optical Signatures of Bacterial Colonies by Digital Holography. AB - The use of light diffraction for the microbiological diagnosis of bacterial colonies was a significant breakthrough with widespread implications for the food industry and clinical practice. We previously confirmed that optical sensors for bacterial colony light diffraction can be used for bacterial identification. This paper is focused on the novel perspectives of this method based on digital in line holography (DIH), which is able to reconstruct the amplitude and phase properties of examined objects, as well as the amplitude and phase patterns of the optical field scattered/diffracted by the bacterial colony in any chosen observation plane behind the object from single digital hologram. Analysis of the amplitude and phase patterns inside a colony revealed its unique optical properties, which are associated with the internal structure and geometry of the bacterial colony. Moreover, on a computational level, it is possible to select the desired scattered/diffracted pattern within the entire observation volume that exhibits the largest amount of unique, differentiating bacterial features. These properties distinguish this method from the already proposed sensing techniques based on light diffraction/scattering of bacterial colonies. The reconstructed diffraction patterns have a similar spatial distribution as the recorded Fresnel patterns, previously applied for bacterial identification with over 98% accuracy, but they are characterized by both intensity and phase distributions. Our results using digital holography provide new optical discriminators of bacterial species revealed in one single step in form of new optical signatures of bacterial colonies: digital holograms, reconstructed amplitude and phase patterns, as well as diffraction patterns from all observation space, which exhibit species-dependent features. To the best of our knowledge, this is the first report on bacterial colony analysis via digital holography and our study represents an innovative approach to the subject. PMID- 26943122 TI - Transposition of the Great Arteries in Fetal Life: Accuracy of Diagnosis and Short-Term Outcome. AB - OBJECTIVE: To review our series of prenatally diagnosed transposition of the great arteries (TGA) to analyze the accuracy of fetal echocardiography for achieving a precise diagnosis of the TGA type (simple vs. complex) and to examine the short-term outcome. METHODS: A total of 94 cases of simple and complex TGA types (ventriculoarterial discordance with atrioventricular concordance) prenatally evaluated in our referral center between 1998 and 2014 were included. Fetuses with additional congenital anomalies and those with incomplete follow-up were excluded. Prenatal diagnostic accuracy and short-term survival were analyzed for the different types of TGA. RESULTS: The TGA type was correctly ascertained prenatally in 93.3%. Most fetuses were diagnosed with simple TGA (62.7%). There were 6 discrepancies: 5 fetuses with simple TGA had postnatally TGA + ventricular septal defect (VSD; n = 3) or TGA + VSD + coarctation of the aorta (n = 2), and 1 fetus with TGA + VSD postnatally showed severe left ventricular outflow tract obstruction. The mortality rate was 6.6%; it was higher in complex versus simple forms (12.8 vs. 1.9%, p = 0.038), and in cases with intramural coronary artery versus those without (60 vs. 3.5%, p < 0.001). We found no relationship between the arrangement of the great arteries and coronary arterial abnormalities. CONCLUSIONS: Simple TGA has a better outcome than the complex forms. A discrepancy rate of 7% with potential influence on the prognosis of survival between the prenatal diagnosis of the TGA type and the definitive diagnosis was found. PMID- 26943123 TI - Behavioral Avoidance - Will Physiological Insecticide Resistance Level of Insect Strains Affect Their Oviposition and Movement Responses? AB - Agricultural organisms, such as insect herbivores, provide unique opportunities for studies of adaptive evolutionary processes, including effects of insecticides on movement and oviposition behavior. In this study, Brassica leaves were treated with one of two non-systemic insecticides and exposed to two individual strains (referred to as single or double resistance) of diamondback moth (Plutella xylostella) (DBM) exhibiting physiological resistance. Behavioral responses by these two strains were compared as part of characterizing the relative effect of levels of physiological resistance on the likelihood of insects showing signs of behavioral avoidance. For each DBM strain, we used choice bioassays to quantify two possible types of behavioral avoidance: 1) females ovipositing predominantly on leaf surfaces without insecticides, and 2) larvae avoiding insecticide-treated leaf surfaces. In three-choice bioassays (leaves with no pesticide, 50% coverage with pesticide, or 100% coverage with pesticide), females from the single resistance DBM strain laid significantly more eggs on water treated leaves compared to leaves with 100% insecticide coverage (both gamma-cyhalothrin and spinetoram). Females from the double resistance DBM strain also laid significantly more eggs on water treated leaves compared to leaves with 100% gamma-cyhalothrin, while moths did not adjust their oviposition behavior in response to spinetoram. Larvae from the single resistance DBM strain showed a significant increase in mobility in response to both insecticides and avoided insecticide-treated portions of leaves when given a choice. On the other hand, DBM larvae from the double resistance strain showed a significant decrease in mobility in response to insecticides, and they did not avoid insecticide-treated portions of leaves when given a choice. Our results suggest that pest populations with physiological resistance may show behavioral avoidance, as resistant females avoided oviposition on leaves without gamma-cyhalothrin. Thus, physiological resistance and behavioral avoidance do not appear to be controlled by the same selection pressures, and the mechanisms responsible for behavioral avoidance may vary among life stages. Our analysis also suggested that a population with lesser physiological resistance to insecticides may be under a stronger selection pressure and therefore be more likely to develop avoidance behaviors than a population with higher levels of physiological resistance. PMID- 26943124 TI - Integration of HIV Care into Community Management of Acute Childhood Malnutrition Permits Good Outcomes: Retrospective Analysis of Three Years of a Programme in Lusaka. AB - BACKGROUND: While HIV has had a major impact on health care in southern Africa, there are few data on its impact on acute malnutrition in children in the community. We report an analysis of outcomes in a large programme of community management of acute malnutrition in the south of Lusaka. PROGRAMME ACTIVITIES AND ANALYSIS: Over 3 years, 68,707 assessments for undernutrition were conducted house-to-house, and children with severe acute malnutrition (SAM) or moderate acute malnutrition (MAM) were enrolled into either Outpatient Therapeutic Programme (OTP) or Supplementary Feeding Programme (SFP) respectively. Case records were analysed using tabulation and unconditional logistic regression. FINDINGS: 1,859 children (889 boys, 970 girls; median age 16 months) with MAM (n = 664) or SAM (n = 1,195) were identified. Of 1,796 children whose parents consented to testing, 185 (10.3%) were HIV positive. Altogether 1,163 (62.6%) were discharged as recovered from acute malnutrition. Case fatality while in the programme was 4.2% in children with SAM and 0.5% in those with MAM (RR of SAM 10.9; 95%CI 3.4,34.8; P<0.0001), and higher in children with HIV infection (RR 5.2, 95%CI 2.9, 9.0; P<0.0001). In multivariate analysis, HIV (OR 5.2; 95%CI 2.6, 10.1; P<0.0001), MUAC <11.5 cm (OR 4.1; 95%CI 2.2, 7.4; P<0.0001) and the first year of the programme (OR 1.9; 95%CI 1.0, 3.4; P = 0.04) all increased mortality. Children with HIV infection who were able to initiate antiretroviral therapy had lower mortality (RR 0.23; 95%CI 0.10, 0.57; P = 0.0008). INTERPRETATION: Our programme suggests that a comprehensive community malnutrition programme, incorporating HIV care, can achieve low mortality even in a population heavily affected by HIV. PMID- 26943126 TI - A Large-Scale Pattern of Ontogenetic Shape Change in Ray-Finned Fishes. AB - Fishes exhibit a remarkable diversity of body shape as adults; however, it is unknown whether this diversity is reflected in larval stage morphology. Here we investigate the relationship between larval and adult body shape as expressed by body elongation. We surveyed a broad range of ray-finned fish species and compared body shape at larval and adult stages. Analysis shows that the vast majority of fish are more elongate at the larval stage than at the adult stage, and that adults display greater interspecies variation than larvae. We found that the superorder Elompomorpha is unique because many species within the group do not follow the observed elongation trends. These results indicate that much of the diversity observed in adults is achieved in post-larval stages. We suggest that larval morphology is subject to common constraints across the phylogeny. PMID- 26943125 TI - IL-33-Dependent Endothelial Activation Contributes to Apoptosis and Renal Injury in Orientia tsutsugamushi-Infected Mice. AB - Endothelial cells (EC) are the main target for Orientia tsutsugamushi infection and EC dysfunction is a hallmark of severe scrub typhus in patients. However, the molecular basis of EC dysfunction and its impact on infection outcome are poorly understood. We found that C57BL/6 mice that received a lethal dose of O. tsutsugamushi Karp strain had a significant increase in the expression of IL-33 and its receptor ST2L in the kidneys and liver, but a rapid reduction of IL-33 in the lungs. We also found exacerbated EC stress and activation in the kidneys of infected mice, as evidenced by elevated angiopoietin (Ang) 2/Ang1 ratio, increased endothelin 1 (ET-1) and endothelial nitric oxide synthase (eNOS) expression. Such responses were significantly attenuated in the IL-33-/- mice. Importantly, IL-33-/- mice also had markedly attenuated disease due to reduced EC stress and cellular apoptosis. To confirm the biological role of IL-33, we challenged wild-type (WT) mice with a sub-lethal dose of O. tsutsugamushi and gave mice recombinant IL-33 (rIL-33) every 2 days for 10 days. Exogenous IL-33 significantly increased disease severity and lethality, which correlated with increased EC stress and activation, increased CXCL1 and CXCL2 chemokines, but decreased anti-apoptotic gene BCL-2 in the kidneys. To further examine the role of EC stress, we infected human umbilical vein endothelial cells (HUVEC) in vitro. We found an infection dose-dependent increase in the expression of IL-33, ST2L soluble ST2 (sST2), and the Ang2/Ang1 ratio at 24 and 48 hours post infection. This study indicates a pathogenic role of alarmin IL-33 in a murine model of scrub typhus and highlights infection-triggered EC damage and IL-33 mediated pathological changes during the course of Orientia infection. PMID- 26943127 TI - Landscape Simplification Constrains Adult Size in a Native Ground-Nesting Bee. AB - Bees provide critical pollination services to 87% of angiosperm plants; however, the reliability of these services may become threatened as bee populations decline. Agricultural intensification, resulting in the simplification of environments at the landscape scale, greatly changes the quality and quantity of resources available for female bees to provision their offspring. These changes may alter or constrain the tradeoffs in maternal investment allocation between offspring size, number and sex required to maximize fitness. Here we investigate the relationship between landscape scale agricultural intensification and the size and number of individuals within a wild ground nesting bee species, Andrena nasonii. We show that agricultural intensification at the landscape scale was associated with a reduction in the average size of field collected A. nasonii adults in highly agricultural landscapes but not with the number of individuals collected. Small females carried significantly smaller (40%) pollen loads than large females, which is likely to have consequences for subsequent offspring production and fitness. Thus, landscape simplification is likely to constrain allocation of resources to offspring through a reduction in the overall quantity, quality and distribution of resources. PMID- 26943128 TI - Randomized Trial of Introduction of Allergenic Foods in Breast-Fed Infants. AB - BACKGROUND: The age at which allergenic foods should be introduced into the diet of breast-fed infants is uncertain. We evaluated whether the early introduction of allergenic foods in the diet of breast-fed infants would protect against the development of food allergy. METHODS: We recruited, from the general population, 1303 exclusively breast-fed infants who were 3 months of age and randomly assigned them to the early introduction of six allergenic foods (peanut, cooked egg, cow's milk, sesame, whitefish, and wheat; early-introduction group) or to the current practice recommended in the United Kingdom of exclusive breast feeding to approximately 6 months of age (standard-introduction group). The primary outcome was food allergy to one or more of the six foods between 1 year and 3 years of age. RESULTS: In the intention-to-treat analysis, food allergy to one or more of the six intervention foods developed in 7.1% of the participants in the standard-introduction group (42 of 595 participants) and in 5.6% of those in the early-introduction group (32 of 567) (P=0.32). In the per-protocol analysis, the prevalence of any food allergy was significantly lower in the early introduction group than in the standard-introduction group (2.4% vs. 7.3%, P=0.01), as was the prevalence of peanut allergy (0% vs. 2.5%, P=0.003) and egg allergy (1.4% vs. 5.5%, P=0.009); there were no significant effects with respect to milk, sesame, fish, or wheat. The consumption of 2 g per week of peanut or egg white protein was associated with a significantly lower prevalence of these respective allergies than was less consumption. The early introduction of all six foods was not easily achieved but was safe. CONCLUSIONS: The trial did not show the efficacy of early introduction of allergenic foods in an intention-to-treat analysis. Further analysis raised the question of whether the prevention of food allergy by means of early introduction of multiple allergenic foods was dose dependent. (Funded by the Food Standards Agency and others; EAT Current Controlled Trials number, ISRCTN14254740.). PMID- 26943129 TI - Detection of Lymph Node Metastases with SERRS Nanoparticles. AB - PURPOSE: The accurate detection of lymph node metastases in prostate cancer patients is important to direct treatment decisions. Our goal was to develop an intraoperative imaging approach to distinguish normal from metastasized lymph nodes. We aimed at developing and testing gold-silica surface-enhanced resonance Raman spectroscopy (SERRS) nanoparticles that demonstrate high uptake within normal lymphatic tissue and negligible uptake in areas of metastatic replacement. PROCEDURES: We evaluated the ability of SERRS nanoparticles to delineate lymph node metastases in an orthotopic prostate cancer mouse model using PC-3 cells transduced with mCherry fluorescent protein. Tumor-bearing mice (n = 6) and non tumor-bearing control animals (n = 4) were injected intravenously with 30 fmol/g SERRS nanoparticles. After 16-18 h, the retroperitoneal lymph nodes were scanned in situ and ex vivo with a Raman imaging system and a handheld Raman scanner and data corroborated with fluorescence imaging for mCherry protein expression and histology. RESULTS: The SERRS nanoparticles demonstrated avid homing to normal lymph nodes, but not to metastasized lymph nodes. In cases where lymph nodes were partially infiltrated by tumor cells, the SERRS signal correctly identified, with sub-millimeter precision, healthy from metastasized components. CONCLUSIONS: This study serves as a first proof-of-principle that SERRS nanoparticles enable high precision and rapid intraoperative discrimination between normal and metastasized lymph nodes. PMID- 26943130 TI - The Experimental Research (In Vitro) of Carrageenans and Fucoidans to Decrease Activity of Hantavirus. AB - The effect of carrageenans and fucoidans on the activity of Hantavirus is studied. It has been found that among carrageenans a significant antiviral effect is exerted by the iota-type, which decreases the viral titer by 2.5 log focus forming units per mL; among fucoidans, by a preparation from Laminaria cichorioides, which reduces the number of infected cells from 27.0 to 5.3 after pretreatment of both the macrophage culture and Hantavirus. The antiviral effect of fucoidan from Laminaria japonica is shown to grow in direct proportion to the increase of dose of the preparation. PMID- 26943131 TI - Impact of the scout view orientation on the radiation exposure and image quality in thoracic and abdominal CT. AB - OBJECTIVES: To assess the impact of the scout view orientation on radiation exposure and image quality in thoracoabdominal CT, when automated tube voltage selection (ATVS) and automated tube current modulation (ATCM) are used in combination with scan planning on a single scout view. METHODS: Fifty patients underwent two thoracoabdominal CT examinations, one planned on an anteroposterior scout view, one planned on a lateral scout view. Both examinations included contrast-enhanced imaging of chest (CH) and abdomen (AB) and non-contrast enhanced imaging of the liver (LI). For all examinations the same imaging protocol was used on the same dual-source CT scanner. The radiation exposure was recorded and objective as well as visual image quality was assessed for all examinations. RESULTS: The median dose-length product was significantly lower in scans planned on a lateral scout view (CH: 179 vs. 218 mGy*cm, LI: 148 vs. 178 mGy*cm, AB: 324 vs. 370 mGy*cm, p < 0.0001). Objective image quality was marginal lower in scans planned on a lateral scout view, whereas the visual image quality was rated as equal. CONCLUSION: At the tested radiation doses, the orientation of the scout view has a significant impact on the radiation exposure but no clinically relevant impact on the image quality. KEY POINTS: * The scout view orientation has a significant impact on the radiation exposure. * The scout view orientation has no clinically relevant impact on image quality. * A lateral scout view should be preferred with regard to radiation exposure. PMID- 26943132 TI - Postprandial changes in secretory flow of pancreatic juice in the main pancreatic duct: evaluation with cine-dynamic MRCP with a spatially selective inversion recovery (IR) pulse. AB - PURPOSE: To evaluate the influence of oral ingestion on the secretory flow dynamics of physiological pancreatic juice within the main pancreatic duct in healthy subjects by using cine-dynamic MRCP with spatially-selective inversion recovery (IR) pulse non-invasively. MATERIALS AND METHODS: Thirty-eight healthy subjects were investigated. MRCP with spatially-selective IR pulse was repeated every 15 s for 5 min to acquire a total of 20 images (cine-dynamic MRCP). A set of 20 MRCP images was repeatedly obtained before and after liquid oral ingestion every 7 min (including 2-min interval) for 40 min (a total of seven sets). Secretion grade of pancreatic juice on cine-dynamic MRCP was compared before and after oral ingestion using the nonparametric Wilcoxon signed-rank test. RESULTS: Median secretion grades of pancreatic juice at 5 min (score = 2.15), 12 min (score = 1.95) and 19 min (score = 2.05) after ingestion were significantly higher than that before ingestion (score = 1.40) (P = 0.004, P = 0.032, P = 0.045, respectively). Secretion grade of pancreatic juice showed a maximum peak of 2.15 at 5 min after ingestion. Thereafter, the secretion grade of pancreatic juice tended to gradually decline. CONCLUSION: Non-invasive cine-dynamic MRCP using spatially-selective IR pulse showed potential for evaluating postprandial changes in the secretory flow dynamics of pancreatic juice as a physiological reaction. KEY POINTS: * Secretion grade of pancreatic juice at cine-dynamic MRCP after ingestion was evaluated. * Secretion grade was significantly increased within 19 min after liquid meal ingestion. * Secretion grade showed maximum peak of 2.15 at 5 min after ingestion. * Postprandial changes in pancreatic juice flow can be assessed by cine-dynamic MRCP. PMID- 26943133 TI - The diagnostic ability of 18F-FDG PET/CT for mediastinal lymph node staging using 18F-FDG uptake and volumetric CT histogram analysis in non-small cell lung cancer. AB - OBJECTIVES: To evaluate the clinical implications of lymph node (LN) density on 18F-FDG PET/CT for mediastinal LN characterization in non-small cell lung cancer (NSCLC). METHODS: One hundred and fifty-two patients with 271 mediastinal LNs who underwent PET/CT and endobronchial ultrasound-guided transbronchial needle aspiration for staging were enrolled. Maximum standardized uptake value (SUVmax), short axis diameter, LN-to-primary cancer ratio of SUVmax, and median Hounsfield unit (HU) based on CT histogram were correlated to histopathology. RESULTS: Of 271 nodes, 162 (59.8 %) were malignant. SUVmax, short axis diameter, and LPR of malignant LNs were higher than those of benign nodes. Among malignant LNs, 71.0 % had median HU between 25 and 45, while 78.9 % of benign LNs had values <25 HU or >45 HU. Using a cutoff value of 4.0, SUVmax showed the highest diagnostic ability for detecting malignant LNs with a specificity of 94.5 %, but showing a sensitivity of 70.4 %. Using additional density criteria (median HU 25-45) in LNs with 2.0< SUVmax <=4.0, the sensitivity increased to 88.3 % with the specificity of 82.6 %. CONCLUSIONS: LN density is useful for the characterization of LNs with mild 18F-FDG uptake. The risk of mediastinal LN metastasis in NSCLC patients could be further stratified using both 18F-FDG uptake and LN density. KEY POINTS: * SUVmax showed the highest diagnostic ability for detecting malignant LNs. * LN density was useful in characterization of LNs with mild FDG uptake. * SUVmax and LN density together could stratify the risk of LN metastasis. PMID- 26943139 TI - Heterosexual Young Adults' Interest, Attitudes, and Experiences Related to Mixed Gender, Multi-Person Sex. AB - There has been little research on threesomes, a form of multi-person sex that involves sexual activity with two other people simultaneously. Therefore, we examined young adults' attitudes toward, interest in, and experiences with one form of threesome, mixed-gender threesomes (MGTs), defined as sexual activity involving three people where at least one member of each gender is present. Participants were 274 (202 women, 72 men) heterosexual young adults who completed an online survey. Overall, 13 % of participants (24 % of men and 8 % of women) reported experience and 64 % reported some interest in engaging in an MGT. However, the overall level of interest was quite low and varied according to contextual variables (i.e., what other persons were involved). Men's interest remained unaffected by third person status as long as the MGT involved familiar others (friends and acquaintances) rather than strangers, whereas women preferred familiar others only for MGTs with which they were the third person, not for those involving a romantic partner. Participants also reported fairly neutral attitudes toward MGTs. Compared to the women, the men reported significantly more positive attitudes and greater interest, and were more likely to report MGT experience. In addition, attitudes, interest, and experience were all positively associated with each other. Taken together, these results suggest that young people are not judgmental about others engaging in MGTs but are not highly motivated to do so themselves. Implications for researchers and sexual health educators are discussed. PMID- 26943135 TI - Benign biliary strictures refractory to standard bilioplasty treated using polydoxanone biodegradable biliary stents: retrospective multicentric data analysis on 107 patients. AB - OBJECTIVES: To assess mid-term outcome of biodegradable biliary stents (BBSs) to treat benign biliary strictures refractory to standard bilioplasty. METHODS: Institutional review board approval was obtained and patient consent was waived. 107 patients (61 males, 46 females, mean age 59 +/- 16 years), were treated. Technical success and complications were recorded. Ninety-seven patients (55 males, 42 females, aged 57 +/- 17 years) were considered for follow-up analysis (mean follow-up 23 +/- 12 months). Fisher's exact test and Mann-Whitney U tests were used and a Kaplan-Meier curve was calculated. RESULTS: The procedure was always feasible. In 2/107 cases (2 %), stent migration occurred (technical success 98 %). 4/107 patients (4 %) experienced mild haemobilia. No major complications occurred. In 19/97 patients (18 %), stricture recurrence occurred. In this group, higher rate of subsequent cholangitis (84.2 % vs. 12.8 %, p = 0.001) and biliary stones (26.3 % vs. 2.5 %, p = 0.003) was noted. Estimated mean time to stricture recurrence was 38 months (95 % C.I 34-42 months). Estimated stricture recurrence rate at 1, 2, and 3 years was respectively 7.2 %, 26.4 %, and 29.4 %. CONCLUSION: Percutaneous placement of a BBS is a feasible and safe strategy to treat benign biliary strictures refractory to standard bilioplasty, with promising results in the mid-term period. KEY POINTS: * Percutaneous placement of a BBS is 100 % feasible. * The procedure appears free from major complications, with few minor complications. * BBSs offer promising results in the mid-term period. * With a BBS, external catheter/drainage can be removed early. * BBSs represent a new option in treating benign biliary stenosis. PMID- 26943134 TI - In vivo proton magnetic resonance spectroscopy (1H-MRS) evaluation of the metabolite concentration of optic radiation in primary open angle glaucoma. AB - OBJECTIVE: To compare the metabolite concentration of optic radiation in glaucoma patients with that of healthy subjects using Proton Magnetic Resonance Spectroscopy (1H-MRS). METHODS: 1H-MRS utilising the Single-Voxel Spectroscopy (SVS) technique was performed using a 3.0Tesla MRI on 45 optic radiations (15 from healthy subjects, 15 from mild glaucoma patients, and 15 from severe glaucoma patients). A standardised Volume of Interest (VOI) of 20 * 20 * 20 mm was placed in the region of optic radiation. Mild and severe glaucoma patients were categorised based on the Hodapp-Parrish-Anderson (HPA) classification. Mean and multiple group comparisons for metabolite concentration and metabolite concentration ratio between glaucoma grades and healthy subjects were obtained using one-way ANOVA. RESULTS: The metabolite concentration and metabolite concentration ratio between the optic radiations of glaucoma patients and healthy subjects did not demonstrate any significant difference (p > 0.05). CONCLUSION: Our findings show no significant alteration of metabolite concentration associated with neurodegeneration that could be measured by single-voxel 1H-MRS in optic radiation among glaucoma patients. KEY POINTS: * Glaucoma disease has a neurodegenerative component. * Metabolite changes have been observed in the neurodegenerative process in the brain. * Using SVS, no metabolite changes in optic radiation were attributed to glaucoma. PMID- 26943142 TI - Bone Quality in Paget's Disease of Bone. AB - Paget's disease of bone is produced by a localized increase in osteoclastic and osteoblastic activity which can progress slowly to involve an entire bone if untreated. A common feature is enlarged bones which are deformed, particularly in weight-bearing regions of the skeleton such as the lower extremity. Pathologic fractures may be a consequence, and nonunion of femoral fractures is not uncommon. Analyses of bone biopsies from patients with Paget's disease indicate that there is a lower, heterogeneous degree of bone mineralization and a younger tissue age than that found in control bone. Pagetic bone also has less resistance to plastic deformation and a straighter crack path than control bone. PMID- 26943141 TI - Post-menopausal Women Exhibit Greater Interleukin-6 Responses to Mental Stress Than Older Men. AB - BACKGROUND: Acute stress triggers innate immune responses and elevation in circulating cytokines including interleukin-6 (IL-6). The effect of sex on IL-6 responses remains unclear due to important limitations of previous studies. PURPOSE: The purpose of this study was to examine sex differences in IL-6 responses to mental stress in a healthy, older (post-menopausal) sample accounting for several moderating factors. METHODS: Five hundred six participants (62.9 +/- 5.60 years, 55 % male) underwent 10 min of mental stress consisting of mirror tracing and Stroop task. Blood was sampled at baseline, after stress, and 45 and 75 min post-stress, and assayed using a high sensitivity kit. IL-6 reactivity was computed as the mean difference between baseline and 45 min and between baseline and 75 min post-stress. Main effects and interactions were examined using ANCOVA models. RESULTS: There was a main effect of time for the IL 6 response (F 3,1512 = 201.57, p = <.0001) and a sex by time interaction (F 3,1512 = 17.07, p = <.001). In multivariate adjusted analyses, IL-6 reactivity was significantly greater in females at 45 min (M = 0.37 +/- 0.04 vs. 0.20 +/- 0.03 pg/mL, p = .01) and at 75 min (M = 0.57 +/- 0.05 vs. 0.31 +/- 0.05 pg/mL, p = .004) post-stress compared to males. Results were independent of age, adiposity, socioeconomic position, depression, smoking and alcohol consumption, physical activity, statin use, testing time, task appraisals, hormone replacement, and baseline IL-6. Other significant predictors of IL-6 reactivity were lower household wealth, afternoon testing, and baseline IL-6. CONCLUSIONS: Healthy, post-menopausal females exhibit substantially greater IL-6 responses to acute stress. Inflammatory responses if sustained over time may have clinical implications for the development and maintenance of inflammatory-related conditions prevalent in older women. PMID- 26943140 TI - Complications From Penile Bead Implantation: Three Cases From China. PMID- 26943143 TI - Clinical and Microbiological Features and Factors Associated with Fluoroquinolone Resistance in Men with Community-Acquired Acute Bacterial Prostatitis. AB - OBJECTIVES: To investigate the clinical and microbiological features in the patients with community-acquired acute bacterial prostatitis (CA-ABP), as well as factors that affect fluoroquinolone resistance. METHODS: A retrospective analysis was performed of 209 patients hospitalized for antibiotic treatment of CA-ABP. We investigated patient age, body mass index, underlying diseases, recurrence, prostate-related factors and results of urine culture examination and antibiotic sensitivity tests. RESULTS: Seventeen patients (8.1%) had fluoroquinolone resistant bacterial colonies. When we divided the subjects into groups according to the fluoroquinolone resistance, the group with resistant bacteria was significantly older, had larger prostates and had greater residual urine volumes. Bacteria were identified in 127 of 209 patients (60.8%), and the most commonly cultured included Escherichia coli (43.5%). The sensitivity of the cultured bacteria to fluoroquinolones was high compared to trimethoprim/sulfamethoxazole and gentamicin, but similar to cefotaxime. The bacteria were more sensitive to amikacin and imipenem than to fluoroquinolone. The multivariate analysis revealed that prostate volume >=40 ml (p = 0.024) and residual urine volume >100 ml (p = 0.004) were independent predictive factors for fluoroquinolone resistance. CONCLUSIONS: Fluoroquinolone monotherapy might be an effective treatment in CA ABP. However, combination antibiotic therapy is recommended in cases with prostate volume >=40 ml or residual urine volume >100 ml, because fluoroquinolone resistance can occur. PMID- 26943144 TI - Organic compound composition in soil and sediments collected in Jackson, Mississippi. AB - The aim of our study was to identify organic pollutants found in soil and sediment samples collected within the Jackson, MS metropolitan area. The chemical characterization of the organic compound fractions in soil and sediment samples was carried out by separating the organic fraction using column chromatography (CC) and quantitatively analyzing the polycyclic aromatic hydrocarbons (PAHs), n alkanes and other organic compounds using gas chromatography-electron impact mass spectrometry (GC-MS). Fifty-six compounds were identified and quantified in the soil samples and 33 compounds were identified and quantified in the sediment samples. The PAHs, n-alkanes and other organic compound profiles in the soil and sediment samples were compared. The percentage contents of the organic compounds in the soil samples were very diverse (from traces to 12.44 +/- 1.47%). The compounds present in the highest concentrations were n-alkanes: n-C31 (12.44 +/- 1.47%), n-C29 (11.64 +/- 1.21%), and n-C33 (8.95 +/- 1.08%). The components occurring in smaller quantities (from 1% to 5%) were 2 PAHs (fluoranthene 1.28 +/ 0.25%, pyrene 1.16 +/- 0.20%), 10 n-alkanes from n-C21 (1.25 +/- 0.29%) to n-C32 (2.67 +/- 0.52%) and 11 other compounds (e.g., 2-pentanol, 4-methyl (3.33 +/- 0.44%), benzyl butyl phthalate (4.25 +/- 0.59%), benzenedicarboxylic acid (1.14 +/- 0.08%), ethane, 1,1-diethoxy (3.15 +/- 0.41) and hexadecanoic acid (2.52 +/- 0.34). The soil samples also contained 30 compounds present in concentrations <1% (e.g., anthracene (0.13 +/- 0.04%), n-C20 (0.84 +/- 0.21%) and acetic acid (0.12 +/- 0.04%). The compounds present in the highest concentrations in the sediment samples were PAHs: pyrene (7.73 +/- 1.15%) and fluoranthene (6.23 +/- 1.07%) and n-alkanes: n-C31 (6.74 +/- 1.21%), n-C29 (6.65 +/- 0.98%) and n-C27 (6.13 +/- 1.09%). The remaining organic compounds were present in smaller quantities (< 5%). PMID- 26943145 TI - Seasonal variations and sources study by way of back trajectories and ANOVA for ambient air pollutants (particulates and metallic elements) within a mixed area at Longjing, central Taiwan: 1-year observation. AB - This study measured the concentrations of particulates and metallic elements in ambient air by using PS-1 sampler (TSP) at Longjing area. And this study focuses on the collection of ambient air particulates, metallic elements, particulate bound mercury Hg(p), concentrations. In addition, the sources of ambient pollutants by way of back trajectory analysis are found. Moreover, test mean concentration variance differences for metallic elements (PM, Hg(p), Mn, Fe, Zn, Cr, Cu, and Pb) among the four seasons (spring, summer, autumn and winter) through ANOVA are calculated. The result indicates that the average highest particulate concentration occurred in winter season, and the order was winter > spring > autumn > summer, and the mostly highest average metallic element (Mn, Fe, Zn, Cr, Cu, Pb) concentrations occurred in autumn. Moreover, the mostly average lowest metallic element concentrations occurred in summer. In addition, the above results of backward trajectories that the major particulate pollutants parcel mainly come from northeastern Taiwan. Moreover, when comparing the results of the first half year to that of the second half year, the they indicated that all metallic elements displayed significant differences in concentrations except those of Hg(p), Mn, Fe, Zn. Finally, metallic element Hg(p) is the only one which showed no significant concentration difference from either seasonal variations or half-year observations. PMID- 26943146 TI - The number of limiting resources in the environment controls the temporal diversity patterns in the algal benthos. AB - The role of the number of limiting resources (NLR) on species richness has been the subject of much theoretical and experimental work. However, how the NLR controls temporal beta diversity and the processes of community assembly is not well understood. To address this knowledge gap, we initiated a series of laboratory microcosm experiments, exposing periphyton communities to a gradient of NLR from 0 to 3, generated by supplementation with nitrogen, phosphorus, iron, and all their combinations. We hypothesized that similarly to alpha diversity, shown to decrease with the NLR in benthic algae, temporal beta diversity would also decline due to filtering. Additionally, we predicted that the NLR would also affect turnover and community nestedness, which would show opposing responses. Indeed, as the NLR increased, temporal beta diversity decreased; turnover, indicative of competition, decreased; and nestedness, suggestive of complementarity, increased. Finally, the NLR determined the role of deterministic versus stochastic processes in community assembly, showing respectively an increasing and a decreasing trend. These results imply that the NLR has a much greater, yet still unappreciated influence on producer communities, constraining not only alpha diversity but also temporal dynamics and community assembly. PMID- 26943147 TI - Early Corneal Cellular and Nerve Fiber Pathology in Young Patients With Type 1 Diabetes Mellitus Identified Using Corneal Confocal Microscopy. AB - PURPOSE: The aim of this study was to quantify epithelial, stromal, and endothelial cell density, and subbasal nerve morphology in young patients with type 1 diabetes mellitus with and without diabetic retinopathy. METHODS: A total of 28 young patients (mean age, 22.86 +/- 9.05 years) with type 1 diabetes, with (n = 18) and without (n = 10) retinopathy, and 17 age-matched healthy control subjects (mean age, 26.53 +/- 2.43 years) underwent corneal confocal microscopy (CCM). RESULTS: We found significantly lower epithelial (P < 0.0001) and endothelial (P = 0.001) cell densities and higher keratocyte cell density (P = 0.024) in patients with type 1 diabetes compared to controls. Significantly lower corneal nerve fiber density (P = 0.004), nerve branch density (P = 0.004), total nerve branch density (P = 0.04), and nerve fiber length (P = 0.001), and greater nerve fiber width (P = 0.04) were observed in patients with type 1 diabetes compared to control subjects. Significantly lower epithelial (P < 0.001) and endothelial (P = 0.02) cell densities, nerve branch density (P = 0.02), and nerve fiber length (P = 0.04), and significantly higher keratocyte cell density (P = 0.02) were found in patients with type 1 diabetes without retinopathy compared to control subjects. CONCLUSIONS: Corneal confocal microscopy identifies corneal cellular and small nerve fiber pathology in young patients with type 1 diabetes without retinopathy, which increases in severity in those with retinopathy. Corneal confocal microscopy appears to have considerable use as an imaging biomarker for early subclinical pathology in young patients with type 1 diabetes mellitus. PMID- 26943148 TI - Notch Signaling in Meibomian Gland Epithelial Cell Differentiation. AB - PURPOSE: Notch1 was previously shown to play a critical role in murine meibomian gland function and maintenance. In this study, we have examined the expression and activation of Notch pathway in human meibomian gland epithelial cells in vitro. METHODS: An immortalized human meibomian gland epithelial cell (HMGEC) line was cultured under proliferative and differentiative conditions. Expression of Notch receptors and ligands were evaluated by quantitative PCR and Western blot. The effect of Notch inhibition and induction on oil production was also assessed. RESULTS: Human meibomian gland epithelial cell expressed Notch1, Notch2, Notch3, Jagged1, Jagged2, Delta-like 1, and Delta-like 3. The level of cleaved (activated) Notch1 strongly increased with differentiation. The expression of Notch3 was inversely correlated with proliferation. Induction and inhibition of Notch1 led to an increase and decrease in the amount of oil production, respectively. CONCLUSIONS: Notch signaling appears to play an important role in human meibomian gland epithelial differentiation and oil production. This may provide a potential therapeutic pathway for treating meibomian gland dysfunction. PMID- 26943149 TI - Impairment of Vision in a Mouse Model of Usher Syndrome Type III. AB - PURPOSE: The purpose of this study was to obtain an Usher syndrome type III mouse model with retinal phenotype. METHODS: Speed congenic method was used to obtain Clrn1 exon 1 knockout (Clrn1-/-) and Clrn1N48K knockin (Clrn1N48K/N48K) mice under A/J background. To study the retinal functions of these mice, we measured scotopic and photopic ERG responses. To observe if there are any structural abnormalities, we conducted light and transmission electron microscopy of fixed retinal specimens. RESULTS: In 3-month-old Clrn1-/- mice, scotopic b-wave amplitude was reduced by more than 25% at the light intensities from -2.2 to 0.38 log cd.s/m2, but scotopic a-wave amplitudes were comparable to those of age matched wild type mice at all the light intensities tested. In 9-month-old Clrn1 /- mice, scotopic b-wave amplitudes were further reduced by more than 35%, and scotopic a-wave amplitude also showed a small decline as compared with wild type mice. Photopic ERG responses were comparable between Clrn1-/- and wild type mice. Those electrophysiological defects were not associated with a loss of rods. In Clrn1N48K/N48K mice, both a- and b-wave amplitudes were not discernable from those of wild type mice aged up to 10 months. CONCLUSIONS: Mutations that are Clrn1-/- biallelic cause visual defects when placed under A/J background. The absence of apparent rod degeneration suggests that the observed phenotype is due to functional defects, and not due to loss of rods. Biallelic Clrn1N48K/N48K mutations did not cause discernible visual defects, suggesting that Clrn1- allele is more severely dysfunctional than ClrnN48K allele. PMID- 26943150 TI - Erratum. Lack of Association Between Corneal Hysteresis and Corneal Resistance Factor With Glaucoma Severity in Primary Angle Closure Glaucoma. PMID- 26943152 TI - Effect of Focal Lamina Cribrosa Defect on Disc Hemorrhage Area in Glaucoma. AB - PURPOSE: The purpose of this study was to evaluate the association between focal lamina cribrosa defect (FLCD) and the topographic characteristics of disc hemorrhage (DH), including area and location. METHODS: We enrolled a total of 98 primary open-angle glaucoma eyes with DH (98 subjects). In vivo lamina cribrosa (LC) images were obtained by swept-source optical coherence tomography (SS-OCT) immediately following the detection of DH. Two masked graders identified FLCD (laminar holes or disinsertions >100 MUm in diameter and >30 MUm in depth), defined by a customized protocol using en face images and 12 radial-orientation raster scans of SS-OCT. En face image/stereo-disc photography overlay images were evaluated to determine the spatial relationship between the respective FLCD and DH locations. A method of comparing the disc area and DH area pixel numbers was used to estimate the DH area. RESULTS: Sixty-eight of 98 eyes with DH (68.4%) had at least one FLCD. Thirty-eight of those 68 eyes with DH and at least one FLCD (55.9%) had a DH corresponding to the FLCD location (within one-half clock-hour distance from the midline). The FLCD-correspondent DHs (39 DHs) showed significantly larger areas (0.092 +/- 0.030 mm2; P < 0.001) and more proximally located proximal ends (P < 0.028) than the noncorresponding ones (33 DHs; 0.065 +/- 0.024 mm2 of area). CONCLUSIONS: The DHs that correspond to FLCD location tend to have larger areas and to be more proximally located than those without correspondence. This suggests that FLCD might affect the topographic characteristics of DH. PMID- 26943154 TI - Relationship of Corneal Pain Sensitivity With Dry Eye Symptoms in Dry Eye With Short Tear Break-Up Time. AB - PURPOSE: The purpose of this prospective comparative study was to investigate corneal sensitivity in subjects with unstable tear film, with and without dry eye (DE) symptoms. METHODS: Forty-one eyes of 41 volunteers (mean age: 45.1 +/- 9.4 years; age range, 23-57 years), with normal tear function and ocular surface except for tear stability, were studied. The eyes were divided into two groups depending on the presence or absence of DE symptoms: 21 eyes with DE symptoms (symptomatic group); and 20 eyes without DE symptoms (asymptomatic group). Three types of corneal sensitivity values were measured using a Cochet-Bonnet esthesiometer: the sensitivity for perception of touch (S-touch), the sensitivity for blinking (S-blink), and the sensitivity for pain (S-pain). RESULTS: Mean S blink and S-pain were significantly higher in the symptomatic group than in the asymptomatic group (P < 0.05), whereas there was no significant difference in mean S-touch between these groups (P > 0.05). CONCLUSIONS: Corneal sensitivity for blinking and pain evoked by increased stimuli was higher in the symptomatic group (subjects with short break-up time DE) compared with subjects who have no DE symptoms despite decreased tear stability. The presence of both tear instability and hyperesthesia, rather than tear instability alone, may contribute to DE pathogenesis. PMID- 26943151 TI - Association Between Photoreceptor Regeneration and Visual Acuity Following Surgery for Rhegmatogenous Retinal Detachment. AB - PURPOSE: The purpose of this study was to evaluate foveal regeneration and the association between retinal restoration and visual acuity following reattachment surgery for rhegmatogenous retinal detachment (RRD). METHODS: Twenty-nine eyes of 29 patients with successfully reattached macula-off RRD were retrospectively analyzed. We used spectral-domain optical coherence tomography to image macular regions and measure retinal thickness and Snellen chart visual acuity (VA) to evaluate best-corrected VA (BCVA) at 1, 2, 3, 6, 9, and 12 months after vitrectomy. Best-corrected visual acuity data were converted to the logarithm of the minimum angle of resolution scale. Opposite eyes were used as controls. RESULTS: The thicknesses of the external limiting membrane (ELM)-ellipsoid zone (EZ) and EZ-retinal pigment epithelium (RPE) were significantly thinner in involved eyes than in corresponding unaffected eyes at 1 month after surgery (P < 0.001 for both), and the thickness increased over time (P < 0.001 for both). Best corrected visual acuity significantly improved over time (P < 0.001), and the improvement correlated with EZ-RPE thickness (r = -0.45, P = 0.021). Multiple regression analysis demonstrated the presence of a foveal bulge as the independent predictor of final BCVA (P < 0.001). Eyes with a foveal bulge had significantly better BCVA and greater EZ-RPE thickness than those without throughout the follow-up period. Significant restoration of the integrity of EZ and cone interdigitation zone (CIZ) was observed over time (P < 0.001 for both) in eyes with a foveal bulge. CONCLUSIONS: The thickness of EZ-RPE and cone density increased during foveal regeneration, as demonstrated by the continuous improvements in CIZ integrity over time, leading to the formation of foveal bulge and good vision following successful reattachment of macula-off RRD. PMID- 26943153 TI - PDGF-BB Enhances the Proliferation of Cells in Human Orbital Fibroblasts by Suppressing PDCD4 Expression Via Up-Regulation of microRNA-21. AB - PURPOSE: The aim of this study was to investigate the effect of platelet-derived growth factor (PDGF)-BB on the proliferation of cells and its possible mechanism in human orbital fibroblasts. METHODS: Human orbital fibroblasts were obtained from orbital fat from decompression surgery in patients with thyroid-associated ophthalmopathy (TAO). The cells were treated with PDGF-BB, and the number of cells was counted using an Advanced Detection and Accurate Measurement (ADAM) automatic cell counter. The expression of programmed cell death 4 (PDCD4) was determined by Western blotting. The effect of PDCD4 on cell proliferation was evaluated using PDCD4 small interfering RNA (siRNA)-transfected cells. The level of microRNA-21 (miRNA-21) was measured by quantitative real-time RT-PCR. In addition, the role of miRNA-21 in the proliferation of PDGF-BB-treated cells was assessed by means of anti-miRNA-21 siRNA and resveratrol (trans-3,4',5 trihydroxys-tilbene), an inhibitor of miRNA-21. RESULTS: PDGF-BB was found to enhance cell proliferation, whereas it inhibited PDCD4 expression in human orbital fibroblasts. Down-regulation of PDCD4 by PDCD4 siRNA transfection significantly increased the number of human orbital fibroblasts. In addition, PDGF-BB increased the level of miRNA-21 in human orbital fibroblasts. Transfection with anti-miRNA-21 and treatment with resveratrol partially restored the expression of PDCD4 and led to a reduction in cell number in PDGF-BB-treated orbital fibroblasts. CONCLUSIONS: PDGF-BB enhances proliferation by suppressing PDCD4 expression by up-regulation of miRNA-21 in human orbital fibroblasts. These results suggest that PDGF-BB stimulates cell proliferation through microRNA-21 mediated PDCD4 down-regulation, leading to the development of TAO. PMID- 26943156 TI - Short-Term Ultraviolet A Irradiation Leads to Dysfunction of the Limbal Niche Cells and an Antilymphangiogenic and Anti-inflammatory Micromilieu. AB - PURPOSE: We analyzed the effects of short-term ultraviolet A (UVA) irradiation on the putative limbal stem cell phenotype, limbal fibroblasts, corneal inflammation, and corneal (lymph)angiogenic privilege. METHODS: Primary human limbal epithelial cells and fibroblasts were irradiated with 5.2 J/cm2 of UVA. The limbal epithelial cell phenotype was assessed using P63a, cytokeratin 15, integrin b1 (marking stem and transient amplifying cells), and cytokeratin 3 (a differentiation marker) as well as by a colony-forming efficiency (CFE) assay. An epithelial-fibroblast coculture model was used to compare the ability of irradiated and nonirradiated fibroblasts to support the putative limbal stem cell phenotype. The effects of the conditioned media of irradiated and nonirradiated cells on proliferation and tube formation of human lymphatic and blood endothelial cells also were tested. The levels of factors related to angiogenesis and inflammation were assessed in a protein array and using ELISA. RESULTS: Ultraviolet A induced phenotypical changes of limbal epithelial cells, as their CFE and putative stem cell/transient amplifying marker expression decreased. Limbal epithelial cells cocultured with UVA-irradiated limbal fibroblasts also exhibited differentiation and CFE decrease. Conditioned media from irradiated limbal epithelial cells and fibroblasts inhibited lymphatic endothelial cell proliferation and tube network complexity. Levels of monocyte chemoattractant protein 1 (MCP1) were reduced following UVA irradiation of both cell populations, while levels of IFN-gamma increased in irradiated limbal epithelial cells. CONCLUSIONS: These data imply a key role of cellular components of the limbal niche following short-term UVA irradiation. Overall, UVA irradiation leads to dysfunction of these cells and a anti(lymph)angiogenic and anti-inflammatory micromilieu. PMID- 26943155 TI - Vergence Adaptation to Short-Duration Stimuli in Early Childhood. AB - PURPOSE: To investigate whether nonstrabismic typically developing young children are capable of exhibiting vergence adaptation. METHODS: Fifteen adults (19.5-35.8 years) and 34 children (2.5-7.3 years) provided usable data. None wore habitual refractive correction. Eye position and accommodation were recorded using Purkinje image eye tracking and eccentric photorefraction (MCS PowerRefractor). Vergence was measured in three conditions while the participant viewed naturalistic targets at 33 cm. Viewing was monocular for at least 60 seconds and then binocular for either 5 seconds (5-second condition), 60 seconds (60-second), or 60 seconds through a 10-pd base-out prism (prism 60-second). The right eye was then occluded again for 60 seconds and an exponential function was fit to these data to assess the impact of adaptation on alignment. RESULTS: The 63% time constant was significantly longer for the prism 60-second condition (mean = 11.5 seconds) compared to both the 5-second (5.3 seconds; P = 0.015) and the 60-second conditions (7.1 seconds; P = 0.035), with no significant difference between children and adults (P > 0.4). Correlations between the 63% time constant (prism 60-second condition) and age, refractive error, interpupillary distance (IPD), or baseline heterophoria were not significant (P > 0.4). The final stable monocular alignment, measured after binocular viewing, was similar to the baseline initial alignment across all conditions and ages. CONCLUSIONS: For a limited-duration near task, 2- to 7-year-old children showed comparable levels of vergence adaptation to adults. In a typically developing visual system, where IPD and refractive error are maturing, this adaptation could help maintain eye alignment. PMID- 26943157 TI - Distribution of Palisade Endings Across Species Suggests They Function in Vergence Eye Movement Control. PMID- 26943158 TI - Instability and Breakup of Model Tear Films. AB - PURPOSE: An experimental platform to replicate the human tear film on a contact lens is presented. The influence of interfacial viscoelasticity in stabilizing in vitro model tear films against breakup and dewetting is investigated using this instrument. METHODS: Model tear films consisting of bovine meibomian lipids (meibum) spread on either PBS or artificial tear solution (ATS) are created. The interfacial shear rheology of these films is measured as a function of temperature. The dewetting dynamics of these films is then investigated using the Interfacial Dewetting and Drainage Optical Platform (i-DDrOP) on top of silicone hydrogel (SiHy) contact lenses at 23 and 35 degrees C. The film breakup times are evaluated using two parameters: onset of film breakup, Tonset for thick films (~100 MUm), and tear breakup times, TBU for thin films (~1 MUm). Thin film thinning rates as a result of evaporation are also calculated. RESULTS: The ATS/meibum films have the largest surface rheology and correspondingly show the largest Tonset times at both 23 and 35 degrees C. The parameter TBU is also significantly larger for ATS/meibum (TBU ~ 40 seconds) compared with that of ATS and PBS/meibum films (TBU ~ 30 seconds) at room temperature. However, at 35 degrees C, all three model tear films exhibit similar TBU ~ 17 seconds and average rate of thinning of -4 MUm/minute. CONCLUSIONS: Tear film stability is influenced by both surface rheology and evaporation. The in vitro tear breakup times and thinning rates of model tear films at 35 degrees C are in good agreement with in vivo measurements previously reported, highlighting the utility of the i-DDrOP for in vitro tear film breakup research. PMID- 26943159 TI - Variation of indoor radon concentration and ambient dose equivalent rate in different outdoor and indoor environments. AB - Subject of this study is an investigation of the variations of indoor radon concentration and ambient dose equivalent rate in outdoor and indoor environments of 40 dwellings, 31 elementary schools and five kindergartens. The buildings are located in three municipalities of two, geologically different, areas of the Republic of Macedonia. Indoor radon concentrations were measured by nuclear track detectors, deployed in the most occupied room of the building, between June 2013 and May 2014. During the deploying campaign, indoor and outdoor ambient dose equivalent rates were measured simultaneously at the same location. It appeared that the measured values varied from 22 to 990 Bq/m(3) for indoor radon concentrations, from 50 to 195 nSv/h for outdoor ambient dose equivalent rates, and from 38 to 184 nSv/h for indoor ambient dose equivalent rates. The geometric mean value of indoor to outdoor ambient dose equivalent rates was found to be 0.88, i.e. the outdoor ambient dose equivalent rates were on average higher than the indoor ambient dose equivalent rates. All measured can reasonably well be described by log-normal distributions. A detailed statistical analysis of factors which influence the measured quantities is reported. PMID- 26943160 TI - Isolation and Functional Characterisation of a fads2 in Rainbow Trout (Oncorhynchus mykiss) with Delta5 Desaturase Activity. AB - Rainbow trout, Oncorhynchus mykiss, are intensively cultured globally. Understanding their requirement for long-chain polyunsaturated fatty acids (LC PUFA) and the biochemistry of the enzymes and biosynthetic pathways required for fatty acid synthesis is important and highly relevant in current aquaculture. Most gnathostome vertebrates have two fatty acid desaturase (fads) genes with known functions in LC-PUFA biosynthesis and termed fads1 and fads2. However, teleost fish have exclusively fads2 genes. In rainbow trout, a fads2 cDNA had been previously cloned and found to encode an enzyme with Delta6 desaturase activity. In the present study, a second fads2 cDNA was cloned from the liver of rainbow trout and termed fads2b. The full-length mRNA contained 1578 nucleotides with an open reading frame of 1365 nucleotides that encoded a 454 amino acid protein with a predicted molecular weight of 52.48 kDa. The predicted Fads2b protein had the characteristic traits of the microsomal Fads family, including an N-terminal cytochrome b5 domain containing the heme-binding motif (HPPG), histidine boxes (HDXGH, HFQHH and QIEHH) and three transmembrane regions. The fads2b was expressed predominantly in the brain, liver, intestine and pyloric caeca. Expression of the fasd2b in yeast generated a protein that was found to specifically convert eicosatetraenoic acid (20:4n-3) to eicosapentaenoic acid (20:5n-3), and therefore functioned as a Delta5 desaturase. Therefore, rainbow trout have two fads2 genes that encode proteins with Delta5 and Delta6 desaturase activities, respectively, which enable this species to perform all the desaturation steps required for the biosynthesis of LC-PUFA from C18 precursors. PMID- 26943162 TI - An optimised protocol to isolate high-quality genomic DNA from seed tissues streamlines the workflow to obtain direct estimates of seed dispersal distances in gymnosperms. AB - Genotyping of maternally derived seed tissues from georefered seeds that moved away from their source tree yield direct estimates of seed dispersal distances when the location and the genotype of the fruiting tree are available. These estimates are instrumental in forecasting the response of plant communities to drivers of global change, such as fragmentation or the expansion of invasive species. Obtaining robust assessments of seed dispersal distances requires comparing reliable multilocus genotypes of maternally derived seed tissues and fruiting trees, as previously shown for angiosperm species. However, robust estimates of seed dispersal distances based on direct methods are rare in non model gymnosperms due to the difficulty in isolating high quality DNA from inconspicuous maternally derived seed tissues. These tissues tend to yield low DNA quantities that increase the frequency of genotyping errors. Here, we deliver a step-by-step visual protocol used to identify and isolate different seed tissues of interest for dispersal studies: embryos (2n, bi-parentally derived), seed coats (2n, maternally derived), and megagametophytes (n, maternally derived). We also provide an optimised lab protocol used to obtain multilocus genotypes from the target seed tissue. These broadly applicable protocols proved successful both in avoiding contamination among different seed tissues and providing reliable multilocus genotypes. PMID- 26943164 TI - Leaf color is fine-tuned on the solar spectra to avoid strand direct solar radiation. AB - The spectral distributions of light absorption rates by intact leaves are notably different from the incident solar radiation spectra, for reasons that remain elusive. Incident global radiation comprises two main components; direct radiation from the direction of the sun, and diffuse radiation, which is sunlight scattered by molecules, aerosols and clouds. Both irradiance and photon flux density spectra differ between direct and diffuse radiation in their magnitude and profile. However, most research has assumed that the spectra of photosynthetically active radiation (PAR) can be averaged, without considering the radiation classes. We used paired spectroradiometers to sample direct and diffuse solar radiation, and obtained relationships between the PAR spectra and the absorption spectra of photosynthetic pigments and organs. As monomers in solvent, the spectral absorbance of Chl a decreased with the increased spectral irradiance (W m(-2) nm(-1)) of global PAR at noon (R(2) = 0.76), and was suitable to avoid strong spectral irradiance (lambdamax = 480 nm) rather than absorb photon flux density (MUmol m(-2) s(-1) nm(-1)) efficiently. The spectral absorption of photosystems and the intact thallus and leaves decreased linearly with the increased spectral irradiance of direct PAR at noon (I dir-max), where the wavelength was within the 450-650 nm range (R(2) = 0.81). The higher-order structure of photosystems systematically avoided the strong spectral irradiance of I dir-max. However, when whole leaves were considered, leaf anatomical structure and light scattering in leaf tissues made the leaves grey bodies for PAR and enabled high PAR use efficiency. Terrestrial green plants are fine-tuned to spectral dynamics of incident solar radiation and PAR absorption is increased in various structural hierarchies. PMID- 26943161 TI - Gene characterization and transcription analysis of two new ammonium transporters in pear rootstock (Pyrus betulaefolia). AB - Ammonium is the primarily nitrogen source for plant growth, but the molecular basis of ammonium acquisition in fruit species remains poorly understood. In this study, we report on the characterization of two new ammonium transporters (AMT) in the perennial tree Pyrus betulaefolia. In silico analyses and yeast complementation assays revealed that both PbAMT1;3 and PbAMT1;5 can be classified in the AMT1 sub-family. The specific expression of PbAMT1;3 in roots and of PbAMT1;5 in leaves indicates that they have diverse functions in ammonium uptake or transport in P. betulaefolia. Their expression was strongly influenced by ammonium availability. In addition, the transcript level of PbAMT1;5 was significantly affected by the diurnal cycle and senescence hormones. They conferred the ability to uptake nitrogen to the yeast strain 31019b; however, the (15)NH4 (+) uptake kinetics of PbAMT1;3 were different from those of PbAMT1;5. Indeed, PbAMT1;3 had a higher affinity for (15)NH4 (+), and pH changes were associated with this substrates' transport in yeast. The present study provides basic gene features and transcriptional information for the two new members of the AMT1 sub-family in P. betulaefolia and will aid in decoding the precise roles of AMTs in P. betulaefolia physiology. PMID- 26943163 TI - Invariant allometric scaling of nitrogen and phosphorus in leaves, stems, and fine roots of woody plants along an altitudinal gradient. AB - Nitrogen (N) to phosphorus (P) allocation in plant organs is of particular interest, as both elements are important to regulate plant growth. We analyzed the scaling relationship of N and P in leaves, stems and fine roots of 224 plant species along an altitudinal transect (500-2,300 m) on the northern slope of Changbai Mountain, China. We tested whether the scaling relationships of N and P were conserved in response to environmental variations. We found that the N and P concentrations of the leaves, stems and fine roots decreased, whereas the N:P ratios increased with increasing altitude. Allometric scaling relationships of N and P were found in the leaves, stems and fine roots, with allometric exponents of 0.78, 0.71 and 0.87, respectively. An invariant allometric scaling of N and P in the leaves, stems and fine roots was detected for woody plants along the altitudinal gradient. These results may advance our understanding of plant responses to climate change, and provide a basis for practical implication of various ecological models. PMID- 26943165 TI - De Novo Transcriptome Analysis of Medicinally Important Plantago ovata Using RNA Seq. AB - Plantago ovata is an economically and medicinally important plant of the family Plantaginaceae. It is used extensively for the production of seed husk for its application in pharmaceutical, food and cosmetic industries. In the present study, the transcriptome of P. ovata ovary was sequenced using Illumina Genome Analyzer platform to characterize the mucilage biosynthesis pathway in the plant. De novo assembly was carried out using Oases followed by velvet. A total of 46,955 non-redundant transcripts (>=100 bp) using ~29 million high-quality paired end reads were generated. Functional categorization of these transcripts revealed the presence of several genes involved in various biological processes like metabolic pathways, mucilage biosynthesis, biosynthesis of secondary metabolites and antioxidants. In addition, simple sequence-repeat motifs, non-coding RNAs and transcription factors were also identified. Expression profiling of some genes involved in mucilage biosynthetic pathway was performed in different tissues of P. ovata using Real time PCR analysis. The study has resulted in a valuable resource for further studies on gene expression, genomics and functional genomics in P. ovata. PMID- 26943166 TI - [Technical principles of incisional hernia surgery]. AB - Many publications are available on the best surgical techniques and treatment of incisional hernias with reports of experiences and randomized clinical studies at the two extremes of the evidence scale. The ultimate proof of the best operative technique has, however, not yet been achieved. In practically no other field of surgery are the variability and the resulting potential aims of surgery so great. The aim of surgery is to provide patients with the optimal recommendation out of a catalogue of possibilities from a holistic perspective. This article describes the surgical techniques using meshes for strengthening (in combination with an anatomical reconstruction) and for replacement of the abdominal wall (with bridging of the defect). PMID- 26943167 TI - [Surgical treatment of benign, premalignant and low-risk tumors of the pancreas : Standard resection or parenchyma preserving, local extirpation]. AB - Cystic neoplasms and neuroendocrine adenomas of the pancreas are detected increasingly more frequently and in up to 50 % as asymptomatic tumors. Intraductal papillary mucinous neoplasms, mucinous cystic neoplasms and solid pseudopapillary neoplasms are considered to be premalignant lesions with different rates of malignant transformation. The most frequent neuroendocrine adenomas are insulinomas. Neuroendocrine adenomas are considered to be potentially malignant, inherent to the lesion and development is unpredictable. Standard surgical treatment for pancreatic tumors are the Kausch-Whipple resection, left hemipancreatectomy and total pancreatectomy depending on the location; however, the application of standard surgical procedures, which are usually multiorgan resections for benign, premalignant and low-risk cancers of the pancreas have to be balanced against the risk for early postoperative morbidity, hospital mortality of 1.5-7 % and loss of endocrine and exocrine pancreatic functions in 12-30 %. Tumor enucleation, pancreatic middle segment resection and duodenum-preserving total pancreatic head (DPPHR-T/S) resection are parenchyma-preserving, local resection procedures, which are associated with a low early postoperative rate of severe complications, hospital mortality up to 1.3 % and maintenance of exocrine and endocrine pancreatic functions in more than 90 %. Tumor enucleation bears the risk of pancreatic fistulas (<33 %) and a limitation is proximity to the pancreatic main duct. The main risk for pancreatic middle segment resection is early postoperative pancreatic fistulas (up to 40 %), early postoperative intra-abdominal hemorrhage and a reintervention frequency up to 15 %. The DPPHR-T/S resection is applied for cystic neoplastic lesions in 90 %, severe postoperative complications are below 15 % and the 90-day hospital mortality is 0.5 %. Pancreatic fistulas are observed in less than 20 % with a recurrence rate of <1 %. These facts and maintenance of exocrine and endocrine pancreatic functions are advantages compared with the Kausch-Whipple resection of the pancreatic head. The use of tumor enucleation, particularly for neuroendocrine tumors and pancreatic middle segment resection as well as total DPPHR resection should replace the pancreatoduodenectomy for lesions in the pancreatic head and hemipancreatectomy for lesions in the pancreatic body and tail. PMID- 26943170 TI - Evaluating beta Diversity as a Surrogate for Species Representation at Fine Scale. AB - Species turnover or beta diversity is a conceptually attractive surrogate for conservation planning. However, there has been only 1 attempt to determine how well sites selected to maximize beta diversity represent species, and that test was done at a scale too coarse (2,500 km2 sites) to inform most conservation decisions. We used 8 plant datasets, 3 bird datasets, and 1 mammal dataset to evaluate whether sites selected to span beta diversity will efficiently represent species at finer scale (sites sizes < 1 ha to 625 km2). We used ordinations to characterize dissimilarity in species assemblages (beta diversity) among plots (inventory data) or among grid cells (atlas data). We then selected sites to maximize beta diversity and used the Species Accumulation Index, SAI, to evaluate how efficiently the surrogate (selecting sites for maximum beta diversity) represented species in the same taxon. Across all 12 datasets, sites selected for maximum beta diversity represented species with a median efficiency of 24% (i.e., the surrogate was 24% more effective than random selection of sites), and an interquartile range of 4% to 41% efficiency. beta diversity was a better surrogate for bird datasets than for plant datasets, and for atlas datasets with 10-km to 14-km grid cells than for atlas datasets with 25-km grid cells. We conclude that beta diversity is more than a mere descriptor of how species are distributed on the landscape; in particular beta diversity might be useful to maximize the complementarity of a set of sites. Because we tested only within taxon surrogacy, our results do not prove that beta diversity is useful for conservation planning. But our results do justify further investigation to identify the circumstances in which beta diversity performs well, and to evaluate it as a cross-taxon surrogate. PMID- 26943171 TI - Queues with Dropping Functions and General Arrival Processes. AB - In a queueing system with the dropping function the arriving customer can be denied service (dropped) with the probability that is a function of the queue length at the time of arrival of this customer. The potential applicability of such mechanism is very wide due to the fact that by choosing the shape of this function one can easily manipulate several performance characteristics of the queueing system. In this paper we carry out analysis of the queueing system with the dropping function and a very general model of arrival process--the model which includes batch arrivals and the interarrival time autocorrelation, and allows for fitting the actual shape of the interarrival time distribution and its moments. For such a system we obtain formulas for the distribution of the queue length and the overall customer loss ratio. The analytical results are accompanied with numerical examples computed for several dropping functions. PMID- 26943169 TI - Clinical characteristics and molecular analysis of hepatitis B virus reactivation in hepatitis B surface antigen-negative patients during or after immunosuppressive or cytotoxic chemotherapy. AB - BACKGROUND AND AIM: Reactivation of hepatitis B virus (HBV) in hepatitis B surface antigen (HBsAg)-positive patients treated with immunosuppressive or cytotoxic chemotherapy is well known and has emerged as an important clinical issue. The risk is low, but reactivation of HBV in HBsAg-negative patients after resolution of HBV infection also occurs; however, the clinical and virological characteristics remain somewhat unclear. We investigated HBsAg-negative patients who developed HBV reactivation during or after immunosuppressive or cytotoxic chemotherapy to clarify the clinical and virological features. METHODS: Reactivation of HBV in 30 previously infected that is HBsAg-negative patients during or after immunosuppressive or cytotoxic chemotherapy was examined. Direct sequencing at the time of reactivation was used to evaluate 11 patients. RESULTS: The majority of patients had diffuse large B cell lymphoma treated by rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisolone. Fulminant hepatic failure developed in three patients, who did not survive. HBV subgenotypes A2/Ae (n = 1), B1/Bj (n = 2), and C2/Ce (n = 8) were detected. There were no significant differences in the prevalence of BCP/PC variants between HBV reactivation and acute self-limited hepatitis patient groups. BCP and PC variants were not associated with development of fulminant hepatic failure from HBV reactivation. The prevalence of HBV S region variants, including immune-escape mutants, among reactivation patients was significantly higher than that in acute self-limited hepatitis patients. CONCLUSIONS: Reactivation risk factors included male sex, advanced age, and hematological malignancy. HBV S gene immune-escape mutants were frequently found in the HBsAg-negative reactivation patients during or after immunosuppressive or cytotoxic chemotherapy. PMID- 26943168 TI - Antiviral effects of anti-HBs immunoglobulin and vaccine on HBs antigen seroclearance for chronic hepatitis B infection. AB - BACKGROUND AND AIMS: Interferon and nucleotide/nucleoside analogues are the main treatments for chronic hepatitis B. These drugs effectively reduce serum hepatitis B virus (HBV) DNA titers but fail to sufficiently reduce hepatitis B surface antigen (HBsAg) levels. Following the recent identification of sodium taurocholate cotransporting polypeptide as a receptor for HBV entry, inhibition of HBV entry has become an attractive therapeutic target for chronic hepatitis B treatment. We therefore evaluated the antiviral effects of antibody to HBsAg (anti-HBs) immunoglobulin (HBIG), which can inhibit HBV entry, by in an vivo study and a clinical trial. METHODS: In the in vivo study, HBV-infected mice were generated from human hepatocyte chimeric mice and treated with HBIG. A clinical trial evaluating HBIG therapy in patients was also performed. RESULTS: In the mouse study, HBV DNA titers were reduced and serum HBsAg titers decreased to undetectable levels following high-dose HBIG injection. On the basis of this result, eight chronic hepatitis B patients, who had received long-term nucleotide analogue treatment, were treated with monthly HBIG injections as an additional treatment. After 1 year of treatment, an HBsAg level reduction of more than 1 log IU/mL was observed in four patients, and three patients became anti-HBs positive. No adverse events occurred during HBIG therapy. CONCLUSION: These results suggest that monthly HBIG injection might benefit patients with chronic hepatitis B whose HBsAg titer becomes lower following long-term nucleotide/nucleoside analogue treatment. PMID- 26943173 TI - Slowing Down Time: An Exploration of Personal Life Extension Desirability as it Relates to Religiosity and Specific Religious Beliefs. AB - As medical technology continues increasing the possibility of living a longer life, the public's valuing of these developments must be considered. This study examines attitudes toward extending the human life span within a student population at a Christian university. Religious factors were hypothesized to affect life extension desirability. Scores on measures of willingness to defer to God's will, meaning derived from religion, positive afterlife beliefs, and intrinsic religiosity were significantly and inversely related to life extension desirability. Implications of these findings are discussed, including encouraging medical practitioners to respect decision-making processes of religious persons who may find life extension interventions undesirable. PMID- 26943172 TI - Type One Protein Phosphatase 1 and Its Regulatory Protein Inhibitor 2 Negatively Regulate ABA Signaling. AB - The phytohormone abscisic acid (ABA) regulates plant growth, development and responses to biotic and abiotic stresses. The core ABA signaling pathway consists of three major components: ABA receptor (PYR1/PYLs), type 2C Protein Phosphatase (PP2C) and SNF1-related protein kinase 2 (SnRK2). Nevertheless, the complexity of ABA signaling remains to be explored. To uncover new components of ABA signal transduction pathways, we performed a yeast two-hybrid screen for SnRK2 interacting proteins. We found that Type One Protein Phosphatase 1 (TOPP1) and its regulatory protein, At Inhibitor-2 (AtI-2), physically interact with SnRK2s and also with PYLs. TOPP1 inhibited the kinase activity of SnRK2.6, and this inhibition could be enhanced by AtI-2. Transactivation assays showed that TOPP1 and AtI-2 negatively regulated the SnRK2.2/3/6-mediated activation of the ABA responsive reporter gene RD29B, supporting a negative role of TOPP1 and AtI-2 in ABA signaling. Consistent with these findings, topp1 and ati-2 mutant plants displayed hypersensitivities to ABA and salt treatments, and transcriptome analysis of TOPP1 and AtI-2 knockout plants revealed an increased expression of multiple ABA-responsive genes in the mutants. Taken together, our results uncover TOPP1 and AtI-2 as negative regulators of ABA signaling. PMID- 26943174 TI - Influence of Religion on Attitude Towards Suicide: An Indian Perspective. AB - This cross-sectional survey was aimed to compare attitudes towards suicide and suicidal behaviour among randomly selected sample (N = 172) belonged to Hindu and Muslim religions. Data were collected through face-to-face interview. Hindus differed from Muslims regarding suicidal attempts among family (chi (2) = 12.356, p < .002) and community members (chi (2) = 20.425, p < .000). Our study also showed that suicidal behaviours were comparatively low among Muslim participants than Hindus. Further, Muslims hold more negative attitudes towards suicide than Hindus. An enhanced understanding of attitudes towards suicide among general population may be crucial to plan educational, intervention and prevention programs. PMID- 26943176 TI - Consensus: soy isoflavones as a first-line approach to the treatment of menopausal vasomotor complaints. AB - The association between an increased uptake of isoflavones and a reduced frequency of menopausal hot flushes was first described in 1992, based on a lower incidence of hot flushes in countries with a high consumption of soy. Since then, numerous clinical trials with various sources of isoflavones including soy and red clover have been presented, with practically all of the studies with adequate design delivering an outcome in favour of isoflavone supplementation. An in-depth risk assessment (EFSA 2015) concludes that the amply available human data does not indicate any suspected harmful effects from a potential interaction of isoflavones with hormone-sensitive tissues in the mammary gland, the uterus and the thyroid gland. Safety was ascertained with long-term intake of up to 150 mg isoflavones per day ingested for the duration of at least 3 years. Moreover, high isoflavone intake was found to have preventive effects with respect to breast cancer. Clinical findings indicate potential benefits of isoflavone exposure even during breast cancer treatment with tamoxifen or anastrozole. PMID- 26943177 TI - Retraction: Biomechanical Characteristics of Hand Coordination in Grasping Activities of Daily Living. PMID- 26943178 TI - Radiographic methods used before removal of mandibular third molars among randomly selected general dental clinics. AB - OBJECTIVES: To assess radiographic methods and diagnostically sufficient images used before removal of mandibular third molars among randomly selected general dental clinics. Furthermore, to assess factors predisposing for an additional radiographic examination. METHODS: 2 observers visited 18 randomly selected clinics in Denmark and studied patient files, including radiographs of patients who had their mandibular third molar(s) removed. The radiographic unit and type of receptor were registered. A diagnostically sufficient image was defined as the whole tooth and mandibular canal were displayed in the radiograph (yes/no). Overprojection between the tooth and mandibular canal (yes/no) and patient reported inferior alveolar nerve sensory disturbances (yes/no) were recorded. Regression analyses tested if overprojection between the third molar and the mandibular canal and an insufficient intraoral image predisposed for additional radiographic examination(s). RESULTS: 1500 mandibular third molars had been removed; 1090 had intraoral, 468 had panoramic and 67 had CBCT examination. 1000 teeth were removed after an intraoral examination alone, 433 after panoramic examination and 67 after CBCT examination. 90 teeth had an additional examination after intraoral. Overprojection between the tooth and mandibular canal was a significant factor (p < 0.001, odds ratio = 3.56) for an additional examination. 63.7% of the intraoral images were sufficient and 36.3% were insufficient, with no significant difference between images performed with phosphor plates and solid state sensors (p = 0.6). An insufficient image predisposed for an additional examination (p = 0.008, odds ratio = 1.8) but was only performed in 11% of the cases. CONCLUSIONS: Most mandibular third molars were removed based on an intraoral examination although 36.3% were insufficient. PMID- 26943179 TI - The accuracy of ultrashort echo time MRI sequences for medical additive manufacturing. AB - OBJECTIVES: Additively manufactured bone models, implants and drill guides are becoming increasingly popular amongst maxillofacial surgeons and dentists. To date, such constructs are commonly manufactured using CT technology that induces ionizing radiation. Recently, ultrashort echo time (UTE) MRI sequences have been developed that allow radiation-free imaging of facial bones. The aim of the present study was to assess the feasibility of UTE MRI sequences for medical additive manufacturing (AM). METHODS: Three morphologically different dry human mandibles were scanned using a CT and MRI scanner. Additionally, optical scans of all three mandibles were made to acquire a "gold standard". All CT and MRI scans were converted into Standard Tessellation Language (STL) models and geometrically compared with the gold standard. To quantify the accuracy of the AM process, the CT, MRI and gold-standard STL models of one of the mandibles were additively manufactured, optically scanned and compared with the original gold-standard STL model. RESULTS: Geometric differences between all three CT-derived STL models and the gold standard were <1.0 mm. All three MRI-derived STL models generally presented deviations <1.5 mm in the symphyseal and mandibular area. The AM process introduced minor deviations of <0.5 mm. CONCLUSIONS: This study demonstrates that MRI using UTE sequences is a feasible alternative to CT in generating STL models of the mandible and would therefore be suitable for surgical planning and AM. Further in vivo studies are necessary to assess the usability of UTE MRI sequences in clinical settings. PMID- 26943180 TI - Testing for the cytosine insertion in the VNTR of the MUC1 gene in a cohort of Italian patients with autosomal dominant tubulointerstitial kidney disease. AB - INTRODUCTION: Medullary cystic kidney disease type 1 (MCKD1; OMIM #174000) is a familial progressive tubule-interstitial nephropathy belonging to the recently defined group of autosomal dominant tubulointerstitial kidney diseases (ADTKD). CASE REPORT: A specific type of cytosine insertion in the extracellular variable number tandem repeat (VNTR) domain of the MUC1 gene causing the disease was tested in a group of 21 families with ADTKD. We identified this type of MUC1 mutation in two families, whose affected members are described in detail in this case report. Affected (ADTKD-MUC1) members developed end-stage renal disease (ESRD) with a higher incidence (p = 0.033) and at a younger age (p = 0.013) than probands with ADTKD but without this type of mutation. All patients with MUC1 associated kidney disease shared a rather unspecific tubule-interstitial laboratory pattern without medullary cysts, leading to ESRD between the age of 33 and 47 years. We were not able to identify any single common extra-renal feature among affected patients, even if they had various comorbidities, which are described in detail. CONCLUSIONS: We identified this type of MUC1 mutation in 9.5 % of families from an ADTKD Italian cohort; larger studies are needed to better define the criteria for genetic testing for this type of mutation. PMID- 26943181 TI - Roles of the kidney in the formation, remodeling and repair of bone. AB - The relationship between the kidney and bone is highly complex, and the kidney plays an important role in the regulation of bone development and metabolism. The kidney is the major organ involved in the regulation of calcium and phosphate homeostasis, which is essential for bone mineralization and development. Many substances synthesized by the kidney, such as 1,25(OH)2D3, Klotho, bone morphogenetic protein-7, and erythropoietin, are involved in different stages of bone formation, remodeling and repair. In addition, some cytokines which can be affected by the kidney, such as osteoprotegerin, sclerostin, fibroblast growth factor -23 and parathyroid hormone, also play important roles in bone metabolism. In this paper, we summarize the possible effects of these kidney-related cytokines on bone and their possible mechanisms. Most of these cytokines can interact with one another, constituting an intricate network between the kidney and bone. Therefore, kidney diseases should be considered among patients presenting with osteodystrophy and disturbances in bone and mineral metabolism, and treatment for renal dysfunction may accelerate their recovery. PMID- 26943182 TI - Recent trends in the prevalence of chronic kidney disease in Korean adults: Korean National Health and Nutrition Examination Survey from 1998 to 2013. AB - BACKGROUND: Chronic kidney disease (CKD) is associated with aging, diabetes, hypertension, dyslipidemia, obesity, and unhealthy lifestyle behaviors and has become a public health burden worldwide. METHODS: We investigated the trends of CKD prevalence over a period of 16 years in Korean adults based on the Korean National Health and Nutrition Examination Survey (KNHANES): phase I (1998), II (2001), III (2005), IV (2007-09), V (2010-2012), and VI (2013). Of the 105,504 individuals aged over 20 years who participated in KNHANES I-VI, 55,191 (23,729 men and 31,462 women) were included in the present study. RESULTS: The sequential percentage of glomerular filtration rate (GFR) <60 ml/min/1.73 m2 in KNHANES I-VI was 1.0, 4.2, 3.2, 1.9, 1.6, and 2.1 % in men and 3.6, 9.3, 10.4, 3.1, 1.6, and 2.0 % in women, respectively. The percentage of proteinuria >=1+ in men rebounded after KNHANES V (3.1, 2.9, 2.8, 1.9, 1.1, and 1.7 % in KNHANES I-VI, respectively), but in women declined across all KNHANES reads (3.4, 2.3, 1.4, 1.6, 1.0, and 0.9 %, respectively). The prevalence of CKD rebounded after KNHANES V for men (3.9, 6.8, 5.5, 3.5, 2.4, and 3.5 % in KNHANES I-VI) while those in women decreased to a plateau level (6.6, 10.9, 11.4, 4.2, 2.4, and 2.4 % in KNHANES I-VI, respectively). CONCLUSIONS: Our study shows that the prevalence of CKD in Korean adults has decreased overall, but since KNHANES V there has been a rebound in men while no changes in women. PMID- 26943183 TI - Remote Magnetic Orientation of 3D Collagen Hydrogels for Directed Neuronal Regeneration. AB - Hydrogel matrices are valuable platforms for neuronal tissue engineering. Orienting gel fibers to achieve a directed scaffold is important for effective functional neuronal regeneration. However, current methods are limited and require treatment of gels prior to implantation, ex-vivo, without taking into consideration the pathology in the injured site. We have developed a method to control gel orientation dynamically and remotely in situ. We have mixed into collagen hydrogels magnetic nanoparticles then applied an external magnetic field. During the gelation period the magnetic particles aggregated into magnetic particle strings, leading to the alignment of the collagen fibers. We have shown that neurons within the 3D magnetically induced gels exhibited normal electrical activity and viability. Importantly, neurons formed elongated cooriented morphology, relying on the particle strings and fibers as supportive cues for growth. The ability to inject the mixed gel directly into the injured site as a solution then to control scaffold orientation remotely opens future possibilities for therapeutic engineered scaffolds. PMID- 26943229 TI - Combined deficiency of PI3KC2alpha and PI3KC2beta reveals a nonredundant role for PI3KC2alpha in regulating mouse platelet structure and thrombus stability. AB - The physiological functions and cellular signaling of Class II phosphoinositide 3 kinases (PI3Ks) remain largely unknown. Platelets express two Class II PI3Ks: PI3KC2alpha and PI3KC2beta. PI3KC2alpha deficiency was recently reported to cause disruption of the internal membrane reserve structure of platelets (open canalicular system, OCS) that results in dysregulated platelet adhesion and impaired arterial thrombosis in vivo. Notably, these effects on platelets occurred despite normal agonist-induced 3-phosphorylated phosphoinositide (3-PPI) production and cellular activation in PI3KC2alpha-deficient platelets. However, the potential compensatory actions of PI3KC2beta in platelets have not yet been investigated. Here, we report the first mice deficient in both PI3KC2alpha and PI3KC2beta (no Class II PI3Ks in platelets) and reveal a nonredundant role for PI3KC2alpha in mouse platelet structure and function. Specifically, we show that the disrupted OCS and impaired thrombus stability observed in PI3KC2alpha deficient platelets does not occur in PI3KC2beta-deficient platelets and is not exaggerated in platelets taken from mice deficient in both enzymes. Furthermore, detailed examination of 3-PPI production in platelets from this series of mice revealed no changes in either unactivated or activated platelets, including those with a complete lack of Class II PI3Ks. These findings indicate a nonredundant role for PI3KC2alpha in regulating platelet structure and function, and suggest that Class II PI3Ks do not significantly contribute to the acute agonist-induced production of 3-PPIs in these cells. PMID- 26943230 TI - Ureteral Stones: Implementation of a Reduced-Dose CT Protocol in Patients in the Emergency Department with Moderate to High Likelihood of Calculi on the Basis of STONE Score. AB - Purpose To determine if a reduced-dose computed tomography (CT) protocol could effectively help to identify patients in the emergency department (ED) with moderate to high likelihood of calculi who would require urologic intervention within 90 days. Materials and Methods The study was approved by the institutional review board and written informed consent with HIPAA authorization was obtained. This was a prospective, single-center study of patients in the ED with moderate to high likelihood of ureteral stone undergoing CT imaging. Objective likelihood of ureteral stone was determined by using the previously derived and validated STONE clinical prediction rule, which includes five elements: sex, timing, origin, nausea, and erythrocytes. All patients with high STONE score (STONE score, 10-13) underwent reduced-dose CT, while those with moderate likelihood of ureteral stone (moderate STONE score, 6-9) underwent reduced-dose CT or standard CT based on clinician discretion. Patients were followed to 90 days after initial imaging for clinical course and for the primary outcome of any intervention. Statistics are primarily descriptive and are reported as percentages, sensitivities, and specificities with 95% confidence intervals. Results There were 264 participants enrolled and 165 reduced-dose CTs performed; of these participants, 108 underwent reduced-dose CT alone with complete follow-up. Overall, 46 of 264 (17.4%) of patients underwent urologic intervention, and 25 of 108 (23.1%) patients who underwent reduced-dose CT underwent a urologic intervention; all were correctly diagnosed on the clinical report of the reduced dose CT (sensitivity, 100%; 95% confidence interval: 86.7%, 100%). The average dose-length product for all standard-dose CTs was 857 mGy . cm +/- 395 compared with 101 mGy . cm +/- 39 for all reduced-dose CTs (average dose reduction, 88.2%). There were five interventions for nonurologic causes, three of which were urgent and none of which were missed when reduced-dose CT was performed. Conclusion A CT protocol with over 85% dose reduction can be used in patients with moderate to high likelihood of ureteral stone to safely and effectively identify patients in the ED who will require urologic intervention. ((c)) RSNA, 2016 Online supplemental material is available for this article. PMID- 26943234 TI - Challenges with bipolar disorder drug discovery. PMID- 26943232 TI - A Simulation Model of the Mass Rearing of Tetranychus urticae Koch (Acari: Tetranychidae) on Beans. AB - The supply of predatory mites as natural enemies is a key component to guarantee the success of biological pest control programs as alternatives to chemical control in commercial crops. To meet the demand for a supply of biologicals, the mass rearing of natural enemies is an option, and the first step must be to develop a standardized system that maximizes the production of prey. One choice for this first step is to use simulation models that can evaluate scenarios that are difficult or complex to address experimentally. In this work, a model was developed to evaluate the current management conditions for the mass rearing of the pest mite Tetranychus urticae Koch. Our aim was to identify alternative scenarios to maximize mite production through mass rearing that could be evaluated in real systems. We assumed that populations of T. urticae were regulated by the conditions of supply-demand theory and modeled the age structure, temperature effects, and individual phenology of T. urticae. The supply-demand theory of resources was used to regulate populations, which involved structured ages and temperature effects for the different stages in the development of individuals. We used the functional response and the paradigm of metabolic pool models to describe resource acquisition and allocation. We demonstrated that 7- to 14-day-old plants infested with 45 or 62 T. urticae/plant could reach 25,000 individuals/plant, being 50% of these preys at the preferred stages by the predator Phytoseiulus persimilis Athias-Henriot. Our theoretical model requires validation in experimental/real systems of mass rearing to better verify the validity of all of the parameters and predictions before commercial implementation. PMID- 26943231 TI - Pulmonary Intravascular Lymphomatosis: Clinical, CT, and PET Findings, Correlation of CT and Pathologic Results, and Survival Outcome. AB - Purpose To describe clinical, computed tomographic (CT), and positron emission tomographic (PET) features, correlation of CT and pathologic results, and survival of patients with pulmonary intravascular lymphomatosis. Materials and Methods The institutional review board approved this retrospective study with waiver of patient consent. Forty-two patients with pulmonary intravascular lymphomatosis were identified, 11 (26%) of whom showed lung involvement. CT features were correlated with histopathologic results. Clinical and survival outcomes were compared between patients with and those without pulmonary involvement by adopting the chi(2), Student t, or Kaplan-Meier analysis with log rank tests. Results At clinical presentation, all 11 patients showed B symptoms (systemic symptoms of fever, night sweats, and weight loss), 10 had respiratory and four had neurologic symptoms, and two had skin lesions. Patients received cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy with (n = 5) or without (n = 6) rituximab, and seven (64%) patients died. Patients with lung involvement showed reduced overall and recurrence-free survival (median; 10.8 and 18.9 months, respectively) compared with those without lung involvement (median, 18.4 and 31.0 months, respectively) (P = .338 and .065, respectively). The most common CT abnormality was bilateral ground-glass opacity (GGO, n = 10), with increased fluorodeoxyglucose uptake at PET/CT (seven of seven patients). GGO correlated histopathologically with the expanded alveolar septal vasculatures and perivascular spaces filled with neoplastic lymphoid cells. Conclusion Pulmonary intravascular lymphomatosis appeared as bilateral GGO on CT images, with increased fluorodeoxyglucose uptake on PET/CT images. GGO on CT images correlated with the area of expanded alveolar septae because of distended vessels filled with neoplastic lymphoid cells. ((c)) RSNA, 2016 Online supplemental material is available for this article. PMID- 26943233 TI - Parallel lives: A phenomenological study of the lived experience of maladaptive daydreaming. AB - This qualitative study describes the lived experience of maladaptive daydreaming (MD), an excessive form of unwanted daydreaming that produces a rewarding experience based on a created fantasy of a parallel reality associated with a profound sense of presence. A total of 21 in-depth interviews with persons who self-identified as struggling with MD were analyzed utilizing a phenomenological approach. Interviewees described how their natural capacity for vivid daydreaming had developed into a time-consuming habit that resulted in serious dysfunction. The phenomenology of MD was typified by complex fantasized mental scenarios that were often laced with emotionally compensatory themes involving competency, social recognition, and support. MD could be activated if several requirements were met. Because social interaction seems to be incompatible with this absorbing mental activity, solitude was necessary. In addition, kinesthetic activity and/or exposure to evocative music also appeared to be essential features. Besides delivering a firsthand description of key characteristics of MD, the study also indicates that MD is associated with dysfunctionality for which participants expressed a substantial need for help. PMID- 26943235 TI - Obese non-Hodgkin lymphoma patients tolerate full uncapped doses of chemotherapy with no increase in toxicity, and a similar survival to that seen in nonobese patients. AB - The aim of this study is to compare the risk of treatment-related toxicities and long-term survival between obese and nonobese patients with non-Hodgkin lymphoma when treated with full uncapped doses of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy. A total of 133 patients and 733 cycles of chemotherapy were analyzed. Obese patients did not experience an increased risk of acute treatment-related toxicities (adjusted odds ratio 0.825, p = 0.197), or delayed toxicities (adjusted odds ratio 0.819, p = 0.779). In the subgroup of diffuse large B-cell lymphoma patients (n = 109), treatment response rate was similar between the two body mass index (BMI) groups, and obese patients tended to have superior overall and progression-free survivals, albeit not statistically significant. Full uncapped doses of R-CHOP chemotherapy administered to obese patients with non-Hodgkin lymphoma (NHL) are safe, well tolerated, and do not lead to inferior treatment response or long-term outcomes. PMID- 26943237 TI - Association of gene expression and methylation of UQCRC1 to the predisposition of Alzheimer's disease in a Chinese population. AB - DNA methylation is an important epigenetic mechanism for gene regulation and it is well established there is association between aging and DNA methylation. Alzheimer's disease (AD) is the most common neurodegenerative disease, characterized by amyloid plaque deposition and formation of neurofibrillary tangles. In this study, we examined the correlation between DNA methylation and gene expression of seven genes including CTSB, CTSD, DDT, TSC1, NRD1, UQCRC1 and NDUFA6 and its effect on the risk of AD in a Chinese population. Our finding showed significantly increased gene expression of these 7 genes in AD patients (2.7-fold-8.6-fold). UQCRC1 was highly methylated in AD patients and there was strong positive correlation between gene expression level and methylation status of UQCRC1 (p < 0.001). Further analysis showed the methylation status of UQCRC1 was significantly associated with gene expression of NRD1, DDT, CTSB and CTSD, suggested the regulatory mechanism on these 4 genes by UQCRC1. Our study further suggested the role of methylation in gene regulation and the role in AD. PMID- 26943236 TI - The safety and efficacy of osimertinib for the treatment of EGFR T790M mutation positive non-small-cell lung cancer. AB - First- and second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the evidence-based first-line treatment for metastatic non-small-cell lung cancers (NSCLCs) that harbor sensitizing EGFR mutations (i.e. exon 19 deletions or L858R). However, acquired resistance to EGFR TKI monotherapy occurs invariably within a median time frame of one year. The most common form of biological resistance is through the selection of tumor clones harboring the EGFR T790M mutation, present in >50% of repeat biopsies. The presence of the EGFR T790M mutation negates the inhibitory activity of gefitinib, erlotinib, and afatinib. A novel class of third-generation EGFR TKIs has been identified by probing a series of covalent pyrimidine EGFR inhibitors that bind to amino-acid residue C797 of EGFR and preferentially inhibit mutant forms of EGFR versus the wild-type receptor. We review the rapid clinical development and approval of the third-generation EGFR TKI osimertinib for treatment of NSCLCs with EGFR-T790M. PMID- 26943238 TI - Investigating Orientational Defects in Energetic Material RDX Using First Principles Calculations. AB - Orientational defects are molecular-scale point defects consisting of misaligned sterically trapped molecules. Such defects have been predicted in alpha-RDX using empirical force fields. These calculations indicate that their concentration should be higher than that of vacancies. In this study we confirm the stability of a family of four orientational defects in alpha-RDX using first-principles calculations and evaluate their formation energies and annealing barrier heights. The charge density distribution in the defective molecules is evaluated and it is shown that all four orientational defects exhibit some level of charge reduction at the midpoint of the N-N bond, which has been previously related to the sensitivity to initiation of the material. We also evaluate the vibrational spectrum of the crystal containing orientational defects and observe band splitting relative to the perfect crystal case. This may assist the experimental identification of such defects by Raman spectroscopy. PMID- 26943241 TI - Benchmark Calculations of Interaction Energies in Noncovalent Complexes and Their Applications. AB - Data sets of benchmark interaction energies in noncovalent complexes are an important tool for quantifying the accuracy of computational methods used in this field, as well as for the development of new computational approaches. This review is intended as a guide to conscious use of these data sets. We discuss their construction and accuracy, list the data sets available in the literature, and demonstrate their application to validation and parametrization of quantum mechanical computational methods. In practical model systems, the benchmark interaction energies are usually obtained using composite CCSD(T)/CBS schemes. To use these results as a benchmark, their accuracy should be estimated first. We analyze the errors of this methodology with respect to both the approximations involved and the basis set size. We list the most prominent data sets covering various aspects of the field, from general ones to sets focusing on specific types of interactions or systems. The benchmark data are then used to validate more efficient computational approaches, including those based on explicitly correlated methods. Special attention is paid to the transition to large systems, where accurate benchmarking is difficult or impossible, and to the importance of nonequilibrium geometries in parametrization of more approximate methods. PMID- 26943240 TI - Interpreting WAIS-III performance after primary brain tumor surgery. AB - The literature lacks information on the performance of patients with brain tumors on the Wechsler Intelligence Scales. This study aimed to explore the Wechsler Adult Intelligence Scale-Third Edition (WAIS-III) performance profile of 23 consecutive patients with brain tumors and 23 matched controls selected from the Portuguese WAIS-III standardization sample, using the technical manual steps recommended for score interpretation. The control group was demographically matched to the tumor group regarding gender, age, education, profession, and geographic region. The technical manual steps recommended for score interpretation were applied. Patients with brain tumors had significantly lower performances on the Performance IQ, Full-Scale IQ, Perceptual Organization Index, Working Memory Index, Processing Speed Index, Arithmetic, Object Assembly, and Picture Arrangement, though all scaled scores were within the normal range according to the manual tables. Only Vocabulary and Comprehension scatter scores were statistically different between groups. No strengths or weaknesses were found for either group. The mean discrepancy scores do not appear to have clinical value for this population. In conclusion, the study results did not reveal a specific profile for patients with brain tumors on the WAIS-III. PMID- 26943242 TI - Substance Use Among Sexual Minority Collegiate Athletes: A National Study. AB - BACKGROUND: The empirical research examining substance use among sexual minority collegiate athletes is sparse. Problematically, this group may be at a greater risk of substance use due to their marginalized status within the context of sport. OBJECTIVES: We examined different types of substance use during the past 30 days, and diagnosis of substance use disorders during the past 12 months, among sexual minority collegiate athletes. METHODS: This study uses data from college students for the fall semester between 2008 and 2012 from the American College Health Association-National College Health Assessment. RESULTS: Sexual minority collegiate athletes had greater odds of past 30-day cigarette use, past 30-day alcohol use, past 30-day marijuana use, and indicating being diagnosed or treated for a substance use disorder during the past 12 months when compared to either heterosexual collegiate athletes or heterosexual nonathletes, but had similar odds on these outcomes when compared to sexual minority nonathletes. Sexual minority collegiate athletes also had greater odds of binge drinking during the past 2 weeks when compared to either heterosexual nonathletes or sexual minority nonathletes, but had similar odds on this outcome when compared to heterosexual collegiate athletes. Additional analyses by gender reveal that male sexual minority athletes are at the greatest risk of being diagnosed or treated for a substance use disorder. CONCLUSIONS: Possible explanations as to why sexual minority collegiate athletes (particularly males) may be at a greater risk of substance use disorders could include the difficulty of trying to maintain an athletic identity within a social environment that is traditionally homophobic. PMID- 26943244 TI - Modular Nuclease-Responsive DNA Three-Way Junction-Based Dynamic Assembly of a DNA Device and Its Sensing Application. AB - Here, we explored a modular strategy for rational design of nuclease-responsive three-way junctions (TWJs) and fabricated a dynamic DNA device in a "plug-and play" fashion. First, inactivated TWJs were designed, which contained three functional domains: the inaccessible toehold and branch migration domains, the specific sites of nucleases, and the auxiliary complementary sequence. The actions of different nucleases on their specific sites in TWJs caused the close proximity of the same toehold and branch migration domains, resulting in the activation of the TWJs and the formation of a universal trigger for the subsequent dynamic assembly. Second, two hairpins (H1 and H2) were introduced, which could coexist in a metastable state, initially to act as the components for the dynamic assembly. Once the trigger initiated the opening of H1 via TWJs driven strand displacement, the cascade hybridization of hairpins immediately switched on, resulting in the formation of the concatemers of H1/H2 complex appending numerous integrated G-quadruplexes, which were used to obtain label free signal readout. The inherent modularity of this design allowed us to fabricate a flexible DNA dynamic device and detect multiple nucleases through altering the recognition pattern slightly. Taking uracil-DNA glycosylase and CpG methyltransferase M.SssI as models, we successfully realized the butt joint between the uracil-DNA glycosylase and M.SssI recognition events and the dynamic assembly process. Furthermore, we achieved ultrasensitive assay of nuclease activity and the inhibitor screening. The DNA device proposed here will offer an adaptive and flexible tool for clinical diagnosis and anticancer drug discovery. PMID- 26943245 TI - Analysis of IgG4-positive clones in affected organs of IgG4-related disease. AB - OBJECTIVE: We investigated class switch reaction (CSR) in affected organs and evaluated whether the same or genetically related clones exist in IgG4-RD. METHODS: We studied three patients with IgG4-RD. Total cellular RNA was extracted from salivary glands and peripheral blood and lung tissue. Activation-induced cytidine deaminase (AID) and immunoglobulin heavy chain third complementarity determining region (IgVH-CDR3) of IgM and IgG4 were detected by reverse transcription polymerase chain reaction (RT-PCR). We analyzed the clonal relationship of infiltrating IgG4-positive cells, as compared with IgM. We determined the existence of common clones among organs and patients. RESULT: AID was expressed in salivary glands of all patients and lung tissue in one. Closely related IgVH-CDR3 sequences in infiltrating IgG4-positive cells were detected in salivary glands and lung tissue. Identical IgVH-CDR3 sequence between IgM and IgG4 in salivary glands was detected in one patient, indicating CSR in salivary glands. Identical IgVH-CDR3 sequences of IgG4-positive cells were detected between salivary glands and peripheral blood in two patients. Four identical sequences of IgVH-CDR3 existed between patients. Interestingly, one of the four sequences was detected in all patients. CONCLUSION: Our results demonstrate the existence of common antigen(s) shared by patients with IgG4-RD. PMID- 26943243 TI - Mevalonate-derived quinonemethide triterpenoid from in vitro roots of Peritassa laevigata and their localization in root tissue by MALDI imaging. AB - Biosynthetic investigation of quinonemethide triterpenoid 22beta-hydroxy-maytenin (2) from in vitro root cultures of Peritassa laevigata (Celastraceae) was conducted using (13)C-precursor. The mevalonate pathway in P. laevigata is responsible for the synthesis of the quinonemethide triterpenoid scaffold. Moreover, anatomical analysis of P. laevigata roots cultured in vitro and in situ showed the presence of 22beta-hydroxy-maytenin (2) and maytenin (1) in the tissues from transverse or longitudinal sections with an intense orange color. MALDI-MS imaging confirmed the distribution of (2) and (1) in the more distal portions of the root cap, the outer cell layers, and near the vascular cylinder of P. laevigata in vitro roots suggesting a role in plant defense against infection by microorganisms as well as in the root exudation processes. PMID- 26943246 TI - Letter to the Editor: Primary spinal epidural cavernous hemangiomas. PMID- 26943239 TI - Yttrium-90 hepatic radioembolization: clinical review and current techniques in interventional radiology and personalized dosimetry. AB - In recent years, yttrium-90 ((90)Y) microsphere radioembolization has been establishing itself as a safe and efficacious treatment for both primary and metastatic liver cancers. This extends to both first-line therapies as well as in the salvage setting. In addition, radioembolization appears efficacious for patients with portal vein thrombosis, which is currently a contraindication for surgery, transplantation and transarterial chemoembolization. This article reviews the efficacy and expanding use of (90)Y microsphere radioembolization with an added emphasis on recent advances in personalized dosimetry and interventional radiology techniques. Directions for future research into combination therapies with radioembolization and expansion into sites other than the liver are also explored. PMID- 26943247 TI - Uremic tumoral calcinosis in the cervical spine: case report. AB - Tumoral calcinosis is an uncommon condition characterized by the calcification of periarticular soft tissue. In uremic patients the disease is secondary to metabolic disturbances in predisposed patients. The authors report the case of a 73-year-old woman who presented with a new painful cervical mass while undergoing continuous ambulatory peritoneal dialysis for long-standing end-stage renal disease (ESRD). A CT scan of the neck showed a lobulated, calcified mass in the left paraspinal soft tissue at C2-3. This mass affected the facet joint and also extended into the neural foramen but did not cause any neurological compromise. Due to the patient's significant medical comorbidities, resection was deferred and the patient was followed in the clinic. Subsequent repeat imaging has shown a significant decrease in the size of the mass. In the context of ESRD, a diagnosis of uremic tumoral calcinosis (UTC) was made. The authors conducted a search of the PubMed and EMBASE databases and identified 7 previously reported cases of UTC of the cervical spine. They present a summary of these cases and discuss the etiology, diagnosis, and management of the condition. Although the metabolic disturbances seen in patients undergoing dialysis can lead to tumoral calcinosis, most reported cases involve large joints such as the shoulder or the hip; however, the spine can also be affected and should be considered in the differential diagnosis of patients with uremia as it can mimic aggressive bone forming neoplasms. PMID- 26943249 TI - Overutilization of bracing in the management of penetrating spinal cord injury from gunshot wounds. AB - OBJECTIVE Penetrating gunshot wounds (GSWs) to the spinal column are stable injuries and do not require spinal orthoses or bracing postinjury. Nonetheless, a high number of GSW-related spinal cord injury (SCI) patients are referred with a brace to national rehabilitation centers. Unnecessary bracing may encumber rehabilitation, create skin breakdown or pressure ulcers, and add excessive costs. The aim of this study was to confirm the stability of spinal column injuries from GSWs and quantify the overutilization rate of bracing based on long term follow-up. METHODS This retrospective cohort study was performed at a nationally renowned rehabilitation center. In total, 487 GSW-related SCI patients were transferred for rehabilitation and identified over the last 14 years. Retrospective chart review and telephone interviews were conducted to identify patients who were braced at the initial treating institution and determine if late instability, deformity, or neurological deterioration resulted in secondary surgery or intervention. In addition, 396 unoperated patients were available for analysis after 91 patients were excluded for undergoing an initial destabilizing surgical dissection or laminectomy, thereby altering the natural history of the injury. All of these 396 patients who presented with a brace had bracing discontinued upon reaching the facility. RESULTS In total, 203 of 396 patients were transferred with a spinal brace, demonstrating an overutilization rate of 51%. No patients deteriorated neurologically or needed later surgery for spinal column deformity or instability attributable to the injury. All patients had stable injuries. The patterns of injury and severity of neurological injury did not vary between patients who were initially braced or unbraced. The average follow-up was 7.8 years (range 1-14 years) and the average age was 25 years (range 10-62 years). CONCLUSIONS The incidence of brace overutilization for penetrating GSW-related SCI was 51%. Long-term follow-up in this study confirmed that these injuries were stable and thus did not require bracing. No patients deteriorated neurologically, whether or not they were initially braced. The unnecessary use of spinal orthoses increases costs and patient morbidity. Reeducation and dissemination of this information is warranted. PMID- 26943250 TI - Use of liposomal bupivacaine in the postoperative management of posterior spinal decompression. AB - OBJECTIVE The aim in this paper was to evaluate the efficacy of long-acting liposomal bupivacaine in comparison with bupivacaine hydrochloride for lowering postoperative analgesic usage in the management of posterior cervical and lumbar decompression and fusion. METHODS A retrospective cohort-matched chart review of 531 consecutive cases over 17 months (October 2013 to February 2015) for posterior cervical and lumbar spinal surgery procedures performed by a single surgeon (J.J.) was performed. Inclusion criteria for the analysis were limited to those patients who received posterior approach decompression and fusion for cervical or lumbar spondylolisthesis and/or stenosis. Patients from October 1, 2013, through December 31, 2013, received periincisional injections of bupivacaine hydrochloride, whereas after January 1, 2014, liposomal bupivacaine was solely administered to all patients undergoing posterior approach cervical and lumbar spinal surgery through the duration of treatment. Patients were separated into 2 groups for further analysis: posterior cervical and posterior lumbar spinal surgery. RESULTS One hundred sixteen patients were identified: 52 in the cervical cohort and 64 in the lumbar cohort. For both cervical and lumbar cases, patients who received bupivacaine hydrochloride required approximately twice the adjusted morphine milligram equivalent (MME) per day in comparison with the liposomal bupivacaine groups (5.7 vs 2.7 MME, p = 0.27 [cervical] and 17.3 vs 7.1 MME, p = 0.30 [lumbar]). The amounts of intravenous rescue analgesic requirements were greater for bupivacaine hydrochloride in comparison with liposomal bupivacaine in both the cervical (1.0 vs 0.39 MME, p = 0.31) and lumbar (1.0 vs 0.37 MME, p = 0.08) cohorts as well. None of these differences was found to be statistically significant. There were also no significant differences in lengths of stay, complication rates, or infection rates. A subgroup analysis of both cohorts of opiate-naive versus opiate-dependent patients found that those patients who were naive had no difference in opiate requirements. In chronic opiate users, there was a trend toward higher opiate requirements for the bupivacaine hydrochloride group than for the liposomal bupivacaine group; however, this trend did not achieve statistical significance. CONCLUSIONS Liposomal bupivacaine did not appear to significantly decrease perioperative narcotic use or length of hospitalization, although there was a trend toward decreased narcotic use in comparison with bupivacaine hydrochloride. While the results of this study do not support the routine use of liposomal bupivacaine, there may be a benefit in the subgroup of patients who are chronic opiate users. Future prospective randomized controlled trials, ideally with dose-response parameters, must be performed to fully explore the efficacy of liposomal bupivacaine, as the prior literature suggests that clinically relevant effects require a minimum tissue concentration. PMID- 26943248 TI - Osteosarcoma of the spine: prognostic variables for local recurrence and overall survival, a multicenter ambispective study. AB - OBJECTIVE Primary spinal osteosarcomas are rare and aggressive neoplasms. Poor outcomes can occur, as obtaining marginal margins is technically demanding; further Enneking-appropriate en bloc resection can have significant morbidity. The goal of this study is to identify prognostic variables for local recurrence and mortality in surgically treated patients diagnosed with a primary osteosarcoma of the spine. METHODS A multicenter ambispective database of surgically treated patients with primary spine osteosarcomas was developed by AOSpine Knowledge Forum Tumor. Patient demographic, diagnosis, treatment, perioperative morbidity, local recurrence, and cross-sectional survival data were collected. Tumors were classified in 2 cohorts: Enneking appropriate (EA) and Enneking inappropriate (EI), as defined by pathology margin matching Enneking recommended surgical margins. Prognostic variables were analyzed in reference to local recurrence and survival. RESULTS Between 1987 and 2012, 58 patients (32 female patients) underwent surgical treatment for primary spinal osteosarcoma. Patients were followed for a mean period of 3.5 +/- 3.5 years (range 0.5 days to 14.3 years). The median survival for the entire cohort was 6.7 years postoperative. Twenty-four (41%) patients died, and 17 (30%) patients suffered a local recurrence, 10 (59%) of whom died. Twenty-nine (53%) patients underwent EA resection while 26 (47%) patients underwent EI resection with a postoperative median survival of 6.8 and 3.7 years, respectively (p = 0.048). EI patients had a higher rate of local recurrence than EA patients (p = 0.001). Patient age, previous surgery, biopsy type, tumor size, spine level, and chemotherapy timing did not significantly influence recurrence and survival. CONCLUSIONS Osteosarcoma of the spine presents a significant challenge, and most patients die in spite of aggressive surgery. There is a significant decrease in recurrence and an increase in survival with en bloc resection (EA) when compared with intralesional resection (EI). The effect of adjuvant and neoadjuvant chemotherapeutics, as well as method of biopsy, requires further exploration. PMID- 26943255 TI - Letter to the Editor: The Brain and Spinal Injury Center score. PMID- 26943253 TI - Utility of 3D SPACE T2-weighted volumetric sequence in the localization of spinal dural arteriovenous fistula. AB - OBJECTIVE The aim of this study was to investigate the utility of a heavily T2 weighted volumetric MRI sequence (3D sampling perfection with application optimized contrasts using different flip-angle evolutions [SPACE]) in the feeder localization of spinal dural arteriovenous fistula (SDAVF). METHODS Patients who were diagnosed with SDAVF and who had 3D SPACE source images available for review were identified from a retrospective review of medical records. A total of 16 patients were identified, and MR images were analyzed separately by 2 blinded observers. The accuracy of the observation and interobserver agreement were measured by Kendall's tau and kappa statistics. RESULTS The site of fistula was accurately predicted by Observers 1 and 2 in 81% and 88% of cases, respectively, which improved to 94% when the level was considered within 1 vertebral level. The observer agreement with gold-standard angiography and interobserver agreement were found to be highly significant (p < 0.0001). CONCLUSIONS The 3D SPACE MRI sequence is valuable in the precise detection of the site of SDAVF. It may help to tailor digital subtraction angiography and thereby reduce the radiation exposure, contrast load, and study time. PMID- 26943254 TI - Clinical and radiographic parameters associated with best versus worst clinical outcomes in minimally invasive spinal deformity surgery. AB - OBJECTIVE Minimally invasive surgery (MIS) techniques are increasingly used to treat adult spinal deformity. However, standard minimally invasive spinal deformity techniques have a more limited ability to restore sagittal balance and match the pelvic incidence-lumbar lordosis (PI-LL) than traditional open surgery. This study sought to compare "best" versus "worst" outcomes of MIS to identify variables that may predispose patients to postoperative success. METHODS A retrospective review of minimally invasive spinal deformity surgery cases was performed to identify parameters in the 20% of patients who had the greatest improvement in Oswestry Disability Index (ODI) scores versus those in the 20% of patients who had the least improvement in ODI scores at 2 years' follow-up. RESULTS One hundred four patients met the inclusion criteria, and the top 20% of patients in terms of ODI improvement at 2 years (best group, 22 patients) were compared with the bottom 20% (worst group, 21 patients). There were no statistically significant differences in age, body mass index, pre- and postoperative Cobb angles, pelvic tilt, pelvic incidence, levels fused, operating room time, and blood loss between the best and worst groups. However, the mean preoperative ODI score was significantly higher (worse disability) at baseline in the group that had the greatest improvement in ODI score (58.2 vs 39.7, p < 0.001). There was no difference in preoperative PI-LL mismatch (12.8 degrees best vs 19.5 degrees worst, p = 0.298). The best group had significantly less postoperative sagittal vertical axis (SVA; 3.4 vs 6.9 cm, p = 0.043) and postoperative PI-LL mismatch (10.4 degrees vs 19.4 degrees , p = 0.027) than the worst group. The best group also had better postoperative visual analog scale back and leg pain scores (p = 0.001 and p = 0.046, respectively). CONCLUSIONS The authors recommend that spinal deformity surgeons using MIS techniques focus on correcting a patient's PI-LL mismatch to within 10 degrees and restoring SVA to < 5 cm. Restoration of these parameters seems to impact which patients will attain the greatest degree of improvement in ODI outcomes, while the spines of patients who do the worst are not appropriately corrected and may be fused into a fixed sagittal plane deformity. PMID- 26943251 TI - Hyaluronic acid scaffold has a neuroprotective effect in hemisection spinal cord injury. AB - OBJECTIVE Spinal cord injury occurs in 2 phases. The initial trauma is followed by inflammation that leads to fibrous scar tissue, glial scarring, and cavity formation. Scarring causes further axon death around and above the injury. A reduction in secondary injury could lead to functional improvement. In this study, hyaluronic acid (HA) hydrogels were implanted into the gap formed in the hemisected spinal cord of Sprague-Dawley rats in an attempt to attenuate damage and regenerate tissue. METHODS A T-10 hemisection spinal cord injury was created in adult male Sprague-Dawley rats; the rats were assigned to a sham, control (phosphate-buffered saline), or HA hydrogel-treated group. One cohort of 23 animals was followed for 12 weeks and underwent weekly behavioral assessments. At 12 weeks, retrograde tracing was performed by injecting Fluoro-Gold in the left L 2 gray matter. At 14 weeks, the animals were killed. The volume of the lesion and the number of cells labeled from retrograde tracing were calculated. Animals in a separate cohort were killed at 8 or 16 weeks and perfused for immunohistochemical analysis and transmission electron microscopy. Samples were stained using H & E, neurofilament stain (neurons and axons), silver stain (disrupted axons), glial fibrillary acidic protein stain (astrocytes), and Iba1 stain (mononuclear cells). RESULTS The lesions were significantly smaller in size and there were more retrograde-labeled cells in the red nuclei of the HA hydrogel-treated rats than in those of the controls; however, the behavioral assessments revealed no differences between the groups. The immunohistochemical analyses revealed decreased fibrous scarring and increased retention of organized intact axonal tissue in the HA hydrogel-treated group. There was a decreased presence of inflammatory cells in the HA hydrogel-treated group. No axonal or neuronal regeneration was observed. CONCLUSIONS The results of these experiments show that HA hydrogel had a neuroprotective effect on the spinal cord by decreasing the magnitude of secondary injury after a lacerating spinal cord injury. Although regeneration and behavioral improvement were not observed, the reduction in disorganized scar tissue and the retention of neurons near and above the lesion are important for future regenerative efforts. In addition, this gel would be useful as the base substrate in the development of a more complex scaffold. PMID- 26943257 TI - Rate of perioperative neurological complications after surgery for cervical spinal cord stimulation. AB - OBJECTIVE Cervical spinal cord stimulation (cSCS) is used to treat pain of the cervical region and upper extremities. Case reports and small series have shown a relatively low risk of complication after cSCS, with only a single reported case of perioperative spinal cord injury in the literature. Catastrophic cSCS associated spinal cord injury remains a concern as a result of underreporting. To aid in preoperative counseling, it is necessary to establish a minimum rate of spinal cord injury and surgical complication following cSCS. METHODS The Nationwide Inpatient Sample (NIS) is a stratified sample of 20% of all patient discharges from nonfederal hospitals in the United States. The authors identified discharges with a primary procedure code for spinal cord stimulation (ICD-9 03.93) associated with a primary diagnosis of cervical pathology from 2002 to 2011. They then analyzed short-term safety outcomes including the presence of spinal cord injury and neurological, medical, and general perioperative complications and compared outcomes using univariate analysis. RESULTS Between 2002 and 2011, there were 2053 discharges for cSCS. The spinal cord injury rate was 0.5%. The rates of any neurological, medical, and general perioperative complications were 1.1%, 1.4%, and 11.7%, respectively. There were no deaths. CONCLUSIONS In the largest series of cSCS, the risk of spinal cord injury was higher than previously reported (0.5%). Nonetheless, this procedure remains relatively safe, and physicians may use these data to corroborate the safety of cSCS in an appropriately selected patient population. This may become a key treatment option in an increasingly opioid-dependent, aging population. PMID- 26943252 TI - Inpatient morbidity and mortality after adult spinal deformity surgery in teaching versus nonteaching hospitals. AB - OBJECTIVE The goal of this study was to compare inpatient morbidity and mortality after adult spinal deformity (ASD) surgery in teaching versus nonteaching hospitals in the US. METHODS The Nationwide Inpatient Sample was used to identify surgical patients with ASD between 2002 and 2011. Only patients > 21 years old and elective cases were included. Patient characteristics, inpatient morbidity, and inpatient mortality were compared between teaching and nonteaching hospitals. A multivariable logistic regression analysis was performed to examine the effect of hospital teaching status on surgical outcomes. RESULTS A total of 7603 patients were identified, with 61.2% (n = 4650) in the teaching hospital group and 38.8% (n = 2953) in the nonteaching hospital group. The proportion of patients undergoing revision procedures was significantly different between groups (5.2% in teaching hospitals vs 3.9% in nonteaching hospitals, p = 0.008). Likewise, complex procedures (defined as fusion of 8 or more segments and/or osteotomy) were more common in teaching hospitals (27.3% vs 21.7%, p < 0.001). Crude overall complication rates were similar in teaching hospitals (47.9%) compared with nonteaching hospitals (49.8%, p = 0.114). After controlling for patient characteristics, case complexity, and revision status, patients treated at teaching hospitals were significantly less likely to develop a complication when compared with patients treated at a nonteaching hospital (OR 0.89; 95% CI 0.82-0.98). The mortality rate was 0.4% in teaching hospitals and < 0.4% in nonteaching hospitals (p = 0.210). CONCLUSIONS Patients who undergo surgery for ASD at a teaching hospital may have significantly lower odds of complication development compared with patients treated at a nonteaching hospital. PMID- 26943259 TI - Solution Structure of Molecular Associations Investigated Using NMR for Polysaccharides: Xanthan/Galactomannan Mixtures. AB - Although the intermolecular nuclear Overhauser effect (NOE) signal was valuable to elucidate molecular association structure, it could not always be observed for associated molecules due to the short spin-spin relaxation time T2 in NMR measurements, especially for high molar mass systems. While almost no study has been reported for high molar mass polymers (>1 * 10(6)), especially for polysaccharide-polysaccharide interactions, NOE signals were observed for the first time between two different types of polysaccharides, xanthan and galactomannan (locust bean gum), forming a synergistic gel, as a direct evidence of intermolecular binding of polysaccharides. The NOE peak was found between pyruvic acid in xanthan and anomeric proton of mannose of galactomannan. This NOE signal was observed only when mixing time >0.5 s, indicating indirect NOEs caused by spin diffusion. Therefore, this NOE could not be used to construct the molecular models. However, it is a direct evidence for the binding between two different types of polysaccharide to elucidate the synergistic gelation. This NOE signal was observed only for low molar mass galactomannans (1.4 * 10(4)). T2 of pyruvate methyl drastically decreased at low temperatures in the presence of synergistic interaction, suggesting that pyruvate group at terminal end of side chain in xanthan plays an essential role in synergistic interaction. PMID- 26943258 TI - Cement leakage in pedicle screw augmentation: a prospective analysis of 98 patients and 474 augmented pedicle screws. AB - OBJECTIVE Loosening and pullout of pedicle screws are well-known problems in pedicle screw fixation surgery. Augmentation of pedicle screws with bone cement, first described as early as 1975, increases the pedicle-screw interface and pullout force in osteoporotic vertebrae. The aim of the present study was to identify cement leakage and pulmonary embolism rates in a large prospective single-center series of pedicle screw augmentations. METHODS All patients who underwent cement-augmented pedicle screw placement between May 2006 and October 2010 at the authors' institution were included in this prospective cohort study. Perivertebral cement leakage and pulmonary cement embolism were evaluated with a CT scan of the area of operation and with a radiograph of the chest, respectively. RESULTS A total of 98 patients underwent placement of cement augmented pedicle screws; 474 augmented screws were inserted in 237 vertebrae. No symptomatic perivertebral cement leakage or symptomatic pulmonary cement embolism was observed, but asymptomatic perivertebral cement leakage was seen in 88 patients (93.6%) and in 165 augmented vertebrae (73.3%). Cement leakage most often occurred in the perivertebral venous system. Clinically asymptomatic pulmonary cement embolism was found in 4 patients (4.1%). CONCLUSIONS Perivertebral cement leakage often occurs in pedicle screw augmentation, but in most cases, it is clinically asymptomatic. Cement augmentation should be performed under continuous fluoroscopy to avoid high-volume leakage. Alternative strategies, such as use of expandable screws, should be examined in more detail for patients at high risk of screw loosening. PMID- 26943256 TI - Stereotactic body radiotherapy for metastatic spinal sarcoma: a detailed patterns of-failure study. AB - OBJECTIVE The aim of this study was to report the first detailed analysis of patterns of failure within the spinal axis of patients treated with stereotactic body radiotherapy (SBRT) for sarcoma spine metastases. METHODS Between 2005 and 2012, 88 consecutive patients with metastatic sarcoma were treated with SBRT for 120 spinal lesions. Seventy-one percent of patients were enrolled on prospective institutional protocols. For patients who underwent routine posttreatment total spine MRI (64 patients, 88 lesions), each site of progression within the entire spinal axis was mapped in relation to the treated lesion. Actuarial rates of local-, adjacent-, and distant-segment failure-free survival (FFS) were calculated using the Kaplan-Meier method. RESULTS The median follow-up for the cohort was 14.4 months, with 81.7% of patients followed up until death. The 12 month actuarial rate of local FFS was 85.9%; however, 83.3% of local failures occurred in conjunction with distant-segment failures. The 12-month actuarial rates of isolated local-, adjacent-, and distant-segment FFS were 98.0%, 97.8%, and 74.7%, respectively. Of patients with any spinal progression (n = 55), only 25.5% (n = 14) had progression at a single vertebral level, with 60.0% (n = 33) having progression at >= 3 sites within the spine simultaneously. Linear regression analysis revealed a relationship of decreasing risk of failure with increasing distance from the treated index lesion (R(2) = 0.87), and 54.1% of failures occurred >= 5 vertebral levels away. Treatment of the index lesion with a lower biological effective dose (OR 3.2, 95% CI 1.1-9.2) and presence of local failure (OR 18.0, 95% CI 2.1-152.9) independently predicted for distant spine failure. CONCLUSIONS Isolated local- and adjacent-segment failures are exceptionally rare for patients with metastatic sarcoma to the spine treated with SBRT, thereby affirming the treatment of the involved level only. The majority of progression within the spinal axis occurs >= 5 vertebral levels away. Thus, total spine imaging is necessary for surveillance posttreatment. PMID- 26943272 TI - Effect of Particulate Contaminants on the Development of Biofilms at Air/Water Interfaces. AB - The development of biofilms at air/water or oil/water interfaces has important ramifications on several applications, but it has received less attention than biofilm formation on solid surfaces. A key difference between the growth of biofilms on solid surfaces versus liquid interfaces is the range of complicated boundary conditions the liquid interface can create that may affect bacteria, as they adsorb onto and grow on the interface. This situation is exacerbated by the existence of complex interfaces in which interfacially adsorbed components can even more greatly affect interfacial boundary conditions. In this work, we present evidence as to how particle-laden interfaces impact biofilm growth at an air/water interface. We find that particles can enhance the rate of growth and final strength of biofilms at liquid interfaces by providing sites of increased adhesive strength for bacteria. The increased adhesion stems from creating localized areas of hydrophobicity that protrude in the water phase and provide sites where bacteria preferentially adhere. This mechanism is found to be primarily controlled by particle composition, with particle size providing a secondary effect. This increased adhesion through interfacial conditions creates biofilms with properties similar to those observed when adhesion is increased through biological means. Because of the generally understood ubiquity of increased bacteria attachment to hydrophobic surfaces, this result has general applicability to pellicle formation for many pellicle-forming bacteria. PMID- 26943262 TI - Simultaneous determination of seven alkaloids in rat plasma by UFLC-MS/MS and its application to a pharmacokinetic study after oral administration of Cerebralcare Granule. AB - An ultra fast liquid chromatography-tandem mass sepectrometry (UFLC-MS/MS) method was developed for simultaneous determination of seven active alkaloid components (tetrahydropalmatine, corydaline, alpha-allocryptopine, tetrahydroberberine, tetrahydrocoptisine, tetrahydrocolumbamine and dehydrocorydaline) in rat plasma after oral administration of Cerebralcare Granule. Plasma samples were pretreated by protein precipitation with acetronitrile containing the internal standard diazepam. Chromatographic separation was achieved on a Phenomenex Kinetex C18 column (100*2.1mm, 2.6MUm) with gradient elution using mobile phase consisting of acetonitrile -0.1% formic acid in water at a flow rate of 0.3mL/min. The detection was performed on an electrospray ionization triple quadrupole tandem mass spectrometer using multiple reaction monitoring (MRM) with positive ionization mode. The established method was fully validated and proved to be sensitive and specific with lower limits of quantification (LLOQs) all less than 0.0265ng/mL in rat plasma. Good linearities of seven alkaloids were obtained in respective concentration ranges (r>0.9923). The intra- and inter-day precisions were below of 15% for all the seven alkaloids in terms of relative standard deviation (RSD), and the accuracies were ranged from -2.7% to 8.3% in terms of relative error (RE). Extraction recovery, matrix effect and stability were within the required limits in rat plasma. The validated method was successfully applied to investigate the pharmacokinetics of the seven alkaloids in rat plasma after oral administration of Cerebralcare Granule (CG). PMID- 26943260 TI - Design of Ionizable Lipids To Overcome the Limiting Step of Endosomal Escape: Application in the Intracellular Delivery of mRNA, DNA, and siRNA. AB - The intracellular delivery of nucleic acid molecules is a complex process involving several distinct steps; among these the endosomal escape appeared to be of particular importance for an efficient protein production (or inhibition) into host cells. In the present study, a new series of ionizable vectors, derived from naturally occurring aminoglycoside tobramycin, was prepared using improved synthetic procedures that allow structural variations on the linker and hydrophobic domain levels. Complexes formed between the new ionizable lipids and mRNA, DNA, or siRNA were characterized by cryo-TEM experiments and their transfection potency was evaluated using different cell types. We demonstrated that lead molecule 30, bearing a biodegradable diester linker, formed small complexes with nucleic acids and provided very high transfection efficiency with all nucleic acids and cell types tested. The obtained results suggested that the improved and "universal" delivery properties of 30 resulted from an optimized endosomal escape, through the lipid-mixing mechanism. PMID- 26943261 TI - Perceived social support in the lives of gay, bisexual and queer Hispanic college men. AB - In this qualitative study, we examined the sources and nature of social support reported by 24 gay, bisexual and queer Hispanic college men at a small liberal arts college and a large university in the USA. We identified four themes of support across the interviews: Shared experiences (46%), Protector (42%), Support in the air (33%) and Gradual support (29%). Shared experiences included support from those who had previous experience with the lesbian, gay or bisexual community. Protector indicated a type of support that was psychologically, emotionally or physically protective in nature. Participants also reported receiving indirect support such as nonverbal behaviours or indirect gestures of endorsement and caring (support in the air). Participants reported that many of their network members came to support them gradually over time (gradual support). Within each theme we found support from both women and men, who provided support in gender-consistent ways. Our results highlight that despite continued prejudice and discrimination in society, sexual and racial/ethnic minority men have strongholds of support from men and women in their lives that enable them to navigate their development successfully. PMID- 26943273 TI - Bioinspired Fabrication of Free-Standing Conducting Films with Hierarchical Surface Wrinkling Patterns. AB - Mechanical instability has been shown to play an important role in the formation of wrinkle structures in biofilms, which not only can adopt instability modes as templates to regulate their 3D architectures but also can tune internal stresses to achieve stable patterns. Inspired by nature, we report a mechanical-chemical coupling method to fabricate free-standing conducting films with instability driven hierarchical micro/nanostructured patterns. When polypyrrole (PPy) film is grown on an elastic substrate via chemical oxidation polymerization, differential growth along with in situ self-reinforcing effect induces stable wrinkle patterns with different scales of wavelengths. The self-reinforcing effect modifies the internal stresses, hence PPy films with intact wrinkles can be removed from substrates and further transferred onto target substrates for functional device fabrication. To understand the buckling mechanics, we construct a model which reveals the formation of hierarchical wrinkle patterns. PMID- 26943264 TI - Robust Chemical Synthesis of Membrane Proteins through a General Method of Removable Backbone Modification. AB - Chemical protein synthesis can provide access to proteins with post-translational modifications or site-specific labelings. Although this technology is finding increasing applications in the studies of water-soluble globular proteins, chemical synthesis of membrane proteins remains elusive. In this report, a general and robust removable backbone modification (RBM) method is developed for the chemical synthesis of membrane proteins. This method uses an activated O-to-N acyl transfer auxiliary to install in the Fmoc solid-phase peptide synthesis process a RBM group with switchable reactivity toward trifluoroacetic acid. The method can be applied to versatile membrane proteins because the RBM group can be placed at any primary amino acid. With RBM, the membrane proteins and their segments behave almost as if they were water-soluble peptides and can be easily handled in the process of ligation, purification, and mass characterizations. After the full-length protein is assembled, the RBM group can be readily removed by trifluoroacetic acid. The efficiency and usefulness of the new method has been demonstrated by the successful synthesis of a two-transmembrane-domain protein (HCV p7 ion channel) with site-specific isotopic labeling and a four transmembrane-domain protein (multidrug resistance transporter EmrE). This method enables practical synthesis of small- to medium-sized membrane proteins or membrane protein domains for biochemical and biophysical studies. PMID- 26943263 TI - TRAIL causes deletions at the HPRT and TK1 loci of clonogenically competent cells. AB - When chemotherapy and radiotherapy are effective, they function by inducing DNA damage in cancerous cells, which respond by undergoing apoptosis. Some adverse effects can result from collateral destruction of non-cancerous cells, via the same mechanism. Therapy-related cancers, a particularly serious adverse effect of anti-cancer treatments, develop due to oncogenic mutations created in non cancerous cells by the DNA damaging therapies used to eliminate the original cancer. Physiologically achievable concentrations of direct apoptosis inducing anti-cancer drugs that target Bcl-2 and IAP proteins possess negligible mutagenic activity, however death receptor agonists like TRAIL/Apo2L can provoke mutations in surviving cells, probably via caspase-mediated activation of the nuclease CAD. In this study we compared the types of mutations sustained in the HPRT and TK1 loci of clonogenically competent cells following treatment with TRAIL or the alkylating agent ethyl methanesulfonate (EMS). As expected, the loss-of-function mutations in the HPRT or TK1 loci triggered by exposure to EMS were almost all transitions. In contrast, only a minority of the mutations identified in TRAIL treated clones lacking HPRT or TK1 activity were substitutions. Almost three quarters of the TRAIL-induced mutations were partial or complete deletions of the HPRT or TK1 genes, consistent with sub-lethal TRAIL treatment provoking double strand breaks, which may be mis-repaired by non-homologous end joining (NHEJ). Mis-repair of double-strand breaks following exposure to chemotherapy drugs has been implicated in the pathogenesis of therapy-related cancers. These data suggest that TRAIL too may provoke oncogenic damage to the genomes of surviving cells. PMID- 26943274 TI - Comparison of Cytotoxicity and Inhibition of Membrane ABC Transporters Induced by MWCNTs with Different Length and Functional Groups. AB - Experimental studies indicate that multiwalled carbon nanotubes (MWCNTs) have the potential to induce cytotoxicity. However, the reports are often inconsistent and even contradictory. Additionally, adverse effects of MWCNTs at low concentration are not well understood. In this study, we systemically compared adverse effects of six MWCNTs including pristine MWCNTs, hydroxyl-MWCNTs and carboxyl-MWCNTs of two different lengths (0.5-2 MUm and 10-30 MUm) on human hepatoma cell line HepG2. Results showed that MWCNTs induced cytotoxicity by increasing reactive oxygen species (ROS) generation and damaging cell function. Pristine short MWCNTs induced higher cytotoxicity than pristine long MWCNTs. Functionalization increased cytotoxicity of long MWCNTs, but reduced cytotoxicity of short MWCNTs. Further, our results indicated that the six MWCNTs, at nontoxic concentration, might not be environmentally safe as they inhibited ABC transporters' efflux capabilities. This inhibition was observed even at very low concentrations, which were 40-1000 times lower than their effective concentrations on cytotoxicity. The inhibition of ABC transporters significantly increased cytotoxicity of arsenic, a known substrate of ABC transporters, indicating a chemosensitizing effect of MWCNTs. Plasma membrane damage was likely the mechanism by which the six MWCNTs inhibited ABC transporter activity. This study provides insight into risk assessments of low levels of MWCNTs in the environment. PMID- 26943285 TI - Seaweed-Derived Route to Fe2O3 Hollow Nanoparticles/N-Doped Graphene Aerogels with High Lithium Ion Storage Performance. AB - We developed a nanoscale Kirkendall effect assisted method for simple and scalable synthesis of three-dimensional (3D) Fe2O3 hollow nanoparticles (NPs)/graphene aerogel through the use of waste seaweed biomass as new precursors. The Fe2O3 hollow nanoparticles with an average shell thickness of ~6 nm are distributed on 3D graphene aerogel, and also act as spacers to make the separation of the neighboring graphene nanosheets. The graphene-Fe2O3 aerogels exhibit high rate capability (550 mA h g(-1) at 5 A g(-1)) and excellent cyclic stability (729 mA h g(-1) at 0.1 A g(-1) for 300 cycles), outperforming all of the reported Fe2O3/graphene hybrid electrodes, due to the hollow structure of the active Fe2O3 NPs and the unique structure of the 3D graphene aerogel framework. The present work represents an important step toward high-level control of high performance 3D graphene-Fe-based NPs aerogels for maximizing lithium storage with new horizons for important fundamental and technological applications. PMID- 26943271 TI - A new scheme for real-time high-contrast imaging in lung cancer radiotherapy: a proof-of-concept study. AB - Visualization of anatomy in real time is of critical importance for motion management in lung cancer radiotherapy. To achieve real-time, and high-contrast in-treatment imaging, we propose a novel scheme based on the measurement of Compton scatter photons. In our method, a slit x-ray beam along the superior inferior direction is directed to the patient, (intersecting the lung region at a 2D plane) containing most of the tumor motion trajectory. X-ray photons are scattered off this plane primarily due to the Compton interaction. An imager with a pinhole or a slat collimator is placed at one side of the plane to capture the scattered photons. The resulting image, after correcting for incoming fluence inhomogeneity, x-ray attenuation, scatter angle variation, and outgoing beam geometry, represents the linear attenuation coefficient of Compton scattering. This allows the visualization of the anatomy on this plane. We performed Monte Carlo simulation studies both on a phantom and a patient for proof-of-principle purposes. In the phantom case, a small tumor-like structure could be clearly visualized. The contrast-resolution calculated using tumor/lung as foreground/background for kV fluoroscopy, cone beam computed tomography (CBCT), and scattering image were 0.037, 0.70, and 0.54, respectively. In the patient case, tumor motion could be clearly observed in the scatter images. Imaging dose to the voxels directly exposed by the slit beam was ~0.4 times of that under a single CBCT projection. These studies demonstrated the potential feasibility of the proposed imaging scheme to capture the instantaneous anatomy of a patient on a 2D plane with a high image contrast. Clear visualization of the tumor motion may facilitate marker-less tumor tracking. PMID- 26943305 TI - [Carcinogenic viruses in etiopathogenesis of skin cancers in patients after organ transplantation]. AB - The latest literature report specifies multifactoral etiology of skin cancer in population of patients after organs transplats. Carcirogenic viruses are one of etiopathogenesis components. Viruses of a vital meaning for skin oncogenesis are called Human papillomavirus - HPV, Human herpesvirus 8 - HHV8 i Merkel cell polyomavirus - MCV. Report on connections exisisting between viruses HPV and skin cancers in the population of patients after organs transplants confirms clinical connection between viruses papillas and cancers centres occuring in similar locations and more frequent appearance of attributes characteristic for HPV infection within the limits of changes in the type of Squamous cell carcinoma (SCC). What's more, coexisting of viruses papillas and SCC is more often noticed in the population of organ recipients than in the population of healthy people. It is not confirmed yet that any specific correlation between subtypes of HPV and greater frequency of morbidity in skin cancers really exist. However, in the population of organ recipients infections of different types of HPV are found within the limits of cancers centres in the case of SCC (63%) as well as in basal cell carcinoma-BCC (55%). DNA of HPV was also fund in healthy parts of organ recipients skin (92-94%). HHV8 is also an oncogenic viruse that influences the development of lymphoma. Infection of that virus may cause ocuuring of Kaposi's sarkoma, which is one of the most frequent types of cancer appearing in population of patients treating by long-term immunosuppression in particular geographical zones. MCV, which belongs to the group called Polyomaviriade, owes a particular meaning in etiopathogenesis of Merkel cell carcinoma - MCC. It is a rare cancer derived from neuroendocrine cells of the basic layers of epidermie. For over 30 years it was supposed that correlation between viruses and skin cancers in population of organ recipient exist. Knowledge of the total viruses influence on skin cancers allows to widen the spectrum of anti-cancers prevention in the future. PMID- 26943307 TI - Dietary fibre as an important constituent of the diet. AB - The intake of fibre in the diet of a child or an adult, through various foods (such as wholegrain foods, nuts, fruits and vegetables), plays an important role in reducing the risk and lowering the incidence of numerous diseases. The interest of researchers and consumers in the role of diet in the prevention or treatment of many illnesses, and maintaining the general and oral health, has been growing lately. The aim of our study was to underline the role of dietary fibre through its effects on many aspects of the human body and metabolism. Evidence has been found that dietary fibre from whole foods or supplements may reduce the risk of cardiovascular disease by improving serum lipids and reducing serum total and low-density lipoprotein (LDL) cholesterol concentrations in adults and children. Increased fibre content decreases the glycaemic index of foods, which leads to a significant improvement in glycaemic response. High fibre intake is associated with reduced risk of colorectal and breast cancer. In contemporary children, the reluctance to chew raw, hard plant foods may result in a risk of malocclusion and a lack of tooth wear, which cause the need for orthodontic intervention. Fibre consumption is associated with high nutritional value and antioxidant status of the diet, enhancing the effects on human health. PMID- 26943276 TI - Survival benefit of radiotherapy to patients with small cell esophagus carcinoma: an analysis of Surveillance Epidemiology and End Results (SEER) data. AB - BACKGROUND AND AIMS: Small cell esophageal carcinoma (SCEC) is a rare malignant tumor. So far, few studies are found to research the effect of radiotherapy (RT) to it. This study is designed to explore the prognostic factors, and analyze survival benefit of RT to patients with SCEC. RESULTS: Patients with SCEC were more likely to be in female, older, higher disease stage than those with non small cell esophageal carcinoma. RT was used in more than 50% SCEC patients. RT tended be reduced as the disease stage raise in SCEC. Univariate and multivariate analysis showed that age, year, disease stage, and RT were the prognostic factors of survival (P < 0.05). RT reduced nearly 75% risks of death in localized stage (P < 0.05), nearly 50% risks of death in regional stage (P > 0.05) and nearly 30% risks of death in distant stage (P > 0.05). METHODS: SCEC patients between 1973 and 2012 were searched from the Surveillance Epidemiology and End Results (SEER) data. Clinical factors including age, year, sex, race, stage, surgery, and RT were summarized. Univariate and multivariate analysis were performed to explore the independent prognostic factors of SCEC. Cox regression survival analysis was performed to evaluate the effect of RT to SCEC based on different stages. CONCLUSIONS: Stage, age, year, and RT are independent prognostic factors of SCEC. Survival benefit of RT exists in any disease stage, but is only statistically significant in localized stage of SCEC. PMID- 26943286 TI - Bidentate Lewis Acid Catalyzed Domino Diels-Alder Reaction of Phthalazine for the Synthesis of Bridged Oligocyclic Tetrahydronaphthalenes. AB - A domino process consisting of an inverse and a normal electron-demand Diels Alder reaction is presented for the formation of bridged tri- and tetracyclic 1,2,3,4-tetrahydronaphthalenes catalyzed by a bidentate Lewis acid. The products were synthesized in a one-pot reaction from commercially available starting materials and contain up to six stereogenic centers. The tetrahydronaphthalenes were isolated as single diastereomers and are derivatives of phenylethylamine, which is well-known as a scaffold of amphetamine or dopamine. PMID- 26943306 TI - [Galectins in hematological malignancies--role, functions and potential therapeutic targets]. AB - Galectins are a family of lectins characterized by an affinity for beta galactosides through the carbohydrate recognition domain (CRD). The extracellular and intracellular presence of Galectins has been described. Their activity and functions are mainly attributed to cell type. The tumor microenviroment is a complex milieu connected with immunosupression, angiogenesis and hypoxic compartments. The studies of interactions between Glycans-Lectins are highly advanced and promising. We are not able to explain the pathogenesis of many diseases only by protein-protein interactions, that is why in these studies is a chance to find a new therapeutic targets. Galectins play a fundametal functions in tumor growth and progression, angiogenesis, adhesion, tumor immune-escape. They are also active in inflammation, fibrosis, organogenesis and immunological functions. The most known Galectin is Gal-3. Depending on the localization Gal-3 may exhibit either pro-apoptotic or anti-apoptotic activity. This publication presents role of Galectins in hematological malignancies and shows potencial prognostoic value and new therapeutic possibilities. PMID- 26943275 TI - Value: Changes in the Detection and Recognition Thresholds of Three Basic Tastes in Lung Cancer Patients Receiving Cisplatin and Paclitaxel and Its Association with Nutritional and Quality of Life Parameters. AB - We evaluated the effects of cisplatin and paclitaxel on taste acuity and their associations with nutritional and health-related quality of life (HRQL) in patients with advanced non-small-cell lung cancer (NSCLC). Forty chemotherapy (CT)-naive patients were assessed at baseline and after two cycles of paclitaxel and cisplatin. The taste evaluation was performed using a rinsing technique to identify detection and recognition thresholds (DT and RT) of bitter, sweet, and umami tastes. At baseline, 37.5% of the patients reported dysgeusia. After CT, the patients showed lower medians DT (p = 0.017) and RT (p = 0.028) for umami taste. These decreases were associated with clinical neuropathy, worse HRQL, and a tendency toward increased appetite loss. Additionally, CT did not significantly reduce the median DT for sweet (p = 0.09), which is associated with lower intake of protein (p = 0.015), animal protein (p = 0.010), fat (p = 0.004), and iron (p = 0.047). CT decreased the median DT for bitter (p = 0.035); however, this decrease was not associated with nutritional parameters or with HRQL. Sensitivity to taste increased with paclitaxel and cisplatin CT, making foods more unpleasant, and it was associated with neuropathy, worse HRQL, and reduced nutrient intake in advanced NSCLC patients. The protocol was registered at clinicaltrials.gov (NCT01540045). PMID- 26943308 TI - Evaluation of potential prognostic value of Bmi-1 gene product and selected markers of proliferation (Ki-67) and apoptosis (p53) in the neuroblastoma group of tumors. AB - INTRODUCTION: Cancer in children is a very important issue in pediatrics. The least satisfactory treatment outcome occurs among patients with clinically advanced neuroblastomas. Despite much research, the biology of this tumor still remains unclear, and new prognostic factors are sought. The Bmi-1 gene product is a currently highly investigated protein which belongs to the Polycomb group (PcG) and has been identified as a regulator of primary neural crest cells. It is believed that Bmi-1 and N-myc act together and are both involved in the pathogenesis of neuroblastoma. The aim of the study was to assess the potential prognostic value of Bmi-1 protein and its relations with mechanisms of proliferation and apoptosis in the neuroblastoma group of tumors. MATERIAL/METHODS: 29 formalin-fixed and paraffin-embedded neuroblastoma tissue sections were examined using mouse monoclonal antibodies anti-Bmi-1, anti-p53 and anti-Ki-67 according to the manufacturer's instructions. RESULTS: There were found statistically significant correlations between Bmi-1 expression and tumor histology and age of patients. CONCLUSIONS: Bmi-1 seems to be a promising marker in the neuroblastoma group of tumors whose expression correlates with widely accepted prognostic parameters. The pattern of BMI-1 expression may indicate that the examined protein is also involved in maturation processes in tumor tissue. PMID- 26943309 TI - [The role of resveratrol in the regulation of cell metabolism--a review]. AB - Moderate wine drinking is associated with reduced risk of cardiovascular, cerebrovascular and peripheral vascular disease, and reduced risk of cancer. This phenomenon is called the "French paradox", since it was observed for the first time in France--a country famous for its wine production. In the literature, the cardioprotective effect of wine is very well described and attributed mainly to contained therein resveratrol. Recently, it has been demonstrated that resveratrol extends the lifespan of yeast through activation of the SirT1 longevity gene, which is also responsible for the longevity caused by caloric restriction. Furthermore, resveratrol exhibits high biological activity, affecting cell structures and contributing to their protection. This paper summarizes the available reports on functional and molecular aspects of resveratrol, wines and grapes as a result of the activation of longevity genes. PMID- 26943312 TI - [Duffy blood group antigens: structure, serological properties and function]. AB - Duffy (Fy) blood group antigens are located on seven-transmembrane glycoprotein expressed on erythrocytes and endothelial cells, which acts as atypical chemokine receptor (ACKR1) and malarial receptor. The biological role of the Duffy glycoprotein has not been explained yet. It is suggested that Duffy protein modulate the intensity of the inflammatory response. The Duffy blood group system consists of two major antigens, Fy(a) and Fy(b), encoded by two codominant alleles designated FY*A and FY*B which differ by a single nucleotide polymorphism (SNP) at position 125G>A of the FY gene that results in Gly42Asp amino acid change in the Fy(a) and Fy(b) antigens, respectively. The presence of antigen Fy(a) and/or Fy(b) on the erythrocytes determine three Duffy-positive phenotypes: Fy(a+b-), Fy(a-b+) and Fy(a+b+), identified in Caucasian population. The Duffy negative phenotype Fy(a-b-), frequent in Africans, but very rare in Caucasians, is defined by the homozygous state of FY*B-33 alleles. The FY*B-33 allele is associated with a SNP -33T>C in the promoter region of the FY gene, which suppresses erythroid expression of this gene without affecting its expression in other tissues. The FY*X allele, found in Caucasians, is correlated with weak expression of Fy(b) antigen. Fy(x) antigen differs from the native Fy(b) by the Arg89Cys and Ala100Thr amino acid substitutions due to SNPs: 265C>T and 298G>A in FY*B allele. The frequency of the FY alleles shows marked geographic disparities, the FY*B-33 allele is predominant in Africans, the FY*B in Caucasians, while the FY*A allele is dominant in Asians and it is the most prevalent allele globally. PMID- 26943315 TI - Serum carnitine concentration is decreased in patients with Lyme borreliosis. AB - BACKGROUND: Lyme borreliosis (LB) is a serious infectious disease. Carnitine plays a crucial role in metabolism and inflammatory responses. Carnitine may be important in improving neuronal dysfunction and loss of neurons. AIM: To evaluate serum carnitine concentration in adult patients with various clinical types of LB. MATERIAL/METHODS: Groups: 1) patients with erythema migrans (EM, n=16), 2) neuroborreliosis (NB, n=10), 3) post-Lyme disease (PLD, n=22) and healthy controls (HC, n=32). Total (TC) and free (FC) carnitine were determined with the spectrophotometric method. RESULTS: TC levels (44.9+/-10.4, 28.0+/-8.4, 35.9+/ 15.6 MUmol/L) in the EM, NB and PLD patients were lower than in HC (54.0+/-11.4 MUmol/L), p < 0.001. FC levels (32.7+/-7.7, 23.6+/-6.8, 26.3+/-11.2 MUmol/L) in the EM, NB and PLD patients were lower than in HC (40.5+/-7.6 MUmol/L), p < 0.001. AC levels (12.2+/-5.2, 4.4+/-2.6, 9.6+/-7.4 MUmol/L) in the EM, NB and PLD patients were lower in the NB and PLD patients than in HC (13.5+/-8.40 MUmol/L), p <0.001. AC/FC ratio was 0.31+/-0.14, 0.18+/-0.09, 0.39+/-0.33 in the EM, NB and PLD patients. CONCLUSIONS: LB patients exhibit a significant decrease of their serum carnitine concentrations. The largest changes were in the NB and PLD patients. To prevent late complications of the disease a possibility of early supplementation with carnitine should be considered. Further studies are required to explain the pathophysiological significance of our findings. PMID- 26943310 TI - [Systemic contact dermatitis]. AB - Systemic contact dermatitis (SCD) is a skin inflammation occurring in a patient after systemic administration of a hapten, which previously caused an allergic contact skin reaction in the same person. Most frequently, hypersensitivity reactions typical for SCD occur after absorption of haptens with food or inhalation. Haptens occur mainly in the forms of metals and compounds present in natural resins, preservatives, food thickeners, flavorings and medicines. For many years, several studies have been conducted on understanding the pathogenesis of SCD in which both delayed type hypersensitivity (type IV) and immediate type I are observed. Components of the complement system are also suspected to attend there. Helper T cells (Th) (Th1 and Th2), cytotoxic T lymphocytes (Tc), and NK cells play a crucial role in the pathogenesis of SCD. They secrete a number of pro-inflammatory cytokines. In addition, regulatory T cells (Tregs) have an important role. They control and inhibit activity of the immune system during inflammation. Tregs release suppressor cytokines and interact directly with a target cell through presentation of immunosuppressive particles at the cell surface. Diagnostic methods are generally the patch test, oral provocation test, elimination diet and lymphocyte stimulation test. There are many kinds of inflammatory skin reactions caused by systemic haptens' distribution. They are manifested in a variety of clinical phenotypes of the disease. PMID- 26943314 TI - [Pancreatic cancer--mechanisms of chemoresistance]. AB - Despite the enormous progress made over the past decades in diagnosis, treatment and prevention of many types of tumor, the survival rate for pancreatic cancer still remains poor. Pancreatic cancer is one of the most malignant and chemotherapy-resistant tumors. That is mainly due to the lack of effective diagnosis at an early stage of tumor development and ineffective therapy. In most patients the disease is diagnosed at an advanced, metastatic stage and only 15 20% of patients are eligible for surgical removal of the tumor, which still remains the only chance for radical treatment. Studies in recent years have not yielded significant progress in the treatment of disease, and gemcitabine or its combinations with other chemotherapeutics such as erlotinib or capecitabine still remains the standard therapy. Although mechanisms of cell death induced by gemcitabine and other chemotherapeutic agents are well known, their effectiveness is limited due to the acquisition of drug resistance by pancreatic cancer cells. So far, mechanisms of resistance have been tested for mutations in many genes- the key to proper functioning of signaling pathways in cancer cells. However, recent studies suggest a significant role of the tumor microenvironment in the development and maintaining resistance to conventionally used chemotherapeutic and targeted therapies. Drug resistance of pancreatic cancer results from multiple mechanisms, which may include the following: mutations in key genes, aberrant gene expression, deregulation of key signaling pathways, apoptotic pathways, the capacity for epithelial-mesenchymal transition (EMT), increased angiogenesis, the presence of cancer stem cells or the presence of a hypoxic microenvironment inside the tumor. PMID- 26943313 TI - [Depression and inflammation in rheumatic diseases]. AB - It is known that the prevalence of depression in rheumatologic patients is higher than in the general population. Socioeconomic factors are not a sufficient explanation of mood disorder in these patients. Symptoms reported by patients with chronic inflammatory diseases resemble changes defined as "sickness behavior". Mood disorders among somatic patients could be explained by disturbances of the immune system according to the monoaminergic theory of depression. Inflammatory factors such as IL-1 (interleukin-1), IL-2 (interleukin 2), IL-6 (interleukin-6), TNF-alpha (tumor necrosis factor alpha), and IFN-gamma (interferon-gamma) act within the CNS (central nervous system). They get through from peripheral tissues as well as being synthesized de novo by neurons. This cytokine activity correlates positively with depression intensity as well as with genetic polymorphism of the serotonin (5-HT) transporter. The theory of glucocorticoid resistance-mediated depression (limbic-hypothalamic-pituitary adrenal [LHPA] axis) is also connected with gained proinflammatory cytokines activity. It might assume the form of a vicious circle. Depressed mood is probably linked with depression in immune-mediated diseases. An elevated level of proinflammatory cytokines is able to activate IDO (indoleamine 2,3-dioxygenase)- an enzyme catabolizing tryptophan (5-HT precursor). Those reactions probably play the main role at the biochemical level. IDO metabolites extensively disturb neurotransmission. 3-Hydroxykynurenine (3OH-KYN), quinolinic acid (Quin) and kynurenic acid (KYNA) are neurotoxic by releasing oxidative stress mediators. Moreover, they activate MAO (monoamine oxidase), which degrades neurotransmitters responsible for stable mood. Bidirectional communication between the neuroendocrine and immune systems is significant for depression treatment, as well as CNS protection against incremental neurodegeneration among seemingly diverse diseases. PMID- 26943311 TI - Metabolism of glycosaminoglycans in the course of juvenile idiopathic arthritis. AB - Juvenile idiopathic arthritis (JIA) is a non-homogeneous autoimmune children's disease which, despite the applied therapy, has a progressive character with recurrences, leading to damage of joint structures. Progressive wearing of the joint cartilage in the course of JIA, which results from the imbalance between the biological strength of the cartilage, its function and exerted pressure forces, is linked to metabolic disorders of extracellular matrix (ECM) components. Among the latter compounds, the proteoglycan (PG) aggrecan plays a particular role in maintaining the mechanical-immunological properties of the cartilage. These functions are directly related to chains of glycosaminoglycans (GAGs), covalently linked to the core protein of PGs. Therefore, every change of GAGs metabolism linked to an increase of the rate of degradation or with a decrease of their biosynthesis may have pathological consequences. In this paper we aim to describe plausible mechanisms leading to observed disorders of aggrecan transformation in children, which are reflected in the profile of plasma GAGs. Therefore, we describe the plausible role of factors related to catabolism and synthesis of PGs/GAGs as well as the contribution of immunological processes to shaping the changes of extracellular matrix components in the course of JIA. PMID- 26943316 TI - Nicotine-induced resistance of non-small cell lung cancer to treatment--possible mechanisms. AB - Cigarette smoking is the leading risk factor of lung cancer. Data from several clinical studies suggest that continuation of smoking during therapy of tobacco related cancers is associated with lower response rates to chemotherapy and/or radiotherapy, and even with decreased survival. Although nicotine--an addictive component of tobacco--is not a carcinogen, it may influence cancer development and progression or effectiveness of anti-cancer therapy. Several in vitro and in vivo trials have evaluated the influence of nicotine on lung cancer cells. The best known mechanisms by which nicotine impacts cancer biology involve suppression of apoptosis induced by certain drugs or radiation, promotion of proliferation, angiogenesis, invasion and migration of cancer cells. This effect is mainly mediated by membranous nicotinic acetylcholine receptors whose stimulation leads to sustained activation of such intracellular pathways as PI3K/Akt/mTOR, RAS/RAF/MEK/ERK and JAK/STAT, induction of NF-kappaB activity, enhanced transcription of mitogenic promoters, inhibition of the mitochondrial death pathway or stimulation of pro-angiogenic factors. We herein summarize the mechanisms underlying nicotine's influence on biology of lung cancer cells and the effectiveness of anti-cancer therapy. PMID- 26943317 TI - The Rqc2/Tae2 subunit of the ribosome-associated quality control (RQC) complex marks ribosome-stalled nascent polypeptide chains for aggregation. AB - Ribosome stalling during translation can potentially be harmful, and is surveyed by a conserved quality control pathway that targets the associated mRNA and nascent polypeptide chain (NC). In this pathway, the ribosome-associated quality control (RQC) complex promotes the ubiquitylation and degradation of NCs remaining stalled in the 60S subunit. NC stalling is recognized by the Rqc2/Tae2 RQC subunit, which also stabilizes binding of the E3 ligase, Listerin/Ltn1. Additionally, Rqc2 modifies stalled NCs with a carboxy-terminal, Ala- and Thr containing extension-the 'CAT tail'. However, the function of CAT tails and fate of CAT tail-modified ('CATylated') NCs has remained unknown. Here we show that CATylation mediates formation of detergent-insoluble NC aggregates. CATylation and aggregation of NCs could be observed either by inactivating Ltn1 or by analyzing NCs with limited ubiquitylation potential, suggesting that inefficient targeting by Ltn1 favors the Rqc2-mediated reaction. These findings uncover a translational stalling-dependent protein aggregation mechanism, and provide evidence that proteins can become specifically marked for aggregation. PMID- 26943319 TI - Exploiting death: apoptotic immunity in microbial pathogenesis. AB - Innate immunity typically is responsible for initial host responses against infections. Independently, nucleated cells that die normally as part of the physiological process of homeostasis in mammals (including humans) suppress immunity. Specifically, the physiological process of cell death (apoptosis) generates cells that are recognized specifically by viable cells of all types and elicit a profound transient suppression of host immunity (termed 'innate apoptotic immunity' (IAI)). IAI appears to be important normally for the maintenance of self-tolerance and for the resolution of inflammation. In addition, pathogens are able to take advantage of IAI through a variety of distinct mechanisms, to enable their proliferation within the host and enhance pathogenicity. For example, the protist pathogen Leishmania amazonensis, at its infective stage, mimics apoptotic cells by expressing apoptotic-like protein determinants on the cell surface, triggering immunosuppression directly. In contrast, the pathogenic bacterium Listeria monocytogenes triggers cell death in host lymphocytes, relying on those apoptotic cells to suppress host immune control and facilitate bacterial expansion. Finally, although the inhibition of apoptotic cell death is a common attribute of many viruses which facilitates their extended replication, it is clear that adenoviruses also reprogram the non apoptotic dead cells that arise subsequently to manifest apoptotic-like immunosuppressive properties. These three instances represent diverse strategies used by microbial pathogens to exploit IAI, focusing attention on the potency of this facet of host immune control. Further examination of these cases will be revealing both of varied mechanisms of pathogenesis and the processes involved in IAI control. PMID- 26943318 TI - Endothelial cell survival during angiogenesis requires the pro-survival protein MCL1. AB - Angiogenesis is essential to match the size of blood vessel networks to the metabolic demands of growing tissues. While many genes and pathways necessary for regulating angiogenesis have been identified, those responsible for endothelial cell (EC) survival during angiogenesis remain largely unknown. We have investigated the in vivo role of myeloid cell leukemia 1 (MCL1), a pro-survival member of the BCL2 family, in EC survival during angiogenesis. EC-specific deletion of Mcl1 resulted in a dose-dependent increase in EC apoptosis in the angiogenic vasculature and a corresponding decline in vessel density. Our results suggest this apoptosis was independent of the BH3-only protein BIM. Despite the known link between apoptosis and blood vessel regression, this was not the cause of reduced vessel density observed in the absence of endothelial MCL1. Rather, the reduction in vessel density was linked to ectopic apoptosis in regions of the angiogenic vasculature where EC proliferation and new vessel growth occurs. We have therefore identified MCL1 as an essential survival factor for ECs that is required for blood vessel production during angiogenesis. PMID- 26943327 TI - Glucocorticoid Programming in Very Preterm Birth. AB - Very preterm (i.e., <32 weeks of gestation) infants admitted to the neonatal intensive care unit are compromised in their abilities to respond adequately to common threats like hemodynamic changes and reduced energy supplies, which is partly attributable to adrenocortical insufficiency. Conversely, later in life, these infants show features of increased glucocorticoid bioactivity, such as abdominal fat distribution, raised blood pressure, insulin resistance and diabetes mellitus type 2. It has been suggested that the very preterm newborn responds to the adverse postnatal environment with a sustained elevation in hypothalamus-pituitary-adrenal axis activity that persists beyond infancy. This has implications for subsequent growth, body composition, metabolism, neurodevelopment and, ultimately, long-term disease risk. The mechanisms underpinning these associations are not fully elucidated yet. This review gives a brief summary of studies that investigated adrenocortical function in very preterm newborns and how the axis changes with age, as a possible explanation for the association between prematurity and long-term outcome. PMID- 26943320 TI - TAp73 loss favors Smad-independent TGF-beta signaling that drives EMT in pancreatic ductal adenocarcinoma. AB - Advances made in pancreatic cancer therapy have been far from sufficient and have allowed only a slight improvement in global survival of patients with pancreatic ductal adenocarcinoma (PDA). Recent progresses in chemotherapy have offered some hope for an otherwise gloomy outlook, however, only a limited number of patients are eligible because of important cytotoxicity. In this context, enhancing our knowledge on PDA initiation and evolution is crucial to highlight certain weaknesses on which to specifically target therapy. We found that loss of transcriptionally active p73 (TAp73), a p53 family member, impacted PDA development. In two relevant and specific engineered pancreatic cancer mouse models, we observed that TAp73 deficiency reduced survival and enhanced epithelial-to-mesenchymal transition (EMT). Through proteomic analysis of conditioned media from TAp73 wild-type (WT) and deficient pancreatic tumor cells, we identified a secreted protein, biglycan (BGN), which is necessary and sufficient to mediate this pro-EMT effect. Interestingly, BGN is modulated by and modulates the transforming growth factor-beta (TGF-beta) pathway, a key regulator of the EMT process. We further examined this link and revealed that TAp73 impacts the TGF-beta pathway by direct regulation of BGN expression and Sma and Mad related proteins (SMADs) expression/activity. Absence of TAp73 leads to activation of TGF-beta signaling through a SMAD-independent pathway, favoring oncogenic TGF-beta effects and EMT. Altogether, our data highlight the implication of TAp73 in the aggressiveness of pancreatic carcinogenesis through modulation of the TGF-beta signaling. By suggesting TAp73 as a predictive marker for response to TGF-beta inhibitors, our study could improve the classification of PDA patients with a view to offering combined therapy involving TGF-beta inhibitors. PMID- 26943324 TI - A blast without power - cell death induced by the tuberculosis-necrotizing toxin fails to elicit adequate immune responses. AB - In this study, we deploy a doxycycline-dependent suicide switch integrated in a tumor challenge model. With this experimental setup, we characterized the immunological consequences of cells dying by four distinct cell death stimuli in vivo. We observed that apoptotic cell death induced by expression of the truncated form of BH3 interacting-domain death agonist (tBid) and a constitutively active form of caspase 3 (revC3), respectively, showed higher immunogenicity than cell death induced by expression of the tuberculosis necrotizing toxin (TNT). Our data indicate that the early release of ATP induces the silent clearance of dying cells, whereas the simultaneous presence of 'find me' signals and danger-associated molecular patterns (DAMPs) promotes inflammatory reactions and increased immunogenicity. This proposed model is supported by findings showing that the production and release of high concentrations of IL-27 by bone-marrow-derived macrophages (BMDM) is limited to BMDM exposed to those forms of death that simultaneously released ATP and the DAMPs heat-shock protein 90 (HSP90) and high-mobility group box-1 protein (HMGB1). These results demonstrate that the tissue microenvironment generated by dying cells may determine the subsequent immune response. PMID- 26943326 TI - Nitro-Arachidonic Acid Prevents Angiotensin II-Induced Mitochondrial Dysfunction in a Cell Line of Kidney Proximal Tubular Cells. AB - Nitro-arachidonic acid (NO2-AA) is a cell signaling nitroalkene that exerts anti inflammatory activities during macrophage activation. While angiotensin II (ANG II) produces an increase in reactive oxygen species (ROS) production and mitochondrial dysfunction in renal tubular cells, little is known regarding the potential protective effects of NO2-AA in ANG II-mediated kidney injury. As such, this study examines the impact of NO2-AA on ANG II-induced mitochondrial dysfunction in an immortalized renal proximal tubule cell line (HK-2 cells). Treatment of HK-2 cells with ANG II increases the production of superoxide (O2? ), nitric oxide (?NO), inducible nitric oxide synthase (NOS2) expression, peroxynitrite (ONOO-) and mitochondrial dysfunction. Using high-resolution respirometry, it was observed that the presence of NO2-AA prevented ANG II mediated mitochondrial dysfunction. Attempting to address mechanism, we treated isolated rat kidney mitochondria with ONOO-, a key mediator of ANG II-induced mitochondrial damage, in the presence or absence of NO2-AA. Whereas the activity of succinate dehydrogenase (SDH) and ATP synthase (ATPase) were diminished upon exposure to ONOO-, they were restored by pre-incubating the mitochondria with NO2 AA. Moreover, NO2-AA prevents oxidation and nitration of mitochondrial proteins. Combined, these data demonstrate that ANG II-mediated oxidative damage and mitochondrial dysfunction is abrogated by NO2-AA, identifying this compound as a promising pharmacological tool to prevent ANG II-induced renal disease. PMID- 26943328 TI - Preventing Food Allergy in Infancy--Early Consumption or Avoidance? PMID- 26943321 TI - Influenza A virus enhances its propagation through the modulation of Annexin-A1 dependent endosomal trafficking and apoptosis. AB - The influenza virus infects millions of people each year and can result in severe complications. Understanding virus recognition and host responses to influenza infection will enable future development of more effective anti-viral therapies. Previous research has revealed diverse yet important roles for the annexin family of proteins in modulating the course of influenza A virus (IAV) infection. However, the role of Annexin-A1 (ANXA1) in IAV infection has not been addressed. Here, we show that ANXA1 deficient mice exhibit a survival advantage, and lower viral titers after infection. This was accompanied with enhanced inflammatory cell infiltration during IAV infection. ANXA1 expression is increased during influenza infection clinically, in vivo and in vitro. The presence of ANXA1 enhances viral replication, influences virus binding, and enhances endosomal trafficking of the virus to the nucleus. ANXA1 colocalizes with early and late endosomes near the nucleus, and enhances nuclear accumulation of viral nucleoprotein. In addition, ANXA1 enhances IAV-mediated apoptosis. Overall, our study demonstrates that ANXA1 plays an important role in influenza virus replication and propagation through various mechanisms and that we predict that the regulation of ANXA1 expression during IAV infection may be a viral strategy to enhance its infectivity. PMID- 26943325 TI - Tissue damage negatively regulates LPS-induced macrophage necroptosis. AB - Infection is a common clinical complication following tissue damage resulting from surgery and severe trauma. Studies have suggested that cell pre-activation by antecedent trauma/tissue damage profoundly impacts the response of innate immune cells to a secondary infectious stimulus. Cell necroptosis, a form of regulated inflammatory cell death, is one of the mechanisms that control cell release of inflammatory mediators from important innate immune executive cells such as macrophages (Mphi), which critically regulate the progress of inflammation. In this study, we investigated the mechanism and role of trauma/tissue damage in the regulation of LPS-induced Mphi necroptosis using a mouse model simulating long-bone fracture. We demonstrate that LPS acting through Toll-like receptor (TLR) 4 promotes Mphi necroptosis. However, necroptosis is ameliorated by high-mobility group box 1 (HMGB1) release from damaged tissue. We show that HMGB1 acting through cell surface receptor for advanced glycation end products (RAGE) upregulates caveolin-1 expression, which in turn induces caveolae mediated TLR4 internalization and desensitization to decrease Mphi necroptosis. We further show that RAGE-MyD88 activation of Cdc42 and subsequent activation of transcription factor Sp1 serves as a mechanism underlying caveolin-1 transcriptional upregulation. These results reveal a previous unidentified protective role of damage-associated molecular pattern (DAMP) molecules in restricting inflammation in response to exogenous pathogen-associated molecular pattern molecules. PMID- 26943323 TI - PACS-2 mediates the ATM and NF-kappaB-dependent induction of anti-apoptotic Bcl xL in response to DNA damage. AB - Nuclear factor kappa B (NF-kappaB) promotes cell survival in response to genotoxic stress by inducing the expression of anti-apoptotic proteins including Bcl-xL, which protects mitochondria from stress-induced mitochondrial outer membrane permeabilization (MOMP). Here we show that the multifunctional sorting protein Pacs-2 (phosphofurin acidic cluster sorting protein-2) is required for Bcl-xL induction following DNA damage in primary mouse thymocytes. Consequently, in response to DNA damage, Pacs-2(-/-) thymocytes exhibit a blunted induction of Bcl-xL, increased MOMP and accelerated apoptosis. Biochemical studies show that cytoplasmic PACS-2 promotes this DNA damage-induced anti-apoptotic pathway by interacting with ataxia telangiectasia mutated (ATM) to drive NF-kappaB activation and induction of Bcl-xL. However, Pacs-2 was not required for tumor necrosis factor-alpha-induced NF-kappaB activation, suggesting a role for PACS-2 selectively in NF-kappaB activation in response to DNA damage. These findings identify PACS-2 as an in vivo mediator of the ATM and NF-kappaB-dependent induction of Bcl-xL that promotes cell survival in response to DNA damage. PMID- 26943335 TI - Effect of Nasal Obstruction on Continuous Positive Airway Pressure Treatment: Computational Fluid Dynamics Analyses. AB - OBJECTIVE: Nasal obstruction is a common problem in continuous positive airway pressure (CPAP) therapy for obstructive sleep apnea and limits treatment compliance. The purpose of this study is to model the effects of nasal obstruction on airflow parameters under CPAP using computational fluid dynamics (CFD), and to clarify quantitatively the relation between airflow velocity and pressure loss coefficient in subjects with and without nasal obstruction. METHODS: We conducted an observational cross-sectional study of 16 Japanese adult subjects, of whom 9 had nasal obstruction and 7 did not (control group). Three dimensional reconstructed models of the nasal cavity and nasopharynx with a CPAP mask fitted to the nostrils were created from each subject's CT scans. The digital models were meshed with tetrahedral cells and stereolithography formats were created. CPAP airflow simulations were conducted using CFD software. Airflow streamlines and velocity contours in the nasal cavities and nasopharynx were compared between groups. Simulation models were confirmed to agree with actual measurements of nasal flow rate and with pressure and flow rate in the CPAP machine. RESULTS: Under 10 cmH2O CPAP, average maximum airflow velocity during inspiration was 17.6 +/- 5.6 m/s in the nasal obstruction group but only 11.8 +/- 1.4 m/s in the control group. The average pressure drop in the nasopharynx relative to inlet static pressure was 2.44 +/- 1.41 cmH2O in the nasal obstruction group but only 1.17 +/- 0.29 cmH2O in the control group. The nasal obstruction and control groups were clearly separated by a velocity threshold of 13.5 m/s, and pressure loss coefficient threshold of approximately 10.0. In contrast, there was no significant difference in expiratory pressure in the nasopharynx between the groups. CONCLUSION: This is the first CFD analysis of the effect of nasal obstruction on CPAP treatment. A strong correlation between the inspiratory pressure loss coefficient and maximum airflow velocity was found. PMID- 26943336 TI - Prevention of Incisional Hernias by Prophylactic Mesh-augmented Reinforcement of Midline Laparotomies for Abdominal Aortic Aneurysm Treatment: A Randomized Controlled Trial. AB - BACKGROUND: The incidence of incisional hernias after abdominal aortic aneurysm repair is high. Prophylactic mesh-augmented reinforcement during laparotomy closure has been proposed in patients at high risk of incisional hernia. METHODS: A multicenter randomized trial was conducted on patients undergoing elective abdominal aortic aneurysm repair through a midline laparotomy (Clinical.Trials.gov: NCT00757133). In the study group, retromuscular mesh augmented reinforcement was performed with a large-pore polypropylene mesh (Ultrapro, width 7.5 cm). The primary endpoint was the incidence of incisional hernias at 2-year follow-up. RESULTS: Between February 2009 and January 2013, 120 patients were recruited at 8 Belgian centers. Patients' characteristics at baseline were similar between groups. Operative and postoperative characteristics showed no difference in morbidity or mortality. The cumulative incidence of incisional hernias at 2-year follow-up after conventional closure was 28% (95% confidence interval [CI], 17%-41%) versus 0% (95% CI, 0%-6%) after mesh-augmented reinforcement (P < 0.0001; Fisher exact test). The estimated "freedom of incisional hernia" curves (Kaplan-Meier estimate) were significantly different across study arms (chi = 19.5, P < 0.0001; Mantel-Cox test). No adverse effect related to mesh-augmented reinforcement was observed, apart from an increased mean time to close the abdominal wall for mesh-augmented reinforcement compared with the control group: 46 minutes (SD, 18.6) versus 30 minutes (SD, 18.5), respectively (P < 0.001; Mann-Whitney U test). CONCLUSIONS: Prophylactic retromuscular mesh-augmented reinforcement of a midline laparotomy in patients with abdominal aortic aneurysm is safe and effectively prevents the development of incisional hernia during 2 years, with an additional mean operative time of 16 minutes. PMID- 26943322 TI - Onto better TRAILs for cancer treatment. AB - Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), also known as Apo-2 ligand (Apo2L), is a member of the TNF cytokine superfamily. By cross linking TRAIL-Receptor (TRAIL-R) 1 or TRAIL-R2, also known as death receptors 4 and 5 (DR4 and DR5), TRAIL has the capability to induce apoptosis in a wide variety of tumor cells while sparing vital normal cells. The discovery of this unique property among TNF superfamily members laid the foundation for testing the clinical potential of TRAIL-R-targeting therapies in the cancer clinic. To date, two of these therapeutic strategies have been tested clinically: (i) recombinant human TRAIL and (ii) antibodies directed against TRAIL-R1 or TRAIL-R2. Unfortunately, however, these TRAIL-R agonists have basically failed as most human tumors are resistant to apoptosis induction by them. It recently emerged that this is largely due to the poor agonistic activity of these agents. Consequently, novel TRAIL-R-targeting agents with increased bioactivity are currently being developed with the aim of rendering TRAIL-based therapies more active. This review summarizes these second-generation novel formulations of TRAIL and other TRAIL-R agonists, which exhibit enhanced cytotoxic capacity toward cancer cells, thereby providing the potential of being more effective when applied clinically than first-generation TRAIL-R agonists. PMID- 26943329 TI - Analysis of Lung Microbiota in Bronchoalveolar Lavage, Protected Brush and Sputum Samples from Subjects with Mild-To-Moderate Cystic Fibrosis Lung Disease. AB - Individuals with cystic fibrosis (CF) often acquire chronic lung infections that lead to irreversible damage. We sought to examine regional variation in the microbial communities in the lungs of individuals with mild-to-moderate CF lung disease, to examine the relationship between the local microbiota and local damage, and to determine the relationships between microbiota in samples taken directly from the lung and the microbiota in spontaneously expectorated sputum. In this initial study, nine stable, adult CF patients with an FEV1>50% underwent regional sampling of different lobes of the right lung by bronchoalveolar lavage (BAL) and protected brush (PB) sampling of mucus plugs. Sputum samples were obtained from six of the nine subjects immediately prior to the procedure. Microbial community analysis was performed on DNA extracted from these samples and the extent of damage in each lobe was quantified from a recent CT scan. The extent of damage observed in regions of the right lung did not correlate with specific microbial genera, levels of community diversity or composition, or bacterial genome copies per ml of BAL fluid. In all subjects, BAL fluid from different regions of the lung contained similar microbial communities. In eight out of nine subjects, PB samples from different regions of the lung were also similar in microbial community composition, and were similar to microbial communities in BAL fluid from the same lobe. Microbial communities in PB samples were more diverse than those in BAL samples, suggesting enrichment of some taxa in mucus plugs. To our knowledge, this study is the first to examine the microbiota in different regions of the CF lung in clinically stable individuals with mild-to-moderate CF-related lung disease. PMID- 26943334 TI - Mixed Methods Survey of Zoonotic Disease Awareness and Practice among Animal and Human Healthcare Providers in Moshi, Tanzania. AB - BACKGROUND: Zoonoses are common causes of human and livestock illness in Tanzania. Previous studies have shown that brucellosis, leptospirosis, and Q fever account for a large proportion of human febrile illness in northern Tanzania, yet they are infrequently diagnosed. We conducted this study to assess awareness and knowledge regarding selected zoonoses among healthcare providers in Moshi, Tanzania; to determine what diagnostic and treatment protocols are utilized; and obtain insights into contextual factors contributing to the apparent under-diagnosis of zoonoses. METHODOLOGY/RESULTS: We conducted a questionnaire about zoonoses knowledge, case reporting, and testing with 52 human health practitioners and 10 livestock health providers. Immediately following questionnaire administration, we conducted semi-structured interviews with 60 of these respondents, using the findings of a previous fever etiology study to prompt conversation. Sixty respondents (97%) had heard of brucellosis, 26 (42%) leptospirosis, and 20 (32%) Q fever. Animal sector respondents reported seeing cases of animal brucellosis (4), rabies (4), and anthrax (3) in the previous 12 months. Human sector respondents reported cases of human brucellosis (15, 29%), rabies (9, 18%) and anthrax (6, 12%). None reported leptospirosis or Q fever cases. Nineteen respondents were aware of a local diagnostic test for human brucellosis. Reports of tests for human leptospirosis or Q fever, or for any of the study pathogens in animals, were rare. Many respondents expressed awareness of malaria over-diagnosis and zoonoses under-diagnosis, and many identified low knowledge and testing capacity as reasons for zoonoses under-diagnosis. CONCLUSIONS: This study revealed differences in knowledge of different zoonoses and low case report frequencies of brucellosis, leptospirosis, and Q fever. There was a lack of known diagnostic services for leptospirosis and Q fever. These findings emphasize a need for improved diagnostic capacity alongside healthcare provider education and improved clinical guidelines for syndrome-based disease management to provoke diagnostic consideration of locally relevant zoonoses in the absence of laboratory confirmation. PMID- 26943330 TI - Blockade of Hedgehog Signaling Synergistically Increases Sensitivity to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Non-Small-Cell Lung Cancer Cell Lines. AB - Aberrant activation of the hedgehog (Hh) signaling pathway has been implicated in the epithelial-to-mesenchymal transition (EMT) and cancer stem-like cell (CSC) maintenance; both processes can result in tumor progression and treatment resistance in several types of human cancer. Hh cooperates with the epidermal growth factor receptor (EGFR) signaling pathway in embryogenesis. We found that the Hh signaling pathway was silenced in EGFR-TKI-sensitive non-small-cell lung cancer (NSCLC) cells, while it was inappropriately activated in EGFR-TKI resistant NSCLC cells, accompanied by EMT induction and ABCG2 overexpression. Upregulation of Hh signaling through extrinsic SHH exposure downregulated E cadherin expression and elevated Snail and ABCG2 expression, resulting in gefitinib tolerance (P < 0.001) in EGFR-TKI-sensitive cells. Blockade of the Hh signaling pathway using the SMO antagonist SANT-1 restored E-cadherin expression and downregulate Snail and ABCG2 in EGFR-TKI-resistant cells. A combination of SANT-1 and gefitinib markedly inhibited tumorigenesis and proliferation in EGFR TKI-resistant cells (P < 0.001). These findings indicate that hyperactivity of Hh signaling resulted in EGFR-TKI resistance, by EMT introduction and ABCG2 upregulation, and blockade of Hh signaling synergistically increased sensitivity to EGFR-TKIs in primary and secondary resistant NSCLC cells. E-cadherin expression may be a potential biomarker of the suitability of the combined application of an Hh inhibitor and EGFR-TKIs in EGFR-TKI-resistant NSCLCs. PMID- 26943338 TI - Rheological behavior of physicochemical sludges during methanogenesis suppression and hydrogen production at different organic loading rates. AB - This study investigated the rheological behavior of raw physicochemical sludges and sludges that were digested at different organic loading rates (OLRs) (1, 5, 10 and 15 gVS L(-1) d(-1)) during methanogenesis suppression to produce hydrogen anaerobically. The Herschel-Bulkley model was used to describe the rheology of these sludges with specific properties. The results indicate that the Herschel Bulkley model adequately described the rheology (tau0 ? 0) of this type of fluids (R(2) > 0.98). In addition, the raw physicochemical sludges and those that were digested at different OLRs had dilatant behaviors (n > 1), which increased with increasing OLR. These results identified the apparent viscosity, yield stress, pH and OLR conditions that allow for the production and suppression of methane, as well as the conditions that guarantee the production of hydrogen. PMID- 26943339 TI - Potassium-based sorbents from fly ash for high-temperature CO2 capture. AB - Potassium-fly ash (K-FA) sorbents were investigated for high-temperature CO2 sorption. K-FAs were synthesised using coal fly ash as source of silica and aluminium. The synthesised materials were also mixed with Li2CO3 and Ca(OH)2 to evaluate their effect on CO2 capture. Temperature strongly affected the performance of the K-FA sorbents, resulting in a CO2 uptake of 1.45 mmol CO2/g sorbent for K-FA 1:1 at 700 degrees C. The CO2 sorption was enhanced by the presence of Li2CO3 (10 wt%), with the K-FA 1:1 capturing 2.38 mmol CO2/g sorbent at 700 degrees C in 5 min. This sorption was found to be similar to previously developed Li-Na-FA (2.54 mmol/g) and Li-FA (2.4 mmol/g) sorbents. The presence of 10 % Li2CO3 also accelerated sorption and desorption. The results suggest that the increased uptake of CO2 and faster reaction rates in presence of K-FA can be ascribed to the formation of K-Li eutectic phase, which favours the diffusion of potassium and CO2 in the material matrix. The cyclic experiments showed that the K-FA materials maintained stable CO2 uptake and reaction rates over 10 cycles. PMID- 26943340 TI - Exposure assessment of a cyclist to particles and chemical elements. AB - Cycle paths can be used as a route for active transportation or simply to cycle for physical activity and leisure. However, exposure to air pollutants can be boosted while cycling, in urban environments, due to the proximity to vehicular emissions and elevated breathing rates. The objective of this work was to assess the exposure of a cyclist to particles and to chemical elements by combining real time aerosol mass concentration reading equipment and biomonitoring techniques. PM10 and PM2.5 were measured on three cycle paths located in Lisbon, during weekdays and weekends and during rush hours and off-peak hours resulting in a total of 60 campaigns. Lichens were exposed along cycle paths for 3 months, and their element contents were measured by instrumental neutron activation analysis using the k 0 methodology (k 0-INAA). Using a bicycle commute route of lower traffic intensity and avoiding rush hours or other times with elevated vehicular congestion facilitate a reduction in exposure to pollutants. The implementation of cycle paths in cities is important to stimulate physical activity and active transportation; however, it is essential to consider ambient air and pollutant sources to create safer infrastructures. PMID- 26943337 TI - Genome-Wide Analysis of the AP2/ERF Gene Family in Physic Nut and Overexpression of the JcERF011 Gene in Rice Increased Its Sensitivity to Salinity Stress. AB - The AP2/ERF transcription factors play crucial roles in plant growth, development and responses to biotic and abiotic stresses. A total of 119 AP2/ERF genes (JcAP2/ERFs) have been identified in the physic nut genome; they include 16 AP2, 4 RAV, 1 Soloist, and 98 ERF genes. Phylogenetic analysis indicated that physic nut AP2 genes could be divided into 3 subgroups, while ERF genes could be classed into 11 groups or 43 subgroups. The AP2/ERF genes are non-randomly distributed across the 11 linkage groups of the physic nut genome and retain many duplicates which arose from ancient duplication events. The expression patterns of several JcAP2/ERF duplicates in the physic nut showed differences among four tissues (root, stem, leaf, and seed), and 38 JcAP2/ERF genes responded to at least one abiotic stressor (drought, salinity, phosphate starvation, and nitrogen starvation) in leaves and/or roots according to analysis of digital gene expression tag data. The expression of JcERF011 was downregulated by salinity stress in physic nut roots. Overexpression of the JcERF011 gene in rice plants increased its sensitivity to salinity stress. The increased expression levels of several salt tolerance-related genes were impaired in the JcERF011-overexpressing plants under salinity stress. PMID- 26943341 TI - Autophagy plays a role in skeletal muscle mitochondrial biogenesis in an endurance exercise-trained condition. AB - Mitochondrial homeostasis is tightly regulated by two major processes: mitochondrial biogenesis and mitochondrial degradation by autophagy (mitophagy). Research in mitochondrial biogenesis in skeletal muscle in response to endurance exercise training has been well established, while the mechanisms regulating mitophagy and the interplay between mitochondrial biogenesis and degradation following endurance exercise training are not yet well defined. The purpose of this study was to examine the effects of a short-term inhibition of autophagy in response to acute endurance exercise on skeletal muscle mitochondrial biogenesis and dynamics in an exercise-trained condition. Male wild-type C57BL/6 mice performed five daily bouts of 1-h swimming per week for 8 weeks. In order to measure autophagy flux in mouse skeletal muscle, mice were treated with or without 2 days of 0.4 mg/kg/day intraperitoneal colchicine (blocking the degradation of autophagosomes) following swimming exercise training. The autophagic flux assay demonstrated that swimming training resulted in an increase in the autophagic flux (~100 % increase in LC3-II) in mouse skeletal muscle. Mitochondrial fusion proteins, Opa1 and MFN2, were significantly elevated, and mitochondrial fission protein, Drp1, was also increased in trained mouse skeletal muscle, suggesting that endurance exercise training promotes both mitochondrial fusion and fission processes. A mitochondrial receptor, Bnip3, was further increased in exercised muscle when treated with colchicine while Pink/Parkin protein levels were unchanged. The endurance exercise training induced increases in mitochondrial biogenesis marker proteins, SDH, COX IV, and a mitochondrial biogenesis promoting factor, PGC-1alpha but this effect was abolished in colchicine-treated mouse skeletal muscle. This suggests that autophagy plays an important role in mitochondrial biogenesis and this coordination between these opposing processes is involved in the cellular adaptation to endurance exercise training. PMID- 26943346 TI - Improvement of short-term hypothermic preservation of microencapsulated hepatocytes. AB - OBJECTIVES: To determine the optimal storage solution containing suitable protective agents for the preservation of microencapsulated hepatocytes at 4 degrees C as well as the optimum incubation time after hypothermic preservation. RESULTS: L15 was the optimum solution for both maintaining microcapsule integrity and cell viability. Furthermore, 5 %(v/v) PEG (20 or 35 kDa) added to Leibovitz 15 medium was optimal for microencapsulated C3A cells, enhancing cell viability and liver-specific functions, including albumin and urea synthesis as well as CYP1A2 and CYP3A4 activities. The transcription levels of several CYP450-related genes were also dramatically increased in cells incubated in the optimal solution. Pre-incubation for 2 h was the optimal time for restoring favorable levels of CYP1A2 and CYP3A4 activities in microencapsulated C3A cells for short term, 2 day storage. CONCLUSIONS: Leibovitz-15 medium supplemented with 5 % (v/v) PEG is a promising cold solution for microencapsulated hepatocytes at 4 degrees C, with an incubation of 2 h at 37 degrees C after hypothermic preservation being the best incubation duration for further cell application. PMID- 26943344 TI - Effects of sleep disruption and high fat intake on glucose metabolism in mice. AB - Poor sleep quality or quantity impairs glycemic control and increases risk of disease under chronic conditions. Recovery sleep may offset adverse metabolic outcomes of accumulated sleep debt, but the extent to which this occurs is unclear. We examined whether recovery sleep improves glucose metabolism in mice subjected to prolonged sleep disruption, and whether high fat intake during sleep disruption exacerbates glycemic control. Adult male C57BL/6J mice were subjected to 18-h sleep fragmentation daily for 9 days, followed by 1 day of recovery. During sleep disruption, one group of mice was fed a high-fat diet (HFD) while another group was fed standard laboratory chow. Insulin sensitivity and glucose tolerance were assessed by insulin and glucose tolerance testing at baseline, after 3 and 7 days of sleep disruption, and at the end of the protocol after 24h of undisturbed sleep opportunity (recovery). To characterize changes in sleep architecture that are associated with sleep debt and recovery, we quantified electroencephalogram (EEG) recordings during sleep fragmentation and recovery periods from an additional group of mice. We now report that 9 days of 18-h daily sleep fragmentation significantly reduces rapid eye movement sleep (REMS) and non rapid eye movement sleep (NREMS). Mice respond with increases in REMS, but not NREMS, during the daily 6-h undisturbed sleep opportunity. However, both REMS and NREMS increase significantly during the 24-h recovery period. Although sleep disruption alone has no effect in this protocol, high fat feeding in combination with sleep disruption impairs glucose tolerance, effects that are reversed by recovery sleep. Insulin sensitivity modestly improves after 3 days of sleep fragmentation and after 24h of recovery, with significantly greater improvements in mice exposed to HFD during sleep disruption. Improvements in both glucose tolerance and insulin sensitivity are associated with NREMS rebound, raising the possibility that this sleep phase contributes to restorative effects of recovery sleep on glycemic control. PMID- 26943347 TI - Motion dominance in binocular rivalry depends on extraretinal motions. AB - In binocular rivalry, moving stimulus is dominant over stationary stimulus. This is called motion dominance. The motion here is usually a motion defined on the retina (retinal motion). However, motion can be defined in several different coordinates. It can be defined with respect to objects in the background (object based motion) or to observers' head or body (spatiotopic motion), as well as to the retinal coordinate. In this study, we examined the role of motions defined by these three coordinates. A dichoptic pair of gratings was presented to create a binocular rivalry, one of which was moving and the other stationary. A fixation point and a reference background were either moving with the grating or stationary, depending on the condition. Different combinations of the three types of motions were created by having the observer track the fixation point or the background when they are moving. It was found that the retinal motion does not necessarily yield motion dominance, and that the motion dominance is determined by the combination of motions defined by different coordinate systems. PMID- 26943349 TI - Adapting to time: Duration channels do not mediate human time perception. AB - Accurately encoding the duration and temporal order of events is essential for survival and important to everyday activities, from holding conversations to driving in fast-flowing traffic. Although there is a growing body of evidence that the timing of brief events (< 1 s) is encoded by modality-specific mechanisms, it is not clear how such mechanisms register event duration. One approach gaining traction is a channel-based model; this envisages narrowly tuned, overlapping timing mechanisms that respond preferentially to different durations. The channel-based model predicts that adapting to a given event duration will result in overestimating and underestimating the duration of longer and shorter events, respectively. We tested the model by having observers judge the duration of a brief (600 ms) visual test stimulus following adaptation to longer (860 ms) and shorter (340 ms) stimulus durations. The channel-based model predicts perceived duration compression of the test stimulus in the former condition and perceived duration expansion in the latter condition. Duration compression occurred in both conditions, suggesting that the channel-based model does not adequately account for perceived duration of visual events. PMID- 26943345 TI - Heart rate variability measure in breast cancer patients and survivors: A systematic review. AB - PURPOSE: In the current study, we aimed to review literature findings showing the clinical importance of cardiac autonomic modulation assessed by heart rate variability analysis in breast cancer (BC) patients and survivors. METHODS: We conducted a systematic review according to The PRISMA Statement in Medline, Scopus and Web of Science (_-2015) databases. The search was limited to articles in English language, published in peer-reviewed journals, and with adult age samples only (e.g., women, patients, or survivors, diagnosed with BC in any stage). We included observational studies and randomized trials. Detailed heart rate variability analysis (instruments, data collection protocol, and analysis methods) was required. Search terms included autonomic nervous system, heart rate variability, sympathetic and parasympathetic nervous system, autonomic dysfunction, vagal nervous and breast neoplasms, breast cancer and breast tumor. RESULTS: Twelve studies were included in this review. The clinical importance of cardiac autonomic modulation assessed by heart rate variability analysis in BC patients and survivors is demonstrated by association with effects of BC surgery, and treatments, and the adverse effects of surgery and treatments on survivors (e.g., cardiotoxicity, fatigue, and stress). LIMITATIONS: The strength of evidence of included studies is low: small samples size and heterogeneity, presence of confounders, and observational studies design. CONCLUSIONS: The heart rate variability analysis could be used as a complementary non-invasive tool for the early diagnosis and better prognosis of autonomic dysfunction, and survival in BC patients. There are many potential clinical applications of heart rate variability analysis in BC patients, and the employment of such approaches could lead to lower impairment of autonomic function in this individuals. PMID- 26943343 TI - Sex hormone manipulation slows reaction time and increases labile mood in healthy women. AB - BACKGROUND: Women show increased risk of depressive symptoms in life phases where ovarian steroid hormone levels fluctuate or decline rapidly. The risk mechanisms may include changes in mental state and affective cognition possibly mediated by serotonergic neurotransmission. METHODS: In a randomized controlled double blinded trial, 61 healthy women (mean age 24.3+/-4.9 years) were tested with measures of affective verbal memory, reaction time, mental distress, and serotonin transporter binding at baseline and at follow-up after receiving gonadotropin-releasing hormone agonist (GnRHa) or placebo intervention. Women also reported daily mood profiles during intervention. We tested direct effects of intervention and indirect effects through changes in serotonin transporter binding on verbal affective memory, simple reaction time and self-reported measures of mental distress, and further effects of GnRHa on daily mood. RESULTS: GnRHa induced an increase in simple reaction time (p=0.03) and more pronounced fluctuations in daily self-reported mood in a manner dependent on baseline mood (p=0.003). Verbal affective memory recall, overall self-perceived mental distress, and serotonin transporter binding were not affected. CONCLUSIONS: In healthy women transient sex-steroid hormone fluctuations decrease speed of information processing and further produce more labile mood only in women with elevated levels of mood disturbances at baseline. PMID- 26943353 TI - Correction to Phosphatidylserine-Induced Factor Xa Dimerization and Binding to Factor Va Are Competing Processes in Solution. PMID- 26943342 TI - False positives in breast cancer screening with one-view breast tomosynthesis: An analysis of findings leading to recall, work-up and biopsy rates in the Malmo Breast Tomosynthesis Screening Trial. AB - OBJECTIVES: To analyse false positives (FPs) in breast cancer screening with tomosynthesis (BT) vs. mammography (DM). METHODS: The Malmo Breast Tomosynthesis Screening Trial (MBTST) is a prospective population-based study comparing one view BT to DM in screening. This study is based on the first half of the MBTST population (n = 7,500). Differences in FP recall rate, findings leading to recall, work-up and biopsy rate between cases recalled on BT alone, DM alone and BT+DM were analysed. RESULTS: The FP recall rate was 1.7 % for BT alone (n = 131), 0.9 % for DM alone (n = 69) and 1.1 % for BT + DM (n = 81). The FP recall rate for BT alone was halved after the initial phase of the trial, stabilising at 1.5 %. BT doubled the recall of stellate distortions compared to DM (n = 64 vs. n = 33). There were fewer fibroadenomas and cysts, and the biopsy rate was slightly lower for FP recalled on BT alone compared to DM alone (15.3 % vs. 27.6 %: p = 0.037 and 33.8 % vs. 36.2 %; p = 0.641, respectively). CONCLUSIONS: FPs increased with BT screening mainly due to the recall of stellate distortions. The FP recall rate was still well within the European guidelines and showed evidence of a learning curve. Characterisation of rounded lesions was improved with BT. KEY POINTS: * Tomosynthesis screening gave a higher false-positive recall rate than mammography * There was a decline in the false-positive recall rate for tomosynthesis * The recall due to stellate distortions simulating malignancy was doubled with tomosynthesis * Tomosynthesis found more radial and postoperative scar tissue than mammography * Tomosynthesis is better at characterising rounded lesions. PMID- 26943350 TI - Isolation, characterization and PCR multiplexing of microsatellite loci for two sub-species of terrestrial isopod Porcellio dilatatus (Crustacea, Oniscidea). AB - Several microsatellite markers have already been developed for different terrestrial isopod species such as Armadillidium vulgare, A. nasatum and Porcellionides pruinosus. In all these species, the endosymbiont Wolbachia has a feminizing effect that generates a female bias in sex ratio and reduces the number of reproductive males. Thus this can potentially decrease the genetic diversity of host populations. However, in some other isopod species, Wolbachia induces cytoplasmic incompatibility (CI); the most commonly described effect of Wolbachia in arthropods. The CI by rendering some crossings incompatible can reduce the gene flow and strengthen genetic differentiation between isopod populations. To date, the influence of Wolbachia inducing CI on population structure of terrestrial isopods has never been investigated. In this study, we developed 10 polymorphic microsatellite markers shared by two sub-species of Porcellio dilatatus. Crossings between the two sub-species are partially incompatible due to two CI-inducing Wolbachia strains. These new microsatellite markers will allow us to investigate the effect of CI on host genetic differentiation in this species complex. PMID- 26943348 TI - Saccadic latency in amblyopia. AB - We measured saccadic latencies in a large sample (total n = 459) of individuals with amblyopia or risk factors for amblyopia, e.g., strabismus or anisometropia, and normal control subjects. We presented an easily visible target randomly to the left or right, 3.5 degrees from fixation. The interocular difference in saccadic latency is highly correlated with the interocular difference in LogMAR (Snellen) acuity-as the acuity difference increases, so does the latency difference. Strabismic and strabismic-anisometropic amblyopes have, on average, a larger difference between their eyes in LogMAR acuity than anisometropic amblyopes and thus their interocular latency difference is, on average, significantly larger than anisometropic amblyopes. Despite its relation to LogMAR acuity, the longer latency in strabismic amblyopes cannot be attributed either to poor resolution or to reduced contrast sensitivity, because their interocular differences in grating acuity and in contrast sensitivity are roughly the same as for anisometropic amblyopes. The correlation between LogMAR acuity and saccadic latency arises because of the confluence of two separable effects in the strabismic amblyopic eye-poor letter recognition impairs LogMAR acuity while an intrinsic sluggishness delays reaction time. We speculate that the frequent microsaccades and the accompanying attentional shifts, made while strabismic amblyopes struggle to maintain fixation with their amblyopic eyes, result in all types of reactions being irreducibly delayed. PMID- 26943354 TI - The relationship between financial strain, perceived stress, psychological symptoms, and academic and social integration in undergraduate students. AB - OBJECTIVE: Financial strain may directly or indirectly (i.e., through perceived stress) impact students' psychological symptoms and academic and social integration, yet few studies have tested these relationships. The authors explored the mediating effect of perceived stress on the relationship between financial strain and 2 important outcomes: psychological symptomology and academic and social integration. PARTICIPANTS: Participants were 157 undergraduate students. Data were collected from December 2013 to March 2014. METHODS: Cross-sectional data collection conducted using online survey software. RESULTS: It was found that perceived stress mediated the relationship between financial strain and (a) psychological symptomology and (b) academic and social integration. Both models included first-generation status as a covariate. CONCLUSIONS: Results suggest that perceived stress is an important intervention target for reducing psychological symptoms and improving academic and social integration for undergraduate students. Implications for university health centers and mental health professionals include incorporating a public health model to minimize stress risk. PMID- 26943352 TI - DNA methylation in normal and malignant hematopoiesis. AB - The study of DNA methylation has been a rapidly expanding field since its dawn in the 1960s. DNA methylation is an epigenetic modification that plays a crucial role in guiding the differentiation of stem cells to their destined lineage, and in maintaining tissue homeostasis. Moreover, aberrant DNA methylation has been well characterized as a significant contributing factor in the pathogenesis of a variety of cancers. Hematopoiesis is a process that is uniquely susceptible to epigenetic changes due to the small pool of actively cycling stem cells that give rise to the entire mature immune-hematopoietic system. Mutations in DNA methyltransferase enzymes have been shown to be initiating events in the development of hematological malignancies such as acute myeloid leukemia and, therefore, have become targets for improved diagnostics and therapy. The spatial and temporal regulation of DNA methylation in the hematopoietic developmental hierarchy is critical to hematopoietic homeostasis. An improved understanding of the roles that DNA methylation plays in normal and malignant hematopoiesis will have a significant impact on the future of regenerative stem cell therapy and clinical treatment of hematopoietic malignancies. This review aims to highlight current developments in the field and prioritize future research directions. PMID- 26943351 TI - Cellular Therapies in Systemic Sclerosis: Recent Progress. AB - Systemic sclerosis (SSc) is a rare autoimmune connective tissue disease with a high mortality and morbidity. While progress has been made in terms of identifying high-risk patients and implementing new treatment strategies, therapeutic options remain limited. In the past few decades, various cellular therapies have emerged, which have been studied in SSc and other conditions. Here, we provide a comprehensive review of currently available cellular therapies and critically assess their merit as disease-modifying treatment for SSc. Currently, hematopoietic stem cell transplantation is the only cellular therapy that has demonstrated clinical effects on the immune system, neoangiogenesis, and fibrosis. Robust mechanistic studies as well as clinical trials are essential to move the field forward. PMID- 26943357 TI - Stress distribution in the transitional peri-implant bone in a single implant supported prosthesis with platform-switching under different angulated loads. AB - A 3D finite element analysis was conducted to evaluate and compare the stress distribution in the peri-implant bone (transitional cortical and trabecular bone) of one single implant-supported crown with platform switching and another without platform switching, under a vertical and an oblique load. Two models were created, simulating an osseointegrated implant (4 * 13 mm, platform 4.1 mm) embedded in the jaw bone. One model simulated a 4.1-mm diameter abutment connection (conventional model) and the other a 3.8-mm diameter abutment connection (platform-switching model). A crown with a Co-Cr alloy framework and feldspathic porcelain veneering was applied over the titanium abutment. Static, vertical and oblique loads (0 degrees , 15 degrees , 30 degrees , 45 degrees ) with a maximum value of 150 N were applied to the crown. For any inclination of the applied load, the stress values in the transitional cortical bone were lower in the platform-switching model than in the conventional model. However, the stress in the transitional trabecular bone was higher in the platform-switching model than in the conventional model. Stress values increased when the load was more oblique at the transitional cortical bone in both models and was slightly reduced at the transitional trabecular bone of the conventional model. The platform-switching technique reduces the stress at the transitional cortical bone. In both models, this stress gradually increases as the load becomes more inclined. The transitional trabecular bone shows lower stress values than the transitional cortical bone. The location of stress is similar in both models. PMID- 26943356 TI - Differences in Gene-Gene Interactions in Graves' Disease Patients Stratified by Age of Onset. AB - BACKGROUND: Graves' disease (GD) is a complex disease in which genetic predisposition is modified by environmental factors. Each gene exerts limited effects on the development of autoimmune disease (OR = 1.2-1.5). An epidemiological study revealed that nearly 70% of the risk of developing inherited autoimmunological thyroid diseases (AITD) is the result of gene interactions. In the present study, we analyzed the effects of the interactions of multiple loci on the genetic predisposition to GD. The aim of our analyses was to identify pairs of genes that exhibit a multiplicative interaction effect. MATERIAL AND METHODS: A total of 709 patients with GD were included in the study. The patients were stratified into more homogeneous groups depending on the age at time of GD onset: younger patients less than 30 years of age and older patients greater than 30 years of age. Association analyses were performed for genes that influence the development of GD: HLADRB1, PTPN22, CTLA4 and TSHR. The interactions among polymorphisms were analyzed using the multiple logistic regression and multifactor dimensionality reduction (MDR) methods. RESULTS: GD patients stratified by the age of onset differed in the allele frequencies of the HLADRB1*03 and 1858T polymorphisms of the PTPN22 gene (OR = 1.7, p = 0.003; OR = 1.49, p = 0.01, respectively). We evaluated the genetic interactions of four SNPs in a pairwise fashion with regard to disease risk. The coexistence of HLADRB1 with CTLA4 or HLADRB1 with PTPN22 exhibited interactions on more than additive levels (OR = 3.64, p = 0.002; OR = 4.20, p < 0.001, respectively). These results suggest that interactions between these pairs of genes contribute to the development of GD. MDR analysis confirmed these interactions. CONCLUSION: In contrast to a single gene effect, we observed that interactions between the HLADRB1/PTPN22 and HLADRB1/CTLA4 genes more closely predicted the risk of GD onset in young patients. PMID- 26943358 TI - [Hypersensitivity reactions to implantable cardiac pacemakers and defibrillators]. AB - Nowadays, for modern electrotherapy of cardiac arrhythmias different pacemaker systems are used. Antibradycardia pacing systems (e. g. single-chamber, two chamber, three-chamber systems, frequency-adapted pacemaker) can be distinguished from antitachycardia pacing systems like implantable or portable cardioverter defibrillators and combined antibradycardia/antitachycardia systems. Cutaneous reactions overlying a pacemaker or defibrillator are often termed "pacemaker dermatitis". In terms of the differential diagnostic workup, these cutaneous reactions can have various causes. After exclusion of infection by analyzing clinical and laboratory-chemical results, "pressure dermatitis" or the often clinically asymptomatic "reticular telangiectatic erythema" (synonym "postimplantation erythema") must be considered. Histological examination of the affected skin can contribute to the diagnosis. In case of suspected contact hypersensitivity to implant material, allergological exploration should be realized. In addition to patch testing with commercially available contact allergens, product-related material metal alloy discs are often available from the pacemaker manufacturer for epicutaneous testing. Due to the lack of additional benefit compared to standardized patch testing, a clear recommendation for such metal alloy discs cannot be given. In selected cases of suspected hypersensitivity reaction, sensitization can eventually be analyzed by the lymphocyte transformation test. Positive reactions must always be critically interpreted taking into consideration the corresponding clinical signs. Depending on the cause, cutaneous reactions are occasionally self-limiting. In many cases, however, removal of the pacemaker is inevitable. PMID- 26943355 TI - The Value of Molecular vs. Morphometric and Acoustic Information for Species Identification Using Sympatric Molossid Bats. AB - A fundamental condition for any work with free-ranging animals is correct species identification. However, in case of bats, information on local species assemblies is frequently limited especially in regions with high biodiversity such as the Neotropics. The bat genus Molossus is a typical example of this, with morphologically similar species often occurring in sympatry. We used a multi method approach based on molecular, morphometric and acoustic information collected from 962 individuals of Molossus bondae, M. coibensis, and M. molossus captured in Panama. We distinguished M. bondae based on size and pelage coloration. We identified two robust species clusters composed of M. molossus and M. coibensis based on 18 microsatellite markers but also on a more stringently determined set of four markers. Phylogenetic reconstructions using the mitochondrial gene co1 (DNA barcode) were used to diagnose these microsatellite clusters as M. molossus and M. coibensis. To differentiate species, morphological information was only reliable when forearm length and body mass were combined in a linear discriminant function (95.9% correctly identified individuals). When looking in more detail at M. molossus and M. coibensis, only four out of 13 wing parameters were informative for species differentiation, with M. coibensis showing lower values for hand wing area and hand wing length and higher values for wing loading. Acoustic recordings after release required categorization of calls into types, yielding only two informative subsets: approach calls and two toned search calls. Our data emphasizes the importance of combining morphological traits and independent genetic data to inform the best choice and combination of discriminatory information used in the field. Because parameters can vary geographically, the multi-method approach may need to be adjusted to local species assemblies and populations to be entirely informative. PMID- 26943360 TI - [Hereditary epidermolysis bullosa in school children and adolescents. Clinical picture and interdisciplinary management]. AB - Hereditary epidermolysis bullosa (EB) represents a clinically heterogeneous group of congenital blistering disorders requiring multiprofessional care. EB is associated with a broad spectrum of potentially severe complications often reaching their full extent during school age and adolescence. This review aims at summarizing cutaneous manifestations of EB as well as extracutaneous complications of this complex disease and their interdisciplinary management. PMID- 26943359 TI - [A brown spot on the sole of the foot]. PMID- 26943361 TI - Grape skin phenolics as inhibitors of mammalian alpha-glucosidase and alpha amylase--effect of food matrix and processing on efficacy. AB - Type-2 diabetes is continuously increasing worldwide. Hence, there is a need to develop functional foods that efficiently alleviate damage due to hyperglycaemia complications while meeting the criteria for a sustainable food processing technology. Inhibition of mammalian alpha-amylase and alpha-glucosidase was studied for white grape skin samples recovered from wineries and found to be higher than that of the drug acarbose. In white grape skins, quercetin and kaempferol derivatives, analysed by UPLC-DAD-MS, and the oligomeric series of catechin/epicatechin units and their gallic acid ester derivatives up to nonamers, analysed by MALDI-TOF-MS were identified. White grape skin was then used for enrichment of a tomato puree (3%) and a flat bread (10%). White grape skin phenolics were found in the extract obtained from the enriched foods, except for the higher mass proanthocyanidin oligomers, mainly due to their binding to the matrix and to a lesser extent to heat degradation. Proanthocyanidin solubility was lower in bread, most probably due to formation of binary proanthocyanin/protein complexes, than in tomato puree where possible formation of ternary proanthocyanidin/protein/pectin complexes can enhance solubility. Enzyme inhibition by the enriched foods was significantly higher than for unfortified foods. Hence, this in vitro approach provided a platform to study potential dietary agents to alleviate hyperglycaemia damage and suggested that grape skin phenolics could be effective even if the higher mass proanthocyanidins are bound to the food matrix. PMID- 26943363 TI - A Low-Cost Simulation Model for R-Wave Synchronized Atrial Pacing in Pediatric Patients with Postoperative Junctional Ectopic Tachycardia. AB - BACKGROUND: Postoperative junctional ectopic tachycardia (JET) occurs frequently after pediatric cardiac surgery. R-wave synchronized atrial (AVT) pacing is used to re-establish atrioventricular synchrony. AVT pacing is complex, with technical pitfalls. We sought to establish and to test a low-cost simulation model suitable for training and analysis in AVT pacing. METHODS: A simulation model was developed based on a JET simulator, a simulation doll, a cardiac monitor, and a pacemaker. A computer program simulated electrocardiograms. Ten experienced pediatric cardiologists tested the model. Their performance was analyzed using a testing protocol with 10 working steps. RESULTS: Four testers found the simulation model realistic; 6 found it very realistic. Nine claimed that the trial had improved their skills. All testers considered the model useful in teaching AVT pacing. The simulation test identified 5 working steps in which major mistakes in performance test may impede safe and effective AVT pacing and thus permitted specific training. The components of the model (exclusive monitor and pacemaker) cost less than $50. Assembly and training-session expenses were trivial. CONCLUSIONS: A realistic, low-cost simulation model of AVT pacing is described. The model is suitable for teaching and analyzing AVT pacing technique. PMID- 26943362 TI - The Tomato Hoffman's Anthocyaninless Gene Encodes a bHLH Transcription Factor Involved in Anthocyanin Biosynthesis That Is Developmentally Regulated and Induced by Low Temperatures. AB - Anthocyanin pigments play many roles in plants, including providing protection against biotic and abiotic stresses. Many of the genes that mediate anthocyanin accumulation have been identified through studies of flowers and fruits; however, the mechanisms of genes involved in anthocyanin regulation in seedlings under low temperature stimulus are less well understood. Genetic characterization of a tomato inbred line, FMTT271, which showed no anthocyanin pigmentation, revealed a mutation in a bHLH transcription factor (TF) gene, which corresponds to the ah (Hoffman's anthocyaninless) locus, and so the gene in FMTT271 at that locus was named ah. Overexpression of the wild type allele of AH in FMTT271 resulted in greater anthocyanin accumulation and increased expression of several genes in the anthocyanin biosynthetic pathway. The expression of AH and anthocyanin accumulation in seedlings was shown to be developmentally regulated and induced by low-temperature stress. Additionally, transcriptome analyses of hypocotyls and leaves from the near-isogenic lines seedlings revealed that AH not only influences the expression of anthocyanin biosynthetic genes, but also genes associated with responses to abiotic stress. Furthermore, the ah mutation was shown to cause accumulation of reactive oxidative species and the constitutive activation of defense responses under cold conditions. These results suggest that AH regulates anthocyanin biosynthesis, thereby playing a protective role, and that this function is particularly important in young seedlings that are particularly vulnerable to abiotic stresses. PMID- 26943364 TI - Blockade of Sphingosine 1-Phosphate Receptor 2 Signaling Attenuates High-Fat Diet Induced Adipocyte Hypertrophy and Systemic Glucose Intolerance in Mice. AB - Sphingosine 1-phosphate (S1P) is known to regulate insulin resistance in hepatocytes, skeletal muscle cells, and pancreatic beta-cells. Among its 5 cognate receptors (S1pr1-S1pr5), S1P seems to counteract insulin signaling and confer insulin resistance via S1pr2 in these cells. S1P may also regulate insulin resistance in adipocytes, but the S1pr subtype(s) involved remains unknown. Here, we investigated systemic glucose/insulin tolerance and phenotypes of epididymal adipocytes in high-fat diet (HFD)-fed wild-type and S1pr2-deficient (S1pr2(-/-)) mice. Adult S1pr2(-/-) mice displayed smaller body/epididymal fat tissue weights, but the differences became negligible after 4 weeks with HFD. However, HFD-fed S1pr2(-/-) mice displayed better scores in glucose/insulin tolerance tests and had smaller epididymal adipocytes that expressed higher levels of proliferating cell nuclear antigen than wild-type mice. Next, proliferation/differentiation of 3T3-L1 and 3T3-F442A preadipocytes were examined in the presence of various S1pr antagonists: JTE-013 (S1pr2 antagonist), VPC-23019 (S1pr1/S1pr3 antagonist), and CYM-50358 (S1pr4 antagonist). S1P or JTE-013 treatment of 3T3-L1 preadipocytes potently activated their proliferation and Erk phosphorylation, whereas VPC-23019 inhibited both of these processes, and CYM-50358 had no effects. In contrast, S1P or JTE-013 treatment inhibited adipogenic differentiation of 3T3-F442A preadipocytes, whereas VPC-23019 activated it. The small interfering RNA knockdown of S1pr2 promoted proliferation and inhibited differentiation of 3T3 F442A preadipocytes, whereas that of S1pr1 acted oppositely. Moreover, oral JTE 013 administration improved glucose tolerance/insulin sensitivity in ob/ob mice. Taken together, S1pr2 blockade induced proliferation but suppressed differentiation of (pre)adipocytes both in vivo and in vitro, highlighting a novel therapeutic approach for obesity/type 2 diabetes. PMID- 26943365 TI - Peripubertal Stress With Social Support Promotes Resilience in the Face of Aging. AB - The peripubertal period of development is a sensitive window, during which adverse experiences can increase the risk for presentation of cognitive and affective dysfunction throughout the lifespan, especially in women. However, such experiences in the context of a supportive social environment can actually ameliorate this risk, suggesting that resilience can be programmed in early life. Affective disorders and cognitive deficits commonly emerge during aging, with many women reporting increased difficulty with prefrontal cortex (PFC)-dependent executive functions. We have developed a mouse model to examine the interaction between peripubertal experience and age-related changes in cognition and stress regulation. Female mice were exposed to peripubertal chronic stress, during which they were either individually housed or housed with social interaction. One year after this stress experience, mice were examined in tasks to access their cognitive ability and flexibility in stress reactive measures. In a test of spatial memory acquisition and reversal learning where aged females normally display a decreased performance, the females that had experienced stress with social interaction a year earlier showed improved performance in reversal learning, a measure of cognitive flexibility. Because peripuberty is a time of major PFC maturation, we performed transcriptomic and biochemical analysis of the aged PFC, in which long-term changes in microRNA expression and in myelin proteins were found. These data suggest that stress in the context of social support experienced over the pubertal window can promote epigenetic reprogramming in the brain to increase the resilience to age-related cognitive decline in females. PMID- 26943367 TI - Accounting for Population Structure in Gene-by-Environment Interactions in Genome Wide Association Studies Using Mixed Models. AB - Although genome-wide association studies (GWASs) have discovered numerous novel genetic variants associated with many complex traits and diseases, those genetic variants typically explain only a small fraction of phenotypic variance. Factors that account for phenotypic variance include environmental factors and gene-by environment interactions (GEIs). Recently, several studies have conducted genome wide gene-by-environment association analyses and demonstrated important roles of GEIs in complex traits. One of the main challenges in these association studies is to control effects of population structure that may cause spurious associations. Many studies have analyzed how population structure influences statistics of genetic variants and developed several statistical approaches to correct for population structure. However, the impact of population structure on GEI statistics in GWASs has not been extensively studied and nor have there been methods designed to correct for population structure on GEI statistics. In this paper, we show both analytically and empirically that population structure may cause spurious GEIs and use both simulation and two GWAS datasets to support our finding. We propose a statistical approach based on mixed models to account for population structure on GEI statistics. We find that our approach effectively controls population structure on statistics for GEIs as well as for genetic variants. PMID- 26943366 TI - Islet Hypersensitivity to Glucose Is Associated With Disrupted Oscillations and Increased Impact of Proinflammatory Cytokines in Islets From Diabetes-Prone Male Mice. AB - Pulsatile insulin release is the primary means of blood glucose regulation. The loss of pulsatility is thought to be an early marker and possible factor in developing type 2 diabetes. Another early adaptation in islet function to compensate for obesity is increased glucose sensitivity (left shift) associated with increased basal insulin release. We provide evidence that oscillatory disruptions may be linked with overcompensation (glucose hypersensitivity) in islets from diabetes-prone mice. We isolated islets from male 4- to 5-week-old (prediabetic) and 10- to 12-week-old (diabetic) leptin-receptor-deficient (db/db) mice and age-matched heterozygous controls. After an overnight incubation in media with 11 mM glucose, we measured islet intracellular calcium in 5, 8, 11, or 15 mM glucose. Islets from heterozygous 10- to 12-week-old mice were quiescent in 5 mM glucose and displayed oscillations with increasing amplitude and/or duration in 8, 11, and 15 mM glucose, respectively. Islets from diabetic 10- to 12-week old mice, in contrast, showed robust oscillations in 5 mM glucose that declined with increasing glucose. Similar trends were observed at 4-5-weeks of age. A progressive left shift in maximal insulin release was also observed in islets as db/db mice aged. Reducing glucokinase activity with 1 mM D-mannoheptulose restored oscillations in 11 mM glucose. Finally, overnight low-dose cytokine exposure negatively impacted oscillations preferentially in high glucose in diabetic islets compared with heterozygous controls. Our findings suggest the following: 1) islets from frankly diabetic mice can produce oscillations, 2) elevated sensitivity to glucose prevents diabetic mouse islets from producing oscillations in normal postprandial (11-15 mM glucose) conditions, and 3) hypersensitivity to glucose may magnify stress effects from inflammation or other sources. PMID- 26943368 TI - Surface and Epitaxial Stresses on Supported Metal Clusters. AB - Surface stress and energy are basic quantities in the Gibbsian formulation of the thermodynamic description of surfaces which is central in the formation and long term behavior of materials at the nanoscale. However, their size dependence is a puzzling issue. It is even unclear whether they decrease or increase with decreasing particle size. In addition, for a given metal, estimates often span over an order of magnitude, far apart from bulk data, which, in the absence of any explicit size-dependence rule, escapes understanding. Here, we combine X-ray absorption and nanoplasmonics data with atomistic simulation to describe alpha Al2O3(0001)-supported silver particles. By comparison to MgO(001)-supported and embedded silver, we distinguish epitaxial and surface stress. The latter is shown to dominate above 3 nm in size. Since the observation mostly relies on surface/bulk ratio, a metal-independent picture emerges that is expected to have far-reaching consequences for the understanding of the energetics of nanoparticles. PMID- 26943370 TI - Introduction of Surgical Case Reports: the second official journal of the Japanese Surgical Society. PMID- 26943372 TI - A case of mesh plug migration into the bladder 5 years after hernia repair. AB - The mesh plug technique is one of the most popular procedures for inguinal hernia repair in Japan. This procedure is quick, easy, and low cost with a low recurrence rate. However, some complications associated with the mesh plug have been reported recently. We hereby present a case of an 80-year-old female admitted to our hospital with swelling and pain in the right lower abdomen 5 years after hernia repair with the PerFix plug. Discharge of urine through the route of exploratory needle puncture demonstrated the fistula of skin and the bladder. Computed tomography (CT), magnetic resonance imaging (MRI), abdominal US, and cystoscope examination revealed that the mesh plug had penetrated into the bladder. As far as we know, this is the first report that a mesh plug has migrated into the bladder. PMID- 26943371 TI - Laparoscopic splenectomy for a wandering spleen complicating gastric varices: report of a case. AB - Wandering spleen is a rare clinical entity, and its chronic torsion of the vascular pedicle result in splenic vein occlusion leading to gastric varices. Here, we present a case of wandering spleen complicating gastric varices in a 40 year-old female. Three-dimensional CT (3D-CT) clearly showed the disruption of the splenic vein at the origin of the vascular pedicle and collateral development of the gastric varices. The patient was electively treated with laparoscopic splenectomy. Difficulty of prediction of the splenic vein recanalization to improve the varices was the reason for the use of splenectomy versus splenopexy. The varices were successfully diminished 3 months after the surgery. After review of cases of complicating gastric varices in the literatures, splenectomy is still a secure way to treat an adult patient with wandering spleen with complicating gastric varices. PMID- 26943369 TI - Acetylation of Lysine 201 Inhibits the DNA-Binding Ability of PhoP to Regulate Salmonella Virulence. AB - The two-component system PhoP-PhoQ is highly conserved in bacteria and regulates virulence in response to various signals for bacteria within the mammalian host. Here, we demonstrate that PhoP could be acetylated by Pat and deacetylated by deacetylase CobB enzymatically in vitro and in vivo in Salmonella Typhimurium. Specifically, the conserved lysine residue 201(K201) in winged helix-turn-helix motif at C-terminal DNA-binding domain of PhoP could be acetylated, and its acetylation level decreases dramatically when bacteria encounter low magnesium, acid stress or phagocytosis of macrophages. PhoP has a decreased acetylation and increased DNA-binding ability in the deletion mutant of pat. However, acetylation of K201 does not counteract PhoP phosphorylation, which is essential for PhoP activity. In addition, acetylation of K201 (mimicked by glutamine substitute) in S. Typhimurium causes significantly attenuated intestinal inflammation as well as systemic infection in mouse model, suggesting that deacetylation of PhoP K201 is essential for Salmonella pathogenesis. Therefore, we propose that the reversible acetylation of PhoP K201 may ensure Salmonella promptly respond to different stresses in host cells. These findings suggest that reversible lysine acetylation in the DNA-binding domain, as a novel regulatory mechanism of gene expression, is involved in bacterial virulence across microorganisms. PMID- 26943373 TI - Acute gastric volvulus in a patient with trisomy 21. AB - Acute gastric volvulus is a torsion of the stomach by more than 180 degrees and a life-threatening condition. We present a 50-year-old male patient with acute abdominal pain who has Down syndrome/trisomy 21. Computed tomography showed a significant distended stomach with features of a severe gastric volvulus. Emergency operation in form of reduction and gastropexy was performed. We are not aware of any similar cases published in the English literature, where as gastric volvulus occurred in a patient with Down syndrome. PMID- 26943375 TI - Staple-line recurrence arising 10 years after functional end-to-end anastomosis for colon cancer: a case report. AB - We report a rare case of late staple-line recurrence arising 10 years after functional end-to-end anastomosis for splenic flexure colon cancer. An 80-year old man, who underwent partial colectomy with functional end-to-end anastomosis for splenic flexure colon cancer 10 years earlier, presented with a chief complaint of anorexia. Complete blood count showed anemia, and the fecal occult blood test was positive. Lower gastrointestinal series showed an irregular defect of the splenic flexure, and colonoscopy showed an ulcerated tumor on the staple line of the primary surgery. Partial colectomy was performed, and the tumor was pathologically diagnosed as moderately differentiated tubular adenocarcinoma, resembling the pathology of primary colon cancer. This case suggests the importance of considering staple-line recurrence after functional end-to-end anastomosis for colon cancer even more than 5 years after primary surgery. PMID- 26943374 TI - Primary intrathoracic malignant neurogenic tumor: report of three cases and comparison with benign neurogenic tumors resected at our institution. AB - We present three patients with intrathoracic malignant neurogenic tumor. Two lesions showed no sign of invasion into adjacent structures, while the third lesion extended to the intraspinal canal with vertebral involvement. Although all three lesions were completely excised, each patient relapsed within 1 year of the initial treatment. One patient with local recurrence underwent radiation therapy, but the recurrent tumor continued to progress. Chemotherapy was subsequently performed. Two patients with distant metastases also received chemotherapy. Because there is no effective chemotherapeutic regimen for intrathoracic malignant neurogenic tumor, all three patients received high-dose chemotherapy followed by hematopoietic stem cell transplantation. Although the relapsed lesions temporarily regressed after treatment, all three patients showed disease recrudescence and ultimately died of their disease. A comparison of the intrathoracic malignant neurogenic tumors and the benign neurogenic tumors resected at our institution revealed no meaningful differences distinguishing malignant from benign neurogenic tumors prior to surgery. PMID- 26943376 TI - Long great saphenous vein grafting as temporary coronary bypass for extended left hepatectomy: report of a case. AB - The right gastroepiploic artery (RGEA) has been used in coronary artery bypass grafting (CABG) as an alternative graft. In particular abdominal surgeries, surgery is required to rescue the graft flow into the coronary artery. A 77-year old male with a history of CABG using RGEA was admitted with a diagnosis of a large hepatocellular carcinoma (HCC) occupying the whole caudate lobe. Preoperative coronary angiography indicated that the graft from the right internal mammary artery to the proximal left circumflex artery was obliterated among three branch bypasses. Following laparotomy, a great saphenous vein was harvested and delivered from the right axial artery to the RGEA graft over the thoracic wall, and the RGEA graft was ligated and divided. Subsequently, extended left hepatectomy was safely performed. Following hepatectomy, the RGEA graft was restored to the former condition, and the temporary graft was removed. After overcoming hyperbilirubinemia, the patient was discharged on postoperative day 28. This experience indicates that temporary bypass using the long great saphenous vein is effective and safe during long and invasive surgeries. PMID- 26943377 TI - A case of mucinous cystic neoplasm of the liver: a case report. AB - A 71-year-old woman was referred to our institution for further investigation of epigastric pain. The patient had been detected to have a multilocular cyst in the medial segment of the liver measuring 69 mm in diameter at another hospital 2 years ago, and the diameter of the cyst had increased to 90 mm. Although the cyst had gradually increased in size, there was no evidence of mural nodules. As we were concerned about the malignant potential of the lesion, a left hepatic segmentectomy was performed. Pathologically, the cyst was lined by columnar and cuboidal epithelium with low-grade atypia. The epithelium covered an ovarian-like stroma, and the diagnosis was mucinous cystic neoplasm of the liver (MCN-L) with low-grade intraepithelial neoplasia. MCN-L is a rare disease and its characteristics are still poorly understood. MCN-L occurs at a lower frequency as compared to the counterpart of MCN of the pancreas, further investigations are necessary to clarify the biological malignancy of MCN-L. PMID- 26943378 TI - A case of giant ileal duplication in an adult, successfully treated with laparoscope-assisted surgery. AB - Alimentary tract duplication is a rare congenital malformation but can occur anywhere along the digestive tract. Most patients become symptomatic in early childhood, and only a few cases of adult patients have been reported in the literature. We herein report a unique case of a giant ileal duplication in an adult, which was successfully treated with laparoscope-assisted surgery. A 60 year-old male was admitted because of abdominal pain. Imaging studies revealed a well-defined cystic mass, measuring 15 cm, in the ileocecal region. We diagnosed it as a duplicated ileum and performed laparoscope-assisted surgery. The duplication was successfully resected with attached normal ileum, and there were no major complications in the postoperative course. PMID- 26943379 TI - Hepatic angiomyolipoma: differential diagnosis from other liver tumors in a special reference to vascular imaging - importance of early drainage vein. AB - A 51-year-old female had been diagnosed with a hemangioma in the hepatic segment 6 (S6). After a 6-year follow-up, enlargement of the tumor was detected. The tumor was clearly enhanced in the arterial phase, and the enhancement remained in the portal phase on computed tomography (CT). Although the primary differential diagnosis on CT was hepatocellular carcinoma (HCC), we worried about the possibility of other vessel system tumors because the tumor remained to be enhanced at the portal phase for HCC and all tumor markers of HCC were negative. We performed angiography to determine the tumor nature and to seek other tumors. Angiography showed tumor stain at the hepatic S6 with an early obvious drainage vein from the tumor flowing through the right hepatic vein into the inferior vena cava. In addition to tumor stain and the drainage vein, there were many small poolings of contrast medium in the whole liver, which were suspected as dilatation of the hepatic peripheral artery. We suspected the tumor as a benign tumor such as hepatocellular adenoma or focal nodular hyperplasia, but the possibility of HCC could not be ruled out. Hepatic posterior sectionectomy was done to completely remove the drainage vein with the tumor. Intraoperative histological examination revealed the tumor as not malignant and not HCC. Later, immunohistochemical analysis uncovered that the tumor had high expression of HMB 45 and, therefore, the final diagnosis was angiomyolipoma. We think that detecting an early drainage vein from the tumor would be a key point for diagnosing hepatic angiomyolipoma. PMID- 26943380 TI - Minimally invasive resection of synchronous thoracic esophageal and gastric carcinomas followed by reconstruction: a case report. AB - We report on a case of synchronous carcinomas of the esophagus and stomach. A 68 year-old man was referred to our hospital for an abnormality found during his medical examination. Further evaluation revealed squamous cell carcinoma in the thoracic lower esophagus and gastric adenocarcinoma located in the middle third of the stomach. Thoracoscopic esophagectomy in the prone position (TSEP), laparoscopic total gastrectomy (LTG) with three-field lymph node dissection, and laparoscopically assisted colon reconstruction (LACR) were performed. The patient did not have any major postoperative complications. His pathological examination revealed no metastases in 56 harvested lymph nodes and no residual tumor. He was followed up for 30 months without recurrence. To our knowledge, this is the first report of esophageal and gastric synchronous carcinomas that were successfully treated with a combination of TSEP, LTG, and LACR. These operations may be a feasible and appropriate treatment for this disease. PMID- 26943381 TI - Mucinous cystic neoplasm of the pancreas activated during pregnancy. AB - The characteristic histological feature of pancreatic mucinous cystic neoplasm (MCN) is ovarian-like stroma (OS) underlying the epithelium and existence of estrogen receptors and progesterone receptors in the nucleus of OS. We experienced a case of pancreatic MCN which was activated during pregnancy and confirmed the existence of estrogen receptors and progesterone receptors. In cases with potential factors for malignancy, surgical resection of MCN may be needed during pregnancy. On the other hand, in cases without these, as female sex hormones may have an influence on the behavior of pancreatic MCN during pregnancy, the timing of surgery should be decided on a case-by-case basis, taking into consideration the status of the malignancy, the stage of the pregnancy, and the condition of the mother and fetus. PMID- 26943382 TI - Chemoradiation therapy with S-1 for primary squamous cell carcinoma of the rectum: report of three cases. AB - PURPOSE: Although successful treatment of squamous cell carcinoma (SCC) of the rectum using chemoradiation therapy (CRT) has been reported, a standard protocol has yet to be established. The aim is to ascertain the effectiveness of CRT with S-1 for three patients with SCC of the rectum. CASE PRESENTATION: We treated three female patients complaining of rectal bleeding. The patients were diagnosed as having primary SCC of the rectum by means of routine examinations; one of them was a very rare case because of the presence of two lesions in the lower rectum. We treated the patients using CRT with S1 at a radiation dose of 1.8 Gy/fraction given five times weekly (Monday to Friday) to a median dose of 59.4 (45 to 59.4) Gy; S-1 (80 mg/m(2)/day) was administered orally during radiation therapy. One of three patients had an adverse event involving massive hemorrhage from the tumor. All patients exhibited an excellent response to CRT with S-1; two patients had a complete response, and one patient had a partial response and underwent a posterior pelvic exenteration with advancement flap reconstruction as a salvage treatment. Pathological examination of the resected specimen and lymph nodes revealed no tumor cells indicating a pathological complete response. In this series, the response rate was 100%. CONCLUSIONS: We suggest that CRT with S-1 be chosen as the first-line therapy for SCC of the rectum. However, a large study will be required to establish a safe and effective regimen. PMID- 26943383 TI - A case of traumatic abdominal wall hernia with delayed bowel obstruction. AB - BACKGROUND: Traumatic abdominal hernia is rare and difficult to diagnose from physical symptoms. PATIENT: A 60-year-old woman was admitted to the emergency department with complaints of vomiting after falling off a bicycle and hitting her abdomen against one of the handlebars 2 days earlier. Computed tomography (CT) demonstrated abdominal wall hernia from blunt trauma to the left upper abdomen. The patient underwent exploratory laparotomy, and the herniated bowel loop was not found to be perforated or gangrenous. Primary hernia repair without resection of the bowel loop was performed. RESULTS: Postoperative course was uneventful. CONCLUSION: Surgical exploration with primary repair of the defect is the definitive treatment in the present case, as the hernia contained an incarcerated loop of small bowel. The use of abdominal CT to confirm the diagnosis before operative repair of the hernia appears to be a safe and efficacious adjunct to physical examination. PMID- 26943384 TI - Segmental ileal dilatation with supernumerary intestinal muscle coat in a neonate. AB - Segmental intestinal dilatation (SID) is a rare developmental anomaly of the midgut, characterized by sharply demarcated dilatation of a gastrointestinal segment with clinical findings of intestinal obstruction. Although morphologic criteria for SID are clearly delineated, etiological origin of dilated intestine is unknown. Histology of the resected segment is usually reported to have normal presence of ganglion cells in the myenteric and submucosal plexuses. Intestinal muscle is hypertrophied, and heterotopic gastric mucosa may also be encountered. A 3-day-old male infant presenting with clinical findings of intestinal obstruction was diagnosed to have SID and had supernumerary intestinal muscle coat (SIMC) in the dilated segment, without any evidence of neurological abnormality. Histopathological findings of the resected ileal segment are reported to discuss the role of architectural malformation of muscularis propria as a cause of SID. PMID- 26943385 TI - Birt-Hogg-Dube syndrome detected incidentally by asymptomatic bilateral pneumothorax in health screening: a case of a young Japanese woman. AB - Birt-Hogg-Dube syndrome (BHD) is an autosomal dominant disease caused by mutations of germline folliculin (FCLN) mapped in the chromosome 17p11.2 region. BHD commonly accompanies renal tumors, fibrofolliculomas, multiple pulmonary cysts, and spontaneous pneumothorax. We report a case of a young Japanese woman in whom asymptomatic bilateral pneumothorax was found incidentally in a health screening, which led to the diagnosis of BHD. She had developed neither renal tumors nor fibrofolliculomas. However, her father, uncle, and aunt also experienced pneumothorax. In Japan, BHD is not yet well known because skin related symptoms of fibrofolliculomas are sometimes absent unlike in most cases in Europe and the United States. On the basis of this case, we propose that BHD should be considered at the time of pneumothorax examination. PMID- 26943386 TI - Laparoscopic resection of a retroperitoneal schwannoma located in the hepatic hilus. AB - Schwannomas are tumors and commonly occur in the head and neck region; however, they rarely present in the retroperitoneum. A 79-year-old man was admitted to our hospital for a follow-up of a tumor in the hepatic hilus. A 2.8 * 2.5 cm solid tumor located between the hepatic hilus and common hepatic artery was originally identified, and the size of the tumor had increased from 2.0 * 2.0 cm to 2.8 * 2.5 cm over the course of 3 years. The patient underwent percutaneous sonopsy, and the tumor was subsequently diagnosed as a benign schwannoma. Since the patient wished to undergo an operation, we performed laparoscopic surgery. During the operation, the tumor was detected in the retroperitoneal space, where it was strongly adhered between the left gastric artery and common hepatic artery. At this point, no major vessels had vascularized the tumor. We then completely removed the tumor from the retroperitoneal space without any complications. The clinical course was uneventful, and the patient was discharged on postoperative day 4 without any symptoms. Later, a definitive histopathologic examination revealed a benign schwannoma. Here, we report this rare case of a retroperitoneal schwannoma located in the hepatic hilus. PMID- 26943387 TI - A case report: right upper lobectomy with middle lobe preservation after right lower lobectomy. AB - Few reports have described right upper and lower lobectomy with preservation of the middle lobe because of the risk of middle lobe torsion or emphysematous change. Herein we describe a successful result following lobectomy with preservation of the middle lobe for metachronous pulmonary metastasis originating from colon cancer in the right upper lobe after initial right lower lobectomy. A 69-year-old man who had undergone right lower lobectomy for pulmonary metastasis originating from colon cancer 3 years earlier was diagnosed as having suspected metachronous pulmonary metastasis in the right upper lobe. Because preoperative computed tomography (CT) indicated that the distance between the tumor and the entrance of the upper bronchus was 20 mm, it was considered difficult to achieve complete resection by a wedge resection or segmentectomy. Furthermore, preoperative CT demonstrated compensatory hypertrophy of the middle lobe and elevation of the right diaphragm, thus reducing the size of the thorax. Therefore, right upper lobectomy with middle lobe preservation was planned. The operation was performed using a totally thoracoscopic approach. Adhesion of the upper lobe to the chest wall was easily detached. As the middle lobe adhered to the chest wall, this served to prevent middle lobe torsion. The fissure between the upper and middle lobes had fused because of adhesion resulting from the initial lower lobectomy. Therefore, an 'anterior fissureless approach' was adopted to avoid any postoperative air leakage. There were no intraoperative problems, and the postoperative course was uneventful. The patient was discharged on postoperative day 6. Pathological examination of the specimen confirmed that the tumor was a metachronous pulmonary metastasis originating from the colon cancer. Four months after the operation, he had no requirement for additional oxygen support, and postoperative CT demonstrated a sufficiently expanded residual middle lobe without emphysematous change. PMID- 26943388 TI - A large mural nodule in branch duct intraductal papillary mucinous adenoma of the pancreas: a case report. AB - Indications for resection of branch duct intraductal papillary mucinous neoplasms (IPMNs) remain controversial because of their low tendency to be malignant. Surgical resection should be recommended if any factors indicating malignancy are present. However, preoperative differentiation between benign and malignant tumors is very difficult, especially in cases of branch duct IPMNs. We herein report a case of branch duct intraductal papillary mucinous adenoma (IPMA) of the pancreas with a large mural nodule of 25 mm. A 74-year-old woman was admitted for examination and treatment for a cystic tumor in the head of the pancreas. Magnetic resonance cholangiopancreatography and computed tomography showed a cystic lesion, 50 mm in diameter, with an irregular mural nodule in the pancreatic head. Endoscopic ultrasonography demonstrated a multicystic tumor connected with the main pancreatic duct (MPD). The mural nodule had a diameter of 18 mm, and the MPD had a slight dilation of 6 mm. These findings suggested a high potential for malignancy. The patient underwent pancreaticoduodenectomy with lymph node dissection. The excised pancreas showed multiple cysts located in the branch pancreatic duct with a maximum diameter of 75 mm. The mural nodule had a maximum diameter of 25 mm. The tumor was diagnosed as an IPMA by pathological examination. After operation, the patient was discharged without any complications. Two years after resection, the patient remains in remission with no evidence of tumor recurrence. PMID- 26943389 TI - Distinguishing between limited systemic scleroderma-associated pseudo-obstruction and peritoneal dissemination. AB - A 78-year-old woman receiving treatment for limited systemic scleroderma (SSc) underwent high anterior resection and partial liver resections for rectosigmoid colon cancer with multiple liver metastases. A year after surgery, an abdominal computed tomography (CT) demonstrated suspicion for peritoneal dissemination with an increase in ascites, and (18)F-fluorodeoxy glucose-positron emission tomography-CT was suggestive of carcinomatosis. We began to decompress the small intestine and administer octreotide. However, the intestinal obstruction did not improve. Although intestinal pseudo-obstruction caused by limited SSc was considered as a differential diagnosis, we performed an exploratory laparotomy because the possibility of peritoneal dissemination-associated obstruction could not be excluded. We observed a moderate amount of serous ascites and dilatation of the small intestine that was white in color, hard, and with limited contractility. There was no evidence of peritoneal dissemination nor of mechanical obstruction. Our experience thus shows the difficulty of distinguishing SSc-associated intestinal pseudo-obstruction from peritoneal dissemination. PMID- 26943390 TI - Secondary reconstruction with a transverse colon covered with a pectoralis major muscle flap and split thickness skin grafts for an esophageal defect and wide skin defects of the anterior chest wall. AB - Necrosis of a reconstructed organ after esophagectomy is a rare postoperative complication. However, in case this complication develops, severe infectious complications can occur, and subsequent surgical reconstruction is quite complicated. To treat esophageal conduit necrosis after esophageal reconstruction with the terminal ileum and ascending colon, we reconstructed the esophagus using a transverse colon, which was covered with a pectoralis major muscle flap to reinforce the anastomotic site. In addition, split thickness skin grafts were applied to the wide skin defect to cover the reconstructed organs at the antesternal route. Widely extended split thickness skin grafts can adhere to the reconstructed organs without excessive tension. Therefore, this method enabled successful treatment of an esophageal defect and wide skin defects of the anterior chest wall. PMID- 26943391 TI - Surgical treatment for rectal cancer with abnormally expanded inferior mesenteric vein resulting from pancreatic arteriovenous malformations. AB - A 52-year-old Japanese man presented for evaluation and treatment of rectal cancer. Screening computed tomography revealed pancreatic arteriovenous malformations (P-AVMs) and abnormally expanded inferior mesenteric vein (IMV) that resulted from P-AVMs. One-stage surgery for rectal cancer was dangerous so we first performed distal pancreatectomy to cure P-AVM and thus normalize the abnormally expanded IMV. After the operation, the IMV was occluded by the thrombi, and then the IMV became normal. We could perform safely radical laparoscopic surgery for rectal cancer. This is the first case report of P-AVMs combined with rectal cancer. PMID- 26943392 TI - Midterm results of left coronary artery reimplantation through the transverse sinus of the pericardium in adult Bland-White-Garland syndrome. AB - The anomalous origin of the left coronary artery from the pulmonary artery - known as Bland-White-Garland syndrome - is a rare congenital malformation that affects 1 in 300,000 live births. Most patients die in infancy without any surgical treatment. Some patients who survive past childhood often have varying symptoms such as myocardial ischemia, impaired left ventricular function, mitral regurgitation, and progressive heart failure, depending on the development collateral circulation. In the present report, we describe a procedure wherein the left coronary artery ostium was translocated through the transverse sinus of the pericardium in a 43-year-old mother with Bland-White-Garland syndrome and concomitant mitral regurgitation and report on the associated midterm results. PMID- 26943393 TI - Thoracoscopic radical esophagectomy and laparoscopic transhiatal lymph node dissection for superficial esophageal cancer associated with lymph node metastases in the dorsal area of the thoracic aorta. AB - Esophageal cancer invading the muscularis mucosa sometimes involves regional lymph node metastases. However, lymph node metastases are rare in the dorsal area of the thoracic aorta. We describe a patient with an intramucosal esophageal cancer invading the muscularis mucosa, accompanied by lymph node metastases in the dorsal area of the thoracic aorta. These lesions were successfully resected by hand-assisted laparoscopic surgery using a transhiatal approach. A 60-year-old man was diagnosed with superficial esophageal cancer during a routine health examination. Endoscopic examination and ultrasonography revealed a superficial cancer, of diameter 6.0 cm, invading the submucosal layer and intramural metastases caudal to the primary tumor. Enhanced computed tomography and F deoxyglucose positron emission tomography demonstrated the two metastatic lymph nodes, one in the dorsal area of the thoracic aorta and the other near the left gastric artery. Thoracoscopic radical esophagectomy with three-field lymph node dissection was performed. The metastatic lymph node in the dorsal area of the thoracic aorta was successfully removed by hand-assisted laparoscopic surgery using a transhiatal approach. Histopathological examination showed primary cancer invading the muscularis mucosa and intramural metastases in the lamina propria mucosa and submucosal layer. The pathological diagnosis according to the Japanese classification of esophageal cancer was MtLt, 47 mm, 0-IIa + IIb, pT1a-MM, ie(+), INF-b, ly3, v0, pN4(4a), pIM1, M0, and pstage IVa. The patient underwent two courses of adjuvant chemotherapy, consisting of CDDP and 5-fluorouracil. At present, 1 year and 8 months after surgery, the patient remains alive without tumor recurrence. Although the lymph node in the dorsal area of the thoracic aorta is not recognized as regional nodes of thoracic esophageal cancer, solitary mediastinal metastases from a mucosal cancer may indicate the existence of direct lymphatic flow from the thoracic esophagus to the retroaortic region. Transhiatal approach by hand-assisted laparoscopic surgery is useful to dissect the metastatic lymph node in the dorsal area of the thoracic aorta. PMID- 26943394 TI - Long-term survival case of a recurrent colon cancer owing to successful resection of a tumor at hepaticojejunostomy: report of a case. AB - With advances in surgical procedures and perioperative management, hepato-biliary pancreatic surgery, including hepatectomy and pancreaticoduodenectomy, has been employed for recurrent colon cancer. However, no report has described a case of major hepatectomy with the combined resection of hepaticojejunostomy following pancreaticoduodenectomy for locoregionally recurrent colon cancer. Here, such a case is reported. The patient, a 37-year-old woman, had undergone pancreaticoduodenectomy for lymph node recurrence along the extrahepatic bile duct from cecal cancer. Thirteen months later, a biliary stricture was found at the hepaticojejunostomy site and right hepatectomy was performed. The resected specimen showed a papillary tumor at the hepaticojejunostomy. Based on its histological features, the pathogenesis of this tumor was considered to be intramural recurrence via lymphatic vessels. Although she underwent resection of a lymph node recurrence at her mesentery 12 months later, she has remained well thereafter, without any sign of further recurrence during 5 years of follow-up after hepatectomy. PMID- 26943395 TI - Superior mesenteric artery syndrome after ileal pouch-anal anastomosis for colon cancer associated with ulcerative colitis: report of a case. AB - Superior mesenteric artery syndrome (SMAS) after a surgical operation is very rare. We experienced an extremely rare case of ileal pouch-anal anastomosis with subsequent development of SMAS requiring duodenojejunostomy. A 74-year-old Asian woman underwent total colectomy, ileal pouch-anal anastomosis (J-pouch), covering ileostomy, splenectomy, and distal pancreatectomy for treatment of descending colon cancer associated with ulcerative colitis. She complained of abdominal discomfort and vomiting 17 days postoperatively. Computed tomography (CT) revealed fluid collection at the pancreatic stump. We diagnosed a pancreatic fistula and performed CT-guided drainage. SMAS was thereafter diagnosed by contrast-enhanced CT, which revealed a narrow aortomesenteric angle of 36 degrees and short aortomesenteric distance of 2 mm. The SMAS did not respond to conservative therapy. Finally, we performed duodenojejunostomy. This case illustrates that ileal pouch-anal anastomosis might induce relative stretching of the superior mesenteric artery and flatten it against the aorta, resulting in SMAS. PMID- 26943396 TI - Intussusception causing postoperative intestinal obstruction following free jejunum transfer in adults: two case reports and review of the literature. AB - Intussusception is a rare cause of postoperative intestinal obstruction in adults. We experienced two cases of bowel obstruction due to the jejuno-jejunal intussusception after harvest of a free jejunum graft for reconstruction after cervical esophagectomy. Bowel obstruction occurred early in the postoperative course, and reoperations were needed in both cases. In both case, the anastomotic site was resected and re-anastomosed in a side-to-side fashion. Recurrence of intussusception has not been observed. In the literature, such a complication has been documented in two case series and a case report. The reported incidence of postoperative intussusception of the case series was 2.8% and 7.4%, respectively. The jejuno-jejunal anastomoses were performed with end-to-end fashion by two layered hand-sewn suture (Albert-Lembert method) in all cases reported. In order to prevent the occurrence of postoperative intussusception, we recommend to harvest a free jejunal graft as far from the Treitz ligament as possible and to avoid reconstruction by an Albert-Lembert end-to-end anastomosis. PMID- 26943397 TI - Successful living-donor liver transplantation after treatment of sinus aspergillosis by endoscopic mycetoma removal and sinus drainage. AB - A 47-year-old female was admitted to our hospital for treatment of end-stage liver disease due to primary biliary cirrhosis. Preoperative routine nasal sinus magnetic resonance imaging revealed diffuse inflammatory mucosal hyperplasia of the right maxillary sinus and mycetoma without invasive fungal sinusitis. Aspergillus antigen was positive. With a diagnosis of sinus aspergillosis, endoscopic sinus drainage and removal of mycetoma were performed. After endoscopic treatment, the right maxillary sinus was irrigated using amphotericin B for 2 weeks and then treated by iodine with gentamicin and ketoconazole for 6 weeks. At 1 month after endoscopic treatment, the mycetoma had disappeared. At 3 months after the endoscopic treatment, the patient underwent living-donor liver transplantation using the left and caudate lobe of her daughter. The patient made a satisfactory recovery and was discharged on 19 days after transplant. As of 44 months after transplant, she remains well without recurrence of aspergillosis. PMID- 26943398 TI - A case of long-term survival following hepatectomy for liver metastasis of Merkel cell carcinoma. AB - BACKGROUND: Merkel cell carcinoma (MCC) is a rare endocrine tumor that presents as a rapidly growing skin nodule of the body, and it is aggressive with regional nodal and distant metastases without clearly defined treatment. There are no reports of long survivors among patients with liver metastasis of MCC. The current case was a patient who underwent surgical resection for liver metastasis of Merkel cell carcinoma. CASE PRESENTATION: This case describes a 73-year-old female with a papule on the dorsal side of the right third finger and liver tumor. The papule of the right third finger was histologically diagnosed as MCC by the skin biopsy. She underwent extensive resection and lymph node dissection of the right third finger and partial resection of the liver. The liver tumor was histologically diagnosed as liver metastasis of MCC. The patient remains well without any evidence of tumor recurrence more than 5 years after surgery. CONCLUSIONS: This is the first report of a long-term survival of more than 5 years following liver metastasis of MCC, which was surgically resected. Patients with small and solitary metastatic liver tumor of MCC may have a chance for a long-term survival following the hepatic resection. PMID- 26943399 TI - Reactive lymphoid hyperplasia of the liver requires differential diagnosis of hepatocellular carcinoma. AB - Reactive lymphoid hyperplasia (RLH) of the liver is a rare and benign nodular lesion. It remains difficult to distinguish RLH from hepatocellular carcinoma (HCC) despite recent advances in imaging modalities. We report five cases of RLH that required differential diagnosis of HCC preoperatively. These cases all occurred in middle-aged women and were associated with autoimmune disease in 40% (2/5). The diameter of the nodule was less than 2 cm in all five of our cases. Four cases had a preoperative diagnosis of HCC. When a liver nodule is found in middle-aged women with an autoimmune disease, the possibility of RLH should be considered. PMID- 26943400 TI - Acute necrotic pancreatitis after esophagectomy: a case report. AB - Acute pancreatitis after esophagectomy is a very rare but fatal complication. This case report describes a 74-year-old man diagnosed with cT2N0M0, cStage IB esophageal squamous cell carcinoma (Union for International Cancer Control, seventh edition). On the basis of the patient's condition, it was decided that he should undergo esophagectomy without thoracotomy. The patient developed pyrexia 3 days after the operation. Chest and abdominal computed tomography revealed severe acute pancreatitis and gastric tube necrosis; therefore, gastrectomy was performed. Subsequent surgical exploration indicated pancreatic necrosis that was diagnosed as acute necrotic pancreatitis. Postoperative management of acute pancreatitis and the general condition of the patient were quite challenging, and rapid deterioration of the respiratory status was observed. The patient experienced multiple organ failure and died 57 days after the second surgery (60 days after the first surgery). This is a report of a patient with acute necrotic pancreatitis after esophagectomy. PMID- 26943401 TI - Simultaneous pulmonary metastases from colon and prostate cancer to the same lobe. AB - Simultaneous pulmonary metastases from different primary tumors to the same lobe are extremely rare, and we herein report the case. Surgical specimen of the pulmonary metastasis from colon cancer contained two additional nodules that were confirmed as metastases from prostate cancer. Pulmonary metastasis from prostate cancer rarely forms nodules, and there is a discrepancy in the incidence of pulmonary metastases between autopsy and clinical findings. This case suggests that different malignant tumors could simultaneously metastasize to the same pulmonary lobe, and more pulmonary metastases from prostate cancer might exist than expected. PMID- 26943402 TI - A case of biliary cystic tumor with repeated hemobilia. AB - Intraductal papillary neoplasm of the bile duct (IPNB) is classified as a biliary cystic tumor with a tendency of causing obstruction. Neoplastic cases involving hemobilia are rarely reported. We herein describe a case of biliary cystic tumor with repeated hemobilia. A 57-year-old woman was histologically diagnosed with cavernous hemangioma. During the follow-up period after transcatheter arterial embolization (TAE), she experienced repeated hemobilia, and multiple other TAE sessions were performed for hemostasis. She was referred to our hospital 8 years after the first surgery owing to a growing tumor. Histopathological examination after extended right hepatectomy and caudate lobectomy indicated IPNB with an associated invasive carcinoma. Six months thereafter, computed tomography revealed a recurrent liver tumor and a nodule in the abdominal cavity. She died 36 months after the second surgery, despite chemotherapy. Our experience suggests that IPNB should be considered during differential diagnosis of dilated hepatobiliary tumors with hemobilia. PMID- 26943403 TI - Inferior vena cava leiomyosarcoma: preoperative diagnosis and surgical management. AB - Inferior vena cava (IVC) leiomyosarcoma is a rare malignant neoplasm more commonly seen in women in the fifth to sixth decade of life. Complete resection of the tumor with negative margins is the only therapeutical option that has demonstrated a survival benefit. This report presents a case of a 67-year-old woman affected by a lower segment IVC leiomyosarcoma incidentally detected during a chronic abdominal pain study. The patient was treated with tumorectomy, resection and ligation of the infrarenal IVC without signs or recurrence on a 12 month follow-up. PMID- 26943404 TI - Surgical removal of calcified amorphous tumor localized to mitral valve leaflet without mitral annular calcification. AB - A cardiac calcified amorphous tumor (CAT) localized to the mitral valve leaflet without mitral annular calcification (MAC) is a rare entity. We report a case of a 69-year-old woman with such a condition, who underwent successful excision of the tumor and mitral valvuloplasty using a glutaraldehyde-treated autologous pericardium. During 38 months of follow-up, no recurrence of a cardiac mass has been recognized. This report addresses questions on the surgical indication for CAT, particularly in cases without MAC, and reviews CATs of the mitral valve. PMID- 26943406 TI - Successful surgical treatment for recurrent cardiac fibroma 21 years after resection. AB - Cardiac fibromas are rare benign tumors usually seen in the pediatric population. Generally, long-term survival after surgical resection is favorable, and recurrence of fibroma has been hardly reported. Herein, we report a case of a 34 year-old woman who presented with ventricular tachycardia 21 years after resection of a cardiac fibroma and was found to have a recurrent giant cardiac fibroma. We performed a complete resection of the recurrent fibroma. At the 2 year follow-up, she remains asymptomatic with no evidence of ventricular tachycardia or recurrence of fibroma. PMID- 26943405 TI - A case study of a collision tumor composed of cancers of the bile duct and pancreas. AB - In this case report, we describe the extremely rare case of a collision tumor comprising cancers of the bile duct and the pancreas. A 70-year-old man was referred to our hospital with a diagnosis of obstructive jaundice. He was diagnosed with pancreatic head cancer, and we performed a pancreaticoduodenectomy with lymph node dissection. At laparotomy, there were two palpable masses in the vicinity of the confluence of the cystic duct and the head of the pancreas. The resected specimen demonstrated tumors at the confluence of the cystic duct and in the pancreatic head. Histopathological examination demonstrated a moderately differentiated tubular adenocarcinoma in the pancreatic head and a well differentiated tubular adenocarcinoma at the confluence of the cystic duct. Immunostaining was negative for p53 and MUC6 in the pancreatic head tumor; however, immunostaining was positive for both in the tumor located at the confluence of the cystic duct. The two tumors were histologically different and were diagnosed as collision cancer caused by the collision of the bile duct and pancreatic cancers. PMID- 26943407 TI - A case of unusual histology of infantile lipoblastoma confirmed by PLAG1 rearrangement. AB - Lipoblastoma, a relatively rare benign adipose neoplasm, predominantly affects children younger than 3 years of age. We herein report the case of a 7-month-old girl with an unusual myxomatous histology of lipoblastoma. A rapidly growing mass was detected in the subcutaneous area of the left buttock. Histologically, the tumor consisted of abundant myxoid stroma exhibiting cellular atypia and a high mitotic activity. Although the histological findings were unusual, the tumor was diagnosed as a lipoblastoma according to both PLAG1 immunohistochemistry and the presence of PLAG1 rearrangement on fluorescence in situ hybridization. PMID- 26943408 TI - Successful closure of a tracheocutaneous fistula after tracheostomy using two skin flaps: a case report. AB - A tracheocutaneous fistula may develop when a tracheostomy orifice epithelializes during a prolonged course of healing or undernutrition. Various techniques for closing such fistulae have been reported. However, a standard procedure has not yet been established. We, herein, present a case involving a 35-year-old woman who developed a tracheocutaneous fistula after tracheostomy. We closed the fistula using two skin flaps to cover the tracheal lumen and skin defect, respectively. The advantage of this technique is that it allows the tracheal lumen to be covered by inversed skin epithelium and ensures that the suture line of the skin does not match up with that of the subcutaneous tissue. PMID- 26943409 TI - Pneumoperitoneum in a non-acute abdomen-pneumatosis cystoides intestinalis. AB - AIM: The aim of this study is to increase the understanding of pneumatosis cystoides intestinalis (PCI) and its incidents. METHOD: We report here a case of PCI in an 88-year-old man with a provisional diagnosis of perforated viscus and possible ischaemic bowels based on CT findings of pneumoperitoneum. The patient was found to have extensive PCI on his small bowels. We then systematically search the PubMed database for case reports for articles containing 'pneumatosis intestinalis' in their titles or key words. RESULTS: The study group consisted of 52 cases on PCI from the period of 2010-2014 with the focus on the adult population. The youngest patient was 18 years old and the oldest was 91 years old. The mean age was 60.4 years (range, 18-91 years old). There were 27 (52 %) females and 25 (48 %) males. The most common symptoms were abdominal pain (79 %) followed by nausea/vomiting (27 %) and abdominal distension (19 %). CT imaging was the most common investigation modality used (94 %). Three (6 %) of the patients had laparoscopic treatment while 20 (38 %) had laparotomy. Thirty-six (69 %) of them recovered uneventfully while 9 (17 %) of the patients died. CONCLUSION: Although there have been more case reports published on PCI in the recent years, the understanding of this condition remains in the infancy stage. PCI can be difficult to diagnose and can be easily misdiagnosed as pneumoperitoneum in an acute abdomen. Often it is identified incidentally during operation. Asymptomatic PCI should be treated conservatively, while emergency laparotomy should be reserved for life threatening abdominal pathology. PMID- 26943410 TI - Spontaneous rupture of non-parasitic or non-neoplastic multiple and giant liver cysts: report of a case. AB - Simple liver cysts occasionally cause pressure symptoms of the abdomen. We herein report an extremely rare case of spontaneous rupture of simple liver cysts. A 65 year-old woman suffered abdominal fullness and dyspnea. Laboratory examinations revealed general inflammation and mild hepatorenal dysfunction. Computed tomography revealed giant polycystic liver and ascites. Echinococcus antibody was not detected. Abdominal paracentesis provided dark brown transparent ascites in which any parasites or tumor cells were not observed. We diagnosed spontaneous rupture of isolated polycystic liver disease (PCLD) and continuously drained the ascites. After the symptoms and laboratory data were improved, resection of liver cysts and left lateral segmentectomy were performed. Histopathologically, simple columnar epithelia inside of cyst walls were observed. The patient remains well without recurrence of the symptoms 10 months after the surgery. We reviewed characteristics of PCLD and considered appropriate treatment for spontaneous rupture of simple liver cysts based on the previous case reports including the present case. PMID- 26943411 TI - Intraductal papillary mucinous neoplasm in an annular pancreas: a case report. AB - Annular pancreas is a rare anomaly in which a ring of pancreatic tissue encircles the second portion of the duodenum. We herein report a case involving a 79-year old Japanese man with an intraductal papillary mucinous neoplasm (IPMN) of the pancreas. Imaging studies showed that the pancreatic tissue encircled the descending part of the duodenum and that a 30-mm-diameter cystic tumor was present in the annular segment, leading to the diagnosis of pancreatic IPMN. Limited pancreatic resection was successfully performed by careful division of the annular segment from the second portion of the duodenum. The postoperative course was uneventful, and the patient's pancreatic function was retained without the need for supplementation. To the best of our knowledge, this is the first report of IPMN occurring in the annular segment of the pancreas. Limited resection of the pancreatic annular segment is a feasible surgical treatment for noninvasive IPMN of the annular pancreas. PMID- 26943412 TI - Infected abdominal aortic aneurysm caused by Streptococcus pneumoniae diagnosed using polymerase chain reaction. AB - We report the case of a 55-year-old man who initially visited the emergency department of our hospital owing to fever, headache, and neck stiffness. He was diagnosed with meningitis because cerebrospinal fluid culture was positive for Streptococcus pneumoniae. After intravenous antibiotic treatment, the patient's condition returned to normal. On hospital day 20, he complained of lumbar pain with abdominal distension. Because an abdominal computed tomography (CT) scan showed a small sacciform infrarenal abdominal aortic aneurysm, an infected aneurysm was suspected. However, cerebrospinal fluid and blood cultures were negative for S. pneumoniae. Seven days later, a second abdominal CT was performed that showed rapid expansion of the sacciform infrarenal abdominal aortic aneurysm. The patient was diagnosed with an infected abdominal aortic aneurysm and underwent surgery for resection of the aneurysm and in situ reconstruction with a rifampicin-soaked vascular prosthesis. Although blood and aneurysmal tissue cultures were negative for S. pneumoniae, the autolysin (lytA) gene, which is the target gene of S. pneumoniae, was detected in the abdominal aortic wall by using polymerase chain reaction (PCR). Therefore, appropriate molecular diagnostic techniques can be used for the rapid detection of pathogens. An accurate diagnosis can be used to direct postoperative antibiotic therapy. PMID- 26943413 TI - A resected case of liver metastases from extra-adrenal retroperitoneal paraganglioma with von Recklinghausen's disease 16 years after the initial surgery. AB - The patient was a 46-year-old man who had undergone resection for a bulky retroperitoneal tumor 16 years previously during a follow-up for von Recklinghausen's disease. Histopathological examination of the resected specimen showed that the tumor was an extra-adrenal paraganglioma. After the surgery, he had survived without any recurrence of the tumor. However, 16 years after the initial surgery, liver tumors were identified, and he was referred to our hospital for further investigation and treatment. Abdominal imaging modalities showed three masses in the left lateral segment of the liver. Fluorodeoxyglucose positron emission tomography/computed tomography showed an abnormal uptake of fluorodeoxyglucose corresponding to the mass lesions. The patient was diagnosed with a metastatic paraganglioma based on histopathological examination of a liver mass biopsy. The patient underwent left lateral sectionectomy of the liver. Histopathological examination of the resected specimen revealed proliferating cells with basophilic cytoplasm and oval densely stained nuclei arranged in an alveolar pattern, which was similar to the findings of the initial resection specimen. Immunohistochemical staining was positive for synaptophysin and chromogranin A. Based on these findings, the resected tumors were histopathologically diagnosed with liver metastases from the retroperitoneal paraganglioma. We concluded that this is an extremely rare case of liver metastases occurring long after the initial resection of extra-adrenal peritoneal paraganglioma with von Recklinghausen's disease. PMID- 26943414 TI - A gastrointestinal stromal tumor at the esophagogastric junction successfully treated by laparoscopic wedge resection with seromuscular layer dissection: a case report. AB - Herein, we report a case of a gastrointestinal stromal tumor (GIST) at the esophagogastric junction (EGJ) that was successfully treated by a laparoscopic wedge resection (LWR) after dissection of the seromuscular layer around the tumor to prevent postoperative deformities and stenosis of the EGJ. Subsequently, the abdominal esophagus was wrapped by the gastric fornix according to Dor's method in order to prevent reflux esophagitis after surgery.A 71-year-old female patient was admitted with a diagnosis of a GIST (23 * 20 * 20 mm) at the EGJ. We performed the abovementioned operation.Gastroduodenal endoscopic examination revealed no deformity or stenosis of the EGJ at 6 months after the operation. The patient has not experienced any reflux symptoms. Tumor recurrence was not noted 26 months after the operation.This procedure is useful in preventing the deformity and stenosis of the EGJ as well as postoperative reflux esophagitis. PMID- 26943415 TI - Spontaneous hemorrhage from splenic tissue 13 years after total splenectomy: report of a case. AB - A 33-year-old man suffered sudden abdominal distension without traumatic episodes. He had undergone total splenectomy for hereditary spherocytosis 13 years ago. He was in shock, and his hemoglobin level was 10.5 g/dl. Contrast enhanced computed tomography revealed a giant mass in the left upper abdomen and extravasation of the contrast material into the mass. Excision of the mass was performed, and microscopic examination showed a giant hematoma surrounded by normal splenic tissue. We speculated that an accessory spleen or splenosis had enlarged for the 13 years and ruptured. The patient remained asymptomatic 4 months after the surgery. Spontaneous hemorrhage from accessory spleens or splenosis is extremely rare, and relevant case reports suggest that surgical resection of bleeding sites yields favorable prognosis although preoperative qualitative diagnosis seems to be difficult. PMID- 26943416 TI - The clinical manifestations and treatment of male breast cancer: a report of three cases. AB - Male breast cancer is an extremely rare malignancy. We treated three male breast cancer patients. All three patients showed clinical N0 and received sentinel lymph node biopsy. Because the sentinel lymph node was positive for metastasis in one patient, a total mastectomy with axillary lymph node dissection was performed. The other two patients were negative for sentinel lymph node metastasis, and a simple mastectomy was performed. Two of the patients were postoperatively treated with tamoxifen; another patient was treated with adjuvant chemotherapy using taxotere and cyclophosphamide before tamoxifen. There was no recurrence in any of the three patients during an average follow-up period of 56.7 months (range 11.8-80.3). A sentinel lymph node biopsy is recommended for node staging in both male and female breast cancer patients as it is associated with a lower incidence of complications. PMID- 26943417 TI - Obstructive jaundice caused by a giant liver hemangioma with Kasabach-Merritt syndrome: a case report. AB - Hemangioma is the most common benign tumor of the liver. Liver hemangioma (LH) usually remains asymptomatic, but the most common symptoms associated with LH are abdominal pain and discomfort. LH is an uncommon cause of bile duct dilatation and obstructive jaundice. An 83-year-old Japanese woman who received hemodialysis at another hospital was referred to our hospital because of abnormal liver function and obstructive jaundice. Abdominal computed tomography and magnetic resonance imaging revealed a 13-cm tumor in liver segments IV-V and intrahepatic bile duct dilatation. Endoscopic retrograde cholangiopancreatography revealed extrinsic compression of the bile duct at the hepatic hilar region. Laboratory tests showed that the patient had low platelet counts and low fibrinogen levels. Because the patient had hyperbilirubinemia and Kasabach-Merritt syndrome, we performed a segmentectomy of liver segments IV and V. Histological examination showed hemangioma of the liver. The patient's thrombocytopenia and coagulopathy improved immediately after surgery. In conclusion, LH is a very rare cause of obstructive jaundice. LH has the potential to compress the bile duct and cause obstructive jaundice. PMID- 26943419 TI - Complicated adult right-sided Bochdalek hernia with Chilaiditi's syndrome: a case report. AB - An extremely rare adult case that underwent surgery for ileus caused by Bochdalek hernia associated with Chilaiditi's syndrome is presented. A 65-year-old woman complaining of upper abdominal pain presented to our hospital. Abdominal plain radiography showed increased intestinal gas, and computed tomography (CT) showed the transverse colon located above the right lobe of the liver, representing Chilaiditi's sign. She was diagnosed as having ileus and treated with decompression therapy by a nasoenteric tube. After hospitalization, the patient developed dyspnea, and CT showed intestinal herniation into the right thoracic cavity. She was diagnosed as having strangulated ileus caused by Bochdalek hernia. An emergent laparotomy was performed, and it showed a hole of 5 cm in diameter at the right hemi-diaphragm. The transverse colon was incarcerated through the hole, it was pulled back to the abdominal cavity, and a right hemicolectomy was performed because of necrotic changes. A small part of the liver was also herniated into the right thoracic cavity, and it was returned to the abdominal cavity. The defect in the diaphragm was closed by direct suture. Although the patient developed an abscess in the thoracic cavity postoperatively, she improved with antibiotic therapy and was discharged 2 months after the operation. PMID- 26943418 TI - Successfully treated advanced esophageal cancer with left axillary lymph node metastasis and synchronous right breast cancer: a case report. AB - The incidence of double cancer of the esophagus and breast is rare, and axillary lymph node metastasis (ALM) in esophageal cancer is also very rare. We report a case of advanced esophageal cancer with left ALM and synchronous right breast cancer. A 64-year-old woman was admitted to our hospital with dysphagia. The clinical diagnosis was esophageal cancer (T3N0M1 stage IV) and right breast cancer (T1cN0M0 stage I). She was initially treated with triple chemotherapy with docetaxel, cisplatin, and 5-fluorouracil. The primary lesion in the esophagus achieved almost complete response as assessed by esophageal endoscopy. A computed tomography scan showed that the left ALM reduced in size and that stable disease was achieved for the right breast cancer. She underwent partial mastectomy of the right breast and bilateral axillary lymph node dissection. The histopathological diagnosis of the breast cancer was T1cN1M0 stage IIA. The lymph nodes from the left axilla contained metastatic cells from the squamous cell carcinoma of the esophagus. Complete response was achieved for the primary lesion in the esophagus following chemoradiotherapy (CRT), and the patient has been relapse free 2 years after treatment. Thus, we report the successful treatment of synchronous double cancers of the esophagus with left ALM and right breast by combination therapy with chemotherapy, CRT, and surgery. PMID- 26943420 TI - A case of transvaginal NOTES partial gastrectomy using new techniques and devices. AB - The latest technique of transvaginal NOTES partial gastrectomy is described in detail. The procedure involves new "over-tube steering" technique and usage of two newly developed endoscopic accessories. The technique is feasible, safe, and practical, since all devices used in the case are off-the-shelf products. PMID- 26943421 TI - Aortopulmonary collateral arteries: a rare complication after arterial switch operation for transposition of the great arteries. AB - Collateral vascular arteries from the descending aorta to the pulmonary arteries are uncommon after arterial switch operation. Here, we report the case of a baby girl treated with coil embolization for abnormal blood flow from the descending aorta to the pulmonary arteries after arterial switch operation. A baby girl weighing 1324 g was delivered at 32 weeks 4 days of gestation, and she had D transposition of the great arteries and a ventricular septal defect. She underwent nitrogen inhalation to reduce pulmonary blood flow before arterial switch operation. After the operation, she presented with left heart failure due to the presence of abnormal blood flow from the descending aorta to the pulmonary arteries, and she was successfully treated with coil embolization. After the treatment, her condition improved dramatically, and she was discharged without any complications. PMID- 26943423 TI - Emergency thoracic aortic stent grafting for acute complicated type B aortic dissection after a previous abdominal endovascular aneurysm repair. AB - We report a case of acute type B aortic dissection with the complication of bowel ischemia and abdominal stent graft compression treated by emergency thoracic aortic stent grafting after endovascular aneurysm repair (EVAR) for abdominal aortic aneurysm (AAA). A 69-year-old male was admitted to our hospital for sudden thoraco-abdominal pain. He had past treatment history of EVAR for AAA half a year ago. A computed tomography (CT) showed acute type B aortic dissection, and conservative treatment was initially performed. Three days after occurrence of aortic dissection, worsened abdominal pain and melena were observed. CT showed that the true lumen and abdominal stent graft was compressed by the false lumen. Emergency thoracic endovascular repair (TEVAR) was performed to close the entry tear. After the operation, the image views and the symptoms were improved. The state was still stable 6 months later. TEVAR for acute type B aortic dissection can become one of the effective treatments. PMID- 26943422 TI - Primary leiomyosarcoma of the pancreas: report of a case treated by local excision and review of the literature. AB - BACKGROUND: First described by Ross in 1951, primary pancreatic leiomyosarcoma is a rare mesenchymal tumour of the pancreas, with nonspecific clinical and radiological features and a poor prognosis, if unresectable. CASE REPORT: A 60 year-old woman presented with abdominal pain. Magnetic resonance imaging (MRI) and computed tomography (CT) scan detected a dishomogeneous egg-shaped 8-cm mass, arising from the pancreatic head, with duodenal compression, without dilation of the Wirsung duct. (18)F-FDG positron-emission tomography (PET)-CT showed a moderate tracer uptake, and the endoscopic ultrasound (US) showed a hypoechoic lesion, arising from the duodenal wall, suspected to be a gastrointestinal stromal tumour (GIST). CEA, CA19-9, NSE, and chromogranin A were normal. At the surgical exploration, a 10-cm mass, adherent to the anterior aspect of the pancreatic head, was found. The lesion was easily separable from the duodenal wall and was totally excised. The frozen intraoperative examination showed a mesenchymal tumour, with spindle-shaped cells, suggesting that a GIST diagnosis was likely. Postoperative course was uneventful. Histology and immunohistochemistry demonstrated a well-differentiated leiomyosarcoma, with five to six mitotic counts per 10 high-power field (HPF) and proliferative index (MIB 1) 10 % (grade 2 according to Federation Nationale des Centres de Lutte Contre le Cancer (FNCLCC)), with positive smooth muscle actin, desmin, and caldesmon but negative CD117 (c-kit) and S-100. The patient is alive and asymptomatic 19 months after surgery, without evidences of disease. CONCLUSIONS: In the English literature, only 44 cases of primary pancreatic leiomyosarcoma have been reported. If a pancreatic mass suspected for primary pancreatic leiomyosarcoma has no adjacent organ/vessel invasion or distant metastases, surgical resection is the therapy of choice. PMID- 26943425 TI - A case of occult intrahepatic cholangiocarcinoma diagnosed by autopsy. AB - Cancer of unknown primary is associated with unknown biology and dismal prognosis. The most common primary sites of cancer of unknown primary were usually the lungs in autopsy studies, and intrahepatic cholangiocarcinoma is rare. We describe the case of a 57-year-old male patient with systemic lymph node metastasis. Imaging examination failed to reveal primary cancer; however, immunostaining of cytokeratins 7, 19, and 20 of a metastatic axillary lymph node suggested a pancreaticobiliary cancer as a primary lesion. He died of liver abscess and sepsis, and then, autopsy indicated occult intrahepatic cholangiocarcinoma. We discuss the clinical course of this rare cholangiocarcinoma including the diagnostic procedure and also present a review of the English literature regarding patients with cancer of unknown primary. PMID- 26943424 TI - Torsion of an accessory spleen: a rare case preoperatively diagnosed and cured by single-port surgery. AB - We report a very rare case of acute abdomen caused by torsion of an accessory spleen that was preoperatively diagnosed and cured by single-port surgery. A 31 year-old woman was admitted to our hospital with severe left abdominal pain. Physical examination revealed a left upper quadrant abdominal tenderness with voluntary guarding. Ultrasound demonstrated a well-defined round mass isoechoic to the spleen, measuring 3.0 cm in diameter in the left upper quadrant adjacent to the spleen. A contrast-enhanced CT scan showed a normally enhanced spleen and a 3.0 * 3.0, hypodense, non-enhancing mass anterior to the spleen with a twisted funicular structure. Torsion of an accessory spleen was suspected, and emergency single-port surgery was performed. During surgery, a rounded violet mass measuring 3.0 cm in diameter, suggestive of an accessory spleen, with a 1800 degrees torsion around a long vascular pedicle along the left side of the greater omentum was discovered. The mass was removed and post-operative recovery was uneventful. A review of the literature revealed 26 cases (including ours) of torsion of an accessory spleen in English. Even with the recent advances in radiologic imaging modalities, making a preoperative diagnosis of this is difficult and most cases are diagnosed during laparotomy. This is the first report preoperatively diagnosed and cured by single-port surgery. We decided to start the operation by using a single port, not only for cosmetic reasons for this young female patient, but also for final confirmation of our diagnosis. We believe that single-port laparoscopy is valuable as a diagnostic tool as long as safety is assured for patients with acute abdomen. Although torsion of an accessory spleen is extremely rare, it should be considered in the differential diagnosis of acute abdomen in children and young adults. PMID- 26943426 TI - A rare combination of pheochromocytoma and gastrointestinal stromal tumour in a patient with neurofibromatosis 1 syndrome-a case report. AB - Neurofibromatosis 1 is a rare inherited autosomal dominant syndrome. It comprises 90 % of neurofibromatosis cases. These patients may develop various types of tumours in early age, especially multiple neurofibromas with a high risk of developing malignant peripheral nerve sheath tumours. Other tumours can also develop like pheochromocytoma, optic nerve and brain stem gliomas, carcinoids and rarely gastrointestinal stromal tumours. A combination of pheochromocytoma and gastrointestinal stromal tumour is very rare. Only a few cases have been reported. Here, we are reporting a case of NF1 syndrome with a combination of pheochromocytoma and gastrointestinal stromal tumour with additional findings of multiple clear cell nodules and brown fat in the periadrenal connective tissue. PMID- 26943427 TI - Paget's disease of the male breast: a case report. AB - The patient was a 91-year-old man with change in nipple appearance, itching and redness, and a palpable breast mass. At presentation, mammary Paget's disease (PD) was clinically suspected. Skin biopsy was performed and showed epidermis invaded by Paget cells, characterized by hyperchromatic nuclei and abundant pale staining cytoplasm. Computed tomography and mammary ultrasonography confirmed the absence of an underlying invasive carcinoma, and the patient underwent right mastectomy and sentinel lymph node biopsy (SLNB). Both sentinel lymph nodes were found to be negative perioperatively, and further axillary dissection was not performed. Pathological results revealed no malignancy under the nipple, yet the Paget cells were more widely spread than expected. The patient was followed up without the need of postoperative chemotherapy. Male mammary PD is an extremely rare breast cancer, and there is no standard preoperative assessment or operative procedure. Mammography is many times unable to detect possible underlying breast carcinoma in female patients with mammary PD, and previous studies have reported that the detection rate was less than 50 %. However, some researchers reported that magnetic resonance imaging (MRI) might be more detectable to confirm the extent of the cancer. The extent of the skin change around the nipple is often different from the actual perimeter of Paget cells. In extra-mammary PD, mapping biopsy is known to be useful to determine areas free of cancer. The benefits of SLNB have also been demonstrated for the management of less invasive breast cancers, and previous reports have shown that the use of SLNB is reasonable for treatment of mammary PD without underlying invasive cancer. MRI, mapping biopsy, and SLNB are all less invasive procedures and thus may be suitable for treatment of male mammary PD. PMID- 26943428 TI - Pathogenic mechanisms of intestinal pneumatosis and portal venous gas: should patients with these conditions be operated immediately? AB - We aimed to histologically observe portal venous gas (PVG)-causing intestinal pneumatosis (IP) and evaluate pathogenic mechanisms and therapeutic strategies, including decisions on whether emergency surgery should be performed. Autopsy was performed in two cases of nonocclusive mesenteric ischemia (NOMI). We directly histologically observed the pathogenic mechanisms of IP caused by gas-producing bacteria and IP considered to be caused by mechanical damage to the intestinal mucosa. IP can be classified hypothetically into the following types according to pathogenesis: (1) infection, (2) rupture (damage) of the intestinal mucosa + increased intestinal intraluminal pressure, and (3) mixed type. In cases of IP caused by gas-producing bacteria or IP associated with intestinal wall damage extending beyond the mucosa to the deep muscular layer, emergency surgery should be considered. However, it is highly possible that patients who test negative for infection with gas-producing bacteria whose intestinal wall damage remains only in the mucosa can be conservatively treated. PMID- 26943429 TI - Multiple skeletal muscle metastases from poorly differentiated gastric adenocarcinoma. AB - We report here a rare case of gastric carcinoma with multiple intramuscular metastases. A 71-year-old man presented with rapidly evolving swelling of his left thigh and severe pain. Three years earlier, he had undergone neoadjuvant chemotherapy followed by gastrectomy for advanced gastric cancer. A computed tomography scan showed unusual swellings in multiple skeletal muscles with no vessel or bone invasion. Importantly, the affected muscles did not contain distinct masses but were diffusely enlarged. Pathological examination of an open muscle biopsy showed a poorly differentiated adenocarcinoma, supporting a diagnosis of gastric cancer metastases in multiple skeletal muscles. PMID- 26943430 TI - Spontaneous regression of bronchogenic cyst accompanied by pneumonia. AB - Bronchogenic cysts arise from abnormal budding of the ventral diverticulum of the foregut or tracheobronchial tree during embryogenesis, are the most common cystic masses in the mediastinum, and are generally asymptomatic. A spontaneous regression in a mediastinal bronchogenic cyst (MBC) with pneumonia is rare. A 30 year-old male had a tumor shadow in the middle mediastinum. When he visited our hospital, he had a mild fever with coughing and sputum. A chest computed tomography (CT) scan showed a decrease in the tumor size and the existence of right pneumonia. MBC may be involved in the etiology of pneumonia; therefore, bronchogenic cysts need to be resected as soon as possible. PMID- 26943431 TI - Pseudolymphoma of the liver: a case report and literature review. AB - Pseudolymphoma is a benign lymphocytic tumor-like lesion, and its occurrence in the liver is rare. Here, we report the case of a 78-year-old woman with pseudolymphoma of the liver. She had a history of tremors for several years. Therefore, she underwent computed tomography (CT) for screening, and liver tumors were incidentally identified. She did not have any history of liver disease. Liver function test results and tumor marker levels were all within normal limits, and viral markers for hepatitis were negative. Contrast-enhanced CT revealed four nodules measuring up to 13 mm in diameter with ring enhancement in both lobes of the liver. On magnetic resonance imaging, the lesions showed slightly high intensity on T2-weighted images and high intensity on diffusion weighted images. Because of atypical imaging findings, the tumors could not be definitively diagnosed. Therefore, we performed laparoscopic limited resection of segments 2, 3, 4, and 8 of the liver. The final pathological diagnosis was pseudolymphoma of the liver. The patient has had no signs of recurrence for 6 months after the surgery. Although pseudolymphoma of the liver is rare, it is necessary to consider it in the differential diagnosis of a liver tumor. PMID- 26943432 TI - Internal inguinal hernia on the transplant side after kidney transplantation: a case report. AB - The patient was a 52-year-old man who presented with right inguinal swelling and pain. He had undergone kidney transplantation in 2005 and bypass surgery using a vascular prosthesis from the left axillary artery to the bilateral femoral arteries in 2008. The vascular prosthesis had invaded the right inguinal canal ventrally. The transplanted ureter had a hazy appearance on a non-enhanced abdominal CT scan. A Lichtenstein operation was performed under a diagnosis of inguinal hernia. A skin incision with pulling of tissue and subcutaneous fat was devised to avoid exposure of the vascular prosthesis. The inguinal canal and spermatic cord were found to have coalesced. The hernia was diagnosed as a supravesical hernia, class II-1. This case shows that a Lichtenstein operation is a suitable procedure for avoidance of damage to the transplanted ureter in treatment of a transplant-side inguinal hernia in a kidney transplant recipient. PMID- 26943433 TI - Epiploic gonadal vein as a new bypass route for extrahepatic portal venous obstruction: report of a case. AB - A 61-year-old man was referred to our hospital to treat extrahepatic portal venous obstruction. Endoscopic injection sclerotherapy (EIS) was performed for the esophageal varices; however, the patient returned with massive hematemesis from gastric varices 6 months after treatment. Although the varices were treated with EIS, gastric devascularization and splenectomy concomitant with shunt surgery were required to treat uncontrollable, frequent diarrhea and abdominal distension. Because the splenic vein, left gastric vein, left portal vein, and inferior vena cava were inadequate for anastomosis, an epiploic gonadal vein bypass was performed. The bypass graft remains patent 7 months after surgery, and the patient is in good health without any clinical symptoms. We describe a new bypass route for extrahepatic portal venous obstruction. PMID- 26943434 TI - Multicentric solid pseudopapillary neoplasms of the pancreas diagnosed by endoscopic ultrasound-guided fine needle aspiration: a case report. AB - Solid pseudopapillary neoplasm (SPN) of the pancreas is a rare tumor. This neoplasm usually arises as a single mass; multicentricity is exceptionally rare. We report the preoperative diagnosis of multicentric SPNs by endoscopic ultrasound-guided fine needle aspiration (EUS-FNA). A 32-year-old woman presented to the hospital with a pancreatic tumor that was detected on abdominal echography. Contrast-enhanced computed tomography (CT) scans revealed a 5-mm low density mass in the body of the pancreas and a 10-mm mass in the tail of the pancreas. Magnetic resonance imaging (MRI) also revealed two tumors in the body and tail of the pancreas. On endoscopic ultrasonography (EUS), two indistinct and heterogeneous echogenic masses were found, and EUS-FNA was performed for each of these tumors. Cytological analysis revealed that the two masses were highly cellular with papillary groups of small, uniform, oval cells surrounding a fibrovascular core. Immunohistochemistry was positive for alpha-1 antitrypsin, vimentin, neuron-specific enolase (NSE), CD10, and progesterone receptor. These features confirmed the preoperative diagnosis of multicentric SPNs. The patient underwent laparoscopic distal pancreatectomy with splenectomy. The final pathologic diagnosis was multicentric SPNs. During 2 years of follow-up, she has not developed any recurrence. PMID- 26943435 TI - A 5-year recurrence-free survivor with over ten colorectal liver metastases undergoing FOLFOX plus bevacizumab followed by two-stage hepatectomy. AB - A 62-year-old male was admitted because of lower left abdominal pain and diarrhea. The patient was diagnosed with rectal cancer and multiple liver metastases. First, the laparoscopic Hartmann operation with a D3 lymph node dissection was performed. After five cycles of folinic acid, 5-fluorouracil and oxaliplatin (FOLFOX) and bevacizumab, and one additional FOLFOX, the tumor markers dramatically decreased; with carcinoembryonic antigen levels ranging from 1096.3 to 7.6 ng/ml and carbohydrate antigen 19-9 levels ranging from 3248.0 to 42.1 U/ml. Computed tomography showed a bilateral 14 colorectal liver metastases which indicated stable disease by the Response Evaluation Criteria In Solid Tumors (RECIST) criteria and optimal morphologic response. A two-stage hepatectomy was performed to complete a curative resection because of the insufficient remnant liver volume. Five partial hepatic resections in the left liver and the right portal vein ligation were performed during the first operation. Thirty-four days later, a right hepatectomy was successfully performed. Pathologically, there was tumor necrosis in 90 percent of the area of the metastasized liver, and viable cells were detected in only a marginal part of the liver. The patient had an uneventful postoperative course and was discharged fifteen days after the second operation. Uracil-tegafur plus leucovorin was administered for 6 months as an adjuvant chemotherapy treatment. The patient is currently alive and has remained disease-free for more than 5 years. In conclusion, an ideal combination of perioperative chemotherapy and curative resection may provide a chance of long-term survival without recurrence of disease for selected patients with more than ten bilateral colorectal liver metastases. PMID- 26943436 TI - Intra-aortic balloon pump-assisted major hepatectomy in a case with coronary disease. AB - Clinically, we often encounter cancer patients who also have cardiovascular disease such as coronary artery disease. We experienced a case of severe coronary artery disease and a large hepatocellular carcinoma in a 69-year-old man. To reduce the risk of a perioperative cardiovascular event during mesohepatectomy, an elective intra-aortic balloon pump (IABP) was used. After an uneventful recovery, the patient was discharged on day 15. While IABP is frequently introduced in cardiac surgery, there have been few reports of its use during liver surgery. Here, we present IABP-assisted major hepatectomy as an option in a patient with both cancer and coronary artery disease. PMID- 26943437 TI - Laparoscopic ovarian transposition prior to pelvic irradiation in a young female patient with advanced rectal cancer. AB - In the report, we describe the first case of laparoscopic ovarian transposition prior to pelvic radio-chemo therapy in a young female patient with advanced rectal cancer in Japan. A 14-year-old female visited a hospital because of consistent diarrhea and melena. Colonoscopy examination showed a bulky tumor of the rectum, which was diagnosed as moderately to poorly differentiated adenocarcinoma. The diagnosis was cT3N2aM1a (due to lymph node in pelvic side wall), cStage IVA. In an attempt to improve local control and sphincter preservation, neoadjuvant concurrent radio-chemo therapy was planned. Considering that pelvic irradiation particularly in young female might cause ovarian failure, laparoscopic ovarian transposition was carried out prior to pelvic irradiation. Sequentially the patient underwent low anterior resection of the rectum and lymphadenectomy including pelvic side wall. The menstruation was maintained with delay for 6 months after adjuvant chemotherapy. There is no evidence of cancer recurrence at 3 years after the surgery.In premenopausal patients with rectal cancer undergoing pelvic irradiation, laparoscopic ovarian transposition is one of the choices to prevent ovarian failure. PMID- 26943438 TI - Adenocarcinoma arising from jejunal ectopic pancreas mimicking peritoneal metastasis from colon cancer: a case report and literature review. AB - Adenocarcinoma arising from jejunal ectopic pancreas is very rare. We report a case of a 69-year-old female with adenocarcinoma arising from jejunal ectopic pancreas after resection of advanced colon cancer. She underwent right hemicolectomy for advanced ascending colon cancer (ypT3N0M0, stage IIA) after chemotherapy. Two and half years after colectomy, her tumor markers were elevated, and computed tomography revealed a mass measuring 20 * 20 mm in the small intestine, having an abnormal uptake of (18)F-fluorodeoxyglucose on (18)F fluorodeoxyglucose-positron emission tomography ((18)FDG-PET). Double-balloon enteroscopy revealed a submucosal tumor in the jejunum, and histopathology of biopsy specimens from that lesion showed ectopic pancreas without malignancy. Therefore, peritoneal metastasis from colon cancer concomitant with ectopic pancreas or adenocarcinoma arising from ectopic pancreas was considered as a differential diagnosis. She underwent laparoscopic jejunectomy. Pathological examination revealed a moderately differentiated adenocarcinoma arising from jejunal ectopic pancreas, not peritoneal metastasis from colon cancer. Even if histopathology of the biopsy specimen shows ectopic pancreas without malignancy, adenocarcinoma arising from ectopic pancreas should be considered when the tumor markers are elevated or the lesion has an abnormal uptake of (18)FDG. PMID- 26943439 TI - Comments on Saint's triad. AB - Yamanaka et al. described two case studies involving coexistent cholelithiasis, hiatal hernia, and umbilical hernias, and discussed clinical similarities with the classical features of the Saint's triad. Cholelithiasis, hiatal hernia, and colonic diverticulosis characterize the classical triad, but some authors have included any type of hernia due to herniosis-a developmental disorder of the extracellular matrix. The main features of this triad, which seem to be underdiagnosed and/or underreported, are discussed. Therefore, the commented manuscript contributed to better understanding the scarcely reported condition. PMID- 26943440 TI - Report of a case with T1a gallbladder poorly differentiated adenocarcinoma, solid type, which developed into lymph node metastases. AB - We experienced a case with gallbladder carcinoma growing limited to the mucosa (T1a), which developed massive lymphatic vessel spread and lymph node metastases.A 72-year-old man was referred to our hospital for the swelling of his gallbladder during a routine ultrasound sonography checkup. We diagnosed the patient with gallbladder carcinoma with lymph node metastasis according to the radiographic findings and performed the open cholecystectomy and lymph node dissection. A histological examination showed poorly differentiated adenocarcinoma, solid type, and the tumor was limited to the mucosa. The number of lymphatic vessels was increased in the tumor and peritumor areas, and cancer cells were observed in the lymphatic vessels, which were detected via D2-40 immunohistochemistry. A careful histological examination and follow-up is required for T1a gallbladder carcinoma. PMID- 26943442 TI - A case of IgG4-related disease coexisted with rectal cancer. AB - A 67-year-old man was referred to our hospital with suspicion of rectal tumor, hilar tumor, and urinary tumor. Colonoscopic findings were intermittent nodular lesions with redness which were atypical to primary rectal cancer. Endoscopic retrograde cholangiopancreatography showed narrowing of the bilateral intrahepatic bile duct. However, the findings were improved 1 month later. Blood biochemistry showed high level of serum IgG4 up to 1140 mg/dl. The patient matched to comprehensive diagnostic criteria for IgG4-related disease as a possible diagnostic case. Laparoscopic low anterior resection with creation of ileostomy was performed for rectal cancer. Histological findings revealed cancer cells spread horizontally at submucosal layer and subserosal layer. There was marked infiltration of the plasma cells and lymphocytes at tumor stroma, and more than half of the plasma cells were positive for IgG4. After surgery, the level of serum IgG4 was decreased to 597 mg/dl. Although the association with IgG4-related disease and colorectal disease is unclear, the tumor progression was atypical for rectal cancer. Some report that the disease may rise up the risk of a malignant disease. It is necessary to perform systemic examination keeping in mind for concurrence of malignancy. PMID- 26943441 TI - Endoscopic biliary drainage as a bridging procedure to single-stage surgery for perforated choledochal cyst: a case report and review of the literature. AB - Choledochal cyst (CC)-a congenital anomaly of the bile duct-is rare. We report a 28-year-old woman complaining of epigastralgia who was transferred to our hospital. Physical examination revealed severe tenderness to abdominal palpation without symptoms of diffuse peritonitis. Urgent contrast-enhanced abdominal computed tomography indicated the dilated common bile duct (CBD) was perforated, with a presumed diagnosis of perforated CC. Endoscopic external biliary drainage was performed immediately as a bridging procedure to the definitive surgery. Additional evaluations confirmed a type IVa CC, according to Todani's classification, but no signs of malignancy. Twenty-two days after biliary drainage, laparotomy was performed. A large cystic mass was found in the CBD with a perforated scar on the right-side wall. Because inflammation around the pancreas head was too severe to perform cyst excision safely, the patient underwent subtotal stomach-preserving pancreatoduodenectomy. The postoperative course was uneventful, and the patient was discharged on the 29th postoperative day. Pathologic examination of a specimen showed no malignancy, and the patient has remained well during the 3-year follow-up. Our experience with this case suggests that definitive single-stage surgery for perforated CC in an adult can be performed safely owing to external biliary drainage as a bridging procedure, if manifestation of diffuse peritonitis is not evident. PMID- 26943443 TI - A case of adenoid cystic carcinoma of the esophagus. AB - Esophageal adenoid cystic carcinoma (EACC) is a very rare form of malignant tumor in the esophagus. Here, we report the case of a 78-year-old man who was diagnosed with EACC by preoperative endoscopic biopsy. Thoracoscopy-assisted subtotal esophagectomy with lymph node dissection was carried out. Microscopic examination of the resected specimen suggested that the tumor invaded to submucosal layer and showed no lymph node metastasis. Histologically, tumor primarily exhibited an alveolar solid pattern with partial cribriform and tubular patterns. Alcian blue staining showed many mucoid materials within the glandular cavity formed by tumor cells. Immunohistochemical studies revealed that the tumor cells reacted with pan cytokeratin immunostains and expressed vimentin and S-100 protein. Collectively, the tumor was diagnosed as primary EACC, T1bN0M0 according to "Japanese Classification of Esophageal Cancer 10th edition." The patient showed no recurrence sign 12 months after the surgery.The current study also reviewed 35 EACC cases reported in Japanese literatures from 1990 to 2014. Combined with our case, we found that EACC is less frequently accompanied by lymph node metastasis as compared to esophageal squamous cell carcinoma, especially at the early stage. The prognosis of EACC is relatively better when tumors have no lymph node metastasis. PMID- 26943445 TI - Malignant phyllodes tumor metastasized to the right ventricle: a case report. AB - Cardiac metastasis of malignant phyllodes tumor is very rare. We herein report a rare case that developed cardiac metastasis from malignant phyllodes tumor. A 38 year-old woman underwent lumpectomy, and the final pathological findings showed the 5-cm malignant phyllodes tumor partially containing 1 cm of squamous cell carcinoma. Four months after the first surgery, a local recurrence of malignant phyllodes tumor and distant metastases to the bone, lung, pulmonary main trunk, and right ventricle were detected. Mass reduction surgery of cardiac metastasis of the malignant phyllodes tumor was performed to avoid sudden death. In immunohistochemical findings, the tumor was suspected to be originated in myoepithelial cells because of the expression of smooth muscle lineage including alpha-smooth muscle actin and Calponin1 and highly malignant characteristics showing MIB-1 and p53 highly positive with angiogenesis. Further studies are needed to clarify the effective treatment to these tumors. PMID- 26943444 TI - Immunoglobulin G4-related sclerosing cholecystitis presenting as gallbladder cancer: a case report. AB - Immunoglobulin G4 (IgG4)-related sclerosing disease is a systemic inflammatory syndrome, and an understanding of its characteristics is currently evolving. IgG4 related cholecystitis is a manifestation of IgG4-related sclerosing disease in the gallbladder. This case report describes the clinical, radiographic, and histopathological findings in a young male patient who presented with a synchronous mass in the gallbladder. Serum levels of IgG4 and the IgG4/IgG ratio were normal, and there was no associated autoimmune pancreatitis. Therefore, establishing a preoperative diagnosis of IgG4-related cholecystitis was very difficult, and a differential diagnosis of gallbladder cancer infiltrating the liver was suggested. Postoperative histopathological examination established a diagnosis of IgG4-related cholecystitis definitively. A preoperative diagnosis of IgG4-related cholecystitis, although possible, would have been highly challenging in this case. It is difficult to establish whether surgical intervention is necessary in IgG4-related cholecystitis. Because malignant tumors are frequently suspected with this clinical presentation, surgical intervention should be undertaken only after due deliberation. PMID- 26943446 TI - Pyoderma gangrenosum in an abdominal surgical site: a case report. AB - Pyoderma gangrenosum (PG) is an uncommon, ulcerative skin disease that is often associated with systemic diseases. Herein, we report a development of PG in a surgical site after cholecystectomy that was difficult to discriminate from surgical site infection. The patient was a 74-year-old man who had previously been diagnosed with myelodysplastic syndrome (MDS). Laparoscopic cholecystectomy was planned under diagnosis of cholecystolithiasis, but we converted to open cholecystectomy. The surgical wound was partially erythematous 4 days after surgery. In spite of opening the wound, cleansing it with sterile saline, and administration of antibiotics, inflammation spread with erosion. The clinical manifestations and histopathologic features of biopsy specimen indicated that diagnosis of PG associated with MDS was most likely. Administration of glucocorticoids made a rapid response of skin inflammation. The differential diagnosis of postoperative wound healing complications that were unresponsive to conventional wound local care and antibiotic therapy should include PG, especially in patients with systemic diseases such as MDS. PMID- 26943447 TI - A case of metastatic carcinoma of anal fistula caused by implantation from rectal cancer. AB - This case involved an 80-year-old man who was seen for melena. Further testing revealed a tubular adenocarcinoma 50 mm in size in the rectum. In addition, an anal fistula was noted behind the anus along with induration. A biopsy of tissue from the external (secondary) opening of the fistula also revealed adenocarcinoma. Nodules suspected of being metastases were noted in both lung fields. The patient was diagnosed with rectal cancer, a cancer arising from an anal fistula, and a metastatic pulmonary tumor, and neoadjuvant chemotherapy was begun. A laparoscopic abdominoperineal resection was performed 34 days after 6 cycles of mFOLFOX-6 therapy. Based on pathology, the rectal cancer was diagnosed as moderately differentiated adenocarcinoma, and this adenocarcinoma had lymph node metastasis (yp T3N2aM1b). There was no communication between the rectal lesion and the anal fistula, and a moderately differentiated tubular adenocarcinoma resembling the rectal lesion was noted in the anal fistula. Immunohistochemical staining indicated that both the rectal lesion and anal fistula were cytokeratin 7 (CK7) (-) and cytokeratin 20 (CK20) (+), and the patient's condition was diagnosed as implantation of rectal cancer in an anal fistula.In instances where an anal fistula develops in colon cancer, cancer implantation in that fistula must also be taken into account, and further testing should be performed prior to surgery. PMID- 26943448 TI - Spontaneous clearance of hepatitis C virus after liver transplantation: a report of four cases. AB - End-stage liver disease associated with hepatitis C virus (HCV) infection is the leading indication for liver transplantation. Hepatitis C virus infection recurrence in the graft is common under immunosuppression, leading to an accelerated rate of graft failure. We report the clinical features of four of our patients: three patients presenting with spontaneous hepatitis C virus clearance after liver transplantation and one presenting with transient disappearance of hepatitis C virus postoperatively. The transitional period from surgery to hepatitis C virus clearance was <5 months for all patients. The immunosuppression therapy included tacrolimus, mycophenolate mofetil, and corticosteroids. One ABO incompatible patient presented spontaneous viral clearance postoperatively for the last 5 years. Two patients had episodes of severe bacterial infection, which resulted in a temporary reduction of immunosuppression. Two patients presented with a transient elevation of transaminase preceding spontaneous hepatitis C virus clearance. These clinical findings suggested that factors including surgical stress, severe bacterial infection, and temporary interruption of immunosuppression were correlated with the reactivation of nonspecific immune responses in the hosts, resulting in spontaneous hepatitis C virus clearance postoperatively. PMID- 26943449 TI - Long-term survival of a patient with small cell carcinoma of the stomach with metachronous lung metastases treated by multimodal therapy: a case report. AB - A 69-year-old man was referred to our institution for treatment of gastric cancer. Type 2 gastric cancer was found on the anterior wall of the lower body of the stomach.The patient underwent distal gastrectomy, D2 lymph node dissection, and Roux-en-Y reconstruction with curative resection. The tumor was diagnosed as a small cell carcinoma of the stomach. Recurrence occurred in the lung after surgery. The patient underwent several chemoradiation therapy regimens, including cisplatin + irinotecan + radiation, S-1 + paclitaxel, amrubicin, carboplatin + etoposide, nogitecan, and docetaxel for lung metastases and radiation for brain and bone metastases for 43 months. He finally died of brain metastases 74 months after surgery (47 months after recognition of the lung metastases). Long continuous multimodal treatment including surgery, regimens for small cell lung cancer, S-1, taxanes, and radiation was thought to prolong the survival of this man with small cell carcinoma of the stomach. PMID- 26943450 TI - Postoperative elevation of CA15-3 due to pernicious anemia in a patient without evidence of breast cancer recurrence. AB - Cancer antigen 15-3 (CA15-3) is considered as a marker for breast cancer recurrence. However, we encountered a case where the patient showed postoperative elevation of the CA15-3 level due to pernicious anemia without evidence of breast cancer recurrence. The patient was a 60-year-old postmenopausal woman. She had undergone partial mastectomy and sentinel lymph node biopsy (SLNB) for her T1 left breast cancer. SLNB had indicated no lymph node metastases. The tumor was positive for hormone receptors and negative for human epidermal growth factor receptor 2. Therefore, an aromatase inhibitor and external beam irradiation had been administered as adjuvant therapy. However, the CA15-3 level was found to be elevated at 6 months postoperatively. Although imaging studies did not indicate breast cancer recurrence, CA15-3 levels continued to increase. Based on the findings of blood tests and gastroendoscopy, a diagnosis of pernicious anemia due to vitamin B12 deficiency was finally confirmed at 2 years and 6 months postoperatively. The CA15-3 level returned to normal after vitamin B12 administration. The possibility of pernicious anemia should be considered in cases of postoperative elevated CA15-3 levels with no evidence of recurrence in patients with early breast cancer. PMID- 26943451 TI - "I'm Going to Shut Down All of Your Tricks": Depictions of Treatment Professionals in Addiction Entertainment. AB - BACKGROUND: Previous research on addiction themed reality television shows has focused on the depiction of addiction and treatment and has concluded that these shows reinforce stigma. Existing research has not investigated the depiction of treatment professionals in these series. OBJECTIVES: This study fills the gap in existing research by analyzing the representations of treatment professionals in reality television shows, including the ways that the shows are edited, the statements made by treatment professionals, and interactions between treatment professionals and laypersons. METHODS: The data for this study was drawn from two popular reality shows Intervention and Celebrity Rehab with Dr. Drew. Using a total of 117 episodes, a qualitative content analysis of the representations of treatment professionals in the two series was conducted. RESULTS: The data reveal the ways that depictions of treatment professionals are carefully controlled compared to those of people with substance use issues. In addition, treatment professionals are granted opportunities to interpret, explain, and diagnose the behaviors and experiences of people with substance use problem. Finally, when confronted with resistance treatment professionals assert their authority and demand compliance with their orders. CONCLUSIONS/IMPORTANCE: In strategically presenting treatment professionals in sharp contrast to people with substance use problems, these portrayals of treatment professionals actually reinforce rather than contradict the stigma of addiction. PMID- 26943452 TI - Modeling Impaired Hippocampal Neurogenesis after Radiation Exposure. AB - Radiation impairment of neurogenesis in the hippocampal dentate gyrus is one of several factors associated with cognitive detriments after treatment of brain cancers in children and adults with radiation therapy. Mouse models have been used to study radiation-induced changes in neurogenesis, however the models are limited in the number of doses, dose fractions, age and time after exposure conditions that have been studied. The purpose of this study is to develop a novel predictive mathematical model of radiation-induced changes to neurogenesis using a system of nonlinear ordinary differential equations (ODEs) to represent the time, age and dose-dependent changes to several cell populations participating in neurogenesis as reported in mouse experiments exposed to low-LET radiation. We considered four compartments to model hippocampal neurogenesis and, consequently, the effects of radiation treatment in altering neurogenesis: (1) neural stem cells (NSCs), (2) neuronal progenitor cells or neuroblasts (NB), (3) immature neurons (ImN) and (4) glioblasts (GB). Because neurogenesis is decreasing with increasing mouse age, a description of the age-related dynamics of hippocampal neurogenesis is considered in the model, which is shown to be an important factor in comparisons to experimental data. A key feature of the model is the description of negative feedback regulation on early and late neuronal proliferation after radiation exposure. The model is augmented with parametric descriptions of the dose and time after irradiation dependences of activation of microglial cells and a possible shift of NSC proliferation from neurogenesis to gliogenesis reported at higher doses (~10 Gy). Predictions for dose-fractionation regimes and for different mouse ages, and prospects for future work are then discussed. PMID- 26943453 TI - Impaired Spatial Memory Performance in Adult Wistar Rats Exposed to Low (5-20 cGy) Doses of 1 GeV/n (56)Fe Particles. AB - Prolonged deep space missions to planets and asteroids will expose astronauts to galactic cosmic radiation, comprised of low-linear energy transfer (LET) ionizing radiations, high-energy protons and high-Z and energy (HZE) particles, such as (56)Fe nuclei. In prior studies with rodents exposed to HZE particle radiation at doses likely to be encountered during deep space missions (<20 cGy) investigators reported impaired hippocampal-dependent neurocognitive performance and further observed substantial variation among the irradiated animals in neurocognitive impairment, ranging from no observable effects to severe impairment. These findings point to the importance of incorporating quantitative measures of interindividual variations into next generation risk assessment models of radiation risks on neurocognition. In this study, 269 male proven breeder Wistar rats were exposed to 1 GeV/n (56)Fe at doses of 0, 5, 10, 15 and 20 cGy, and tested for spatial memory performance on the Barnes maze at three months after exposure. The radiation response data were compared using changes in mean cohort performance and by the proportion of poor responders using the performance benchmark of two standard deviations below the mean value among the sham irradiated cohort. Acute exposures to mission-relevant doses of 1 GeV/n (56)Fe reduced the mean spatial memory performance at three months after exposure (P < 0.002) and increased the proportions of poor performers, 2- to 3-fold. However, a substantial fraction of animals in all exposure cohorts showed no detectable change in performance, compared to the distribution of sham-irradiated animals. Our findings suggest that individualized metrics of susceptibility or resistance to radiation-induce changes in neurocognitive performance will be advantageous to the development of probabilistic risk assessment models for HZE-induced neurocognitive impairment. PMID- 26943455 TI - Enhancement of oral insulin bioavailability: in vitro and in vivo assessment of nanoporous stimuli-responsive hydrogel microparticles. AB - OBJECTIVE: Oral insulin administration suffers gastrointestinal tract (GIT) degradation and inadequate absorption from the intestinal epithelium resulting in poor bioavailability. This study entails in vitro and in vivo assessment of stimuli-responsive hydrogel microparticles (MPs) in an attempt to circumvent GI barrier and enhance oral insulin bioavailability. METHODS: Bacterial cellulose-g poly(acrylic acid) (BC-g-P(AA)) hydrogel MPs were evaluated for morphology, swelling, entrapment efficiency (EE), in vitro insulin release and enzyme inhibition. The ex vivo mucoadhesion, insulin degradation and transport were investigated in excised intestinal tissues. The effect of MPs on paracellular transport was studied in Caco-2/HT29-MTX monolayers. The in vivo hypoglycemic effect and pharmacokinetics of insulin-loaded MPs were investigated in diabetic rats. RESULTS: Hydrogel MPs efficiently entrapped insulin (EE up to 84%) and exhibited pH-responsive in vitro release. The MPs decreased the proteolytic activity of trypsin (up to 60%). Insulin transport across monolayers was increased up to 5.9-times by MPs. Histological assessment of GI tissues confirmed the non-toxicity of MPs. Orally administered insulin-loaded MPs showed higher hypoglycemic effect as compared to insulin solution and enhanced relative oral bioavailability of insulin up to 7.45-times. CONCLUSION: These findings suggest that BC-g-P(AA) MPs are promising biomaterials to overcome the barriers of oral insulin delivery and enhancing its bioavailability. PMID- 26943454 TI - Neural correlates of self-perceptions in adolescents with major depressive disorder. AB - Alteration in self-perception is a salient feature in major depression. Hyperactivity of anterior cortical midline regions has been implicated in this phenomenon in depressed adults. Here, we extend this work to depressed adolescents during a developmental time when neuronal circuitry underlying the sense of self matures by using task-based functional magnetic resonance imaging (fMRI) and connectivity analyses. Twenty-three depressed adolescents and 18 healthy controls (HC) viewed positive and negative trait words in a scanner and judged whether each word described them ('self' condition) or was a good trait to have ('general' condition). Self-perception scores were based on participants' endorsements of positive and negative traits during the fMRI task. Depressed adolescents exhibited more negative self-perceptions than HC. Both groups activated cortical midline regions in response to self-judgments compared to general-judgments. However, depressed adolescents recruited the posterior cingulate cortex/precuneus more for positive self-judgments. Additionally, local connectivity of the dorsal medial prefrontal cortex was reduced during self reflection in depressed adolescents. Our findings highlight differences in self referential processing network function between depressed and healthy adolescents and support the need for further investigation of brain mechanisms associated with the self, as they may be paramount to understanding the etiology and development of major depressive disorder. PMID- 26943456 TI - Outcomes and management of lenalidomide-associated rash in patients with multiple myeloma. AB - The immunomodulatory drugs thalidomide, lenalidomide, and pomalidomide (IMiDs) are an important component of myeloma treatment; one of six available drug classes for this incurable disease. Rash is a frequent side effect of IMiDs, particularly lenalidomide, often leading to treatment discontinuation. We retrospectively reviewed 52 patients (7.2% of patients seen during that time) with IMiD associated at a median of 3 weeks after exposure. Nearly all rashes were morbilliform, and 45% of evaluable rashes were grade 3-4 by NCI-CTCAE criteria. IMiDs were initially held in 33 patients (62%), and 25% received a short course of higher dose steroids. Seventy-nine percent of patients were reexposed to the same IMiD, often with dose reduction, and 57% were switched from weekly dexamethasone to thrice-weekly prednisone. Ninety-three percent of patients reexposed to the same IMiD with these interventions were able to tolerate and continue treatment, and only 14% had rash with reexposure, predominantly grade 1-2. PMID- 26943457 TI - A new look at the ALK gene in cancer: copy number gain and amplification. AB - To date, ALK-rearrangement is a molecular target in several cancers, i.e. NSCLC. The dramatic benefits of crizotinib have prompted research into identifying other possible patients carrying ALK gene alterations with possible clinical significance. The ALK gene is involved not only in several rearrangements but also in other alterations such as amplification. ALK-amplification (ALK-A) is a common genetic event in several cancers, generally associated with poor outcome and more aggressive behaviour. Here we review the role of ALK-A in cancer as a prognostic and predictive biomarker. Furthermore, several critical issues regarding ALK-A in relation to; methods of detection, acquired resistance and ALK second generation inhibitors are analyzed. We conclude that ALK-A could be an intriguing alteration in the context of targeted therapy. PMID- 26943458 TI - State-to-State Dynamics of the Ne + HeH(+) (v = 0, j = 0) -> NeH(+)(v', j') + He Reaction. AB - The dynamics of the Ne + HeH(+)(v = 0, j = 0) -> NeH(+)(v', j') + He reaction was analyzed in detail at the state-to-state level. A time-independent quantum mechanical (TIQM) method was applied to calculate rovibrational distributions and differential cross sections (DCSs), in comparison with quasi-classical trajectory and statistical quantum predictions. Possible changes in the dynamical mechanisms that define the process were also investigated as a function of the collision energy. At the lowest energy regime, the TIQM results produce a noticeably different cross section in comparison with previously reported time-dependent wave packet results. Although the statistical methods reproduce some dynamical features, especially as the energy increases, the marked preference for the forward scattering direction on the DCSs suggests that the reaction mainly follows a direct mechanism. PMID- 26943459 TI - Wernicke's aphasia and attempted suicide. PMID- 26943461 TI - A 15-year-old with seizures: late diagnosis of pyridoxine-dependent epilepsy. PMID- 26943460 TI - Spontaneous intracranial hypotension with pseudo-subarachnoid hemorrhage. PMID- 26943462 TI - Factors affecting the quality of life in drug-resistant epilepsy patients. AB - Epilepsy patients whose seizures cannot be controlled by treatment have a lower quality of life (QoL). The aim of the present study was to compare the potential factors affecting the QoL in patients who were seizure-free with medication or who had drug-resistant epilepsy. The study included 46 drug-resistant and 42 seizure-free epilepsy patients. The demographic and clinical features of the patients were investigated for their effects on patient QoL. The QoL was assessed by the QoL in Epilepsy Inventory-89 and depression was detected by the Beck Depression Inventory. The QoL was significantly lower in the drug-resistant patients than in the seizure-free epilepsy patients (p < 0.001). Depression, lower education level, and unemployment were associated with lower QoL scores (p < 0.001, p < 0.01, p < 0.001, respectively). After adjusting for lower education level and unemployment, depression remained as an independent factor affecting QoL (p < 0.05). In addition to their efforts to control and stop seizures, clinicians should remain aware of depression and treat it effectively to improve the QoL of drug-resistant epilepsy patients. PMID- 26943464 TI - Delta Activity at Sleep Onset and Cognitive Performance in Community-Dwelling Older Adults. AB - STUDY OBJECTIVES: Frontal intermittent rhythmic delta activity (FIRDA) has long been considered to be an abnormal variant in the electroencephalogram (EEG) among older adults. Prior work also indicates a predominance of slow wave EEG activity among patients with dementia. However, instability of state control occurring with aging generally and among many neurodegenerative diseases raises the possibility that FIRDA might represent the intrusion of sleep related elements of the EEG into the waking state. We examined delta activity at sleep onset (DASO) in community-dwelling, older adults without dementia, and examined whether this activity is related to poorer cognitive performance. METHODS: 153 community dwelling, older adults without dementia underwent overnight polysomnography and measures of global cognition, delayed verbal memory, information processing speed, attention, inhibition, verbal naming, and visuospatial ability. Delta activity during sleep/wake transitions (scored either as Waking or N1) was analyzed visually. RESULTS: Participants were 83 women and 70 men, mean age 71.3 +/- 0.6 y. DASO was present in 30 participants (19.6%). Age, years of education, sex, and body mass index did not differ between DASO (+) and (-) groups. Multiple regression analyses indicated faster reading of the Stroop color words in DASO (+) subjects (P = 0.007). None of the other cognitive domains differed between the two groups. CONCLUSIONS: DASO was relatively common in our sample of community-dwelling, older adults without dementia. DASO was not associated with poorer performance on any cognitive domain. Instead, individuals with DASO demonstrated better performance on a simple reading task. Although these findings suggest that an abnormal EEG activity may represent normal variation, our work underscores the importance of distinguishing DASO from FIRDA when examining sleep in older adults. COMMENTARY: A commentary on this article appears in this issue on page 725. PMID- 26943463 TI - Hybrid surgical guidance based on the integration of radionuclear and optical technologies. AB - With the evolution of imaging technologies and tracers, the applications for nuclear molecular imaging are growing rapidly. For example, nuclear medicine is increasingly being used to guide surgical resections in complex anatomical locations. Here, a future workflow is envisioned that uses a combination of pre operative diagnostics, navigation and intraoperative guidance. Radioguidance can provide means for pre-operative and intraoperative identification of "hot" lesions, forming the basis of a virtual data set that can be used for navigation. Luminescence guidance has shown great potential in the intraoperative setting by providing optical feedback, in some cases even in real time. Both of these techniques have distinct drawbacks, which include inaccuracy in areas that contain a background signal (radioactivity) or a limited degree of signal penetration (luminescence). We, and others, have reasoned that hybrid/multimodal approaches that integrate the use of these complementary modalities may help overcome their individual weaknesses. Ultimately, this will lead to advancement of the field of interventional molecular imaging/image-guided surgery. In this review, an overview of clinically applied hybrid surgical guidance technologies is given, whereby the focus is placed on tracers and hardware. PMID- 26943465 TI - Regional Patterns of Elevated Alpha and High-Frequency Electroencephalographic Activity during Nonrapid Eye Movement Sleep in Chronic Insomnia: A Pilot Study. AB - STUDY OBJECTIVES: To examine nonrapid eye movement (NREM) sleep in insomnia using high-density electroencephalography (EEG). METHODS: All-night sleep recordings with 256 channel high-density EEG were analyzed for 8 insomnia subjects (5 females) and 8 sex and age-matched controls without sleep complaints. Spectral analyses were conducted using unpaired t-tests and topographical differences between groups were assessed using statistical non-parametric mapping. Five minute segments of deep NREM sleep were further analyzed using sLORETA cortical source imaging. RESULTS: The initial topographic analysis of all-night NREM sleep EEG revealed that insomnia subjects had more high-frequency EEG activity (> 16 Hz) compared to good sleeping controls and that the difference between groups was widespread across the scalp. In addition, the analysis also showed that there was a more circumscribed difference in theta (4-8 Hz) and alpha (8-12 Hz) power bands between groups. When deep NREM sleep (N3) was examined separately, the high frequency difference between groups diminished, whereas the higher regional alpha activity in insomnia subjects persisted. Source imaging analysis demonstrated that sensory and sensorimotor cortical areas consistently exhibited elevated levels of alpha activity during deep NREM sleep in insomnia subjects relative to good sleeping controls. CONCLUSIONS: These results suggest that even during the deepest stage of sleep, sensory and sensorimotor areas in insomnia subjects may still be relatively active compared to control subjects and to the rest of the sleeping brain. PMID- 26943466 TI - Inhibition of Orexin Signaling Promotes Sleep Yet Preserves Salient Arousability in Monkeys. AB - STUDY OBJECTIVES: In addition to enhancing sleep onset and maintenance, a desirable insomnia therapeutic agent would preserve healthy sleep's ability to wake and respond to salient situations while maintaining sleep during irrelevant noise. Dual orexin receptor antagonists (DORAs) promote sleep by selectively inhibiting wake-promoting neuropeptide signaling, unlike global inhibition of central nervous system excitation by gamma-aminobutyric acid (GABA)-A receptor (GABAaR) modulators. We evaluated the effect of DORA versus GABAaR modulators on underlying sleep architecture, ability to waken to emotionally relevant stimuli versus neutral auditory cues, and performance on a sleepiness-sensitive cognitive task upon awakening. METHODS: DORA-22 and GABAaR modulators (eszopiclone, diazepam) were evaluated in adult male rhesus monkeys (n = 34) with continuous polysomnography recordings in crossover studies of sleep architecture, arousability to a classically conditioned salient versus neutral acoustical stimulus, and psychomotor vigilance task (PVT) performance if awakened. RESULTS: All compounds decreased wakefulness, but only DORA-22 sleep resembled unmedicated sleep in terms of underlying sleep architecture, preserved ability to awaken to salient-conditioned acoustic stimuli while maintaining sleep during neutral acoustic stimuli, and no congnitive impairment in PVT performance. Although GABAaR modulators induced lighter sleep, monkeys rarely woke to salient stimuli and PVT performance was impaired if monkeys were awakened. CONCLUSIONS: In nonhuman primates, DORAs' targeted mechanism for promoting sleep protects the ability to selectively arouse to salient stimuli and perform attentional tasks unimpaired, suggesting meaningful differentiation between a hypnotic agent that works through antagonizing orexin wake signaling versus the sedative hypnotic effects of the GABAaR modulator mechanism of action. PMID- 26943467 TI - Spontaneous Swallowing during All-Night Sleep in Patients with Parkinson Disease in Comparison with Healthy Control Subjects. AB - STUDY OBJECTIVES: Spontaneous saliva swallows (SS) appear especially during sleep. The rate of SS was rarely investigated in all-night sleep in patients with Parkinson disease (PD). Dysphagia is a frequent symptom in PD, but the rate of SS was never studied with an all-night sleep electroencephalogram (EEG). METHODS: A total of 21 patients with PD and 18 age-matched healthy controls were included in the study. Frequencies of SS and coughing were studied in all-night sleep recordings of patients with PD and controls. During all-night sleep, video-EEG 12 channel recording was used including the electromyography (EMG) of the swallowing muscles, nasal airflow, and recording of vertical laryngeal movement using a pair of EEG electrodes over the thyroid cartilage. RESULTS: The total number of SS was increased while the mean duration of sleep was decreased in PD when compared to controls. Sialorrhea and clinical dysphagia, assessed by proper questionnaires, had no effect in any patient group. The new finding was the so-called salvo type of consecutive SS in one set of swallowing. The amount of coughing was significantly increased just after the salvo SS. CONCLUSIONS: In PD, the rate of SS was not sufficient to demonstrate the swallowing disorder, such as oropharyngeal dysphagia, but the salvo type of SS was quite frequent. This is a novel finding and may contribute to the understanding of swallowing problems in patients with dysphagic or nondysphagic PD. PMID- 26943468 TI - Sleep Disordered Breathing and Risk of Stroke in Older Community-Dwelling Men. AB - STUDY OBJECTIVES: Men with sleep disordered breathing (SDB) may be at increased stroke risk, due to nocturnal hypoxemia, sleep loss or fragmentation, or other mechanisms. We examined the association of SDB with risk of incident stroke in a large cohort of older men. METHODS: Participants were 2,872 community-dwelling men (mean age 76 years) enrolled in the MrOS Sleep Study, which gathered data from 2003 to 2005 at six clinical sites in the Unites States. SDB predictors (obstructive apnea-hypopnea index, apnea-hypopnea index, central apnea index, and nocturnal hypoxemia) were measured using overnight polysomnography. Incident stroke over an average follow-up of 7.3 years was centrally adjudicated by physician review of medical records. RESULTS: One hundred fifty-six men (5.4%) had a stroke during follow-up. After adjustment for age, clinic site, race, body mass index, and smoking status, older men with severe nocturnal hypoxemia (>= 10% of the night with SpO2 levels below 90%) had a 1.8-fold increased risk of incident stroke compared to those without nocturnal hypoxemia (relative hazard = 1.83; 95% confidence interval 1.12-2.98; P trend = 0.02). Results were similar after further adjustment for other potential covariates and after excluding men with a history of stroke. Other indices of SDB were not associated with incident stroke. CONCLUSIONS: Older men with severe nocturnal hypoxemia are at significantly increased risk of incident stroke. Measures of overnight oxygen saturation may better identify older men at risk for stroke than measures of apnea frequency. PMID- 26943469 TI - Cerebrospinal Fluid Orexin A Levels and Autonomic Function in Kleine-Levin Syndrome. AB - STUDY OBJECTIVES: Kleine-Levin syndrome (KLS) is a rare disorder of relapsing sleepiness. The hypothesis was that the syndrome is related to a change in the vigilance peptide orexin A. METHODS: From 2002 to 2013, 57 patients with relapsing hypersomnolence were clinically assessed in a referral academic center in Beijing, China, and 44 (28 males and 16 females; mean age 18.3 +/- 8.9 y (mean +/- standard deviation, range 9-57 y) were determined to have clinical and behavioral criteria consistent with KLS. Cerebrospinal fluid orexin A levels and diurnal blood pressure were measured in relapse versus remission in a subgroup of patients. RESULTS: Presenting symptoms included relapsing or remitting excessive sleepiness-associated parallel complaints of cognitive changes (82%), eating disorders (84%); depression (45%); irritability (36%); hypersexuality (18%); and compulsions (11%). Episodes were 8.2 +/- 3.3 days in duration. In relapse, diurnal values for blood pressure and heart rate were lower (P < 0.001). In a subgroup (n = 34), cerebrospinal fluid orexin A levels were ~31% lower in a relapse versus remission (215.7 +/- 81.5 versus 319.2 +/- 95.92 pg/ml, P < 0.001); in three patients a pattern of lower levels during subsequent relapses was documented. CONCLUSIONS: There are lower orexin A levels in the symptomatic phase than in remission and a fall and rise in blood pressure and heart rate, suggesting a role for orexin dysregulation in KLS pathophysiology. PMID- 26943470 TI - Nonbenzodiazepine Sedative Hypnotics and Risk of Fall-Related Injury. AB - STUDY OBJECTIVES: The objective of this study was to test the hypothesis that use of zolpidem, eszopiclone, and zaleplon would be associated with increased risk of traumatic brain injury (TBI) and hip fracture. METHODS: We conducted a case crossover study on a 5% random sample of Medicare beneficiaries age 65 y or older hospitalized with either TBI (n = 15,031) or hip fracture (n = 37,833) during 2007-2009. Use of zolpidem, eszopiclone, or zaleplon during the 30-day period prior to injury hospitalization was compared to use during four control periods at 3, 6, 9, and 12 mo prior to injury. The primary outcome was hospitalization for TBI or hip fracture. RESULTS: Zolpidem use during the month prior to injury was associated with increased risk of TBI (odds ratio [OR] 1.87; 95% confidence interval [CI] 1.56, 2.25); however, eszopiclone use during the same period was not associated with increased risk (OR 0.67; 95% CI 0.40, 1.13). Zolpidem use during the month prior to injury was associated with increased risk of hip fracture (OR 1.59; 95% CI 1.41, 1.79); however, eszopiclone use during the same period was not associated with increased risk (OR 1.12; 95% CI 0.83, 1.50). Analysis of zaleplon use in the month prior to injury was limited by low drug utilization but was not associated with increased risk of TBI (OR 0.85; 95% CI 0.21, 3.34) or hip fracture (OR 0.92; 95% CI 0.40, 2.13) in this study. CONCLUSIONS: For the treatment of insomnia in older adults, eszopiclone may present a safer alternative to zolpidem, in terms of fall-related injuries. PMID- 26943471 TI - Aberrant Insular Functional Network Integrity in Patients with Obstructive Sleep Apnea. AB - STUDY OBJECTIVES: Obstructive sleep apnea (OSA) is accompanied by tissue injury to the insular cortices, areas that regulate autonomic pain, dyspnea, and mood, all of which are affected in the syndrome. Presumably, the dysregulation of insular-related functions are mediated by aberrant functional connections with other brain regions; however, the integrity of the functional connectivity (FC) to other sites is undescribed. Our aim was to examine resting-state FC of the insular cortices to other brain areas in OSA, relative to control subjects. METHODS: We collected resting-state functional magnetic resonance imaging (MRI) data from 67 newly diagnosed, treatment-naive OSA and 75 control subjects using a 3.0-Tesla MRI scanner. After standard processing, data were analyzed for the left and right insular FC. RESULTS: OSA subjects showed complex aberrant insular FC to several brain regions, including frontal, parietal, cingulate, temporal, limbic, basal ganglia, thalamus, occipital, cerebellar, and brainstem regions. Areas of altered FC in OSA showed linear relationships with magnitudes of sleep related and neuropsychologic-related variables, whereas control subjects showed no such relationships with those measures. CONCLUSIONS: Brain functional connections from insular sites to other brain regions in OSA subjects represent abnormal autonomic, affective, sensorimotor, and cognitive control networks that may affect both impaired parasympathetic and sympathetic interactions, as well as abnormal sensorimotor integration, affected in the condition. The functional changes likely result from the previously reported structural changes in OSA subjects, as demonstrated by diverse neuroimaging studies. PMID- 26943472 TI - Prevalence and Predictors of Prescription Sleep Aid Use among Individuals with DSM-5 Insomnia: The Role of Hyperarousal. AB - STUDY OBJECTIVES: Despite mounting evidence for the overuse of prescription sleep aids (PSA), reliable data on PSA use among insomniacs are unavailable. Current studies focus on trends in PSA use at the general population level, and thus do not distinguish between transient sleep disturbance and insomnia disorder. Therefore, we prospectively examined the prevalence and predictors of baseline and chronic PSA use in a well-defined sample of individuals with insomnia. METHODS: We analyzed longitudinal data from an urban, community-based cohort of 649 adults (48.1 +/- 11.6 y; 69.3% female) with Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5)-based insomnia disorder. Participants completed standardized measures of sleep disturbance, daytime alertness, depression, and anxiety at baseline and follow-up 1 y later. They also reported whether and with what frequency they used PSA at both time points. RESULTS: Approximately 19% of the sample used PSA at baseline, the majority (69.4%) of whom continued use 1 y later. Anxiety and daytime alertness were the only independent predictors of both acute and chronic PSA use. An increase of 1 standard deviation (SD) in alertness was associated with a 33% increase in the odds of chronic PSA use (chi(2) = 4.98; odds ratio [OR] = 1.33; 95% confidence interval [CI]: 1.04-1.72; P < 0.05), and a 1-SD increase in anxiety was associated with a 41% increase (chi(2) = 6.95; OR = 1.41; 95% CI: 1.09-1.82; P < 0.05). Chronic PSA users did not report any significant improvements in sleep from baseline to follow-up relative to nonusers. CONCLUSIONS: Hyperarousal, as indexed by daytime alertness and anxiety, is a strong determinant of PSA use among individuals with insomnia. These findings are consistent with emerging data showing that insomnia is not just a nocturnal sleep disorder, but one characterized by 24-h arousal. Though current research targets sleep disturbance, this study highlights the role of the arousal system in pharmacological treatment seeking. PMID- 26943474 TI - Healthy School Start Times: Can We Do a Better Job in Reaching Our Goals? PMID- 26943475 TI - The Abbreviated Westmead Post-traumatic Amnesia Scale and Pocket Concussion Recognition Tool: Data from amateur sports players in live-match conditions. AB - Sports-related concussion is a growing public health concern. A short, simple sideline assessment tool is essential for evaluation of concussion at an amateur participation level. The current study examined responses to sideline assessment measures in a sample of amateur Australian Rules Football players competing in real-time live matches who had not sustained a concussion on the day of testing. Participants (N = 127) completed the Abbreviated Westmead Post-traumatic Amnesia Scale (A-WPTAS) and the Pocket Concussion Recognition Tool (Pocket CRT), which contains the Maddocks Questions (assessing orientation and recent memory) and the Postconcussion Symptom Scale (PCSS). The study showed 98.4% of participants passed the A-WPTAS, while 81.9% passed the Maddocks Questions. Participants endorsed a mean of 4.16 (SD = 4.02) symptoms on the PCSS, with 86.6% endorsing at least 1 symptom at a mild level or greater and 40.2% endorsing at least 1 symptom at a moderate or severe level. The current results suggest the Maddocks Questions may not be sufficient for use in an amateur sports context. To reduce the risk for a false positive diagnosis of concussion, it is recommended that the Pocket CRT be complemented with the A-WPTAS for use in an amateur sports context. PMID- 26943476 TI - Application of a Brief Measure of Delay Discounting to Examine the Relationship Between Delay Discounting and the Initiation of Substance Use Among Adolescents. AB - BACKGROUND: Higher rate of Delay Discounting (DD) is associated with increased risk for the initiation and development of substance use disorders in adolescents. OBJECTIVES: This study aimed to provide a preliminary assessment of the validity of a brief self-report measure of DD by examining discounting rates across 3 periods of increasing delay and subsequently examining the extent to which overall DD scores are associated with having initiated tobacco, alcohol and cannabis use. METHODS: Data were collected in the 2012 fall cycle of the British Columbia Adolescent Substance Use Survey. The sample consisted of 1,143 adolescents (61% female) in grades 10 and 11. A brief self-report measure of DD was developed to assess the tendency of adolescents to discount a delayed monetary reward of $100 over a period of 1-year, 1-month, and 1-week. The area under the curve was calculated for each participant's DD responses and coded into quartiles. RESULTS: The amount of discounting increased as reward delay increased from 1-week to 1-month to 1-year. Compared to participants in the lowest DD quartile, being in the second, third, or fourth quartile was associated with significantly greater odds of having initiated tobacco use, binge drinking, and cannabis use after controlling for sex, age, maternal education, and ethnicity. CONCLUSIONS: These results provide preliminary support for the validity of the brief measure of DD presented in this study and support the emerging body of evidence suggesting that DD is an important indicator of increased risk for the initiation of substance use among adolescents. PMID- 26943473 TI - Orexin Plays a Role in Growth Impediment Induced by Obstructive Sleep Breathing in Rats. AB - STUDY OBJECTIVES: The mechanisms linking sleep disordered breathing with impairment of sleep and bone metabolism/architecture are poorly understood. Here, we explored the role of the neuropeptide orexin, a respiratory homeostasis modulator, in growth retardation induced in an upper airway obstructed (AO) rat model. METHODS: The tracheae of 22-day-old rats were narrowed; AO and sham control animals were monitored for 5 to 7 w. Growth parameters, food intake, sleep/wake activity, and serum hormones were measured. After euthanasia, growth plate (GP) histology, morphometry, orexin receptors (OXR), and related mediators were analyzed. The effect of dual orexin receptor antagonist (almorexant 300 mg/kg) on sleep and GP histology were also investigated. RESULTS: The AO group slept 32% less; the time spent in slow wave and paradoxical sleep during light period and slow wave activity was reduced. The AO group gained 46% less body weight compared to the control group, despite elevated food intake; plasma ghrelin increased by 275% and leptin level decreased by 44%. The impediment of bone elongation and bone mass was followed by a 200% increase in OX1R and 38% reduction of local GP ghrelin proteins and growth hormone secretagogue receptor 1a. Sry-related transcription factor nine (Sox9), a molecule mediating cartilage ossification, was downregulated and the level of transcription factor peroxisome proliferator-activated receptor gamma was upregulated, explaining the bone architecture abnormalities. Administration of almorexant restored sleep and improved GP width in AO animals. CONCLUSIONS: In AO animals, enhanced expression of orexin and OX1R plays a role in respiratory induced sleep and growth abnormalities. PMID- 26943477 TI - Complication rate of uterine morcellation in laparoscopic supracervical hysterectomy: a retrospective cohort study. AB - BACKGROUND: Over the last decades minimally invasive surgical techniques are increasingly used to treat symptomatic leiomyomas, providing the patient decreased morbidity and more rapid return to daily activities. Morcellation is the fragmentation of a large mass into smaller pieces to make resection through port incisions possible. Over the last year there has been a discussion worldwide about the safety of morcellation. OBJECTIVE: The aim of our study was to identify the complication rate of power morcellation at our institution. STUDY DESIGN: We performed a retrospective chart analysis of patients undergoing laparoscopic supracervical hysterectomy with morcellation. We compared the outcomes of patients undergoing laparoscopic supracervical hysterectomy with the use of power morcellation with a control group of women who underwent laparoscopic-assisted vaginal hysterectomy without morcellation. Women who underwent hysterectomy because of suspected malignancy were excluded. RESULTS: A total of 358 patients underwent laparoscopic hysterectomy between 2004 and 2013; 186 laparoscopic supracervical hysterectomies and 172 laparoscopic-assisted vaginal hysterectomies. The main indication for laparoscopic supracervical hysterectomy was heavy menstrual bleeding and pelvic pressure or pain (94.5%). Baseline characteristics were not significantly different except for body mass index, with a mean of 25.7 in laparoscopic supracervical hysterectomy and 27.0 in laparoscopic-assisted vaginal hysterectomy. There was a significant greater uterine weight in the laparoscopic supracervical hysterectomy group (260g vs. 202g). The overall conversion rate was 5.3% (n=19), with no significant difference between the two groups and 79% of conversions being performed for strategic reasons. There was no statistical difference in intra-operative complication rate (2.1% vs. 1.2%). Pathology reports showed no unexpected malignancies. There was no statistical difference in the complication rate post operatively (2.2% vs. 2.9%). The overall complication rate of laparoscopic supracervical hysterectomy was 4.3% (n=8). Need for reoperation after laparoscopic supracervical hysterectomy was necessary in 7 patients (3.8%), with cervical amputation being the most common type of reoperation (n=5). In the laparoscopic-assisted vaginal hysterectomy group there were significantly more adhesiolysis performed (n=4). Parasitic myomas were discovered in 1 patient two years after morcellation (0.5%). CONCLUSION: Our study showed no injuries directly related to morcellation. There were no unexpected malignancies morcellated and only one case of parasitic myomas (0.5%). PMID- 26943478 TI - Synthesis and anti-acetylcholinesterase activity of scopoletin derivatives. AB - A series of scopoletin derivatives incorporated with the pyridinium moiety was synthesized and evaluated for their acetylcholinesterase (AChE) inhibitory activity by the colorimetric Ellman's method. A 2-fluorobenzylpyridinium derivative was the most potent among the tested compounds, with an IC50 value of 0.215+/-0.015MUM, which was greatly improved from that of scopoletin. Docking studies revealed that the scopoletin portion of the mentioned compound was bound to the peripheral anionic site of the AChE, whereas the N-benzylpyridinium residue to the catalytic anionic site. PMID- 26943479 TI - Combretastatin linked 1,3,4-oxadiazole conjugates as a Potent Tubulin Polymerization inhibitors. AB - A new class of combretastatin linked 1,3,4-oxadiazoles were designed, synthesized and screened for their cytotoxic activity against five human cancer cell lines such as HeLa, DU-145, A549, MDA-MB-231 and B16. These compounds showed significant cytotoxicity with IC50 values in the range 0.118-54.32MUM. Conjugate 5m displayed potent antiproliferative activity against DU-145 cell line. Flow cytometric analysis revealed that these compounds arrested the cell cycle in G2/M phase. Moreover, the tubulin polymerization assay and immunofluorescence analysis indicate that 5m exhibits potent inhibitory effect on the tubulin assembly. Further, DNA fragmentation and Hoecst staining assays confirm that 5m induces apoptosis. Molecular docking studies and competitive binding assay indicated that 5m effectively bind at the colchicine binding site of the tubulin. PMID- 26943481 TI - Phase-transition W/O Microemulsions for Ocular Delivery: Evaluation of Antibacterial Activity in the Treatment of Bacterial Keratitis. AB - PURPOSE: Moxifloxacin (MXN) is widely prescribed for the treatment of bacterial keratitis. The conventional MXN solution has several limitations, including short precorneal residence time and poor intrastromal bioavailability, requiring frequent instillation of the drug to achieve the desired therapeutic effect. To circumvent this problem, the W/O (water-in-oil) microemulsion (ME) system was utilized for sustained release and improved precorneal retention. METHODS: The pseudo-ternary phase diagrams were developed and various MEs were prepared using two non-ionic surfactants, Tween 80 and Span 20, with isopropyl myristate and acetate buffer. Physicochemical parameters, in vitro drug release and in vitro antibacterial activity were studied. The in vivo antimicrobial efficacy of optimized microemulsion (ME 10) was studied in an experiment on bacterial keratitis in rabbit eyes and compared with that of the marketed eye drops. RESULTS: The optimized microemulsion (ME 10) displays as an average globule size of <40 nm. The developed MEs showed acceptable physico-chemical behaviour, good stability for 3 months and exhibited sustained drug release. Greater efficacy in experimental bacterial keratitis in rabbit eyes was also observed in comparison with marketed drug solution. CONCLUSIONS: The developed MEs are a viable alternative to conventional eye drops, because of its ability to enhance bioavailability through its longer precorneal residence time and its ability to sustain the release of the drug. PMID- 26943482 TI - Establishing Atmospheric Pressure Chemical Ionization Efficiency Scale. AB - Recent evidence has shown that the atmospheric pressure chemical ionization (APCI) mechanism can be more complex than generally assumed. In order to better understand the processes in the APCI source, for the first time, an ionization efficiency scale for an APCI source has been created. The scale spans over 5 logIE (were IE is ionization efficiency) units and includes 40 compounds with a wide range of chemical and physical properties. The results of the experiments show that for most of the compounds the ionization efficiency order in the APCI source is surprisingly similar to that in the ESI source. Most of the compounds that are best ionized in the APCI source are not small volatile molecules. Large tetraalkylammonium cations are a prominent example. At the same time, low polarity hydrocarbons pyrene and anthracene are ionized in the APCI source but not in the ESI source. These results strongly imply that in APCI several ionization mechanisms operate in parallel and a mechanism not relying on evaporation of neutral molecules from droplets has significantly higher influence than commonly assumed. PMID- 26943483 TI - The Elliott-Yafet theory of spin relaxation generalized for large spin-orbit coupling. AB - We generalize the Elliott-Yafet (EY) theory of spin relaxation in metals with inversion symmetry for the case of large spin-orbit coupling (SOC). The EY theory treats the SOC to the lowest order but this approach breaks down for metals of heavy elements (such as e.g. caesium or gold), where the SOC energy is comparable to the relevant band-band separation energies. The generalized theory is presented for a four-band model system without band dispersion, where analytic formulae are attainable for arbitrary SOC for the relation between the momentum- and spin-relaxation rates. As an extended description, we also consider an empirical pseudopotential approximation where SOC is deduced from the band potential (apart from an empirical scaling constant) and the spin-relaxation rate can be obtained numerically. Both approaches recover the usual EY theory for weak SOC and give that the spin-relaxation rate approaches the momentum-relaxation rate in the limit of strong SOC. We argue that this limit is realized in gold by analyzing spin relaxation data. A calculation of the g-factor shows that the empirical Elliott-relation, which links the g-factor and spin-relaxation rate, is retained even for strong SOC. PMID- 26943480 TI - Time dependent impact of perinatal hypoxia on growth hormone, insulin-like growth factor 1 and insulin-like growth factor binding protein-3. AB - Hypoxic-ischemia (HI) is a widely used animal model to mimic the preterm or perinatal sublethal hypoxia, including hypoxic-ischemic encephalopathy. It causes diffuse neurodegeneration in the brain and results in mental retardation, hyperactivity, cerebral palsy, epilepsy and neuroendocrine disturbances. Herein, we examined acute and subacute correlations between neuronal degeneration and serum growth factor changes, including growth hormone (GH), insulin-like growth factor 1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3) after hypoxic-ischemia (HI) in neonatal rats. In the acute phase of hypoxia, brain volume was increased significantly as compared with control animals, which was associated with reduced GH and IGF-1 secretions. Reduced neuronal survival and increased DNA fragmentation were also noticed in these animals. However, in the subacute phase of hypoxia, neuronal survival and brain volume were significantly decreased, accompanied by increased apoptotic cell death in the hippocampus and cortex. Serum GH, IGF-1, and IGFBP-3 levels were significantly reduced in the subacute phase of HI. Significant retardation in the brain and body development were noted in the subacute phase of hypoxia. Here, we provide evidence that serum levels of growth-hormone and factors were decreased in the acute and subacute phase of hypoxia, which was associated with increased DNA fragmentation and decreased neuronal survival. PMID- 26943484 TI - Intranasal midazolam administration enhances amnesic effect in rats. AB - Intranasal (i.n.) administration of midazolam has been shown to be effective and safe for its sedative, anxiolytic, and anticonvulsant effects. However, there has been no investigation on the influence of i.n. administration on midazolam induced anterograde amnesia. In addition, although the potential of direct drug delivery from the nose to the central nervous system (CNS) has recently become a topic of great interest, it remains unclear whether this pathway is also involved after i.n. midazolam. In this study, we examined the efficacy and the underlying mechanism of i.n. administration compared with intramuscular (i.m.) administration on midazolam-induced amnesia in rats. Equivalent doses of 0.6 mg/kg midazolam were administered via either the i.m or the i.n. route. Anterograde amnesia was assessed by a contextual/cued fear conditioning test. Each animal was conditioned 20 min after drug administration and then tested for a freezing response 24 h later. Midazolam administration by either route produced a similar level of light sedation (minimum spontaneous activity). However, i.n. administration of midazolam induced significantly less freezing behavior compared with i.m. midazolam. Furthermore, in rats with disrupted electrical input from the olfactory epithelium after an olfactotoxicant 3-methylindole administration, the i.n.-mediated enhanced amnesic effect of midazolam was not observed. Our findings indicate that i.n midazolam could probably generate olfactory signals to the brain via benzodiazepine receptors and, compared with i.m. administration, can produce a more significant amnesic effect without alteration in sedative levels. Further clinical studies are warranted. PMID- 26943485 TI - Comparing face-to-face intubation with different devices. PMID- 26943487 TI - Circular Dichroism of DNA G-Quadruplexes: Combining Modeling and Spectroscopy To Unravel Complex Structures. AB - We report on the comparison between the computational and experimental determination of electronic circular dichroism spectra of different guanine quadruplexes obtained from human telomeric sequences. In particular the difference between parallel, antiparallel, and hybrid structures is evidenced, as well as the induction of transitions between the polymorphs depending on the solution environment. Extensive molecular dynamics simulations (MD) are used to probe the conformational space of the different quadruplexes, and subsequently state-of-the-art hybrid quantum mechanics/molecular mechanics (QM/MM) techniques coupled with excitonic semiempirical Hamiltonian are used to simulate the macromolecular induced circular dichroism. The coupling of spectroscopy and molecular simulation allows an efficient one-to-one mapping between structures and optical properties, offering a way to disentangle the rich, yet complicated, quantity of information embedded in circular dichroism spectra. We show that our methodology is robust and efficient and allows us to take into account subtle conformational changes. As such, it could be used as an efficient tool to investigate structural modification upon DNA/drug interactions. PMID- 26943486 TI - Inhibitory effect of Pterocarpus indicus Willd water extract on IgE/Ag-induced mast cell and atopic dermatitis-like mouse models. AB - Pterocarpus indicus Willd has been widely used as a traditional medicine to treat edema, cancer, and hyperlipidemia, but its antiallergic properties and underlying mechanisms have not yet been studied. The purpose of this study was to evaluate the antiallergic activity of Pterocarpus indicus Willd water extract (PIW) using activated mast cells and an atopic dermatitis (AD)-like mouse model. PIW decreased IgE/Ag-induced mast cell degranulation and the phosphorylation of Syk and downstream signaling molecules such as PLC-gamma, Akt, Erk 1/2, JNK compared to stimulated mast cells. In DNCB-induced AD-like mice, PIW reduced IgE level in serum, as well as AD-associated scratching behavior and skin severity score. These results indicate that PIW inhibits the allergic response by reducing mast cell activation and may have clinical potential as an antiallergic agent for disorders such as AD. PMID- 26943488 TI - Polysubstance use patterns and trajectories in vocational students--a latent transition analysis. AB - BACKGROUND: The transition from late adolescence to early adulthood (16-20 years) represents a time of exploration and self-discovery for many young people. As such, it is often associated with experimentation in substance use. Vocational students in particular report high substance use. Thus, the aim of this study is to examine patterns and trajectories of their substance use behavior. METHODS: On two occasions (interval 18 months), we investigated 5214 students (M=19.39 years; 54% male) from 49 vocational schools in seven German federal states. We identified classes of substance use and trajectories via latent transition analysis, controlling for gender, age, and socio-economic status. Additionally, we investigated work-related (job demands/stress/satisfaction) and psychopathological (depressive symptoms) predictors of substance use via multinomial regressions. RESULTS: We found three latent stages of substance use: low use (baseline: 43%/follow-up: 44%), mainly alcohol use (50%/45%), and polysubstance use (7%/11%). Over time, 10% of alcohol users at baseline transitioned to polysubstance use at follow-up, while there were smaller transition rates (2-9%) between the other stages. Compared to low use, polysubstance use at follow-up was predicted by high job stress (aOR=1.45, 1.07 1.96) at baseline. CONCLUSIONS: High alcohol use is associated with bidirectional transitions in young adults. Hence, future research needs to identify mechanisms of change to identify protective factors. Regarding vocational practice, early stress management seems to be a viable path to prevent polysubstance use in vocational students. PMID- 26943490 TI - Experimental and theoretical investigations on spectroscopic properties of the imidazole-fused phenanthroline and its derivatives. AB - Two phenanthroline derivatives, 1H-imidazo[4,5-f][1,10]phenanthroline (imPhen) and 2-(9H-fluoren-2-yl)-1H-imidazo[4,5-f][1,10]phenanthroline (Flu-imPhen), have been synthesized and characterized and the corresponding absorption and emission spectroscopic properties have been studied in CH2Cl2 solution. The imPhen exhibits the main two absorption bands at 282 nm and 229 nm and these bands are assigned as the typical pi->pi*(Phen) state. In addition, the weak absorption bands at 313 nm associated with a shoulder near 302 nm were assigned to the pi >pi*(Phen) state with partial charge transfer (CT) character. A similar absorption spectra are observed in the case of the Flu-imPhen in the region of 200-300 nm, while the region of 300-400 nm of the spectra are dominated by the characteristic pi->pi* transition of the fluorene moiety. imPhen shows the typical ligand-centered (1)pi->pi* emission, while Flu-imPhen emits from the mixed (1)pi->pi*/CT states. Density functional theory (DFT) and time-dependent density functional theory (TDDFT) were employed to rationalize the photophysical properties of these ligands studied. The theoretical data confirm the assignment of the experimental absorption spectra and the nature of the emitting states. PMID- 26943491 TI - NMR-Based Determination of the 3D Structure of the Ligand-Protein Interaction Site without Protein Resonance Assignment. AB - Molecular replacement in X-ray crystallography is the prime method for establishing structure-activity relationships of pharmaceutically relevant molecules. Such an approach is not available for NMR. Here, we establish a comparable method, called NMR molecular replacement (NMR(2)). The method requires experimentally measured ligand intramolecular NOEs and ligand-protein intermolecular NOEs as well as a previously known receptor structure or model. Our findings demonstrate that NMR(2) may open a new avenue for the fast and robust determination of the interaction site of ligand-protein complexes at atomic resolution. PMID- 26943489 TI - Discovery of Bifunctional Oncogenic Target Inhibitors against Allosteric Mitogen Activated Protein Kinase (MEK1) and Phosphatidylinositol 3-Kinase (PI3K). AB - The synthesis of a series of single entity, bifunctional MEK1/PI3K inhibitors achieved by covalent linking of structural analogs of the ATP-competitive PI3K inhibitor ZSTK474 and the ATP-noncompetitive MEK inhibitor PD0325901 is described. Inhibitors displayed potent in vitro inhibition of MEK1 (0.015 < IC50 (nM) < 56.7) and PI3K (54 < IC50 (nM) < 341) in enzymatic inhibition assays. Concurrent MEK1 and PI3K inhibition was demonstrated with inhibitors 9 and 14 in two tumor cell lines (A549, D54). Inhibitors produced dose-dependent decreased cell viability similar to the combined administration of equivalent doses of ZSTK474 and PD0325901. In vivo efficacy of 14 following oral administration was demonstrated in D54 glioma and A549 lung tumor bearing mice. Compound 14 showed a 95% and 67% inhibition of tumor ERK1/2 and Akt phosphorylation, respectively, at 2 h postadministration by Western blot analysis, confirming the bioavailability and efficacy of this bifunctional inhibitor strategy toward combined MEK1/PI3K inhibition. PMID- 26943492 TI - Grasp and index finger reach zone during one-handed smartphone rear interaction: effects of task type, phone width and hand length. AB - Recently, some smartphones have introduced index finger interaction functions on the rear surface. The current study investigated the effects of task type, phone width, and hand length on grasp, index finger reach zone, discomfort, and muscle activation during such interaction. We considered five interaction tasks (neutral, comfortable, maximum, vertical, and horizontal strokes), two device widths (60 and 90 mm) and three hand lengths. Horizontal (vertical) strokes deviated from the horizontal axis in the range from -10.8 degrees to -13.5 degrees (81.6-88.4 degrees ). Maximum strokes appeared to be excessive as these caused 43.8% greater discomfort than did neutral strokes. The 90-mm width also appeared to be excessive as it resulted in 12.3% increased discomfort relative to the 60-mm width. The small-hand group reported 11.9-18.2% higher discomfort ratings, and the percent maximum voluntary exertion of their flexor digitorum superficialis muscle, pertaining to index finger flexion, was also 6.4% higher. These findings should be considered to make smartphone rear interaction more comfortable. Practitioner Summary: Among neutral, comfortable, maximum, horizontal, and vertical index finger strokes on smartphone rear surfaces, maximum vs. neutral strokes caused 43.8% greater discomfort. Horizontal (vertical) strokes deviated from the horizontal (vertical) axis. Discomfort increased by 12.3% with 90-mm- vs. 60-mm-wide devices. Rear interaction regions of five commercialised smartphones should be lowered 20 to 30 mm for more comfortable rear interaction. PMID- 26943497 TI - Monte Carlo calculation of beam quality correction factors in proton beams using detailed simulation of ionization chambers. AB - This work calculates beam quality correction factors (kQ) in monoenergetic proton beams using detailed Monte Carlo simulation of ionization chambers. It uses the Monte Carlo code penh and the electronic stopping powers resulting from the adoption of two different sets of mean excitation energy values for water and graphite: (i) the currently ICRU 37 and ICRU 49 recommended Iw = 75 eV and Ig = 78 eV and (ii) the recently proposed Iw = 78 eV and Ig = 81.1 eV. Twelve different ionization chambers were studied. The k Q factors calculated using the two different sets of I-values were found to agree with each other within 1.6% or better. k Q factors calculated using current ICRU I-values were found to agree within 2.3% or better with the k Q factors tabulated in IAEA TRS-398, and within 1% or better with experimental values published in the literature. k Q factors calculated using the new I-values were also found to agree within 1.1% or better with the experimental values. This work concludes that perturbation correction factors in proton beams--currently assumed to be equal to unity--are in fact significantly different from unity for some of the ionization chambers studied. PMID- 26943498 TI - Lipid Bilayer Membrane Perturbation by Embedded Nanopores: A Simulation Study. AB - A macromolecular nanopore inserted into a membrane may perturb the dynamic organization of the surrounding lipid bilayer. To better understand the nature of such perturbations, we have undertaken a systematic molecular dynamics simulation study of lipid bilayer structure and dynamics around three different classes of nanopore: a carbon nanotube, three related cyclic peptide nanotubes differing in the nature of their external surfaces, and a model of a beta-barrel nanopore protein. Periodic spatial distributions of several lipid properties as a function of distance from the nanopore were observed. This was especially clear for the carbon nanotube system, for which the density of lipids, the bilayer thickness, the projection of lipid head-to-tail vectors onto the membrane plane, and lipid lateral diffusion coefficients exhibited undulatory behavior as a function of the distance from the surface of the channel. Overall, the differences in lipid behavior as a function of the nanopore structure reveal local adaptation of the bilayer structure and dynamics to different embedded nanopore structures. Both the local structure and dynamic behavior of lipids around membrane-embedded nanopores are sensitive to the geometry and nature of the outer surface of the macromolecule/molecular assembly forming the pore. PMID- 26943499 TI - Shape-Dependent Surface Reactivity and Antimicrobial Activity of Nano-Cupric Oxide. AB - Shape of engineered nanomaterials (ENMs) can be used as a design handle to achieve controlled manipulation of physicochemical properties. This tailored material property approach necessitates the establishment of relationships between specific ENM properties that result from such manipulations (e.g., surface area, reactivity, or charge) and the observed trend in behavior, from both a functional performance and hazard perspective. In this study, these structure-property-function (SPF) and structure-property-hazard (SPH) relationships are established for nano-cupric oxide (n-CuO) as a function of shape, including nanospheres and nanosheets. In addition to comparing these shapes at the nanoscale, bulk CuO is studied to compare across length scales. The results from comprehensive material characterization revealed correlations between CuO surface reactivity and bacterial toxicity with CuO nanosheets having the highest surface reactivity, electrochemical activity, and antimicrobial activity. While less active than the nanosheets, CuO nanoparticles (sphere-like shape) demonstrated enhanced reactivity compared to the bulk CuO. This is in agreement with previous studies investigating differences across length-scales. To elucidate the underlying mechanisms of action to further explain the shape dependent behavior, kinetic models applied to the toxicity data. In addition to revealing different CuO material kinetics, trends in observed response cannot be explained by surface area alone. The compiled results contribute to further elucidate pathways toward controlled design of ENMs. PMID- 26943500 TI - The Effect of Preoperative Oral Immunonutrition on Complications and Length of Hospital Stay After Elective Surgery for Pancreatic Cancer--A Randomized Controlled Trial. AB - Major gastrointestinal surgery is associated with immune suppression and a high risk of postoperative complications. The aim of this open, randomized controlled trial was to examine the effect of supplementary per oral immunonutrition (IN) seven days before surgery for pancreatic cancer (PC) on postoperative complications and length of hospital stay (LOS). Secondary outcomes were the changes in functional capability and body weight (BW). Consecutive patients referred for surgery for diagnosed or plausible PC were included. The patients in the intervention group received supplementary IN (Oral Impact(r), Nestle) to reach a goal of 1.5 g protein/kg BW. The control group continued their habitual diet. Complications and LOS were independently assessed by the surgical staff. Secondary outcomes were measured 10, 20, and 30 days postoperatively. Thirty-five patients were included, of whom 19 (54%) were allocated to the intervention group. The doses of IN ranged from 250 to 1000 ml per day and the median compliance was 100 (0-100%). Based on the principle of intention-to-treat, no significant differences were found between the groups. We conclude that the lack of effect could be due to the limited dosage of IN, and/or because only 40% of the patients were at nutritional risk. PMID- 26943501 TI - Auxin effects on ion transport in Chara corallina. AB - The plant hormone auxin has been widely studied with regard to synthesis, transport, signaling and functions among the land plants while there is still a lack of knowledge about the possible role for auxin regulation mechanisms in algae with "plant-like" structures. Here we use the alga Chara corallina as a model to study aspects of auxin signaling. In this respect we measured auxin on membrane potential changes and different ion fluxes (K(+), H(+)) through the plasma membrane. Results showed that auxin, mainly IAA, could hyperpolarize the membrane potential of C. corallina internodal cells. Ion flux measurements showed that the auxin-induced membrane potential change may be based on the change of K(+) permeability and/or channel activity rather than through the activation of proton pumps as known in land plants. PMID- 26943510 TI - Intense Pulsed Light Sintering of CH3NH3PbI3 Solar Cells. AB - Perovskite solar cells utilizing a two-step deposited CH3NH3PbI3 thin film were rapidly sintered using an intense pulsed light source. For the first time, a heat treatment has shown the capability of sintering methylammonium lead iodide perovskite and creating large crystal sizes approaching 1 MUm without sacrificing surface coverage. Solar cells with an average efficiency of 11.5% and a champion device of 12.3% are reported. The methylammonium lead iodide perovskite was subjected to 2000 J of energy in a 2 ms pulse of light generated by a xenon lamp, resulting in temperatures significantly exceeding the degradation temperature of 150 degrees C. The process opens up new opportunities in the manufacturability of perovskite solar cells by eliminating the rate-limiting annealing step, and makes it possible to envision a continuous roll-to-roll process similar to the printing press used in the newspaper industry. PMID- 26943511 TI - Extreme Violation of Local Realism in Quantum Hypergraph States. AB - Hypergraph states form a family of multiparticle quantum states that generalizes the well-known concept of Greenberger-Horne-Zeilinger states, cluster states, and more broadly graph states. We study the nonlocal properties of quantum hypergraph states. We demonstrate that the correlations in hypergraph states can be used to derive various types of nonlocality proofs, including Hardy-type arguments and Bell inequalities for genuine multiparticle nonlocality. Moreover, we show that hypergraph states allow for an exponentially increasing violation of local realism which is robust against loss of particles. Our results suggest that certain classes of hypergraph states are novel resources for quantum metrology and measurement-based quantum computation. PMID- 26943512 TI - Assisted Distillation of Quantum Coherence. AB - We introduce and study the task of assisted coherence distillation. This task arises naturally in bipartite systems where both parties work together to generate the maximal possible coherence on one of the subsystems. Only incoherent operations are allowed on the target system, while general local quantum operations are permitted on the other; this is an operational paradigm that we call local quantum-incoherent operations and classical communication. We show that the asymptotic rate of assisted coherence distillation for pure states is equal to the coherence of assistance, an analog of the entanglement of assistance, whose properties we characterize. Our findings imply a novel interpretation of the von Neumann entropy: it quantifies the maximum amount of extra quantum coherence a system can gain when receiving assistance from a collaborative party. Our results are generalized to coherence localization in a multipartite setting and possible applications are discussed. PMID- 26943513 TI - Universal Steering Criteria. AB - We propose a general framework for constructing universal steering criteria that are applicable to arbitrary bipartite states and measurement settings of the steering party. The same framework is also useful for studying the joint measurement problem. Based on the data-processing inequality for an extended Renyi relative entropy, we then introduce a family of steering inequalities, which detect steering much more efficiently than those inequalities known before. As illustrations, we show unbounded violation of a steering inequality for assemblages constructed from mutually unbiased bases and establish an interesting connection between maximally steerable assemblages and complete sets of mutually unbiased bases. We also provide a single steering inequality that can detect all bipartite pure states of full Schmidt rank. In the course of study, we generalize a number of results intimately connected to data-processing inequalities, which are of independent interest. PMID- 26943514 TI - Nonlocal Measurements via Quantum Erasure. AB - Nonlocal observables play an important role in quantum theory, from Bell inequalities and various postselection paradoxes to quantum error correction codes. Instantaneous measurement of these observables is known to be a difficult problem, especially when the measurements are projective. The standard von Neumann Hamiltonian used to model projective measurements cannot be implemented directly in a nonlocal scenario and can, in some cases, violate causality. We present a scheme for effectively generating the von Neumann Hamiltonian for nonlocal observables without the need to communicate and adapt. The protocol can be used to perform weak and strong (projective) measurements, as well as measurements at any intermediate strength. It can also be used in practical situations beyond nonlocal measurements. We show how the protocol can be used to probe a version of Hardy's paradox with both weak and strong measurements. The outcomes of these measurements provide a nonintuitive picture of the pre- and postselected system. Our results shed new light on the interplay between quantum measurements, uncertainty, nonlocality, causality, and determinism. PMID- 26943515 TI - Proposal for an Optomechanical Bell Test. AB - Photons of a laser beam driving the upper motional sideband of an optomechanical cavity can decay into photon-phonon pairs by means of an optomechanical parametric process. The phononic state can subsequently be mapped to a photonic state by exciting the lower sideband, hence creating photon-photon pairs out of an optomechanical system. Here we show that these pairs can violate a Bell inequality when they are measured with photon counting techniques preceded by small displacement operations in phase space. The consequence of such a violation as well as the experimental requirements are intensively discussed. PMID- 26943516 TI - Proposal to Test Bell's Inequality in Electromechanics. AB - Optomechanical and electromechanical systems offer an effective platform to test quantum theory and its predictions at macroscopic scales. To date, all experiments presuppose the validity of quantum mechanics, but could in principle be described by a hypothetical local statistical theory. Here we suggest a Bell test using the electromechanical Einstein-Podolski-Rosen entangled state recently generated by Palomaki et al., Science 342, 710 (2013), which would rule out any local and realistic explanation of the measured data without assuming the validity of quantum mechanics at macroscopic scales. It additionally provides a device-independent way to verify electromechanical entanglement. The parameter regime required for our scheme has been demonstrated or is within reach of current experiments. PMID- 26943517 TI - Driven Markovian Quantum Criticality. AB - We identify a new universality class in one-dimensional driven open quantum systems with a dark state. Salient features are the persistence of both the microscopic nonequilibrium conditions as well as the quantum coherence of dynamics close to criticality. This provides a nonequilibrium analogue of quantum criticality, and is sharply distinct from more generic driven systems, where both effective thermalization as well as asymptotic decoherence ensue, paralleling classical dynamical criticality. We quantify universality by computing the full set of independent critical exponents within a functional renormalization group approach. PMID- 26943518 TI - Multiparticle Bound-State Formation following a Quantum Quench to the One Dimensional Bose Gas with Attractive Interactions. AB - We consider quantum quenches from an ideal Bose condensate to the Lieb-Liniger model with an arbitrary attractive interaction strength. We focus on the properties of the stationary state reached at late times after the quench. Using recently developed methods based on integrability, we obtain an exact description of the stationary state for a large number of bosons. A distinctive feature of this state is the presence of a hierarchy of multiparticle bound states. We determine the dependence of their densities on interaction strength and obtain an exact expression for the stationary value of the local pair correlation g_{2}. We discuss ramifications of our results for cold atom experiments. PMID- 26943519 TI - Certifying the Presence of a Photonic Qubit by Splitting It in Two. AB - We present an implementation of photonic qubit precertification that performs the delicate task of detecting the presence of a flying photon without destroying its qubit state, allowing loss-sensitive quantum cryptography and tests of nonlocality even over long distance. By splitting an incoming single photon in two via parametric down-conversion, we herald the photon's arrival from an independent photon source while preserving its quantum information with up to (92.3+/-0.6)% fidelity. With reduced detector dark counts, precertification will be immediately useful in quantum communication. PMID- 26943520 TI - Efficient Measurement of Multiparticle Entanglement with Embedding Quantum Simulator. AB - The quantum measurement of entanglement is a demanding task in the field of quantum information. Here, we report the direct and scalable measurement of multiparticle entanglement with embedding photonic quantum simulators. In this embedding framework [R. Di Candia et al. Phys. Rev. Lett. 111, 240502 (2013)], the N-qubit entanglement, which does not associate with a physical observable directly, can be efficiently measured with only two (for even N) and six (for odd N) local measurement settings. Our experiment uses multiphoton quantum simulators to mimic dynamical concurrence and three-tangle entangled systems and to track their entanglement evolutions. PMID- 26943521 TI - Measuring Entanglement in a Photonic Embedding Quantum Simulator. AB - Measuring entanglement is a demanding task that usually requires full tomography of a quantum system, involving a number of observables that grows exponentially with the number of parties. Recently, it was suggested that adding a single ancillary qubit would allow for the efficient measurement of concurrence, and indeed any entanglement monotone associated with antilinear operations. Here, we report on the experimental implementation of such a device-an embedding quantum simulator-in photonics, encoding the entangling dynamics of a bipartite system into a tripartite one. We show that bipartite concurrence can be efficiently extracted from the measurement of merely two observables, instead of 15, without full tomographic information. PMID- 26943522 TI - Entanglement Quantification Made Easy: Polynomial Measures Invariant under Convex Decomposition. AB - Quantifying entanglement in composite systems is a fundamental challenge, yet exact results are available in only a few special cases. This is because hard optimization problems are routinely involved, such as finding the convex decomposition of a mixed state with the minimal average pure-state entanglement, the so-called convex roof. We show that under certain conditions such a problem becomes trivial. Precisely, we prove by a geometric argument that polynomial entanglement measures of degree 2 are independent of the choice of pure-state decomposition of a mixed state, when the latter has only one pure unentangled state in its range. This allows for the analytical evaluation of convex roof extended entanglement measures in classes of rank-2 states obeying such a condition. We give explicit examples for the square root of the three-tangle in three-qubit states, and we show that several representative classes of four-qubit pure states have marginals that enjoy this property. PMID- 26943523 TI - Large Deviations of Surface Height in the Kardar-Parisi-Zhang Equation. AB - Using the weak-noise theory, we evaluate the probability distribution P(H,t) of large deviations of height H of the evolving surface height h(x,t) in the Kardar Parisi-Zhang equation in one dimension when starting from a flat interface. We also determine the optimal history of the interface, conditioned on reaching the height H at time t. We argue that the tails of P behave, at arbitrary time t>0, and in a proper moving frame, as -lnP~|H|^{5/2} and ~|H|^{3/2}. The 3/2 tail coincides with the asymptotic of the Gaussian orthogonal ensemble Tracy-Widom distribution, previously observed at long times. PMID- 26943524 TI - Hidden Cosmic-Ray Accelerators as an Origin of TeV-PeV Cosmic Neutrinos. AB - The latest IceCube data suggest that the all-flavor cosmic neutrino flux may be as large as 10^{-7} GeV cm^{-2} s^{-1} sr^{-1} around 30 TeV. We show that, if sources of the TeV-PeV neutrinos are transparent to gamma rays with respect to two-photon annihilation, strong tensions with the isotropic diffuse gamma-ray background measured by Fermi are unavoidable, independently of the production mechanism. We further show that, if the IceCube neutrinos have a photohadronic (pgamma) origin, the sources are expected to be opaque to 1-100 GeV gamma rays. With these general multimessenger arguments, we find that the latest data suggest a population of cosmic-ray accelerators hidden in GeV-TeV gamma rays as a neutrino origin. Searches for x-ray and MeV gamma-ray counterparts are encouraged, and TeV-PeV neutrinos themselves will serve as special probes of dense source environments. PMID- 26943525 TI - End Point of Black Ring Instabilities and the Weak Cosmic Censorship Conjecture. AB - We produce the first concrete evidence that violation of the weak cosmic censorship conjecture can occur in asymptotically flat spaces of five dimensions by numerically evolving perturbed black rings. For certain thin rings, we identify a new, elastic-type instability dominating the evolution, causing the system to settle to a spherical black hole. However, for sufficiently thin rings the Gregory-Laflamme mode is dominant, and the instability unfolds similarly to that of black strings, where the horizon develops a structure of bulges connected by necks which become ever thinner over time. PMID- 26943526 TI - New Results from the Search for Low-Mass Weakly Interacting Massive Particles with the CDMS Low Ionization Threshold Experiment. AB - The CDMS low ionization threshold experiment (CDMSlite) uses cryogenic germanium detectors operated at a relatively high bias voltage to amplify the phonon signal in the search for weakly interacting massive particles (WIMPs). Results are presented from the second CDMSlite run with an exposure of 70 kg day, which reached an energy threshold for electron recoils as low as 56 eV. A fiducialization cut reduces backgrounds below those previously reported by CDMSlite. New parameter space for the WIMP-nucleon spin-independent cross section is excluded for WIMP masses between 1.6 and 5.5 GeV/c^{2}. PMID- 26943531 TI - Ultrafast Molecular Three-Electron Auger Decay. AB - Three-electron Auger decay is an exotic and elusive process, in which two outer shell electrons simultaneously refill an inner-shell double vacancy with emission of a single Auger electron. Such transitions are forbidden by the many-electron selection rules, normally making their decay lifetimes orders of magnitude longer than the few-femtosecond lifetimes of normal (two-electron) Auger decay. Here we present theoretical predictions and direct experimental evidence for a few femtosecond three-electron Auger decay of a double inner-valence-hole state in CH_{3}F. Our analysis shows that in contrast to double core holes, double inner valence vacancies in molecules can decay exclusively by this ultrafast three electron Auger process, and we predict that this phenomenon occurs widely. PMID- 26943530 TI - Single and Double Beta-Decay Q Values among the Triplet ^{96}Zr, ^{96}Nb, and ^{96}Mo. AB - The atomic mass relations among the mass triplet ^{96}Zr, ^{96}Nb, and ^{96}Mo have been determined by means of high-precision mass measurements using the JYFLTRAP mass spectrometer at the IGISOL facility of the University of Jyvaskyla. We report Q values for the ^{96}Zr single and double beta decays to ^{96}Nb and ^{96}Mo, as well as the Q value for the ^{96}Nb single beta decay to ^{96}Mo, which are Q_{beta}(^{96}Zr)=163.96(13), Q_{betabeta}(^{96}Zr)=3356.097(86), and Q_{beta}(^{96}Nb)=3192.05(16) keV. Of special importance is the ^{96}Zr single beta-decay Q value, which has never been determined directly. The single beta decay, whose main branch is fourfold unique forbidden, is an alternative decay path to the ^{96}Zr betabeta decay, and its observation can provide one of the most direct tests of the neutrinoless betabeta-decay nuclear-matrix-element calculations, as these can be simultaneously performed for both decay paths with no further assumptions. The theoretical single beta-decay rate has been re evaluated using a shell-model approach, which indicates a ^{96}Zr single beta decay lifetime within reach of an experimental verification. The uniqueness of the decay also makes such an experiment interesting for an investigation into the origin of the quenching of the axial-vector coupling constant g_{A}. PMID- 26943529 TI - Thermal Photon Radiation in High Multiplicity p+Pb Collisions at the Large Hadron Collider. AB - The collective behavior of hadronic particles has been observed in high multiplicity proton-lead collisions at the Large Hadron Collider, as well as in deuteron-gold collisions at the Relativistic Heavy-Ion Collider. In this work we present the first calculation, in the hydrodynamic framework, of thermal photon radiation from such small collision systems. Owing to their compact size, these systems can reach temperatures comparable to those in central nucleus-nucleus collisions. The thermal photons can thus shine over the prompt background, and increase the low p_{T} direct photon spectrum by a factor of 2-3 in 0%-1% p+Pb collisions at 5.02 TeV. This thermal photon enhancement can therefore serve as a signature of the existence of a hot quark-gluon plasma during the evolution of these small collision systems, as well as validate hydrodynamic behavior in small systems. PMID- 26943532 TI - Agreement of Experiment and Theory on the Single Ionization of Helium by Fast Proton Impact. AB - Even though the study of ion-atom collisions is a mature field of atomic physics, large discrepancies between experiment and theoretical calculations are still common. Here we present experimental results with high momentum resolution on the single ionization of helium induced by 1-MeV protons, and we compare these to theoretical calculations. The overall agreement is strikingly good, and even the first Born approximation yields good agreement between theory and experiment. This has been expected for several decades, but so far has not been accomplished. The influence of projectile coherence effects on the measured data is briefly discussed in terms of an ongoing dispute on the existence of nodal structures in the electron angular emission distributions. PMID- 26943533 TI - Observation of Four-Photon Orbital Angular Momentum Entanglement. AB - We demonstrate genuine multipartite quantum entanglement of four photons in their orbital angular momentum degrees of freedom, where a high-dimensional discrete Hilbert space is attached to each photon. This can encode more quantum information compared to the qubit case, but it is a long-standing problem to entangle more than two such photons. In our experiment we use pulsed spontaneous parametric down-conversion to produce the photon quadruplets, which allows us to detect about one four-photon event per second. By means of quantum state reconstruction and a suitable witness operator we find that the photon quadruplets form a genuine multipartite entangled symmetric Dicke state. This opens a new tool for addressing foundational questions in quantum mechanics, and for exploration of novel high-dimensional multiparty quantum information applications such as secret sharing. PMID- 26943534 TI - Stopped Light at High Storage Efficiency in a Pr^{3+}:Y_{2}SiO_{5} Crystal. AB - We demonstrate efficient storage and retrieval of light pulses by electromagnetically induced transparency (EIT) in a Pr^{3+}:Y_{2}SiO_{5} crystal. Using a ring-type multipass configuration, we increase the optical depth (OD) of the medium up to a factor of 16 towards OD~96. Combining the large optical depth with optimized conditions for EIT, we reach a light storage efficiency of (76.3+/ 3.5)%. In addition, we perform extended systematic measurements of the storage efficiency versus optical depth, control Rabi frequency, and probe pulse duration. The data confirm the theoretically expected behavior of an EIT-driven solid-state memory. PMID- 26943535 TI - Coherent Amplification of Ultrafast Molecular Dynamics in an Optical Oscillator. AB - Optical oscillators present a powerful optimization mechanism. The inherent competition for the gain resources between possible modes of oscillation entails the prevalence of the most efficient single mode. We harness this "ultrafast" coherent feedback to optimize an optical field in time, and show that, when an optical oscillator based on a molecular gain medium is synchronously pumped by ultrashort pulses, a temporally coherent multimode field can develop that optimally dumps a general, dynamically evolving vibrational wave packet, into a single vibrational target state. Measuring the emitted field opens a new window to visualization and control of fast molecular dynamics. The realization of such a coherent oscillator with hot alkali dimers appears within experimental reach. PMID- 26943536 TI - Ultrafast Excitation of an Inner-Shell Electron by Laser-Induced Electron Recollision. AB - Extreme ultraviolet attosecond pulses, generated by a process known as laser induced electron recollision, are a key ingredient for attosecond metrology, providing a tool to precisely initiate and probe subfemtosecond dynamics in atoms, molecules, and solids. However, extending attosecond metrology to scrutinize the dynamics of the inner-shell electrons is a challenge, that is because of the lower efficiency in generating the required soft x-ray (homega>300 eV) attosecond bursts. A way around this problem is to use the recolliding electron to directly initiate the desired inner-shell process, instead of using the currently low flux x-ray attosecond sources. Such an excitation process occurs in a subfemtosecond time scale, and may provide the necessary "pump" step in a pump-probe experiment. Here we used a few cycle infrared (lambda_{0}~1800 nm) source and observed direct evidence for inner-shell excitations through the laser-induced electron recollision process. It is the first step toward time resolved core-hole studies in the keV energy range with subfemtosecond time resolution. PMID- 26943528 TI - Identification of Nuclear Effects in Neutrino-Carbon Interactions at Low Three Momentum Transfer. AB - Two different nuclear-medium effects are isolated using a low three-momentum transfer subsample of neutrino-carbon scattering data from the MINERvA neutrino experiment. The observed hadronic energy in charged-current nu_{MU} interactions is combined with muon kinematics to permit separation of the quasielastic and Delta(1232) resonance processes. First, we observe a small cross section at very low energy transfer that matches the expected screening effect of long-range nucleon correlations. Second, additions to the event rate in the kinematic region between the quasielastic and Delta resonance processes are needed to describe the data. The data in this kinematic region also have an enhanced population of multiproton final states. Contributions predicted for scattering from a nucleon pair have both properties; the model tested in this analysis is a significant improvement but does not fully describe the data. We present the results as a double-differential cross section to enable further investigation of nuclear models. Improved description of the effects of the nuclear environment are required by current and future neutrino oscillation experiments. PMID- 26943538 TI - Optimal Length Scale for a Turbulent Dynamo. AB - We demonstrate that there is an optimal forcing length scale for low Prandtl number dynamo flows that can significantly reduce the required energy injection rate. The investigation is based on simulations of the induction equation in a periodic box of size 2piL. The flows considered are the laminar and turbulent ABC flows forced at different forcing wave numbers k_{f}, where the turbulent case is simulated using a subgrid turbulence model. At the smallest allowed forcing wave number k_{f}=k_{min}=1/L the laminar critical magnetic Reynolds number Rm_{c}^{lam} is more than an order of magnitude smaller than the turbulent critical magnetic Reynolds number Rm_{c}^{turb} due to the hindering effect of turbulent fluctuations. We show that this hindering effect is almost suppressed when the forcing wave number k_{f} is increased above an optimum wave number k_{f}L?4 for which Rm_{c}^{turb} is minimum. At this optimal wave number, Rm_{c}^{turb} is smaller by more than a factor of 10 than the case forced in k_{f}=1. This leads to a reduction of the energy injection rate by 3 orders of magnitude when compared to the case where the system is forced at the largest scales and thus provides a new strategy for the design of a fully turbulent experimental dynamo. PMID- 26943537 TI - Imaging Hidden Objects with Spatial Speckle Intensity Correlations over Object Position. AB - We present a coherent optical method for wavelength-resolution imaging of moving objects hidden within thick randomly scattering media. Spatial speckle intensity correlations as a function of object position are shown to provide access to the spatially dependent dielectric constant of the moving object. This speckle correlation imaging method yields field-based information previously inaccessible in heavily scattering environments. Proof of concept experimental results show excellent agreement with the theory. This new imaging approach will be valuable in high resolution imaging in tissue and other scattering environments where natural motion occurs or the object position can be controlled. PMID- 26943539 TI - Signatures of the Self-Similar Regime of Strongly Coupled Stimulated Brillouin Scattering for Efficient Short Laser Pulse Amplification. AB - Plasma-based laser amplification is considered as a possible way to overcome the technological limits of present day laser systems and achieve exawatt laser pulses. Efficient amplification of a picosecond laser pulse by stimulated Brillouin scattering (SBS) of a pump pulse in a plasma requires to reach the self similar regime of the strongly coupled (SC) SBS. In this Letter, we report on the first observation of the signatures of the transition from linear to self-similar regimes of SC-SBS, so far only predicted by theory and simulations. With a new fully head-on collision geometry, subpicosecond pulses are amplified by a factor of 5 with energy transfers of few tens of mJ. We observe pulse shortening, frequency spectrum broadening, and down-shifting for increasing gain, signatures of SC-SBS amplification entering the self-similar regime. This is also confirmed by the power law dependence of the gain on the amplification length: doubling the interaction length increases the gain by a factor 1.4. Pump backward Raman scattering (BRS) on SC-SBS amplification has been measured for the first time, showing a strong decrease of the BRS amplitude and frequency bandwidth when SBS seed amplification occurs. PMID- 26943540 TI - Ionic Transport Coefficients of Dense Plasmas without Molecular Dynamics. AB - We present a theoretical model that allows a fast and accurate evaluation of ionic transport properties of realistic plasmas spanning from warm and dense to hot and dilute conditions, including mixtures. This is achieved by combining a recent kinetic theory based on effective interaction potentials with a model for the equilibrium radial density distribution based on an average atom model and the integral equations theory of fluids. The model should find broad use in applications where nonideal plasma conditions are traversed, including inertial confinement fusion, compact astrophysical objects, solar and extrasolar planets, and numerous present-day high energy density laboratory experiments. PMID- 26943541 TI - Generation and Beaming of Early Hot Electrons onto the Capsule in Laser-Driven Ignition Hohlraums. AB - In hohlraums for inertial confinement fusion (ICF) implosions on the National Ignition Facility, suprathermal hot electrons, generated by laser plasma instabilities early in the laser pulse ("picket") while blowing down the laser entrance hole (LEH) windows, can preheat the capsule fuel. Hard x-ray imaging of a Bi capsule surrogate and of the hohlraum emissions, in conjunction with the measurement of time-resolved bremsstrahlung spectra, allows us to uncover for the first time the directionality of these hot electrons and infer the capsule preheat. Data and Monte Carlo calculations indicate that for most experiments the hot electrons are emitted nearly isotropically from the LEH. However, we have found cases where a significant fraction of the generated electrons are emitted in a collimated beam directly towards the capsule poles, where their local energy deposition is up to 10* higher than the average preheat value and acceptable levels for ICF implosions. The observed "beaming" is consistent with a recently unveiled multibeam stimulated Raman scattering model [P. Michel et al., Phys. Rev. Lett. 115, 055003 (2015)], where laser beams in a cone drive a common plasma wave on axis. Finally, we demonstrate that we can control the amount of generated hot electrons by changing the laser pulse shape and hohlraum plasma. PMID- 26943542 TI - Optical Control of Magnetic Feshbach Resonances by Closed-Channel Electromagnetically Induced Transparency. AB - We control magnetic Feshbach resonances in an optically trapped mixture of the two lowest hyperfine states of a ^{6}Li Fermi gas, using two optical fields to create a dark state in the closed molecular channel. In the experiments, the narrow Feshbach resonance is tuned by up to 3 G. For the broad resonance, the spontaneous lifetime is increased to 0.4 s at the dark-state resonance, compared to 0.5 ms for single-field tuning. We present a new model of light-induced loss spectra, employing continuum-dressed basis states, which agrees in shape and magnitude with loss measurements for both broad and narrow resonances. Using this model, we predict the trade-off between tunability and loss for the broad resonance in ^{6}Li, showing that our two-field method substantially reduces the two-body loss rate compared to single-field methods for the same tuning range. PMID- 26943543 TI - Macrodeformation Twins in Single-Crystal Aluminum. AB - Deformation twinning in pure aluminum has been considered to be a unique property of nanostructured aluminum. A lingering mystery is whether deformation twinning occurs in coarse-grained or single-crystal aluminum at scales beyond nanotwins. Here, we present the first experimental demonstration of macrodeformation twins in single-crystal aluminum formed under an ultrahigh strain rate (~10^{6} s^{ 1}) and large shear strain (200%) via dynamic equal channel angular pressing. Large-scale molecular dynamics simulations suggest that the frustration of subsonic dislocation motion leads to transonic deformation twinning. Deformation twinning is rooted in the rate dependences of dislocation motion and twinning, which are coupled, complementary processes during severe plastic deformation under ultrahigh strain rates. PMID- 26943544 TI - Chemomechanical Origin of Hydrogen Trapping at Grain Boundaries in fcc Metals. AB - Hydrogen embrittlement of metals is widely observed, but its atomistic origins remain little understood and much debated. Combining a unique identification of interstitial sites through polyhedral tessellation and first-principles calculations, we study hydrogen adsorption at grain boundaries in a variety of face-centered cubic metals of Ni, Cu, gamma-Fe, and Pd. We discover the chemomechanical origin of the variation of adsorption energetics for interstitial hydrogen at grain boundaries. A general chemomechanical formula is established to provide accurate assessments of hydrogen trapping and segregation energetics at grain boundaries, and it also offers direct explanations for certain experimental observations. The present study deepens our mechanistic understanding of the role of grain boundaries in hydrogen embrittlement and points to a viable path towards predictive microstructure engineering against hydrogen embrittlement in structural metals. PMID- 26943545 TI - Sampling Polymorphs of Ionic Solids using Random Superlattices. AB - Polymorphism offers rich and virtually unexplored space for discovering novel functional materials. To harness this potential approaches capable of both exploring the space of polymorphs and assessing their realizability are needed. One such approach devised for partially ionic solids is presented. The structure prediction part is carried out by performing local density functional theory relaxations on a large set of random supperlattices (RSLs) with atoms distributed randomly over different planes in a way that favors cation-anion coordination. Applying the RSL sampling on MgO, ZnO, and SnO_{2} reveals that the resulting probability of occurrence of a given structure offers a measure of its realizability explaining fully the experimentally observed, metastable polymorphs in these three systems. PMID- 26943546 TI - Strong Amplification of Coherent Acoustic Phonons by Intraminiband Currents in a Semiconductor Superlattice. AB - Sound amplification in an electrically biased superlattice (SL) is studied in optical experiments with 100 fs time resolution. Coherent SL phonons with frequencies of 40, 375, and 410 GHz give rise to oscillatory reflectivity changes. With currents from 0.5 to 1.3 A, the Fourier amplitude of the 410 GHz phonon increases by more than a factor of 2 over a 200 ps period. This amplification is due to stimulated Cerenkov phonon emission by electrons undergoing intraminiband transport. The gain coefficient of 8*10^{3} cm^{-1} is reproduced by theoretical calculations and holds potential for novel sub-THz phonon emitters. PMID- 26943547 TI - Isotropic Kink and Quasiparticle Excitations in the Three-Dimensional Perovskite Manganite La_{0.6}Sr_{0.4}MnO_{3}. AB - In order to reveal the many-body interactions in three-dimensional perovskite manganites that show colossal magnetoresistance, we performed an in situ angle resolved photoemission spectroscopy on La_{0.6}Sr_{0.4}MnO_{3} and investigated the behavior of quasiparticles. We observed quasiparticle peaks near the Fermi momentum in both the electron and the hole bands, and clear kinks throughout the entire hole Fermi surface in the band dispersion. This isotropic behavior of quasiparticles and kinks suggests that polaronic quasiparticles produced by the coupling of electrons with Jahn-Teller phonons play an important role in the colossal magnetoresistance properties of the ferromagnetic metallic phase of three-dimensional manganites. PMID- 26943548 TI - Enhancement of Photoinduced Charge-Order Melting via Anisotropy Control by Double Pulse Excitation in Perovskite Manganites: Pr_{0.6}Ca_{0.4}MnO_{3}. AB - To control the efficiency of photoinduced charge-order melting in perovskite manganites, we performed femtosecond pump-probe spectroscopy using double-pulse excitation on Pr_{0.6}Ca_{0.4}MnO_{3}. The results revealed that the transfer of the spectral weight from the near-infrared to infrared region by the second pump pulse is considerably enhanced by the first pump pulse and that the suppression of crystal anisotropy, that is, the decrease of long-range lattice deformations due to the charge order by the first pump pulse is a key factor to enhance the charge-order melting. This double-pulse excitation method can be applied to various photoinduced transitions in complex materials with electronic and structural instabilities. PMID- 26943549 TI - Generation of Transient Photocurrents in the Topological Surface State of Sb_{2}Te_{3} by Direct Optical Excitation with Midinfrared Pulses. AB - We combine tunable midinfrared (mid-IR) pump pulses with time- and angle-resolved two-photon photoemission to study ultrafast photoexcitation of the topological surface state (TSS) of Sb_{2}Te_{3}. It is revealed that mid-IR pulses permit a direct excitation from the occupied to the unoccupied part of the TSS across the Dirac point. The novel optical coupling induces asymmetric transient populations of the TSS at +/-k_{?}, which reflects a macroscopic photoexcited electric surface current. By observing the decay of the asymmetric population, we directly investigate the dynamics of the long-lived photocurrent in the time domain. Our discovery promises important advantages of photoexcitation by mid-IR pulses for spintronic applications. PMID- 26943558 TI - Generating Soap Bubbles by Blowing on Soap Films. AB - Making soap bubbles by blowing air on a soap film is an enjoyable activity, yet a poorly understood phenomenon. Working either with circular bubble wands or long lived vertical soap films having an adjustable steady state thickness, we investigate the formation of such bubbles when a gas is blown through a nozzle onto a film. We vary film size, nozzle radius, space between the film and nozzle, and gas density, and we measure the gas velocity threshold above which bubbles are formed. The response is sensitive to containment, i.e., the ratio between film and jet sizes, and dissipation in the turbulent gas jet, which is a function of the distance from the film to the nozzle. We rationalize the observed four different regimes by comparing the dynamic pressure exerted by the jet on the film and the Laplace pressure needed to create the curved surface of a bubble. This simple model allows us to account for the interplay between hydrodynamic, physicochemical, and geometrical factors. PMID- 26943551 TI - Emergent Non-Fermi-Liquid at the Quantum Critical Point of a Topological Phase Transition in Two Dimensions. AB - We study the effects of Coulomb interaction between 2D Weyl fermions with anisotropic dispersion which displays relativistic dynamics along one direction and nonrelativistic dynamics along the other. Such a dispersion can be realized in phosphorene under electric field or strain, in TiO_{2}/VO_{2} superlattices, and, more generally, at the quantum critical point between a nodal semimetal and an insulator in systems with a chiral symmetry. Using the one-loop renormalization group approach in combination with the large-N expansion, we find that the system displays interaction-driven non-Fermi liquid behavior in a wide range of intermediate frequencies and marginal Fermi liquid behavior at the smallest frequencies. In the non-Fermi liquid regime, the quasiparticle residue Z at energy E scales as Z?E^{a} with a>0, and the parameters of the fermionic dispersion acquire anomalous dimensions. In the marginal Fermi-liquid regime, Z?(|logE|)^{-b} with universal b=3/2. PMID- 26943552 TI - Amplitude Control of the Spin-Triplet Supercurrent in S/F/S Josephson Junctions. AB - Josephson junctions made with conventional s-wave superconductors and containing multiple layers of ferromagnetic materials can carry spin-triplet supercurrent in the presence of certain types of magnetic inhomogeneity. In junctions containing three ferromagnetic layers, the triplet supercurrent is predicted to be maximal when the magnetizations of the adjacent layers are orthogonal, and zero when the magnetizations of any two adjacent layers are parallel. Here we demonstrate on off control of the spin-triplet supercurrent in such junctions, achieved by rotating the magnetization direction of one of the three layers by 90 degrees . We obtain "on-off" ratios of 5, 7, and 19 for the supercurrent in the three samples that have been studied so far. These observations directly confirm one of the most salient predictions of the theory, and they pave the way for applications of spin-triplet Josephson junctions in the nascent area of "superconducting spintronics". PMID- 26943559 TI - What Determines the Static Force Chains in Stressed Granular Media? AB - The determination of the normal and transverse (frictional) interparticle forces within a granular medium is a long-standing, daunting, and yet unresolved problem. We present a new formalism that employs the knowledge of the external forces and the orientations of contacts between particles (of any given size), to compute all the interparticle forces. Having solved this problem, we exemplify the efficacy of the formalism showing that the force chains in such systems are determined by an expansion in the eigenfunctions of a newly defined operator. PMID- 26943550 TI - Magnetic Interactions at the Nanoscale in Trilayer Titanates. AB - We report on the phase diagram of competing magnetic interactions at the nanoscale in engineered ultrathin trilayer heterostructures of LaTiO_{3}/SrTiO_{3}/YTiO_{3}, in which the interfacial inversion symmetry is explicitly broken. Combined atomic layer resolved scanning transmission electron microscopy with electron energy loss spectroscopy and electrical transport have confirmed the formation of a spatially separated two-dimensional electron liquid and high density two-dimensional localized magnetic moments at the LaTiO_{3}/SrTiO_{3} and SrTiO_{3}/YTiO_{3} interfaces, respectively. Resonant soft x-ray linear dichroism spectroscopy has demonstrated the presence of orbital polarization of the conductive LaTiO_{3}/SrTiO_{3} and localized SrTiO_{3}/YTiO_{3} electrons. Our results provide a route with prospects for exploring new magnetic interfaces, designing a tunable two-dimensional d-electron Kondo lattice, and potential spin Hall applications. PMID- 26943554 TI - Gyrotropic Magnetic Effect and the Magnetic Moment on the Fermi Surface. AB - The current density j^{B} induced in a clean metal by a slowly-varying magnetic field B is formulated as the low-frequency limit of natural optical activity, or natural gyrotropy. Working with a multiband Pauli Hamiltonian, we obtain from the Kubo formula a simple expression for alpha_{ij}^{GME}=j_{i}^{B}/B_{j} in terms of the intrinsic magnetic moment (orbital plus spin) of the Bloch electrons on the Fermi surface. An alternate semiclassical derivation provides an intuitive picture of the effect, and takes into account the influence of scattering processes in dirty metals. This "gyrotropic magnetic effect" is fundamentally different from the chiral magnetic effect driven by the chiral anomaly and governed by the Berry curvature on the Fermi surface, and the two effects are compared for a minimal model of a Weyl semimetal. Like the Berry curvature, the intrinsic magnetic moment should be regarded as a basic ingredient in the Fermi liquid description of transport in broken-symmetry metals. PMID- 26943553 TI - Evolution of High-Temperature Superconductivity from a Low-T_{c} Phase Tuned by Carrier Concentration in FeSe Thin Flakes. AB - We report the evolution of superconductivity in an FeSe thin flake with systematically regulated carrier concentrations by the liquid-gating technique. With electron doping tuned by the gate voltage, high-temperature superconductivity with an onset at 48 K can be achieved in an FeSe thin flake with T_{c} less than 10 K. This is the first time such high temperature superconductivity in FeSe is achieved without either an epitaxial interface or external pressure, and it definitely proves that the simple electron-doping process is able to induce high-temperature superconductivity with T_{c}^{onset} as high as 48 K in bulk FeSe. Intriguingly, our data also indicate that the superconductivity is suddenly changed from a low-T_{c} phase to a high-T_{c} phase with a Lifshitz transition at a certain carrier concentration. These results help to build a unified picture to understand the high-temperature superconductivity among all FeSe-derived superconductors and shed light on the further pursuit of a higher T_{c} in these materials. PMID- 26943562 TI - Comment on "Elastic Membrane Deformations Govern Interleaflet Coupling of Lipid Ordered Domains". PMID- 26943560 TI - Consistent Treatment of Hydrophobicity in Protein Lattice Models Accounts for Cold Denaturation. AB - The hydrophobic effect stabilizes the native structure of proteins by minimizing the unfavorable interactions between hydrophobic residues and water through the formation of a hydrophobic core. Here, we include the entropic and enthalpic contributions of the hydrophobic effect explicitly in an implicit solvent model. This allows us to capture two important effects: a length-scale dependence and a temperature dependence for the solvation of a hydrophobic particle. This consistent treatment of the hydrophobic effect explains cold denaturation and heat capacity measurements of solvated proteins. PMID- 26943564 TI - Erratum: Half-Quantum Vortices in an Antiferromagnetic Spinor Bose-Einstein Condensate [Phys. Rev. Lett. 115, 015301 (2015)]. PMID- 26943556 TI - Enhanced Spin Pumping Efficiency in Antiferromagnetic IrMn Thin Films around the Magnetic Phase Transition. AB - We report the measurement of a spin pumping effect due to fluctuations of the magnetic order of IrMn thin films. A precessing NiFe ferromagnet injected spins into IrMn spin sinks, and enhanced damping was observed around the IrMn magnetic phase transition. Our data were compared to a recently developed theory and converted into interfacial spin mixing conductance enhancements. By spotting the spin pumping peak, the thickness dependence of the IrMn critical temperature could be determined and the characteristic length for the spin-spin interactions was deduced. PMID- 26943557 TI - Coulomb Mediated Hybridization of Excitons in Coupled Quantum Dots. AB - We report Coulomb mediated hybridization of excitonic states in optically active InGaAs quantum dot molecules. By probing the optical response of an individual quantum dot molecule as a function of the static electric field applied along the molecular axis, we observe unexpected avoided level crossings that do not arise from the dominant single-particle tunnel coupling. We identify a new few-particle coupling mechanism stemming from Coulomb interactions between different neutral exciton states. Such Coulomb resonances hybridize the exciton wave function over four different electron and hole single-particle orbitals. Comparisons of experimental observations with microscopic eight-band k.p calculations taking into account a realistic quantum dot geometry show good agreement and reveal that the Coulomb resonances arise from broken symmetry in the artificial semiconductor molecule. PMID- 26943561 TI - Effective Interaction between Active Colloids and Fluid Interfaces Induced by Marangoni Flows. AB - We show theoretically that near a fluid-fluid interface a single active colloidal particle generating, e.g., chemicals or a temperature gradient experiences an effective force of hydrodynamic origin. This force is due to the fluid flow driven by Marangoni stresses induced by the activity of the particle; it decays very slowly with the distance from the interface, and can be attractive or repulsive depending on how the activity modifies the surface tension. We show that, for typical systems, this interaction can dominate the dynamics of the particle as compared to Brownian motion, dispersion forces, or self-phoretic effects. In the attractive case, the interaction promotes the self-assembly of particles into a crystal-like monolayer at the interface. PMID- 26943555 TI - Dynamics of Bound Monopoles in Artificial Spin Ice: How to Store Energy in Dirac Strings. AB - Dirac strings in spin ices are lines of reversed dipoles joining two quasiparticle excitations. These excitations behave as unbound emergent monopoles if the tension of Dirac strings vanishes. In this Letter, analytical and numerical analysis are used to study the dynamics of two-dimensional dipolar spin ices, artificially created analogs of bulk spin ice, in the regime of bound monopoles. It is shown that, in this regime, strings, rather than monopoles, are effective degrees of freedom explaining the finite-width band of Pauling states. A measurable prediction of path-time dependence of endpoints of a stretched and, then, released Dirac string is made and verified via simulations. It is shown that string dynamics is defined by the characteristic tension-to-mass ratio, which is determined by the fine structure constant and lattice dependent parameter. It is proposed to use string tension to achieve spontaneous magnetic currents. A concept of an energy storing device on the basis of this principle is proposed and illustrated by an experimental demonstration. A scheme of independent measurement at the nanoscale is proposed. PMID- 26943563 TI - Galimzyanov et al. Reply. PMID- 26943574 TI - Inhibition of estrogen biosynthesis enhances lymphoma growth in mice. AB - Most lymphomas show higher incidence and poorer prognosis in males compared to females. However, the endocrine contribution to this gender difference is not entirely known. Here we show that castration accelerates lymphoma growth in C57BL6 male mice grafted with murine EG7 T cell lymphoma cells. However, the androgen receptor antagonist Bicalutamide did not affect lymphoma growth, suggesting no impact of androgen receptor signaling on lymphoma progression. In contrast, inhibition of androgen-to-estrogen conversion by the aromatase inhibitor (AI) Letrozole induced faster lymphoma growth in mice, suggesting that androgens impact lymphoma growth through its conversion to estrogens. This was supported by the inability of dihydrotestosterone, which is not converted to estrogens by aromatase, to influence lymphoma growth in castrated male mice. Lymphoma growth was also stimulated in immunocompromised mice grafted with human B cell lymphoma (Granta-519) and treated with either reversible or irreversible AIs, showing that the blockage of estrogen synthesis caused enhanced growth of both murine T and human B cell lymphomas and with different AIs. Additionally, AI treated EG7 lymphomas showed accelerated growth not only in male but also in intact female mice. Altogether, our results demonstrate that aromatase inhibition accelerates lymphoma growth but not androgens per se, highlighting a protective role of estrogens in lymphoma pathogenesis. These results also raise concern that the use of AIs in women with breast cancer might enhance lymphoma progression. PMID- 26943575 TI - Oncogene and therapeutic target analyses in atypical fibroxanthomas and pleomorphic dermal sarcomas. AB - BACKGROUND: Until now, almost nothing is known about the tumorigenesis of atypical fibroxanthoma (AFX) and pleomorphic dermal sarcoma (PDS). Our hypothesis is that AFX is the non-infiltrating precursor lesion of PDS. MATERIALS AND METHODS: We performed the world-wide most comprehensive immunohistochemical and mutational analysis in well-defined AFX (n=5) and PDS (n=5). RESULTS: In NGS based mutation analyses of selected regions by a 17 hotspot gene panel of 102 amplicons we could detect TP53 mutations in all PDS as well as in the only analyzed AFX and PDS of the same patient. Besides, we detected mutations in the CDKN2A, HRAS, KNSTRN and PIK3CA genes.Performing immunohistochemistry for CTNNB1, KIT, CDK4, c-MYC, CTLA-4, CCND1, EGFR, EPCAM, ERBB2, IMP3, INI-1, MKI67, MDM2, MET, p40, TP53, PD-L1 and SOX2 overexpression of TP53, CCND1 and CDK4 was seen in AFX as well as in PDS. IMP3 was upregulated in 2 AFX (weak staining) and 4 PDS (strong staining).FISH analyses for the genes FGFR1, FGFR2 and FGFR3 revealed negative results in all tumors. CONCLUSIONS: UV-induced TP53 mutations as well as CCND1/CDK4 changes seem to play essential roles in tumorigenesis of PDS. Furthermore, we found some more interesting mutated genes in other oncogene pathways (activating mutations of HRAS and PIK3CA). All AFX and PDS investigated immunohistochemically presented with similar oncogene expression profiles (TP53, CCND1, CDK4 overexpression) and the single case with an AFX and PDS showed complete identical TP53 and PIK3CA mutation profiles in both tumors. This reinforces our hypothesis that AFX is the non-infiltrating precursor lesion of PDS. PMID- 26943579 TI - Development of a novel HAC-based "gain of signal" quantitative assay for measuring chromosome instability (CIN) in cancer cells. AB - Accumulating data indicates that chromosome instability (CIN) common to cancer cells can be used as a target for cancer therapy. At present the rate of chromosome mis-segregation is quantified by laborious techniques such as coupling clonal cell analysis with karyotyping or fluorescence in situ hybridization (FISH). Recently, a novel assay was developed based on the loss of a non essential human artificial chromosome (HAC) carrying a constitutively expressed EGFP transgene ("loss of signal" assay). Using this system, anticancer drugs can be easily ranked on by their effect on HAC loss. However, it is problematic to covert this "loss of signal" assay into a high-throughput screen to identify drugs and mutations that increase CIN levels. To address this point, we re designed the HAC-based assay. In this new system, the HAC carries a constitutively expressed shRNA against the EGFP transgene integrated into human genome. Thus, cells that inherit the HAC display no green fluorescence, while cells lacking the HAC do. We verified the accuracy of this "gain of signal" assay by measuring the level of CIN induced by known antimitotic drugs and added to the list of previously ranked CIN inducing compounds, two newly characterized inhibitors of the centromere-associated protein CENP-E, PF-2771 and GSK923295 that exhibit the highest effect on chromosome instability measured to date. The "gain of signal" assay was also sensitive enough to detect increase of CIN after siRNA depletion of known genes controlling mitotic progression through distinct mechanisms. Hence this assay can be utilized in future experiments to uncover novel human CIN genes, which will provide novel insight into the pathogenesis of cancer. Also described is the possible conversion of this new assay into a high throughput screen using a fluorescence microplate reader to characterize chemical libraries and identify new conditions that modulate CIN level. PMID- 26943573 TI - Insights from HuR biology point to potential improvement for second-line ovarian cancer therapy. AB - This retrospective study aimed to investigate the role that an RNA-binding protein, HuR, plays in the response of high-grade serous ovarian tumors to chemotherapeutics. We immunohistochemically stained sections of 31 surgically debulked chemo-naive ovarian tumors for HuR and scored the degree of HuR cytoplasmic staining. We found no correlation between HuR intracellular localization in tumor sections and progression free survival (PFS) of these patients, 29 of whom underwent second-line gemcitabine/platin combination therapy for recurrent disease. Ribonucleoprotein immunoprecipitation (RNP-IP) analysis of ovarian cancer cells in culture showed that cytoplasmic HuR increases deoxycytidine kinase (dCK), a metabolic enzyme that activates gemcitabine. The effects of carboplatin treatment on HuR and WEE1 (a mitotic inhibitor) expression, and on cell cycle kinetics, were also examined. Treatment of ovarian cancer cells with carboplatin results in increased HuR cytoplasmic expression and elevated WEE1 expression, arresting cell cycle G2/M transition. This may explain why HuR cytoplasmic localization in chemo-naive tumors is not predictive of therapeutic response and PFS following second-line gemcitabine/platin combination therapy. These results suggest treatment of recurrent ovarian tumors with a combination of gemcitabine, carboplatin, and a WEE1 inhibitor may be potentially advantageous as compared to current clinical practices. PMID- 26943578 TI - ROCK1 via LIM kinase regulates growth, maturation and actin based functions in mast cells. AB - Understanding mast cell development is essential due to their critical role in regulating immunity and autoimmune diseases. Here, we show how Rho kinases (ROCK) regulate mast cell development and can function as therapeutic targets for treating allergic diseases. Rock1 deficiency results in delayed maturation of bone marrow derived mast cells (BMMCs) in response to IL-3 stimulation and reduced growth in response to stem cell factor (SCF) stimulation. Further, integrin-mediated adhesion and migration, and IgE-mediated degranulation are all impaired in Rock1-deficient BMMCs. To understand the mechanism behind altered mast cell development in Rock1-/- BMMCs, we analyzed the activation of ROCK and its downstream targets including LIM kinase (LIMK). We observed reduced activation of ROCK, LIMK, AKT and ERK1/2 in Rock1-deficient BMMCs in response to SCF stimulation. Further, loss of either Limk1 or Limk2 also demonstrated altered BMMC maturation and growth; combined deletion of both Limk1 and Limk2 resulted in further reduction in BMMC maturation and growth. In passive cutaneous anaphylaxis model, deficiency of Rock1 or treatment with ROCK inhibitor Fasudil protected mice against IgE-mediated challenge. Our results identify ROCK/LIMK pathway as a novel therapeutic target for treating allergic diseases involving mast cells. PMID- 26943576 TI - Pin1 is required for sustained B cell proliferation upon oncogenic activation of Myc. AB - The c-myc proto-oncogene is activated by translocation in Burkitt's lymphoma and substitutions in codon 58 stabilize the Myc protein or augment its oncogenic potential. In wild-type Myc, phosphorylation of Ser 62 and Thr 58 provides a landing pad for the peptidyl prolyl-isomerase Pin1, which in turn promotes Ser 62 dephosphorylation and Myc degradation. However, the role of Pin1 in Myc-induced lymphomagenesis remains unknown. We show here that genetic ablation of Pin1 reduces lymphomagenesis in EMU-myc transgenic mice. In both Pin1-deficient B cells and MEFs, the proliferative response to oncogenic Myc was selectively impaired, with no alterations in Myc-induced apoptosis or mitogen-induced cell cycle entry. This proliferative defect wasn't attributable to alterations in either Ser 62 phosphorylation or Myc-regulated transcription, but instead relied on the activity of the ARF-p53 pathway. Pin1 silencing in lymphomas retarded disease progression in mice, making Pin1 an attractive therapeutic target in Myc driven tumors. PMID- 26943581 TI - Concordance of folate receptor-alpha expression between biopsy, primary tumor and metastasis in breast cancer and lung cancer patients. AB - Folate receptor alpha (FRalpha) is known to be upregulated in a variety of cancers, including non-small cell lung cancer (NSCLC) and breast cancer. To ensure reliable implementation of diagnostic- and therapeutic agents, concordance of FRalpha expression between biopsy, primary tumor and metastases is important. Using immunohistochemistry (Mab 26B3.F2) these concordances were investigated in 60 NSCLC and 40 breast cancer patients. False positivity of FRalpha expression on breast and lung cancer biopsies was limited to less than 5%. In NSCLC, FRalpha expression was shown in 21/34 adenocarcinomas and 4/26 squamous cell carcinomas (SCC). Concordance of FRalpha expression between biopsy and primary tumor was achieved in respectively 83% and 91% of adenocarcinomas and SCCs. Approximately 80% of all local and distant metastases of NSCLC patients showed concordant FRalpha expression as their corresponding primary tumor. In breast cancer, FRalpha positivity was shown in 12/40 biopsies, 20/40 lumpectomies and 6/20 LN metastases, with concordance of 68% between biopsy and primary tumor and 60% between primary tumor and LN metastases. In conclusion, this study shows high concordance rates of FRalpha expression between biopsies and metastases compared to primary NSCLC and breast cancers, underscoring the applicability of FRalpha targeted agents in these patients. PMID- 26943580 TI - Altered expression of neuropeptide Y receptors caused by focal cortical dysplasia in human intractable epilepsy. AB - Focal cortical dysplasia (FCD) is a common cause of pharmacologically-intractable epilepsy, however, the precise mechanisms underlying the epileptogenicity of FCD remains to be determined. Neuropeptide Y (NPY), an endogenous anticonvulsant in the central nervous system, plays an important role in the regulation of neuronal excitability. Increased expression of NPY and its receptors has been identified in the hippocampus of patients with mesial temporal lobe epilepsy, presumed to act as an endogenous anticonvulsant mechanism. Therefore, we investigated whether expression changes in NPY receptors occurs in patients with FCD. We specifically investigated the expression of seizure-related NPY receptor subtypes Y1, Y2, and Y5 in patients with FCD versus autopsy controls. We found that Y1R and Y2R were up-regulated at the mRNA and protein levels in the temporal and frontal lobes in FCD lesions. By contrast, there was no significant change in either receptor detected in parietal lesions. Notably, overexpression of Y5R was consistently observed in all FCD lesions. Our results demonstrate the altered expression of Y1R, Y2R and Y5R occurs in FCD lesions within the temporal, frontal and parietal lobe. Abnormal NPY receptor subtype expression may be associated with the onset and progression of epileptic activity and may act as a therapeutic candidate for the treatment of refractory epilepsy caused by FCD. PMID- 26943577 TI - Diagnostic and prognostic relevance of circulating exosomal miR-373, miR-200a, miR-200b and miR-200c in patients with epithelial ovarian cancer. AB - Exosomes are membrane vesicles that mediate intercellular communication by transporting their molecular cargo from cell to cell. We investigated whether serum levels of exosomal miR-373, miR-200a, miR-200b and miR-200c and circulating exosomes have diagnostic and prognostic relevance in a cohort of 163 epithelial ovarian cancer (EOC) patients using TaqMan MicroRNA assays and ELISA. The serum concentrations of exosomal miR-373 (p = 0.0001), miR-200a (p = 0.0001), miR-200b (p = 0.0001) and miR-200c (p = 0.028) were significantly higher in EOC patients than healthy women. The levels of miR-200a (p = 0.0001), miR-200b (p = 0.0001) and miR-200c (p = 0.019) could distinguish between malignant and benign ovarian tumors. While the levels of miR-373 and miR-200a were increased in all FIGO/lymph node stages (p = 0.0001), the levels of miR-200b and miR-200c were higher in patients with FIGO stage III-IV (p = 0.0001, p = 0.008, respectively) including lymph node metastasis (p = 0.0001, p = 0.004, respectively) than FIGO stages I II. The increased levels of miR-200b and miR-200c were also associated with CA125 values (p = 0.0001, p = 0.0001, respectively) and a shorter overall survival (p = 0.007, p = 0.017, respectively). The levels of exosomes were excessively elevated in EOC patients (p = 0.0001). In all three cohorts, they were positively associated with the serum levels of exosomal miR-373 (p = 0.004), miR-200a (p = 0.0001), miR-200b (p = 0.0001) and miR-200c (p = 0.008). In conclusion, the increased levels of exosomal miR-200b and miR-200c mainly observed in advanced EOC suggest that these microRNAs may be involved in tumor progression. The high concentrations of exosomes in EOC patients imply an excessive, active exosomal secretion in EOC. PMID- 26943584 TI - PGC-1alpha overexpression protects against aldosterone-induced podocyte depletion: role of mitochondria. AB - Growing evidence has shown that podocyte number is a critical determinant for the development of glomerulosclerosis and progressive renal failure. We previously reported that mitochondrial dysfunction (MtD) is an early event in podocyte injury. Peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC 1alpha) is an important modulator of mitochondrial biogenesis. Here, we investigated the role of PGC-1alpha overexpression in podocyte depletion and the involvement of mitochondria in this process. Following chronic aldosterone (Aldo) infusion for 14 days, we observed a remarkable podocyte loss, podocyte phenotypic changes, and albuminuria in WT mice. However, all these abnormalities were significantly attenuated in PGC-1alpha transgenic mice. Next, we examined mitochondrial function in both genotypes with or without Aldo infusion. As expected, Aldo-induced MtD in glomeruli was markedly improved in PGC-1alpha transgenic mice. In vitro, Aldo induced podocyte detachment and phenotypic changes in line with MtD in dose- and time-dependent manners. Similarly, ethidium bromide, an inducer of MtD, mimicked Aldo effects on podocyte detachment and phenotypic alterations. Notably, overexpression of PGC-1alpha in podocytes entirely reversed Aldo-induced podocyte detachment, phenotypic changes, and MtD. Taken together, these findings demonstrate that PGC-1alpha protects against podocyte depletion and phenotypic changes possibly by maintaining normal mitochondrial function. PMID- 26943586 TI - Loss of p53-mediated cell-cycle arrest, senescence and apoptosis promotes genomic instability and premature aging. AB - Although p53-mediated cell cycle arrest, senescence and apoptosis are well accepted as major tumor suppression mechanisms, the loss of these functions does not directly lead to tumorigenesis, suggesting that the precise roles of these canonical activities of p53 need to be redefined. Here, we report that the cells derived from the mutant mice expressing p533KR, an acetylation-defective mutant that fails to induce cell-cycle arrest, senescence and apoptosis, exhibit high levels of aneuploidy upon DNA damage. Moreover, the embryonic lethality caused by the deficiency of XRCC4, a key DNA double strand break repair factor, can be fully rescued in the p533KR/3KR background. Notably, despite high levels of genomic instability, p533KR/3KRXRCC4-/- mice, unlike p53-/- XRCC4-/- mice, are not succumbed to pro-B-cell lymphomas. Nevertheless, p533KR/3KR XRCC4-/- mice display aging-like phenotypes including testicular atrophy, kyphosis, and premature death. Further analyses demonstrate that SLC7A11 is downregulated and that p53-mediated ferroptosis is significantly induced in spleens and testis of p533KR/3KRXRCC4-/- mice. These results demonstrate that the direct role of p53 mediated cell cycle arrest, senescence and apoptosis is to control genomic stability in vivo. Our study not only validates the importance of ferroptosis in p53-mediated tumor suppression in vivo but also reveals that the combination of genomic instability and activation of ferroptosis may promote aging-associated phenotypes. PMID- 26943582 TI - Cancer therapeutic approach based on conformational stabilization of mutant p53 protein by small peptides. AB - The p53 tumor suppressor serves as a major barrier against malignant transformation. Over 50% of tumors inactivate p53 by point mutations in its DNA binding domain. Most mutations destabilize p53 protein folding, causing its partial denaturation at physiological temperature. Thus a high proportion of human tumors overexpress a potential potent tumor suppressor in a non-functional, misfolded form. The equilibrium between the properly folded and misfolded states of p53 may be affected by molecules that interact with p53, stabilizing its native folding and restoring wild type p53 activity to cancer cells. To select for mutant p53 (mutp53) reactivating peptides, we adopted the phage display technology, allowing interactions between mutp53 and random peptide libraries presented on phages and enriching for phage that favor the correctly folded p53 conformation. We obtained a large database of potential reactivating peptides. Lead peptides were synthesized and analyzed for their ability to restore proper p53 folding and activity. Remarkably, many enriched peptides corresponded to known p53-binding proteins, including RAD9. Importantly, lead peptides elicited dramatic regression of aggressive tumors in mouse xenograft models. Such peptides might serve as novel agents for human cancer therapy. PMID- 26943588 TI - Analysis of plasma microRNA expression profiles revealed different cancer susceptibility in healthy young adult smokers and middle-aged smokers. AB - Cigarette smoking is a world-wide habit and an important risk factor for cancer. It was known that cigarette smoking can change the expression of circulating microRNAs (miRNAs) in healthy middle-aged adults. However, it remains unclear whether cigarette smoking can change the levels of circulating miRNAs in young healthy smokers and whether there are differences in cancer susceptibility for the two cases. In this study, the miRNA expression profiles of 28 smokers and 12 non-smokers were determined by Agilent human MicroRNA array. We further performed bioinformatics analysis for the differentially expressed miRNAs. The result showed that 35 miRNAs were differentially expressed. Among them, 24 miRNAs were up-regulated and 11 miRNAs were down-regulated in smokers. Functional enrichment analysis showed that the deregulated miRNAs are related to immune system and hormones regulation. Strikingly, the up-regulated miRNAs are mostly associated with hematologic cancers, such as lymphoma, leukemia. As a comparison, the up regulated plasma miRNAs in middle-aged smokers are mostly associated with solid cancers, such as hepatocellular carcinoma and lung cancer, suggesting that smoking could have different influences on young adults and middle-aged adults. In a conclusion, we identified the circulating miRNAs deregulated by cigarette smoking and revealed that the age-dependent deregulated miRNAs tend to be mainly involved in different types of human cancers. PMID- 26943571 TI - Molecular alterations in hepatocellular carcinoma associated with hepatitis B and hepatitis C infections. AB - Chronic infections with hepatitis B (HBV) and hepatitis C viruses (HCV) are the leading cause of cirrhosis and hepatocellular carcinoma (HCC) worldwide. Both viruses encode multifunctional regulatory proteins activating several oncogenic pathways, which induce accumulation of multiple genetic alterations in the infected hepatocytes. Gene mutations in HBV- and HCV-induced HCCs frequently impair the TP53, Wnt/b-catenin, RAS/RAF/MAPK kinase and AKT/mTOR pathways, which represent important anti-cancer targets. In this review, we highlight the molecular mechanisms underlying the pathogenesis of primary liver cancer, with particular emphasis on the host genetic variations identified by high-throughput technologies. In addition, we discuss the importance of genetic alterations, such as mutations in the telomerase reverse transcriptase (TERT) promoter, for the diagnosis, prognosis, and tumor stratification for development of more effective treatment approaches. PMID- 26943572 TI - Combining BRAF inhibitor and anti PD-L1 antibody dramatically improves tumor regression and anti tumor immunity in an immunocompetent murine model of anaplastic thyroid cancer. AB - The interaction of programmed cell death-1 and its ligand is widely studied in cancer. Monoclonal antibodies blocking these molecules have had great success but little is known about them in thyroid cancer. We investigated the role of PD-L1 in thyroid cancer with respect to BRAF mutation and MAP kinase pathway activity and the effect of anti PD-L1 antibody therapy on tumor regression and intra tumoral immune response alone or in combination with BRAF inhibitor (BRAFi). BRAFV600E cells showed significantly higher baseline expression of PD-L1 at mRNA and protein levels compared to BRAFWT cells. MEK inhibitor treatment resulted in a decrease of PD-L1 expression across all cell lines. BRAFi treatment decreased PD-L1 expression in BRAFV600E cells, but paradoxically increased its expression in BRAFWT cells. BRAFV600E mutated patients samples had a higher level of PD-L1 mRNA compared to BRAFWT (p=0.015). Immunocompetent mice (B6129SF1/J) implanted with syngeneic 3747 BRAFV600E/WT P53-/- murine tumor cells were randomized to control, PLX4720, anti PD-L1 antibody and their combination. In this model of aggressive thyroid cancer, control tumor volume reached 782.3+/-174.6mm3 at two weeks. The combination dramatically reduced tumor volume to 147.3+/-60.8, compared to PLX4720 (439.3+/-188.4 mm3, P=0.023) or PD-L1 antibody (716.7+/-62.1, P<0.001) alone. Immunohistochemistry analysis revealed intense CD8+ CTL infiltration and cytotoxicity and favorable CD8+:Treg ratio compared to each individual treatment. Our results show anti PD-L1 treatment potentiates the effect of BRAFi on tumor regression and intensifies anti tumor immune response in an immunocompetent model of ATC. Clinical trials of this therapeutic combination may be of benefit in patients with ATC. PMID- 26943587 TI - A BRCA1 deficient, NFkappaB driven immune signal predicts good outcome in triple negative breast cancer. AB - Triple negative (TNBCs) and the closely related Basal-like (BLBCs) breast cancers are a loosely defined collection of cancers with poor clinical outcomes. Both show strong similarities with BRCA1-mutant breast cancers and BRCA1 dysfunction, or 'BRCAness', is observed in a large proportion of sporadic BLBCs. BRCA1 expression and function has been shown in vitro to modulate responses to radiation and chemotherapy. Exploitation of this knowledge in the treatment of BRCA1-mutant patients has had varying degrees of success. This reflects the significant problem of accurately detecting those patients with BRCA1 dysfunction. Moreover, not all BRCA1 mutations/loss of function result in the same histology/pathology or indeed have similar effects in modulating therapeutic responses. Given the poor clinical outcomes and lack of targeted therapy for these subtypes, a better understanding of the biology underlying these diseases is required in order to develop novel therapeutic strategies.We have discovered a consistent NFkappaB hyperactivity associated with BRCA1 dysfunction as a consequence of increased Reactive Oxygen Species (ROS). This biology is found in a subset of BRCA1-mutant and triple negative breast cancer cases and confers good outcome. The increased NFkappaB signalling results in an anti-tumour microenvironment which may allow CD8+ cytotoxic T cells to suppress tumour progression. However, tumours lacking this NFkappaB-driven biology have a more tumour-promoting environment and so are associated with poorer prognosis. Tumour derived gene expression data and cell line models imply that these tumours may benefit from alternative treatment strategies such as reprogramming the microenvironment and targeting the IGF and AR signalling pathways. PMID- 26943593 TI - Connecting science with industry: lessons learned transferring a novel plasmonic mercury sensor from the bench to the field. AB - Mercury is a pollutant of pressing global concern. National and international efforts are focused on reducing mercury in the environment to prevent its adverse health impacts. Better sensors would aid in these efforts. This paper details ongoing efforts to deploy novel plasmonic mercury sensors. The authors describe the research efforts to develop the fundamental technology in a research lab and the experience translating that fundamental research into a viable field-ready sensor. Lessons learned along the way are explored. PMID- 26943585 TI - Novel Mad2-targeting miR-493-3p controls mitotic fidelity and cancer cells' sensitivity to paclitaxel. AB - The molecular pathways that contribute to the proliferation and drug response of cancer cells are highly complex and currently insufficiently characterized. We have identified a previously unknown microRNA-based mechanism that provides cancer cells means to stimulate tumorigenesis via increased genomic instability and, at the same time, evade the action of clinically utilized microtubule drugs. We demonstrate miR-493-3p to be a novel negative regulator of mitotic arrest deficient-2 (MAD2), an essential component of the spindle assembly checkpoint that monitors the fidelity of chromosome segregation. The microRNA targets the 3' UTR of Mad2 mRNA thereby preventing translation of the Mad2 protein. In cancer cells, overexpression of miR-493-3p induced a premature mitotic exit that led to increased frequency of aneuploidy and cellular senescence in the progeny cells. Importantly, excess of the miR-493-3p conferred resistance of cancer cells to microtubule drugs. In human neoplasms, miR-493-3p and Mad2 expression alterations correlated with advanced ovarian cancer forms and high miR-493-3p levels were associated with reduced survival of ovarian and breast cancer patients with aggressive tumors, especially in the paclitaxel therapy arm. Our results suggest that intratumoral profiling of miR-493-3p and Mad2 levels can have diagnostic value in predicting the efficacy of taxane chemotherapy. PMID- 26943590 TI - Differences in mean arterial pressure of young and elderly people measured by oscilometry during inflation and deflation of the arm cuff. AB - Systemic arterial blood pressure (BP) is one of the most important parameters of the cardiovascular system. An oscillometric NIBP monitor was specifically designed to measure oscillometric pulsations and mean arterial pressure (MAP) during inflation and deflation of the cuff. Nineteen healthy young (age 23.1+/ 1.7 years; mean+/-SD) and 35 elderly (83.9+/-7.9 years; mean+/-SD) subjects were studied. Differential analysis of MAP during inflation and deflation show mean |DeltaMAP|=2.9+/-2.6 mm Hg in the young group (mean+/-SD) and |DeltaMAP|=6.3+/ 5.2 mm Hg for seniors (mean+/-SD). There was a significant difference (p<0.05) in means of |DeltaMAP| measured during cuff inflation and cuff deflation between both groups. In about 50% of elderly subjects |DeltaMAP| was higher than 5 mm Hg. Potential clinical relevance of the method needs to be further evaluated. PMID- 26943583 TI - Anti-TNF-alpha treatment modulates SASP and SASP-related microRNAs in endothelial cells and in circulating angiogenic cells. AB - Endothelial cell senescence is characterized by acquisition of senescence associated secretory phenotype (SASP), able to promote inflammaging and cancer progression. Emerging evidence suggest that preventing SASP development could help to slow the rate of aging and the progression of age-related diseases, including cancer. Aim of this study was to evaluate whether and how adalimumab, a monoclonal antibody directed against tumor necrosis factor-alpha (TNF-alpha), a major SASP component, can prevent the SASP. A three-pronged approach has been adopted to assess the if adalimumab is able to: i) modulate a panel of classic and novel senescence- and SASP-associated markers (interleukin [IL]-6, senescence associated-beta-galactosidase, p16/Ink4a, plasminogen activator inhibitor 1, endothelial nitric oxide synthase, miR-146a-5p/Irak1 and miR-126-3p/Spred1) in human umbilical vein endothelial cells (HUVECs); ii) reduce the paracrine effects of senescent HUVECs' secretome on MCF-7 breast cancer cells, through wound healing and mammosphere assay; and iii) exert significant decrease of miR-146a-5p and increase of miR-126-3p in circulating angiogenic cells (CACs) from psoriasis patients receiving adalimumab in monotherapy.TNF-alpha blockade associated with adalimumab induced significant reduction in released IL-6 and significant increase in eNOS and miR-126-3p expression levels in long-term HUVEC cultures.A significant reduction in miR-146a-5p expression levels both in long-term HUVEC cultures and in CACs isolated from psoriasis patients was also evident. Interestingly, conditioned medium from senescent HUVECs treated with adalimumab was less consistent than medium from untreated cells in inducing migration- and mammosphere- promoting effects on MCF-7 cells.Our findings suggest that adalimumab can induce epigenetic modifications in cells undergoing senescence, thus contributing to the attenuation of SASP tumor-promoting effects. PMID- 26943591 TI - Hydrophobic forces as a key factor in crystalline biofilm formation on ureteral stents. AB - BACKGROUND: Current discussions about biofilm formation focus on the solid/liquid interface between a medical device and body fluids. Yet it has been shown that gas bubbles (GB) can stably form on ureteral stents in artificial urine and that their fate depends on the stent's surface properties. The liquid/gas interface constitutes an adhesion site for precipitating salts as well as hydrophobic organic molecules. MATERIALS AND METHODS: The surface wettability of polyurethane stents is varied by coating with amorphous hydrogenated carbon (a-C:H). GB and crystalline biofilm formation on the stents are investigated in a novel encrustation device which avoids gravitation- or sample-position-related influences on the results. RESULTS: Bigger and more stable GB form on hydrophobic stents than on hydrophilic, coated stents. Appearance and amount of crystalline deposits differ significantly between the surfaces. With decreasing wettability the number of hollow crystalline spheres and the mass of precipitate increase. CONCLUSIONS: On hydrophobic surfaces, stable GB increase precipitation of salts and become incorporated in the growing encrustation layer in vitro. In contrast, GB quickly lift off from hydrophilic surfaces taking part of the precipitate with them. This self-cleaning mechanism slows down the encrustation process. A similar effect may explain the prolonged complication-free indwelling time of amorphous carbon coated stents in vivo. PMID- 26943592 TI - Analysis of compound action potentials elicited with specific current stimulating pulses in an isolated rat sciatic nerve. AB - The ability to selectively stimulate Aalpha, Abeta-fibers and Adelta-fibers in an isolated rat sciatic nerve (SNR) was assessed. The stimulus used was a current, biphasic pulse with a quasitrapezoidal cathodic phase and rectangular anodic phase where parameters were systematically varied: intensity of the cathodic phase (ic); width of the cathodic phase (tc); width of the cathodic exponential decay (texp) and time constant of the exponential decay (tauexp). A SNR was stimulated using a pair of hook electrodes while conduction velocity (CV) and compound action potentials (CAP) were measured at two sites along the SNR using another two pairs of electrodes. Results showed that the highest CAP1 (8.5-9 mV), shall be expected when parameters of the stimulus were within the following range: ic=3.8-4 mA, tc=350-400 MUs and texp=330-440 MUs. Results also showed that with ascending tc and texp, CV of the corresponding superficial region of the SNR was reduced in both, conduction velocity of CAP1 and conduction velocity of CAP2. It was concluded that action potentials (APs) were activated in the Abeta-fibers and Adelta-fibers along with a slight AP inhibition in the Abeta-fibers. The obtained results, could serve as a tool for developing multi-electrode systems that potentially enable fiber-type selective stimulation of nerve fibers. PMID- 26943589 TI - Accelerated geroncogenesis in hereditary breast-ovarian cancer syndrome. AB - The geroncogenesis hypothesis postulates that the decline in metabolic cellular health that occurs naturally with aging drives a "field effect" predisposing normal tissues for cancer development. We propose that mutations in the cancer susceptibility genes BRCA1/2 might trigger "accelerated geroncogenesis" in breast and ovarian epithelia. By speeding up the rate at which the metabolic threshold becomes "permissive" with survival and expansion of genomically unstable pre tumoral epithelial cells, BRCA haploinsufficiency-driven metabolic reprogramming would operate as a bona fide oncogenic event enabling malignant transformation and tumor formation in BRCA carriers. The metabolic facet of BRCA1 one-hit might involve tissue-specific alterations in acetyl-CoA, alpha-ketoglutarate, NAD+, FAD, or S-adenosylmethionine, critical factors for de/methylation or de/acetylation dynamics in the nuclear epigenome. This in turn might induce faulty epigenetic reprogramming at the "install phase" that directs cell-specific differentiation of breast/ovarian epithelial cells, which can ultimately determine the penetrance of BRCA defects during developmental windows of susceptibility. This model offers a framework to study whether metabolic drugs that prevent or revert metabolic reprogramming induced by BRCA haploinsufficiency might displace the "geroncogenic risk" of BRCA carriers to the age typical for those without the mutation. The identification of the key nodes that directly communicate changes in cellular metabolism to the chromatin in BRCA haploinsufficient cells may allow the epigenetic targeting of genomic instability using exclusively metabolic means. The validation of accelerated geroncogenesis as an inherited "one-hit" metabolic "field effect" might offer new strategies to therapeutically revisit the apparently irreversible genetic-hereditary fate of women with hereditary breast-ovarian cancer syndrome. PMID- 26943597 TI - Cancer surveillance and research on environmental contributions to cancer. AB - Cancer surveillance is a fundamental component of national or sub-national cancer control planning and research. Cancer incidence and mortality data allow countries to monitor change in cancer incidence, mortality, and survival over time, by geographic region, and by demographic characteristics. Such data provide important clues to form hypotheses for cancer etiologic research, including research to examine environmental contributions to cancer. Strengthening cancer surveillance systems is urgently needed to conduct high quality research in environmental pollution and cancer in many countries. The United States National Cancer Institute Center for Global Health organized the first symposium on Environmental Contributions to Cancer during the 16th International Conference of Pacific Basin Consortium (PBC) for Environment and Health. PBC provided an important forum for dialog to establish partnerships and collaborations among researchers of environmental pollution and cancer. PMID- 26943595 TI - Hydraulic fracturing for natural gas: impact on health and environment. AB - Shale deposits exist in many parts of the world and contain relatively large amounts of natural gas and oil. Recent technological developments in the process of horizontal hydraulic fracturing (hydrofracturing or fracking) have suddenly made it economically feasible to extract natural gas from shale. While natural gas is a much cleaner burning fuel than coal, there are a number of significant threats to human health from the extraction process as currently practiced. There are immediate threats to health resulting from air pollution from volatile organic compounds, which contain carcinogens such as benzene and ethyl-benzene, and which have adverse neurologic and respiratory effects. Hydrogen sulfide, a component of natural gas, is a potent neuro- and respiratory toxin. In addition, levels of formaldehyde are elevated around fracking sites due to truck traffic and conversion of methane to formaldehyde by sunlight. There are major concerns about water contamination because the chemicals used can get into both ground and surface water. Much of the produced water (up to 40% of what is injected) comes back out of the gas well with significant radioactivity because radium in subsurface rock is relatively water soluble. There are significant long-term threats beyond cancer, including exacerbation of climate change due to the release of methane into the atmosphere, and increased earthquake activity due to disruption of subsurface tectonic plates. While fracking for natural gas has significant economic benefits, and while natural gas is theoretically a better fossil fuel as compared to coal and oil, current fracking practices pose significant adverse health effects to workers and near-by residents. The health of the public should not be compromized simply for the economic benefits to the industry. PMID- 26943594 TI - Diabetes in Native Americans: elevated risk as a result of exposure to polychlorinated biphenyls (PCBs). AB - We have studied rates of diabetes in 601 members of the Mohawk Nation at Akwesasne, ages 18-84 years, in relation to serum concentrations of 101 polychlorinated biphenyl (PCB) congeners and three chlorinated pesticides [dichlorodiphenyldichloroethylene (DDE), hexachlorobenzene (HCB) and mirex]. Diabetes was determined from either a diagnosis by a physician or by having a fasting glucose concentration of >125 mg/dL. Rates of diabetes are high in this community. Three models were used. In the first model rate ratios (RR) were determined for quartiles of total PCBs after adjustment for age, sex, body mass index (BMI) and total serum lipids. For total PCBs RR=2.21 (1.2-4.2), while for total pesticides RR=3.75 (1.3-10.7). When the total PCB results were also adjusted for total pesticides and the total pesticide results were also adjusted for total PCBs (Model 2) the RRs were somewhat reduced. In Model 3 we considered subgroups of PCBs based on numbers of chlorines on the molecule (tri-/tetra, penta-/hexa, hepta plus) and numbers of ortho chlorines (non-/mono; di-, tri /tetra-), and considered each of the pesticides individually after adjustment for all other contaminants as well as age, sex, BMI and serum lipids. We found a highly significant association between diabetes and PCBs with only three or four chlorines (RR=5.02), but no significant association with those with greater chlorination. When evaluating PCBs based on numbers of ortho chlorines only, those with no or one ortho chlorine showed significant associations. As mono ortho PCBs include some with dioxin-like activity, we compared those with and without a TEF, and found that the association with diabetes was exclusively with the non-dioxin-like congeners. Of the pesticides only hexachlorobenzene showed a small but significant association with diabetes. Because lower chlorinated PCBs are more volatile and do not greatly accumulate in fish, these results suggest that inhalation is the major route of exposure to those PCBs that increase risk of diabetes. PMID- 26943598 TI - E-waste issues in Sri Lanka and the Basel Convention. AB - E-waste is hazardous, complex and expensive to treat in an environmentally sound manner. The management of e-waste is considered a serious challenge in both developed and developing countries and Sri Lanka is no exception. Due to significant growth in the economy and investments and other reasons the consumption of electronic and electrical equipment in Sri Lanka has increased over the years resulting in significant generation of e-waste. Several initiatives such as introduction of hazardous waste management rules, ratification of the Basel Convention in 1992 and the introduction of a National Corporate E-waste Management Program have been undertaken in Sri Lanka to manage e-waste. Strengthening policy and legislation, introducing methods for upstream reduction of e-waste, building capacity of relevant officers, awareness raising among school children and the general public and development of an e-waste information system are vital. Research on e-waste needs to be developed in Sri Lanka. The health sector could play a leading role in the provision of occupational health and safety for e-waste workers, advocacy, capacity building of relevant staff and raising awareness among the general public about e-waste. Improper e-waste management practices carried out by informal sector workers need to be addressed urgently in Sri Lanka. PMID- 26943596 TI - Particulate matter 2.5 (PM2.5) personal exposure evaluation on mechanics and administrative officers at the motor vehicle testing center at Pulo Gadung, DKI Jakarta. AB - Exposure to fine particulate matter (PM2.5) in both the short and long term has been known to cause deaths and health effects, especially related to the heart, blood vessels, and lungs. Based on this information, researchers conducted this study at a motor vehicle testing center unit at Pulo Gadung, in Jarkarta, to determine the concentration of PM2.5 that workers were exposed to. The major source of PM2.5 in this area is from the exhaust of gas emissions from motor vehicles, which is one of the largest contributors to the levels of PM in urban areas. Ten mechanics were picked from 16 mechanics that work in this station. Four administration workers from different posts were also picked to participate. The researcher conducted the PM2.5 personal exposure measurement during weekdays from 6 to 14 April 2015 (2 workers/day). This research was conducted to measure the particle number concentration with size <2.5 MUm. The average personal exposure concentrations of PM2.5 in the study period received by the group of mechanics amounted to 149.01 MUm/m3 while the administrative officer group that consisted of four administrative workers were exposed to an average of 103.28 MUm/m3. Once converted and compared with the World Health Organization Air Quality Guidelines, the PM2.5 exposure of the mechanics and administrative officers exceeded the recommended exposure (25 MUm/m3). PMID- 26943602 TI - Pilot-scale UV/H2O2 study for emerging organic contaminants decomposition. AB - Human behaviors including consumption of drugs and use of personal care products, climate change, increased international travel, and the advent of water reclamation for direct potable use have led to the introduction of significant amounts of emerging organic contaminants into the aqueous environment. In addition, the lower detection limits associated with improved scientific methods of chemical analysis have resulted in a recent increase in documented incidences of these contaminants which previously were not routinely monitored in water. Such contaminants may cause known or suspected adverse ecological and/or human health effects at very low concentrations. Conventional drinking water treatment processes may not effectively remove these organic contaminants. Advanced oxidation process (AOP) is a promising treatment process for the removal of most of these emerging organic contaminants, and has been accepted worldwide as a suitable treatment process. In this study, different groups of emerging contaminants were studied for decomposition efficiency using pilot-scale UV/H2O2 oxidation setup, including EDCs, PPCPs, taste and odor (T&O), and perfluorinated compounds. Results found that MP UV/H2O2 AOP was efficient in removing all the selected contaminants except perfluorinated compounds. Study of the kinetics of the process showed that both light absorption and quantum yield of each compound affected the decomposition performance. Analysis of water quality parameters of the treated water indicated that the outcome of both UV photolysis and UV/H2O2 processes can be affected by changes in the feed water quality. PMID- 26943599 TI - Pollution, health and development: the need for a new paradigm. AB - BACKGROUND: Pollution is the largest cause of death in low- and middle-income countries. WHO estimates that 8.9 million persons die each year of diseases caused by pollution - 94% of them in poor countries. By comparison, HIV/AIDS causes 1.5 million deaths per year, and malaria and tuberculosis cause fewer than 1 million each. Diseases caused by pollution are very costly. PREVENTION: Pollution can be prevented. In high-income countries, legal and technical control strategies have been developed and yielded great health and economic benefits. The removal of lead from gasoline increased the mean IQ of all American children and has generated an annual economic benefit of $213 billion. Unmet need: Despite its enormous human and economic costs, pollution has been overlooked in the international development agenda. Pollution control currently receives <0.5% of development spending. SOLUTION: We have formed The Lancet-GAHP-Mount Sinai Commission on Pollution, Health and Development. This Commission will develop robust analyses of the impacts of pollution on health, economics, and development. It will inform heads of state and global funders about the enormous scale pollution's effects. The ultimate goal is to raise the priority of pollution and increase the resources allocated to control of this urgent public health problem. PMID- 26943600 TI - Sustainable development through a gendered lens: climate change adaptation and disaster risk reduction. AB - The UN General Assembly has just adopted the post 2015 Sustainable Development Agenda articulated in the 17 Sustainable Development Goals (SDGs). Achieving the SDGs will be furthered by the closer integration of the climate change adaptation (CCA) and disaster risk reduction (DRR) agendas. Gender provides us a valuable portal for considering this integration. Acknowledging that gender relaters to both women and men and that men and women experience climate variability and disasters differently, in this paper the role of women in both CCA and DRR is explored, shifting the focus from women as vulnerable victims to women as critical agents for change with respect to climate change mitigation and adaptation and reduction of disaster risks. Appropriately targeted interventions can also empower women and contribute to more just and inclusive sustainable development. PMID- 26943603 TI - Is there a sex difference in fetal behavior? A comparison of the KANET test between male and female fetuses. AB - AIM: To evaluate the sex difference in fetal behavior between male and female fetuses. METHODS: Fetal behavior was assesed by Kurjak's antenatal neurodevelopmental test (KANET) using four-dimensional (4D) ultrasound between 28 and 39 weeks of gestation. Fifty-nine male and 53 female fetuses in middle- and high-class nulliparaous Japanese women were studied. The total value of the KANET score and values of each parameter (eight parameters) were compared. RESULTS: The total KANET score was normal in both groups, and there was no significant difference in the total KANET score. When individual KANET parameters were compared, no significant differences were noted in all eight parameters. CONCLUSION: Our results show that there is no difference in fetal behavior between male and female fetuses in the third trimester of pregnancy. These results suggest that 4D ultrasound study examining fetal behavior does not need to consider the factor of fetal sex. PMID- 26943601 TI - CALUX bioassay: a cost-effective rapid screening technique for screening dioxins like compounds. AB - Xenobiotic detection systems-chemically activated luciferase expression (XDS CALUX) bioassay in determining the toxic equivalency (TEQ) of PCDD/Fs from contaminated sites reported in several papers has been discussed in this study. CALUX bioassay method has been validated by an effective combined column clean-up system followed by addition of samples to monolayer cell cultures of H1L6.1c3 cell line in 96 well plates. Cultures are then examined under microscope after 24 h incubation followed by rinsing with 75 MUL phosphate buffer saline and 30 MUL of cell culture lysis. The response is observed in the luminometer and expressed in relative light unit (RLUs). CALUX-TEQ is estimated from a TCDD standard curve for unknown samples. Quality control in CALUX is done by selecting the range of CALUX values falling in the center of the linear standard curve. For developing nations CALUX biossay can be used as a cost effective and rapid screening technique for screening xenobiotic compounds from the hotspots like open solid waste burning sites, informal e-waste recycling workshops and industrial zones where constant monitoring for such compounds is required. PMID- 26943606 TI - The impact of renal function on the clinical performance of FLC measurement in AL amyloidosis. AB - BACKGROUND: The measurement of circulating free light chains (FLC) is of utmost importance in immunoglobulin light chain (AL) amyloidosis, being a fundamental part of the diagnostic workup, prognostic stratification and assessment of response to therapy. Renal failure is a common feature of AL amyloidosis and can considerably affect the concentration of FLC. METHODS: We assessed the impact of renal failure on the clinical performance of the Freelite assay in 982 consecutive, newly diagnosed patients with AL amyloidosis, 822 with estimated glomerular filtration rate (eGFR) >=30 mL/min/1.73 m2, and 160 with eGFR <30 mL/min/1.73 m2. RESULTS: The diagnostic sensitivity of the kappa/lambda FLC ratio was lower for lambda amyloidogenic FLC in patients with renal failure (81% vs. 60%, p<0.001) and the FLC concentration had no independent prognostic significance in patients with severe renal dysfunction. However, FLC response to chemotherapy could still discriminate patients with better outcome. CONCLUSIONS: Renal failure is a relevant interference factor when using the Freelite assay for the identification of the amyloidogenic light chain and for prognostic assessment in patients with AL amyloidosis and renal failure. PMID- 26943604 TI - A novel nonsense mutation in the WFS1 gene causes the Wolfram syndrome. AB - Wolfram syndrome is a rare autosomal recessive neurodegenerative disorder, which is mostly caused by mutations in the WFS1 gene. The WFS1 gene product, which is called wolframin, is thought to regulate the function of endoplasmic reticulum. The endoplasmic reticulum has a critical role in protein folding and material transportation within the cell or to the surface of the cell. Identification of new mutations in WFS1 gene will unravel the molecular pathology of WS. The aim of this case report study is to describe a novel mutation in exon 4 of the WFS1 gene (c.330C>A) in a 9-year-old boy with WS. PMID- 26943607 TI - Serum protein S100 as marker of postoperative delirium after off-pump coronary artery bypass surgery: secondary analysis of two prospective randomized controlled trials. AB - BACKGROUND: To investigate the predictive value of S100 (biochemical marker of neuroglial injury) for the occurrence of postoperative delirium (POD) in patients undergoing off-pump coronary artery bypass (OPCAB)-surgery. METHODS: We enrolled 92 patients older than 18 years undergoing elective OPCAB-surgery. Serum-levels of S100 were determined at baseline (BL), end of surgery (EOS) and on the first postoperative day (PD1). Postoperatively, all-patients were evaluated daily until PD5 for the presence of POD using the confusion assessment method (CAM) or the confusion assessment method for the intensive care unit (CAM-ICU) for patients in the intensive care unit (ICU). RESULTS: The overall incidence of POD was 21%. S100-values on PD1 significantly predicted the occurrence of POD during the later hospital stay [area under the curve (AUC)=0.724 (95% confidence interval (CI): 0.619-0.814); p=0.0001] with an optimal cut-off level of 123 pg mL-1 (sensitivity 100%, specificity 44%). Below this value, the absence of POD was predicted correctly in 43.66% of patients without POD [negative predictive value (NPV) of 100% (95%CI: 88.8%-100.0%) - positive predictive value of 29.8% (95%CI: 18.4% 43.4%) and likelihood ratio (LR) of the negative result of 0.0]. CONCLUSIONS: S100-levels <123 pg mL-1 measured on PD1 reliably rule out the development of POD after elective OPCAB-surgery. This finding warrants testing whether S100-levels could be used for a risk stratification of cardiac surgical patients and for the initiation of preventive measures against POD in patients with high postoperative S100-levels. PMID- 26943608 TI - Analytical issues of serum free light chain assays and the relative performance of polyclonal and monoclonal based reagents. AB - Serum free light chain (FLC) assays have been incorporated into routine clinical practice and their use is recommended in international guidelines for the management of monoclonal gammopathies. Given that FLCs are not simple analytes, laboratories should be aware of potential analytical issues when using FLC assays, including antigen excess, lot-to-lot variation and non-linearity. Whilst manufacturers of monoclonal antibody-based assays claim that they overcome such issues, the evidence available to date does not support this. Here we review and compare the technical performance of both polyclonal and monoclonal antibody based assays. The evidence suggests that the Freelite assay, based on polyclonal antisera, gives a broader recognition of monoclonal FLCs than the N Latex assay, based on monoclonal antisera, and despite being cited as a technical concern, we show that lot-to-lot variation of the Freelite assay is good. Both non-linearity and antigen excess are characteristic of FLC analysis and laboratories should be aware of these phenomena regardless of the assay system they use. Comparisons of the absolute values of sFLCs determined using monoclonal and polyclonal antibody based assays show poor quantitative agreement and, because current guidelines have been established using the polyclonal antibody-based Freelite assay, it should not be assumed that assays utilizing monoclonal antibodies will give compliance with these guidelines. PMID- 26943605 TI - Regulation of neuronal-glial fate specification by long non-coding RNAs. AB - Neural stem cell transplantation is becoming a promising and attractive cell based treatment modality for repairing the damaged central nervous system. One of the limitations of this approach is that the proportion of functional cells differentiated from stem cells still remains at a low level. In recent years, novel long non-coding RNAs (lncRNAs) are being discovered at a growing pace, suggesting that this class of molecules may act as novel regulators in neuronal glial fate specification. In this review, we first describe the general features of lncRNAs that are more likely to be relevant to reveal their function. By this, we aim to point out the specific roles of a number of lncRNAs whose function has been described during neuronal and glial cell differentiation. There is no doubt that investigation of the lncRNAs will open a new window in studying neuronal glial fate specification. PMID- 26943609 TI - Clinical utility of urinary liver-type fatty acid binding protein measured by latex-enhanced turbidimetric immunoassay in chronic kidney disease. AB - BACKGROUND: Urinary liver-type fatty acid binding protein (L-FABP) measured by enzyme-linked immunosorbent assay method (ELISA) was approved as a clinical biomarker of tubular damage by the Japanese Ministry of Health, Labor and Welfare (MHLW) in 2011. We evaluated a new latex-enhanced immunoturbidimetric assay (LTIA) to evaluate the clinical utility of urinary L-FABP measured by LTIA versus an ELISA assay. METHODS: LTIA with anti-human L-FABP mouse monoclonal antibodies was performed using an automated clinical chemistry analyzer. Five positive samples with low, medium and high L-FABP concentrations were analyzed to determine the within-run precision. In patients with chronic kidney disease (CKD) (n=91), urinary L-FABP levels were measured by ELISA and LTIA. RESULTS: Measurement of urinary L-FABP revealed urinary L-FABP levels within 30 min. The within-run coefficient of variation was 10.0% for 1.4 ng/mL, 4.4% for 2.5 ng/mL, 3.2% for 9.8 ng/mL, 1.5% for 50.1 ng/mL, and 1.2% for 102.7 ng/mL. Concentrations of urinary L-FABP measured by LTIA were significantly correlated with those measured by ELISA (rho=0.932). Proportional systematic error was almost within limits of agreement (LOA). Urinary L-FABP levels measured by LTIA were significantly correlated with urinary albumin (rho=0.634), urinary NAG (rho=0.688) and eGFR (rho=-0.561). CONCLUSIONS: Measurement of urinary L-FABP by LITA was simple, speedy, and similar in quality to ELISA results. Therefore, this method was approved as external body diagnosing medicines by the Japanese MHLW in 2014. Urinary L-FABP is expected to be widely used in various pathophysiological conditions by measuring urinary L-FABP using LTIA. PMID- 26943610 TI - Is there a role for vitamin D in human reproduction? AB - Vitamin D is a steroid hormone with canonical roles in calcium metabolism and bone modeling. However, in recent years there has been a growing body of literature presenting associations between vitamin D levels and a variety of disease processes, including metabolic disorders such as diabetes and prediabetes and autoimmune conditions such as thyroid disease. This review focuses on the potential role of vitamin D in both male and female reproductive function. The vitamin D receptor (VDR) is expressed throughout central and peripheral organs of reproduction. VDR is often co-localized with its metabolizing enzymes, suggesting the importance of tissue specific modulation of active vitamin D levels. Both animal and human studies in males links vitamin D deficiency with hypogonadism and decreased fertility. In females, there is evidence for its role in polycystic ovary syndrome (PCOS), endometriosis, leiomyomas, in-vitro fertilization, and pregnancy outcomes. Studies evaluating the effects of replacing vitamin D have shown variable results. There remains some concern that the effects of vitamin D on reproduction are not direct, but rather secondary to the accompanying hypocalcemia or estrogen dysregulation. PMID- 26943611 TI - The FGF23/Klotho axis in the regulation of mineral and metabolic homeostasis. AB - The function of fibroblast growth factor (FGF) 23 has been suggested to be multifaceted beyond its canonical function as a regulator of mineral metabolism. FGF23 was originally shown to play a central role in phosphate (Pi) and vitamin D metabolism, and a number of diseases associated with dysregulated Pi metabolism have been attributed to abnormal FGF23 signaling activities. The discovery of Klotho as a co-receptor for FGF23 signaling has also accelerated understanding on the molecular mechanisms underlying Pi and vitamin D metabolism. In addition to these canonical functions, FGF23 has recently been implicated in a number of metabolic diseases including chronic kidney disease-associated complications, cardiovascular diseases, and obesity-related disorders; however, the physiological significance and molecular mechanisms of these emerging roles of FGF23 remain largely unknown. Molecular and functional insights into the FGF23 pathway will be discussed in the present review, with an emphasis on its role in human disorders related to dysregulated Pi metabolism as well as metabolic disorders. PMID- 26943612 TI - Impact of visceral fat volume and fat density on biochemical outcome after radical prostatectomy and postoperative radiotherapy. AB - BACKGROUND: To assess the predictive value of visceral adipose tissue (VAT) and adipose tissue density after both radical prostatectomy (RP) and adjuvant or salvage external beam radiotherapy (EBRT). MATERIALS AND METHODS: We randomly selected 201 patients treated with RP and EBRT between 2005 and 2015. Visceral adipose tissue and subcutaneous adipose tissue volumes were manually contoured and corresponding tissue densities in Hounsfield units (HU) calculated. Time to biochemical recurrence (BCR) was calculated using the Kaplan-Meier method and comparisons were made using the log-rank test. Cox regression analysis was done for multivariate analysis. RESULTS: Median time to BCR or last follow-up was 32 months. In univariate analysis for BCR, VAT volume and fat density were both associated with a better outcome (p=0.025 and p=0.024, respectively) as well as seminal vesicle involvement (p=0.024). Body mass index (BMI) was not predictive of BCR (p=0.32). In a multivariate model including seminal vesicle involvement, both a VAT volume above the median (HR2.5, 95%CI 1.1-5.7, p=0.03) and a VAT density (HR 2.4, 95%CI 1.1-5.1, p=0.028) above the median remained predictive for a better biochemical outcome. Adjusting for BMI did not significantly change the model. CONCLUSIONS: In both univariate and multivariate analysis, patients with both a larger VAT volume and density had a better biochemical outcome. The interaction between prostate cancer aggressiveness and visceral fat volume and density needs to be further evaluated to provide a better understanding of this disease. PMID- 26943613 TI - Mechanisms linking energy balance and reproduction: impact of prenatal environment. AB - The burgeoning field of metabolic reproduction regulation has been gaining momentum due to highly frequent discoveries of new neuroendocrine factors regulating both energy balance and reproduction. Universally throughout the animal kingdom, energy deficits inhibit the reproductive axis, which demonstrates that reproduction is acutely sensitive to fuel availability. Entrainment of reproductive efforts with energy availability is especially critical for females because they expend large amounts of energy on gestation and lactation. Research has identified an assortment of both central and peripheral factors involved in the metabolic regulation of reproduction. From an evolutionary perspective, these mechanisms likely evolved to optimize reproductive fitness in an environment with an unpredictable food supply and regular bouts of famine. To be effective, however, the mechanisms responsible for the metabolic regulation of reproduction must also retain developmental plasticity to allow organisms to adapt their reproductive strategies to their particular niche. In particular, the prenatal environment has emerged as a critical developmental window for programming the mechanisms responsible for the metabolic control of reproduction. This review will discuss the current knowledge about hormonal and molecular mechanisms that entrain reproduction with prevailing energy availability. In addition, it will provide an evolutionary, human life-history framework to assist in the interpretation of findings on gestational programming of the female reproductive function, with a focus on pubertal timing as an example. Future research should aim to shed light on mechanisms underlying the prenatal modulation of the adaptation to an environment with unstable resources in a way that optimizes reproductive fitness. PMID- 26943614 TI - Endocrine control of epigenetic mechanisms in male reproduction. AB - Endocrine control of reproduction is very well known and has been echoed by many research groups. However, recent developments point to the ability of toxic endocrine disrupting chemicals (EDC) to alter epigenetic information of the gametes which gets transferred to the developing embryo and affects the immediate reproductive outcome or even persists transgenerationally. These epigenetic aberrations contribute to the ensuing pathophysiology of reproductive disorders. Investigations of the female in cases of poor reproductive outcome have been the main strategy towards diagnosis. However, despite the male partner contributing half of his genome to the progeny, thorough investigations in the male have been ignored. Environmental pollutants are all pervading and are encountered in our day-to-day life. Many of these pollutants have potential to disrupt the endocrine system. Here, we discuss how the male gametes (spermatozoa) are susceptible to a myriad of epigenetic insults inflicted by exposure to endocrine disruptors and how important is the contribution of the epigenetic marks of the spermatozoa in healthy reproduction. We advocate that sperm epigenetics should be considered as a significant contributor to reproductive health and should be researched further and be subsequently included in routine diagnostic workup in cases of poor reproductive outcome. PMID- 26943615 TI - Preface to special issue on Peripheral and Central Control of Human Reproduction: Endocrine Aspects--Part 2. PMID- 26943616 TI - Garlic capsule and selenium-vitamins ACE combination therapy modulate key antioxidant proteins and cellular adenosine triphosphate in lisinopril-induced lung damage in rats. AB - BACKGROUND: Garlic capsule (GAR) and/or selenium- vitamin A, C, E (S-VACE) might be useful in the treatment of lung diseases. The present study evaluated the toxicity of lisinopril (LIS) in the lungs of male rats and the reversal effect of GAR and/or selenium-vitamins A, C, and E (S-VACE). METHODS: Group I served as the control, whereas animals in groups II, III, IV, and V received 28 mg of LIS/kg body weight by gavage. Group III was co-treated with GAR at a therapeutic dosage of 250 mg/kg body weight per day. Group IV was co-treated with S-VACE at dosage of 500 mg/kg body weight per day. Lastly, group V was co-treated with GAR and S VACE at dosages of 250 and 500 mg/kg body weight per day, respectively. The experiment lasted for 8 days (sub-acute exposure). RESULTS: Administration of therapeutic dose of LIS to male rats depleted enzymatic antioxidants (superoxide dismutase and catalase) and cellular adenosine triphosphate content with concomitant increase in lipid peroxidation. Histopathology examination showed damage to the epithelial cells of the airways. These effects were prevented by both single and combination treatment of GAR and S-VACE in male rats with LIS induced lung toxicity. CONCLUSIONS: We therefore concluded that the combination of GAR and S-VACE can be a novel therapy for the management of lung diseases in humans. PMID- 26943617 TI - The structure and dynamics of secretory component and its interactions with polymeric immunoglobulins. AB - As a first-line vertebrate immune defense, the polymeric immunoglobulin receptor (pIgR) transports polymeric IgA and IgM across epithelia to mucosal secretions, where the cleaved ectodomain (secretory component; SC) becomes a component of secretory antibodies, or when unliganded, binds and excludes bacteria. Here we report the 2.6A crystal structure of unliganded human SC (hSC) and comparisons with a 1.7A structure of teleost fish SC (tSC), an early pIgR ancestor. The hSC structure comprises five immunoglobulin-like domains (D1-D5) arranged as a triangle, with an interface between ligand-binding domains D1 and D5. Electron paramagnetic resonance measurements confirmed the D1-D5 interface in solution and revealed that it breaks upon ligand binding. Together with binding studies of mutant and chimeric SCs, which revealed domain contributions to secretory antibody formation, these results provide detailed models for SC structure, address pIgR evolution, and demonstrate that SC uses multiple conformations to protect mammals from pathogens. PMID- 26943618 TI - Contrasting roles for parvalbumin-expressing inhibitory neurons in two forms of adult visual cortical plasticity. AB - The roles played by cortical inhibitory neurons in experience-dependent plasticity are not well understood. Here we evaluate the participation of parvalbumin-expressing (PV+) GABAergic neurons in two forms of experience dependent modification of primary visual cortex (V1) in adult mice: ocular dominance (OD) plasticity resulting from monocular deprivation and stimulus selective response potentiation (SRP) resulting from enriched visual experience. These two forms of plasticity are triggered by different events but lead to a similar increase in visual cortical response. Both also require the NMDA class of glutamate receptor (NMDAR). However, we find that PV+ inhibitory neurons in V1 play a critical role in the expression of SRP and its behavioral correlate of familiarity recognition, but not in the expression of OD plasticity. Furthermore, NMDARs expressed within PV+ cells, reversibly inhibited by the psychotomimetic drug ketamine, play a critical role in SRP, but not in the induction or expression of adult OD plasticity. PMID- 26943620 TI - Chasing the elusive Euryarchaeota class WSA2: genomes reveal a uniquely fastidious methyl-reducing methanogen. AB - The ecophysiology of one candidate methanogen class WSA2 (or Arc I) remains largely uncharacterized, despite the long history of research on Euryarchaeota methanogenesis. To expand our understanding of methanogen diversity and evolution, we metagenomically recover eight draft genomes for four WSA2 populations. Taxonomic analyses indicate that WSA2 is a distinct class from other Euryarchaeota. None of genomes harbor pathways for CO2-reducing and aceticlastic methanogenesis, but all possess H2 and CO oxidation and energy conservation through H2-oxidizing electron confurcation and internal H2 cycling. As the only discernible methanogenic outlet, they consistently encode a methylated thiol coenzyme M methyltransferase. Although incomplete, all draft genomes point to the proposition that WSA2 is the first discovered methanogen restricted to methanogenesis through methylated thiol reduction. In addition, the genomes lack pathways for carbon fixation, nitrogen fixation and biosynthesis of many amino acids. Acetate, malonate and propionate may serve as carbon sources. Using methylated thiol reduction, WSA2 may not only bridge the carbon and sulfur cycles in eutrophic methanogenic environments, but also potentially compete with CO2 reducing methanogens and even sulfate reducers. These findings reveal a remarkably unique methanogen 'Candidatus Methanofastidiosum methylthiophilus' as the first insight into the sixth class of methanogens 'Candidatus Methanofastidiosa'. PMID- 26943619 TI - Genomic epidemiology of artemisinin resistant malaria. AB - The current epidemic of artemisinin resistant Plasmodium falciparum in Southeast Asia is the result of a soft selective sweep involving at least 20 independent kelch13 mutations. In a large global survey, we find that kelch13 mutations which cause resistance in Southeast Asia are present at low frequency in Africa. We show that African kelch13 mutations have originated locally, and that kelch13 shows a normal variation pattern relative to other genes in Africa, whereas in Southeast Asia there is a great excess of non-synonymous mutations, many of which cause radical amino-acid changes. Thus, kelch13 is not currently undergoing strong selection in Africa, despite a deep reservoir of variations that could potentially allow resistance to emerge rapidly. The practical implications are that public health surveillance for artemisinin resistance should not rely on kelch13 data alone, and interventions to prevent resistance must account for local evolutionary conditions, shown by genomic epidemiology to differ greatly between geographical regions. PMID- 26943621 TI - Complete ecological isolation and cryptic diversity in Polynucleobacter bacteria not resolved by 16S rRNA gene sequences. AB - Transplantation experiments and genome comparisons were used to determine if lineages of planktonic Polynucleobacter almost indistinguishable by their 16S ribosomal RNA (rRNA) sequences differ distinctively in their ecophysiological and genomic traits. The results of three transplantation experiments differing in complexity of biotic interactions revealed complete ecological isolation between some of the lineages. This pattern fits well to the previously detected environmental distribution of lineages along chemical gradients, as well as to differences in gene content putatively providing adaptation to chemically distinct habitats. Patterns of distribution of iron transporter genes across 209 Polynucleobacter strains obtained from freshwater systems and representing a broad pH spectrum further emphasize differences in habitat-specific adaptations. Genome comparisons of six strains sharing ?99% 16S rRNA similarities suggested that each strain represents a distinct species. Comparison of sequence diversity among genomes with sequence diversity among 240 cultivated Polynucleobacter strains indicated a large cryptic species complex not resolvable by 16S rRNA sequences. The revealed ecological isolation and cryptic diversity in Polynucleobacter bacteria is crucial in the interpretation of diversity studies on freshwater bacterioplankton based on ribosomal sequences. PMID- 26943623 TI - Multi-year assessment of coastal planktonic fungi reveals environmental drivers of diversity and abundance. AB - Mycoplankton have so far been a neglected component of pelagic marine ecosystems, having been poorly studied relative to other plankton groups. Currently, there is a lack of understanding of how mycoplankton diversity changes through time, and the identity of controlling environmental drivers. Using Fungi-specific high throughput sequencing and quantitative PCR analysis of plankton DNA samples collected over 6 years from the coastal biodiversity time series site Station L4 situated off Plymouth (UK), we have assessed changes in the temporal variability of mycoplankton diversity and abundance in relation to co-occurring environmental variables. Mycoplankton diversity at Station L4 was dominated by Ascomycota, Basidiomycota and Chytridiomycota, with several orders within these phyla frequently abundant and dominant in multiple years. Repeating interannual mycoplankton blooms were linked to potential controlling environmental drivers, including nitrogen availability and temperature. Specific relationships between mycoplankton and other plankton groups were also identified, with seasonal chytrid blooms matching diatom blooms in consecutive years. Mycoplankton alpha diversity was greatest during periods of reduced salinity at Station L4, indicative of riverine input to the ecosystem. Mycoplankton abundance also increased during periods of reduced salinity, and when potential substrate availability was increased, including particulate organic matter. This study has identified possible controlling environmental drivers of mycoplankton diversity and abundance in a coastal sea ecosystem, and therefore sheds new light on the biology and ecology of an enigmatic marine plankton group. Mycoplankton have several potential functional roles, including saprotrophs and parasites, that should now be considered within the consensus view of pelagic ecosystem functioning and services. PMID- 26943622 TI - Predicting taxonomic and functional structure of microbial communities in acid mine drainage. AB - Predicting the dynamics of community composition and functional attributes responding to environmental changes is an essential goal in community ecology but remains a major challenge, particularly in microbial ecology. Here, by targeting a model system with low species richness, we explore the spatial distribution of taxonomic and functional structure of 40 acid mine drainage (AMD) microbial communities across Southeast China profiled by 16S ribosomal RNA pyrosequencing and a comprehensive microarray (GeoChip). Similar environmentally dependent patterns of dominant microbial lineages and key functional genes were observed regardless of the large-scale geographical isolation. Functional and phylogenetic beta-diversities were significantly correlated, whereas functional metabolic potentials were strongly influenced by environmental conditions and community taxonomic structure. Using advanced modeling approaches based on artificial neural networks, we successfully predicted the taxonomic and functional dynamics with significantly higher prediction accuracies of metabolic potentials (average Bray-Curtis similarity 87.8) as compared with relative microbial abundances (similarity 66.8), implying that natural AMD microbial assemblages may be better predicted at the functional genes level rather than at taxonomic level. Furthermore, relative metabolic potentials of genes involved in many key ecological functions (for example, nitrogen and phosphate utilization, metals resistance and stress response) were extrapolated to increase under more acidic and metal-rich conditions, indicating a critical strategy of stress adaptation in these extraordinary communities. Collectively, our findings indicate that natural selection rather than geographic distance has a more crucial role in shaping the taxonomic and functional patterns of AMD microbial community that readily predicted by modeling methods and suggest that the model-based approach is essential to better understand natural acidophilic microbial communities. PMID- 26943624 TI - Phylogenetic organization of bacterial activity. AB - Phylogeny is an ecologically meaningful way to classify plants and animals, as closely related taxa frequently have similar ecological characteristics, functional traits and effects on ecosystem processes. For bacteria, however, phylogeny has been argued to be an unreliable indicator of an organism's ecology owing to evolutionary processes more common to microbes such as gene loss and lateral gene transfer, as well as convergent evolution. Here we use advanced stable isotope probing with (13)C and (18)O to show that evolutionary history has ecological significance for in situ bacterial activity. Phylogenetic organization in the activity of bacteria sets the stage for characterizing the functional attributes of bacterial taxonomic groups. Connecting identity with function in this way will allow scientists to begin building a mechanistic understanding of how bacterial community composition regulates critical ecosystem functions. PMID- 26943625 TI - Seasonal determinations of algal virus decay rates reveal overwintering in a temperate freshwater pond. AB - To address questions about algal virus persistence (i.e., continued existence) in the environment, rates of decay of infectivity for two viruses that infect Chlorella-like algae, ATCV-1 and CVM-1, and a virus that infects the prymnesiophyte Chrysochromulina parva, CpV-BQ1, were estimated from in situ incubations in a temperate, seasonally frozen pond. A series of experiments were conducted to estimate rates of decay of infectivity in all four seasons with incubations lasting 21 days in spring, summer and autumn, and 126 days in winter. Decay rates observed across this study were relatively low compared with previous estimates obtained for other algal viruses, and ranged from 0.012 to 11% h(-1). Overall, the virus CpV-BQ1 decayed most rapidly whereas ATCV-1 decayed most slowly, but for all viruses the highest decay rates were observed during the summer and the lowest were observed during the winter. Furthermore, the winter incubations revealed the ability of each virus to overwinter under ice as ATCV-1, CVM-1 and CpV-BQ1 retained up to 48%, 19% and 9% of their infectivity after 126 days, respectively. The observed resilience of algal viruses in a seasonally frozen freshwater pond provides a mechanism that can support the maintenance of viral seed banks in nature. However, the high rates of decay observed in the summer demonstrate that virus survival and therefore environmental persistence can be subject to seasonal bottlenecks. PMID- 26943626 TI - Ralstonia solanacearum lipopeptide induces chlamydospore development in fungi and facilitates bacterial entry into fungal tissues. AB - Ralstonia solanacearum is a globally distributed soil-borne plant pathogenic bacterium, which shares a broad ecological range with many plant- and soil associated fungi. We sought to determine if R. solanacearum chemical communication directs symbiotic development of polymicrobial consortia. R. solanacearum produced a diffusible metabolite that induced conserved morphological differentiation in 34 species of fungi across three diverse taxa (Ascomycetes, Basidiomycetes and Zygomycetes). Fungi exposed to this metabolite formed chlamydospores, survival structures with thickened cell walls. Some chlamydospores internally harbored R. solanacearum, indicating a newly described endofungal lifestyle for this important plant pathogen. Using imaging mass spectrometry and peptidogenomics, we identified an undescribed lipopeptide, ralsolamycin, produced by an R. solanacearum non-ribosomal peptide synthetase polyketide synthase hybrid. Inactivation of the hybrid non-ribosomal peptide synthetase-polyketide synthase gene, rmyA, abolished ralsolamycin synthesis. R. solanacearum mutants lacking ralsolamycin no longer induced chlamydospore development in fungal coculture and invaded fungal hyphae less well than wild type. We propose that ralsolamycin contributes to the invasion of fungal hyphae and that the formation of chlamydospores may provide not only a specific niche for bacterial colonization but also enhanced survival for the partnering fungus. PMID- 26943627 TI - Capturing the most wanted taxa through cross-sample correlations. AB - The Human Microbiome Project (HMP) identified the 16S rRNA gene sequences of 'most wanted' taxa-prevalent in the healthy human microbiota but distant from previously known sequences. Since 2012, few of the corresponding genomes have been isolated and sequenced, and only through advanced isolation techniques. We demonstrate that the genomes of the most wanted taxa can be identified computationally through their correlation in abundance across multiple public metagenomic data sets. We link over 200 most wanted sequences with nearly complete genome sequences, including half of the taxa identified as high-priority targets by the HMP. The genomes we identify have strong similarity to genomes reconstructed through expensive isolation techniques, and provide a more complete functional characterization of these organisms than can be extrapolated from their 16S rRNA gene. We also provide insights into the function of organisms for which 16S rRNA gene signatures were recently reported to be associated with health and host genetic factors. PMID- 26943628 TI - Metatranscriptomic evidence of pervasive and diverse chemolithoautotrophy relevant to C, S, N and Fe cycling in a shallow alluvial aquifer. AB - Groundwater ecosystems are conventionally thought to be fueled by surface-derived allochthonous organic matter and dominated by heterotrophic microbes living under often-oligotrophic conditions. However, in a 2-month study of nitrate amendment to a perennially suboxic aquifer in Rifle (CO), strain-resolved metatranscriptomic analysis revealed pervasive and diverse chemolithoautotrophic bacterial activity relevant to C, S, N and Fe cycling. Before nitrate injection, anaerobic ammonia-oxidizing (anammox) bacteria accounted for 16% of overall microbial community gene expression, whereas during the nitrate injection, two other groups of chemolithoautotrophic bacteria collectively accounted for 80% of the metatranscriptome: (1) members of the Fe(II)-oxidizing Gallionellaceae family and (2) strains of the S-oxidizing species, Sulfurimonas denitrificans. Notably, the proportion of the metatranscriptome accounted for by these three groups was considerably greater than the proportion of the metagenome coverage that they represented. Transcriptional analysis revealed some unexpected metabolic couplings, in particular, putative nitrate-dependent Fe(II) and S oxidation among nominally microaerophilic Gallionellaceae strains, including expression of periplasmic (NapAB) and membrane-bound (NarGHI) nitrate reductases. The three most active groups of chemolithoautotrophic bacteria in this study had overlapping metabolisms that allowed them to occupy different yet related metabolic niches throughout the study. Overall, these results highlight the important role that chemolithoautotrophy can have in aquifer biogeochemical cycling, a finding that has broad implications for understanding terrestrial carbon cycling and is supported by recent studies of geochemically diverse aquifers. PMID- 26943630 TI - Differential-Evolution Control Parameter Optimization for Unmanned Aerial Vehicle Path Planning. AB - The differential evolution algorithm has been widely applied on unmanned aerial vehicle (UAV) path planning. At present, four random tuning parameters exist for differential evolution algorithm, namely, population size, differential weight, crossover, and generation number. These tuning parameters are required, together with user setting on path and computational cost weightage. However, the optimum settings of these tuning parameters vary according to application. Instead of trial and error, this paper presents an optimization method of differential evolution algorithm for tuning the parameters of UAV path planning. The parameters that this research focuses on are population size, differential weight, crossover, and generation number. The developed algorithm enables the user to simply define the weightage desired between the path and computational cost to converge with the minimum generation required based on user requirement. In conclusion, the proposed optimization of tuning parameters in differential evolution algorithm for UAV path planning expedites and improves the final output path and computational cost. PMID- 26943634 TI - Fibroblast Growth Factor 23 Concentrations Reflect Sex Differences in Mineral Metabolism and Growth in Early Infancy. AB - BACKGROUND: The role of fibroblast growth factor 23 (FGF23) in the regulation of mineral homeostasis in early life is inadequately understood. We aimed to explore the effects of vitamin D supplementation on serum FGF23 and to elucidate longitudinal changes in FGF23, in addition to studying its association with mineral metabolism in early infancy. METHODS: Altogether 113 healthy infants received vitamin D3 10, 30 or 40 ug/day from age 0.5 to 3.0 months. Cord blood at birth and capillary blood samples at 3 months were analyzed for serum 25 hydroxyvitamin D, parathyroid hormone, phosphate, calcium and intact and C terminal FGF23. RESULTS: In repeated-measures ANCOVA, intact FGF23 concentration increased with time (p < 0.001) and C-terminal FGF23 decreased (p < 0.001). At 3 months, girls had a higher concentration of intact FGF23 (51 vs. 26 pg/ml, p < 0.001) and a greater increase over time (x0394;FGF23 intact 45 vs. 16 pg/ml, p = 0.001) than boys. Vitamin D did not affect serum intact or C-terminal FGF23 concentrations. Girls showed a positive correlation between phosphate and intact FGF23 (p = 0.004), whereas in boys phosphate and C-terminal FGF23 correlated inversely (p = 0.006). CONCLUSIONS: A substantial sex-related difference in intact FGF23 concentration exists during early infancy, possibly related to differences in skeletal growth between boys and girls. PMID- 26943629 TI - Zika Virus Infection in Pregnant Women in Rio de Janeiro. AB - BACKGROUND: Zika virus (ZIKV) has been linked to central nervous system malformations in fetuses. To characterize the spectrum of ZIKV disease in pregnant women and infants, we followed patients in Rio de Janeiro to describe clinical manifestations in mothers and repercussions of acute ZIKV infection in infants. METHODS: We enrolled pregnant women in whom a rash had developed within the previous 5 days and tested blood and urine specimens for ZIKV by reverse transcriptase-polymerase-chain-reaction assays. We followed women prospectively to obtain data on pregnancy and infant outcomes. RESULTS: A total of 345 women were enrolled from September 2015 through May 2016; of these, 182 women (53%) tested positive for ZIKV in blood, urine, or both. The timing of acute ZIKV infection ranged from 6 to 39 weeks of gestation. Predominant maternal clinical features included a pruritic descending macular or maculopapular rash, arthralgias, conjunctival injection, and headache; 27% had fever (short-term and low-grade). By July 2016, a total of 134 ZIKV-affected pregnancies and 73 ZIKV unaffected pregnancies had reached completion, with outcomes known for 125 ZIKV affected and 61 ZIKV-unaffected pregnancies. Infection with chikungunya virus was identified in 42% of women without ZIKV infection versus 3% of women with ZIKV infection (P<0.001). Rates of fetal death were 7% in both groups; overall adverse outcomes were 46% among offspring of ZIKV-positive women versus 11.5% among offspring of ZIKV-negative women (P<0.001). Among 117 live infants born to 116 ZIKV-positive women, 42% were found to have grossly abnormal clinical or brain imaging findings or both, including 4 infants with microcephaly. Adverse outcomes were noted regardless of the trimester during which the women were infected with ZIKV (55% of pregnancies had adverse outcomes after maternal infection in the first trimester, 52% after infection in the second trimester, and 29% after infection in the third trimester). CONCLUSIONS: Despite mild clinical symptoms in the mother, ZIKV infection during pregnancy is deleterious to the fetus and is associated with fetal death, fetal growth restriction, and a spectrum of central nervous system abnormalities. (Funded by Ministerio da Saude do Brasil and others.). PMID- 26943635 TI - Improved Survival After Primary Tumor Surgery in Metastatic Breast Cancer: A Propensity-adjusted, Population-based SEER Trend Analysis. AB - BACKGROUND: There is ongoing debate about nonpalliative primary tumor surgery in metastatic breast cancer patients. This issue has become even more relevant with the introduction of increasingly sensitive imaging modalities. METHODS: Metastatic breast cancer patients were identified in the SEER registry between 1998 and 2009. The effect of primary tumor surgery on overall and cancer-specific mortality using risk-adjusted Cox proportional hazard regression modeling and stratified propensity score matching was assessed. RESULTS: Overall, 16,247 women with metastatic breast cancer were included. Of those 7600 women underwent primary tumor surgery although 8647 did not have any surgery at all. Primary tumor surgery decreased from 62.0% in 1998 to 39.1% in 2009 (P < 0.001). Primary tumor surgery was associated with decreased overall mortality (hazard ratio (HR) = 0.53, 95% CI 0.50-0.55, P < 0.001) and cancer-specific mortality (HR = 0.51, 95% CI 0.48-0.54, P < 0.001) in the propensity score-matched model. The benefit of primary tumor surgery increased from 1998 to 2009 for overall mortality (1998: HR = 0.72, 95% CI 0.59-0.89, 2009: HR = 0.42, 95% CI 0.35-0.50) and cancer specific mortality (1998: HR = 0.72, 95% CI 0.58-0.89, 2009: HR = 0.40, 95% CI 0.33-0.48). CONCLUSIONS: The present study-the first population-based analysis using propensity score methods-provides evidence of a favorable impact of primary tumor surgery on mortality in metastatic breast cancer patients. Most importantly, the benefit of primary tumor surgery increased over time from 1998 to 2009. Although the final results of ongoing randomized studies are awaited, currently available evidence should be discussed with metastatic breast cancer patients. PMID- 26943636 TI - Perceptions and Attitudes towards Medical Research in the United Arab Emirates: Results from the Abu Dhabi Cohort Study (ADCS) Focus Group Discussions. AB - BACKGROUND: In developing medical research, particularly in regions where medical research is largely unfamiliar, it is important to understand public perceptions and attitudes towards medical research. In preparation for starting the first cohort study in the United Arab Emirates, the Abu Dhabi Cohort Study (ADCS), we sought to understand how we could improve the quality of the research process for participants and increase public trust and awareness of research. METHODS: We conducted six focus groups (FG), consisting of Emirati men and women aged above 18 years to resemble the target population for the ADCS. Sampling was purposive and convenient. Data collection was an iterative process until saturation was reached with no new themes identified. Text from each FG was analyzed separately by identifying emerging issues and organizing related concepts into categories or themes. A coding tree was developed, consisting of the main concepts, themes, subthemes and corresponding quotes. Both themes and main ideas were identified using inductive analysis. RESULTS: Forty-two participants enrolled at 3 academic centers (New York University Abu Dhabi, UAE University, Zayed University) and the Abu Dhabi blood bank. Focus group participants described lack of awareness of research as a challenge to participation in clinical research studies. Altruism, personal relevance of the research, and the use of role models were commonly identified motivators. Participants were generally satisfied with the informed consent process for the ADCS, but would be disappointed if not provided test results or study outcomes. Fear of a breach in confidentiality was a frequently expressed concern. CONCLUSIONS: Participants join research studies for varied, complex reasons, notably altruism and personal relevance. Based on these insights, we propose specific actions to enhance participant recruitment, retention and satisfaction in the ADCS. We identified opportunities to improve the research experience through improved study materials and communication to participants and the broader community. PMID- 26943637 TI - Biological manganese oxidation by Pseudomonas putida in trickling filters. AB - Biological oxidation has been researched as a viable alternative for treating waters with high manganese (Mn) concentrations, typically found in mine drainage or in some geological formations. In this study, laboratory-scale trickling filters were constructed to compare the Mn removal efficiency between filters inoculated with the Mn oxidizing bacteria, Pseudomonas putida, and filters without inoculation. Manganese oxidation and removal was found to be significantly greater in trickling filters with Pseudomonas putida after startup times of only 48 h. Mn oxidation in Pseudomonas putida inoculated trickling filters was up to 75% greater than non-inoculated filters. One-dimensional advective-dispersive models were formulated to describe the transport of Mn in trickling filter porous media. Based on the experimental transport parameters obtained, the model predicted that a filter depth of only 16 cm is needed to reduce influent concentration of 10 mg L(-1) to 0.05 mg L(-1). PMID- 26943638 TI - A Novel Method for Optimum Global Positioning System Satellite Selection Based on a Modified Genetic Algorithm. AB - In this paper, a novel method for selecting a navigation satellite subset for a global positioning system (GPS) based on a genetic algorithm is presented. This approach is based on minimizing the factors in the geometric dilution of precision (GDOP) using a modified genetic algorithm (MGA) with an elite conservation strategy, adaptive selection, adaptive mutation, and a hybrid genetic algorithm that can select a subset of the satellites represented by specific numbers in the interval (4 ~ n) while maintaining position accuracy. A comprehensive simulation demonstrates that the MGA-based satellite selection method effectively selects the correct number of optimal satellite subsets using receiver autonomous integrity monitoring (RAIM) or fault detection and exclusion (FDE). This method is more adaptable and flexible for GPS receivers, particularly for those used in handset equipment and mobile phones. PMID- 26943639 TI - Polymorphisms in Plasmodium vivax Circumsporozoite Protein (CSP) Influence Parasite Burden and Cytokine Balance in a Pre-Amazon Endemic Area from Brazil. AB - Mechanisms involved in severe P. vivax malaria remain unclear. Parasite polymorphisms, parasite load and host cytokine profile may influence the course of infection. In this study, we investigated the influence of circumsporozoite protein (CSP) polymorphisms on parasite load and cytokine profile in patients with vivax malaria. A cross-sectional study was carried out in three cities: Sao Luis, Cedral and Buriticupu, Maranhao state, Brazil, areas of high prevalence of P. vivax. Interleukin (IL)-2, IL-4, IL-10, IL-6, IL-17, tumor necrosis factor alpha (TNF-alpha, interferon gamma (IFN-gamma and transforming growth factor beta (TGF-beta were quantified in blood plasma of patients and in supernatants from peripheral blood mononuclear cell (PBMC) cultures. Furthermore, the levels of cytokines and parasite load were correlated with VK210, VK247 and P. vivax-like CSP variants. Patients infected with P. vivax showed increased IL-10 and IL-6 levels, which correlated with the parasite load, however, in multiple comparisons, only IL-10 kept this association. A regulatory cytokine profile prevailed in plasma, while an inflammatory profile prevailed in PBMC culture supernatants and these patterns were related to CSP polymorphisms. VK247 infected patients showed higher parasitaemia and IL-6 concentrations, which were not associated to IL-10 anti-inflammatory effect. By contrast, in VK210 patients, these two cytokines showed a strong positive correlation and the parasite load was lower. Patients with the VK210 variant showed a regulatory cytokine profile in plasma, while those infected with the VK247 variant have a predominantly inflammatory cytokine profile and higher parasite loads, which altogether may result in more complications in infection. In conclusion, we propose that CSP polymorphisms is associated to the increase of non-regulated inflammatory immune responses, which in turn may be associated with the outcome of infection. PMID- 26943642 TI - Providers' Perspectives on Program Collaboration and Service Integration for Persons Who Use Drugs. PMID- 26943640 TI - Inhibition of Nickel Nanoparticles-Induced Toxicity by Epigallocatechin-3-Gallate in JB6 Cells May Be through Down-Regulation of the MAPK Signaling Pathways. AB - With the rapid development in nanotechnology, nickel nanoparticles (Ni NPs) have emerged in the application of nanomedicine in recent years. However, the potential adverse health effects of Ni NPs are unclear. In this study, we examined the inhibition effects of epigallocatechin-3-gallate (EGCG) on the toxicity induced by Ni NPs in mouse epidermal cell line (JB6 cell). MTT assay showed that Ni NPs induced cytotoxicity in a dose-dependent manner while EGCG exerted a certain inhibition on the toxicity. Additionally, EGCG could reduce the apoptotic cell number and the level of reactive oxygen species (ROS) in JB6 cells induced by Ni NPs. Furthermore, we observed that EGCG could down-regulate Ni NPs induced activator protein-1 (AP-1) and nuclear factor-kappaB (NF-kappaB) activation in JB6 cells, which has been shown to play pivotal roles in tumor initiation, promotion and progression. Western blot indicated that EGCG could alleviate the toxicity of Ni NPs through regulating protein changes in MAPK signaling pathways. In summary, our results suggest that careful evaluation on the potential health effects of Ni NPs is necessary before being widely used in the field of nanomedicine. Inhibition of EGCG on Ni NPs-induced cytotoxicity in JB6 cells may be through the MAPK signaling pathways suggesting that EGCG might be useful in preventing the toxicity of Ni NPs. PMID- 26943641 TI - Conditional Inducible Triple-Transgenic Mouse Model for Rapid Real-Time Detection of HCV NS3/4A Protease Activity. AB - Hepatitis C virus (HCV) frequently establishes persistent infections that can develop into severe liver disease. The HCV NS3/4A serine protease is not only essential for viral replication but also cleaves multiple cellular targets that block downstream interferon activation. Therefore, NS3/4A is an ideal target for the development of anti-HCV drugs and inhibitors. In the current study, we generated a novel NS3/4A/Lap/LC-1 triple-transgenic mouse model that can be used to evaluate and screen NS3/4A protease inhibitors. The NS3/4A protease could be conditionally inducibly expressed in the livers of the triple-transgenic mice using a dual Tet-On and Cre/loxP system. In this system, doxycycline (Dox) induction resulted in the secretion of Gaussia luciferase (Gluc) into the blood, and this secretion was dependent on NS3/4A protease-mediated cleavage at the 4B5A junction. Accordingly, NS3/4A protease activity could be quickly assessed in real time simply by monitoring Gluc activity in plasma. The results from such monitoring showed a 70-fold increase in Gluc activity levels in plasma samples collected from the triple-transgenic mice after Dox induction. Additionally, this enhanced plasma Gluc activity was well correlated with the induction of NS3/4A protease expression in the liver. Following oral administration of the commercial NS3/4A-specific inhibitors telaprevir and boceprevir, plasma Gluc activity was reduced by 50% and 65%, respectively. Overall, our novel transgenic mouse model offers a rapid real-time method to evaluate and screen potential NS3/4A protease inhibitors. PMID- 26943644 TI - Methylene blue-induced serotonin syndrome presenting with ocular clonus and failure of emergence from general anesthesia. PMID- 26943643 TI - The importance of clinical stage among patients with a complete pathologic response at radical cystectomy after neoadjuvant chemotherapy. AB - PURPOSE: Patients without evidence of disease at radical cystectomy (RC) following neoadjuvant chemotherapy (NAC) have the greatest potential for survival in muscle-invasive bladder cancer. Historically, 15 % of such patients will experience disease recurrence and cancer-specific mortality. We sought to evaluate the effect of pre-treatment clinical factors on the risk of recurrence in patients who were ypT0N0 at RC. METHODS: We performed a multi-institutional review of patients treated with NAC + RC for muscle-invasive bladder cancer (>=cT2) without pathologic evidence of disease at surgery (ypT0N0). The association of pre-treatment clinicopathologic features with recurrence was evaluated using Cox proportional hazards. RESULTS: A total of 78 patients were identified with ypT0 disease at RC after NAC. Median postoperative follow-up was 32.4 months (IQR 16.8, 60.0), during which time 17 patients recurred at a median of 6.4 months after RC. Estimated 3-year recurrence-free survival (RFS) of this cohort was 74.8 %. In univariate analysis, cT4 disease (HR 3.12; p = 0.04) and time to RC (HR 1.17 for each month increase; p < 0.01) were associated with inferior RFS. CONCLUSION: Patients without evidence of disease at the time of RC are still at risk of recurrence and death from bladder cancer. Higher clinical stage and increased time to RC were associated with an increased risk of recurrence and subsequent death. These data highlight the importance of timely RC and the continued risk of recurrence in higher clinically staged patients underscoring the need for close monitoring and patient counseling. PMID- 26943527 TI - Search for Narrow Resonances Decaying to Dijets in Proton-Proton Collisions at ?[s]=13 TeV. AB - A search for narrow resonances in proton-proton collisions at sqrt[s]=13 TeV is presented. The invariant mass distribution of the two leading jets is measured with the CMS detector using a data set corresponding to an integrated luminosity of 2.4 fb^{-1}. The highest observed dijet mass is 6.1 TeV. The distribution is smooth and no evidence for resonant particles is observed. Upper limits at 95% confidence level are set on the production cross section for narrow resonances with masses above 1.5 TeV. When interpreted in the context of specific models, the limits exclude string resonances with masses below 7.0 TeV, scalar diquarks below 6.0 TeV, axigluons and colorons below 5.1 TeV, excited quarks below 5.0 TeV, color-octet scalars below 3.1 TeV, and W^{'} bosons below 2.6 TeV. These results significantly extend previously published limits. PMID- 26943645 TI - Safety and comparative costs of preoperative assessments for cataract surgery: traditional mandatory assessment versus a novel graded assessment system. AB - PURPOSE: We conducted this study to evaluate the safety and costs of traditional mandatory preoperative assessment for cataract surgery patients compared with a novel graded preoperative assessment system. METHODS: Patients were recruited at a high-volume surgical centre from May to November 2013. Patients completed a health-related questionnaire which allowed for a graded preoperative assessment of all participants. Based on responses to the questionnaire, patients were classified preoperatively into a) low-risk patients not requiring a preoperative assessment and b) high-risk patients requiring this assessment. Anesthesiologists still assessed all patients immediately before surgery but with staff blinded to preoperative assessment information for low-risk patients. Observed complication rates and costs were compared with those expected in the mandatory assessment system. RESULTS: We examined 3,347 cataract surgeries on 2,766 patients and categorized 59.9% of patients as low risk. In the graded system cohort, there were no major complications and a low rate of minor complications occurred. Wherever a complication occurred in a low-risk patient, the anesthesiologist doubted that the preoperative assessment information would have prevented the complication. If implemented, the graded system would save approximately 4,414 preoperative assessments per year in our region, with an associated cost of approximately $40.00 per surgery, or $359,000 in total. The cost to prevent a single minor complication with the mandatory system was approximately $8,976, with a number needed to treat of 223. CONCLUSION: The graded system resulted in no major complications and a low rate of minor complications. The information obtained from the mandatory assessment is unlikely to prevent complications. Additionally, the cost effectiveness of the mandatory system was poor. This novel graded preoperative assessment system for cataract surgery patients can save time and resources by eliminating unnecessary patient visits. PMID- 26943647 TI - The legacy of Nico H. Frijda (1927-2015). PMID- 26943646 TI - Mental health and substance use of sexual minority college athletes. AB - OBJECTIVE: Assess the mental health and substance use of sexual minority collegiate student-athletes in the United States, as compared with heterosexual college students and heterosexual student-athletes. PARTICIPANTS: Undergraduate students (N = 196,872) who completed the American College Health Association's National College Health Assessment (Fall 2008-Fall 2012 administrations). METHODS: Written cross-sectional survey. RESULTS: Sexual minority student athletes had a higher risk of experiencing mental health difficulties than their heterosexual athlete peers. There were no significant differences in mental health between sexual minority male athletes and nonathletes. Sexual minority female athletes appeared to fare better than nonathlete peers. Substance use was greater among sexual minority students (athlete and nonathlete) and was mediated by mental health. CONCLUSIONS: Participation in athletics does not appear to be associated with an elevated risk of negative mental health outcomes for sexual minority participants; however, there are disparities in mental health outcomes by sexual orientation regardless of athletics participation. PMID- 26943649 TI - Distinct roles of TNF-related apoptosis-inducing ligand (TRAIL) in viral and bacterial infections: from pathogenesis to pathogen clearance. AB - INTRODUCTION: Apoptotic death of different cells observed during infection is thought to limit overwhelming inflammation in response to microbial challenge. However, the underlying apoptotic death mechanisms have not been well defined. Tumor necrosis factor (TNF) related apoptosis-inducing ligand (TRAIL) is a type II transmembrane protein belonging to the TNF superfamily, which is involved not only in tumor growth suppression but in infection control and also in the regulation of both innate and adaptive immune responses. FINDINGS: In this review, we have summarized data of recent studies on the influence of the TRAIL/TRAIL receptor (TRAIL-R) system on the development of viral and bacterial infections. TRAIL may have a dual function in the immune system being able to kill infected cells and also to participate in the pathogenesis of multiple infections. Moreover, many pathogens have evolved mechanisms to manipulate TRAIL signaling thus increasing pathogen replication. CONCLUSION: Present data highlight an essential role for the TRAIL/TRAIL-R system in the regulation and modulation of apoptosis and show that TRAIL has distinct roles in pathogenesis and pathogen elimination. Knowledge of the factors that determine whether TRAIL is helpful or harmful supposes its potential therapeutic implications that are only beginning to be explored. PMID- 26943648 TI - Hyaluronidase decreases neutrophils infiltration to the inflammatory site. AB - OBJECTIVE: To evaluate the in vivo anti-inflammatory potential of bovine hyaluronidase (HYAL) using two different models of acute inflammation. METHODS: Air pouches were produced in the dorsal subcutaneous of mice and injected with phosphate saline solution or HYAL. The antiinflammatory action of HYAL was evaluated in carrageenan (Cg)-inflamed air pouches. After 4 and 24 h the cellular influx, protein exudation, cytokines and lipid mediators were evaluated. The action of HYAL on the rolling and adhesion of leukocytes was investigated in the LPS-stimulated mesenteric microcirculation by intravital microscopic. RESULTS: Treatment with HYAL reduced the cellular influx and protein exudation in non inflamed and inflamed air pouches. HYAL treatment of Cg-inflamed air pouch reduced the production of tumor necrosis factor-alpha (TNF-alpha), interleukin-8 (IL-8), leukotriene B4 (LTB4) and LTC4, whereas prostaglandins E2 (PGE2) and D2 (PGD2) concentrations were unchanged. Histological analyses showed that HYAL administration diminished cell infiltration in the air-pouch lining. In LPS stimulated mesenteric microcirculation, HYAL usage decreased rolling and adhesion of leukocytes, but did not affect the blood vessels diameters. CONCLUSION: The results demonstrate that HYAL inhibited cellular recruitment, edema formation and pro-inflammatory mediators production, resulting in decreased adherence of leukocytes to blood vessels and tissue infiltration. Our data suggest that HYAL may be considered an effective candidate to ameliorate acute inflammation. PMID- 26943650 TI - Prevalence, risk factors and treatment practices in diarrhoeal diseases in south India. AB - OBJECTIVES: This study was done to determine the risk factors, management practices and awareness about diarrhoea. METHODS: It was a cross sectional study done in a semi urban and rural areas of South Canara district of India in February 2013. A total of 167 households (575 study population) chosen systematic randomly were visited and one adult member in each house was interviewed. The houses were also inspected to assess the living conditions. RESULTS: Mean age of study population was 31.1 +/- 20.2 years. The period prevalence of diarrhoea was 69 (12 %). Commonest associated symptoms in cases of diarrhoea were fever 30 (43.4 %) followed by abdominal cramps 29 (42 %). Nearly half of the cases with diarrhoea 34 (49.3 %) did not take any medications. Commonest treatment taken was allopathic medicines 26 (37.8 %) followed by home remedies 8 (22.9 %). Age <=10 years (p < 0.001) was associated with risk of developing diarrhoea using binary logistic regression analysis. Among the 167 participants, awareness level about the disease was poor among 16 (9.6 %) and moderate among 149 (89.2 % participants). Awareness level was more among females (p = 0.001) and literate participants (p = 0.013). One hundred and sixteen (69.5 %) participants were not aware of any sign or symptom of dehydration other than loose stools. Majority of the participants 138 (82.6 %) preferred home remedies as the initial management of diarrhoea. Misconception about fluid restriction in diarrhoea was stated by 12(7.2 %) participants. CONCLUSION: Public education program on proper feeding and management practices is required to address the various issues identified and for containment of diarrhoea cases in future. PMID- 26943653 TI - Quality by design approach for development of suspension nasal spray products: a case study on budesonide nasal suspension. AB - The objective of this study was to provide quality by design (QbD) approach for development of suspension type nasal spray products. Quality target product profile (QTPP) of test product budesonide nasal suspension (B-NS) was defined and critical quality attributes (CQAs) were identified. Critical formulation, process and delivery device variables were recognized. Risk assessment was performed by using failure mode and effect analysis (FMEA) methodology. Selected variables were further assessed using a Plackett Burman screening study. A response surface design consisting of the critical factors was used to study the interactions between the study variables. Formulation variable X2: median particle size of budesonide (D50) (u) has strikingly influenced dissolution (%) (Y1), while D50 droplet size distribution (um) (Y2) was significantly impacted by formulation variable X1: Avicel RC 591 (%) and process variable X4: homogenization speed (rpm). A design space plot within which the CQAs remained unchanged was established at lab scale. A comprehensive approach for development of B-NS product based on the QbD methodology has been demonstrated. The accuracy and robustness of the model were confirmed by comparability of the predicted value generated by model with the observed value. PMID- 26943652 TI - Selective expression of transthyretin in subtypes of lung cancer. AB - Transthyretin (TTR) is expressed primarily in liver, choroid plexus of brain and pancreatic islet A and B cells. It is also synthesized in some endocrine tumors. In the present study, the protein expression of TTR in lung cancer tissues and cell lines was investigated by western blot. The mRNA expression of TTR in 24 pairs of frozen lung cancer tissues was examined by RT-PCR. The specific expression and cellular distribution of TTR were also evaluated in 104 paraffin embedded lung cancer samples and 3 normal lung tissues by immunohistochemistry. Similarly, the subcellular localization and expression of TTR were further analyzed in lung cancer cell lines. With the exception of mucinous adenocarcinoma, the expression of TTR protein was observed in all tested subtypes of lung carcinoma. Adenocarcinoma displayed the highest positive expression rate of TTR, accounting for 84.4 %, and the positive expression rate of TTR was up to 85.7 % at stages III and IV. The secretory bubbles with strong TTR staining were observed in luminal cells of lung cancer. Furthermore, the localization of TTR in the cytoplasm of lung cancer cells and the secretion of TTR into extracellular milieu were also confirmed. Taken together, TTR is selectively synthesized in lung cancer cells and can be secreted extracellularly. PMID- 26943654 TI - The Need for Governance by Experimentation: The Case of Biofuels. AB - The policies of the European Union concerning the development of biofuels can be termed a lock-in. Biofuels were initially hailed as a green, sustainability technology. However evidence to the contrary quickly emerged. The European Commission proposed to alter its policies to accommodate for these effects but met with fierce resistance from a considerable number of member states who have an economic interest in these first generation biofuels. In this paper I argue that such a lock-in might have been avoided if an experimental approach to governance had been adopted. Existing approaches such as anticipation and niche management either do not reduce uncertainty sufficiently or fail to explicitly address conflicts between values motivating political and economic support for new technologies. In this paper, I suggest to apply an experimental framework to the development of sustainable biobased technologies. Such an approach builds on insights from adaptive management and transition management in that it has the stimulation of learning effects at its core. I argue that these learning effects should occur on the actual impacts of new technologies, on the institutionalisation of new technologies and most specifically on the norms and values that underly policies supporting new technologies. This approach can be relevant for other emerging technologies. PMID- 26943655 TI - The FIB-4 index is a significant prognostic factor in patients with non-B non-C hepatocellular carcinoma after curative surgery. AB - PURPOSE: The aspartate aminotransferase to platelet ratio index (APRI) and fibrosis-4 (FIB-4) index were developed as a non-invasive parameter for predicting liver fibrosis. This study aimed to validate the APRI and FIB-4 indexes in patients treated with curative therapy for non-B non-C (NBNC) hepatocellular carcinoma (HCC). METHODS: Accumulated database comprising 399 patients who underwent hepatectomy was reviewed retrospectively. Analyses were performed to evaluate whether the APRI and FIB-4 indexes are predictors of liver cirrhosis and/or the prognosis in patients with NBNC-HCC. Forty-seven patients with NBNC-HCC who underwent curative radiofrequency ablation therapy (RFA) in the same period were enrolled as the validation set. RESULTS: The APRI and FIB-4 indexes were significantly higher in the cirrhosis group than in the no-cirrhosis group (P = 0.001 and P < 0.001, respectively). A receiver operating characteristic curve analysis showed that the FIB-4 index was more accurate in predicting background liver cirrhosis than the APRI. According to a multivariate analysis, an FIB-4 index larger than 2.7 (hazard ratio 2.11 and 2.21, 95 % confidence interval 1.06-4.18 and 1.38-3.54, P = 0.033 and P = 0.001) remained significant independent predictors of overall and recurrence-free survival, respectively. CONCLUSIONS: The present findings showed that the FIB-4 index is a significant predictor of background liver cirrhosis and the prognosis after curative resection for NBNB-HCC. PMID- 26943656 TI - Characterization and Localization of Citrullinated Proteoglycan Aggrecan in Human Articular Cartilage. AB - BACKGROUND: Rheumatoid arthritis (RA) is an autoimmune disease of the synovial joints. The autoimmune character of RA is underscored by prominent production of autoantibodies such as those against IgG (rheumatoid factor), and a broad array of joint tissue-specific and other endogenous citrullinated proteins. Anti citrullinated protein antibodies (ACPA) can be detected in the sera and synovial fluids of RA patients and ACPA seropositivity is one of the diagnostic criteria of RA. Studies have demonstrated that RA T cells respond to citrullinated peptides (epitopes) of proteoglycan (PG) aggrecan, which is one of the most abundant macromolecules of articular cartilage. However, it is not known if the PG molecule is citrullinated in vivo in human cartilage, and if so, whether citrulline-containing neoepitopes of PG (CitPG) can contribute to autoimmunity in RA. METHODS: CitPG was detected in human cartilage extracts using ACPA+ RA sera in dot blot and Western blot. Citrullination status of in vitro citrullinated recombinant G1 domain of human PG (rhG1) was confirmed by antibody-based and chemical methods, and potential sites of citrullination in rhG1 were explored by molecular modeling. CitPG-specific serum autoantibodies were quantified by enzyme linked immunosorbent assays, and CitPG was localized in osteoarthritic (OA) and RA cartilage using immunohistochemistry. FINDINGS: Sera from ACPA+ RA patients reacted with PG purified from normal human cartilage specimens. PG fragments (mainly those containing the G1 domain) from OA or RA cartilage extracts were recognized by ACPA+ sera but not by serum from ACPA- individuals. ACPA+ sera also reacted with in vitro citrullinated rhG1 and G3 domain-containing fragment(s) of PG. Molecular modeling suggested multiple sites of potential citrullination within the G1 domain. The immunohistochemical localization of CitPG was different in OA and RA cartilage. CONCLUSIONS: CitPG is a new member of citrullinated proteins identified in human joints. CitPG could be found in both normal and diseased cartilage specimens. Antibodies against CitPG may trigger or augment arthritis by forming immune complexes with this autoantigen in the joints of ACPA+ RA patients. PMID- 26943658 TI - Andreas Vesalius' 500th Anniversary: First Description of the Mammary Suspensory Ligaments. AB - Sir Astley Paston Cooper has, to date, been acknowledged to be the first to describe the suspensory ligaments of the breast, or Cooper's ligaments, in 1840. We found these ligaments to be recorded in the first edition of 'De Humani Corporis Fabrica Libri Septem' by Andreas Vesalius, published in 1543. To commemorate Vesalius' 500th birthday, we quote and discuss this earlier record. Vesalius' record of the nature and function of the fleshy membrane between mammary gland and pectoral muscle, the hard fat intervening the mammary glands, and the fibers running from the fleshy membrane to the skin are a clear representation of posterior layer of the superficial fascial system, the fibro adipose stroma surrounding and linking the mammary glandular elements, and the suspensory ligaments as we know them. Vesalius recorded the anatomy and function of the latter structures nearly 300 years before Sir Astley Paston Cooper did. PMID- 26943659 TI - Laparoscopic Roux en-Y Gastric Bypass Using a Modified Retrocolic-Supracolic Approach: Outcomes from 300 Patients. AB - BACKGROUND: Laparoscopic Roux en-Y gastric bypass (LRYGB) achieves sustained long term weight loss and reduced mortality in morbidly obese patients. It is routinely performed using an ante- or retrocolic approach with the jejuno jejunostomy constructed in the infracolic compartment. We have modified the standard technique of performing LRYGB by constructing both anastomoses in the supracolic compartment. This study describes the outcomes of consecutive primary LRYGB performed using this novel retrocolic-supracolic approach. METHODS: Data were prospectively collected on consecutive primary LRYGB performed in a tertiary referral Bariatric Centre in the United Kingdom from September 2009 to March 2013. Data included demographics, operative outcomes (duration of surgery, postoperative anastomotic leak/bleeding/reoperations), development of strictures, length of stay, excess weight loss (EWL) and resolution of diabetes mellitus. RESULTS: Hand-sewn LRYGB was successfully performed using the retrocolic supracolic approach in 300 of 307 (98 %) consecutive patients (72 % female). Median (IQR) age, weight and baseline body mass index were 49 (41-56) years, 146 (134-163) kg and 52.9 (48.8-57.2) kg/m(2), respectively. There were 4 (1.3 %) anastomotic leaks and 8 (2.6 %) postoperative bleeds. The 30-day reoperation rate was 1.6 %. Median (IQR) hospital stay was 2 (2-2) days. Postoperative dysphagia requiring endoscopic balloon dilatation occurred in 19 (6.3 %) patients. Mean +/- SD 12-month EWL was 69.9 +/- 19.0 %. Within the follow-up period, 81 % of patients with type II diabetes mellitus achieved remission and 19 % reduced dosage of diabetes medication. CONCLUSIONS: LRYGB performed using the retrocolic supracolic approach was safe, feasible, technically advantageous and resulted in clinical outcomes akin to the standard infracolic approach. PMID- 26943661 TI - Comparison of Reconstruction Algorithms for Decreasing the Exposure Dose During Digital Tomosynthesis for Arthroplasty: a Phantom Study. AB - To explore the possibility of decreasing the radiation dose during digital tomosynthesis (DT) for arthroplasty, we compared the image qualities of several reconstruction algorithms, such as filtered back projection (FBP) and two iterative reconstruction (IR), methods maximum likelihood expectation maximization (MLEM) and the simultaneous iterative reconstruction technique (SIRT) under different radiation doses. The three algorithms were implemented using a DT system and experimentally evaluated by contrast-to-noise ratio (CNR), artifact spread function (ASF), and power spectrum measurements on a prosthesis phantom. The CNR and ASF data were statistically analyzed by a one-way analysis of variance. The effectiveness of each technique for enhancing the visibility of the prosthesis phantom was quantified by the CNR (reference dose vs. 20 % reduced dose in FBP, P = 0.62; reference vs. 37 % reduced dose in FBP, P = 0.16; reference vs. 55 % reduced dose in FBP, P < 0.05; reference vs. 20 % reduced dose in IR, P = 0.92; reference vs. 37 % reduced dose in IR, P = 0.40; reference vs. 55 % reduced dose in IR, P < 0.05) and ASF (reference dose vs. 20 % reduced dose in FBP, P = 0.25; reference vs. 37 and 55 % reduced dose in FBP, P < 0.05; reference vs. 20 % reduced dose in IR, P = 0.16; reference vs. 37 and 55 % reduced dose in IR, P < 0.05). The power spectra under the reference and reduced doses are equivalent. In this phantom study, the radiation dose of the reference dose could be decreased by 20 % with FBP and IR for consideration of common factors. PMID- 26943662 TI - [STHLM3 test could help improve prostate cancer screening]. PMID- 26943660 TI - Toward Data-Driven Radiology Education-Early Experience Building Multi Institutional Academic Trainee Interpretation Log Database (MATILDA). AB - The residency review committee of the Accreditation Council of Graduate Medical Education (ACGME) collects data on resident exam volume and sets minimum requirements. However, this data is not made readily available, and the ACGME does not share their tools or methodology. It is therefore difficult to assess the integrity of the data and determine if it truly reflects relevant aspects of the resident experience. This manuscript describes our experience creating a multi-institutional case log, incorporating data from three American diagnostic radiology residency programs. Each of the three sites independently established automated query pipelines from the various radiology information systems in their respective hospital groups, thereby creating a resident-specific database. Then, the three institutional resident case log databases were aggregated into a single centralized database schema. Three hundred thirty residents and 2,905,923 radiologic examinations over a 4-year span were catalogued using 11 ACGME categories. Our experience highlights big data challenges including internal data heterogeneity and external data discrepancies faced by informatics researchers. PMID- 26943657 TI - Guidelines for Perioperative Care in Bariatric Surgery: Enhanced Recovery After Surgery (ERAS) Society Recommendations. AB - BACKGROUND: During the last two decades, an increasing number of bariatric surgical procedures have been performed worldwide. There is no consensus regarding optimal perioperative care in bariatric surgery. This review aims to present such a consensus and to provide graded recommendations for elements in an evidence-based "enhanced" perioperative protocol. METHODS: The English-language literature between January 1966 and January 2015 was searched, with particular attention paid to meta-analyses, randomised controlled trials and large prospective cohort studies. Selected studies were examined, reviewed and graded. After critical appraisal of these studies, the group of authors reached a consensus recommendation. RESULTS: Although for some elements, recommendations are extrapolated from non-bariatric settings (mainly colorectal), most recommendations are based on good-quality trials or meta-analyses of good-quality trials. CONCLUSIONS: A comprehensive evidence-based consensus was reached and is presented in this review by the enhanced recovery after surgery (ERAS) Society. The guidelines were endorsed by the International Association for Surgical Metabolism and Nutrition (IASMEN) and based on the evidence available in the literature for each of the elements of the multimodal perioperative care pathway for patients undergoing bariatric surgery. PMID- 26943664 TI - [The diagnostic and therapeutic challenges of bilateral renal oncocytosis : Illustrative case presentations and a review of the literature]. AB - Bilateral oncocytosis along with multiple tumours in both kidneys represents a very rare pathology that is accompanied by diagnostic and therapeutic challenges. We report the case of a 60-year old male patient who underwent computer tomography with incidental detection of multiple bilateral and contrast enhancing renal tumours of different size. Subsequently the patient underwent nephron sparing tumor resection, first on the right side and 4 weeks later on the left side. The histology of all removed tumors showed evidence of pure oncocytoma. There were no postoperative complications and renal function reached a stable state within 6 months follow-up. The major challenge regarding diagnostic process and therapy of this pathology is to distinguish benign oncocytoma from chromophobe renal cell carcinoma and hybrid tumours, which can all be associated with renal oncocytosis. Because of limitations concerning imaging processes and biopsy, all patients should undergo nephron-sparing surgery as far as possible. On the other hand alternative therapies should - regarding to therapy-associated morbidity and the basically benign prognosis of oncocytoma - be well discussed to obtain informed consent. In this case report different therapy options and the international literature concerning renal oncocytosis will be discussed. PMID- 26943666 TI - [Multimodal therapy of locally advanced prostate cancer]. AB - Locally advanced prostate cancer (LAPCA) comprises about 5-10 % of all newly diagnosed prostate cancers and is associated with the highest prostate cancer specific mortality (approximately 8-20 %). LAPCA is defined by the presence of extraprostatic extension, seminal vesicle invasion, and bladder neck infiltration of pelvic lymph node metastases. It is evident that prognosis can only be improved by interdisciplinary multimodality treatment strategies. Adequate local staging by multiparametric MRI is one of the cornerstones for an individualized, risk-adapted treatment approach. This might consist of extended radical prostatectomy with an extended pelvic lymphadenectomy or intensity-modulated radiation therapy with androgen deprivation as the primary local therapeutic approach. Both treatment strategies may be combined with neoadjuvant or adjuvant radiation therapy or salvage surgery. Combination with neoadjuvant or adjuvant chemotherapy and new androgen receptor pathway inhibitors might also be possible. This article summarizes the current treatment strategies for LAPCA. PMID- 26943668 TI - Seasonal Variation in Biting Rates of Simulium damnosum sensu lato, Vector of Onchocerca volvulus, in Two Sudanese Foci. AB - BACKGROUND: The abundance of onchocerciasis vectors affects the epidemiology of disease in Sudan, therefore, studies of vector dynamics are crucial for onchocerciasis control/elimination programs. This study aims to compare the relative abundance, monthly biting-rates (MBR) and hourly-based distribution of onchocerciasis vectors in Abu-Hamed and Galabat foci. These seasonally-based factors can be used to structure vector control efforts to reduce fly-biting rates as a component of onchocerciasis elimination programs. METHODS: A cross sectional study was conducted in four endemic villages in Abu-Hamed and Galabat foci during two non-consecutive years (2007-2008 and 2009-2010). Both adults and aquatic stages of the potential onchocerciasis vector Simulium damnosum sensu lato were collected following standard procedures during wet and dry seasons. Adult flies were collected using human landing capture for 5 days/month. The data was recorded on handheld data collection sheets to calculate the relative abundance, MBR, and hourly-based distribution associated with climatic factors. The data analysis was carried out using ANOVA and Spearman rank correlation tests. RESULTS: Data on vector surveillance revealed higher relative abundance of S. damnosum s.l. in Abu- Hamed (39,934 flies) than Galabat (8,202 flies). In Abu Hamed, vector populations increased in January-April then declined in June-July until they disappeared in August-October. Highest black fly density and MBR were found in March 2007 (N = 9,444, MBR = 58,552.8 bites/person/month), and March 2010 (N = 2,603, MBR = 16,138.6 bites/person/month) while none of flies were collected in August-October (MBR = 0 bites/person/month). In Galabat, vectors increased in September-December, then decreased in February-June. The highest vector density and MBR were recorded in September 2007 (N = 1,138, MBR = 6,828 bites/person/month) and September 2010 (N = 1,163, MBR = 6,978 bites/person/month), whereas, none appeared in collection from April to June. There was a significant difference in mean monthly density of S. damnosum s.l. across the two foci in 2007-2008 (df = 3, F = 3.91, P = 0.011). Minimum temperature showed significant correlation with adult flies counts in four areas sampled; the adult counts were increased in Nady village (rs = 0.799) and were decreased in Kalasecal (rs = -0.676), Gumaiza (rs = -0.585), and Hilat Khateir (rs = -0.496). Maximum temperature showed positive correlation with black fly counts only in Galabat focus. Precipitation was significantly correlated with adult flies counts in Nady village, Abu-Hamed, but no significance was found in the rest of the sampled villages in both foci. Hourly-based distribution of black flies showed a unimodal pattern in Abu-Hamed with one peak (10:00-18:00), while a bimodal pattern with two peaks (07:00-10:00) and (14:00-18:00) was exhibited in Galabat. CONCLUSION: Transmission of onchocerciasis in both foci showed marked differences in seasonality, which may be attributed to ecology, microclimate and proximity of breeding sites to collection sites. The seasonal shifts between the two foci might be related to variations in climate zones. This information on black fly vector seasonality, ecology, distribution and biting activity has obvious implications in monitoring transmission levels to guide the national and regional onchocerciasis elimination programs in Sudan. PMID- 26943670 TI - Fast Atomic-Scale Chemical Imaging of Crystalline Materials and Dynamic Phase Transformations. AB - Atomic-scale phenomena fundamentally influence materials form and function that makes the ability to locally probe and study these processes critical to advancing our understanding and development of materials. Atomic-scale chemical imaging by scanning transmission electron microscopy (STEM) using energy dispersive X-ray spectroscopy (EDS) is a powerful approach to investigate solid crystal structures. Inefficient X-ray emission and collection, however, require long acquisition times (typically hundreds of seconds), making the technique incompatible with electron-beam sensitive materials and study of dynamic material phenomena. Here we describe an atomic-scale STEM-EDS chemical imaging technique that decreases the acquisition time to as little as one second, a reduction of more than 100 times. We demonstrate this new approach using LaAlO3 single crystal and study dynamic phase transformation in beam-sensitive Li[Li0.2Ni0.2Mn0.6]O2 (LNMO) lithium ion battery cathode material. By capturing a series of time-lapsed chemical maps, we show for the first time clear atomic-scale evidence of preferred Ni-mobility in LNMO transformation, revealing new kinetic mechanisms. These examples highlight the potential of this approach toward temporal, atomic scale mapping of crystal structure and chemistry for investigating dynamic material phenomena. PMID- 26943669 TI - Effects of colchicine treatment on mean platelet volume and the inflammatory markers in recurrent aphthous stomatitis. AB - OBJECTIVE: Recurrent aphthous stomatitis (RAS) is the most commonly seen inflammatory disease in the oral mucosa affecting 5%-25% of the general population. The etiology of RAS is still not fully understood and its treatment is very challenging. With its anti-inflammatory affects, colchicine is used for systematic treatment of RAS. In this study, we want to examine the effects of colchicine on platelet density, mean platelet volume (MPV), neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR) and red cell distribution width (RDW) of the patients with RAS. METHODS: Fifteen male and 45 female RAS patients that were taking colchicine were investigated retrospectively. The whole blood parameters of the patients were observed before starting colchicine treatment and in the third month of colchicine treatment. RESULTS: Significant decrease in the levels of NLR, white blood cell count and RDW of the RAS patients under colchicine treatment was observed. Moreover, no changes were seen on MPVs, PLRs and hemoglobin (Hb) levels. CONCLUSION: It was determined that colchicine lowers the levels of NLR, white blood cell count and RDW. Furthermore, no changes were seen on MPVs, PLRs and Hb levels. PMID- 26943671 TI - Oxalate Concentrations in Human Gastrointestinal Fluid. AB - BACKGROUND AND PURPOSE: Urinary oxalate excretion is a risk factor for nephrolithiasis and is a result of endogenous metabolism and gastrointestinal processes. Gastrointestinal absorption of oxalate has been well demonstrated but to our knowledge evidence for secretion of oxalate is absent in humans. The objective of this study was to measure the amount and conformation of oxalate in the stomach and small intestine of adult subjects undergoing gastrointestinal endoscopy. MATERIALS AND METHODS: Eleven adults participated in this study. Gastrointestinal fluid was collected from the stomach and small intestine during endoscopy. A determination of the soluble and insoluble components of oxalate was made by centrifugation of the sample and subsequent acidification of the resultant pellet and supernatant. Samples were processed and the amount of oxalate was measured by ion chromatography, the limit of which is 1.6 MUM. RESULTS: The majority of small intestinal samples contained some degree of oxalate. This is in contrast to the stomach where minimal oxalate was detected. There was a wide range of oxalate concentrations and a greater degree of insoluble oxalate in small intestinal samples. CONCLUSIONS: Our results suggest that some degree of oxalate secretion in the small intestine may occur in the fasted state while this is less likely in the stomach. Further studies are warranted to provide definitive evidence of gastrointestinal secretion of oxalate. PMID- 26943672 TI - "Tazomoka Is Not a Problem". Local Perspectives on Malaria, Fever Case Management and Bed Net Use in Madagascar. AB - BACKGROUND: Although its incidence has been decreasing during the last decade, malaria is still a major public health issue in Madagascar. The use of Long Lasting Insecticidal Nets (LLIN) remains a key malaria control intervention strategy in Madagascar, however, it encounters some obstacles. The present study aimed to explore the local terminology related to malaria, information channels about malaria, attitude towards bed nets, and health care seeking practices in case of fever. This article presents novel qualitative findings about malaria. Until now, no such data has been published for Madagascar. METHODS: A comparative qualitative study was carried out at four sites in Madagascar, each differing by malaria epidemiology and socio-cultural background of the populations. Seventy one semi-structured interviews were conducted with biomedical and traditional caregivers, and members of the local population. In addition, observations of the living conditions and the uses of bed net were conducted. RESULTS: Due to the differences between local and biomedical perspectives on malaria, official messages did not have the expected impact on population in terms of prevention and care seeking behaviors. Rather, most information retained about malaria was spread through informal information circulation channels. Most interviewees perceived malaria as a disease that is simple to treat. Tazomoka ("mosquito fever"), the Malagasy biomedical word for malaria, was not used by populations. Tazo ("fever") and tazomahery ("strong fever") were the terms more commonly used by members of the local population to refer to malaria related symptoms. According to local perceptions in all areas, tazo and tazomahery were not caused by mosquitos. Each of these symptoms required specific health recourse. The usual fever management strategies consisted of self-medication or recourse to traditional and biomedical caregivers. Usage of bed nets was intermittent and was not directly linked to protection against malaria in the eyes of most Malagasy people. CONCLUSIONS: This article highlights the conflicting understanding of malaria between local perceptions and the biomedical establishment in Madagascar. Local perceptions of malaria present a holistic vision of the disease that includes various social and cultural dimensions, rather than reflecting one universal understanding, as in the biomedical image. The consideration of this "holistic vision" and other socio-cultural aspects surrounding the understanding of malaria is essential in implementing successful control intervention strategies. PMID- 26943673 TI - A Numerically Subdominant CD8 T Cell Response to Matrix Protein of Respiratory Syncytial Virus Controls Infection with Limited Immunopathology. AB - CD8 T cells are involved in pathogen clearance and infection-induced pathology in respiratory syncytial virus (RSV) infection. Studying bulk responses masks the contribution of individual CD8 T cell subsets to protective immunity and immunopathology. In particular, the roles of subdominant responses that are potentially beneficial to the host are rarely appreciated when the focus is on magnitude instead of quality of response. Here, by evaluating CD8 T cell responses in CB6F1 hybrid mice, in which multiple epitopes are recognized, we found that a numerically subdominant CD8 T cell response against DbM187 epitope of the virus matrix protein expressed high avidity TCR and enhanced signaling pathways associated with CD8 T cell effector functions. Each DbM187 T effector cell lysed more infected targets on a per cell basis than the numerically dominant KdM282 T cells, and controlled virus replication more efficiently with less pulmonary inflammation and illness than the previously well-characterized KdM282 T cell response. Our data suggest that the clinical outcome of viral infections is determined by the integrated functional properties of a variety of responding CD8 T cells, and that the highest magnitude response may not necessarily be the best in terms of benefit to the host. Understanding how to induce highly efficient and functional T cells would inform strategies for designing vaccines intended to provide T cell-mediated immunity. PMID- 26943676 TI - Patterns of Betel Quid, Cigarette, and Alcohol Use, and Their Correlates With Betel Quid Cessation in a Male Inmate Population. AB - BACKGROUND: There are few published studies addressing multiple substance uses and their effects on subsequent cessation of betel quid (BQ) chewing in the Asia Pacific region. OBJECTIVES: This study aims to investigate the usage patterns of BQ chewing, cigarette smoking, and alcohol drinking, and their correlates with subsequent BQ cessation among a male inmate population. METHODS: Data from 473 male inmates with a history of BQ use who were incarcerated in Taiwan Kaohsiung Prison was used for this analysis. Participants were asked to report their lifetime usage patterns of cigarette, alcohol, and BQ, and their cessation status of each substance. A stepwise logistic regression analysis was performed to identify predictors of voluntary BQ cessation. RESULTS: Seventy-five percent of all participants reported habitual use of all three substances. A total of 185 (39%) participants reported voluntary cessation of BQ prior to incarceration, and 288 (61%) reported cessation because of incarceration. Inmates who quit smoking before incarceration were more likely to voluntarily quit BQ. Inmates who had drinking habits were less likely to quit BQ, but those who quit drinking before incarceration were more likely to quit BQ. Inmates who preferred the type of BQ known as lao-hwa quid were more likely to quit BQ, and a longer chewing history correlated with a lower likelihood of quitting BQ. CONCLUSIONS IMPORTANCE: Our data suggest that coexisting habitual use of cigarette, alcohol, and BQ is very common in this inmate population. BQ cessation is significantly associated with not only inmates' usage patterns of cigarette and alcohol, but also their cessation status of these substances. PMID- 26943674 TI - Indoor Spatial Updating with Reduced Visual Information. AB - PURPOSE: Spatial updating refers to the ability to keep track of position and orientation while moving through an environment. People with impaired vision may be less accurate in spatial updating with adverse consequences for indoor navigation. In this study, we asked how artificial restrictions on visual acuity and field size affect spatial updating, and also judgments of the size of rooms. METHODS: Normally sighted young adults were tested with artificial restriction of acuity in Mild Blur (Snellen 20/135) and Severe Blur (Snellen 20/900) conditions, and a Narrow Field (8 degrees ) condition. The subjects estimated the dimensions of seven rectangular rooms with and without these visual restrictions. They were also guided along three-segment paths in the rooms. At the end of each path, they were asked to estimate the distance and direction to the starting location. In Experiment 1, the subjects walked along the path. In Experiment 2, they were pushed in a wheelchair to determine if reduced proprioceptive input would result in poorer spatial updating. RESULTS: With unrestricted vision, mean Weber fractions for room-size estimates were near 20%. Severe Blur but not Mild Blur yielded larger errors in room-size judgments. The Narrow Field was associated with increased error, but less than with Severe Blur. There was no effect of visual restriction on estimates of distance back to the starting location, and only Severe Blur yielded larger errors in the direction estimates. Contrary to expectation, the wheelchair subjects did not exhibit poorer updating performance than the walking subjects, nor did they show greater dependence on visual condition. DISCUSSION: If our results generalize to people with low vision, severe deficits in acuity or field will adversely affect the ability to judge the size of indoor spaces, but updating of position and orientation may be less affected by visual impairment. PMID- 26943677 TI - Pulmonary hepatoid adenocarcinoma: report of a case. AB - Hepatoid adenocarcinoma (HAC) is a rare neoplasm with aberrant hepatocellular differentiation. HAC occurs in extrahepatic organs such as the gastrointestinal tract, testes, ovaries, and lungs and frequently produces alpha-fetoprotein. A 69 year-old patient was diagnosed clinically with T2aN0M0, stage IB, non-small cell lung carcinoma. Because the tumor showed tight adhesion to the chest wall, we performed left upper lobectomy, combined resection of the 3rd and 4th ribs, and lymph node dissection. Pathological examination confirmed the diagnosis of HAC of the lung (pathological T2aN0M0, stage IB), and four courses of cisplatin and gemcitabine were administered as adjuvant chemotherapy. Genetic analysis of the epidermal growth factor receptor showed wild type. Preoperative serum alpha fetoprotein level, a useful marker of disease progression, was elevated to 4497 ng/ml, decreasing within the normal range by about 3 months postoperatively. The patient remains alive without recurrence as of 51 months after surgery. PMID- 26943675 TI - Demographically-Based Evaluation of Genomic Regions under Selection in Domestic Dogs. AB - Controlling for background demographic effects is important for accurately identifying loci that have recently undergone positive selection. To date, the effects of demography have not yet been explicitly considered when identifying loci under selection during dog domestication. To investigate positive selection on the dog lineage early in the domestication, we examined patterns of polymorphism in six canid genomes that were previously used to infer a demographic model of dog domestication. Using an inferred demographic model, we computed false discovery rates (FDR) and identified 349 outlier regions consistent with positive selection at a low FDR. The signals in the top 100 regions were frequently centered on candidate genes related to brain function and behavior, including LHFPL3, CADM2, GRIK3, SH3GL2, MBP, PDE7B, NTAN1, and GLRA1. These regions contained significant enrichments in behavioral ontology categories. The 3rd top hit, CCRN4L, plays a major role in lipid metabolism, that is supported by additional metabolism related candidates revealed in our scan, including SCP2D1 and PDXC1. Comparing our method to an empirical outlier approach that does not directly account for demography, we found only modest overlaps between the two methods, with 60% of empirical outliers having no overlap with our demography-based outlier detection approach. Demography-aware approaches have lower-rates of false discovery. Our top candidates for selection, in addition to expanding the set of neurobehavioral candidate genes, include genes related to lipid metabolism, suggesting a dietary target of selection that was important during the period when proto-dogs hunted and fed alongside hunter-gatherers. PMID- 26943679 TI - Secondary abdominal compartment syndrome required decompression laparotomy during minimally invasive mitral valve repair. AB - We treated a 77-year-old patient with secondary abdominal compartment syndrome that caused failure to maintain cardiopulmonary bypass while undergoing elective minimally invasive right mini-thoracotomy mitral valve and tricuspid valve repair procedures. During the operation, a decompression laparotomy was needed to relieve elevated intraabdominal pressure that caused instability of the cardiopulmonary bypass. Due to poor oxygenation and the long cardiopulmonary bypass time, the patient required peripheral extracorporeal membrane oxygenation before recovery. We alert surgeons to this rare complication that can occur even in patients undergoing minimally invasive surgery with a right mini-thoracotomy. PMID- 26943678 TI - Primary squamous cell carcinoma of the ampulla of Vater: a case report. AB - BACKGROUND: Primary squamous cell carcinoma of the ampulla of Vater is a very rare type of tumor, and the prognosis is not well known mainly due to a limited number of cases reported. Here, we aimed to report a case with primary squamous cell carcinoma of the ampulla of Vater. CASE PRESENTATION: A 54-year-old woman presented with weight loss, jaundice, and pain in the epigastric and right upper quadrant of the abdomen. With extensive radiological imaging, the patient was diagnosed with periampullary tumor and Whipple's procedure was performed. The immunohistochemical analyses supported the diagnosis of primary squamous cell carcinoma. The postoperative course was uneventful. The patient was discharged, and adjuvant chemotherapy was recommended. CONCLUSION: Primary squamous cell carcinoma of the ampulla of Vater is a very rare histological type with an unclear pathogenesis. A better understanding of pathogenesis might be helpful in optimizing the treatment for this specific rare type of tumor. PMID- 26943680 TI - Successful treatment for sorafenib-induced liver dysfunction: a report of case with liver biopsy. AB - Sorafenib is an oral multikinase inhibitor with anti-proliferative and anti angiogenic effects and is used worldwide for the treatment of advanced or metastatic hepatocellular carcinoma (HCC). While the significant survival benefit of sorafenib in patients with advanced HCC was demonstrated, various treatment related adverse events might happen. Of them, the incidence of drug-related severe liver dysfunction rarely occurs (<1 %) but is one of the serious adverse events by sorafenib. The authors highlight the case of a 71-year-old man with metastatic HCC with sorafenib-related fatal liver dysfunction (T-Bil 28.6 mg/dL, AST 1611 IU/L, ALT 1098 IU/L) 2 months later even without either intrahepatic viable HCC or hepatitis B virus (HBV) reactivation. Then, the liver dysfunction was improved following aggressive treatment using hyperbaric oxygen. A liver biopsy demonstrated cholestasis, degeneration, and necrosis in hepatocytes with lymphocyte infiltration. Thus, sorafenib rarely can induce liver dysfunction characterized by cholestatic and hepatocellular injury types, and it could be a fatal event. Clinicians should pay attention to any increase in the liver enzymes in these patients. PMID- 26943681 TI - Bile duct carcinoma associated with congenital biliary dilatation in a 16-year old female: a case report and literature review. AB - We encountered a very rare case of bile duct carcinoma associated with congenital biliary dilatation (CBD) in a 16-year-old female who was admitted to our hospital because of right upper abdominal pain and vomiting. Abdominal computed tomography demonstrated a cystic dilatation of the common bile duct measuring 7 cm in diameter and two enhanced tumors 4 cm in diameter located in the inferior bile duct and middle bile duct. Magnetic resonance cholangiopancreatography clearly demonstrated a cystic dilatation of the extrahepatic bile duct (Todani's CBD classification: type 4-A). Endoscopic retrograde cholangiopancreatography also revealed two tumors. Biopsy results of one of the tumors confirmed adenocarcinoma. Excision of the perihilar bile duct and subtotal stomach preserving pancreaticoduodenectomy with dissection of the major lymph nodes were performed. A postoperative histopathologic examination revealed a well differentiated tubular adenocarcinoma, which remained within the mucosal layer, and no lymph node metastasis was found. The postoperative course was uneventful, and the patient was discharged 10 days after surgery and has remained disease free for 21 months. PMID- 26943682 TI - Arteriovenous malformation of the pancreas: a case report. AB - Arteriovenous malformation (AVM) of the pancreas is uncommon in the gastrointestinal tract. We present a case of AVM of the pancreatic head in a 59 year-old male. He was admitted to a hospital with hematemesis and tarry stool and referred to our hospital in March 2014 on the diagnosis of pancreatic artery pseudoaneurysm. A computed tomography scan showed the presence of irregular dilated and/or stenotic vessels with meandering in the pancreatic head. Magnetic resonance imaging showed strong enhancement of the conglomeration in the pancreatic head. Selective angiography showed the proliferation of a vascular network in the pancreatic head and an early visualization of the portal vein at the arterial phase. The patient qualified for surgery with a preoperative diagnosis of AVM of the pancreatic head. We performed pylorus-preserving pancreaticoduodenectomy. The histological results confirmed the presence of irregular dilated tortuous arteries and veins in the pancreatic head. Surgical treatment may represent definitive management of symptomatic AVM. PMID- 26943683 TI - A case of arterial switch operation with coronary elongation technique. AB - A 28-day-old infant with D-transposition of the great arteries underwent arterial switch operation. The coronary pattern was Yacoub type A, in which coronary transfer is usually thought to be easy. However, a dominant conus branch diverged from the proximal portion of the left coronary artery (LCA). Moreover, the LCA ostium itself was near the remote commissure in sinus 1, very far from the target re-implantation point. All of these conditions made LCA transfer very difficult. We used a coronary elongation technique to solve this problem. An inverted U shaped flap was made in the wall of the neoaorta, and the LCA cuff was anastomosed to this flap (the inferior half from the neoaortic flap and the superior half from the LCA cuff). To prevent compression of the LCA, the neopulmonary trunk was shifted rightward. Postoperative echocardiography showed good left ventricular wall motion, and the LCA was easily visualized on chest computed tomography, with no compression from the neopulmonary artery. PMID- 26943684 TI - A case of breast cancer involving a ventriculoperitoneal shunt. AB - An 84-year-old woman was examined for an enlargement of an induration in the left breast. A ventriculoperitoneal shunt had been placed for postoperative normal pressure hydrocephalus of a cerebral hemorrhage, and it had penetrated the mass according to the computed tomography findings. Breast cancer was diagnosed after a close examination; however, close observation was selected because her family rejected treatment. She developed somnolence 7 months after the initial examination, and ventricular dilatation and expansion of the low-density region around the ventricle were noted on computed tomography, suggesting that the enlarged tumor had excluded the shunt and caused obstruction. The growth of breast carcinoma involving a shunt tube can be the cause of obstruction of a ventriculoperitoneal shunt. Our findings suggest that a breast lesion should be evaluated at both pre- and postoperation. PMID- 26943685 TI - Laparoscopic management of foramen of Winslow incarcerated hernia. AB - Foramen of Winslow hernia (FWH) is a rare and often overlooked diagnosis with a high mortality rate. Widespread availability of cross-sectional imaging allows early diagnosis and prompt management. In this setting, before ischemia occurs, explorative laparoscopy would be the most suitable approach. Experience, however, remains sparse, and technical difficulties may be encountered. This is the case of a 38-year-old Caucasian woman who presented to the emergency department for a sudden epigastric pain. Physical exam was unremarkable, and routine blood tests were within normal range. An abdominal computed tomography (CT) scan confirmed the diagnosis of ileocaecal herniation through the foramen of Winslow. Under urgent laparoscopy, the caecum appeared viable but incarcerated in the lesser sac. Caecal puncture was the key to achieving atraumatic reduction of the hernia and bowel salvage. PMID- 26943686 TI - Cavernous hemangioma in the thymus: a case report. AB - Cavernous hemangioma is not a neoplasm, but rather a congenital venous malformation with the potential to develop in all parts of the body, though it is very rarely seen in the thymus. We report a case of cavernous hemangioma in the thymus partially resected. A 71-year-old woman presented with pericardial discomfort, and chest computed tomography (CT) showed a left lateral mediastinal mass which was 2.0 * 1.2 * 1.8 cm in size, with border regularity and without calcification. Its interior was partially enhanced. Three-dimensional chest computed tomography image showed a tortuous vessel connecting to the tumor. Surgical resection was performed for the purpose of providing a definitive diagnosis and treatment because a mediastinal tumor such as thymoma or teratoma was suspected. Partial resection of the thymus including the mass was done by utilizing a three-port, left-sided video-assisted thoracic surgery (VATS) approach with hoisting of the third rib with the patient in a spinal position. A wine-colored mass bulging from the surface of the left lobe of the thymus was identified along with the communicating vessel which could only be cut with an energy device. It is considered that thymic partial resection using VATS is a better option for small and non-infiltrative lesions. PMID- 26943687 TI - Bladder and rectal incontinence without paraplegia or paraparesis after endovascular aneurysm repair. AB - Spinal cord ischemia is a well-known potential complication of endovascular aneurysm repair (EVAR), and it is usually manifested by paraplegia or paraparesis. We describe a case in which spinal cord ischemia after EVAR presented by isolated bladder and rectal incontinence without other neurological deficits. A 63-year-old woman presented with intermittent claudication secondary to an infrarenal abdominal aortic aneurysm (AAA), and a left common iliac artery obstruction, for which she underwent EVAR using an aorto-uniiliac (AUI) device and ilio-femoral artery bypass. On postoperative day 3, she developed urinary and fecal incontinence without signs of paraplegia or paraparesis. Magnetic resonance imaging (MRI) showed a hyper-intense signal in the spinal cord. She received hyperbaric oxygen (HBO) therapy and was discharged after 18 days when her urinary and fecal incontinence were almost resolved. This report suggests that spinal cord ischemia after EVAR for aortoiliac occlusive disease might present as bladder and rectal incontinence without other neurological manifestations. PMID- 26943688 TI - Long-term survival of a recurrent gallbladder carcinoma patient with lymph node and peritoneal metastases after multidisciplinary treatments: a case report. AB - BACKGROUND: Gallbladder carcinoma with peritoneal metastasis has a poor prognosis, with a median survival time of 4.8 months. We report the survival of a patient with gallbladder carcinoma with peritoneal metastasis for 7.6 months owing to treatment with tumor resection after chemoradiotherapy. CASE PRESENTATION: A 69-year-old man was referred to our hospital for gallbladder carcinoma with hepatic invasion. Cholecystectomy was performed along with S4a and S5 hepatectomy and extrahepatic bile duct resection with lymph node dissection. The postoperative pathological diagnosis was moderately differentiated adenocarcinoma, T3, N0, M0, stage IIIA by the International Union Against Cancer TNM classification. Despite treatment with gemcitabine, the common hepatic artery and para-aortic lymph nodes showed metastases after 3 months from surgery. Although a combination of cisplatin, gemcitabine, and radiotherapy reduced the size of the lymph node metastasis, the peritoneal metastasis persisted. The peritoneal metastasis responded to chemoradiotherapy using tegafur-uracil and leucovorin, but it recurred. The metastasis was resected after 3 years and 9 months from the first surgery, and chemotherapy was discontinued. Seven years and 6 months after the initial surgery, the patient exhibited no signs of tumor recurrence or metastasis. CONCLUSIONS: Multidisciplinary treatment including resection without residual tumors could achieve complete remission of gallbladder carcinoma with lymph node and peritoneal metastases in the selected patient. PMID- 26943690 TI - Integrally calcified solitary fibrous tumor in the retroperitoneum: a case report and review of the literature. AB - Solitary fibrous tumor (SFT) is a rare stromal neoplasm and usually occurs in the thoracic cavity. We here report a case of retroperitoneal SFT with prominent calcification. A 64-year-old man presented with an incidentally detected retroperitoneal mass in the right upper abdomen. Imaging tests indicated an integrally calcified mass. The lesion was observed for 2 years and laparoscopically resected according to the patient's wish. Microscopically, the mass was mostly occupied by calcification and proliferous spindle cells were scattered with positive CD34 expression. We diagnosed morphologically benign SFT and the patient remained disease-free 1 year after the excision. There has been no report of such integrally calcified SFT. Retroperitoneal SFT is difficult to make a preoperative diagnosis, and careful follow-up after the excision is recommended because morphological malignancy does not always correspond to clinical malignancy. PMID- 26943691 TI - Poorly cohesive adenocarcinoma of the ampulla of Vater: a case report. AB - A 47-year-old Japanese male was submitted to pancreaticoduodenectomy for an ampullary cancer. Pathologically, the ampullary cancer was poorly cohesive adenocarcinoma without tubular structure. Moreover, locoregional lymph nodes were swollen with hypervascularity, plasmacytes infiltration, and hemorrhage. Our case seems to be different from usual poorly differentiated adenocarcinoma. PMID- 26943693 TI - Damage control management of innominate artery injury with tracheostomy. AB - Innominate artery injury is a rare, but catastrophic complication of tracheostomy. We present a case of severe hemorrhagic shock in a 79-year-old male with innominate artery injury that occurred during tracheostomy. Despite temporary innominate artery isolation, the regional forehead saturation was 60 % without laterality. Because adequate cerebral blood flow was apparently maintained through collateral flow, we ligated the innominate, right carotid, and subclavian arteries. We confirmed adequate blood flow to the brain and the right subclavian artery through collateral circulation after ligation using computed tomographic angiography. A damage control management, which involves ligating the injured innominate artery to arrest hemorrhage and monitoring regional forehead saturation for brain ischemia, can be a considerable procedure for the treatment of severe hemorrhagic shock due to innominate artery injury. PMID- 26943692 TI - Abnormal branch of right pulmonary artery (A7): a case report and literature review. AB - In thoracic surgery, anatomic variations of pulmonary artery increase the risks for vessel injury and critical mistakes during pulmonary artery resection. We report a case of lung cancer with an extremely rare branch, a mediastinal A7 pulmonary artery. Some case reports of the mediastinal pulmonary artery exist until now. However, to the best of our knowledge, this is the first case of a medial basal segmental artery (from the following, it is referred to as A7) branching directly from main pulmonary artery in the literature. Therefore, there is no report that showed three-dimensional computed tomography (3D-CT) and operative findings. So, these information is very useful for thoracic surgeon. A 67-year-old man was admitted to our hospital in order to undergo operation for the treatment of lung cancer. We detected the anomalies preoperatively by 3D-CT. The 3D-CT shows the A7 pulmonary artery branches from the right main pulmonary artery directly. According to previous literature, the cases of a single branch from main pulmonary artery to lower lobe are only five cases. And, the only two of them are right side including our case. In spite of an extremely rare case, we were able to successfully perform a right middle lobectomy because the information obtained from the 3D-CT findings was sufficiently understood preoperatively. PMID- 26943694 TI - Induction of potentially lethal hypermagnesemia, ischemic colitis, and toxic megacolon by a preoperative mechanical bowel preparation: report of a case. AB - A 67-year-old man was diagnosed with rectal cancer. The tumor invaded the subserosal layer, but it was not large, and there was no sign of obstruction. Neo adjuvant chemotherapy reduced the size of the tumor. The patient was admitted to our hospital for surgery. For mechanical bowel preparation, he ingested 34 g of magnesium citrate (Magcorol P(r)), but then developed severe shock, a disturbance of consciousness, and acidemia, and he required catecholamines and mechanical ventilation. X-ray, CT, and laboratory tests revealed ischemic colitis, toxic megacolon, and hypermagnesemia (16.3 mg/dL). After 2 days of temporary hemodialysis and an enema to reduce his blood magnesium concentration, he recovered and left the intensive care unit. However, the left side of his colon had suffered ischemic damage and become irreversibly atrophied. One month later, he underwent laparoscopic abdominoperineal resection and left-side colectomy for the rectal cancer and severe ischemic colitis of the left side of the colon. Histopathology confirmed the rectal cancer with a grade 2 chemotherapeutic effect and severe ischemic colitis of the left side of the colon. Hence, the present case suggests that severe ischemic colitis, toxic megacolon, and hypermagnesemia can occur after taking a magnesium laxative without obstruction of the intestine. PMID- 26943696 TI - Ciliated foregut cyst in the triangle of Calot: the first report. AB - Ciliated foregut cysts are rare anomalies arising from remnants of aberrant embryological development. Around 100 reports on the presence of these congenital masses in the tracheobronchial tree, mediastinum, liver, pancreas and, rarely, the gallbladder have been described. In this article, the case of a 33-year-old woman, who was operated for a laparoscopic cholecystectomy, is presented. During the dissection of the triangle of Calot, a cystic mass, attached to the common hepatic duct, was discovered incidentally. This cyst was dissected off the hepatic duct, and no communication between both structures was found. The histopathological diagnosis was consistent with a ciliated foregut cyst. The postoperative course was uneventful. After reviewing the literature on this pathological entity, we found that this is the first report of a ciliated foregut cyst that is located in the triangle of Calot and found separate from the biliary structures, the gallbladder and the liver. We present a review of the literature on this entity, discussing diagnostic measures and therapeutic options. PMID- 26943695 TI - Hepatopancreatoduodenectomy for local recurrence of cholangiocarcinoma after excision of a type IV-A congenital choledochal cyst: a case report. AB - Surgical resection is the only curative treatment for biliary tract cancer (BTC); however, the recurrence rate remains high even after curative resection. There are limited data regarding the effectiveness of surgical resection for recurrent BTC. We report the favorable survival outcome of a patient who underwent a hepatopancreatoduodenectomy for local recurrence of cholangiocarcinoma after excision of a type IV-A congenital choledochal cyst. The patient, a 25-year-old woman, had undergone excision of a type IV-A congenital choledochal cyst with hepaticojejunostomy. The resected specimen revealed an early cholangiocarcinoma. The local recurrence at the site of anastomosis was detected 4 years and 4 months after surgery. We performed a left trisectionectomy with caudate lobectomy combined with hepatic artery and portal vein resections and a pancreaticoduodenectomy. Histological examination revealed a moderately differentiated adenocarcinoma, and the final diagnosis was recurrence of cholangiocarcinoma. There are a few reports of extensive resection for recurrence of BTC; however, aggressive surgery is possible and may offer favorable survival in selected patients. PMID- 26943697 TI - Effect of work:rest cycle duration on [Formula: see text] fluctuations during intermittent exercise. AB - The succession of on-transient phases that induce a repetition of metabolic changes is a possible mechanism responsible for the greater response to intermittent training (IT). The objective of this study was to quantify [Formula: see text] fluctuations during intermittent exercise characterised by the same work:rest ratio, but different durations and identify which duration leads to the greatest fluctuations. Ten participants (24 +/- 5 years; [Formula: see text]: 42 +/- 7 mL.min-1.kg-1) performed (1) an incremental test to exhaustion to determine peak work rate (WRpeak) and oxygen uptake ([Formula: see text]), (2), and three 1 h intermittent exercises alternating work period at 70% WRpeak with passive recovery period of different 1:1 work:recovery duty cycles (30 s:30 s, 60 s:60 s, 120 s:120 s). [Formula: see text] response analysis revealed differences in the fluctuations across the intermittent conditions despite an identical total energy expenditure. The sum of the cycle's nadir-to-peak [Formula: see text] differences (SigmaDelta[Formula: see text]) and the oxygen fluctuation index (OFI) were both greater in the 60 s:60 s condition (SigmaDelta[Formula: see text]: +38% +/- 13% and +19% +/- 18% vs. 120 s:120 s and 30 s:30 s, P < 0.05; OFI: +41% +/- 29% and +67% +/- 62% vs. 120 s:120 s and 30:30 s, P < 0.05). [Formula: see text] fluctuation analysis was successful in identifying the intermittent condition associated with the greatest disturbances: the 60 s:60 s duty cycle induces more [Formula: see text] fluctuations. The present findings also demonstrate that the selection of the duty cycle duration for submaximal intermittent exercise (70% of WRpeak) prescription is of interest to produce high [Formula: see text] fluctuations. PMID- 26943698 TI - The safety of treatment options for elderly people with acute myeloid leukemia. AB - INTRODUCTION: Life expectancy in elderly patients with acute myeloid leukemia (AML) is a function of age, disability, and co-morbidity, combined with leukemia characteristics. There is currently no consensus regarding the optimal therapeutic strategy for older adults with AML. Although selected older adults with AML can benefit from intensive therapies, recent evidence supports the use of lower-intensity therapies in most patients and emphasizes the importance of tolerability and quality of life. AREAS COVERED: Results of the current clinical trials and safety data are reviewed. EXPERT OPINION: Treatment recommendations for elderly patients with AML need to be individualized. In order to avoid toxicities, hematologists should collaborate more with geriatricians to identify clues of vulnerability in elderly patients through the study of functional physical, physiological, cognitive, social, and psychological parameters. PMID- 26943699 TI - Wei Zhang, Bao-an Chen, Jun-fei Jin, You-ji He, and Yi-qi Niu, Involvement of c Jun N-terminal kinase in reversal of multidrug resistance of human leukemia cells in hypoxia by 5-bromotetrandrine. November 2013;54(11):2506-2516. http://dx.doi.org/10.3109/10428194.2013.776681. PMID- 26943700 TI - Does obesity promote the development of colorectal cancer? PMID- 26943701 TI - XP-PCM Calculations of High Pressure Structural and Vibrational Properties of P4S3. AB - The structure and the vibrational properties of the P4S3 crystal at high pressures are discussed by application of the XP-PCM method. The vibrational assignment has been clarified. The structure and the electron distribution changes as a function of pressure are analyzed. The pressure effect on the vibrational frequencies is satisfactorily reproduced and discussed in terms of confinement and structure relaxation contributions. PMID- 26943702 TI - Myeloid-derived suppressor cells in patients with myeloproliferative neoplasm. AB - Although BCR-ABL negative myeloproliferative neoplasms (MPN)--and especially myelofibrosis (MF)--are recognized to be associated with autoimmune phenomena, immune derangements in MPN have been much less studied. Myeloid-derived suppressor cells (MDSC) are one type of important immune modulator cell. Therefore, we studied MDSCs in MPN disease. MDSCs were studied in two cohorts: the first cohort was 55 patients including 16 primary myelofibrosis (PMF), 7 post polycythemia vera (PV)-MF, 2 post-essential thrombocythemia (ET)-MF, 11 ET, 17 PV, 2 undefined MPN disorder, and 23 normal controls; the second cohort included 38 patients: 17 ET, 7 PMF, 3 ET-MF, 2 PV-MF, 9 PV patients, and 20 normal volunteers. The second cohort was studied using freshly collected specimens and a comparable age group as controls. CD11b(+), CD14(-), and CD33(+) cells were defined as MDSCs in both cohorts by flow cytometry. Since there are no differences in MDSC levels among different MPN categories, they were grouped as MPNs. The results showed that MDSCs were significantly elevated in MPNs compared with controls in both cohorts. We also performed RT-PCR and found that MPN patients have significantly elevated arginase-1 mRNA compared with controls, and sorted MDSCs were found to have suppressor T cell activity in MPNs, substantiating the hypothesis that levels of MDSCs are, in fact, deranged in MPNs. MDSC levels were not correlated with JAK2 status, white blood cells, Hb levels, platelet counts, splenomegaly, or the degree of bone marrow fibrosis (in MF). Further studies in immune therapy involving MDSC inhibitors or differentiation may be developed to treat MPN disease. PMID- 26943703 TI - A phase I study of intermediate dose cytarabine in combination with lenalidomide in relapsed/refractory acute myeloid leukemia. AB - Relapsed/refractory (r/r) Acute Myeloid Leukemia (AML) remains a therapeutic challenge. Cytarabine arabinoside (AraC) forms the backbone of most regimens, with complete responses (CR) ranging from 17 to 20%. Lenalidomide (Len) is approved by the FDA for multiple myeloma and myelodysplasia and has demonstrated activity in AML. We developed a phase I study to evaluate the safety and tolerability of Len in combination with intermediate dose AraC (1.5 g/m(2)/day given on days 1-5) in adults with r/r AML. The maximally tolerated dose for this combination was 10mg daily on days 6-26 of a 28 day cycle. Dose de-escalation from 25mg was required due to rash, liver function abnormalities, and hypokalemia. Of 32 evaluable patients, five achieved CR (16%), 5CRi (16%) and 3 had hematological improvements for an overall response rate of 41% (13/32). Median overall survival (95% confidence interval) for patients treated on study was 5.8 (2.5-10.6) months and disease free survival was 3.4 (2.3-6.2) months. This single institute phase I trial of Len and intermediate dose AraC was associated with marked skin and other toxicities. At the dose and schedule tested, this combination did not appear to result in improved CR over single agent AraC for r/r AML. PMID- 26943704 TI - Dynamic ultrasound of peroneal tendon instability. AB - Ankle snapping may be caused by peroneal tendon instability. Anterior instability occurs after traumatic superior peroneal retinaculum injury, whereas peroneal tendon intrasheath subluxation is atraumatic. Whereas subluxation is mainly dynamic, ultrasound allows for the diagnosis and classification of peroneal instability because it allows for real-time exploration. The purpose of this review is to describe the anatomic and physiologic bases for peroneal instability and to heighten the role of dynamic ultrasound in the diagnosis of snapping. PMID- 26943705 TI - The Real Role of Sensitivity, Specificity and Predictive Values in the Clinical Assessment. PMID- 26943706 TI - Expanding Patient Access to Quality Sleep Health Care through Telemedicine. PMID- 26943707 TI - Consistency and Clarity in Sleep Medicine Terminology. PMID- 26943708 TI - Haskell Wexler: Who Needs Sleep? PMID- 26943710 TI - Respiratory Variability during Sleep in Methadone Maintenance Treatment Patients. AB - STUDY OBJECTIVES: Methadone maintenance treatment (MMT) patients have a high prevalence of central sleep apnea and ataxic breathing related to damage to central respiratory rhythm control. However, the quantification of sleep apnea indices requires laborious manual scoring, and ataxic breathing pattern is subjectively judged by visual pattern recognition. This study proposes a semi automated technique to characterize respiratory variability in MMT patients. METHODS: Polysomnography, blood, and functional outcomes of sleep questionnaire (FOSQ) from 50 MMT patients and 20 healthy subjects with matched age, sex, and body mass index, were analyzed. Inter-breath intervals (IBI) were extracted from the nasal cannula pressure signal. Variability of IBI over 100 breaths was quantified by standard deviation (SD), coefficient of variation (CV), and scaling exponent (alpha) from detrended fluctuation analysis. The relationships between these variability measures and blood methadone concentration, central sleep apnea index (CAI), apnea-hypopnea index (AHI), and clinical outcome (FOSQ), were then examined. RESULTS: MMT patients had significantly higher SD and CV during all sleep stages. During NREM sleep, SD and CV were correlated with blood methadone concentration (Spearman R = 0.52 and 0.56, respectively; p < 0.01). SD and CV were also correlated with CAI (R = 0.63 and 0.71, p < 0.001, respectively), and AHI (R = 0.45 and 0.58, p < 0.01, respectively). Only alpha showed significant correlation with FOSQ (R = -0.33, p < 0.05). CONCLUSIONS: MMT patients have a higher respiratory variability during sleep than healthy controls. Semi-automated variability measures are related to apnea indices obtained by manual scoring and may provide a new approach to quantify opioid-related sleep-disordered breathing. PMID- 26943709 TI - Medium Increased Risk for Central Sleep Apnea but Not Obstructive Sleep Apnea in Long-Term Opioid Users: A Systematic Review and Meta-Analysis. AB - STUDY OBJECTIVE: Opioids are associated with higher risk for ataxic breathing and sleep apnea. We conducted a systematic literature review and meta-analysis to assess the influence of long-term opioid use on the apnea-hypopnea and central apnea indices (AHI and CAI, respectively). METHODS: A systematic review protocol (Cochrane Handbook guidelines) was developed for the search and analysis. We searched Embase, Medline, ACP Journal Club, and Cochrane Database up to November 2014 for three topics: (1) narcotics, (2) sleep apnea, and (3) apnea-hypopnea index. The outcome of interest was the variation in AHI and CAI in opioid users versus non-users. Two reviewers performed the data search and extraction, and disagreements were resolved by discussion. Results were combined by standardized mean difference using a random effect model, and heterogeneity was tested by chi(2) and presented as I(2) statistics. RESULTS: Seven studies met the inclusion criteria, for a total of 803 patients with obstructive sleep apnea (OSA). We compared 2 outcomes: AHI (320 opioid users and 483 non-users) and 790 patients with CAI (315 opioid users and 475 non-users). The absolute effect size for opioid use was a small increased in apnea measured by AHI = 0.25 (95% CI: 0.02 0.49) and a medium for CAI = 0.45 (95% CI: 0.27-0.63). Effect consistency across studies was calculated, showing moderate heterogeneity at I(2) = 59% and 29% for AHI and CAI, respectively. CONCLUSIONS: The meta-analysis results suggest that long-term opioid use in OSA patients has a medium effect on central sleep apnea. PMID- 26943711 TI - The Impact of Sleep Debt on Excess Adiposity and Insulin Sensitivity in Patients with Early Type 2 Diabetes Mellitus. AB - STUDY OBJECTIVES: We examined cross-sectional and prospective associations between sleep debt and adiposity measures, as well as homeostatic model assessment-insulin resistance (HOMA-IR) in early type 2 diabetes. METHODS: Prospective data analysis from participants of a randomized controlled trial based on an intensive lifestyle intervention (usual care, diet, or diet and physical activity). Data were collected at baseline, 6 months, and 12 months post intervention. The study was performed across five secondary care centers in the United Kingdom. Patients (n = 593) with a recent diagnosis of type 2 diabetes were recruited. Objective height and weight were ascertained for obesity status (body mass index [BMI]; >= 30 kg/m(2)), waist circumference (cm) for central adiposity, and fasting blood samples drawn to examine insulin resistance (IR). Seven-day sleep diaries were used to calculate weekday sleep debt at baseline, calculated as average weekend sleep duration minus average weekday sleep duration. RESULTS: At baseline, compared to those without weekday sleep debt, those with weekday sleep debt were 72% more likely to be obese (OR = 1.72 [95% CI:1.03-2.88]). At six months, weekday sleep debt was significantly associated with obesity and IR after adjustment, OR = 1.90 (95% CI:1.10-3.30), OR = 2.07 (95% CI:1.02-4.22), respectively. A further increase at 12 months was observed for sleep debt with obesity and IR: OR = 2.10 (95% CI:1.14-3.87), OR = 3.16 (95% CI:1.38-7.24), respectively. For every 30 minutes of weekday sleep debt, the risk of obesity and IR at 12 months increased by 18% and 41%, respectively. CONCLUSIONS: Sleep debt resulted in long-term metabolic disruption, which may promote the progression of type 2 diabetes in newly diagnosed patients. Sleep hygiene/education could be an important factor for future interventions to target early diabetes. PMID- 26943712 TI - Abnormal Nocturnal Behavior due to Hypoglycemia in a Patient with Type 2 Diabetes. AB - Abnormal nocturnal behavior can have many causes, including primary sleep disorder, nocturnal seizures, and underlying medical or neurological disorders. A 79-year-old woman with type 2 diabetes was admitted for evaluation of abnormal nocturnal behavior. Every night at around 04:30 she was observed displaying abnormal behavior including leg shaking, fumbling with bedclothes, crawling around the room with her eyes closed, and non-responsiveness to verbal communication. Polysomnography with 20-channel electroencephalography (EEG) was performed. EEG showed that the posterior dominant rhythm was slower than that observed in the initial EEG, with diffuse theta and delta activities intermixed, and no epileptiform activity. The serum glucose level was 35 mg/dL at that time, and both the EEG findings and clinical symptoms were resolved after an intravenous injection of 50 mL of 50% glucose. These results indicate that nocturnal hypoglycemia should be considered as one of the possible etiologies in patients presenting with abnormal nocturnal behavior. PMID- 26943713 TI - Examining the Frequency of Stimulant Misuse among Patients with Primary Disorders of Hypersomnolence: A Retrospective Cohort Study. AB - STUDY OBJECTIVES: Narcolepsy and idiopathic hypersomnia are commonly treated by sleep specialists and encountered by other medical providers. Although pharmacotherapy with modafinil and traditional stimulants is considered the mainstay of treatment, physicians are often uncomfortable with their prescription because of concerns regarding misuse. The goal of this study was to assess the frequency of stimulant misuse in this population. METHODS: A retrospective cohort study was performed evaluating patients 18 years and older diagnosed with narcolepsy with and without cataplexy and idiopathic hypersomnia with and without long sleep between 2003-2008. Patients were included if they obtained stimulant prescriptions from and had at least one follow-up visit subsequent to initial diagnosis at our center. Stimulant misuse was defined by multiple prescription sources or early refill requests, which are systematically entered into the record by nursing staff. RESULTS: A total of 105 patients met inclusion criteria for the study; 45 (42%) were male. Mean age at multiple sleep latency test was 42 (+/- 16). Twelve (11%) patients had a history of illicit substance misuse, and one (1%) patient demonstrated previous stimulant misuse. Fifty-seven (54%) patients carried psychiatric diagnoses, 88% of whom reported depression. Median duration of monitored stimulant therapy was 26 months (range 1-250). None of the 105 patients was found to have evidence of stimulant misuse. CONCLUSION: This study suggests that the frequency of stimulant misuse in patients with narcolepsy and idiopathic hypersomnia is extremely low. Concerns regarding drug misuse should not leverage decisions to provide long-term therapy. PMID- 26943714 TI - A Case of Recurrent Insomnia: Extending the Spectrum of Autoimmune Encephalitis. AB - ABSTRACT: Recurrent insomnia is an uncommon manifestation that is encountered rarely in a sleep clinic. We report a woman with recurrent insomnia due to an autoimmune process that resolved after a course of immunotherapy. PMID- 26943715 TI - Sleep Disordered Breathing Mimicking Myasthenia Crisis in a Patient with Myasthenia Gravis. AB - ABSTRACT: Myasthenia gravis (MG) can result in weakness of the respiratory muscles in 30% of patients. A life-threatening exacerbation, MG crisis can cause respiratory insufficiency requiring mechanical ventilation. Sleep disordered breathing (SDB) is seen in 40% to 60% of stable MG patients. Factors associated with SDB include age, male sex, obesity, and steroid use. Continuous positive airway pressure (CPAP) can reverse paradoxical weakness in MG patients with obstructive sleep apnea (OSA), but whether SDB can contribute to respiratory failure in MG and whether CPAP works in such patients remain unclear. This report presents a 54-year-old woman with MG with a history of 7 episodes of respiratory failure requiring mechanical ventilation. For each episode, she was treated for MG crisis using plasmapheresis and high-dose steroids. Later, OSA and obesity hypoventilation syndrome were confirmed by polysomnography with transcutaneous CO2 monitoring. Thereafter, the patient had no further recurrence of MG crisis for 5 years, using pyridostigmine and CPAP only. PMID- 26943716 TI - Big-Data or Slim-Data: Predictive Analytics Will Rule with World. PMID- 26943718 TI - Utility of the Neurobehavioral Symptom Inventory Validity-10 index to detect symptom exaggeration: An analogue simulation study. AB - The Neurobehavioral Symptom Inventory (NSI) has been recommended by the interagency Traumatic Brain Injury (TBI) Outcome Workgroup as an outcome measure for TBI research. A new symptom exaggeration index-the NSI Validity-10-can be calculated from its items, but its utility has not been evaluated in a malingering simulation study. Data from a prior analogue study were reanalyzed to examine the NSI Validity-10 test properties. The data were from a sample of 85 Australian undergraduate students. A battery of measures was completed under 1 of 3 experimental conditions: control (i.e., honest responding, n = 24), feign postconcussional disorder (PCD; n = 29), and feign posttraumatic stress disorder (PTSD; n = 32). Participants who feigned PTSD or PCD had significantly higher scores on the NSI Validity-10 compared with controls. There were minimal differences between the 2 feigning groups. Using the combined data from the feigning groups and assuming a 35% symptom exaggeration base rate, the optimal NSI Validity-10 cutoff score was >=10. This cutoff score identified "probable exaggeration" (sensitivity = .75, specificity = 1.0, positive predictive power = 1.0, negative predictive power = .88). Diagnostic efficiency statistics for 25% and 45% base rates were also generated. The cutoff score identified in this study is lower than previously reported. Its properties are promising, but its usage requires careful consideration. PMID- 26943717 TI - Horizontal transfer of RNA and proteins between cells by extracellular microvesicles: 14 years later. AB - Extracellular microvesicles (ExMVs) are part of the cell secretome, and evidence has accumulated for their involvement in several biological processes. Fourteen years ago our team demonstrated for the first time that ExMVs carry functional RNA species and proteins from one cell to another, an observation that opened up the new research field of horizontal transfer of bioactive molecules in cell-to cell communication. Moreover, the presence of mRNA, noncoding RNA, and miRNA in ExMVs in blood and other biological fluids opened up the possibility of employing ExMVs as new detection markers for pathological processes, and ExMVs became a target for "liquid biopsy" approaches. While ExMV-derived mRNAs may be translated in target cells into appropriate proteins, miRNAs regulate expression of corresponding mRNA species, and both RNA-depended ExMV-mediated mechanisms lead to functional changes in the target cells. Following from this observation, several excellent papers have been published that confirm the existence of the horizontal transfer of RNA. Moreover, in addition to RNA, proteins, bioactive lipids, infectious particles and intact organelles such as mitochondria may follow a similar mechanism. In this review we will summarize the impressive progress in this field-14 years after initial report. PMID- 26943719 TI - Management of Hypoparathyroidism: Summary Statement and Guidelines. AB - OBJECTIVE: Hypoparathyroidism is a rare disorder characterized by hypocalcemia and absent or deficient PTH. This report presents a summary of current information about epidemiology, presentation, diagnosis, clinical features, and management and proposes guidelines to help clinicians diagnose, evaluate, and manage this disorder. PARTICIPANTS: Participants in the First International Conference on the Management of Hypoparathyroidism represented a worldwide constituency with acknowledged interest and expertise in key basic, translational, and clinical aspects of hypoparathyroidism. Three Workshop Panels were constituted to address questions for presentation and discussion at the Conference held in Florence, Italy, May 7-9, 2015. At that time, a series of presentations were made, followed by in-depth discussions in an open forum. Each Workshop Panel also met in closed sessions to formulate the three evidence-based reports that accompany this summary statement. An Expert Panel then considered this information, developed summaries, guidelines, and a research agenda that constitutes this summary statement. EVIDENCE: Preceding the conference, each Workshop Panel conducted an extensive literature search as noted in the individual manuscripts accompanying this report. All presentations were based upon the best peer-reviewed information taking into account the historical and current literature. CONSENSUS PROCESS: This report represents the Expert Panel's synthesis of the conference material placed in a context designed to be relevant to clinicians and those engaged in cutting-edge studies of hypoparathyroidism. CONCLUSIONS: This document not only provides a summary of our current knowledge but also places recent advances in its management into a context that should enhance future advances in our understanding of hypoparathyroidism. PMID- 26943722 TI - Stenting for symptomatic intracranial vertebrobasilar artery stenosis: 30-day results in a high-volume stroke center. AB - OBJECTIVES: Symptomatic intracranial vertebrobasilar artery stenosis (IVBS) carries a high annual risk of recurrent stroke. Endovascular therapy was a promising technique but recent trials suggest it may carry a risk of periprocedual complications especially in inexperienced hands. This prospective study was to evaluate the safety of endovascular therapy for severe symptomatic IVBS in a high volume stroke centre. PATIENTS AND METHOD: Patients with symptomatic IVBS caused by 70-99% stenosis despite medical treatment of at least one antiplatelet agent and statin were enrolled. The patients were treated either with balloon-mounted stent or balloon pre-dilation plus self-expanding stent as determined by the operators following a guideline. The primary outcome was 30-day stroke, transient ischemic attack (TIA) and death after stenting. The secondary outcome was successful stent deployment. The baseline characteristics and outcomes of patients with basilar artery (BA) lesions and patients with vertebral artery V4 segment lesions (BA group vs V4 group) were compared. And the outcome of different Mori type lesions was also compared. RESULT: From September 2013 to September 2014, 105 patients with stroke or TIA due to intracranial IVBS were screened and 97 patients were treated by stenting, including 52 patients with BA stenosis and 45 patients with V4 stenosis. The rate of 30-day stroke, TIA and death was 7.1%. All the three strokes happened in the BA group and were perforator strokes. The successful stent deployment rate was 100%. General anesthesia was more preferred in the BA group than in the V4 groups (96.2% vs 75.6%, p=0.005). The Apollo stent was used more for Mori A lesions (30.5% vs 7.9%, p=0.011) and had lower degree of residual stenosis (8.6% vs 12.6%, p=0.014) than Wingspan stent. Mori C lesions were more likely to have higher degree of residual stenosis than Mori A lesion (15.3% vs 7.4%, p=0.005). CONCLUSION: The short-term safety of endovascular stenting for patients with severe symptomatic IVBS in a high volume stroke centre was acceptable. Mori A lesions may have lower residual stenosis rate than the Mori C type lesions. PMID- 26943721 TI - Presentation of Hypoparathyroidism: Etiologies and Clinical Features. AB - CONTEXT: Understanding the etiology, diagnosis, and symptoms of hypoparathyroidism may help to improve quality of life and long-term disease outcomes. This paper summarizes the results of the findings and recommendations of the Working Group on Presentation of Hypoparathyroidism. EVIDENCE ACQUISITION: Experts convened in Florence, Italy, in May 2015 and evaluated the literature and recent data on the presentation and long-term outcomes of patients with hypoparathyroidism. EVIDENCE SYNTHESIS: The most frequent etiology is surgical removal or loss of viability of parathyroid glands. Despite precautions and expertise, about 20-30% of patients develop transient and 1-7% develop permanent postsurgical hypoparathyroidism after total thyroidectomy. Autoimmune destruction is the main reason for nonsurgical hypoparathyroidism. Severe magnesium deficiency is an uncommon but correctable cause of hypoparathyroidism. Several genetic etiologies can result in the loss of parathyroid function or action causing isolated hypoparathyroidism or a complex syndrome with other symptoms apart from those of hypoparathyroidism or pseudohypoparathyroidism. Neuromuscular signs or symptoms due to hypocalcemia are the main characteristics of the disease. Hyperphosphatemia can contribute to major long-term complications such as ectopic calcifications in the kidney, brain, eye, or vasculature. Bone turnover is decreased, and bone mass is increased. Reduced quality of life and higher risk of renal stones, renal calcifications, and renal failure are seen. The risk of seizures and silent or symptomatic calcifications of basal ganglia is also increased. CONCLUSIONS: Increased awareness of the etiology and presentation of the disease and new research efforts addressing specific questions formulated during the meeting should improve the diagnosis, care, and long-term outcome for patients. PMID- 26943720 TI - Epidemiology and Diagnosis of Hypoparathyroidism. AB - CONTEXT: Hypoparathyroidism is a disorder characterized by hypocalcemia due to insufficient secretion of PTH. Pseudohypoparathyroidism is a less common disorder due to target organ resistance to PTH. This report summarizes the results of the findings and recommendations of the Working Group on Epidemiology and Diagnosis of Hypoparathyroidism. EVIDENCE ACQUISITION: Each contributing author reviewed the recent published literature regarding epidemiology and diagnosis of hypoparathyroidism using PubMed and other medical literature search engines. EVIDENCE SYNTHESIS: The prevalence of hypoparathyroidism is an estimated 37 per 100 000 person-years in the United States and 22 per 100 000 person-years in Denmark. The incidence in Denmark is approximately 0.8 per 100 000 person-years. Estimates of prevalence and incidence of hypoparathyroidism are currently lacking in most other countries. Hypoparathyroidism increases the risk of renal insufficiency, kidney stones, posterior subcapsular cataracts, and intracerebral calcifications, but it does not appear to increase overall mortality, cardiovascular disease, fractures, or malignancy. The diagnosis depends upon accurate measurement of PTH by second- and third-generation assays. The most common etiology is postsurgical hypoparathyroidism, followed by autoimmune disorders and rarely genetic disorders. Even more rare are etiologies including parathyroid gland infiltration, external radiation treatment, and radioactive iodine therapy for thyroid disease. Differentiation between these different etiologies is aided by the clinical presentation, serum biochemistries, and in some cases, genetic testing. CONCLUSIONS: Hypoparathyroidism is often associated with complications and comorbidities. It is important for endocrinologists and other physicians who care for these patients to be aware of recent advances in the epidemiology, diagnosis, and genetics of this disorder. PMID- 26943723 TI - Management of vestibular schwannoma: A pilot case series with postoperative ABR monitoring. AB - OBJECTIVE: Auditory brainstem response (ABR) monitoring is regularly used in surgery of vestibular schwannoma to achieve hearing preservation. Despite ABR preservation at the end of surgery, there are cases with postoperative deafness. To date it is unclear whether these are false positive ABR data or cases of secondary hearing loss. In this pilot study, we focused on the early postoperative phase and possible ABR changes in this period. PATIENT AND METHOD: In a prospective study from March 2008 to April 2009, eleven patients (5 female and 6 male) with vestibular schwannoma and preoperative residual hearing were investigated by repeated postoperative ABR investigation at seven dates during the first week. ABR results, hearing function and tumor extension were categorized according to Hannover classification system. The postoperative developments of the first week after surgery are described. RESULTS: Hearing preservation was achieved in 55% (6 of 11) of the patients. In the early postoperative phase, three patients with an ABR loss at the end of surgery showed some kind of recovery. In one case, a permanent recovery could be reproduced and developed step by step during the early postoperative phase. Three patients showed a postoperative deterioration resulting in a complete ABR loss. In one of these cases, it was probably a technical problem, but in the two other cases it was a real impairment. In 8 of 11 ABR, quality changed considerably during the early postoperative phase. CONCLUSION: This pilot study identifies considerable change of ABR formation occurring in a considerable proportion of patients early after vestibular schwannoma resection. Obviously, in some patients, the endoperative state of the ABR is not the final state. Some patients show a postoperative improvement and some a deterioration towards a complete loss of all ABR components. Whether secondary hearing loss could be presented by early detection, will be a matter of further studies. PMID- 26943724 TI - In Response to: Jeon and Lee's 'Cytomegalovirus Retinitis in a Human Immunodeficiency Virus-negative Cohort: Long-term Management and Complications'. PMID- 26943725 TI - Isolation, Identification and Molecular Typing of Cryptococcus neoformans from Pigeon Droppings and Other Environmental Sources in Tripoli, Libya. AB - Cryptococcus neoformans and C. gattii are the major cause of fungal meningitis, a potentially lethal mycosis. Since pigeon excreta and other environmental sources can be considered a significant environmental reservoir of this species in urban areas, 100 samples of pigeon excreta and 420 samples from Eucalyptus camaldulensis and Olea europaea (olive tree) around the city of Tripoli, Libya, were collected. C. neoformans was isolated and identified using standard biochemical assays from 46 samples: 34 from pigeon droppings, 3 from Eucalyptus trees and 9 from olive trees. Molecular typing revealed that all isolates from pigeon droppings belonged to molecular type VNI (C. neoformans var. grubii) and mating type alphaA, whereas those from trees included also the molecular type VNII and VNIII (AD hybrids). The present study reports, for the first time, information about the distribution of species, mating types and molecular types of C. neoformans/C. gattii species complex in Libya. PMID- 26943727 TI - Disulfides with Anti-inflammatory Activity from the Brown Alga Dictyopteris membranacea. AB - Six new (1, 2, and 4-7) and two previously reported (3 and 8) disulfides, along with 4-butyl-2,6-cycloheptadienone, gamma-tocopherol, and delta-tocopherol, were isolated from an organic extract of the brown alga Dictyopteris membranacea, collected at Gerolimenas Bay, Greece. The structure elucidation of the isolated natural products was based on analysis of their spectroscopic data. Compounds 1, 3-6, and 8 were evaluated for their antibacterial and anti-inflammatory activities. None of the compounds displayed antibacterial activity against two resistant strains of Staphylococcus aureus and one strain of Escherichia coli. In contrast, metabolite 5 was able to cause strong inhibition of NO production with an IC50 value of 3.8 MUM using an LPS stimulation assay. PMID- 26943730 TI - Dissecting the Molecular Structure of the Air/Water Interface from Quantum Simulations of the Sum-Frequency Generation Spectrum. AB - The molecular characterization of the air/water interface is a key step in understanding fundamental multiphase phenomena ranging from heterogeneous chemical processes in the atmosphere to the hydration of biomolecules. The apparent simplicity of the air/water interface, however, masks an underlying complexity associated with the dynamic nature of the water hydrogen-bond network that has so far hindered an unambiguous characterization of its microscopic properties. Here, we demonstrate that the application of quantum many-body molecular dynamics, which enables spectroscopically accurate simulations of water from the gas to the condensed phase, leads to a definitive molecular-level picture of the interface region. For the first time, excellent agreement is obtained between the simulated vibrational sum-frequency generation spectrum and the most recent state-of-the-art measurements, without requiring any empirical frequency shift or ad hoc scaling of the spectral intensity. A systematic dissection of the spectral features demonstrates that a rigorous representation of nuclear quantum effects as well as of many-body energy and electrostatic contributions is necessary for a quantitative reproduction of the experimental data. The unprecedented accuracy of the simulations presented here indicates that quantum many-body molecular dynamics can enable predictive studies of aqueous interfaces, which by complementing analogous experimental measurements will provide unique molecular insights into multiphase and heterogeneous processes of relevance in chemistry, biology, materials science, and environmental research. PMID- 26943726 TI - Genotyping of Fusarium Isolates from Onychomycoses in Colombia: Detection of Two New Species Within the Fusarium solani Species Complex and In Vitro Antifungal Susceptibility Testing. AB - Fusariosis have been increasing in Colombia in recent years, but its epidemiology is poorly known. We have morphologically and molecularly characterized 89 isolates of Fusarium obtained between 2010 and 2012 in the cities of Bogota and Medellin. Using a multi-locus sequence analysis of rDNA internal transcribed spacer, a fragment of the translation elongation factor 1-alpha (Tef-1alpha) and of the RNA-dependent polymerase subunit II (Rpb2) genes, we identified the phylogenetic species and circulating haplotypes. Since most of the isolates studied were from onychomycoses (nearly 90 %), we carried out an epidemiological study to determine the risk factors associated with such infections. Five phylogenetic species of the Fusarium solani species complex (FSSC), i.e., F. falciforme, F. keratoplasticum, F. lichenicola, F. petroliphilum, and FSSC 6 as well as two of the Fusarium oxysporum species complex (FOSC), i.e., FOSC 3 and FOSC 4, were identified. The most prevalent species were FOSC 3 (38.2%) followed by F. keratoplasticum (33.7%). In addition, our isolates were distributed into 23 haplotypes (14 into FOSC and nine into FSSC). Two of the FSSC phylogenetic species and two haplotypes of FSSC were not described before. Our results demonstrate that recipients of pedicure treatments have a lower probability of acquiring onychomycosis than those not receiving such treatments. The antifungal susceptibility of all the isolates to five clinically available agents showed that amphotericin B was the most active drug, while the azoles exhibited lower in vitro activity. PMID- 26943728 TI - Emodin attenuates TNF-alpha-induced apoptosis and autophagy in mouse C2C12 myoblasts though the phosphorylation of Akt. AB - Emodin, a major component of Rheum palmatum, has been reported to significantly protect neural tissue against apoptosis and autophagy. However, the effects and underlying mechanisms of action of emodin in muscle atrophy are still poorly defined. In this study, we investigated the protective effects and the underlying mechanisms by which emodin acts on tumor necrosis factor alpha (TNF-alpha) induced apoptosis and autophagy in mouse C2C12 myoblasts. Emodin, at various concentrations, decreased TNF-alpha-induced apoptosis in C2C12 myoblasts, which were analyzed by Hoechst 33342 staining and annexin V/PI analysis. Emodin also inhibited the collapse of the mitochondrial membrane potential and the generation of reactive oxygen species in TNF-alpha-stimulated C2C12 myoblasts. Consistent with these results, the expression of Bcl-2 was increased, whereas the expression of Bax, cleaved-caspase 3 and cleaved-PARP was decreased after emodin treatment. These data demonstrate that emodin attenuated apoptosis in TNF-alpha-stimulated C2C12 myoblasts through mitochondrial signaling pathways. In addition, emodin inhibited autophagy in TNF-alpha-stimulated C2C12 myoblasts by suppressing the expression of LC3-II, Beclin-1 and Atg7. Emodin also resulted in the upregulation of the phosphorylated forms of Akt. Taken together, these results suggest that emodin inhibited apoptosis and autophagy in TNF-alpha-induced C2C12 myoblasts, possibly through the activation of phosphorylated Akt. Our findings suggest that emodin could be a potential therapeutic agent in the treatment of muscle atrophy. PMID- 26943738 TI - Inflammatory response and blood hypercoagulable state induced by low level co exposure with silica nanoparticles and benzo[a]pyrene in zebrafish (Danio rerio) embryos. AB - Given the severe situation of world-wide particulate matter air pollution, it is urgent to explore the combined effects of particulate matter components on cardiovascular system. Using zebrafish model, this study was aimed to determine whether the low level co-exposure to silica nanoparticles (SiNPs) and benzo[a]pyrene (B[a]P) had a pronounced cardiovascular toxicity than the single exposure to either SiNPs or B[a]P alone. The FTIR and TGA analysis showed that the co-exposure system possessed of high absorption and thermal stability. Embryos exposed to SiNPs or B[a]P alone did not show cardiac toxicity phenotype at the NOAEL level. However, embryos co-exposed to SiNPs and B[a]P exhibited pericardial edema and bradycardia. While ROS generation remained unaffected, the co-exposure induced significant neutrophil-mediated inflammation and caused erythrocyte aggregation in caudal vein of embryos. Microarray analysis and STC analysis were performed to screen the cardiovascular-related differential expression genes and the expression trend of genes in each group. The co-exposure of SiNPs and B[a]P significantly enhanced the expression of proinflammatory and procoagulant genes. Moreover, the co-exposure markedly increased the phosphorylated AP-1/c-Jun and induced TF expression, but not NF-kappaB p65. This study for the first time demonstrated the inflammatory response and blood hypercoagulable state were triggered by the combination of SiNPs and B[a]P at low level exposure. PMID- 26943739 TI - Influence of sludge age on the performance of MFC treating winery wastewater. AB - The objective of this paper was to determine the influence of sludge age on microbial fuel cell (MFC) performance for generating electricity and removing organic matter from winery wastewater. Six Solid Retention Times (SRT) were used: 1.2, 1.4, 1.8, 2.3, 3.5 and 7.0 d. Results demonstrate that the electricity generation increases by decreasing the SRT, selecting electrogenic microorganisms, once the specific organic loading rate (SOLR) increased and the competition for substrate was reduced. Decreasing the SRT, coulombic efficiency can be increased from 3.4% to almost 42.2% and maximum power density from 58 to 890 mW m(-2). However the SRT did not influence on organic matter removal in biological treatment, because only a small part of COD was removed oscillating around 600 mg L(-1) d(-1)and it was very similar at all SRT studied. PMID- 26943740 TI - Effects of experimental calcium availability and anthropogenic metal pollution on eggshell characteristics and yolk carotenoid and vitamin levels in two passerine birds. AB - The maternal investment into egg quality depends on the condition of the female, the quality of the mate, and the quality of the environment. In that sense, availability of nutrients and exposure to pollutants are essential parameters to consider. The main aim of this study is to assess the effects of calcium (Ca) availability and anthropogenic metal pollution on early-stage reproduction in two passerine species, great tits (Parus major) and pied flycatchers (Ficedula hypoleuca), inhabiting a Ca-poor and metal-polluted area in SW Finland. Both species were able to obtain sufficient Ca for eggshell formation, and metal pollution was below the level of having negative effects in the egg size and eggshell characteristics. However, metal polluted environment negatively affected yolk lutein and vitamin D3 levels in both species, probably because of a lower access to carotenoid-rich diet and higher metal interference with vitamin D3 metabolism. The higher levels of vitamin D3 in yolks in the unpolluted zone could also be due to upregulated D3 levels as a response to the lower natural Ca availability. Yolk carotenoids and vitamin D3 were positively associated with nestling growth and size, supporting their importance for the appropriate chick development. The interspecific differences in yolk nutrient concentrations possibly reflect the different growth rate of these species. Pied flycatchers are likely adapted to low Ca availability through an efficient vitamin D3 metabolism, but their Ca intake could be close to a deficient level. PMID- 26943741 TI - EDTA retention and emissions from remediated soil. AB - EDTA-based remediation is reaching maturity but little information is available on the state of chelant in remediated soil. EDTA soil retention was examined after extracting 20 soil samples from Pb contaminated areas in Slovenia, Austria, Czech Republic and USA with 120 mM kg(-1) Na2H2EDTA, CaNa2EDTA and H4EDTA for 2 and 24 h. On average, 73% of Pb was removed from acidic and 71% from calcareous soils (24 h extractions). On average, 15% and up to 64% of applied EDTA was after remediation retained in acidic soils. Much less; in average 1% and up to the 22% of EDTA was retained in calcareous soils. The secondary emissions of EDTA retained in selected remediated soil increased with the acidity of the media: the TCLP (Toxicity Characteristic Leaching Procedure) solution (average pH end point 3.6) released up to 36% of EDTA applied in the soil (28.1 mmol kg(-1)). Extraction with deionised water (pH > 6.0) did not produce measurable EDTA emissions. Exposing soil to model abiotic (thawing/freezing cycles) and biotic (ingestion by earthworms Lumbricus rubellus) ageing factors did not induce additional secondary emissions of EDTA retained in remediated soil. PMID- 26943742 TI - Studies on biomarkers of oxidative stress and associated genotoxicity and histopathology in Channa punctatus from heavy metal polluted canal. AB - Some investigations were made on the Satha canal water and health of dwelling fish Channa punctatus at Satha village, district Aligarh (U.P). Metal bioaccumulation and induction of biomarkers such as lipid peroxidation (LPO), superoxide dismutase (SOD), catalase (CAT), glutathione S transferase (GST), reduced glutathione (GSH), DNA damage and histopathology are potential indicators of stress in C. punctatus exposed to effluents. In canal water Cr, Mn, Fe and Ni concentrations were exceeding the permissible limits set by both Bureau of Indian standards (BIS) and WHO. Fe (74%) was highly bioavailable and accumulated in all organs (gill, liver, kidney, muscle and integument). The highest metal pollution index (MPI) value of 53 was observed in gills and the lowest 6 in liver tissue. SOD and LPO were significantly higher in all tissues, whereas CAT, GST and GSH levels declined significantly compared to fish from the reference site. Concomitant damage to DNA was observed with significantly higher mean tail length in the exposed fish gill cells (19 MUm) and in liver (12.7 MUm) compared to reference fish (5 and 4 MUm respectively). Histopathology in gill and liver also show significant damage. Therefore, it can be concluded that the sugar mill effluent has the potential to cause oxidative stress, DNA damage and histopathology in C. punctatus. This canal is a prime source of water and fish food to the local residents of the area. Therefore, the consumers may suffer adverse health effects like that in indicator organism. PMID- 26943743 TI - The sediment-contact test using the ostracod Heterocypris incongruens: Effect of fine sediments and determination of toxicity thresholds. AB - The toxicity test using freshwater ostracods of the species Heterocypris incongruens is a sub-chronic static test that exposes individuals to whole sediments over a period of 6 d, the endpoints being mortality and growth. We tested the hypothesis that endpoints of the sediment bioassay using Heterocypris incongruens are affected by the presence of fine sediment particles by testing control sediment supplied with the commercial test kit with increasing proportions of kaolin clay as a proxy for fines. While mortality was not affected, the results showed that increasing the presence of clay reduced ostracod growth. Based on the variability in growth, a sublethal toxicity threshold of 35% is proposed to distinguish effects due to sediment properties from those due to toxicity. The relevance of this threshold was verified using data from toxicity tests of ambient sediment samples with low levels of contamination. PMID- 26943749 TI - Quantitative myocardial perfusion imaging in a porcine ischemia model using a prototype spectral detector CT system. AB - We optimized and evaluated dynamic myocardial CT perfusion (CTP) imaging on a prototype spectral detector CT (SDCT) scanner. Simultaneous acquisition of energy sensitive projections on the SDCT system enabled projection-based material decomposition, which typically performs better than image-based decomposition required by some other system designs. In addition to virtual monoenergetic, or keV images, the SDCT provided conventional (kVp) images, allowing us to compare and contrast results. Physical phantom measurements demonstrated linearity of keV images, a requirement for quantitative perfusion. Comparisons of kVp to keV images demonstrated very significant reductions in tell-tale beam hardening (BH) artifacts in both phantom and pig images. In phantom images, consideration of iodine contrast to noise ratio and small residual BH artifacts suggested optimum processing at 70 keV. The processing pipeline for dynamic CTP measurements included 4D image registration, spatio-temporal noise filtering, and model independent singular value decomposition deconvolution, automatically regularized using the L-curve criterion. In normal pig CTP, 70 keV perfusion estimates were homogeneous throughout the myocardium. At 120 kVp, flow was reduced by more than 20% on the BH-hypo-enhanced myocardium, a range that might falsely indicate actionable ischemia, considering the 0.8 threshold for actionable FFR. With partial occlusion of the left anterior descending (LAD) artery (FFR < 0.8), perfusion defects at 70 keV were correctly identified in the LAD territory. At 120 kVp, BH affected the size and flow in the ischemic area; e.g. with FFR ~ 0.65, the anterior-to-lateral flow ratio was 0.29 +/- 0.01, over-estimating stenosis severity as compared to 0.42 +/- 0.01 (p < 0.05) at 70 keV. On the non ischemic inferior wall (not a LAD territory), the flow ratio was 0.50 +/- 0.04 falsely indicating an actionable ischemic condition in a healthy territory. This ratio was 1.00 +/- 0.08 at 70 keV. Results suggest that projection-based keV imaging with the SDCT system and proper processing could enable useful myocardial CTP, much improved over conventional CT. PMID- 26943750 TI - Visualization of Grain Structure and Boundaries of Polycrystalline Graphene and Two-Dimensional Materials by Epitaxial Growth of Transition Metal Dichalcogenides. AB - The presence of grain boundaries in two-dimensional (2D) materials is known to greatly affect their physical, electrical, and chemical properties. Given the difficulty in growing perfect large single-crystals of 2D materials, revealing the presence and characteristics of grain boundaries becomes an important issue for practical applications. Here, we present a method to visualize the grain structure and boundaries of 2D materials by epitaxially growing transition metal dichalcogenides (TMDCs) over them. Triangular single-crystals of molybdenum disulfide (MoS2) epitaxially grown on the surface of graphene allowed us to determine the orientation and size of the graphene grains. Grain boundaries in the polycrystalline graphene were also visualized reflecting their higher chemical reactivity than the basal plane. The method was successfully applied to graphene field-effect transistors, revealing the actual grain structures of the graphene channels. Moreover, we demonstrate that this method can be extended to determine the grain structure of other 2D materials, such as tungsten disulfide (WS2). Our visualization method based on van der Waals epitaxy can offer a facile and large-scale labeling technique to investigate the grain structures of various 2D materials, and it will also contribute to understand the relationship between their grain structure and physical properties. PMID- 26943751 TI - Cyanobacteria Affect Fitness and Genetic Structure of Experimental Daphnia Populations. AB - Zooplankton communities can be strongly affected by cyanobacterial blooms, especially species of genus Daphnia, which are key-species in lake ecosystems. Here, we explored the effect of microcystin/nonmicrocystin (MC/non-MC) producing cyanobacteria in the diet of experimental Daphnia galeata populations composed of eight genotypes. We used D. galeata clones hatched from ephippia 10 to 60 years old, which were first tested in monocultures, and then exposed for 10 weeks as mixed populations to three food treatments consisting of green algae combined with cyanobacteria able/unable of producing MC. We measured the expression of nine genes potentially involved in Daphnia acclimation to cyanobacteria: six protease genes, one ubiquitin-conjugating enzyme gene, and two rRNA genes, and then we tracked the dynamics of the genotypes in mixed populations. The expression pattern of one protease and the ubiquitin-conjugating enzyme genes was positively correlated with the increased fitness of competing clones in the presence of cyanobacteria, suggesting physiological plasticity. The genotype dynamics in mixed populations was only partially related to the growth rates of clones in monocultures and varied strongly with the food. Our results revealed strong intraspecific differences in the tolerance of D. galeata clones to MC/non MC-producing cyanobacteria in their diet, suggesting microevolutionary effects. PMID- 26943752 TI - Resveratrol Potentiates Growth Inhibitory Effects of Rapamycin in PTEN-deficient Lipoma Cells by Suppressing p70S6 Kinase Activity. AB - Patients with phosphatase and tensin homolog (PTEN) hamartoma tumor syndrome and germline mutations in PTEN frequently develop lipomatosis, for which there is no standard treatment. Rapamycin was shown to reduce the growth of lipoma cells with heterozygous PTEN deficiency in vitro, but concomitantly induced an upregulation of AKT phosphorylation. Since it was shown that resveratrol stabilizes PTEN, we asked whether co-incubation with resveratrol could suppress the rapamycin-induced AKT phosphorylation in PTEN-deficient lipoma cells. Resveratrol incubation resulted in decreased lipoma cell viability by inducing G1-phase cell cycle arrest and apoptosis. PTEN expression and AKT phosphorylation were not significantly changed, whereas p70S6 kinase (p70S6K) phosphorylation was reduced in PTEN-deficient lipoma cells after resveratrol incubation. Rapamycin/resveratrol co-incubation significantly decreased viability further at lower doses of resveratrol and resulted in decreased p70S6K phosphorylation compared to rapamycin incubation alone, suggesting that resveratrol potentiated the growth inhibitory effects of rapamycin by reducing p70S6K activation. Both viability and p70S6K phosphorylation of primary PTEN wild-type preadipocytes were less affected compared to PTEN-deficient lipoma cells by equimolar concentrations of resveratrol. These results support the concept of combining chemopreventive natural compounds with mammalian target of rapamycin (mTOR) inhibitors to increase the efficacy of chemotherapeutic drugs for patients suffering from overgrowth syndromes. PMID- 26943759 TI - Redissolution of Flower-Shaped Graphene Oxide Powder with High Density. AB - As a sort of scalable precursor of graphene, single-layer graphene oxide (GO) has received widespread attention. However, producing dried GO powder which can redisperse in solvents on a molecular level is still under challenge. Here, we have developed a strategy to obtain flower-shaped GO powder (fGO) via a low temperature spray-drying method. Such GO powder can be redissolved in various solvents including water, with a concentration higher than 3 wt %. The excellent solubility of fGO is totally preserved even after being compressed into a high density disk (1.26 g/cm(3)). The aqueous solution of fGO can form liquid crystals, which can be assembled into macroscopic graphene papers. By tracking the dissolution process of fGO, we reveal a "swelling-dissociation-stretching" behavior of the GO particles. For the first time, nuclear magnetic resonance (NMR) solution relaxation is applied to in situ monitor the degree of unfolding (DU) of fGO during dissolution. We discover that the classic polymer dissolution mechanism of linear polymer can extend to GO, a two-dimensional macromolecule. Our findings not only provide a solution for the problems in the transportation, storage and applications of GO, but also open a new way to adjust the microstructure of crumpled GO in large scale. PMID- 26943760 TI - Peer support for people with chronic conditions in rural areas: a scoping review. AB - INTRODUCTION: Chronic conditions are a growing healthcare concern. People living in rural regions are particularly affected because many barriers exist to accessing services and supports. Peer support for chronic condition self management, where people living with chronic conditions learn about how to care for themselves and maintain their health from people also living with chronic conditions, is one approach gaining recognition. What remains unknown are the unique challenges and strategies associated with peer support for chronic condition self-management in rural contexts. In order to inform the development of peer supports in the authors' local context in rural eastern Canada, a scoping review was undertaken to discover community-based peer support initiatives for adults in rural settings living with chronic conditions. METHODS: The authors followed established scoping review methods to answer the research question What is known from the existing literature about the key features and potential formats of community-based peer support initiatives for adults living with chronic conditions in rural settings? Six databases (CINAHL, PubMed, Sociological Abstracts, Embase, Cochrane Libraries and PsycInfo) were searched using the following concepts: chronic conditions, peer support, community-based and rural context. Two researchers reviewed the titles and/or abstracts of the 1978 articles retrieved from the initial search to include articles that were in English, published in 2000 to 2014, and that explicitly discussed rural programs/interventions with peers that were community-based. The initial screen excluded 1907 articles, leaving 71 articles, which were read by two research members in light of the inclusion/exclusion criteria. Thirteen articles representing 10 separate programs were included and analyzed using qualitative content analysis. RESULTS: Included programs were from the USA, Australia and Canada. A range of formats (telecommunications only, in-person meetings only, or a combination of both) were used. Peer leaders had varied experiences with chronic conditions and received training in content and facilitation skills. Peer leaders were provided with ongoing support. Program participants received training on chronic conditions, and programs provided opportunities for social support and the development of new skills. Programs focused on creating social connections, reducing stigma, ensuring relevance and promoting empowerment. Of the nine programs that reported outcomes, eight reported positive outcomes and one reported mixed results. DISCUSSION: Consistent with the extant literature, the programs identified unique issues faced by people with chronic conditions in rural areas that these programs addressed. The key findings of this scoping review are as follows: 1. A combination of telecommunications with some face-to face meetings can support the accessibility of peer support programs in rural areas. 2. Core elements of these programs are the provision of social support and skill development. 3. Peer leaders benefit from skills training and ongoing support. 4. Sustainability of such programs is complex and requires multiple strategies. CONCLUSIONS: Cultural relevance, ongoing support and the use of telecommunications were key features of rural peer support programs. Guiding questions to facilitate a community consultation around these findings are provided. Peer support chronic condition self-management programs require further research. PMID- 26943768 TI - Nomograms for predicting Gleason upgrading in a contemporary Chinese cohort receiving radical prostatectomy after extended prostate biopsy: development and internal validation. AB - The current strategy for the histological assessment of prostate cancer (PCa) is mainly based on the Gleason score (GS). However, 30-40% of patients who undergo radical prostatectomy (RP) are misclassified at biopsy pathologically. Thus, we developed and validated nomograms for the prediction of Gleason score upgrading (GSU) in patients who underwent radical prostatectomy after extended prostate biopsy in a Chinese population. This retrospective study included a total of 411 patients who underwent radical prostatectomy at our institute after having prostate biopsies between 2011 and 2015. The final pathologic GS was upgraded in 151 (36.74%) of the cases in all patients and 92 (60.13%) cases in men with GS=6. In multivariate analyses, the primary biopsy GS, secondary biopsy GS and obesity were predictive of GSU in the patient cohort assessed. In patients with GS=6, the significant predictors of GSU included the body mass index (BMI), prostate specific antigen density(PSAD) and percentage of positive cores. The area under the curve (AUC) of the prediction models was 0.753 for the entire patient population and 0.727 for the patients with GS=6. Both nomograms were well calibrated, and decision curve analysis demonstrated a high net benefit across a wide range of threshold probabilities. This study may be relevant for improved risk assessment and clinical decision-making in PCa patients. PMID- 26943769 TI - The role and potential mechanisms of LncRNA-TATDN1 on metastasis and invasion of non-small cell lung cancer. AB - The invasion and metastasis of malignant tumor cells lead to normal tissue destruction and are major prognostic factors for many malignant cancers. Long non coding RNA (LncRNA) is associated with occurrence, development and prognoses of non-small cell lung cancer (NSCLC), but its mechanisms of action involved in tumor invasion and metastasis are not clear. In this study, we screened and detected the expression of LncRNA in two NSCLC lines 95D and 95C by using high throughput LncRNA chip. We found that TATDN1 (Homo sapiens TatD DNase domain containing 1, TATDN1), one of LncRNAs, was highly expressed in 95D cells and NSCLC tumor tissues compared to 95C cells. Knockdown of TATDN1-1 by shRNA significantly inhibited cell proliferation, adhesion, migration and invasion in 95D cells. Further mechanism study showed that TATDN1 knockdown suppressed the expression of E-cadherin, HER2, beta-catenin and Ezrin. Moreover, knockdown TATDN1 also inhibited tumor growth and metastasis in a 95D mouse model in vivo by inhibiting beta-catenin and Ezrin. These data indicate that TATDN1 expression is associated with 95D cells' higher potential of invasion and metastasis, and suggest that TATDN1 may be a potential prognostic factor and therapeutic target for NSCLCs. PMID- 26943770 TI - Improved muscle function and quality after diet intervention with leucine enriched whey and antioxidants in antioxidant deficient aged mice. AB - Antioxidant (AOX) deficiencies are commonly observed in older adults and oxidative stress has been suggested to contribute to sarcopenia. Here we investigate if 1) low levels of dietary antioxidants had a negative impact on parameters of muscle mass, function and quality, and 2) to study if nutritional interventions with AOX and/or leucine-enriched whey protein could improve these muscle parameters in aged mice. 18-months-old mice were fed a casein-based antioxidant-deficient (lowox) diet or a casein-based control-diet (CTRL) for 7 months. During the last 3 months, lowox-mice were subjected to either: a) continued lowox, b) supplementation with vitamin A/E, Selenium and Zinc (AOX), c) substitution of casein with leucine-enriched whey protein (PROT) or d) a combination of both AOX and PROT (TOTAL). After 7 months lowox-mice displayed lower muscle strength and more muscle fatigue compared to CTRL. Compared to lowox mice, PROT-mice showed improved muscle power, grip strength and less muscle fatigue. AOX-mice showed improved oxidative status, less muscle fatigue, improved grip strength and mitochondrial dynamics compared to lowox-mice. The TOTAL-mice showed the combined effects of both interventions compared to lowox-mice. In conclusion, nutritional intervention with AOX and/or leucine-enriched whey protein can play a role in improving muscle health in a AOX-deficient mouse model. PMID- 26943771 TI - Identification and characterization of lncRNA mediated transcriptional dysregulation dictates lncRNA roles in glioblastoma. AB - Long non-coding RNAs (lncRNAs) modulate gene expression, and lncRNA misregulation is associated with cancer. However, precise functional roles in biological and disease processes have been described for only a few lncRNAs. Identification of genome-wide lncRNA-mediated transcriptional dysregulations may improve cancer treatments. In the present study, we used a computational framework that combined lncRNA and gene expression profiles with transcription factor (TF)-target relationships to comprehensively identify dysregulatory lncRNA-TF-gene triplets. In glioblastoma (GBM), we found that most lncRNAs affect multiple targets and primarily affect TF activity in trans. Six different classes of lncRNA-mediated transcriptional dysregulations were identified, with most lncRNAs either enhancing or attenuating target gene expression. Functional analysis of lncRNAs via their dysregulated targets implicated lncRNA modulators in some hallmarks of cancer, providing a new way to predict lncRNA function. Finally, we identified several lncRNA-TF-gene triplets (including HOTAIR-MXI1-CD58/PRKCE and HOTAIR-ATF5 NCAM1) that are associated with glioblastoma prognosis. The integration of lncRNA modulators into transcriptional regulatory networks will further enhance our understanding of lncRNA functions in cancer. PMID- 26943773 TI - Identification of FGF19 as a prognostic marker and potential driver gene of lung squamous cell carcinomas in Chinese smoking patients. AB - Comprehensive genomic characterizations of lung squamous cell carcinoma (LSCC) have been performed, but the differences between smokers (S-LSCC) and never smokers (NS-LSCC) are not clear, as NS-LSCC could be considered as a different disease from S-LSCC. In this study we delineated genomic alterations in a cohort of 21 NS-LSCC and 16 S-LSCC patients, and identified common gene mutations and amplifications as previously reported. Inclusion of more NS-LSCC patients enabled us to identify unreported S-LSCC- or NS-LSCC-specific alterations. Importantly, an amplification region containing FGF19, FGF3, FGF4 and CCND1 was found five times more frequent in S-LSCC than in NS-LSCC. Amplification of FGF19 was validated in independent LSCC samples. Furthermore, FGF19 stimulated LSCC cell growth in vitro. These data implicate FGF19 as a potential driver gene in LSCC with clinic characteristics as smoking. PMID- 26943772 TI - Dicer suppresses the malignant phenotype in VHL-deficient clear cell renal cell carcinoma by inhibiting HIF-2alpha. AB - Both the von Hippel-Lindau (VHL)/hypoxia-inducible factor (HIF) pathway and microRNA (miRNA) regulation are important mechanisms underlying the development and progression of clear cell renal cell carcinoma (ccRCC). Here we demonstrate that VHL deficiency leads to downregulation of Dicer and, in turn, defects in the miRNA biogenesis machinery in ccRCCs. Dicer inhibited expression of HIF-2alpha, which was a direct target of Dicer-dependent miR-182-5p in VHL-deficient ccRCCs. Ectopic Dicer expression in VHL-deficient ccRCCs suppressed tumor growth and angiogenesis by inhibiting HIF-2alpha both in vitro and in vivo. Reduced Dicer mRNA levels served as an independent prognostic factor for poor survival in patients with VHL-deficient ccRCC. Our results indicate that downregulation of Dicer in VHL-deficient ccRCCs contributes to high levels of HIF-2alpha and a malignant phenotype, which suggests Dicer could be a useful therapeutic target for managing this disease. PMID- 26943774 TI - Nuclear heat shock protein 110 expression is associated with poor prognosis and chemotherapy resistance in gastric cancer. AB - Heat shock protein (HSP) expression is induced by the exposure to stress, such as fever, oxidative stress, chemical exposure, and irradiation. In cancer, HSP promotes the survival of malignant cells by inhibiting the induction of apoptosis. In colorectal cancer, a loss-of-function mutation of HSP110 (HSP110DeltaE9) has been identified. HSP110DeltaE9 inhibits the nuclear translocation of wild-type HSP110, which is important for its chaperone activity and anti-apoptotic effects. The patients carrying HSP110DeltaE9 mutation exhibit high sensitivity to anticancer agents, such as oxaliplatin and 5-fluorouracil. There is still insufficient information about HSP110 localization, the clinicopathological significance of HSP110 expression, and its association with chemotherapy resistance in gastric cancer. Here, we found that high nuclear expression of HSP110 in gastric cancer tissues is associated with cancer progression, poor prognosis, and recurrence after adjuvant chemotherapy. In vitro results showed that HSP110 suppression increases the sensitivity to 5 fluorouracil and cisplatin of human gastric cancer cell lines. Our results suggest that nuclear HSP110 may be a new drug sensitivity marker for gastric cancer and a potential molecular therapeutic target for the treatment of gastric cancer patients with acquired anticancer drug resistance. PMID- 26943775 TI - Amplexicaule A exerts anti-tumor effects by inducing apoptosis in human breast cancer. AB - Chemotherapy is the main treatment for patients with breast cancer metastases, but natural alternatives have been receiving attention for their potential as novel anti-tumor reagents. Amplexicaule A (APA) is a flavonoid glucoside isolated from rhizomes of Polygonum amplexicaule D. Don var. sinense Forb (PADF). We found that APA has anti-tumor effects in a breast cancer xenograft mouse model and induces apoptosis in breast cancer cell lines. APA increased levels of cleaved caspase-3,-8,-9 and PARP, which resulted from suppression of MCL-1 and BCL-2 expression in the cells. APA also inactivated the Akt/mTOR pathway in breast cancer cells. Thus, APA exerts a strong anti-tumor effect on breast cancer cells, most likely through induction of apoptosis. Our study is the first to identify this novel anti-tumor compound and provides a new strategy for isolation and separation of single compounds from herbs. PMID- 26943776 TI - Oncogenic kinase fusions: an evolving arena with innovative clinical opportunities. AB - Cancer biology relies on intrinsic and extrinsic deregulated pathways, involving a plethora of intra-cellular and extra-cellular components. Tyrosine kinases are frequently deregulated genes, whose aberrant expression is often caused by major cytogenetic events (e.g. chromosomal translocations). The resulting tyrosine kinase fusions (TKFs) prompt the activation of oncogenic pathways, determining the biological and clinical features of the associated tumors. First reported half a century ago, oncogenic TKFs are now found in a large series of hematologic and solid tumors. The molecular basis of TKFs has been thoroughly investigated and tailored therapies against recurrent TKFs have recently been developed. This review illustrates the biology of oncogenic TKFs and their role in solid as well as hematological malignancies. We also address the therapeutic implications of TKFs and the many open issues concerning their clinical impact. PMID- 26943778 TI - The auditory representation of speech sounds in human motor cortex. AB - In humans, listening to speech evokes neural responses in the motor cortex. This has been controversially interpreted as evidence that speech sounds are processed as articulatory gestures. However, it is unclear what information is actually encoded by such neural activity. We used high-density direct human cortical recordings while participants spoke and listened to speech sounds. Motor cortex neural patterns during listening were substantially different than during articulation of the same sounds. During listening, we observed neural activity in the superior and inferior regions of ventral motor cortex. During speaking, responses were distributed throughout somatotopic representations of speech articulators in motor cortex. The structure of responses in motor cortex during listening was organized along acoustic features similar to auditory cortex, rather than along articulatory features as during speaking. Motor cortex does not contain articulatory representations of perceived actions in speech, but rather, represents auditory vocal information. PMID- 26943777 TI - Effect of alpha-lipoic acid on radiation-induced small intestine injury in mice. AB - PURPOSE: Radiation therapy is a highly effective treatment for patients with solid tumors. However, it can cause damage and inflammation in normal tissues. Here, we investigated the effects of alpha-lipoic acid (ALA) as radioprotection agent for the small intestine in a mouse model. MATERIALS AND METHODS: Whole abdomen was evenly irradiated with total a dose of 15 Gy. Mice were treated with either ALA (100 mg/kg, intraperitoneal injection [i.p.]) or saline (equal volume, i.p.) the prior to radiation as 100 mg/kg/day for 3 days. Body weight, food intake, histopathology, and biochemical parameters were evaluated. RESULTS: Significant differences in body weight and food intake were observed between the radiation (RT) and ALA + RT groups. Moreover, the number of crypt cells was higher in the ALA + RT group. Inflammation was decreased and recovery time was shortened in the ALA + RT group compared with the RT group. The levels of inflammation-related factors (i.e., phosphorylated nuclear factor kappa B and matrix metalloproteinase-9) and mitogen-activated protein kinases were significantly decreased in the ALA + RT group compared with those in the RT group. CONCLUSIONS: ALA treatment prior to radiation decreases the severity and duration of radiation-induced enteritis by reducing inflammation, oxidative stress, and cell death. PMID- 26943781 TI - Clinical Results and Outcome Improvement Over Time in Traumatic Brain Injury. AB - Prognostic models for traumatic brain injury (TBI) are important tools both in clinical practice and research if properly validated, preferably by external validation. Prognostic models also offer the possibility of monitoring performance by comparing predicted outcomes with observed outcomes. In this study, we applied the prognostic models developed by the International Mission on Prognosis and Analysis of Clinical Trials in TBI (IMPACT) in an Italian multi center database (Neurolink) with two aims: to compare observed with predicted outcomes and to check for a possible improvement of clinical outcome over the 11 years of patient inclusion in Neurolink. We applied the IMPACT models to patients included in Neurolink between 1997 and 2007. Performance of the models was assessed by determining calibration (with calibration plots) and discrimination (by the area under the receiver operating characteristic curve [AUC]). Logistic regression analysis was used to analyze a possible trend in outcomes over time, adjusted for predicted outcomes. A total of 1401 patients were studied. Patients had a median age of 40 years and 51% had a Glasgow Coma Scale motor score of 5 or 6. The models showed good discrimination, with AUCs of 0.86 (according to the Core Model) and 0.88 (Extended Model), and adequate calibration, with the overall observed risk of unfavorable outcome and mortality being less than predicted. Outcomes significantly improved over time. This study shows that the IMPACT models performed reasonably well in the Neurolink data and can be used for monitoring performance. After adjustment for predicted outcomes with the prognostic models, we observed a substantial improvement of patient outcomes over time in the three Neurolink centers. PMID- 26943780 TI - Rare neurological channelopathies--networks to study patients, pathogenesis and treatment. AB - Each of the thousands of rare neurological diseases requires a widely distributed network of centres, investigators and patients, so as to foster multidisciplinary investigations and involve sufficient numbers of patients in the discovery of disease pathogenesis and novel treatment. In this Review, we highlight the value of this collaborative approach in patient-oriented research into rare neurological channelopathies. Two networks, the Consortium for Clinical Investigations of Neurological Channelopathies (CINCH) and the Clinical Research Consortium for Studies of Cerebellar Ataxias (CRC-SCA), provide a link between patients with rare channelopathies and investigators who are studying disease pathogenesis and developing novel treatments. Interactions between patients, researchers and advocacy groups promote shared agendas that benefit patient education and recruitment, research collaboration and funding, and training and mentoring of junior investigators who are attracted to the study of the diseases that provide the focus for the two networks. Here, we discuss how linkage of national and international centres has enabled recruitment of study participants, provided opportunities for novel studies of pathogenesis, and facilitated successful clinical trials. PMID- 26943785 TI - Effects of Minority Stress, Group-Level Coping, and Social Support on Mental Health of German Gay Men. AB - OBJECTIVE: According to epidemiological studies, gay men are at a higher risk of mental disorders than heterosexual men. In the current study, the minority stress theory was investigated in German gay men: 1) it was hypothesized that minority stressors would positively predict mental health problems and that 2) group-level coping and social support variables would moderate these predictions negatively. METHODS: Data from 1,188 German self-identified gay men were collected online. The questionnaire included items about socio-demographics, minority stress (victimization, rejection sensitivity, and internalized homonegativity), group level coping (disclosure of sexual orientation, homopositivity, gay affirmation, gay rights support, and gay rights activism), and social support (gay social support and non-gay social support). A moderated multiple regression was conducted. RESULTS: Minority stressors positively predicted mental health problems. Group-level coping did not interact with minority stressors, with the exception of disclosure and homopositivity interacting marginally with some minority stressors. Further, only two interactions were found for social support variables and minority stress, one of them marginal. Gay and non-gay social support inversely predicted mental health problems. In addition, disclosure and homopositivity marginally predicted mental health problems. CONCLUSIONS: The findings imply that the minority stress theory should be modified. Disclosure does not have a relevant effect on mental health, while social support variables directly influence mental health of gay men. Group-level coping does not interact with minority stressors relevantly, and only one relevant interaction between social support and minority stress was found. Further longitudinal or experimental replication is needed before transferring the results to mental health interventions and prevention strategies for gay men. PMID- 26943786 TI - Building SERS-active heteroassemblies for ultrasensitive Bisphenol A detection. AB - Bisphenol A (BPA) usually exists in daily plastic products, as one of the most important endocrine disrupting chemicals. A sensitive surface-enhanced Raman scattering (SERS)-encoded aptasensor for the detection of BPA was developed, for the first time, based on gold nanoparticle-nanorod heteroassemblies. The high electromagnetic enhancement in narrow gaps between metal nanoparticles of these heteroassemblies led to marked Raman signals. It was found that the assembly degree and the corresponding SERS signals were in inverse correlation to the BPA concentrations over a wide linear range of 0.001-1ng/mL and the limit of detection was as low as 3.9pg/mL. Excellent recovery ranging from 91% to 95.3% was obtained to assess the feasibility of this method for real sample detection, indicating promising application for the detection of BPA. PMID- 26943787 TI - A novel and facile synthesis of carbon quantum dots via salep hydrothermal treatment as the silver nanoparticles support: Application to electroanalytical determination of H2O2 in fetal bovine serum. AB - A simple, low-cost, and green process was used for the synthesis of carbon quantum dots (CQDs) through the hydrothermal treatment of salep as a novel bio polymeric carbon source in presence of only pure water. The silver nanoparticles (AgNPs) were embedded on the surface of CQDs by ultra-violate (UV) irradiation to the CQDs and silver nitrate mixture solution. The as-synthesized CQDs and AgNPs decorated CQDs nanohybrid (AgNPs/CQDs) were characterized by UV-vis and photoluminescence spectroscopy, Fourier transform-infrared spectroscopy, transmission electron microscopy, atomic force microcopy, X-ray diffraction, and field emission scanning electron microscopy. Then, the AgNPs/CQDs nanohybrid was casted on the glassy carbon electrode in order to prepare an amperometric hydrogen peroxide (H2O2) sensor. The electrochemical investigations show that the AgNPs/CQDs nanohybrid possesses an excellent performance toward the H2O2 reduction. In the optimum condition, the linear range of H2O2 determination was achieved from 0.2 to 27.0MUM with high sensitivity (1.5MUA/uM) and the limit of detection was obtained about 80nM (S/N=3). Finally, the prepared nanohybrid modified electrode was effectively applied to the H2O2 detection in the disinfected fetal bovine serum samples, and the recovery was obtained about 98%. The achieved results indicate that the AgNPs/CQDs nanohybrid with high reproducibility, repeatability, and stability has a favorable capability in electrochemical sensors improvement. PMID- 26943779 TI - Disease-modifying therapies and infectious risks in multiple sclerosis. AB - Immunomodulatory and immunosuppressive treatments for multiple sclerosis (MS) are associated with an increased risk of infection, which makes treatment of this condition challenging in daily clinical practice. Use of the expanding range of available drugs to treat MS requires extensive knowledge of treatment-associated infections, risk-minimizing strategies and approaches to monitoring and treatment of such adverse events. An interdisciplinary approach to evaluate the infectious events associated with available MS treatments has become increasingly relevant. In addition, individual stratification of treatment-related infectious risks is necessary when choosing therapies for patients with MS, as well as during and after therapy. Determination of the individual risk of infection following serial administration of different immunotherapies is also crucial. Here, we review the modes of action of the available MS drugs, and relate this information to the current knowledge of drug-specific infectious risks and risk-minimizing strategies. PMID- 26943788 TI - The Clinicopathologic Heterogeneity of Grade 3 Gastroenteropancreatic Neuroendocrine Neoplasms: Morphological Differentiation and Proliferation Identify Different Prognostic Categories. AB - BACKGROUND/AIMS: Gastroenteropancreatic (GEP) neuroendocrine carcinomas (NECs) are defined as neuroendocrine neoplasms (NENs) with a Ki-67 index >20% according to the 2010 WHO classification. Some reports suggest that this category is heterogeneous. We retrospectively studied a series of 136 patients affected by grade 3 GEP-NECs with the aim to clarify the prognostic role of tumor morphological differentiation, proliferation, defect in mismatch repair proteins (MMRd), CD117 expression, and site of origin. The primary endpoint was the correlation between these parameters and the overall survival (OS). METHODS: Univariate and multivariable Cox proportional hazards regression analyses were used to assess the prognostic significance of various clinical and histopathologic features. RESULTS: With a median follow-up of 81 months, the median OS was 12.9 months. At multivariate analysis, morphological differentiation, Ki-67 index, MMRd, stage, and CD117 expression were independent prognostic markers in NECs. Three different prognostic categories of NECs were identified according to the degree of morphologic differentiation (well vs. poorly differentiated) and Ki-67 index (<55% vs. >=55%). On this basis, median OS was 43.6 months in well-differentiated neoplasms with a Ki-67 index 20-55% (named type A), 24.5 months in poorly differentiated neoplasms with a Ki-67 index 20-55% (type B), and 5.3 months (p < 0.0001) in poorly differentiated neoplasms with a Ki-67 index >=55% (type C). CONCLUSIONS: The present study suggests that GEP-NECs represent a heterogeneous group of neoplasms which can be better classified in different prognostic categories using both tumor morphology and Ki-67 index. PMID- 26943789 TI - Cost-Effectiveness of Five Commonly Used Prosthesis Brands for Total Knee Replacement in the UK: A Study Using the NJR Dataset. AB - BACKGROUND: There is a lack of evidence on the effectiveness or cost effectiveness of alternative brands of prosthesis for total knee replacement (TKR). We compared patient-reported outcomes, revision rates, and costs, and estimated the relative cost-effectiveness of five frequently used cemented brands of unconstrained prostheses with fixed bearings (PFC Sigma, AGC Biomet, Nexgen, Genesis 2, and Triathlon). METHODS: We used data from three national databases for patients who had a TKR between 2003 and 2012, to estimate the effect of prosthesis brand on post-operative quality of life (QOL) (EQ-5D-3L) in 53 126 patients at six months. We compared TKR revision rates by brand over 10 years for 239 945 patients. We used a fully probabilistic Markov model to estimate lifetime costs and quality-adjusted life years (QALYs), incremental cost effectiveness ratios (ICERs), and the probability that each prosthesis brand is the most cost effective at alternative thresholds of willingness-to-pay for a QALY gain. FINDINGS: Revision rates were lowest with the Nexgen and PFC Sigma (2.5% after 10 years in 70-year-old women). Average lifetime costs were lowest with the AGC Biomet (L9 538); mean post-operative QOL was highest with the Nexgen, which was the most cost-effective brand across all patient subgroups. For example, for 70 year-old men and women, the ICERs for the Nexgen compared to the AGC Biomet were L2 300 per QALY. At realistic cost per QALY thresholds (L10 000 to L30 000), the probabilities that the Nexgen is the most cost-effective brand are about 98%. These results were robust to alternative modelling assumptions. CONCLUSIONS: AGC Biomet prostheses are the least costly cemented unconstrained fixed brand for TKR but Nexgen prostheses lead to improved patient outcomes, at low additional cost. These results suggest that Nexgen should be considered as a first choice prosthesis for patients with osteoarthritis who require a TKR. PMID- 26943790 TI - Sarcoptes scabiei: The Mange Mite with Mighty Effects on the Common Wombat (Vombatus ursinus). AB - Parasitism has both direct and indirect effects on hosts. Indirect effects (such as behavioural changes) may be common, although are often poorly described. This study examined sarcoptic mange (caused by the mite Sarcoptes scabiei) in the common wombat (Vombatus ursinus), a species that shows severe symptoms of infection and often causes mortality. Wombats showed alterations to above ground behaviours associated with mange. Infected wombats were shown to be active outside of the burrow for longer than healthy individuals. Additionally, they spent more time scratching and drinking, and less time walking as a proportion of time spent above ground when compared with healthy individuals. They did not spend a higher proportion of time feeding, but did have a slower feeding rate and were in poorer body condition. Thermal images showed that wombats with mange lost considerably more heat to the environment due to a diminished insulation layer. Infection status did not have an effect on burrow emergence time, although this was strongly dependent on maximum daily temperature. This study, through the most detailed behavioural observations of wombats to date, contributes to a broader understanding of how mange affects wombat health and abundance, and also to our understanding of the evolution of host responses to this parasite. Despite being globally dispersed and impacting over 100 species with diverse intrinsic host traits, the effects of mange on hosts are relatively poorly understood, and it is possible that similar effects of this disease are conserved in other host species. The indirect effects that we observed may extend to other pathogen types. PMID- 26943791 TI - Towards Improving Point-of-Care Diagnosis of Non-malaria Febrile Illness: A Metabolomics Approach. AB - INTRODUCTION: Non-malaria febrile illnesses such as bacterial bloodstream infections (BSI) are a leading cause of disease and mortality in the tropics. However, there are no reliable, simple diagnostic tests for identifying BSI or other severe non-malaria febrile illnesses. We hypothesized that different infectious agents responsible for severe febrile illness would impact on the host metabolome in different ways, and investigated the potential of plasma metabolites for diagnosis of non-malaria febrile illness. METHODOLOGY: We conducted a comprehensive mass-spectrometry based metabolomics analysis of the plasma of 61 children with severe febrile illness from a malaria-endemic rural African setting. Metabolite features characteristic for non-malaria febrile illness, BSI, severe anemia and poor clinical outcome were identified by receiver operating curve analysis. PRINCIPAL FINDINGS: The plasma metabolome profile of malaria and non-malaria patients revealed fundamental differences in host response, including a differential activation of the hypothalamic-pituitary adrenal axis. A simple corticosteroid signature was a good classifier of severe malaria and non-malaria febrile patients (AUC 0.82, 95% CI: 0.70-0.93). Patients with BSI were characterized by upregulated plasma bile metabolites; a signature of two bile metabolites was estimated to have a sensitivity of 98.1% (95% CI: 80.2-100) and a specificity of 82.9% (95% CI: 54.7-99.9) to detect BSI in children younger than 5 years. This BSI signature demonstrates that host metabolites can have a superior diagnostic sensitivity compared to pathogen detecting tests to identify infections characterized by low pathogen load such as BSI. CONCLUSIONS: This study demonstrates the potential use of plasma metabolites to identify causality in children with severe febrile illness in malaria-endemic settings. PMID- 26943792 TI - A Rapid and Versatile Method for Generating Proteins with Defined Ubiquitin Chains. AB - Ubiquitin and polyubiquitin chains target proteins for a wide variety of cellular processes. Ubiquitin-mediated targeting is regulated by the lysine through which the ubiquitins are linked as well as the broader ubiquitin landscape on the protein. The mechanisms of this regulation are not fully understood. For example, the canonical proteasome targeting signal is a lysine 48-linked polyubiquitin chain, and the canonical endocytosis signal is a lysine 63-linked polyubiquitin chain. However, lysine 63-linked polyubiquitin chains can also target substrates for degradation. Biochemical studies of ubiquitinated proteins have been limited by the difficulty of building proteins with well-defined polyubiquitin chains. Here we describe an efficient and versatile method for synthesizing ubiquitin chains of defined linkage and length. The synthesized ubiquitin chains are then attached to any protein containing a ubiquitin moiety. These proteins can be used to study ubiquitin targeting in in vitro assays in the tightly controlled manner required for biochemical studies. PMID- 26943794 TI - Large-Scale Land Acquisition and Its Effects on the Water Balance in Investor and Host Countries. AB - This study examines the validity of the assumption that international large-scale land acquisition (LSLA) is motivated by the desire to secure control over water resources, which is commonly referred to as 'water grabbing'. This assumption was repeatedly expressed in recent years, ascribing the said motivation to the Gulf States in particular. However, it must be considered of hypothetical nature, as the few global studies conducted so far focused primarily on the effects of LSLA on host countries or on trade in virtual water. In this study, we analyse the effects of 475 intended or concluded land deals recorded in the Land Matrix database on the water balance in both host and investor countries. We also examine how these effects relate to water stress and how they contribute to global trade in virtual water. The analysis shows that implementation of the LSLAs in our sample would result in global water savings based on virtual water trade. At the level of individual LSLA host countries, however, water use intensity would increase, particularly in 15 sub-Saharan states. From an investor country perspective, the analysis reveals that countries often suspected of using LSLA to relieve pressure on their domestic water resources--such as China, India, and all Gulf States except Saudi Arabia--invest in agricultural activities abroad that are less water-intensive compared to their average domestic crop production. Conversely, large investor countries such as the United States, Saudi Arabia, Singapore, and Japan are disproportionately externalizing crop water consumption through their international land investments. Statistical analyses also show that host countries with abundant water resources are not per se favoured targets of LSLA. Indeed, further analysis reveals that land investments originating in water stressed countries have only a weak tendency to target areas with a smaller water risk. PMID- 26943793 TI - Identification and Analysis of the Porcine MicroRNA in Porcine Cytomegalovirus Infected Macrophages Using Deep Sequencing. AB - Porcine cytomegalovirus (PCMV; genus Cytomegalovirus, subfamily Betaherpesvirinae, family Herpesviridae) is an immunosuppressive virus that mainly inhibits the immune function of T lymphocytes and macrophages, which has caused substantial damage in the farming industry. In this study, we obtained the miRNA expression profiles of PCMV-infected porcine macrophages via high throughput sequencing. The comprehensive analysis of miRNA profiles showed that 239 miRNA database-annotated and 355 novel pig-encoded miRNAs were detected. Of these, 130 miRNAs showed significant differential expression between the PCMV infected and uninfected porcine macrophages. The 10 differentially expressed pig encoded miRNAs were further determined by stem-loop reverse-transcription polymerase chain reaction, and the results were consistent with the high throughput sequencing. Gene Ontology analysis of the target genes of miRNAs in PCMV-infected porcine macrophages showed that the differentially expressed miRNAs are mainly involved in immune and metabolic processes. This is the first report of the miRNA transcriptome in porcine macrophages and an analysis of the miRNA regulatory mechanisms during PCMV infection. Further research into the regulatory mechanisms of miRNAs during immunosuppressive viral infections should contribute to the treatment and prevention of immunosuppressive viruses. PMID- 26943795 TI - The evolutionary emergence of what we call "emotions". AB - The term "emotion" is not precise. It refers to an assemblage of processes that contribute to how we relate to the social and physical world. We need to understand the functional bases of such processes, and one such basis is action readiness. Action readiness is the preparation for movement or action. Preparation for movement occurs in all animals. In more recently evolved species, such as birds and mammals, preparation for directed action is found as well. Action readiness is the basis for the states we now call emotions, but its importance goes far beyond emotions: action readiness is an elementary aspect of the way autonomous living beings regulate their interactions with the world. PMID- 26943796 TI - Ephedrine alkaloids-free Ephedra Herb extract: a safer alternative to ephedra with comparable analgesic, anticancer, and anti-influenza activities. AB - It is generally accepted that the primary pharmacological activities and adverse effects of Ephedra Herb are caused by ephedrine alkaloids. Interestingly, our research shows that Ephedra Herb also has ephedrine alkaloid-independent pharmacological actions, such as c-MET inhibitory activity. This study describes the preparation of an ephedrine alkaloids-free Ephedra Herb extract (EFE) by ion exchange column chromatography, as well as in vitro and in vivo evaluation of its pharmacological actions and toxicity. We confirmed that EFE suppressed hepatocyte growth factor (HGF)-induced cancer cell motility by preventing both HGF-induced phosphorylation of c-Met and its tyrosine kinase activity. We also investigated the analgesic effect of EFE. Although the analgesic effect of Ephedra Herb has traditionally been attributed to pseudoephedrine, oral administration of EFE reduced formalin-induced pain in a dose-dependent manner in mice. Furthermore, we confirmed the anti-influenza virus activity of EFE by showing inhibition of MDCK cell infection in a concentration-dependent manner. All assessments of toxicity, even after repeated oral administration, suggest that EFE would be a safer alternative to Ephedra Herb. The findings described here suggest that EFE has c Met inhibitory action, analgesic effect, and anti-influenza activity, and that it is safer than Ephedra Herb extract itself. Therefore, EFE could be a useful pharmacological agent. PMID- 26943797 TI - [Bilateral amaurosis after spinal trauma]. AB - This article presents the case of a 72-year-old male patient who suffered severe trauma of the spinal column. The patient developed persistent, bilateral, complete blindness after prolonged emergency neurosurgical treatment in a prone position. A bilateral surgical posterior ischemic optic neuropathy (PION) was diagnosed, which is a rare but severe complication of prolonged non-ocular surgery with circulatory stress. The massive, mostly bilateral, irreversible visual loss up to complete blindness leads to severe and permanent impairment of affected patients. PMID- 26943798 TI - Erratum to: Total tumor volume predicts survival following liver resection in patients with hepatocellular carcinoma. PMID- 26943799 TI - DNA methylation and histone acetylation regulate the expression of MGMT and chemosensitivity to temozolomide in malignant melanoma cell lines. AB - Malignant melanoma is an aggressive, highly lethal dermatological malignancy. Chemoresistance and rapid metastasis limit the curative effect of multimodal therapies like surgery or chemotherapy. The suicide enzyme O6-methylguanine-DNA methyltransferase (MGMT) removes adducts from the O6-position of guanine to repair DNA damage. High MGMT expression is associated with resistance to therapy in melanoma. However, it is unknown if MGMT is regulated by DNA methylation or histone acetylation in melanoma. We examined the effects of the DNA methylation inhibitor 5-Aza-2'-deoxycytidine and histone deacetylase inhibitor Trichostatin A alone or in combination on MGMT expression and promoter methylation and histone acetylation in A375, MV3, and M14 melanoma cells. This study demonstrates that MGMT expression, CpG island methylation, and histone acetylation vary between melanoma cell lines. Combined treatment with 5-Aza-2'-deoxycytidine and Trichostatin A led to reexpression of MGMT, indicating that DNA methylation and histone deacetylation are associated with silencing of MGMT in melanoma. This study provides information on the role of epigenetic modifications in malignant melanoma that may enable the development of new strategies for treating malignant melanoma. PMID- 26943800 TI - Treatment of lung large cell neuroendocrine carcinoma. AB - Lung large cell neuroendocrine carcinoma (L-LCNEC) is a rare, aggressive, and difficult-to-treat tumor. It is classified as a neuroendocrine subtype of large cell lung carcinoma (LCLC) belonging to the non-small cell lung cancer (NSCLC) group, but it is also included in the neuroendocrine tumor (NET) group. Most of the available data related to its treatment derive from retrospective analyses or small case series. For patients with L-LCNEC, prognosis is generally very poor. In early stages (I-II-III), surgery is recommended but does not seem to be sufficient. Platinum-based adjuvant chemotherapy may be useful while the role of neoadjuvant chemotherapy is still not well defined. In patients with advanced L LCNEC, the chemotherapy regimens used in SCLC still remain the standard of treatment, but results are not satisfactory. Due to their peculiar clinical and biological features and the lack of literature data, there is an emerging need for a consensus on the best treatment strategy for L-LCNEC and for the identification of new therapeutic options. In this review, we will discuss the key aspects of L-LCNEC management with the aim to clarify the most controversial issues. PMID- 26943801 TI - The important role of biochemical and functional studies in the diagnostics of peroxisomal disorders. AB - Peroxisomes are dynamic organelles that play an essential role in a variety of metabolic pathways. Peroxisomal dysfunction can lead to various biochemical abnormalities and result in abnormal metabolite levels, such as increased very long-chain fatty acid or reduced plasmalogen levels. The metabolite abnormalities in peroxisomal disorders are used in the diagnostics of these disorders. In this paper we discuss in detail the different diagnostic tests available for peroxisomal disorders and focus specifically on the important role of biochemical and functional studies in cultured skin fibroblasts in reaching the right diagnosis. Several examples are shown to underline the power of such studies. PMID- 26943804 TI - Emotional Reactivity, Behavior Problems, and Social Adjustment at School Entry in a High-risk Sample. AB - Prior research suggests that heightened emotional reactivity to emotionally distressing stimuli may be associated with elevated internalizing and externalizing behaviors, and contribute to impaired social functioning. These links were explored in a sample of 169 economically-disadvantaged kindergarteners (66 % male; 68 % African American, 22 % Hispanic, 10 % Caucasian) oversampled for elevated aggression. Physiological measures of emotional reactivity (respiratory sinus arrhythmia [RSA], heart rate [HR], and cardiac pre-ejection period [PEP]) were collected, and teachers and peers provided ratings of externalizing and internalizing behavior, prosocial competence, and peer rejection. RSA withdrawal, HR reactivity, and PEP shortening (indicating increased arousal) were correlated with reduced prosocial competence, and RSA withdrawal and HR reactivity were correlated with elevated internalizing problems. HR reactivity was also correlated with elevated externalizing problems and peer rejection. Linear regressions controlling for age, sex, race, verbal proficiency, and resting physiology showed that HR reactivity explained unique variance in both teacher rated prosocial competence and peer rejection, and contributed indirectly to these outcomes through pathways mediated by internalizing and externalizing problems. A trend also emerged for the unique contribution of PEP reactivity to peer-rated prosocial competence. These findings support the contribution of emotional reactivity to behavior problems and social adjustment among children living in disadvantaged urban contexts, and further suggest that elevated reactivity may confer risk for social difficulties in ways that overlap only partially with internalizing and externalizing behavior problems. PMID- 26943806 TI - Anti-interleukin-17 treatment of psoriasis. AB - Psoriasis is a chronic, immune-mediated, inflammatory dermatosis, affecting 2-3% of the US population. While first-generation cytokine antagonists targeting tumor necrosis factor alpha (TNF-alpha)-dependent pathways have produced favorable responses in the treatment of psoriasis, higher levels of efficacy in a greater proportion of patients have been shown in trials with antibodies targeting interleukin (IL)-17A and the IL-17 receptor subunit. This examines the role of IL 17 inhibitors in the treatment of plaque psoriasis. The efficacy and safety results from the phase-3 trials with monoclonal antibodies targeting IL-17RA (brodalumab) and IL-17A (ixekizumab and secukinumab) validate IL-17 as a highly effective therapeutic target for the treatment of plaque psoriasis. PMID- 26943807 TI - Induced Superconductivity and Engineered Josephson Tunneling Devices in Epitaxial (111)-Oriented Gold/Vanadium Heterostructures. AB - We report a unique experimental approach to create topological superconductors by inducing superconductivity into epitaxial metallic thin film with strong spin orbit coupling. Utilizing molecular beam epitaxy technique under ultrahigh vacuum conditions, we are able to achieve (111) oriented single phase of gold (Au) thin film grown on a well-oriented vanadium (V) s-wave superconductor film with clean interface. We obtained atomically smooth Au thin films with thicknesses even down to below a nanometer showing near-ideal surface quality. The as-grown V/Au bilayer heterostructure exhibits superconducting transition at around 3.9 K. Clear Josephson tunneling and Andreev reflection are observed in S-I-S tunnel junctions fabricated from the epitaxial bilayers. The barrier thickness dependent tunneling and the associated subharmonic gap structures (SGS) confirmed the induced superconductivity in Au (111), paving the way for engineering thin film heterostructures based on p-wave superconductivity and nano devices exploiting Majorana Fermions for quantum computing. PMID- 26943803 TI - Long noncoding RNAs in regulating adipogenesis: new RNAs shed lights on obesity. AB - Long noncoding RNAs (lncRNAs) are an emerging class of regulators involved in a myriad of biological processes. Recent studies have revealed that many lncRNAs play pivotal roles in regulating adipocyte development. Due to the prevalence of obesity and the serious effects of adiposity on human health and society development, it is necessary to summarize functions and recent advances of lncRNAs in adipogenesis. In this review, we highlight functional lncRNAs contributed to the regulation of adipogenesis, discussing their potential use as therapeutic targets to combat human obesity. PMID- 26943802 TI - Contribution of MicroRNAs to autoimmune diseases. AB - MicroRNAs are a class of evolutionarily conserved, short non-coding RNAs that post-transcriptionally modulate the expression of multiple target genes. They are implicated in almost every biological process, including pathways involved in immune homeostasis, such as immune cell development, central and peripheral tolerance, and T helper cell differentiation. Alterations in miRNA expression and function can lead to major dysfunction of the immune system and mediate susceptibility to autoimmune disease. Here, we discuss the role of miRNAs in the maintenance of immune tolerance to self-antigens and the gain or loss of miRNA functions on tissue inflammation and autoimmunity. PMID- 26943808 TI - Allelic expression of mammalian imprinted genes in a matrotrophic lizard, Pseudemoia entrecasteauxii. AB - Genomic imprinting is a process that results in the differential expression of genes depending on their parent of origin. It occurs in both plants and live bearing mammals, with imprinted genes typically regulating the ability of an embryo to manipulate the maternal provision of nutrients. Genomic imprinting increases the potential for selection to act separately on paternally and maternally expressed genes, which increases the number of opportunities that selection can facilitate embryonic control over maternal nutrient provision. By looking for imprinting in an independent matrotrophic lineage, the viviparous lizard Pseudemoia entrecasteauxii (Scincidae), we test the hypothesis that genomic imprinting facilitates the evolution of substantial placental nutrient transport to embryos (matrotrophy). We sequenced transcriptomes from the embryonic component of lizard placentae to determine whether there are parent-of origin differences in expression of genes that are imprinted in mammals. Of these genes, 19 had sufficiently high expression in the lizard to identify polymorphisms in transcribed sequences. We identified bi-allelic expression in 17 genes (including insulin-like growth factor 2), indicating that neither allele was imprinted. These data suggest that either genomic imprinting has not evolved in this matrotrophic skink or, if it has, it has evolved in different genes to mammals. We outline how these hypotheses can be tested. This study highlights important differences between mammalian and reptile pregnancy and the absence of any shared imprinting genes reflects fundamental differences in the way that pregnancy has evolved in these two lineages. PMID- 26943810 TI - Glucocorticoids for treating Takotsubo syndrome? PMID- 26943811 TI - Percutaneous Endovascular Radiofrequency Ablation for Malignant Portal Obstruction: An Initial Clinical Experience. AB - PURPOSE: The HabibTM VesOpen Catheter is a new endovascular radiofrequency ablation (RFA) device used to treat malignant portal obstruction. The purpose of this study was to evaluate the clinical feasibility and safety of RFA with this device. METHODS: We collected the clinical records and follow-up data of patients with malignant portal obstruction treated with percutaneous endovascular portal RFA using the HabibTM VesOpen Catheter. Procedure-related complications, improvement of symptoms, portal patency, survival, and postoperative biochemical tests were investigated. RESULTS: The 31 patients enrolled in the study underwent 41 successful endovascular portal RFA procedures. Patients were divided into a portal-stenting (PS) group (n = 13), which underwent subsequent portal stenting with self-expandable metallic stents, and a non-stenting (NS) group (n = 18), which did not undergo stenting. No procedure-related abdominal hemorrhage or portal rupture occurred. Postablation complications included abdominal pain (n = 26), fever (n = 13), and pleural effusion (n = 15). Improvements in clinical manifestations were observed in 27 of the 31 patients. Of the 17 patients experiencing portal restenosis, 10 underwent successful repeat RFA. The rate of successful repeat RFA was significantly higher in the NS group than in the PS group. Median portal patency was shorter in the PS group than in the NS group. No mortality occurred during the 4 weeks after percutaneous endovascular portal RFA. CONCLUSIONS: Percutaneous endovascular portal RFA is a feasible and safe therapeutic option for malignant portal obstruction. Prospective investigations should be performed to evaluate clinical efficacy, in particular, the need to evaluate the necessity for subsequent portal stenting. PMID- 26943809 TI - Contrasting Roles of Islet Resident Immunoregulatory Macrophages and Dendritic Cells in Experimental Autoimmune Type 1 Diabetes. AB - The innate immune system critically shapes diabetogenic adaptive immunity during type 1 diabetes (T1D) pathogenesis. While the role of tissue-infiltrating monocyte-derived macrophages in T1D is well established, the role of their tissue resident counterparts remains undefined. We now demonstrate that islet resident macrophages (IRMs) from non-autoimmune mice have an immunoregulatory phenotype and powerfully induce FoxP3+ Tregs in vitro. The immunoregulatory phenotype and function of IRMs is compromised by TLR4 activation in vitro. Moreover, as T1D approaches in NOD mice, the immunoregulatory phenotype of IRMs is diminished as is their relative abundance compared to immunostimulatory DCs. Our findings suggest that maintenance of IRM abundance and their immunoregulatory phenotype may constitute a novel therapeutic strategy to prevent and/or cure T1D. PMID- 26943812 TI - Is leptin coming back? A short introduction to the presentations in this symposium session at the 2015 annual meeting of the EASD. PMID- 26943813 TI - Salinity Adaptation and the Contribution of Parental Environmental Effects in Medicago truncatula. AB - High soil salinity negatively influences plant growth and yield. Some taxa have evolved mechanisms for avoiding or tolerating elevated soil salinity, which can be modulated by the environment experienced by parents or offspring. We tested the contribution of the parental and offspring environments on salinity adaptation and their potential underlying mechanisms. In a two-generation greenhouse experiment, we factorially manipulated salinity concentrations for genotypes of Medicago truncatula that were originally collected from natural populations that differed in soil salinity. To compare population level adaptation to soil salinity and to test the potential mechanisms involved we measured two aspects of plant performance, reproduction and vegetative biomass, and phenological and physiological traits associated with salinity avoidance and tolerance. Saline-origin populations had greater biomass and reproduction under saline conditions than non-saline populations, consistent with local adaptation to saline soils. Additionally, parental environmental exposure to salt increased this difference in performance. In terms of environmental effects on mechanisms of salinity adaptation, parental exposure to salt spurred phenological differences that facilitated salt avoidance, while offspring exposure to salt resulted in traits associated with greater salt tolerance. Non-saline origin populations expressed traits associated with greater growth in the absence of salt while, for saline adapted populations, the ability to maintain greater performance in saline environments was also associated with lower growth potential in the absence of salt. Plastic responses induced by parental and offspring environments in phenology, leaf traits, and gas exchange contribute to salinity adaptation in M. truncatula. The ability of plants to tolerate environmental stress, such as high soil salinity, is likely modulated by a combination of parental effects and within-generation phenotypic plasticity, which are likely to vary in populations from contrasting environments. PMID- 26943814 TI - miR-22 regulates cell invasion, migration and proliferation in vitro through inhibiting CD147 expression in tongue squamous cell carcinoma. AB - OBJECTIVES: Tongue squamous cell carcinoma (TSCC) is the most common type of head and neck squamous cell carcinoma (HNSCC) in China, and its survival rate remains unsatisfactory. miR-22 has been identified as a tumor suppressor in many human cancers, and high expression of CD147 occurs in many tumors. The aim of the present study was to investigate the expression and function of miR-22 in TSCC and its relationship with the expression of CD147. METHODS: TCA8113 cells were transiently transfected with a miR-22 mimic/inhibitor. Subsequently, a validation with Real-time RT-PCR was performed to analyze the miR-22 expression level, and a CCK-8 proliferation assay and transwell migration and invasion assays were carried out. Cotransfections using As-miR-22/si-CD147 mRNA or a miR-22/CD147 overexpression vector were applied, and we investigated the biological effects on cotranscribed TCA8113 cells. RESULTS: qRT-PCR confirmed that miR-22 or As-miR-22 were successfully transfected into TCA8113 cells. Suppressing miR-22 resulted in a promotion of cell proliferation and motility and an up-regulation of CD147 in TCA8113 cells in vitro. In contrast, increasing miR-22 inhibited cell proliferation and motility and down-regulated CD147. Furthermore, the reduction or overexpression of CD147 can reverse the promoting or suppressive effects of miR-22, respectively. CONCLUSIONS: The down-expression of miR-22 can regulate cell growth and motility in TSCC cells, which indicates that miR-22 acts as a tumor suppressor in TSCC. Additionally, CD147 is subsequently up-regulated when miR-22 inhibited. Taken together, the findings of this research defined a novel relationship between the down-regulation of miR-22 and the up-regulation of CD147 and demonstrated that CD147 is a downstream factor of miR-22. PMID- 26943815 TI - Biomechanical investigation into the role of the periodontal ligament in optimising orthodontic force: a finite element case study. AB - OBJECTIVES: This paper aimed to precisely locate centres of resistance (CRe) of maxillary teeth and investigate optimal orthodontic force by identifying the effective zones of orthodontic tooth movement (OTM) from hydrostatic stress thresholds in the periodontal ligament (PDL). METHODS: We applied distally directed tipping and bodily forces ranging from 0.075 N to 3 N (7.5 g to 300 g) onto human maxillary teeth. The hydrostatic stress was quantified from nonlinear finite element analysis (FEA) and compared with normal capillary and systolic blood pressure for driving the tissue remodelling. Two biomechanical stimuli featuring localised and volume-averaged hydrostatic stresses were introduced to describe OTM. Locations of CRe were determined through iterative FEA simulation. RESULTS: Accurate locations of CRes of teeth and ranges of optimal orthodontic forces were obtained. By comparing with clinical results in literature, the volume average of hydrostatic stress in PDL was proved to describe the process of OTM more indicatively. The optimal orthodontic forces obtained from the in-silico modelling study echoed with the clinical results in vivo. CONCLUSIONS: A universal moment to force (M/F) ratio is not recommended due to the variation in patients and loading points. Accurate computational determination of CRe location can be applied in practice to facilitate orthodontic treatment. Global measurement of hydrostatic pressure in the PDL better characterised OTM, implying that OTM occurs only when the majority of PDL volume is critically stressed. The FEA results provide new insights into relevant orthodontic biomechanics and help establish optimal orthodontic force for a specific patient. PMID- 26943816 TI - Evaluation and Exploration of Favorable QTL Alleles for Salt Stress Related Traits in Cotton Cultivars (G. hirsutum L.). AB - Soil salinization is one of the major problems in global agricultural production. Cotton is a pioneer crop with regard to salt stress tolerance, and can be used for saline-alkali land improvement. The large-scale detection of salt tolerance traits in cotton accessions, and the identification of elite quantitative trait loci (QTLs)/genes for salt-tolerance have been very important in salt tolerance breeding. Here, 43 advanced salt-tolerant and 31 highly salt-sensitive cultivars were detected by analyzing ten salt tolerance related traits in 304 upland cotton cultivars. Among them, 11 advanced salt-tolerance and eight highly salt-sensitive cultivars were consistent with previously reported results. Association analysis of ten salt-tolerance related traits and 145 SSRs was performed, and a total of 95 significant associations were detected; 17, 41, and 37 of which were associated with germinative index, seedling stage physiological index, and four seedling stage biochemical indexes, respectively. Of these associations, 20 SSR loci were simultaneously associated with two or more traits. Furthermore, we detected 117 elite alleles associated with salt-tolerance traits, 4 of which were reported previously. Among these loci, 44 (37.60%) were rare alleles with a frequency of less than 5%, 6 only existed in advanced salt-tolerant cultivars, and 2 only in highly salt-sensitive cultivars. As a result, 13 advanced salt tolerant cultivars were selected to assemble the optimal cross combinations by computer simulation for the development of salt-tolerant accessions. This study lays solid foundations for further improvements in cotton salt-tolerance by referencing elite germplasms, alleles associated with salt-tolerance traits, and optimal crosses. PMID- 26943818 TI - Analyzing the Relationship between Nonmedical Prescription-Opioid use and Heroin USE. PMID- 26943817 TI - The Myeloid LSECtin Is a DAP12-Coupled Receptor That Is Crucial for Inflammatory Response Induced by Ebola Virus Glycoprotein. AB - Fatal Ebola virus infection is characterized by a systemic inflammatory response similar to septic shock. Ebola glycoprotein (GP) is involved in this process through activating dendritic cells (DCs) and macrophages. However, the mechanism is unclear. Here, we showed that LSECtin (also known as CLEC4G) plays an important role in GP-mediated inflammatory responses in human DCs. Anti-LSECtin mAb engagement induced TNF-alpha and IL-6 production in DCs, whereas silencing of LSECtin abrogated this effect. Intriguingly, as a pathogen-derived ligand, Ebola GP could trigger TNF-alpha and IL-6 release by DCs through LSECtin. Mechanistic investigations revealed that LSECtin initiated signaling via association with a 12-kDa DNAX-activating protein (DAP12) and induced Syk activation. Mutation of key tyrosines in the DAP12 immunoreceptor tyrosine-based activation motif abrogated LSECtin-mediated signaling. Furthermore, Syk inhibitors significantly reduced the GP-triggered cytokine production in DCs. Therefore, our results demonstrate that LSECtin is required for the GP-induced inflammatory response, providing new insights into the EBOV-mediated inflammatory response. PMID- 26943819 TI - Simple Solution for a Complex Problem: Rewriting the Script. PMID- 26943820 TI - Acetaminophen, a Reasonable Option, but not a Panacea. PMID- 26943821 TI - Gene Network Polymorphism Illuminates Loss and Retention of Novel RNAi Silencing Components in the Cryptococcus Pathogenic Species Complex. AB - RNAi is a ubiquitous pathway that serves central functions throughout eukaryotes, including maintenance of genome stability and repression of transposon expression and movement. However, a number of organisms have lost their RNAi pathways, including the model yeast Saccharomyces cerevisiae, the maize pathogen Ustilago maydis, the human pathogen Cryptococcus deuterogattii, and some human parasite pathogens, suggesting there may be adaptive benefits associated with both retention and loss of RNAi. By comparing the RNAi-deficient genome of the Pacific Northwest Outbreak C. deuterogattii strain R265 with the RNAi-proficient genomes of the Cryptococcus pathogenic species complex, we identified a set of conserved genes that were lost in R265 and all other C. deuterogattii isolates examined. Genetic and molecular analyses reveal several of these lost genes play roles in RNAi pathways. Four novel components were examined further. Znf3 (a zinc finger protein) and Qip1 (a homolog of N. crassa Qip) were found to be essential for RNAi, while Cpr2 (a constitutive pheromone receptor) and Fzc28 (a transcription factor) are involved in sex-induced but not mitosis-induced silencing. Our results demonstrate that the mitotic and sex-induced RNAi pathways rely on the same core components, but sex-induced silencing may be a more specific, highly induced variant that involves additional specialized or regulatory components. Our studies further illustrate how gene network polymorphisms involving known components of key cellular pathways can inform identification of novel elements and suggest that RNAi loss may have been a core event in the speciation of C. deuterogattii and possibly contributed to its pathogenic trajectory. PMID- 26943823 TI - Lomitapide for use in patients with homozygous familial hypercholesterolemia: a narrative review. AB - Lomitapide is a drug recently approved for the treatment of patients with homozygous familial hypercholesterolemia. In this article we discuss briefly the pharmacology of this drug followed by a comprehensive narrative review of the available preclinical and clinical data on its safety and efficacy. Only data published as full papers are presented, with the exception of one long-term open label extension study, which is available only in abstract form. PMID- 26943822 TI - Comprehensive Identification of Kruppel-Like Factor Family Members Contributing to the Self-Renewal of Mouse Embryonic Stem Cells and Cellular Reprogramming. AB - Pluripotency is maintained in mouse embryonic stem (ES) cells and is induced from somatic cells by the activation of appropriate transcriptional regulatory networks. Kruppel-like factor gene family members, such as Klf2, Klf4 and Klf5, have important roles in maintaining the undifferentiated state of mouse ES cells as well as in cellular reprogramming, yet it is not known whether other Klf family members exert self-renewal and reprogramming functions when overexpressed. In this study, we examined whether overexpression of any representative Klf family member, such as Klf1-Klf10, would be sufficient for the self-renewal of mouse ES cells. We found that only Klf2, Klf4, and Klf5 produced leukemia inhibitory factor (LIF)-independent self-renewal, although most KLF proteins, if not all, have the ability to occupy the regulatory regions of Nanog, a critical Klf target gene. We also examined whether overexpression of any of Klf1-Klf10 would be sufficient to convert epiblast stem cells into a naive pluripotent state and found that Klf5 had such reprogramming ability, in addition to Klf2 and Klf4. We also delineated the functional domains of the Klf2 protein for LIF-independent self-renewal and reprogramming. Interestingly, we found that both the N-terminal transcriptional activation and C-terminal zinc finger domains were indispensable for this activity. Taken together, our comprehensive analysis provides new insight into the contribution of Klf family members to mouse ES self-renewal and cellular reprogramming. PMID- 26943824 TI - [In silico analysis of the identity of lipocalin of dog, cat, horse, cow, hamster and hen. Possible role in allergic diseases]. AB - BACKGROUND: Lipocalins seem to explain the cross-reactivity between some pets such as cat and dog. However, its role in other animals and its possible clinical impact in allergy diseases have been scarcely studied. OBJECTIVE: To analyze by bioinformatics techniques, the identity between lipocalin of some animals and to explore the clinical impact on allergic diseases. MATERIAL AND METHOD: An in silico study was done to search for lipocalin sequences using the BLAST program of NCBI Database. The protein sequences were aligned with CLUSTAL Omega UniProt version 1.2.1 software. The base sequences for alignments were lipocalins dogs and cats. The defined percentage identity was compared with the frequency of sensitization to animals exposed in a population of 284 patients with suspected allergic diseases. RESULTS: Identities between sequences were 10% to 70%. The highest values were found with Can f 6-Fel d 4 (68%) and Fel d 4-Equ c 1 (68%). The lower identity was found with lipocalin porpurin and retinol binding (<20%). We observed a relationship between sensitization and the percent identity between the species studied. CONCLUSION: Lipocalins as Can f 6, Fel de 4 and Equ c 1 seem to play an important role in the cross-reactivity to cat, horse and dog but not for the co-sensitization to hamster, cow or birds. Fel de 4 and Equ c 1 could be a prevalent allergen for horse and cat. These results come from predictive analysis and must be confirmed by in vitro and in vivo studies. PMID- 26943826 TI - [Total immunoglobulin E as marker of allergy at Northeast of Mexico]. AB - BACKGROUND: Relationship of total serum IgE and allergy has been studied to determine if it could be a useful complement allergy diagnosis. OBJECTIVE: To determine whether serum total IgE is a useful tool in diagnosis of allergy in pediatric population attending outpatient pediatric allergy Regional General Hospital No. 1, Ciudad Obregon, Sonora, Mexico. MATERIAL AND METHOD: An epidemiological, observational, retrospective, transversal and analytical study of diagnostic test was done including files of children 3-15 years 11 months old, treated in pediatric allergy. For statistical analysis SPSS V-22 was used and through tetrachoric table, sensitivity, specificity of IgE for allergy diagnosis were determined, taking skin tests as a gold standard for diagnosing allergies; p value between the study variables was determined using Student t test. RESULTS: 248 records were studied; male gender was more frequent (59%). IgE sensitivity was 85% and specificity was 20%, cutoff point found was 148 IU/mL, elevated levels of IgE in skin tests to airborne allergens and presence of respiratory symptoms. CONCLUSION: IgE determination is a useful initial screening test in patients with suspected allergy. PMID- 26943825 TI - [Sensitivity and specificity of prick skin test with two concentrations of standardized extract of Culex quinquefasciatus in allergic children]. AB - BACKGROUND: Diagnostic options for immune reactions to mosquito bites are limited. In Cuba, IgE-mediated reactions are frequently related to Culex quinquefasciatus bite. OBJECTIVE: To determine the sensitivity and specificity of skin prick test with two doses of standardized extract in nitrogen protein units (PNU of Culex quinquefasciatus (BIOCEN, Cuba). MATERIAL AND METHOD: An analytical study was conducted on 100 children between 2 and 15 years old. Fifty atopic patients with a history of allergy to mosquito bite and positive specific serum IgE Culex quinquefasciatus and fifty atopic patients without a history of allergy to mosquito bite and negative specific serum IgE to Culex quinquefasciatus. Skin prick tests (SPT) were performed by duplicates on the forearms of the patients. Investigated doses were 100 PNU/mL and 10 PNU/mL. RESULTS: SPT with the highest concentration obtained a mean wheal size of 22.09 mm2 and for lower doses of 8.09 mm2, a statistically significant difference (p=0.001, Student's t test). Positive skin test correlated in 100% of patients with the presence of specific IgE. Testing with both doses showed a 94% of specificity and 88% of sensitivity. CONCLUSION: The diagnostic accuracy of SPT using both doses of standardized extract was similar, which justifies its use for diagnosis of sensitization to Culex quinquefasciatus in patients with symptoms of allergy to mosquito bite. PMID- 26943827 TI - [Identification of microorganisms related to chronic rhinosinusitis in adult patients with variable common immunodeficiency]. AB - BACKGROUND: The prevalence of chronic rhinosinusitis in adult patients with common variable immunodeficiency (CVID) is 52%. The patients with CVID show higher incidence of chronic rhinosinusitis, which is an inflammatory disease that affects the lining of one or more paranasal sinuses and nasal cavity. OBJECTIVE: To identify the microorganisms in the middle meatus secretion obtained by endoscopy associated with chronic rhinosinusitis in adult patients with common variable immunodeficiency (CVID). MATERIAL AND METHOD: A descriptive, cross sectional study, which included adult patients with CVID, from whom a sample endoscopic middle meatus secretion from both nostrils was obtained and sent to culture for aerobic, anaerobic bacteria and fungi. Informed consent of all patients was obtained. RESULTS: 29 patients were studied: 18 women and 11 men with a mean age of 40+/-13 years. The results were: 2 samples showed no microbial growth, 24 showed growth of aerobic bacteria, 3 cases had fungal growth without development of anaerobic bacteria. CONCLUSIONS: Our results show that the most common microorganisms associated with CSR in adult patients are: Moraxella catarrhalis, Staphylococcus, Sphingomonas paucimobilis and Citrobacter koseri, and associated fungal agents were: Candida albicans and Aspergillus fumigatus. PMID- 26943829 TI - [Common and inductors factors of inflammation in asthma and obesity]. AB - The incidence of asthma and obesity is increasing, therefore they have been classified as public health problems; epidemiology suggests a link between these diseases. It has been detected a relationship between the body mass index and lung function, moreover some works show a direct correlation between the aforementioned index and severity of asthma. By a search for articles in indexed journals from medical databases with the key words asthma and obesity: pathogenesis, inflammation, adipokines, hypoxia, nutrition, pregnancy, this paper deeps in the knowledge about basic elements that offer an asthma and obesity link. It was found that the association between body mass index and asthma is more frequent in women. Asthma and obesity might be influenced by genetic elements and fetal programming; at the same time obesity could influence asthma by several mechanisms such as inflammation, hormones and mechanical respiratory dysfunction. The existing coincidence between several inducers and factors which exacerbate these diseases as well as in some molecular routes shows a potential relation between both pathological entities. PMID- 26943828 TI - [Rhinitis and asthma as a cause of absenteeism and poor work/school performance in a population from Latin-American tropic]. AB - BACKGROUND: Asthma and rhinitis are the most frequent chronic respiratory diseases. Their high impact is associated with the loss of working days, as well as a decrease in academic performance. OBJECTIVE: To assess and compare the impact of rhinitis and asthma as causes of absenteeism and low work performance in a population of children and adults. MATERIAL AND METHOD: A cross sectional study was performed in 10 schools of two cities in Colombia. The student population between 6 to 17 years, as well as the faculty staff over 18 were invited to participate. All of the participants filled a questionnaire assessing parameters related to clinical background, and a review of scores in Math and Spanish, curriculum vitae and number of missed day during the last academic period completed was performed. RESULTS: A total of 1,413 participants were enrolled. The frequency of asthma and/or rhinitis was 36%, there was a greater frequency of absenteeism in the population of children with respiratory symptoms (2.8 vs 1.2 days/year/patient, p<0.01) and there was both a lower academic (failure in 17% vs 9%, p<0.05) and work performance (0.43 vs 0.27, p<0.05) in the symptomatic population. We observed that those patients with good adherence to pharmacologic treatment displayed lower absenteeism and an improved performance. CONCLUSION: Both rhinitis and asthma are associated with lower performance in children and adults and absenteeism in the school; however, adequate treatment may improve clinical control and reduce backlash against job performance. PMID- 26943830 TI - [Lymphocytes B and primary immunodeficiencies]. AB - Primary antibody deficiencies represent the most frequent genetic diseases of the immune system and the first to be recognized along immunology history. The antibodies were recognized as part of the humoral immune system long ago, and after immunoglobulin discovery, the first antibody immunodeficiency were recognized and named as "agammaglobulinemia", followed by the common variable immunoendeficiency and the hyper-IgM syndrome. The following discoveries in immunology history made possible the understanding of these pathologies, for example: the discoveries of B cells, pre-B cells, the signaling pathway directed by the antigen receptor and many other cellular and molecular mechanisms. Primary antibody deficiencies have been studied for a long time and the discoveries of new syndromes have been helpful in the understanding of immunological mechanisms that take place in our organism. Then, this manuscript pretends to review the relevant findings in the history of immunology, focused on the B cells and the connection with the description of representative clinical entities of primary antibody deficiencies. The aim of this manuscript is to show to the reader that the generation of scientific knowledge has a direct application in the understanding of the molecular mechanisms that are affected in these diseases. PMID- 26943831 TI - [B lymphocyte ontogeny]. AB - The B cell development from hematopoietic stem cells is a continuous and highly regulated process where multiple differentiation potentials are gradually lost while acquiring lineage specialized functions. At 50 years of the B cell discovery, the current knowledge of its early differentiation largely derive from the isolation and characterization of bone marrow early progenitor cells initiating the lymphoid program, and from the definition of transcriptional activity patterns that control cell fate decisions. Of particular relevance has been the intercommunication between B cell precursors and key components of the hematopoietic microenvironment, both for generation of novel models integrating all regulatory elements of this complex process, and for the understanding of this branch of the adaptive immune system in disease settings. This review provides an overview of the complex process of lymphoid differentiation: from the hierarchical organization and biological characteristics of primitive cells involved in its earliest stages, to the principles governing its interdependence with the hematopoietic microenvironment. PMID- 26943832 TI - [The research protocol II: study designs in clinical research]. AB - In clinical research that takes place in health-care areas, most of the studies are performed with human beings as research subjects. The main objectives of these studies are to know the characteristics of one or more groups, the behavior of human diseases, the etiology or causes of diseases, to identify the best diagnostic tools, or to establish the best treatment for a condition or disease in particular. Additionally, some studies are classified as basic bio-medical research; in these investigations, the subjects of study are laboratory animals, tissues, cells, or molecules. In general terms, the objectives of these studies are to understand the physiology, pathogenesis, or biological mechanisms that could explain functions or alterations in one or more systems or body organs. This article will only address clinical research designs. PMID- 26943833 TI - [Hemophagocytic syndrome associated to hepatitis]. AB - Hemophagocytic syndrome is characterized by increased proliferation and activation of antigen presenting cells (histiocytes) in bone marrow and other organs of the reticuloendothelial system as well as CD8+ T cells that threatens life of patients. The predominant clinical manifestations such as fever, cytopenia, hepatitis, coagulopathy, neurological symptoms and multiple organ failure are related to systemic inflammation. We report the case of an infant who started with jaundice, abdominal pain, vomiting and malaise, at admission, hepatomegaly, splenomegaly and biochemically with features suggestive of hepatocellular inflammation and progressive cholestasis with poor outcome, it was added persistent fever, seizures, anemia, thrombocytopenia, leukopenia, elevated ferritin and hypertriglyceridemia integrating hemophagocytic syndrome with fatal outcome despite immunosuppressive therapy. PMID- 26943834 TI - [Hematopoietic progenitors transplantation in a patient with chronic granulomatous disease in Mexico]. AB - The incidence of chronic granulomatous disease in international reports is 1:250,000; however, in Mexico it is unknown. At the National Institute of Pediatrics of Mexico a project for facilitating the diagnosis of the disease was implemented by us in 2009. From the start of such project up to date 68 cases have been studied; 80% of those are X-linked forms (LX) and moreover, it has become noticeable the diagnosis at a younger age. The new challenge we are facing its to provide a successful treatment to those patients diagnosed with chronic granulomatous disease (CGD). We are reporting the case of a one-month old newborn patient diagnosed with CGD-LX that was successfully transplanted in Mexico. PMID- 26943835 TI - [Cereal-dependent exercise-induced anaphylaxis]. AB - Wheat-dependent exercise-induced anaphylaxis (WDEIA) is increasing. In vitro test such as omega-5-gliadin levels are useful in the diagnosis, while oral single blind challenge tests (OCT) with wheat plus exercise continuous being the gold standard diagnostic method. This paper reports the case of a 38-year-old woman, with several episodes of anaphylaxis after eating different foods and doing exercise after ingestion. An allergy study was performed with positive skin prick tests for wheat, barley and rye. Total IgE 238.0KU/L, positive specific IgE (>100KU/L) to wheat, barley and rye, and negative to rTri-a-19 omega-5 gliadin. OCT with bread and exercise was positive. In this case of wheat-dependent exerciseinduced anaphylaxis (WDEIA) with negative serum specific IgE to omega-5 gliadin, negative results with gamma, alpha, bheta y omega-gliadin doesn't exclude the diagnosis of WDEIA. PMID- 26943836 TI - Development and validation of a visual grading scale for assessing image quality of AP pelvis radiographic images. AB - OBJECTIVE: The aim of this article was to apply psychometric theory to develop and validate a visual grading scale for assessing the visual perception of digital image quality anteroposterior (AP) pelvis. METHODS: Psychometric theory was used to guide scale development. Seven phantom and seven cadaver images of visually and objectively predetermined quality were used to help assess scale reliability and validity. 151 volunteers scored phantom images, and 184 volunteers scored cadaver images. Factor analysis and Cronbach's alpha were used to assess scale validity and reliability. RESULTS: A 24-item scale was produced. Aggregated mean volunteer scores for each image correlated with the rank order of the visually and objectively predetermined image qualities. Scale items had good interitem correlation (>=0.2) and high factor loadings (>=0.3). Cronbach's alpha (reliability) revealed that the scale has acceptable levels of internal reliability for both phantom and cadaver images (alpha = 0.8 and 0.9, respectively). Factor analysis suggested that the scale is multidimensional (assessing multiple quality themes). CONCLUSION: This study represents the first full development and validation of a visual image quality scale using psychometric theory. It is likely that this scale will have clinical, training and research applications. ADVANCES IN KNOWLEDGE: This article presents data to create and validate visual grading scales for radiographic examinations. The visual grading scale, for AP pelvis examinations, can act as a validated tool for future research, teaching and clinical evaluations of image quality. PMID- 26943837 TI - Performance validity test and neuropsychological assessment battery screening module performances in an active-duty sample with a history of concussion. AB - The current retrospective investigation sought to replicate previous findings demonstrating the significant impact of performance validity test (PVT) performance and evaluation context on neuropsychological testing. We examined differences on performance validity testing between active-duty service members undergoing neurocognitive screening for concussion who were seen in a clinical context and those who were seen in a disability-seeking context, as well as the overall impact of PVT performance on a neurocognitive screening battery. Overall, 38.2% of the sample failed the Word Memory Test (WMT). Of those involved in a disability evaluation, the failure rate was 51.9%, which was significantly higher than the 36.8% failure rate among those evaluated in a clinical context. The effect size of WMT performance on a cognitive screening measure was also large. The current retrospective analysis served to replicate previous work. PMID- 26943838 TI - Identification of Proteins and Peptide Biomarkers for Detecting Banned Processed Animal Proteins (PAPs) in Meat and Bone Meal by Mass Spectrometry. AB - The outbreak of bovine spongiform encephalopathy (BSE) in the United Kingdom in 1986, with processed animal proteins (PAPs) as the main vector of the disease, has led to their prohibition in feed. The progressive release of the feed ban required the development of new analytical methods to determine the exact origin of PAPs from meat and bone meal. We set up a promising MS-based method to determine the species and the source (legal or not) present in PAPs: a TCA acetone protein extraction followed by a cleanup step, an in-solution tryptic digestion of 5 h (with a 1:20 protein/trypsin ratio), and mass spectrometry analyses, first without any a priori, with a Q-TOF, followed by a targeted triple quadrupole analysis. Using this procedure, we were able to overcome some of the major limitations of the official methods to analyze PAPs, detecting and identifying prohibited animal products in feedstuffs by the monitoring of peptides specific for cows, pigs, and sheep in PAPs. PMID- 26943840 TI - Outpatient brain tumor craniotomy under general anesthesia. AB - OBJECTIVE Outpatient craniotomy has many advantages to the psychological and physical well-being of patients, as well as benefits to the health care system. Its efficacy and safety have been well demonstrated, but barriers to its widespread adoption remain. Among the challenges is a perception that its application is limited to cases performed under conscious sedation, which is not always feasible given certain patient or surgeon factors. The object of this study was to characterize the rate of patient discharge from the day surgery unit (DSU) following craniotomy for tumor resection in a patient under general anesthesia. The authors identify postoperative complications and discuss appropriate patient selection for day surgery craniotomy. METHODS Patients undergoing elective craniotomy for supratentorial tumors between January 2010 and June 2014 were prospectively considered for outpatient management. Authors of the present study performed a retrospective chart review of these patients, analyzing cases by intention to treat. RESULTS Of 318 craniotomies undertaken in the study period, 141 were performed with the patient under general anesthesia. The day surgery protocol was initiated in 44 cases and completed in 38 (86%). Five patients required admission from the DSU, and 1 was discharged but admitted within the 1st postoperative day. In-hospital medical complications were fewer in the outpatient group, and no patients experienced an adverse outcome due to early discharge. CONCLUSIONS Close clinical and imaging surveillance in the early postoperative period allows for safe discharge of patients following craniotomy for tumor resection performed under general anesthesia. Therefore, general anesthesia does not preclude the application of outpatient craniotomy. PMID- 26943839 TI - Benefits of group cognitive remediation therapy in anorexia nervosa: case series. AB - BACKGROUND: Cognitive remediation therapy (CRT) is a treatment targeting cognitive difficulties in psychiatric disorders. CRT has been used with patients with severe anorexia nervosa (AN) in individual and group formats. Research of group CRT in AN is limited. METHODS: Evaluation of a series of CRT groups delivered in inpatient and intensive daycare services was performed. Participants' self-reported cognitive flexibility and central coherence, as well as motivation to change were assessed pre- and post-group. Additionally, patients' evaluative feedback was collected after completion of the group. RESULTS: There was a significant improvement in the patients' self-reported cognitive flexibility and bigger picture thinking, as well as in their self efficacy to change. The feedback questionnaires highlighted that patients found the sessions useful and reported confidence in using some of the skills and strategies they learnt in the group. CONCLUSION: In line with evidence from small scale reports, this larger scale case series study indicates that group CRT leads to increased flexibility and bigger picture thinking, as well as improved confidence in the ability to change for participants. CRT in a group format seems to be a practical and helpful intervention for patients with AN in intensive treatment programmes. PMID- 26943841 TI - The influence of depth of anesthesia on motor evoked potential response during awake craniotomy. AB - OBJECTIVE Motor evoked potentials (MEPs) are a critical indicator for monitoring motor function during neurological surgery. In this study, the influence of depth of anesthesia on MEP response was assessed. METHODS Twenty-eight patients with brain tumors who underwent awake craniotomy were included in this study. From a state of deep anesthesia until the awake state, MEP amplitude and latency were measured using 5-train electrical bipolar stimulations on the same site of the precentral gyrus each minute during the surgery. The depth of anesthesia was evaluated using the bispectral index (BIS). BIS levels were classified into 7 stages: < 40, and from 40 to 100 in groups of 10 each. MEP amplitude and latency of each stage were compared. The deviation of the MEP measurements, which was defined as a fluctuation from the average in every BIS stage, was also considered. RESULTS A total of 865 MEP waves in 28 cases were evaluated in this study. MEP amplitude was increased and latency was decreased in accordance with the increases in BIS level. The average MEP amplitudes in the > 90 BIS level was approximately 10 times higher than those in the < 40 BIS level. Furthermore, the average MEP latencies in the > 90 BIS level were 1.5-3.1 msec shorter than those in the < 60 BIS level. The deviation of measured MEP amplitudes in the > 90 BIS level was significantly stabilized in comparison with that in the < 60 BIS level. CONCLUSIONS MEP amplitude and latency were closely correlated with depth of anesthesia. In addition, the deviation in MEP amplitude was also correlated with depth of anesthesia, which was smaller during awake surgery (high BIS level) than during deep anesthesia. Therefore, MEP measurement would be more reliable in the awake state than under deep anesthesia. PMID- 26943842 TI - Pipeline Embolization Device for small paraophthalmic artery aneurysms with an emphasis on the anatomical relationship of ophthalmic artery origin and aneurysm. AB - OBJECTIVE Contemporary treatment for paraophthalmic artery aneurysms includes flow diversion utilizing the Pipeline Embolization Device (PED). Little is known, however, about the potential implications of the anatomical relationship of the ophthalmic artery (OA) origin and aneurysm, especially in smaller aneurysms. METHODS Four major academic institutions in the United States provided data on small paraophthalmic aneurysms (<= 7 mm) that were treated with PED between 2009 and 2015. The anatomical relationship of OA origin and aneurysm, radiographic outcomes of aneurysm occlusion, and patency of the OA were assessed using digital subtraction angiography. OA origin was classified as follows: Type 1, OA separate from the aneurysm; Type 2, OA from the aneurysm neck; and Type 3, OA from the aneurysm dome. Clinical outcome was assessed using the modified Rankin Scale, and visual deficits were categorized as transient or permanent. RESULTS The cumulative number of small paraophthalmic aneurysms treated with PED between 2009 and 2015 at the 4 participating institutions was 69 in 52 patients (54.1 +/- 13.7 years of age) with a male-to-female ratio of 1:12. The distribution of OA origin was 72.5% for Type 1, 17.4% for Type 2, and 10.1% for Type 3. Radiographic outcome at the last follow-up (median 11.5 months) was available for 54 aneurysms (78.3%) with complete, near-complete, and incomplete occlusion rates of 81.5%, 5.6%, and 12.9%, respectively. Two aneurysms (3%) resulted in transient visual deficits, and no patient experienced a permanent visual deficit. At the last follow-up, the OA was patent in 96.8% of treated aneurysms. Type 3 OA origin was associated with a lower rate of complete aneurysm occlusion (p = 0.0297), demonstrating a trend toward visual deficits (p = 0.0797) and a lower rate of OA patency (p = 0.0783). CONCLUSIONS Pipeline embolization treatment of small paraophthalmic aneurysms is safe and effective. An aneurysm where the OA arises from the aneurysm dome may be associated with lower rates of aneurysm occlusion, OA patency, and higher rates of transient visual deficits. PMID- 26943843 TI - Progressive hemorrhagic injury after severe traumatic brain injury: effect of hemoglobin transfusion thresholds. AB - OBJECT There is limited literature available to guide transfusion practices for patients with severe traumatic brain injury (TBI). Recent studies have shown that maintaining a higher hemoglobin threshold after severe TBI offers no clinical benefit. The present study aimed to determine if a higher transfusion threshold was independently associated with an increased risk of progressive hemorrhagic injury (PHI), thereby contributing to higher rates of morbidity and mortality. METHODS The authors performed a secondary analysis of data obtained from a recently performed randomized clinical trial studying the effects of erythropoietin and blood transfusions on neurological recovery after severe TBI. Assigned hemoglobin thresholds (10 g/dl vs 7 g/dl) were maintained with packed red blood cell transfusions during the acute phase after injury. PHI was defined as the presence of new or enlarging intracranial hematomas on CT as long as 10 days after injury. A severe PHI was defined as an event that required an escalation of medical management or surgical intervention. Clinical and imaging parameters and transfusion thresholds were used in a multivariate Cox regression analysis to identify independent risk factors for PHI. RESULTS Among 200 patients enrolled in the trial, PHI was detected in 61 patients (30.5%). The majority of patients with PHI had a new, delayed contusion (n = 29) or an increase in contusion size (n = 15). The mean time interval between injury and identification of PHI was 17.2 +/- 15.8 hours. The adjusted risk of severe PHI was 2.3 times higher for patients with a transfusion threshold of 10 g/dl (95% confidence interval 1.1-4.7; p = 0.02). Diffuse brain injury was associated with a lower risk of PHI events, whereas higher initial intracranial pressure increased the risk of PHI (p < 0.001). PHI was associated with a longer median length of stay in the intensive care unit (18.3 vs 14.4 days, respectively; p = 0.04) and poorer Glasgow Outcome Scale scores (42.9% vs 25.5%, respectively; p = 0.02) at 6 months. CONCLUSIONS A higher transfusion threshold of 10 g/dl after severe TBI increased the risk of severe PHI events. These results indicate the potential adverse effect of using a higher hemoglobin transfusion threshold after severe TBI. PMID- 26943844 TI - Infraorbital nerve: a surgically relevant landmark for the pterygopalatine fossa, cavernous sinus, and anterolateral skull base in endoscopic transmaxillary approaches. AB - OBJECTIVE Endoscopic transmaxillary approaches (ETMAs) address pathology of the anterolateral skull base, including the cavernous sinus, pterygopalatine fossa, and infratemporal fossa. This anatomically complex region contains branches of the trigeminal nerve and external carotid artery and is in proximity to the internal carotid artery. The authors postulated, on the basis of intraoperative observations, that the infraorbital nerve (ION) is a useful surgical landmark for navigating this region; therefore, they studied the anatomy of the ION and its relationships to critical neurovascular structures and the maxillary nerve (V2) encountered in ETMAs. METHODS Endoscopic anatomical dissections were performed bilaterally in 5 silicone-injected, formalin-fixed cadaveric heads (10 sides). Endonasal transmaxillary and direct transmaxillary (Caldwell-Luc) approaches were performed, and anatomical correlations were analyzed and documented. Stereotactic imaging of each specimen was performed to correlate landmarks and enable precise measurement of each segment. RESULTS The ION was readily identified in the roof of the maxillary sinus at the beginning of the surgical procedure in all specimens. Anatomical dissections of the ION and the maxillary branch of the trigeminal nerve (V2) to the cavernous sinus suggested that the ION/V2 complex has 4 distinct segments that may have implications in endoscopic approaches: 1) Segment I, the cutaneous segment of the ION and its terminal branches (5-11 branches) to the face, distal to the infraorbital foramen; 2) Segment II, the orbitomaxillary segment of the ION within the infraorbital canal from the infraorbital foramen along the infraorbital groove (length 12 +/- 3.2 mm); 3) Segment III, the pterygopalatine segment within the pterygopalatine fossa, which starts at the infraorbital groove to the foramen rotundum (13 +/- 2.5 mm); and 4) Segment IV, the cavernous segment from the foramen rotundum to the trigeminal ganglion (15 +/- 4.1 mm), which passes in the lateral wall of the cavernous sinus. The relationship of the ION/V2 complex to the contents of the cavernous sinus, carotid artery, and pterygopalatine fossa is described in the text. CONCLUSIONS The ION/V2 complex is an easily identifiable and potentially useful surgical landmark to the foramen rotundum, cavernous sinus, carotid artery, pterygopalatine fossa, and anterolateral skull base during ETMAs. PMID- 26943845 TI - Ventricular catheter development: past, present, and future. AB - Cerebrospinal fluid diversion via ventricular shunting is the prevailing contemporary treatment for hydrocephalus. The CSF shunt appeared in its current form in the 1950s, and modern CSF shunts are the result of 6 decades of significant progress in neurosurgery and biomedical engineering. However, despite revolutionary advances in material science, computational design optimization, manufacturing, and sensors, the ventricular catheter (VC) component of CSF shunts today remains largely unchanged in its functionality and capabilities from its original design, even though VC obstruction remains a primary cause of shunt failure. The objective of this paper is to investigate the history of VCs, including successful and failed alterations in mechanical design and material composition, to better understand the challenges that hinder development of a more effective design. PMID- 26943846 TI - Transulcal parafascicular minimally invasive approach to deep and subcortical cavernomas: technical note. AB - Cavernomas comprise 8%-15% of intracranial vascular lesions, usually supratentorial in location and superficial. Cavernomas in the thalamus or subcortical white matter represent a unique challenge for surgeons in trying to identify and then use a safe corridor to access and resect the pathology. Previous authors have described specific open microsurgical corridors based on pathology location, often with technical difficulty and morbidity. This series presents 2 cavernomas that were resected using a minimally invasive approach that is less technically demanding and has a good safety profile. The authors report 2 cases of cavernoma: one in the thalamus and brainstem with multiple hemorrhages and the other in eloquent subcortical white matter. These lesions were resected through a transulcal parafascicular approach with a port-based minimally invasive technique. In this series there was complete resection with no neurological complications. The transulcal parafascicular minimally invasive approach relies on image interpretation and trajectory planning, intraoperative navigation, cortical cannulation and subcortical space access, high-quality optics, and resection as key elements to minimize exposure and retraction and maximize tissue preservation. The authors applied this technique to 2 patients with cavernomas in eloquent locations with excellent outcomes. PMID- 26943847 TI - Stereotactic radiosurgery for cerebral arteriovenous malformations: evaluation of long-term outcomes in a multicenter cohort. AB - OBJECTIVE In this multicenter study, the authors reviewed the results following Gamma Knife radiosurgery (GKRS) of cerebral arteriovenous malformations (AVMs), determined predictors of outcome, and assessed predictive value of commonly used grading scales based upon this large cohort with long-term follow-up. METHODS Data from a cohort of 2236 patients undergoing GKRS for cerebral AVMs were compiled from the International Gamma Knife Research Foundation. Favorable outcome was defined as AVM obliteration and no posttreatment hemorrhage or permanent symptomatic radiation-induced complications. Patient and AVM characteristics were assessed to determine predictors of outcome, and commonly used grading scales were assessed. RESULTS The mean maximum AVM diameter was 2.3 cm, with a mean volume of 4.3 cm3. A mean margin dose of 20.5 Gy was delivered. Mean follow-up was 7 years (range 1-20 years). Overall obliteration was 64.7%. Post-GRKS hemorrhage occurred in 165 patients (annual risk 1.1%). Radiation induced imaging changes occurred in 29.2%; 9.7% were symptomatic, and 2.7% had permanent deficits. Favorable outcome was achieved in 60.3% of patients. Patients with prior nidal embolization (OR 2.1, p < 0.001), prior AVM hemorrhage (OR 1.3, p = 0.007), eloquent location (OR 1.3, p = 0.029), higher volume (OR 1.01, p < 0.001), lower margin dose (OR 0.9, p < 0.001), and more isocenters (OR 1.1, p = 0.011) were more likely to have unfavorable outcomes in multivariate analysis. The Spetzler-Martin grade and radiosurgery-based AVM score predicted outcome, but the Virginia Radiosurgery AVM Scale provided the best assessment. CONCLUSIONS GKRS for cerebral AVMs achieves obliteration and avoids permanent complications in the majority of patients. Patient, AVM, and treatment parameters can be used to predict long-term outcomes following radiosurgery. PMID- 26943848 TI - The utility of a multimaterial 3D printed model for surgical planning of complex deformity of the skull base and craniovertebral junction. AB - Utilizing advanced 3D printing techniques, a multimaterial model was created for the surgical planning of a complex deformity of the skull base and craniovertebral junction. The model contained bone anatomy as well as vasculature and the previously placed occipital cervical instrumentation. Careful evaluation allowed for a unique preoperative perspective of the craniovertebral deformity and instrumentation options. This patient-specific model was invaluable in choosing the most effective approach and correction strategy, which was not readily apparent from standard 2D imaging. Advanced 3D multimaterial printing provides a cost-effective method of presurgical planning, which can also be used for both patient and resident education. PMID- 26943849 TI - Intraoperative middle cerebral artery pressure measurements during superficial temporal artery to middle cerebral artery bypass procedures in patients with cerebral atherosclerotic disease. AB - OBJECTIVE No previous study has monitored middle cerebral artery (MCA) pressure during the superficial temporal artery (STA)-MCA bypass procedure for cerebral atherosclerotic disease. In this paper, the authors describe their method of monitoring MCA pressure and report their initial data on intraoperative MCA pressure and its relationship with hemodynamics prior to and after the bypass procedures. METHODS The results from a total of 39 revascularization procedures performed between 2004 and 2014 were analyzed. The patient group included 27 men and 12 women, and their mean age at surgery was 67.6 years (range 39-83 years). The authors investigated the MCA pressure via the STA during STA-MCA bypass procedures. After one branch of the STA was anastomosed to the MCA, the other branch was connected to an arterial line, and a clip was placed temporally on the main STA trunk to monitor the pre-anastomosis MCA pressure. Simultaneously, the radial artery (RA) pressure was determined before removing the temporal clip to measure the post-anastomosis MCA pressure. The relationship between MCA pressures and single photon emission computed tomography findings and the risk factors for hyperperfusion after STA-MCA bypass were analyzed. RESULTS The MCA/RA (%) pressure was significantly correlated with that of the resting stenotic/normal side cerebral blood flow (CBF) ratio (%) in the linear regression analysis (slope 1.200, r2 = 0.3564, F = 20.49, p < 0.0001). The intraoperative MCA pressure was 39.3% of RA pressure in patients with Powers' Stage 2 cerebral atherosclerotic disease. After 1 branch of the STA was anastomosed, the intraoperative MCA pressure increased to 75.3% of the RA pressure. The rate of increase in pressure was significantly correlated with the increase in the STA diameter in the linear regression analysis (slope 2.59, r2 = 0.205, F = 9.549, p = 0.0038). Hyperperfusion occurred in 2 cases. When mean values for these 2 patients were compared with those for the 37 patients without hyperperfusion, significant differences were found in the stenotic/normal side CBF ratio (p = 0.0001), pre anastomosis MCA pressure (p = 0.02), rate of increase in pressure (p = 0.02), pre anastomotic MCA/RA pressure ratio (p = 0.01), vascular reserve (p = 0.0489), and STA diameter (p = 0.0002). CONCLUSIONS The measurement of intraoperative MCA pressure may be a useful technique to assess cerebral perfusion and for predicting the risk of hyperperfusion. Monitoring MCA pressure is recommended during STA-MCA bypass procedures for atherosclerotic disease. PMID- 26943852 TI - Role of Coherent Low-Frequency Motion in Excited-State Proton Transfer of Green Fluorescent Protein Studied by Time-Resolved Impulsive Stimulated Raman Spectroscopy. AB - Green fluorescent protein (GFP) from jellyfish Aequorea victoria, an essential bioimaging tool, luminesces via excited-state proton transfer (ESPT) in which the phenolic proton of the p-hydroxybenzylideneimidazolinone chromophore is transferred to Glu222 through a hydrogen-bond network. In this process, the ESPT mediated by the low-frequency motion of the chromophore has been proposed. We address this issue using femtosecond time-resolved impulsive stimulated Raman spectroscopy. After coherently exciting low-frequency modes (<300 cm(-1)) in the excited state of GFP, we examined the excited-state structural evolution and the ESPT dynamics within the dephasing time of the low-frequency vibration. A clear anharmonic vibrational coupling is found between one high-frequency mode of the chromophore (phenolic CH bend) and a low-frequency mode at ~104 cm(-1). However, the data show that this low-frequency motion does not substantially affect the ESPT dynamics. PMID- 26943851 TI - Which elderly newly diagnosed glioblastoma patients can benefit from radiotherapy and temozolomide? A PERNO prospective study. AB - The role of temozolomide concurrent with and adjuvant to radiotherapy (RT/TMZ) in elderly patients with glioblastoma (GBM) remains unclear. We evaluated the outcome of patients >70 years in the context of the Project of Emilia-Romagna Region in Neuro-Oncology (PERNO), the first Italian prospective observational population-based study in neuro-oncology. For this analysis the criteria for selecting patients enrolled in the PERNO study were: age >70 years; PS 0-3; histologically confirmed GBM; postoperative radiotherapy (RT) after surgery with or without concomitant temozolomide (TMZ) or postsurgical TMZ alone. Between January 2009 and December 2010, 76 GBM elderly patients were identified in the prospective PERNO study. Twenty-three patients did not receive any treatment after surgery, and 53 patients received postsurgical treatments (25 patients received RT alone and 28 patients RT/TMZ). Median survival was 11.1 months (95 % CI 8.8-13.5), adding temozolomide concomitant and adjuvant to radiotherapy it was 11.6 months (95 % CI 8.6-14.6), and 9.3 months (95 % CI 8.1-10.6) in patients treated with RT alone (P = 0.164). However, patients with MGMT methylated treated with RT/TMZ obtained a better survival (17.2 months, 95 % CI 11.5-22.9) (P = 0.042). No difference in terms of survival were observed if patients with MGMT unmethylated tumor received RT alone, or RT/TMZ or, in MGMT methylated tumor, if patients received radiotherapy alone. In elderly patients RT/TMZ represent a widely used approach but it is effective with methylated MGMT tumors only. PMID- 26943853 TI - Hypomethylation of repetitive elements in blood leukocyte DNA and risk of gastric lesions in a Chinese population. AB - BACKGROUND: To explore the association between hypomethylation of repetitive elements (LINE-1, Sat2, and ALU) in blood leukocyte DNA and risks of gastric lesions, and development of gastric cancer (GC), a population-based study was conducted in a high-risk area of GC in China. MATERIALS: Methylation levels were determined by MethyLight in 902 subjects with various gastric lesions from two cohort studies at baseline and 276 subjects with long-term follow-up data. RESULTS: The frequency of LINE-1 or Sat2 hypomethylation was significantly increased in subjects with dysplasia (DYS) compared with superficial gastritis/chronic atrophic gastritis. The odds ratios (ORs) were 2.22 [95% confidence interval (CI): 1.45-3.40] for LINE-1 and 1.58 (95% CI: 1.14-2.21) for Sat2. A dose-response pattern was found for the risk of DYS and LINE-1 hypomethylation (P-trend<0.001). Further stratified analysis indicated that the frequency of LINE-1 or Sat2 hypomethylation was higher in subjects with Helicobacter pylori infection. The ORs were 1.83 (95% CI: 1.12-2.99) for LINE-1 and 1.44 (95% CI: 1.01-2.05) for Sat2. The follow-up data indicated that the risk of progression to GC was increased in intestinal metaplasia (IM) subjects with LINE-1 hypomethylation (OR=2.82; 95% CI: 1.17-6.77) or Sat2 hypomethylation (OR=2.78; 95% CI: 1.15-6.74). The risk of progression to GC was also increased in DYS subjects with Sat2 hypomethylation (OR=5.24; 95% CI: 2.00-13.74). CONCLUSIONS: These findings suggest that hypomethylation of repetitive elements in blood leukocytes is associated with the risks of advanced gastric lesions and development of GC. PMID- 26943854 TI - Reduced incidence of skin cancer in patients with alopecia areata: A retrospective cohort study. AB - The risk of skin cancer in patients with alopecia areata (AA) is unknown. While the risk of skin cancer in chronic inflammatory alopecias may be elevated, AA shares many characteristics with vitiligo, an autoimmune illness associated with decreased risk of melanoma and non-melanoma skin cancers. In this retrospective cohort study, we determined the risk of developing skin cancer among patients with AA in a validated cohort relative to matched controls at two tertiary care hospitals in Massachusetts. There was a significantly decreased risk of NMSC in AA patients than controls (OR=0.63, 95% CI=0.48-0.81). There was a trend towards a protective effect of AA associated with melanoma (OR=0.65, 95% CI=0.39-1.09). There was no difference in anatomic distribution of skin cancer between patients with AA and controls. Our study demonstrates a decreased risk of nonmelanoma skin cancer and a trend towards reduced risk of melanoma in patients with AA. PMID- 26943850 TI - Comparative Developmental Transcriptomics Reveals Rewiring of a Highly Conserved Gene Regulatory Network during a Major Life History Switch in the Sea Urchin Genus Heliocidaris. AB - The ecologically significant shift in developmental strategy from planktotrophic (feeding) to lecithotrophic (nonfeeding) development in the sea urchin genus Heliocidaris is one of the most comprehensively studied life history transitions in any animal. Although the evolution of lecithotrophy involved substantial changes to larval development and morphology, it is not known to what extent changes in gene expression underlie the developmental differences between species, nor do we understand how these changes evolved within the context of the well-defined gene regulatory network (GRN) underlying sea urchin development. To address these questions, we used RNA-seq to measure expression dynamics across development in three species: the lecithotroph Heliocidaris erythrogramma, the closely related planktotroph H. tuberculata, and an outgroup planktotroph Lytechinus variegatus. Using well-established statistical methods, we developed a novel framework for identifying, quantifying, and polarizing evolutionary changes in gene expression profiles across the transcriptome and within the GRN. We found that major changes in gene expression profiles were more numerous during the evolution of lecithotrophy than during the persistence of planktotrophy, and that genes with derived expression profiles in the lecithotroph displayed specific characteristics as a group that are consistent with the dramatically altered developmental program in this species. Compared to the transcriptome, changes in gene expression profiles within the GRN were even more pronounced in the lecithotroph. We found evidence for conservation and likely divergence of particular GRN regulatory interactions in the lecithotroph, as well as significant changes in the expression of genes with known roles in larval skeletogenesis. We further use coexpression analysis to identify genes of unknown function that may contribute to both conserved and derived developmental traits between species. Collectively, our results indicate that distinct evolutionary processes operate on gene expression during periods of life history conservation and periods of life history divergence, and that this contrast is even more pronounced within the GRN than across the transcriptome as a whole. PMID- 26943870 TI - Thirty-day mortality after hip fractures: has anything changed? AB - Bone density insufficiency is the main cause for significant musculoskeletal trauma in the elderly population following low-energy falls. Hip fractures, in particular, represent an important public health concern taking into account the complicated needs of the patients due to their medical comorbidities as well as their rehabilitation and social demands. The annual cost for the care of these patients is estimated at around 2 billion pounds (L) in the UK and is ever growing. An increased early and late mortality rate is also recognised in these injuries together with significant adversities for the patients. Lately, in order to improve the outcomes of this special cohort of patients, fast-track care pathways and government initiatives have been implemented. It appears that these measures have contributed in a steady year-by-year reduction of the 30-day mortality rates. Whether we have currently reached a plateau or whether an ongoing reduction in mortality rates will continue to be observed is yet to be seen. PMID- 26943871 TI - Clinical outcomes of two minimally invasive transforaminal lumbar interbody fusion (TLIF) for lumbar degenerative diseases. AB - BACKGROUND: There are two modified TLIF, including MIS-TLIF and TLIF through Wiltse approach (W-TLIF). Although both of the two minimally invasive surgical procedures can be effective in the treatment for lumbar degenerative diseases, no comparative analysis has been made so far regarding their clinical outcomes. OBJECTIVE: To compare the clinical outcomes of MIS-TLIF and W-TLIF for the treatment for single-segment degenerative lumbar diseases. METHODS: Ninety-seven patients with single-segment degenerative lumbar disorders were included in this study. Forty-seven underwent MIS-TLIF surgery (group A). For group B, fifty patients underwent W-TLIF. The Japanese Orthopedic Association (JOA) score, the visual analog scale (VAS) of low back pain (LBP) and leg pain, MRI score and atrophy rate of CSA, interbody fusion rate were assessed during the postoperative follow-up. RESULTS: Incision length, blood loss, operative time, CPK, and postoperative incision pain VAS were better in group A (P < 0.05). The seconds of intraoperative fluoroscopy in groups A and B were 76 +/- 9 and 7 +/- 2, respectively (P < 0.05). In group B, The blood loss and CPK at L5-S1 were significantly higher than those at L4-5. Postoperative JOA scores, VAS of leg pain, and fusion rate were statistically the same between the two groups. VAS of LBP, MRI score, and atrophy rate of CSA was better in group A than in group B (P < 0.05). CONCLUSION: Both methods are effective in the treatment for lumbar degenerative disease. MIS-TLIF has less blood loss, shorter surgical incision, and less lower postoperative back pain, while W-TLIF is less expensive for hospital stay with lower exposure to X-rays. PMID- 26943872 TI - Atypical femur fractures in patients receiving bisphosphonate therapy: etiology and management. AB - Osteoporosis is a growing problem that is projected to affect more than 50% of American adults by 2020. Bisphosphonate therapy is currently the primary mode of treating osteoporosis in this population. While bisphosphonate therapy has been successful in increasing bone mineral density, data has shown an increased risk of atypical femur fractures with prolonged therapy. Atypical femur fractures are characterized by low-energy or atraumatic injuries that occur in the subtrochanteric region. They originate on the medial cortex, travel transversely, and typically have little or no comminution. Conservative therapy is indicated for patients with incomplete fractures without prodromal symptoms. Patients with incomplete fractures and significant prodromal symptoms or visible fracture line on radiographs, those who have failed conservative management, and those with complete fractures should be treated with intramedullary nail fixation. Evaluation should involve imaging of the contralateral femur. Teriparatide therapy may be considered for patients without contraindications. While the incidence of these fractures is low, it is likely that these rates will increase with the aging population and increased prevalence of patients being treated with bisphosphonate therapy. PMID- 26943873 TI - Occurrence, removal and risk assessment of pharmaceutical and personal care products (PPCPs) in an advanced drinking water treatment plant (ADWTP) around Taihu Lake in China. AB - The occurrence and removal of 39 selected pharmaceutical and personal care products (PPCPs) were investigated in an advanced drinking water treatment plant (ADWTP) around Taihu Lake. Fourteen of 39 targeted pharmaceuticals were detected in the raw water. After a series of purification processes, only indomethacin, caffeine and sulfamethoxazole were found in effluent, albeit at concentrations less than 2 ng L(-1). The results of principal component analysis suggested that three main purification processes, oxidation, coagulation combined with sedimentation and filtration combined with bio-degradation, influenced the removal performance of PPCPs. The ecotoxicological and human health risk assessment confirmed that drugs detected in effluent posed no potential toxicity and also suggested that two PPCPs (roxithromycin and sulfamethoxazole), especially sulfamethoxazole, should be seriously considered as candidates for regulatory monitoring and prioritization. Finally, the correlation between removal efficiency and risk quotient indicated that uniform removal efficiency for all PPCPs may not reflect an equal risk control in the ADWTP. PMID- 26943874 TI - Exposure to2,2',4,4'-tetrabromodiphenyl ether (BDE-47) alters thyroid hormone levels and thyroid hormone-regulated gene transcription in manila clam Ruditapes philippinarum. AB - Polybrominated diphenyl ethers (PBDEs) have the potential to disturb the thyroid endocrine system in vertebrates, but little is known about the disruptive effects of PBDEs on marine bivalves. In this study, we first examined the effects of BDE 47 exposure on growth of juvenile manila clams Ruditapes philippinarum. The result showed that 1.0 and 10 MUg L(-1) BDE-47 had adverse effects on 14-d shell length growth of juvenile clams. Then, one-year-old adult clams were exposed to 0, 0.1 and 1 MUg L(-1) BDE-47 for 15 d. BDE-47 (1 MUg L(-1)) exposure caused significant decreases of total T4 (thyroxine) by 40% and T3 (3,5,3' triiodothyronine) by 75% concentrations in haemolymph of the clams. Transcription of genes involved in thyroid hormone synthesis and metabolism were also studied by quantitative RT-PCR. Gene expression levels of sodium iodide symporter (rp NIS), iodothyronine deiodinase (rp-Deio) and thyroid peroxidase (rp-TPO) were increased in a dose-dependent manner at day 5 and day 10, while monocarboxylate transporter 8 (rp-Mct8) was downregulated at day 5, day 10 and day 15. The effect and preliminary mechanism observed in the present study were consistent with the results from previous studies on rodent and fish, implying that exposure to BDE 47 may pose threat to thyroid hormone homeostasis in bivalves through thyroid synthesis and metabolism pathways. This study may provide a first step towards understanding of the thyroid function disruptive effects of PBDEs on marine bivalves and the underlying mechanism across taxonomic groups and phyla. PMID- 26943881 TI - Characterization of the microbunch time structure of proton pencil beams at a clinical treatment facility. AB - Proton therapy is an advantageous treatment modality compared to conventional radiotherapy. In contrast to photons, charged particles have a finite range and can thus spare organs at risk. Additionally, the increased ionization density in the so-called Bragg peak close to the particle range can be utilized for maximum dose deposition in the tumour volume. Unfortunately, the accuracy of the therapy can be affected by range uncertainties, which have to be covered by additional safety margins around the treatment volume. A real-time range and dose verification is therefore highly desired and would be key to exploit the major advantages of proton therapy. Prompt gamma rays, produced in nuclear reactions between projectile and target nuclei, can be used to measure the proton's range. The prompt gamma-ray timing (PGT) method aims at obtaining this information by determining the gamma-ray emission time along the proton path using a conventional time-of-flight detector setup. First tests at a clinical accelerator have shown the feasibility to observe range shifts of about 5 mm at clinically relevant doses. However, PGT spectra are smeared out by the bunch time spread. Additionally, accelerator related proton bunch drifts against the radio frequency have been detected, preventing a potential range verification. At OncoRay, first experiments using a proton bunch monitor (PBM) at a clinical pencil beam have been conducted. Elastic proton scattering at a hydrogen-containing foil could be utilized to create a coincident proton-proton signal in two identical PBMs. The selection of coincident events helped to suppress uncorrelated background. The PBM setup was used as time reference for a PGT detector to correct for potential bunch drifts. Furthermore, the corrected PGT data were used to image an inhomogeneous phantom. In a further systematic measurement campaign, the bunch time spread and the proton transmission rate were measured for several beam energies between 69 and 225 MeV as well as for variable momentum limiting slit openings. We conclude that the usage of a PBM increases the robustness of the PGT method in clinical conditions and that the obtained data will help to create reliable range verification procedures in clinical routine. PMID- 26943883 TI - Computational Study of Fluorinated Diglyoxime-Iron Complexes: Tuning the Electrocatalytic Pathways for Hydrogen Evolution. AB - The ability to tune the properties of hydrogen-evolving molecular electrocatalysts is important for developing alternative energy sources. Fluorinated diglyoxime-iron complexes have been shown to evolve hydrogen at moderate overpotentials. Herein two such complexes, [(dAr(F)gBF2)2Fe(py)2], denoted A, and [(dAr(F)g2H-BF2)Fe(py)2], denoted B [dAr(F)g = bis(pentafluorophenyl-glyoximato); py = pyridine], are investigated with density functional theory calculations. B differs from A in that one BF2 bridge is replaced by a proton bridge of the form O-H-O. According to the calculations, the catalytic pathway for A involves two consecutive reduction steps, followed by protonation of an Fe(0) species to generate the active Fe(II)-hydride species. B is found to proceed via two parallel pathways, where one pathway is similar to that for A, and the additional pathway arises from protonation of the O-H-O bridge, followed by spontaneous reduction to an Fe(0) intermediate and intramolecular proton transfer from the ligand to the metal center or protonation by external acid to form the same active Fe(II)-hydride species. Simulated cyclic voltammograms (CVs) based on these mechanisms are in qualitative agreement with experimental CVs. The two parallel pathways identified for B arise from an equilibrium between the protonated and unprotonated ligand and result in two catalytic peaks in the CVs. The calculations predict that the relative probabilities for the two pathways, and therefore the relative magnitudes of the catalytic peaks, could be tuned by altering the pK(a) of the acid or the substituents on the ligands of the electrocatalyst. The ability to control the catalytic pathways through acid strength or ligand substituents is critical for designing more effective catalysts for energy conversion processes. PMID- 26943882 TI - Assessing the Potential for Drug-Nanoparticle Surface Interactions To Improve Drug Penetration into the Skin. AB - There is continued debate as to how nanomaterials enhance the passive diffusion of drugs through the skin. This study examined if drug-nanoparticle surface interactions, which occurred during topical application, had the capability to enhance percutaneous penetration. Atomic force microscopy force adhesion measurements were used to demonstrate that a model drug, tetracaine, strongly adsorbed to the surface of a negatively charged carboxyl-modified polystyrene nanoparticle (NanoPSCOOH) through both its methyl and amine functionalities (up to a 6- and 16-fold greater adhesion force respectively compared with the CH3-CH3 control). These drug-particle adhesion forces were significantly reduced (p < 0.05) to values that were lower than the CH3-CH3 control measurements when tetracaine interacted with a silica nanoparticle (NanoSiO2). This reduction in adhesion was attributed to the lower surface charge of the NanoSiO2 (ca. -23 mV) compared to the NanoPSCOOH (ca. -40 mV), which diminished the electrostatic interactions between positive amine of tetracaine and the negative particle. Mixing NanoPSCOOH with tetracaine on the skin retarded percutaneous drug penetration compared to the control (tetracaine saturated solution without nanoparticles), but the NanoSiO2, which still adsorbed the tetracaine, produced a 3.6-fold enhancement in percutaneous penetration compared to the same control. These data demonstrated the capability of moderate nanoparticle surface interactions that occurred within the application vehicle to promote drug percutaneous penetration. PMID- 26943884 TI - New Approach for Treatment of Primary Liver Tumors: The Role of Quercetin. AB - Hepatocellular carcinoma (HCC) is the most common primary liver tumor (PLT), with cholangiocarcinoma (CC) being the second most frequent. Glucose transporter 1 (GLUT-1) expression is increased in PLTs and therefore it is suggested as a therapeutic target. Flavonoids, like quercetin, are GLUT-1 competitive inhibitors and may be considered as potential therapeutic agents for PLTs. The objective of this study was evaluation of quercetin anticancer activity in three human HCC cell lines (HepG2, HuH7, and Hep3B2.1-7) and in a human CC cell line (TFK-1). The possible synergistic effect between quercetin and sorafenib, a nonspecific multikinase inhibitor used in clinical practice in patients with advanced HCC, was also evaluated. It was found that in all the cell lines, quercetin induced inhibition of the metabolic activity and cell death by apoptosis, followed by increase in BAX/BCL-2 ratio. Treatment with quercetin caused DNA damage in HepG2, Hep3B2.1-7, and TFK-1 cell lines. The effect of quercetin appears to be independent of P53. Incubation with quercetin induced an increase in GLUT-1 membrane expression and a consequent reduction in the cytoplasmic fraction, observed as a decrease in (18)F-FDG uptake, indicating a GLUT-1 competitive inhibition. The occurrence of synergy when sorafenib and quercetin were added simultaneously to HCC cell lines was noticed. Thus, the use of quercetin seems to be a promising approach for PLTs through GLUT-1 competitive inhibition. PMID- 26943894 TI - Creating Reversible p-n Junction on Graphene through Ferritin Adsorption. AB - An alternative way to construct a stable p-n junction on graphene-based field effect transistor (G-FET) through physical adsorption of ferritin (spherical protein shell) is presented. The produced p-n junction on G-FET could also operate through water-gate. Native ferritins are known to be negatively charged in wet condition; however, we found that native negatively charged ferritins became positively charged after performing electron beam (EB)-irradiation. We utilized this property to construct p-n junction on G-FET. We found also that EB irradiation could remove the effect of charged impurity adsorbed on graphene layer, thus the Dirac point was adjusted to gate voltage Vg = 0. PMID- 26943895 TI - Nanopharmaceutical approach using pelargonidin towards enhancement of efficacy for prevention of alloxan-induced DNA damage in L6 cells via activation of PARP and p53. AB - Alloxan is an environmental food contaminant that causes DNA damage in living cells and induces hyperglycemia. Pelargonidin (PG), an active ingredient found in extract of various fruits and vegetables, has been nanoencapsulated (NPG) with poly-lactide-co-glycolide (PLGA) and tested for efficacy in prevention of alloxan (ALX)-induced DNA damage in L6 cells in vitro. Glucose uptake, reactive oxygen species (ROS) generation, glucose transporter 4, glucokinase levels and mechanism of activation of DNA repair proteins (PARP and p53) have been studied in ALX induced L6 cells. Drug-DNA interaction has been analyzed using calf thymus DNA as target through circular dichroism and melting temperature profile. NPGs were physico-chemically characterized by standard protocols using dynamic light scattering and transmission electron microscopy. Pre-treatment with both PG and/or NPG was effective in reducing ALX-induced oxidative stress and showed favourable effects for protection against DNA damage by activating DNA repair cascades. Results suggested ~10-fold increase in efficacy of NPG than PG in prevention of alloxan-induced oxidative stress and DNA damage. PMID- 26943896 TI - Effects of maternal exposure to di-n-butyl phthalate during pregnancy and breastfeeding on ovarian development and function of F1 female rats. AB - This study aimed to investigate the effects of maternal exposure to di-n-butyl phthalate (DBP) during pregnancy and breastfeeding on F1 ovarian development and function. A rat model of maternal exposure to DBP during pregnancy and breastfeeding was established by gavage feeding female Sprague Dawley rats with 0, 10, 100, or 600mg/kg/day DBP from gestational day (GD) 12 to postnatal day (PND) 21. F1 offspring were weaned on PND21 and were not exposed to DBP afterward. The age of vaginal opening and estrus onset, estrous cyclicity, c-Kit ligand expression on ovarian granulosa cells, and the weight of ovaries and uterus of F1 female offspring were not affected, whereas serum levels of estradiol and progesterone were increased significantly by maternal exposure to 10mg/kg/day DBP from GD12 to PND21. Although F1 ovarian function may not be adversely affected by maternal exposure to DBP, the increased reproductive hormone levels may interfere in F1 rat fertility. PMID- 26943897 TI - Identification of a Novel CRF01_AE/CRF07_BC Recombinant Form in Men Who Have Sex with Men in Sichuan, China. AB - A novel second-generation CCR5-tropic HIV-1 recombinant virus (XC2014EU09) was identified here, which was isolated from a HIV-positive man who had sex with men (MSM) in Sichuan, China. Phylogenic analyses showed that XC2014EU09 was composed of two well-established circulating recombinant forms (CRF01_AE and CRF07_BC). Different from the other four reported CRF01_AE/CRF07_BC recombinant forms, three recombinant breakpoints of XC2014EU09 with four fragments were observed in the vpr, env, and nef genes, respectively, as follows: ICRF01_AE (636-5,843 nt), IICRF07_BC (5,844-8,393 nt), IIICRF01_AE (8,394-9,119 nt), and IVCRF07_BC (9,120 9,600 nt). The emergence of CRF01_AE/CRF07_BC recombinant strain indicates the increasing complexity of the HIV-1 epidemic among the MSM group in China. PMID- 26943898 TI - Corrigendum: Hinge-like structure induced unusual properties of black phosphorus and new strategies to improve the thermoelectric performance. PMID- 26943899 TI - Registered report: The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2 hydroxyglutarate. AB - The Reproducibility Project: Cancer Biology seeks to address growing concerns about reproducibility in scientific research by conducting replications of selected experiments from a number of high-profile papers in the field of cancer biology. The papers, which were published between 2010 and 2012, were selected on the basis of citations and Altmetric scores (Errington et al., 2014). This Registered Report describes the proposed replication plan of key experiments from "The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate" by Ward and colleagues, published in Cancer Cell in 2010 (Ward et al., 2010). The experiments that will be replicated are those reported in Figures 2, 3 and 5. Ward and colleagues demonstrate the mutations in isocitrate dehydrogenase 2 (IDH2), commonly found in acute myeloid leukemia (AML), abrogate the enzyme's wild-type activity and confer to the mutant neomorphic activity that produces the oncometabolite 2-hydroxyglutarate (2-HG) (Figures 2 and 3). They then show that elevated levels of 2-HG are correlated with mutations in IDH1 and IDH2 in AML patient samples (Figure 5). The Reproducibility Project: Cancer Biology is a collaboration between the Center for Open Science and Science Exchange and the results of the replications will be published by eLife. PMID- 26943900 TI - Registered report: Coding-independent regulation of the tumor suppressor PTEN by competing endogenous mRNAs. AB - The Reproducibility Project: Cancer Biology seeks to address growing concerns about reproducibility in scientific research by conducting replications of selected experiments from a number of high-profile papers in the field of cancer biology. The papers, which were published between 2010 and 2012, were selected on the basis of citations and Altmetric scores (Errington et al., 2014). This Registered Report describes the proposed replication plan of key experiments from "Coding-Independent Regulation of the Tumor Suppressor PTEN by Competing Endogenous 'mRNAs' by Tay and colleagues, published in Cell in 2011 (Tay et al., 2011). The experiments to be replicated are those reported in Figures 3C, 3D, 3G, 3H, 5A and 5B, and in Supplemental Figures 3A and B. Tay and colleagues proposed a new regulatory mechanism based on competing endogenous RNAs (ceRNAs), which regulate target genes by competitive binding of shared microRNAs. They test their model by identifying and confirming ceRNAs that target PTEN. In Figure 3A and B, they report that perturbing expression of putative PTEN ceRNAs affects expression of PTEN. This effect is dependent on functional microRNA machinery (Figure 3G and H), and affects the pathway downstream of PTEN itself (Figures 5A and B). The Reproducibility Project: Cancer Biology is a collaboration between the Center for Open Science and Science Exchange, and the results of the replications will be published by eLife. PMID- 26943902 TI - Reconstruction of bremsstrahlung spectra from attenuation data using generalized simulated annealing. AB - A generalized simulated annealing algorithm, combined with a suitable smoothing regularization function is used to solve the inverse problem of X-ray spectrum reconstruction from attenuation data. The approach is to set the initial acceptance and visitation temperatures and to standardize the terms of objective function to automate the algorithm to accommodate different spectra ranges. Experiments with both numerical and measured attenuation data are presented. Results show that the algorithm reconstructs spectra shapes accurately. It should be noted that in this algorithm, the regularization function was formulated to guarantee a smooth spectrum, thus, the presented technique does not apply to X ray spectrum where characteristic radiation are present. PMID- 26943903 TI - Visible to infrared low temperature photoluminescence of rare earth doped bismuth germanate crystals. AB - In this paper, the influence of a series of rare earth (Eu, Tm, Nd) and Cr ion doping on the optical properties of BGO was investigated by means of photoluminescence (PL) from visible to IR region in the 10-300K temperature range using different types of detectors, namely, photomultiplier tube (PMT), InGaAs (IGA), and Si. Several samples were investigated having dopants concentrations of 0.3wt%Nd, 0.4wt%Tm, 0.06wt% Cr and 3ppm Eu. The PL spectra of the samples showed different luminescence behaviour which is assigned to the 4f intra shell transition from rare earth ions. The temperature dependence of the PL from rare earth doped BGO crystals is also examined. PMID- 26943901 TI - Development and Feasibility Testing of a Critical Care EEG Monitoring Database for Standardized Clinical Reporting and Multicenter Collaborative Research. AB - PURPOSE: The rapid expansion of the use of continuous critical care electroencephalogram (cEEG) monitoring and resulting multicenter research studies through the Critical Care EEG Monitoring Research Consortium has created the need for a collaborative data sharing mechanism and repository. The authors describe the development of a research database incorporating the American Clinical Neurophysiology Society standardized terminology for critical care EEG monitoring. The database includes flexible report generation tools that allow for daily clinical use. METHODS: Key clinical and research variables were incorporated into a Microsoft Access database. To assess its utility for multicenter research data collection, the authors performed a 21-center feasibility study in which each center entered data from 12 consecutive intensive care unit monitoring patients. To assess its utility as a clinical report generating tool, three large volume centers used it to generate daily clinical critical care EEG reports. RESULTS: A total of 280 subjects were enrolled in the multicenter feasibility study. The duration of recording (median, 25.5 hours) varied significantly between the centers. The incidence of seizure (17.6%), periodic/rhythmic discharges (35.7%), and interictal epileptiform discharges (11.8%) was similar to previous studies. The database was used as a clinical reporting tool by 3 centers that entered a total of 3,144 unique patients covering 6,665 recording days. CONCLUSIONS: The Critical Care EEG Monitoring Research Consortium database has been successfully developed and implemented with a dual role as a collaborative research platform and a clinical reporting tool. It is now available for public download to be used as a clinical data repository and report generating tool. PMID- 26943904 TI - Multiple detectors "Influence Method". AB - The "Influence Method" is conceived for the absolute determination of a nuclear particle flux in the absence of known detector efficiency and without the need to register coincidences of any kind. This method exploits the influence of the presence of one detector in the count rate of another detector, when they are placed one behind the other and define statistical estimators for the absolute number of incident particles and for the efficiency (Rios and Mayer, 2015a). Its detailed mathematical description was recently published (Rios and Mayer, 2015b) and its practical implementation in the measurement of a moderated neutron flux arising from an isotopic neutron source was exemplified in (Rios and Mayer, 2016). With the objective of further reducing the measurement uncertainties, in this article we extend the method for the case of multiple detectors placed one behind the other. The new estimators for the number of particles and the detection efficiency are herein derived. PMID- 26943905 TI - Fluorescence Visualization of the Enteric Nervous Network in a Chemically Induced Aganglionosis Model. AB - Gastrointestinal motility disorders, severe variants in particular, remain a therapeutic challenge in pediatric surgery. Absence of enteric ganglion cells that originate from neural crest cells is a major cause of dysmotility. However, the limitations of currently available animal models of dysmotility continue to impede the development of new therapeutics. Indeed, the short lifespan and/or poor penetrance of existing genetic models of dysmotility prohibit the functional evaluation of promising approaches, such as stem cell replacement strategy. Here, we induced an aganglionosis model using topical benzalkonium chloride in a P0 Cre/GFP transgenic mouse in which the neural crest lineage is labeled by green fluorescence. Pathological abnormalities and functional changes in the gastrointestinal tract were evaluated 2-8 weeks after chemical injury. Laparotomy combined with fluorescence microscopy allowed direct visualization of the enteric neural network in vivo. Immunohistochemical evaluation further confirmed the irreversible disappearance of ganglion cells, glial cells, and interstitial cell of Cajal. Remaining stool weight and bead expulsion time in particular supported the pathophysiological relevance of this chemically-induced model of aganglionosis. Interestingly, we show that chemical ablation of enteric ganglion cells is associated with a long lifespan. By combining genetic labeling of neural crest derivatives and chemical ablation of enteric ganglion cells, we developed a newly customized model of aganglionosis. Our results indicate that this aganglionosis model exhibits decreased gastrointestinal motility and shows sufficient survival for functional evaluation. This model may prove useful for the development of future therapies against motility disorders. PMID- 26943906 TI - Three Recombinant Engineered Antibodies against Recombinant Tags with High Affinity and Specificity. AB - We describe three recombinant engineered antibodies against three recombinant epitope tags, constructed with divalent binding arms to recognize divalent epitopes and so achieve high affinity and specificity. In two versions, an epitope is inserted in tandem into a protein of interest, and a homodimeric antibody is constructed by fusing a high-affinity epitope-binding domain to a human or mouse Fc domain. In a third, a heterodimeric antibody is constructed by fusing two different epitope-binding domains which target two different binding sites in GFP, to polarized Fc fragments. These antibody/epitope pairs have affinities in the low picomolar range and are useful tools for many antibody based applications. PMID- 26943908 TI - Burkholderia pseudomallei Colony Morphotypes Show a Synchronized Metabolic Pattern after Acute Infection. AB - BACKGROUND: Burkholderia pseudomallei is a water and soil bacterium and the causative agent of melioidosis. A characteristic feature of this bacterium is the formation of different colony morphologies which can be isolated from environmental samples as well as from clinical samples, but can also be induced in vitro. Previous studies indicate that morphotypes can differ in a number of characteristics such as resistance to oxidative stress, cellular adhesion and intracellular replication. Yet the metabolic features of B. pseudomallei and its different morphotypes have not been examined in detail so far. Therefore, this study aimed to characterize the exometabolome of B. pseudomallei morphotypes and the impact of acute infection on their metabolic characteristics. METHODS AND PRINCIPAL FINDINGS: We applied nuclear magnetic resonance spectroscopy (1H-NMR) in a metabolic footprint approach to compare nutrition uptake and metabolite secretion of starvation induced morphotypes of the B. pseudomallei strains K96243 and E8. We observed gluconate production and uptake in all morphotype cultures. Our study also revealed that among all morphotypes amino acids could be classified with regard to their fast and slow consumption. In addition to these shared metabolic features, the morphotypes varied highly in amino acid uptake profiles, secretion of branched chain amino acid metabolites and carbon utilization. After intracellular passage in vitro or murine acute infection in vivo, we observed a switch of the various morphotypes towards a single morphotype and a synchronization of nutrient uptake and metabolite secretion. CONCLUSION: To our knowledge, this study provides first insights into the basic metabolism of B. pseudomallei and its colony morphotypes. Furthermore, our data suggest, that acute infection leads to the synchronization of B. pseudomallei colony morphology and metabolism through yet unknown host signals and bacterial mechanisms. PMID- 26943907 TI - The Curcumin Analog C-150, Influencing NF-kappaB, UPR and Akt/Notch Pathways Has Potent Anticancer Activity In Vitro and In Vivo. AB - C-150 a Mannich-type curcumin derivative, exhibited pronounced cytotoxic effects against eight glioma cell lines at micromolar concentrations. Inhibition of cell proliferation by C-150 was mediated by affecting multiple targets as confirmed at transcription and protein level. C-150 effectively reduced the transcription activation of NFkB, inhibited PKC-alpha which are constitutively over-expressed in glioblastoma. The effects of C-150 on the Akt/ Notch signaling were also demonstrated in a Drosophila tumorigenesis model. C-150 reduced the number of tumors in Drosophila with similar efficacy to mitoxantrone. In an in vivo orthotopic glioma model, C-150 significantly increased the median survival of treated nude rats compared to control animals. The multi-target action of C-150, and its preliminary in vivo efficacy would render this curcumin analogue as a potent clinical candidate against glioblastoma. PMID- 26943909 TI - Analysing How People Orient to and Spread Rumours in Social Media by Looking at Conversational Threads. AB - As breaking news unfolds people increasingly rely on social media to stay abreast of the latest updates. The use of social media in such situations comes with the caveat that new information being released piecemeal may encourage rumours, many of which remain unverified long after their point of release. Little is known, however, about the dynamics of the life cycle of a social media rumour. In this paper we present a methodology that has enabled us to collect, identify and annotate a dataset of 330 rumour threads (4,842 tweets) associated with 9 newsworthy events. We analyse this dataset to understand how users spread, support, or deny rumours that are later proven true or false, by distinguishing two levels of status in a rumour life cycle i.e., before and after its veracity status is resolved. The identification of rumours associated with each event, as well as the tweet that resolved each rumour as true or false, was performed by journalist members of the research team who tracked the events in real time. Our study shows that rumours that are ultimately proven true tend to be resolved faster than those that turn out to be false. Whilst one can readily see users denying rumours once they have been debunked, users appear to be less capable of distinguishing true from false rumours when their veracity remains in question. In fact, we show that the prevalent tendency for users is to support every unverified rumour. We also analyse the role of different types of users, finding that highly reputable users such as news organisations endeavour to post well grounded statements, which appear to be certain and accompanied by evidence. Nevertheless, these often prove to be unverified pieces of information that give rise to false rumours. Our study reinforces the need for developing robust machine learning techniques that can provide assistance in real time for assessing the veracity of rumours. The findings of our study provide useful insights for achieving this aim. PMID- 26943910 TI - A Current Perspective on the Historical Geographic Distribution of the Endangered Muriquis (Brachyteles spp.): Implications for Conservation. AB - The muriqui (Brachyteles spp.), endemic to the Atlantic Forest of Brazil, is the largest primate in South America and is endangered, mainly due to habitat loss. Its distribution limits are still uncertain and need to be resolved in order to determine their true conservation status. Species distribution modeling (SDM) has been used to estimate potential species distributions, even when information is incomplete. Here, we developed an environmental suitability model for the two endangered species of muriqui (Brachyteles hypoxanthus and B. arachnoides) using Maxent software. Due to historical absence of muriquis, areas with predicted high habitat suitability yet historically never occupied, were excluded from the predicted historical distribution. Combining that information with the model, it is evident that rivers are potential dispersal barriers for the muriquis. Moreover, although the two species are environmentally separated in a large part of its distribution, there is a potential contact zone where the species apparently do not overlap. This separation might be due to either a physical (i.e., Serra da Mantiqueira mountains) or a biotic barrier (the species exclude one another). Therefore, in addition to environmental characteristics, physical and biotic barriers potentially shaped the limits of the muriqui historical range. Based on these considerations, we proposed the adjustment of their historical distributional limits. Currently only 7.6% of the predicted historical distribution of B. hypoxanthus and 12.9% of B. arachnoides remains forested and able to sustain viable muriqui populations. In addition to measurement of habitat loss we also identified areas for conservation concern where new muriqui populations might be found. PMID- 26943911 TI - Semiquantitative assessment of optic nerve injury using manganese-enhanced MRI. AB - OBJECTIVE: To evaluate the capability of manganese (Mn(2+))-enhanced MRI (MEMRI) in a continuously semiquantitative assessment of rat optic nerve (ON) injury. METHODS: Forty rats were divided into three groups: (I) a control group that was submitted to MEMRI or to fluorescent labeling of retinal ganglion cells (RGCs) (n = 10); (II) an ON injury group that was submitted to MEMRI (n = 15); (III) an ON injury group that was submitted to fluorescent labeling of RGCs (n = 15). Groups II and III were examined at 3, 7, and 14 days post-lesion (dpl), when the contrast-to-noise ratio (CNR) of the retina and ON was measured on MEMRI images and the RGCs were counted by fluorescence microscopy and compared between the groups. RESULTS: In the control group, the intact visual pathway from the retina to the contralateral superior colliculus was visualized by MEMRI. In group II, continuous Mn(2+) enhancement was seen from the retina to the lesion site of the optic nerves at 3, 7, and 14 dpl. However, no Mn(2+) enhancement was observed distal to the lesion site at those time points. The observed Mn(2+) enhancement proximal to the ON lesion site declined between 7 and 14 dpl. The decrease in Mn(2+)-enhanced signal intensity at these sites at 7 and 14 dpl when compared to that at 3 dpl was significant (P < 0.05). The RGC density dropped by 6.84, 45.31, and 72.36 % at 3, 7, and 14 dpl, respectively. CONCLUSION: MEMRI can be used to evaluate the structural changes after optic nerve injury. PMID- 26943913 TI - Intratumoral estrogen production and actions in luminal A type invasive lobular and ductal carcinomas. AB - The great majority of invasive lobular carcinoma (ILC) is estrogen-dependent luminal A type carcinoma but the details of estrogen actions and its intratumoral metabolism have not been well studied compared to invasive ductal carcinoma (IDC). We first immunolocalized estrogen-related enzymes including estrogen sulfotransferase (EST), estrogen sulfatase (STS), 17beta-hydroxysteroid dehydrogenase (HSD) 1/2, and aromatase. We then evaluated the tissue concentrations of estrogens in ILC and IDC and subsequently estrogen-responsive gene profiles in these tumors in order to explore the possible differences and/or similarity of intratumoral estrogen environment of these two breast cancer subtypes. The status of STS and 17betaHSD1 was significantly lower in ILCs than IDCs (p = 0.022 and p < 0.0001), but that of EST and 17betaHSD2 vice versa (p < 0.0001 and p = 0.0106). In ILCs, tissue concentrations of estrone and estradiol were lower than those in IDCs (p = 0.0709 and 0.069). In addition, the great majority of estrogen response genes tended to be lower in ILCs. Among those genes above, FOXP1 was significantly higher in ILCs than in IDCs (p = 0.002). FOXP1 expression was reported to be significantly higher in relapse-free IDC patients treated with tamoxifen. Therefore, tamoxifen may be considered an option of endocrine therapy for luminal A type ILC patients. This is the first study to demonstrate the detailed and comprehensive status of intratumoral production and metabolism of estrogens and the status of estrogen response genes in luminal A like ILC with comparison to those in luminal A-like IDCs. PMID- 26943912 TI - DPPIV/CD26: a tumor suppressor or a marker of malignancy? AB - Dipeptidyl peptidase IV (DPPIV/CD26) is a multifunctional protein with intrinsic peptidase activity that inactivates or degrades some bioactive peptides. It is the main cellular binding protein for ecto-adenosine deaminase and interacts with extracellular matrix proteins, besides participating in different signaling pathways. Due to these multiple functions, DPPIV/CD26 has been shown to be closely related to the tumor process. It has been reported that the progression of certain types of cancer is accompanied by a decrease in DPPIV/CD26 expression, and studies have shown that the malignant phenotype can be reverted when DPPIV/CD26 expression is induced in these cancer cells, characterizing this protein as a tumor suppressor. On the other hand, DPPIV/CD26 was described as a protein associated with invasion and metastatic spread, characterizing it as a marker of malignancy. Thus, this review explores the roles of DPPIV/CD26 expression in tumor progression in different types of cancer and demonstrates the importance of this protein as a promising therapeutic target and tumor biomarker. PMID- 26943914 TI - BCS Biowaivers: Similarities and Differences Among EMA, FDA, and WHO Requirements. AB - The Biopharmaceutics Classification System (BCS), based on aqueous solubility and intestinal permeability, has enjoyed wide use since 1995 as a mechanism for waiving in vivo bioavailability and bioequivalence studies. In 2000, the US-FDA was the first regulatory agency to publish guidance for industry describing how to meet criteria for requesting a waiver of in vivo bioavailability and bioequivalence studies for highly soluble, highly permeable (BCS Class I) drugs. Subsequently, the World Health Organization (WHO) and European Medicines Agency (EMA) published guidelines recommending how to obtain BCS biowaivers for BCS Class III drugs (high solubility, low permeability), in addition to Class I drugs. In 2015, the US-FDA became better harmonized with the EMA and WHO following publication of two guidances for industry outlining criteria for obtaining BCS biowaivers for both Class I and Class III drugs. A detailed review and comparison of the BCS Class I and Class III criteria currently recommended by the US-FDA, EMA, and WHO revealed good convergence of the three agencies with respect to BCS biowaiver criteria. The comparison also suggested that, by applying the most conservative of the three jurisdictional approaches, it should be possible for a sponsor to design the same set of BCS biowaiver studies in preparing a submission for worldwide filing to satisfy US, European, and emerging market regulators. It is hoped that the availability of BCS Class I and Class III biowaivers in multiple jurisdictions will encourage more sponsors to request waivers of in vivo bioavailability/bioequivalence testing using the BCS approach. PMID- 26943916 TI - The chasm between public health and reproductive research: what history tells us about Zika virus. AB - Zika transmission from mother to fetus and its possible sexual transmission have become a media focus in the past months as a major public health concern. While mother-to-fetus transmission, fetal neurologic manifestations or sexual transmission have never been documented for this virus before, other viruses that belong to the same family are very well known to reproductive health workers, clinicians, and researchers. As a member of Flaviviridae family, including hepatitis C and bovine viral diarrhea virus (BVDV), Zika's pathogenesis may have some parallels with these infections which may pose future questions for public health and research. Vertical transmission of hepatitis C virus from mother to child is known to occur in up to 10 % of pregnancies. BVDV, a member of Pestivirus genus of Flaviviridae family is not known to be transmitted to humans but is known for its vertical transmission in cattle. BVDV infection at different stages of gestation may lead to a spectrum of adverse pregnancy outcomes, including pregnancy loss and neurologic manifestations (including deformations such as hydrocephalus and microcephaly) in the offspring. Similar to hepatitis C, which is a virus of Hepacivirus genus, BVDV is capable of persistent infection, meaning that virus may stay in mother and future generations of calves may be infected as well, which may, in turn, result in persistence of infection in offspring. Would this be a case with Zika virus? Along with mother-to-fetus transmission, sexual transmission is a concerning implication for Zika virus. Would woman become a persistent career or male be able to persistently carry virus with its sperm is yet unknown; yet, there is a concern for the reservoir of infection. Animal models of the disease are urgently needed not only to demonstrate the mother-to-fetus transmission and confirm the fetal neurologic manifestations but also to address the effects of virus on life-long host's immunity and reproductive health. Along those lines, women desiring pregnancies who are identified to travel, have a partner traveling to, or living in the areas of Zika infections should be encouraged to have a preconception consultation with maternal-fetal medicine. PMID- 26943915 TI - Preclinical Pharmacokinetics Study of R- and S-Enantiomers of the Histone Deacetylase Inhibitor, AR-42 (NSC 731438), in Rodents. AB - AR-42, a new orally bioavailable, potent, hydroxamate-tethered phenylbutyrate class I/IIB histone deacetylase inhibitor currently is under evaluation in phase 1 and 2 clinical trials and has demonstrated activity in both hematologic and solid tumor malignancies. This report focuses on the preclinical characterization of the pharmacokinetics of AR-42 in mice and rats. A high-performance liquid chromatography-tandem mass spectrometry assay has been developed and applied to the pharmacokinetic study of the more active stereoisomer, S-AR-42, when administered via intravenous and oral routes in rodents, including plasma, bone marrow, and spleen pharmacokinetics (PK) in CD2F1 mice and plasma PK in F344 rats. Oral bioavailability was estimated to be 26 and 100% in mice and rats, respectively. R-AR-42 was also evaluated intravenously in rats and was shown to display different pharmacokinetics with a much shorter terminal half-life compared to that of S-AR-42. Renal clearance was a minor elimination pathway for parental S-AR-42. Oral administration of S-AR-42 to tumor-bearing mice demonstrated high uptake and exposure of the parent drug in the lymphoid tissues, spleen, and bone marrow. This is the first report of the pharmacokinetics of this novel agent, which is now in early phase clinical trials. PMID- 26943917 TI - Methotrexate does not affect ovarian reserve or subsequent assisted reproductive technology outcomes. AB - PURPOSE: The purpose of this research was to study whether methotrexate (MTX) as treatment for ectopic pregnancy (EP) impacts the future fertility of women undergoing assisted reproductive technology (ART) METHODS: In a systematic review and multi-center retrospective cohort from four academic and private fertility centers, 214 women underwent an ART cycle before and after receiving MTX as treatment for an EP. Measures of ovarian reserve and responsiveness and rates of clinical pregnancy (CP) and live birth (LB) were compared in the ART cycles prior and subsequent to MTX. RESULTS: Seven studies were identified in the systematic review, and primary data from four institutions was included in the final analysis. Women were significantly older in post-MTX cycles (35.3 vs 34.7 years). There were no differences in follicle stimulating hormone, antral follicle count, duration of stimulation, oocytes retrieved, or fertilization rate between pre- and post-MTX cycles. However, post-MTX cycles received a significantly higher total dose of gonadotropins (4206 vs 3961 IU). Overall, 42 % of women achieved a CP and 35 % achieved a LB in the post-MTX ART cycle, which is similar to national statistics. Although no factors were identified that were predictive of LB in young women, the number of oocytes retrieved in the previous ART cycle and current AFC were predictive of LB (AUC 0.76, 0.75) for the older women. CONCLUSIONS: MTX does not influence ovarian reserve, response to gonadotropin stimulation, and CP or LB rate after ART. MTX remains a safe and effective treatment option for women with asymptomatic EPs. PMID- 26943918 TI - Female patients with lymphoma demonstrate diminished ovarian reserve even before initiation of chemotherapy when compared with healthy controls and patients with other malignancies. AB - PURPOSE: The purpose of this study is to investigate if female patients with lymphoma demonstrate diminished ovarian reserve prior to initiation of the lymphoma treatment. METHODS: Sixty-four patients with newly diagnosed lymphoma undergoing controlled ovarian hyperstimulation for fertility preservation were compared with 365 healthy controls undergoing elective oocyte cryopreservation (controlled ovarian hyperstimulation (COH)) and 128 patients with other types of malignancy prompting fertility preservation. The data of all lymphoma patients, all elective, and all the patients with other types of malignancy who met the inclusion criteria and underwent COH for fertility preservation during the study period were retrospectively analyzed. Primary outcomes included serum anti Mullerian hormone (AMH) levels (ng/mL) and antral follicle count (AFC). RESULTS: Patients in the lymphoma group demonstrated significantly lower AMH levels and AFC and had less oocytes harvested and cryopreserved when compared to healthy controls as well as patients with other malignancies. CONCLUSION: Patients with lymphoma demonstrate diminished ovarian reserve when compared with healthy controls and patients with other malignancies. This should be taken into consideration when deciding on the dose for COH. PMID- 26943919 TI - Age- and function-related regional changes in cortical folding of the default mode network in older adults. AB - Healthy aging is accompanied by changes in the functional architecture of the default mode network (DMN), e.g. a posterior to anterior shift (PASA) of activations. The putative structural correlate for this functional reorganization, however, is largely unknown. Changes in gyrification, i.e. decreases of cortical folding were found to be a marker of atrophy of the brain in later decades of life. Therefore, the present study assessed local gyrification indices of the DMN in relation to age and cognitive performance in 749 older adults aged 55-85 years. Age-related decreases in local gyrification indices were found in the anterior part of the DMN [particularly; medial prefrontal cortex (mPFC)] of the right hemisphere, and the medial posterior parts of the DMN [particularly; posterior cingulate cortex (PCC)/precuneus] of both hemispheres. Positive correlations between cognitive performance and local gyrification indices were found for (1) selective attention and left PCC/precuneus, (2) visual/visual-spatial working memory and bilateral PCC/precuneus and right angular gyrus (AG), and (3) semantic verbal fluency and right AG and right mPFC. The more pronounced age-related decrease in local gyrification indices of the posterior parts of the DMN supports the functionally motivated PASA theory by correlated structural changes. Surprisingly, the prominent age-related decrease in local gyrification indices in right hemispheric ROIs provides evidence for a structural underpinning of the right hemi-aging hypothesis. Noticeably, the performance-related changes in local gyrification largely involved the same parts of the DMN that were subject to age-related local gyrification decreases. Thus, the present study lends support for a combined structural and functional theory of aging, in that the functional changes in the DMN during aging are accompanied by comparably localized structural alterations. PMID- 26943920 TI - The Brewed Rice Vinegar Kurozu Increases HSPA1A Expression and Ameliorates Cognitive Dysfunction in Aged P8 Mice. AB - Kurozu is a traditional Japanese rice vinegar. During fermentation and aging of the Kurozu liquid in an earthenware jar over 1 year, a solid residue called Kurozu Moromi is produced. In the present study, we evaluated whether concentrated Kurozu or Kurozu Moromi could ameliorate cognitive dysfunction in the senescence-accelerated P8 mouse. Senescence-accelerated P8 mice were fed 0.25% (w/w) concentrated Kurozu or 0.5% (w/w) Kurozu Moromi for 4 or 25 weeks. Kurozu suppressed cognitive dysfunction and amyloid accumulation in the brain, while Kurozu Moromi showed a tendency to ameliorate cognitive dysfunction, but the effect was not significant. We hypothesize that concentrated Kurozu has an antioxidant effect; however, the level of lipid peroxidation in the brain did not differ in senescence-accelerated P8 mice. DNA microarray analysis indicated that concentrated Kurozu increased HSPA1A mRNA expression, a protein that prevents protein misfolding and aggregation. The increase in HSPA1A expression by Kurozu was confirmed using quantitative real-time PCR and immunoblotting methods. The suppression of amyloid accumulation by concentrated Kurozu may be associated with HSPA1A induction. However, concentrated Kurozu could not increase HSPA1A expression in mouse primary neurons, suggesting it may not directly affect neurons. PMID- 26943921 TI - [A series of cases--too old for a pacemaker?]. AB - We report three patients with an age above 90 years presented with symptomatic bradycardia and higher grade AV block in our clinic. The oldest patient was 100 years. All three patients could be supplied safely and without complications with a dual chamber pacemaker. Our case series shows that a dual chamber pacemaker implantation is safe and feasible in patients in very advanced age. A surgical management with local anesthetic (lidocaine), fentanyl and midazolam in individual cases is possible. This and a short hospital stay reduce the risk of delirium. It is a group of patients, which will increase in the future and requires more intensive care than the standard pacemaker patient. PMID- 26943922 TI - [Cancer stem cells as the therapeutic target of tomorrow]. AB - The concept of hierarchical organization of tumour cell population, with cancer stem cells positioned at the apex of the cell hierarchy, can explain at least some crucial aspects of biological and clinical behaviour of cancer, like its propensity to relapse as well as the development of therapeutic resistance. The underlying biological properties of cancer stem cells are crucially dependent on various signals, inhibition of which provides an attractive opportunity to attack pharmacologically cancer stem cells. Currently, a lot of such stemness-inhibitors undergo various phases of clinical testing. Interestingly, numerous old drugs that are in routine use in human and veterinary medicine for non-oncological indications appear to be able to specifically target cancer stem cells as well. As cancer stem cells, at least for most tumours, represent usually only a minor tumour cell fraction, it is quite probable that the main focus of the clinical use of the stemness inhibitors would consist in their rational combinations with traditional anticancer treatment modalities. A highly important goal for the future research is to identify reliable and clinically applicable predictive markers that would allow to apply these novel anticancer drugs on the individual basis within the context of personalized medicine. PMID- 26943923 TI - Enzyme replacement therapy with galsulfase for mucopolysaccharidosis type VI. AB - BACKGROUND: Mucopolysaccharidosis type VI or Maroteaux-Lamy syndrome is a rare genetic disorder caused by the deficiency of arylsulphatase B. The resultant accumulation of dermatan sulphate causes lysosomal damage.The clinical symptoms are related to skeletal dysplasia (i.e. short stature and degenerative joint disease). Other manifestations include cardiac disease, impaired pulmonary function, ophthalmological complications, hepatosplenomegaly, sinusitis, otitis, hearing loss and sleep apnea. Intellectual impairment is generally absent. Clinical manifestation is typically by two or three years of age; however, slowly progressive cases may not present until adulthood.Enzyme replacement therapy with galsulfase is considered a new approach for treating mucopolysaccharidosis type VI. OBJECTIVES: To evaluate the effectiveness and safety of treating mucopolysaccharidosis VI by enzyme replacement therapy with galsulfase compared to other interventions, placebo or no intervention. SEARCH METHODS: Eletronic searches were performed on the Cystic Fibrosis and Genetic Disorders Group's Inborn Errors of Metabolism Trials Register, in CENTRAL, MEDLINE, LILACS, the Journal of Inherited Metabolic Disease and ClinicalTrials.gov. Date of the last search of the Cystic Fibrosis and Genetic Disorders Group's Inborn Errors of Metabolism Trials Register: 05 February 2016. SELECTION CRITERIA: Randomized and quasi-randomized controlled clinical studies of enzyme replacement therapy with galsulfase compared to other interventions or placebo. DATA COLLECTION AND ANALYSIS: Two authors independently screened the studies, assessed the risk of bias and extracted data. MAIN RESULTS: One study was included involving 39 participants who received either enzyme replacement therapy with galsulfase (recombinant human arylsulphatase B) or placebo. This small study was considered to be of overall unclear quality, since the authors did not report how both the allocation generation and concealment were performed.The key finding at 24 weeks in the 12-minute walk test was a statistically significant mean difference of 92.00 meters between the two groups in favour of the galsulfase group (95% confidence interval 11.00 to 172.00). While week 24 results for the three-minute stair climb demonstrated some improvement in the treatment group as compared to the placebo group, this was not significant, mean difference 5.70 (95% confidence interval -0.10 to 11.50).A significant decrease in the urinary glycosaminoglycan levels was observed in favour of the galsulfase group at 24 weeks, mean difference -227.00 (95% confidence interval -264.00 to -190.00).In general, the dose of galsulfase was well tolerated and there were no significant differences in relation to adverse events. These events include drug-related adverse events, serious and severe adverse events, those during infusion, drug-related adverse events during infusion, and deaths. More infusion-related reactions were observed in the galsulfase group and were managed with interruption or slowing of infusion rate or administration of antihistamines or corticosteroids drugs. No deaths occurred during the study. AUTHORS' CONCLUSIONS: The results of one small study (based on 24-week randomised phase of the study and prior to the open-label extension) demonstrated that galsulfase is more effective than placebo in people with MPS VI, with significant improvements in the 12-minute walk test and a reduction in urinary glycosaminoglycans.There were no significant changes in cardiac or pulmonary functions, liver or spleen volume, overnight apnea-hypopnea, height and weight, quality of life and adverse effects.Further studies are needed to obtain more information on the long-term effectiveness and safety of enzyme replacement therapy with galsulfase. PMID- 26943924 TI - Attachment Status Affects Heart Rate Responses to Experimental Ostracism in Inpatients with Depression. AB - Depression is assumed to be both a risk factor for rejection and a result of it, and as such constitutes an important factor in rejection research. Attachment theory has been applied to understand psychological disorders, such as depression, and can explain individual differences in responses to rejection. Research on autonomic nervous system activity to rejection experiences has been contradictory, with opposing strings of argumentation (activating vs. numbing). We investigated autonomic nervous system-mediated peripheral physiological responses (heart rate) to experimentally manipulated ostracism (Cyberball) in 97 depressed patients with organized (n = 52) and disorganized attachment status (n = 45). Controlling for baseline mean heart rate levels, depressed patients with disorganized attachment status responded to ostracism with significantly higher increases in heart rate than depressed patients with organized attachment status (p = .029; etap2 = .051). These results suggest that attachment status may be a useful indicator of autonomic responses to perceived social threat, which in turn may affect the therapeutic process and the patient-therapist relationship. PMID- 26943925 TI - Effect of Health Literacy on Quality of Life amongst Patients with Ischaemic Heart Disease in Australian General Practice. AB - BACKGROUND: Appropriate understanding of health information by patients with cardiovascular disease (CVD) is fundamental for better management of risk factors and improved morbidity, which can also benefit their quality of life. OBJECTIVES: To assess the relationship between health literacy and health-related quality of life (HRQoL) in patients with ischaemic heart disease (IHD), and to investigate the role of sociodemographic and clinical variables as possible confounders. METHODS: Cross-sectional study of patients with IHD recruited from a stratified sample of general practices in two Australian states (Queensland and South Australia) between 2007 and 2009. Health literacy was measured using a validated questionnaire and classified as inadequate, marginal, or adequate. Physical and mental components of HRQoL were assessed using the Medical Outcomes Study Short Form (SF12) questionnaire. Analyses were adjusted for confounders (sociodemographic variables, clinical history of IHD, number of CVD comorbidities, and CVD risk factors) using multiple linear regression. RESULTS: A total sample of 587 patients with IHD (mean age 72.0+/-8.4 years) was evaluated: 76.8% males, 84.2% retired or pensioner, and 51.4% with up to secondary educational level. Health literacy showed a mean of 39.6+/-6.7 points, with 14.3% (95%CI 11.8-17.3) classified as inadequate. Scores of the physical component of HRQoL were 39.6 (95%CI 37.1-42.1), 42.1 (95%CI 40.8-43.3) and 44.8 (95%CI 43.3 46.2) for inadequate, marginal, and adequate health literacy, respectively (p value for trend = 0.001). This association persisted after adjustment for confounders. Health literacy was not associated with the mental component of HRQoL (p-value = 0.482). Advanced age, lower educational level, disadvantaged socioeconomic position, and a larger number of CVD comorbidities adversely affected both, health literacy and HRQoL. CONCLUSION: Inadequate health literacy is a contributing factor to poor physical functioning in patients with IHD. Increasing health literacy may improve HRQoL and reduce the impact of IHD among patients with this chronic CVD. PMID- 26943926 TI - The Bacterial Flagellar Type III Export Gate Complex Is a Dual Fuel Engine That Can Use Both H+ and Na+ for Flagellar Protein Export. AB - The bacterial flagellar type III export apparatus utilizes ATP and proton motive force (PMF) to transport flagellar proteins to the distal end of the growing flagellar structure for self-assembly. The transmembrane export gate complex is a H+-protein antiporter, of which activity is greatly augmented by an associated cytoplasmic ATPase complex. Here, we report that the export gate complex can use sodium motive force (SMF) in addition to PMF across the cytoplasmic membrane to drive protein export. Protein export was considerably reduced in the absence of the ATPase complex and a pH gradient across the membrane, but Na+ increased it dramatically. Phenamil, a blocker of Na+ translocation, inhibited protein export. Overexpression of FlhA increased the intracellular Na+ concentration in the presence of 100 mM NaCl but not in its absence, suggesting that FlhA acts as a Na+ channel. In wild-type cells, however, neither Na+ nor phenamil affected protein export, indicating that the Na+ channel activity of FlhA is suppressed by the ATPase complex. We propose that the export gate by itself is a dual fuel engine that uses both PMF and SMF for protein export and that the ATPase complex switches this dual fuel engine into a PMF-driven export machinery to become much more robust against environmental changes in external pH and Na+ concentration. PMID- 26943927 TI - Inferring Population Size History from Large Samples of Genome-Wide Molecular Data - An Approximate Bayesian Computation Approach. AB - Inferring the ancestral dynamics of effective population size is a long-standing question in population genetics, which can now be tackled much more accurately thanks to the massive genomic data available in many species. Several promising methods that take advantage of whole-genome sequences have been recently developed in this context. However, they can only be applied to rather small samples, which limits their ability to estimate recent population size history. Besides, they can be very sensitive to sequencing or phasing errors. Here we introduce a new approximate Bayesian computation approach named PopSizeABC that allows estimating the evolution of the effective population size through time, using a large sample of complete genomes. This sample is summarized using the folded allele frequency spectrum and the average zygotic linkage disequilibrium at different bins of physical distance, two classes of statistics that are widely used in population genetics and can be easily computed from unphased and unpolarized SNP data. Our approach provides accurate estimations of past population sizes, from the very first generations before present back to the expected time to the most recent common ancestor of the sample, as shown by simulations under a wide range of demographic scenarios. When applied to samples of 15 or 25 complete genomes in four cattle breeds (Angus, Fleckvieh, Holstein and Jersey), PopSizeABC revealed a series of population declines, related to historical events such as domestication or modern breed creation. We further highlight that our approach is robust to sequencing errors, provided summary statistics are computed from SNPs with common alleles. PMID- 26943928 TI - Readmission for Acute Exacerbation within 30 Days of Discharge Is Associated with a Subsequent Progressive Increase in Mortality Risk in COPD Patients: A Long-Term Observational Study. AB - BACKGROUND AND OBJECTIVE: Twenty per cent of chronic obstructive pulmonary disease (COPD) patients are readmitted for acute exacerbation (AECOPD) within 30 days of discharge. The prognostic significance of early readmission is not fully understood. The objective of our study was to estimate the mortality risk associated with readmission for acute exacerbation within 30 days of discharge in COPD patients. METHODS: The cohort (n = 378) was divided into patients readmitted (n = 68) and not readmitted (n = 310) within 30 days of discharge. Clinical, laboratory, microbiological, and severity data were evaluated at admission and during hospital stay, and mortality data were recorded at four time points during follow-up: 30 days, 6 months, 1 year and 3 years. RESULTS: Patients readmitted within 30 days had poorer lung function, worse dyspnea perception and higher clinical severity. Two or more prior AECOPD (HR, 2.47; 95% CI, 1.51-4.05) was the only variable independently associated with 30-day readmission. The mortality risk during the follow-up period showed a progressive increase in patients readmitted within 30 days in comparison to patients not readmitted; moreover, 30 day readmission was an independent risk factor for mortality at 1 year (HR, 2.48; 95% CI, 1.10-5.59). In patients readmitted within 30 days, the estimated absolute increase in the mortality risk was 4% at 30 days (number needed to harm NNH, 25), 17% at 6-months (NNH, 6), 19% at 1-year (NNH, 6) and 24% at 3 years (NNH, 5). CONCLUSION: In conclusion a readmission for AECOPD within 30 days is associated with a progressive increased long-term risk of death. PMID- 26943930 TI - Elbasvir/Grazoprevir: First Global Approval. AB - A fixed-dose combination tablet of the hepatitis C virus (HCV) NS5A inhibitor elbasvir and the HCV NS3/4A protease inhibitor grazoprevir (elbasvir/grazoprevir; ZepatierTM) is under development by Merck. Oral elbasvir/grazoprevir 50/100 mg once daily has been approved in the USA for the treatment of adults with chronic HCV genotype 1 or 4 infection. This article summarizes the milestones in the development of elbasvir/grazoprevir leading to this first global approval for chronic HCV genotype 1 or 4 infection. PMID- 26943931 TI - Human IgE is efficiently produced in glycosylated and biologically active form in lepidopteran cells. AB - TH2-biased immunity to parasites and allergens is often associated with increased levels of antigen-specific and high affinity IgE. The role in reacting against minute amounts of target structures and to provoke severe anaphylactic reactions renders IgE a mechanistically outstanding isotype. IgE represents the least abundant serum antibody isotype and exhibits a variety of peculiarities including structure, extensive glycosylation and effector functions. Despite large progress in antibody technologies, however, the recombinant access to isotypes beyond IgG such as IgE still is scarce. The capacity of expression systems has to meet the complex structural conformations and the extensive posttranslational modifications that are indispensable for biological activity. In order to provide alternatives to mammalian expression systems with often low yield and a more complex glycosylation pattern we established the recombinant production of the highly complex IgE isotype in insect cells. Recombinant IgE (rIgE) was efficiently assembled and secreted into the supernatant in yields of >30 mg/L. Purification from serum free medium using different downstream processing methods provided large amounts of rIgE. This exhibited a highly specific interaction with its antigen, therapeutic anti-IgE and its high affinity receptor, the FcepsilonRI. Lectins and glyco-proteomic analyses proved the presence of prototypic insect type N-glycans on the epsilon heavy chain. Mediator release assays demonstrated a biological activity of the rIgE comparable to IgE derived from mammalian cells. In summary the expression in insect cells provides rIgE with variant glycosylation pattern, but retained characteristics and biological activity. Therefore our data contribute to the understanding of functional and structural aspects and potential use of the IgE isotype. PMID- 26943929 TI - Pharmacotherapy for Neonatal Seizures: Current Knowledge and Future Perspectives. AB - Seizures are the most common neurological emergencies in the neonatal period and are associated with poor neurodevelopmental outcomes. Seizures affect up to five per 1000 term births and population-based studies suggest that they occur even more frequently in premature infants. Seizures are a sign of an underlying cerebral pathology, the most common of which is hypoxic-ischaemic encephalopathy in term infants. Due to a growing body of evidence that seizures exacerbate cerebral injury, effective diagnosis and treatment of neonatal seizures is of paramount importance to reduce long-term adverse outcomes. Electroencephalography is essential for the diagnosis of seizures in neonates due to their subtle clinical expression, non-specific neurological presentation and a high frequency of electro-clinical uncoupling in the neonatal period. Hypoxic-ischaemic encephalopathy may require neuroprotective therapeutic hypothermia, accompanying sedation with opioids, anticonvulsant drugs or a combination of all of these. The efficacy, safety, tolerability and pharmacokinetics of seven anticonvulsant drugs (phenobarbital, phenytoin, levetiracetam, lidocaine, midazolam, topiramate and bumetanide) are reviewed. This review is focused only on studies reporting electrographically confirmed seizures and highlights the knowledge gaps that exist in optimal treatment regimens for neonatal seizures. Randomised controlled trials are needed to establish a safe and effective treatment protocol for neonatal seizures. PMID- 26943932 TI - Optimization of the moving-bed biofilm sequencing batch reactor (MBSBR) to control aeration time by kinetic computational modeling: Simulated sugar-industry wastewater treatment. AB - A novel approach was applied for optimization of a moving-bed biofilm sequencing batch reactor (MBSBR) to treat sugar-industry wastewater (BOD5=500-2500 and COD=750-3750 mg/L) at 2-4 h of cycle time (CT). Although the experimental data showed that MBSBR reached high BOD5 and COD removal performances, it failed to achieve the standard limits at the mentioned CTs. Thus, optimization of the reactor was rendered by kinetic computational modeling and using statistical error indicator normalized root mean square error (NRMSE). The results of NRMSE revealed that Stover-Kincannon (error=6.40%) and Grau (error=6.15%) models provide better fits to the experimental data and may be used for CT optimization in the reactor. The models predicted required CTs of 4.5, 6.5, 7 and 7.5 h for effluent standardization of 500, 1000, 1500 and 2500 mg/L influent BOD5 concentrations, respectively. Similar pattern of the experimental data also confirmed these findings. PMID- 26943933 TI - Insight into the short- and long-term effects of inorganic phosphate on anammox granule property. AB - The short- and long-term effects of inorganic phosphate on property of anaerobic ammonium oxidation (anammox) granule were investigated in this study. Acute exposure to high-level phosphate (?50 mM) induced the cytoplasm leakage. During a 195-day continuous-flow operation, the gradually increasing phosphate (up to 500 mgP L(-1)) slightly affected the specific anammox activity, hardly impacted the heme c content, remarkably decreased the extracellular polymeric substances production and significantly stimulated the dehydrogenase activity of anammox granules. Microbial community analysis showed no shift in the dominant anammox strain and higher population but lower relative abundance of anaerobic ammonium oxidizing bacteria compared to the control granules. Interestingly, novel anammox granules with a hydroxyapatite core were cultivated, which possessed excellent settleability, huge granule diameter and superior mechanical strength. This study supported the application of granule-based anammox process as a pre-processing treatment in phosphate-containing and ammonia-rich wastewaters. PMID- 26943934 TI - Bioethanol production from deacetylated yellow poplar pretreated with oxalic acid recovered through electrodialysis. AB - Electrodialysis (ED) was used to develop a multistage oxalic acid recovery and pretreatment system to produce ethanol from deacetylated yellow poplar. Pretreatment of the biomass was performed at 150 degrees C for 42 min using 0.16 M oxalic acid. The efficiency of oxalic acid recovery from the hydrolysate reached up to 92.32% in all the stages. Ethanol production and ethanol yield of ED-treated hydrolysate in each stage showed a uniform pattern ranging from 6.81 g/L to 7.21 g/L and 0.40 g/g to 0.43 g/g, respectively. The results showed that efficiency of ethanol production increased when deacetylated biomass and ED process was used. Ethanol yield from the pretreated biomass using simultaneous saccharification and fermentation (SSF) was in the range of 80.59-83.36% in all the stages. The structural characterization of the pretreated biomass at each stage was investigated and structural changes were not significantly different among the various pretreated biomass. PMID- 26943935 TI - Comparison of axial vibration membrane and submerged aeration membrane in microalgae harvesting. AB - The submerged aeration membrane (SAM) system and axial vibration membrane (AVM) system can mitigate membrane fouling. In this study, both systems were investigated to compare the performance of filtration and the membrane fouling in algae filtration. In 5-h filtration, the transmembrane pressure (TMP) of SAM reached to 70.0 kPa, while there was almost no increase in TMP for AVM. After continuous filtration, it could be found that there was hardly any algae cells on the membrane of AVM (0.11 g/m(2)), which was about 32.4 times less than that of SAM (3.56 g/m(2)). Compared with the SAM system, AVM had a lesser membrane fouling, regardless of the reversible fouling or irreversible fouling. By SEM, FTIR and EEM, it could be found there was less irreversible extracellular organic matter (EOM) on the membrane of AVM. By MW distribution, it could be observed that less EOM with high-MW adhered to membrane of AVM. PMID- 26943936 TI - Production of cellulosic ethanol from sugarcane bagasse by steam explosion: Effect of extractives content, acid catalysis and different fermentation technologies. AB - The production of cellulosic ethanol was carried out using samples of native (NCB) and ethanol-extracted (EECB) sugarcane bagasse. Autohydrolysis (AH) exhibited the best glucose recovery from both samples, compared to the use of both H3PO4 and H2SO4 catalysis at the same pretreatment time and temperature. All water-insoluble steam-exploded materials (SEB-WI) resulted in high glucose yields by enzymatic hydrolysis. SHF (separate hydrolysis and fermentation) gave ethanol yields higher than those obtained by SSF (simultaneous hydrolysis and fermentation) and pSSF (pre-hydrolysis followed by SSF). For instance, AH gave 25, 18 and 16 g L(-1) of ethanol by SHF, SSF and pSSF, respectively. However, when the total processing time was taken into account, pSSF provided the best overall ethanol volumetric productivity of 0.58 g L(-1) h(-1). Also, the removal of ethanol-extractable materials from cane bagasse had no influence on the cellulosic ethanol production of SEB-WI, regardless of the fermentation strategy used for conversion. PMID- 26943938 TI - Genomic legacies of the progenitors and the evolutionary consequences of allopolyploidy. AB - The formation of an allopolyploid species involves the merger of genomes with separate evolutionary histories and thereby different genomic legacies. Contrary to expectations from theory, genes from one are often lost preferentially in allopolyploids - there is biased fractionation. Here, we provide an overview of two ways in which the genomic legacies of the progenitors may impact the fate of duplicated genes in allopolyploids. Specifically, we discuss the role of homeolog expression biases in setting the stage for biased fractionation, and the evidence for transposable element silencing as a possible mechanism for homeolog expression biases. Finally, we highlight how differences between the progenitors with respect to accumulation of deleterious variation may affect trajectories of duplicate gene evolution in allopolyploids. PMID- 26943939 TI - Systems genetics of wood formation. AB - In woody plants, xylogenesis is an exceptionally strong carbon sink requiring robust transcriptional control and dynamic coordination of cellular and metabolic processes directing carbon allocation and partitioning into secondary cell wall biosynthesis. As a biological process, wood formation is an excellent candidate for systems modeling due to the strong correlation patterns and interconnectedness observed for transcriptional and metabolic component traits contributing to complex phenotypes such as cell wall chemistry and ultrastructure. Genetic variation in undomesticated tree populations provides abundant perturbation of systems components, adding another dimension to plant systems biology (besides spatial and temporal variation). High-throughput analysis of molecular component traits in adult trees has provided the first insights into the systems genetics of wood, an important renewable feedstock for biomaterials and bioenergy. PMID- 26943937 TI - Signal Transduction at the Domain Interface of Prokaryotic Pentameric Ligand Gated Ion Channels. AB - Pentameric ligand-gated ion channels are activated by the binding of agonists to a site distant from the ion conduction path. These membrane proteins consist of distinct ligand-binding and pore domains that interact via an extended interface. Here, we have investigated the role of residues at this interface for channel activation to define critical interactions that couple conformational changes between the two structural units. By characterizing point mutants of the prokaryotic channels ELIC and GLIC by electrophysiology, X-ray crystallography and isothermal titration calorimetry, we have identified conserved residues that, upon mutation, apparently prevent activation but not ligand binding. The positions of nonactivating mutants cluster at a loop within the extracellular domain connecting beta-strands 6 and 7 and at a loop joining the pore-forming helix M2 with M3 where they contribute to a densely packed core of the protein. An ionic interaction in the extracellular domain between the turn connecting beta strands 1 and 2 and a residue at the end of beta-strand 10 stabilizes a state of the receptor with high affinity for agonists, whereas contacts of this turn to a conserved proline residue in the M2-M3 loop appear to be less important than previously anticipated. When mapping residues with strong functional phenotype on different channel structures, mutual distances are closer in conducting than in nonconducting conformations, consistent with a potential role of contacts in the stabilization of the open state. Our study has revealed a pattern of interactions that are crucial for the relay of conformational changes from the extracellular domain to the pore region of prokaryotic pentameric ligand-gated ion channels. Due to the strong conservation of the interface, these results are relevant for the entire family. PMID- 26943941 TI - Effort-reward imbalance at work and the risk of antidepressant treatment in the Danish workforce. AB - BACKGROUND: Previous studies have shown that high effort-reward imbalance (ERI) at work is a risk factor for the onset of self-reported depressive symptoms. In this study, we examined whether ERI predicts risk of treatment with antidepressant medication in a representative sample of the Danish workforce. METHODS: We linked survey data on ERI and covariates of 4541 participants from the Danish Work Environment Cohort Study 2000 with the Danish National Prescription Registry that includes all legally purchased prescription drugs at pharmacies in Denmark since 1995. Participants with a history of antidepressant treatment or with self-reported depressive symptoms at baseline were excluded. Using Cox proportional hazard analyses we examined the prospective association between ERI at baseline and incident antidepressant treatment while adjusting for potential confounders. Time of follow-up was 5 years. RESULTS: A total of 309 (6.8%) participants started antidepressant treatment during follow-up. Exposure to ERI at baseline was not related to risk of antidepressant treatment (hazard ratio: 0.91, 95% CI=0.81-1.03 after adjustment for potential confounders). LIMITATIONS: The use of antidepressant treatment as an indicator for onset of depression might have led to misclassification, because (a) antidepressants are also used to treat other conditions than depression and (b) a considerable proportion of individuals with depression are not treated with antidepressants. CONCLUSIONS: ERI did not predict incident antidepressant treatment, contradicting previous findings on ERI and self-reported depression. To clarify the association of ERI with risk of depression, we recommend further prospective studies using non-self-reported measures of ERI, clinical assessments of depression, or both. PMID- 26943942 TI - Differentiating between Transient and Enduring distress on the Edinburgh Depression Scale within screening contexts. AB - BACKGROUND: Research has shown that women screened as being 'possibly depressed' on the Edinburgh Depression Scale consist of two distinct duration types: those with Transient distress, and those with Enduring distress. This paper reports on the exploration of antenatal data to ascertain if information from the initial EDS screening can help determine which women may have Transient, and which Enduring, distress after just a few weeks. METHODS: Data from three antenatal studies were explored, where the EDS had been given twice within a psychosocial screening setting. Repeat testing of the EDS, together with a diagnostic interview, was conducted 2-5 weeks later. RESULTS: Women with Enduring distress (those scoring high on both occasions) were significantly more likely to meet criteria for a depressive disorder than those with Transient distress. They also scored significantly and clinically meaningfully higher on their initial EDS, though no cut-off score was optimal in discriminating between the two duration categories. Differentiation could also not be made from the endorsement of the self-harm question, but was best when women were asked to predict how they would be feeling, and why. LIMITATIONS: The data come from three studies just with English-speaking women with slightly different methodologies, producing information on a fairly small number of women with Transient (n=12-29) and Enduring (n=14-25) distress. In addition the EDS re-test interval of between 2 and 5 weeks was quite wide. CONCLUSIONS: Clinical implications are that women who score high initially on the EDS are most likely to continue to score high (have Enduring distress) if they themselves think this will be the case, or if they only give wishful thinking as the reason as to why they think they will feel better. Research studies should also therefore analyse their data taking into account this duration category. PMID- 26943940 TI - High frequency heart-rate variability predicts adolescent depressive symptoms, particularly anhedonia, across one year. AB - BACKGROUND: Few prospective studies examine the link between lower heart rate variability (HRV) and depression symptoms in adolescents. A recent animal model specifically links HRV to anhedonia, suggesting a potential translational model for human research. METHOD: We investigated the association between spectral measures of resting HRV and depressive symptoms measured one year later, among 73 adolescents, aged 11-18 years. We evaluated (1) the predictive power of relative high frequency (HF) HRV, relative low frequency (LF) and relative very low frequency (VLF) HRV for depressive symptoms; and (2) the relative strength of association between HF HRV and depressive symptomatology (anhedonia, negative mood, interpersonal problems, ineffectiveness, negative self-esteem). RESULTS: HF HRV significantly predicted self-reported depressive symptoms across one year, controlling for age, puberty and sex. HF HRV was most strongly associated with anhedonia one year later, after considering other facets of depressive symptomatology. CONCLUSIONS: Results provide support for the prospective relationship between relative HF HRV and depressive symptoms among adolescents across one year. Findings concur with rodent models that suggest a specific link between HF HRV and anhedonia. LIMITATIONS: We investigated relative spectral power HF HRV and depressive symptom dimensions. We cannot make strong claims about these associations in clinical depression. Physical activity levels could be controlled in future work. PMID- 26943943 TI - Visualization and Quantification of Nasal and Olfactory Deposition in a Sectional Adult Nasal Airway Cast. AB - PURPOSE: To compare drug deposition in the nose and olfactory region with different nasal devices and administration techniques. A Sar-Gel based colorimetry method will be developed to quantify local deposition rates. METHODS: A sectional nasal airway cast was developed based on an MRI-based nasal airway model to visualize deposition patterns and measure regional dosages. Four nasal spray pumps and four nebulizers were tested with both standard and point-release administration techniques. Delivered dosages were measured using a high-precision scale. The colorimetry correlation for deposited mass was developed via image processing in Matlab and its performance was evaluated through comparison to experimental measurements. RESULTS: Results show that the majority of nasal spray droplets deposited in the anterior nose while only a small fraction (less than 4.6%) reached the olfactory region. For all nebulizers considered, more droplets went beyond the nasal valve, leading to distinct deposition patterns as a function of both the nebulizer type (droplet size and initial speed) and inhalation flow rate. With the point-release administration, up to 9.0% (+/-1.9%) of administered drugs were delivered to the olfactory region and 15.7 (+/-2.4%) to the upper nose using Pari Sinus. CONCLUSIONS: Standard nasal devices are inadequate to deliver clinically significant olfactory dosages without excess drug losses in other nasal epitheliums. The Sar-Gel based colorimetry method appears to provide a simple and practical approach to visualize and quantify regional deposition. PMID- 26943944 TI - QSPR models for predicting generator-column-derived octanol/water and octanol/air partition coefficients of polychlorinated biphenyls. AB - Octanol/water (K(OW)) and octanol/air (K(OA)) partition coefficients are two important physicochemical properties of organic substances. In current practice, K(OW) and K(OA) values of some polychlorinated biphenyls (PCBs) are measured using generator column method. Quantitative structure-property relationship (QSPR) models can serve as a valuable alternative method of replacing or reducing experimental steps in the determination of K(OW) and K(OA). In this paper, two different methods, i.e., multiple linear regression based on dragon descriptors and hologram quantitative structure-activity relationship, were used to predict generator-column-derived log K(OW) and log K(OA) values of PCBs. The predictive ability of the developed models was validated using a test set, and the performances of all generated models were compared with those of three previously reported models. All results indicated that the proposed models were robust and satisfactory and can thus be used as alternative models for the rapid assessment of the K(OW) and K(OA) of PCBs. PMID- 26943945 TI - Nigral involvement in atypical parkinsonisms: evidence from a pilot study with ultra-high field MRI. AB - Ten healthy subjects (HS) and 15 patients with atypical parkinsonisms underwent 7 T susceptibility-weighted-imaging MR to evaluate substantia nigra (SN). All HS were judged "normal". Twelve out of 15 patients exhibited bilateral abnormal SN while three patients with corticobasal degeneration (CBD) showed bilateral normal aspect of SN. Anatomical changes of SN at 7 T occur in multiple system atrophy and progressive supranuclear palsy as previously reported in Parkinson's disease. Preserved SN in CBD confirms the pathological heterogeneity of this disease. PMID- 26943946 TI - Psychrophile spoilers dominate the bacterial microbiome in musculature samples of slaughter pigs. AB - The aim of this study was to disentangle the microbial diversity on porcine musculature. The hypervariable V1-V2 region of the 16S rRNA gene was amplified from DNA samples of clinically healthy slaughter pigs (n=8). Pyrosequencing yielded 37,000 quality-controlled reads and a diverse microbiome with 54-159 OTUs per sample was detected. Interestingly, 6 out of 8 samples were strongly dominated by 1-2 highly abundant OTUs (best hits of highly abundant OTUs: Serratia proteamaculans, Pseudomonas syringae, Aeromonas allosaccharophila, Brochothrix thermosphacta, Acidiphilium cryptum and Escherichia coli). In 1g musculature scraping, 3.20E+06 16S rRNA gene copies and 4.45E+01 Enterobacteriaceae rRNA gene copies were detected with qPCR. We conclude that i.) next-generation sequencing technologies help encompass the full content of complex, bacterial contamination, ii.) psychrophile spoilers dominated the microbiota and iii.) E. coli is an effective marker species for pork contamination, as it was one of very few abundant species being present in all samples. PMID- 26943947 TI - Clinical utility of topiramate extended-release capsules (USL255): Bioequivalence of USL255 sprinkled and intact capsule in healthy adults and an in vitro evaluation of sprinkle delivery via enteral feeding tubes. AB - OBJECTIVE: The objectives of these two studies were to determine if beads from extended-release topiramate capsules sprinkled onto soft food are bioequivalent to the intact capsule and if beads from the capsule can be passed through enteral gastrostomy (G-) and jejunostomy (J-) feeding tubes. METHODS: Bioequivalence of 200-mg USL255 (Qudexy XR [topiramate] extended-release capsules) sprinkled onto soft food (applesauce) versus the intact capsule was evaluated in a phase 1, randomized, single-dose, crossover study (N=36). Pharmacokinetic evaluations included area under the curve (AUC), maximum plasma concentration (Cmax), time to Cmax (Tmax), and terminal elimination half-life (t1/2). If 90% confidence intervals (CI) of the ratio of geometric least-squares means were between 0.80 and 1.25, AUC and Cmax were considered bioequivalent. In separate in vitro experiments, 100-mg USL255 beads were passed through feeding tubes using gentle syringe pressure to develop a clog-free bead-delivery method. Multiple tube sizes (14- to 18-French [Fr] tubes), dilutions (5 mg/15 mL-25 mg/15 mL), and diluents (deionized water, apple juice, Ketocal, sparkling water) were tested. RESULTS: Area under the curve and Cmax for USL255 beads sprinkled onto applesauce were bioequivalent to the intact capsule (GLSM [90% CI]: AUC0-t 1.01 [0.97-1.04], AUC0 infinity 1.02 [0.98-1.05]; Cmax 1.09 [1.03-1.14]). Median Tmax was 4h earlier for USL255 sprinkled versus the intact capsule (10 vs 14 h; p=0.0018), and t1/2 was similar (84 vs 82 h, respectively). In 14-Fr G-tubes, USL255 beads diluted in Ketocal minimized bead clogging versus deionized water. Recovery of USL255 beads diluted in deionized water was nearly 100% in 16-Fr G-, 18-Fr G-, and 18-Fr J tubes. SIGNIFICANCE: For patients with difficulty swallowing pills, USL255 sprinkled onto applesauce offers a useful once-daily option for taking topiramate. USL255 beads were also successfully delivered in vitro through >=14 Fr G- or J-tubes, with tube clogging minimized by portioning the dose and using glidant diluents for smaller tubes. PMID- 26943948 TI - A cognitive behavioral intervention (HOBSCOTCH) improves quality of life and attention in epilepsy. AB - OBJECTIVE: Cognitive difficulties in epilepsy are common and add to disability beyond seizures alone. A self-management intervention targeting cognitive dysfunction was developed and assessed for whether it improves quality of life, objective memory, and mood in adults with epilepsy. METHODS: The HOme Based Self management and COgnitive Training CHanges lives (HOBSCOTCH) program was developed to incorporate (1) psychoeducation, (2) self-awareness training, (3) compensatory strategies, and (4) application of these strategies in day-to-day life using problem solving therapy. Adults aged 18-65 years with epilepsy (n=66) were randomized into 3 groups, to receive 8 weeks of HOBSCOTCH, with (H+) or without (H) additional working memory training on a commercial gaming device, or to a waitlisted control group. The primary outcome was quality of life (Quality of Life in Epilepsy scale, QOLIE-31) with secondary outcomes of objective cognition measured with the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and depression (as measured by PHQ9 and NDDIE). RESULTS: Both intervention arms showed a significant improvement in quality of life, as compared with controls who demonstrated a decline in QOLIE-31 scores. There was significant improvement in objective cognitive performance among the intervention groups, most notably in attention, compared with the waitlisted controls. There was no significant change in depression scores. SIGNIFICANCE: The HOBSCOTCH program significantly improved quality of life and appeared to be an effective intervention to address cognitive dysfunction in adults with epilepsy. Further studies are needed to assess the generalizability and cost-effectiveness of this intervention. PMID- 26943949 TI - Simple and Robust Realtime QRS Detection Algorithm Based on Spatiotemporal Characteristic of the QRS Complex. AB - The purpose of this research is to develop an intuitive and robust realtime QRS detection algorithm based on the physiological characteristics of the electrocardiogram waveform. The proposed algorithm finds the QRS complex based on the dual criteria of the amplitude and duration of QRS complex. It consists of simple operations, such as a finite impulse response filter, differentiation or thresholding without complex and computational operations like a wavelet transformation. The QRS detection performance is evaluated by using both an MIT BIH arrhythmia database and an AHA ECG database (a total of 435,700 beats). The sensitivity (SE) and positive predictivity value (PPV) were 99.85% and 99.86%, respectively. According to the database, the SE and PPV were 99.90% and 99.91% in the MIT-BIH database and 99.84% and 99.84% in the AHA database, respectively. The result of the noisy environment test using record 119 from the MIT-BIH database indicated that the proposed method was scarcely affected by noise above 5 dB SNR (SE = 100%, PPV > 98%) without the need for an additional de-noising or back searching process. PMID- 26943950 TI - Layer Number Dependence of Li(+) Intercalation on Few-Layer Graphene and Electrochemical Imaging of Its Solid-Electrolyte Interphase Evolution. AB - A fundamental question facing electrodes made out of few layers of graphene (FLG) is if they display chemical properties that are different to their bulk graphite counterpart. Here, we show evidence that suggests that lithium ion intercalation on FLG, as measured via stationary voltammetry, shows a strong dependence on the number of layers of graphene that compose the electrode. Despite its extreme thinness and turbostratic structure, Li ion intercalation into FLG still proceeds through a staging process, albeit with different signatures than bulk graphite or multilayer graphene. Single-layer graphene does not show any evidence of ion intercalation, while FLG with four graphene layers displays limited staging peaks, which broaden and increase in number as the layer number increases to six. Despite these mechanistic differences on ion intercalation, the formation of a solid-electrolyte interphase (SEI) was observed on all electrodes. Scanning electrochemical microscopy (SECM) in the feedback mode was used to demonstrate changes in the surface conductivity of FLG during SEI evolution. Observation of ion intercalation on large area FLG was conditioned to the fabrication of "ionic channels" on the electrode. SECM measurements using a recently developed Li-ion sensitive imaging technique evidenced the role of these channels in enabling Li ion intercalation through localized flux measurements. This work highlights the impact of nanostructure and microstructure on macroscopic electrochemical behavior and provides guidance to the mechanistic control of ion intercalation using graphene, an atomically thin interface where surface and bulk reactivity converge. PMID- 26943951 TI - Effect of Trolox on sperm quality in normozospermia and oligozospermia during cryopreservation. AB - This study evaluated the effects of different concentrations of Trolox supplementation to cryoprotective agent (CPA) on post-thaw apoptosis-like events that include translocation of phosphatidyl serine (PS) to the cell surface, alterations in mitochondrial membrane potential (MMP), and DNA integrity of normozoospermic and oligoozoospermic semen samples. Spermatozoa from 20 normozoospermic men and 20 patients with oligoozoospermia were cryopreserved with cryo-protective agent containing 0, 20, 40, and 80 MUM Trolox. Pre cryopreservation and post-thaw sperm MMP, PS externalization and DNA fragmentation were evaluated by flow cytometry. Sperm frozen in extender with Trolox had greater MMP, lower DNA fragmentation and externalization of PS in both groups, though the most effective dose of Trolox in normozoospermic and oligoozoospermic semen samples were different. These findings support the use of Trolox as freezing extender supplement to improve the quality of cryopreserved human sperm, measured in terms of early apoptosis changes and DNA integrity, in both normozoospermic and oligoozoospermic men. PMID- 26943952 TI - Leucine-rich repeat kinase 2 is a regulator of B cell function, affecting homeostasis, BCR signaling, IgA production, and TI antigen responses. AB - LRRK2 is the causal molecule of autosomal dominant familial Parkinson's disease. B2 cells express a much higher LRRK2 mRNA level than B1 cells. To reveal the function of LRRK2 in B cells, we analyzed B cell functions in LRRK2-knockout (LRRK2(-/-)) mice. LRRK2(-/-) mice had significantly higher counts of peritoneal B1 cells than wild-type mice. After BCR stimulation, phosphor-Erk1/2 of splenic B2 cells was enhanced to a higher degree in LRRK2(-/-) mice. LRRK2(-/-) mice had a significantly higher serum IgA level, and TNP-Ficoll immunization increased the titer of serum anti-TNP IgM antibody. LRRK2 may play important roles in B cells. PMID- 26943954 TI - Disease specific enrichment of circulating let-7 family microRNA in MuSK+ myasthenia gravis. AB - Myasthenia gravis (MG) patients with antibodies against the muscle specific tyrosine kinase (MuSK+) have predominantly involvement of cranio-bulbar muscles and do not display thymus pathology, as do acetylcholine receptor antibody seropositive (AChR+) MG patients. In search of novel biomarkers for MuSK+ MG, we evaluated circulating serum microRNAs. Four analyzed microRNAs were specifically elevated in MuSK+ MG patient serum samples: let-7a-5p, let-7f-5p, miR-151a-3p and miR-423-5p. The circulating microRNA profile in MuSK+ MG differs from the profile previously observed in the serum of AChR+ MG, thus indicating the etiological difference between these two entities. We propose that the identified microRNAs could serve as potential serum biomarkers for MuSK+ MG. PMID- 26943953 TI - TrkB agonist, 7,8-dihydroxyflavone, reduces the clinical and pathological severity of a murine model of multiple sclerosis. AB - 7,8-Dihydroxyflavone (DHF), is a recently described TrkB agonist that readily crosses the blood brain barrier. We treated C57Bl/6 mice with MOG--induced EAE daily with DHF starting on the day of disease induction. Clinical severity of impairment was reduced throughout the course of disease. Pathological examination of brains and spinal cords on day 28 showed that DHF treatment increased the phosphorylation of TrkB and activated downstream signaling pathways including AKT and STAT3 and reduced inflammation, demyelination and axonal loss compared to EAE controls. DHF treatment duplicated the central nervous system effects of brain derived neurotrophic factor in the EAE. PMID- 26943955 TI - Emerging roles of the acute phase protein pentraxin-3 during central nervous system disorders. AB - Pentraxin-3 (PTX3) is an acute phase protein (APP) and a member of the long pentraxin family that is recognised for its role in peripheral immunity and vascular inflammation in response to injury, infection and diseases such as atherosclerosis, cancer and respiratory disease. Systemic levels of PTX3 are highly elevated in these conditions, and PTX3 is now recognised as a new biomarker of disease risk and progression. There is extensive evidence demonstrating that central nervous system (CNS) disorders are primarily characterised by central activation of innate immunity, as well as activation of a potent peripheral acute phase response (APR) that influences central inflammation and contributes to poor outcome. PTX3 has been recently recognised to play important roles in CNS disorders, having both detrimental and neuroprotective effects. The present review aims to give an up-to-date account of the emerging roles of PTX3 in CNS disorders, and to provide a critical comparison between peripheral and central actions of PTX3 in inflammatory diseases. PMID- 26943956 TI - A gene expression study denies the ability of 25 candidate biomarkers to predict the interferon-beta treatment response in multiple sclerosis patients. AB - We studied the baseline expression level of 25 interferon-regulated genes (MxA, GPR3, IL17RC, ISG15, TRAIL, OASL, IFIT1, IFIT2, RSAD2, OAS3, IFI44L, TRIM22, IL10, CXCL10, STAT1, OAS1, OAS2, IFNAR1, IFNAR2, IFNbeta, ISG20, IFI6, PKR, IRF7, USP18), recurrently proposed in the literature as predictive biomarkers of interferon-beta treatment response, in whole blood of 10 "responders" and 10 "non responders" multiple sclerosis relapsing-remitting patients, retrospectively selected on the basis of stringent clinical criteria after a five years follow up. However, we cannot confirm the predictive value of these candidate biomarkers. PMID- 26943957 TI - Cerebrospinal fluid concentration of Galectin-9 is increased in secondary progressive multiple sclerosis. AB - Galectin-9 is produced by activated astrocytes, induces a pro-inflammatory response in microglia and may be important to the pathogenesis of secondary progressive MS. In this study, Galectin-9 concentrations in CSF samples from healthy controls and two independent patient cohorts of MS patients were determined by ELISA. Patients from one of the cohorts underwent MRI as well. Galectin-9 concentrations in CSF were higher in SPMS patients than healthy controls and RRMS patients in both cohorts. Galectin-9 concentrations correlated with the number of lesions on T1-weighted images, but not with gadolinium enhancing lesions, IgG index or CSF cell count. PMID- 26943958 TI - Aggression as an independent entity even in psychosis- the role of inflammatory cytokines. AB - BACKGROUND: Aggression is very common in psychosis (prevalence ranging from 34% to 70%) and is often the main or first symptom for which the patient receives medical attention. Studies have associated alteration in cytokine profiles among healthy persons with aggressive traits. We hypothesise that even among those with psychosis, aggression is an independent entity, irrespective of psychotic state and is associated with cytokine alterations. To our knowledge, this is the first study attempting to look at the inflammatory cytokines in aggressive psychotic patients. METHODS: Study included 80 participants divided into four groups viz. aggressive diseased, non aggressive diseased, aggressive non diseased and non aggressive non diseased depending upon presence or absence of aggression and psychosis. Interferon gamma(IFN-G), Interleukin 10(IL10) plasma concentrations and their ratio were measured using ELISA based assay kits read at absorbance of 450 nm wavelength using Double beam spectrophotometer. The four groups were compared on measures of aggression, psychosis, Interferon Gamma levels, Interleukin 10 levels, Proinflammatory: Antiinflammatory cytokine ratio using standard statistical instruments. RESULTS: In patients with psychosis, the cytokines IFN-G and IL10 were significantly lower compared to those without. The cytokines IFN-G and IL10 are both significantly associated both with aggression and psychosis. IL10, but not IFN-G is associated with aggression in absence of psychosis. The proinflammatory: antiinflammatory cytokine ratio, is more significantly associated with aggression, irrespective of psychosis. In fact, there is no significant relationship between the above ratio and psychosis. Strong correlation exists between the proinflammatory: antiinflammatory cytokine ratio and aggression scores, even after controlling for severity of psychosis. CONCLUSIONS: It may be concluded from this study that in spite of a high prevalence of aggression in patients of psychosis, it is more likely to be an independent entity associated with individual cytokine changes and increased proinflammatory: antiinflammatory cytokine ratio as its hallmark. PMID- 26943959 TI - YKL-40 is a CSF biomarker of intrathecal inflammation in secondary progressive multiple sclerosis. AB - YKL-40 (CHI3L1) is a glycoprotein predominantly produced by reactive astrocytes in chronic active MS lesions, which are common in secondary progressive MS. In this study, YKL-40 was investigated in different stages of MS and in relation to MRI findings. YKL-40 levels in CSF samples from two independent patient cohorts of MS patients were determined with ELISA. CSF YKL-40 was increased in patients with active relapsing-remitting MS and correlated with the number of gadolinium enhancing lesions. Patients with secondary progressive MS had similar high levels of YKL-40, whereas not active relapsing-remitting MS patients had YKL-40 levels comparable to healthy controls. PMID- 26943960 TI - Metformin ameliorates the development of experimental autoimmune encephalomyelitis by regulating T helper 17 and regulatory T cells in mice. AB - Immoderate immunoreaction of antigen-specific Th17 and Treg cell dysfunction play critical roles in the pathogenesis of multiple sclerosis. We examined Th17/Treg immune responses and the underlying mechanisms in response to metformin in C57BL/6 mice with experimental autoimmune encephalomyelitis (EAE). Metformin reduced Th17 and increased Treg cell percentages along with the levels of associated cytokines. Molecules involved in cellular metabolism were altered in mice with EAE. Suppressed activation of mTOR and its downstream target, HIF 1alpha, likely mediated the protective effects of metformin. Our findings demonstrate that regulation of T cell metabolism represents a new therapeutic target for CNS autoimmune disorders. PMID- 26943962 TI - Immunomodulation by vitamin D in multiple sclerosis: More than IL-17. PMID- 26943963 TI - Diagnosis of myasthenia gravis: Comparison of anti-nicotinic acetyl choline receptor antibodies, repetitive nerve stimulation and Neostigmine tests at a tertiary neuro care centre in India, a ten year study. AB - Anti-nicotinic AChR antibodies (Anti-nAChR antibodies), Repetitive Nerve Stimulation (RNS) and Neostigmine test are used for diagnosis of myasthenia gravis (MG). We compared their diagnostic agreement in a cohort of 486 MG patients over a period of ten years. Anti-nAChR antibodies, RNS and Neostigmine test showed positivity of 57.36%, 51.78%, and 93.4% respectively in ocular myasthenia and 93.77%, 82.35%, and 97.92% respectively in generalized myasthenia group. Neostigmine test showed higher positivity than anti-nAChR antibodies and RNS test in both groups. A marginal to fair agreement was observed between these tests highlighting their significance in the diagnosis of the disease. PMID- 26943961 TI - Dicer and microRNA expression in multiple sclerosis and response to interferon therapy. AB - Dysregulation of microRNA expression has been shown in multiple sclerosis (MS); however, the mechanisms underlying these changes, their response to therapy and the impact of microRNA changes in MS are not completely understood. Dicer mediates the cleavage of precursor microRNAs to mature microRNAs and is dysregulated in multiple pathologies. Having shown that interferons regulate Dicer in vitro, we hypothesized that MS patient IFNbeta1a treatment could potentially alter Dicer expression. Dicer mRNA and protein levels, as well as microRNA expression, were determined in MS patient and healthy control PBL. Acute responses to IFNbeta1a were assessed in 50 patients. We found that Dicer protein but not mRNA levels decreases in MS patients while both are selectively induced in patients responding well to IFNbeta1a. Potential microRNA biomarkers for relapsing remitting multiple sclerosis (RRMS), secondary progressive multiple sclerosis (SPMS) and IFNbeta1a response are described. Contrasts in Dicer and microRNA expression levels between patient populations may offer insight into mechanisms underlying disease courses and responses to IFNbeta1a therapy. This work identifies Dicer regulation as both a potential mediator of MS pathology and a therapeutic target. PMID- 26943964 TI - Progesterone modulates pro-inflammatory cytokine expression profile after spinal cord injury: Implications for neuropathic pain. AB - Neuropathic pain is a frequent complication of spinal cord injury (SCI), still refractory to conventional treatment. Glial cell activation and cytokine production contribute to the pathology of central neuropathic syndromes. In this study we evaluated the effects of progesterone, a neuroactive steroid, on pain development and the spinal expression of IL-1beta, its receptors (IL-1RI and IL 1RII) and antagonist (IL-1ra), IL-6 and TNFalpha, and NR1 subunit of NMDAR. Our results show that progesterone, by modulating the expression of pro-inflammatory cytokines and neuronal IL-1RI/NR1 colocalization, emerges as a promising agent to prevent chronic pain after SCI. PMID- 26943965 TI - Differential screening-selected gene aberrative in neuroblastoma (DAN) is increased in the CSF of patients with MS and may be induced by therapy with interferon-beta. AB - Bone morphogenic proteins (BMPs) signaling blockade induce neurogenesis and oligodendrogenesis. Differential screening-selected gene aberrative in neuroblastoma (DAN) is a glycoprotein that antagonizes BMPs. We found that DAN levels were higher in CSF compared to serum in all participants. CSF-DAN levels were elevated in RR-and progresssive MS patients compared to controls. Moreover, serum-DAN levels were reduced in those patients, but elevated in IFN-beta1a treated patients. The main source of DAN is apparently CNS- resident cells. The enhanced levels of CSF-DAN in MS patients suggest a tendency to induce neurogenesis/oligodendrogenesis in the patients CNS. Our results suggest an unreported mode of action of IFN-beta1a. PMID- 26943966 TI - The role of dopamine in modulation of Th-17 immune response in multiple sclerosis. AB - Neuromediators may modulate neuroinflammation, particularly in multiple sclerosis (MS). We investigated the effects of dopamine (DA) on the pro-inflammatory Th17 branch of immunity in 43 patients with relapsing-remitting MS and 20 healthy subjects. Serum DA was lower in MS relapse, whereas percentages of blood CD4(+)CD26(+)CD161(+)CD196(+) Th17-cells and production of interleukin-17 (IL-17) and interferon-gamma by anti-CD3/anti-CD28-stimulated peripheral blood mononuclear cells (PBMC) were higher in MS relapse than in remission or healthy subjects. DA suppressed IL-17 production by PBMC from MS patients and healthy subjects. The suppressive effect of DA was abolished in the presence of an antagonist of D2-like receptors (sulpiride). These data suggest an anti inflammatory role for DA in MS. PMID- 26943967 TI - Association of ICAM-1 (K469E) and MCP-1 -2518 A>G gene polymorphism with brain abscess. AB - Brain abscess develops in response to a parenchymal infection. Intercellular adhesion molecule-1 (ICAM-1) and monocyte chemoattractant protein-1 (MCP-1) play vital role in central nervous system (CNS) diseases. We studied ICAM-1 (K469E) and MCP-1 (-2518 A>G) polymorphisms among brain abscess patients. The genotypic distributions of ICAM-1 (K469E) and MCP-1 (-2518 A>G) were significantly different between patients and controls. Further, patient with predisposing factors, and also with culture result, we found significant association. The study revealed that the polymorphisms of these molecules lead to increased production, which appears to be a risk for the development of brain abscess. PMID- 26943968 TI - Titin antibodies in "seronegative" myasthenia gravis--A new role for an old antigen. AB - Myasthenia gravis (MG) is an autoimmune disease caused by antibodies targeting the neuromuscular junction of skeletal muscles. Triple-seronegative MG (tSN-MG, without detectable AChR, MuSK and LRP4 antibodies), which accounts for ~10% of MG patients, presents a serious gap in MG diagnosis and complicates differential diagnosis of similar disorders. Several AChR antibody positive patients (AChR-MG) also have antibodies against titin, usually detected by ELISA. We have developed a very sensitive radioimmunoprecipitation assay (RIPA) for titin antibodies, by which many previously negative samples were found positive, including several from tSN-MG patients. The validity of the RIPA results was confirmed by western blots. Using this RIPA we screened 667 MG sera from 13 countries; as expected, AChR-MG patients had the highest frequency of titin antibodies (40.9%), while MuSK-MG and LRP4-MG patients were positive in 14.6% and 16.4% respectively. Most importantly, 13.4% (50/372) of the tSN-MG patients were also titin antibody positive. None of the 121 healthy controls or the 90 myopathy patients, and only 3.6% (7/193) of other neurological disease patients were positive. We thus propose that the present titin antibody RIPA is a useful tool for serological MG diagnosis of tSN patients. PMID- 26943971 TI - Obesity and infertility: the importance of ART policies and practice standards. PMID- 26943970 TI - Vitamin D3 alters microglia immune activation by an IL-10 dependent SOCS3 mechanism. AB - Microglia become activated immune cells during infection or disease in the central nervous system (CNS). However, the mechanisms that downregulate activated microglia to prevent immune-mediated damage are not completely understood. Vitamin D3 has been suggested to have immunomodulatory affects, and high levels of vitamin D3 have been correlated with a decreased risk for developing some neurological diseases. Recent studies have demonstrated the synthesis of active vitamin D3, 1,25-dihydroxyvitamin D3, within the CNS, but its cellular source and neuroprotective actions remain unknown. Therefore, we wanted to determine whether microglia can respond to vitamin D3 and whether vitamin D3 alters immune activation of microglia. We have previously shown that microglia become activated by IFNgamma or LPS or by infection with virus to express pro-inflammatory cytokines, chemokines, and effector molecules. In this study, activated microglia increased the expression of the vitamin D receptor and Cyp27b1, which encodes the enzyme for converting vitamin D3 into its active form, thereby enhancing their responsiveness to vitamin D3. Most importantly, the activated microglia exposed to vitamin D3 had reduced expression of pro-inflammatory cytokines, IL-6, IL-12, and TNFalpha, and increased expression of IL-10. The reduction in pro inflammatory cytokines was dependent on IL-10 induction of suppressor of cytokine signaling-3 (SOCS3). Therefore, vitamin D3 increases the expression of IL-10 creating a feedback loop via SOCS3 that downregulates the pro-inflammatory immune response by activated microglia which would likewise prevent immune mediated damage in the CNS. PMID- 26943972 TI - T cell fitness in the liver: How can T cells keep it up? PMID- 26943969 TI - Characterization of neuropathology in the HIV-1 transgenic rat at different ages. AB - The transgenic HIV-1 rat (Tg) is a commonly used neuroHIV model with documented neurologic/behavioral deficits. Using immunofluorescent staining of the Tg brain, we found astrocytic dysfunction/damage, as well as dopaminergic neuronal loss/dysfunction, both of which worsening significantly in the striatum with age. We saw mild microglial activation in young Tg brains, but this decreased with age. There were no differences in neurogenesis potential suggesting a neurodegenerative rather than a neurodevelopmental process. Gp120 CSF levels exceeded serum gp120 levels in some animals, suggesting local viral protein production in the brain. Further probing of the pathophysiology underlying astrocytic injury in this model is warranted. PMID- 26943973 TI - Poly(ethylene glycol) enclatherated pectin-mucin submicron matrices for intravaginal anti-HIV-1 drug delivery. AB - This paper explores the potential of polyethylene glycol enclatherated pectin mucin (PEG-encl-PEC:MUC) submicron matrices (SMMs) as an intravaginal drug delivery system capable of delivering an anti-HIV-1 agent (zidovudine; AZT) over a prolonged duration. A three factor and three level (3(3)) Box-Behnken statistical design was employed to optimize the SMMs. Optimized PEG-encl-PEC:MUC SMMs prepared as a stable W/O emulsion (determined by the degree of reversible colloidal phenomena) were spherical with a mean particle size of 270.6 +/- 5.533 nm and mean zeta potential of -34.4 +/- 0.539 mV. The microencapsulation of AZT and the hydrogen bonding mediated shielding of AZT by SMMs was confirmed by Fourier Transform Infrared (FTIR) analysis. The thermochemical (differential scanning calorimetry and thermogravimetric analysis) data proposed that Ca(2+) based macromolecular ionic crosslinking as well as the intermolecular interactions may be responsible for the thermal stability of the delivery system. The partially amorphous nature of drug-loaded SMMs, as confirmed by X-ray diffraction patterns, further strengthened the matricization of AZT into the pectin-mucin matrix. In vitro drug release studies from the SMMs showed approximately 91% zidovudine release in simulated vaginal fluid (SVF) and 94% in phosphate buffered saline (PBS) in 24h. The mean dissolution time (MDT) of zidovudine from the SMMs was 5.974 h. The attainment of required dimensional structure and drug release profiles from SMMs highlights the potential of their inclusion into a secondary carrier system for extended and controlled intravaginal stay. PMID- 26943974 TI - Freeze-drying of emulsified systems: A review. AB - Colloidal systems such as emulsions, microemulsions and nanoemulsions are able to transport active molecules, enhance their solubility and stability and minimize their side effects. However, since they are dispersions with an aqueous continuous phase they have some disadvantages such as the risk of microbiological contamination, degradation by hydrolysis, physico-chemical instability and loss of pharmacological activity of the drug. Freeze drying, in which the water is removed from the preparation by sublimation under vacuum, has been suggested as a means to resolve these problems. Lyophilized products are very stable and are easy to transport and store. However, there is very little information in the literature about the application of this technique to emulsified systems. The aim of this review is to evaluate the lyophilization process as a tool for increasing the shelf life of emulsified systems such as emulsions, microemulsions and nanoemulsions. In addition, the mechanism of cryoprotection and the techniques that can be used to characterize the freeze-dried systems are discussed. PMID- 26943975 TI - Design and evaluation of an innovative floating and bioadhesive multiparticulate drug delivery system based on hollow structure. AB - In this study a gastric-retentive delivery system was prepared by a novel method which is reported here for the first time. An innovative floating and bioadhesive drug delivery system with a hollow structure was designed and prepared. The floating and bioadhesive drug delivery system was composed of a hollow spherical shell, a waterproof layer (Stearic acid), a drug layer (Ofloxacin), a release retarding film (the novel blended coating materials) and a bioadhesive layer (Carbomer 934P) prepared by using a liquid multi-layering process. A novel blended coating material was designed and investigated to solve the problem of the initial burst release of the formulation and the release mechanism of the novel material was analyzed in this study. The optimized formulation provided the sustained release characteristic and was able to float for 24h. The SEM cross section images showed that the particulates were hollow with a spherical shell. X ray images and pharmacokinetic studies (Frel = 124.1 +/- 28.9%) in vivo showed that the gastric-retentive delivery system can be retained in the stomach for more than 6h. The floating and bioadhesive particulate drug delivery system based on a hollow structure with a dual function presented here is a viable alternative to other for gastroretentive drug delivery system. PMID- 26943977 TI - One-year cardiovascular outcomes of drug-eluting stent versus bare-metal stent implanted in diabetic patients with acute coronary syndrome. AB - BACKGROUND: The outcomes of drug-eluting stent (DES) versus bare-metal stent (BMS) use in patients with diabetic mellitus (DM) and acute coronary syndrome (ACS) are rarely reported in Taiwan. This study aimed to investigate the 1-year cardiovascular outcomes of DESs versus BMSs implanted in Taiwanese patients with DM and ACS. METHODS: For this study, we collected and analyzed patient information from the database of the Taiwan ACS Full Spectrum registry regarding characteristics and cardiovascular events in participants with DM and ACS who received implantation of either BMS (BMS group) or DES (DES group) from October 2008 to January 2010. RESULTS: We found that several characteristics significantly varied between the groups. Compared with the BMS group (n = 575), the DES group (n = 199) had significantly lower rates of in-hospital cardiogenic shock (1.5% vs. 4.9%, p = 0.037) and acute renal failure (0.5% vs. 4.5%, p = 0.008), all-cause mortality (5.0% vs. 8.9%, p = 0.048), and major adverse cardiac events (MACEs) at 1 year (11.1% vs. 18.6%, p = 0.006) with an identical target vessel revascularization (TVR) rate (6.0% vs. 7.3%, p = 0.395). The BMS group had significantly higher risk-adjusted all-cause mortality [hazard ratio (HR) = 2.4, 95% confidence interval (CI) 1.0-5.7; p = 0.048] and MACE (HR = 2.2, 95% CI 1.2 3.9; p = 0.011) at 1 year with identical risks of TVR (HR = 1.3, 95% CI 0.6-2.9; p = 0.505) and nonfatal myocardial infarction (HR = 1.5, 95% CI 0.5-4.4; p = 0.478). CONCLUSION: The results of this study support the use of DES over BMS in Taiwanese patients with DM and ACS, providing the clinical benefits of lower rates of total mortality and MACE, and without increased TVR at 1 year in a real world setting. PMID- 26943978 TI - Severe fever with thrombocytopenia syndrome with myocardial dysfunction and encephalopathy: A case report. AB - Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease in China, Korea and Japan caused by a novel bunyavirus, SFTS virus (SFTSV). Although central nervous system manifestations are common in SFTS patients, the pathogenesis has not been elucidated; and there are few reports of myocardial dysfunction. Here we report an elderly Japanese patient with reversible myocardial dysfunction and encephalopathy. A previously healthy 65 year-old male engaged in forestry got a tick bite and developed fever and fatigue in 3 days. Three days after onset, he presented to a local hospital where the diagnosis of SFTS with hemophagocytotic syndrome was made. The blood test showed leukopenia and thrombocytopenia as well as elevated levels of alanine aminotransferase and aspartate aminotransferase. Marked hemophagocytosis was found on bone marrow smear. Peripheral blood was positive for SFTSV gene by reverse-transcription polymerase chain reaction. On day 7, the patient was transferred to our hospital. We observed disturbance of consciousness, Kernig sign and myoclonus to face and limbs. Decreased blood flow of whole cerebral cortex was detected by single photon emission computed tomography (SPECT). Chest X-ray revealed cardiomegaly and electrocardiography (ECG) showed abnormal T waves. These data suggested acute encephalopathy and myocardial dysfunction. We treated him with corticosteroid and blood transfusion, which resulted in the complete recovery of the above abnormal symptoms and laboratory data including the findings in SPECT and ECG in about a month. This case demonstrated transient myocardial dysfunction and encephalopathy can occur in addition to typical clinical manifestation of SFTS. PMID- 26943976 TI - Developmental stress and lead (Pb): Effects of maternal separation and/or Pb on corticosterone, monoamines, and blood Pb in rats. AB - The level of lead (Pb) exposure in children has decreased dramatically since restrictions on its use were implemented. However, even with restrictions, children are exposed to Pb and still present with cognitive and behavioral deficits. One prominent aspect of the exposome of these children is that many come from low social economic status (SES) conditions, and low SES is associated with stress. In order to compare the combined effects of early stress and Pb, Sprague-Dawley rats were exposed to vehicle or Pb either alone or in combination with maternal separation stress during brain development (i.e., postnatal day (P)4-P11, P19, or P28). Maternally separated/isolated pups had lower body and thymus weights during exposure and had increased levels of blood Pb compared with vehicle controls. Isolation, but not Pb, affected the response to an acute stressor (standing in shallow water) when assessed on P19 and P29, but not earlier on P11. Interactions of Pb and isolation were found on monoamines in the neostriatum, hippocampus, and hypothalamus on turnover but not on levels, and most changes were on dopamine turnover. Isolation had greater short-term effects than Pb. Interactions were dependent on age, sex, and acute stress. PMID- 26943979 TI - Technology for Diagnosis, Treatment, and Prevention of Cardiometabolic Disease in India. AB - Cardiometabolic diseases (CMD) are a major cause of mortality, morbidity and disability worldwide. Among Indians, CMD onset is at a much younger age and is prevalent in all sections of the society. Prevention, control and management of CMD and its risk factors is a major public health challenge, and alternative approaches need to be explored and integrated into public health programs. Advancements in the fields of computers, electronics, telecommunication and medicine have resulted in the rapid development of health-related technology. In this paper we provide an overview of the major technological advances in diagnosis, treatment and prevention within the field of CMD in the last few decades. This non-exhaustive review focuses on the most promising technologies that the authors feel might be of relevance in the Indian context. Some of the techniques detailed include advances in imaging and mobile phone technology, surgical techniques, electronic health records, Nano medicine, telemedicine and decision support systems. PMID- 26943980 TI - HIV Infection and Primary Prevention of Cardiovascular Disease: Lights and Shadows in the HAART Era. AB - With the progressive increase in life-expectancy of human immunodeficiency virus (HIV)-positive patients in the "highly active antiretroviral therapy" (HAART) era, co-morbidities, particularly cardiovascular (CV) diseases (CVD) are emerging as an important concern. The pathophysiology of CVD in this population is complex, due to the interaction of classical CV risk factors, viral infection and the effects of antiretroviral therapy (ARV). The role of ARV drugs in HIV is double edged. While these drugs reduce systemic inflammation, an important factor in CV development, they may at the same time be proatherogenic by inducing dyslipidemia, body fat redistribution and insulin resistance. In these patients primary prevention is challenging, considering the lower median age at which acute coronary syndromes occur. Furthermore prevention is still limited by the lack of robust evidence-based, HIV-specific recommendations. Therefore we performed a comprehensive evaluation of the literature to analyze current knowledge on CVD prevalence in HIV-infected patients, traditional and HIV specific risk factors and risk stratification, and to summarize the recommendations for primary prevention of CVD in this HIV population. PMID- 26943981 TI - Utility of Consumer Physical Activity Trackers as an Intervention Tool in Cardiovascular Disease Prevention and Treatment. AB - Consumer activity trackers have grown in popularity over the last few years. These devices are typically worn on the hip or wrist and provide the user with information about physical activity measures such as steps taken, energy expenditure, and time spent in moderate to vigorous physical activity. The consumer may also use the computer interface (e.g. device websites, smartphone applications) to monitor and track achievement of PA goals and compete with other users. This review will describe some of the most popular consumer devices and discuss the user feedback tools. We will also present the limited evidence available about the accuracy of these devices and highlight how they have been used in cardiovascular disease management. We conclude with some recommendations for future research, focusing on how consumer devices might be used to assess effectiveness of various cardiovascular treatments. PMID- 26943982 TI - CKD and Infectious Diseases in Asia Pacific: Challenges and Opportunities. AB - The exact number of patients with chronic kidney disease (CKD) in Asia Pacific is uncertain. In numeric terms, the region is home to the largest population of patients with untreated chronic kidney failure. The climatic, geographic, social, cultural, economic, and environmental diversity within this region is higher than in any other part of the world. Large parts of the region face a climate-related burden of infectious diseases. Infections contribute to the development and progression of CKD and complicate the course of patients with pre-existing CKD (especially those on dialysis therapy or who are immunosuppressed), increase the cost of CKD care, and contribute to mortality and morbidity. Kidney involvement is a feature of several infectious diseases prevalent in Asia Pacific. Examples include malaria, leptospirosis, scrub typhus, tuberculosis, hepatitis B and C virus, dengue hemorrhagic fever, and Hantaan virus infections. The contribution of infection-associated acute kidney injury to the overall burden of CKD has not been evaluated systematically. Research is needed to quantify the impact of infections on kidney health by undertaking prospective studies. Nephrologists need to work with infectious disease research groups and government infection surveillance and control programs. PMID- 26943983 TI - Controversies Regarding Lipid Management and Statin Use for Cardiovascular Risk Reduction in Patients With CKD. AB - Adults with chronic kidney disease (CKD) are at heightened risk for dying of cardiovascular disease. Results from randomized clinical trials of statin drugs versus placebo demonstrate that statin drugs or statin plus ezetimibe reduce the absolute risk for coronary heart disease and mortality among adults with non dialysis-dependent CKD. The Kidney Disease: Improving Global Outcomes 2013 clinical practice guideline for lipid management in CKD recommends that adults 50 years or older with non-dialysis-dependent CKD be treated with a statin or statin plus ezetimibe regardless of low-density lipoprotein cholesterol levels. However, at least 9 guidelines published during the last 5 years address lipid management for primary and secondary prevention of atherosclerotic cardiovascular disease, and not all guidelines address the utility of lipid-lowering therapy in adults with CKD. Because most patients with CKD receive most of their clinical care from non-nephrologists, differences in recommendations for lipid-lowering therapy for cardiovascular disease prevention may negatively affect the clinical care of adults with CKD and cause confusion for both patients and providers. This review addresses the identification and management of lipid levels in patients with CKD and discusses the existing controversies regarding testing and treatment of lipid levels in the CKD population. PMID- 26943984 TI - Progression to musculoskeletal deformity in childhood dystonia. AB - AIM: Dystonia is a movement disorder characterized by involuntary muscle contractions, resulting in abnormalities of posture and movement. Children with dystonia are at risk of developing fixed musculoskeletal deformities (FMDs). FMDs cause pain, limit function and participation and interfere with care. We aimed to explore factors relating to the development of FMD in a large cohort of children with dystonia. METHOD: The case notes of all children referred to our Complex Motor Disorder service between July 2005 and December 2011 were reviewed. Data from 279 children (median age 9 years 10 months, Standard Deviation 4 years 2 months) with motor disorders including a prominent dystonic element were analyzed. Parametric accelerated failure time regression was used to identify the factors related to development of contractures. RESULTS: FMDs were present at referral in more than half (n = 163, 58%) of cases. Three quarters (n = 120, 74%) of children with FMD had deformities around the hip, and 42% had spinal deformity (n = 68). Compared to pure primary dystonia, FMD onset was earlier with a diagnosis of secondary or heredodegenerative dystonia, and a mixed spastic dystonic phenotype (all p < 0.001). FMD onset was also earlier with increasing Gross Motor Function Classification System (GMFCS) level (p < 0.001). The effect of aetiological classification was lost when controlling for GMFCS level and motor phenotype. INTERPRETATION: Children with secondary or heredodegenerative dystonia are at greater risk of progression to FMD compared to primary dystonia, likely due to more severe dystonia within these groups. Children with additional spasticity are at particular risk, requiring close monitoring. PMID- 26943985 TI - Congenital Harlequin syndrome as an isolated phenomenon: A case report and review of the literature. AB - Harlequin syndrome (HS) is a rare autonomic disorder due to a hemifacial cutaneous sympathetic denervation. It is characterized by unilateral diminished sweating and flushing of the face even though after heat or prolonged exercise. It is typically acquired. Congenital cases only represent a 6% of all individuals with HS. All congenital HS cases reported so far showed a concomitant Horner syndrome, probably due to a stellate ganglion involvement. HS represents an uncommon autonomic disorder due to a hemifacial cutaneous sympathetic denervation. It is clinically characterized by a dramatic alteration in facial appearance: ipsilateral denervated pale and dry half from the other intact red and moist half. CONCLUSION: We present, to the best of our knowledge, the first case of a patient with a congenital HS as an isolated phenomenon. PMID- 26943986 TI - Factors influencing left atrial volume in a population with preserved ejection fraction: Left ventricular diastolic dysfunction or clinical factors? AB - BACKGROUND: Increased left atrial volume (LAV) predicts a higher incidence of cardiovascular events and is widely recognized as a major surrogate marker of left ventricular (LV) diastolic dysfunction (DD). Although the pathophysiology of LA enlargement is probably multifactorial, few studies have examined comprehensively the clinical factors that lead to LA enlargement in the absence of valvular disease or LV systolic dysfunction. Therefore, we investigated associations between LAV and several clinical and echocardiographic parameters including DD. METHODS: We enrolled 557 subjects without significant valve disease or LV systolic dysfunction from the health check-up clinic retrospectively. We performed univariable and multivariable linear regression using lnLAV index as the dependent variable and the following independent variables: gender, age, smoking status, drinking habit, hypertension, diabetes, body mass index (BMI), LV ejection fraction, DD, LV mass index, hemoglobin, serum creatinine, serum total cholesterol, serum uric acid, serum sodium, and serum iron. RESULTS: In multivariable analysis, LAV index was independently associated with BMI, lower hemoglobin, and moderate and severe DD compared with normal diastolic function (p<0.001), but not with mild DD (p=0.70). CONCLUSIONS: LA enlargement was independently associated with moderate and severe DD, but not with mild DD. Furthermore, obesity and lower hemoglobin were associated with LAV independently of DD. PMID- 26943987 TI - A Phase Ib Open-Label Study to Assess the Safety and Tolerability of Everolimus in Combination With Eribulin in Triple-Negative Breast Cancers. AB - BACKGROUND: The VERITAS (A Phase 1B open-label study to assess the safety and tolerability of everolimus in combination with eribulin in triple-negative breast cancers) trial (EudraCT number: 2014-000135-17) is a phase Ib, open label, multicenter, dose-escalation, safety, pharmacokinetic, and pharmacodynamic study based on the combination of everolimus with eribulin in sequential cohorts of metastatic triple negative breast cancer (TNBC) patients. PATIENTS AND METHODS: The primary objective of the study is to identify the recommended dose of everolimus in combination with eribulin. Secondary endpoints include the assessment of pharmacokinetics and antitumor activity of the experimental treatment. The sample size is based on the Bayesisan approach with regards to the maximum tolerated dose (MTD) and maximum tolerated dose (MTD) observed. An average sample size of approximately 12 patients is deemed reasonable based on simulations. CONCLUSION: The VERITAS trial is expected to determine the recommended dose of everolimus in combination with eribulin in TBNC. This study may open the way for further analysis of this combination in phase II studies in this orphan disease of active drug combination such as the TNBC subset. PMID- 26943988 TI - Long-Term Disease-Free Survival in a Young Patient With Hormone Receptor-Positive Breast Cancer and Oligometastatic Disease in the Brain. PMID- 26943989 TI - Effect of Aromatase Inhibitor Therapy on the Cardiovascular Health of Black and White Breast Cancer Patients. AB - BACKGROUND: The present study examined racial differences in the cardiovascular health effects of aromatase inhibitors. PATIENTS AND METHODS: Data were analyzed from 77 white and 35 black patients with early-stage breast cancer initiating aromatase inhibitor therapy and subsequently followed for 1 year. At baseline and a 1-year follow-up clinic visit, a comprehensive cardiovascular health assessment was conducted, which included measurement of carotid intima-medial thickness and a blood draw to measure high-sensitivity C-reactive protein and cholesterol concentrations. A detailed questionnaire was also completed. The information collected was used to calculate each patient's 10-year risk of atherosclerotic cardiovascular disease events at both measurement points. Paired t tests were used to examine the changes in the continuous outcome variables within groups during the study period. Independent t tests were conducted to examine the changes over time between the 2 groups. RESULTS: No statistically significant changes in carotid intima-medial thickness, atherosclerotic cardiovascular disease risk score, or the other cardiovascular-related outcomes (high sensitivity C-reactive protein, cholesterol levels, blood pressure) during the first year of aromatase inhibitor therapy were observed among either the black or white breast cancer patients or between the 2 groups. Mean grip strength in the dominant hand decreased significantly and similarly during the 1-year period for the white and black breast cancer patients. CONCLUSION: The findings from the present study suggest no large adverse cardiovascular health effects from aromatase inhibitors during the first year of therapy among either black or white breast cancer patients. However, the results of the present study cannot rule out the potential for long-term adverse changes over the duration of aromatase inhibitor therapy or beyond. PMID- 26943990 TI - Post-Mastectomy Radiation Therapy for Invasive Lobular Carcinoma: A Comparative Utilization and Outcomes Study. AB - BACKGROUND: To date, there have been no analyses to assess factors that influence post-mastectomy radiation therapy (PMRT) utilization in invasive lobular carcinoma (ILC) or to quantify the benefit of PMRT in ILC as compared with invasive ductal carcinoma (IDC). We compared histology-specific utilization of PMRT by tumor and patient characteristics and estimated the effect of PMRT on overall and breast cancer-specific survival in ILC and IDC patients meeting American College of Radiology (ACR) criteria for PMRT. PATIENTS AND METHODS: We used the Surveillance, Epidemiology, and End Results database to identify women diagnosed with ILC or IDC from 2004 to 2009 who underwent mastectomy. We assessed utilization of PMRT by T and N stage, analyzed factors associated with PMRT use, and quantified the histology-specific survival benefit of PMRT using log-rank tests and multivariate Cox regression analysis. RESULTS: We identified 86,098 IDC and 12,703 ILC patients. Within this cohort, 18.7% of IDC patients and 26.1% of ILC met ACR criteria for PMRT. Among patients with a definite indication, PMRT was more commonly employed in ILC than in IDC (59.6% vs. 56.3%; P = .0004). Among patients with a definite indication for PMRT, radiation improved 5-year breast cancer-specific survival from 71.4% to 77.0% for IDC (P < .0001) and from 80.9% to 84.7% for ILC (P = .0003). CONCLUSIONS: PMRT was used more commonly in ILC than in IDC. PMRT significantly improves 5-year overall survival and breast cancer-specific survival for ILC patients to a degree comparable with that seen in IDC. Moreover, among ILC and IDC patients who meet ACR criteria, PMRT appears to be significantly underutilized. PMID- 26943991 TI - Sorafenib Plus Ixabepilone as First-Line Treatment of Metastatic HER2-Negative Breast Cancer: A Sarah Cannon Research Institute Phase I/II Trial. AB - BACKGROUND: The purposes of the present phase I/II trial were (1) to define tolerable doses of ixabepilone and sorafenib when used in combination and (2) to evaluate the efficacy and toxicity of this combination in the treatment of patients with human epidermal growth factor receptor-negative metastatic breast cancer (MBC). PATIENTS AND METHODS: The eligible patients had human epidermal growth factor receptor-negative MBC and had not received previous chemotherapy in the metastatic setting. All patients received ixabepilone intravenously on day 1 of each 21-day treatment cycle; sorafenib was administered orally twice daily. Patients in phase II received the maximum doses identified in phase I. The patients were reevaluated after the completion of 3 treatment cycles; treatment continued until disease progression or intolerable toxicity. A total of 67 patients were required in phase II to demonstrate increased median progression free survival from 4.2 to 6.2 months (90% power, alpha = 0.05). RESULTS: Ten patients entered the phase I portion; the maximum tolerated doses were ixabepilone 32 mg/m(2) and sorafenib 400 mg orally twice daily. A total of 76 patients were treated at the phase II dose. The median progression-free survival was 4.8 months (95% confidence interval, 3.5-6.3 months). The overall response rate was 37%. The regimen was difficult to tolerate for many patients; 20 patients discontinued because of toxicity, and dose reductions were frequent. The common toxicities included neutropenia, fatigue, rash, and neuropathy. CONCLUSION: The combination of ixabepilone and sorafenib was poorly tolerated as first-line treatment of patients with MBC. The activity of the combination was similar to the activity previously reported with single-agent ixabepilone or taxanes. Further development of this combination is not recommended. PMID- 26943992 TI - Identification of causative Leishmania species in Giemsa-stained smears prepared from patients with cutaneous leishmaniasis in Peru using PCR-RFLP. AB - A PCR-Restriction Fragment Length Polymorphism (RFLP) targeting the mannose phosphate isomerase gene was established to differentiate Leishmania species distributed near the Department of Huanuco, Peru. The technique was applied to 267 DNA samples extracted from Giemsa-stained smears of cutaneous lesions taken from patients suspected for cutaneous leishmaniasis in the area, and the present status of causative Leishmania species was identified. Of 114 PCR-amplified samples, 22, 19, 24 and 49 samples were identified to be infected by Leishmania (Viannia) braziliensis, L. (V.) peruviana, L. (V.) guyanensis, and a hybrid of L. (V.) braziliensis/L. (V.) peruviana, respectively, and the validity of PCR-RFLP was confirmed by sequence analysis. Since PCR-RFLP is simple and rapid, the technique will be a useful tool for the epidemiological study of leishmaniasis. PMID- 26943994 TI - A meta-analysis of contagious caprine pleuropneumonia (CCPP) in Ethiopia. AB - This systematic literature review was initiated due to lack of comprehensive information on the status and distribution of contagious caprine pleuropneumonia (CCPP) in Ethiopia. The objectives of the review were thus to provide a pooled prevalence estimate of CCPP in the country and asses the level of in between study variance among the available reports. Manual and electronic search was conducted between 8th of January and 25th of June 2015. A total of twelve published articles and one MSc thesis was retrieved from 19 initially identified studies. Twenty five animal level datasets were extracted at regional level considering some hypothesized predictors. The retrieved data were summarized in a meta-analytical approach. Accordingly, the pooled prevalence estimate of CCPP was 25.7% (95% CI:20.9,31.0). The inverse variance square (I(2)) that explains the variation in effect size attributed to reports true heterogeneity was 95.7%.The sub-group analysis was also computed for assumed predictors including, age, sex, type of study population, production systems and regional states. Among these predictors, study population type revealed statistically significant difference (P<0.05). Accordingly, the prevalence estimate for samples collected at abattoir was 39.2%, while that of samples collected at field level was 22.4%. In the final model, type of study population fitted the multivariable meta-regression model accounting for 22.87% of the explainable proportion of heterogeneity among the presumed predictors. Evidence on isolation and confirmation of Mycoplasma capricolum subspp. capripneumonie in the country was obtained from five regional states. In conclusion, it is recommended to further investigate facilities related with transportation and collection premises along with potential role of sheep in the epidemiology of CCPP. Finally, the review emphasizes the need for monitoring the ongoing CCPP control intervention and introduces amendments based on the findings. Besides more surveys are needed in some of the regions where no or few valid data was available. PMID- 26943993 TI - The TLR2 and TLR4 gene polymorphisms in Moroccan visceral leishmaniasis patients. AB - Visceral leishmaniasis (VL) is endemic in the Mediterranean basin and leads to the most severe form of Leishmania infection, lethal if left untreated. However, most infections are sub-clinical or asymptomatic, reflecting the influence of host genetic background on disease outcome. This study aimed to investigate possible association of TLR4 Asp299Gly, TLR4 Thr399Ile and TLR2 Arg753Gln polymorphisms with VL in Moroccan children. We enrolled 119 children with VL caused by Leishmania infantum as well as 138 unrelated children, 95 asymptomatic subjects and 43 healthy individuals who had no evidence of present or past infection. Polymorphisms were genotyped by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) and amplification refractory mutation system assay (ARMS-PCR). Results showed significant differences in genotype Thr399Ile and recessive model frequencies between VL and delayed-type hypersensitivity (DTH+) groups (p=0.018, OR=0.414CI 0.195-0.880; p=0.029, OR=0.448CI 0.214-0.938], respectively) by having the amino-acid threonine polymorphism as a reference in the VL group. Concerning the Asp299Gly there were a significant associations when comparing VL vs DTH+ (Asp299Gly genotype p=0.002, OR=0.326CI 0.158-0.671, allele frequencies p=0.033, OR=0.396CI 0.164-0.959, recessive model p=0.002, OR=0.343CI 0.172-0.681) and DTH+ vs DTH- groups (Asp299Gly genotype p=2.160E-4, OR=3.065CI 1.672-5.618, Gly299Gly genotype p=0.047, OR=0.368CI 0.299-0.452, allele frequencies p=1.406E-7, OR=29.571CI 3.907 223.8, recessive model p=4.370E-14, OR=36.965CI 8.629-158.3), by having the aspartic acid polymorphism as a reference these results suggest that the allele A (savage) confer protection against the clinical manifestations but not against the infection. Furthermore, there was a significant association regarding the Arg753Gln genotype (p=0.002, OR=0.326CI 0.158-0.671), allele frequencies (p=0.033, OR=0.396CI 0.164-0.959) and when applying a recessive model (p=0.002, OR=0.343CI 0.172-0.681) in the VL vs DTH+ groups. The same results was observed when comparing DTH+ vs DTH- groups (p=4.136E-6, OR=0.211CI 0.104-0.428), allele frequencies (p=0.008, OR=0.327CI 0.137-0.779) and recessive model (p=1.748E-5, OR=0.244CI 0.124-0.480). The results provide evidence that allele C in Thr399Ile and allele G in Arg753Gln polymorphisms may lead to protection against the clinical disease. Our data provide insights into the possible role of TLR2 and TLR4 variations in VL susceptibility. PMID- 26943995 TI - Molecular epidemiological surveillance to assess emergence and re-emergence of tick-borne infections in tick samples from China evaluated by nested PCRs. AB - An investigation was performed to detect eight pathogens in ticks collected from grass tips or animals in the southern, central and northeast regions of China. DNA samples extracted from ticks were collected from ten different locations in eight provinces of China and subjected to screening for tick-borne pathogens, including Borrelia burgdorferi sensu lato, Ehrlichia spp., Rickettsia spp., Babesia/Theileria spp., Ehrlichia ruminantium, Coxiella burnetii, and Francisella tularensis, using nested PCR assays and sequencing analysis. The results indicated that Borrelia spp., Rickettsia spp., and Babesia/Theileria spp. were detected in all of the investigated provinces. Ehrlichia spp. was also found in all of the surveyed areas, except Guangxi, Luobei and Tonghe counties in Heilongjiang province. The average prevalence of these pathogens was 18.4% (95% CI=12.8-42.5), 60.3% (95% CI=18.2-65.3), 26.0% (95% CI=25.8-65.1), and 28.7% (95% CI=5.6-35.2), respectively. A sequencing analysis of the pCS20 gene of E. ruminantium revealed an E. ruminantium-like organism (1/849, 0.1%, 95% CI=0-0.3) in one tick DNA sample extracted from Rhipicephalus (Boophilus) microplus in Hunan. In addition, Borrelia americana in Ixodes persulcatus, Babesia occultans in Haemaphysalis qinghaiensis and both Rhipicephalus sanguineus and an Ehrlichia muris-like organism in R. (B.) microplus was detected, possibly for the first time in China. Four DNA sequences closely related to Borrelia carolinensis and/or Borrelia bissettii from Haemaphysalis longicornis, Candidatus Rickettsia principis from H. qinghaiensis, and I. persulcatus and Ehrlichia canis (named E. canis-like) from Haemaphysalis bispinosa were also detected in this work. PMID- 26943996 TI - Ultrastructure of immature stages of the black dump fly: Ophyra aenescens (Wiedemann, 1830) (Diptera: Muscidae: Azeliinae). AB - Ophyra aenescens (black dump fly) originally belonged to the New World, however, now it is spread worldwide. This fly is a mechanical vector of some pathogenic microorganisms and eggs of the human botfly (Dermatobia hominis). The adults are associated with decaying matter and the immature stages colonize animal and human corpses. It is considered an important muscid species for forensic entomology. The aim of this study was to describe the morphology of the eggs, the three larval instars and the puparia of O. aenescens using scanning electron microscopy (SEM). The spiracular opening of the first instar has an interruption in the middle of its length. Comparing to the other instar, the ventral tubercles are only developed in the first instar. The anterior spiracles have a variation in the numbers of spiracular ramification. The puparia morphology is similar to the third instar larvae, however the cephalic region is retracted and on the third thoracic segment, a respiratory structure is present. In conclusion, the SEM technique used and the results obtained are helpful to describe and differentiate the immature stages of O. aenescens and consequently support forensic and medical entomology. PMID- 26943997 TI - Identification and genetic characterization of chikungunya virus from Aedes mosquito vector collected in the Lucknow district, North India. AB - Chikungunya fever is an emerging mosquito-borne disease caused by the infection with chikungunya virus (CHIKV). The CHIKV has been rarely detected in mosquito vectors from Northern India, since vector surveillance is an effective strategy in controlling and preventing CHIKV transmission. Thus, virological investigation for CHIKV among mosquitoes of Aedes (A.) species was carried out in the Lucknow district during March 2010 to October 2011. We collected adult mosquitoes from areas with CHIKV positive patients. The adult Aedes mosquito samples were pooled, homogenized, clarified and tested for CHIKV by nonstructural protein 1 (nsP1) gene based polymerase chain reaction (PCR). A total 91 mosquito pools comprising of adult A. aegypti and A. albopictus were tested for CHIKV. The partial envelope protein (E1) gene sequences of mosquito-borne CHIKV strains were analyzed for genotyping. Of 91 pools, 6 pools of A. aegypti; and 2 pools of A. albopictus mosquitoes were identified positive for CHIKV by PCR. The phylogenetic analysis revealed clustering of CHIKV strains in two sub-lineages within the monophyletic East-Central South African (ECSA) genotype. Novel amino acid changes at the positions 294 (P294L) and 295 (S295F) were observed during analysis of amino acid sequence of the partial E1 gene. This study demonstrates the genetic diversity of circulating CHIKV strains and reports the first detection of CHIKV strains in Aedes vector species from the state of Uttar Pradesh. These findings have implication for vector control strategies to mitigate vector population to prevent the likelihood of CHIKV epidemic in the near future. PMID- 26943998 TI - Deltamethrin-mediated survival, behavior, and oenocyte morphology of insecticide susceptible and resistant yellow fever mosquitos (Aedes aegypti). AB - Insecticide use is the prevailing control tactic for the mosquito Aedes aegypti, a vector of several human viruses, which leads to ever-increasing problems of insecticide resistance in populations of this insect pest species. The underlying mechanisms of insecticide resistance may be linked to the metabolism of insecticides by various cells, including oenocytes. Oenocytes are ectodermal cells responsible for lipid metabolism and detoxification. The goal of this study was to evaluate the sublethal effects of deltamethrin on survival, behavior, and oenocyte structure in the immature mosquitoes of insecticide-susceptible and resistant strains of A. aegypti. Fourth instar larvae (L4) of both strains were exposed to different concentrations of deltamethrin (i.e., 0.001, 0.003, 0.005, and 0.007 ppm). After exposure, L4 were subjected to behavioral bioassays. Insecticide effects on cell integrity after deltamethrin exposure (at 0.003 or 0.005 ppm) were assessed by processing pupal oenocytes for transmission electron microscopy or TUNEL reaction. The insecticide resistant L4 survived all the tested concentrations, whereas the 0.007-ppm deltamethrin concentration had lethal effects on susceptible L4. Susceptible L4 were lethargic and exhibited less swimming activity than unexposed larvae, whereas the resistant L4 were hyperexcited following exposure to 0.005 ppm deltamethrin. No sublethal effects and no significant cell death were observed in the oenocytes of either susceptible or resistant insects exposed to deltamethrin. The present study illustrated the different responses of susceptible and resistant strains of A. aegypti following exposure to sublethal concentration of deltamethrin, and demonstrated how the behavior of the immature stage of the two strains varied, as well as oenocyte structure following insecticide exposure. PMID- 26943999 TI - Characterization and expression analysis of gene encoding heme peroxidase HPX15 in major Indian malaria vector Anopheles stephensi (Diptera: Culicidae). AB - The interaction of mosquito immune system with Plasmodium is critical in determining the vector competence. Thus, blocking the crucial mosquito molecules that regulate parasite development might be effective in controlling the disease transmission. In this study, we characterized a full-length AsHPX15 gene from the major Indian malaria vector Anopheles stephensi. This gene is true ortholog of Anopheles gambiae heme peroxidase AgHPX15 (AGAP013327), which modulates midgut immunity and regulates Plasmodium falciparum development. We found that AsHPX15 is highly induced in mosquito developmental stages and blood fed midguts. In addition, this is a lineage-specific gene that has identical features and 65-99% amino acids identity with other HPX15 genes present in eighteen worldwide distributed anophelines. We discuss that the conserved HPX15 gene might serve as a common target to manipulate mosquito immunity and arresting Plasmodium development inside the vector host. PMID- 26944000 TI - Stress impairs the efficacy of immune stimulation by CpG-C: Potential neuroendocrine mediating mechanisms and significance to tumor metastasis and the perioperative period. AB - We recently reported that immune stimulation can be compromised if animals are simultaneously subjected to stressful conditions. To test the generalizability of these findings, and to elucidate neuroendocrine mediating mechanisms, we herein employed CpG-C, a novel TLR-9 immune-stimulating agent. Animals were subjected to ongoing stress (20-h of wet cage exposure) during CpG-C treatment, and antagonists to glucocorticoids, beta-adrenoceptor, COX2, or opioids were employed (RU486, nadolol, etodolac, naltrexone). In F344 rats, marginating-pulmonary NK cell numbers and cytotoxicity were studied, and the NK-sensitive MADB106 experimental metastasis model was used. In Balb/C mice, experimental hepatic metastases of the CT-26 colon tumor were studied; and in C57BL/6J mice, survival rates following excision of B16 melanoma was assessed - both mouse tumor models involved surgical stress. The findings indicated that simultaneous blockade of glucocorticoid and beta-adrenergic receptors improved CpG-C efficacy against MADB106 metastasis. In mice bearing B16 melanoma, long-term survival rate was improved by CpG-C only when employed simultaneously with blockers of glucocorticoids, catecholamines, and prostaglandins. Prolonged stress impaired CpG-C efficacy in potentiating NK activity, and in resisting MADB106 metastasis in both sexes, as also supported by in vitro studies. This latter effect was not blocked by any of the antagonists or by adrenalectomy. In the CT26 model, prolonged stress only partially reduced the efficacy of CpG-C. Overall, our findings indicate that ongoing behavioral stress and surgery can jeopardize immune-stimulatory interventions and abolish their beneficial metastasis-reducing impacts. These findings have implications for the clinical setting, which often involve psychological and physiological stress responses during immune stimulation. PMID- 26944001 TI - Diagnosis, treatment and long-term outcomes of autoimmune pancreatitis in Spain based on the International Consensus Diagnostic Criteria: A multi-centre study. AB - OBJECTIVES: Autoimmune pancreatitis (AIP) is a form of chronic pancreatitis that has been reported worldwide for the last two decades. The aim of this study is to analyse the clinical profile of patients from Spain with AIP, as well as treatments, relapses and long-term outcomes. METHODS: Data from 59 patients with suspected AIP that had been diagnosed in 15 institutions are retrospectively analysed. Subjects are classified according to the International Consensus Diagnostic Criteria (ICDC). Patients with type 1 AIP (AIP1) and type 2 AIP (AIP2) are compared. Kaplan-Meier methodology is used to estimate the overall survival without relapses. RESULTS: Fifty-two patients met ICDC, 45 patients were AIP1 (86.5%). Common manifestations included abdominal pain (65.4%) and obstructive jaundice (51.9%). Diffuse enlargement of pancreas was present in 51.0%; other organ involvement was present in 61.5%. Serum IgG4 increased in 76.7% of AIP1 patients vs. 20.0% in AIP2 (p = 0.028). Tissue specimens were obtained in 76.9%. Initial successful treatment with steroids or surgery was achieved in 79.8% and 17.3%, respectively. Maintenance treatment was given in 59.6%. Relapses were present in 40.4% of AIP1, with a median of 483 days. Successful long-term remission was achieved in 86.4%. CONCLUSIONS: AIP1 is the most frequent form of AIP in Spain in our dataset. Regularly, ICDC allows AIP diagnosis without the need for surgery. Steroid and chirurgic treatments were effective and safe in most patients with AIP, although maintenance was required many times because of their tendency to relapse. Long-term serious consequences were uncommon. PMID- 26944002 TI - Baculovirus-challenge and poor nutrition inflict within-generation fitness costs without triggering transgenerational immune priming. AB - Invertebrate hosts that survive pathogen challenge can produce offspring that are more resistant to the same pathogen via immune priming, thereby improving the fitness of their offspring in the same pathogen environment. Most evidence for immune priming comes from exposure to bacteria and there are limited data on other groups of pathogens. Poor parental nutrition has also been shown to result in the transgenerational transfer of pathogen resistance and increased immunocompetence. Here, we combine exposure to an insect DNA virus with a change in the parental diet to examine both parental costs and transgenerational immune priming. We challenged the cabbage looper, Trichoplusia ni, with a low dose of the baculovirus, Autographa californica multiple nucleopolyhedrovirus (AcMNPV) and altered dietary protein to carbohydrate ratio (p:c ratio) after virus exposure. Insects fed a low protein diet had lower haemolymph protein concentrations, and exhibited costs of smaller pupae and slower development, while survivors of virus challenge developed more slowly, irrespective of p:c ratio, and those that were virus-challenged and fed on a low protein diet showed a reduction in haemocyte density. In addition, AcMNPV-challenged parents laid fewer eggs earlier in egg laying although egg size was the same as for unchallenged parents. There was no evidence for increased resistance to AcMNPV (immune priming) or changes in haemocyte number (as proxy for constitutive cellular immunity) in the offspring either as a result of parental AcMNPV challenge or low dietary p:c ratio. Therefore, although pathogen-challenge and nutritional changes can affect host development and reproduction, this does not necessarily translate into transgenerational immune priming. Our findings contrast with an earlier study on another type of baculovirus, a granulovirus, where immune priming was suggested. This indicates that transgenerational immune priming is not universal in invertebrates and is likely to depend on the host pathogen system, or the level of pathogen exposure and the type of dietary manipulation. Identifying whether immune priming or transgenerational effects are relevant in field populations, remains a challenge. PMID- 26944003 TI - Working in a danger zone: A qualitative study of Taiwanese nurses' work experiences in a negative pressure isolation ward. AB - BACKGROUND: Hospital nurses are frontline health care workers in controlling the spread of infectious diseases. It is not known if nurses working in negative pressure isolation wards (NPIWs) are better prepared than before to safely care for patients with common infectious diseases. METHODS: For this qualitative descriptive study, 10 nurses were interviewed in depth about their experiences caring for patients in an NPIW. Tape recordings were transcribed verbatim and analyzed by qualitative content analysis. RESULTS: The following 5 themes were identified: (1) complexity of patient care, (2) dissatisfaction with the quantity and quality of protective equipment, (3) shortage of nursing staff, (4) continued worries about being infected, and (5) sensitivity to self-protection. Our participants' anxiety and uncertainty about being infected in the NPIW were increased by the complexity of patients' health problems and organizational factors. To protect themselves against infection before and during patient care, participants also developed sensitivity to, concepts about, and strategies to improve self-protection. CONCLUSIONS: NPIW administrators should pay more attention to nurses' concerns about improving the NPIW working environment, supply good quality protective equipment, and provide appropriate psychologic support and ongoing education to ensure that nurses feel safe while working. This ongoing education should refresh and update nurses' knowledge about disease transmission, therefore decreasing unnecessary anxiety based on misunderstandings about becoming infected. PMID- 26944005 TI - Learning from the patient: Human factors engineering in outpatient parenteral antimicrobial therapy. PMID- 26944004 TI - Intensive care unit-acquired infections in a tertiary care hospital: An epidemiologic survey and influence on patient outcomes. AB - BACKGROUND AND OBJECTIVE: Nosocomial infections are common in intensive care units (ICUs), but the pattern of infections and the distribution of microorganisms vary. We studied the ICU-acquired infections and their effect on patient outcomes in our ICU. METHODS: Patients admitted to our ICU for >48 hours were studied prospectively over a year. Infections were diagnosed based on Centers for Disease Control and Prevention guidelines. Antibiotics were administered based on culture and sensitivity. Univariate and multivariate logistic regressions were carried out to determine the factors associated with infection. RESULTS: One hundred ninety-eight patients were studied. The crude infection rate was 50% with ventilator-associated pneumonia (40%) and bloodstream infection (21%) being the most common. Acinetobacter calcoaceticus-baumannii complex, Pseudomonas aeruginosa, and Klebsiella pneumoniae were the most common microorganisms. More than 90% of patients received antibiotics, the most common being beta lactam-beta lactamase inhibitors, aminoglycosides, fluoroquinolones, and carbapenems. Thirty-five percent of staphylococci were methicillin-resistant, 50% of Enterococcus strains were vancomycin-resistant, and 68% of Acinetobacter calcoaceticus-baumannii complex, 47% of Pseudomonas strains, and 35% of Klebsiella strains were multidrug-resistant. A longer duration of ventilation was associated with infection. The overall ICU mortality rate was 24% and was similar in patients with or without infection. CONCLUSIONS: The incidence of infection and the multidrug resistance in the ICU was high. Infection was associated with duration of ventilation but not mortality. PMID- 26944006 TI - Status of drug-resistant tuberculosis in China: A systematic review and meta analysis. AB - BACKGROUND: We conducted a systematic review and meta-analysis on drug-resistant tuberculosis in China to provide useful data for tuberculosis (TB) surveillance and treatment. METHODS: Several databases, including PubMed, Embase, and the Chinese Biological Medical Database, were systematically searched between January 1, 1999, and August 31, 2015, using strict inclusion and exclusion criteria. RESULTS: The corresponding drug-resistant TB prevalence between the new and previously treated cases was significantly different in almost all of the economic regions. The Eastern coastal region is the most developed economic region with the lowest total drug-resistant TB prevalence (any drug resistance: 28%; 95% confidence interval [CI], 25%-32%; multidrug resistance: 9%; 95% CI, 8% 12%) and the lowest number of new cases (any drug resistance: 21%; 95% CI, 19% 23%; multidrug resistance: 4%; 95% CI, 3%-5%). The Northwest is the least developed area with the lowest drug-resistant TB prevalence for previously treated cases (any drug resistance: 45%; 95% CI, 36%-55%; multidrug resistance: 17%; 95% CI, 11%-26%). The prevalence (multidrug and first-line drug resistance) exhibited a downward trend from 1996-2014. The extensively drug-resistant prevalence in China was 3% (95% CI, 2%-5%) in this review. CONCLUSIONS: Overall, the status of drug-resistant tuberculosis in China is notably grim and exhibits regional epidemiologic characteristics. We are in urgent need of several comprehensive and effective control efforts to reverse this situation. PMID- 26944008 TI - Injury rates from peripheral catheters with or without safety devices in a Brazilian public hospital. PMID- 26944007 TI - Hospital Clostridium difficile infection (CDI) incidence as a risk factor for hospital-associated CDI. AB - BACKGROUND: Environmental risk factors for Clostridium difficile infections (CDIs) have been described at the room or unit level but not the hospital level. To understand the environmental risk factors for CDI, we investigated the association between institutional- and individual-level CDI. METHODS: We performed a retrospective cohort study using the Healthcare Cost and Utilization Project state inpatient databases for California (2005-2011). For each patient's hospital stay, we calculated the hospital CDI incidence rate corresponding to the patient's quarter of discharge, while excluding each patient's own CDI status. Adjusting for patient and hospital characteristics, we ran a pooled logistic regression to determine individual CDI risk attributable to the hospital's CDI rate. RESULTS: There were 10,329,988 patients (26,086 cases and 10,303,902 noncases) who were analyzed. We found that a percentage point increase in the CDI incidence rate a patient encountered increased the odds of CDI by a factor of 1.182. CONCLUSIONS: As a point of comparison, a 1-percentage point increase in the CDI incidence rate that the patient encountered had roughly the same impact on their odds of acquiring CDI as a 55.8-day increase in their length of stay or a 60-year increase in age. Patients treated in hospitals with a higher CDI rate are more likely to acquire CDI. PMID- 26944009 TI - Fecal microbiota transplantation for recurrent Clostridium difficile infection: The patient experience. AB - BACKGROUND: Although effectiveness of fecal microbiota transplantation (FMT) has been adequately documented, the patient experience of undergoing FMT has not. METHODS: We carried out a qualitative interview study using semistructured questions relating to aspects of health pre-FMT, during FMT, and post-FMT periods with 17 participants. Inductive coding was used to identify core themes during the periods. RESULTS: Pre-FMT themes included physical (continuous diarrhea and weight loss), mental (depression, wanting to die, and fear), quality of life (unable to perform normal activities), social support, and financial (medication costs) factors. Provider resistance/limited awareness were barriers to FMT. Participants reached a tipping point, experiencing feelings of hopelessness, which led them to pursue FMT. During FMT, participants commented on lack of a so called ick factor. During the posttreatment period, participants experienced symptom relief, but had residual fears. Patient activation was present during all phases, including information seeking and empowerment. CONCLUSIONS: During the pre-FMT period, participants experienced extreme discomfort and encountered FMT barriers. Undergoing FMT was reported as easy but residual fear remained. There were displays of patient activation at all FMT time periods, including the seeking of FMT. Participants could have benefited from having undergone FMT sooner, demonstrating a need for improvement in provider education and health system barriers regarding FMT. PMID- 26944010 TI - More PPE protects better against Ebola. PMID- 26944011 TI - Laboratory-acquired skin infections in a clinical microbiologist: Is wearing only gloves really safe? AB - Laboratory-acquired infection is one of the leading occupational health hazards. On a laboratory worker's hands, carbuncles occurred. Staphylococcus aureus was isolated from pus samples of the carbuncles, with the same pulsed field gel electrophoresis band pattern with one of the recently studied strains in the laboratory. Incorrect or inadequate application of infection control measures may result in pathogen acquisition from the clinical samples, and wearing only gloves is not sufficient for the biosafety of laboratory workers in clinical diagnostic laboratories. PMID- 26944012 TI - A well-sampled phylogenetic analysis of the polystichoid ferns (Dryopteridaceae) suggests a complex biogeographical history involving both boreotropical migrations and recent transoceanic dispersals. AB - Intercontinental disjunctions in ferns have often been considered as the result of long-distance dispersal (LDD) events rather than of vicariance. However, in many leptosporangiate groups, both processes appear to have played a major role in shaping current geographical distribution. In this study, we reconstructed the phylogenetic relationships and inferred the ancestral distribution areas of the polystichoid ferns (Cyrtomium, Phanerophlebia, and Polystichum), to evaluate the relative impact of vicariance and LDD on the biogeography of this group. We used a molecular dataset including 3346 characters from five plastid loci. With 190 accessions our taxon coverage was about three times as large as any previous worldwide sampling. Biogeographical analyses were performed using S-DIVA and S DEC and divergence times were estimated by integrating fossil and secondary calibrations. The polystichoid ferns are a monophyletic clade that may have originated in East Asia during the Eocene, an age much younger than previously estimated. Three transoceanic disjunctions between East Asia and New World were identified in the Paleogene: one for Phanerophlebia during late Eocene (34Ma, 19 51Ma), and two in Polystichum at the Eocene-Oligocene boundary (30Ma, 18-43Ma; 28Ma, 19-39Ma respectively). During the Neogene, further range expansions took place from Asia to Africa, Hawaii, and the Southwestern Indian Ocean region. Our results indicate that early transfers between the Old and the New World are compatible with a boreotropical migration scenario. After evolving in Asia during the Eocene, the polystichoid ferns reached the New World in independent migrations at the Eocene-Oligocene boundary through the boreotropical belt. However, although less likely, the alternative hypothesis of independent transoceanic dispersals from the Old to the New World cannot be ruled out. Further range expansion during the Neogene was most likely the result of long distance dispersal (LDD). PMID- 26944013 TI - Phylogeny and biogeography of hogfishes and allies (Bodianus, Labridae). AB - Bodianus wrasses comprise one of the most diverse genera of labrids. Also known as hogfishes due to the presence of a large pig-like snout, Bodianus species are found in warm waters across the Pacific, Atlantic and Indian Oceans. To this date no densely sampled molecular phylogeny is available for this group, and a single morphological study did not include two genera (Clepticus and Semicossyphus) that have been shown to belong within hogfishes by molecular studies. Our study produced the first multi-locus molecular phylogeny of Bodianus species, and corroborated the non-monophyly of this group without the inclusion of the Creole wrasse (Clepticus) and the sheepheads (Semicossyphus). We further showed that hogfishes and allies started to radiate during the Early Miocene, ~20Ma, and that while this group originated in the Indo-western and South-western Pacific, it experienced multiple episodes during which it successfully invaded different geographic regions and/or ocean basins. PMID- 26944014 TI - Rationing for Total Hip and Knee Arthroplasty Using the New Zealand Orthopaedic Association Score: Effectiveness and Comparison With Patient-Reported Scores. AB - BACKGROUND: There is increasing interest in scoring systems to prioritize patients for hip and knee arthroplasty. The purpose of this study was to determine the effectiveness of the New Zealand Orthopaedic Association (NZOA) score and compare it with patient-reported scores of patients listed for hip and knee arthroplasty. METHODS: Over a 1-year period, all patients listed for primary hip and knee arthroplasty were scored by a prioritization nurse. The NZOA score, outcome, preoperative Oxford hip or knee score (OHKS) and reduced Western Ontario McMaster osteoarthritis index (WOMAC) score (RWS) were collected. RESULTS: Overall, 608 patients were listed for hip (319) or knee (289) arthroplasty. The mean scores for knees were all better than hips (P < .001). On initial scoring, 324 patients (53%) were given certainty (mean NZOA, 80.5; OHKS, 10.0; RWS, 35.1), 90 (15%) given clinical over-ride (NZOA, 69.6; OHKS, 12.0; RWS, 33.2), and 194 (32%) returned to general practitioner (NZOA, 64; OHKS, 14.2; RWS, 30.8). Knees (38%) were more likely to be returned than hips (26%; P = .002). Fifty (26%) were re-referred during the study period (mean, 5 months) and given certainty or over ride. The difference at final outcome between patients with certainty and clinical over-ride was NZOA, 10.3 points; Oxford, 1.6 points; and RWS, 1.4 points. The difference between clinical over-ride and returned to general practitioner was NZOA, 7.2; Oxford, 4.4; RWS, 5.3. CONCLUSION: The NZOA score is an effective tool for rationing for joint arthroplasty. Patients around the threshold score of 70 may not have a clinically important difference compared with those above threshold. PMID- 26944015 TI - Psychological Traits in Patients Waiting for Total Knee Arthroplasty. A Cross sectional Study. AB - BACKGROUND: To determine the prevalence of psychiatric distress in an Australian patient population waiting for total knee arthroplasty and to assess the associations between psychological distress and other baseline characteristics. METHODS: This is a cross-sectional study of prospectively collected data from patients with knee arthritis participating in the New South Wales Osteoarthritis Chronic Care Program. Participants were divided into 2 groups based on the Depression Anxiety and Stress Score. The prevalence of psychological distress was compared to reported prevalence in the Australian community. Between-group comparisons of a number of variables were made, including demographic and socioeconomic data, health and psychiatric data, patient-reported knee and quality-of-life scores, and measured function. RESULTS: Data from 3103 patients were available and 2809 patients were eligible for inclusion, with 1740 (62%) females. Mean patient age was 68 years, and mean body mass index was 33.8. We found 753 (26.8%, standard deviation: 0.44) of participants reported psychological distress. Those reporting distress were more likely to be female (P = .025), younger (66.6 vs 68.8 years, P < .001), with a higher body mass index (34.5 vs 32.7, P < .001), and had more comorbidities (3.4 vs 2.8, P < .001). The distressed group had significantly worse knee pain (visual analog scale: 7.1 vs 6.2, P < .001; Knee Injury and Osteoarthritis Score pain component: 28.9 vs 41.2, P < .001), knee function, and general quality-of-health scores (P < .001). CONCLUSION: Psychological health is an important and often overlooked predictor of severity of symptoms and dysfunction in patients with knee arthritis. As it can affect the outcome for surgery, psychological health should be better assessed and treated before surgery to help reduce preoperative dysfunction and improve postoperative outcomes of total knee arthroplasty. PMID- 26944016 TI - Antibiotic drug rifabutin is effective against lung cancer cells by targeting the eIF4E-beta-catenin axis. AB - The essential roles of overexpression of eukaryotic translation initiation factor 4E (eIF4E) and aberrant activation of beta-catenin in lung cancer development have been recently identified. However, whether there is a direct connection between eIF4E overexpression and beta-catenin activation in lung cancer cells is unknown. In this study, we show that antibiotic drug rifabutin targets human lung cancer cells via inhibition of eIF4E-beta-catenin axis. Rifabutin is effectively against lung cancer cells in in vitro cultured cells and in vivo xenograft mouse model through inhibiting proliferation and inducing apoptosis. Mechanistically, eIF4E regulates beta-catenin activity in lung cancer cells as shown by the increased beta-catenin phosphorylation and activity in cells overexpressing eIF4E, and furthermore that the regulation is dependent on phosphorylation at S209. Rifabutin suppresses eIF4E phosphorylation, leads to decreased beta-catenin phosphorylation and its subsequent transcriptional activities. Depletion of eIF4E abolishes the inhibitory effects of rifabutin on beta-catenin activities and overexpression of beta-catenin reverses the inhibitory effects of rifabutin on cell growth and survival, further confirming that rifabutin acts on lung cancer cells via targeting eIF4E- beta-catenin axis. Our findings identify the eIF4E- beta-catenin axis as a critical regulator of lung cancer cell growth and survival, and suggest that its pharmacological inhibition may be therapeutically useful in lung cancer. PMID- 26944017 TI - TAK-242 attenuates acute cigarette smoke-induced pulmonary inflammation in mouse via the TLR4/NF-kappaB signaling pathway. AB - The present study determined the effect of TAK-242 on attenuating acute cigarette smoke induced pulmonary inflammation and attempted to dissect its underlying mechanisms of action. When administered to the C57BL/6J mice after a 3 days period of cigarettes exposure,TAK-242 significantly decreased the accumulation of macrophages, neutrophils, lymphocytes and DCs, and upregulation of IL-6, IL-8 and TNF-alpha in BAL fluid and lungs in a dose-dependent manner, except MCP-1, IL 1beta and IFN-gamma, which demonstrated that TAK-242 inhibits release of various inflammatory mediators induced by cigarette smoke. TAK-242 also significantly suppressed the expression of TLR4, MyD88 and the activation of NF-kappaB in lungs, suggesting that TAK-242-mediated inhibition occurred largely through the TLR4/NF-kappaB signal pathway. Our results support TAK-242 as a potent therapeutic agent in the treatment of cigarette smoke induced-pulmonary inflammation, and warrants further pharmaceutical investigation. PMID- 26944018 TI - Disturbance of proteasomal and autophagic protein degradation pathways by amyotrophic lateral sclerosis-linked mutations in ubiquilin 2. AB - Ubiquilin (UBQLN), a member of the ubiquitin-like (UBL)-ubiquitin-associated (UBA) family, is a dual regulator of both the proteasomal and autophagic branches of the cellular protein degradation system. Mutations in the UBQLN2 gene encoding ubiquilin 2 cause X-linked amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD), and UBQLN2-positive inclusions have been identified in ALS patients with UBQLN2 mutations as well as in cases of both familial and sporadic ALS without UBQLN2 mutations. Compelling evidence links UBQLN2 to disturbance of the protein quality control network in neurons, but the pathomechanisms remain obscure. This study aimed to clarify how ALS-linked mutations in UBQLN2 affect the protein degradation system. Overexpression of a UBQLN2 with ALS-associated mutations resulted in the accumulation of polyubiquitinated proteins in neuronal cells, including the ALS-associated protein TDP-43. This effect was dependent on the UBA domain but not on inclusion formation. Immunocytochemistry and protein fractionation analysis of IVm-UBQLN2 cellular distribution indicated that it sequesters ubiquitinated substrates from both the proteasomal and autophagic branches of the protein degradation system, resulting in accumulation of polyubiquitinated substrates. These findings provide a molecular basis for the development of ALS/FTD-associated proteinopathy and establish novel therapeutic targets for ALS. PMID- 26944019 TI - P-glycoprotein ATPase activity requires lipids to activate a switch at the first transmission interface. AB - P-glycoprotein (P-gp) is an ABC (ATP-Binding Cassette) drug pump. A common feature of ABC proteins is that they are organized into two wings. Each wing contains a transmembrane domain (TMD) and a nucleotide-binding domain (NBD). Drug substrates and ATP bind at the interface between the TMDs and NBDs, respectively. Drug transport involves ATP-dependent conformational changes between inward- (open, NBDs far apart) and outward-facing (closed, NBDs close together) conformations. P-gps crystallized in the presence of detergent show an open structure. Human P-gp is inactive in detergent but basal ATPase activity is restored upon addition of lipids. The lipids might cause closure of the wings to bring the NBDs close together to allow ATP hydrolysis. We show however, that cross-linking the wings together did not activate ATPase activity when lipids were absent suggesting that lipids may induce other structural changes required for ATPase activity. We then tested the effect of lipids on disulfide cross linking of mutants at the first transmission interface between intracellular loop 4 (TMD2) and NBD1. Mutants L443C/S909C and L443C/R905C but not G471C/S909C and V472C/S909C were cross-linked with oxidant when in membranes. The mutants were then purified and cross-linked with or without lipids. Mutants G471C/S909C and V472C/S909C cross-linked only in the absence of lipids whereas mutants L443C/S909C and L443C/R905C were cross-linked only in the presence of lipids. The results suggest that lipids activate a switch at the first transmission interface and that the structure of P-gp is different in detergents and lipids. PMID- 26944020 TI - Inflammatory mediator bradykinin increases population of sensory neurons expressing functional T-type Ca(2+) channels. AB - T-type Ca(2+) channels are important regulators of peripheral sensory neuron excitability. Accordingly, T-type Ca(2+) currents are often increased in various pathological pain conditions, such as inflammation or nerve injury. Here we investigated effects of inflammation on functional expression of T-type Ca(2+) channels in small-diameter cultured dorsal root ganglion (DRG) neurons. We found that overnight treatment of DRG cultures with a cocktail of inflammatory mediators bradykinin (BK), adenosine triphosphate (ATP), norepinephrine (NE) and prostaglandin E2 (PGE2) strongly increased the population size of the small diameter neurons displaying low-voltage activated (LVA, T-type) Ca(2+) currents while having no effect on the peak LVA current amplitude. When applied individually, BK and ATP also increased the population size of LVA-positive neurons while NE and PGE2 had no effect. The PLC inhibitor U-73122 and B2 receptor antagonist, Hoe-140, both abolished the increase of the population of LVA-positive DRG neurons. Inflammatory treatment did not affect CaV3.2 mRNA or protein levels in DRG cultures. Furthermore, an ubiquitination inhibitor, MG132, did not increase the population of LVA-positive neurons. Our data suggest that inflammatory mediators BK and ATP increase the abundance of LVA-positive DRG neurons in total neuronal population by stimulating the recruitment of a 'reserve pool' of CaV3.2 channels, particularly in neurons that do not display measurable LVA currents under control conditions. PMID- 26944021 TI - Design considerations for a pilot trial using a novel approach for evaluating smoking-cessation medication in methadone-maintained smokers. AB - The prevalence of smoking in methadone-maintained (MM) patients is over 80% and smoking-abstinence rates are strikingly low, even with the use of first-line smoking-cessation medications. Research has found that cigarettes increase the reinforcing properties of methadone; this interaction may be an additional, daily, challenge to smoking cessation in MM-smokers. This paper describes a novel approach in which patients who experience a particular barrier to achieving smoking abstinence are selected, and the impact of smoking-cessation medications on the identified barrier is evaluated. This is a 7-week, outpatient, randomized, within-subject, placebo-controlled, crossover trial with a follow-up visit at week 8. MM-smokers, who smoke >=40% of their total daily cigarettes in the 4-h post-methadone-dosing period, as assessed with a Quitbit electronic cigarette lighter, will be recruited from a methadone program in Cincinnati, Ohio. Eligible participants will be randomized to receive four interventions (nicotine nasal spray (1mg per dose, up to 40 times per day), placebo nicotine nasal spray, varenicline (2mg/day), and varenicline placebo) in one of four orders to mitigate potential order effects. The primary outcome analysis will consist of two sets of statistical analyses, one comparing the effect of nicotine nasal spray to its placebo, and one comparing the effect of varenicline to its placebo, on the proportion of daily cigarettes smoked during the 4-h post-methadone-dosing period. This trial is of interest both as an efficient, precision-medicine-based approach to testing smoking-cessation interventions and as a specific strategy for identifying effective smoking-cessation treatment for MM-smokers. PMID- 26944024 TI - Aedes aegypti control in Brazil. PMID- 26944023 TI - Efficacy and safety study of cenicriviroc for the treatment of non-alcoholic steatohepatitis in adult subjects with liver fibrosis: CENTAUR Phase 2b study design. AB - BACKGROUND: Non-alcoholic steatohepatitis (NASH) is often accompanied by liver fibrosis, which can progress to cirrhosis; C-C chemokine receptors type 2 and 5 (CCR2/CCR5), which mediate interactions driving inflammation and fibrosis, are promising treatment targets. Cenicriviroc (CVC), a dual-CCR2/CCR5 antagonist, has potent anti-inflammatory and antifibrotic activity in animal models; in HIV positive subjects it reduced soluble CD14 levels, aspartate aminotransferase-to platelet count ratio index, and non-invasive hepatic fibrosis risk scores; favorable tolerability was demonstrated in ~600 subjects. Efficacy and safety of CVC 150 mg for treating NASH with liver fibrosis are being evaluated over 2 years (primary endpoint at Year 1 [Y1]). DESIGN: Phase 2b, randomized, double-blind, placebo-controlled, multinational study (CENTAUR; NCT02217475). Adults with histological evidence of NASH, non-alcoholic fatty liver disease activity score (NAS) >= 4, and liver fibrosis (stages 1-3 NASH clinical research network system) enrolled. Subjects have increased risk of progression to cirrhosis due to >=1 characteristic: type 2 diabetes; body mass index > 25 kg/m(2) with >=1 feature of metabolic syndrome; bridging fibrosis and/or NAS >= 5. Liver biopsy evaluation at Screening, Y1, and Year 2 (Y2). OBJECTIVES: Assess histologic improvement (>=2 point in NAS with >=1-point improvement in >1 category) without worsening of fibrosis at Y1 (primary); evaluate complete NASH resolution without worsening of fibrosis at Y2 (key secondary). DISCUSSION: CENTAUR is the first prospective study evaluating an oral agent exclusively enrolling subjects with NASH and liver fibrosis, with increased risk of developing cirrhosis. It will compare shorter versus longer CVC treatment and assess correlations between decreased inflammation and fibrosis. PMID- 26944022 TI - Rationale, design, and baseline findings from HIPP: A randomized controlled trial testing a home-based, individually-tailored physical activity print intervention for African American women in the Deep South. AB - African American women report high rates of physical inactivity and related health disparities. In our previous formative research, we conducted a series of qualitative assessments to examine physical activity barriers and intervention preferences among African American women in the Deep South. These data were used to inform a 12-month Home-based, Individually-tailored Physical activity Print (HIPP) intervention, which is currently being evaluated against a wellness contact control condition among 84 post-menopausal African American women residing in the metropolitan area of Birmingham, Alabama. This paper reports the rationale, design and baseline findings of the HIPP trial. The accrued participants had an average age of 57 (SD=4.7), a BMI of 32.1 kg/m(2) (SD=5.16) with more than half (55%) having a college education and an annual household income under $50,000 (53.6%). At baseline, participants reported an average of 41.5 min/week (SD=49.7) of moderate intensity physical activity, and 94.1% were in the contemplation or preparation stages of readiness for physical activity. While social support for exercise from friends and family was low, baseline levels of self-efficacy, cognitive and behavioral processes of change, decisional balance, outcome expectations, and enjoyment appeared promising. Baseline data indicated high rates of obesity and low levels of physical activity, providing strong evidence of need for intervention. Moreover, scores on psychosocial measures suggested that such efforts may be well received. This line of research in technology-based approaches for promoting physical activity in African American women in the Deep South has great potential to address health disparities and impact public health. PMID- 26944025 TI - Tocolysis and preterm labour. PMID- 26944026 TI - Nifedipine versus atosiban for threatened preterm birth (APOSTEL III): a multicentre, randomised controlled trial. AB - BACKGROUND: In women with threatened preterm birth, delay of delivery by 48 h allows antenatal corticosteroids to improve neonatal outcomes. For this reason, tocolytics are often administered for 48 h; however, there is no consensus about which drug results in the best maternal and neonatal outcomes. In the APOSTEL III trial we aimed to compare the effectiveness and safety of the calcium-channel blocker nifedipine and the oxytocin inhibitor atosiban in women with threatened preterm birth. METHODS: We did this multicentre, randomised controlled trial in ten tertiary and nine teaching hospitals in the Netherlands and Belgium. Women with threatened preterm birth (gestational age 25-34 weeks) were randomly assigned (1:1) to either oral nifedipine or intravenous atosiban for 48 h. An independent data manager used a web-based computerised programme to randomly assign women in permuted block sizes of four, with groups stratified by centre. Clinicians, outcome assessors, and women were not masked to treatment group. The primary outcome was a composite of adverse perinatal outcomes, which included perinatal mortality, bronchopulmonary dysplasia, sepsis, intraventricular haemorrhage, periventricular leukomalacia, and necrotising enterocolitis. Analysis was done in all women and babies with follow-up data. The study is registered at the Dutch Clinical Trial Registry, number NTR2947. FINDINGS: Between July 6, 2011, and July 7, 2014, we randomly assigned 254 women to nifedipine and 256 to atosiban. Primary outcome data were available for 248 women and 297 babies in the nifedipine group and 255 women and 294 babies in the atosiban group. The primary outcome occurred in 42 babies (14%) in the nifedipine group and in 45 (15%) in the atosiban group (relative risk [RR] 0.91, 95% CI 0.61 1.37). 16 (5%) babies died in the nifedipine group and seven (2%) died in the atosiban group (RR 2.20, 95% CI 0.91-5.33); all deaths were deemed unlikely to be related to the study drug. Maternal adverse events did not differ between groups. INTERPRETATION: In women with threatened preterm birth, 48 h of tocolysis with nifedipine or atosiban results in similar perinatal outcomes. Future clinical research should focus on large placebo-controlled trials, powered for perinatal outcomes. FUNDING: ZonMw (the Netherlands Organisation for Health Research and Development). PMID- 26944027 TI - Zika virus infection in French Polynesia. PMID- 26944028 TI - Infectious Zika viral particles in breastmilk. PMID- 26944029 TI - Unlocked Nucleic Acids for miRNA detection using two dimensional nano-graphene oxide. AB - In this study we have used Unlocked Nucleic Acids (UNAs) to discriminate a breast cancer oncomiR from two other miRNAs in the same RNA family using two-dimensional graphene oxide nanoassemblies. Fluorescently labeled single stranded probe strands and graphene oxide nanoassemblies have been used to detect miR-10b and discriminate it from miR-10a, which differs by only a single nucleotide (12th base from the 5' end), and miR-10c, which differs by only two nucleotides (12th and 16th bases from the 5' end). We have determined the discrimination efficacy and detection capacity of a DNA probe with two inserted UNA monomers (UNA2), and compared it to the DNA probe with two purposefully inserted mutations (DNAM2) and full complementary sequence (DNAfull). We have observed that UNA2 is 50 times more powerful than DNAfull in discriminating miR-10b from miR-10c while generating an equally high fluorescence signal. This fluorescence signal was then further enhanced with the use of the highly specific endonuclease dsDNase for an enzymatic amplification step. The results demonstrate that the underutilized UNAs have enormous potential for miRNA detection and offer remarkable discrimination efficacy over single and double mismatches. PMID- 26944030 TI - Single-Molecule Investigation of Initiation Dynamics of an Organometallic Catalyst. AB - The action of molecular catalysts comprises multiple microscopic kinetic steps whose nature is of central importance in determining catalyst activity and selectivity. Single-molecule microscopy enables the direct examination of these steps, including elucidation of molecule-to-molecule variability. Such molecular diversity is particularly important for the behavior of molecular catalysts supported at surfaces. We present the first combined investigation of the initiation dynamics of an operational palladium cross-coupling catalyst at the bulk and single-molecule levels, including under turnover conditions. Base initiated kinetics reveal highly heterogeneous behavior indicative of diverse catalyst population. Unexpectedly, this distribution becomes more heterogeneous at increasing base concentration. We model this behavior with a two-step saturation mechanism and identify specific microscopic steps where chemical variability must exist in order to yield observed behavior. Critically, we reveal how structural diversity at a surface translates into heterogeneity in catalyst behavior, while demonstrating how single-molecule experiments can contribute to understanding of molecular catalysts. PMID- 26944031 TI - Detection and Quantification of Mosaic Mutations in Disease Genes by Next Generation Sequencing. AB - The identification of mosaicism is important in establishing a disease diagnosis, assessing recurrence risk, and genetic counseling. Next-generation sequencing (NGS) with deep sequence coverage enhances sensitivity and allows for accurate quantification of the level of mosaicism. NGS identifies low-level mosaicism that would be undetectable by conventional Sanger sequencing. A customized DNA probe library was used for capturing targeted genes, followed by deep NGS analysis. The mean coverage depth per base was approximately 800*. The NGS sequence data were analyzed for single-nucleotide variants and copy number variations. Mosaic mutations in 10 cases/families were detected and confirmed by NGS analysis. Mosaicism was identified for autosomal dominant (JAG1, COL3A1), autosomal recessive (PYGM), and X-linked (PHKA2, PDHA1, OTC, and SLC6A8) disorders. The mosaicism was identified either in one or more tissues from the probands or in a parent of an affected child. When analyzing data from patients with unusual testing results or inheritance patterns, it is important to further evaluate the possibility of mosaicism. Deep NGS analysis not only provides insights into the spectrum of mosaic mutations but also underlines the importance of the detection of mosaicism as an integral part of clinical molecular diagnosis and genetic counseling. PMID- 26944032 TI - The "Four-Leaf Clover" Treatment Algorithm: A Practical Approach to Manage Disorders of the Distal Radioulnar Joint. AB - Most symptomatic distal radioulnar joint (DRUJ) conditions result from derangements to several structures that may include the length, shape, and/or orientation of the articulating surfaces; the cartilage of the DRUJ and/or ulnocarpal joint; the DRUJ and/or ulnocarpal joint ligaments; and the extensor carpi ulnaris and/or pronator quadratus muscle. Once a complete diagnosis is made, often only one of these components is addressed, which results in suboptimal clinical outcomes. In this article, we present a treatment algorithm (the Four-Leaf Clover algorithm) to guide treatment of DRUJ pathology. The Four Leaf Clover principle is a guiding algorithm, not a document forcing the surgeon to adopt one particular treatment. Its purpose is to provide treating physicians with a checklist that helps ensure that they do not miss any of the different components that need to be addressed for a complete treatment. Using the treatment algorithm, we should achieve satisfactory resolution of patients' symptoms after addressing the particular components in a stepwise approach. PMID- 26944033 TI - Commentary: Concurrent administration of PTH and antiresorptives: Additive effects or DXA cosmetics. AB - Osteoanabolic therapy with parathyroid hormone (PTH(1-84)) or the PTH analogues teriparatide (PTH(1-34), TPTD) and abaloparatide induces a positive remodeling balance and increases modeling and remodeling activity on bone surfaces. As the anabolic action of PTH is primarily remodeling based increased bone turnover maximizes bone accrual. Increased remodeling, however, also increases cortical porosity and reduces mineralization of newly formed bone, which may cause initial reductions in BMD, particularly at sites rich in cortical bone. Increased cortical porosity may also have negative consequences for bone strength. Consequently, an interest developed in concurrent therapies offsetting the potential early negative cortical bone effects developed, and several studies using varying concurrent combinations of TPTD or PTH(1-84) with various antiresorptive (anti-catabolic) agents (estrogen, SERMs, bisphosphonates and denosumab) have been published. This commentary addresses the discrepancy between changes in areal bone mineral density (BMD) and bone turnover markers (BTM) in concurrent therapy studies leading to possible misinterpretations of the results. In studies of concurrent therapies increases in BMD are generally accompanied by decreases in biochemical markers of bone turnover. This includes Procollagen Type I N-Terminal Propetide (PINP), which has emerged as a reliable marker of bone formation during osteoanabolic therapy. We therefore want to submit, that the larger increases in BMD seen initially in patients on concurrent therapy mask the potential for later reduced osteoanabolic action of PTH. This notion is corroborated by: 1) the lesser impairment of bone anabolism seen with milder antiresorptive modalities like hormone replacement therapy (HRT) or Selective Estrogen Receptor Modulators (SERMs); 2) the changes in BMD seen in extension studies where treatment naive patients previously treated with PTH alone are crossed over to antiresorptive drugs. We therefore advise against a general use of concurrent therapy with PTH and antiresorptive agents, as it entails blunting of osteoanabolic action of PTH in the long run. PMID- 26944034 TI - Radiology's Golden Age: Our Best Years Are Ahead of Us. PMID- 26944035 TI - Big Data. PMID- 26944036 TI - Here Come the Baby Boomers. PMID- 26944037 TI - ACR Appropriateness Criteria Radiologic Management of Hepatic Malignancy. AB - Management of primary and secondary hepatic malignancy is a complex problem. Achieving optimal care for this challenging population often requires the involvement of multiple medical and surgical disciplines. Because of the wide variety of potential therapies, treatment protocols for various malignancies continue to evolve. Consequently, development of appropriate therapeutic algorithms necessitates consideration of medical options, such as systemic chemotherapy; surgical options, such as resection or transplantation; and loco regional therapies, such as thermal ablation and transarterial embolization techniques. This article provides a review of treatment strategies for the three most common subtypes of hepatic malignancy treated with loco-regional therapies: hepatocellular carcinoma, neuroendocrine metastases, and colorectal metastases. The ACR Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every three years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment. PMID- 26944038 TI - A Call for the Structured Physicist Report. PMID- 26944039 TI - Effect of Training on Qualitative Mammographic Density Assessment. AB - PURPOSE: The aim of this study was to evaluate the accuracy of visual mammographic breast density assessment and determine if training can improve this assessment, to compare the accuracy of qualitative density assessment before and after training with a quantitative assessment tool, and to evaluate agreement between qualitative and quantitative density assessment methods. METHODS: Consecutive screening mammograms performed over a 4-month period were visually assessed by two study breast radiologists (the leads), who selected 200 cases equally distributed among the four BI-RADS density categories. These 200 cases were shown to 20 other breast radiologists (the readers) before and after viewing a training module on visual density assessment. Agreement between reader assessment and lead radiologist assessment was calculated for both reading sessions. Quantitative volumetric density of the 200 mammograms, determined using a commercially available tool, was compared with both sets of reader assessment and with lead radiologist assessment. RESULTS: Compared with lead radiologist assessment, reader accuracy of breast density assessment increased from 65% before training to 72% after training (odds ratio, 1.41; P < .0001). Training specifically improved assignment to BI-RADS categories 1 (P < .0001) and 4 (P < .10). Compared with quantitative assessment, reader accuracy showed statistically nonsignificant improvement with training (odds ratio, 1.1; P = .26). Substantial agreement between qualitative and quantitative breast density assessment was demonstrated (kappa = 0.78). CONCLUSIONS: Training may improve the accuracy of mammographic breast density assessment. Substantial agreement between qualitative and quantitative breast density assessment exists. PMID- 26944040 TI - New Frontiers in Education: Facebook as a Vehicle for Medical Information Delivery. PMID- 26944041 TI - Transition to Value: Signposts for Change. PMID- 26944042 TI - A before-after interventional trial of dispatcher-assisted cardio-pulmonary resuscitation for out-of-hospital cardiac arrests in Singapore. AB - AIM: To evaluate the effects of a comprehensive dispatcher-assisted CPR (DACPR) training program on bystander CPR (BCPR) rate and the outcomes of out-of-hospital cardiac arrest (OHCA) in Singapore. METHODS: This is an initial program evaluation of a national DACPR intervention. A before-after analysis was conducted using OHCA cases retrieved from a local registry and DACPR information derived from audio recordings and ambulance notes. The primary outcomes were survival to admission, survival at 30 days post-arrest and good functional recovery. RESULTS: Data was collected before the intervention (April 2010 to December 2011), during the run-in period (January 2012 to June 2012) and after the intervention (July 2012 to February 2013). A total of 2968 cases were included in the study with a mean age of 65.6. Overall survival rate was 3.9% (116) with good functional recovery in 2.2% (66) of the patients. BCPR rate increased from 22.4% to 42.1% (p<0.001) with odds ratio (OR) of 2.52 (95% confidence interval [CI]: 2.09-3.04) and ROSC increased significantly from 26.5% to 31.2% (p=0.02) with OR of 1.26 (95%CI: 1.04-1.53) after the intervention. Significantly higher survival at 30 days was observed for patients who received BCPR from a trained person as compared to no BCPR (p=0.001, OR=2.07 [95%CI: 1.41 3.02]) and DACPR (p=0.04, OR=0.30 [95%CI: 0.04-2.18]). CONCLUSION: A significant increase in BCPR and ROSC was observed after the intervention. There was a trend to suggest improved survival outcomes with the intervention pending further results from the trial. PMID- 26944043 TI - TAKE10: A community approach to teaching compression-only CPR to high-risk zip codes. AB - OBJECTIVE: Bystander cardiopulmonary resuscitation (CPR) for out-of-hospital cardiac arrest (OHCA) has the ability to improve patient survival. However, the rates at which CPR occurs are suboptimal. We hypothesized that targeted CPR training in neighborhoods with low bystander CPR and high incidence of cardiac arrests would increase the incidence of bystander CPR for adult OHCA. METHODS: This study is a descriptive observation and analysis of the TAKE 10 program, which recruited City of Austin and Travis County residents to teach fellow community members compression-only CPR. Twelve zip codes in Austin and Travis County were identified as "high-risk," based on low bystander CPR rates and high incidences of cardiac arrest. Data was collected on bystander CPR for OHCA over the study period of July 2008 to September 2013. Incidence of cardiac arrest and bystander CPR were calculated yearly and overall. RESULTS: Over the study period, a total of 11,242 community members completed compression-only CPR training. While there was no significant difference in the number of individuals trained in high-risk zip codes compared to the other zip codes (High-Risk [n+/-sd] 263+/ 235; General 212+/-193; p-value 0.46), the amount of people trained in the high risk zip codes did trend upwards over the study period. Additionally, there was an increase in percent of bystander CPR per eligible cardiac arrest in the high risk zip codes (2009: [n+/-sd] 0.28+/-0.34 to 2013: 0.39+/-0.28). CONCLUSIONS: Targeted compression-only CPR training in high-risk neighborhoods may be associated with increased bystander CPR rates over time. PMID- 26944044 TI - No evidence for the involvement of the argasid tick Ornithodoros faini in the enzootic maintenance of marburgvirus within Egyptian rousette bats Rousettus aegyptiacus. AB - BACKGROUND: The cave-dwelling Egyptian rousette bat (ERB; Rousettus aegyptiacus) was recently identified as a natural reservoir host of marburgviruses. However, the mechanisms of transmission for the enzootic maintenance of marburgviruses within ERBs are unclear. Previous ecological investigations of large ERB colonies inhabiting Python Cave and Kitaka Mine, Uganda revealed that argasid ticks (Ornithodoros faini) are hematophagous ectoparasites of ERBs. Yet, their potential role as transmission vectors for marburgvirus has not been sufficiently assessed. FINDINGS: In the present study, 3,125 O. faini were collected during April 2013 from the rock crevices of Python Cave, Uganda. None of the ticks tested positive for marburgvirus-specific RNA by Q-RT-PCR. The probability of failure to detect marburgvirus at a conservative prevalence of 0.1 % was 0.05. CONCLUSIONS: The absence of marburgvirus RNA in O. faini suggests they do not play a significant role in the transmission and enzootic maintenance of marburgvirus within their natural reservoir host. PMID- 26944045 TI - Women with Neck Pain on Long-Term Sick Leave-Approaches Used in the Return to Work Process: A Qualitative Study. AB - Purpose There are difficulties in the process of return to work (RTW) from long term sick leave, both in general and regarding sick leave because of neck pain in particular. Neck pain is difficult to assess, problematic to rehabilitate, and hard to cure; and it is not always easy to decide whether the pain is work related. The outcome of RTW could be dependent upon individuals' approaches, defensive or offensive behaviors, and choices related to their self-efficacy. The aim of this study was to identify approaches used in the RTW process among women with neck pain on long-term sick leave from human service organizations. Methods This is a qualitative descriptive study based on grounded theory. A Swedish cohort of 207 women with a history of long-term sick leave with neck pain from human service organizations answered open-ended written questions at 0, 6, and 12 months, and 6 years; and 16 women were interviewed. Results Individuals expressed their coping approaches in terms of fluctuating in work status over time: either as a strategy or as a consequence. Periods of sick leave were interwoven with periods of work. The women were either controlling the interaction or struggling in the interaction with stakeholders. Conclusions Return to work outcomes may be improved if the fluctuating work status over time is taken into account in the design of rehabilitation efforts for women with a history of long-term sick leave and with chronical musculoskeletal conditions. PMID- 26944046 TI - Prevalence of antibody to Hepatitis B core antigen and Hepatitis B virus DNA in HBsAg negative healthy blood donors. AB - BACKGROUND: Hepatitis B virus is one of the most important blood born viruses. Although the sensitivity of screening tests has been considerably increased, transmission may still occur due to window period or occult hepatitis B infections (OBIs). This study was aimed at evaluating the prevalence of the anti HBc and identifying the HBV DNA in HBsAg negative blood donors. METHODS: The Blood samples from 2031 HBsAg-negative blood donors were divided into three aliquots and tested for anti-HBc, anti-HBs and HBV DNA. Serologic screening including anti-HBc and anti-HBs was performed. As a confirmatory test, all positive results for anti-HBc were retested with another kit. Two positive results were considered for anti-HBc positivity. All HBsAg negative selected donations were tested by PCR assay on pooled specimens (five samples per pool), plasma samples found to be HBsAg negative but anti-HBc positive were selected for a single-unit specimen Real-Time assay. RESULTS: The study population had a mean age of 33.25 +/- 10.09 years were mainly composed of males (94.8 %). The seroprevalance rate was 4.9 % for Anti-HBc and 31.9 % for HBsAb. The majority (58.6 %) of Anti-HBc positive cases were regular blood donors with 42-49 years being the largest age group (41.4 %). Neither individual NAT nor pooled NAT test detected any HBV DNA. CONCLUSION: However, Screening of anti-HBc Ab is proposed as a method to identify previous contact with HBV, but there is controversy in literature data regarding the cost-benefit of exclusion of positive anti-HBc Ab in blood donors. Our data does not suggest HBc-Ab test as a screening tool in the study setting. PMID- 26944048 TI - Temporal flux in beta-lactam resistance among Klebsiella pneumoniae in Western Australia. AB - Our aim was to identify long-term beta-lactam resistance trends in local Klebsiella pneumoniae isolates, which are a common cause of sepsis in Western Australia. We studied three collections of K. pneumoniae isolates from Western Australia between 1977 and 2015 comprising contemporary blood culture (n = 98), multiresistant (n = 21) and historical (n = 50) isolates. Antimicrobial resistance was determined by Clinical and Laboratory Standards Institute agar dilution methods. PCR DNA sequencing identified beta-lactamase variants and porin mutations contributing to beta-lactam resistance. Isolates were genotyped by PFGE, multilocus sequence typing and a variable number tandem repeat method. From 1989 onwards, we detected the SHV-2a extended-spectrum beta-lactamase (ESBL) in ceftriaxone-resistant isolates, and in ceftazidime- and aztreonam-resistant isolates from 1993. Ceftriaxone, ceftazidime and aztreonam resistance persisted, with blaCTX-M types becoming the dominant ESBLs by 2010. CTX-M-15 was encountered in both multiresistant and blood culture isolates. Meropenem resistance was detected for the first time in 2011 in a locally isolated blaIMP-4-positive K. pneumoniae. We found sequence types ST23 and ST86 that occurred in multiple isolates from invasive infections. ST86 was the most common and maintained a high degree (90 %) of similarity by PFGE since 1977. Ceftazidime-resistant K. pneumoniae sequence types have caused invasive infections in Western Australia since 1993. Invasive isolates producing CTX-M-14 and CTX-M-15 appeared in Western Australia during the last decade, before the appearance of carbapenemases. The diversity of beta-lactam resistance and beta-lactamase resistance mechanisms in Western Australian K. pneumoniae has increased since ESBLs were first described locally. PMID- 26944047 TI - Severe maternal morbidity and near misses in tertiary hospitals, Kelantan, Malaysia: a cross-sectional study. AB - BACKGROUND: Severe maternal conditions have increasingly been used as alternative measurements of the quality of maternal care and as alternative strategies to reduce maternal mortality. We aimed to study severe maternal morbidity and maternal near miss among women in two tertiary hospitals in Kota Bharu, Kelantan, Malaysia. METHODS: A cross-sectional study with record review was conducted in 2014. Severe maternal morbidity and maternal near miss were classified using the new World Health Organization criteria. Health indicators for obstetric care were calculated and descriptive analyses were performed using SPSS version 22.0. RESULTS: In total, 21,579 live births, 395 women with severe maternal morbidity, 47 women with maternal near miss and two maternal deaths were analysed. The severe maternal morbidity incidence ratio was 18.3 per 1000 live births and the maternal near miss incidence ratio was 2.2 per 1000 live births. The maternal near miss mortality ratio was 23.5 and the mortality index was 4.1 %. The process indicators for essential interventions were almost 100.0 %. Haemorrhagic disorders were the most common event for severe maternal morbidity (68.6 %) and maternal near miss (80.9 %) and management-based criteria accounted for 85.1 %. CONCLUSIONS: Comprehensive emergency care and intensive care as well as overall improvements in the quality of maternal health care need to be achieved to substantial reduce maternal death. PMID- 26944049 TI - Primary diffuse leptomeningeal gliomatosis as a rare cause of pain in cervical spine. AB - BACKGROUND: Primary diffuse leptomeningeal gliomatosis (PDLG) is a very rare neuro-oncological disease, with only 90 cases of PDLG described in medical literature so far. CASE PRESENTATION: We present a case report of a 56-years-old female patient, who was originally hospitalized due to cervical spine pain lasting several months. Despite complex diagnostics and treatment, the neurological state of the patient progressively deteriorated. Patient died 10 months after the first reported symptom. Postmortem pathological findings resulted in the diagnosis of PDLG. CONCLUSIONS: Affection of the cervical spine in early stages of PDLG is rare and has been described in only six patients so far. PDLG is a fatal neuro-oncological disease and it must be kept in mind in the differential diagnosis of persistent back pain syndromes. PMID- 26944050 TI - Incidence of post-cataract endophthalmitis with intracameral cefuroxime. PMID- 26944051 TI - Small-scale land-use variability affects Anopheles spp. distribution and concomitant Plasmodium infection in humans and mosquito vectors in southeastern Madagascar. AB - BACKGROUND: Deforestation and land-use change have the potential to alter human exposure to malaria. A large percentage of Madagascar's original forest cover has been lost to slash-and-burn agriculture, and malaria is one of the top causes of mortality on the island. In this study, the influence of land-use on the distribution of Plasmodium vectors and concomitant Plasmodium infection in humans and mosquito vectors was examined in the southeastern rainforests of Madagascar. METHODS: From June to August 2013, health assessments were conducted on individuals living in sixty randomly selected households in six villages bordering Ranomafana National Park. Humans were screened for malaria using species-specific rapid diagnostic tests (RDTs), and surveyed about insecticide treated bed net (ITN) usage. Concurrently, mosquitoes were captured in villages and associated forest and agricultural sites. All captured female Anopheline mosquitoes were screened for Plasmodium spp. using a circumsporozoite enzyme linked immunosorbent assay (csELISA). RESULTS: Anopheles spp. dominated the mosquito communities of agricultural and village land-use sites, accounting for 41.4 and 31.4 % of mosquitoes captured respectively, whereas Anopheles spp. accounted for only 1.6 % of mosquitoes captured from forest sites. Interestingly, most Anopheles spp. (67.7 %) were captured in agricultural sites in close proximity to animal pens, and 90.8 % of Anopheles mosquitoes captured in agricultural sites were known vectors of malaria. Three Anopheline mosquitoes (0.7 %) were positive for malaria (Plasmodium vivax-210) and all positive mosquitoes were collected from agricultural or village land-use sites. Ten humans (3.7 %) tested were positive for P. falciparum, and 23.3 % of those surveyed reported never sleeping under ITNs. CONCLUSIONS: This study presents the first report of malaria surveillance in humans and the environment in southeastern Madagascar. These findings suggest that even during the winter, malaria species are present in both humans and mosquitoes; with P. falciparum found in humans, and evidence of P. vivax-210 in mosquito vectors. The presence of P. vivax in resident vectors, but not humans may relate to the high incidence of humans lacking the Duffy protein. The majority of mosquito vectors were found in agricultural land-use sites, in particular near livestock pens. These findings have the potential to inform and improve targeted malaria control and prevention strategies in the region. PMID- 26944052 TI - Acute phenylalanine/tyrosine depletion of phasic dopamine in the rat brain. AB - RATIONALE: Dopamine plays a critical role in striatal and cortical function, and depletion of the dopamine precursors phenylalanine and tyrosine is used in humans to temporarily reduce dopamine and probe the role of dopamine in behavior. This method has been shown to alter addiction-related behaviors and cognitive functioning presumably by reducing dopamine transmission, but it is unclear what specific aspects of dopamine transmission are altered. OBJECTIVES: We performed this study to confirm that administration of an amino acid mixture omitting phenylalanine and tyrosine (Phe/Tyr[-]) reduces tyrosine tissue content in the prefrontal cortex (PFC) and nucleus accumbens (NAc), and to test the hypothesis that Phe/Tyr[-] administration reduces phasic dopamine release in the NAc. METHODS: Rats were injected with a Phe/Tyr[-] amino acid mixture, a control amino acid mixture, or saline. High-performance liquid chromatography was used to determine the concentration of tyrosine, dopamine, or norepinephrine in tissue punches from the PFC and ventral striatum. In a separate group of rats, phasic dopamine release was measured with fast-scan cyclic voltammetry in the NAc core after injection with either the Phe/Tyr[-] mixture or the control amino acid solution. RESULTS: Phe/Tyr[-] reduced tyrosine content in the PFC and NAc, but dopamine and norepinephrine tissue content were not reduced. Moreover, Phe/Tyr[-] decreased the frequency of dopamine transients, but not their amplitude, in freely moving rats. CONCLUSIONS: These results indicate that depletion of tyrosine via Phe/Tyr[-] decreases phasic dopamine transmission, providing insight into the mechanism by which this method modifies dopamine-dependent behaviors in human imaging studies. PMID- 26944055 TI - Notification that new names of prokaryotes, new combinations and new taxonomic opinions have appeared in volume 65, part 11, of the IJSEM. AB - This listing of names of prokaryotes published in a previous issue of the IJSEM is provided as a service to bacteriology to assist in the recognition of new names and new combinations. This procedure was proposed by the Judicial Commission [Minute 11(ii), Int J Syst Bacteriol 41 (1991), p. 185]. The names given herein are listed according to the Rules of priority (i.e. page number and order of valid publication of names in the original articles). PMID- 26944053 TI - Characterization of passive permeability at the blood-tumor barrier in five preclinical models of brain metastases of breast cancer. AB - The blood-brain barrier (BBB) is compromised in brain metastases, allowing for enhanced drug permeation into brain. The extent and heterogeneity of BBB permeability in metastatic lesions is important when considering the administration of chemotherapeutics. Since permeability characteristics have been described in limited experimental models of brain metastases, we sought to define these changes in five brain-tropic breast cancer cell lines: MDA-MB-231BR (triple negative), MDA-MB-231BR-HER2, JIMT-1-BR3, 4T1-BR5 (murine), and SUM190 (inflammatory HER2 expressing). Permeability was assessed using quantitative autoradiography and fluorescence microscopy by co-administration of the tracers (14)C-aminoisobutyric acid (AIB) and Texas red conjugated dextran prior to euthanasia. Each experimental brain metastases model produced variably increased permeability to both tracers; additionally, the magnitude of heterogeneity was different among each model with the highest ranges observed in the SUM190 (up to 45-fold increase in AIB) and MDA-MB-231BR-HER2 (up to 33-fold in AIB) models while the lowest range was observed in the JIMT-1-BR3 (up to 5.5-fold in AIB) model. There was no strong correlation observed between lesion size and permeability in any of these preclinical models of brain metastases. Interestingly, the experimental models resulting in smaller mean metastases size resulted in shorter median survival while models producing larger lesions had longer median survival. These findings strengthen the evidence of heterogeneity in brain metastases of breast cancer by utilizing five unique experimental models and simultaneously emphasize the challenges of chemotherapeutic approaches to treat brain metastases. PMID- 26944054 TI - Evaluation of DISCOVAR de novo using a mosquito sample for cost-effective short read genome assembly. AB - BACKGROUND: De novo reference assemblies that are affordable, practical to produce, and of sufficient quality for most downstream applications, remain an unattained goal for many taxa. Insects, which may yield too little DNA from individual specimens for long-read sequencing library construction and often have highly heterozygous genomes, can be particularly hard to assemble using inexpensive short-read sequencing data. The large number of insect species with medical or economic importance makes this a critical problem to address. RESULTS: Using the assembler DISCOVAR de novo, we assembled the genome of the African malaria mosquito Anopheles arabiensis using 250 bp reads from a single library. The resulting assembly had a contig N50 of 22,433 bp, and recovered the gene set nearly as well as the ALLPATHS-LG AaraD1 An. arabiensis assembly produced with reads from three sequencing libraries and much greater resources. DISCOVAR de novo appeared to perform better than ALLPATHS-LG in regions of low complexity. CONCLUSIONS: DISCOVAR de novo performed well assembling the genome of an insect of medical importance, using simpler sequencing input than previous anopheline assemblies. We have shown that this program is a viable tool for cost-effective assembly of a modestly-sized insect genome. PMID- 26944056 TI - The use of reflective diaries in end of life training programmes: a study exploring the impact of self-reflection on the participants in a volunteer training programme. AB - BACKGROUND: A training programme was developed and delivered to a cohort of volunteers who were preparing for a unique role to provide companionship to dying patients in the acute hospital setting. This comprehensive programme aimed to provide an opportunity for participants to fully understand the nature and responsibilities of the role, whilst also allowing sufficient time to assess the qualities and competencies of participants for their ongoing volunteering role. Participants completed reflective diaries throughout the training course to record their ongoing thoughts and feelings. The purpose of this paper is to present a phenomenological analysis of these entries to understand participants' experiences, perceptions and motivations. METHOD: The wider study was structured into three phases. Phase 1 was the delivery of a 12 week, bespoke training programme; Phase 2 involved a 26 week pilot implementation of the Care of the Dying Volunteer Service and Phase 3 was the research evaluation of the training and implementation which would inform the further development of the training programme. Self-reflection is a common component of End of Life training programmes and volunteers in this study completed a reflective diary after participation in each of the training sessions. A thematic analysis was undertaken to explore and understand the participants' experience, perceptions and motivations in relation to their participation in the training. RESULTS: All 19 volunteers completed the reflective diaries. From a potential 228 diary entries over the 12 week training programme, 178 diary entries were submitted (78 %). The following key themes were identified: Dying Alone and the importance of being present, Personal loss and the reconstruction of meaning, Self-Awareness and Personal growth, Self-preservation and Coping strategies and group unity/cohesion. CONCLUSIONS: The participants in this study demonstrated that they were able to use the diaries as an appropriate medium for reflection. Their reflections were also instrumental in the ongoing revision and development of the training programme. Analysis of their entries illustrated that the diaries could provide the opportunity for a reappraisal of their world view and personal philosophy around death and dying. Further research is undoubtedly required, however this paper suggests that self-reflection in this way, supports preparation in honing the appropriate attitudes and qualities required to work in this role. PMID- 26944057 TI - Armc8 regulates the invasive ability of hepatocellular carcinoma through E cadherin/catenin complex. AB - Armc8 (armadillo-repeat-containing protein 8) was proved to promote disruption of E-cadherin complex through regulating alpha-catenin degradation. In this study, we investigated Armc8 expression in hepatocellular carcinoma using immunohistochemistry (IHC). The positive rate of Armc8 expression in hepatocellular carcinoma was 53.9 % and higher than that in normal hepatic tissues (9.2 %) (p < 0.05). Clinicopathological analysis shows that Armc8 expression in hepatocellular carcinoma was significantly associated with larger tumor size (>=5 cm), multiple tumor numbers, higher pathological grade (media and poor), advanced TNM stages (II/III), and advanced BCLC stages (B/C). Western blot study also detected higher Armc8 expression in hepatocellular carcinoma cells including HepG2, HCC97L, and SMMC-7721 than in human hepatic cell Bel-7402. We further use specific small interfering RNAs (siRNAs) to knock down Armc8 expression in HepG2 cells and found that knockdown of Armc8 expression significantly inhibited the invasive ability of HepG2 cells. Downregulation of Armc8 expression significantly upregulated alpha-catenin, beta-catenin, and E cadherin expression in HepG2 cells. Immunofluorescent study shows that knockdown of Armc8 expression restored E-cadherin expression in membrane of HepG2 cells. These results indicate that Armc8 may be a potential cancer marker in hepatocellular carcinoma and may regulate cancer invasion through E cadherin/catenin complex. PMID- 26944058 TI - Plexin-B1 indirectly affects glioma invasiveness and angiogenesis by regulating the RhoA/alphavbeta3 signaling pathway and SRPK1. AB - Gliomas are one of the most common primary brain tumors in adults. They display aggressive invasiveness, are highly vascular, and have a poor prognosis. Plexin B1 is involved in numerous cellular processes, especially cellular migration and angiogenesis. However, the role and regulatory mechanisms of Plexin-B1 in gliomas are not understood and were thus investigated in this study. By using multiple and diverse experimental techniques, we investigated cell apoptosis, mitochondrial membrane potential, cell migration and invasion, angiogenesis, PI3K and Akt phosphorylation, and also the levels of SRPK1 and alphavbeta3 in glioma cells and animal glioma tissues. The results indicated that Plexin-B1 expression in glioma cell lines is increased compared to normal human astrocytes. Plexin-B1 mediates RhoA/integrin alphavbeta3 involved in the PI3K/Akt pathway and SRPK1 to influence the growth of glioma cell, angiogenesis, and motility in vitro and in vivo. Thus, Plexin-B1 signaling regulates the Rho/alphavbeta3/PI3K/Akt pathway and SRPK1, which are involved in glioma invasiveness and angiogenesis. Therefore, the new drug research should focus on Plexin-B1 as a target for the treatment of glioma invasion and angiogenesis. PMID- 26944059 TI - Variations in and predictors of the occurrence of depressive symptoms and mood symptoms in multiple sclerosis: a longitudinal two-year study. AB - BACKGROUND: There is limited knowledge regarding how depressive symptoms and a cluster of specific mood symptoms in people with multiple sclerosis (MS) vary over time and how they are influenced by contributing factors. Therefore, the aims of this study were a) to describe variations over 2 years in the occurrence of depressive symptoms and mood symptoms in a sample of people with MS, and b) to investigate the predictive value of sex, age, coping capacity, work status, disease severity, disease course, fatigue, cognition, frequency of social/lifestyle activities, and perceived impact of MS on health, on the occurrence of depressive symptoms and mood symptoms. METHODS: Through using a protocol of measures of functioning and perceived impact of MS on health, comprising of the Beck Depression Inventory, 219 people with MS were assessed at 0, 12 and 24 months. Predictive values were explored with Generalised Estimating Equations. RESULTS: Proportions with depressive symptoms varied significantly (p < 0.001) from 21 to 30% between the three time points. Proportions with mood symptoms varied significantly (p < 0.001) from 14 to 17% between the three time points. Weak coping capacity and reduced frequency of social/lifestyle activities predicted the occurrence of depressive symptoms and mood symptoms, as did the psychological impact of MS on health in interaction with time. For people with MS of working age, not working predicted the occurrence of depressive symptoms and mood symptoms, as did the physical impact of MS on health on the occurrence of mood symptoms. CONCLUSIONS: The occurrence of depressive symptoms and mood symptoms in people with MS vary over a 2-year time period; almost half have depressive symptoms at least once. Health care services should develop strategies aimed at identifying people with MS who are depressed or who develop depressive symptoms. Interventions for alleviating depressive symptoms should consider the individual's coping capacity and perceived impact of MS on health, and facilitate their ability to maintain participation in valued everyday activities. PMID- 26944060 TI - The Synergistic Effect of Serine with Selenocompounds on the Expression of SelP and GPx in HepG2 Cells. AB - We explored the synergistic effect of serine combined with several selenocompounds or used alone on the expression of selenoprotein P (SelP) and glutathione peroxidase (GPx) in this study. We first compared the SelP and GPx expression difference between HepG2 and Hela cells treated with serine and finally chose HepG2 as experimental cell. In the serine-used-alone experiment, three kinds of selenium nutritional models (low-, adequate-, and high-selenium) were established and serine was 10 times gradient diluted (0.01 to 100 MUmol/L). In the combined experiment, the selenocompound doses were set as 0.01, 0.1, and 1 MUmol Se/L and serine was set according to its molar ratio with the selenocompounds. We found that SelP and GPx concentrations in the low-, adequate , and high-selenium models increased following with serine dose. When the concentration of sodium selenite and SeMet was 1 MUmol Se/L while MeSeCys was 0.1 and 1 MUmol Se/L, SelP concentrations for serine combined with selenocompounds groups were significantly higher than that of selenocompounds used alone. When the concentration of sodium selenite was 0.1 MUmol Se/L, SeMet was 0.1 and 1 MUmol Se/L while MeSeCys was 0.01 and 1 MUmol Se/L, GPx concentrations for serine combined with selenocompounds groups were significantly higher than that of selenocompounds used alone. Our preliminary result indicated the beneficial effect of serine on the expression of SelP and GPx, which suggested that it might be a candidate for combined selenium supplement. PMID- 26944062 TI - Cross-sectional area of the ulnar nerve after decompression at the cubital tunnel. AB - A total of 48 patients undergoing surgical decompression of the ulnar nerve at the cubital tunnel between February 2010 and May 2013 were retrospectively studied to determine changes in the cross-sectional area of the nerve by the technique of neurosonography. The mean follow-up was 46 months. Post-operative follow-up examination of the cross-sectional area of the ulnar nerve showed a slight reduction in the mean value from 13.8 mm(2) (pre-operative) to 12.9 mm(2) (post-operative). Of the 48 patients, 36 showed a reduction in the cross sectional area. No correlation was detected between the clinical and sonographic outcomes. Ultrasound seems to be of limited value in the post-operative assessment of patients with entrapment neuropathy of the ulnar nerve. LEVEL OF EVIDENCE: IV. PMID- 26944061 TI - Weighted gene co-expression network analysis identifies specific modules and hub genes related to coronary artery disease. AB - BACKGROUND: The analysis of the potential molecule targets of coronary artery disease (CAD) is critical for understanding the molecular mechanisms of disease. However, studies of global microarray gene co-expression analysis of CAD still remain limited. METHODS: Microarray data of CAD (GSE23561) were downloaded from Gene Expression Omnibus, including peripheral blood samples from CAD patients (n = 6) and controls (n = 9). Limma package in R was used to identify the differentially expressed genes (DEGs) between CAD and control samples. Using weighted gene co-expression network analysis (WGCNA) package in R, WGCNA was performed to identify significant modules in the network. Then, functional and pathway enrichment analyses were conducted for genes in the most significant module using DAVID software. Moreover, hub genes in the module were analyzed by isubpathwayminer package in R and GenCLiP 2.0 tool to identify the significant sub-pathways. RESULTS: Total 3711 DEGs and 21 modules for them were identified in CAD samples. The most significant module was associated with the pathways of hypertrophic cardiomyopathy and membrane related functions. In addition, the top 30 hub genes with high connectivity in the module were selected, and two genes (G6PD and S100A7) were taken as key molecules via sub-pathway screening and data mining. CONCLUSIONS: A module associated with hypertrophic cardiomyopathy pathway was detected in CAD samples. G6PD and S100A7 were the potential targets in CAD. Our finding might provide novel insight into the underlying molecular mechanism of CAD. PMID- 26944063 TI - US hospitals make progress against healthcare associated infections. PMID- 26944064 TI - Rhabdoid Myomelanocytic Tumor (PEComa) of the Ovary: A Clinically Benign Case Followed for 7 Years. AB - A 3.0 * 2.5 cm rhabdoid myomelanocytic tumor was incidentally found in the left ovary of a 43-year-old black woman. The tumor cells were cytologically bland with minimal proliferation rate, multifocally weakly or moderately expressed TFE3, strongly expressed smooth muscle markers and SMARCB1/INI1, and focally expressed HMB45. They contained numerous paranuclear whorls of intermediate filaments that were verified by ultrastructure. No other lines of differentiation were detected within the tumor. Neither translocation nor increased number of copies of the TFE3 gene at Xp11.22 was detected by fluorescence in situ hybridization. The patient remains well, free of tumor, 7 years after surgery. A rhabdoid variant of myomelanocytic tumor is a rarity, with only a single case described previously. PMID- 26944065 TI - An enigmatic clinical entity: A new case of olfactory schwannoma. AB - Olfactory schwannomas, also described as subfrontal or olfactory groove schwannomas, are very rare tumors, whose pathogenesis is still largely debated. We report a case of olfactory schwannoma in a 39-year-old woman who presented with anosmia and headache. The clinical examination did not show lesions in the nose-frontal region and there was no history of neurofibromatosis. Head MRI and CT scan revealed a lobulated extra-axial mass localized in the right anterior cranial fossa that elevated the ipsilateral frontal pole. Bilateral frontal craniotomy demonstrated a tumor strictly attached to the right portion of the cribriform plate that surrounded the right olfactory tract, not clearly identifiable. The immunohistochemical analysis suggested the diagnosis of typical schwannoma. The patient was discharged without any neurological deficit and a four-month postoperative MRI scan of the brain showed no residual or recurrent tumor. PMID- 26944066 TI - Current status of neonatal intensive care in India. AB - Globally, newborn health is now considered as high-level national priority. The current neonatal and infant mortality rate in India is 29 per 1000 live births and 42 per 1000 live births, respectively. The last decade has seen a tremendous growth of neonatal intensive care in India. The proliferation of neonatal intensive care units, as also the infusion of newer technologies with availability of well-trained medical and nursing manpower, has led to good survival and intact outcomes. There is good care available for neonates whose parents can afford the high-end healthcare, but unfortunately, there is a deep divide and the poor rural population is still underserved with lack of even basic newborn care in few areas! There is increasing disparity where the 'well to do' and the 'increasingly affordable middle class' is able to get the most advanced care for their sick neonates. The underserved urban poor and those in rural areas still contribute to the overall high neonatal morbidity and mortality in India. The recent government initiative, the India Newborn Action Plan, is the step in the right direction to bridge this gap. A strong public-private partnership and prioritisation is needed to achieve this goal. This review highlights the current situation of neonatal intensive care in India with a suggested plan for the way forward to achieve better neonatal care. PMID- 26944068 TI - The status and developments of leather solid waste treatment: A mini-review. AB - Leather making is one of the most widespread industries in the world. The production of leather goods generates different types of solid wastes and wastewater. These wastes will pollute the environment and threat the health of human beings if they are not well treated. Consequently, the treatment of pollution caused by the wastes from leather tanning is really important. In comparison with the disposal of leather wastewater, the treatment of leather solid wastes is more intractable. Hence, the treatment of leather solid wastes needs more innovations. To keep up with the rapid development of the modern leather industry, various innovative techniques have been newly developed. In this mini-review article, the major achievements in the treatment of leather solid wastes are highlighted. Emphasis will be placed on the treatment of chromium-tanned solid wastes; some new approaches are also discussed. We hope that this mini-review can provide some valuable information to promote the broad understanding and effective treatment of leather solid wastes in the leather industry. PMID- 26944067 TI - TNF-Related Apoptosis-Inducing Ligand (TRAIL)-Armed Exosomes Deliver Proapoptotic Signals to Tumor Site. AB - PURPOSE: Exosomes deliver signals to target cells and could thus be exploited as an innovative therapeutic tool. We investigated the ability of membrane TRAIL armed exosomes to deliver proapoptotic signals to cancer cells and mediate growth inhibition in different tumor models. EXPERIMENTAL METHODS AND RESULTS: K562 cells, transduced with lentiviral human membrane TRAIL, were used for the production of TRAIL(+) exosomes, which were studied by nanoparticle tracking analysis, cytofluorimetry, immunoelectronmicroscopy, Western blot, and ELISA. In vitro, TRAIL(+) exosomes induced more pronounced apoptosis (detected by Annexin V/propidium iodide and activated caspase-3) in TRAIL-death receptor (DR)5(+) cells (SUDHL4 lymphoma and INT12 melanoma), with respect to the DR5(-)DR4(+)KMS11 multiple myeloma. Intratumor injection of TRAIL(+) exosomes, but not mock exosomes, induced growth inhibition of SUDHL4 (68%) and INT12 (51%), and necrosis in KMS11 tumors. After rapid blood clearance, systemically administered TRAIL(+) exosomes accumulated in the liver, lungs, and spleen and homed to the tumor site, leading to a significant reduction of tumor growth (58%) in SUDHL4-bearing mice. The treatment of INT12-bearing animals promoted tumor necrosis and a not statistically significant tumor volume reduction. In KMS11-bearing mice, despite massive perivascular necrosis, no significant tumor growth inhibition was detected. CONCLUSIONS: TRAIL-armed exosomes can induce apoptosis in cancer cells and control tumor progression in vivo Therapeutic efficacy was particularly evident in intratumor setting, while depended on tumor model upon systemic administration. Thanks to their ability to deliver multiple signals, exosomes thus represent a promising therapeutic tool in cancer. Clin Cancer Res; 22(14); 3499-512. (c)2016 AACR. PMID- 26944069 TI - IL-17A plays a central role in the expression of psoriasis signature genes through the induction of IkappaB-zeta in keratinocytes. AB - In psoriasis lesions, a diverse mixture of cytokines is up-regulated that influence each other generating a complex inflammatory situation. Although this is the case, the inhibition of IL-17A alone showed unprecedented clinical results in patients, indicating that IL-17A is a critical inducer of psoriasis pathogenesis. To elucidate IL-17A-driven keratinocyte-intrinsic signaling pathways, we treated monolayers of normal human epidermal keratinocytes in vitro with a mixture of six cytokines (IL-17A, TNF-alpha, IL-17C, IL-22, IL-36gamma and IFN-gamma) involved in psoriasis to mimic the inflammatory milieu in psoriasis lesions. Microarray and gene set enrichment analysis revealed that this cytokine mixture induced similar gene expression changes with the previous transcriptome studies using psoriasis lesions. Importantly, we identified a set of IL-17A regulated genes in keratinocytes, which recapitulate typical psoriasis genes exemplified by DEFB4A, S100A7, IL19 and CSF3, based on the differences in the expression profiles of cells stimulated with six cytokines versus cells stimulated with only five cytokines lacking IL-17A. Furthermore, a specific IL 17A-induced gene, NFKBIZ, which encodes IkappaB-zeta, a transcriptional regulator for NF-kappaB, was demonstrated to have a significant role for IL-17A-induced gene expression. Thus, we present novel in vitro data from normal human keratinocytes that would help elucidating the IL-17A-driven keratinocyte activation in psoriasis. PMID- 26944070 TI - Discriminant validity of the Hospital Anxiety and Depression Scale, Beck Depression Inventory (II) and Beck Anxiety Inventory to confirmed clinical diagnosis of depression and anxiety in patients with chronic obstructive pulmonary disease. AB - The objective of this study was to investigate the discriminant validity of commonly used depression and anxiety screening tools in order to determine the most suitable tool for patients with chronic obstructive pulmonary disease (COPD). COPD patients (n = 56) completed the Hospital Anxiety and Depression Scale (HADS), Beck Depression Inventory (BDI-II) and Beck Anxiety Inventory (BAI). These scores were compared to confirmed clinical diagnoses of depression and anxiety using the Mini Neuropsychiatric Interview. HADS depression subscale (HADS-D) sensitivity/specificity was 78/81%; BDI-II 89/77%; HADS anxiety subscale (HADS-A) 71/81%; and BAI 89/62%. HADS-D sensitivity/specificity was improved (100/83%) with the removal of Q4 'I feel as if I am slowed down' and adjusted cut off (>=5). Removal of BDI-II Q21 'Loss of interest in sex' with adjusted cut-off >=12 resulted in similar improvement (100/79%). No problematic items were identified for HADS-A or BAI. Previously reported low sensitivity/specificity of the HADS for COPD patients was not replicated. Furthermore, simple modifications of the HADS-D markedly improved sensitivity/specificity for depression.BDI-II, HADS-A and BAI produced acceptable sensitivity/specificity unmodified. Pending further research for COPD patients we recommend continued use of the HADS-A with standard cut-off (>=8) and removal of Q4 of the HADS-D with lower cut-off >=5. PMID- 26944071 TI - Ranolazine and Ivabradine: two different modalities to act against ischemic heart disease. AB - Among the innovative drugs recently introduced for the management of chronic stable angina, Ranolazine and ivabradine represent two most true innovations. In fact, even if both drugs act by reducing myocardial work and thus oxygen consumption, this happens by a peculiar mechanism unlike that of conventional antischemic drugs. Ranolazine mediates its antianginal effects by the inhibition of cardiac late sodium current. This improves myocardial relaxation favoring myocardial perfusion. Ivabradine is a selective If channel blocker and acts by reducing firing rate of pacemaker cells in the sinoatrial node, without affecting the duration of action potential. The reduction of heart rate causes a reduction of left ventricular end diastolic pressure and increases the time useful to coronary flow by a prolongation of the diastole. A body of evidence found that two drugs are useful in ischemic patients whether at rest or during exercise. In addition, they can be used in monotherapy or in association with other conventional anti-ischemic drugs. The two medications could be used with advantage also in microvascular angina when standard therapy is ineffective. Thus, the two drugs represent an adjunctive and powerful therapeutic modality for the treatment of chronic stable angina, especially when conventional antianginal drugs were insufficient or inadequate. PMID- 26944072 TI - Blood pressure treatment goals in hypertension. PMID- 26944073 TI - Early HCC treatment: a future strategy against interferon/miR-484 axis to revert precancerous lesions? PMID- 26944074 TI - Antimicrobial resistance in the WHO African region: current status and roadmap for action. AB - The high burden of communicable diseases in African countries engenders extensive antimicrobial use and subsequent resistance with substantial health, financial and societal implications. A desktop analysis to ascertain whether countries in the WHO African region have implemented the WHO Policy Package to combat antimicrobial resistance (AMR) revealed that just two countries (4.3%) have national AMR plans in place, 14.9% (7) have overarching national infection prevention and control (IPC) policies, 93.6% (44) have essential medicines lists and 91.5% (43) have national medicines policies and treatment guidelines intimating rational use. None currently have representative national surveillance systems nor do any incentivize research and development into new medicines and diagnostics. A regional situational analysis to identify scalable good practices within African, resource-constrained country contexts under the auspices of WHO AFRO is a necessary initial step towards the development of national and regional action plans in concert with incremental progress towards achieving the objectives of the policy package and global action plan. While it is clearly the responsibility of governments to develop, resource and implement plans, regular reporting to and/or monitoring and evaluation by an overarching body such as WHO AFRO will ensure persistent incremental progress within continuous quality and accountability improvement paradigms. PMID- 26944075 TI - Has increasing public health awareness influenced the size of testicular tumours among adult populations over the last 40 years? AB - Background: Testicular cancer is the commonest malignancy in young men. Improvements in survival rates have led to campaigns to raise awareness in at risk men. We assessed the changing size of testicular tumours given the public health initiatives promoting testicular self-examination (TSE). Methods: Retrospective analysis of men (>=16 years) undergoing orchidectomy for testicular cancer at our institution over two time periods (1975-85 and 2007-12) were identified using our cancer registry. Histopathology reports were used to record testicular tumour size as the maximum measured dimension. Significance was indicated by P < 0.05. Results: Of 305 orchidectomies performed, 215 had histopathology reports available. Median age was 34 years (16-75 years). Mean tumour size was 7.2 cm in 1975-85 and 4.1 cm in 2007-12 showing a significant reduction (P = 0.02). Significant reduction was seen in all age groups except >60 years. Furthermore there was a significant increase in proportion of men presenting in the youngest age group (16-29 years) in the 2007-12 cohort (43 versus 29%, P = 0.02). Conclusion: The trend in reduction of tumour size at presentation and increased proportion of younger men presenting with testicular cancer supports an increased awareness. Promotion of TSE and public education should remain important initiatives given the increasing incidence of testicular cancer. Awareness still needs addressing in older men. PMID- 26944077 TI - Switching the Cleavage Sites in Palladium on Carbon-Catalyzed Carbon-Carbon Bond Disconnection. AB - We have demonstrated a palladium on carbon-catalyzed approach to regioselectively alter the cleavage sites of the C-C bonds of cinnamaldehyde derivatives by a slight change in the reaction conditions in isopropanol under an O2 atmosphere. Styrene derivatives could be selectively formed by the addition of Na2CO3 in association with the dissociation of carbon monoxide, while benzaldehyde derivatives were generated by the addition of CuCl and morpholine instead of Na2CO3. PMID- 26944078 TI - Oscillation helps to get division right. PMID- 26944079 TI - NbCSPR underlies age-dependent immune responses to bacterial cold shock protein in Nicotiana benthamiana. AB - Plants use receptor kinases (RKs) and receptor-like proteins (RLPs) as pattern recognition receptors (PRRs) to sense pathogen-associated molecular patterns (PAMPs) that are typical of whole classes of microbes. After ligand perception, many leucine-rich repeat (LRR)-containing PRRs interact with the LRR-RK BRI1 ASSOCIATED KINASE 1 (BAK1). BAK1 is thus expected to interact with unknown PRRs. Here, we used BAK1 as molecular bait to identify a previously unknown LRR-RLP required for the recognition of the csp22 peptide derived from bacterial cold shock protein. We established a method to identify proteins that interact with BAK1 only after csp22 treatment. BAK1 was expressed transiently in Nicotiana benthamiana and immunopurified after treatment with csp22. BAK1-associated proteins were identified by mass spectrometry. We identified several proteins including known BAK1 interactors and a previously uncharacterized LRR-RLP that we termed RECEPTOR-LIKE PROTEIN REQUIRED FOR CSP22 RESPONSIVENESS (NbCSPR). This RLP associates with BAK1 upon csp22 treatment, and NbCSPR-silenced plants are impaired in csp22-induced defense responses. NbCSPR confers resistance to bacteria in an age-dependent and flagellin-induced manner. As such, it limits bacterial growth and Agrobacterium-mediated transformation of flowering N. benthamiana plants. Transgenic expression of NbCSPR into Arabidopsis thaliana conferred responsiveness to csp22 and antibacterial resistance. Our method may be used to identify LRR-type RKs and RLPs required for PAMP perception/responsiveness, even when the active purified PAMP has not been defined. PMID- 26944080 TI - Layered hydrogels accelerate iPSC-derived neuronal maturation and reveal migration defects caused by MeCP2 dysfunction. AB - Probing a wide range of cellular phenotypes in neurodevelopmental disorders using patient-derived neural progenitor cells (NPCs) can be facilitated by 3D assays, as 2D systems cannot entirely recapitulate the arrangement of cells in the brain. Here, we developed a previously unidentified 3D migration and differentiation assay in layered hydrogels to examine how these processes are affected in neurodevelopmental disorders, such as Rett syndrome. Our soft 3D system mimics the brain environment and accelerates maturation of neurons from human induced pluripotent stem cell (iPSC)-derived NPCs, yielding electrophysiologically active neurons within just 3 wk. Using this platform, we revealed a genotype-specific effect of methyl-CpG-binding protein-2 (MeCP2) dysfunction on iPSC-derived neuronal migration and maturation (reduced neurite outgrowth and fewer synapses) in 3D layered hydrogels. Thus, this 3D system expands the range of neural phenotypes that can be studied in vitro to include those influenced by physical and mechanical stimuli or requiring specific arrangements of multiple cell types. PMID- 26944081 TI - Satellite retrieval of cloud condensation nuclei concentrations by using clouds as CCN chambers. AB - Quantifying the aerosol/cloud-mediated radiative effect at a global scale requires simultaneous satellite retrievals of cloud condensation nuclei (CCN) concentrations and cloud base updraft velocities (Wb). Hitherto, the inability to do so has been a major cause of high uncertainty regarding anthropogenic aerosol/cloud-mediated radiative forcing. This can be addressed by the emerging capability of estimating CCN and Wb of boundary layer convective clouds from an operational polar orbiting weather satellite. Our methodology uses such clouds as an effective analog for CCN chambers. The cloud base supersaturation (S) is determined by Wb and the satellite-retrieved cloud base drop concentrations (Ndb), which is the same as CCN(S). Validation against ground-based CCN instruments at Oklahoma, at Manaus, and onboard a ship in the northeast Pacific showed a retrieval accuracy of +/-25% to +/-30% for individual satellite overpasses. The methodology is presently limited to boundary layer not raining convective clouds of at least 1 km depth that are not obscured by upper layer clouds, including semitransparent cirrus. The limitation for small solar backscattering angles of <25 degrees restricts the satellite coverage to ~25% of the world area in a single day. PMID- 26944082 TI - SDTNBI: an integrated network and chemoinformatics tool for systematic prediction of drug-target interactions and drug repositioning. AB - Computational prediction of drug-target interactions (DTIs) and drug repositioning provides a low-cost and high-efficiency approach for drug discovery and development. The traditional social network-derived methods based on the naive DTI topology information cannot predict potential targets for new chemical entities or failed drugs in clinical trials. There are currently millions of commercially available molecules with biologically relevant representations in chemical databases. It is urgent to develop novel computational approaches to predict targets for new chemical entities and failed drugs on a large scale. In this study, we developed a useful tool, namely substructure-drug-target network based inference (SDTNBI), to prioritize potential targets for old drugs, failed drugs and new chemical entities. SDTNBI incorporates network and chemoinformatics to bridge the gap between new chemical entities and known DTI network. High performance was yielded in 10-fold and leave-one-out cross validations using four benchmark data sets, covering G protein-coupled receptors, kinases, ion channels and nuclear receptors. Furthermore, the highest areas under the receiver operating characteristic curve were 0.797 and 0.863 for two external validation sets, respectively. Finally, we identified thousands of new potential DTIs via implementing SDTNBI on a global network. As a proof-of-principle, we showcased the use of SDTNBI to identify novel anticancer indications for nonsteroidal anti inflammatory drugs by inhibiting AKR1C3, CA9 or CA12. In summary, SDTNBI is a powerful network-based approach that predicts potential targets for new chemical entities on a large scale and will provide a new tool for DTI prediction and drug repositioning. The program and predicted DTIs are available on request. PMID- 26944084 TI - iFORM/eQTL: an ultrahigh-dimensional platform for inferring the global genetic architecture of gene transcripts. AB - Knowledge about how changes in gene expression are encoded by expression quantitative trait loci (eQTLs) is a key to construct the genotype-phenotype map for complex traits or diseases. Traditional eQTL mapping is to associate one transcript with a single marker at a time, thereby limiting our inference about a complete picture of the genetic architecture of gene expression. Here, we implemented an ultrahigh-dimensional variable selection model to build a computing platform that can systematically scan main effects and interaction effects among all possible loci and identify a set of significant eQTLs modulating differentiation and function of gene expression. This platform, named iFORM/eQTL, was assembled by forward-selection-based procedures to tackle complex covariance structures of gene-gene interactions. iFORM/eQTL can particularly discern the role of cis-QTLs, trans-QTLs and their epistatic interactions in gene expression. Results from the reanalysis of a published genetic and genomic data set through iFORM/eQTL gain new discoveries on the genetic origin of gene expression differentiation in Caenorhabditis elegans, which could not be detected by a traditional one-locus/one-transcript analysis approach. PMID- 26944083 TI - Comparative evaluation of isoform-level gene expression estimation algorithms for RNA-seq and exon-array platforms. AB - Given that the majority of multi-exon genes generate diverse functional products, it is important to evaluate expression at the isoform level. Previous studies have demonstrated strong gene-level correlations between RNA sequencing (RNA-seq) and microarray platforms, but have not studied their concordance at the isoform level. We performed transcript abundance estimation on raw RNA-seq and exon-array expression profiles available for common glioblastoma multiforme samples from The Cancer Genome Atlas using different analysis pipelines, and compared both the isoform- and gene-level expression estimates between programs and platforms. The results showed better concordance between RNA-seq/exon-array and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) platforms for fold change estimates than for raw abundance estimates, suggesting that fold change normalization against a control is an important step for integrating expression data across platforms. Based on RT-qPCR validations, eXpress and Multi-Mapping Bayesian Gene eXpression (MMBGX) programs achieved the best performance for RNA seq and exon-array platforms, respectively, for deriving the isoform-level fold change values. While eXpress achieved the highest correlation with the RT-qPCR and exon-array (MMBGX) results overall, RSEM was more highly correlated with MMBGX for the subset of transcripts that are highly variable across the samples. eXpress appears to be most successful in discriminating lowly expressed transcripts, but IsoformEx and RSEM correlate more strongly with MMBGX for highly expressed transcripts. The results also reinforce how potentially important isoform-level expression changes can be masked by gene-level estimates, and demonstrate that exon arrays yield comparable results to RNA-seq for evaluating isoform-level expression changes. PMID- 26944085 TI - A comprehensive overview of lncRNA annotation resources. AB - Long noncoding RNAs (lncRNAs) are emerging as a class of important regulators participating in various biological functions and disease processes. With the widespread application of next-generation sequencing technologies, large numbers of lncRNAs have been identified, producing plenty of lncRNA annotation resources in different contexts. However, at present, we lack a comprehensive overview of these lncRNA annotation resources. In this study, we reviewed 24 currently available lncRNA annotation resources referring to > 205 000 lncRNAs in over 50 tissues and cell lines. We characterized these annotation resources from different aspects, including exon structure, expression, histone modification and function. We found many distinct properties among these annotation resources. Especially, these resources showed diverse chromatin signatures, remarkable tissue and cell type dependence and functional specificity. Our results suggested the incompleteness and complementarity of current lncRNA annotations and the necessity of integration of multiple resources to comprehensively characterize lncRNAs. Finally, we developed 'LNCat' (lncRNA atlas, freely available at http://biocc.hrbmu.edu.cn/LNCat/), a user-friendly database that provides a genome browser of lncRNA structures, visualization of different resources from multiple angles and download of different combinations of lncRNA annotations, and supports rapid exploration, comparison and integration of lncRNA annotation resources. Overall, our study provides a comprehensive comparison of numerous lncRNA annotations, and can facilitate understanding of lncRNAs in human disease. PMID- 26944086 TI - Phosphatidylcholine kinetics in neonatal rat lungs and the effects of rhuKGF and betamethasone. AB - Surfactant, synthesized by type II pneumocytes (PN-II), mainly comprises phosphatidylcholine (PC) and is essential to prevent neonatal respiratory distress. Furthermore, PC is essential to lung tissue growth and maintenance as a membrane component. Recent findings suggest that the lung contributes to systemic lipid homeostasis via PC export through ABC-A1 transporter expression. Hence it is important to consider pharmacological interventions in neonatal lung PC metabolism with respect to such export. Five-day-old rats were treated with carrier (control), intraperitoneal betamethasone, subcutaneous recombinant human keratinocyte growth factor (rhuKGF), or their combination for 48 h. Animals were intraperitoneally injected with 50 mg/kg [D9-methyl]choline chloride 1.5, 3.0, and 6.0 h before death at day 7, and lung lavage fluid (LLF) and tissue were harvested. Endogenous PC, D9-labeled PC species, and their water-soluble precursors (D9-)choline and (D9-)phosphocholine were determined by tandem mass spectrometry. Treatment increased secreted and tissue PC pools but did not change equilibrium composition of PC species in LLF. However, all treatments increased specific surfactant components in tissue. In control rats, peak D9-PC in lavaged lung was reached after 3 h and was decreased at 6 h. Only 13% of this net loss in lavaged lung was found in LLF. Such decrease was not present in lungs treated with betamethasone and/or with rhuKGF. D9-PC loss at 3-6 h and PC synthesis calculated from D9 enrichment of phosphocholine indicated that daily synthesis rate is higher than total pool size. We conclude that lung tissue contributes to systemic PC homeostasis in neonatal rats, which is altered by glucocorticoid and rhuKGF treatment. PMID- 26944087 TI - Dissecting the inflammatory twitch in allergically inflamed mice. AB - We have previously advanced the hypothesis that the allergic inflammatory response in the lungs occurs as a self-limited sequence of events that begins with the onset of inflammation and then resolves back to baseline over a predetermined time course (Pothen JJ, Poynter ME, Bates JH. J Immunol 190: 3510 3516, 2013). In the present study we tested a key prediction of this hypothesis, which is that the instigation of the allergic inflammatory response should be accompanied by a later refractory period during which the response cannot be reinitiated. We challenged groups of ovalbumin-sensitized BALB/c mice for 3, 14, 21 and 31 consecutive days with aerosolized ovalbumin. We measured airways responsiveness as well as cell counts and cytokines in bronchoalveolar lavage fluid after the final challenge in subgroups from each group. In other subgroups we performed the same measurements following rest periods and after a final single recall challenge with antigen. We determined that the refractory periods for GM-CSF, KC, and IL-5 are no longer than 10 days, while those for IFNgamma and IL-10 are no longer than 28 days. The refractory periods for total leukocytes and neutrophils were no greater than 28 days, while that for eosinophils was more than 28 days. The refractory period for airways resistance was less than 17, while for lung elastance it was longer than 28 days. Our results thus demonstrate that the components of the allergic inflammatory response in the lung have finite refractory periods, with the refractory period of the entire response being in the order of a month. PMID- 26944088 TI - Flow-cytometric method for simultaneous analysis of mouse lung epithelial, endothelial, and hematopoietic lineage cells. AB - Flow cytometry is a powerful tool capable of simultaneously analyzing multiple parameters on a cell-by-cell basis. Lung tissue preparation for flow cytometry requires creation of a single-cell suspension, which often employs enzymatic and mechanical dissociation techniques. These practices may damage cells and cause cell death that is unrelated to the experimental conditions under study. We tested methods of lung tissue dissociation and sought to minimize cell death in the epithelial, endothelial, and hematopoietic lineage cellular compartments. A protocol that involved flushing the pulmonary circulation and inflating the lung with Dispase, a bacillus-derived neutral metalloprotease, at the time of tissue harvest followed by mincing, digestion in a DNase and collagenase solution, and filtration before staining with fluorescent reagents concurrently maximized viable yields of epithelial, endothelial, and hematopoietic lineage cells compared with a standard method that did not use enzymes at the time of tissue harvest. Flow cytometry identified each population-epithelial (CD326(+)CD31( )CD45(-)), endothelial (CD326(-)CD31(+)CD45(-)), and hematopoietic lineage (CD326(-)CD31(-)CD45(+))-and measured cellular viability by 7-aminoactinomycin D (7-AAD) staining. The Dispase method permitted discrimination of epithelial vs. endothelial cell death in a systemic lipopolysaccharide model of increased pulmonary vascular permeability. We conclude that application of a dissociative enzyme solution directly to the cellular compartments of interest at the time of tissue harvest maximized viable cellular yields of those compartments. Investigators could employ this dissociation method to simultaneously harvest epithelial, endothelial, and hematopoietic lineage and other lineage-negative cells for flow-cytometric analysis. PMID- 26944090 TI - Microparticles as biomarkers of lung disease: enumeration in biological fluids using lipid bilayer microspheres. AB - Extracellular vesicles, specifically microparticles (MPs), are rapidly gaining attention for their capacity to act as biomarkers for diagnosis, prognosis, or responsiveness to therapy in lung disease, in keeping with the concept of precision medicine. However, MP analysis by high-sensitivity flow cytometry (FCM) is complicated by a lack of accurate means for MP enumeration. To address this gap, we report here an enhanced FCM MP gating and enumeration technique based on the use of novel engineered lipid bilayer microspheres (LBMs). By comparison of LBM-based MP enumeration with conventional bead- or fluorescent-based FCM enumeration techniques and a gravimetric consumption gold standard, we found LBMs to be superior to commercial bead preparations, showing the smallest fixed bias and limits of agreement in Bland Altman analyses. LBMs had simultaneous capacity to aid FCM enumeration of MPs in plasma, BAL, and cell culture supernatants. LBM enumeration detected differences in MP counts in mice exposed to intraperitoneal lipopolysaccharide or saline. LBMs provided for 1) higher sensitivity for gating MPs populations, 2) reduced background within MP gates, 3) more appropriate size, and 4) an inexpensive alternative amenable to different fluorescent tags. LBM based MP enumeration was useful for a series of different FCM systems assessed, whereas LBM gating benefited high- but not low-sensitivity FCM systems compared with fluorescence gating. By offering exclusive advantages over current means of gating and enumerating MPs, LBMs are uniquely suited to realizing the potential of MPs as biomarkers in biological lung fluids and facilitating precision medicine in lung disease. PMID- 26944091 TI - The provision of ecosystem services in response to global change: Evidences and applications. AB - As a consequence of the global increase in economic and societal prosperity, ecosystems and natural resources have been substantially exploited, degraded, or even destroyed in the last century. To prevent further deprivation of the quality of ecosystems, the ecosystem services concept has become a central issue in environmental studies. A growing number of environmental agencies and organizations worldwide are now embracing integrated approaches to plan and manage ecosystems, sharing a goal to maintain the long-term provision of ecosystem services for sustainability. A daunting challenge in this process is to move from general pronouncements about the tremendous benefits that ecosystems provide to society to defensible assessments of their services. In other words, we must move beyond the scientific evidences of the ecosystem services concept to its practical applications. In this work, we discuss the theoretical foundations and applications of ecosystem services with a focus on the assessment of ecosystem service trade-offs and synergies at various spatial and temporal scales. Here, we offer examples of the main factors related to land use management that may affect the provision of ecosystem services and provide direction for future research on ecosystem services and related nature-based solutions. We also provide a briefing on the major topics covered in this Special Issue, which focuses on the provision of ecosystem services in the context of global change. PMID- 26944092 TI - Resolution of the Band Gap Prediction Problem for Materials Design. AB - An important property with any new material is the band gap. Standard density functional theory methods grossly underestimate band gaps. This is known as the band gap problem. Here, we show that the hybrid B3PW91 density functional returns band gaps with a mean absolute deviation (MAD) from experiment of 0.22 eV over 64 insulators with gaps spanning a factor of 500 from 0.014 to 7 eV. The MAD is 0.28 eV over 70 compounds with gaps up to 14.2 eV, with a mean error of -0.03 eV. To benchmark the quality of the hybrid method, we compared the hybrid method to the rigorous GW many-body perturbation theory method. Surprisingly, the MAD for B3PW91 is about 1.5 times smaller than the MAD for GW. Furthermore, B3PW91 is 3-4 orders of magnitude faster computationally. Hence, B3PW91 is a practical tool for predicting band gaps of materials before they are synthesized and represents a solution to the band gap prediction problem. PMID- 26944089 TI - alpha-Smooth muscle actin is an inconsistent marker of fibroblasts responsible for force-dependent TGFbeta activation or collagen production across multiple models of organ fibrosis. AB - Fibrosis is a common pathological sequela of tissue injury or inflammation, and is a major cause of organ failure. Subsets of fibroblasts contribute to tissue fibrosis in multiple ways, including generating contractile force to activate integrin-bound, latent TGFbeta and secreting excess amounts of collagens and other extracellular matrix proteins (ECM) that make up pathologic scar. However, the precise fibroblast subsets that drive fibrosis have been poorly understood. In the absence of well-characterized markers, alpha-smooth muscle actin (alphaSMA) is often used to identify pathologic fibroblasts, and some authors have equated alphaSMA(+) cells with contractile myofibroblasts and proposed that these cells are the major source of ECM. Here, we investigated how well alphaSMA expression describes fibroblast subsets responsible for TGFbeta activation and collagen production in three commonly used models of organ fibrosis that we previously reported could be inhibited by loss of alphav integrins on all fibroblasts (using PDGFRbeta-Cre). Interestingly, alphaSMA-directed deletion of alphav integrins protected mice from CCl4-induced hepatic fibrosis, but not bleomycin-induced pulmonary or unilateral ureteral obstruction-induced renal fibrosis. Using Col-EGFP/alphaSMA-RFP dual reporter mice, we found that only a minority of collagen-producing cells coexpress alphaSMA in the fibrotic lung and kidney. Notably, Col-EGFP(+)alphaSMA-RFP(-) cells isolated from the fibrotic lung and kidney were equally capable of activating TGFbeta as were Col-EGFP(+)alphaSMA RFP(+) cells from the same organ, and this TGFbeta activation was blocked by a TGFbeta-blocking antibody and an inhibitor of nonmuscle myosin, respectively. Taken together, our results suggest that alphaSMA is an inconsistent marker of contractile and collagen-producing fibroblasts in murine experimental models of organ fibrosis. PMID- 26944093 TI - Protein tyrosine kinase 7 is essential for tubular morphogenesis of the Wolffian duct. AB - The Wolffian duct, the proximal end of the mesonephric duct, undergoes non branching morphogenesis to achieve an optimal length and size for sperm maturation. It is important to examine the mechanisms by which the developing mouse Wolffian duct elongates and coils for without proper morphogenesis, male infertility will result. Here we show that highly proliferative epithelial cells divide in a random orientation relative to the elongation axis in the developing Wolffian duct. Convergent extension (CE)-like of cell rearrangements is required for elongating the duct while maintaining a relatively unchanged duct diameter. The Wolffian duct epithelium is planar polarized, which is characterized by oriented cell elongation, oriented cell rearrangements, and polarized activity of regulatory light chain of myosin II. Conditional deletion of protein tyrosine kinase 7 (PTK7), a regulator of planar cell polarity (PCP), from mesoderm results in loss of the PCP characteristics in the Wolffian duct epithelium. Although loss of Ptk7 does not alter cell proliferation or division orientation, it affects CE and leads to the duct with significantly shortened length, increased diameter, and reduced coiling, which eventually results in loss of sperm motility, a key component of sperm maturation. In vitro experiments utilizing inhibitors of myosin II results in reduced elongation and coiling, similar to the phenotype of Ptk7 knockout. This data suggest that PTK7 signaling through myosin II regulates PCP, which in turn ensures CE-like of cell rearrangements to drive elongation and coiling of the Wolffian duct. Therefore, PTK7 is essential for Wolffian duct morphogenesis and male fertility. PMID- 26944094 TI - ROCK inhibition abolishes the establishment of the aquiferous system in Ephydatia muelleri (Porifera, Demospongiae). AB - The Rho associated coiled-coil protein kinase (ROCK) plays crucial roles in development across bilaterian animals. The fact that the Rho/Rock pathway is required to initiate epithelial morphogenesis and thus to establish body plans in bilaterians makes this conserved signaling pathway key for studying the molecular mechanisms that may control early development of basally branching metazoans. The purpose of this study was to evaluate whether or not the main components of this signaling pathway exist in sponges, and if present, to investigate the possible role of the regulatory network in an early branching non-bilaterian species by evaluating ROCK function during Ephydatia muelleri development. Molecular phylogenetic analyses and protein domain predictions revealed the existence of Rho/Rock components in all studied poriferan lineages. Binding assays revealed that both Y-27632 and GSK429286A are capable of inhibiting Em-ROCK activity in vitro. Treatment with both drugs leads to impairment of growth and formation of the basal pinacoderm layer in the developing sponge. Furthermore, inhibition of Em-Rock prevents the establishment of a functional aquiferous system, including the absence of an osculum. In contrast, no effect of ROCK inhibition was observed in juvenile sponges that already possess a fully developed and functional aquiferous system. Thus, the Rho/Rock pathway appears to be essential for the proper development of the freshwater sponge, and may play a role in various cell behaviors (e.g. cell proliferation, cell adhesion and cell motility). Taken together, these data are consistent with an ancestral function of Rho/Rock signaling in playing roles in early developmental processes and may provide a new framework to study the interaction between Wnt signaling and the Rho/Rock pathway. PMID- 26944095 TI - Physiological adjustments to hypohydration: Impact on thermoregulation. AB - Sufficient body water is required to sustain thermoregulatory function, thus losses in total body water (TBW) can challenge the thermoregulatory system. A TBW deficit >=2% body mass (hypohydration) is recognized as the threshold when thermoregulatory function becomes measurably altered. Hypohydration may occur from voluntary fluid restriction, insufficient fluid availability, or thermoregulatory sweating. The secretion and evaporation of sweat important avenues of body heat loss, and if the water lost is not replaced, hypohydration will decrease plasma volume and increase plasma osmotic pressure (hyperosmotic hypovolemia). Both osmotic and/or volume stressors delay the onset and/or reduce the sensitivity of sweating and blood flow responses. The magnitude of hypohydration, environmental heat stress, the population and circumstances of interest will determine the degree, significance and outcome of these thermoregulatory alterations and their contribution to physiological stress. PMID- 26944097 TI - Adenosine as a Multi-Signalling Guardian Angel in Human Diseases: When, Where and How Does it Exert its Protective Effects? AB - The importance of adenosine for human health cannot be overstated. Indeed, this ubiquitous nucleoside is an integral component of ATP, and regulates the function of every tissue and organ in the body. Acting via receptor-dependent and independent mechanisms [the former mediated via four G-protein-coupled receptors (GPCRs), A1, A2A, A2B, and A3,], it has a significant role in protecting against cell damage in areas of increased tissue metabolism, and combating organ dysfunction in numerous pathological states. Accordingly, raised levels of adenosine have been demonstrated in epilepsy, ischaemia, pain, inflammation, and cancer, in which its behaviour can be likened to that of a guardian angel, even though there are instances in which overproduction of adenosine is pathological. In this review, we condense the current body of knowledge on the issue, highlighting when, where, and how adenosine exerts its protective effects in both the brain and the periphery. PMID- 26944099 TI - PK/PD analysis of a novel pH-dependent antigen-binding antibody using a dynamic antibody-antigen binding model. AB - Previously, we have reported novel engineered antibody with pH-dependent antigen binding (recycling antibody), and with both pH-dependent antigen-binding and increased FcRn-binding at neutral pH (sweeping antibody). The purpose of this study is to perform PK/PD predictions to better understand the potential applications of the antibodies as therapeutics. To demonstrate the applicability of recycling and sweeping antibodies over conventional antibodies, PK/PD analyses were performed. PK/PD parameters for antibody and antigen dynamics were estimated from the results of a pharmacokinetic study in human FcRn transgenic mice. A simulation study was performed using the estimated PK/PD parameters with various target antigen profiles. In comparison to conventional antibody, recycling antibody enhanced antibody-antigen complex clearance by 3 folds, while sweeping antibody accelerated antigen clearance by 10 folds in a pharmacokinetic study. Simulation results showed that recycling and sweeping antibodies can improve dosage frequency and reduce the required dose for target antigens with various clearances, plasma concentrations or binding kinetics. Moreover, importance of the association rate constant to enhance the beneficial effect of antibodies was shown. These results support the conclusion that recycling and sweeping antibodies can be applied to various target antigens with different profiles, and expand the number of antigens that antibodies can target. PMID- 26944098 TI - Rapid annotation of interictal epileptiform discharges via template matching under Dynamic Time Warping. AB - BACKGROUND: EEG interpretation relies on experts who are in short supply. There is a great need for automated pattern recognition systems to assist with interpretation. However, attempts to develop such systems have been limited by insufficient expert-annotated data. To address these issues, we developed a system named NeuroBrowser for EEG review and rapid waveform annotation. NEW METHODS: At the core of NeuroBrowser lies on ultrafast template matching under Dynamic Time Warping, which substantially accelerates the task of annotation. RESULTS: Our results demonstrate that NeuroBrowser can reduce the time required for annotation of interictal epileptiform discharges by EEG experts by 20-90%, with an average of approximately 70%. COMPARISON WITH EXISTING METHOD(S): In comparison with conventional manual EEG annotation, NeuroBrowser is able to save EEG experts approximately 70% on average of the time spent in annotating interictal epileptiform discharges. We have already extracted 19,000+ interictal epileptiform discharges from 100 patient EEG recordings. To our knowledge this represents the largest annotated database of interictal epileptiform discharges in existence. CONCLUSION: NeuroBrowser is an integrated system for rapid waveform annotation. While the algorithm is currently tailored to annotation of interictal epileptiform discharges in scalp EEG recordings, the concepts can be easily generalized to other waveforms and signal types. PMID- 26944100 TI - Detection of CYP2D6 polymorphism using Luminex xTAG technology in autism spectrum disorder: CYP2D6 activity score and its association with risperidone levels. AB - CYP2D6 is involved in the biotransformation of a large number of drugs, including risperidone. This study was designed to detect CYP2D6 polymorphisms with a Luminex assay, including assessment the relationship of CYP2D6 polymorphisms and risperidone plasma concentration in autism spectrum disorder children (ASD) treated with risperidone. All 84 ASD patients included in this study had been receiving risperidone at least for 1 month. The CYP2D6 genotypes were determined by Luminex assay. Plasma concentrations of risperidone and 9-hydroxyrisperidone were measured using LC/MS/MS. Among the 84 patients, there were 46 (55.42%) classified as EM, 33 (39.76%) as IM, and 4(4.82%) as UM. The plasma concentration of risperidone and risperidone/9-hydroxyrisperidone ratio in the patients were significant differences among the CYP2D6 predicted phenotype group (P = 0.001 and P < 0.0001 respectively). Moreover, the plasma concentration of risperidone and risperidone/9-hydroxyrisperidone ratio in the patients with CYP2D6 activity score 0.5 were significantly higher than those with the CYP2D6 activity score 2.0 (P = 0.004 and P = 0.002 respectively). These findings suggested that the determination of the accurate CYP2D6 genotype-predicted phenotype is essential in the clinical setting and individualization of drug therapy. The use of the Luminex assay for detection of CYP2D6 polymorphisms could help us more accurately identify an individual's CYP2D6 phenotype. PMID- 26944096 TI - Getting into the brain: Potential of nanotechnology in the management of NeuroAIDS. AB - In spite of significant advances in antiretroviral (ARV) therapy, the elimination of human immunodeficiency virus (HIV) reservoirs from the periphery and the central nervous system (CNS) remains a formidable task. The incapability of ARV to go across the blood-brain barrier (BBB) after systemic administration makes the brain one of the dominant HIV reservoirs. Thus, screening, monitoring, and elimination of HIV reservoirs from the brain remain a clinically daunting and key task. The practice and investigation of nanomedicine possesses potentials for therapeutics against neuroAIDS. This review highlights the advancements in nanoscience and nanotechnology to design and develop specific size therapeutic cargo for efficient navigation across BBB so as to recognize and eradicate HIV brain reservoirs. Different navigation and drug release strategies, their biocompatibility and efficacy with related challenges and future prospects are also discussed. This review would be an excellent platform to understand nano enable multidisciplinary research to formulate efficient nanomedicine for the management of neuroAIDS. PMID- 26944103 TI - Preface. PMID- 26944102 TI - Calcium and Vitamin D in Obesity and Related Chronic Disease. AB - There is a pandemic of lifestyle-related diseases. In both developed and lesser developed countries of the world, an inadequacy of calcium intake and low vitamin D status is common. In this chapter, we explore a mechanistic framework that links calcium and vitamin D status to chronic conditions including obesity, systemic inflammation, endothelial dysfunction, dyslipidemia and cardiovascular disease, and type 2 diabetes mellitus. We also update the available clinical evidence, mainly from randomized controlled trials, to provide a synthesis of evidence in favor or against these hypotheses. There is consistent data to support calcium increasing whole body fat oxidation and increasing fecal fat excretion, while there is good cellular evidence for vitamin D reducing inflammation. Clinical trials support a marginal reduction in circulating lipids and some meta-analysis support an increase in insulin sensitivity following vitamin D. However, these mechanistic pathways and intermediate biomarkers of disease do not consistently transcribe into measurable health outcomes. Cementing the benefits of calcium and vitamin D for extraskeletal health needs a reexamination of the target 25(OH)D level to be achieved and the minimum duration of future trials. PMID- 26944101 TI - Oats-From Farm to Fork. AB - Oats have a long history of use as human food and animal feed. From its origins in the Fertile Crescent, the oat has adapted to a wide range of climatic conditions and geographic regions. Its unique macro-, micro-, and phytonutrient composition, high nutritional value, and relatively low agricultural input requirements makes oats unique among cereal crops. The health benefits of the oats are becoming well established. While the connection between oat beta-glucan fiber in reducing the risk of cardiovascular disease and controlling glycemia have been unequivocally established, other potential benefits including modulation of intestinal microbiota and inflammation continue to be explored. Advances in food technology are continuing to expand the diversity of oat-based foods, creating opportunities to deliver the health benefits of oats to a larger segment of the population. PMID- 26944104 TI - False memories: Healthcare Professionals' claims of having seen a patient returning to normal activity after CPR. PMID- 26944105 TI - Biomarkers in sepsis. PMID- 26944106 TI - Percutaneous tracheostomy in post-cervical spine fixation patients: challenging the dogma. PMID- 26944107 TI - Bedside sonographic measurement of optic nerve sheath diameter as a predictor of intracranial pressure in ED. AB - BACKGROUND: Ocular ultrasonography of optic nerve sheath diameter (ONSD) to determine intracranial pressure (ICP) has become favorable in recent years. OBJECTIVE: To demonstrate the efficacy of ONSD measurement in determining the ICP increase due to nontraumatic events in the emergency department. METHODS: A total of 100 patients with suspected nontraumatic intracranial event were enrolled in this prospective study. Patients were divided equally into 2 groups including 50 patients as group I with pathology on cranial computed tomography (CT) and group II with normal cranial CT. Prior to CT scans, patients underwent ONSD measurement by a radiologist using 11- and 14-MHz transducers. RESULTS: The ONSD values of groups I and II were 5.4+/-1.1and 4.1+/-0.5mm, respectively. Optic nerve sheath diameter was found to be larger on the side of lesion in patients with a lesion (P<.05). The cutoff value of the difference between ONSD values of both eyes in the presence of pathology was determined as 0.45 (sensitivity, 80%; specificity, 60%; the area under the curve, 0.794; 95% confidence interval, 0.705-0.883). The between-ONSD and midline shift size was statistically significant (r=0.366, P=.009). The cutoff value of ONSD for the detection of midline shift was determined as 5.3mm (sensitivity, 70%; specificity, 74%; the area under the curve, 0.728; 95% confidence interval, 0.585-0.871). CONCLUSION: Optic nerve sheath diameter measurement via bedside ocular ultrasonography in patients with suspected intracranial event in the emergency department is a useful method to determine ICP increase and its severity. PMID- 26944108 TI - Municipal wastewater affects adipose deposition in male mice and increases 3T3-L1 cell differentiation. AB - Trace concentration of EDs (endocrine disrupting compounds) in water bodies caused by wastewater treatment plant effluents is a recognized problem for the health of aquatic organisms and their potential to affect human health. In this paper we show that continuous exposure of male mice from early development to the adult life (140 days) to unrestricted drinking of wastewater collected from a municipal sewage treatment plant, is associated with an increased adipose deposition and weight gain during adulthood because of altered body homeostasis. In parallel, bisphenol A (BPA) at the administration dose of 5 MUg/kg/body weight, shows an increasing effect on total body weight and fat mass. In vitro, a solid phase extract (SPE) of the wastewater (eTW), caused stimulation of 3T3-L1 adipocyte differentiation at dilutions of 0.4 and 1 % in the final culture medium which contained a concentration of BPA of 40 nM and 90 nM respectively. Pure BPA also promoted adipocytes differentiation at the concentration of 50 and 80 MUM. BPA effect in 3T3-L1 cells was associated to the specific activation of the estrogen receptor alpha (ERalpha) in undifferentiated cells and the estrogen receptor beta (ERbeta) in differentiated cells. BPA also activated the Peroxisome Proliferator Activated Receptor gamma (PPARgamma) upregulating a minimal 3XPPARE luciferase reporter and the PPARgamma-target promoter of the aP2 gene in adipose cells, while it was not effective in preadipocytes. The pure estrogen receptor agonist diethylstilbestrol (DES) played an opposite action to that of BPA inhibiting PPARgamma activity in adipocytes, preventing cell differentiation, activating ERalpha in preadipocytes and inhibiting ERalpha and ERbeta regulation in adipocytes. The results of this work show that the drinking of chemically contaminated wastewater promotes fat deposition in male mice and that EDs present in sewage are likely responsible for this effect through a nuclear receptor mediated mechanism. PMID- 26944109 TI - Longitudinal relationship between chronic kidney disease and distribution of cerebral microbleeds in patients with ischemic stroke. AB - BACKGROUND: Chronic kidney disease (CKD) has been reported to be independently associated with cerebral microbleeds (CMB). Since both glomerular afferent arterioles and cerebral perforating arteries are strain vessels, CKD and CMB may share similar dynamic changes. OBJECTIVE: To clarify whether CKD and CKD progression are related to the distribution and evolution of CMB in patients with ischemic stroke. METHODS: We retrospectively examined the data from the CASISP study. 500 patients with ischemic stroke were analyzed. The number and distribution of CMB were assessed using Microbleed Anatomical Rating Scale. Renal function was evaluated by the estimated glomerular filtration rate (eGFR) and proteinuria. RESULTS: 51 (10.2%) and 158 (31.6%) had decreased eGFR (<60ml/min/1.73m(2)) and CMB at baseline, respectively; 31 (6.6%) and 84 (16.8%) had CKD and CMB progression. Decreased eGFR at baseline (OR=1.533, 95% CI: 1.111 2.114; p=0.009), proteinuria (OR=1.778, 95% CI: 1.026-3.083; p=0.040), CKD progression (OR=2.004, 95% CI: 1.191-3.370; p=0.009) and history of hypertension (OR=2.084, 95% CI: 1.241-3.49; p=0.005) were independently associated with the presence of deep or infratentorial CMB at follow-up. CMB progression in deep or infratentorial area was more frequent in patients with CKD progression than those without (29.0% versus 13.1%, p=0.028). Logistic regression analyses showed that CKD progression (OR=2.577, 95% CI: 1.393-4.769; p=0.003) was independently associated with the progression of deep or infratentorial CMB. CONCLUSION: CKD and CKD progression are independently associated with presence and evolution of deep or infratentorial CMB, but not lobar CMB. PMID- 26944110 TI - Longitudinal course of mild parkinsonian signs in elderly people: A population based study in Japan. AB - We aimed to clarify the longitudinal course of mild parkinsonian signs (MPS) and their association with dementia and functional disability by conducting a comprehensive epidemiological study, including brain MRI, and assessments of cognition, depression, and sleep, in people aged >=65years living in Ama-cho. We diagnosed MPS and parkinsonism (PS) using a modified Unified Parkinson's Disease Rating Scale. The phase I study was conducted between 2008 and 2010 (n=729) and the phase II between 2011 and 2013 (n=436). By phase II, 8.5% of the phase I participants without PS had developed PS. In addition to older age, a lower Mini Mental State Examination (MMSE) score, and lower body mass index, the MPS rigidity subtype was a significant independent predictor of PS onset. By phase II, 10.1% of the participants without dementia or PS at phase I had developed dementia. Older age, lower MMSE score, and the axial dysfunction and tremor MPS subtypes were significant independent predictors of dementia development. By phase II, 38.8% of participants with MPS at phase I showed no motor symptoms. Younger age and adequate sleep were significant predictors for this reversion. Periventricular and deep white matter hyperintensity Fazekas scores increased with the evolution of parkinsonian signs. MPS is therefore critically, although sometimes reversibly, associated with PS and dementia development in elderly people. PMID- 26944111 TI - Sensorimotor modulation by botulinum toxin A in post-stroke arm spasticity: Passive hand movement. AB - INTRODUCTION: In post-stroke spasticity, functional imaging may uncover modulation in the central sensorimotor networks associated with botulinum toxin type A (BoNT) therapy. Investigations were performed to localize brain activation changes in stroke patients treated with BoNT for upper limb spasticity using functional magnetic resonance imaging (fMRI). METHODS: Seven ischemic stroke patients (4 females; mean age 58.86) with severe hand paralysis and notable spasticity were studied. Spasticity was scored according to the modified Ashworth scale (MAS). fMRI examination was performed 3 times: before (W0) and 4 (W4) and 11weeks (W11) after BoNT. The whole-brain fMRI data were acquired during paced repetitive passive movements of the plegic hand (flexion/extension at the wrist) alternating with rest. Voxel-by-voxel statistical analysis using the General Linear Model (GLM) implemented in FSL (v6.00)/FEAT yielded group session-wise statistical maps and paired between-session contrasts, thresholded at the corrected cluster-wise significance level of p<0.05. RESULTS: As expected, BoNT transiently lowered MAS scores at W4. Across all the sessions, fMRI activation of the ipsilesional sensorimotor cortex (M1, S1, and SMA) dominated. At W4, additional clusters transiently emerged bilaterally in the cerebellum, in the contralesional sensorimotor cortex, and in the contralesional occipital cortex. Paired contrasts demonstrated significant differences W4>W0 (bilateral cerebellum and contralesional occipital cortex) and W4>W11 (ipsilesional cerebellum and SMA). The remaining paired contrast (W0>W11) showed activation decreases mainly in the ipsilesional sensorimotor cortex (M1, S1, and SMA). CONCLUSIONS: The present study confirms the feasibility of using passive hand movements to map the cerebral sensorimotor networks in patients with post-stroke arm spasticity and demonstrates that BoNT-induced spasticity relief is associated with changes in task-induced central sensorimotor activation, likely mediated by an altered afferent drive from the spasticity-affected muscles. PMID- 26944112 TI - The melanocortin ACTH 1-39 promotes protection of oligodendrocytes by astroglia. AB - Damage to myelin and oligodendroglia (OL) in multiple sclerosis (MS) results from a wide array of mechanisms including excitotoxicity, neuroinflammation and oxidative stress. We previously showed that ACTH 1-39, a melanocortin, protects OL in mixed glial cultures and enriched OL cultures, inhibiting OL death induced by staurosporine, ionotropic glutamate receptors, quinolinic acid or reactive oxygen species (ROS), but not nitric oxide (NO) or kynurenic acid. OL express melanocortin receptor 4 (MC4R), suggesting a direct protective effect of ACTH 1 39 on OL. However, these results do not rule out the possibility that astroglia (AS) or microglia (MG) also play roles in protection. To investigate this possibility, we prepared conditioned medium (CM) from AS and MG treated with ACTH, then assessed the protective effects of the CM on OL. CM from AS treated with ACTH protected OL from glutamate, NMDA, AMPA, quinolinic acid and ROS but not from kainate, staurosporine, NO or kynurenic acid. CM from MG treated with ACTH did not protect from any of these molecules, nor did CM from AS or MG not treated with ACTH. While protection of OL by ACTH from several toxic molecules involves direct effects on OL, ACTH can also stimulate AS to produce mediators that protect against some molecules but not others. Thus the cellular mechanisms underlying the protective effects of ACTH for OL are complex, varying with the toxic molecules. PMID- 26944113 TI - Arachidonate 5-lipoxygenase (ALOX5) gene polymorphism is associated with Alzheimer's disease and body mass index. AB - Dementias of old age, in particular Alzheimer's disease (AD), pose a growing threat to the longevity and quality of life of individuals as well as whole societies world-wide. The risk factors are both genetic and environmental (life style) and there is an overlap with similar factors predisposing to cardiovascular diseases (CVD). Using a case-control genetic approach, we have identified a SNP (rs10507391) in ALOX5 gene, previously associated with an increased risk of stroke, as a novel genetic risk factor for AD. ALOX5 gene encodes a 5'-lipoxygenase (5'-LO) activating protein (FLAP), a crucial component of the arachidonic acid/leukotriene inflammatory cascade. A-allele of rs4769874 polymorphism increases the risk of AD 1.41-fold (p<0.0001), while AA genotype does so 1.79-fold (p<0.0001). In addition, GG genotype of rs4769874 polymorphism is associated with a modest increase in body mass index (BMI). We discuss potential biochemical mechanisms linking the SNP to AD and suggest possible preventive pharmacotherapies some of which are based on commonly available natural products. Finally, we set the newly identified AD risk factors into a broader context of similar CVD risk factors to generate a more comprehensive picture of interacting genetics and life-style habits potentially leading to the deteriorating mental health in the old age. PMID- 26944114 TI - Early administration of tissue-plasminogen activator improves the long-term clinical outcome at 5years after onset. AB - BACKGROUND AND PURPOSE: Data on long-term outcomes after tissue-plasminogen activator (tPA) therapy are limited. We evaluated the rate of favorable outcomes and mortality at 5years after tPA therapy and investigated factors related to long-term clinical outcomes. METHODS: Telephone interviews or interview letters were used to assess the modified Rankin Scale (mRS) scores at 3months, 6months, 1year, 2years, 3years, 4years, and 5years after tPA therapy. Favorable outcome was defined as mRS 0-2. Multivariate logistic regression analysis was conducted to investigate factors associated with favorable outcomes and mortality at 5years after tPA therapy. RESULTS: From 2005 to 2013, 256 (median age, 77 [interquartile range, 68-84] years; 157 [61%] males; median National Institutes of Health Stroke Scale score, 11 [5-18]) patients were enrolled. Kaplan-Meier curve showed that favorable outcomes after 5years after tPA therapy occurred in 45% of the patients and that the mortality rate was 40%. Univariate analysis showed that onset-to treatment time (OTT) was 121 (107-172) minutes in patients with favorable outcomes and 156 (126-171) minutes in patients with unfavorable outcomes (p=0.016). In addition, OTT was 157 (133-172) minutes in the death group and 123 (106-169) minutes in the survival group (p=0.001). Multivariate regression analysis indicated that OTT was an independent factor related to favorable outcomes (odds ratio 0.96, 95% confidence interval 0.93-0.99, p=0.004) and mortality (odds ratio 1.04, 95% confidence interval 1.02-1.06, p=0.001). CONCLUSION: Early tPA administration can improve long-term clinical outcomes. PMID- 26944115 TI - Autoimmune atypical parkinsonism - A group of treatable parkinsonism. AB - BACKGROUND: Immunological causes of atypical parkinsonism/Parkinson plus syndromes are rare. OBJECTIVE: To study the clinical and laboratory features and treatment outcome of autoimmune atypical parkinsonism. METHODS: Retrospective case series. Patients with atypical parkinsonism and positive antibodies were identified retrospectively. Those who received immunotherapy (intravenous methyl prednisolone 1g daily for five days followed by mycophenylate mofetil 2g daily or azathioprine 2-3mg/kg/day) and consented for publication of non-anonymized videos were included. RESULTS: There were ten cases (nine males, age range 49-75years, disease duration 2months to 13years, follow-up 1-7months) of atypical parkinsonism [probable multiple system atrophy (MSA)-2, possible progressive supranuclear palsy (PSP)-1, probable PSP-3]. Eight had new uncharacterized neuronal antibodies, leucine rich glioma associated protein 1 (LGI1) antibody in one, and the other had another uncharacterized neuronal antibody along with LGI1 antibody. Four had abnormal CSF. There was a prompt, dramatic improvement in terms of Unified Parkinson Disease Rating Scale motor scale and or modified Rankin Scale as well as improvement in eye movement, postural instability, cerebellar, autonomic and non-motor symptoms. Two had reappearance of symptoms on discontinuing steroids and improvement on restarting. One died of infection despite good recovery of encephalopathy and parkinsonism. CONCLUSION: Autoimmune atypical parkinsonism is characterized by atypical parkinsonism with neuronal specific antibodies, sometimes associated with abnormal CSF and significant response to immunotherapy. PMID- 26944116 TI - PARK16 polymorphisms, interaction with smoking, and sporadic Parkinson's disease in Japan. AB - Epidemiological evidence on the relationships between PARK16 single nucleotide polymorphisms (SNPs) and Parkinson's disease (PD) is inconsistent. We examined this issue in Japan. Included were 229 cases within six years of PD onset. Controls were 356 patients without neurodegenerative disease. Compared with subjects with the AA genotype of SNP rs823128, those with the AG genotype, but not the GG genotype, had a significantly reduced risk of sporadic PD. Compared with the AA genotype of SNP rs947211, both the AG genotype and the GG genotype were significantly related to an increased risk of sporadic PD. Using subjects with the AA genotype of SNP rs823156 as a reference group, there were significant inverse relationships under the additive and dominant models. No significant relationships were found between SNPs rs16856139 or rs11240572 and sporadic PD. The CAAAC, the TGAGA, and the CAGAC haplotypes were significantly related to sporadic PD. The additive interaction between SNP rs823128 and smoking affecting sporadic PD was significant, although the multiplicative interaction was not significant. The PARK16 SNPs rs823128, rs947211, and rs823156 and the CAAAC, TGAGA, and CAGAC haplotypes may be significantly associated with sporadic PD in Japan. New evidence of an additive interaction between SNP rs823156 and smoking is suggested. PMID- 26944117 TI - Elevation of serum CXC chemokine ligand-12 levels predicts poor outcome after aneurysmal subarachnoid hemorrhage. AB - OBJECTIVE: CXC chemokine ligand-12 (CXCL12) is involved in the innate immune system. Elevation of its level in the peripheral blood is associated with severity and outcome of ischemic stroke. This study aimed to investigate its relation to severity and prognosis following aneurysmal subarachnoid hemorrhage (aSAH). METHODS: Serum CXCL12 levels were determined in a total of 182 controls and 182 aSAH patients. Hemorrhagic severity was assessed using the World Federation of Neurological Surgeons (WFNS) scale and modified Fisher grading scale. Unfavorable outcome was defined as Glasgow outcome scale score of 1-3. Prognostic predictors of 6-month mortality and unfavorable outcome were identified using multivariate analysis. RESULTS: The serum CXCL12 levels were significantly higher in patients as compared to controls (14.5+/-6.7ng/mL vs. 1.7+/-0.6ng/mL, P<0.001) and were independently associated with WFNS scores (t=5.927, P<0.001) and modified Fisher scores (t=5.506, P<0.001). Serum CXCL12 levels predicted 6-month mortality and 6-month unfavorable outcome with the area under curves of 0.815 [95% confidence (CI), 0.751-0.868] and 0.809 (95% CI, 0.745 0.864) respectively and were related independently to 6-month mortality (odds ratio, 4.428; 95% CI, 1.977-12.031; P=0.004) and 6-month unfavorable outcome (odds ratio, 3.821; 95% CI, 1.097-9.251; P=0.001). Moreover, the predictive values of CXCL12 levels were in the range of WFNS scores and modified Fisher scores. CONCLUSIONS: Elevation of serum CXCL12 levels is associated highly with hemorrhagic severity and poor outcome after aSAH, suggesting CXCL12 might have the potential to be a prognostic predictive biomarker of aSAH. PMID- 26944118 TI - Orthostatic hypotension and cardiac sympathetic denervation in Parkinson disease patients with REM sleep behavioral disorder. AB - BACKGROUND: Rapid eye movement (REM) sleep behavioral disorder (RBD), orthostatic hypotension (OH), and cardiac sympathetic denervation were commonly observed in PD and are related in both the premotor and motor periods. This study is intended to evaluate if the OH and cardiac sympathetic denervation found in PD are associated with RBD. METHODS: Among 94 non-medicated and mild PD patients, 53 had RBD. Orthostatic vital signs and ambulatory 24-hour blood pressure values were recorded. (123)I-metaiodobenzylguanidine (MIBG) cardiac scintigraphy as obtained in all patients. The association between orthostatic hypotension, supine hypertension, nocturnal hypertension, non-dipping, myocardial MIBG uptake, and RBD was analyzed. RESULTS: RBD was associated with orthostatic hypotension. Patients with RBD had higher systolic blood pressure changes during orthostasis and lower myocardial MIBG uptake than patients without RBD and controls. Patients with OH also had lower mean H/M ratios those in the non-OH group. CONCLUSION: This study showed that RBD was closely associated with OH and cardiac sympathetic denervation in patients with early and mild PD. The result also suggests that impaired cardiac sympathetic innervation could be the mechanism behind OH in PD. This association may be closely correlated with Braak alpha-synuclein pathogenetic sequences, which would account for the clinical spectrum of PD. PMID- 26944119 TI - Lumbar decompression for dorsiflexion palsy. PMID- 26944120 TI - Nurse led telephone assessment of expanded disability status scale assessment in MS patients at high levels of disability. AB - BACKGROUND: In clinical trials drop out bias reduces the validity of results. This is a particular problem in long-term multiple sclerosis (MS) studies, particularly when patients become progressively disabled and have increasing difficulty attending assessment clinics. OBJECTIVE: To assess the validity of nurse led telephone assessment of Expanded Disability Status Scale (TEDSS) in MS patients with EDSS scores >6.0. METHODS: We performed a multi-centre, single blind trial to assess nurse derived TEDSS against physician face-to-face EDSS scores derived from neurological examination (FEDSS) in patients with clinically definite MS and EDSS >6.0. RESULTS: Ninety patients (n=15 primary progressive MS, n=74 secondary progressive MS, n=1 relapsing remitting MS) had a mean baseline FEDSS of 7.5. TEDSS correlated with FEDSS (r=0.76, p<0.0001) and kappa scores for perfect agreement, within 0.5 of an EDSS points, and within 1 EDSS point were 0.25, 0.86, and 1.0 respectively. Intra-class correlation between the scoring systems was 0.88, representing a high level of agreement. CONCLUSION: Nurse-led telephone assessment of EDSS gives good agreement with physician derived face-to face EDSS in MS patients with higher disability scores. This may be a valuable tool to improve clinical follow-up in routine clinical practice and improve patient retention in long-term outcome studies. PMID- 26944121 TI - Multiple sclerosis influences on the augmentation of serum Klotho concentration. AB - We have already shown that the concentration of secreted form of Klotho decreases in the cerebrospinal fluid of patients with relapsing-remitting multiple sclerosis (RRMS). The current study aimed at assessing possible changes in the serum Klotho concentration of MS patients. Participants involved 15 new cases of RRMS patients in the relapse phase, 15 RRMS patients who had been suffering from the disease for more than three years and were under regular treatments (interferon beta-1a) and, finally, 15 non-MS patients who constituted the control group. Beside thorough neurological examinations, demographic and clinical data (e.g. gender, age, duration of disease and expanded disability status scale) were obtained. Serum Klotho concentration was measured using ELISA method. The results showed no statistically meaningful difference between new cases of RRMS (585.56pg/ml+/-153.99) and control group (556.81pg/ml+/-120.36; P=0.859). The serum Klotho level, however, was significantly higher in patients with prolonged disease duration (696.94pg/ml+/-170.52; P=0.037) in comparison with the subjects in the control group. In conclusion, this study showed that serum Klotho concentration tends to be higher in MS patients when compared to control group. This finding might be attributed to treatment of MS patients with immunomodulatory drugs or a compensatory response to enhance CNS regeneration and/or vitamin D biosynthesis. Further studies are required to elucidate the role of Klotho in MS pathophysiology. PMID- 26944122 TI - Association between Helicobacter pylori infection and carotid atherosclerosis in patients with vascular dementia. AB - BACKGROUND AND PURPOSE: Accumulating evidence indicates that various infections contribute to the pathogenesis of atherosclerosis. Helicobacter pylori (Hp) has been implicated as a risk factor of atherosclerosis for stroke and other cardiovascular disease, but limited data exist regarding vascular dementia (VD). This study aimed to investigate the relationship between Hp infection and carotid atherosclerosis in patients with VD. METHODS: A total of 354 patients who were diagnosed with VD were enrolled. Patients were divided into Hp positive VD group (n=208) and Hp negative VD group (n=156) using the (13)C-urea breath test ((13)C UBT). Serum YKL-40, a marker for inflammation, were analyzed by ELISA. Traditional atherosclerotic risk factors including age, gender, body mass index (BMI), total cholesterol (TC), low density lipoprotein cholesterol (LDL), high density lipoprotein cholesterol (HDL), triglycerides (TG), systolic blood pressure (SBP), diastolic blood pressure (DBP) and fasting blood glucose (FBG) were collected or detected. Carotid intima-media thickness (CIMT) was determined by color Doppler ultrasound. RESULTS: CIMT values and serum YKL-40 significantly increased in Hp positive VD group in comparison with Hp negative VD group (p<0.05). In Hp positive VD group, serum YKL-40 was positively correlated with CIMT (r=0.412, p<0.05), and the association was independent of traditional atherosclerotic risk factors (beta=0.381, p<0.001). CONCLUSIONS: CIMT and serum YKL-4 were significantly higher in Hp positive patients than Hp negative patients. Hp-induced inflammation may be a risk factor for atherosclerosis in patients with VD. PMID- 26944123 TI - CSF tap test - Obsolete or appropriate test for predicting shunt responsiveness? A systemic review. AB - OBJECTIVES: There is no accurate test for diagnosing normal pressure hydrocephalus or for screening for patients who will benefit from shunt surgery. Additional tests, such as cerebrospinal fluid tap test (CSF-TT), are often used in practice to provide further predictive value in detecting suitable patients for shunting. We performed a systematic review of the literature to evaluate the CSF-TT's effect on the outcome of main symptoms and on validity parameters in screening patients suitable for shunting. METHODS: In February 2015 we searched electronic databases from their inception to the current date, using the following key words: normal pressure hydrocephalus, idiopathic normotensive hydrocephalus, shunt operation, CSF tap test, predictive value, validity. The search retrieved 8 articles explicitly addressing the topic. RESULTS: There was a very high positive predictive value of CSF-TT: 92% (range from 73% to 100%) but a low negative predictive value: 37% (18%-50%). Also, the CSF-TT has high specificity: 75% (33%-100%) but average sensitivity: 58% (26%-87%). The overall accuracy of the test was 62% (45%-83%). CONCLUSIONS: This systematic review did not provide unambiguous validity of the CSF-TT in the screening of patients for shunting. The validity of the CSF-TT is good for patient inclusion for shunting due to the fact that the positive response to the test is very reliable. Unfortunately, the negative response to the test does not reliably make these patients ineligible for shunting. Further studies are needed to improve and standardize the methodology in order to optimize the detection power of the test. PMID- 26944124 TI - Cognition, mood, and purpose in life in neuromyelitis optica spectrum disorder. PMID- 26944126 TI - Optic neuritis with positive HLA-B27: Characteristic phenotype in the Chinese population. AB - PURPOSE: This study retrospectively reviewed the clinical features of optic neuritis (ON) with positive HLA-B27. METHOD: Clinical data were reviewed for HLA B27-positive ON in the Chinese People's Liberation Army General Hospital from January 2009 through June 2015. The prevalence of HLA-B27 and spondyloarthropathies was analyzed. Clinical features of HLA-B27-positive ON based on serum aquaporin 4-antibody (AQP4-Ab) were compared. RESULTS: A total of 22 ON patients (14 female/8 male, 38 involved eyes) with positive HLA-B27 were collected from 410 ON patients. Recurrent episodes were observed in 14/22 patients, and seven patients presented as bilateral simultaneous ON. A total of 68.4% (22/38) of involved eyes exhibited severe visual impairment (<0.1) at onset. A total of 8/22 patients were seropositive for AQP4-Ab, and clinical features did not differ based on AQP4-Ab status. Bilateral sacroiliitis was revealed in over 50% (7/13) of patients screened using pelvic computed tomography. Three patients were diagnosed with ankylosing spondylitis (AS), and one patient experienced co-occurrence of active AS and bilateral ON. CONCLUSIONS: HLA-B27-positive ON may presented recurrent episodes and severe visual impairment at onset. The co-occurrence of ON and AS, and the frequent presence of bilateral sacroiliitis may indicate an underlying alternation of autoimmune background in this condition. PMID- 26944127 TI - Adenosine A1 receptors mediate the intracisternal injection of orexin-induced antinociceptive action against colonic distension in conscious rats. AB - We have recently demonstrated that orexin acts centrally through the brain orexin 1 receptors to induce an antinociceptive action against colonic distension in conscious rats. Adenosine signaling is capable of inducing an antinociceptive action against somatic pain; however, the association between changes in the adenosinergic system and visceral pain perception has not been investigated. In the present study, we hypothesized that the adenosinergic system may be involved in visceral nociception, and thus, adenosine signaling may mediate orexin-induced visceral antinociception. Visceral sensation was evaluated based on the colonic distension-induced abdominal withdrawal reflex (AWR) in conscious rats. Subcutaneous (0.04-0.2mg/rat) or intracisternal (0.8-4MUg/rat) injection of N(6) cyclopentyladenosine (CPA), an adenosine A1 receptor (A1R) agonist, increased the threshold volume of colonic distension-induced AWR in a dose-dependent manner, thereby suggesting that CPA acts centrally in the brain to induce an antinociceptive action against colonic distension. Pretreatment with theophylline, an adenosine antagonist, or 1,3-dipropyl-8-cyclopentylxanthine, an A1R antagonist, subcutaneously injected potently blocked the centrally injected CPA- or orexin-A-induced antinociceptive action against colonic distension. These results suggest that adenosinergic signaling via A1Rs in the brain induces visceral antinociception and that adenosinergic signaling is involved in the central orexin-induced antinociceptive action against colonic distension. PMID- 26944125 TI - Atorvastatin enhances angiogenesis to reduce subdural hematoma in a rat model. AB - BACKGROUND AND PURPOSE: Statins are active in reducing plasma lipids, suppressing inflammation and promoting angiogenesis. Because angiogenesis is critical for the absorbance of subdural hematoma (SDH), we hypothesize that atorvastatin promotes angiogenesis to enhance hematoma absorption. METHODS: SDH was induced in adult Wistar rats and treated with 3mg/kg, 8mg/kg of atorvastatin, or vehicle saline daily for 7days. The treated rats were examined for the level of CD34+/CD133+ endothelial progenitor cells (EPCs) in the circulation by flow cytometry, hematoma volumes by magnetic resonance imaging (MRI), and changes in cognitive functions. We also examined angiogenesis in the hematoma wall by transmission electronic microscopy and immunohistochemistry for the expression of vascular endothelial growth factor (VEGF), matrix metalloprotease 9 (MMP 9) and angiopoietin. RESULTS: SDH volume was significantly reduced and neurological deficits improved in rats receiving the low dose atorvastatin compared to those receiving either the high dose of atorvastatin or saline. Consistent with these outcome measures, the low dose atorvastatin increased the expression of angiopoient-1 and VEGF and reduced MMP9 expression in the connective tissue of the SDH wall, resulting in an increased vascular density and enhanced vascular maturation. CONCLUSIONS: The low-dose atorvastatin is effective in reducing SDH and improving neurological deficits in a rat model, primarily by promoting angiogenesis and vascular maturation. PMID- 26944128 TI - A novel hemizygous SACS mutation identified by whole exome sequencing and SNP array analysis in a Chinese ARSACS patient. AB - The array of autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) has expanded worldwide after the first description in the Charlevoix-Saguenay region of Quebec. Here, we report a Chinese ARSACS patient presenting progressive peripheral neuropathy (CMTNS2=15) with horizontal gaze nystagmus and mild spastic gait. Genetic studies including whole exome sequencing (WES), Sanger sequencing and single nucleotide polymorphism (SNP) array analysis revealed a novel hemizygous nonsense mutation (c.11803C>T, p.Gln3935X) of SACS and a 1.33Mb deletion involved in SACS on chromosome 13q12.12 in the patient. Our findings highlight the necessity of SACS mutation screening in the gene panel of inherited peripheral neuropathies, and stress the need of testing copy number variation (CNV) in SACS mutation screening. PMID- 26944130 TI - Does education modify motor compensation in Parkinson's disease? AB - BACKGROUND: In Alzheimer's disease, higher educational attainment is associated with fewer cognitive deficits despite similar pathological lesions. In animal models of Parkinson's disease (PD), enhanced levels of cognitive and physical stimulation can reduce motor deficits due to dopaminergic neuronal loss. Therefore, in this study, we tested whether higher educational attainment has a beneficial influence on PD motor symptoms. METHODS: We included data from 182 patients with de novo PD without dementia, who underwent dopamine transporter (DAT) scans for an initial diagnostic work-up. Patients were divided into 2 groups according to their educational attainment; high education (HE-PD; >=12years of education) and low education (LE-PD; <12years of education). RESULTS: The HE-PD group exhibited significantly higher mini-mental state exam scores, fewer motor deficits, and lower DAT binding to the posterior putamen than the LE-PD group, despite a similar duration of PD symptoms. A general linear model revealed that this difference in motor deficits remained statistically significant after controlling for potential confounding factors (p=0.032). CONCLUSION: These results suggest that higher educational attainment can lead to reduced motor deficits in PD despite greater reductions in dopamine levels. PMID- 26944129 TI - Reaction time and rhythm of movement in Huntington's disease. AB - Huntington disease (HD) is characterized by several hyperkinesias though motor slowness is also another cardinal in this disease. In addition, self-paced timing movements are also disturbed in HD, which may also affect several rhythmic voluntary movements such as gait. Motor slowness can be measured with clinical scales such as the Unified Huntington's Disease Rating Scale (UHDRS) and timed tests, but also with the reaction time (RT) paradigm. We evaluated RT as a measure of motor slowness in 30 patients with genetically confirmed Huntington's disease and 24 control subjects. We also evaluated self-paced timing precision (SPTP) by applying a simple software program devised by our group. Clinical assessment was performed according to the UHDRS, including motor section, total functional capacity (TFC) and cognitive section (verbal fluency test, symbol digit, and Stroop test) The mean values obtained for RT and SPTP were statistically different in HD as compared with those from controls (p<0.0005). We observed a statistically significant correlation between RT and TFC scores (rs= 0.57, p<0.005 Spearman's correlation) and also between SPTP values and TFC scores (rs=-0.40, p<0.05 Spearman's correlation). In addition, RT and SPTP significantly correlated with cognitive scores (including digit symbol, verbal fluency and Stroop tests). Simple tests such as RT and SPTP provide an objective evaluation of motor impairment in HD yielding measures that correlate with clinical assessment and functional disability. PMID- 26944131 TI - Relationship between symptom change, relapse activity and disability progression in multiple sclerosis. AB - BACKGROUND: Symptom changes may serve as a risk factor for relapse activity (RA) and disability progression (DP), which could facilitate multiple sclerosis (MS) treatment decisions. OBJECTIVE: To assess the relationship of symptom change with RA and DP. METHODS: We evaluated the relationship of symptom change with subsequent RA and DP using NARCOMS registry data reported over a five-year period. Symptom change was evaluated using both symptom worsening (SW) and average of Performance Scales (APS) scores. Disability progression was defined as a one-point or more increase in Patient-Determined Disease Steps (PDDS) score between two consecutive updates. Repeated measures logistic regression was used to investigate the relationship between symptom change and RA and DP. RESULTS: SW and APS were both significant predictors of subsequent RA and DP. Both SW and APS have a significant interaction with levels of disability (Mildly Impaired versus Highly Impaired) for the prediction of the subsequent RA or DP. For Mildly Impaired MS subjects, both SW and APS were significant predictors of both RA and DP. However, for Highly Impaired MS subjects, SW did not significantly predict future RA and neither SW nor APS predicted disability progression. CONCLUSION: Changes in self-reported overall symptomatology may precede and predict clinical relapse and future disability progression. The predictive power of symptom changes may only be present at lower levels of disability. PMID- 26944132 TI - Increased (18)F-FDG uptake in the trapezius muscle in patients with spinal accessory neuropathy. AB - To investigate (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET) signal changes of denervated muscles in patients with electrophysiologically confirmed neuropathy. METHODS: This is a case series of three cancer patients who were referred to the electromyography laboratory in 2013 due to shoulder discomfort after surgery including neck dissection. Spinal accessory neuropathy was diagnosed based on electrophysiological studies. Patients' medical history, electrophysiological data, and FDG-PET images were reviewed retrospectively. Mean standard uptake values (SUV) of trapezius muscles were measured. RESULTS: The patients (3 men, aged 61-78years) showed spinal accessory neuropathy with different degrees of severity. In all patients, preoperative or postoperative FDG PET showed increased FDG uptake in the ipsilateral trapezius muscle. These results were compatible with previously reported glucose hypermetabolism in denervated skeletal muscles. CONCLUSION: This is the first clinical report of increased FDG uptake by denervated muscles in electrophysiologically confirmed neuropathy. PMID- 26944135 TI - Bilateral simultaneous sudden sensorineural hearing loss. AB - OBJECTIVE: This study adopted an inner ear test battery and MR imaging in patients with bilateral sudden sensorineural hearing loss (SSNHL) to investigate their causes, disease extent, and evaluate hearing outcome. PATIENTS AND METHODS: From 1995 to 2014, 16 patients with bilateral SSNHL received audiometry, caloric test and MR imaging. Vestibular-evoked myogenic potential (VEMP) test was added to the test battery after 2000. RESULTS: Percentages of abnormal mean hearing level (MHL), cervical VEMP test, ocular VEMP test, and caloric test in patients with bilateral SSNHL were 100% (32/32), 100% (12/12), 100% (4/4), and 81% (26/32), respectively, implying that not only the cochlear part but also the vestibular part was severely affected in both ears. Causes of bilateral SSNHL were neoplasm in 5 patients, stroke in 5, meningitis in 1, and unknown in 5. Post treatment MHL did not significantly differ from pre-treatment MHL indicating poor hearing outcome. Seven patients (44%) had passed away within 5years after onset, 2 patients were lost, and 7 patients survived. CONCLUSION: Via MR imaging, causes of bilateral SSNHL were identified for 69% of cases. Both cochlear and vestibular endorgans/afferents were identified to be severely affected bilaterally by the vestibular test battery and resulted in poor hearing outcome. A high mortality rate (44%) indicates that bilateral SSNHL is an ominous sign for a more sinister underlying disease. PMID- 26944134 TI - Serial MRI findings in a case of the Parkinson variant of multiple system atrophy: Clinical usefulness of diffusion-weighted imaging at B1000 in early stages of the disease. PMID- 26944136 TI - Unusual case of cerebral small vessel disease with a heterozygous nonsense mutation in HTRA1. PMID- 26944133 TI - Neurotoxicity to DRG neurons varies between rodent strains treated with cisplatin and bortezomib. AB - Chemotherapy-induced peripheral neuropathy (CIPN) is a major dose limiting side effect that can lead to long-term morbidity. Approximately one-third of patients receiving chemotherapy with taxanes, vinca alkaloids, platinum compounds or proteasome inhibitors develop this toxic side effect. It is not possible to predict who will get CIPN, however, genetic susceptibility may play a role. We explored this hypothesis using an established in vitro dorsal root ganglia neurite outgrowth (DRG-NOG) assay to assess possible genetic influences for cisplatin- and bortezomib-induced neurotoxicity. Almost all previous in vitro studies have used rats or mice. We compared DRG-NOG between four genetically defined, inbred mouse strains (C57BL/6J, DBA/2J, BALB/cJ, and C3H/HeJ) and one rat strain (Sprague Dawley). Our studies found differences in cisplatin and bortezomib-induced neurotoxicity between mouse and rat strains and between the different mouse strains. C57BL/6J and Balb/cJ DRG-NOG was more sensitive to cisplatin than DBA/2J and C3H/HeJ DRG-NOG, and all mouse strains were more sensitive to cisplatin than rat. Bortezomib induced a biphasic dose response in DBA/2J and C3H/H3J mice. C57BL/6J DRG-NOG was most sensitive and Balb/cJ DRG-NOG was least sensitive to bortezomib. Our animal data supports the hypothesis that genetic background may play a role in CIPN and care must be taken when rodent models are used to better understand the contribution of genetics in patient susceptibility to CIPN. PMID- 26944137 TI - Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS): Canadian contribution to the international validation project. AB - BACKGROUND: Given the high prevalence of cognitive dysfunction in people with multiple sclerosis (PWMS) and the lack of availability of specialized neuropsychological services in most MS Clinics, there is a need for a brief cognitive monitoring tool that can be easily administered by MS clinic staff. OBJECTIVE: We aimed to establish the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) as a feasible cognitive monitoring tool and provide Canadian data toward the international validation effort. Secondary considerations were to determine if BICAMS correlates with self-reported cognition and predicted vocational status. METHODS: 57 PWMS were matched to 51 healthy controls (age, sex, education). Participants completed the BICAMS battery which includes the Symbol Digit Modalities Test, and the learning trials from the California Verbal Learning Test-II and the Brief Visuospatial Memory Test Revised. Depression, self-reported cognition, and fatigue were assessed. Participants were re-tested 15.6 (SD 2.0) days later. RESULTS: With impairment defined as "one or more abnormal tests," 57.9% of MS sample was cognitively impaired. Participants were more likely to be impaired on the BVMT-R (43.9%). On the SDMT and CVLT-II, 28.1% and 26.3% of MS participants were impaired. Sensitivity and specificity were highest for the SDMT. The BICAMS was reliable over time (r value range from 0.69 for BVMT-R to 0.87 for SDMT) with the SDMT being most robust. There was no relationship between BICAMS and subjective cognition. The BVMT-R reliably predicted employment. CONCLUSIONS: The BICAMS detected cognitive impairment to a comparable degree to more comprehensive neuropsychological batteries and is a valid measure of cognition in MS. Reliability of components varies, suggesting care be taken when interpreting serial testing results. The BICAMS is a feasible cognitive assessment tool in Canadians and yields comparable results to other cultures. PMID- 26944138 TI - Progressive central nervous system vasculopathy in sarcoidosis: A case report. PMID- 26944139 TI - Low-signal-intensity rim on susceptibility-weighted imaging is not a specific finding to progressive multifocal leukoencephalopathy. AB - BACKGROUND: Low-signal-intensity (LSI) rim along deep layers of the cerebral cortex is reportedly a susceptibility-weighted imaging (SWI) finding in progressive multifocal leukoencephalopathy (PML). We aimed to evaluate whether this finding can be identified in diseases other than PML. METHODS: We retrospectively reviewed brain MR images from 5605 patients who underwent SWI at 3T; 370 patients with various diseases, who showed cortical and subcortical FLAIR high-signal lesions including U-fiber, were enrolled. The presence or absence of LSI rim on thin-slice SWI and hyperintense cortical signal (HCS) on T1-weighted images adjacent to LSI rim was analyzed. Signal changes of the LSI rim were assessed on serial SWI, if available. RESULTS: Twenty-five of the 370 patients (6.8%) showed SWI LSI rim, in infarct (n=22) and encephalitis (n=3). HCS was apparent adjacent to SWI LSI rim in 17 patients (15 infarct, 2 encephalitis). Serial SWI was available for 17 patients, of whom 10 patients (8 infarct, 2 encephalitis) presented LSI rim later than 45days after onset. CONCLUSION: LSI rim can be observed in infarct and encephalitis. Therefore, this finding is not specific to PML. LSI rim appears to be associated with HCS. PMID- 26944140 TI - Cerebral gas embolism associated with central venous catheter: Systematic review. AB - OBJECTIVE: Cerebral gas embolism (CGE) is a potentially catastrophic complication of central venous catheters (CVCs) manipulation or accidental disconnection, which is rarely reported in the literature. This systematic review aims to characterize the clinical manifestations, imaging features and outcome of CGE associated with CVCs. METHODS: Systematic literature search of all published cases of CGE associated with CVCs, and identification of previously unreported local cases. Descriptive analysis of all cases, mortality analysis for cases with individualized data. RESULTS: Of the 158 patients with CGE associated with CVCs found, 71.8% were male and mean age was 56.4years. CGE symptoms frequently occurred while in the upright position. The most frequent neurological manifestation was sudden-onset focal neurological sign (67.7%), followed by coma (59.5%), epileptic seizures (24.7%) and encephalopathy (21.5%). Imaging revealed intracranial air bubbles in 69.1% and cerebral ischemia or edema was demonstrated in 66.7%. Overall mortality was 21.7%, and clinical predictors of mortality were increasing age (p<0.001), coma (p=0.001), cardiorespiratory arrest shortly after symptom onset (p<0.001) and male sex (p=0.035). CONCLUSIONS: CGE associated with CVCs may mimic ischemic stroke, but patients frequently present a severe vigilance disturbance and epileptic seizures. Mortality occurs in 1/5 of patients, which substantiates implementation of protocols and measures to prevent this severe complication of CVC use. PMID- 26944141 TI - A suggested minimum standard deep brain stimulation evaluation for essential tremor. AB - BACKGROUND: A comprehensive, multidisciplinary screening process for deep brain stimulation (DBS) candidates is recommended, but is often time-consuming. OBJECTIVE: To determine the number of essential tremor (ET) referrals excluded from surgery and why, in order to develop recommendations for a minimum standard DBS evaluation process. METHODS: We reviewed the referrals of 100 consecutive potential DBS candidates with presumed ET at our center, identified reasons for excluding patients from DBS, and the point at which they dropped out of our evaluation process. RESULTS: Of the 100 tremor patients referred for DBS, 36 patients were approved for surgery. Patients were mainly excluded because of the movement disorders neurologist and neuropsychologist evaluations. Reasons included an inadequate medication trial (n=20), incorrect diagnosis (n=3), dementia (n=3), and antagonistic interactions with the team (n=1). 37 patients did not present, were uninterested or lost to follow-up. Neither neurosurgical evaluation nor brain imaging excluded candidates in this study, but are needed to proceed with DBS. CONCLUSIONS: Our suggested minimum standard DBS screening process begins with a movement disorders neurologist and neuropsychologist evaluation in order to determine eligibility. Neurosurgical evaluation and brain imaging can then be performed if candidates are deemed eligible. PMID- 26944142 TI - Opsoclonus in a patient with increased titers of anti-GAD antibody provides proof for the conductance-based model of saccadic oscillations. AB - Paucity in gamma-amino butyric acid (GABA) due to blockage in the action of glutamic acid decarboxylase (GAD), as seen in the syndrome of anti-GAD antibody, causes adult onset cerebellar ataxia, muscle rigidity, and episodic spasms. Downbeat nystagmus, saccadic dysmetria, impaired ocular pursuit, and impaired cancelation of vestibular ocular reflex are typical ocular motor deficits in patients with syndrome of anti-GAD antibody. We describe opsoclonus, in addition to downbeat nystagmus, in a patient with increased titers of anti-GAD antibody. Paucity in GABA leading to disinhibition to Purkinje target neurons at deep cerebellar and vestibular nuclei might have caused downbeat nystagmus in our patient. Anti-GAD antibody can also increase levels of glutamate the precursor of GABA and the substrate for the action of GAD. We propose that opsoclonus might be due to increased levels of glutamate and subsequent hyperexcitability of excitatory and inhibitory burst neurons leading to reverberation in their reciprocally innervating circuit. PMID- 26944143 TI - Intraspinal delivery of bone marrow stromal cell-derived neural stem cells in patients with amyotrophic lateral sclerosis: A safety and feasibility study. AB - BACKGROUND: Stem cells have been used in several studies with different methodologies to treat patients with ALS. METHODS: In this safety and feasibility study, 11 patients with definite or probable ALS according to El Escorial criteria were selected. 3 patients were excluded due to inadequate bone marrow or safety measures after acquisition of bone marrow. Bone marrow stromal cell derived neural stem cells were injected in C7-T1 spinal cord under general anesthesia. Patients were followed for 12months after injection with manual muscle testing, ALSFRS-R, quality of life changes, pulmonary function test and electromyography. RESULTS: None of the patients had perioperative mortality or major morbidity. One patient had temporary deterioration in lower extremities after injection which improved after a few weeks. In the 12months post-injection, only one patient died due to pulmonary embolism. From the remaining 7 patients, all had a stable course after 4months and 5 were stable for the first 8months post-injection and deteriorated afterwards. DISCUSSION: In this study, intraspinal injection of bone marrow derived neural stem cells appears to be safe. Patients experienced a temporary stabilization for the first few months post-injection and then gradually deteriorated. PMID- 26944144 TI - Heart failure and the risk of ischemic stroke recurrence: A systematic review and meta-analysis. AB - Heart failure (HF) is known to be a major risk factor for first-ever ischemic stroke (IS), and is associated with greater stroke severity and higher rates of early mortality and residual disability. There are limited data regarding the association of HF with stroke recurrence. We sought to evaluate the relationship between HF and recurrent IS using a comprehensive meta-analytical approach. We performed a systematic literature review according to PRISMA guidelines to identify all prospective study protocols (randomized clinical trials or observational cohorts) that reported rates of IS recurrence in patients with concomitant HF. We pooled independently the reported corresponding risk ratios (RRs) and hazard ratios (HRs) from each study protocol using the random effects model. Heterogeneity across included studies was evaluated using Cochran Q and I(2) statistics. Our literature search identified 7 eligible studies including 9173 IS patients (18.2% with HF). The reported mean follow-up period in the included studies ranged from 7days to 5years. The pooled estimate of RRs and HRs for recurrent IS was 1.96 (95% CI: 1.49-2.60; p<0.0001) and 1.93 (95% CI: 1.47 2.53; p<0.0001). We found no evidence of heterogeneity within studies in both the RR (I(2)=13.5%, p for Cochran Q statistic: 0.325) and HR (I(2)=0%, p for Cochran Q statistic: 0.629) analyses. HF is associated with a continuous two-fold increase in the risk of IS recurrence in patients with prior history of cerebral ischemia. The benefit of anticoagulation in this high-risk group of patients may be studied along with additional risk factor modifications. PMID- 26944145 TI - Ultrasound of the nerves - An appropriate addition to nerve conduction studies to differentiate paraproteinemic neuropathies. AB - OBJECTIVE: To investigate the use of peripheral nerve ultrasound (PNUS) in addition to nerve conduction studies (NCS) in the diagnosis of paraproteinemic neuropathies (PN). METHODS: PNUS/NCS of predefined peripheral nerves and the 5th/6th cervical roots were performed in patients with chronic inflammatory demyelinating polyneuropathy (CIDP) (+/-paraprotein), patients with anti-MAG neuropathy, and patients with neuropathy and multiple myeloma or monoclonal gammopathy of uncertain significance (MGUS) - summarized as M-protein associated neuropathies (MPAN) and compared to controls (+/-paraprotein). RESULTS: 39 patients and 27 age-matched controls were included. Nerve enlargement was most marked in patients with CIDP, while in anti-MAG neuropathies enlargement was significant in the legs. In MPAN, no nerve enlargement is found regularly. However, in two cases, the diagnostic steps were influenced by the finding of multiple enlarged nerves and finally immunotherapy response was successfully initiated. By the use of the ultrasound pattern sum score (UPSS), differentiation of PN can be simplified. DISCUSSION: Due to the heterogeneous findings in NCS, correct diagnosis of PN, and straightforward therapeutic decisions often may be controversial. Particularly in cases of M-protein related neuropathy, the finding of multiple nerve enlargements facilitates the decision for therapeutic approaches or nerve biopsy. The UPSS enables the distinction of different PN from each other. CONCLUSION: The use of an ultrasound quantification tool in addition to NCS facilitates a differentiation of PN. PMID- 26944146 TI - Pneumocephalus associated with Pott's puffy tumor. PMID- 26944147 TI - Outcomes after acute ischemic stroke in patients with thrombocytopenia or thrombocytosis. AB - INTRODUCTION: Thrombocytopenia may be associated with a greater risk of cerebral hemorrhage and thrombocytosis may be associated with a greater risk of cerebral thrombosis. There is a paucity of studies focused on the potential association between blood platelet count (BPC) and outcomes after acute ischemic stroke (AIS). We hypothesized that abnormal BPC is associated with poorer outcomes after AIS. METHODS: This study included data from the Ontario Stroke Registry on consecutive patients with AIS admitted between July 2003 and March 2008. Patients were divided into groups as follows: low BPC (<150,000/mm(3)), normal BPC (150,000 to 450,000/mm(3)) and high BPC (>450,000/mm(3)). Primary outcome measures were the frequency of moderate/severe strokes on admission (Canadian Neurologic Scale: <8), greater degree of disability at discharge (modified Rankin score: 3-6), and 30-day and 90-day mortality. RESULTS: We included 9230 patients. Both low and high BPC were associated with higher 30-day mortality (p<=0.0335) and 90-day mortality (p<=0.048) following AIS. The Kaplan-Meier curves indicate that abnormal BPC is associated with greater mortality after AIS (p=0.0002). Nonetheless, abnormal BPC was not associated with initial stroke severity (p>=0.225), degree of disability (p>=0.3761), or length of stay in the acute stroke care center (p>=0.7818) after adjustment for major potential confounders. CONCLUSIONS: Thrombocytopenia and thrombocytosis on the initial admission are associated with higher mortality after AIS. Abnormal BPC does not adversely affect the degree of initial impairment, disability at discharge, or length of stay in the acute care hospital after AIS. PMID- 26944148 TI - Granulomatosis with polyangiitis and posterior reversible encephalopathy syndrome. PMID- 26944149 TI - Transorbital sonography in CIDP patients: No evidence for optic nerve hypertrophy. AB - Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an acquired, chronic progressive or relapsing immune mediated disorder of the peripheral nervous system. Thickening of cranial nerves as a sign of central nerve involvement is increasingly reported in the last years. Our aim was to assess systematically for the first time the frequency of optic nerve hypertrophy in patients with CIDP by means of transorbital sonography (TOS). Thirty-four optic nerves of 17 patients with CIDP (age=60.8+/-13.3y, range=39-82y; 7 female) were examined by TOS. The diameter of Optic nerve (OND) as well as the intern and extern diameters of the sheath (ONDSi, ONSDe) was measured 3mm behind the optic disc. Findings were compared to the data of 15 healthy controls. CIDP-patients showed a mean OND of 2.8+/-0.4mm, an ONSDi of 4.7+/-0.7mm, and an ONSDe of 6.3+/ 0.9mm. No papilledema was detectable. There was no significant difference to the healthy control group. Our study revealed no evidence for a frequent optic nerve involvement in CIDP. Reported cases seem to represent exceptions. Transorbital sonography could be a useful tool in these rare cases with optic nerve hypertrophy. PMID- 26944150 TI - Test-retest reliability of single and paired pulse transcranial magnetic stimulation parameters in healthy subjects. AB - OBJECTIVE: To determine the influence of different factors on test-retest reliability of frequently used transcranial magnetic stimulation (TMS) parameters while controlling for potential confounders in healthy subjects. METHODS: TMS was applied in 93 healthy volunteers (61% male) twice (mean retest interval of 34.0 +/- 25.6 (SD) days) between 7 am and 2 pm by four investigators (sessions n investigator A=47, investigator B=95, investigator C=28, investigator D=16). Women were assessed in their follicular phase. Test stimulus (TS), resting motor threshold (RMT), short latency intracortical inhibition (SICI), intracortical facilitation (ICF) and cortical silent period (SCP) were analyzed. RESULTS: Good test-retest reliabilities were observed for TS (r=.880) and RMT (r=.826), moderate for visual and automated analyzed CSP durations (resp. r=.466, r=.486), and poor for ICF (r=-.159). Reliable change indexes are reported. Gender (e.g. automated CSP women: r=.538 vs. men: r=.422), re-test interval and method of CSP analysis did not influence reliabilities. CONCLUSIONS: In a large sample of healthy volunteers we found good to moderate test-retest reliabilities in all but one TMS-parameter. Automated analysis of the CSP did not prove to be more reliable than visual determination. SIGNIFICANCE: This study contains analyses of re-test reliability in TMS considering several confounding factors. For the first time it presents reliable change indices for all frequently used TMS parameters. PMID- 26944151 TI - Relationship of circulatory BDNF with cognitive deficits in people with Parkinson's disease. AB - BACKGROUND: Brain-derived neurotrophic factor (BDNF) and cognitive function are diminished in people with Parkinson's disease (PD). The relationship of cognitive function and serum level of BDNF, however is yet to be examined. The aim of this study was to examine serum BDNF levels in PD. Subsequently, the relationship of cognitive function to the serum levels of BDNF was evaluated. METHODS: Serum BDNF levels were measured in 29 idiopathic PD subjects and 30 healthy-matched controls using ELISA technique. Cognitive function was assessed using the Montreal Cognitive Assessment (MOCA) scale. RESULTS: Serum BDNF levels and MOCA total score were significantly lower (P<0.001) in PD patients versus healthy controls. MOCA total score correlated with serum BDNF (r=0.44; P=0.012) but not with age, years of education, duration of disease and severity of symptoms. The regression analysis showed that serum BDNF accounted (P=0.019) for 19% of MOCA total score variance. CONCLUSIONS: The data confirm lowered serum BDNF in PD. Additionally; it suggests that BDNF may play a role in the cognitive deficit of PD. Further studies are required to identify association of BDNF in cognitive decline with PD. PMID- 26944152 TI - Septic cerebral venous sinus thrombosis. AB - Septic cerebral venous sinus thrombosis, once a common and deadly disease, has fortunately become rare now. Not only that the incidence has fallen significantly after the antibiotic era, the morbidity and mortality has also decreased substantially. Cavernous sinus thrombosis is by far the commonest form of septic cerebral venous sinus thrombosis. Due to its rare occurrence, a lot of current generation clinicians have not encountered the entity in person. Despite all the advances in diagnostic modalities, a high index of clinical suspicion remains the mainstay in prompt diagnosis and management of this potentially lethal condition. Keeping this in view, the authors have reviewed the subject including the old literature and have summarized the current approach to diagnosis and management. Septic cavernous thrombosis is a fulminant disease with dramatic presentation in most cases comprised of fever, periorbital pain and swelling, associated with systemic symptoms and signs. The preceding infection is usually in the central face or paranasal sinuses. The disease rapidly spreads to contralateral side and if remains undiagnosed and untreated can result in severe complications or even death. Prompt diagnosis using radiological imaging in suspected patient, early use of broad spectrum antibiotics, and judicial use of anticoagulation may save the life and prevent disability. Surgery is used only to treat the nidus of infection. PMID- 26944153 TI - GPi deep brain stimulation for palliation of hemidystonia and hemibody jerking in a patient with suspected adult onset neuronal ceroid lipofuscinosis. PMID- 26944154 TI - Neuralgic amyotrophy mimicking Vernet syndrome. PMID- 26944155 TI - Objectifying eye movements during rapid number naming: Methodology for assessment of normative data for the King-Devick test. AB - OBJECTIVE: Concussion is a major public health problem and considerable efforts are focused on sideline-based diagnostic testing to guide return-to-play decision making and clinical care. The King-Devick (K-D) test, a sensitive sideline performance measure for concussion detection, reveals slowed reading times in acutely concussed subjects, as compared to healthy controls; however, the normal behavior of eye movements during the task and deficits underlying the slowing have not been defined. METHODS: Twelve healthy control subjects underwent quantitative eye tracking during digitized K-D testing. RESULTS: The total K-D reading time was 51.24 (+/-9.7) seconds. A total of 145 saccades (+/-15) per subject were generated, with average peak velocity 299.5 degrees /s and average amplitude 8.2 degrees . The average inter-saccadic interval was 248.4 ms. Task specific horizontal and oblique saccades per subject numbered, respectively, 102 (+/-10) and 17 (+/-4). Subjects with the fewest saccades tended to blink more, resulting in a larger amount of missing data; whereas, subjects with the most saccades tended to make extra saccades during line transitions. CONCLUSIONS: Establishment of normal and objective ocular motor behavior during the K-D test is a critical first step towards defining the range of deficits underlying abnormal testing in concussion. Further, it sets the groundwork for exploration of K-D correlations with cognitive dysfunction and saccadic paradigms that may reflect specific neuroanatomic deficits in the concussed brain. PMID- 26944156 TI - Relevance of endoglin, IL-1alpha, IL-1beta and anti-ovarian antibodies in females with multiple sclerosis. AB - Few studies support the concept of reduced fertility in females with multiple sclerosis (MS). Recently we reported on reduced serum levels of Anti-Mullerian Hormone (AMH) in reproductive-age females with MS, suggestive of reduced ovarian reserve. The cause for this observation is not evident and remains speculative. The aim of the study is to examine possible immunological mechanisms interfering with fertility, as well as ovarian reserve that might affect the reproductive potential in women with MS. ELISA experiments were done to detect anti-ovarian antibodies (AOA), endoglin and interleukin (IL)-1alpha/-1beta in sera of 85 MS females, including 15 women with known low AMH level as a marker of ovarian reserve, compared to 63 healthy controls. Groups did not differ with respect to age, smoking habits, BMI, and use of oral contraceptives. MS females showed significantly increased endoglin values compared to healthy controls. Remarkable, the highest endoglin values were found in subjects with low AMH. AOA were neither detectable in MS patients nor control subjects. IL-1alpha and IL-1beta levels did not differ between groups. Our data established no relevance of IL-1alpha/-1beta or AOA in ovarian insufficiency/dysfunction but suggests the involvement of endoglin in RRMS. PMID- 26944157 TI - Extracranial and intracranial vertebral artery dissections: A comparison of clinical findings. AB - BACKGROUND: The diagnostic criteria for extracranial vertebral artery dissection (VAD) have not been standardized among stroke centers. Recent studies have shown that extracranial (EVAD) and intracranial (IVAD) VAD may be different clinical entities. In this study, we reviewed clinical findings, including image findings of VAD cases, and compared these findings to EVAD and IVAD cases to highlight the clinical characteristics of EVAD. METHODS: We searched our database to identify VAD cases registered between April 2008 and October 2014. We performed retrospective chart reviews to obtain detailed clinical information and compared clinical characteristics and radiological findings between EVAD and IVAD cases. RESULTS: We identified 10 patients with EVAD and 113 patients with IVAD. Clinically, patients with EVAD had initial symptoms that included significantly higher frequencies of neck pain, nausea, and vertigo, whereas medical hypertension and alcohol consumption were more commonly associated with IVAD cases. EVAD cases were also more likely to manifest as ischemic stroke. Radiologically, intramural hematomas were more commonly observed by magnetic resonance imaging (MRI) in patients with EVAD, whereas MRI and computed tomography more frequently revealed aneurysm formation in IVAD cases. CONCLUSIONS: Our data identified the clinical differences between patients with EVAD and IVAD. When relatively young patients complain of sudden-onset neck pain and/or other neurological symptoms, MRI studies may be useful to diagnose EVAD, especially when associated with mechanical stress. PMID- 26944158 TI - High-intensity resistance training in multiple sclerosis - An exploratory study of effects on immune markers in blood and cerebrospinal fluid, and on mood, fatigue, health-related quality of life, muscle strength, walking and cognition. AB - BACKGROUND: High-intensity resistance training is unexplored in people with multiple sclerosis. OBJECTIVES: To evaluate effects of high-intensity resistance training on immune markers and on measures of mood, fatigue, health-related quality of life, muscle strength, walking and cognition. Further, to describe participants' opinion and perceived changes of the training. METHODS: Twenty patients with relapsing-remitting multiple sclerosis performed high-intensity resistance training at an intensity of 80% of one-repetition maximum, twice a week for 12 weeks. Blood and optional cerebrospinal fluid samples, and data on secondary outcome measures were collected before and after intervention. A study specific questionnaire was used for capturing participants' opinion. RESULTS: Seventeen participants completed the study. Plasma cytokine levels of tumor necrosis factor were significantly decreased post-intervention (p=0.001). Exploratory cytokine analyses in cerebrospinal fluid (n=8) did not reveal major changes. Significant and clinically important improvements were found in fatigue (p=0.001) and health-related quality of life (p=0.004). Measures of mood (p=0.002), muscle strength (p <= 0.001), walking speed (p=0.013) and cognition (p=0.04) were also improved. A majority of participants evaluated the training as very good and perceived changes to the better. CONCLUSION: High-intensity resistance training in persons with relapsing remitting multiple sclerosis with low disability had positive effects on peripheral pro-inflammatory cytokine levels, led to clinically relevant improvements in measures of fatigue and health related quality of life, and was well tolerated. These results provide a basis for a larger randomized trial. PMID- 26944159 TI - Association between urine protein/creatinine ratio and cognitive dysfunction in Lewy body disorders. AB - BACKGROUND: Impaired renal function and proteinuria have been associated with cognitive impairment and dementia. Chronic kidney disease is considered to be an independent risk factor for Lewy body spectrum disorders (LBD). However, few studies have mentioned an association between proteinuria and cognition in LBD. We investigated the relationship between proteinuria and cognitive dysfunction in patients with Parkinson's disease (PD) and dementia with Lewy bodies (DLB). METHODS: Among 186 patients with LBD, 53 had PD-normal cognition (PD-NC), 76 had PD-mild cognitive impairment (PD-MCI), 43 had PD-dementia (PDD) and 14 had DLB. The urine protein/creatinine ratio was calculated using the spot urine test and brain magnetic resonance scans was obtained in all patients. RESULTS: The urine protein/creatinine ratio was significantly higher in patients with PDD and DLB than in those with PD-MCI, PD-NC patients and healthy controls, and was correlated with white matter hyperintensities on magnetic resonance imaging. All abnormal neuropsychological test results were associated with increased urine protein/creatinine ratio. After controlling for age, education, symptom duration, diabetes mellitus, hypertension, and parkinsonian motor severity, the urine protein/creatinine ratio was significantly associated with decreased cognition. CONCLUSION: The urine protein/creatinine ratio was associated with cognitive status in LBD. These finding suggests that increased protein excretion is associated with cognitive dysfunction in patients with LBD. PMID- 26944160 TI - The spectrum of neurological presentations in an outpatient clinic of rural Zimbabwe. AB - BACKGROUND: Previous studies to estimate burden of neurological disorders in Africa are limited to inpatients in urban hospitals. The spectrum of neurological conditions in rural Africa remains unclear. OBJECTIVE: To determine the spectrum of neurological presentations in an outpatient setting in rural Zimbabwe. METHODS: Clinical data was collected from outpatient records at Karanda Mission Hospital, a rural community hospital in Northern Zimbabwe from February 2013 to February 2014. Each patient visit was entered in an outpatient record book by a registered nurse or a nurse trainee. Demographic details such as age, sex, weight and address of the patient, and clinical details such as diagnosis on discharge and medications prescribed were recorded in the record book following assessment by a physician or nurse practitioner. Each visit corresponded to a separate entry in the study. RESULTS: We recorded a total of 19,206 visits in the outpatient registry. The average age was 46.41 years (standard deviation=21.46), and there were more visits from women (57.81%). 11.63% (2233) of all visits had a neurological diagnosis at discharge. The most common neurological diagnoses were epilepsy/seizures (24.38%), followed by neuropathies (13.63%), headaches (11.4%) and strokes (4.6%). CONCLUSIONS: One in ten cases in an outpatient setting in rural Zimbabwe were neurologically related. Further studies are required to determine the public health burden of neurological disorders in rural Africa. The development and funding of educational initiatives in resource-limited areas is needed to improve neurological diagnosis and care. PMID- 26944161 TI - Effects of tafamidis treatment on transthyretin (TTR) stabilization, efficacy, and safety in Japanese patients with familial amyloid polyneuropathy (TTR-FAP) with Val30Met and non-Val30Met: A phase III, open-label study. AB - INTRODUCTION: The efficacy and safety of tafamidis in transthyretin (TTR) familial amyloid polyneuropathy (TTR-FAP) were evaluated in this open-label study. METHODS: Japanese TTR-FAP patients (n=10; mean age 60.1 years) received tafamidis meglumine (20mg daily; median treatment duration 713.5 days). The primary endpoint was TTR stabilization at Week 8. Secondary endpoints included Neuropathy Impairment Score-Lower Limb (NIS-LL), Norfolk QOL-DN total quality of life (TQOL), and modified body mass index (mBMI). RESULTS: TTR stabilization was achieved in all patients at Weeks 8 and 26, 9 out of 10 patients at Week 52, and 8 out of 10 patients at Week 78. The percentage (95% CI) of NIS-LL responders (increase from baseline in NIS-LL<2) was 80.0% (44.4, 97.5), 60.0% (26.2, 87.8), and 40.0% (12.2, 73.8) and mean(SD) NIS-LL change from baseline was 2.1 (5.6), 3.6 (4.4), and 3.3 (4.7), at Weeks 26, 52, and 78, respectively. Mean (SD) changes from baseline in TQOL and mBMI at Weeks 26, 52, and 78 were 11.8 (20.0), 9.1 (12.5), and 10.8 (13.7) for TQOL, and 26.6 (61.9), 64.9 (80.0), and 53.7 (81.4) for mBMI, respectively. Ambulation status was preserved in 4 out of 8 patients at Week 78. Most adverse events (AEs) were mild/moderate, with no discontinuations due to AEs. CONCLUSIONS: Tafamidis stabilized TTR, was safe and well-tolerated, and was effective over 1.5 years in slowing neurologic progression and maintaining TQOL and nutrition status in TTR-FAP. PMID- 26944162 TI - Tremor frequency characteristics in Parkinson's disease under resting-state and stress-state conditions. AB - Tremor characteristics-amplitude and frequency components-are primary quantitative clinical factors for diagnosis and monitoring of tremors. Few studies have investigated how different patient's conditions affect tremor frequency characteristics in Parkinson's disease (PD). Here, we analyzed tremor characteristics under resting-state and stress-state conditions. Tremor was recorded using an accelerometer on the finger, under resting-state and stress state (calculation task) conditions, during rest tremor and postural tremor. The changes of peak power, peak frequency, mean frequency, and distribution of power spectral density (PSD) of tremor were evaluated across conditions. Patients whose tremors were considered more than "mild" were selected, for both rest (n=67) and postural (n=25) tremor. Stress resulted in both greater peak powers and higher peak frequencies for rest tremor (p<0.001), but not for postural tremor. Notably, peak frequencies were concentrated around 5 Hz under stress-state condition. The distributions of PSD of tremor were symmetrical, regardless of conditions. Tremor is more evident and typical tremor characteristics, namely a lower frequency as amplitude increases, are different in stressful condition. Patient's conditions directly affect neural oscillations related to tremor frequencies. Therefore, tremor characteristics in PD should be systematically standardized across patient's conditions such as attention and stress levels. PMID- 26944163 TI - Recombinant human soluble thrombomodulin ameliorates cerebral ischemic injury through a high-mobility group box 1 inhibitory mechanism without hemorrhagic complications in mice. AB - BACKGROUND: It has been reported that recombinant human soluble thrombomodulin (rhsTM) has a high-mobility group box (HMGB)1 inhibitory effect. Some investigators reported that HMGB1 is associated with ischemic stroke. However, there have been no previous studies to determine whether rhsTM can ameliorate cerebral ischemic injury through its HMGB1 inhibitory mechanism in ischemic stroke. We investigated the effects of rhsTM on cerebral ischemic injury in a 4-h middle cerebral artery occlusion (MCAO) murine model. METHODS: rhsTM (1 or 5mg/kg, i.v.) was administered immediately after 4-h MCAO. Infarct volume, motor coordination, plasma HMGB1 level, and hemorrhage volume were evaluated 24h after 4-h MCAO. RESULTS: The infarct volume (P<0.05) was reduced by rhsTM in mice subjected to 4-h MCAO in a dose-dependent manner. Moreover, rhsTM (5mg/kg) significantly improved motor coordination determined by the rotarod test (P<0.05), and significantly decreased plasma HMGB1 level compared with vehicle treated controls (P<0.001). In addition, there was no difference in hemorrhage volume between vehicle-treated controls and the rhsTM treatment group. CONCLUSIONS: This represents the first report that rhsTM ameliorates cerebral ischemic injury through an HMGB1 inhibitory mechanism without hemorrhagic complications in mice. Taken together, these observations indicate a palliative effect of rhsTM and suggest new therapeutic possibilities for treatment of ischemic stroke via inhibition of HMGB1. PMID- 26944164 TI - Gene promoter methylation and expression of Pin1 differ between patients with frontotemporal dementia and Alzheimer's disease. AB - Frontotemporal Dementia (FTD) and Alzheimer's Disease (AD) share the accumulation of fibrillar aggregates of misfolded proteins. To better understand these neurodegenerative diseases and identify biomarkers in easily accessible cells, we investigated DNA methylation at Pin1 gene promoter and its expression in peripheral blood mononuclear cells of FTD patients. We found a lower gene expression of Pin1 with a higher DNA methylation in three CpG sites at Pin1 gene promoter analysed in FTD subjects, in contrast to a higher gene expression with a lower methylation in AD subjects and controls. These data suggest an important and distinct involvement of Pin1 in these two types of dementia. PMID- 26944165 TI - Mitochondrial dysfunction in hereditary spastic paraparesis with mutations in DDHD1/SPG28. AB - Mutations in DDHD1 cause the SPG28 subtype of hereditary spastic paraplegia (HSP). Recent studies suggested that mitochondrial dysfunction occurs in SPG28. Here we describe two siblings with SPG28, and report evidence of mitochondrial impairment in skeletal muscle and skin fibroblasts. Patient 1 (Pt1) was a 35-year old man with spastic paraparesis and urinary incontinence, while his 25-year-old brother (Pt2) had gait spasticity and motor axonal neuropathy. In these patients we identified the novel homozygous c.1429C>T/p.R477* mutation in DDHD1, using a next-generation sequencing (NGS) approach. Histochemical analyses in muscle showed mitochondrial alterations, and multiple mitochondrial DNA (mtDNA) deletions were evident. In Pt1, respiratory chain enzyme activities were altered in skeletal muscle, mitochondrial ATP levels reduced, and analysis of skin fibroblasts revealed mitochondrial fragmentation. It seems possible that the novel nonsense mutation identified abolishes DDHD1 protein function thus altering oxidative metabolism. Qualitative alterations of mtDNA could have a pathogenetic significance. We suggest to perform DDHD1 analysis in patients with multiple mtDNA deletions. PMID- 26944166 TI - Diffusion tensor imaging of the extracorticospinal network in the brains of patients with Wilson disease. AB - OBJECTIVE: To evaluate damage to the extracorticospinal tract in Wilson disease (WD) patients using diffusion tensor imaging (DTI). METHODS: 70 patients with WD, including 50 with cerebral type and 20 with hepatic type, and 20 age-matched healthy controls were enrolled. Neurological symptoms were scored using the modified Young Scale. Patients with cerebral type WD were divided into four subgroups: those with (1) hypokinesia, (2) parkinsonism, (3) mouth and throat dystonia, and (4) psychiatric symptoms. All study subjects underwent DTI of the brain. Five regions of interest (ROIs) were chosen. Fractional anisotropy (FA) and fiber volumes between ROIs were determined, and the relationships between DTI metrics and clinical status were evaluated. RESULTS: FA values and fiber volumes between subcortical nuclei were lower in WD patients. Fiber volumes between the putamen (PU) and the globus pallidus (GP), substantia nigra (SN), and thalamus (TH); between the head of the caudate nucleus (CA) and the GP and TH; and between the TH and cerebellum were lower in group 1 than in the other groups of WD patients. Fiber volumes between the GP and the SN and TH were lower in group 2, and fiber volumes between the SN and TH were lower in group 3. DTI metrics differed between patients with the cerebral and hepatic types of WD. CONCLUSIONS: DTI can reconstruct the network of the extracorticospinal tract. Fiber projection between subcortical nuclei was abnormal in WD patients. Damage to fiber connections may correlate with neurological symptoms in WD patients. PMID- 26944167 TI - Blepharospasm in a multiplex African-American pedigree. AB - BACKGROUND: Isolated blepharospasm (BSP) is a late-onset focal dystonia characterized by involuntary contractions of the orbicularis oculi muscles. Genetic studies of BSP have been limited by the paucity of large multiplex pedigrees. Although sequence variants (SVs) in THAP1 have been reported in rare cases of BSP, the genetic causes of this focal dystonia remain largely unknown. Moreover, in the absence of family history and strong in silico or in vitro evidence of deleteriousness, the pathogenicity of novel SVs in THAP1 and other dystonia-associated genes can be indeterminate. METHODS: A large African-American pedigree with BSP was phenotypically characterized and screened for mutations in THAP1, TOR1A and GNAL with Sanger sequencing. Whole-exome sequencing of the proband was used to examine other dystonia-associated genes for potentially pathogenic SVs. In silico and co-segregation analyses were performed for a novel THAP1 SV identified in the proband. RESULTS: Seven family members exhibited increased blinking and/or stereotyped bilateral and synchronous orbicularis oculi spasms with age of onset ranging from early childhood to late adult life (7 to 54 years). The proband was found to harbor a novel THAP1 SV (c.314T>C, p.L105S). However, the p.L105S SV did not co-segregate with blepharospasm in the pedigree. Moreover, in silico analyses suggest that p.L105S is benign. No pathogenic or likely pathogenic SVs in other dystonia-associated genes were identified with whole-exome sequencing. CONCLUSIONS: Blepharospasm can be familial and may be hereditary in African-Americans. A comprehensive array of in silico tools, and, if possible, co-segregation analysis should be used to classify SVs in dystonia associated genes. PMID- 26944168 TI - Probable high prevalence of limb-girdle muscular dystrophy type 2D in Taiwan. AB - Limb-girdle muscular dystrophy type 2D (LGMD2D), an autosomal-recessive inherited LGMD, is caused by the mutations in SGCA. SGCA encodes alpha-sarcoglycan (SG) that forms a heterotetramer with other SGs in the sarcolemma, and comprises part of the dystrophin-glycoprotein complex. The frequency of LGMD2D is variable among different ethnic backgrounds, and so far only a few patients have been reported in Asia. We identified five patients with a novel homozygous mutation of c.101G>T (p.Arg34Leu) in SGCA from a big aboriginal family ethnically consisting of two tribes in Taiwan. Patient 3 is the maternal uncle of patients 1 and 2. All their parents, heterozygous for c.101G>T, denied consanguineous marriages although they were from the same tribe. The heterozygous parents of patients 4 and 5 were from two different tribes, originally residing in different geographic regions in Taiwan. Haplotype analysis showed that all five patients shared the same mutation associated haplotype, indicating the probability of a founder effect and consanguinity. The results suggest that the carrier rate of c.101G>T in SGCA may be high in Taiwan, especially in the aboriginal population regardless of the tribes. It is important to investigate the prevalence of LGMD2D in Taiwan for early diagnosis and treatment. PMID- 26944169 TI - FDG-PET study of patients with Leigh syndrome. AB - We conducted a [(18)F]fluorodeoxyglucose positron emission tomography (FDG-PET) study in five patients (median age 11 (range 4-13) years) with Leigh syndrome to evaluate its usefulness for understanding the functional brain dysfunction in this disease and in future drug trials. Four patients were found to have reported mitochondrial DNA gene mutations. The brain T2-weighted magnetic resonance imaging (MRI) showed high-intensity areas in the putamen bilaterally in five patients, caudate bilaterally in four, thalamus bilaterally in two, and brainstem in one. Cerebellar atrophy was observed in older two patients. For disease control, seven age-matched epilepsy patients who had normal MRI and FDG-PET studies were selected. For semiquantitative analysis of the lesions with decreased (18)F-FDG uptake, the mean standard uptake value (SUV) was calculated in regions of interest (ROIs) placed in each brain structure. We compared the SUV of nine segments (the frontal, temporal, parietal, and occipital lobes, thalami, basal ganglia, mid-brain, pons, and cerebellum) between patients with Leigh syndrome and controls. The glucose uptake was decreased significantly in the cerebellum and basal ganglia, which could explain the ataxia and dystonia in patients with Leigh syndrome. Although this study had some limitations, FDG-PET might be useful for evaluating the brain dysfunction and treatment efficacy of new drugs in patients with Leigh syndrome. Further study with more patients using advanced methods to quantify glucose uptake is needed before drawing a conclusion. PMID- 26944171 TI - Synaptotagmin XI in Parkinson's disease: New evidence from an association study in Spain and Mexico. AB - INTRODUCTION: The pathophysiology of PD (Parkinson's disease) has been related to the ubiquitin proteasome system and oxidative stress. Parkin acts as ubiquitin ligase on several substrates. Because genetic variants often have different frequencies across populations, population specific analyses are necessary to complement and validate results from genome-wide association studies. METHODS: We carried out an association study with genes coding for parkin substrates and cellular stress components in the Galician population (Northern Spain). SNCA and MAPT SNPs were also analyzed. We studied 75 SNPs in a discovery sample of 268 PD patients and 265 controls from Galicia. A replication sample of 271 patients and 260 controls was recruited from Mexico City. RESULTS: We observed significant association between PD and SNPs in MAPT. Nominal p-values<0.05 were obtained in the Galician cohort for SNPs in SYT11, coding for synaptotagmin XI. These results were replicated in the Mexican sample. DISCUSSION: The associated markers lie within a ~140kb strong linkage disequilibrium segment that harbors several candidate genes, including SYT11. SNPs from the GBA-SYT11-RAB25 region have been previously associated with PD, however the functionally relevant variants remain unknown. Our data support a likely role of genetic factors within 1q22 in PD susceptibility. PMID- 26944170 TI - Effects of anodal transcranial direct current stimulation (tDCS) on behavioral and spatial memory during the early stage of traumatic brain injury in the rats. AB - Transcranial direct current stimulation (tDCS) is a noninvasive technique to modulate the neural membrane potential. Its effects in the early stage of traumatic brain injury (TBI) have rarely been investigated. This study assessed the effects of anodal tDCS on behavioral and spatial memory in a rat model of traumatic brain injury. Thirty six rats underwent lateral fluid percussion and were then randomly assigned to one of three groups: control (n=12), five-day tDCS over peri-lesional cortex at one (1W, n=12), or two (2W, n=12) weeks post-injury. The Barnes maze (BM) and Rotarod (RR) tests were evaluated in a blind manner on day 1, week 3 and week 5 post-injury. After three weeks, both the 1W and 2W groups showed significant improvements in the BM ratio (P<0.05), whereas only group 2W obtained a significant improvement in the RR ratio compared with the control group (P<0.05). However, there were no significant differences between any of the groups at five weeks after TBI. Immunohistochemistry revealed that only group 2W had a significantly higher brain-derived neurotrophic factor (BDNF) expression in the peri-lesional cortex, which was significantly correlated with the improvement of the Rotarod test at 3-week post-injury. However, BDNF expression in the ipsi-lesional hippocampus was not significantly different among the three groups. Group 1W tended to have increased choline/creatine ratios, as measured by magnetic resonance spectroscopy in the peri-lesional cortex, than the control group (P=0.051). Neither regimen aggravated the lesion volume or brain edema measured by MRI. These beneficial effects were not observed with either regimen at five weeks post-injury. In conclusions, anodal tDCS ameliorated behavioral and spatial memory function in the early phase after TBI when it is delivered two weeks post-injury. Earlier stimulation (one week post-injury) improves spatial memory only. However, the beneficial effects did not persist after cessation of the anodal stimulation. PMID- 26944172 TI - Liver function in Huntington's disease assessed by blood biochemical analyses in a clinical setting. AB - Huntington's disease (HD) is a dominantly inherited, progressive neurological disorder caused by a CAG repeat elongation in the huntingtin gene. In addition to motor-, psychiatric- and cognitive dysfunction, peripheral disease manifestations in the form of metabolic changes and cellular dysfunction are seen. Blood levels of a wide range of hormones, metabolites and proteins have been analyzed in HD patients, identifying several changes associated with the disease. However, a comprehensive panel of liver function tests (LFT) has not been performed. We investigated a cohort of manifest and premanifest HD gene-expansion carriers and controls, using a clinically applied panel of LFTs. Here, we demonstrate that the level of alkaline phosphatase is increased in manifest HD gene-expansion carriers compared to premanifest HD gene-expansion carriers and correlate with increased disease severity indicated by the Unified Huntington's disease rating scale-Total Functional Capacity Score (UHDRS-TFC). For gamma-glutamyl transferase, elevated levels were more frequent in the manifest groups than in both the HD gene expansion negative controls and premanifest HD gene-expansion carriers. Finally, the manifest HD gene-expansion carriers displayed moderate increases in total cholesterol and blood glucose relative to the premanifest HD gene-expansion carriers, as well as increased C-reactive protein relative to HD gene-expansion negative controls. Our results show that LFT values are elevated more frequently in manifest compared to premanifest HD gene-expansion carriers and controls. The majority of the manifest HD gene-expansion carriers receive medication, and it is possible that this can influence the liver function tests performed in this study. PMID- 26944173 TI - Angiopoietin-like protein 4 serum levels and gene polymorphisms are associated with large artery atherosclerotic stroke. AB - BACKGROUND: Angiopoietin-like protein 4 (ANGPTL4) is a central player in lipid metabolism and atherosclerosis and may thus be involved in ischaemic stroke. However, no study in humans has investigated the association of ANGPTL4 gene polymorphisms or serum levels with ischaemic stroke. METHODS: We investigated the influence of the tagged single nucleotide polymorphisms (tSNPs) rs4076317 (c.207C>G) and rs1044250 (c.797C>T; T266M) of the ANGPTL4 gene on ischaemic stroke risk in a large group of 712 large artery atherosclerotic (LAA) stroke patients and 828 controls. In addition, we examined the association of the serum ANGPTL4 levels with lipid metabolism, LAA stroke severity and ischaemic volume in a sample of 302 LAA stroke patients and 307 controls. RESULTS: The findings reveal that rs4076317 exerts a co-dominant effect on lower serum TG levels compared with common homozygotes. Fewer stroke cases were homozygous for variants of rs4076317 compared with the controls (7.0% vs. 10.9%). The serum ANGPTL4 levels in patients were significantly higher than those in the controls in a univariate manner (P=0.001) and after adjustment for other risk factors (1.463 [1.215-1.835]; P<0.001). Consistently, the ANGPTL4 levels were statistically correlated with higher NIHSS scores (r=0.172, P=0.003) and larger lesion volumes (r=0.124, P=0.031). CONCLUSION: We concluded that the tagged SNPs and high serum levels of ANGPTL4 are associated with LAA stroke and the lipid characteristics. PMID- 26944174 TI - Basal ganglia alterations appearing in transcranial sonography prior to MRI in a patient with Creutzfeld-Jacob Disease. PMID- 26944175 TI - Cidofovir for treatment of progressive multifocal leukoencephalopathy in a newly diagnosed sarcoidosis patient - a valid therapeutic option? PMID- 26944176 TI - Punding in non-demented Parkinson's disease patients: Relationship with psychiatric and addiction spectrum comorbidity. AB - Punding is a stereotyped behavior characterized by an intense fascination with a complex, excessive, non-goal oriented, repetitive activity, associated with dopaminergic replacement therapy (DRT) in patients affected by Parkinson's disease (PD) and with dopamine agonists in several conditions. We studied 25 PD patients with punding behaviors, and compared them to 130 PD controls. The psychiatric evaluation included: the Snaith-Hamilton Pleasure Scale (SHAPS); the SCales for Outcomes in PArkinson's disease-Psychiatric Complications (SCOPA-PC); the Barratt Impulsiveness Scale, Version 11 (BIS-11); the Mood Disorder Questionnaire; the Hamilton Depression Rating Scale (HDRS) and Hamilton Anxiety Rating Scale (HARS). The occurrence of impulse control disorders (ICDs) was diagnosed through a psychiatric interview. Significantly more punding patients (96% vs. 68%; p<0.01) were in treatment with DA agonists, receiving significantly higher DA agonists levodopa equivalent daily dose (LEDD). Punding behaviors were found to be associated with psychiatric comorbidity, particularly with psychosis and bipolar disorder. In addition, higher anhedonic symptoms were reported by punders. High rate of co-occurring addictive behaviors (pathological gambling, hedonistic homeostatic dysregulation) and ICDs were found. In conclusion, presented data confirm that DRT, in a subset of PD patients, is strongly associated with addiction-like behavioral issues. Punding shares similarities with addictive behaviors and is associated to other psychiatric symptoms involving dopamine system alterations. PMID- 26944177 TI - Perinatal thiamine deficiency causes cochlear innervation abnormalities in mice. AB - Neonatal thiamine deficiency can cause auditory neuropathy in humans. To probe the underlying cochlear pathology, mice were maintained on a thiamine-free or low thiamine diet during fetal development or early postnatal life. At postnatal ages from 18 days to 22 wks, cochlear function was tested and cochlear histopathology analyzed by plastic sections and cochlear epithelial whole-mounts immunostained for neuronal and synaptic markers. Although none of the thiamine-deprivation protocols resulted in any loss of hair cells or any obvious abnormalities in the non-sensory structures of the cochlear duct, all the experimental groups showed significant anomalies in the afferent or efferent innervation. Afferent synaptic counts in the inner and outer hair cell areas were reduced, as was the efferent innervation density in both the outer and inner hair cell areas. As expected for primary neural degeneration, the thresholds for distortion product otoacoustic emissions were not affected, and as expected for subtotal hair cell de afferentation, the suprathreshold amplitudes of auditory brainstem responses were more affected than the response thresholds. We conclude that the auditory neuropathy from thiamine deprivation could be produced by loss of inner hair cell synapses. PMID- 26944178 TI - Diagnostic performance of isolated orbital CT scan for assessment of globe rupture in acute blunt facial trauma. AB - OBJECTIVES: We determine the diagnostic performance of emergent orbital computed tomography (CT) scans for assessing globe rupture in patients with blunt facial trauma. METHODS: We performed a retrospective cohort study based on prospectively collected trauma registry and acute care surveillance data in a tertiary-care hospital. Patients aged at least 18 years who underwent isolated orbital CT scanning for assessing potential ocular trauma were examined. Analyses were performed to evaluate the magnitude of agreement between diagnosis by CT scanning and ophthalmic assessment, including globe rupture. RESULTS: Our study cohort comprised 136 patients, 30% of whom (41 patients) sustained orbital wall fractures. Concordance for orbital CT diagnosis and the ophthalmic assessment of globe rupture was substantial (k=0.708). The relative risk of globe rupture was 0.692 (95% confidence interval (CI): 0.054-8.849) for superior wall fractures, 0.459 (95% CI: 0.152-1.389) for inferior wall fractures, 2.286 (95% CI: 1.062 4.919) for lateral wall fractures, and 0.637 (95% CI: 0.215-1.886) for medial wall fractures. According to multivariate analysis, lateral wall fractures were an independent risk factor for globe ruptures (adjusted odds ratio (OR)=12.01, P=0.011), and medial or inferior wall fracture was a protective factor (adjusted OR=0.14, P=0.012). In the stratified analysis of diagnostic performance of CT scan, specificity was highest among patients with orbital wall fractures (97.2%), followed by negative predictive volume (NPV, 97%), and accuracy (95.1%). CONCLUSION: Among patients with blunt facial trauma who underwent isolated orbital CT scanning as part of ocular trauma assessment, the diagnostic performance of CT in detecting globe rupture is more accurate in patients with orbital wall fractures. Nevertheless, isolated orbital CT alone does not have a sufficiently high diagnostic performance to be reliable to rule out all globe ruptures. Lateral orbital wall fractures in blunt facial trauma patients, in particular, should prompt thorough evaluation by an ophthalmologist. PMID- 26944179 TI - A hybrid approach to mid-shaft clavicle fixation. AB - BACKGROUND: The purpose of this study was to demonstrate the strength characteristics of a hybrid uni-cortical construct for clavicle fixation. The technique reported aims to combine benefits of uni-cortical fixation with stability comparable to traditional bi-cortical fixation. The approach utilises long, oblique uni-cortical screws at the distal ends of the plate acting as surrogate bi-cortical screws. Locked uni-cortical screws positioned centrally provide bending and torsion strength to the construct. This alternative hybrid uni-cortical technique does not require far cortex screw or drill penetration required in bi-cortical fixation techniques, thus avoiding potentially catastrophic vascular and or neurologic injury. The purpose of this study was to compare the mechanical behaviour of the hybrid uni-cortical construct to standard bi-cortical fixations under both torsion and bending loads. METHOD: Thirty osteotomized human cadaveric clavicles were randomly allocated to three surgical fixation techniques: bi-cortical locked screw fixation, bi-cortical non-locked screw fixation and hybrid uni-cortical screw fixation. Each clavicle construct was tested non-destructively under torsional loading, and then under cantilever bending to failure. Construct bending and torsional stiffness, as well as ultimate failure strength, were measured. RESULTS: There were no significant differences between uni-cortical or bi-cortical fixation constructs in either bending stiffness or ultimate bending moment (p>0.05); however, there was a trend towards greater bending stiffness in the hybrid construct. The uni-cortical hybrid fixation technique displayed a significantly lower mean torsional stiffness value when compared with the bi-cortical locked screw fixation (mean difference: 134.4 Nmm/degrees, 95% confidence interval [32.3, 236.4], p=0.007). CONCLUSION: A hybrid uni-cortical approach to clavicle plate fixation that may improve screw purchase and reduce risk of intra-operative vascular damage demonstrates comparable bending strength to current bi-cortical approaches. PMID- 26944180 TI - Editorial Comment. PMID- 26944181 TI - Evaluating the impact of infliximab use on surgical outcomes in pediatric Crohn's disease. AB - BACKGROUND: The impact of infliximab (IFX) on surgical outcomes is poorly defined in pediatric Crohn's disease (CD). We evaluated our institution's experience with IFX on postoperative complications and surgical recurrence. METHODS: A retrospective review of children who underwent intestinal resection with primary anastomosis for CD from 1/2002 to 10/2014 was performed. Data collected included IFX use and surgical outcomes. Preoperative IFX use was within 3months of surgery. RESULTS: Seventy-three patients were included with median age 15years (range: 9-18). The most frequent indications for operation were obstruction (n=26) and fistulae (n=19). Nine patients (13%) had a surgical recurrence at a median of 2.3years (IQR 0.7-3.5). Twenty-two patients received preoperative IFX at median of 26days (IQR 14-46). There were 7 postoperative complications: 2 bowel obstructions, and 5 superficial wound infections. Outcomes of patients stratified by IFX were not different. When stratified by indication, refractory disease was associated with higher preoperative IFX use (IFX use 55% vs. no IFX use 28%, p=0.027). No specific indication was associated with increased reoperation rates. CONCLUSION: Pediatric CD patients treated with preoperative IFX undergo intestinal resection with primary anastomosis with acceptable morbidity. The heterogeneous approach to medical management underscores the need for guidelines to direct treatment. PMID- 26944182 TI - Hospital preference of laparoscopic versus open appendectomy: Effects on outcomes in simple and complicated appendicitis. AB - PURPOSE: We hypothesize that laparoscopic (LA) or open appendectomy (OA) outcomes are associated with hospital procedure preference. METHODS: We queried Kids' Inpatient Database (1997-2009) for simple (ICD-9-CM 540.9) and complicated (540.0, 540.1) appendicitis. RESULTS: On PS-matched analysis of simple appendicitis (91,118 LA vs. 97,496 OA), LA had increased transfusion (1.7) rates, but lower wound infection (0.6) and perforation/laceration (0.3) rates. LA had shorter length of stay (LOS; 1.7 vs. 2.1days), but higher total charges (TC; 19,501 vs. 13,089 USD) and cost (7121 vs. 5968) vs. OA. For complicated appendicitis (28,793 LA vs. 30,782 OA), LA had increased nausea/vomiting rates (1.9), but lower wound infection (0.5) and transfusion (0.6) rates. LA had shorter LOS (5.1 vs. 5.9), but higher TC (32,251 vs. 28,209). MVA demonstrated shorter LOS (0.9) for LA at laparoscopic-preferring hospitals vs. open-preferring hospitals for simple appendicitis. For complicated appendicitis, higher complication rates (1.1) were associated with OA at laparoscopic-preferring hospitals. Laparoscopic-preferring hospitals had higher TC in all categories. CONCLUSION: Complications and resource utilization for appendicitis are associated with surgical technique and hospital procedure preference. Laparoscopic-preferring hospitals had higher complication rates with OA for complicated appendicitis and higher charges regardless of appendectomy technique or appendicitis type. LEVEL OF EVIDENCE: 2c, Outcomes Research. PMID- 26944183 TI - The 47th annual meeting of the Canadian Association of Pediatric Surgeons. PMID- 26944184 TI - Laparoscopy in pediatric surgery: Implementation in Canada and supporting evidence. AB - BACKGROUND/PURPOSE: The purpose of this study was to assess the diffusion of laparoscopy usage in Canadian pediatric centers and the relationship between uptake of laparoscopic surgery and the level of evidence supporting its use. METHODS: National data on four pediatric laparoscopic operations (appendectomy, pyloromyotomy, cholecystectomy, splenectomy) were analyzed using the Canadian Institute for Health Information Discharge Database (2002-2013). The highest level of evidence to support the use of each procedure was identified from Cochrane, Embase, and Pubmed databases. Chi-square test for trend was used to determine significance and time to plateau. RESULTS: There were 28,843 operations (open: 12,048; laparoscopic: 16,795). Use of laparoscopic procedures increased over time (p<0.0001). A plateau was reached for cholecystectomy (2006), splenectomy (2007), and appendectomy (2012), but not for pyloromyotomy. Laparoscopic pyloromyotomy in 2013 remains less diffused than the other procedures (p<0.0001). Laparoscopic appendectomy and pyloromyotomy are supported by level-1a evidence in children, whereas cholecystectomy and splenectomy are supported by level-1a evidence in adults but level-3 in children. CONCLUSIONS: In Canada, it has taken a long time to reach high-level implementation of laparoscopic surgery in children. Laparoscopic cholecystectomy first reached plateau, whereas laparoscopic pyloromyotomy continues to increase but remains low despite high level of evidence in support of its usage compared to open surgery. PMID- 26944185 TI - Formula-feeding and hypertrophic pyloric stenosis: is there an association? A case-control study. AB - BACKGROUND: The etiology of infantile hypertrophic pyloric stenosis (HPS) is not fully understood. The objective of this study was to determine whether formula feeding is associated with increased incidence. METHODS: This case-control study included HPS cases and controls admitted between 1992 and 2012. Demographic data including feeding method were collected from patient charts and analyzed. RESULTS: We identified 882 HPS cases and 955 controls. The highest incidence of HPS presentation was in summer (P=0.0028). Infants with HPS were more likely to have been exclusively formula-fed, have a family history of HPS, and be male compared to infants in the control group (P<0.001); they were also more likely to live in rural areas, although not significantly so. After adjusting for family history, sex, place of residence, and season of presentation, exclusively formula fed infants were 1.36 times more likely to develop HPS compared with exclusively breastfed infants (RR 1.36, 95% CI 1.18-1.57, P<0.005). CONCLUSIONS: Formula feeding is associated with significantly increased risk of HPS. Further investigation may help to determine the components of formula that simulate hypertrophy of the pylorus muscle, or the components of breast milk that are protective, as well as other influencing factors. LEVEL OF EVIDENCE: 3b. PMID- 26944186 TI - Vasa previa: diagnosis and management. AB - BACKGROUND: Vasa previa is a rare condition that is associated with a high rate of fetal or neonatal death when not diagnosed antenatally. The majority of available studies are either small, do not include antepartum data, limited to single institutions, or are biased by inclusion of patients from registries and online vasa previa support groups. OBJECTIVE: The purpose of this study was to investigate the diagnostic and management strategies for this potentially catastrophic entity and to describe further maternal and placental risk factors that may aid in the establishment of a screening protocol for vasa previa. STUDY DESIGN: This was a retrospective multicenter descriptive study that included all pregnancies that were complicated by vasa previa that delivered between January 1, 2000, and December 31, 2012. Nine maternal fetal medicine practices and the hospitals in which they practice participated in data collection of diagnosis, treatment, and maternal-neonatal outcomes. RESULTS: Sixty-eight pregnancies were identified that included the diagnosis of vasa previa or "possible vasa previa" either in the ultrasound record or in the hospital record at the time of delivery. Four cases (5.8%) appeared to resolve on repeat ultrasound examination. Fifteen of the 64 cases that were suspected of having vasa previa could not be verified or were not documented at delivery. Of the remaining 49 cases, where vasa previa was documented, 47 cases (96%) were diagnosed by ultrasound scanning antenatally. Known risk factors for vasa previa were present in 41 of 47 cases (87%). Of the 49 cases, 41 were delivered by planned cesarean delivery at a mean gestational age of 34.7 weeks, and 8 cases required emergent cesarean delivery at a mean gestational age of 34.6 weeks (range, 32.4-36.0 weeks gestation). Seven of these emergent cesarean deliveries had been diagnosed previously; 1 case had not. All of the emergent cesarean deliveries were for vaginal bleeding; 1 case was also for a concerning fetal heart rate, but only 1 of the known cases had a documented ruptured fetal vessel. None of these cases were found to have cervical shortening before the onset of bleeding. One of the undiagnosed cases resulted in a ruptured fetal vessel and a baby with no heart beat at birth who survived but had periventricular leukomalacia at 1 month of age with mild white-matter atrophy. Of the remaining neonates in this group, there were no deaths and no major complications beyond mild respiratory distress syndrome in 9 cases. There were no other major neonatal complications, which included no cases of periventricular leukomalacia, neonatal sepsis, necrotizing enterocolitis, or any grade of intraventricular hemorrhage in the confirmed cases of vasa previa. CONCLUSION: This study confirms most current recommendations that include risk based ultrasound screening, early hospitalization at 30-34 weeks gestation, antenatal corticosteroids at 30-32 weeks gestation, and elective delivery at 33 34 weeks gestation. Thus, with these recommendations for current identification and management of vasa previa in this series of geographically diverse mostly private practice maternal fetal medicine practices, we have confirmed recent reports that show a dramatic improvement in neonatal survival and complications compared with earlier reports. PMID- 26944187 TI - Self-reported human papillomavirus vaccination does not have an impact on the risk for high-grade cervical intraepithelial neoplasia among women referred for colposcopy. PMID- 26944188 TI - Transcutaneous Vagus Nerve Stimulation (taVNS) for Major Depressive Disorder: An Open Label Proof-of-Concept Trial. PMID- 26944190 TI - Circadian modulation of proteasome activity and accumulation of oxidized protein in human embryonic kidney HEK 293 cells and primary dermal fibroblasts. AB - The circadian system orchestrates the timing of physiological processes of an organism living in daily environmental changes. Disruption of circadian rhythmicity has been shown to result in increased oxidative stress and accelerated aging. The circadian regulation of antioxidant defenses suggests that other redox homeostasis elements such as oxidized protein degradation by the proteasome, could also be modulated by the circadian clock. Hence, we have investigated whether proteasome activities and oxidized protein levels would exhibit circadian rhythmicity in synchronized cultured mammalian cells and addressed the mechanisms underlying this process. Using synchronized human embryonic kidney HEK 293 cells and primary dermal fibroblasts, we have shown that the levels of carbonylated protein and proteasome activity vary rhythmically following a 24h period. Such a modulation of proteasome activity is explained, at least in part, by the circadian expression of both Nuclear factor (erythroid derived 2)-like 2 (Nrf2) and the proteasome activator PA28alphabeta. HEK 293 cells showed an increased susceptibility to oxidative stress coincident with the circadian-dependent lower activity of the proteasome. Finally, in contrast to young fibroblasts, no circadian modulation of the proteasome activity and carbonylated protein levels was evidenced in senescent fibroblasts. This paper reports a novel role of the circadian system for regulating proteasome function. In addition, the observation that proteasome activity is modulated by the circadian clock opens new avenues for both the cancer and the aging fields, as exemplified by the rhythmic resistance of immortalized cells to oxidative stress and loss of rhythmicity of proteasome activity in senescent fibroblasts. PMID- 26944189 TI - Increasing extracellular H2O2 produces a bi-phasic response in intracellular H2O2, with peroxiredoxin hyperoxidation only triggered once the cellular H2O2 buffering capacity is overwhelmed. AB - Reactive oxygen species, such as H2O2, can damage cells but also promote fundamental processes, including growth, differentiation and migration. The mechanisms allowing cells to differentially respond to toxic or signaling H2O2 levels are poorly defined. Here we reveal that increasing external H2O2 produces a bi-phasic response in intracellular H2O2. Peroxiredoxins (Prx) are abundant peroxidases which protect against genome instability, ageing and cancer. We have developed a dynamic model simulating in vivo changes in Prx oxidation. Remarkably, we show that the thioredoxin peroxidase activity of Prx does not provide any significant protection against external rises in H2O2. Instead, our model and experimental data are consistent with low levels of extracellular H2O2 being efficiently buffered by other thioredoxin-dependent activities, including H2O2-reactive cysteines in the thiol-proteome. We show that when extracellular H2O2 levels overwhelm this buffering capacity, the consequent rise in intracellular H2O2 triggers hyperoxidation of Prx to thioredoxin-resistant, peroxidase-inactive form/s. Accordingly, Prx hyperoxidation signals that H2O2 defenses are breached, diverting thioredoxin to repair damage. PMID- 26944192 TI - Rapid emergence of high-level tigecycline resistance in Escherichia coli strains harbouring blaNDM-5 in vivo. AB - Tigecycline (TIG) resistance is a growing concern because this antibiotic is regarded as one of the last resorts to treat infections caused by multidrug resistant and extensively drug-resistant (XDR) bacteria. Information regarding TIG-resistant Escherichia coli isolates is scarce. In this study, we report the emergence of high-level TIG resistance in a longitudinal series of XDR E. coli isolates collected during TIG treatment. Whole-genome sequencing was performed for six E. coli strains harbouring bla(NDM-5) and genomic comparison revealed two amino acid substitutions. Mutation in rpsJ could be a significant factor conferring TIG resistance in these isolates. The fitness cost of TIG resistance in resistant strains was evaluated by determining the relative growth rate, indicating that TIG resistance reduced fitness by ca. 7%. This study is the first report to demonstrate high-level TIG resistance in E. coli in vivo. In addition, we report the first treatment-emergent minimum inhibitory concentration (MIC) development of TIG from 1mg/L to 64 mg/L in E. coli. Clinicians should be aware of the risk of an increase in the MIC of TIG under therapy. PMID- 26944191 TI - MnTE-2-PyP reduces prostate cancer growth and metastasis by suppressing p300 activity and p300/HIF-1/CREB binding to the promoter region of the PAI-1 gene. AB - To improve radiation therapy-induced quality of life impairments for prostate cancer patients, the development of radio-protectors is needed. Our previous work has demonstrated that MnTE-2-PyP significantly protects urogenital tissues from radiation-induced damage. So, in order for MnTE-2-PyP to be used clinically as a radio-protector, it is fully necessary to explore the effect of MnTE-2-PyP on human prostate cancer progression. MnTE-2-PyP inhibited prostate cancer growth in the presence and absence of radiation and also inhibited prostate cancer migration and invasion. MnTE-2-PyP altered p300 DNA binding, which resulted in the inhibition of HIF-1beta and CREB signaling pathways. Accordingly, we also found that MnTE-2-PyP reduced the expression of three genes regulated by HIF 1beta and/or CREB: TGF-beta2, FGF-1 and PAI-1. Specifically, MnTE-2-PyP decreased p300 complex binding to a specific HRE motif within the PAI-1 gene promoter region, suppressed H3K9 acetylation, and consequently, repressed PAI-1 expression. Mechanistically, less p300 transcriptional complex binding is not due to the reduction of binding between p300 and HIF-1/CREB transcription factors, but through inhibiting the binding of HIF-1/CREB transcription factors to DNA. Our data provide an in depth mechanism by which MnTE-2-PyP reduces prostate cancer growth and metastasis, which validates the clinical use of MnTE-2-PyP as a radio-protector to enhance treatment outcomes in prostate cancer radiotherapy. PMID- 26944193 TI - Improvement of the in vitro safety profile and cytoprotective efficacy of amifostine against chemotherapy by PEGylation strategy. AB - Amifostine, an organic thiophosphate prodrug, has been clinically utilized for selective protection of normal tissues with high expression of alkaline phosphatase from oxidative damage elicited by chemotherapy or radiotherapy. However, the patients receiving amifostine suffer from severe dose-dependent adverse effects. Strategies for improvement of the protective efficacy and toxicity profile of amifostine are urgently required. Here we constructed a PEGylated amifostine (PEG-amifostine) through conjugation of amifostine to the 4 arm PEG (5000 Da) by a mild one-step reaction. The relatively large PEG amifostine molecules clustered into spherical nanoparticles, resulting in distinct hydrolysis properties, cell uptake profile and antioxidative activity compared with the free small molecules. PEGylation prolonged the hydrolysis time of amifostine, providing sustained transformation to its functional metabolites. PEG-amifostine could be internalized into cells and translocated to acidic organelles in a time-dependent manner. The intrinsic cytotoxicity of amifostine, which is related to the reductive reactivity of its metabolites and their ability to diffuse readily, was attenuated after PEGylation. This modification impeded the interaction between free sulfhydryls and functional biomolecules, providing PEG-amifostine with an improved safety profile in vitro. Moreover, PEG-amifostine showed higher efficiency in the elimination of reactive oxygen species and prevention of cisplatin-induced cytotoxicity compared with free amifostine. Overall, our study for the first time developed a PEGylated form of amifostine which significantly improved the efficacy and decreased the adverse effects of this antioxidant in vitro with great promise for clinical translation. In vivo study is urgently needed to confirm and redeem the cytoprotective effects of the PEG-amifostine in chemotherapy. PMID- 26944196 TI - Certifying the medical necessity for skilled nursing and skilled therapy services. PMID- 26944194 TI - Aryl hydrocarbon receptor (AHR) regulation of L-Type Amino Acid Transporter 1 (LAT-1) expression in MCF-7 and MDA-MB-231 breast cancer cells. AB - The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that is regulated by environmental toxicants that function as AHR agonists such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). L-Type Amino Acid Transporter 1 (LAT1) is a leucine transporter that is overexpressed in cancer. The regulation of LAT1 by AHR in MCF-7 and MDA-MB-231 breast cancer cells (BCCs) was investigated in this report. Ingenuity pathway analysis (IPA) revealed a significant association between TCDD-regulated genes (TRGs) and molecular transport. Overlapping the TCDD-RNA-Seq dataset obtained in this study with a published TCDD-ChIP-seq dataset identified LAT1 as a primary target of AHR dependent TCDD induction. Short interfering RNA (siRNA)-directed knockdown of AHR confirmed that TCDD-stimulated increases in LAT1 mRNA and protein required AHR expression. TCDD-stimulated increases in LAT1 mRNA were also inhibited by the AHR antagonist CH-223191. Upregulation of LAT1 by TCDD coincided with increases in leucine uptake by MCF-7 cells in response to TCDD. Chromatin immunoprecipitation quantitative PCR (ChIP-qPCR) assays revealed increases in AHR, AHR nuclear translocator (ARNT) and p300 binding and histone H3 acetylation at an AHR binding site in the LAT1 gene in response to TCDD. In MCF-7 and MDA-MB-231 cells, endogenous levels of LAT1 mRNA and protein were reduced in response to knockdown of AHR expression. Knockdown experiments demonstrated that proliferation of MCF-7 and MDA-MB-231 cells is dependent on both LAT1 and AHR. Collectively, these findings confirm the dependence of cancer cells on leucine uptake and establish a mechanism for extrinsic and intrinsic regulation of LAT1 by AHR. PMID- 26944197 TI - Knee osteoarthritis pain following medial meniscectomy in the nonhuman primate. AB - OBJECTIVE: A number of promising compounds developed for osteoarthritic pain have failed to demonstrate clinical efficacy. To enhance preclinical translational research for osteoarthritis, a model of knee osteoarthritis pain was developed in Macaca fascicularis and the effects of two distinct pharmacological classes of drugs were tested on pain-related behavior. DESIGN: Behavioral assessments were developed specifically for the macaque. Baseline knee pressure threshold and weight bearing were assessed prior to a unilateral medial meniscectomy (MMx). Fifteen days following MMx, macaques underwent a once daily exercise regimen for 36 days. Sixty-seven days following MMx, macaques were assigned to one of three treatment groups (n = 3/group), either non-steroidal anti-inflammatory drug (NSAID) diclofenac, NK1 receptor antagonist aprepitant or vehicle, and treated for 5 days. Animals were tested 3-4 h after p.o. dosing and testing was performed blinded. Treatment utilized a crossover design-each animal received all treatments-and a 9-day washout period was utilized between treatments. RESULTS: Vehicle-treated macaques consistently demonstrated decreased ipsilateral pressure threshold ("hyperalgesia") and decreased weight bearing. While diclofenac increased weight bearing and pressure threshold, full attenuation of pain was not obtained. No significant improvement of either knee pressure or weight bearing was observed with aprepitant. CONCLUSIONS: Unilateral MMx in the macaque evoked pain-related behaviors and knee joint pathology reminiscent of osteoarthritis. The behavioral endpoints were sensitive to NSAID treatment but not sensitive to NK1 receptor block, which parallel clinical findings. The current macaque osteoarthritis model could be used to test potential treatments for osteoarthritis pain. PMID- 26944198 TI - Genetic Mutation that May Contribute to Failure of Prolapse Surgery in White Women: A Case-Control Study. AB - OBJECTIVE: To identify a potential genetic basis for early failure after prolapse surgery. DESIGN: Case-control study (Canadian Task Force classification II). SETTING: This study was carried out in 1 academic community medical center referral practice, and all patients had surgery at 1 of 2 hospitals. PATIENTS: Ten women with early, multicompartment prolapse recurrence after robotic sacrocolpopexy compared with 40 control subjects with known success after the same procedure. INTERVENTIONS: Patients were treated with robotic sacrocolpopexy. MEASUREMENTS AND MAIN RESULTS: DNA was isolated and initially genotyped on a single nucleotide polymorphism (SNP) array to direct more detailed exome analyses. Exome sequences were mapped to the Human Genome Reference Sequence (GRCh37), and variants were compared between groups and to participants in the 1000 Genomes Project. Statistical analyses were performed using a software package commonly used in genetics research. TaqMan assay was used for verification, and p values were adjusted using the false discovery rate. Demographics of groups were compared using chi(2), Mann-Whitney U, and t tests. A SNP [rs171821] located near the ZFYVE16 gene was associated with patients but not control subjects, and the false discovery rate-adjusted p value was .046 (odds ratio, 45.2; 95% confidence interval, 5.06-403). Exome analyses of this gene yielded another SNP [rs249038 (G/A)] in 6 of 10 patients and none of the control subjects (p = .02). This SNP causes a heterozygous missense mutation of glycine to serine predicted to be deleterious by the Protein Variation Effect Analyzer and was also very rare among participants in the 1000 Genomes Project (p < .001). CONCLUSIONS: Two SNPs located near the ZFYVE16 gene on chromosome 5 may have played a role in the early, multicompartment sacrocolpopexy failure experienced by our patients. (www.clinicaltrials.gov Identifier: NCT01614587). PMID- 26944195 TI - Deciphering the Structure and Function of Nuclear Pores Using Single-Molecule Fluorescence Approaches. AB - Due to its central role in macromolecular trafficking and nucleocytoplasmic information transfer, the nuclear pore complex (NPC) has been studied in great detail using a wide spectrum of methods. Consequently, many aspects of its architecture, general function, and role in the life cycle of a cell are well understood. Over the last decade, fluorescence microscopy methods have enabled the real-time visualization of single molecules interacting with and transiting through the NPC, allowing novel questions to be examined with nanometer precision. While initial single-molecule studies focused primarily on import pathways using permeabilized cells, it has recently proven feasible to investigate the export of mRNAs in living cells. Single-molecule assays can address questions that are difficult or impossible to answer by other means, yet the complexity of nucleocytoplasmic transport requires that interpretation be based on a firm genetic, biochemical, and structural foundation. Moreover, conceptually simple single-molecule experiments remain technically challenging, particularly with regard to signal intensity, signal-to-noise ratio, and the analysis of noise, stochasticity, and precision. We discuss nuclear transport issues recently addressed by single-molecule microscopy, evaluate the limits of existing assays and data, and identify open questions for future studies. We expect that single-molecule fluorescence approaches will continue to be applied to outstanding nucleocytoplasmic transport questions, and that the approaches developed for NPC studies are extendable to additional complex systems and pathways within cells. PMID- 26944199 TI - Gut Microbiota-Induced Immunoglobulin G Controls Systemic Infection by Symbiotic Bacteria and Pathogens. AB - The gut microbiota is compartmentalized in the intestinal lumen and induces local immune responses, but it remains unknown whether the gut microbiota can induce systemic response and contribute to systemic immunity. We report that selective gut symbiotic gram-negative bacteria were able to disseminate systemically to induce immunoglobulin G (IgG) response, which primarily targeted gram-negative bacterial antigens and conferred protection against systemic infections by E. coli and Salmonella by directly coating bacteria to promote killing by phagocytes. T cells and Toll-like receptor 4 on B cells were important in the generation of microbiota-specific IgG. We identified murein lipoprotein (MLP), a highly conserved gram-negative outer membrane protein, as a major antigen that induced systemic IgG homeostatically in both mice and humans. Administration of anti-MLP IgG conferred crucial protection against systemic Salmonella infection. Thus, our findings reveal an important function for the gut microbiota in combating systemic infection through the induction of protective IgG. PMID- 26944201 TI - MAP Kinase Inhibition Promotes T Cell and Anti-tumor Activity in Combination with PD-L1 Checkpoint Blockade. AB - Targeted inhibition of mitogen-activated protein kinase (MAPK) kinase (MEK) can induce regression of tumors bearing activating mutations in the Ras pathway but rarely leads to tumor eradication. Although combining MEK inhibition with T-cell directed immunotherapy might lead to more durable efficacy, T cell responses are themselves at least partially dependent on MEK activity. We show here that MEK inhibition did profoundly block naive CD8(+) T cell priming in tumor-bearing mice, but actually increased the number of effector-phenotype antigen-specific CD8(+) T cells within the tumor. MEK inhibition protected tumor-infiltrating CD8(+) T cells from death driven by chronic TCR stimulation while sparing cytotoxic activity. Combining MEK inhibition with anti-programmed death-ligand 1 (PD-L1) resulted in synergistic and durable tumor regression even where either agent alone was only modestly effective. Thus, despite the central importance of the MAP kinase pathway in some aspects of T cell function, MEK-targeted agents can be compatible with T-cell-dependent immunotherapy. PMID- 26944200 TI - The Vaccine Adjuvant Chitosan Promotes Cellular Immunity via DNA Sensor cGAS STING-Dependent Induction of Type I Interferons. AB - The cationic polysaccharide chitosan is an attractive candidate adjuvant capable of driving potent cell-mediated immunity, but the mechanism by which it acts is not clear. We show that chitosan promotes dendritic cell maturation by inducing type I interferons (IFNs) and enhances antigen-specific T helper 1 (Th1) responses in a type I IFN receptor-dependent manner. The induction of type I IFNs, IFN-stimulated genes and dendritic cell maturation by chitosan required the cytoplasmic DNA sensor cGAS and STING, implicating this pathway in dendritic cell activation. Additionally, this process was dependent on mitochondrial reactive oxygen species and the presence of cytoplasmic DNA. Chitosan-mediated enhancement of antigen specific Th1 and immunoglobulin G2c responses following vaccination was dependent on both cGAS and STING. These findings demonstrate that a cationic polymer can engage the STING-cGAS pathway to trigger innate and adaptive immune responses. PMID- 26944203 TI - Testing an anxiety process biomarker: Generalisation from an auditory to a visual stimulus. AB - We have previously reported an anxiolytic-sensitive human EEG biomarker, goal conflict specific rhythmicity (GCSR), using an auditory stop signal task (SST). Here we test if a visual SST could allow testing of GCSR in people with hearing impairments. The visual SST produced GCSR within the 4-12Hz band at the expected right frontal site, F8, but to a lesser extent than in previous auditory SSTs, possibly due to response instability. Positive GCSR appeared to be reduced by both buspirone (10mg), and triazolam (0.25mg), as previously; negative GCSR was increased. However, neuroticism, trait anxiety and Behavioural Inhibition System scores failed to show consistent positive correlations with GCSR, contrary to prediction. The visual SST generates anxiolytic-sensitive GCSR; but its limited extent and unexpected personality correlations suggest it needs further development to obtain quantitative equivalence with the auditory SST. PMID- 26944202 TI - Independent Roles of Switching and Hypermutation in the Development and Persistence of B Lymphocyte Memory. AB - Somatic hypermutation (SHM) and class-switch recombination (CSR) increase the affinity and diversify the effector functions of antibodies during immune responses. Although SHM and CSR are fundamentally different, their independent roles in regulating B cell fate have been difficult to uncouple because a single enzyme, activation-induced cytidine deaminase (encoded by Aicda), initiates both reactions. Here, we used a combination of Aicda and antibody mutant alleles that separate the effects of CSR and SHM on polyclonal immune responses. We found that class-switching to IgG1 biased the fate choice made by B cells, favoring the plasma cell over memory cell fate without significantly affecting clonal expansion in the germinal center (GC). In contrast, SHM reduced the longevity of memory B cells by creating polyreactive specificities that were selected against over time. Our data define the independent contributions of SHM and CSR to the generation and persistence of memory in the antibody system. PMID- 26944204 TI - Response to letter 'A cumulative meta-analysis on the association of toll-like receptor 4 gene Asp299Gly polymorphism with cancer risk'. PMID- 26944206 TI - Bilateral solar retinopathy. Autofluorescence and optical coherence tomography. AB - CASE REPORT: A 33-year-old man referred decreased bilateral visual acuity for five years, with no history of interest. Military profession and probably previous sun exposure. Focal pigmented lesions in the macular area of the fundus were observed, with impairment of the photoreceptor layer in the fovea, observed by optical coherence tomography (OCT), in various sectors of the fovea. DISCUSSION: Solar retinopathy is associated with professions at risk of sun exposure. The diagnosis is based on autofluorescence and macular OCT, that later will provide key data to establish the cause. PMID- 26944207 TI - Usefulness of optical coherence tomography in the diagnosis of the vitreous cavity dislocated by an iridociliary cyst. PMID- 26944208 TI - "Poppers maculopathy?" in Spain. A new ophthalmological disease. AB - INTRODUCTION: The term "poppers" refers to products made of volatile alkyl nitrites used for recreational practices. CLINICAL CASE: 40 year old man reported blurred vision in both eyes and photophobia, and admitted regular use of "poppers". Best corrected visual acuity was 0.63/1 in both eyes. Bilateral yellowish vitelliform macular lesions were present in both eyes in the funduscopy, as well as a disruption of the IS/OS line in the optical coherence tomography. DISCUSSION: This is the first case of "poppers maculopathy" registered in Spain. Clinical findings and symptoms are similar to previous reported cases. PMID- 26944205 TI - Calcium signaling in skeletal muscle development, maintenance and regeneration. AB - Skeletal muscle-specific stem cells are pivotal for tissue development and regeneration. Muscle plasticity, inherent in these processes, is also essential for daily life activities. Great advances and efforts have been made in understanding the function of the skeletal muscle-dedicated stem cells, called muscle satellite cells, and the specific signaling mechanisms that activate them for recruitment in the repair of the injured muscle. Elucidating these signaling mechanisms may contribute to devising therapies for muscular injury or disease. Here we review the studies that have contributed to our understanding of how calcium signaling regulates skeletal muscle development, homeostasis and regeneration, with a focus on the calcium dynamics and calcium-dependent effectors that participate in these processes. PMID- 26944209 TI - Biomarkers of lipid peroxidation in the aqueous humor of primary open-angle glaucoma patients. AB - OBJECTIVE: To investigate the lipid peroxidation (PEROX) processes in primary open-angle glaucoma (POAG) patients, and whether this mechanism may be related to disease progression. MATERIAL AND METHODS: A prospective, observational, cross sectional, non-experimental, and analytical study was conducted on a case and a comparison group, consisting of 175 surgical patients divided into: 1) POAG group (GG; n=88) and 2) comparison group of patients with cataracts (CG; n=87). Demographic data, patient characteristics, lifestyle data, as well as ophthalmological examination were registered in an Excel spreadsheet. Biochemical data were obtained by processing the aqueous humor collected at the beginning of surgery. Determination of malondialdehyde/thiobarbituric acid reactive substances (MDA/TBARS) and total antioxidant activity (AAO) was assayed using enzymatic colorimetric methods in the aqueous humor samples. Statistical analysis was performed using SPSS 15.0 software. RESULTS: Aqueous humor MDA/TBARS levels were significantly higher (P<.001) and the AAO significantly lower (P<.001) in the GG than in the GC. The MDA/TBARS directly correlated with intraocular pressure (IOP) values and the cup-to-disc ratio (CDR). Decreased AAO activity correlated inversely with IOP and CDR. Differences between groups were noticeably higher in the GG as regards obesity, alcohol consumption, anxiety, depression, and sedentary lifestyle. In the multivariate analysis, the variables that showed a better predictive ability were: MDA/TBARS, PIO, AAO, CDR, and depression. CONCLUSIONS: The POAG patients have a PEROX background that is reflected in the aqueous humor by variations in MDA/TBARS and AAO. Moreover, both the MDA/TBARS and AAO correlated with IOP values and the CDR. We propose that determination of MDA/TBARS and AAO in the aqueous humor of POAG patients can be used as biomarkers for monitoring the disease, as well the changes in lifestyle and other related risk factors. PMID- 26944210 TI - Cotreatment with Smac mimetics and demethylating agents induces both apoptotic and necroptotic cell death pathways in acute lymphoblastic leukemia cells. AB - Treatment resistance in acute lymphoblastic leukemia (ALL) is often caused by defects in programmed cell death, e.g. by overexpression of Inhibitor of Apoptosis (IAP) proteins. Here, we report that small-molecule Smac mimetics (i.e. BV6, LCL161, birinapant) that neutralize x-linked IAP (XIAP), cellular IAP (cIAP)1 and cIAP2 cooperate with demethylating agents (i.e. 5-azacytidine (5AC) or 5-aza-2'-deoxycytidine (DAC)) to induce cell death in ALL cells. Molecular studies reveal that induction of cell death is preceded by BV6-mediated depletion of cIAP1 protein and involves tumor necrosis factor (TNF)alpha autocrine/paracrine signaling, since the TNFalpha-blocking antibody Enbrel significantly reduces BV6/5AC-induced cell death. While BV6/5AC cotreatment induces caspase-3 activation, the broad-range caspase inhibitor N benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (zVAD.fmk) only partly rescues ALL cells from BV6/5AC-induced cell death. This indicates that BV6/5AC cotreatment engages non-apoptotic cell death upon caspase inhibition. Indeed, genetic silencing of key components of necroptosis such as Receptor-Interacting Protein (RIP)3 or mixed lineage kinase domain-like (MLKL) in parallel with administration of zVAD.fmk provides a significantly better protection against BV6/5AC-induced cell death compared to the use of zVAD.fmk alone. Similarly, concomitant administration of pharmacological inhibitors of necroptosis (i.e. necrostatin-1s, GSK'872, dabrafenib, NSA) together with zVAD.fmk is superior in rescuing cells from BV6/5AC-induced cell death compared to the use of zVAD.fmk alone. These findings demonstrate that in ALL cells BV6/5AC-induced cell death is mediated via both apoptotic and necroptotic pathways. Importantly, BV6/5AC cotreatment triggers necroptosis in ALL cells that are resistant to apoptosis due to caspase inhibition. This opens new perspectives to overcome apoptosis resistance with important implications for the development of new treatment strategies for ALL. PMID- 26944212 TI - Differences in Access to and Preferences for Using Patient Portals and Other eHealth Technologies Based on Race, Ethnicity, and Age: A Database and Survey Study of Seniors in a Large Health Plan. AB - BACKGROUND: Patients are being encouraged to go online to obtain health information and interact with their health care systems. However, a 2014 survey found that less than 60% of American adults aged 65 and older use the Internet, with much lower usage among black and Latino seniors compared with non-Hispanic white seniors, and among older versus younger seniors. OBJECTIVE: Our aims were to (1) identify race/ethnic and age cohort disparities among seniors in use of the health plan's patient portal, (2) determine whether race/ethnic and age cohort disparities exist in access to digital devices and preferences for using email- and Web-based modalities to interact with the health care system, (3) assess whether observed disparities in preferences and patient portal use are due simply to barriers to access and inability to use the Internet, and (4) learn whether older adults not currently using the health plan's patient portal or website have a potential interest in doing so in the future and what kind of support might be best suited to help them. METHODS: We conducted two studies of seniors aged 65-79 years. First, we used administrative data about patient portal account status and utilization in 2013 for a large cohort of English-speaking non Hispanic white (n=183,565), black (n=16,898), Latino (n=12,409), Filipino (n=11,896), and Chinese (n=6314) members of the Kaiser Permanente Northern California health plan. Second, we used data from a mailed survey conducted in 2013-2014 with a stratified random sample of this population (final sample: 849 non-Hispanic white, 567 black, 653 Latino, 219 Filipino, and 314 Chinese). These data were used to examine race/ethnic and age disparities in patient portal use and readiness and preferences for using digital communication for health-related purposes. RESULTS: Adults aged 70-74 and 75-79 were significantly less likely than 65-69 year olds to be registered to use the patient portal, and among those registered, to have used the portal to send messages, view lab test results, or order prescription refills. Across all age groups, non-Hispanic whites and Chinese seniors were significantly more likely than black, Latino, and Filipino seniors to be registered and to have performed these actions. The survey found that black, Latino, and Filipino seniors and those 75 years old and older were significantly less likely to own digital devices (e.g., computers, smartphones), use the Internet and email, and be able and willing to use digital technology to perform health care-related tasks, including obtaining health information, than non-Hispanic whites, Chinese, and younger seniors (aged 65-69), respectively. The preference for using non-digital modalities persisted even among Internet users. CONCLUSIONS: Health plans, government agencies, and other organizations that serve diverse groups of seniors should include social determinants such as race/ethnicity and age when monitoring trends in eHealth to ensure that eHealth disparities do not induce greater health status and health care disparities between more privileged and less privileged groups. PMID- 26944213 TI - Microvascular decompression for elderly patients with trigeminal neuralgia. AB - Microvascular decompression (MVD) has been demonstrated to be an excellent surgical treatment approach in younger patients with trigeminal neuralgia (TN). However, it is not clear whether there are additional morbidity and mortality risks for MVD in the elderly population. We performed a systematic literature review using six electronic databases for studies that compared outcomes for MVD for TN in elderly (cut-off ?60, 65, 70years) versus younger populations. Outcomes examined included success rate, deaths, strokes, thromboembolism, meningitis, cranial nerve deficits and cerebrospinal fluid leaks. There were 1524 patients in the elderly cohort and 3488 patients in the younger cohort. There was no significant difference in success rates in elderly versus younger patients (87.5% versus 84.8%; P=0.47). However, recurrence rates were lower in the elderly (11.9% versus 15.6%; P=0.03). The number of deaths in the elderly cohort was higher (0.9% versus 0.1%; P=0.003). Rates of stroke (2.5% versus 1%) and thromboembolism (1.1% versus 0%) were also higher for elderly TN patients. No differences were found for rates of meningitis, cranial nerve deficits or cerebrospinal fluid leak. MVD remains an effective and reasonable strategy in the elderly population. There is evidence to suggest that rates of complications such as death, stroke, and thromboembolism may be significantly higher in the elderly population. The presented results may be useful in the decision-making process for MVD in elderly patients with TN. PMID- 26944214 TI - Infiltrating spinal cord astrocytomas: Epidemiology, diagnosis, treatments and future directions. AB - Spinal cord gliomas, consisting mostly of ependymomas and astrocytomas, are rare entities. Of the gliomas, infiltrating astrocytomas are particularly challenging entities to treat due to their invasive nature. Surgical resection is oftentimes not possible without subjecting patients to permanent neurological deficits because of the difficulty in establishing clear tissue planes. As more is learned about the molecular genetics, genomics, and biology of these tumors, it is becoming more apparent that there are important differences between these tumors and their more common intracranial counterparts. There also appears to be important clinical differences between low-grade and high-grade astrocytomas. A multidisciplinary approach is needed to optimize the treatment of these difficult tumors. PMID- 26944211 TI - No further increase in the parent reported prevalence of allergies in Bavarian preschool children: Results from three cross-sectional studies. AB - BACKGROUND: After three decades of an increase in the prevalence of asthma and allergies, new findings show a plateau in the prevalence of industrialized nations. The objective of this study was to determine whether there was a change in the parent reported prevalence of asthma and allergies among Bavarian preschool children since 2004. METHODS: A parent questionnaire was administered as part of the Bavarian school entrance examination in three cross-sectional studies from 2004/2005, 2006/2007 and 2012/2013. The questionnaire included items on allergy testing history, identified allergens, symptoms (e.g. wheezing, itchy eyes, rash), medically diagnosed asthma, hay fever and atopic dermatitis. Logistic regression was performed to observe time patterns and adjust for risk factors. RESULTS: Data were available for 6350 (2004/2005), 6483 (2006/2007) and 5052 (2012/2013) individuals. Symptoms and diseases were more frequent in boys, except for allergies which affect the skin. From 2004 to 2012 the parent reported prevalence of asthma (2.6% to 2.8%), hay fever (4.7% to 4.0%) and atopic dermatitis (12.4% to 11.1%) either remained quite stable or decreased not significantly. CONCLUSIONS: Results from these three cross-sectional surveys of parent reports suggest that the parent reported prevalences of asthma and allergies are quite stable with small fluctuations since 2004 for Bavarian preschool children. Future research is needed to determine if this trend will continue. PMID- 26944215 TI - Optimising treatment strategies in spinal ependymoma based on 20years of experience at a single centre. AB - Spinal ependymomas are rare tumours, with total resection favoured where possible. Several case series assessing the outcome following neurosurgical treatment for spinal ependymoma advocate the usage of adjuvant radiotherapy in cases of subtotal resection, or in unencapsulated tumours. We assessed the outcome of 61 consecutive cases of spinal ependymoma in a single centre over a 20year period using a variety of outcome measures. Sex distribution was equal, with a mean age at surgery of 43.6years (range 5-76years). Overall, most tumours occurred in the lumbosacral region (70.5%), with fewer in the thoracic (27.9%) and cervical regions (18.0%). Myxopapillary features were seen in 41.0% of tumours, and were more common when occurring in the lumbar region (51.2%). Gross total resection was achieved in 52.5%, subtotal resection in 37.7% and biopsy alone in 9.8% of patients and 31.1% received adjuvant radiotherapy. Two-thirds of patients achieved an excellent post-operative neurological outcome (Frankel grade E). Tumour recurrence was rare. Gross total resection and good preoperative neurological condition were most strongly predictive of good outcome. Post operative radiotherapy did not seem to confer survival benefit in this case series, even in cases of incomplete resection, leading us to question its utility for all cases of spinal cord ependymoma. PMID- 26944216 TI - The many faces of the flavivirus NS1 protein offer a multitude of options for inhibitor design. AB - The flavivirus non-structural protein, NS1, is an unusual viral gene product. Despite the recent unveiling of its atomic structure (Akey et al., 2014), and a growing list of host molecules with which it has been found associated, the primary function of NS1 remains elusive. It assumes many diverse roles including direct participation in the flaviviral replication complex and virion maturation. In its secreted form it is a hexameric lipoparticle that is involved in systemic immune and endothelial cell modulation. In this review we highlight recent advances in elucidating the molecular mechanisms underpinning NS1 function and present the current state of play and some future prospects for NS1 targeted antiviral strategies. This article forms part of a symposium on flavivirus drug discovery in Antiviral Research. PMID- 26944218 TI - Cognition without Cortex. AB - Assumptions on the neural basis of cognition usually focus on cortical mechanisms. Birds have no cortex, but recent studies in parrots and corvids show that their cognitive skills are on par with primates. These cognitive findings are accompanied by neurobiological discoveries that reveal avian and mammalian forebrains are homologous, and show similarities in connectivity and function down to the cellular level. But because birds have a large pallium, but no cortex, a specific cortical architecture cannot be a requirement for advanced cognitive skills. During the long parallel evolution of mammals and birds, several neural mechanisms for cognition and complex behaviors may have converged despite an overall forebrain organization that is otherwise vastly different. PMID- 26944217 TI - Mast cell stabilizers obviate high fat diet-induced renal dysfunction in rats. AB - The present study investigated the infiltration of mast cells into the kidney tissue and the preventive role of mast cell stabilizers against high fat diet (HFD)-induced renal injury in rats. The animals were fed on HFD (30% fat) for 12 consecutive weeks to induce renal injury. The HFD-induced obesity was assessed by calculating obesity index, adiposity index, and estimation of total cholesterol, triglycerides, and high density lipoproteins in plasma. The renal dysfunction was evaluated by measuring creatinine clearance, blood urea nitrogen, uric acid, electrolytes and microproteinuria. The oxidative stress in renal tissues was determined by myeloperoxidase activity, thiobarbituric acid reactive substances, superoxide anion generation and reduced glutathione level. The systolic blood pressure (SBP) was monitored using non-invasive blood pressure measuring apparatus. Histamine and hydroxyproline contents were quantified in renal tissues. Gross histopathological changes, mast cell density and collagen deposition in the renal tissue was determined by means of histopathology. The mast cell stabilizers, sodium cromoglycate and ketotifen were administered daily for 12 weeks. The HFD fed rats demonstrated significant increase in lipid profile, kidney injury with marked increase in renal oxidative stress, SBP, mast cell density, histamine content and hydroxyproline content that was attenuated by sodium cromoglycate and ketotifen treatment. Hence, the novel findings of this investigation suggest that HFD induced mast cells infiltration into kidney tissue seems to play an important role in renal pathology, and treatment with mast cell stabilizers serves as potential therapy in management of HFD induced renal dysfunction in rats. PMID- 26944219 TI - Object Domain and Modality in the Ventral Visual Pathway. AB - The nature of domain-specific organization in higher-order visual cortex (ventral occipital temporal cortex, VOTC) has been investigated both in the case of visual experience deprivation and of modality of stimulation in sighted individuals. Object domain interacts in an intriguing and revelatory way with visual experience and modality of stimulation: selectivity for artifacts and scene domains is largely immune to visual deprivation and is multi-modal, whereas selectivity for animate items in lateral posterior fusiform gyrus is present only with visual stimulation. This domain-by-modality interaction is not readily accommodated by existing theories of VOTC representation. We conjecture that these effects reflect a distinction between the visual features that characterize different object domains and their interaction with different types of downstream computational systems. PMID- 26944220 TI - Is Birdsong More Like Speech or Music? AB - Music and speech share many acoustic cues but not all are equally important. For example, harmonic pitch is essential for music but not for speech. When birds communicate is their song more like speech or music? A new study contrasting pitch and spectral patterns shows that birds perceive their song more like humans perceive speech. PMID- 26944222 TI - [Local experience with the use of direct-acting oral anticoagulants in patients with atrial fibrillation and significant valvulopathy or biological prosthesis]. PMID- 26944221 TI - The Anatomy of Suffering: Understanding the Relationship between Nociceptive and Empathic Pain. AB - Pain features centrally in numerous illnesses and generates enormous public health costs. Despite its ubiquity, the psychological and neurophysiological nature of pain remains controversial. Here, we survey one controversy in particular: the relation between nociceptive pain, which is somatic in origin, and empathic pain, which arises from observing others in pain. First, we review evidence for neural overlap between nociceptive and empathic pain and what this overlap implies about underlying mental representations. Then, we propose a framework for understanding the nature of the psychological and neurophysiological correspondence across these types of 'pain'. This framework suggests new directions for research that can better identify shared and dissociable representations underlying different types of distress, and can inform theories about the nature of pain. PMID- 26944223 TI - Application of Ce-TZP/Al2O3 nanocomposite to the framework of an implant-fixed complete dental prosthesis and a complete denture. AB - PATIENT: A 69-year-old Japanese male visited Nihon University Dental Hospital for refabrication of his mandibular implant-supported complete fixed prosthesis (ISCFPD) and maxillary complete denture, which had been fabricated 15 years previously. In this case, Ce-TZP/Al2O3 nanocomposite (Ce-TZP/A) was applied to the framework of the mandibular ISCFPD and maxillary complete denture. Three years after deliver of the framework, no particularly notable biological or prosthetic complications were observed, and a high level of patient satisfaction had been achieved. DISCUSSION: Conventional ISCFPD frameworks were fabricated by casting gold alloys; however, with the recent advancement of CAD/CAM technology, titanium (Ti) or yttria tetragonal zirconia polycrystal (Y-TZP) frameworks have become more common. In contrast, the main fabrication method for Ti or Co-Cr frameworks of removable dental prostheses has shifted from the conventional casting method to CAD/CAM fabrication. Ce-TZP/A, which was chosen as the framework material this time, shows higher strength and greater toughness than Y TZP. However, since it has a low light-transmitting property and exhibits an opaque white color, the range of its application in fixed prostheses, particularly in the esthetic area, is limited. CONCLUSION: We described a case in which Ce-TZP/A was applied to the frameworks of a mandibular ISCFPD and a maxillary complete denture. No particularly notable biological or prosthetic complications were observed in the mandibular ISCFPD or the maxillary complete denture, and a high level of patient satisfaction was achieved. Medium- and long term observations with a greater number of cases are essential to obtain information concerning various phenomena related to this procedure. PMID- 26944224 TI - Phosphate excretion is decreased in older cardiac patients with normal kidney function: an emerging dietary risk factor? AB - Serum phosphate independently predicts cardiovascular events and mortality. Sixteen healthy adults and 9 adults with cardiovascular disease (CVD) ingested 500 mg of sodium phosphate after an over-night fast. In control subjects, the urine phosphate/creatinine ratio was significantly higher at 2 h (3.12 +/- 1.02) than at baseline (1.98 +/- 0.58, p < 0.001) but no change was observed in CVD patients. Decreased postprandial urinary excretion of phosphate could accelerate vascular calcification and may be an under-recognized risk factor for CVD. PMID- 26944225 TI - Dietary glycemic index and glycemic load and their relationship to cardiovascular risk factors in Chinese children. AB - The purpose of this study was to examine the cross-sectional associations between dietary glycemic index (GI) and glycemic load (GL) and cardiovascular disease (CVD) risk factors in Chinese children. A total of 234 Chinese schoolchildren aged 8-11 years in Guangdong participated in the study. Dietary intake was assessed via a 3-day dietary record. Seven established cardiovascular indicators were analyzed in this study: fasting plasma glucose (FPG), fasting triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), systolic blood pressure, and diastolic blood pressure. Higher dietary GI was significantly associated with higher TG levels (P = 0.037) and lower HDL-C levels (P = 0.005) after adjusting for age, sex, nutritional intake, physical activity, and body mass index z score. LDL-C was found to differ across tertiles of dietary GL. The middle tertile tended to show the highest level of LDL-C. TC, FPG, and blood pressure were independent of both dietary GI and GL. Our findings suggest that higher dietary GI is differentially associated with some CVD risk factors, including lower HDL-C and higher TG, in school-aged children from south China. PMID- 26944226 TI - Infertility and recurrent miscarriage with complex II deficiency-dependent mitochondrial oxidative stress in animal models. AB - Oxidative stress is associated with some forms of both male and female infertility. However, there is insufficient knowledge of the influence of oxidative stress on the maintenance of a viable pregnancy, including pregnancy complications and fetal development. There are a number of animal models for understanding age-dependent decrease of reproductive ability and diabetic embryopathy, especially abnormal spermatogenesis, oogenesis and embryogenesis with mitochondrial dysfunctions. Several important processes occur in mitochondria, including ATP synthesis, calcium ion storage, induction of apoptosis and production of reactive oxygen species (ROS). These events have different effects on the several aspects of reproductive function. Tet-mev-1 conditional transgenic mice, developed after studies with the mev-1 mutant of the nematode C. elegans, offer the ability to carefully regulate expression of doxycycline-induced mutated SDHC(V69E) levels and hence modulate endogenous oxidative stress. The mev-1 models have served to illuminate the effects of complex II deficiency-dependent mitochondrial ROS production, although interestingly they maintain normal mitochondrial and intracellular ATP levels. In this review, the reproductive dysfunctions are presented focusing on fertility potentials in each gamete, early embryogenesis, maternal conditions with placental function and neonatal development. PMID- 26944227 TI - Circulating leptin and adiponectin concentrations in healthy exceptional longevity. AB - People reaching exceptional longevity free of major age-related diseases represent the paradigm of successful aging. Adipose tissue function declines as we age, potentially resulting in changes of circulating adipokines (e.g., leptin and adiponectin). Here, we measured circulating levels of leptin and adiponectin in healthy centenarians (n=81; 100-104 years) and younger elderly controls (n=46; 70-80 years). Centenarians had significant higher serum levels of leptin compared with controls (p<0.001), whereas no significant differences were observed for adiponectin. Further research including also other blood variables will be needed to elucidate whether high leptin levels could serve as a hallmark of healthy exceptional longevity. PMID- 26944229 TI - How does consumer knowledge affect environmentally sustainable choices? Evidence from a cross-country latent class analysis of food labels. AB - This paper examines consumers' knowledge and lifestyle profiles and preferences regarding two environmentally labeled food staples, potatoes and ground beef. Data from online choice experiments conducted in Canada and Germany are analyzed through latent class choice modeling to identify the influence of consumer knowledge (subjective and objective knowledge as well as usage experience) on environmentally sustainable choices. We find that irrespective of product or country under investigation, high subjective and objective knowledge levels drive environmentally sustainable food choices. Subjective knowledge was found to be more important in this context. Usage experience had relatively little impact on environmentally sustainable choices. Our results suggest that about 20% of consumers in both countries are ready to adopt footprint labels in their food choices. Another 10-20% could be targeted by enhancing subjective knowledge, for example through targeted marketing campaigns. PMID- 26944228 TI - Eat, play, view, sleep: Exploring Mexican American mothers' perceptions of decision making for four behaviors associated with childhood obesity risk. AB - OBJECTIVE: This mixed methods study sought to understand who makes decisions about whether preschool-aged Mexican American children engage in eating, outdoor play, sleep, and screen time behaviors. METHODS: Forty Mexican American mothers of children ages 3-4 participated in two interviews, during which both closed- and open-ended questions elicited perceptions of who made decisions for the four behaviors, as well as who was present, mealtime rules, and food choice values. Interviews were transcribed, coded for emergent themes, and compared across participants. RESULTS: Participants generally perceived themselves to be primary decision makers for all four behaviors; however, food decisions often seemed to be made collaboratively with the child. Fathers were most likely to participate in evening television decisions. Other family members were rarely mentioned. Selecting foods that children liked was a strong food choice value, while cost was rarely mentioned. Participants appeared to have low perceived control over their child's behaviors relative to their perceived roles in decision making. CONCLUSIONS: Mothers may be the primary audience for obesity prevention messages for preschool-aged, Mexican American children; however, health promotion programs may need to increase mothers' awareness of their control over children's behaviors. Understanding how children's behaviors are regulated is an important aspect of obesity prevention for low-income, Mexican American children. PMID- 26944230 TI - MY APPROACH to chest pain with normal coronary arteries. PMID- 26944231 TI - MY APPROACH to early repolarization syndrome. PMID- 26944232 TI - Increasing the availability of nerve transfer for cervical spinal cord injury. PMID- 26944233 TI - A convenient flap for repairing the donor area of a distally based sural flap: Gastrocnemius perforator island flap. AB - OBJECTIVE: The reconstruction of complex lower leg and foot defects is difficult for plastic surgeons. The distally based sural flap (DBSF) is an option for non free flap lower leg reconstruction. However, one of the major drawbacks of the DBSF is its aesthetically non-acceptable donor area scarring. MATERIALS AND METHODS: Eight patients (six men and two women) who had lower leg or foot defects were evaluated in this study. We used an ipsilateral or cross-leg DBSF to repair the defect. A medial or lateral gastrocnemius perforator island flap (average size 8.1 * 6.1 cm) was used to cover the donor area of the DBSF in a two-stage operative procedure. RESULTS: We did not observe any complications with the gastrocnemius perforator island flap. Two patients had local infections under the DBSF and were treated with bacteria-specific antibiotherapy. All patients were followed up for 1 year postoperatively. The donor areas of the distally based sural flaps were aesthetically acceptable. Patients gained ambulatory status during the follow-up period. CONCLUSIONS: Reconstruction of the donor area of a DBSF with a gastrocnemius perforator island flap allows for more acceptable aesthetics and functional results than do other reconstructive procedures. PMID- 26944235 TI - Ximenia caffra Sond. (Ximeniaceae) in sub-Saharan Africa: A synthesis and review of its medicinal potential. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Ximenia caffra Sond. (Ximeniaceae), commonly known as "sour plum" is traditionally used, both topically and orally to treat a wide range of human diseases and ailments such as wounds, sexually transmitted infections (STIs), infertility, stomach ache, fever, eye problems, diarrhoea, bilharzia, menorrhagia, malaria, intestinal worms, impotence and coughs. The bark and fruits are used by small-scale farmers as ethnoveterinary medicine to treat dermatophilosis, foot rot, saddle sores and control ectoparasites. Oil from X. caffra seed is traditionally used as a moisturiser, soap and shampoo for dry, fragile and damaged hair. AIM OF THE REVIEW: The aim of this study was to comprehensively summarize the research that has been done on the botany, ethnomedicinal uses, phytochemistry and biological activities of X. caffra in different locations throughout its geographical range in the sub-Saharan African region so as to understand its importance and potential in primary healthcare systems. MATERIALS AND METHODS: This study was carried out using a comprehensive and systematic literature search on the ethnomedicinal uses, phytochemistry and biological activities of the species throughout its distributional range. Literature sources included papers published in international journals, reports from international, regional and national organizations, conference papers, books and theses. PubMed and Scopus, search engines such as Google Scholar and online collection ScienceDirect were used. RESULTS: This study showed that X. caffra is used as traditional medicine in 83.3% of the countries in tropical Africa where it is indigenous. A total of 65 human and animal ailments and diseases are recorded for X. caffra, with a high degree of consensus for wounds, sexually transmitted infections (STIs), infertility, stomach ache, fever, eye problems, diarrhoea, bilharzia, menorrhagia, malaria, intestinal worms and coughs. Phytochemical investigation of X. caffra revealed that the species has various compounds including flavonoids, phenols, phytosterols, tannins and fatty acids. Different plant parts, aqueous and organic extracts exhibited anti-amoebic, antibacterial, antifungal, anti-inflammatory, antioxidant, antiparasitic, antiproliferative, HIV-1 reverse transcriptase (RT) inhibitory, insecticidal, non mutagenic and toxicity activities. CONCLUSION: In this review, the ethnomedicinal uses, phytochemistry, biological activities and toxicity of different extracts and compounds of X. caffra have been summarized. Although many of the ethnomedicinal uses of X. caffra have been validated by phytochemical and pharmacological studies, there are still some gaps where current knowledge could be improved. There are very few to nil experimental animal studies, randomized clinical trials and target-organ toxicity studies involving X. caffra and its derivatives that have been carried out so far. At the present moment, there is not sufficient evidence to interpret the specific chemical mechanisms associated with some of the documented biological activities of the species. Therefore, future studies should identify the bioactive components, details of the molecular modes or mechanisms of action, pharmacokinetics and physiological pathways for specific bioactives of X. caffra. PMID- 26944234 TI - A Comparison of Natural Language Processing Methods for Automated Coding of Motivational Interviewing. AB - Motivational interviewing (MI) is an efficacious treatment for substance use disorders and other problem behaviors. Studies on MI fidelity and mechanisms of change typically use human raters to code therapy sessions, which requires considerable time, training, and financial costs. Natural language processing techniques have recently been utilized for coding MI sessions using machine learning techniques, rather than human coders, and preliminary results have suggested these methods hold promise. The current study extends this previous work by introducing two natural language processing models for automatically coding MI sessions via computer. The two models differ in the way they semantically represent session content, utilizing either 1) simple discrete sentence features (DSF model) and 2) more complex recursive neural networks (RNN model). Utterance- and session-level predictions from these models were compared to ratings provided by human coders using a large sample of MI sessions (N=341 sessions; 78,977 clinician and client talk turns) from 6 MI studies. Results show that the DSF model generally had slightly better performance compared to the RNN model. The DSF model had "good" or higher utterance-level agreement with human coders (Cohen's kappa>0.60) for open and closed questions, affirm, giving information, and follow/neutral (all therapist codes); considerably higher agreement was obtained for session-level indices, and many estimates were competitive with human-to-human agreement. However, there was poor agreement for client change talk, client sustain talk, and therapist MI-inconsistent behaviors. Natural language processing methods provide accurate representations of human derived behavioral codes and could offer substantial improvements to the efficiency and scale in which MI mechanisms of change research and fidelity monitoring are conducted. PMID- 26944236 TI - Ethnobotany, phytochemistry and neuropharmacological effects of Petiveria alliacea L. (Phytolaccaceae): A review. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Petiveria alliacea L. commonly grows in the tropical regions of the Americas such as the Amazon forest, Central America, Caribbean islands and Mexico, as well as specific regions of Africa. Popularly known by several different names including 'mucuracaa', 'guine' and 'pipi', P. alliacea has been used in traditional medicine for the treatment of various central nervous system (CNS) disorders, such as anxiety, pain, memory deficits and seizures, as well as for its anaesthetic and sedative properties. Furthermore, the use of this species for religious ceremonies has been reported since the era of slavery in the Americas. Therefore, the present review aims to provide a critical and comprehensive overview of the ethnobotany, phytochemistry and pharmacological properties of P. alliacea, focusing on CNS pharmacological effects, in order to identify scientific lacunae and to open new perspectives for future research. MATERIALS AND METHODS: A literature search was performed on P. alliacea using ethnobotanical textbooks, published articles in peer-reviewed journals, unpublished materials, government survey reports and scientific databases such as PubMed, Scopus, Web of Science, Science Direct and Google Scholar. The Plant List, International Plant Name Index and Kew Botanical Garden Plant name databases were used to validate the scientific names. RESULTS AND DISCUSSION: Crude extracts, fractions and phytochemical constituents isolated from various parts of P. alliacea show a wide spectrum of neuropharmacological activities including anxiolytic, antidepressant, antinociceptive and anti seizure, and as cognitive enhancers. Phytochemistry studies of P. alliacea indicate that this plant contains a diversity of biologically active compounds, with qualitative and quantitative variations of the major compounds depending on the region of collection and the harvest season, such as essential oil (Petiverina), saponinic glycosides, isoarborinol-triterpene, isoarborinol acetate, isoarborinol-cinnamate, steroids, alkaloids, flavonoids and tannins. Root chemical analyses have revealed coumarins, benzyl-hydroxy-ethyl-trisulphide, benzaldehyde, benzoic acid, dibenzyl trisulphide, potassium nitrate, b sitosterol, isoarborinol, isoarborinol-acetate, isoarborinol-cinnamate, polyphenols, trithiolaniacine, glucose and glycine. CONCLUSIONS: Many traditional uses of P. alliacea have now been validated by modern pharmacology research. The available data reviewed here support the emergence of P. alliacea as a potential source for the treatment of different CNS disorders including anxiety, depression, pain, epilepsy and memory impairments. However, further studies are certainly required to improve the knowledge about the mechanisms of action, toxicity and efficacy of the plant as well as about its bioactive compounds before it can be approved in terms of its safety for therapeutic applications. PMID- 26944238 TI - Wild food plants used in traditional vegetable mixtures in Italy. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Mixtures of wild food plants, part of the Mediterranean diet, have potential benefits for their content in bioactive compounds, minerals and fibers. In Italy, wild plants are still consumed in various ways, for their taste, effects on health and nutritional value. In this paper, we provide a list of wild plants used in vegetable mixtures, indicating their phytochemical and nutritional profile, highlighting those not yet studied. AIM OF THE STUDY: We provide a first complete review of traditional uses of wild food plants used as vegetables and their preparations (e.g., salads, soups, rustic pies). We also highlight their phytochemical constituents. MATERIALS AND METHODS: We carried out an extensive literature review of ethnobotanical publications from 1894 to date for finding plants used in traditional vegetable mixtures. We also performed an online search for scientific papers providing the phytochemical profile of plants that were cited at least twice in recipes found in the literature. RESULTS: We list a total of 276 wild taxa used in traditional vegetable mixtures, belonging to 40 families. Among these, the most represented are Asteraceae (88), Brassicaceae (33), Apiaceae (21), Amaranthaceae (12). Many plants are cited in many recipes across several Italian regions. Among the most cited plant we note: Reichardia picroides (L.) Roth, Sanguisorba minor Scop., Taraxacum campylodes G. E. Haglund, Urtica dioica L. Tuscany is the region with the highest number of food recipes that incorporate wild plants used as vegetables. We also list the phytochemical constituents and some pharmacological activities of the plants cited at least twice. Finally, we discuss topics such as the taste of plants used in the recipes. CONCLUSIONS: Nineteen edible wild plants, such as Asparagus albus L., Campanula trachelium L., Hypochaeris laevigata (L.) Benth. & Hook f., Phyteuma spicatum L., Scolymus grandiflorus Desf., are not yet studied as regards their phytochemical and nutritional profile. Some plants should be avoided due to the presence of toxic compounds such as Adenostyles alliariae (Gouan) A. Kern or Ranunculus repens L. PMID- 26944237 TI - Anti-inflammatory and antinociceptive activities of Croton urucurana Baillon bark. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Croton urucurana (Euphorbiaceae) is popularly used in Brazil to treat inflammatory processes, pain, and gastric ulcers. AIM OF STUDY: To evaluate the anti-inflammatory and antinociceptive properties of the methanol extract from the bark of C. urucurana (MECu) in mice and identify its chemical constituents. MATERIALS AND METHODS: The extract was characterized by UHPLC-DAD-ESI-Q-TOF-MS/MS. Extract doses of 25, 100, and 400mg/kg were employed in the biological assays. Evaluation of anti-inflammatory activity was based on paw edema and leukocyte recruitment into the peritoneal cavity of mice, both induced by carrageenan. Abdominal writhing caused by acetic acid and duration of formalin-induced paw-licking were the models employed to evaluate antinociceptive activity. RESULTS: Ten compounds were identified in the extract: (+) gallocatechin (1), procyanidin B3 (2), (+)-catechin (3), (-)-epicatechin (4), tembetarine (5), magnoflorine (6), taspine (7), methyl-3-oxo-12-epi-barbascoate (8), methyl-12-epi-barbascoate (9), and hardwickiic acid (10). This is the first report of compounds 2, 4, 6, 7, and 10 in C. urucurana and compound 5 in the genus Croton. In addition to inhibiting paw edema and leukocyte recruitment (particularly of polymorphonuclear cells) into the peritoneal cavity of mice, MECu reduced the number of abdominal writhings induced by acetic acid and the duration of formalin-induced paw licking. CONCLUSIONS: The methanol extract of C. urucurana bark exhibited anti-inflammatory and antinociceptive properties, corroborating its use in folk medicine. These effects may be related to the presence of diterpenes, alkaloids, and flavonoids. PMID- 26944239 TI - Nonobstructive Hypertrophic Cardiomyopathy: Overlooked But Not Forgotten. PMID- 26944240 TI - The Natural History of Nonobstructive Hypertrophic Cardiomyopathy. AB - OBJECTIVE: To describe the survival of a large nonobstructive hypertrophic cardiomyopathy (NO-HCM) cohort and to identify risk factors for increased mortality in this population. PATIENTS AND METHODS: Patients were identified from the Mayo Clinic HCM database from January 1, 1975, through November 30, 2006, for this retrospective observational study. Patients with resting or provocable left ventricular outflow tract gradients were excluded. Echocardiographic, clinical, and genetic data were compared between subgroups, and survival data were compared with expected population rates. RESULTS: A total of 706 patients with NO-HCM were identified. During median follow-up of 5 years (mean, 7 years), there were 208 deaths. Overall survival was no different than expected compared with age- and sex-matched white US population mortality rates (P=.77). Independent predictors of death were age at diagnosis, "burned out" HCM, and history of transient ischemic attack or stroke; use of an implantable cardioverter defibrillator (ICD) was inversely related to death. After exclusion of patients with an ICD, there was no difference in survival compared with age- and sex- matched individuals (P=.39); age, previous transient ischemic attack/stroke, and burned out HCM were predictors of death. CONCLUSION: In this cohort, patients with NO-HCM had similar survival rates as age- and sex-matched white US population mortality rates. Although use of an ICD was inversely related to death, no differences in overall survival were seen after those patients were excluded. Burned out HCM was independently associated with an increased risk of death, identifying a subset of patients who may benefit from more aggressive therapies. PMID- 26944242 TI - Central Neuropathic Pain Syndromes. AB - Chronic pain is common in patients with neurologic complications of a central nervous system insult such as stroke. The pain is most commonly musculoskeletal or related to obligatory overuse of neurologically unaffected limbs. However, neuropathic pain can result directly from the central nervous system injury. Impaired sensory discrimination can make it challenging to differentiate central neuropathic pain from other pain types or spasticity. Central neuropathic pain may also begin months to years after the injury, further obscuring recognition of its association with a past neurologic injury. This review focuses on unique clinical features that help distinguish central neuropathic pain. The most common clinical central pain syndromes-central poststroke pain, multiple sclerosis related pain, and spinal cord injury-related pain-are reviewed in detail. Recent progress in understanding of the pathogenesis of central neuropathic pain is reviewed, and pharmacological, surgical, and neuromodulatory treatments of this notoriously difficult to treat pain syndrome are discussed. PMID- 26944241 TI - Outcome of Whole Exome Sequencing for Diagnostic Odyssey Cases of an Individualized Medicine Clinic: The Mayo Clinic Experience. AB - OBJECTIVE: To describe the experience and outcome of performing whole-exome sequencing (WES) for resolution of patients on a diagnostic odyssey in the first 18 months of an individualized medicine clinic (IMC). PATIENTS AND METHODS: The IMC offered WES to physicians of Mayo Clinic practice for patients with suspected genetic disease. DNA specimens of the proband and relatives were submitted to WES laboratories. We developed the Genomic Odyssey Board with multidisciplinary expertise to determine the appropriateness for IMC services, review WES reports, and make the final decision about whether the exome findings explain the disease. This study took place from September 30, 2012, to March 30, 2014. RESULTS: In the first 18 consecutive months, the IMC received 82 consultation requests for patients on a diagnostic odyssey. The Genomic Odyssey Board deferred 7 cases and approved 75 cases to proceed with WES. Seventy-one patients met with an IMC genomic counselor. Fifty-one patients submitted specimens for WES testing, and the results have been received for all. There were 15 cases in which a diagnosis was made on the basis of WES findings; thus, the positive diagnostic yield of this practice was 29%. The mean cost per patient for this service was approximately $8000. Medicaid supported 27% of the patients, and 38% of patients received complete or partial insurance coverage. CONCLUSION: The significant diagnostic yield, moderate cost, and notable health marketplace acceptance for WES compared with conventional genetic testing make the former method a rational diagnostic approach for patients on a diagnostic odyssey. PMID- 26944243 TI - Head and Neck Squamous Cell Carcinoma: Update on Epidemiology, Diagnosis, and Treatment. AB - Squamous cell carcinoma arises from multiple anatomic subsites in the head and neck region. The risk factors for development of cancers of the oral cavity, oropharynx, hypopharynx, and larynx include tobacco exposure and alcohol dependence, and infection with oncogenic viruses is associated with cancers developing in the nasopharynx, palatine, and lingual tonsils of the oropharynx. The incidence of human papillomavirus-associated oropharyngeal cancer is increasing in developed countries, and by 2020, the annual incidence could surpass that of cervical cancer. The treatment for early-stage squamous cell cancers of the head and neck is generally single modality, either surgery or radiotherapy. The treatment for locally advanced head and neck cancers is multimodal, with either surgery followed by adjuvant radiation or chemoradiation as indicated by pathologic features or definitive chemoradiation. For recurrent disease that is not amenable to a salvage local or regional approach and for metastatic disease, chemotherapy with or without a biological agent is indicated. To date, molecular testing has not influenced treatment selection in head and neck cancer. This review will focus on the changing epidemiology, advances in diagnosis, and treatment options for squamous cell cancers of the head and neck, along with data on risk stratification specific to oropharyngeal cancer, and will highlight the direction of current trials. PMID- 26944244 TI - Lowering the High Cost of Cancer Drugs--II. PMID- 26944245 TI - Lowering the High Cost of Cancer Drugs--I. PMID- 26944246 TI - Lowering the High Cost of Cancer Drugs--III. PMID- 26944247 TI - Lowering the High Cost of Cancer Drugs--IV. PMID- 26944248 TI - In Reply--Lowering the High Cost of Cancer Drugs. PMID- 26944249 TI - Plummer-Vinson Syndrome. PMID- 26944250 TI - Diagnosing a Kidney Tumor. PMID- 26944252 TI - Otto Wichterle--Inventor of the First Soft Contact Lenses. PMID- 26944253 TI - Evaluation of the motion of lung tumors during stereotactic body radiation therapy (SBRT) with four-dimensional computed tomography (4DCT) using real-time tumor-tracking radiotherapy system (RTRT). AB - PURPOSE: We investigated the usefulness of four-dimensional computed tomography (4DCT) performed before stereotactic body radiation therapy (SBRT) in determining the internal margins for peripheral lung tumors. METHODS AND MATERIALS: The amplitude of the movement of a fiducial marker near a lung tumor measured using the maximum intensity projection (MIP) method in 4DCT imaging was acquired before the SBRT (AmpCT) and compared with the mean amplitude of the marker movement during SBRT (Ampmean) and with the maximum amplitude of the marker movement during SBRT (Ampmax) using a real-time tumor-tracking radiotherapy (RTRT) system with 22 patients. RESULTS: There were no significant differences between the means of the Ampmean and the means of the AmpCT in all directions (LR, P = 0.45; CC, P = 0.80; AP, P = 0.65). The means of the Ampmax were significantly larger than the means of the AmpCT in all directions (LR, P < 0.01; CC, P = 0.03; AP, P < 0.01). In the lower lobe, the mean difference of the AmpCT from the mean of the Ampmax was 5.7 +/- 8.0 mm, 12.5 +/- 16.7 mm, and 6.8 +/- 8.5 mm in the LR, CC, and AP directions, respectively. CONCLUSIONS: Acquiring 4DCT MIP images before the SBRT treatment is useful to establish the mean amplitude for a patient during SBRT but it underestimates the maximum amplitude during actual SBRT. Caution must be paid to determine the margin with the 4DCT especially for tumors at the lower lobe where it is of the potentially greatest benefit. PMID- 26944255 TI - Job strain and resting heart rate: a cross-sectional study in a Swedish random working sample. AB - BACKGROUND: Numerous studies have reported an association between stressing work conditions and cardiovascular disease. However, more evidence is needed, and the etiological mechanisms are unknown. Elevated resting heart rate has emerged as a possible risk factor for cardiovascular disease, but little is known about the relation to work-related stress. This study therefore investigated the association between job strain, job control, and job demands and resting heart rate. METHODS: We conducted a cross-sectional survey of randomly selected men and women in Vastra Gotalandsregionen, Sweden (West county of Sweden) (n = 1552). Information about job strain, job demands, job control, heart rate and covariates was collected during the period 2001-2004 as part of the INTERGENE/ADONIX research project. Six different linear regression models were used with adjustments for gender, age, BMI, smoking, education, and physical activity in the fully adjusted model. Job strain was operationalized as the log-transformed ratio of job demands over job control in the statistical analyses. RESULTS: No associations were seen between resting heart rate and job demands. Job strain was associated with elevated resting heart rate in the unadjusted model (linear regression coefficient 1.26, 95 % CI 0.14 to 2.38), but not in any of the extended models. Low job control was associated with elevated resting heart rate after adjustments for gender, age, BMI, and smoking (linear regression coefficient -0.18, 95 % CI -0.30 to -0.02). However, there were no significant associations in the fully adjusted model. CONCLUSIONS: Low job control and job strain, but not job demands, were associated with elevated resting heart rate. However, the observed associations were modest and may be explained by confounding effects. PMID- 26944254 TI - Bleeding, thrombosis, and anticoagulation in myeloproliferative neoplasms (MPN): analysis from the German SAL-MPN-registry. AB - BACKGROUND: Patients with Ph-negative myeloproliferative neoplasms (MPN), such as polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), are at increased risk for thrombosis/thromboembolism and major bleeding. Due to the morbidity and mortality of these events, antiplatelet and/or anticoagulant agents are commonly employed as primary and/or secondary prophylaxis. On the other hand, disease-related bleeding complications (i.e., from esophageal varices) are common in patients with MPN. This analysis was performed to define the frequency of such events, identify risk factors, and assess antiplatelet/anticoagulant therapy in a cohort of patients with MPN. METHODS: The MPN registry of the Study Alliance Leukemia is a non-interventional prospective study including adult patients with an MPN according to WHO criteria (2008). For statistical analysis, descriptive methods and tests for significant differences as well as contingency tables were used to identify the odds of potential risk factors for vascular events. RESULTS: MPN subgroups significantly differed in sex distribution, age at diagnosis, blood counts, LDH levels, JAK2V617F positivity, and spleen size (length). While most thromboembolic events occurred around the time of MPN diagnosis, one third of these events occurred after that date. Splanchnic vein thrombosis was most frequent in post-PV-MF and MPN-U patients. The chance of developing a thromboembolic event was significantly elevated if patients suffered from post-PV-MF (OR 3.43; 95% CI = 1.39-8.48) and splenomegaly (OR 1.76; 95% CI = 1.15-2.71). Significant odds for major bleeding were previous thromboembolic events (OR = 2.71; 95% CI = 1.36-5.40), splenomegaly (OR = 2.22; 95% CI 1.01-4.89), and the administration of heparin (OR = 5.64; 95% CI = 1.84-17.34). Major bleeding episodes were significantly less frequent in ET patients compared to other MPN subgroups. CONCLUSIONS: Together, this report on an unselected "real-world" cohort of German MPN patients reveals important data on the prevalence, diagnosis, and treatment of thromboembolic and major bleeding complications of MPN. PMID- 26944256 TI - The CG balloon is an innovative condom balloon tamponade for the management of postpartum hemorrhage in low-resource settings. PMID- 26944257 TI - Exploring the spatiotemporal drivers of malaria elimination in Europe. AB - BACKGROUND: Europe once had widespread malaria, but today it is free from endemic transmission. Changing land use, agricultural practices, housing quality, urbanization, climate change, and improved healthcare are among the many factors thought to have played a role in the declines of malaria seen, but their effects and relative contributions have rarely been quantified. METHODS: Spatial datasets on changes in climate, wealth, life expectancy, urbanization, and land use trends over the past century were combined with datasets depicting the reduction in malaria transmission across 31 European countries, and the relationships were explored. Moreover, the conditions in current malaria-eliminating countries were compared with those in Europe at the time of declining transmission and elimination to assess similarities. RESULTS/CONCLUSIONS: Indicators relating to socio-economic improvements such as wealth, life expectancy and urbanization were strongly correlated with the decline of malaria in Europe, whereas those describing climatic and land use changes showed weaker relationships. Present-day malaria-elimination countries have now arrived at similar socio-economic indicator levels as European countries at the time malaria elimination was achieved, offering hope for achievement of sustainable elimination. PMID- 26944258 TI - 'The money is important but all women anyway go to hospital for childbirth nowadays' - a qualitative exploration of why women participate in a conditional cash transfer program to promote institutional deliveries in Madhya Pradesh, India. AB - BACKGROUND: In 2005-06, only 39 % of Indian women delivered in a health facility. Given that deliveries at home increase the risk of maternal mortality, it was in this context in 2005, that the Indian Government implemented the Janani Suraksha Yojana program that incentivizes poor women to give birth in a health facility by providing them with a cash transfer upon discharge. JSY helped raise institutional delivery to 74 % in the eight years since its implementation. Despite the success of the JSY in raising institutional delivery proportions, the large number of beneficiaries (105 million), and the cost of the program, there have been few qualitative studies exploring why women participate (or not) in the program. The objective of this paper was to explore this. METHODS: In March 2013, we conducted 24 individual in-depth interviews with women who delivered within the previous 12 months in two districts of Madhya Pradesh, India. Qualitative framework analysis was used to analyze the data. RESULTS: Our findings suggest that women's increased participation in the program reflect a shift in the social norm. Drivers of the shift include social pressure from the Accredited Social Health Activist (ASHA) to deliver in a health facility, and a growing individual perception of the importance for 'safe' and 'easy' delivery which was most likely an expression of the new social norm. While the incentive was an important influence on many women's choices, others did not perceive it as an important consideration in their decision to deliver in a health facility. Many women reported procedural difficulties to receive the benefit. Retaining the cash incentive was also an issue due to out-of-pocket expenditures incurred at the facility. Non-participation was often unintentional and caused by personal circumstances, poor geographic access or driven by a perception of poor quality of care provided in program facilities. CONCLUSIONS: In summary, while the cash incentive was important for some women in facilitating an institutional birth, the shift in social norm (possibly in part facilitated by the program) and therefore their own perceptions has played a major role in them giving birth in facilities. PMID- 26944259 TI - The relationship between sodium concentrations in spot urine and blood pressure increases: a prospective study of Japanese general population: the Circulatory Risk in Communities Study (CIRCS). AB - BACKGROUND: Although several cross-sectional and intervention studies showed that sodium intake or excretion was associated with blood pressure levels, no prospective study has examined the long-term association between sodium excretion in spot urine and blood pressure changes. METHODS: We conducted a prospective study of 889 normotensive subjects (295 men and 594 women, mean age 57.3 years) who underwent the baseline survey including spot urine test in 2005 and the follow-up survey in 2009 to 2011 (mean follow-up period: 5.8 years). We examined the association between sodium concentration in spot urine, a validated index of sodium excretion occurring over 24-h, and blood pressure changes between baseline and follow-up survey in all, non-overweight (body mass index(BMI) <= 25 kg/m(2)) and overweight normotensives. RESULTS: For all subjects, sodium concentrations in spot urine were not associated with either systolic or diastolic blood pressure changes. When stratified by BMI at baseline survey, sodium concentrations were positively associated with systolic blood pressure changes in non-overweight subjects, but not in overweight subjects. After adjustment for age, sex, BMI, alcohol intake status, current smoking and estimated glomerular filtration rate, the multivariable-adjusted mean values of the systolic blood pressure change among non-overweight subjects was +7.3 mmHg in the highest quartiles of sodium concentrations, while it was +3.9 mmHg in the lowest quartile (P for difference = 0.021, P for trend = 0.040). After further adjustment of baseline blood pressure levels, the association was slightly weakened; the multivariable-adjusted mean values of the systolic blood pressure changes were +7.0 mmHg and +4.2 mmHg (P for difference = 0.047, P for trend = 0.071). CONCLUSIONS: High sodium concentrations in spot urine were associated with subsequent systolic blood pressure increases among non-overweight normotensive individuals. (272 words). PMID- 26944260 TI - Comparative transcriptomics of the nematode gut identifies global shifts in feeding mode and pathogen susceptibility. AB - BACKGROUND: The nematode Pristionchus pacificus has been established as a model for comparative studies using the well known Caenorhabditis elegans as a reference. Despite their relatedness, previous studies have revealed highly divergent development and a number of morphological differences including the lack of a pharyngal structure, the grinder, used to physically lyse the ingested bacteria in C. elegans. RESULTS: To complement current knowledge about developmental and ecological differences with a better understanding of their feeding modes, we have sequenced the intestinal transcriptomes of both nematodes. In total, we found 464 intestine-enriched genes in P. pacificus and 724 in C. elegans, of which the majority (66%) has been identified by previous studies. Interestingly, only 15 genes could be identified with shared intestinal enrichment in both species, of which three genes are Hedgehog signaling molecules supporting a highly conserved role of this pathway for intestinal development across all metazoa. At the level of gene families, we find similar divergent trends with only five families displaying significant intestinal enrichment in both species. We compared our data with transcriptomic responses to various pathogens. Strikingly, C. elegans intestine-enriched genes showed highly significant overlaps with pathogen response genes whereas this was not the case for P. pacificus, indicating shifts in pathogen susceptibility that might be explained by altered feeding modes. CONCLUSIONS: Our study reveals first insights into the evolution of feeding systems and the associated changes in intestinal gene expression that might have facilitated nematodes of the P. pacificus lineage to colonize new environments. These findings deepen our understanding about how morphological and genomic diversity is created during the course of evolution. PMID- 26944261 TI - An iNTT system for the large-scale screening of differentially expressed, nuclear targeted proteins: cold-treatment-induced nucleoproteins in Rye (Secale cereale L.). AB - BACKGROUND: Nuclear proteins play critical roles in regulating mRNA transcription and processing, DNA replication, and epigenetic genome modification. Therefore, the ability to monitor changes in nuclear proteins is helpful not only to identify important regulatory proteins but also to study the mechanisms of actions of nuclear proteins. However, no effective methods have been developed yet. Rye is strongly resistant to various biotic and abiotic stresses; however, few genes have been functionally characterized to date due to the complexity of its genome and a lack of genomic sequence information. RESULTS: We developed an integrative Nuclear Transportation Trap (iNTT) system that includes an improved nuclear transportation trap and utilizes the "after suppression subtraction" method. Oligonucleotides encoding a nuclear localization signal (NLS) or a transcription factor, GmAREB, were inserted into pLexAD or pLexAD-NES, respectively, and then transformed into yeast cells (EGY48). We showed that the pLexAD vector expressing a cDNA library in the iNTT system was more efficient for screening than the vector pLexAD-NES, which has previously been used in an NTT system. We used the iNTT system to screen a cDNA library of cold-treated rye. A total of 241 unique genes were identified, including 169 differentially expressed proteins; of these, 106 were of known and 63 were of unknown function. Moreover, 82 genes (49 %) among the 169 differentially expressed genes were predicted to contain an NLS domain. Thirty-three (31 %) of the 106 functionally known proteins have DNA-binding activity. To test the specificity of the nuclear proteins identified using the iNTT screen, four of the proteins differentially expressed in response to temperature stress, ScT1 (a heat shock protein), ScT36 (a MYB-like transcription factor), ScT133 (an ERF-like transcription factor) and ScT196 (a protein of unknown function), were studied in more depth. These proteins were shown to exclusively localize to the nucleus, and their expression levels were increased in response to low-temperature stress. To identify the function of these screened nuclear proteins, ScT1- and ScT36-transgenic Arabidopsis plants were constructed, and ScT1 or ScT36 overexpression was found to enhance tolerance to high-temperature or freezing stresses, respectively. CONCLUSIONS: The newly developed iNTT system provides an effective method for identifying nuclear targeted proteins and monitoring induced expression levels. ScT1 and ScT36 might be good candidate genes for improving the stress tolerance of plants by genetic transformation. PMID- 26944264 TI - Symmetric Asymptomatic Plantar Nodules in an Infant. PMID- 26944262 TI - A randomised phase II trial of Stereotactic Ablative Fractionated radiotherapy versus Radiosurgery for Oligometastatic Neoplasia to the lung (TROG 13.01 SAFRON II). AB - BACKGROUND: Stereotactic ablative body radiotherapy (SABR) is emerging as a non invasive method for precision irradiation of lung tumours. However, the ideal dose/fractionation schedule is not yet known. The primary purpose of this study is to assess safety and efficacy profile of single and multi-fraction SABR in the context of pulmonary oligometastases. METHODS/DESIGN: The TROG 13.01/ALTG 13.001 clinical trial is a multicentre unblinded randomised phase II study. Eligible patients have up to three metastases to the lung from any non-haematological malignancy, each < 5 cm in size, non-central targets, and have all primary and extrathoracic disease controlled with local therapies. Patients are randomised 1:1 to a single fraction of 28Gy versus 48Gy in four fractions of SABR. The primary objective is to assess the safety of each treatment arm, with secondary objectives including assessment of quality of life, local efficacy, resource use and costs, overall and disease free survival and time to distant failure. Outcomes will be stratified by number of metastases and origin of the primary disease (colorectal versus non-colorectal primary). Planned substudies include an assessment of the impact of online e-Learning platforms for lung SABR and assessment of the effect of SABR fractionation on the immune responses. A total of 84 patients are required to complete the study. DISCUSSION: Fractionation schedules have not yet been investigated in a randomised fashion in the setting of oligometastatic disease. Assuming the likelihood of similar clinical efficacy in both arms, the present study design allows for exploration of the hypothesis that cost implications of managing potentially increased toxicities from single fraction SABR will be outweighed by costs associated with delivering multiple fraction SABR. TRIALS REGISTRATION: ACTRN12613001157763 , registered 17th October 2013. PMID- 26944263 TI - Implementing the care programme for the last days of life in an acute geriatric hospital ward: a phase 2 mixed method study. AB - BACKGROUND: To improve the quality of end-of-life care in geriatric hospital wards we developed the Care Programme for the Last Days of Life. It consists of 1) the Care Guide for the Last Days of Life, 2) supportive documentation and 3) an implementation guide. The aim of this study is (1) to determine the feasibility of implementing the Care Programme for the Last Days of Life in the acute geriatric hospital setting and (2) to explore the health care professionals' perceptions of the effects of the Care Programme on end-of-life care. METHODS: A phase 2 mixed methods study according with the MRC framework was performed in the acute geriatric ward of Ghent University Hospital between 1 April and 30 September 2013. During the implementation process a mixed methods approach was used including observation, interviews and the use of a quantitative process evaluation tool. This tool measured the success of implementation using several indicators, such as whether a steering group was formed, whether and how much of the health care staff was informed and trained and how many patients were cared for according to the Care Guide for the Last Days of Life. RESULTS: The process evaluation tool showed that implementing the Care Programme for the Last Days of Life in the geriatric ward was successful and thus feasible; a steering group was formed consisting of two facilitators, health care staff of the geriatric ward were trained in using the Care Guide for the Last Days of Life which was subsequently introduced onto the ward and approximately 57% of all dying patients were cared for according to the Care Guide for the Last Days of Life. With regard to health care professionals' perceptions, nurses and physicians experienced the Care Guide for the Last Days of Life as improving the overall documentation of care, improving communication among health care staff and between health care staff and patient/family and improving the quality of end of-life care. Barriers to implementing the Care Programme for the Last Days of Life successfully are, among others, difficulties with the content of the documents used within the Care Programme for the Last Days of Life and the low participation rate of physicians in the training sessions and audits. CONCLUSIONS: Results of this mixed methods study suggest that implementing the Care Programme for the Last Days of Life is feasible and that it has favorable effects on end-of-life care as reported by health care professionals. Based on the identified barriers during the implementation process, we were able to make recommendations for future implementation and further refine the Care Programme for the Last Days of Life before implementing it in a phase 3 cluster randomized controlled trial for the evaluation of its effectiveness. PMID- 26944265 TI - Risk Factors and In-Hospital Outcomes following Tracheostomy in Infants. AB - OBJECTIVE: To describe the epidemiology, risk factors, and in-hospital outcomes of tracheostomy in infants in the neonatal intensive care unit. STUDY DESIGN: We analyzed electronic medical records from 348 neonatal intensive care units for the period 1997 to 2012, and evaluated the associations among infant demographics, diagnoses, and pretracheostomy cardiopulmonary support with in hospital mortality. We also determined the trends in use of infant tracheostomy over time. RESULTS: We identified 885 of 887 910 infants (0.1%) who underwent tracheostomy at a median postnatal age of 72 days (IQR, 27-119 days) and a median postmenstrual age of 42 weeks (IQR, 39-46 weeks). The most common diagnoses associated with tracheostomy were bronchopulmonary dysplasia (396 of 885; 45%), other upper airway anomalies (202 of 885; 23%), and laryngeal anomalies (115 of 885; 13%). In-hospital mortality after tracheostomy was 14% (125 of 885). On adjusted analysis, near-term gestational age (GA), small for GA status, pulmonary diagnoses, number of days of forced fraction of inspired oxygen >0.4, and inotropic support before tracheostomy were associated with increased in-hospital mortality. The proportion of infants requiring tracheostomy increased from 0.01% in 1997 to 0.1% in 2005 (P < .001), but has remained stable since. CONCLUSION: Tracheostomy is not commonly performed in hospitalized infants, but the associated mortality is high. Risk factors for increased in-hospital mortality after tracheostomy include near-term GA, small for GA status, and pulmonary diagnoses. PMID- 26944266 TI - Nursing workload in the acute-care setting: A concept analysis of nursing workload. AB - BACKGROUND: A pressing need in the field of nursing is the identification of optimal staffing levels to ensure patient safety. Effective staffing requires comprehensive measurement of nursing workload to determine staffing needs. Issues surrounding nursing workload are complex, and the volume of workload is growing; however, many workload systems do not consider the numerous workload factors that impact nursing today. PURPOSE: The purpose of this concept analysis was to better understand and define nursing workload as it relates to the acute-care setting. METHODS: Rogers' evolutionary method was used for this literature-based concept analysis. DISCUSSION: Nursing workload is influenced by more than patient care. The proposed definition of nursing workload may help leaders identify workload that is unnoticed and unmeasured. CONCLUSION: These findings could help leaders consider and identify workload that is unnecessary, redundant, or more appropriate for assignment to other members of the health care team. PMID- 26944267 TI - Effectiveness and safety of CT-guided (125)I seed brachytherapy for postoperative locoregional recurrence in patients with non-small cell lung cancer. AB - PURPOSE: To retrospectively evaluate the effectiveness and safety of CT-guided (125)I seed brachytherapy (CTISB) in 38 non-small cell lung cancer (NSCLC) patients with locoregional recurrence (LRR). METHODS AND MATERIALS: In total, we analyzed 38 NSCLC patients with LRR treated with percutaneous CTISB in our hospital between 2001 and 2008; among them, 15 also received combined chemotherapy: 1-6 cycles (median, 2) of platinum-based regimens. The change in tumor volume was evaluated based on followup contrast material-enhanced CT or positron emission tomography scans. RESULTS: The median Day 0 dosimetry was as follows: The volume treated with the prescription dose (V100) was 96.3% (90.1 123.5%), and the minimum dose received by at least 90% of the tumor volume (D90) was 124.8 Gy (116.0-130.7 Gy). The median duration of the followup period calculated from the first CTISB treatment was 22.5 months (range, 8-98 months). Two months after CTISB, complete response, partial response, and progressive disease were observed in 50%, 37%, and 8% of patients, respectively. Median overall survival (OS) after CTISB was 21 months (95% confidence interval, 7.4 34.6), and the rates of 2-year OS, progression-free survival, and local control were 47.4%, 39.5%, and 83.5%, respectively. Both univariate and multivariate analysis indicated that D90 was significant prognostic factors for OS and progression-free survival. CONCLUSION: For selected NSCLC patients with limited LRR, CTISB is effective and can provide a high rate of local cancer control with minimal trauma. PMID- 26944269 TI - Cognitive decline in classic infantile Pompe disease: An underacknowledged challenge. PMID- 26944270 TI - Radiotherapy-induced hemichorea. PMID- 26944268 TI - Examining the effects of comorbidities on disease-modifying therapy use in multiple sclerosis. AB - OBJECTIVE: Comorbidities are common in multiple sclerosis (MS) and adversely affect health outcomes. However, the effect of comorbidity on treatment decisions in MS remains unknown. We aimed to examine the effects of comorbidity on initiation of injectable disease-modifying therapies (DMTs) and on the choice of the initial DMT in MS. METHODS: We conducted a retrospective observational analysis using population-based health administrative and linked clinical databases in 3 Canadian provinces. MS cases were defined as any individual with >=3 diagnostic codes for MS. Cohort entry (index date) was the first recorded demyelinating disease-related claim. The outcomes included choice of initial first-line DMTs and time to initiating a DMT. Logistic and Cox regression models were used to examine the association between comorbidity status and study outcomes, adjusting for sex, age, year of index date, and socioeconomic status. Meta-analysis was used to estimate overall effects across the 3 provinces. RESULTS: We identified 10,698 persons with incident MS, half of whom had >=1 comorbidities. As the total number of comorbidities increased, the likelihood of initiating a DMT decreased. Comorbid anxiety and ischemic heart disease were associated with reduced initiation of a DMT. However, patients with depression were 13% more likely to initiate a DMT compared to those without depression at the index date (adjusted hazard ratio 1.13; 95% confidence interval 1.00-1.27). CONCLUSIONS: Comorbidities are associated with treatment decisions regarding DMTs in MS. A better understanding of the effects of comorbidity on effectiveness and safety of DMTs is needed. PMID- 26944271 TI - The syndrome of polymicrogyria, thalamic hypoplasia, and epilepsy with CSWS. AB - OBJECTIVE: We explored the long-term follow-up of continuous spike-and-wave complexes during sleep (CSWS) in polymicrogyria and the anatomic volumetric variables that influence the risk of developing this age-related epileptic encephalopathy. METHODS: We performed prospective follow-up of 27 patients with polymicrogyria/CSWS (mean follow-up 14.3 years; range 2-31 years) and comparative volumetric analysis of the polymicrogyric hemispheres and ipsilateral thalami vs 3 subgroups featuring polymicrogyria without CSWS, benign rolandic epilepsy (BRE), and headache. Receiver operator characteristic analysis of the power of volumetric values was determined to predict CSWS. RESULTS: CSWS peaked between 5 and 7 years (mean age at onset 4.7 years). Remission occurred within 2 years from onset in 21%, within 4 years in 50%, and by age 13 years in 100%. We found smaller thalamic and hemispheric volumes in polymicrogyria/CSWS with respect to polymicrogyria without CSWS (p = 0.0021 for hemispheres; p = 0.0003 for thalami), BRE, and controls with headache (p < 0.0001). Volumes of the malformed hemispheres and ipsilateral thalami reliably identified the risk of incurring CSWS, with a 68-fold increased risk for values lower than optimal diagnostic cutoffs (436,150 mm(3) for malformed hemispheres or 4,616 mm(3) for ipsilateral thalami; sensitivity 92.54%; specificity 84.62%). The risk increased by 2% for every 1,000 mm(3) reduction of the polymicrogyric hemispheres and by 15% for every 100 mm(3) reduction of ipsilateral thalami. CONCLUSIONS: The polymicrogyria/CSWS syndrome is likely caused by a cortico-thalamic malformation complex and is characterized by remission of epilepsy within early adolescence. Early assessment of hemispheric and thalamic volumes in children with polymicrogyria and epilepsy can reliably predict CSWS. PMID- 26944272 TI - Restless legs syndrome associated with major diseases: A systematic review and new concept. AB - Recent publications on both the genetics and environmental factors of restless legs syndrome (RLS) defined as a clinical disorder suggest that overlapping genetic risk factors may play a role in primary (idiopathic) and secondary (symptomatic) RLS. Following a systematic literature search of RLS associated with comorbidities, we identified an increased prevalence of RLS only in iron deficiency and kidney disease. In cardiovascular disease, arterial hypertension, diabetes, migraine, and Parkinson disease, the methodology of studies was poor, but an association might be possible. There is insufficient evidence for conditions such as anemia (without iron deficiency), chronic obstructive pulmonary disease, multiple sclerosis, headache, stroke, narcolepsy, and ataxias. Based on possible gene-microenvironmental interaction, the classifications primary and secondary RLS may suggest an inappropriate causal relation. We recognize that in some conditions, treatment of the underlying disease should be achieved as far as possible to reduce or eliminate RLS symptoms. RLS might be seen as a continuous spectrum with a major genetic contribution at one end and a major environmental or comorbid disease contribution at the other. PMID- 26944274 TI - Orthostatic myoclonus associated with Caspr2 antibodies. PMID- 26944273 TI - Neurologic involvement in patients with atypical Chediak-Higashi disease. AB - OBJECTIVE: To delineate the developmental and progressive neurodegenerative features in 9 young adults with the atypical form of Chediak-Higashi disease (CHD) enrolled in a natural history study. METHODS: Patients with atypical clinical features, but diagnostically confirmed CHD by standard evaluation of blood smears and molecular genotyping, underwent complete neurologic evaluation, MRI of the brain, electrophysiologic examination, and neuropsychological testing. Fibroblasts were collected to investigate the cellular phenotype and correlation with the clinical presentation. RESULTS: In 9 mildly affected patients with CHD, we documented learning and behavioral difficulties along with developmental structural abnormalities of the cerebellum and posterior fossa, which are apparent early in childhood. A range of progressive neurologic problems emerge in early adulthood, including cerebellar deficits, polyneuropathies, spasticity, cognitive decline, and parkinsonism. CONCLUSIONS: Patients with undiagnosed atypical CHD manifesting some of these wide-ranging yet nonspecific neurologic complaints may reside in general and specialty neurology clinics. The absence of the typical bleeding or infectious diathesis in mildly affected patients with CHD renders them difficult to diagnose. Identification of these individuals is important not only for close surveillance of potential CHD-related systemic complications but also for a full understanding of the natural history of CHD and the potential role of the disease-causing protein, LYST, to the pathophysiology of other neurodevelopmental and neurodegenerative disorders. PMID- 26944275 TI - Brivaracetam add-on for refractory focal epilepsy: A systematic review and meta analysis. AB - OBJECTIVE: To evaluate the efficacy and safety of the new antiepileptic drug brivaracetam (BRV) as add-on treatment for drug-resistant partial epilepsy using meta-analytical techniques. METHODS: Randomized, placebo-controlled, single- or double-blind, add-on trials of BRV in adult patients with drug-resistant partial epilepsy were identified through a systematic literature search. The following outcomes were assessed: 50% or greater reduction in seizure frequency, seizure freedom, incidence of treatment-emergent adverse events (TEAEs), and treatment withdrawal. Risk ratio (RR) with 95% confidence interval was estimated for each outcome. RESULTS: Six trials were included involving 2,399 participants according to the intent-to-treat, 1,715 for BRV, and 684 for placebo groups, respectively. The pooled RRs for the 50% responders and seizure freedom were 1.79 (1.51-2.12) and 4.74 (2.00-11.25), respectively. The subanalysis by levetiracetam (LEV) status did not show a statistically significant difference in the 50% responder rate when comparing BRV with placebo in patients with concomitant assumption of LEV. The TEAEs significantly associated with BRV were irritability (2.99 [1.28 6.97]), fatigue (2.19 [1.44-3.33]), somnolence (1.97 [1.45-2.68]), and dizziness (1.66 [1.19-2.31]). The overall RRs for treatment withdrawal due to TEAEs or any reason were 1.58 (1.04-2.40) and 1.27 (0.93-1.73), respectively. CONCLUSIONS: In adults with drug-refractory focal epilepsy, add-on BRV was effective to reduce seizure frequency and fairly well-tolerated. Further studies are needed to draw definitive conclusions about its efficacy in non-LEV-naive participants and evaluate its long-term safety profile. PMID- 26944276 TI - Roles for long non-coding RNAs in physiology and disease. AB - While the vast majority of the genome is transcribed into RNA, only a small fraction of these transcripts have protein-coding potential. A large fraction of the transcribed RNA belongs to the class known as long non-coding RNAs (lncRNAs). Several recent studies have shown that at least some of these lncRNA transcripts represent functional RNA molecules. LncRNAs can utilize a wide range of mechanisms to regulate the RNA and/or the protein content of a cell on the transcriptional and the post-transcriptional levels. So far, many studies have identified differentially expressed lncRNAs in various physiological contexts, genetic disorders and human diseases. A steadily increasing number of studies could establish functional roles for some of these lncRNAs in developmental processes, cancer and tissue homeostasis. Taken together, these functions provide an additional layer of gene regulation and contribute to the high complexity of physiological and disease-related phenotypes. PMID- 26944277 TI - Postinjection Endophthalmitis Rates and Characteristics Following Intravitreal Bevacizumab, Ranibizumab, and Aflibercept. AB - PURPOSE: To compare the incidence and clinical outcomes of endophthalmitis following intravitreal injections of bevacizumab, ranibizumab, and aflibercept. DESIGN: Multicenter, retrospective cohort study. METHODS: All included patients had received intravitreal injections of bevacizumab, ranibizumab, or aflibercept between January 1, 2009 and September 30, 2013 at 5 retina practices. Billing records were used to identify the total number of anti-vascular endothelial growth factor (VEGF) injections administered. Patients who developed endophthalmitis were ascertained from endophthalmitis logs and billing records. Chart review of these patients was performed to confirm that the endophthalmitis was related to the antecedent anti-VEGF injection. Visual outcomes, causative organisms, and clinical course were also recorded. RESULTS: A total of 503 890 anti-VEGF injections were included, from which 183 cases of presumed endophthalmitis were identified. The rate of endophthalmitis for bevacizumab was 0.039% (60/153 812), which was similar to ranibizumab 0.035% (109/309 722; P = .522) and aflibercept 0.035% (14/40 356; P = .693). Similarly, there was no difference in the rates between ranibizumab and aflibercept (P = .960). The culture-positive rate of the vitreous/aqueous tap was 38% for both bevacizumab and ranibizumab and was 43% for aflibercept. Furthermore, visual acuity remained decreased at 3 months follow-up for bevacizumab (P = .005), ranibizumab (P < .001), and aflibercept (P = .07) compared to vision at causative injection. CONCLUSIONS: Endophthalmitis following intravitreal bevacizumab, ranibizumab, and aflibercept injection appears to occur at similar rates and have comparable visual outcomes. This study suggests that the choice of anti-VEGF agent should be primarily based on efficacy and patient response rather than concern for risk of infection. PMID- 26944278 TI - Customized Corneal Cross-linking: One-Year Results. AB - PURPOSE: To compare the efficacy of customized corneal cross-linking (CXL) with standard CXL. DESIGN: Prospective, nonrandomized comparative clinical study. METHODS: In a prospective study at the Institut fur Refraktive und Ophthalmo Chirurgie (IROC), Zurich, Switzerland, 40 eyes of 40 patients with documented progressive primary keratoconus were treated with customized CXL (n = 20) or standard CXL (n = 20) and followed for 1 year. Customized irradiation patterns had an energy fluence of 9 mW/cm(2) and total energy levels ranging from 5.4 J/cm(2) up to 10 J/cm(2) and were centered on the maximum of the posterior float. The control group received homogenous irradiation with a fluence of 9 mW/cm(2) and a total energy of 5.4 J/cm(2). Scheimpflug tomographies, endothelium cell count, best spectacle-corrected visual acuity (BSCVA), and anterior segment optical coherence tomography (OCT) were compared preoperatively and 1 year postoperatively. RESULTS: Pachymetry and DeltaKmax showed significant changes 1 year postoperatively within each group. Epithelial healing time, DeltaKmax, and regularization index (RI) were significantly better in the customized CXL group. Two out of 19 eyes (11%) in the standard group but 7 out of 19 eyes (37%) in the customized CXL group showed a flattening of 2 or more diopters (P = .03). The RI was 5.2 +/- 2.7 D in the customized group vs 4.1 +/- 3.1 D in the control group (P = .03). Statistically significant correlations between RI and preoperative Kmax, preoperative pachymetry, and preoperative posterior float were found only in the customized group. CONCLUSIONS: Customized CXL seems to be as safe as standard CXL with stronger flattening in Kmax and RI, and a faster epithelial healing period. PMID- 26944279 TI - Systematic Identification, Characterization and Target Gene Analysis of microRNAs Involved in Osteoarthritis Subchondral Bone Pathogenesis. AB - This study aimed to identify the microRNAs associated with sclerotic status of subchondral bone in the pathogenesis of osteoarthritis (OA). Total RNA was extracted from non-sclerotic and sclerotic OA subchondral bone from patients undergoing knee replacement surgeries. miRCURYTM LNA miRNA chip and qRT-PCR were used to profile and validate differential microRNA expression. In addition, we further confirmed profiles of altered miRNAs in an OA rat meniscectomy animal model and their putative targets of the miRNAs were predicted using ingenuity (IPA) software. Finally, five short-listed miRNAs were reactivated by transient in vitro overexpression (miRNA mimics) in subchondral bone osteoblasts and their phenotypes were assessed. Functional screening identified 30 differentiated miRNAs in sclerotic subchondral bone compared to non-sclerotic bone of OA patients. Data integration resulted in confirmation of the eight miRNAs, with aberrant expression in independent human OA bone sample set. In silico analysis (IPA) identified 732 mRNA transcripts as putative targets of the eight altered miRNAs, of which twenty genes were validated to be differentially expressed in sclerotic compared to non-sclerotic bone samples. Out of eight dysregulated miRNA's, five of them showed consistent time-dependent downregulation in a rat OA model. Furthermore, synthetic miR-199a-3p, miR-199a-5p, miR-590-5p, and miR-211 5p mimics rescued the abnormal osteoarthritic subchondral bone osteoblast gene expression and mineralization. We have identified four novel miRNAs that play important roles in subchondral bone pathogenesis in OA. Additional studies are required to develop these miRNAs into therapeutic modalities for OA. PMID- 26944280 TI - Screening Anti-Cancer Drugs against Tubulin using Catch-and-Release Electrospray Ionization Mass Spectrometry. AB - Tubulin, which is the building block of microtubules, plays an important role in cell division. This critical role makes tubulin an attractive target for the development of chemotherapeutic drugs to treat cancer. Currently, there is no general binding assay for tubulin-drug interactions. The present work describes the application of the catch-and-release electrospray ionization mass spectrometry (CaR-ESI-MS) assay to investigate the binding of colchicinoid drugs to alphabeta-tubulin dimers extracted from porcine brain. Proof-of-concept experiments using positive (ligands with known affinities) and negative (non binders) controls were performed to establish the reliability of the assay. The assay was then used to screen a library of seven colchicinoid analogues to test their binding to tubulin and to rank their affinities. PMID- 26944281 TI - Ion Mobility Separation of Peptide Isotopomers. AB - Differential or field asymmetric waveform ion mobility spectrometry (FAIMS) operating at high electric fields fully resolves isotopic isomers for a peptide with labeled residues. The naturally present isotopes, alone and together with targeted labels, also cause spectral shifts that approximately add for multiple heavy atoms. Separation qualitatively depends on the gas composition. These findings may enable novel strategies in proteomic and metabolomic analyses using stable isotope labeling. PMID- 26944282 TI - Development of ten microsatellite markers from the keystone mistletoe Tristerix corymbosus (Loranthaceae) using 454 next generation sequencing and their applicability to population genetic structure studies. AB - Tristerix corymbosus (Loranthaceae) is a keystone mistletoe from the South American temperate rainforests. As most mistletoes, T. corymbosus relies on biotic pollination and seed dispersal, which may cause population structure. For a better understanding of its ecology, we isolated and characterized ten polymorphic microsatellite loci for this species. We used 454 Next Generation Sequencing to build a microsatellite library from a high quality DNA sample. We tested 90 sequences from which we obtained ten polymorphic markers. In order to assess their variability, the novel markers were tested in 48 individuals from three locations of the Valdivian Coastal Reserve in Chile. We also estimated genetic differences between pairs of populations using the FST statistic. The mean number of alleles per locus in the 48 individuals studied was 7.1 (2-17 alleles per locus). The observed and expected heterozygosity ranged from 0.298 to 0.634 and from 0.310 to 0.881, respectively. There were genetic differences among the three populations assessed, according to the FST values (ranging from 0.048 to 0.100, all significant) and, the number of alleles per locus ranged from 3.9 to 5.1. These are the first microsatellite markers developed for T. corymbosus, and they arise as a powerful tool for studying population structure, genetic diversity and gene flow at the landscape scale, along its distribution. PMID- 26944283 TI - Prolonged Induction of miR-212/132 and REST Expression in Rat Striatum Following Cocaine Self-Administration. AB - Chronic exposure to cocaine in vivo induces long-term synaptic plasticity associated with the brain's circuitry that underlies development of repetitive and automatic behaviors called habits. In fact, prolonged drug consumption results in aberrant expression of protein-coding genes and small regulatory RNAs, including miRNAs that are involved in synaptic plasticity and neuroadaptations. However, the mechanisms mediating cocaine use disorder are still not fully understood. The present study is designed to examine the expression of miR-124, miR-132, miR-134, and miR-212, as well as the levels of the Ago2, Pum2, and REST mRNAs and proteins implicated in their regulation. We applied rat cocaine self administration (SA) and extinction training procedures with a yoked triad to assess the changes in the levels of four miRNAs and three protein-coding genes and corresponding proteins in the dorsal striatum. We demonstrated that elevated expression of mature miR-212 and miR-132 is long-lasting and persists in the drug free period (till 10-day abstinence). Moreover, mRNA and protein of REST, a regulator of neuronal transcription, was raised selectively in cocaine self administering rats and Ago2 transcript decreased after cocaine treatment. Unexpectedly, the expression level of Ago2 and Pum2 proteins changed only in the active cocaine-receiving animals. These results point out the important aspects of long-lasting alterations in microRNAs, genes, and protein expressions involved in the control of synaptic plasticity associated with reward and motivation learning related to cocaine addiction. PMID- 26944284 TI - A Tale of the Good and Bad: Remodeling of the Microtubule Network in the Brain by Cdk5. AB - Cdk5, a cyclin-dependent kinase family member, is a global orchestrator of neuronal cytoskeletal dynamics. During embryogenesis, Cdk5 is indispensable for brain development. In adults, it is essential for numerous neuronal processes, including higher cognitive functions such as learning and memory formation, drug addiction, pain signaling, and long-term behavior changes through long-term potentiation and long-term depression, all of which rely on rapid alterations in the cytoskeleton. Cdk5 activity becomes deregulated in various brain disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, attention-deficit hyperactivity disorder, epilepsy, schizophrenia, and ischemic stroke; these all result in profound remodeling of the neuronal cytoskeleton. This Commentary specifically focuses on the pleiotropic contribution of Cdk5 in regulating neuronal microtubule remodeling. Because the vast majority of the physiological substrates of Cdk5 are associated with the neuronal cytoskeleton, our emphasis is on the Cdk5 substrates, such as CRMP2, stathmin, drebrin, dixdc1, axin, MAP2, MAP1B, doublecortin, kinesin-5, and tau, that have allowed to unravel the molecular mechanisms through which Cdk5 exerts its divergent roles in regulating neuronal microtubule dynamics, both in healthy and disease states. PMID- 26944285 TI - Neuroprotective Effect of Fisetin Against Amyloid-Beta-Induced Cognitive/Synaptic Dysfunction, Neuroinflammation, and Neurodegeneration in Adult Mice. AB - Alzheimer's disease (AD) is a devastating and progressive neurodegenerative disease and is characterized pathologically by the accumulation of amyloid beta (Abeta) and the hyperphosphorylation of tau proteins in the brain. The deposition of Abeta aggregates triggers synaptic dysfunction, hyperphosphorylation of tau, and neurodegeneration, which lead to cognitive disorders. Here, we investigated the neuroprotective effect of fisetin in the Abeta1-42 mouse model of AD. Single intracerebroventricular injections of Abeta1-42 (3 MUl/5 min/mouse) markedly induced memory/synaptic deficits, neuroinflammation, and neurodegeneration. Intraperitoneal injections of fisetin at a dose of 20 mg/kg/day for 2 weeks starting 24 h after Abeta1-42 injection significantly decreased the Abeta1-42 induced accumulation of Abeta, BACE-1 expression, and hyperphosphorylation of tau protein at serine 413. Fisetin treatment also markedly reversed Abeta1-42-induced synaptic dysfunction by increasing the levels of both presynaptic (SYN and SNAP 25) and postsynaptic proteins (PSD-95, SNAP-23, p-GluR1 (Ser 845), p-CREB (Ser 133) and p-CAMKII (Thr 286) and ultimately improved mouse memory, as observed in the Morris water maze test. Fisetin significantly activated p-PI3K, p-Akt (Ser 473), and p-GSK3beta (Ser 9) expression in Abeta1-42-treated mice. Moreover, fisetin prevented neuroinflammation by suppressing various activated neuroinflammatory mediators and gliosis; it also suppressed the apoptotic neurodegeneration triggered by Abeta1-42 injections in the mouse hippocampus. Fluorojade-B and immunohistochemical staining for caspase-3 revealed that fisetin prevented neurodegeneration in Abeta1-42-treated mice. Our results suggest that fisetin has a potent neuroprotective effect against Abeta1-42-induced neurotoxicity. These results demonstrate that polyphenolic flavonoids such as fisetin could be a beneficial, effective and safe neuroprotective agent for preventing neurological disorders such as AD. PMID- 26944291 TI - The ecological risk of heavy metals in sediment from the Danube Delta. AB - The objectives of this study were to assess the sediment contamination with heavy metals and to investigate accordingly the ecological risk posed in the SE of the Danube Delta. Sediments are important in assessing the contamination as they act as reservoirs, transporters and contamination sources. Sediment samples were collected and analysed for lead, cadmium, arsenic and mercury, revealing levels higher than the background, especially for cadmium and mercury (Pb > As > Cd > Hg). Concentrations exceeding the probable effect limit were noticed for arsenic and mercury. The contamination indexes describe the study area as having almost half of the samples as contaminated (pollution load index-PLI 1.04), however the contamination is mostly low-to moderate (modified contamination degree-mCd 1.36). The sediment contamination poses mostly a low ecological risk (RI 94.8). The sediment quality guideline quotient (SQG-Q 0.29) describes a moderate impact, while the probable effect concentration quotient (PEC-Q 0.16) confirms that there are no levels likely to affect the aquatic biota. In our study area, the main Branch of the Danube River and the Secondary Delta are the most affected by contamination, while the narrow, reed abundant channels as the preferred habitat of most aquatic organisms, have a low contamination level. PMID- 26944293 TI - Simultaneous sequential monitoring of efficacy and safety led to masking of effects. AB - OBJECTIVE: Usually, sequential designs for clinical trials are applied on the primary (=efficacy) outcome. In practice, other outcomes (e.g., safety) will also be monitored and influence the decision whether to stop a trial early. Implications of simultaneous monitoring on trial decision making are yet unclear. This study examines what happens to the type I error, power, and required sample sizes when one efficacy outcome and one correlated safety outcome are monitored simultaneously using sequential designs. STUDY DESIGN AND SETTING: We conducted a simulation study in the framework of a two-arm parallel clinical trial. Interim analyses on two outcomes were performed independently and simultaneously on the same data sets using four sequential monitoring designs, including O'Brien Fleming and Triangular Test boundaries. Simulations differed in values for correlations and true effect sizes. RESULTS: When an effect was present in both outcomes, competition was introduced, which decreased power (e.g., from 80% to 60%). Futility boundaries for the efficacy outcome reduced overall type I errors as well as power for the safety outcome. CONCLUSION: Monitoring two correlated outcomes, given that both are essential for early trial termination, leads to masking of true effects. Careful consideration of scenarios must be taken into account when designing sequential trials. Simulation results can help guide trial design. PMID- 26944292 TI - Clinical Ethics and Nutrition Support Practice: Implications for Practice Change and Curriculum Development. PMID- 26944294 TI - Three challenges described for identifying participants with missing data in trials reports, and potential solutions suggested to systematic reviewers. AB - OBJECTIVE: To categorize the challenges in determining the extent of missing participant data in randomized trials and suggest potential solutions for systematic review authors. STUDY DESIGN AND SETTING: During the process of updating a series of Cochrane systematic reviews on the topic of anticoagulation in patients with cancer, we identified challenges and used an iterative approach to improve, and a consensus process to agree on the challenges identified, and to suggest potential ways of dealing with them. The five systematic reviews included 58 trials and 75 meta-analyses for patient-important dichotomous outcomes with 27,037 randomized participants. RESULTS: We identified three categories of challenges: (1) Although systematic reviewers require information about missing data to be reported by outcome, trialists typically report the information by participant; (2) It is not always clear whether the trialists followed up participants in certain categories (e.g., noncompliers), that is, whether some categories of participants did or did not have missing data; (3) It is not always clear how the trialists dealt with missing data in their analysis (e.g., exclusion from the denominator vs. assumptions made for the numerator). We discuss potential solutions for each one of these challenges and suggest further research work. CONCLUSION: Current reporting of missing data is often not explicit and transparent, and although our potential solutions to problems of suboptimal reporting may be helpful, reliable and valid characterization of the extent and nature of missing data remains elusive. Reporting of missing data in trials needs further improvement. PMID- 26944290 TI - Tracking pan-continental trends in environmental contamination using sentinel raptors-what types of samples should we use? AB - Biomonitoring using birds of prey as sentinel species has been mooted as a way to evaluate the success of European Union directives that are designed to protect people and the environment across Europe from industrial contaminants and pesticides. No such pan-European evaluation currently exists. Coordination of such large scale monitoring would require harmonisation across multiple countries of the types of samples collected and analysed-matrices vary in the ease with which they can be collected and the information they provide. We report the first ever pan-European assessment of which raptor samples are collected across Europe and review their suitability for biomonitoring. Currently, some 182 monitoring programmes across 33 European countries collect a variety of raptor samples, and we discuss the relative merits of each for monitoring current priority and emerging compounds. Of the matrices collected, blood and liver are used most extensively for quantifying trends in recent and longer-term contaminant exposure, respectively. These matrices are potentially the most effective for pan European biomonitoring but are not so widely and frequently collected as others. We found that failed eggs and feathers are the most widely collected samples. Because of this ubiquity, they may provide the best opportunities for widescale biomonitoring, although neither is suitable for all compounds. We advocate piloting pan-European monitoring of selected priority compounds using these matrices and developing read-across approaches to accommodate any effects that trophic pathway and species differences in accumulation may have on our ability to track environmental trends in contaminants. PMID- 26944295 TI - Exploring personality traits related to dopamine D2/3 receptor availability in striatal subregions of humans. AB - While several studies have examined how particular personality traits are related to dopamine D2/3 receptor (D2/3R) availability in the striatum of humans, few studies have reported how multiple traits measured in the same persons are differentially related to D2/3R availability in different striatal sub-regions. We examined how personality traits measured with the Karolinska Scales of Personality are related to striatal D2/3R availability measured with [(11)C] raclopride in 30 healthy humans. Based on previous the literature, five personality traits were hypothesized to be most likely related to D2/3R availability: impulsiveness, monotony avoidance, detachment, social desirability, and socialization. We found self-reported impulsiveness was negatively correlated with D2/3R availability in the ventral striatum and globus pallidus. After controlling for age and gender, monotony avoidance was also negatively correlated with D2/3R availability in the ventral striatum and globus pallidus. Socialization was positively correlated with D2/3R availability in the ventral striatum and putamen. After controlling for age and gender, the relationship between socialization and D2/3R availability in these regions survived correction for multiple comparisons (p-threshold=.003). Thus, within the same persons, different personality traits are differentially related to in vivo D2/3R availability in different striatal sub-regions. PMID- 26944297 TI - Auraptene induces oligodendrocyte lineage precursor cells in a cuprizone-induced animal model of demyelination. AB - We investigated the effects of auraptene on mouse oligodendroglial cell lineage in an animal model of demyelination induced by cuprizone. Auraptene, a citrus coumarin, was intraperitoneally administered to mice fed the demyelinating agent cuprizone. Immunohistochemical analysis of the corpus callosum and/or Western blotting analysis of brain extracts revealed that cuprizone reduced immunoreactivity for myelin-basic protein, a marker of myelin, whereas it increased immunoreactivity to platelet derived-growth factor receptor-alpha, a marker of oligodendrocyte precursor cells. Administration of auraptene enhanced the immunoreactivity to oligodendrocyte transcription factor 2, a marker of oligodendrocyte precursor cells and oligodendrocyte lineage precursor cells, but had no effect on immunoreactivity to myelin-basic protein or platelet-derived growth factor receptor-alpha. These findings suggest that auraptene promotes the production of oligodendrocyte lineage precursor cells in an animal model of demyelination and may be useful for individuals with demyelinating diseases. PMID- 26944298 TI - Commentary on: Saper CB, Loewy AD, Swanson LW, Cowan WM. (1976) Direct hypothalamo-autonomic connections. Brain Research 117:305-312. AB - The 1970s saw the introduction of new technologies for tracing axons both anterogradely and retrogradely. These methods allowed us to visualize fine, unmyelinated pathways for the first time, such as the hypothalamic pathways that control the autonomic nervous system. As a result, we were able to identify the paraventricular nucleus and lateral hypothalamus as the key sites that provide direct inputs to the autonomic preganglionic neurons in the medulla and spinal cord. These findings revolutionized our understanding of hypothalamic control of the autonomic nervous system. PMID- 26944296 TI - Contemporary views on the genetics of anorexia nervosa. AB - Anorexia nervosa (AN) is a serious mental illness characterized by severe dietary restriction that leads to high rates of morbidity, chronicity, and mortality. Unfortunately, effective treatment is lacking and few options are available. High rates of familial aggregation and significant heritability suggested that the complex etiology of AN is affected by both genetic and environmental factors. In this paper, we review studies that reported common and rare genetic variation that influence susceptibility of AN through candidate gene studies, genome-wide association studies, and sequencing-based studies. We also discuss gene expression, methylation, imaging genetics, and pharmacogenetics to demonstrate that these studies have collectively advanced our knowledge of how genetic variation contributes to AN susceptibility and clinical course. Lastly, we highlight the importance of gene by environment interactions (G*E) and share our enthusiasm for the use of nutritional genomic approaches to elucidate the interaction among nutrients, metabolic intermediates, and genetic variation in AN. A deeper understanding of how nutrition alters genome stability, how genetic variation influences uptake and metabolism of nutrients, and how response to food components affects disordered eating, will lead to personalized dietary interventions and effective nutraceutical and pharmacological treatments for AN. PMID- 26944299 TI - Presynaptic D1 heteroreceptors and mGlu autoreceptors act at individual cortical release sites to modify glutamate release. AB - The aim of this work was to study release of glutamic acid (GLU) from one-axon terminal or bouton at-a-time using cortical neurons grown in vitro to study the effect of presynaptic auto- and heteroreceptor stimulation. Neurons were infected with release reporters SypHx2 or iGluSnFR at 7 or 3 days-in-vitro (DIV) respectively. At 13-15 DIV single synaptic boutons were identified from images obtained from a confocal scanning microscope before and after field electrical stimulation. We further stimulated release by raising intracellular levels of cAMP with forskolin (10uM). Forskolin-mediated effects were dependent on protein kinase A (PKA) and did not result from an increase in endocytosis, but rather from an increase in the size of the vesicle readily releasable pool. Once iGluSnFR was confirmed as more sensitive than SypHx2, it was used to study the participation of presynaptic auto- and heteroreceptors on GLU release. Although most receptor agonizts (carbamylcholine, nicotine, dopamine D2, BDNF) did not affect electrically stimulated GLU release, a significant increase was observed in the presence of metabotropic D1/D5 heteroreceptor agonist (SKF38393 10uM) that was reversed by PKA inhibitors. Interestingly, stimulation of group II metabotropic mGLU2/3 autoreceptors (LY379268 50nM) induced a decrease in GLU release that was reversed by the specific mGLU2/3 receptor antagonist (LY341495 1uM) and also by PKA inhibitors (KT5720 200nM and PKI14-22 400nM). These changes in release probability at individual release sites suggest another level of control of the distribution of transmitter substances in cortical tissue. PMID- 26944300 TI - Enhancement of forward suppression begins in the ventral cochlear nucleus. AB - A neuron's response to a sound can be suppressed by the presentation of a preceding sound. It has been suggested that this suppression is a direct correlate of the psychophysical phenomenon of forward masking, however, forward suppression, as measured in the responses of the auditory nerve, was insufficient to account for behavioural performance. In contrast the neural suppression seen in the inferior colliculus and auditory cortex was much closer to psychophysical performance. In anaesthetised guinea-pigs, using a physiological two-interval forced-choice threshold tracking algorithm to estimate suppressed (masked) thresholds, we examine whether the enhancement of suppression can occur at an earlier stage of the auditory pathway, the ventral cochlear nucleus (VCN). We also compare these responses with the responses from the central nucleus of the inferior colliculus (ICc) using the same preparation. In both nuclei, onset-type neurons showed the greatest amounts of suppression (16.9-33.5dB) and, in the VCN, these recovered with the fastest time constants (14.1-19.9ms). Neurons with sustained discharge demonstrated reduced masking (8.9-12.1dB) and recovery time constants of 27.2-55.6ms. In the VCN the decrease in growth of suppression with increasing suppressor level was largest for chopper units and smallest for onset type units. The threshold elevations recorded for most unit types are insufficient to account for the magnitude of forward masking as measured behaviourally, however, onset responders, in both the cochlear nucleus and inferior colliculus demonstrate a wide dynamic range of suppression, similar to that observed in human psychophysics. PMID- 26944301 TI - Long-Term Outcome of Low Scrotal Approach Orchiopexy without Ligation of the Processus Vaginalis. AB - PURPOSE: We performed low scrotal approach orchiopexy in patients with prescrotal cryptorchidism. The processus vaginalis was not ligated if it was not widely patent. We retrospectively evaluated the long-term outcomes of low scrotal approach orchiopexy without processus vaginalis ligation. MATERIALS AND METHODS: A total of 137 patients (227 testes) were diagnosed with prescrotal cryptorchidism between October 2009 and April 2014. All patients underwent low scrotal approach orchiopexy. Mean age at surgery was 34.9 months. The processus vaginalis was deemed to be not widely patent when a sound could not be passed into the abdominal cavity through the internal inguinal ring, and the processus vaginalis was not ligated in such cases. RESULTS: Intraoperative findings revealed that the processus vaginalis was widely patent in 10 testes and was not widely patent in 217. A widely patent processus vaginalis was closed via scrotal approach in 5 testes, while an inguinal approach was necessary in 5. Median followup was 44 months (range 20 to 73). Postoperative complications included reascending testis in 1 case where an inguinal approach was necessary. No patient manifested testicular atrophy or inguinal hernia. CONCLUSIONS: Low scrotal approach orchiopexy is a useful and safe procedure for treating patients with prescrotal cryptorchidism. Ligation is unnecessary when the processus vaginalis is not widely patent. PMID- 26944302 TI - Gender Identity and Sex Role of Patients Operated on for Bladder Exstrophy Epispadias. AB - PURPOSE: We evaluated whether genital deformity has an impact on gender identity and sex role in patients operated on for bladder exstrophy-epispadias complex. MATERIALS AND METHODS: A total of 62 adolescents and adults operated on for bladder exstrophy-epispadias complex were mailed questionnaires evaluating gender identity (Gender Identity/Gender Dysphoria Questionnaire for Adolescents and Adults) and sex role (Bem Sex Role Inventory). Of the patients 33 responded and the results were compared with 99 gender matched controls. RESULTS: On the gender identity questionnaire female patients had median scores similar to those of their gender matched controls (4.93 vs 4.89, p = 0.412) but in males the score was lower compared to controls (4.87 vs 4.96, p = 0.023), indicating somewhat more conflicted gender identity. However, no patient had gender dysphoria. Female sex role index was higher in female patients vs controls (5.9 vs 5.3, p = 0.003) but was comparable between male patients and controls (5.2 vs 5.0, p = 0.459). Masculine sex role indices were comparable between female patients and controls as well as between male patients and controls. Of 32 patients 17 were considered to have androgynous sex role, as were 24 of 97 controls (p = 0.004). The exact diagnosis (bladder exstrophy or epispadias) or dissatisfaction with appearance of the genitals had no impact on gender identity or on sex role indices. CONCLUSIONS: Male patients had lower gender identity scores compared to controls and female sex role was enhanced among female patients. Androgynous sex role was more common in patients vs controls. Gender dysphoria was not noted in any patient. PMID- 26944303 TI - Revealing the production process of Joaquin Albarran's Les Tumeurs de la Vessie 125 years after its writing. AB - OBJECTIVE: Investigate how in 1891 Joaquin Albarran organised and wrote his Les Tumeurs de la Vessie, a manuscript printed by Georges Steinheil in 1892. MATERIAL AND METHODS: An analysis was conducted of the manuscript that compiles the casuistry set forth in the work, which helps us understand his production process. The contents of the text are analysed, revealing the originality and value of the text in the manuscript. RESULTS: The book describes the author's personal histopathology findings from surgical and autopsied cases in Necker Hospital between 1868 and 1891: 28 numbered autopsy specimens and 67 identified by the patient's name (or, in lieu thereof, the physician's name, bed, ward and date of surgery). The notebook also contains the preliminary design of a number of photomicrographs printed in the book. Histopathology data are provided on the classification of bladder cancer, the pathway of lymphocytic spread, the genesis of cancer, tumoural heterogeneity and a number of original descriptions (squamous cell carcinoma, Von Brunn nests). Other notable clinical concepts include diagnostic symptomatology, prognosis assessment, extirpation by vesical height (with primary closure of the bladder and abdominal wall), the role of nascent endoscopic tumour extirpation and the experimental development of radical cystectomy with urinary diversion. CONCLUSIONS: Joaquin Albarran analysed his experience and that of professors Reverdin, Guyon and Horteloup. He reviewed autopsies and surgical specimens from patients and performed the histopathology study in each case. The main original observations from the work are discussed. PMID- 26944305 TI - Predictive Markers for the Efficacy of Anti-PD-1/PD-L1 Antibodies in Lung Cancer. AB - Blockade of the programmed death protein 1 (PD-1)/programmed death ligand 1 (PD L1) axis using antibodies against the associated receptors and ligands has yielded good clinical responses and improved overall survival in patients with non-small cell lung cancer (NSCLC). Once patients show a response to anti-PD-1/PD L1 antibody, the median duration of response is often longer than that achieved using existing cytotoxic agents and even some molecular targeted agents. However, the response rates to these antibodies are only 15% to 20% in unselected patients with NSCLC and the cost of this therapy is high. Therefore, there is an urgent need for effective predictive biomarkers to identify patients likely to benefit. PD-L1 expression, which can be detected by immunohistochemical analysis, is a rational biomarker for selecting responders to anti-PD-1/PD-L1 antibody treatments, and this selection method has been introduced into clinical practice. However, the response rate to anti-PD-1/PD-L1 antibody in PD-L1-expressing patients with NSCLC is only 15% to 45%, response can occur in PD-L1-negative patients, and predictability based on PD-L1 expression may differ between nonsquamous NSCLC and squamous cell NSCLC. In addition, the methods of immunohistochemical analysis and evaluation of its results differ for different anti-PD-1/PD-L1 agents. This article reviews the existing data on predictive markers for the efficacy of anti-PD-1/PD-L1 antibodies in NSCLC. PMID- 26944304 TI - The IASLC Lung Cancer Staging Project: Background Data and Proposed Criteria to Distinguish Separate Primary Lung Cancers from Metastatic Foci in Patients with Two Lung Tumors in the Forthcoming Eighth Edition of the TNM Classification for Lung Cancer. AB - INTRODUCTION: It can be difficult to distinguish between a second primary and a metastasis in patients with lung cancer who have more than one pulmonary site of cancer. METHODS: A systematic review of the literature was conducted by a subcommittee of the International Association for the Study of Lung Cancer Staging and Prognostic Factors Committee to develop recommendations to identify second primary lung cancers. The process entailed review of knowledge relating to the mechanism of metastasis, determination of clonality, and outcomes of patients with resected tumors. RESULTS: It is easier to determine that two tumors are different than that they are the same; finding similarities does not establish that they are the same. For example, most second primary lung cancers are of the same histotype. Few criteria are reliable by themselves; these include different histologic cancer types or matching DNA breakpoints by sequencing and a comprehensive histologic assessment of resected specimens. Characteristics that are suggestive but associated with potential misclassification include the presence or absence of biomarkers, imaging characteristics, and the presence or absence of nodal involvement. CONCLUSIONS: Clinical and pathologic (i.e., after resection) criteria are presented to identify two foci as separate primary lung cancers versus a metastasis. Few features are definitive; many commonly used characteristics are suggestive but associated with a substantial rate of misclassification. Careful review by a multidisciplinary tumor board, considering all available information, is recommended. PMID- 26944306 TI - p44/42MAPK and p90RSK modulate thermal stressed physiology response in Apostichopus japonicus. AB - Reversible protein phosphorylation (RPP) plays a key role in signal transduction, enzyme activity and metabolic maintenance in response to extreme changes in the environment. In this study, we identified 55 phosphorylated proteins in Apostichopus japonicus coelomocytes by iTRAQ analysis, and sixteen proteins displayed differently expressed profiles between thermal stressed and control groups. Mitogen-activated protein kinase (MAPK) signaling cascade was further characterized by Western blot. Spatial expression analysis revealed that phospho p44/42MAPK levels were mainly detected in coelomocytes and muscle, and no signal in intestine and respiratory trees, although the protein were constitutively expressed in all examined tissues. Time-course expression analysis shown that the amount of phospho-p44/42MAPK decreased by 57-60% in coelomocytes and 29-40% in muscle in acute exposure stage of 20 degrees C and 25 degrees C, respectively. In higher temperature remaining stage, phospho-p44/42MAPK was both induced with 1.7 fold increase at 20 degrees C and 5.2-fold at 25 degrees C at the first 12h in coelomocytes, which was consistent with the change of p44/42MAPK. Similarly, 2.5 fold and 2.7-fold increases were detected in muscle at corresponding exposure temperature. In contrast, the p44/42MAPK in muscle showed depressed expression profiles. As time progressed, phospho-p44/42MAPK levels were all decreased significantly both in coelomocytes and in muscles. A reduction in phosphorylation levels was detected at 84h in 20 degrees C exposed coelomocytes with 0.42-fold decrease, and at 36h in 25 degrees C challenged muscle by 0.80-fold decrease. Correlated expression profiles between phospho-p90RSK and phospho-p44/42MAPK suggest that p44/42MAPK may be involved in temperature-induced metabolic suppression through targeting p90RSK in A. japonicus. PMID- 26944308 TI - Comparative analysis of expression profiling of the trypsin and chymotrypsin genes from Lepidoptera species with different levels of sensitivity to soybean peptidase inhibitors. AB - Peptidase inhibitors (PIs) are essential proteins involved in plant resistance to herbivorous insects, yet many insect species are able to escape the negative effects of these molecules. We compared the effects of acute and chronic ingestion of soybean peptidase inhibitors (SPIs) on Spodoptera frugiperda and Diatraea saccharalis, two Lepidoptera species with different sensitivities to SPI ingestion. We analyzed the trypsin and chymotrypsin gene expression profiles in both species. Acute exposure of S. frugiperda to the inhibitors activated seven genes (SfChy5, SfChy9, SfChy19, SfChy22, SfTry6, SfTry8, and SfTry10), whereas chronic exposure activated 16 genes (SfChy2, SfChy4, SfChy5, SfChy8, SfChy9, SfChy11, SfChy12, SfChy15, SfChy17, SfChy21, SfChy22, SfTry6, SfTry8, SfTry9, SfTry10, and SfTry12). By contrast, the challenge of D. saccharalis with SPIs did not differentially induce the expression of trypsin- or chymotrypsin-encoding genes, with the exception of DsChy7. Bayesian phylogenetic analysis of S. frugiperda trypsin protein sequences revealed two gene clades: one composed of genes responsive to the SPIs and a second composed of the unresponsive genes. D. saccharalis trypsin proteins were clustered nearest to the S. frugiperda unresponsive genes. Overall, our findings support a hypothesized mechanism of resistance of Noctuidae moths to SPIs, involving gene number expansion of trypsin and chymotrypsin families and regulation of gene expression, which could also explain the variable susceptibility between S. frugiperda and D. saccharalis to these plant inhibitors. PMID- 26944307 TI - Molecular cloning and functional characterization of spexin in orange-spotted grouper (Epinephelus coioides). AB - Spexin is a newly discovered neuropeptide in vertebrates. Comprehensive comparative studies are required to unveil its biological functions. In order to ascertain the neuroendocrine function of spexin in orange-spotted grouper, its full-length cDNA and genomic DNA sequences were cloned and analyzed. Sequence analyses showed that the spexin gene structure is composed of six exons and five introns, and the amino acids of mature peptide (spexin-14) in grouper are identical to that of other fish. Tissue expression analysis found that grouper spexin is highly expressed in the brain, liver and ovary. Real time-PCR analysis demonstrated that the hypothalamic expression of spexin declined gradually during the ovarian development, and was up-regulated by food deprivation. Intraperitoneal administration of spexin-14 peptides to grouper significantly elevated the mRNA levels of proopiomelanocortin (pomc) and suppressed the orexin expression in the hypothalamus, but could not change the hypothalamic expression of gonadotropin releasing hormone 1 (gnrh1). Both in vivo and in vitro administration of spexin could not significantly influence the expression of follicle-stimulating hormone beta (fshbeta) and luteinizing hormone beta (lhbeta) in the pituitary with the exception of an inhibition of gh expression. Our data suggested that the spexin has a significant role in the regulation of energy metabolism and food intake in orange-spotted grouper. PMID- 26944309 TI - New pricing approaches for bundled payments: Leveraging clinical standards and regional variations to target avoidable utilization. AB - OBJECTIVES: Develop pricing models for bundled payments that draw inputs from clinician-defined best practice standards and benchmarks set from regional variations in utilization. DATA: Health care utilization and claims data for a cohort of incident Ontario ischemic and hemorrhagic stroke episodes. Episodes of care are created by linking incident stroke hospitalizations with subsequent health service utilization across multiple datasets. STUDY DESIGN: Costs are estimated for episodes of care and constituent service components using setting specific case mix methodologies and provincial fee schedules. Costs are estimated for five areas of potentially avoidable utilization, derived from best practice standards set by an expert panel of stroke clinicians. Alternative approaches for setting normative prices for stroke episodes are developed using measures of potentially avoidable utilization and benchmarks established by the best performing regions. PRINCIPAL FINDINGS: There are wide regional variations in the utilization of different health services within episodes of stroke care. Reconciling the best practice standards with regional utilization identifies significant amounts of potentially avoidable utilization. Normative pricing models for stroke episodes result in increasingly aggressive redistributions of funding. CONCLUSIONS: Bundled payment pilots to date have been based on the costs of historical service patterns, which effectively 'bake in' unwarranted and inefficient variations in utilization. This study demonstrates the feasibility of novel clinically informed episode pricing approaches that leverage these variations to target reductions in potentially avoidable utilization. PMID- 26944310 TI - Using MRI to Reveal (and Resolve) the Complexity of Obstructive Lung Disease. PMID- 26944312 TI - Commentary on Murray and Hernan. PMID- 26944311 TI - Rapid acquisition of HPV around the time of sexual debut in adolescent girls in Tanzania. AB - BACKGROUND: No reports exist on genotype-specific human papillomavirus (HPV) acquisition in girls after first sex in sub-Saharan Africa, despite high HPV prevalence and cervical cancer incidence. METHODS: We followed 503 HP unvaccinated girls aged 15-16 years in Mwanza, Tanzania, 3-monthly for 18 months with interviews and self-administered vaginal swabs. Swabs were tested for 13 higHRisk and 24 low-risk HPV genotypes. Incidence, clearance and duration of overall HPV and genotype-specific infections were calculated and associated factors evaluated. RESULTS: A total of 106 participants reported first sex prior to enrolment (N = 29) or during follow-up (N = 77). One was HIV-positive at the final visit. The remaining 105 girls contributed 323 adequate specimens. Incidence of any new HPV genotype was 225/100 person-years (pys), and incidence of vaccine types HPV-6, -11, -16 and -18 were 12, 2, 2 and 7/100 pys, respectively. Reporting sex in the past 3 months and knowing the most recent sexual partner for a longer period before sex were associated with HPV acquisition. Median time from reported sexual debut to first HPVinfection was 5 months, and infection duration was 6 months. CONCLUSION: This is the first description of HPV acquisition after first sex in sub-Saharan Africa where the incidence of cervical cancer is amongst the highest in the world. HPV incidence was very high after first sex, including some vaccine genotypes, and infection duration was short. This very high HPV incidence may help explain high cervical cancer rates, and supports recommendations that the HPV vaccine should be given to girls before first sex. PMID- 26944313 TI - NUMB inactivation confers resistance to imatinib in chronic myeloid leukemia cells. AB - Chronic myeloid leukemia (CML) progresses from a chronic to a blastic phase, where the leukemic cells are proliferative and undifferentiated. The CML is nowadays successfully treated with BCR-ABL kinase inhibitors as imatinib and its derivatives. NUMB is an evolutionary well-conserved protein initially described as a functional antagonist of NOTCH function. NUMB is an endocytic protein associated with receptor internalization, involved in multiple cellular functions. It has been reported that MSI2 protein, a NUMB inhibitor, is upregulated in CML blast crisis, whereas NUMB itself is downregulated. This suggest that NUMB plays a role in the malignant progression of CML. Here we have generated K562 cells (derived from CML in blast crisis) constitutively expressing a dominant negative form of NUMB (dnNUMB). We show that dnNUMB expression confers a high proliferative phenotype to the cells. Importantly, dnNUMB triggers a partial resistance to imatinib in these cells, antagonizing the apoptosis mediated by the drug. Interestingly, imatinib resistance is not linked to p53 status or NOTCH signaling, as K562 lack p53 and imatinib resistance is reproduced in the presence of NOTCH inhibitors. Taken together, our data support the hypothesis that NUMB activation could be a new therapeutic target in CML. PMID- 26944315 TI - Nuclear accumulation of Yes-Associated Protein (YAP) maintains the survival of doxorubicin-induced senescent cells by promoting survivin expression. AB - Although chemotherapeutic drugs can induce senescence to prohibit further division of tumor cells, senescence could also promote tumorigenesis mainly through a senescence-associated secretory phenotype. Therefore, senescent tumor cells should be eliminated immediately to prevent drug resistance and recurrence. Here, we used a doxorubicin-induced senescence model to explore the mechanism underlying the survival of therapy-induced senescent cells. After low-dose doxorubicin treatment, tumor cells turned on a senescence program and became large and flattened, increasing their contact area with the extracellular matrix (ECM). Furthermore, Yes-associated protein (YAP) accumulated in the nucleus and YAP activity was increased in doxorubicin-induced senescent cells. Knockdown of YAP increased the sensitivity of cells to low-dose doxorubicin treatment, causing apoptosis rather than senescence. Moreover, the anti-apoptotic gene survivin, a YAP target gene, was overexpressed in senescent cells. Inhibition of survivin could lead to selective elimination of senescent cells through apoptosis. Our study indicates that nuclear accumulation of YAP could promote the survival of senescent cells by increasing survivin expression. Therefore, targeting YAP or survivin might be a new strategy for clearing senescent cancer cells during drug treatment. PMID- 26944316 TI - Hexamethylene amiloride engages a novel reactive oxygen species- and lysosome dependent programmed necrotic mechanism to selectively target breast cancer cells. AB - Anticancer chemotherapeutics often rely on induction of apoptosis in rapidly dividing cells. While these treatment strategies are generally effective in debulking the primary tumor, post-therapeutic recurrence and metastasis are pervasive concerns with potentially devastating consequences. We demonstrate that the amiloride derivative 5-(N,N-hexamethylene) amiloride (HMA) harbors cytotoxic properties particularly attractive for a novel class of therapeutic agent. HMA is potently and specifically cytotoxic toward breast cancer cells, with remarkable selectivity for transformed cells relative to non-transformed or primary cells. Nonetheless, HMA is similarly cytotoxic to breast cancer cells irrespective of their molecular profile, proliferative status, or species of origin, suggesting that it engages a cell death mechanism common to all breast tumor subtypes. We observed that HMA induces a novel form of caspase- and autophagy-independent programmed necrosis relying on the orchestration of mitochondrial and lysosomal pro-death mechanisms, where its cytotoxicity was attenuated with ROS-scavengers or lysosomal cathepsin inhibition. Overall, our findings suggest HMA may efficiently target the heterogeneous populations of cancer cells known to reside within a single breast tumor by induction of a ROS- and lysosome-mediated form of programmed necrosis. PMID- 26944317 TI - SOX7 is associated with the suppression of human glioma by HMG-box dependent regulation of Wnt/beta-catenin signaling. AB - SOX7 has been recently recognized as a tumor suppressor belonging to the SOX (SRY related HMG-box) family of a transcription factor. However, its role in human gliomas is unknown. Our study showed that SOX7 expression was significantly downregulated in human gliomas. Statistical analysis showed that SOX7 suppression was associated with higher histological grades of tumors in glioma tissues. SOX7 could suppress tumor properties both in vivo and in vitro, and depletion of the HMG domain abolishes its tumor suppressive roles. In vitro assays demonstrated that SOX7 could downregulate Wnt/beta-catenin transcription and decrease the expression of Cyclin D1 and c-Myc, while the mutant SOX7 lost these functions. These results suggested that the HMG-box is a key domain of SOX7 for negatively regulating the Wnt/beta-catenin signaling pathway when functioning as a tumor suppressor in a glioma. PMID- 26944318 TI - MicroRNA-379-5p inhibits tumor invasion and metastasis by targeting FAK/AKT signaling in hepatocellular carcinoma. AB - Some microRNAs (miRNAs) have been implicated in hepatocellular carcinoma (HCC) development and progression. However, the roles and mechanisms of several miRNAs in HCC remain poorly understood. Here, we report that miR-379-5p, which is down regulated in HCC tissues and cell lines, is associated with advanced TNM stage and metastasis in HCC. The ectopic overexpression of miR-379-5p inhibited HCC cell migration, invasion, epithelial-to-mesenchymal transition (EMT) and metastasis both in vitro and in vivo. Conversely, miR-379 knockdown increased migration, invasion and EMT in HCC cells. Moreover, miR-379-5p exerted this function by directly targeting focal adhesion kinase (FAK) 3'-UTR and repressing FAK expression, thus leading to suppression of AKT signaling. Furthermore, the tumor suppressive effects of miR-379-5p in HCC cells were reversed by activating AKT signaling or restoring FAK expression. In clinical samples of HCC, miR-379-5p negatively correlated with FAK, which was up-regulated in HCC. Taken together, our findings highlight the important role of miR-379-5p in regulating the EMT and metastasis of HCC by targeting FAK/AKT signaling, suggesting that miR-379-5p may represent a novel potential therapeutic target and prognostic marker for HCC. PMID- 26944319 TI - Correlation between the radiation responses of fibroblasts cultured from individual patients and the risk of late reaction after breast radiotherapy. AB - Late normal tissue toxicity varies widely between patients and limits breast radiotherapy dose. Here we aimed to determine its relationship to DNA damage responses of fibroblast cultures from individual patients. Thirty-five breast cancer patients, with minimal or marked breast changes after breast-conserving therapy consented to receive a 4 Gy test irradiation to a small skin field of the left buttock and have punch biopsies taken from irradiated and unirradiated skin. Early-passage fibroblast cultures were established by outgrowth and irradiated in vitro with 0 or 4 Gy. 53BP1 foci, p53 and p21/CDKN1A were detected by immunofluorescence microscopy. Residual 53BP1 foci counts 24 h after in vitro irradiation were significantly higher in fibroblasts from RT-sensitive versus RT resistant patients. Furthermore, significantly larger fractions of p53- but not p21/CDKN1A-positive fibroblasts were found in cultures from RT-sensitive patients without in vitro irradiation, and 2 h and 6 d post-irradiation. Exploratory analysis showed a stronger p53 response 2 h after irradiation of fibroblasts established from patients with severe reaction. These results associate the radiation response of fibroblasts with late reaction of the breast after RT and suggest a correlation with severity. PMID- 26944320 TI - A Critical Evaluation of the Methodological Obstacles to Translating Cell-Based Research Into an Effective Treatment for People With Parkinson's Disease. AB - The remarkable scientific and technological advances in the field of cell research have not been translated into viable restorative therapies for brain disorders. In this article, we examine the best available evidence for the clinical efficacy of reconstructive intracerebral transplantation in people with Parkinson's disease (PD), with the aim of identifying methodological obstacles to the translation process. The major stumbling block is the fact that the potential contributions of people with neural grafts and the effects of the physical and social environment in which they recover have not been adequately investigated and applied to advancing the clinical stages of the research program. We suggest that the biopsychosocial model along with emerging evidence of targeted rehabilitation can provide a useful framework for conducting research and evaluation that will ensure the best possible outcomes following intracerebral transplantation for PD. PMID- 26944321 TI - Cardiac surgeons at Birmingham hospital must submit weekly mortality data after higher than expected deaths. PMID- 26944322 TI - Threshold for NIH stroke scale in predicting vessel occlusion and functional outcome after stroke thrombolysis can change. PMID- 26944314 TI - Radiogenomics: A systems biology approach to understanding genetic risk factors for radiotherapy toxicity? AB - Adverse reactions in normal tissue after radiotherapy (RT) limit the dose that can be given to tumour cells. Since 80% of individual variation in clinical response is estimated to be caused by patient-related factors, identifying these factors might allow prediction of patients with increased risk of developing severe reactions. While inactivation of cell renewal is considered a major cause of toxicity in early-reacting normal tissues, complex interactions involving multiple cell types, cytokines, and hypoxia seem important for late reactions. Here, we review 'omics' approaches such as screening of genetic polymorphisms or gene expression analysis, and assess the potential of epigenetic factors, posttranslational modification, signal transduction, and metabolism. Furthermore, functional assays have suggested possible associations with clinical risk of adverse reaction. Pathway analysis incorporating different 'omics' approaches may be more efficient in identifying critical pathways than pathway analysis based on single 'omics' data sets. Integrating these pathways with functional assays may be powerful in identifying multiple subgroups of RT patients characterised by different mechanisms. Thus 'omics' and functional approaches may synergise if they are integrated into radiogenomics 'systems biology' to facilitate the goal of individualised radiotherapy. PMID- 26944323 TI - Phosphodiesterase inhibitor KMUP-3 displays cardioprotection via protein kinase G and increases cardiac output via G-protein-coupled receptor agonist activity and Ca(2+) sensitization. AB - KMUP-3 (7-{2-[4-(4-nitrobenzene) piperazinyl]ethyl}-1, 3-dimethylxanthine) displays cardioprotection and increases cardiac output, and is suggested to increase cardiac performance and improve myocardial infarction. To determine whether KMUP-3 improves outcomes in hypoperfused myocardium by inducing Ca(2+) sensitization to oppose protein kinase (PK)G-mediated Ca(2+) blockade, we measured left ventricular systolic blood pressure, maximal rates of pressure development, mean arterial pressure and heart rate in rats, and measured contractility and expression of PKs/RhoA/Rho kinase (ROCK)II in beating guinea pig left atria. Hemodynamic changes induced by KMUP-3 (0.5-3.0 mg/kg, intravenously) were inhibited by Y27632 [(R)-(+)-trans-4-1-aminoethyl)-N-(4 Pyridyl) cyclohexane carboxamide] and ketanserin (1 mg/kg, intravenously). In electrically stimulated left guinea pig atria, positive inotropy induced by KMUP 3 (0.1-100MUM) was inhibited by the endothelial NO synthase (eNOS) inhibitors N nitro-l-arginine methyl ester (L-NAME) and 7-nitroindazole, cyclic AMP antagonist SQ22536 [9-(terahydro-2-furanyl)-9H-purin-6-amine], soluble guanylyl cyclase (sGC) antagonist ODQ (1H-[1,2,4] oxadiazolo[4,3-a] quinoxalin-1-one), RhoA inhibitor C3 exoenzyme, beta-blocker propranolol, 5-hydroxytryptamine 2A antagonist ketanserin, ROCK inhibitor Y27632 and KMUP-1 (7-{2-[4-(2 chlorobenzene) piperazinyl]ethyl}-1, 3-dimethylxanthine) at 10MUM. Western blotting assays indicated that KMUP-3 (0.1-10MUM) increased PKA, RhoA/ROCKII, and PKC translocation and CIP-17 (an endogenous 17-kDa inhibitory protein) activation. In spontaneous right atria, KMUP-3 induced negative chronotropy that was blunted by 7-nitroindazole and atropine. In neonatal myocytes, L-NAME inhibited KMUP-3-induced eNOS phosphorylation and RhoA/ROCK activation. In H9c2 cells, Y-27632 (50MUM) and PKG antagonist KT5823 [2,3,9,10,11,12-hexahydro-10R- methoxy-2,9-dimethyl-1-oxo-9S,12R-epoxy-1H-diindolo(1,2,3-fg:3',2',1'-kl) pyrrolo(3,4-i)(1,6)benzodiazocine-10-carboxylic acid, methyl ester] (3MUM) reversed KMUP-3 (1-100MUM)-induced Ca(2+)-entry blockade. GPCR agonist activity of KMUP-3 appeared opposed to KMUP-1, and increased cardiac output via Ca(2+) sensitization, and displayed cardioprotection via cyclic GMP/PKG-mediated myocardial preconditioning in animal studies. PMID- 26944324 TI - Anticancer effects of clinically acceptable colchicine concentrations on human gastric cancer cell lines. AB - Colchicine is a very cheap microtubule destabilizer. Because microtubules are an ideal target for anticancer drugs, the purpose of this study was to investigate whether clinically acceptable colchicine concentrations have anticancer effects on gastric cancer cells, and its possible anticancer mechanisms. Two human gastric cancer cell lines (i.e., AGS and NCI-N87) were investigated by proliferative assay, microarray, quantitative reverse transcriptase-polymerase chain reaction, and a nude mice study using clinically acceptable colchicine concentrations (2 ng/mL and 6 ng/mL for in vitro tests and 0.07 mg colchicine/kg/d for in vivo tests). Our results showed that colchicine had the same inhibitory effects on the proliferation of both cell lines. The antiproliferative effects of colchicine on both cell lines were achieved only at the concentration of 6 ng/mL (p < 0.0001). In both cell lines, 18 genes were consistently upregulated and 10 genes were consistently downregulated by 6 ng/mL colchicine, compared with 2 ng/mL colchicine. Among these genes, only the upregulated DUSP1 gene may contribute to the antiproliferative effects of colchicine on gastric cancer cells. The nude mice (BALB/c-nu) experiment showed that colchicine-treated mice after 14 days of treatment had lower increased tumor volume ratios (p = 0.0199) and tumor growth rates (p = 0.024) than the control mice. In conclusion, colchicine has potential for the palliative treatment of gastric cancer. However, the anticancer effects are achieved only at high clinically acceptable colchicine concentrations. Monitoring the colchicine plasma concentration is mandatory if this drug is applied for the palliative treatment of gastric cancer. PMID- 26944325 TI - Predictive values of vascular endothelial growth factor and microvessel-density levels in initial biopsy for prostate cancer. AB - Angiogenesis is an important factor in the development and progression of prostate cancer (PCA). We aimed to investigate the values of vascular-endothelial growth-factor (VEGF) expression level and microvessel density (MVD) in the prediction of PCA diagnosis at repeated prostate biopsy (re-PBx). We retrospectively evaluated 167 patients with re-PBx according to elevated prostate specific antigen levels, suspicious digital rectal examination, and the presence of premalignant lesions. Patients with PCA on re-PBx were included in the cancer group (n = 17). Patients with benign prostatic hyperplasia or normal tissues on re-PBx were included in the control group (n = 21). The groups were compared according to the expression level of VEGF and MVD in initial prostate biopsy. There was no statistically significant difference between groups according to age and serum prostate-specific-antigen values. The mean VEGF scores of the cancer and control groups were 232.64 +/- 11.14 and 183.09 +/- 14.56, respectively (p < 0.05). The mean MVD of the biopsy samples in the cancer and control groups were 246.47 +/- 17.59 n/mm(2) and 197.33 +/- 16.26 n/mm(2), respectively (p < 0.05). The cutoff values of VEGF scores and MVD were set as 200 and 215, respectively, for PCA detection in our study. Our results showed that the expression level of VEGF and MVD significantly increased in the initial prostate-biopsy samples of patients with PCA diagnosed with re-PBx. The evaluation of VEGF expression level and MVD might have an important value in the prediction of PCA at re-PBx. The expression level of VEGF and MVD should be kept in mind as PCA-related histopathological changes that indicate the increased angiogenesis in prostatic tissue. PMID- 26944326 TI - Comparison of sugammadex and neostigmine-atropine on intraocular pressure and postoperative effects. AB - During surgery, changes in intraocular pressure (IOP) can be observed resulting from several factors, such as airway manipulations and drugs used. We aimed to investigate the effects of sugammadex and neostigmine on IOP, hemodynamic parameters, and complications after extubation. Our study comprised 60 patients, aged 18-65 years, with a risk status of the American Society of Anesthesiologists I-II who underwent arthroscopic surgery under general anesthesia. The patients were randomly assigned into two groups. At the end of the surgery, the neuromuscular block was reversed using neostigmine (50 MUg/kg) plus atropine (15 MUg/kg) in Group 1, and sugammadex (4 mg/kg) in Group 2. Neuromuscular blockade was monitored using acceleromyography and a train-of-four mode of stimulation. IOP was measured before induction and at 30 seconds, 2 minutes, and 10 minutes after extubation. A Tono-Pen XL applanation tonometer was used to measure IOP. This showed that elevation in IOP of patients reversed using sugammadex was similar to that recorded in patients reversed using neostigmine-atropine. When heart rate was compared, there was a significant difference between basal values and those obtained at 30 seconds and 10 minutes after extubation in the neostigmine-atropine group. Extubation time (time from withdrawal of anesthetic gas to extubation) was significantly shorter in the sugammadex group (p = 0.003) than in the neostigmine-atropine group. The postextubation IOP values of the sugammadex group were similar to the neostigmine-atropine group. Extubation time (time from withdrawal of anesthetic gas to extubation) was significantly shorter in the sugammadex group (p = 0.003) than in the neostigmine-atropine group. PMID- 26944328 TI - The relationship between platelet-lymphocyte ratio and severity of erectile dysfunction. AB - The prognostic importance of platelet-lymphocyte ratio (PLR) is already known for various artery diseases. In this study, the relationship between PLR and severity of erectile dysfunction (ED) is examined in patients with impotence. The data from patients suffering from erection problems was screened retrospectively. Detailed medical history, age, International Index of Erectile Function-5 (IIEF 5) scores, fasting blood glucose, lipid, whole blood count, and hormone profile values were examined. Patients with no ED were selected as the control group. All men answered the IIEF-5 questions and were then classified according to their scores. Patients were determined to have severe ED (scores 5-7), moderate ED (scores 8-16), or mild ED (scores 17-21). An IIEF-5 score greater than 21 was accepted for the control group. The PLR values from both patient and control groups were evaluated. Demographic data were similar in both groups. Mean PLR value was 104 in control and 118 in the patient group (p < 0.001). PLR value increased depending on the severity of ED. Mean PLR values were 108 in mild, 116 in moderate, and 130 in severe ED groups. Compared with the control group, this value was statistically significant for patients with moderate and severe ED (p = 0.04 and p < 0.001). PLR showed weak negative but significant correlation with IIEF-5 scores (r = -0.27 and p < 0.001). The PLR value was found to be higher in patients with ED. PLR value may be related to ED and its severity in patients with impotence. PMID- 26944327 TI - Usefulness of the platelet-to-lymphocyte ratio in predicting the severity of carotid artery stenosis in patients undergoing carotid angiography. AB - Carotid artery stenosis (CAS) is primarily caused by atherosclerotic plaque. Progressive inflammation may contribute to the rupture of an atherosclerotic plaque. The platelet-to-lymphocyte ratio (PLR) is a new and simple marker that indicates inflammation. In this study, we aimed to investigate the use of the PLR to determine the severity of CAS. One hundred forty patients were chosen from among patients who underwent carotid angiography in our institution. Symptomatic patients with stenosis >50% in the carotid arteries and asymptomatic patients with stenosis >80% were diagnosed via carotid angiography as having critical stenosis. Patients were classified into two groups. Group 1 included patients who had critical CAS, whereas Group 2 included patients with noncritical CAS, as determined by carotid angiography. Correlations between the PLR and the severity of CAS were analyzed. There were no significant differences in sex and age between the two groups. The PLR was 162.5 +/- 84.7 in the noncritical CAS group patients and 94.9 +/- 60.3 in the critical CAS group patients (p < 0.0001). The PLR value of 117.1 had 89% sensitivity and 68% specificity for CAS [95% confidence interval, 0.043-0.159; area under the curve, 0.101 +/- 0.03)]. In this study, we have shown that PLR values may be associated with critical stenosis in at least one of the carotid arteries. Furthermore, PLR values may be used to predict critical stenosis in the carotid arteries. PMID- 26944329 TI - Anti-HIV seropositivity was related to HBsAg seropositivity among injecting drug users in Taiwan. AB - In Taiwan, the number of new cases of human immunodeficiency virus (HIV) infection via drug injection has been increasing since 2003. Due to HIV and hepatitis B virus (HBV) having similar transmission routes, HBV and HIV infections among injecting drug users (IDUs) has become an important public health issue. The aim of this study was explore the prevalence of HBV infection among IDUs with and without HIV infection, and examine whether HIV infection is associated with HBV infection among IDUs in Southern Taiwan. We enrolled 566 IDUs, including 87 anti-HBV positive IDUs and 479 anti-HBV negative IDUs, and also analyzed the results of liver function tests, HBV DNA, anti-HIV, HIV RNA, and CD4 cell count. The results showed that the prevalence of HBV infection among IDUs was 15.4%. The prevalence of hepatitis B surface antigen (HBsAg) was higher among individuals born before 1985 (15.9% vs. 4.0%), but this was not significant. Anti-HIV seropositivity was related to HBsAg seropositivity [odds ratio (OR) = 2.47, 95% confidence interval = 1.26-4.82, p = 0.008). Anti-HCV and anti-HIV were risk factors for abnormal alanine aminotransferase (ALT; OR = 2.11, 95% confidence interval = 1.005-4.42, p = 0.048 and OR = 1.47, 95% confidence interval = 1.02-2.10, p = 0.04, respectively), and HBsAg was not a factor related to abnormal ALT. In conclusion, the prevalence of HBV infection was similar in the general population and in IDUs, and due to anti-HIV seropositivity being significantly related to HBsAg seropositivity, HBV infection among IDUs is still important. We suggest that for IDUs, HBsAg should be monitored closely. PMID- 26944330 TI - Anxiety and depression among adolescents with attention-deficit/hyperactivity disorder: The roles of behavioral temperamental traits, comorbid autism spectrum disorder, and bullying involvement. AB - The aim of this study was to examine the associations of behavioral temperamental traits, comorbid autism spectrum disorder (ASD), and bullying involvement with anxiety and depression among adolescents with attention-deficit/hyperactivity disorder (ADHD) in Taiwan. A total of 287 adolescents aged 11-18 years diagnosed with ADHD participated in this study. Their severities of anxiety and depression were assessed. Multiple regression analysis was used to examine the correlates of anxiety and depression. The results show that adolescents with ADHD who reported a higher behavioral inhibition system (BIS) score, had comorbid ASD, and were bullying victims, reported more severe anxiety and depressive symptoms. Adolescents with ADHD who bullied others reported more severe depressive symptoms than those who did not bully. The results of this study indicated that behavioral temperamental traits on the BIS, comorbid ASD, and bullying involvement were significantly associated with anxiety and depression among the adolescents with ADHD. PMID- 26944331 TI - Paramedian pons infarction with wall-eye monocular internuclear ophthalmoplegia syndrome. PMID- 26944332 TI - DSS1/Sem1, a Multifunctional and Intrinsically Disordered Protein. AB - DSS1/Sem1 is a versatile intrinsically disordered protein. Besides being a bona fide subunit of the 26S proteasome, DSS1 associates with other protein complexes, including BRCA2-RPA, involved in homologous recombination; the Csn12-Thp3 complex, involved in RNA splicing; the integrator, involved in transcription; and the TREX-2 complex, involved in nuclear export of mRNA and transcription elongation. As a subunit of the proteasome, DSS1 functions both in complex assembly and possibly as a ubiquitin receptor. Here, we summarise structural and functional aspects of DSS1/Sem1 with particular emphasis on its multifunctional and disordered properties. We suggest that DSS1/Sem1 can act as a polyanionic adhesive to prevent nonproductive interactions during construction of protein assemblies, uniquely employing different structures when associating with the diverse multisubunit complexes. PMID- 26944333 TI - BDNF pathway is involved in the protective effects of SS-31 on isoflurane-induced cognitive deficits in aging mice. AB - Mitochondrial dysfunction has been linked to the earliest pathogenesis of isoflurane-induced cognitive impairments in developing or aging mammalian brain. However, its molecular mechanism is poorly understood and a pharmacologic treatment to rapidly reverse mitochondrial dysfunction is lacking. Fifteen-month old male C57BL/6 mice were exposed to isoflurane for two hours following intraperitoneal administration of mitochondrion-targeted peptide SS-31 or vehicle with 30min interval. The hippocampus was immediately removed for biochemical assays and mitochondria isolation after inhalation. Behavioral tests were evaluated by the open field test and fear conditioning test 24h after the experiment. We showed that cognitive deficits induced by exposure of the aging mice to isoflurane were accompanied by mitochondrial dysfunction in hippocampus due to loss of the enzymatic activity of complex I. This loss resulted in the increase of reactive oxygen species production, decrease of ATP production and mitochondrial membrane potential, and opening of mitochondrial permeability transition pore. Further, we provided evidence that the BDNF signaling pathway was involved in this process to regulate synaptic plasticity-related proteins, for instance, downregulation of synapsin 1, PSD-95 and p-CREB, and upregulation of NR2A, NR2B, CaMKIIalpha and CaMKIIbeta. Of note, the isoflurane-induced cognitive deficits were rescued by SS-31 through reversal of mitochondrial dysfunction, which facilitated the regulation of BDNF signaling including the expression reversal of aforementioned important synaptic-signaling proteins in aging mice. Our data demonstrate that reversing mitochondrial dysfunction by SS 31 enhances BDNF signaling pathway and synaptic plasticity, and provides protective effects on cognitive function, thereby support the notion that SS-31 may have therapeutic benefits for elderly humans undertaking anesthesia. PMID- 26944334 TI - Nitric oxide pathway activity modulation alters the protective effects of ( )Epigallocatechin-3-gallate on reserpine-induced impairment in rats. AB - Reserpine (RES) has been reported to increase the brain's neural oxidative stress and cause cognitive dysfunction. Having powerful antioxidative properties, green tea catechins, especially (-)epigallocatechin-3-gallate (EGCG), are able to protect against many oxidative injuries. In this study, we examined the protecting properties of EGCG on RES-induced impairment of short-term memory in three-month-old male Wistar rats. RES (1mg/kg i.p.) induced memory impairment (p<0.001) as evaluated by the social recognition task. EGCG treatment (100mg/kg i.p. for 7days, starting 6days before RES injection) was able to improve the impaired memory caused by RES. RES treatment increased the nitric oxide (NO) level and lipid peroxidation (LPO) production, and decreased the antioxidation power in hippocampi. EGCG treatment was able to counteract the RES-induced NO level and LPO production, as well as enhanced the hippocampal antioxidation power in RES-treated rats. In order to examine the implication of NO pathway activity in RES treatment, either NO precursor (L-arginine; L-A) or NO synthase inhibitor (L-NAME; L-N) was co-pretreated with EGCG; NO precursor treatment eliminated the protective effect of EGCG, in contrast to that NO synthase inhibitor treatment significantly increased the EGCG effects on cognitive and biochemical protection in RES-treated rats. These results suggested that the NO pathway was implicated, at least in part, in the RES-induced impairment, as well as in the protective effect of EGCG in treating RES-induced impairment of memory. The above evidence provides a clinically relevant value for EGCG in preventing RES-induced cognitive dysfunction. PMID- 26944335 TI - Internet Searching About Disease Elicits a Positive Perception of Own Health When Severity of Illness Is High: A Longitudinal Questionnaire Study. AB - BACKGROUND: The Internet is one of the primary sources for health information. However, in research, the effects of Internet use on the perception of one's own health have not received much attention so far. OBJECTIVE: This study tested how Internet use for acquiring health information and severity of illness influence patients with a chronic disease with regard to the perception of their own health. Negative psychological states are known to lead to preferential processing of positive information. In particular, the self-directed nature of Internet use provides room for such biases. Therefore, we predicted that patients experiencing negative health states more frequently, due to more frequent episodes of a chronic illness, will gain a more positive perception of their health if they use the Internet frequently to gain health information, but not if they use the Internet rarely. This effect was not expected for other sources of information. METHODS: A longitudinal questionnaire study with two measurement points-with a 7-month time lag-tested the hypothesis in a sample of patients with chronic inflammatory bowel disease (n=208). This study assessed patients' frequency of Internet use, their participation in online social support groups, their use of other sources of health information, and several indicators of the participants' perceptions of their own health. A structure equation model (SEM) was used to test the predictions separately for Internet searches and other sources of information. RESULTS: Data analysis supported the prediction; the interaction between frequency of health-related information searches and frequency of episodes at the first measurement point (T1) was related to participants' positive perceptions of their own health at the second measurement point (T2) (B=.10, SE=.04, P=.02) above and beyond the perceptions of their own health at T1. When participants used the Internet relatively rarely (-1 SD), there was no relationship between frequency of episodes and positive perceptions of their own health (B=-.11, SE=.14, t203=-0.82, P=.41). In contrast, when participants used the Internet relatively often (+1 SD), the more frequently they had those episodes the more positive were the perceptions of their own health (B=.36, SE=.15, t203=2.43, P=.02). Additional SEM analyses revealed that this effect occurs exclusively when information is searched for on the Internet, but not when other sources of information are consulted, nor when online social support groups are joined. CONCLUSIONS: The results of this study suggest that patients might process information from the Internet selectively, in an unbalanced, biased fashion, with the formation of a self-serving (ie, positive) perception of own health. At the same time, this bias contributes to the ability of patients to cope psychologically with their disease. PMID- 26944336 TI - Initial management and timing of endoscopy in nonvariceal upper GI bleeding. PMID- 26944337 TI - Comparison of two chromogenic media and enrichment broth for the detection of carbapenemase-producing Enterobacteriaceae on screening rectal swabs from hospitalized patients. PMID- 26944339 TI - Childhood Sexual Abuse and Antisocial Traits and Behaviors: A Gendered Examination of the Factors Associated With Perpetration of Intimate Partner Violence. AB - The current study addressed the relationship between child sexual abuse (CSA) and perpetration of physical intimate partner violence, examining the possible mediating effect of antisocial traits and behaviors, as well as the differences in these relationships between men and women. Data came from the International Dating Violence Study. Hypotheses were tested on a sample of 13,659 university students from 68 sites and 32 countries using hierarchical linear modeling. Results indicated that CSA was significantly associated with perpetration of physical intimate partner violence for both men and women. The slope of the relationships, however, varied across sites for women. Antisocial traits and behaviors fully mediated the relationship between CSA and perpetration of physical intimate partner violence for women but only partially mediated this relationship for men. Increased focus needs to be paid to gender differences on the effect of CSA on the development of antisocial traits and behaviors, the relationship between these factors and perpetration of intimate partner violence, and the variation of these relationships across nations. PMID- 26944338 TI - Applying evidence-based management to anorexia nervosa. AB - AIM: This paper considers how the three principles of evidence based practice (clinical expertise, scientific evidence, and patient preference) can be applied to the complexity of treatment for anorexia nervosa AN. METHOD: A narrative review of the evidence of these three domains is presented. Clinical cases are used to illustrate how the formulation and management can be put into practice at different stages of illness. RESULTS: The management of anorexia nervosa is complex. First, individuals with the illness do not regard the manifestations of the illness as a source of concern rather they are embraced and integrated into their identity. This contrasts to the reaction of other people who are terrified by the overt signs of ill health. Thus engagement into treatment is problematic. Second, the core symptom restricted eating, produces malnutrition which impacts on brain, body, and the social network. Thus a mixture of psychological and physical problems gradually accumulates over the course of the illness. This means that the treatment targets increase over time. CONCLUSION: Thus treatment has to work with motivation and readiness to change and tackle the various domains of ill health. PMID- 26944340 TI - Sexual Assault Supportive Attitudes: Rape Myth Acceptance and Token Resistance in Greek and Non-Greek College Students From Two University Samples in the United States. AB - Colleges are rape-prone cultures with high rates of sexual victimization. Fraternities' and sororities' relationships with sexual assault are consistent themes in literature focusing on sexual violence among college students. Previous research suggests that fraternity men are more likely to endorse rape-supportive attitudes compared with non-Greek men or sorority women. The present study examines rape-supportive attitudes as well as rape and sexual assault victimization in college students with a focus on gender and Greek-life (i.e., involvement in fraternities or sororities) status variables. College students ( N = 1,002) completed a survey including the Token Resistance to Sex Scale (TRSS), Illinois Rape Myth Acceptance Scale-Short Form (IRMA-S), and items related to past experiences of nonconsensual sex. Two regression models tested predictors of token resistance and rape myth acceptance. Chi-square analyses tested between group differences of experiencing rape and sexual assault. Gender ( p < .001), Greek status ( p < .001), and race/ethnicity ( p < .001) were predictors for TRSS scores. For IRMA scores, gender ( p < .001), Greek status ( p < .001), and race/ethnicity variables ( p < .001) were also significant. Interaction terms revealed that Greek men had higher token resistance and rape myth acceptance than any other group. Chi-square analyses indicate women more frequently report experiences of rape (chi2 = 25.57, df = 1, p < .001) and sexual assault (chi2 = 31.75, df = 1, p < .001). Men report high rates (40.8%) of experiencing sexual assault "because refusing was useless." No differences of victimization rates were found between Greeks and non-Greeks. Gender and sexual scripting theory can help explain gender differences in attitudes and experiences. Greater endorsement of rape myth acceptance and token resistance by Greeks, who influence college party culture, could be contributing to a culture conducive to rape. Findings demonstrate a continued need for interventions focused on shifting sociocultural dynamics (e.g., traditional roles and sexual scripting) on college campuses. PMID- 26944341 TI - Psychroflexus aestuariivivens sp. nov., isolated from a tidal flat. AB - A Gram-stain-negative, aerobic, non-flagellated, non-gliding and ovoid or rod shaped bacterium, designated DB-3T, was isolated from a tidal flat on the Yellow Sea in South Korea, and subjected to a taxonomic study using a polyphasic approach. Strain DB-3T grew optimally at 30 degrees C, at pH 7.0-8.0 and in the presence of 2.0-3.0 % (w/v) NaCl. Phylogenetic trees based on 16S rRNA gene sequences showed that strain DB-3T fell within the clade comprising the type strains of species of the genus Psychroflexus. Strain DB-3T exhibited 16S rRNA gene sequence similarities of 93.2-96.9 % to the type strains of species of the genus Psychroflexus. Strain DB-3T contained MK-6 as the predominant menaquinone and iso-C15:0, anteiso-C15:0 and iso-C17:0 3-OH as the major fatty acids. The major or significant amounts of polar lipids detected in strain DB-3T were phosphatidylethanolamine, an unidentified aminolipid and seven unidentified lipids. The DNA G+C content was 34.7 mol%. Differential phenotypic properties, together with phylogenetic distinctiveness, revealed that strain DB-3T is separated from recognized species of the genus Psychroflexus. On the basis of the data presented, strain DB-3T is considered to represent a novel species of the genus Psychroflexus, for which the name Psychroflexus aestuariivivens sp. nov. is proposed. The type strain is DB-3T (=KCTC 52037T=NBRC 111757T). PMID- 26944344 TI - Reductions in access to HIV prevention and care services are associated with arrest and convictions in a global survey of men who have sex with men. AB - OBJECTIVES: Men who have sex with men (MSM) are disproportionately impacted by HIV. Criminalisation of homosexuality may impede access to HIV services. We evaluated the effect of the enforcement of laws criminalising homosexuality on access to services. METHODS: Using data from a 2012 global online survey that was published in a prior paper, we conducted a secondary analysis evaluating differences in perceived accessibility to health services (ie, 'how accessible are ____' services) between MSM who responded 'yes'/'no' to: 'have you ever been arrested or convicted for being gay/MSM?' RESULTS: Of the 4020 participants who completed the study and were included in the analysis, 8% reported ever being arrested or convicted under laws relevant to being MSM. Arrests and convictions were most common in sub-Saharan Africa (23.6% (58/246)), Eastern Europe/Central Asia (18.1% (123/680)), the Caribbean (15% (15/100)), Middle East/North Africa (13.2% (10/76)) and Latin America (9.7% (58/599)). Those arrested or convicted had significantly lower access to sexually transmitted infection treatment (adjusted OR (aOR)=0.81; 95% CI 0.67 to 0.97), condoms (aOR=0.77; 95% CI 0.61 to 0.99) and medical care (aOR=0.70; 95% CI 0.54 to 0.90), compared with other MSM, while accounting for clustering by country and adjusting for age, HIV status, education and country-level income. CONCLUSIONS: Arrests and convictions under laws relevant to being MSM have a strong negative association with access to HIV prevention and care services. Creating an enabling legal and policy environment, and increasing efforts to mitigate antihomosexuality stigma to ensure equitable access to HIV services are needed, along with decriminalisation of homosexuality, to effectively address the public health needs of this population. PMID- 26944345 TI - How to use information technology in the clinic to improve patient experience. PMID- 26944343 TI - Natural Genetic Variation Differentially Affects the Proteome and Transcriptome in Caenorhabditis elegans. AB - Natural genetic variation is the raw material of evolution and influences disease development and progression. An important question is how this genetic variation translates into variation in protein abundance. To analyze the effects of the genetic background on gene and protein expression in the nematode Caenorhabditis elegans, we quantitatively compared the two genetically highly divergent wild type strains N2 and CB4856. Gene expression was analyzed by microarray assays, and proteins were quantified using stable isotope labeling by amino acids in cell culture. Among all transcribed genes, we found 1,532 genes to be differentially transcribed between the two wild types. Of the total 3,238 quantified proteins, 129 proteins were significantly differentially expressed between N2 and CB4856. The differentially expressed proteins were enriched for genes that function in insulin-signaling and stress-response pathways, underlining strong divergence of these pathways in nematodes. The protein abundance of the two wild-type strains correlates more strongly than protein abundance versus transcript abundance within each wild type. Our findings indicate that in C. elegans only a fraction of the changes in protein abundance can be explained by the changes in mRNA abundance. These findings corroborate with the observations made across species. PMID- 26944346 TI - From flat into concave shape in soft tissue free flaps in oral cavity reconstruction: The origami technique. PMID- 26944342 TI - Novel Entropically Driven Conformation-specific Interactions with Tomm34 Protein Modulate Hsp70 Protein Folding and ATPase Activities. AB - Co-chaperones containing tetratricopeptide repeat (TPR) domains enable cooperation between Hsp70 and Hsp90 to maintain cellular proteostasis. Although the details of the molecular interactions between some TPR domains and heat shock proteins are known, we describe a novel mechanism by which Tomm34 interacts with and coordinates Hsp70 activities. In contrast to the previously defined Hsp70/Hsp90-organizing protein (Hop), Tomm34 interaction is dependent on the Hsp70 chaperone cycle. Tomm34 binds Hsp70 in a complex process; anchorage of the Hsp70 C terminus by the TPR1 domain is accompanied by additional contacts formed exclusively in the ATP-bound state of Hsp70 resulting in a high affinity entropically driven interaction. Tomm34 induces structural changes in determinants within the Hsp70-lid subdomain and modulates Hsp70/Hsp40-mediated refolding and Hsp40-stimulated Hsp70 ATPase activity. Because Tomm34 recruits Hsp90 through its TPR2 domain, we propose a model in which Tomm34 enables Hsp70/Hsp90 scaffolding and influences the Hsp70 chaperone cycle, providing an additional role for co-chaperones that contain multiple TPR domains in regulating protein homeostasis. PMID- 26944347 TI - Photoamperometric flow injection analysis of glucose based on dehydrogenase modified quantum dots-carbon nanotube nanocomposite electrode. AB - In this work, a core-shell quantum dot (QD, ZnS-CdS) was electrodeposited onto multiwalled carbon nanotube modified glassy carbon electrode (ZnS-CdS/MWCNT/GCE) and following glucose dehydrogenase (GDH) was immobilized onto QD modified electrode. The proposed electrode (GDH/ZnS-CdS/MWCNT/GCE) was effectively used for the photoelectrochemical biosensing of glucose in flow injection analysis (FIA) system using a home-made flow cell. Results from cyclic voltammetric and FI amperometric measurements have revealed that GDH/ZnS-CdS/MWCNT/GCE is capable of signaling photoelectrocatalytic activity toward NADH when the surface of enzyme modified electrode was irradiated with a light source (250W Halogen lamp). Thus, photoelectrochemical biosensing of glucose was monitored by recording current time curve of enzymatically produced NADH at optimized conditions. The biosensor response was found linear over the range 0.010-2.0mM glucose with detection limits of 6.0 and 4.0MUM for amperometric and photoamperometric methods, respectively. The relative standard deviations (n=5) for 0.5mM glucose were 5.8% and 3.8% for photoamperometric and amperometric results, respectively. The photoelectrochemical biosensor was successfully applied to the real samples. The results with this biosensor showed good selectivity, repeatability and sensitivity for monitoring glucose in amperometric and photoamperometric FIA studies. PMID- 26944348 TI - Conduction Abnormalities and Pacemaker Implantations After SAPIEN 3 Vs SAPIEN XT: Depending on Who Is Implanted and How You Implant. Response. PMID- 26944349 TI - Should We Anticoagulate Patients at High Risk of Atrial Fibrillation? PMID- 26944350 TI - Conduction Abnormalities and Pacemaker Implantations After SAPIEN 3 Vs SAPIEN XT: Depending on Who Is Implanted and How You Implant. PMID- 26944351 TI - Gleason Misclassification Rate Is Independent of Number of Biopsy Cores in Systematic Biopsy. AB - OBJECTIVE: To compare the utility of saturation core biopsy and 12-core biopsy in detecting true Gleason grades, using final pathology in prostatectomy specimens as outcome measures, with a particular interest in Gleason upgrading. PATIENTS AND METHODS: We compared the concordance rates of Gleason grades diagnosed on biopsies and prostatectomy specimens in 375 consecutive patients, including 106 saturation biopsies (18-33 cores, median = 20 cores) and 269 12-core biopsies. Grading bias was addressed by a central rereview of all cases that had discordance in reporting high Gleason grades (Gleason grade >= 4) on biopsies and prostatectomy specimens. RESULTS: For patients with high Gleason grades on final pathology, saturation and 12-core biopsy schemes had a comparable sensitivity, specificity, negative and positive predictive values (72.5% vs 69.5%, 91.9% vs 97.6%, 64.2% vs 58.4%, and 94.3% vs 98.5%, respectively) in detecting high Gleason grades. On multivariate analysis, prebiopsy serum prostate-specific antigen and clinical T stage independently predicted Gleason upgrading; saturation biopsy was not a significant predictor. Approximately one-third of cases where high Gleason grade was not present in the biopsy were attributed to the confinement of high-grade tumors to unusual anatomic locations such as anterior lobes, apex, bladder neck, and parasagittal zones. CONCLUSION: Our study showed that Gleason misclassification rate is independent of the number of biopsy cores in systematic biopsy. One of the reasons for missing high Gleason grade tumors on systematic biopsy was unusual tumor location outside of the biopsy grid, supporting the need for improved detection technique such as magnetic resonance imaging-guided targeted biopsies. PMID- 26944352 TI - Pollen structure and function in caesalpinioid legumes. AB - PREMISE OF THE STUDY: A diverse range of pollen morphologies occurs within the large, paraphyletic legume subfamily Caesalpinioideae, especially among early branching lineages. Previous studies have hypothesized an association between surface ornamentation and pollination syndrome or other aspects of pollen function such as desiccation tolerance and adaptations to accommodate volume changes. METHODS: We reviewed caesalpinioid pollen morphology using light microscopy, scanning and transmission electron microscopy, in combination with a literature survey of pollination vectors. KEY RESULTS: Pollen structural diversity is greatest in the early-branching tribes Cercideae and Detarieae, whereas Cassieae and Caesalpinieae are relatively low in pollen diversity. Functional structures to counter desiccation include opercula (lids) covering apertures and reduced aperture size. Structures preventing wall rupture during dehydration and rehydration include different forms of colpi (syncolpi, parasyncolpi, pseudocolpi), striate supratectal ornamentation, and columellate or granular wall structures that resist tensile or compressive forces respectively. Specialized aperture structures (Zwischenkorper) may be advantageous for efficient germination of the pollen tube. CONCLUSIONS: In Detarieae and Cercideae in particular, there is potential to utilize pollen characters to estimate pollination systems where these are unknown. Supratectal verrucae and gemmae have apparently evolved iteratively in Cercideae and Detarieae. At the species level, there is a potential correlation between striate/verrucate patterns and vertebrate pollination. PMID- 26944353 TI - Shape analysis of moss (Bryophyta) sporophytes: Insights into land plant evolution. AB - PREMISE OF THE STUDY: The alternation of generations life cycle represents a key feature of land-plant evolution and has resulted in a diverse array of sporophyte forms and modifications in all groups of land plants. We test the hypothesis that evolution of sporangium (capsule) shape of the mosses-the second most diverse land-plant lineage-has been driven by differing physiological demands of life in diverse habitats. This study provides an important conceptual framework for analyzing the evolution of a single, homologous character in a continuous framework across a deep expanse of time, across all branches of the tree of life. METHODS: We reconstruct ancestral sporangium shape and ancestral habitat on the largest phylogeny of mosses to date, and use phylogenetic generalized least squares regression to test the association between habitat and sporangium shape. In addition, we examine the association between shifts in sporangium shape and species diversification. RESULTS: We demonstrate that sporangium shape is convergent, under natural selection, and associated with habitat type, and that many shifts in speciation rate are associated with shifts in sporangium shape. CONCLUSIONS: Our results suggest that natural selection in different microhabitats results in the diversity of sporangium shape found in mosses, and that many increasing shifts in speciation rate result in changes in sporangium shape across their 480 million year history. Our framework provides a way to examine if diversification shifts in other land plants are also associated with massive changes in sporophyte form, among other morphological traits. PMID- 26944354 TI - Effect of inbreeding on pollen tube growth in diploid and tetraploid Chamerion angustifolium: Do polyploids mask mutational load in pollen? AB - PREMISE OF THE STUDY: Deleterious recessive mutations are an important determinant of fitness (mutational load) in the sporophytic phase of plants and a major cause of inbreeding depression; however, their role in gametophyte function is less well documented but may account for variation in pollen tube growth and siring ability, especially between diploid and polyploid plants, which can mask the load. METHODS: We investigated the role of mutational load in pollen performance using the perennial polyploid Chamerion angustifolium by comparing tube growth of pollen, in styles and in growth medium, from inbred (selfed) and outbred diploids to that of inbred and outbred tetraploids. Pollen from tetraploids is expected to mask deleterious mutations more effectively in the outbred condition but reveal them after inbreeding. In contrast, gametophytes from diploids should express the same genetic load in inbred or outbred plants. KEY RESULTS: Pollen tube growth measured in growth medium was highest in outbred tetraploids and generally lower in inbred than outbred plants. The effect of selfing was significant in pollen from tetraploids but not diploids. The differential effect of selfing was also evident in the proportion of pollen reaching the base of styles, but the ploidy * pollination interaction was not significant. Selfing also had a negative effect on sporophyte fitness but was greater in diploids than tetraploids. CONCLUSIONS: Pollen performance is influenced by the expression of mutational load, which is masked in polyploids. This effect may partly explain strong siring success of tetraploids in this species. PMID- 26944355 TI - Should a pregnancy test be required before scuba diving? PMID- 26944356 TI - Effects of early rehabilitation following operative repair of Achilles tendon rupture (PEDro synthesis). PMID- 26944357 TI - Check'n Burn: removing caloric surplus through physical activity. PMID- 26944358 TI - Intracellular angiotensin II as a regulator of muscle tone in vascular resistance vessels. Pathophysiological implications. AB - The influence of intracellular angiotensin II on the regulation of potassium current and membrane potential of smooth muscle cells of mesenteric arteries and its relevance for the regulation of vascular tone was reviewed. The presence of components of the renin angiotensin system (RAS) in different cells of the cardiovascular system, was discussed including their presence in the nuclei and mitochondria. Emphasis was given to the opposite effects of intracellular and extracellular angiotensin II (Ang II) on the regulation of potassium current, membrane potential and contractility of vascular resistance vessels and its implication to vascular physiology and pathology and the possible role of epigenetic factors on the expression of angiotensin II (Ang II) and renin in vascular resistance vessels as well as its possible pathophysiological role in hypertension and other cardiovascular diseases. PMID- 26944359 TI - Endovascular Thrombolysis in the Management of Iliofemoral Thrombosis in Children: A Multi-Institutional Experience. AB - PURPOSE: To evaluate technical feasibility, complications, and clinical outcomes of endovascular thrombolysis for iliofemoral thrombosis at two tertiary-care children's hospitals. MATERIALS AND METHODS: Institutional review board-approved retrospective review from March 2003 through June 2013 showed that venous thrombolysis for iliofemoral thrombosis was performed in 57 children (64 limbs) with a median age of 16.1 years (mean age, 14.5 y; range, 1.0-17.8 y). Techniques included catheter-directed thrombolysis (CDT), percutaneous mechanical thrombectomy (PMT), and pharmacomechanical catheter-directed thrombolysis (PCDT) with adjunctive angioplasty and/or stent placement. Villalta and modified Villalta scales were applied retrospectively to follow-up data to assess postthrombotic syndrome (PTS). RESULTS: Technical success (>= 50% thrombolysis) rate was 93.7%: grade III (100%) in 19 limbs, grade II (50%-99%) in 41 limbs, and grade I (< 50%) in four limbs. Techniques included CDT with PCDT (32.8%) or PMT (35.9%), CDT alone (26.6%), PCDT alone (4.7%) or with adjunctive angioplasty (54.7%), and stent placement (6.3%). Mean duration of CDT was 36.5 hours (range, 2.9-89.6 h). There was one major complication (1.8%) of bleeding requiring transfusion. Minor complications (ie, bleeding) occurred in seven patients (12.2%). Median follow-up was 1.5 years (range, 30 d to 7 y). Seven patients underwent repeat thrombolysis for recurrent thrombosis. The PTS rate was 59.3% per modified Villalta scale but only 2.1% per Villalta scale. CONCLUSIONS: Endovascular thrombolysis is technically feasible and safe for iliofemoral thrombosis in children. Variable results were seen with two scales to assess PTS, suggesting an acute need for standardization of outcome measurement in children. PMID- 26944360 TI - Percutaneous High-Energy Microwave Ablation for the Treatment of Pulmonary Tumors: A Retrospective Single-Center Experience. AB - PURPOSE: To evaluate the safety and efficacy of percutaneous high-energy microwave ablation (MWA) for the treatment for pulmonary tumors. MATERIALS AND METHODS: A retrospective review was undertaken of 44 patients (21 men, 23 women; median age, 66 y; range, 17-89 y) who underwent 62 sessions of high-energy MWA for 87 pulmonary tumors at a single tertiary referral center between June 2012 and June 2014. Primary tumor origin was sarcoma (n = 23), colorectal (n = 16), lung (n = 2), esophageal (n = 1), breast (n = 1), and bladder (n = 1). Median tumor size was 12 mm (range, 6-45 mm). Technical success was recorded contemporaneously, complication rate at 30 days was recorded prospectively, and technique effectiveness was assessed by longitudinal follow-up CT scan. RESULTS: Primary technical success was achieved in 94% of ablation sessions. The median follow-up interval was 15 months (range, 6.2-29.5 mo) during which time local tumor progression was observed in two of 87 tumors (technique effectiveness 98%). Pneumothorax requiring chest tube insertion occurred in 19%; delayed pneumothorax occurred in four patients. No hemoptysis, infection, or other complications were recorded. CONCLUSIONS: High-energy MWA is safe and effective for the destruction of lung tumors. PMID- 26944361 TI - Bodily isomerism is an independent risk factor for pulmonary hypertension in adults with congenital heart disease. AB - INTRODUCTION: Bodily isomerism, or heterotaxy is a unique entity on which there is mirror imagery in various organ systems, leading to a deviation from the normal lateral arrangements of the viscera. Adults with such isomerism and associated congenital malformations of the heart are now reaching adulthood and developing long-term complications. This study investigates the prevalence and characteristics of pulmonary hypertension in adults with isomerism. METHODS: The 2012 iteration of the Nationwide Inpatient Sample was utilized and patients were identified as having or not having bodily isomerism and having or not having pulmonary hypertension. Univariate analysis utilizing Chi-square tabulation was done to assess characteristics associated with pulmonary hypertension. Next, a multivariate analysis was done on all patients to identify predictors of pulmonary hypertension followed by a multivariate analysis of patients with only isomerism to identify predictors of pulmonary hypertension specific to this subset. RESULTS: A total of 6,907,109 admissions were included in the analysis. Of these, 861 had isomerism (0.01%). Of those with isomerism, 5.6% were found to have pulmonary hypertension. When all patients were included in the multivariate analysis, isomerism was found to be an independent risk factor for pulmonary hypertension with an odds ratio of approximately 1.79. When only patients with isomerism were included in the multivariate analysis, advanced age, obesity, and history of anomalous pulmonary venous connection were independent risk factors of pulmonary hypertension. CONCLUSION: Pulmonary hypertension is more common in those with isomerism, with isomerism being an independent risk factor for pulmonary hypertension. The prevalence of pulmonary hypertension is 5.6% in the setting of isomerism. Independent risk factors for pulmonary hypertension in patients with isomerism include age, obesity, and history of anomalous pulmonary venous connection. PMID- 26944363 TI - Diagnostic yield of electromagnetic navigational bronchoscopy. AB - OBJECTIVES: Peripheral lung nodules (PLNs) are a common and diagnostically challenging finding. Electronavigational bronchoscopy (ENB) is used to increase the diagnostic yield and is considered safe. Multiple factors have been correlated with a better diagnostic yield. We sought to assess the effect of nodule characteristics and prior workup on the diagnostic yield in ENB. METHODS: This was a retrospective chart review of 98 ENB procedures in a community referral center. Two investigators reviewed patients' charts and images independently. Multiple logistic regression analyses was used to determine if factors such as bronchus sign, ground glass opacification (GGO), distance from pleura, prior use of endobronchial ultrasound (EBUS) and positron emission tomography (PET) had an impact on the diagnostic yield. RESULTS: We evaluated 98 ENBs performed in 92 patients. Most of the lesions were in the upper lobes. The diagnostic yield was 60%. A PET scan was performed prior to ENB in 47% of cases. EBUS was performed in 24% of cases. Bronchus sign was present in 60% of cases and GGO in only 6% of nodules. The odds ratio for diagnostic yield with a bronchus sign was 1.89 [95% confidence interval (CI): 0.83-4.33] and with nodules showing GGO characteristics it was 4.51 (95% CI: 0.51-39.68). Pneumothorax occurred in 6% of cases. CONCLUSION: In our cohort, diagnostic yield was 60% with a 6% pneumothorax rate. A suggestive trend for the presence of bronchus sign on computed tomography scan, albeit statistically nonsignificant, as a predictor for improved diagnostic yield needs to be validated in a larger cohort. PMID- 26944364 TI - The intensity of breast cancer patients' relationships with their surgeons after the first meeting: Evidence that relationships are not 'built' but arise from attachment processes. AB - BACKGROUND: Cancer clinicians are exhorted to build clinical relationships with their patients over time using patient-centred communication skills. An alternative view is that patients' sense of relationship is a response to clinicians' expertise and authority and therefore is normally present from the start. OBJECTIVE: We measured the intensity of breast cancer patients' sense of relationship with their surgeon after their first brief, diagnostically focused meeting in order to compare it with published reports from patients in other types and stages of clinical relationship. PARTICIPANTS: Women (N = 133) over 18 years old and due to undergo surgery for primary breast cancer were recruited consecutively from pre-operative clinics. DESIGN: Patients reported the intensity of their relationship with the surgeon on a standardised questionnaire (Working Alliance Inventory). We compared their ratings with published reports over the last 15 years, in which patients in other types of clinical relationship completed the same questionnaire. RESULTS: Patients' alliance with their surgeons was very high (mean 6.13, 95% CI: 5.99, 6.27, on a 1-7 scale), and at 90(th) percentile when compared with scores from other settings, including those characterized by many hours of talk addressing patients' emotional needs. CONCLUSIONS: Patients with breast cancer feel an intense sense of relationship with the surgeon from the first meeting, consistent with the view that their sense of relationship arises primarily from their recognition of the surgeon's expertise and authority. The challenge for surgeons is therefore not usually to 'build a relationship' but to support the sense of relationship that patients have from the start. PMID- 26944362 TI - Risk of pneumonitis in cancer patients treated with immune checkpoint inhibitors: a meta-analysis. AB - BACKGROUND: A meta-analysis of the risk of pneumonitis associated with the use of immune checkpoint inhibitors in cancer patients has been conducted. METHODS: Eligible publications included randomized trials of cancer patients on immune checkpoint inhibitors, describing events of all-grade and high-grade pneumonitis. RESULTS: After exclusion of noneligible citations, a total of 11 clinical trials were eligible for the meta-analysis. The odds ratio was 3.96 [95% confidence interval (CI): 2.02-7.79; p < 0.0001] for all-grade pneumonitis and 2.87 (95% CI: 0.90-9.20; p = 0.08) for high-grade pneumonitis. Moreover, the odds ratio of all grade pneumonitis with a nivolumab/ipilimumab combination versus ipilimumab monotherapy was 3.68 (95% CI: 1.59-8.50; p = 0.002) and, for high-grade pneumonitis, it was 1.86(95% CI: 0.36-9.53; p = 0.46). Subgroup analysis did not reveal a difference between lung cancer patients and other cancer patients in the risk of pneumonitis. CONCLUSIONS: Our analysis provided evidence that the use of immune checkpoint inhibitors is associated with an increased risk of all-grade pneumonitis compared with chemotherapy or placebo controls. PMID- 26944365 TI - A study of margin width and local recurrence in breast conserving therapy for invasive breast cancer. AB - PURPOSE: Debate continues on what is an adequate margin width to define a clear margin and whether there is a need to excise pectoral fascia or remove skin in breast conserving surgery. This study set out to provide answers to these questions. PATIENTS AND METHODS: 1411 patients with invasive breast cancer were treated by breast conserving surgery and post-operative whole breast radiotherapy from January 2000 to December 2005. Distance from each margin to any in situ or invasive cancer was measured and recorded. If full thickness of breast tissue was removed no re excision of anterior and posterior margins was performed even if disease was <1 mm from a margin. Patients <=50 years of age and those with anterior or posterior margins <1 mm to invasive cancer had a radiation boost. Median follow-up time was 6.4 years. RESULTS: Local in breast tumour relapse (IBTR) occurred in 50 patients. The overall actuarial IBTR rate at 5 years was 2.2%. There was no difference in IBTR when comparing patients with radial margins of 1-5 mm or 5-10 mm. Anterior and posterior margins <1 mm or with ink on tumour cells were not associated with an increase in IBTR. CONCLUSION: There is no justification for radial margins of greater than 1 mm. If the anterior or posterior margin is <1 mm and full thickness of breast tissue has been removed, then re excision of these margins is unnecessary if boost radiotherapy is delivered. PMID- 26944366 TI - Prevention of neck infection by endoscopic suture closure of pyriform sinus fistulae: a report of two cases. PMID- 26944367 TI - Reduced levels of cytosolic DNA sensor AIM2 are associated with impaired cytokine responses in healthy elderly. AB - OBJECTIVE: Human aging is associated with remodeling of the immune system. While most studies on immunosenescence have focused on adaptive immunity, the effects of aging on innate immunity are not well understood. Here, we investigated whether aging affects cytokine responses to a wide range of well-defined pattern recognition receptor (PRR) ligands, such as ligands for Toll-like receptors (TLRs), C-type lectin receptors (CLRs), NOD-like receptors (NLRs), retinoic-acid inducible gene-I like receptors (RLRs) and the cytosolic DNA sensor absent in melanoma 2 (AIM2). METHOD: Blood was collected from 16 young (20-39 years) and 18 elderly (60-84 years) healthy participants. Pro-inflammatory cytokine (TNF-alpha, IL-1beta, IL-6, and IL-8) production in a whole blood assay (WBA) after stimulation with TLR ligands (Pam3csk4, poly(I:C), LPS, CpG), CLR ligand (beta glucan), NLR ligand (MDP), RLR ligands (5'ppp-dsDNA and poly(I:C)/lyovec) and the AIM2 ligand (poly(dA:dT) was assessed by ELISA. TLR2 and TLR4 expression by leukocytes and monocytes was determined by flow-cytometry. Expression of AIM2 by peripheral blood mononuclear cells (PBMC) was assessed by qRT-PCR and Western blot. RESULT: Cytokine responses to Pam3csk4, poly(I:C) and CpG, beta-glucan, MDP, 5'ppp-dsDNA and poly(I:C)/lyovec were comparable between young and old participants. We observed a higher IL-8 response following stimulation of elderly blood samples with the TLR4 ligand LPS, which was associated with higher proportions of TLR4 expressing monocytes. Interestingly, stimulation of whole blood cells with the AIM2 ligand poly(dA:dT) resulted in significantly lower cytokine responses in old participants. Moreover, these lower cytokine responses were associated with lower AIM2 protein expression and activation in PBMC of old participants. CONCLUSION: Our findings reveal an age-dependent reduction of AIM2 expression and activation which may explain reduced cytokine responses to the cytosolic DNA mimic poly(dA:dT) in healthy elderly individuals. Reduced AIM2 mediated sensing with age may contribute to increased vulnerability to bacterial or viral infections in the elderly. PMID- 26944368 TI - Protective effect of myostatin gene deletion on aging-related muscle metabolic decline. AB - While myostatin gene deletion is a promising therapy to fight muscle loss during aging, this approach induces also skeletal muscle metabolic changes such as mitochondrial deficits, redox alteration and increased fatigability. In the present study, we evaluated the effects of aging on these features in aged wild type (WT) and mstn knockout (KO) mice. Moreover, to determine whether an enriched antioxidant diet may be useful to prevent age-related disorders, we orally administered to the two genotypes a melon concentrate rich in superoxide dismutase for 12 weeks. We reported that mitochondrial functional abnormalities persisted (decreased state 3 and 4 of respiration; p<0.05) in skeletal muscle from aged KO mice; however, differences with WT mice were attenuated at old age in line with reduced difference on running endurance between the two genotypes. Interestingly, we showed an increase in glutathione levels, associated with lower lipid peroxidation levels in KO muscle. Enriched antioxidant diet reduced the aging-related negative effects on maximal aerobic velocity and running limit time (p<0.05) in both groups, with systemic adaptations on body weight. The redox status and the hypertrophic phenotype appeared to be beneficial to KO mice, mitigating the effect of aging on the skeletal muscle metabolic remodeling. PMID- 26944369 TI - Invasive aspergillosis presenting as an intracardiac mass in an immunocompetent host. AB - Invasive aspergillosis is a severe fungal infection that primarily affects immunocompromised patients. We report a case of invasive aspergillosis presenting as a febrile respiratory infection with a cardiac mass in an immunocompetent patient. Excision of the intracardiac mass followed by histopathological examination confirmed the diagnosis. The patient was managed with voriconazole, to which he responded well. Rare occurrence of an intracardiac mass with systemic aspergillosis in an immunocompetent host is discussed in this case report. PMID- 26944370 TI - Erythema induratum of Bazin and Poncet's arthropathy as epiphenomena of hepatic tuberculosis. AB - A 42-year-old black woman presented with fever, polyarthritis, livedo reticularis, subcutaneous calf nodules and hepatomegaly. She had been diagnosed with depression 6 weeks prior. Blood analysis showed anaemia, elevated erythrocyte sedimentation rate and C reactive protein, elevated liver enzymes, and positive antinuclear and antiribonucleoprotein antibodies. Abdominal ultrasound revealed heterogeneous hepatomegaly with necrotic lymphadenopathy around the caeliac trunk and splenic hilum. We considered the following diagnoses: lymphoma, connective tissue disease, tuberculosis and sarcoidosis. Subcutaneous nodule histology was compatible with erythema induratum of Bazin, and liver biopsy evidenced granulomatous hepatitis. Although microbiological examinations were negative in tissue samples, a presumptive diagnosis of hepatic tuberculosis was admitted. Having excluded other causes, erythema of Bazin, livedo reticularis and polyarticular involvement (Poncet's arthropathy) were accepted as immunological epiphenomena associated with tuberculosis. Empirical antituberculous treatment was started and after 3 weeks the patient improved substantially. This clinical response was a further confirmation of the diagnosis. PMID- 26944371 TI - Should the norepinephrine maximal dosage rate be greatly increased in late shock? AB - Any advanced shock eventually degenerates into vasoplegia, which responds weakly to vasopressors. The highest reported norepinephrine flow rate is 3 MUg/kg/min. We present the case of a young explosion victim, who was transferred in late haemorrhagic shock. Apart from usual treatment (hydration, mass transfusion protocol), single-agent norepinephrine was used to maintain a mean arterial pressure (MAP) of >60-65 mm Hg. For several hours, norepinephrine flow was 7-10 times the aforementioned (highest reported) in order to achieve our goal; during which, further hydration or transfusion would not contribute to MAP elevation. Sequential Organ Failure Assessment (SOFA) severity score was 18 (expected mortality >99%). The patient survived without underperfusion-related damage. We conclude that norepinephrine dosages could potentially be greatly increased in late shock. We must resist giving up flow escalation based on its numerical value. PMID- 26944373 TI - Pancreatic cystosis in cystic fibrosis. PMID- 26944372 TI - Navigating care for Bedouin patients with diabetes. AB - The Bedouin Arab population in the southern Negev region of Israel has faced health problems as a result of transitioning rapidly from a nomadic agricultural lifestyle to a more modern urban lifestyle. Like many populations around the world, the Bedouins have changed their diets and become more sedentary and this has led to a high rate of diabetes. In this case report, we examine how diabetes has affected the life of an influential man in the Bedouin community and the significance this case has in the greater context of a global rise in chronic disease. PMID- 26944374 TI - Pipeline embolization device induced collateral channels in elective flow diversion treatment. AB - The pipeline embolization device (PED) is a well recognized treatment for intracranial aneurysms. However, uncertainty remains regarding its effects on flow alteration, which is particularly highlighted by persistently perfused aneurysmal remnants and non-regressing, non-perfused aneurysmal masses. Here we present a 68-year-old woman with an incidental giant fusiform right paraophthalmic aneurysm electively treated with a PED. After lowering her antiplatelet therapy to promote aneurysm thrombosis, she was found to have a progressively enlarging perfused aneurysmal remnant. Angiography revealed PED occlusion, but curiously the development of a peri-construct collateral channel which feeds the aneurysmal remnant, and gives rise to distal branches and contributes to middle cerebral artery flow. The large 'thrombosed' aneurysmal mass showed tiny internal vessels on cone beam CT angiography as well as florid enhancement on MRI, further confirming that apparently thrombosed remnants are biologically active and may be remodeled depending on flow demand. PMID- 26944375 TI - An annoyance from an anomalous OS. PMID- 26944376 TI - Unusual presentation of Paget's disease of bone. PMID- 26944377 TI - Oedema and thoracoepigastric vein dilation on bilateral legs: adrenal gland tumour with inferior vena cava tumour thrombus. PMID- 26944379 TI - Elephantiasis nostras verrucosa secondary to congestive cardiac failure. PMID- 26944378 TI - Corynebacterium striatum empyema and osteomyelitis in a patient with advanced rheumatoid arthritis. AB - Corynebacterium striatum, which is a common coloniser of human skin and mucous membranes, is increasingly being recognised as an emerging pathogen. We present a case of a 69-year-old woman with empyema and osteomyelitis caused by C. striatum. To the best of our knowledge, this is the first case where these two infections from this bacterium were identified together in the same individual. PMID- 26944380 TI - Imipenem/cilastatin-induced acute eosinophilic pneumonia. AB - Drugs, toxins, and infections are known to cause acute eosinophilic pneumonia. Daptomycin and minocycline are the commonly reported antibiotics associated with acute eosinophilic pneumonia. In this study, we present a case of imipenem/cilastatin-induced acute eosinophilic pneumonia. The patient presented with fever, acute hypoxic respiratory distress, and diffuse ground-glass opacities on the chest CT a day after the initiation of imipenem/cilastatin. Patient also developed peripheral eosinophilia. A reinstitution of imipenem/cilastatin resulted in recurrence of the signs and symptoms. A bronchoscopy with bronchoalveolar lavage showed 780 nucleated cells/mm(3) with 15% eosinophil. The patient's clinical condition improved significantly after the discontinuation of imipenem/cilastatin therapy and the treatment with corticosteroid. PMID- 26944381 TI - Unusual cause for overt upper gastrointestinal bleeding. PMID- 26944382 TI - [Chondroma adjacent to Meckel's cave mimicking a fifth cranial nerve neurinoma. A case report]. AB - Cranial chondromas are tumours arising from chondrocyte embryonic remnants cells that usually appear in the skull base synchondrosis. In contrast to the rest of the organism, where chondroid tumours are the most common primary bone tumour just behind the haematopoietic lineage ones, they are a rarity at cranial level, with an incidence of less than 1% of intracranial tumours. The case is reported on a 42 year-old male referred to our clinic due to the finding of an extra-axial lesion located close to the Meckel's cave region, with extension to the posterior fossa and brainstem compression after progressive paraparesis of 6 months onset. With the diagnosis of trigeminal schwannoma, a subtotal tumour resection was performed using a combined supra-infratentorial pre-sigmoidal approach. The postoperative histopathology report confirmed the diagnosis of cranial chondroma. PMID- 26944383 TI - Survival analysis of surgically evacuated supratentorial spontaneous intracerebral hemorrhage with intraventricular extension. AB - OBJECTIVE: To conduct a survival study and evaluation of surgical treatment in a cohort of patients with diagnosis of supratentorial spontaneous intracerebral hemorrhage (ICH). MATERIALS AND METHODS: The study included all consecutive patients with supratentorial ICH admitted to the Intensive Care Units of three Spanish hospitals with Neurosurgery Department between 2009 and 2012. DATA COLLECTED: age, APACHE-II, Glasgow Coma Score (GCS), and pupillary anomalies on admission, intracerebral hemorrhage (ICH) score, location/volume of hematoma, intraventricular hemorrhage (IVH), surgical evacuation alone or with additional external ventricular drain, and 30-days survival and at hospital discharge RESULTS: A total of 263 patients were included. Mean age: 59.74+/-14.14 years. GCS: 8+/-4 points, APACHE II: 20.7+/-7.68 points. ICH Score: 2.32+1.04 points. Pupillary anomalies were observed in 30%. The 30-day mortality: 51.3% (45.3% predicted by ICH-score), and 53.2% at hospital discharge. A significant difference (p=0.004) was observed in hospital mortality rates between surgically treated patients (39.7%, n=78) versus those conservatively managed (58.9%, n=185); specifically in those with IVH surgically treated (34.2%, n=38) versus non-operated IVH (67.2%, n=125), p<0.001. No significant difference was found between mortality rates in patients without IVH. Multiple logistic regression analysis showed an OR for surgery of 1.04 (95% CI; 0.33-3.22) in patients without IVH versus 0.19 (95% CI; 0.07-0.53) in patients with IVH (decreased mortality with surgical treatment). The propensity score analysis for IVH patients showed improved survival of operated group (OR 0.23, 95% CI; 0.07-0.75), p=0.01. CONCLUSIONS: Hospital mortality was lower in patients who underwent surgery compared to patients conservatively managed, specifically for the subgroup of patients with intraventricular hemorrhage. PMID- 26944384 TI - [Competency-based Neurosurgery Residency Programme]. AB - A programme proposal for competency-based Neurosurgery training adapted to the specialization project is presented. This proposal has been developed by a group of neurosurgeons commissioned by the SENEC (Spanish Society of Neurosurgery) and could be modified to generate a final version that could come into force coinciding with the implementation of the specialization programme. This document aims to facilitate the test of the new programme included in the online version of our journal. DURATION OF THE PROGRAMME: Total training period is 6 years; initial 2 years belong to the surgery specialization and remaining 4 years belong to core specialty period. STRUCTURE OF THE PROGRAMME: It is a competency-based programmed based on the map used by the US Accreditation Council for Graduate Medical Education (ACGME) including the following domains of clinical competency: Medical knowledge, patient care, communication skills, professionalism, practice based learning and improvement, health systems, interprofessional collaboration and professional and personal development. Subcompetencies map in the domains of Knowledge and Patient care (including surgical competencies) was adapted to the one proposed by AANS and CNS (annex 1 of the programme). A subcompetency map was also used for the specialization rotations. INSTRUCTION METHODS: Resident's training is based on personal study (self-learning) supported by efficient use of information sources and supervised clinical practice, including bioethical instruction, clinical management, research and learning techniques. EVALUATION METHODS: Resident evaluation proposal includes, among other instruments, theoretical knowledge tests, objective and structured evaluation of the level of clinical competency with real or standardised patients, global competency scales, 360-degree evaluation, clinical record audits, milestones for residents progress and self-assessment (annex 2). Besides, residents periodically assess the teaching commitment of the department's neurosurgeons and other professors participating in rotations, and annually assess the overall operation of the programme. Results of evaluations are registered, together with other relevant data, in the Resident's Book. PROGRAMME'S NATIONAL COMMITTEE: The creation of a Programme Committee directly attached to the SENEC (National Commission) that, aside from generating a final version of the programme, monitors its implementation (level of adherence and operation in the different departments), assumes the creation of test banks and the centralized administration of knowledge tests (in the middle of the residency and/or at the end of it) and centralizes information collected by tutors that could be used for re accreditation of the services, is proposed. PMID- 26944385 TI - Effects of midazolam or tramadol premedication on early cognitive function in endoscopic retrograde cholangiopancreatography (ERCP): A randomized, controlled, double-blind study. AB - OBJECTIVE: To evaluate the sedative efficacy and effects on early period cognitive function of premedication in endoscopic retrograde cholangiopancreatography (ERCP). METHODS: Forty patients (18-70 years; American Society of Anesthesiology risk category I-III) undergoing elective ERCP were randomized to receive oral premedication with 0.15 mg/kg midazolam or 1 mg/kg tramadol. Cognitive function was determined by mini-mental test (MMT). Target scores for effective sedation were determined as a Bispectral index score of 70 90 and modified Ramsay Sedation Scale score (mRSS) of 2-4. RESULTS: Global MMT score was not significantly different between treatment groups at 60 min post ERCP. A significant deterioration in the MMT subcategory of recall was determined in with midazolam versus tramadol. Level of sedation (mRSS) was higher in with midazolam compared with tramadol reaching statistical significance at 30 min after drug administration. CONCLUSIONS: Although more effective sedation was obtained with midazolam in patients undergoing ERCP, there was a dysfunction in memory recall. It was concluded, however, that early cognitive functions were generally preserved with both drugs. PMID- 26944386 TI - Vitamin D deficiency and related risk factors in patients with diabetic nephropathy. AB - OBJECTIVES: To investigate serum 25-hydroxyvitamin D (25[OH]D) levels in patients with diabetic nephropathy, analyse the relationship between 25(OH)D and clinical indexes, and identify risk factors for vitamin D deficiency in diabetic nephropathy. METHODS: Patients with diabetic nephropathy were sequentially enrolled and grouped according to diabetic nephropathy stage. Serum 25(OH)D levels were measured. A control group of healthy subjects was used for comparison. RESULTS: Out of 240 patients with diabetic nephropathy and 60 healthy controls, 25(OH)D levels were lower in diabetic nephropathy patients than in controls, and showed a gradually decreasing trend with diabetic nephropathy stage. Serum 25(OH)D levels were significantly correlated with age, sex, diabetes history, body mass index, systolic blood pressure, albumin excretion rate (AER), estimated glomerular filtration rate, fasting blood glucose, glycosylated haemoglobin (HbA1c), haemoglobin, serum albumin, creatinine clearance rate, blood urea nitrogen and complicated diabetic retinopathy. Moreover, age, body mass index, AER, haemoglobin, and HbA1c were independent risk factors of 25(OH)D deficiency in diabetic nephropathy. CONCLUSIONS: Vitamin D deficiency is prevalent in patients with diabetic nephropathy and increases in severity with diabetic nephropathy progression. Age, obesity, glucose level and renal function largely affect 25(OH)D deficiency in diabetic nephropathy. PMID- 26944387 TI - Postoperative renormalization of C-reactive protein with adjuvant lienal polypeptide and its association with tumour recurrence in T1 clear cell renal cell carcinoma. AB - OBJECTIVES: To evaluate the effect of pre- and postoperative C-reactive protein (CRP) levels on tumour recurrence following curative nephrectomy in patients with stage T1 clear cell renal cell carcinoma (CCRCC). METHODS: Patients with stage T1 CCRCC were recruited. CRP was quantified 3 days before and 4 weeks after surgery. Patients were followed-up for clinical outcome every 3 months. A subset of patients received lienal polypeptide as adjuvant treatment. RESULTS: Patients with elevated preoperative CRP levels (>=8.2 mg/l; n = 61) had higher grade tumours, were more likely to require radical nephrectomy and were more likely to experience recurrence than those with normal CRP levels. Non-normalization of elevated preoperative CRP was associated with tumour recurrence, but elevated CRP was not an independent risk factor of tumour recurrence. CONCLUSION: Postoperative renormalization of elevated CRP is associated with decreased risk of recurrence in CCRCC. PMID- 26944388 TI - Multiple pulmonary metastases in recurrent intracranial meningioma: Case report and literature review. AB - Multiple pulmonary metastases from meningioma are rare. We report here a 59-year old man with multiple pulmonary metastases from a recurrent intracranial meningioma. The primary intracranial tumour in the left occiput was totally excised in 2009. Pathological examination confirmed the diagnosis of atypical meningioma and adjuvant radiotherapy was given to help prevent recurrence. However, recurrence occurred in the left occipital region in 2011 and the meningioma was re-excised in 2012. At the same time, multiple metastases in the right pulmonary lobe were found and excised 3 months after the second craniotomy. The patient has not developed any further recurrence or metastases to date. Neurosurgeons should be aware of the occurrence of pulmonary metastases in patients with intracranial meningioma; potential predictive factors include atypical meningioma, venous sinus invasion, recurrence or previous intracranial surgery, and loss of heterozygosity. PMID- 26944389 TI - Ease and difficulty of pre-hospital airway management in 425 paediatric patients treated by a helicopter emergency medical service: a retrospective analysis. AB - BACKGROUND: Pre-hospital paediatric airway management is complex. A variety of pitfalls need prompt response to establish and maintain adequate ventilation and oxygenation. Anatomical disparity render laryngoscopy different compared to the adult. The correct choice of endotracheal tube size and depth of insertion is not trivial and often challenged due to the initially unknown age of child. METHODS: Data from 425 paediatric patients (<17 years of age) with any airway manipulation treated by a Swiss Air-Ambulance crew between June 2010 and December 2013 were retrospectively analysed. Endpoints were: 1) Endotracheal intubation success rate and incidence of difficult airway management in primary missions. 2) Correlation of endotracheal tube size and depth of insertion with patient's age in all (primary and secondary) missions. RESULTS: In primary missions, the first laryngoscopy-guided endotracheal intubation attempt was successful in 95.3% of cases, with an overall success rate of 98.6%. Difficult airway management was reported in 10 (4.7%) patients. Endotracheal tube size was frequently chosen inadequately large (overall 50 of 343 patients: 14.6%), especially and statistically significant in the age group below 1 year (19 of 33 patients; p < 0.001). Tubes were frequently and distinctively more deeply inserted (38.9%) than recommended by current formulae. CONCLUSION: Difficult airway management, including cannot intubate and cannot ventilate situations during pre-hospital paediatric emergency treatment was rare. In contrast, the success rate of endotracheal intubation at the first attempt was very high. High numbers of inadequate endotracheal tube size and deep placement according to patient age require further analysis. Practical algorithms need to be found to prevent potentially harmful treatment. PMID- 26944390 TI - Neighborhood clustering of non-communicable diseases: results from a community based study in Northern Tanzania. AB - BACKGROUND: In order to begin to address the burden of non-communicable diseases (NCDs) in sub-Saharan Africa, high quality community-based epidemiological studies from the region are urgently needed. Cluster-designed sampling methods may be most efficient, but designing such studies requires assumptions about the clustering of the outcomes of interest. Currently, few studies from Sub-Saharan Africa have been published that describe the clustering of NCDs. Therefore, we report the neighborhood clustering of several NCDs from a community-based study in Northern Tanzania. METHODS: We conducted a cluster-designed cross-sectional household survey between January and June 2014. We used a three-stage cluster probability sampling method to select thirty-seven sampling areas from twenty nine neighborhood clusters, stratified by urban and rural. Households were then randomly selected from each of the sampling areas, and eligible participants were tested for chronic kidney disease (CKD), glucose impairment including diabetes, hypertension, and obesity as part of the CKD-AFRiKA study. We used linear mixed models to explore clustering across each of the samplings units, and we estimated absolute-agreement intra-cluster correlation (ICC) coefficients (rho) for the neighborhood clusters. RESULTS: We enrolled 481 participants from 346 urban and rural households. Neighborhood cluster sizes ranged from 6 to 49 participants (median: 13.0; 25th-75th percentiles: 9-21). Clustering varied across neighborhoods and differed by urban or rural setting. Among NCDs, hypertension (rho = 0.075) exhibited the strongest clustering within neighborhoods followed by CKD (rho = 0.440), obesity (rho = 0.040), and glucose impairment (rho = 0.039). CONCLUSION: The neighborhood clustering was substantial enough to contribute to a design effect for NCD outcomes including hypertension, CKD, obesity, and glucose impairment, and it may also highlight NCD risk factors that vary by setting. These results may help inform the design of future community-based studies or randomized controlled trials examining NCDs in the region particularly those that use cluster-sampling methods. PMID- 26944391 TI - Unmet mental health care needs in U.S. children with medical complexity, 2005 2010. AB - OBJECTIVE: Children with special healthcare needs (CSHCN) are those who have or are at elevated risk for a chronic physical, developmental, behavioral or emotional condition and need healthcare services of a type or quantity beyond that required by children generally. Within CSHCN, a small group of children with medical complexity have medical vulnerability and intensive care needs that are not easily met by existing healthcare models. This study estimated the national prevalence of unmet mental healthcare needs among CSHCN with and without medical complexity. METHODS: Secondary data analysis (N=80,965) based on the National Survey of CSHCN 2005-2006 and 2009-2010 waves. RESULTS: During 2005-2010, 7.66% of CSHCN in the U.S. were with medical complexity. The prevalence of unmet needs for mental healthcare services among CSHCN increased from 3.71% in 2005-2006 to 5.62% in 2009-2010. In 2005-2006 the prevalence of unmet mental healthcare needs among children with medical complexity was 9.92%, tripling the prevalence among CSHCN without medical complexity of 3.10%. The prevalence of unmet mental healthcare needs among children with medical complexity further increased to 13.71% in 2009-2010, whereas that among CSHCN without medical complexity increased to 5.07%. Among CSHCN with medical complexity, older children and children living in poorer households were more likely to have an unmet need for mental healthcare services. CONCLUSION: Substantial disparities in access to mental healthcare services between CSHCN with and without medical complexity were present, and the prevalence of unmet mental healthcare needs among both groups had noticeably increased during 2005-2010. PMID- 26944392 TI - Clinical value of DSM IV and DSM 5 criteria for diagnosing the most prevalent somatoform disorders in patients with medically unexplained physical symptoms (MUPS). AB - OBJECTIVE: This study aimed (1) to describe frequencies of DSM IV somatisation disorder, undifferentiated somatoform disorder and pain disorder versus DSM 5 somatic symptom disorder (SSD) in a multi-setting population of patients with medically unexplained physical symptoms (MUPS), (2) to investigate differences in sociodemographic and (psycho)pathological characteristics between these diagnostic groups and (3) to explore the clinical relevance of the distinction between mild and moderate DSM 5 SSD. METHODS: We used baseline data of a cohort of 325 MUPS patients. Measurements included questionnaires about symptom severity, physical functioning, anxiety, depression, health anxiety and illness perceptions. These questionnaires were used as proxy measures for operationalization of DSM IV and DSM 5 diagnostic criteria. RESULTS: 92.9% of participants fulfilled criteria of a DSM IV somatoform disorder, while 45.5% fulfilled criteria of DSM 5 SSD. Participants fulfilling criteria of DSM 5 SSD suffered from more severe symptoms than those only fulfilling criteria of a DSM IV somatoform disorder(mean PHQ-15 score of 13.98 (SD 5.17) versus 11.23 (SD 4.71), P-value<0.001). Furthermore their level of physical functioning was significantly lower. Compared to patients with mild SSD, patients with moderate SSD suffered from significantly lower physical functioning and higher levels of depression. CONCLUSION: Within a population of MUPS patients DSM 5 SSD criteria are more restrictive than DSM IV criteria for somatoform disorders. They are associated with higher symptom severity and lower physical functioning. However, further specification of the positive psychological criteria of DSM 5 SSD may improve utility in research and practice. PMID- 26944394 TI - Evidence of Big-Five personality changes following acquired brain injury from a prospective longitudinal investigation. AB - OBJECTIVE: Many studies using different assessment methods have reported personality changes after acquired brain injury (ABI). However, to our knowledge, no prospective study has yet been conducted to examine whether previous cross sectional and retrospective results can be replicated in a longitudinal prospective design. Further, because clinical control groups were only rarely used, it remains debatable if the personality changes found are unique to patients with ABI or if they also affect patients with other disabilities. METHODS: This study examined personality change in 114 participants with different kinds of ABI, 1321 matched controls (general control, GC), and 746 matched participants with restrictive impairments other than brain injury (clinical control, CC) in a prospective longitudinal design using data from the panel survey Household, Income and Labour Dynamics in Australia (HILDA). RESULTS: Participants with ABI showed significantly larger declines in Extraversion and Conscientiousness compared with the GC group. When the ABI participants were compared with the CC group, only the difference in Conscientiousness remained significant. CONCLUSION: Our prospective data corroborate evidence from previous cross-sectional studies that patients with ABI experience larger declines in Extraversion and Conscientiousness than the general population. Whereas the effect on Conscientiousness was unique to patients with ABI, the decline in Extraversion was also observed in participants with other impairments. PMID- 26944393 TI - Associations between DSM-IV mental disorders and subsequent onset of arthritis. AB - OBJECTIVE: We investigated the associations between DSM-IV mental disorders and subsequent arthritis onset, with and without mental disorder comorbidity adjustment. We aimed to determine whether specific types of mental disorders and increasing numbers of mental disorders were associated with the onset of arthritis later in life. METHOD: Data were collected using face-to-face household surveys, conducted in 19 countries from different regions of the world (n=52,095). Lifetime prevalence and age at onset of 16 DSM-IV mental disorders were assessed retrospectively with the World Health Organization (WHO) Composite International Diagnostic Interview (WHO-CIDI). Arthritis was assessed by self report of lifetime history of arthritis and age at onset. Survival analyses estimated the association of initial onset of mental disorders with subsequent onset of arthritis. RESULTS: After adjusting for comorbidity, the number of mood, anxiety, impulse-control, and substance disorders remained significantly associated with arthritis onset showing odds ratios (ORs) ranging from 1.2 to 1.4. Additionally, the risk of developing arthritis increased as the number of mental disorders increased from one to five or more disorders. CONCLUSION: This study suggests links between mental disorders and subsequent arthritis onset using a large, multi-country dataset. These associations lend support to the idea that it may be possible to reduce the severity of mental disorder-arthritis comorbidity through early identification and effective treatment of mental disorders. PMID- 26944395 TI - An experimental paradigm to repeatedly induce somatic symptoms. AB - OBJECTIVE: Experimental research in the field of medically unexplained physical symptoms (MUPS) is rare. We examined a method of script driven imagery in terms of manipulating the intensity of the symptom, the impairment by the symptom and the symptom tolerance. Additionally, we identified relevant predictors for the efficacy of symptom induction. METHODS: We assessed the most impairing symptom in 48 subjects suffering from multiple, chronic MUPS and a severe physical illness that 48 age-matched healthy controls suffered from in the past. An individual script including thoughts and sensations accompanying the symptom was recorded. During the experiment, participants were exposed to the script repeatedly and then rated the intensity of, impairment by and tolerance of the symptom on a visual analog scale (VAS). RESULTS: A mixed model repeated-measures-ANOVA revealed a significant main effect for the factor time (pre- and post-induction assessment; p<.001) but not for group (MUPS- vs. control-groups; p=.159-.314) indicating that the manipulation of all VASs was effective for both groups. The interaction time*group was significant for tolerance and post-hoc analyses showed no significant reduction for tolerance in the MUPS-group. The number of somatic symptoms and endurance behavior predicted higher induction efficacy in the MUPS group for intensity. For healthy controls, endurance behavior and pain persistence were associated with lower induction efficacy for all VAS. CONCLUSION: Script-driven imagery could be a promising research procedure in the field of MUPS. It could be used to investigate short term effects of psychological interventions as well as physiological and cognitive processes accompanying symptom manipulation. PMID- 26944396 TI - Exploring the relationship between posttraumatic stress disorder symptoms and momentary heart rate variability. AB - OBJECTIVE: Exposure to trauma-related cues has been associated with a prolonged decrease in heart rate variability (HRV) under laboratory conditions, however the relationship between PTSD symptoms and HRV has not been evaluated during everyday life. The present study sought to determine whether Posttraumatic Stress Disorder (PTSD) symptoms reported during everyday life were related to reduced HRV. METHODOLOGY: Eighty-three young adults with PTSD underwent 24-hour Holter monitoring, during which PTSD symptoms were measured using ecological momentary assessment (EMA). Multilevel modeling was used to examine the association between PTSD symptom severity and low frequency (LF) and high frequency (HF) HRV. RESULTS: PTSD symptoms were associated with reductions in LF HRV, independently of age and activity level. There was no significant association between PTSD symptom levels and HF HRV. CONCLUSIONS: These results indicate that an association between momentary PTSD symptom severity and reduced LF HRV is significant and observable in young adults with PTSD. Findings highlight the need for cardiovascular screening in young adults with PTSD and early interventions that target physiological reactivity in PTSD. PMID- 26944397 TI - Posttraumatic stress disorder and somatic complaints: Contrasting Vietnam and OIF/OEF Veterans' experiences. AB - OBJECTIVE: To replicate and expand upon the relationship of somatic symptoms and posttraumatic stress disorder (PTSD) by comparing symptoms among service eras in US Veterans. METHOD: Data were collected from 226 Vietnam and 132 Operation Iraqi Freedom/Operation Enduring Freedom (OIF/OEF) Veterans who were referred to a Veterans Affairs (VA) hospital PTSD outpatient clinic between 2005 and 2013. Veterans were administered self-report inventories and a clinical interview to measure somatic symptoms and PTSD severity. A subset of Veterans (n=185) screening positive for PTSD were administered the Clinician Administered PTSD Scale (CAPS) to measure PTSD severity. Multiple moderated linear regressions were used to examine the influence of service era on the relationship between somatic and PTSD symptoms. RESULTS: There were no significant differences between service eras in pain severity, pain interference, and total somatic symptoms reported. Vietnam Veterans were more likely to report limb/join pain (p<.05), fainting (p<.01), and shortness of breath (p<.001), whereas OIF/OEF Veterans were more likely to complain of headaches (p<.001). A significant interaction effect occurred between service era and dizziness (p<.05) and chest pain (p<.01), with OIF/OEF Veterans reporting higher levels of these symptoms significantly more likely than Vietnam Veterans to also experience more severe PTSD. CONCLUSION: Findings are consistent with previous research demonstrating the relationship of somatic symptoms and PTSD across service eras but provide additional data concerning similarities and differences of somatic symptoms between eras. Potential explanations for observed service era differences in somatic symptoms are discussed. PMID- 26944398 TI - Health- and work-related predictors of work disability among employees with a cardiometabolic disease--A cohort study. AB - OBJECTIVE: The proportion of aging employees with cardiometabolic diseases, such as heart or cerebrovascular disease, diabetes and chronic hypertension is on the rise. We explored the extent to which health- and work-related factors were associated with the risk of disability pension among individuals with such cardiometabolic disease. METHODS: A cohort of 4798 employees with and 9716 employees without a cardiometabolic disease were followed up for 7years (2005 2011) for disability pension. For these participants, register and survey data (from 2004) were linked to records on disability pensions. Cox proportional hazards modeling was used for estimating the hazard ratios (HR) with 95% confidence intervals (CI). RESULTS: Individuals with heart or cerebrovascular disease had 2.88-fold (95% CI=2.50-3.31) higher risk of all-cause disability pension compared to employees with no cardiometabolic disease. Diabetes was associated with a 1.84-fold (95% CI=1.52-2.23) and hypertension a 1.50-fold (95% CI=1.31-1.72) increased risk of disability pension. Obesity in cases of diabetes and hypertension (15%) and psychological distress in cases of heart or cerebrovascular disease (9%) were the strongest contributing factors. All 12 health- and work-related risk factors investigated accounted for 24% of the excess work disability in hypertension, 28% in diabetes, and 11% in heart or cerebrovascular disease. Cause-specific analyses (disability pension due to mental, musculoskeletal and circulatory system diseases) yielded similar results. CONCLUSIONS: In this study, modifiable risk factors, such as obesity and mental comorbidity, predicted permanent exit from the labor market due to disability in individuals with cardiometabolic disease. PMID- 26944399 TI - Rumination and behavioural factors in Parkinson's disease depression. AB - OBJECTIVE: Parkinson's disease is associated with high rates of depression. There is growing interest in non-pharmacological management including psychological approaches such as Cognitive Behaviour Therapy. To date, little research has investigated whether processes that underpin cognitive models of depression, on which such treatment is based, apply in patients with Parkinson's disease. The study aimed to investigate the contribution of core psychological factors to the presence and degree of depressive symptoms. METHODS: 104 participants completed questionnaires measuring mood, motor disability and core psychological variables, including maladaptive assumptions, rumination, cognitive-behavioural avoidance, illness representations and cognitive-behavioural responses to symptoms. RESULTS: Regression analyses revealed that a small number of psychological factors accounted for the majority of depression variance, over and above that explained by overall disability. Participants reporting high levels of rumination, avoidance and symptom focusing experienced more severe depressive symptoms. In contrast, pervasive negative dysfunctional beliefs did not independently contribute to depression variance. CONCLUSION: Specific cognitive (rumination and symptom focusing) and behavioural (avoidance) processes may be key psychological markers of depression in Parkinson's disease and therefore offer important targets for tailored psychological interventions. PMID- 26944401 TI - Prevalence of left atrial enlargement and its risk factors in general Chinese population. AB - BACKGROUND: Left atrial enlargement (LAE) has been proven to be significantly related to stroke and cardiovascular diseases. In China, few studies related to LAE have been conducted, especially in the general population. To the best of our knowledge, our study is the first to explore the prevalence of LAE and associated risk factors in the general Chinese population. METHODS: This study included a total of 11,956 subjects aged >=35 years. All participants completed a questionnaire, and underwent complete physical examination, electrocardiogram (ECG) and echocardiogram. We defined LAE as a LA diameter exceeding 4.0 cm in men and 3.8 cm in women. We conducted a multivariable logistic regression analysis and a linear regression analysis to identify independent factors of LAE. RESULTS: The overall prevalence of LAE was 6.43 % for subjects aged over 35 years. The prevalence of LAE was 6.78 % in women and 6.02 % in men. The major risk factors of LAE were female sex (odds ration [OR]: 1.229, beta: 0.197), advancing age (OR: 1.015, beta: 0.036), high systolic blood pressure (OR: 2.331, beta: 0.185), high body mass index (BMI) (OR: 3.956, beta: 0.373), diabetes (OR: 1.498, beta: 0.030), high left ventricular myocardial index (OR: 1.003, beta: 0.073), and low left ventricular ejection fraction, low heart rate, and low estimated glomerular filtration rate. Additionally, the association between BMI and LAE was the most obvious. CONCLUSIONS: Female sex, advancing age, high systolic blood pressure, high BMI, diabetes, high left ventricular myocardial index, low estimated glomerular filtration rate, low left ventricular ejection fraction, and low heart rate were proven to be risk factors of LAE. PMID- 26944400 TI - Pairing nuts and dried fruit for cardiometabolic health. AB - Certain dietary patterns, in which fruits and nuts are featured prominently, reduce risk of diabetes and cardiovascular disease. However, estimated fruit consumption historically in the U.S. has been lower than recommendations. Dried fruit intake is even lower with only about 6.9 % of the adult population reporting any consumption. The 2015 Dietary Guidelines Advisory Committee identified a gap between recommended fruit and vegetable intakes and the amount the population consumes. Even fewer Americans consume tree nuts, which are a nutrient-dense food, rich in bioactive compounds and healthy fatty acids. Consumption of fruits and nuts has been associated with reduced risk of cardiometabolic disease. An estimated 5.5 to 8.4 % of U.S. adults consume tree nuts and/or tree nut butter. This review examines the potential of pairing nuts and dried fruit to reduce cardiometabolic risk factors and focuses on emerging data on raisins and pistachios as representative of each food category. Evidence suggests that increasing consumption of both could help improve Americans' nutritional status and reduce the risk of chronic diseases. PMID- 26944402 TI - Linear trends and seasonality of births and perinatal outcomes in Upper East Region, Ghana from 2010 to 2014. AB - BACKGROUND: Seasonal variations greatly influence birth patterns differently from country to country. In Ghana, there is paucity of information on birth seasonal patterns. This retrospective study described the trends and seasonality of births and perinatal outcomes in Upper East Region of Ghana. METHODS: Births occurring in each month of the calendar years (2010-2014; inclusive) were extracted from the District Health Information Management System (DHIMS2) database of the Bolgatanga Municipal Health Directorate and exported into Microsoft Excel spread sheet and Epi Ifo for analysis. Analysis was carried out by calculating average number of births per month correcting for unequal month length using 30 days. A Chi-square test for trend was performed to check for statistical significance (p < 0.05) in trends and seasonality of birth and perinatal outcomes. RESULTS: There were 24,171 health facility deliveries, of which 97.7% were singleton deliveries and 2.3% were multiple (two or three) deliveries. There was a consistent rise in the annual health facility deliveries controlled for the number of fertile women, from 4169 in 2010 to 5474 in 2014 (p < 0.0001). Monthly birth distribution displayed a periodic pattern with peaks in May, September and October and troughs during the months of January, February and July (p < 0.0001). Women were likely to give birth during the raining season than the dry season. Caesarean Section (CS) rate showed a steady rise over the years (124 per 1000 births in 2010 to 185 per 1000 births in 2014 (p < 0.0001) with overall rate of 14.6%. Stillbirth (SB) rate, however decreased slightly over the years from 29 per 1000 births to 23 per 1000 births (p = 0.197) with overall SB rate of 2.6%. Similarly, Low Birth Weight (LBW) declined from 77 per 1000 live births to 71 per 1000 live births from 2010 to 2014 (p < 0.0001). Seasonal (rainy and dry) distributions did not show a clear difference in birth frequencies. CONCLUSION: Health facility delivery was persistently high in the Bolgatanga Municipality with birth peaking in May, September and October. Despite the rising rate of caesarean section, stillbirth rate did not significantly improved over the years. A prospective study may reveal the reasons for the increasing caesarean section rate. Additionally, understanding the factors that affect the decreasing trends of low birth weight in the municipality is crucial to public health policy makers in Ghana. PMID- 26944404 TI - Majority of shrimp-allergic patients are allergic to mealworm. PMID- 26944403 TI - Comparative study of equine mesenchymal stem cells from healthy and injured synovial tissues: an in vitro assessment. AB - BACKGROUND: Bone marrow and adipose tissues are known sources of mesenchymal stem cells (MSCs) in horses; however, synovial tissues might be a promising alternative. The aim of this study was to evaluate phenotypic characteristics and differentiation potential of equine MSCs from synovial fluid (SF) and synovial membrane (SM) of healthy joints (SF-H and SM-H), joints with osteoarthritis (SF OA and SM-OA) and joints with osteochondritis dissecans (SF-OCD and SM-OCD) to determine the most suitable synovial source for an allogeneic therapy cell bank. METHODS: Expression of the markers CD90, CD105, CD44, and CD34 in SF-H, SM-H, SF OA, SM-OA, SF-OCD and SM-OCD was verified by flow cytometry, and expression of cytokeratin, vimentin, PGP 9.5, PCNA, lysozyme, nanog, and Oct4 was verified by immunocytochemistry. MSCs were cultured and evaluated for their chondrogenic, osteogenic and adipogenic differentiation potential. Final quantification of extracellular matrix and mineralized matrix was determined using AxioVision software. A tumorigenicity test was conducted in Balb-C(nu/nu) mice to verify the safety of the MSCs from these sources. RESULTS: Cultured cells from SF and SM exhibited fibroblastoid morphology and the ability to adhere to plastic. The time elapsed between primary culture and the third passage was approximately 73 days for SF-H, 89 days for SF-OCD, 60 days for SF-OA, 68 days for SM-H, 57 days for SM OCD and 54 days for SM-OA. The doubling time for SF-OCD was higher than that for other cells at the first passage (P < 0.05). MSCs from synovial tissues showed positive expression of the markers CD90, CD44, lysozyme, PGP 9.5, PCNA and vimentin and were able to differentiate into chondrogenic (21 days) and osteogenic (21 days) lineages, and, although poorly, into adipogenic lineages (14 days). The areas staining positive for extracellular matrix in the SF-H and SM-H groups were larger than those in the SF-OA and SM-OA groups (P < 0.05). The positive mineralized matrix area in the SF-H group was larger than those in all the other groups (P < 0.05). The studied cells exhibited no tumorigenic effects. CONCLUSIONS: SF and SM are viable sources of equine MSCs. All sources studied provide suitable MSCs for an allogeneic therapy cell bank; nevertheless, MSCs from healthy joints may be preferable for cell banking purposes because they exhibit better chondrogenic differentiation capacity. PMID- 26944406 TI - Method to improve passive fit of frameworks on implant-supported prostheses: An in vitro study. AB - STATEMENT OF PROBLEM: The passivity of the superstructure to the abutments of implant-supported prostheses is necessary for implant-prosthesis success. Improvements are needed in the methods of verifying passivity. PURPOSE: The purpose of this in vitro study was to evaluate an inexpensive, easy to make, and user-friendly device to verify the position of the implant abutment replicas of the definitive cast and to avoid framework misfit before fabrication. MATERIAL AND METHODS: Eighty stone devices were constructed on a metal base for the in vitro tests. The horizontal, vertical, and angled positions of the implant replicas were created to simulate misfits. The devices were fitted on the abutment replicas, and their ability to identify misfits was evaluated. A statistical analysis was not indicated, because the probability of fracture of the stone devices was 0 or 1. Two mathematical models were built using computer aided design software (SolidWorks Premium; Dassault Systemes SolidWorks Corp), and the finite element method was used (Ansys; ANSYS Inc) to simulate the structural behavior of 2 implant configurations (4 and 6 implants). RESULTS: Horizontal misfits of 150 MUm, vertical misfits of 50 MUm, and angled misfits of 1 degree were detected during the in vitro tests. Different loads and bone quality in the mathematical models did not change stress in the prosthesis configurations on 4 or 6 implants in a relevant way. CONCLUSIONS: The fabricated device was easily able to detect the misfits in accordance with the defined parameters. PMID- 26944405 TI - Preterm birth and air pollution: Critical windows of exposure for women with asthma. AB - BACKGROUND: Ambient air pollutants may increase preterm birth (PTB) risk, but critical exposure windows are uncertain. The interaction of asthma and pollutant exposure is rarely studied. OBJECTIVE: We sought to assess the interaction of maternal asthma and air pollutant exposures in relation to PTB risk. METHODS: Electronic medical records for 223,502 US deliveries were linked with modified Community Multiscale Air Quality model outputs. Logistic regression with generalized estimating equations estimated the odds ratio and 95% CIs for PTB on the basis of the interaction of maternal asthma and particulate matter with aerodynamic diameter of less than 2.5 microns and particulate matter with aerodynamic diameter of less than 10 microns, ozone (O3), nitrogen oxides (NOx), sulfur dioxide (SO2), and carbon monoxide (CO) per interquartile range. For each gestational week 23 to 36, exposures among women who delivered were compared with those remaining pregnant. Three-month preconception, whole pregnancy, weeks 1 to 28, and the last 6 weeks of gestation averages were also evaluated. RESULTS: On assessing PTB by gestational week, we found that significant asthma interactions were sporadic before 30 weeks but more common during weeks 34 to 36, with higher risk among mothers with asthma for NOx, CO, and SO2 exposure and an inverse association with O3 in week 34. Odds of PTB were significantly higher among women with asthma for CO and NOx exposure preconception and early in pregnancy. In the last 6 weeks of pregnancy, PTB risk associated with particulate matter with aerodynamic diameter of less than 10 microns was higher among women with asthma. CONCLUSIONS: Mothers with asthma may experience a higher risk for PTB after exposure to traffic-related pollutants such as CO and NOx, particularly for exposures 3-months preconception and in the early weeks of pregnancy. PMID- 26944407 TI - Clinical Effects of Lactobacillus rhamnosus in Non-Surgical Treatment of Chronic Periodontitis: A Randomized Placebo-Controlled Trial With 1-Year Follow-Up. AB - BACKGROUND: Probiotics are living microorganisms that provide beneficial effects for the host when administered in proper quantities. The aim of this double masked placebo-controlled parallel-arm randomized clinical trial is to evaluate the clinical effects of a Lactobacillus rhamnosus SP1-containing probiotic sachet as an adjunct to non-surgical therapy. METHODS: Twenty-eight systemically healthy volunteers with chronic periodontitis were recruited and monitored clinically at baseline and 3, 6, 9, and 12 months after therapy. Clinical parameters measured included plaque accumulation, bleeding on probing, probing depths (PDs), and clinical attachment loss. Patients received non-surgical therapy, including scaling and root planing (SRP), and were assigned randomly to a test (SRP + probiotic, n = 14) or control (SRP + placebo, n = 14) group. The intake, once a day for 3 months, of an L. rhamnosus SP1 probiotic sachet commenced after the last session of SRP. RESULTS: Both test and control groups showed improvements in clinical parameters at all time points evaluated. However, the test group showed greater reductions in PD than the control. Also, at initial visits and after 1 year follow-up, the test group showed a statistically significant reduction in the number of participants with PD >=6 mm, indicating a reduced need for surgery, in contrast to the placebo group. CONCLUSION: The results of this trial indicate that oral administration of L. rhamnosus SP1 resulted in similar clinical improvements compared with SRP alone. PMID- 26944409 TI - Marginal Bone Loss in Implants Placed in the Maxillary Sinus Grafted With Anorganic Bovine Bone: A Prospective Clinical and Radiographic Study. AB - BACKGROUND: Sinus elevation is a reliable and often-used technique. Success of implants placed in such situations, even with bone substitutes alone, prompted the authors of this study to strive for bone loss close to zero and research variables that cause higher or lower rates of resorption. The objective of this study is to evaluate survival rates and marginal bone loss (MBL) around implants placed in sites treated with maxillary sinus augmentation using anorganic bovine bone (ABB), and identify surgical and prosthetic prognostic variables. METHODS: Fifty-five implants were placed in 30 grafted maxillary sinuses in 24 patients. Periapical radiographs were evaluated immediately after implant placement (baseline), 6 months, and at the most recent follow-up. MBL was calculated from the difference between initial and final measurements, taking into account a distortion rate for each radiograph compared with original implant measurements. RESULTS: Survival rate was 98.2%, with only one implant lost (100% survival rate after loading) over a mean follow-up time of 2.0 +/- 0.9 years. MBL ranged from 0 to 2.85 mm: 75.9% of mesial sites and 83.4% of distal sites showed <1 mm of MBL, whereas 35.2% of mesial sites and 37% of distal sites exhibited no bone loss. MBL was significantly (P <0.05) greater in open-flap compared with flapless surgery. CONCLUSIONS: Within the limitations of the present study, it was concluded that maxillary sinus elevation with 100% ABB gives predictable results, and that flapless surgery results in less MBL compared with traditional open-flap surgery. PMID- 26944408 TI - Aloin Inhibits Interleukin (IL)-1beta-Stimulated IL-8 Production in KB Cells. AB - BACKGROUND: Interleukin (IL)-1beta, which is elevated in oral diseases including gingivitis, stimulates epithelial cells to produce IL-8 and perpetuate inflammatory responses. This study investigates stimulatory effects of salivary IL-1beta in IL-8 production and determines if aloin inhibits IL-1beta-stimulated IL-8 production in epithelial cells. METHODS: Saliva was collected from volunteers to determine IL-1beta and IL-8 levels. Samples from volunteers were divided into two groups: those with low and those with high IL-1beta levels. KB cells were stimulated with IL-1beta or saliva with or without IL-1 receptor agonist or specific mitogen-activated protein kinase (MAPK) inhibitors. IL-8 production was measured by enzyme-linked immunosorbent assay (ELISA). MAPK protein expression involved in IL-1beta-induced IL-8 secretion was detected by Western blot. KB cells were pretreated with aloin, and its effect on IL-1beta induced IL-8 production was examined by ELISA and Western blot analysis. RESULTS: Saliva with high IL-1beta strongly stimulated IL-8 production in KB cells, and IL 1 receptor agonist significantly inhibited IL-8 production. Low IL-1beta containing saliva did not increase IL-8 production. IL-1beta treatment of KB cells induced activation of MAPK signaling molecules as well as nuclear factor kappa B. IL-1beta-induced IL-8 production was decreased by p38 and extracellular signal-regulated kinase (ERK) inhibitor treatment. Aloin pretreatment inhibited IL-1beta-induced IL-8 production in a dose-dependent manner and inhibited activation of the p38 and ERK signaling pathway. Finally, aloin pretreatment also inhibited saliva-induced IL-8 production. CONCLUSIONS: Results indicated that IL 1beta in saliva stimulates epithelial cells to produce IL-8 and that aloin effectively inhibits salivary IL-1beta-induced IL-8 production by mitigating the p38 and ERK pathway. Therefore, aloin may be a good candidate for modulating oral inflammatory diseases. PMID- 26944410 TI - A new allele for aluminium tolerance gene in barley (Hordeum vulgare L.). AB - BACKGROUND: Aluminium (Al) toxicity is the main factor limiting the crop production in acid soils and barley (Hordeum vulgare L.) is one of the most Al sensitive of the small-grained cereals. The major gene for Al tolerance in barley is HvAACT1 (HvMATE) on chromosome 4H which encodes a multidrug and toxic compound extrusion (MATE) protein. The HvAACT1 protein facilitates the Al-activated release of citrate from root apices which protects the growing cells and enables root elongation to continue. A 1 kb transposable element-like insert in the 5' untranslated region (UTR) of HvAACT1 is associated with increased gene expression and tolerance and a PCR-based marker is available to score for this insertion. RESULTS: We screened a wide range of barley genotypes for Al tolerance and identified a moderately tolerant Chinese genotype named CXHKSL which did not show the typical allele in the 5' UTR of HvAACT1 associated with tolerance. We investigated the mechanism of Al tolerance in CXHKSL and concluded it also relies on the Al-activated release of citrate from roots. Quantitative trait loci (QTL) analysis of double haploid lines generated with CXHKSL and the Al-sensitive variety Gairdner mapped the tolerance locus to the same region as HvAACT1 on chromosome 4H. CONCLUSIONS: Our results show that the Chinese barley genotype CXHKSL possesses a novel allele of the major Al tolerance gene HvAACT1. PMID- 26944413 TI - Linear quantification of a streptavidin-alkaline phosphatase probe for enzyme linked immuno mass spectrometric assay. AB - The alkaline phosphatase-streptavidin (AP-SA) probe released adenosine (~267.2 Da) from the substrate adenosine monophosphate (AMP), where a signal may be detected from as little as 0.5 MUl of a 0.1-pg/ml dilution of the probe (2.6 * 10(-22) mol). The signal from the AP-SA probe was linear from 1 to 50 pg/ml by monitoring adenosine release at 268 m/z (M + H) with liquid chromatography, electrospray ionization, and quadrupole mass spectrometry (LC-ESI-MS). The safe limit of detection and quantification of the AP-SA probe was approximately 0.5 pg/well or 5 pg/ml. Enzyme-linked immuno mass spectrometric assay (ELIMSA) using the AP-SA probe provided a linear signal response for prostate-specific antigen (PSA) against external standards from 1 to 500 pg/ml. The ELIMSA showed a safe limit of detection and quantification at 5 pg PSA/well or 50 pg/ml (false positive detection rate P <= 0.01). Female samples of 100 MUl plasma/well were read against standards and blanks made in normal female plasma, and the lowest sample quantified was approximately 9.8 pg/well or 98 pg/ml. Here ELIMSA was applied to measure PSA in plasma from female, normal male, prostatectomy patient, and cancer patient samples that showed significant differences by analysis of variance (ANOVA). PMID- 26944414 TI - Nocardia and Aspergillus Coinfection in a Patient with Ulcerative Colitis during Golimumab Therapy. PMID- 26944412 TI - Role of matrix metalloproteinases in the pathogenesis of idiopathic pulmonary fibrosis. AB - Idiopathic pulmonary fibrosis (IPF) is a progressive and devastating lung disorder of unknown origin, with very poor prognosis and no effective treatment. The disease is characterized by abnormal activation of alveolar epithelial cells, which secrete numerous mediators involved in the expansion of the fibroblast population, its differentiation to myofibroblasts, and in the exaggerated accumulation of extracellular matrix provoking the loss of lung architecture. Among the excessively produced mediators are several matrix metalloproteases (MMPs) which may contribute to modify the lung microenvironment by various mechanisms. Thus, these enzymes can not only degrade all the components of the extracellular matrix, but they are also able to release, cleave and activate a wide range of growth factors, cytokines, chemokines and cell surface receptors affecting numerous cell functions including adhesion, proliferation, differentiation, recruiting and transmigration, and apoptosis. Therefore, dysregulated expression of MMPs may have profound impact on the biopathological mechanisms implicated in the development of IPF. This review focuses on the current and emerging evidence regarding the role of MMPs on the fibrotic processes in IPF as well as in mouse models of lung fibrosis. PMID- 26944411 TI - Local iron homeostasis in the breast ductal carcinoma microenvironment. AB - BACKGROUND: While the deregulation of iron homeostasis in breast epithelial cells is acknowledged, iron-related alterations in stromal inflammatory cells from the tumor microenvironment have not been explored. METHODS: Immunohistochemistry for hepcidin, ferroportin 1 (FPN1), transferrin receptor 1 (TFR1) and ferritin (FT) was performed in primary breast tissues and axillary lymph nodes in order to dissect the iron-profiles of epithelial cells, lymphocytes and macrophages. Furthermore, breast carcinoma core biopsies frozen in optimum cutting temperature (OCT) compound were subjected to imaging flow cytometry to confirm FPN1 expression in the cell types previously evaluated and determine its cellular localization. RESULTS: We confirm previous results by showing that breast cancer epithelial cells present an 'iron-utilization phenotype' with an increased expression of hepcidin and TFR1, and decreased expression of FT. On the other hand, lymphocytes and macrophages infiltrating primary tumors and from metastized lymph nodes display an 'iron-donor' phenotype, with increased expression of FPN1 and FT, concomitant with an activation profile reflected by a higher expression of TFR1 and hepcidin. A higher percentage of breast carcinomas, compared to control mastectomy samples, present iron accumulation in stromal inflammatory cells, suggesting that these cells may constitute an effective tissue iron reservoir. Additionally, not only the deregulated expression of iron-related proteins in epithelial cells, but also on lymphocytes and macrophages, are associated with clinicopathological markers of breast cancer poor prognosis, such as negative hormone receptor status and tumor size. CONCLUSIONS: The present results reinforce the importance of analyzing the tumor microenvironment in breast cancer, extending the contribution of immune cells to local iron homeostasis in the tumor microenvironment context. PMID- 26944415 TI - Dietary Non-digestible Polysaccharides Ameliorate Intestinal Epithelial Barrier Dysfunction in IL-10 Knockout Mice. AB - BACKGROUND: Enteral nutrition [EN] was reported to be as effective as steroids in achieving short-term remission in patients with Crohn's disease [CD], and exclusive EN [EEN] is widely used as primary therapy in children with CD. The aim of this study was to investigate the effect of a specific multi-fibre mix [MF], designed to match the fibre content of a healthy diet, on intestinal epithelial barrier function in IL-10 knockout [IL-10(-/-)] mice with spontaneous chronic colitis. METHODS: IL-10(-/-) mice aged 16 weeks, with established colitis, were used for the experiments with multi-fibre mix diet [MF] for 4 weeks. Severity of colitis, levels of short cahin fatty acids [SCFA] in caecum contents, expression of STAT 3 and STAT 4 proteins, CD4(+) CD45(+) lymphocytes, CD4(+)Foxp3(+) regulatory T cells [Tregs] and cytokines in the lamina propria [LP], epithelial expression of tight junction proteins, TNF-alpha/TNFR2 mRNA expression, and epithelial apoptosis in the proximal colon were measured at the end of the experiment. RESULTS: MF feeding effectively attenuated disease activity index and colitis associated with decreased lamina propria CD4(+) CD45(+) lymphocytes, IFN gamma/IL-17A mRNA expression, and p-STAT 3 and p-STAT 4 expression in colonic mucosa of IL-10(-/-) mice [p < 0.05]. Furthermore, CD4(+)Foxp3(+) Tregs in the LP and concentrations of total SCFA, acetate, propionate, and butyrate in the caecum were markedly increased after MF feeding in IL-10(-/-) mice. After MF feeding, increased epithelial expression and correct localisation of tight junction proteins [occludin and zona occludens protein 1], as well as reduced TNF alpha/TNFR2 mRNA expression and epithelial apoptosis, were also observed in IL 10(-/-) mice. CONCLUSIONS: These results indicated that EEN supplemented with the tested fibre mix, known to modulate the intestinal microbiota composition and SCFA production, could possibly improve efficacy in inducing remission in patients with active CD. PMID- 26944416 TI - Effectiveness Research in Inflammatory Bowel Disease: A Necessity and a Methodological Challenge. AB - Efficacy, safety and economic issues are the main factors influencing the use of inflammatory bowel disease [IBD]-related medications. The best level of evidence comes from randomised clinical trials. The benefit of the intervention observed in a clinical trial could be reduced once it is implemented in clinical practice: its real-life efficacy, known as effectiveness, could be questioned. That is why effectiveness research based on observational studies is required to obtain-long term data on natural history, including surgery or hospitalisation, and safety. Before starting these real-life studies, it is crucial to be aware of the inherent risks of bias and confounding, to develop a good study plan, and to select the optimal design. Even if the choice of the design is optimal and if the risks of bias and confounding are minimised, the implementation of robust statistical methodology is necessary to increase the validity of the results and allow their dissemination into clinical practice. The objective of this paper is to highlight some inherent methodological problems in effectiveness research and to review some statistical tools with a focus on IBD studies and trials. PMID- 26944417 TI - Expression and potential roles of IL-33/ST2 in the immune regulation during Clonorchis sinensis infection. AB - During clonorchiasis, immune responses of hosts are responsible for the removal of the worms and also are involved in the progress of the pathological damage caused by Clonorchis sinensis. Interleukin-33 (IL-33), a recently described cytokine signaling through the ST2 receptor, has emerged as a potent inducer to bile duct proliferation and fibrosis; however, little is known of this signaling in the pathogen-caused periductal inflammation and fibrosis. In the present study, using immunohistochemistry, real-time PCR, enzyme-linked immunosorbent assay (ELISA), and flow cytometry, we studied the expression of IL-33/ST2 during C. sinensis infection, as well as their potential roles in C. sinensis-induced host immune responses. The results showed that a higher level of IL-33 was detected in the sera of patients of clonorchiasis (n = 45), compared with in those of healthy donors (n = 16). Similarly, in FVB mice experimentally infected with C. sinensis, a higher level of IL-33 was detected at latent stage both in the serum and in the liver, as well as the up-regulated expression of ST2 receptor on the inflammatory cells, especially on CD4(+) T cells in the liver of infected mice. Our results, for the first time, indicated that the increased IL 33/ST2 may be involved in the regulation of immunopathology induced by C. sinensis. PMID- 26944418 TI - Aptitude of Lymnaea palustris and L. stagnalis to Fasciola hepatica larval development through the infection of several successive generations of 4-mm-high snails. AB - Bimiracidial infections of Lymnaea palustris and Lymnaea stagnalis (shell height at exposure, 4 mm) with Fasciola hepatica were carried out during six successive snail generations to determine if prevalence and intensity of snail infection increased over time through descendants issuing from eggs laid by parents already exposed to this digenean. Controls were constituted by a French population of Galba truncatula (a single generation) infected according to the same protocol. In a first experiment performed with the F1 to F5 generations of L. palustris, the prevalence and intensity of F. hepatica infection in snails progressively increased. Immature rediae and a few cercariae-containing rediae of the digenean were observed in L. stagnalis from the F3 generation, but no free cercaria was noted in the bodies of this lymnaeid from the F4 to F6 generations. In another experiment carried out with the F6 generation of L. palustris, the prevalence of F. hepatica infection and the number of shed cercariae were significantly lower in L. palustris than in G. truncatula. This mode of snail infection suggests an explanation for cases of human fasciolosis occurring in central France after the collection of wild watercress from beds where L. palustris was the sole lymnaeid. PMID- 26944420 TI - Towards a trial-based definition of vitamin D deficiency. PMID- 26944419 TI - Elderly patients treated with psychotropic medicines admitted to hospital: associated characteristics and inappropriate use. AB - PURPOSE: The purpose of this study is to describe the characteristics of older patients treated with psychotropic medicines and the associated factors and to assess their inappropriate use. METHODS: An observational, prospective study was carried out in 672 elderly patients admitted to seven hospitals for a year. A comparison of sociodemographic characteristics, geriatric variables, multimorbidity and the number of prescribed medicines taken in the preceding month before hospitalization between patients treated with psychotropics and those not treated was performed. To assess factors associated with psychotropics, multivariate logistic regression analyses were performed. Inappropriate use was assessed using the Beers and the STOPP criteria. RESULTS: A total of 57.5 % patients (median [Q1-Q3] age 81.7 [78.2-86.1], 65.7 % female) were treated with psychotropics (44.2 % anxiolytics, 22.6 % antidepressants and 10.8 % antipsychotics). Independent factors associated with the use of psychotropics were female gender (OR = 2.3; CI 95 %,1.6-3.5), some degree of disability on admission (slight [OR = 2.2; 1.2-4.2], moderate [OR = 3.2, 1.6-6.6], severe [OR = 3.4; 1.4-8] and very severe [OR = 5.1; 2.0-12.8]) and polypharmacy (5-9 medicines [OR = 3.0; 1.3-6.9] and >=10 medicines [OR = 6.0; 2.7-13.6]). The associated factors varied depending on the different types of psychotropics. In patients treated with psychotropics, the percentage of those with at least one Beers (61.6 %) or at least one STOPP (71.4 %) criteria was significantly higher in comparison with those not treated with psychotropics (30.7 and 47.7 %, respectively, p < 0.001). CONCLUSIONS: Psychotropics are widely used in the elderly population and often their use is inappropriate. Female gender, a poor functional status and polypharmacy, are the characteristics linked to their use. Interventional strategies should be focused on patients with these characteristics. PMID- 26944422 TI - Co-spray dried resveratrol and budesonide inhalation formulation for reducing inflammation and oxidative stress in rat alveolar macrophages. AB - Oxidative stress is instrumental in the pathogenesis and progression of chronic obstructive pulmonary disease (COPD). Novel therapeutic strategies that target macrophages, based on the use of antioxidant compounds, could be explored to improve corticosteroid responses in COPD patients. In this study, inhalable microparticles containing budesonide (BD) and resveratrol (RES) were prepared and characterized. This approach was undertaken to develop a multi-drug inhalable formulation with anti-oxidant and anti-inflammatory activities for treatment of chronic lung diseases. The inhalable microparticles containing different ratios of BD and RES were prepared by spray drying. The physico-chemical properties of the formulations were characterized in terms of surface morphology, particle size, physical and thermal stability. Additionally, in vitro aerosol performances of these formulations were evaluated with the multi-stage liquid impinger (MSLI) at 60 and 90 l/min, respectively. The cytotoxicity effect of the formulations was evaluated using rat alveolar macrophages. The biological responses of alveolar macrophages in terms of cytokine expressions, nitric oxide (NO) production and free radical scavenging activities were also tested. The co-spray dried (Co-SD) microparticles of all formulations exhibited morphologies appropriate for inhalation administration. Analysis of the deposition profiles showed an increase in aerosol performance proportional to BD concentration. Cell viability assay demonstrated that alveolar macrophages could tolerate a wide range of RES and BD concentrations. In addition, RES and BD were able to decrease the levels of tumour necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6) in lipopolysaccharide (LPS) induced alveolar macrophages. This study has successfully established the manufacture of Co-SD formulations of RES and BD with morphology and aerosol properties suitable for inhalation drug delivery, negligible in vitro toxicity and enhanced efficacy to control inflammation and oxidative stress in LPS-induced alveolar macrophages. PMID- 26944421 TI - Maternal gestational vitamin D supplementation and offspring bone health (MAVIDOS): a multicentre, double-blind, randomised placebo-controlled trial. AB - BACKGROUND: Maternal vitamin D status has been associated with bone mass of offspring in many, but not all, observational studies. However, maternal vitamin D repletion during pregnancy has not yet been proven to improve offspring bone mass in a randomised controlled trial. We aimed to assess whether neonates born to mothers supplemented with vitamin D during pregnancy have greater whole-body bone mineral content (BMC) at birth than those of mothers who had not received supplementation. METHODS: The Maternal Vitamin D Osteoporosis Study (MAVIDOS) was a multicentre, double-blind, randomised, placebo-controlled trial that recruited pregnant women from three study sites in the UK (Southampton, Oxford, and Sheffield). Eligible participants were older than 18 years, with a singleton pregnancy, gestation of less than 17 weeks, and a serum 25-hydroxyvitamin D (25[OH]D) concentration of 25-100 nmol/L at 10-17 weeks' gestation. P'articipants were randomly assigned (1:1), in randomly permuted blocks of ten, to either cholecalciferol 1000 IU/day or matched placebo, taken orally, from 14 weeks' gestation (or as soon as possible before 17 weeks' gestation if recruited later) until delivery. Participants and the research team were masked to treatment allocation. The primary outcome was neonatal whole-body BMC, assessed within 2 weeks of birth by dual-energy x-ray absorptiometry (DXA), analysed in all randomly assigned neonates who had a usable DXA scan. Safety outcomes were assessed in all randomly assigned participants. This trial is registered with the International Standard Randomised Controlled Trial registry, ISRCTN 82927713, and the European Clinical Trials Database, EudraCT 2007-001716-23. FINDINGS: Between Oct 10, 2008, and Feb 11, 2014, we randomly assigned 569 pregnant women to placebo and 565 to cholecalciferol 1000 IU/day. 370 (65%) neonates in the placebo group and 367 (65%) neonates in the cholecalciferol group had a usable DXA scan and were analysed for the primary endpoint. Neonatal whole-body BMC of infants born to mothers assigned to cholecalciferol 1000 IU/day did not significantly differ from that of infants born to mothers assigned to placebo (61.6 g [95% CI 60.3-62.8] vs 60.5 g [59.3-61.7], respectively; p=0.21). We noted no significant differences in safety outcomes, apart from a greater proportion of women in the placebo group with severe post-partum haemorrhage than those in the cholecalciferol group (96 [17%] of 569 mothers in the placebo group vs 65 [12%] of 565 mothers in the cholecalciferol group; p=0.01). No adverse events were deemed to be treatment related. INTERPRETATION: Supplementation of women with cholecalciferol 1000 IU/day during pregnancy did not lead to increased offspring whole-body BMC compared with placebo, but did show that 1000 IU of cholecalciferol daily is sufficient to ensure that most pregnant women are vitamin D replete, and it is safe. These findings support current approaches to vitamin D supplementation in pregnancy. Results of the ongoing MAVIDOS childhood follow-up study are awaited. FUNDING: Arthritis Research UK, Medical Research Council, Bupa Foundation, and National Institute for Health Research. PMID- 26944425 TI - Economic evaluation of health losses from air pollution in Beijing, China. AB - Aggravated air pollution in Beijing, China has caused serious health concern. This paper comprehensively evaluates the health losses from illness and premature death caused by air pollution in monetary terms. We use the concentration of PM10 as an indicator of the pollution since it constitutes the primary pollutant in Beijing. By our estimation, air pollution in Beijing caused a health loss equivalent to ?583.02 million or 0.03 % of its GDP. Most of the losses took the form of depreciation in human capital that resulted from premature death. The losses from premature deaths were most salient for people of either old or young ages, with the former group suffering from the highest mortality rates and the latter group the highest per capital losses of human capitals from premature death. Policies that target on PM10 emission reduction, urban vegetation expansion, and protection of vulnerable groups are all proposed as possible solutions to air pollution risks in Beijing. PMID- 26944424 TI - Modeling indoor TV/screen viewing and adult physical and mental health: Health Survey for England, 2012. AB - The aim of the present study was to model indoor TV/screen viewing and a series of adult health conditions and cognitive performance in a country-wide, population-based setting in recent years. Data was retrieved from Health Survey for England, 2012. Information on demographics, lifestyle factors, self-reported health conditions, and TV and/or screen watching hours in adults was collected by household interviews. Chi-square test and survey-weighted logistic and multi nominal modeling were performed. Of 8114 English adults aged 18-98, 4138 people (51.1 %) watched TV and/or screen daily for 2 h or more on average. Two thousand five-hundred people (30.9 %) watched for 3 h or more. TV and/or screening watching for 2+ hours was associated with endocrine or metabolic disorders, diabetes, mental disorders (including poor scores in General Health Questionnaire and Warwick-Edinburgh Mental Well-being Scale), nervous system disorders, eye complaints, circulatory system disorders, respiratory system disorders, musculoskeletal system disorders, and self-rated health. TV and/or screen watching for 3+ hours was associated with digestive disorders and clotting disorder. TV and/or screen watching for 5+ hours was associated with cancer. TV and/or screen watching for 6+, 8+, or 11+ hours was associated with bladder disease, genito-urinary system disorders or bowel disease, respectively. There were no risk associations (within 20 h) found with ear complaints, infectious disease, and blood system disorders. Future educational and public health programs minimizing TV and/or screen viewing in order to protect from physical inactivity and X-radiation might be needed while research on the combined effect of physical inactivity and X-radiation should be explored. PMID- 26944423 TI - Still searching for the engram. AB - For nearly a century, neurobiologists have searched for the engram-the neural representation of a memory. Early studies showed that the engram is widely distributed both within and across brain areas and is supported by interactions among large networks of neurons. Subsequent research has identified engrams that support memory within dedicated functional systems for habit learning and emotional memory, but the engram for declarative memories has been elusive. Nevertheless, recent years have brought progress from molecular biological approaches that identify neurons and networks that are necessary and sufficient to support memory, and from recording approaches and population analyses that characterize the information coded by large neural networks. These new directions offer the promise of revealing the engrams for episodic and semantic memories. PMID- 26944426 TI - Influence of livestock activities on residue antibiotic levels of rivers in Hong Kong. AB - Occurrence of 10 antibiotics in the Yuen Long (YLR), Kam Tin (KTR), and Shing Mun (SMR) rivers of Hong Kong and possible influence of livestock activities on the concentrations of antibiotics were investigated. Tetracycline (30-497 ng/L), sulfadiazine (2-80 ng/L), sulfamethoxazole (2-152 ng/L), ofloxacin (5-227 ng/L), and erythromycin (1-315 ng/L) were detected in all the three rivers; chlortetracycline (23-227 ng/L), oxytetracycline (7-104 ng/L), ciprofloxacin (12 68 ng/L), and roxithromycin (1-105 ng/L) were detected in YLR and KTR, whereas norfloxacin (3-34 ng/L) was detected in KTR only. Significant correlation between livestock population and antibiotic contamination was observed in YLR only, indicating the influences of other sources in KTR and SMR. Among the antibiotics, significant correlation was observed between tetracyclines and sulfonamides indicating the major influence of livestock farms, whereas tetracyclines/sulfonamides were negatively correlated with fluoroquinolones/macrolides implying the differential origin of the latter class of antibiotics. Water quality of KTR and YLR were highly influenced by the non point source pollutions, while of SMR was relatively good. Particularly, Escherichia coli populations of the YLR and KTR were 3-4 logs higher than those of the SMR indicating the involvement of livestock farms and sewerages. Good correlation between tetracyclines (TCs)/sulfonamides (SAs) and number of livestock farms and a negative correlation between TCs/SAs and fluoroquinolones (FQs)/macrolides (MLs) could be used as an indicator to trace the possible source of pollution. PMID- 26944427 TI - Effects of Roundup formulations, nutrient addition, and Western mosquitofish (Gambusia affinis) on aquatic communities. AB - Aquatic communities can be affected by herbicides, nutrient addition, and non native fish species. We conducted a mesocosm experiment to examine the direct and interactive effects of three stressors: (1) Roundup formulations (Roundup Weed and Grass Killer((r)) and Roundup Poison Ivy and Tough Brush Killer Plus((r))), (2) nutrient addition, and (3) the presence of the non-native Western mosquitofish (Gambusia affinis), on experimental pond communities. Roundup formulations had the most widespread effects on the zooplankton community, but effects varied between formulations and among taxa. The only significant effect of nutrient addition was a lowering of Daphnia abundance in the nutrient addition treatments. The abundances of Daphnia, mid-sized cladocerans, and total zooplankton were lowered by mosquitofish, but no other taxa showed significant mosquitofish effects. We found several two-way and three-way interactions among the stressors, but these varied among zooplankton taxa. Chlorophyll a levels were higher with nutrient addition but were not significantly affected by Roundup formulation or mosquitofish. Our results suggest toxicity of Roundup formulations varies among taxa, and Roundup formulations differ in their toxicity to zooplankton, but with no cascading effects on primary producers. In addition, interactions among stressors affected the zooplankton community. PMID- 26944428 TI - Acetylation of oil palm empty fruit bunch fiber as an adsorbent for removal of crude oil. AB - Removal of oil spillage from the environment is a global concern. Various methods, including the use of fibers as sorbents, have been developed for oil spill control. Oil palm empty fruit bunch (OPEFB) fiber is a plant biomass that may be acetylated by acetic anhydride using N-bromosuccinimide (NBS) as a catalyst; here, the extent of acetylation may be calculated in terms of weight percent gain (WPG). The modified fiber was used to remove Tapis and Arabian crude oils. The optimum time, temperature, and catalyst concentration were 4 h, 120 degrees C, and 3 %, respectively, and these parameters could achieve an 11.49 % increase in WPG. The optimized parameters improved the adsorption capacity of OPEFB fibers for crude oil removal. The acetylated OPEFB fibers were characterized by using Fourier transform infrared spectroscopy and field emission scanning electron microscopy to observe the functional groups available and morphology. Kinetic and isotherm studies were conducted using different contact times and oil/water ratios. The rate of oil sorption onto the OPEFB fibers can be adequately described by the pseudo-second-order equation. Adsorption studies revealed that adsorption of crude oil on treated OPEFB fiber could be best described by the Langmuir isotherm model. PMID- 26944429 TI - Fundus Examination: A Key to Spot the Spotted Fever! PMID- 26944430 TI - Pulmonary Function Tests in Sickle Cell Disease. AB - OBJECTIVE: To determine pulmonary function abnormalities in children with Sickle Cell Disease (SCD) from Western India. METHODS: In this cross sectional study conducted at Surat, Gujarat, India; equal number of age and gender matched children i.e., 99 in the age group of 6-18 y was recruited in case (children with SCD) and control (non-SCD healthy children) groups respectively. Weight, height, body mass index (BMI) and hemoglobin (Hb) were assessed as baseline characteristics and spirometry was performed to assess the pulmonary function. RESULTS: The two groups of children were comparable in the baseline characteristics such as weight, height and BMI, however mean hemoglobin was significantly low in SCD as compared to healthy controls [9.1 +/- 1.52 vs. 11.4 +/- 1.04 (p=0.001)]. Mean (% predicted) Forced expiratory volume in 1 s (FEV1) (86.79 +/- 11.6 vs. 94.3 +/- 16.1) and FVC (84.4 +/- 11.5 vs. 91.75 +/- 15.2) values were significantly low (p < 0.001) in cases. CONCLUSIONS: The present study revealed that the difference of pulmonary function tests between sickle cell patients and normal age matched controls were statistically significant but this difference was not clinically significant. PMID- 26944431 TI - Weber-Christian Panniculitis: Is it a Disorder of Immune System? PMID- 26944432 TI - Antidiabetic efficacy of citronellol, a citrus monoterpene by ameliorating the hepatic key enzymes of carbohydrate metabolism in streptozotocin-induced diabetic rats. AB - Diabetes mellitus is a clinically complex disease characterized by chronic hyperglycemia with metabolic disturbances. During diabetes, endogenous hepatic glucose production is increased as a result of impaired activities of the key enzymes of carbohydrate metabolism. The purpose of the present study was to evaluate the antidiabetic efficacy of citronellol, a citrus monoterpene in streptozotocin (STZ)-induced diabetic rats. Diabetes mellitus was induced by a single intraperitoneal injection of STZ (40 mg/kg b.w). STZ induced diabetic rats received citronellol orally at the doses of 25, 50, and 100 mg/kg b.w for 30 days. In this study the levels of plasma glucose, insulin, hemoglobin (Hb), glycated hemoglobin (HbA1C), glycogen, and the activities of carbohydrate metabolic enzymes, liver and kidney markers were evaluated. Oral administration of citronellol (50 mg/kg) for 30 days dose dependently improved the levels of insulin, Hb and hepatic glycogen with significant decrease in glucose and HbA1C levels. The altered activities of carbohydrate metabolic enzymes, hepatic and kidney markers were restored to near normal. Citronellol supplement was found to be effective in preserving the normal histological appearance of hepatic cells and insulin-positive beta-cells in STZ-rats. Our results suggest that administration of citronellol attenuates the hyperglycemia in the STZ-induced diabetic rats by ameliorating the key carbohydrate metabolic enzymes and could be developed as a functional and nutraceutical ingredient in combating diabetes mellitus. PMID- 26944433 TI - Novel cinnamohydroxamic acid derivatives as HDAC inhibitors with anticancer activity in vitro and in vivo. AB - A novel series of cinnamohydroxamic acid derivatives were synthesized and their biological activities against HDAC were assessed. Our results showed that the compound with more strong inhibitory activity to HDAC would exhibited more significant anti-proliferative effect on tumor cells. Among these compounds, 7e displayed clearly inhibitory effects on HDAC and tumor cell growth. Furthermore, HDAC isoforms enzyme data indicated that, compared to HDAC pan-inhibitor SAHA, 7e owned an enhanced inhibitory effect on HDAC1, 3 and 6 isoforms. Meanwhile, it also significantly suppressed cell growth of lung cancer cells compared to SAHA, but with lower toxicity in normal cells. Mechanistically, 7e prompted acetylation of histone3 and histone4, led to up-regulation of p21, and then mediated cell cycle arrest and pro-apoptosis. Moreover, the in vivo study indicated that compound 7e could retard tumor growth of A549 xenograft models. These findings support the further investigation on the anti-tumor potential of this class of compounds as HDAC inhibitor. PMID- 26944434 TI - Structural differences in diarylheptanoids analogues from Alnus viridis and Alnus glutinosa influence their activity and selectivity towards cancer cells. AB - Diarylheptanoids represent a group of plant secondary metabolites that possess multiple biological properties and are increasingly recognized for their therapeutic potential. A comparative study was performed on structurally analogous diarylheptanoids isolated from the bark of green (Alnus viridis) and black alder (Alnus glutinosa) to address their biological effects and determine structure-activity relationship. The structures and configurations of all compounds were elucidated by NMR, HR-ESI-MS, UV and IR. Diarylheptanoids actions were studied in human non-small cell lung carcinoma cells (NCI-H460) and normal keratinocytes (HaCaT). A. viridis compounds 3v, 5v, 8v and 9v that possess a carbonyl group at C-3 were considerably more potent than compounds without this group. A. viridis/A. glutinosa analogue pairs, 5v/5g and 9v/9g, which differ in the presence of 3' and 3"-OH groups, were evaluated for anticancer activity and selectivity. 5v and 9v that do not possess 3' and 3"-OH groups showed significantly higher cytotoxicity compared to analogues 5g and 9g. In addition, these two A. viridis compounds induced a more prominent apoptosis in both cell lines and an increase in subG0 cell cycle phase, compared to their A. glutinosa analogues. 5v and 9v treatment triggered intracellular superoxide anion accumulation and notably decreased mitochondrial transmembrane potential. In HaCaT cells, 9v and 9g with a 4,5 double bond caused a more prominent loss of mitochondrial transmembrane potential compared to 5v and 5g which possess a 5 methoxy group instead. Although green alder diarylheptanoids 5v and 9v displayed higher cytotoxicity, their analogues from black alder 5g and 9g could be more favorable for therapeutic use since they were more active in cancer cells than in normal keratinocytes. These results indicate that minor differences in the chemical structure can greatly influence the effect of diarylheptanoids on apoptosis and redox status and determine their selectivity towards cancer cells. PMID- 26944435 TI - UV spectrophotometry for monitoring the performance of a yeast-based deoxygenation process to treat ships' ballast water. AB - This study assessed the usefulness of UV spectrophotometry for the monitoring of a yeast-based deoxygenation process proposed for ships' ballast water treatment to prevent the transfer of aquatic invasive species. Ten-day laboratory experiments using three treatment concentrations and different water types were conducted and resulted in complete oxygen depletion of treated waters. The treatment performance and quality of treated waters were determined by measuring the UV-visible absorbance spectra of water samples taken over time. Samples were also used for laboratory analysis of water quality properties. The UV absorbance spectra values were strongly correlated (r = 0.96) to yeast cell density in treated waters. The second-order derivative (D (2)) of the spectra varied greatly over time, and the spectrum profiles could be divided into two groups corresponding to the oxygenated and anoxic phases of the treatment. The D (2) value at 215 nm was strongly correlated (r = 0.94) to ammonia levels, which increased over time. The D (2) value at 225 nm was strongly correlated (r > 0.97) to DO concentration. Our results showed that UV spectrophotometry may provide a rapid assessment of the behavior and performance of the yeast bioreactor over time by quantifying (1) the density of yeast cells, (2) the time at which anoxic conditions were reached, and (3) a water quality index of the treated water related to the production of ammonia. We conclude that the rapidity of the technique confers a solid advantage over standard methods used for water quality analysis in laboratory and would permit the direct monitoring of the treatment performance on-board ships. PMID- 26944437 TI - New potential chemotherapy for ovarian cancer - Combined therapy with WP 631 and epothilone B. AB - Despite more modern therapeutics approaches and the use of new drugs for chemotherapy, patients with ovarian cancer still have poor prognosis and therefore, new strategies for its cure are highly needed. One of the promising ways is combined therapy, which has many advantages as minimizing drug resistance, enhancing efficacy of treatment, and reducing toxicity. Combined therapy has rich and successful history in the field of ovarian cancer treatment. Currently use therapy is usually based on platinum-containing agent (carboplatin or cisplatin) and a member of taxanes (paclitaxel or docetaxel). In the mid-2000s this standard regimen has been expanded with bevacizumab, monoclonal antibody directed to Vascular Endothelial Growth Factor (VEGF). Another drug combination with promising perspectives is WP 631 given together with epothilone B (Epo B). WP 631 is a bisanthracycline composed of two molecules of daunorubicin linked with a p-xylenyl linker. Epo B is a 16-membered macrolide manifesting similar mechanism of action to taxanes. Their effectiveness against ovarian cancer as single agents is well established. However, the combination of WP 631 and Epo B appeared to act synergistically, meaning that it is much more potent than the single drugs. The mechanism lying under its efficacy includes disturbing essential cell cycle-regulating proteins leading to mitotic slippage and following apoptosis, as well as affecting EpCAM and HMGB1 expression. In this article, we summarized the current state of knowledge regarding combined therapy based on WP 631 and Epo B as a potential way of ovarian cancer treatment. PMID- 26944436 TI - Diabetes-mediated middle cerebral artery remodeling is restored by linagliptin: Interaction with the vascular smooth muscle cell endothelin system. AB - INTRODUCTION: Endothelin-1 (ET-1) mediates cerebrovascular remodeling in vascular smooth muscle layer of the middle cerebral arteries (MCA) in type-2 diabetic Goto Kakizaki (GK) rats. While metformin, oral glucose lowering agent, prevent/restores vascular remodeling and reduce systemic and local ET-1 levels whether this effect was specific to metformin remained unknown. Our working hypotheses were 1) linagliptin, a DPP-IV inhibitor, can reverse diabetes-mediated cerebrovascular remodeling and this is associated with decreased ET-1, and 2) linagliptin prevents the high glucose induced increase in ET-1 and ET receptors in brain vascular smooth muscle cells (bVSMCs). METHODS: Diabetic and non diabetic GK rats were treated with linagliptin (4weeks). MCAs were fixed in buffered 4% paraformaldehyde and used for morphometry. Human bVSMCs incubated in normal glucose (5.5mM)/high glucose (25mM) conditions were treated with the linagliptin (100nM; 24h). ET-1 secretion and ET receptors were measured in media and cell lysate respectively. Immunostaining was performed for ET-A and ET-B receptor. ET receptors were also measured in cells treated with ET-1 (100nM) and linagliptin. RESULTS: Linagliptin treatment regressed vascular remodeling of MCAs in diabetic animals but had no effect on blood glucose. bVSMCs in normal/high glucose condition did not show any significant difference in ET-1 secretion or ET A and ET-B receptor expression. ET-1 treatment in high glucose condition significantly increased the ET-A receptors and this effect was inhibited by linagliptin. CONCLUSIONS: Linagliptin is effective in reversing established pathological cerebrovascular remodeling associated with diabetes. Attenuation of the ET system could be a pleiotropic effect of linagliptin that provides vascular protection. PMID- 26944438 TI - SphK1 inhibitor SKI II inhibits the proliferation of human hepatoma HepG2 cells via the Wnt5A/beta-catenin signaling pathway. AB - AIM: Sphingosine 1-phosphate (S1P) promotes cell growth, proliferation and survival. Sphingosine kinase 1 (SphK1), which converts sphingosine to S1P, is a key promoter in cancer. We previously found that the SphK1 inhibitor II (SKI II), suppresses the cell growth and induces apoptosis in human hepatoma HepG2 cells. However, the precise regulatory mechanism and signaling pathway on SKI II inhibiting tumor growth remains unknown. MAIN METHODS: The expressions of beta catenin and related molecules of Wnt/beta-catenin signal were detected by western blot in HepG2 cells. And the mRNA expression of beta-catenin was detected by RT PCR. The Wnt5A gene was silenced by siRNA. The colony formation was determined by staining with crystal violet. And the cell growth was examined by SRB assay and BrdU assay. KEY FINDINGS: We found that SKI II decreased the expression of beta catenin and the downstream molecules of beta-catenin signal pathway and promotes the beta-catenin degradation. In addition, SKI II induced the expression of Wnt5A, and then triggered beta-catenin degradation. Furthermore, silencing Wnt5A decreased the anti-tumor effects of SKI II through recovering the expressions of beta-catenin and downstream molecules of beta-catenin signal pathway. SIGNIFICANCE: SKI II-induced downregulation of HepG2 cell proliferation was associated with Wnt signaling pathway through Wnt5A-mediated beta-catenin degradation. Our study revealed that a novel signal pathway was involved in SKI II-inhibited cell proliferation in human hepatoma cells. PMID- 26944440 TI - Opioid-induced functional esophagogastric junction obstruction. PMID- 26944439 TI - Enhanced ADAM17 expression is associated with cardiac remodeling in rats with acute myocardial infarction. AB - AIM: This study aimed to investigate the dynamic expression of A-disintegrin-and metalloproteinase-17 (ADAM17) during cardiac remodeling after acute myocardial infarction (AMI). MAIN METHODS: Forty male Wistar rats with a permanent ligation of the left anterior descending artery were equally divided into four groups based on predefined sacrifice time: MI1d, MI1w, MI4w and MI12w. As controls, 36 rats only with left thoracotomy were equally divided into four groups. Cardiac remodeling was assessed by echocardiography and hematoxylin and eosin (H&E) staining. ADAM17 mRNA was detected by real-time reverse transcription polymerase chain reaction, and protein expression of ADAM17, tissue inhibitor of metalloproteinases-3 (TIMP-3) and TNF-alpha was analyzed by western blotting. KEY FINDINGS: The systolic function was sharply worsened in the MI1w group (versus the Con1w group, P<0.05), but left ventricular weight index was significantly increased after 4weeks post-MI (P<0.05). H&E staining revealed that one week after AMI, myocardial tissue in the epicardial border zone of the infarcted heart was mixed with broken mitochondrial cristae and decreased matrix density. ADAM17 mRNA and protein expression was significantly increased, accompanied by decreased TIMP-3 and upregulated TNF-alpha expression in the MI1w group (versus the MI1d group, all P<0.05). Moreover, dynamic ADAM17 mRNA expression was positively correlated with enlarged LVEDd and LVESd (P=0.001, P=0.003) and negatively with LVEF (P=0.039) in AMI rats. SIGNIFICANCE: Enhanced ADAM17 expression, along with decreased TIMP-3 and increased TNF-alpha expression, especially within one week after AMI, is associated with cardiac remodeling. PMID- 26944441 TI - Melanosis coli due to diacerein. PMID- 26944442 TI - Cytomegalovirus ileitis in an immunocompetent patient. PMID- 26944444 TI - Evidence for common ancestry among viruses isolated from wild birds in Beringia and highly pathogenic intercontinental reassortant H5N1 and H5N2 influenza A viruses. AB - Highly pathogenic clade 2.3.4.4 H5N8, H5N2, and H5N1 influenza A viruses were first detected in wild, captive, and domestic birds in North America in November December 2014. In this study, we used wild waterbird samples collected in Alaska prior to the initial detection of clade 2.3.4.4 H5 influenza A viruses in North America to assess the evidence for: (1) dispersal of highly pathogenic influenza A viruses from East Asia to North America by migratory birds via Alaska and (2) ancestral origins of clade 2.3.4.4 H5 reassortant viruses in Beringia. Although we did not detect highly pathogenic influenza A viruses in our sample collection from western Alaska, we did identify viruses that contained gene segments sharing recent common ancestry with intercontinental reassortant H5N2 and H5N1 viruses. Results of phylogenetic analyses and estimates for times of most recent common ancestry support migratory birds sampled in Beringia as maintaining viral diversity closely related to novel highly pathogenic influenza A virus genotypes detected in North America. Although our results do not elucidate the route by which highly pathogenic influenza A viruses were introduced into North America, genetic evidence is consistent with the hypothesized trans-Beringian route of introduction via migratory birds. PMID- 26944443 TI - Genotyping of Enterocytozoon bieneusi (Microsporidia) isolated from various birds in China. AB - Enterocytozoon bieneusi is a common opportunistic pathogen causing diarrhea in humans and animals. However, epidemiological data on E. bieneusi infections in birds are relatively scare worldwide, especially in China. To understand the prevalence and genetic diversity of E. bieneusi in birds and to assess the zoonotic potential of bird-derived E. bieneusi isolates, 194 fecal specimens from Gruidae, Anatidae and Columbidae in Heilongjiang Province, China, were analyzed by PCR and sequencing of the single internal transcribed spacer region of the rRNA gene. The average prevalence of E. bieneusi was 22.2%, with 12.5% for Gruidae, 15.9% for Anatidae and 44.0% for Columbidae. Altogether seven genotypes of E. bieneusi were identified, including four known genotypes-Peru6 (n=29), BEB6 (n=5), D (n=3) and EbpA (n=1)-and three novel genotypes named CHN-B1 (n=1), CHN B2 (n=3) and CHN-B3 (n=1). All the known genotypes obtained here were previously detected in humans. All the novel genotypes were clustered into the zoonotic group 1 in phylogenetic analysis. The results indicate that these birds may play a potential role in the transmission of E. bieneusi to humans. PMID- 26944445 TI - Mucoadhesive polymers in the treatment of dry X syndrome. AB - Mucoadhesive polymers are an essential tool in the treatment of diseases where dry mucosal surfaces are involved. In this review, we focus on the application of mucoadhesive polymers in the context of dry eye, dry mouth, and dry vagina syndrome, collectively named 'dry X syndrome'. With a prolonged residence time on mucosal membranes, mucoadhesive materials are as targeted treatment option, with the mucosa as an intended site of action. Thus, mucoadhesive polymers are able to ease local irritation or itching, alleviate chewing difficulties, improve tear film break-up time, and help to restore physiological conditions. Here, we discuss the different classes of mucoadhesive material and their performance in the treatment of dry X syndrome. PMID- 26944446 TI - Autochthonous cutaneous larva migrans infection in Guipuzcoa. AB - INTRODUCTION: Cutaneous larva migrans (LM) infection forms a serpiginous eruption caused by the migration of nematode helminths through the epidermis. The parasites are acquired when the skin comes into contact with soil contaminated by the feces of infected animals. Until now, infections have been believed to be imported from tropical and subtropical regions. Our aim was to study cases of cutaneous LM diagnosed in residents of the Spanish province of Guipuzcoa who had not recently traveled to such regions. MATERIAL AND METHODS: Cross-sectional observational study of LM cases diagnosed in Hospital Universitario Donostia from 2011 to 2015 in patients who had not visited a region where this nematode infection is endemic. Clinical diagnoses were based on characteristic lesions. We studied the following variables: age, sex, site of lesions, date of onset of symptoms, possible source of contagion, pathologic findings, treatment, and clinical course. RESULTS: We found 4 cases, all in men (mean age, 60 years). Lesions were on the lower extremities in 3 patients and on the trunk in 1 patient. All had been in contact with soil that could have been contaminated by feces and was the most likely source of the parasite. The lesions disappeared after treatment with oral albendazole. CONCLUSIONS: The appearance of cases of autochthonous LM in Europe requires investigation of the culprit species, a review of the epidemiology of this infection, which was once considered imported, and the planning of public health measures to prevent it from becoming endemic. PMID- 26944447 TI - Localized Lipoatrophy in a Boy After an Intramuscular Injection of Penicillin. PMID- 26944448 TI - Histologic Features Associated with Deep Invasion in Dermatofibrosarcoma Protuberans. AB - BACKGROUND: Dermatofibrosarcoma protuberans (DFSP) is a rare, slow-growing cutaneous tumor that can invade the subcutaneous tissue, muscle tissue, and even bone. OBJECTIVE: To identify histologic features associated with greater depth of invasion, i.e., local aggressiveness, in DFSP. MATERIAL AND METHODS: We analyzed associations between histologic features of DFSP (e.g., type of subcutaneous invasion, histologic pattern, cell type, areas of fibrosarcoma) and the presence and absence of muscle fascia involvement. RESULTS: We studied 155 cases of DFSP. The following histologic characteristics were significantly associated with involvement of the muscle fascia: the presence of a sheetlike pattern, a high degree of cellular pleomorphism, and more than 1 mitotic figure. The tumor did not extend beyond the subcutaneous tissue in the majority of cases (62.6%), but there was involvement of the fascia or galea aponeurotica in 17 cases (11%) and of the muscle tissue in 36 cases (23.2%). CONCLUSIONS: Histologic patterns, degree of pleomorphism, and number of mitotic figures are important predictors of deep invasion (fascia or muscle) in DFSP; these layers can be involved in up to 30% of cases. PMID- 26944449 TI - PreImplantation factor (PIF*) regulates systemic immunity and targets protective regulatory and cytoskeleton proteins. AB - Secreted by viable embryos, PIF is expressed by the placenta and found in maternal circulation. It promotes implantation and trophoblast invasion, achieving systemic immune homeostasis. Synthetic PIF successfully transposes endogenous PIF features to non-pregnant immune and transplant models. PIF affects innate and activated PBMC cytokines and genes expression. We report that PIF targets similar proteins in CD14+, CD4+ and CD8+ cells instigating integrated immune regulation. PIF-affinity chromatography followed by mass-spectrometry, pathway and heatmap analysis reveals that SET-apoptosis inhibitor, vimentin, myosin-9 and calmodulin are pivotal for immune regulation. PIF acts on macrophages down-stream of LPS (lipopolysaccharide-bacterial antigen) CD14/TLR4/MD2 complex, targeting myosin-9, thymosin-alpha1 and 14-3-3eta. PIF mainly targets platelet aggregation in CD4+, and skeletal proteins in CD8+ cells. Pathway analysis demonstrates that PIF targets and regulates SET, tubulin, actin b, and S100 genes expression. PIF targets systemic immunity and has a short circulating half-life. Collectively, PIF targets identified; protective, immune regulatory and cytoskeleton proteins reveal mechanisms involved in the observed efficacy against immune disorders. PMID- 26944450 TI - Approaches to minimize castration in the treatment of advanced prostate cancer. AB - BACKGROUND: Androgen deprivation therapy (ADT) remains the cornerstone of primary systemic treatment for men with metastatic disease and is a commonly applied therapy in the biochemically relapsed setting. Despite the high response rate with ADT, resistance is universal. Furthermore, over the past decade, there has been a growing appreciation for the significant short-term and long-term toxicities of continuous ADT (CADT). The rationale to develop alternative androgen receptor (AR) targeting strategies that seek to minimize or eliminate the need for upfront castration therapy is 2-fold-(1) delay the emergence of AR independent disease, potentially improving long-term disease outcomes and (2) mitigate the short-term and long-term side effects of CADT, improving quality of life and potentially lessening comorbidities related to ADT including osteoporosis, diabetes, and potentially cardiovascular disease. The 2 most rigorously studied alternatives to CADT include intermittent ADT and peripheral androgen blockade with the use of first-generation or second-generation AR antagonists. Both intermittent ADT and peripheral androgen blockade have been evaluated in the biochemically relapsed and metastatic setting in multiple phase 2 and 3 studies. AIM: In the current review, we aim to discuss the data from these studies, as well as the emerging noncastrating strategies. PMID- 26944451 TI - Quality of life in patients with cisplatin-resistant urothelial cancer: Typical ailments and effect of paclitaxel-based salvage therapy. AB - INTRODUCTION: Efficacy of palliative second-line treatment in patients suffering from advanced urothelial cancer (aUC) is limited. Accordingly, careful observation of patient-reported and treatment-related changes of quality of life (QoL) is mandatory. Therefore, we evaluated "typical" ailments and treatment related QoL changes in these patients. PATIENTS AND METHODS: Results of the EORTC QLQ-C30 questionnaire were reviewed in 129 patients included in 2 prospective trials on paclitaxel-based treatment of cisplatin-resistant aUC (gemcitabine/paclitaxel: 102 patients [AB 20/99]; paclitaxel/everolimus: 27 patients [AB 35/09]). Eligible patients had completed EORTC QLQ-C30 questionnaire questionnaire before treatment start and available data on response. Global health status (QL), functional scales (FuSc) and symptom scales (SySc) were compared with published normative data for patients suffering from metastatic/recurrent cancers. Treatment related changes of QoL were evaluated. For statistical evaluation 2-way analysis of variance was used. RESULTS: A total of 87 patients were eligible (63 men and 24 women, median age = 65 [interquartile range: 60-71]y, AB 20/99: 63 patients [72%], AB 35/09: 24 patients [28%]). Compared with metastatic/recurrent cancers normative data, impaired emotional FuSc (-11.6 [95% CI:-21.0 to-2.1] points, P<0.01) and higher pain SySc (+12.9 [CI: 3.7-22.1] points, P<0.001) were the most relevant differences. QL and further FuSc/SySc were comparable. Pain SySc was significantly lower after 3 ( 15.8 [CI:-31.4 to-0.7] points, P<0.01] and 4 cycles (-13.6 [CI:-29.2-2.1] points, P<0.05). Further changes of QL, FuSc or SySc during treatment were not observed. QL, FuSc, and SySc at baseline and during treatment did not differ between responders and nonresponders. CONCLUSIONS: Patients with aUC who received additional treatment demonstrated QoL changes similar to persons with other recurrent/metastatic cancers. Special emphasis should be attributed to pain and emotional problems. Despite treatment related side effects, patients did not report impairment of QoL. PMID- 26944452 TI - Calcium homeostasis modulator 1 gene P86L polymorphism and the risk for alzheimer's disease: A meta-analysis. AB - OBJECTIVES: Recently, many epidemiological studies have demonstrated an association between P86L polymorphism of calcium homeostasis modulator 1 (CALHM1) and risk for Alzheimer's disease (AD). However, the results of these association studies are inconsistent. In this study, we re-evaluated the relation between CALHM1 P86L polymorphism and risk for AD in a meta-analysis. METHODS: This meta analysis was performed using the PubMed, Science Direct, Scopus and Google Scholar databases up to June 2015 using the search terms "CALHM1" and "polymorphism or SNP or variant" in combination with "Alzheimer's disease". A meta-analysis with pooled odds ratios and 95% confidence intervals was carried out to assess the associations between P86L polymorphism and the risks for Alzheimer's disease under four genetic models with fixed or random effects models. RESULTS: Sixteen studies (twenty-four subgroup studies involving 9795 cases and 15,335 controls) were included in our meta-analysis. Our meta-analysis results indicated that several genetic models of CALHM1 P86L polymorphism were significantly associated with increased risk for AD in overall and Caucasian populations. CONCLUSIONS: In conclusion, our comprehensive meta-analysis indicated that P86L polymorphism is significantly associated with an increased risk for AD. Our data suggest that CALHM1 polymorphism may be potential biomarker in patients with AD. PMID- 26944453 TI - In vitro thermosensitivity of rat lateral parabrachial neurons. AB - The lateral parabrachial (LPB) neurons play a pivotal role in the thermoregulatory afferent pathway by transmitting cutaneous thermosensory signals received from spinal neurons directly to the thermoregulatory command center, the preoptic area (POA). The present study was conducted to electrophysiologically characterize the local temperature responsiveness of rat LPB neurons in brain slices to evaluate their local thermosensitivity and permit comparison with thermosensitive neurons in POA and spinal cord slices under consistent experimental conditions. In current clamp, warm- and cold-sensitive neurons were recorded in LPBel, LPBc and LPBd, the three LPB subnuclei responsible for the transmission of cutaneous feedforward signals. Of the 92 spontaneously firing LPB neurons, 27% were warm sensitive, 10% were cold sensitive, and 63% were temperature insensitive, and the spontaneous firing rate of the warm-sensitive neurons was significantly greater than that of the temperature-insensitive neurons. These proportions and spontaneous activity are similar to results obtained in the POA and spinal cord. Furthermore, the thermosensitivity was also present in 38% of silent neurons evoked by injection of a small amount of depolarizing current. Warm-sensitive neurons in the LPB were similar in thermoresponsiveness to those in the POA and spinal cord. However, cold sensitivity in the LPB was distinct from that in the POA. The firing rate of most cold-sensitive neurons changed steeply at a relatively narrow band of temperature, and some of them were silent near thermoneutrality. The percentages of thermosensitive and insensitive neurons within the three LPB subnuclei were not significantly different, nor were the mean maximal thermal coefficients of the thermosensitive neurons. These results suggest that LPB have local thermosensory functions as POA and spinal cord, and might be an important extrahypothalamic "thermoregulator". PMID- 26944454 TI - Effects of treatment with estrogen and progesterone on the methamphetamine induced cognitive impairment in ovariectomized rats. AB - Methamphetamine (METH) is one of the most powerful psychostimulant that leads to long lasting cognitive impairment. Earlier researches demonstrated that ovarian hormones including estrogen and progesterone ameliorate cognitive function against various central nervous system disorders. Moreover, recent studies demonstrate a neuroprotective role against methamphetamine toxicity. In current study the effects of estrogen and progesterone alone or in combination, on spatial learning and memory in METH-exposed ovariectomized (OVX) rats are investigated. Three weeks after ovariectomy, the animals were treated by estrogen (1mg/kg, i.p.) and progesterone (8mg/kg, i.p.) alone and in combination or vehicle during 14 consecutive days. On the 28th day, rats were exposed to a single-day METH regimens (four injections of 6mg/kg, s.c, at 2h intervals) 30min after the hormones treatment. Finally, spatial learning and memory were examined using the Morris water maze 2days after the last treatment. The findings showed that estrogen and progesterone did not have significant effect on spatial learning and memory in non METH-exposed OVX rats. The treatment with estrogen and progesterone alone in METH-exposed rats, significantly improved spatial learning and memory impairment. On the other hand, the cognitive performance of animals that received combination of estrogen plus progesterone in METH-exposed rats did not significantly differ from that of METH-exposed animals that received vehicle injections. Taken together, the present findings suggest that treatment with ovarian hormones can partially improve spatial learning and memory deficits induced by methamphetamine in OVX rats. PMID- 26944455 TI - Improvement of exopolysaccharide production by Porphyridium marinum. AB - With the aim to optimize the production of exopolysaccharide (EPS) by Porphyridium marinum, cultures in photobioreactors were conducted on a modified Provasoli medium (P) and compared to a new medium (Pm) with an elemental composition of N0.0205S0.0597P0.005. Cultivation on this medium allowed the increase of EPS concentration up to 2.5gL(-1), without modification of the EPS productivity (0.096gL(-1)) and EPS structure. In a second time, photosynthetic activity of the strain was monitored as a function of irradiance and temperature, allowing improvement of kinetic parameters of growth and EPS production. A semi continuous culture, carried out with the Pm medium, an optimal irradiance and temperature of respectively 360MUmolphotonsm(-2)s(-1) and 28 degrees C led to an EPS process productivity of 0.031gh(-1) instead of 0.020gh(-1) in batch culture. PMID- 26944456 TI - Analysis of operational methane emissions from pressure relief valves from biogas storages of biogas plants. AB - The study presents the development of a method for the long term monitoring of methane emissions from pressure relief valves (PRV(1)) of biogas storages, which has been verified during test series at two PRVs of two agricultural biogas plants located in Germany. The determined methane emission factors are 0.12gCH4kWhel(-1) (0.06% CH4-loss, within 106days, 161 triggering events, winter season) from biogas plant A and 6.80/7.44gCH4kWhel(-1) (3.60/3.88% CH4-loss, within 66days, 452 triggering events, summer season) from biogas plant B. Besides the operational state of the biogas plant (e.g. malfunction of the combined heat and power unit), the mode of operation of the biogas flare, which can be manually or automatically operated as well as the atmospheric conditions (e.g. drop of the atmospheric pressure) can also affect the biogas emission from PRVs. PMID- 26944457 TI - Limited adsorption selectivity of active carbon toward non-saccharide compounds in lignocellulose hydrolysate. AB - Prehydrolysis of lignocellulose produces abundant hemicellulose-derived saccharides (HDS). To obtain pure HDS for application in food or pharmaceutical industries, the prehydrolysis liquor (PHL) must be refined to remove non saccharide compounds (NSC) derived from lignin depolymerization and carbohydrate degradation. In this work, activated carbon (AC) adsorption was employed to purify HDS from NSC with emphasis on adsorption selectivity. The adsorption isotherms showed the priority of NSC to be absorbed over HDS at low AC level. However, increase of AC over 90% of NSC removal made adsorption non-selective due to competitive adsorption between NSC and HDS. Size exclusion chromatography showed that the adsorption of oligomeric HDS was dominant while monomeric HDS was inappreciable. The limited selectivity suggested that AC adsorption is infeasibility for HDS purification, but applicable as a pretreatment method. PMID- 26944458 TI - Biogas production and microbial community shift through neutral pH control during the anaerobic digestion of pig manure. AB - Laboratory-scale reactors, in which the pH could be auto-adjusted, were employed to investigate the mesophilic methane fermentation with pig manure (7.8% total solids) at pH 6.0, 7.0, and 8.0. Results showed that the performance of anaerobic digestion was strongly dependent on pH value. Biogas production and methane content at neutral pH 7.0 were significantly higher (16,607mL, 51.81%) than those at pH 6.0 (6916mL, 42.9%) and 8.0 (9739mL, 35.6%). Denaturing gradient gel electrophoresis fingerprinting and Shannon's index indicated that the samples contained highly diverse microbial communities. The major genus at pH 7.0 was Methanocorpusculum, compared with that was Methanosarcina at both pH 6.0 and 8.0. Our research revealed that cultures maintained at pH 7.0 could support increased biogas production, which has significant implications for the scale-up biogas engineering. PMID- 26944459 TI - Time to integrate sexual function in the health-related quality of life of patients with left ventricular assist devices. PMID- 26944460 TI - Hormones and Female Sexual Dysfunction: Beyond Estrogens and Androgens--Findings from the Fourth International Consultation on Sexual Medicine. AB - INTRODUCTION: In recent years, multiple hormones have been investigated in relation to female sexual function. Because consumers can easily purchase products claiming to contain these hormones, a clear statement regarding the current state of knowledge is required. AIM: To review the contribution of hormones, other than estrogens and androgens, to female sexual functioning and the evidence that specific endocrinopathies in women are associated with female sexual dysfunction (FSD) and to update the previously published International Society of Sexual Medicine Consensus on this topic. METHODS: The literature was searched using several online databases with an emphasis on studies examining the physiologic role of oxytocin, prolactin, and progesterone in female sexual function and any potential therapeutic effect of these hormones. The association between common endocrine disorders, such as polycystic ovary syndrome, pituitary disorders, and obesity, and FSD also was examined. MAIN OUTCOME MEASURES: Quality of data published in the literature and recommendations were based on the Grading of Recommendations Assessment, Development and Education system. RESULTS: There is no evidence to support the use of oxytocin or progesterone for FSD. Treating hyperprolactinemia might lessen FSD. Polycystic ovary syndrome, obesity, and metabolic syndrome could be associated with FSD, but data are limited. There is a strong association between diabetes mellitus and FSD. CONCLUSION: Further research is required; in particular, high-quality, large-scale studies of women with common endocrinopathies are needed to determine the impact of these prevalent disorders on female sexual function. PMID- 26944462 TI - Role of Estrogens and Estrogen-Like Compounds in Female Sexual Function and Dysfunction. AB - INTRODUCTION: Sex steroids are important in female sexual function and dysfunction. AIM: To review the role of estrogens in the physiology and pathophysiology of female sexual functioning and the evidence for efficacy of estrogen therapy for female sexual dysfunction to update the previously published International Society of Sexual Medicine Consensus on this topic. METHODS: Panel members reviewed the published literature using online databases for studies pertaining to estrogen in female sexual function and dysfunction. Attention was specifically given to clinical trials that had reported on sexual function outcomes in women treated with estrogen. MAIN OUTCOME MEASURES: Quality of data published in the literature and recommendations were based on the GRADES system. RESULTS: Observational studies that have considered relationship factors and physical or mental health have reported that these factors contribute more to sexual functioning than menopausal status or estrogen levels. Few clinical trials have investigated estrogen therapy with sexual function as a primary outcome. The available data do not support systemic estrogen therapy for the treatment of female sexual dysfunction. Topical vaginal estrogen therapy improves sexual function in postmenopausal women with vulvovaginal atrophy (VVA) and is considered first-line treatment of VVA. Oral ospemifene, a selective estrogen receptor modulator, is effective for the treatment of VVA and might have independent systemic effects on female sexual function. CONCLUSION: For sexual problems, the treatment of VVA remains the most pertinent indication for estrogen therapy. When systemic symptoms are absent, estrogen therapy ideally can be administered by a vaginal preparation alone. Systemic estrogen therapy with combined estrogen and progestin in non-hysterectomized women is indicated for women who require treatment for vasomotor and/or other systemic estrogen deficiency symptoms. The improvement in well-being achieved by relief of vasomotor and other symptoms might improve libido in some women and abrogate further intervention. PMID- 26944461 TI - Vulvodynia: Definition, Prevalence, Impact, and Pathophysiological Factors. AB - INTRODUCTION: Vulvodynia constitutes a highly prevalent form of chronic genital pain in women, and current information regarding its definition, prevalence, impact, and pathophysiologic factors involved is needed. AIM: To update the scientific evidence published in 2010 from the Third International Consultation of Sexual Medicine pertaining to the definition, prevalence, impact, and pathophysiologic factors of women's sexual pain. METHODS: An expert committee, as part of the Fourth International Consultation of Sexual Medicine, comprised of researchers and clinicians from biological and social science disciplines, reviewed the scientific evidence on the definition, prevalence, impact, and pathophysiologic factors related to chronic genital pain. MAIN OUTCOME MEASURES: A review of the definition, prevalence, impact, and pathophysiological factors involved in vulvodynia. RESULTS: Vulvodynia is a prevalent and highly impactful genital pain condition. Numerous factors have been implicated in its development and maintenance. CONCLUSION: What is becoming increasingly apparent is that it likely represents the end point of different factors that can differ from patient to patient. Longitudinal research is needed to shed light on risk factors involved in the expression of vulvodynia, as well as in potential subgroups of affected patients, in order to develop an empirically supported treatment algorithm. PMID- 26944463 TI - Endocrinologic Control of Men's Sexual Desire and Arousal/Erection. AB - INTRODUCTION: Several hormones and neurotransmitters orchestrate men's sexual response, including the appetitive (sexual desire) and consummative (arousal and penile erection) phases. AIM: To provide an overview and recommendations regarding endocrinologic control of sexual desire and arousal and erection and their disturbances. METHODS: Medical literature was reviewed by the subcommittee of the International Consultation of Sexual Medicine, followed by extensive internal discussion, and then public presentation and discussion with other experts. The role of pituitary (prolactin, oxytocin, growth hormone, and alpha melanocyte-stimulating hormone), thyroid, and testicular hormones was scrutinized and discussed. MAIN OUTCOME MEASURES: Recommendations were based on grading of evidence-based medical literature, followed by interactive discussion. RESULTS: Testosterone has a primary role in controlling and synchronizing male sexual desire and arousal, acting at multiple levels. Accordingly, meta-analysis indicates that testosterone therapy for hypogonadal individuals can improve low desire and erectile dysfunction. Hyperprolactinemia is associated with low desire that can be successfully corrected by appropriate treatments. Oxytocin and alpha melanocyte-stimulating hormone are important in eliciting sexual arousal; however, use of these peptides, or their analogs, for stimulating sexual arousal is still under investigation. Evaluation and treatment of other endocrine disorders are suggested only in selected cases. CONCLUSION: Endocrine abnormalities are common in patients with sexual dysfunction. Their identification and treatment is strongly encouraged in disturbances of sexual desire and arousal. PMID- 26944464 TI - Effect of Midurethral Sling Surgery on Vaginal Sensation. AB - INTRODUCTION: Previous studies have reported changes in the sensory functioning of the vagina in women with pelvic floor disorder. AIM: To evaluate vaginal and clitoral sensation before and after surgery with trans-obturator tape (TVT-O, Ethicon Johnson & Johnson). METHODS: Quantitative sensory thresholds for warm, cold, and vibratory sensations were measured at the vagina and clitoris 1 day before and 12 +/- 4 months after surgery. MAIN OUTCOME MEASURES: Differences in thresholds to warm, cold, and vibratory sensations at a predetermined anatomic area of the genital region. RESULTS: Twenty-two women were admitted for midurethral sling surgery, and four were lost to follow-up. For the remaining 18 (mean age = 52 years, range = 37-65), we found a significant sensory decrease at the clitoral region to cold, warm, and vibratory stimuli after surgery. In contrast, in the anterior vaginal wall, there was a significant decrease only to warm stimuli after surgery. CONCLUSION: TVT-O can cause sensory loss in the clitoral and anterior vaginal wall region that can be measured and quantified. The effect of such sensory loss on sexual function and quality of sexual life needs further investigation. PMID- 26944465 TI - Risk Factors for Non-Suicidal Self-Injury Among Trans Youth. AB - INTRODUCTION: Previous research has reported high levels of non-suicidal self injury (NSSI) in trans populations and younger age has been identified as a risk factor. AIMS: To explore the prevalence of NSSI in a large group of young trans people and to identify risk factors for this group. MAIN OUTCOME MEASURES: Sociodemographic variables and measurements of NSSI (Self-Injury Questionnaire), psychopathology (Symptom Checklist-90-Revised), self-esteem (Rosenberg Self Esteem Scale), victimization (Experiences of Transphobia Scale), interpersonal functioning (Inventory of Interpersonal Problems), and social support (Multidimensional Scale of Perceived Social Support). METHODS: Two hundred sixty eight young people attending a national gender clinic completed questionnaires assessing presence and frequency of NSSI and levels of general psychopathology, depression, anxiety, interpersonal problems, self-esteem, social support, transphobia, and information on hormone treatment. RESULTS: A lifetime presence of NSSI was identified in 46.3% of patients and 28.73% reported currently engaging in NSSI (within at least the past few months). Analyses showed that those with a lifetime presence of NSSI had significantly greater general psychopathology, lower self-esteem, had suffered more transphobia, and experienced greater interpersonal problems than those without NSSI. Findings were similar when comparing current with non-current NSSI. Overall, natal male patients reported less social support than natal female patients, but current NSSI was more common in natal female patients. Regression analyses confirmed that natal female gender and greater general psychopathology predicted current and lifetime NSSI. Further analyses confirmed that general psychopathology itself could be predicted by transphobic experiences, low self-esteem, and interpersonal problems, but not by the use of cross-sex hormones. CONCLUSION: These findings confirm that NSSI is common in trans youth and emphasize the need for interventions that decrease transphobia, increase social support, and help trans youth navigate their relationships with others to decrease psychopathology and NSSI. PMID- 26944466 TI - Recovery of Baseline Erectile Function in Men Following Radical Prostatectomy for High-Risk Prostate Cancer: A Prospective Analysis Using Validated Measures. AB - INTRODUCTION: Recovery of baseline erectile function (EF) after robotic radical prostatectomy in men with high-risk prostate cancer is under-reported. Published studies have selectively reported on low-risk disease using non-validated and poorly defined thresholds for EF recovery. AIM: To assess return to baseline EF in men after robotic radical prostatectomy for high-risk prostate cancer. MATERIALS: Five hundred thirty-one men underwent robotic radical prostatectomy for high-risk prostate cancer from February 2010 through July 2014. Pre- and postoperative EF was prospectively assessed using the International Index of Erectile Dysfunction (IIEF-5) questionnaire. Multivariate logistic regression analysis determined the effect of age, preoperative function, comorbidities, body mass index, prostate-specific antigen level, cancer stage or grade, nerve-sparing status, adjuvant therapy, and continence on EF return (defined as postoperative return to baseline EF with or without use of phosphodiesterase type 5 inhibitors). Kaplan-Meier analysis and log-rank test were used to analyze return over time. Mann-Whitney U-test was used to compare IIEF-5 scores. MAIN OUTCOME MEASURES: Pre- and postoperative EF was assessed using the IIEF-5 Sexual Health Inventory for Men at 3 months, 6 months, 1 year, 2 years, 3 years, and 4 years postoperatively. RESULTS: Overall, return of EF was seen in 23.5% of patients at 18 months. This was significantly increased in men no older than 60 years (P = .024), with a preoperative IIEF-5 score of at least 22 (P = .042), and after undergoing neurovascular bundle preservation (34.9% of patients, P < .001). There was no significant change in IIEF-5 scores from 3 to 36 months in patients who were treated with phosphodiesterase type 5 inhibitors in the non-neurovascular bundle preservation group (P = .87), although there was significant improvement in those receiving second- or third-line therapies (P = .042). Other than preoperative hypertension (P = .03), none of the other comorbidities predicted return of EF. CONCLUSION: In this study, 23.5% of men recovered to baseline EF. Of those who underwent bilateral neurovascular bundle preservation robotic radical prostatectomy, 70% recovered baseline EF; however, this accounted for only 9.6% of all patients. Only 4% of men who underwent non-neurovascular bundle preservation had baseline recovery with phosphodiesterase type 5 inhibitors up to 36 months. There was significant improvement after use of second- or third-line therapies, indicating the need for earlier institution of these treatment modalities. PMID- 26944467 TI - Conceptualization of the Sexual Response Models in Men: Are there Differences Between Sexually Functional and Dysfunctional Men? AB - INTRODUCTION: Research to validate models of sexual response empirically in men with and without sexual dysfunction (MSD), as currently defined, is limited. AIM: To explore the extent to which the traditional linear or the Basson circular model best represents male sexual response for men with MSD and sexually functional men. METHODS: In total, 573 men completed an online questionnaire to assess sexual function and aspects of the models of sexual response. In total, 42.2% of men (242) were sexually functional, and 57.8% (331) had at least one MSD. Models were built and tested using bootstrapping and structural equation modeling. MAIN OUTCOME MEASURES: Fit of models for men with and without MSD. RESULTS: The linear model and the initial circular model were a poor fit for men with and without MSD. A modified version of the circular model demonstrated adequate fit for the two groups and showed important interactions between psychological factors and sexual response for men with and without MSD. CONCLUSION: Male sexual response was not represented by the linear model for men with or without MSD, excluding possible healthy responsive desire. The circular model provided a better fit for the two groups of men but demonstrated that the relations between psychological factors and phases of sexual response were different for men with and without MSD as currently defined. PMID- 26944468 TI - Psychometric properties, validity, and reliability of the Temporal Experience of Pleasure Scale state version in an opioid-dependent sample. AB - BACKGROUND: Individuals with substance dependence commonly experience anhedonia. Theories of anhedonia distinguish between anticipatory and consummatory reward deficits, with the Temporal Experience of Pleasure Scale (TEPS) the first self report scale to separately measure these two constructs. Several psychometric studies have analysed the trait version of the TEPS, but the state version of the TEPS has not been previously validated. METHODS: We examined the psychometric properties of the state version of the TEPS in 121 individuals with opiate dependence (81% Australian-born), to confirm its 2-factor structure and examine the internal consistency, convergent and divergent validity, test-retest reliability, and performance as a state measure. RESULTS: Confirmation of the 2 factor solution required removal of two items and allowing correlation between residuals of three pairs of highly-similar items. The resulting consummatory and anticipatory scales correlated strongly with each other (r=.76), suggesting poor divergent validity between them. Nevertheless, the scale showed good internal consistency (Chronbach's alpha: anticipatory=.90; consummatory=.84; total=.92), convergent (TEPS total and Snaith-Hamilton Pleasure Scale r=-.76) and divergent validity (-.38=40 years who were free of cardiovascular disease at baseline and consented to be linked to the National Death Registry. Respondents reported participation in light- or moderate-intensity dancing and walking in the past 4 weeks. Physical activity amount was calculated based on frequency, duration, and intensity of participation in various types of exercise. The main outcome was cardiovascular disease mortality based on ICD-9 codes 390 459 or ICD-10 codes I01-I99. RESULTS: During 444,045 person-years, 1,714 deaths caused by cardiovascular disease were documented. Moderate-intensity, but not light-intensity, dancing and walking were both inversely associated with cardiovascular disease mortality. In Cox regression models, the hazard ratios for cardiovascular disease mortality, adjusted for age, sex, SES, smoking, alcohol, BMI, chronic illness, psychosocial distress, and total physical activity amount, were 0.54 (95% CI=0.34, 0.87) for moderate-intensity dancing and 0.67 (95% CI=0.52, 0.87) for moderate-intensity walking. CONCLUSIONS: Moderate-intensity dancing was associated with a reduced risk for cardiovascular disease mortality to a greater extent than walking. The association between dance and cardiovascular disease mortality may be explained by high-intensity bouts during dancing, lifelong adherence, or psychosocial benefits. PMID- 26944524 TI - A 2-year physical activity program for sedentary older adults does not improve cognitive functioning more than a health education program. PMID- 26944522 TI - A blow to the fly - Lucilia cuprina draft genome and transcriptome to support advances in biology and biotechnology. AB - The blow fly, Lucilia cuprina (Wiedemann, 1830) is a parasitic insect of major global economic importance. Maggots of this fly parasitize the skin of animal hosts, feed on excretions and tissues, and cause severe disease (flystrike or myiasis). Although there has been considerable research on L. cuprina over the years, little is understood about the molecular biology, biochemistry and genetics of this parasitic fly, as well as its relationship with its hosts and the disease that it causes. This situation might change with the recent report of the draft genome and transcriptome of this blow fly, which has given new and global insights into its biology, interactions with the host animal and aspects of insecticide resistance at the molecular level. This genomic resource will likely enable many fundamental and applied research areas in the future. The present article gives a background on L. cuprina and myiasis, a brief account of past and current treatment, prevention and control approaches, and provides a perspective on the impact that the L. cuprina genome should have on future research of this and related parasitic flies, and the design of new and improved interventions for myiasis. PMID- 26944527 TI - [Varicella with palmoplantar involvement: Presentation of a case]. PMID- 26944528 TI - Echogenicity of the Common Carotid Artery Intima-Media Complex in Stroke. AB - The grey-scale median of the common carotid artery intima-media complex (IM-GSM) characterizes arterial wall composition, and a low IM-GSM is associated with increased cardiovascular mortality in the elderly. We aimed to determine differences in the IM-GSM between a cohort with cerebrovascular disease and a healthy cohort. Eighty-two healthy individuals (control group: 63.2 +/- 8.7 y) and 96 patients with either stroke or transient ischemic attacks (CRVD group: 68.6 +/- 9.8 y) were studied. Common carotid artery intima-media thickness and IM GSM obtained by ultrasound were analyzed using semi-automated edge-detection software. The IM-GSM was significantly lower in the CRVD group than in the control group (106 +/- 24 vs. 124 +/- 27 au, p < 0.001). The IM-GSM was similar for the infarct and non-infarct sides in CRVD. In the pooled cohort of all participants, the lower the quartile of IM-GSM, the greater were the carotid artery intima-media thickness and carotid artery remodeling. These results suggest the presence of an altered atherosclerotic phenotype in the intima-media complex of CRVD patients that can be detected by ultrasound. PMID- 26944529 TI - Efficacy of Ablation Therapy for Secondary Hyperparathyroidism by Ultrasound Guided Percutaneous Thermoablation. AB - The objective of this study was to explore the value of ultrasound-guided percutaneous microwave thermoablation to treat secondary hyperparathyroidism (SHPT). One hundred and thirty-eight parathyroid glands from 56 patients with SHPT were ablated in this study. All the parathyroid glands were evaluated by real-time contrast-enhanced ultrasound before, during and after ablation. Changes in serum parathyroid hormone (sPTH) levels were measured before treatment and at 1 h, 1 wk, 1 mo and 6 mo after thermoablation treatment. All 56 cases had a 1-mo follow-up, and 34 cases had a 6-mo follow-up. The sPTH level of the 54 cases 1 mo after ablation was significantly lower than that before (p < 0.05). In the 34 cases that had a 6-mo follow-up, the sPTH levels were also significantly lower at 6 mo after ablation than before (p < 0.05). Bone pain in patients improved post operatively (p < 0.05), but itchiness and insomnia did not improve (p > 0.05). Ultrasound-guided percutaneous microwave thermoablation is a feasible and effective non-surgical alternative treatment for SHPT patients. PMID- 26944530 TI - Management of extremity arterial pseudoaneurysms associated with osteochondromas. AB - Arterial pseudoaneurysms associated with osteochondromas are rare and most publications on this topic are case reports. The management of this double entity is not standardized. We wanted to update it. Literature searches on MEDLINE and EMBASE were performed using the keywords "artery pseudoaneurysm" and "osteochondroma". Patient demographics, clinical presentations, diagnostic and therapeutic modalities were reviewed. In sum, 101 cases were analyzed. Overall, young adults represented the majority of the affected population with a masculine preponderancy (86%). Painful swelling (51%) was the most commonly physical finding. Distal femur was the most common site of the osteochondroma (86%). Multiple hereditary exostosis was seldom reported (36%). Diagnostic confirmation was dominated by arteriography (55%). Popliteal artery (77%) was the most commonly injured vessel. The treatment was open surgery with vascular repair and optimal exostectomy. Arterial repair was performed with saphenous vein grafting (40%) or lateral suture (39%). Postoperative courses were often uneventful (97%). Arterial pseudoaneurysms resulted from osteochondromas were dominated by those involving the popliteal artery. The use of arteriography to confirm the diagnosis may be limited to the benefit of non-invasive radiological methods because endovascular treatment is not relevant in the setting of osteochondroma-induced arterial pseudoaneurysm. PMID- 26944531 TI - Place of death in rural palliative care: A systematic review. AB - BACKGROUND: There have been many studies on the actual and preferred place of care and death of palliative patients; however, most have been whole population surveys and/or urban focused. Data and preferences for terminally ill rural patients and their unofficial carers have not been systematically described. AIM: To describe the actual place of death and preferred place of care and/or death in rural palliative care settings. METHOD: A systematic mixed studies review using Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. DATA SOURCE: PubMed, PsychINFO, Scopus and CINAHL databases were searched (September to December 2014); eligible quantitative and qualitative studies included preferred and/or actual place of death/care of rural, regional or remote residents; rural data that are clearly identifiable; death due to palliative condition (malignant and non-malignant) or survey of participants with current or hypothetical life-limiting illness. RESULTS: A total of 25 studies described actual place of death; 12 preferred place of care or death (2 studies reported both); most deaths occurred in hospital with home as the preferred place of care/death; however qualitative studies suggest that preferences are not absolute; factors associated with place are not adequately described as rurality was an independent variable; significant heterogeneity (rural setting and participants), however, many areas had a greater chance of home death than in cities; rural data are embedded in population reports rather than from specific rural studies. CONCLUSION: Home is the preferred place of rural death; however, more work is needed to explore influencing factors, absolute importance of preferences and experience of providing and receiving palliative care in rural hospitals which often function as substitute hospice. PMID- 26944533 TI - Music therapy for end-of-life care: An updated systematic review. AB - BACKGROUND: Music therapy during palliative and end-of-life care is well established and positive benefits for patients have been reported. AIM: Assess the effectiveness of music therapy versus standard care alone or standard care in combination with other therapies for improving psychological, physiological and social outcomes among adult patients in any palliative care setting. DATA SOURCES: In order to update an existing Cochrane systematic review, we searched MEDLINE, CINAHL, EMBASE, PsycINFO, CENTRAL, ClinicalTrials.gov register and Current Controlled Trials register to identify randomised or quasi-randomised controlled trials published between 2009 and April 2015. Nine electronic music therapy journals were searched from 2009 until April 2015, along with reference lists and contact was made with key experts in music therapy. Only studies published in English were eligible for inclusion. Two reviewers independently screened titles, abstracts, assessed relevant studies for eligibility, extracted data and judged risk of bias for included studies. Disagreements were resolved through discussion with a third reviewer. Data were synthesised in Revman using the random effects model. Heterogeneity was assessed using I(2). RESULTS: Three studies were included in the review. Findings suggest that music therapy may be effective for helping to reduce pain in palliative care patients (standard mean deviation = -0.42, 95% confidence interval = -0.68 to -0.17, p = 0.001). CONCLUSION: Available evidence did not support the use of music therapy to improve overall quality of life in palliative care. While this review suggests that music therapy may be effective for reducing pain, this is based on studies with a high risk of bias. Further high-quality research is required. PMID- 26944532 TI - The bereavement experiences of lesbian, gay, bisexual and/or trans* people who have lost a partner: A systematic review, thematic synthesis and modelling of the literature. AB - BACKGROUND: Socially excluded populations have poorer access to care; however, little attention has been paid to lesbian, gay, bisexual and/or trans* people. Lesbian, gay, bisexual and/or trans* people are at increased risk of certain life limiting illnesses and may not receive the care and support they need at the end of life and into bereavement. AIM: To identify and appraise the evidence of the bereavement experiences of lesbian, gay, bisexual and/or trans* people who have lost a partner and develop an explanatory model of lesbian, gay, bisexual and/or trans* partner bereavement. DESIGN: Systematic review (in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines) and thematic synthesis with assessment of reporting and rigour. Quantitative or qualitative articles reporting bereavement experiences of lesbian, gay, bisexual and/or trans* partners were included, excluding articles reporting multiple losses in the context of HIV or AIDS. DATA SOURCES: PsycINFO, MEDLINE, Web of Science, Scopus, Cochrane Library. Inclusion dates: database inception - 30 April 2015. RESULTS: A total of 23 articles reporting on 13 studies were identified. Studies described universal experiences of the pain of losing a partner; however, additional barriers and stressors were reported for lesbian, gay, bisexual and/or trans* people, including homophobia, failure to acknowledge the relationship, additional legal and financial issues and the 'shadow' of HIV or AIDS. A novel model was developed to explain how the experience for lesbian, gay, bisexual and/or trans* people is shaped by whether the relationship was disclosed and acknowledged in life and into bereavement and how this impacts upon needs and access to care. CONCLUSION: There is a need for healthcare providers to avoid hetero-normative assumptions; be mindful of additional stressors in bereavement for lesbian, gay, bisexual and/or trans* people; and consider additional sources of support to deliver individualised holistic care. PMID- 26944534 TI - Improving the wellbeing of staff who work in palliative care settings: A systematic review of psychosocial interventions. AB - BACKGROUND: Staff in palliative care settings perform emotionally demanding roles which may lead to psychological distress including stress and burnout. Therefore, interventions have been designed to address these occupational risks. AIM: To investigate quantitative studies exploring the effectiveness of psychosocial interventions that attempt to improve psychological wellbeing of palliative care staff. DESIGN: A systematic review was conducted according to methodological guidance from UK Centre for Reviews and Dissemination. DATA SOURCES: A search strategy was developed based on the initial scans of palliative care studies. Potentially eligible research articles were identified by searching the following databases: CINAHL, MEDLINE (Ovid), PsycINFO and Web of Science. Two reviewers independently screened studies against pre-set eligibility criteria. To assess quality, both researchers separately assessed the remaining studies using the Quality Assessment Tool for Quantitative Studies. RESULTS: A total of 1786 potentially eligible articles were identified - nine remained following screening and quality assessment. Study types included two randomised controlled trials, two non-randomised controlled trial designs, four one-group pre-post evaluations and one process evaluation. Studies took place in the United States and Canada (5), Europe (3) and Hong Kong (1). Interventions comprised a mixture of relaxation, education, support and cognitive training and targeted stress, fatigue, burnout, depression and satisfaction. The randomised controlled trial evaluations did not improve psychological wellbeing of palliative care staff. Only two of the quasi-experimental studies appeared to show improved staff wellbeing although these studies were methodologically weak. CONCLUSION: There is an urgent need to address the lack of intervention development work and high quality research in this area. PMID- 26944535 TI - EURECCA oesophago-gastric cancer project. PMID- 26944536 TI - The impact of economic recession on the association between youth unemployment and functional somatic symptoms in adulthood: a difference-in-difference analysis from Sweden. AB - BACKGROUND: The impact of macroeconomic conditions on health has been extensively explored, as well as the relationship between individual unemployment and health. There are, however, few studies taking both aspects into account and even fewer studies looking at the relationship in a life course perspective. In this study the aim was to assess the role of macroeconomic conditions, such as national unemployment level, for the long-term relationship between individual unemployment and functional somatic symptoms (FSS), by analysing data from two longitudinal cohorts representing different periods of unemployment level in Sweden. METHODS: A difference-in-difference (DiD) analysis was applied, looking at the difference over time between recession and pre-recession periods for unemployed youths (age 21 to 25) on FSS in adulthood. FSS was constructed as an index of ten self-reported items of somatic ill-health. Covariates for socioeconomics, previous health status and social environment were included. RESULTS: An association was found in the difference of adult FSS between unemployed and employed youths in the pre-recession and recession periods, remaining in the adjusted model for the pre-recession period. The DiD analysis between unemployed youths showed that men had significantly lower adult FSS during the recession compared to men in the pre-recession time. CONCLUSIONS: Adulthood FSS showed to be significantly lower among unemployed youths, in particular among men, during recession compared to pre-recession times. Since this is a fairly unexplored research field, more research is needed to explore the role of macroeconomic conditions for various health outcomes, long-term implications and gender differences. PMID- 26944537 TI - Personnel attitudes toward people with mental illness at a psychiatric hospital in Taiwan. AB - BACKGROUND: The attitudes of psychiatric hospital personnel are critically related to the quality of mental health care, but few studies have investigated this issue. AIMS: This study is aimed at an exploration of the attitudes of psychiatric hospital personnel toward people with mental illness and at an examination of the associated factors. METHOD: A self-report questionnaire, the Mental Illness Attitude Scale (MIAS), was used to collect data from psychiatric hospital personnel in Taiwan (n = 290). The MIAS included 46 items and 4 dimensions: acceptance, rehabilitation and prognosis, social distance and recommendations for interventions. RESULTS: Rehabilitation and prognosis had the highest item average scores (4.03) and social distance had the lowest item average scores (3.22). Stigmatization and the number of different types of contacted clients were two significantly associated attitude factors. CONCLUSION: Psychiatric hospital personnel in Taiwan tend to have positive attitudes toward people with mental illness in general situations but hold less positive attitudes in terms of community integration-related issues and intimate relationships. More evidence-based community services should be conducted to decrease personnel concerns about the successful community integration of those who are mentally ill. Future studies can investigate the concept and impact of stigmatization more deeply. PMID- 26944538 TI - Establishment of conditions for ovum pick up and IVM of jennies oocytes toward the setting up of efficient IVF and in vitro embryos culture procedures in donkey (Equus asinus). AB - Most wild and domestic donkey breeds are currently endangered or threatened. Their preservation includes the creation of a Genome Resource Bank. Embryos cryopreservation allows the preservation of genetics from both male and female and is the fastest method to restore a breed. Because embryo production in vivo is limited in equids, our objective was to establish conditions for in vitro production of embryos in donkey using ovum pick up (OPU), IVM, IVF, and in vitro culture of zygotes. Donkey cumulus-oocyte complexes (COCs) were collected by transvaginal ultrasound-guided aspirations OPU in adult cyclic jennies and in vitro matured in tissue culture medium 199 supplemented with fetal calf serum and epidermal growth factor for 24, 30, 34, or 38 hours. They were preincubated with oviductal fluid for 30 minutes, coincubated with frozen-thawed donkey semen treated with procaine for 18 hours, and cultured for 30 hours in Dulbecco's Modified Eagle Medium-F12 supplemented with NaHCO3, fetal calf serum, and gentamycin. From the five OPU sessions, we collected 92 COCs in 193 follicles (48%) with an average of 4.2 COCs per jenny. All COCs were expanded after more than 24-hour IVM. At collection, jennies oocytes contained a germinal vesicle. Metaphase 1 oocytes were observed after 30-hour IVM and 44% were in metaphase 2 after 34-hour IVM. In our conditions, IVM of donkey oocytes was slower than IVM of equine oocytes and optimal duration for donkey oocytes IVM may be 34 hours. Only 15% of jennies oocytes contained two pronuclei after coincubation with donkey spermatozoa and none of them developed further after 48 hours post-IVF. Moreover, some parthenogenetic activation occurred. Thus, the treatment of donkey sperm with procaine may not be efficient for IVF. In conclusion, we established for the first time conditions for OPU in jennies with high recovery rates. We reported that IVM of jennies oocytes can produce 44% of metaphase 2 oocytes after 34 hours in culture and we described for the first time the chronology of IVM of donkey oocytes. Further studies are in progress to establish efficient conditions for IVF and development of donkey zygotes. PMID- 26944539 TI - Extending the duration of treatment with progesterone and equine chorionic gonadotropin improves fertility in suckled beef cows with low body condition score subjected to timed artificial insemination. AB - The objective of this study was to evaluate the effect of an extended progesterone treatment on follicular development and fertility in postpartum, suckled beef cows subjected to timed artificial insemination (TAI). In experiment 1, cows (n = 24) with body condition score (BCS) >=4.5 received either a 2-g progesterone intravaginal device on Day -23 or a 0.558-g progesterone intravaginal device on Day -9. Then, all cows received 2 mg of estradiol benzoate on Day -9; removal of the device, 1-mg estradiol cypionate, and PGF2alpha on Day 2; and TAI on Day 0. Metabolic status was assessed between Days -9 and -2. Ovarian structures and plasma progesterone were determined weekly from Day -23 to -9, daily from Day -9 to 0, and weekly until Day 28. In experiment 2, cows (n = 302) with BCS >=4.5 received identical treatment to cows in experiment 1, but on Day -2, cows received 400 IU of two different commercial preparations of equine chorionic gonadotropin (eCG). Ovarian structures were determined on Days -23 and 9 on a subset of cows (n = 40). Pregnancy was determined 39 days after TAI. In experiment 3, multiparous cows (n = 244) with BCS <5.0 received identical treatment as cows in experiment 1 initiated on Day -18, and on Day -2, cows received 400 IU of eCG or no treatment. Ovarian structures were determined in a subset of cows (n = 31) on Days -3, -2, -1, 0, 1, and on Day 10. Pregnancy was determined 39 days after TAI. The results indicated that in experiment 1, plasma progesterone was higher in treated than nontreated (control cows) during the first 14 days (P = 0.0001). The extended progesterone treatment increased the size of the largest follicle between Days -23 and Day -5 (Group by Day, P = 0.04) and tended to increase the size of the dominant follicle from Day -5 to Day -1 (Group by Day, P = 0.06). There was no effect of metabolic status or interaction between metabolic status and day on follicular growth. In experiment 2, extended progesterone treatment tended to increase the size of the largest follicle between Day -23 and -9 (P = 0.06). There was no effect of Group, eCG, BCS, and parity on pregnancy per AI. In experiment 3, extended progesterone treatment combined with eCG increased the size of the dominant follicle (P = 0.01). Both extended progesterone treatment (P = 0.02) and eCG (P = 0.03) increased pregnancy per AI. In conclusion, an extended progesterone treatment stimulated follicular growth postpartum and improved fertility only in cows with low BCS. PMID- 26944541 TI - Exploding myths about medically unexplained symptoms. PMID- 26944540 TI - Dynamics of postpartum endometrial cytology and bacteriology and their relationship to fertility in dairy cows. AB - Endometrial samples were obtained from 56 consecutively calving dairy cows examined for endometrial cytology and for aerobic and anaerobic bacterial growth. Changes over time, correlations between different cell types and between cell and bacterial populations and with fertility measures were calculated. The proportion of neutrophils in cytologic preparations decreased with time postpartum. Other cell types did not change significantly with time. The proportion of neutrophils early (Day 0 and 7) postpartum was negatively correlated with neutrophil proportion at 5 or 7 weeks postpartum and positively correlated with fertility. Cows with high proportion of neutrophils at 7 days postpartum (>40%) were significantly more likely to become pregnant than those with lower proportions of neutrophils. Escherichia coli were the bacteria most frequently isolated at 0 or 7 days postpartum but were uncommon after that. Trueperella pyogenes were most prevalent at 3 weeks postpartum and were more likely to infect cows that had previously been infected with E coli. The presence of T pyogenes at 3 weeks postpartum increased the risk of concomitant or later infection with gram negative anaerobes. The presence of T pyogenes at 3 weeks postpartum significantly reduced the risk of pregnancy at 150 days in milk. The presence of alpha-hemolytic Streptoccus spp. at 7 days postpartum was associated with improved reproductive performance. The proportion of neutrophils at 5 and 7 weeks postpartum was related to concomitant bacterial infection. These findings suggest that rapid mobilization of neutrophils to the postpartum uterus is a beneficial response for uterine health in dairy cows. PMID- 26944542 TI - How social policies can improve financial accessibility of healthcare: a multi level analysis of unmet medical need in European countries. AB - BACKGROUND: The article explores in how far financial accessibility of healthcare (FAH) is restricted for low-income groups and identifies social protection policies that can supplement health policies in guaranteeing universal access to healthcare. The article is aimed to advance the literature on comparative European social epidemiology by focussing on income-related barriers of healthcare take-up. METHOD: The research is carried out on the basis of multi level cross-sectional analyses using 2012 EU-SILC data for 30 European countries. The social policy data stems from EU-SILC beneficiary information. RESULTS: It is argued that unmet medical needs are a reality for many individuals within Europe not only due to direct user fees but also due to indirect costs such as waiting time, travel costs, time not spent working. Moreover, low FAH affects not only the lowest income quintile but also the lower middle income class. The study observes that social allowance increases the purchasing power of both household types, thereby helping them to overcome financial barriers to healthcare uptake. CONCLUSION: Alongside healthcare system reform aimed at improving the pro-poor availability of healthcare facilities and financing, policies directed at improving FAH should aim at providing a minimum income base to the low-income quintile. Moreover, categorical policies should address households exposed to debt which form the key vulnerable group within the low-income classes. PMID- 26944543 TI - Differential role of Id1 in MLL-AF9-driven leukemia based on cell of origin. AB - Inhibitor of DNA binding 1 (Id1) functions as an E protein inhibitor, and overexpression of Id1 is seen in acute myeloid leukemia (AML) patients. To define the effects of Id1 on leukemogenesis, we expressed MLL-AF9 in fetal liver (FL) cells or bone marrow (BM) cells isolated from wild-type, Id1(-/-), p21(-/-), or Id1(-/-)p21(-/-) mice, and transplanted them into syngeneic recipient mice. We found that although mice receiving MLL-AF9-transduced FL or BM cells develop AML, loss of Id1 significantly prolonged the median survival of mice receiving FL cells but accelerated leukemogenesis in recipients of BM cells. Deletion of Cdkn1a (p21), an Id1 target gene, can rescue the effect of Id1 loss in both models, suggesting that Cdkn1a is a critical target of Id1 in leukemogenesis. It has been suggested that the FL transplant model mimics human fetal-origin (infant) MLL fusion protein (FP)-driven leukemia, whereas the BM transplantation model resembles postnatal MLL leukemia; in fact, the analysis of clinical samples from patients with MLL-FP(+) leukemia showed that Id1 expression is elevated in the former and reduced in the latter type of MLL-FP(+) AML. Our findings suggest that Id1 could be a potential therapeutic target for infant MLL-AF9-driven leukemia. PMID- 26944545 TI - A new statistical method for curve group analysis of longitudinal gene expression data illustrated for breast cancer in the NOWAC postgenome cohort as a proof of principle. AB - BACKGROUND: The understanding of changes in temporal processes related to human carcinogenesis is limited. One approach for prospective functional genomic studies is to compile trajectories of differential expression of genes, based on measurements from many case-control pairs. We propose a new statistical method that does not assume any parametric shape for the gene trajectories. METHODS: The trajectory of a gene is defined as the curve representing the changes in gene expression levels in the blood as a function of time to cancer diagnosis. In a nested case-control design it consists of differences in gene expression levels between cases and controls. Genes can be grouped into curve groups, each curve group corresponding to genes with a similar development over time. The proposed new statistical approach is based on a set of hypothesis testing that can determine whether or not there is development in gene expression levels over time, and whether this development varies among different strata. Curve group analysis may reveal significant differences in gene expression levels over time among the different strata considered. This new method was applied as a "proof of concept" to breast cancer in the Norwegian Women and Cancer (NOWAC) postgenome cohort, using blood samples collected prospectively that were specifically preserved for transcriptomic analyses (PAX tube). Cohort members diagnosed with invasive breast cancer through 2009 were identified through linkage to the Cancer Registry of Norway, and for each case a random control from the postgenome cohort was also selected, matched by birth year and time of blood sampling, to create a case-control pair. After exclusions, 441 case-control pairs were available for analyses, in which we considered strata of lymph node status at time of diagnosis and time of diagnosis with respect to breast cancer screening visits. RESULTS: The development of gene expression levels in the NOWAC postgenome cohort varied in the last years before breast cancer diagnosis, and this development differed by lymph node status and participation in the Norwegian Breast Cancer Screening Program. The differences among the investigated strata appeared larger in the year before breast cancer diagnosis compared to earlier years. CONCLUSIONS: This approach shows good properties in term of statistical power and type 1 error under minimal assumptions. When applied to a real data set it was able to discriminate between groups of genes with non-linear similar patterns before diagnosis. PMID- 26944544 TI - Circulating T follicular helper cells with increased function during chronic graft-versus-host disease. AB - Chronic graft-versus-host disease (cGVHD) remains a major late complication of allogeneic hematopoietic stem cell transplantation (HSCT). Previous studies have established that both donor B and T cells contribute to immune pathology in cGVHD but the mechanisms responsible for coordinated B- and T-cell responses directed against recipient antigens have not been understood. T follicular helper cells (TFH) play an important role in the regulation of B-cell immunity. We performed extensive phenotypic and functional analysis of circulating TFH (cTFH) and B cells in 66 patients after HSCT. Patients with active cGVHD had a significantly lower frequency of cTFH compared with patients without cGVHD. This was associated with higher CXCL13 plasma levels suggesting increased homing of TFH to secondary lymphoid organs. In patients with active cGVHD, cTFH phenotype was skewed toward a highly activated profile with predominance of T helper 2 (Th2)/Th17 subsets. Activated cTFH in patients with cGVHD demonstrated increased functional ability to promote B-cell immunoglobulin secretion and maturation. Moreover, the activation signature of cTFH was highly correlated with increased B-cell activation and plasmablast maturation in patients after transplant. These studies provide new insights into the immune pathogenesis of human cGVHD and identify TFH as a key coordinating element supporting B-cell involvement in this disease. PMID- 26944547 TI - Case Report: The risks associated with chronic theophylline therapy and measures designed to improve monitoring and management. AB - BACKGROUND: Symptoms of theophylline toxicity and factors that augment the risk of developing it are well documented in the literature. However these appear to be poorly considered in clinical practice. This case underlines the challenges in recognising and managing theophylline toxicity; moreover the requirement for improved application of knowledge of its pharmacokinetics to our practice. CASE PRESENTATION: In this case we observe how theophylline toxicity can be overlooked due to the presence of non-specific symptoms and lack of a structured system to mitigate error in detection, in both hospital medicine and general practice. Here, the initial theophylline concentration measurement was documented as 59.3 mg/l in a patient taking the medication long-term, with the previous concentration being recorded one year prior. Management consisted of suspension of theophylline along with best supportive care, however in the process other conditions were exacerbated and the patient ultimately died in hospital. Congestive cardiac failure, congestive liver disease and polypharmacy were factors isolated from this case that expedited the patients' development of theophylline toxicity. This was perpetuated by delay in diagnosis due to presentation with generalised symptoms including tachycardia, vomiting and neurological symptoms. CONCLUSIONS: Findings from this case necessitate a requirement for more stringent monitoring of theophylline when taken chronically in those who demonstrate risk factors for toxicity. This would aim to prevent accumulation of the drug, toxicity onset and subsequent acute presentation to hospital. Intervention, through charcoal haemoperfusion may provide a means of enhanced recovery to reduce sequelae of toxicity. PMID- 26944546 TI - Mitogen-activated protein kinase signaling causes malignant melanoma cells to differentially alter extracellular matrix biosynthesis to promote cell survival. AB - BACKGROUND: Intrinsic and acquired resistance to drug therapies remains a challenge for malignant melanoma patients. Intratumoral heterogeneities within the tumor microenvironment contribute additional complexity to the determinants of drug efficacy and acquired resistance. METHODS: We use 3D biomimetic platforms to understand dynamics in extracellular matrix (ECM) biogenesis following pharmaceutical intervention against mitogen-activated protein kinases (MAPK) signaling. We further determined temporal evolution of secreted ECM components by isogenic melanoma cell clones. RESULTS: We found that the cell clones differentially secrete and assemble a myriad of ECM molecules into dense fibrillar and globular networks. We show that cells can modulate their ECM biosynthesis in response to external insults. Fibronectin (FN) is one of the key architectural components, modulating the efficacy of a broad spectrum of drug therapies. Stable cell lines engineered to secrete minimal levels of FN showed a concomitant increase in secretion of Tenascin-C and became sensitive to BRAF(V600E) and ERK inhibition as clonally- derived 3D tumor aggregates. These cells failed to assemble exogenous FN despite maintaining the integrin machinery to facilitate cell- ECM cross-talk. We determined that only clones that increased FN production via p38 MAPK and beta1 integrin survived drug treatment. CONCLUSIONS: These data suggest that tumor cells engineer drug resistance by altering their ECM biosynthesis. Therefore, drug treatment may induce ECM biosynthesis, contributing to de novo resistance. PMID- 26944548 TI - American Society for Metabolic and Bariatric Surgery position statement on long term survival benefit after metabolic and bariatric surgery. AB - The following position statement has been issued by the American Society for Metabolic and Bariatric Surgery in response to numerous inquiries made to the Society by patients, physicians, society members, hospitals, health insurance payors, the media, and others regarding the benefit of metabolic and bariatric surgery on long-term survival. An overview of the current available published peer-reviewed scientific evidence is presented. PMID- 26944549 TI - Goal-directed program after sleeve gastrectomy improves weight loss. AB - BACKGROUND: The aim of our study is to determine if a goal-directed program improves weight loss after sleeve gastrectomy. METHODS: Our goal-directed program involves setting excess weight loss targets at fixed intervals after sleeve gastrectomy. We identified patients in 3 bariatric centers between April 2010 and July 2013 and compared the center that has a goal-directed weight loss program (goal-directed program) with the other 2 centers (standard program). RESULTS: A total of 211 patients were included, with 129 patients in the goal-directed weight loss program. The 2 groups were similar in terms of gender distribution, ethnicity distribution, age, and preoperative weight, preoperative body mass index, and surgical technique. The follow-up rates at 3, 6, 9, and 12 months for patients in the goal-directed program was 84.5%, 75.2%, 59.7%, and 82.2%, respectively, compared with 65.9%, 68.3%, 51.2%, and 68.3% for the standard program. The percentage total weight loss at 3, 6, 9, and 12 months was 17.1%, 23.3%, 26.8%, and 28.6%, respectively, for the goal-directed program, compared with 15.3%, 21.8%, 24.4%, and 25.4%, respectively, for the standard program. The mean excess weight loss at 3, 6, 9, and 12 months were 40%, 54%, 62%, and 67%, respectively, for the goal-directed program group, and 36%, 50%, 54%, and 55%, respectively, for the standard program, where statistical significance (P<.005) was achieved at 12 months. CONCLUSION: Our results suggest that a goal-directed protocol may improve weight loss outcomes after laparoscopic sleeve gastrectomy. PMID- 26944550 TI - Superior staple formation with powered stapling devices. PMID- 26944552 TI - Effects of high voltage nanosecond pulsed plasma and micro DBD plasma on seed germination, growth development and physiological activities in spinach. AB - In this study, we analyzed seed germination, seedling growth, and physiological aspects after treatment with high voltage nanosecond pulsed plasma and micro DBD plasma in spinach (Spinacia oleracea L.), a green leafy vegetable known to have low germination rate. Both germination and dry weight of seedlings increased after high voltage pulse shots were applied to spinach seeds. However seeds treated with many shots (10 shots) showed a decrease in germination rate and seedling growth. Seeds treated with air DBD plasma exhibited slightly higher germination and subsequent seedling growth than those treated with N2 plasma. Seed surface was degenerated after treated with high voltage pulsed plasma and micro DBD plasma but no significant difference in the degree of degeneration was observed among micro DBD plasma treatment time. Level of GA3 hormone and mRNA expression of an amylolytic enzyme-related gene in seeds were elevated 1 day after treatment with high voltage pulsed plasma. The relative amount of chlorophyll and total polyphenols in spinach seedlings grown from seeds treated with air DBD plasma was increased in 30 s, 1 min, and 3 min treatments. Taken together, our results suggest a possibility that plasma can enhance seed germination by triggering biochemical processes in seeds. PMID- 26944551 TI - Genomic and transcriptomic analysis of the streptomycin-dependent Mycobacterium tuberculosis strain 18b. AB - BACKGROUND: The ability of Mycobacterium tuberculosis to establish a latent infection (LTBI) in humans confounds the treatment of tuberculosis. Consequently, there is a need to discover new therapeutic agents that can kill M. tuberculosis both during active disease and LTBI. The streptomycin-dependent strain of M. tuberculosis, 18b, provides a useful tool for this purpose since upon removal of streptomycin (STR) it enters a non-replicating state that mimics latency both in vitro and in animal models. RESULTS: The 4.41 Mb genome sequence of M. tuberculosis 18b was determined and this revealed the strain to belong to clade 3 of the ancient ancestral lineage of the Beijing family. STR-dependence was attributable to insertion of a single cytosine in the 530 loop of the 16S rRNA and to a single amino acid insertion in the N-terminal domain of initiation factor 3. RNA-seq was used to understand the genetic programme activated upon STR withdrawal and hence to gain insight into LTBI. This revealed reconfiguration of gene expression and metabolic pathways showing strong similarities between non replicating 18b and M. tuberculosis residing within macrophages, and with the core stationary phase and microaerophilic responses. CONCLUSION: The findings of this investigation confirm the validity of 18b as a model for LTBI, and provide insight into both the evolution of tubercle bacilli and the functioning of the ribosome. PMID- 26944553 TI - Assessment of microcrystal quality by transmission electron microscopy for efficient serial femtosecond crystallography. AB - Serial femtosecond crystallography (SFX) employing high-intensity X-ray free electron laser (XFEL) sources has enabled structural studies on microcrystalline protein samples at non-cryogenic temperatures. However, the identification and optimization of conditions that produce well diffracting microcrystals remains an experimental challenge. Here, we report parallel SFX and transmission electron microscopy (TEM) experiments using fragmented microcrystals of wild type (WT) homoprotocatechuate 2,3-dioxygenase (HPCD) and an active site variant (H200Q). Despite identical crystallization conditions and morphology, as well as similar crystal size and density, the indexing efficiency of the diffraction data collected using the H200Q variant sample was over 7-fold higher compared to the diffraction results obtained using the WT sample. TEM analysis revealed an abundance of protein aggregates, crystal conglomerates and a smaller population of highly ordered lattices in the WT sample as compared to the H200Q variant sample. While not reported herein, the 1.75 A resolution structure of the H200Q variant was determined from ~16 min of beam time, demonstrating the utility of TEM analysis in evaluating sample monodispersity and lattice quality, parameters critical to the efficiency of SFX experiments. PMID- 26944554 TI - Sarcomere length dependent effects on the interaction between cTnC and cTnI in skinned papillary muscle strips. AB - Sarcomere length dependent activation (LDA) of myocardial force development is the cellular basis underlying the Frank-Starling law of the heart, but it is still elusive how the sarcomeres detect the length changes and convert them into altered activation of thin filament. In this study we investigated how the C domain of cardiac troponin I (cTnI) functionally and structurally responds to the comprehensive effects of the Ca(2+), crossbridge, and sarcomere length of chemically skinned myocardial preparations. Using our in situ technique which allows for simultaneous measurements of time-resolved FRET and mechanical force of the skinned myocardial preparations, we measured changes in the FRET distance between cTnI(167C) and cTnC(89C), labeled with FRET donor and acceptor, respectively, as a function of [Ca(2+)], crossbridge state and sarcomere length of the skinned muscle preparations. Our results show that [Ca(2+)], cross-bridge feedback and sarcomere length have different effects on the structural transition of the C-domain cTnI. In particular, the interplay between crossbridges and sarcomere length has significant impacts on the functional structural change of the C-domain of cTnI in the relaxed state. These novel observations suggest the importance of the C-domain of cTnI and the dynamic and complex interplay between various components of myofilament in the LDA mechanism. PMID- 26944555 TI - Integrating transcriptomics and metabolomics to characterise the response of Astragalus membranaceus Bge. var. mongolicus (Bge.) to progressive drought stress. AB - BACKGROUND: Astragalus membranaceus Bge. var. mongolicus (Bge.) Hsiao (A. mongolicus) is an important traditional Chinese herb that is cultivated on a large scale in northwestern China. Understanding plant responses to drought has important effects on ecological environment recovery and local economic development. Here, we combined transcriptomics (Illumina Hiseq 2000) and metabolomics ((1)H-NMR) to investigate how the roots of two-year-old A. mongolicus responded to 14 days of progressive drought stress. RESULTS: The dried soil reduced the relative water content (RWC) of the leaves and biomass, induced the differential expression of a large fraction of the transcriptome and significantly altered the metabolic processes. PCA analysis demonstrated that the sucrose, proline, and malate metabolites contributed greatly to the separation. Strikingly, proline was increased by almost 60-fold under severe stress compared to the control. Some backbone pathways, including glycolysis, tricarboxylic acid (TCA) cycle, glutamate-mediated proline biosynthesis, aspartate family metabolism and starch and sucrose metabolism, were significantly affected by drought. An integrated analysis of the interaction between key genes and the altered metabolites involved in these pathways was performed. CONCLUSIONS: Our findings demonstrated that the expression of drought-responsive genes showed a strong stress-dose dependency. Analysis of backbone pathways of the transcriptome and metabolome revealed specific genotypic responses to different levels of drought. The variation in molecular strategies to the drought may play an important role in how A. mongolicus and other legume crops adapt to drought stress. PMID- 26944556 TI - Management of intraocular pressure elevation during hemodialysis of neovascular glaucoma: a case report. AB - BACKGROUND: It is generally accepted that dialysis may lower plasma osmolality at a faster rate than changes in ocular osmolality. This osmotic difference causes water to migrate from the plasma into the aqueous humor, increasing intraocular pressure. Certain authors have described IOP increase in patients with narrow angles. CASE PRESENTATION: Here we report a neovascular glaucoma patient who experienced a substantial increase in IOP associated with severe eye pain and blurred vision during sessions of dialysis. The patient had been refractory to several antiglaucoma drugs and improved after intravenous administration of 20% hyperosmotic glucose solution with dialysis and pan-retinal photocoagulation. CONCLUSION: It is the first report in which intravenous glucose administration and reduction of neovascularization by argon laser pan-retinal photocoagulation successfully managed IOP increase during dialysis in neovascular glaucoma. Further clinical studies are required to confirm our results. PMID- 26944558 TI - Usefulness of 18F-FDG PET/CT in thyroid carcinoma. PMID- 26944557 TI - Interleukin-1beta mediates high glucose induced phenotypic transition in human aortic endothelial cells. AB - BACKGROUND: Previous studies have shown that high glucose (HG) induced endothelial cell (EC) damage via a phenotypic transition of EC. There is increasing evidence suggesting the role of inflammatory cytokines in mediated HG induced EC damage. However, little is known about the potential role of interleukin-1beta (IL-1beta) in the process. The aim of present study was to investigate whether IL-1beta mediated HG-induced phenotypic transition in human aortic endothelial cells (HAECs) and to determine the possible underlying mechanism. METHODS: Primary HAECs were exposed to normal glucose (NG, 5.5 nM), high glucose (HG,30 nM), IL-1beta (10 ng/ml), HG + IL-1beta (10 ng/ml) and HG + anti-IL-1beta antibodies (1000 ng/ml) or HG + IL-1beta small interfering RNA (siRNA). Pathological changes were investigated using confocal microscopy and electron microscopy. Confocal microscopy was performed to detect the co expression of CD31 and fibroblast specific protein 1 (FSP1). To study the effect of protein kinase C-beta (PKCbeta) activation on IL-1beta in HAECs, HAECs were stimulated with 30 nM PMA (PKCbeta activator) and 0.3 MUM PKCbeta inhibition (LY317615) for 48 h in the NG or HG group. The expressions of PKCbeta and IL 1beta were detected by RT-PCR and Western blot. And the concentration of IL-1beta in the supernatant of HAECs was measured by ELISA. The expressions of FSP1, a-SMA and CD31 were detected by Western blot. RESULTS: It was shown that the HG resulted in significant increase in the expressions of PKCbeta and IL-1beta in dose-and time-dependent manners. The HG or exogenous IL-1beta alone inhibited the expression of CD31 and markly increased the expressions of FSP1 and alpha-SMA. Furthermore, we observed that the HG and IL-1beta synergistically increased FSP1 and a-SMA expressions compared with the HG or IL-1beta alone group (P < 0.05). Confocal microscopy revealed a colocalization of CD31 and FSP1 and that some cells acquired spindle-shaped morphologies and a loss of CD31 staining. Electron microscopy showed that the HG resulted in the increased microfilamentation and a roughened endoplasmic reticulum structure in the cytoplasm. However, the changes above were attenuated by the intervention of anti-IL-1beta antibodies or IL-1beta siRNA (P < 0.05). In addition, the PMA induced the expressions of PKCbeta and IL 1beta in HAECs. The PKCbeta activation may mediate the effect of the HG on IL 1beta production, which could be attenuated by the PKCbeta selective inhibitor (LY317615) (P < 0.05). CONCLUSIONS: Our findings suggested that HG-induced phenotypic transition of HAECs might require IL-beta activation via the PKCbeta pathway. PMID- 26944559 TI - MyoD promotes porcine PPARgamma gene expression through an E-box and a MyoD binding site in the PPARgamma promoter region. AB - Peroxisome proliferator-activated receptor gamma (PPARgamma) is a key transcription factor in adipogenesis and can be regulated by adipogenesis-related factors. However, little information is available regarding its regulation by myogenic factors. In this study, we found that over-expression of MyoD enhanced porcine adipocyte differentiation and up-regulated PPARgamma expression, whereas small interfering RNA against MyoD significantly attenuated porcine adipocyte differentiation and inhibited PPARgamma expression. The MyoD-binding sites in the PPARgamma promoter region at -412 to -396 and -155 to -150 were identified by promoter deletion analysis and site-directed mutagenesis. Electrophoretic mobility shift assays and chromatin immunoprecipitation further showed that these two regions are MyoD-binding sites, both in vitro and in vivo, indicating that MyoD directly interacts with the porcine PPARgamma promoter. Thus, our results demonstrate that an Enhancer box and a binding site for a cooperative co activator of MyoD are present in the promoter region of porcine PPARgamma; furthermore, MyoD up-regulates PPARgamma expression and promotes porcine adipocyte differentiation. PMID- 26944560 TI - Collagen VI-NG2 axis in human tendon fibroblasts under conditions mimicking injury response. AB - In response to injury, tendon fibroblasts are activated, migrate to the wound, and contribute to tissue repair by producing and organizing the extracellular matrix. Collagen VI is a microfibrillar collagen enriched in the pericellular matrix of tendon fibroblasts with a potential regulatory role in tendon repair mechanism. We investigated the molecular basis of the interaction between collagen VI and the cell membrane both in tissue sections and fibroblast cultures of human tendon, and analyzed the deposition of collagen VI during migration and myofibroblast trans-differentiation, two crucial events for tendon repair. Tendon fibroblast displayed a collagen VI microfibrillar network closely associated with the cell surface. Binding of collagen VI with the cell membrane was mediated by NG2 proteoglycan, as demonstrated by in vitro perturbation of collagen VI-NG2 interaction with a NG2-blocking antibody. Cultures subjected to wound healing scratch assay displayed collagen VI-NG2 complexes at the trailing edge of migrating cells, suggesting a potential role in cell migration. In fact, the addition of a NG2-blocking antibody led to an impairment of cell polarization and delay of wound closure. Similar results were obtained after in vitro perturbation of collagen VI extracellular assembly with the 3C4 anti-collagen VI antibody and in collagen VI-deficient tendon cultures of a Ullrich congenital muscular dystrophy patient carrying mutations in COL6A2 gene. Moreover, in vitro treatment with transforming growth factor beta1 (TGFbeta1) induced a dramatic reduction of NG2 expression, both at protein and mRNA transcript level, and the impairment of collagen VI association with the cell membrane. Instead, collagen VI was still detectable in the extracellular matrix in association with ED-A fibronectin and collagen I, which were strongly induced by TGFbeta1 treatment. Our findings reveal a critical role of the NG2 proteoglycan for the binding of collagen VI to the surface of tendon fibroblasts. By interacting with NG2 proteoglycan and other extracellular matrix proteins, collagen VI regulates fibroblasts behavior and the assembly of tendon matrix, thereby playing a crucial role in tendon repair. PMID- 26944562 TI - Effects of discontinuation of growth hormone replacement in adult GH-deficient patients: a cohort study and a systematic review of the literature. AB - BACKGROUND: Recombinant human growth hormone (rhGH) replacement is advocated in adult growth hormone-deficient (GHD) patients to increase bone mass and improve lipid profile, body composition, and quality of life. The long-term effects of discontinuation of rhGh replacement are unknown. METHODS: This cohort study and systematic review aim to evaluate the long-term metabolic effects of discontinuation of rhGh replacement in adult GHD patients, with a subgroup analyses according to age (< or > 60 years). Data on anthropometry, lipids, glucose, and bone mass density (BMD) were assessed for 3 years after discontinuation. RESULTS: Cohort study included 64 patients who had discontinued rhGh replacement for >12 months. Fat percentage increased from 31.5+/-9.5% to 33.8+/-9.0% (mean difference 2.3, P=0.003). BMI decreased only in subjects <60 years (P=0.014). Glucose, total cholesterol, and LDL-cholesterol levels did not change; however, the percentage of patients on statins increased slightly from 39% to 44%. HDL-C concentration increased only in patients <60 years (mean difference 0.2, P=0.043). Lumbar spine BMD did not change; however, femoral neck BMD and bone turnover markers decreased in subjects <60 years (P=0.001). Systematic review included eight studies (n=166 patients) with a follow-up duration of 6-18 months. Of the Please check the edit of the sentence 'Of the eight studies "'.eight studies, three qualified as low risk of bias and five as having an intermediate risk of bias. None of the studies reported handling of statins, bisphosphonates, and glucose-lowering medication or excluded patients using these medications. CONCLUSIONS: In this study, discontinuation of rhGh replacement resulted in metabolic changes only in patients <60 years after 3 years. Further research warrants to determine the optimal strategies for (dis)continuation of rhGh replacement in adult patients with GHD. PMID- 26944563 TI - Association of initial rhythm with neurologically favorable survival in non shockable out-of-hospital cardiac arrest without a bystander witness or bystander cardiopulmonary resuscitation. AB - BACKGROUND: Out-of-hospital cardiac arrest (OHCA) has a predominantly non shockable rhythm. Non-shockable rhythm, and the absence of a bystander witness or bystander cardiopulmonary resuscitation (CPR) are associated with poor outcomes. However, the association between the type of non-shockable rhythm and outcomes is not well known. OBJECTIVE: To examine the association between the initial rhythm and neurologically favorable outcomes after non-shockable OHCA without a bystander witness or bystander CPR. METHODS: In a nationwide, population-based, cohort study, we analyzed 213,984 adult OHCA patients with a non-shockable rhythm who had neither a bystander witness nor bystander CPR. They were identified through the Japanese national OHCA registry data from January 1, 2005 to December 31, 2010. The primary outcome was neurologically favorable survival. RESULTS: Among 213,984 patients, the initial rhythm was Pulseless Electrical Activity (PEA) in 31,179 patients (14.6%) and Asystole in 182,805 patients (85.4%). The neurological outcome was more favorable in PEA than in Asystole (1.4% vs. 0.2%, p<0.0001). After adjusting for age, sex, etiology of arrest, epinephrine administration, advanced airway management, time from call to contact with patient, and calendar year, PEA was associated with an increased neurologically favorable survival rate (odds ratio 7.86; 95% confidence interval 6.81-9.07). In subgroup analysis stratified by age group (18-64, 65-84, or >=85years), the neurologically favorable survival rate was >=1% in PEA, even for patients aged >=85years, but <1% in Asystole among all age groups. CONCLUSION: PEA and Asystole should not be considered to be identical to non-shockable rhythm, but rather should be clearly distinguished from each other from the perspective of quantitative medical futility. PMID- 26944561 TI - Airborne Bacterial Diversity from the Low Atmosphere of Greater Mexico City. AB - Greater Mexico City is one of the largest urban centers in the world, with an estimated population by 2010 of more than 20 million inhabitants. In urban areas like this, biological material is present at all atmospheric levels including live bacteria. We sampled the low atmosphere in several surveys at different points by the gravity method on LB and blood agar media during winter, spring, summer, and autumn seasons in the years 2008, 2010, 2011, and 2012. The colonial phenotype on blood agar showed alpha, beta, and gamma hemolytic activities among the live collected bacteria. Genomic DNA was extracted and convenient V3 hypervariable region libraries of 16S rDNA gene were high-throughput sequenced. From the data analysis, Firmicutes, Proteobacteria, and Actinobacteria were the more abundant phyla in all surveys, while the genera from the family Enterobacteriaceae, in addition to Bacillus spp., Pseudomonas spp., Acinetobacter spp., Erwinia spp., Gluconacetobacter spp., Proteus spp., Exiguobacterium spp., and Staphylococcus spp. were also abundant. From this study, we conclude that it is possible to detect live airborne nonspore-forming bacteria in the low atmosphere of GMC, associated to the microbial cloud of its inhabitants. PMID- 26944564 TI - Coexisting chronic conditions in the older population: Variation by health indicators. AB - BACKGROUND: This study analyzes the prevalence and patterns of coexisting chronic conditions in older adults. DESIGN: Cross-sectional. PARTICIPANT AND SETTING: A sample of 3363 people >=60years living in Stockholm were examined from March 2001 through August 2004. MEASUREMENTS: Chronic conditions were measured with: 1) multimorbidity (>=2 concurrent chronic diseases); 2) the Cumulative Illness Rating Scale, 3) polypharmacy (>=5 prescribed drugs), and 4) complex health problems (chronic diseases and/or symptoms along with cognitive and/or functional limitations). RESULTS: A total of 55.6% of 60-74year olds and 13.4% of those >=85years did not have chronic conditions according to the four indicators. Multimorbidity and polypharmacy were the most prevalent indicators: 38% aged 60 74 and 76% aged >=85 had multimorbidity; 24.3% aged 60-74 and 59% aged >=85 had polypharmacy. Prevalence of chronic conditions as indicated by the comorbidity index and complex health problems ranged from 16.5% and 1.5% in the 60-74year olds to 38% and 36% in the 85+ year olds, respectively. Prevalence of participants with 4 indicators was low, varying from 1.6% in those aged 60-74 to 14.9% in those aged >=85years. Older age was associated with higher odds of each of the 4 indicators; being a woman, with all indicators but multimorbidity; and lower educational level, only with complex health problems. CONCLUSIONS: Prevalence of coexisting chronic conditions varies greatly by health indicator used. Variation increases when age, sex, and educational level are taken into account. These findings underscore the need of different indicators to capture health complexity in older adults. PMID- 26944565 TI - Cost-minimization analysis favors outpatient quick diagnosis unit over hospitalization for the diagnosis of potentially serious diseases. AB - BACKGROUND: Quick diagnosis units (QDUs) are a promising alternative to conventional hospitalization for the diagnosis of suspected serious diseases, most commonly cancer and severe anemia. Although QDUs are as effective as hospitalization in reaching a timely diagnosis, a full economic evaluation comparing both approaches has not been reported. AIMS: To evaluate the costs of QDU vs. conventional hospitalization for the diagnosis of cancer and anemia using a cost-minimization analysis on the proven assumption that health outcomes of both approaches were equivalent. METHODS: Patients referred to the QDU of Bellvitge University Hospital of Barcelona over 51 months with a final diagnosis of severe anemia (unrelated to malignancy), lymphoma, and lung cancer were compared with patients hospitalized for workup with the same diagnoses. The total cost per patient until diagnosis was analyzed. Direct and non-direct costs of QDU and hospitalization were compared. RESULTS: Time to diagnosis in QDU patients (n=195) and length-of-stay in hospitalized patients (n=237) were equivalent. There were considerable costs savings from hospitalization. Highest savings for the three groups were related to fixed direct costs of hospital stays (66% of total savings). Savings related to fixed non-direct costs of structural and general functioning were 33% of total savings. Savings related to variable direct costs of investigations were 1% of total savings. Overall savings from hospitalization of all patients were ?867,719.31. CONCLUSION: QDUs appear to be a cost-effective resource for avoiding unnecessary hospitalization in patients with anemia and cancer. Internists, hospital executives, and healthcare authorities should consider establishing this model elsewhere. PMID- 26944566 TI - Rapid diagnosis of common deletional alpha-thalassemia in the Chinese population by qPCR based on identical primer homologous fragments. AB - OBJECTIVE: In China, -(SEA), -alpha(3.7) and -alpha(4.2) are common deletional alpha-thalassemia alleles. Gap-PCR is the currently used detection method for these alleles, whose disadvantages include time-consuming procedure and increased potential for PCR product contamination. Therefore, this detection method needs to be improved. Based on identical-primer homologous fragments, a qPCR system was developed for deletional alpha-thalassemia genotyping, which was composed of a group of quantitatively-related primers and their corresponding probes plus two groups of qualitatively-related primers and their corresponding probes. In order to verify the accuracy of the qPCR system, known genotype samples and random samples are employed. RESULT: The standard curve result demonstrated that designed primers and probes all yielded good amplification efficiency. In the tests of known genotype samples and random samples, sample detection results were consistent with verification results. CONCLUSIONS: In detecting alphaalpha, (SEA), -alpha(3.7) and -alpha(4.2) alleles, deletional alpha-thalassemia alleles are accurately detected by this method. In addition, this method is provided with a wider detection range, greater speed and reduced PCR product contamination risk when compared with current common gap-PCR detection reagents. PMID- 26944567 TI - Aberrant DNA methylation in the pathogenesis of atherosclerosis. AB - Atherosclerosis, a multifactorial disease of large- and intermediate-sized arteries, is characterized by the accumulation of lipids and the proliferation of arterial smooth muscle cells, chronic inflammatory cells, and fibrous materials. DNA methylation involves inherent and acquired gene transcription changes, which occur independently of the DNA sequence. DNA methylation in the genome plays a major role in the development and progression of atherosclerosis. DNA methylation is a distinct and crucial mechanism that regulates genes governing cell proliferation, thereby linking environmental insults with gene regulation. DNA methyltransferases are crucial in maintaining endothelial cell integrity, promoting smooth muscle cell proliferation, and inducing the formation of arteriosclerosis in animal models. These enzymes, which influence DNA methylation in vascular cells, may be utilized to develop new diagnoses and treatments for atherosclerosis-related diseases. In this review, we focus on recent advances in the description and functional interpretation of the DNA methylome of cells and tissues involved in atherosclerosis. We also discuss the regulatory mechanism and the involvement of DNA methylation in the development and pathogenesis of atherosclerosis. PMID- 26944568 TI - The apelin-APJ axis: A novel potential therapeutic target for organ fibrosis. AB - Apelin, an endogenous ligand of the G-protein-coupled receptor APJ, is expressed in a diverse number of organs. The apelin-APJ axis helps to control the processes of pathological and physiological fibrosis, including renal fibrosis, cardiac fibrosis, liver fibrosis and pulmonary fibrosis. However, the role of apelin-APJ in organ fibrosis remains controversial due to conflicting study results. The apelin-APJ axis is a detrimental mechanism which promotes liver fibrosis mainly via up-regulation the expression of collagen-II and platelet-derived growth factor receptor beta (PDGFRbeta). On the contrary, the apelin-APJ axis is beneficial for renal fibrosis, cardiac fibrosis and pulmonary fibrosis. The apelin-APJ axis alleviates renal fibrosis by restraining the expression of transforming growth factor-beta1 (TGF-beta1). In addition, the apelin-APJ axis attenuates cardiac fibrosis through multiple pathways. Furthermore, the apelin APJ axis has beneficial effects on experimental bronchopulmonary dysplasia (BPD) and acute respiratory distress syndrome (ARDS) which suggest the apelin-APJ axis potentially alleviates pulmonary fibrosis. In this article, we review the controversies associated with apelin-APJ in organ fibrosis and introduce the drugs that target apelin-APJ. We conclude that future studies should place more emphasis on the relationship among apelin isoforms, APJ receptor subtypes and organ fibrosis. The apelin-APJ axis will be a potential therapeutic target and those drugs targeted for apelin-APJ may constitute a novel therapeutic strategy for renal fibrosis, cardiac fibrosis, liver fibrosis and pulmonary fibrosis. PMID- 26944569 TI - Monitoring two transitions by LC-MS/MS may not be sufficient to positively identify benzoylecgonine in patient urine samples. PMID- 26944570 TI - The change of plasma galectin-3 concentrations after traumatic brain injury. AB - BACKGROUND: Galectin-3 plays a significant role in microglia activation. Its increased circulating concentration has been associated with some inflammatory diseases. In-hospital major adverse events (IMAEs), including acute traumatic coagulopathy, progressive hemorrhagic injury and posttraumatic cerebral infarction, have high prevalence and are strong predictors of mortality after severe traumatic brain injury (STBI). The present study was designed to investigate the relationships between plasma galectin-3 concentrations and trauma severity, in-hospital mortality and IMAEs following STBI. METHODS: Plasma galectin-3 concentrations of 100 STBI patients and 100 controls were determined. Diagnosis of progressive hemorrhagic injury and posttraumatic cerebral infarction was made on the follow-up computerized tomography scan. Acute traumatic coagulopathy was defined based on coagulation test. RESULTS: Plasma galectin-3 concentrations were significantly higher in patients as compared to controls and also associated highly with Glasgow Coma Scale scores and plasma C-reactive protein concentrations. Galectin-3 emerged as an independent predictor for in hospital mortality and IMAEs. Areas under receiver operating characteristic curve of plasma galectin-3 concentrations were similar to those of Glasgow Coma Scale scores for prediction of in-hospital morality and IMAEs. CONCLUSIONS: Plasma galectin-3 concentrations have close relation to inflammation, trauma severity and clinical outcome, suggesting that galectin-3 should have the potential to be a good prognostic biomarker after STBI. PMID- 26944571 TI - Imbalanced cholesterol metabolism in Alzheimer's disease. AB - Alzheimer's disease (AD) is a complex and multifactorial neurodegenerative disease that is mainly caused by beta-amyloid accumulation. A large number of studies have shown that elevated cholesterol levels may perform a function in AD pathology, and several cholesterol-related gene polymorphisms are associated with this disease. Although numerous studies have shown the important function of cholesterol in AD pathogenesis and development, the underlying mechanism remains unclear. To further elucidate cholesterol metabolism disorder and AD, we first, review metabolism and regulation of the cholesterol in the brain. Second, we summarize the literature stating that hypercholesterolemia is one of the risk factors of AD. Third, we discuss the main mechanisms of abnormal cholesterol metabolism that increase the risk of AD. Finally, the relationships between AD and apolipoprotein E, PCSK9, and LRP1 are discussed in this article. PMID- 26944572 TI - Biomechanical Role of Capsular Continuity in Superior Capsule Reconstruction for Irreparable Tears of the Supraspinatus Tendon. AB - BACKGROUND: Patients with irreparable rotator cuff tears have a defect of the superior capsule, which creates discontinuity of the shoulder capsule in the transverse direction (anterior-posterior direction). This effect is one of the causes underlying shoulder instability after rotator cuff tears. PURPOSE/HYPOTHESIS: The purpose of this study was to assess the effects of anterior and posterior continuity on shoulder biomechanics after superior capsule reconstruction (SCR). The hypothesis was that capsular continuity in the transverse direction would improve glenohumeral stability after SCR. STUDY DESIGN: Controlled laboratory study. METHODS: Seven fresh-frozen cadaveric shoulders were tested by using a custom shoulder testing system. Subacromial peak contact pressure, glenohumeral superior translation, glenohumeral compression force, and glenohumeral range of motion (ROM) were compared among 5 conditions: (1) intact shoulder, (2) simulated irreparable supraspinatus tendon tear, (3) SCR without side-to-side suturing, (4) SCR with posterior side-to-side suturing, and (5) SCR with both anterior and posterior side-to-side suturing. RESULTS: The creation of an irreparable supraspinatus tear significantly increased glenohumeral superior translation (0 degrees of abduction: 254% of intact [P = .04]; 30 degrees of abduction: 200% of intact [P = .04]) and subacromial peak contact pressure (0 degrees of abduction: 302% of intact [P = .0001]; 30 degrees of abduction: 239% of intact [P = .0006]), decreased glenohumeral compression force (0 degrees of abduction: 85% of intact [P = .004]; 30 degrees of abduction: 87% of intact [P = .0002]; 60 degrees of abduction: 88% of intact [P = .0001]), and increased total ROM (0 degrees of abduction: 16 degrees increase [P = .008]). SCR without side-to-side suturing significantly decreased subacromial peak contact pressure (0 degrees of abduction: 79% of intact [P = .0001]; 30 degrees of abduction: 91% of intact [P = .001]; 60 degrees of abduction: 55% of intact [P = .04]) but did not inhibit glenohumeral superior translation. By adding posterior side-to-side sutures, both glenohumeral superior translation (0 degrees of abduction: 93% of intact [P = .02]; 30 degrees of abduction: 110% of intact [P = .04]) and subacromial peak contact pressure decreased significantly (0 degrees of abduction: 56% of intact [P = .0001]; 30 degrees of abduction: 83% of intact [P = .0003]; 60 degrees of abduction: 46% of intact [P = .04]). Neither SCR with nor SCR without side-to-side suturing ameliorated the tear-associated decrease in glenohumeral compression force and increase in total ROM. Adding anterior side-to-side sutures did not change any measurements compared with SCR with posterior side-to-side suturing. CONCLUSION: SCR with side-to-side suturing completely restored the superior stability of the shoulder joint by establishing posterior continuity between the graft, residual infraspinatus tendon, and underlying shoulder capsule. CLINICAL RELEVANCE: Side to-side suturing between the graft, residual infraspinatus tendon, and underlying shoulder capsule is recommended for SCR in patients with irreparable supraspinatus tendon tears to restore superior stability after surgery. PMID- 26944573 TI - Plate Versus Intramedullary Nail Fixation of Anterior Tibial Stress Fractures: A Biomechanical Study. AB - BACKGROUND: Anterior midtibial stress fractures are an important clinical problem for patients engaged in high-intensity military activities or athletic training activities. When nonoperative treatment has failed, intramedullary (IM) nail and plate fixation are 2 surgical options used to arrest the progression of a fatigue fracture and allow bone healing. HYPOTHESIS: A plate will be more effective than an IM nail in preventing the opening of a simulated anterior midtibial stress fracture from tibial bending. STUDY DESIGN: Controlled laboratory study. METHODS: Fresh-frozen human tibias were loaded by applying a pure bending moment in the sagittal plane. Thin transverse saw cuts, 50% and 75% of the depth of the anterior tibial cortex, were created at the midtibia to simulate a fatigue fracture. An extensometer spanning the defect was used to measure the fracture opening displacement (FOD) before and after the application of IM nail and plate fixation constructs. IM nails were tested without locking screws, with a proximal screw only, and with proximal and distal screws. Plates were tested with unlocked bicortical screws (standard compression plate) and locked bicortical screws; both plate constructs were tested with the plate edge placed 1 mm from the anterior tibial crest (anterior location) and 5 mm posterior to the crest. RESULTS: For the 75% saw cut depth, the mean FOD values for all IM nail constructs were 13% to 17% less than those for the saw cut alone; the use of locking screws had no significant effect on the FOD. The mean FOD values for all plate constructs were significantly less than those for all IM nail constructs. The mean FOD values for all plates were 28% to 46% less than those for the saw cut alone. Anterior plate placement significantly decreased mean FOD values for both compression and locked plate constructs, but the mean percentage reductions for locked and unlocked plates were not significantly different from each other for either plate placement. The percentage FOD reductions for all plate constructs and the unlocked IM nail were significantly less with a 50% saw cut depth. CONCLUSION: Plate fixation was superior to IM nail fixation in limiting the opening of a simulated midtibial stress fracture, and anterior-posterior placement of the plate was an important variable for this construct. CLINICAL RELEVANCE: Results from these tests can help guide the selection of fixation hardware for patients requiring surgical treatment for a midtibial stress fracture. PMID- 26944574 TI - Effect of Glenoid Version and Width on Outcomes of Arthroscopic Posterior Shoulder Stabilization. AB - BACKGROUND: Despite an increased awareness of the condition, the diagnosis, classification, and treatment of recurrent posterior shoulder instability remain challenging. No clear relationship has been established between glenohumeral morphologic characteristics and the risk for posterior shoulder instability or with outcomes after treatment. PURPOSE: To examine the structure of the glenoid in a large series of athletic patients with symptomatic unidirectional posterior instability and to correlate these findings with the objective and subjective clinical outcome of arthroscopic posterior capsulolabral repair. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: A total of 118 magnetic resonance arthrograms of athletes with unidirectional recurrent posterior shoulder instability treated with an arthroscopic posterior capsulolabral repair were reviewed, and measurements of glenoid labral, chondral, and bone version and labral and bone width were performed. The patients were evaluated preoperatively and postoperatively with the American Shoulder and Elbow Surgeons (ASES) scoring system and with standardized subjective pain and stability scales. RESULTS: The mean glenoid labral, chondral, and bone versions were 10.8 degrees , 10.1 degrees , and 9.5 degrees , respectively. The mean labral width was 30.9 mm and the mean bone width 28.9 mm. Patients with wider and more retroverted glenoid bone had better mean preoperative pain and ASES scores than did those with narrow and more anteverted glenoid bone. At final postoperative follow-up, patients with wider glenoids continued to have better pain and ASES scores and decreased risk of failure. In contrast, no significant differences in outcome scores were detected among subjects with regard to glenoid bone version. There was no correlation between chondral and labral width or version with any outcome measure preoperatively or postoperatively. Thirteen patients had unsuccessful initial capsulolabral repairs (ASES scores <60 and stability scores >=6), demonstrating a 3.0-mm smaller overall labral width and 3 degrees less labral retroversion but no bony version differences when compared with the successful cohort. CONCLUSION: Although higher glenoid retroversion was noted in this patient population as compared with previous studies in normal populations, there were no significant differences in outcomes after treatment among subjects with regard to glenoid version. However, increased glenoid width did predict better outcomes after posterior capsulolabral repair. PMID- 26944576 TI - A comparison of methods to combine speed and accuracy measures of performance: A rejoinder on the binning procedure. AB - In cognitive research, speed and accuracy are two important aspects of performance. When analyzed separately, these performance variables sometimes lead to contradictory conclusions about the effect of a manipulation. To avoid such conflicts, several measures that integrate speed and accuracy have been proposed, but the added value of using such measures remains unclear. The present paper compares the relative utility of seven integrated performance measures, namely four variations on a binning procedure that weights response times of correct and incorrect trials differently, and three measures that combine averaged speed and accuracy scores. The properties of these integrated measures were explored in three simulation studies. The first study compared three binning measures and showed that one measure failed to grasp the performance difference between two conditions. The second study showed that the sampling distributions of the measures were symmetric, except for a strong skewness on the rate correct score. The third study varied the trade-off and the effect sizes of speed and accuracy in four different combinations of size and direction of speed and accuracy effects. These studies highlighted some further shortcomings of the binning measures. The combination measures performed well, but linear integration of speed and accuracy and rate correct score were most efficient in detecting effects and accounting for a larger proportion of the variance. The paper concludes that these combination measures are useful provided that the speed and accuracy data are also inspected. PMID- 26944575 TI - Effect of Medial Patellofemoral Ligament Reconstruction Method on Patellofemoral Contact Pressures and Kinematics. AB - BACKGROUND: There remains a lack of evidence regarding the optimal method when reconstructing the medial patellofemoral ligament (MPFL) and whether some graft constructs can be more forgiving to surgical errors, such as overtensioning or tunnel malpositioning, than others. HYPOTHESIS: The null hypothesis was that there would not be a significant difference between reconstruction methods (eg, graft type and fixation) in the adverse biomechanical effects (eg, patellar maltracking or elevated articular contact pressure) resulting from surgical errors such as tunnel malpositioning or graft overtensioning. STUDY DESIGN: Controlled laboratory study. METHODS: Nine fresh-frozen cadaveric knees were placed on a customized testing rig, where the femur was fixed but the tibia could be moved freely from 0 degrees to 90 degrees of flexion. Individual quadriceps heads and the iliotibial tract were separated and loaded to 205 N of tension using a weighted pulley system. Patellofemoral contact pressures and patellar tracking were measured at 0 degrees , 10 degrees , 20 degrees , 30 degrees , 60 degrees , and 90 degrees of flexion using pressure-sensitive film inserted between the patella and trochlea, in conjunction with an optical tracking system. The MPFL was transected and then reconstructed in a randomized order using a (1) double-strand gracilis tendon, (2) quadriceps tendon, and (3) tensor fasciae latae allograft. Pressure maps and tracking measurements were recorded for each reconstruction method in 2 N and 10 N of tension and with the graft positioned in the anatomic, proximal, and distal femoral tunnel positions. Statistical analysis was undertaken using repeated-measures analyses of variance, Bonferroni post hoc analyses, and paired t tests. RESULTS: Anatomically placed grafts during MPFL reconstruction tensioned to 2 N resulted in the restoration of intact medial joint contact pressures and patellar tracking for all 3 graft types investigated (P > .050). However, femoral tunnels positioned proximal or distal to the anatomic origin resulted in significant increases in the mean medial joint contact pressure, medial patellar tilt, and medial patellar translation during knee flexion or extension, respectively (P < .050), regardless of graft type, as did tensioning to 10 N. CONCLUSION: The importance of the surgical technique, specifically correct femoral tunnel positioning and graft tensioning, in restoring normal patellofemoral joint (PFJ) kinematics and articular cartilage contact stresses is evident, and the type of MPFL graft appeared less important. CLINICAL RELEVANCE: The correct femoral tunnel position and graft tension for restoring normal PFJ kinematics and articular cartilage contact stresses appear to be more important than graft selection during MPFL reconstruction. These findings emphasize the importance of the surgical technique when undertaking this procedure. PMID- 26944577 TI - Measuring individual differences in statistical learning: Current pitfalls and possible solutions. AB - Most research in statistical learning (SL) has focused on the mean success rates of participants in detecting statistical contingencies at a group level. In recent years, however, researchers have shown increased interest in individual abilities in SL, either to predict other cognitive capacities or as a tool for understanding the mechanism underlying SL. Most if not all of this research enterprise has employed SL tasks that were originally designed for group-level studies. We argue that from an individual difference perspective, such tasks are psychometrically weak, and sometimes even flawed. In particular, the existing SL tasks have three major shortcomings: (1) the number of trials in the test phase is often too small (or, there is extensive repetition of the same targets throughout the test); (2) a large proportion of the sample performs at chance level, so that most of the data points reflect noise; and (3) the test items following familiarization are all of the same type and an identical level of difficulty. These factors lead to high measurement error, inevitably resulting in low reliability, and thereby doubtful validity. Here we present a novel method specifically designed for the measurement of individual differences in visual SL. The novel task we offer displays substantially superior psychometric properties. We report data regarding the reliability of the task and discuss the importance of the implementation of such tasks in future research. PMID- 26944578 TI - Rated age-of-acquisition norms for over 3,200 German words. AB - Words that have been learned early in life are responded to faster than words that have been acquired later. Subjective ratings of acquisition ages have been successfully employed to study the effect of age of acquisition (AoA). Although a large number of norms exist in many languages, fewer are available for German. Therefore, subjective AoA ratings for 3,259 German words were collected online, including 2,363 nouns and 473 verbs. These words were presented in lists of 140 words, and participants rated the age in years at which they had first learned each word. A split-half correlation testified to a high internal reliability. There were also high correlations with rated AoA values for subsets of the items that had been collected in previous studies, in both German and English. Age and gender were found to influence the ratings very weakly, in that older and male participants tended to give slightly higher age ratings. Education, multilingualism, and frequent usage of languages other than German did not exert an influence on the rating values. These new ratings will extend the currently existing norms available for language and reading research across languages and will provide researchers with a wider choice of word stimuli. The ratings are available expressed in two measurements: age in years, and AoA rated on a 7-point Likert scale. PMID- 26944579 TI - The Calgary semantic decision project: concrete/abstract decision data for 10,000 English words. AB - Psycholinguistic research has been advanced by the development of word recognition megastudies. For instance, the English Lexicon Project (Balota et al., 2007) provides researchers with access to naming and lexical-decision latencies for over 40,000 words. In the present work, we extended the megastudy approach to a task that emphasizes semantic processing. Using a concrete/abstract semantic decision (i.e., does the word refer to something concrete or abstract?), we collected decision latencies and accuracy rates for 10,000 English words. The stimuli were concrete and abstract words selected from Brysbaert, Warriner, and Kuperman's (2013) comprehensive list of concreteness ratings. In total, 321 participants provided responses to 1,000 words each. Whereas semantic effects tend to be quite modest in naming and lexical decision studies, analyses of the concrete/abstract semantic decision responses show that a substantial proportion of variance can be explained by semantic variables. The item-level and trial level data will be useful for other researchers interested in the semantic processing of concrete and abstract words. PMID- 26944580 TI - TACIT: An open-source text analysis, crawling, and interpretation tool. AB - As human activity and interaction increasingly take place online, the digital residues of these activities provide a valuable window into a range of psychological and social processes. A great deal of progress has been made toward utilizing these opportunities; however, the complexity of managing and analyzing the quantities of data currently available has limited both the types of analysis used and the number of researchers able to make use of these data. Although fields such as computer science have developed a range of techniques and methods for handling these difficulties, making use of those tools has often required specialized knowledge and programming experience. The Text Analysis, Crawling, and Interpretation Tool (TACIT) is designed to bridge this gap by providing an intuitive tool and interface for making use of state-of-the-art methods in text analysis and large-scale data management. Furthermore, TACIT is implemented as an open, extensible, plugin-driven architecture, which will allow other researchers to extend and expand these capabilities as new methods become available. PMID- 26944581 TI - Zika virus: a new threat from mosquitoes. PMID- 26944582 TI - Identification and analysis of mouse non-coding RNA using transcriptome data. AB - Transcripts are expressed spatially and temporally and they are very complicated, precise and specific; however, most studies are focused on protein-coding related genes. Recently, massively parallel cDNA sequencing (RNA-seq) has emerged to be a new and promising tool for transcriptome research, and numbers of non-coding RNAs, especially lincRNAs, have been widely identified and well characterized as important regulators of diverse biological processes. In this study, we used ultra-deep RNA-seq data from 15 mouse tissues to study the diversity and dynamic of non-coding RNAs in mouse. Using our own criteria, we identified totally 16,249 non-coding genes (21,569 non-coding RNAs) in mouse. We annotated these non-coding RNAs by diverse properties and found non-coding RNAs are generally shorter, have fewer exons, express in lower level and are more strikingly tissue-specific compared with protein-coding genes. Moreover, these non-coding RNAs show significant enrichment with transcriptional initiation and elongation signals including histone modifications (H3K4me3, H3K27me3 and H3K36me3), RNAPII binding sites and CAGE tags. The gene set enrichment analysis (GSEA) result revealed several sets of lincRNAs associated with diverse biological processes such as immune effector process, muscle development and sexual reproduction. Taken together, this study provides a more comprehensive annotation of mouse non-coding RNAs and gives an opportunity for future functional and evolutionary study of mouse non-coding RNAs. PMID- 26944583 TI - The repetitive use of non-thermal dielectric barrier discharge plasma boosts cutaneous microcirculatory effects. AB - BACKGROUND: Non-thermal atmospheric plasma has proven its benefits in sterilization, cauterization and even in cancer reduction. Furthermore, physical plasma generated by dielectric barrier discharge (DBD) promotes wound healing in vivo and angiogenesis in vitro. Moreover, cutaneous blood flow and oxygen saturation can be improved in human skin. These effects are mostly explained by reactive oxygen species (ROS), but electric fields, currents and ultraviolet radiation may also have an impact on cells in the treated area. Usually, single session application is used. The aim of this study was to evaluate the effects of the repetitive use of cold atmospheric plasma (rCAP) on cutaneous microcirculation. HYPOTHESIS: The repetitive use of non-thermal atmospheric plasma boosts cutaneous microcirculation effects. METHODS: Microcirculatory data was assessed at a defined skin area of the radial forearm of 20 healthy volunteers (17 males, 3 females; mean age 39.1+/-14.8years; BMI 26.4+/ 4.6kg/m(2)). Microcirculatory measurements were performed under standardized conditions using a combined laser Doppler and photospectrometry system. After baseline measurement, CAP was applied by a DBD plasma device for 90s and cutaneous microcirculation was assessed for 10min. Afterwards, a second session of CAP application was performed and microcirculation was measured for another 10min. Then, the third application was made and another 20min of microcirculatory parameters were assessed. RESULTS: Tissue oxygen saturation and postcapillary venous filling pressure significantly increased after the first application and returned to baseline values within 10min after treatment. After the second and third applications, both parameters increased significantly vs. baseline until the end of the 40-minute measuring period. Cutaneous blood flow was significantly enhanced for 1min after the first application, with no significant differences found during the remainder of the observation period. The second application improved and prolonged the effect significantly until 7min and the third application until 13min. CONCLUSION: These data indicate that the repetitive use of non-thermal atmospheric plasma boosts and prolongs cutaneous microcirculation and might therefore be a potential tool to promote wound healing. PMID- 26944584 TI - Predictors of Changes in Medication Adherence in Blacks with Hypertension: Moving Beyond Cross-Sectional Data. AB - BACKGROUND: Many studies have examined the multiple correlates of non-adherence in Blacks. However, they are largely cross-sectional; thus, these studies are unable to examine their predictive value on long-term medication adherence. PURPOSE: The purpose of this study is to examine the predictive role of key psychosocial and interpersonal factors on changes in medication adherence over a 1-year period. METHODS: Data were collected from 815 Black patients with hypertension followed in community health centers. Hypothesized predictor variables included self-efficacy, depressive symptoms, social support, and patient-provider communication measured at baseline, 6, and 12 months. The dependent variable, medication adherence was assessed at baseline, 6, and 12 months. Latent Growth Modeling was used to evaluate the pathways between the latent predictor variables and medication adherence. RESULTS: Participants were mostly female, low-income, with high school education or less, and mean age of 57 years. At baseline, high self-efficacy was associated with low depressive symptoms (beta = -0.22, p = 0.05), collaborative patient-provider communication (beta = 0.17, p = 0.006), and better medication adherence (beta = 1.04, p < 0.001). More social support and collaborative patient-provider communication were associated with low depressive symptoms (beta = -0.08, p = 0.02; beta = -0.18, p = 0.01). More social support was positively associated with collaborative patient provider communication (beta = 0.32, p < 0.001). In the longitudinal model, increasing self-efficacy over time predicted improvements in medication adherence 1 year later (beta = 1.76, p < 0.001; CFI = 0.95; RMSEA = 0.04; SRMR = 0.04; Chi Squared Index of Model Fit = 1128.54). CONCLUSIONS: Self-efficacy is a key predictor of medication adherence over time in Black patients with hypertension. Initial levels of self-efficacy are influenced by the presence of depressive symptoms as well as the perceived quality of patient-provider communication. PMID- 26944585 TI - ESPEN guidelines on chronic intestinal failure in adults. AB - BACKGROUND & AIMS: Chronic Intestinal Failure (CIF) is the long-lasting reduction of gut function, below the minimum necessary for the absorption of macronutrients and/or water and electrolytes, such that intravenous supplementation is required to maintain health and/or growth. CIF is the rarest organ failure. Home parenteral nutrition (HPN) is the primary treatment for CIF. No guidelines (GLs) have been developed that address the global management of CIF. These GLs have been devised to generate comprehensive recommendations for safe and effective management of adult patients with CIF. METHODS: The GLs were developed by the Home Artificial Nutrition & Chronic Intestinal Failure Special Interest Group of ESPEN. The GRADE system was used for assigning strength of evidence. Recommendations were discussed, submitted to Delphi rounds, and accepted in an online survey of ESPEN members. RESULTS: The following topics were addressed: management of HPN; parenteral nutrition formulation; intestinal rehabilitation, medical therapies, and non-transplant surgery, for short bowel syndrome, chronic intestinal pseudo-obstruction, and radiation enteritis; intestinal transplantation; prevention/treatment of CVC-related infection, CVC-related occlusion/thrombosis; intestinal failure-associated liver disease, gallbladder sludge and stones, renal failure and metabolic bone disease. Literature search provided 623 full papers. Only 12% were controlled studies or meta-analyses. A total of 112 recommendations are given: grade of evidence, very low for 51%, low for 39%, moderate for 8%, and high for 2%; strength of recommendation: strong for 63%, weak for 37%. CONCLUSIONS: CIF management requires complex technologies, multidisciplinary and multiprofessional activity, and expertise to care for both the underlying gastrointestinal disease and to provide HPN support. The rarity of the condition impairs the development of RCTs. As a consequence, most of the recommendations have a low or very low grade of evidence. However, two-thirds of the recommendations are considered strong. Specialized management and organization underpin these recommendations. PMID- 26944586 TI - Predictive factors for central lymph node metastasis in patients with cN0 papillary thyroid carcinoma: A systematic review and meta-analysis. AB - BACKGROUND AND OBJECTIVES: Recently, some single-institution studies have reported risk factors of CLNM in cN0 PTC patients, but results from those studies are not consistent. The meta-analysis aimed to identify some risk factors that can be predictive of CLNM in cN0 PTC patients. METHODS: We performed a systematic search for relevant literature published prior to December 2015 using the following search engines: PubMed, EMBASE, Ovid and Web of Science. We included retrospective, prospective, and observational studies that investigated the risk factors for CLNM in patients with cN0 PTC. RESULTS: Thirty-one studies, including 37,355 patients with cN0 PTC from seven countries were included in the meta analysis. The pooled analysis indicated that age<45 years (OR = 1.57, 95%CI:1.48 1.66, P < 0.001), male gender (OR = 1.79, 95%CI: 1.69-1.91, P < 0.001), tumor size>10 mm (OR = 2.61, 95%CI:2.27-3.00, P < 0.001), bilaterality (OR = 1.52, 95%CI:1.31-1.77, P < 0.001), multifocality (OR = 1.46, 95%CI: 1.31-1.61, P < 0.001), extracapsular invasion (OR = 2.10, 95%CI:1.81-2.43, P < 0.001), angiolymphatic invasion (OR = 8.02, 95%CI:5.00-12.87, P < 0.001), high histologic risk (OR = 2.62, 95%CI:2.13-3.22, P < 0.001) and BRAF(V600E) mutation (OR:1.78, 95%CI:1.38-2.30, P < 0.001) were significantly associated with CLNM, and upper third location (OR = 0.54, 95%CI:0.43-0.67, P < 0.001) and lymphocytic thyroiditis (OR = 0.64, 95%CI:0.42-0.97, P = 0.034) were decreased risk factors of CLNM. CONCLUSIONS: We identified several predictive factors for CLNM in cN0 PTC patients. Some certain risk factors could be considered in preoperative clinical decision regarding the necessity of prophylactic central lymph node dissection in cN0 PTC patients. PMID- 26944587 TI - Spinal epidural angiolipoma. PMID- 26944588 TI - Cervicomedullary junction compression in a toddler with achondroplasia. PMID- 26944589 TI - Thoracolumbar intramedullary lipoma without dysraphism causing paraplegia in a pediatric patient. PMID- 26944590 TI - Retrospective Descriptive Study of Cerebral Palsy in Nepal. AB - There is very little data pertaining to cerebral palsy (CP) from Nepal. In this retrospective study it was observed that dyskinetic CP was seen in 29 % and the sex ratio of males to females was two in the study population of children with CP. Both of these are much higher than data from developed countries. Hence, further randomized cross-sectional community based study is recommended to enquire into this pattern. Data regarding early identification was encouraging as majority of the cases (56 %) were diagnosed before 4 years of age. There is a stark necessity of early screening and rehabilitation program with provision for follow-up for the affected children, which must also be accessible to the disadvantaged and marginalized groups in Nepal. PMID- 26944591 TI - Brief Report: Autism Spectrum Disorder and Substance Use Disorder: A Review and Case Study. AB - There is limited literature available on the comorbidity between autism spectrum disorder (ASD) and substance use disorder (SUD). This paper reviews existing literature and exemplifies the challenges of treating this population with a case report of an adult male with ASD and DSM-5 alcohol use disorder. This review and case study seeks to illustrate risk factors which predispose individuals with ASD to developing SUD and discuss the obstacles to and modifications of evidence based treatments for SUD. A review of the therapeutic interventions implemented in the treatment of this young male are described to highlight potential recommendations for the general management of SUD in those with ASD. PMID- 26944592 TI - Brief Report: The Feasibility and Effectiveness of an Advocacy Program for Latino Families of Children with Autism Spectrum Disorder. AB - Latino, Spanish-speaking families of children with autism spectrum disorder (ASD) face unique barriers in special education advocacy. Although advocacy programs are becoming more common in the United States, none of these programs target Latino families. This is a pilot study to examine the feasibility and effectiveness of an advocacy program for Latino families of children with ASD. Using a quasi-experimental design, 40 Latino family members of children with ASD participated in this study. Results demonstrated consistent attendance, low attrition, and high participant satisfaction. Intervention (versus control) group participants demonstrated significantly increased empowerment and special education knowledge, and stronger family-school partnerships. Findings provide preliminary support for advocacy programs for Latino families of children with ASD. PMID- 26944593 TI - Predictors of mental complaints among Norwegian male farmers. AB - BACKGROUND: In the Job Demand-Control (JDC) model and the Job Demand-Resource (JDR) model, the individual worker's potential to influence their work, through job control, is associated with better health. Among self-employed farmers, this job control dimension could be analogous to a sense of independence as this occupational group often highlights this as the best thing about the profession. AIMS: To analyse how work demands, sense of independence and number of close friends, and the interaction between independence and work demands predicted mental health among male farmers in Norway. METHODS: The sample consisted of male farmers working 1700h or more on the farm annually in 2012. We used the Lisrel structural equation modelling to estimate the direct effects and the interactive effect of independence and work demands. RESULTS: There were 926 participants. Decrease in work demands, a strong sense of independence and a high number of close friends predicted lower levels of mental complaints. A strong sense of independence buffered the adverse consequences of work demands on mental health. CONCLUSIONS: In this sample of self-employed full-time male farmers in Norway, we found that sense of independence was important for their mental health; farmers with a high sense of independence seemed to be able to manage high work demands more effectively, thus reducing the level of mental health problems. In addition, we also found that work demands and social relationships were associated with mental health outcomes. PMID- 26944594 TI - The impact of poverty on self-efficacy: an Australian longitudinal study. AB - BACKGROUND: People with strong feelings of 'self-efficacy', i.e. how much a person feels they have control over their life, perform better in the workplace. However, little is known about negative influences on feelings of self-efficacy. In view of the increasing number of people whose income places them below the poverty line despite being in employment, poverty may negatively influence feelings of self-efficacy and hence workplace productivity. AIMS: To assess whether falling into poverty lowers self-efficacy. METHODS: Longitudinal analysis of waves 7 to 11 of the nationally representative Household, Income and Labour Dynamics in Australia (HILDA) survey, using linear regression models. RESULTS: Those who fell into multidimensional poverty (income poverty plus poor health or insufficient level of education attainment) had significantly lower self-efficacy scores (up to 18% lower (95% CI -31% to -1%, P < 0.05)) than those never in poverty, after accounting for initial self-efficacy score and other confounding factors. Income uniquely accounted for 3% of the variance in self-efficacy scores, physical health for 10%, mental health for 78% and education for 1%. CONCLUSIONS: Given the known links between self-efficacy and workplace productivity, workers who are below the poverty line may be at risk of poor productivity due to the experience of poverty. In addition to the poor outcomes from the employer's perceptive, this may also lead to a negative spiral for the employee. PMID- 26944595 TI - Revisiting detachment techniques in human-biting ticks. AB - BACKGROUND: Early and complete removal of ticks using the right technique is important to reduce tick-transmitted diseases. Several chemical and mechanical detachment techniques have been described previously. OBJECTIVE: We aimed to compare the performance of 4 tick-detachment techniques that are widely used in human beings and to determine the optimal method from these techniques. METHODS: A cross-sectional study was conducted on 160 patients between April and June 2010. Patients with reported tick bite were reviewed retrospectively and divided into the following 4 groups according to the tick-detachment technique used: card detachment, lassoing, freezing, and tweezers. Performance of each technique was evaluated according to the number of fully detached, nondetached, and crushed ticks and the duration of application. RESULTS: Of the 160 tick-bite cases assessed, we found the following efficacy rates: 82.5% (33/40), technique using tweezers; 47.5% (19/40), lassoing technique; 7.5% (3/40), card detachment; and 0% (0/40), freezing technique. The efficacy rate of the technique using tweezers was significantly higher than that of the other 3 techniques (P < .05). LIMITATIONS: This was a relatively small sample size and not designed as a randomized clinical trial. CONCLUSION: Tick detachment using tweezers, performed in an appropriate manner, is the easiest and most effective technique. PMID- 26944596 TI - Vulvar hidradenoma papilliferum (HP) is located on the sites of mammary-like anogenital glands (MLAGs): Analysis of the photographs of 52 tumors. AB - BACKGROUND: Hidradenoma papilliferum (HP) is a benign tumor that primarily affects the anogenital area of adult women. Previously considered apocrine tumors, anogenital HP tumors are now interpreted as adenomas of mammary-like anogenital glands based on their histologic features. OBJECTIVE: This clinical study was undertaken to determine whether vulvar HP is located on mammary-like anogenital gland sites and to describe its morphologic features. METHODS: The clinical photographs of 52 histologically confirmed vulvar HP provided by 7 vulva specialists were analyzed. RESULTS: In all, 90.4% of the HP were located on the interlabial sulcus, adjacent zone, or the perineum. These tumors were polymorphous in terms of number (1 or multiple), size (<1-4.5 cm), color (pink, red, blue), surface (ulcerated or not), and architecture (unilobular or multilobular). LIMITATIONS: Eight histologic reports could not be reviewed by the authors but the contributors confirmed that the photographs sent were only those of histologically confirmed HPs. CONCLUSIONS: Vulvar HP is mainly located on mammary-like anogenital gland sites, thereby providing further evidence to their histogenesis. Although a nonulcerated or ulcerated tumor of the interlabial sulcus should evoke a HP diagnosis, the latter must be confirmed histologically. PMID- 26944597 TI - Segmental stiff skin syndrome (SSS): A distinct clinical entity. AB - BACKGROUND: Stiff skin syndrome (SSS) is a noninflammatory, fibrosing condition of the skin, often affecting the limb girdles. OBJECTIVE: We present 4 new patients with SSS with largely unilateral, segmental distribution. To date, reported cases of SSS have been grouped based on generally accepted clinical and histopathologic findings. The purpose of this study was to analyze differences in clinical and histopathologic findings between previously reported SSS cases. METHODS: This is a retrospective review of 4 new cases and 48 previously published cases of SSS obtained from PubMed search. RESULTS: Of 52 total cases, 18 (35%) were segmentally distributed and 34 (65%) were widespread. The average age of onset was 4.1 years versus 1.6 years for segmental versus widespread SSS, respectively. Limitation in joint mobility affected 44% of patients with segmental SSS and 97% of patients with widespread SSS. Histopathologic findings were common between the 2 groups. LIMITATIONS: This was a retrospective study of previously published cases limited by the completeness and accuracy of the reviewed cases. CONCLUSIONS: We propose a distinct clinical entity, segmental SSS, characterized by a segmental distribution, later age of onset, and less severe functional limitation. Both segmental SSS and widespread SSS share common diagnostic histopathologic features. PMID- 26944598 TI - The utility of full-thickness skin grafts (FTSGs) for auricular reconstruction. AB - BACKGROUND: Full-thickness skin grafts (FTSGs) are a common repair option on the external ear, but there are few large case series examining graft sublocations, dimensions, and outcomes. OBJECTIVE: We sought to report our experience with FTSGs for repair of postsurgical defects of the external ear. METHODS: We conducted a retrospective review of all FTSGs on the ear performed by 2 surgeons (J. C., 2000-2014; B. C. L., 2007-2014) after clearance by Mohs micrographic surgery at a single institution. RESULTS: A total of 1519 FTSGs on the ear were performed between June 2000 and March 2014. The most common sublocations were the superior helix (38.8%), the crura of the antihelix or scapha (18.9%), and the back of ear/back of helix (15.4%). The overall complication rate was 1.6%, and the most common complication was graft failure (1.2%). LIMITATIONS: Data were collected retrospectively from a single institution. Follow-up beyond 3 months was limited. A standardized assessment tool for aesthetic outcomes was not performed. CONCLUSION: By taking advantage of predictable "pincushioning" and combining with local flaps or cartilage grafts, FTSGs can provide more volumetric replacement than previously described. They reliably preserve the height and complex topography of the ear with a low complication rate. PMID- 26944599 TI - Early Impact on Renal Parenchymal Vascularization of Chimney Grafts Versus Fenestrated Grafts. AB - OBJECTIVE: The primary objective of this retrospective study was to analyze the early impact of chimney (CG) versus fenestrated grafts (FG) on renal parenchymal vascularization and function. METHODS: All consecutive patients with juxta-renal abdominal aortic aneurysm (JR-AAA) treated by endovascular repair from December 2013 to July 2014 at the vascular unit, Pellegrin University Hospital, Bordeaux, France, were included. Serum creatinine (SCr) and estimated glomerular filtration rate (eGFR) were reported at baseline and at J2 for acute kidney injury (AKI) incidence, and at J7 for AKI staging (KDIGO criteria); renal resistive indices (RRI) were reported for renal parenchymal repercussion at J-1, J0, and J1. RESULTS: Ten patients were included in the CG group and 25 in the FG group, with 13 and 50 renal target vessels, respectively. Successful target vessel revascularization was achieved in 92.3% and 100.0% of patients. The incidence of AKI (10% and 32%), baseline SCr, and eGFR did not differ significantly. SCr was more elevated in the FG group at J1 (p = .025), J2 (p = .051), and J7 (p = .052), and eGFR was significantly lower from baseline to J1 (p = .015) and J2 (p = .014). RRI did not differ significantly between both groups. RRI augmentation was only noted in the FG group from J-1 to J0 (p = .039) and J-1 to J1 (p = .059). Patients with a KDIGO score <2 versus >=2 showed significantly different RRI at J0 (p = .038) and J1 (p = .007). ROC curve analysis showed that RRI measures could be a predictive factor for AKI at J0 (cutoff = 0.72, sensitivity [Se] = 50%, specificity [Sp] = 86%) and J1 (cutoff = 0.71, Se = 70%, Sp = 84%). CONCLUSIONS: This study showed no significant difference in terms of RRI, eGFR, and the incidence of AKI or CKD between CG and FG. However, post-operative SCr levels were higher with FG, which was corroborated by comparison between pre- and post-operative RRI. Results are limited by the small sample size, but early repeated measures of RRI could be helpful in alerting the clinician to post operative renal degradation, allowing better-informed attempts to preserve renal function. PMID- 26944601 TI - Complicated Arm Ischemia After Pregnancy. PMID- 26944600 TI - Editor's Choice - Long-term Outcome After EndoVAC Hybrid Repair of Infected Vascular Reconstructions. AB - OBJECTIVE/BACKGROUND: Vascular graft infection is a serious and challenging complication. In situations when neither traditional radical surgery nor conservative negative pressure wound therapy (VAC) alone, are considered feasible or safe, for example due to bleeding, adverse anatomy, or severe comorbidity, a novel hybrid procedure was developed. The EndoVAC technique consists of (i) relining of the infected reconstruction with a stent graft; (ii) surgical revision (without clamping the reconstruction); and (iii) VAC therapy, to permit granulation and secondary delayed healing, and long-term antibiotic treatment. The aim of the study is to report long-term follow up data of this new treatment modality. METHODS: From November 2007 to June 2015, 17 EndoVAC procedures were performed in 16 patients (eight men, aged 16-91 years): six infected carotid patches after carotid endarterectomy, three infected neck deviations, two infected femoro-popliteal bypasses, three infected patches after femoral thrombo endarterectomy, and two infected vascular accesses. Surveillance was performed routinely every 3-6 months and included clinical examination, hematologic tests, duplex ultrasonography, and imaging techniques, including 18F-fluorodeoxyglucose positron emission tomography/computed tomography. RESULTS: Primary technical success rate was 100%. Antibiotics were prescribed for a median of 3 months (range 1-20 months). The median duration of VAC treatment was 14 days (range 9-57 days). Complications included early, transient stroke (n = 1), temporary hypoglossal palsy (n = 1), and late, asymptomatic occluded bypasses (n = 2), stent graft thrombosis (n = 1), and moderate carotid stenosis (n = 1). After a median of 5 years (range 1-90 months) of follow up, all patients had healed graft infections with no recurrence was observed. Eight patients died as a result of severe comorbidities, unrelated to the infection or hybrid procedure, 1 month-7 years after treatment. CONCLUSION: The EndoVAC technique is an alternative, less invasive, option for treatment of infected vascular reconstructions in selected cases, when neither traditional radical surgery, nor conservative simple negative pressure wound therapy are considered feasible or safe. The exact indications for this alternative hybrid treatment need to be established. PMID- 26944602 TI - Gene therapy by proteasome activator, PA28gamma, improves motor coordination and proteasome function in Huntington's disease YAC128 mice. AB - Huntington's disease (HD) is neurologically characterized by involuntary movements, associated with degeneration of the medium-sized spiny neurons (MSNs) and ubiquitin-positive neuronal intranuclear inclusions (NIIs). It has been reported that the proteolytic activities of the ubiquitin-proteasome system (UPS) are generally inhibited in HD patient's brain. We previously discovered that a proteasome activator (PA), PA28gamma enhances proteasome activities and cell survival in in vitro HD model. In this study, we aimed to find whether PA28gamma gene transfer improves the proteasome activities and pathological symptoms in in vivo HD model. We stereotaxically injected lenti-PA28gamma virus into the striatum of mutant (MT) YAC128 HD mice and littermate (LM) controls at 14 18months of age, and validated their behavioral and biochemical changes at 12weeks after the injection. YAC128 mice showed a significant increase in their peptidyl-glutamyl preferring hydrolytic (PGPH) proteasome activity and the mRNA or protein levels of brain-derived neurotrophic factor (BDNF) and pro-BDNF after lenti-PA28gamma injection. The number of ubiquitin-positive inclusion bodies was reduced in the striatum of YAC128 mice after lenti-PA28gamma injection. YAC128 mice showed significant improvement of latency to fall on the rota-rod test after lenti-PA28gamma injection. These data demonstrate that the gene therapy with PA, PA28gamma can improve UPS function as well as behavioral abnormalities in HD model mice. PMID- 26944603 TI - Quercetin attenuates neuronal death against aluminum-induced neurodegeneration in the rat hippocampus. AB - Aluminum is a light weight and toxic metal present ubiquitously on earth, which has gained considerable attention due to its neurotoxic effects. It also has been linked ecologically and epidemiologically to several neurological disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), Guamanian Parkinsonian complex and Amyotrophic lateral sclerosis (ALS). The mechanism of aluminum neurotoxicity is poorly understood, but it is well documented that aluminum generates reactive oxygen species (ROS). Enhanced ROS production leads to disruption of cellular antioxidant defense systems and release of cytochrome c (cyt-c) from mitochondria to cytosol resulting in apoptotic cell death. Quercetin (a natural flavonoid) protects it from oxidative damage and has been shown to decrease mitochondrial damage in various animal models of oxidative stress. We hypothesized that if oxidative damage to mitochondria does play a significant role in aluminum-induced neurodegeneration, and then quercetin should ameliorate neuronal apoptosis. Administration of quercetin (10 mg/kg body wt/day) reduced aluminum (10 mg/kg body wt/day)-induced oxidative stress (decreased ROS production, increased mitochondrial superoxide dismutase (MnSOD) activity). In addition, quercetin also prevents aluminum-induced translocation of cyt-c, and up regulates Bcl-2, down-regulates Bax, p53, caspase-3 activation and reduces DNA fragmentation. Quercetin also obstructs aluminum-induced neurodegenerative changes in aluminum-treated rats as seen by Hematoxylin and Eosin (H&E) staining. Further electron microscopic studies revealed that quercetin attenuates aluminum induced mitochondrial swelling, loss of cristae and chromatin condensation. These results indicate that treatment with quercetin may represent a therapeutic strategy to attenuate the neuronal death against aluminum-induced neurodegeneration. PMID- 26944604 TI - Mechanisms underlying the formation of the amygdalar fear memory trace: A computational perspective. AB - Recent experimental and modeling studies on the lateral amygdala (LA) have implicated intrinsic excitability and competitive synaptic interactions among principal neurons (PNs) in the formation of auditory fear memories. The present modeling studies, conducted over an expanded range of intrinsic excitability in the network, revealed that only excitable PNs that received tone inputs participate in the competition. Strikingly, the number of model PNs integrated into the fear memory trace remained constant despite the much larger range considered, and model runs highlighted several conditioning-induced tone responsive characteristics of the various PN populations. Furthermore, these studies showed that although excitation was important, disynaptic inhibition among PNs is the dominant mechanism that keeps the number of plastic PNs stable despite large variations in the network's excitability. Finally, we found that the overall level of inhibition in the model network determines the number of projection cells integrated into the fear memory trace. PMID- 26944606 TI - Recovery from ketamine-induced amnesia by blockade of GABA-A receptor in the medial prefrontal cortex of mice. AB - Ketamine and other noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonists are known to induce deficits in learning and cognitive performance sensitive to prefrontal cortex (PFC) functions. The interaction of a glutamatergic and GABAergic systems is essential for many cognitive behaviors. In order to understand the effect of gamma-aminobutyric acid (GABA)/glutamate interactions on learning and memory, we investigated the effects of intra medial prefrontal cortex (mPFC) injections of GABAergic agents on ketamine-induced amnesia using a one-trial passive avoidance task in mice. Pre-training systemic administration of ketamine (5, 10 and 15mg/kg, i.p.) dose-dependently decreased the memory acquisition of a one-trial passive avoidance task. Pre-training intra mPFC injection of muscimol, GABAA receptor agonist (0.05, 0.1 and 0.2MUg/mouse) and baclofen GABAB receptor agonist (0.05, 0.1, 0.5 and 1MUg/mouse), impaired memory acquisition. However, co-pretreatment of different doses of muscimol and baclofen with a lower dose of ketamine (5mg/kg), which did not induce amnesia by itself, caused inhibition of memory formation. Our data showed that sole pre training administration of bicuculline, GABA-A receptor antagonist and phaclofen GABA-B receptor antagonist into the mPFC, did not affect memory acquisition. In addition, the amnesia induced by pre-training ketamine (15mg/kg) was significantly decreased by the pretreatment of bicuculline (0.005, 0.1 and 0.5MUg/mouse). It can be concluded that GABAergic system of the mPFC is involved in the ketamine-induced impairment of memory acquisition. PMID- 26944605 TI - Repetitive acute intermittent hypoxia increases growth/neurotrophic factor expression in non-respiratory motor neurons. AB - Repetitive acute intermittent hypoxia (rAIH) increases growth/trophic factor expression in respiratory motor neurons, thereby eliciting spinal respiratory motor plasticity and/or neuroprotection. Here we demonstrate that rAIH effects are not unique to respiratory motor neurons, but are also expressed in non respiratory, spinal alpha motor neurons and upper motor neurons of the motor cortex. In specific, we used immunohistochemistry and immunofluorescence to assess growth/trophic factor protein expression in spinal sections from rats exposed to AIH three times per week for 10weeks (3*wAIH). 3*wAIH increased brain derived neurotrophic factor (BDNF), its high-affinity receptor, tropomyosin receptor kinase B (TrkB), and phosphorylated TrkB (pTrkB) immunoreactivity in putative alpha motor neurons of spinal cervical 7 (C7) and lumbar 3 (L3) segments, as well as in upper motor neurons of the primary motor cortex (M1). 3*wAIH also increased immunoreactivity of vascular endothelial growth factor A (VEGFA), the high-affinity VEGFA receptor (VEGFR-2) and an important VEGF gene regulator, hypoxia-inducible factor-1alpha (HIF-1alpha). Thus, rAIH effects on growth/trophic factors are characteristic of non-respiratory as well as respiratory motor neurons. rAIH may be a useful tool in the treatment of disorders causing paralysis, such as spinal injury and motor neuron disease, as a pretreatment to enhance motor neuron survival during disease, or as preconditioning for cell-transplant therapies. PMID- 26944607 TI - Modified pressure cooker technique: An easier way to control onyx reflux. AB - The use of onyx enabled the treatment of various intracranial vascular diseases more effectively than cyanoacrylate. The pressure cooker technique allowed definitive control of reflux and was made possible via detachable microcatheters. We present a variation of this technique called the modified pressure cooker to make reflux control easier and more reproducible and thus simplifying the procedure. We also extended the application of the technique to other diseases beyond arteriovenous malformations including dural arteriovenous fistulas and hypervascular tumors. PMID- 26944608 TI - What is a representative voiding pattern in children with lower urinary tract symptoms? Lack of consistent findings in ambulatory and conventional urodynamic tests. AB - BACKGROUND: Conventional urodynamics (CU) is a highly standardized evaluation of lower urinary tract function. However, in pediatric patients there is concern that the reliability of measurements could be influenced by development effects and measurement variability, as well as by the unfamiliar clinical environment. Ambulatory urodynamics (AU) provides an alternative to this - it uses natural filling, is measured over a prolonged period, and is conducted in a child friendly environment. OBJECTIVE: The aim of this study was to conduct a comparative analysis of AU and CU to evaluate the consistency in voiding patterns obtained with these two methods of urodynamic testing. STUDY DESIGN: Urodynamic parameters obtained by AU and CU methods in 50 pediatric patients aged >5 years were retrospectively analyzed. Voiding patterns were categorized into six types: coordinated contraction, detrusor after-contraction, fluctuated contraction, pre void contraction, relief voiding, and weak or absent contraction. Voiding patterns were used to determine the repeatability within urodynamic tests and to identify consistency between AU and CU tests. Five urodynamic parameters were quantified and compared between AU and CU: voided volume, flow rate, maximum detrusor pressure, and detrusor pressure at peak flow rate. For inter-observer variation analysis, 100 voiding curves were randomly selected and categorized by two independent observers; inter-observer agreement was evaluated using the kappa statistic. RESULTS: A single pattern of voiding was identified in five patients using AU and 37 using CU. Consistency of a single pattern between AU and CU was identified in three patients, and consistency between a predominant pattern with AU, defined by one type of voiding occurring >50% of one's voids, and a single pattern with CU was identified in 10 patients (summary table). Flow rates were similar between methods; however, higher maximum detrusor pressure and detrusor pressure at peak flow and lower voided volume were recorded with AU. DISCUSSION: AU resulted in more diverse voiding patterns. Along with the differences in measured urodynamic parameters challenges the application of findings from one method to form a clinical diagnosis. Furthermore, CU may not be as sensitive as AU to the variability in lower urinary tract pathophysiology. CONCLUSIONS: More diverse voiding patterns were identified in AU compared with CU, with a lack of consistency in identified voiding pattern in both methods. Therefore, the urodynamic findings in children may have to be analyzed in more detail, taking the variations into account. PMID- 26944610 TI - Photoperiod and aggression induce changes in ventral gland compounds exclusively in male Siberian hamsters. AB - Chemical communication is a critical component of social behavior as it facilitates social encounters, allows for evaluation of the social partner, defines territories and resources, and advertises information such as sex and physiological state of an animal. Odors provide a key source of information about the social environment to rodents; however, studies identifying chemical compounds have thus far focused primarily on few species, particularly the house mouse. Moreover, considerably less attention has been focused on how environmental factors, reproductive phenotype, and behavioral context alter these compounds outside of reproduction. We examined the effects of photoperiod, sex, and social context on chemical communication in the seasonally breeding Siberian hamster. We sampled ventral gland secretions in both male and female hamsters before and after an aggressive encounter and identified changes in a range of volatile compounds. Next, we investigated how photoperiod, reproductive phenotype, and aggression altered ventral gland volatile compound composition across the sexes. Males exhibited a more diverse chemical composition, more sex specific volatiles, and showed higher levels of excretion compared to females. Individual volatiles were also differentially excreted across photoperiod and reproductive phenotype, as well as differentially altered in response to an aggressive encounter. Female volatile compound composition, in contrast, did not differ across photoperiods or in response to aggression. Collectively, these data contribute to a greater understanding of context-dependent changes in chemical communication in a seasonally breeding rodent. PMID- 26944611 TI - Understanding persuasion contexts in health gamification: A systematic analysis of gamified health behavior change support systems literature. AB - BACKGROUND: Gamification is increasingly used as a design strategy when developing behavior change support systems in the healthcare domain. It is commonly agreed that understanding the contextual factors is critical for successful gamification, but systematic analyses of the persuasive contexts have been lacking so far within gamified health intervention studies. OBJECTIVES AND METHODS: Through a persuasion context analysis of the gamified health behavior change support systems (hBCSSs) literature, we inspect how the contextual factors have been addressed in the prior gamified health BCSS studies. The implications of this study are to provide the practitioners and researchers examples of how to conduct a systematic analysis to help guide the design and research on gamified health BCSSs. The ideas derived from the analysis of the included studies will help identify potential pitfalls and shortcomings in both the research and implementations of gamified health behavior change support systems. RESULTS: We systematically analyzed the persuasion contexts of 15 gamified health intervention studies. According to our results, gamified hBCSSs are implemented under different facets of lifestyle change and treatments compliance, and use a multitude of technologies and methods. We present a set of ideas and concepts to help improve endeavors in studying gamified health intervention through comprehensive understanding of the persuasive contextual factors. CONCLUSIONS: Future research on gamified hBCSSs should systematically compare the different combinations of contextual factors, related theories, chosen gamification strategies, and the study of outcomes to help understand how to achieve the most efficient use of gamification on the different aspects of healthcare. Analyzing the persuasion context is essential to achieve this. With the attained knowledge, those planning health interventions can choose the 'tried-and-tested' approaches for each particular situation, rather than develop solutions in an ad-hoc manner. PMID- 26944609 TI - Effects of basal and acute cortisol on cognitive flexibility in an emotional task switching paradigm in men. AB - The stress hormone cortisol is assumed to influence cognitive functions. While cortisol-induced alterations of declarative memory in particular are well investigated, considerably less is known about its influence on executive functions. Moreover, most research has been focused on slow effects, and rapid non-genomic effects have not been studied. The present study sought to investigate the impact of acute cortisol administration as well as basal cortisol levels on cognitive flexibility, a core executive function, within the non genomic time frame. Thirty-eight healthy male participants were randomly assigned to intravenously receive either cortisol or a placebo before performing a task switching paradigm with happy and angry faces as stimuli. Cortisol levels were measured at six points during the experiment. Additionally, before the experiment, basal cortisol measures for the cortisol awakening response were collected on three consecutive weekdays immediately following awakening and 30, 45, and 60min after. First and foremost, results showed a pronounced impact of acute and basal cortisol on reaction time switch costs, particularly for angry faces. In the placebo group, low basal cortisol was associated with minimal switch costs, whereas high basal cortisol was related to maximal switch costs. In contrast, after cortisol injection, basal cortisol levels showed no impact. These results show that cognitive flexibility-enhancing effects of acute cortisol administration are only seen in men with high basal cortisol levels. This result supports the context dependency of cortisol administration and shows the relevance of taking basal cortisol levels into account. PMID- 26944612 TI - Biological evaluation and molecular docking studies of new curcuminoid derivatives: Synthesis and characterization. AB - In the present study, three series of dimethylamino curcuminoids viz. 4 phenylaminomethyl curcumin (3a-d), arylidene curcumin (3e) and pyrazole curcumin (3f-i) derivatives have been synthesized and studied for their in vitro anti inflammatory, antioxidant and antibacterial activities. Synthesized dimethylamino curcuminoid derivatives namely 3d, 3e, 3h and 3i have shown potent anti inflammatory properties than parent curcumin. Molecular docking interactions of dimethylamino curcuminoids derivatives against cyclooxygenase enzymes (COX-1 and COX-2) were studied. PMID- 26944613 TI - A metal-free turn-on fluorescent probe for the fast and sensitive detection of inorganic azides. AB - Sodium azide is toxic and widely used in agricultural, commercial products, and research laboratories. Thus it is of a significant environmental concern and there is a need for the development of a rapid detection method. A fluorogenic dibenzylcyclooctyne derivative (Fl-DIBO) is herein described as a fluorescent probe for the rapid detection of inorganic azide via Strain-Promoted Azide-Alkyne Cycloaddition (SPAAC). Fl-DIBO was found to be highly selective toward NaN3 in comparison to other common anions with good sensitivity and detection limit of 10MUM. PMID- 26944615 TI - Target beta-catenin/CD44/Nanog axis in colon cancer cells by certain N'-(2 oxoindolin-3-ylidene)-2-(benzyloxy)benzohydrazides. AB - Cell surface molecule CD44 plays a major role in regulation of cancer stem cells CSCs on both phenotypic and functional level, however chemical inhibition approach of CD44 to targets CSCs is poorly studied. Herein, we report the discovery of certain N'-(2-oxoindolin-3-ylidene)-2-(benzyloxy)benzohydrazides as a novel inhibitor of CD44. Molecular docking study showed interference of the scaffold of these compounds with beta-catenin/TCF-4 complex, building a direct relationship between CD44 inhibition and observed well-fitted binding domain. Compound 11a, most potent member elicits inhibition effect on TCF/LEF reporter activity conformed the involvement of Wnt pathway inhibition as a mechanism of action. Furthermore, the treatment by the mentioned compound leads to inhibition of embryonic transcriptional factor Nanog but not Sox2 or Oct-4 suggested specific targeted effect. Moreover, the cytotoxicity and cell cycle effect of this series seems to be dependent on CD44 expression. PMID- 26944614 TI - Synthesis and antiproliferative activity of 6,7-disubstituted-4-phenoxyquinoline derivatives bearing the 2-oxo-4-chloro-1,2-dihydroquinoline-3-carboxamide moiety. AB - A series of 6,7-disubstituted-4-phenoxyquinoline derivatives bearing the 2-oxo-4 chloro-1,2-dihydroquinoline-3-carboxamide moiety were synthesized, and evaluated for their antiproliferative activity against 5 cancer cell lines (H460, HT-29, MKN-45, A549, and U87MG). Most compounds showed moderate to excellent potency, and compared to foretinib, the most promising analog 42 (c-Met/Flt-3 IC50=1.21/2.15nM) showed a 6.1-fold increase in activity against H460 cell line in vitro. The enzymatic assays (c-Met, VEGFR-2, Flt-3, PDGFR-beta, c-Kit, and EGFR) of compound 42 were evaluated in vitro. Docking analysis showed that compound 42 could form three hydrogen bonds with c-Met. Structure-activity relationship studies indicated that a more water-soluble cyclic tertiary amine and electron-withdrawing groups at 4-position of the phenyl ring contribute to the antitumour activity. PMID- 26944616 TI - Synthesis of tetracyclic iminosugars fused benzo[e][1,3]thiazin-4-one and their HIV-RT inhibitory activity. AB - Several aza-C-pseudonucleosides bearing 1,3-benzothiazin-4-one (6 and 7) were prepared by the one-pot three-component condensation from the iminosugar aldehyde 3, amino acid ethyl/methyl ester hydrochlorides 4(a-c), and 2-mercaptobenzoic acid 5. After removal of Boc and the isopropylidene groups, the target novel tetracyclic iminosugars fused benzo[e][1,3]thiazin-4-one 1(a-c) and 2(a-b) were first afforded by the intramolecular cyclo-amidation reaction. Their structures were determined by their (1)H, (13)C NMR, and HRMS (ESI) spectra and X-ray. The tetracyclic iminosugars 1(a-c) and 2(a-b) were examined for their HIV reverse transcriptase (RT) inhibitory activities. The result showed that all compounds could effectively inhibit RT activity. Among them, compound 2a was the best one with the IC50 value of RT inhibitory activity of 0.82MUM. Structure-activity relationship analysis suggested that 1'R configuration in the tetracyclic azasugars was of benefit to their anti-HIV RT activity. PMID- 26944617 TI - New Insights on Thylakoid Biogenesis in Plant Cells. AB - Photosynthetic membranes, or thylakoids, are the most extensive membrane system found in the biosphere. They form flattened membrane cisternae in the cytosol of cyanobacteria and in the stroma of chloroplasts. The efficiency of light energy capture and conversion, critical for primary production in ecosystems, relies on the rapid expansion of thylakoids and their versatile reorganization in response to light changes. Thylakoid biogenesis results from the assembly of a lipid matrix combined with the incorporation of protein components. Four lipid classes are conserved from cyanobacteria to chloroplasts: mono- and digalactosyldiacylglycerol, sulfoquinovosyldiacylglycerol, and phosphatidyldiacylglycerol. This review focuses on the production and biophysical properties of galactolipids, making them determinant factors for the nonvesicular/nonlamellar biogenesis and for the three-dimensional architecture of nascent thylakoids. The regulation of MGD1, the committing enzyme of galactolipid biosynthesis in Arabidopsis, via feedback regulatory loops and control of protein binding to membranes, is also detailed. PMID- 26944618 TI - Tailoring Grain Storage Reserves for a Healthier Rice Diet and its Comparative Status with Other Cereals. AB - A global rise of diet-related noncommunicable diseases calls for a focus on diet based nutritional intervention across the entire socioeconomic consumer spectrum. We review recent reports in the area of healthier rice aimed at developing rice grains with improved dietary fiber compositions (increased amounts of nonstarch polysaccharides and resistant starch), and less digestible starch (higher amylose and phospholipid complex in the endosperm) resulting in reduced glycemic impact upon grain consumption. We furthermore elaborate on the interconnections of elevated amounts of protein and a balanced composition of essential amino acids. The importance of a nutritious aleurone layer and its role in lipid storage and micronutrient composition is discussed briefly in the context of brown rice benefits. We identify gene targets for precision breeding that will facilitate the production of rice grains and rice-based products to mitigate the impact of nutrition-related preventable diseases. PMID- 26944619 TI - Recent Advances in Molecular Mechanisms of Taste Signaling and Modifying. AB - The sense of taste conveys crucial information about the quality and nutritional value of foods before it is ingested. Taste signaling begins with taste cells via taste receptors in oral cavity. Activation of these receptors drives the transduction systems in taste receptor cells. Then particular transmitters are released from the taste cells and activate corresponding afferent gustatory nerve fibers. Recent studies have revealed that taste sensitivities are defined by distinct taste receptors and modulated by endogenous humoral factors in a specific group of taste cells. Such peripheral taste generations and modifications would directly influence intake of nutritive substances. This review will highlight current understanding of molecular mechanisms for taste reception, signal transduction in taste bud cells, transmission between taste cells and nerves, regeneration from taste stem cells, and modification by humoral factors at peripheral taste organs. PMID- 26944620 TI - Regulation of Notch Signaling Through Intracellular Transport. AB - The highly conserved Notch-signaling pathway performs a central role in cell differentiation, survival, and proliferation. A major mechanism by which cells modulate signaling is by controlling the intracellular transport itinerary of Notch. Indeed, Notch removal from the cell surface and its targeting to the lysosome for degradation is one way in which Notch activity is downregulated since it limits receptor exposure to ligand. In contrast, Notch-signaling capacity is maintained through repeated rounds of receptor recycling and redelivery of Notch to the cell surface from endosomal stores. This review discusses the molecular mechanisms by which Notch transit through the endosome is controlled and how various intracellular sorting decisions are thought to impact signaling activity. PMID- 26944621 TI - Retromer in Polarized Protein Transport. AB - Retromer is an evolutionary conserved protein complex required for endosome-to Golgi retrieval of receptors for lysosomal hydrolases. It is constituted by a heterotrimer encoded by the vacuolar protein sorting (VPS) gene products Vps26, Vps35, and Vps29, which selects cargo, and a dimer of phosphoinositide-binding sorting nexins, which deforms the membrane. Recent progress in the mechanism of retromer assembly and functioning has strengthened the link between sorting at the endosome and cytoskeleton dynamics. Retromer is implicated in endosomal sorting of many cargos and plays an essential role in plant and animal development. Although it is best known for endosome sorting to the trans-Golgi network, it also intervenes in recycling to the plasma membrane. In polarized cells, such as epithelial cells and neurons, retromer may also be utilized for transcytosis and long-range transport. Considerable evidence implicates retromer in establishment and maintenance of cell polarity. That includes sorting of the apical polarity module Crumbs; regulation of retromer function by the basolateral polarity module Scribble; and retromer-dependent recycling of various cargoes to a certain surface domain, thus controlling polarized location and cell homeostasis. Importantly, altered retromer function has been linked to neurodegeneration, such as in Alzheimer's or Parkinson's disease. This review will underline how alterations in retromer localization and function may affect polarized protein transport and polarity establishment, thereby causing developmental defects and disease. PMID- 26944622 TI - New Insights Into the Mechanism of COP9 Signalosome-Cullin-RING Ubiquitin-Ligase Pathway Deregulation in Urological Cancers. AB - Urological cancers are a very common type of cancer worldwide and have alarming high incidence and mortality rates, especially in kidney cancers, illustrate the urgent need for new therapeutic targets. Recent publications point to a deregulated COP9 signalosome (CSN)-cullin-RING ubiquitin-ligase (CRL) pathway which is here considered and investigated as potential target in urological cancers with strong focus on renal cell carcinomas (RCC). The CSN forms supercomplexes with CRLs in order to preserve protein homeostasis and was found deregulated in several cancer types. Examination of selected CSN-CRL pathway components in RCC patient samples and four RCC cell lines revealed an interesting deregulated p27(Kip1)-Skp2-CAND1 axis and two p27(Kip1) point mutations in 786-O cells; p27(Kip1)V109G and p27(Kip1)I119T. The p27(Kip1) mutants were detected in patients with RCC and appear to be responsible for an accelerated growth rate in 786-O cells. The occurrence of p27(Kip1)V109G and p27(Kip1)I119T in RCC makes the CSN-CRL pathway an attractive therapeutic target. PMID- 26944623 TI - Dual Protein Localization to the Envelope and Thylakoid Membranes Within the Chloroplast. AB - The chloroplast houses various metabolic processes essential for plant viability. This organelle originated from an ancestral cyanobacterium via endosymbiosis and maintains the three membranes of its progenitor. Among them, the outer envelope membrane functions mainly in communication with cytoplasmic components while the inner envelope membrane houses selective transport of various metabolites and the biosynthesis of several compounds, including membrane lipids. These two envelope membranes also play essential roles in import of nuclear-encoded proteins and in organelle division. The third membrane, the internal membrane system known as the thylakoid, houses photosynthetic electron transport and chemiosmotic phosphorylation. The inner envelope and thylakoid membranes share similar lipid composition. Specific targeting pathways determine their defined proteomes and, thus, their distinct functions. Nonetheless, several proteins have been shown to exist in both the envelope and thylakoid membranes. These proteins include those that play roles in protein transport, tetrapyrrole biosynthesis, membrane dynamics, or transport of nucleotides or inorganic phosphate. In this review, we summarize the current knowledge about proteins localized to both the envelope and thylakoid membranes in the chloroplast, discussing their roles in each membrane and potential mechanisms of their dual localization. Addressing the unanswered questions about these dual-localized proteins should help advance our understanding of chloroplast development, protein transport, and metabolic regulation. PMID- 26944624 TI - Evaluation of next generation sequencing for the analysis of Eimeria communities in wildlife. AB - Next-generation sequencing (NGS) techniques are well-established for studying bacterial communities but not yet for microbial eukaryotes. Parasite communities remain poorly studied, due in part to the lack of reliable and accessible molecular methods to analyse eukaryotic communities. We aimed to develop and evaluate a methodology to analyse communities of the protozoan parasite Eimeria from populations of the Australian marsupial Petrogale penicillata (brush-tailed rock-wallaby) using NGS. An oocyst purification method for small sample sizes and polymerase chain reaction (PCR) protocol for the 18S rRNA locus targeting Eimeria was developed and optimised prior to sequencing on the Illumina MiSeq platform. A data analysis approach was developed by modifying methods from bacterial metagenomics and utilising existing Eimeria sequences in GenBank. Operational taxonomic unit (OTU) assignment at a high similarity threshold (97%) was more accurate at assigning Eimeria contigs into Eimeria OTUs but at a lower threshold (95%) there was greater resolution between OTU consensus sequences. The assessment of two amplification PCR methods prior to Illumina MiSeq, single and nested PCR, determined that single PCR was more sensitive to Eimeria as more Eimeria OTUs were detected in single amplicons. We have developed a simple and cost-effective approach to a data analysis pipeline for community analysis of eukaryotic organisms using Eimeria communities as a model. The pipeline provides a basis for evaluation using other eukaryotic organisms and potential for diverse community analysis studies. PMID- 26944625 TI - Synthesis, biological evaluation and structural analysis of novel peripherally active morphiceptin analogs. AB - Morphiceptin (Tyr-Pro-Phe-Pro-NH2), a tetrapeptide amide, is a selective ligand of the MU-opioid receptor (MOR). This study reports the synthesis and biological evaluation of a series of novel morphiceptin analogs modified in positions 2 or/and 4 by introduction of 4,4-difluoroproline (F2Pro) in l or d configuration. Depending on the fluorinated amino acid configuration and its position in the sequence, new analogs behaved as selective full MOR agonists showing high, moderate, or relatively low potency. The most potent analog, Tyr-F2Pro-Phe-D F2Pro-NH2, was also able to activate the kappa-opioid receptor (KOR), although with low potency. Docking studies and the comparison of results with the high resolution crystallographic structure of a MOR-agonist complex revealed possible structure-activity relationships of this compound family. PMID- 26944626 TI - Do Echocardiography Appropriate Use Criteria Really Matter? PMID- 26944628 TI - A Paean to ASE's Annual Scientific Sessions. PMID- 26944627 TI - Right Ventricular Systolic Function Responses to Acute and Chronic Pulmonary Hypertension: Assessment with Myocardial Deformation. AB - BACKGROUND: The distinction between right ventricular (RV) dysfunction due to an acute etiology (pulmonary embolism [PE]) or chronic afterload (pulmonary arterial hypertension [PAH]) has important therapeutic implications. The aim of this study was to test the hypothesis that RV remodeling would alter RV free wall strain (RVFWS) and differentiate chronic from acute RV afterload. METHODS: In this retrospective study, patients with PE (n = 45) who underwent echocardiography within 48 hours of computed tomographic pulmonary angiography were matched 1:1 for age, gender, and pulmonary artery systolic pressure with patients with PAH (n = 45) and a larger unmatched PAH control group (n = 116). RV function was evaluated with end-diastolic area, fractional area change (FAC), and RVFWS by two dimensional speckle-tracking. The ability of RVFWS to distinguish acute from chronic RV dysfunction was assessed using receiver operating characteristic curves, and its incremental value was sought with stepwise models. RESULTS: RV end-diastolic area, FAC, and RVFWS were significantly impaired in patients with PE (P < .001), with no significant differences in other clinical variables. In matched patients, receiver operating characteristic curve analysis revealed that RVFWS had significantly better discriminative power than the McConnell sign (P = .02), with a cutoff of -17.9%, sensitivity of 87.5%, specificity of 62.5%, and an area under the curve of 0.76. Sequential logistic regression demonstrated an incremental and independent benefit of using RVFWS to predict acute PE versus chronic PAH (P = .01). Observer concordance was superior for RVFWS compared with FAC (P < .01). CONCLUSIONS: RVFWS is more predictive than RV end-diastolic area and less variable than FAC in distinguishing acute from chronic RV pressure overload. RVFWS adds incremental and independent information to standard measures of RV function in assessing the acuity of pulmonary hypertension. PMID- 26944629 TI - Reorganizing to meet the demands of the future: Part two in a two-part series on sonographer registry. PMID- 26944630 TI - Embracing the Goals of 2016. PMID- 26944631 TI - Investigations into methods to improve the antibacterial activity of Acticoat. AB - Multiple studies have shown that the antibacterial dressing Acticoat can inhibit growth of bacteria but is unable to completely clear a wound of infection, which could leave patients vulnerable to sepsis. Agar inoculated with four different Staphylococcus aureus strains and overlain with Acticoat showed growth inhibition beneath and within a 1 mm perimeter of the dressing after 24 h. When lifted from inoculated agar and briefly blotted onto fresh agar plates, Acticoat transferred viable bacteria. Scanning electron microscopy of the surface of Acticoat that overlaid meticillin-resistant S. aureus for 24, 48 and 72 h showed dense clusters of apparently undamaged bacteria distributed across the mesh. The number of bacteria growing on inoculated pig skin, underneath and on the surface of Acticoat, was lower than on controls for the first 8 h, but after 24 h the number of bacteria on the skin was 2.3-fold greater than the untreated controls. In contrast, after 24 h the number of bacteria surviving on the surface of the Acticoat was 11.9 % of controls. Acticoat moistened with 10 % glycerol plus antimicrobial peptides (AMPs) mel12-26 or bac8c (50 MUg ml- 1) reduced the numbers of bacteria on the dressing and on the skin underneath to below 10 % and 0.01 % of the controls, respectively. When lysozyme (1 mg ml- 1) was added to Acticoat wetted with glycerol and the AMP bac8c, the dressing was able to prevent the survival of bacteria on densely inoculated pig skin and on the surface of Acticoat for up to 24 h. In effect, biocompatible solvents and AMPs significantly enhance the bactericidal efficacy of Acticoat. PMID- 26944632 TI - Beyond medicalization: Self-injuring acts revisited. AB - For too long, medical/psychiatric and psychological studies, with focus on emotional sensitivity, personality traits, and correlation with psychopathology, have dominated research on self-injuring acts. The phenomenon thus has been defined as a predominantly medical issue. However, a large body of community prevalence studies show self-injuring acts to be a common phenomenon in society, and most of those who self-injure are unknown in psychiatric or other clinical settings. This article describes and analyzes the medicalization of self-injuring acts and argues a need to move research on self-injuring acts out of the medical paradigm. There is a need to explicitly explore the impact of social, cultural, structural, and gendered factors surrounding and influencing self-injuring acts. A non-medical approach, beyond the limits of the medical perspective, would feed research forward and create a more nuanced view on this widespread social phenomenon. PMID- 26944633 TI - Private versus social incentives for pharmaceutical innovation. AB - We provide a theoretical framework to contribute to the current debate regarding the tendency of pharmaceutical companies to direct their R&D toward marketing products that are "follow-on" drugs of already existing drugs, rather than toward the development of breakthrough drugs. We construct a model with a population of patients who can be treated with drugs that are horizontally and vertically differentiated. In addition to a pioneering drug, a new drug can be marketed as the result of an innovative process. We analyze physician prescription choices and the optimal pricing decision of an innovative firm. We also characterize the incentives of the innovative firm to conduct R&D activities, disentangling the quest for breakthrough drugs from the firm effort to develop follow-on drugs. Our results offer theoretical support for the conventional wisdom that pharmaceutical firms devote too many resources to conducting R&D activities that lead to incremental innovations. PMID- 26944634 TI - Proteus cibarius sp. nov., a swarming bacterium from Jeotgal, a traditional Korean fermented seafood, and emended description of the genus Proteus. AB - A novel Proteus-like, Gram-stain-negative, facultatively anaerobic, rod-shaped bacterium, designated strain JS9T, was isolated from Korean fermented seafood, Jeotgal. Phylogenetic analysis based on the 16S rRNA gene sequence revealed that strain JS9T belonged to the genus Proteus in the family Enterobacteriaceae. The highest 16S rRNA gene sequence similarity of strain JS9T was to Proteus vulgaris KCTC 2579T (98.98 %) and the genomic DNA G+C content is 39.0 mol%. DNA-DNA hybridization values were measured and strain JS9T showed <20.8 % genomic relatedness with closely-related members of the genus Proteus. The isolate showed bacterial motility and swarming activity similar to those of pathogenic Proteus mirabilis but distinct from those of other species of the genus Proteus. The isolate grows optimally at 30 degrees C, at pH 7, and in the presence of 2 % (w/v) NaCl. The main respiratory quinones are ubiquinone Q-8 and Q-10, and the major cellular fatty acids are C16 : 0, summed feature 3 and summed feature 8. The polar lipids comprise phosphatidylglycerol, phosphatidylethanolamine, diphosphatidylglycerol, an unidentified amino lipid, two unidentified amino phospholipids, and three unidentified lipids. Based on phylogenetic, phenotypic, chemotaxonomic and genotypic analyses, strain JS9T represents a novel species of the genus Proteus, for which the name Proteus cibarius sp. nov. is proposed. The type strain is JS9T (=KACC 18404T=JCM 30699T). An emended description of the genus Proteus is also provided. PMID- 26944635 TI - Transgenerational response to stress in plants and its application for breeding. AB - A growing number of reports indicate that plants possess the ability to maintain a memory of stress exposure throughout their ontogenesis and even transmit it faithfully to the following generation. Some of the features of transgenerational memory include elevated genome instability, a higher tolerance to stress experienced by parents, and a cross-tolerance. Although the underlying molecular mechanisms of this phenomenon are not clear, a likely contributing factor is the absence of full-scale reprogramming of the epigenetic landscape during gametogenesis; therefore, epigenetic marks can occasionally escape the reprogramming process and can be passed on to the progeny. To date, it is not entirely clear which part of the epigenetic landscape is more likely to escape the reprogramming events, and whether such a process is random or directed and sequence specific. The identification of specific epigenetic marks associated with specific stressors would allow generation of stress-tolerant plants through the recently discovered techniques for precision epigenome engineering. The engineered DNA-binding domains (e.g. ZF, TALE, and dCas9) fused to particular chromatin modifiers would make it possible to target epigenetic modifications to the selected loci, probably allowing stress tolerance to be achieved in the progeny. This approach, termed epigenetic breeding, along with other methods has great potential to be used for both the assessment of the propagation of epigenetic marks across generations and trait improvement in plants. In this communication, we provide a short overview of recent reports demonstrating a transgenerational response to stress in plants, and discuss the underlying potential molecular mechanisms of this phenomenon and its use for plant biotechnology applications. PMID- 26944636 TI - Long-distance plant signaling pathways in response to multiple stressors: the gap in knowledge. AB - Plants require the capacity for quick and precise recognition of external stimuli within their environment for survival. Upon exposure to biotic (herbivores and pathogens) or abiotic stressors (environmental conditions), plants can activate hydraulic, chemical, or electrical long-distance signals to initiate systemic stress responses. A plant's stress reactions can be highly precise and orchestrated in response to different stressors or stress combinations. To date, an array of information is available on plant responses to single stressors. However, information on simultaneously occurring stresses that represent either multiple, within, or across abiotic and biotic stress types is nascent. Likewise, the crosstalk between hydraulic, chemical, and electrical signaling pathways and the importance of each individual signaling type requires further investigation in order to be fully understood. The overlapping presence and speed of the signals upon plant exposure to various stressors makes it challenging to identify the signal initiating plant systemic stress/defense responses. Furthermore, it is thought that systemic plant responses are not transmitted by a single pathway, but rather by a combination of signals enabling the transmission of information on the prevailing stressor(s) and its intensity. In this review, we summarize the mode of action of hydraulic, chemical, and electrical long-distance signals, discuss their importance in information transmission to biotic and abiotic stressors, and suggest future research directions. PMID- 26944637 TI - [Not Available]. PMID- 26944638 TI - [Not Available]. PMID- 26944639 TI - [Melanoma, from diagnosis to treatment]. AB - Skin cancers represent a major public health problem. Cutaneous melanoma, the incidence of which is constantly increasing, has the particularity of metastasising when it is detected too late. Its treatment at the metastatic stage has evolved significantly over recent years with the arrival of targeted therapies and immunotherapies which can increase patients' survival. PMID- 26944641 TI - [Choroidal melanoma]. AB - Choroidal melanoma is the most common form of eye cancer in adults. Treatments enabling the tumour to be destroyed or removed while preserving the eye socket are mainly based on surgery, proton therapy and brachytherapy. PMID- 26944640 TI - [Prevention, early detection and monitoring of cutaneous melanoma]. AB - In parallel to the development of new treatments, considerable work remains to be done with regard on the one hand to early detection, and on the other, to the prevention of the main extrinsic risk factor, namely ultraviolet rays. Caregivers have an important educational role to play with patients and their families concerning these different aspects. PMID- 26944642 TI - [The nurses involved in therapeutic innovation]. AB - Clinical research nurses (CRNs) play an important role within the teams involved in the fight against cancer and in therapeutic innovation. In the dermatology department of the Gustave-Roussy Institute, patients treated for melanoma and taking part in clinical trials are supported along their care pathway by a CRN who, in addition to her clinical expertise, acts as a link between the different players concerned. PMID- 26944644 TI - [Fighting melanoma together]. AB - Patients and their families often become involved in non-profit organisations which undertake actions to combat a disease. In the case of melanoma, in addition to promoting research, associations work to encourage prevention and early detection. PMID- 26944643 TI - [Global management of melanoma in the palliative phase]. AB - The priority of the care management of people with melanoma in the palliative stage is to treat symptoms causing discomfort and to provide psychological support. The commitment of caregivers is important, both on the professional as well as human level. A team in Lyon shares its practices. PMID- 26944645 TI - [Intensive care, a department where relational care counts]. AB - The intensive care unit is a department where the seriousness of the patients' condition requires a high level of technical skill. It is also a place where professionals need to demonstrate relational care in their practice. A nurse shares her experience of what she describes as an extremely rewarding role. PMID- 26944646 TI - [Supporting the clinical assessment: from a printed handbook to its digital version]. AB - Nurses from a palliative care network questioned the methods of the global clinical assessment performed in patients' homes. Going back to the very foundations of the profession, they drew up a handbook on this subject aimed at home care professionals. An embedded digital version has been developed enabling caregivers to consult it at any time on their mobile telephone. PMID- 26944647 TI - [Experience of a young graduate nurse overseas]. AB - A young, recently graduated nurse chose, as her first job, a position on the archipelago of Saint-Pierre and Miquelon. Through her dual perspective as a young graduate and a native of metropolitan France, we discover the nursing care and the questions she raises, between the proximity resulting from the demographics of the islands and the young teams with a high staff turnover. PMID- 26944648 TI - [A different approach to the care of patients with MS]. AB - Therapeutic patient education comprises multi-disciplinary support to help patients accept and manage a chronic pathology. Nurses are at the heart of this team approach. Two nurses from Brest military teaching hospital share their experience in this field with patients with multiple sclerosis, which provides benefits for the patient as well as added value for a reflexive nursing practice. PMID- 26944649 TI - [Not Available]. PMID- 26944650 TI - Type I Diabetes in Early Adulthood. PMID- 26944651 TI - [Not Available]. PMID- 26944652 TI - [Not Available]. PMID- 26944653 TI - [Not Available]. PMID- 26944654 TI - Antithrombotic therapy in medically managed patients with non-ST-segment elevation acute coronary syndromes. PMID- 26944655 TI - Carotid artery stenting. PMID- 26944656 TI - Drugs related to monoamine oxidase activity. AB - Progress in understanding the role of monoamine neurotransmission in pathophysiology of neuropsychiatric disorders was made after the discovery of the mechanisms of action of psychoactive drugs, including monoamine oxidase (MAO) inhibitors. The increase in monoamine neurotransmitter availability, decrease in hydrogen peroxide production, and neuroprotective effects evoked by MAO inhibitors represent an important approach in the development of new drugs for the treatment of mental disorders and neurodegenerative diseases. New drugs are synthesized by acting as multitarget-directed ligands, with MAO, acetylcholinesterase, and iron chelation as targets. Basic information is summarized in this paper about the drug-induced regulation of monoaminergic systems in the brain, with a focus on MAO inhibition. Desirable effects of MAO inhibition include increased availability of monoamine neurotransmitters, decreased oxidative stress, decreased formation of neurotoxins, induction of pro survival genes and antiapoptotic factors, and improved mitochondrial functions. PMID- 26944657 TI - Molecular and environmental factors governing non-covalent bonding interactions and conformations of phosphorous functionalized gamma-cyclodextrin hydrate systems. AB - Recent strategies in molecular drugs-design shift efforts to nanomedicine. Large supra-molecular inclusion systems are implemented as therapeutics. The sophistication of design is based on major advances of cyclodextrins (CDs) as host molecules. They are friendly towards biological environment. CDs have good (bio)compatibility as well. CDs can form host-guest macromolecular systems incorporating small molecules with suitable shapes due to non-covalent interactions. Innovative strategies yield to polymeric nano-particles; micelles; linear polymers and/or CDs-functionalized dendrimeric nanostructures; nanofibers as well as hydrogels. Attractive are phosphorous containing (bio)matrerials, having high selectivity toward biological active molecules. The non-covalent interactions in aquatic CD-systems contribute to stability of host-guest systems under physiological conditions, determining conformational preferences of host-CD macromolecule and guest small molecular template. In this paper we have reported complementation application of mass spectrometric (MS) and quantum chemical analysis of phosphorous chemically substituted gamma-cyclodextrin hydrates gamma CDPO/nH2O (n ? [0-14]), studying neutral and polynegatively charged molecules as an effort to describe realistic a representative scale of physiological conditions. The binding affinity and molecular conformations are discussed. The 250 neutral and charged systems (gamma-CDPOHm/nH2O, n ? [10][0,14], m ? [0,15], gamma-CDPOH-8/nH2O.8Na(+), and gamma-CDPOH-16/nH2O.16Na(+)) in four main domains of non-covalent hydrogen bonding interactions are studied. PMID- 26944658 TI - Determining the roles of a conserved tyrosine residue in a Mip-like peptidyl prolyl cis-trans isomerase. AB - The FKBP22 and the related peptidyl-prolyl cis-trans isomerases dimerize using their N-terminal domains. Conversely, their C-terminal domains possess both the substrate and inhibitor binding sites. To delineate the roles of a conserved Tyr residue at their N-terminal domains, we have studied a FKBP22 mutant that carries an Ala in place of the conserved Tyr at position 15. We have demonstrated that the Tyr 15 of FKBP22 is indispensable for preserving its dimerization ability, catalytic activity, and structure. The residue, however, little contributed to its inhibitor binding ability and stability. The mode of action of Tyr 15 has been discussed at length. PMID- 26944659 TI - The physicochemical characterisation of pepsin degraded pig gastric mucin. AB - Mucins are the main macromolecular components of the mucus secretions that cover the oral cavity, gastrointestinal and urogenital tracts of animals. The properties of the mucus secretions are therefore directly correlated with the physicochemical properties of mucin glycoproteins. In this study, mucins were obtained from pig gastric mucous after digestion with pepsin at 37 degrees C for 4h, these mucins were characterised in terms of compositional and hydrodynamic properties. Compositional analysis showed that this mucin contains protein (15%), carbohydrates (55%) of which the constituents are: fucose (4%), galactose (9%), glucosamine (55%), glucosamine (33%) and sialic acid (2%). The latter component gives the mucin polymer a pH-dependant negative charge, with a zeta-potential of 3mV at pH 1.2 up to -11mV at pH 7.4. The weight average molar mass was ~1*10(6)g/mol and intrinsic viscosity was ~0.42dL/g although there was a small pH dependency due to the polyelectrolyte behavior of the polymer. The measurements of viscosity versus shear rate showed shear thinning behavior and the critical overlap concentration was determined to be 10-11% w/v indicating a compact structure. Knowledge of these properties is fundamental to the understanding interactions of mucins, with for example, novel drug delivery systems. PMID- 26944660 TI - Protective effect of hyaluronic acid on cryopreserved boar sperm. AB - This study aimed to evaluate the effects of supplementing freezing and thawing media with hyaluronic acid (HA) on the quality parameters of frozen-thawed boar spermatozoa. Boar semen samples were collected from seven mature Yorkshire boars once a week using the gloved hand technique; these samples were frozen-thawed in the extender with added HA. Boar sperm was cryopreserved in the extender with HA added at concentrations of 0 (used as control), 4, 6, 8, 8 and 12mg/L, and their effects on the quality of frozen-thawed boar sperm were evaluated. HA addition to the extender significantly improved sperm motility, sperm membrane integrity, mitochondrial activity, acrosomal integrity, superoxide dismutase and catalase activity, but decreased sperm malondialdehyde level (p<0.05). Therefore, HA could be a promising cryoprotectant for boar sperm. PMID- 26944661 TI - Structural features of immunostimulatory polysaccharide purified from pectinase hydrolysate of barley leaf. AB - Four polysaccharide fractions were isolated from young barley leaves treated with or without pectinase followed by ethanol fractionation. Among the polysaccharide fractions, BLE-P isolated from pectinase digested with a high molecular weight had the most enhanced macrophage stimulatory activity, indicating that pectinase digestion of barley leaf is a useful method for enhancement of its activity. BLE P was further purified by column chromatography to identify the chemical and structural properties. BLE-P-I eluted in void volume fraction showed potent macrophage stimulatory activity. Monosaccharide composition and linkage analysis indicated that at least three kinds of polysaccharide, that is, glucuronoarabinoxylan (GAX; 40-45%), rhamnogalacturonan-I (RG-I) with branching mainly involving a type II arabinogalactan (AG-II) side chain (30-35%), and linear glucan such as starch and cellulose (less than 10%) coexisted in BLE-P-I. Given the association with macrophage stimulatory activity, it is likely that the GAX and to the RG-I polysaccharide branched with an AG-II side chain may be important for expression of the activity in barley leaf. PMID- 26944662 TI - Aqueous Co(II) adsorption using 8-hydroxyquinoline anchored gamma-Fe2O3@chitosan with Co(II) as imprinted ions. AB - A novel, bio-based 8-hydroxyquinoline (8-HQ) anchored magnetic chitosan using Co(II) as imprinted ions was prepared and applied for selective removal of Co(II) from aqueous solutions. At first, gamma-Fe2O3 has been synthesized by solvent free precipitation route and then combined with 8-hydroxyquinoline anchored chitosan using epichlorohydrin (EPH) as crosslinking agent. The FT- IR spectra showed that 8-HQ has been successfully anchored onto chitosan structure. Moreover, TEM analysis confirmed that the nanocomposite has core-shell structure. The experimental results showed that equilibrium time was 10min moreover, the maximum adsorption capacity of Co(II) with non-imprinted and surface imprinted polymer at pH 8 were 66.6 and 100mgg(-1), respectively. The selectivity coefficient of Co(II) ions relative to Cd(II), Ni(II) and Pb(II) were 11, 42 and 2, respectively. Prepared biosorbent represented good stability and good repeatability after three cycle of sorption and desorption using 0.5molL-(1) of HNO3 as eluent. Kinetic and thermodynamic behavior were also investigated and result showed that cobalt adsorption followed second order model and endothermic path. PMID- 26944663 TI - Constructing a novel zwitterionic surface of PVDF membrane through the assembled chitosan and sodium alginate. AB - A novel zwitterionic surface of PVDF membrane with significantly improved antifouling properties was prepared though pressure-assisted layer by layer self assembly method based on the electrostatic interactions of chitosan (CS), sodium alginate (SA) and polyfunctional lysine. For the modified C-S-C-S-L membrane, the contact angle decreased to 35 degrees , the bovine serum albumin (BSA) adsorption mass of static fouling on the membrane surface decreased to 10MUg/cm(2), and the secondary water flux recovery rate (FRR) of dynamic fouling of BSA and humic acid (HA) pollutants increased to 98% and 99%, respectively, exhibiting excellent antifouling performance. The results demonstrated that using charged bio macromolecules and amino acids to build zwitterionic surface was effective and convenient to change the interface properties of the separation membrane through the pressure-assisted self-assembly modification method, and provided a new way for the industrial scale hydrophilic modification of hydrophobic porous membrane materials. PMID- 26944664 TI - Novel guar gum/Al2O3 nanocomposite as an effective photocatalyst for the degradation of malachite green dye. AB - Guar gum/Al2O3 (GG/AO) nanocomposite was prepared using simple and cost effective sol-gel method. This nanocomposite was characterized by several analytical techniques viz. scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray diffraction (XRD), thermal analysis (TGA/DTA), Fourier transform infrared spectroscopy (FTIR) and ultraviolet-visible spectroscopy (UV vis). The FTIR analysis confirmed that GG/AO composite material was formed. TEM images inferred the particle size in the range between 20 and 45nm. GG/AO nanocomposite exhibited good photocatalytic performance for malachite green (MG) dye (dye initial concentration 1.5*10(-5)M) degradation from aqueous phase. The adsorption followed by photocatalysis and coupled adsorption/photocatalysis reaction achieved about 80% and 90% degradation of MG dye under solar irradiation. Antibacterial test showed the excellent activity of GG/AO nanocomposite against Staphylococcus aureus. PMID- 26944665 TI - The crystal structure of Escherichia coli CsdE. AB - Sulfur incorporations both in the biosynthesis of sulfur-containing cofactors and in the sulfur-modifications of certain tRNAs are all mediated by the sulfur initially delivered from the cysteine desulfurases. Sulfur generated as persulfide from cysteine is transferred to the sulfur acceptor protein to further allow delivery to the required steps within an enzymatic process. CsdA which is one of the three cysteine desulfurases identified in Escherichia coli transfers sulfur to the non Fe-S sulfur-acceptor CsdE, however, the consequence of CsdE accepted sulfur is mostly unknown. In this study, we report the 2.4A structure of free CsdE determined using X-ray crystallography, and compare the structure with the CsdE structure determined using NMR and also CsdE within the crystal CsdA CsdE complex. Further analysis suggests that the positive electrostatic potential surfaces of CsdE may mediate interaction with a yet unidentified protein or possibly tRNA to deliver sulfur. PMID- 26944666 TI - High prevalence of Mycobacterium tuberculosis mixed infection in the capital of moderate tuberculosis incidence country. AB - OBJECTIVE: Recent studies using molecular epidemiological techniques have demonstrated mixed infection with multiple strains of Mycobacterium tuberculosis especially in countries with high tuberculosis (TB) burden. We aimed to determine the prevalence of mixed infection among patients with TB in the capital of Iran as a country with moderate incidence rate. METHODS: Samples were collected randomly from January 2011 to December 2013 in Tehran, capital of Iran. A total of 75 M. tuberculosis isolates were genotyped by 24 loci mycobacterial interspersed repetitive unit-variable number tandem repeat typing (MIRU-VNTR) for screening the mixed infection. RESULTS: Twenty patients (20/75) were identified with mixed infection, and the estimated rate of mixed infection was 26.6%. Thirteen out of the 24 loci were able to detect the mixed infection in our study. CONCLUSIONS: Mixed infections occur at high prevalence among studied Iranian TB patients. Further research is inevitable to evaluate the association of mixed infection and disease progression and treatment. PMID- 26944667 TI - Radiographic Evidence of Hip Microinstability in Elite Ballet. AB - PURPOSE: To determine prevalence, magnitude, and predisposing radiographic features of hip subluxation in elite ballet dancers. METHODS: A cross-sectional investigation of professional male and female ballet dancers was performed using 5 plain radiographs. A "splits" anteroposterior (AP) radiograph was performed with legs abducted parallel to the trunk in the coronal plane (splits position; grand ecart facial). Hip center position (HCP) was measured on standing AP pelvis and AP pelvis splits views and the difference calculated (subluxation distance) to determine prevalence and magnitude of femoral head subluxation. Student t test compared HCP on AP pelvis and splits radiographs. Pearson correlations were used to correlate splits HCP with radiographic measures of femoroacetabular impingement and dysplasia. RESULTS: Analyzing 47 dancers (21 men, 26 women; 23.8 +/- 5.4 years), mean HCP on standing AP pelvis was 9.39 +/- 3.33 mm versus 10.8 +/- 2.92 mm on splits radiograph, with mean subluxation distance of 1.41 mm (P = .035). Forty-two dancers' femoral heads translated laterally with splits positioning, and 17 dancers (36%) exhibited a "vacuum sign" (bilateral in 71% of subjects with at least 1 hip vacuum sign). There was strong positive correlation (r = 0.461, P = .001) with splits HCP and alpha angle (Dunn 45 degrees ), and moderate negative correlation (r = -0.332, P = .022) with subluxation distance and neck-shaft angle. In men, splits HCP increased as lateral center edge angle (CEA) decreased (r = -0.437, P = .047), as anterior CEA decreased (r = -0.482, P = .027), as Tonnis angle increased (r = 0.656, P = .001), and as femoral head extrusion index increased (r = 0.511, P = .018). In women, there was moderate negative correlation (r = -0.389, P = .049) with subluxation distance and neck shaft angle. CONCLUSIONS: Hip subluxation occurs during splits in most professional ballet dancers, with a significantly greater magnitude of subluxation in women than men. Subluxation magnitude increases with increasing alpha angle and decreasing neck-shaft angle. In men, the magnitude increases with severity of dysplasia. Women had subluxation regardless of acetabular morphology but increased subluxation with decreased neck-shaft angle. This provides radiographic support for hip microinstability in elite ballet. LEVEL OF EVIDENCE: Level IV, diagnostic. PMID- 26944668 TI - Biomechanical Performance of Hip Labral Repair Techniques. AB - PURPOSE: To determine the strength of various suture techniques and the impact of suture passer size on cyclically loaded hip labra. METHODS: We assigned 63 bovine hip labra to 9 simple knotless suture technique groups using OrthoCord suture: (1) penetrating grasper (2.6 mm)-placed horizontal mattress, (2) penetrating grasper-placed vertical mattress, (3) SutureLasso (1.8 mm)-placed vertical mattress, (4) penetrating grasper-placed oblique repair, (5) penetrating grasper placed vertical mattress plus radiofrequency, (6) SutureLasso-placed horizontal mattress, (7) SutureLasso-placed oblique mattress, (8) SutureLasso-placed horizontal mattress plus radiofrequency, and (9) SutureLasso-placed oblique mattress plus radiofrequency. After 20 cycles of uniaxial tensile loading (5 to 80 N), destructive testing was performed. RESULTS: Penetrating grasper-placed horizontal mattress sutures showed lower ultimate failure loads than vertical and oblique mattress sutures (P < .05). Penetrating grasper-placed vertical mattress sutures had higher peak-to-peak displacement than SutureLasso-placed vertical mattress sutures (P = .04). SutureLasso-placed oblique mattress sutures had a higher ultimate load (P < .01) and stiffness (P = .04) than SutureLasso-placed horizontal mattress sutures. SutureLasso-placed horizontal mattress sutures had lower cyclic elongation than penetrating grasper-placed horizontal mattress sutures (P = .01) and lower ultimate load (P < .01) and stiffness than SutureLasso-placed vertical mattress sutures (P < .01). Horizontal mattress sutures with radiofrequency had a higher ultimate load (P = .02), stiffness, and cyclic elongation (P < .01) than without radiofrequency. CONCLUSIONS: A horizontal mattress hip labrum stitch shows a lower ultimate failure load than vertical or oblique mattress stitches. Smaller-diameter suture-passing devices show less cyclic displacement and elongation than larger-diameter devices. Radiofrequency labral treatment does not alter vertical stitch strength but does alter horizontal mattress stitch strength. CLINICAL RELEVANCE: Vertical and oblique stitches are stronger than horizontal stitches. A 1.8-mm passing device shows a better cyclic loading performance than a 2.6-mm device. PMID- 26944669 TI - Early Cartilage Changes After Anterior Cruciate Ligament Injury: Evaluation With Imaging and Serum Biomarkers-A Pilot Study. AB - PURPOSE: To determine if magnetic resonance imaging markers of cartilage matrix and morphology and circulating serum biomarkers of inflammation and matrix degradation differ over time in patients with anterior cruciate ligament (ACL) injury and bone marrow edema lesions (BMELs) when compared with matched control subjects. METHODS: We performed a case-control study, in which 11 ACL-injured subjects scheduled to undergo reconstruction and 11 matched control subjects were scheduled for testing. Participants were selected for the ACL reconstruction (ACLR) group if they injured their ACL while participating in sports, were aged 14 to 30 years, had 1 or more BMELs, and were scheduled to undergo bone-patellar tendon-bone ACLR. Testing required patients to undergo magnetic resonance imaging for measurement of T2 relaxation times in standardized regions of interest over the medial and lateral tibial plateaus and femoral condyles and have blood drawn for measurement of cartilage oligomeric matrix protein (COMP) and C-reactive protein levels before ligament reconstruction and 1 year after surgery. RESULTS: ACL patients had prolonged T2 relaxation times, indicative of cartilage matrix degradation, in the superficial central lateral tibial plateau (P = .02) and deep medial tibial plateau when compared with control subjects (P = .0001). Prolonged T2 relaxation times were also noted over the lateral femoral condyle at baseline for ACL patients compared with control subjects (P = .001), but the differences resolved by 1 year (P = .98). Circulating serum COMP levels were greater in ACL patients (233.23 +/- 88.26 ng/mL) compared with control subjects (169.05 +/- 64.53 ng/mL, P = .05). CONCLUSIONS: T2 mapping showed prolonged relaxation times in the lateral compartment of the knee in ACLR patients with lateral BMELs. Furthermore, prolonged T2 relaxation times were apparent in the medial compartment of the knee in ACL-injured patients where bone marrow lesions were not present. Higher serum COMP levels were present in ACL-injured subjects when compared with control subjects. LEVEL OF EVIDENCE: Level II, prospective case control study. PMID- 26944670 TI - Comment on: Post-transplant lymphoproliferative disease in heart and lung transplantation: Defining risk and prognostic factors. PMID- 26944671 TI - Treatment of hepatitis C in a lung transplant recipient with sofosbuvir and daclatasvir. PMID- 26944672 TI - Serotonergic agents increase the incidence of gastrointestinal bleeds in patients with continuous-flow left ventricular assist devices. PMID- 26944673 TI - HeartMate 3 implantation via left lateral thoracotomy with outflow graft anastomosis to the descending aorta. PMID- 26944674 TI - Making choices-how stochastic decisions determine disease progression. AB - In this issue of Genes & Development, Ginart and colleagues (pp. 567-578) study a mouse model for Russell-Silver syndrome (RSS) and show that similar cells within one individual can display distinct gene expression patterns because of epigenetic marks that are established stochastically during early development. Their results provide an excellent explanation for phenotypes seen in RSS and other imprinting disorders and especially help us understand how patients with similar or even identical genetic mutations can display distinct disease profiles. PMID- 26944675 TI - Coupling pre-mRNA splicing and 3' end formation to mRNA export: alternative ways to punch the nuclear export clock. AB - How does a mammalian cell determine when newly synthesized mRNAs are fully processed and appropriate for nuclear export? Muller-McNicoll and colleagues (pp. 553-566) expand on mechanisms known to be mediated by nuclear export factor 1 (NXF1) by describing SR proteins as NXF1 adaptors that flag alternatively spliced and polyadenylated mRNA isoforms as cargo ready for the cytoplasm. PMID- 26944677 TI - betalinc1 encodes a long noncoding RNA that regulates islet beta-cell formation and function. AB - Pancreatic beta cells are responsible for maintaining glucose homeostasis; their absence or malfunction results in diabetes mellitus. Although there is evidence that long noncoding RNAs (lncRNAs) play important roles in development and disease, none have been investigated in vivo in the context of pancreas development. In this study, we demonstrate that betalinc1 (beta-cell long intergenic noncoding RNA 1), a conserved lncRNA, is necessary for the specification and function of insulin-producing beta cells through the coordinated regulation of a number of islet-specific transcription factors located in the genomic vicinity of betalinc1. Furthermore, deletion of betalinc1 results in defective islet development and disruption of glucose homeostasis in adult mice. PMID- 26944676 TI - Mechanisms of metabolic dysfunction in cancer-associated cachexia. AB - Metabolic dysfunction contributes to the clinical deterioration observed in advanced cancer patients and is characterized by weight loss, skeletal muscle wasting, and atrophy of the adipose tissue. This systemic syndrome, termed cancer associated cachexia (CAC), is a major cause of morbidity and mortality. While once attributed solely to decreased food intake, the present description of cancer cachexia is a disorder of multiorgan energy imbalance. Here we review the molecules and pathways responsible for metabolic dysfunction in CAC and the ideas that led to the current understanding. PMID- 26944678 TI - UTX inhibition as selective epigenetic therapy against TAL1-driven T-cell acute lymphoblastic leukemia. AB - T-cell acute lymphoblastic leukemia (T-ALL) is a heterogeneous group of hematological tumors composed of distinct subtypes that vary in their genetic abnormalities, gene expression signatures, and prognoses. However, it remains unclear whether T-ALL subtypes differ at the functional level, and, as such, T ALL treatments are uniformly applied across subtypes, leading to variable responses between patients. Here we reveal the existence of a subtype-specific epigenetic vulnerability in T-ALL by which a particular subgroup of T-ALL characterized by expression of the oncogenic transcription factor TAL1 is uniquely sensitive to variations in the dosage and activity of the histone 3 Lys27 (H3K27) demethylase UTX/KDM6A. Specifically, we identify UTX as a coactivator of TAL1 and show that it acts as a major regulator of the TAL1 leukemic gene expression program. Furthermore, we demonstrate that UTX, previously described as a tumor suppressor in T-ALL, is in fact a pro-oncogenic cofactor essential for leukemia maintenance in TAL1-positive (but not TAL1 negative) T-ALL. Exploiting this subtype-specific epigenetic vulnerability, we propose a novel therapeutic approach based on UTX inhibition through in vivo administration of an H3K27 demethylase inhibitor that efficiently kills TAL1 positive primary human leukemia. These findings provide the first opportunity to develop personalized epigenetic therapy for T-ALL patients. PMID- 26944679 TI - AMPK governs lineage specification through Tfeb-dependent regulation of lysosomes. AB - Faithful execution of developmental programs relies on the acquisition of unique cell identities from pluripotent progenitors, a process governed by combinatorial inputs from numerous signaling cascades that ultimately dictate lineage-specific transcriptional outputs. Despite growing evidence that metabolism is integrated with many molecular networks, how pathways that control energy homeostasis may affect cell fate decisions is largely unknown. Here, we show that AMP-activated protein kinase (AMPK), a central metabolic regulator, plays critical roles in lineage specification. Although AMPK-deficient embryonic stem cells (ESCs) were normal in the pluripotent state, these cells displayed profound defects upon differentiation, failing to generate chimeric embryos and preferentially adopting an ectodermal fate at the expense of the endoderm during embryoid body (EB) formation. AMPK(-/-) EBs exhibited reduced levels of Tfeb, a master transcriptional regulator of lysosomes, leading to diminished endolysosomal function. Remarkably, genetic loss of Tfeb also yielded endodermal defects, while AMPK-null ESCs overexpressing this transcription factor normalized their differential potential, revealing an intimate connection between Tfeb/lysosomes and germ layer specification. The compromised endolysosomal system resulting from AMPK or Tfeb inactivation blunted Wnt signaling, while up-regulating this pathway restored expression of endodermal markers. Collectively, these results uncover the AMPK pathway as a novel regulator of cell fate determination during differentiation. PMID- 26944680 TI - SR proteins are NXF1 adaptors that link alternative RNA processing to mRNA export. AB - Nuclear export factor 1 (NXF1) exports mRNA to the cytoplasm after recruitment to mRNA by specific adaptor proteins. How and why cells use numerous different export adaptors is poorly understood. Here we critically evaluate members of the SR protein family (SRSF1-7) for their potential to act as NXF1 adaptors that couple pre-mRNA processing to mRNA export. Consistent with this proposal, >1000 endogenous mRNAs required individual SR proteins for nuclear export in vivo. To address the mechanism, transcriptome-wide RNA-binding profiles of NXF1 and SRSF1 7 were determined in parallel by individual-nucleotide-resolution UV cross linking and immunoprecipitation (iCLIP). Quantitative comparisons of RNA-binding sites showed that NXF1 and SR proteins bind mRNA targets at adjacent sites, indicative of cobinding. SRSF3 emerged as the most potent NXF1 adaptor, conferring sequence specificity to RNA binding by NXF1 in last exons. Interestingly, SRSF3 and SRSF7 were shown to bind different sites in last exons and regulate 3' untranslated region length in an opposing manner. Both SRSF3 and SRSF7 promoted NXF1 recruitment to mRNA. Thus, SRSF3 and SRSF7 couple alternative splicing and polyadenylation to NXF1-mediated mRNA export, thereby controlling the cytoplasmic abundance of transcripts with alternative 3' ends. PMID- 26944683 TI - Combine body mass index and body fat percentage measures to improve the accuracy of obesity screening in young adults. AB - INTRODUCTION: Obesity screening among young adult groups is meaningful. Body mass index (BMI) is limited to discriminate between fat and lean mass. Asian young adult group tends to have lower BMI and higher body fat percentage (BFP) than other ethnic groups. Accuracy of obesity screening by commonly used BMI criteria is unclear in young Taiwanese population. MATERIAL AND METHODS: A total of 894 young adults (447 males and 447 females) aged 20-26 were recruited. BMI, regional fat percentage and BFP determined by bioelectrical impedance analysis (BIA) were measured. BMI cutoff points were based on the criteria adopted by the Ministry of Health and Welfare in Taiwan. Cutoff points of low or high BFP were defined as 24% in men and 31.4% in women. RESULTS: Prevalence of BFP defining obesity was 14.8% in young men and 27.3% in young women. 23.2% of young men and only 8.3% of young women were classified to overweight or obesity categories according to the BMI criteria. Disagreement was noticed mainly among overweight males and normal weight females. 68.7% of BMI defining overweight young men had low BFP; however, 29.7% of young women of BMI defining normal group had high BFP. Up to 69.7% of young women with high BFP would be missed by BMI category only. CONCLUSION: Disagreement between BMI and BFP was significant among young adults, especially young women. We suggest combining BMI and BIA for obesity and overweight screening in Asian young adults. PMID- 26944685 TI - Tobacco-free but not tobacco industry free. PMID- 26944681 TI - Visualizing allele-specific expression in single cells reveals epigenetic mosaicism in an H19 loss-of-imprinting mutant. AB - Imprinting is a classic mammalian epigenetic phenomenon that results in expression from a single parental allele. Imprinting defects can lead to inappropriate expression from the normally silenced allele, but it remains unclear whether every cell in a mutant organism follows the population average, which would have profound implications for human imprinting disorders. Here, we apply a new fluorescence in situ hybridization method that measures allele specific expression in single cells to address this question in mutants exhibiting aberrant H19/Igf2 (insulin-like growth factor 2) imprinting. We show that mutant primary embryonic mouse fibroblasts are comprised of two subpopulations: one expressing both H19 alleles and another expressing only the maternal copy. Only in the latter cell population is Igf2 expression detected. Furthermore, the two subpopulations are stable in that cells do not interconvert between the two expression patterns. Combined small input methylation analysis and transcriptional imaging revealed that these two mutant subpopulations exhibit distinct methylation patterns at their imprinting control regions. Consistently, pharmacological inhibition of DNA methylation reduced the proportion of monoallelic cells. Importantly, we observed that the same two subpopulations are also present in vivo within murine cardiac tissue. Our results establish that imprinting disorders can display striking single-cell heterogeneity in their molecular phenotypes and suggest that such heterogeneity may underlie epigenetic mosaicism in human imprinting disorders. PMID- 26944684 TI - Does Need for Cognition Have the Same Meaning at Different Ages? AB - Determining whether Need for Cognition (NC) has the same meaning across age may help understand why there are dramatically different age trends for cognitive abilities and for NC in adulthood. Data from 5,004 participants aged between 18 and 99 years were used to examine both internal relations and external relations of NC. Internal relations were investigated with measures of reliability, examination of factor invariance, and test-retest coefficients across three age groups. External relations were investigated by examining relations of NC with cognitive abilities, engagement, personality, self-rated cognition, and affect. Results suggest that NC may be a broad construct that could reflect motivation to seek out intellectual challenge. In addition, examination of both internal and external relations of NC indicated that the meaning of the construct may be the same across the life span. Finally, the current article showed that the strongest predictor of NC was Openness to Experience, at any age. PMID- 26944682 TI - Diverse and pervasive subcellular distributions for both coding and long noncoding RNAs. AB - In a previous analysis of 2300 mRNAs via whole-mount fluorescent in situ hybridization in cellularizing Drosophila embryos, we found that 70% of the transcripts exhibited some form of subcellular localization. To see whether this prevalence is unique to early Drosophila embryos, we examined ~8000 transcripts over the full course of embryogenesis and ~800 transcripts in late third instar larval tissues. The numbers and varieties of new subcellular localization patterns are both striking and revealing. In the much larger cells of the third instar larva, virtually all transcripts observed showed subcellular localization in at least one tissue. We also examined the prevalence and variety of localization mechanisms for >100 long noncoding RNAs. All of these were also found to be expressed and subcellularly localized. Thus, subcellular RNA localization appears to be the norm rather than the exception for both coding and noncoding RNAs. These results, which have been annotated and made available on a recompiled database, provide a rich and unique resource for functional gene analyses, some examples of which are provided. PMID- 26944686 TI - Qualitative study of Singaporean youths' perception of antismoking campaigns: what works and what does not. AB - BACKGROUND: Youths are more likely to rebel against messages perceived to inhibit their independence. In order for antismoking campaigns to be effective with this population, adopting evidence-based strategies is crucial. In this study, we examined youths' reaction to past and ongoing antismoking campaigns, and delineate effective and ineffective components of campaigns as identified by them. METHODS: 12 focus group discussions were conducted with 91 youth smokers aged 15-29 years. Data were analysed using qualitative content analysis. A codebook was derived through an iterative process. The data were coded systematically by three coders, using Nvivo V.10. RESULTS: Fear appeals that had no immediate relevance to youths, and campaigns involving humour or sports/dance activities that distracted youths from the antismoking messages, were deemed ineffective. In contrast, elements identified to be efficacious were: positive tone, low-fear visual images, 'low-controlling language' and a genuine spokesperson. Youth tended to favour campaigns circulating on social media platforms. Importantly, youths voiced a lack of tangible support for their efforts to quit smoking. CONCLUSIONS: Participants expressed a preference towards antismoking messages that were less authoritative, and perceived a distinct lack of support for their intentions to quit smoking. There is room for incorporating suggestions by participants in future antismoking campaigns. Future research is needed to identify barriers to accessing available support. PMID- 26944687 TI - How accurately can subject-specific finite element models predict strains and strength of human femora? Investigation using full-field measurements. AB - Subject-specific finite element models have been proposed as a tool to improve fracture risk assessment in individuals. A thorough laboratory validation against experimental data is required before introducing such models in clinical practice. Results from digital image correlation can provide full-field strain distribution over the specimen surface during in vitro test, instead of at a few pre-defined locations as with strain gauges. The aim of this study was to validate finite element models of human femora against experimental data from three cadaver femora, both in terms of femoral strength and of the full-field strain distribution collected with digital image correlation. The results showed a high accuracy between predicted and measured principal strains (R(2)=0.93, RMSE=10%, 1600 validated data points per specimen). Femoral strength was predicted using a rate dependent material model with specific strain limit values for yield and failure. This provided an accurate prediction (<2% error) for two out of three specimens. In the third specimen, an accidental change in the boundary conditions occurred during the experiment, which compromised the femoral strength validation. The achieved strain accuracy was comparable to that obtained in state-of-the-art studies which validated their prediction accuracy against 10 16 strain gauge measurements. Fracture force was accurately predicted, with the predicted failure location being very close to the experimental fracture rim. Despite the low sample size and the single loading condition tested, the present combined numerical-experimental method showed that finite element models can predict femoral strength by providing a thorough description of the local bone mechanical response. PMID- 26944688 TI - Sensory enhancing insoles improve athletic performance during a hexagonal agility task. AB - Athletes incorporate afferent signals from the mechanoreceptors of their plantar feet to provide information about posture, stability, and joint position. Sub threshold stochastic resonance (SR) sensory enhancing insoles have been shown to improve balance and proprioception in young and elderly participant populations. Balance and proprioception are correlated with improved athletic performance, such as agility. Agility is defined as the ability to quickly change direction. An athlete's agility is commonly evaluated during athletic performance testing to assess their ability to participate in a competitive sporting event. Therefore, the purpose of this study was to examine the effects of SR insoles during a hexagonal agility task routinely used by coaches and sports scientists. Twenty recreational athletes were recruited to participate in this study. Each athlete was asked to perform a set of hexagonal agility trials while SR stimulation was either on or off. Vicon motion capture was used to measure feet position during six successful trials for each stimulation condition. Stimulation condition was randomized in a pairwise fashion. The study outcome measures were the task completion time and the positional accuracy of footfalls. Pairwise comparisons revealed a 0.12s decrease in task completion time (p=0.02) with no change in hopping accuracy (p=0.99) when SR stimulation was on. This is the first study to show athletic performance benefits while wearing proprioception and balance improving equipment on healthy participants. With further development, a self contained sensory enhancing insole device could be used by recreational and professional athletes to improve movements that require rapid changes in direction. PMID- 26944689 TI - Determination of the mechanical and physical properties of cartilage by coupling poroelastic-based finite element models of indentation with artificial neural networks. AB - One of the most widely used techniques to determine the mechanical properties of cartilage is based on indentation tests and interpretation of the obtained force time or displacement-time data. In the current computational approaches, one needs to simulate the indentation test with finite element models and use an optimization algorithm to estimate the mechanical properties of cartilage. The modeling procedure is cumbersome, and the simulations need to be repeated for every new experiment. For the first time, we propose a method for fast and accurate estimation of the mechanical and physical properties of cartilage as a poroelastic material with the aid of artificial neural networks. In our study, we used finite element models to simulate the indentation for poroelastic materials with wide combinations of mechanical and physical properties. The obtained force time curves are then divided into three parts: the first two parts of the data is used for training and validation of an artificial neural network, while the third part is used for testing the trained network. The trained neural network receives the force-time curves as the input and provides the properties of cartilage as the output. We observed that the trained network could accurately predict the properties of cartilage within the range of properties for which it was trained. The mechanical and physical properties of cartilage could therefore be estimated very fast, since no additional finite element modeling is required once the neural network is trained. The robustness of the trained artificial neural network in determining the properties of cartilage based on noisy force-time data was assessed by introducing noise to the simulated force-time data. We found that the training procedure could be optimized so as to maximize the robustness of the neural network against noisy force-time data. PMID- 26944690 TI - Effects of follower load and rib cage on intervertebral disc pressure and sagittal plane curvature in static tests of cadaveric thoracic spines. AB - The clinical relevance of mechanical testing studies of cadaveric human thoracic spines could be enhanced by using follower preload techniques, by including the intact rib cage, and by measuring thoracic intervertebral disc pressures, but studies to date have not incorporated all of these components simultaneously. Thus, this study aimed to implement a follower preload in the thoracic spine with intact rib cage, and examine the effects of follower load, rib cage stiffening and rib cage removal on intervertebral disc pressures and sagittal plane curvatures in unconstrained static conditions. Intervertebral disc pressures increased linearly with follower load magnitude. The effect of the rib cage on disc pressures in static conditions remains unclear because testing order likely confounded the results. Disc pressures compared well with previous reports in vitro, and comparison with in vivo values suggests the use of a follower load of about 400N to approximate loading in upright standing. Follower load had no effect on sagittal plane spine curvature overall, suggesting successful application of the technique, although increased flexion in the upper spine and reduced flexion in the lower spine suggest that the follower load path was not optimized. Rib cage stiffening and removal both increased overall spine flexion slightly, although with differing effects at specific spinal locations. Overall, the approaches demonstrated here will support the use of follower preloads, intact rib cage, and disc pressure measurements to enhance the clinical relevance of future studies of the thoracic spine. PMID- 26944691 TI - Elastic energy within the human plantar aponeurosis contributes to arch shortening during the push-off phase of running. AB - During locomotion, the lower limb tendons undergo stretch and recoil, functioning like springs that recycle energy with each step. Cadaveric testing has demonstrated that the arch of the foot operates in this capacity during simple loading, yet it remains unclear whether this function exists during locomotion. In this study, one of the arch's passive elastic tissues (the plantar aponeurosis; PA) was investigated to glean insights about it and the entire arch of the foot during running. Subject specific computer models of the foot were driven using the kinematics of eight subjects running at 3.1m/s using two initial contact patterns (rearfoot and non-rearfoot). These models were used to estimate PA strain, force, and elastic energy storage during the stance phase. To examine the release of stored energy, the foot joint moments, powers, and work created by the PA were computed. Mean elastic energy stored in the PA was 3.1+/-1.6J, which was comparable to in situ testing values. Changes to the initial contact pattern did not change elastic energy storage or late stance PA function, but did alter PA pre-tensioning and function during early stance. In both initial contact patterns conditions, the PA power was positive during late stance, which reveals that the release of the stored elastic energy assists with shortening of the arch during push-off. As the PA is just one of the arch's passive elastic tissues, the entire arch may store additional energy and impact the metabolic cost of running. PMID- 26944692 TI - Management of type 2 diabetes in China: the Happy Life Club, a pragmatic cluster randomised controlled trial using health coaches. AB - OBJECTIVE: To assess the effectiveness of a coach-led motivational interviewing (MI) intervention in improving glycaemic control, as well as clinical, psychosocial and self-care outcomes of individuals with type 2 diabetes mellitus (T2DM) compared with usual care. DESIGN: Pragmatic cluster randomised controlled trial (RCT). SETTING: Community Health Stations (CHSs) in Fengtai district, Beijing, China. PARTICIPANTS: Of the 41 randomised CHSs (21 intervention and 20 control), 21 intervention CHSs (372 participants) and 18 control CHSs (296 participants) started participation. INTERVENTION: Intervention participants received telephone and face-to-face MI health coaching in addition to usual care from their CHS. Control participants received usual care only. Medical fees were waived for both groups. OUTCOME MEASURES: Outcomes were assessed at baseline, 6 and 12 months. Primary outcome measure was glycated haemoglobin (HbA1c). Secondary outcomes included a suite of anthropometric, blood pressure (BP), fasting blood, psychosocial and self-care measures. RESULTS: At 12 months, no differential treatment effect was found for HbA1c (adjusted difference 0.02, 95% CI -0.40 to 0.44, p=0.929), with both treatment and control groups showing significant improvements. However, two secondary outcomes: psychological distress (adjusted difference -2.38, 95% CI -4.64 to -0.12, p=0.039) and systolic BP (adjusted difference -3.57, 95% CI -6.08 to -1.05, p=0.005) were robust outcomes consistent with significant differential treatment effects, as supported in sensitivity analyses. Interestingly, in addition to HbA1c, both groups displayed significant improvements in triglycerides, LDL cholesterol and HDL cholesterol. CONCLUSIONS: In line with the current Chinese primary healthcare reform, this study is the first large-scale cluster RCT to be implemented within real-world CHSs in China, specifically addressing T2DM. Although a differential treatment effect was not observed for HbA1c, numerous outcomes (including HbA1c) improved in both groups, supporting the establishment of regular, free clinical health checks for people with T2DM in China. TRIAL REGISTRATION NUMBER: ISRCTN01010526; Pre-results. PMID- 26944693 TI - Rationale, design and methodology of a trial evaluating three strategies designed to improve sedation quality in intensive care units (DESIST study). AB - OBJECTIVES: To describe the rationale, design and methodology for a trial of three novel interventions developed to improve sedation-analgesia quality in adult intensive care units (ICUs). PARTICIPANTS AND SETTING: 8 clusters, each a Scottish ICU. All mechanically ventilated sedated patients were potentially eligible for inclusion in data analysis. DESIGN: Cluster randomised design in 8 ICUs, with ICUs randomised after 45 weeks baseline data collection to implement one of four intervention combinations: a web-based educational programme (2 ICUs); education plus regular sedation quality feedback using process control charts (2 ICUs); education plus a novel sedation monitoring technology (2 ICUs); or all three interventions. ICUs measured sedation-analgesia quality, relevant drug use and clinical outcomes, during a 45-week preintervention and 45-week postintervention period separated by an 8-week implementation period. The intended sample size was >100 patients per site per study period. MAIN OUTCOME MEASURES: The primary outcome was the proportion of 12 h care periods with optimum sedation-analgesia, defined as the absence of agitation, unnecessary deep sedation, poor relaxation and poor ventilator synchronisation. Secondary outcomes were proportions of care periods with each of these four components of optimum sedation and rates of sedation-related adverse events. Sedative and analgesic drug use, and ICU and hospital outcomes were also measured. ANALYTIC APPROACH: Multilevel generalised linear regression mixed models will explore the effects of each intervention taking clustering into account, and adjusting for age, gender and APACHE II score. Sedation-analgesia quality outcomes will be explored at ICU level and individual patient level. A process evaluation using mixed methods including quantitative description of intervention implementation, focus groups and direct observation will provide explanatory information regarding any effects observed. CONCLUSIONS: The DESIST study uses a novel design to provide system level evaluation of three contrasting complex interventions on sedation-analgesia quality. Recruitment is complete and analysis ongoing. TRIAL REGISTRATION NUMBER: NCT01634451. PMID- 26944694 TI - Observational study of the effects of traumatic injury, haemorrhagic shock and resuscitation on the microcirculation: a protocol for the MICROSHOCK study. AB - INTRODUCTION: The microcirculation is the physiological site of oxygen and substrate exchange. Its effectiveness during circulatory shock is vital for the perfusion of tissues, and has a bearing on subsequent organ function and prognosis. Microcirculatory dysfunction following traumatic haemorrhagic shock (THS) has been understudied compared with other pathologies such as sepsis. The aim of the MICROSHOCK study is to investigate changes seen in the microcirculation of patients following THS, and to assess its response to resuscitation. A greater understanding of the behaviour and mechanisms of microcirculatory dysfunction in this context may direct future avenues of goal directed resuscitation for these patients. METHODS AND ANALYSIS: This multicentre prospective longitudinal observational study includes patients who present as an emergency with THS. Microcirculatory parameters are recorded using sublingual incident dark field microscopy alongside measurements of global flow (oesophageal Doppler and transthoracic echocardiography). Patients are enrolled into the study as soon as feasible after they arrive in hospital, and then at subsequent daily time points. Blood samples are taken for investigation into the mechanisms of microcirculatory dysfunction. Sequential Organ Failure Assessment scores will be analysed with microcirculatory parameters to determine whether they correlate with greater fidelity than more conventional, global circulatory parameters. ETHICS AND DISSEMINATION: Research Ethics Committee approval has been granted for this study (Reference: 14/YH/0078). Owing to the nature of THS, capacity for informed consent will be absent on patient enrolment. This will be addressed according to the Mental Health Capacity Act 2005. The physician in charge of the patient's care (nominated consultee) may consent on behalf of the patient. Consent will also be sought from a personal consultee (close relative or friend). After capacity is regained, the participant will be asked for their consent. Results will be submitted for publication in peer-reviewed journal format and presented at relevant academic meetings. TRIAL REGISTRATION NUMBER: NCT02111109; Pre-results. PMID- 26944695 TI - Neuroradiological features of cervical and cervicothoracic intraspinal subependymomas: a study of five cases. AB - AIM: To characterize the magnetic resonance imaging (MRI) findings in a series of five patients with cervical and cervicothoracic intraspinal subependymomas and to increase awareness of this neoplasm. MATERIALS AND METHODS: The clinical and radiological profiles of five patients who were diagnosed with subependymoma based on histopathological findings were retrospectively studied and compared with previously reported cases. All patients underwent enhanced MRI. RESULTS: One patient presented with a subependymoma of the cervical spine, one patient harboured a thoracic spinal subependymoma, and the other patients presented with cervicothoracic subependymomas. All lesions were hypointense on T1-weighted images and hyperintense on T2-weighted images. One lesion grew centrally, whereas the others demonstrated eccentricity. Partially faint enhancement was noted in four cases, and one case demonstrated multinodular moderate enhancement. CONCLUSION: Cervical and cervicothoracic intraspinal subependymomas can be distinguished on MRI images. Specifically, a faintly enhanced or non-enhanced heterogeneous intramedullary lesion that exhibits a slowly deteriorating clinical course may be indicative of a subependymoma. In such cases, resection is expected to yield favourable outcomes. PMID- 26944698 TI - Imaging of rare medullary adrenal tumours in adults. AB - Although adrenal medullary tumours are rare, they have important clinical implications. They form a heterogeneous group of tumours, ranging from benign, non-secretory, incidental masses to hormonally active tumours presenting acutely, or malignant tumours with disseminated disease and a poor prognosis. Increasingly, benign masses are incidentally detected due to the widespread use of imaging and routine medical check-ups. This review aims to illustrate the multimodality imaging appearances of rare adrenal medullary tumours, excluding the more common phaeochromocytomas, with clues to the diagnosis and to summarise relevant epidemiological and clinical data. Careful correlation of clinical presentation, hormone profile, and various imaging techniques narrow the differential diagnosis. Image-guided percutaneous adrenal biopsy can provide a definitive diagnosis, allowing for conservative management in selected cases. A close collaboration between the radiologist, endocrinologist, and surgeon is of the utmost importance in the management of these tumours. PMID- 26944697 TI - Heterogeneity of non-cancerous liver parenchyma on gadoxetic acid-enhanced MRI: an imaging biomarker for hepatocellular carcinoma development in chronic liver disease. AB - AIM: To clarify whether the heterogeneity of non-cancerous liver parenchyma (NLP) in the hepatobiliary phase on gadoxetic acid enhanced magnetic resonance imaging (MRI) is correlated with hepatocellular carcinoma (HCC) development. MATERIALS AND METHODS: Institutional review board approval was obtained, and the requirements for informed consent were waived for this retrospective study. The imaging characteristics of 84 patients with chronic liver disease who underwent gadoxetic acid-enhanced 3T MRI between January 2013 and October 2014 were examined retrospectively. For the evaluation of the heterogeneity of the intensity in the hepatobiliary phase, the largest possible region of interest was placed on the NLP, and the skewness and kurtosis were calculated using ImageJ software. Skewness is the degree of asymmetry of a histogram, and kurtosis is a measure of the peak. Based on the median values of kurtosis and skewness, the patients were classified into four categories and the categories were compared between the 49 patients with HCC (HCC group) and the 35 patients without HCC (non HCC group). RESULTS: Kurtosis was significantly higher in the HCC group compared to the non-HCC group (1.19+/-1.15 versus 0.43+/-0.83; p=0.0006). Skewness was significantly lower in the HCC group than in the non-HCC group (1.19+/-1.15 versus 0.43+/-0.83; p=0.0152). In a multivariate logistic analysis, the category showing lower-than-the-median (-0.1185) skewness and higher-than-the-median (0.547) kurtosis was significantly and independently associated with HCC development (p=0.0031). CONCLUSION: The heterogeneity of NLP in the hepatobiliary phase on gadoxetic acid enhanced MRI may reflect the development of HCC. PMID- 26944699 TI - Predictor of massive bleeding following stent placement for malignant oesophageal stricture/fistulae: a multicentre study. AB - AIM: To evaluate retrospectively the incidence and predictors of massive bleeding after stent placement for malignant oesophageal stricture/fistulae. MATERIALS AND METHODS: This retrospective study comprised 519 patients with malignant oesophageal stricture/fistulae that were successfully treated with stent placement at three hospitals. The patients were divided into two groups based on the occurrence of massive bleeding. Univariate and multivariate analysis was performed to evaluate predictive factors of massive bleeding. RESULTS: Massive bleeding occurred in 54 of 519 patients 1-37 days following stent placement. All of the patients who developed massive bleeding died within 24 hours of the event. Univariate analysis showed massive bleeding was associated with the presence of a concomitant tracheal stent (p<0.001), the existence of concomitant oesophageal fistulae (p<0.001), and prior radiotherapy (p<0.001). Multivariate analysis exhibited that concomitant tracheal stent insertion (odds ratio [OR], 23.134; 95% confidence interval [CI], 9.523-56.199; p<0.001), the presence of oesophageal fistulae (OR, 3.724; 95% CI, 1.677-8.269; p=0.001), and prior radiotherapy (OR, 13.310; 95% CI, 5.464-32.421; p<0.001) were predictors of massive bleeding following stenting. CONCLUSIONS: The presence of oesophageal fistulae, prior radiotherapy, and concomitant tracheal stent are important factors contributing to bleeding after stenting. PMID- 26944700 TI - Assessment of concentration, bioaccumulation and sources of polycyclic aromatic hydrocarbons in zooplankton of Chabahar Bay. AB - The amounts and sources of polycyclic aromatic hydrocarbons (PAHs) and their bioaccumulation factors (BAFs) in the zooplankton community of Chabahar Bay were investigated. The highest amounts of total PAHs (tPAHs) in the water and zooplankton samples were 62.2ngL(-1) and 1478.6ngg(-1) dry weights, in near the Shahid Beheshti Port and desalination, respectively. The greatest amount of BAF (51,780) was obtained in the entry of Bay, and it was related to the phenanthrene accumulation. Using molecular ratio, the results showed that the major input source of PAH compounds in zooplankton of Chabahar Bay was pyrolytic (fuel) source. PMID- 26944701 TI - "I have surly passed a limit, it is simply too much": women's and men's experiences of stress and wellbeing when living within a process of housework resignation. AB - BACKGROUND: Gender inequality within paid and unpaid work exposes women and men to different environments and responsibilities. These gender patterns shape living conditions for women and men, either negatively or positively, by affecting the prospect of good health. Most public health studies of gender and housework are quantitative, and knowledge about the relationship between housework experiences and health for women and men is limited. The aim of this study was to explore the housework experiences and practices of women and men and their experiences of stress and perceived wellbeing from a gender perspective. METHODS: We conducted thematic interviews with four women and four men living in Sweden, and performed an analysis using the Grounded Theory method. FINDINGS: We found that stereotypical gender practices in housework influenced experiences of stress and perceived wellbeing among women and men. Despite proposing gender equality in housework as a means of improving wellbeing, inequality was amplified by the way women and men handle the gendered division of housework. We call this recurring theme "The process of housework resignation", which also constitute the core category in our analysis. "The process of housework resignation" was theorised from the categories "Gender practices in housework", "Experiencing stress and wellbeing" and "Managing daily life". CONCLUSIONS: Stereotypical gender practices in housework can increase experiences of stress among women and men. Challenging stereotypical masculinities can be a key for breaking the process of resignation in housework and for facilitating improved health among both women and men in heterosexual couple relationships within a Swedish context. PMID- 26944696 TI - Advanced flow MRI: emerging techniques and applications. AB - Magnetic resonance imaging (MRI) techniques provide non-invasive and non-ionising methods for the highly accurate anatomical depiction of the heart and vessels throughout the cardiac cycle. In addition, the intrinsic sensitivity of MRI to motion offers the unique ability to acquire spatially registered blood flow simultaneously with the morphological data, within a single measurement. In clinical routine, flow MRI is typically accomplished using methods that resolve two spatial dimensions in individual planes and encode the time-resolved velocity in one principal direction, typically oriented perpendicular to the two dimensional (2D) section. This review describes recently developed advanced MRI flow techniques, which allow for more comprehensive evaluation of blood flow characteristics, such as real-time flow imaging, 2D multiple-venc phase contrast MRI, four-dimensional (4D) flow MRI, quantification of complex haemodynamic properties, and highly accelerated flow imaging. Emerging techniques and novel applications are explored. In addition, applications of these new techniques for the improved evaluation of cardiovascular (aorta, pulmonary arteries, congenital heart disease, atrial fibrillation, coronary arteries) as well as cerebrovascular disease (intra-cranial arteries and veins) are presented. PMID- 26944703 TI - Interdisciplinary approach for somatoprosthetic rehabilitation of a patient with clino-syndactyly and unusual dermatoglyphics. AB - BACKGROUND: Traumatic injuries are the most common cause of finger amputations. Therapeutic amputations are less common but may be essential in some patients with congenital malformations of digits. CASE DESCRIPTION AND METHODS: A 21-year old female patient reported for esthetic management of malformed middle and ring finger of right hand. Examination revealed clino-syndactyly with unusual dermatoglyphics. She was successfully rehabilitated by collaborative efforts of plastic surgeon and prosthodontist, by therapeutic amputation with surgical recontouring and fabrication of somatoprosthesis. FINDINGS AND OUTCOMES: The patient was satisfied with esthetics of the prosthesis and somatoprosthesis improved function. At 6-month recall, no alterations or repair of prosthesis was required. CONCLUSION: Individualized treatment planning with integration of modifications involving a multidisciplinary approach is required to meet needs of patients with congenital digital malformations. The duplication of unusual dermatoglyphics made the prosthesis more realistic. CLINICAL RELEVANCE: An individualized treatment plan with modifications to conventional techniques is required to cater to rehabilitative needs of patients with congenital digital malformations. PMID- 26944702 TI - Depletion of Abundant Sequences by Hybridization (DASH): using Cas9 to remove unwanted high-abundance species in sequencing libraries and molecular counting applications. AB - Next-generation sequencing has generated a need for a broadly applicable method to remove unwanted high-abundance species prior to sequencing. We introduce DASH (Depletion of Abundant Sequences by Hybridization). Sequencing libraries are 'DASHed' with recombinant Cas9 protein complexed with a library of guide RNAs targeting unwanted species for cleavage, thus preventing them from consuming sequencing space. We demonstrate a more than 99 % reduction of mitochondrial rRNA in HeLa cells, and enrichment of pathogen sequences in patient samples. We also demonstrate an application of DASH in cancer. This simple method can be adapted for any sample type and increases sequencing yield without additional cost. PMID- 26944704 TI - Life History Traits, Protein Evolution, and the Nearly Neutral Theory in Amniotes. AB - The nearly neutral theory of molecular evolution predicts that small populations should accumulate deleterious mutations at a faster rate than large populations. The analysis of nonsynonymous (dN) versus synonymous (dS) substitution rates in birds versus mammals, however, has provided contradictory results, questioning the generality of the nearly neutral theory. Here we analyzed the impact of life history traits, taken as proxies of the effective population size, on molecular evolutionary and population genetic processes in amniotes, including the so far neglected reptiles. We report a strong effect of species body mass, longevity, and age of sexual maturity on genome-wide patterns of polymorphism and divergence across the major groups of amniotes, in agreement with the nearly neutral theory. Our results indicate that the rate of protein evolution in amniotes is determined in the first place by the efficiency of purifying selection against deleterious mutations-and this is true of both radical and conservative amino acid changes. Interestingly, the among-species distribution of dN/dS in birds did not follow this general trend: dN/dS was not higher in large, long-lived than in small, short-lived species of birds. We show that this unexpected pattern is not due to a more narrow range of life history traits, a lack of correlation between traits and Ne, or a peculiar distribution of fitness effects of mutations in birds. Our analysis therefore highlights the bird dN/dS ratio as a molecular evolutionary paradox and a challenge for future research. PMID- 26944705 TI - An in vitro alveolar macrophage assay for predicting the short-term inhalation toxicity of nanomaterials. AB - BACKGROUND: Most in vitro studies investigating nanomaterial pulmonary toxicity poorly correlate to in vivo inhalation studies. Alveolar macrophages (AMs) play an outstanding role during inhalation exposure since they effectively clear the alveoli from particles. This study addresses the applicability of an in vitro alveolar macrophage assay to distinguish biologically active from passive nanomaterials. METHODS: Rat NR8383 alveolar macrophages were exposed to 18 inorganic nanomaterials, covering AlOOH, BaSO4, CeO2, Fe2O3, TiO2, ZrO2, and ZnO NMs, amorphous SiO2 and graphite nanoplatelets, and two nanosized organic pigments. ZrO2 and amorphous SiO2 were tested without and with surface functionalization. Non-nanosized quartz DQ12 and corundum were used as positive and negative controls, respectively. The test materials were incubated with the cells in protein-free culture medium. Lactate dehydrogenase, glucuronidase, and tumour necrosis factor alpha were assessed after 16 h. In parallel, H2O2 was assessed after 1.5 h. Using the no-observed-adverse-effect concentrations (NOAECs) from available rat short-term inhalation studies (STIS), the test materials were categorized as active (NOAEC < 10 mg/m(3)) or passive. RESULTS: In vitro data reflected the STIS categorization if a particle surface area-based threshold of <6000 mm(2)/mL was used to determine the biological relevance of the lowest observed significant in vitro effects. Significant effects that were recorded above this threshold were assessed as resulting from test material unspecific cellular 'overload'. Test materials were assessed as active if >=2 of the 4 in vitro parameters undercut this threshold. They were assessed as passive if 0 or 1 parameter was altered. An overall assay accuracy of 95 % was achieved. CONCLUSIONS: The in vitro NR8383 alveolar macrophage assay allows distinguishing active from passive nanomaterials. Thereby, it allows determining whether in vivo short-term inhalation testing is necessary for hazard assessment. Results may also be used to group nanomaterials by biological activity. Further work should aim at validating the assay. PMID- 26944706 TI - Unexpected perturbations training improves balance control and voluntary stepping times in older adults - a double blind randomized control trial. AB - BACKGROUND: Falls are common among elderly, most of them occur while slipping or tripping during walking. We aimed to explore whether a training program that incorporates unexpected loss of balance during walking able to improve risk factors for falls. METHODS: In a double-blind randomized controlled trial 53 community dwelling older adults (age 80.1+/-5.6 years), were recruited and randomly allocated to an intervention group (n = 27) or a control group (n = 26). The intervention group received 24 training sessions over 3 months that included unexpected perturbation of balance exercises during treadmill walking. The control group performed treadmill walking with no perturbations. The primary outcome measures were the voluntary step execution times, traditional postural sway parameters and Stabilogram-Diffusion Analysis. The secondary outcome measures were the fall efficacy Scale (FES), self-reported late life function (LLFDI), and Performance-Oriented Mobility Assessment (POMA). RESULTS: Compared to control, participation in intervention program that includes unexpected loss of balance during walking led to faster Voluntary Step Execution Times under single (p = 0.002; effect size [ES] =0.75) and dual task (p = 0.003; [ES] = 0.89) conditions; intervention group subjects showed improvement in Short-term Effective diffusion coefficients in the mediolateral direction of the Stabilogram Diffusion Analysis under eyes closed conditions (p = 0.012, [ES] = 0.92). Compared to control there were no significant changes in FES, LLFDI, and POMA. CONCLUSIONS: An intervention program that includes unexpected loss of balance during walking can improve voluntary stepping times and balance control, both previously reported as risk factors for falls. This however, did not transferred to a change self-reported function and FES. TRIAL REGISTRATION: ClinicalTrials.gov REGISTRATION NUMBER: NCT01439451 . PMID- 26944707 TI - Erratum to: Population attributable risks of modifiable reproductive factors for breast and ovarian cancers in Korea. PMID- 26944708 TI - Detection and Interpretation of Impossible and Improbable Coma Recovery Scale Revised Scores. AB - OBJECTIVE: To determine the frequency with which specific Coma Recovery Scale Revised (CRS-R) subscale scores co-occur as a means of providing clinicians and researchers with an empirical method of assessing CRS-R data quality. DESIGN: We retrospectively analyzed CRS-R subscale scores in hospital inpatients diagnosed with disorders of consciousness (DOCs) to identify impossible and improbable subscore combinations as a means of detecting inaccurate and unusual scores. Impossible subscore combinations were based on violations of CRS-R scoring guidelines. To determine improbable subscore combinations, we relied on the Mahalanobis distance, which detects outliers within a distribution of scores. Subscore pairs that were not observed at all in the database (ie, frequency of occurrence=0%) were also considered improbable. SETTING: Specialized DOC program and university hospital. PARTICIPANTS: Patients diagnosed with DOCs (N=1190; coma: n=76, vegetative state: n=464, minimally conscious state: n=586, emerged from minimally conscious state: n=64; 794 men; mean age, 43+/-20y; traumatic etiology: n=747; time postinjury, 162+/-568d). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: Impossible and improbable CRS-R subscore combinations. RESULTS: Of the 1190 CRS-R profiles analyzed, 4.7% were excluded because they met scoring criteria for impossible co-occurrence. Among the 1137 remaining profiles, 12.2% (41/336) of possible subscore combinations were classified as improbable. CONCLUSIONS: Clinicians and researchers should take steps to ensure the accuracy of CRS-R scores. To minimize the risk of diagnostic error and erroneous research findings, we have identified 9 impossible and 36 improbable CRS-R subscore combinations. The presence of any one of these subscore combinations should trigger additional data quality review. PMID- 26944709 TI - Validity of the Timed Up and Go Test as a Measure of Functional Mobility in Persons With Multiple Sclerosis. AB - OBJECTIVE: To examine the validity of the timed Up and Go (TUG) test as a measure of functional mobility in persons with multiple sclerosis (MS) by using a comprehensive framework based on construct validity (ie, convergent and divergent validity). DESIGN: Cross-sectional study. SETTING: Hospital setting. PARTICIPANTS: Community-residing persons with MS (N=47). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Main outcome measures included the TUG test, timed 25-foot walk test, 6-minute walk test, Multiple Sclerosis Walking Scale-12, Late-Life Function and Disability Instrument, posturography evaluation, Activities-specific Balance Confidence scale, Symbol Digits Modalities Test, Expanded Disability Status Scale, and the number of steps taken per day. RESULTS: The TUG test was strongly associated with other valid outcome measures of ambulatory mobility (Spearman rank correlation, rs=.71-.90) and disability status (rs=.80), moderately to strongly associated with balance confidence (rs=.66), and weakly associated with postural control (ie, balance) (rs=.31). The TUG test was moderately associated with cognitive processing speed (rs=.59), but not associated with other nonambulatory measures (ie, Late-Life Function and Disability Instrument-upper extremity function). CONCLUSIONS: Our findings support the validity of the TUG test as a measure of functional mobility. This warrants its inclusion in patients' assessment alongside other valid measures of functional mobility in both clinical and research practice in persons with MS. PMID- 26944710 TI - Rehabilitation Needs of Stroke Survivors After Discharge From Hospital in India. AB - OBJECTIVE: To assess the rehabilitation needs of stroke survivors in Chennai, India, after discharge from the hospital. DESIGN: Mixed-methods research design. SETTING: Home-based. PARTICIPANTS: Stroke survivors (n=50; mean age +/- SD, 58.9+/-10.5y) and primary caregivers of these stroke survivors (n=50; mean age +/ SD, 43.1+/-11.8y) took part in the quantitative survey. A subsample of stroke survivors (n=12), primary caregivers (n=10), and health care professionals (n=8) took part in the qualitative in-depth interviews. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: Rehabilitation needs after hospital discharge. RESULTS: About 82% of the needs expressed by stroke survivors and 92% of the needs expressed by caregivers indicated that they had a substantial need for information. The proportion of financial needs reported by the stroke survivors and the caregivers was 70% and 75%, respectively. The qualitative data revealed major gaps in access to stroke rehabilitation services. Service providers identified availability and affordability of services as key problems. Stroke survivors and their caregivers identified lack of information about stroke as major barriers to accessibility of stroke rehabilitation services. Caregivers expressed a tremendous need for support to manage family dynamics. CONCLUSIONS: The study highlights a considerable unmet need for poststroke rehabilitation services. Given the lack of rehabilitation resources in India, developing an accessible, innovative, patient-centered, culturally sensitive rehabilitation intervention is of public health importance. It is crucial for low- and middle income countries like India to develop technology-driven stroke rehabilitation strategies to meet the growing rehabilitation needs of stroke survivors. PMID- 26944711 TI - Universal varicella vaccine immunization in Japan. AB - In 1974, Japanese scientists developed a live attenuated varicella vaccine based on the Oka strain. The efficacy of the vaccine for the prevention of varicella has been primarily demonstrated in studies conducted in the United States following the adoption of universal immunization using the Oka strain varicella vaccine in 1996. Although the vaccine was developed by Japanese scientists, until recently, the vaccine has been administered on a voluntary basis in Japan resulting in a vaccine coverage rate of approximately 40%. Therefore, Japan initiated universal immunization using the Oka strain varicella vaccine in November 2014. Given the transition from voluntary to universal immunization in Japan, it will also be important to monitor the epidemiology of varicella and herpes zoster. The efficacy and safety of co-administration of the varicella vaccine and measles, mumps, and rubella vaccine have been demonstrated in many countries; however, there was no data from Japan. In order to adopt the practice of universal immunization using the Oka strain varicella vaccine in Japan, data demonstrating the efficacy and safety of co-administration of varicella vaccine and measles and rubella (MR) vaccine were required. Additionally, we needed to elucidate the appropriate time interval between the first and second administrations of the vaccine. It is also important to differentiate between wild type and Oka vaccine type strains in herpes zoster patient with past history of varicella vaccine. Thus, there are many factors to consider regarding the adoption of universal immunization in Japan to control varicella zoster virus (VZV) infections. PMID- 26944712 TI - The economic cost of measles: Healthcare, public health and societal costs of the 2012-13 outbreak in Merseyside, UK. AB - BACKGROUND: Measles is a highly contagious vaccine-preventable infection that caused large outbreaks in England in 2012 and 2013 in areas which failed to achieve herd protection levels (95%) consistently. We sought to quantify the economic costs associated with the 2012-13 Merseyside measles outbreak, relative to the cost of extending preventative vaccination to secure herd protection. METHODS: A costing model based on a critical literature review was developed. A workshop and interviews were held with key stakeholders in the Merseyside outbreak to understand the pathway of a measles case and then quantify healthcare activity and costs for the main NHS providers and public health team incurred during the initial four month period to May 2012. These data were used to model the total costs of the full outbreak to August 2013, comprising those to healthcare providers for patient treatment, public health and societal productivity losses. The modelled total cost of the full outbreak was compared to the cost of extending the preventative vaccination programme to achieve herd protection. FINDINGS: The Merseyside outbreak included 2458 reported cases. The estimated cost of the outbreak was L 4.4m (sensitivity analysis L 3.9 m to L 5.2m) comprising 15% (L 0.7 m) NHS patient treatment costs, 40% (L 1.8m) public health costs and 44% (L 2.0m) for societal productivity losses. In comparison, over the previous five years in Cheshire and Merseyside a further 11,793 MMR vaccinations would have been needed to achieve herd protection at an estimated cost of L 182,909 (4% of the total cost of the measles outbreak). INTERPRETATION: Failure to consistently reach MMR uptake levels of 95% across all localities and sectors (achieve herd protection) risks comparatively higher economic costs associated with the containment (including healthcare costs) and implementation of effective public health management of outbreaks. FUNDING: Commissioned by the Cheshire and Merseyside Public Health England Centre. PMID- 26944713 TI - Long term aspirin may reduce overall cancer risk. PMID- 26944714 TI - Non-Traditional Wives With Traditional Husbands: Gender Ideology and Husband-to Wife Physical Violence in Chinese Society. AB - Feminist scholars have argued that husband gender traditionalism is one of the root causes of spousal violence against women. Using couple-level data from Hong Kong (N = 871 couples), this article argues that a second mechanism-couple gender value mismatch-also explains husband-to-wife physical assault. Our findings show that a husband's gender traditionalism is positively associated with husband-to wife physical assault only when the husband is coupled with a wife who has non traditional gender attitudes. Similarly, egalitarian gender attitudes in wives are positively associated with husband-to-wife physical assault only when a non traditional wife is coupled with a traditional husband. PMID- 26944715 TI - Gender-Blind Sexism and Rape Myth Acceptance. AB - The purpose of this article is to explore whether gender-blind sexism, as an extension of Bonilla-Silva's racialized social system theory, is an appropriate theoretical framework for understanding the creation and continued prevalence of rape myth acceptance. Specifically, we hypothesize that individuals who hold attitudes consistent with the frames of gender-blind sexism are more likely to accept common rape myths. Data for this article come from an online survey administered to the entire undergraduate student body at a large Midwestern institution (N = 1,401). Regression analysis showed strong support for the effects of gender-blind sexism on rape myth acceptance. PMID- 26944717 TI - Comparative policy analysis for alcohol and drugs: Current state of the field. AB - BACKGROUND: A central policy research question concerns the extent to which specific policies produce certain effects - and cross-national (or between state/province) comparisons appear to be an ideal way to answer such a question. This paper explores the current state of comparative policy analysis (CPA) with respect to alcohol and drugs policies. METHODS: We created a database of journal articles published between 2010 and 2014 as the body of CPA work for analysis. We used this database of 57 articles to clarify, extract and analyse the ways in which CPA has been defined. Quantitative and qualitative analysis of the CPA methods employed, the policy areas that have been studied, and differences between alcohol CPA and drug CPA are explored. RESULTS: There is a lack of clear definition as to what counts as a CPA. The two criteria for a CPA (explicit study of a policy, and comparison across two or more geographic locations), exclude descriptive epidemiology and single state comparisons. With the strict definition, most CPAs were with reference to alcohol (42%), although the most common policy to be analysed was medical cannabis (23%). The vast majority of papers undertook quantitative data analysis, with a variety of advanced statistical methods. We identified five approaches to the policy specification: classification or categorical coding of policy as present or absent; the use of an index; implied policy differences; described policy difference and data-driven policy coding. Each of these has limitations, but perhaps the most common limitation was the inability for the method to account for the differences between policy-as-stated versus policy-as-implemented. CONCLUSION: There is significant diversity in CPA methods for analysis of alcohol and drugs policy, and some substantial challenges with the currently employed methods. The absence of clear boundaries to a definition of what counts as a 'comparative policy analysis' may account for the methodological plurality but also appears to stand in the way of advancing the techniques. PMID- 26944716 TI - Dietary vitamin C deficiency depresses the growth, head kidney and spleen immunity and structural integrity by regulating NF-kappaB, TOR, Nrf2, apoptosis and MLCK signaling in young grass carp (Ctenopharyngodon idella). AB - This study investigated the effects of dietary vitamin C on the growth, and head kidney, spleen and skin immunity, structural integrity and related signaling molecules mRNA expression levels of young grass carp (Ctenopharyngodon idella). A total of 540 grass carp (264.37 +/- 0.66 g) were fed six diets with graded levels of vitamin C (2.9, 44.2, 89.1, 133.8, 179.4 and 224.5 mg/kg diet) for 10 weeks. Subsequently, a challenge test was conducted by injection of Aeromonas hydrophila and the survival rate recorded for 14 days. The results indicated that compared with optimal vitamin C supplementation, vitamin C deficiency (2.9 mg/kg diet) decreased lysozyme (LA) and acid phosphatase (ACP) activities, and complement 3 and complement 4 (C4) contents (P < 0.05), down-regulated the mRNA levels of antimicrobial peptides [liver expressed antimicrobial peptide (LEAP) 2A, LEAP-2B, hepcidin, beta-defensin] and anti-inflammatory cytokines-related factors, interleukin (IL) 4/13A, IL-4/13B (only in head kidney), IL-10, IL-11, transforming growth factor (TGF) beta1, TGF-beta2, inhibitor of kappaBalpha and eIF4E-binding protein 1 (P < 0.05), and up-regulated pro-inflammatory cytokines related factors, tumor necrosis factor alpha, interferon gamma2, IL-1beta, IL-6, IL-8, IL-12 P35 (only in spleen), IL-12 P40, IL-15, IL-17D, nuclear factor kappaB p65, IkappaB kinases (IKKalpha, IKKbeta, IKKgamma), target of rapamycin and ribosomal protein S6 kinase 1 mRNA levels (P < 0.05) in the head kidney and spleen under injection fish of A. hydrophila, suggesting that vitamin C deficiency could decrease fish head kidney and spleen immunity and cause inflammation. Meanwhile, compared with optimal vitamin C supplementation, vitamin C deficiency decreased the activities and mRNA levels of copper/zinc superoxide dismutase, manganese superoxide dismutase (MnSOD), catalase, glutathione peroxidase, glutathione S-transferases and glutathione reductase (P < 0.05), and down-regulated zonula occludens (ZO) 1, ZO-2, Claudin-b, -c, -3c, -7a, -7b, B cell lymphoma-2, inhibitor of apoptosis protein, NF-E2-related factor 2 mRNA levels (P < 0.05), increased reactive oxygen species (ROS), malondialdehyde (MDA) and protein carbonyl contents (P < 0.05), and up-regulated Claudin-12, 15a, -15b, Fas ligand, mitogen-activated protein kinase kinase 6, p38 mitogen-activated protein kinase, B-cell lymphoma protein 2 associated X protein, apoptotic protease activating factor-1, caspase-3, -7, -8, -9, Kelch-like ECH-associating protein (Keap) 1a and Keap 1b mRNA levels (P < 0.05) in the head kidney and spleen under injection fish of A. hydrophila, suggesting that vitamin C deficiency could decrease fish head kidney and spleen structural integrity through depression of antioxidative ability, induction of apoptosis and disruption of tight junctional complexes. In addition, except the activities of ACP and MnSOD, and mRNA expression levels of TGF-beta1, Occludin and MnSOD, the effect of vitamin C on fish head kidney, spleen and skin immunity and structural integrity other indicators model are similar under infection of A. hydrophila. Finally, the vitamin C requirement for the growth performance (PWG) of young grass carp was estimated to be 92.8 mg/kg diet. Meanwhile, the vitamin C requirement for against skin lesion morbidity of young grass carp was estimated to be 122.9 mg/kg diet. In addition, based on the biochemical indices [immune indices (LA activity in the head kidney and C4 content in the spleen) and antioxidant indices (MDA content in the head kidney and ROS content in the spleen)] the vitamin C requirements for young grass carp were estimated to be 131.2, 137.5, 135.8 and 129.8 mg/kg diet, respectively. PMID- 26944718 TI - Tightening the Dutch coffee shop policy: Evaluation of the private club and the residence criterion. AB - BACKGROUND: The Dutch coffee shop policy was tightened in 2012. Two additional criteria that coffee shops must adhere to in order for them to be tolerated came into force: the private club and the residence criterion. Coffee shops were only permitted to give access to members and only residents of the Netherlands were permitted to become a member. This tightened policy sought to make coffee shops smaller and more controllable, to reduce the nuisance associated with coffee shops and to reduce the number of foreign visitors attracted by the coffee shops. Enforcement began in the southern provinces. The private club criterion was abolished at the end of 2012. METHODS: A sample of fourteen municipalities with coffee shops was drawn. Seven in the south were treated as an 'experimental group' and the others as 'comparison group'. A baseline assessment and follow-ups at six and 18 months were performed. A combination of methods was applied: interviews with local experts, surveys with neighbourhood residents, coffee shop visitors and cannabis users, and ethnographic field work. RESULTS: Drugs tourism to coffee shops swiftly declined in 2012. The coffee shops also lost a large portion of their local customers, since users did not want to register as a member. The illegal market expanded. Neighbourhood residents experienced a greater amount of nuisance caused by dealer activities. After abolishment of the private club criterion, residents of the Netherlands largely returned to the coffee shops. Drug tourists still remained largely absent. Neighbourhood residents experienced more nuisance from coffee shops again. Illegal cannabis sale was tempered. No effect on cannabis use was found. CONCLUSION: The quick and robust shifts in the users' market in reaction to the policy changes illustrate the power of policy, but also the limitations caused by the dynamic and resilient nature of the Dutch cannabis supply market. PMID- 26944719 TI - Plasma netrin-1 levels significantly increase in smokers. AB - OBJECTIVES: Netrin-1 is a laminin like protein that has recently been suggested to involve in the pathophysiology of atherosclerosis and treatment targets. The relationship between netrin-1 and atherosclerosis has not been evaluated in a human research previously and the effect of smoking on plasma netrin-1 levels as well. In this study, we aimed to evaluate plasma netrin-1 levels in smokers and non-smokers and the impact of smoking on netrin-1 levels. Our second aim was to evaluate the existence of peripheral artery disease in these groups by means of ankle brachial index (ABI) measurements and the relation between plasma netrin-1 levels and peripheral artery disease. DESIGN AND METHODS: Smoker and non-smoker male patients were contributed in the study, 112 males in each group. ABI of all patients was determined with an automatic device and plasma netrin-1 levels were quantified with an enzyme-linked immunosorbent assay. Netrin-1 levels were compared between smoker and non-smoker cases, and the cases with and without peripheral arterial disease. RESULTS: Plasma netrin-1 levels of smokers (4.54+/ 2.87pg/mL) were significantly higher than in non-smokers (3.81+/-1.26pg/mL) (p=0.015). Similarly, netrin-1 levels of cases with peripheral arterial disease (6.21+/-2.16pg/mL) were significantly higher than the ones without peripheral arterial disease (4.07+/-2.16pg/mL) (p=0.002). Amount of smoking (packet?year) and ABI were found to be significantly related with netrin-1 levels. The relationship between PAD and netrin-1 levels remained significant after adjusting for smoking status. CONCLUSION: We can conclude that plasma netrin-1 levels significantly increase in smokers and peripheral artery disease is significantly related with netrin-1 levels after adjusting for smoking status. PMID- 26944720 TI - Polymorphisms in the long non-coding RNA CDKN2B-AS1 may contribute to higher systolic blood pressure levels in hypertensive patients. AB - OBJECTIVES: Hypertension (HT) is a complex disorder influenced by both genetic and environmental factors. Recent genome-wide association studies have identified a major risk locus for atherosclerosis on chromosome 9p21.3. SNPs within the coding sequences of CDKN2A/B and the long non-coding RNA CDKN2B-AS1 could potentially contribute to HT development. Thus, this study aimed to investigate whether the frequency of four SNPs on chromosome 9p21.3 affects blood pressure (BP) levels in Turkish HT patients, and to examine correlations between these SNPs, specific SNP haplotypes, and HT. DESIGN AND METHODS: This is a case-control study comparing HT patients and healthy controls. Real-time polymerase chain reaction (RT-PCR) analysis was utilized to detect SNPs rs10757274, rs2383207, rs10757278, and rs1333049 in 170 HT patients and 180 healthy controls. RESULTS: Each SNP was detected at significantly higher frequencies in HT patients than in controls (p values 0.001); however, there was no significant link between rs10757274, rs2383207, rs10757278, and rs1333049 SNPs and HT grades. Furthermore, there was a significant association between elevated systolic BP levels and rs1333049 GG genotype (p=0.047), while weight gain and increased fasting glucose levels were significantly associated with rs2383207 AA genotype (p=0.020 and p=0.009, respectively). Lastly, we detected a correlation between GG, GA, and AG haplotypes in block 1 (rs10757274, rs2383207) and GC and AG haplotypes in block 2 (rs10757278, rs1333049) and HT. CONCLUSIONS: Our findings suggest that SNPs rs10757274, rs2383207, rs10757278, and rs1333049, particularly those within the CDKN2B-AS1 gene, and related haplotypes may confer increased susceptibility to HT development. PMID- 26944721 TI - A genome-wide expression profile analysis reveals active genes and pathways coping with phosphate starvation in soybean. AB - BACKGROUND: Phosphorus is one of the most important macronutrients that is required for plant growth and development. However, stress under low-P conditions has become a limiting factor that affects crop yields and qualities. Plants have developed strategies to cope with this, while few genes associated with low-P tolerance have been identified in soybean. RESULTS: Genome-wide analyses were performed on the roots and leaves of a low-P-tolerant accession and a low-P sensitive accession which were identified by hydroponic experiments under different P treatments. Through comparative analyses on the differently expressed genes, we explored 42 common genes that were highly correlated to low-P stress. The functional classification of these genes revealed 24 Gene Ontology (GO) terms of biological process including response to oxidation reduction, hormone stimuli, and biotic and abiotic stimuli. Additionally, three common pathways were identified. CONCLUSIONS: These results could not only promote the work on the molecular regulation mechanism under low-P stress in soybean, but also facilitate the cultivation of high-phosphorus-acquisition and high-phosphorus-utilization soybean varieties. PMID- 26944722 TI - Effects of cataracts on flicker electroretinograms recorded with RETevalTM system: new mydriasis-free ERG device. AB - BACKGROUND: The purpose of this study was to evaluate the effects of cataracts on the flicker electroretinograms (ERGs) recorded with the RETevalTM system under mydriatic-free conditions. METHODS: This was a retrospective study of 82 eyes of 60 patients with cataracts and 52 eyes of 38 patients who were pseudophakic. Flicker ERGs were recorded with the RETevalTM system (LKC Technologies, Gaithersburg, MD) under mydriatic-free condition with skin electrodes. Flicker ERGs were elicited by white light delivered at a frequency of 28.3 Hz and intensity of 8 Td-s. The implicit times and amplitudes of the ERGs recorded from the Grade 2 cataract, Grade 3 cataract, and pseudophakic groups were compared. RESULTS: The mean amplitude was significantly smaller in both cataract groups than the pseudophakic group (Grade 2 cataract vs pseudophakic group, P < 0.0001; Grade 3 cataract vs pseudophakic group, P < 0.0001; Grade 2 cataract vs Grade 3 cataract, P = 0.027). The mean implicit times was significantly longer in both cataract groups than the pseudophakic group (Grade 2 cataract vs pseudophakic group, P = 0.046; Grade 3 cataract vs pseudophakic group, P = 0.0004; Grade 2 cataract vs Grade 3 cataract, P = 0.0084). CONCLUSIONS: The results indicate that the presence of Grade 2 or more cataracts will affect both the amplitude and the implicit time of the flicker ERGs. The presence of cataracts should be taken into consideration when interpreting the flicker ERG recorded with RETevalTM. PMID- 26944723 TI - Frequency of CCR5 genotypes in HIV-infected patients in Roraima, Brazil. PMID- 26944725 TI - Impact of totally laparoscopic combined management of colorectal cancer with synchronous hepatic metastases on severity of complications: a propensity-score based analysis. AB - BACKGROUND: Thanks to widespread diffusion of minimally invasive approach in the setting of both colorectal and hepatic surgeries, the interest in combined resections for colorectal cancer and synchronous liver metastases (SCLM) by totally laparoscopic approach (TLA) has increased. Aim of this study was to compare outcome of combined resections for SCLM performed by TLA or by open approach, in a propensity-score-based study. STUDY DESIGN: All 25 patients undergoing combined TLA for SCLM at San Raffaele Hospital in Milano were compared in a case-matched analysis with 25 out of 91 patients undergoing totally open approach (TOA group). Groups were matched with 1:2 ratio using propensity scores based on covariates representing disease severity. Main endpoints were postoperative morbidity and long-term outcome. The Modified Accordion Severity Grading System was used to quantify complications. RESULTS: The groups resulted comparable in terms of patients and disease characteristics. The TLA group, as compared to the TOA group, had lower blood loss (350 vs 600 mL), shorter postoperative stay (9 vs 12 days), lower postoperative morbidity index (0.14 vs 0.20) and severity score for complicated patients (0.60 vs 0.85). Colonic anastomosis leakage had the highest fractional complication burden in both groups. In spite of comparable long-term overall survival, the TLA group had better recurrence-free survival. CONCLUSION: TLA for combined resections is feasible, and its indications can be widened to encompass a larger population of patients, provided its benefits in terms of reduced overall risk and severity of complications, rapid functional recovery and favorable long-term outcomes. PMID- 26944724 TI - The coexistence of carotid and lower extremity atherosclerosis further increases cardio-cerebrovascular risk in type 2 diabetes. AB - BACKGROUND: Both carotid and lower limb atherosclerosis are associated with increased cardiovascular and cerebrovascular risks. However, it is still unclear whether the concomitant presence of carotid and lower extremity atherosclerosis further increases the cardiovascular and cerebrovascular risks. Therefore, our aim is to investigate whether the coexistence of carotid and lower extremity atherosclerosis was associated with higher cardiovascular and cerebrovascular risks in patients with type 2 diabetes. METHODS: This cross-sectional study was performed in 2830 hospitalized patients with type 2 diabetes. Based on carotid and lower limb Doppler ultrasound results, the patients were divided into three groups including 711 subjects without atherosclerosis, 999 subjects with either carotid or lower limb atherosclerosis, and 1120 subjects with both carotid and lower limb atherosclerosis. And we compared the clinical characteristics and prevalence of both cardio-cerebrovascular events (CCBVEs) and self-reported cardio- cerebrovascular diseases (CCBVDs) among the three groups. RESULTS: After adjusting for age, sex, and duration of diabetes, there were significant increases in the prevalence of both CCBVEs (3.8 vs. 11.8 vs. 26.4 %, p < 0.001 for trend) and self-reported CCBVDs (6.9 vs. 19.9 vs. 36.5 %, p < 0.001 for trend) across the three groups (diabetics without atherosclerosis, diabetics with either carotid or lower limb atherosclerosis, and diabetics with both carotid and lower extremity atherosclerosis). A fully adjusted logistic regression analysis also revealed that compared with those without atherosclerosis, those with either carotid or lower limb atherosclerosis had higher risk of CCBVEs (OR 1.724, 95 % CI 1.001-2.966) and self-reported CCBVDs (OR 1.705, 95 % CI 1.115-2.605), and those with concomitant presence of carotid and lower extremity atherosclerosis had the highest risk of CCBVEs (OR 2.869, 95 % CI 1.660-4.960) and self-reported CCBVDs (2.147, 95 % CI 1.388-3.320)(p < 0.001 for trend in CCBVEs and p = 0.002 for trend in CCBVDs, respectively). CONCLUSIONS: Either carotid or lower limb atherosclerosis was obviously related to increased cardio-cerebrovascular risk in type 2 diabetes. The concomitant presence of carotid and lower extremity atherosclerosis further increased cardio-cerebrovascular risk in patients with type 2 diabetes. The combined application of carotid and lower extremity ultrasonography may help identify type 2 diabetics with higher cardio cerebrovascular risk. PMID- 26944726 TI - Endoscopic submucosal dissection with the Nestis(r) jet injector system with a bifunctional catheter: first prospective clinical trial (NCT: 2012-A00272-41). AB - BACKGROUND: The Enki-2 water jet system (Nestis SAS(r), Lyon, France) with dual injection and dissection capability significantly reduced ESD procedure time and perforation rates in animal studies. The study aim was to evaluate its efficacy and safety in patients with superficial neoplastic lesions. METHODS: A prospective study including 18 patients with esophageal, gastric and rectal superficial neoplasms treated by ESD using Enki-2 was designed. RESULTS: Eighteen lesions (6 esophageal, 3 gastric, 9 rectal, mean diameter 43.5 mm) in 17 patients (10 men, mean age 65.9) were included. The mean procedure time was 65.6 min. One patient needed clipping for an incomplete muscle tear during procedure; there were neither delayed bleedings nor perforation. The "en bloc" resection rate was 100 %, the R0 resection rate was 88.9 % (16/18 lesions), and the curative resection rate was 77.8 %. The 3-month disease-free rate was 92.3 % (12/13 patients, 13/14 lesions, 1 patient lost to follow-up). The 12-month disease-free rate was 69.2 % (9/13 patients, 10/14 lesions, 4 patients lost to follow-up). CONCLUSIONS: ESD with Enki-2 water jet system is effective and safe for superficial neoplastic digestive lesions. PMID- 26944727 TI - One-trocar versus multiport hybrid laparoscopic appendectomy: What's the best option for children with acute appendicitis? Results of an international multicentric study. AB - BACKGROUND: One-trocar laparoscopic appendectomy (OTA) is routinely adopted in children with acute appendicitis. In case of a difficult appendectomy, it is necessary to add additional trocar/s to safely complete the procedure. This technique is called multiport hybrid laparoscopic appendectomy (HLA). We aimed to compare the outcome of multiport HLA versus OTA. METHODS: We retrospectively reviewed the data of 1,092 patients underwent LA in 5 European centers of pediatric surgery in the last 5 years. We compared 2 groups: G1 of 575 patients (52.6 %) (average age 10 years) underwent OTA and G2 of 517 patients (47.4 %) (average age 8.2 years) underwent multiport HLA. RESULTS: No intra-operative complications occurred in both groups. An additional pathology was treated in 12 cases (8 Meckel's diverticulum, 2 carcinoids, 2 ovarian cysts) in G2. Operative time was significantly shorter in G2 compared to G1 (47.8 vs 58.6 min; p < .001). The average analgesic requirement was significantly shorter in G2 compared to G1 (44 vs 56 h; p < .001). As for postoperative complications, the incidence of port site infections was similar between the two groups, while the incidence of postoperative abdominal abscesses (PAA) was significantly higher in G1 compared to G2 (4.7 vs 0.2 %; p < .001). The cosmetic outcome was excellent in all patients of both groups. A subgroup analysis between complicated and uncomplicated appendicitis showed that only in complicated cases, the average operative time, the average VAS pain score, the average analgesic requirements and the incidence of PAA were significantly higher in OTA group compared to multiport HLA group (p < .001). CONCLUSIONS: Our results suggest that OTA is a valid and safe procedure for the uncomplicated cases, while additional trocars are required in case of complicated appendicitis. Multiport HLA significantly reduces the operative time, the incidence of abdominal abscesses and the analgesic requirements compared to OTA. PMID- 26944728 TI - Potential sexual function improvement by using transanal mesorectal approach for laparoscopic low rectal cancer excision. AB - OBJECTIVE: Preliminary results of the transanal approach for low rectal cancer suggest better oncological outcomes than the conventional laparoscopic approach. We currently report the functional results. METHODS: From 2008 to 2012, 100 patients with low rectal cancer and suitable for sphincter-saving resection were randomized between transanal and laparoscopic low rectal dissection. Patients derived from this randomized trial were enrolled for functional assessment. End points were bowel function (LARS bowel and Wexner continence scores) and urogenital function (IPSS, IIEF-5 and FSFI-6 scores) obtained by questionnaires sent to patients with a follow-up more than 12 months. RESULTS: Overall, 76 patients were eligible and 72 responded to the questionnaire: 38 in the transanal group and 34 in the laparoscopic group. The bowel function did not differ between the transanal and the laparoscopic groups: LARS 36 versus 37 (p = 0.941) and Wexner 9 versus 10 (p = 0.786). The urologic function was also similar between the two groups: IPSS 5.5 versus 3.5 (p = 0.821). Among sexually active patients before surgery, 20 of 28 (71 %) patients in the transanal group and 9 of 23 (39 %) in the laparoscopic group maintained an activity after surgery (p = 0.02). Erectile function was also better in men after transanal compared to laparoscopic low rectal dissection: IIEF 17 versus 7 (p = 0.119). CONCLUSION: Transanal approach for low rectal cancer did not change bowel and urologic functions compared to the conventional laparoscopic approach. However, there was a trend to a better erectile function with a significantly higher rate of sexual activity in the transanal group. PMID- 26944729 TI - Age is highly associated with stereo blindness among surgeons: a cross-sectional study. AB - BACKGROUND: The prevalence of stereo blindness in the general population varies greatly within a range of 1-30 %. Stereo vision adds an extra dimension to aid depth perception and gives a binocular advantage in task completion. Lack of depth perception may lower surgical performance, potentially affecting surgical outcome. 3D laparoscopy offers stereoscopic vision of the operative field to improve depth perception and is being introduced to several surgical specialties; however, a normal stereo vision is a prerequisite. The aim of this study was to establish the prevalence of stereo blindness among surgeons in the field of general surgery, gynecology, and urology as these are potential users of 3D laparoscopy. METHODS: The study was conducted according to the STROBE guidelines for cross-sectional studies. Medical doctors from the department of general surgery, gynecology, and urology were recruited and stereo tested by the use of the Random Dot E stereo test. Upon stereo testing, a demographic questionnaire was completed. Multivariate logistic regression analysis was employed to assess the association between stereo blindness and the variables resulting from the univariate analysis. RESULTS: Three hundred medical doctors completed the study. Of these 9.7 % were stereo blind. There were 47 % women and 53 % men, aged 25-71 years. General surgery was represented with 64 % of the participants, gynecology with 26 %, and urology with 10 %. Age (OR 5.6; CI 1.7-18.9; P = 0.005) and not being aware of having any vision anomaly in need for correction (OR 4; CI 1.4 11.4; P = 0.010) were significantly associated with stereo blindness. CONCLUSION: Approximately one in ten medical doctors in general surgery, gynecology, and urology were stereo blind with an increasing prevalence with age. This is relevant since stereo blind surgeons will not benefit from the implementation of 3D laparoscopy. PMID- 26944731 TI - Dynamics of size-fractionated bacterial communities during the coastal dispersal of treated municipal effluents. AB - Everyday huge amount of treated municipal wastewater is discharged into the coastal seawater. However, microbial biomarkers for the municipal effluent instead of the fecal species from raw sewage have not been proposed. Meanwhile, bacterial taxa for degrading large amounts of input organics have not been fully understood. In this study, raw effluent and serial water samples were collected from the coastal dispersal of two sewage treatment plants in Xiamen, China. Free living (FL) and particle-associated (PA) bacterial communities were analyzed via high-throughput sequencing of 16S rRNA gene and quantitative PCR to measure bacterial abundance. The PA bacterial communities in our samples exhibited higher cell abundance, alpha diversity, and population dynamics than the FL bacterial communities, which supports greater environmental significance of the PA bacterial communities. Two non-fecal but typical genera in activated sludge, Zoogloea and Dechloromonas, exhibited decreased but readily detectable abundance along the effluent dispersal distance. Furthermore, the dominating microbial species near the outfalls were related to well-known marine indigenous taxa, such as SAR11 clade, OM60 clade, low-GC Actinobacteria, and unclassified Flavobacteriales, as well as the less understood taxa like Pseudohongiella and Microbacteriaceae. It is interesting that these taxa exhibited two types of correlation patterns with COD concentration. Our study suggested Zoogloea as a potential indicator of municipal effluents and also proposed potential utilizers of residual effluent COD in marine environments. PMID- 26944730 TI - Efficacy of the endoscopic management of postoperative fistulas of leakages after esophageal surgery for cancer: a retrospective series. AB - BACKGROUND AND AIMS: Anastomotic leakages are severe and often lethal adverse events of surgery for esophageal cancer. The endoscopic treatment is growing up in such indications. The aim was to evaluate the efficacy and describe the strategy of the endoscopic management of anastomotic leakages/fistulas after esophageal oncologic surgery. METHODS: Single-center retrospective study on 126 patients operated for esophageal carcinomas between 2010 and 2014. Thirty-five patients with postoperative fistulas/leakages (27 %) were endoscopically managed and included. The primary endpoint was the efficacy of the endoscopic treatment. The secondary endpoints were: delays between surgery, diagnosis, endoscopy and recovery; number of procedures; material used; and adverse events rate. Uni- and multivariate analyses were carried out to determine predictive factors of success. RESULTS: There were mostly men, with a median age of 61.7 years +/- 8.9 [43-85]. 48.6 % underwent Lewis-Santy surgery and 45.7 % Akiyama's. 71.4 % patients received neo-adjuvant chemo-radiation therapy. The primary and secondary efficacy was 48.6 and 68.6 %, respectively. The delay between surgery and endoscopy was 8.5 days [6.00-18.25]. Eighty-eight percentages of the patients were treated using double-type metallic stents, with removability and migration rates of 100 and 18 %, respectively. In the other cases, we used over-the-scope clips, naso-cystic drain or combined approach. The mean number of endoscopy was 2.6 +/- 1.57 [1-10]. The mortality rate was 17 %, none being related to procedures. No predictive factor of efficacy could be identified. CONCLUSIONS: The endoscopic management of leakages or fistulas after esophageal surgery reached an efficacy rate of 68.8 %, mostly using stents, without significant adverse events. The mortality rate could be decreased from 40-100 to 17 %. PMID- 26944733 TI - Long-term evaluation of dabigatran 150 vs. 110 mg twice a day in patients with non-valvular atrial fibrillation. AB - AIMS: The Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial allowed patients who completed the trial receiving their assigned dabigatran 150 mg (D150) or 110 mg (D110) twice a day to continue into the Long term Multicenter Extension of Dabigatran Treatment in Patients with Atrial Fibrillation (RELY-ABLE) trial. This permitted assessment of outcomes over a median of 4.6 and a maximum of 6.7 years, respectively. METHODS AND RESULTS: The analysed population included only those patients who completed RE-LY on dabigatran and continued into RELY-ABLE without interruption of assigned dabigatran. Cumulative risk was expressed as Kaplan-Meier plots. Outcomes were compared using Cox proportional hazard modelling. Stroke or systemic embolization rates were 1.25 and 1.54% per year (D150 and D110, respectively); hazard ratio (HR) 0.81 [95% confidence interval (CI): 0.68-0.96] (P = 0.02). Ischaemic stroke was 1.03 (D150) and 1.29%/year (D110); HR 0.79 (95% CI: 0.66-0.95) (P = 0.01). Haemorrhagic stroke rates were 0.11 (D150) and 0.13%/year (D110); HR 0.91 (95% CI: 0.51-1.62) (P = 0.75). Rates of major haemorrhage were 3.34 (D150) and 2.76%/year (D110); HR 1.22 (95% CI: 1.08-1.37) (P = 0.0008). Intracranial haemorrhage rates were 0.32 (D150) and 0.23%/year (D110); HR 1.37 (95% CI: 0.93 2.01) (P = 0.11). Mortality was 3.43 (D150) and 3.55%/year (D110); HR 0.97 (95% CI: 0.87-1.08) (P = 0.54). CONCLUSION: Annualized rates of all outcomes were constant with better efficacy of D150, less major bleeding with D110, and low intracerebral haemorrhage rates for both doses. There were no additional safety concerns. This is the longest continuous randomized experience of a novel anticoagulant. PMID- 26944734 TI - For avid glucose tumors, the SUV peak is the most reliable parameter for [(18)F]FDG-PET/CT quantification, regardless of acquisition time. AB - BACKGROUND: This study is an assessment of the impact of acquisition times on SUV with [(18)F]FDG-PET/CT on healthy livers (reference organ with stable uptake over time) and on tumors. METHODS: One hundred six [(18)F]FDG-PET/CT were acquired in list mode over a single-bed position (livers (n = 48) or on tumors (n = 58)). Six independent datasets of different durations were reconstructed (from 1.5 to 10 min). SUVmax (hottest voxel), SUVpeak (maximum average SUV within a 1-cm(3) spherical volume), and SUVaverage were measured within a 3-cm-diameter volume of interest (VOI) in the right lobe of the liver. For [(18)F]FDG avid tumors (SUVmax >= 5), the SUVmax, SUVpeak, and SUV41% (isocontour threshold method) were computed. RESULTS: For tumors, SUVpeak values did not vary with acquisition time. SUVmax displayed significant differences between 1.5- and 5-10-min reconstruction times. SUV41% was the most time-dependent parameter. For the liver, the SUVaverage was the sole parameter that did not vary over time. CONCLUSIONS: For [(18)F]FDG avid tumors, with short acquisition times, i.e., with new generations of PET systems, the SUVpeak may be more robust than the SUVmax. The SUVaverage over a 3-cm-diameter VOI in the right lobe of the liver appears to be a good method for a robust and reproducible assessment of the hepatic metabolism. PMID- 26944735 TI - Characterization of post-translational modifications in full-length human BMP-1 confirms the presence of a rare vicinal disulfide linkage in the catalytic domain and highlights novel features of the EGF domain. AB - Bone morphogenetic protein 1 (BMP-1) is an essential metalloproteinase to trigger extracellular matrix assembly and organogenesis. Previous structural studies on the refolded catalytic domain of BMP-1 produced in E. coli have suggested the existence of a rare vicinal disulfide linkage near the active site. To confirm that this was not an artifact of the refolding procedure, the full-length human BMP-1 produced in mammalian cells was investigated via sequence-dependent enzyme cleavage under native conditions followed by high mass accuracy and high resolution LC-MS/MS analysis to interrogate the post-translational modifications. Ten disulfide linkages of BMP-1, including the vicinal disulfide linkage C185 C186 could be unambiguously identified. Further, around 50% of this vicinal disulfide bond was found to be modified by N-ethylmaleimide (NEM), a cysteine protease inhibitor supplied when the BMP-1-containing medium was collected, suggesting that this bond was highly unstable. In the absence of NEM, BMP-1 has a higher tendency to form aggregates, but after aggregate removal, C185 and C186 are almost quantitatively engaged in the vicinal disulfide bond and BMP-1 activity remains unchanged. In addition, three consensus N-glycosylation sites at N142, N363, and N599 could be identified together with a previously unknown O glycosylation site and an Asn-hydroxylation. SIGNIFICANCE: An in-depth characterization of post-translational modifications of the full-length human BMP 1 produced in mammalian cells by MS was performed. A rare vicinal disulfide bond in the catalytic domain could be confirmed for the first time by mass spectrometry along with nine other proposed disulfide linkages of mature BMP-1. This vicinal disulfide bond can transiently open to form covalent adducts with the cysteine protease inhibitor (NEM) supplied in cell medium during protein harvesting. Further, we report a previously unknown O-glycosylation site and Asn hydroxylation site, indicating a novel feature of BMP-1 in the EGF domain. The study clearly outlines the benefit of in-depth characterization of overexpressed proteins to deduce important protein modifications. PMID- 26944732 TI - Elevated kynurenine pathway metabolism during neurodevelopment: Implications for brain and behavior. AB - The kynurenine pathway (KP) of tryptophan degradation contains several neuroactive metabolites that may influence brain function in health and disease. Mounting focus has been dedicated to investigating the role of these metabolites during neurodevelopment and elucidating their involvement in the pathophysiology of psychiatric disorders with a developmental component, such as schizophrenia. In this review, we describe the changes in KP metabolism in the brain from gestation until adulthood and illustrate how environmental and genetic factors affect the KP during development. With a particular focus on kynurenic acid, the antagonist of alpha7 nicotinic acetylcholine (alpha7nACh) and N-methyl-d aspartate (NMDA) receptors, both implicated in modulating brain development, we review animal models designed to ascertain the role of perinatal KP elevation on long-lasting biochemical, neuropathological, and behavioral deficits later in life. We present new data demonstrating that combining perinatal choline supplementation, to potentially increase activation of alpha7nACh receptors during development, with embryonic kynurenine manipulation is effective in attenuating cognitive impairments in adult rat offspring. With these findings in mind, we conclude the review by discussing the advancement of therapeutic interventions that would target not only symptoms, but potentially the root cause of central nervous system diseases that manifest from a perinatal KP insult. This article is part of the Special Issue entitled 'The Kynurenine Pathway in Health and Disease'. PMID- 26944736 TI - Comprehensive tissue-specific proteome analysis of drought stress responses in Pennisetum glaucum (L.) R. Br. (Pearl millet). AB - Pearl millet is the fifth most important cereal crop worldwide and cultivated especially by small holder farmers in arid and semi-arid regions because of its drought and salt tolerance. The molecular mechanisms of drought stress tolerance in Pennisetum remain elusive. We have used a shotgun proteomics approach to investigate protein signatures from different tissues under drought and control conditions. Drought stressed plants showed significant changes in stomatal conductance and increased root growth compared to the control plants. Root, leaf and seed tissues were harvested and 2281 proteins were identified and quantified in total. Leaf tissue showed the largest number of significant changes (120), followed by roots (25) and seeds (10). Increased levels of root proteins involved in cell wall-, lipid-, secondary- and signaling metabolism and the concomitantly observed increased root length point to an impaired shoot-root communication under drought stress. The harvest index (HI) showed a significant reduction under drought stress. Proteins with a high correlation to the HI were identified using sparse partial least square (sPLS) analysis. Considering the importance of Pearl millet as a stress tolerant food crop, this study provides a first reference data set for future investigations of the underlying molecular mechanisms. BIOLOGICAL SIGNIFICANCE: Drought stress is the most limiting factor for plant growth and crop production worldwide. At the same time drought susceptible cereal crops are among the largest producers worldwide. In contrast, Pearl millet is a drought and salt tolerant cereal crop especially used in arid and semi-arid regions by small farmers. The multifactorial molecular mechanisms of this unique drought tolerance are not known. Here, we employ shotgun proteomics for a first characterization of the Pearl millet drought stress proteome. The experimental setup and the data set generated from this study reveal comprehensive physiological and proteomic responses of the drought stressed Pearl millet plants. Our study reveals statistically significant tissue-specific protein signatures during the adaptation to drought conditions. Thus, the work provides a first reference study of the drought stress proteome and related drought responsive proteins (DRP's) in Pearl millet. PMID- 26944738 TI - Stakeholder Involvement in Forensic Psychiatry: The Brazilian Experience. PMID- 26944737 TI - Current applications and future directions for the CDISC Operational Data Model standard: A methodological review. AB - INTRODUCTION: In order to further advance research and development on the Clinical Data Interchange Standards Consortium (CDISC) Operational Data Model (ODM) standard, the existing research must be well understood. This paper presents a methodological review of the ODM literature. Specifically, it develops a classification schema to categorize the ODM literature according to how the standard has been applied within the clinical research data lifecycle. This paper suggests areas for future research and development that address ODM's limitations and capitalize on its strengths to support new trends in clinical research informatics. METHODS: A systematic scan of the following databases was performed: (1) ABI/Inform, (2) ACM Digital, (3) AIS eLibrary, (4) Europe Central PubMed, (5) Google Scholar, (5) IEEE Xplore, (7) PubMed, and (8) ScienceDirect. A Web of Science citation analysis was also performed. The search term used on all databases was "CDISC ODM." The two primary inclusion criteria were: (1) the research must examine the use of ODM as an information system solution component, or (2) the research must critically evaluate ODM against a stated solution usage scenario. Out of 2686 articles identified, 266 were included in a title level review, resulting in 183 articles. An abstract review followed, resulting in 121 remaining articles; and after a full text scan 69 articles met the inclusion criteria. RESULTS: As the demand for interoperability has increased, ODM has shown remarkable flexibility and has been extended to cover a broad range of data and metadata requirements that reach well beyond ODM's original use cases. This flexibility has yielded research literature that covers a diverse array of topic areas. A classification schema reflecting the use of ODM within the clinical research data lifecycle was created to provide a categorized and consolidated view of the ODM literature. The elements of the framework include: (1) EDC (Electronic Data Capture) and EHR (Electronic Health Record) infrastructure; (2) planning; (3) data collection; (4) data tabulations and analysis; and (5) study archival. The analysis reviews the strengths and limitations of ODM as a solution component within each section of the classification schema. This paper also identifies opportunities for future ODM research and development, including improved mechanisms for semantic alignment with external terminologies, better representation of the CDISC standards used end-to-end across the clinical research data lifecycle, improved support for real-time data exchange, the use of EHRs for research, and the inclusion of a complete study design. CONCLUSIONS: ODM is being used in ways not originally anticipated, and covers a diverse array of use cases across the clinical research data lifecycle. ODM has been used as much as a study metadata standard as it has for data exchange. A significant portion of the literature addresses integrating EHR and clinical research data. The simplicity and readability of ODM has likely contributed to its success and broad implementation as a data and metadata standard. Keeping the core ODM model focused on the most fundamental use cases, while using extensions to handle edge cases, has kept the standard easy for developers to learn and use. PMID- 26944739 TI - The Prison Rape Elimination Act and Correctional Psychiatrists. PMID- 26944740 TI - The Mock Trial: Revisiting a Valuable Training Strategy. AB - The number of forensic psychiatrists has increased dramatically over the past 40 years. With this welcome development has also come some challenges for educating future generations of practitioners, specifically the greater demands on training programs and the need to divide practice hours among a larger pool of individuals. Junior trainees and experienced practitioners alike can benefit by supplementing work experience with well-designed, theoretically informed simulations. In this article, the theoretical perspectives of simulation, deliberate practice, and experiential education are discussed and linked to the design of mock trials, a form of simulation used to teach the essential skill of expert testimony. My argument is that, by explicitly linking the mock trial to learning theory, its efficacy and range of application can be increased. I provide recommendations for effective design and application. PMID- 26944741 TI - Anders Breivik: Extreme Beliefs Mistaken for Psychosis. AB - The case of Anders Breivik, who committed mass murder in Norway in 2011, stirred controversy among forensic mental health experts. His bizarrely composed compendium and references to himself as the "Knights Templar" raised concerns that he had a psychotic mental illness. Beliefs such as Mr. Breivik's that precede odd, unusual, or extremely violent behavior present a unique challenge to the forensic evaluator, who sometimes struggles to understand those beliefs. Psychotic disorder frequently is invoked to characterize odd, unusual, or extreme beliefs, with a classification that has evolved over time. However, the important concept of overvalued idea, largely ignored in American psychiatry, may better characterize these beliefs in some cases. We discuss the definitions of delusion and overvalued ideas in the context of Anders Breivik's rigidly held extreme beliefs. We also review the British definition of overvalued idea and discuss McHugh's construct, to introduce the term "extreme overvalued belief" as an aid in sharpening the forensic evaluator's conceptualization of these and similar beliefs. PMID- 26944742 TI - At a Loss for Words: Nosological Impotence in the Search for Justice. AB - The assessment and trial of Norwegian mass-murderer Anders Breivik, including disparate opinions about his sanity, raise questions about distinguishing "bad" from "mad." Although he was ultimately found criminally responsible, the tenacity and pervasiveness of his beliefs suggested delusional thinking. The author reflects on the difficulty psychiatrists have with nomenclature generally and on the application of imprecise classification to criminal justice. Ideally, a classification system should "carve nature at its joints." Barring that, psychiatry needs operational definitions to appreciate the differences between idiosyncratic, psychotic thinking, and shared subcultural beliefs or ideologies. The concept of extreme overvalued belief provides a basis for making this distinction, when applied in the criminal justice context. PMID- 26944743 TI - Experience and Opinions of Forensic Psychiatrists Regarding PTSD in Criminal Cases. AB - By the end of 2014, 1.5 million veterans of the Second Iraq and Afghan wars were to have returned home, up to 35 percent with PTSD. The potential use of PTSD as the basis for legal claims in criminal defense is therefore a pressing problem. Using a Web-based survey, we examined the experiences and attitudes of members of the American Academy of Psychiatry and the Law (AAPL) regarding PTSD in the criminal forensic setting. Of 238 respondents, 50 percent had been involved in a criminal case involving PTSD, 41 percent in the previous year. Eighty-six percent of cases involved violent crime and 40 percent homicides. Forty-two percent of defendants were soldiers in active service or veterans, of whom 89 percent had had combat exposure, mostly in the Second Iraq and Afghan wars. Outcomes reported were not guilty by reason of insanity (NGRI) (7%), guilty on the original charge (40%), and pleading guilty to a lesser charge (23%). The findings suggest that many forensic psychiatrists will be asked to evaluate PTSD in the criminal setting, with a growing number of cases related to combat exposure in recent veterans. The implications of these findings for the practice of forensic psychiatry are discussed. PMID- 26944744 TI - Between Belief and Delusion: Cult Members and the Insanity Plea. AB - Cults are charismatic groups defined by members' adherence to a set of beliefs and teachings that differ from those of mainstream religions. Cult beliefs may appear unusual or bizarre to those outside of the organization, which can make it difficult for an outsider to know whether a belief is cult-related or delusional. In accordance with these beliefs, or at the behest of a charismatic leader, some cult members may participate in violent crimes such as murder and later attempt to plead not guilty by reason of insanity (NGRI). It is therefore necessary for forensic experts who evaluate cult members to understand how the court has responded to such individuals and their beliefs when they mount a defense of NGRI for murder. Based on a review of extant appellate court case law, cult member defendants have not yet successfully pleaded NGRI on the basis of cult involvement, despite receiving a broad array of psychiatric diagnoses that could qualify for such a defense. With the reintroduction of cult involvement in the DSM-5 criteria for other specified dissociative disorder, however, there may be a resurgence of dissociative-type diagnoses in future cult-related cases, both criminal and civil. PMID- 26944745 TI - MMPI-2 Item Endorsements in Dissociative Identity Disorder vs. Simulators. AB - Elevated scores on some MMPI-2 (Minnesota Multiphasic Inventory-2) validity scales are common among patients with dissociative identity disorder (DID), which raises questions about the validity of their responses. Such patients show elevated scores on atypical answers (F), F-psychopathology (Fp), atypical answers in the second half of the test (FB), schizophrenia (Sc), and depression (D) scales, with Fp showing the greatest utility in distinguishing them from coached and uncoached DID simulators. In the current study, we investigated the items on the MMPI-2 F, Fp, FB, Sc, and D scales that were most and least commonly endorsed by participants with DID in our 2014 study and compared these responses with those of coached and uncoached DID simulators. The comparisons revealed that patients with DID most frequently endorsed items related to dissociation, trauma, depression, fearfulness, conflict within family, and self-destructiveness. The coached group more successfully imitated item endorsements of the DID group than did the uncoached group. However, both simulating groups, especially the uncoached group, frequently endorsed items that were uncommonly endorsed by the DID group. The uncoached group endorsed items consistent with popular media portrayals of people with DID being violent, delusional, and unlawful. These results suggest that item endorsement patterns can provide useful information to clinicians making determinations about whether an individual is presenting with DID or feigning. PMID- 26944746 TI - Minors and Sexting: Legal Implications. AB - Sexting is the sending or forwarding of sexually explicit photographs or videos of the sender or someone known to the sender via cell phone. It has become common practice among young people, as cell phones are being given to adolescents at ever younger ages. Youths often send messages without giving appropriate thought to the content of the images. In studies on the subject, rates of minors who have sent sexual images range from 4 to 25 percent, depending on the age of the youths surveyed, the content of the messages and other factors. Because transferring and viewing sexually explicit material when the subject is a minor can be considered child pornography, there can be serious legal consequences. Several states have enacted legislation to help differentiate between child pornography and sexting by minors. The trend reflected in statutes has been that minors involved in sexting without other exacerbating circumstances should be charged with a less serious offense. There is no clear national consensus on how sexting by minors is adjudicated, and therefore we compared several statutes. Case examples are used to illustrate the range of legal outcomes, from felony charges to no charges. Two sexting episodes that were followed by suicide are described. We also address the role of the forensic mental health professional. PMID- 26944747 TI - Clozapine's Effect on Recidivism Among Offenders with Mental Disorders. AB - Mental disorder is associated with criminal reoffending, especially violent acts of offending. Features of mental disorder, psychosocial stresses, substance use disorder, and personality disorder combine to increase the risk of criminal recidivism. Clozapine, an atypical antipsychotic, is indicated in the treatment of patients with psychotic disorders. This article is the report of a community follow-up study of a matched control of those treated with clozapine (n = 41) and those treated with other antipsychotics (n = 21). Rates of reoffending behavior in the general, nonviolent, violent, and sexual categories were calculated after two years of follow-up. Although not statistically significant, the two-year criminal conviction rates of those treated with other antipsychotics in all offense categories except sexual reoffending were two-fold higher than in those treated with clozapine. The time from release to the first offense and crime-free time in the community were significantly longer in the clozapine group. By prolonging the time it takes from release to first offense, clozapine confers additional crime-reduction advantages. PMID- 26944748 TI - Comparison of Certification and Recertification Examinee Performance on Multiple Choice Items in Forensic Psychiatry. AB - Research on the association between age and performance on tests of medical knowledge has generally shown an inverse relationship, which is of concern because of the positive association between measures of knowledge and measures of clinical performance. Because the certification and maintenance of certification (MOC) examinations in the subspecialty of forensic psychiatry draw on a common item bank, performance of the two groups of examinees on the same items could be compared. In addition, the relationship between age and test performance was analyzed. Performance on items administered to certification and MOC examinees did not differ significantly, and the mean amount of time spent on each item was similar for the two groups. Although the majority (five of eight) of the correlations between age and test score on the certification and MOC examinations were negative, only three were significant, and the amount of variance explained by age was small. In addition, examination performance for those younger than 50 was similar to those 60 and older, and diplomates recertifying for the second time outperformed those doing so for the first time. These results indicate that in this subspecialty, there is no clear evidence of an age-related decline in knowledge as assessed by multiple-choice items. PMID- 26944749 TI - Assessing Adaptive Functioning in Death Penalty Cases after Hall and DSM-5. AB - DSM-5 and Hall v. Florida (2014) have dramatically refocused attention on the assessment of adaptive functioning in death penalty cases. In this article, we address strategies for assessing the adaptive functioning of defendants who seek exemption from capital punishment pursuant to Atkins v. Virginia (2002). In particular, we assert that evaluations of adaptive functioning should address assets as well as deficits; seek to identify credible and reliable evidence concerning the developmental period and across the lifespan; distinguish incapacity from the mere absence of adaptive behavior; adhere faithfully to test manual instructions for using standardized measures of adaptive functioning; and account for potential bias on the part of informants. We conclude with brief caveats regarding the standard error of measurement (SEM) in light of Hall, with reference to examples of ordinary life activities that directly illuminate adaptive functioning relevant to capital cases. PMID- 26944750 TI - Rediscovering the Concept of Asylum for Persons with Serious Mental Illness. AB - Treating persons with serious mental illness is a complex and challenging endeavor. One intervention that has received little attention in recent years is the need for asylum. Asylum means a sanctuary, a place that lowers levels of stress and provides protection, safety, security, and social support, as well as an array of treatment services. The concept of "asylum" may have lost favor because it was equated with the abysmal conditions found in the state psychiatric hospitals of the past. Among the reasons persons with serious mental illness have been arrested and incarcerated is society's failure to provide adequate levels of asylum. With the release of tens of thousands of mentally ill inmates from state and federal jails and prisons, it is time to revisit this concept, not only for these persons but for those who have not been criminalized. Asylum can be found in various settings, including with family in the patient's home, in a board-and care facility, or in a psychiatric hospital if necessary. Not all persons with a major mental illness are capable of achieving high levels of social and vocational functioning; however, living in a place that provides asylum can promote a higher quality of life. The value of asylum for many persons with serious mental illness should not be underestimated. PMID- 26944751 TI - Oregon Supreme Court Ruling Prohibits Hospital from Refusing a Sell Order. AB - In a recent decision involving a capital murder case, Oregon State Hospital v. Butts, the Oregon Supreme Court conducted a mandamus hearing to ascertain whether Oregon State Hospital (OSH) had a legal duty to comply with a Sell order from a county trial court to provide antipsychotic medications to an incompetent defendant, despite its belief, as an institution, that medication was not clinically indicated. The case is reviewed and important implications, including the court's being granted the ability to circumvent the medical decision-making process, are discussed. PMID- 26944752 TI - Trajectories of Older Adults' Leisure Time Activity and Functional Disability: a 12-Year Follow-Up. AB - PURPOSE: This study explored how changes in leisure time activities interplayed with changes in functional disability among Taiwanese older adults. METHOD: A parallel process and multiple-indicator latent growth curve modeling was adopted for analysis of the data. Longitudinal data from four waves of the Taiwan Longitudinal Study on Aging, collected between 1996 and 2007, were used for analysis. Data included responses of 5451 older adults with a mean age of 67.16 years (SD = 2.51) in 1996. RESULTS: Compared to baseline level of leisure time activities, increasing the rate of change in leisure time activities has more than three times the effect on slowing down the progression of functional disabilities. The baseline functional disabilities did not significantly predict the changes in leisure time activity participation. CONCLUSION: Engagement in leisure time activity in later life is associated with a slower speed of progression toward functional disability. Early functional disability may not inhibit leisure time activity participation in later life. PMID- 26944753 TI - The Clustering of Lifestyle Behaviours in New Zealand and their Relationship with Optimal Wellbeing. AB - PURPOSE: The purpose of this research was to determine (1) associations between multiple lifestyle behaviours and optimal wellbeing and (2) the extent to which five lifestyle behaviours-sleep, physical activity, sedentary behaviour, sugary drink consumption, and fruit and vegetable intake-cluster in a national sample. METHOD: A national sample of New Zealand adults participated in a web-based wellbeing survey. Five lifestyle behaviours-sleep, physical activity, sedentary behaviour, sugary drink consumption, and fruit and vegetable intake-were dichotomised into healthy (meets recommendations) and unhealthy (does not meet recommendations) categories. Optimal wellbeing was calculated using a multi dimensional flourishing scale, and binary logistic regression analysis was used to calculate the relationship between multiple healthy behaviours and optimal wellbeing. Clustering was examined by comparing the observed and expected prevalence rates (O/E) of healthy and unhealthy two-, three-, four-, and five behaviour combinations. RESULTS: Data from 9425 participants show those engaging in four to five healthy behaviours (23 %) were 4.7 (95 % confidence interval (CI) 3.8-5.7) times more likely to achieve optimal wellbeing compared to those engaging in zero to one healthy behaviour (21 %). Clustering was observed for healthy (5 %, O/E 2.0, 95 % CI 1.8-2.2) and unhealthy (5 %, O/E 2.1, 95 % CI 1.9 2.3) five-behaviour combinations and for four- and three-behaviour combinations. At the two-behaviour level, healthy fruit and vegetable intake clustered with all behaviours, except sleep which did not cluster with any behaviour. CONCLUSION: Multiple lifestyle behaviours were positively associated with optimal wellbeing. The results show lifestyle behaviours cluster, providing support for multiple behaviour lifestyle-based interventions for optimising wellbeing. PMID- 26944754 TI - Reply. PMID- 26944755 TI - Outcomes of 27 Gauge Microincision Vitrectomy Surgery for Posterior Segment Disease. PMID- 26944756 TI - Reply. PMID- 26944758 TI - Possible Genetic Pathway to Melanoma. PMID- 26944757 TI - Habitual coffee consumption and risk of cognitive decline/dementia: A systematic review and meta-analysis of prospective cohort studies. AB - OBJECTIVE: Findings from epidemiologic studies of coffee consumption and risk for cognitive decline or dementia are inconclusive. The aim of this study was to conduct a meta-analysis of prospective studies to assess the association between coffee consumption and the risk for cognitive decline and dementia. METHODS: Relevant studies were identified by searching PubMed and Embase databases between 1966 and December 2014. Prospective cohorts that reported relative risk (RRs) and 95% confidence intervals (CIs) for the association of coffee consumption with dementia incidence or cognitive changing were eligible. Study-specific RRs were combined by using a random-effects model. RESULTS: Eleven prospective studies, including 29,155 participants, were included in the meta-analysis. The combined RR indicated that high coffee consumption was not associated with the different measures of cognitive decline or dementia (summary RR, 0.97; 95% CI, 0.84-1.11). Subgroup analyses suggested a significant inverse association between highest coffee consumption and the risk for Alzheimer disease (summary RR, 0.73; 95% CI, 0.55-0.97). The dose-response analysis, including eight studies, did not show an association between the increment of coffee intake and cognitive decline or dementia risk (an increment of 1 cup/d of coffee consumed; summary RR, 1.00; 95% CI, 0.98-1.02). CONCLUSIONS: The present study suggests that higher coffee consumption is associated with reduced risk for Alzheimer disease. Further randomized controlled trials or well-designed cohort studies are needed to determine the association between coffee consumption and cognitive decline or dementia. PMID- 26944759 TI - Naming and Staging Lung Cancers. PMID- 26944760 TI - New Clinical Trial Designs Hasten Approvals for Targeted Therapies. PMID- 26944761 TI - American Academy of Pediatrics Wants Smoking and Vaping Age Raised to 21 Years. PMID- 26944764 TI - Treatment of Persistent Deep Infection After Total Ear Canal Ablation and Lateral Bulla Osteotomy. AB - Persistent deep infection originating from remnants of an incompletely excised ear canal, or epithelium and debris left in the osseous ear canal or tympanic cavity after surgery total ear canal ablation and lateral bulla osteotomy can be debilitating. Clinical signs including pain elicited on deep palpation over the affected bulla or when opening the mouth, or draining sinuses may be delayed months to years. Localization of the nidus via CT imaging is important for surgical planning. Although antibiotic therapy usually reduces or eliminates the clinical signs of deep infection, relapses are common. Surgery more consistently results in permanent resolution. PMID- 26944766 TI - Pregnane glycosides from the antidepressant active fraction of cultivated Cynanchum otophyllum. AB - Based on the bioactive screening results, four new pregnane glycosides, namely cynanotophyllosides A-D (1-4) were isolated from the anti-depressant active fraction of cultivated Cynanchum otophyllum, along with thirteen known compounds (5-17). The new compounds were characterized as qingyangshengenin 3-O-beta-D glucopyranosyl-(1->4)-beta-D-cymaropyranosyl-(1->4)-beta-D-oleandropyranosyl-(1 >4)-beta-D-cymaropyranosyl-(1->4)-beta-D-cymaropyranoside (1), qingyangshengenin 3-O-beta-D-glucopyranosyl-(1->4)-beta-D-glucopyranosyl-(1->4)-beta-D oleandropyranosyl-(1->4)-beta-D-cymaropyranosyl-(1->4)-alpha-L-cymaropyranosyl-(1 >4)-beta-D-cymaropyranoside (2), caudatin-3-O-beta-D-glucopyranosyl-(1->4)-beta-D thevetopyranosyl-(1->4)-beta-D-cymaropyranosyl-(1->4)-beta-D-digitoxopyranoside (3) caudatin-3-O-beta-D-glucopyranosyl -(1->4)-beta-D-thevetopyranosyl-(1->4) beta-D-cymaropyranosyl-(1->4)-beta-D-cymaropyranoside (4), by detailed spectroscopic analysis and acidic hydrolysis. PMID- 26944765 TI - Insomnia symptoms and heart rate recovery among patients in cardiac rehabilitation. AB - Insomnia symptoms (i.e., difficulty falling asleep, difficulty staying asleep, and early morning awakenings) are common among people with cardiovascular disease, and have been linked to adverse cardiovascular health outcomes. Reduced parasympathetic tone is one pathway through which risk may be conferred. The purpose of this study was to evaluate whether insomnia symptoms are associated with lower parasympathetic tone in cardiac rehabilitation patients with suspected insomnia. Participants (N = 121) completed a self-report measure of insomnia severity. 1-min heart rate recovery (HRR), an index of parasympathetic tone, was obtained during a maximal exercise test. Difficulty falling asleep, but not difficulty staying asleep or early awakenings, was associated with attenuated 1 min HRR. When analyses were restricted to participants with moderate and severe insomnia severity (n = 51), the strength of this association increased. In a sample of cardiac rehabilitation patients with insomnia, only the symptom of difficulty falling asleep was associated with lower parasympathetic tone, suggesting that individual insomnia symptoms may show specificity in their associations with physiological mechanisms. PMID- 26944767 TI - [Pseudoxanthoma elasticum-like disease with deficiency of vitamin K-dependent clotting factors and cutis laxa features]. AB - BACKGROUND: Pseudoxanthoma elasticum (PXE)-like syndrome is characterized by the association of PXE and cutis laxa (CL) features with a deficiency of vitamin K dependent clotting factors. It was first described in 1971 and was identified as a distinct genetic entity in 2007 with analysis of the GGCX (gamma-glutamyl carboxylase) gene, which is involved in congenital deficiency in vitamin K dependent clotting factors. Here we report a new case of this extremely rare syndrome. PATIENTS AND METHODS: A 23-year-old female patient was seen for the emergence of loose and redundant skin following extensive weight loss. She also presented a deficiency of vitamin K-dependent clotting factors. Physical examination revealed excessive, leathery skin folds in the axillary and neck regions. A skin biopsy revealed polymorphous and fragmented elastic fibers in the reticular dermis. These were mineralized, as was demonstrated by Von Kossa staining. The clinical features of CL associated with the histopathological features of PXE and vitamin K-dependent clotting factor deficiency led us to a diagnosis of PXE-like syndrome. A molecular study of the GGCX gene showed compound heterozygosity. DISCUSSION: The GGCX gene is usually responsible for PXE like syndrome. GGCX encodes a gamma-glutamyl carboxylase necessary for activation of gla-proteins. Gla-proteins are involved both in coagulation factors in the liver and in the prevention of ectopic mineralization of soft tissues. Uncarboxylated forms of gla-proteins in fibroblast would thus enable mineralization and fragmentation of elastic fibers. PMID- 26944768 TI - [Cutaneous sarcoidosis: Correlation between dermatopathology and dermoscopy]. PMID- 26944769 TI - [Tranverse acro-osteolysis: A rare cause of nail dystrophy]. AB - BACKGROUND: Acro-osteolysis (AO) involves partial or total destruction of the distal phalanges of the fingers or toes. The range of forms of AO is extremely wide. A distinction is generally made between the acquired forms and the genetic and idiopathic forms. Herein we report a case of idiopathic transverse single finger AO associated with onychopathy. PATIENT AND METHODS: A 48-year-old woman consulted for a nail lesion involving brachyonychia in the right index finger alone (pseudo-clubbing appearance of the finger). The remainder of the clinical examination was normal, particularly in terms of neurological and dermatological investigations. Standard x-rays revealed transverse osteolysis of the middle third of the distal phalanx, occurring solely in the right index finger. DISCUSSION: While certainty regarding diagnosis of AO depends upon radiological findings, the radiological appearance is not specific. Two subgroups suggesting aetiological diagnosis may be distinguished: transverse AO with banding and longitudinal AO. With transverse AO, the diaphysis of the distal phalanx presents osteolysis with banding, but with sparing of the base of the band (pseudo fracture appearance); this appearance is suggestive of toxic causes, congenital familial conditions or repetitive micro-trauma. Upon x-ray examination, the longitudinal forms exhibit concentric resorption of the band and these forms are more often seen in a setting of neurological, vascular or metabolic disorders. The associated nail involvement frequently present helps clarify the diagnosis, with nail plate shape being dependent on the integrity of the underlying bone. CONCLUSION: Herein we report the first case of transverse AO in a single finger associated with brachyonychia, and with no discernible cause. PMID- 26944770 TI - Clinical Impact of Gastric Acid-Suppressing Medication Use on the Efficacy of Erlotinib and Gefitinib in Patients With Advanced Non-Small-Cell Lung Cancer Harboring EGFR Mutations. AB - BACKGROUND: Gastric acid-suppressing medications (AS), namely, proton pump inhibitors and histamine-2 receptor antagonists, increase gastric pH, which may reduce the absorption of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors-erlotinib and gefitinib. PATIENTS AND METHODS: From 2008 to 2011, 130 consecutive patients with advanced non-small-cell lung cancer (NSCLC) harboring EGFR mutations were treated with either erlotinib or gefitinib at our institution. The clinical characteristics of the patients were reviewed, and the efficacy and toxicity of erlotinib and gefitinib were compared for patients receiving and not receiving AS. RESULTS: Among the 130 patients, 47 received AS (AS users group), while the remaining 83 patients did not (AS non-users group). The overall response rate (ORR) and median progression-free survival (PFS) in the subject population was 60% and 10 months, respectively. In the AS users and non users groups, the ORR was 64% and 63% (P = .92), while the median PFS was 8.7 and 10.7 months (P = .13), respectively. No significant difference in either ORR or PFS was observed between the 2 groups. With regard to the toxicity, the frequencies of rash (83% vs. 86%; P = .60) and diarrhea (34% vs. 29%; P = .55) were similar for both groups. A multivariate analysis identified that AS use was not a significant factor for either PFS or OS. CONCLUSION: Concurrent use of AS did not affect the efficacy or toxicity of erlotinib and gefitinib in patients with advanced NSCLC harboring EGFR mutations. PMID- 26944771 TI - Immunogenicity screening assay development for a novel human-mouse chimeric anti CD147 monoclonal antibody (Metuzumab). AB - The clinical effect of patient immune responses to therapeutic antibodies affect product safety and efficacy, which makes the development of valid, sensitive immune assays a key aspect of antibody drug development. In this paper, we reported the generations of mouse monoclonal and Cynomolgus monkey polyclonal antibodies against the anti-CD147 antibody (Metuzumab) as the internal standards and the positive controls. Seven mouse monoclonal antibodies were shown to recognize both (Fab)2 and full length of Metuzumab, but not the control normal human IgGs, and monoclonal anti-Metuzumab, Clone 2D9 was chosen to be used as the internal standard for anti-Metuzumab study. A Bridging ELISA assay was developed by coating the wells with the antibody drug, and the anti-drug antibody (ADA) in the animal sera were detected by enzyme-labeled antibody. Its limit of detection (LOD) was determined to be 0.39ng/ml of anti-Metuzumab antibody (ADA) with linear range between 0.39-50ng/ml and R(2)=0.994. For normal monkey sera, a minimal dilution was determined to be 1:80. However, very different from peptide or other protein drugs, strong interferences from the residual antibody drugs were observed from most of the testing monkey sera in the preclinical study. It was experimentally determined that the concentration of the residual antibody drug in the assay have to be lower than 1MUg/ml, so the assays were carried out at 1:100 dilution of the monkey sera. In the pre-clinical study, 32 monkeys were treated with escalating doses of Metuzumab between 0, 10, 50, 200mg/kg for 13 times over 13weeks of time period. 16 of them were terminated right after the last injection, while the other 16 were rested for additional 4weeks before termination. Afraid to miss any positive response to antibody drug, sera samples were collected at six time points, including 2-, 6- and 10-weeks post 1st dose, prior to last dose, and 2-, 4-weeks into recovery. The highest positive rates were seen with the Medium- and High-dose group 2-weeks post the first injection, 6 out 8 monkeys in the High-dose were positive for free ADA. However, no significant pathologic and clinic adversary effect was observed in those monkeys. PMID- 26944772 TI - Reproductive outcomes of Alpine goats primed with progesterone and treated with human chorionic gonadotropin during the anestrus-to-estrus transition season. AB - This study aimed to determine the possible effects of a single injection of human chorionic gonadotropin (hCG) as a means for estrus induction in acyclic French Alpine goats during the reproductive transition period at 25 degrees N, 103 degrees W. The potential effects of hCG upon ovarian function and reproductive performance of goats were also assessed. Multiparous acyclic French-Alpine goats (n = 39; 37.4 +/- 8 .5 kg) were primed with 20mg progesterone (P4) 1 day prior to hCG administration. Thereafter, does were treated either with saline (hCG-0; n = 10), 50 (hCG-50; n = 9), 100 (hCG-100; n = 10), or 300 IU of hCG (hCG-300; n = 10). Ovarian structures and pregnancy were monitored by transrectal ultrasonography. In addition, after hCG application, goats were monitored twice daily (0800 and 1800 h) to detect estrus signs, with the use of aproned, sexually active bucks treated with testosterone. Goats were bred 12h after the onset of estrus. Two days after hCG administration, the number of large follicles was higher (P < 0.05) in the hCG-50 and hCG-300 groups (1.7 +/- 0.1 and 1.8 +/- 0.2, respectively) compared with the hCG-100 and hCG-0 groups (1.4 +/- 0.2 and 1.1 +/- 0.1, respectively). Although none of the hCG-0-goats depicted estrus, the estrus response from the hCG-50, hCG-100, and hCG-300 groups over the 7-d breeding period was 67%, 100%, and 90%, respectively (P > 0.05), being always accompanied by ovulation. Pregnancy rate (67, 100, and 70%), kidding rate (55%, 80%, and 70%), and litter size (1.6 +/- 0.5, 1.5 +/- 0.5, and 1.5 +/- 0.5) for hCG-50, hCG 100, and hCG-300, respectively, did not differ among the hCG-treated does. Therefore, the combined use of P4-priming plus a 100-IU hCG injection is an effective protocol for inducing estrus in non-cycling Alpine goats during the anestrus-to-estrus transition period, which is of key importance for both goat producers and industrializers. PMID- 26944774 TI - Sexual Medicine: New Challenges. PMID- 26944773 TI - Endosomes: Emerging Platforms for Integrin-Mediated FAK Signalling. AB - Integrins are vital cell adhesion receptors with the ability to transmit extracellular matrix (ECM) cues to intracellular signalling pathways. ECM integrin signalling regulates various cellular functions such as cell survival and movement. Integrin signalling has been considered to occur exclusively from adhesion sites at the plasma membrane (PM). However, recent data demonstrates integrin signalling also from endosomes. Integrin-mediated focal adhesion kinase (FAK) signalling is strongly dependent on integrin endocytosis, and endosomal FAK signalling facilitates cancer metastasis by supporting anchorage-independent growth and anoikis resistance. Here we discuss the possible mechanisms and functions of endosomal FAK signalling compared with its previously known roles in other cellular locations and discuss the potential of endosomal FAK as novel target for future cancer therapies. PMID- 26944775 TI - The Asia-Pacific Flexible Dose Study of Dapoxetine and Patient Satisfaction in Premature Ejaculation Therapy: The PASSION Study. AB - INTRODUCTION: Dapoxetine is a short-acting selective serotonin reuptake inhibitor for treatment of premature ejaculation (PE). AIM: To evaluate the efficacy and safety of dapoxetine 30 and 60 mg as needed in Asia-Pacific men with PE. METHODS: The study was a prospective, 12-week, open-label study to evaluate the efficacy and safety of flexible-dose dapoxetine in men with PE diagnosed by a Premature Ejaculation Diagnostic Tool score of at least 11, a self-estimated intravaginal ejaculation latency time (IELT) no longer than 2 minutes, and an International Index of Erectile Function erectile function domain score of at least 21. MAIN OUTCOME MEASURES: Percentage of subjects reporting their PE as at least "slightly better" using the Clinical Global Impression of Change (CGIC) question. RESULTS: Two hundred eighteen of 285 randomized subjects completed the study. The mean subject age was 45.9 years and 57.7% were Korean. Dosages 1 (30 mg), 2 (30 -> 60 mg), and 3 (30 -> 60 -> 30 mg) were used in 141, 124, and 13 subjects, respectively. At study end, a PE CGIC rating of at least "slightly better" was reported by 77.3%, 92.8%, and 100% of subjects for dosages 1, 2, and 3, respectively (P = .49). At study end, a CGIC rating of "slightly better" was reported by 85.2% and 85.3% of subjects with lifelong PE and acquired PE, respectively (P = .50). At study end, a CGIC rating of "slightly better" was reported by 84.1% and 86.4% of subjects with an estimated baseline IELT no longer than and at least <=1 minute, respectively (P = .16). The incidence of a CGIC rating of at least "slightly better" was lower in subjects reporting an adverse event of moderate or severe severity and in subjects who increased to and maintained a dapoxetine dose of 60 mg and higher in subjects older than 50 years and in subjects with a baseline estimated IELT of at least 1 minute. CONCLUSION: In this study, flexible dosing of dapoxetine (30 and 60 mg) appeared effective in the treatment of PE. PMID- 26944776 TI - Cabergoline in the Treatment of Male Orgasmic Disorder-A Retrospective Pilot Analysis. AB - INTRODUCTION: Male orgasmic disorder is common, with few treatment options. Cabergoline is a dopamine agonist that acts centrally to normalize serum prolactin that could improve orgasmic dysfunction. AIMS: To determine whether cabergoline increases the potential for orgasm in men with orgasmic disorder. METHODS: A retrospective chart review of men treated in a single andrology clinic for delayed orgasm or anorgasmia in a pilot study using cabergoline 0.5 mg twice weekly was performed. Duration of treatment and response were noted. Medical records were examined for other factors including history of prostatectomy and concomitant androgen supplementation. MAIN OUTCOME MEASURES: Subjective improvement in orgasmic function resulting from cabergoline treatment. RESULTS: Of 131 men treated with cabergoline for orgasmic disorder, 87 (66.4%) reported subjective improvement in orgasm and 44 (33.6%) reported no change in orgasm. Duration of therapy (P = .03) and concomitant testosterone therapy (P = .02) were associated with a significant positive response to cabergoline treatment. No differences were found between injectable and non-injectable testosterone formulations (P = .90), and neither age (P = .90) nor prior prostatectomy (P = .41) influenced the outcome of cabergoline treatment. Serum testosterone levels before (P = .26) and after (P = .81) treatment were not significantly different in responders vs non-responders. CONCLUSION: Cabergoline is a potentially effective and easy-to-administer treatment for male orgasmic disorder, the efficacy of which appears to be independent of patient age or orgasmic disorder etiology. Prospective randomized trials are needed to determine the true role of cabergoline in the treatment of this disorder. PMID- 26944777 TI - Cross-Cultural Adaptation of the Male Genital Self-Image Scale in Iranian Men. AB - INTRODUCTION: Certain sexual health problems in men can be attributed to genital self-image. Therefore, a culturally adapted version of a Male Genital Self-Image Scale (MGSIS) could help health professionals understand this concept and its associated correlates. AIM: To translate the original English version of the MGSIS into Persian and to assess the psychometric properties of this culturally adapted version (MGSIS-I) for use in Iranian men. METHODS: In total, 1,784 men were recruited for this cross-sectional study. Backward and forward translations of the MGSIS were used to produce the culturally adapted version. Reliability of the MGSIS-I was assessed using Cronbach alpha and intra-class correlation coefficients. Divergent and convergent validities were examined using Pearson correlation and known-group validity was assessed in subgroups of participants with different sociodemographic statuses. Factor validity of the scale was investigated using exploratory and confirmatory factor analyses. MAIN OUTCOME MEASURES: Demographic information, the International Index of Erectile Function, the Body Appreciation Scale, the Rosenberg Self-Esteem Scale, and the MGSIS. RESULTS: Mean age of participants was 38.13 years (SD = 11.45) and all men were married. Cronbach alpha of the MGSIS-I was 0.89 and interclass correlation coefficients ranged from 0.70 to 0.94. Significant correlations were found between the MGSIS-I and the International Index of Erectile Function (P < .01), whereas correlation of the scale with non-similar scales was lower than with similar scale (confirming convergent and divergent validity). The scale could differentiate between subgroups in age, smoking status, and income (known-group validity). A single-factor solution that explained 70% variance of the scale was explored using exploratory factor analysis (confirming uni-dimensionality); confirmatory factor analysis indicated better fitness for the five-item version than the seven-item version of the MGSIS-I (root mean square error of approximation = 0.05, comparative fit index > 1.00 vs root mean square error of approximation = 0.10, comparative fit index > 0.97, respectively). CONCLUSION: The MGSIS-I is a useful instrument to assess genital self-image in Iranian men, a concept that has been associated with sexual function. Further investigation is needed to identify the applicability of the scale in other cultures or populations. PMID- 26944778 TI - Gender Preference in the Sexual Attractions, Fantasies, and Relationships of Voluntarily Castrated Men. AB - INTRODUCTION: Some men seek castration outside a clear medical need. This study explored how their sexuality changed after castration. AIM: To explore changes in preferred gender(s) of sexual attraction, fantasy, and relationships in voluntarily castrated men with or without gonadal hormone therapy. METHODS: A questionnaire was posted at http://www.eunuch.org that yielded data on men who had been voluntarily castrated physically (n = 198) or chemically (n = 96). MAIN OUTCOME MEASURES: Respondents were asked to report retrospectively on their sexuality, including their sexual activity and which gender(s) they were sexually attracted to, fantasized about, or had sexual relations with 6 months to 1 year before and after castration. RESULTS: A substantial proportion of men remained sexually active after castration; 37% had sex at least several times per week. Most respondents did not report a change in preferred gender(s) of attraction (65%, n = 181), fantasies (62%, n = 169), or sexual relationships (66%, n = 163), although approximately 20% to 30% of respondents did report such changes and 8% to 11% became non-sexual after castration. Respondents who were attracted to and fantasized about "only men" or who had sexual relationship with "only women" before castration were the least likely to report a change subsequent to castration. Respondents who were taking neither supplemental testosterone nor estrogen were more likely to report (i) becoming attracted to no one, (ii) fantasizing about no one, and (iii) becoming sexually inactive. CONCLUSION: Sexual changes in voluntarily castrated men vary and can be influenced by various factors including the use of supplemental testosterone or estrogen therapy. PMID- 26944780 TI - Social and biological determinants of growth and development in underprivileged societies. PMID- 26944779 TI - Long-Term Follow-Up of Individuals Undergoing Sex-Reassignment Surgery: Somatic Morbidity and Cause of Death. AB - INTRODUCTION: Studies of mortality and somatic well-being after sex-reassignment surgery (SRS) of transsexual individuals are equivocal. Accordingly, the present study investigated mortality and somatic morbidity using a sample of transsexual individuals who comprised 98% (n = 104) of all surgically reassigned transsexual individuals in Denmark. AIMS: To investigate somatic morbidity before and after SRS and cause of death and its relation to somatic morbidity after SRS in Danish individuals who underwent SRS from 1978 through 2010. METHODS: Somatic morbidity and mortality in 104 sex-reassigned individuals were identified retrospectively by data from the Danish National Health Register and the Cause of Death Register. MAIN OUTCOME MEASURES: Somatic morbidity and cause of death. RESULTS: Overall, 19.2% of the sample were registered with somatic morbidity before SRS and 23.1% after SRS (P = not significant). In total, 8.6% had somatic morbidity before and after SRS. The most common diagnostic category was cardiovascular disease, affecting 18 individuals, 9 before and 14 after SRS, and 5 of those 14 who were affected after SRS had cardiovascular disease before and after SRS. Ten individuals died after SRS at an average age of 53.5 +/- 7.9 years (male to female) and 53.5 +/- 7.3 years (female to male). CONCLUSION: Of 98% of all Danish transsexuals who officially underwent SRS from 1978 through 2010, one in three had somatic morbidity and approximately 1 in 10 had died. No significant differences in somatic morbidity or mortality were found between male-to-female and female-to-male individuals. Despite the young average age at death and the relatively larger number of individuals with somatic morbidity, the present study design does not allow for determination of casual relations between, for example, specific types of hormonal or surgical treatment received and somatic morbidity and mortality. PMID- 26944781 TI - Faint electric treatment-induced rapid and efficient delivery of extraneous hydrophilic molecules into the cytoplasm. AB - Effective delivery of extraneous molecules into the cytoplasm of the target cells is important for several drug therapies. Previously, we showed effective in vivo transdermal delivery of naked siRNA into skin cells induced by faint electric treatment (ET) iontophoresis, and significant suppression of target mRNA levels (Kigasawa et al., Int. J. Pharm., 2010). This result indicates that electricity promoted the delivery of siRNA into cytoplasm. In the present study, we analyzed the intracellular delivery of naked anti-luciferase siRNA by faint ET, and found that the luciferase activity of cells expressing luciferase was reduced by in vitro ET like in vivo iontophoresis. Cellular uptake of fluorescent-label siRNA was increased by ET, while low temperature exposure, macropinocytosis inhibitor amiloride and caveolae-mediated endocytosis inhibitor filipin significantly prevented siRNA uptake. These results indicate that the cellular uptake mechanism involved endocytosis. In addition, voltage sensitive fluorescent dye DiBAC4 (3) penetration was increased by ET, and the transient receptor potential channel inhibitor SKF96365 reduced siRNA uptake, suggesting that faint ET reduced membrane potentials by changing intracellular ion levels. Moreover, to analyze cytoplasmic delivery, we used in-stem molecular beacon (ISMB), which fluoresces upon binding to target mRNA in the cytoplasm. Surprisingly, cytoplasmic ISMB fluorescence appeared rapidly and homogeneously after ET, indicating that cytoplasmic delivery is markedly enhanced by ET. In conclusion, we demonstrated for the first time that faint ET can enhance cellular uptake and cytoplasmic delivery of extraneous molecules. PMID- 26944782 TI - Endocrine therapy in post-menopausal women with metastatic breast cancer: From literature and guidelines to clinical practice. AB - Current international guidelines recommend endocrine therapy as the initial treatment of choice in hormone receptor positive advanced breast cancer. Endocrine therapy has been a mainstay of hormone responsive breast cancer treatment for more than a century. To date it is based on different approaches,such as blocking the estrogen receptor through selective receptor estrogen modulators, depleting extragonadal peripheral estrogen synthesis by aromatase inhibitors or inducing estrogen receptor degradation using selective down-regulators. Despite estrogen and/or progesterone receptor positive status, up to a quarter of patients could be either primarily resistant to hormone therapies or will develop hormone resistance during the course of their disease. Different mechanisms, either intrinsic or acquired, could be implicated in endocrine resistance. In the present work available endocrine therapies and their appropriate sequences have been reviewed, and the most promising strategies to overcome endocrine resistance have been highlighted. PMID- 26944783 TI - The expression of light-related leaf functional traits depends on the location of individual leaves within the crown of isolated Olea europaea trees. AB - BACKGROUND: The spatial arrangement and expression of foliar syndromes within tree crowns can reflect the coupling between crown form and function in a given environment. Isolated trees subjected to high irradiance and concomitant stress may adjust leaf phenotypes to cope with environmental gradients that are heterogeneous in space and time within the tree crown. The distinct expression of leaf phenotypes among crown positions could lead to complementary patterns in light interception at the crown scale. METHODS: We quantified eight light-related leaf traits across 12 crown positions of ten isolated Olea europaea trees in the field. Specifically, we investigated whether the phenotypic expression of foliar traits differed among crown sectors and layers and five periods of the day from sunrise to sunset. We investigated the consequences in terms of the exposed area of the leaves at the tree scale during a single day. KEY RESULTS: All traits differed among crown positions except the length-to-width ratio of the leaves. We found a strong complementarity in the patterns of the potential exposed area of the leaves among day periods as a result of a non-random distribution of leaf angles across the crown. Leaf exposure at the outer layer was below 60 % of the displayed surface, reaching maximum interception during morning periods. Daily interception increased towards the inner layer, achieving consecutive maximization from east to west positions within the crown, matching the sun's trajectory. CONCLUSIONS: The expression of leaf traits within isolated trees of O. europaea varies continuously through the crown in a gradient of leaf morphotypes and leaf angles depending on the exposure and location of individual leaves. The distribution of light-related traits within the crown and the complementarity in the potential exposure patterns of the leaves during the day challenges the assumption of low trait variability within individuals. PMID- 26944784 TI - Phylogenetic origin of limes and lemons revealed by cytoplasmic and nuclear markers. AB - BACKGROUND AND AIMS: The origin of limes and lemons has been a source of conflicting taxonomic opinions. Biochemical studies, numerical taxonomy and recent molecular studies suggested that cultivated Citrus species result from interspecific hybridization between four basic taxa (C. reticulata,C. maxima,C. medica and C. micrantha). However, the origin of most lemons and limes remains controversial or unknown. The aim of this study was to perform extended analyses of the diversity, genetic structure and origin of limes and lemons. METHODS: The study was based on 133 Citrus accessions. It combined maternal phylogeny studies based on mitochondrial and chloroplastic markers, and nuclear structure analysis based on the evaluation of ploidy level and the use of 123 markers, including 73 basic taxa diagnostic single nucleotide polymorphism (SNP) and indel markers. KEY RESULTS: The lime and lemon horticultural group appears to be highly polymorphic, with diploid, triploid and tetraploid varieties, and to result from many independent reticulation events which defined the sub-groups. Maternal phylogeny involves four cytoplasmic types out of the six encountered in the Citrus genus. All lime and lemon accessions were highly heterozygous, with interspecific admixture of two, three and even the four ancestral taxa genomes. Molecular polymorphism between varieties of the same sub-group was very low. CONCLUSIONS: Citrus medica contributed to all limes and lemons and was the direct male parent for the main sub-groups in combination with C. micrantha or close papeda species (for C. aurata, C. excelsa, C. macrophylla and C. aurantifolia--'Mexican' lime types of Tanaka's taxa), C. reticulata(for C. limonia, C. karna and C. jambhiri varieties of Tanaka's taxa, including popular citrus rootstocks such as 'Rangpur' lime, 'Volkamer' and 'Rough' lemons), C. aurantium (for C. limetta and C. limon- yellow lemon types--varieties of Tanaka's taxa) or the C. maxima * C. reticulate hybrid (for C. limettioides--'Palestine sweet' lime types--and C. meyeri). Among triploid limes, C. latifolia accessions ('Tahiti' and 'Persian' lime types) result from the fertilization of a haploid ovule of C. limon by a diploid gamete of C. aurantifolia, while C. aurantifolia triploid accessions ('Tanepao' lime types and 'Madagascar' lemon) probably result from an interspecific backcross (a diploid ovule of C. aurantifolia fertilized by C. medica). As limes and lemons were vegetatively propagated (apomixis, horticultural practices) the intra-sub group phenotypic diversity results from asexual variations. PMID- 26944788 TI - [Toddler's fracture]. PMID- 26944787 TI - [Primary lymphoedema outside the neonatal period]. PMID- 26944785 TI - Reproductive patterns, genetic diversity and inbreeding depression in two closely related Jumellea species with contrasting patterns of commonness and distribution. AB - BACKGROUNDS AND AIMS: Theory predicts that the long-term persistence of plant populations exposed to size reduction can be threatened by a loss of genetic diversity and increased inbreeding. However, several life-history and ecological traits can influence the response to population size reduction. The reproductive patterns, levels of genetic diversity and magnitude of inbreeding depression of the rare and fragmented Jumellea fragrans and of its widespread congener J. rossii were studied. The aim was to evaluate the effects of over-collection and fragmentation on J. fragrans and to enhance our knowledge of the biology and ecology of the two species, used for their aromatic and medicinal properties on Reunion. METHODS: Hand pollination experiments were conducted to determine the breeding system and to evaluate the potential for inbreeding depression in both species. Nuclear microsatellite markers were used to investigate selfing rates and levels of genetic diversity. KEY RESULTS: Jumellea rossii revealed a mixed mating system, and inbreeding depression at the germination stage (delta = 0.66). Levels of genetic diversity were relatively high [allelic richness (AR) = 8.575 and expected heterozygosity (He) = 0.673]. In J. fragrans, selfing rates suggest a mainly outcrossing mating system. Genetic diversity was lower than in J. rossii, but not yet critically low (AR = 4.983 and He = 0.492), probably because of the mainly outcrossing mating system and the relatively high density of individuals in the studied population. Jumellea fragrans did not show inbreeding depression, and it is hypothesized that the population had progressively purged its genetic load during successive fragmentation events. CONCLUSIONS: Even if the persistence of the J. fragrans population is not threatened in the short term, its genetic diversity has probably been reduced by fragmentation and over collection. In situ conservation actions for J. fragrans and ex situ cultivation of both species are recommended in order to meet the demand of local people. PMID- 26944789 TI - [Pyocele as a complication peritonitis in an preschooler]. PMID- 26944790 TI - [Ethical attitudes of intensive care paediatricians as regards patients with spinal muscular atrophy type 1]. AB - INTRODUCTION: Spinal muscular atrophy type 1 (SMA-1) is a progressive and fatal disease that leads to ethical problems for Paediatric professionals. Our objective was to determine the ethical options of Paediatric Intensive Care Unit (PICU) paediatricians as regards a child with SMA-1 and respiratory failure. MATERIAL AND METHODS: A cross-sectional descriptive study was conducted using an anonymous questionnaire sent to PICUs in Spain (which can be accessed through the Spanish Society of Paediatric Critical Care web page). RESULTS: Of the 124 responses analysed, 70% were from women, 51% younger than 40 years, 54% from a PICU with more than 10 beds, 69% with prior experience in such cases, and 53% with religious beliefs. In the last patient cared for, most paediatricians opted for non-invasive mechanical ventilation (NIV) and limitation of therapeutic effort (LET) in case of NIV failure. Confronted with a future hypothetical case, half of paediatricians would opt for the same plan (NIV+LET), and 74% would support the family's decision, even in case of disagreement. Age, prior experience and sex were not related to the preferred options. Paediatricians with religious beliefs were less in favour of initial LET. Less than two-thirds (63%) scored the quality of life of a child with SMA-1 and invasive mechanical ventilation as very poor. CONCLUSIONS: Faced with child with SMA-1 and respiratory failure, most paediatricians are in favour of initiating NIV and LET when such support is insufficient, but they would accept the family's decision, even in case of disagreement. PMID- 26944791 TI - Atherosclerotic renal artery stenosis in the post-CORAL era part 1: the renal penumbra concept and next-generation functional diagnostic imaging. AB - After three neutral trials in which renal artery stenting failed to improve renal function or reduce cardiovascular and renal events, the controversy surrounding diagnosis and treatment of atherosclerotic renal artery stenosis and renovascular hypertension has led to paradigm shifts in the diagnostic algorithm. Noninvasive determination of earlier events (cortex hypoxia and renal artery hemodynamic changes) will supersede late sequelae (calcific stenosis, renal cortical thinning). Therefore, this review proposes the concept of renal penumbra in defining at-risk ischemic renal parenchyma. The complex field of functional renal magnetic resonance imaging will be reviewed succinctly in a clinician-directed fashion. PMID- 26944792 TI - Regulation and production of Tcf, a cable-like fimbriae from Salmonella enterica serovar Typhi. AB - tcf (Typhi colonization factor) is one of the 12 putative chaperone/usher fimbrial clusters present in the Salmonella enterica serovar Typhi genome. We investigated the production, expression and regulation of tcf as well as its role during interaction with human cells. The tcf gene cluster was cloned and induced in Escherichia coli and S. Typhi, and the production of intertwined fibres similar to the Cbl (cable) pili of Burkholderia cepacia was observed on the bacterial surface by electron microscopy. In S. Typhi, tcf was expressed more after growth in M63 minimal medium than in standard Luria-Bertani medium. Analysis of the promoter region identified putative binding sites for the global regulators RcsB, ArgR and Fur. The expression of tcf was measured in isogenic strains lacking these global regulators. Under the conditions tested, the results showed that tcf expression was higher in the fur mutant and was regulated by iron concentration. Fur may regulate these fimbriae indirectly via the small RNAs RyhB1 and RyhB2. An isogenic mutant harbouring a deletion of the tcf cluster did not demonstrate any defect in adhesion or invasion of human epithelial cells, or in phagocytosis or survival in macrophages, when compared to the WT serovar Typhi strain. However, the tcf cluster contributed to adherence to human epithelial cells when introduced into E. coli. Thus, tcf genes encode functional fimbriae that can act as an adhesin and may contribute to colonization during typhoid fever. PMID- 26944793 TI - Next Generation Prokaryotic Engineering: The CRISPR-Cas Toolkit. AB - The increasing demand for environmentally friendly production processes of green chemicals and fuels has stimulated research in microbial metabolic engineering. CRISPR-Cas-based tools for genome editing and expression control have enabled fast, easy, and accurate strain development for established production platform organisms, such as Escherichia coli and Saccharomyces cerevisiae. However, the growing interest in alternative production hosts, for which genome editing options are generally limited, requires further developing such engineering tools. In this review, we discuss established and emerging CRISPR-Cas-based tools for genome editing and transcription control of model and non-model prokaryotes, and we analyse the possibilities for further improvement and expansion of these tools for next generation prokaryotic engineering. PMID- 26944795 TI - Honouring the past and shaping the future. PMID- 26944794 TI - Biological Synthesis of Nanoparticles from Plants and Microorganisms. AB - Nanotechnology has become one of the most promising technologies applied in all areas of science. Metal nanoparticles produced by nanotechnology have received global attention due to their extensive applications in the biomedical and physiochemical fields. Recently, synthesizing metal nanoparticles using microorganisms and plants has been extensively studied and has been recognized as a green and efficient way for further exploiting microorganisms as convenient nanofactories. Here, we explore and detail the potential uses of various biological sources for nanoparticle synthesis and the application of those nanoparticles. Furthermore, we highlight recent milestones achieved for the biogenic synthesis of nanoparticles by controlling critical parameters, including the choice of biological source, incubation period, pH, and temperature. PMID- 26944796 TI - Modified siRNA effectively silence inducible immunoproteasome subunits in NSO cells. AB - The pathogenesis of autoimmune and neurodegenerative diseases involves overexpression of inducible subunits of the immunoproteasome. However, the clinical application of inhibitors to inducible subunits of the immunoproteasome has been limited due to systemic toxicity. Here, we designed siRNAs that efficiently silence LMP2, LMP7 and MECL-1 gene expression. Inducible subunits of the immunoproteasome are complex siRNA targets because they have a long half life; therefore, we introduced 2'-O-methyl modifications into nuclease-sensitive sites. This led to 90-95% silencing efficiency and prolonged silencing, eliminating the need for multiple transfections. Furthermore, we showed that in the absence of transfection reagent, siRNAs with lipophilic residues were able to penetrate cells more effectively and decrease the expression of inducible immunoproteasome subunits by 35% after 5 days. These results show that siRNA targeted to inducible immunoproteasome subunits have great potential for the development of novel therapeutics for autoimmune and neurodegenerative diseases. PMID- 26944797 TI - Valproic acid reduces insulin-resistance, fat deposition and FOXO1-mediated gluconeogenesis in type-2 diabetic rat. AB - Recent evidences highlighted the role of histone deacetylases (HDACs) in insulin resistance, gluconeogenesis and islet function. HDACs can modulate the expression of various genes, which directly or indirectly affect glucose metabolism. This study was aimed to evaluate the role of valproic acid (VPA) on fat deposition, insulin-resistance and gluconeogenesis in type-2 diabetic rat. Diabetes was developed in Sprague-Dawley rats by the combination of high-fat diet and low dose streptozotocin. VPA at the doses of 150 and 300 mg/kg/day and metformin (positive control) 150 mg/kg twice daily for 10 weeks were administered by oral gavage. Insulin-resistance, dyslipidemia and glycemia were evaluated by biochemical estimations, while fat accumulation and structural alteration were assessed by histopathology. Protein expression and insulin signaling were evaluated by western blot and immunohistochemistry. VPA treatment significantly reduced the plasma glucose, HbA1c, insulin-resistance, fat deposition in brown adipose tissue, white adipose tissue and liver, which are comparable to metformin treatment. Further, VPA inhibited the gluconeogenesis and glucagon expression as well as restored the histopathological alterations in pancreas and liver. Our findings provide new insights on the anti-diabetic role of VPA in type-2 diabetes mellitus by the modulation of insulin signaling and forkhead box protein O1 (FOXO1)-mediated gluconeogenesis. Since VPA is a well established clinical drug, the detailed molecular mechanisms of the present findings can be further investigated for possible clinical use. PMID- 26944798 TI - Classification of Nonomuraea sp. ATCC 39727, an actinomycete that produces the glycopeptide antibiotic A40926, as Nonomuraea gerenzanensis sp. nov. AB - Strain ATCC 39727, which produces the antibiotic A40926 (the natural precursor of the antibiotic dalbavancin), was isolated from a soil sample collected in India, and it was originally classified as a member of the genus Actinomadura on the base of morphology and cell-wall composition. A phylogenetic analysis based on 16S rRNA gene sequences indicates that the strain forms a distinct clade within the genus Nonomuraea, and it is most closely related to Nonomuraea angiospora DSM 43173T (98.72 % similarity) and Nonomuraea jabiensis A4036T (98.69 %). The strain forms an extensively branched substrate mycelium and aerial hyphae that form spiral chains of spores with ridged surfaces. The cell wall contains meso diaminopimelic acid and the whole-cell sugars are glucose, ribose, galactose, mannose and madurose (madurose as the diagnostic sugar). The N-acyl type of muramic acid is acetyl. The predominant menaquinone is MK-9(H4), with minor amounts of MK-9(H2), MK-9(H6) and MK-9(H0). The polar-lipid profile includes diphosphatidylglycerol, phosphatidylethanolamine, hydroxyphosphatidylethanolamine, phosphatidylmethylethanolamine, hydroxyphosphatidylmethylethanolamine, phosphatidylinositol and a series of uncharacterized phospholipids, glycolipids and phosphoglycolipids. The major cellular fatty acids are iso-C16 : 0 and 10-methyl C17 : 0. The genomic DNA G+C content is 71.2 mol%. Significant differences in the morphological, chemotaxonomic and biochemical data, together with DNA-DNA relatedness between strain ATCC 39727 and closely related type strains, clearly demonstrated that strain ATCC 39727 represents a novel species of the genus Nonomuraea, for which the name Nonomuraea gerenzanensis sp. nov. is proposed. The type strain is ATCC 39727T ( = DSM 100948T). PMID- 26944800 TI - Translational Science for School Nursing and School Health Services: Implications for Authors. PMID- 26944799 TI - Pseudoroseicyclus aestuarii gen. nov., sp. nov., isolated from a tidal flat. AB - A Gram-stain-negative, non-motile, aerobic and coccoid, ovoid or rod-shaped bacterial strain, designated DB-4T, was isolated from a tidal flat of the Yellow Sea, South Korea. Strain DB-4T grew optimally at 30 degrees C, at pH 7.0-8.0 and in the presence of approximately 1.0-2.0 % (w/v) NaCl. Phylogenetic trees based on 16S rRNA gene sequences revealed that strain DB-4T clustered with the type strain of Roseicyclus mahoneyensis, showing sequence similarity of 94.8 %. It exhibited sequence similarity values of 95.6-96.1 % to the type strains of Loktanella soesokkakensis, Loktanella hongkongensis, Loktanella variabilis, Loktanella aestuariicola and Loktanella cinnabarina. Strain DB-4T contained Q-10 as the predominant ubiquinone and C18:1omega7c and cyclo C19:0omega8c as the major fatty acids. The major polar lipids of strain DB-4T were phosphatidylcholine, phosphatidylglycerol and one unidentified aminolipid. The fatty acid and polar lipid profiles of strain DB-4T were distinguished from those of the type strains of R. mahoneyensis and some phylogenetically related Loktanella species. The DNA G+C content of strain DB-4T was 69.2 mol%. On the basis of the phylogenetic, chemotaxonomic and other phenotypic properties, strain DB-4T is considered to represent a novel species of a new genus within the family Rhodobacteraceae, for which the name Pseudoroseicyclus aestuarii gen. nov., sp. nov. is proposed. The type strain ofPseudoroseicyclus aestuarii is DB-4T (=KCTC 52038T=CECT 9025T). PMID- 26944801 TI - Characterization of a dual-CRD galectin in the silkworm Bombyx mori. AB - Galectins (S-type lectins) are an ancient family of lectins with the beta galactoside binding activity. In mammals, galectins play essential roles in many biological processes, such as development, immune homeostasis and tumor progression. However, few studies have been devoted to their functions in insects. Here, we characterized the only dual-CRD galectin in the silkworm Bombyx mori (BmGalectin-4). BmGalectin-4 cDNA possesses an open reading frame of 1089 bp, which encodes a putative galectin of 363 amino acids containing tandem carbohydrate recognition domains (CRDs). BmGalectin-4 was expressed in various tissues but the protein was most abundant in fertilized eggs. Its transcript level in fertilized eggs was upregulated upon bacterial challenge. Recombinant BmGalectin-4 purified from Escherichia coli bound to bacterial cell wall components and bacterial cells. In addition, the recombinant protein induced bacterial agglutination, but did not have antibacterial activity against selected microorganisms. Taken together, our results suggest that BmGalectin-4 may function as a pattern recognition receptor primarily in silkworm fertilized eggs. PMID- 26944802 TI - Bjcul, a snake venom lectin, modulates monocyte-derived macrophages to a pro inflammatory profile in vitro. AB - Macrophages are cells of high plasticity and can act in different ways to ensure that the appropriate immune response remains controlled. This study shows the effects of the C-type Bothrops jararacussu venom lectin (BJcuL) on the activation of human macrophages derived from the U937 cell line. BJcuL binds on the cell surface, and this event is inhibited by its specific carbohydrate. It induced phagocytosis and production of H2O2, and expression of antigen presentation molecules. It also enhanced the production of TNF-alpha, GM-CSF and IL-6 by macrophages and indirectly induced T cells to an increased production of TNF alpha, IFN-gamma and IL-6 in the presence of LPS. Our results suggest that BJcuL can modulate macrophage functional activation towards an M1 state. PMID- 26944804 TI - Social Activities, Incident Cardiovascular Disease, and Mortality. AB - OBJECTIVE: This study examined the relationships between social activities, incident cardiovascular disease (CVD), and non-CVD mortality among older adults in the United States. METHOD: Data from the Health and Retirement Study (2006 2010) were employed. Two measures of social engagement, volunteering and informal helping, along with two measures of social participation, attendance at religious services and social group meetings, were included. Mediation models for health behaviors were estimated. RESULTS: Multinomial logistic regression models demonstrated that volunteering provided the most consistent results in terms of a lower risk of incident CVD and mortality. Furthermore, volunteering at higher time commitments is related to lower CVD incidence and death; informally helping others at a modest time commitment is related to lower risk of death only. Health behaviors mediated the relationships. Social participation was not related to either CVD or mortality. DISCUSSION: Social activity is a modifiable behavior that may be considered a potential health intervention. PMID- 26944803 TI - Activities of xenobiotic metabolizing enzymes in rat placenta and liver in vitro. AB - In order to assess whether the placental metabolism of xenobiotic compounds should be taken into consideration for physiologically-based toxicokinetic (PBTK) modelling, the activities of seven phase I and phase II enzymes have been quantified in the 18-day placenta of untreated Wistar rats. To determine their relative contribution, these activities were compared to those of untreated adult male rat liver, using commonly accepted assays. The enzymes comprised cytochrome P450 (CYP), flavin-containing monooxygenase (FMO), alcohol dehydrogenase (ADH), aldehyde dehydrogenase (ALDH), esterase, UDP-glucuronosyltransferase (UGT), and glutathione S-transferase (GST). In contrast to liver, no activities were measurable for 7-ethylresorufin-O-dealkylase (CYP1A), 7-pentylresorufin-O dealkylase (CYP2B), 7-benzylresorufin-O-dealkylase (CYP2B, 2C and 3 A), UGT1, UGT2 and GST in placenta, indicating that the placental activity of these enzymes was well below their hepatic activity. Low activities in placenta were determined for FMO (4%), and esterase (8%), whereas the activity of placental ADH and ALDH accounted for 35% and 40% of the hepatic activities, respectively. In support of the negligible placental CYP activity, testosterone and six model azole fungicides, which were readily metabolized by rat hepatic microsomes, failed to exhibit any metabolic turnover with rat placental microsomes. Hence, with the possible exception of ADH and ALDH, the activities of xenobiotic-metabolizing enzymes in rat placenta are too low to warrant consideration in PBTK modelling. PMID- 26944806 TI - Sub-Ethnic and Geographic Variations in Out-of-Pocket Private Health Insurance Premiums Among Mid-Life Asians. AB - OBJECTIVE: This study examined out-of-pocket premium burden of mid-life Asian Americans by comparing six sub-groups of Asians after controlling for geographic clustering at the county and state levels. METHOD: The 2007-2011 National Health Interview Survey was linked to community-level data and analyzed for 4,628 Asians (ages 50-64), including 697 Asian Indians, 1,125 Chinese, 1,393 Filipinos, 434 Japanese, 524 Koreans, and 455 Vietnamese. Non-Hispanic Whites were included as a comparison group ( n = 48,135). Three-level multilevel modeling (state > county > individual) was conducted. RESULTS: Koreans and Vietnamese were found as vulnerable sub-groups considering their lower private health insurance rates and higher uninsured rates. Among those with private insurance, Asians, specifically Filipinos, paid significantly less than non-Hispanic Whites. Moderate but significant variations in the county- and state-level variance in out-of-pocket premiums were found, especially among mid-life Asians. DISCUSSION: This study demonstrates the importance of examining within-group heterogeneity and geographic variations in understanding premium burden among mid-life Asians. PMID- 26944805 TI - Access to Care and Diabetes Management Among Older American Indians With Type 2 Diabetes. AB - OBJECTIVE: To examine the relationship between health care access and diabetes management among a geographically diverse sample of American Indians (AIs) aged 50 and older with type 2 diabetes. METHOD: We examined the relationship between access to care and diabetes management, as measured by HbA1c, using 1998-1999 data from the Strong Heart Family Study. A series of bivariate and multivariate linear models examined the relationships between nine access-related variables and HbA1c levels. RESULTS: In bivariate analyses, out-of-pocket costs were associated with higher HbA1c levels. No other access-related characteristics were significantly associated with diabetes management in bivariate or in multivariate models. DISCUSSION: Access-related barriers were not associated with worse diabetes management in multivariate analyses. The study concludes with implications for clinicians working with AI populations to enhance opportunities for diabetes management. PMID- 26944807 TI - Task-Specific Fatigue Among Older Primary Care Patients. AB - OBJECTIVE: Fatigue is a common condition contributing to disability among older patients. We studied self-reported task-specific fatigue and its relation with mobility task performance among community-dwelling primary care patients. METHOD: Cross-sectional analysis of baseline demographic and health data from a prospective cohort study of 430 primary care patients aged 65 years or older. Fatigue was measured using the Avlund Mobility-Tiredness Scale. Performance tasks included rising from a chair, walking 4 m, and climbing two flights of stairs. RESULTS: Among demographic and health factors, pain was the only attribute consistently predictive of fatigue status. Self-reported chair rise fatigue and walking fatigue were associated with specific task performance. Stair climb fatigue was not associated with stair climb time. DISCUSSION: Pain is strongly associated with fatigue while rising from a chair, walking indoors, and climbing stairs. This study supports the validity of self-reported chair rise fatigue and walking fatigue as individual test items. PMID- 26944808 TI - Reducing Sedentary Behavior Versus Increasing Moderate-to-Vigorous Intensity Physical Activity in Older Adults. AB - OBJECTIVE: To compare the effects of behavioral interventions targeting decreased sedentary behavior versus increased moderate-to-vigorous intensity physical activity (MVPA) in older adults. METHOD: Inactive older adults ( N = 38, 68 +/- 7 years old, 71% female) were randomized to 12-week interventions targeting decreased sedentary behavior ( Sit Less) or increased MVPA ( Get Active). The SenseWear armband was used to objectively assess activity in real time. Assessments included a blinded armband, the Community Health Activites Model Program for Senior (CHAMPS) questionnaire, 400-meter walk, and the Short Physical Performance Battery (SPPB). RESULTS: Objectively measured MVPA increased in Get Active (75 +/- 22 min/week, p < .001); self-reported MVPA increased in both groups ( p < .05). Sedentary behavior did not change in either group (all p > .05). Only the Sit Less group improved the SPPB score (0.5 +/- 0.3, p = .046). DISCUSSION: Targeting reduced sedentary behavior had a greater effect on physical function among inactive but high functioning older adults over 12 weeks. Future studies of longer duration and combining increased MVPA with reduced sedentary behavior are needed. PMID- 26944809 TI - Race Differences in Advance Directive Completion. AB - OBJECTIVE: Rates of advance directive completion have increased over the past decade, but significant race differences remain. This study examined how overall increases in advance directive completion have affected disparities between White and African American older adults. METHOD: Data were taken from the Health and Retirement Study (HRS). Using logistic regression models, the odds of having an advance directive among a sample of older African Americans and Whites who died between 2001 and 2012 were compared ( N = 5,832). RESULTS: Odds for African Americans were 16% of the odds for Whites, p < .001, 95% confidence interval (CI) = [0.11, 0.23]. There were no significant interactions between race and year of death before 2010. During 2010-2012, the increase in the odds for African Americans was greater than for Whites, odds ratio (OR) = 1.95, p = .02, 95% CI = [1.14, 3.35]. DISCUSSION: Although race disparities remain, the gap between Whites and African Americans has begun to narrow. PMID- 26944810 TI - Can We Resolve the Disconnect Between How Communication Interventions Work and How We Evaluate Them? PMID- 26944811 TI - [Addictions: Motivated or forced care]. AB - Patients presenting with addictions are often obliged to consult. This constraint can be explicit (partner, children, parents, doctor, police, justice) or can be implicit (for their children, for their families, or for their health). Thus, beyond the fact that the caregiver faces the paradox of caring for subjects who do not ask treatment, he faces as well a double bind considered to be supporter of the social order or helper of patients. The transtheoretical model of change is complex showing us that it was neither fixed in time, nor perpetual for a given individual. This model includes ambivalence, resistance and even relapse, but it still considers constraint as a brake than an effective tool. Therapist must have adequate communication tools to enable everyone (forced or not) understand that involvement in care will enable him/her to regain his free will, even though it took to go through coercion. We propose in this article to detail the first steps with the patient presenting with addiction looking for constraint (implicit or explicit), how to work with constraint, avoid making resistances ourselves and make of constraint a powerful motivator for change. PMID- 26944812 TI - [Hypnosis for anxiety and phobic disorders: A review of clinical studies]. AB - OBJECTIVE: Hypnosis is classically presented as a useful psychotherapy for various psychiatric conditions, especially in the field of stress and anxiety. However, its place in therapeutic of chronic anxiety disorders remains unclear and questioned. Thus, the goal of this systematic review was to analyse the papers reporting clinical data on the efficacy of hypnosis in anxiety disorders. METHODS: A literature search was conducted on Pubmed to retrieve all original papers, published between 1980 and 2015, reporting clinical information on the efficacy of hypnosis in six categories of anxiety disorders. Each paper has been assessed from a methodological point of view, and the results have been analysed. RESULTS: Only three controlled studies have been identified, one in panic disorder and two in post-traumatic stress disorder (PTSD). The other papers related open-design studies (4 articles), or single case reports (20 articles). The controlled study conducted in panic disorder suggested that the combination of hypnosis with cognitive-behavior therapy was not an effective strategy, and this negative result was also obtained in one of the studies conducted in PTSD. The third study, including 48 Indonesian children with PTSD, showed a significant improvement with a specific hypnosis technique adapted to the local culture. Other papers related also positive results but in non-controlled studies or in case reports, their conclusions cannot be generalized. CONCLUSION: To date, evidence is negative or insufficient to support the efficacy of hypnosis in chronic anxiety disorders, in any categories whatsoever - including phobia or PTSD. Specific further studies are needed to identify some potential profiles predictive of response to hypnosis in these conditions. PMID- 26944813 TI - [Bacterial meningoencephalitis secondary to sinusitis: Imputability of nonsteroidal anti-inflammatory drugs?]. PMID- 26944814 TI - Self-reported dyspnea is associated with impaired global longitudinal strain in ambulatory type 1 diabetes patients with normal ejection fraction and without known heart disease - The Thousand & 1 Study. AB - AIMS: Identification of early signs and symptoms of heart disease is important in type 1 diabetes (T1DM). Global longitudinal strain (GLS) by speckle-tracking echocardiography can detect subtle impairments in myocardial function. We investigated the association between myocardial function and degree of dyspnea in patients with normal left ventricular ejection fraction (LVEF) and without known heart disease. METHODS: Ambulatory patients from Steno Diabetes Center. Conventional echocardiography and GLS was performed. Patients reported degree of dyspnea according to the NYHA classification. Patients with LVEF<=45% were excluded. Data were analyzed in uni-and multivariable models. RESULTS: A total of 1075 T1DM patients were included. Mean age 49.5years, 52% men, mean diabetes duration 25.8years; 835 (77.7%) reported no dyspnea, 156 (14.5%) NYHA I, 68 (6.3%) NYHA II, and 16 (1.5%) NYHA III-IV. LVEF did not differ between groups of dyspnea in neither univariable nor multivariable models (p>0.1). E/e' was associated with degree of dyspnea in both univariable (p<0.001) and multivariable models (p=0.048). GLS was associated with degree of dyspnea in a dose-response relationship in both univariable (p<0.001) and multivariable models (p<0.001). CONCLUSIONS: Degree of dyspnea is independently associated with impaired myocardial function by GLS in T1DM patients with normal LVEF and without known heart disease. PMID- 26944815 TI - Outpatient Latarjet surgery for gleno-humeral instability: Prospective comparative assessment of feasibility and safety. AB - BACKGROUND: Some surgical procedures are rarely done on an outpatient basis. The primary objective of this study was to assess the safety of outpatient surgical shoulder stabilisation using the Latarjet procedure. HYPOTHESIS: The Latarjet procedure is safe when performed on an outpatient basis provided the patients are managed according to a specifically designed programme starting at the decision to undergo surgery and ending at the end of the early postoperative period. PATIENTS AND METHODS: Consecutive patients with unidirectional anterior shoulder instability managed in 2013-2014 by primary open, minimally invasive surgery involving coracoid process transfer as described by Latarjet was included prospectively. One of the surgeons routinely offered outpatient surgery to patients who met none of the usual exclusion criteria (age>60years, ASA 3-4, and long distance from home to hospital). Standardised protocols were applied for anaesthesia and analgesia. The primary evaluation criterion was failure of the admission modality, defined as inpatient admission of a patient after outpatient surgery either without prior discharge or within 1week after discharge. Secondary evaluation criteria were early postoperative symptoms and functional outcomes after at least 1year. All self-reported criteria were entered online by the patients. RESULTS: Of 46 included patients, 17 had outpatient surgery and 29 inpatient surgery. There were 41 males and 5 females, with a mean age of 25.3+/ 6.4years. No significant baseline differences were found between the two groups. None of the outpatients required inpatient admission or readmission. No postoperative complications were recorded. After a mean follow-up of 18.5+/ 5.2months, the two groups showed no significant differences for return to sports, apprehension, avoidance behaviours, or functional outcomes. Most patients were satisfied with their management and outcomes. CONCLUSION: No serious adverse events were recorded in this first French prospective evaluation of the safety of open, minimally invasive shoulder stabilisation by the Latarjet procedure performed on an outpatient basis. Thus, in selected patients, the risks of outpatient surgery are similar to those of inpatient surgery. LEVEL OF EVIDENCE: III, prospective, comparative, non-randomised study. PMID- 26944816 TI - What is new in neuro-musculoskeletal interactions? From brains to babies. PMID- 26944818 TI - Whole body vibration training improves vibration perception threshold in healthy young adults: A randomized clinical trial pilot study. AB - OBJECTIVES: Loss of foot sensitivity is a relevant parameter to assess and prevent in several diseases. It is crucial to determine the vibro-tactile sensitivity threshold response to acute conditions to explore innovative monitor tools and interventions to prevent and treat this challenge. The aims were: 1) to analyze the acute effects of a single whole body vibration session (4min-18Hz 4mm) on vibro-tactile perception threshold in healthy young adults. 2) to analyze the 48 hours effects of 3 whole body vibration sessions on vibro-tactile perception threshold in healthy young adults. METHODS: A randomized controlled clinical trial over 3 sessions of whole body vibration intervention or 3 sessions of placebo intervention. Twenty-eight healthy young adults were included: 11 experimental group and 12 placebo group. The experimental group performed 3 sessions of WBV while the placebo group performed 3 sessions of placebo intervention. RESULTS: The vibro-tactile threshold increased right after a single WBV session in comparison with placebo. Nevertheless, after 3 whole body vibration sessions and 48 hours, the threshold decreased to values lower than the initial. CONCLUSIONS: The acute response of the vibro-tactile threshold to one whole body vibration session increased, but the 48 hours short-term response of this threshold decreased in healthy young adults. PMID- 26944817 TI - Improvement in muscle performance after one-year cessation of low-magnitude high frequency vibration in community elderly. AB - OBJECTIVES: To investigate the effects on muscle performance after one-year cessation of 18-month low-magnitude high-frequency vibration (LMHFV) intervention in the untrained community elderly. METHODS: This is a case-control study with 59 community elderly women (25 control without any treatment; 34 received 18-month LMHFV but discontinued for 1 year from our previous clinical study). Muscle strength, balancing ability, occurrence of fall/fracture, quality of life (QoL) were assessed 1-year after cessation of intervention. The 30-month results were compared with baseline and 18-month treatment endpoint data between groups. RESULTS: At 30 months (i.e. one year post-intervention), the muscle strengths of dominant and non-dominant legs relative to baseline in treatment group were significantly better than those of control. In balancing ability test, reaction time, movement velocity and maximum excursion of treatment group (relative to baseline) remained significantly better than the control group. The muscle strength, balancing ability and quality of life at 30 months relative to 18 months did not show significant differences between the two groups. CONCLUSION: The benefits of LMHFV for balancing ability, muscle strength and risk of falling in elderly were retained 1 year after cessation of LMHFV. PMID- 26944819 TI - The negative effect of sitting time on bone is mediated by lean mass in pubertal children. AB - OBJECTIVE: Effects of time in moderate to vigorous physical activity (MVPA) and sitting (SIT) on bone were tested, hypothesizing that high MVPA would be positively associated with bone size and strength, offset effects of high SIT, and be mediated by lean mass. METHODS: 155 children (79 male, 58 pubertal), 6-20 years (10.2+/-3.5 yr) were measured by dual-energy x-ray absorptiometry (DXA) and peripheral quantitative computed tomography (pQCT). MVPA and SIT were measured by 7-day activity recall. Regression analyses tested effects of MVPA and SIT on bone. Mediation analysis was conducted to determine if lean mass mediated the effect of activity on bone. RESULTS: In pubertal boys, SIT was negatively associated with tibial endosteal and periosteal circumference as well as bone strength (beta= -0.19, -0.14, and -5.68, respectively; all p<0.05). Effects of SIT on bone circumferences and strength were mediated by lean mass. MVPA did not offset the effects of SIT. In pubertal girls, MVPA was positively associated with cortical thickness (beta=0.01, p<0.05) and the association was not mediated by lean mass. CONCLUSIONS: Current health communications that encourage increased physical activity should include additional messaging to decrease time spent sitting, especially in pubertal boys. PMID- 26944820 TI - Safety and efficacy of denosumab in children with osteogenesis imperfect--a first prospective trial. AB - OBJECTIVES: Osteogenesis imperfecta (OI) is a rare hereditary disease leading to bone fragility. Denosumab as a RANK ligand antibody inhibiting osteoclast maturation has been approved for osteoporosis treatment in adults. Aim of this study was a 48-week, open-label, pilot study of the safety and efficacy of denosumab in 10 children with OI. METHODS: Ten patients (age range: 5.0-11.0 years; at least two years of prior bisphosphonate treatment) with genetically confirmed OI were studied. Denosumab was administered subcutaneously every 12 weeks with 1 mg/kg body weight. Primary endpoint was change of areal bone mineral density (aBMD) using dual energy x-ray absorptiometry of the lumbar spine after 48 weeks. Safety was assessed by bone metabolism markers and adverse event reporting. RESULTS: Mean relative change of lumbar aBMD was +19 % (95%-CI: 7 31%). Lumbar spine aBMD Z-Scores increased from -2.23+/-2.03 (mean+/-SD) to 1.27+/-2.37 (p=0.0006). Mobility did not change (GMFM-88 +2.72+/-4.62% (p=0.16); one-minute walking test +11.00+/-15.82 m (p=0.15). No severe side effects occurred. CONCLUSIONS: On average, there was a significant increase in lumbar spine aBMD percent change after 48 weeks of denosumab. There was no change in mobility parameters and no serious adverse events. Further trials are necessary to assess long-term side effects and efficacy. PMID- 26944821 TI - Patella bone density is lower in knee osteoarthritis patients experiencing moderate-to-severe pain at rest. AB - OBJECTIVE: To determine differences in patellar subchondral bone mineral density (BMD) between knee osteoarthritis (OA) patients with differing levels of pain at rest. METHODS: The preoperative knee of 41 total knee replacement (TKR) patients was scanned using QCT and scored for pain using Western Ontario McMasters Osteoarthritis Index (WOMAC). 'Pain at rest' was defined as average pain while lying//sitting and nocturnal pain. Participants were divided into groups: 'mild to-no pain at rest' and 'moderate-to-severe pain at rest'. We used a depth specific CT-based mapping technique to measure patellar subchondral BMD at depths of 0-2.5 mm, 2.5-5 mm, and 5-7.5 mm from the subchondral surface. Mean lateral and medial facet BMD were compared between groups using MANCOVA. RESULTS: Mean adjusted BMD was lower in participants with 'moderate-to-severe pain at rest' over the total lateral facet at depths of 0-2.5 mm (10% lower, p=0.041), 2.5-5 mm (20% lower, p=0.017), and 5-7.5 mm (25% lower, p=0.004), and over the total medial facet at 2.5-5 mm (22% lower, p=0.033) and 5-7.5 mm (28% lower, p=0.016). CONCLUSIONS: In OA patients with 'moderate-to-severe pain at rest', depth specific density measures demonstrated up to 28% lower lateral and medial subchondral BMD. Patients with high levels of pain at rest may have reduced amounts of native bone prior to TKR. PMID- 26944822 TI - Vibratory sense deficits in patients with symptomatic femoroacetabular impingement. AB - OBJECTIVE: Sensory deficits, measured through vibratory perception threshold (VPT), have been recognized in hip and knee osteoarthritis (OA), but have not been evaluated in femoroacetabular impingement (FAI), thought to be a pre-OA condition. This study aimed to assess VPT in symptomatic FAI pre- and 6-months post-arthroscopy vs. METHODS: FAI patients and controls were assessed for VPT at the first metatarsophalangeal joint. Pain was assessed using a visual analog pain scale. FAI participants were evaluated again 6-months after surgery for FAI. Differences between groups and pre- and post- surgery were evaluated with independent and paired sample t-tests, respectively. Secondary analysis was performed using repeated-measures ANOVA to evaluate the effect of pain and time since surgery on VPT pre- and post-operatively. RESULTS: No differences in age and BMI were seen between groups (p>0.05). Reduced VPT (higher value is worse) was evident in the pre- (8.0+/-3.9V, t=2.81, p=0.009) and post-operative (6.8+/ 2.8V, t=2.34, p=0.027) patients compared to controls (4.7+/-1.3V). After hip arthroscopy, there was a trend toward improved VPT (t=1.97, p=0.068). Preoperative and 6-months postoperative pain and time since surgery were not found to influence VPT (F-ratio?0.00, p?0.427). CONCLUSION: Sensory deficits were observed in FAI patients both before and 6-months after hip arthroscopy. PMID- 26944823 TI - Osteocytic connexin 43 is not required for the increase in bone mass induced by intermittent PTH administration in male mice. AB - OBJECTIVE: To investigate whether osteocytic connexin 43 (Cx43) is required for the bone response to intermittent PTH administration, and whether the connexin is involved in maintaining the bone matrix. METHODS: Human PTH(1-34) was injected to adult male mice expressing (Cx43(fl/fl)) or not osteocytic Cx43 (Cx43(fl/fl);DMP1 8kb-Cre) daily (100 ug/kg/d) for 14 days. RESULTS: Cx43(fl/fl);DMP1-8kb-Cre mice have no difference in body weight and BMD from 1 to 4 months of age. Intermittent PTH administration increased BMD and BV/TV and induced a similar increase in type I collagen, alkaline phosphatase, runx2, osteocalcin, and bone sialoprotein expression in mice from both genotypes. On the other hand, osteocytic deletion of Cx43 did not alter mRNA levels of glycosaminoglycans, proteoglycans, collagens and osteoblast-related genes. In addition, expression of collagens assessed by immunohistochemistry was not affected by deleting osteocytic Cx43. However, PTH administration increased type II collagen only in Cx43(fl/fl) control mice, whereas hormone increased type I collagen expression only in Cx43(fl/fl);DMP1-8kb Cre mice. Furthermore, PTH increased maturity of collagen fibers in control, but not in Cx43-deficient mice. CONCLUSION: Expression of Cx43 in osteocytes is dispensable for bone anabolism induced by intermittent PTH administration; but it can modulate, at least in part, the effect of PTH on the bone matrix environment. PMID- 26944824 TI - Effects of short term water immersion on peripheral reflex excitability in hemiplegic and healthy individuals: A preliminary study. AB - BACKGROUND: Reflex excitability is increased in hemiplegic patients compared to healthy controls. One challenge of stroke rehabilitation is to decrease the effects of hyperreflexia, which may be possible with water immersion. Methods/Aims: The present study examined the effects of acute water immersion on electrically-evoked Hmax:Mmax ratios (a measure of reflex excitability) in 7 hyperreflexive hemiplegic patients and 7 age-matched healthy people. Hmax:Mmax ratios were measured from soleus on dry land (L1), immediately after (W1) and 5 minutes after immersion (W5), and again after five minutes on land (L5). RESULTS: Water immersion led to an acute increase in Hmax:Mmax ratio in both groups. However, after returning to dry land, there was a non-significant decrease in the Hmax:Mmax ratio of 8% in the hemiplegic group and 10% in healthy controls compared to pre-immersion values. INTERPRETATION: A short period of water immersion can decrease peripheral reflex excitability after returning to dry land in both healthy controls and post-stroke patients, although longer immersion periods may be required for sustainable effects. Water immersion may offer promise as a low-risk, non-invasive and non-pharmaceutical method of decreasing hyperreflexivity, and could thus support aquatic rehabilitation following stroke. PMID- 26944825 TI - Repeatability of knee impulsive loading measurements with skin-mounted accelerometers and lower limb surface electromyographic recordings during gait in knee osteoarthritic and asymptomatic individuals. AB - OBJECTIVES: To determine the repeatability of knee joint impulsive loading measurements with skin-mounted accelerometers (SMAs) and lower limb surface electromyography (EMG) recordings during gait. METHODS: Triaxial SMA and EMG from 4 muscles during level and stair walking in nine healthy and nine knee osteoarthritis (OA) subjects were used. The initial peak acceleration (IPA), root mean square (RMS), maximal acceleration transient rate (ATRmax) and mean EMG activity (EMGact) were calculated. The coefficient of variation (CV) and the intraclass correlation coefficient (ICC) were calculated to measure repeatability. RESULTS: The CV and ICC of RMS accelerations ranged from 4.9% to 10.9% and from 0.69 to 0.96 in both study groups during level walking. The CV and ICC of IPA and ATRmax varied from 7.7% to 14.2% and from 0.85 to 0.99 during level and stairs up walking in healthy subjects. The CV and ICC of EMGact ranged from 8.3% to 31.7% and from 0.16 to 0.97 in both study groups. CONCLUSIONS: RMS accelerations exhibited good repeatability during walking in healthy and knee OA subjects. The repeatability of EMG measurements was acceptable in healthy subjects depending on the measured muscles. PMID- 26944827 TI - Gorham-Stout disease of the pelvis: Seven years follow up with complete radiological evaluation. PMID- 26944826 TI - Atypical femoral fracture in a beta-thalassemia major patient with previous bisphosphonate use: case report and a review of the literature. AB - There are numerous studies presenting the beneficial effect of bisphosphonates (BPs) on bone disease of patients suffering from beta-thalassemia major (TM). Although BPs have been widely used, adverse events have been described including atypical femoral fractures (AFF). In the present case, a male adult patient suffering from TM sustained an AFF fulfilling all major and two minor criteria. Before AFF, the patient had been treated with zoledronic acid for three years and remained another one year without osteoporosis therapy. To our knowledge, this is the first reported case of AFF in a patient suffering from TM, probably due to the small sample size of patients with thalassemia. The purpose of the present case is to increase the awareness amongst haematologists, who mainly deal with TM patients, of the adverse events of BP use. PMID- 26944828 TI - Reactive airways dysfunction syndrome after hydrofluoric acid inhalation. PMID- 26944829 TI - Inner nuclear membrane localization of epidermal growth factor receptor (EGFR) in spontaneous canine model of invasive micropapillary carcinoma of the mammary gland. AB - The epidermal growth factor receptor (EGFR) has been described in the nucleus of primary tumors. Accumulation of EGFR at the nucleus is linked to DNA synthesis and cell proliferation, but the pathological significance of nuclear EGFR is not completely understood. The aim of this study was to investigate the nuclear localization of EGFR in invasive micropapillary carcinoma (IMPC) that is an aggressive neoplasm of canine mammary gland. Confocal immunofluorescence of formalin and paraffin-embedded tissue was used to access the subcellular localization of EGFR. Our results demonstrated that EGFR co-localizes with the inner nuclear envelope marker, Lamin B1 in IMPC. Furthermore, EGFR was not localized within the nucleus or at the inner nuclear envelope membrane in mammary carcinoma in mixed tumor (CMT) that is associated with a better prognosis than other malignant histological types. This finding could be useful as a predictive biomarker of therapeutic response for IMPC. PMID- 26944830 TI - Protective effects of Nigella sativa on gamma radiation-induced jejunal mucosal damage in rats. AB - INTRODUCTION: The aim of this study was to compare the efficacy of Nigella sativa in protection of jejunal mucosa against harmful effects of gamma radiation. METHODS: Radiotherapy group received abdominal gamma radiation of 15Gy in addition to physiological saline. Radiotherapy+Nigella sativa treatment group received abdominal gamma radiation of 15Gy in addition to Nigella sativa treatment in the amount of 400mg/kg. Radiotherapy and treatment groups were sacrificed 3 days after the exposure to irradiation. Then, jejunum samples were harvested for biochemical and histological assessment of mucosal injury. RESULTS: Nigella sativa treatment was found to significantly lower elevated tissue malondialdehyde (MDA) levels and, to raise reduced glutathione peroxidase (GSH Px) and superoxide dismutase (SOD) activity in intestinal tissues samples. Single dose 15Gy gamma-irradiation was noted to result in a marked jejunal mucosal injury. Three days after exposure to irradiation, the villi and Lieberkuhn crypts were observed as denuded, and villous height diminished. Concomitantly with inflammatory cell invasion, capillary congestion and ulceration were observed in the atrophic mucosa. Nigella sativa treatment significantly attenuated the radiation induced morphological changes in the irradiated rat jejunal mucosa. CONCLUSION: Nigella sativa has protective effects against radiation-induced damage, suggesting that clinical transfer is feasible. PMID- 26944831 TI - miR-34a inhibits the in vitro cell proliferation and migration in human esophageal cancer. AB - BACKGROUND: Increasing studies demonstrate that reduced expression of miR-34a is involved in the initiation and progression of cancers, and it has been characterized as a tumor suppressor in various types of cancers. In present study, we investigated the expression and role of miR-34a in esophageal cancer. METHODS: qRT-PCR assays were performed to analyze the expression of miR-34a in human esophageal cancer tissues and adjacent esophageal tissues. CCK8 assay, flow cytometry analysis and in vitro migration assays were performed to analyze the role of miR-34a in human esophageal cancer cell. MSP assay was performed to analyze the DNA methylation of the miR-34a promoter. RESULTS: The expression of miR-34a was down-regulated in human esophageal cancer tissues. miR-34a ectopic expression affected esophageal cancer cells survival, proliferation and capabilities of migration in vitro. p53 status was not correlated with miR-34a. Subsequently, aberrant DNA methylation of the miR-34a promoter was found in human esophageal cancer, and 5-AZA-dC inhibited DNA methylation of the miR-34a promoter. CONCLUSIONS: our data showed that miR-34a acted as a tumor suppressor in human esophageal cancer. PMID- 26944832 TI - Cytokeratin 7-negative mammary Paget's disease: A diagnostic pitfall. AB - Pathologists should be aware of the existence of a rare CK7-negative variant of breast carcinoma in general, and of Paget's disease in particular. Cytokeratin 7 negative Paget's disease and CK7-negative ductal intraepithelial neoplasia (ductal carcinoma in situ) present a major diagnostic challenge for pathologists since there is limited awareness of their existence. When there is classic Paget's morphology on H&E sections, GATA3 positivity should resolve any doubts about the diagnosis in the setting of a CK7-negative neoplastic cell population. PMID- 26944833 TI - Influence of carboxylic ion-pairing reagents on retention of peptides in thin layer chromatography systems with C18 silica-based adsorbents. AB - One of the main problems related to chromatography of peptides concerns adverse interactions of their strong basic groups with free silanol groups of the silica based stationary phase. Influence of type and concentration of ion-pairing regents on peptide retention in reversed-phase high-performance liquid chromatography (RP-HPLC) systems has been discussed before. Here we present influence of these mobile phase additives on retention of some peptide standards in high-performance thin-layer chromatography (HPTLC) systems with C18 silica based adsorbents. We prove, that due to different characteristic of adsorbents used in both techniques (RP HPLC and HPTLC), influence of ion-pairing reagents on retention of basic and/or amphoteric compounds also may be quite different. C18 silica-based HPTLC adsorbents provide more complex mechanism of retention and should be rather considered as mixed-mode adsorbents. PMID- 26944834 TI - Inversion of type of separation system in planar chromatography of peptides, using C18 silica-based adsorbents. AB - Our previous results show, that C18 silica-based adsorbents used in high performance thin-layer chromatography (HPTLC), provide complex retention mechanism basing on various polar and nonpolar interactions. Here we present, that in chromatography of peptides, due to mixed-mode properties of these adsorbents, there is a simple way to obtain inversion of separation system type (from reversed-phase, RP, to normal-phase, NP, and vice versa). The results presented provide detailed information how to obtain inversion mentioned and reflect the extent (the type and concentration of organic solvent, the type and concentration of ion-pairing reagent in the mobile phase) of this phenomenon. We show, that the system type inversion results in significant change of selectivity of separation, which may be especially useful in 2D separation of complex samples of basic/amphoteric compounds such as peptides. This results from the fact, that C18 silica-based HPTLC adsorbents, may be used in hydrophilic interaction chromatography (HILIC) or RP chromatography, in dependence on mobile phase composition. PMID- 26944835 TI - Cracked Teeth: Distribution, Characteristics, and Survival after Root Canal Treatment. AB - INTRODUCTION: The aims of this study were to analyze the distribution and characteristic features of cracked teeth and to evaluate the outcome of root canal treatments (RCTs) for cracked teeth. The prognostic factors for tooth survival were investigated. METHODS: Over the 5-year study period, 175 teeth were identified as having cracks. Data were collected regarding the patients' age, sex, tooth type, location and direction of cracks, probing depth, pulp vitality, type of restoration, cavity classification, opposing teeth, and previous endodontic treatment history. Cracked teeth were managed via various treatment methods, and the 2-year survival rate after RCT was analyzed using the Kaplan Meier method in which significance was identified using the log-rank test. Possible prognostic factors were investigated using Cox multivariate proportional hazards modeling. RESULTS: One hundred seventy-five teeth were diagnosed with cracks. Most of the patients were aged 50-60 years (32.0%) or over 60 (32.6%). The lower second molar was the most frequently (25.1%) affected tooth. Intact teeth (34.3%) or teeth with class I cavity restorations (32.0%) exhibited a higher incidence of cracks. The 2-year survival rate of 88 cracked teeth after RCT was 90.0%. A probing depth of more than 6 mm was a significant prognostic factor for the survival of cracked teeth restored via RCT. The survival rate of root-filled cracked teeth with a probing depth of more than 6 mm was 74.1%, which is significantly lower than that of teeth with probing depths of less than 6 mm (96.8%) (P = .003). CONCLUSIONS: Cracks were commonly found in lower second molars and intact teeth. RCT was a reliable treatment for cracked teeth with a 2 year survival rate of 90.0%. Deep probing depths were found to be a significant clinical factor for the survival of cracked teeth treated with RCT. PMID- 26944836 TI - Calcium Hypochlorite Solutions: Evaluation of Surface Tension and Effect of Different Storage Conditions and Time Periods over pH and Available Chlorine Content. AB - INTRODUCTION: The aim of this study was to evaluate the pH and the available chlorine content from sodium hypochlorite (NaOCl) and calcium hypochlorite (Ca[OCl]2) solutions stored in different conditions and time periods and the surface tension of Ca(OCl)2 solutions in comparison with NaOCl. METHODS: Solutions at 0.5%, 1%, 2.5%, and 5.25% concentrations were prepared. The pH level and the available chlorine content of freshly prepared solutions and solutions stored for 30, 60, and 90 days at 25 degrees C, 4 degrees C, or 37 degrees C were evaluated in a digital pH meter and by titration, respectively. Surface tension was tested using a Du Nouy tensiometer (Sigma 702, Force Tensiometer; Attension, Espoo, Finland). Descriptive and inferential statistical analyses were performed. RESULTS: A precipitate formed by 2.5% and 5.25% Ca(OCl)2 solutions was observed. Ca(OCl)2 showed a higher concentration of available chlorine than NaOCl. Both 2.5% and 5.25% NaOCl and Ca(OCl)2 had a decrease in the available chlorine content when compared with freshly prepared solutions; 0.5% and 1% NaOCl tend to have a lower pH compared with 0.5% and 1% Ca(OCl)2. NaOCl, 5.25%, showed higher pH compared with 5.25% Ca(OCl)2. NaOCl and Ca(OCl)2 in 0.5% and 1% concentrations tend to show a reduced pH level, whereas 2.5% and 5.25% solutions showed an increase in pH. The heat contributed to the instability of the solutions. NaOCl showed lower surface tension values than Ca(OCl)2. CONCLUSIONS: Ca(OCl)2 solutions are extremely alkaline and tend to have more available chlorine content than NaOCl but have a higher surface tension than NaOCl. Regarding the available chlorine content, these solutions tend to be stable to 30 days of storage when kept at 4 degrees C or at 25 degrees C. PMID- 26944837 TI - Adherence to Asthma Guidelines in Children, Tweens, and Adults in Primary Care Settings: A Practice-Based Network Assessment. AB - OBJECTIVE: To assess primary care adherence to 2007 US asthma guidelines. PATIENTS AND METHODS: Patients with persistent asthma aged 5 to 65 years from 22 primary care participating practices provided the data for this analysis of baseline information from the pragmatic randomized clinical trial the Asthma Tools Study. Using a combination of abstracted medical record data and patient reported demographic information, we assessed the medical record documentation for elements of the 2007 US asthma guidelines. Elements assessed included documentation of (1) assessment of control, (2) factors that affect control (medication adherence evaluation, inhaler technique education, and evaluation for triggers), (3) self-management support (action plan), and (4) asthma medications prescribed (short-acting beta-agonists and daily maintenance therapy). The baseline data was collected from March 16, 2009, to May 1, 2014. RESULTS: In 1176 patients (285 children, 211 tweens, and 680 adults) from 16 family medicine and 6 pediatric practices across the United States, documented guideline adherence was highest for prescription of medications (88.0% for short-acting beta-agonists and 70.4% for maintenance medications) and lowest for an asthma action plan (3.1%). Documentation of control (15.0%) and factors that affect control (inhaler technique education, 7.6%; medication adherence assessment, 32.5%; and allergy evaluation, 32.5%) was not common and even less common for adults compared with children. A total of 22.2% of the enrolled patients had no asthma-related visit in the year before enrollment. Adherence to the nonmedication elements were higher in practices located in cities of more than 250,000 people and cities that used electronic medical records. Older patient age was negatively associated with guideline adherence. CONCLUSION AND RELEVANCE: Adherence to asthma guidelines is poor in primary care practices, leaving many opportunities for improvement. PMID- 26944838 TI - Time for a New Paradigm for Asthma Management. PMID- 26944839 TI - Extraction of Aerosol-Deposited Yersinia pestis from Indoor Surfaces To Determine Bacterial Environmental Decay. AB - Public health and decontamination decisions following an event that causes indoor contamination with a biological agent require knowledge of the environmental persistence of the agent. The goals of this study were to develop methods for experimentally depositing bacteria onto indoor surfaces via aerosol, evaluate methods for sampling and enumerating the agent on surfaces, and use these methods to determine bacterial surface decay. A specialized aerosol deposition chamber was constructed, and methods were established for reproducible and uniform aerosol deposition of bacteria onto four coupon types. The deposition chamber facilitated the control of relative humidity (RH; 10 to 70%) following particle deposition to mimic the conditions of indoor environments, as RH is not controlled by standard heating, ventilation, and air conditioning (HVAC) systems. Extraction and culture-based enumeration methods to quantify the viable bacteria on coupons were shown to be highly sensitive and reproducible. To demonstrate the usefulness of the system for decay studies,Yersinia pestis persistence as a function of surface type at 21 degrees C and 40% RH was determined to be >40%/min for all surfaces. Based upon these results, at typical indoor temperature and RH, a 6-log reduction in titer would expected to be achieved within 1 h as the result of environmental decay on surfaces without active decontamination. The developed approach will facilitate future persistence and decontamination studies with a broad range of biological agents and surfaces, providing agent decay data to inform both assessments of risk to personnel entering a contaminated site and decontamination decisions following biological contamination of an indoor environment. IMPORTANCE: Public health and decontamination decisions following contamination of an indoor environment with a biological agent require knowledge of the environmental persistence of the agent. Previous studies on Y. pestis persistence have utilized large liquid droplet deposition to provide persistence data. As a result, methods were developed to deposit aerosols containing bacteria onto indoor surfaces, reproducibly enumerate bacteria harvested from coupons, and determine surface decay utilizing Y. pestis The results of this study provide foundational methods required to evaluate surface decay of bacteria and potentially other biological agents, such as viruses, in aerosol particles as a function of surface type and environment. Integrating the data from both aerosol and liquid deposition surface decay studies will provide medical and public health personnel with a more complete understanding of agent persistence on surfaces in contaminated areas for assessment of health risks and to inform decontamination decisions. PMID- 26944840 TI - Thermal Inactivation of Mycobacterium avium subsp. paratuberculosis in Artificially Contaminated Milk by Direct Steam Injection. AB - The efficiency of direct steam injection (DSI) at 105 degrees C for 3 s to inactivate Mycobacterium avium subsp. paratuberculosis in milk at a pilot-plant scale was investigated. Milk samples were artificially contaminated with M. avium subsp. paratuberculosis and also with cow fecal material naturally infected with M. avium subsp. paratuberculosis. We also tested milk artificially contaminated with Mycobacterium smegmatis as a candidate surrogate to compare thermal inactivation between M. smegmatis and M. avium subsp. paratuberculosis. Following the DSI process, no viable M. avium subsp. paratuberculosis or M. smegmatis was recovered using culture methods for both strains. For pure M. avium subsp. paratuberculosis cultures, a minimum reduction of 5.6 log10 was achieved with DSI, and a minimum reduction of 5.7 log10 was found with M. smegmatis. The minimum log10 reduction for wild-type M. avium subsp. paratuberculosis naturally present in feces was 3.3. In addition, 44 dairy and nondairy powdered infant formula (PIF) ingredients used during the manufacturing process of PIF were tested for an alternate source for M. avium subsp. paratuberculosis and were found to be negative by quantitative PCR (qPCR). In conclusion, the results obtained from this study indicate that a >7-fold-log10 reduction of M. avium subsp. paratuberculosis in milk can be achieved with the applied DSI process. IMPORTANCE: M. avium subsp. paratuberculosis is widespread in dairy herds in many countries. M. avium subsp. paratuberculosis is the causative agent of Johne's disease in cattle, and infected animals can directly or indirectly (i.e., fecal contamination) contaminate milk. Despite much research and debate, there is no conclusive evidence that M. avium subsp. paratuberculosis is a zoonotic bacterium, i.e., one that causes disease in humans. The presence of M. avium subsp. paratuberculosis or its DNA has been reported in dairy products, including pasteurized milk, cheese, and infant formula. In light of this, it is appropriate to evaluate existing mitigation measures to inactivate M. avium subsp. paratuberculosis in dairy products. The work conducted in this study describes the efficacy of direct steam injection, a thermal process commonly used in the dairy industry, to eliminate M. avium subsp. paratuberculosis and a surrogate bacterium in milk, thus ensuring the absence of M. avium subsp. paratuberculosis in dairy products subject to these process conditions. PMID- 26944842 TI - Diversity of Clinical and Environmental Isolates of Vibrio cholerae in Natural Transformation and Contact-Dependent Bacterial Killing Indicative of Type VI Secretion System Activity. AB - The bacterial pathogen Vibrio cholerae can occupy both the human gut and aquatic reservoirs, where it may colonize chitinous surfaces that induce the expression of factors for three phenotypes: chitin utilization, DNA uptake by natural transformation, and contact-dependent bacterial killing via a type VI secretion system (T6SS). In this study, we surveyed a diverse set of 53 isolates from different geographic locales collected over the past century from human clinical and environmental specimens for each phenotype outlined above. The set included pandemic isolates of serogroup O1, as well as several serogroup O139 and non O1/non-O139 strains. We found that while chitin utilization was common, only 22.6% of the isolates tested were proficient at chitin-induced natural transformation, suggesting that transformation is expendable. Constitutive contact-dependent killing of Escherichia coli prey, which is indicative of a functional T6SS, was rare among clinical isolates (only 4 of 29) but common among environmental isolates (22 of 24). These results bolster the pathoadaptive model in which tight regulation of T6SS-mediated bacterial killing is beneficial in a human host, whereas constitutive killing by environmental isolates may give a competitive advantage in natural settings. Future sequence analysis of this set of diverse isolates may identify previously unknown regulators and structural components for both natural transformation and T6SS. PMID- 26944841 TI - Transcriptional Repression of the VC2105 Protein by Vibrio FadR Suggests that It Is a New Auxiliary Member of the fad Regulon. AB - Recently, our group along with others reported that the Vibrio FadR regulatory protein is unusual in that, unlike the prototypical fadR product of Escherichia coli, which has only one ligand-binding site, Vibrio FadR has two ligand-binding sites and represents a new mechanism for fatty acid sensing. The promoter region of the vc2105 gene, encoding a putative thioesterase, was mapped, and a putative FadR-binding site (AA CTG GTA AGA GCA CTT) was proposed. Different versions of the FadR regulatory proteins were prepared and purified to homogeneity. Both electrophoretic mobility shift assay (EMSA) and surface plasmon resonance (SPR) determined the direct interaction of the vc2105 gene with FadR proteins of various origins. Further, EMSAs illustrated that the addition of long-chain acyl coenzyme A (CoA) species efficiently dissociates the vc2105 promoter from the FadR regulator. The expression level of the Vibrio cholerae vc2105 gene was elevated 2- to 3-fold in a fadR null mutant strain, validating that FadR is a repressor for the vc2105 gene. The beta-galactosidase activity of a vc2105-lacZ transcriptional fusion was increased over 2-fold upon supplementation of growth medium with oleic acid. Unlike the fadD gene, a member of the Vibrio fad regulon, the VC2105 protein played no role in bacterial growth and virulence-associated gene expression of ctxAB (cholera toxin A/B) and tcpA (toxin coregulated pilus A). Given that the transcriptional regulation of vc2105 fits the criteria for fatty acid degradation (fad) genes, we suggested that it is a new member of the Vibrio fad regulon. IMPORTANCE: The Vibrio FadR regulator is unusual in that it has two ligand-binding sites. Different versions of the FadR regulatory proteins were prepared and characterized in vitro and in vivo. An auxiliary fad gene (vc2105) from Vibrio was proposed that encodes a putative thioesterase and has a predicted FadR-binding site (AAC TGG TA A GAG CAC TT). The function of this putative binding site was proved using both EMSA and SPR. Further in vitro and in vivo experiments revealed that the Vibrio FadR is a repressor for the vc2105 gene. Unlike fadD, a member of the Vibrio fad regulon, VC2105 played no role in bacterial growth and expression of the two virulence-associated genes (ctxAB and tcpA). Therefore, since transcriptional regulation of vc2105 fits the criteria for fad genes, it seems likely that vc2105 acts as a new auxiliary member of the Vibrio fad regulon. PMID- 26944843 TI - Functional Responses of Salt Marsh Microbial Communities to Long-Term Nutrient Enrichment. AB - Environmental nutrient enrichment from human agricultural and waste runoff could cause changes to microbial communities that allow them to capitalize on newly available resources. Currently, the response of microbial communities to nutrient enrichment remains poorly understood, and, while some studies have shown no clear changes in community composition in response to heavy nutrient loading, others targeting specific genes have demonstrated clear impacts. In this study, we compared functional metagenomic profiles from sediment samples taken along two salt marsh creeks, one of which was exposed for more than 40 years to treated sewage effluent at its head. We identified strong and consistent increases in the relative abundance of microbial genes related to each of the biochemical steps in the denitrification pathway at enriched sites. Despite fine-scale local increases in the abundance of denitrification-related genes, the overall community structures based on broadly defined functional groups and taxonomic annotations were similar and varied with other environmental factors, such as salinity, which were common to both creeks. Homology-based taxonomic assignments of nitrous oxide reductase sequences in our data show that increases are spread over a broad taxonomic range, thus limiting detection from taxonomic data alone. Together, these results illustrate a functionally targeted yet taxonomically broad response of microbial communities to anthropogenic nutrient loading, indicating some resolution to the apparently conflicting results of existing studies on the impacts of nutrient loading in sediment communities. IMPORTANCE: In this study, we used environmental metagenomics to assess the response of microbial communities in estuarine sediments to long-term, nutrient-rich sewage effluent exposure. Unlike previous studies, which have mainly characterized communities based on taxonomic data or primer-based amplification of specific target genes, our whole-genome metagenomics approach allowed an unbiased assessment of the abundance of denitrification-related genes across the entire community. We identified strong and consistent increases in the relative abundance of gene sequences related to denitrification pathways across a broad phylogenetic range at sites exposed to long-term nutrient addition. While further work is needed to determine the consequences of these community responses in regulating environmental nutrient cycles, the increased abundance of bacteria harboring denitrification genes suggests that such processes may be locally upregulated. In addition, our results illustrate how whole-genome metagenomics combined with targeted hypothesis testing can reveal fine-scale responses of microbial communities to environmental disturbance. PMID- 26944844 TI - Functional Redundancy of Linuron Degradation in Microbial Communities in Agricultural Soil and Biopurification Systems. AB - The abundance of libA, encoding a hydrolase that initiates linuron degradation in the linuron-metabolizing Variovorax sp. strain SRS16, was previously found to correlate well with linuron mineralization, but not in all tested environments. Recently, an alternative linuron hydrolase, HylA, was identified in Variovorax sp. strain WDL1, a strain that initiates linuron degradation in a linuron mineralizing commensal bacterial consortium. The discovery of alternative linuron hydrolases poses questions about the respective contribution and competitive character of hylA- and libA-carrying bacteria as well as the role of linuron mineralizing consortia versus single strains in linuron-exposed settings. Therefore, dynamics of hylA as well as dcaQ as a marker for downstream catabolic functions involved in linuron mineralization, in response to linuron treatment in agricultural soil and on-farm biopurification systems (BPS), were compared with previously reported libA dynamics. The results suggest that (i) organisms containing either libA or hylA contribute simultaneously to linuron biodegradation in the same environment, albeit to various extents, (ii) environmental linuron mineralization depends on multispecies bacterial food webs, and (iii) initiation of linuron mineralization can be governed by currently unidentified enzymes. IMPORTANCE: A limited set of different isofunctional catabolic gene functions is known for the bacterial degradation of the phenylurea herbicide linuron, but the role of this redundancy in linuron degradation in environmental settings is not known. In this study, the simultaneous involvement of bacteria carrying one of two isofunctional linuron hydrolysis genes in the degradation of linuron was shown in agricultural soil and on-farm biopurification systems, as was the involvement of other bacterial populations that mineralize the downstream metabolites of linuron hydrolysis. This study illustrates the importance of the synergistic metabolism of pesticides in environmental settings. PMID- 26944845 TI - Metagenomic Signatures of Bacterial Adaptation to Life in the Phyllosphere of a Salt-Secreting Desert Tree. AB - The leaves of Tamarix aphylla, a globally distributed, salt-secreting desert tree, are dotted with alkaline droplets of high salinity. To successfully inhabit these organic carbon-rich droplets, bacteria need to be adapted to multiple stress factors, including high salinity, high alkalinity, high UV radiation, and periodic desiccation. To identify genes that are important for survival in this harsh habitat, microbial community DNA was extracted from the leaf surfaces of 10 Tamarix aphylla trees along a 350-km longitudinal gradient. Shotgun metagenomic sequencing, contig assembly, and binning yielded 17 genome bins, six of which were >80% complete. These genomic bins, representing three phyla (Proteobacteria,Bacteroidetes, and Firmicutes), were closely related to halophilic and alkaliphilic taxa isolated from aquatic and soil environments. Comparison of these genomic bins to the genomes of their closest relatives revealed functional traits characteristic of bacterial populations inhabiting the Tamarix phyllosphere, independent of their taxonomic affiliation. These functions, most notably light-sensing genes, are postulated to represent important adaptations toward colonization of this habitat. IMPORTANCE: Plant leaves are an extensive and diverse microbial habitat, forming the main interface between solar energy and the terrestrial biosphere. There are hundreds of thousands of plant species in the world, exhibiting a wide range of morphologies, leaf surface chemistries, and ecological ranges. In order to understand the core adaptations of microorganisms to this habitat, it is important to diversify the type of leaves that are studied. This study provides an analysis of the genomic content of the most abundant bacterial inhabitants of the globally distributed, salt-secreting desert tree Tamarix aphylla Draft genomes of these bacteria were assembled, using the culture-independent technique of assembly and binning of metagenomic data. Analysis of the genomes reveals traits that are important for survival in this habitat, most notably, light-sensing and light utilization genes. PMID- 26944846 TI - Global Genomic Epidemiology of Salmonella enterica Serovar Typhimurium DT104. AB - It has been 30 years since the initial emergence and subsequent rapid global spread of multidrug-resistant Salmonella entericaserovar Typhimurium DT104 (MDR DT104). Nonetheless, its origin and transmission route have never been revealed. We used whole-genome sequencing (WGS) and temporally structured sequence analysis within a Bayesian framework to reconstruct temporal and spatial phylogenetic trees and estimate the rates of mutation and divergence times of 315S Typhimurium DT104 isolates sampled from 1969 to 2012 from 21 countries on six continents. DT104 was estimated to have emerged initially as antimicrobial susceptible in ~1948 (95% credible interval [CI], 1934 to 1962) and later became MDR DT104 in ~1972 (95% CI, 1972 to 1988) through horizontal transfer of the 13-kb Salmonella genomic island 1 (SGI1) MDR region into susceptible strains already containing SGI1. This was followed by multiple transmission events, initially from central Europe and later between several European countries. An independent transmission to the United States and another to Japan occurred, and from there MDR DT104 was probably transmitted to Taiwan and Canada. An independent acquisition of resistance genes took place in Thailand in ~1975 (95% CI, 1975 to 1990). In Denmark, WGS analysis provided evidence for transmission of the organism between herds of animals. Interestingly, the demographic history of Danish MDR DT104 provided evidence for the success of the program to eradicate Salmonellafrom pig herds in Denmark from 1996 to 2000. The results from this study refute several hypotheses on the evolution of DT104 and suggest that WGS may be useful in monitoring emerging clones and devising strategies for prevention of Salmonella infections. PMID- 26944847 TI - Influence of Low-Shear Modeled Microgravity on Heat Resistance, Membrane Fatty Acid Composition, and Heat Stress-Related Gene Expression in Escherichia coli O157:H7 ATCC 35150, ATCC 43889, ATCC 43890, and ATCC 43895. AB - We previously showed that modeled microgravity conditions alter the physiological characteristics of Escherichia coli O157:H7. To examine how microgravity conditions affect bacterial heat stress responses, D values, membrane fatty acid composition, and heat stress-related gene expression (clpB, dnaK, grpE, groES, htpG, htpX, ibpB, and rpoH), E. coli O157:H7 ATCC 35150, ATCC 43889, ATCC 43890, and ATCC 43895 were cultured under two different conditions: low-shear modeled microgravity (LSMMG, an analog of spaceflight conditions) and normal gravity (NG, Earth-like conditions). When 24-h cultures were heated to 55 degrees C, cells cultured under LSMMG conditions showed reduced survival compared with cells cultured under NG conditions at all time points (P < 0.05). D values of all tested strains were lower after LSMMG culture than after NG culture. Fourteen of 37 fatty acids examined were present in the bacterial membrane: nine saturated fatty acids (SFA) and five unsaturated fatty acids (USFA). The USFA/SFA ratio, a measure of membrane fluidity, was higher under LSMMG conditions than under NG conditions. Compared with control cells grown under NG conditions, cells cultured under LSMMG conditions showed downregulation of eight heat stress-related genes (average, -1.9- to -3.7-fold). The results of this study indicate that in a simulated space environment, heat resistance of E. coli O157:H7 decreased, and this might be due to the synergistic effects of the increases in membrane fluidity and downregulated relevant heat stress genes. IMPORTANCE: Microgravity is a major factor that represents the environmental conditions in space. Since infectious diseases are difficult to deal with in a space environment, comprehensive studies on the behavior of pathogenic bacteria under microgravity conditions are warranted. This study reports the changes in heat stress resistance of E. coli O157:H7, the severe foodborne pathogen, under conditions that mimic microgravity. The results provide scientific clues for further understanding of the bacterial response under the simulated microgravity conditions. It will contribute not only to the improvement of scientific knowledge in the academic fields but also ultimately to the development of a prevention strategy for bacterial disease in the space environment. PMID- 26944848 TI - In Situ Biomineralization and Particle Deposition Distinctively Mediate Biofilm Susceptibility to Chlorine. AB - Microbial biofilms and mineral precipitation commonly co-occur in engineered water systems, such as cooling towers and water purification systems, and both decrease process performance. Microbial biofilms are extremely challenging to control and eradicate. We previously showed that in situ biomineralization and the precipitation and deposition of abiotic particles occur simultaneously in biofilms under oversaturated conditions. Both processes could potentially alter the essential properties of biofilms, including susceptibility to biocides. However, the specific interactions between mineral formation and biofilm processes remain poorly understood. Here we show that the susceptibility of biofilms to chlorination depends specifically on internal transport processes mediated by biomineralization and the accumulation of abiotic mineral deposits. Using injections of the fluorescent tracer Cy5, we show that Pseudomonas aeruginosa biofilms are more permeable to solutes after in situ calcite biomineralization and are less permeable after the deposition of abiotically precipitated calcite particles. We further show that biofilms are more susceptible to chlorine killing after biomineralization and less susceptible after particle deposition. Based on these observations, we found a strong correlation between enhanced solute transport and chlorine killing in biofilms, indicating that biomineralization and particle deposition regulate biofilm susceptibility by altering biocide penetration into the biofilm. The distinct effects of in situ biomineralization and particle deposition on biocide killing highlight the importance of understanding the mechanisms and patterns of biomineralization and scale formation to achieve successful biofilm control. PMID- 26944849 TI - Mycelium-Like Networks Increase Bacterial Dispersal, Growth, and Biodegradation in a Model Ecosystem at Various Water Potentials. AB - Fungal mycelia serve as effective dispersal networks for bacteria in water unsaturated environments, thereby allowing bacteria to maintain important functions, such as biodegradation. However, poor knowledge exists on the effects of dispersal networks at various osmotic (Psio) and matric (Psim) potentials, which contribute to the water potential mainly in terrestrial soil environments. Here we studied the effects of artificial mycelium-like dispersal networks on bacterial dispersal dynamics and subsequent effects on growth and benzoate biodegradation at DeltaPsio and DeltaPsim values between 0 and -1.5 MPa. In a multiple-microcosm approach, we used a green fluorescent protein (GFP)-tagged derivative of the soil bacterium Pseudomonas putida KT2440 as a model organism and sodium benzoate as a representative of polar aromatic contaminants. We found that decreasing DeltaPsio and DeltaPsim values slowed bacterial dispersal in the system, leading to decelerated growth and benzoate degradation. In contrast, dispersal networks facilitated bacterial movement at DeltaPsio and DeltaPsim values between 0 and -0.5 MPa and thus improved the absolute biodegradation performance by up to 52 and 119% for DeltaPsio and DeltaPsim, respectively. This strong functional interrelationship was further emphasized by a high positive correlation between population dispersal, population growth, and degradation. We propose that dispersal networks may sustain the functionality of microbial ecosystems at low osmotic and matric potentials. PMID- 26944851 TI - A case report of the new PolyzeneTM-F COBRA PzFTM Nanocoated Coronary Stent System (NCS): Addressing an unmet clinical need. AB - Because of anticipated antiplatelet medication risks, patients who are not DES candidates or who are at particularly high risk for bleeding events have been targeted initially for treatment with the COBRA PzF Coronary Stent System. We report the case of a successful experience with a new, PolyzeneTM-F COBRA PzFTM Coronary Stent System, designed to impart thrombo-resistance and reduce inflammation, to achieve shorter dual antiplatelet therapy duration while reducing restenosis incidence in a high risk patient with atrial fibrillation. PMID- 26944850 TI - Parametric techniques for characterizing myocardial tissue by magnetic resonance imaging (part 1): T1 mapping. AB - The development of myocardial fibrosis is a common process in the appearance of ventricular dysfunction in many heart diseases. Magnetic resonance imaging makes it possible to accurately evaluate the structure and function of the heart, and its role in the macroscopic characterization of myocardial fibrosis by late enhancement techniques has been widely validated clinically. Recent studies have demonstrated that T1-mapping techniques can quantify diffuse myocardial fibrosis and the expansion of the myocardial extracellular space in absolute terms. However, further studies are necessary to validate the usefulness of this technique in the early detection of tissue remodeling at a time when implementing early treatment would improve a patient's prognosis. This article reviews the state of the art for T1 mapping of the myocardium, its clinical applications, and its limitations. PMID- 26944852 TI - Self-expanding stent for complex percutaneous coronary interventions: A real life experience. AB - AIM: Self-expanding stents represent a re-emerging option for percutaneous coronary interventions. Their application covers a wide spectrum of angiographic situations, i.e., coronary bifurcations, acute coronary syndromes with large thrombotic burden and stenosis of ectatic coronaries. We review our experience with self-expanding stents for different clinical and angiographic indications, with long clinical follow-up. METHODS: From 2011 to 2013 we used self-expanding STENTYS(r) stents in 40 consecutive patients followed-up for death from any cause and from cardiovascular cause, myocardial infarction, target lesion revascularization (TLR), stent thrombosis (mean 21+/-13months). We also revised rate of procedural outcomes, acute stent thrombosis and TLR in patients treated with conventional stents for similar clinical/angiographic situations, in the same period at our institution. RESULTS: We identified three anatomical settings of STENTYS(r) use: coronary bifurcations with proximal/distal main branch diameter discrepancy (55% of cases), massive thrombotic burden in the setting of acute coronary syndrome (35% of cases) and stenosis of ectatic coronaries (15%). We observed one death related to acute heart failure and 1 case (2.5%) of acute stent thrombosis (2.5% in the control group). During follow-up 2 cases of stent restenosis leading to TLR (5%) occurred (6.25% in the control group). CONCLUSIONS: According to our real life experience, self-expanding STENTYS(r) stents appear to be an effective tool for different angiographic situations in which they may be preferable to balloon-expandable stents, showing a low rate of complications and good results at long term follow-up. PMID- 26944854 TI - Correction: Restoration of miR17/20a in Solid Tumor Cells Enhances the Natural Killer Cell Antitumor Activity by Targeting Mekk2. PMID- 26944855 TI - The multitude of iron-sulfur clusters in respiratory complex I. AB - Respiratory complex I couples the electron transfer from NADH to ubiquinone with the translocation of protons across the membrane. Complex I contains one non covalently bound flavin mononucleotide and, depending on the species, up to ten iron-sulfur (Fe/S) clusters as cofactors. The reason for the presence of the multitude of Fe/S clusters in complex I remained enigmatic for a long time. The question was partly answered by investigations on the evolution of the complex revealing the stepwise construction of the electron transfer domain from several modules. Extension of the ancestral to the modern electron input domain was associated with the acquisition of several Fe/S-proteins. The X-ray structure of the complex showed that the NADH oxidation-site is connected with the quinone reduction site by a chain of seven Fe/S-clusters. Fast enzyme kinetics revealed that this chain of Fe/S-clusters is used to regulate electron-tunneling rates within the complex. A possible function of the off-pathway cluster N1a is discussed. This article is part of a Special Issue entitled 'EBEC 2016: 19th European Bioenergetics Conference, Riva del Garda, Italy, July 2-6, 2016', edited by Prof. Paolo Bernardi. PMID- 26944853 TI - Quadriceps autograft to treat Achilles Chronic tears: a simple surgical technique. AB - BACKGROUND: Chronic Achilles tendon tears could hinder patients and represent a challenge to surgeons. Although many different surgical techniques have been proposed for reconstruction of a neglected Achilles tendon rupture, there is no clear evidence to support one technique over the others, but the use of a technique that could allow for an "anatomical" reconstructions seems desirable. METHODS: The present paper describes a new anatomic Achilles tendon reconstruction for chronic tears, using a quadriceps tendon autograft as graft source, with PRP injected into the graft and the neighbor tissue, and fixation in a bone trough with a simple small fragments screw. RESULTS: Autologous quadriceps tendon graft seems an excellent option, although -surprisingly- has received little attention until now. CONCLUSIONS: Autologous Quadriceps tendon graft (in bone-tendon configuration) is a simple technique that could allow surgeons to reconstruct tissue defects in the Achilles tendon with non-expensive hardware. PMID- 26944856 TI - Smash and DASH with Cas9. AB - DeRisi and colleagues present a creative application for Cas9 in vitro, using it to deplete unwanted sequence from DNA libraries. It seems plausible that the in vitro use of CRISPR/Cas9 has unrealized potential to revolutionize the practice of molecular biology well beyond genome editing. PMID- 26944857 TI - The prevalence of ESBL-producing Enterobacteriaceae in a nursing home setting compared with elderly living at home: a cross-sectional comparison. AB - BACKGROUND: The aim of the study was to investigate the prevalence of faecal carriage of extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae among residents living in nursing homes and to compare it with a corresponding group of elderly people living in their own homes. METHODS: A total of 160 persons participated in the study between February and April 2014, 91 were residents in nursing homes (n = 10) and the remaining 69 were elderly living in their own homes. In addition to performing faecal samples, all participants answered a standardized questionnaire regarding known risk factors for ESBL carriage. RESULTS: There was no significant difference between the groups, as 10 of the 91 (11%) residents from nursing homes were ESBL-carriers compared with 6 of 69 (8,7%) elderly living in their own homes. There was no significant difference between the groups. The total prevalence was 10%. A univariate analysis revealed that the only studied risk factor significantly associated with ESBL-carriage was recent foreign travel (p = 0,017). All ESBL-positive isolates were Escherichia coli and there was a high degree of co-resistance to other antibiotics. All isolates (n = 17) were susceptible to imipenem and amikacin. CONCLUSION: Residents of nursing homes as well as elderly living in their own homes have high rates of faecal carriage of ESBL-producing bacteria. These findings may affect the choice of empirical antibiotic treatment of severe infections in older adults. PMID- 26944859 TI - Impact of task-related changes in heart rate on estimation of hemodynamic response and model fit. AB - The blood oxygen level dependent (BOLD) signal, as measured using functional magnetic resonance imaging (fMRI), is widely used as a proxy for changes in neural activity in the brain. Physiological variables such as heart rate (HR) and respiratory variation (RV) affect the BOLD signal in a way that may interfere with the estimation and detection of true task-related neural activity. This interference is of particular concern when these variables themselves show task related modulations. We first establish that a simple movement task reliably induces a change in HR but not RV. In group data, the effect of HR on the BOLD response was larger and more widespread throughout the brain than were the effects of RV or phase regressors. The inclusion of HR regressors, but not RV or phase regressors, had a small but reliable effect on the estimated hemodynamic response function (HRF) in M1 and the cerebellum. We next asked whether the inclusion of a nested set of physiological regressors combining phase, RV, and HR significantly improved the model fit in individual participants' data sets. There was a significant improvement from HR correction in M1 for the greatest number of participants, followed by RV and phase correction. These improvements were more modest in the cerebellum. These results indicate that accounting for task-related modulation of physiological variables can improve the detection and estimation of true neural effects of interest. PMID- 26944858 TI - ICA-derived cortical responses indexing rapid multi-feature auditory processing in six-month-old infants. AB - The abilities of infants to perceive basic acoustic differences, essential for language development, can be studied using auditory event-related potentials (ERPs). However, scalp-channel averaged ERPs sum volume-conducted contributions from many cortical areas, reducing the functional specificity and interpretability of channel-based ERP measures. This study represents the first attempt to investigate rapid auditory processing in infancy using independent component analysis (ICA), allowing exploration of source-resolved ERP dynamics and identification of ERP cortical generators. Here, we recorded 60-channel EEG data in 34 typically developing 6-month-old infants during a passive acoustic oddball paradigm presenting 'standard' tones interspersed with frequency- or duration-deviant tones. ICA decomposition was applied to single-subject EEG data. The best-fitting equivalent dipole or bilaterally symmetric dipole pair was then estimated for each resulting independent component (IC) process using a four layer infant head model. Similar brain-source ICs were clustered across subjects. Results showed ERP contributions from auditory cortex and multiple extra-auditory cortical areas (often, bilaterally paired). Different cortical source combinations contributed to the frequency- and duration-deviant ERP peak sequences. For ICs in an ERP-dominant source cluster located in or near the mid cingulate cortex, source-resolved frequency-deviant response N2 latency and P3 amplitude at 6 months-of-age predicted vocabulary size at 20 months-of-age. The same measures for scalp channel F6 (though not for other frontal channels) showed similar but weaker correlations. These results demonstrate the significant potential of ICA analyses to facilitate a deeper understanding of the neural substrates of infant sensory processing. PMID- 26944861 TI - The Brain's Tendency to Bind Audiovisual Signals Is Stable but Not General. AB - Previous studies have shown a surprising amount of between-subjects variability in the strength of interactions between sensory modalities. For the same set of stimuli, some subjects exhibit strong interactions, whereas others exhibit weak interactions. To date, little is known about what underlies this variability. Sensory integration in the brain could be governed by a global mechanism or by task-specific mechanisms that could be either stable or variable across time. We used a rigorous quantitative tool (Bayesian causal inference) to investigate whether integration (i.e., binding) tendencies generalize across tasks and are stable across time. We report for the first time that individuals' binding tendencies are stable across time but are task-specific. These results provide evidence against the hypothesis that sensory integration is governed by a single, global parameter in the brain. PMID- 26944860 TI - High expression of the human equilibrative nucleoside transporter 1 gene predicts a good response to decitabine in patients with myelodysplastic syndrome. AB - BACKGROUND: Despite the efficacy of decitabine treatment in myelodysplastic syndrome (MDS), no definite predictor of response is known. In this study, we investigated whether the expression levels of human equilibrative nucleoside transporter 1 (hENT1), hENT2, deoxycytidine kinase (DCK) and cytidine deaminase (CDA) genes could predict response to decitabine in MDS. METHODS: We performed quantitative real-time PCR in marrow mononuclear cells to examine the expression of hENT1, hENT2, DCK, and CDA prior to therapy in 98 MDS patients initially treated with decitabine. Response and overall survival of patients treated with decitabine were analyzed according to gene expression levels. HENT1 knockdown was performed by shRNA in the SKM-1 cell line, and the effect of this on the demethylation ability of decitabine on long interspersed nucleotide element 1 (LINE1) was investigated. RESULTS: Patients responding to decitabine presented with significantly higher hENT1 expression levels than non-responders (p = 0.004). Overall response, complete response, and cytogenetic complete response rate in patients with high hENT1 expression (79.4, 41.3, and 43.8 %) were significantly higher than those in patients with low hENT1 expression (48.6, 20.0, and 5.9 %, respectively) (p = 0.004, 0.033, and 0.006, respectively). In higher-risk MDS, patients with high hENT1 expression showed prolonged survival compared with those with low hENT1 expression (22.0 vs 14.0 months; p = 0.027). However, the expression levels of hENT2, DCK, and CDA did not affect response rate. Knockdown of hENT1 in SKM-1 cells weakened the demethylation effect on LINE1 induced by decitabine. CONCLUSIONS: High expression of hENT1 appears to predict a good response to decitabine and a prolonged survival in higher-risk MDS patients treated with decitabine. HENT1 expression knockdown weakens the demethylation effect of decitabine. PMID- 26944862 TI - Neutrophil-to-lymphocyte ratio is a prognostic marker in bladder cancer patients after radical cystectomy. AB - BACKGROUND: There is no reliable biomarker for predicting the prognosis of patients who undergo radical cystectomy for bladder cancer. Recent studies have shown that the neutrophil-to-lymphocyte ratio (NLR) could function as a useful prognostic factor in several types of malignancies. This study aimed to assess the usefulness of NLR in bladder cancer. METHODS: A total of 74 patients who underwent radical cystectomy in our institutions from 1999 to 2014 were analyzed. The NLR was calculated using the patients' neutrophil and lymphocyte counts before radical cystectomy. An immunohistochemical analysis was also performed to detect tumor infiltrating neutrophils (CD66b) and lymphocytes (CD8) in bladder cancer specimens. RESULTS: A univariate analysis showed that the patients with a high NLR (>=2.38; HR = 4.84; p = 0.007), high C-reactive protein level (>0.08; HR = 10.06; p = 0.030), or pathological lymph node metastasis (HR = 4.73; p = 0.030) had a significantly higher risk of cancer-specific mortality. Kaplan-Meier and log-rank tests further revealed that NLR was strongly correlated with overall survival (p = 0.018), but not progression-free survival (p = 0.137). In a multivariate analysis, all of these were found to be independent risk factors (HR = 4.62, 10.8, and 12.35, respectively). The number of CD8-positive lymphocytes was significantly increased in high-grade (p = 0.001) and muscle-invasive (p = 0.012) tumors, in comparison to low-grade and non-muscle-invasive tumors, respectively. CONCLUSIONS: The NLR predicted the prognosis of patients who underwent radical cystectomy and might therefore function as a reliable biomarker in cases of invasive bladder cancer. PMID- 26944863 TI - Preference for and efficacy of oral levonorgestrel for emergency contraception with concomitant placement of a levonorgestrel IUD: a prospective cohort study. AB - OBJECTIVES: We assessed intrauterine device (IUD) preference among women presenting for emergency contraception (EC) and the probability of pregnancy among concurrent oral levonorgestrel (LNG) plus LNG 52 mg IUD EC users. METHODS: We offered women presenting for EC at a single family planning clinic the CuT380A IUD (copper IUD) or oral LNG 1.5 mg plus the LNG 52 mg IUD. Two weeks after IUD insertion, participants reported the results of a self-administered home urine pregnancy test. The primary outcome, EC failure, was defined as pregnancies resulting from intercourse occurring within five days prior to IUD insertion. RESULTS: One hundred eighty-eight women enrolled and provided information regarding their current menstrual cycle and recent unprotected intercourse. Sixty seven (36%) chose the copper IUD and 121 (64%) chose oral LNG plus the LNG IUD. The probability of pregnancy two weeks after oral LNG plus LNG IUD EC use was 0.9% (95% CI 0.0-5.1%). The only positive pregnancy test after treatment occurred in a woman who received oral LNG plus the LNG IUD and who had reported multiple episodes of unprotected intercourse including an episode more than 5 days prior to treatment. CONCLUSIONS: Study participants seeking EC who desired an IUD preferentially chose oral LNG 1.5 mg with the LNG 52 mg IUD over the copper IUD. Neither group had EC treatment failures. Including the option of oral LNG 1.5 mg with concomitant insertion of the LNG 52 mg IUD in EC counseling may increase the number of EC users who opt to initiate highly effective reversible contraception. IMPLICATIONS: Consideration should be given to LNG IUD insertion with concomitant use of oral LNG 1.5 mg for EC. Use of this combination may increase the number of women initiating highly effective contraception at the time of their EC visit. PMID- 26944864 TI - How to improve WEEE management? Novel approach in mobile collection with application of artificial intelligence. AB - In global demand of improvement of electrical and electronic waste management systems, stakeholders look for effective collection systems that generate minimal costs. In this study we propose a novel model for application in mobile collection schemes - on demand that waste be taken back from household residents. This type of the waste equipment collection is comfortable for residents as they can indicate day and time windows for the take-back. Collecting companies are interested in lowering operational costs required for service. This lowering includes selection of a sufficient number of vehicles and employees, and then minimising the routes' length in order to achieve savings in fuel consumption, and lowering of emissions. In the proposed model we use a genetic algorithm for optimisation of the route length and number of vehicles and fuzzy logic for representation of the household residents' satisfaction on the take-back service provided by collection companies. Also, modern communication channels like websites or mobile phone applications can be used to send the waste equipment take-back request from the household, so it has the potential to be developed in future applications. The operation of the model has been presented in the case study of a city in southern Poland. The results can be useful for collecting companies and software producers for preparation of new applications to be used in waste collection. PMID- 26944865 TI - Anaerobic digestion of grape pomace: Biochemical characterization of the fractions and methane production in batch and continuous digesters. AB - In this study, we have estimated the biogas and methane production from grape pomace (variety Cabernet Franc). The physical and chemical characteristics of the raw material were determined, and the structural polysaccharides were identified and analyzed by the Van Soest method. Batch anaerobic digestions were carried out to assess the methane production of the grape pomace, pulp and seeds. The obtained cumulative methane productions are 0.125, 0.165 and 0.052 Nm(3) kg COD( 1) for grape pomace, pulps and seeds, respectively. The effect of grinding on the methane potential of the substrates, as a mechanical pretreatment, was evaluated. We found that it increased the anaerobic biodegradability for grape pomace, pulp and seeds by 13.1%, 4.8% and 22.2%, respectively. On the other hand, the methane potential of the grape pomace was determined in a laboratory pilot plant (12L) continuously mixed with an organic loading rate of 2.5 kg COD m(3) d(-1) and a hydraulic retention time of 30 days. The corresponding biogas production was 6.43 * 10(-3) Nm(3) d(-1), with a methane content of 62.3%. Thus, the pilot plant's efficiency compared to that achieved in the batch process was 81.2%. Finally, a significant correlation was found between the biochemical content and methane production. PMID- 26944866 TI - Beneficiation and recovery of indium from liquid-crystal-display glass by hydrometallurgy. AB - Considering indium scarcity, the end-of-life (EOL) LCD, which accounts for up to 90% of market share can be a feasible secondary resource upon successful recycling. In the preferred hydrometallurgical process of such critical metals, leaching is the essential primary and essential phase has been investigated. In this process, LCD was mechanically separated along with other parts from EOL TVs through a smartly engineered process developed at our institute, Institute for Advanced Engineering (IAE), the Republic of Korea. After removing plastics and metals from the LCD, it was mechanically shredded for size reduction. The mechanically shredded LCD waste was leached with HCl for recovery of indium. Possible leaching parameters such as; effect of acid concentration, pulp density, temperature and effect of oxidant H2O2 concentration were investigated to identify the best conditions for indium extraction. Indium (76.16*10-3g/L) and tin (10.24*10-3g/L) leaching was achieved at their optimum condition, i.e. lixiviant of 5M HCl, a pulp density of 500g/L, temperature 75 degrees C, agitation speed of 400rpm and time for 120min. At optimum condition the glass, plastic and the valuable metal indium have completely been separated. From indium enriched leach liquor, indium can be purified and recovered through hydrometallurgy. PMID- 26944868 TI - Moderators of intervention dose effects on diet quality and physical activity changes in a church-based, multicomponent, lifestyle study: Delta Body and Soul III. AB - Many community-based lifestyle interventions targeting African Americans have reported positive effects on participants' dietary choices and physical activity habits. However, these effects vary and not all participants will have outcome changes. Moderation analysis can help explain differential effects observed, but are not often reported. Hence, the objective of this secondary analysis was to explore potential moderators of intervention dose effects on diet quality and physical activity outcomes in an effective lifestyle intervention. Delta Body and Soul III, conducted from 2011 to 2012, was a 6-month, church-based, multicomponent, educational intervention designed to improve diet quality and increase physical activity in rural Southern African American adults. Generalized linear mixed models were used to determine associations among indicators of intervention dose received by participants, potential moderators and health outcome changes. Results indicated only three baseline characteristics-employment status, food shopping frequency and individual with primary responsibility for meal preparation-moderated the effects of education session attendance on diet quality changes. No evidence for moderation of exercise class attendance effects on physical activity changes was found. Thus, this culturally targeted, multicomponent lifestyle intervention did induce positive health changes in participants with a range of sociodemographic characteristics and food shopping and eating behaviors. PMID- 26944867 TI - A qualitative analysis of the concepts of fidelity and adaptation in the implementation of an evidence-based HIV prevention intervention. AB - Continued debate about the relative value of fidelity versus adaptation, and lack of clarity about the meaning of fidelity, raise concerns about how frontline service providers resolve similar issues in their daily practice. We use SISTA ('Sisters Informing Sisters on Topics about acquired immune deficiency syndrome'), an evidence-based human immunodeficiency virus (HIV) prevention intervention for African American women, to understand how facilitators and program directors interpret and enact implementation fidelity with the need for adaptation in real-world program delivery. We conducted 22 in-depth, semi structured interviews with service providers from four agencies implementing SISTA. Facilitators valued their skills as group leaders and ability to emotionally engage participants as more critical to program effectiveness than delivering the intervention with strict fidelity. Consequently, they saw program manuals as guides rather than static texts that should never be changed and, moreover, viewed the prescriptive nature of manuals as undermining their efforts to fully engage with participants. Our findings suggest that greater consideration should be given to understanding the role of facilitators in program effectiveness over and above the question of whether they implement the program with fidelity. Moreover, training curricula should provide facilitators with transferable skills through general facilitator training rather than only program-specific or manual-specific training. PMID- 26944869 TI - Sustainability of physical activity promoting environments and influences on sustainability following a structural intervention in residential children's homes. AB - Research examining sustainability of health promotion programs within organizational settings is limited. The Environmental Interventions in Residential Children's Homes (ENRICH) was a structural intervention that trained Wellness Teams (WTs) within residential children's homes (RCH) to target environmental changes that promote physical activity (PA) among residential youth. This study examines the sustainability of PA promoting environments and influences on sustainability within RCHs. A sustainability survey was administered to 14 RCHs 2 years after receiving ENRICH. Variables included sustainability of PA promoting environments, Organizational Influences, perceived organizational and individual benefits, and implementation of PA and general (i.e. Global) wellness activities. Activities reported as sustained and barriers were used descriptively to inform sustainability. Path analyses explained the relationship between sustainability influences and sustainability of PA promoting environments. Sustainability was found in 8 of 14 (57%) RCHs. Sustained activities reflected greater Global versus PA implementation. Global implementation mediated the relationship between Organizational Influences and sustainability, which may have been more easily achieved since Global activities were most likely controlled by WTs and did not require extensive organizational support from RCH administrators. Results highlight the importance of defining and assessing different implementation types when measuring sustainability and influences on sustainability within RCHs organizations. PMID- 26944872 TI - Neural processing around 200 ms after stimulus-onset correlates with subjective visual awareness. AB - Does visual awareness correlate with early activity in visual cortex or with later wide-spread neural activation? This question was studied by presenting liminal targets in one of the four quadrants of the screen and asking the participants to make forced-choice localization responses and to rate their subjective visual awareness of each target, while electroencephalography was measured. In the analyses of event-related potential (ERP) correlates of awareness, response accuracy was kept constant so that only the subjectively rated awareness varied between high-awareness ('seen' rating) and low-awareness ('unseen' rating) targets. High-awareness-correct trials were associated with enhanced contralateral N200 at 180-280 ms as compared with low-awareness-correct trials. This effect (visual awareness negativity, VAN) also correlated with aware sensitivity to the presence vs. absence of the stimulus (d'). In addition, high awareness-correct trials were associated with later enhanced P3 amplitudes (after 350 ms), but this effect correlated only with the response bias (c). ERPs to low awareness-correct trials elicited larger contralateral N200 than ERPs to low awareness-incorrect trials, and this effect correlated with conservative response bias, suggesting that it reflected weak awareness rather than unconscious processing. The results suggest that the enhanced N200 correlates with graded awareness. The results support theories of visual awareness in which early activity in visual cortex gives rise to subjective visual experiences. PMID- 26944871 TI - Glycemic Index, Glycemic Load, and Lung Cancer Risk in Non-Hispanic Whites. AB - BACKGROUND: Postprandial glucose (PPG) and insulin responses play a role in carcinogenesis. We evaluated the association between dietary glycemic index (GI) and glycemic load (GL), markers of carbohydrate intake and PPG, and lung cancer risk in non-Hispanic whites. METHODS: GL and GI were assessed among 1,905 newly diagnosed lung cancer cases recruited from the University of Texas MD Anderson Cancer Center (Houston, TX) and 2,413 healthy controls recruited at Kelsey Seybold Clinics (Houston, TX). We assessed associations between quintiles of GI/GL and lung cancer risk and effect modification by various risk factors. ORs and 95% confidence intervals (CI) were estimated using multivariable logistic regression. RESULTS: We observed a significant association between GI [5th vs. 1st quintile (Q) OR = 1.49; 95% CI, 1.21-1.83; P(trend) <0.001] and lung cancer risk and GI(ac) (5th vs. 1st Q OR = 1.48; 95% CI, 1.20-1.81; P(trend) = 0.001) and lung cancer risk. We observed a more pronounced association between GI and lung cancer risk among never smokers (5th vs. 1st Q OR = 2.25; 95% CI, 1.42 3.57), squamous cell carcinomas (SCC; 5th vs. 1st Q OR = 1.92; 95% CI, 1.30 2.83), and those with less than 12 years of education (5th vs. 1st Q OR = 1.75; 95% CI, 1.19-2.58, P(interaction) = 0.02). CONCLUSION: This study suggests that dietary GI and other lung cancer risk factors may jointly and independently influence lung cancer etiology. IMPACT: Understanding the role of GI in lung cancer could inform prevention strategies and elucidate biologic pathways related to lung cancer risk. PMID- 26944873 TI - Discrimination of tonal and atonal music in congenital amusia: The advantage of implicit tasks. AB - Congenital amusia is a neurodevelopmental disorder of music perception and production, which has been attributed to a major deficit in pitch processing. While most studies and diagnosis tests have used explicit investigation methods, recent studies using implicit investigation approaches have revealed some unimpaired pitch structure processing in congenital amusia. The present study investigated amusic individuals' processing of tonal structures (e.g., musical structures respecting the Western tonal system) via three different questions. Amusic participants and their matched controls judged tonal versions (original musical excerpts) and atonal versions (with manipulated pitch content to remove tonal structures) of 12 musical pieces. For each piece, participants answered three questions that required judgments from different perspectives: an explicit structural one, a personal, emotional one and a more social one (judging the perception of others). Results revealed that amusic individuals' judgments differed between tonal and atonal versions. However, the question type influenced the extent of the revealed structure processing: while amusic individuals were impaired for the question requiring explicit structural judgments, they performed as well as their matched controls for the two other questions. Together with other recent studies, these findings suggest that congenital amusia might be related to a disorder of the conscious access to music processing rather than music processing per se. PMID- 26944875 TI - Cannabis use in psychotic patients is linked to worse outcomes. PMID- 26944874 TI - Cognitive and anatomic double dissociation in the representation of concrete and abstract words in semantic variant and behavioral variant frontotemporal degeneration. AB - We examine the anatomic basis for abstract and concrete lexical representations in semantic memory by assessing patients with focal neurodegenerative disease. Prior evidence from healthy adult studies suggests that there may be an anatomical dissociation between abstract and concrete representations: abstract words more strongly activate the left inferior frontal gyrus relative to concrete words, while concrete words more strongly activate left anterior-inferior temporal regions. However, this double dissociation has not been directly examined. We test this dissociation in two patient groups with focal cortical atrophy in each of these regions, the behavioral variant of Frontotemporal Degeneration (bvFTD) and the semantic variant of Primary Progressive Aphasia (svPPA). We administered an associativity judgment task for abstract and concrete words, where subjects select which of two words is best associated with a given target word. Both bvFTD and svPPA patients were significantly impaired in their overall performance compared to controls. While controls treated concrete and abstract words equally, we found a category-specific double dissociation in patients' judgments: bvFTD patients showed a concreteness effect (CE), with significantly worse performance for abstract compared to concrete words, while svPPA patients showed reversal of the CE, with significantly worse performance for concrete over abstract words. Regression analyses also revealed an anatomic double dissociation: The CE is associated with inferior frontal atrophy in bvFTD, while reversal of the CE is associated with left anterior-inferior temporal atrophy in svPPA. These results support a cognitive and anatomic model of semantic memory organization where abstract and concrete representations are supported by dissociable neuroanatomic substrates. PMID- 26944877 TI - Detection of pregnancy-associated glycoproteins in milk and blood as a test for early pregnancy in dairy cows. AB - The objective of our study was to evaluate 2 pregnancy-associated glycoprotein (PAG)-based enzyme-linked immunosorbent assays (ELISAs) for use with either blood or milk. From 12 dairy farms, 116 Montbeliarde or Holstein cows were selected that had either undergone artificial insemination (AI; n = 102) or had calved (n = 14) 2-3 months earlier and had not undergone any further AI. Serum, plasma, and milk were obtained from all cows; serum and plasma were analyzed using the blood pregnancy test and milk using the milk pregnancy test. No false-positive results were observed when samples of the 14 noninseminated cows were tested. Cows undergoing AI were sampled at ~16, 30, and 41 days post-AI. An additional milk sample was taken at ~53 days post-AI. To establish whether the inseminated cows were pregnant, the cows were subjected to transrectal ultrasonography (TU) on or around day 41. Of the 102 inseminated cows, 63 were confirmed pregnant by TU. By day 30, the serum, plasma, and milk ELISAs demonstrated 100%, 100%, and 98.1% sensitivity and 88.6%, 88.9%, and 90.3% specificity, respectively, with potential pregnancy losses 30-41 days post-AI. Accuracy obtained on serum, plasma, and milk at ~41 days post-AI and on milk at ~53 days post-AI ranged from 97.4% to 100%. There were no differences of practical significance in performance between the blood and milk ELISAs for the sampling dates chosen. This new diagnostic capability with milk samples offers a major improvement in bovine reproductive management. PMID- 26944876 TI - Two superoxide dismutases from TnOtchr are involved in detoxification of reactive oxygen species induced by chromate. AB - BACKGROUND: Superoxide dismutases (SOD) have been reported as the most relevant bacterial enzymes involved in cells protection from reactive oxygen species (ROS). These toxic species are often the product of heavy metal stress. RESULTS: Two genes, chrC and chrF, from TnOtchr genetic determinant of strain Ochrobactrum tritici 5bvl1 were cloned in Escherichia coli in order to overexpress the respective proteins. Both proteins were purified and characterized as superoxide dismutases. ChrC was confirmed as being a Fe-SOD, and the enzymatic activity of the ChrF, not inhibited by hydrogen peroxide or potassium cyanide, suggested its inclusion in the Mn-SOD family. This identification was supported by chemical quantification of total metal content in purified enzyme. Both enzymes showed a maximum activity between pH 7.2-7.5. ChrF retained nearly full activity over a broader range of pH and was slightly more thermostable than ChrC. The genes encoding these enzymes in strain O. tritici 5bvl1 were inactivated, developing single and double mutants, to understand the contribution of these enzymes in detoxification mechanism of reactive oxygen species induced by chromate. During chromate stress, assays using fluorescent dyes indicated an increase of these toxic compounds in chrC, chrF and chrC/chrF mutant cells. CONCLUSIONS: In spite of the multiple genes coding for putative superoxide dismutase enzymes detected in the genome of O. tritici 5bvl1, the ChrC and ChrF might help the strain to decrease the levels of reactive oxygen species in cells. PMID- 26944878 TI - The valley system of the Jihlava river and Mohelno reservoir with enhanced tritium activities. AB - The Dukovany nuclear power plant (NPP Dukovany) releases liquid effluents, including HTO, to the Mohelno reservoir, located in a deep valley. Significantly enhanced tritium activities were observed in the form of non-exchangeable organically bound tritium in the surrounding biota which lacks direct contact with the water body. This indicates a tritium uptake by plants from air moisture and haze, which is, besides the uptake by roots from soil, one of the most important mechanisms of tritium transfer from environment to plants. Results of a pilot study based on four sampling campaigns in 2011-2015 are presented and discussed, with the aim to provide new information on tritium transport in the Mohelno reservoir - Jihlava River - plants ecosystems. PMID- 26944879 TI - The impact of armed conflict on adolescent transitions: a systematic review of quantitative research on age of sexual debut, first marriage and first birth in young women under the age of 20 years. AB - BACKGROUND: Young women in conflict-affected regions are at risk of a number of adverse outcomes as a result of violence, economic deterioration and the breakdown of community structures and services. This paper presents the findings of a systematic review of quantitative literature reporting how key sexual and reproductive health (SRH) outcomes among young women under the age of 20 years are affected by exposure to armed conflict; namely, sexual debut, first marriage and first birth. Increases in these outcomes among young women are all associated with potential negative public health consequences. It also examines and documents possible causal pathways for any changes seen. METHODS: To fit with our inclusion criteria, all reviewed studies included outcomes for comparable populations not exposed to conflict either temporally or spatially. A total of 19 studies with results from 21 countries or territories met our inclusion criteria; seven presented findings on marriage, four on fertility and eight on both of these outcomes. Only one study reporting on sexual debut met our criteria. RESULTS: Findings show clear evidence of both declines and increases in marriage and childbirth among young women in a range of conflict-affected settings. Several studies that showed increases in marriage below the age of 20 years reported that such increases were concentrated in the younger teenagers. Trends in fertility were predominantly driven by marriage patterns. Suggested causal pathways for the changes observed could be grouped into three categories: involuntary, gender and psycho-social and economic and material factors. CONCLUSION: The review reveals a paucity of literature on the impact of conflict on SRH outcomes of young women. Further quantitative and qualitative studies are needed to explore how conflict influences SRH events in young women over both the short- and longer-term. PMID- 26944880 TI - Heterologous production of raspberry ketone in the wine yeast Saccharomyces cerevisiae via pathway engineering and synthetic enzyme fusion. AB - BACKGROUND: Raspberry ketone is the primary aroma compound found in raspberries and naturally derived raspberry ketone is a valuable flavoring agent. The economic incentives for the production of raspberry ketone, combined with the very poor yields from plant tissue, therefore make this compound an excellent target for heterologous production in synthetically engineered microbial strains. METHODS: A de novo pathway for the production of raspberry ketone was assembled using four heterologous genes, encoding phenylalanine/tyrosine ammonia lyase, cinnamate-4-hydroxlase, coumarate-CoA ligase and benzalacetone synthase, in an industrial strain of Saccharomyces cerevisiae. Synthetic protein fusions were also explored as a means of increasing yields of the final product. RESULTS: The highest raspberry ketone concentration achieved in minimal media exceeded 7.5 mg/L when strains were fed with 3 mM p-coumaric acid; or 2.8 mg/L for complete de novo synthesis, both of which utilized a coumarate-CoA ligase, benzalacetone synthase synthetic fusion protein that increased yields over fivefold compared to the native enzymes. In addition, this strain was shown to be able to produce significant amounts of raspberry ketone in wine, with a raspberry ketone titer of 3.5 mg/L achieved after aerobic fermentation of Chardonnay juice or 0.68 mg/L under anaerobic winemaking conditions. CONCLUSIONS: We have shown that it is possible to produce sensorially-relevant quantities of raspberry ketone in an industrial heterologous host. This paves the way for further pathway optimization to provide an economical alternative to raspberry ketone derived from plant sources. PMID- 26944881 TI - The Prenatal Environment in Twin Studies: A Review on Chorionicity. AB - A literature search was conducted to identify articles examining the association of chorionicity (e.g., whether twins share a single chorion and thus placenta or have separate chorions/placentas) and genetics, psychiatry/behavior, and neurological manifestations in humans twins and higher-order multiples. The main aim was to assess how frequently chorionicity has been examined in relation to heritability estimates, and to assess which phenotypes may be most sensitive to, or affected by, bias in heritability estimates because of chorionicity. Consistent with the theory that some chorionicity effects could lead to overestimation and others to underestimation of heritability, there were instances of each across the many phenotypes reviewed. However, firm conclusions should not be drawn since some of the outcomes were only examined in one or few studies and often sample sizes were small. While the evidence for bias due to chorionicity was mixed or null for many outcomes, results do, however, consistently suggest that heritability estimates are underestimated for measures of birth weight and early growth when chorionicity is not taken into account. PMID- 26944883 TI - Abscess Formation in a Nonfunctioning Pituitary Adenoma. AB - BACKGROUND: Pituitary abscesses are rare clinical entities that can occur in the setting of a normal gland or underlying disease, including adenoma, craniopharyngioma, or Rathke cleft cyst. Although once believed to be indolent, when these secondary abscesses occur in the setting of an adenoma, they can be associated with significant clinical morbidity. Most patients present with visual disturbances or headache without fever or meningitis. CASE DESCRIPTION: We present the case of a 63-year-old woman with remote history of Staphylococcus osteomyelitis who presented with 1 week of diplopia, partial left third nerve palsy, and bitemporal hemianopsia who was found to have a pituitary abscess in the setting of an adenoma. She underwent drainage of the abscess and resection of her adenoma followed by complete resolution of her symptoms. CONCLUSIONS: This case highlights the need for prompt treatment of pituitary abscesses, with the possibility of excellent neurologic recovery. PMID- 26944882 TI - Incidental Pineal Cysts: Is Surveillance Necessary? AB - OBJECTIVE: The natural history of incidental pineal cysts is poorly understood. Neurosurgeons and neuroradiologists are more frequently faced with this disease in the advent of higher-resolution magnetic resonance imaging (MRI) scanning. We aim to suggest a suitable surveillance strategy for these patients. METHODS: All patients who had MRI of the brain between June 2007 and January 2014 (n = 42,099) at The Walton Centre for Neurology and Neurosurgery were included. Radiologic reports containing the terms "pineal" and "cyst" were reviewed to identify patients. RESULTS: A total of 281 patients were identified with pineal cysts. The principal indication for head MRI was headache (50.2%), although no symptoms were deemed attributable to pineal disease. A total of 178 patients (63.3%) were female, and the age at diagnosis ranged from 16 to 84 years. The median size of pineal cyst at diagnosis was 10 mm. A total of 181 patients had subsequent follow up at a median time of 6 months (range, 1-68). Eleven pineal cysts (6%) changed size during the follow-up period. Four patients had a reduction in cyst size; the median change was 2.5 mm. A further 7 pineal cysts increased in cyst size; the median change was 2 mm. No patients developed complications. CONCLUSIONS: Incidental pineal cysts typically show a benign course. In the adult population, they do not require long-term neurosurgical follow-up, because pineal cysts tend to remain a stable size. In asymptomatic patients, we recommend a single follow up MRI scan at 12 months to confirm diagnosis. The patient should then be discharged if the cyst remains stable. PMID- 26944884 TI - Managing Post-tPA Intracranial Hemorrhage: Time Is Still Brain. PMID- 26944886 TI - Current Trends in Craniosynostosis. PMID- 26944885 TI - The Use of Closed Suction Drainage in Lumbar Spinal Surgery: Is It Really Necessary? AB - BACKGROUND: Closed wound suction drainage after spine surgery is commonly used in clinical practice. However, no consensus has been reached for using drainage versus nondrainage after lumbar spinal surgery until now. OBJECTIVE: The purpose of this study was to determine the clinical outcomes of using closed suction drainage versus nondrainage after lumbar spinal surgery. METHODS: We conducted a systematic review and meta-analysis to identify relevant studies from PubMed, MEDLINE, EMBASE, Cochrane Library, and Google scholar up to September 2015. All randomized, quasi-randomized, and controlled clinical studies, which compared the clinical outcomes of using closed suction drainage versus nondrainage in patients who underwent lumbar spinal surgery, were included. Data extraction and quality assessment were according to Cochrane Collaboration guidelines. RESULTS: Five studies involving 1295 patients were included in this meta-analysis. By pooling the clinical outcomes, there were no significant differences between patients with drainage and nondrainage in terms of the incidence of wound infection (odds ratio [OR], 1.48; 95% confidence interval [CI], 0.47-4.71; P = 0.50), wound hematoma (OR, 0.45; 95% CI, 0.01-29.31, P = 0.71), and reoperation (OR, 1.36; 95% CI, 0.22-8.27; P = 0.74). Drainage after lumbar surgery was associated with more blood loss and significantly greater blood transfusions (OR, 3.68; 95% CI, 1.80 7.54; P < 0.01) compared with nondrainage. However, more patients contracted postoperative fever in the nondrainage group than did those in drainage group. CONCLUSIONS: Based on this systematic review and meta-analysis, there is insufficient evidence to suggest routine use of prophylactic closed suction drainage after lumbar spinal surgery. However, a decision to use or not use drainage should be individualized for each patient because many factors affect the outcomes. PMID- 26944887 TI - Historical Perspective and the Role of Endoscopy in Intracranial Aneurysm Surgery. PMID- 26944888 TI - Spinal Cord Injury, Steroids and Latin America. PMID- 26944889 TI - Importance of Developing Stroke Systems of Care to Improve Access to Endovascular Therapies. PMID- 26944890 TI - Atrial flutter and atrial fibrillation ablation - sequential or combined? A cost benefit and risk analysis of primary prevention pulmonary vein ablation. AB - BACKGROUND: Recent studies have tested the hypothesis that preventive pulmonary vein isolation (PVI) at time of atrial flutter ablation in patients who have not had atrial fibrillation (AF) will reduce future incidence of AF. OBJECTIVE: To model relative procedural costs, risks, and benefits of sequential versus combined ablation strategies. METHODS: The decision model compares a sequential ablation strategy of atrial flutter ablation, followed by future PVI if necessary, with an initial combined flutter and preventive PVI ablation strategy. Assumptions are AF incidence 20% per year, PVI success rate 70%, PVI complication rate 4%, atrial flutter complication rate 1%, and costs $13,056 for PVI and $8,466 for atrial flutter ablation. RESULTS: The sequential ablation strategy is less expensive, at 1.4 vs 1.6 expected flutter ablation equivalents (FAE) ($11,852 vs $13,545) per patient, and entails less average risk, at 2% vs 4%. A combined ablation strategy is more expensive if the relative cost of PVI is more than 24.6% higher than atrial flutter ablation. A combined ablation strategy has higher total risk if PVI procedural risk is 24.6% more than atrial flutter ablation. CONCLUSIONS: Under base case assumptions of relative cost of PVI to flutter ablation 1.5 and relative risk 4, a sequential ablation approach has less total expected cost and less expected risk. There appears to be no compelling reason to adopt a combined ablation approach into standard practice. Nomograms are presented to allow the reader to assess which strategy is preferred according to local relative costs and risk. PMID- 26944891 TI - Alteration of Skin Mechanical Properties in Patients Undergoing Botulinum Toxin Type A Injections of Forehead Rhytides. AB - BACKGROUND: Although application of botulinum toxin type A (BTX-A) for the treatment of forehead rhytides has become very popular, the effects of its intramuscular injections on the skin mechanical properties remain unclear. OBJECTIVES: We prospectively investigated the alterations in the mechanical properties of the skin of patients who received intramuscular injections of botulinum toxin A (BTX-A) for forehead rhytides and compared two injection doses. METHODS: Of the 42 enrolled patients, one randomly assigned half received intramuscular injections of two units (group I), and the other half received four units (group II) of BTX-A in each injection point. The baseline and post treatment skin mechanical parameters, including gross elasticity (R2), net elasticity (R5), viscoelastic ratio (R6) and biological elasticity (R7), were measured using the Cutometer((r)) and compared. RESULTS: Treatment with BTX-A resulted in significant overall alterations in the mechanical properties of skin at the injection sites of both treatment groups during the 16-week period, and no significant differences were observed between groups. Significant decreases in biological elasticity, net elasticity and viscoelasticity properties were observed at 2 weeks follow-up and began to recover at that time. All of the skin mechanical properties recovered to baseline levels by 16 weeks of follow-up in both dosage groups, which indicates that the higher dosage (4 units) did not delay relapse compared to the two-unit dosage. CONCLUSIONS: We concluded that intramuscular injections of BTX-A significantly regulated the gross elasticity, net elasticity, functional elasticity and viscoelastic elasticity at the injection point over a radius of 1.5 cm at 2, 4 and 8 weeks follow-up. The alteration in the skin measurements had completely diminished by the 16-week follow-up. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 26944892 TI - [Identification of knowledge deficits of pharmacy students at the beginning of the fifth year of pharmacy practice experience: Proposals to change the content of academic programs]. AB - INTRODUCTION: In France, community pharmacy students performed a hospital pharmacy practice experience during the 5th year of the university curriculum. The purpose of a part of the content of the academic teaching program delivered before this practice experience is to prepare the students for their future hospital activities. It should enable them for the practical use of knowledge in order to improve pharmacotherapy, laboratory diagnosis and monitoring of patients' care. The aim of this study was to show if there are gaps in this program. METHODS: Fourteen students performing their clerkship in a teaching hospital were invited to highlight these gaps when they were gradually immersed in the pharmaceutical care. They did so under the careful observation of hospital pharmacist preceptors. These practitioners referred to professional guidelines, documentary tools used in daily clinical practice and publications supporting their pharmaceutical care practices. RESULTS: Shortcomings and gaps identified were: how to communicate with other healthcare professionals and the content of verbal exchanges, how to conduct a patient-centered consultation, documentation tools required for relevant pharmacist' interventions, codification of pharmacist's interventions, risks related to drug packaging and benefit risk assessment of health information technologies. DISCUSSION: These gaps represent a handicap by delaying the process that led to move from student to healthcare professional. Hospital pharmacist preceptors have to fill in these gaps before engaging students in pharmaceutical care. CONCLUSION: These results invite to revise partly the content of the academic teaching program delivered before the 5th year hospital pharmacy practice experience. PMID- 26944893 TI - Protein expression of CYP1A1, CYP1B1, ALDH1A1, and ALDH2 in young patients with oral squamous cell carcinoma. AB - The purpose of this study was to evaluate the expression of the enzymes involved in the biotransformation of tobacco and alcohol. A study group of 41 young patients (<=40 years old) with oral squamous cell carcinoma (OSCC) was compared to 59 control subjects (>=50 years old) with tumours of similar clinical stages and topographies. The immunohistochemical expression of CYP1A1, CYP1B1, ALDH1A1, and ALDH2 was evaluated using the tissue microarray technique. There was a predominance of males, smokers, and alcohol drinkers in both groups. Most tumours were located in the tongue (43.9% vs. 50.8%), were well-differentiated (63.4% vs. 56.6%), and were in clinical stages III or IV (80.5% vs. 78.0%). No difference was observed in the expression of CYP1A1, ALDH1A1, or ALDH2 between the two groups. CYP1A1 and ALDH2 protein expression had no influence on the prognosis. The immunoexpression of CYP1B1 was significantly higher in the control group than in the young group (P<0.001). The 5-year relapse-free survival was better in patients with CYP1B1 overexpression vs. protein underexpression (64% vs. 25%; P<0.05), regardless of age. ALDH1A1 expression improved relapse-free survival in young patients. These results suggest a lower risk of recurrence with increased metabolism of carcinogens by CYP1B1. Further studies involving other genes and proteins are necessary to complement the results of this research. PMID- 26944894 TI - Association of searching for health-related information online with self-rated health in the European Union. AB - BACKGROUND: The Internet is widely accessed for health information, but poor quality information may lead to health-worsening behaviours (e.g. non compliance). Little is known about the health of individuals who use the Internet for health information. METHODS: Using the Flash Eurobarometer survey 404, European Union (EU) citizens aged >=15 (n = 26 566) were asked about Internet utilisation for health information ('general' or 'disease-specific'), the sources used, self-rated health, and socioeconomic variables. Multivariable logistic regression was employed to assess the likelihood of bad self-rated health and accessing different health information sources (social networks, official website, online newspaper, dedicated websites, search engines). RESULTS: Those searching for general information were less likely to report bad health [odds ratios (OR) = 0.80; 95% confidence intervals (CI): 0.70-0.92], whilst those searching for disease-specific information were more likely (OR = 1.22; 95% CI: 1.07-1.38). Higher education and frequent doctor visits were associated with use of official websites and dedicated apps for health. Variation between EU member states in the proportion of people who had searched for general or disease specific information online was high. CONCLUSIONS: Searching for general health information may be more conducive to better health, as it is easier to understand, and those accessing it may already be or looking to lead healthier lives. Disease-specific information may be harder to understand and assimilate into appropriate care worsening self-rated health. It may also be accessed if health services fail to meet individuals' needs, and health status is currently poor. Ensuring individuals' access to quality health services and health information will be key to addressing inequalities in health. PMID- 26944895 TI - Out-of-pocket expenditure by private households for dental services - empirical evidence from Austria. AB - AIMS: Dental services differ from other health services in several dimensions. One important difference is that a substantial share of costs of dental services especially costs beyond routine dental treatment-is paid directly by the patient out-of-pocket. SETTINGS AND DESIGN: This study analyses the socio-economic determinants of out-of-pocket expenditure for dental services (OOPE) in Austria at the household level. METHODS AND MATERIAL: Cross-sectional information on OOPE and household characteristics provided by the Austrian household budget survey 2009/10 was analysed. STATISTICAL ANALYSIS USED: A two-part model (Logit/GLM) and one-part GLM was applied. RESULTS: The probability of OOPE is strongly affected by the life cycle (structure) of the household. It is higher for higher age classes, higher income, and partially higher levels of education. The type of public insurance has an influence on expenditure probability while the existence of private health insurance has no significant effect. In contrast to the highly statistically significant coefficients in the first stage, the covariates of the second stage remain predominantly insignificant. According to the results, the level of expenditure is driven mainly by the level of education and income. The results of the one-part GLM confirm the results of the two-part model. CONCLUSIONS: The results allow new insights into the determinants of OOPE for dental care. The household level turns out to be an adequate basis to study the determinants of OOPE, although caution should be applied before jumping to conclusions for the individual level. PMID- 26944896 TI - Presence of blaPER-1 and blaVEB-1 beta-lactamase genes among isolates of Pseudomonas aeruginosa from South West of Iran. AB - Pseudomonas aeruginosa isolates have acquired resistance to antibiotics such as novel beta-lactams. The aim of this study was to investigate the blaPER-1, blaVEB 1, and blaPSE-1 genes among isolates of P. aeruginosa among intensive care unit (ICU) patients. Sixty-five isolates were collected. The antibiotic susceptibility testing and combined disk tests were performed to detect the isolates producing extended spectrum beta-lactamases (ESBLs) among ceftazidime-resistant isolates. Polymerase chain reaction (PCR) amplification of blaPER-1, blaVEB-1, and blaPSE-1 genes was conducted. Ten (15.3%) isolates were ESBL-positive, of which 40% (n=4) belonged to males and 60% (n=6) were collected from females. Moreover, two and one isolates harbored blaPER-1 and blaVEB-1 genes, respectively. PMID- 26944898 TI - What is the right approach to infection prevention and control for children living at home with invasive devices? PMID- 26944897 TI - The expression of beta-galactosidase during long-term cultured goat skin fibroblasts and the effect of donor cell passage on in vitro development of nuclear transfer embryos. AB - The present study aimed to detect the expression of beta-galactosidase during long-term cultured goat skin fibroblasts and investigate the effects of donor goat age, sex, and cell passage on senescence and the effects of donor cell passage on in vitro development of nuclear transfer embryos. The results showed that, in the same cell passage, more beta-galactosidase-positive cells were detected in cells from older donors than younger donors. Irrespective of the donor age, the number of positive cells was higher in later passages from passages 20 to 50. In the same passage from 20 to 50, the beta-galactosidase positive rate was higher in cells from 5-yr female goat than 5-yr male goat. Using fibroblasts from male goats at various passages as donor cells, reconstructed embryos had similar fusion and cleavage rates, but the blastocyst rate was higher for cells at passages 10 and 20 than passage 30. In conclusion, donor goat age and cell passage had significant effects on the beta-galactosidase positive rate; also, cells from 5-yr female goat had a higher beta-galactosidase positive rate than those from 5-yr male goat, and the donor cell passage affected the developmental potential of nuclear transfer embryos. PMID- 26944899 TI - Viral hepatitis B and C outbreak related to parenteral treatment at an oncological department in Slovakia. AB - The Regional Public Health Authority was notified about four cases of viral hepatitis (B and C) among patients with pre-event history of hospitalization at an oncological ward. An outbreak investigation was commenced in response. Forty seven cases of viral hepatitis B and C in 39 patients hospitalized during the period from September 2009 to July 2010 were registered. We found an association between parenteral treatment and disease (hepatitis B: chi(2) = 49.53; P < 0.001; hepatitis C: chi(2) = 22.42; P < 0.001). Despite using disposable materials, there remains a risk of transmission of bloodborne virus infections in hospitals due to poor adherence to standard procedures. PMID- 26944900 TI - Length of stay and mortality associated with healthcare-associated urinary tract infections: a multi-state model. AB - BACKGROUND: The emergence of antimicrobial resistance is of particular concern with respect to urinary tract infections, since the majority of causative agents are Gram-negative bacteria. Healthcare-associated urinary tract infections (HAUTIs) are frequently associated with instrumentation of the urinary tract, specifically with indwelling catheters. AIM: To evaluate the current incidence, mortality, and length of hospital stay associated with HAUTIs. METHODS: A non concurrent cohort study design was used, conducted between January 1st, 2010 and June 30th, 2014. All patients admitted to one of the eight participating Australian hospitals and who were hospitalized for more than two days were included. The primary outcome measures were the incidence, mortality, and excess length of stay associated with HAUTIs. FINDINGS: From 162,503 patient admissions, 1.73% [95% confidence interval (CI): 1.67-1.80] of admitted patients acquired a HAUTI. Using a multi-state model, the expected extra length of stay due to HAUTI was four days (95% CI: 3.1-5.0 days). Using a Cox regression model, infection significantly reduced the rate of discharge (hazard ratio: 0.78; 95% CI: 0.73 0.83). Women were less likely to die (0.71; 0.66-0.75), whereas older patients were more likely to die (1.40; 1.38-1.43). Death was rarer in a tertiary referral hospital compared to other hospitals, after adjusting for age and sex (0.74; 0.69 0.78). CONCLUSION: This study is the first to explore the burden of HAUTIs in hospitals using appropriate statistical methods in a developed country. Our study indicates that the incidence of HAUTI, in addition to its associated extra length of stay in hospital, presents a burden to the hospital system. With increasing incidence of UTI due to antimicrobial-resistant organisms, surveillance and interventions to reduce the incidence of HAUTI are required. PMID- 26944901 TI - Five-year decreased incidence of surgical site infections following gastrectomy and prosthetic joint replacement surgery through active surveillance by the Korean Nosocomial Infection Surveillance System. AB - BACKGROUND: Surveillance of healthcare-associated infection has been associated with a reduction in surgical site infection (SSI). AIM: To evaluate the Korean Nosocomial Infection Surveillance System (KONIS) in order to assess its effects on SSI since it was introduced. METHODS: SSI data after gastrectomy, total hip arthroplasty (THA), and total knee arthroplasty (TKA) between 2008 and 2012 were analysed. The pooled incidence of SSI was calculated for each year; the same analyses were also conducted from hospitals that had participated in KONIS for at least three consecutive years. Standardized SSI rates for each year were calculated by adjusting for SSI risk factors. SSI trends were analysed using the Cochran-Armitage test. FINDINGS: The SSI rate following gastrectomy was 3.12% (522/16,918). There was a significant trend of decreased crude SSI rates over five years. This trend was also evident in analysis of hospitals that had participated for more than three years. The SSI rate for THA was 2.05% (157/7656), which decreased significantly from 2008 to 2012. The risk factors for SSI after THA included the National Nosocomial Infections Surveillance risk index, trauma, reoperation, and age (60-69 years). The SSI rate for TKA was 1.90% (152/7648), which also decreased significantly during a period of five years. However, the risk-adjusted analysis of SSI did not show a significant decrease for all surgical procedures. CONCLUSION: The SSI incidence of gastrectomy and prosthetic joint replacement declined over five years as a result of active surveillance by KONIS. PMID- 26944902 TI - Combined education and skin antisepsis intervention for persistently high blood culture contamination rates in neonatal intensive care. AB - Contaminated blood cultures represent challenges regarding diagnosis, duration of hospitalization, antimicrobial use, pharmacy and laboratory costs. Facing problematic neonatal blood culture contamination (3.8%), we instigated a successful intervention combining skin antisepsis using sterile applicators with 2% chlorhexidine gluconate in 70% isopropanol prior to phlebotomy (replacing 70% isopropanol) and staff education. In the six months prior to intervention, 364 neonatal peripheral blood samples were collected. Fourteen (3.8%) were contaminated. In the post-intervention six months, 314 samples were collected. Three (0.96%) were contaminated, representing significant improvement (Fisher's exact test: P = 0.0259). No dermatological sequelae were observed. The improvement has been sustained. PMID- 26944903 TI - What happens in hospitals does not stay in hospitals: antibiotic-resistant bacteria in hospital wastewater systems. AB - Hospitals are hotspots for antimicrobial-resistant bacteria (ARB) and play a major role in both their emergence and spread. Large numbers of these ARB will be ejected from hospitals via wastewater systems. In this review, we present quantitative and qualitative data of extended-spectrum beta-lactamase (ESBL) producing Escherichia coli, vancomycin-resistant enterococci and Pseudomonas aeruginosa in hospital wastewaters compared to community wastewaters. We also discuss the fate of these ARB in wastewater treatment plants and in the downstream environment. Published studies have shown that hospital effluents contain ARB, the burden of these bacteria being dependent on their local prevalence. The large amounts of antimicrobials rejected in wastewater exert a continuous selective pressure. Only a few countries recommend the primary treatment of hospital effluents before their discharge into the main wastewater flow for treatment in municipal wastewater treatment plants. Despite the lack of conclusive data, some studies suggest that treatment could favour the ARB, notably ESBL-producing E. coli. Moreover, treatment plants are described as hotspots for the transfer of antibiotic resistance genes between bacterial species. Consequently, large amounts of ARB are released in the environment, but it is unclear whether this release contributes to the global epidemiology of these pathogens. It is reasonable, nevertheless, to postulate that it plays a role in the worldwide progression of antibiotic resistance. Antimicrobial resistance should now be seen as an 'environmental pollutant', and new wastewater treatment processes must be assessed for their capability in eliminating ARB, especially from hospital effluents. PMID- 26944904 TI - Efficacy of chlorine dioxide disinfection to non-fermentative Gram-negative bacilli and non-tuberculous mycobacteria in a hospital water system. AB - BACKGROUND: Chlorinated tap water in hospitals often contains low levels of non fermentative Gram-negative bacilli (NFGNB) and non-tuberculous mycobacteria (NTM). Measures are needed to ensure a safe water supply in hospitals to prevent nosocomial infections from these waterborne pathogens. AIM: To evaluate the efficacy of ClO2 treatment of a hospital water system on the levels of NFGNB and NTM in the water. METHODS: Our institution is a 1000-bed medical centre with two main buildings (B1 and B2). B1 has three intensive care units (ICUs) and transplant wards and polyethylene water pipes. B2 (control) has no ICUs and galvanized water pipes. A ClO2 generating unit was installed in the water system of B1 in April 2012 and water samples were collected in B1 and B2 before and eight times after installation. All samples were cultured for NFGNB and NTM. FINDINGS: The ClO2 concentration was significantly lower in the hot water than in the cold water (P<0.001). After 40 weeks of ClO2 use, the overall NFGNB colonies decreased significantly (hot water: 160+/-143 vs 2+/-4cfu/mL, P<0.001; cold water: 108+/-138 vs 3+/-7cfu/mL, P<0.001). Highly prevalent nosocomial NFGNB, such as Pseudomonas spp. and Stenotrophomonas spp., were undetected three months after ClO2 disinfection; Sphingomonas spp. persisted but had lower colony counts. NTM was present in 25% (three out of 12) of sampling locations initially, but was not detected at two weeks after ClO2 disinfection. The ICUs had no overall change in the number of NFGNB nosocomial infections after the intervention. CONCLUSION: Addition of a ClO2 disinfection unit to our hospital water system reduced the numbers of NTM and NFGNB in the hot and cold water systems. PMID- 26944905 TI - Clostridium difficile infections: analysis of recurrence in an area with low prevalence of 027 strain. PMID- 26944906 TI - Heat-resistant, extended-spectrum beta-lactamase-producing Klebsiella pneumoniae in endoscope-mediated outbreak. AB - BACKGROUND: We describe an outbreak with an extended-spectrum beta-lactamase producing Klebsiella pneumoniae strain in an intensive care unit in a secondary care hospital in Norway. The outbreak source was a fibreoptic intubation endoscope in which the outbreak strain survived despite chemothermal disinfection in a decontaminator designated for such use. The genetic marker clpK, which increases microbial heat resistance, has previously been described in K. pneumoniae outbreak strains. AIM: To investigate the role of clpK in biofilm formation and heat-shock stability in the outbreak strain. METHODS: The outbreak investigation was done by review of clinical records, screening of patients and culture from intubation endoscopes and bronchoscopes. Amplified fragment length polymorphism was used to identify the outbreak strain. clpK detection was performed by polymerase chain reaction, followed by mutant construction and heat shock assays. FINDINGS: Five patients and one intubation endoscope contained K. pneumoniae with the same amplified fragment length polymorphism pattern. The outbreak strain contained the clpK genetic marker, which rendered the strain its increased heat resistance. The survival rate of the strain grown as biofilm following heat treatment was also strongly dependent on clpK. CONCLUSION: Although clpK has been associated with clinical isolates of K. pneumoniae in earlier outbreaks, this is the first time that a ClpK-producing strain has been isolated from an environmental outbreak source. Heat resistance of certain K. pneumoniae strains may facilitate survival in biofilms on medical equipment and hence increase the potential of those strains to persist and disperse in the hospital environment. PMID- 26944907 TI - Efficacy of two hydrogen peroxide vapour aerial decontamination systems for enhanced disinfection of meticillin-resistant Staphylococcus aureus, Klebsiella pneumoniae and Clostridium difficile in single isolation rooms. AB - BACKGROUND: Hydrogen peroxide vapour (HPV) disinfection systems are being used to reduce patients' exposure to hospital pathogens in the environment. HPV whole room aerial disinfection systems may vary in terms of operating concentration and mode of delivery. AIM: To assess the efficacy of two HPV systems (HPS1 and HPS2) for whole-room aerial disinfection of single isolation rooms (SIRs). METHODS: Ten SIRs were selected for manual terminal disinfection after patient discharge. Test coupons seeded with biological indicator (BI) organisms [~10(6) colony-forming units (cfu) of meticillin-resistant Staphylococcus aureus (MRSA) or Klebsiella pneumoniae, or ~10(5)cfu Clostridium difficile 027 spores] prepared in a soil challenge were placed at five locations per room. For each cycle, 22 high frequency-touch surfaces in SIRs were sampled with contact plates (~25cm(2)) before and after HPV decontamination, and BIs were assayed for the persistence of pathogens. FINDINGS: Approximately 95% of 214 sites were contaminated with bacteria after manual terminal disinfection, with high numbers present on the SIR floor (238.0-352.5cfu), bed control panel (24.0-33.5cfu), and nurse call button (21.5-7.0cfu). Enhanced disinfection using HPV reduced surface contamination to low levels: HPS1 [0.25cfu, interquartile range (IQR) 0-1.13] and HPS2 (0.5cfu, IQR 0-2.0). Both systems demonstrated similar turnaround times (~2-2.5h), and no differences were observed in the efficacy of the two systems against BIs (C. difficile ~5.1log10 reduction; MRSA/K. pneumoniae ~6.3log10 reduction). Despite different operating concentrations of hydrogen peroxide, MRSA persisted on 27% of coupons after HPV decontamination. CONCLUSION: Enhanced disinfection with HPV reduces surface contamination left by manual terminal cleaning, minimizing the risks of cross-contamination. The starting concentration and mode of delivery of hydrogen peroxide may not improve the efficacy of decontamination in practice, and therefore the choice of HPV system may be based upon other considerations such as cost, convenience and logistics. PMID- 26944909 TI - The impact of sleep amount and sleep quality on glycemic control in type 2 diabetes: A systematic review and meta-analysis. AB - Recent epidemiological studies have suggested that there is an association between glycemic control and sleep disturbances in patients with type 2 diabetes, but the extent is unclear. A systematic literature search was performed in nine electronic databases from inception until August 2015 without any language restriction. The search identified 20 studies (eight studies reporting duration of sleep and 15 studies evaluating sleep quality), and 15 were included in the meta-analysis. Short and long sleep durations were associated with an increased hemoglobin A1c (HbA1c) (weighted mean difference (WMD): 0.23% [0.10-0.36], short sleep; WMD: 0.13% [0.02-0.25], long sleep) compared to normal sleep, suggesting a U-shaped dose-response relationship. Similarly, poor sleep quality was associated with an increased HbA1c (WMD: 0.35% [0.12-0.58]). Results of this study suggest that amount of sleep as well as quality of sleep is important in the metabolic function of type 2 diabetes patients. Further studies are needed to identify for the potential causal role between sleep and altered glucose metabolism. PMID- 26944908 TI - Effects of cyclopiazonic acid and dexamethasone on serotonin-induced calcium responses in vascular smooth muscle cells. AB - We previously observed that sarcoendoplasmic reticulum Ca(2+) ATPase (SERCA) blockade by cyclopiazonic acid (CPA) significantly potentiates serotonin (5 hydroxytryptamine (5-HT))-induced vascular contractions. Furthermore, 5-HT receptor antagonist methysergide partially inhibited CPA-potentiated 5-HT contractions. In the present study, we further investigated whether SERCA inhibition potentiates 5-HT-induced Ca(2+) responses along with attenuating the receptor antagonism by store-operated Ca(2+) (SOC) entry and protein kinase C (PKC)-mediated mechanisms. The effects of dexamethasone that was previously shown to induce SOC entry and enhance 5-HT responses were also tested. For this purpose, intracellular Ca(2+) levels were monitored in A7r5 embryonic rat vascular smooth muscle cells by spectrofluorometry using the fluorescent indicator fura-2. The results showed that CPA, although not dexamethasone, significantly potentiated 5-HT-induced Ca(2+) elevations. Ketanserin partially decreased 5-HT-induced and CPA-potentiated Ca(2+) elevations whereas both PKC inhibitor D-sphingosine and SOC entry blocker 2-aminoethoxydiphenyl borate (2 APB) abolished the remaining responses. The data suggests that diminished antagonistic effect on 5-HT-induced Ca(2+) elevations in the presence of SERCA inhibition is induced by SOC entry and PKC activation. PMID- 26944910 TI - Prevalence and Correlates of Neuropsychiatric Symptoms in Nursing Home Patients With Young-Onset Dementia: The BEYOnD Study. AB - OBJECTIVE: Young-onset dementia (YOD) is defined as dementia that develops before the age of 65. Neuropsychiatric symptoms (NPS) have important clinical consequences for patients and their family members. To date, knowledge about the prevalence and correlates of NPS in YOD is limited, but essential to establish specific tailored care for patients with YOD. The aim of this study was to explore the prevalence and correlates of NPS in nursing home residents with YOD. DESIGN/SETTING: Cross-sectional cohort study in Dutch long-term care facilities providing specialized care for YOD. PARTICIPANTS: Participants included 230 institutionalized patients with YOD. MEASUREMENTS: NPS were assessed using the Cohen-Mansfield Agitation Inventory (CMAI) and the Neuropsychiatric Inventory Nursing Home version (NPI-NH). The influence of gender, dementia severity, type of dementia, and disease awareness on clusters of relevant NPS was investigated using multivariate logistic regression analysis and subsequently corrected for the possible confounders of age, duration of institutionalization, and psychoactive medication use. RESULTS: Ninety percent of the nursing home residents with YOD showed 1 or more neuropsychiatric symptoms, 88% showed significant agitation, and 56% showed relevant apathy. No gender differences were found. Although physically aggressive behavior, non-physically aggressive behavior, and apathy were more common in patients with (very) severe cognitive decline (Global Deterioration Scale [GDS] stage 6-7), verbally agitated behavior was common in patients in all except the most severe stages of dementia (GDS 2 6). Apathy was more prevalent in alcohol-related dementia. Low levels of awareness were associated with more physically aggressive behavior and aberrant motor behavior. CONCLUSION: The prevalence of NPS was high and was associated with the severity and type of dementia and disease awareness. Agitation and apathy are the most important symptoms to focus on in YOD. The high prevalence of NPS supports the idea of care delivery in special care units. Further research is needed on potentially influencing environmental correlates of NPS in YOD. PMID- 26944911 TI - [Inappropriate prescription and administration of medications in 10 nursing homes in Alsace, France]. AB - BACKGROUND: Medication care is a complicated process in nursing homes. The aim of the study was to offer an overview of inappropriate medication prescription and administration practices in nursing homes in Alsace in order to propose improvement actions to remedy the weaknesses identified. METHODS: This study was conducted prospectively in 10 nursing homes under contract with community pharmacies in Alsace. The practices of prescription were examined to determine the prevalence of potentially inappropriate medications, inappropriate and contraindicated medication associations. Crushing and opening practices were also assessed, daily treatment costs were calculated. RESULTS: Two hundred and eighty four residents were included (age: 87.1 +/- 5.6 years). The average number of drugs per resident was 8.1 +/- 4.0 (daily treatment cost: 4.19 +/- 5.21 ?). On average, 1.5 drugs +/- 1.4 per prescription were considered as potentially inappropriate (daily treatment cost: 0.49 +/- 0.76 ?). The contraindication associations concerned 8 % of prescriptions and involved potentially inappropriate drugs in 60 % of cases. Inappropriate associations mainly concerned nervous system drugs. Thirty-three residents were taking more than 2 psychotropic drugs; 23 had more than one benzodiazepine. Regarding drug administration, practices differed from one nursing home to another. Crushing was performed in 8 nursing homes. It concerned 20 residents (7 %) and 69 drugs. In 50 %, the crushing decision was made by nurses without physician or pharmacist supervision. Fifty-seven percent of crushed drugs had a formulation which did not allow crushing (n=39 drugs). The analysis of those items led to the proposal of improvement actions. CONCLUSION: This study pointed out inappropriate medication practices. Tracking tools for inappropriate clinical practices could be operated by physicians, pharmacists and nursing teams through coordinated multidisciplinary approaches. PMID- 26944913 TI - Periungual and subungual congenital melanocytic nevus on the foot: A rare case report. AB - A 5-year-old caucasian child is described with a congenital melanocytic periungual and subungual nevus on the right second toe. Histopathologic examination revealed a junctional nevus. Congenital subungual nevi in this location are rare. To the best of our knowledge, this represents the first case of lesion on the right second toe to be reported in the literature. PMID- 26944915 TI - Quality of Life in Adults with Neurofibromatosis 1 in Brazil. AB - Neurofibromatosis type 1 (NF1) is a neurocutaneous genetic disorder that can be associated with severe complications, and it may shorten patients' lifespan and affect their quality of life negatively. This study aimed to examine quality of life constructs among adults with NF1 in Brazil. It is an exploratory, descriptive and cross-sectional study consisting of two stages, involving thirteen adult patients with NF1. The first stage was developed using a quantitative methodology, namely the WHOQOL-100 questionnaire; responses for the 13 patients were compared to a matched control group. The second stage comprised clinical-qualitative research whereby participants took part in a semi-structured interview; these data were analyzed using the categorical thematic analysis technique. There were no statistically significant differences in the questionnaire domains between the NF1 patients and the control subjects. Eighteen main themes were extracted from the interviews, showing interference of the NF1 visibility principally in psychological aspects and social relationships. Patients mentioned curiosity about NF1 and confusion about the distinctions between NF1 and contagious diseases, which lead to prejudice. They were concerned about the future and how the disease would develop in themselves and their offspring, and emphasized difficulties acquiring proper healthcare. These findings may help in planning healthcare for Brazilian NF1 patients and improving their quality of life. PMID- 26944912 TI - Cost-effectiveness of Tyrosine Kinase Inhibitor Treatment Strategies for Chronic Myeloid Leukemia in Chronic Phase After Generic Entry of Imatinib in the United States. AB - BACKGROUND: We analyzed the cost-effectiveness of treating incident chronic myeloid leukemia in chronic phase (CML-CP) with generic imatinib when it becomes available in United States in 2016. In the year following generic entry, imatinib's price is expected to drop 70% to 90%. We hypothesized that initiating treatment with generic imatinib in these patients and then switching to the other tyrosine-kinase inhibitors (TKIs), dasatinib or nilotinib, because of intolerance or lack of effectiveness ("imatinib-first") would be cost-effective compared with the current standard of care: "physicians' choice" of initiating treatment with any one of the three TKIs. METHODS: We constructed Markov models to compare the five-year cost-effectiveness of imatinib-first vs physician's choice from a US commercial payer perspective, assuming 3% annual discounting ($US 2013). The models' clinical endpoint was five-year overall survival taken from a systematic review of clinical trial results. Per-person spending on incident CML-CP treatment overall care components was estimated using Truven's MarketScan claims data. The main outcome of the models was cost per quality-adjusted life-year (QALY). We interpreted outcomes based on a willingness-to-pay threshold of $100 000/QALY. A panel of European LeukemiaNet experts oversaw the study's conduct. RESULTS: Both strategies met the threshold. Imatinib-first ($277 401, 3.87 QALYs) offered patients a 0.10 decrement in QALYs at a savings of $88 343 over five years to payers compared with physician's choice ($365 744, 3.97 QALYs). The imatinib-first incremental cost-effectiveness ratio was approximately $883 730/QALY. The results were robust to multiple sensitivity analyses. CONCLUSION: When imatinib loses patent protection and its price declines, its use will be the cost-effective initial treatment strategy for CML-CP. PMID- 26944914 TI - Linking DNA Damage and Hormone Signaling Pathways in Cancer. AB - DNA damage response and repair (DDR) is a tightly controlled process that serves as a barrier to tumorigenesis. Consequently, DDR is frequently altered in human malignancy, and can be exploited for therapeutic gain either through molecularly targeted therapies or as a consequence of therapeutic agents that induce genotoxic stress. In select tumor types, steroid hormones and cognate receptors serve as major drivers of tumor development/progression, and as such are frequently targets of therapeutic intervention. Recent evidence suggests that the existence of crosstalk mechanisms linking the DDR machinery and hormone signaling pathways cooperate to influence both cancer progression and therapeutic response. These underlying mechanisms and their implications for cancer management will be discussed. PMID- 26944916 TI - The Dimensionality of Genomic Information and Its Effect on Genomic Prediction. AB - The genomic relationship matrix (GRM) can be inverted by the algorithm for proven and young (APY) based on recursion on a random subset of animals. While a regular inverse has a cubic cost, the cost of the APY inverse can be close to linear. Theory for the APY assumes that the optimal size of the subset (maximizing accuracy of genomic predictions) is due to a limited dimensionality of the GRM, which is a function of the effective population size (Ne). The objective of this study was to evaluate these assumptions by simulation. Six populations were simulated with approximate effective population size (Ne) from 20 to 200. Each population consisted of 10 nonoverlapping generations, with 25,000 animals per generation and phenotypes available for generations 1-9. The last 3 generations were fully genotyped assuming genome length L = 30. The GRM was constructed for each population and analyzed for distribution of eigenvalues. Genomic estimated breeding values (GEBV) were computed by single-step GBLUP, using either a direct or an APY inverse of GRM. The sizes of the subset in APY were set to the number of the largest eigenvalues explaining x% of variation (EIGx, x = 90, 95, 98, 99) in GRM. Accuracies of GEBV for the last generation with the APY inverse peaked at EIG98 and were slightly lower with EIG95, EIG99, or the direct inverse. Most information in the GRM is contained in ~NeL largest eigenvalues, with no information beyond 4NeL Genomic predictions with the APY inverse of the GRM are more accurate than by the regular inverse. PMID- 26944918 TI - Molecular Basis of Valine-Citrulline-PABC Linker Instability in Site-Specific ADCs and Its Mitigation by Linker Design. AB - The degree of stability of antibody-drug linkers in systemic circulation, and the rate of their intracellular processing within target cancer cells are among the key factors determining the efficacy of antibody-drug conjugates (ADC) in vivo Previous studies demonstrated the susceptibility of cleavable linkers, as well as auristatin-based payloads, to enzymatic cleavage in rodent plasma. Here, we identify Carboxylesterase 1C as the enzyme responsible for the extracellular hydrolysis of valine-citrulline-p-aminocarbamate (VC-PABC)-based linkers in mouse plasma. We further show that the activity of Carboxylesterase 1C towards VC-PABC based linkers, and consequently the stability of ADCs in mouse plasma, can be effectively modulated by small chemical modifications to the linker. While the introduced modifications can protect the VC-PABC-based linkers from extracellular cleavage, they do not significantly alter the intracellular linker processing by the lysosomal protease Cathepsin B. The distinct substrate preference of the serum Carboxylesterase 1C offers the opportunity to modulate the extracellular stability of cleavable ADCs without diminishing the intracellular payload release required for ADC efficacy. Mol Cancer Ther; 15(5); 958-70. (c)2016 AACR. PMID- 26944917 TI - Whole-Genome Analysis of Individual Meiotic Events in Drosophila melanogaster Reveals That Noncrossover Gene Conversions Are Insensitive to Interference and the Centromere Effect. AB - A century of genetic analysis has revealed that multiple mechanisms control the distribution of meiotic crossover events. In Drosophila melanogaster, two significant positional controls are interference and the strongly polar centromere effect. Here, we assess the factors controlling the distribution of crossovers (COs) and noncrossover gene conversions (NCOs) along all five major chromosome arms in 196 single meiotic divisions to generate a more detailed understanding of these controls on a genome-wide scale. Analyzing the outcomes of single meiotic events allows us to distinguish among different classes of meiotic recombination. In so doing, we identified 291 NCOs spread uniformly among the five major chromosome arms and 541 COs (including 52 double crossovers and one triple crossover). We find that unlike COs, NCOs are insensitive to the centromere effect and do not demonstrate interference. Although the positions of COs appear to be determined predominately by the long-range influences of interference and the centromere effect, each chromosome may display a different pattern of sensitivity to interference, suggesting that interference may not be a uniform global property. In addition, unbiased sequencing of a large number of individuals allows us to describe the formation of de novo copy number variants, the majority of which appear to be mediated by unequal crossing over between transposable elements. This work has multiple implications for our understanding of how meiotic recombination is regulated to ensure proper chromosome segregation and maintain genome stability. PMID- 26944920 TI - Development of Novel Quaternary Ammonium Linkers for Antibody-Drug Conjugates. AB - A quaternary ammonium-based drug-linker has been developed to expand the scope of antibody-drug conjugate (ADC) payloads to include tertiary amines, a functional group commonly present in biologically active compounds. The linker strategy was exemplified with a beta-glucuronidase-cleavable auristatin E construct. The drug linker was found to efficiently release free auristatin E (AE) in the presence of beta-glucuronidase and provide ADCs that were highly stable in plasma. Anti-CD30 conjugates comprised of the glucuronide-AE linker were potent and immunologically specific in vitro and in vivo, displaying pharmacologic properties comparable with a carbamate-linked glucuronide-monomethylauristatin E control. The quaternary ammonium linker was then applied to a tubulysin antimitotic drug that contained an N-terminal tertiary amine that was important for activity. A glucuronide-tubulysin quaternary ammonium linker was synthesized and evaluated as an ADC payload, in which the resulting conjugates were found to be potent and immunologically specific in vitro, and displayed a high level of activity in a Hodgkin lymphoma xenograft. Furthermore, the results were superior to those obtained with a related tubulysin derivative containing a secondary amine N terminus for conjugation using previously known linker technology. The quaternary ammonium linker represents a significant advance in linker technology, enabling stable conjugation of payloads with tertiary amine residues. Mol Cancer Ther; 15(5); 938-45. (c)2016 AACR. PMID- 26944921 TI - Development of ASG-15ME, a Novel Antibody-Drug Conjugate Targeting SLITRK6, a New Urothelial Cancer Biomarker. AB - SLITRK6 is a member of the SLITRK family of neuronal transmembrane proteins that was discovered as a bladder tumor antigen using suppressive subtractive hybridization. Extensive immunohistochemistry showed SLITRK6 to be expressed in multiple epithelial tumors, including bladder, lung, and breast cancer as well as in glioblastoma. To explore the possibility of using SLITRK6 as a target for an antibody-drug conjugate (ADC), we generated a panel of fully human mAbs specific for SLITRK6. ADCs showed potent in vitro and in vivo cytotoxic activity after conjugation to Monomethyl Auristatin E or Monomethyl Auristatin F. The most potent ADC, ASG-15ME, was selected as the development candidate and given the product name AGS15E. ASG-15ME is currently in phase I clinical trials for the treatment of metastatic urothelial cancer. This is the first report that SLITRK6 is a novel antigen in bladder cancer and also the first report of the development of ASG-15ME for the treatment of metastatic bladder cancer. Mol Cancer Ther; 15(6); 1301-10. (c)2016 AACR. PMID- 26944922 TI - Evaluation of a Low-Cost Aerosol Sensor to Assess Dust Concentrations in a Swine Building. AB - Exposure to dust is a known occupational hazard in the swine industry, although efforts to measure exposures are labor intensive and costly. In this study, we evaluated a Dylos DC1100 as a low-cost (~$200) alternative to assess respirable dust concentrations in a swine building in winter. Dust concentrations were measured with collocated monitors (Dylos DC1100; an aerosol photometer, the pDR 1200; and a respirable sampler analyzed gravimetrically) placed in two locations within a swine farrowing building in winter for 18-24-h periods. The particle number concentrations measured with the DC1100 were converted to mass concentration using two methods: Physical Property Method and Regression Method. Raw number concentrations from the DC1100 were highly correlated to mass concentrations measured with the pDR-1200 with a coefficient of determination (R (2)) of 0.85, indicating that the two monitors respond similarly to respirable dust in this environment. Both methods of converting DC1100 number concentrations to mass concentrations yielded strong linear relationships relative to that measured with the pDR-1200 (Physical Property Method: slope = 1.03, R (2) = 0.72; Regression Method: slope = 0.72, R (2) = 0.73) and relative to that measured gravimetrically (Physical Property Method: slope = 1.08, R (2) = 0.64; Regression Method: slope = 0.75, R (2) = 0.62). The DC1100 can be used as a reasonable indicator of respirable mass concentrations within a CAFO and may have broader applicability to other agricultural and industrial settings. PMID- 26944919 TI - Edelfosine Promotes Apoptosis in Androgen-Deprived Prostate Tumors by Increasing ATF3 and Inhibiting Androgen Receptor Activity. AB - Edelfosine is a synthetic alkyl-lysophospholipid that possesses significant antitumor activity in several human tumor models. Here, we investigated the effects of edelfosine combined with androgen deprivation (AD) in LNCaP and VCaP human prostate cancer cells. This treatment regimen greatly decreased cell proliferation compared with single agent or AD alone, resulting in higher levels of apoptosis in LNCaP compared with VCaP cells. Edelfosine caused a dose dependent decrease in AKT activity, but did not affect the expression of total AKT in either cell line. Furthermore, edelfosine treatment inhibited the expression of androgen receptor (AR) and was associated with an increase in activating transcription factor 3 (ATF3) expression levels, a stress response gene and a negative regulator of AR transactivation. ATF3 binds to AR after edelfosine + AD and represses the transcriptional activation of AR as demonstrated by PSA promoter studies. Knockdown of ATF3 using siRNA-ATF3 reversed the inhibition of PSA promoter activity, suggesting that the growth inhibition effect of edelfosine was ATF3 dependent. Moreover, expression of AR variant 7 (ARv7) and TMPRSS2-ERG fusion gene were greatly inhibited after combined treatment with AD and edelfosine in VCaP cells. In vivo experiments using an orthotopic LNCaP model confirmed the antitumor effects of edelfosine + AD over the individual treatments. A significant decrease in tumor volume and PSA levels was observed when edelfosine and AD were combined, compared with edelfosine alone. Edelfosine shows promise in combination with AD for the treatment of prostate cancer patients. Mol Cancer Ther; 15(6); 1353-63. (c)2016 AACR. PMID- 26944923 TI - The resistance gene complement of D4, a multiply antibiotic-resistant ST25 Acinetobacter baumannii isolate, resides in two genomic islands and a plasmid. PMID- 26944925 TI - Comment on: Antifungal therapy: drug-drug interactions at your fingertips. PMID- 26944924 TI - Trends and molecular mechanisms of antimicrobial resistance in clinical staphylococci isolated from companion animals over a 16 year period. AB - OBJECTIVES: The objective of this study was to investigate the evolution of resistance to antimicrobials, corresponding mechanisms and molecular characteristics of Staphylococcus spp., between 1999 and 2014. METHODS: Susceptibility to 38 antimicrobials was determined for 632 clinical staphylococcal isolates obtained from companion animals (dogs, cats, horses and other animals). Twenty antimicrobial resistance genes, including mecA and mecC, were screened by PCR. Methicillin-resistant staphylococci were characterized by spa (Staphylococcus aureus), SCCmec, MLST and PFGE typing. Statistical analyses were performed using SAS v9.3 and differences were considered relevant if P <= 0.05. RESULTS: The mecA gene was identified in 74 staphylococcal isolates (11.6%): 11 MRSA (40.7%), 40 methicillin-resistant Staphylococcus pseudintermedius (MRSP; 8.7%) and 23 methicillin-resistant CoNS (26.7%). Resistance to the majority of antimicrobials and the number of mecA-positive isolates increased significantly over time. Eighteen spa types were identified, including two new ones. MRSA isolates were divided into three PFGE clusters that included ST22-IV, ST105-II, ST398-V and ST5-VI. Most methicillin-resistant Staphylococcus epidermidis isolates were of clonal complex (CC) 5, including a new ST, and clustered in eight PFGE clusters. MRSP were grouped into five PFGE clusters and included ST45-NT, ST71-II-III, ST195-III, ST196-V, ST339-NT, ST342 IV and the new ST400-III. Methicillin-resistant Staphylococcus haemolyticus clustered in two PFGE clusters. CONCLUSIONS: The significant increase in antimicrobial-resistant and mecA-positive isolates in recent years is worrying. Furthermore, several isolates are MDR, which complicates antimicrobial treatment and increases the risk of transfer to humans or human isolates. Several clonal lineages of MRSA and methicillin-resistant S. epidermidis circulating in human hospitals and the community were found, suggesting that companion animals can become infected with and contribute to the dissemination of highly successful human clones. Urgent measures, such as determination of clinical breakpoints and guidelines for antimicrobial use, are needed. PMID- 26944926 TI - Roles of Lon protease and its substrate MarA during sodium salicylate-mediated growth reduction and antibiotic resistance in Escherichia coli. AB - The cellular proteolytic machinery orchestrates protein turnover and regulates several key biological processes. This study addresses the roles of Lon, a major ATP-dependent protease, in modulating the responses of Escherichia coli strain MG1655 to low and high amounts of sodium salicyclate (NaSal), a widely used clinically relevant analgesic. NaSal affects several bacterial responses, including growth and resistance to multiple antibiotics. The loss of lon reduces growth in response to high, but not low, amounts of NaSal. From amongst a panel of Lon substrates, MarA was identified to be the downstream target of Lon. Thus, stabilization of MarA in the absence of lon lowers growth of the strain in the presence of higher amounts of NaSal. The steady-state transcript levels of marA and its target genes, acrA, acrB and tolC, are higher in the Deltalon strain compared with the WT strain. Consequently, the resistance to antibiotics, e.g. tetracycline and nalidixic acid, is enhanced in Deltalon in a marA-dependent manner. Furthermore, the target genes of MarA, i.e. acrB and tolC, are responsible for NaSal-mediated antibiotic resistance. Studies using atomic force microscopy demonstrated that ciprofloxacin led to greater cell filamentation, which is lower in the Deltalon strain due to higher levels of MarA. Overall, this study delineates the roles of Lon protease, its substrate MarA and downstream targets of MarA, e.g. acrB and tolC, during NaSal-mediated growth reduction and antibiotic resistance. The implications of these observations in the adaptation of E. coli under different environmental conditions are discussed. PMID- 26944927 TI - T Cell Priming by Activated Nlrc5-Deficient Dendritic Cells Is Unaffected despite Partially Reduced MHC Class I Levels. AB - NLRC5, a member of the NOD-like receptor (NLR) protein family, has recently been characterized as the master transcriptional regulator of MHCI molecules in lymphocytes, in which it is highly expressed. However, its role in activated dendritic cells (DCs), which are instrumental to initiate T cell responses, remained elusive. We show in this study that, following stimulation of DCs with inflammatory stimuli, not only did NLRC5 level increase, but also its importance in directing MHCI transcription. Despite markedly reduced mRNA and intracellular H2-K levels, we unexpectedly observed nearly normal H2-K surface display in Nlrc5(-/-) DCs. Importantly, this discrepancy between a strong intracellular and a mild surface defect in H2-K levels was observed also in DCs with H2-K transcription defects independent of Nlrc5. Hence, alongside with demonstrating the importance of NLRC5 in MHCI transcription in activated DCs, we uncover a general mechanism counteracting low MHCI surface expression. In agreement with the decreased amount of neosynthesized MHCI, Nlrc5(-/-) DCs exhibited a defective capacity to display endogenous Ags. However, neither T cell priming by endogenous Ags nor cross-priming ability was substantially affected in activated Nlrc5(-/-) DCs. Altogether, these data show that Nlrc5 deficiency, despite significantly affecting MHCI transcription and Ag display, is not sufficient to hinder T cell activation, underlining the robustness of the T cell priming process by activated DCs. PMID- 26944928 TI - Achieving Potent Autologous Neutralizing Antibody Responses against Tier 2 HIV-1 Viruses by Strategic Selection of Envelope Immunogens. AB - Advancement in immunogen selection and vaccine design that will rapidly elicit a protective Ab response is considered critical for HIV vaccine protective efficacy. Vaccine-elicited Ab responses must therefore have the capacity to prevent infection by neutralization-resistant phenotypes of transmitted/founder (T/F) viruses that establish infection in humans. Most vaccine candidates to date have been ineffective at generating Abs that neutralize T/F or early variants. In this study, we report that coimmunizing rhesus macaques with HIV-1 gp160 DNA and gp140 trimeric protein selected from native envelope gene sequences (envs) induced neutralizing Abs against Tier 2 autologous viruses expressing cognate envelope (Env). The Env immunogens were selected from envs emerging during the earliest stages of neutralization breadth developing within the first 2 years of infection in two clade B-infected human subjects. Moreover, the IgG responses in macaques emulated the targeting to specific regions of Env known to be associated with autologous and heterologous neutralizing Abs developed within the human subjects. Furthermore, we measured increasing affinity of macaque polyclonal IgG responses over the course of the immunization regimen that correlated with Tier 1 neutralization. In addition, we report firm correlations between Tier 2 autologous neutralization and Tier 1 heterologous neutralization, as well as overall TZM-bl breadth scores. Additionally, the activation of Env-specific follicular helper CD4 T cells in lymphocytes isolated from inguinal lymph nodes of vaccinated macaques correlated with Tier 2 autologous neutralization. These results demonstrate the potential for native Env derived from subjects at the time of neutralization broadening as effective HIV vaccine elements. PMID- 26944929 TI - CD44 Antibody Inhibition of Macrophage Phagocytosis Targets Fcgamma Receptor- and Complement Receptor 3-Dependent Mechanisms. AB - Targeting CD44, a major leukocyte adhesion molecule, using specific Abs has been shown beneficial in several models of autoimmune and inflammatory diseases. The mechanisms contributing to the anti-inflammatory effects of CD44 Abs, however, remain poorly understood. Phagocytosis is a key component of immune system function and can play a pivotal role in autoimmune states where CD44 Abs have shown to be effective. In this study, we show that the well-known anti inflammatory CD44 Ab IM7 can inhibit murine macrophage phagocytosis of RBCs. We assessed three selected macrophage phagocytic receptor systems: Fcgamma receptors (FcgammaRs), complement receptor 3 (CR3), and dectin-1. Treatment of macrophages with IM7 resulted in significant inhibition of FcgammaR-mediated phagocytosis of IgG-opsonized RBCs. The inhibition of FcgammaR-mediated phagocytosis was at an early stage in the phagocytic process involving both inhibition of the binding of the target RBC to the macrophages and postbinding events. This CD44 Ab also inhibited CR3-mediated phagocytosis of C3bi-opsonized RBCs, but it did not affect the phagocytosis of zymosan particles, known to be mediated by the C-type lectin dectin-1. Other CD44 Abs known to have less broad anti-inflammatory activity, including KM114, KM81, and KM201, did not inhibit FcgammaR-mediated phagocytosis of RBCs. Taken together, these findings demonstrate selective inhibition of FcgammaR and CR3-mediated phagocytosis by IM7 and suggest that this broadly anti inflammatory CD44 Ab inhibits these selected macrophage phagocytic pathways. The understanding of the immune-regulatory effects of CD44 Abs is important in the development and optimization of therapeutic strategies for the potential treatment of autoimmune conditions. PMID- 26944930 TI - Modification of Antigen Impacts on Memory Quality after Adenovirus Vaccination. AB - The establishment of robust T cell memory is critical for the development of novel vaccines for infections and cancers. Classical memory generated by CD8(+)T cells is characterized by contracted populations homing to lymphoid organs. T cell memory inflation, as seen for example after CMV infection, is the maintenance of expanded, functional, tissue-associated effector memory cell pools. Such memory pools may also be induced after adenovirus vaccination, and we recently defined common transcriptional and phenotypic features of these populations in mice and humans. However, the rules that govern which epitopes drive memory inflation compared with classical memory are not fully defined, and thus it is not currently possible to direct this process. We used our adenoviral model of memory inflation to first investigate the role of the promoter and then the role of the epitope context in determining memory formation. Specifically, we tested the hypothesis that conventional memory could be converted to inflationary memory by simple presentation of the Ag in the form of minigene vectors. When epitopes from LacZ and murine CMV that normally induce classical memory responses were presented as minigenes, they induced clear memory inflation. These data demonstrate that, regardless of the transgene promoter, the polypeptide context of a CD8(+)T cell epitope may determine whether classical or inflating memory responses are induced. The ability to direct this process by the use of minigenes is relevant to the design of vaccines and understanding of immune responses to pathogens. PMID- 26944931 TI - Control of the Physical and Antimicrobial Skin Barrier by an IL-31-IL-1 Signaling Network. AB - Atopic dermatitis, a chronic inflammatory skin disease with increasing prevalence, is closely associated with skin barrier defects. A cytokine related to disease severity and inhibition of keratinocyte differentiation is IL-31. To identify its molecular targets, IL-31-dependent gene expression was determined in three-dimensional organotypic skin models. IL-31-regulated genes are involved in the formation of an intact physical skin barrier. Many of these genes were poorly induced during differentiation as a consequence of IL-31 treatment, resulting in increased penetrability to allergens and irritants. Furthermore, studies employing cell-sorted skin equivalents in SCID/NOD mice demonstrated enhanced transepidermal water loss following s.c. administration of IL-31. We identified the IL-1 cytokine network as a downstream effector of IL-31 signaling. Anakinra, an IL-1R antagonist, blocked the IL-31 effects on skin differentiation. In addition to the effects on the physical barrier, IL-31 stimulated the expression of antimicrobial peptides, thereby inhibiting bacterial growth on the three dimensional organotypic skin models. This was evident already at low doses of IL 31, insufficient to interfere with the physical barrier. Together, these findings demonstrate that IL-31 affects keratinocyte differentiation in multiple ways and that the IL-1 cytokine network is a major downstream effector of IL-31 signaling in deregulating the physical skin barrier. Moreover, by interfering with IL-31, a currently evaluated drug target, we will have to consider that low doses of IL-31 promote the antimicrobial barrier, and thus a complete inhibition of IL-31 signaling may be undesirable. PMID- 26944932 TI - Dendritic Cells Guide Islet Autoimmunity through a Restricted and Uniquely Processed Peptidome Presented by High-Risk HLA-DR. AB - Identifying T cell epitopes of islet autoantigens is important for understanding type 1 diabetes (T1D) immunopathogenesis and to design immune monitoring and intervention strategies in relationship to disease progression. Naturally processed T cell epitopes have been discovered by elution from HLA-DR4 of pulsed B lymphocytes. The designated professional APC directing immune responses is the dendritic cell (DC). To identify naturally processed epitopes, monocyte-derived DC were pulsed with preproinsulin (PPI), glutamic acid decarboxylase (65-kDa isoform; GAD65), and insulinoma-associated Ag-2 (IA-2), and peptides were eluted of HLA-DR3 and -DR4, which are associated with highest risk for T1D development. Proteome analysis confirmed uptake and processing of islet Ags by DC. PPI peptides generated by DC differed from those processed by B lymphocytes; PPI signal-sequence peptides were eluted from HLA-DR4 and -DR3/4 that proved completely identical to a primary target epitope of diabetogenic HLA-A2 restricted CD8 T cells. HLA-DR4 binding was confirmed. GAD65 peptides, eluted from HLA-DR3 and -DR4, encompassed two core regions overlapping the two most immunodominant and frequently studied CD4 T cell targets. GAD65 peptides bound to HLA-DR3. Strikingly, the IA-2 ligandome of HLA-DR was exclusively generated from the extracellular part of IA-2, whereas most previous immune studies have focused on intracellular IA-2 epitopes. The newly identified IA-2 peptides bound to HLA DR3 and -DR4. Differential T cell responses were detected against the newly identified IA-2 epitopes in blood from T1D patients. The core regions to which DC may draw attention from autoreactive T cells are largely distinct and more restricted than are those of B cells. GAD65 peptides presented by DC focus on highly immunogenic T cell targets, whereas HLA-DR-binding peptides derived from IA-2 are distinct from the target regions of IA-2 autoantibodies. PMID- 26944933 TI - Actinocorallia lasiicapitis sp. nov., an actinomycete isolated from the head of an ant (Lasius fuliginosus L.). AB - A novel actinomycete, designated strain 3H-GS17T, was isolated from the head of an ant (Lasius fuliginosus L.) and characterized using a polyphasic approach. 16S rRNA gene sequence similarity studies showed that strain 3H-GS17T belongs to the genus Actinocorallia with high sequence similarity to Actinocorallia glomerata JCM 9376T (98.13 %) and Actinocorallia longicatena JCM 9377T (97.64 %). The chemotaxonomic properties of strain 3H-GS17T were also consistent with those of members of the genus Actinocorallia. The cell wall contained meso-diaminopimelic acid and whole-cell sugars were ribose, mannose, glucose, galactose and madurose. The predominant menaquinones were MK-9(H4), MK-9(H6) and MK-9(H8). The phospholipid profile consisted of diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylinositol and phosphatidylinositol mannoside. The major fatty acids were C16 : 0 and C18 : 1omega7s. A combination of DNA-DNA hybridization experiments and phenotypic tests were carried out between strain 3H-GS17T and its closely related strains, which further clarified their relatedness and demonstrated that 3H-GS17T could be distinguished from these strains. Therefore, strain 3H-GS17T is concluded to represent a novel species of the genus Actinocorallia, for which the name Actinocorallia lasiicapitis sp. nov. is proposed. The type strain is 3H-GS17T (=DSM 100595T=CGMCC 4.7282T). PMID- 26944935 TI - Development of the Psychiatric Nursing Intervention Providing Structure: An International Delphi Study. AB - BACKGROUND: Psychiatric nurses commonly refer to "providing structure" (PS) as a key intervention. But no consensus exists about what PS entails. PS can be understood as a complex intervention. In four previous studies, a definition, activities, and context variables were described that were presented to experts in a Delphi study. OBJECTIVE: To reach consensus about the definition of PS, its activities, and context variables. DESIGN: In a qualitative study, a Delphi study is used to gather the opinions of experts. The Delphi study consisted of three rounds with statements to score in each round. RESULTS: Experts reached consensus about a definition of PS, its activities, and context variables. Eleven statements related to the definition were accepted. Fourteen statements of a total of 17 statements related to the specific activities reached sufficient agreement, and 4 statements related to context variables were accepted. CONCLUSIONS: A definition could be given of PS with 4 general PS activities, 15 specific activities, and 3 context variables. Psychiatric nurses can use the information about PS to reflect on the use of PS activities within their own working environment, and these insights can help nurses develop their professional growth. PMID- 26944934 TI - PPAR-alpha Agonist Fenofibrate Decreased RANTES Levels in Type 2 Diabetes Patients with Hypertriglyceridemia. AB - BACKGROUND Regulated upon activation, normal T cells expressed and secreted (RANTES) is associated with inflammation and atherosclerosis. We investigated the effect of fenofibrate, a peroxisome proliferator-activated receptor-alpha (PPAR alpha) agonist, on RANTES in type 2 diabetes mellitus (T2DM) patients with hypertriglyceridemia. MATERIAL AND METHODS This study evaluated cross-sectional and interventional studies of 25 T2DM patients with hypertriglyceridemia (group A) and 32 controls (group B). Group A was treated with fenofibrate (200 mg/day) for 8 weeks. Serum RANTES and clinical characteristics were examined. RESULTS Serum RANTES was significantly higher in group A compared with group B (59.04+/ 16.74 vs. 38.57+/-12.98 ng/ml, P<0.001) and correlated with triglycerides (TG) (r=0.535, P<0.001), fasting blood glucose (FBG) (r=0.485, P<0.001), glycosylated hemoglobin (HbA1c) (r=0.485, P<0.001), homocysteine (Hcy) (r=0.520, P<0.001), and high-sensitivity C-reactive protein (hsCRP) (r=0.701, P<0.001). In multiple regression analysis after controlling for confounders, increased hsCRP levels (beta=7.430, P<0.001) and T2DM with hypertriglyceridemia (beta=11.496, P=0.002) were independently related to high serum RANTES levels. After 8 weeks of fenofibrate treatment, serum RANTES significantly decreased in group A compared with baseline (52.75+/-17.41 vs. 59.04+/-16.74 ng/ml, P=0.018). CONCLUSIONS Fenofibrate decreased serum RANTES levels in T2DM patients with hypertriglyceridemia, indicating that PPAR-a agonists may play an important role in inhibiting inflammatory responses. PMID- 26944936 TI - Dental caries status of students from migrant primary schools in Shanghai Pudong New Area. AB - BACKGROUND: In China, there is a large migrant population. A significant proportion of children of the migrant population in China are not able to attend public schools due to the lack of local household registration (HuKou). They turn to privately-operated migrant schools, which are usually under-funded, have bad environmental facilities and are inadequately staffed compared to public schools. This study aims to describe the dental caries status of students from migrant primary schools in Shanghai Pudong New Area and factors that influence their caries status. METHODS: Children (7-12 years old) from migrant primary schools in Shanghai Pudong New Area were randomly selected through a multi-stage cluster sampling method. Following the recommendation of the World Health Organization, caries experiences were recorded using the dmft index. A questionnaire to survey the children's socio-demographic characteristics and oral health-related behaviours was completed by the children's parents or guardians. RESULTS: A total of 1385 children in migrant primary schools were invited, of which 1323 joined the survey (95.5 %). Among all the surveyed subjects, the prevalence rate of dental caries was 74.7 % (65.7 % for primary teeth and 28.1 % for permanent teeth). The mean (SD) dmft scores were 3.17 (3.12), 2.74 (3.02) for the primary teeth and 0.44 (0.84) for the permanent teeth, and 99.5 % of the carious teeth received no treatment. CONCLUSIONS: Students from migrant primary schools in Shanghai Pudong New Area had bad conditions of dental caries and most of the carious teeth were left untreated. The caries experience was associated with tooth brushing habits, snacking habits, dental visit and gender. PMID- 26944937 TI - Development and validation of an electronic frailty index using routine primary care electronic health record data. AB - BACKGROUND: frailty is an especially problematic expression of population ageing. International guidelines recommend routine identification of frailty to provide evidence-based treatment, but currently available tools require additional resource. OBJECTIVES: to develop and validate an electronic frailty index (eFI) using routinely available primary care electronic health record data. STUDY DESIGN AND SETTING: retrospective cohort study. Development and internal validation cohorts were established using a randomly split sample of the ResearchOne primary care database. External validation cohort established using THIN database. PARTICIPANTS: patients aged 65-95, registered with a ResearchOne or THIN practice on 14 October 2008. PREDICTORS: we constructed the eFI using the cumulative deficit frailty model as our theoretical framework. The eFI score is calculated by the presence or absence of individual deficits as a proportion of the total possible. Categories of fit, mild, moderate and severe frailty were defined using population quartiles. OUTCOMES: outcomes were 1-, 3- and 5-year mortality, hospitalisation and nursing home admission. STATISTICAL ANALYSIS: hazard ratios (HRs) were estimated using bivariate and multivariate Cox regression analyses. Discrimination was assessed using receiver operating characteristic (ROC) curves. Calibration was assessed using pseudo-R(2) estimates. RESULTS: we include data from a total of 931,541 patients. The eFI incorporates 36 deficits constructed using 2,171 CTV3 codes. One-year adjusted HR for mortality was 1.92 (95% CI 1.81-2.04) for mild frailty, 3.10 (95% CI 2.91 3.31) for moderate frailty and 4.52 (95% CI 4.16-4.91) for severe frailty. Corresponding estimates for hospitalisation were 1.93 (95% CI 1.86-2.01), 3.04 (95% CI 2.90-3.19) and 4.73 (95% CI 4.43-5.06) and for nursing home admission were 1.89 (95% CI 1.63-2.15), 3.19 (95% CI 2.73-3.73) and 4.76 (95% CI 3.92 5.77), with good to moderate discrimination but low calibration estimates. CONCLUSIONS: the eFI uses routine data to identify older people with mild, moderate and severe frailty, with robust predictive validity for outcomes of mortality, hospitalisation and nursing home admission. Routine implementation of the eFI could enable delivery of evidence-based interventions to improve outcomes for this vulnerable group. PMID- 26944940 TI - In vivo and in vitro effects of pentavalent antimony on mouse liver cytochrome P450s. AB - Pentavalent antimonial (Sb5+) drugs such as meglumine antimoniate (MA) are the mainstay treatment of leishmaniases in developing countries. The effects of these compounds on drug-metabolizing enzymes have not been characterized and their potential pharmacokinetic interactions with other drugs are therefore unknown. The present study investigated whether treatment with MA (300 mg Sb5+/kg body weight/day, subcutaneously) for 24 days affected the activities of cytochrome P450 (CYP)1A (ethoxyresorufin- O-deethylase), CYP2A5 (coumarin 7-hydroxylase), CYP2E1 ( p-nitrophenol-hydroxylase), CYP2B9/10 (benzyloxy-resorufin- O debenzylase), or CYP3A11 (erythromycin- N-demethylase) in the livers of Swiss Webster (SW) and DBA-2 male and female mice. The results showed that CYP2A5-, CYP2E1-, and CYP3A11-catalyzed reactions were unaffected by MA treatment. A decrease in CYP2B9/10 activity was noted in DBA-2 females (but not males) and was not observed in SW males or females. However, repeated MA administration reduced mouse liver CYP1A activity. CYP1A2 messenger RNA (mRNA) levels were not affected by MA and in vitro exposure of mouse liver microsomes to Sb3+ and Sb5+ did not reduce CYP1A activity. These findings suggested that in vivo treatment with Sb5+ drugs depressed CYP1A activity, without downregulating CYP1A2 mRNA expression. Since in vitro treatment of liver microsomes failed to inhibit CYP1A activity, this effect may require intact cells. PMID- 26944938 TI - Using a tailored health information technology- driven intervention to improve health literacy and medication adherence in a Pakistani population with vascular disease (Talking Rx) - study protocol for a randomized controlled trial. AB - BACKGROUND: Vascular disease, manifesting as myocardial infarction and stroke, is a major cause of morbidity and mortality, especially in low- and middle-income countries. Current estimates are that only one in six patients have good adherence to medications and very few have sufficient health literacy. Our aim is to explore the effectiveness and acceptability of Prescription Interactive Voice Response (IVR) Talking Prescriptions (Talking Rx) and SMS reminders in increasing medication adherence and health literacy in Pakistani patients with vascular disease. METHODS: This is a randomized, controlled, single center trial. Adult participants, with access to a cell phone and a history of vascular disease, taking multiple risk-modifying medications (inclusive of anti-platelets and statins) will be selected from cerebrovascular and cardiovascular clinics. They will be randomized in a 1:1 ratio via a block design to the intervention or the control arm with both groups having access to a helpline number to address their queries in addition to standard of care as per institutional guidelines. Participants in the intervention group will also have access to Interactive Voice Response (IVR) technology tailored to their respective prescriptions in the native language (Urdu) and will have the ability to hear information about their medication dosage, correct use, side effects, mechanism of action and how and why they should use their medication, as many times as they like. Participants in the intervention arm will also receive scheduled SMS messages reminding them to take their medications. The primary outcome measure will be the comparison of the difference in adherence to anti-platelet and statin medication between baseline and at 3-month follow-up in each group measured by the Morisky Medication Adherence Scale. To ascertain the impact of our intervention on health literacy, we will also compare a local content-validated and modified version of Test of Health Literacy in Adults (TOFHLA) between the intervention and the control arm. We estimate that a sample size of 86 participants in each arm will be able to detect a difference of 1 point on the MMAS with a power of 90 % and significance level of 5 %. Accounting for an attrition rate of 15 %, we plan to enroll 100 participants in each arm (total study population = 200). We hypothesize that a linguistically tailored health IT intervention based on IVR and SMS will be associated with an improvement in adherence (to anti-platelet and lipid-lowering medications) and an improvement in health literacy in Pakistani patients with vascular disease. DISCUSSION: This innovative study will provide early data for the feasibility of the use of IT based prescriptions in an lower middle incorme country setting with limited numeracy and literacy skills. TRIAL REGISTRATION: Clinical Trials.gov: NCT02354040 - 2 February 2015. PMID- 26944939 TI - Synergistic Activation of ERalpha by Estrogen and Prolactin in Breast Cancer Cells Requires Tyrosyl Phosphorylation of PAK1. AB - Serine/threonine kinase PAK1 is activated by estrogen and plays an important role in breast cancer. However, the integration of PAK1 into the estrogen response is not fully understood. In this study, we investigated the mechanisms underlying the hormone-induced activation of estrogen receptor (ERalpha, ESR1). We show that estrogen activated PAK1 through both the ERalpha and GPER1 membrane receptors. Estrogen-dependent activation of PAK1 required the phosphorylation of tyrosine residues by Etk/Bmx and protein kinase A (PKA) within an assembled signaling complex comprising pTyr-PAK1, Etk/Bmx, the heterotrimer G-protein subunits Gbeta1, Ggamma2, and/or Ggamma5, PAK-associated guanine nucleotide exchange factor (betaPIX, ARHGEF7), and PKA. Moreover, the PKA RIIbeta subunit is a direct target of PAK1, and thus in response to estrogen, the activated pTyr-PAK1 complex reciprocally potentiated PKA activity, suggesting a positive feedback mechanism. We also demonstrate that PKA phosphorylated Ser305-ERalpha in response to estrogen, but pTyr-PAK1 phosphorylated Ser305-ERalpha in response to prolactin (PRL), implying that maximal ERalpha phosphorylation is achieved when cells are exposed to both PRL and estrogen. Furthermore, S305-ERalpha activation led to enhanced phosphorylation of Ser118-ERalpha and promoted cell proliferation and tumor growth. Together, these data strongly support a critical interplay between PRL and estrogen via PAK1 and suggest that ligand-independent activation of ERalpha through PRL/PAK1 may impart resistance to anti-estrogen therapies. Cancer Res; 76(9); 2600-11. (c)2016 AACR. PMID- 26944941 TI - Ketamine may be related to reduced ejection fraction in children during the procedural sedation. AB - OBJECTIVE: Ketamine is a dissociative anesthetic agent with sympathomimetic effects used commonly for procedural sedation in emergency department. The present study aimed to reveal the effect of ketamine on myocardium by measuring ejection fraction (EF). METHODS: Patients less than 9 years old undergoing procedural sedation with ketamine secondary to minor trauma composed the study population by convenience sampling. Study patients received ketamine at a dose of 1.5 mg/kg. A cardiologist performed the measurements of cardiac contractility pre ketamine and 10 min after the ketamine administration. RESULTS: A total of 22 patients were enrolled into the study. Patient recruitment has been ceased after the 22nd patient because of the thought that more patients would not provide additional information. The study subjects had a mean age of 3.5 +/- 2.2 years and 14 (64%) of them were male. EF reduced in 14 (63.6%) patients (mean: 5.6 +/- 3.1; median: 5; interquartile range (IQR): 3.75-7; minimum-maximum (min-max): 1 14). Systolic blood pressures reduced in 10 of 14 patients with decreased EF and increased in 8 of 10 patients without decreased EF. The changes in systolic blood pressure in patients with decreased EF ( n = 14) were as follows: -7.6 +/- 10.9; median: -7.5; IQR: -16.5 to 1.75; and min-max: -30 to 9. There were two patients with elevated high-sensitive troponin. CONCLUSION: Ketamine may reduce EF and systolic blood pressure in children less than 9 years old undergoing procedural sedation. PMID- 26944942 TI - Placental PHLDA2 expression is increased in cases of fetal growth restriction following reduced fetal movements. AB - BACKGROUND: Maternal perception of reduced fetal movements (RFM) is associated with increased risk of fetal growth restriction (FGR) and stillbirth, mediated by placental insufficiency. The maternally expressed imprinted gene PHLDA2 controls fetal growth, placental development and placental lactogen production in a mouse model. A number of studies have also demonstrated abnormally elevated placental PHLDA2 expression in human growth restricted pregnancies. This study examined whether PHLDA2 was aberrantly expressed in placentas of RFM pregnancies resulting in delivery of an FGR infant and explored a possible relationship between PHLDA2 expression and placental lactogen release from the human placenta. METHODS: Villous trophoblast samples were obtained from a cohort of women reporting RFM (N = 109) and PHLDA2 gene expression analysed. hPL levels were assayed in the maternal serum (N = 74). RESULTS: Placental PHLDA2 expression was significantly 2.3 fold higher in RFM pregnancies resulting in delivery of an infant with FGR (p < 0.01), with highest levels of PHLDA2 expression in the most severe cases. Placental PHLDA2 expression was associated with maternal serum hPL levels (r = 0.30, p = 0.008, n = 74) although this failed to reach statistical significance in multiple linear regression analysis controlling for birth weight (p = 0.07). CONCLUSIONS: These results further highlight a role for placental PHLDA2 in poor perinatal outcomes, specifically FGR associated with RFM. Furthermore, this study suggests a potential relationship between placental PHLDA2 expression and hPL production by the placenta, an association that requires further investigation in a larger cohort. PMID- 26944943 TI - Modeling immune response and its effect on infectious disease outbreak dynamics. AB - BACKGROUND: In recent epidemiological models, immunity is incorporated as a simplified value that determines the capacity of an individual to become infected or to transmit the disease. Moreover, the quality of the immune response determines the chances of infection and the length of time an individual is capable to infect others. We present a model that incorporates individuals' immune responses to, further, examine the role of the collective immune response of individuals in a population during an infectious outbreak. METHODS: We constructed a contagion model that incorporates the collective immune response of individuals represented by the superposition of individual immune responses (PIR). Multiple probability distributions are used to represent the immunocompetence of different age groups, thereby modeling the concept of Population Immune Response (PIR). Multiple experiments were conducted in which the population is divided in different age groups for which each group has a unique immune response quality and thus a different length for its immune periods. Finally, we explored the effects of implementing different vaccination strategies in the population. RESULTS: The experiments displayed important variations in the outbreak dynamics as a consequence of incorporating PIR in homogeneous and mixed populations. The experiments showed that individuals with weak immune responses and those who are immune to the pathogen play a significant role in shaping the outbreak dynamics. Finally, after implementing different vaccination strategies, the results suggest that if vaccination resources are limited, the vaccination should be targeted towards individuals that spread the disease for a longer period of time. CONCLUSIONS: Our results suggest that it is essential for the public health establishment to increase their understanding of the characteristics of regional demographics that could impact the quality of the immune response of the individuals. The results indicate that it is necessary to further investigate mitigation strategies to limit the capacity to transmit the disease by individuals that spread the pathogen for extended periods of time. Ultimately, this study suggests that it is crucial for public health researchers to identify appropriate targeted vaccination regimes and to explore the link between PIR and outbreak dynamics to improve the monitoring and mitigating efforts of ongoing and future epidemics. PMID- 26944945 TI - Unintended Consequences of Invoking the "Natural" in Breastfeeding Promotion. PMID- 26944946 TI - Mental Health in Children Born Extremely Preterm Without Severe Neurodevelopmental Disabilities. AB - OBJECTIVE: To describe the prevalence and gender characteristics of mental health problems in extremely preterm/extremely low birth weight (EP/ELBW) children without intellectual disabilities, blindness, deafness, or severe cerebral palsy compared with a reference group at 11 years of age. METHODS: In a national cohort of EP/ELBW children, mental health was assessed by parental and teacher report by using the Autism Spectrum Screening Questionnaire, the Swanson, Noland, and Pelham Questionnaire IV (attention-deficit/hyperactivity disorder), the Screen for Child Anxiety Related Emotional Disorders, symptoms of obsessive-compulsive disorder (OCD), and a total difficulties score from the Strength and Difficulties Questionnaire. Pervasive rating was defined as both parent and teacher scoring the child >=95th percentile (>=90th percentile for total difficulties score) of the reference group, which was the population-based Bergen Child Study. RESULTS: Of eligible children, 216 (64%) EP/ELBW and 1882 (61%) reference children participated. EP/ELBW children were at significantly increased risk of pervasive rated symptoms of autism (odds ratio 4.3, 95% confidence interval 2.0-9.3), inattention (8.3, 4.4-15), anxiety (2.3, 1.4-3.7), OCD (2.6, 1.4-3.7), and >=90th percentile for total difficulties score (4.9, 2.9-8.2). Reported by either parents or teachers, 54% of the EP/ELBW and 21% of the reference children had >=1 mental health problem (odds ratio 4.5, 95% confidence interval 3.3-6.1). There were no significant interactions between EP/ELBW and gender in mental health outcomes. CONCLUSIONS: EP/ELBW children without severe disabilities had increased risk of symptoms of autism, inattention, anxiety, and OCD. Gender differences were comparable to the reference group. PMID- 26944947 TI - Flecainide-Responsive Myotonia Permanens With SNEL Onset: A New Case and Literature Review. AB - Sodium channel myotonias are inherited muscle diseases linked to mutations in the voltage-gated sodium channel. These diseases may also affect newborns with variable symptoms. More recently, severe neonatal episodic laryngospasm (SNEL) has been described in a small number of patients. A timely diagnosis of SNEL is crucial because a specific treatment is now available that will likely reduced laryngospasm and improve vital and cerebral outcomes. We report here on an 8-year old girl who had presented, at birth, with SNEL who subsequently developed myotonia permanens starting at age 3 years. Results of molecular analysis revealed a de novo SCN4A G1306E mutation. The girl was treated with carbamazepine, acetazolamide, and mexiletine, with little improvement; after switching her treatment to flecainide, she experienced a dramatic reduction in muscle stiffness and myotonic symptoms as well as an improvement in behavior. PMID- 26944944 TI - On Predicting lung cancer subtypes using 'omic' data from tumor and tumor adjacent histologically-normal tissue. AB - BACKGROUND: Adenocarcinoma (ADC) and squamous cell carcinoma (SCC) are the most prevalent histological types among lung cancers. Distinguishing between these subtypes is critically important because they have different implications for prognosis and treatment. Normally, histopathological analyses are used to distinguish between the two, where the tissue samples are collected based on small endoscopic samples or needle aspirations. However, the lack of cell architecture in these small tissue samples hampers the process of distinguishing between the two subtypes. Molecular profiling can also be used to discriminate between the two lung cancer subtypes, on condition that the biopsy is composed of at least 50 % of tumor cells. However, for some cases, the tissue composition of a biopsy might be a mix of tumor and tumor-adjacent histologically normal tissue (TAHN). When this happens, a new biopsy is required, with associated cost, risks and discomfort to the patient. To avoid this problem, we hypothesize that a computational method can distinguish between lung cancer subtypes given tumor and TAHN tissue. METHODS: Using publicly available datasets for gene expression and DNA methylation, we applied four classification tasks, depending on the possible combinations of tumor and TAHN tissue. First, we used a feature selector (ReliefF/Limma) to select relevant variables, which were then used to build a simple naive Bayes classification model. Then, we evaluated the classification performance of our models by measuring the area under the receiver operating characteristic curve (AUC). Finally, we analyzed the relevance of the selected genes using hierarchical clustering and IPA(r) software for gene functional analysis. RESULTS: All Bayesian models achieved high classification performance (AUC > 0.94), which were confirmed by hierarchical cluster analysis. From the genes selected, 25 (93 %) were found to be related to cancer (19 were associated with ADC or SCC), confirming the biological relevance of our method. CONCLUSIONS: The results from this study confirm that computational methods using tumor and TAHN tissue can serve as a prognostic tool for lung cancer subtype classification. Our study complements results from other studies where TAHN tissue has been used as prognostic tool for prostate cancer. The clinical implications of this finding could greatly benefit lung cancer patients. PMID- 26944949 TI - Homogeneous Liquid-Liquid Microextraction for Determination of Organophosphorus Pesticides in Environmental Water Samples Prior to Gas Chromatography-Flame Photometric Detection. AB - In this study, homogeneous liquid-liquid microextraction (HLLME) was developed for preconcentration and extraction of 15 organophosphorus pesticides (OPPs) from water samples coupling with gas chromatography followed by a flame photometric detector (HLLME-GC-FPD). In this method, OPPs were extracted by the homogeneous phase in a ternary solvent system (water/acetic acid/chloroform). The homogeneous solution was excluded by the addition of sodium hydroxide as a phase separator reagent and a cloudy solution was formed. After centrifugation (3 min at 5,000 rpm), the fine particles of extraction solvent (chloroform) were sedimented at the bottom of the conical test tube (10.0 +/- 0.5 uL). Furthermore, 0.5 uL of the sedimented phase was injected into the GC for separation and determination of OPPs. Optimal results were obtained under the following conditions: volume of the extracting solvent (chloroform), 53 uL; volume of the consolute solvent (acetic acid), 0.76 mL and concentration of sodium hydroxide, 40% (w/v). Under the optimum conditions, the enrichment factors of (260-665), the extraction percent of 75.8-104%, the dynamic linear range of 0.03-300 ug L(-1) and the limits of detection of 0.004-0.03 ug L(-1) were obtained for the OPPs. This method was successfully applied for the extraction and determination of the OPPs in environmental water samples. PMID- 26944948 TI - Preeclampsia and Inflammatory Preterm Labor Alter the Human Placental Hematopoietic Niche. AB - BACKGROUND: The human placenta is a source of hematopoietic stem and progenitor cells (HSPCs). The RUNX1 transcription factor is required for the formation of functional HSPCs. The impact of preeclampsia (PE) and preterm labor (PTL, spontaneous preterm labor [sPTL] and inflammatory preterm labor [iPTL]) on HSPC localization and RUNX1 expression in the human placenta is unknown. METHODS: We compared the frequency and density of HSPC in control samples from sPTL (n = 6) versus PE (n = 6) and iPTL (n = 6). We examined RUNX1 protein and RNA expression in placentas from normal pregnancies (5-22 weeks, n = 8 total) and in placentas from the aforementioned pregnancy complications (n = 5/group). RESULTS: Hematopoietic stem and progenitor cells were rare cell types, associated predominantly with the vasculature of placental villi. The HSPC density was greater in the chorionic plate (CP) compared to the villi (P < .001) and greater in PE and iPTL samples as compared to controls within the CP (not significant) and overall (P < .05). During the fetal period, RUNX1 was expressed in the mesenchyme of the CP and villi. Inflammatory PTL samples were more likely to exhibit intraluminal RUNX1(+) cell populations (P < .001) and RUNX1(+) cell clusters attached to arterial endothelial cells. CONCLUSION: Placental HSPCs likely arise from hematopoietic niches comprised RUNX1(+) mesenchyme and vascular endothelium. Pregnancy complications that result in preterm birth differentially affect placental HSPC localization and RUNX1 expression. Our results support previous findings that inflammation positively regulates hematopoiesis. We present new evidence that hemogenic endothelium may be active at later stages of human fetal development in the context of inflammation. PMID- 26944951 TI - David Oliver: The real world for NHS doctors. PMID- 26944950 TI - Gene expression profiling of the venom gland from the Venezuelan mapanare (Bothrops colombiensis) using expressed sequence tags (ESTs). AB - BACKGROUND: Bothrops colombiensis is a highly dangerous pit viper and responsible for over 70% of snakebites in Venezuela. Although the composition in B. colombiensis venom has been identified using a proteome analysis, the venom gland transcriptome is currently lacking. RESULTS: We constructed a cDNA library from the venom gland of B. colombiensis, and a set of 729 high quality expressed sequence tags (ESTs) was identified. A total number of 344 ESTs (47.2% of total ESTs) was related to toxins. The most abundant toxin transcripts were metalloproteinases (37.5%), phospholipases A2s (PLA2, 29.7%), and serine proteinases (11.9%). Minor toxin transcripts were linked to waprins (5.5%), C type lectins (4.1%), ATPases (2.9%), cysteine-rich secretory proteins (CRISP, 2.3%), snake venom vascular endothelium growth factors (svVEGF, 2.3%), L-amino acid oxidases (2%), and other putative toxins (1.7%). While 160 ESTs (22% of total ESTs) coded for translation proteins, regulatory proteins, ribosomal proteins, elongation factors, release factors, metabolic proteins, and immune response proteins. Other proteins detected in the transcriptome (87 ESTs, 11.9% of total ESTs) were undescribed proteins with unknown functions. The remaining 138 (18.9%) cDNAs had no match with known GenBank accessions. CONCLUSION: This study represents the analysis of transcript expressions and provides a physical resource of unique genes for further study of gene function and the development of novel molecules for medical applications. PMID- 26944952 TI - Adherence to exercise referral schemes by participants - what do providers and commissioners need to know? A systematic review of barriers and facilitators. AB - BACKGROUND: Physical inactivity levels are rising worldwide with major implications for the health of the population and the prevalence of non communicable diseases. Exercise referral schemes (ERS) continue to be a popular intervention utilised by healthcare practitioners to increase physical activity. We undertook a systematic review of views studies in order to inform guidance from the UK National Institute of Health and Care Excellence (NICE) on exercise referral schemes to promote physical activity. This paper reports on the participant views identified, to inform those seeking to refine schemes to increase attendance and adherence. METHODS: Fifteen databases and a wide range of websites and grey literature sources were searched systematically for publications from 1995 to June 2013. In addition, a range of supplementary methods including, a call for evidence by NICE, contacting authors, reference list checking and citation tracking were utilised to identify additional research. Studies were included where they detailed schemes for adults aged 19 years or older who were 'inactive' (i.e. they are not currently meeting UK physical activity guidelines). Study selection was conducted independently in duplicate. Quality assessment was undertaken by one reviewer and checked by a second, with 20 % of papers being considered independently in duplicate. Papers were coded in qualitative data analysis software Atlas.ti. This review was reported in accordance with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement). RESULTS: Evidence from 33 UK-relevant studies identified that support from providers, other attendees and family was an important facilitator of adherence and 'making exercise a habit' post programme, as was the variety and personalised nature of sessions offered. Barriers to attendance included the inconvenient timing of sessions, their cost and location. An intimidating gym atmosphere, a dislike of the music and TV and a lack of confidence in operating gym equipment were frequently reported. CONCLUSIONS: These findings provide valuable insights that commissioners and providers should consider. The main themes were consistent across a large number of studies and further research should concentrate on programmes that reflect these findings. PMID- 26944953 TI - Lin28A and androgen receptor expression in ER-/Her2+ breast cancer. AB - The aim of this study was to examine the expression of Lin28A and androgen receptor (AR) in ER-/Her2+ breast cancer, and to research the association of Lin28A and AR co-expression status with patients' prognosis. The expression of Lin28A and AR in formalin-fixed and paraffin-embedded surgical sections from 305 patients with ER-/Her2+ breast cancer was analyzed by immunohistochemistry, and the co-expression patterns in breast cancer cells were investigated by immunofluorescent staining. The impact of the expression of Lin28A and AR in prognosis was also assessed by the Kaplan-Meier, univariate, and multivariate logistic regression models. This study included 305 cases ER-/Her2+ breast cancer patients. Lin28A and AR were expressed in 240 cases (78.7 %) and 220 cases (72.1 %), respectively. Lin28A tended to be higher in AR-positive patients (75.0 %). Lin28A and AR co-expression (Lin28+/AR+) was significantly associated with high tumor grade (G3) (p = 0.023) and high Ki67 index (p = 0.020). The mRNA and protein expression levels of Lin28A and AR were higher in MDA-MB-453 cells (ER /Her2+) than in the MDA-MB-231 cells (ER-/Her2-). In univariate analysis, Lin28A+/AR+ was significant risk factors associated with unfavorable OS (p = 0.049) and RFS (p = 0.019). Kaplan-Meier analysis showed that Lin28A+/AR+ expression showed lower RFS rates compared with Lin28A-/AR+ (p = 0.043) and Lin28A-/AR- patients(p = 0.019). Multivariate cox model showed that Lin28A+/AR+ remained an independent negative prognostic factor for RFS. Our study showed that Lin28A and AR co-expressed in ER-/Her-2+ breast cancer and correlated with poor prognosis. The possibility that Lin28A may drive AR expression via a positive feedback mechanism remains to be tested. PMID- 26944954 TI - Intra-Operative Indocyanine Green Angiography of the Parathyroid Gland. AB - Major complications of thyroid and parathyroid surgery are recurrent laryngeal nerve injuries and definitive hypoparathyroidism. The use of intra-operative Indocyanine Green Angiography for confirmation of vascular status of the parathyroid gland is reported here. PMID- 26944955 TI - Factors influencing Malawian women's willingness to self-collect samples for human papillomavirus testing. AB - BACKGROUND: Malawi has the highest incidence of cervical cancer in the world. Only 3% of Malawian women have ever been screened for cervical cancer. Self collection of samples for human papillomavirus (HPV) testing could increase screening among under-screened and hard-to-reach populations. However, little is known about the acceptability of self-collection in rural African settings. AIM: We aimed to characterise Malawian women's willingness to self-collect vaginal samples for HPV testing and to identify potential barriers. DESIGN: We used data from the baseline wave of a community-based cohort study, collected from July 2014 to February 2015. SETTING: Participants were enrolled from the catchment area of a clinic in rural Lilongwe District, Malawi. METHODS: We enrolled women aged 15-39 years (n=824). Participants answered questions assessing willingness to self-collect a sample for HPV testing, concerns about testing and other hypothesised correlates of willingness to self-collect. RESULTS: Two-thirds (67%) of the women reported willingness to self-collect a vaginal sample in their homes. Awareness of cervical cancer, supportive subjective norms, perceived behavioural control, and clinician recommendations were all positively associated with increased willingness to self-collect samples for HPV testing. Identified barriers to self-testing endorsed by women included: concerns that the test might hurt (22%), that they might not do the test correctly (21%), and that the test might not be accurate (17%). CONCLUSIONS: This study suggests that self collection for HPV testing could be an acceptable cervical cancer screening method in this rural population. Findings identify modifiable beliefs and barriers that can inform the development of effective screening programmes. PMID- 26944957 TI - Impact of broiler egg storage on the relative expression of selected blastoderm genes associated with apoptosis, oxidative stress, and fatty acid metabolism. AB - Cool temperature storage of eggs prior to incubation is a frequent practice by commercial broiler hatcheries. However, continued storage beyond 7 d leads to a progressive increase in the rate of early embryonic mortality. In this study, we examined the relative expression of 31 genes associated with fatty acid metabolism (8), apoptosis (7), and oxidative stress (16) pathways to better understand the basis of embryo mortality during egg storage. A total of 642 broiler eggs in 2 separate trials were subjected to the following egg treatments: stored 4 d (Control 1, C1); stored 21 d but subjected to short periods of incubation during egg storage (SPIDES); stored un-manipulated 21 d (NonSPIDES, NS); and stored 4 d then incubated for 10 h to advance the embryos to the same developmental stages as the SPIDES embryos (Control 2, C2). Hatchability trials (277 eggs) confirmed the efficacy of SPIDES compared to NS treatments in both trials. To determine relative expression of 31 selected genes, 365 blastoderms were isolated, staged, and flash frozen in batches of 5 to 10 blastoderms per vial (7 vials per egg treatment) prior to RNA extractions. Analysis of gene expression was performed using qRT-PCR and the results presented as relative expression normalized to C1. The relative expression of genes in which the SPIDES and C2 treatments were significantly up- or down-regulated in tandem indicated that the stage-specific expression of those genes was maintained by the SPIDES treatment. This study provides the relative gene expressions of blastodermal cells before and after prolonged egg storage as well as insight as to how SPIDES impacts blastodermal cell gene expression. PMID- 26944956 TI - The Use of Oral Disease-Modifying Therapies in Multiple Sclerosis. AB - Three oral disease-modifying drugs-fingolimod, teriflunomide, and dimethyl fumarate (DMF)-are available for treatment of relapsing forms of multiple sclerosis (MS). All three agents were approved in the last decade, primarily on the basis of a moderate to substantial reduction in the occurrence of MS relapses and central nervous system lesion formation detected by MRI. In the trials leading to approval, the first oral disease-modifying drug, fingolimod, reduced the annualized relapse rate (ARR) from 0.40 in placebo-treated patients to 0.18 (FREEDOMS) and from 0.33 in patients treated with interferon beta1a intramuscularly to 0.16 (TRANSFORMS). Teriflunomide, approved on the basis of the two placebo-controlled trials TEMSO and TOWER, demonstrated a reduction in the ARR from 0.54 to 0.37 and from 0.50 to 0.32 respectively. The latest oral MS medication, approved in 2014, is DMF, which had been used in a different formulation for treatment of psoriasis for decades. In the 2-year DEFINE study, the proportion of patients with a relapse was reduced to 27 %, compared with 46 % in placebo arm, whereas in the CONFIRM trial, the ARR was reduced from 0.40 (placebo) to 0.22 in the DMF-treated group of patients. In this review, we will elucidate the mechanisms of action of these three medications and compare their efficacy, safety, and tolerability as a practical guideline for their use. We will further discuss effects other than relapse reduction these small molecules may exert, including potential activities within the central nervous system, and briefly summarize emerging data on new oral MS drugs in clinical development. PMID- 26944958 TI - Synergistic effects of thymoquinone and curcumin on immune response and anti viral activity against avian influenza virus (H9N2) in turkeys. AB - The main objective of this study was to determine the possible effects of thymoquinone (TQ) and curcumin (Cur) on immune-response and pathogenesis of H9N2 avian influenza virus (AIV) in turkeys. The experiment was performed on 75 non vaccinated mixed-sex turkey poults, divided into 5 experimental groups (A, B, C, D, and E) of 15 birds each. Group A was kept as non-infected and a non-treated negative control (ctrl group) while group B was kept as infected and non-treated positive control (H9N2 group). Turkeys in groups A and B received normal commercial feed while turkeys in groups C and D received TQ, and Cur respectively, and group E concurrently received TQ and Cur from d one through the entire experiment period. All groups were challenged intra-nasally with H9N2 AIV (A/chicken/Pakistan/10RS3039-284-48/2010) at the fourth wk of age except group A. Infected turkeys showed clinical signs of different severity, showing the most prominent disease signs in turkeys in group B. All infected turkeys showed positive results for virus shedding; however, the pattern of virus shedding was different, and with turkeys in group B showing more pronounced virus secretion than the turkeys in the other groups receiving different levels of TQ and Cur. Moreover, significantly higher antibody titer against H9N2 AIV in turkeys shows the immunomodulatory nature of TQ and Cur. Similarly, increased cytokine gene expression suggests antiviral behavior of TQ and Cur especially in combination, leading to suppressed pathogenesis of H9N2 viruses. However, reduced virus shedding and enhanced immune responses were more pronounced in those turkeys receiving TQ and Cur concurrently. This study showed that supplements of TQ and Cur in combination would significantly enhance immune responsiveness and suppress pathogenicity of influenza viruses in turkeys. PMID- 26944959 TI - GRP78 is required for cell proliferation and protection from apoptosis in chicken embryo fibroblast cells. AB - Chicken serum has been suggested as a supplement to promote chicken cell proliferation and development. However, the molecular mechanisms by which chicken serum stimulates chicken cell proliferation remain unknown. Here, we evaluated the effects of chicken serum supplementation on chicken embryo fibroblast (CEF) and DF-1 cell proliferation. We also sought to elucidate the molecular pathways involved in mediating the effects of chicken serum on fibroblasts and DF-1 cells by overexpression of chicken 78 kDa glucose-regulated protein (chGRP78), which is important for cell growth and the prevention of apoptosis. Our data demonstrated that the addition of 5% chicken serum significantly enhanced fibroblast proliferation. Moreover, knockdown of chGRP78 using siRNA decreased fibroblast proliferation and increased apoptosis. Based on these results, we suggest that the chGRP78-mediated signaling pathway plays a critical role in chicken serum stimulated fibroblast survival and anti-apoptosis. Therefore, our findings have important implications for the maintenance of chicken fibroblast cells through the inhibition of apoptosis and may lead to the development of new treatments for avian disease. PMID- 26944960 TI - Genetic selection to increase bone strength affects prevalence of keel bone damage and egg parameters in commercially housed laying hens. AB - The prevalence of keel bone damage as well as external egg parameters of 2 pure lines divergently selected for high (H) and low (L) bone strength were investigated in 2 aviary systems under commercial conditions. A standard LSL hybrid was used as a reference group. Birds were kept mixed per genetic line (77 hens of the H and L line and 201 or 206 hens of the LSL line, respectively, per pen) in 8 pens of 2 aviary systems differing in design. Keel bone status and body mass of 20 focal hens per line and pen were assessed at 17, 18, 23, 30, 36, 43, 52, and 63 wk of age. External egg parameters (i.e., egg mass, eggshell breaking strength, thickness, and mass) were measured using 10 eggs per line at both 38 and 57 wk of age. Body parameters (i.e. tarsus and third primary wing feather length to calculate index of wing loading) were recorded at 38 wk of age and mortality per genetic line throughout the laying cycle. Bone mineral density (BMD) of 15 keel bones per genetic line was measured after slaughter to confirm assignment of the experimental lines. We found a greater BMD in the H compared with the L and LSL lines. Fewer keel bone fractures and deviations, a poorer external egg quality, as well as a lower index of wing loading were found in the H compared with the L line. Mortality was lower and production parameters (e.g., laying performance) were higher in the LSL line compared with the 2 experimental lines. Aviary design affected prevalence of keel bone damage, body mass, and mortality. We conclude that selection of specific bone traits associated with bone strength as well as the related differences in body morphology (i.e., lower index of wing loading) have potential to reduce keel bone damage in commercial settings. Also, the housing environment (i.e., aviary design) may have additive effects. PMID- 26944961 TI - The effects of eggshell temperature fluctuations during incubation on welfare status and gait score of broilers. AB - The aim of the current study was to determine the effects of different eggshell temperatures (EST); low (33.3 to 36.7 degrees C), control (37.8 to 38.2 degrees C), and high (38.9 to 40.0 degrees C) during 10 to 18 days of incubation on welfare status including foot pad dermatitis (FPD), hock dermatitis (HD) and feathering status, and gait score in broilers. Score 2, 4, and 5 of FPD were found to be similar among the treatment groups, whereas a score of 3 was found to be higher in the control and high EST groups (27.7% and 29.2%) compred to the low EST group (16.9%). The eggshell temperature fluctuations were significantly affected the incidence of HD, whereas broiler sex did not. All of the broilers in the high EST group had HD with various scores, while a percentage of 21.1% and 6.9% of broilers had the score 1 of HD in the low and control EST groups, respectively. Feathering status showed a difference between body parts including wing, neck, back, and vent and also a general mean score of broilers from low EST treatment had the highest score for feathering. A higher incidence of gait score was observed in broilers from the control EST treatment than low and high EST groups. This can be attributed to a higher live weight of broilers from the control EST group. On the other hand, the incidence of a gait score of 3 and 4 was found for broilers from control and high EST treatment groups. Male and female broilers from the high EST group had the higher gait score. In conclusion, gait score and welfare status of broilers were affected by fluctuations in EST between 10 and 18 days of incubation. PMID- 26944963 TI - The efficacy of a commercial competitive exclusion product on Campylobacter colonization in broiler chickens in a 5-week pilot-scale study. AB - The efficacy of the commercial competitive exclusion product Broilact against Campylobacter jejuni was evaluated in broiler chickens in a 5-week pilot-scale study. Newly-hatched broiler chicks were brought from a commercial hatchery. After arrival 50 seeder chicks were challenged orally with approximately 10(3) cfu of C. jejuni, wing marked, and placed back in a delivery box and moved to a separate room. The rest of the chicks (contact chicks) were placed in floor pens, 100 chicks per pen. Birds in two pens were treated orally on the day of hatch with the commercial competitive exclusion (CE) product Broilact, and three pens were left untreated. The following day 10 seeder chicks were introduced into the Broilact treated and untreated control pens. One pen was left both untreated and unchallenged (0-control). Each week the ceca of 10 contact chicks and one seeder chick were examined quantitatively for Campylobacter The treatment prevented or significantly reduced the colonization of the challenge organism in the ceca during the two first weeks; the percentage of colonized birds being 0% after the first week and 30% after the second week in the Broilact treated groups but was 100% in the control groups the entire 5-week rearing period. During the third rearing week the proportion of Campylobacter positive birds started to increase in the treated pens, being 80% after the third week and 95 and 90% after the fourth and fifth rearing weeks, respectively. Similarly the average count of Campylobacter in the cecal contents of the Broilact treated chicks started to increase, the difference between the treated and control chicks being 1.4 logs at the end of the rearing period. Although the protective effect was temporary and occurred only during the first two weeks of the rearing period, the results of this study support the earlier observations that CE flora designed to protect chicks from Salmonella may also reduce Campylobacter colonization of broiler chickens. PMID- 26944962 TI - Age-related energy values of bakery meal for broiler chickens determined using the regression method. AB - A study was conducted to determine the ileal digestible energy (IDE), ME, and MEn contents of bakery meal using the regression method and to evaluate whether the energy values are age-dependent in broiler chickens from zero to 21 d post hatching. Seven hundred and eighty male Ross 708 chicks were fed 3 experimental diets in which bakery meal was incorporated into a corn-soybean meal-based reference diet at zero, 100, or 200 g/kg by replacing the energy-yielding ingredients. A 3 * 3 factorial arrangement of 3 ages (1, 2, or 3 wk) and 3 dietary bakery meal levels were used. Birds were fed the same experimental diets in these 3 evaluated ages. Birds were grouped by weight into 10 replicates per treatment in a randomized complete block design. Apparent ileal digestibility and total tract retention of DM, N, and energy were calculated. Expression of mucin (MUC2), sodium-dependent phosphate transporter (NaPi-IIb), solute carrier family 7 (cationic amino acid transporter, Y(+) system, SLC7A2), glucose (GLUT2), and sodium-glucose linked transporter (SGLT1) genes were measured at each age in the jejunum by real-time PCR. Addition of bakery meal to the reference diet resulted in a linear decrease in retention of DM, N, and energy, and a quadratic reduction (P < 0.05) in N retention and ME. There was a linear increase in DM, N, and energy as birds' ages increased from 1 to 3 wk. Dietary bakery meal did not affect jejunal gene expression. Expression of genes encoding MUC2, NaPi-IIb, and SLC7A2 linearly increased (P < 0.05) with age. Regression-derived MEn of bakery meal linearly increased (P < 0.05) as the age of birds increased, with values of 2,710, 2,820, and 2,923 kcal/kg DM for 1, 2, and 3 wk, respectively. Based on these results, utilization of energy and nitrogen in the basal diet decreased when bakery meal was included and increased with age of broiler chickens. PMID- 26944964 TI - Efficacy of HVT-IBD vector vaccine compared to attenuated live vaccine using in ovo vaccination against a Korean very virulent IBDV in commercial broiler chickens. AB - The production performance, efficacy, and safety of two types of vaccines for infectious bursal disease virus (IBDV) were compared with in-ovo vaccination of Cobb 500 broiler chickens for gross and microscopic examination of the bursa of Fabricius, bursa/body weight (b/B) ratio, flow cytometry, and serologic response to Newcastle disease virus (NDV) vaccination. One vaccine was a recombinant HVT IBD vector vaccine (HVT as for herpesvirus of turkeys) and the other was an intermediate plus live IBDV vaccine. A significant difference was detected at 21 d. Eight of 10 chickens that received the IBDV live vaccine had severe bursal lesions and a relatively low b/B ratio of 0.95, and an inhibited NDV vaccine response. On the other hand, the HVT-IBD vector vaccine resulted in mild bursal lesions and a b/B ratio of 1.89. Therefore, the live vaccine had lower safety than that of the HVT-IBD vector vaccine. To determine the protective efficacy, chickens were intraocularly challenged at 24 d. Eight of 10 chickens in the IBDV live vaccination group showed gross and histological lesions characterized by hemorrhage, cyst formation, lymphocytic depletion, and a decreased b/B ratio. In contrast, the HVT-IBD vector vaccinated chickens showed mild gross and histological lesions in three of 10 chickens with a b/B ratio of 1.36, which was similar to that of the unchallenged controls. Vaccinated chickens showed a significant increase in IBDV antibody titers, regardless of the type of vaccine used. In addition, significantly better broiler flock performance was observed with the HVT-IBD vector vaccine compared to that of the live vaccine. Our results revealed that the HVT-IBD vector vaccine could be used as an alternative vaccine to increase efficacy, and to have an improved safety profile compared with the IBDV live vaccine using in-ovo vaccination against the Korean very virulent IBDV in commercial broiler chickens. PMID- 26944965 TI - Differential antibacterial response of chicken granulosa cells to invasion by Salmonella serovars. AB - In the United States, Salmonella enterica ser. Enteritidis (SE) is among the leading bacterial cause of foodborne illness via consumption of raw or undercooked eggs. The top Salmonella serovars implicated in U.S. foodborne outbreaks associated with chicken consumption include SE, Typhimurium (ST), Heidelberg (SH), Montevideo, Mbandka, Braenderup, and Newport. While enforcement actions target the eradication of SE from layer hens, there is a growing concern that other serovars could occupy this niche and be a cause of egg-transmitted human salmonellosis. Therefore, we tested the invasion and survival of SE, SH, ST, and Salmonella enterica ser. Hadar (S. Hadar) at 4 and 20 h post infection (hpi) in chicken ovarian granulosa cells (cGC); a cellular layer which surrounds the previtelline layer and central yolk in egg-forming follicles. We also evaluated cGC transcriptional changes, using an antibacterial response PCR array, to assess host response to intracellular SalmonellaWe observed that invasion of cGC by SE, SH, and ST was significantly higher than invasion by S. Hadar, with ST showing the highest level of invasion. The Bacterial Survival Index, defined as the ratio of intracellular bacteria at 20 and 4 h, were 18.94, 7.35, and 15.27 for SE, SH, and ST, respectively, with no significant difference in survival between SE or ST compared to SH. Evaluation of cGC anti-Salmonella gene responses indicated that at 4 hpi there was a significant decrease in Toll-like receptor (TLR)-4 mRNA in cGC infected with SE, whereas TLR5 and myeloid differentiation primary response gene 88 were significantly down regulated across all serovars. At 4 hpi, invasion by Salmonella serovars resulted in significant upregulation of several antimicrobial genes, and proinflammatory cytokines and chemokines (PICs). At 20 hpi, all the serovars induced PICs with SH being the strongest inducer. Additionally, SE, SH and ST differentially induced signal transduction pathways. Although only a single strain from each serovar was tested, cGC presents a useful ex vivo cell culture model to assess the virulence potential of Salmonella serovars. PMID- 26944966 TI - Early intestinal development and mucin transcription in the young poult with probiotic and mannan oligosaccharide prebiotic supplementation. AB - Alternative and adjunctive approaches to decreasing the use of dietary antibiotics are becoming popular areas of study. Supplemental probiotics (commensal microbes) and prebiotics (indigestible complex carbohydrates) are 2 dietary approaches to facilitating the intestinal colonization of beneficial bacteria to compete with potential pathogens, thus creating a healthy mucosal environment. The intestinal mucosa is composed of mucin glycoproteins, which play a key role in preventing the attachment of pathogenic bacteria. At hatch, the neonatal turkey intestine is relatively aseptic and vulnderable to bacterial colonization by both commensal and pathogenic microbes. In the current study, we determined the transcription of MUC2, the primary mucin protein produced by goblet cells within the small intestine, and we also measured intestinal morphology immediately post-hatch through d 11. Poults were fed a conventional starter diet, the starter diet supplemented with one of 2 commercial probiotics (A, B), or a commercial mannan oligosaccharide. MUC2 transcription increased from d zero to d 4 post-hatch (P< 0.05), but there was no effect of probiotic or prebiotic supplementation. Villus height and villus area both increased with Probiotic B and mannan oligosaccharide supplementation (P<0.05) and there was a significant d X treatment interaction effect for crypt depth (P=0.007). These results suggest that probiotic and prebiotic supplementation can positively alter the intestinal microenvironment. PMID- 26944967 TI - Dietary threonine response of Pekin ducks from hatch to 14 d of age based on performance, serology, and intestinal mucin secretion. AB - Two experiments were conducted to determine the dietary threonine (Thr) requirement of Pekin ducks from hatch to 14 d of age. In experiment 1, practical corn-soybean meal diets were formulated to contain 0.78, 0.84, 0.90, 0.96, and 1.02% Thr (0.74, 0.83, 0.88, 0.92, and 1.00% Thr on an analyzed basis). In experiment 2, corn-soybean meal diets supplemented with 11 crystalline amino acids were formulated to contain 0.60, 0.70, 0.80, 0.90, 1.00, and 1.10% Thr (0.60, 0.75, 0.89, 0.95, 1.01, and 1.09% Thr on an analyzed basis). In both experiments, diets were fed to 8 replicate cages with 6 male ducks per cage. Body weight and feed intake from each cage were recorded weekly. At 14 d of age, breast meat, ileal digesta, and serum were collected to determine breast meat yield, mucin secretion, and serology parameters. In both studies, the estimated Thr requirement (expressed as % dietary Thr basis) for 14 d BW and BW gain (BWG) by quadratic broken-line (QBL) regression were similar, which were 0.87 and 0.86%, respectively. Additional measures in both experiments resulted in Thr requirements via QBL regression in rank order of crude mucin secretion < breast meat yield < serum immune activity. Summing up the estimates from both studies, the Thr requirement ranged from a low of 0.81% to maximize feed intake (FI) to a high of 1.00% to maximize serum Rb L100 by QBL regression. Correspondingly, the Thr requirement varied between a low of 0.90% to maximize crude mucin secretion on a dry matter intake (DMI) basis and a high of 0.98% to maximize feed-to-gain when using quadratic regression. PMID- 26944968 TI - Relative bioavailability of copper in tribasic copper chloride to copper in copper sulfate for laying hens based on egg yolk and feather copper concentrations. AB - This experiment was conducted to determine the relative bioavailability (RBV) of Cu in tribasic copper chloride (TBCC) to Cu in copper sulfate (monohydrate form; CuSO4.H2O) for layer diets based on egg yolk and feather Cu concentrations. A total of 252, 72-wk-old Hy-Line Brown laying hens were allotted to 1 of 7 treatments with 6 replicates consisting of 6 hens per replicate in a completely randomized design. Hens were fed corn-soybean meal-based basal diets supplemented with 0 (basal), 100, 200, or 300 mg/kg Cu from CuSO4 or TBCC for 4 wk. Results indicated that egg production, egg weight, and egg mass were not affected by dietary treatments. However, increasing inclusion levels of Cu in diets from CuSO4 decreased (P < 0.05) feed conversion ratio (FCR), whereas increasing inclusion levels of Cu in diets from TBCC did not affect FCR, indicating significant interaction (P < 0.05). Increasing inclusion levels of Cu from TBCC or CuSO4 increased (P < 0.05) Cu concentrations of egg yolk and feathers. Feather Cu concentrations were greater (P < 0.01) for hens fed diets containing CuSO4 than for hens fed diets containing TBCC. The values for the RBV of Cu in TBCC to Cu in CuSO4 based on log10 transformed egg yolk and feather Cu concentrations were 107.4% and 69.5%, respectively. These values for the RBV of Cu in TBCC did not differ from Cu in CuSO4 (100%). The RBV measured in egg yolk did not differ from the RBV measured in feather. In conclusion, the RBV of Cu in TBCC to Cu in CuSO4 can be determined using Cu concentrations of egg yolk and feathers although the values depend largely on target tissues of laying hens. For a practical application, however, the RBV value of Cu in TBCC to Cu in CuSO4 could be 88.5% when the RBV values determined using egg yolk and feather Cu concentrations were averaged. PMID- 26944969 TI - A multi-pronged approach to the search for an alternative to formaldehyde as an egg disinfectant without affecting worker health, hatching, or broiler production parameters. AB - Research was carried out to determine the effectiveness of 4 hatching eggs disinfection processes (i.e., disinfecting products and administration method) using a multi-pronged approach assessing the reduction of microbial eggshell contamination, the effects on worker exposure, hatching results and broiler performance, and, finally, suitability for use in commercial hatcheries. The 4 disinfection processes were: sodium dichlorocyanurate (DC) by thermonebulization, hydrogen peroxide 6% by nebulization (HP6), electrolyzed oxidizing water (EOW) by fogging, and hydrogen peroxide 30% vapor (HP30). In order to meet commercial hatchery conditions, the tested products were applied in an experimental hatchery by aerial disinfection in a dedicated room, not sprayed directly onto the eggs. Compared to the untreated control group, eggshell microbial load was significantly decreased by over 1 log10 cfu per egg in groups DC and HP30. These results were confirmed during a second experiment. In addition, these 2 products comply with legal requirements on worker exposure. Fertility and hatching results were significantly higher in group HP30 than in group DC, with no impact on chick quality and subsequent broiler performance. Under these study conditions, the disinfection process (i.e., administration of the product, contact with the eggs and aeration) lasted 65 min in group DC vs. 135 min in group HP30. When considering commercial hatchery conditions, this difference in application time confers a clear advantage on the DC process. Moreover, the investment required for HP30 is much higher than for DC. Overall, HP30 presented a clear advantage for hatching results whereas DC is a relatively more practical and less expensive disinfection process. To our knowledge, this is the first report on the use of hydrogen peroxide vapor as an egg disinfection process. Further research is needed to confirm the results of this study under commercial hatchery conditions. PMID- 26944970 TI - Probiotic form effects on growth performance, digestive function, and immune related biomarkers in broilers. AB - The aim of this work was to assess the effect of dietary viable or heat inactivated probiotic forms (PF) combined or not with avilamycin (AV) used as a growth promoter, on broiler growth performance, nutrient digestibility, digestive enzyme activities, and expression of immune response related genes.Depending on the type of PF (i.e., no addition, viable, inactivated) and AV addition (no/yes), 450 one-day-old Cobb male broilers were allocated in the following 6 treatments according to a 3 * 2 factorial arrangement with 5 replicates of 15 broilers each for 6 wk: CoN: diet without any addition; CoN+A: combination of CoN with AV; ViP: viable PF - no AV; ViP+A: combination of ViP with AV; InP: inactivated PF - no AV; InP+A: combination of InP with AV.There were no interactions (P > 0.05) for overall performance parameters. In contrast, PF or AV addition improved BW gain (PPF= 0.015; PAV < 0.001), FCR (PPF < 0.001; PAV < 0.001) and production efficiency factor (PPF= 0.001; PAV= 0.001).Significant (PPF*AV <= 0.05) interaction effects regarding ileal digestibility (IAD) of DM and total tract apparent digestibility (TTAD) of DM and ether extracts (EE) were noted. In addition, PF affected IAD and TTAD of CP (PPF < 0.001, PPF= 0.004, respectively). Inactivated PF increased (PPR= 0.024) lipase activity in jejunal digesta.At spleen level InP and ViP+A down-regulated TGF-beta4 (PPF * AV = 0.035) compared to CoN and ViP, whereas ViP+A up-regulated iNOS (PPF * AV = 0.022). An anti inflammatory effect of live and inactive PF and/or AV addition at cecal tonsils was shown by iNOS down-regulation (PPF * AV= 0.015) compared to CoN. Furthermore, AV down-regulated IFN-gamma (PAV= 0.002).In conclusion, viable probiotic, as well as inactivated probiotic alone or in combination with avilamycin, improved nutrient digestibility. All dietary additives affected growth performance positively and induced an anti-inflammatory response at cecal level. PMID- 26944971 TI - Developmental changes of Insulin-like growth factors in the liver and muscle of chick embryos. AB - The insulin-like growth factors ( IGFS: ) are synthesized in tissues and play an important role in embryonic development of avian via autocrine/paracrine mechanisms. In the study, mRNA expression of IGFs were detected by real-time PCR in the muscle and liver from d 10 to 20 of chick embryo ( E10: to E20: ). Methylation of IGF1 promoter in the muscle was analyzed by bisulfite sequencing PCR as well as IGF2 promoter in the liver. These results showed that there was obviously IGF1 expression in liver at E19 and E20. The higher IGF1 expression in muscle was found during E15 to E18 with the peak on E17, and then declined. Correspondingly, the lowest methylation level of IGF1 promoter was detectable on the same embryonic d 17. Expression of IGF2 in muscle increased gradually during embryonic growth and showed higher level in the later stages (E17 to E20) when IGF1 expression began to decrease. IGF2 expression in liver reached the first peak on E14, then declined but gradually elevated from E17. IGF2 promoter methylation in liver showed gradual decline on d 12, 15, 17 and 19 of incubation, meanwhile IGF2 expression of liver increased gradually. These results suggested that IGF1 and IGF2 might separately be more important for muscle and liver growth in chick embryonic development. Variation of IGFs expression during the incubation might be concerned with the methylation of gene promoter. The profile of IGFs expression in chick embryonic tissues may be meaningful for understanding organ growth and embryonic development in chick. PMID- 26944972 TI - Effect of the rooster semen enrichment with oleic acid on the quality of semen during chilled storage. AB - Liquid storage of avian spermatozoa is currently being employed in programs utilizing the artificial insemination to optimize the management of genetically superior males. It is mandatory to use efficient semen storage techniques in order to prevent the reduction of the fertilizing ability of stored semen. The present study was designated to evaluate the effect of oleic acid on rooster semen quality stored at 4 degrees C for 48 h. Semen was collected from 10 roosters twice a week. Good quality ejaculates were pooled and after dilution, the semen was enriched with 0 (control), 0.125 (O 0.125), 0.25 (O 0.25), 0.5 (O 0.5), and 1 (O1) millimolar oleate. Forward progressive motility and viability of spermatozoa were evaluated at 0, 24, and 48 h. Moreover, malondialdehyde (MDA) and total antioxidant activity (AOA) levels were measured in seminal plasma and spermatozoa at the mentioned time points. Motility was 80.33 +/- 1.45, 80.00 +/- 2.08, and 66.00 +/- 2.30% at 24 h and 56.33 +/- 1.45, 57.33 +/- 2.18, and 41.33 +/- 2.02% at 48 h in O 0.125, O 0.25, and control, respectively (P < 0.001). Total AOA concentrations of seminal plasma were significantly higher in oleate treated groups than the control at 24 and 48 h (P < 0.03). Moreover, concentrations of AOA in spermatozoa revealed that oleate treated group showed higher AOA values compared to the control group at 24 and 48 h (P < 0.001). MDA concentrations of seminal plasma and spermatozoa were lower in oleate treated groups in comparison with control group at 24 and 48 h (P < 0.05). In conclusion, rooster semen enrichment with low doses of oleate would exert beneficial effects on the quality of semen during cooled storage. PMID- 26944973 TI - Comparison of eggshell surface sanitization technologies and impacts on consumer acceptability. AB - Shell eggs can be contaminated with many types of microorganisms, including bacterial pathogens, and thus present a risk for the transmission of foodborne disease to consumers. Currently, most United States egg processors utilize egg washing and sanitization systems to decontaminate surfaces of shell eggs prior to packaging. However, previous research has indicated that current shell egg sanitization technologies employed in the commercial egg industry may not completely eliminate bacteria from the surface of eggshells, and thus alternative egg sanitization technologies with the potential for increased microbial reductions on eggshells should be investigated. The objectives of this study were to compare the antimicrobial efficacy and consumer sensory attributes of industry available eggshell sanitization methods (chlorine and quaternary ammonium compounds (QAC) applied via spray) to various alternative egg sanitization technologies. Eggs (White Leghorn hens; n=195) were obtained for evaluation of sanitizer-induced reduction in mesophilic aerobic bacteria (n=90) or inoculated Salmonella Enteritidis (SE) reduction (n=105). Sanitizing treatments evaluated in this experiment were: chlorine spray (100 ppm available chlorine), QAC spray (200 ppm), peracetic acid spray (PAA; 135 ppm) alone or in combination with ultraviolet light (UV; 254 nm), and hydrogen peroxide (H2O2; 3.5% solution) spray in combination with UV (H2O2+UV). For enumeration of aerobic bacteria, eggs were sampled at 0, 7, and 14 days of storage at 4 degrees C; surviving SE cells from inoculated eggs were enumerated by differential plating. Sensory trials were conducted to determine consumer liking of scrambled eggs made from eggs sanitized with chlorine, QAC, H2O2+UV, or no treatment (control). The H2O2 and UV treatment resulted in the greatest reductions in eggshell aerobic plate counts compared to other treatments throughout egg storage (P<0.05). All treatments utilized reduced SE below the limit of detection by eggshell rinse. There were no differences in consumers' liking of overall flavor between the 4 treatments evaluated. The application of H2O2+UV treatment to shell eggs represents a novel technology that could have important implications for egg quality and safety preservation. PMID- 26944974 TI - Effects of probiotics feeding on meat quality of chicken breast during postmortem storage. AB - This study evaluated the effects of dietary probiotic supplement and postmortem storage on meat quality of chicken breast during retail display. A total of 35 birds were randomly obtained from 3 feeding groups (control without probiotic supplement, 250 ppm Sporulin, and 500 ppm PoultryStar). The probiotic supplement had no influence on feed conversion ratio and body weight gain, as well as body weight at 29 and 44 d (P > 0.05). After slaughter, each side of the breast muscles (M. Pectoralis major) was assigned to either one d or 5 d of postmortem storage. Probiotic supplement had no influence on the rate of pH decline of chicken breast muscles during the initial 6 h postmortem (P > 0.05). No interactions between probiotic supplement and postmortem storage on meat quality were found (P > 0.05). Postmortem storage decreased drip loss from 25.30 to 18.05% (P < 0.05). Probiotics-fed chicken groups, particularly PoultryStar treatment, had a higher myofibrillar fragmentation index than the control group (P < 0.05). However, shear force values were not affected by the probiotic treatments. Decreases in color and lipid stabilities of breast muscles were found during display (P < 0.05), but were not affected by the probiotic supplement (P > 0.05). Our result suggests that probiotic supplement had no adverse impacts on proteolysis and oxidative changes during 5 d postmortem display storage. PMID- 26944976 TI - Colonization of internal organs by Salmonella Enteritidis in experimentally infected laying hens housed in enriched colony cages at different stocking densities. AB - Epidemiologic analyses have linked the frequency of human infections with Salmonella enterica subspecies enterica serovar Enteritidis to the consumption of contaminated eggs and thus to the prevalence of this pathogen in commercial egg laying flocks. Contamination of the edible contents of eggs by Salmonella Enteritidis is a consequence of the colonization of reproductive tissues in systemically infected hens. The animal welfare implications of laying hen housing systems have been widely debated, but no definitive consensus has yet emerged about the food safety significance of poultry housing options. The present study sought to determine the effects of two different bird stocking densities on the invasion of internal organs by Salmonella Enteritidis in groups of experimentally infected laying hens housed in colony cages enriched with perching and nesting areas. In two trials, groups of laying hens were distributed at two different stocking densities into colony cages and (along with a group housed in conventional cages) orally inoculated with doses of 1.0 * 10(7) cfu of Salmonella Enteritidis. At 5 to 6 d post-inoculation, hens were euthanized and samples of internal organs were removed for bacteriologic culturing. For both trials combined, Salmonella Enteritidis was recovered at a significantly (P < 0.05) greater frequency from hens in enriched colony cages at the higher stocking density than at the lower density from livers (75.0% vs. 51.4%) and ovaries (51.4% vs. 30.6%). However, spleens from hens in enriched colony cages at the higher stocking density were significantly less often positive for Salmonella Enteritidis than from hens in conventional cages at that same density (90.3% vs. 68.1%). These results suggest that stocking density can influence the susceptibility of hens to Salmonella Enteritidis, but other housing systems parameters may also contribute to the outcome of infections. PMID- 26944975 TI - Effects of prebiotics, probiotics, and their combination on growth performance, small intestine morphology, and resident Lactobacillus of male broilers. AB - Effects of commercial antimicrobials and the individual and combinational use of commercial prebiotics and probiotics in feed from d zero to 41 on the growth performance, small intestine size, jejunal morphology, and ileal resident bacteria population of broiler chickens were determined. A total of 1,040 one-day old male Ross * Ross 708 broilers were randomly distributed to 80 floor pens (5 treatments, 16 replications per treatment, 13 chicks per pen). Five dietary treatments were employed: 1) a corn soybean-meal basal diet (served as a negative control diet, NC); 2) a basal diet supplemented with a commercial prebiotic product (Pre); 3) a basal diet supplemented with a probiotic product containing Bacillus subtilis spores (Pro); 4) a basal diet supplemented with both prebiotic and probiotic products (Pre + Pro); and 5) a basal diet supplemented with commercial antimicrobials (served as a positive control diet, PC). At d 14, Pre diets improved the relative level of Lactobacillus in ileal mucosa as compared to NC, Pro, or PC diets (P = 0.045) without improving broiler BW. Broilers fed PC diets exhibited the highest BW gain from d 15 to 27, the lowest duodenum, jejunum, and ileum relative weights as percentage of BW at d 27, and the highest breast weight at d 42 (P = 0.026, 0.035, 0.002, 0.025, and 0.035, respectively). Broilers fed Pro or Pre + Pro diets exhibited higher BW gain from d 28 to 41 (P = 0.005) and higher overall BW gain from d zero to 41 (P = 0.039) than those fed other diets. Dietary treatments did not affect jejunal morphology or ileal resident Escherichia coli level at any age. From our results, including spores of Bacillus subtilis in feed may stimulate growth at a later age and may facilitate broilers in reaching their target weight sooner. Therefore, probiotics are recommended as potential alternatives to antimicrobials in chicken diets, especially in grower and finisher feed. PMID- 26944977 TI - Interactive effects of dietary protein concentration and aflatoxin B1 on performance, nutrient digestibility, and gut health in broiler chicks. AB - A 20-day trial was conducted to determine the impact of aflatoxin B1 (AFB1) and dietary protein concentration on performance, nutrient digestibility, and gut health in broiler chicks. The 6 dietary treatments were arranged in a 2 * 3 factorial with 3 crude protein (CP) concentrations (16, 22, and 26%) with or without 1.5 mg/kg AFB1 Each diet was fed to 6 replicate cages (6 chicks per cage) from zero to 20 d of age. Endogenous N and amino acid loss were estimated from birds fed a N-free diet with or without 1.5 mg/kg AFB1 A significant interaction between AFB1 and CP concentration was observed for growth performance, where reduction of BW gain, feed intake, gain:feed ratio, and breast muscle weight by AFB1 were most profound in birds fed the 16%-CP diet, and were completely eliminated when birds were fed the 26%-CP diet (AFB1 by CP interaction; P <= 0.023). Similarly, AFB1 reduced serum albumin, total protein, and globulin concentrations in birds fed 16 and 22% CP diets, but not in those fed the 26%-CP (AFB1 by CP interaction; P <= 0.071). Gut permeability was increased in birds fed AFB1-contamiated diets as measured by serum lactulose/rhamnose ratio (main effect; P = 0.04). Additionally, AFB1 tended to increase endogenous N loss (P = 0.09), and significantly reduced apparent ileal digestible energy and standardized ileal N and amino acid digestibility in birds fed the 16%-CP diet, while birds fed higher dietary CP were not affected (AFB1 by CP interaction; P <= 0.01). Further, AFB1 increased the translation initiation factor 4E-binding protein (4EBP1), claudin1, and multiple jejunal amino acid transporters expression (main effect; P <= 0.04). Results from this study indicate that a 1.5 mg AFB1/kg diet significantly impairs growth, major serum biochemistry measures, gut barrier, endogenous loss, and energy and amino acid digestibility. Aflatoxicosis can be augmented by low dietary CP, while higher dietary CP completely eliminated the impairment of performance, serum proteins, and nutrient digestibility from aflatoxicosis in zero to 20 d broiler chicks. PMID- 26944978 TI - MiR-122 targets the vanin 1 gene to regulate its expression in chickens. AB - As the most abundant microRNA (miRNA) in the liver, miR-122 plays important roles in the growth and development of liver, lipid metabolism, and liver diseases. Vanin 1 (VNN1) plays an important role in hepatic lipid metabolism, and VNN1 may serve as a potential therapeutic target for the treatment of metabolic diseases caused by overactivated gluconeogenesis. In our previous RNA-seq study, we found the expression of VNN1 increased significantly when the expression of miR-122 (gga-miR-122-5p) was knocked down in primary chicken hepatocytes. In this study, we verified this result by real-time qRT-PCR, and we also found that the chicken VNN1 was highly expressed in the liver. By bioinformatics analyses, we found the 3'UTR of VNN1 contained sequences completely complementary to the nucleotides 1 to 8 of miR-122. Co-transfection and dual-luciferase reporter assays showed that overexpression of miR-122 decreased the expression of luciferase reporter gene linked to the 3'UTR of chicken VNN1 in the Chinese hamster ovary cells (P<0.01), and the decrease was further demonstrated to be dependent on the predicted miR 122 binding sites by site mutation analyses. These results further support miR 122 as a negative regulator of VNN1 expression in chicken hepatocytes. Overall, this study suggests that miR-122 might play an important role in lipid metabolism in the chicken liver by negatively regulating the expression of the VNN1 gene. PMID- 26944979 TI - Circadian clock genes are rhythmically expressed in specific segments of the hen oviduct. AB - In animals, core clock genes are expressed in many peripheral tissues throughout the body that contribute to tissue specific temporal regulation including those that comprise the reproductive system. The chicken ovulatory cycle seems to provide an example of a system in which circadian and interval timing mechanisms operate during ovulation-oviposition. However, little is known about the possible role of circadian regulation during egg formation and laying. To this end, we determined the rhythmic expression of several known canonical clock genes and clock controlled genes in the 4 segments of the chicken oviduct (infundibulum, magnum, isthmus, and uterus) taken from the same biological state (laying sequence and oviposition time) using real time RT-PCR. Except for Cry1, the other genes we analyzed were expressed in all 4 segments of the oviduct. Intriguingly, in a daily light-dark cycle, Bmal1, Clock, Per2, Per3, Cry2, and Rev-erbbeta have highly significant rhythmic expression in the infundibulum and uterus but not in the magnum and isthmus. These results show that there is spatial specificity in the localization of clock cells in the hen reproductive tract and that peripheral clocks might have a direct role in the infundibulum and uterus where yolk is captured and the eggshell is formed, respectively. PMID- 26944980 TI - Effect of chicken skin on the quality characteristics of semi-dried restructured jerky. AB - The objective of this study was to evaluate the effect of skin on the textural properties of semi-dried jerky produced with different acid treatments. Jerky was prepared with no skin (control) or with 1, 3, or 5% chicken skin. After hand mixing (for 3 min) and tumbling (for 30 min) to distribute the curing ingredients, the cured meats were dried for 180 min at 55 degrees C, for 180 min at 65 degrees C, and finally for 60 min at 75 degrees C. The presence of skin was shown to result in a higher fat content, TBA value, and metmyoglobin due to the high fat content of the skin. In contrast, acid treatment decreased the TBA value and metmyoglobin in jerky relative to samples that were not subjected to acid treatment. The presence of skin also improved the moisture contents, processing yields, and mechanical tenderness. PMID- 26944981 TI - The excretion and environmental effects of amoxicillin, ciprofloxacin, and doxycycline residues in layer chicken manure. AB - The excretion rates and ecological risk to the environment of three commonly used veterinary antibiotics (VAs), amoxicillin, ciprofloxacin, and doxycycline, in layer hen manure during the application and withdrawal periods were investigated in a study consisting of a control group fed with VA-free basal diet and nine treatment groups consisted of three levels (200 mg/kg, 100 mg/kg, and 50 mg/kg) of amoxicillin (AMX), ciprofloxacin (CIP), or doxycycline (DOC). Each treatment group was replicated seven times with three layer hens per replication. Results of the study showed that the average excretion rates of AMX in the 200, 100, and 50 mg/kg groups were 67.88, 55.82, and 66.15%, respectively, while those for CIP and DOC were 47.84, 51.85, and 44.87% and 82.67, 94.39, and 95.72%, respectively. The concentrations of the above veterinary drugs in manure decreased sharply in the withdrawal period (7, 28, and 10 d, respectively), for AMX, DOC, and CIP. Neither AMX nor DOC was detected in the manure after the withdrawal period. In contrast to AMX and DOC, the excretion rate of CIP was significantly lower and thus had a longer residence time. Ecological risk study, estimated using hazard quotient values, showed that AMX in the 100 and 50 mg/kg groups posed no risk to the environment after d 1 of withdrawal, while CIP in the 50 mg/kg group posed no risk to the environment from d 5 of withdrawal. CIP in the 200 and 100 mg/kg groups required 10 d withdrawal in order to pose no risk to the environment. In contrast, DOC residue during withdrawal in the manure posed no risk to the environment, thus making it more environmentally safe. PMID- 26944982 TI - The effect of northern fowl mite (Ornithonyssus sylviarum) infestation on hen physiology, physical condition, and egg quality. AB - The northern fowl mite (NFM),Ornithonyssus sylviarum, is the most common ectoparasite of laying hens in North America. Infestation can cause a reduction in egg production, egg weights, and feed conversion efficiency. However, there is a lack of information on the effects of NFM on hen physiology, physical condition, and egg quality. Singly caged beak-trimmed White Leghorn hens (N=32) were infested with mites at 25 wk of age. The condition of each hen was assessed at wk 0 (infestation) and wk 5 and 7 post-infestation to determine comb temperatures and feather, skin, and comb condition. Heterophil-lymphocyte (H/L) ratios and body weight (BW) were evaluated at wk 0 and wk 1, 3, 5, and 7 post infestation. Egg weight, egg specific gravity, yolk color, Haugh unit (HU), and eggshell thickness were determined prior to infestation (wk -1) and at 1, 3, 5, and 7 wk post-infestation. The H/L ratio (P<0.0001), HU (P<0.0001), and egg specific gravity (P=0.001) were lowest, and the egg yolk color was lightest (P=0.087) at wk 5, the peak of infestation. At wk 5 and 7, more than 65% of the hens had red skin and more than 75% had scabs on the vent; in addition more than 84% had grey-black vent feathers. There were no effects of infestation on comb color, comb temperature, feather cover, BW, or eggshell thickness. It was concluded that infestation with NFM has negative effects on interior egg quality and hen integument. A decrease in H/L ratio was also observed at the peak of infestation. However, the effects of NFM on the immune system are unclear, and H/L ratio might not be a good stress measure in hens highly infested with NFM. PMID- 26944983 TI - Higher inclusion rate of canola meal under high ambient temperature for broiler chickens. AB - Extruded canola meal (ECM) was included in diet of broiler chickens at 0, 10, 20, and 30% (wt/wt) from 1 to 35 days of age. A total of 240 day-old male chicks were assigned in groups of 5 to 48 battery cages in environmentally controlled chambers and diets were replicated with 12 cages/treatment. From d 29 to 35, birds from each dietary group were exposed to either thermoneutral (23 +/- 1 degrees C; unheated) or high (36 +/- 1 degrees C; heated) temperature conditions. High ambient temperature, irrespective of ECM inclusion, depressed the growth performance of birds. Inclusion of ECM increased feed conversion ratio (FCR) linearly in unheated birds during d 1 to 28 (P < 0.001) and d 29 to 35 (P = 0.001). However, no adverse effects of ECM inclusion were observed on the growth performance of heated birds. The absence of these detrimental effects could be associated with the lack of triiodothyronine (T3) elevation by ECM inclusion in heated birds. In conclusion, ECM can be fed, at least, up to 30%, without any adverse effect on growth performance of broiler chickens raised under chronic high ambient temperature. PMID- 26944984 TI - Characterization of primary structure and post-hatching increase in chicken cytosolic acetoacetyl-coA thiolase in the liver. AB - Acetoacetyl-CoA thiolase (EC 2.3.1.9) catalyzes the cleavage of acetoacetyl-CoA into acetyl-CoA and its reverse reaction, the synthesis of acetoacetyl-CoA. Cytosolic acetoacetyl-CoA thiolase ( CT: ) is a key enzyme in the initial step of the cholesterol synthesis pathway. In the present study, we characterized the amino acid sequence of chicken CT and the tissue distribution of its mRNA and protein, together with their developmental changes in the liver. The amino acid sequence encoded by the nucleotide sequence of chicken CT cDNA showed a higher overall identity with those of human (74.3%) and rat (74.6%) CTs. Amino acid residues known to participate in enzymatic activity in human CT are conserved in chicken CT. Real-time PCR analysis revealed the expression of CT mRNA in the liver, kidney, adrenal gland, jejunum and ovary of adult hens, with higher levels in the liver, kidney, adrenal gland and ovary. Western blot analysis detected an immunoreactive protein of 41 kDa from cytoplasmic fraction but not particulate fractions of adult chicken liver. The immunoreactive protein was detected in all the tissues. The mRNA levels in the liver rapidly increased after hatching, with a maximum on d 5 post-hatching, after which they gradually decreased to adult levels. A similar change was observed in the protein levels. The increase in transcription and protein synthesis of CT suggests that the synthetic pathway of cholesterol from acetyl-CoA produced by CT replaces the hydrolysis of accumulated cholesteryl ester in the liver, in response to a change in the nutrient source from the lipid-rich yolk to a lower-lipid diet during the early post-hatching period. PMID- 26944986 TI - Chemometric applications to assess quality and critical parameters of virgin and extra-virgin olive oil. A review. AB - Today virgin and extra-virgin olive oil (VOO and EVOO) are food with a large number of analytical tests planned to ensure its quality and genuineness. Almost all official methods demand high use of reagents and manpower. Because of that, analytical development in this area is continuously evolving. Therefore, this review focuses on analytical methods for EVOO/VOO which use fast and smart approaches based on chemometric techniques in order to reduce time of analysis, reagent consumption, high cost equipment and manpower. Experimental approaches of chemometrics coupled with fast analytical techniques such as UV-Vis spectroscopy, fluorescence, vibrational spectroscopies (NIR, MIR and Raman fluorescence), NMR spectroscopy, and other more complex techniques like chromatography, calorimetry and electrochemical techniques applied to EVOO/VOO production and analysis have been discussed throughout this work. The advantages and drawbacks of this association have also been highlighted. Chemometrics has been evidenced as a powerful tool for the oil industry. In fact, it has been shown how chemometrics can be implemented all along the different steps of EVOO/VOO production: raw material input control, monitoring during process and quality control of final product. PMID- 26944985 TI - The Effects of an Educational Intervention on Preventing Cervical Cancer Among Vietnamese Women in Southern Taiwan. AB - This paper aims to conduct and evaluate an educational intervention on preventing cervical cancer among married immigrant women of Vietnamese origin. The study design was a quasi-experimental method with two groups. In total, 260 married immigrant women of Vietnamese origin with national health insurance at least 30 years of age were recruited from November 2013 to January 2015 in southern Taiwan. The effects of the educational intervention, including cervical cancer and Papanicolaou test knowledge, attitudes towards cervical cancer, fatalism, barriers to receiving Papanicolaou tests, intention for receiving Papanicolaou tests within the next year, and intention for receiving Papanicolaou tests within the next 3 years, were evaluated. Repeated measures analyses of variance showed significant interactions between the intervention group and time for cervical cancer knowledge, knowledge of Papanicolaou test, attitudes towards cervical cancer, and intention for receiving a Papanicolaou test within the next 3 years; in addition, 71.4 % reported being satisfied or very satisfied with the intervention. The results of this study can provide information for governments to make appropriate health policies for screening behavior of cervical cancer, increase healthcare professionals' competencies towards Vietnamese women, and increase Papanicolaou test screening rates to decrease cervical cancer mortality. Effective interventions may require particular consideration of married immigrant women. PMID- 26944988 TI - A tutorial review for employing enzymes for the construction of G-quadruplex based sensing platforms. AB - With rapid advances in the field of DNA chemistry, nucleic acids and DNA modifying enzymes have recently emerged as versatile components for the construction of oligonucleotide-based sensors. Meanwhile, the G-quadruplex motif has been widely employed for the development of DNA-based assays due to its diverse structural variety. In this tutorial, we introduce the principles of G quadruplex-based sensing and the use of DNA-modifying enzymes for sensor platform development. We also highlight recent studies of the application of DNA-modifying enzymes for the development of G-quadruplex-based luminescent detection platforms with a view towards how those enzymes play an important role in sensitivity enhancement. PMID- 26944987 TI - Applications of capillary electrophoresis with chemiluminescence detection in clinical, environmental and food analysis. A review. AB - This paper reviews the latest developments and analytical applications of chemiluminescence detection coupled to capillary electrophoresis (CE-CL). Different sections considering the most common CL systems have been included, such as the tris(2,2'-bipyridine)ruthenium(II) system, the luminol and acridinium derivative reactions, the peroxyoxalate CL or direct oxidations. Improvements in instrumental designs, new strategies for improving both resolution and sensitivity, and applications in different fields such as clinical, pharmaceutical, environmental and food analysis have been included. This review covers the literature from 2010 to 2015. PMID- 26944989 TI - Optimization of a liquid chromatography ion mobility-mass spectrometry method for untargeted metabolomics using experimental design and multivariate data analysis. AB - High-resolution mass spectrometry coupled with pattern recognition techniques is an established tool to perform comprehensive metabolite profiling of biological datasets. This paves the way for new, powerful and innovative diagnostic approaches in the post-genomic era and molecular medicine. However, interpreting untargeted metabolomic data requires robust, reproducible and reliable analytical methods to translate results into biologically relevant and actionable knowledge. The analyses of biological samples were developed based on ultra-high performance liquid chromatography (UHPLC) coupled to ion mobility - mass spectrometry (IM MS). A strategy for optimizing the analytical conditions for untargeted UHPLC-IM MS methods is proposed using an experimental design approach. Optimization experiments were conducted through a screening process designed to identify the factors that have significant effects on the selected responses (total number of peaks and number of reliable peaks). For this purpose, full and fractional factorial designs were used while partial least squares regression was used for experimental design modeling and optimization of parameter values. The total number of peaks yielded the best predictive model and is used for optimization of parameters setting. PMID- 26944990 TI - Preparation of molecularly imprinted solid-phase microextraction fiber for the selective removal and extraction of the antiviral drug abacavir in environmental and biological matrices. AB - In the present study, a molecularly imprinted solid-phase microextraction fiber (MIP-SPMEf) was synthesized and applied for the selective removal and extraction of the antiviral drug, abacavir (ABA). Morphology and structure characterization of fibers were performed by scanning electron microscopy and Fourier transform infrared spectra, respectively. The effects on the adsorption behavior of the process parameters were studied and the equilibrium data were fitted by the Langmuir, Freundlich and Langmuir-Freundlich models. The maximum adsorption capability (Qmax) was determined by Langmuir- Freundlich model and was 149 mg/g for MIP-SPMEf. In the next step, SPME methodology followed by liquid desorption and liquid chromatography with mass spectrometry (LC/MS) has been developed and evaluated for the determination of the target compound in environmental and biological matrices (surface waters, wastewaters and urine). Parameters that could influence SPME efficiency were investigated. Then, optimization of stirring speed, extraction time and salt content was carried out by using a central composite design (CCD) and response surface methodology (RSM). A quadratic model between dependent and independent variables was built. Under the optimum conditions (extraction time 40 min, stirring rate 650 rpm and salt content 0.3% NaCl w/v) the validated method presented a high sensitivity and selectivity with LODs and LOQs in the range of 10.1-13.6 and 33.3-43.9 ng/L, respectively. The developed method was successfully applied to the analysis of ABA in real samples. The percentage extraction efficiency ranged from 88 to 99% revealing good accuracy and absence of matrix effects. PMID- 26944992 TI - A simpler sampling interface of venturi easy ambient sonic-spray ionization mass spectrometry for high-throughput screening enzyme inhibitors. AB - High-throughput screening (HTS) is often required in enzyme inhibitor drugs screening. Mass spectrometry (MS) provides a powerful method for high-throughput screening enzyme inhibitors because its high speed, sensitivity and property of lable free. However, most of the MS methods need complicated sampling interface system. Overall throughput was limited by sample loading in these cases. In this study, we develop a simple interface which coupled droplet segmented system to a venturi easy ambient sonic-spray ionization mass spectrometer. It is fabricated by using a single capillary to act as both sampling probe and the emitter, which simplifies the construction, reduces the cost and shorten the sampling time. Samples sucked by venturi effect are segmented to nanoliter plugs by air, then the plugs can be detected by MS directly. This system eliminated the need for flow injection which was popular used in classic scheme. The new system is applied to screen angiotensin converting enzyme inhibitors. High-throughput was achieved in analyzing 96 samples at 1.6 s per sample. The plugs formation was at 0.5s per sample. Carry-over between samples was less than 5%, the peak height RSD was 2.92% (n = 15). Dose-response curves of 3 known inhibitors were also measured to validate its potential in drug discovery. The calculated IC50 agreed well with reported values. PMID- 26944991 TI - Preparation and evaluation of a novel molecularly imprinted polymer coating for selective extraction of indomethacin from biological samples by electrochemically controlled in-tube solid phase microextraction. AB - In the present work, an automated on-line electrochemically controlled in-tube solid-phase microextraction (EC-in-tube SPME) coupled with HPLC-UV was developed for the selective extraction and preconcentration of indomethacin as a model analyte in biological samples. Applying an electrical potential can improve the extraction efficiency and provide more convenient manipulation of different properties of the extraction system including selectivity, clean-up, rate, and efficiency. For more enhancement of the selectivity and applicability of this method, a novel molecularly imprinted polymer coated tube was prepared and applied for extraction of indomethacin. For this purpose, nanostructured copolymer coating consisting of polypyrrole doped with ethylene glycol dimethacrylate was prepared on the inner surface of a stainless-steel tube by electrochemical synthesis. The characteristics and application of the tubes were investigated. Electron microscopy provided a cross linked porous surface and the average thickness of the MIP coating was 45 MUm. Compared with the non-imprinted polymer coated tubes, the special selectivity for indomethacin was discovered with the molecularly imprinted coated tube. Moreover, stable and reproducible responses were obtained without being considerably influenced by interferences commonly existing in biological samples. Under the optimal conditions, the limits of detection were in the range of 0.07-2.0 MUg L(-1) in different matrices. This method showed good linearity for indomethacin in the range of 0.1-200 MUg L(-1), with coefficients of determination better than 0.996. The inter- and intra-assay precisions (RSD%, n = 3) were respectively in the range of 3.5-8.4% and 2.3-7.6% at three concentration levels of 7, 70 and 150 MUg L(-1). The results showed that the proposed method can be successfully applied for selective analysis of indomethacin in biological samples. PMID- 26944993 TI - Uranium aqueous speciation in the vicinity of the former uranium mining sites using the diffusive gradients in thin films and ultrafiltration techniques. AB - The performance of the Diffusive Gradients in Thin films (DGT) technique with Chelex((r))-100, MetsorbTM and Diphonix((r)) as binding phases was evaluated in the vicinity of the former uranium mining sites of Chardon and L'Ecarpiere (Loire Atlantique department in western France). This is the first time that the DGT technique with three different binding agents was employed for the aqueous U determination in the context of uranium mining environments. The fractionation and speciation of uranium were investigated using a multi-methodological approach using filtration (0.45 MUm, 0.2 MUm), ultrafiltration (500 kDa, 100 kDa and 10 kDa) coupled to geochemical speciation modelling (PhreeQC) and the DGT technique. The ultrafiltration data showed that at each sampling point uranium was present mostly in the 10 kDa truly dissolved fraction and the geochemical modelling speciation calculations indicated that U speciation was markedly predominated by CaUO2(CO3)3(2-). In natural waters, no significant difference was observed in terms of U uptake between Chelex((r))-100 and MetsorbTM, while similar or inferior U uptake was observed on Diphonix((r)) resin. In turn, at mining influenced sampling spots, the U accumulation on DGT-Diphonix((r)) was higher than on DGT-Chelex((r))-100 and DGT-MetsorbTM, probably because their performance was disturbed by the extreme composition of the mining waters. The use of Diphonix((r)) resin leads to a significant advance in the application and development of the DGT technique for determination of U in mining influenced environments. This investigation demonstrated that such multi-technique approach provides a better picture of U speciation and enables to assess more accurately the potentially bioavailable U pool. PMID- 26944995 TI - Kernel principal component analysis residual diagnosis (KPCARD): An automated method for cosmic ray artifact removal in Raman spectra. AB - A new, fully automated, rapid method, referred to as kernel principal component analysis residual diagnosis (KPCARD), is proposed for removing cosmic ray artifacts (CRAs) in Raman spectra, and in particular for large Raman imaging datasets. KPCARD identifies CRAs via a statistical analysis of the residuals obtained at each wavenumber in the spectra. The method utilizes the stochastic nature of CRAs; therefore, the most significant components in principal component analysis (PCA) of large numbers of Raman spectra should not contain any CRAs. The process worked by first implementing kernel PCA (kPCA) on all the Raman mapping data and second accurately estimating the inter- and intra-spectrum noise to generate two threshold values. CRA identification was then achieved by using the threshold values to evaluate the residuals for each spectrum and assess if a CRA was present. CRA correction was achieved by spectral replacement where, the nearest neighbor (NN) spectrum, most spectroscopically similar to the CRA contaminated spectrum and principal components (PCs) obtained by kPCA were both used to generate a robust, best curve fit to the CRA contaminated spectrum. This best fit spectrum then replaced the CRA contaminated spectrum in the dataset. KPCARD efficacy was demonstrated by using simulated data and real Raman spectra collected from solid-state materials. The results showed that KPCARD was fast (<1 min per 8400 spectra), accurate, precise, and suitable for the automated correction of very large (>1 million) Raman datasets. PMID- 26944994 TI - Protein-bound tyrosine oxidation, nitration and chlorination by-products assessed by ultraperformance liquid chromatography coupled to tandem mass spectrometry. AB - BACKGROUND: Free radicals cause alterations in cellular protein structure and function. Oxidized, nitrated, and chlorinated modifications of aromatic amino acids including phenylalanine and tyrosine are reliable biomarkers of oxidative stress and inflammation in clinical conditions. OBJECTIVE: To develop, validate and apply a rapid method for the quantification of known hallmarks of tyrosine oxidation, nitration and chlorination in plasma and tissue proteins providing a snapshot of the oxidative stress and inflammatory status of the organism and of target organs respectively. MATERIAL AND METHODS: The extraction and clean up procedure entailed protein precipitation, followed by protein re-suspension and enzymatic digestion with pronase. An Ultra Performance Liquid Chromatography tandem Mass Spectrometry (UPLC-MS/MS) method was developed to quantify protein released ortho-tyrosine (o-Tyr), meta-tyrosine (m-Tyr), 3-nitrotyrosine (3NO2 Tyr) and 3-chlorotyrosine (3Cl-Tyr) as well as native phenylalanine (Phe) and tyrosine (p-Tyr) in plasma and tissue from a validated hypoxic newborn piglet experimental model. RESULTS: In plasma there was a significant increase in the 3NO2-Tyr/p-Tyr ratio. On the other hand m-Tyr/Phe and 3Cl-Tyr/p-Tyr ratios were significantly increased in liver of hypoxic compared with normoxic animals. Although no significant differences were found in brain tissue, a clear tendency to increased ratios was observed under hypoxic conditions. CONCLUSIONS: UPLC MS/MS has proven suitable for the analysis of plasma and tissue samples from newborn piglets. The analysis of biomarkers of protein oxidation, nitration and chlorination will be applied in future studies aiming to provide a deeper insight into the mechanisms of oxidation-derived protein modification caused during neonatal asphyxia and resuscitation. PMID- 26944996 TI - Silver nanoparticles coated graphene electrochemical sensor for the ultrasensitive analysis of avian influenza virus H7. AB - A new, highly sensitive electrochemical immunosensor with a sandwich-type immunoassay format was designed to quantify avian influenza virus H7 (AIV H7) by using silver nanoparticle-graphene (AgNPs-G) as trace labels in clinical immunoassays. The device consists of a gold electrode coated with gold nanoparticle-graphene nanocomposites (AuNPs-G), the gold nanoparticle surface of which can be further modified with H7-monoclonal antibodies (MAbs). The immunoassay was performed with H7-polyclonal antibodies (PAbs) that were attached to the AgNPs-G surface (PAb-AgNPs-G). This method of using PAb-AgNPs-G as detection antibodies shows high signal amplification and exhibits a dynamic working range of 1.6 * 10(-3)~16 ng/mL, with a low detection limit of 1.6 pg/mL at a signal-to-noise ratio of 3sigma. In summary, we showed that this novel immunosensor is highly specific and sensitive to AIV H7, and the established assay could potentially be applied to rapidly detect other pathogenic microorganisms. PMID- 26944997 TI - Direct growth of MnOOH nanorod arrays on a carbon cloth for high-performance non enzymatic hydrogen peroxide sensing. AB - Novel MnOOH nanorod arrays directly growing on a flexible carbon cloth substrate (MnOOH/CC) is first synthesized through a facile hydrothermal technique and utilized as an electrocatalyst for non-enzymatic detection of hydrogen peroxide. The as-prepared MnOOH nanorods are uniformly distributed on the carbon cloth with a 3D porous network structure, which provides a high specific surface area and numerous electroactive sites. The electrode based on the carbon cloth-supported MnOOH nanorod arrays exhibits a higher sensitivity (692.42 MUA mM(-1) cm(-2)) and a wider linear range (20 MUm-9.67 mM) with a detection limit of 3.2 MUM (S/N = 3) compared with the electrode based on the rigid graphite substrate supported the random distributed MnOOH nanorods. Further, the MnOOH/CC possesses an outstanding flexibility and can conveniently be assembled into the required shape for a specific use, thus the arc-shaped MnOOH/CC electrodes are fabricated whose electrocatalytic activity toward the hydrogen peroxide reduction remains nearly unchanged in comparison with the unbent state. Due to its excellent sensitivity, reproducibility, anti-interference and stability, the electrode based on the carbon cloth-supported MnOOH nanorod arrays is believed to be promising for applications in high efficiency flexible hydrogen peroxide sensing. PMID- 26944999 TI - Metabolite profiling of licorice (Glycyrrhiza glabra) from different locations using comprehensive two-dimensional liquid chromatography coupled to diode array and tandem mass spectrometry detection. AB - Profiling of the main metabolites from several licorice (Glycyrrhiza glabra) samples collected at different locations is carried out in this work by using comprehensive two-dimensional liquid chromatography (LC * LC) coupled to diode array (DAD) and mass spectrometry (MS) detectors. The optimized method was based on the application of a HILIC-based separation in the first dimension combined with fast RP-based second dimension separation. This set-up was shown to possess powerful separation capabilities allowing separating as much as 89 different metabolites in a single sample. Identification and grouping of metabolites according to their chemical class were achieved using the DAD, MS and MS/MS data. Triterpene saponins were the most abundant metabolites followed by glycosylated flavanones and chalcones, whereas glycyrrhizic acid, as expected, was confirmed as the main component in all the studied samples. LC * LC-DAD-MS/MS was able to resolve these complex licorice samples providing with specific metabolite profiles to the different licorice samples depending on their geographical origin. Namely, from 19 to 50 specific compounds were exclusively determined in the 2D-chromatograms from the different licorice samples depending on their geographical origin, which can be used as a typical pattern that could potentially be related to their geographical location and authentication. PMID- 26945000 TI - Extension of the two-dimensional mass channel cluster plot method to fast separations utilizing low thermal mass gas chromatography with time-of-flight mass spectrometry. AB - Implementation of a data reduction and visualization method for use with high speed gas chromatography and time-of-flight mass spectrometry (GC-TOFMS) is reported. The method, called the "2D m/z cluster method" facilitates analyte detection, deconvolution, and identification, by accurately measuring peak widths and retention times using a fast TOFMS sampling frequency (500 Hz). Characteristics and requirements for high speed GC are taken into consideration: fast separations with narrow peak widths and high peak capacity, rapid data collection rate, and effective peak deconvolution. Transitioning from standard GC (10-60+ minute separations) to fast GC (1-10 min separations) required consideration of how to properly analyze the data. This report validates use of the 2D m/z cluster method with newly developed GC technology that produces ultra fast separations (~1 min) with narrow analyte peak widths. Low thermal mass gas chromatography (LTM-GC) operated at a heating rate of 250 degrees C/min coupled to a LECO Pegasus III TOFMS analyzed a 115 component test mixture in 120 s with peak widths-at-base, wb (4sigma), of 350 ms (average) to produce a separation with a high peak capacity, nc ~ 340 (at unit resolution Rs = 1). The 2D m/z cluster method is shown to separate overlapped analytes to a limiting Rs ~ 0.03, so the effective peak capacity was increased nearly 30-fold to nc ~10,000 in the 120 s separation. The method, when coupled with LTM-GC-TOFMS, is demonstrated to provide unambiguous peak rank (i.e. the number of analytes per overlapped peak in the total ion current (TIC)), by visualizing locations of pure and chromatographically overlapped m/z. Hence, peak deconvolution and identification using MCR-ALS (multivariate curve resolution - alternating least squares) is demonstrated. PMID- 26944998 TI - Gold nanostar-enhanced surface plasmon resonance biosensor based on carboxyl functionalized graphene oxide. AB - A new high-sensitivity surface plasmon resonance (SPR) biosensor based on biofunctional gold nanostars (AuNSs) and carboxyl-functionalized graphene oxide (cGO) sheets was described. Compared with spherical gold nanoparticles (AuNPs), the anisotropic structure of AuNSs, which concentrates the electric charge density on its sharp tips, could enhance the local electromagnetic field and the electronic coupling effect significantly. cGO was obtained by a diazonium reaction of graphene oxide (GO) with 4-aminobenzoic acid. Compared with GO, cGO could immobilize more antibodies due to the abundant carboxylic groups on its surface. Testing results show that there are fairly large improvements in the analytical performance of the SPR biosensor using cGO/AuNSs-antigen conjugate, and the detection limit of the proposed biosensor is 0.0375 MUg mL(-1), which is 32 times lower than that of graphene oxide-based biosensor. PMID- 26945001 TI - Can Doctors Maintain Good Character? An Examination of Physician Lives. AB - Can doctors maintain good character? This paper shifts the focus from patient care to ethical considerations that bear on the physician and impact her as a person. By decentering patient care, the paper highlights certain factors that habituate a particular way of reasoning that is not conducive to inculcating good character. Such factors include, standards of professionalism, being influenced by external monitors, and emphasis on adherence to guidelines. While such factors may benefit patients, they often adversely affect the character of physicians. PMID- 26945002 TI - Two Canine Papillomaviruses Associated With Metastatic Squamous Cell Carcinoma in Two Related Basenji Dogs. AB - Papillomaviruses (PV) are associated with benign mucosal and cutaneous epithelial proliferations. In dogs, PV-associated pigmented plaques and papillomas can undergo malignant transformation, but this is rare, and most cases of canine squamous cell carcinoma do not arise from PV-induced precursor lesions. We describe herein the progression of pigmented plaques to invasive and metastatic squamous cell carcinoma associated with 2 canine papillomaviruses (CPV) in 2 related Basenji dogs. Immunohistochemistry for PV antigen revealed strong nuclear immunoreactivity within keratinocytes from pigmented plaques from both dogs, consistent with a productive viral infection. Polymerase chain reaction (PCR) using degenerate primers for the L1 gene revealed PV DNA sequences from 2 different CPVs. In situ hybridization for CPV revealed strong hybridization signals within the pigmented plaques and neoplastic squamous epithelial cells from both dogs. We report here progression of PV-associated pigmented plaques to metastatic squamous cell carcinoma within 2 Basenji dogs associated with 2 different CPVs. PMID- 26945003 TI - Regulatory T Cells and Their Role in Animal Disease. AB - In humans and mouse models, Foxp3(+) regulatory T cells are known to control all aspects of immune responses. However, only limited information exists on these cells' role in diseases of other animals. In this review, we cover the most important features and different types of regulatory T cells, which include those that are thymus-derived and peripherally induced, the mechanisms by which they control immune responses by targeting effector T cells and antigen-presenting cells, and most important, their role in animal health and diseases including cancer, infections, and other conditions such as hypersensitivities and autoimmunity. Although the literature regarding regulatory T cells in domestic animal species is still limited, multiple articles have recently emerged and are discussed. Moreover, we also discuss the evidence suggesting that regulatory T cells might limit the magnitude of effector responses, which can have either a positive or negative result, depending on the context of animal and human disease. In addition, the issue of plasticity is discussed because plasticity in regulatory T cells can result in the loss of their protective function in some microenvironments during disease. Lastly, the manipulation of regulatory T cells is discussed in assessing the possibility of their use as a treatment in the future. PMID- 26945004 TI - Postmortem Changes in Animal Carcasses and Estimation of the Postmortem Interval. AB - A thorough understanding of the physical and chemical changes that occur in the body after death is critical for accurate interpretation of gross and microscopic pathology at autopsy. Furthermore, knowledge of the postmortem processes and the factors that affect them will aid in the estimation of the postmortem interval (PMI). The estimation of the PMI is important in many human and animal death investigations. Despite many decades of research, accuracy in estimation of the time of death has not significantly improved, and no single method can be reliably used to accurately estimate the time of death. Great care should be taken when formulating such an estimate, for it is dependent on multiple circumstantial and environmental factors, and the accuracy and precision of the estimate decrease as the PMI increases. The majority of the research in the field has been conducted on human bodies, but many relevant conclusions may be drawn regarding the expected postmortem changes in animals and the estimation of the PMI. The veterinary pathologist must use great caution when attempting to extrapolate data and apply formulas designed for use in humans. Methods reviewed include gross changes, microscopic changes, temperature-based methods, postmortem chemistry, molecular methods, microbial assay, ocular changes, radiography, entomology, and others. Although only several of these methods are currently practical for use in the workup of cases, it is expected that future research will result in improved techniques with enhanced accuracy in the estimation of the PMI, which will benefit both human and veterinary forensic investigations. PMID- 26945005 TI - Trajectories of Personality Traits Preceding Dementia Diagnosis. AB - Background: Several retrospective studies using informant report have shown that individuals with dementia demonstrate considerable personality change. Two prospective studies, also using informant report, have shown that individuals who develop dementia show some personality changes prior to diagnosis. The current study is the first to assess personality trait change prior to dementia diagnosis using self-report measures from longitudinal data. Method: This study used data from the Swedish OCTO-Twin Study, a longitudinal panel of 702 twins aged 80 and older. Analysis was restricted to 86 individuals who completed the Eysenck Personality Inventory and received a dementia diagnosis during follow-up occasions. Latent growth curve analyses were used to examine trajectories of extraversion and neuroticism preceding dementia diagnosis. Results: Controlling for sex, age, education, depressive symptoms, and the interaction between age and education, growth curve analyses revealed a linear increase in neuroticism and stability in extraversion. Individuals who were eventually diagnosed with dementia showed a significant increase in neuroticism preceding diagnosis of dementia. Discussion: Personality change, specifically an increase in neuroticism, may be an early indicator of dementia. Identification of early indicators of dementia may facilitate development of screening assessments and aid in early care strategies and planning. PMID- 26945006 TI - Stable, Nonviral Expression of Mutated Tumor Neoantigen-specific T-cell Receptors Using the Sleeping Beauty Transposon/Transposase System. AB - Neoantigens unique to each patient's tumor can be recognized by autologous T cells through their T-cell receptor (TCR) but the low frequency and/or terminal differentiation of mutation-specific T cells in tumors can limit their utility as adoptive T-cell therapies. Transfer of TCR genes into younger T cells from peripheral blood with a high proliferative potential could obviate this problem. We generated a rapid, cost-effective strategy to genetically engineer cancer patient T cells with TCRs using the clinical Sleeping Beauty transposon/transposase system. Patient-specific TCRs reactive against HLA-A*0201 restriced neoantigens AHNAK(S2580F) or ERBB2(H473Y) or the HLA-DQB*0601 restricted neoantigen ERBB2IP(E805G) were assembled with murine constant chains and cloned into Sleeping Beauty transposons. Patient peripheral blood lymphocytes were coelectroporated with SB11 transposase and Sleeping Beauty transposon, and transposed T cells were enriched by sorting on murine TCRbeta (mTCRbeta) expression. Rapid expansion of mTCRbeta(+) T cells with irradiated allogeneic peripheral blood lymphocytes feeders, OKT3, interleukin-2 (IL-2), IL-15, and IL 21 resulted in a preponderance of effector (CD27(-)CD45RA(-)) and less differentiated (CD27(+)CD45RA(+)) T cells. Transposed T cells specifically mounted a polyfunctional response against cognate mutated neoantigens and tumor cell lines. Thus, Sleeping Beauty transposition of mutation-specific TCRs can facilitate the use of personalized T-cell therapy targeting unique neoantigens. PMID- 26945007 TI - Germline ESR2 mutation predisposes to medullary thyroid carcinoma and causes up regulation of RET expression. AB - Familial medullary thyroid cancer (MTC) and its precursor, C cell hyperplasia (CCH), is associated with germline RET mutations causing multiple endocrine neoplasia type 2. However, some rare families with apparent MTC/CCH predisposition do not have a detectable RET mutation. To identify novel MTC/CCH predisposition genes we undertook exome resequencing studies in a family with apparent predisposition to MTC/CCH and no identifiable RET mutation. We identified a novel ESR2 frameshift mutation, c.948delT, which segregated with histological diagnosis following thyroid surgery in family members and demonstrated loss of ESR2-encoded ERbeta expression in the MTC tumour. ERalpha and ERbeta form heterodimers binding DNA at specific oestrogen-responsive elements (EREs) to regulate gene transcription. ERbeta represses ERalpha-mediated activation of the ERE and the RET promoter contains three EREs. In vitro, we showed that ESR2 c.948delT results in unopposed ERalpha mediated increased cellular proliferation, activation of the ERE and increased RET expression. In vivo, immunostaining of CCH and MTC using an anti-RET antibody demonstrated increased RET expression. Together these findings identify germline ESR2 mutation as a novel cause of familial MTC/CCH and provide important insights into a novel mechanism causing increased RET expression in tumourigenesis. PMID- 26945009 TI - Breast cancer genetic risk profile is differentially associated with interval and screen-detected breast cancers. PMID- 26945008 TI - A single amino acid change in the hypervariable region 1 of hepatitis C virus genotype 4a aids humoral immune escape. AB - Longitudinal analysis of chronic hepatitis C virus (HCV) infection has shown that the virus has several adaptive strategies that maintain persistence and infectivity over time. We examined four serum samples from the same chronically infected HCV genotype 4a patient for the presence of IgG antibody-associated virus. RNA was isolated from antibody-associated and antibody-free virions. Subsequent to sequence analysis, 27 aa hypervariable region 1 (HVR1) peptides were used to test the humoral immune escape. We demonstrated that differential peptide binding of Fab was associated with a single amino acid change. We provide direct evidence of natural humoral immune escape by HCV within HVR1. PMID- 26945010 TI - A phase II/III randomized study to compare the efficacy and safety of rigosertib plus gemcitabine versus gemcitabine alone in patients with previously untreated metastatic pancreatic cancer. PMID- 26945011 TI - The caregiver burden in male romantic partners of women with non-metastatic breast cancer: The protective role of couple satisfaction. AB - We examined the evolution of the subjective burden of romantic partners caring for women with non-metastatic breast cancer and investigated the moderating role of couple satisfaction on caring stress. Forty-seven partners filled out questionnaires 3 and 12 months after surgery. Using a stress process model, we examined caring stressors and moderating factors (couple satisfaction, coping and social support) as predictors of subjective burden. Results showed that subjective burden decreases over time and that the couple satisfaction largely explains it above and beyond other influential variables. Partners dissatisfied with their couple relationship are especially vulnerable to the stress of caregiving. PMID- 26945012 TI - Human cerebrospinal fluid microRNA: temporal changes following subarachnoid hemorrhage. AB - Aneurysmal subarachnoid hemorrhage (aSAH) is a devastating form of hemorrhagic stroke with 30-day mortality between 33 and 45%. Delayed cerebral ischemia (DCI) is the chief cause of morbidity and mortality in patients who survive the initial aSAH. DCI accounts for almost 50% of deaths in patients surviving to treatment of the ruptured aneurysm. The mechanisms for brain injury after aSAH and the brain's response to this injury are not fully understood in humans. MicroRNAs (miRs) are 22- to 25-nucleotide single-stranded RNA molecules that inhibit the expression of specific messenger RNA targets. In this work, miR profiling of human cerebrospinal fluid from eight patients after aSAH was performed daily for 10 days with the goal of identifying changes in miR abundance. Using the nanoString nCounter Expression Assay, we identified two specific clusters of miR that were differentially regulated over time. Quantitative RT-PCR was performed on select miRs from each cluster. The first cluster contained miRs known to be present in blood and decreased in abundance over time. miRs in this group include miR-92a and let-7b. The second cluster contained several poorly characterized miRs that increased in abundance over time. miRs in this group included miR-491. This second cluster of miRs may be released into the CSF by the brain itself as a result of the initial SAH. Temporal changes in the abundance of specific miRs in human CSF after aSAH may provide novel insight into the role of miRs in brain injury and the brain's response. PMID- 26945014 TI - Healthcare leaders urge Hunt to resume talks on juniors' contract. PMID- 26945013 TI - Time Is of the Essence: The Impact of Delayed Antibiotic Therapy on Patient Outcomes in Hospital-Onset Enterococcal Bloodstream Infections. AB - BACKGROUND: With increasing prevalence of vancomycin-resistant enterococci (VRE), appropriate antibiotic therapy for enterococcal bloodstream infections (EBSI) can be delayed. Data regarding the impact of delayed therapy on EBSI outcomes are conflicting, and the time delay most strongly associated with poor outcomes has not been defined. METHODS: This was a single-center, retrospective cohort study of adult, nonneutropenic patients with hospital-onset EBSI from 2010 to 2014. Classification and regression tree (CART) analysis was used to determine the delay in appropriate therapy most predictive of 30-day mortality. Appropriate therapy was defined as antibiotic therapy to which the enterococci and copathogen, where applicable, were susceptible. Outcomes and clinical characteristics were compared between patients receiving early or delayed therapy, defined by CART timepoint. Poisson regression was employed to determine the independent association of delayed therapy on 30-day mortality and predictors of delayed therapy. RESULTS: Overall, 190 patients were included. A breakpoint in time to appropriate therapy was identified at 48.1 hours, where 30-day mortality was substantially increased (14.6% vs 45.3%; P < .001). Patients receiving appropriate therapy after 48.1 hours also experienced higher in-hospital mortality and longer EBSI duration. After adjustment for severity of illness and comorbidity, delayed therapy >=48.1 hours was associated with a 3-fold increase in 30-day mortality (risk ratio, 3.16 [95% confidence interval, 1.96-5.09]). Vancomycin resistance was the only independent predictor of delayed therapy. CONCLUSIONS: In patients with hospital-onset EBSI, receipt of appropriate therapy within the first 48 hours was associated with reduced mortality, underscoring the potential role of rapid diagnostic testing for early identification of VRE. PMID- 26945015 TI - The direct interaction of NME3 with Tip60 in DNA repair. AB - Cellular supply of dNTPs via RNR (ribonucleotide reductase) is crucial for DNA replication and repair. It has been shown that DNA-damage-site-specific recruitment of RNR is critical for DNA repair efficiency in quiescent cells. The catalytic function of RNR produces dNDPs. The subsequent step of dNTP formation requires the function of NDP kinase. There are ten isoforms of NDP kinase in human cells. In the present study, we identified NME3 as one specific NDP kinase that interacts directly with Tip60, a histone acetyltransferase, to form a complex with RNR. Our data reveal that NME3 recruitment to DNA damage sites depends on this interaction. Disruption of interaction of NME3 with Tip60 suppressed DNA repair in serum-deprived cells. Thus Tip60 interacts with RNR and NME3 to provide site-specific synthesis of dNTP for facilitating DNA repair in serum-deprived cells which contain low levels of dNTPs. PMID- 26945016 TI - Effects of Progressive Muscle Relaxation Therapy in Colorectal Cancer Patients. AB - This study aimed to examine the effect of progressive muscle relaxation therapy (PMRT) on cortisol level, the Stress Arousal Checklist (SACL) score, blood pressure, and heart rate in colorectal cancer patients undergoing laparoscopic surgery. Forty-six patients were divided into control and experimental groups. Cortisol levels, blood pressure, and heart rate were measured before surgery and between 8:00 and 11:00 a.m. on the first, third, and fifth days after surgery. SACL score was measured before surgery and on the fifth day after surgery at the same time points. PMRT was performed twice a day for 5 days. Analyses of covariance with advanced covariate levels and t tests showed that PMRT helps colorectal cancer patients achieve a lower stress response and provides an important basis for stress control. PMID- 26945018 TI - Hourly analysis of cerebrospinal fluid glucose shows large diurnal fluctuations. AB - Cerebrospinal fluid analysis is important in the diagnostics of many neurological disorders. Since the influence of food intake on the cerebrospinal fluid glucose concentration and the cerebrospinal fluid/plasma glucose ratio is largely unknown, we studied fluctuations in these parameters in healthy adult volunteers during a period of 36 h. Our observations show large physiological fluctuations of cerebrospinal fluid glucose and the cerebrospinal fluid/plasma glucose ratio, and their relation to food intake. These findings provide novel insights into the physiology of cerebral processes dependent on glucose levels such as energy formation (e.g. glycolysis), enzymatic reactions (e.g. glycosylation), and non enzymatic reactions (e.g. advanced endproduct glycation). PMID- 26945017 TI - Gut microbiota impact on stroke outcome: Fad or fact? AB - Microbiota and its contribution to brain function and diseases has become a hot topic in neuroscience. We discuss the emerging role of commensal bacteria in the course of stroke. Further, we review potential pitfalls in microbiota research and their impact on how we interpret the available evidence, emerging results, and on how we design future studies. PMID- 26945020 TI - Preexisting Rotator Cuff Tears as a Predictor of Outcomes in National Football League Athletes. AB - BACKGROUND: A preexisting rotator cuff tear may affect the draft status and career performance of National Football League (NFL) players. HYPOTHESIS: Preexisting rotator cuff tears decrease a player's draft status, performance, and longevity in the NFL. STUDY DESIGN: Retrospective cohort study. LEVEL OF EVIDENCE: Level 3. METHODS: Medical reports of prospective NFL players during the NFL Scouting Combine from 2003 to 2011 were evaluated to identify players with a previous rotator cuff tear. Athletes were matched to control draftees without documented shoulder pathology by age, position, year drafted, and round drafted. Career statistics and performance scores were calculated. RESULTS: Between 2003 and 2011, 2965 consecutive athletes were evaluated. Forty-nine athletes had preexisting rotator cuff tears: 22 athletes underwent surgical intervention for their tear and 27 were treated nonoperatively. Those with a rotator cuff tear were significantly less likely to be drafted than those without a previous injury (55.1% vs 77.5%, P = 0.002). The 27 drafted athletes with preexisting rotator cuff tears started significantly fewer games (23.7 vs 43.0, P = 0.02) and played significantly fewer years (4.3 vs 5.7, P = 0.04) and significantly fewer games (47.1 vs 68.4, P = 0.04) than matched control athletes without rotator cuff tears. CONCLUSION: Athletes with a preexisting rotator cuff tear were less likely to be drafted and had decreased career longevity. PMID- 26945019 TI - Comparison of cerebral blood flow measurement with [15O]-water positron emission tomography and arterial spin labeling magnetic resonance imaging: A systematic review. AB - Noninvasive imaging of cerebral blood flow provides critical information to understand normal brain physiology as well as to identify and manage patients with neurological disorders. To date, the reference standard for cerebral blood flow measurements is considered to be positron emission tomography using injection of the [(15)O]-water radiotracer. Although [(15)O]-water has been used to study brain perfusion under normal and pathological conditions, it is not widely used in clinical settings due to the need for an on-site cyclotron, the invasive nature of arterial blood sampling, and experimental complexity. As an alternative, arterial spin labeling is a promising magnetic resonance imaging technique that magnetically labels arterial blood as it flows into the brain to map cerebral blood flow. As arterial spin labeling becomes more widely adopted in research and clinical settings, efforts have sought to standardize the method and validate its cerebral blood flow values against positron emission tomography based cerebral blood flow measurements. The purpose of this work is to critically review studies that performed both [(15)O]-water positron emission tomography and arterial spin labeling to measure brain perfusion, with the aim of better understanding the accuracy and reproducibility of arterial spin labeling relative to the positron emission tomography reference standard. PMID- 26945021 TI - Improving Diagnostic Accuracy and Efficiency of Suspected Bone Stress Injuries. AB - CONTEXT: Lower extremity stress fractures among athletes and military recruits cause significant morbidity, fiscal costs, and time lost from sport or training. During fiscal years (FY) 2012 to 2014, 1218 US Air Force trainees at Joint Base San Antonio-Lackland, Texas, were diagnosed with stress fracture(s). Diagnosis relied heavily on bone scans, often very early in clinical course and often in preference to magnetic resonance imaging (MRI), highlighting the need for an evidence-based algorithm for stress injury diagnosis and initial management. EVIDENCE ACQUISITION: To guide creation of an evidence-based algorithm, a literature review was conducted followed by analysis of local data. Relevant articles published between 1995 and 2015 were identified and reviewed on PubMed using search terms stress fracture, stress injury, stress fracture imaging, and stress fracture treatment. Subsequently, charts were reviewed for all Air Force trainees diagnosed with 1 or more stress injury in their outpatient medical record in FY 2014. STUDY DESIGN: Clinical review. LEVEL OF EVIDENCE: Level 4. RESULTS: In FY 2014, 414 trainees received a bone scan and an eventual diagnosis of stress fracture. Of these scans, 66.4% demonstrated a stress fracture in the symptomatic location only, 21.0% revealed stress fractures in both symptomatic and asymptomatic locations, and 5.8% were negative in the symptomatic location but did reveal stress fracture(s) in asymptomatic locations. Twenty-one percent (18/85) of MRIs performed a mean 6 days (range, 0- 21 days) after a positive bone scan did not demonstrate any stress fracture. CONCLUSION: Bone stress injuries in military training environments are common, costly, and challenging to diagnose. MRI should be the imaging study of choice, after plain radiography, in those individuals meeting criteria for further workup. PMID- 26945023 TI - The contribution of antiphospholipid antibodies to organ damage in systemic lupus erythematosus. AB - OBJECTIVES: The objective of this study was to assess the contribution of clinically significant antiphospholipid antibodies (aPL) to organ damage in systemic lupus erythematosus (SLE). METHODS: Patients with disease duration of less than 10 years and at least 5 years of follow-up were identified from two SLE registries. A clinically significant antiphospholipid antibody (aPL) profile was defined as: positive lupus anticoagulant, anticardiolipin IgG/M >= 40 G phospholipid units (GPL)/M phospholipid units (MPL), and/or anti-beta2 glycoprotein-I IgG/M >= 99th percentile on two or more occasions, at least 12 weeks apart. Organ damage was assessed by the Systemic Lupus International Collaborating Clinics Damage Index (SDI). Univariate and multivariate analysis compared SLE patients with and without SDI increase during a 15-year follow-up. RESULTS: Among 262 SLE patients, 33% had a clinically significant aPL profile, which was associated with an increased risk of organ damage accrual during a 5 year follow-up in univariate analysis, and during a 15-year follow-up in the multivariate analysis adjusting for age, gender, race, disease duration at registry entry, and time. In the multivariate analysis, older age at diagnosis and male gender were also associated with SDI increase at each time point. CONCLUSION: A clinically significant aPL profile is associated with an increased risk of organ damage accrual during a 15-year follow-up in SLE patients. PMID- 26945024 TI - Do polypills lead to neglect of lifestyle risk factors? Findings from an individual participant data meta-analysis among 3140 patients at high risk of cardiovascular disease. AB - AIM: The aim of this study was to investigate whether polypill-based care for the prevention of cardiovascular disease (CVD) is associated with a change in lifestyle risk factors when compared with usual care, among patients with CVD or high calculated cardiovascular risk. METHODS: We conducted an individual participant data meta-analysis of three trials including patients from Australia, England, India, Ireland, the Netherlands and New Zealand that compared a strategy using a polypill containing aspirin, statin and antihypertensive therapy with usual care in patients with a prior CVD event or who were at high risk of their first event. Analyses investigated any differential effect on anthropometric measures and self-reported lifestyle behaviours. RESULTS: Among 3140 patients (75% male, mean age 62 years and 76% with a prior CVD event) there was no difference in lifestyle risk factors in those randomised to polypill-based care compared with usual care over a median of 15 months, either across all participants combined, or in a range of subgroups. Furthermore, narrow confidence intervals (CIs) excluded any major effect; for example differences between the groups in body mass index was -0.1 (95% CI -0.2 to 0.1) kg/m(2), in weekly duration of moderate intensity physical activity was -2 (-26 to 23) minutes and the proportion of smokers was 16% vs 17% (RR 0.98, 0.84 to 1.15) at the end of trial. DISCUSSION: This analysis allays concern that polypill-based care may lead to neglect of lifestyle risk factors, at least among high-risk patients. Maximally effective preventive approaches should address lifestyle factors alongside pharmaceutical interventions, as recommended by major international guidelines. PMID- 26945022 TI - Fragment C Domain of Tetanus Toxin Mitigates Methamphetamine Neurotoxicity and Its Motor Consequences in Mice. AB - BACKGROUND: The C-terminal domain of the heavy chain of tetanus toxin (Hc-TeTx) is a nontoxic peptide with demonstrated in vitro and in vivo neuroprotective effects against striatal dopaminergic damage induced by 1-methyl-4 phenylpyridinium and 6-hydoxydopamine, suggesting its possible therapeutic potential in Parkinson's disease. Methamphetamine, a widely abused psychostimulant, has selective dopaminergic neurotoxicity in rodents, monkeys, and humans. This study was undertaken to determine whether Hc-TeTx might also protect against methamphetamine-induced dopaminergic neurotoxicity and the consequent motor impairment. METHODS: For this purpose, we treated mice with a toxic regimen of methamphetamine (4mg/kg, 3 consecutive i.p. injections, 3 hours apart) followed by 3 injections of 40 ug/kg of Hc-TeTx into grastrocnemius muscle at 1, 24, and 48 hours post methamphetamine treatment. RESULTS: We found that Hc TeTx significantly reduced the loss of dopaminergic markers tyrosine hydroxylase and dopamine transporter and the increases in silver staining (a well stablished degeneration marker) induced by methamphetamine in the striatum. Moreover, Hc TeTx prevented the increase of neuronal nitric oxide synthase but did not affect microglia activation induced by methamphetamine. Stereological neuronal count in the substantia nigra indicated loss of tyrosine hydroxylase-positive neurons after methamphetamine that was partially prevented by Hc-TeTx. Importantly, impairment in motor behaviors post methamphetamine treatment were significantly reduced by Hc-TeTx. CONCLUSIONS: Here we demonstrate that Hc-TeTx can provide significant protection against acute methamphetamine-induced neurotoxicity and motor impairment, suggesting its therapeutic potential in methamphetamine abusers. PMID- 26945025 TI - Amino acids trigger down-regulation of superoxide via TORC pathway in the midgut of Rhodnius prolixus. AB - Sensing incoming nutrients is an important and critical event for intestinal cells to sustain life of the whole organism. The TORC is a major protein complex involved in monitoring the nutritional status and is activated by elevated amino acid concentrations. An important feature of haematophagy is that huge amounts of blood are ingested in a single meal, which results in the release of large quantities of amino acids, together with the haemoglobin prosthetic group, haem, which decomposes hydroperoxides and propagates oxygen-derived free radicals. Our previous studies demonstrated that reactive oxygen species (ROS) levels were diminished in the mitochondria and midgut of the Dengue fever mosquito, Aedes aegypti, immediately after a blood meal. We proposed that this mechanism serves to avoid oxidative damage that would otherwise be induced by haem following a blood meal. Studies also performed in mosquitoes have shown that blood or amino acids controls protein synthesis through TORC activation. It was already proposed, in different models, a link between ROS and TOR, however, little is known about TOR signalling in insect midgut nor about the involvement of ROS in this pathway. Here, we studied the effect of a blood meal on ROS production in the midgut of Rhodnius prolixus We observed that blood meal amino acids decreased ROS levels in the R. prolixus midgut immediately after feeding, via lowering mitochondrial superoxide production and involving the amino acid-sensing TORC pathway. PMID- 26945026 TI - Health professionals' and managers' definitions of developmentally appropriate healthcare for young people: conceptual dimensions and embedded controversies. AB - OBJECTIVES: We aimed to (i) explore how health professionals and managers who work with young people seek to define developmentally appropriate healthcare (DAH), (ii) identify the range of conceptual dimensions present in their definitions and (iii) explore the controversies embedded in their characterisations of DAH. METHODS: A qualitative multisite ethnographic study was conducted across three hospitals in England. We undertook face-to-face semi structured interviews with health professionals and managers; and non-participant observation in clinics, wards and meetings. Anonymised field notes and interview transcripts were analysed using thematic analysis. The theme 'conceptualisations of DAH' was then further analysed, and the resulting themes categorised to form conceptual dimensions. RESULTS: We recruited 192 participants and conducted 65 interviews (41 with health professionals and 24 with managers) and approximately 1600 hours of non-participant observations (involving 103 health professionals and 72 managers). Despite the wide range of definitions provided by participants, five conceptual dimensions of DAH were identified: (i) biopsychosocial development and holistic care, (ii) acknowledgement of young people as a distinct group, (iii) adjustment of care as the young person develops, (iv) empowerment of the young person by embedding health education and health promotion and (v) interdisciplinary and interorganisational work. Also, some controversies were identified within most dimensions. CONCLUSIONS: This study illustrates the lack of a generalised definition of DAH for young people among UK health professionals and managers, and presents a set of five core dimensions that can inform future research to help define and evaluate DAH for young people. PMID- 26945027 TI - Three-Dimensional Printing for Planning Occlusion Procedure for a Double-Lobed Left Atrial Appendage. PMID- 26945028 TI - Massive Amplification at an Unselected Locus Accompanies Complex Chromosomal Rearrangements in Yeast. AB - Gene amplification has been observed in different organisms in response to environmental constraints, such as limited nutrients or exposure to a variety of toxic compounds, conferring them with specific phenotypic adaptations via increased expression levels. However, the presence of multiple gene copies in natural genomes has generally not been found in the absence of specific functional selection. Here, we show that the massive amplification of a chromosomal locus (up to 880 copies per cell) occurs in the absence of any direct selection, and is associated with low-order amplifications of flanking segments in complex chromosomal alterations. These results were obtained from mutants with restored phenotypes that spontaneously appeared from genetically engineered strains of the yeast Saccharomyces cerevisiae suffering from severe fitness reduction. Grossly extended chromosomes (macrotene) were formed, with complex structural alterations but sufficient stability to propagate unchanged over successive generations. Their detailed molecular analysis, including complete genome sequencing, identification of sequence breakpoints, and comparisons between mutants, revealed novel mechanisms causing their formation, whose combined action underlies the astonishing dynamics of eukaryotic chromosomes and their consequences. PMID- 26945030 TI - Electroretinography and Visual Evoked Potentials in Childhood Brain Tumor Survivors. AB - This population-based cross-sectional study evaluates the clinical value of electroretinography and visual evoked potentials in childhood brain tumor survivors. A flash electroretinography and a checkerboard reversal pattern visual evoked potential (or alternatively a flash visual evoked potential) were done for 51 survivors (age 3.8-28.7 years) after a mean follow-up time of 7.6 (1.5-15.1) years. Abnormal electroretinography was obtained in 1 case, bilaterally delayed abnormal visual evoked potentials in 22/51 (43%) cases. Nine of 25 patients with infratentorial tumor location, and altogether 12 out of 31 (39%) patients who did not have tumors involving the visual pathways, had abnormal visual evoked potentials. Abnormal electroretinographies are rarely observed, but abnormal visual evoked potentials are common even without evident anatomic lesions in the visual pathway. Bilateral changes suggest a general and possibly multifactorial toxic/adverse effect on the visual pathway. Electroretinography and visual evoked potential may have clinical and scientific value while evaluating long-term effects of childhood brain tumors and tumor treatment. PMID- 26945029 TI - Mapping Challenging Mutations by Whole-Genome Sequencing. AB - Whole-genome sequencing provides a rapid and powerful method for identifying mutations on a global scale, and has spurred a renewed enthusiasm for classical genetic screens in model organisms. The most commonly characterized category of mutation consists of monogenic, recessive traits, due to their genetic tractability. Therefore, most of the mapping methods for mutation identification by whole-genome sequencing are directed toward alleles that fulfill those criteria (i.e., single-gene, homozygous variants). However, such approaches are not entirely suitable for the characterization of a variety of more challenging mutations, such as dominant and semidominant alleles or multigenic traits. Therefore, we have developed strategies for the identification of those classes of mutations, using polymorphism mapping in Caenorhabditis elegans as our model for validation. We also report an alternative approach for mutation identification from traditional recombinant crosses, and a solution to the technical challenge of sequencing sterile or terminally arrested strains where population size is limiting. The methods described herein extend the applicability of whole-genome sequencing to a broader spectrum of mutations, including classes that are difficult to map by traditional means. PMID- 26945031 TI - The substrate of increased cortical FA in MS: A 7T post-mortem MRI and histopathology study. AB - BACKGROUND: Using diffusion tensor imaging (DTI), it was previously found that demyelinated gray matter (GM) lesions have increased fractional anisotropy (FA) when compared to normal-appearing gray matter (NAGM) in multiple sclerosis (MS). The biological substrate underlying this FA change is so far unclear; both neurodegenerative changes and microglial activation have been proposed as causal contributors. OBJECTIVE: To test the proposed hypothesis that microglia activation is responsible for increased FA in cortical GM lesions. METHODS: We investigated post-mortem cortical DTI changes in hemispheric, coronally cut sections and investigated the underlying histopathology using immunohistochemistry. RESULTS: Overall, there were few activated microglia/macrophages, and no difference between GM lesions and NAGM was observed. However, cell density was increased in GM lesions compared to NAGM (309.67 +/- standard deviation (SD) 124.44 vs 249.95 +/- SD 56.75, p = 0.002). CONCLUSION: FA increase was not due to lesional and non-lesional differences in microglia activation and/or proliferation. We found an increase in general cellular density without a notable difference in cellular size, that is, tissue compaction, as a possible alternative explanation. PMID- 26945032 TI - TFG-Related Neurologic Disorders: New Insights Into Relationships Between Endoplasmic Reticulum and Neurodegeneration. AB - The tropomyosin-receptor kinase fused gene(TFG), which is located on chromosome 3q12.2, was originally identified as a fusion partner that results in the formation of oncogenic products associated with multiple cancers. TFG protein interacts directly with Sec16, the scaffolding protein for coat protein II-coated vesicles that regulate endoplasmic reticulum (ER)-to-Golgi transport at ER exit sites. In 2012, a heterozygous mutation of TFG was identified as the causative gene for autosomal-dominant hereditary motor and sensory neuropathy with proximal dominant involvement. In 2013, a homozygous mutation of TFG was reported in a family with early onset spastic paraplegia, optic atrophy, and neuropathy. Another novel mutation in TFG was discovered in 2014 as a cause of dominant axonal Charcot-Marie-Tooth disease type 2. These findings suggest that mutations of TFG cause ER dysfunction and neurodegeneration in this disease spectrum, which is tightly associated with ER function. Here, we review the clinical phenotypes of these diseases and present recent insights that suggest causal roles of ER dysfunction in TFG-related neurologic disorders. Although the precise pathogenetic mechanisms underlying these TFG mutations remain to be elucidated, experimental manipulations suggest that the dysregulations of ER homeostasis that occur due to mutations in TFG lead to neurodegeneration. PMID- 26945033 TI - Delayed Gelatinase Inhibition Induces Reticulon 4 Receptor Expression in the Peri Infarct Cortex. AB - Matrix metalloproteinase (MMP) inhibition can potentially prevent hemorrhagic transformation following cerebral infarction; however, delayed-phase MMP activity is also necessary for functional recovery after experimental stroke. We sought to identify potential mechanisms responsible for the impaired recovery associated with subacute MMP inhibition in a transient middle cerebral artery occlusion model of focal ischemia in CD rats. Gelatinase inhibition was achieved by intracerebral injection of the Fn-439 MMP inhibitor 7 days after stroke. Treatment efficacy was determined on day 9 by in situ gelatin zymography. The peri-infarct cortex was identified by triphenyl tetrazolium chloride staining, and tissue samples were dissected for TaqMan array gene-expression study. Of 84 genes known to influence poststroke regeneration, we found upregulation of mRNA for the reticulon 4 receptor (Rtn4r), a major inhibitor of regenerative nerve growth in the adult CNS, and borderline expression changes for 3 additional genes (DCC, Jun, and Ngfr). Western blot confirmed increased Rtn4r protein in the peri infarct cortex of treated animals, and double immunolabeling showed colocalization primarily with the S100 astrocyte marker. These data suggest that increased Rtn4 receptor expression in the perilesional cortex may contribute to the impaired regeneration associated with MMP inhibition in the subacute phase of cerebral infarction. PMID- 26945034 TI - The Spatiotemporal Pattern of Degeneration in the Cerebellum of the Wobbler Mouse. AB - Amyotrophic lateral sclerosis (ALS) is a common neurodegenerative disease that affects motor neurons in the spinal cord and motor cortex. Various mouse models have been used to investigate the progression of the pathology of sporadic and familial ALS. Degeneration in the spinal cord and motor cortex in the Wobbler mouse model of sporadic ALS have been documented, but alterations of the cerebellum during disease progression have not been well characterized. We analyzed neurodegeneration and inflammatory responses in the cerebellar cortex of preclinical (p20), clinical (p40), and late (p60) stages in these mice. We did not identify evidence of neuron cell death, but we observed an inflammatory response detected by IL1B and TNFA expression by quantitative PCR, increased activated microglia and astrocytosis by immunohistochemistry, and ultrastructural abnormalities in the cerebella of Wobbler mice at late stages. These alterations may be caused by protein aggregations and variations in the distribution of cytoskeletal proteins; they might be reflected in the early manifestation of head tremor, which precedes motor deficits in these mice. Thus, we conclude that, in addition to the motor cortex and spinal cord, the cerebellum is affected by neurodegenerative and inflammatory processes in the Wobbler mouse model of ALS. PMID- 26945035 TI - Whole Chromosome 7 Gain Predicts Higher Risk of Recurrence in Pediatric Pilocytic Astrocytomas Independently From KIAA1549-BRAF Fusion Status. AB - The most frequent genetic alteration identified in pediatric pilocytic astrocytomas and pilomyxoid variant is the KIAA1549-BRAF fusion, which typically results from a 2.0 Mb tandem duplication in chromosome band 7q34. Less frequent abnormalities include fusion genes,BRAF, FGFR, KRAS, and NF1 point mutations, and whole chromosome gains. To correlate genetic alterations with clinical course data, we retrospectively analyzed the tumors with pilocytic and pilomyxoid histology of a cohort of 116 pediatric patients, aged 5 months to 23 years. Gross total resection was associated with a decreased risk of recurrence (p = 0.001), supporting previous findings that complete tumor excision correlates with long term and disease-free survival. We found no significant association between recurrence rate and the presence of the KIAA1549-BRAF fusion or BRAF mutation (p = 0.167). Interestingly, gain of whole chromosome 7 (WC7) was associated with a 4.7-fold increased risk of tumor recurrence, even after adjusting for surgical status (p = 0.025), and other genetic alterations. Using fluorescence in situ hybridization, we demonstrated that when WC7 gain accompanies the KIAA1549-BRAF fusion, the fusion likely arises first. This study highlights the utility of genetic studies for risk assessment of pilocytic and pilomyxoid astrocytomas, which may impact treatment selections. PMID- 26945038 TI - Cell wall integrity signaling in plants: "To grow or not to grow that's the question". AB - Plants, like yeast, have the ability to monitor alterations in the cell wall architecture that occur during normal growth or in changing environments and to trigger compensatory changes in the cell wall. We discuss how recent advances in our understanding of the cell wall architecture provide new insights into the role of cell wall integrity sensing in growth control. Next we review the properties of membrane receptor-like kinases that have roles in pH control, mechano-sensing and reactive oxygen species accumulation in growing cells and which may be the plant equivalents of the yeast cell wall integrity (CWI) sensors. Finally, we discuss recent findings showing an increasing role for CWI signaling in plant immunity and the adaptation to changes in the ionic environment of plant cells. PMID- 26945036 TI - Neuronal Injury, Gliosis, and Glial Proliferation in Two Models of Temporal Lobe Epilepsy. AB - It is estimated that 30%-40% of epilepsy patients are refractory to therapy and animal models are useful for the identification of more efficacious therapeutic agents. Various well-characterized syndrome-specific models are needed to assess their relevance to human seizure disorders and their validity for testing potential therapies. The corneal kindled mouse model of temporal lobe epilepsy (TLE) allows for the rapid screening of investigational compounds, but there is a lack of information as to the specific inflammatory pathology in this model. Similarly, the Theiler murine encephalomyelitis virus (TMEV) model of TLE may prove to be useful for screening, but quantitative assessment of hippocampal pathology is also lacking. We used immunohistochemistry to characterize and quantitate acute neuronal injury and inflammatory features in dorsal CA1 and dentate gyrus regions and in the directly overlying posterior parietal cortex at 2 time points in each of these TLE models. Corneal kindled mice were observed to have astrogliosis, but not microgliosis or neuron cell death. In contrast, TMEV injected mice had astrogliosis, microgliosis, neuron death, and astrocyte and microglial proliferation. Our results suggest that these 2 animal models might be appropriate for evaluation of distinct therapies for TLE. PMID- 26945039 TI - Lean and the perfect patient experience. PMID- 26945037 TI - SOX10 Distinguishes Pilocytic and Pilomyxoid Astrocytomas From Ependymomas but Shows No Differences in Expression Level in Ependymomas From Infants Versus Older Children or Among Molecular Subgroups. AB - SOX10 is important in nonneoplastic oligodendroglial development, but mRNA transcripts and protein expression are identified in a wider variety of CNS glial neoplasms than oligodendrogliomas. We previously demonstrated high levels of SOX10 mRNA and protein in pilocytic astrocytomas (PAs) but not ependymomas (EPNs). We now extend these studies to investigate subsets of these 2 tumors that affect infants, pilomyxoid astrocytomas (PMAs) and infant (<1 year) ependymomas (iEPNs). By gene expression microarray analysis, we found that iEPNs and all EPNs in older children showed very low SOX10 expression levels, on average 7.1-fold below normal control tissues. EPN groups showed no significant difference in SOX10 expression between iEPN and EPN. PAs/PMAs had 24.1/29.4-fold higher transcript levels, respectively, than those in normal tissues. Using immunohistochemical analysis of adult, pediatric, and infantile EPNs and of PAs/PMAs, we found that EPNs from multiple anatomical locations and both age groups (n = 228) never showed 3+ diffuse nuclear immunostaining for SOX10; the majority were scored at 0 or 1+. Conversely, almost all pediatric and adult PAs and PMAs (n = 47) were scored as 3+. These results suggest that in select settings, SOX10 immunohistochemistry can supplement the diagnosis of PMA and PA and aid in distinguishing them from EPNs. PMID- 26945041 TI - Hsp90 protein interacts with phosphorothioate oligonucleotides containing hydrophobic 2'-modifications and enhances antisense activity. AB - RNase H1-dependent antisense oligonucleotides (ASOs) are chemically modified to enhance pharmacological properties. Major modifications include phosphorothioate (PS) backbone and different 2'-modifications in 2-5 nucleotides at each end (wing) of an ASO. Chemical modifications can affect protein binding and understanding ASO-protein interactions is important for better drug design. Recently we identified many intracellular ASO-binding proteins and found that protein binding could affect ASO potency. Here, we analyzed the structure activity-relationships of ASO-protein interactions and found 2'-modifications significantly affected protein binding, including La, P54nrb and NPM. PS-ASOs containing more hydrophobic 2'-modifications exhibit higher affinity for proteins in general, although certain proteins, e.g. Ku70/Ku80 and TCP1, are less affected by 2'-modifications. We found that Hsp90 protein binds PS-ASOs containing locked nucleic-acid (LNA) or constrained-ethyl-bicyclic-nucleic-acid ((S)-cEt) modifications much more avidly than 2'-O-methoxyethyl (MOE). ASOs bind the mid domain of Hsp90 protein. Hsp90 interacts with more hydrophobic 2' modifications, e.g. (S)-cEt or LNA, in the 5'-wing of the ASO. Reduction of Hsp90 protein decreased activity of PS-ASOs with 5'-LNA or 5'-cEt wings, but not with 5'-MOE wing. Together, our results indicate Hsp90 protein enhances the activity of PS/LNA or PS/(S)-cEt ASOs, and imply that altering protein binding of ASOs using different chemical modifications can improve therapeutic performance of PS-ASOs. PMID- 26945040 TI - Local potentiation of stress-responsive genes by upstream noncoding transcription. AB - It has been postulated that a myriad of long noncoding RNAs (lncRNAs) contribute to gene regulation. In fission yeast, glucose starvation triggers lncRNA transcription across promoter regions of stress-responsive genes including fbp1 (fructose-1,6-bisphosphatase1). At the fbp1 promoter, this transcription promotes chromatin remodeling and fbp1 mRNA expression. Here, we demonstrate that such upstream noncoding transcription facilitates promoter association of the stress responsive transcriptional activator Atf1 at the sites of transcription, leading to activation of the downstream stress genes. Genome-wide analyses revealed that ~50 Atf1-binding sites show marked decrease in Atf1 occupancy when cells are treated with a transcription inhibitor. Most of these transcription-enhanced Atf1 binding sites are associated with stress-dependent induction of the adjacent mRNAs or lncRNAs, as observed in fbp1 These Atf1-binding sites exhibit low Atf1 occupancy and high histone density in glucose-rich conditions, and undergo dramatic changes in chromatin status after glucose depletion: enhanced Atf1 binding, histone eviction, and histone H3 acetylation. We also found that upstream transcripts bind to the Groucho-Tup1 type transcriptional corepressors Tup11 and Tup12, and locally antagonize their repressive functions on Atf1 binding. These results reveal a new mechanism in which upstream noncoding transcription locally magnifies the specific activation of stress-inducible genes via counteraction of corepressors. PMID- 26945042 TI - Kinetics of the CRISPR-Cas9 effector complex assembly and the role of 3'-terminal segment of guide RNA. AB - CRISPR-Cas9 is widely applied for genome engineering in various organisms. The assembly of single guide RNA (sgRNA) with the Cas9 protein may limit the Cas9/sgRNA effector complex function. We developed a FRET-based assay for detection of CRISPR-Cas9 complex binding to its targets and used this assay to investigate the kinetics of Cas9 assembly with a set of structurally distinct sgRNAs. We find that Cas9 and isolated sgRNAs form the effector complex efficiently and rapidly. Yet, the assembly process is sensitive to the presence of moderate concentrations of non-specific RNA competitors, which considerably delay the Cas9/sgRNA complex formation, while not significantly affecting already formed complexes. This observation suggests that the rate of sgRNA loading into Cas9 in cells can be determined by competition between sgRNA and intracellular RNA molecules for the binding to Cas9. Non-specific RNAs exerted particularly large inhibitory effects on formation of Cas9 complexes with sgRNAs bearing shortened 3'-terminal segments. This result implies that the 3'-terminal segment confers sgRNA the ability to withstand competition from non-specific RNA and at least in part may explain the fact that use of sgRNAs truncated for the 3' terminal stem loops leads to reduced activity during genomic editing. PMID- 26945043 TI - Introns regulate the production of ribosomal proteins by modulating splicing of duplicated ribosomal protein genes. AB - Most budding yeast introns exist in the many duplicated ribosomal protein genes (RPGs) and it has been posited that they remain there to modulate the expression of RPGs and cell growth in response to stress. However, the mechanism by which introns regulate the expression of RPGs and their impact on the synthesis of ribosomal proteins remain unclear. In this study, we show that introns determine the ratio of ribosomal protein isoforms through asymmetric paralog-specific regulation of splicing. Exchanging the introns and 3' untranslated regions of the duplicated RPS9 genes altered the splicing efficiency and changed the ratio of the ribosomal protein isoforms. Mutational analysis of the RPS9 genes indicated that splicing is regulated by variations in the intron structure and the 3' untranslated region. Together these data suggest that preferential splicing of duplicated RPGs provides a means for adjusting the ratio of different ribosomal protein isoforms, while maintaining the overall expression level of each ribosomal protein. PMID- 26945045 TI - Clinical and Echocardiographic Outcomes After Bariatric Surgery in Obese Patients With Left Ventricular Systolic Dysfunction. AB - BACKGROUND: Obesity is a risk factor for development of left ventricular systolic dysfunction (LVSD) and can complicate LVSD management, especially for individuals in whom cardiac transplantation is indicated. Bariatric surgery is increasingly recognized as a safe and effective intervention to achieve marked weight loss, but experience is limited in the LVSD population. METHODS AND RESULTS: We retrospectively reviewed patients with obesity and left ventricular ejection fraction (LVEF) <50% who underwent bariatric surgery at a tertiary center 2004 to 2013. An analysis of outcomes and efficacy compared 42 surgical patients with LVSD to 2588 without known LVSD. The LVSD group had greater baseline prevalence of comorbidities and showed a slight excess of early postoperative heart failure and myocardial infarction. However, patients with LVSD achieved good weight loss efficacy (mean decrease 22.6%) and no excess in mortality at 1 year. An overlapping cohort of 38 patients with LVSD had both pre- and postoperative echocardiographic images available for review by 2 blinded readers. Obese nonsurgical controls were matched on age, sex, initial LVEF, and interval between echocardiograms. There was a mean pre- to postoperative LVEF improvement of +5.1% +/-8.3 (P=0.0005) for surgical subjects, but not for controls (+3.4%+/-10.5, P=0.056). Among surgical subjects, 11 patients had an LVEF improvement of >10%, whereas only 6 improved by >10% among nonsurgical controls. CONCLUSIONS: At experienced centers, bariatric surgery may be a safe and effective intervention for obese patients with LVSD. Bariatric surgery was associated with an improvement in LVEF, although the magnitude of change was on the cusp of clinical significance. PMID- 26945046 TI - Bariatric Surgery in Patients With Left Ventricular Systolic Dysfunction: Effective, But Is It Safe? PMID- 26945044 TI - Bidirectional promoters link cAMP signaling with irreversible differentiation through promoter-associated non-coding RNA (pancRNA) expression in PC12 cells. AB - Bidirectional promoters are the major source of gene activation-associated noncoding RNA (ncRNA). PC12 cells offer an interesting model for understanding the mechanism underlying bidirectional promoter-mediated cell cycle control. Nerve growth factor (NGF)-stimulated PC12 cells elongate neurites, and are in a reversible cell-cycle-arrested state. In contrast, these cells irreversibly differentiate and cannot re-enter the normal cell cycle after NGF plus cAMP treatment. In this study, using directional RNA-seq, we found that bidirectional promoters for protein-coding genes with promoter-associated ncRNA (pancRNA) were enriched for cAMP response element consensus sequences, and were preferred targets for transcriptional regulation by the transcription factors in the cAMP dependent pathway. A spindle-formation-associated gene, Nusap1 and pancNusap1 were among the most strictly co-transcribed pancRNA-mRNA pairs. This pancRNA-mRNA pair was specifically repressed in irreversibly differentiated PC12 cells. Knockdown (KD) and overexpression experiments showed that pancNusap1 positively regulated the Nusap1 expression in a sequence-specific manner, which was accompanied by histone acetylation at the Nusap1 promoter. Furthermore, pancNusap1 KD recapitulated the effects of cAMP on cell cycle arrest. Thus, we conclude that pancRNA-mediated histone acetylation contributes to the establishment of the cAMP-induced transcription state of the Nusap1 locus and contributes to the irreversible cell cycle exit for terminal differentiation of PC12 cells. PMID- 26945047 TI - Individualized Statin Benefit for Determining Statin Eligibility in the Primary Prevention of Cardiovascular Disease. AB - BACKGROUND: Current guidelines recommend statins in the primary prevention of cardiovascular disease on the basis of predicted cardiovascular risk without directly considering the expected benefits of statin therapy based on the available randomized, controlled trial evidence. METHODS AND RESULTS: We included 2134 participants representing 71.8 million American residents potentially eligible for statins in primary prevention from the National Health and Nutrition Examination Survey for the years 2005 to 2010. We compared statin eligibilities using 2 separate approaches: a 10-year risk-based approach (>=7.5% 10-year risk) and an individualized benefit approach (ie, based on predicted absolute risk reduction over 10 years [ARR10] >=2.3% from randomized, controlled trial data). A risk-based approach led to the eligibility of 15.0 million (95% confidence interval, 12.7-17.3 million) Americans, whereas a benefit-based approach identified 24.6 million (95% confidence interval, 21.0-28.1 million). The corresponding numbers needed to treat over 10 years were 21 (range, 9-44) and 25 (range, 9-44). The benefit-based approach identified 9.5 million lower-risk (<7.5% 10-year risk) Americans not currently eligible for statin treatment who had the same or greater expected benefit from statins (>=2.3% ARR10) compared with higher-risk individuals. This lower-risk/acceptable-benefit group includes younger individuals (mean age, 55.2 versus 62.5 years; P<0.001 for benefit based versus risk based) with higher low-density lipoprotein cholesterol (140 versus133 mg/dL; P=0.01). Statin treatment in this group would be expected to prevent an additional 266 508 cardiovascular events over 10 years. CONCLUSIONS: An individualized statin benefit approach can identify lower-risk individuals who have equal or greater expected benefit from statins in primary prevention compared with higher-risk individuals. This approach may help develop guideline recommendations that better identify individuals who meaningfully benefit from statin therapy. PMID- 26945048 TI - CURLY LEAF Regulates Gene Sets Coordinating Seed Size and Lipid Biosynthesis. AB - CURLY LEAF (CLF), a histone methyltransferase of Polycomb Repressive Complex 2 (PRC2) for trimethylation of histone H3 Lys 27 (H3K27me3), has been thought as a negative regulator controlling mainly postgermination growth in Arabidopsis (Arabidopsis thaliana). Approximately 14% to 29% of genic regions are decorated by H3K27me3 in the Arabidopsis genome; however, transcriptional repression activities of PRC2 on a majority of these regions remain unclear. Here, by analysis of transcriptome profiles, we found that approximately 11.6% genes in the Arabidopsis genome were repressed by CLF in various organs. Unexpectedly, approximately 54% of these genes were preferentially repressed in siliques. Further analyses of 118 transcriptome datasets uncovered a group of genes that was preferentially expressed and repressed by CLF in embryos at the mature-green stage. This observation suggests that CLF mediates a large-scale H3K27me3 programming/reprogramming event during embryonic development. Plants of clf-28 produced bigger and heavier seeds with higher oil content, larger oil bodies, and altered long-chain fatty acid composition compared with wild type. Around 46% of CLF-repressed genes were associated with H3K27me3 marks; moreover, we verified histone modification and transcriptional repression by CLF on regulatory genes. Our results suggest that CLF silences specific gene expression modules. Genes operating within a module have various molecular functions, but they cooperate to regulate a similar physiological function during embryo development. PMID- 26945049 TI - A Drought-Inducible Transcription Factor Delays Reproductive Timing in Rice. AB - The molecular mechanisms underlying photoperiod or temperature control of flowering time have been recently elucidated, but how plants regulate flowering time in response to other external factors, such as water availability, remains poorly understood. Using a large-scale Hybrid Transcription Factor approach, we identified a bZIP transcriptional factor, O. sativa ABA responsive element binding factor 1 (OsABF1), which acts as a suppressor of floral transition in a photoperiod-independent manner. Simultaneous knockdown of both OsABF1 and its closest homologous gene, OsbZIP40, in rice (Oryza sativa) by RNA interference results in a significantly earlier flowering phenotype. Molecular and genetic analyses demonstrate that a drought regime enhances expression of the OsABF1 gene, which indirectly suppresses expression of the Early heading date 1 (Ehd1) gene that encodes a key activator of rice flowering. Furthermore, we identified a drought-inducible gene named OsWRKY104 that is under the direct regulation of OsABF1 Overexpression of OsWRKY104 can suppress Ehd1 expression and confers a later flowering phenotype in rice. Together, these findings reveal a novel pathway by which rice modulates heading date in response to the change of ambient water availability. PMID- 26945053 TI - A Swiss army knife for estimating kidney function: why new equations will not solve the real problem. PMID- 26945052 TI - Development of Polyspermic Rice Zygotes. AB - Fertilization is a general feature of eukaryotic uni- and multicellular organisms to restore a diploid genome from female and male gamete haploid genomes. In most animals and fucoid algae, polyspermy block occurs at the plasmogamy step. Because the polyspermy barrier in animals and in fucoid algae is incomplete, polyspermic zygotes are generated by multiple fertilization events. However, these polyspermic zygotes with extra centrioles from multiple sperms show aberrant nuclear and cell division. In angiosperms, polyspermy block functions in the egg cell and the central cell to promote faithful double fertilization, although the mechanism of polyspermy block remains unclear. In contrast to the case in animals and fucoid algae, polyspermic zygotes formed in angiosperms are not expected to die because angiosperms lack centrosomes. However, there have been no reports on the developmental profiles of polyspermic zygotes at cellular level in angiosperms. In this study, we produced polyspermic rice zygotes by electric fusion of an egg cell with two sperm cells, and monitored their developmental profiles. Two sperm nuclei and an egg nucleus fused into a zygotic nucleus, and the triploid zygote divided into a two-celled embryo via mitotic division with a typical bipolar microtubule spindle, as observed during mitosis of a diploid zygote. The two-celled proembryos further developed and regenerated into triploid plants. These findings suggest that polyspermic plant zygotes have the potential to form triploid embryos. Polyspermy in angiosperms might be a pathway for the formation of triploid plants, which can contribute significantly to the formation of autopolyploids. PMID- 26945050 TI - Plant Aquaporin AtPIP1;4 Links Apoplastic H2O2 Induction to Disease Immunity Pathways. AB - Hydrogen peroxide (H2O2) is a stable component of reactive oxygen species, and its production in plants represents the successful recognition of pathogen infection and pathogen-associated molecular patterns (PAMPs). This production of H2O2 is typically apoplastic but is subsequently associated with intracellular immunity pathways that regulate disease resistance, such as systemic acquired resistance and PAMP-triggered immunity. Here, we elucidate that an Arabidopsis (Arabidopsis thaliana) aquaporin (i.e. the plasma membrane intrinsic protein AtPIP1;4) acts to close the cytological distance between H2O2 production and functional performance. Expression of the AtPIP1;4 gene in plant leaves is inducible by a bacterial pathogen, and the expression accompanies H2O2 accumulation in the cytoplasm. Under de novo expression conditions, AtPIP1;4 is able to mediate the translocation of externally applied H2O2 into the cytoplasm of yeast (Saccharomyces cerevisiae) cells. In plant cells treated with H2O2, AtPIP1;4 functions as an effective facilitator of H2O2 transport across plasma membranes and mediates the translocation of externally applied H2O2 from the apoplast to the cytoplasm. The H2O2-transport role of AtPIP1;4 is essentially required for the cytoplasmic import of apoplastic H2O2 induced by the bacterial pathogen and two typical PAMPs in the absence of induced production of intracellular H2O2 As a consequence, cytoplasmic H2O2 quantities increase substantially while systemic acquired resistance and PAMP-triggered immunity are activated to repress the bacterial pathogenicity. By contrast, loss-of-function mutation at the AtPIP1;4 gene locus not only nullifies the cytoplasmic import of pathogen- and PAMP-induced apoplastic H2O2 but also cancels the subsequent immune responses, suggesting a pivotal role of AtPIP1;4 in apocytoplastic signal transduction in immunity pathways. PMID- 26945051 TI - Differential Regulation of Clathrin and Its Adaptor Proteins during Membrane Recruitment for Endocytosis. AB - In plants, clathrin-mediated endocytosis (CME) is dependent on the function of clathrin and its accessory heterooligomeric adaptor protein complexes, ADAPTOR PROTEIN2 (AP-2) and the TPLATE complex (TPC), and is negatively regulated by the hormones auxin and salicylic acid (SA). The details for how clathrin and its adaptor complexes are recruited to the plasma membrane (PM) to regulate CME, however, are poorly understood. We found that SA and the pharmacological CME inhibitor tyrphostin A23 reduce the membrane association of clathrin and AP-2, but not that of the TPC, whereas auxin solely affected clathrin membrane association, in Arabidopsis (Arabidopsis thaliana). Genetic and pharmacological experiments revealed that loss of AP2MU or AP2sigma partially affected the membrane association of other AP-2 subunits and that the AP-2 subunit AP2sigma, but not AP2MU, was required for SA- and tyrphostin A23-dependent inhibition of CME Furthermore, we show that although AP-2 and the TPC are both required for the PM recruitment of clathrin in wild-type cells, the TPC is necessary for clathrin PM association in AP-2-deficient cells. These results indicate that developmental signals may differentially modulate the membrane recruitment of clathrin and its core accessory complexes to regulate the process of CME in plant cells. PMID- 26945055 TI - Structural damage in rheumatoid arthritis: comparison between tendon damage evaluated by ultrasound and radiographic damage. AB - OBJECTIVE: To compare structural damage assessed by conventional radiography and tendon damage assessed by musculoskeletal US (MSUS) at wrist and ankle in RA patients. METHODS: We evaluated 72 consecutive patients [56 (77.8%) females] with RA. The MSUS evaluation consisted in a B-mode examination of bilateral extensor carpi ulnaris and tibialis posterior tendons. Tendon damage was defined and scored according to OMERACT. A total score for the tendon damage score (TDS) was calculated by summing the grades for each tendon. For the radiographic evaluations we used the van der Heijde score; a total radiographic score (RTS) was calculated by summing a bone erosion score (ERS) and a joint space narrowing score (JSNS). RESULTS: We evaluated 288 tendons. The mean (s.d.) of TDS was 2.3 (1.8). Fifty-four (75%) patients presented tendon damage of at least one tendon. From all evaluated tendons, 134 (46.5%) had no tendon damage, 146 (50.7%) had grade 1 and 8 (2.8%) had grade 2 tendon damage. The mean (s.d.) for RTS was 91.4 (97), for ERS was 47.3 (61.9) and for JSNS was 44.1 (37.2). We found a significant correlation between disease duration and both TDS and RTS (r = 0.413 and r = 0.560, respectively; P < 0.0001). We found a good significant correlation between TDS and all variables of radiographic structural damage (RTS, r = 0.65; ERS, r = 0.637; JSNS, r = 0.618; P < 0.001). CONCLUSION: The MSUS assessment of only four tendons can be an additional feasible method to assess structural damage in RA patients. PMID- 26945054 TI - Frequent monitoring of mineral metabolism in hemodialysis patients with secondary hyperparathyroidism: associations with achievement of treatment goals and with adjustments in therapy. AB - Background: Dialysis guidelines in Japan recommend more frequent measurement of mineral metabolism markers than the Kidney Disease: Improving Global Outcomes guidelines. However, the extent to which frequent marker measurement contributes to achievement of target ranges and to therapy adjustment is unknown. Methods: This multicenter cohort study involved 3276 hemodialysis patients with secondary hyperparathyroidism. Data on laboratory measurements and drug prescriptions were collected every 3 months. Main exposures were frequencies of measuring serum calcium and phosphorus [weekly/biweekly/monthly (reference)] and serum parathyroid hormone (PTH) [monthly/bimonthly/trimonthly (reference)] levels. Outcomes were achievement of guideline-specified ranges of mineral metabolism markers when serum levels were over, and maintenance of ranges when levels were already within, respective specified ranges, use of intravenous vitamin D receptor activator (VDRA) and initiation of cinacalcet use. Associations were examined via generalized estimating equations. Results: When serum marker levels exceeded the target range, weekly measurement of calcium and phosphorus was positively associated with achievement of the guideline-specified calcium range [adjusted odds ratio (AOR): 1.57, 95% confidence interval (CI) 1.09-2.26] but not phosphorus range (AOR: 0.99, 95% CI 0.74-1.33). Monthly measurement of PTH was positively associated with achievement of the guideline-specified PTH range (AOR: 1.14, 95% CI 1.01-1.27). When serum marker levels were within the guideline specified range, increased frequency of measurements was not associated with in range maintenance of marker levels for any of the three mineral markers assessed. Regarding treatment regimen, relatively frequent measurement of serum calcium and phosphorus was positively associated with cinacalcet initiation and relatively frequent measurement of serum PTH with cinacalcet initiation and intravenous VDRA use. Conclusions: Our results suggest that increasing frequency of measurements is helpful when serum marker levels exceed the target range, partially via adjustment in the therapeutic regimen. We found no evidence that frequent measurements are helpful when mineral levels are already within target ranges. PMID- 26945056 TI - Pheochromocytoma in association with focal dermatomyositis. PMID- 26945057 TI - Dynamic internalization and recycling of a metal ion transporter: Cu homeostasis and CTR1, the human Cu+ uptake system. AB - Cu ion (Cu) entry into human cells is mediated by CTR1 (also known as SLC31A1), the high-affinity Cu transporter. When extracellular Cu is raised, the cell is protected against excess accumulation by rapid internalization of the transporter. When Cu is lowered, the transporter returns to the membrane. We show in HEK293 cells overexpressing CTR1 that expression of either the C-terminal domain of AP180 (also known as SNAP91), a clathrin-coat assembly protein that sequesters clathrin, or a dominant-negative mutant of dynamin, decreases Cu induced endocytosis of CTR1, as does a dynamin inhibitor and clathrin knockdown using siRNA. Utilizing imaging, siRNA techniques and a new high-throughput assay for endocytosis employing CLIP-tag methodology, we show that internalized CTR1 accumulates in early sorting endosomes and recycling compartments (containing Rab5 and EEA1), but not in late endosomes or lysosomal pathways. Using live cell fluorescence, we find that upon extracellular Cu removal CTR1 recycles to the cell surface through the slower-recycling Rab11-mediated pathway. These processes enable cells to dynamically alter transporter levels at the plasma membrane and acutely modulate entry as a safeguard against excess cellular Cu. PMID- 26945060 TI - TrkA mediates retrograde semaphorin 3A signaling through plexin A4 to regulate dendritic branching. AB - Semaphorin 3A (Sema3A), a secretory semaphorin, exerts various biological actions through a complex between neuropilin-1 and plexin-As (PlexAs). Sema3A induces retrograde signaling, which is involved in regulating dendritic localization of GluA2 (also known as GRIA2), an AMPA receptor subunit. Here, we investigated a possible interaction between retrograde signaling pathways for Sema3A and nerve growth factor (NGF). Sema3A induces colocalization of PlexA4 (also known as PLXNA4) signals with those of tropomyosin-related kinase A (TrkA, also known as NTRK1) in growth cones, and these colocalized signals were then observed along the axons. The time-lapse imaging of PlexA4 and several TrkA mutants showed that the kinase and dynein-binding activity of TrkA were required for Sema3A-induced retrograde transport of the PlexA4-TrkA complex along the axons. The inhibition of the phosphoinositide 3-kinase (PI3K)-Akt signal, a downstream signaling pathway of TrkA, in the distal axon suppressed Sema3A-induced dendritic localization of GluA2. The knockdown of TrkA suppressed Sema3A-induced dendritic localization of GluA2 and that suppressed Sema3A-regulated dendritic branching both in vitro and in vivo These findings suggest that by interacting with PlexA4, TrkA plays a crucial role in redirecting local Sema3A signaling to retrograde axonal transport, thereby regulating dendritic GluA2 localization and patterning. PMID- 26945059 TI - PP2A binds to the LIM domains of lipoma-preferred partner through its PR130/B" subunit to regulate cell adhesion and migration. AB - Here, we identify the LIM protein lipoma-preferred partner (LPP) as a binding partner of a specific protein phosphatase 2A (PP2A) heterotrimer that is characterised by the regulatory PR130/B"alpha1 subunit (encoded by PPP2R3A). The PR130 subunit interacts with the LIM domains of LPP through a conserved Zn2+ finger-like motif in the differentially spliced N-terminus of PR130. Isolated LPP associated PP2A complexes are catalytically active. PR130 colocalises with LPP at multiple locations within cells, including focal contacts, but is specifically excluded from mature focal adhesions, where LPP is still present. An LPP-PR130 fusion protein only localises to focal adhesions upon deletion of the domain of PR130 that binds to the PP2A catalytic subunit (PP2A/C), suggesting that PR130 LPP complex formation is dynamic and that permanent recruitment of PP2A activity might be unfavourable for focal adhesion maturation. Accordingly, siRNA-mediated knockdown of PR130 increases adhesion of HT1080 fibrosarcoma cells onto collagen I and decreases their migration in scratch wound and Transwell assays. Complex formation with LPP is mandatory for these PR130-PP2A functions, as neither phenotype can be rescued by re-expression of a PR130 mutant that no longer binds to LPP. Our data highlight the importance of specific, locally recruited PP2A complexes in cell adhesion and migration dynamics. PMID- 26945058 TI - Deep RNA profiling identified CLOCK and molecular clock genes as pathophysiological signatures in collagen VI myopathy. AB - Collagen VI myopathies are genetic disorders caused by mutations in collagen 6 A1, A2 and A3 genes, ranging from the severe Ullrich congenital muscular dystrophy to the milder Bethlem myopathy, which is recapitulated by collagen-VI null (Col6a1(-/-)) mice. Abnormalities in mitochondria and autophagic pathway have been proposed as pathogenic causes of collagen VI myopathies, but the link between collagen VI defects and these metabolic circuits remains unknown. To unravel the expression profiling perturbation in muscles with collagen VI myopathies, we performed a deep RNA profiling in both Col6a1(-/-)mice and patients with collagen VI pathology. The interactome map identified common pathways suggesting a previously undetected connection between circadian genes and collagen VI pathology. Intriguingly, Bmal1(-/-)(also known as Arntl) mice, a well-characterized model displaying arrhythmic circadian rhythms, showed profound deregulation of the collagen VI pathway and of autophagy-related genes. The involvement of circadian rhythms in collagen VI myopathies is new and links autophagy and mitochondrial abnormalities. It also opens new avenues for therapies of hereditary myopathies to modulate the molecular clock or potential gene-environment interactions that might modify muscle damage pathogenesis. PMID- 26945061 TI - DNA Mismatch Repair Interacts with CAF-1- and ASF1A-H3-H4-dependent Histone (H3 H4)2 Tetramer Deposition. AB - DNA mismatch repair (MMR) is required for the maintenance of genome stability and protection of humans from several types of cancer. Human MMR occurs in the chromatin environment, but little is known about the interactions between MMR and the chromatin environment. Previous research has suggested that MMR coincides with replication-coupled assembly of the newly synthesized DNA into nucleosomes. The first step in replication-coupled nucleosome assembly is CAF-1-dependent histone (H3-H4)2 tetramer deposition, a process that involves ASF1A-H3-H4 complex. In this work we used reconstituted human systems to investigate interactions between MMR and CAF-1- and ASF1A-H3-H4-dependent histone (H3-H4)2 tetramer deposition. We have found that MutSalpha inhibits CAF-1- and ASF1A-H3-H4 dependent packaging of a DNA mismatch into a tetrasome. This finding supports the idea that MMR occurs before the DNA mismatch is packaged into the tetrasome. Our experiments have also revealed that CAF-1- and ASF1A-H3-H4-dependent deposition of the histone (H3-H4)2 tetramers does not interfere with MMR reactions. In addition, we have established that unnecessary degradation of the discontinuous strand that takes place in both DNA polymerase delta (Pol delta)- and DNA polymerase epsilon (Pol epsilon)-dependent MMR reactions is suppressed by CAF-1- and ASF1A-H3-H4-dependent deposition of the histone (H3-H4)2 tetramers. These data suggest that CAF-1- and ASF1A-H3-H4-dependent deposition of the histone (H3 H4)2 tetramers is compatible with MMR and protects the discontinuous daughter strand from unnecessary degradation by MMR machinery. PMID- 26945062 TI - Capillary Isoelectric Focusing of Akt Isoforms Identifies Highly Dynamic Phosphorylation in Neuronal Cells and Brain Tissue. AB - The PI3K/PTEN/Akt pathway has been established as a core signaling pathway that is crucial for the integration of neurons into neuronal circuits and the maintenance of the architecture and function of neurons in the adult brain. Akt1 3 kinases are specifically activated by two phosphorylation events on residues Thr(308) and Ser(473) upon growth factor signaling, which subsequently phosphorylate a vast cohort of downstream targets. However, we still lack a clear understanding of the complexity and regulation of isoform specificity within the PI3K/PTEN/Akt pathway. We utilized a capillary-based isoelectric focusing method to study dynamics of Akt phosphorylation in neuronal cells and the developing brain and identify previously undescribed features of Akt phosphorylation and activation. First, we show that the accumulation of multiple phosphorylation events on Akt forms occur concurrently with Ser(473) and Thr(308) phosphorylation upon acute PI3K activation and provide evidence for uncoupling of Ser(473) and Thr(308) phosphorylation, as well as differential sensitivities of Akt1 forms upon PI3K inhibition. Second, we detect a transient shift in Akt isoform phosphorylation and activation pattern during early postnatal brain development, at stages corresponding to synapse development and maturation. Third, we show differential sensitivities of Ser(473)-Akt species to PTEN deletion in mature neurons, which suggests inherent differences in the Akt pools that are accessible to growth factors as compared with the pools that are controlled by PTEN. Our study demonstrates the presence of complex phosphorylation events of Akt in a time- and signal-dependent manner in neurons. PMID- 26945063 TI - Biochemical Analysis of Yeast Suppressor of Ty 4/5 (Spt4/5) Reveals the Importance of Nucleic Acid Interactions in the Prevention of RNA Polymerase II Arrest. AB - RNA polymerase II (RNAPII) undergoes structural changes during the transitions from initiation, elongation, and termination, which are aided by a collection of proteins called elongation factors. NusG/Spt5 is the only elongation factor conserved in all domains of life. Although much information exists about the interactions between NusG/Spt5 and RNA polymerase in prokaryotes, little is known about how the binding of eukaryotic Spt4/5 affects the biochemical activities of RNAPII. We characterized the activities of Spt4/5 and interrogated the structural features of Spt5 required for it to interact with elongation complexes, bind nucleic acids, and promote transcription elongation. The eukaryotic specific regions of Spt5 containing the Kyrpides, Ouzounis, Woese domains are involved in stabilizing the association with the RNAPII elongation complex, which also requires the presence of the nascent transcript. Interestingly, we identify a region within the conserved NusG N-terminal (NGN) domain of Spt5 that contacts the non-template strand of DNA both upstream of RNAPII and in the transcription bubble. Mutating charged residues in this region of Spt5 did not prevent Spt4/5 binding to elongation complexes, but abrogated the cross-linking of Spt5 to DNA and the anti-arrest properties of Spt4/5, thus suggesting that contact between Spt5 (NGN) and DNA is required for Spt4/5 to promote elongation. We propose that the mechanism of how Spt5/NGN promotes elongation is fundamentally conserved; however, the eukaryotic specific regions of the protein evolved so that it can serve as a platform for other elongation factors and maintain its association with RNAPII as it navigates genomes packaged into chromatin. PMID- 26945064 TI - The Most Prevalent Freeman-Sheldon Syndrome Mutations in the Embryonic Myosin Motor Share Functional Defects. AB - The embryonic myosin isoform is expressed during fetal development and rapidly down-regulated after birth. Freeman-Sheldon syndrome (FSS) is a disease associated with missense mutations in the motor domain of this myosin. It is the most severe form of distal arthrogryposis, leading to overcontraction of the hands, feet, and orofacial muscles and other joints of the body. Availability of human embryonic muscle tissue has been a limiting factor in investigating the properties of this isoform and its mutations. Using a recombinant expression system, we have studied homogeneous samples of human motors for the WT and three of the most common FSS mutants: R672H, R672C, and T178I. Our data suggest that the WT embryonic myosin motor is similar in contractile speed to the slow type I/beta cardiac based on the rate constant for ADP release and ADP affinity for actin-myosin. All three FSS mutations show dramatic changes in kinetic properties, most notably the slowing of the apparent ATP hydrolysis step (reduced 5-9-fold), leading to a longer lived detached state and a slowed Vmax of the ATPase (2-35-fold), indicating a slower cycling time. These mutations therefore seriously disrupt myosin function. PMID- 26945065 TI - The Sodium Glucose Cotransporter SGLT1 Is an Extremely Efficient Facilitator of Passive Water Transport. AB - The small intestine is void of aquaporins adept at facilitating vectorial water transport, and yet it reabsorbs ~8 liters of fluid daily. Implications of the sodium glucose cotransporter SGLT1 in either pumping water or passively channeling water contrast with its reported water transporting capacity, which lags behind that of aquaporin-1 by 3 orders of magnitude. Here we overexpressed SGLT1 in MDCK cell monolayers and reconstituted the purified transporter into proteoliposomes. We observed the rate of osmotic proteoliposome deflation by light scattering. Fluorescence correlation spectroscopy served to assess (i) SGLT1 abundance in both vesicles and plasma membranes and (ii) flow-mediated dilution of an aqueous dye adjacent to the cell monolayer. Calculation of the unitary water channel permeability, pf, yielded similar values for cell and proteoliposome experiments. Neither the absence of glucose or Na(+), nor the lack of membrane voltage in vesicles, nor the directionality of water flow grossly altered pf Such weak dependence on protein conformation indicates that a water impermeable occluded state (glucose and Na(+) in their binding pockets) lasts for only a minor fraction of the transport cycle or, alternatively, that occlusion of the substrate does not render the transporter water-impermeable as was suggested by computational studies of the bacterial homologue vSGLT. Although the similarity between the pf values of SGLT1 and aquaporin-1 makes a transcellular pathway plausible, it renders water pumping physiologically negligible because the passive flux would be orders of magnitude larger. PMID- 26945067 TI - Streptococcus pyogenes Employs Strain-dependent Mechanisms of C3b Inactivation to Inhibit Phagocytosis and Killing of Bacteria. AB - Evasion of complement-mediated opsonophagocytosis enables group A Streptococcus pyogenes (GAS) to establish infection. Different strain-dependent mechanisms are employed by the host to accomplish this goal. In general, GAS inhibits the amplification of the complement cascade on its cell surface by facilitating the degradation of C3b, an opsonin, to an inactive product, inactivated C3b (iC3b), in a step catalyzed by factor I (FI) and its cofactor, factor H (FH), with or without the participation of human host plasmin (hPm). GAS recruits FH to its cell surface via FH receptors, which are transcriptionally controlled by the two component cluster of virulence responder-sensor system. The manner in which FI-FH and hPm function together on GAS cells is unknown. Using GAS strain AP53, which strongly binds host human plasminogen/plasmin (hPg/hPm) directly via an hPg/hPm surface receptor (PAM), we show that both FI-FH and hPm sequentially cleave C3b. Whereas FI-FH proteolytically cleaves C3b into iC3b, PAM-bound hPm catalyzes cleavage of iC3b into multiple smaller peptides. Unlike AP53, GAS strain M23ND weakly binds FH and recruits hPg/hPm to its cell surface indirectly via fibrinogen bound to M-protein, M23. In this case, FH-FI cleaves C3b into iC3b, with negligible degradation of iC3b by hPm that is bound to fibrinogen on the cells. AP53 and M23ND display similar resistance to human neutrophil-mediated phagocytosis, which results in a corresponding high lethality in mice after injection of these cells. These results suggest that GAS utilizes diverse mechanisms to degrade C3b and thus to protect bacterial cells from the complement response of the host. PMID- 26945066 TI - Oxidant-induced Interprotein Disulfide Formation in Cardiac Protein DJ-1 Occurs via an Interaction with Peroxiredoxin 2. AB - The role and responses of the dimeric DJ-1 protein to cardiac oxidative stress is incompletely understood. H2O2 induces a 50-kDa DJ-1 interprotein homodimer disulfide, known to form between Cys-53 on each subunit. A trimeric 75-kDa DJ-1 complex that mass spectrometry shows contained 2-Cys peroxiredoxin also formed and precedes the appearance of the disulfide dimer. These observations may represent peroxiredoxin sensing and transducing the oxidant signal to DJ-1. The dimeric disulfide DJ-1 complex was stabilized by auranofin, suggesting that thioredoxin recycles it in cells. Higher concentrations of H2O2 concomitantly induce DJ-1 Cys-106 hyperoxidation (sulfination or sulfonation) in myocytes, perfused heart, or HEK cells. An oxidation-resistant C53A DJ-1 shows potentiated H2O2-induced Cys-106 hyperoxidation. DJ-1 also forms multiple disulfides with unknown target proteins during H2O2 treatment, the formation of which is also potentiated in cells expressing the C53A mutant. This suggests that the intersubunit disulfide induces a conformational change that limits Cys-106 forming heterodisulfide protein complexes or from hyperoxidizing. High concentrations of H2O2 also induce cell death, with DJ-1 Cys-106 sulfonation appearing causal in these events, as expressionof C53A DJ-1 enhanced both Cys-106 sulfonation and cell death. Nonetheless, expression of the DJ-1 C106A mutant, which fully prevents hyperoxidation, also showed exacerbated cell death responses to H2O2 A rational explanation for these findings is that DJ-1 Cys-106 forms disulfides with target proteins to limit oxidant-induced cell death. However, when Cys-106 is hyperoxidized, formation of these potentially protective heterodimeric disulfide complexes is limited, and so cell death is exacerbated. PMID- 26945068 TI - Grp94 Protein Delivers gamma-Aminobutyric Acid Type A (GABAA) Receptors to Hrd1 Protein-mediated Endoplasmic Reticulum-associated Degradation. AB - Proteostasis maintenance of gamma-aminobutyric acid type A (GABAA) receptors dictates their function in controlling neuronal inhibition in mammalian central nervous systems. However, as a multisubunit, multispan, integral membrane protein, even wild type subunits of GABAA receptors fold and assemble inefficiently in the endoplasmic reticulum (ER). Unassembled and misfolded subunits undergo ER-associated degradation (ERAD), but this degradation process remains poorly understood for GABAA receptors. Here, using the alpha1 subunits of GABAA receptors as a model substrate, we demonstrated that Grp94, a metazoan specific Hsp90 in the ER lumen, uses its middle domain to interact with the alpha1 subunits and positively regulates their ERAD. OS-9, an ER-resident lectin, acts downstream of Grp94 to further recognize misfolded alpha1 subunits in a glycan-dependent manner. This delivers misfolded alpha1 subunits to the Hrd1 mediated ubiquitination and the valosin-containing protein-mediated extraction pathway. Repressing the initial ERAD recognition step by inhibiting Grp94 enhances the functional surface expression of misfolding-prone alpha1(A322D) subunits, which causes autosomal dominant juvenile myoclonic epilepsy. This study clarifies a Grp94-mediated ERAD pathway for GABAA receptors, which provides a novel way to finely tune their function in physiological and pathophysiological conditions. PMID- 26945069 TI - Fascin Rigidity and L-plastin Flexibility Cooperate in Cancer Cell Invadopodia and Filopodia. AB - Invadopodia and filopodia are dynamic, actin-based protrusions contributing to cancer cell migration, invasion, and metastasis. The force of actin bundles is essential for their protrusive activity. The bundling protein fascin is known to play a role in both invadopodia and filopodia. As it is more and more acknowledged that functionally related proteins cooperate, it is unlikely that only fascin bundles actin in these protrusions. Another interesting candidate is L-plastin, normally expressed in hematopoietic cells, but considered a common marker of many cancer types. We identified L-plastin as a new component of invadopodia, where it contributes to degradation and invasiveness. By means of specific, high-affinity nanobodies inhibiting bundling of fascin or L-plastin, we further unraveled their cooperative mode of action. We show that the bundlers cannot compensate for each other due to strikingly different bundling characteristics: L-plastin bundles are much thinner and less tightly packed. Composite bundles adopt an intermediate phenotype, with fascin delivering the rigidity and strength for protrusive force and structural stability, whereas L plastin accounts for the flexibility needed for elongation. Consistent with this, elevated L-plastin expression promotes elongation and reduces protrusion density in cells with relatively lower L-plastin than fascin levels. PMID- 26945070 TI - Structural Insights into the Transport Mechanism of the Human Sodium-dependent Lysophosphatidylcholine Transporter MFSD2A. AB - Major facilitator superfamily domain containing 2A (MFSD2A) was recently characterized as a sodium-dependent lysophosphatidylcholine transporter expressed at the blood-brain barrier endothelium. It is the primary route for importation of docosohexaenoic acid and other long-chain fatty acids into fetal and adult brain and is essential for mouse and human brain growth and function. Remarkably, MFSD2A is the first identified major facilitator superfamily member that uniquely transports lipids, implying that MFSD2A harbors unique structural features and transport mechanism. Here, we present three three-dimensional structural models of human MFSD2A derived by homology modeling using MelB- and LacY-based crystal structures and refined by biochemical analysis. All models revealed 12 transmembrane helices and connecting loops and represented the partially outward open, outward-partially occluded, and inward-open states of the transport cycle. In addition to a conserved sodium-binding site, three unique structural features were identified as follows: a phosphate headgroup binding site, a hydrophobic cleft to accommodate a hydrophobic hydrocarbon tail, and three sets of ionic locks that stabilize the outward-open conformation. Ligand docking studies and biochemical assays identified Lys-436 as a key residue for transport. It is seen forming a salt bridge with the negative charge on the phosphate headgroup. Importantly, MFSD2A transported structurally related acylcarnitines but not a lysolipid without a negative charge, demonstrating the necessity of a negatively charged headgroup interaction with Lys-436 for transport. These findings support a novel transport mechanism by which lysophosphatidylcholines are "flipped" within the transporter cavity by pivoting about Lys-436 leading to net transport from the outer to the inner leaflet of the plasma membrane. PMID- 26945072 TI - Spotlight on atrial fibrillation in Cardiovascular Research. PMID- 26945071 TI - Caspase Cleavages of the Lymphocyte-oriented Kinase Prevent Ezrin, Radixin, and Moesin Phosphorylation during Apoptosis. AB - The lymphocyte-oriented kinase (LOK), also called serine threonine kinase 10 (STK10), is synthesized mainly in lymphocytes. It is involved in lymphocyte migration and polarization and can phosphorylate ezrin, radixin, and moesin (the ERM proteins). In a T lymphocyte cell line and in purified human lymphocytes, we found LOK to be cleaved by caspases during apoptosis. The first cleavage occurs at aspartic residue 332, located between the kinase domain and the coiled-coil regulation domain. This cleavage generates an N-terminal fragment, p50 N-LOK, containing the kinase domain and a C-terminal fragment, which is further cleaved during apoptosis. Although these cleavages preserve the entire kinase domain, p50 N-LOK displays no kinase activity. In apoptotic lymphocytes, caspase cleavages of LOK are concomitant with a decrease in ERM phosphorylation. When non-apoptotic lymphocytes from mice with homozygous and heterozygous LOK knockout were compared, the latter showed a higher level of ERM phosphorylation, but when apoptosis was induced, LOK(-/-) and LOK(+/-) lymphocytes showed the same low level, confirming in vivo that LOK-induced ERM phosphorylation is prevented during lymphocyte apoptosis. Our results demonstrate that cleavage of LOK during apoptosis abolishes its kinase activity, causing a decrease in ERM phosphorylation, crucial to the role of the ERM proteins in linking the plasma membrane to actin filaments. PMID- 26945074 TI - Dynamics of PKA phosphorylation and gain of function in cardiac pacemaker cells: a computational model analysis. AB - Cardiac pacemaker cell function is regulated by a coupled-clock system that integrates molecular cues on the cell-membrane surface (i.e., membrane clock) and on the sarcoplasmic reticulum (SR) (i.e., Ca(2+) clock). A recent study has shown that cotransfection of spontaneous beating cells (HEK293 cells and neonatal rat myocytes) with R524Q-mutant human hyperpolarization-activated cyclic nucleotide gated molecules (the dominant component of funny channels) increases the funny channel's sensitivity to cAMP and leads to a decrease in spontaneous action potential (AP) cycle length (i.e., tachycardia). We hypothesize that in rabbit pacemaker cells, the same behavior is expected, and because of the coupled-clock system, the resultant steady-state decrease in AP cycle length will embody contributions from both clocks: the initial decrease in the spontaneous AP beating interval, arising from increased sensitivity of the f-channel to cAMP, will be accompanied by an increase in the adenylyl cyclase (AC)-cAMP-PKA dependent phosphorylation activity, which will further decrease this interval. To test our hypothesis, we used the recently developed Yaniv-Lakatta pacemaker cell numerical model. This model predicts the cAMP signaling dynamics, as well as the kinetics and magnitude of protein phosphorylation in both normal and mutant pacemaker cells. We found that R524Q-mutant pacemaker cells have a shorter AP firing rate than that of wild-type cells and that gain in pacemaker function is the net effect of the R514Q mutation on the functioning of the coupled-clock system. Specifically, our results directly support the hypothesis that changes in Ca(2+)-activated AC-cAMP-PKA signaling are involved in the development of tachycardia in R524Q-mutant pacemaker cells. PMID- 26945073 TI - Advanced age decreases local calcium signaling in endothelium of mouse mesenteric arteries in vivo. AB - Aging is associated with vascular dysfunction that impairs tissue perfusion, physical activity, and the quality of life. Calcium signaling in endothelial cells (ECs) is integral to vasomotor control, exemplified by localized Ca(2+) signals within EC projections through holes in the internal elastic lamina (IEL). Within these microdomains, endothelium-derived hyperpolarization is integral to smooth muscle cell (SMC) relaxation via coupling through myoendothelial gap junctions. However, the effects of aging on local EC Ca(2+) signals (and thereby signaling between ECs and SMCs) remain unclear, and these events have not been investigated in vivo. Furthermore, it is unknown whether aging affects either the number or the size of IEL holes. In the present study, we tested the hypothesis that local EC Ca(2+) signaling is impaired with advanced age along with a reduction in IEL holes. In anesthetized mice expressing a Ca(2+)-sensitive fluorescent protein (GCaMP2) selectively in ECs, our findings illustrate that for mesenteric arteries controlling splanchnic blood flow the frequency of spontaneous local Ca(2+) signals in ECs was reduced by ~85% in old (24-26 mo) vs. young (3-6 mo) animals. At the same time, the number (and total area) of holes per square millimeter of IEL was reduced by ~40%. We suggest that diminished signaling between ECs and SMCs contributes to dysfunction of resistance arteries with advanced age.Listen to this article's corresponding podcast at http://ajpheart.podbean.com/e/aging-impairs-endothelial-ca2-signaling/. PMID- 26945075 TI - Ac-SDKP suppresses TNF-alpha-induced ICAM-1 expression in endothelial cells via inhibition of IkappaB kinase and NF-kappaB activation. AB - N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is a naturally occurring tetrapeptide that prevents inflammation and fibrosis in hypertension and other cardiovascular diseases. We previously showed that, in angiotensin II-induced hypertension, Ac-SDKP decreased the activation of nuclear transcription factor NF kappaB, whereas, in experimental autoimmune myocarditis and hypertension animal models, it also reduced the expression of endothelial leukocyte adhesion molecule ICAM-1. However, the mechanisms by which Ac-SDKP downregulated ICAM-1 expression are still unclear. TNF-alpha is a proinflammatory cytokine that induces ICAM-1 expression in various cell types via TNF receptor 1 and activation of the classical NF-kappaB pathway. We hypothesized that in endothelial cells Ac-SDKP suppresses TNF-alpha-induced ICAM-1 expression by decreasing IKK phosphorylation that as a consequence leads to a decrease of IkappaB phosphorylation and NF kappaB activation. To test this hypothesis, human coronary artery endothelial cells were treated with Ac-SDKP and then stimulated with TNF-alpha. We found that TNF-alpha-induced ICAM-1 expression was significantly decreased by Ac-SDKP in a dose-dependent manner. Ac-SDKP also decreased TNF-alpha-induced NF-kappaB translocation from cytosol to nucleus, as assessed by electrophoretic mobility shift assay, which correlated with a decrease in IkappaB phosphorylation. In addition, we found that Ac-SDKP decreased TNF-alpha-induced IKK phosphorylation and IKK-beta expression. However, Ac-SDKP had no effect on TNF-alpha-induced phosphorylation of p38 MAP kinase or ERK. Thus we conclude that Ac-SDKP inhibition of TNF-alpha activation of canonical, i.e., IKK-beta-dependent, NF kappaB pathway and subsequent decrease in ICAM-1 expression is achieved via inhibition of IKK-beta. PMID- 26945077 TI - Influence of passive stretch on muscle blood flow, oxygenation and central cardiovascular responses in healthy young males. AB - The aim of this study was to examine the effect of skeletal muscle stretching on peripheral, central, and autonomic cardiovascular responses in humans. Twelve healthy males completed a controlled passive stretch of the plantar flexors for 4 min at three different intensities. Doppler ultrasound velocimetry and imaging techniques assessed mean leg blood flow (MLBF), antegrade blood flow, and retrograde blood flow of the popliteal artery. Near-infrared spectroscopy assessed the concentration of deoxygenated hemoglobin + myoglobin ([HHb]) and the sum of its deoxygenated and oxygenated forms [i.e., blood volume ([Hbtot])]. Heart rate (HR) and mean arterial pressure were measured simultaneously to peripheral hemodynamic responses. During stretch there was an increase (P < 0.05) in antegrade and retrograde blood flow along with [HHb] and [Hbtot] relative to baseline, whereas MLBF was not altered. HR increased (P < 0.01) in a stretch intensity- and time-dependent manner, suggesting a threshold tension must be met that results in a mechanoreflex-mediated increase in HR. After stretch there was an increase (P < 0.05) in [Hbtot] and MLBF in each condition, suggesting that stretch creates a poststretch hyperemic response. Furthermore, retrograde blood flow was decreased (P < 0.05) after stretch in each stretch condition. Mean arterial pressure was decreased (P < 0.05) after moderate-intensity stretching. Collectively, our data provide novel mechanistic evidence on cardiovascular responses to skeletal muscle stretching in humans. Moreover, the reductions in MAP and retrograde blood flow suggest that stretch transiently reduces myogenic vascular tone in a poststretch resting period. PMID- 26945076 TI - A mathematical model of coronary blood flow control: simulation of patient specific three-dimensional hemodynamics during exercise. AB - This work presents a mathematical model of the metabolic feedback and adrenergic feedforward control of coronary blood flow that occur during variations in the cardiac workload. It is based on the physiological observations that coronary blood flow closely follows myocardial oxygen demand, that myocardial oxygen debts are repaid, and that control oscillations occur when the system is perturbed and so are phenomenological in nature. Using clinical data, we demonstrate that the model can provide patient-specific estimates of coronary blood flow changes between rest and exercise, requiring only the patient's heart rate and peak aortic pressure as input. The model can be used in zero-dimensional lumped parameter network studies or as a boundary condition for three-dimensional multidomain Navier-Stokes blood flow simulations. For the first time, this model provides feedback control of the coronary vascular resistance, which can be used to enhance the physiological accuracy of any hemodynamic simulation, which includes both a heart model and coronary arteries. This has particular relevance to patient-specific simulation for which heart rate and aortic pressure recordings are available. In addition to providing a simulation tool, under our assumptions, the derivation of our model shows that beta-feedforward control of the coronary microvascular resistance is a mathematical necessity and that the metabolic feedback control must be dependent on two error signals: the historical myocardial oxygen debt, and the instantaneous myocardial oxygen deficit. PMID- 26945079 TI - NADPH oxidase 4 attenuates cerebral artery changes during the progression of Marfan syndrome. AB - Marfan syndrome (MFS) is a connective tissue disorder that is often associated with the fibrillin-1 (Fbn1) gene mutation and characterized by cardiovascular alterations, predominantly ascending aortic aneurysms. Although neurovascular complications are uncommon in MFS, the improvement in Marfan patients' life expectancy is revealing other secondary alterations, potentially including neurovascular disorders. However, little is known about small-vessel pathophysiology in MFS. MFS is associated with hyperactivated transforming growth factor (TGF)-beta signaling, which among numerous other downstream effectors, induces the NADPH oxidase 4 (Nox4) isoform of NADPH oxidase, a strong enzymatic source of H2O2 We hypothesized that MFS induces middle cerebral artery (MCA) alterations and that Nox4 contributes to them. MCA properties from 3-, 6-, or 9 mo-old Marfan (Fbn1(C1039G/+)) mice were compared with those from age/sex-matched wild-type littermates. At 6 mo, Marfan compared with wild-type mice developed higher MCA wall/lumen (wild-type: 0.081 +/- 0.004; Marfan: 0.093 +/- 0.002; 60 mmHg; P < 0.05), coupled with increased reactive oxygen species production, TGF beta, and Nox4 expression. However, wall stiffness and myogenic autoregulation did not change. To investigate the influence of Nox4 on cerebrovascular properties, we generated Marfan mice with Nox4 deficiency (Nox4(-/-)). Strikingly, Nox4 deletion in Marfan mice aggravated MCA wall thickening (cross sectional area; Marfan: 6,660 +/- 363 MUm(2); Marfan Nox4(-/-): 8,795 +/- 824 MUm(2); 60 mmHg; P < 0.05), accompanied by decreased TGF-beta expression and increased collagen deposition and Nox1 expression. These findings provide the first evidence that Nox4 mitigates cerebral artery structural changes in a murine model of MFS. PMID- 26945078 TI - Depolarization of mitochondria in neurons promotes activation of nitric oxide synthase and generation of nitric oxide. AB - The diverse signaling events following mitochondrial depolarization in neurons are not clear. We examined for the first time the effects of mitochondrial depolarization on mitochondrial function, intracellular calcium, neuronal nitric oxide synthase (nNOS) activation, and nitric oxide (NO) production in cultured neurons and perivascular nerves. Cultured rat primary cortical neurons were studied on 7-10 days in vitro, and endothelium-denuded cerebral arteries of adult Sprague-Dawley rats were studied ex vivo. Diazoxide and BMS-191095 (BMS), activators of mitochondrial KATP channels, depolarized mitochondria in cultured neurons and increased cytosolic calcium levels. However, the mitochondrial oxygen consumption rate was unaffected by mitochondrial depolarization. In addition, diazoxide and BMS not only increased the nNOS phosphorylation at positive regulatory serine 1417 but also decreased nNOS phosphorylation at negative regulatory serine 847. Furthermore, diazoxide and BMS increased NO production in cultured neurons measured with both fluorescence microscopy and electron spin resonance spectroscopy, which was sensitive to inhibition by the selective nNOS inhibitor 7-nitroindazole (7-NI). Diazoxide also protected cultured neurons against oxygen-glucose deprivation, which was blocked by NOS inhibition and rescued by NO donors. Finally, BMS induced vasodilation of endothelium denuded, freshly isolated cerebral arteries that was diminished by 7-NI and tetrodotoxin. Thus pharmacological depolarization of mitochondria promotes activation of nNOS leading to generation of NO in cultured neurons and endothelium-denuded arteries. Mitochondrial-induced NO production leads to increased cellular resistance to lethal stress by cultured neurons and to vasodilation of denuded cerebral arteries. PMID- 26945080 TI - Endothelial SK3 channel-associated Ca2+ microdomains modulate blood pressure. AB - Activation of vascular endothelial small- (KCa2.3, SK3) or intermediate- (KCa3.1, IK1) conductance Ca(2+)-activated potassium channels induces vasorelaxation via an endothelium-derived hyperpolarization (EDH) pathway. Although the activation of SK3 and IK1 channels converges on EDH, their subcellular effects on signal transduction are different and not completely clear. In this study, a novel endothelium-specific SK3 knockout (SK3(-/-)) mouse model was utilized to specifically examine the contribution of SK3 channels to mesenteric artery vasorelaxation, endothelial Ca(2+) dynamics, and blood pressure. The absence of SK3 expression was confirmed using real-time quantitative PCR and Western blot analysis. Functional studies showed impaired EDH-mediated vasorelaxation in SK3( /-) small mesenteric arteries. Immunostaining results from SK3(-/-) vessels confirmed the absence of SK3 and further showed altered distribution of transient receptor potential channels, type 4 (TRPV4). Electrophysiological recordings showed a lack of SK3 channel activity, while TRPV4-IK1 channel coupling remained intact in SK3(-/-) endothelial cells. Moreover, Ca(2+) imaging studies in SK3(-/ ) endothelium showed increased Ca(2+) transients with reduced amplitude and duration under basal conditions. Importantly, SK3(-/-) endothelium lacked a distinct type of Ca(2+) dynamic that is sensitive to TRPV4 activation. Blood pressure measurements showed that the SK3(-/-) mice were hypertensive, and the blood pressure increase was further enhanced during the 12-h dark cycle when animals are most active. Taken together, our results reveal a previously unappreciated SK3 signaling microdomain that modulates endothelial Ca(2+) dynamics, vascular tone, and blood pressure. PMID- 26945081 TI - Extracellular sodium dependence of the conduction velocity-calcium relationship: evidence of ephaptic self-attenuation. AB - Our laboratory previously demonstrated that perfusate sodium and potassium concentrations can modulate cardiac conduction velocity (CV) consistent with theoretical predictions of ephaptic coupling (EpC). EpC depends on the ionic currents and intercellular separation in sodium channel rich intercalated disk microdomains like the perinexus. We suggested that perinexal width (WP) correlates with changes in extracellular calcium ([Ca(2+)]o). Here, we test the hypothesis that increasing [Ca(2+)]o reduces WP and increases CV. Mathematical models of EpC also predict that reducing WP can reduce sodium driving force and CV by self-attenuation. Therefore, we further hypothesized that reducing WP and extracellular sodium ([Na(+)]o) will reduce CV consistent with ephaptic self attenuation. Transmission electron microscopy revealed that increasing [Ca(2+)]o (1 to 3.4 mM) significantly decreased WP Optically mapping wild-type (WT) (100% Cx43) mouse hearts demonstrated that increasing [Ca(2+)]o increases transverse CV during normonatremia (147.3 mM), but slows transverse CV during hyponatremia (120 mM). Additionally, CV in heterozygous (~50% Cx43) hearts was more sensitive to changes in [Ca(2+)]o relative to WT during normonatremia. During hyponatremia, CV slowed in both WT and heterozygous hearts to the same extent. Importantly, neither [Ca(2+)]o nor [Na(+)]o altered Cx43 expression or phosphorylation determined by Western blotting, or gap junctional resistance determined by electrical impedance spectroscopy. Narrowing WP, by increasing [Ca(2+)]o, increases CV consistent with enhanced EpC between myocytes. Interestingly, during hyponatremia, reducing WP slowed CV, consistent with theoretical predictions of ephaptic self-attenuation. This study suggests that serum ion concentrations may be an important determinant of cardiac disease expression. PMID- 26945083 TI - The impact of scaled boundary conditions on wall shear stress computations in atherosclerotic human coronary bifurcations. AB - The aim of this study was to determine if reliable patient-specific wall shear stress (WSS) can be computed when diameter-based scaling laws are used to impose the boundary conditions for computational fluid dynamics. This study focused on mildly diseased human coronary bifurcations since they are predilection sites for atherosclerosis. Eight patients scheduled for percutaneous coronary intervention were imaged with angiography. The velocity proximal and distal of a bifurcation was acquired with intravascular Doppler measurements. These measurements were used for inflow and outflow boundary conditions for the first set of WSS computations. For the second set of computations, absolute inflow and outflow ratios were derived from geometry-based scaling laws based on angiography data. Normalized WSS maps per segment were obtained by dividing the absolute WSS by the mean WSS value. Absolute and normalized WSS maps from the measured-approach and the scaled-approach were compared. A reasonable agreement was found between the measured and scaled inflows, with a median difference of 0.08 ml/s [-0.01; 0.20]. The measured and the scaled outflow ratios showed a good agreement: 1.5 percentage points [-19.0; 4.5]. Absolute WSS maps were sensitive to the inflow and outflow variations, and relatively large differences between the two approaches were observed. For normalized WSS maps, the results for the two approaches were equivalent. This study showed that normalized WSS can be obtained from angiography data alone by applying diameter-based scaling laws to define the boundary conditions. Caution should be taken when absolute WSS is assessed from computations using scaled boundary conditions. PMID- 26945082 TI - Exercise-induced protection against reperfusion arrhythmia involves stabilization of mitochondrial energetics. AB - Mitochondria influence cardiac electrophysiology through energy- and redox sensitive ion channels in the sarcolemma, with the collapse of energetics believed to be centrally involved in arrhythmogenesis. This study was conducted to determine if preservation of mitochondrial membrane potential (DeltaPsim) contributes to the antiarrhythmic effect of exercise. We utilized perfused hearts, isolated myocytes, and isolated mitochondria exposed to metabolic challenge to determine the effects of exercise on cardiac mitochondria. Hearts from sedentary (Sed) and exercised (Ex; 10 days of treadmill running) Sprague Dawley rats were perfused on a two-photon microscope stage for simultaneous measurement of DeltaPsim and ECG. After ischemia-reperfusion, the collapse of DeltaPsim was commensurate with the onset of arrhythmia. Exercise preserved DeltaPsim and decreased the incidence of fibrillation/tachycardia (P < 0.05). Our findings in intact hearts were corroborated in isolated myocytes exposed to in vitro hypoxia-reoxygenation, with Ex rats demonstrating enhanced redox control and sustained DeltaPsim during reoxygenation. Finally, we induced anoxia reoxygenation in isolated mitochondria using high-resolution respirometry with simultaneous measurement of respiration and H2O2 Mitochondria from Ex rats sustained respiration with lower rates of H2O2 emission than Sed rats. Exercise helps sustain postischemic mitochondrial bioenergetics and redox homeostasis, which is associated with preserved DeltaPsim and protection against reperfusion arrhythmia. The reduction of fatal ventricular arrhythmias through exercise induced mitochondrial adaptations indicates that mitochondrial therapeutics may be an effective target for the treatment of heart disease. PMID- 26945084 TI - Concomitant bidirectional transport during peritoneal dialysis can be explained by a structured interstitium. AB - Clinical and animal studies suggest that peritoneal absorption of fluid and protein from dialysate to peritoneal tissue, and to blood and lymph circulation, occurs concomitantly with opposite flows of fluid and protein, i.e., from blood to dialysate. However, until now a theoretical explanation of this phenomenon has been lacking. A two-phase distributed model is proposed to explain the bidirectional, concomitant transport of fluid, albumin and glucose through the peritoneal transport system (PTS) during peritoneal dialysis. The interstitium of this tissue is described as an expandable two-phase structure with phase F (water rich, colloid-poor region) and phase C (water-poor, colloid-rich region) with fluid and solute exchange between them. A low fraction of phase F is assumed in the intact tissue, which can be significantly increased under the influence of hydrostatic pressure and tissue hydration. The capillary wall is described using the three-pore model, and the conditions in the peritoneal cavity are assumed commencing 3 min after the infusion of glucose 3.86% dialysis fluid. Computer simulations demonstrate that peritoneal absorption of fluid into the tissue, which occurs via phase F at the rate of 1.8 ml/min, increases substantially the interstitial pressure and tissue hydration in both phases close to the peritoneal cavity, whereas the glucose-induced ultrafiltration from blood occurs via phase C at the rate of 15 ml/min. The proposed model delineating the phenomenon of concomitant bidirectional transport through PTS is based on a two-phase structure of the interstitium and provides results in agreement with clinical and experimental data. PMID- 26945085 TI - Prostaglandin D2 Modulates Neuronal Excitation of the Trigeminal Ganglion to Augment Allergic Rhinitis in Guinea Pigs. AB - Prostaglandin D2(PGD2) is involved in the pathogenesis of allergic rhinitis. However, the sensory nervous system-mediated contributions of PGD2to the symptoms of allergic rhinitis remain unclear. We investigated the involvement of PGD2in these symptoms and in neuronal excitation by in vivo and ex vivo experiments. In an ovalbumin-induced model of allergic rhinitis in guinea pigs, the number of sneezing, nasal rubbing, and nasal secretion events were assessed after the nasal cavity instillation of PGD2, histamine, or a combination of PGD2and histamine. In situ hybridization for PGD2receptor 1 (DP1) mRNA transcripts and immunohistochemical analysis of histamine H1receptor protein expression in guinea pig trigeminal ganglion (TRG) were performed. The effects of DP1receptor activation on the excitability of TRG neurons to electrical and histamine stimuli were assessed using whole-cell patch-clamp recordings. Histamine induced more sneezing, nasal rubbing, and nasal secretion events than PGD2 PGD2augmented histamine-induced responses, whereas pretreatment with a DP1receptor-selective antagonist completely suppressed PGD2-induced augmentation. DP1receptor mRNA transcripts and H1receptor protein expression could be detected in TRG neurons. Moreover, a DP1receptor agonist caused significant increases in the number of histamine-induced action potentials and depolarization, and reduced the current threshold in small-diameter neurons. Our findings show that PGD2-DP1receptor signaling augments the symptoms of allergic rhinitis via the sensory nervous system by modulating nasal neuronal activation to various stimuli, such as histamine. These findings suggest that DP1receptor antagonist has therapeutic potential for the treatment of allergic rhinitis. PMID- 26945086 TI - Role of Prostaglandin D2 and DP1 Receptor on Japanese Cedar Pollen-Induced Allergic Rhinitis in Mice. AB - Although we previously demonstrated the contribution of the DP1receptor in nasal obstruction using animals sensitized with ovalbumin in the presence of adjuvant, the contribution of the DP1receptor in sneezing is unclear. Here, we developed a mouse model of Japanese cedar (JC:Cryptomeria japonica) pollinosis to evaluate the symptoms of sneezing. To achieve this, we used JC pollen crude extract in the absence of adjuvant to sensitize mice to develop a model closer to the pathophysiology of human JC pollinosis. The immunologic and pharmacologic features of this model are highly similar to those observed in JC pollinosis in humans. Using this model, we found that DP1receptor antagonists suppressed JC pollen extract-induced sneezing and that a DP1receptor agonist induced sneezing. Moreover, JC pollen extract-induced sneezing was diminished in DP1receptor knockout mice. In conclusion, we developed a novel mouse model of allergic rhinitis that closely mimics human JC pollinosis. A strong contribution of DP1receptor signaling to sneezing was demonstrated using this model, suggesting that DP1receptor antagonists could suppress sneezing and nasal obstruction, and therefore these agents could be a new therapeutic option for allergic rhinitis. PMID- 26945087 TI - Histamine H3 Receptor Regulates Sensorimotor Gating and Dopaminergic Signaling in the Striatum. AB - The brain histamine system has been implicated in regulation of sensorimotor gating deficits and in Gilles de la Tourette syndrome. Histamine also regulates alcohol reward and consumption via H3 receptor (H3R), possibly through an interaction with the brain dopaminergic system. Here, we identified the histaminergic mechanism of sensorimotor gating and the role of histamine H3R in the regulation of dopaminergic signaling. We found that H3R knockout mice displayed impaired prepulse inhibition (PPI), indicating deficiency in sensorimotor gating. Histamine H1 receptor knockout and histidine decarboxylase knockout mice had similar PPI as their controls. Dopaminergic drugs increased PPI of H3R knockout mice to the same level as in control mice, suggesting that changes in dopamine receptors might underlie deficient PPI response when H3R is lacking. Striatal dopamine D1 receptor mRNA level was lower, and D1 and D2 receptor-mediated activation of extracellular signal-regulated kinase 1/2 was absent in the striatum of H3R knockout mice, suggesting that H3R is essential for the dopamine receptor-mediated signaling. In conclusion, these findings demonstrate that H3R is an important regulator of sensorimotor gating, and the lack of H3R significantly modifies striatal dopaminergic signaling. These data support the usefulness of H3R ligands in neuropsychiatric disorders with preattentional deficits and disturbances in dopaminergic signaling. PMID- 26945089 TI - Effect of Habitat Size, Quality, and Isolation on Functional Groups of Beetles in Hollow Oaks. AB - One of the largest threats to biodiversity is land use change and habitat loss. Hollow oaks (Quercus spp. L.) are well-defined patches that are hotspots for biodiversity and red-listed species, but they are often rare and fragmented in the landscape. We investigated the effect of patch size, habitat quality, and isolation on functional groups and red-listed saproxylic beetles in hollow oaks (n = 40) in Norway. The groups were defined by host tree association, trophic grouping, and red-listed status. Habitat quality, represented by tree form was most important in explaining species richness for most groups. Patch size, represented by circumference and amount of dead branches, was most important in explaining abundance. Isolation, that is single oaks compared with oaks in groups, had a negative effect on the abundance of beetles feeding both on wood and fungi (xylomycethopagous), as well as on species associated with broadleaved trees (oak semi-specialists), but did not affect species richness. This indicates that at this scale and in this landscape, isolated oaks are as species rich and valuable for conservation as other oaks, although some functional groups may be more vulnerable to isolation than others. The red-listed species only responded to patch size, indicating that oaks with large circumference and many dead branches are especially important for red-listed species and for conservation. PMID- 26945090 TI - Evidence of Male Hair Pencil Pheromone in Choristoneura fumiferana (Lepidoptera: Tortricidae). AB - Male Lepidoptera often possess specialized scales, called hair pencils that emit volatiles that are critical to mating success. Spruce budworm, Choristoneura fumiferana (Clemens) (Lepidoptera: Tortricidae), males will display hair pencils to females before attempting copulation. The importance of volatiles on these hair pencils is, however, not clear. We compared the proportion of successful copulations in unmanipulated mating pairs to pairs where males had their hair pencils either removed or chemically washed, and to pairs where females were antennectomized. Mean proportions of successful matings were significantly lower in pairs where hair pencils had been manipulated or where females had been antennectomized compared with unmanipulated mating pairs. There was no significant difference in mating success between treatments where hair pencils had been manipulated; however, mating success was significantly lower in hair pencil treatments than in antennectomized treatments. Mean copulation proportions in hair pencil/antennectomized treatments were also significantly less than in respective sham-operated treatments. Our results suggest that volatiles are associated with hair pencils, and they may be required for mating success in C. fumiferana. PMID- 26945088 TI - Genetic and Epigenetic Regulation of PD-1 Expression. AB - The inhibitory immune receptor programmed cell death-1 (PD-1) is intricately regulated. In T cells, PD-1 is expressed in response to most immune challenges, but it is rapidly downregulated in acute settings, allowing for normal immune responses. On chronically stimulated Ag-specific T cells, PD-1 expression remains high, leading to an impaired response to stimuli. Ab blockade of PD-1 interactions during chronic Ag settings partially restores immune function and is now used clinically to treat a variety of devastating cancers. Understanding the regulation of PD-1 expression may be useful for developing novel immune-based therapies. In this review, the molecular mechanisms that drive dynamic PD-1 expression during acute and chronic antigenic stimuli are discussed. An array of cis-DNA elements, transcription factors, and epigenetic components, including DNA methylation and histone modifications, control PD-1 expression. The interplay between these regulators fine-tunes PD-1 expression in different inflammatory environments and across numerous cell types to modulate immune responses. PMID- 26945092 TI - Circular RNAs: a new frontier in the study of human diseases. AB - Circular RNAs (circRNAs) are recently discovered new endogenous non-coding RNAs and an area of much research activity. In addition to their potential as major gene regulators, reports are linking heterogeneous circRNA groups with many different human disorders, especially cancer. In this review, we focus on the rapidly advancing field of circRNAs that play a part in human diseases. We list tools (eg, public databases) that scan genome spans of interest to identify known circRNAs; describe the relationship between dysregulated circRNAs and human disease, highlighting their specific roles; and consider the possible use of current and potential circRNA research applications in treating human diseases. Specifically, we review the role of circRNAs as biomarkers, drug targets and therapeutic agents. PMID- 26945093 TI - Selective down-regulation of KV2.1 function contributes to enhanced arterial tone during diabetes. PMID- 26945091 TI - Disialylated apolipoprotein C-III proteoform is associated with improved lipids in prediabetes and type 2 diabetes. AB - The apoC-III proteoform containing two sialic acid residues (apoC-III2) has different in vitro effects on lipid metabolism compared with asialylated (apoC III0) or the most abundant monosialylated (apoC-III1) proteoforms. Cross sectional and longitudinal associations between plasma apoC-III proteoforms (by mass spectrometric immunoassay) and plasma lipids were tested in two randomized clinical trials: ACT NOW, a study of pioglitazone in subjects with impaired glucose tolerance (n = 531), and RACED (n = 296), a study of intensive glycemic control and atherosclerosis in type 2 diabetes patients. At baseline, higher relative apoC-III2 and apoC-III2/apoC-III1 ratios were associated with lower triglycerides and total cholesterol in both cohorts, and with lower small dense LDL in the RACED. Longitudinally, changes in apoC-III2/apoC-III1 were inversely associated with changes in triglycerides in both cohorts, and with total and small dense LDL in the RACED. apoC-III2/apoC-III1 was also higher in patients treated with PPAR-gamma agonists and was associated with reduced cardiovascular events in the RACED control group. Ex vivo studies of apoC-III complexes with higher apoC-III2/apoC-III1 showed attenuated inhibition of VLDL uptake by HepG2 cells and LPL-mediated lipolysis, providing possible functional explanations for the inverse association between a higher apoC-III2/apoC-III1 and hypertriglyceridemia, proatherogenic plasma lipid profiles, and cardiovascular risk. PMID- 26945094 TI - The arithmetic of reducing relative and absolute inequalities in health: a theoretical analysis illustrated with European mortality data. AB - BACKGROUND: Reducing inequalities in health is a great challenge for public health, but how relative and absolute inequalities in mortality respond to changes in mortality by socioeconomic group is not well understood. METHODS: We derived arithmetically what combinations of changes and starting levels of mortality by socioeconomic group produce narrowing, and what combinations produce widening of relative and absolute inequalities in mortality. We then determined empirically how often these scenarios actually occur with data on inequalities in cause-specific mortality in five European countries spanning four decades (1970 2010). RESULTS: Changes in the rate ratio depend exclusively on the ratio of relative mortality change between socioeconomic groups, whereas changes in the rate difference depend on whether the ratio of relative mortality change between socioeconomic groups is larger or smaller than the rate ratio. This implies that, in case of declining mortality and faster relative mortality decline in higher socioeconomic groups, the rate difference will increase until the rate ratio becomes equal to the ratio of relative mortality decline, but will then start to decline. In the most common scenario in our data set (starting rate ratio above 1.00 and faster relative mortality decline in higher than lower socioeconomic groups), the rate ratio indeed always goes up but the rate difference goes down in about half of all cases, sometimes after a period of growth. CONCLUSIONS: A narrowing of absolute inequalities occurs under a wider range of conditions than a narrowing of relative inequalities in mortality. PMID- 26945095 TI - Self-reported suicide ideation and attempts, and medical care for intentional self-harm in lesbians, gays and bisexuals in Sweden. AB - BACKGROUND: Minority sexual orientation is a robust risk indicator for self reported suicidal ideation and attempts. However, little is known about patterns of medical care for intentional self-harm in this vulnerable population. We investigate sexual orientation-related differences in self-reported lifetime suicide symptoms and medical care for intentional self-harm between 1969 and 2010, including age at initial treatment and recurrence. METHODS: We used data from the Stockholm Public Health Cohort, a population-based sample of 874 lesbians/gays, 841 bisexuals and 67 980 heterosexuals, whose self-administered surveys have been linked to nationwide registers. Estimates of risk for medical care were calculated as incidence rate ratios (IRR) with 95% CIs. RESULTS: Both suicidal ideation and attempts were more commonly reported by lesbian/gay and bisexual (LGB) individuals. Adjusting for risk-time and confounding, lesbians (IRR 3.8, 95% CI 2.7 to 5.4) and bisexual women (IRR 5.4, 95% CI 4.4 to 6.6) experienced elevated risk for medical care for intentional self-harm, as compared to heterosexual women. Gay men evidenced higher risk (IRR 2.1, 95% CI 1.3 to 3.4) as compared to heterosexual men. Recurrent medical care was more frequent in LGB individuals, especially in bisexual women and gay men. Lesbian and bisexual women were also younger than heterosexual women when they first received medical care for intentional self-harm. CONCLUSIONS: Positive histories of suicidal ideation, attempts and medical care for intentional self-harm, including higher levels of recurrence, are more prevalent among LGB individuals in contrast to heterosexuals. Lesbian/bisexual women evidence an earlier age of onset of treatment. Tailored prevention efforts are urgently needed. PMID- 26945097 TI - Role for male reconstruction in the era of assisted reproductive technology. PMID- 26945098 TI - A question of time: tissue adaptation to mechanical forces. AB - While much attention has been focused on the force-generating mechanisms responsible for shaping developing embryos, less is known about the ways in which cells in animal tissues respond to mechanical stimuli. Forces will arise within a tissue as the result of processes such as local cell death, growth and division, but they can also be an indirect consequence of morphogenetic movements in neighbouring tissues or be imposed from the outside, for example, by gravity. If not dealt with, the accumulation of stress and the resulting tissue deformation can pose a threat to tissue integrity and structure. Here we follow the time course of events by which cells and tissues return to their preferred state following a mechanical perturbation. In doing so, we discuss the spectrum of biological and physical mechanisms known to underlie mechanical homeostasis in animal tissues. PMID- 26945099 TI - The improved antibody response against HIV-1 after a vaccination based on intrastructural help is complemented by functional CD8+ T cell responses. AB - Despite more than three decades of intense research, a prophylactic HIV-1 vaccine remains elusive. Four vaccine modalities have been evaluated in clinical efficacy studies, but only one demonstrated at least modest efficacy, which correlated with polyfunctional antibody responses to the HIV surface protein Env. To be most effective, a HIV-1 vaccine probably has to induce both, functional antibody and CD8(+) T cell responses. We therefore analyzed DNA/DNA and DNA/virus-like particle (VLP) regimens for their ability to induce humoral and cellular immune responses. Here, DNA vaccination of mice induced strong CD8(+) responses against Env and Gag. However, the humoral response to Env was dominated by IgG1, a subclass known for its low functionality. In contrast, priming only with the Gag encoding plasmid followed by a boost with VLPs consisting of Gag and Env improved the quality of the anti-Env antibody response via intrastructural help (ISH) provided by Gag-specific T cells to Env-specific B cells. Furthermore, the Gag specific CD8(+) T cells induced by the DNA prime immunization could still protect from a lethal infection with recombinant vaccinia virus encoding HIV Gag. Therefore, this immunization regimen represents a promising approach to combine functional antibody responses toward HIV Env with strong CD8(+) responses controlling early viral replication. PMID- 26945100 TI - Peripherally administered sera antibodies recognizing amyloid-beta oligomers mitigate Alzheimer's disease-like pathology and cognitive decline in aged 3* Tg AD mice. AB - Active and passive immunotherapy targeting amyloid-beta (Abeta) may be the most promising strategy to prevent or treat Alzheimer's disease (AD). Previously, immunization with the recombinant 6Abeta15-T antigen generated robust anti-Abeta serum antibodies that strongly recognized Abeta42 oligomers in different mice, markedly reduced the amyloid burden, and improved behavioral performance of immunized older AD mice. Here, we further determined that these anti-6Abeta15-T serum antibodies from different strains of mice displayed anti-Abeta antibody responses against the same epitopes in the Abeta1-15 region. Peripheral administration of anti-6Abeta15-T serum antibodies was also effective to mitigate AD-like pathology and cognitive decline in aged 3* Tg-AD mice. Specifically, the levels of Abeta and tau in the brains of 3* Tg-AD mice were significantly reduced after passive immunotherapy, which seemed necessary or beneficial to ameliorate memory impairment. In addition, our results showed that this immunotherapy also prevented presynaptic dynamin 1 degradation, which might help to further protect synaptic functions and allow functional recovery of cognition. Moreover, immunization with 6Abeta15-T in rabbits induced a similar antibody response as that in mice, and the rabbit serum antibodies reacted strongly with Abeta42 oligomers and inhibited oligomer-mediated neurotoxicity. We concluded that passive immunization with Abeta42 oligomer conformation-sensitive anti-6Abeta15-T serum antibodies is effective in providing potentially therapeutic effects in aged 3* Tg-AD mice by reducing Abeta and tau. PMID- 26945096 TI - Local and systemic factors and implantation: what is the evidence? AB - Significant progress has been made in the understanding of embryonic competence and endometrial receptivity since the inception of assisted reproductive technology. The endometrium is a highly dynamic tissue that plays a crucial role in the establishment and maintenance of normal pregnancy. In response to steroid sex hormones, the endometrium undergoes marked changes during the menstrual cycle that are critical for acceptance of the nascent embryo. There is also a wide body of literature on systemic factors that impact assisted reproductive technology outcomes. Patient prognosis is impacted by an array of factors that tip the scales in her favor or against success. Recognizing the local and systemic factors will allow clinicians to better understand and optimize the maternal environment at the time of implantation. This review will address the current literature on endometrial and systemic factors related to impaired implantation and highlight recent advances in this area of reproductive medicine. PMID- 26945102 TI - Study on the impact of pair production interaction on D-T controllable neutron density logging. AB - This paper considers the effect of pair production on the precision of D-T controllable neutron source density logging. Firstly, the principle of the traditional density logging and pulsed neutron density logging are analyzed and then gamma ray cross sections as a function of energy for various minerals are compared. In addition, the advantageous areas of Compton scattering and pair production interactions on high-energy gamma ray pulse height spectrum and the errors of a controllable source density measurement are studied using a Monte Carlo simulation method. The results indicate that density logging mainly utilizes the Compton scattering of gamma rays, while the attenuation of neutron induced gamma rays and the precision of neutron gamma density measurements are affected by pair production interactions, particularly in the gamma rays with energy higher than 2MeV. By selecting 0.2-2MeV energy range and performing proper lithology correction, the effect of pair production can be eliminated effectively and the density measurement error can be rendered close to the precision of chemical source density logging. PMID- 26945101 TI - CD4/CD8 ratio as a predictor of the response to HBV vaccination in HIV-positive patients: A prospective cohort study. AB - BACKGROUND: Hepatitis B virus (HBV) and human immunodeficiency virus (HIV) share transmission mechanisms and thus coinfection is frequent. Active immunization against HBV is essential in HIV patients. Reports using standard and reinforced HBV vaccination schedules vary widely in seroconversion rates depending on the characteristics of the included patients. Regional data concerning HBV vaccination in HIV patients are scarce. We aim to determine the serological response to HBV vaccination using standard schedule in HIV-positive patients and to evaluate characteristics that predict seroconversion. MATERIALS AND METHODS: We performed a single centre prospective study of HBV vaccination with standard schedule in HIV-positive patients. Adults with negative markers of HBV infection were included between November 2012 and December 2014. Anti-HBs titres were measured 4-8 weeks after completion of vaccination schedule. Clinical, laboratory values and HIV characteristics were analyzed to determine their association with seroconversion and adherence to the HBV vaccination schedule. RESULTS: The study included 245 HIV-positive patients, 68.9% were male and the mean age was 42.1 years. A total of 80.7% of the patients had undetectable HIV viral loads, 86.1% had CD4 counts >200, and 94.7% were on HAART. The response to vaccination was positive in 62% (95% CI, 56-68%) and mean anti-HBs titres of 646 IU/ml. 85.5% of the responders had anti-HBs titres >100 IU/ml. An age less than 45 years, no tobacco use and a CD4/CD8 ratio >0.4 were associated with seroconversion in multivariate analysis. The seroconversion rates were 86% in the subgroup of patients who met these criteria. A total of 97.9% of the study population completed the vaccination schedule. CONCLUSION: The CD4/CD8 ratio was the primary factor associated with positive serological conversion in the multivariate analysis. The seroconversion rates were higher in a selected group of patients who were particularly suitable for the use of the standard HBV vaccination schedule. PMID- 26945103 TI - A thioredoxin domain-containing protein 12 from black rockfish Sebastes schlegelii: Responses to immune challenges and protection from apoptosis against oxidative stress. AB - Thioredoxin (TXN) superfamily proteins are identified by the presence of a thioredoxin active site with a conserved CXXC active motif. TXN members are involved in a wide range of biochemical and biological functions including redox regulation, refolding of disulfide containing proteins, and regulation of transcription factors. In the present study, a thioredoxin domain-containing protein 12 was identified and characterized from black rockfish, Sebastes schlegelii (RfTXNDC12). The full length of RfTXNDC12 consists of a 522-bp coding region encoding a 173-amino acid protein. It has a 29-amino acid signal peptide and a single TXN active site with a consensus atypical WCGAC active motif. Multiple sequence alignment revealed that the active site is conserved among vertebrates. RfTXNDC12 shares highest identity with its Epinephelus coioides homolog. Transcriptional analysis revealed its ubiquitous expression in a wide range of tissues with the highest expression in the ovary. Immune challenges conducted with Streptococcus iniae and poly I:C caused upregulation of RfTXNDC12 transcript levels in gills and peripheral blood cells (PBCs), while lipopolysaccharide injection caused downregulation of RfTXNDC12 in gills and upregulation in PBCs. Similar to TXN, RfTXNDC12 exhibited insulin disulfide reducing activity. Interestingly, the recombinant protein showed significant protection of LNCaP cells against apoptosis induced by H2O2-mediated oxidative stress in a concentration dependent manner. Collectively, the present data indicate that RfTXNDC12 is a TXN superfamily member, which could function as a potential antioxidant enzyme and be involved in a defense mechanism against immune challenges. PMID- 26945104 TI - Adolescents growing with HIV/AIDS: experiences of the transition from pediatrics to adult care. AB - The main objective of this work is to describe the formation of the Transition Adolescent Clinic (TAC) and understand the process of transitioning adolescents with HIV/AIDS from pediatric to adult care, from the vantage point of individuals subjected to this process. A qualitative method and an intentional sample selected by criteria were adopted for this investigation, which was conducted in Sao Paulo, Brazil. An in-depth semi-structured interview was conducted with sixteen HIV-infected adolescents who had been part of a transitioning protocol. Adolescents expressed the need for more time to become adapted in the transition process. Having grown up under the care of a team of health care providers made many participants have reluctance toward transitioning. Concerns in moving away from their pediatricians and feelings of disruption, abandonment, or rejection were mentioned. Participants also expressed confidence in the pediatric team. At the same time they showed interest in the new team and expected to have close relationships with them. They also ask to have previous contacts with the adult health care team before the transition. Their talks suggest that they require slightly more time, not the time measured in days or months, but the time measured by constitutive experiences capable of building an expectation of future. This study examines the way in which the adolescents feel, and help to transform the health care transition model used at a public university. Listening to the adolescents' voices is crucial to a better understanding of their needs. They are those who can help the professionals reaching alternatives for a smooth and successful health care transition. PMID- 26945105 TI - A rare cause of seizures: brucellar brain abscess. PMID- 26945108 TI - Do group-specific equations provide the best estimates of stature? AB - An estimate of stature can be used by a forensic anthropologist with the preliminary identification of an unknown individual when human skeletal remains are recovered. Fordisc is a computer application that can be used to estimate stature; like many other methods it requires the user to assign an unknown individual to a specific group defined by sex, race/ancestry, and century of birth before an equation is applied. The assumption is that a group-specific equation controls for group differences and should provide the best results most often. In this paper we assess the utility and benefits of using group-specific equations to estimate stature using Fordisc. Using the maximum length of the humerus and the maximum length of the femur from individuals with documented stature, we address the question: Do sex-, race/ancestry- and century-specific stature equations provide the best results when estimating stature? The data for our sample of 19th Century White males (n=28) were entered into Fordisc and stature was estimated using 22 different equation options for a total of 616 trials: 19th and 20th Century Black males, 19th and 20th Century Black females, 19th and 20th Century White females, 19th and 20th Century White males, 19th and 20th Century any, and 20th Century Hispanic males. The equations were assessed for utility in any one case (how many times the estimated range bracketed the documented stature) and in aggregate using 1-way ANOVA and other approaches. This group-specific equation that should have provided the best results was outperformed by several other equations for both the femur and humerus. These results suggest that group-specific equations do not provide better results for estimating stature while at the same time are more difficult to apply because an unknown must be allocated to a given group before stature can be estimated. PMID- 26945109 TI - Road network safety evaluation using Bayesian hierarchical joint model. AB - Safety and efficiency are commonly regarded as two significant performance indicators of transportation systems. In practice, road network planning has focused on road capacity and transport efficiency whereas the safety level of a road network has received little attention in the planning stage. This study develops a Bayesian hierarchical joint model for road network safety evaluation to help planners take traffic safety into account when planning a road network. The proposed model establishes relationships between road network risk and micro level variables related to road entities and traffic volume, as well as socioeconomic, trip generation and network density variables at macro level which are generally used for long term transportation plans. In addition, network spatial correlation between intersections and their connected road segments is also considered in the model. A road network is elaborately selected in order to compare the proposed hierarchical joint model with a previous joint model and a negative binomial model. According to the results of the model comparison, the hierarchical joint model outperforms the joint model and negative binomial model in terms of the goodness-of-fit and predictive performance, which indicates the reasonableness of considering the hierarchical data structure in crash prediction and analysis. Moreover, both random effects at the TAZ level and the spatial correlation between intersections and their adjacent segments are found to be significant, supporting the employment of the hierarchical joint model as an alternative in road-network-level safety modeling as well. PMID- 26945107 TI - Glioma-Derived Platelet-Derived Growth Factor-BB Recruits Oligodendrocyte Progenitor Cells via Platelet-Derived Growth Factor Receptor-alpha and Remodels Cancer Stroma. AB - Glioma is an aggressive and incurable disease, and is frequently accompanied by augmented platelet-derived growth factor (PDGF) signaling. Overexpression of PDGF B ligand characterizes a specific subclass of glioblastoma multiforme, but the significance of the ligand remains to be elucidated. For this end, we implanted a glioma-cell line transfected with PDGF-BB-overexpressing vector (GL261-PDGF-BB) or control vector (GL261-vector) into wild-type mouse brain, and examined the effect of glioma-derived PDGF on the tumor microenvironment. The volume of GL261 PDGF-BB rapidly increased compared with GL261-vector. Recruitment of many PDGF receptor (PDGFR)-alpha and Olig2-positive oligodendrocyte precursor cells and frequent hemorrhages were observed in GL261-PDGF-BB but not in GL261-vector. We then implanted GL261-PDGF-BB into the mouse brain with and without Pdgfra gene inactivation, corresponding to PDGFRalpha-knockout (KO) and Flox mice, respectively. The recruitment of oligodendrocyte precursor cells was largely suppressed in PDGFRalpha-KO than in Flox, whereas the volume of GL261-PDGF-BB was comparable between the two genotypes. Frequent hemorrhage and increased IgG leakage were associated with aberrant vascular structures within the area where many recruited oligodendrocyte precursor cells accumulated in Flox. In contrast, these vascular phenotypes were largely normalized in PDGFRalpha-KO. Increased matrix metalloproteinase-9 in recruited oligodendrocyte precursor cells and decreased claudin-5 in vasculature may underlie the vascular abnormality. Glioma derived PDGF-B signal induces cancer stroma characteristically seen in high-grade glioma, and should be therapeutically targeted to improve cancer microenvironment. PMID- 26945106 TI - miR-133b Regulation of Connective Tissue Growth Factor: A Novel Mechanism in Liver Pathology. AB - miRNAs are involved in liver regeneration, and their expression is dysregulated in hepatocellular carcinoma (HCC). Connective tissue growth factor (CTGF), a direct target of miR-133b, is crucial in the ductular reaction (DR)/oval cell (OC) response for generating new hepatocyte lineages during liver injury in the context of hepatotoxin-inhibited hepatocyte proliferation. Herein, we investigate whether miR-133b regulation of CTGF influences HCC cell proliferation and migration, and DR/OC response. We analyzed miR-133b expression and found it to be down-regulated in HCC patient samples and induced in the rat DR/OC activation model of 2-acetylaminofluorene with partial hepatectomy. Furthermore, overexpression of miR-133b via adenoviral system in vitro led to decreased CTGF expression and reduced proliferation and Transwell migration of both HepG2 HCC cells and WBF-344 rat OCs. In vivo, overexpression of miR-133b in DR/OC activation models of 2-acetylaminofluorene with partial hepatectomy in rats, and 3,5-diethoxycarbonyl-1,4-dihydrocollidine in mice, led to down-regulation of CTGF expression and OC proliferation. Collectively, these results show that miR-133b regulation of CTGF is a novel mechanism critical for the proliferation and migration of HCC cells and OC response. PMID- 26945110 TI - Synthesis and evaluation of the cytotoxic activity of novel ethyl 4-[4-(4 substitutedpiperidin-1-yl)]benzyl-phenylpyrrolo[1,2-a]quinoxaline-carboxylate derivatives in myeloid and lymphoid leukemia cell lines. AB - Leukemia is the most common blood cancer, and its development starts at diverse points, leading to distinct subtypes that respond differently to therapy. This heterogeneity is rarely taken into account in therapies, so it is still essential to look for new specific drugs for leukemia subtypes or even for therapy resistant cases. Among heterocyclic compounds that attracted a lot of attention because of its wide spread biological activities, the pyrrolo[1,2-a]quinoxaline heterocyclic framework has been identified as interesting scaffolds for antiproliferative activity against various human cancer cell lines. In the present study, novel ethyl 4-[4-(4-substitutedpiperidin-1-yl)]benzyl phenylpyrrolo[1,2-a]quinoxaline-carboxylate derivatives 1a-l have been designed and synthesized. Their cytotoxicities were evaluated against five different leukemia cell lines, including Jurkat and U266 (lymphoid cell lines), and K562, U937, HL60 (myeloid cell lines), as well as normal human peripheral blood mononuclear cells (PBMNCs). Then, apoptosis study was performed with the more interesting compounds. The new pyrrolo[1,2-a]quinoxaline series showed promising cytotoxic potential against all leukemia cell lines tested, and some compounds showed better results than the reference compound A6730. Some compounds, such as 1a, 1e, 1g and 1h are promising because of their high activity against leukemia and their low activity against normal hematopoietic cells. Structure-activity relationships of these new synthetic compounds 1a-l are here also discussed. PMID- 26945111 TI - A new series of 2-phenol-4-aryl-6-chlorophenyl pyridine derivatives as dual topoisomerase I/II inhibitors: Synthesis, biological evaluation and 3D-QSAR study. AB - As a continuous effort to develop novel antitumor agents, a new series of forty five 2-phenol-4-aryl-6-chlorophenyl pyridine compounds were synthesized and evaluated for cytotoxicity against four different human cancer cell lines (DU145, HCT15, T47D, and HeLa), and topoisomerase I and II inhibitory activity. Several compounds (10-15, 20, 22, 24, 28, 42, and 49) displayed strong to moderate dual topoisomerase I and II inhibitory activity at 100 MUM. It was observed that hydroxyl and chlorine moiety at meta or para position of phenyl ring is favorable for dual topoisomerase inhibitory activity and cytotoxicity. Most of the compounds displayed stronger cytotoxicities than those of all positive controls against the HCT15 and T47D cell lines. For investigation of the structure activity relationships, a 3D-QSAR analysis using the method of comparative molecular field analysis (CoMFA) was performed. The generated 3D contour maps can be used for further rational design of novel terpyridine derivatives as highly selective and potent cytotoxic agents. PMID- 26945112 TI - Design, synthesis and Structure-activity relationship studies of new thiazole based free fatty acid receptor 1 agonists for the treatment of type 2 diabetes. AB - The free fatty acid receptor 1 (FFA1/GPR40) has attracted interest as a novel target for the treatment of type 2 diabetes. Several series of FFA1 agonists including TAK-875, the most advanced compound terminated in phase III studies due to concerns about liver toxicity, have been hampered by relatively high molecular weight and lipophilicity. Aiming to develop potent FFA1 agonists with low risk of liver toxicity by decreasing the lipophilicity, the middle phenyl of TAK-875 was replaced by 11 polar five-membered heteroaromatics. Subsequently, systematic exploration of SAR and application of molecular modeling, leads to the identification of compound 44, which was an excellent FFA1 agonist with robustly hypoglycemic effect both in normal and type 2 diabetic mice, low risks of hypoglycemia and liver toxicity even at the twice molar dose of TAK-875. Meanwhile, two important findings were noted. First, the methyl group in our thiazole series occupied a small hydrophobic subpocket which had no interactions with TAK-875. Furthermore, the agonistic activity revealed a good correlation with the dihedral angle between thiazole core and the terminal benzene ring. These results promote the understanding of ligand-binding pocket and might help to design more promising FFA1 agonists. PMID- 26945113 TI - Amyloid cascade in Alzheimer's disease: Recent advances in medicinal chemistry. AB - Alzheimer's disease is of major concern all over the world due to a number of factors including (i) an aging population (ii) increasing life span and (iii) lack of effective pharmacotherapy options. The past decade has seen intense research in discovering disease-modifying multitargeting small molecules as therapeutic options. The pathophysiology of Alzheimer's disease is attributed to a number of factors such as the cholinergic dysfunction, amyloid/tau toxicity and oxidative stress/mitochondrial dysfunction. In recent years, targeting the amyloid cascade has emerged as an attractive strategy to discover novel neurotherapeutics. Formation of beta-amyloid species, with different degrees of solubility and neurotoxicity is associated with the gradual decline in cognition leading to dementia. The two commonly used approaches to prevent beta-amyloid accumulation in the brain include (i) development of beta-secretase inhibitors and (ii) designing direct inhibitors of beta-amyloid (self-induced) aggregation. This review highlights the amyloid cascade hypothesis and the key chemical features required to design small molecules that inhibit lower and higher order beta-amyloid aggregates. Several recent examples of small synthetic molecules with disease-modifying properties were considered and their molecular docking studies were conducted using either a dimer or steric-zipper assembly of beta amyloid. These investigations provide a mechanistic understanding on the structural requirements needed to design novel small molecules with anti-amyloid aggregation properties. Significantly, this work also demonstrates that the structural requirements to prevent aggregation of various amyloid species differs considerably, which explains the fact that many small molecules do not exhibit similar inhibition profile toward diverse amyloid species such as dimers, trimers, tetramers, oligomers, protofibrils and fibrils. PMID- 26945114 TI - Environmental applications of inorganic-organic clays for recalcitrant organic pollutants removal: Bisphenol A. AB - Bisphenol-A (BPA) adsorption onto inorganic-organic clays (IOCs) was investigated. For this purpose, IOCs synthesised using octadecyltrimethylammonium bromide (ODTMA, organic modifier) and hydroxy aluminium (Al13, inorganic modifier) were used. Three intercalation methods were employed with varying ODTMA concentration in the synthesis of IOCs. Molecular interactions of clay surfaces with ODTMA and Al13 and their arrangements within the interlayers were determined using Fourier transform infrared spectroscopy (FTIR). Surface area and porous structure of IOCs were determined by applying Brunauer, Emmett, and Teller (BET) method to N2 adsorption-desorption isotherms. Surface area decreased upon ODTMA intercalation while it increased with Al13 pillaring. As a result, BET specific surface area of IOCs was considerably higher than those of organoclays. Initial concentration of BPA, contact time and adsorbent dose significantly affected BPA adsorption into IOCs. Pseudo-second order kinetics model is the best fit for BPA adsorption into IOCs. Both Langmuir and Freundlich adsorption isotherms were applicable for BPA adsorption (R(2)>0.91) for IOCs. Langmuir maximum adsorption capacity for IOCs was as high as 109.89mgg(-1) and it was closely related to the loaded ODTMA amount into the clay. Hydrophobic interactions between long alkyl chains of ODTMA and BPA are responsible for BPA adsorption into IOCs. PMID- 26945115 TI - Preparation of concentrated stable dispersions of uniform Ag nanoparticles using resorcinol as reductant. AB - Uniform silver nanoparticles ranging in size from 12 to 80nm were prepared by reducing silver ammonia complex with resorcinol in presence of Arabic gum. Despite the high ionic strength of the system, the precipitation process yields stable dispersions at metal concentrations as high as 4.0wt% (0.38moldm(-3)). Stable dispersions with higher solids concentration up to 20wt% silver (1.9moldm( 3)) were obtained by subjecting the 'as precipitated' dispersions to ultrafiltration. The effects of reaction parameters (pH, concentration of reactants, metal/stabilizer ratio, and temperature) on particle size and dispersion stability are discussed and a mechanism for the reduction of silver is proposed. PMID- 26945116 TI - Simple and versatile one-step synthesis of FeS2 nanoparticles by ultrasonic irradiation. AB - The synthesis of stable pyrite nanocrystals (NCs) in a simple way is very difficult. A facile and single-stage ultrasonic synthesis route has been successfully developed for the preparation of pyrite (FeS2) NCs in 10min and 70 degrees C. In this study, the influences of reaction time, temperature, and acoustic power on the formation of the target compound were considered. In addition, a comparison was made of the synthesis of pyrite NCs by sonication with 20kHz apparatus and by the classical method (without ultrasound). The as-prepared pyrite was characterized by X-ray diffraction (XRD), Fourier transform infrared (FT-IR), scanning electron microscopy (SEM), Raman spectrophotometry and energy dispersive X-ray spectroscopy (EDS). The XRD of the sample prepared by classical method indicated a typical cubic FeS2 with space group Pa3 and the average size of 16nm. Sulfur as an impurity in the sample was verified by XRD analysis. The sample prepared by ultrasound showed two phases of pyrite, cubic and marcasite structures. The space groups were pa3 and pnnm, respectively and the average size was 28.8nm. According to the SEM images, the morphology of the synthesized pyrite using the two methods are closely the same. The FT-IR and Raman spectra presented the FeS, FeS and SS functional groups. In addition, the sono-synthesis of pyrite was done under milder conditions and in shorter time with better features than classical method. PMID- 26945117 TI - Interaction of an anti-cancer photosensitizer with a genomic DNA: From base pair specificity and thermodynamic landscape to tuning the rate of detergent sequestered dissociation. AB - A detailed characterization of the binding interaction of a potent cancer cell photosensitizer, norharmane (NHM) with a genomic DNA (herring sperm; hsDNA) is undertaken with particular emphasis on deciphering the strength, mode, dynamics, energetics and kinetics of binding. A major focus of the study underlies a successful exploration of the concept of detergent-sequestered dissociation of drug from the drug-DNA complex. Biophysical techniques such as absorption, steady state and time-resolved fluorescence spectroscopy, circular dichroism, DNA helix melting, stopped-flow fluorescence kinetics and calorimetry have been used. A primarily intercalative mode of binding of NHM with DNA is shown. However, the overall interaction is governed by more than one type of binding forces. We demonstrate that the essential prerequisite of a slower dissociation rate of drug from DNA helix is achieved by tenable choice surfactants. Our results also highlight an effective tunability of the rate of dissociation of the DNA intercalated drug via detergent-sequestration. A detailed isothermal titration calorimetric study unveils the key role of hydrophobic force underlying NHM-hsDNA association. This is further substantiated by the enthalpy-entropy compensation behavior. The major entropic contribution in detergent-induced dissociation of NHM from NHM-hsDNA complex is also demonstrated. Our results present not only a comprehensive structural and thermodynamic profile, base pair specificity, association kinetics for binding of NHM with DNA but also explore the thermodynamic and kinetic aspects of dissociation of bound drug. Characterization and tuning of the essential prerequisites for a drug to be efficient in anti cancer functionality bear direct and widespread significance in contemporary global research. PMID- 26945119 TI - Reply by Authors. PMID- 26945118 TI - Stability of plasma treated superhydrophobic surfaces under different ambient conditions. AB - Plasma hydrophilizing of superhydrophobic substrates has become an important area of research, for example, superhydrophobic-(super)hydrophilic patterned surfaces have significant practical applications such as lab-on-chip systems, cell adhesion, and control of liquid transport. However, the stability of plasma induced hydrophilicity is always considered as a key issue since the wettability tends to revert back to the untreated state (i.e. aging behavior). This paper focuses on the stability of plasma treated superhydrophobic surface under different ambient conditions (e.g. temperature and relative humidity). Water contact angle measurement and X-ray photoelectron spectroscopy are used to monitor the aging process. Results show that low temperature and low relative humidity are favorable to retard the aging process and that pre-storage at low temperature (-10 degrees C) disables the treated surface to recover superhydrophobicity. When the aging is performed in water, a long-lasting hydropholicity is obtained. As the stability of plasma-induced hydrophilcity over a desired period of time is a very important issue, this work will contribute to the optimization of storage conditions of plasma treated superhydrophobic surfaces. PMID- 26945120 TI - Editorial Comment. PMID- 26945121 TI - Editorial Comment. PMID- 26945122 TI - Reusable fluorescent sensor for captopril based on energy transfer from photoluminescent graphene oxide self-assembly multilayers to silver nanoparticles. AB - In this work we designed a self-assembly multilayers, in which photoluminescent graphene oxide was employed as a fluorescence probe. This multilayers film can effectively recognize captopril by resonance energy transfer from graphite oxide to silver nanoparticles. A new interfacial sensing method for captopril with high signal to noise ratio was established, by means of that multilayers was quenched by silver nanoparticles and subsequently recovered by adding captopril. The linear relation between intensity and captopril concentration was good, and the detection limit was found to be 0.1578 MUM. Also, this novel detection platform demonstrated intriguing reusable properties, and the sensor could be repeated more than ten times without obviously losing its sensing performance. PMID- 26945123 TI - Synthesis, spectral studies and biological evaluation of 2-aminonicotinic acid metal complexes. AB - We synthesized 2-aminonicotinic acid (2-ANA) complexes with metals such as Co(II), Fe(III), Ni(II), Mn(II), Zn(II), Ag(I),Cr(III), Cd(II) and Cu(II) in aqueous media. The complexes were characterized and elucidated using FT-IR, UV Vis, a fluorescence spectrophotometer and thermo gravimetric analysis (TGA). TGA data showed that the stoichiometry of complexes was 1:2 metal/ligand except for Ag(I) and Mn(II) where the ratio was 1:1. The metal complexes showed varied antibacterial, fungicidal and nematicidal activities. The silver and zinc complexes showed highest activity against Bacillus subtilis and Bacillus licheniformis respectively. Fusarium oxysporum was highly susceptible to nickel and copper complexes whereas Macrophomina phaseolina was completely inert to the complexes. The silver and cadmium complexes were effective against the root-knot nematode Meloidogyne javanica. PMID- 26945124 TI - Determinants of maternal antenatal state-anxiety in mid-pregnancy: Role of maternal feelings about the pregnancy. AB - BACKGROUND: The current state of research into antenatal anxiety is lacking in a comprehensive understanding of determinants. This study aims to expand knowledge in this area, with the main objective being to determine potential determinants of maternal antenatal state-anxiety. METHODS: Data used for this cross-sectional study were obtained from the Prenatal Health Project: a population cohort study of 2357 women in London, Ontario. 1992 women in their second trimester met inclusion criteria for this study. The primary hypothesis was that "feelings about the pregnancy" would be a determinant of antenatal state-anxiety after controlling for other potential covariates. The abbreviated version of the Spielberger State and Trait Anxiety Inventory (STAI) was used to measure state anxiety. Univariate analyses and multiple linear regression were performed to identify variables predictive of state-anxiety. RESULTS: Stress, feeling unsure/unhappy about the pregnancy and having low self-esteem, low mastery and low social support from one's partner and family were statistically significant determinants of state-anxiety during the second trimester. In addition, anxiety was found to be inversely related to gestational age. LIMITATIONS: The two main limitations of the study were the use of a self-report screening tool (STAI) as the measure of anxious symptoms rather than a clinical diagnosis, and possible recall bias of feelings about the pregnancy. CONCLUSIONS: We concluded that how a woman feels about her pregnancy was a determinant of state-anxiety. This study contributes knowledge aiming to help women improve their mental health during pregnancy by identifying important determinants of state-anxiety. PMID- 26945125 TI - Mechanical circulatory support for destination therapy: why are we so late? PMID- 26945126 TI - Early and late surgical outcomes of ileal pouch-anal anastomosis within a defined population in Sweden. AB - OBJECTIVE: Ileal pouch-anal anastomosis (IPAA), has become the procedure of choice in patients requiring reconstructive surgery for ulcerative colitis or familial adenomatous polyposis. The aim of this population-based study was to present data prospectively registered and retrospectively evaluated on the short term and the long-term results of 124 consecutive IPAA performed chronologically by three surgeons in a single referral centre. MATERIALS AND METHODS: All patients who underwent IPAA from 1993 to 2012 were included. Early and late morbidity and mortality were evaluated. RESULTS: Early complications were observed in 25 patients. There was one death from cardiac failure, high output stoma occurred in six patients and wound infection occurred in four patients. Complications were associated with higher BMI (P=0.032). Four patients had to be reoperated. Peroperative bleeding was reduced when using an ultrasonically activated scalpel for the perimuscular dissection (P<0.00001). Clavien-Dindo grade III-V affected five patients. Only one patient developed anastomotic leak and septic complications.Late complications occurred in 61 patients. There was no procedure-related mortality. Pouchitis was the most common complication (n=37). Primary sclerosing cholangitis and age younger than 40 years were associated significantly with a three- and two-fold increased risk of pouchitis, respectively. Small bowel obstruction was the second most common complication (n=16), more common in women (P=0.031). The pouch failure rate was low: 2.4%. Clavien-Dindo grade III-V affected 13 patients. CONCLUSION: In the hands of experienced high-volume surgeons, IPAA is a safe procedure associated with a relatively low early morbidity as well as an acceptable late morbidity. PMID- 26945127 TI - Evaluation of the concordance between the stage of the disease and Ki-67 proliferation index in gastroenteropancreatic neuroendocrine tumors. AB - AIM: This study aimed to determine the degree of concordance between TNM staging used in the determination of the prognosis of gastroenteropancreatic neuroendocrine tumor (GEP-NET) patients and the Ki-67 proliferation index value used in the grading of these tumors and investigate the most reliable prognostic parameter among them. MATERIALS AND METHODS: The medical files of the patients with GEP-NET who were diagnosed or followed up in Erciyes University Faculty of Medicine were retrospectively examined and demographic characteristics, survival times, grade of these tumors, histopathologically detected Ki-67 values, and histopathological characteristics were recorded and evaluated statistically. RESULTS: The mean age (53.09+/-14.6 years; range, 16-85 years) of all (n=141) the patients was estimated. The patient population included 72 (51.1%) female and 69 (48.9%) male patients, with a male/female ratio of 0.95. The most frequently encountered primary sites were the stomach (33.3%), and then in decreasing oder of frequency the pancreas (27%), colon-rectum (15.6%), the small intestine (12.8%), and the appendix (11.3%). The GEP-NET of the patients was in grade 1 (G1) (n: 103; 73%), grade 2 (G2) (n: 24; 17%), and grade 3 (G3) (n: 14; 10%). The GEP-NET of the patients was stage I (n: 66; 46.8%), stage II (n: 14; 9.9%), stage III (n: 12; 8.5%), and stage IV (n: 49; 34.8%). In the statistical analysis, Ki 67 increased in parallel with the stage of the disease (P<0.001). As Ki-67 increased at a rate of 1%, survival rates of the patients decreased 1.027 times (P=0.01). Five-year survival rates of the patients were 88% in G1, 44% in G2, and 24% in G3. Patients in G2 and G3 had a 6.67 and 12.38 times lower chance of survival compared with G1 patients, respectively. Survival rates of stage IV patients were 5.6 times lower relative to stages I and II patients, respectively (P<0.001). The median 5-year survival rates of the patients were 90% in stage I, 100% in stage II, 47% in stage III, and 46% in stage IV. In univariate analysis, age of the patients, grade, stage of the tumor, and lymph node metastases were found to be parameters that affected overall survival, whereas no significant correlation was found between the sex of the patient and the primary organ from which the tumor originated and survival rates. However, in the multivariate analysis, survival rates decreased inversely with age, whereas no significant correlation was found between grade and stage of the tumor and survival rates. CONCLUSION: In conclusion, a decrease in the average survival rate in parallel with an increase in the grade of the tumor was more prominent compared with a decrease in survival rates in accordance with an increase in the stage of the tumor. This indicates that in the prediction of prognosis in patients with GEP NET, the Ki-67 value can be a more important evaluation factor relative to staging. PMID- 26945128 TI - Percutaneous Transforaminal Endoscopic Discectomy for Lumbar Disk Herniation. AB - Percutaneous transforaminal endoscopic discectomy (PTED) is a minimally invasive technique to treat lumbar disk herniation from a lateral approach. Performed under local anesthesia, the incision size for PTED is around 8 mm with no paraspinal muscle cutting or detachment from their insertion. PTED has been associated with less blood loss, faster rehabilitation, and less scarring of tissue than conventional open microdiscectomy. High-quality randomized controlled trials comparing PTED with open microdiscectomy have not been conducted yet. However, PTED has been proven to be an effective technique allowing patients to return home only 2 hours after surgery. By the means of this article and video (Supplemental Digital Content 1, http://links.lww.com/CLINSPINE/A1), we would like to show the spine surgeon the PTED technique for the treatment of a single level lumbar disk herniation. PMID- 26945129 TI - Minimally Invasive/Less Invasive Microdiscectomy. AB - Herniated disks in the lumbar spine typically present with the sudden onset of back and leg pain in a myodermatomal distribution. Symptoms may include radicular pain, paresthesias, and in extreme cases weakness or foot drop. Typically patients are treated conservatively for 6-8 weeks with a combination of steroids, nonsteroidal anti-inflammatory drugs, physical therapy, epidural steroid injections, and rest. In the absence of symptom improvement, surgical intervention typically with a microdisectomy is recommended to patients who are refractory to at least 6 weeks of nonoperative treatment. Earlier intervention may be considered in patients with severe or progressive neurological deficits. This paper reviews the preoperative and postoperative considerations, as well as the surgical technique, for a minimally invasive/less invasive microdisectomy. PMID- 26945130 TI - Steroid Use in Adult Patients With Incomplete Spinal Cord Injuries. PMID- 26945131 TI - Adult Degenerative Scoliosis. AB - The treatment of adult degenerative scoliosis begins in the outpatient setting when evaluating a patient both radiographically. Assessing the flexibility of the deformity is essential in determining what techniques will be required to achieve the goals of correction. Ultimately the surgeon's comfort and experience and the patient's medical risk stratification determine the strategy needed to address either a focal pathology or ultimate deformity correction. PMID- 26945132 TI - Profiling post-translational modifications of histones in neural differentiation of embryonic stem cells using liquid chromatography-mass spectrometry. AB - The neural differentiation of embryonic stem cells (ESCs) is of great significance for understanding of the mechanism of diseases. Histone post translational modifications (HPTMs) play a key role in the regulation of ESCs differentiation. Here, we combined the stable isotope chemical derivatization with nano-HPLC-mass spectrometry (MS) for comprehensive analysis and quantification of histone post-translational modifications (HPTMs) in mouse embryonic stem cells (mESCs) and neural progenitor cells (mNPCs) that was derived from ESCs. We identified 85 core HPTM sites in ESCs and 78HPTM sites in NPCs including some novel lysine modifications. Our quantitative analysis results further revealed the changes of HPTMs from ESCs to NPCs and suggested effect of combinational HPTMs in the differentiation. This study demonstrates that HPLC-MS based quantitative proteomics has a considerable advantage on quantification of combinational PTMs and expands our understanding of HPTMs in the differentiation. PMID- 26945134 TI - An improved LC-MS/MS method for the simultaneous determination of pyrazinamide, pyrazinoic acid and 5-hydroxy pyrazinoic acid in human plasma for a pharmacokinetic study. AB - In the present work the plasma levels of PZA and its two active metabolites, pyrazinoic acid (PA) and 5-hydroxy pyrazinoic acid (5-OH PA) were determined by a sensitive and rapid LC-MS/MS method. The analytes and their labeled internal standards were extracted from 200MUL plasma samples by liquid-liquid extraction with methyl tert-butyl ether: diethyl ether (90:10, v/v) under acidic conditions. Their separation was achieved on a Zorbax Eclipse XDB C18 (100*4.6mm, 3.5MUm) column using methanol and 0.1% acetic acid (65:35, v/v) as the mobile phase within 4.0min. Detection and quantitation were done by multiple reaction monitoring on a triple quadrupole mass spectrometer following the transitions, m/z 124.1->81.1,m/z 125.0->80.9 and m/z 141.0->81.0 for PZA, PA and 5-OH PA respectively in the positive ionization mode. All the analytes were baseline resolved with a resolution factor of 3.3 and 6.4 between PZA and its metabolites, PA and 5-OH PA respectively. The calibration curves were linear from 0.100 30.0MUg/mL, 0.03-9.00MUg/mL and 0.002-0.600MUg/mL for PZA, PA and 5-OH PA respectively with r(2)>=0.9980 for all the analytes. The intra-batch and inter batch accuracy and precision (% CV) across quality controls varied from 93.5 106.7% and 1.10-4.57 respectively for all the analytes. The mean extraction recovery of PZA, PA and 5-OH PA was 83.7%, 89.2% and 80.8% respectively, which was consistent at higher as well as lower concentration levels. The% change in the stability of analytes under different storage conditions ranged -6.7 to 7.1 for all the analytes. The method was applied to assess the comparative bioavailability of a 500mg PZA test and reference formulation in healthy subjects. The assay reproducibility was also tested by reanalysis of 22 incurred subject samples. PMID- 26945133 TI - A novel method for analysing key corticosteroids in polar bear (Ursus maritimus) hair using liquid chromatography tandem mass spectrometry. AB - This paper presents the development and evaluation of a methodology for extraction, clean-up and analysis of three key corticosteroids (aldosterone, cortisol and corticosterone) in polar bear hair. Such a methodology can be used to monitor stress biomarkers in polar bears and may provide as a useful tool for long-term and retrospective information. We developed a combined pressurized liquid extraction (PLE)-solid phase extraction (SPE) procedure for corticosteroid extraction and clean-up followed by high pressure liquid chromatography tandem mass spectrometry (HPLC-MS/MS) analysis. This procedure allows for the simultaneous determination of multiple steroids, which is in contrast to previous polar bear studies based on ELISA techniques. Absolute method recoveries were 81%, 75% and 60% for cortisol, corticosterone and aldosterone, respectively. We applied the developed method on a hair sample pooled from four East Greenland polar bears. Herein cortisol and corticosterone were successfully determined in levels of 0.32+/-0.02ng/g hair and 0.13+/-0.02ng/g hair, respectively. Aldosterone was below limit of detection (LOD<0.17ng/g). The cortisol hair concentration found in these East Greenland polar bears was consistent with cortisol levels previously determined in the Southern Hudson Bay and James Bay in Canada using ELISA kits. PMID- 26945135 TI - Benzothiazole derivatives bearing amide moiety: potential cytotoxic and apoptosis inducing agents against cervical cancer. AB - Cervical cancer is a major cause of morbidity and mortality in women worldwide. In recent years, benzothiazole analogues have attracted considerable attention in anticancer research. Therefore, in this study, the earlier reported amide series of benzothiazole derivatives were investigated for their antiproliferative activity. The activity of amide derivatives was evaluated using the 3-(4, 5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, flow cytometric analysis, apoptosis assay, and DNA fragmentation on two human cervical cancer cell lines: SiHa and C33-A. The data reported from this investigation indicated that benzothiazole derivatives show pronounced cytotoxicity in the HPV16-positive SiHa cells compared with HPV-negative C-33A cells. The in-vitro cytotoxicity of the compounds on the HEK-293 noncancer cell line was evaluated to establish selectivity. Cells treated with benzothiazole derivatives showed prominent morphological features as evidenced by cell shrinkage, membrane blebbing, apoptotic nuclei, and DNA fragmentation. The benzothiazole derivatives show accumulation of cells in the sub-G1 and S-phase of the cell cycle in SiHa and C33 A, respectively. In addition, these derivatives exert their beneficial effect by inducing apoptosis, in the chemoprevention of cervical cancer cells, and were further ascertained using a DNA fragmentation assay. The compounds studied showed potent cytotoxic and apoptotic properties against SiHa and C33-A cancer cell lines and thus represent an excellent starting point for further optimization of therapeutically effective anticancer drugs. PMID- 26945136 TI - Androgen and breast cancer: an update. AB - PURPOSE OF REVIEW: The review is targeted at describing the advances in our understanding of androgen actions in the breast over the last 18 months. Androgens are current 'hot topics' in breast cancer because of their potential as therapeutics in situations where we currently do not have good clinical options. This is true for both estrogen receptor alpha (ERalpha) negative and ERalpha positive cancers. RECENT FINDINGS: The review has focused on examining associations between androgen receptor and patient prognosis and outcomes in different breast cancer subtypes. A logical extension of this is covering the timely topic of the use of androgen-directed therapy in these patients. The principle settings in which this is being considered is in ERalpha positive cancer with therapeutic resistance to ER-directed therapies and in ERalpha negative breast cancer that lack current standard targeted therapies. Finally interactions between mutations, and the potential role of androgen in the normal hierarchy of mammary cell differentiation and the relationship of this to cancer, are considered. SUMMARY: Androgens are firmly established as important factors across multiple breast cancer subtypes. The future challenge for basic researchers and important development for clinicians is going to be translating this understanding into effective therapeutics for the benefit of breast cancer patients. PMID- 26945137 TI - Expression analysis of bone morphogenetic protein 4 between fat and lean birds in adipose tissue and serum. AB - The objectives of the present study were to characterize the tissue expression of chicken (Gallus gallus) bone morphogenetic protein 4 (BMP4) and compare differences in its expression in abdominal fat tissue and serum between fat and lean birds and to determine a potential relationship between the expression of BMP4 and abdominal fat tissue growth and development. The results showed that chicken BMP4 messenger RNA (mRNA) and protein were expressed in various tissues, and the expression levels of BMP4 transcript and protein were relatively higher in adipose tissues. In addition, the mRNA and protein expression levels of BMP4 in abdominal fat tissue of fat males were lower than those of lean males at 1, 2, 5, and 7 wk of age (P < 0.05). Furthermore, the serum BMP4 content of fat males was lower than that of lean males at 7 wk of age (P < 0.05). BMP4 mRNA expression levels were significantly higher in preadipocytes than those in mature adipocytes (P < 0.05), and the expression level decreased during differentiation in vitro (P < 0.05). These results suggested that chicken BMP4 might affect abdominal fat deposition through differences in its expression level. The results of this study will provide basic molecular information for studying the role of BMP4 in the regulation of adipogenesis in avian species. PMID- 26945138 TI - Importance of First Impressions for Potential Nursing Student Applicants With Disabilities. PMID- 26945139 TI - Bottlenecks and opportunities for delivering integrated pediatric HIV services in Nepal. AB - BACKGROUND: In children, integration of HIV in MNCH services has been shown to incr. ease uptake of early infant diagnosis. This article examines bottlenecks and opportunities for scaling up integrated pediatric HIV services in Nepal. METHODS: This is a descriptive study using both mixed qualitative and quantitative methods, conducted in January 2015 in 19 facilities in five regions of Nepal most affected by HIV epidemic. The qualitative methods comprised in depth structured interviews with key informants (leadership of The National Center for AIDS and STD Control and National Public Health Laboratory, district management teams, medical officers in charge of health facilities and HIV clinics, frontline staff at antenatal care and HIV clinics and laboratory). The quantitative methods were used to abstract data of HIV-infected pregnant women seen between January and December 2014, HIV-exposed infants aged less than 12 months, and HIV infected children aged less than 15 years who were initiated HIV treatment from 2010 to 2014. Structured tools were used to collect data which were analysed using IBM SPSS. RESULTS: Of the 19 facilities assessed, 18(98%), 18(98%), 14(75%), and 11(58%) provided prevention of mother-to-child transmission (PMTCT), Expanded Program on Immunization (EPI), pediatric ART and nutrition rehabilitation services, respectively. However, only 1(5%) facility collected onsite dried blood spots (DBS) for PCR HIV testing and 6(32%) facilities provided counselling and referral for DBS. In 2014, of the 121 HIV-exposed infants recorded, only 21(17%) received PCR test. The median turnaround time of the PCR test results was 54 days. Of the 21 records with PCR test, 11(52.5%) were from PMTCT clinics, 7(33%) from Nutritional rehabilitation clinics, and 3(14.5%) from pediatric outpatient clinic.Conversely, 934 children were initiated ART between 2010 and 2014, of which 5% were infants and 29% aged between 1 and 5 years. 298(32%) had comorbidities of which 64% had malnutrition. A total of 534(57%) had tuberculosis (TB) status assessed of which 58(11%) had active TB. Infants had lowest retention (63%), high mortality (17.4%), and loss to follow-up (10.9%). CONCLUSION: Few facilities collect DBS and few children receive PCR tests with limited linkage to ART. This has led to late ART initiation, comorbidities, including TB coinfections and poor outcomes. The results indicate that there are opportunities for improving HIV case finding among HIV-exposed infants in PMTCT, EPI, TB, and nutrition services if provider initiated testing and counselling at the point of service delivery is institutionalized in these settings. PMID- 26945140 TI - Expanding access to HIV testing and counseling and exploring vulnerabilities among spouses of HIV-positive men who inject drugs in Pakistan. AB - OBJECTIVES: To explore the utility of home and community-based HIV testing and counseling (HTC) to increase detection of undiagnosed HIV among female spouses and children of HIV-positive PWID in Punjab province, Pakistan. DESIGN: Between March 2014 and March 2015, home-based HTC was provided by a local NGO to spouses of HIV-positive PWID in Lahore, Faisalabad, and Sargodha. Convenience sampling was used to identify 2400 married, HIV-positive men who inject drugs and who were currently registered and receiving harm reduction services from the NGO 'Roshan Rasta' and seek consent to approach their wives. METHOD: Trained outreach teams conducted HTC and administered a short sociodemographic and behavioral questionnaire to consenting spouses in their homes. HIV-exposed children were also tested with parental consent. RESULTS: of the 2400 married HIV positive male injecting drug users, only 1959 spouses were approached and 1896 agreed to HTC (96.8%). HIV prevalence was 5.3% (n = 101) among spouses and they had very low level of HIV-related knowledge and protective behaviors CONCLUSION: Home and community-based HTC was effective in identifying undiagnosed HIV among spouses of PWID, the majority of whom reported low rates of prior HIV testing and low HIV related knowledge. Expansion of HIV prevention services and linkages to treatment and care including PMTCT are urgently needed for this group. PMID- 26945141 TI - Getting to 90-90-90 targets for children and adolescents HIV in low and concentrated epidemics: bottlenecks, opportunities, and solutions. PMID- 26945142 TI - Use of technology in follow-up of HIV positive pregnant women and their babies till 18 months of age- an innovation by Maharashtra State AIDS Control Society (MSACS), India. AB - OBJECTIVE: The purpose of this study is to assess the utility of web-based mobile technology monitoring tool, for ensuring linkages, and tracking of HIV-exposed child until 18 months of age. METHODS: The 'early infant diagnosis (EID) Follow up System' was designed as a tool for reminding the field level staff for follow up of HIV-exposed babies. Using Java Swing Framework, software was developed which generates automatic advance SMS alerts regarding patient information to the Counsellor of the respective Integrated Counselling and Testing Center and district supervisor, 7 days prior to due dates. Simultaneously, system generated e-mail is sent to district program officer for monitoring and updating the line list. RESULTS: Before the introduction of 'EID Follow-up System' in June 2013, only 55.9% (637/1139) of the HIV-exposed babies born were tested at 6 weeks for DNA-Polymerase Chain Reaction during April 2011-March 2012. However, after its introduction, 68.4% (1117/1631) of them were tested during April 2012-March 2013. Correspondingly, the 18 months confirmatory HIV testing in eligible babies increased from 45.6% (934/2044) to 54.7%(1118/2044) during the same period. CONCLUSION: The replicable technology driven initiative would help in strengthening the follow-up mechanisms and reach every HIV-exposed child for EID. PMID- 26945143 TI - Operational feasibility of using whole blood in the rapid HIV testing algorithm of a resource-limited settings like Bangladesh. AB - BACKGROUND: Serum-based rapid HIV testing algorithm in Bangladesh constitutes operational challenge to scaleup HIV testing and counselling (HTC) in the country. This study explored the operational feasibility of using whole blood as alternative to serum for rapid HIV testing in Bangladesh. METHODS: Whole blood specimens were collected from two study groups. The groups included HIV-positive patients (n = 200) and HIV-negative individuals (n = 200) presenting at the reference laboratory in Dhaka, Bangladesh. The specimens were subjected to rapid HIV tests using the national algorithm with A1 = Alere Determine (United States), A2 = Uni-Gold (Ireland), and A3 = First Response (India). The sensitivity and specificity of the test results, and the operational cost were compared with current serum-based testing. RESULTS: The sensitivities [95% of confidence interval (CI)] for A1, A2, and A3 tests using whole blood were 100% (CI: 99.1 100%), 100% (CI: 99.1-100%), and 97% (CI: 96.4-98.2%), respectively, and specificities of all test kits were 100% (CI: 99.1-100%). Significant (P < 0.05) reduction in the cost of establishing HTC centre and consumables by 94 and 61%, respectively, were observed. The cost of administration and external quality assurance reduced by 39 and 43%, respectively. Overall, there was a 36% cost reduction in total operational cost of rapid HIV testing with blood when compared with serum. CONCLUSION: Considering the similar sensitivity and specificity of the two specimens, and significant cost reduction, rapid HIV testing with whole blood is feasible. A review of the national HIV rapid testing algorithm with whole blood will contribute toward improving HTC coverage in Bangladesh. PMID- 26945144 TI - Point of care HIV testing with oral fluid among returnee migrants in a rural area of Bangladesh. AB - OBJECTIVES: To determine HIV prevalence and assess the acceptability of HIV testing using oral fluid as a point of care (PoC) test method among returnee migrants in a rural area of Bangladesh. DESIGN: A cross-sectional study. METHODS: Matlab is a rural area southeast of Dhaka where icddr,b hosts a health and demographic surveillance system covering 225,826 people of whom 934 are returnee migrants. The sample size of 304 was proportionately distributed among randomly selected households. HIV antibodies in oral fluid were tested using OraQuick Rapid HIV 1/2 antibody test. To understand reasons of acceptability a short questionnaire was applied and 32 in-depth interviews were conducted. RESULTS: Of 304 returnee migrants approached, 97.4% accepted the test. The prevalence of HIV was 0.3% without a confirmatory blood test. Reasons for acceptance included easy accessibility of the test at the door-step which saved resources (i.e., time and money), comfortable test-procedure without any pain and fear, and receiving quick results with confidentiality. Some described knowing HIV status as a way to 'get certified' (of sexual fidelity) and to confront a prevailing silent stigma against migrants. Acceptability was moreover found to be grounded in icddr,b's institutional reputation and its close relationship with the local community. CONCLUSIONS: The PoC oral fluid test for HIV has shown for the first time that assessment of HIV prevalence in rural-based returnee migrants is possible. Findings also suggest that PoC oral fluid test has the potential of increasing accessibility to HIV testing as it was found to be highly acceptable. PMID- 26945145 TI - The use of vouchers in HIV prevention, referral treatment, and care for young MSM and young transgender people in Dhaka, Bangladesh: experience from 'HIM' initiative. AB - INTRODUCTION: The study described the effectiveness of a voucher scheme to access sexual and reproductive health and HIV services among young MSM and transgender people aged 15-24 years in Dhaka, Bangladesh, a country with HIV prevalence of less than 0.1%. METHODS: Descriptive and analytical methods were used to assess the net effects of biodemographic factors of the respondents on the voucher scheme. Effectiveness of the scheme was contextualized as target population coverage, and turnaround time of voucher redemption to access services. RESULTS AND DISCUSSION: A total of 210 (87.9%) out of the 239 vouchers distributed were redeemed. The mean age of the identified young people was 19.6 years (SD = +2.6 years). The coverage of the scheme against the target population of 200 young MSM and 936 young transgender people was 88% (n = 175) and 4% (n = 35) respectively, with P < 0.001. The median turnaround time for voucher redemption was 7 days. The predictors of voucher turnaround time were age, education, and population group (P < 0.001). HIV testing and counselling was accessed by 160 (76%) respondents, one was positive and linked to antiretroviral treatment and 110 (52%) were diagnosed and treated for sexually transmitted infections. CONCLUSION: The voucher scheme was effective in linking young MSM with sexual and reproductive health and HIV services in Dhaka, Bangladesh. The findings are consistent with the low HIV prevalence in the country. The scheme is, however, not optimal for linking young transgender people with services. PMID- 26945146 TI - Descriptive study of the utility of individual tracking tool in program monitoring for prevention of mother-to-child transmission of HIV, Maharashtra, India. AB - OBJECTIVE: The objective is to describe the utility of prevention of parent-to child transmission tracking tool in terms of the in-depth information that it provides for better decision making to improve the services. METHODS: The excel based tracking tool is initiated by 578 Integrated Counselling and Testing Centre (ICTC) Counsellor and shared with 70 antiretroviral treatment (ART) centres. Between April and September 2014, total of 1118 HIV-infected pregnant women were registered in the tool. The secondary data for this period that is captured in the prevention of parent-to-child transmission tracking tool has been analyzed and presented in this descriptive study. RESULTS: Of the total 1118 HIV-positive pregnant women, registered in the tool, 760 (68%) were newly detected with HIV infection and 358 (32%) had already been detected before their current pregnancy. In total, 1095 (98%) pregnant women were registered at ART centre out of which 1007 (91%) were initiated on lifelong ART. The average time delay between HIV detection and registration at ART centre was 12 days (n = 844). In this cohort of 1118 pregnant women, 45% delivered live babies, 7% underwent medical termination of pregnancy, 2% were stillbirths and abortions, and 46% were yet to deliver. Only 29 infants were tested for HIV at 6 weeks of age and six were found reactive. CONCLUSION: The tracking tool provides in-depth information regarding the pregnant women registered in the program and in the tracking tool. The information throws more light on the characteristics of the registered women and the various services provided to them and highlight key areas where the program has to be improved. The tool is effective for assessing the treatment status of HIV-positive pregnant woman, retention in care and early infant diagnosis of the baby. The tool has identified programmatic bottlenecks component wise such as the need to focus on earlier detection of HIV-positive women during pregnancy, decreasing the time delay between detection and ART registration, and improving the early infant diagnosis. PMID- 26945147 TI - Strategies to target HIV-1 in the central nervous system. AB - PURPOSE OF REVIEW: To review current knowledge of viral reservoirs in the central nervous system (CNS) and identify the CNS-specific barriers and strategies to cure human immunodeficiency virus type 1 (HIV-1) within the brain. RECENT FINDINGS: The cumulative data of HIV-1 infection of the CNS support the ability of the CNS to act as a viral reservoir for HIV-1. The HIV-1 viral strains found in the CNS are distinct to those found in other parts of the body. These differences have been well documented for env and also extend to the viral promoter, the long terminal repeat, and influence the ability of the virus to replicate, establish latency and respond to latency-reversing agents (LRAs). In addition, the bioavailability and activity of LRAs and antiretrovirals within the CNS suggest altered properties compared with the blood, which may influence their effectiveness. Selected LRAs were shown to have reduced effectiveness against CNS derived viral strains compared with blood-derived strains from the same patients. Finally, altered immune surveillance within the CNS may also interfere with the efficiency of cure strategies within this compartment. SUMMARY: Together, these data suggest that the CNS viral reservoir is unique and presents a distinct set of challenges that need to be overcome to ensure successful viral elimination within this compartment. Future studies will need to develop CNS-active LRAs and biomarkers to enable monitoring and evaluation of treatment outcomes within the CNS during HIV-1 cure clinical trials. PMID- 26945148 TI - Interdisciplinary education: Learning together from the same playbook. PMID- 26945149 TI - New drugs 2016, part 1. PMID- 26945150 TI - Gammaherpesvirus targets peritoneal B-1 B cells for long-term latency. AB - Gammaherpesviruses establish life-long infection in most adults and are associated with the development of B cell lymphomas. While the interaction between gammaherpesviruses and splenic B cells has been explored, very little is known about gammaherpesvirus infection of B-1 B cells, innate-like B cells that primarily reside in body cavities. This study demonstrates that B-1 B cells harbor the highest frequency of latently infected cells in the peritoneum throughout chronic infection, highlighting a previously unappreciated feature of gammaherpesvirus biology. PMID- 26945151 TI - The Asian-American variant of human papillomavirus type 16 exhibits higher activation of MAPK and PI3K/AKT signaling pathways, transformation, migration and invasion of primary human keratinocytes. AB - Asian-American (AA) HPV-16 variants are associated with higher risk of cancer. Abnormal activation of intracellular signaling play a critical role in cancer development and progression. Our aim was to elucidate mechanisms underlying the higher oncogenic potential attributed to AA variant. We evaluated activation of MAPK and PI3K/AKT pathways in primary human keratinocytes (PHKs) transduced with E6/E7 of three HPV-16 variants: E-P, AA, E-350G. Phenotypes examined included migration, anchorage independent growth and invasion. AA PHKs presented the highest levels of active proteins involved in all cascades analyzed: MAPK-ERK, MAPK-p38 and PI3K-AKT. AA PHKs were more efficient in promoting anchorage independent growth, and in stimulating cell migration and invasion. MEK1 inhibition decreased migration. The mesenchymal phenotype marker vimentin was increased in AA PHKs. Our results suggest that MEK1, ERK2, AKT2 hyperactivation influence cellular behavior by means of GSK-3b inactivation and EMT induction prompting AA immortalized PHKs to more efficiently surpass carcinogenesis steps. PMID- 26945152 TI - Research With an "I". PMID- 26945153 TI - Transcutaneous vocal cord ultrasonography after oral and maxillofacial surgery requiring intermaxillary fixation: A technical report. PMID- 26945154 TI - Surgical Risk Preoperative Assessment System (SURPAS): II. Parsimonious Risk Models for Postoperative Adverse Outcomes Addressing Need for Laboratory Variables and Surgeon Specialty-specific Models. AB - OBJECTIVE: To develop parsimonious prediction models for postoperative mortality, overall morbidity, and 6 complication clusters applicable to a broad range of surgical operations in adult patients. SUMMARY BACKGROUND DATA: Quantitative risk assessment tools are not routinely used for preoperative patient assessment, shared decision making, informed consent, and preoperative patient optimization, likely due in part to the burden of data collection and the complexity of incorporation into routine surgical practice. METHODS: Multivariable forward selection stepwise logistic regression analyses were used to develop predictive models for 30-day mortality, overall morbidity, and 6 postoperative complication clusters, using 40 preoperative variables from 2,275,240 surgical cases in the American College of Surgeons National Surgical Quality Improvement Program data set, 2005 to 2012. For the mortality and overall morbidity outcomes, prediction models were compared with and without preoperative laboratory variables, and generic models (based on all of the data from 9 surgical specialties) were compared with specialty-specific models. In each model, the cumulative c-index was used to examine the contribution of each added predictor variable. C-indexes, Hosmer-Lemeshow analyses, and Brier scores were used to compare discrimination and calibration between models. RESULTS: For the mortality and overall morbidity outcomes, the prediction models without the preoperative laboratory variables performed as well as the models with the laboratory variables, and the generic models performed as well as the specialty-specific models. The c-indexes were 0.938 for mortality, 0.810 for overall morbidity, and for the 6 complication clusters ranged from 0.757 for infectious to 0.897 for pulmonary complications. Across the 8 prediction models, the first 7 to 11 variables entered accounted for at least 99% of the c-index of the full model (using up to 28 nonlaboratory predictor variables). CONCLUSIONS: Our results suggest that it will be possible to develop parsimonious models to predict 8 important postoperative outcomes for a broad surgical population, without the need for surgeon specialty-specific models or inclusion of laboratory variables. PMID- 26945155 TI - A Novel Prediction Model of Prognosis After Gastrectomy for Gastric Carcinoma: Development and Validation Using Asian Databases. AB - OBJECTIVE: The prognoses of gastric cancer patients vary greatly among countries. Meanwhile, tumor-node-metastasis (TNM) staging system shows limited accuracy in predicting patient-specific survival for gastric cancer. The objective of this study was to create a simple, yet universally applicable survival prediction model for surgically treated gastric cancer patients. SUMMARY BACKGROUND DATA: A prediction model of 5-year overall survival for surgically treated gastric cancer patients regardless of curability was developed using a test data set of 11,851 consecutive patients. METHODS: The model's coefficients were selected based on univariate and multivariate analysis of patient, tumor, and surgical factors shown to significantly impact survival using a Cox proportional hazards model. For internal validation, discrimination was calculated with the concordance index (C-statistic) using the bootstrap method and calibration assessed. The model was externally validated using 4 data sets from 3 countries. RESULTS: Our model's C statistic (0.824) showed better discrimination power than current tumor-node metastasis staging (0.788) (P < 0.0001). Bootstrap internal validation demonstrated that coefficients remained largely unchanged between iterations, with an average C-statistic of 0.822. The model calibration was accurate in predicting 5-year survival. In the external validation, C-statistics showed good discrimination (range: 0.798-0.868) in patient data sets from 4 participating institutions in 3 different countries. CONCLUSIONS: Utilizing clinically practical patient, tumor, and surgical information, we developed a universally applicable prediction model for accurately determining the 5-year overall survival of gastric cancer patients after gastrectomy. Our predictive model was also valid in patients who underwent noncurative resection or inadequate lymphadenectomy. PMID- 26945156 TI - Evaluation of the Effects of CHF6001, an Inhaled PDE4 Inhibitor, on Cardiac Repolarization and Cardiac Arrhythmias in Healthy Volunteers. AB - Chronic obstructive pulmonary disease (COPD) is a multicomponent condition characterized by airway inflammation and associated to comorbidities, including cardiovascular diseases. Among anti-inflammatory agents in development for COPD, the phosphodiesterase inhibitors administrated by inhalation have the potential for increased efficacy and reduced systemic side effects. CHF6001 is an inhaled PDE4 inhibitor with proven anti-inflammatory properties in animal models. This randomized, double-blind, placebo-controlled study was aimed to demonstrate its cardiovascular safety and tolerability in healthy male volunteers with normal electrocardiogram and cardiac parameters. Single and multiple ascending doses (7 days of administration) of CHF6001 were administered. Three electrocardiograms were recorded at several pharmacokinetic time points and at each time points, postdose heart rate, QRS and PR intervals, and presence of arrhythmia were evaluated. In single ascending dose, QTcF intervals did not increase more than 30 milliseconds from the baseline, all heart rate was between 45 and 100 bpm, and no statistically significant differences were observed in PR and QRS intervals. In multiple ascending dose, cardiac parameters did not differ significantly from baseline. In the pharmacokinetic/pharmacodynamic analysis, no medically or clinically significant changes were found. Further studies are ongoing to demonstrate that CHF6001 is safe and well tolerated in COPD patients as well. PMID- 26945157 TI - Recombinant Human Alpha-1 Antitrypsin-Fc Fusion Protein Reduces Mouse Myocardial Inflammatory Injury After Ischemia-Reperfusion Independent of Elastase Inhibition. AB - BACKGROUND: Alpha-1-antitrypsin (AAT) is an abundant plasma protein with neutrophil elastase-inhibiting activity, and AAT is available as a plasma-derived therapeutic (pAAT). In experimental myocardial infarction, pAAT reduced acute inflammatory injury because of ischemia-reperfusion. The aim of the present study was to assess the properties of a recombinant protein composed of human AAT fused to the human immunoglobulin (Ig) G1 Fc fragment (rhAAT-Fc) in experimental myocardial infarction. METHODS: Ten-week-old CD1 male mice underwent transient occlusion (30 minutes) of the left anterior coronary artery. rhAAT-Fc (2 mg/kg) or pAAT (60 mg/kg) were administered upon reperfusion. We used human plasma derived Ig (2 mg/kg) or a matching volume of NaCl 0.9% as control solutions. After 24 hours, infarct size and caspase-1 activity were quantified. The left ventricular ejection fraction (LVEF) was measured by echocardiography at 24 hours and 7 days. A variant of rhAAT-Fc lacking elastase inhibition activity, rhAAT-Fc, was also tested. RESULTS: The rhAAT-Fc induced a significant reduction in infarct size (P < 0.01 vs. all controls, P > 0.05 vs. pAAT). Caspase-1 activity was reduced to the same degree with rhAAT-Fc and pAAT (-70%; P < 0.05; P > 0.05 rhAAT Fc vs. pAAT). The effects on infarct size after a single administration were reflected by preservation of LVEF at 24 hours and 7 days (all P < 0.05). rhAAT-Fc without elastase inhibiting activity, rhAAT-Fc, conferred comparable effects on infarct size, caspase-1 activity, and LVEF (P > 0.2 vs. rhAAT-Fc). CONCLUSIONS: The pAAT and recombinant human AAT-Fc reduce the acute myocardial inflammatory injury after ischemia-reperfusion in the mouse leading to preservation of viable myocardium and systolic function, independent on the effects on neutrophil elastase. PMID- 26945159 TI - Phenomenological features of dreams: Results from dream log studies using the Subjective Experiences Rating Scale (SERS). AB - Self-ratings of dream experiences were obtained from 144 college women for 788 dreams, using the Subjective Experiences Rating Scale (SERS). Consistent with past studies, dreams were characterized by a greater prevalence of vision, audition, and movement than smell, touch, or taste, by both positive and negative emotion, and by a range of cognitive processes. A Principal Components Analysis of SERS ratings revealed ten subscales: four sensory, three affective, one cognitive, and two structural (events/actions, locations). Correlations (Pearson r) among subscale means showed a stronger relationship among the process-oriented features (sensory, cognitive, affective) than between the process-oriented and content-centered (structural) features--a pattern predicted from past research (e.g., Bulkeley & Kahan, 2008). Notably, cognition and positive emotion were associated with a greater number of other phenomenal features than was negative emotion; these findings are consistent with studies of the qualitative features of waking autobiographical memory (e.g., Fredrickson, 2001). PMID- 26945158 TI - Eicosapentaenoic Acid Inhibits Oxidation of ApoB-containing Lipoprotein Particles of Different Size In Vitro When Administered Alone or in Combination With Atorvastatin Active Metabolite Compared With Other Triglyceride-lowering Agents. AB - Eicosapentaenoic acid (EPA) is a triglyceride-lowering agent that reduces circulating levels of the apolipoprotein B (apoB)-containing lipoprotein particles small dense low-density lipoprotein (sdLDL), very-low-density lipoprotein (VLDL), and oxidized low-density lipoprotein (LDL). These benefits may result from the direct antioxidant effects of EPA. To investigate this potential mechanism, these particles were isolated from human plasma, preincubated with EPA in the absence or presence of atorvastatin (active) metabolite, and subjected to copper-initiated oxidation. Lipid oxidation was measured as a function of thiobarbituric acid reactive substances formation. EPA inhibited sdLDL (IC50 ~2.0 MUM) and LDL oxidation (IC50 ~2.5 MUM) in a dose dependent manner. Greater antioxidant potency was observed for EPA in VLDL. EPA inhibition was enhanced when combined with atorvastatin metabolite at low equimolar concentrations. Other triglyceride-lowering agents (fenofibrate, niacin, and gemfibrozil) and vitamin E did not significantly affect sdLDL, LDL, or VLDL oxidation compared with vehicle-treated controls. Docosahexaenoic acid was also found to inhibit oxidation in these particles but over a shorter time period than EPA. These data support recent clinical findings and suggest that EPA has direct antioxidant benefits in various apoB-containing subfractions that are more pronounced than those of other triglyceride-lowering agents and docosahexaenoic acid. PMID- 26945161 TI - Addiction: etiology and therapeutics. PMID- 26945160 TI - Mechanical circulatory support for destination therapy. AB - Patients with chronic heart failure who are not eligible for heart transplant and whose life expectancy depends mainly on the heart disease may benefit from mechanical circulatory support. Mechanical circulatory support restores adequate cardiac output and organ perfusion and eventually improves patients' clinical condition, quality of life and life expectancy. This treatment is called destination therapy (DT) and we estimate that in Switzerland more than 120 patients per year could benefit from it. In the last 10 years, design of the devices, implantation techniques and prognoses have changed dramatically. The key to successful therapy with a left ventricular assist device is appropriate patient selection, although we are still working on the definition of reliable inclusion and exclusion criteria and optimal timing for surgical implantation. Devices providing best long-term results are continuous flow, rotary or axial blood pumps implanted using minimally invasive techniques on a beating heart. These new devices (Thoratec HeartMate II and HeartWare HVAD) have only a single moving part, and have improved durability with virtually 10 years freedom from mechanical failure. In selected patients, the overall actuarial survival of DT patients is 75% at 1 year and 62% at 2 years, with a clear improvement in quality of life compared with medical management only. Complications include bleeding and infections; their overall incidence is significantly lower than with previous devices and their management is well defined. DT is evolving into an effective and reasonably cost-effective treatment option for a growing population of patients not eligible for heart transplant, showing encouraging survival rates at 2 years and providing clear improvement in quality of life. The future is bright for people suffering from chronic heart failure. PMID- 26945162 TI - Relationships between surface roughness/stiffness of chitosan coatings and fabrication of corneal keratocyte spheroids: Effect of degree of deacetylation. AB - Fabrication of the cell spheroids from corneal keratocytes has important implications to the advance in tissue engineering while stimulation from the interface of a biopolymer coating has the ability to modulate this event. This study aims to investigate the dependence of keratocyte migration, proliferation, and differentiation on the surface roughness/stiffness of the chitosan coatings through modifications by degree of deacetylation (DD). After a series of deacetylation process, chitosan coatings with increasing DD exhibited significantly decreased surface roughness and increased surface stiffness. Relationships between the behaviors of rabbit corneal keratocytes (RCKs) and biopolymer coatings with varying DDs (between 75% and 96%) were also found during in vitro cultivation. Both the surface roughness increase and stiffness decrease could lead to enhanced cell migration, which is the main driving force for the early stage spheroid formation on chitosan substrates (e.g., within 8h). With these stimulations from the substrate interfaces, the size and morphology of RCK spheroids were greatly affected by the DD of chitosan. When fabricated on a lowered DD of chitosan material, the spheroids had a larger size with abundant extracellular matrix produced around the cells. At a later stage of spheroid cultivation (e.g., 5 days), significantly higher amount of RCKs on chitosan coatings was noted with increasing DD, indicating the substrate interface effects on cell proliferation. The keratocan expression of RCK spheroids grown on a lowered DD of chitosan was up-regulated, suggesting that both the surface roughness increase and stiffness decrease may facilitate the microenvironment for preservation of cellular phenotype. Overall, our work contributes to the scientific understanding of the keratocyte behaviors and spheroid fabrications in response to DD-mediated surface roughness/stiffness of chitosan coatings. PMID- 26945163 TI - pH-responsive copolymers based on pluronic P123-poly(beta-amino ester): Synthesis, characterization and application of copolymer micelles. AB - A novel amphiphilic and pH-responsive copolymer, pluronie P123-poly(beta-amino ester) (P123-PAE), was firstly designed and synthesized using a Michael-type step polymerization. Nano-sized polymeric micelles based on P123-PAE block copolymer were prepared by self-assembly. Curcumin (Cur), a potential cancer therapy drug, was efficiently encapsulated into the P123-PAE micelles to enhance anticancer efficacy. The obtained Cur loaded P123-PAE micelles (Cur-P123-PAE) presented a spherical shape and high drug loading (18.4%). Interestingly, when the media pH decreased from 7.4 to 5.5, the particle size of the micelles shrank from 152.5nm to 122.1nm due to the protonation of PAE blocks, and the zeta potential of the P123-PAE micelles changed from weakly positive (1.5mV) to highly positive (9.0mV) over a pH range from 7.4 to 5.5. In vitro drug release studies demonstrated that the release rate of Cur was markedly influenced by pH. In vitro cytotoxicity tests showed that all the blank micelles were non-toxic. Cur-P123-PAE exhibited similar antitumor effect against MCF-7 and HepG2 cells compared to solubilized Cur solution. Using Coumarin-6 as a fluorescence probe, it was observed that Cur P123-PAE micelles experienced longer circulation followed by accumulation at tumor tissues with stronger fluorescence intensity. The results of pharmacokinetics studies showed that the P123-PAE micelles could significantly prolong the retention time of Cur in vivo. PMID- 26945164 TI - Monosodium glutamate derived tricolor fluorescent carbon nanoparticles for cell imaging application. AB - Fluorescent carbon nanoparticle (FCN) is a new type of carbon-based materials. Because of its wide raw material sources, excellent optical properties and good biocompatibility, FCN is getting more and more attentions. However, its synthesis from resources at low cost under mild conditions is still a challenge. Here we report a novel and simple method derived from monosodium glutamate carbonization to make tricolor fluorescent carbon nanoparticles with an average size below 10nm, a high yield up to 35.2% based on the carbon content in the resource, a long life-time of 3.71ns, and a high fluorescence quantum yield up to 51.5% by using quinine sulfate as the standard substance. We discovered that the fluorescent stability of the FCNs was very excellent under UV irradiation for hours in aqueous solutions of pH ranged from 2.0 to 9.0. The cell viability tested under a pretty high concentration of FCNs indicated their safety for biological applications. Based on their high fluorescence quantum efficiency and the advantages mentioned above, these FCNs were then used for cell imaging and exhibited a perfect performance under 3 kinds of excitation bands (UV, blue, and green lights). Thus, they can be practically applied to immune labeling and imaging in vivo in the near future. PMID- 26945165 TI - Co-liposomes having anisamide tagged lipid and cholesteryl tryptophan trigger enhanced gene transfection in sigma receptor positive cells. AB - Selective gene transfection could be strategy of interest for reducing off-target gene expression and toxicity. In this respect, sigma receptors are found to be over-expressed in many human tumors and liposomal formulations with ability to target these sigma receptors may improve the transfection efficiency to a significant level. To this direction, six novel lipids have been synthesized with different hydrophobic segments such as a long hydrophobic chain or a cholesteryl group and L-tryptophan as the head group. Three of them, Lipid 1, 3 and 5 possessed cationic Me3N(+) moiety at the distal end. In contrast each of the other three Lipid 2, 4 and 6 possessed sigma receptor targeting anisamide group with no cationic charge. Mixing of cationic and anisamide counterparts of the same lipid in a molar ratio of 1:1 produced co-liposomes L-M-1 (Lipid 1+2), L-M-2 (Lipid 3+4) and L-M-3 (Lipid 5+6). These co-liposomes, while keeping the sigma targeting anisamide tag intact, showed good DNA binding and release which were optimized from EB intercalation and gel electrophoresis assays. Inclusion of a zwitterionic, fusogenic natural lipid, DOPE, into the co-liposomes further improved the binding efficiencies of the lipid mixtures with DNA. These co liposomes having cationic and anisamide lipids and DOPE were highly selective toward sigma positive HEK293 and HEK293T cells compared to the sigma negative HeLa cells. As evidenced from both FACS and luciferase assay, a lipid mixture comprising Lipid 3, 4 and DOPE in a molar ratio of 1:1:1 (L-M-2D1) was the best for transfection of reporter pEGFP-C3 and functional pCEP4-p53 gene plasmids. Anisamide mediated sigma receptor selectivity was further probed by pre incubating the transfecting cells with lipids possessing anisamide and by quantification of the un-transfected plasmid DNA. Also each formulation was highly non-toxic in the cell lines examined. PMID- 26945166 TI - Microbial growth inhibition caused by Zn/Ag-Y zeolite materials with different amounts of silver. AB - Different loadings of silver exchanged on bimetallic Zn/Ag-NaY zeolite materials were studied for antimicrobial properties against four reference microorganisms. The sensitive indicator strains used were two bacteria (Escherichia coli and Bacillus subtilis) and two yeast species (Saccharomyces cerevisiae and Candida albicans). The bimetallic materials were compared with the monometallic materials prepared with the same concentrations of silver. A synergistic effect between the two metals, zinc and silver, was evidenced on the antimicrobial activity of the materials. All mono and bimetallic materials showed strong efficacy against bacteria and yeasts, although the later overall displayed lower MIC values. The results of X-ray photoelectron spectroscopy (XPS) confirm the presence of silver and zinc as ions, not homogeneously distributed throughout the zeolite framework, which implies that the metal ions are located in different sites of the faujasite structure. PMID- 26945167 TI - The Use of Cell Transplantation in Spinal Cord Injuries. AB - Acute spinal cord injuries are life-changing events that lead to substantial morbidity and mortality, but the role of cell-based treatment for these injuries is unclear. Cell therapy is a rapidly evolving treatment methodology, with basic science and early phase I/II human trials showing promise. Multiple cell lines can be used in cell therapy, including adult or embryonic stem cells, Schwann cells, olfactory ensheathing cells, and induced pluripotent stem cells. Adult stem cells, Schwann cells, and olfactory ensheathing cells are readily available but lack the ability to differentiate into cells of the central nervous system. Mesenchymal stem cells can decrease cell death by modifying the local environment into which they are introduced. Peripheral nerve cells, such as Schwann cells and olfactory ensheathing cells, can myelinate existing axons and foster axonal growth in the central nervous system, and embryonic stem cells can differentiate into neural progenitor stem cells of the central nervous system. Induced pluripotent stem cells are the basis of an emerging technology that has yet to be implemented in human trials but may offer a means of cell therapy without the ethical dilemmas associated with embryonic cells. PMID- 26945168 TI - Injuries of the Scapholunate Interosseous Ligament: An Update. PMID- 26945169 TI - Favourable effects of Bacillus subtilis and Bacillus licheniformis on experimental periodontitis in rats. AB - OBJECTIVES: The purposes of this study were to evaluate, in rats: i) the effects of Bacillus species on the development of experimental periodontitis (EP) via microtomographic, immunological and hematological assays (Experiment 1-E1); ii) the effects of Bacillus species as adjuncts to scaling and root planing (SRP) for the treatment of EP via histomorphometric and immunohistochemical analyses (Experiment 2-E2). METHODS: In E1, 24 rats were divided into groups C1 (control), PROB1, EP1 and EP-PROB1. In groups with EP, the mandibular first molar of each animal received a ligature for 14 days. In groups PROB1, animals received Bacillus species for 44 days, starting 30 days before EP induction in Group EP PROB1. In E2, 24 rats were assigned to groups C2 (control), PROB2, EP-SRP2 and EP SRP-PROB2. In groups with SRP, EP was induced as described in E1. The ligatures were removed after 14 days and SRP was performed. In groups PROB2, animals received Bacillus species for 15 days, starting after SRP in Group EP-SRP-PROB2. RESULTS: In E1, Group EP1 presented bone loss (BL) and eosinophil numbers greater than Group EP-PROB1 (P<0.05). In Group EP-PROB1, the receptor activator of nuclear factor-kB ligand (RANKL)/osteoprotegerin (OPG) ratio was similar to that of groups without EP. In E2, Group EP-SRP-PROB2 presented fewer TRAP-positive osteoclasts, lower immunolabeling pattern for a proinflammatory cytokine and decreased BL and attachment loss than Group EP-SRP2 (P<0.05). CONCLUSIONS: Bacillus species supplementation provided a protective effect against BL and enhanced the effects of SRP in the treatment of EP in rats. PMID- 26945170 TI - Effect of cavity depth on dentine sensitivity in man. AB - OBJECTIVE: To determine if dentine at the enamel-dentine junction (EDJ) in man is more sensitive to hydrostatic pressure stimuli then deeper dentine. DESIGN: Cavities (1mm diam.) were cut at the tips of the buccal and lingual cusps of 8 premolars in 3 subjects (ages: 22-25 years). Both cavities were initially deepened to expose the EDJ then one (the test cavity) was deepened in steps of 0.5mm to a maximum of 2.0 mm below the EDJ. The cavities were tested at each stage, before and after etching, with 5s, hydrostatic pressure stimuli between 400 mm above, and 400 mm below atmospheric. The intensity of any pain produced was recorded on a VAS scale and electrodes were placed in both cavities in an attempt to monitor any action potentials evoked in intradental nerves. RESULTS: In all the teeth, the intensity of the pain produced by a stimulus tended to increase as the cavity was deepened, as did the number of action potentials recorded (in 6 of the 8 teeth). The responses were greater from etched than unetched dentine, and negative pressures evoked greater responses than the corresponding positive pressures. CONCLUSION: There was no evidence that dentine close to the EDJ was more sensitive to hydrostatic pressure stimuli than deeper dentine. It may however be more sensitive to mechanical stimuli as it is more compliant. PMID- 26945171 TI - Salivary pellicles equalise surfaces' charges and modulate the virulence of Candida albicans biofilm. AB - INTRODUCTION: Numerous environmental factors influence the pathogenesis of Candida biofilms and an understanding of these is necessary for appropriate clinical management. AIMS: To investigate the role of material type, pellicle and stage of biofilm development on the viability, bioactivity, virulence and structure of C. albicans biofilms. METHODS: The surface roughness (SR) and surface free energy (SFE) of acrylic and titanium discs was measured. Pellicles of saliva, or saliva supplemented with plasma, were formed on acrylic and titanium discs. Candida albicans biofilms were then generated for 1.5 h, 24h, 48 h and 72 h. The cell viability in biofilms was analysed by culture, whilst DNA concentration and the expression of Candida virulence genes (ALS1, ALS3 and HWP1) were evaluated using qPCR. Biofilm metabolic activity was determined using XTT reduction assay, and biofilm structure analysed by Scanning Electron Microscopy (SEM). RESULTS: Whilst the SR of acrylic and titanium did not significantly differ, the saliva with plasma pellicle increased significantly the total SFE of both surface. The number of viable microorganisms and DNA concentration increased with biofilm development, not differing within materials and pellicles. Biofilms developed on saliva with plasma pellicle surfaces had significantly higher activity after 24h and this was accompanied with higher expression of virulence genes at all periods. CONCLUSION: Induction of C. albicans virulence occurs with the presence of plasma proteins in pellicles, throughout biofilm growth. To mitigate such effects, reduction of increased plasmatic exudate, related to chronic inflammatory response, could aid the management of candidal biofilm related infections. PMID- 26945172 TI - Living an everyday life with head and neck cancer 2-2.5 years post-diagnosis - A qualitative prospective study of 56 patients. AB - RATIONALE: There are many studies available describing how patients are affected by head and neck cancer (HNC) and its treatment. Usually these studies are quantitative and focus on assessing patients' quality of life or distress post treatment. These studies are important, but they are of limited value if we are interested in understanding more about HNC in an everyday life context. OBJECTIVE: The purpose was to determine how life was lived and valued during and after treatment for HNC and to detect different transitions in returning to everyday life. METHODS: During 2009-2012, 56 patients with HNC were consecutively included, and interviewed at 6, 12, and 24 months post-treatment about how they lived their lives. All patients received primary treatment at a tertiary referral university hospital in Sweden. RESULTS: Four different trajectories and transitions emerged. The first group (n = 15) evaluated their illness experience as a past parenthesis in their life suggesting that they had psychologically left the illness behind. In the second group (n = 9), the impact of the disease seemed to be diluted by other strains in their life, and although these patients to some extent were still hampered by side effects, they regarded them as 'no big deal'. The cancer really made a difference in the third group (n = 12) in both positive and negative ways and seemed to reflect a balance between such effects. In the fourth group (n = 20), the physical and/or psychological problems predominated and the patients' lives had changed for the worse. CONCLUSION: The narratives showed that being afflicted by HNC has different impacts depending on how the patients live their lives - it is a matter of individual transition in an everyday life context. This idiosyncrasy challenges the meaningfulness of screening efforts to identify vulnerable groups for psychosocial intervention. PMID- 26945173 TI - Reply. PMID- 26945174 TI - Effect of Gaze Position and Blur on Stepping Accuracy in Older Adults. AB - PURPOSE: To examine the effects of gaze position and optical blur, similar to that used in multifocal corrections, on stepping accuracy for a precision stepping task among older adults. METHODS: Nineteen healthy older adults (mean age, 71.6 +/- 8.8 years) with normal vision performed a series of precision stepping tasks onto a fixed target. The stepping tasks were performed using a repeated-measures design for three gaze positions (fixating on the stepping target as well as 30 and 60 cm farther forward of the stepping target) and two visual conditions (best-corrected vision and with +2.50DS blur). Participants' gaze position was tracked using a head-mounted eye tracker. Absolute, anteroposterior, and mediolateral foot placement errors and within-subject foot placement variability were calculated from the locations of foot and floor mounted retroreflective markers captured by flash photography of the final foot position. RESULTS: Participants made significantly larger absolute and anteroposterior foot placement errors and exhibited greater foot placement variability when their gaze was directed farther forward of the stepping target. Blur led to significantly increased absolute and anteroposterior foot placement errors and increased foot placement variability. Furthermore, blur differentially increased the absolute and anteroposterior foot placement errors and variability when gaze was directed 60 cm farther forward of the stepping target. CONCLUSIONS: Increasing gaze position farther ahead from stepping locations and the presence of blur negatively impact the stepping accuracy of older adults. These findings indicate that blur, similar to that used in multifocal corrections, has the potential to increase the risk of trips and falls among older populations when negotiating challenging environments where precision stepping is required, particularly as gaze is directed farther ahead from stepping locations when walking. PMID- 26945175 TI - Microbial Contamination of Periorbital Tissues and Accessories of Children. AB - PURPOSE: To investigate normal flora of children with and without orthokeratology (ortho-k) treatment, and the associations between carriage of Staphylococcus aureus and Gram-negative rods with contamination of contact lenses and lens cases in ortho-k subjects and with spectacles of control subjects. METHODS: Twenty three ortho-k subjects (treatment >12 months) and 20 control myopic subjects aged 7-14 years were recruited. Samples were collected from four sites surrounding the left eye (lower conjunctiva, upper and lower eyelids, and eyelashes) for all subjects, spectacles for control subjects and contact lens accessories for ortho k subjects. Samples were cultured, total numbers enumerated, and isolates identified using chromogenic agars. RESULTS: Ortho-k subjects had significantly less total isolates in the conjunctiva than controls (p = 0.009). Otherwise, carriage rates in normal flora levels of the peri-orbital tissues were not significantly different between the two groups (p > 0.19). The total isolates and carriage rates of normal flora on spectacles, contact lenses, and lens cases were similar to those identified on the skin tissues. Small numbers of bacteria were identified from the multipurpose solution of two ortho-k subjects. Although the association between the carriage of S. aureus with contamination of accessories was statistically significant only in control subjects (p = 0.03), ortho-k subjects not yielding S. aureus and Gram-negative rods from samples of their peri orbital tissues tended to be less likely to have these organisms in their accessories. No Pseudomonas was isolated from any of the sites sampled and no Acinetobacter was isolated from any of the accessories. CONCLUSIONS: Ortho-k may lower the total number of bacteria in conjunctiva due to the use of solution and lenses, but the physiologic effect of this treatment on the types of normal flora in children was minimal and should not increase the risk of microbial keratitis in children with good compliance. PMID- 26945176 TI - Corneal Swelling with Cosmetic etafilcon A Lenses versus No Lens Wear. AB - PURPOSE: To determine if the use of pigments or adding polyvinyl pyrrolidone during the fabrication of 1-DAY ACUVUE DEFINE (AD) brand contact lenses impacts open-eye corneal swelling compared with no lens wear (NLW). METHODS: A partial double-masked, randomized, bilateral crossover study was conducted in 24 Asian subjects using AD, 1-DAY ACUVUE DEFINE with Lacreon (ADL), NLW, and a control lens with no tint (1-DAY ACUVUE MOIST [AM]). Central corneal thickness was measured before insertion and immediately after removal after 8 +/- 1 h of open eye wear using an optical pachymeter in one eye. Corneal thickness along a 10-mm cord was measured in the contralateral eye using the Visante optical coherence tomographer (OCT). Corneal swelling was tested for noninferiority using a 5% margin. The endothelial bleb response was measured at baseline and 20 min after lens insertion using specular microscopy. Subjective grading of corneal staining and limbal/bulbar hyperemia were also monitored. RESULTS: After 8 +/- 1 h of open eye wear, central corneal swelling across the study lenses with either optical pachymeter or OCT methods was negligible. Peripheral corneal swelling least square mean differences with OCT were -0.03% (95% confidence interval [95% CI], 0.65 to 0.58%) and -0.26% (95% CI, -0.87 to 0.36%) between AD and ADL and the control lens (AM), respectively, and 1.67% (95% CI, 1.06 to 2.29%) and 1.45% (95% CI, 0.84 to 2.06%) between AD and ADL and NLW, respectively. No endothelial blebs were observed. No clinically significant differences were distinguished between the lenses and NLW for corneal staining and limbal/bulbar hyperemia. CONCLUSIONS: After 8 +/- 1 h of open-eye wear, central and peripheral corneal swelling along the horizontal meridian with AD, ADL, AM, and NLW were equivalent. These results confirm that the addition of polyvinyl pyrrolidone or pigments to etafilcon A to obtain a limbal ring design have no impact on corneal swelling or limbal/bulbar hyperemia during normal open-eye wear. PMID- 26945177 TI - Controlled Release of Multiple Therapeutics from Silicone Hydrogel Contact Lenses. AB - PURPOSE: The majority of contact lens wearers experience a significant level of ocular discomfort associated with lens wear, often within hours of wear, related to dry lenses, inflammation, protein adhesion to the lens surface, etc. Application of controlled drug release techniques has focused on the incorporation and/or release of a single comfort molecule from a lens including high molecular weight comfort agents or pharmaceutical agents. Previous studies have sought to mitigate the occurrence of only single propagators of discomfort. Clinical studies with eye drop solutions have shown that a mixture of diverse comfort agents selected to address multiple propagators of discomfort provide the greatest and longest lasting sensations of comfort for the patient. In this paper, multiple propagators of discomfort are addressed through the simultaneous release of four molecules from a novel contact lens to ensure high level of lens wear comfort. METHODS: Silicone hydrogel contact lenses were engineered via molecular imprinting strategies to simultaneously release up to four template molecules including hydropropyl methylcellulose (HPMC), trehalose, ibuprofen, and prednisolone. RESULTS: By adjusting the ratio of functional monomer to comfort molecule, a high level of control was demonstrated over the release rate. HPMC, trehalose, ibuprofen, and prednisolone were released at therapeutically relevant concentrations with varying rates from a single lens. CONCLUSIONS: The results indicate use as daily disposable lenses for single day release or extended-wear lenses with multiple day release. Imprinted lenses are expected to lead to higher efficacy for patients compared to topical eye drops by improving compliance and mitigating concentration peaks and valleys associated with multiple drops. PMID- 26945180 TI - Component-resolved diagnosis in anaphylaxis. AB - PURPOSE OF REVIEW: Component-resolved diagnosis (CRD) is an advanced tool capable of aiding the clinician in fine tuning the diagnosis of the causal allergens of a reaction with the added value of providing information of severity risk, potential cross-reactivity, and subsequently, guiding management measures. This review will focus on the advantages of CRD of anaphylaxis in clinical practice. RECENT FINDINGS: Research is continuously providing insight to which molecules are associated with genuine sensitization and/or potential severity risk for hymenoptera venom (Api m1, Ves v 1, Ves v 5, and Pol d 5), food allergy (seed storage proteins and nonspecific lipid transfer proteins), cofactor-enhanced food allergy (omega-5-gliadine, nonspecific lipid transfer proteins), red meat delayed anaphylaxis (alpha-gal), latex allergy (Hev b 1, Hev b 3, Hev b 5, and Hev b 6), and Anisakis allergy (Ani s 1, Ani s 4, Ani s 7, and Ani s 13); other molecules are primary associated with nonclinically relevant sensitizations, cross reactivity, or mild reactions (carbohydrate determinants and profilins). New molecules, some minor allergens, are being identified as new potential biomarkers of severity. SUMMARY: The usefulness of CRD in anaphylaxis is self-evident, since it improves the recognition of sensitization profiles associated with specific clinical outcomes and provides information to guide further management. PMID- 26945179 TI - Brief Report: Highly Active Antiretroviral Therapy Mitigates Liver Disease in HIV Infection. AB - To determine the impact of highly active antiretroviral therapy (HAART) on liver disease, we analyzed changes in the aspartate aminotransferase to platelet ratio index (APRI) pre- and post-HAART initiation among 441 HIV-monoinfected and 53 HIV viral hepatitis-coinfected men. Before HAART, APRI increased 17% and 34% among the HIV-monoinfected and coinfected men, respectively. With HAART initiation, APRI decreased significantly in men who achieved HIV RNA of <500 copies per milliliter: 16% for HIV-monoinfected and 22% for coinfected men. Decreases in APRI were dependent on HIV suppression. This protective effect of HAART decreased after 2 years, particularly in the HIV-monoinfected men. PMID- 26945181 TI - Label-free in-situ real-time DNA hybridization kinetics detection employing microfiber-assisted Mach-Zehnder interferometer. AB - A label-free DNA biosensor based on microfiber-assisted Mach-Zehnder interferometer (MAMZI) for in-situ real-time DNA hybridization kinetics detection has been proposed and experimentally demonstrated. A microfiber of hundreds of microns in length is fabricated by tapering a segment of standard single-mode fiber (SMF) to construct the U-shaped microcavity between the lead-in and lead out SMFs. Thanks to the mode field mismatching between the SMF and microfiber, the incident guided mode light would separate into two beams that respectively propagate in the air microcavity and the microfiber. Consequently, interference between different light modes would occur at the joint between the microfiber and the lead-out SMF. Experimental results indicate that owing to the participation of opening cavity modes in the modal interference process, the interferometric spectrum of our proposed microcavity sensor is highly sensitive to the variation of environmental refractive index (RI), especially for the RI range around 1.34 which is useful for most biological applications. The microfiber functionalization is achieved by stepwise modifying the microfiber with monolayer Poly-l-lysine (PLL) and single-stranded DNA (ssDNA) probes to produce the sensitive surface that could uniquely attach specific target ssDNAs. The fiber surface functionalization as well as DNA hybridization processes have been experimentally investigated for different target ssDNA solutions in real time. The interferometric transmission spectrum shows large wavelength shift for different biological phases, and a detection limit conservatively down to 0.0001pmol/MUL has been acquired by employing the U-shaped microcavity of 176.88MUm in length. Our proposed DNA biosensor possesses several advantages such as compact size, ease of fabrication, and strong response for DNA hybridization, which make it a promising candidate for potential applications in such rapidly expanding areas as medical diagnosis, cancer screenings, medicine examination and environmental engineering, etc. PMID- 26945182 TI - Sensitive and rapid detection of aflatoxin M1 in milk utilizing enhanced SPR and p(HEMA) brushes. AB - The rapid and sensitive detection of aflatoxin M1 (AFM1) in milk by using surface plasmon resonance (SPR) biosensor is reported. This low molecular weight mycotoxin is analyzed using an indirect competitive immunoassay that is amplified by secondary antibodies conjugated with Au nanoparticles. In order to prevent fouling on the sensor surface by the constituents present in analyzed milk samples, an interface with poly(2-hydroxyethyl methacrylate) p(HEMA) brush was employed. The study presents a comparison of performance characteristics of p(HEMA)-based sensor with a regularly used polyethylene glycol-based architecture relying on mixed thiol self-assembled monolayer. Both sensors are characterized in terms of surface mass density of immobilized AFM1 conjugate as well as affinity bound primary and secondary antibodies. The efficiency of the amplification strategy based on Au nanoparticle is discussed. The biosensor allowed for highly sensitive detection of AFM1 in milk with a limit of detection (LOD) as low as 18pgmL(-1) with the analysis time of 55min. PMID- 26945183 TI - An in-situ infection detection sensor coating for urinary catheters. AB - We describe a novel infection-responsive coating for urinary catheters that provides a clear visual early warning of Proteus mirabilis infection and subsequent blockage. The crystalline biofilms of P. mirabilis can cause serious complications for patients undergoing long-term bladder catheterisation. Healthy urine is around pH 6, bacterial urease increases urine pH leading to the precipitation of calcium and magnesium deposits from the urine, resulting in dense crystalline biofilms on the catheter surface that blocks urine flow. The coating is a dual layered system in which the lower poly(vinyl alcohol) layer contains the self-quenching dye carboxyfluorescein. This is capped by an upper layer of the pH responsive polymer poly(methyl methacrylate-co-methacrylic acid) (Eudragit S100(r)). Elevation of urinary pH (>pH 7) dissolves the Eudragit layer, releasing the dye to provide a clear visual warning of impending blockage. Evaluation of prototype coatings using a clinically relevant in vitro bladder model system demonstrated that coatings provide up to 12h advanced warning of blockage, and are stable both in the absence of infection, and in the presence of species that do not cause catheter blockage. At the present time, there are no effective methods to control these infections or provide warning of impending catheter blockage. PMID- 26945184 TI - Ratiometric electrochemical immunoassay based on internal reference value for reproducible and sensitive detection of tumor marker. AB - A ratiometric assay in an electrochemical immunosensor for tumor marker, herein carcinoembryonic antigen (CEA) was chosen as a model analyte, was developed to improve simplicity and accuracy. The immunosensor was fabricated via the simple expedient way of using Polythionine-gold (PTh-Au) as electrode modified material to be an internal reference signal and K3[Fe(CN)6] in electrolyte as an indicator signal. When the CEA was fixed on the modified electrode via immunoreaction, only the indicator signal sensitively altered; by contrast, the internal reference signal of PTh-Au remained constant at a suitable pH of the electrolyte. The ratio between the alterations of the indicator signal of K3[Fe(CN)6] and the constant internal reference signal can be used to monitor the concentration of CEA reliably, reproducibly, and sensitively. The prepared ratiometric electrochemical immunosensor could detect CEA with good specificity within a wide linear range from 0.005ng/ml to 40ng/ml with a detection limit of 2.2pg/ml. Additionally, experimental results confirm that our proposed method is practical. Thus, this method can expand to recognize and test other protein markers. PMID- 26945185 TI - Comparison of long-term prognostic value of baseline SYNTAX and clinical SYNTAX scores in ST-segment elevation myocardial infarction patients with multivessel disease. AB - BACKGROUND: The prognostic value of baseline SYNTAX (SS) and clinical SYNTAX (cSS) scores has been shown in different populations with coronary artery disease. However, their prognostic value has not been compared in patients with ST-segment elevation myocardial infarction (STEMI) and multivessel disease. METHODS: Patients who had undergone a primary percutaneous coronary intervention (PCI) for STEMI and had at least one critical lesion other than the culprit artery were recruited retrospectively. SS and cSS were calculated from medical records and angiograms and were compared in coronary artery by-pass grafting (CABG) and PCI groups. Long-term major adverse cardiac events (MACE) were defined as mortality, reinfarction, and target vessel revascularization. RESULTS: A total of 460 patients (214 in the CABG group and 246 in the PCI group) were analyzed. The baseline SS and the cSS were significantly higher in the CABG group compared with the PCI group (30.1+/-6.7 vs. 22.5+/-5.6; P<0.01 and 41.4+/-21.2 vs. 27.2+/ 15.9; P<0.01, respectively). During a follow-up period of 32+/-8 months, 15 patients from the CABG group and 12 patients from the PCI group died (P=0.33), but the rate of MACE was higher in the PCI group (31 vs. 20%, P<0.01). Receiver operating curve analysis and univariate Cox regression analysis indicated that SS and cSS have prognostic value in the CABG group, but not in the PCI group. In the CABG group, SS and cSS showed significant discriminative power for long-term mortality (for SS>33 sensitivity 73.3%, specificity 71.4% and for cSS>38.4 sensitivity 93.3%, specificity 58.3%) and for MACE (for SS>34.5 sensitivity 50%, specificity 81.4% and for cSS>43.5 sensitivity 66.7%, specificity 73.8%). CONCLUSION: SS and cSS scores have prognostic value in STEMI patients with multivessel disease treated with CABG surgery. cSS may be superior to SS for prediction of long-term adverse events in CABG patients. PMID- 26945186 TI - Intracoronary administration of different doses of anisodamine in primary percutaneous coronary intervention: protective effect in patients with ST-segment elevation myocardial infarction. AB - OBJECTIVE: The aim of this study was to evaluate the effects of intracoronary administration of anisodamine on myocardial reperfusion in patients with ST segment elevation myocardial infarction (STEMI) undergoing a primary percutaneous coronary intervention (pPCI). METHODS: Patients with acute STEMI undergoing pPCI were enrolled in this randomized-controlled study (January 2014-June 2015) and divided randomly into four groups: group A (normal saline), group B (1000 MUg anisodamine), group C (2000 MUg anisodamine), and group D (4000 MUg anisodamine). RESULTS: The study group included 140 patients. Percentages of thrombolysis in myocardial infarction (TIMI) myocardial perfusion grade 3, increased values of TIMI myocardial perfusion grade after stenting, and decreased values of corrected TIMI frame count in groups B, C, and D were all significantly higher than those in group A (P=0.031, 0.027, 0.003, and P<0.001, respectively). TIMI frame count after stenting in groups B, C, and D was significantly lower than that in group A (P=0.001). Left ventricular ejection fraction at 1 week after pPCI and at the 3 month follow-up, as well as the major adverse cardiac event-free survival rate in groups B, C, and D were higher than those in group A (P=0.027, 0.016, and 0.019, respectively). CONCLUSION: Intracoronary administration of anisodamine at different doses improved myocardial reperfusion in patients with STEMI undergoing pPCI and reduced major adverse cardiac events. The protective effect of anisodamine at a dose of 4000 MUg might be better than the doses at 1000 and 2000 MUg. PMID- 26945187 TI - Indications, algorithms, and outcomes for coronary artery bypass surgery in patients with acute coronary syndromes. AB - For patients with a non-ST-segment elevation acute coronary syndrome (NSTE-ACS), guideline recommendations and treatment pathways focus on revascularization for definitive treatment if the patient is an appropriate candidate. Despite the widespread use of revascularization for NSTE-ACS, most patients undergo a percutaneous coronary intervention, whereas a minority of patients undergo coronary artery bypass grafting. Focusing specifically on the USA, the contemporary utilization, preoperative and perioperative considerations, and outcomes of NSTE-ACS patients undergoing coronary artery bypass grafting have not been comprehensively reviewed. PMID- 26945188 TI - Characteristics and settling behaviour of particles from blast furnace flue gas washing. AB - A lot of particles from iron-making are removed with blast furnace off-gas and routed to the gas cleaning system. As water is used for cleaning the gas, the produced wash water contains a large amount of particles such as valuable Fe and C. However, the presence of zinc prevents recycling. In addition, the high amount of calcium results in uncontrolled scaling. Therefore, the properties of the wash water from scrubber and sludge, from the Finnish metal industry (SSAB Raahe), were evaluated in this study. Size fractionation of wash water revealed that Fe, Zn, Al, Mn, V, Cr and Cd appeared mainly in the larger fractions (>1.2 MUm) and Na, Mg, Si, Ni, K, Cu and As appeared mainly in the smaller fractions (<1.2 MUm) or in dissolved form. Calcium was found both in the larger fractions and dissolved (~60 mg/L). Most of the particles in wash water were included in the 1.2-10 MUm particle size and were settled effectively. However, a clear benefit was observed when using a chemical to enhance particle settling. In comparison to 2.5 h of settling without chemical, the turbidity was further decreased by about 94%, iron 85% and zinc 50%. Coagulation-flocculation experiments indicated that both low and high molecular weight cationic polymers could provide excellent purification results in terms of turbidity. Calcium should be removed by other methods. The particles in sludge were mostly in the 2-4 MUm or 10-20 MUm fractions. Further sludge settling resulted in high solids removal. PMID- 26945189 TI - Assessment of plant availability and environmental risk of biosolids-phosphorus in a U.S. Midwest Corn-Belt Soil. AB - A field experiment was conducted from 2005 to 2008 in Fulton County, Western Illinois with biosolids from conventional wastewater treatment applied as corn fertilizer in a series of P rates (0, 163, 325, 488, 650 kg P ha(-1)) along with commercial P fertilizer - triple superphosphate P (TSP) as reference to assess biosolids-P plant availability and potential loss to waterbodies through runoff. Air-dried biosolids and TSP were incorporated into surface soil at end of 2005, and corn (Zea mays) was planted for three consecutive years (2006-2008). Concentrations of soil extractable P except for Mehlich-3 P were always lower in the biosolids than TSP treatments at the same P rates. The soil potentially available P in water extractable P (WEP) and Olsen P derived from biosolids-P estimated by the exponential depletion model was 2-4% and 15-24% of total P in the applied biosolids, respectively. The residence time of biosolids-induced WEP and Olsen P in Midwest soil under annual corn cropping was 5 and 2 years, respectively. Corn tissue analysis showed lower increase in P concentration by biosolids-P than TSP. The elevation rate of soluble reactive P (SRP) concentration in simulated runoff was less by biosolids than TSP. Based on the data in this study, the plant availability and environmental risk of biosolids-P are lower than those of TSP in the Midwest soil, thus use of biosolids as P nutrient for corn would not cause a major impairment to water sources even P applied through biosolids was not completely used by annual crop. PMID- 26945190 TI - Pediatric Emergency Department Study of Cardiac Risk in the Novel Patient (PED SCReeN). AB - OBJECTIVE: We compare pediatric cardiac risk classification and management recommendations between emergency physicians (EPs) and pediatric cardiologists (PCs) in children with a suspected new cardiac disorder. METHODS: We prospectively compared the work-up, assessment, classification, and disposition of patients aged 0 to 21 years presenting to the emergency department with a potential cardiac etiology in whom an electrocardiogram (ECG) was performed. The criterion standard was a blinded assessment by the PC-electrophysiologist after review of the history, physical examination, ancillary tests, and ECG. RESULTS: In 508 subjects, the median age was 15 years (interquartile range, 11-17 years), with a slight female predominance (281, 55.3%). The most common reasons for obtaining an ECG were: chest pain (158, 31.1%) and syncope, presyncope, or possible seizure (146, 28.7%). The most common auxiliary study was a chest radiograph (432, 85% of subjects). A total of 617 electrocardiographic diagnoses were made by EPs and 984 diagnoses by PCs. Sensitivities and specificities varied by discrete class, but disposition decisions were concordant (home or admission). The EPs were highly accurate for the need for emergent cardiology involvement (area under the curve, 0.89). CONCLUSIONS: The EPs and PCs agreed on the evaluation and disposition of children at either low risk or high risk for an acute cardiac presentation in the emergency department. There was considerable variation in management recommendations in the intermediate risk children needing cardiology outpatient follow-up. We recommend the development and implementation of focused training modules on emergency pediatric cardiology and increased communication with pediatric cardiology to improve patient safety and resource utilization. PMID- 26945191 TI - Emergency Department Use and Postvisit Care for Anxiety and Stress Disorders Among Children: A Population-Based Cohort Study in Alberta, Canada. AB - OBJECTIVE: We examined sociodemographic trends in emergency department ED visits and postvisit health care for anxiety and stress disorders. METHODS: Emergency department visits (N = 11,289) by children younger than 18 years were extracted from population-based administrative databases from Alberta, Canada (2002-2011). We examined health services use by demographics and socioeconomic proxy (First Nations status, family subsidy type: government, human services program, none). We calculated visit rates and described physician visits after discharge (n = 8075 children). Multivariable survival analyses (with 95% confidence intervals [CIs]) estimate time to first physician visit and ED return. RESULTS: During 2002 2011, visit rates increased by age, First Nations, and subsidy status. The largest increase was for children (all ages) from families receiving government subsidy (491.43/100,000, P < 0.001). Thirty days after an index visit, most physician follow-up visits were made by children aged 15 to 17 years (61.0%) and from families receiving no subsidy (66.5%). The median time to physician follow up for First Nations children was 32 days (95% CI, 27-37) compared with 19 days for children from families receiving government subsidy whose median time was shortest (95% CI, 18-23). Children (all ages) in the government and human services program subsidy groups and those who had First Nations status returned earlier to the ED compared with children in the no subsidy group. CONCLUSIONS: Adolescents had high ED use and physician follow-up, whereas First Nations children and those from families receiving subsidy (all ages) had high ED use and low physician follow-up. Efforts to improve disorder identification and treatment among high ED user groups and low physician follow-up user groups are needed. PMID- 26945192 TI - Restrictive Diet Control as a Means of Child Abuse. AB - We have recently encountered a series of cases where an obese caretaker is juxtaposed to a severely starved, malnourished dependent. The cases described all share a common characteristic: that the primary perpetrator was an obese caretaker who tried to exert absolute control over their victim's daily life in a way that included either a severe restriction or complete denial of food. Because the pathophysiology of both child abuse and obesity are incredibly complex and multifactorial, these cases are presented to encourage further discussion and more rigorous investigation into the validity of a hypothesis that has been derived from this set of cases: that the obesity of a child's caretaker may be an additional risk factor for child maltreatment by starvation. PMID- 26945193 TI - Size Matters: Point-of-Care Ultrasound in Pediatric Appendicitis. AB - Ultrasound is the initial diagnostic modality of choice for evaluation of pediatric appendicitis. We report a case that highlights the importance of pain control, distraction, focusing on the appearance of the appendix and the surrounding structures, the value of size cutoff points for appendicitis, and repeating ultrasound examinations to optimize yield. PMID- 26945194 TI - Lyme Myocarditis Presenting as Chest Pain in an Adolescent Girl. AB - A previously healthy adolescent girl presented to the emergency department with new onset chest and right upper quadrant abdominal pain. Laboratory studies and imaging were consistent with myocarditis. She developed heart block after admission and required stabilization in the cardiac intensive care unit. Lyme serology returned positive, and her condition was diagnosed as Lyme disease associated myocarditis. PMID- 26945195 TI - Can Telemedicine Improve Adherence to Resuscitation Guidelines for Critically Ill Children at Community Hospitals? A Randomized Controlled Trial Using High Fidelity Simulation. AB - OBJECTIVES: Children transferred from community hospitals lacking specialized pediatric care are more seriously ill than those presenting to pediatric centers. Pediatric consultation and adherence to management guidelines improve outcomes. The aims of the study were (1) to assess whether telemedicine consultation in critical situations is feasible and (2) to compare the impact of pediatric critical care medicine (PCCM) consultation via telemedicine versus telephone on community hospital adherence to resuscitation guidelines through a randomized controlled telemedicine trial. METHODS: In situ, high-fidelity simulation scenarios of critically ill children presenting to a community hospital and progressing to cardiopulmonary arrest were performed. Scenarios were randomized to PCCM consultation via telephone (control) or telemedicine (intervention). Primary outcome measure was proportion of teams who successfully defibrillated in 180 seconds or less from presentation of pulseless ventricular tachycardia. RESULTS: The following 30 scenarios were completed: 15 control and 15 intervention. Only 11 (37%) of 30 teams, defibrillated in 180 seconds or less from presentation of pulseless ventricular tachycardia; control: 6 (40%) of 15 versus intervention: 5 (33%) of 15, P = 0.7. Request for or use of backboard during cardiopulmonary resuscitation occurred in 24 (80%) of 30 scenarios; control: 9 (60%) of 15 versus intervention: 15 (100%) of 15, P = 0.006. Request for or use of stepstool during cardiopulmonary resuscitation occurred in 6 (20%) of 30 scenarios; control: 1 (7%) of 15 versus intervention: 5 (33%) of 15, P = 0.07. CONCLUSIONS: This study demonstrates the feasibility of using telemedicine to support acute management of children who present to community hospitals. Neither study arm adhered to current resuscitation guidelines and telemedicine consultation with PCCM experts was not associated with improvement. However, further research on optimizing telemedicine impact on the quality of pediatric care at community hospitals is warranted. PMID- 26945196 TI - How Long Does it Take to Diagnose Appendicitis? Time Point Process Mapping in the Emergency Department. AB - OBJECTIVES: Appendicitis is the most common surgical emergency encountered in the pediatric emergency department (ED). We analyzed the time course of children evaluated for suspected appendicitis in relation to implementation of a risk stratified ultrasound scoring system and structured reporting template (Appy Score). METHODS: In July 2013, a 6-level ultrasound (US)-based appendicitis scoring system was developed and implemented. The records of children (age <=18 years) who underwent limited abdominal US exams for suspected appendicitis at a large academic pediatric ED were reviewed retrospectively. Time periods evaluated were from January 1 to April 1, 2013 (before implementation of the US scoring system, "PRE") and July 1 to October 1, 2013 (after implementation of the US scoring system, "POST"). Times are presented as medians with interquartile range. RESULTS: A total of 926 children were included (median age, 9.5 years [range, 0.1 18 years]; 49% female). Four hundred eighty-one patients were evaluated PRE and 445 POST. When comparing the 2 groups, there were no differences in the PRE and POST periods with regard to time from US ordered to first read (102 vs 112 minutes, P = 0.30), US ordered to disposition (215 vs 208 minutes, P = 0.40) and operating room posting (121 vs 122 minutes, P = 0.59), and overall ED stay (329 vs 333 minutes, P = 0.39). CONCLUSIONS: The development of a radiographic appendicitis score, although allowing for a standardized reporting method, did not significantly alter the ED process flow for evaluation of appendicitis. This reflects the complexities in ED throughput and reveals the need for additional factors to change to improve patient flow. PMID- 26945197 TI - Antimicrobial Stewardship Programs: A Lot of Working Parts Within the Machine. PMID- 26945198 TI - Is There a Concerning Trend in Extracorporeal Life Support Utilization for Single Ventricle Patients? PMID- 26945199 TI - A Single Catheter to Monitor Both Central Venous Pressure and Left Atrial Pressure. PMID- 26945200 TI - Polycythemia, Prognostication, and Plausibility After the Norwood Operation. PMID- 26945201 TI - Family-Clinician Communication Within Critical Care Settings: Unraveling the Complex and Valuing the Hidden. PMID- 26945202 TI - Kernicterus in Neonatal Jaundice--Finding the Needle in the Haystack. PMID- 26945203 TI - Opportunities for Enhancing Patient Recruitment in Clinical Research: Building an Evidence Base for Critical Care Medicine. PMID- 26945204 TI - Pediatric Donation After Circulatory Determination of Death: Past, Present, and Hopeful Future Changes. PMID- 26945205 TI - Intensive Care Outcomes for Hematopoietic Stem Cell Transplant Recipients: More of the Same. PMID- 26945206 TI - PICU Propofol Use, Where Do We Go From Here? PMID- 26945207 TI - Pediatric Traumatic Brain Injury: Is It Time to Consider Gender-Based Treatments? PMID- 26945208 TI - Dosing of Vasopressin in Critically Ill Children: Implications for Medication Safety. PMID- 26945209 TI - The author replies. PMID- 26945210 TI - Exogenous melatonin improves corn (Zea mays L.) embryo proteome in seeds subjected to chilling stress. AB - Melatonin (MEL; N-acetyl-5-methoxytryptamine) plays an important role in plant stress defense. Various plant species rich in this indoleamine have shown a higher capacity for stress tolerance. Moreover, it has great potential for plant biostimulation, is biodegradable and non-toxic for the environment. All this indicates that our concept of seed enrichment with exogenous MEL is justified. This work concerns the effects of corn (Zea mays L.) seed pre-sowing treatments supplemented with MEL. Non-treated seeds (nt), and those hydroprimed with water (H) or with MEL solutions 50 and 500 MUM (HMel50, HMel500) were compared. Positive effects of seed priming are particularly apparent during germination under suboptimal conditions. The impact of MEL applied by priming on seed protein profiles during imbibition/germination at low temperature has not been investigated to date. In order to identify changes in the corn seed proteome after applying hydropriming techniques, purified protein extracts of chilling stressed seed embryos (14 days, 5 degrees C) were separated by two-dimensional electrophoresis. Then proteome maps were graphically and statistically compared and selected protein spots were qualitatively analyzed using mass spectrometry techniques and identified. This study aimed to analyze the priming-induced changes in maize embryo proteome and at identifying priming-associated and MEL associated proteins in maize seeds subjected to chilling. We attempt to explain how MEL expands plant capacity for stress tolerance. PMID- 26945211 TI - Barriers and Facilitators to Exercise Participation in People with Hip and/or Knee Osteoarthritis: Synthesis of the Literature Using Behavior Change Theory. AB - Exercise is recommended for hip and knee osteoarthritis (OA). Patient initiation of, and adherence to, exercise is key to the success of managing symptoms. This study aimed to (1) identify modifiable barriers and facilitators to participation in intentional exercise in hip and/or knee OA, and (2) synthesize findings using behavior change theory. A scoping review with systematic searches was conducted through March 2015. Two reviewers screened studies for eligibility. Barriers and facilitators were extracted and synthesized according to the Theoretical Domains Framework (TDF) by two independent reviewers. Twenty-three studies (total of 4633 participants) were included. The greatest number of unique barriers and facilitators mapped to the Environmental Context and Resources domain. Many barriers were related to Beliefs about Consequences and Beliefs about Capabilities, whereas many facilitators were related to Reinforcement. Clinicians should take a proactive role in facilitating exercise uptake and adherence, rather than trusting patients to independently overcome barriers to exercise. Strategies that may be useful include a personalized approach to exercise prescription, considering environmental context and available resources, personalized education about beneficial consequences of exercise and reassurance about exercise capability, and use of reinforcement strategies. Future research should investigate the effectiveness of behavior change interventions that specifically target these factors. PMID- 26945212 TI - Fatigue Fracture of the Calcaneus: From Early Diagnosis to Treatment: A Case Report of a Triathlon Athlete. AB - Stress fractures are frequently underdiagnosed and undertreated despite being common in sports. Early diagnosis is crucial; therefore, a high index of clinical suspicion is required. Complementary examinations are essential for diagnosis and follow-up. The authors report a clinical case of a young adult triathlon athlete referring mechanical pain in the rear left foot, with 2 weeks' progression. An earlier increase in daily training intensity was recorded. Complementary examinations confirmed a calcaneal fatigue fracture. Immobilization and no weight bearing were introduced for an initial period of 4 weeks, and the rehabilitation process was started. Progressive weight bearing was introduced between fourth and eighth weeks. Sports activity started at the 12th week. Boundaries to sports activity were eliminated by the 24th week, without pain or functional limitation. Repetitive overload to the heel and intense axial weight bearing in association to repetitive concentric/eccentric gastrocnemius contraction are related to calcaneal stress fracture, the second most common stress fracture in the foot. Calcaneal stress fractures can be adequately treated with activity modification, without casting or surgical intervention. When in the presence of bilateral stress fractures, metabolic and nutritional issues must be considered. The case report highlights the importance of sports medicine examination for detecting intrinsic and extrinsic fatigue fracture risk factors. PMID- 26945214 TI - Diagnosis and Rehabilitation of a Middle Cuneiform Fracture in a Hockey Player. AB - Isolated cuneiform fractures are rare and are often missed on plain radiographs, leading to delayed diagnosis and delayed return to sport. The authors of this study present a 32-year-old male ice hockey player who sustained trauma to his dorsal midfoot from a slap shot. Radiographs were negative for fracture. After inability to wean out of the controlled ankle movement boot, magnetic resonance imaging was ordered, demonstrating a middle cuneiform fracture. The patient was seen in physical therapy, where aquatic therapy, strength training, and cardiovascular conditioning were progressed. He was able to wean out of the controlled ankle movement boot at 7 weeks after injury and return to playing ice hockey. Here, we outline rehabilitation and a diagnostic and rehabilitative algorithm for those who sustain trauma to the dorsal midfoot with suspected fracture. PMID- 26945213 TI - Biglycan Inhibits Capsaicin-Induced Substance P Release by Cultured Dorsal Root Ganglion Neurons. AB - OBJECTIVE: The purpose of this study was to examine the inhibitory effects of biglycan on substance P release from cultured sensory neurons in response to capsaicin. STUDY DESIGN: In vitro study of cultured primary sensory neurons from the rabbit dorsal root ganglion (DRG). We interrogated the culture system function with capsaicin. Biglycan is an important structural component of the intervertebral disc that may regulate growth factors and inflammatory mediators. We tested the hypothesis that biglycan inhibits substance P release in response to capsaicin. RESULTS: The DRG cultures were shown to contain both neurons and astrocytes by immunostaining using antibodies recognizing neuron and glial cell markers. Cultured DRG cells respond to capsaicin in a dose- and time-dependent manner (capsaicin dose ranges from 5 to 500 MUmol/L; stimulation time ranges from 0 to 60 minutes). The neurons preincubated with biglycan released 27% less substance P compared with neurons without biglycan (n = 4, P = 0.036). CONCLUSION: We have established a DRG cell culture system, which contains both sensory neurons and the supporting astrocytes. Biglycan, an inhibitor of substance P release by DRG cultures, may serve as an ingredient in intradiscal injectables to reduce back pain. PMID- 26945215 TI - Ultrasound-Guided Steroid Injections for Two Painful Neuromas in the Stump of a Below-Elbow Amputee. PMID- 26945216 TI - Comparison of the Effectiveness of Transcutaneous Electrical Nerve Stimulation and Interferential Therapy on the Upper Trapezius in Myofascial Pain Syndrome: A Randomized Controlled Study. AB - OBJECTIVE: The aim of this study was to compare the effectiveness of transcutaneous electrical nerve stimulation and interferential therapy (IFT) both in combination with hot pack, myofascial release, active range of motion exercise, and a home exercise program on myofascial pain syndrome patients with upper trapezius myofascial trigger point. DESIGN: A total of 105 patients with an upper trapezius myofascial trigger point were recruited to this single-blind randomized controlled trial. Following random allocation of patients to three groups, three therapeutic regimens-control-standard care (hot pack, active range of motion exercises, myofascial release, and a home exercise program with postural advice), transcutaneous electrical nerve stimulation-standard care and IFT-standard care-were administered eight times during 4 wks at regular intervals. Pain intensity and cervical range of motions (cervical extension, lateral flexion to the contralateral side, and rotation to the ipsilateral side) were measured at baseline, immediately after the first treatment, before the eighth treatment, and 1 wk after the eighth treatment. RESULTS: Immediate and short-term improvements were marked in the transcutaneous electrical nerve stimulation group (n = 35) compared with the IFT group (n = 35) and the control group (n = 35) with respect to pain intensity and cervical range of motions (P < 0.05). The IFT group showed significant improvement on these outcome measurements than the control group did (P < 0.05). CONCLUSION: Transcutaneous electrical nerve stimulation with standard care facilitates recovery better than IFT does in the same combination. PMID- 26945217 TI - Sonographic Tracking of the Lower Limb Peripheral Nerves: A Pictorial Essay and Video Demonstration. AB - Compared with the upper limbs, sonographic tracking of peripheral nerves in the lower limbs is more challenging. The overlying muscles are larger, hindering visualization of the deeply embedded nerves by using a linear transducer. The use of a curvilinear transducer-providing an extended view with better penetration for the field of interest-may be useful for scanning the nerves in the hip and thigh. Application of the Doppler mode helps localization of the target nerve by identifying the accompanying vessels. Aiming to demonstrate the relevant tracking techniques, the present article comprises a series of ultrasound images and videos showing how to scan the nerves in the lower limb, that is, femoral, obturator, pudendal, lateral femoral cutaneous, sciatic, saphenous, sural, tibial, and peroneal nerves. PMID- 26945218 TI - The Quality of Reporting of Abstracts in Physical Therapy Literature is Suboptimal: Cross-Sectional, Bibliographic Analysis. AB - OBJECTIVE: The quality of abstract reporting in physical therapy literature is unknown. The purpose of this study was to provide baseline data for judging the future impact of the 2010 Consolidated Standards of Reporting Trials statement specifically referencing the 2008 Consolidated Standards of Reporting Trials statement for reporting of abstracts of randomized controlled trials across and between a broad sample and a core sample of physical therapy literature. DESIGN: A cross-sectional, bibliographic analysis was conducted. Abstracts of randomized controlled trials from 2009 were retrieved from PubMed, PEDro, and CENTRAL. Eligibility was determined using PEDro criteria. For outcomes measures, items from the Consolidated Standards of Reporting Trials statement for abstract reporting were used for assessment. Raters were not blinded to citation details. RESULTS: Using a computer-generated set of random numbers, 150 abstracts from 112 journals comprised the broad sample. A total of 53 abstracts comprised the core sample. Fourteen of 20 Consolidated Standards of Reporting Trials items for both samples were reported in less than 50% of the abstracts. Significantly more abstracts in the core sample reported (% difference core - broad; 95% confidence interval) title (28.4%; 12.9%-41.2%), blinding (15.2%; 1.6%-29.8%), setting (47.6%; 32.4%-59.4%), and confidence intervals (13.1%; 5.0%-25.1%). CONCLUSIONS: These findings provide baseline data for determining if continuing efforts to improve abstract reporting are heeded. PMID- 26945219 TI - The Diagnostic Value of Nerve Ultrasound in an Atypical Palmar Cutaneous Nerve Lesion. AB - Detailed knowledge of the fascicular anatomy of peripheral nerves is important for microsurgical repair and functional electrostimulation.We report a patient with a lesion on the left palmar cutaneous branch of the median nerve (PCBMN) and sensory signs expanding outside the PCBMN cutaneous innervation territory. Nerve conduction study showed the absence of left PCBMN sensory nerve action potential, but apparently, no median nerve (MN) involvement. Nerve ultrasound documented a neuroma of the left PCBMN and a coexistent lateral neuroma of the left MN in the carpal tunnel after the PCBMN left the main nerve trunk.Nerve ultrasound may offer important information in patients with peripheral nerve lesions and atypical clinical and/or nerve conduction study findings. The present case may shed some light on the somatotopy of MN fascicles at the wrist. PMID- 26945220 TI - A New Neural Tract Between Injured Fornix and Brainstem Cholinergic Nucleus in a Stroke Patient. PMID- 26945221 TI - Dynamic Ultrasound Imaging for Ulnar Nerve Subluxation and Snapping Triceps Syndrome. PMID- 26945222 TI - Dynamic and Doppler Ultrasound Imaging for the Diagnosis of Triangular Fibrocartilage Complex Injury and Ulnocarpal Wrist Instability. PMID- 26945223 TI - Comparison of Cardiorespiratory Demand and Rate of Perceived Exertion During Propulsion in a Natural Environment With and Without the Use of a Mobility Assistance Dog in Manual Wheelchair Users. AB - OBJECTIVE: The aim of this study was to compare cardiorespiratory demand during manual wheelchair (MWC) propulsion among MWC users with a spinal cord injury (SCI) in a natural environment with and without the use of a trained mobility assistance dog (MAD). DESIGN: In this quasi-experimental repeated-measures analysis of difference, 13 experienced MWC users with an SCI propelled themselves with and without their trained MAD at a self-selected natural speed along a standardized 630-m course in a natural environment. Participants were equipped with a portable gas analyzer to measure their oxygen consumption, ventilation, tidal volume, respiratory quotient, respiratory rate, and heart rate before, during, and after completing the course. Participants also rated their perceived exertion on a modified Borg scale following each trial. RESULTS: All cardiorespiratory outcome measures decreased significantly with the use of a MAD (P <= 0.013; mean difference, -9% to -38%). Furthermore, most participants completed the course significantly faster (P <= 0.001; mean difference, -34%), while reporting considerably lower perceived exertion rates (P = 0.007; mean difference, -65%). CONCLUSIONS: A trained MAD decreases cardiorespiratory demand and rate of perceived exertion during MWC propulsion on a 630-m course among experienced MWC users with SCI. Trained MADs represent a valuable mobility assistive technology option for MWC users. PMID- 26945224 TI - Carpal Tunnel Syndrome Confounded by Electromyography Disease: A Case Report. PMID- 26945225 TI - Limb-Kinetic Apraxia Due to Injury of the Corticofugal Tract from the Secondary Motor Area in a Stroke Patient. PMID- 26945226 TI - Randomized Trial of Peripheral Nerve Stimulation to Enhance Modified Constraint Induced Therapy After Stroke. AB - BACKGROUND: Constraint-based therapy and peripheral nerve stimulation can significantly enhance movement function after stroke. No studies have investigated combining these interventions for cases of chronic, mild-to-moderate hemiparesis following stroke. OBJECTIVE: This study aims to determine the effects of peripheral nerve stimulation paired with a modified form of constraint-induced therapy on upper extremity movement function after stroke. Nineteen adult stroke survivors with mild-to-moderate hemiparesis more than 12 mo after stroke received 2 hours of either active (n = 10) or sham (n = 9) peripheral nerve stimulation preceding 4 hours of modified constraint-induced therapy (10 sessions). RESULTS: Active peripheral nerve stimulation enhanced modified constraint-induced therapy more than sham peripheral nerve stimulation (significance at P < 0.05), both immediately after intervention (Wolf Motor Function Test: P = 0.006 (timed score); P = 0.001 (lift score); Fugl-Meyer Assessment: P = 0.022; Action Research Arm Test: P = 0.007) and at 1-mo follow-up (Wolf Motor Function Test: P = 0.025 (timed score); P = 0.007 (lift score); Fugl-Meyer Assessment: P = 0.056; Action Research Arm Test: P = 0.028). CONCLUSION: Pairing peripheral nerve stimulation with modified constraint-induced therapy can lead to significantly more improvement in upper extremity movement function than modified constraint-induced therapy alone. Future research is recommended to help establish longitudinal effects of this paired intervention, particularly as it affects movement function and daily life participation. TO CLAIM CME CREDITS: Complete the self-assessment activity and evaluation online at http://www.physiatry.org/JournalCME CME OBJECTIVES:: Upon completion of this article, the reader should be able to: (1) Understand the role that afferent input plays with regard to movement function; (2) Understand general concepts of delivering modified constraint-based therapy in stroke rehabilitation research; and (3) Understand the rationale for applying an adjuvant intervention to optimize outcomes of constraint-based therapy following stroke. LEVEL: Advanced ACCREDITATION: : The Association of Academic Physiatrists is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The Association of Academic Physiatrists designates this activity for a maximum of 1.5 AMA PRA Category 1 Credit(s). Physicians should only claim credit commensurate with the extent of their participation in the activity. PMID- 26945227 TI - Exercise physiology in chronic mechanical circulatory support patients: vascular function and beyond. AB - PURPOSE OF REVIEW: The majority of patients currently implanted with left ventricular assist devices have the expectation of support for more than 2 years. As a result, survival alone is no longer a sufficient distinctive for this technology, and there have been many studies within the last few years examining functional capacity and exercise outcomes. RECENT FINDINGS: Despite strong evidence for functional class improvements and increases in simple measures of walking distance, there remains incomplete normalization of exercise capacity, even in the presence of markedly improved resting hemodynamics. Reasons for this remain unclear. Despite current pumps being run at a fixed speed, it is widely recognized that pump outputs significantly increase with exercise. The mechanism of this increase involves the interaction between preload, afterload, and the intrinsic pump function curves. The role of the residual heart function is also important in determining total cardiac output, as well as whether the aortic valve opens with exercise. Interactions with the vasculature, with skeletal muscle blood flow and the state of the autonomic nervous system are also likely to be important contributors to exercise performance. SUMMARY: Further studies examining optimization of pump function with active pump speed modulation and options for optimization of the overall patient condition are likely to be needed to allow left ventricular assist devices to be used with the hope of full functional physiological recovery. PMID- 26945228 TI - Unusual hand postures but not familiar tools show motor equivalence with precision grasping. AB - A central question in sensorimotor control is whether or not actions performed with the hands and corresponding actions performed with tools share a common underlying motor plan, even though different muscles and effectors are engaged. There is certainly evidence that tools used to extend the reach of the limb can be incorporated into the body schema after training. But even so, it is not clear whether or not actions such as grasping with tools and grasping with the fingers share the same programming network, i.e. show 'motor equivalence'. Here we first show that feedback-appropriate motor programming for grasps with atypical hand postures readily transfers to stereotypical precision grasps. In stark contrast, however, we find no evidence for an analogous transfer of the programming for grasps using tools to the same stereotypical precision grasps. These findings have important implications for our understanding of body schema. Although the extension of the limb that is afforded by tool use may be incorporated into the body schema, the programming of a grasping movement made with tools appears to resist such incorporation. It could be the case that the proprioceptive signals from the limb can be easily updated to reflect the end of a tool held in the hand, but the motor programs and sensory signals associated with grasping with the thumb and finger cannot be easily adapted to control the opening and closing of a tool. Instead, new but well-practiced motor programs are put in place for tool use that do not exhibit motor equivalence with manual grasping. PMID- 26945229 TI - Body painting to promote self-active learning of hand anatomy for preclinical medical students. AB - BACKGROUND: The purpose of this study was to use the body painting method to teach hand anatomy to a group of preclinical medical students. METHODS: Students reviewed hand anatomy using the traditional method and body painting exercise. Feedback and retention of the anatomy-related information were examined by a questionnaire and multiple-choice questions, respectively, immediately and 1 month after the painting exercise. RESULTS: Students agreed that the exercise was advantageous and helped facilitate self-active learning after in-class anatomy lessons. While there was no significant difference in knowledge retention between the control and experimental groups, the students appreciated the exercise in which they applied body paint to the human body to learn anatomy. CONCLUSION: The body painting was an efficient tool for aiding the interactive learning of medical students and increasing the understanding of gross anatomy. PMID- 26945230 TI - Potency of pre-post treatment of coenzyme Q10 and melatonin supplement in ameliorating the impaired fatty acid profile in rodent model of autism. AB - BACKGROUND: Abnormalities in fatty acid metabolism and membrane fatty acid composition play a part in a wide range of neurodevelopmental and psychiatric disorders. Altered fatty acid homeostasis as a result of insufficient dietary supplementation, genetic defects, the function of enzymes involved in their metabolism, or mitochondrial dysfunction contributes to the development of autism. OBJECTIVE: This study evaluates the association of altered brain lipid composition and neurotoxicity related to autism spectrum disorders in propionic acid (PA)-treated rats. DESIGN: Forty-eight young male western albino rats were used in this study. They were grouped into six equal groups with eight rats in each. The first group received only phosphate buffered saline (control group). The second group received a neurotoxic dose of buffered PA (250 mg/kg body weight/day for 3 consecutive days). The third and fourth groups were intoxicated with PA as described above followed by treatment with either coenzyme Q (4.5 mg/kg body weight) or melatonin (10 mg/kg body weight) for 1 week (therapeutically treated groups). The fifth and sixth groups were administered both compounds for 1 week prior to PA (protected groups). Methyl esters of fatty acid were extracted with hexane, and the fatty acid composition of the extract was analyzed on a gas chromatography. RESULTS: The obtained data proved that fatty acids are altered in brain tissue of PA-treated rats. All saturated fatty acids were increased while all unsaturated fatty acids were significantly decreased in the PA-treated group and relatively ameliorated in the pre-post melatonin and coenzyme Q groups. CONCLUSIONS: Melatonin and coenzyme Q were effective in restoring normal level of most of the impaired fatty acids in PA intoxicated rats which could help suggest both as supplements to ameliorate the autistic features induced in rat pups. PMID- 26945231 TI - Effect of different home-cooking methods on the bioaccessibility of zinc and iron in conventionally bred cowpea (Vigna unguiculata L. Walp) consumed in Brazil. AB - BACKGROUND: The cowpea (Vigna unguiculata L. Wap.) is an excellent source of iron and zinc. However, iron from plant sources is poorly absorbed compared with iron from animal sources. OBJECTIVES: The objective of this study was to evaluate iron and zinc bioaccessibility in cowpea cultivars after processing. METHODS: Zinc and iron bioaccessibilities in cowpea samples were determined based on an in vitro method involving simulated gastrointestinal digestion with suitable modifications. RESULTS: When water-soaked beans were cooked in a regular pan, the highest percentage of bioaccessible iron obtained was 8.92%, whereas when they were cooked in a pressure cooker without previous soaking, the highest percentage was 44.33%. Also, the percentage of bioaccessible zinc was 52.78% when they were cooked in a regular pan without prior soaking. Higher percentages of bioaccessible iron were found when cooking was done in a pressure cooker compared with regular pan cooking. In all cultivars, cooking of cowpea beans in both pressure cooker and in a regular pan yielded higher percentages of bioaccessible zinc compared with availability of bioaccessible iron. CONCLUSIONS: Iron bioaccessibility values suggest that cooking in a regular pan did not have a good effect on iron availability, since the percentage of bioaccessible iron was lower than that of zinc. The determination of iron and zinc bioaccessibility makes it possible to find out the actual percentage of absorption of such minerals and allows the development of efficient strategies for low-income groups to access foods with high levels of these micronutrients. PMID- 26945232 TI - Effect of Launaea procumbens extract on oxidative marker, p53, and CYP 2E1: a randomized control study. AB - BACKGROUND: Ethyl acetate extracts of Launaea procumbens is used for the treatment of liver dysfunction as an herbal medicine in Pakistan. In this study, the protective effects of ethyl acetate extracts were evaluated against CCl4 induced liver injuries in rat. METHODS: To examine the protective effects against oxidative stress of carbon tetrachloride in rats, 30 male rats were equally divided into 5 groups (6 rats). Among five groups, one was treated with CCl4 (3 ml/kg i.p. in olive oil b.w.) twice a week for 4 weeks. Others were orally fed with extracts (100, 200 mg/kg b.w.), with CCl4 twice a week for 4 weeks. RESULTS: Administration of CCl4 altered the serum marker enzymes, lipid profile, CYP 2E1, p53 expression, antioxidant enzymes, nuclear organizer regions (AgNORs), and DNA. Supplement of L. procumbens ameliorated the effects of CCl4, improved CYP 2E1, p53, and increased the activities of antioxidant enzymes while activity of liver marker enzymes (ALP, ALT, AST, g-GT) and contents of lipid per oxidation contents (TBARS), AgNORs, and DNA fragmentation were decreased. Similarly body weight was increased while liver and relative liver weight was decreased with co administration of various extracts, suggesting that L. procumbens effectively protect liver against the CCl4-induced oxidative damage in rats. CONCLUSION: The hepatoprotective and free radical scavenging effects might be due to the presence of bioactive constituents in the extract. PMID- 26945233 TI - Body mass but not vitamin D status is associated with bone mineral content and density in young school children in northern Sweden. AB - BACKGROUND: High latitude of residence where sun exposure is limited affects vitamin D status. Although vitamin D levels have been associated with poor bone health, cut-off values for optimising bone health are yet to be decided. OBJECTIVE: To assess vitamin D intake and status among young school children living at latitude 63-64 degrees N, in northern Sweden and to examine the association between vitamin D status and bone mineral content (BMC) and bone mineral density (BMD). DESIGN: In a cross-sectional study, diet was assessed by a 4-day food diary and a food frequency questionnaire in 8- to 9-year-old children (n=120). Energy, vitamin D, and calcium intakes were calculated. Physical activity was assessed using a pedometer for 7 days. Serum 25-hydroxyvitamin D (S 25[OH]D) levels were analysed by high-pressure liquid chromatography-atmospheric pressure chemical ionisation-mass spectrometry (n=113). BMC and BMD were assessed by dual energy X-ray absorptiometry scan. Height and weight were measured by standard procedures and BMI z-score was calculated using WHO AnthroPlus programme. RESULTS: The majority of children, 91%, did not reach the recommended vitamin D intake of 7.5 ug/day and 50% had insufficient S-25[OH]D levels defined as <50 nmol/l. The highest concentrations of S-25[OH]D were observed during the summer months (p=0.01). Body mass (p<0.01) but not S-25[OH]D was associated with measures of BMC and BMD. Furthermore, boys had higher total BMC (p=0.01), total body less head BMC (p=0.02), fat free mass (p<0.01), and a higher degree of physical activity (p=0.01) compared to girls. CONCLUSIONS: Body mass was related to BMC and BMD measures in a population of prepubertal school children living at high latitudes in Sweden. Despite insufficient S-25[OH]D levels and low vitamin D intake, this did not appear to affect bone parameters. Prospective studies with repeated assessment of vitamin D status are needed to examine cut-off values for optimising bone health. PMID- 26945234 TI - Pain in acquired inflammatory demyelinating polyneuropathies. PMID- 26945235 TI - Relieving patients' pain with expectation interventions: a meta-analysis. AB - Patients' expectations are important predictors of the outcome of analgesic treatments, as demonstrated predominantly in research on placebo effects. Three commonly investigated interventions that have been found to induce expectations (verbal suggestion, conditioning, and mental imagery) entail promising, brief, and easy-to-implement adjunctive procedures for optimizing the effectiveness of analgesic treatments. However, evidence for their efficacy stems mostly from research on experimentally evoked pain in healthy samples, and these findings might not be directly transferable to clinical populations. The current meta analysis investigated the effects of these expectation inductions on patients' pain relief. Five bibliographic databases were systematically searched for studies that assessed the effects of brief verbal suggestion, conditioning, or imagery interventions on pain in clinical populations, with patients experiencing experimental, acute procedural, or chronic pain, compared with no treatment or control treatment. Of the 15,955 studies retrieved, 30 met the inclusion criteria, of which 27 provided sufficient data for quantitative analyses. Overall, a medium-sized effect of the interventions on patients' pain relief was observed (Hedges g = 0.61, I = 73%), with varying effects of verbal suggestion (k = 18, g = 0.75), conditioning (always paired with verbal suggestion, k = 3, g = 0.65), and imagery (k = 6, g = 0.27). Subset analyses indicated medium to large effects on experimental and acute procedural pain and small effects on chronic pain. In conclusion, patients' pain can be relieved with expectation interventions; particularly, verbal suggestion for acute procedural pain was found to be effective. PMID- 26945236 TI - Multimodal Imaging of Diabetic Retinopathy in a Patient With Fovea Plana. PMID- 26945237 TI - NEW DYE INJECTION TECHNIQUE BY MEANS OF THE "DRIP DROPPER" DEVICE. PMID- 26945238 TI - TISSUE PLASMINOGEN ACTIVATOR FOR SUBFOVEAL HEMORRHAGE DUE TO AGE-RELATED MACULAR DEGENERATION: Comparison of 3 Treatment Modalities. AB - PURPOSE: To analyze and compare the effects of three common treatment modalities for a thick subfoveal hemorrhage due to exudative age-related macular degeneration on final visual acuity and the size of the final subretinal scar. DESIGN: Retrospective case series. SETTING: Single-site, tertiary referral center. PATIENTS: Thirty-nine patients with exudative age-related macular degeneration and acute SMH greater than 250 MUm. INTERVENTION: Patients received vitrectomy with a subretinal tissue plasminogen activator (tPA) injection, pneumatic displacement (PD) with intravitreal tPA, or PD without tPA within 2 weeks of presentation. MAIN OUTCOME MEASURE: Functional outcome was determined by Snellen visual acuity. Anatomical outcome was determined as the final disciform scar size. RESULTS: Treatment groups did not differ in age, sex, initial visual acuity, the initial area of the thick subfoveal hemorrhage, follow-up duration, lens status, duration of exudative age-related macular degeneration, previous intravitreal bevacizumab injections, or time from last given injection to the acute thick subfoveal hemorrhage. Final visual acuity improved significantly in both the vitrectomy and subretinal tPA injection group (P < 0.001), and the intravitreal tPA injection group (P = 0.002) but not with PD alone. Patients treated with subretinal tPA achieved 40% +/- 54% reduction in final scar area, in contrast to 27% +/- 35% decrease in patients treated with intravitreal tPA (P = 0.001). CONCLUSION: Treatment with tPA improves the functional and anatomical outcomes in patients with thick subfoveal hemorrhage due to subfoveal choroidal neovascular membrane secondary to exudative age-related macular degeneration and was superior to PD without tPA. Vitrectomy with subretinal tPA injection reduced the final disciform scar compared with PD with or without intravitreal tPA. PMID- 26945239 TI - Annual dynamics of perfluorinated compounds in sediment: A case study in the Morava River in Zlin district, Czech Republic. AB - Two groups of perfluorined compounds (PFCs), i.e. perfluoroalkyl sulfonates (PFASs) and perfluoroalkyl carboxylates (PFCAs) were analysed during a period of 1 year in monthly collected riverbed sediment samples from five sampling sites in an industrial region in Morava River catchment in Czech Republic. Levels of PFCs determined in sediment samples were up to 6.8 MUg kg(-1) of dry weight. Among PFCs analysed, mainly short-chain PFASs (C6 to C8) including PFOS were found in sediment samples and their levels were similar to those found in comparable river basins in other parts of Europe. Concentrations of PFCs were correlated with organic carbon content and their variations were mainly correlated by high flow events on Morava River and its tributaries. The changes in PFC concentrations were induced by displacing of PFCs containing particles to the river sediment during these elevated flow events. PMID- 26945240 TI - Microalgal sensitivity varies between a diuron-resistant strain and two wild strains when exposed to diuron and irgarol, alone and in mixtures. AB - A wild strain of Chaetoceros calcitrans and wild and diuron-resistant strains of Tetraselmis suecica, were exposed to the PSII inhibitor herbicides diuron and irgarol, individually and in mixtures. The effects of three concentrations of diuron and irgarol and four binary mixtures were evaluated on doubling time, relative reactive oxygen species and lipid content by flow cytometry, and on photosynthetic efficiency by pulse amplitude modulated fluorescence. In both wild strains, significant effects were observed for each molecule at the highest concentration tested: at irgarol 0.5 MUg L(-1), C. calcitrans was shown to be more sensitive than T. suecica (+52% and +19% in doubling time, respectively), whereas at diuron 5 MUg L(-1), T. suecica was more affected (+125% in doubling time) than C. calcitrans (+21%). Overall, irgarol had a higher toxicity at a lower concentration than diuron (no effect at diuron 0.5 MUg L(-1)) for both wild strains. The strongest mixture (irgarol 0.5 MUg L(-1) + diuron 5 MUg L(-1)) increased doubling time by 356% for T. suecica, thus showing amplified effects when the two compounds were mixed. Sequencing of the diuron-resistant strain demonstrated a single mutation in the psbA gene coding sequence. Although resistance of this strain to diuron was confirmed with no effect at the highest diuron concentration, no resistance to irgarol was shown. In addition, the mutant strain exposed to the strongest mixture showed a 3.5-fold increase in doubling time compared with irgarol alone, thereby supporting the hypothesis of a biochemical interaction between these two compounds. PMID- 26945241 TI - Screening of organic and metal contaminants in Australian humpback dolphins (Sousa sahulensis) inhabiting an urbanised embayment. AB - As a marine mammal species that inhabits shallow nearshore waters, humpback dolphins are likely exposed to a wide range of pollutants from adjacent land based activities. Increased mortality rates of Australian humpback dolphins (Sousa sahulensis) in waters off a major urbanised centre triggered investigations into the threats to these species, including their contaminant exposure. The present study utilised archived tissues from 6 stranded animals to screen for a range of pollutants (PCDD/Fs, PBDEs, PCBs, organochlorine pesticides, PAHs, organotins, essential and non-essential elements) to inform future biopsy based biomonitoring strategies. Concentrations of PCBs and DDXs in blubber of some of these animals were remarkably high, at levels near or above toxicological thresholds associated with immune- and reproductive toxicity or population declines in other marine mammals. PBDEs, PAHs, HCB, organotins, 'drins' as well as other organic pesticides were not detected, or present at relatively low concentrations. Profiles of elements were similar in epidermis compared to other tissues, and apart from some exceptions (e.g. Fe, Cr, Co, Cu) their concentrations fell within 25th-75th percentiles of cetacean baselines in four of the five animals. Non-essential elements (Al, V, Pb, Ba, Ni, Cd) were notably elevated in one specimen which may have experienced poor health or nutritional status. These data provide a first insight into the contaminant status of a rare and poorly studied population inhabiting an urbanised area. The results highlight a need for future biomonitoring of live populations, and inform on priorities in the typically limited blubber and skin sample volumes obtained through biopsies. PMID- 26945242 TI - Combined chemoassay and mass spectrometric approach to study the reactive potential of electrophiles towards deoxynucleosides as model for DNA. AB - The modification of DNA by adduct formation is a potential molecular initiating event of genotoxicity. A chemoassay was established to study adduct formation of electrophiles with deoxynucleosides. Liquid chromatography-mass spectrometry was used to determine the reactivity of the model electrophiles para-benzoquinone, hydroquinone, and 1,4-naphthoquinone with deoxynucleoside (deoxyadenosine (dA), deoxyguanosine (dG), deoxycytidine (dC) and thymidine (dT)) to detect formation of adducts via constant neutral loss scan of deoxyribose (116 Da), and to elucidate adduct structures using high resolution mass spectrometry. Of the four deoxynucleosides dG was most susceptible, followed by dC and para-benzoquinone was the most reactive electrophile. With this approach five dG and four dC adducts were detected, formed by Michael addition and subsequent condensation. Also oxidation occurred with reactive oxygen species (ROS). Three of the adducts formed by benzoquinone have not been reported before. This chemoassay combined with mass spectrometry offers a way (a) to screen a large number of chemicals for their genotoxic potential, (b) to determine novel adducts that may be searched for in in vitro and in vivo studies and thus (c) to better understand the reaction of electrophiles with nucleobases. PMID- 26945243 TI - Modulated expression and enzymatic activities of Darkbarbel catfish, Pelteobagrus vachelli for oxidative stress induced by acute hypoxia and reoxygenation. AB - Large changes in oxygen availability in aquatic environments, ranging from anoxia through to hyperoxia, can lead to corresponding wide variation in the production of reactive oxygen species (ROS) by fish with aquatic respiration. In order to evaluate the effects of hypoxia and reoxygenation on oxidative stress in fish, the mRNA and protein expression of SODs (Cu/Zn-SOD and Mn-SOD) as well as indices (CP, LPO and MDA) and enzymatic activities (SOD, CAT, GPx, GR and GST) were analyzed in liver and brain tissues of Pelteobagrus vachelli. Predominant expression of PvSOD2 was detected in heart, brain, and liver. In contrast, PvSOD1 was highly expressed in liver. Based on the expression patterns of above parameters, we inferred that brain tissue of P. vachelli under 0.7 mg/L degree of acute hypoxia condition could experience hypometabolic states or no suffering stress, but brain tissue has effective mechanisms to minimize or prevent oxidative stress during the transition from hypoxia to reoxygenation. Our results also demonstrated an increased expression of SODs and enzymatic activities for oxidative stress in liver under hypoxic conditions, which supports the hypothesis that anticipatory preparation takes place in order to deal with the encountered oxidative stress during the recovery from hypoxia as proposed by M. Hermes-Lima. Therefore, this study will provide a clue to better understand the action mode of antioxidant genes and enzymes under oxidative stress in fish. PMID- 26945244 TI - Factors in Surgical Decision Making for Thoracolumbar/Lumbar AIS: It's About More Than Just the Curve Magnitude. AB - STUDY DESIGN: A retrospective review of prospective data OBJECTIVE:: The purpose of this study was to compare operative and nonoperative patients with similar curve magnitudes to determine motivating factors associated with surgical correction in "smaller" curves. SUMMARY OF BACKGROUND DATA: Despite traditional treatment recommendations on major curve angle measurements, many patients with thoracolumbar/lumbar (TH/L) curves of smaller magnitudes are unhappy and desire correction. METHODS: A prospectively enrolled multicenter adolescent idiopathic scoliosis database was queried. Patients with major TH/L curves <50 degrees and low risk of progression (Risser 3, 4, and 5) were identified and grouped based on their treatment (operative vs. nonoperative). Preoperative demographic, radiographic, Scoliosis Research Society (SRS) outcome scores, and trunk shape values were compared. RESULTS: A total of 126 patients undergoing surgical intervention and 17 patients pursuing nonoperative treatment were analyzed. The average lumbar curve of the operative group was 43 degrees (range, 35 to 49 degrees) and for the nonoperative group was 39 degrees (range, 26 to 49 degrees). The operative group was significantly younger, had larger lumbar major curve angles, lower thoracic to lumbar curve ratio, increased TH/L apical translation, and greater trunk shift (P<0.05). Only lumbar curve (P=0.018, OR=1.19) and trunk shift (P=0.01, OR=3.22) remained significant predictors of surgery in a multivariate regression analysis. SRS scores were significantly lower in the operative group for pain, self-image, function, mental health, and total (P<0.05). When SRS total score was entered into the regression, it was the only significant predictor of surgical intervention (P=0.004, OR=0.03). CONCLUSIONS: Many patients with smaller lumbar curves have clinical deformities that are more consistent with larger curves. These smaller curves can produce similar coronal imbalance and trunk shift, with lower SRS domains that may drive patients to seek surgical treatment. What is unclear is the reason for this greater degree of imbalance in this select group of patients and whether the natural history is different for a more balanced TH/L curve. LEVEL OF EVIDENCE: Level II-Prognostic. PMID- 26945245 TI - The Open Bankart Repair for Traumatic Anterior Shoulder Instability in Teenage Athletes. AB - BACKGROUND: Traumatic anterior shoulder instability from recurrent dislocations or subluxations is a debilitating problem for the teenage athlete. The risk of recurrent instability is high in this adolescent population. We performed a retrospective case series analysis of adolescent athletes with recurrent instability treated with open Bankart repair and evaluated functional outcomes as well as redislocation rates. METHODS: The retrospective study included 21 teenage patients with Bankart lesions and recurrent anterior shoulder instability. There were 19 males (90%) and 2 females (10%) with an average age of 16 years (range, 14 to 18 y). Patients were evaluated based on Rowe and UCLA shoulder scores, return to previous level of sport, external rotation, and recurrence. RESULTS: The average number of anchors used to repair the Bankart lesion was 3 (range, 2 to 5). One patient was lost to follow-up at 6 months after surgery. The remaining 20 patients all had at least 2-year follow-up. The recurrent instability rate was zero. In total, 100% of patients had an excellent result based on an average Rowe score of 96.5 points of 100 points (a score of 90 to 100 is an excellent result). In total, 100% of patients had good/excellent result based on an average UCLA shoulder score of 34 of 35 (a score >27 is a good/excellent result). At final follow-up, 7 patients (34%) had lost an average of 11 degrees of external rotation (range, 5 to 20 degrees) on the injured shoulder with the arm at the side compared with the noninjured shoulder. CONCLUSIONS: Contact teenage athletes with recurrent anterior shoulder instability can be treated with open Bankart repair with a low recurrence, excellent functional shoulder outcomes, and return to sport. A small amount of external rotation may be lost with this technique. Care must be taken when considering this method with throwing athletes (ie, quarterback or pitcher). The open Bankart should remain a viable alternative for the adolescent population with recurrent anterior instability. LEVEL OF EVIDENCE: Level IV. PMID- 26945246 TI - Ultrathin Endoscopy-Guided Pericardiocentesis: A Pilot Study in a Swine Model. AB - BACKGROUND: Pericardiocentesis under echocardiography guidance is a common procedure, but still poses a risk of injury to surrounding tissues. Nowadays, pericardiocentesis is being performed in patients with normal pericardium, for epicardial ablation or atrial appendage exclusion. Access to the normal pericardial space with the conventional needle procedure is very difficult. Thus, development of a novel method enabling safer pericardiocentesis is necessary. The present study aimed to assess the feasibility of using an originally developed ultrathin endoscopy-guided pericardiocentesis device in a swine model. METHODS AND RESULTS: We developed a novel ultrathin endoscopy-guided pericardiocentesis device. The device comprised a 1.2 mm ultrathin endoscope, a 20 G needle, and a grasping forceps. Pericardiocentesis was conducted as follows. A 12 Fr introducer sheath was inserted between the pericardium and the diaphragm under fluoroscopy. The pericardium was grasped with the originally developed forceps under endoscopy guidance to create a space in the pericardial sac. The 20 G needle was then inserted and a coiled-tip guidewire was placed into the pericardial sac. Five independent operators performed pericardiocentesis twice using this technique in a healthy pig with a body weight of approximately 25 kg. Procedural success rate and procedure time were assessed as the primary endpoints. The procedural success rate was 100% in all operators. The average procedure time was 65 +/- 40 seconds (median, 46 seconds; interquartile range, 40-85 seconds). No procedure-related complications were noted. CONCLUSIONS: The study results indicate that ultrathin endoscopy-guided pericardiocentesis for normal pericardial space is feasible and safe. PMID- 26945247 TI - Transradial Approach for Post-Coronary Artery Bypass Graft Angiography: What Works From the Leg, Works From the Wrist! PMID- 26945248 TI - Efficacy and Safety of Novel NovaCross Microcatheter for Chronic Total Occlusions: First-in-Human Study. AB - OBJECTIVES: The aim of this first-in-human (FIH) study was to evaluate the efficacy and safety of the novel NovaCross microcatheter system in eligible consecutive patients with chronic total occlusion (CTO). BACKGROUND: CTOs remain the most challenging lesion subset in percutaneous coronary intervention (PCI). Failure to cross to the distal true lumen with the guidewire is one of the major causes of procedural failure in CTO-PCI. The NovaCross microcatheter (Nitiloop, Ltd) is designed to improve antegrade recanalization success. METHODS: This study was a prospective, non-randomized, FIH investigational study. Patients with total occlusion of a coronary artery determined to be more than 3 months old and accepted for coronary CTO-PCI with an intended antegrade strategy were enrolled. RESULTS: Twenty-four patients were enrolled in this study. Despite the high complexity of the lesions (including 80% J-CTO score >=3 and 50% of the cases having had a previous failed CTO-PCI attempt), technical success was 81.8%. No patients reported any major adverse cardiac event up to and including 30 days post procedure. CONCLUSION: In this FIH study, the NovaCross microcatheter exhibited the potential to stabilize guidewires and enhance crossing of coronary CTO lesions. PMID- 26945249 TI - Role of Novel Guidewire Support Devices for Crossing Coronary Artery Chronic Total Occlusions. PMID- 26945250 TI - Utility of Frequency Domain Optical Coherence Tomographic Evaluation of Angiographically Optimized Stented Lesions. AB - BACKGROUND: Given its high resolution, optical coherence tomography (OCT) may be a useful clinical tool to optimize stent deployment. METHODS: We reviewed 100 patients with post-PCI OCT who had angiographically optimized coronary stent implantation to determine the frequency of further intervention based on OCT pathology. OCT pathology was classified as "significant" if an OCT finding prompted further intervention. RESULTS: OCT pathology was found in 90% of patients and considered significant in 52%. Stent strut malapposition by OCT was the most common reason for prompting further treatment, with approximately one half due to relative stent undersizing. Based on OCT findings, 42% underwent balloon dilation, 9% underwent another stent implantation, and 3% underwent treatment with a glycoprotein IIb/IIIa inhibitor. Minor plaque protrusion was present in 11%, which prompted no further intervention. CONCLUSION: Post-PCI OCT in angiographically optimized vessels was helpful in improving stent deployment in more than one-half of the cases. Our findings suggest that post-PCI OCT may be a clinically useful tool in angiographically optimized stenting. Prospective studies will provide further clarity on the place of OCT in this setting. PMID- 26945251 TI - OCT-Guided PCI: Are We There Yet? PMID- 26945252 TI - Effectiveness of Alcohol Septal Ablation in Obstructive Hypertrophic Cardiomyopathy With Versus Without Extreme Septal Hypertrophy. AB - AIMS: Data on the effectiveness of alcohol septal ablation (ASA) in patients with hypertrophic cardiomyopathy (HCM) and extreme septal hypertrophy (ESH) are lacking. This study aimed to compare the effectiveness of ASA in patients with vs without ESH. METHODS: Clinical profiles of 17 patients with ESH and 256 patients without ESH were compared. RESULTS: Baseline pressure gradient and limiting symptoms were comparable between patients with and without ESH. At median 1.1 years of follow-up after ASA, pressure gradient was 48.5 +/- 40.4 mm Hg in the ESH group and 40.9 +/- 35.2 mm Hg in the non-ESH (N-ESH) group (P=.33). Patients with New York Heart Association class III/IV represented 5.9% of the ESH group and 16.9% of the N-ESH group (P=.39). Patients with Canadian Cardiovascular Society class III/IV represented 5.9% of the ESH group and 10.2% of the N-ESH group (P=.87). CONCLUSION: The effectiveness of ASA seems comparable between patients with and without ESH. PMID- 26945253 TI - Success, Safety, and Efficacy of the Mynx Femoral Closure Device in a Real-World Cohort: Single-Center Experience. AB - BACKGROUND: Femoral artery closure device use following percutaneous cannulation allows earlier mobilization, reduced staff burden, and improved comfort for patients compared with manual compression. The Mynx device (Access Closure, Inc), a novel extravascular closure device, uses a water-soluble non-thrombogenic polyethylene glycol plug. METHODS: We report retrospective analysis of success, complication rates, and associated factors in 432 consecutive patients undergoing elective outpatient coronary angiography in a single United Kingdom center. RESULTS: Six Fr sheaths were used in 62.1% and 5 Fr sheaths were used in 37.8%, with 100% successful deployment using a Mynx device. A total of 57.5% of patients were male. In 79.4%, this was the first procedure requiring femoral arteriotomy, while 20.6% had a previous procedure. Overall, 3.2% required conversion to manual compression/ FemoStop (St. Jude Medical) due to impending hematoma. In all, 99.5% of patients were discharged on the same day. Confirmed hematoma >5 cm was noted in 0.7% patients, with only 2 patients (0.5%) reporting "any discomfort" during deployment and the same requiring overnight hospitalization. Use of a 6 Fr sheath (compared with 5 Fr) was associated with conversion to manual compression and complications (P<.05), as was valvular heart disease as the indication for angiography (P<.05). Hematoma formation was associated with higher diastolic and mean arterial pressure (107.4 mm Hg vs 99.6 mm Hg; P<.01). There was no increase in complications associated with use of antiplatelet/anticoagulants, previous stroke, myocardial infarction/ischemic heart disease, peripheral vascular disease, diabetes, high body mass index, or previous angiographic procedure. CONCLUSIONS: Postangiography use of the Mynx closure device is highly successful, safe, and well-tolerated with a low complication rate, allowing safe same-day discharge. PMID- 26945254 TI - The Impact of Residual MR After Percutaneous Mitral Repair. PMID- 26945255 TI - Coronary Artery Perforation Following Percutaneous Coronary Intervention. AB - Coronary artery perforation (CAP) is a rare but serious complication of percutaneous coronary intervention. Risk factors for CAP include female gender, older age, and lesion complexity. The most common causes of CAP include wire perforation, atherectomy, and aggressive sizing of balloons and stents. Complications of CAP vary greatly from clinical insignificance to hemodynamic collapse and death, depending on the severity of the CAP. Early recognition is of utmost importance to surviving CAP. Generally accepted treatment options depend on lesion severity, and include balloon inflation to tamponade the vessel, reversal of anticoagulation, covered stents, and embolization. Emergent pericardiocentesis or surgical evacuation may be required for the most severe cases. PMID- 26945256 TI - Ultrasound-Accelerated Thrombolysis in Patients With Intracardiac Thrombi: A Case Series. AB - We describe a case series of 3 patients presenting with intracardiac thrombi treated with standard anticoagulation therapy and intervention with ultrasound accelerated thrombolysis therapy. Right-sided intracardiac thrombi portend significant mortality due to their susceptibility for embolization and pulmonary embolus despite the continuation of current standard of therapy of parenteral anticoagulation and surgical embolectomy if warranted. We demonstrate the safety and clinical efficacy of ultrasound-accelerated thrombolysis therapy with the EkoSonic Endovascular System infusion catheter system (EKOS Corporation) and highlight its use in resolving intracardiac thrombi and impeding the propagation of pulmonary emboli. PMID- 26945257 TI - Minimal Acute Recoil Following Bioresorbable Scaffold Implantation in Fibrocalcific Lesion Detected by Optical Frequency-Domain Imaging. AB - We report a case of minimal acute recoil detected by optical frequency-domain imaging (OFDI) following bioresorbable scaffold (BRS) implantation for the treatment of a fibrocalcific lesion. The second OFDI pullback (8 minutes later) was performed to evaluate the distal dissection. We measured scaffold area every 0.25 mm and acquired a total of 115 paired cross-sections. Paired t-test demonstrated that minimal acute recoil was observed in this fibrous lesion and uncompressed dissection site with calcified plaque. This case demonstrates that acute recoil appears to be dependent upon plaque characteristics and the presence of malapposed struts after BRS implantation. PMID- 26945258 TI - Nursing Strategies to Increase Medication Safety in Inpatient Settings. AB - Using data obtained through 2 multidisciplinary studies focused on medication safety effectiveness, this article provides nursing recommendations to decrease medication delivery errors. Strategies to minimize and address interruptions/distractions are proposed for the 3 most problematic time frames in which medication errors typically arise: medication acquisition, transportation, and bedside delivery. With planned interventions such as programmed scripts and hospital-based protocols to manage interruptions and distractions, patient safety can be maintained in the inpatient setting. PMID- 26945259 TI - WITHDRAWN: Surgical management of localised renal cell carcinoma. PMID- 26945260 TI - Abuse in older persons: why physicians need to be aware. PMID- 26945261 TI - Assessing the quality of care for haemophilia at the Yaounde reference treatment Centre of Cameroon. AB - With a recently established Haemophilia Treatment Centre (HTC) in Yaounde, Cameroon, over a hundred people living with haemophilia have been recruited and followed up at this centre. This study aimed at assessing the quality of haemophilia care provided at the HTC, in order to monitor and improve patient care. In February 2014, the HTC was assessed using recommended markers. Although few, the logistics and reagents for the diagnosis and treatment of haemophilia were available. There were seven trained workers involved with haemophilia care, but the multidisciplinary care team was incomplete. A total of 113 people living with haemophilia (all males) had been registered and regularly followed up at the HTC. This study showed that the HTC of the Yaounde University Teaching Hospital, although not yet ideal, allows for some degree of haemophilia patient care. Hence, it may be recommended to improve the centre and make it fully established in Cameroon. PMID- 26945262 TI - 'Sailing in troubled waters': a review of the use of anticoagulation in adult cancer patients with thrombocytopenia. AB - Simply providing anticoagulation therapy is not as straightforward of a solution in cancer patients who have concurrent thrombocytopenia owing to the increased risk of bleeding complications. Currently, few guidelines are in place to assist clinicians in safely managing thrombocytopenic cancer patients on anticoagulation. The purpose of this review is to critically examine the available body of biomedical literature surrounding anticoagulant use against the backdrop of cancer-related thrombocytopenia in adult patients. Available evidence for the use of parenteral anticoagulants (low molecular weight heparins, unfractionated heparin, pentasaccharides, and direct thrombin inhibitors) and oral anticoagulants (vitamin K antagonists and novel oral anticoagulants) in thrombocytopenic cancer patients is described. The review revealed many inconsistencies between reports on this topic, which made it difficult to draw firm conclusions as to, for example, the ideal well tolerated anticoagulant dose in thrombocytopenic cancer patients? Intriguingly, critical clinical information including (but not limited) patient platelet nadirs, platelet counts during bleeding episodes, and platelet transfusion support was absent from a not-so insignificant number of publications. Despite these shortcomings, the review sets out to formulate recommendations on the management of anticoagulation, at prophylactic or treatment doses, in adult cancer patients who also have concurrent thrombocytopenia. It also enlists a call for the medical community, by mapping select clinical guideposts, for further research in this setting. With the inclusion of these criteria in future studies, only then formal recommendations on the ideal safe dosage of anticoagulants in cancer patients, based on solid evidence, are conceived. PMID- 26945263 TI - Activation of the tissue factor-dependent extrinsic pathway and its relation to JAK2 V617F mutation status in patients with essential thrombocythemia. AB - Thrombotic complications may occur in 7.6-29.4% of patients with essential thrombocythemia. According to the cellular theory, tissue factor (TF) activating extrinsic blood coagulation pathway is essential for the activation of blood clotting. The aim of the study was to evaluate the activation of the TF-dependent extrinsic pathway in patients with essential thrombocythemia, depending on the presence or absence of the Janus kinase 2 (JAK2) V617F mutation. The study included 74 newly diagnosed patients (F/M: 47/27; mean age 61 years) with essential thrombocythemia (Tefferi and Vardiman, Leukemia 2008; 22(1):14-22). Patients were diagnosed in the Department of Clinical Hematology and Hematological Malignancies University Hospital No. 2, Bydgoszcz, Poland. The control group consisted of 30 healthy volunteers (F/M: 17/13; mean age 49 years). The concentration and activity of TF and TF pathway inhibitor (TFPI) were measured using ELISA method. In patients with essential thrombocythemia, we observed a higher concentration of TF [median (Me) = 686.90 vs 164.28 pg/ml] and over 10-fold higher activity of TF (Me = 46.05 vs 4.01 pmol/l) when compared with the control group. We also reported significantly higher activity of TFPI compared with the control group (Me = 1.93 vs 1.78 U/ml). Moreover, a concentration of TFPI was significantly lower in patients with essential thrombocythemia with JAK2 V617F mutation as compared with patients without the mutation (Me = 1.90 vs 2.16 U/ml; P = 0.039639). Increased TF activity and concentration is responsible for higher procoagulant potential in patients with essential thrombocythemia. Reduced activity of TFPI in patients with essential thrombocythemia with JAK2 V617F mutation indicates an increased prothrombotic risk in this group of patients. PMID- 26945264 TI - Hemopericardium under dabigatran for stroke prevention in atrial fibrillation. AB - Spontaneous hemopericardium is a complication of anticoagulant therapy with not only vitamin-K-antagonists, but also with nonvitamin-K-antagonist oral anticoagulants. We report a polymorbid 75-year old male under a therapy with dabigatran, valsartan, amlodipine, nicorandil, furosemide, atorvastatin, bisoprolol, metformin, tizanidine, pantoprazole, and tramadol. He suffered from chest pain for 4 months. Coronary angiography showed only ectatic coronary arteries. He started taking nonsteroidal anti-inflammatory drugs. He was hospitalized because of dyspnea starting 10 days before admission, melena, and renal failure. Hemopericardium was diagnosed and pericardiocentesis yielded 2000 ml hemorrhagic fluid. Review of previous echocardiograms showed a 4 mm echo-free space, epicardial fat or pericardial effusion. A small (<10 mm) echo-free space in a patient on anticoagulant therapy should not be considered as trivial, but additional imaging studies should be carried out. If a pericardial effusion is newly diagnosed in a patient during anticoagulant therapy, the pharmacotherapy should be revised concerning potentially interacting drugs, like nonsteroidal anti-inflammatory drugs, and dosage of the anticoagulant drug. Vitamin-K antagonists with their possibility of laboratory monitoring and availability of an antidote should be preferred over nonvitamin-K-antagonist oral anticoagulants. PMID- 26945265 TI - Clinical Comparison of 2 Trial-of-Void Methods After Outpatient Midurethral Sling Placement. AB - OBJECTIVES: This study aimed to assess the efficacy, efficiency, and costs of 2 methods of trial of void (TOV) after midurethral sling (MUS) placement. METHODS: A retrospective chart review was performed on women who underwent outpatient MUS between January 2013 and April 2014 by 3 urologists. Patients were excluded if they had a concomitant prolapse repair, hysterectomy, bladder/urethral injury, or any procedure that may prolong recovery room (RR) stay. Trial of void was performed by either (1) bladder instillation, catheter removal in the operating room (OR) fill with attempted void in RR, or (2) bladder instillation and catheter removal with immediate attempted void in the RR fill. Intraoperative, postoperative, and cost data were analyzed. RESULTS: Ninety-one of 183 women (mean age, 55.9 +/- 12 years; mean body mass index, 28.8 +/- 5.8 kg/m) met inclusion criteria. Eighty-three had a transobturator sling. Forty-nine (54%) had an OR fill and 42 (46%) had an RR fill; age and body mass index were similar between groups. The OR fill group had shorter median operative time (15 vs 22 minutes; P = 0.003) and median RR time (138 vs 161, P = 0.033). The OR fill and RR fill groups did not differ in TOV failure rate (3/49 vs 6/42; P = 0.29), overall mean LOS (4.96 vs 5.51 hours; P = 0.055), and median RR costs ($627 vs $678; P = 0.065). No patient had urinary retention after successful TOV. CONCLUSIONS: After MUS placement, both OR fill and RR fill TOV methods are effective and efficient with similar TOV failure rates. PMID- 26945266 TI - Cervical Flap After Trachelectomy to Maintain Vaginal Length. AB - BACKGROUND: Anterior colporrhaphy is associated with a reduction in vaginal length after repair. These 2 case reports describe a potential solution for cervical elongation and prolapse in the setting of shortened vaginal length after anterior colporrhaphy. CASES: Two sexually active women underwent anterior colporrhaphies by outside providers. They quickly re-presented with cervical prolapse and compromised anterior vaginal lengths. In each case, sacrocolpopexy with supracervical hysterectomy was performed, establishing a new vaginal apex. When cervical elongation subsequently occurred, trachelectomy was performed using part of the cervix as a cervical flap to maintain vaginal length. CONCLUSIONS: These 2 case reports illustrate the use of a cervical flap after trachelectomy to preserve vaginal length. We were unable to find reports in the literature describing a similar technique. PMID- 26945267 TI - Validation of the Fecal Incontinence Severity Index in a Turkish Population. AB - AIM: The aim of this study was to validate the Turkish-translated version of the Fecal Incontinence Severity Index (FISI) for Turkish-speaking patients. METHODS: This prospective cohort study included 58 patients: 22 (37.9%) scored 0 (no incontinence), and the remaining 36 (62.1%) scored at least 1 (any level of gas, mucus, liquid, solid incontinence, pad wear, or lifestyle alteration). Test retest reliability analysis, internal consistency analysis, content-face validity, and criterion validity were used to evaluate the Turkish version of the FISI. Validity of the criteria was assessed through correlation analyses between patient and surgeon scores of FISI and manometric measurement between patients with or without anal incontinence symptoms. RESULTS: The 2-week test-retest revealed significant correlation (P < 0.001). The Cronbach alpha values of the translated version for total scores of the scale were 0.735 and 0.734 for patient rated scores and surgeon-rated scores, respectively, and indicate a high degree of internal consistency in each item of the questionnaire. Total and all subgroup scores of the FISI scale showed significant correlation with the maximal squeeze pressure and resting pressure values. Comparison of maximal squeeze pressure and resting pressure values of both groups showed significant differences between women with no incontinence and women with any form of incontinence. CONCLUSIONS: The Turkish-translated version of the FISI is a reliable, consistent, and valid instrument for assessing the patient-rated symptom severity among women with anal incontinence in a Turkish-speaking population. PMID- 26945268 TI - Care-Seeking for Stress Incontinence and Overactive Bladder Among Parous Women in the First Two Decades After Delivery. AB - OBJECTIVE: This study aimed to establish the extent to which care-seeking for urinary incontinence is a function of symptom bother; and to identify bother score thresholds that predict care-seeking in the first 2 decades after delivery. METHODS: In this longitudinal cohort, women were assessed annually for symptom bother related to stress urinary incontinence (SUI) and overactive bladder (OAB), as well as for recent episodes of care-seeking for urinary symptoms. Because the goal was to model care-seeking as a function of the woman's characteristics at her prior visit, women who completed 2 or more consecutive visits were included. The population was randomly divided into "training" (model development) and "testing" (model validation) sets. The predictive model was developed in the training set. For SUI and OAB bother scores, we identified thresholds to define statistically distinct probabilities of care-seeking. A multivariable model was created, including SUI and OAB bother categories as well as characteristics associated with care seeking at the P < 0.05 level. The resultant prediction model was then applied to the "testing set"; predicted and observed care-seeking frequencies were compared. RESULTS: Care-seeking was strongly associated with SUI and OAB bother. We defined 3 categories for OAB score and 4 categories for SUI score. The resulting 12 risk categories were then collapsed into 5 distinct risk groups. These groups accurately predicted care-seeking in the testing set (area under the receiver operating curve, 0.760; 95% confidence interval, 0.713-0.807). Inclusion of other risk factors did not improve the model. CONCLUSIONS: Symptom bother is a strong determinant of care-seeking in the first 2 decades after delivery. These results define 5 ordinal categories that predict seeking care for urinary symptoms in a community population. PMID- 26945269 TI - Investigation of Sacral Needle Depth in Minimally Invasive Sacrocolpopexy. AB - PURPOSE: The aims of the study were to optimize surgical safety and to minimize vertebral disc puncture during sacral needle placement at the time of minimally invasive sacrocolpopexy. Cadaveric studies report that the anterior longitudinal ligament (ALL), which covers the vertebral disc and vertebrae, has a reported thickness of only 1.4 to 2.3 mm at L5-S1. Intervertebral disc puncture can accelerate disc degeneration, disc herniation, and loss of disc height, a risk that may be avoidable. MATERIALS AND METHODS: After institutional review board approval, research consent was obtained from women undergoing primary laparoscopic sacrocolpopexy. Intraoperatively, sacral sutures were placed in the ALL with a 1.5 cm diameter CV-2 needle using Gore-Tex suture. Depth measurements were collected using a laparoscopic ultrasound transducer positioned on the sacral promontory (SP) between the 2 ends of the needle visible through the ALL. Two still-frame US images of the single needle were taken using the BK Medical software. Needle depth was calculated by measuring the distance from the top of the ALL to the needle. RESULTS: Two satisfactory intraoperative images were obtained for all 9 participants. The mean needle depth at the SP was 3.96 mm. The interpatient needle depth varied from 2.07 to 9.04 mm. CONCLUSIONS: In most participants (78%), the sacral needle depth exceeded 2.3 mm, suggesting that there may be risk to sacral suture placement without depth guidance at the promontory. During minimally invasive sacrocolpopexy, the depth of the ALL and the placement of the needle at the SP may result in inadvertent disc penetration. Surgeons should be conscious of the minimal depth of the ALL and consider placing the suture below the promontory to avoid the disc. PMID- 26945270 TI - Anal Sphincter Injuries After Operative Vaginal Versus Spontaneous Delivery-Is There a Difference in Postpartum Symptoms? AB - OBJECTIVE: The aim of this study was to determine whether there is a difference in pelvic floor symptoms between women who had obstetric anal sphincter injuries (OASIS) after an operative vaginal delivery versus those who had OASIS after a spontaneous delivery. METHODS: This was a secondary analysis of a prospective cohort study of women who sustained OASIS. Women were evaluated at 1 week postpartum and again at 12 weeks; at both of these visits, they completed a battery of validated questionnaires including a visual analog scale for pain, Patient Health Questionnaire 9 depression inventory, Fecal Incontinence Severity Index, Urogenital Distress Inventory 6, and Incontinence Impact Questionnaire 7. RESULTS: Two hundred sixty-eight women with OASIS were included in this analysis (194 operative vaginal, 74 spontaneous). Ninety-one percent of those with operative vaginal delivery had a forceps-assisted delivery. After multivariate regression, operative OASIS was independently associated with greater Urogenital Distress Inventory 6 scores (P = 0.02), Fecal Incontinence Severity Index scores (P = 0.04), and visual analog scale pain scores (P = 0.03) and higher rates of urgency urinary incontinence (P = 0.04), stress urinary incontinence (P = 0.02), and anal incontinence (P = 0.04) at 1 week postpartum. At 3 months postpartum, symptoms were no different between the groups. CONCLUSIONS: Women who sustain OASIS secondary to operative vaginal delivery report more bothersome urinary symptoms and higher rates of anal incontinence immediately postpartum as compared with women with OASIS secondary to spontaneous delivery. These differences may resolve by 3 months postpartum. PMID- 26945271 TI - Combined Tolterodine and Vaginal Estradiol Cream for Overactive Bladder Symptoms After Randomized Single-Therapy Treatment. AB - OBJECTIVES: The aims of this study were to compare 12-week outcomes of single therapy tolterodine (Detrol LA) extended release to intravaginal estrogen (Estrace) for overactive bladder (OAB) symptoms and characterize 24- and 52-week outcomes in women undergoing combined therapy. METHODS: A single-site randomized, open-label trial in women with urinary frequency, urgency, nocturia, and/or urgency urinary incontinence symptoms was performed. Fifty-eight participants were randomized to oral tolterodine extended release daily or intravaginal estradiol cream nightly for 6 weeks then twice per week. The primary outcome was change in Overactive Bladder Questionnaire (OAB-q) symptom bother score at 12 weeks. Secondary outcomes included the Health-Related Quality of Life Questionnaire (HRQL) of the OAB-q and a 3-day bladder diary. At 12 weeks, subjects were offered addition of the alternative therapy with follow-up at 24 and 52 weeks. RESULTS: There was no difference in symptom bother score improvement between the tolterodine and intravaginal estradiol groups baseline to 12 weeks (20.6 +/- 21.7, -15.8 +/- 23.3, respectively, P = 0.45). There was a significant within-group decrease in symptom bother score from baseline to 12 weeks (tolterodine, P < 0.0001, and intravaginal estradiol, P = 0.002). Secondary outcome improvement within groups was noted in the HRQL total, urinary incontinence episodes, and median voiding frequency (all P <= 0.03) in the tolterodine group and in the HRQL total score (P = 0.03) in the intravaginal estradiol group, with no differences between groups. Combined therapy outcomes at 24 and 52 weeks compared with single therapy at 12 weeks revealed significant improvement in symptom bother score in the intravaginal estradiol + tolterodine group at 24 and 52 weeks (20.0 +/- 23.9, P = 0.008; -16.7 +/- 23.3, P = 0.02, respectively). CONCLUSIONS: Significant within-group improvement in OAB-q symptom bother was noted in both the intravaginal estradiol and tolterodine groups for OAB symptoms, with no difference between groups. Greater improvement from 12-week single therapy to 24 and 52 weeks of combined therapy was noted in the group originally assigned to intravaginal estradiol. The role of combined medical therapy for OAB symptoms needs further investigation. PMID- 26945272 TI - Prevalence of Occult Malignancy Within Morcellated Specimens Removed During Laparoscopic Sacrocolpopexy. AB - OBJECTIVE: This study aimed to determine the prevalence of occult malignancy found in morcellated specimens removed in the context of pelvic organ prolapse repair operations. METHODS: A total of 786 cases were reviewed from a single health system between October 2006 and July 2015. Thorough chart reviews were performed to include pathological specimens. Demographic, perioperative, and postoperative data were collected. RESULTS: Four occult malignancies were identified including 3 endometrial adenocarcinomas of the uterus and 1 papillary serous carcinoma of the uterus. The overall prevalence of occult malignancy within morcellated specimens was 0.5% (4 of 786). On adopting universal screening with endometrial biopsy, 5 malignancies were identified (5 of 176) before morcellation and no postoperative malignancies in the remaining patients. CONCLUSIONS: Power morcellation is a low-risk procedure with laparoscopic supracervical hysterectomy and sacrocolpopexy. Universal screening is highly effective in detecting occult malignancy and in our small series eliminated the risk; studies in multiple institutions will be needed to determine its effectiveness in other hospital systems. PMID- 26945273 TI - Factors Influencing Selection of Vaginal, Open Abdominal, or Robotic Surgery to Treat Apical Vaginal Vault Prolapse. AB - OBJECTIVES: This study aimed to determine factors influencing the selection of Mayo-McCall culdoplasty (MMC), open abdominal sacrocolpopexy (ASC), or robotic sacrocolpopexy (RSC) for posthysterectomy vaginal vault prolapse. METHODS: We retrospectively searched for the records of patients undergoing posthysterectomy apical vaginal prolapse surgery between January 1, 2000, and June 30, 2012, at our institution. Baseline characteristics and explicit selection factors were abstracted from the electronic medical records. Factors were compared between groups using chi tests for categorical variables, analysis of variance for continuous variables, and Kruskal-Wallis tests for ordinal variables. RESULTS: Among the 512 patients identified who met inclusion criteria, the MMC group (n = 174) had more patients who were older, had American Society of Anesthesiologists class 3+ or greater, had anterior vaginal prolapse grade 3+, desired to avoid abdominal surgery, and did not desire a functional vagina. Patients in the ASC (n = 237) and RSC (n = 101) groups had more failed prolapse surgeries, suspected abdominopelvic pathologic processes, and chronic pain. Advanced prolapse was more frequently cited as an explicit selection factor for ASC than for either MMC or RSC. CONCLUSIONS: The most common factors that influenced the type of apical vaginal vault prolapse surgery overlapped with characteristics that differed at baseline. In general, MMC was chosen for advanced anterior vaginal prolapse and baseline characteristics that increased surgical risks, ASC for advanced apical prolapse, and ASC or RSC for recurrent prolapse, suspected abdominal pathology, and patients with chronic pain or lifestyles including heavy lifting. Thus, efforts should be made to attempt to control for selection bias when comparing these procedures. PMID- 26945274 TI - Treating decay in the US oral healthcare system. PMID- 26945275 TI - Physician assistants and nurse practitioners are not interchangeable. PMID- 26945276 TI - Surgical management for Hirschsprung disease: A review for primary care providers. AB - Primary care providers may encounter infants and children with Hirschsprung disease, a congenital colonic defect. Although primarily a surgical problem, the disease requires extensive supportive care and a multidisciplinary approach that often extends beyond surgical correction. This article reviews the management of Hirschsprung disease. PMID- 26945277 TI - The mitochondrial metabolic checkpoint and aging of hematopoietic stem cells. AB - PURPOSE OF REVIEW: Cell-cycle checkpoints are surveillance mechanisms in eukaryotic cells that monitor the condition of the cell, repair cellular damages, and allow the cell to progress through the various phases of the cell cycle when conditions become favorable. We review recent advances in hematopoietic stem cell (HSC) biology, highlighting a mitochondrial metabolic checkpoint that is essential for HSCs to return to the quiescent state. RECENT FINDINGS: As quiescent HSCs enter the cell cycle, mitochondrial biogenesis is induced, which is associated with increased mitochondrial protein folding stress and mitochondrial oxidative stress. Mitochondrial unfolded protein response and mitochondrial oxidative stress response are activated to alleviate stresses and allow HSCs to exit the cell cycle and return to quiescence. Other mitochondrial maintenance mechanisms include mitophagy and asymmetric segregation of aged mitochondria. SUMMARY: Because loss of HSC quiescence results in the depletion of the HSC pool and compromised tissue regeneration, deciphering the molecular mechanisms that regulate the mitochondrial metabolic checkpoint in HSCs will increase our understanding of hematopoiesis and how it becomes dysregulated under pathological conditions and during aging. More broadly, this knowledge is instrumental for understanding the maintenance of cells that convert between quiescence and proliferation to support their physiological functions. PMID- 26945278 TI - Safety of the Gadolinium-Based Contrast Agents for Magnetic Resonance Imaging, Focusing in Part on Their Accumulation in the Brain and Especially the Dentate Nucleus. AB - The established class of intravenous contrast media for magnetic resonance imaging is the gadolinium chelates, more generally referred to as the gadolinium based contrast agents (GBCAs). These can be differentiated on the basis of stability in vivo, with safety and tolerability of the GBCAs dependent upon chemical and biologic inertness. This review discusses first the background in terms of development of these agents and safety discussions therein, and second their relative stability based both on in vitro studies and clinical observations before and including the advent of nephrogenic systemic fibrosis. This sets the stage for the subsequent focus of the review, the current knowledge regarding accumulation of gadolinium in the brain and specifically the dentate nucleus after intravenous administration of the GBCAs and differentiation among agents on this basis. The information available to date, from the initial conception of these agents in 1981 to the latest reports concerning safety, demonstrates a significant difference between the macrocyclic and linear chelates. The review concludes with a discussion of the predictable future, which includes, importantly, a reassessment of the use of the linear GBCAs or a subset thereof. PMID- 26945279 TI - Congenital Chylothorax: A Unique Presentation of Nonimmune Hydrops Fetalis in a Preterm Infant. AB - BACKGROUND: Nonimmune hydrops fetalis secondary to congenital chylothorax (CC) is a rare disease process associated with high morbidity and mortality related to abnormal formation of the lymphatic system and disrupted management of fetal fluid. Hydrops fetalis is typically diagnosed prenatally by the presence of pleural effusions or other fluid collection on ultrasonography. Congenital chylothorax is diagnosed when the analysis of pleural fluid is deemed chylous. Neonatal presentation is often respiratory distress secondary to lung compression or pulmonary hypoplasia. Management ranges from supportive medical management such as high-frequency ventilation, chest drainage, and nutrition support, to controversial therapies such as octreotide administration and chemical pleurodesis, to surgical interventions such as thoracic duct ligation and mechanical pleurodesis. PURPOSE: To discuss a range of management techniques and supportive therapies for hydrops fetalis and CC. METHODS/SEARCH STRATEGY: PubMed and CINAHL were searched using the terms "hydrops fetalis," "congenital," "chylothorax," "neonate," and "preterm." Twenty-two English language articles published within the last five years were identified and included to determine the current body of evidence surrounding treatment options for hydrops fetalis and CC. CASE FINDINGS: In this case, a preterm male infant presented at birth with prenatally known bilateral pleural effusions and ascites, later diagnosed as nonimmune hydrops fetalis secondary to CC. A combination of supportive medical management, octreotide therapy, and surgical intervention effectively resolved this infant's chylothorax and hydrops. IMPLICATIONS FOR PRACTICE: Antenatal intervention may be appropriate for some infants, otherwise supportive medical management including respiratory and nutrition therapies should be prioritized for infants born with hydrops fetalis and CC. IMPLICATIONS FOR RESEARCH: Nonimmune hydrops fetalis secondary to CC presents a complex challenge for neonatal providers, as no definitive treatment strategy currently exists. Further research is needed to determine the safety and efficacy of controversial therapies including octreotide. PMID- 26945280 TI - Assessment Tools for Evaluation of Oral Feeding in Infants Younger Than 6 Months. AB - BACKGROUND: Feeding difficulty is common in infants younger than 6 months. Identification of infants in need of specialized treatment is critical to ensure appropriate nutrition and feeding skill development. Valid and reliable assessment tools help clinicians objectively evaluate feeding. PURPOSE: To identify and evaluate assessment tools available for clinical assessment of bottle- and breastfeeding in infants younger than 6 months. METHODS/SEARCH STRATEGY: CINAHL, HaPI, PubMed, and Web of Science were searched for "infant feeding" and "assessment tool." The literature (n = 237) was reviewed for relevant assessment tools. A secondary search was conducted in CINAHL and PubMed for additional literature on identified tools. FINDINGS/RESULTS: Eighteen assessment tools met inclusion criteria. Of these, 7 were excluded because of limited available literature or because they were intended for use with a specific diagnosis or in research only. There are 11 assessment tools available for clinical practice. Only 2 of these were intended for bottle-feeding. All 11 indicated that they were appropriate for use with breastfeeding. None of the available tools have adequate psychometric development and testing. IMPLICATIONS FOR PRACTICE: All of the tools should be used with caution. The Early Feeding Skills Assessment and Bristol Breastfeeding Assessment Tool had the most supportive psychometric development and testing. IMPLICATIONS FOR RESEARCH: Feeding assessment tools need to be developed and tested to guide optimal clinical care of infants from birth through 6 months. A tool that assesses both bottle- and breastfeeding would allow for consistent assessment across feeding methods. PMID- 26945281 TI - Journey to Becoming a Neonatal Nurse Practitioner: Making the Decision to Enter Graduate School. AB - BACKGROUND: Neonatal nurse practitioners (NNPs) play an important role in caring for premature and ill infants. Currently, there is a shortage of NNPs to fill open positions. Understanding how nurses decide to become NNPs will help practicing nurse practitioners, managers, and faculty encourage and support nurses in considering the NNP role as a career choice. PURPOSE: To describe how nurses decide to enter graduate school to become nurse practitioners. METHODS: A qualitative study using semistructured interviews to explore how 11 neonatal intensive care unit nurses decided to enter graduate school to become NNPs. RESULTS: Key elements of specialization, discovery, career decision, and readiness were identified. Conditions leading to choosing the NNP role include working in a neonatal intensive care unit and deciding to stay in the neonatal area, discovering the NNP role, deciding to become an NNP, and readiness to enter graduate school. Important aspects of readiness are developing professional self confidence and managing home, work, and financial obligations and selecting the NNP program. IMPLICATIONS FOR PRACTICE: Neonatal nurse practitioners are both positive role models and mentors to nurses considering the role. Unit managers are obligated to provide nurses with opportunities to obtain leadership skills. Faculty of NNP programs must be aware of the impact NNP students and graduates have on choices of career and schools. IMPLICATIONS FOR RESEARCH: Exploring the decision to become an NNP in more geographically diverse populations will enhance understanding how neonatal intensive care unit nurses decide to become NNPs. PMID- 26945282 TI - Infantile Hemangiomas: Pathogenesis and Review of Propranolol Use. AB - BACKGROUND: Infantile hemangiomas are complex benign vascular tumors that present after birth. Hemangioma lesions have a predictable course of growth, but little is understood about the mechanism behind their development. Infantile hemangiomas are considered proliferative lesions of the endothelial cells. PURPOSE: To effectively manage infants with infantile hemangiomas, a clear understanding of the pathogenic pathways is important and can assist the healthcare provider with effective treatment. This understanding will facilitate a relationship of support with the families of affected infants. METHODS/SEARCH STRATEGIES: EBSCO host and Ovid database search for key words of infantile hemangiomas, propranolol, vascular lesion, and proliferative lesion was utilized. Articles on pathophysiology along with recent research studies were include in the search. FINDINGS/RESULTS: The use of propranolol is a recent development in the treatment of infantile hemangiomas, which has shown a high rate of response in decreasing the size and reducing the potential for life-long complications. Different studies have shown the same success rate with the use of propranolol but with different variables. IMPLICATIONS FOR PRACTICE: As a healthcare team member, better identification and customized care of these patients can reduce the rare but devastating complications of infantile hemangiomas. IMPLICATIONS FOR RESEARCH: Future research can help identify the most effective dose and course of propranolol administration. PMID- 26945283 TI - Accuracy of a Weight-Based Formula for Neonatal Gastric Tube Insertion Length. AB - BACKGROUND: Gastric tubes are used in nurseries on a daily basis. Various methods of estimating gastric tube length for insertion using anatomical landmarks are used to assist correct placement. Sometimes, however, they can be up to 55% inaccurate. In 2012, we published a weight-based formula to estimate gastric tube length for insertion. PURPOSE: This study reviews the rates of correct gastric tube placement, as confirmed by radiography, after the incorporation of this weight-based formula into bedside practice. METHODS: A 6-month prospective study was performed in a tertiary neonatal intensive care unit. The formula estimating gastric tube length for insertion had been derived in an earlier study. This was incorporated into the hospital's policies and procedures guideline for the insertion of gastric tubes. Neonates with gastric tubes who required radiography for clinical reasons were included. The infant's weight and the type (orogastric or nasogastric) and length of tube were documented. A single radiologist assessed the tube position to be high, borderline, correct, or long. RESULTS: A total of 195 chest radiographs were obtained. Correct tube position was found in 84% of instances. This was a statistically and clinically significant improvement. IMPLICATIONS FOR PRACTICE: Implementation of a simple weight-based estimate for gastric tube length improves correct position rates. IMPLICATIONS FOR RESEARCH: Further studies comparing accuracy of length/height and weight-based estimations for gastric tube insertion lengths in very preterm and extremely preterm infants are needed. PMID- 26945284 TI - Fractionated elution using the TEKCIS technetium-99m generator. AB - The TEKCIS technetium-99m (Tc) generator was designed to allow dry column shipment and automatized conception. A high Tc radioactive concentration is required in a subset of radiopharmacy procedures. Fractionated elution can be a useful tool to meet this requirement, especially when current elution is close to the generator expiration date. The aim of our study was to assess TEKCIS generator elution kinetics and to determine the optimal fractionated elution time to fit with procedures requiring the highest Tc radioactive concentration in clinical use. After duplicate elution at several predetermined elution times, the volume and activity of each eluate were measured. Two optimal time points were selected to perform fractionated elution and repeatability (n=34 and 33) assessed on TEKCIS generators calibrated at 6 or 8 GBq. The complete eluate volume (5 ml) was collected after 60 s of elution. A logarithmic equation was established between eluate volume (v, ml) from elapsed elution time (t, s): v=1.8335ln(t) 2.5965. Using the reciprocal equation, elution times required to obtain some commonly eluted volumes were calculated. Fractionated elutions during 15 and 20 s were selected and an average elution volume from 2.74 to 3.27 ml was collected, with an average elution yield of approximately 90 and 100%, respectively. Our work provides a simple and reliable methodology for the use of fractionated elution with the new TEKCIS generator. PMID- 26945285 TI - Dietary patterns and colorectal cancer risk: a meta-analysis. AB - The analysis of dietary patterns has recently drawn considerable attention as a method of investigating the association between the overall whole diet and the risk of colorectal cancer. However, the results have yielded conflicting findings. Here, we carried out a meta-analysis to identify the association between dietary patterns and the risk of colorectal cancer. A total of 40 studies fulfilled the inclusion criteria and were included in this meta-analysis. The highest category of 'healthy' dietary pattern compared with the lowest category was apparently associated with a decreased risk for colorectal cancer [odds ratio (OR)=0.75; confidence interval (CI): 0.68-0.83; P<0.00001]. An increased risk of colorectal cancer was shown for the highest compared with the lowest category of a 'western-style' dietary pattern (OR=1.40; CI: 1.26-1.56; P<0.00001). There was an increased risk of colorectal cancer in the highest compared with the lowest category of 'alcohol-consumption' pattern (OR=1.44; CI: 1.13-1.82; P=0.003). The results of this meta-analysis indicate that a 'healthy' dietary pattern may decrease the risk of colorectal cancer, whereas 'western-style' and 'alcohol consumption' patterns may increase the risk of colorectal cancer. PMID- 26945286 TI - Metformin and the risk of renal cell carcinoma: a case-control analysis. AB - Metformin use has been associated previously with a decreased risk of cancer, but its association with renal cell carcinoma has not yet been investigated in observational studies. We aimed to explore the association between the use of metformin and other antidiabetic drugs and the risk of renal cell carcinoma (RCC). We carried out a case-control analysis in the UK-based Clinical Practice Research Datalink. We included individuals with an incident RCC between January 1995 and December 2013 younger than the age of 90 years. Six controls per case were matched on age, sex, calendar time, general practice, and number of years of active history in the Clinical Practice Research Datalink before the index date. We included BMI, smoking, alcohol consumption, hypertension, and diabetes mellitus as potential confounders in a multivariate model using conditional logistic regression to calculate odds ratios with 95% confidence intervals, and we carried out a sensitivity analysis restricted only to diabetic cases and controls. Long-term use of metformin was not associated with an altered relative risk of RCC (>=30 prescriptions, adjusted odds ratio 1.18, 95% confidence interval 0.88-1.58), nor was use of other antidiabetic drugs. Results in the sensitivity analysis including only diabetic cases and controls were largely the same. Use of metformin or other antidiabetic drugs was not associated with a materially altered risk of RCC. Further studies are warranted. PMID- 26945287 TI - From the Editor. PMID- 26945288 TI - Rethinking Medicare Payment Adjustments for Quality. AB - Payment reforms aimed at linking payment and quality have largely been based on the adherence to process measures. As a result, the attempt to pay for value is getting lost in an overly complex attempt to measure value. The "Incentivizing Health Care Quality Outcomes Act of 2014" (HR 5823) proposes to replace the existing patchwork of process and outcomes quality measures with a uniform, coordinated, and comprehensive outcomes-based quality measurement system. The Outcomes Act represents a shift in payment policy toward getting value instead of an increasingly complex attempt to measure value. PMID- 26945289 TI - If We Pay for Value, Will We Get It? AB - Quality measurement and performance-based payment systems are intended to promote high-value health care. Medicare is beginning to shift from process to population based outcome measures, but the service (rather than the outcome) remains the focus under fee-for-service payment. An emerging challenge: how to mesh the differing perspectives of payers, providers, and consumers on what constitutes value in health care. PMID- 26945290 TI - Improving Performance, Not Just What's Measured: Does the Inpatient Prospective Payment System Provide Useful Lessons? AB - The interesting article by Averill and colleagues succinctly makes the case why the aspiration for using payment reform to improve health care value has gotten off track, namely, that instead of focusing on actually getting more value, policy has focused on an increasingly complex attempt to measure value. But instead they undermine that insight by recommending their own favored measures for use in pay-for-performance. Without question, their potentially preventable events concept as the target for measurement not only is an improvement over current and Congressionally mandated ones but also presents undiscussed measurement complexity. I argue that the lessons of the successful Inpatient Prospective Payment System they detail do not support their rationale for endorsing even a better version of pay-for-performance. PMID- 26945291 TI - Potentially Preventable Events: A Focus to Increase Value and Appropriately Align Incentives. PMID- 26945292 TI - Can a Focus on Preventable Events Help Untangle the Quality Measurement Mess? AB - The success of a shift from paying for volume to paying for value depends on our ability to measure quality. Unfortunately, current approaches to measuring quality and linking quality to payment have frustrated providers and failed to provide essential information to patients. Shifting to a focus on preventable events could go a long way toward clarifying and simplifying quality measurement, but successful adoption of that approach requires overcoming several substantive and political challenges. PMID- 26945293 TI - Merit Based Incentive Payment System. PMID- 26945294 TI - Challenges in Moving to "Pay for Outcomes". PMID- 26945295 TI - Thinking About Clinical Outcomes in Medicaid. AB - As Medicaid expands in scope and influence, it is evolving toward being a "purchaser" of quality health care. This commentary discusses measurement and incentivization of clinical outcomes in Medicaid. Advantages and disadvantages of outcome versus process measures are discussed. Distinctions are drawn between the roles of Medicare and Medicaid, including the implications of the growth in Medicaid managed care. Medicaid's influence is particularly notable for obstetric, pediatric, newborn, and long-term care. We provide data on 3 Medicaid outcomes: potentially preventable hospital admissions, readmissions, and complications. The commentary concludes with suggestions for choosing and implementing outcome-oriented value-based purchasing initiatives in Medicaid. PMID- 26945296 TI - Rethinking Payment Adjustments for Quality: A View From New York State. PMID- 26945297 TI - Response to Commentaries on "Rethinking Medicare Payment Adjustments for Quality". PMID- 26945298 TI - Paying for On-Patent Pharmaceuticals: Limit Prices and the Emerging Role of a Pay for Outcomes Approach. AB - In this article we propose a new approach to pricing for patent-protected (on patent) pharmaceuticals. We describe and define limit pricing as a method for drug companies to maximize revenue for their investment by offering budget neutral pricing to encourage early adoption by payers. Under this approach, payers are incentivized to adopt innovative but expensive drugs more quickly if drug companies provide detailed analyses of the net impact of the new pharmaceutical upon total health budgets. For payers to adopt use of a new pharmaceutical, they would require objective third-party evaluation and pharmaceutical manufacturer accountability for projected outcomes efficacy of their treatments on population health. The pay for outcomes underpinning of this approach falls within the wider aspirations of health reform. PMID- 26945299 TI - Commentary on "Paying for On-Patent Pharmaceuticals: Limit Prices and the Emerging Role of a Pay for Outcomes Approach". PMID- 26945300 TI - Commentary on "Paying for On-Patent Pharmaceuticals: Limit Prices and the Emerging Role of a Pay for Outcomes Approach" by Richard Fuller and Norbert Goldfield. PMID- 26945301 TI - Response to Commentaries on "Paying for On-Patent Pharmaceuticals: Limit Prices and the Emerging Role of a Pay for Outcomes Approach". PMID- 26945302 TI - Comparison of the Properties of Regression and Categorical Risk-Adjustment Models. AB - Clinical risk-adjustment, the ability to standardize the comparison of individuals with different health needs, is based upon 2 main alternative approaches: regression models and clinical categorical models. In this article, we examine the impact of the differences in the way these models are constructed on end user applications. PMID- 26945303 TI - Commentary on "Comparison of the Properties of Regression and Categorical Risk Adjustment Models". PMID- 26945304 TI - Commentary on Fuller and Colleagues: A False Dichotomy That Cannot Move Risk Adjustment Efforts Forward. PMID- 26945305 TI - Response to Commentaries on "Comparison of the Properties of Regression and Categorical Risk-Adjustment Models". PMID- 26945306 TI - Junior Doctors in England Strike for the First Time in 40 Years. AB - The UK government recently stated its intention to impose a new junior doctor contract in England. Related negotiations between the British Medical Association and government representatives started in 2013. These have to-date failed to reassure doctors, who are concerned about risks to their welfare, patient safety, and the future of England's National Health Service. With the impending imposition of the new contract, and lack of progress, junior doctors felt the risks of striking had fallen below those of inaction. Hence, the first strike staged by the English medical workforce for 40 years occurred in January 2016. PMID- 26945308 TI - Patient with chronic renal failure undergoing surgery. AB - PURPOSE OF REVIEW: Chronic kidney disease (CKD) is an increasing health problem worldwide and is associated with a number of clinical challenges. In this paper, we review recent studies that deal with strategies for the management of patients with CKD undergoing surgery. RECENT FINDINGS: Effective strategies for nephroprotection are crucial for the handling of patients with CKD in the perioperative setting to prevent complications and to avoid the progression of CKD. Due to the lack of perioperative studies with CKD patients there are only level 2 recommendations. First of all, this requires the identification of CKD patients through risk assessment and preoperative laboratory tests. In this regard, biomarkers, such as cystatin C may facilitate the detection of chronically impaired renal function. Secondly, particular attention should be paid to the maintenance of hemodynamic stability, including an adequate blood pressure and cardiac index and the preservation of intravascular volume. There is clear evidence that an unimpaired renal perfusion, guaranteed through hemodynamic stability, and an undisturbed fluid balance both reduce the incidence of acute kidney injury (AKI) and consequently the further deterioration of renal function. Thirdly, several studies demonstrate that tight glycemic control is associated with less renal impairment and better survival for patients with CKD. Lastly, the highest priority for the patient with CKD should be assigned to the prevention of AKI, which is an action of proven efficacy. SUMMARY: Identification and risk stratification is crucial for the perioperative management of patients with CKD. To improve clinical outcomes, nonemergent procedures should be postponed, renal function optimized, nephrotoxic drugs avoided, and AKI prevented. PMID- 26945309 TI - Injury Risk Is Increased by Changes in Perceived Recovery of Team Sport Players. AB - OBJECTIVE: The aim of this study is to investigate if changes in perceived stress and recovery over the course of a season are risk factors for acute and overuse injuries. DESIGN: A prospective nonexperimental cohort design. SETTING: Data were gathered at the SportsFieldLab Groningen and at the facilities of the participating teams. PARTICIPANTS: Eighty-six male and female basketball, volleyball, and korfball players aged 21.9 +/- 3.5 years. INTERVENTIONS: In this 10-month observational study, the independent variables are the changes in perceived stress and recovery. MAIN OUTCOME MEASURES: The Recovery-Stress Questionnaire for Athletes (RESTQ-Sport) was filled out every 3 weeks throughout the season to assess changes in perceived stress and recovery. Acute and overuse injuries were registered by the teams' physical therapists. Odds ratios and 95% confidence intervals were calculated. RESULTS: During one season, 66 acute and 62 overuse injuries were registered. Multinomial regression analysis showed that perceived General Recovery, shown in the scales Social Recovery and General Well Being, decreased in the 6-week period before an acute injury (OR 0.59 and 0.61, respectively, P <= 0.05) compared with healthy periods. Risk of overuse injuries increased when perceived Sport Recovery, shown in the Personal Accomplishment scale, decreased in the 3-week period before the injury (OR 0.59, P <= 0.05) compared with healthy periods. CONCLUSIONS: Therefore, decreased perceived recovery can indicate an increased injury risk. General Recovery affects acute injury risk and Sport Recovery affects the risk of an overuse injury. Monitoring perceived recovery over the course of a season could give guidance for recovery enhancing practices to prevent injuries. PMID- 26945310 TI - Selective Laser Trabeculoplasty in Primary Angle-closure Glaucoma After Laser Peripheral Iridotomy: A Case-Control Study. AB - PURPOSE: To evaluate the outcomes of selective laser trabeculoplasty (SLT) in patients with primary angle closure (PAC/PACG) following a YAG peripheral laser iridotomy (PI) compared with primary open-angle glaucoma (POAG). METHODS: A case control study compared the effectiveness of SLT in PAC/PACG to POAG. Data from patients who underwent SLT after a successful PI for PAC/PACG (PAC/PACG group) with an opening of the angle for at least 180 degrees were compared with a POAG group that was randomly matched to the PAC/PACG group for age, baseline intraocular pressure (IOP), and severity of glaucoma. Data were collected on the change in IOP from baseline and reduction in number of medications following SLT in both groups. SLT was considered successful when IOP decreased by >=20% of the baseline IOP without further medical or surgical intervention or a reduction in glaucoma medications by >=1 from the baseline number while maintaining the target IOP. RESULTS: In the PAC/PACG group, 59 eyes with persistent IOP elevation after successful PI underwent SLT in areas where the angle was open for at least 180 degrees; 41% (n=24) of PAC/PACG had scattered peripheral anterior synechiae (PAS) of <=180 degrees. In the POAG group, 59 eyes underwent SLT. Fifty-nine percent in the PAC/PACG group and 85% in POAG group had 360-degree treatment, with 74 and 78 shots at 0.53 and 0.62 mJ per laser application, respectively. In the PAC/PACG group, IOP was 19.3+/-6.5 mm Hg at baseline and 15+/-3.5 mm Hg10 months after SLT, and the number of medications decreased from 2.3 at baseline to 1.4 at 10 months postoperatively. In the POAG group, IOP was 19.6+/-5.6 mm Hg at baseline, and 16.1+/-3.7 mm Hg 11 months after SLT and the glaucoma medications decreased from 2.3 to 1.1. The postoperative IOP reduction in the PAC/PACG and POAG was not significantly different (P=0.66). The success rate of achieving clinically significant IOP reduction of 20% or more from baseline, or discontinuation of one or more of glaucoma medications was 84.7% in the PAC/PACG group and 79.6% in the POAG group (P=0.47). An IOP spike occurred in 10% (n=6) in PACG/PAC and 5% (n=3) in POAG and was controlled with topical medications (P=0.49). CONCLUSION: The safety and efficacy of SLT was equivalent in PAC/PACG and POAG. PMID- 26945311 TI - Congenital Stapes Ankylosis in Children: Surgical Findings and Results in 35 Cases. AB - OBJECTIVE: To evaluate surgical findings and hearing results in children undergoing middle ear surgery for congenital stapes ankylosis with or without other ossicular malformations (Teunissen and Cremers class I and class II malformations). STUDY DESIGN: A nonrandomized, nonblinded case series of prospectively collected data. SETTING: A tertiary referral center. PATIENTS: Twenty-eight consecutive pediatric patients who underwent 35 surgical procedures for congenital stapes ankylosis with or without other ossicular malformations and had available postoperative pure-tone audiometry. INTERVENTION: Primary stapedotomy with vein graft interposition and reconstruction with a Teflon piston, bucket handle prosthesis or total ossicular replacement prosthesis. MAIN OUTCOME MEASURES: Pre- and postoperative audiometric evaluation using four frequency (0.5, 1, 2, and 4 kHz) audiometry. Air-conduction thresholds, bone conduction thresholds, and air-bone gaps (ABGs) were measured. Postoperative audiometry was performed at 3, 6, 9, 12, 18, and 24 months after surgery and at a yearly interval thereafter. RESULTS: Overall, a postoperative ABG closure of 10 dB or less was achieved in 73% of class I cases and in 50% of class II cases. A postoperative ABG closure of 20 dB or less was achieved in 77% of class I cases and 67% of class II cases. Postoperative sensorineural hearing loss occurred in one class I case (4%) and none of the class II cases. CONCLUSION: Stapedotomy is a safe and feasible treatment option in children with congenital stapes ankylosis. PMID- 26945312 TI - Assessment of Vestibulo-oculomotor Reflex in Meniere's Disease: Defining an Instrumental Profile. AB - OBJECTIVES: To analyze and compare, in two groups of patients affected by definite Meniere's disease (MD) but treated differently, the Video Head Impulse Test findings especially by putting them in relationship with canal paresis, hearing loss, and duration of the disease. STUDY DESIGN: Retrospective chart review. PATIENTS: Seventy patients affected by unilateral definite MD (16 in Group 1 and 54 in Group 2) observed between March 2014 and May 2015 in a tertiary referral center were retrospectively studied and then divided into two groups: Group 1 was previously treated with intratympanic gentamicin, whereas Group 2 underwent only a conservative therapy. Instrumental tests included audiometry, caloric test, and Video Head Impulse Test. All the findings were statistically analyzed; significance was set at p = 0.005. INTERVENTION: Diagnostic. MAIN OUTCOMES MEASURES: If MD is treated conservatively the high-frequency vestibulo oculomotor reflex gain determined with Video Head Impulse Test is normal; it is pathological if MD is treated with gentamicin. RESULTS: High-frequency vestibulo oculomotor reflex gain showed a statistically significant reduction in Group 1; at the same time, it showed no correlation in both groups with hearing loss, duration of disease or canal paresis. CONCLUSION: High-frequency vestibulo oculomotor reflex is naturally preserved even in late stage MD if the patient has been treated conservatively; the dissociation between Caloric Test and Video Head Impulse Test findings could be considered an instrumental hallmark of MD. Gentamicin significantly reduces high-frequency vestibulo-oculomotor reflex gain: this reduction can be taken into account when determining the effectiveness of an ablative treatment. PMID- 26945313 TI - Comparison of Middle Ear Visualization With Endoscopy and Microscopy. AB - INTRODUCTION: The primary goal of chronic ear surgery is the creation of a safe, clean dry ear. For cholesteatomas, complete removal of disease is dependent on visualization. Conventional microscopy is adequate for most dissection, but various subregions of the middle ear are better visualized with endoscopy. OBJECTIVE: The purpose of the present study was to quantitatively assess the improved visualization that endoscopes afford as compared with operating microscopes. METHODS: Microscopic and endoscopic views were simulated using a three-dimensional model developed from temporal bone scans. Surface renderings of the ear canal and middle ear subsegments were defined and the percentage of visualization of each middle ear subsegment, both with and without ossicles, was then determined for the microscope as well as for 0-, 30-, and 45-degree endoscopes. Using this information, we analyzed which mode of visualization is best suited for dissection within a particular anatomical region. RESULTS: Using a 0-degree scope provides significantly more visualization of every subregion, except the antrum, compared with a microscope. In addition, angled scopes permit visualizing significantly more surface area of every subregion of the middle ear than straight scopes or microscopes. CONCLUSIONS: Endoscopes offer advantages for cholesteatoma dissection in difficult-to-visualize areas including the sinus tympani and epitympanum. PMID- 26945314 TI - Insertion of Cochlear Implant Electrode Array Using the Underwater Technique for Preserving Residual Hearing. AB - OBJECTIVE: To describe a method of cochlear implantation in which the opening of the cochlea and the electrode array insertion are performed under water (underwater technique). STUDY DESIGN: Retrospective patient review. SETTING: Academic tertiary referral center. PATIENTS: Fifteen implantations in children and adult patients with residual hearing at the frequencies 250, 500, and 1000 Hz on the unaided preoperative pure-tone audiometry were included in this study. INTERVENTION(S): Cochlear implantation with a conventional full-length electrode, in which the opening of the cochlea and the electrode array insertion are performed after the tympanic cavity was filled with body-temperature Ringer solution. MAIN OUTCOME MEASURE(S): Changes on residual hearing 6 to 8 weeks after surgery and at subsequent follow-up appointments were analyzed. Preservation of residual hearing was defined as measurable postoperative threshold at the frequencies 250, 500, and 1000 Hz. RESULTS: Overall postimplant hearing preservation 6 to 8 weeks after implantation was achieved in 13 of the patients (87%). Subsequent follow-up was performed on average 15.2 months after surgery (range, 7-32) in 14 out of 15 patients. At this late postoperative evaluation preservation of hearing was recorded in nine patients (64%), whereas in the remaining five patients (36%) no residual hearing was measured. CONCLUSION: The underwater technique offers a reliable nontraumatic method for electrode array insertions during cochlear implantation. The method respects the physiology of the cochlea und minimizes the pressure variations during cochlear opening and implantation. PMID- 26945315 TI - Controlled Clinical Trial on Bone-anchored Hearing Implants and a Surgical Technique With Soft-tissue Preservation. AB - OBJECTIVE: To compare the clinical and audiological outcomes after linear incision with soft-tissue preservation and standard linear incision with soft tissue reduction for placement of percutaneous bone-anchored hearing implants. STUDY DESIGN: Clinical trial with historical control-group from a previous randomized controlled trial. SETTING: Tertiary referral center. PATIENTS AND INTERVENTIONS: Twenty-five patients were enrolled in a prospective cohort of bone anchored hearing implant placement with linear incision and tissue preservation with a follow-up of 6 months. The control-group consisted of 25 patients from a previous randomized controlled trial in the same tertiary referral center. All sound processors were fitted 3 weeks after surgery. MAIN OUTCOME MEASURES: Numbness around the abutment, length of surgery, soft-tissue reactions according to Holgers' classification, Patient and Observer Scar Assessment Scale, implant loss, Implant Stability Quotient, and audiological outcome. RESULTS: Tissue preservation resulted in better results on sensibility (mean percentage correct responses 98% [SD 4.4] versus 89% [SD 15.0], p = 0.003), on the Patient and Observer Scar Assessment Scale (mean observer score 15.3 [SD 4.3] versus 19.4 [SD 6.3], p = 0.006), and shorter total surgery time (mean 24.6 min [SD 6.2] versus 31.9 min [SD 6.5], p < 0.001). More adverse soft-tissue reactions as measured by the Holgers classification were observed in the test-group (n = 7 [28%] versus n = 1 [4%], p = 0.049). For Implant Stability Quotient and audiology the study did not provide evidence that tissue preservation is better or worse compared with tissue reduction. CONCLUSION: Tissue preservation compared with tissue reduction leads to a generally favorable clinical outcome, comparable audiology results, and significantly shorter surgery time. Longer follow-up is warranted to conclude on the increased adverse soft-tissue reactions after 6 months. PMID- 26945316 TI - Sudden Death Due to Vestibular Schwannoma: Caution in Emergent Management. AB - OBJECTIVE: To enhance understanding of the possible dangers of large vestibular schwannomas and their potential to cause sudden death through rare situations such as brain herniation precipitated by cerebrospinal fluid pressure shifts. PATIENT: An otherwise healthy 32-year-old woman with a magnetic resonance imaging demonstrating a cystic cerebellopontine angle mass, presumptive for vestibular schwannoma, experienced sudden onset of headaches, nausea, and vomiting. INTERVENTION: The patient was admitted to the intensive care unit, started on anticonvulsants, investigated with serial computed tomography (CT) scans, and then elective intubation and ventriculostomy when her condition worsened. MAIN OUTCOME MEASURE(S): Clinical and radiological findings, as well as outcome of interventions. RESULTS: In the first hours of admission, the patient underwent serial CT scans that demonstrated fourth ventricle compression and hydrocephalus. When the patient's condition worsened, elective intubation was undertaken and an external ventricular drain was inserted. Very high intracranial pressures were noted despite cerebrospinal fluid drainage. Postoperative CT and magnetic resonance imaging demonstrated ascending transtentorial and tonsillar herniation as well as scattered cortical infarcts. Brain death was determined and care was withdrawn 5 days later. CONCLUSION: This is a very rare patient report of sudden death caused by a large vestibular schwannoma despite assertive emergent management. There was no intratumoral or intracranial haemorrhage. Brain death was likely a result of ascending transtentorial herniation that can occur with large posterior fossa tumors and be exacerbated by cerebrospinal fluid shifts after ventriculostomy. PMID- 26945317 TI - Assessment of Cochlear Trauma During Cochlear Implantation Using Electrocochleography and Cone Beam Computed Tomography. AB - OBJECTIVE: To assess cochlear trauma during cochlear implantation by electrocochleography (ECoG) and cone beam computed tomography (CBCT) and to correlate intraoperative cochlear trauma with postoperative loss of residual hearing. METHODS: ECoG recordings to tone bursts at 250, 500, 750, and 1000 Hz and click stimuli were recorded before and after insertion of the cochlear implant electrode array, using an extracochlear recording electrode. CBCTs were conducted within 6 weeks after surgery. Changes of intraoperative ECoG recordings and CBCT findings were correlated with postoperative threshold shifts in pure tone audiograms. RESULTS: Fourteen subjects were included. In three subjects a decrease of low-frequency ECoG responses at 250, 500, 750, and 1000 Hz occurred after insertion of the electrode array. This was associated with no or minimal residual hearing 4 weeks after surgery. ECoG responses to click stimuli were present in six subjects and showed a decrease after insertion of the electrode array in three. This was associated with a mean hearing loss of 21 dB in postoperative pure-tone audiograms. Scalar dislocation of the electrode array was assumed in one subject because of CBCT findings and correlated with a decrease of low-frequency ECoG responses and a complete loss of residual hearing. CONCLUSION: Hearing loss of <=11 dB is not associated with detectable decrease in ECoG recordings during cochlear implantation. However, in a majority of patients with threshold shifts of >11 dB or complete hearing loss, an intraoperative decrease of high- or low-frequency ECoG signals occurs, suggesting acute cochlear trauma. PMID- 26945318 TI - Effects of a Single Dose Dexmedetomidine on Surgical Field Visibility During Middle Ear Microsurgery: A Randomized Study. AB - OBJECTIVES: To investigate whether a single dose of dexmedetomidine (DEX) improves surgical field visibility. STUDY DESIGN: Randomized, prospective, double blind study. SETTING: Tertiary teaching hospital. INTERVENTIONS: ASA I or II patients undergoing tympanoplasty with ossiculoplasty were randomly assigned to receive either 0.8 MUg/kg DEX (Group D) or the same volume of saline (Group N) 10 min before anesthesia induction. MAIN OUTCOMES: The primary outcome was the visibility of the surgical field rated by surgeons by Boezaart score. The secondary outcomes were consumption of anesthesia, hemodynamic profiles, and subsequent recovery. RESULTS: Boezaart scores for surgical visibility were lower in Group D than in Group N (1.3 +/- 0.8 versus 1.8 +/- 0.9, P = 0.014). Minimum alveolar concentrations of sevoflurane (Group D 1 [0.9/1.1] versus Group N 1 [1/1.2], P = 0.018) and remifentanil consumption (Group D 370 [218/504] MUg versus Group N 583 [300/1028] MUg, P = 0.002) were less in Group D. Except for a transient increase in blood pressure and a decrease in heart rate during DEX infusion, hemodynamic profiles were more stable in Group D than in Group N. More patients needed morphine rescue and presented with postoperative nausea and vomiting in Group N than in Group D (Group D 1 versus Group N 8, P = 0.029). Recovery time was comparable between the two groups (Group D 19 min versus Group N 18 min, P = 0.569). CONCLUSION: Use of a single dose of DEX resulted in improved surgical visibility, less consumption of anesthesia, and more favorable hemodynamic profile while not delaying recovery time. PMID- 26945319 TI - Hypothermic machine perfusion in kidney transplantation. AB - PURPOSE OF REVIEW: This article summarizes novel developments in hypothermic machine perfusion (HMP) as an organ preservation modality for kidneys recovered from deceased donors. RECENT FINDINGS: HMP has undergone a renaissance in recent years. This renewed interest has arisen parallel to a shift in paradigms; not only optimal preservation of an often marginal quality graft is required, but also improved graft function and tools to predict the latter are expected from HMP. The focus of attention in this field is currently drawn to the protection of endothelial integrity by means of additives to the perfusion solution, improvement of the HMP solution, choice of temperature, duration of perfusion, and machine settings. HMP may offer the opportunity to assess aspects of graft viability before transplantation, which can potentially aid preselection of grafts based on characteristics such as perfusate biomarkers, as well as measurement of machine perfusion dynamics parameters. SUMMARY: HMP has proven to be beneficial as a kidney preservation method for all types of renal grafts, most notably those retrieved from extended criteria donors. Large numbers of variables during HMP, such as duration, machine settings and additives to the perfusion solution are currently being investigated to improve renal function and graft survival. In addition, the search for biomarkers has become a focus of attention to predict graft function posttransplant. PMID- 26945320 TI - Mechanisms of lung ischemia-reperfusion injury. AB - PURPOSE OF REVIEW: Lungs are extremely susceptible to injury, and despite advances in surgical management and immunosuppression, outcomes for lung transplantation are the worst of any solid organ transplant. The success of lung transplantation is limited by high rates of primary graft dysfunction because of ischemia-reperfusion injury characterized by robust inflammation, alveolar damage, and vascular permeability. This review will summarize major mechanisms of lung ischemia-reperfusion injury with a focus on the most recent findings in this area. RECENT FINDINGS: Over the past 18 months, numerous studies have described strategies to limit lung ischemia-reperfusion injury in experimental settings, which often reveal mechanistic insight. Many of these strategies involved the use of various antioxidants, anti-inflammatory agents, mesenchymal stem cells, and ventilation with gaseous molecules. Further advancements have been achieved in understanding mechanisms of innate immune cell activation, neutrophil infiltration, endothelial barrier dysfunction, and oxidative stress responses. SUMMARY: Methods for prevention of primary graft dysfunction after lung transplant are urgently needed, and understanding mechanisms of ischemia reperfusion injury is critical for the development of novel and effective therapeutic approaches. In doing so, both acute and chronic outcomes of lung transplant recipients will be significantly improved. PMID- 26945321 TI - Nonablative Fractional Laser Resurfacing for Acne Scarring in Patients With Fitzpatrick Skin Phototypes IV-VI. AB - BACKGROUND: There is a paucity of studies investigating laser resurfacing in Fitzpatrick skin phototypes (SPT) IV to VI. OBJECTIVE: To assess the efficacy and safety of fractional nonablative laser resurfacing in the treatment of acne scarring in patients with SPT IV to VI. METHODS AND MATERIALS: The authors conducted a randomized, investigator-blinded and rater-blinded, split-face comparative study of adults with SPT IV to VI and facial acne scars treated with 2 different density settings and the same fluence. RESULTS: Quantitative global scarring grading system (QGSGS) scores were significantly improved from baseline at 16 and 24 weeks (p = .0277). Improvements in QGSGS scores after higher and lower density treatments were statistically similar (p = .96). The live-blinded dermatologist, the blinded dermatologist photoraters, and the patients rated scars as being significantly more improved by visual analog scale at weeks 16 and 24 compared with baseline (p < .001) for both treatment densities. Five of 7 and 3 of 7 patients in the higher and lower density group, respectively, experienced mild or moderate hyperpigmentation as an investigator observed site reaction. CONCLUSION: The nonablative 1550-nm fractional laser is safe and efficacious in treating acne scaring in Fitzpatrick skin types IV to VI. Self-limited postinflammatory hyperpigmentation was a common occurrence, especially with higher treatment densities. PMID- 26945322 TI - Refractory Cutaneous Alternariosis Successfully Treated With Mohs Surgery and Full-Thickness Skin Grafting. PMID- 26945323 TI - Pediatric Cardiac Intensive Care Society 10th International Conference 2014 Consensus Statement: Pharmacotherapies in Cardiac Critical Care. PMID- 26945324 TI - Pediatric Cardiac Intensive Care Society 2014 Consensus Statement: Pharmacotherapies in Cardiac Critical Care Antihypertensives. AB - OBJECTIVE: Hypertension remains a common condition in pediatric cardiac intensive care. The physiologic effects of hypertension in this population are complex and are impacted by patient age, comorbidities, and primary cardiac disease. The objective of this study is to review current pharmacotherapies for the management of systemic hypertension in the pediatric cardiac ICU. DATA SOURCES: Relevant literature to the treatment of systemic hypertension in children was included. Specific focus was given to literature studying the use of therapies in critically ill children and those with heart disease. Reference textbooks and drug packaging inserts were used for drug-specific pediatric guidelines. STUDY SELECTION: A search of MEDLINE, PubMed, and the Cochrane Database was performed to find literature about the management of hypertension in children. Metaanalyses and pediatric-specific studies were primarily considered and cross-referenced. Pertinent adult studies were included. DATA EXTRACTION: Once the studies for inclusion were finalized, priority for data extraction was given to pediatric specific studies that focused on children with heart disease and critical illness. CONCLUSIONS: Systemic hypertension is common, and there is significant heterogeneity in the patient population with critical heart disease. There are limited large, prospective analyses of safety and efficacy for pediatric drug antihypertensive agents. Despite patient heterogeneity, most pharmacotherapies are safe and efficacious. PMID- 26945325 TI - Pediatric Cardiac Intensive Care Society 2014 Consensus Statement: Pharmacotherapies in Cardiac Critical Care Treatment of Acute Heart Failure. AB - OBJECTIVES: To provide an evidence-based review of pharmacotherapies to treat acute heart failure. To accomplish this objective, we will discuss circulatory physiology, vasoactive agents, and their indications in the management of acute heart failure. DATA SOURCE: A MEDLINE-baseline review of the literature. CONCLUSIONS: The optimal selection of vasoactive agents requires a consideration of circulatory physiology and the tailored application of pharmacotherapies to treat patients with acute heart failure. PMID- 26945326 TI - Pediatric Cardiac Intensive Care Society 2014 Consensus Statement: Pharmacotherapies in Cardiac Critical Care Chronic Heart Failure. AB - OBJECTIVE: Heart failure is a serious complication that can occur in patients with a variety of congenital and acquired disorders including congenital heart disease, cardiomyopathy, and myocarditis. Furthermore, heart failure patients comprise an increasing number of ICU admissions. Thus, it is important for those caring for patients with critical cardiovascular disease to have a thorough understanding of the medications used for the treatment of heart failure. The aim of this review is to provide an overview, rationale, indications, and adverse effects of medications used in the treatment of chronic heart failure. DATA SOURCES: PubMed, Medline, Cochrane Database of Systemic Reviews. STUDY SELECTION: Studies were selected on their relevance for pediatric heart failure. When limited data on pediatric heart failure were available, studies in adult patients were selected. DATA EXTRACTION: Relevant findings from studies were selected by the authors. DATA SYNTHESIS: The rationale for the efficacy of most heart failure medications used in pediatric patients is extrapolated from studies in adult heart failure. Commonly used medications for chronic heart failure include beta receptor antagonists (e.g., carvedilol and metoprolol), and medications aimed at blocking the renin-angiotensin-aldosterone system (e.g., angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, aldosterone receptor antagonists). In addition, diuretics are useful for symptoms of fluid overload. For patients with impaired perfusion, inotropic agents are useful acutely, but may be associated with worse outcomes when used chronically. Newer medications that have been recently approved in adults (e.g., serelaxin, ivabradine, and neprilysin inhibitor [angiotensin receptor blocker]) may prove to be important in pediatric heart failure. CONCLUSIONS: Heart failure patients are in an important population of critically ill children. The pharmacologic approach to these patients is aimed at treating symptoms of congestion and/or poor perfusion and improving long-term outcomes. PMID- 26945327 TI - Pediatric Cardiac Intensive Care Society 2014 Consensus Statement: Pharmacotherapies in Cardiac Critical Care: Sedation, Analgesia and Muscle Relaxant. AB - OBJECTIVE: This article reviews pharmacotherapies currently available to manage sedation, analgesia, and neuromuscular blockade for pediatric cardiac critical patients. DATA SOURCES: The knowledge base of an expert panel of pharmacists, cardiac anesthesiologists, and a cardiac critical care physician involved in the care of pediatric cardiac critical patients was combined with a comprehensive search of the medical literature to generate the data source. STUDY SELECTION: The panel examined all studies relevant to management of sedation, analgesia, and neuromuscular blockade in pediatric cardiac critical patients. DATA EXTRACTION: Each member of the panel was assigned a specific subset of the studies relevant to their particular area of expertise (pharmacokinetics, pharmacodynamics, and clinical care) to review and analyze. DATA SYNTHESIS: The panel members each crafted a comprehensive summary of the literature relevant to their area of expertise. The panel, as a whole, then collaborated to cohesively summarize all the available, relevant literature. CONCLUSIONS: In the cardiac ICU, management of the cardiac patient requires an individualized sedative and analgesic strategy that maintains hemodynamic stability. Multiple pharmacological therapies exist to achieve these goals and should be selected based on the patient's underlying physiology, hemodynamic vulnerabilities, desired level of sedation and analgesia, and the projected short- or long-term recovery trajectory. PMID- 26945328 TI - Pediatric Cardiac Intensive Care Society 2014 Consensus Statement: Pharmacotherapies in Cardiac Critical Care Fluid Management. AB - OBJECTIVE: In this Consensus Statement, we review the etiology and pathophysiology of fluid disturbances in critically ill children with cardiac disease. Clinical tools used to recognize pathologic fluid states are summarized, as are the mechanisms of action of many drugs aimed at optimal fluid management. DATA SOURCES: The expertise of the authors and a review of the medical literature were used as data sources. DATA SYNTHESIS: The authors synthesized the data in the literature in order to present clinical tools used to recognize pathologic fluid states. For each drug, the physiologic rationale, mechanism of action, and pharmacokinetics are synthesized, and the evidence in the literature to support the therapy is discussed. CONCLUSIONS: Fluid management is challenging in critically ill pediatric cardiac patients. A myriad of causes may be contributory, including intrinsic myocardial dysfunction with its associated neuroendocrine response, renal dysfunction with oliguria, and systemic inflammation with resulting endothelial dysfunction. The development of fluid overload has been associated with adverse outcomes, including acute kidney injury, prolonged mechanical ventilation, increased vasoactive support, prolonged hospital length of stay, and mortality. An in-depth understanding of the many factors that influence volume status is necessary to guide optimal management. PMID- 26945329 TI - Pediatric Cardiac Intensive Care Society 2014 Consensus Statement: Pharmacotherapies in Cardiac Critical Care Antiarrhythmics. AB - OBJECTIVE: Arrhythmias are a common occurrence in critically ill pediatric patients. Pharmacotherapy is a usual modality for treatment and prevention of arrhythmias in this patient population. This review will highlight particular arrhythmias in the pediatric critical care population and discuss salient points of pharmacotherapy of these arrhythmias. The mechanisms of action for the various agents, potential adverse events, place in therapy, and evidence for their use will be summarized. DATA SOURCES: The literature was searched for articles related to the topic. Expertise of the authors and a consensus of the editors were additional sources of data in the article. DATA SYNTHESIS: The author team synthesized the current pharmacology and recommendations and present them in this review. Tables were generated to summarize the state of the art evidence-based practice. CONCLUSION: Specialized knowledge as to the safe and effective use of the antiarrhythmic pharmacotherapy in the intensive care setting can lead to safe and effective rhythm management in patients with complex heart disease. PMID- 26945330 TI - Pediatric Cardiac Intensive Care Society 2014 Consensus Statement: Pharmacotherapies in Cardiac Critical Care Hormone Replacement Therapy. AB - OBJECTIVE: To provide an overview of the current literature on the use of hormone replacement therapies in pediatric cardiac critical care. DATA SOURCES: PubMed, EMBASE, and the Cochrane Library were searched using keywords relevant to the hormonal therapy, with no limits on language but restricting the search to children 0-18 years old. STUDY SELECTION: All clinical studies believed to have relevance were considered. Where studies in children were sparse, additional evidence was sought from adult studies. DATA EXTRACTION: All relevant studies were reviewed, and the most relevant data were incorporated in this review. DATA SYNTHESIS: All authors of this review contributed to the appraisal of the data extracted. Challenges and revisions by the authors were conducted by group e-mail debate. CONCLUSIONS: Glycemic control: although it is likely that some children could benefit, the routine use of tight glycemic control cannot be recommended in children after cardiac surgery. Thyroid hormone replacement: routine use of thyroid hormone replacement to normalize levels after cardiac surgery cannot be recommended on current evidence. Until further evidence from adequately powered studies is available, therapeutic decisions should be based on individual patient circumstances. Corticosteroids: 1) cardiopulmonary bypass: although studies seem to favor steroid administration during surgery with cardiopulmonary bypass, a large randomized controlled trial is required before strong recommendations can be made; 2) refractory hypotension: the evidence for the use of steroid replacement in refractory hypotension is poor, and no firm recommendations can be made; and 3) abnormal adrenal function after cardiac surgery: there is inadequate evidence on which to make recommendations on the use of corticosteroid replacement in children with critical illness-related corticosteroid insufficiency in children following cardiac surgery. PMID- 26945331 TI - Pediatric Cardiac Intensive Care Society 2014 Consensus Statement: Pharmacotherapies in Cardiac Critical Care Immune Therapy. AB - OBJECTIVE: In this Consensus Statement, we review the etiology and pathophysiology of inflammatory processes seen in critically ill children with cardiac disease. Immunomodulatory therapies aimed at improving outcomes in patients with myocarditis, heart failure, and transplantation are extensively reviewed. DATA SOURCES: The author team experience and along with an extensive review of the medical literature were used as data sources. DATA SYNTHESIS: The authors synthesized the data in the literature to present current immumodulatory therapies. For each drug, the physiologic rationale, mechanism of action, and pharmacokinetics are synthesized, and the evidence in the literature to support the therapy is discussed. CONCLUSIONS: Immunomodulation has a crucial role in the treatment of certain pediatric cardiac diseases. Immunomodulatory treatments that have been used to treat myocarditis include corticosteroids, IV immunoglobulin, cyclosporine, and azathioprine. Contemporary outcomes of pediatric transplant recipients have improved over the past few decades, partly related to improvements in immunomodulatory therapy to prevent rejection of the donor heart. Immunosuppression therapy is commonly divided into induction, maintenance, and acute rejection therapy. Common induction medications include antithymocyte globulin, muromonab-CD3, and basiliximab. Maintenance therapy includes chronic medications that are used daily to prevent rejection episodes. Examples of maintenance medications are corticosteroids, cyclosporine, tacrolimus, sirolimus, everolimus, azathioprine, and mycophenolate mofetil. Rejection of the donor heart is diagnosed either by clinically or by biopsy and is treated with intensification of immunosuppression. PMID- 26945332 TI - Pediatric Cardiac Intensive Care Society 2014 Consensus Statement: Pharmacotherapies in Cardiac Critical Care Anticoagulation and Thrombolysis. AB - OBJECTIVE: Thrombotic complications are increasingly being recognized as a significant cause of morbidity and mortality in pediatric and congenital heart disease. The objective of this article is to review the medications currently available to prevent and treat such complications. DATA SOURCES: Online searches were conducted using PubMed. STUDY SELECTION: Studies were selected for inclusion based on their scientific merit and applicability to the pediatric cardiac population. DATA EXTRACTION: Pertinent information from each selected study or scientific review was extracted for inclusion. DATA SYNTHESIS: Four classes of medications were identified as potentially beneficial in this patient group: anticoagulants, antiplatelet agents, thrombolytic agents, and novel oral anticoagulants. Data on each class of medication were synthesized into the follow sections: mechanism of action, pharmacokinetics, dosing, monitoring, reversal, considerations for use, and evidence to support. CONCLUSIONS: Anticoagulants, antiplatelet agents, and thrombolytic agents are routinely used successfully in the pediatric patient with heart disease for the prevention and treatment of a wide range of thrombotic complications. Although the novel oral anticoagulants have been approved for a limited number of indications in adults, studies on the safety and efficacy of these agents in children are pending. PMID- 26945334 TI - The role of anticitrullinated protein antibodies in the early stages of rheumatoid arthritis. AB - PURPOSE OF REVIEW: This review provides an update on the recent discoveries on the role of anticitrullinated protein antibodies (ACPA) in early rheumatoid arthritis (RA). RECENT FINDINGS: RA is characterized by an immune response against posttranslationally modified proteins, in particular citrullinated proteins. Recent studies have found that the ACPA response matures shortly before clinical disease manifests itself and is characterized by an increase in titre, isotype switching, antigen-recognition profile, and a change in the Fc glycosylation pattern. To date, many citrullinated autoantigens have been identified and novel studies suggest that the human leucocyte antigen class II locus may directly influence the maturation of the ACPA response via antigen specific T cells. Clinical studies have demonstrated that effective treatment of arthritis can lead to reduced ACPA levels or a change in composition of ACPA. In addition to ACPA, autoantibodies targeting other posttranslational modifications have been identified and may be associated with disease prognosis. SUMMARY: Key studies have demonstrated that autoimmunity against citrullinated proteins is already present in preclinical RA and matures over time. Future studies are required to reveal whether autoantibodies and the B cells that produce them play a role in disease development or can function as biomarkers for disease maturation. PMID- 26945333 TI - Pediatric Cardiac Intensive Care Society 2014 Consensus Statement: Pharmacotherapies in Cardiac Critical Care Pulmonary Hypertension. AB - OBJECTIVE: To review the pharmacologic treatment options for pulmonary arterial hypertension in the cardiac intensive care setting and summarize the most-recent literature supporting these therapies. DATA SOURCES AND STUDY SELECTION: Literature search for prospective studies, retrospective analyses, and case reports evaluating the safety and efficacy of pulmonary arterial hypertension therapies. DATA EXTRACTION: Mechanisms of action and pharmacokinetics, treatment recommendations, safety considerations, and outcomes for specific medical therapies. DATA SYNTHESIS: Specific targeted therapies developed for the treatment of adult patients with pulmonary arterial hypertension have been applied for the benefit of children with pulmonary arterial hypertension. With the exception of inhaled nitric oxide, there are no pulmonary arterial hypertension medications approved for children in the United States by the Food and Drug Administration. Unfortunately, data on treatment strategies in children with pulmonary arterial hypertension are limited by the small number of randomized controlled clinical trials evaluating the safety and efficacy of specific treatments. The treatment options for pulmonary arterial hypertension in children focus on endothelial-based pathways. Calcium channel blockers are recommended for use in a very small, select group of children who are responsive to vasoreactivity testing at cardiac catheterization. Phosphodiesterase type 5 inhibitor therapy is the most-commonly recommended oral treatment option in children with pulmonary arterial hypertension. Prostacyclins provide adjunctive therapy for the treatment of pulmonary arterial hypertension as infusions (IV and subcutaneous) and inhalation agents. Inhaled nitric oxide is the first-line vasodilator therapy in persistent pulmonary hypertension of the newborn and is commonly used in the treatment of pulmonary arterial hypertension in the ICU. Endothelin receptor antagonists have been shown to improve exercise tolerance and survival in adult patients with pulmonary arterial hypertension. Soluble guanylate cyclase stimulators are the first drug class to be Food and Drug Administration approved for the treatment of chronic thromboembolic pulmonary hypertension. CONCLUSIONS: Literature and data supporting the safe and effective use of pulmonary arterial hypertension therapies in children in the cardiac intensive care are limited. Extrapolation of adult data has afforded safe medical treatment of pulmonary hypertension in children. Large multicenter trials are needed in the search for safe and effective therapy of pulmonary hypertension in children. PMID- 26945335 TI - Retinal vasculitis. AB - PURPOSE OF REVIEW: Ophthalmologists and rheumatologists frequently have a miscommunication among themselves, and as a result differ in their opinion for patients consulting them with retinal vasculitis. This report seeks to establish a common understanding of the term, retinal vasculitis, and to review recent studies on this diagnosis. RECENT FINDINGS: The genetic basis of some rare forms of retinal vascular disease has recently been described. Identified genes include CAPN5, TREX1, and TNFAIP3; Behcet's disease is a systemic illness that is very commonly associated with occlusive retinal vasculitis; retinal imaging, including fluorescein angiography and other newer imaging modalities, has proven crucial to the identification and characterization of retinal vasculitis and its complications; although monoclonal antibodies to interleukin-17A or interleukin-1 beta failed in trials for Behcet's disease, antibodies to TNF-alpha, either infliximab or adalimumab, have demonstrated consistent benefit in managing this disease. Interferon treatment and B-cell depletion therapy via rituximab may be beneficial in certain types of retinal vasculitis. SUMMARY: Retinal vasculitis is an important entity for rheumatologists to understand. Retinal vasculitis associated with Behcet's disease responds to monoclonal antibodies that neutralize TNF, but the many other forms of noninfectious retinal vasculitis may require alternate therapeutic management. PMID- 26945336 TI - Introduction: the future of rheumatoid arthritis management. PMID- 26945337 TI - Immunohistochemistry for 2-Succinocysteine (2SC) and Fumarate Hydratase (FH) in Cutaneous Leiomyomas May Aid in Identification of Patients With HLRCC (Hereditary Leiomyomatosis and Renal Cell Carcinoma Syndrome). AB - Hereditary leiomyomatosis and renal cell carcinoma syndrome (HLRCC) is caused by germline mutations in the fumarate hydratase (FH) gene and predisposes to cutaneous and uterine leiomyomas and renal cell carcinoma (RCC). HLRCC-associated renal tumors are clinically aggressive, and patients would benefit from surveillance and early detection. Cutaneous leiomyomas that occur in association with HLRCC typically present early and are multiple. Thus far, the presence of certain morphologic features (large eosinophilic macronucleoli surrounded by halos and eosinophilic cytoplasmic inclusions) in RCC and uterine leiomyomas has been shown to correlate with FH mutations. Immunohistochemistry (IHC) for 2 succinocysteine (2SC) and FH has also been shown to correlate well with FH gene mutation status in RCC and uterine leiomyomas. The aim of this study was to assess the effectiveness of morphologic features and IHC at predicting FH gene mutations in cutaneous leiomyomas. We identified 22 patients with multiple cutaneous leiomyomas (40 total MCLs) and 25 patients with single leiomyomas (25 SCLs). Mutations in the FH gene were detected in 11 of 13 (85%) sequenced MCLs and 1 of 11 (9%) SCLs. A strong association was observed between 2SC positivity by IHC and presence of FH gene mutation (P=0.0028 for 2SC) but not with FH loss by IHC (P=0.4 for FH). All 11 MCLs with an FH mutation showed positive staining for 2SC, whereas 6 of 11 showed complete loss of FH staining. Our study suggests that the presence of MCLs should raise the possibility of HLRCC. IHC for FH and 2SC is helpful in detection of FH gene mutations and should be considered in all newly diagnosed cutaneous leiomyomas. PMID- 26945338 TI - Anastomosing Hemangiomas Arising in Unusual Locations: A Clinicopathologic Study of 17 Soft Tissue Cases Showing a Predilection for the Paraspinal Region. AB - Anastomosing hemangioma, a recently recognized benign vascular neoplasm originally described in the kidney, may be confused with well-differentiated angiosarcoma. Rare cases of anastomosing hemangiomas have been described in the liver and in nonrenal genitourinary sites. We report a series of 17 anastomosing hemangiomas occurring in unusual locations, in particular in the paravertebral soft tissues. The 17 tumors occurred in 10 male and 6 female patients, ranging in age from 2 to 85 years. One patient had bilateral, synchronous tumors involving the right paracaval and left para-aortic soft tissues. Thirteen (76%) cases involved the soft tissues near the vertebral column, including the paravertebral region (n=4), the psoas muscle (n=2), the costovertebral angle (n=2), para-aortic soft tissue (n=2), and the paracaval, parasacral, and retroperitoneal soft tissues (n=1 each). Other locations included the anterior mediastinum, uterine cornu, infundibular pelvic ligament, and upper arm (n=1 each). Imaging studies, available in 13 cases, were not felt to be diagnostic of a hemangioma. The tumors ranged from 1.5 to 7.5 cm (median, 3.6 cm) in size and were grossly well demarcated. All cases showed typical morphologic features of anastomosing hemangiomas, including a nonlobular architecture, an anastomosing proliferation of capillary-sized vessels with mild endothelial cell nuclear variability, scattered hobnailed endothelial cells, and small fibrin thrombi. Mitotic activity was rare or absent. Adipocytic metaplasia and extramedullary hematopoiesis were present in subsets of cases. When performed, immunohistochemical studies showed expression of endothelial markers (eg, CD31, CD34). In only 1 case did the submitting pathologist favor a diagnosis of anastomosing hemangioma; 4 cases were submitted specifically to exclude a well-differentiated angiosarcoma. Clinical follow-up available in 13 cases has not revealed any local recurrences or metastases. This series, the first formal description of anastomosing hemangiomas involving soft tissue locations, shows these tumors to have a notable predilection for the paraspinal region. The diagnosis of soft tissue anastomosing hemangioma may be challenging, as imaging studies do not show classical features of hemangioma and as these tumors may be sampled with limited needle biopsies. Awareness of this entity, and appreciation that they may occur in nongenitourinary sites, should allow its confident distinction from potentially more aggressive lesions, in particular angiosarcoma. PMID- 26945339 TI - Incidental and Isolated Follicular Lymphoma In Situ and Mantle Cell Lymphoma In Situ Lack Clinical Significance. AB - Follicular lymphoma in situ (FLIS) and mantle cell lymphoma in situ (MCLIS) are histopathologic findings of undetermined clinical significance. We studied a series of 341 consecutive lymph node resection specimens from patients diagnosed with colorectal (201 cases) and breast (140 cases) adenocarcinoma between 1998 and 2000. Incidental and isolated FLIS was identified in 11/341 patients (3.23%), whereas incidental and isolated MCLIS was found in 2/341 patients (0.59%). None of these cases developed overt lymphoma. A second series of 17 cases of FLIS (16 cases) and MCLIS (1 case) from consultation files was analyzed. Five cases with incidental and isolated FLIS were identified. None of these cases developed overt lymphoma. Overall, none of the 16 cases with incidental and isolated FLIS in both series developed overt FL after a median follow-up of 54 months (range, 7 to 187 mo). However, 12 of these cases with a clinical suspicion of lymphoproliferative disorder showed the association (in different lymph nodes) or combination (in the same sample) of FLIS or MCLIS with other lymphoid neoplasms (FL, splenic marginal zone lymphoma, nodal marginal zone lymphoma, Hodgkin lymphoma, diffuse large B cell lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma, multiple myeloma). In conclusion, the clinical relevance of FLIS and MCLIS seems to strictly depend on the clinical context. Incidental FLIS or MCLIS seem to have a very low risk for transformation, which recommends careful clinical examination after histopathologic diagnosis and conservative management with follow-up for a limited period of time. PMID- 26945340 TI - Recurrent BCOR Internal Tandem Duplication and YWHAE-NUTM2B Fusions in Soft Tissue Undifferentiated Round Cell Sarcoma of Infancy: Overlapping Genetic Features With Clear Cell Sarcoma of Kidney. AB - Soft tissue undifferentiated round cell sarcoma (URCS) occurring in infants is a heterogenous group of tumors, often lacking known genetic abnormalities. On the basis of a t(10;17;14) karyotype in a pelvic URCS of a 4-month-old boy showing similar breakpoints with clear cell sarcoma of kidney (CCSK), we have investigated the possibility of shared genetic abnormalities in CCSK and soft tissue URCS. Most CCSKs are characterized by BCOR exon 16 internal tandem duplications (ITDs), whereas a smaller subset shows YWHAE-NUTM2B/E fusions. Because of overlapping clinicopathologic features, we have also investigated these genetic alterations in the so-called primitive myxoid mesenchymal tumor of infancy (PMMTI). Among the 22 infantile URCSs and 7 PMMTIs selected, RNA sequencing was performed in 5 and 2 cases, with frozen tissue, respectively. The remaining cases with archival material were tested for YWHAE-NUTM2B/E by fluorescence in situ hybridization (FISH) or reverse transcription-polymerase chain reaction (RT-PCR), and BCOR ITD by PCR. A control group of 4 CCSKs and 14 URCSs in older children or adults without known gene fusion and 20 other sarcomas with similar histomorphology or age at presentation were also tested. A YWHAE NUTM2B fusion was confirmed in the index case by FISH and RT-PCR, whereas BCOR ITD was lacking. An identical YWHAE-NUTM2B fusion was found in another URCS case of a 5-month-old girl with a back lesion. The remaining cases and control group lacked YWHAE gene rearrangements; instead, consistent BCOR ITDs, similar to CCSK, were found in 15/29 (52%) infantile sarcoma cases (9/22 infantile URCS and 6/7 PMMTI). In the control cohort, BCOR ITD was found only in 3 CCSK cases but not in the other sarcomas. Histologically, URCS with both genotypes and PMMTI shared significant histologic overlap, with uniform small blue round cells with fine chromatin and indistinct nucleoli. A prominent capillary network similar to CCSK, rosette structures, and varying degree of myxoid change were occasionally seen. BCOR ITD-positive tumors occurred preferentially in the somatic soft tissue of the trunk, abdomen, and head and neck, sparing the extremities. RNAseq showed high BCOR mRNA levels in BCOR ITD-positive cases, compared with other URCSs. In summary, we report recurrent BCOR exon 16 ITD and YWHAE-NUTM2B fusions in half of infantile soft tissue URCS and most PMMTI cases, but not in other pediatric sarcomas. These findings suggest a significant overlap between infantile URCS and CCSK, such as age at presentation, histologic features, and genetic signature, thus raising the possibility of a soft tissue counterpart to CCSK. PMID- 26945341 TI - Neuroendocrine Carcinoma of the Endometrium: A Clinicopathologic Study of 25 Cases. AB - Neuroendocrine carcinoma (NECa) of the endometrium is an uncommon tumor. In this study, we present the clinicopathologic features of 25 such cases. The patients ranged in age from 37 to 87 years (median, 57 y) and most commonly presented with vaginal bleeding. The tumors were either pure NECa (10) or mixed with other histotypes (15), most commonly endometrioid carcinoma. The NECas were large cell type (15), small cell type (4), or a mixture of both (6). NECa was underrecognized in 89% of referral/consultation cases. All tumors were positive for >=1 neuroendocrine marker (chromogranin, synaptophysin, CD56). Additional immunohistochemical (IHC) studies were obtained in 18 cases, with positive results as follows: keratin cocktail (17), diffuse p16 (6), PAX-8 (6), CD117 (6), and TTF-1 (1). Mismatch-repair protein expression by IHC was abnormal in 8 of 18 cases (6 MLH1/PMS2 loss; 1 MSH2/MSH6 loss; 1 MSH6 loss). According to FIGO staging, cases were distributed as follows: I (6), II (2), III (10), and IV (7). All patients underwent surgical treatment, and 20 patients received adjuvant therapy. Twelve patients died of disease (mean survival 12.3 mo). Eleven patients were alive 5 to 134 months after diagnosis, including 7 who achieved a 5-year survival (3 stage I; 4 stage III). In summary, most of our endometrial NECas were large cell type, mixed with other histotypes, and underrecognized. These tumors tend to be PAX-8 negative and may be associated with microsatellite instability. The recognition of NECa may have an impact on the treatment of the patients affected by this disease. Although NECa usually has an aggressive behavior, 28% of our patients survived at least 5 years. PMID- 26945342 TI - Diagnostic criteria for cancer cachexia: data versus dogma. AB - PURPOSE OF REVIEW: Cachexia limits cancer therapy, quality of life, and survival of patients with cancer. Challenges identifying and diagnosing cachexia are due to disparities in diagnostic criteria. A framework for classification of cancer cachexia was recently defined by international consensus. This review describes recent efforts to use this framework to develop definitive diagnostic criteria for cancer cachexia. RECENT FINDINGS: The principle proposed in the cancer cachexia framework for development of diagnostic criteria is that 'definitive cutoffs for variables could be determined from large contemporary datasets by determining the values that relate optimally to meaningful patient-centered outcomes.' Clearly defined statistical methods to examine distributions of diagnostic criteria in relation to an outcome are used to achieve this task. As a first step, a dataset of more than 11 000 cancer patients from Europe and Canada was compiled, and used to develop and validate a new grading system for cancer associated weight loss, based on a risk stratification with survival as the outcome. The next refinements for diagnostic criteria will be enabled by the emergence of rich datasets including key variables further specifying the nature of cachexia such as skeletal muscle depletion, reduced food intake, and inflammation. SUMMARY: Development of diagnostic criteria for cancer cachexia is based on a solid conceptual foundation and is moving toward defining the type of assessments, optimal values, and combinations of criteria that best define cachexia. Large contemporary datasets representing different cancer populations, candidate cachexia diagnostic criteria, and clinical outcomes will further ensure developmental and validation efforts. PMID- 26945344 TI - Pediatric isthmic spondylolisthesis showing radiologic evidence of slippage after physis injury. AB - The pathogenesis of slippage in pediatric spondylolisthesis is still unclear, although epiphyseal injury may account for many cases based on preclinical studies. However, no reports have described a pediatric case of isthmic spondylolisthesis showing radiologic evidence of epiphyseal injury. We report such evidence in a 13-year-old boy with low-back pain. Radiography revealed rounding of the S1 surface, a fracture line below the S1 endplate surface, and a bone marrow lesion in addition to slippage. Slippage and the rounding deformity were partially reversed (from 20 to 14% and from 42 to 27%, respectively) with conservative treatment and natural bone remodeling. PMID- 26945343 TI - Elevation and persistence of CD8 T-cells in HIV infection: the Achilles heel in the ART era. AB - INTRODUCTION: HIV infection leads to a disturbed T-cell homeostasis, featured by a depletion of CD4 T-cells and a persistent elevation of CD8 T-cells over disease progression. Most effort of managing HIV infection has been focused on CD4 T-cell recovery, while changes in the CD8 compartment were relatively underappreciated in the past. METHODS: A comprehensive literature review of publications in English language was conducted using major electronic databases. Our search was focused on factors contributing to CD8 T-cell dynamics in HIV infection and following antiretroviral therapy (ART). DISCUSSION: Normalization of CD8 counts is seldom observed even with optimal CD4 recovery following long-term treatment. Initiation of ART in primary HIV infection leads to enhanced normalization of CD8 count compared with long-term ART initiated in chronic infection. Importantly, such CD8 elevation in treated HIV infection is associated with an increased risk of inflammatory non-AIDS-related clinical events independent of CD4 T-cell recovery. The mechanisms underlying CD8 persistence remain largely unknown, which may include bystander activation, exhaustion and immunosenescence of CD8 T-cells. The information provided herein will lead to a better understanding of factors associated with CD8 persistence and contribute to the development of strategies aiming at CD8 normalization. CONCLUSIONS: Persistence of CD8 T-cell elevation in treated HIV-infected patients is associated with an increased risk of non-AIDS related events. Now that advances in ART have led to decreased AIDS-related opportunistic diseases, more attention has been focused on reducing non-AIDS events and normalizing persistent CD8 T-cell elevation. PMID- 26945345 TI - Optimizing bone health in Brazilian teens: using a population-based survey to guide targeted interventions to increase dietary calcium intake. PMID- 26945346 TI - Inactivation of Microcystis aeruginosa by hydrogen-terminated porous Si wafer: Performance and mechanisms. AB - We proposed a method to inactivate Microcystis aeruginosa by using hydrogen terminated porous Si (H-PSi) wafer. The influences of oxidation time on the removal of M. aeruginosa were investigated. Samples oxidized by H-PSi wafer were subsequently grown under illuminated culture conditions. The results demonstrated that the optimal oxidation time was about 1h, which could control the growth of M. aeruginosa about 65%, after 3days culture. Simultaneously, extracellular microcystins was decreased from 14.65 to 7.06MUgL(-1) and remain relative integrity of M. aeruginosa cells which could avoid secretion of large amounts of organic material. Multiple analysis techniques including fluorescence excitation emission matrix (EEM) and fluorescence microscope were used to reveal the inhibition mechanisms of M. aeruginosa. Meanwhile, analyses of reactive oxygen level, malondialdehyde content, and superoxide dismutase activity indicated that the damage and inactivate of M. aeruginosa cells are mainly due to accumulation of lipid peroxidation and inhibition of normal physiological metabolism by free radicals produced by H-PSi wafer under visible light irradiation. In conclusion, these results suggest that H-PSi wafer may be useful in controlling growth and survival of M. aeruginosa in many large lakes and reservoirs, thus mitigating many of the economic, esthetic ecological impacts of the invasive alga. PMID- 26945347 TI - Depressive and Anxiety Symptoms Predict Sustained Quality of Life Deficits in HIV Positive Ugandan Adults Despite Antiretroviral Therapy: A Prospective Cohort Study. AB - The impact of psychosocial status at onset of antiretroviral therapy on changes in quality of life (QOL) and subjectively rated health (SRH) among adults on highly active antiretroviral therapy (HAART) in resource-limited settings is poorly understood. Therefore, we evaluate the association between stigma, anxiety, depression, and social support and change in QOL and SRH in HIV-infected Ugandan adults during an 18-month period. Psychosocial indicators were assessed at enrollment using structured questionnaires. QOL and SRH measures were assessed at months 0, 6, 12, and 18 using the Medical Outcomes Survey-HIV. Linear mixed models determined risk estimated differences in QOL and SRH in relation to quartiles of each psychosocial status indicator. Repeated measures generalized estimating equations modeling was implemented to assess differences in likelihood of improved versus nonimproved SRH during follow-up.QOL scores and SRH improved significantly for all participants over 18 months (P < 0.0001). The gain in QOL increased dose-dependently as baseline depressive symptoms (time*depression P < 0.001) and anxiety levels (time*anxiety P < 0.001) declined. Lower social support was associated with worse QOL at baseline (P = 0.0005) but QOL improvement during follow-up was not dependent on baseline level of social support (time*social support P = 0.8943) or number of stigmatizing experiences (time*stigma P = 0.8662). Psychosocial determinants did not predict changes in SRH in this study. High levels of depression and anxiety symptoms at HAART initiation predicts lower gains in QOL for HIV-positive patients for as long as 18 months. Long-term QOL improvements in HIV-infected adults may be enhanced by implementation of psychosocial interventions to reduce depression and anxiety in HIV-infected adults. PMID- 26945348 TI - Correlation of Preoperative Renal Insufficiency With Mortality and Morbidity After Aortic Valve Replacement: A Propensity Score Matching Analysis. AB - Preoperative end-stage renal disease carries a high mortality and morbidity risk after aortic valve replacement (AVR), but the effect of renal insufficiency remains to be clarified. Through propensity score analysis, we compared the preoperative demographics, perioperative profiles, and outcomes between patients with and without renal insufficiency. From August 2005 to November 2014, 770 adult patients underwent AVR in a single institution. Patients were classified according to their estimated glomerular infiltration rate (eGFR) as renal insufficiency (eGFR: 30-89 mL/min/1.73 m) or normal (eGFR, >=90 mL/min/1.73 m). Propensity scoring was performed with a 1:1 ratio, resulting in a matched cohort of 88 patients per group. Demographics, comorbidities, and surgical procedures were well balanced between the 2 groups, except for diabetes mellitus and eGFR. Patients with renal insufficiency had higher in-hospital mortality (19.3% versus 3.4%, P < 0.001), a greater need for postoperative hemodialysis (14.8% versus 3.1%, P = 0.009), and prolonged intubation times (>72 hour; 25% versus 9.1%, P = .008), intensive care unit stays (8.9 +/- 9.9 versus 4.9 +/- 7.5 days, P = .046), and hospital stays (35.3 +/- 31.7 versus 24.1 +/- 20.3 days, P = .008), compared with those with normal renal function. Multivariate analysis confirmed that preoperative renal insufficiency was an in-hospital mortality predictor (odds ratio, 2.33; 95% confidence interval, 1.343-4.043; P = .003), as were prolonged cardiopulmonary bypass time, intraaortic balloon pump support, and postoperative hemodialysis. The 1-year survival significantly differed between the 2 groups including (normal 87.5% versus renal insufficiency 67.9%, P < .001) or excluding in-hospital mortality (normal 90.7% versus renal insufficiency 82.1%, P = .05). Patients with preoperative renal insufficiency who underwent AVR had higher in hospital mortality rates and increased morbidities, especially those associated with hemodynamic instabilities requiring intraaortic balloon pump support or hemodialysis. Earlier surgical intervention for severe aortic valve disease should be considered in patients who show deteriorating renal function during follow-up. PMID- 26945349 TI - Isocitrate Dehydrogenase (IDH)1/2 Mutations as Prognostic Markers in Patients With Glioblastomas. AB - The purpose of this study was to perform a meta-analysis examining the association of isocitrate dehydrogenase (IDH)1/2 mutations with overall survival (OS) and progression-free survival (PFS) in patients with glioblastomas. Medline, Cochrane, EMBASE, and Google Scholar were searched from inception to January 28, 2015, using combinations of the following keywords: IDH mutation, brain tumor, glioma, glioblastoma, oligodendroglioma, prognosis. Randomized controlled trials, and prospective and retrospective studies of patients with glioblastomas that provided IDH mutation and survival data were included. OS and PFS were used to evaluate the association of IDH1 and IDH1/2 mutations and prognosis. Hazard ratios (HRs) with corresponding 95% confidence intervals (CIs) for OS and PFS were calculated and compared between patients with and without mutations. Of 165 studies that were identified, 136 nonrelevant studies were excluded. Twenty-nine full-text articles were assessed, and of these, 5 were excluded as they did not provide a quantitative outcome. Therefore, 24 studies were included in the qualitative synthesis. The pooled HR of 0.358 (95% CI 0.264-0.487, P < 0.001) indicated that IDH mutations were associated with better OS. Similarly, the pooled HR of 0.322 (95% CI 0.24200.455, P < 0.001) indicated that IDH mutations were associated with better PFS. When patients were stratified by surgery versus no surgery or IDH1 versus IDH1/2 mutations, the results also indicated that the presence of IDH mutations was associated with better OS and PFS. The IDH mutations are associated with improved survival in patients with glioblastomas. PMID- 26945350 TI - Preoperative Volume-Based PET Parameter, MTV2.5, as a Potential Surrogate Marker for Tumor Biology and Recurrence in Resected Pancreatic Cancer. AB - This study aims to evaluate the role of volume-based positron emission tomography parameters as potential surrogate markers for tumor recurrence in resected pancreatic cancer. Between January 2008 and October 2012, medical records of patients who underwent surgical resection for pancreatic ductal adenocarcinoma and completed 18F-fluorodeoxyglucose positron emission tomography/CT as a part of preoperative staging work-up were retrospectively reviewed. Not only clinicopathologic variables but also positron emission tomography parameters such as SUVmax, MTV2.5 (metabolic tumor volume), and TLG (total lesion glycolysis) were obtained. Twenty-six patients were women and 31 were men with a mean age of 62.9 +/- 9.1 years. All patients were preoperatively determined to resectable pancreatic cancer except 1 case with borderline resectability. R0 resection was achieved in all patients and 45 patients (78.9%) received postoperative adjuvant chemotherapy with or without radiation therapy. Median overall disease-free survival was 12.8 months with a median overall disease-specific survival of 25.1 months. SUVmax did not correlate with radiologic tumor size (P = 0.501); however, MTV2.5 (P = 0.001) and TLG (P = 0.009) were significantly associated with radiologic tumor size. In addition, MTV2.5 (P < 0.001) and TLG (P < 0.001) were significantly correlated with a tumor differentiation. There were no significant differences in TLG and SUVmax according to lymph node ratio; only MTV2.5 was related to lymph node ratio with marginal significance (P = 0.055). In multivariate analysis, lymph node ratio (Exp [beta] = 2.425, P = 0.025) and MTV2.5 (Exp[beta] = 2.273, P = 0.034) were identified as independent predictors of tumor recurrence following margin-negative resection. Even after tumor size matched analysis, MTV2.5 was still identified as significant prognostic factor in resected pancreatic cancer (P < 0.05). However, preoperative neoadjuvant treatment attenuated adverse oncologic impact of high preoperative MTV2.5 (P = 0.210). Preoperatively determined volume-based PET parameter, MTV2.5, can potentially be used as a surrogate marker to estimate tumor biology and tumor recurrence. Individual treatment strategies for pancreatic cancer can be suggested based on patients' preoperative MTV2.5. PMID- 26945351 TI - Stressful Life Events as a Predictor for Nonsuicidal Self-Injury in Southern Chinese Adolescence: A Cross-Sectional Study. AB - Stressful life events have been implicated in the etiology of kinds of psychopathology related to nonsuicidal self-injury (NSSI); however, few studies have examined the association between NSSI and stressful life events directly in Chinese school adolescents. In this study, we aim to estimate the prevalence rate of NSSI and examine its association with stressful life events in Southern Chinese adolescents. A total sample of 4405 students with age ranged from 10 to 22 years was randomly selected from 12 schools in 3 cities of Guangdong Province, China. NSSI, stressful life events, self-esteem, emotional management, and coping methods were measured by structured questionnaires. Multinomial logistic regression was used to examine the association of NSSI with stressful life events. Results showed the 1 year self-reported NSSI was 29.2%, with 22.6% engaged in "minor" NSSI (including hitting self, pulling hair, biting self, inserting objects under nails or skin, picking at a wound) and 6.6% in "moderate/sever" NSSI (including cutting/carving, burning, self-tattooing, scraping, and erasing skin). Self-hitting (15.9%), pulling hair out (10.9%), and self-inserting objects under nails or skin picking areas to dram blood (18.3%) were the most frequent types of NSSI among adolescents. Results also showed that "Minor NSSI" was associated with stressful life events on interpersonal, loss and health adaption, and "moderate/severe NSSI" was associated with life events on interpersonal, health adaption in Southern Chinese adolescents, even after adjusted for sex, age, residence, self-esteem, coping style, and emotional management. Results further suggested stressful life events were significantly associated with less risk of NSSI in those who had good emotional management ability. PMID- 26945352 TI - Adverse Effects of Oral Nonselective and cyclooxygenase-2-Selective NSAIDs on Hospitalization for Acute Kidney Injury: A Nested Case-Control Cohort Study. AB - To investigate the association between the use of nonselective or cyclooxygenase (COX)-2-selective nonsteroidal antiinflammatory drugs (NSAIDs) and risk of acute kidney injury (AKI) in a general Asian population. We conducted an observational, nationwide, nested case-control cohort study using Taiwan's National Health Insurance Research Database between 2010 and 2012. AKI cases were defined as hospitalization with a principle diagnosis of AKI. Each case was matched to 4 randomly selected controls based on age, sex, and the month and year of cohort entry. Odds ratios (ORs) were used to demonstrate the association between hospitalization for AKI and current, recent, or past use of an oral NSAID. During the study period, we identified 6199 patients with AKI and 24,796 matched controls. Overall, current users (adjusted OR 2.73, 95% confidence interval [CI] 2.28-3.28) and recent users (adjusted OR 1.17, 95% CI 1.01-1.35) were associated with increased risk of hospitalization for AKI. The risk was also similar for nonselective NSAIDs. However, neither current nor recent use of COX-2 inhibitors was significantly associated with AKI events. Our study supported that the initiation of nonselective NSAIDs rather than COX-2 inhibitors is associated with an increased risk of AKI requiring hospitalization. Future randomized trials are needed to elucidate these findings. PMID- 26945353 TI - Perioperative Ventilatory Management in Cardiac Surgery: A French Nationwide Survey. AB - Protective ventilation is associated with a lower incidence of pulmonary complications. However, there are few published data on routine pulmonary management in adult cardiac surgery. The present study's primary objective was to survey pulmonary management in this high-risk population, as practiced by anesthesiologists in France. All 460 registered France-based cardiac anesthesiologists were invited (by e-mail) to participate in an online survey in January-February 2015. The survey's questionnaire was designed to assess current practice in pre-, per-, and postoperative pulmonary management. In all, 198 anesthesiologists (43% of those invited) participated in the survey. Other than during the cardiopulmonary bypass (CPB) per se, 179 anesthesiologists (91% of respondees) [95% confidence interval (CI): 87-95] used a low-tidal-volume approach (6-8 mL/kg), whereas techniques based on positive end-expiratory pressure and recruitment maneuvers vary greatly from 1 anesthesiologist to another. During CPB, 104 (53%) [95% CI: 46-60] anesthesiologists withdrew mechanical ventilation (with disconnection, in some cases) and 97 (49%) [95% CI: 42-56] did not prescribe positive end-expiratory pressure. One hundred sixty-five (83%) [95% CI: 78-88] anesthesiologists stated that a written protocol for peroperative pulmonary management was not available. Twenty (10%) [95% CI: 6-14] and 11 (5%) [95% CI: 2-8] anesthesiologists stated that they did use protocols for ventilator use and recruitment maneuvers, respectively. The preoperative period (pulmonary examinations and prescription of additional assessments) and the postoperative period (extubation, and noninvasive ventilation) periods vary greatly from 1 anesthesiologist to another. The great majority of French cardiac anesthesiologists use a low tidal volume during cardiac surgery (other than during CPB per se). However, pulmonary management procedures varied markedly from 1 anesthesiologist to another. There is a clear need for large clinical studies designed to identify best practice in pulmonary management. PMID- 26945354 TI - Unidimensional Measurement May Evaluate Target Lymph Nodal Response After Induction Chemotherapy for Nasopharyngeal Carcinoma. AB - The aim of the study was to evaluate whether short axis and long axis on axial and coronal magnetic resonance imaging planes would reflect the tumor burden or alteration in size after induction chemotherapy in nasopharyngeal carcinoma. Patients with pathologically confirmed nasopharyngeal carcinoma (n = 37) with at least 1 positive cervical lymph node (axial short axis >=15 mm) were consecutively enrolled in this prospective study. Lymph nodal measurements were performed along its short axis and long axis in both axial and coronal magnetic resonance imaging planes at diagnosis and after 2 cycles of induction chemotherapy. In addition, lymph nodal volumes were automatically calculated in 3D treatment-planning system, which were used as reference standard. Student's t test or nonparametric Mann-Whitney U test was used to compare the continuous quantitative variables. Meanwhile, the kappa statistic and McNemar's test were used to evaluate the degree of agreement and discordance in response categorization among different measurements. Axial short axis was significantly associated with volumes at diagnosis (P < 0.001). A good agreement (kappa=0.583) was found between axial short axis and volumetric criteria. However, the inconsistent lymph nodal shrinkage in 4 directions was observed. Axial short-axis shrinking was more rapid than the other 3 parameters. Interestingly, when utilizing the alternative planes for unidimensional measurements to assess tumor response, coronal short-axis showed the best concordance (kappa=0.792) to the volumes. Axial short axis may effectively reflect tumor burden or change in tumor size in the assessment of target lymph nodal response after induction chemotherapy for nasopharyngeal carcinoma. However, it should be noted that axial short axis may amplify the therapeutic response. In addition, the role of coronal short axis in the assessment of tumor response needs further evaluation. PMID- 26945355 TI - Increased Expression of CSF-1 Associates With Poor Prognosis of Patients With Gastric Cancer Undergoing Gastrectomy. AB - Clinical significance of diametrically polarized tumor-associated macrophages in gastric cancer has been elucidated in our previous study, whereas the role of cytokines that orchestrate tumor-associated macrophages polarization in gastric cancer remains elusive. The study aims to evaluate the prognostic value of colony stimulating factor-1 expression in patients with gastric cancer. We examined the colony-stimulating factor-1 expression in tumor tissues by immunohistochemical staining in retrospectively enrolled 365 patients with gastric cancer undergoing gastrectomy at Zhongshan Hospital during 2008. Kaplan-Meier analysis and Cox regression models were used to evaluate the prognostic value of colony stimulating factor-1 expression and its association with clinicopathological factors. A predictive nomogram by integrating colony-stimulating factor-1 expression with the TNM staging system was generated for overall survival evaluation of the patients. High colony-stimulating factor-1 expression predicted an unfavorable outcome in gastric cancer. The colony-stimulating factor-1 expression in tumor tissue could give a further discrimination for the prognosis of gastric cancer patients. Cox multivariate analysis identified the colony stimulating factor-1 expression as an independent prognostic factor. The generated nomogram performed well in predicting the 3- and 5-year overall survival of gastric cancer patients.T he colony-stimulating factor-1 is a potential independent adverse prognosticator for gastric cancer patients, which could be integrated with the tumor-associated macrophages staging system to improve the predictive accuracy for overall survival, especially in advanced tumors. PMID- 26945356 TI - Patient-reported Outcomes in Asian Patients With Chronic Hepatitis C Treated With Ledipasvir and Sofosbuvir. AB - Prevalence of chronic hepatitis C (CH-C) infection in patients of Asian ancestry ranges between 1% and 20%. Interferon (IFN)- and ribavirin (RBV)-containing regimens for CH-C have a negative impact on patient-reported outcomes (PROs) during treatment. The aim of this study was to assess the impact of IFN-free RBV free sofosbuvir (SOF)-based regimens on PROs in CH-C patients of Asian ancestry. In this observational retrospective study, the PRO data from 12 multicenter multinational phase 3 clinical trials (2012-2015, conducted in Europe, North America, Australia, and New Zealand) of SOF-based regimens with and without IFN, ledipasvir (LDV), and/or RBV were used. At baseline, during treatment, and post treatment, patients completed 4 validated PRO questionnaires (SF-36, CLDQ-HCV, FACIT-F, and WPAI:SHP). The resulting PROs in Asian patients were compared across the treatment regimens. Of 4485 of the trials' participants, 106 patients were of Asian ancestry (55.7% male, 69.8% treatment-naive, 17.0% cirrhotic). In comparison with other patients, the Asian CH-C cohort was younger, had lower BMI, and lower rates of pre-treatment psychiatric comorbidities (anxiety, depression, sleep disorders) (all P < .05). At baseline, Asian patients also had lower SF-36 physical functioning scores (on average, by -5.6% on a normalized 0-100% PRO scale, P = .001). During treatment, Asian CH-C patients experienced a decline in their PRO scores while receiving IFN and/or RBV-containing regimens (up to 19.6%, P < .001). In contrast, patients receiving LDV/SOF experienced no PRO decrement and improvement of some PRO scores during treatment (+9.0% in general health of SF-36, P = .03). After achieving SVR-12, some of the PRO scores in Asian patients improved regardless of the regimen (up to +9.3%, P < .001). In multivariate analysis of Asian patients, the use of LDV/SOF was independently associated with higher PRO scores during and soon after the end of treatment (betas +15.0% to +29.3%, all P < .05). Other predictors of PRO impairment included depression, type 2 diabetes mellitus, and cirrhosis. The use of IFN- and RBV-free LDV/SOF regimens leads to PRO improvement in Asian patients with CH-C during treatment. Achieving SVR-12 results in improvement of PRO scores. PMID- 26945357 TI - Three-Dimensional Quantitative Evaluation of the Segmental Functional Reserve in the Cirrhotic Liver Using Multi-Modality Imaging. AB - To quantitatively evaluate the regional functional reserve in the cirrhotic liver and to seek related index that reflects diminished segmental liver function. A 3D system for quantitative evaluation of the liver was used to fuse technetium-99m galactosyl human serum albumin single-photon emission computed tomography and computed tomography images from 20 patients with cirrhotic liver and hepatocellular carcinoma. A set of parameters reflecting liver function including morphological liver volume, functional liver volume, functional liver density (FLD), and the drug absorption rate constant for hepatic cells (GSA-K) was calculated. Differences in FLD and GSA-K in intrahepatic segments were compared in patients with a tumor embolus (Group Y) and those without such an embolus (Group N) in the right portal vein. Differences in FLD and GSA-K in tumor-bearing (T+ group) and tumor-free (T- group) segments in patients with no tumor embolus (Group N) were also compared. Eleven living donor liver transplantation donor served as the control group. The FLD of the liver as a whole was significantly lower in patients with cirrhosis than in the control group (0.53 +/- 0.13 vs 0.68 +/- 0.10, P = 0.010). The FLD in segments of the right hemiliver was significantly lower than that in segments of the left hemiliver in Group Y (0.31 +/- 0.21 vs 0.58 +/- 0.12, P = 0.002) but not in Group N (0.60 +/- 0.19 vs 0.55 +/- 0.13, P = 0.294). FLD was 0.45 +/- 0.17 in the T+ group and 0.60 +/- 0.08 in the T- group (P = 0.008). Differences in GSA-K in intrahepatic segments were not significant. In the control group, differences in FLD and GSA-K in intrahepatic segments were not significant. The segmental liver functional reserve can be quantitatively calculated. FLD, but not GSA-K, is an index that reflects diminished regional liver function caused by portal flow obstruction or tumor compression. PMID- 26945358 TI - Impact of Albumin on Coagulation Competence and Hemorrhage During Major Surgery: A Randomized Controlled Trial. AB - For patients exposed to a massive blood loss during surgery, maintained coagulation competence is important. It is less obvious whether coagulation competence influences bleeding during elective surgery where patients are exposed to infusion of a crystalloid or a colloid. This randomized controlled trial evaluates whether administration of 5% human albumin (HA) or lactated Ringer solution (LR) affects coagulation competence and in turn blood loss during cystectomy due to bladder cancer. Forty patients undergoing radical cystectomy were included to receive either 5% HA (n = 20) or LR (n = 20). Nineteen patients were analyzed in the HA group and 20 patients in the lactated Ringer group. Blinded determination of the blood loss was similar in the 2 groups of patients: 1658 (800-3300) mL with the use of HA and 1472 (700-4330) mL in the lactated Ringer group (P = 0.45). Yet, by thrombelastography (TEG) evaluated coagulation competence, albumin affected clot growth (TEG-angle 69 +/- 5 vs 74 degrees +/- 3 degrees , P < 0.01) and strength (TEG-MA: 59 +/- 6 vs 67 +/- 6 mm, P < 0.001) more than LR. Furthermore, by multivariate linear regression analyses reduced TEG MA was independently associated with the blood loss (P = 0.042) while administration of albumin was related to the changes in TEG-MA (P = 0.029), aPPT (P < 0.022), and INR (P < 0.033). This randomized controlled trial demonstrates that administration of HA does not affect the blood loss as compared to infusion of LR. Also the use of HA did not affect the need for blood transfusion, the incidence of postoperative complications, or the hospital in-stay. Yet, albumin decreases coagulation competence during major surgery and the blood loss is related to TEG-MA rather than to plasma coagulation variables. PMID- 26945359 TI - A Comprehensive Meta-Analysis of MicroRNAs for Predicting Colorectal Cancer. AB - Colorectal cancer (CRC) has been defined as a common malignancy due to its prevailing incidence in both males and females. Recently, the intrinsic value of microRNAs (miRNAs) with respect to early cancer diagnosis has been contentious as the diagnostic accuracy of miRNAs significantly varied across different studies. As a result of this, this pioneer meta-analysis was proposed to address this issue. Qualified studies were obtained through electronic systematical searching in Medline, Embase, and PubMed. On the basis of the random-effects model, we calculated the pooled sensitivity (SEN), specificity (SPE), and area under the receiver operating characteristics curve (AUC) to assess the diagnostic accuracy of miRNAs. Subgroup analysis and meta-regression were implemented to determine how different confounding factors affect the overall diagnostic accuracy which were considered important sources of heterogeneity. All the statistical analyses were conducted with R 3.2.1 software. We incorporated 103 studies from 36 articles with a total of 3124 CRC patients and 2579 healthy individuals. MiRNAs have a good performance with the following pooled estimates: SEN = 0.769 (95% CI = 0.733-0.802), SPE = 0.806 (95% CI = 0.781-0.829), AUC = 0.857, and partial AUC = 0.773. As suggested by subgroup analyses and meta-regression, multiple miRNAs appeared to be more favorable than single miRNA (AUC: 0.918 > 0.813, partial AUC: 0.848 > 0.701, sensitivity = 0.853 > 0.718, specificity = 0.860 > 0.772). Compared with samples of plasma, blood, tissue, and feces, miRNA obtained from serum samples were more powerful for detecting CRC particularly in Asian. Our study provided exclusive evidence that multiple miRNAs extracted from serum samples had superior diagnostic performance over single miRNA for screening CRC. Therefore, this approach that is characterized by high specificity and noninvasive nature may assist in early diagnosis of CRC particularly in Asian. PMID- 26945360 TI - False Appearance of Gene-Environment Interactions in Genetic Association Studies. AB - Under the assumption of gene-environment independence, unknown/unmeasured environmental factors, irrespective of what they may be, cannot confound the genetic effects. This may lead many people to believe that genetic heterogeneity across different levels of the studied environmental exposure should only mean gene-environment interaction--even though other environmental factors are not adjusted for. However, this is not true if the odds ratio is the effect measure used for quantifying genetic effects. This is because the odds ratio is a "noncollapsible" measure--a marginal odds ratio is not a weighted average of the conditional odds ratios, but instead has a tendency toward the null. In this study, the authors derive formulae for gene-environment interaction bias due to noncollapsibility. They use computer simulation and real data example to show that the bias can be substantial for common diseases. For genetic association study of nonrare diseases, researchers are advised to use collapsible measures, such as risk ratio or peril ratio. PMID- 26945361 TI - Whole Grain Intake Reduces Pancreatic Cancer Risk: A Meta-Analysis of Observational Studies. AB - Mounting evidence from epidemiology studies suggests that whole grain intake may reduce pancreatic cancer risk, but convincing evidence is scarce. We conducted a meta-analysis to assess the association between whole grain intake and pancreatic cancer risk. Relevant observational studies were identified by searching PubMed, Embase, Scopus, and Cochrane library databases for the period from January 1980 to July 2015, with no restrictions. We calculated the summary odds ratios (ORs) for pancreatic cancer using random-effects model meta-analysis. Between-study heterogeneity was analyzed using the I statistic. A total of 8 studies regarding whole grain intake were included in the meta-analysis. The pooled OR of pancreatic cancer for those with high versus low whole grain intake was 0.76 (95% confidence interval [CI], 0.64-0.91; P = 0.002). There was no significant heterogeneity across these studies (I2 = 11.7%; Pheterogeneity = 0.339). In the subgroup analysis by geographic area, the summary ORs of developing pancreatic cancer were 0.64 (95% CI, 0.53-0.79; P < 0.001; I 2= 0%; Pheterogeneity = 0.482) in the United States (n = 4) and 0.95 (95% CI, 0.63-1.43; P = 0.803; I 2= 45.6%; Pheterogeneity = 0.175) in Europe (n = 2). In the subgroup analysis by type of whole grain, the summary ORs were 0.72 (95% CI, 0.60-0.87; P = .001; I2 = 0; Pheterogeneity = 0.876) for grains (n = 4) and 0.74 (95% CI, 0.27-2.02; P = 0.554; I2 = 86.3%; Pheterogeneity = 0.007) for wheat (n = 2). A high intake of whole grains was associated with a reduced risk of pancreatic cancer. Because of the absent of more cohort studies, further prospective studies need to be conducted to ensure conclusions that are more robust. PMID- 26945362 TI - Optimizing Prophylactic Antibiotic Practice for Cardiothoracic Surgery by Pharmacists' Effects. AB - Pharmacists' role may be ideal for improving rationality of drug prescribing practice. We aimed to study the impact of multifaceted pharmacist interventions on antibiotic prophylaxis in patients undergoing clean or clean-contaminated operations in cardiothoracic department. A pre-test-post-test quasiexperimental study was conducted in a cardiothoracic ward at a tertiary teaching hospital in Suzhou, China. Patients admitted to the ward were collected as baseline group (2011.7-2012.12) and intervention group (2013.7-2014.12), respectively. The criteria of prophylaxis antibiotic utilization were established on the basis of the published guidelines and official documents. During the intervention phase, a dedicated pharmacist was assigned and multifaceted interventions were implemented in the ward. Then we compared the differences in antibiotic utilization, bacterial resistance, clinical and economic outcomes between the 2 groups. Furthermore, patients were collected after the intervention (2015.1-2015.6) to evaluate the sustained effects of pharmacist interventions. 412 and 551 patients were included in the baseline and intervention groups, while 156 patients in postintervention group, respectively. Compared with baseline group, a significant increase was found in the proportion of antibiotic prophylaxis, the proportion of rational antibiotic selection, the proportion of suitable prophylactic antibiotic duration, and the proportion of suitable timing of administration of the first preoperative dose (P < 0.001). Meanwhile, a significant reduction was seen in the rate of unnecessary replacement of antibiotics and the rate of unnecessary combinations (P < 0.001). Besides, pharmacist intervention resulted in favorable outcomes with significantly decreased rates of surgical site infections, prophylactic antibiotic cost, and significantly shortened length of stay (P < 0.05). Furthermore, there were also significant decreases of the rates of antibiotic resistant enterobacter cloacae, klebsiella pneumonia, and staphylococcus aureus (P < 0.05). Moreover, the effects were sustained after discontinuation of the active interventions, as shown in prophylactic antibiotic utilization data. Pharmacist interventions in cardiothoracic surgery result in a high adherence to evidence-based treatment guidelines and a profound culture change in drug prescribing with favorable outcomes. The effects of pharmacist intervention are sustained and the role of pharmacists is emphasized for rational medication and optimal outcomes in clinical treatment. PMID- 26945363 TI - Multiple Brain Abscesses Due to Aspergillus Fumigatus in a Patient With Liver Cirrhosis: A Case Report. AB - Invasive cerebral aspergillosis always developed in immunocompromised host. Early diagnosis may save life in this critical condition; however, it is difficult to reach. Herein, we presented an unusual case of invasive cerebral aspergillosis in a cirrhotic patient. A 47-year-old man presented with progressive deterioration of consciousness for three days. The patient had a history of alcoholic liver cirrhosis, Child-Pugh class C. Magnetic resonance imaging (MRI) of brain showed multi-focal parenchymal lesions, which was consistent with multiple brain abscesses. The diagnosis of invasive cerebral aspergillosis was made by molecular based laboratory methods including Aspergillus galactomannan antigen assay and oligonucleotide array. Despite treatment with the antifungal agent, Amphotericin B, the patient died at the ninth day of hospitalization. Our findings suggest that liver cirrhosis can be one of risk factors of invasive cerebral aspergillosis, and support the diagnosing usefulness of MRI, Aspergillus galactomannan antigen assay, and oligonucleotide array. PMID- 26945364 TI - Association Between Insulin Resistance and Luminal B Subtype Breast Cancer in Postmenopausal Women. AB - Currently, there is limited information on the clinical characteristics of breast cancer patients with insulin resistance. Hence, the purpose of this study was to investigate the association between insulin resistance and clinicopathological factors in newly diagnosed breast cancer patients without diabetes. We assessed 760 patients with breast cancer treated between 2012 and 2014. We compared the clinicopathological characteristics between patients with and without insulin resistance using univariate and multivariate analyses, including after stratification by menopausal status. Insulin resistance was defined according to the homeostatic model assessment of insulin resistance. Of 760 patients, 26.4% had insulin resistance. Age, menopausal status, body mass index, tumor size, histologic grade, Ki-67 expression, and breast cancer subtype significantly differed according to the presence of insulin resistance. Multivariate analysis revealed that postmenopausal status and obesity were significantly associated with insulin resistance. In postmenopausal women, older age, obesity, larger tumor size, advanced stage, and high proliferative luminal B subtype were significantly associated with insulin resistance. In contrast, in premenopausal patients, only obesity was related to insulin resistance. Multivariate analysis indicated that insulin resistance was independently correlated with obesity, larger tumor size, and the luminal B/human epidermal growth factor receptor-2 negative subtype in postmenopausal but not premenopausal patients. Insulin resistance was significantly associated with larger tumors and proliferative luminal B subtype breast cancer in postmenopausal women only. These findings suggest that insulin resistance could mechanistically induce tumor progression and might be a good prognostic factor, and that it could represent a therapeutic target in postmenopausal patients with breast cancer. PMID- 26945365 TI - Paradoxical Herniation After Unilateral Decompressive Craniectomy Predicts Better Patient Survival: A Retrospective Analysis of 429 Cases. AB - Paradoxical herniation (PH) is a life-threatening emergency after decompressive craniectomy. In the current study, we examined patient survival in patients who developed PH after decompressive craniectomy versus those who did not. Risk factors for, and management of, PH were also analyzed. This retrospective analysis included 429 consecutive patients receiving decompressive craniectomy during a period from January 2007 to December 2012. Mortality rate and Glasgow Outcome Scale (GOS) were compared between those who developed PH (n = 13) versus those who did not (n = 416). A stepwise multivariate logistic regression analysis was carried out to examine the risk factors for PH. The overall mortality in the entire sample was 22.8%, with a median follow-up of 6 months. Oddly enough, all 13 patients who developed PH survived beyond 6 months. Glasgow Coma Scale did not differ between the 2 groups upon admission, but GOS was significantly higher in subjects who developed PH. Both the disease type and coma degree were comparable between the 13 PH patients and the remaining 416 patients. In all PH episodes, patients responded to emergency treatments that included intravenous hydration, cerebral spinal fluid drainage discontinuation, and Trendelenburg position. A regression analysis indicated the following independent risk factors for PH: external ventriculostomy, lumbar puncture, and continuous external lumbar drainage. The rate of PH is approximately 3% after decompressive craniectomy. The most intriguing findings of the current study were the 0% mortality in those who developed PH versus 23.6% mortality in those who did not develop PH and significant difference of GOS score at 6-month follow-up between the 2 groups, suggesting that PH after decompressive craniectomy should be managed aggressively. The risk factors for PH include external ventriculostomy, ventriculoperitoneal shunt, lumbar puncture, and continuous external lumbar drainage. PMID- 26945366 TI - Risk Factors for Incident Diabetes in a Cohort Taking First-Line Nonnucleoside Reverse Transcriptase Inhibitor-Based Antiretroviral Therapy. AB - Efavirenz is the preferred nonnucleoside reverse transcriptase inhibitor (NNRTI) in first-line antiretroviral therapy (ART) regimens in low- and middle-income countries, where the prevalence of diabetes is increasing. Randomized control trials have shown mild increases in plasma glucose in participants in the efavirenz arms, but no association has been reported with overt diabetes. We explored the association between efavirenz exposure and incident diabetes in a large Southern African cohort commencing NNRTI-based first-line ART. Our cohort included HIV-infected adults starting NNRTI-based ART in a private sector HIV disease management program from January 2002 to December 2011. Incident diabetes was identified by the initiation of diabetes treatment. Patients with prevalent diabetes were excluded. We included 56,298 patients with 113,297 patient-years of follow-up (PYFU) on first-line ART. The crude incidence of diabetes was 13.24 per 1000 PYFU. Treatment with efavirenz rather than nevirapine was associated with increased risk of developing diabetes (hazard ratio 1.27 (95% confidence interval (CI): 1.10-1.46)) in a multivariate analysis adjusting for age, sex, body mass index, baseline CD4 count, viral load, NRTI backbone, and exposure to other diabetogenic medicines. Zidovudine and stavudine exposure were also associated with an increased risk of developing diabetes. We found that treatment with efavirenz, as well as stavudine and zidovudine, increased the risk of incident diabetes. Interventions to detect and prevent diabetes should be implemented in ART programs, and use of antiretrovirals with lower risk of metabolic complications should be encouraged. PMID- 26945367 TI - Soft Tissue Necrosis in Head and Neck Cancer Patients After Transoral Robotic Surgery or Wide Excision With Primary Closure Followed by Radiation Therapy. AB - Risk factors were evaluated for surgical bed soft tissue necrosis (STN) in head and neck cancer patients treated with postoperative radiation therapy (PORT) after transoral robotic surgery (TORS) or wide excision with primary closure. Sixty-seven patients were evaluated. STN was defined as ulceration and necrosis of the surgical bed or persistently unhealed high-grade acute mucositis with pain after PORT. The median RT dose of primary site was 63.6 Gy (range, 45-67.15 Gy) with 2 Gy/fx (range 1.8-2.2 Gy/fx). Total 41 patients (61.2%) were treated with concurrent chemoradiotherapy. The median follow-up period was 26 months. STN was diagnosed in 13 patients (19.4%). Most of the patients were treated with oral steroids, antibiotics, and analgesics and the lesions were eventually improved (median of 6 months after PORT). STN did not influence local control. A depth of invasion (DOI > 1.4 cm, odds ratio [OR] 14.04, p = 0.004) and maximum dose/fraction (CTVpmax/fx > 2.3 Gy, OR 6.344, p = 0.043) and grade 3 acute mucositis (OR 6.090, p = 0.054) were related to STN. The 12 (23.5%) of 51 oropharyngeal cancer patients presented STN, and the risk factors were DOI > 1.2 cm (OR 21.499, P = 0.005), CTVpmax/fx > 2.3 Gy (OR 12.972, P = 0.021) and grade 3 acute mucositis (OR 10.537, P = 0.052). Patients treated with TORS or WE with primary closure followed by PORT had a high risk of surgical bed STN. STN risk factors included DOI (>1.2-1.4 cm) and CTVpmax/fx (>2.3 Gy). Radiation therapy after TORS must be carefully designed to prevent STN. PMID- 26945368 TI - Quantified Aortic Luminal Irregularity as a Predictor of Complications and Prognosis After Endovascular Aneurysm Repair. AB - Atheromatous degeneration of the aorta is considered to be a risk factor for postoperative embolic complications after endovascular treatment, and is associated with a high incidence of vascular events in the long term. We devised a method to quantify the shagginess of the aorta using contrast-enhanced computed tomography (CT) images. This study examined the method's validity and prognostic usefulness in patients undergoing elective endovascular abdominal aortic aneurysm repair (EVAR). We retrospectively investigated 427 patients who underwent elective EVAR between 2007 and 2013. Preoperative contrast-enhanced CT images with a slice thickness of 1 mm were analyzed using a workstation, and the degree of aortic luminal irregularity from the level of the left subclavian artery ostium to that of the celiac artery ostium was quantified by computing a shagginess score. We compared the computed scores with subjective visual assessments of aortic shagginess. Subsequently, we evaluated the relationship between the computed scores and postoperative prognosis. The shagginess scores were significantly correlated with the visual assessments of the aortic lumen, which were performed by 5 experienced vascular surgeons (rho ranged from 0.564 0.654, all P < 0.001). Multiple logistic regression analysis demonstrated that the shagginess score was independently associated with the development of renal impairment within a month after EVAR (odds ratio, 2.78; 95% confidence interval [CI], 1.83-4.22, P < 0.001). The shagginess score was significantly higher in patients who suffered postoperative intestinal and peripheral ischemic complications, as compared with those who did not (P < 0.001). The mean postoperative follow-up period was 1207 +/- 641 days. Cox proportional hazards regression showed that the shagginess score was a significant independent predictor of all-cause and cardiovascular mortality (hazard ratio [HR], 1.37; 95% CI, 1.09-1.72, P = 0.007, and HR, 1.51; 95% CI, 1.04-2.18, P = 0.030, respectively). The results suggest that the shagginess score provides a quantitative reflection of aortic luminal irregularity. It may serve as a useful predictive factor for postoperative renal function deterioration, embolic complications, and long-term mortality after elective EVAR. PMID- 26945369 TI - Factors Associated With High Sodium Intake Based on Estimated 24-Hour Urinary Sodium Excretion: The 2009-2011 Korea National Health and Nutrition Examination Survey. AB - Although reducing dietary salt consumption is the most cost-effective strategy for preventing progression of cardiovascular and renal disease, policy-based approaches to monitor sodium intake accurately and the understanding factors associated with excessive sodium intake for the improvement of public health are lacking. We investigated factors associated with high sodium intake based on the estimated 24-hour urinary sodium excretion, using data from the 2009 to 2011 Korea National Health and Nutrition Examination Survey (KNHANES). Among 21,199 adults (>=19 years of age) who participated in the 2009 to 2011 KNHANES, 18,000 participants (weighted n = 33,969,783) who completed urinary sodium and creatinine evaluations were analyzed in this study. The 24-hour urinary sodium excretion was estimated using Tanaka equation. The mean estimated 24-hour urinary sodium excretion level was 4349 (4286-4413) mg per day. Only 18.5% (weighted n = 6,298,481/3,396,973, unweighted n = 2898/18,000) of the study participants consumed less the 2000 mg sodium per day. Female gender (P < 0.001), older age (P < 0.001), total energy intake >=50 percentile (P < 0.005), and obesity (P < 0.001) were associated with high sodium intake, even after adjusting for potential confounders. Senior high school/college graduation in education and managers/professionals in occupation were associated with lower sodium intake (P < 0.001). According to hypertension management status, those who had hypertension without medication consumed more sodium than those who were normotensive. However, those who receiving treatment for hypertension consumed less sodium than those who were normotensive (P < 0.001). The number of family members, household income, and alcohol drinking did not affect 24-hour urinary sodium excretion. The logistic regression analysis for the highest estimated 24-hour urinary sodium excretion quartile (>6033 mg/day) using the abovementioned variables as covariates yielded identical results. Our data suggest that age, sex, education level, occupation, total energy intake, obesity, and hypertension management status are associated with excessive sodium intake in Korean adults using nationally representative data. Factors associated with high sodium intake should be considered in policy-based interventions to reduce dietary salt consumption and prevent cardiovascular disease as a public health target. PMID- 26945370 TI - Efficacy and Outcome Predictors of Gonadotropin Treatment for Male Congenital Hypogonadotropic Hypogonadism: A Retrospective Study of 223 Patients. AB - Gonadotropin induces masculinization and spermatogenesis in men with congenital hypogonadotropic hypogonadism (CHH). However, large cohort studies for the efficacy and reliable predictors of this therapy need to be conducted. The aim of this study was to investigate the efficacy of gonadotropin treatment in a large cohort of male CHH patients and analyze putative predictors for successful spermatogenesis. This retrospective study included 223 CHH azoospermic patients without puberty development treated between 2005 and 2014. All patients received combined human chorionic gonadotropin (HCG) and human menopausal gonadotropin (HMG) and were followed up for >6 months (5109 person-months). Serum total testosterone level, testicular size, spermatogenesis, and pregnancy outcome were recorded at each visit. After gonadotropin therapy, testicular size was enlarged from 2.1 +/- 1.6 to 8.1 +/- 4.6 mL (P < 0.001) and serum total testosterone was elevated from 0.9 +/- 0.5 to 15.1 +/- 8.2 nmol/L (P < 0.001). Spermatogenesis (>0/mL) occurred at a median period of 15 months (95% confidence interval 13.5 16.5). Larger basal testicular volume (P = 0.012) and noncryptorchidism history (P = 0.028) are independent predictors for earlier sperm appearance. Sixty four percent (143/223) of patients succeeded in producing sperms and the average time for initial sperm detection was 14 +/- 8 months. However, their sperm concentrations (11.7 [2.1, 24.4] million/mL) and sperm progressive motility (A + B 36.9% +/- 20.2%) are significantly lower than World Health Organization standards. Of the 34 patients who desired for fathering children, 19 patients impregnanted their partners during the treatment. Gonadotropin therapy induces spermatogenesis in male CHH patients. A larger basal testicular size and noncryptorchidism history are favorable indicators for earlier spermatogenesis. PMID- 26945371 TI - Influenza Vaccination Reduces Dementia Risk in Chronic Kidney Disease Patients: A Population-Based Cohort Study. AB - Taiwan has the highest prevalence of chronic kidney disease (CKD) worldwide. CKD, a manifestation of vascular diseases, is associated with a high risk of dementia. Here, we estimated the association between influenza vaccination and dementia risk in patients with CKD. Data from the National Health Insurance Research Database of Taiwan were used in this study. The study cohort included all patients diagnosed with CKD (according to International Classification of Disease, Ninth Revision, Clinical Modification codes) at healthcare facilities in Taiwan (n = 32,844) from January 1, 2000, to December 31, 2007. Each patient was followed up to assess dementia risk or protective factors: demographic characteristics of age and sex; comorbidities of diabetes, hypertension, dyslipidemia, cerebrovascular diseases, parkinsonism, epilepsy, substance and alcohol use disorders, mood disorder, anxiety disorder, psychotic disorder, and sleep disorder; urbanization level; monthly income; and statin, metformin, aspirin, and angiotensin-converting enzyme inhibitor (ACEI) use. A propensity score was derived using a logistic regression model for estimating the effect of vaccination by accounting for covariates that predict receiving the intervention (vaccine). A time-dependent Cox proportional hazard model was used to calculate the hazard ratios (HRs) of dementia among vaccinated and unvaccinated CKD patients. The study population comprised 11,943 eligible patients with CKD; 5745 (48%) received influenza vaccination and the remaining 6198 (52%) did not. The adjusted HRs (aHRs) of dementia decreased in vaccinated patients compared with those in unvaccinated patients (influenza season, noninfluenza season, and all seasons: aHRs = 0.68, 0.58, and 0.64; P < 0.0001, P < 0.0001, and P < 0.0001, respectively). In the sensitivity analysis, adjustments were made to estimate the association of age and sex; diabetes, dyslipidemia, hypertension, cerebrovascular diseases, anxiety disorder; and statin, metformin, ACEI, and aspirin use with the incidence of dementia in various models. A stronger protective effect against dementia risk was demonstrated during the noninfluenza season. Regardless of comorbidities or drug use, influenza vaccination was an independent protective factor and dose-dependently reduced the risk of dementia in CKD patients. Influenza vaccination exerts dose-response and synergistic protective effects against dementia in CKD patients with dementia risk factors by reducing the incidence of dementia. PMID- 26945372 TI - Gastric Carcinomas in Young (Younger than 40 Years) Chinese Patients: Clinicopathology, Family History, and Postresection Survival. AB - Little is known about clinicopathological characteristics of gastric carcinoma (GC) in young (<=40 years) Chinese patients. We aimed in this study to analyze those features along with family history and prognostic factors after resection. We retrospectively reviewed all 4671 GC resections (surgical and endoscopic) performed at our center from 2004 to 2014 and identified 152 (3.2%) consecutive young patients. Patient demographics, clinical results, family history, and endoscopic-pathological findings were analyzed along with the older (>41 years) GC controls recruited in the same study period. Clinicopathological factors related to postresection outcomes were assessed statistically. The trend of GC resections in young patients was not changed over the study period. Compared to old GCs, the young GC cohort was predominant in women, positive family history, middle gastric location, the diffuse histology type, shorter duration of symptoms, and advanced stage (pIII+pIV, 53.3%). Radical resection was carried out in 90.1% (n = 137) with a better 5-year survival rate (70.3%) than palliative surgery (0%, n = 15). There was no significant difference in clinicopathological characteristics between familial GC (FGC, n = 38) and sporadic GC (SGC, n = 114) groups. Very young patients (<= 30 years, n = 38) showed lower Helicobacter pylori (Hp) infection and significantly higher perineural invasion rates, compared to older (31-40 years) patients. Hp infection was more commonly seen in the Lauren's intestinal type and early pT stages (T1+T2). Independent prognostic factors for worse outcomes included higher serum CA 72-4, CA 125 levels, positive resection margin, and stage pIII-pIV tumors. The 5-year survival rate was significantly higher in patients with radical resection than those without. GCs in young Chinese patients were prevalent in women with advanced stages but showed no significant differences in clinicopathology between FGC and SGC groups. High serum CA 72-4 and CA 125 levels may help identify patients with worse outcomes. Radical resection improved postresection survival. PMID- 26945373 TI - A Case Report of Clonazepam Dependence: Utilization of Therapeutic Drug Monitoring During Withdrawal Period. AB - Clonazepam is long-acting benzodiazepine agonist used in short-acting benzodiazepine withdrawal; however, recent observations suggest the existence of its abuse. We demonstrate a 40-year-old man with a 20-year history of psychiatric care with recently benzodiazepine dependence (daily intake of ~60 mg of clonazepam and 10 mg of alprazolam). High serum levels of both drugs were analyzed 3 weeks before admission to hospitalization (clonazepam 543.9 ng/mL, alprazolam 110 ng/mL) and at the time of admission (clonazepam 286.2 ng/mL, alprazolam 140 ng/mL) without any signs of benzodiazepine intoxication. Gradual withdrawal of clonazepam with monitoring of its serum levels and increase of gabapentin dose were used to minimize physical signs and symptoms of clonazepam withdrawal. Alprazolam was discontinued promptly. Clinical consequences of the treatment were controllable tension, intermittent headache, and rarely insomia. It is the first case report showing utilization of therapeutic drug monitoring during withdrawal period in the patient with extreme toleration to severe benzodiazepine dependence. PMID- 26945374 TI - Sudden Unexplained Nocturnal Death Syndrome in Central China (Hubei): A 16-Year Retrospective Study of Autopsy Cases. AB - A retrospective study was conducted at Tongji Forensic Medical Center in Hubei (TFMCH) from 1999 to 2014. Forty-nine cases of sudden unexplained nocturnal death syndrome (SUNDS) were collected. The SUNDS rate was 1.0% in the total number of cases, in which an incidence was fluctuating over the years. Interestingly, April and January, and 3:00 to 6:00 AM were the peak months and times of death. Among the decedents, farmers and migrant workers accounted for 67.3%. The syndrome predominantly attacked males in their 30s. One victim had sinus tachycardia. Thirteen victims (26.5%) were witnessed and had abnormal symptoms near death. Macroscopically, compared to sudden noncardiac deaths, the weights of brain, heart, and lungs had no statistical difference in SUNDS. Microscopically, the incidence of lung edema (45 cases, 91.8%) was significantly higher in SUNDS group than in the control group (27 cases, 55.1%). 82.9% of 35 SUNDS cases examined displayed minor histological anomalies of the cardiac conduction system (CCS), including mild or moderate fatty, fibrous or fibrofatty tissue replacement, insignificant stenosis of node artery, and punctate hemorrhage in the node area. These findings suggested that minor CCS abnormalities might be the substrates for some SUNDS deaths. Therefore, SUNDS victims might suffer ventricular fibrillation and acute cardiopulmonary failure before death. Further in-depth studies are needed to unveil the underlying mechanisms of SUNDS. PMID- 26945375 TI - Unenhanced Computed Tomography to Visualize Hollow Viscera and/or Mesenteric Injury After Blunt Abdominal Trauma: A Single-Institution Experience. AB - To identify and describe the major features of unenhanced computed tomography (CT) images of blunt hollow viscera and/or mesenteric injury (BHVI/MI) and to determine the value of unenhanced CT in the diagnosis of BHVI/MI. This retrospective study included 151 patients who underwent unenhanced CT before laparotomy for blunt abdominal trauma between January 2011 and December 2013. According to surgical observations, patients were classified as having BHVI/MI (n = 73) or not (n = 78). Sensitivity, specificity, P values, and likelihood ratios were calculated by comparing CT findings between the 2 groups. Six significant CT findings (P < 0.05) for BHVI/MI were identified and their sensitivity and specificity values determined, as follows: bowel wall thickening (39.7%, 96.2%), mesentery thickening (46.6%, 88.5%), mesenteric fat infiltration (12.3%, 98.7%), peritoneal fat infiltration (31.5%, 87.1%), parietal peritoneum thickening (30.1%, 85.9%), and intra- or retro-peritoneal air (34.2%, 96.2%). Unenhanced CT scan was useful as an initial assessment tool for BHVI/MI after blunt abdominal trauma. Six key features on CT were correlated with BHVI/MI. PMID- 26945376 TI - Identifying Distinct Healthcare Pathways During Episodes of Chronic Obstructive Pulmonary Disease Exacerbations. AB - Healthcare pathways are important to measure because they are expected to affect outcomes. However, they are challenging to define because patients exhibit heterogeneity in their use of healthcare services. The objective of this study was to identify and describe healthcare pathways during episodes of chronic obstructive pulmonary disease (COPD) exacerbations. Linked administrative databases from Saskatchewan, Canada were used to identify a cohort of newly diagnosed COPD patients and their episodes of healthcare use for disease exacerbations. Latent class analysis (LCA) was used to classify the cohort into homogeneous pathways using indicators of respiratory-related hospitalizations, emergency department (ED) visits, general and specialist physician visits, and outpatient prescription drug dispensations. Multinomial logistic regression models tested patients' demographic and disease characteristics associated with pathway group membership. The most frequent healthcare contact sequences in each pathway were described. Tests of mean costs across groups were conducted using a model-based approach with chi2 statistics. LCA identified 3 distinct pathways for patients with hospital- (n = 963) and ED-initiated (n = 364) episodes. For the former, pathway group 1 members followed complex pathways in which multiple healthcare services were repeatedly used and incurred substantially higher costs than patients in the other pathway groups. For patients with an ED-initiated episode, pathway group 1 members also had higher costs than other groups. Pathway groups differed with respect to patient demographic and disease characteristics. A minority of patients were discharged from ED or hospital, but did not have any follow-up care during the remainder of their episode.Patients who followed complex pathways could benefit from case management interventions to streamline their journeys through the healthcare system. The minority of patients whose pathways were not consistent with recommended follow-up care should be further investigated to fully align COPD treatment in the province with recommended care practices. PMID- 26945377 TI - Recognition of Anterior Peritoneal Reflections and Their Relationship With Rectal Tumors Using Rectal Magnetic Resonance Imaging. AB - Our goal was to explore the factors influencing the visualization of anterior peritoneal reflections (APRs) using rectal MRI. We evaluated the usefulness of rectal MRI in measuring the distance from the anal verge to the APR and determining the relationship between the APR and the rectal tumor. Clinical and imaging data from 319 patients who underwent surgery after MRI examination between October 2010 and December 2013 were retrospectively analyzed. The distance from the anal verge to the APR and the relationship between the APR and the location of the rectal tumor was evaluated. analysis of variance, logistic regression, independent samples t tests, and Kappa tests were used for statistical analysis. The APR was visible in 283 of 319 cases using rectal MRI. The APR was more readily observed in patients who were older than 58 years (P = 0.046), in patients whose subcutaneous fat thicknesses were >22.2 mm (P = 0.004), in patients with nondistended bladders (P = 0.001), and in those with an anteversion of the uterus (P = 0.001). There was a significant difference between the distance from the anal verge to the APR between females (10.4 +/- 1.1 cm) and males (10.0 +/- 1.2 cm; P = 0.014). The accuracy in predicting tumor location with respect to the APR was 70%, 50%, 98.2%, respectively for patients with tumors located above, at, and below the APR (compared with the location determined during surgery). Most of the APRs were visible using rectal MRI, whereas certain internal factors influence visualization. Rectal MRI could be a useful tool for evaluating the distance from the anal verge to the APR and relationship between rectal tumors and the APR. PMID- 26945378 TI - Characterization of Patients With Lupus Nephritis Included in a Large Cohort From the Spanish Society of Rheumatology Registry of Patients With Systemic Lupus Erythematosus (RELESSER). AB - The aim of the study was to profile those patients included in the RELESSER registry with histologically proven renal involvement in order to better understand the current state of lupus nephritis (LN) in Spain. RELESSER-TRANS is a multicenter cross-sectional registry with an analytical component. Information was collected from the medical records of patients with systemic lupus erythematosus who were followed at participating rheumatology units. A total of 359 variables including demographic data, clinical manifestations, disease activity, severity, comorbidities, LN outcome, treatments, and mortality were recorded. Only patients with a histological confirmation of LN were included. We performed a descriptive analysis, chi-square or Student's t tests according to the type of variable and its relationship with LN. Odds ratio and confidence intervals were calculated by using simple logistic regression. LN was histologically confirmed in 1092/3575 patients (30.5%). Most patients were female (85.7%), Caucasian (90.2%), and the mean age at LN diagnosis was 28.4 +/- 12.7 years. The risk for LN development was higher in men (M/F:47.85/30.91%, P < 0.001), in younger individuals (P < 0.001), and in Hispanics (P = 0.03). Complete response to treatment was achieved in 68.3% of patients; 10.35% developed ESRD, which required a kidney transplant in 45% of such cases. The older the patient, the greater was the likelihood of complete response (P < 0.001). Recurrences were associated with persistent lupus activity at the time of the last visit (P < 0.001) and with ESRD (P < 0.001). Thrombotic microangiopathy was a risk factor for ESRD (P = 0.04), as for the necessity of dialysis (P = 0.01) or renal transplantation (P = 0.03). LN itself was a poor prognostic risk factor of mortality (OR 2.4 [1.81-3.22], P < 0.001). Patients receiving antimalarials had a significantly lower risk of developing LN (P < 0.001) and ESRD (P < 0.001), and responded better to specific treatments for LN (P = 0.014). More than two-thirds of the patients with LN from a wide European cohort achieved a complete response to treatment. The presence of positive anti-Sm antibodies was associated with a higher frequency of LN and a decreased rate of complete response to treatment. The use of antimalarials reduced both the risk of developing renal disease and its severity, and contributed to attaining a complete renal response. PMID- 26945379 TI - Annual Average Changes in Adult Obesity as a Risk Factor for Papillary Thyroid Cancer: A Large-Scale Case-Control Study. AB - We evaluated the association between weight change in middle-aged adults and papillary thyroid cancer (PTC) based on a large-scale case-control study. Our study included data from 1551 PTC patients (19.3% men and 80.7% women) who underwent thyroidectomy at the 3 general hospitals in Korea and 15,510 individually matched control subjects. The subjects' weight history, epidemiologic information, and tumor characteristics confirmed after thyroidectomy were analyzed. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were determined for the annual average changes in weight and obesity indicators (body mass index (BMI), body surface area, and body fat percentage (BF%) in subjects since the age of 35 years. Subjects with a total weight gain >=10 kg after age 35 years were more likely to have PTC (men, OR, 5.39, 95% CI, 3.88-7.49; women, OR, 3.36, 95% CI, 2.87-3.93) compared with subjects with a stable weight (loss or gain <5 kg). A marked increase in BMI since age 35 years (annual average change of BMI >=0.3 kg/m/yr) was related to an elevated PTC risk, and the association was more pronounced for large-sized PTC risks (<1 cm, OR, 2.34, 95% CI, 1.92-2.85; >=1 cm, OR, 4.00, 95% CI, 2.91-5.49, P heterogeneity = 0.005) compared with low PTC risks. Weight gain and annual increases in obesity indicators in middle-aged adults may increase the risk of developing PTC. PMID- 26945380 TI - Apolipoprotein E epsilon4 Allele was Associated With Nonlesional Mesial Temporal Lobe Epilepsy in Han Chinese Population. AB - Apolipoprotein E (APOE) gene has been implicated as one of the genes susceptible to temporal lobe epilepsy (TLE), but the association is inconsistent. We carried out a study to investigate the association of APOEepsilon4 allele with a subtype of TLE-nonlesional mesial temporal lobe epilepsy (NLMTLE) in Han Chinese people.T he study consisted of total 308 NLMTLE patients and 302 controls in Han Chinese. The APOE polymorphisms were genotyped using polymerase chain reaction (PCR) DNA sequencing. We compared the frequency of APOEepsilon4 allele and carrying status between NLMTLE patients and control subjects to test for the association of APOEepsilon4 allele with NLMTLE clinical status. Carrying status of APOEepsilon4 allele was significantly associated with the risk of NLMTLE. No effect of APOEepsilon4 allele was found on the age of onset, duration of epilepsy, or frequency of seizure. Moreover, there was no association between APOEepsilon4 allele and hippocampal sclerosis (HS) or febrile convulsion (FC) history.O ur study provided an evidence that APOEepsilon4 allele was a possible risk factor for NLMTLE, and further study with a larger sample is needed to warrant this finding. PMID- 26945381 TI - Diagnostic Accuracy of Perioperative Measurement of Basal Anterior Pituitary and Target Gland Hormones in Predicting Adrenal Insufficiency After Pituitary Surgery. AB - The insulin tolerance test (ITT) is the gold standard for diagnosing adrenal insufficiency (AI) after pituitary surgery. The ITT is unpleasant for patients, requires close medical supervision and is contraindicated in several comorbidities. The aim of this study was to analyze whether tumor size, remission rate, preoperative, and early postoperative baseline hormone concentrations could serve as predictors of AI in order to increase the diagnostic accuracy of morning serum cortisol. This prospective study enrolled 70 consecutive patients with newly diagnosed pituitary adenomas. Thirty-seven patients had nonfunctioning pituitary adenomas (NPA), 28 had prolactinomas and 5 had somatotropinomas. Thyroxin (T4), thyrotropin (TSH), prolactin, follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone, and insulin-like growth factor 1 (IGF-I) were measured preoperatively and on the sixth postoperative day. Serum morning cortisol was measured on the third postoperative day (CORT3) as well as the sixth postoperative day (CORT6). Tumor mass was measured preoperatively and remission was assessed 3 months after surgery. An ITT was performed 3 to 6 months postoperatively. Remission was achieved in 48% of patients and AI occurred in 51%. Remission rates and tumor type were not associated with AI. CORT3 had the best predictive value for AI (area under the curve (AUC) 0.868, sensitivity 82.4%, specificity 83.3%). Tumor size, preoperative T4, postoperative T4, and TSH were also associated with AI in a multivariate regression model. A combination of all preoperative and postoperative variables (excluding serum cortisol) had a sensitivity of 75.0% and specificity of 77.8%. The predictive power of CORT3 substantially improved by adding those variables into the model (AUC 0.921, sensitivity 94.1%, specificity 78.3%, PPV 81.9%, NPV of 92.7%). In a subgroup analysis that included only female patients with NPA, LH had exactly the same predictive value as CORT3. The addition of baseline LH to CORT3, increased sensitivity to 100.0%, specificity to 88.9%, PPV to 90.4%, and NPV to 100.0%. Besides CORT3, tumor size, thyroid hormones, and gonadotropins can serve as predictors of AI. LH in postmenopausal female patients with NPA has similar diagnostic accuracy as CORT3. Further studies are needed in order to validate the scoring system proposed by this study. PMID- 26945382 TI - Acupuncture and Related Therapies for Symptom Management in Palliative Cancer Care: Systematic Review and Meta-Analysis. AB - Available systematic reviews showed uncertainty on the effectiveness of using acupuncture and related therapies for palliative cancer care. The aim of this systematic review and meta-analysis was to summarize current best evidence on acupuncture and related therapies for palliative cancer care. Five international and 3 Chinese databases were searched. Randomized controlled trials (RCTs) comparing acupuncture and related therapies with conventional or sham treatments were considered. Primary outcomes included fatigue, paresthesia and dysesthesias, chronic pain, anorexia, insomnia, limb edema, constipation, and health-related quality of life, of which effective conventional interventions are limited. Thirteen RCTs were included. Compared with conventional interventions, meta analysis demonstrated that acupuncture and related therapies significantly reduced pain (2 studies, n = 175, pooled weighted mean difference: -0.76, 95% confidence interval: -0.14 to -0.39) among patients with liver or gastric cancer. Combined use of acupuncture and related therapies and Chinese herbal medicine improved quality of life in patients with gastrointestinal cancer (2 studies, n = 111, pooled standard mean difference: 0.75, 95% confidence interval: 0.36-1.13). Acupressure showed significant efficacy in reducing fatigue in lung cancer patients when compared with sham acupressure. Adverse events for acupuncture and related therapies were infrequent and mild. Acupuncture and related therapies are effective in reducing pain, fatigue, and in improving quality of life when compared with conventional intervention alone among cancer patients. Limitations on current evidence body imply that they should be used as a complement, rather than an alternative, to conventional care. Effectiveness of acupuncture and related therapies for managing anorexia, reducing constipation, paresthesia and dysesthesia, insomnia, and limb edema in cancer patients is uncertain, warranting future RCTs in these areas. PMID- 26945383 TI - An Evaluation of Thyromental Distance-based Method or Weight-based Method in Determining the Size of the Laryngeal Mask Airway Supreme: A Randomized Controlled Study. AB - The successful placement of Laryngeal Mask Airway (LMA) Supreme in adults largely depends on right selection of its size. Most anesthesiologists determine the size of LMA according to patients' body weight, which does not always work well. An alternative method should be established to guarantee higher efficacy of ventilation through LMA Supreme placement. This controlled study was designed to compare the efficacy of LMA Supreme placement, when the size of it is determined by body weight or by thyromental distance. Eighty healthy individuals with American Society of Anesthesiologists physical status 1 to 2 scheduled for elective ambulatory surgery were randomly allocated into 2 groups: thyromental distance-based group (n = 40) and weight-based group (n = 40). Efficacy of controlled ventilation through LMA, easy of device placement, and pharyngeal sealing were evaluated between the groups. The tidal volume under 10 cm H2O pressure-controlled ventilation in thyromental distance-based group was significantly higher than that in weight-based group (523.9 +/- 135.4 vs 477.1 +/ 185.6; P = 0.031). The number of patients who achieved "excellent" tidal volume (>8 mL/kg) were significantly more in the thyromental distance-based group (24/40 vs 13/40; P = 0.019). Among overweight patients (body mass index >23), those who achieved "excellent" tidal volume (>8 mL/kg) under 10 cm H2O pressure-controlled ventilation were also more in thyromental distanced-based group than in weight based group (11/24 vs 2/24; P = 0.031). The time taken for successful insertion was shorter with the thyromental distance-based group compared with the weight based group (54.6 +/- 33.6 vs 87.8 +/- 98.9; P = 0.021). Oropharyngeal leak pressure was pretty close between the 2 groups (26.4 +/- 5.1 vs 25.0 +/- 5.7 cm H2O; P = 0.180). In terms of guaranteeing better positive pressure ventilation, facilitating device placement, and reliable pharyngeal sealing, thyromental distance-based method can be a better option compared with the weight-based method for LMA Supreme size selection. PMID- 26945384 TI - Metabolic Syndrome and Risk of Cervical Human Papillomavirus Incident and Persistent Infection. AB - Few studies have been conducted on the relationship between metabolic syndrome (MetS) and cervical human papillomavirus (HPV) incidence and persistent infection. We performed a prospective cohort study including 8598 female employees in Hunan, China. First, the subjects were stratified into HPV-negative (N = 7282) and HPV-positive (N = 1316) subgroups, according to the results of an HPV DNA test at baseline. Second, comparisons of the risks of HPV incident and persistent infection between MetS-positive (exposed) and MetS-negative (unexposed) groups were conducted among the HPV-negative and -positive subgroups, respectively. There were 976 (11.39%) subjects diagnosed with MetS and 1316 subjects diagnosed with HPV infection at baseline. The 12-month cumulative incidence of any type of HPV and high-risk type HPV were 7.28% (530/7282) and 6.26% (456/7282), respectively. Obesity was a modifier of the association between MetS and HPV incident infection. As long as obesity presented, MetS and hypertriglyceridemia were significantly associated with an increased risk of HPV incident infection (any-type or high-risk type) (adjusted risk ratios (RR) were 2.88 (95% confidence interval (CI): 1.16, 7.19) and 3.29 (95% CI: 1.47, 7.38), respectively). Among those infected with HPV at baseline, the 12-month type specific persistence rates were 51.67% and 53.38% for any-type and high-risk type HPV, respectively. No interaction was found between obesity and MetS with regard to the risk of HPV persistence. After adjustment for confounding factors, MetS was still associated with increased risk of any-type HPV persistence (RRadj = 1.21, 95% CI: 1.05, 1.41) and high-risk type HPV persistence (RRadj = 1.25, 95% CI: 1.09, 1.46). No single metabolic component was associated with the risk of HPV persistence. The prevalence of MetS was 11.39% among the Hunan female occupational population. MetS was associated with an increased risk of persistent cervical HPV infection and also with an increased risk of HPV incident infection when obesity presented as well. PMID- 26945385 TI - A Preoperative Assessment of Significant Coronary Stenosis Based on a Semiquantitative Analysis of Coronary Artery Calcification on Noncontrast Computed Tomography in Aortic Stenosis Patients Undergoing Aortic Valve Replacement. AB - Invasive coronary angiography (ICA) is the recommended assessment for coronary artery disease in patients undergoing elective aortic valve replacement (AVR). Noncontrast computed tomography (CT) is useful for evaluating lung lesions and calcifications at the cannulation site of the ascending aorta. The purpose of this study was to evaluate the role of noncontrast CT in the visual assessment of coronary artery calcification (CAC) in patients undergoing AVR. We retrospectively identified patients with significant aortic stenosis (AS) who were referred for AVR between January 2006 and December 2013. Among these, we included 386 patients (53.6% males, 69.2 +/- 8.4 years) who underwent both noncontrast CT and ICA. Significant coronary artery stenosis (CAS) in the ICA was defined as luminal stenosis >=70%. The 4 main coronary arteries were visually assessed on noncontrast CT and were scored based on the Weston score as follows: 0, no visually detected calcium; 1, a single high-density pixel detected; 3, calcium was dense enough to create a blooming artifact; and 2, calcium in between 1 and 3. Four groups were reclassified by the sum of the Weston scores from each vessel, as follows: noncalcification (0); mild calcification (1-4); moderate calcification (5-8); and severe calcification (9-12). Receiver-operating characteristic (ROC) analysis was generated to identify the cutoff Weston score values for predicting significant CAS. Diagnostic estimates were calculated based on these cutoffs. In the ICA analysis, 62 of the 386 patients (16.1%) had significant CAS. All patients were divided into 4 groups. The noncalcification group had 97 subjects (Weston score 0), the mild degree group had 100 (2.6 +/- 1.0), the moderate calcification group had 114 (6.6 +/- 1.1), and the severe calcification group had 75 (10.7 +/- 1.1). The prevalence of significant CAS in the noncalcification, mild, moderate, and severe groups was 1% (1/97), 5% (5/100), 24% (27/114), and 39% (29/75), respectively. The group with CAS had significantly more CAC than the group without CAS (8.37 +/- 2.93 vs 4.01 +/- 3.75, P < 0.001). The cutoff value (by Weston score) for predicting significant CAS is >=5 (sensitivity 90.3%, specificity 59.0%, positive predictive value 29.6%, and negative predictive value 97%). The degree of CAC detected on noncontrast CT can help to predict significant CAS in AS patients who are referred for AVR. For the clinicians, the visual assessment of CAC on noncontrast CT was easy and useful for estimating CAS. Therefore, ICA should be recommended to selective patients based on patients' CAC and Weston scores during the preoperative evaluation for elective AVR. PMID- 26945386 TI - Ocular Decompression Retinopathy Following Canaloplasty for Primary Open Angle Glaucoma: A Case Report. AB - Ocular decompression retinopathy (ODR), a rare postoperative complication following glaucoma surgery, is characterized by the transient appearance of scattered retinal hemorrhages. Here, we present a unique case of ODR in a patient with primary open angle glaucoma who underwent canaloplasty. A 31-year-old male patient presented with an intraocular pressure (IOP) of 60 mm Hg in the right eye. The IOP remained over 40 mm Hg, even when treated with maximum tolerated antiglaucoma medication. Canaloplasty drastically lowered IOP in the right eye from 40 to 7 mm Hg. However, fundus examination revealed ODR after surgery. The patient was treated with tobramycin and dexamethasone. Three months after canaloplasty, IOP remained in control at 16 mm Hg and all retinal hemorrhages had completely resolved. This case demonstrates that ODR can occur following canaloplasty and physicians should be aware of this potential complication in patients with severely elevated IOP. Sufficiently lowering IOP before surgery and gradually decreasing IOP during surgery may prevent ODR from occurring. PMID- 26945387 TI - The Value of PET/CT in Detecting Bone Marrow Involvement in Patients With Follicular Lymphoma. AB - Follicular lymphoma (FL) is the 2nd most common type of lymphoma diagnosed in the Western World. Bone marrow (BM) involvement is an adverse prognostic factor in FL, routinely assessed by an arbitrary biopsy of the iliac crest. This study was aimed to investigate the role of positron emission tomography/computed tomography (PET/CT) in identifying BM involvement by FL. In this retrospective, single center study we reviewed the records of consecutive patients with FL at diagnosis or relapse who underwent staging/restaging workup visual assessment of BM uptake was categorized as either normal, diffusely increased, or focally increased. Quantitative BM fluorine-18-fluro-deoxyglucose (FDG) uptake was measured using mean standardized uptake value (BM-SUVmean). The diagnosis of BM involvement was based on either BM histological findings or disappearance of increased uptake at end-treatment PET/CT in patients who responded to treatment. Sixty eight cases with FL were included. Sixteen (23.5%) had BM involvement, 13 (19.1%) had a biopsy proven involvement, and 3 (4.4%) had a negative BM biopsy, but increased medullary uptake that normalized post-treatment. BM FDG uptake in these patients was diffuse in 8 (50%) and focal in 8 (50%). Focal increased uptake was indicative of BM involvement; however, diffuse uptake was associated with 17 false positive cases (32.7%). Overall, visual assessment of BM involvement had a negative predictive value (NPV) of 100% and a positive predictive value (PPV) of 48.5%. On a quantitative assessment, BM-SUVmean was significantly higher in patients with BM involvement (SUVmean of 3.7 [1.7-6] vs 1.4 [0.4-2.65], P < 0.001). On receiver operator curve (ROC) analysis, BM-SUVmean > 2.7 had a PPV of 100% for BM involvement (sensitivity of 68%), while BM-SUVmean < 1.7 had an NPV of 100% (specificity of 73%). Visual assessment of PET/CT is appropriate for ruling out BM involvement by FL. Although focal increased uptake indicates marrow involvement, diffuse uptake is nonspecific. SUV measurement improves PET/CT diagnostic accuracy, identifying additional 19% of patients with BM involvement that would have been otherwise missed. PMID- 26945388 TI - Risk of Migraine in Patients With Asthma: A Nationwide Cohort Study. AB - Asthma has been described as an "acephalic migraine" and "pulmonary migraine." However, no study has investigated the temporal frequency of migraine development in patients with asthma, and the results of previous studies may be difficult to generalize.We investigated the effect of asthma on the subsequent development of migraine by using a population-based data set in Taiwan.We retrieved our study sample from the National Health Insurance Research Database. Specifically, 25,560 patients aged 12 years and older with newly diagnosed asthma were identified as the asthma group, and 102,238 sex and age-matched patients without asthma were identified as the nonasthma group. Cox proportional-hazards regression models were employed to measure the risk of migraine for the asthmatic group compared with that for the nonasthmatic group.The risk of migraine in the asthmatic group was 1.45-fold higher (95% confidence interval 1.33-1.59) than that in the nonasthmatic group after adjustment for sex, age, the Charlson comorbidity index, common medications prescribed for patients with asthma, and annual outpatient department visits. An additional stratified analysis revealed that the risk of migraine remained significantly higher in both sexes and all age groups older than 20 years.Asthma could be an independent predisposing risk factor for migraine development in adults. PMID- 26945389 TI - A Case Report: Systemic Lymph Node Tuberculosis Mimicking Lymphoma on 18F-FDG PET/CT. AB - F-fluorodeoxyglucose positron emission tomography--an established modality for evaluating malignancies--exhibits increased uptake under inflammatory conditions. A 21-year-old man came to our hospital with persistent pain in his right lower quadrant of abdomen for more than 1 month, but had no diarrhea, fever, chills, weight loss, or other constitutional symptoms. Colonoscopy analysis showed no organic diseases in his colorectum. Ultrasound results revealed multiple enlarged lymph nodes in the bilateral neck, axilla, and groin. Positron emission tomography analysis was performed and showed intense 18F-fluorodeoxyglucose accumulation in the bilateral neck, supraclavicular, pulmonary hilar, mediastinum, gastric paracardial, and mesenterium lymph node. These findings were considered typical for lymphoma. To confirm the diagnosis, we obtained a diagnostic biopsy in the left supraclavicular lymph node. The diagnosis of tuberculosis was confirmed in the final pathology. This uncommon case underscores the necessity of considering lymph node tuberculosis as a possible differential diagnosis in lymphoma. PMID- 26945390 TI - Nationwide Multicenter Reference Interval Study for 28 Common Biochemical Analytes in China. AB - A nationwide multicenter study was conducted in the China to explore sources of variation of reference values and establish reference intervals for 28 common biochemical analytes, as a part of the International Federation of Clinical Chemistry and Laboratory Medicine, Committee on Reference Intervals and Decision Limits (IFCC/C-RIDL) global study on reference values. A total of 3148 apparently healthy volunteers were recruited in 6 cities covering a wide area in China. Blood samples were tested in 2 central laboratories using Beckman Coulter AU5800 chemistry analyzers. Certified reference materials and value-assigned serum panel were used for standardization of test results. Multiple regression analysis was performed to explore sources of variation. Need for partition of reference intervals was evaluated based on 3-level nested ANOVA. After secondary exclusion using the latent abnormal values exclusion method, reference intervals were derived by a parametric method using the modified Box-Cox formula. Test results of 20 analytes were made traceable to reference measurement procedures. By the ANOVA, significant sex-related and age-related differences were observed in 12 and 12 analytes, respectively. A small regional difference was observed in the results for albumin, glucose, and sodium. Multiple regression analysis revealed BMI-related changes in results of 9 analytes for man and 6 for woman. Reference intervals of 28 analytes were computed with 17 analytes partitioned by sex and/or age. In conclusion, reference intervals of 28 common chemistry analytes applicable to Chinese Han population were established by use of the latest methodology. Reference intervals of 20 analytes traceable to reference measurement procedures can be used as common reference intervals, whereas others can be used as the assay system-specific reference intervals in China. PMID- 26945391 TI - A Quasi-Experimental Analysis of Elementary School Absences and Fine Particulate Air Pollution. AB - Fine particulate air pollution (PM2.5) has been associated with many adverse health outcomes including school absences. Specifically, a previous study in the Utah Valley area, conducted during a time with relatively high air pollution exposure, found significant positive correlations between school absences and air pollution. We examined the hypothesis that ambient PM2.5 exposures are associated with elementary school absences using a quasi-natural experiment to help control for observed and unobserved structural factors that influence school absences. The Alpine, Provo, and Salt Lake City school districts are located in valleys subject to daily mean PM2.5 concentrations almost twice as high as those in the Park City School District. We used seminonparametric generalized additive Poisson regression models to evaluate associations between absences and daily PM2.5 levels in the 3 districts that were exposed to the most pollution while using Park City absences as a quasi-control. The study covered 3 school years (2011/12 2013/14). School absences were most strongly associated with observed structural factors such as seasonal trends across school years, day-of-week effects, holiday effects, weather, etc. However, after controlling for these structural factors directly and using a control district, a 10 MUg/m increase in PM2.5 was associated with an approximately 1.7% increase in daily elementary school absences. Exposure to ambient air pollution can contribute to elementary school absences, although this effect is difficult to disentangle from various other factors. PMID- 26945392 TI - Identifying Mutations of the Tetratricopeptide Repeat Domain 37 (TTC37) Gene in Infants With Intractable Diarrhea and a Comparison of Asian and Non-Asian Phenotype and Genotype: A Global Case-report Study of a Well-Defined Syndrome With Immunodeficiency. AB - Syndromic diarrhea/tricho-hepato-enteric syndrome (SD/THE) is a rare, autosomal recessive and severe bowel disorder mainly caused by mutations in the tetratricopeptide repeat domain 37 (TTC37) gene which act as heterotetrameric cofactors to enhance aberrant mRNAs decay. The phenotype and immune profiles of SD/THE overlap those of primary immunodeficiency diseases (PIDs). Neonates with intractable diarrhea underwent immunologic assessments including immunoglobulin levels, lymphocyte subsets, lymphocyte proliferation, superoxide production, and IL-10 signaling function. Candidate genes for PIDs predisposing to inflammatory bowel disease were sequencing in this study. Two neonates, born to nonconsanguineous parents, suffered from intractable diarrhea, recurrent infections, and massive hematemesis from esopharyngeal varices due to liver cirrhosis or accompanying Trichorrhexis nodosa that developed with age and thus guided the diagnosis of SD/THE compatible to TTC37 mutations (homozygous DelK1155H, Fs*2; heterozygous Y1169Ter and InsA1143, Fs*3). Their immunologic evaluation showed normal mitogen-stimulated lymphocyte proliferation, superoxide production, and IL-10 signaling, but low IgG levels, undetectable antibody to hepatitis B surface antigen and decreased antigen-stimulated lymphocyte proliferation. A PubMed search for bi-allelic TTC37 mutations and phenotypes were recorded in 14 Asian and 12 non-Asian cases. They had similar presentations of infantile onset refractory diarrhea, facial dysmorphism, hair anomalies, low IgG, low birth weight, and consanguinity. A higher incidence of heart anomalies (8/14 vs 2/12; P = 0.0344, Chi-square), nonsense mutations (19 in 28 alleles), and hot spot mutations (W936Ter, 2779-2G>A, and Y1169Ter) were found in the Asian compared with the non-Asian patients. Despite immunoglobulin therapy in 20 of the patients, 4 died from liver cirrhosis and 1 died from sepsis. Patients of all ethnicities with SD/THE with the characteristic triad of T nodosa, hepatic cirrhosis, and intractable enteropathy have low IgG, poor vaccine response and/or decreased antigen-stimulated lymphocyte proliferation. This is now better classified into the subgroup of "well-defined syndromes with immunodeficiency" (the update termed as "combined immunodeficiencies with associated or syndromic features") than "predominantly antibody deficiencies" in the update PIDs classification, and requires optimal interventions. PMID- 26945393 TI - Maintaining Optimal Surgical Conditions With Low Insufflation Pressures is Possible With Deep Neuromuscular Blockade During Laparoscopic Colorectal Surgery: A Prospective, Randomized, Double-Blind, Parallel-Group Clinical Trial. AB - Carbon dioxide (CO2) absorption and increased intra-abdominal pressure can adversely affect perioperative physiology and postoperative recovery. Deep muscle relaxation is known to improve the surgical conditions during laparoscopic surgery. We aimed to compare the effects of deep and moderate neuromuscular block in laparoscopic colorectal surgery, including intra-abdominal pressure. In this prospective, double-blind, parallel-group trial, 72 adult patients undergoing laparoscopic colorectal surgery were randomized using an online randomization generator to achieve either moderate (1-2 train-of-four response, n = 36) or deep (1-2 post-tetanic count, n = 36) neuromuscular block by receiving a continuous infusion of rocuronium. Adjusted intra-abdominal pressure, which was titrated by a surgeon with maintaining the operative field during pneumoperitoneum, was recorded at 5-minute intervals. Perioperative hemodynamic parameters and postoperative outcomes were assessed. Six patients from the deep and 5 from the moderate neuromuscular block group were excluded, leaving 61 for analysis. The average adjusted IAP was lower in the deep compared to the moderate neuromuscular block group (9.3 vs 12 mm Hg, P < 0.001). The postoperative pain scores (P < 0.001) and incidence of postoperative shoulder tip pain were lower, whereas gas passing time (P = 0.002) and sips of water time (P = 0.005) were shorter in the deep neuromuscular block than in the moderate neuromuscular block group. Deep neuromuscular blocking showed several benefits compared to conventional moderate neuromuscular block, including a greater intra-abdominal pressure lowering effect, whereas surgical conditions are maintained, less severe postoperative pain and faster bowel function recovery. PMID- 26945394 TI - Serum Hepcidin Levels in Childhood-Onset Ischemic Stroke: A Case-Control Study. AB - Recently, hepcidin, an antimicrobial-like peptide hormone, has evolved as the master regulator of iron homeostasis. Despite the growing evidence of iron imbalance in childhood-onset ischemic stroke, serum hepcidin level in those patients has not yet been researched. In this study, we aimed to estimate serum (hepcidin) level in acute ischemic stroke (AIS) patients and to investigate whether subcutaneous enoxaparin sodium, which is a low-molecular-weight heparin (LMWH) derivative, could modulate serum hepcidin level in those patients. This was a case-control study included 60 (AIS) cases, and 100 healthy children with comparable age and gender as control group. For all subjects' serum hepcidin, interleukin-6 (IL-6), and soluble transferrin receptor [sTfR]) levels were assessed by (enzyme-linked immunosorbent assay [ELISA] method). Iron parameters including (serum iron, ferritin, transferrin, and total iron binding capacity [TIBC]) were also measured. The patients were subdivided according to treatment with an LMWH derivative into 2 groups and serum hepcidin levels were assessed initially and 1 week after stroke onset for all cases. We found that AIS cases had higher serum iron, ferritin, and IL6 levels compared to the control group (all P < 0.01). Serum hepcidin was significantly higher in AIS cases (median, 36[15-73]ng/mL) compared to the control group (median, 24[10-41]ng/mL; P < 0.01). On the 1st day of AIS diagnosis, serum hepcidin levels were similar in both stroke subgroups (P > 0.05). However, on the 7th day of diagnosis serum hepcidin level decreased significantly in AIS cases treated with LMWH (group 1) (median, 36 vs 21 ng/mL; P < 0.01, respectively). Meanwhile, no significant change was observed in serum hepcidin level in AIS cases not treated with LMWH (group 2) (P > 0.05). Serum hepcidin showed significant positive correlations with serum iron, transferrin saturation, ferritin, and IL6 (r = 0.375, P < 0.05; r = 0.453, P < 0.05; r = 0.687, P < 0.01; r = 0.515, P < 0.01; respectively). Our data brought a novel observation of elevated serum hepcidin level in pediatric AIS patients and pointed out that treatment with LMWH could modulate hepcidin level in those patients. PMID- 26945395 TI - Length of Menstrual Cycle and Risk of Endometriosis: A Meta-Analysis of 11 Case Control Studies. AB - Endometriosis is a complex disease that affects a large number of women worldwide and may cause pain and infertility. To systematically review published studies evaluating the relationship between menstrual cycle length and risk of endometriosis. We searched the Cochrane Library, PubMed, Web of Science, and EMBASE in databases in July 2014 using the keywords "case-control studies," "epidemiologic determinants," "risk factors," "menstrual cycle," "menstrual length," "menstrual character," and "endometriosis." We included case-control studies published in English that investigated cases of surgically confirmed endometriosis and examined the relationship between endometriosis risk and menstrual cycle. Eleven articles that met the inclusion criteria included data of 3392 women with endometriosis and 5006 controls. Fixed-effects and random-effects models were used for the evaluation. For the association of risk of endometriosis and menstrual cycle length shorter than or equal to 27 days (SEQ27) or length longer than or equal to 29 days (LEQ29), the odds ratio was 1.22 (95% confidence interval [CI]: 1.05-1.43) and 0.68 (95% CI: 0.48-0.96), respectively. In conclusion, this meta-analysis suggests that menstrual cycle length SEQ27 increase the risk of endometriosis and cycle length LEQ29 decrease the risk. PMID- 26945396 TI - Accuracy of Nurse-Performed Lung Ultrasound in Patients With Acute Dyspnea: A Prospective Observational Study. AB - In clinical practice lung ultrasound (LUS) is becoming an easy and reliable noninvasive tool for the evaluation of dyspnea. The aim of this study was to assess the accuracy of nurse-performed LUS, in particular, in the diagnosis of acute cardiogenic pulmonary congestion. We prospectively evaluated all the consecutive patients admitted for dyspnea in our Medicine Department between April and July 2014. At admission, serum brain natriuretic peptide (BNP) levels and LUS was performed by trained nurses blinded to clinical and laboratory data. The accuracy of nurse-performed LUS alone and combined with BNP for the diagnosis of acute cardiogenic dyspnea was calculated. Two hundred twenty-six patients (41.6% men, mean age 78.7 +/- 12.7 years) were included in the study. Nurse performed LUS alone had a sensitivity of 95.3% (95% CI: 92.6-98.1%), a specificity of 88.2% (95% CI: 84.0-92.4%), a positive predictive value of 87.9% (95% CI: 83.7-92.2%) and a negative predictive value of 95.5% (95% CI: 92.7 98.2%). The combination of nurse-performed LUS with BNP level (cut-off 400 pg/mL) resulted in a higher sensitivity (98.9%, 95% CI: 97.4-100%), negative predictive value (98.8%, 95% CI: 97.2-100%), and corresponding negative likelihood ratio (0.01, 95% CI: 0.0, 0.07). Nurse-performed LUS had a good accuracy in the diagnosis of acute cardiogenic dyspnea. Use of this technique in combination with BNP seems to be useful in ruling out cardiogenic dyspnea. Other studies are warranted to confirm our preliminary findings and to establish the role of this tool in other settings. PMID- 26945397 TI - A Case Report of Probable Paliperidone ER-Induced Serotonin Syndrome in a 17-Year Old Taiwanese Female With New Onset Psychosis. AB - A 17-year-old female with new-onset psychosis was treated with paliperidone. After increasing the paliperidone dose to 12 mg per day the patient developed a series of side effects; Tachycardia (140 bpm), severe drooling, restlessness, diaphoresis, whole-body tremor, inducible foot clonus, predominant lower limbs rigidity, bilateral pupil dilation, increased bowel sounds with watery diarrhea, and muscle hypertonicity. The symptoms subsided after stopping the paliperidone, and recurred after resuming paliperidone 9 mg per day. To our knowledge, this is the first case of a very clear and close relationship between the symptoms of serotonin syndrome and the use of paliperidone. We have to cautiously consider the diagnosis of serotonin syndrome in potential cases. PMID- 26945398 TI - Schwannoma in Sellar Region Mimics Invasive Pituitary Macroadenoma: Literature Review With One Case Report. AB - In central nervous system, schwannomas, as ubiquitous tumors, mostly originate from sensory nerves like auditory and trigeminal nerves. However, intrasellar schwannomas are extremely rare. They are often misdiagnosed as pituitary adenomas. We report a rare case of schwannoma in the sellar region--a challenging diagnosis guided by clinical presentations, radiological signs, and postoperative pathological test. We represent a 65-year-old woman who had suffered from headaches, hypothyroidism, and visual disturbance. Her MRI revealed an abnormal sellar region mixed-signal mass lesion with suprasellar, left parasellar, and sellar floor invasiveness. We present detailed analysis of the patient's disease course and review relevant literatures. Written informed consent was obtained from the patient for publication of this article. A copy of the written consent is available for review by the editors of MEDICINE. Because this article does not involve any human or animal trials, there is no need to conduct special ethic review and the ethical approval is not necessary. When surgically treated, her specimen revealed a typical histopathology pattern of schwannoma. The patient's symptoms improved a lot after surgery and he continues to be under observation. Despite its rarity, intrasellar schwannoma should be considered in the differential diagnosis of sellar lesions that mimic pituitary adenomas. PMID- 26945399 TI - Cancer Risk in Patients With Empyema: A Nationwide Population-Based Study. AB - This study aimed to evaluate cancer risk and possible risk factors in patients diagnosed with empyema. A total of 31,636 patients with newly diagnosed empyema between January 1, 1999 and December 31, 2010 were included in this study. Standardized incidence ratios (SIRs) were calculated to compare the cancer incidence in these empyema patients to that in the general population. Adjusted hazard ratios were also calculated to investigate whether characteristics increased cancer risk. During the 12-year study period, 2,654 cancers occurred in 31,636 patients with empyema, yielding an SIR of 2.67 (95% confidence interval [CI] 2.57-2.78). We excluded cancer that occurred within 1 year to avoid surveillance bias. The cancer risk remained significantly increased (SIR 1.50, 95% CI 1.41-1.58). Specifically, patients with empyema had higher SIR of cancers of the head and neck (1.50, 95% CI 1.41-1.58), esophagus (2.56, 95% CI 1.92 3.33), stomach (1.49, 95% CI 1.16-1.89), liver and biliary tract (2.18, 95% CI 1.93-2.45), and lung and mediastinum (1.62, 95% CI 1.39-1.86). Age >= 60, male sex, diabetes mellitus, and liver cirrhosis were independent risk factors for cancer development. Our study demonstrates an increased incidence of cancer development in patients with empyema, and patients' age >= 60, men, and those with diabetes mellitus and liver cirrhosis showed a higher incidence of developing cancer compared to the general population. The association between such kind of infection and secondary malignancy may be elucidated by further study. PMID- 26945400 TI - A Comparison of Uremic Pruritus in Patients Receiving Peritoneal Dialysis and Hemodialysis. AB - Uremic pruritus is common and bothersome in patients receiving either peritoneal dialysis (PD) or hemodialysis (HD). To date, the preferred dialysis modality regarding the alleviation of uremic pruritus remains controversial. We conducted this cross-sectional study to compare the prevalence, intensity, and characteristics of uremic pruritus between PD and HD patients. Patients receiving maintenance dialysis at a referral medical center in Taiwan were recruited. Dialysis modality, patient demographic, clinical characteristics, and laboratory data were recorded. The intensity of uremic pruritus was measured using visual analogue scale (VAS) scores. Multivariate linear regression analysis was conducted to compare the severity of uremic pruritus between PD and HD patients. Generalized additive models were applied to detect nonlinear effects between pruritus intensity and continuous covariates. A total of 380 patients completed this study, with a mean age of 60.3 years and 49.2% being female. Uremic pruritus was presented in 24 (28.6%) of the 84 PD patients and 113 (38.2%) of the 296 HD patients (P = .12). The VAS score of pruritus intensity was significantly lower among the PD patients than the HD patients (1.32 +/- 2.46 vs 2.26 +/- 3.30, P = .04). Multivariate linear regression analysis showed that PD was an independent predictor for lower VAS scores of pruritus intensity compared with HD (beta-value -0.88, 95% confidence interval -1.62 to -0.13). The use of active vitamin D was also an independent predictor for a lower intensity of uremic pruritus, whereas hyperphosphatemia and higher serum levels of triglyceride and aspartate transaminase were significantly associated with higher pruritus intensity. There was a trend toward a less affected body surface area of uremic pruritus in the PD patients than in the HD patients, but the difference did not reach statistical significance (P = .13).In conclusion, the severity of uremic pruritus was lower among PD patients than HD patients, and PD may provide better alleviation of pruritus symptoms. The result provides a valuable reference for clinicians and patients when choosing a dialysis modality. PMID- 26945401 TI - Acinetobacter seifertii Isolated from China: Genomic Sequence and Molecular Epidemiology Analyses. AB - Clinical infections caused by Acinetobacter spp. have increasing public health concerns because of their global occurrence and ability to acquire multidrug resistance. Acinetobacter calcoaceticus-Acinetobacter baumannii (ACB) complex encompasses A. calcoaceticus, A. baumannii, A. pittii (formerly genomic species 3), and A nosocomial (formerly genomic species 13TU), which are predominantly responsible for clinical pathogenesis in the Acinetobacter genus. In our previous study, a putative novel species isolated from 385 non-A. baumannii spp. strains based on the rpoB gene phylogenetic tree was reported. Here, the putative novel species was identified as A. seifertii based on the whole-genome phylogenetic tree. A. seifertii was recognized as a novel member of the ACB complex and close to A. baumannii and A. nosocomials. Furthermore, we studied the characteristics of 10 A. seifertii isolates, which were distributed widely in 6 provinces in China and mainly caused infections in the elderly or children. To define the taxonomic status and characteristics, the biochemical reactions, antimicrobial susceptibility testing, pulsed field gel electrophoresis (PFGE), multilocus sequence typing (MLST), and whole-genome sequence analysis were performed. The phenotypic characteristics failed to distinguish A. serfertii from other species in the ACB complex. Most of the A. seifertii isolates were susceptible to antibiotics commonly used for nosocomial Acinetobacter spp. infections, but one isolate (strain A362) was resistant to ampicillin/sulbactam, ceftazidime and amikacin. The different patterns of MLST and PFGE suggested that the 10 isolates were not identical and lacked clonal relatedness. Our study reported for the first time the molecular epidemiological and genomic features of widely disseminated A. seifertii in China. These observations could enrich the knowledge of infections caused by non-A. baumannii and may provide a scientific basis for future clinical treatment. PMID- 26945402 TI - Controlled Ovarian Stimulation Using Medroxyprogesterone Acetate and hMG in Patients With Polycystic Ovary Syndrome Treated for IVF: A Double-Blind Randomized Crossover Clinical Trial. AB - Ovarian hyperstimulation syndrome (OHSS) during ovarian stimulation is a current challenge for patients with polycystic ovarian syndrome (PCOS). Our previous studies indicated that progestin can prevent premature luteinizing hormone (LH) surge or moderate/severe OHSS in the general subfertile population, both in the follicular-phase and luteal-phase ovarian stimulation but it is unclear if this is true for patients with PCOS. The aim of the article was to analyze cycle characteristics and endocrinological profiles using human menopausal gonadotropin (hMG) in combination with medroxyprogesterone acetate (MPA) for PCOS patients who are undergoing IVF/intracytoplasmic sperm injection (ICSI) treatments and investigate the subsequently pregnancy outcomes of frozen embryo transfer (FET). In the randomized prospective controlled study, 120 PCOS patients undergoing IVF/ICSI were recruited and randomly classified into 2 groups according to the ovarian stimulation protocols: hMG and MPA (group A, n = 60) or short protocol (group B, n = 60). In the study group, hMG (150-225IU) and MPA (10 mg/d) were administered simultaneously beginning on cycle day 3. Ovulation was cotriggered by a gonadotropinreleasing hormone (GnRH) agonist (0.1 mg) and hCG (1000IU) when dominant follicles matured. A short protocol was used as a control. The primary end-point was the ongoing pregnancy rate per transfer and incidence of OHSS. Doses of hMG administrated in group A are significantly higher than those in the controls. LH suppression persisted during ovarian stimulation and no incidence of premature LH surge was seen in both groups. The fertilization rate and the ongoing pregnant rate in the study group were higher than that in the control. The number of oocytes retrieved, mature oocytes, clinical pregnancy rates per transfer, implantation rates, and cumulative pregnancy rates per patient were comparable between the 2 groups. The incidence of OHSS was low between the 2 groups, with no significant difference. The study showed that MPA has the advantages of an oral administration route, easy access, more control over LH levels. A possible reduction in the incidence of moderate or severe OHSS with the MPA protocol should be viewed with caution as the data is small. Large randomized trials with adequate sample size remain necessary. PMID- 26945403 TI - Risk Factors and Clinical Outcomes for Patients With Acinetobacter baumannii Bacteremia. AB - Acinetobacter (A.) baumannii, an opportunistic nosocomial pathogen that can cause significant morbidity and mortality, has emerged as a worldwide problem. This study aimed to analyze the clinical features and outcomes of patients with A. baumannii bacteremia and determine the factors influencing survival by using 14 day mortality as the primary endpoint. A 6-year retrospective study of 122 cases with monomicrobial A. baumannii bacteremia was conducted in Chinese People's Liberation Army (PLA) General Hospital from January 2008 to April 2014. Predictors of 14-day mortality were identified by logistic regression analysis. The overall 14-day mortality rate was 40.2% (49 of 122 patients). Multivariable analysis revealed that independent predictors of 14-day mortality included severity of illness defined by Pitt Bacteremia Score (PBS) (odds ratio [OR], 0.46; 95% confidence interval [CI], 0.340-0.619; P < 0.001), neutropenia (OR, 18.02; 95% CI, 1.667-194.67; P = 0.017), and malignancy (OR, 4.63; 95% CI, 1.292 16.588; P = 0.019). The effect of malignancy was influenced by neutropenia (OR for interaction term, 1.60; 95% CI, 1.15-2.22; P = 0.005). A subgroup analysis revealed that 14-day mortality rate for patients with underlying hematological malignancies and solid tumors was 75% (12/16) and 40% (12/30), respectively. Survival analysis revealed that mortality in patients with hematological malignancies was higher than that in patients with solid tumors (P = 0.032). The outcomes of patients with A. baumannii bacteremia were related to PBS, neutropenia, and malignancy. Compared with solid tumors, patients with hematological malignancies had a higher mortality in the setting of A. baumannii bacteremia. PMID- 26945404 TI - Risk of Cerebrovascular Events in Pneumoconiosis Patients: A Population-based Study, 1996-2011. AB - Pneumoconiosis is a parenchymal lung disease that develops through the inhalation of inorganic dust at work. Cerebrovascular and cardiovascular events are leading causes of mortality and adult disability worldwide. This retrospective cohort study investigated the association between pneumoconiosis, and cerebrovascular and cardiovascular events by using a nationwide population-based database in Taiwan. The data analyzed in this study was retrieved from the Taiwan National Health Insurance Research Database. We selected 6940 patients with pneumoconiosis from the database as our study cohort. Another 27,760 patients without pneumoconiosis were selected and matched with those with pneumoconiosis according to age and sex as the comparison cohort. We used univariate and multivariate Cox proportional-hazard regression analyses to determine the association between pneumoconiosis and the risk of cerebrovascular and cardiovascular events after adjusting for medical comorbidities. After adjustment for age, sex, and comorbidities, the patients with pneumoconiosis exhibited a significantly higher incidence of ischemic stroke (hazard ratio [HR] 1.14, 95% confidence interval [CI] 1.05-1.24) than did those without pneumoconiosis. The incidence of hemorrhagic stroke was higher, but not significant, in the pneumoconiosis patients (HR 1.20, 95% CI 0.99-1.46). No statistically significant differences were observed between the pneumoconiosis and nonpneumoconiosis groups in acute coronary syndrome (HR 1.10, 95% CI 0.95-1.26). The findings of this study reveal an association between pneumoconiosis and a higher risk of cerebrovascular events after adjustment for comorbidities. Healthcare providers should control the related risk factors for primary prevention of stroke in pneumoconiosis patients. PMID- 26945405 TI - Internal Versus External Fixation for the Treatment of Distal Radial Fractures: A Systematic Review of Overlapping Meta-Analyses. AB - Although a serious of meta-analyses have been published to compare the effects of internal versus external fixation (IF vs EF) for treating distal radial fractures (DRF), no consensus was obtained.B y performing a systematic review of overlapping meta-analyses comparing IF versus EF for the treatment of distal radial fractures, we attempted to evaluate the methodology and reporting quality of these meta-analyses, interpret the source of discordant results, and therefore determine the dominant strategy for the treatment of distal radial fractures based on the best evidence currently. An electronic databases search was conducted in MEDLINE, Embase, and Cochrane library to retrieve meta-analyses comparing IF versus EF for treating DRF. Reference lists of relevant literatures were also screened manually to retrieve additional ones. Two investigators independently assessed the eligibility of retrieved articles using predefined inclusion and exclusion criteria. All characteristics as well as outcome variables including functional outcomes, range of motion, radiological results, and complication rates with relevant heterogeneity information presented in each included study were extracted. Heterogeneity was thought to be significant when I2 > 50%. We adopted the Oxford Levels of Evidence and the Assessment of Multiple Systematic Reviews (AMSTAR) Instrument to assess the methodological quality of every included study, and applied the Jadad decision algorithm to select studies with more likely reliable conclusions. A total of 8 studies met the inclusion criteria. The AMSTAR scores ranged from 5 to 9 with a median of 7.75. Following the Jadad algorithm, the meta-analyses with most reliable results can be selected based on the search strategies and application of selection. Finally, 2 meta analyses with most RCTs and highest AMSTAR scores were selected in this systematic review of overlapping meta-analysis. The best available evidence suggested that compared with EF, IF was significantly associated with lower Disabilities of the Arm, Shoulder and Hand (DASH) scores, better rehabilitation of volar tilt and radial inclination, and lower infection rate at 1-year follow up. Therefore, we could conclude that internal fixation is superior to external fixations for the treatment of distal radial fractures. PMID- 26945406 TI - AST to Platelet Ratio Index Predicts Mortality in Hospitalized Patients With Hepatitis B-Related Decompensated Cirrhosis. AB - Aspartate aminotransferase to platelet ratio index (APRI) has originally been considered as a noninvasive marker for detecting hepatic fibrosis in patients with chronic hepatitis B and C. APRI has been used for predicting liver-related mortality in patients with chronic hepatitis C virus infection or alcoholic liver disease. However, whether APRI could be useful for predicting mortality in chronic hepatitis B virus (HBV) infection remains unevaluated. This study aims to address this knowledge gap. A total of 193 hospitalized chronic HBV-infected patients (cirrhosis, n = 100; noncirrhosis, n = 93) and 88 healthy subjects were retrospectively enrolled. All patients were followed up for 4 months. Mortality that occurred within 90 days of hospital stay was compared among patients with different APRI. APRI predictive value was evaluated by univariate and multivariate regression embedded in a Cox proportional hazards model. APRI varied significantly in our cohort (range, 0.16-10.00). Elevated APRI was associated with increased severity of liver disease and 3-month mortality in hospitalized patients with HBV-related cirrhosis. Multivariate analysis demonstrated that APRI (odds ratio: 1.456, P < 0.001) and the model for end-stage liver disease score (odds ratio: 1.194, P < 0.001) were 2 independent markers for predicting mortality. APRI is a simple marker that may serve as an additional predictor of 3 month mortality in hospitalized patients with HBV-related decompensated cirrhosis. PMID- 26945407 TI - Efficacy and Safety of 1-Hour Infusion of Recombinant Human Atrial Natriuretic Peptide in Patients With Acute Decompensated Heart Failure: A Phase III, Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial. AB - The aim of the study was to evaluate the efficacy and safety of 1-h infusion of recombinant human atrial natriuretic peptide (rhANP) in combination with standard therapy in patients with acute decompensated heart failure (ADHF). This was a phase III, randomized, double-blind, placebo-controlled, multicenter trial. Eligible patients with ADHF were randomized to receive a 1-h infusion of either rhANP or placebo at a ratio of 3:1 in combination with standard therapy. The primary endpoint was dyspnea improvement (a decrease of at least 2 grades of dyspnea severity at 12 h from baseline). Reduction in pulmonary capillary wedge pressure (PCWP) 1 h after infusion was the co-primary endpoint for catheterized patients. Overall, 477 patients were randomized: 358 (93 catheterized) patients received rhANP and 118 (28 catheterized) received placebo. The percentage of patients with dyspnea improvement at 12 h was higher, although not statistically significant, in the rhANP group than in the placebo group (32.0% vs 25.4%, odds ratio=1.382, 95% confidence interval [CI]: 0.863-2.212, P = 0.17). Reduction in PCWP at 1 h was significantly greater in patients treated with rhANP than in patients treated with placebo (-7.74 +/- 5.95 vs -1.82 +/- 4.47 mm Hg, P < 0.001). The frequencies of adverse events and renal impairment within 3 days of treatment were similar between the 2 groups. Mortality at 1 month was 3.1% in the rhANP group vs 2.5% in the placebo group (hazard ratio = 1.21, 95% CI: 0.34-4.26; P > 0.99). 1-h rhANP infusion appears to result in prompt, transient hemodynamic improvement with a small, nonsignificant, effect on dyspnea in ADHF patients receiving standard therapy. The safety of 1-h infusion of rhANP seems to be acceptable. (WHO International Clinical Trials Registry Platform [ICTRP] number, ChiCTR-IPR-14005719.). PMID- 26945408 TI - Is MDM2 SNP309 Variation a Risk Factor for Head and Neck Carcinoma?: An Updated Meta-Analysis Based on 11,552 Individuals. AB - Murine double minute-2 (MDM2) is a negative regulator of P53, and its T309G polymorphism has been suggested as a risk factor for a variety of cancers. Increasing evidence has shown the association of MDM2 T309G polymorphism with head and neck carcinoma (HNC) risk. However, the results are inconsistent. Thus, we performed a meta-analysis to elucidate the association. The meta-analysis retrieved studies published up to August 2015, and essential information was extracted for analysis. Separate analyses on ethnicity, source of controls, sample size, detection method, and cancer types were also conducted. Odds ratios (ORs) and their 95% confidence intervals (CIs) were used to estimate the association. Pooled data from 16 case-control studies including 4625 cases and 6927 controls failed to indicate a significant association. However, in the subgroup analysis of sample sizes, an increased risk was observed in the largest sample size group (>1000) under a recessive model (OR = 1.52; 95% CI = 1.08 2.13). Increased risks were also found in the nasopharyngeal cancer in the subgroup analysis of cancer types (GG vs TT: OR = 2.07; 95% CI = 1.38-3.12; dominant model: OR = 1.48; 95% CI = 1.13-1.93; recessive model: OR = 1.76; 95% CI = 1.17-2.65). The results suggest that homozygote GG alleles of MDM2 SNP309 may be a low-penetrant risk factor for HNC, and G allele may confer nasopharyngeal cancer susceptibility. PMID- 26945409 TI - Viridans Group Streptococcal Infections in Children After Chemotherapy or Stem Cell Transplantation: A 10-year Review From a Tertiary Pediatric Hospital. AB - Viridans Group Streptococci (VGS) are associated with high mortality rates in febrile neutropenia; yet there are no recent European pediatric studies to inform antimicrobial therapy. The aim of this study was to describe the characteristics, outcome, and resistance patterns of children with VGS bacteremia (VGSB) undergoing treatment of malignancy or hematopoietic stem cell transplant. Patients aged 0 to 18 years, admitted to a tertiary pediatric hemato-oncology center with VGSB, from 2003 to 2013, were included in the study. All data were collected retrospectively from medical records. A total of 54 bacteremic episodes occurred in 46 patients. The most common underlying diagnosis was relapsed acute lymphoblastic leukemia. Streptococcus mitis was the most frequent organism. A total of 30% of isolates were resistant to penicillin and 100% sensitive to vancomycin. There were 8 episodes (14.8%) of Viridans Group Streptococcal Shock Syndrome; 6 resulted in admission to intensive care and 3 of these patients died of multiorgan failure. The potentially fatal nature of VGSB is confirmed. The high risk in relapsed acute lymphoblastic leukemia is of note. Research is needed to develop risk-stratification scores that identify children at risk of Viridans Group Streptococcal Shock Syndrome to guide empirical antimicrobial therapy in febrile neutropenia. PMID- 26945410 TI - Using a Web-Based Approach to Assess Test-Retest Reliability of the "Hypertension Self-Care Profile" Tool in an Asian Population: A Validation Study. AB - Essential hypertension often requires affected patients to self-manage their condition most of the time. Besides seeking regular medical review of their life long condition to detect vascular complications, patients have to maintain healthy lifestyles in between physician consultations via diet and physical activity, and to take their medications according to their prescriptions. Their self-management ability is influenced by their self-efficacy capacity, which can be assessed using questionnaire-based tools. The "Hypertension Self-Care Profile" (HTN-SCP) is 1 such questionnaire assessing self-efficacy in the domains of "behavior," "motivation," and "self-efficacy." This study aims to determine the test-retest reliability of HTN-SCP in an English-literate Asian population using a web-based approach. Multiethnic Asian patients, aged 40 years and older, with essential hypertension were recruited from a typical public primary care clinic in Singapore. The investigators guided the patients to fill up the web-based 60 item HTN-SCP in English using a tablet or smartphone on the first visit and refilled the instrument 2 weeks later in the retest. Internal consistency and test-retest reliability were evaluated using Cronbach's Alpha and intraclass correlation coefficients (ICC), respectively. The t test was used to determine the relationship between the overall HTN-SCP scores of the patients and their self-reported self-management activities. A total of 160 patients completed the HTN-SCP during the initial test, from which 71 test-retest responses were completed. No floor or ceiling effect was found for the scores for the 3 subscales. Cronbach's Alpha coefficients were 0.857, 0.948, and 0.931 for "behavior," "motivation," and "self-efficacy" domains respectively, indicating high internal consistency. The item-total correlation ranges for the 3 scales were from 0.105 to 0.656 for Behavior, 0.401 to 0.808 for Motivation, 0.349 to 0.789 for Self-efficacy. The corresponding ICC scores of 0.671, 0.762, and 0.720 for these respective domains showed good test-retest reliability. The correlation of the HTN-SCP scores and patients' reported self-management measures were significant, except for keeping their food diary. HTN-SCP showed satisfactory internal consistency and test-retest reliability in an English literate Asian population. A web-based approach is feasible if similar studies are needed to validate its translated versions of the tool for wider application in the local multilingual population. PMID- 26945411 TI - Familial Gigantiform Cementoma: Case Report of an Unusual Clinical Manifestation and Possible Mechanism Related To "Calcium Steal Disorder". AB - Familial gigantiform cementoma is an exceedingly rare but distinct subtype of cemento-osseous-fibrous lesion. Undocumented radiographic changes and related bone metabolism disorder are herein hypothesized and discussed. We present an adolescent case with recurrent familial gigantiform cementoma who received surgical intervention in our hospital. Apart from typical multiquadrant and expansile abnormalies involving both jaws, he also suffered from several times of fractures in lower extremity. Furthermore, radiographic examinations of calvaria, pelvis, femoris, tibia, and fibula all revealed radiolucent areas signifying diffuse osteopenic bone losses. Some of his consanguineous relatives bore the same burden of fractures during pubertal period.Considering these polyostotic conditions, a correlation of congenital bone metabolism disorder in cases with familial gigantiform cementoma, named "calcium steal disorder," was thus proposed. Familial gigantiform cementoma is closely associated with "calcium steal disorder." Whole-body dual-energy absorptiometry should be considered as a routine examination for fracture-related risk prediction. PMID- 26945412 TI - Risk of Esophageal Cancer Following Percutaneous Endoscopic Gastrostomy in Head and Neck Cancer Patients: A Nationwide Population-Based Cohort Study in Taiwan. AB - Esophageal cancers account for majority of synchronous or metachronous head and neck cancers. This study examined the risk of esophageal cancer following percutaneous endoscopic gastrostomy (PEG) in head and neck cancer patients using the Taiwan National Health Insurance Research Database. From 1997 to 2010, we identified and analyzed 1851 PEG patients and 3702 sex-, age-, and index date matched controls. After adjusting for esophagitis, esophagus stricture, esophageal reflux, and primary sites, the PEG cohort had a higher adjusted hazard ratio (2.31, 95% confidence interval [CI] = 1.09-4.09) of developing esophageal cancer than the controls. Primary tumors in the oropharynx, hypopharynx, and larynx were associated with higher incidence of esophageal cancer. The adjusted hazard ratios were 1.49 (95% CI = 1.01-1.88), 3.99 (95% CI = 2.76-4.98), and 1.98 (95% CI = 1.11-2.76), respectively. Head and neck cancer patients treated with PEG were associated with a higher risk of developing esophageal cancer, which could be fixed by surgically placed tubes. PMID- 26945413 TI - CT and MR Imaging Findings of Pancreatic Paragangliomas: A Case Report. AB - Previous studies on pancreatic paraganglioma, a rare neoplasm, have primarily reported its ultrasound and routine and contrast-enhanced computed tomography (CT) findings. To our knowledge, we are the first to report the contrast-enhanced magnetic resonance imaging (MRI) and diffusion-weighted imaging (DWI) sequence findings of pancreatic paraganglioma. A male patient, ages 41 years, was admitted to our hospital due to a pancreatic space-occupying lesion that had been present for more than 10 days. The patient had no obvious discomfort. He had a history of hypertension and hyperthyroidism. Physical examination revealed upper abdominal tenderness without a palpable mass. Routine and contrast-enhanced abdominal CT showed a soft tissue mass at the pancreatic head/uncinate process, with patchy calcification within the lesion. On a contrast-enhanced CT scan, severe enhancement of the mass in the arterial phase was noted, as was slightly reduced but still marked enhancement in the venous phase. The celiac trunk and superior mesenteric artery segment were wrapped by the tumor. Thickened, tortuous vessels were observed at the lesion edges, around which there were multiple enlarged lymph nodes. The main pancreatic duct was markedly dilated. Routine and contrast enhanced pancreatic MRI demonstrated an abnormal nodular signal in the pancreatic head/uncinate process that was approximately 4.3 * 6.4 cm2 in size. T1-weighted imaging (T1WI) revealed hypointensity, whereas T2-weighted imaging (T2WI) revealed nonhomogeneous, slight hyperintensity. Patchy hypointensity on both T1WI and T2WI was observed within the lesion. DWI showed slight hyperintensity. Grossly heterogeneous enhancement of the mass was observed on a contrast-enhanced MRI scan, with the tumor wrapped around the adjacent vasculature, and multiple enlarged lymph nodes were observed peripherally. After preoperative preparation, the patient underwent pancreatoduodenectomy. Histopathology and immunohistochemistry of the resected tumor indicated pancreatic paraganglioma. After surgery, the patient recovered well, without presenting any recurrence or metastasis during short-term follow-up. For hypervascular pancreatic tumors on contrast-enhanced CT or MRI, and particularly those occurring in the pancreatic head, with a clear display of draining veins, the possibility of pancreatic paraganglioma should be considered. These tumors usually exhibit necrosis or cystic changes and are occasionally accompanied by calcification. PMID- 26945414 TI - Role of T1 Pelvic Angle in Assessing Sagittal Balance in Outpatients With Unspecific Low Back Pain. AB - The aim of the study was to explore the significance of T1 pelvic angle (TPA) for assessment of sagittal balance in a cohort of Chinese patients with unspecific low back pain. TPA has been commonly used to assess sagittal balance in adult spinal deformity. However, whether TPA could be used to assess sagittal balance in patients with unspecific low back pain effectively remains unanswered. Medical records of outpatients with unspecific low back pain who received treatment in our outpatient clinic between September 2013 and November 2014 were reviewed. Demographic data and radiographic data were collected. Correlation coefficients between TPA and other sagittal parameters were analyzed, and the intraclass correlation coefficient (ICC) analysis was performed to assess the inter- and intra-observer reliability of TPA. Patients were divided into 2 groups according to whether they were well-aligned (TPA <= 20 degrees ) or poorly aligned (TPA > 20 degrees ), and then demographic and sagittal parameters were compared between the 2 groups of patients. A total of 97 patients with unspecific low back pain were included in this study. The inter- and intraobserver reliability of the TPA measure had excellent agreement (ICC = 0.985 and 0.919, respectively). There were significant correlations between TPA and age, LL, PT, PI, T1SPI, SVA, and NRS (all P < 0.05). Of the 38 well-aligned patients in Group A, SVA was <=5 cm in 33 (86.84%) patients and >5 cm in the other 5 (13.16%) patients, and of the 59 poorly aligned patients in Group B, SVA was >5 cm in 42 (71.19%) patients and <=5 cm in the other 17 (28.81%) patients. There were significant differences in age, LL, SS, PT, PI, T1SPI, SVA, and NRS between the 2 groups of patients, but no significant difference was observed in TK and TL. TPA could be used to assess sagittal balance in outpatients with unspecific low back pain effectively. PMID- 26945415 TI - Environmental and Occupational Lead Exposure Among Children in Cairo, Egypt: A Community-Based Cross-Sectional Study. AB - The aim of this study was to assess childhood lead exposure in a representative sample of Cairo, and to investigate the possible risk factors and sources of exposure. This cross-sectional study was conducted from November 2014 through April 2015. The target population was children aged 6 to 18 years, recruited into 4 groups, garbage city, moderate-living standard area, urban and suburban schools, and workshops in the city of Cairo. Blood lead levels (BLLs) and hemoglobin (Hb) concentrations were measured. Also, potential local environmental sources were assessed for hazardous lead contamination. Analysis on 400 participants has been carried out. A total of 113 children had BLLs in the range 10 to 20 MUg/dL. Smoking fathers, housing conditions, playing outdoors, and exposure to lead in residential areas were significantly correlated with high BLLs. The mean values of hemoglobin were inversely correlated with BLLs. Children involved in pottery workshops had the highest BLLs and the lowest Hb values with a mean of (43.3 MUg/dL and 8.6 g/dL, respectively). The mean value of environmental lead in workshop areas exceeded the recommended levels. Also, those values measured in dust and paint samples of garbage city were significantly high. Moreover, the mean lead levels in the soil samples were significantly higher in urban schools (P = 0.03) than the suburban ones. Childhood lead poisoning accounts for a substantial burden in Egypt, which could be preventable. Development of national prevention programs including universal screening program should be designed to reduce incidence of lead toxicity among children. PMID- 26945416 TI - Prenatal and Early Postnatal Diagnosis of Congenital Toxoplasmosis in a Setting With No Systematic Screening in Pregnancy. AB - To determine the risk of congenital toxoplasmosis (CT) and provide early (pre- or postnatal) identification of cases of CT in the absence of systematic screening in pregnancy.I n the presented cross-sectional study, serological criteria were used to date Toxoplasma gondii infection versus conception in 80 pregnant women with fetal abnormalities or referred to as suspected of acute infection, and in 16 women after delivery of symptomatic neonates. A combination of serological, molecular (qPCR), and biological (bioassay) methods was used for prenatal and/or postnatal diagnosis of CT. Most (77.5%) pregnant women were examined in advanced pregnancy. Of all the examined seropositive women (n = 90), infection could not be ruled out to have occurred during pregnancy in 93.3%, of which the majority (69%) was dated to the periconceptual period. CT was diagnosed in 25 cases, of which 17 prenatally and 8 postnatally. Molecular diagnosis proved superior, but the diagnosis of CT based on bioassay in 7 instances and by Western blot in 2 neonates shows that other methods remain indispensable. In the absence of systematic screening in pregnancy, maternal infection is often diagnosed late, or even only when fetal/neonatal infection is suspected. In such situations, use of a complex algorithm involving a combination of serological, biological, and molecular methods allows for prenatal and/or early postnatal diagnosis of CT, but lacks the preventive capacity provided by early maternal treatment. PMID- 26945417 TI - The White Matter Microintegrity Alterations of Neocortical and Limbic Association Fibers in Major Depressive Disorder and Panic Disorder: The Comparison. AB - The studies regarding to the comparisons between major depressive disorder (MDD) and panic disorder (PD) in the microintegrity of white matter (WM) are uncommon. Therefore, we tried to a way to classify the MDD and PD. Fifty-three patients with 1st-episode medication-naive PD, 54 healthy controls, and 53 patients with 1st-episode medication-naive MDD were enrolled in this study. The controls and patients were matched for age, gender, education, and handedness. The diffusion tensor imaging scanning was also performed. The WM microintegrity was analyzed and compared between 3 groups of participants (ANOVA analysis) with age and gender as covariates. The MDD group had lower WM microintegrity than the PD group in the left anterior thalamic radiation, left uncinate fasciculus, left inferior fronto-occipital fasciculus, and bilateral corpus callosum. The MDD group had reductions in the microintegrity when compared to controls in the bilateral superior longitudinal fasciculi, inferior longitudinal fasciculi, inferior fronto occipital fasciculi, and corpus callosum. The PD group had lower microintegrity in bilateral superior longitudinal fasciculi and left inferior fronto-occipital fasciculus when compared to controls. The widespread pattern of microintegrity alterations in fronto-limbic WM circuit for MDD was different from restrictive pattern of alterations for PD. PMID- 26945418 TI - Prognostic Value of Lymph Node Ratio in Locally Advanced Rectal Cancer Patients After Preoperative Chemoradiotherapy Followed by Total Mesorectal Excision. AB - Although the absolute number of positive lymph nodes (LNs) has been established as 1 of the most important prognostic factors in rectal cancers, many researchers have proposed that the lymph node ratio (LNR) may have better predicted outcomes. We conducted a retrospective study to compare the predictive ability of LNR and ypN category in rectal cancer. A total of 264 locally advanced rectal cancer (LARC) patients who underwent preoperative chemoradiotherapy (CRT) followed by total mesorectal excision (TME) between 2005 and 2012 were reviewed. All patients were categorized into 3 groups or patients with metastatic LNs were categorized into 2 groups according to the LNR. The prognostic effect on overall survival (OS) and disease-free survival (DFS) was evaluated. With a median follow-up of 45 months, the OS and DFS were 68.4% and 59.3% for the entire cohort, respectively. The respective 5-year OS and DFS rates for the 3 groups (LNR = 0, 0 < LNR <= 0.20, and 0.20 < LNR <= 1.0) were as follows: 83.2%, 72.6%, and 49.4% (P < 0.001) and 79.5%, 57.3%, and 33.5% (P < 0.001), respectively. Multivariate analysis revealed that LNR and differentiation, but not the number of positive LNs, had independent prognostic value for OS (hazard ratio [HR] = 2.328, 95% confidence interval [CI]: 1.850-4.526, P < 0.001) and DFS (HR = 3.004, 95% CI: 1.616-5.980, P < 0.001). As for patients with positive LNs, the respective 5-year OS and DFS rates for the 2 groups (0 < LNR <= 0.20, and 0.20 < LNR <= 1.0) were 72.6% and 49.4% (P < 0.001) and 57.3% and 33.5% (P < 0.001), respectively. Multivariate analysis revealed that only LNR was an independent factor for OS (HR = 3.214, 95% CI: 1.726-5.986, P < 0.001) and DFS (HR = 4.230, 95% CI: 1.825-6.458, P < 0.001). Subgroups analysis demonstrated that the ypN category had no impact on survival whereas increased LNR was a significantly prognostic indicator for worse survival in the LNs < 12 subgroup. LNR is an independent prognostic factor in LARC patients treated with preoperative CRT followed by TME. It may be a better independent staging method than the number of metastatic LNs when <12 LNs are harvested after preoperative CRT. PMID- 26945419 TI - The Risk of Cancer in Patients With Obsessive-Compulsive Disorder: A Nationwide Population-Based Retrospective Cohort Study. AB - Previous studies suggest a link between anxiety disorders and cancer. The aim of the study was to evaluate the risk of cancer among patients with obsessive compulsive disorder (OCD) using a nationwide population-based dataset. We recruited newly diagnosed OCD patients without antecedent cancer from the Taiwan National Health Insurance Research Database between 2002 and 2011. The standardized incidence ratios (SIRs) were estimated for 22 specific cancer types among OCD patients and we determined the SIRs for subgroups according to age and sex group. In addition, because of a potential detection bias, a subgroup analysis stratified with the duration of the OCD diagnosis was carried out. Among the 52,656 OCD patients, who were followed up for 259,945 person-years (median follow-up = 4.9 years), there were 718 cases of cancer. Patients with OCD did not exhibit an increased overall cancer risk relative to the general population (SIR 1.05, 95% confidence interval [CI] 0.98-1.13). An increased SIR was observed among OCD patients only within the first year of OCD diagnosis (SIR 1.21, 95% CI 1.01-1.43).This study indicated that the overall cancer risk was not elevated among OCD patients. An increased SIR observed among OCD patients within the first year of OCD diagnosis may be caused by a surveillance bias, and because paraneoplastic manifestations presented with obsessive-compulsive behaviors. Prospective study is necessary to confirm these findings. PMID- 26945420 TI - Prognostic Value of the Sum of Metabolic Tumor Volume of Primary Tumor and Lymph Nodes Using 18F-FDG PET/CT in Patients With Cervical Cancer. AB - This is an observational study to determine the most relevant parameter of 18F fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) for predicting recurrence in cervical cancer. Fifty-six patients with International Federation of Gynecology and Obstetrics (FIGO) stage IIB-IVA cervical cancer who underwent pretreatment 18F-FDG PET/CT were enrolled. PET parameters including maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) of both primary tumor and pelvic and/or para-aortic lymph nodes were analyzed. SUVmax-S was defined as the sum of the SUVmax of primary tumor and the higher SUVmax of either pelvic or para-aortic lymph nodes. MTV-S was defined as the sum of the MTV of primary tumor and pelvic and para-aortic lymph nodes. TLG-S was calculated in the same way as MTV-S. We evaluated the relationship between these PET parameters and recurrence-free survival (RFS). Univariate analysis revealed that higher FIGO stage (hazard ratio [HR] = 5.61, 95% confidence interval [CI]: 1.68-18.68, P = 0.005), lymph node metastasis (HR = 3.42, 95% CI: 1.08-10.84, P = 0.037), MTV of primary tumor >47.81 cm3 (HR = 6.20, 95% CI: 1.35-28.48, P = 0.019), TLG of primary tumor >215.02 (HR = 11.82, 95% CI: 1.52-91.96, P = 0.018), MTV-S > 59.01 cm3 (HR = 8.24, 95% CI: 1.80-37.77, P = 0.007), and TLG-S > 224.15 (HR = 13.09, 95% CI: 1.68-101.89, P = 0.014) were associated with RFS. In multivariate analysis, FIGO stage (HR = 4.87, 95% CI: 1.38-17.18, P = 0.014) and MTV-S > 59.01 cm3 (HR = 7.37, 95% CI: 1.54-35.16, P = 0.012) were determined to be independent predictive factors for RFS. Our preliminary results reveal that MTV-S is an independent prognostic factor for RFS in patients with cervical cancer treated by definitive chemoradiotherapy. PMID- 26945421 TI - Background Parenchymal Enhancement on Preoperative Magnetic Resonance Imaging: Association With Recurrence-Free Survival in Breast Cancer Patients Treated With Neoadjuvant Chemotherapy. AB - To retrospectively investigate whether background parenchymal enhancement (BPE) of the contralateral breast on preoperative dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is associated with therapeutic outcomes following neoadjuvant chemotherapy (NAC) in unilateral invasive breast cancer. The institutional review board approved this study, and informed consent was waived. Between 2009 and 2011, 93 women with unilateral invasive breast cancer (43 premenopausal women who performed pre-NAC MRI between days 7 and 20 of the menstrual cycle and 50 postmenopausal women) underwent NAC with pre- and post-NAC DCE-MRI before surgery. MRI features (BPE [minimal, mild, moderate, marked] of the contralateral breast, lesion size and number, lesion kinetics, and changes in lesion size) and clinicopathologic features were analyzed. Patients were grouped according to BPE category (high [moderate or marked] or low [minimal or mild]). Cox regression modeling was used to determine associations between MRI features and recurrence-free survival (RFS) after controlling for clinicopathologic variables. The mean follow-up period was 48.2 months. Twenty-three recurrences occurred (2 ipsilateral breasts, 6 regional, and 15 distant). On multivariate analysis, high BPE on pre-NAC MRI (hazard ratio [HR] = 3.851, P = 0.006) and triple-negative cancer (HR = 3.192, P = 0.002) were independent factors associated with worse RFS. A greater reduction of lesion size on post-NAC MRI (HR = 0.984, P = 0.021) was associated with better RFS. High BPE on pre-NAC MRI is significantly associated with worse RFS in an NAC setting. This study suggests that BPE on pre-NAC DCE-MRI may have potential as a predictor of long-term outcomes in breast cancer patients who undergo NAC. PMID- 26945422 TI - Atrial Fibrillation Increases the Risk of Peripheral Arterial Disease With Relative Complications and Mortality: A Population-Based Cohort Study. AB - Atrial fibrillation (AF), an increasing prevalent cardiac arrhythmia due to aging general population, has many common risk factors with peripheral arterial disease (PAD). However, it is unclear whether AF is associated with a risk of PAD. We investigated the prevalence of AF and PAD in the general population and the risk of PAD among the AF population. This longitudinal, nationwide, population-based cohort study was conducted using data from the Taiwan National Health Insurance Research Database recorded during 2000 to 2011. In total, 3814 and 15,364 patients were included in the AF and non-AF cohorts, respectively. Univariate and multivariate Cox proportional hazard regression models were used for examining the effects of AF on the risk of outcomes. The average follow-up periods of PAD were 4.96 +/- 3.28 and 5.29 +/- 3.35 years for the AF and non-AF cohorts, respectively. Overall, the risk of PAD showed a significantly higher risk in the AF cohort (adjusted HR=1.31, 95% CI=1.19-1.45) compared with the non-AF cohort. Similar results were observed for heart failure and stroke, where the AF cohort had a 1.83-fold and 2.53-fold higher risk of developing heart failure and stroke. The AF cohort also had a significant increased risk for mortality (adjusted HR=1.66, 95% CI=1.49-1.84). The present study indicated that the incidence of PAD, heart failure, stroke, and overall mortality is higher in patients with AF than in those without it. PMID- 26945423 TI - Clinicopathologic Significance of HNF-1beta, AIRD1A, and PIK3CA Expression in Ovarian Clear Cell Carcinoma: A Tissue Microarray Study of 130 Cases. AB - Ovarian clear cell carcinoma (CCC) is a distinct histologic subtype with relatively poor survival. No prognostic or predictive molecular marker is currently available. Recent studies have shown that AT-rich interactive domain 1A (ARID1A) and phosphatidylinositol 3-kinase catalytic subunit alpha (PIK3CA) mutations are common genetic changes in ovarian CCC. Hepatocyte nuclear factor 1beta (HNF-1beta) expression has been proven to be highly sensitive and specific for clear cell histology. However, the correlations between these biomarkers and clinicopathologic variables and survival outcomes are controversial. The immunohistochemical analysis for HNF-1beta, ARID1A, and PIK3CA was performed on a tissue microarray (TMA) consisting of 130 cases of ovarian CCC (237 tissue blocks) linked with clinical information. The immunostaining results were interpreted in a manner consistent with previous publications. The associations between biomarker expression and clinical and prognostic features were examined. All statistical analyses were conducted using 2-sided tests, and a value of P < 0.05 was considered significant. HNF-1beta was expressed in 92.8% of all primary ovarian tumors, while the loss of ARID1A and PIK3CA was noted in 56.2% and 45.0%, respectively. Early-stage tumors tended to have high levels of HNF-1beta immunoreactivity and expression of ARID1A (P = 0.02 and P = 0.03). Most patients (76.9%, 20/26) with concurrent endometriosis stained negative for ARID1A (P = 0.02). No relation was found between PIK3CA expression and clinical features. Low level HNF-1beta expression and loss of ARID1A were more commonly observed in patients with tumor recurrence (P = 0.02 and P < 0.001). Antibody expression was not associated with platinum-based chemotherapy response. Patients with negative ARID1A expression had worse survival outcome in terms of both overall survival (OS) and progression-free survival (PFS) (P = 0.03 and P = 0.01, respectively). On the contrary, patients with high-level HNF-1beta were associated with good prognosis (P = 0.02 for OS and P = 0.01 for PFS). PIK3CA expression had no impact on survival. For univariate and multivariate analyses, only HNF-1beta expression seemed to be a prognostic factor for favorable OS (P = 0.04). The loss of ARID1A was correlated with late-stage and endometriosis-associated tumors. The measurement of ARID1A expression might be a method to predict the risk of recurrence. Among the 3 biomarkers, only high-level HNF-1beta expression proved to be a positive predictor for OS. PMID- 26945424 TI - Systematic Review and Network Meta-Analysis of Randomized Controlled Trials: Comparative Effectiveness and Safety of Direct-Acting Antiviral Agents for Treatment-Naive Hepatitis C Genotype 1. AB - All possible direct-acting antiviral agent (DAA) regimens for treatment-naive hepatitis C genotype 1 were evaluated by many randomized controlled trials (RCTs). However, the optimum regimen remains inconclusive. We aim to compare interventions in terms of sustained virological response at 12 (SVR12) and 24 (SVR24) weeks after the end of treatment and adverse effects (AEs) (fatigue, headache, nausea, insomnia). PubMed, Embase, and the Cochrane Library were searched for RCTs until July 31, 2015. We estimated odds ratios (ORs) between treatments on clinical outcomes. Twenty-two eligible RCTs were included. Compared with peginterferon-ribavirin (PR), daclatasvir plus PR (OR 8.90, P < 0.001), faldaprevir plus PR (OR 3.72, P < 0.001), simeprevir plus PR (OR 3.59, P < 0.001), sofosbuvir plus PR (OR 4.69, P < 0.001) yield a significant effect in improving SVR12. Consistently, simeprevir plus PR (OR 3.49, P < 0.001), sofosbuvir plus PR (OR 4.51, P < 0.001), daclatasvir plus PR (OR 4.77, P < 0.001) also improved the rates of SVR24 significantly compared with PR. With respect to AEs, compared with PR, ledipasvir plus sofosbuvir plus PR (OR 2.13, P < 0.001) confer a significant AE in nausea, whereas daclatasvir plus PR (OR 0.20, P < 0.001 and OR 0.18, P < 0.001, respectively) lowered the incidence of fatigue and nausea significantly when compared with ledipasvir plus sofosbuvir plus PR. Daclatasvir plus PR was the most effective in SVR12 and SVR24, but caused an increased AEs profile (headache and insomnia). Combined ledipasvir with sofosbuvir or combination of PR was associated with higher incidence of fatigue and nausea. PMID- 26945425 TI - Injury of the Arcuate Fasciculus in the Dominant Hemisphere in Patients With Mild Traumatic Brain Injury: A Retrospective Cross-Sectional Study. AB - Little is known about injury of the arcuate fasciculus (AF) in patients with mild traumatic brain injury (TBI). We investigated injury of the AF in the dominant hemisphere in patients with mild TBI, using diffusion tensor tractography (DTT). We recruited 25 patients with injury of the left AF among 64 right-handed consecutive patients with mild TBI and 20 normal control subjects. DTTs of the left AF were reconstructed, and fractional anisotropy (FA), apparent diffusion coefficient (ADC), and fiber number of the AF were measured. Among 64 consecutive patients, 25 (39%) patients showed injury of the left AF. The patient group showed lower FA value and fiber number with higher ADC value than the control group (P < 0.05). On K-WAB evaluation, aphasia quotient and language quotient were 95.9 +/- 4.1 (range 85-100) and 95.0 +/- 5.4 (range 80-100), respectively. However, 23 (92.0%) of 25 patients complained of language-related symptoms after TBI; paraphasia in 12 (48.0%) patients, deficits of comprehension in 4 (16.0%) patients, deficits of speech production in 1 (4.0%) patient, and >2 language symptoms in 6 (24.0%) patients. We found that a significant number (39%) of patients with mild TBI had injury of the AF in the dominant hemisphere and these patients had mild language deficit. These results suggest that DTT could provide useful information in detecting injury of the AF and evaluation of the AF using DTT would be necessary even in the case of a patient with mild TBI who complains of mild language deficit. PMID- 26945426 TI - Pulmonary Toxicities of Gefitinib in Patients With Advanced Non-Small-Cell Lung Cancer: A Meta-Analysis of Randomized Controlled Trials. AB - Gefitinib is a selective tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR) used to treat adults with EGFR mutation-positive non-small-cell lung cancer (NSCLC). Clinical benefits of gefitinib administration in NSCLC patients have been observed in clinical practice, but the extent of the pulmonary toxicity of gefitinib in patients with advanced NSCLC remains unclear. The aim of this systematic review was to evaluate the overall incidence and risk of gefitinib-related pulmonary toxicity in advanced NSCLC patients. Relevant trials were identified from the databases of Pubmed, Embase, Cochrane Library, and the clinicaltrials.gov of the U.S. National Institutes of Health. The outcomes included the overall incidence, odds ratios (ORs), and 95% confidence intervals (CIs). Fixed-effects models were used in the statistical analyses according to the heterogeneity of the included studies. According to the data from the included trials, the overall incidence of high-grade hemoptysis, pneumonia, pneumonitis, and interstitial lung disease (ILD) was 0.49% (95% CI: 0.24%-0.99%), 2.33% (95% CI: 1.47%-3.66%), 2.24% (95% CI: 1.34%-3.72%), and 1.43% (95% CI: 0.98%-2.09%), respectively. The pooled ORs of high-grade hemoptysis, pneumonia, pneumonitis, and ILD were 1.73 (95% CI: 0.46-6.52; P = 0.42), 0.99 (95% CI: 0.66 1.49; P = 0.95), 4.70 (95% CI: 1.48-14.95; P = 0.0087), and 2.64 (95% CI: 1.22 5.69; P = 0.01), respectively. Gefitinib was associated with a significantly increased risk of high-grade/fatal ILD and pneumonitis compared with the controls, whereas the risk of other high-grade pulmonary events (pneumonia and hemoptysis) was not significant. Careful surveillance of gefitinib-related pulmonary toxicity is critical for the safe use of this drug. PMID- 26945427 TI - Different Prognostic Implications of 18F-FDG PET Between Histological Subtypes in Patients With Cervical Cancer. AB - This study aimed to investigate whether the predictive values of intensity- and volume-based PET parameters are different between histological subtypes in patients with cervical cancer. Ninety patients, 65 with squamous cell carcinoma (SCC) and 25 with non-SCC (NSCC), who underwent pretreatment 18F-FDG PET/CT and pelvic MRI, were studied retrospectively. In addition to SUVmax and SUVmean, metabolic-tumor-volume (MTV) was determined by thresholding of 40% SUVmax and total-lesion-glycolysis (TLG) was calculated. Clinical factors and PET metabolic indices were compared between SCC and NSCC. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method with cut-offs determined by ROC analyses to stratify SCC and NSCC patients separately. Factors associated with survival were assessed with univariate and multivariate analyses using the Cox regression model. No significant differences were observed in clinical factors other than tumor size or 18F-FDG PET metabolic indices between SCC and NSCC. The Kaplan-Meier estimates of 2-year PFS and OS rates were 60% and 70% for SCC and 40% and 76% for NSCC, respectively. Multivariate analyses showed that MTV and TLG were the independent prognostic factors for PFS and OS in SCC; in contrast, SUVmax was the independent prognostic factor for PFS and OS in NSCC. Metabolic burden (MTV and TLG) could be beneficial for the prognostic prediction of cervical SCC patients; in contrast, metabolic intensity (SUVmax) could be beneficial for the prognostic prediction of NSCC patients. The different prognostic implications might be based on the differences of tissue integrity and histological heterogeneity between SCC and NSCC. PMID- 26945428 TI - Application of a Clinical Whole-Transcriptome Assay for Staging and Prognosis of Prostate Cancer Diagnosed in Needle Core Biopsy Specimens. AB - Molecular and genomic analysis of microscopic quantities of tumor from formalin fixed, paraffin-embedded biopsy specimens has many unique challenges. Herein, we evaluated the feasibility of obtaining transcriptome-wide RNA expression to measure prognostic classifiers in diagnostic prostate needle core biopsy specimens. One-hundred fifty-eight samples from diagnostic needle core biopsy specimens (BX) and radical prostatectomies (RPs) were collected from 33 patients at three hospitals; each patient provided up to six tumor and benign samples. Genome-wide transcriptomic profiles were generated using Affymetrix Human Exon arrays for comparison of gene expression alterations and prognostic signatures between the BX and RP samples. A sufficient amount of RNA (>100 ng) was obtained from all RP specimens (n = 77) and from 72 of 81 of BX specimens. Of transcriptomic features detected in RP, 95% were detectable in BX tissues and demonstrated a high correlation (r = 0.96). Likewise, an expression signature pattern validated on RPs (Decipher prognostic test) showed correlation between BX and RP (r = 0.70). Of matched BX and RP pairs, 25% showed discordant molecular subtypes. Genome-wide exon arrays yielded data of comparable quality from biopsy and RP tissues. The high concordance of tumor-associated gene expression changes between BX and RP samples provides evidence for the adequate performance of the assay platform with samples from prostate needle biopsy specimens with limited tumor volume. PMID- 26945429 TI - Inter-cultivar variation in soil-to-plant transfer of radiocaesium and radiostrontium in Brassica oleracea. AB - Radiocaesium and radiostrontium enter the human food chain primarily via soil plant transfer. However, uptake of these radionuclides can differ significantly within species (between cultivars). The aim of this study was to assess inter cultivar variation in soil-to-plant transfer of radiocaesium and radiostrontium in a leafy crop species, Brassica oleracea. This study comprised four independent experiments: two pot experiments in a controlled environment artificially contaminated with radiocaesium, and two field experiments in an area contaminated with radiocaesium and radiostrontium in the Chernobyl Exclusion Zone. Radiocaesium concentration ratios varied 35-fold among 27 cultivars grown in pots in a controlled environment. These 27 cultivars were then grown with a further 44 and 43 other cultivars in the Chernobyl Exclusion Zone in 2003 and 2004, respectively. In the field-grown cultivars radiocaesium concentration ratios varied by up to 35-fold and radiostrontium concentration ratios varied by up to 23-fold. In three of these experiments (one pot experiment, two field experiments) one out of the 27 cultivars was found to have a consistently lower radiocaesium concentration ratio than the other cultivars. The two field experiments showed that, five out of the 66 cultivars common to both experiments had consistently lower radiocaesium concentration ratios, and two cultivars had consistently lower radiostrontium concentration ratios. One cultivar had consistently lower radiocaesium and radiostrontium concentration ratios. The identification of cultivars that have consistently lower radiocaesium and/or radiostrontium concentration ratios suggests that cultivar selection or substitution may be an effective remediation strategy in radiologically contaminated areas. Future research should focus on plant species that are known to be the largest contributors to human dose. PMID- 26945430 TI - A New Framework and Practice Center for Adapting, Translating, and Scaling Evidence-Based Health/Wellness Programs for People With Disabilities. AB - Supporting the transition of people with newly acquired and existing disability from rehabilitation into community-based health/wellness programs, services, and venues requires rehabilitation professionals to build evidence by capturing successful strategies at the local level, finding innovative ways to translate successful practices to other communities, and ultimately to upgrade and maintain their applicability and currency for future scale-up. This article describes a knowledge-to-practice framework housed in a national resource and practice center that will support therapists and other rehabilitation professionals in building and maintaining a database of successful health/wellness guidelines, recommendations, and adaptations to promote community health inclusion for people with disabilities. A framework was developed in the National Center on Health, Physical Activity and Disability (NCHPAD) to systematically build and advance the evidence base of health/wellness programs, practices, and services applicable to people with disabilities. N-KATS (NCHPAD Knowledge Adaptation, Translation, and Scale-up) has 4 sequencing strategies: strategy 1-new evidence- and practice based knowledge is collected and adapted for the local context (ie, community); strategy 2-customized resources are effectively disseminated to key stakeholders including rehabilitation professionals with appropriate training tools; strategy 3-NCHPAD staff serve as facilitators assisting key stakeholders in implementing recommendations; strategy 4-successful elements of practice (eg, guideline, recommendation, adaptation) are archived and scaled to other rehabilitation providers. The N-KATS framework supports the role of rehabilitation professionals as knowledge brokers, facilitators, and users in a collaborative, dynamic structure that will grow and be sustained over time through the NCHPAD.Video abstract available for additional insights from the authors (see Video, Supplemental Digital Content 1, http://links.lww.com/JNPT/A130). PMID- 26945431 TI - Use of Tablet Computers to Promote Physical Therapy Students' Engagement in Knowledge Translation During Clinical Experiences. AB - BACKGROUND AND PURPOSE: Physical therapists strive to integrate research into daily practice. The tablet computer is a potentially transformational tool for accessing information within the clinical practice environment. The purpose of this study was to measure and describe patterns of tablet computer use among physical therapy students during clinical rotation experiences. METHODS: Doctor of physical therapy students (n = 13 users) tracked their use of tablet computers (iPad), loaded with commercially available apps, during 16 clinical experiences (6-16 weeks in duration). RESULTS: The tablets were used on 70% of 691 clinic days, averaging 1.3 uses per day. Information seeking represented 48% of uses; 33% of those were foreground searches for research articles and syntheses and 66% were for background medical information. Other common uses included patient education (19%), medical record documentation (13%), and professional communication (9%). The most frequently used app was Safari, the preloaded web browser (representing 281 [36.5%] incidents of use). Users accessed 56 total apps to support clinical practice. DISCUSSION AND CONCLUSIONS: Physical therapy students successfully integrated use of a tablet computer into their clinical experiences including regular activities of information seeking. Our findings suggest that the tablet computer represents a potentially transformational tool for promoting knowledge translation in the clinical practice environment.Video Abstract available for more insights from the authors (see Supplemental Digital Content 1, http://links.lww.com/JNPT/A127). PMID- 26945432 TI - Metal mixtures in urban and rural populations in the US: The Multi-Ethnic Study of Atherosclerosis and the Strong Heart Study. AB - BACKGROUND: Natural and anthropogenic sources of metal exposure differ for urban and rural residents. We searched to identify patterns of metal mixtures which could suggest common environmental sources and/or metabolic pathways of different urinary metals, and compared metal-mixtures in two population-based studies from urban/sub-urban and rural/town areas in the US: the Multi-Ethnic Study of Atherosclerosis (MESA) and the Strong Heart Study (SHS). METHODS: We studied a random sample of 308 White, Black, Chinese-American, and Hispanic participants in MESA (2000-2002) and 277 American Indian participants in SHS (1998-2003). We used principal component analysis (PCA), cluster analysis (CA), and linear discriminant analysis (LDA) to evaluate nine urinary metals (antimony [Sb], arsenic [As], cadmium [Cd], lead [Pb], molybdenum [Mo], selenium [Se], tungsten [W], uranium [U] and zinc [Zn]). For arsenic, we used the sum of inorganic and methylated species (?As). RESULTS: All nine urinary metals were higher in SHS compared to MESA participants. PCA and CA revealed the same patterns in SHS, suggesting 4 distinct principal components (PC) or clusters (?As-U-W, Pb-Sb, Cd Zn, Mo-Se). In MESA, CA showed 2 large clusters (?As-Mo-Sb-U-W, Cd-Pb-Se-Zn), while PCA showed 4 PCs (Sb-U-W, Pb-Se-Zn, Cd-Mo, ?As). LDA indicated that ?As, U, W, and Zn were the most discriminant variables distinguishing MESA and SHS participants. CONCLUSIONS: In SHS, the ?As-U-W cluster and PC might reflect groundwater contamination in rural areas, and the Cd-Zn cluster and PC could reflect common sources from meat products or metabolic interactions. Among the metals assayed, ?As, U, W and Zn differed the most between MESA and SHS, possibly reflecting disproportionate exposure from drinking water and perhaps food in rural Native communities compared to urban communities around the US. PMID- 26945433 TI - Association between statin treatment and LDL-cholesterol levels on the rate of ST elevation myocardial infarction among patients with acute coronary syndromes: ACS Israeli Survey (ACSIS) 2002-2010. AB - BACKGROUND: STEMI is thought to occur as a result of a vulnerable coronary plaque rupture. Statins possess hypolipidemic and pleotropic effects that stabilize coronary plaque. We sought to determine the association between LDL-C levels, statin use prior to the index event on the type of acute coronary syndrome (ACS) presentation: STEMI vs. non-STEMI/unstable angina. METHODS: Data was drawn from the ACS Israeli Survey (ACSIS), a biennial prospective survey of ACS patients hospitalized in all CCU/Cardiology departments during 2002-2010. RESULTS: Among 6790 patients, 2760 (41%) reported statin use prior to the index ACS event. The proportion of STEMI was significantly lower among statin treated vs. statin naive patients (36% vs. 57%, p<0.0001). At each LDL-C level, the proportion of STEMI was significantly lower only among statin treated patients (p<0.0001). LDL-C<70 mg/dL was associated with a lower proportion of STEMI only among statin treated but not among statin naive patients (33% vs. 57%, p<0.0001). Multivariate analysis revealed that statin use was independently associated with a lower probability of presenting with STEMI (ORadj=0.73, p=0.007), but not LDL-C<70 mg/dL (ORadj=1.13, p=0.32). Patients on high-intensity statin therapy (HIST) were less likely to present with STEMI as compared with low-intensity statin therapy (LIST) or statin naive patients (27%, 38%, 56%, respectively, p for trend <0.0001; HIST ORadj=0.28, p=0.01; LIST ORadj=0.48, p=0.026). CONCLUSIONS: Among patients admitted with ACS, statin use but not LDL-C level, was associated with a lower probability of presenting with STEMI. Patients on HIST had the lowest likelihood of presenting with STEMI. PMID- 26945434 TI - 3D-printing model for complex aortic transcatheter valve treatment. PMID- 26945435 TI - Cross-professional improvement actions to reduce time from first ECG to primary PCI in patients with ST-elevation myocardial infarction. PMID- 26945436 TI - Cardiac output as a predictor in congenital heart disease: Are we stating the obvious? AB - BACKGROUND: Significant pulmonary regurgitation, declining right-sided ejection fraction, increased right ventricular (RV) volumes as well as left ventricular (LV) dysfunction have all been identified as predictors of poor outcomes in patients with congenital heart disease (CHD). The prognostic value of the cardiac output (CO) in these patients however has never been studied. METHODS: All consecutive ambulatory adult patients with CHD referred for magnetic resonance imaging (MRI) at the Montreal Children's Hospital between June 2007 and May 2009 were included. Right ventricular (RV) and left ventricular (LV) variables including end diastolic and end systolic volumes (EDV, ESV respectively), ejection fractions (EF) and regurgitant volumes were obtained. Cardiac index (CI) was calculated. Patients were followed for cardiac-related hospitalizations and cardiac interventions. RESULTS: Ninety-six patients were included. Median follow up was 3.9 +/- 1.4 years. Nineteen percent of patients had a systemic CI<2.4 l/min/m(2). LVEDV, LVEF and RVEF were significantly diminished in the low CI group with a significant increase in RVESV and total regurgitant volume. Best predictors of low CI were LVEF (AUC=0.74), RVEF (AUC=0.71), total RV regurgitant volume (AUC=0.64) and RVESV (AUC=0.563). Low systemic CI was the best predictor of cardiac-related hospitalizations (hazard ratio 3.5, 95% confidence interval 1.5-8.5) and cardiac interventions (hazard ratio 2.2, 95% confidence interval 1.3 4.0), superior to LVEF, RVEF, total regurgitant volume and RVESV parameters. CONCLUSIONS: In patients with congenital heart disease, cardiac index is the best predictor of cardiac hospitalizations and cardiac interventions. PMID- 26945437 TI - Creating a model of diseased artery damage and failure from healthy porcine aorta. AB - Large quantities of diseased tissue are required in the research and development of new generations of medical devices, for example for use in physical testing. However, these are difficult to obtain. In contrast, porcine arteries are readily available as they are regarded as waste. Therefore, reliable means of creating from porcine tissue physical models of diseased human tissue that emulate well the associated mechanical changes would be valuable. To this end, we studied the effect on mechanical response of treating porcine thoracic aorta with collagenase, elastase and glutaraldehyde. The alterations in mechanical and failure properties were assessed via uniaxial tension testing. A constitutive model composed of the Gasser-Ogden-Holzapfel model, for elastic response, and a continuum damage model, for the failure, was also employed to provide a further basis for comparison (Calvo and Pena, 2006; Gasser et al., 2006). For the concentrations used here it was found that: collagenase treated samples showed decreased fracture stress in the axial direction only; elastase treated samples showed increased fracture stress in the circumferential direction only; and glutaraldehyde samples showed no change in either direction. With respect to the proposed constitutive model, both collagenase and elastase had a strong effect on the fibre-related terms. The model more closely captured the tissue response in the circumferential direction, due to the smoother and sharper transition from damage initiation to complete failure in this direction. Finally, comparison of the results with those of tensile tests on diseased tissues suggests that these treatments indeed provide a basis for creation of physical models of diseased arteries. PMID- 26945438 TI - A preliminary investigation of daily variability of stuttering in adults. AB - PURPOSE: Variability in frequency of stuttering has made the results of treatment outcome studies difficult to interpret. Many factors that affect variability have been investigated; yet the typical range of variability experienced by speakers remains unknown. This study examined the day-to-day variability in the percentage of syllables containing stuttered and nonstuttered disfluencies in the speech of six adult speakers in three spontaneous speaking situations and two reading tasks. METHODS: The frequency of moments stuttering during the tasks were compared within and between speakers and days to document the degree of variability in stuttering frequency and explore whether there were any consistent patterns. The Stuttering Severity Instrument-Fourth Edition (SSI-4) and Overall Assessment of the Speaker's Experience of Stuttering for Adults (OASES-A) were also tested for day-to-day variability. Correlations between frequency, severity, and life impact were made. RESULTS: The primary result of this study was the large range over which frequency of stuttering varied from day to day for the same individual. This variability did not correlate with any measures of stuttering severity but did correlate with life impact as measured by the OASES A. No global pattern was detected in variability from day to day within or between participants. However, there were significantly more nonstuttered disfluencies present during the spontaneous speaking tasks than during the reading tasks. The day-to-day variability in the life impact of the disorder (OASES-A) was less than the day-to-day variability in observable stuttering behavior (percentage of syllables stuttered and SSI-4). CONCLUSION: Frequency of stuttering varies significantly from situation to situation and day to day, with observed variability exceeding the degree of change often reported in treatment outcomes studies from before to after treatment. This variability must be accounted for in future clinical and scientific work. PMID- 26945439 TI - Global exponential stability of neural networks with time-varying delay based on free-matrix-based integral inequality. AB - This paper is concerned with global exponential stability problem for a class of neural networks with time-varying delays. Using a new proposed inequality called free-matrix-based integral inequality, a less conservative criterion is proposed, which is expressed by linear matrix inequalities. Two numerical examples are given to show the effectiveness and superiority of the obtained criterion. PMID- 26945440 TI - Towards holographic "brain" memory based on randomization and Walsh-Hadamard transformation. AB - The holographic conceptual approach to cognitive processes in the human brain suggests that, in some parts of the brain, each part of the memory (a neuron or a group of neurons) contains some information regarding the entire data. In Dolev and Frenkel (2010, 2012) we demonstrated how to encode data in a holographic manner using the Walsh-Hadamard transform. The encoding is performed on randomized information, that is then represented by a set of Walsh-Hadamard coefficients. These coefficients turn out to have holographic properties. Namely, any portion of the set of coefficients defines a "blurry image" of the original data. In this work, we describe a built-in error correction technique--enlarging the width of the matrix used in the Walsh-Hadamard transform to produce a rectangular Hadamard matrix. By adding this redundancy, the data can bear more errors, resulting in a system that is not affected by missing coefficients up to a certain threshold. Above this threshold, the loss of data is reflected by getting a "blurry image" rather than a concentrated damage. We provide a heuristic analysis of the ability of the technique to correct errors, as well as an example of an image saved using the system. Finally, we give an example of a simple implementation of our approach using neural networks as a proof of concept. PMID- 26945441 TI - Can early hepatic fibrosis stages be discriminated by combining ultrasonic parameters? AB - In this study, we put forward a new approach to classify early stages of fibrosis based on a multiparametric characterization using backscatter ultrasonic signals. Ultrasonic parameters, such as backscatter coefficient (Bc), speed of sound (SoS), attenuation coefficient (Ac), mean scatterer spacing (MSS), and spectral slope (SS), have shown their potential to differentiate between healthy and pathologic samples in different organs (eye, breast, prostate, liver). Recently, our group looked into the characterization of stages of hepatic fibrosis using the parameters cited above. The results showed that none of them could individually distinguish between the different stages. Therefore, we explored a multiparametric approach by combining these parameters in two and three, to test their potential to discriminate between the stages of liver fibrosis: F0 (normal), F1, F3, and/without F4 (cirrhosis), according to METAVIR Score. Discriminant analysis showed that the most relevant individual parameter was Bc, followed by SoS, SS, MSS, and Ac. The combination of (Bc, SoS) along with the four stages was the best in differentiating between the stages of fibrosis and correctly classified 85% of the liver samples with a high level of significance (p<0.0001). Nevertheless, when taking into account only stages F0, F1, and F3, the discriminant analysis showed that the parameters (Bc, SoS) and (Bc, Ac) had a better classification (93%) with a high level of significance (p<0.0001). The combination of the three parameters (Bc, SoS, and Ac) led to a 100% correct classification. In conclusion, the current findings show that the multiparametric approach has great potential in differentiating between the stages of fibrosis, and thus could play an important role in the diagnosis and follow-up of hepatic fibrosis. PMID- 26945442 TI - Emerging Role of Nestin as an Angiogenesis and Cancer Stem Cell Marker in Epithelial Ovarian Cancer: Immunohistochemical Study. AB - Ovarian cancer is the most fatal gynecologic malignancy and the existing second line treatments have not been confirmed to be effective. Cancer stem cells research has a leading role to explore promising therapeutic applications. Nestin was postulated to reflect cancer stem cell properties in various tumors, correlating with poor prognosis. Furthermore, nestin is proposed as a reliable neovascularization marker. This study aimed to elucidate the status of nestin expression in various epithelial ovarian cancers (EOCs), its neoangiogenic properties, and investigate its potential association with clinicopathologic parameters. A total of 80 primary EOCs (37 serous, 20 Mucinous, 13 endometrioid, and 10 clear cell carcinomas) were immunohistochemically stained with nestin. Staining intensity and automated microvascular density (MVD) were assessed. Positive nestin expression was defined in ~47.5% of all EOC; more commonly in ~60% of the serous tumors. It was noticeably expressed in tumor spheroids. Nestin expression significantly correlated with overall tumor grade, lymph node, distant metastasis, and stage. Nestin neoangiogenesis was detectable in all cases (average=60.1). The nestin expression in tumor cells significantly correlated with Nestin/MVD. The average Nestin/MVD was significantly an independent predictor of high tumor stage. As a stem cell marker, nestin is expressed in cells of EOC including those growing as spherules and correlated with poor prognosis. Thus, nestin may be a novel therapeutic target for tumor angiogenesis and a combination therapy that includes nestin-targeting agents may be an effective therapeutic approach. In addition, detection of Nestin/stem cells and Nestin/MVD can be used as predictors of disease. PMID- 26945443 TI - Comparative Analysis of Methods for Detecting Isocitrate Dehydrogenase 1 and 2 Mutations and Their Metabolic Consequence, 2-Hydroxyglutarate, in Different Neoplasms. AB - Isocitrate dehydrogenase (IDH) mutations have been recognized in a few neoplasms including glioma, acute myeloid leukemia, chondrosarcoma, cholangiocarcinoma, and angioimmunoblastic T-cell lymphoma. The direct methods to detect IDH mutations include DNA sequencing, immunohistochemistry (IHC), or by measuring its byproduct, 2-hydroxyglutarate (2-HG), in the blood or urine. Moreover, conventional magnetic resonance imaging can be modified to magnetic resonance spectroscopy (MRS) to measure 2-HG in tumor. By conducting a search in Medline/PubMed and ISI/Web of Science for the published articles in English related to the methods for detection of IDH mutations and its byproduct 2-HG, we compared different methodologies to detect these mutations and discuss advantages and limitations of each method. Studies in which a methodology of detection was compared with another modality were included. Multiple studies have shown that both DNA sequencing and IHC are reliable methods for detecting IDH mutations in glioma and other solid neoplasms. IHC appeared to be less costly, easier to perform, and may be slightly more accurate than DNA sequencing. 2-HG has also been measured in bone marrow aspirate, serum and urine of patients with mutant IDH acute myeloid leukemia, and correlated very well with sequencing and IHC. Lastly, in some glioma patients, MRS detected IDH mutations noninvasively and reliably with excellent correlations with other modalities such as IHC and sequencing. In conclusion, IHC, MRS, and 2-HG detection all are clinically useful and comparable with DNA sequencing in identifying IDH mutations in different neoplasms. 2-HG and MRS can be utilized for monitoring treatment response in a variety of neoplasms. PMID- 26945444 TI - Comparison of a Panel of Biomarkers Between Gastric Primary Cancer and the Paired Krukenberg Tumor. AB - To compare a panel of selected biomarkers between gastric primary cancer and the paired Krukenberg tumor, a total of 21 cases of metastatic tumors originating from stomach and the paired gastric primary cancers were collected. The expressions of a panel of selected biomarkers were tested by IHC. FISH was used to determine the status of HER2/neu in cases scored IHC 2+. The differences of the expressions of the biomarkers were evaluated between metastatic tumors and the paired gastric primary cancers. Bcl-2 was negative in all the cases. The HER2/neu expression was consistent between the gastric primary cancers and the paired metastatic tumors in 17 patients. In the other 4 cases, the HER2/neu expression was negative in gastric primary cancers but positive in the matched metastatic tumors. The concordance rate of c-MET, p53, and Ki-67 expression was 71.4%, 81.0%, and 76.2%, respectively. In conclusion, the expression of Bcl-2 is negative in all gastric primary tumors and the paired metastatic cancers. There is major concordance of the expression of HER2/neu, c-MET, p53, and Ki-67 between gastric primary cancers and the paired metastatic tumors, which suggests that the status of these biomarkers remain stable during the metastatic process. PMID- 26945445 TI - GRB7 Expression and Correlation With HER2 Amplification in Invasive Breast Carcinoma. AB - Growth factor receptor-bound protein 7 (GRB7) gene is located adjacent to the HER2 gene on the 17q12-21 amplicon, is often coamplified with HER2 in a subset of breast cancers, and has been implicated in resistance to anti-HER2 and antiestrogen therapy. This study investigated the correlation of GRB7 expression by immunohistochemistry with HER2 expression, HER2 amplification, increased chromosome 17 copy number, and other prognostic and predictive factors in invasive breast cancer, including histologic grade, pathologic stage, and ER, PR, and p53 status. Paraffin-embedded samples of 188 invasive breast carcinomas with documented HER2, ER, and PR testing were collected and divided into 3 groups: cases positive for HER2 overexpression/gene amplification (n=60), negative for HER2 overexpression (n=97), and cases with increased chromosome 17 copy number without HER2 amplification (n=31). GRB7 expression was evaluated on all 188 cases. In addition, p53 immunohistochemistry was performed on 13 HER2+/GRB7+ cases and 39 HER2+/GRB7- cases. GRB7 expression correlated strongly with HER2 overexpression. GRB7 expression was present in 20/60 (33.33%) of HER2+ cases, compared with 1/97 (1.03%) HER2- cases, and 1/31 (3.22%) increased chromosome 17 copy number cases (P<0.0001). In HER2+ cases, GRB7 expression was found to correlate significantly with a greater degree of HER2 amplification. The mean+/ SEM HER2 copy number was 21.14+/-2.59 in GRB7+ cases, compared with 9.8+/-1.38 in GRB7- cases (P=0.0001). GRB7 expression correlated significantly with ER negativity (P=0.012) and p53 positivity (P=0.03). GRB7 expression did not correlate with histologic grade, pathologic stage, or PR expression. Our data shows that GRB7 expression in invasive breast cancer correlates with markers of a more aggressive phenotype, including HER2 overexpression, a greater degree of HER2 amplification, ER negativity, and p53 positivity. PMID- 26945446 TI - Infrequent Immunohistochemical Expression of Napsin A in Endometrial Carcinomas. AB - INTRODUCTION: Many studies described napsin A as a specific diagnostic marker that aids in differentiating lung adenocarcinomas from other respiratory tumors. This study describes the expression phenotype of napsin A in endometrial neoplasms, it investigates the relationship between this expression profile and the clinicopathologic parameters, and assess its utilization as an independent predictive marker. METHODS: A total of 76 cases of previously diagnosed endometrial carcinoma (including 53 endometrioid adenocarcinomas, 6 endometrioid adenocarcinomas with squamous differentiation, 9 serous adenocarcinomas, 6 clear cell adenocarcinomas, and 2 malignant mixed mullerian tumors) and 30 tissue samples of noncancerous endometrium (including 16 proliferative endometriums, 10 secretory endometriums and 4 endometrial polyps) were retrieved from the archives of Pathology Department at King Abdulaziz University, Jeddah, Saudi Arabia. For napsin A detection, tissue microarrays and immunostaining were used. RESULTS: A total number of 12 (15.78%) cases were positive for napsin A immunostaining. Brown granular cytoplasmic expression of napsin A was detected in 9.4% of endometrioid adenocarcinomas, 16.7% of endometrioid adenocarcinomas with squamous differentiation, 22.2% of papillary serous endometrial carcinomas, and 66.7% of clear cell carcinomas. Three (10%) control cases showed similar granular cytoplasmic expression. Positive napsin A immunostaining was more frequent in clear cell carcinoma, and there is a significant association between positive napsin A immunostaining and clear cell carcinoma (P-value=0.007). Significant associations have been found also between napsin A expression and older ages (above 60 y) and higher stage (IVB), the P-values of which were 0.035 and 0.043, respectively, but not with the tumor recurrence or survival rate. CONCLUSIONS: Although napsin A is infrequently expressed in endometrial carcinomas, positive results of napsin A immunostaining in endometrial neoplasms might support the diagnosis of clear cell carcinoma when the pathologic differential diagnosis includes other histologic subtypes. PMID- 26945447 TI - False ALK Rearrangement Signals in Inflammatory Cells: A Pitfall in the Interpretation of ALK Fluorescence In Situ Hybridization in Non-Small Cell Lung Cancer. AB - Searching for ALK rearrangements has now become mandatory for the treatment of patients with advanced non-small cell lung cancer with anti-ALK-targeted therapy. The fluorescence in situ hybridization test is considered the "gold standard" to diagnose ALK-rearranged tumors. Nevertheless, some technical pitfalls may cause false-positive signals mimicking ALK rearrangements. In this technical article, we point out the importance of taking into account both histopathologic and ALK immunohistochemical features to interpret ALK fluorescence in situ hybridization analyses in inflammatory and necrotic tumors. This confrontation is crucial to avoid misdiagnosis and inappropriate therapeutic management. PMID- 26945448 TI - Comparison of Clinicopathologic Parameters and Survivals Between Epstein-Barr Virus-positive and Her2-positive Gastric Cancers. AB - Gastric carcinomas are highly mortal neoplasms for which new therapeutic options are being searched. The molecular subtyping of gastric adenocarcinomas was proposed recently, and the relationship between etiopathogenetic types is still under investigation. Here we compared histopathologic, prognostic, and survival differences between Epstein-Barr virus (EBV)-positive and Her2-positive gastric adenocarcinomas. In a retrospective design, we searched the EBV status with Epstein Barr Virus encoded small RNA (EBER) in situ hybridization, and the Her2 status both by immunohistochemistry and by chromogenic in situ hybridization of 106 gastrectomized gastric carcinomas. Histologic and clinical prognostic parameters and survival information were determined, and retrieved from archival tissues and clinical notes. The Her2 positivity rate was 12.3% and the EBV positivity rate was 7.6%. Among EBER-positive cases, Her2 positivity was not detected. Her2 positivity was detected more in intestinal differentiated tumors, whereas EBER positivity was detected in undifferentiated tumors (P=0.003). There was no correlation of Her2 or EBER positivity with the tumor stage. Median survivals of EBER-positive, Her2-positive, and both negative cases were 11.5, 18, and 20.5 months, respectively. The tumor stage and distant metastasis were found to be significant for survival in the multivariate analysis. In our 106 gastrectomized gastric carcinoma cases, EBV-positive and Her2-positive groups were found to be unrelated as proposed in the upcoming classification of gastric carcinomas. PMID- 26945449 TI - Expression of Cancer Stem Cell Markers OCT4 and CD133 in Transitional Cell Carcinomas. AB - BACKGROUND: Treatment failure, recurrence, and metastasis in bladder cancer are attributed to a subset of tumor cells expressing cancer stem cell (CSC) markers. This study aimed to explore the expression levels and the clinical significance of putative CSC markers OCT4 and CD133 in bladder cancer. MATERIALS AND METHODS: Tissue microarray-based immunohistochemical analysis was applied to investigate the expression patterns of potential CSC markers OCT4 and CD133 in bladder cancer samples. The correlation between the expressions of each marker and clinicopathologic parameters was then analyzed. RESULTS: There was a significant association between OCT4 expression and the TNM stage of bladder cancer (P<0.001). Our analysis demonstrated a significant association between the intensity of staining and the presence of lamina propria and muscularis propria invasion (P=0.02 and 0.02, respectively), whereas a relative inverse correlation was found between CD133 expression with lamina propria invasion (P=0.051) and muscularis propria invasion (P=0.07). CONCLUSIONS: The correlation of OCT4, but not CD133, with the invasiveness of bladder cancer revealed that OCT4 can be considered as a key regulator of tumor progression, aggressive behavior, and metastasis; therefore, OCT4 can be a potential marker for targeted therapy of bladder cancer. PMID- 26945450 TI - Alcohol issues prior to training in the United States Air Force. AB - The negative impact of alcohol is a significant concern to the US military given the costs associated with alcohol-related offenses. Despite considerable research in active duty personnel, relatively little is known about the current extent of alcohol use among incoming recruits. We examined the history of alcohol use and harmful patterns of alcohol consumption among recruits entering the United States Air Force (USAF; N=50,549) over the span of 4 years (2010-2014). Across all years, drinking rates reflected national average trends for those aged 18-24 (NIDA, 2014). However, when abstainers were excluded, those under 21 (n=10,568) reported an average of 18.4 drinks per week, whereas those age 21 and over (n=14,188) reported an average of 14.1 drinks per week, suggesting that for those who drink, those under 21 are exhibiting more risky drinking rates. Alcohol Use Disorders Identification Task (AUDIT) scores for drinkers reflected these same trends. For those under 21, 58% scored in risk categories of 2 or higher (risky drinking warranting attention), compared with 40% for those age 21 and over. These scores indicate that for recruits in the USAF, approximately half report alcohol use immediately prior to basic training, resulting in the inheritance of these potential alcohol related issues for those conducting training of these recruits. Based upon these numbers, brief alcohol interventions could have a potential positive impact on individuals in their initial training stages of the USAF to prevent these baseline issues from resulting in problems later in their military careers. PMID- 26945451 TI - As time goes by: Oxytocin influences the subjective perception of time in a social context. AB - Time perception depends on an event's emotional relevance to the beholder; a subjective time dilation effect is associated with self-relevant, emotionally salient stimuli. Previous studies have revealed that oxytocin modulates the salience of social stimuli and attention to social cues. However, whether the oxytocin system is involved in human subjective time perception is unknown. The aim of the present study was to investigate whether increased oxytocin levels would induce a time dilation effect for self-relevant, positive social cues. In a double-blind, placebo-controlled, between-subject design, heterosexual men were administered intranasal oxytocin or placebo. After about 50min, participants completed a time-bisection task in which they estimated lengths of exposure to happy female faces (self-relevant positive stimuli, based on sexual orientation), emotionally neutral and negative female faces (control), and happy, neutral, and negative male faces (control). Oxytocin induced a subjective time dilation effect for happy female faces and a time compression effect for happy male faces. Our results provide evidence that oxytocin influences time perception, a primary form of human subjectivity. PMID- 26945452 TI - Optimising the recovery and re-use of phosphorus from wastewater effluent for sustainable fertiliser development. AB - Recovery and re-use of phosphorus (P) from wastewater treatment systems as agricultural fertiliser presents an important and viable target for P waste reduction and recycling. In this study novel biochar materials for P filtration of wastewater were designed and produced using waste feedstocks, with consideration of the plant accessibility of the P captured by the biochars. The biochars were produced using batch slow pyrolysis at 450 degrees C and 550 degrees C from a) AD: anaerobically digested sewage sludge and b) OCAD: a 1:1 mixture of anaerobically digested sewage sludge and ochre, a mineral product from mine drainage treatment. A set of experiments was designed using pH buffering to provide a robust framework for assessing the P recovery capacity and affinity of the biochars compared to other potential P recovery materials (unprocessed ochre, activated carbon and zeolite). After 5 days of repeated exposure to a P solution at a wastewater-relevant concentration (0.02 g P l(-1)) replenished each 24 h, relatively high masses of P were recovered by ochre (1.73 +/- 8.93*10(-3) mg P g( 1)) and the biochars OCAD550 (1.26 +/- 4.66*10(-3) mg P g(-1)), OCAD450 (1.24 +/- 2.10*10(-3) mg P g(-1)), AD450 (1.06 +/- 3.84*10(-3) mg P g(-1)), and AD550 (0.986 +/- 9.31*10(-3) mg P g(-1)). The biochar materials had higher removal rates than both activated carbon (0.884 +/- 1.69*10(-2) mg P g(-1)) and zeolite (0.130 +/- 1.05*10(-2) mg P g(-1)). To assess the extractability of recovered P, P exposure was followed by repeated extraction for 4 days with pH 7-buffered deionised water. The AD biochars retained 55% of the P recovered, OCAD biochars 78% and ochre 100%. Assessment of potentially toxic element concentrations in the biochars against guideline values indicated low risk associated with their use in the environment. Our successful demonstration of biochar materials highlights the potential for further development of P filters for wastewater treatment systems from anaerobic digestate produced and pyrolysed on-site with energy recovery. PMID- 26945453 TI - High-resolution phylogenetic analysis of residual bacterial species of fouled membranes after NaOCl cleaning. AB - Biofouling is one of the major problems during wastewater treatment using membrane bioreactors (MBRs). In this regard, sodium hypochlorite (NaOCl) has been widely used to wash fouled membranes for maintenance and recovery purposes. Advanced chemical and biological characterization was conducted in this work to evaluate the performance of aqueous NaOCl solutions during washing of polyacrylonitrile membranes. Fouled membranes from MBR operations supplemented with artificial wastewater were washed with 0.1% and 0.5% aqueous NaOCl solutions for 5, 10 and 30 min. The changes in organics composition on the membrane surface were directly monitored by an attenuated total reflection Fourier transform infrared (ATR-FT-IR) spectrometer. In addition, high-throughput Illumina sequencing of 16S rRNA genes was applied to detect any residual microorganisms. Results from ATR-FT-IR analysis indicated the complete disappearance of functional groups representing different fouling compounds after at least 30 min of treatment with 0.1% NaOCl. However, the biomolecular survey revealed the presence of residual bacteria even after 30 min of treatment with 0.5% NaOCl solution. Evaluation of microbial diversity of treated samples using Chao1, Shannon and Simpson reciprocal indices showed an increase in evenness while no significant decline in richness was observed. These implied that only the population of dominant species was mainly affected. The high-resolution phylogenetic analysis revealed the presence of numerous operational taxonomic units (OTUs) whose close relatives exhibit halotolerance. Some OTUs related to thermophilic and acid-resistant strains were also identified. Finally, the taxonomic analysis of recycled membranes that were previously washed with NaOCl also showed the presence of numerous halotolerant-related OTUs in the early stage of fouling. This further suggested the possible contribution of such chemical tolerance on their survival against NaOCl washing, which in turn affected their re-fouling potential. PMID- 26945454 TI - Survival after splanchnic vein thrombosis: A 20-year nationwide cohort study. AB - INTRODUCTION: Splanchnic vein thrombosis (SVT) is a rare condition with a poorly understood prognosis. MATERIALS AND METHODS: We conducted a population-based cohort study (1994-2013), using data from Danish nationwide medical registries, to examine the short- and long-term prognosis of SVT. We identified 1915 incident cases of SVT and a matched comparison cohort of 18,267 persons without SVT (matched by cancer, cirrhosis, pancreatitis, alcohol-related disease, atrial fibrillation/flutter, venous thromboembolism, heart failure, and inflammatory bowel disease). We used the Kaplan-Meier method to calculate absolute risk of death. Using stratified Cox regression, we computed mortality rate ratios (MRRs) with 95% confidence intervals (CIs), comparing SVT patients with the comparison cohort. RESULTS: We identified 1,500 (78%) patients with portal vein thrombosis, 204 (11%) with hepatic vein thrombosis, and 211 (11%) with mesenteric vein thrombosis. The mortality risks were markedly higher for SVT patients than for the comparison cohort during the first 5years of follow-up (30-day risk: 20.6% vs. 0.7%; 31-364-day risk: 21.7% vs. 4.7%; and 1-5-year risk: 25.4% vs. 17.7%). The corresponding MRRs were 40.7 (95% CI: 32.4-51.1), 7.4 (95% CI: 6.4-8.6), and 2.4 (95% CI: 2.1-2.8), respectively. The 30-day mortality was higher after mesenteric vein thrombosis than portal and hepatic vein thrombosis, whereas portal vein thrombosis had a stronger impact on mortality after 30days than hepatic and mesenteric vein thrombosis. CONCLUSIONS: Splanchnic vein thrombosis has a poor short- and long-term prognosis that varies according to subtype of thrombosis. Reasons for the increased mortality in patients with SVT need further clarification. PMID- 26945455 TI - Tumor acidity-sensitive linkage-bridged block copolymer for therapeutic siRNA delivery. AB - The design of ideal nanoparticle delivery systems should be capable of meeting the requirements of several stages of drug delivery, including prolonged circulation, enhanced accumulation and penetration in the tumor, facilitated cellular internalization and rapid release of the active drug in the tumor cells. However, among the current design strategies, meeting the requirements of one stage often conflicts with the other. Herein, a tumor pH-labile linkage-bridged block copolymer of poly(ethylene glycol) with poly(lacide-co-glycolide) (PEG Dlinkm-PLGA) was used for siRNA delivery to fulfill all aforementioned requirements of these delivery stages. The obtained siRNA-encapsulating PEG Dlinkm-PLGA nanoparticle gained efficiently prolonged circulation in the blood and preferential accumulation in tumor sites via the PEGylation. Furthermore, the PEG surface layer was detached in response to the tumor acidic microenvironment to facilitate cellular uptake, and the siRNA was rapidly released within tumor cells due to the hydrophobic PLGA layer. Hence, PEG-Dlinkm-PLGA nanoparticles met the requirements of several stages of drug delivery, and resulted in the enhanced therapeutic effect of the nanoparticular delivery systems. PMID- 26945456 TI - PLGA-based microcarriers induce mesenchymal stem cell chondrogenesis and stimulate cartilage repair in osteoarthritis. AB - In the present study, we aimed at evaluating the ability of novel PLGA-P188-PLGA based microspheres to induce the differentiation of mesenchymal stem/stromal cells (MSC) into chondrocytes. To this aim, we tested microspheres releasing TGFbeta3 (PAM-T) in vitro and in situ, in a pathological osteoarthritic (OA) environment. We first evaluated the chondrogenic differentiation of human MSCs seeded onto PAM-T in vitro and confirmed the up-regulation of chondrogenic markers while the secretome of the cells was not changed by the 3D environment. We then injected human MSC seeded onto PAM-T in the knee joints of mice with collagenase-induced OA. After 6 weeks, histological analysis revealed that formation of a cartilage-like tissue occurred at the vicinity of PAM-T that was not observed when MSCs were seeded onto PAM. We also noticed that the endogenous articular cartilage was less degraded. The extent of cartilage protection was further analysed by confocal laser microscopy. When MSCs seeded onto PAM-T were injected early after OA induction, protection of cartilage against degradation was evidenced and this effect was associated to a higher survival of MSCs in presence of TGFbeta3. This study points to the interest of using MSCs seeded onto PAM for cartilage repair and stimulation of endogenous cartilage regeneration. PMID- 26945457 TI - Potential of activatable FAP-targeting immunoliposomes in intraoperative imaging of spontaneous metastases. AB - Despite intensive research and medical advances met, metastatic disease remains the most common cause of death in cancer patients. This results from late diagnosis, poor therapeutic response and undetected micrometastases and tumor margins during surgery. One approach to overcome these challenges involves fluorescence imaging, which exploits the properties of fluorescent probes for diagnostic detection of molecular structures at the onset of transformation and for intraoperative detection of metastases and tumor margins in real time. Considering these benefits, many contrast agents suitable for fluorescence imaging have been reported. However, most reports only demonstrate the detection of primary tumors and not the detection of metastases or their application in models of image-guided surgery. In this work, we demonstrate the influence of fibroblast activation protein (FAP) on the metastatic potential of fibrosarcoma cells and elucidate the efficacy of activatable FAP-targeting immunoliposomes (FAP-IL) for image-guided detection of the spontaneous metastases in mice models. Furthermore, we characterized the biodistribution and cellular localization of the liposomal fluorescent components in mice organs and traced their excretion over time in urine and feces. Taken together, activatable FAP-IL enhances intraoperative imaging of metastases. Their high accumulation in metastases, subsequent localization in the bile canaliculi and liver kupffer cells and suitable excretion in feces substantiates their potency as contrast agents for intraoperative imaging. PMID- 26945458 TI - The interactive effect of the MAOA-VNTR genotype and childhood abuse on aggressive behaviors in Chinese male adolescents. AB - OBJECTIVE: Gene-environment interactions that moderate aggressive behavior have been identified in association with the MAOA (monoamine oxidase A) gene. The present study examined the moderating effect of MAOA-VNTR (variable number of tandem repeats) on aggression behavior relating to child abuse among Chinese adolescents. MATERIALS AND METHODS: A sample of 507 healthy Chinese male adolescents completed the Child Trauma Questionnaire-Short Form (CTQ-SF) and Youth Self-report of the Child Behavior Checklist. The participants' buccal cells were sampled and subjected to DNA analysis. The effects of childhood abuse (CTQ SF scores), MAOA-VNTR [high-activity allele (H) versus low-activity allele (L)], and their interaction in aggressive behaviors were analyzed by linear regression. RESULTS: Child maltreatment was found to be a significant independent factor in the manifestation of aggressive behavior, whereas MAOA activity was not. There was a significant interaction between MAOA-VNTR and childhood maltreatment in the exhibition of aggressive behaviors. In the context of physical or emotional abuse, boys in the MAOA-L group showed a greater tendency toward aggression than those in the MAOA-H group. CONCLUSION: Aggressive behavior arising from childhood maltreatment is moderated by MAOA-VNTR, which may be differentially sensitive to the subtype of childhood maltreatment experienced, among Chinese adolescents. PMID- 26945459 TI - Association study of DISC1 genetic variants with the risk of schizophrenia. AB - Our previous study confirmed that the 'AA' genotype carriers of DISC1 single nucleotide polymorphism (SNP) rs821616 had a significantly increased risk for schizophrenia (SCZ) in comparison with noncarriers. To further explore the relationship of DISC1 genetic variants with the risk of SCZ in Han Chinese, we designed the present two-step study. We sequenced the promoter and untranslated regions of the DISC1 gene using genomic DNA of 100 SCZ patients and identified 17 SNPs. All SNPs were then genotyped and analyzed through a case-control study with 1154 healthy controls and 1447 patients. In an association analysis, neither allelic nor genotypic modeling indicated a significant association between the risk of SCZ and all SNPs. In addition, we observed that a two-marker haplotype was nominally associated with protection for SCZ (P = 0.0476). The present findings, at least in part, provide some clues for further investigating the association of DISC1 variants with SCZ susceptibility. PMID- 26945460 TI - Patient non-specific algorithm for seizures detection in scalp EEG. AB - Epilepsy is a brain disorder that affects about 1% of the population in the world. Seizure detection is an important component in both the diagnosis of epilepsy and seizure control. In this work a patient non-specific strategy for seizure detection based on Stationary Wavelet Transform of EEG signals is developed. A new set of features is proposed based on an average process. The seizure detection consisted in finding the EEG segments with seizures and their onset and offset points. The proposed offline method was tested in scalp EEG records of 24-48h of duration of 18 epileptic patients. The method reached mean values of specificity of 99.9%, sensitivity of 87.5% and a false positive rate per hour of 0.9. PMID- 26945461 TI - Functional grouping of similar genes using eigenanalysis on minimum spanning tree based neighborhood graph. AB - Gene expression data clustering is an important biological process in DNA microarray analysis. Although there have been many clustering algorithms for gene expression analysis, finding a suitable and effective clustering algorithm is always a challenging problem due to the heterogeneous nature of gene profiles. Minimum Spanning Tree (MST) based clustering algorithms have been successfully employed to detect clusters of varying shapes and sizes. This paper proposes a novel clustering algorithm using Eigenanalysis on Minimum Spanning Tree based neighborhood graph (E-MST). As MST of a set of points reflects the similarity of the points with their neighborhood, the proposed algorithm employs a similarity graph obtained from k(') rounds of MST (k(')-MST neighborhood graph). By studying the spectral properties of the similarity matrix obtained from k(')-MST graph, the proposed algorithm achieves improved clustering results. We demonstrate the efficacy of the proposed algorithm on 12 gene expression datasets. Experimental results show that the proposed algorithm performs better than the standard clustering algorithms. PMID- 26945462 TI - Optimum wavelet based masking for the contrast enhancement of medical images using enhanced cuckoo search algorithm. AB - Unsharp masking techniques are a prominent approach in contrast enhancement. Generalized masking formulation has static scale value selection, which limits the gain of contrast. In this paper, we propose an Optimum Wavelet Based Masking (OWBM) using Enhanced Cuckoo Search Algorithm (ECSA) for the contrast improvement of medical images. The ECSA can automatically adjust the ratio of nest rebuilding, using genetic operators such as adaptive crossover and mutation. First, the proposed contrast enhancement approach is validated quantitatively using Brain Web and MIAS database images. Later, the conventional nest rebuilding of cuckoo search optimization is modified using Adaptive Rebuilding of Worst Nests (ARWN). Experimental results are analyzed using various performance matrices, and our OWBM shows improved results as compared with other reported literature. PMID- 26945463 TI - Predicting bacteriophage proteins located in host cell with feature selection technique. AB - A bacteriophage is a virus that can infect a bacterium. The fate of an infected bacterium is determined by the bacteriophage proteins located in the host cell. Thus, reliably identifying bacteriophage proteins located in the host cell is extremely important to understand their functions and discover potential anti bacterial drugs. Thus, in this paper, a computational method was developed to recognize bacteriophage proteins located in host cells based only on their amino acid sequences. The analysis of variance (ANOVA) combined with incremental feature selection (IFS) was proposed to optimize the feature set. Using a jackknife cross-validation, our method can discriminate between bacteriophage proteins located in a host cell and the bacteriophage proteins not located in a host cell with a maximum overall accuracy of 84.2%, and can further classify bacteriophage proteins located in host cell cytoplasm and in host cell membranes with a maximum overall accuracy of 92.4%. To enhance the value of the practical applications of the method, we built a web server called PHPred (). We believe that the PHPred will become a powerful tool to study bacteriophage proteins located in host cells and to guide related drug discovery. PMID- 26945464 TI - Robust semi-automated quantification of cardiac MR perfusion using level set: Application to hypertrophic cardiomyopathy patient data. AB - BACKGROUND: Recently there have been several clinical MR perfusion studies in patients with hypertrophic cardiomyopathy (HCM) who may suffer from myocardial ischemia due to coronary microvascular dysfunction. In these studies, data analysis relied on a manual procedure of tracing epicardial and endocardial borders. The goal of this work is to develop and validate a robust semi-automated analysis method for myocardial perfusion quantification in clinical HCM data. METHOD: Dynamic multi-slice stress perfusion MRI data were acquired from 18 HCM patients. The proposed semi-automated method required user input of two landmark selections: LV center point and RV insertion point. Automated segmentations of the endocardial and epicardial borders were performed in three short-axis slices using distance regularized level set evolution on RV, LV, and myocardial enhancement frames. RESULTS: The proposed automated epicardial border detection method resulted in average radial distance errors of 7.5%, 9.5%, and 11.6% in basal, mid, and apical slices, respectively, when compared to manual tracing of the borders as a reference. In linear regression analysis, the highest correlation of myocardial upslope measurements was observed between the manual method and the proposed method in the anterolateral section (r=0.964), and the lowest correlation was observed in the inferoseptal section (r=0.866). CONCLUSION: The proposed semi-automated method for myocardial MR perfusion quantification is feasible in HCM patients who typically show (1) irregular myocardial shape and (2) low image contrast between the myocardium and its surrounding regions due to coronary microvascular disease. PMID- 26945465 TI - Quantification of liver fat: A comprehensive review. AB - Fat accumulation in the liver causes metabolic diseases such as obesity, hypertension, diabetes or dyslipidemia by affecting insulin resistance, and increasing the risk of cardiac complications and cardiovascular disease mortality. Fatty liver diseases are often reversible in their early stage; therefore, there is a recognized need to detect their presence and to assess its severity to recognize fat-related functional abnormalities in the liver. This is crucial in evaluating living liver donors prior to transplantation because fat content in the liver can change liver regeneration in the recipient and donor. There are several methods to diagnose fatty liver, measure the amount of fat, and to classify and stage liver diseases (e.g. hepatic steatosis, steatohepatitis, fibrosis and cirrhosis): biopsy (the gold-standard procedure), clinical (medical physics based) and image analysis (semi or fully automated approaches). Liver biopsy has many drawbacks: it is invasive, inappropriate for monitoring (i.e., repeated evaluation), and assessment of steatosis is somewhat subjective. Qualitative biomarkers are mostly insufficient for accurate detection since fat has to be quantified by a varying threshold to measure disease severity. Therefore, a quantitative biomarker is required for detection of steatosis, accurate measurement of severity of diseases, clinical decision-making, prognosis and longitudinal monitoring of therapy. This study presents a comprehensive review of both clinical and automated image analysis based approaches to quantify liver fat and evaluate fatty liver diseases from different medical imaging modalities. PMID- 26945466 TI - Neuronal polarity: remodeling microtubule organization. AB - Cell polarization generates morphological and functional asymmetry, and is crucial for the development and proper functioning of many cell types. Recent data have revealed that the microtubule cytoskeleton is a major determinant in the establishment and maintenance of neuronal polarity. Microtubules provide the structural basis for neuronal polarization, because of their intrinsic properties including inherent polarity. Moreover, the polarized microtubule network also forms the basis for selective cargo trafficking into axons and dendrites. Here we review recent studies examining the molecular processes that control microtubule remodeling and polarized cargo sorting, and propose that changes in microtubule organization play an instructive role in the initial polarization. PMID- 26945467 TI - Irradiation with low-dose gamma ray enhances tolerance to heat stress in Arabidopsis seedlings. AB - Gamma irradiation at low doses can stimulate the tolerance to environmental stress in plants. However, the knowledge regarding the mechanisms underlying the enhanced tolerance induced by low-dose gamma irradiation is far from fully understood. In this study, to investigate the physiological and molecular mechanisms of heat stress alleviated by low-dose gamma irradiation, the Arabidopsis seeds were exposed to a range of doses before subjected to heat treatment. Our results showed that 50-Gy gamma irradiation maximally promoted seedling growth in response to heat stress. The production rate of superoxide radical and contents of hydrogen peroxide and malondialdehyde in the seedlings irradiated with 50-Gy dose under heat stress were significantly lower than those of controls. The activities of antioxidant enzymes, glutathione (GSH) content and proline level in the gamma-irradiated seedlings were significantly increased compared with the controls. Furthermore, transcriptional expression analysis of selected genes revealed that some components related to heat tolerance were stimulated by low-dose gamma irradiation under heat shock. Our results suggest that low-dose gamma irradiation can modulate the physiological responses as well as gene expression related to heat tolerance, thus alleviating the stress damage in Arabidopsis seedlings. PMID- 26945468 TI - Polarity and asymmetric cell division in the control of lymphocyte fate decisions and function. AB - Polarity is important in several lymphocyte processes including lymphocyte migration, formation of the immunological synapse, and asymmetric cell division (ACD). While lymphocyte migration and immunological synapse formation are relatively well understood, the role of lymphocyte ACD is less clear. Recent advances in measuring polarity enable more robust analyses of asymmetric cell division. Use of these new methods has produced crucial quantification of ACD at precise phases of lymphocyte development and activation. These developments are leading to a better understanding of the drivers of fate choice during lymphocyte activation and provide a context within which to explain the effects of ACD. PMID- 26945469 TI - Surface water disinfection by chlorination and advanced oxidation processes: Inactivation of an antibiotic resistant E. coli strain and cytotoxicity evaluation. AB - The release of antibiotics into the environment can result in antibiotic resistance (AR) spread, which in turn can seriously affect human health. Antibiotic resistant bacteria have been detected in different aquatic environments used as drinking water source. Water disinfection may be a possible solution to minimize AR spread but conventional processes, such as chlorination, result in the formation of dangerous disinfection by-products. In this study advanced oxidation processes (AOPs), namely H2O2/UV, TiO2/UV and N-TiO2/UV, have been compared with chlorination in the inactivation of an AR Escherichia coli (E. coli) strain in surface water. TiO2 P25 and nitrogen doped TiO2 (N-TiO2), prepared by sol-gel method at two different synthesis temperatures (0 and -20 degrees C), were investigated in heterogeneous photocatalysis experiments. Under the investigated conditions, chlorination (1.0 mg L(-1)) was the faster process (2.5 min) to achieve total inactivation (6 Log). Among AOPs, H2O2/UV resulted in the best inactivation rate: total inactivation (6 Log) was achieved in 45 min treatment. Total inactivation was not observed (4.5 Log), also after 120 min treatment, only for N-doped TiO2 synthesized at 0 degrees C. Moreover, H2O2/UV and chlorination processes were evaluated in terms of cytotoxicity potential by means of 3-(4,5-dime-thylthiazol-2-yl)-2,5-diphenylte-trazolium colorimetric test on a human-derived cell line and they similarly affected HepG2 cells viability. PMID- 26945470 TI - Chronic depression symptoms and salivary NOx are associated with retinal vascular dysregulation: The SABPA study. AB - BACKGROUND: Depression has been associated with impaired nitric oxide (NO) mediated vasodilation and vascular dysregulation (VD). Whether depression and NO levels will disturb retinal haemodynamics is not clear. OBJECTIVES AND METHODS: Associations between the retinal vasculature, diastolic ocular perfusion pressure (DOPP) as measure of hypoperfusion, NO metabolites (NOx) and depression symptoms were assessed. Chronic VD risk markers [depression symptoms (Patient Health Questionnaire/PHQ-9 >= 10) and 24 h pulse pressure] were determined in a bi ethnic cohort (n = 313; 48.6 +/- 9 years; 53.9% men). At 3 year follow-up, retinal vessel calibre and retinopathy signs were quantified from digital images. Salivary NOx was obtained pre- and post-flicker light-induced provocation (FLIP). DOPP was defined as diastolic blood pressure minus intraocular pressure. RESULTS: Chronic VD risk was evident in Blacks opposed to acute risk in Whites (P < 0.05). At follow-up, retinopathy (Blacks 60.4%/Whites 39.6%), lower pre-FLIP (MUM) and higher post-FLIP NOx (changes from baseline, %), arteriolar narrowing and wider venular calibre values were evident in Blacks compared to Whites, independent of confounders. A wider venular calibre, an index of stroke risk, was associated with chronic depression symptoms [cut point 248 MU: Area under the curve 0.61 (95% CI: 0.51, 0.72); 71% sensitivity; 55% specificity] as well as with hypoperfusion in the Blacks. In this group, arteriolar narrowing was associated with hypoperfusion; and attenuated arteriolar dilation with increased post-FLIP NOx responses. CONCLUSIONS: Chronic depression symptoms may alter NO regulation and facilitate VD. NO-mediated vasoconstriction presumably impeded perfusion, retinal haemodynamics and -remodelling; potentiating stroke risk in Blacks. PMID- 26945471 TI - Discrepancy analysis of driving performance of taxi drivers and non-professional drivers for red-light running violation and crash avoidance at intersections. AB - Due to comfort, convenience, and flexibility, taxis have become increasingly more prevalent in China, especially in large cities. However, many violations and road crashes that occurred frequently were related to taxi drivers. This study aimed to investigate differences in driving performance between taxi drivers and non professional drivers from the perspectives of red-light running violation and potential crash involvement based on a driving simulation experiment. Two typical scenarios were established in a driving simulator, which includes the red-light running violation scenario and the crash avoidance scenario. There were 49 participants, including 23 taxi drivers (14 males and 9 females) and 26 non professional drivers (13 males and 13 females) recruited for this experiment. The driving simulation experiment results indicated that non-professional drivers paid more attention to red-light running violations in comparison to taxi drivers who had a higher probability of red-light running violation. Furthermore, it was found that taxi drivers were more inclined to turn the steering wheel in an attempt to avoid a potential collision and non-professional drivers had more abrupt deceleration behaviors when facing a potential crash. Moreover, the experiment results showed that taxi drivers had a smaller crash rate compared to non-professional drivers and had a better performance in terms of crash avoidance at the intersection. PMID- 26945472 TI - A semiparametric negative binomial generalized linear model for modeling over dispersed count data with a heavy tail: Characteristics and applications to crash data. AB - Crash data can often be characterized by over-dispersion, heavy (long) tail and many observations with the value zero. Over the last few years, a small number of researchers have started developing and applying novel and innovative multi parameter models to analyze such data. These multi-parameter models have been proposed for overcoming the limitations of the traditional negative binomial (NB) model, which cannot handle this kind of data efficiently. The research documented in this paper continues the work related to multi-parameter models. The objective of this paper is to document the development and application of a flexible NB generalized linear model with randomly distributed mixed effects characterized by the Dirichlet process (NB-DP) to model crash data. The objective of the study was accomplished using two datasets. The new model was compared to the NB and the recently introduced model based on the mixture of the NB and Lindley (NB-L) distributions. Overall, the research study shows that the NB-DP model offers a better performance than the NB model once data are over-dispersed and have a heavy tail. The NB-DP performed better than the NB-L when the dataset has a heavy tail, but a smaller percentage of zeros. However, both models performed similarly when the dataset contained a large amount of zeros. In addition to a greater flexibility, the NB-DP provides a clustering by-product that allows the safety analyst to better understand the characteristics of the data, such as the identification of outliers and sources of dispersion. PMID- 26945473 TI - General aviation accidents related to exceedance of airplane weight/center of gravity limits. AB - BACKGROUND: Obesity, affects a third of the US population and its corollary occupant weight adversely impacts safe flight operations. Increased aircraft weight results in longer takeoff/landing distances, degraded climb gradients and airframe failure may occur in turbulence. In this study, the rate, temporal changes, and lethality of accidents in piston-powered, general aviation aircraft related to exceeding the maximum aircraft weight/center of gravity (CG) limits were determined. METHODS: Nation-wide person body mass were from the National Health and Nutrition Examination Survey. The NTSB database was used to identify accidents related to operation of aircraft outside of their weight/CG envelope. Statistical analyses employed T-tests, proportion tests and a Poisson distribution. RESULTS: While the average body mass climbed steadily (p<0.001) between 1999 and 2014 the rate of accidents related to exceedance of the weight/CG limits did not change (p=0.072). However, 57% were fatal, higher (p<0.001) than the 21% for mishaps attributed to other causes/factors. The majority (77%) of accidents were due to an overloaded aircraft operating within its CG limits. As to the phase of flight, accidents during takeoff and those occurring enroute carried the lowest (50%) and highest (85%) proportion of fatal accidents respectively. CONCLUSION: While the rate of general aviation accidents related to operating an aircraft outside of its weight/CG envelope has not increased over the past 15 years, these types of accidents carry a high risk of fatality. Airmen should be educated as to such risks and to dispel the notion held by some that flights may be safely conducted with an overloaded aircraft within its CG limits. PMID- 26945474 TI - Therapeutic hypothermia for neonatal hypoxic-ischaemic encephalopathy had favourable outcomes at a referral hospital in a middle-income country. AB - AIM: This South African study documented the survival and neurodevelopmental outcomes of infants with hypoxic-ischaemic encephalopathy (HIE) after introducing cooling to a neonatal intensive care unit and identified early markers for neurodevelopmental outcome. METHODS: We retrospectively reviewed infants that received cooling according to the Total Body Hypothermia trial protocol from 2008 to 2011. Infants were screened with the Bayley Scales of Infant and Toddler Development, Third Edition, at one year of age and underwent neurological and hearing assessments. RESULTS: Data on 99 infants with HIE showed that 45% of cases were moderate, 23% severe and 32% mild. An abnormal amplitude integrated electro-encephalogram (aEEG) background was documented in 45 cases within 24 hours. Magnetic resonance imaging (MRI) scans were consistent with HIE in all but one case. We reviewed 50 traceable survivors at one year. Development was significantly impaired in nine and 41 were normal or mildly impaired. A severely abnormal aEEG background, severe HIE and an abnormal MRI were associated with death and severe impairment. A good suck, mild HIE, primiparity and normal MRI were associated with good outcomes. CONCLUSION: Most infants with HIE survived without major impairment. Previously described predictors of neurodevelopmental outcome were good surrogate markers in this population. PMID- 26945475 TI - A Two-Stroke, Two-Cylinder Piston Rotaxane Motor. AB - We introduce a model for a rotaxane motor. This uses two major themes of rotaxane physics, that is, the ability to change the potential of different regions of the axle (switching) and the entropy associated with free rings. The motor is based on free rings being trapped and released by potential stripes or stations. We calculate the power produced by such a motor, which is in the femtoWatt range. The power is proportional to the square of the number of rings. PMID- 26945476 TI - Abnormal cognitive network interactions in Lennox-Gastaut syndrome: A potential mechanism of epileptic encephalopathy. AB - OBJECTIVE: In patients with Lennox-Gastaut syndrome (LGS), recurrent epileptic activity is thought to contribute to impaired cognition (epileptic encephalopathy). Using concurrent electroencephalography-functional magnetic resonance imaging (EEG-fMRI), we recently showed that epileptiform discharges in LGS recruit large-scale networks that normally support key cognitive processes. In LGS, given that epileptic activity engages cognitive networks, and cognition is pervasively impaired, we hypothesized that cognitive network interactions in LGS are persistently abnormal. METHODS: We studied 15 LGS patients (mean age +/- 1 standard deviation [SD] = 28.7 +/- 10.6 years) and 17 healthy controls (mean age +/- 1 SD = 27.6 +/- 6.6 years) using task-free EEG-fMRI. Four networks of interest (default-mode, dorsal attention, executive control, and anterior salience) were defined using group-level independent components analysis (ICA). Functional connectivity within and between networks was determined for each subject, and then LGS network interactions were compared to network behavior in the control group. To test whether group differences were present in periods without scalp-detectable epileptiform discharges (i.e., persistent), we separately assessed discharge-affected and discharge-unaffected epochs in six patients with sufficient data for this analysis. RESULTS: In LGS, cognitive networks showed (1) reduced within-network integration, including weaker connectivity within the default-mode network, and (2) impaired between-network segregation, including stronger connectivity between the default-mode and dorsal attention networks. Abnormal interactions were present during fMRI periods with and without discharges, indicating that impaired network behavior may endure during periods without scalp-detectable epileptic activity. SIGNIFICANCE: In LGS, cognitive network interactions are persistently abnormal. Given that cognition typically worsens with the onset of LGS, and may improve after seizure control, our findings are consistent with the hypothesis that the epileptic process in LGS may initiate and perhaps sustain abnormal network behavior. We propose that epileptic encephalopathy may be a consequence of persistently disrupted cognitive network interactions. PMID- 26945477 TI - Bednar Tumor (Pigmented Dermatofibrosarcoma Protuberans). PMID- 26945478 TI - Enjoying food without caloric cost: The impact of brief mindfulness on laboratory eating outcomes. AB - OBJECTIVE: Mindfulness-based interventions have been increasingly applied to treat eating-related problems ranging from obesity to eating disorders. Yet few studies have empirically examined the mechanisms of a mindful approach to eating. The current studies examine the potential of brief mindfulness instructions to enhance the psychological and behavioral dimensions of eating. METHODS: In three experiments (total N = 319 undergraduates), we examined whether brief mindfulness instructions would enhance the positive sensory experience involved in tasting food as well as healthy eating behaviors. RESULTS: Relative to distraction control instructions, the first two studies demonstrated that brief mindfulness instructions increased the enjoyment of a commonly pleasurable food (chocolate; Study 1), and a food with generally more mixed associations (raisins; Study 2). The third study replicated and extended these findings to show that brief mindfulness instructions also led to lower calorie consumption of unhealthy food relative to distracted or no-instruction control conditions, an effect mediated by greater eating enjoyment. CONCLUSIONS: Findings demonstrated the power of brief mindfulness instructions to positively impact both health-relevant behavior and sensory experience associated with eating food. Implications for both theory and clinical applications of mindfulness are discussed. PMID- 26945479 TI - Hepatic miR-33a/miR-144 and their target gene ABCA1 are associated with steatohepatitis in morbidly obese subjects. AB - BACKGROUND AND AIM: Abnormal cholesterol metabolism may contribute to the pathogenesis of non-alcoholic steatohepatitis (NASH) and fibrosis. miR-33 and miR 144 regulate adenosine triphosphate binding cassette transporter (ABCA1) and other target genes involved in cholesterol efflux, fatty acid oxidation and inflammation. We explored relationships between non-alcoholic fatty liver disease (NAFLD) and the hepatic expression of ABCA1/ABCG1, as well as other target genes regulated by miR-33 (carnitine O-octanoyltransferase, CROT and hydroxyacyl-CoA dehydrogenase beta-subunit, HADHB) and miR-144 (toll-like receptor-2, TLR2). Moreover, we evaluated whether the expression of these genes is correlated with miR-33a/b and miR-144 expression in Mexican individuals with morbid obesity. METHODS: Eighty-four morbidly obese subjects undergoing bariatric surgery were included in this study. Liver biopsies were obtained to measure hepatic triglyceride and free cholesterol contents, as well as ABCA1, ABCG1, CROT, HADHB, TLR2, miR-33a/b and miR-144 expression. RESULTS: Hepatic free cholesterol content was significantly increased in NASH as compared to non-NASH subjects, while ABCA1 and ABCG1 protein levels significantly decreased with NASH and fibrosis progression. The relative expression of miR-33a and miR-144 correlated inversely with ABCA1 but not with ABCG1 protein levels. Moreover, both miRNAs increased significantly in NASH individuals. miR-33 target genes CROT and HADHB correlated inversely with miR-33a. However, the expression of these genes was not associated with NASH. CONCLUSIONS: miR-33a/144 and their target gene ABCA1 may contribute to the pathogenesis of NASH in morbidly obese subjects. PMID- 26945480 TI - Graphene oxide modulates root growth of Brassica napus L. and regulates ABA and IAA concentration. AB - Researchers have proven that nanomaterials have a significant effect on plant growth and development. To better understand the effects of nanomaterials on plants, Zhongshuang 11 was treated with different concentrations of graphene oxide. The results indicated that 25-100mg/l graphene oxide treatment resulted in shorter seminal root length compared with the control samples. The fresh root weight decreased when treated with 50-100mg/l graphene oxide. The graphene oxide treatment had no significant effect on the Malondialdehyde (MDA) content. Treatment with 50mg/l graphene oxide increased the transcript abundance of genes involved in ABA biosynthesis (NCED, AAO, and ZEP) and some genes involved in IAA biosynthesis (ARF2, ARF8, IAA2, and IAA3), but inhibited the transcript levels of IAA4 and IAA7. The graphene oxide treatment also resulted in a higher ABA content, but a lower IAA content compared with the control samples. The results indicated that graphene oxide modulated the root growth of Brassica napus L. and affected ABA and IAA biosynthesis and concentration. PMID- 26945481 TI - Anandamide interferes with human endometrial stromal-derived cell differentiation: An effect dependent on inhibition of cyclooxygenase-2 expression and prostaglandin E2 release. AB - The human endometrium undergoes cyclical growth, differentiation, and regression periods throughout the reproductive life. The process in which endometrial stromal cells proliferate and differentiate into decidual cells, named decidualization, prepares a receptive endometrium for implantation. Prostaglandins (PGs) and endocannabinoids (eCBs) are crucial mediators of this process. We have recently reported that the eCB anandamide (AEA) interferes with rat stromal cell differentiation, and on the other hand, PGs are also crucial for decidualization. Therefore, in this study, we analyzed the AEA levels, both in nondifferentiated and in decidualizing human endometrial stromal cells by liquid chromatography-mass spectrometry, and investigated the impact of AEA on PG release and cyclooxygenase-2 (COX-2) expression in human endometrial stromal derived cell differentiation. For that, an ultra-performance liquid chromatography-mass spectrometry/mass spectrometry method to measure prostaglandin E2 (PGE2 ) and prostaglandin F2alpha in biological samples was developed and validated. We demonstrate that AEA levels in decidualizing cells are lower than those in nondifferentiated cells, whereas PGE2 levels and COX-2 expression are up-regulated. Thus, low AEA levels may be essential for the onset of decidualization. On the contrary, in AEA-treated cells undergoing decidualization, a decrease of COX-2 protein levels and PGE2 production, in a manner dependent on cannabinoid receptor 1 activation, was observed. Overall, these findings suggest that a deregulation of the intricate network that drives cell differentiation may compromise pregnancy and fertility. It is clinically relevant to understand the mechanisms that influence eCB and PG levels in the endometrium because they may shed light on the sequence of events that lead to a successful pregnancy. (c) 2016 BioFactors, 42(3):277-286, 2016. PMID- 26945482 TI - Risk analysis for dengue suitability in Africa using the ArcGIS predictive analysis tools (PA tools). AB - BACKGROUND: Risk maps identifying suitable locations for infection transmission are important for public health planning. Data on dengue infection rates are not readily available in most places where the disease is known to occur. METHODS: A newly available add-in to Esri's ArcGIS software package, the ArcGIS Predictive Analysis Toolset (PA Tools), was used to identify locations within Africa with environmental characteristics likely to be suitable for transmission of dengue virus. RESULTS: A more accurate, robust, and localized (1 km * 1 km) dengue risk map for Africa was created based on bioclimatic layers, elevation data, high resolution population data, and other environmental factors that a search of the peer-reviewed literature showed to be associated with dengue risk. Variables related to temperature, precipitation, elevation, and population density were identified as good predictors of dengue suitability. Areas of high dengue suitability occur primarily within West Africa and parts of Central Africa and East Africa, but even in these regions the suitability is not homogenous. CONCLUSION: This risk mapping technique for an infection transmitted by Aedes mosquitoes draws on entomological, epidemiological, and geographic data. The method could be applied to other infectious diseases (such as Zika) in order to provide new insights for public health officials and others making decisions about where to increase disease surveillance activities and implement infection prevention and control efforts. The ability to map threats to human and animal health is important for tracking vectorborne and other emerging infectious diseases and modeling the likely impacts of climate change. PMID- 26945483 TI - Hemoglobin guided nanocarrier for specific delivery of amphotericin B to Leishmania infected macrophage. AB - Leishmania donovani being an intracellular parasite poses many challenges against the attempted chemotherapy. After the resistance towards the first line of antileishmanial drug, Amphotericin B has been the treatment of choice against visceral leishmaniasis, a fatal tropical disease. However, unfavorable toxicity profile, severe side effects, prolonged parenteral administration procedure limits the use of Amphotericin B. Lack of available specific delivery system also makes this drug unsafe for the prolonged use. In this current study, a chitosan chondroitin sulfate based nanodelivery vehicle has been introduced. Hemoglobin has been attached on the surface of the delivery system for specifically targeting the leishmania infected macrophage taking the advantage of Leishmania being highly auxotrophic for heme. This cheap and biodegradable delivery vehicle has improved the toxicity profile and lowered LD50 value of the drug significantly compared to traditional way of its direct administration. PMID- 26945484 TI - Lidocaine self-sacrificially improves the skin permeation of the acidic and poorly water-soluble drug etodolac via its transformation into an ionic liquid. AB - Poor transdermal penetration of active pharmaceutical ingredients (APIs) impairs both bioavailability and therapeutic benefits and is a major challenge in the development of transdermal drug delivery systems. Here, we transformed a poorly water-soluble drug, etodolac, into an ionic liquid in order to improve its hydrophobicity, hydrophilicity and skin permeability. The ionic liquid was prepared by mixing etodolac with lidocaine (1:1, mol/mol). Both the free drug and the transformed ionic liquid were characterized by differential scanning colorimetry (DSC), infrared spectroscopy (IR), and saturation concentration measurements. In addition, in vitro skin-permeation testing was carried out via an ionic liquid-containing patch (Etoreat patch). The lidocaine and etodolac in ionic liquid form led to a relatively lower melting point than either lidocaine or etodolac alone, and this improved the lipophilicity/hydrophilicity of etodolac. In vitro skin-permeation testing demonstrated that the Etoreat patch significantly increased the skin permeation of etodolac (9.3-fold) compared with an etodolac alone patch, although an Etoreat patch did not increase the skin permeation of lidocaine, which was consistent with the results when using a lidocaine alone patch. Lidocaine appeared to self-sacrificially improve the skin permeation of etodolac via its transformation into an ionic liquid. The data suggest that ionic liquids composed of approved drugs may substantially expand the formulation preparation method to meet the challenges of drugs which are characterized by poor rates of transdermal absorption. PMID- 26945485 TI - Fusion or gemination? An unusual mandibular second molar. AB - Fusion and gemination is not an uncommon finding and affected most primary dentition and the permanent maxillary incisors. These changes can develop a series of complication. A 11-year-old male presented radiography finding: an unusual mandibular second molar. A well-documented case brings a challenge for radiologists classify between fusion and gemination. In conclusion, this alteration although common in other regions, there are no case in the literature involving "second and third" molar. PMID- 26945486 TI - Primary omental gangrene mimicking appendicular perforation peritonitis-A case report. AB - INTRODUCTION: Primary omental torsion is a rare cause of acute abdomen in adults and presents with variable signs and symptoms. Establishing a preoperative diagnosis may be difficult in the emergency setting. It is rarely diagnosed preoperatively as it mimics common surgical emergencies such as acute appendicitis, appendicular perforation, acute cholecystitis and perforated peptic ulcers and can lead to the clinical deterioration of patient if missed PRESENTATION OF CASE: A 47 years old male was taken to the operating room with a diagnosis of appendicular perforation peritonitis and during surgery was found to have a primary omental gangrene with pyoperitoneum, for which omentectomy and peritoneal lavage was performed. DISCUSSION: Torsion of the omentum is a condition in which the organ twists on its long axis to such an extent that its vascularity is compromised. Omental torsion can be primary (idiopathic) or secondary, depending on an underlying cause. Primary omental torsion was first described by Eitel in 1899. However, very few cases have been reported. Our case was a rare case presenting with omental gangrene with pyoperitoneum mimicking appendicular perforation peritonitis. CONCLUSION: Primary omental torsion is a rare diagnosis. A high index of clinical suspicion is required for a preoperative diagnosis. In doubtful cases a CT scan may be helpful. Surgical excision of the omentum remains the treatment of choice; however, conservative management may be attempted in an uncomplicated omental torsion. PMID- 26945487 TI - Pancreatic manifestations in von Hippel-Lindau disease: A case report. AB - INTRODUCTION: Pancreatic manifestations in Von Hippel-Lindau (VHL) disease can present as a multitude of forms, and their management can be challenging. PRESENTATION OF THE CASE: A 66-year-old woman presented with increasing abdominal girth without other associated symptoms of nausea, vomiting, abdominal pain, weight-loss, and jaundice. Her medical and surgical histories were significant for type II diabetes, cerebral tumor resection, bilateral nephrectomies, and laser photocoagulation of retinal hemangiomas. Computed tomography (CT) of the abdomen showed a massive multi-cystic lesion in the pancreas and the patient was referred to our hepatopancreatic biliary center. DISCUSSION: The findings on the subsequent cross-sectional MRI imaging signified pancreatic manifestations in VHL disease. CONCLUSION: The management of VHL disease-associated benign pancreatic cystic lesions involves interval monitoring with cross-sectional imaging for malignant changes/development. PMID- 26945489 TI - An enlarged intramuscular venous malformation in the femoral region successfully treated with complete resection. AB - INTRODUCTION: Intramuscular venous malformations have been previously described as intramuscular hemangiomas, and various therapies have been applied for their treatment. This condition is relatively rare, and therefore, physicians often struggle to determine the appropriate therapy. We presented a case of an enlarged intramuscular venous malformation relapsed after surgery successfully treated with complete resection. PRESENTATION OF CASE: We presented a case of an enlarged intramuscular venous malformation with postoperative recurrence successfully treated with complete resection. A 63-year-old woman presented with a subcutaneous mass in the right distal thigh. She experienced swelling in the right thigh 19 years previously and was diagnosed with a venous aneurysm. Three dimensional CT angiography confirmed the presence of an irregular vessel assumed to be the feeding vessel, which was dendritically branched from the deep femoral artery. We performed surgical complete resection. Her pain and gait disturbance improved after surgery, and she has not experienced recurrence of the mass for the past 2 years. DISCUSSION: Conservative therapy is initially used for venous malformations. Sclerotherapy, laser therapy, or surgical resection is considered after low-dose aspirin therapy, in combination with the use of compressive garments. Surgical resection is indicated for completely resectable lesions and is appropriate for large lesions in terms of cosmetic benefit. However, partial resection may result in excessive bleeding or postoperative recurrence. CONCLUSION: The therapy for venous malformations should be decided based on the degree of disability in daily living, adjacent tissue damage, and cosmetic concerns after appropriate differential diagnostic investigations and biopsy. PMID- 26945488 TI - Successful treatment of recurrent carotid in-stent restenosis and drug-eluting balloon failure with a coronary bioresorbable vascular scaffold: A case report. AB - INTRODUCTION: Carotid in-stent restenosis is associated with substantial risk of recurrent restenosis, even after drug-eluting balloon usage. PRESENTATION OF CASE: We hereby report the case of a patient with recurrent carotid in-stent restenosis and drug-eluting balloon failure treated with a coronary bioresorbable vascular scaffold, achieving a satisfactory acute and long-term result, as disclosed by duplex ultrasound scan performed more than 1 year after the procedure. DISCUSSION/CONCLUSION: While awaiting for external validation, this clinical vignette supports expanding the armamentarium of endovascular specialists focusing on carotid artery disease, while providing further proof of the safety and efficacy of current bioresorbable vascular scaffolds. PMID- 26945490 TI - Granulocyte-colony stimulating factor-producing gallbladder carcinoma-include analysis all case reports: A case report. AB - INTRODUCTION: It is extremely rare for gallbladder carcinoma to produce granulocyte-colony stimulating factor (G-CSF) and such tumors have a poor prognosis. PRESENTATION OF CASE: A 67-year-old man was admitted with continuous fever. Laboratory tests showed a leukocyte count of 27,980/MUL, serum C-reactive protein (CRP) of 9.2mg/dL and serum G-CSF of 225pg/mL. Imaging revealed an irregular gallbladder mass about 90mm in diameter with peripheral enhancement that also involved the liver and transverse colon. G-CSF producing gallbladder carcinoma was diagnosed. We performed cholecystectomy, partial resection of segments 4 and 5 of the liver, partial resection of the transverse colon, and gastrostomy. Histopathological examination showed gallbladder carcinoma (pT3, pN0, M0, G2, and pStage IIIA by the UICC classification, version 7). On immunohistochemical staining, tumor cells were positive for G-CSF. The leukocyte count was normalized postoperatively and fever subsided immediately after surgery. Two months later, the leukocyte count rose to 56,820/MUL and metastases to the liver and lymph nodes were detected by CT. Chemotherapy (gemcitabine plus cisplatin) was started and the leukocyte count was normalized after the first course. The patient has continued chemotherapy and has survived for 16 months postoperatively. DISCUSSION: G-CSF producing gallbladder carcinoma has a poor prognosis and most patients die within 12 months of starting therapy. It is rare for patients with recurrence to survive for 16 months after surgery, as in the present case. CONCLUSION: Multidisciplinary therapy (surgery and chemotherapy) may prolong the survival of patients with G-CSF producing gallbladder carcinoma, especially those with recurrence. PMID- 26945491 TI - How clinical registries can make a difference in hip fracture care. PMID- 26945492 TI - Young Children Treat Robots as Informants. AB - Children ranging from 3 to 5 years were introduced to two anthropomorphic robots that provided them with information about unfamiliar animals. Children treated the robots as interlocutors. They supplied information to the robots and retained what the robots told them. Children also treated the robots as informants from whom they could seek information. Consistent with studies of children's early sensitivity to an interlocutor's non-verbal signals, children were especially attentive and receptive to whichever robot displayed the greater non-verbal contingency. Such selective information seeking is consistent with recent findings showing that although young children learn from others, they are selective with respect to the informants that they question or endorse. PMID- 26945493 TI - The discovery of IgE 50 years later. PMID- 26945494 TI - Immunoglobulin E, what is it good for? PMID- 26945495 TI - Allergic sensitization patterns identified through latent class analysis among children with and without asthma. AB - BACKGROUND: Specific patterns of allergic sensitization to common allergens may provide relevant clinical insight into asthma risk. OBJECTIVE: To identify patterns of allergic sensitization based on multiple individual allergens and link these to current and persistent asthma using baseline and 3-year follow-up data. METHODS: Children 7 to 8 years old with (n = 196) and without (n = 136) asthma from the New York City Neighborhood Asthma and Allergy Study were studied. IgE against a panel of 112 antigens was measured using the ISAC multiplex panel array. Latent class analysis (LCA) was used to identify patterns of allergic sensitization among the 26 most common allergens against which children had measurable IgE. The association between patterns of allergic sensitization and risk of asthma and other allergic diseases was examined. RESULTS: LCA identified 4 patterns of allergic sensitization as follows: low risk of sensitization (prevalence of 53% in children with asthma and 76% in children without asthma), indoor (prevalence of 23% in children with asthma and 15% in children without asthma), pollen and indoor group 1 (prevalence of 16% in children with asthma and 5% in children without asthma), and pollen and indoor group 2 (prevalence of 9% in children with asthma and 4% in children without asthma). Compared with the low risk of sensitization pattern, children belonging to the 3 sensitized patterns had significantly higher risk of asthma at ages 7 to 8 years and 3 years later, with the highest risk for children in the pollen and indoor group 1 pattern. CONCLUSIONS: LCA facilitates the study of sensitization profiles to a large number of common allergens. Analyzing patterns of allergic sensitization from multiple allergens reveals additional relevant associations with asthma than the study of a single allergen or total IgE. PMID- 26945496 TI - Natural history of Hymenoptera venom allergy in children not treated with immunotherapy. AB - BACKGROUND: Differences in treatment approach still exist for children after systemic sting reactions. In addition, there are still some doubts about when systemic reactors should be treated with venom immunotherapy (VIT). OBJECTIVE: To determine the rate of sting recurrence and natural history of Hymenoptera venom allergy (HVA) in children not treated with VIT. METHODS: A total of 219 children diagnosed as having HVA who were not treated with VIT were identified in 3 pediatric allergology centers. Survey by telephone or mail with the use of a standardized questionnaire was conducted. The number of field re-stings, subsequent symptoms, and provided treatment were analyzed. RESULTS: A total of 130 of the 219 patients responded to the survey, for a response rate of 59.4%. During the median follow-up period of 72 months (interquartile range, 52-85 months), 44 children (77% boys) were stung 62 times. Normal reactions were most common, occurring in 27 patients (62%). Severe systemic reactions (SSRs) occurred in 8 (18%) of those who were re-stung. The subsequent reaction was significantly milder (P < 0.001), especially in the case of patients re-stung by the same insect (P < .001). None of the children with prediagnostic large local reactions and negative test results for venom specific IgE developed SSRs after re-sting by the culprit insect (P = .03). In children with SSRs, median time from diagnosis to re-sting was 2 times longer than that in those with large local reactions and normal reactions (P = .007). CONCLUSIONS: Most children with HVA not treated with VIT reported milder reactions after a re-sting. Probability of SSR to re-sting increases along with the severity of initial reaction. PMID- 26945497 TI - Immunologic alterations and efficacy of subcutaneous immunotherapy with Dermatophagoides pteronyssinus in monosensitized and polysensitized patients. AB - BACKGROUND: There is a continuing debate about whether monoallergen subcutaneous immunotherapy (SCIT) is able to modulate immune and clinical responses toward main causal allergen in polysensitized patients. OBJECTIVE: To investigate short term immunologic changes and clinical effectiveness of SCIT with Dermatophagoides pteronyssinus in monosensitized and polysensitized patients who have rhinitis with or without asthma. METHODS: Nineteen monosensitized and 24 polysensitized patients participated in this prospective, self-placebo-controlled, interventional study. Cluster immunotherapy with D pteronyssinus was administered after 2 months of placebo in both groups. Immunologic parameters, including CD203c expression on basophils after allergen stimulation, total IgE, specific IgE, and specific IgG4, were evaluated at baseline, after placebo, and after immunotherapy. Clinical effectiveness was assessed using monthly symptom medication scores, visual analog scale, quality-of-life questionnaire, and nasal allergen provocation test. RESULTS: At baseline, polysensitized patients had higher CD203c expression on basophils than monosensitized patients (P = .007). Activated basophils expressing CD203c, total IgE, and specific IgG4 were significantly increased after immunotherapy compared with baseline and placebo in the polysensitized group (P < .025). After immunotherapy, specific IgE and D pteronyssinus-induced CD203c expression were significantly higher in polysensitized than monosensitized patients (P < .05). The total symptom scores and the Mini Rhinoconjunctivitis Quality of Life Questionnaire scores in polysensitized patients and the visual analog scale scores in both groups were lower after immunotherapy compared with baseline and placebo (P < .025). Titrated nasal allergen provocation test with D pteronyssinus increased after immunotherapy in the monosensitized group (P < .05). CONCLUSION: This study indicates that monosensitized and polysensitized patients have distinct humoral response and basophil behavior to SCIT. However, a single-allergen immunotherapy corresponding to the most clinically troublesome allergy in polysensitized patients can lead to early clinical efficacy comparable to that seen in monosensitized patients. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01795846. PMID- 26945498 TI - Thromboembolic stroke: a sequela of Hymenoptera venom-induced anaphylaxis. PMID- 26945499 TI - Refractory anaphylaxis: further considerations for emergency care providers. PMID- 26945500 TI - Authors' response. PMID- 26945501 TI - Recently published anaphylaxis practice parameter. PMID- 26945502 TI - Authors' response. PMID- 26945503 TI - Living on the edge: emergence of spontaneous gac mutations in Pseudomonas protegens during swarming motility. AB - Swarming motility is a flagella-driven multicellular behaviour that allows bacteria to colonize new niches and escape competition. Here, we investigated the evolution of specific mutations in the GacS/GacA two-component regulatory system in swarming colonies of Pseudomonas protegens Pf-5. Experimental evolution assays showed that repeated rounds of swarming by wildtype Pf-5 drives the accumulation of gacS/gacA spontaneous mutants on the swarming edge. These mutants cannot swarm on their own because they lack production of the biosurfactant orfamide A, but they do co-swarm with orfamide-producing wildtype Pf-5. These co-swarming assays further demonstrated that DeltagacA mutant cells indeed predominate on the edge and that initial DeltagacA:wildtype Pf-5 ratios of at least 2:1 lead to a collapse of the swarming colony. Subsequent whole-genome transcriptome analyses revealed that genes associated with motility, resource acquisition, chemotaxis and efflux were significantly upregulated in DeltagacA mutant on swarming medium. Moreover, transmission electron microscopy showed that DeltagacA mutant cells were longer and more flagellated than wildtype cells, which may explain their predominance on the swarming edge. We postulate that adaptive evolution through point mutations is a common feature of range-expanding microbial populations and that the putative fitness benefits of these mutations during dispersal of bacteria into new territories are frequency-dependent. PMID- 26945504 TI - A profile of protein-protein interaction: Crystal structure of a lectin-lectin complex. AB - Proteins may utilize complex networks of interactions to create/proceed signaling pathways of highly adaptive responses such as programmed cell death. Direct binary interactions study of proteins may help propose models for protein-protein interaction. Towards this goal we applied a combination of thermodynamic kinetics and crystal structure analyses to elucidate the complexity and diversity in such interactions. By determining the heat change on the association of two galactose specific legume lectins from Butea monosperma (BML) and Spatholobus parviflorus (SPL) belonging to Fabaceae family helped to compute the binding equilibrium. It was extended further by X-ray structural analysis of BML-SPL binary complex. In order to chart the proteins interacting mainly through their interfaces, identification of the nature of forces which stabilized the association of the lectin-lectin complex was examined. Comprehensive analysis of the BMLSPL complex by isothermal titration calorimetry and X-ray crystal structure threw new light on the lectin-lectin interactions suggesting of their use in diverse areas of glycobiology. PMID- 26945506 TI - The asymmetrical influence of increasing time-on-task on attentional disengagement. AB - Increasing time-on-task leads to fatigue and, as shown by previous research, differentially affects the deployment of visual attention towards the left and the right visual space. In healthy participants, an increasing rightward bias is commonly observed with increasing time-on-task. Yet, it is unclear whether specific mechanisms involved in the spatial deployment of visual attention are differentially affected by increasing time-on-task. The aim of the present study was to investigate whether prolonged time-on-task would affect a specific mechanism of visuospatial attentional deployment, namely attentional disengagement, in an asymmetrical fashion. For this purpose, we administered to healthy participants a prolonged gap/overlap saccadic paradigm, with left- and right-sided target stimuli. This oculomotor paradigm allowed to quantify disengagement costs according to the direction of the subsequent attentional shifts, and to evaluate the temporal development of disengagement costs with increasing time-on-task. Our results show that, with increasing time-on-task, participants demonstrated significantly lower disengagement costs for rightward compared to leftward saccades. These effects were specific, since concurring side differences of saccadic latencies were found for overlap trials (requiring attentional disengagement), but not for gap trials (requiring no or less attentional disengagement). Moreover, the results were paralleled by a non lateralised decrease in saccadic peak velocity with increasing time-on-task, a common finding indicating an increasing level of fatigue. Our findings support the idea that non-spatial attentional aspects, such as fatigue due to increasing time-on-task, can have a substantial influence on the spatial deployment of visual attention, in particular on its disengagement, depending on the direction of the subsequent attentional shift. PMID- 26945507 TI - Second Pallister-Opitz Genetics Symposium, Helena, Montana, July 2015. PMID- 26945505 TI - The role of the right hemisphere in semantic control: A case-series comparison of right and left hemisphere stroke. AB - Semantic control processes guide conceptual retrieval so that we are able to focus on non-dominant associations and features when these are required for the task or context, yet the neural basis of semantic control is not fully understood. Neuroimaging studies have emphasised the role of left inferior frontal gyrus (IFG) in controlled retrieval, while neuropsychological investigations of semantic control deficits have almost exclusively focussed on patients with left-sided damage (e.g., patients with semantic aphasia, SA). Nevertheless, activation in fMRI during demanding semantic tasks typically extends to right IFG. To investigate the role of the right hemisphere (RH) in semantic control, we compared nine RH stroke patients with 21 left-hemisphere SA patients, 11 mild SA cases and 12 healthy, aged-matched controls on semantic and executive tasks, plus experimental tasks that manipulated semantic control in paradigms particularly sensitive to RH damage. RH patients had executive deficits to parallel SA patients but they performed well on standard semantic tests. Nevertheless, multimodal semantic control deficits were found in experimental tasks involving facial emotions and the 'summation' of meaning across multiple items. On these tasks, RH patients showed effects similar to those in SA cases - multimodal deficits that were sensitive to distractor strength and cues and miscues, plus increasingly poor performance in cyclical matching tasks which repeatedly probed the same set of concepts. Thus, despite striking differences in single-item comprehension, evidence presented here suggests semantic control is bilateral, and disruption of this component of semantic cognition can be seen following damage to either hemisphere. PMID- 26945508 TI - Ultrasound-Guided Superior Hypogastric Plexus Block: A Cadaveric Feasibility Study with Fluoroscopic Confirmation. AB - Plancarte first described a fluoroscopy-guided superior hypogastric plexus block to manage pelvic pain in 1990. Modifications have since been described using different imaging modalities. Ultrasound-guided approach has been described in a clinical outcome study. However, the accuracy of an ultrasound-guided method has never been validated by alternative imaging. We conducted an experiment aiming to develop ultrasound-guided superior hypogastric plexus block using human cadavers in the supine position. Final needle position and spread of a radiopaque contrast was verified by fluoroscopy, a standard imaging tool. The needle approach to the L5 vertebral body was performed in the short axis as has been recommended. Injection of radiopaque contrast revealed unilateral and cephalad spread to the L5/S1 disk. Additional transabdominal long-axis scanning of the lumbosacral segment was and the needle trajectory was modified to aim for the apex of the L5/S1 disk. Bilateral spread was achieved by strict midline placement of the needle tip and real-time observation of injection. The modified ultrasound-guided technique resulted in a similar spread of injectate as the traditional fluoroscopy-guided technique that in a clinical scenario would offer complete block of the superior hypogastric plexus. PMID- 26945510 TI - Inherently irrational? A computational model of escalation of commitment as Bayesian Updating. AB - Monte Carlo simulations were performed to analyze the degree to which two-, three and four-step learning histories of losses and gains correlated with escalation and persistence in extended extinction (continuous loss) conditions. Simulated learning histories were randomly generated at varying lengths and compositions and warranted probabilities were determined using Bayesian Updating methods. Bayesian Updating predicted instances where particular learning sequences were more likely to engender escalation and persistence under extinction conditions. All simulations revealed greater rates of escalation and persistence in the presence of heterogeneous (e.g., both Wins and Losses) lag sequences, with substantially increased rates of escalation when lags comprised predominantly of losses were followed by wins. These methods were then applied to human investment choices in earlier experiments. The Bayesian Updating models corresponded with data obtained from these experiments. These findings suggest that Bayesian Updating can be utilized as a model for understanding how and when individual commitment may escalate and persist despite continued failures. PMID- 26945509 TI - Hypochlorhydria-induced calcium malabsorption does not affect fracture healing but increases post-traumatic bone loss in the intact skeleton. AB - Efficient calcium absorption is essential for skeletal health. Patients with impaired gastric acidification display low bone mass and increased fracture risk because calcium absorption is dependent on gastric pH. We investigated fracture healing and post-traumatic bone turnover in mice deficient in Cckbr, encoding a gastrin receptor that affects acid secretion by parietal cells. Cckbr-/- mice display hypochlorhydria, calcium malabsorption, and osteopenia. Cckbr-/- and wildtype (WT) mice received a femur osteotomy and were fed either a standard or calcium-enriched diet. Healed and intact bones were assessed by biomechanical testing, histomorphometry, micro-computed tomography, and quantitative backscattering. Parathyroid hormone (PTH) serum levels were determined by enzyme linked immunosorbent assay. Fracture healing was unaffected in Cckbr-/- mice. However, Cckbr-/- mice displayed increased calcium mobilization from the intact skeleton during bone healing, confirmed by significantly elevated PTH levels and osteoclast numbers compared to WT mice. Calcium supplementation significantly reduced secondary hyperparathyroidism and bone resorption in the intact skeleton in both genotypes, but more efficiently in WT mice. Furthermore, calcium administration improved bone healing in WT mice, indicated by significantly increased mechanical properties and bone mineral density of the fracture callus, whereas it had no significant effect in Cckbr-/- mice. Therefore, under conditions of hypochlorhydria-induced calcium malabsorption, calcium, which is essential for callus mineralization, appears to be increasingly mobilized from the intact skeleton in favor of fracture healing. Calcium supplementation during fracture healing prevented systemic calcium mobilization, thereby maintaining bone mass and improving fracture healing in healthy individuals whereas the effect was limited by gastric hypochlorhydria. (c) 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1914-1921, 2016. PMID- 26945511 TI - Representation of illusory and physical rotations in human MST: A cortical site for the pinna illusion. AB - Visual illusions have fascinated mankind since antiquity, as they provide a unique window to explore the constructive nature of human perception. The Pinna illusion is a striking example of rotation perception in the absence of real physical motion. Upon approaching or receding from the Pinna-Brelstaff figure, the observer experiences vivid illusory counter rotation of the two rings in the figure. Although this phenomenon is well known as an example of integration from local cues to a global percept, the visual areas mediating the illusory rotary perception in the human brain have not yet been identified. In the current study we investigated which cortical area in the human brain initially mediates the Pinna illusion, using psychophysical tests and functional magnetic resonance imaging (fMRI) of visual cortices V1, V2, V3, V3A, V4, and hMT+ of the dorsal and ventral visual pathways. We found that both the Pinna-Brelstaff figure (illusory rotation) and a matched physical rotation control stimulus predominantly activated subarea MST in hMT+ with a similar response intensity. Our results thus provide neural evidence showing that illusory rotation is initiated in human MST rather than MT as if it were physical rotary motion. The findings imply that illusory rotation in the Pinna illusion is mediated by rotation-sensitive neurons that normally encode physical rotation in human MST, both of which may rely on a cascade of similar integrative processes from earlier visual areas. Hum Brain Mapp 37:2097-2113, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26945512 TI - Metformin administration induces hepatotoxic effects in paraoxonase-1-deficient mice. AB - Metformin is the first-line pharmacological treatment of diabetes. In these patients, metformin reduces body weight and decreases the risk of diabetes related complications such as cardiovascular disease. However, whether metformin elicits beneficial effects on liver histology is a controversial issue and, as yet, there is no consensus. Paraoxonase-1 (PON1), an enzyme synthesized mainly by the liver, degrades lipid peroxides and reduces oxidative stress. PON1 activities are decreased in chronic liver diseases. We evaluated the effects of metformin in the liver of PON1-deficient mice which, untreated, present a mild degree of liver steatosis. Metformin administration aggravated inflammation in animals given a standard mouse chow and in those fed a high-fat diet. Also, it was associated with a higher degree of steatosis in animals fed a standard chow diet. This report is a cautionary note regarding the prescription of metformin for the treatment of diabetes in patients with concomitant liver impairment. PMID- 26945513 TI - Histamine may contribute to vortioxetine's procognitive effects; possibly through an orexigenic mechanism. AB - Vortioxetine is a novel multimodal antidepressant that acts as a serotonin (5 HT)3, 5-HT7, and 5-HT1D receptor antagonist; 5-HT1B receptor partial agonist; 5 HT1A receptor agonist; and 5-HT transporter inhibitor in vitro. In preclinical and clinical studies vortioxetine demonstrates positive effects on cognitive dysfunction. Vortioxetine's effect on cognitive function likely involves the modulation of several neurotransmitter systems. Acute and chronic administration of vortioxetine resulted in changes in histamine concentrations in microdialysates collected from the rat prefrontal cortex and ventral hippocampus. Based on these results and a literature review of the current understanding of the interaction between the histaminergic and serotonergic systems and the role of histamine on cognitive function, we hypothesize that vortioxetine through an activation of the orexinergic system stimulates the tuberomammilary nucleus and enhances histaminergic neurotransmission, which contributes to vortioxetine's positive effects on cognitive function. PMID- 26945514 TI - Proteomic insights into floral biology. AB - The flower is the most important biological structure for ensuring angiosperms reproductive success. Not only does the flower contain critical reproductive organs, but the wide variation in morphology, color, and scent has evolved to entice specialized pollinators, and arguably mankind in many cases, to ensure the successful propagation of its species. Recent proteomic approaches have identified protein candidates related to these flower traits, which has shed light on a number of previously unknown mechanisms underlying these traits. This review article provides a comprehensive overview of the latest advances in proteomic research in floral biology according to the order of flower structure, from corolla to male and female reproductive organs. It summarizes mainstream proteomic methods for plant research and recent improvements on two dimensional gel electrophoresis and gel-free workflows for both peptide level and protein level analysis. The recent advances in sequencing technologies provide a new paradigm for the ever-increasing genome and transcriptome information on many organisms. It is now possible to integrate genomic and transcriptomic data with proteomic results for large-scale protein characterization, so that a global understanding of the complex molecular networks in flower biology can be readily achieved. This article is part of a Special Issue entitled: Plant Proteomics--a bridge between fundamental processes and crop production, edited by Dr. Hans Peter Mock. PMID- 26945515 TI - Post-translational modifications of plant cell wall proteins and peptides: A survey from a proteomics point of view. AB - Plant cell wall proteins (CWPs) and peptides are important players in cell walls contributing to their assembly and their remodeling during development and in response to environmental constraints. Since the rise of proteomics technologies at the beginning of the 2000's, the knowledge of CWPs has greatly increased leading to the discovery of new CWP families and to the description of the cell wall proteomes of different organs of many plants. Conversely, cell wall peptidomics data are still lacking. In addition to the identification of CWPs and peptides by mass spectrometry (MS) and bioinformatics, proteomics has allowed to describe their post-translational modifications (PTMs). At present, the best known PTMs consist in proteolytic cleavage, N-glycosylation, hydroxylation of P residues into hydroxyproline residues (O), O-glycosylation and glypiation. In this review, the methods allowing the capture of the modified proteins based on the specific properties of their PTMs as well as the MS technologies used for their characterization are briefly described. A focus is done on proteolytic cleavage leading to protein maturation or release of signaling peptides and on O glycosylation. Some new technologies, like top-down proteomics and terminomics, are described. They aim at a finer description of proteoforms resulting from PTMs or degradation mechanisms. This article is part of a Special Issue entitled: Plant Proteomics--a bridge between fundamental processes and crop production, edited by Dr. Hans-Peter Mock. PMID- 26945516 TI - Proteomics of the 26S proteasome in Spodoptera frugiperda cells infected with the nucleopolyhedrovirus, AcMNPV. AB - Baculoviruses are large DNA viruses that infect insect species such as Lepidoptera and are used in biotechnology for protein production and in agriculture as insecticides against crop pests. Baculoviruses require activity of host proteasomes for efficient reproduction, but how they control the cellular proteome and interact with the ubiquitin proteasome system (UPS) of infected cells remains unknown. In this report, we analyzed possible changes in the subunit composition of 26S proteasomes of the fall armyworm, Spodoptera frugiperda (Sf9), cells in the course of infection with the Autographa californica multiple nucleopolyhedrovirus (AcMNPV). 26S proteasomes were purified from Sf9 cells by an immune affinity method and subjected to 2D gel electrophoresis followed by MALDI-TOF mass spectrometry and Mascot search in bioinformatics databases. A total of 34 homologues of 26S proteasome subunits of eukaryotic species were identified including 14 subunits of the 20S core particle (7 alpha and 7 beta subunits) and 20 subunits of the 19S regulatory particle (RP). The RP contained homologues of 11 of RPN-type and 6 of RPT-type subunits, 2 deubiquitinating enzymes (UCH-14/UBP6 and UCH-L5/UCH37), and thioredoxin. Similar 2D-gel maps of 26S proteasomes purified from uninfected and AcMNPV-infected cells at 48hpi confirmed the structural integrity of the 26S proteasome in insect cells during baculovirus infection. However, subtle changes in minor forms of some proteasome subunits were detected. A portion of the alpha5(zeta) cellular pool that presumably was not associated with the proteasome underwent partial proteolysis at a late stage in infection. PMID- 26945517 TI - Energy-dependent effects of resveratrol in Saccharomyces cerevisiae. AB - The metabolic effects induced by resveratrol have been associated mainly with the consumption of high-calorie diets; however, its effects with standard or low calorie diets remain unclear. To better understand the interactions between resveratrol and cellular energy levels, we used Saccharomyces cerevisiae as a model. Herein it is shown that resveratrol: (a) decreased cell viability in an energy-dependent manner; (b) lessening of cell viability occurred specifically when cells were under cellular respiration; and (c) inhibition of oxygen consumption in state 4 occurred at low and standard energy levels, whereas at high energy levels oxygen consumption was promoted. These findings indicate that the effects of resveratrol are dependent on the cellular energy status and linked to metabolic respiration. Importantly, our study also revealed that S. cerevisiae is a suitable and useful model to elucidate the molecular targets of resveratrol under different nutritional statuses. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26945518 TI - The implications of endemic IMP-4 carbapenemase for clinical laboratory susceptibility testing. AB - A local predominance of carbapenemase producing Enterobacteriaceae with low minimum inhibitory concentrations (MIC) to meropenem prompted a review of methods available for carbapenemase detection. We report on results using two selective media, temocillin discs, CarbaNP test, GeneXpert Carba-R assay and an in-house PCR assay. PMID- 26945519 TI - Metabolism of clofibric acid in zebrafish embryos (Danio rerio) as determined by liquid chromatography-high resolution-mass spectrometry. AB - The zebrafish embryo (ZFE) is increasingly used in ecotoxicology research but detailed knowledge of its metabolic potential is still limited. This study focuses on the xenobiotic metabolism of ZFE at different life-stages using the pharmaceutical compound clofibric acid as study compound. Liquid chromatography with quadrupole-time-of-flight mass spectrometry (LC-QToF-MS) is used to detect and to identify the transformation products (TPs). In screening experiments, a total of 18 TPs was detected and structure proposals were elaborated for 17 TPs, formed by phase I and phase II metabolism. Biotransformation of clofibric acid by the ZFE involves conjugation with sulfate or glucuronic acid, and, reported here for the first time, with carnitine, taurine, and aminomethanesulfonic acid. Further yet unknown cyclization products were identified using non-target screening that may represent a new detoxification pathway. Sulfate containing TPs occurred already after 3h of exposure (7hpf), and from 48h of exposure (52hpf) onwards, all TPs were detected. The detection of these TPs indicates the activity of phase I and phase II enzymes already at early life-stages. Additionally, the excretion of one TP into the exposure medium was observed. The results of this study outline the high metabolic potential of the ZFE with respect to the transformation of xenobiotics. Similarities but also differences to other test systems were observed. Biotransformation of test chemicals in toxicity testing with ZFE may therefore need further consideration. PMID- 26945520 TI - ROS dependent copper toxicity in Hydra-biochemical and molecular study. AB - Copper, an essential microelement, is known to be toxic to aquatic life at concentrations higher than that could be tolerated. Copper-induced oxidative stress has been documented in vitro, yet the in vivo effects of metal-induced oxidative stress have not been extensively studied in the lower invertebrates. The objective of the present study has been to find the effect of ROS-mediated toxicity of environmentally relevant concentrations of copper at organismal and cellular levels in Hydra magnipapillata. Exposure to copper at sublethal concentrations (0.06 and 0.1mg/L) for 24 or 48h resulted in generation of significant levels of intracellular reactive oxygen species (ROS). We infer that the free radicals here originate predominantly at the lysosomes but partly at the mitochondria also as visualized by H2-DHCFDA staining. Quantitative real-time PCR of RNA extracted from copper-exposed polyps revealed dose-dependent up-regulation of all antioxidant response genes (CAT, SOD, GPx, GST, GR, G6PD). Concurrent increase of Hsp70 and FoxO genes suggests the ability of polyps to respond to stress, which at 48h was not the same as at 24h. Interestingly, the transcript levels of all genes were down-regulated at 48h as compared to 24h incubation period. Comet assay indicated copper as a powerful genotoxicant, and the DNA damage was dose- as well as duration-dependent. Western blotting of proteins (Bax, Bcl-2 and caspase-3) confirmed ROS-mediated mitochondrial cell death in copper-exposed animals. These changes correlated well with changes in morphology, regeneration and aspects of reproduction. Taken together, the results indicate increased production of intracellular ROS in Hydra on copper exposure. PMID- 26945521 TI - ABC transporters and xenobiotic defense systems in early life stages of rainbow trout (Oncorhynchus mykiss). AB - Embryos of oviparous fish, in contrast to (ovo) viviparous species, develop in the aquatic environment, and therefore need solute transport systems at their body surfaces for maintaining internal homeostasis and defending against potentially harmful substances. We hypothesized that solute transporters undergo changes in tissue distribution from the embryo to the larval stage. We therefore studied the mRNA profiles of eight ABC transporters (abcb1a, abcb1b, abcc1, abcc2, abcc3, abcc4, abcc5, abcg2) and three solute carriers (oatp1d, putative oatp2 putative, mate1) in different body regions (head, yolk sac epithelium, abdominal viscera, skin/muscles) of developing rainbow trout. Additionally, we investigated mRNA levels of phase I (cyp1a, cyp3a) and phase II (gstp, putative ugt1, putative ugt2) biotransformation enzymes. The study covered the developmental period from the eleuthero-embryo stage to the first-feeding larval stage (1-20days post-hatch, dph). At 1dph, transcripts of abcc2, abcc4, abcg2, cyp3a, gstp, putative mate1, and putative oatp2 occurred primarily in the yolk sac epithelium, whereas at later stages expression of these genes was predominantly observed in the abdominal viscera. The functional activity of ABC transporters in fish early life stages was assessed by rhodamine B accumulation assays. Finally, we investigated the potential impact of xenobiotics (clotrimazole, clofibric acid) on the ABC and biotransformation systems of trout early life stages. While clofibric acid had no effect, clotrimazole lead to an increased rhodamine B accumulation. The results provide evidence that the transition from the eleuthero-embryo to the larval stage is accompanied by a major alteration in tissue expression of ABC transporters. PMID- 26945522 TI - A new diatom growth inhibition assay using the XTT colorimetric method. AB - Marine biofouling, which leads to significant operational stress and economic damage on marine infrastructures, is a major problem in marine related industries. Currently, the most common way to avoid marine biofouling involves the use of biocidal products in surface coatings. However, the need for environmentally friendly antibiofouling compounds has increased rapidly with the recent global prohibition of harmful antifoulants, such as tributyltin (TBT). In particular, periphytic diatoms have been shown to contribute significantly to biofilms, which play an important role in biofouling. Therefore, inhibiting the proliferation of fouling diatoms is a very important step in the prevention of marine biofouling. In this study, we developed a new, rapid, accurate, and convenient growth inhibition assay using the XTT colorimetric method to prevent the growth of the fouling periphytic diatom, Nitzschia amabilis Hidek. Suzuki (replaced synonym, Nitzschia laevis Hustedt). The feasibility of this method was verified by determining the growth inhibition activities of two standard photosynthetic inhibitors, DCMU and CuSO4. However, neither inhibitor had any cytotoxic activities at the range of concentrations tested. Moreover, this method was applied by screening and purification of herbicidic but non-cytotoxic compounds from cyanobacteria extracts. Our results demonstrate the utility of this newly established growth inhibition assay for the identification of marine anti-biofouling compounds. PMID- 26945523 TI - Programmable Site-Specific Nucleases for Targeted Genome Engineering in Higher Eukaryotes. AB - Recent advances in the targeted genome engineering enable molecular biologists to generate sequence specific modifications with greater efficiency and higher specificity in complex eukaryotic genomes. Programmable site-specific DNA cleavage reagents and cellular DNA repair mechanisms have made this possible. These reagents have become powerful tools for delivering a site-specific genomic double-strand break (DSB) at the desired chromosomal locus, which produces sequence alterations through error-prone non-homologous end joining (NHEJ) resulting in gene inactivations/knockouts. Alternatively, the DSB can be repaired through homology-directed repair (HDR) using a donor DNA template, which leads to the introduction of desired sequence modifications at the predetermined site. Here, we summarize the role of three classes of nucleases; zinc finger nucleases (ZFNs), transcription activator like effector nucleases (TALENs), and clustered regularly interspaced palindromic repeats (CRISPR)/CRISPR associated protein 9 (Cas9) system in achieving targeted genome modifications. Further, we discuss the progress towards the applications of programmable site-specific nucleases (SSNs) in treating human diseases and other biological applications in economically important higher eukaryotic organisms such as plants and livestock. J. Cell. Physiol. 231: 2380-2392, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26945524 TI - A whole-genome, radiation hybrid mapping resource of hexaploid wheat. AB - Generating a contiguous, ordered reference sequence of a complex genome such as hexaploid wheat (2n = 6x = 42; approximately 17 GB) is a challenging task due to its large, highly repetitive, and allopolyploid genome. In wheat, ordering of whole-genome or hierarchical shotgun sequencing contigs is primarily based on recombination and comparative genomics-based approaches. However, comparative genomics approaches are limited to syntenic inference and recombination is suppressed within the pericentromeric regions of wheat chromosomes, thus, precise ordering of physical maps and sequenced contigs across the whole-genome using these approaches is nearly impossible. We developed a whole-genome radiation hybrid (WGRH) resource and tested it by genotyping a set of 115 randomly selected lines on a high-density single nucleotide polymorphism (SNP) array. At the whole genome level, 26 299 SNP markers were mapped on the RH panel and provided an average mapping resolution of approximately 248 Kb/cR1500 with a total map length of 6866 cR1500 . The 7296 unique mapping bins provided a five- to eight-fold higher resolution than genetic maps used in similar studies. Most strikingly, the RH map had uniform bin resolution across the entire chromosome(s), including pericentromeric regions. Our research provides a valuable and low-cost resource for anchoring and ordering sequenced BAC and next generation sequencing (NGS) contigs. The WGRH developed for reference wheat line Chinese Spring (CS-WGRH), will be useful for anchoring and ordering sequenced BAC and NGS based contigs for assembling a high-quality, reference sequence of hexaploid wheat. Additionally, this study provides an excellent model for developing similar resources for other polyploid species. PMID- 26945525 TI - Measurement instruments to assess posture, gait, and balance in Parkinson's disease: Critique and recommendations. AB - BACKGROUND: Disorders of posture, gait, and balance in Parkinson's disease (PD) are common and debilitating. This MDS-commissioned task force assessed clinimetric properties of existing rating scales, questionnaires, and timed tests that assess these features in PD. METHODS: A literature review was conducted. Identified instruments were evaluated systematically and classified as "recommended," "suggested," or "listed." Inclusion of rating scales was restricted to those that could be used readily in clinical research and practice. RESULTS: One rating scale was classified as "recommended" (UPDRS-derived Postural Instability and Gait Difficulty score) and 2 as "suggested" (Tinetti Balance Scale, Rating Scale for Gait Evaluation). Three scales requiring equipment (Berg Balance Scale, Mini-BESTest, Dynamic Gait Index) also fulfilled criteria for "recommended" and 2 for "suggested" (FOG score, Gait and Balance Scale). Four questionnaires were "recommended" (Freezing of Gait Questionnaire, Activities specific Balance Confidence Scale, Falls Efficacy Scale, Survey of Activities, and Fear of Falling in the Elderly-Modified). Four tests were classified as "recommended" (6-minute and 10-m walk tests, Timed Up-and-Go, Functional Reach). CONCLUSION: We identified several questionnaires that adequately assess freezing of gait and balance confidence in PD and a number of useful clinical tests. However, most clinical rating scales for gait, balance, and posture perform suboptimally or have been evaluated insufficiently. No instrument comprehensively and separately evaluates all relevant PD-specific gait characteristics with good clinimetric properties, and none provides separate balance and gait scores with adequate content validity for PD. We therefore recommend the development of such a PD-specific, easily administered, comprehensive gait and balance scale that separately assesses all relevant constructs. (c) 2016 International Parkinson and Movement Disorder Society. PMID- 26945526 TI - Adult polycystic liver disease concomitant with severe anemia due to intracystic bleeding is an indication for liver transplantation: case report and review of literature. PMID- 26945527 TI - Characterization of pollen and bacterial community composition in brood provisions of a small carpenter bee. AB - Many insects obtain gut microbes from their diet, but how a mother's foraging patterns influence the microbes found in her offspring's food remains an open question. To address this gap, we studied a bee that forages for pollen from multiple species of plants and may therefore acquire diverse bacteria from different plants. We tested the hypothesis that pollen diversity correlates with bacterial diversity by simultaneously characterizing these two communities in bee brood provisions for the first time. We used deep sequencing of the plant RBCL gene and the bacterial 16S rRNA gene to characterize pollen and bacterial diversity. We then tested for associations between pollen and bacterial species richness and community composition, as well as co-occurrence of specific bacteria and pollen types. We found that both pollen and bacterial communities were extremely diverse, indicating that mother bees visit a wide variety of flowers for pollen and nectar and subsequently bring a diversity of microbes back into their nests. Pollen and bacterial species richness and community composition, however, were not correlated. Certain pollen types significantly co-occurred with the most proportionally abundant bacteria, indicating that the plants these pollen types came from may serve as reservoirs for these bacteria. Even so, the overall diversity of these communities appears to mask these associations at a broader scale. Further study of these pollen and bacteria associations will be important for understanding the complicated relationship between bacteria and wild bees. PMID- 26945528 TI - University students' cognitive performance under temperature cycles induced by direct load control events. AB - As one of the most common strategies for managing peak electricity demand, direct load control (DLC) of air-conditioners involves cycling the compressors on and off at predetermined intervals. In university lecture theaters, the implementation of DLC induces temperature cycles which might compromise university students' learning performance. In these experiments, university students' learning performance, represented by four cognitive skills of memory, concentration, reasoning, and planning, was closely monitored under DLC-induced temperature cycles and control conditions simulated in a climate chamber. In Experiment 1 with a cooling set point temperature of 22 degrees C, subjects' cognitive performance was relatively stable or even slightly promoted by the mild heat intensity and short heat exposure resulting from temperature cycles; in Experiment 2 with a cooling set point of 24 degrees C, subjects' reasoning and planning performance observed a trend of decline at the higher heat intensity and longer heat exposure. Results confirm that simpler cognitive tasks are less susceptible to temperature effects than more complex tasks; the effect of thermal variations on cognitive performance follows an extended-U relationship with performance being relatively stable across a range of temperatures. DLC appears to be feasible in university lecture theaters if DLC algorithms are implemented judiciously. PMID- 26945529 TI - Interactions of Enolizable Barbiturate Dyes. AB - The specific barbituric acid dyes 1-n-butyl-5-(2,4-dinitro-phenyl) barbituric acid and 1-n-butyl-5-{4-[(1,3-dioxo-1H-inden-(3 H) ylidene)methyl]phenyl}barbituric acid were used to study complex formation with nucleobase derivatives and related model compounds. The enol form of both compounds shows a strong bathochromic shift of the UV/Vis absorption band compared to the rarely coloured keto form. The keto-enol equilibria of the five studied dyes are strongly dependent on the properties of the environment as shown by solvatochromic studies in ionic liquids and a set of organic solvents. Enol form development of the barbituric acid dyes is also associated with alteration of the hydrogen bonding pattern from the ADA to the DDA type (A=hydrogen bond acceptor site, D=donor site). Receptor-induced altering of ADA towards DDA hydrogen bonding patterns of the chromophores are utilised to study supramolecular complex formation. As complementary receptors 9-ethyladenine, 1-n butylcytosine, 1-n-butylthymine, 9-ethylguanidine and 2,6-diacetamidopiridine were used. The UV/Vis spectroscopic response of acid-base reaction compared to supramolecular complex formation is evaluated by (1)H NMR titration experiments and X-ray crystal structure analyses. An increased acidity of the barbituric acid derivative promotes genuine salt formation. In contrast, supramolecular complex formation is preferred for the weaker acidic barbituric acid. PMID- 26945530 TI - Resting-state functional connectivity of emotion regulation networks in euthymic and non-euthymic bipolar disorder patients. AB - BACKGROUND: Previous functional magnetic resonance imaging studies in bipolar disorder (BD) have evidenced changes in functional connectivity (FC) in brain areas associated with emotion processing, but how these changes vary with mood state and specific clinical symptoms is not fully understood. METHODS: We investigated resting-state FC between a priori regions of interest (ROIs) from the default-mode network and key structures for emotion processing and regulation in 27 BD patients and 27 matched healthy controls. We further compared connectivity patterns in subgroups of 15 euthymic and 12 non-euthymic patients and tested for correlations of the connectivity strength with measures of mood, anxiety, and rumination tendency. No correction for multiple comparisons was applied given the small population sample and pre-defined target ROIs. RESULTS: Overall, regardless of mood state, BD patients exhibited increased FC of the left amygdala with left sgACC and PCC, relative to controls. In addition, non-euthymic BD patients showed distinctive decrease in FC between right amygdala and sgACC, whereas euthymic patients showed lower FC between PCC and sgACC. Euthymic patients also displayed increased FC between sgACC and right VLPFC. The sgACC-PCC and sgACC-left amygdala connections were modulated by rumination tendency in non euthymic patients, whereas the sgACC-VLPFC connection was modulated by both the current mood and tendency to ruminate. CONCLUSION: Our results suggest that sgACC amygdala coupling is critically affected during mood episodes, and that FC of sgACC play a pivotal role in mood normalization through its interactions with the VLPFC and PCC. However, these preliminary findings require replication with larger samples of patients. PMID- 26945531 TI - Preface to Journal of Dermatology special issue: Inherited keratinization disorders. PMID- 26945532 TI - Inherited ichthyosis: Non-syndromic forms. AB - Inherited ichthyoses are a group of genetic disorders characterized by generalized dry skin, scaling and hyperkeratosis, and often associated with erythroderma. These manifestations are due to mutations in genes mostly involved in skin barrier formation. Inherited ichthyoses consist of non-syndromic ichthyoses and ichthyosis syndromes. Non-syndromic ichthyoses are characterized by the phenotypic expression of the disorder being seen only in the skin. Non syndromic ichthyoses include ichthyosis vulgaris, recessive X-linked ichthyosis, autosomal recessive congenital ichthyosis, keratinopathic ichthyosis and other forms. This review focuses on updates for each type of non-syndromic ichthyosis, highlighting molecular mechanisms and phenotype/genotype correlations. Included in autosomal recessive congenital ichthyosis are three of the major phenotypes (harlequin ichthyosis, lamellar ichthyosis and congenital ichthyosiform erythroderma) and three of the minor subtypes (self-healing collodion baby, acral self-healing collodion baby and bathing suit ichthyosis). Keratinopathic ichthyosis is proposed as an umbrella term for ichthyoses caused by mutations in keratin genes. Next-generation sequencing technologies have become powerful tools for the diagnosis of inherited ichthyoses and the discovery of their genetic causes. This article reviews the current understanding of molecular pathomechanisms for non-syndromic ichthyoses and explores future perspectives. PMID- 26945533 TI - Inherited ichthyosis: Syndromic forms. AB - Among diseases that cause ichthyosis as one of the symptoms, there are some diseases that induce abnormalities in organs other than the skin. Of these, diseases with characteristic signs are regarded as syndromes. Although these syndromes are very rare, Netherton syndrome, Sjogren-Larsson syndrome, Conradi Hunermann-Happle syndrome, Dorfman-Chanarin syndrome, ichthyosis follicularis, atrichia and photophobia (IFAP) syndrome, and Refsum syndrome have been described in texts as representative ones. It is important to know the molecular genetics and pathomechanisms in order to establish an effective therapy and beneficial genetic counseling including a prenatal diagnosis. PMID- 26945534 TI - Hereditary palmoplantar keratoderma "clinical and genetic differential diagnosis". AB - Hereditary palmoplantar keratoderma (PPK) is a heterogeneous group of disorders characterized by hyperkeratosis of the palm and the sole skin. Hereditary PPK are divided into four groups--diffuse, focal, striate and punctate PPK--according to the clinical patterns of the hyperkeratotic lesions. Each group includes simple PPK, without associated features, and PPK with associated features, such as involvement of nails, teeth and other organs. PPK have been classified by a clinically based descriptive system. In recent years, many causative genes of PPK have been identified, which has confirmed and/or rearranged the traditional classifications. It is now important to diagnose PPK by a combination of the traditional morphological classification and genetic testing. In this review, we focus on PPK without associated features and introduce their morphological features, genetic backgrounds and new findings from the last decade. PMID- 26945535 TI - Darier disease. AB - Darier disease (DD) is a type of inherited keratinizing disorder that exhibits autosomal dominant inheritance. DD is caused by the mutations of ATP2A2, which encodes an endoplasmic reticulum calcium pump, sarco/endoplasmic reticulum ATPase type 2 (SERCA2). DD often develops in childhood, persists through adolescence, and causes small papules predominantly in seborrheic areas such as the face, chest and back. Further, scales and scabs may gradually develop. DD may be accompanied by non-dermal symptoms, including psychiatric symptoms. Histologically, DD is characterized by corps ronds and grains in addition to suprabasal cleavage. There are no currently validated curative treatments available for DD, with the majority of cases treated symptomatically. Despite demonstrating efficacy in the treatment of DD, the use of oral retinoids has been limited due to the association with various adverse effects. PMID- 26945536 TI - Erythrokeratodermia variabilis et progressiva. AB - Erythrokeratodermia variabilis et progressiva (EKVP) is a rare inherited skin disease characterized by fixed hyperkeratotic plaques and transient erythematous patches. EKVP is most often transmitted in an autosomal dominant manner. Causal mutations were found in the GJB3, GJB4 and GJA1 genes encoding connexins 31, 30.3 and 43, respectively. Approximately 50% of affected individuals develop palmoplantar keratoderma. Connexins are components of gap junctions, which are intercellular channels that are found in almost all tissues including the skin. Treatment of EKVP usually involves use of topical keratolytics and emollients resulting in some improvement in hyperkeratosis. Low-dose systemic retinoid may be beneficial. Novel therapies targeting connexin hemichannels and gap junctions may become available in the future. PMID- 26945537 TI - Evaluation of a mobile team dedicated to behavioural disorders as recommended by the Alzheimer Cooperative Valuation in Europe joint action: observational cohort study. AB - BACKGROUND AND PURPOSE: Preventing behavioural crises appears to be crucial to promote quality of life of the patient-caregiver dyad, to reduce inappropriate hospitalizations and to delay institutionalization. The Alzheimer Cooperative Valuation in Europe promotes mobile care to prevent patients from severe behavioural and psychological symptoms in dementia. This study assessed the potential efficacy of a mobile team for Alzheimer's disease on hospitalization sparing and behavioural disorder reduction. METHODS: A cohort study was set up from 1 January 2012 to 31 December 2013 by the Clinical and Research Memory Centre of Lyon (France). It included patients with behavioural and psychological symptoms living at home or in a nursing home. An interview explored the alternative patient pathways used by general practitioners (GPs) if the mobile team had not existed (hospitalization sparing). The Neuropsychiatry Inventory score was assessed at inclusion and 30 days later. The sample included 424 consecutive patients with Alzheimer's disease or related disorders and behavioural disorders at any cognitive and functional stage of the disease, taken in charge by the mobile team. RESULTS: Amongst the 424 patients (84.0 +/- 7.2 years), 220 (51.9%) hospitalizations were considered by their GPs and 181 (82.3%) were avoided. The Neuropsychiatric Inventory score declined after mobile team intervention (45.8-29.9, P < 0.001). Sleep and appetite disorders, endangered situation and caregiver burnout were associated with higher risk of hospitalization at 30 days. CONCLUSIONS: The mobile team for Alzheimer's disease allows a high proportion of hospitalizations related to behavioural disorders to be avoided and may help to reduce behavioural disorders. PMID- 26945538 TI - Maternal oral administration of osteocalcin protects offspring from metabolic impairment in adulthood. AB - OBJECTIVE: Maternal diet during pregnancy has been found to influence the health of offspring. However, strategies for modulation of maternal energy metabolism without an adverse effect on the fetus have remained limited. It was recently shown that oral administration of uncarboxylated osteocalcin (GluOC) improves metabolic status in adult female mice. Whether maternal GluOC administration during gestation might improve the metabolic status of offspring was investigated. METHODS: Female C57BL/6 mice were fed a normal diet (ND) or high fat, high-sucrose diet (HFS) and were given saline or GluOC by oral administration during pregnancy. The resulting offspring were in turn assigned to ND- or HFS-fed groups immediately after weaning, and their body weight, glucose metabolism, serum lipid parameters, and level of adipose tissue inflammation were subsequently assessed. RESULTS: Maternal HFS feeding during gestation had adverse effects on glucose and lipid parameters, body weight, and adipose tissue inflammation in female offspring fed the same diet, and these effects were attenuated by maternal oral GluOC administration. CONCLUSIONS: Maternal oral administration of GluOC protects HFS-fed female offspring from metabolic disorders induced by maternal obesity. PMID- 26945539 TI - Can ecological history influence response to pollutants? Transcriptomic analysis of Manila clam collected in different Venice lagoon areas and exposed to heavy metal. AB - Chronic exposure to environmental pollutants can exert strong selective pressures on natural populations, favoring the transmission over generations of traits that enable individuals to survive and thrive in highly impacted environments. The lagoon of Venice is an ecosystem subject to heavy anthropogenic impact, mainly due to the industrial activities of Porto Marghera (PM), which led to a severe chemical contamination of soil, groundwater, and sediments. Gene expression analysis on wild Manila clams collected in different Venice lagoon areas enabled to identify differences in gene expression profiles between clams collected in PM and those sampled in clean areas, and the definition of molecular signatures of chemical stress. However, it remains largely unexplored to which extent modifications of gene expression patterns persists after removing the source of contamination. It is also relatively unknown whether chronic exposure to xenobiotics affects the response to other chemical pollutants. To start exploring such issues, in the present study a common-garden experiment was coupled with transcriptomic analysis, to compare gene expression profiles of PM clams with those of clams collected in the less impacted area of Chioggia (CH) during a period under the same control conditions. Part of the two experimental groups were also exposed to copper for seven days to assess whether different "ecological history" does influence response to such pollutant. The results obtained suggest that the chronic exposure to chemical pollution generated a response at the transcriptional level that persists after removal for the contaminated site. These transcriptional changes are centered on key biological processes, such as defense against either oxidative stress or tissue/protein damage, and detoxification, suggesting an adaptive strategy for surviving in the deeply impacted environment of Porto Marghera. On the other hand, CH clams appeared to respond more effectively to copper exposure than PM animals, proposing that chronic exposure to chemical toxicants either lowers the sensitivity to additional toxicants or blunts the capacity to respond to novel chemical challenges in PM clams. PMID- 26945540 TI - Fe reduced hepatic lipid deposition in Synechogobius hasta exposed to waterborne Cu. AB - Recent evidences suggested that Fe influenced Cu metabolism in vertebrates. The present study was conducted to test the hypothesis that Fe could alleviate Cu induced change of lipid deposition in the fish species. Synechogobius hasta were exposed to 0, 0.606 and 1.212MUM Cu, in combination with 0 and 1.128MUM Fe, respectively. Sampling occurred on day 28 and day 56, respectively. Growth performance, hepatic lipid deposition, Fe and Cu level, and activities and mRNA expression of enzymes and genes involved in lipid metabolism were analyzed. Fe addition in water improved survival in S. hasta exposed to the highest waterborne Cu concentration on day 56. Fe addition also increased hepatic Fe content both at day 28 and day 56, and reduced hepatic Cu content. Fe exposure tended to reduce the activities and mRNA expressions of lipogenic enzymes and genes (G6PD and FAS), and up-regulated the mRNA expression of ATGL. With the same Cu concentration, Fe addition tended to down-regulate mRNA levels of SREBP-1 and PPARgamma, and up-regulate PPARalpha mRNA level on day 28. However, on day 56, the mRNA levels of SREBP-1, PPARgamma and PPARalpha are very variable and not related with waterborne Fe addition. Some correlative relationship was observed between the mRNA of transcriptional factors, and the activities of enzymes and the mRNA expression of genes encoding them, implying their transcription regulation of these enzymatic genes by transcriptional factors after Fe addition. Overall, Fe addition mitigated Cu-induced changes of lipid deposition in fish by down-regulation of lipogenesis and up-regulation of lipolysis. Different response patterns of these enzyme activities and gene expressions in the liver of S. hasta following waterborne Fe exposure indicated that Fe effects on Cu-induced change of lipid metabolism are time-dependent. PMID- 26945541 TI - Calcium/Calmodulin-Dependent Kinase IV Facilitates the Recruitment of Interleukin 17-Producing Cells to Target Organs Through the CCR6/CCL20 Axis in Th17 Cell Driven Inflammatory Diseases. AB - OBJECTIVE: The recruitment of interleukin-17 (IL-17)-producing T helper (Th17) cells to inflammatory sites has been implicated in the development of organ damage in inflammatory and autoimmune diseases including systemic lupus erythematosus (SLE). To define the mechanism of calcium/calmodulin-dependent kinase IV (CaMKIV) activation of Th17 cell recruitment to target tissues, we performed anti-glomerular basement membrane antibody-induced glomerulonephritis (AIGN) experiments in mice and studied samples from patients with SLE. METHODS: We induced experimental AIGN in CaMKIV-sufficient or CaMKIV-deficient mice and compared histology, Th17 cell-related chemokine expression, and numbers of IL-17 producing cells in kidneys. We also evaluated the efficacy of the CaMKIV inhibitor KN-93 in AIGN-induced kidney disease. The expression of CCR6 in memory CD4+ T cells before AIGN induction was analyzed by flow cytometry. We investigated the correlation between CCR6 expression in peripheral blood and the severity of glomerulonephritis in patients with SLE. RESULTS: CaMKIV-deficient mice displayed less glomerular injury after induction of AIGN. Kidney infiltration by IL-17-producing CD4+ T cells along with CCR6 and CCL20 expression were significantly decreased in CaMKIV-deficient mice. Similarly, treatment of mice with KN-93 improved clinical and pathologic outcomes. Expression and function of CCR6 in peripheral blood memory CD4+ T cells was decreased in CaMKIV deficient mice. Expression of CCR6 correlated positively with severity of organ damage in SLE patients. CONCLUSION: CaMKIV inhibition represents a novel therapeutic strategy for treatment of Th17 cell-mediated tissue damage in inflammatory diseases. PMID- 26945542 TI - Percutaneous exclusion of a rapidly enlarging left main coronary artery aneurysm using coils and an AmplatzerTM septal occluder. AB - Coronary artery aneurysms (CAAs) are often an incidental finding amongst patients undergoing coronary angiography. Most CAAs are managed conservatively; rarely a larger CAA can lead to intramural thrombus formation and coronary artery embolization/obstruction even without the presence of significant stenosis. Despite these clinical implications, therapeutic options are limited to case reports and no clearly defined guidelines have been established for treatment. In this article, we present a unique case of a rapidly enlarging left main CAA, with no identifiable etiology that was treated with percutaneous exclusion via coil embolization and an AmplatzerTM septal occluder device. We also discuss existing literature, pathophysiology, and management options for CAAs. (c) 2016 Wiley Periodicals, Inc. PMID- 26945543 TI - Comprehensive outcomes of on- and off-antiviral prophylaxis in hepatitis B patients undergoing cancer chemotherapy: A competing risks analysis. AB - Although antiviral prophylaxis is essential in hepatitis B patients in the context of cancer chemotherapy, there is little evidence-based consensus regarding the appropriate prevention strategy depending on the underlying type of cancer and viral status. This retrospective study included a comprehensive cohort of 302 hepatitis B surface antigen-positive patients with various cancers undergoing chemotherapy and antiviral prophylaxis. The rates of hepatitis B virus (HBV) reactivation during antiviral therapy (>1 log10 IU/mL increase or positive conversion of serum HBV DNA) and relapse when off antivirals ([re]appearance of HBV DNA >2,000 IU/ml with related alanine aminotransferase elevation) were evaluated, together with the associated risk factors, in a competing risks analysis where cancer death was considered as the competing event. During antiviral prophylaxis, HBV was reactivated in six patients (1.9%), who had leukemia (n = 4) or lymphoma (n = 2) and were treated with lamivudine (n = 4) or entecavir (n = 2). The incidence rate of HBV relapse in 127 off-prophylaxis patients was 21.3% during a median post-antiviral period of 11.7 months. Lymphoma, pre-prophylactic HBV DNA >=2,000 IU/ml, and age >=50 years were independent predictors of off-treatment HBV relapse (adjusted hazard ratios 5.25, 3.07, and 0.34, respectively; Ps < 0.05). Antiviral and anticancer drugs, duration of consolidation on antiviral prophylaxis, and HBeAg positivity were not independent predictors. In conclusion, hepatitis B flare-ups are not rare in patients receiving cancer chemotherapy during and after anti-HBV prophylaxis, even when potent antivirals are used. Patients with hematopoietic or lymphoid neoplasms or high viral burdens should receive prolonged and powerful HBV prophylaxis. J. Med. Virol. 88:1576-1586, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26945545 TI - Simultaneous effect of disabling conditions on primary health care use through a capability approach. AB - There is evidence of social disparities in the use of primary health services in most European countries, and these disparities particularly affect people with disabilities. Many determinants of disabilities interact to limit access to health care (e.g. impairments, functional limitations, educational level). However, these determinants have typically been examined separately. We adopted a capabilities perspective to define multidimensional disability. Capabilities refer to individuals' real opportunities to achieve possible outcomes. In this context, we aimed to assess disability through latent capabilities (shaped by personal, social and environmental variables) and to simultaneously analyze their effects on primary health care use (GP and nurse care; cervical, breast, and colorectal cancer screenings). We used a structural equation modeling framework, which allowed complete and simultaneous tests of relationships taking into account measurement errors. The data source was the 2008 French Health and Disability Survey (29,931 individuals). Potential disability-related determinants were selected to measure five latent variables: health condition and cognitive, physical, societal, and socioeconomic capabilities. All things being equal, we did not identify any specific barriers to GP care use. We found a lower likelihood of nursing care use among people with lower cognitive capabilities. Unlike usual findings, we did not observe a significant influence of either cognitive or physical capabilities for any type of cancer screening use. However, cancer screening participation was mainly affected by societal and socioeconomic capabilities. Considering the capability approach, which suggests public action oriented toward restoring capabilities of individuals, future programs should seek to increase societal support to compensate for disability. This approach could be helpful in reducing inequalities in health care access. PMID- 26945544 TI - When can parents most influence their child's development? Expert knowledge and perceived local realities. AB - Compelling evidence for the long-term impact of conditions in gestation and early childhood on both physical and psychosocial functioning and productivity has stimulated a focus in global health policy and social services on the "first 1000 days". Consequently, related initiatives may assume that rationale for this orientation and the agency of parents during this period is self-evident and widely shared among parents and communities. In 2012, we tested this assumption among a sample of 38 township-dwelling caregivers in Cape Town, by asking a question identified during a study of cultural models of parenting, namely: At what age or stage can a parent or caregiver have the most influence on a child's development? Formal cultural consensus analysis of responses met criteria for strong agreement that the period for greatest impact of parenting on a child's development occurs at adolescence, at a median age of 12 years. In follow-up focus groups and structured interviews, caregivers articulated clear ecological and developmental reasons for this view, related to protection both of developmental potential and against powerful, context-specific ecological risks (early pregnancy, substance ab/use, violence and gangs) that emerge during adolescence. Such risks threaten educational attainment, reproductive health, and social derailment with enduring consequences for lifetime well-being that caregivers are highly motivated to prevent. Developmental needs in pregnancy and early childhood, by contrast, were considered more manageable. These findings resonate with emerging evidence for multiple sensitive periods with corresponding developmental needs, and urge the value of complementing efforts to optimize early development with those to sustain and enhance it during later windows of developmental opportunity such as adolescence. Our results also indicate the need to consult local views of developmental risk and parenting practice in communicating with caregivers and planning interventions, and the value of using available methodological tools to do so. PMID- 26945546 TI - 'I knew before I was told': Breaches, cues and clues in the diagnostic assemblage. AB - Diagnosis can be both a 'diagnostic moment', but also a process over time. This paper uses secondary analysis of narrative interviews on ovarian cancer, antenatal screening and motor neurone disease to explore how people relate assembling procedural, spatial and interactional evidence before the formal diagnostic moment. We offer the idea of a diagnostic assemblage to capture the ways in which individuals connect to and re-order signs and events that come to be associated with their bodies. Building on the empirical work of Poole and Lyne (2000) in the field of breast cancer diagnosis, we identify how patients describe being alerted to their diagnosis, either through 'clues' they report picking up (often inadvertently) or through 'cues', perceived as a more intentional prompt given by a health professional, or an organisational process. For patients, these clues frequently represent a breach in the expected order of their encounter with healthcare. Even seemingly mundane episodes or behaviours take on meanings which health professionals may not themselves anticipate. Our findings speak to an emergent body of work demonstrating that experiences of formal healthcare during the lead-up to diagnosis shape patients' expectations, degree of trust in professionals, and even health outcomes. PMID- 26945548 TI - Novel Oral Therapies for Opioid-induced Bowel Dysfunction in Patients with Chronic Noncancer Pain. AB - Opioid analgesics are frequently prescribed and play an important role in chronic pain management. Opioid-induced bowel dysfunction, which includes constipation, hardened stool, incomplete evacuation, gas, and nausea and vomiting, is the most common adverse event associated with opioid use. Mu-opioid receptors are specifically responsible for opioid-induced bowel dysfunction, resulting in reduced peristaltic and secretory actions. Agents that reverse these actions in the bowel without reversing pain control in the central nervous system may be preferred over traditional laxatives. The efficacy and safety of these agents in chronic noncancer pain were assessed from publications identified through Ovid and PubMed database searches. Trials that evaluated the safety and efficacy of oral agents for opioid-induced constipation or opioid-induced bowel dysfunction, excluding laxatives, were reviewed. Lubiprostone and naloxegol are approved in the United States by the Food and Drug Administration for use in opioid-induced constipation. Axelopran (TD-1211) and sustained-release naloxone have undergone phase 2 and phase 1 studies, respectively, for the same indication. Naloxegol and axelopran are peripherally acting MU-opioid receptor antagonists. Naloxone essentially functions as a peripherally acting MU-opioid receptor antagonist when administered orally in a sustained-release formulation. Lubiprostone is a locally acting chloride channel (CIC-2) activator that increases secretions and peristalsis. All agents increase spontaneous bowel movements and reduce other bowel symptoms compared with placebo in patients with noncancer pain who are chronic opioid users. The most common adverse events were gastrointestinal in nature, and none of the drugs were associated with severe adverse or cardiovascular events. Investigations comparing these agents to regimens using standard laxative and combination therapy and trials in special populations and patients with active cancer are needed to further define their role in therapy. PMID- 26945547 TI - Efficacy and safety of prophylactic levetiracetam in supratentorial brain tumour surgery: a systematic review and meta-analysis. AB - AIMS: The aim of this study was to perform an up-to-date systematic review and meta-analysis on the efficacy and safety of prophylactic administration of levetiracetam in brain tumour patients. METHOD: A systematic review of studies published until April 2015 was conducted using Scopus/Elsevier, EMBASE and MEDLINE. The search was limited to articles reporting results from adult patients, suffering from brain tumour, undergoing supratentorial craniotomy for tumour resection or biopsy and administered levetiracetam in the perioperative period for seizure prophylaxis. Outcomes included the efficacy and safety of levetiracetam, as well as the tolerability of the specific regimen, defined by the discontinuation of the treatment due to side effects. RESULTS: The systematic review included 1148 patients from 12 studies comparing levetiracetam with no treatment, phenytoin and valproate, while only 243 patients from three studies, comparing levetiracetam vs phenytoin efficacy and safety, were included in the meta-analysis. The combined results from the meta-analysis showed that levetiracetam administration was followed by significantly fewer seizures than treatment with phenytoin (OR = 0.12 [0.03-0.42]: chi(2) = 1.76: I(2) = 0%). Analysis also showed significantly fewer side effects in patients receiving levetiracetam, compared to other groups (P < 0.05). The combined results showed fewer side effects in the levetiracetam group compared to the phenytoin group (OR = 0.65 [0.14-2.99]: chi(2) = 8.79: I(2) = 77%). CONCLUSIONS: The efficacy of prophylaxis with levetiracetam seems to be superior to that with phenytoin and valproate administration. Moreover, levetiracetam use demonstrates fewer side effects in brain tumour patients. Nevertheless, high risk of bias and moderate methodological quality must be taken into account when considering these results. PMID- 26945549 TI - Bruton's Tyrosine Kinase Deficiency Inhibits Autoimmune Arthritis in Mice but Fails to Block Immune Complex-Mediated Inflammatory Arthritis. AB - OBJECTIVE: Bruton's tyrosine kinase (BTK) is a B cell signaling protein that also contributes to innate immunity. BTK inhibitors prevent autoimmune arthritis but have off-target effects, and the mechanisms of protection remain unknown. We undertook these studies using genetic deletion to investigate the role of BTK in adaptive and innate immune responses that drive inflammatory arthritis. METHODS: BTK-deficient K/BxN mice were generated to study the role of BTK in a spontaneous model that requires both adaptive and innate immunity. The K/BxN serum-transfer model was used to bypass the adaptive system and elucidate the role of BTK in innate immune contributions to arthritis. RESULTS: BTK deficiency conferred disease protection to K/BxN mice, confirming outcomes of BTK inhibitors. B lymphocytes were profoundly reduced, more than in other models of BTK deficiency. Subset analysis revealed loss of B cells at all developmental stages. Germinal center B cells were also decreased, with downstream effects on numbers of follicular helper T cells and greatly reduced autoantibodies. In contrast, total IgG was only mildly decreased. Strikingly, and in contrast to small molecule inhibitors, BTK deficiency had no effect in the serum-transfer model of arthritis. CONCLUSION: BTK contributes to autoimmune arthritis primarily through its role in B cell signaling and not through innate immune components. PMID- 26945550 TI - Intra-tumour heterogeneity - going beyond genetics. AB - Cancer patients die primarily due to disease recurrence after transient treatment responses. The emergence of therapy-resistant escape variants is fuelled by intra tumour heterogeneity, underpinned by interference and Darwinian evolution among continuously developing sub-clones in the mutating tumour. Novel cancer cell variants build upon the pre-existing genetic landscape and tumour heterogeneity is often ascribed largely to genetic variability. While mutations are required for cancer development and studies of genetic evolution of tumours have improved our understanding of cancer biology, genetics only represents one dimension of the fitness of each cancer cell. Beyond the mutations, several non-genetic factors also add significant variability, resulting in a complex and highly dynamic tumour cell population that can drive disease under almost any condition. This viewpoint article summarizes the genetic basis of intra-tumour heterogeneity, before dissecting four major interdependent non-genetic factors we think critically contribute to the overall variability of tumour cells in all types of cancer: epigenetic regulation, cellular differentiation hierarchies, gene expression stochasticity and tumour microenvironment. We finally present the relevant technological approaches to address the combined contribution of both genetic and non-genetic factors to intra-tumour heterogeneity, focusing on genomic profiling, cellular lineage tracing and single-cell RNA sequencing technologies. This strategy will ultimately allow dissection of the full range and depth of intra-tumour heterogeneity. We thus believe that understanding how cancer genetics synergize with the emerging non-genetic factors will be key for development of therapies able to tackle tumour escape and thereby improve cancer patient survival. PMID- 26945551 TI - The mechanism of inward rectification in Kir channels: A novel kinetic model with non-equilibrium thermodynamics approach. AB - The mechanisms of the strong inward rectification in inward rectifier K(+) (Kir) channels are controversial because the drop in electrical potential due to the movement of the blocker and coupling ions is insufficient to explain the steep voltage-dependent block near the equilibrium potential. Here, we study the "driving force"-dependent block in Kir channels with a novel approach incorporating concepts from the non-equilibrium thermodynamics of small systems, and computer kinetic simulations based on the experimental data of internal Ba(2+) block on Kir2.1 channels. The steep exponential increase in the apparent binding rate near the equilibrium potential is explained, when the encounter frequency is construed as the likelihood of transfer events down or against the electrochemical potential gradient. The exponent of flux ratio, nf=2.62, implies that the blockage of the internal blocker may be coupled with the outward transport of 2 to 3K(+) ions. The flux-coupled block in the single-file multi-ion pore can be demonstrated by the concentration gradient alone, as well as when the driving force is the electrochemical potential difference across the membrane. PMID- 26945552 TI - Postoperative anemia and early functional outcomes after fast-track hip arthroplasty: a prospective cohort study. AB - BACKGROUND: Postoperative anemia is prevalent in fast-track hip arthroplasty (THA) where patients are mobilized and discharged early, but whether anemia impairs functional recovery after discharge has not been adequately evaluated previously. This study aimed to evaluate whether postoperative anemia influenced recovery of mobility and quality of life (Qol) during the first 2 weeks after discharge from THA. STUDY DESIGN AND METHODS: This was a prospective observational study in 122 THA patients more than 65 years of age. Mobility and Qol were assessed pre- and postoperatively by the 6-minute walk test (6MWT; primary outcome), the timed up-and-go test, and the FACT-anemia subscale. Twenty four-hour mobility at home was assessed by activity monitoring on Days 1 to 6 after discharge. Hemoglobin (Hb) at discharge (HbD) and the Hb decrease from preoperatively (DeltaHb) were compared to mobility and Qol the first 2 weeks after discharge using bivariate and multivariate linear regression. RESULTS: Mean (+/-SD) HbD and DeltaHb values were 11.1 (+/-1.4) and 2.8 (+/-1.2) g/dL and correlated weakly to 6MWT 2 weeks after discharge (r = 0.23 and r = -0.20 respectively; p < 0.05) but HbD levels were not correlated to other mobility or Qol measures. After adjustment for preoperative patient-related factors, HbD explained 6% (95% confidence interval, 0%-9%; p < 0.05) of the variation in 6MWT recovery. CONCLUSION: Despite a weak, but significant, correlation between postoperative Hb and the recovery of 6MWT, all other mobility and Qol measures were not influenced by postoperative Hb. Thus, moderate postoperative anemia has limited impact on early postdischarge functional recovery after fast-track THA. PMID- 26945553 TI - Catalytic Enantioselective Synthesis of Halocyclopropanes. AB - A catalytic asymmetric synthesis of halocyclopropanes is described. The developed method is based on a carbenoid cyclopropanation of 2-haloalkenes with tert-butyl alpha-cyano-alpha-diazoacetate using a chiral rhodium catalyst that permits access to a broad range of highly functionalized chiral halocyclopropanes (F, Cl, Br, and I) in good yields, moderate diastereoselectivity, and excellent enantiomeric ratios. The reported methodology represents the first general catalytic enantioselective approach to halocyclopropanes. PMID- 26945554 TI - What Should Be the Cut Point for Classification Criteria of Studies in Gout? A Conjoint Analysis. AB - OBJECTIVE: To determine the acceptable level of positive predictive value (PPV) and negative predictive value (NPV) for classification criteria for gout, given the type of study. METHODS: We conducted an international web-based survey with 91 general practitioners and rheumatologists experienced in gout. Conjoint analysis was used as the framework for designing and analyzing pairs of 2 profiles, each describing a study type, a PPV, and an NPV. There were 5 study types presented: a phase III randomized controlled trial (RCT) of a nonsteroidal antiinflammatory drug versus prednisone for acute gout flares, a phase III RCT of a biologic agent for acute gout flares, a phase II RCT of a novel uricosuric drug of unknown efficacy and limited toxicity data, a case-control, genome-wide association study of gout, and a cohort study examining long-term outcomes of gout. PPV and NPV both had 5 levels ranging from 60-99%. RESULTS: The panelists in majority were male (65%) rheumatologists (93%) with an average of 19 years of practice, seeing 5 to 60 gout patients monthly. PPV was most highly weighted in decision making: the relative importance was 59% for PPV, 29% for NPV, and 13% for study type. The preferred PPV was 90% or 80%, with an accompanying NPV of 70% or 80%, dependent on study type. CONCLUSION: Preferred PPVs and NPVs range between 70% and 90% and differ by study type. A single cut point can be a reasonable approach for all study types if a PPV of 90% and NPV of 80% is approximated. PMID- 26945555 TI - Clostridium difficile infection after restorative proctocolectomy and ileal pouch anal anastomosis for ulcerative colitis. AB - AIM: Clostridium difficile infection (CDI) of the ileal pouch following restorative proctocolectomy (RPC) is becoming increasingly recognized. We aimed to understand better (i) the associated risk factors, (ii) treatment practices and (iii) the pouch diversion and failure rate in patients who developed CDI of the pouch after RPC for ulcerative colitis (UC). METHOD: Patients who tested positive for C. difficile of the pouch between 2007 and 2010 were included in the analysis. Data collected included patient demographics, time from RPC to documented CDI, the treatment of CDI and rate of excision of the pouch. RESULTS: Of 2785 patients recorded in the hospital CDI database, 15 had had an RPC with ileal pouch anal anastomosis. The median age was 44 years and the median interval from RPC to first documented episode of CDI was 3 years. Thirteen (81%) patients had had multiple episodes of pouchitis before and after CDI infection, and all were symptomatic at the time of testing for CDI. Within 30 days of the diagnosis of CDI, six (40%) patients were taking immunosuppressive medication, seven (47%) were taking a proton pump inhibitor and 12 (80%) had received antibiotics. Five patients required hospitalization for CDI and four had severe infections characterized by a serum creatinine more than 1.5 times baseline (n = 3) and a white cell count above 15 000 (n = 1). Six patients who underwent endoscopy had severe inflammation of the pouch including the presence of a pseudomembrane in one case. Ten patients were treated with metronidazole alone and five with vancomycin. Two patients had recurrent CDI of the pouch during a median follow-up period of 2.9 years and one had CDI refractory to medical management. This patient required diversion of the pouch with an ileostomy for refractory CDI but no patient required excision of the pouch. CONCLUSION: All 15 patients developing CDI of the pouch were successfully treated with antibiotics and only one required surgery in the form of an ileostomy. PMID- 26945556 TI - Confocal laser endomicroscopy in ulcerative colitis: a longitudinal study of endomicroscopic changes and response to medical therapy (with videos). AB - BACKGROUND AND AIMS: Confocal laser endomicroscopy enables real-time in vivo microscopy during endoscopy and can predict relapse in patients with inflammatory bowel disease in remission. However, little is known about how endomicroscopic features change with time. The aim of this longitudinal study was to correlate colonic confocal laser endomicroscopy (CLE) in ulcerative colitis with histopathology and macroscopic appearance before and after intensification of medical treatment. METHODS: Twenty-two patients with ulcerative colitis in clinical relapse and 7 control subjects referred for colonoscopy were enrolled. The colonic mucosa was examined with high-definition colonoscopy, histopathology, and CLE at 4 colonic sites. Subsequently, patients requiring medical treatment escalation were referred for repeat endoscopy with CLE after 6 to 8 weeks. RESULTS: The baseline frequency of fluorescein leakage (P < .001), microerosions (P < .001), tortuosity of the crypts (P = .001), distortion of the crypts openings (P = .001), presence of inflammatory infiltrates (P < .001), and decreased crypt density (P < .001) were significantly higher in active ulcerative colitis compared with inactive ulcerative colitis and control subjects. A decrease in histopathologic score after medical treatment escalation was correlated with improvement in crypt tortuosity (rs = .35, P = .016), distortion of crypt openings (rs = .30, P = .045), and decreased crypt density (rs = .33, P = .026) but not in other features. CONCLUSIONS: CLE is an emerging endoscopic technique that reproducibly identifies mucosal changes in ulcerative colitis. With the exception of crypt changes, endomicroscopic features appear to improve slowly with time after medical treatment. ( CLINICAL TRIAL REGISTRATION NUMBER: NCT01684514.). PMID- 26945557 TI - EUS-guided portal pressure gradient measurement with a novel 25-gauge needle device versus standard transjugular approach: a comparison animal study. AB - BACKGROUND AND AIMS: Portal hypertension (PH) is a serious adverse event of liver cirrhosis. The hepatic venous pressure gradient (HVPG) accurately reflects the degree of PH and is the single best prognostic factor in liver disease. Currently, portal pressure gradient (PPG) measurement is performed at interventional radiology (IR) with a standard transjugular approach requiring radiation and intravenous contrast. The aim of this study was to develop a novel EUS-guided system using a 25G FNA needle and compact manometer to directly measure PPG and to evaluate its performance and clinical feasibility. METHODS: Experiments were performed in 3 swine that were under general anesthesia. Manometry was performed in venous (baseline and PH) and arterial (aorta) systems. The PH model was created by rapid Dextran-40 infusion peripherally. Under EUS guidance a 25G FNA needle with attached manometer was used to puncture (transgastric-transhepatic approach) and measure pressures in the portal vein, right hepatic vein (RHV), inferior vena cava (IVC), and aorta. With the IR approach, RHV (free and wedged), IVC, and aorta pressure were measured with an occlusion balloon. Pressure correlation was divided into 3 groups; low pressure (baseline), medium pressure (noncirrhotic portal hypertensive model), and high pressure (arterial). Correlation between the 2 methods of measurement was charted in scatter plots, and the Pearson's correlation coefficient (R) was calculated. RESULTS: EUS identification, access, and manometry was successful in all targeted vessels. There was excellent correlation (R, .985-.99) between EUS and IR methods in all pressure ranges. No adverse event occurred. CONCLUSIONS: This novel technique of EUS-PPG measurement using a 25G needle and novel manometer was feasible and demonstrated excellent correlation with the standard transjugular method throughout low, medium, and high pressure ranges. PMID- 26945558 TI - beta-Ag3 RuO4, a Ruthenate(V) Featuring Spin Tetramers on a Two-Dimensional Trigonal Lattice. AB - Open-shell solids exhibit a plethora of intriguing physical phenomena that arise from a complex interplay of charge, spin, orbital, and spin-state degrees of freedom. Comprehending these phenomena is an indispensable prerequisite for developing improved functional materials. This type of understanding can be achieved, on the one hand, by experimental and theoretical investigations into known systems, or by synthesizing new solids displaying unprecedented structural and/or electronic features. beta-Ag3 RuO4 may serve as such a model system because it possesses a remarkable anionic structure, consisting of tetrameric polyoxoanions (Ru4 O16 )(12-) , and is an embedded fragment of a 2D trigonal MO2 lattice. The notorious frustration of antiferromagnetic (AF) exchange couplings on such lattices is thus lifted, and instead strong AF occurs within the oligomeric anion, where only one exchange path remains frustrated among the relevant six. The strong magnetic anisotropy of the [Ru4 O16 ](12-) ion, and the effectively orbital nature of its net magnetic moment, implies that this anion may reveal the properties of a single-molecule magnet if well-diluted in a diamagnetic matrix. PMID- 26945559 TI - Antifungal, antiradical and cytotoxic activities of extractives obtained from Tagetes patula L. (Asteraceae), a potential acaricide plant species. AB - Tagetes patula L. shows a complex chemical composition, ranging from glycosylated flavonoids and thiophenes in extracts until terpenoids in the essential oil. In the present study, due to this rich flavonoidic constitution, its antioxidant potential was determined, having shown values of antiradical percentage superior to reference compounds, mainly the extracts prepared with flowers. Previous studies performed emphasized the acaricide potential of T. patula and thus, the present study aimed to verify the action of extractives obtained from aerial parts on growth of entomopathogenic fungi related to biological control of brown dog tick Rhipicephalus sanguineus and the action against pathogenic fungi closely associated with pets. None of the samples inhibited the growth of strains of Beauveria bassiana or Metarhizium anisopliae, enabling feasible future studies of synergism on acaricide activity of formulations containing fungi and extracts. The antimicrobial activity of ethanolic extract of flowers (FlEtOH70%) against Microsporum canis and Trichophyton rubrum was significant (193.3 MUg/mL and 253.9 MUg/mL, respectively), as well as ethanolic extract from aerial parts (APEtOH70%) against T. rubrum (312.5 MUg/mL). In order to ensure the safety of a topical formulation containing the extractives of T. patula, the cytotoxic potential of these samples were tested in murine macrophages cells. At higher concentrations all extracts were quite lethal, with IC50 ranging from 210.96 MUg/mL to 468.75 MUg/mL for APEtOH70% and FlEtOH70%, respectively. These results suggest that the application of a product containing T. patula extractives in the control of ticks could be used, at principle, only on the environment. PMID- 26945560 TI - Influence of experimental Anaplasma marginale infection and splenectomy on NTPDase and 5'nucleotidase activities in platelets of cattle. AB - The objective of this paper was to evaluate NTPDase and 5'-nucleotidase activities in platelets of bovine with and without spleen and infected by Anaplasma marginale. Our results demonstrate that infection along with splenectomy is able of inducing a profile of cellular protection, which showed an increase in the degradation of the nucleotides ATP and ADP by NTPDase, in addition to AMP by 5'nucleotidase to form the nucleoside adenosine in platelets, i.e., the enzymatic activities of platelets were increased in splenectomized animals when compared to non-splenectomized group. It notes that adenosine is a molecule with anti-inflammatory function. But this profile is related to a deficiency in immune signaling triggered by nucleotide ATP, which may be related to the increase in bacteremia and disability in combating the parasite in splenectomized host. PMID- 26945561 TI - Influence of lipopolysaccharide outer-core in the intrinsic resistance to antimicrobial peptides and virulence in Edwardsiella ictaluri. AB - The genus Edwardsiella consists of bacteria with an intrinsic resistance to cyclic cationic antimicrobial peptides (CAMPs). Edwardsiella ictaluri, a pathogen of the catfish (Ictalurus punctatus) and the causative agent of a systemic infection, is highly resistant to CAMPs. Previously, we determined that the oligo polysaccharide (O-PS) of the lipopolysaccharide (LPS) does not play a role in the E. ictaluri CAMP resistance and an intact core-lipid A structure is necessary for CAMPs resistance. Here, we evaluated the influence of the outer-core in the CAMPs resistance and fish virulence. E. ictaluri wabG, a gene that encodes for the UDP glucuronic acid transferase that links the lipid A-inner-core to the outer-core oligopolysaccharides, was deleted. Deletion of DeltawabG caused a pleiotropic effect, influencing LPS synthesis, CAMPs resistance, growth, and biofilm formation. E. ictaluri DeltawabG was attenuated in zebrafish indicating the important role of LPS during fish pathogenesis. Also, we evaluated the inflammatory effects of wabG LPS in catfish ligated loop model, showing a decreased inflammatory effect at the gut level respects to the E. ictaluri wild type. We conclude that E. ictaluri CAMPs resistance is related to the molecules present in the LPS outer-core and that fish gut inflammation triggered by E. ictaluri is LPS dependent, reinforcing the hypothesis that fish gut recognizes LPS in an O-PS dependent fashion. PMID- 26945562 TI - Heterogeneity in resistant fecal Bacteroides fragilis group collected from healthy people. AB - Normal nonpathogenic flora would represent a constant lake of resistance genes potentially transferable to human pathogens. To assess the prevalence of resistance genes and genetic variability of Bacteroides fragilis group (BFG) from normal flora, 177 Bacteroides isolates obtained from the fecal samples of healthy individuals. These isolates were subjected to antibiotic susceptibility testing and pulsed field gel electrophoresis (PFGE). The isolates were further tested for the presence of ermF, tetQ and bft genes by PCR. Our results indicated the presence of different clonal strains (1 common type and 57 single types) among the resistant isolates. The resistance rate for the six antibiotics in this study was between 1% and 95%. Most of the isolates (99%) were susceptible to metronidazole. ermF and tetQ were detected in all erythromycin and tetracycline resistant isolates. None of the isolates were carried bft gene. These data suggest dissemination of heterogenic clonal groups in healthy persons and resistance to 5 high commonly used antibiotics. PMID- 26945563 TI - Serum levels of soluble programmed death-1 and programmed death ligand-1 in systemic sclerosis: Association with extent of skin sclerosis. AB - The interaction of programmed death-1 (PD-1) with its ligand, programmed death ligand-1 (PD-L1), has been considered to play a key role in the negative regulation of immune responses. Patients with diffuse cutaneous systemic sclerosis (SSc) had higher levels of soluble PD-1 (sPD-1) than those with limited cutaneous SSc and healthy individuals. Serum sPD-1 levels positively correlated with the severity of skin sclerosis. In contrast, serum sPD-L1 levels were significantly increased in patients with SSc compared with healthy individuals. Moreover, serum sPD-L1 levels were not associated with the extent of skin sclerosis and were elevated not only in patients with diffuse cutaneous SSc, but also in those with limited cutaneous SSc. These results suggested that serum sPD 1 levels may increase in patients with SSc and correlate with the severity of skin sclerosis. PD-1/PD-L1 interaction may contribute to the development of skin sclerosis in SSc. PMID- 26945564 TI - Midodrine for the weaning of vasopressor infusions. AB - WHAT IS KNOWN AND OBJECTIVE: Midodrine, an orally available alpha1-agonist indicated for the treatment of orthostatic hypotension, has been used at our institution as an adjunctive treatment to provide haemodynamic support to facilitate intravenous (IV) vasopressor weaning. Limited published data exist for this off-label use; thus, the objective of this study was to evaluate outcomes in patients who received midodrine for IV vasopressor weaning compared to control patients. METHODS: This retrospective comparison included adult ICU patients admitted to our institution from January 2007 to March 2012. The primary outcome was the time to IV vasopressor discontinuation after midodrine initiation. Secondary outcomes included a comparison between midodrine and control patients of the time from IV vasopressor discontinuation to ICU discharge, hospital and ICU length of stay (LOS), and the number of ICU readmissions. RESULTS AND DISCUSSION: The analysis included 188 patients (94 midodrine and 94 control). Patients discontinued IV vasopressors a median of 1.2 days (IQR 0.5-2.8) after midodrine initiation. ICU discharge occurred sooner after IV vasopressor discontinuation (0.8 vs. 1.5 days, P = 0.01), and 96% of patients remained off IV vasopressors after midodrine treatment. Hospital LOS was longer in midodrine patients (P < 0.01), but there were no differences in ICU LOS or readmissions. Adverse event rates after midodrine use were consistent with those observed in other studies. WHAT IS NEW AND CONCLUSION: Midodrine may serve as a useful adjunct to wean IV vasopressors in difficult-to-wean patients. Further studies are needed to assess the efficacy and safety of midodrine for this indication. PMID- 26945566 TI - Patterns of Care in the Administration of Neo-adjuvant Chemotherapy for Breast Cancer. A Population-Based Study. AB - Neo-adjuvant chemotherapy (NAC) is used to facilitate radical surgery for initially irresectable or locally advanced breast cancer. The indication for NAC has been extended to clinically node negative (cN0) patients in whom adjuvant systemic therapy is foreseen. A population-based study was conducted to evaluate the increasing use of NAC, breast conserving surgery (BCS) after NAC and timing of the sentinel node biopsy (SNB). All female breast cancer patients, treated in 10 hospitals in the Eindhoven Cancer Registry area in the Netherlands between January 2003 and June 2012 were included (N = 18,427). In total, 1,402 patients (7.6%) received NAC. The administration increased from 2.5% in 2003 to 13.0% in 2011 (p < 0.001). Use of NAC increased from 0.5% to 2.3% for cT1 tumors, from 2.8% to 27.0% for cT2, from 30.6% to 70.9% for cT3, and from 40.5% to 58.1% for cT4 tumors (p < 0.001). In cN0 patients, use of NAC increased from 1.0% to 4.4% and in clinically node positive patients from 12.0% to 57.5% (p < 0.001). Downsizing of the tumor and BCS are achieved increasingly. In 2011, in three hospitals NAC was administered in <10% of patients, in five hospitals in 10-15% and in two hospitals the proportion of patients receiving NAC was >20% (p < 0.001). Of the 1,402 patients with NAC, 495 patients underwent SNB, 91.5% of whom prior to NAC. In the Netherlands up to one in eight patients receive NAC. The administration of NAC and the percentage of BCS increased over the past decade, especially in cT2 tumors. Considerable hospital variation in the administration of NAC exists. PMID- 26945565 TI - The china patient-centered evaluative assessment of cardiac events (PEACE) prospective study of percutaneous coronary intervention: Study design. AB - BACKGROUND: The number of percutaneous coronary interventions (PCI) in China has increased more than 20-fold over the last decade. Consequently, there is a need for national-level information to characterize PCI indications and long-term patient outcomes, including health status, to understand and improve evolving practice patterns. OBJECTIVES: This nationwide prospective study of patients receiving PCI is to: (1) measure long-term clinical outcomes (including death, acute myocardial infarction [AMI], and/or revascularization), patient-reported outcomes (PROs), cardiovascular risk factor control and adherence to medications for secondary prevention; (2) determine patient- and hospital-level factors associated with care process and outcomes; and (3) assess the appropriateness of PCI procedures. METHODS: The China Patient-centered Evaluative Assessment of Cardiac Events (PEACE) Prospective Study of PCI has enrolled 5,000 consecutive patients during 2012-2014 from 34 diverse hospitals across China undergoing PCI for any indication. We abstracted details of patient's medical history, treatments, and in-hospital outcomes from medical charts, and conducted baseline, 1-, 6-, and 12-month interviews to characterize patient demographics, risk factors, clinical presentation, healthcare utilization, and health status using validated PRO measures. The primary outcome, a composite measure of death, AMI and/or revascularization, as well as PROs, medication adherence and cardiovascular risk factor control, was assessed throughout the 12-month follow up. Blood and urine samples were collected at baseline and 12 months and stored for future analyses. To validate reports of coronary anatomy, 2,000 angiograms are randomly selected and read by two independent core laboratories. Hospital characteristics regarding their facilities, processes and organizational characteristics are assessed by site surveys. CONCLUSION: China PEACE Prospective Study of PCI will be the first study to generate novel, high-quality, comprehensive national data on patients' socio-demographic, clinical, treatment, and metabolic/genetic factors, and importantly, their long-term outcomes following PCI, including health status. This will build the foundation for PCI performance improvement efforts in China. (c) 2016 The Authors. Catheterization and Cardiovascular Interventions. Published by Wiley Periodicals, Inc. PMID- 26945567 TI - Facial swelling: an atypical presentation of cutaneous lymphoma. AB - BACKGROUND: Cutaneous lymphomas (primary and secondary lymphomas involving the skin) are a heterogeneous group with various clinical manifestations, histological features, and prognoses. METHODS: We describe eight cases of cutaneous lymphoma presenting with facial swelling. RESULTS: Our case series included three cases of primary cutaneous extranodal natural killer/T-cell lymphoma, one case of secondary cutaneous extranodal natural killer/T-cell lymphoma, one case of subcutaneous panniculitis-like T-cell lymphoma, one case of cutaneous CD4+ small/medium pleomorphic T-cell lymphoma, and two cases of peripheral T-cell lymphoma (unspecified). CONCLUSIONS: This collection of cases and literature review emphasizes the need for clinical suspicion of cutaneous lymphoma in the differential diagnosis of patients with refractory facial swelling. PMID- 26945568 TI - Metal-assisted polyatomic SIMS and laser desorption/ionization for enhanced small molecule imaging of bacterial biofilms. AB - Mass spectrometry imaging (MSI) has become an important analytical tool for many sectors of science and medicine. As the application of MSI expands into new areas of inquiry, existing methodologies must be adapted and improved to meet emerging challenges. Particularly salient is the need for small molecule imaging methods that are compatible with complex multicomponent systems, a challenge that is amplified by the effects of analyte migration and matrix interference. With a focus on microbial biofilms from the opportunistic pathogen Pseudomonas aeruginosa, the relative advantages of two established microprobe-based MSI techniques-polyatomic secondary ion mass spectrometry (SIMS) and laser desorption/ionization-are compared, with emphasis on exploring the effect of surface metallization on small molecule imaging. A combination of qualitative image comparison and multivariate statistical analysis demonstrates that sputtering microbial biofilms with a 2.5 nm layer of gold selectively enhances C60-SIMS ionization for several molecular classes including rhamnolipids and 2 alkyl-quinolones. Metallization also leads to the reduction of in-source fragmentation and subsequent ionization of media-specific background polymers, which improves spectral purity and image quality. These findings show that the influence of metallization upon ionization is strongly dependent on both the surface architecture and the analyte class, and further demonstrate that metal assisted C60-SIMS is a viable method for small molecule imaging of intact molecular ions in complex biological systems. PMID- 26945569 TI - Subjective taste and smell changes in treatment-naive people with solid tumours. AB - PURPOSE: Taste and smell changes (TSCs) are common in head and neck (H&N) cancer and during and after chemotherapy (CT) and radiotherapy (RT). It is an area that has been under-investigated, particularly in the treatment-naive, but can negatively impact nutritional status. This study examined the prevalence, severity and characteristics of TSCs in people with non-H&N solid tumours, before CT and RT, and their relationship with co-occurring symptoms. METHODS: A prospective, observational study was conducted. Forty consecutive pre-treatment cancer patients, referred to radiation oncology outpatients over 6 weeks, were recruited. Data on TSCs, symptoms and nutritional status were obtained using the 'Taste and Smell Survey' and the 'abridged Patient-Generated Subjective Global Assessment' (abPG-SGA). BMI was measured. SPSS(r) was used for statistical analysis. Two-sided P values <0.05 were considered statistically significant. RESULTS: Most patients were newly diagnosed (n = 28; 70 %). Nineteen (48 %) reported TSCs; nine noted a stronger sweet and seven a stronger salt taste. Of these, four reported a stronger and four a weaker smell sensation. Those at nutritional risk reported more TSCs (n = 13/20). TSCs were significantly associated with dry mouth (P < 0.01), early satiety (P < 0.05) and fatigue (P < 0.05). CONCLUSIONS: TSCs preceded CT or RT in almost half of treatment-naive patients with solid tumours, notably stronger sweet and salt tastes. Half of the study group were at nutritional risk; the majority of these reported TSCs. TSCs were significantly associated with other symptoms. Future research and clinical guidelines, with a common terminology for assessment, diagnosis and management of cancer TSCs, are needed. PMID- 26945570 TI - Impact of a behavioral weight loss intervention on comorbidities in overweight and obese breast cancer survivors. AB - PURPOSE: Comorbid medical conditions are common among breast cancer survivors, contribute to poorer long-term survival and increased overall mortality, and may be ameliorated by weight loss. This secondary analysis evaluated the impact of a weight loss intervention on comorbid medical conditions immediately following an intervention (12 months) and 1-year postintervention (24 months) using data from the Exercise and Nutrition to Enhance Recovery and Good health for You (ENERGY) trial-a phase III trial which was aimed at and successfully promoted weight loss. METHODS: ENERGY randomized 692 overweight/obese women who had completed treatment for early stage breast cancer to either a 1-year group-based behavioral intervention designed to achieve and maintain weight loss or to a less intensive control intervention. Minimal support was provided postintervention. New medical conditions, medical conditions in which non-cancer medications were prescribed, hospitalizations, and emergency room visits, were compared at baseline, year 1, and year 2. Changes over time were analyzed using chi-squared tests, Kaplan Meier, and logistic regression analyses. RESULTS: At 12 months, women randomized to the intervention had fewer new medical conditions compared to the control group (19.6 vs. 32.2 %, p < 0.001); however, by 24 months, there was no longer a significant difference. No difference was observed in each of the four conditions for which non-cancer medications were prescribed, hospital visits, or emergency visits at either 12 or 24 months. CONCLUSIONS: These results support a short-term benefit of modest weight loss on the likelihood of comorbid conditions; however, recidivism and weight regain likely explain no benefit at 1-year postintervention follow-up. PMID- 26945571 TI - Palliative care specialists' beliefs about spiritual care. AB - PURPOSE: A previous survey of the Multinational Association of Supportive Care in Cancer (MASCC) members found low frequency of spiritual care provision. We hypothesized that physicians with special training in palliative medicine would demonstrate an increased sense of responsibility for and higher self-reported adequacy to provide spiritual care to patients than health professionals with general training. METHODS: We surveyed members of the Australian and New Zealand Palliative Medicine Society (ANZSPM) to ascertain their spiritual care practices. We sent 445 e-mails on four occasions, inviting members to complete the online survey. Tabulated results were analyzed to describe the results. RESULTS: One hundred and fifty-eight members (35.5 %) responded. Physicians working primarily in palliative care comprised the majority (95 %) of the sample. Significantly more of the ANZSPM than MASCC respondents had previously received training in spiritual care and had pursued training in the previous 2 years. There was a significant difference between the two groups with regard to interest in and self reported ability to provide spiritual care. Those who believed it was their responsibility to provide spiritual care were more likely to have had training, feel they could adequately provide spiritual care, and were more likely to refer patients if they could not provide spiritual care themselves. CONCLUSIONS: Training in spiritual care was more common in healthcare workers who had received training in palliative care. ANZSPM members gave higher scores for both the importance of spiritual care and self-reported ability to provide it compared to MASCC members. PMID- 26945572 TI - JMJD1A promotes tumorigenesis and forms a feedback loop with EZH2/let-7c in NSCLC cells. AB - Lung cancer is the most common cause of cancer-related deaths worldwide, and non small cell lung cancer (NSCLC) accounts for 80 to 85 % of all lung cancer. Although the standard treatment regimen has been established, long-term survival for NSCLC patients is still generally poor. The histone demethylase Jumonji domain containing 1A (JMJD1A) has been proposed as an oncogene in several types of human cancer, but its clinical significance and functional roles in NSCLC remain largely unclear. In the present study, JMJD1A was frequently upregulated in NSCLC compared with para-carcinoma tissues. JMJD1A knockdown significantly inhibited NSCLC cell growth, migration, and invasion in vitro and tumorigenesis in vivo. Further experiments demonstrated that JMJD1A knockdown could decrease the expression of EZH2, which has been shown to play a crucial role in the carcinogenesis of NSCLC and, in turn, increase the expression of anti-tumor microRNA let-7c. Also, let-7c directly targeted the 3'-untranslated regions of JMJD1A and EZH2. Taken together, JMJD1A could promote NSCLC tumorigenesis. JMJD1A/EZH2/let-7c constituted a feedback loop and might represent a promising therapeutic target for NSCLC. PMID- 26945573 TI - The value of serum RASSF10 hypermethylation as a diagnostic and prognostic tool for gastric cancer. AB - The tumor-suppressing role of Ras-association domain family 10 (RASSF10) has been described in several types of cancers. Here, we evaluated the potential use of the hypermethylation status of the RASSF10 promoter in serum as a new diagnostic and prognostic tool in gastric cancer (GC). We used bisulfite sequencing polymerase chain reaction to examine RASSF10 methylation levels in serum and/or tumor samples from 82 GC, 45 chronic atrophic gastritis (CAG), and 50 healthy control patients. In the serum of GC patients, the median level of RASSF10 methylation was higher at 47.84 % than those in the serum of CAG and healthy control patients at 11.89 and 11.35 %, respectively. The median level of RASSF10 methylation in GC tumor tissue was similarly high at 62.70 %. Furthermore, RASSF10 methylation levels were highly correlated between paired serum and tumor samples from GC patients. We performed receiver-operating characteristic curve analyses to verify that serum RASSF10 methylation levels could effectively distinguish GC from control patients. Moreover, multivariate analyses showed that high serum RASSF10 methylation levels in GC patients were associated with large tumors, lymph node metastasis, and high carcinoembryonic antigen (CEA) levels. Survival analyses showed that GC patients with high serum RASSF10 methylation levels had shorter overall and disease-free survival after D2 lymphadenectomy than those with low levels. High serum RASSF10 methylation levels were also an independent predictor of tumor recurrence and GC patient survival. In conclusion, serum RASSF10 promoter methylation levels can serve as a valuable indicator for the diagnosis and prognosis of GC in the clinic. PMID- 26945574 TI - Muscle-specific acute changes in passive stiffness of human triceps surae after stretching. AB - PURPOSE: It remains unclear whether the acute effect of stretching on passive muscle stiffness differs among the synergists. We examined the muscle stiffness responses of the medial (MG) and lateral gastrocnemii (LG), and soleus (Sol) during passive dorsiflexion before and after a static stretching by using ultrasound shear wave elastography. METHODS: Before and after a 5-min static stretching by passive dorsiflexion, shear modulus of the triceps surae and the Achilles tendon (AT) during passive dorsiflexion in the knee extended position were measured in 12 healthy subjects. RESULTS: Before the static stretching, shear modulus was the greatest in MG and smallest in Sol. The stretching induced significant reductions in shear modulus of MG, but not in shear modulus of LG and Sol. The slack angle was observed at more plantar flexed position in the following order: AT, MG, LG, and Sol. After the stretching, the slack angles of each muscle and AT were significantly shifted to more dorsiflexed positions with a similar extent. When considering the shift in slack angle, the change in MG shear modulus became smaller. CONCLUSION: The present study indicates that passive muscle stiffness differs among the triceps surae, and that the acute effect of a static stretching is observed only in the stiff muscle. However, a large part of the reduction of passive muscle stiffness at a given joint angle could be due to an increase in the slack length. PMID- 26945576 TI - Effect of Medium pH on Rhodosporidium toruloides NCYC 921 Carotenoid and Lipid Production Evaluated by Flow Cytometry. AB - The effect of the culture medium pH (3.5-6.0) on the carotenoid and lipid (as fatty acids) production by the yeast Rhodosporidium toruloides NCYC 921 was studied. Flow cytometry was used to evaluate the yeast's physiological response to different culture medium pH values. The yeast biomass concentration and lipid content were maxima at pH 4.0 (5.90 g/L and 21.85 % w/w, respectively), while the maximum carotenoid content (63.37 MUg/g) was obtained at pH 5.0. At the exponential phase, the yeast cell size and internal complexity were similar, at different medium pH. At the stationary phase, the yeast cell size and internal complexity decreased as the medium pH increased. At the exponential phase, the proportion of cells with polarized membranes was always high (>80 %) but at the stationary phase, the proportion of yeast cells with depolarized membranes was dominant (>65 %) and increased with the medium pH increase. The results here reported may contribute for yeast bioprocesses optimization. For the first time, multiparameter flow cytometry was used to evaluate the impact of medium pH changes on the yeast cell physiological status, specifically on the yeast membrane potential, membrane integrity, cell size and internal complexity. PMID- 26945577 TI - Metabolite and Mechanistic Basis of Antifungal Property Exhibited by Endophytic Bacillus amyloliquefaciens BmB 1. AB - Plants are ubiquitously colonized by endophytic microorganisms which contribute significantly to plant health through production of plant growth regulators or disease suppression. In the present study, an endophytic bacterial isolate designated as BmB 1 with significant antifungal and plant growth promoting properties was isolated from the stem tissue of Bacopa monnieri (L.) Pennell. The isolate was studied in detail for the molecular and chemical basis of its bioactivity which proved it to have the presence of surfactin, iturin, and type I polyketide synthase (PKS) genes. For the analysis of the chemical basis of antifungal property, extract of the isolate was initially checked for its activity on test pathogens and LC-MS/MS based analysis further confirmed the presence of bacillomycin (m/z (M+H(+)) 1031.8) and surfactin (m/z (M+H(+)) 1008.6 and 1022.6) in the extract prepared. The light microscopic and SEM analysis of the treated and untreated mycelia of the pathogens clearly revealed the hypal destruction caused by the compounds produced by the selected isolate. This confirms the ability of the organism to directly inhibit the growth of the tested pathogens. The GC-MS analysis also confirmed the isolate to have the presence of volatile compounds with the expected role to induce induced systemic resistance (ISR) of the plant. Because of the multitargeted antifungal property, the isolate which was identified as Bacillus amyloliquefaciens can have potential biocontrol applications. PMID- 26945575 TI - Clinical effectiveness, quality of life and cost-effectiveness of Flaminal(r) versus Flamazine(r) in the treatment of partial thickness burns: study protocol for a randomized controlled trial. AB - BACKGROUND: Partial thickness burns are painful, difficult to manage and can have a negative effect on quality of life through scarring, permanent disfigurement and loss of function. The aim of burn treatment in partial thickness burns is to save lives, stimulate wound healing by creating an optimumly moist wound environment, to have debriding and analgesic effects, protect the wound from infection and be convenient for the patient and caregivers. However, there is no consensus on the optimal treatment of partial thickness wounds. Flaminal(r) and Flamazine(r) are two standard treatment options that provide the above mentioned properties in burn treatment. Nevertheless, no randomized controlled study has yet compared these two common treatment modalities in partial thickness burns. Thus, the aim of this study is to evaluate the clinical effectiveness, quality of life and cost-effectiveness of Flaminal(r) versus Flamazine(r) in the treatment of partial thickness burns. METHODS/DESIGN: In this two-arm open multi-center randomized controlled trial, 90 patients will be randomized between Flaminal(r) and Flamazine(r) and followed for 12 months. The study population will consist of competent or temporarily non-competent (because of sedation and/or intubation) patients, 18 years of age or older, with acute partial thickness burns and a total body surface area (TBSA) of less than 30 %. The main study outcome is time to complete re-epithelialization (greater than 95 %). Secondary outcome measures include need for grafting, wound colonization/infection, number of dressing changes, pain and anxiety, scar formation, health-related quality of life (HRQoL), and costs. DISCUSSION: This study will contribute to the optimal treatment of patients with partial thickness burn wounds and will provide evidence on the (cost-)effectiveness and quality of life of Flaminal(r) versus Flamazine(r) in the treatment of partial thickness burns. TRIAL REGISTRATION: Netherlands Trial Register NTR4486 , registered on 2 April 2014. PMID- 26945578 TI - Whole Body Vibration Improves Insulin Resistance in db/db Mice: Amelioration of Lipid Accumulation and Oxidative Stress. AB - Insulin resistance (IR) is the hallmark of type 2 diabetes mellitus (T2DM), which is one of the most important chronic noncommunicable diseases. Effective and feasible strategies to treat IR are still urgently needed. Previous research studies reported that whole body vibration (WBV) was beneficial for IR in clinical; however, its underlying mechanisms remains unknown. In the present study, db/db mice were treated with WBV administration 60 min/day for 12 weeks and the impaired insulin sensitivity was improved. Besides, liver steatosis was also ameliorated. Further explorations revealed that WBV could reduce the expression of SREBP1c and increase the expression of GSH-Px and consequently suppress oxidative stress. In conclusion, WBV attenuates oxidative stress to ameliorate liver steatosis and thus improves insulin resistance in db/db mice. Therefore, WBV administration is a promising treatment for individuals who suffered from central obesity and IR. PMID- 26945579 TI - A giant mucinous cystadenocarcinoma of the appendix: a case report and review of the literature. AB - BACKGROUND: Mucinous cystadenocarcinoma is the second most common etiology of appendiceal mucocele. We report a relatively rare case of a giant appendiceal mucocele caused by mucinous cystadenocarcinoma, which occupied the entire abdomen of an adult woman. CASE PRESENTATION: A 63-year-old woman presented with a chief complaint of abdominal distention. Imaging studies showed a giant cystic mass occupying her entire abdomen. Laparotomy confirmed a giant appendiceal mucocele, and the patient underwent ileocecal resection. A mucinous deposit was not found in her abdominal cavity, and the ovaries were grossly normal bilaterally. The pathological diagnosis was mucinous adenocarcinoma with a low-grade mucinous neoplasm that invaded the subserosa. Regional lymph node metastasis was not found. She has had recurrence-free survival for 5 years. CONCLUSIONS: The present case is the largest appendiceal cystadenocarcinoma ever reported. The optimal treatment of an appendiceal neoplasm requires further research based on consensus terminology of an appendiceal mucocele. PMID- 26945580 TI - Pencil beam scanning proton therapy for pediatric intracranial ependymoma. AB - To assess the clinical outcome and late side effect profile of pencil beam scanning proton therapy (PT) delivered to children with intracranial ependymoma. Between July-2004 and March-2013, 50 patients with intracranial ependymoma (n = 46, grade 3) received involved-field PT at Paul Scherrer Institute (PSI). Median age at time of PT was 2.6 years (range 1.1-15.2). Thirty-six patients had infratentorial and 14 supratentorial ependymomas. Seventeen patients presented with macroscopic residual disease after subtotal resection before starting PT (8 with <=1.5 cc and 9 with >1.5 cc residual tumor respectively). Forty-three (86 %) patients received post-operative chemotherapy before PT according to protocols; 44 (88 %) patients younger than 5 years required general anesthesia. Median prescribed dose was 59.4 Gy (RBE) (range 54-60) delivered in 1.8-2 Gy (RBE) per fraction. Late toxicity was assessed according to CTCAE v4.0. With a mean follow up time of 43.4 months (range 8.5-113.7) seven patients experienced local failure (6 with infratentorial tumors and 1 with supratentorial tumor); four of the local failures were in patients with residual disease >=1.5 cc at the time of PT and 3 without residual macroscopic disease. Five patients died from tumor progression. Actuarial 5-year Local Control rates were 78 +/- 7.5 % and 5-year OS rates were 84 +/- 6.8 %. Three patients developed grade >=3 toxicity: 2 developed unilateral deafness (infratentorial tumors infiltrating into the internal acoustic canal), one patient developed a fatal brainstem necrosis. Repeated general anesthesia in children younger than 5 years was delivered without complications. Our data indicate the safety and the effectiveness of PT for pediatric ependymomas. Local control and survival rates are encouraging considering the high grade histology in 92 % of the patients and the number of patients with residual tumor >=1.5 cc. The rates of late effects compare favorably with published photon-treated cohorts. PMID- 26945582 TI - A multi-time-scale analysis of chemical reaction networks: II. Stochastic systems. AB - We consider stochastic descriptions of chemical reaction networks in which there are both fast and slow reactions, and for which the time scales are widely separated. We develop a computational algorithm that produces the generator of the full chemical master equation for arbitrary systems, and show how to obtain a reduced equation that governs the evolution on the slow time scale. This is done by applying a state space decomposition to the full equation that leads to the reduced dynamics in terms of certain projections and the invariant distributions of the fast system. The rates or propensities of the reduced system are shown to be the rates of the slow reactions conditioned on the expectations of fast steps. We also show that the generator of the reduced system is a Markov generator, and we present an efficient stochastic simulation algorithm for the slow time scale dynamics. We illustrate the numerical accuracy of the approximation by simulating several examples. Graph-theoretic techniques are used throughout to describe the structure of the reaction network and the state-space transitions accessible under the dynamics. PMID- 26945581 TI - Superselective intraarterial cerebral infusion of cetuximab after osmotic blood/brain barrier disruption for recurrent malignant glioma: phase I study. AB - Objective To establish a maximum tolerated dose of superselective intraarterial cerebral infusion (SIACI) of Cetuximab after osmotic disruption of the blood brain barrier (BBB) with mannitol, and examine safety of the procedure in patients with recurrent malignant glioma. Methods A total of 15 patients with recurrent malignant glioma were included in the current study. The starting dose of Cetuximab was 100 mg/m(2) and dose escalation was done to 250 mg/m(2). All patients were observed for 28 days post-infusion for any side effects. Results There was no dose-limiting toxicity from a single dose of SIACI of Cetuximab up to 250 mg/m(2) after osmotic BBB disruption with mannitol. A tolerable rash was seen in 2 patients, anaphylaxis in 1 patient, isolated seizure in 1 patient, and seizure and cerebral edema in 1 patient. Discussion SIACI of mannitol followed by Cetuximab (up to 250 mg/m(2)) for recurrent malignant glioma is safe and well tolerated. A Phase I/II trial is currently underway to determine the efficacy of SIACI of cetuximab in patients with high-grade glioma. PMID- 26945583 TI - Overlapping and Non-overlapping Practices in Usual and Evidence-Based Care for Youth Anxiety. AB - This study compared consistencies and discrepancies in usual care with practices derived from the evidence-base (PDEB) for youth anxiety in a public mental health system. Youth-level factors (diagnosis, functional impairment) as predictors of the discrepancies were also examined. Psychosocial and service data from 2485 youth with an anxiety disorder and/or receiving services for an anxiety treatment target were extracted. Therapists (N = 616) identified the treatment targets and practices youth received. Although many PDEB for youth anxiety were used by therapists in this sample, Exposure was only used in 15% of cases. Practices not consistent with youth anxiety treatment were also reported and included: PDEB for other conditions, practices common to all therapies, and practices that are not consistent with evidence-based care. Age and diagnosis predicted the delivery of PDEB for youth anxiety. Usual care incorporated many components of evidence-based care but was more diffuse and less focused on well-supported practices. PMID- 26945584 TI - Senegenin Ameliorate Acute Lung Injury Through Reduction of Oxidative Stress and Inhibition of Inflammation in Cecal Ligation and Puncture-Induced Sepsis Rats. AB - The purpose of this study was to assess the protective effect of senegenin on acute lung injury (ALI) in rats induced by sepsis. Rat ALI model was reproduced by cecal ligation and puncture (CLP). All rats were randomly divided into five groups: group 1 (control), group 2 (CLP), group 3 (CLP + senegenin 15 mg/kg), group 4 (CLP + senegenin 30 mg/kg), and group 5 (CLP + senegenin 60 mg/kg). CLP + senegenin groups received senegenin by gavage daily for consecutive 5 days, respectively, while the mice in control and CLP groups were given an equivalent volume of saline. We detected the lung wet/dry weight ratios and the histopathology of the lung. The levels of lung tissue myeloperoxidase (MPO), malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione (GSH) were determined. Meanwhile, the nuclear factor-kappa B (NF-kappaB) activation, tumor necrosis factor-alpha (TNF-alpha), and interleukin-1beta (IL-1beta) levels were studied. The results demonstrated that senegenin treatment significantly attenuated CLP-induced lung injury, including reduction of lung wet/dry weight ratio, protein leak, infiltration of leukocytes, and MPO activity. In addition, senegenin markedly decreased MDA content and increased SOD activity and GSH level. Serum levels of TNF-alpha and IL-1beta were also decreased by senegenin administration. Furthermore, senegenin administration inhibited the nuclear translocation of NF-kappaB in the lungs. These findings indicate that senegenin exerts protective effects on CLP-induced septic rats. Senegenin may be a potential therapeutic agent against sepsis. PMID- 26945585 TI - Social Context of Adherence in an Open-Label 1 % Tenofovir Gel Trial: Gender Dynamics and Disclosure in KwaZulu-Natal, South Africa. AB - CAPRISA 008, an open-label extension study of tenofovir gel with coitally-related dosing, provided an opportunity to explore the relationship between product adherence and gender dynamics in a context where women knew they were receiving an active product with evidence of HIV prevention effectiveness. Interviews with 63 CAPRISA 008 participants and 13 male partners in KwaZulu-Natal, South Africa, highlighted that the process of negotiating gel use was determined in part by relationship dynamics including the duration of the relationship, the living situation, an evaluation of the relationship (e.g., partner intimacy and relationship expectations) and culturally-defined steps for formalizing the relationship. While disclosure facilitated adherence for many, others reported using the gel effectively with no disclosure, and in some situations disclosure was a barrier to adherence. Women should be supported in their choice about what to disclose and have opportunity to use this and similar products without their partners' knowledge or acquiescence. PMID- 26945586 TI - Creating opportunities through mentorship, parental involvement, and safe spaces (COMPASS) program: multi-country study protocol to protect girls from violence in humanitarian settings. AB - BACKGROUND: Violence against adolescent girls in humanitarian settings is of urgent concern given their additional vulnerabilities to violence and unique health and well-being needs that have largely been overlooked by the humanitarian community. In order to understand what works to prevent violence against adolescent girls, a multi-component curriculum-based safe spaces program (Creating Opportunities through Mentorship, Parental involvement and Safe Spaces COMPASS) will be implemented and evaluated. The objectives of this multi-country study are to understand the feasibility, acceptability and effectiveness of COMPASS programming to prevent violence against adolescent girls in diverse humanitarian settings. METHODS/DESIGN: Two wait-listed cluster-randomized controlled trials are being implemented in conflict-affected communities in eastern Democratic Republic of Congo (N = 886 girls aged 10-14 years) and in refugee camps in western Ethiopia (N = 919 girls aged 13-19 years). The intervention consists of structured facilitated sessions delivered in safe spaces by young female mentors, caregiver discussion groups, capacity-building activities with service providers, and community engagement. In Ethiopia, the research centers on the overall impact of COMPASS compared to a wait-list group. In DRC, the research objective is to understand the incremental effectiveness of the caregiver component in addition to the other COMPASS activities as compared to a wait-list group. The primary outcome is change in sexual violence. Secondary outcomes include decreased physical and emotional abuse, reduced early marriage, improved gender norms, and positive interpersonal relationships, among others. Qualitative methodologies seek to understand girls' perceptions of safety within their communities, key challenges they face, and to identify potential pathways of change. DISCUSSION: These trials will add much needed evidence for the humanitarian community to meet the unique needs of adolescent girls and to promote their safety and well-being, as well as contributing to how multi component empowerment programming for adolescent girls could be adapted across humanitarian settings. TRIAL REGISTRATION: Clinical Trials NCT02384642 (Registered: 2/24/15) & NCT02506543 (Registered: 7/19/15). PMID- 26945587 TI - Unravelling the potential mechanisms behind hospitalization-associated disability in older patients; the Hospital-Associated Disability and impact on daily Life (Hospital-ADL) cohort study protocol. AB - BACKGROUND: Over 30 % of older patients experience hospitalization-associated disability (HAD) (i.e., loss of independence in Activities of Daily Living (ADLs)) after an acute hospitalization. Despite its high prevalence, the mechanisms that underlie HAD remain elusive. This paper describes the protocol for the Hospital-Associated Disability and impact on daily Life (Hospital-ADL) study, which aims to unravel the potential mechanisms behind HAD from admission to three months post-discharge. METHODS/DESIGN: The Hospital-ADL study is a multicenter, observational, prospective cohort study aiming to recruit 400 patients aged >=70 years that are acutely hospitalized at departments of Internal Medicine, Cardiology or Geriatrics, involving six hospitals in the Netherlands. Eligible are patients hospitalized for at least 48 h, without major cognitive impairment (Mini Mental State Examination score >=15), who have a life expectancy of more than three months, and without disablement in all six ADLs. The study will assess possible cognitive, behavioral, psychosocial, physical, and biological factors of HAD. Data will be collected through: 1] medical and demographical data; 2] personal interviews, which includes assessment of cognitive impairment, behavioral and psychosocial functioning, physical functioning, and health care utilization; 3] physical performance tests, which includes gait speed, hand grip strength, balance, bioelectrical impedance analysis (BIA), and an activity tracker (Fitbit Flex), and; 4] analyses of blood samples to assess inflammatory and metabolic markers. The primary endpoint is additional disabilities in ADLs three months post-hospital discharge compared to ADL function two weeks prior to hospital admission. Secondary outcomes are health care utilization, health-related quality of life (HRQoL), physical performance tests, and mortality. There will be at least five data collection points; within 48 h after admission (H1), at discharge (H3), and at one (P1; home visit), two (P2; by telephone) and three months (P3; home visit) post-discharge. If the patient is admitted for more than five days, additional measurements will be planned during hospitalization on Monday, Wednesday, and Friday (H2). DISCUSSION: The Hospital-ADL study will provide information on cognitive, behavioral, psychosocial, physical, and biological factors associated with HAD and will be collected during and following hospitalization. These data may inform new interventions to prevent or restore hospitalization-associated disability. PMID- 26945588 TI - Combining somatic mutations present in different in vivo affinity-matured antibodies isolated from immunized Lama glama yields ultra-potent antibody therapeutics. AB - Highly potent human antibodies are required to therapeutically neutralize cytokines such as interleukin-6 (IL-6) that is involved in many inflammatory diseases and malignancies. Although a number of mutagenesis approaches exist to perform antibody affinity maturation, these may cause antibody instability and production issues. Thus, a robust and easy antibody affinity maturation strategy to increase antibody potency remains highly desirable. By immunizing llama, cloning the 'immune' antibody repertoire and using phage display, we selected a diverse set of IL-6 antagonistic Fabs. Heavy chain shuffling was performed on the Fab with lowest off-rate, resulting in a panel of variants with even lower off rate. Structural analysis of the Fab:IL-6 complex suggests that the increased affinity was partly due to a serine to tyrosine switch in HCDR2. This translated into neutralizing capacity in an in vivo model of IL-6 induced SAA production. Finally, a novel Fab library was designed, encoding all variations found in the natural repertoire of VH genes identified after heavy chain shuffling. High stringency selections resulted in identification of a Fab with 250-fold increased potency when re-formatted into IgG1. Compared with a heavily engineered anti-IL-6 monoclonal antibody currently in clinical development, this IgG was at least equally potent, showing the engineering process to have had led to a highly potent anti-IL-6 antibody. PMID- 26945589 TI - Mechanical thrombectomy in pediatric acute ischemic stroke: Clinical outcomes and literature review. AB - There are limited data on outcomes of mechanical thrombectomy for pediatric stroke using modern devices. In this study, we report two cases of pediatric acute ischemic stroke treated with mechanical thrombectomy, both with good angiographic result (TICI 3) and clinical outcome (no neurological deficits at 90 days). In addition, we conducted a literature review of all previously reported cases describing the use of modern thrombectomy devices. Including our two cases, the aggregate rate of partial or complete vessel recanalization was 100% (22/22), and the aggregate rate of favorable clinical outcome was 91% (20/22). This preliminary evidence suggests that mechanical thrombectomy with modern devices may be a safe and effective treatment option in pediatric patients with acute ischemic stroke. PMID- 26945590 TI - Cyclic dipeptide cyclo(l-leucyl-l-prolyl) from marine Bacillus amyloliquefaciens mitigates biofilm formation and virulence in Listeria monocytogenes. AB - This study was intentionally focused on cyclo(l-leucyl-l-prolyl) (CLP), a cyclic dipeptide with myriad pharmaceutical significance, to explore its antivirulence efficacy against the predominant foodborne pathogen,Listeria monocytogenes(LM). Minimum inhibitory concentration (MIC) of CLP against LM ATCC 19111 was found to be 512 MUg mL(-1) CLP at sub-MICs (64 128, 256 MUg mL(-1)) demonstrated a profound non-bactericidal dose-dependent antibiofilm efficacy (on polystyrene and glass) against LM, which was further confirmed through confocal and scanning electron microscopic analysis (on stainless steel surface).In vitrobioassays divulged the phenomenal inhibitory efficacy of CLP towards various virulence traits of LM, specifically its overwhelming suppression of swimming and swarming motility. Data ofin vivoassay usingCaenorhabditis eleganssignified that the plausible mechanism of CLP could be by impeding the pathogen's initial adhesion and thereby attenuating the biofilm assemblage and its associated virulence. This was further confirmed by significant decrease in extracellular polymeric substance, autoaggregation, hydrophobicity index and extracellular DNA of the CLP treated LM cells. Collectively, this study unveils the antivirulence efficacy of CLP against the Gram-positive foodborne pathogen and the strainBacillus amyloliquefaciensaugurs well to be a promising probiotic in controlling infections associated with LM. PMID- 26945591 TI - An audit of expedited treatment for uncomplicated Chlamydia trachomatis index cases at the community pharmacy. AB - Expedited treatment of index patients testing positive for uncomplicated Chlamydia trachomatis via paper treatment vouchers that can be redeemed at a community pharmacy is feasible. PMID- 26945592 TI - Regular STI testing amongst men who have sex with men and use social media is suboptimal - a cross-sectional study. AB - Sexually transmitted infections (STIs) disproportionately affect men who have sex with men, with marked increases in most STIs in recent years. These are likely underpinned by coterminous increases in behavioural risks which have coincided with the development of Internet and geospatial sociosexual networking. Current guidelines advocate regular, annual sexually transmitted infection testing amongst sexually active men who have sex with men (MSM), as opposed to symptom driven testing. This paper explores sexually transmitted infection testing regularity amongst MSM who use social and sociosexual media. Data were collected from 2668 men in Scotland, Wales, Northern Ireland and the Republic of Ireland, recruited via social and gay sociosexual media. Only one-third of participants report regular (yearly or more frequent) STI testing, despite relatively high levels of male sex partners, condomless anal intercourse and high-risk unprotected anal intercourse. The following variables were associated with regular STI testing; being more 'out' (adjusted odds ratio = 1.79; confidence interval = 1.20-2.68), HIV-positive (adjusted odds ratio = 14.11; confidence interval = 7.03-28.32); reporting >=10 male sex partners (adjusted odds ratio = 2.15; confidence interval = 1.47-3.14) or regular HIV testing (adjusted odds ratio = 48.44; confidence interval = 28.27-83.01). Men reporting long-term sickness absence from work/carers (adjusted odds ratio = 0.03; confidence interval = 0.00-0.48) and men aged <=25 years (adjusted odds ratio = 0.36; 95% confidence interval = 0.19-0.69) were less likely to test regularly for STIs. As such, we identify a complex interplay of social, health and behavioural factors that each contribute to men's STI testing behaviours. In concert, these data suggest that the syndemics placing men at elevated risk may also mitigate against access to testing and prevention services. Moreover, successful reduction of STI transmission amongst MSM will necessitate a comprehensive range of approaches which address these multiple interrelated factors that underpin MSM's STI testing. PMID- 26945593 TI - Shigellosis in men who have sex with men: an overlooked opportunity to counsel with pre-exposure prophylaxis for HIV. AB - In the absence of other epidemiological exposures, shigellosis in men who have sex with men (MSM) suggests engagement in high-risk sexual encounters. Infection and diagnosis of shigellosis in MSM presents a potentially overlooked opportunity to discuss the availability of pre-exposure prophylaxis medications to prevent incident HIV infections. PMID- 26945594 TI - Thermal impacts on the growth, development and ontogeny of critical swimming speed in Atlantic herring larvae. AB - Increases in swimming ability have a profound influence on larval fish growth and survival by increasing foraging success, predator avoidance and the ability to favorably influence transport. Understanding how development and environmental factors combine to influence swimming performance in aquatic organisms is particularly important during the transition from viscous to inertial environments. We measured the growth, development and ontogenetic changes in critical swimming speed (Ucrit) in Atlantic herring (Clupea harengus) larvae reared at three temperatures (7, 11, 15 degrees C). Temperature had a significant effect on growth rates (from 0.21 at 7 degrees C to 0.34mm.d(-1) at 15 degrees C), and larval morphology-at-length (increased dry weight (DW), body height and developmental rate at warmer temperatures). Temperature-dependent differences in morphology influenced swimming performance (e.g. the exponential increase in Ucrit with increasing body size was faster at warmer temperatures). Larvae entered the transition to an inertial environment (Reynolds numbers >=300) at body lengths between 15 (15 degrees C) and 17mm (7 degrees C). Inter-individual differences in Ucrit were not related to nutritional condition (RNA.DNA(-1) or DNA.DW(-1)), but were negatively correlated to length-at-age, suggesting a trade off between growth rate and locomotor activity. The Ucrit data from this and previously published studies suggest that Atlantic herring pass through four activity phases: 1) yolk-sac (<0.6cm.s(-1)), 2) pre-flexion (0.6-3.0cm.s(-1), temperature effect changes with body size), 3) post-flexion (up to 6-8cm.s(-1), Q10~1.8-2.0), 4) juvenile-adult period (20-170cm.s(-1)). PMID- 26945595 TI - Thermal acclimation to cold alters myosin content and contractile properties of rainbow smelt, Osmerus mordax, red muscle. AB - Rainbow smelt (Osmerus mordax), a eurythermal fish, live in environments from 1.8 to 20 degrees C, with some populations facing substantial annual variation in environmental temperature. These different temperature regimes pose distinct challenges to locomotion by smelt. Steady swimming performance, red muscle function and muscle myosin content were examined to assess the prediction that cold acclimation by smelt will lead to improved steady swimming performance and that any performance shift will be associated with changes in red muscle function and in its myosin heavy chain composition. Cold acclimated (4 degrees C) smelt had a faster maximum steady swimming speed and swam with a higher tailbeat frequency than warm acclimated (10 degrees C) smelt when tested at the same temperature (10 degrees C). Muscle mechanics experiments demonstrated faster contractile properties in the cold acclimated fish when tested at 10 degrees C. The red muscle of cold acclimated smelt had a shorter twitch times, a shorter relaxation times and a higher maximum shortening velocity. In addition, red muscle from cold acclimated fish displayed reduced thermal sensitivity to cold, maintaining higher force levels at 4 degrees C compared to red muscle from warm acclimated fish. Immunohistochemistry suggests shifts in muscle myosin composition and a decrease in muscle cross-sectional area with cold acclimation. Dot blot analysis confirmed a shift in myosin content. Rainbow smelt do show a significant thermal acclimation response to cold. An examination of published values of maximum muscle shortening velocity in fishes suggests that smelt are particularly well suited to high levels of activity in very cold water. PMID- 26945596 TI - Identification of a heat shock protein 90 gene involved in resistance to temperature stress in two wing-morphs of Nilaparvata lugens (Stal). AB - The brown planthopper, Nilaparvata lugens, is one of the most destructive pests damaging rice in Asia and exhibits wing dimorphism, with brachypters possessing severely reduced wings and macropters bearing fully developed wings. Previous studies have shown that macropters are more heat resistant than brachypters. To understand the molecular mechanism underlying the differential thermotolerance abilities of these two morphs, a full-length Hsp gene, NlHsp90 was cloned from N. lugen. Our results showed that the relative expression levels of NlHsp90 in N. lugens females increased with the rise of temperature. Interestingly, NlHsp90 in macropters females could be induced at lower temperature (32 degrees C) than that in brachypters (34 degrees C), and the NlHsp90 mRNA levels in macropters were significantly higher than those in brachypters from 34 to 40 degrees C. In addition, the maximum expression levels of NlHsp90 were achieved much earlier in macropters, and NlHsp90 mRNA levels in macropters were significantly higher than those in brachypters from 1 to 6h of recovery after temperature stress. Furthermore, knockdown of NlHsp90 by dsRNA injection reduced survival in both morphs with a greater reduction in the macropters relative to that of the brachyters. These results indicated that NlHsp90 plays an important role for thermotolerance in N. lugens, and there is difference on induction between two morphs. PMID- 26945597 TI - Infrared thermography: A non-invasive window into thermal physiology. AB - Infrared thermography is a non-invasive technique that measures mid to long-wave infrared radiation emanating from all objects and converts this to temperature. As an imaging technique, the value of modern infrared thermography is its ability to produce a digitized image or high speed video rendering a thermal map of the scene in false colour. Since temperature is an important environmental parameter influencing animal physiology and metabolic heat production an energetically expensive process, measuring temperature and energy exchange in animals is critical to understanding physiology, especially under field conditions. As a non contact approach, infrared thermography provides a non-invasive complement to physiological data gathering. One caveat, however, is that only surface temperatures are measured, which guides much research to those thermal events occurring at the skin and insulating regions of the body. As an imaging technique, infrared thermal imaging is also subject to certain uncertainties that require physical modelling, which is typically done via built-in software approaches. Infrared thermal imaging has enabled different insights into the comparative physiology of phenomena ranging from thermogenesis, peripheral blood flow adjustments, evaporative cooling, and to respiratory physiology. In this review, I provide background and guidelines for the use of thermal imaging, primarily aimed at field physiologists and biologists interested in thermal biology. I also discuss some of the better known approaches and discoveries revealed from using thermal imaging with the objective of encouraging more quantitative assessment. PMID- 26945598 TI - Digital modeling technology for full dental crown tooth preparation. AB - A dental defect is one of the most common oral diseases, and it often requires a full crown restoration. In this clinical operation, the dentist must manually prepare the affected tooth for the full crown so that it has a convergence angle between 4 degrees and 10 degrees , no undercuts, and uniform and even shoulder widths and depths using a high speed diamond bur in the patient's mouth within one hour, which is a difficult task that requires visual-manual operation. The quality of the tooth preparation has an important effect on the success rate of the subsequent prosthodontic treatment. This study involved research into digital modeling technology for full dental crown tooth preparation. First, the margin line of the tooth preparation was designed using a semi-automatic interactive process. Second, the inserting direction was automatically computed. Then, the characteristic parameters and the constraints on the tooth preparation were defined for the model. Next, the shoulder and axial surface of the tooth preparation were formed using parametric modeling. Finally, the implicit surface of a radial basis function was used to construct the tooth preparation's occlusal surface. The experimental results verified that the method of digital modeling for full crown preparation proposed in this study can quickly and accurately implement personalized designs of various parameters, such as the shoulder width and the convergence angle; it provides a digital design tool for full crown preparation. PMID- 26945599 TI - In silico design of high-affinity ligands for the immobilization of inulinase. AB - Using computer modeling, virtual screening of high-affinity ligands for immobilization of inulinase - an enzyme that cleaves inulin and fructose containing polymers to fructose - has been performed. The inulinase molecule from Aspergillus ficuum (pdb: 3SC7) taken from the database of protein structures was used as a protein model and the target for flexible docking. The set of ligands studied included simple sugars (activators, inhibitors, products of enzymatic catalysis), as well as high-molecular weight compounds (polycation and polyanion exchange resins, glycoproteins, phenylalanine-proline peptide, polylactate, and caffeine). Based on the comparative analysis of the values of the total energy and the localization of ligand binding sites, we made several assumptions concerning the mechanisms of interaction of the suggested matrices for the immobilization of enzyme molecules and the structural features of such complexes. It was also assumed that the candidates for immobilization agents meeting the industrial requirements may be glycoproteins, for which we propose an additional incorporation of cysteine residues into their structure, aimed to create disulfide "anchors" to the surface. PMID- 26945600 TI - Formation of reentrant circuits in the mid-myocardial infarct border zone. AB - INTRODUCTION: In this study, the mechanisms for onset and maintenance of mid myocardial (intramural) reentrant circuits are considered, based upon anatomical structure. METHOD: A model of electrical activation wavefront curvature in the mid-myocardial postinfarction border zone is developed. Two arrhythmogenic structures are considered: 1. a constrained slab of viable tissue, and 2. a strand of surviving myocardial fibers with distal expansion. Equations are formulated to estimate activation coupling intervals, and ranges in taper and circuit dimensions, that will support functional conduction block during premature stimulation and reentrant ventricular tachycardia. RESULTS: For onset and maintenance of reentry, the arrhythmogenic regions forming both slab and strand circuits are in the range of 50-600um at their thinnest dimension. For constrained slabs, unidirectional block leading to reentry forms in the thin-to thick direction during premature stimulation, and functional block at lateral boundaries enable formation of a double-loop circuit. The activation wavefront proceeds around the impediment and then curves in the opposite direction through the slab, reentering the previously excited tissue. For strands, unidirectional block forms at a distal expansion in response to premature stimulation. The strand reentrant circuit is bounded by infarcted tissue causing anatomical block, and can be single-loop or coaxial. For all architectures, circuit dimensions ranging from 1.6*1.6mm to 3.5*3.5mm support functional block when premature stimulus coupling intervals are 117-150ms and ventricular tachycardia cycle lengths are 160-350ms. CONCLUSIONS: For slab and strand mid-myocardial arrhythmogenic structures, taper and circuit dimensions govern ranges in premature excitation coupling intervals and tachycardia cycle lengths necessary to support functional block. PMID- 26945601 TI - The clinical utility of CK-MB measurement in patients suspected of acute coronary syndrome. AB - BACKGROUND: This study aims to assess the clinical utility of CK-MB measurement in patients suspected of acute coronary syndrome (ACS). METHODS: All CK-MB and troponin T measurements performed <1h apart during the study period were obtained and analyzed for concordance. A total of 1214 cases with discordant biomarkers results were found. Retrospective review of electronic health records (EHRs) was performed to assess the clinical impact, if any, of the discordant biomarkers results. RESULTS: In 401 cases, CK-MB concentrations were increased whereas troponin T concentrations were negative at <0.01 ng/ml. In this group, clinical interpretations included, rhabdomyolysis, demand ischemia, and drug intoxication. No additional investigations for ACS were conducted in this group. Among the remaining 813 cases, troponin T concentrations were increased in the presence of a normal CK-MB result. In this group, the discordant normal CK-MB lowered suspicion for ACS in only 22 cases (2.7%). Most common interpretations for isolated positive troponin were demand ischemia and impaired renal function. In most cases, discordant CK-MB results were not considered a significant finding. CONCLUSIONS: In the setting of suspected ACS, CK-MB has limited clinical impact when contemporary troponin assay results are available. PMID- 26945602 TI - Surgery accelerates the development of endometriosis in mice. AB - BACKGROUND: Surgery is currently the mainstay treatment for solid tumors and many benign diseases, including endometriosis, and women tend to receive substantially more surgeries than men mainly because of gynecological and cosmetic surgeries. Despite its cosmetic, therapeutic, or even life-saving benefits, surgery is reported to increase the cancer risk and promotes cancer metastasis. Surgery activates adrenergic signaling, which in turn suppresses cell-mediated immunity and promotes angiogenesis and metastasis. Because immunity, angiogenesis, and invasiveness are all involved in the pathophysiology of endometriosis, it is unclear whether surgery may accelerate the development of endometriosis. OBJECTIVE: The objective of the study was to test the hypothesis that surgery activates adrenergic signaling, increases angiogenesis, and accelerates the growth of endometriotic lesions. STUDY DESIGN: This was a prospective, randomized experimentation. The first experiment used 42 female adult Balb/C mice, and the second used 90 female adult Balb/C mice. In experiment 1, 3 days after the induction of endometriosis, mice were randomly divided into 3 groups of approximately equal sizes, control, laparotomy, and mastectomy. In experiment 2, propranolol infusion via Alzet pumps was used to forestall the effect of sympathetic nervous system activation by surgery. In both experiments, mice were evaluated 2 weeks after surgery. Lesion size, hotplate latency, and immunohistochemistry analysis of vascular endothelial growth factor, CD31 positive microvessels, proliferating cell nuclear antigen, phosphorylated cyclic adenosine monophosphate-responsive element-binding protein, beta2-adrenergic receptor (ADRB)-2, ADRB1, ADRB3, ADRA1, and ADRA2 in ectopic implants. RESULTS: Both mastectomy and laparotomy increased lesion weight and exacerbated hyperalgesia, increased microvessel density and elevated the immunoreactivity against ADRB2, phosphorylated cyclic adenosine monophosphate-responsive element binding protein, vascular endothelial growth factor, and proliferating cell nuclear antigen but not ADRB1, ADRB3, ADRA1, and ADRA2, suggesting activated adrenergic signaling, increased angiogenesis, and accelerated growth of endometriotic lesions. beta-Blockade completely abrogated the facilitory effect of surgery, further underscoring the critical role of beta-adrenergic signaling in mediating the effect of surgery. CONCLUSION: Surgery activates adrenergic signaling, increases angiogenesis, and accelerates the growth of endometriotic lesions in the mouse, but such a facilitory effect of surgery can be completely abrogated by beta-blockade. Whether surgery can promote the development of endometriosis in humans warrants further investigation. PMID- 26945603 TI - Males are from Mars, and females are from Venus: sex-specific fetal brain gene expression signatures in a mouse model of maternal diet-induced obesity. AB - BACKGROUND: Maternal obesity is associated with adverse neurodevelopmental outcomes in children, including autism spectrum disorders, developmental delay, and attention-deficit hyperactivity disorder. The underlying mechanisms remain unclear. We previously identified second-trimester amniotic fluid and term cord blood gene expression patterns suggesting dysregulated brain development in fetuses of obese compared with lean women. OBJECTIVE: We sought to investigate the biological significance of these findings in a mouse model of maternal diet induced obesity. We evaluated sex-specific differences in fetal growth, brain gene expression signatures, and associated pathways. STUDY DESIGN: Female C57BL/6J mice were fed a 60% high-fat diet or 10% fat control diet for 12-14 weeks prior to mating. During pregnancy, obese dams continued on the high-fat diet or transitioned to the control diet. Lean dams stayed on the control diet. On embryonic day 17.5, embryos were weighed and fetal brains were snap frozen. RNA was extracted from male and female forebrains (10 per diet group per sex) and hybridized to whole-genome expression arrays. Significantly differentially expressed genes were identified using a Welch's t test with the Benjamini Hochberg correction. Functional analyses were performed using ingenuity pathways analysis and gene set enrichment analysis. RESULTS: Embryos of dams on the high fat diet were significantly smaller than controls, with males more severely affected than females (P = .01). Maternal obesity and maternal obesity with dietary change in pregnancy resulted in significantly more dysregulated genes in male vs female fetal brains (386 vs 66, P < .001). Maternal obesity with and without dietary change in pregnancy was associated with unique brain gene expression signatures for each sex, with an overlap of only 1 gene. Changing obese dams to a control diet in pregnancy resulted in more differentially expressed genes in the fetal brain than maternal obesity alone. Functional analyses identified common dysregulated pathways in both sexes, but maternal obesity and maternal dietary change affected different aspects of brain development in males compared with females. CONCLUSION: Maternal obesity is associated with sex-specific differences in fetal size and fetal brain gene expression signatures. Male fetal growth and brain gene expression may be more sensitive to environmental influences during pregnancy. Maternal diet during pregnancy has a significant impact on the embryonic brain transcriptome. It is important to consider both fetal sex and maternal diet when evaluating the effects of maternal obesity on fetal neurodevelopment. PMID- 26945604 TI - Effects of lactation on postpartum blood pressure among women with gestational hypertension and preeclampsia. AB - BACKGROUND: Women with a history of hypertensive disorders of pregnancy are at an increased risk of hypertension and cardiovascular disease in later life. Lactation has been associated with a reduced risk of maternal hypertension, both in the postpartum period and later life. However, little is known about whether lactation is also cardioprotective in women with hypertensive disorders of pregnancy such as preeclampsia or gestational hypertension. OBJECTIVE: This study aimed to characterize the relationship between lactation and postpartum blood pressure among women with preeclampsia and gestational hypertension. STUDY DESIGN: Data were obtained from women who participated in the Prenatal Exposures and Preeclampsia Prevention study (n = 379; 66% African American; 85% overweight or obese). Women enrolled during pregnancy and attended a postpartum visit (on average, 9.1 months after delivery) during which data on lactation duration and blood pressure were collected. The significance of the associations between postpartum blood pressure and lactation among women who remained normotensive during pregnancy, developed gestational hypertension, or developed preeclampsia were assessed with an analysis of variance. Linear regression models were used to adjust for maternal age, race, education, prepregnancy weight, and time since delivery. RESULTS: Gestational hypertension affected 42 subjects (11%) and preeclampsia affected 33 (9%). Lactation was reported by 217 (57%) with 78 (21%) reporting >= 6 months of lactation. Women who lactated were somewhat older, more educated, and had higher socioeconomic status. Among women who had gestational hypertension, lactation was associated with lower systolic blood pressure (P = .02) and diastolic blood pressure (P = .02). This association persisted after adjustment for age, race, education, prepregnancy weight, and time since delivery. However, for women who had preeclampsia and women who remained normotensive during pregnancy, lactation was not associated with postpartum blood pressure in either bivariate or multivariate analyses. CONCLUSION: This study found that lactation is associated with lower postpartum blood pressure among overweight women who develop gestational hypertension but not among women who develop preeclampsia. Future studies are needed to explore the association of lactation and blood pressure in later life for women with hypertensive disorders of pregnancy. PMID- 26945605 TI - Surgical outcomes for low-volume vs high-volume surgeons in gynecology surgery: a systematic review and meta-analysis. AB - OBJECTIVE: The aim of this study was to determine the impact of gynecological surgeon volumes on patient outcomes. DATA SOURCES: Eligible studies were selected through an electronic literature search from database inception up until September 2015 and references in published studies. Search terms included surgical volume, surgeon volume, low-volume or high-volume, and gynecology or hysterectomy or sling or pelvic floor repair or continence procedure. STUDY ELIGIBILITY: The literature search was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We defined a low-volume surgeon (LVS) as one performing the procedure once a month or less, and studies were excluded if their definition of LVS was > +/-33% of our definition. Primary outcomes were total complications, intraoperative complications, and postoperative complications. STUDY APPRAISAL AND SYNTHESIS METHODS: All outcome data for individual studies were entered into systematic review software. When 2 or more studies evaluated a designated outcome, a meta analysis of the entered data was undertaken as per the Cochrane database methodology. Data analysis was entered into a software product, which generated a summary of findings table that included structured and qualified grading (very low to high) of the quality for the evidence of the individual outcomes and provided a measure of effect. RESULTS: Fourteen peer-reviewed studies with 741,760 patients were included in the systematic review. For gynecology the LVS group had an increased rate of total complications (odds ratio [OR], 1.3, 95% confidence interval [CI], 1.2-1.5), intraoperative complications (OR, 1.6, 95% CI, 1.2-2.1), and postoperative complications (OR, 1.4 95% CI, 1.3-1.4). In gynecological oncology, the LVS group had higher mortality (OR, 1.9, 95% CI, 1.3 2.6). In the urogynecology group, a single study reported that the LVS group had a higher rate of any complication (risk ratio [RR], 1.4, 95% CI, -1.2-1.6). Another single study found that LVS had higher rates of reoperation for mesh complications after midurethral sling procedures (RR, 1.4, 95% CI, 1.2-1.5). The evidence is of moderate to very low quality. CONCLUSION: Gynecologists performing procedures approximately once a month or less were found to have higher rates of adverse outcomes in gynecology, gynecological oncology, and urogynecology, with higher mortality in gynecological oncology. PMID- 26945607 TI - Reply. PMID- 26945606 TI - Serum vitamin D status and bacterial vaginosis prevalence and incidence in Zimbabwean women. AB - BACKGROUND: Bacterial vaginosis, a highly prevalent vaginal condition, is correlated with many adverse reproductive outcomes. In some studies, low vitamin D status (measured as serum 25-hydroxyvitamin D, 25[OH]D) has been associated with increased prevalence of bacterial vaginosis. OBJECTIVES: We examined the cross-sectional association between vitamin D status and prevalence of bacterial vaginosis, separately for pregnant and nonpregnant women. Using prospectively collected data, we also characterized the effect of time-varying vitamin D status on incident bacterial vaginosis. STUDY DESIGN: We quantified 25(OH)D in stored sera collected quarterly from 571 Zimbabwean women participating in the Hormonal Contraception and Risk of HIV Acquisition Study. The analysis was restricted to women not using hormonal contraception. We characterized associations between vitamin D insufficiency (defined as 25[OH]D <= 30 ng/mL vs > 30 ng/mL) and prevalence of bacterial vaginosis among nonpregnant women at the enrollment visit and among pregnant women at the first follow-up visit that pregnancy was detected. Among women who were negative for bacterial vaginosis at enrollment (n = 380), we also assessed the effect of time-varying vitamin D status on incident bacterial vaginosis. We used the Liaison 25(OH)D total assay to measure 25(OH)D. Bacterial vaginosis was diagnosed via Nugent score. RESULTS: At enrollment, the prevalence of bacterial vaginosis was 31% and overall median 25(OH)D was 29.80 ng/mL (interquartile range, 24.70-34.30 ng/mL): 29.75 ng/mL (interquartile range, 25.15-33.95 ng/mL) among women with bacterial vaginosis, and 29.90 ng/mL (interquartile range, 24.70-34.50 ng/mL) among women without bacterial vaginosis. Among pregnant women, the prevalence of bacterial vaginosis was 27% and overall median 25(OH)D was 29.90 ng/mL (interquartile range, 24.10-34.00 ng/mL): 30.80 ng/mL (interquartile range, 26.10-36.90 ng/mL) among women with bacterial vaginosis, and 29.10 ng/mL (interquartile range, 23.80-33.45 ng/mL) among women without bacterial vaginosis. Vitamin D levels <= 30 ng/mL were not associated with a prevalence of bacterial vaginosis in nonpregnant women (adjusted prevalence ratio, 1.04; 95% confidence interval, 0.81-1.34) or pregnant women (adjusted prevalence ratio, 0.88, 95% confidence interval, 0.51-1.54). Vitamin D levels <= 30 ng/mL were similarly not associated with incident bacterial vaginosis (adjusted hazard ratio, 0.98, 95% confidence interval, 0.73-1.31). Our findings were robust to alternative specifications of vitamin D status including using a cut point for vitamin D deficiency of < 20 ng/mL vs >= 20 ng/mL and modeling 25(OH)D as a continuous variable. CONCLUSION: Among reproductive-age Zimbabwean women, insufficient vitamin D was not associated with increased bacterial vaginosis prevalence or incidence. Given established associations between bacterial vaginosis and poor reproductive outcomes, identification of factors leading to high bacterial vaginosis prevalence is urgently needed. PMID- 26945608 TI - Multimodal nociceptive mechanisms underlying chronic pelvic pain. PMID- 26945609 TI - Validation of infertility treatment and assisted reproductive technology use on the birth certificate in eight states. PMID- 26945610 TI - Long-term nonsurgical control with ulipristal acetate of multiple uterine fibroids, enabling pregnancy. PMID- 26945611 TI - A systematic review of the treatment for abdominal cutaneous nerve entrapment syndrome. AB - BACKGROUND: Abdominal cutaneous nerve entrapment syndrome (ACNES) is a frequently overlooked cause of chronic abdominal pain. We aim to outline the current available literature concerning the treatment of patients diagnosed with ACNES. DATA SOURCES: A systematic search in PubMed, EMBASE, CINAHL, and Cochrane databases was performed. Seven studies were included; describing trigger point injection (TPI) or anterior neurectomy as stand-alone procedure, TPI followed by anterior neurectomy as stepwise regimen, and nerve stimulation and phenolization. After TPI, 86% of the patients showed successful response, 76% at long-term follow-up. Two other studies report successful treatment in 50% of patients. In the included trial using anterior neurectomy, 73% vs 18% of the patients demonstrate a successful pain response in the neurectomy and sham group, respectively. Two cohort studies showed that 69% and 61% of the neurectomy group reported to be satisfied at 18 months and 32 months follow-up, respectively. CONCLUSIONS: There is significant pain relief after injections and anterior neurectomy. Awareness of the diagnosis is important. The validity of currently used diagnostic criteria needs to be evaluated in additional studies. PMID- 26945613 TI - Fungicide prochloraz induces oxidative stress and DNA damage in vitro. AB - Prochloraz is widely used in horticulture and agriculture, e.g. as a post-harvest anti-mold treatment. Prochloraz is a known endocrine disruptor causing developmental toxicity with multiple mechanisms of action. However, data are scarce concerning other toxic effects. Since oxidative stress response, with formation of reactive oxygen species (ROS), is a common mechanism for different toxic endpoints, e.g. genotoxicity, carcinogenicity and teratogenicity, the aim of this study was to investigate if prochloraz can induce oxidative stress and/or DNA damage in human cells. A cell culture based in vitro model was used to study oxidative stress response by prochloraz, as measured by the activity of the nuclear factor erythroid 2-related factor 2 (Nrf2), a key molecule in oxidative defense mechanisms. It was observed that prochloraz induced oxidative stress in cultured human adrenocortical H295R and hepatoma HepG2 cells at non-toxic concentrations. Further, we used Comet assay to investigate the DNA damaging potential of prochloraz, and found that non-toxic concentrations of prochloraz induced DNA damage in HepG2 cells. These are novel findings, contradicting previous studies in the field of prochloraz and genotoxicity. This study reports a new mechanism by which prochloraz may exert toxicity. Our findings suggest that prochloraz might have genotoxic properties. PMID- 26945612 TI - Orexin/hypocretin receptor 1 signaling mediates Pavlovian cue-food conditioning and extinction. AB - Learned food cues can drive feeding in the absence of hunger, and orexin/hypocretin signaling is necessary for this type of overeating. The current study examined whether orexin also mediates cue-food learning during the acquisition and extinction of these associations. In Experiment 1, rats underwent two sessions of Pavlovian appetitive conditioning, consisting of tone-food presentations. Prior to each session, rats received either the orexin 1 receptor antagonist SB-334867 (SB) or vehicle systemically. SB treatment did not affect conditioned responses during the first conditioning session, measured as food cup behavior during the tone and latency to approach the food cup after the tone onset, compared to the vehicle group. During the second conditioning session, SB treatment attenuated learning. All groups that received SB, prior to either the first or second conditioning session, displayed significantly less food cup behavior and had longer latencies to approach the food cup after tone onset compared to the vehicle group. These findings suggest orexin signaling at the 1 receptor mediates the consolidation and recall of cue-food acquisition. In Experiment 2, another group of rats underwent tone-food conditioning sessions (drug free), followed by two extinction sessions under either SB or vehicle treatment. Similar to Experiment 1, SB did not affect conditioned responses during the first session. During the second extinction session, the group that received SB prior to the first extinction session, but vehicle prior to the second, expressed conditioned food cup responses longer after tone offset, when the pellets were previously delivered during conditioning, and maintained shorter latencies to approach the food cup compared to the other groups. The persistence of these conditioned behaviors indicates impairment in extinction consolidation due to SB treatment during the first extinction session. Together, these results demonstrate an important role for orexin signaling during Pavlovian appetitive conditioning and extinction. PMID- 26945614 TI - Citizen scientist lepidopterists exposed to potential carcinogens. AB - Lepidopterists use substantial volumes of solvents, such as chloroform, 1,1,2,2 tetrachloroethane and xylene, in their traps when collecting faunistic and phenological data. A majority of them are citizen scientists and thus in part not identified by occupational healthcare as being at risk due to solvent handling. We surveyed the extent of solvent use, the frequency and extent of potential exposure and the safety precautions taken in trapping and catch handling by Finnish lepidopterists. Chloroform and 1,1,2,2-tetrachloroethane were the most frequently used anaesthetics. Potential for exposure prevailed during trap maintenance and exploration and catch sorting. Adequate protection against vapours or spills was worn by 17% during trap exploration. Subjects completed a median of 100 trap explorations per season. Dermal or mucosal spills were recorded at a median rate of one spill per ten (chloroform) to 20 (1,1,2,2 tetrachloroethane and xylene) trap explorations. Median annual cumulative durations of 8 and 20 h of exposure to chloroform and 1,1,2,2-tetrachloroethane at levels above odour detection threshold were reported. Subjective adverse findings possibly related solvents had been noticed by 24 (9.8%) lepidopterists. All the events had been mild to moderate. No factor predicting unsafe procedures or adverse reactions was recorded despite thorough statistical testing. PMID- 26945616 TI - Amitriptyline and carbamazepine utilize voltage-gated ion channel suppression to impair excitability of sensory dorsal horn neurons in thin tissue slice: An in vitro study. AB - Amitriptyline, carbamazepine and gabapentin are often used for the treatment of neuropathic pain. However, their analgesic action on central sensory neurons is still not fully understood. Moreover, the expression pattern of their target ion channels is poorly elucidated in the dorsal horn of the spinal cord. Thus, we performed patch-clamp investigations in visualized neurons of lamina I-III of the spinal cord. The expression of the different voltage-gated ion channels, as the targets of these drugs, was detected by RT-PCR and immunohistochemistry. Neurons of the lamina I-III express the TTX-sensitive voltage-gated Na(+) as well as voltage-gated K(+) subunits assembling the fast inactivating (A-type) currents and the delayed rectifier K(+) currents. Our pharmacological studies show that tonically-firing, adapting-firing and single spike neurons responded dose dependently to amitriptyline and carbamazepine. The ion channel inhibition consecutively reduced the firing rate of tonically-firing and adapting-firing neurons. This study provides evidence for the distribution of voltage-gated Na(+) and K(+) subunits in lamina I-III of the spinal cord and for the action of drugs used for the treatment of neuropathic pain. Our work confirms that modulation of voltage-gated ion channels in the central nervous system contributes to the antinociceptive effects of these drugs. PMID- 26945617 TI - Role of the vestibular nuclear complex in facilitating the jaw-opening reflex following stimulation of the red nucleus. AB - According to our previous studies, stimulation of the red nucleus (RN) facilitates the low-threshold afferent-evoked jaw-opening reflex (L-JOR). It has been reported that the RN projects to the superior (SVN), lateral (LVN) and inferior vestibular (IVN) nuclei. The SVN and the LVN have reciprocal intrinsic connections with the medial vestibular nucleus (MVN). Our previous study demonstrated that stimulation of the vestibular nuclear complex (VN) modulates the L-JOR. These facts suggest that RN-induced facilitation of the L-JOR is mediated via the VN. In the present work we investigated whether electrically induced lesions of the VN, or microinjection of muscimol into the VN, affects RN induced facilitation of the L-JOR. The L-JOR was evoked by electrical stimulation of the inferior alveolar nerve. The stimulus intensity was 1.2 times the evocation threshold. Lesions of the MVN or the LVN or the SVN, and the muscimol injection into the MVN or the LVN or the SVN, reduced the RN-induced facilitation of the L-JOR. Conversely, lesions of the IVN, and the muscimol injection into the IVN, increased the RN-induced facilitation of the L-JOR. These results suggest that the RN-induced facilitation of the L-JOR is mediated by a relay in the VN. PMID- 26945618 TI - Homeostatic changes in neuronal network oscillations in response to continuous hypoperfusion in the mouse forebrain. AB - Neuronal activity is highly sensitive to changes in oxygen tension. In this study, we examined the impact of hypoxic/ischemic conditions on neuronal ensemble activity patterns in the mouse brain using in vivo extracellular electrophysiological recordings from up to 8 sites in the thalamus, dorsal hippocampus, and neocortex, while cerebral hypoperfusion was induced by unilateral carotid artery occlusion. After a few minutes, the occlusion triggered a rapid change in the power of the local field oscillations. In the hippocampus, but not in the neocortex, the absolute power changes at all frequency ranges (relative to the baseline) became less pronounced with time, and no significant changes were observed 30min after the occlusion-induced hypoperfusion. We also tested whether continuous hypoperfusion induced by the occlusion for up to 1 week alters neuronal activity. In the hippocampus and the thalamus, the chronic occlusion did not lead to a reduction in the power of the local field oscillations. These results indicate that certain neuronal populations have the ability to maintain internal neurophysiological homeostasis against continuous hypoperfusion. PMID- 26945615 TI - Osteophyte formation and matrix mineralization in a TMJ osteoarthritis mouse model are associated with ectopic hedgehog signaling. AB - The temporomandibular joint (TMJ) is a diarthrodial joint that relies on lubricants for frictionless movement and long-term function. It remains unclear what temporal and causal relationships may exist between compromised lubrication and onset and progression of TMJ disease. Here we report that Proteoglycan 4 (Prg4)-null TMJs exhibit irreversible osteoarthritis-like changes over time and are linked to formation of ectopic mineralized tissues and osteophytes in articular disc, mandibular condyle and glenoid fossa. In the presumptive layer of mutant glenoid fossa's articulating surface, numerous chondrogenic cells and/or chondrocytes emerged ectopically within the type I collagen-expressing cell population, underwent endochondral bone formation accompanied by enhanced Ihh expression, became entrapped into temporal bone mineralized matrix, and thereby elicited excessive chondroid bone formation. As the osteophytes grew, the roof of the glenoid fossa/eminence became significantly thicker and flatter, resulting in loss of its characteristic concave shape for accommodation of condyle and disc. Concurrently, the condyles became flatter and larger and exhibited ectopic bone along their neck, likely supporting the enlarged condylar heads. Articular discs lost their concave configuration, and ectopic cartilage developed and articulated with osteophytes. In glenoid fossa cells in culture, hedgehog signaling stimulated chondrocyte maturation and mineralization including alkaline phosphatase, while treatment with hedgehog inhibitor HhAntag prevented such maturation process. In sum, our data indicate that Prg4 is needed for TMJ integrity and long-term postnatal function. In its absence, progenitor cells near presumptive articular layer and disc undergo ectopic chondrogenesis and generate ectopic cartilage, possibly driven by aberrant activation of Hh signaling. The data suggest also that the Prg4-null mice represent a useful model to study TMJ osteoarthritis-like degeneration and clarify its pathogenesis. PMID- 26945619 TI - Using silicone wristbands to evaluate preschool children's exposure to flame retardants. AB - Silicone wristbands can be used as passive sampling tools for measuring personal environmental exposure to organic compounds. Due to the lightweight and simple design, the wristband may be a useful technique for measuring children's exposure. In this study, we tested the stability of flame retardant compounds in silicone wristbands and developed an analytical approach for measuring 41 flame retardants in the silicone wristband in order to evaluate exposure to these compounds in preschool-aged children. To evaluate the robustness of using wristbands to measure flame retardants, we evaluated the stability of 3 polybrominated diphenyl ethers (BDEs), and 2 organophosphate flame retardants (OPFRs) in wristbands over 84 days and did not find any evidence of significant loss over time at either 4 or -20 degrees C (p>0.16). We recruited a cohort of 92 preschool aged children in Oregon to wear the wristband for 7 days in order to characterize children's acceptance of the technology, and to characterize their exposure to flame retardants. Seventy-seven parents returned the wristbands for analysis of 35 BDEs, 4 OPFRs, and 2 other brominated flame retardants although 5 were excluded from the exposure assessment due to protocol deviations (n=72). A total of 20 compounds were detected above the limit of quantitation, and 11 compounds including 4 OPFRs and 7 BDEs were detected in over 60% of the samples. Children's gender, age, race, recruitment site, and family context were not significantly associated with returning wristbands or compliance with protocols. Comparisons between flame retardant data and socio-demographic information revealed significant differences in total exposures to both SigmaBDEs and SigmaOPFRs based on age of house, vacuuming frequency, and family context. These results demonstrate that preschool children in Oregon are exposed to BDEs that are no longer being produced in the United States and to OPFRs that have been used as an alternative to polybrominated compounds. Silicone wristbands were well tolerated by young children and were useful for characterizing personal exposure to flame retardants that were not bound to particulate matter. PMID- 26945620 TI - Exposure to air pollution and cognitive functioning across the life course--A systematic literature review. AB - OBJECTIVES: Air pollution is associated with increased risk of respiratory, cardiovascular and cerebrovascular disease, but its association with cognitive functioning and impairment is unclear. The aim of this systematic review was to examine whether a relationship exists between these variables across the life course. METHODS: We searched Web of Knowledge, Pubmed, SciVerse Scopus, CINAHL, PsychInfo and Science Direct up to October 2015 to identify studies that investigated the association between air pollution and performance on neurocognitive tests. RESULTS: Variations in exposure assessment and outcome measures make meta-analysis impossible. Thirty one studies published between 2006 and 2015, from the Americas (n=15), Asia (n=5) and Europe (n=11), met the criteria for inclusion. Many showed weak but quantified relationships between various air pollutants and cognitive function. Pollution exposure in utero has been associated with increased risk of neuro-developmental delay. Exposure in childhood has been inversely associated with neuro-developmental outcomes in younger children and with academic achievement and neurocognitive performance in older children. In older adults, air pollution has been associated with accelerated cognitive decline. CONCLUSIONS: The evidence to date is coherent in that exposure to a range of largely traffic-related pollutants has been associated with quantifiable impairment of brain development in the young and cognitive decline in the elderly. There is insufficient evidence at present to comment on consistency, in view of the different indices of pollution and end points measured, the limited number of studies, and the probability at this stage of publication bias. However, plausible toxicological mechanisms have been demonstrated and the evidence as a whole suggests that vehicular pollution, at least, contributes to cognitive impairment, adding to pressure on governments and individuals to continue to reduce air pollution. PMID- 26945621 TI - Multiple germline functional VL genes contribute to the IgL repertoire in ducks. AB - In the immunoglobulin light chain gene loci of nearly all bird species examined to date, there is only a single functional variable gene segment that can recombine with joining gene segments. Thus, Ig light chain diversity relies on gene conversion using pseudogenes as sequence donors to modify the single rearranged variable gene. In the present study, we have sequenced a bacterial artificial chromosome (BAC) clone containing the entire duck Iglambda light chain gene locus. Although only a single pair of Jlambda and Clambda was found, 88 Vlambda gene segments were identified upstream of the Jlambda and Clambda segments. Among the identified Vlambda gene segments, 79 appear to be pseudogenes, the remaining 9 are structurally intact and all are able to functionally rearrange with the Jlambda. Phylogenetic analyses suggest that the 9 functional variable genes may have been derived from a single gene through duplication events. Although these multiple functional variable gene segments can be subject to VJ recombination, both gene conversion and somatic hypermutation are also actively involved in the generation of diversity in duck Iglambda light chains. These data provide significant insight into understanding the duck Ig system. PMID- 26945622 TI - Long-lived effects of administering beta-glucans: Indications for trained immunity in fish. AB - Over the past decades, it has become evident that immune-modulation of fish with beta-glucans, using injection, dietary or even immersion routes of administration, has stimulating but presumed short-lived effects on both intestinal and systemic immunity and can increase protection against a subsequent pathogenic challenge. Although the exact effects can be variable depending on, among others, fish species and administration route, the immune-stimulating effects of beta-glucans on the immune system of fish appear to be universal. This review provides a condensed update of the most recent literature describing the effects of beta-glucans on the teleost fish immune system. We shortly discuss possible mechanisms influencing immune-stimulation by beta-glucans, including microbial composition of the gut, receptor recognition and downstream signalling. Of interest, in mammalian monocytes, beta-glucans are potent inducers of trained immunity. First, we screened the literature for indications of this phenomenon in fish. Criteria that we applied include indications for at least one out of three features considered characteristic of trained immunity; (i) providing protection against a secondary infection in a T- and B-lymphocyte independent manner, (ii) conferring increased resistance upon re-infection and, (iii) relying on key roles for innate immune cell types such as natural killer cells and macrophages. We conclude that several indications exist that support the notion that the innate immune system of teleost fish can be trained. Second, we screened the literature for indications of long-lived effects on innate immunity of fish after administering beta-glucans, a criterion which could help to identify key roles for macrophages on resistance to infection. We discuss whether beta-glucans, as well-known immune-stimulants, are able to train the immune system of fish and argue in favour of further studies designed to specifically investigate this phenomenon in fish. PMID- 26945623 TI - Shrimp miRNAs regulate innate immune response against white spot syndrome virus infection. AB - MicroRNAs are short noncoding RNAs of RNA interference pathways that regulate gene expression through partial complementary base-pairing to target mRNAs. In this study, miRNAs that are expressed in white spot syndrome virus (WSSV) infected Penaeus monodon, were identified using next generation sequencing. Forty six miRNA homologs were identified from WSSV-infected shrimp hemocyte. Stem-loop real-time RT-PCR analysis showed that 11 out of 16 selected miRNAs were differentially expressed upon WSSV infection. Of those, pmo-miR-315 and pmo-miR 750 were highly responsive miRNAs. miRNA target prediction revealed that the miRNAs were targeted at 5'UTR, ORF, and 3'UTR of several immune-related genes such as genes encoding antimicrobial peptides, signaling transduction proteins, heat shock proteins, oxidative stress proteins, proteinases or proteinase inhibitors, proteins in blood clotting system, apoptosis-related proteins, proteins in prophenoloxidase system, pattern recognition proteins and other immune molecules. The highly conserved miRNA homolog, pmo-bantam, was characterized for its function in shrimp. The pmo-bantam was predicted to target the 3'UTR of Kunitz-type serine protease inhibitor (KuSPI). Binding of pmo-bantam to the target sequence of KuSPI gene was analyzed by luciferase reporter assay. Correlation of pmo-bantam and KuSPI expression was observed in lymphoid organ of WSSV-infected shrimp. These results implied that miRNAs might play roles as immune gene regulators in shrimp antiviral response. PMID- 26945624 TI - The emerging role of galectins in cardiovascular disease. AB - Galectins are an ancient family of beta-galactoside-specific lectins and consist of 15 different types, each with a specific function. They play a role in the immune system, inflammation, wound healing and carcinogenesis. In particular the role of galectin in cancer is widely studied. Lately, the role of galectins in the development of cardiovascular disease has gained attention. Worldwide cardiovascular disease is still the leading cause of death. In ischemic heart disease, atherosclerosis limits adequate blood flow. Angiogenesis and arteriogenesis are highly important mechanisms relieving ischemia by restoring perfusion to the post-stenotic myocardial area. Galectins act ambiguous, both relieving ischemia and accelerating atherosclerosis. Atherosclerosis can ultimately lead to myocardial infarction or ischemic stroke, which are both associated with galectins. There is also a role for galectins in the development of myocarditis by their influence on inflammatory processes. Moreover, galectin acts as a biomarker for the severity of myocardial ischemia and heart failure. This review summarizes the association between galectins and the development of multiple cardiovascular diseases such as myocarditis, ischemic stroke, myocardial infarction, heart failure and atrial fibrillation. Furthermore it focuses on the association between galectin and more general mechanisms such as angiogenesis, arteriogenesis and atherosclerosis. PMID- 26945626 TI - Synonymous codon usage pattern in glycoprotein gene of rabies virus. AB - Rabies virus (RABV) is the causative agent of a fatal nervous system ailment. The disease is zoonotic and prevalent in many developing countries. The glycoprotein (G) of RABV is the major antigenic determinant of the virus and plays a pivotal role in its neurovirulence. Various aspects of 'G' protein biology have been explored, but the factors affecting the nucleotide choice and synonymous codon usage have never been reported. In the present study, we have analyzed the relative synonymous codon usage and effective number of codons (Nc) using 132 'G' protein genes of RABV. Corresponding analysis was used to calculate major trends in codon usage. The correlation between base composition and codon usage as well as the plot between Nc and GC3 suggest that mutational pressure is the major factor that influences the codon usage in the G gene of RABV. In addition, factors like aromaticity, aliphatic index and hydropathy have shown slight correlation suggesting that natural selection also contributes to the codon usage variations of the 'G' gene. In conclusion, codon usage bias in 'G' gene of RABV is mainly by mutational pressure and natural selection. PMID- 26945627 TI - Transgenic medaka that overexpress growth hormone have a skin color that does not indicate the activation or inhibition of somatolactin-alpha signal. AB - Teleosts have two paralogous growth-hormone receptors (GHRs). In vitro studies demonstrated that both receptors bind to and transmit the signal of the growth hormone (GH). However, one of the GHRs (GHR1) was shown to bind more strongly to somatolactin-alpha (SLalpha), a fish-specific peptide hormone that is closely related to GH, and is, therefore, termed somatolactin receptor (SLR). In this study, we questioned whether the dual binding of GHR1/SLR causes a crosstalk (reciprocal activation or inhibition) between GH and SLalpha signals in vivo. For this purpose, we newly established a transgenic medaka that overexpresses GH (Actb-GH:GFP) and assessed its phenotype. The body weight of these transgenic medaka is about twice that of wild-type fish, showing that functional GH was successfully overexpressed in Actb-GH:GFP fish. The transgenic medaka, especially female fish, showed severe infertility, which was a common side effect in GH transgenesis. The skin color, which reflects the effects of SLalpha most conspicuously in medaka, was similar to that of neither the SLalpha overexpressing nor the SLalpha-deficient medaka, indicating that GH overexpression does not enhance or suppress the SLalpha signal. We also verified that a transgenic medaka that overexpressed SLalpha grew and reproduced normally. Therefore, regardless of the in vitro binding relationships, the GH and SLalpha signals seem not to crosstalk significantly in vivo even when these hormones are overexpressed. PMID- 26945625 TI - Structure and function of the AAA+ ATPase p97/Cdc48p. AB - p97 (also known as valosin-containing protein (VCP) in mammals or Cdc48p in Saccharomyces cerevisiae) is an evolutionarily conserved ATPase present in all eukaryotes and archaebacteria. In conjunction with a collection of cofactors and adaptors, p97/Cdc48p performs an array of biological functions mostly through modulating the stability of 'client' proteins. Using energy from ATP hydrolysis, p97/Cdc48p segregates these molecules from immobile cellular structures such as protein assemblies, membrane organelles, and chromatin. Consequently, the released polypeptides can be efficiently degraded by the ubiquitin proteasome system or recycled. This review summarizes our current understanding of the structure and function of this essential cellular chaperoning system. PMID- 26945628 TI - Bombyx mori cecropin A has a high antifungal activity to entomopathogenic fungus Beauveria bassiana. AB - A cDNA encoding cecropin A (CecA) was cloned from the larvae of silkworm, Bombyx mori, using RT-PCR. It encodes a protein of 63 amino acids, containing a 22 amino acid signal peptide and a 37 amino acid mat peptide of functional domain. The CecA secondary structure contains two typical amphiphilic alpha-helices. Real time qPCR analysis revealed that CecA was expressed in all the tissues tested, including cuticle, fat body, hemocytes, Malpighian tubule, midgut and silk gland in the silkworm larvae with the highest expression in the fat body and hemocytes. The gene expression of B. mori CecA was rapidly induced by Beauveria bassiana challenge and reached maximum levels at 36h after inoculation in third instar larvae. In the fifth instar larvae infected with B. bassiana, the relative expression level of CecA was upregulated in fat body and hemocytes, but not in cuticle, Malpighian tubule, midgut and silk gland. The cDNA segment of the CecA was inserted into the expression plasmid pET-30a(+) to construct a recombinant expression plasmid. Western blot results revealed that his-tagged fusion protein was successfully expressed and purified. Then the mat peptide of CecA was chemically synthesized with C-terminus amidation for in vivo antifungal assay and purity achieved 93.7%. Mass spectrometry and SDS-PAGE showed its molecular weight to be 4046.95Da. Antifungal assays indicated that the B. mori CecA had a high antifungal activity to entomopathogenic fungus B. bassiana both in vitro and in vivo in the silkworm larvae. This is the first report that the CecA is effective to inhibit B. bassiana inside the body of silkworm. PMID- 26945630 TI - Structural and biological function of NYD-SP15 as a new member of cytidine deaminases. AB - Recent studies were mainly focus on the cytidine deaminase family genes, which contained a lot of members that varied on the function of catalytic deamination in RNA or DNA and were involved in the process of growth maintenance, host immunity, retroviral infection, tumorigenesis, and drug resistance with a feature of C-U deamination. In this study, we identified a new member of cytidine deaminase family, NYD-SP15. Previous work showed that the deduced structure of the protein contained two dCMP_cyt_deam domains, which were involved in zinc ion binding. NYD-SP15 was expressed variably in a wide range of tissues, indicating its worthy biological function and creative significances. Sequence analysis, RT PCR, western blot, flow cytometry, direct-site mutation and GST pull-down assay were performed to analyze the construction and function of NYD-SP15. The results in our studies showed that NYD-SP15 was closely related to deoxycytidylate deaminase and cytidine deaminase, with authentic cytidine deaminase activity in vivo and vitro as well as homo dimerization effects. NYD-SP15 contained nuclear localization sequence (NLS) and nuclear export-signal (NES) and could dynamically shuttle between the nucleus and cytoplasm. Furthermore, NYD-SP15 gene over expression reduced the cells growth and blocked G1 to S phase, which implied a potential inhibition effect on cell growth. PMID- 26945629 TI - Serum amyloid A1: Structure, function and gene polymorphism. AB - Inducible expression of serum amyloid A (SAA) is a hallmark of the acute-phase response, which is a conserved reaction of vertebrates to environmental challenges such as tissue injury, infection and surgery. Human SAA1 is encoded by one of the four SAA genes and is the best-characterized SAA protein. Initially known as a major precursor of amyloid A (AA), SAA1 has been found to play an important role in lipid metabolism and contributes to bacterial clearance, the regulation of inflammation and tumor pathogenesis. SAA1 has five polymorphic coding alleles (SAA1.1-SAA1.5) that encode distinct proteins with minor amino acid substitutions. Single nucleotide polymorphism (SNP) has been identified in both the coding and non-coding regions of human SAA1. Despite high levels of sequence homology among these variants, SAA1 polymorphisms have been reported as risk factors of cardiovascular diseases and several types of cancer. A recently solved crystal structure of SAA1.1 reveals a hexameric bundle with each of the SAA1 subunits assuming a 4-helix structure stabilized by the C-terminal tail. Analysis of the native SAA1.1 structure has led to the identification of a competing site for high-density lipoprotein (HDL) and heparin, thus providing the structural basis for a role of heparin and heparan sulfate in the conversion of SAA1 to AA. In this brief review, we compares human SAA1 with other forms of human and mouse SAAs, and discuss how structural and genetic studies of SAA1 have advanced our understanding of the physiological functions of the SAA proteins. PMID- 26945631 TI - Multilayered polycaprolactone/gelatin fiber-hydrogel composite for tendon tissue engineering. AB - Regeneration of injured tendon and ligament (T&L) remains a clinical challenge due to their poor intrinsic healing capacity. Tissue engineering provides a promising alternative treatment approach to facilitate T&L healing and regeneration. Successful tendon tissue engineering requires the use of three dimensional (3D) biomimetic scaffolds that possess the physical and biochemical features of native tendon tissue. We report here the development and characterization of a novel composite scaffold fabricated by co-electrospinning of poly-epsilon-caprolactone (PCL) and methacrylated gelatin (mGLT). We found that photocrosslinking retained mGLT, resulted in a uniform distribution of mGLT throughout the depth of scaffold and also preserved scaffold mechanical strength. Moreover, photocrosslinking was able to integrate stacked scaffold sheets to form multilayered constructs that mimic the structure of native tendon tissues. Importantly, cells impregnated into the constructs remained responsive to topographical cues and exogenous tenogenic factors, such as TGF-beta3. The excellent biocompatibility and highly integrated structure of the scaffold developed in this study will allow the creation of a more advanced tendon graft that possesses the architecture and cell phenotype of native tendon tissues. STATEMENT OF SIGNIFICANCE: The clinical challenges in tendon repair have spurred the development of tendon tissue engineering approaches to create functional tissue replacements. In this study, we have developed a novel composite scaffold as a tendon graft consisting of aligned poly-epsilon-caprolactone (PCL) microfibers and methacrylated gelatin (mGLT). Cell seeding and photocrosslinking between scaffold layers can be performed simultaneously to create cell impregnated multilayered constructs. This cell-scaffold construct combines the advantages of PCL nanofibrous scaffolds and photocrosslinked gelatin hydrogels to mimic the structure, mechanical anisotropy, and cell phenotype of native tendon tissue. The scaffold engineered here as a building block for multilayer constructs should have applications beyond tendon tissue engineering in the fabrication of tissue grafts that consist of both fibrous and hydrogel components. PMID- 26945633 TI - Scaffold-free parathyroid tissue engineering using tonsil-derived mesenchymal stem cells. AB - To restore damaged parathyroid function, parathyroid tissue engineering is the best option. Previously, we reported that differentiated tonsil-derived mesenchymal stem cells (dTMSC) restore in vivo parathyroid function, but only if they are embedded in a scaffold. Because of the limited biocompatibility of Matrigel, however, here we developed a more clinically applicable, scaffold-free parathyroid regeneration system. Scaffold-free dTMSC spheroids were engineered in concave microwell plates made of polydimethylsiloxane in control culture medium for the first 7days and differentiation medium (containing activin A and sonic hedgehog) for next 7days. The size of dTMSC spheroids showed a gradual and significant decrease up to day 5, whereafter it decreased much less. Cells in dTMSC spheroids were highly viable (>80%). They expressed high levels of intact parathyroid hormone (iPTH), the parathyroid secretory protein 1, and cell adhesion molecule, N-cadherin. Furthermore, dTMSC spheroids-implanted parathyroidectomized (PTX) rats revealed higher survival rates (50%) over a 3 month period with physiological levels of both serum iPTH (57.7-128.2pg/mL) and ionized calcium (0.70-1.15mmol/L), compared with PTX rats treated with either vehicle or undifferentiated TMSC spheroids. This is the first report of a scaffold-free, human stem cell-based parathyroid tissue engineering and represents a more clinically feasible strategy for hypoparathyroidism treatment than those requiring scaffolds. STATEMENT OF SIGNIFICANCE: Herein, we have for the first time developed a scaffold-free parathyroid tissue spheroids using differentiated tonsil-derived mesenchymal stem cells (dTMSC) to restore in vivo parathyroid cell functions. This new strategy is effective, even for long periods (3months), and is thus likely to be more feasible in clinic for hypoparathyroidism treatment. Development of TMSC spheroids may also provide a convenient and efficient scaffold-free platform for researchers investigating conditions involving abnormal calcium homeostasis, such as osteoporosis. PMID- 26945634 TI - A rapid and comprehensive quality assessing method of Yin-Qiao-Jie-Du tablets using UHPLC-QTOF-MS in combination with multivariate statistical analysis. AB - Yin-Qiao-Jie-Du (YQJD) tablet is a well-known non-prescription Chinese patent drug widely used for the prevention and treatment of diseases in China. However, documented studies for assessing and controlling the quality of YQJD tablet are limited. In this article, a rapid and comprehensive method for the quality assessment and control of YQJD tablets was developed, via qualitative and quantitative analysis of the major active ingredients of YQJD tablets by ultra high performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS) in combination with multivariate statistical analysis. The samples of YQJD tablets were triturated and then extracted with methanol, and the extracts were analyzed by UHPLC-QTOF-MS. A good separation was achieved within 30 min by using an Agilent RRHD SB-C18 (150 mm * 2.1mm I.D., 1.8 MUm) column with a gradient elution of water (0.5% formic acid) and acetonitrile. Forty-one major chromatographic peaks were obtained, and 31 of them were identified according to the obtained data from the measurements of accurate mass, isotopic composition, and collision-induced dissociation. Among them, 21 were confirmed by the comparison of retention times, MS, and MS/MS information with those of their references. Quantitative analysis was performed based on the peak areas of extracted ion chromatograms of the exact pseudo-molecular ions (with a 0.01 Da window), and the result of method validation demonstrated that the proposed method possessed desirable specificity, linearity, precision, and accuracy. Subsequently, the method was utilized to analyze the major constituents in YQJD tablets of 18 batches produced by different manufacturers. The obtained contents of the 21 confirmed ingredients were applied for orthogonal partial least squares to latent structures discriminant analysis (OPLS-DA). An assessment of the quality consistency and stability as well as tracing the origins of the investigated YQJD tablets were successfully achieved by OPLS-DA. All of these results demonstrated that the UHPLC-QTOF-MS method developed in this study was a rapid and desirable approach for differentiating the origin, discriminating the authenticity, and assessing and controlling the quality of YQJD tablets. PMID- 26945632 TI - Stable engineered vascular networks from human induced pluripotent stem cell derived endothelial cells cultured in synthetic hydrogels. AB - Here, we describe an in vitro strategy to model vascular morphogenesis where human induced pluripotent stem cell-derived endothelial cells (iPSC-ECs) are encapsulated in peptide-functionalized poly(ethylene glycol) (PEG) hydrogels, either on standard well plates or within a passive pumping polydimethylsiloxane (PDMS) tri-channel microfluidic device. PEG hydrogels permissive towards cellular remodeling were fabricated using thiol-ene photopolymerization to incorporate matrix metalloproteinase (MMP)-degradable crosslinks and CRGDS cell adhesion peptide. Time lapse microscopy, immunofluorescence imaging, and RNA sequencing (RNA-Seq) demonstrated that iPSC-ECs formed vascular networks through mechanisms that were consistent with in vivo vasculogenesis and angiogenesis when cultured in PEG hydrogels. Migrating iPSC-ECs condensed into clusters, elongated into tubules, and formed polygonal networks through sprouting. Genes upregulated for iPSC-ECs cultured in PEG hydrogels relative to control cells on tissue culture polystyrene (TCP) surfaces included adhesion, matrix remodeling, and Notch signaling pathway genes relevant to in vivo vascular development. Vascular networks with lumens were stable for at least 14days when iPSC-ECs were encapsulated in PEG hydrogels that were polymerized within the central channel of the microfluidic device. Therefore, iPSC-ECs cultured in peptide-functionalized PEG hydrogels offer a defined platform for investigating vascular morphogenesis in vitro using both standard and microfluidic formats. STATEMENT OF SIGNIFICANCE: Human induced pluripotent stem cell-derived endothelial cells (iPSC-ECs) cultured in synthetic hydrogels self-assemble into capillary networks through mechanisms consistent with in vivo vascular morphogenesis. PMID- 26945635 TI - Simultaneous determination of mangiferin and neomangiferin in rat plasma by UPLC MS/MS and its application for pharmacokinetic study. AB - In this study, a sensitive and rapid ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method was developed to determine mangiferin and neomangiferin in rat plasma simultaneously. Chromatographic separation was carried out on an Acquity UPLC BEH C18 column and mass spectrometric analysis was performed using a Xevo TQD triple quadruple mass spectrometer coupled with an electrospray ionization (ESI) source. The MRM transitions of m/z 423.2 -> 303.1 and m/z 585.0 -> 273.1 were used to quantify for mangiferin and neomangiferin, respectively. The linearity of this method was found to be within the concentration range of 5-2000 ng/mL for mangiferin, and 2 1000 ng/mL for neomangiferin in rat plasma, respectively. Only 3.0 min was needed for an analytical run. This assay was used to support a preclinical study to investigate the pharmacokinetics of mangiferin and neomangiferin in rats. PMID- 26945636 TI - Determination of a potential antitumor quassinoid in rat plasma by UPLC-MS/MS and its application in a pharmacokinetic study. AB - A sensitive UPLC-MS/MS method was developed and validated for the determination of brusatol in rat plasma. Chromatographic separation was carried out on a C18 column using methanol and 10mM ammonium acetate containing 0.1% (v/v) formic acid (55:45, v/v). The lower limit of quantification (LLOQ) was 1.0 ng/mL for brusatol in plasma. The intra- and inter-day precision for the analyte ranged from 3.2% to 9.2% and 1.3% to 7.8%, and the accuracy was between 97.3% and 108.5%. The method was successfully applied in a pharmacokinetic study of brusatol following intravenous injection (0.5, 1.0, and 2.0mg/kg) of brusatol. PMID- 26945637 TI - Theoretical study of chlordecone and surface groups interaction in an activated carbon model under acidic and neutral conditions. AB - Activated carbons (ACs) are widely used in the purification of drinking water without almost any knowledge about the adsorption mechanisms of the persistent organic pollutants. Chlordecone (CLD, Kepone) is an organochlorinated synthetic compound that has been used mainly as agricultural insecticide. CLD has been identified and listed as a persistent organic pollutant by the Stockholm Convention. The selection of the best suited AC for this type of contaminants is mainly an empirical and costly process. A theoretical study of the influence of AC surface groups (SGs) on CLD adsorption is done in order to help understanding the process. This may provide a first selection criteria for the preparation of AC with suitable surface properties. A model of AC consisting of a seven membered ring graphene sheet (coronene) with a functional group on the edge was used to evaluate the influence of the SGs over the adsorption. Multiple Minima Hypersurface methodology (MMH) coupled with PM7 semiempirical Hamiltonian was employed in order to study the interactions of the chlordecone with SGs (hydroxyl and carboxyl) at acidic and neutral pH and different hydration conditions. Selected structures were re-optimized using CAM-B3LYP to achieve a well-defined electron density to characterize the interactions by the Quantum Theory of Atoms in Molecules approach. The deprotonated form of surface carboxyl and hydroxyl groups of AC models show the strongest interactions, suggesting a chemical adsorption. An increase in carboxylic SGs content is proposed to enhance CLD adsorption onto AC at neutral pH conditions. PMID- 26945638 TI - [Correlation between gait speed and muscular strength with balance for reducing falls among elderly]. AB - BACKGROUND: Evidence of the benefit on propioceptive neuromuscular facilitation for reducing falls in older people does not exist. OBJECTIVE: The aim of this study is to evaluate the effects of propioceptive facilitation over falls and biomechanical variables, in comparison to standard treatment and control groups. MATERIALS AND METHODS: Series cases comparative for the 24 participants were recruited and randomnly assigned to 3 groups. Group 1, propioceptive neuromuscular facilitation, group 2, standard treatment, and 3 control. Falls and biomechanic variables were measured before and after. Chi(2) was used for falls and multiple regression for biomechanical variables, RESULTS: Participants had similar falls in previous year. Women had higher falls in a relation 7:1 women men. After intervention, there was no difference between 3 groups. A correlation exista between muscular strength and gait speed with one foot position time r(2) = 0.67, p = 0.02. CONCLUSIONS: Improving 1kilogram-force of muscular strength of pelvic limb and 0.1meter/second in gait speed, balance (unipodal position time) increases balance by 11.3%. After 3 months of intervention group 2 got 7.9kg force and 0.26m/s of profit, while group 1 had 4.1kg-force and 0.15m/s and control group 2.4kg-force and 0.1m/s. PMID- 26945639 TI - The prevalence and related factors of restless leg syndrome in the community dwelling elderly; in Kayseri, Turkey: A cross-sectional study. AB - AIM: The aim of this study is to determine the prevalence and related factors of restless leg syndrome (RLS) in the community-dwelling elderly living in Kayseri. METHODS: This is a cross-sectional population based study in 960 community dwelling elderly living in an urban area. We sampled 1/100 of elderly people aged 60 years and older. The diagnosis of RLS was made according to the criteria of the International RLS Study Group. The demographic data were collected by face-to face interviews. Additionally, the Mini-Mental State Examination, Geriatric Depression Scale and anthropometric measurements were used. Logistic regression analyses were performed to define risk factors for RLS. RESULTS: We excluded elderly people with cognitive impairment (295). One hundred and five (15.8%) of the remaining 665 elderly subjects met the criteria to diagnose RLS. There was female predominance (3/1). Gender, length of education, employment status, smoking, hypertension, diabetes mellitus, depressive mood, high body mass index, and high waist circumferences, sleep quality, sleep duration, and difficulty in falling asleep in the first 30min were all detected as risk factors for RLS. However in logistic regression analysis, being a housewife, sleeping less than 6h a day and having diabetes was found as significantly related risk factors for RLS. CONCLUSION: This is the first epidemiologic study of RLS conducted in the Turkish community-dwelling elderly in an urban area. RLS is a common but underestimated disease in the elderly. Although RLS is prevalent we found very few risk factors for RLS. PMID- 26945640 TI - Cardiomyocyte generation from somatic sources - current status and future directions. AB - Transdifferentiation of one cell type to another has garnered significant research efforts in recent years. As cardiomyocyte loss following myocardial infarction becomes debilitating for cardiac patients, the option of an autologous source of cardiomyocytes not derived from multi/pluripotent stem cell sources is an attractive option. Such direct programming has been clearly realized with the use of transcription factors, microRNAs and more recently small molecule delivery to enhance epigenetic modifications, all albeit with low efficiencies in vitro. In this review, we aim to present a brief overview of the current in vitro and in vivo transdifferentiation strategies in the generation of cardiomyocytes from somatic sources. The interdisciplinary fields of tissue, cell, material and regenerative engineering offer many opportunities to synergistically achieve directly programmed cardiac tissue in vitro and enhance transdifferentiation in vivo. This review aims to present a concise outlook on this topic with these fields in mind. PMID- 26945642 TI - Focussing reduced representation CpG sequencing through judicious restriction enzyme choice. AB - Current restriction enzyme based reduced representation methylation analyses aim for limited, but unbiased, methylome coverage. As the current best estimate suggests that only ~20% of CpGs are dynamically regulated, we characterised the CpG and genomic context surrounding all suitable restriction enzyme sites to identify those that were located in regions rich in dynamically methylated CpGs. The restriction-site distributions for MspI, BstUI, and HhaI were non-random. CpGs in CGI and shelf+shore could be enriched, particularly in gene bodies for all genomic regions, promoters (TSS1500, TSS200), intra- (1st exon, gene body, 3'UTR, 5'UTR) and inter-genic regions. HpyCH4IV enriched CpG elements in the open sea for all genomic elements. Judicious restriction enzyme choice improves the focus of reduced representation approaches by avoiding the monopolization of read coverage by genomic regions that are irrelevant, unwanted or difficult to map, and only sequencing the most informative fraction of CpGs. PMID- 26945641 TI - Myxozoan infections of caecilians demonstrate broad host specificity and indicate a link with human activity. AB - Myxozoans are parasitic cnidarians that infect a wide variety of hosts. Vertebrates typically serve as intermediate hosts whereas definitive hosts are invertebrates, including annelids and bryozoans. Myxozoans are known to exploit species in two of the three extant amphibian orders (Anura: frogs and toads; Caudata: newts and salamanders). Here we use museum collections to determine, to our knowledge for the first time, whether myxozoans also exploit the third amphibian order (Gymnophiona: caecilians). Caecilians are a poorly known group of limbless amphibians, the ecologies of which range from aquatic to fully terrestrial. We examined 12 caecilian species in seven families (148 individuals total) characterised by a diversity of ecologies and life histories. Using morphological and molecular surveys, we discovered the presence of the myxozoan Cystodiscus axonis in two South American species (one of seven examined families) of aquatic caecilians - Typhlonectes natans and Typhlonectes compressicauda. All infected caecilians had been maintained in captivity in the United Kingdom prior to their preservation. Cystodiscus axonis is known from several Australian frog species and its presence in caecilians indicates a capacity for infecting highly divergent amphibian hosts. This first known report of myxozoan infections in caecilians provides evidence of a broad geographic and host range. However, the source of these infections remains unknown and could be related to exposure in South America, the U.K. or to conditions in captivity. PMID- 26945643 TI - Nucleotide 9-mers characterize the type II diabetic gut metagenome. AB - Discoveries of new biomarkers for frequently occurring diseases are of special importance in today's medicine. While fully developed type II diabetes (T2D) can be detected easily, the early identification of high risk individuals is an area of interest in T2D, too. Metagenomic analysis of the human bacterial flora has shown subtle changes in diabetic patients, but no specific microbes are known to cause or promote the disease. Moderate changes were also detected in the microbial gene composition of the metagenomes of diabetic patients, but again, no specific gene was found that is present in disease-related and missing in healthy metagenome. However, these fine differences in microbial taxon- and gene composition are difficult to apply as quantitative biomarkers for diagnosing or predicting type II diabetes. In the present work we report some nucleotide 9-mers with significantly differing frequencies in diabetic and healthy intestinal flora. To our knowledge, it is the first time such short DNA fragments have been associated with T2D. The automated, quantitative analysis of the frequencies of short nucleotide sequences seems to be more feasible than accurate phylogenetic and functional analysis, and thus it might be a promising direction of diagnostic research. PMID- 26945644 TI - Alkyl and aryl sulfonyl p-pyridine ethanone oximes are efficient DNA photo cleavage agents. AB - Sulfonyloxyl radicals, readily generated upon UV irradiation of p-pyridine sulfonyl ethanone oxime derivatives, effectively cleave DNA, in a pH independent manner, and under either aerobic or anaerobic conditions. p-Pyridine sulfonyl ethanone oxime derivatives were synthesized from the reaction of p-pyridine ethanone oxime with the corresponding sulfonyl chlorides in good to excellent yields. All compounds, at a concentration of 100MUM, were irradiated at 312nm for 15min, after incubation with supercoiled circular pBluescript KS II DNA and resulted in extended single- and double- strand cleavages. The cleavage ability was found to be concentration dependent, with some derivatives exhibiting activity even at nanomolar levels. Besides that, p-pyridine sulfonyl ethanone oxime derivatives showed good affinity to DNA, as it was observed with UV interaction and viscosity experiments with CT DNA and competitive studies with ethidium bromide. The compounds interact to CT DNA probably by non-classical intercalation (i.e. groove-binding) and at a second step they may intercalate within the DNA base pairs. The fluorescence emission spectra of pre-treated EB DNA exhibited a significant or moderate quenching. Comparing with the known aryl carbonyloxyl radicals the sulfonyloxyl ones are more powerful, with both aryl and alkyl sulfonyl substituted derivatives to exhibit DNA photo-cleaving ability, in significantly lower concentrations. These properties may serve in the discovery of new leads for "on demand" biotechnological and medical applications. PMID- 26945646 TI - Length of hydrocarbon chain influences location of curcumin in liposomes: Curcumin as a molecular probe to study ethanol induced interdigitation of liposomes. AB - Using fluorescence quenching of curcumin in 1,2-dipalmitoyl-sn-glycero-3 phosphocholine (DPPC) and 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) liposomes by brominated derivatives of fatty acids, the location of curcumin has been studied, which indicates length of hydrocarbon chain has an effect on the location of curcumin in liposomes. Change of fluorescence intensity of curcumin with temperature in the presence of liposomes helps to estimate the phase transition temperature of these liposomes, thus, influence of cholesterol on liposome properties has been studied using curcumin as a molecule probe. The cooperativity due to the interactions between the hydrocarbon chains during melting accelerates the phase transition of DPPC liposomes in the presence of high percentage of cholesterol whereas high percentage of cholesterol generates a rather rigid DMPC liposome over a wide range of temperatures. We used ethanol to induce interdigitation between the hydrophobic chains of the lipids and studied this effect using curcumin as fluorescence probe. As a result of interdigitation, curcumin fluorescence is quenched in liposomes. The compact arrangement of the acyl chains prevents curcumin from penetrating deep near the midplane. In the liquid crystalline phase ethanol introduces a kind of order to the more fluid liposome, and does not leave space for curcumin to be inserted away from water. PMID- 26945645 TI - Protein binding and anticancer activity studies of ruthenium(II) polypyridyl complexes toward BEL-7402 cells. AB - Four new ruthenium(II) polypyridyl complexes [Ru(dmb)2(dqtbt)](ClO4)2 (1) (dqtbt=12-(2,3-diphenyl-quinoxalin-6-yl)-4,5,10,13-tetraazabenzo[b]triphenylene, dmb=4,4'-dimethyl-2,2'-bipyridine), [Ru(bpy)2(dqtbt)](ClO4)2 (2) (bpy=2,2' bipyridine), [Ru(phen)2(dqtbt)](ClO4)2 (3) (phen=1,10-phenanthroline) and [Ru(dmp)2(dqtbt)](ClO4)2 (4) (dmp=2,9-dimethyl-1,10-phenanthroline) were synthesized and characterized. The cytotoxicity in vitro of the complexes was evaluated against human BEL-7402, A549, HeLa, HepG-2 and MG-63 cancer cell lines. These complexes are sensitive to BEL-7402 cells, the IC50 values are 4.9+/-0.5, 4.6+/-0.4, 7.7+/-1.8 and 1.9+/-0.3MUM toward BEL-7402 cells. The complexes can increase the levels of reactive oxygen species and induce the decrease of mitochondrial membrane potential. Morphological and comet assay studies show that the complexes can effectively induce apoptosis in BEL-7402 cells. Complexes 1-4 inhibit the cell growth at G0/G1 phase in BEL-7402 cell line. The complexes can downregulate the expression of Bcl-2 and Bcl-x proteins and upregulate the levels of Bid protein in BEL-7402 cells. The results show that the complexes induce BEL 7402 cell apoptosis through a ROS-mediated mitochondrial dysfunction pathway. In addition, the complexes show strong protein-binding affinities. PMID- 26945647 TI - One pot synthesis and characterization of gold nanocatalyst using Sacha inchi (Plukenetia volubilis) oil: Green approach. AB - In this report, a simple and cost-effective methodology has been developed to obtain gold nanoparticles (AuNPs) using Sacha inchi (Plukenetia volubilis) oil in the presence of sunlight. The spectroscopic and morphological properties of AuNPs were characterized by using UV-vis spectroscopy, transmission electron microscopy (TEM), particle size analyzer, and X-ray diffraction (XRD). UV-vis and TEM reveal that the nanostructure of the gold particles has surfaced plasmon resonance at 515-520nm and is almost spherical in shape with an average size of 5-15nm. XRD studies confirmed the face cubic center (fcc) unit cell structure of AuNPs. The as-synthesized AuNPs showed remarkable photocatalytic decomposition of the methylene blue (>75%) without using any reducing agent and weak antioxidant activity (21-16%) against 1,1-diphenyl-2-picrylhydrazyl at the different sunlight exposure times. The experimental approach is promising and suggested that the sunlight is a good source of energy for enhancement of AuNP synthesis via Sacha inchi oil and its photocatalytic activity. PMID- 26945648 TI - Seasonality in circadian locomotor activity and serum testosterone level in the subtropical tree sparrow (Passer montanus). AB - Seasonality in daily locomotor activity pattern was investigated in the subtropical tree sparrow by exposing a group of birds to natural day lengths (NDL) for 30days and another group to 12L/12D for 14days followed by transfer to constant dim light (LLdim) for another 15days in four different seasons of the year. Serum testosterone levels were also measured during different seasons. Sparrows, under NDL, exhibited distinct circadian rhythmicity in their locomotor activity with almost similar general pattern in different seasons that restricted mainly to the light hours. However, they showed season-dependent differences in the characteristics of circadian locomotor activity rhythm. Birds, when exposed to 12L/12D, showed entrainment of their locomotor activity rhythm with the activity confined mainly during the light phase. Though, tau (tau) under free run conditions did not show any significant difference, the activity period varied significantly in different seasons. The highest level of testosterone was recorded in the spring season that corresponded with the maximum locomotor activity in spring months. The seasonality in daily locomotor activity correlates with the seasonal changes in testosterone levels suggesting the influence of gonadal steroids on endogenous circadian system which is indicative of adaptation of tree sparrow to local photoperiodic conditions. PMID- 26945649 TI - Effect of Obesity on Prone Percutaneous Nephrolithotomy Outcomes: A Systemic Review. AB - PURPOSE: With decreased physical activity, growing sedentary lifestyle, and high fat diet, obesity has become a pandemic disease all over the world. In this review, we aim to assess the effect of obesity on prone percutaneous nephrolithotomy.(PNL) outcomes. MATERIALS AND METHODS: We performed a comprehensive review of the published articles in PubMed®, Medline, Scopus, Cochrane database from January 1, 2004 through June 31, 2015, using the key words; body mass index, obesity, morbid obesity, super obese, urolithiasis, nephrolithiasis, percutaneous nephrolithotomy and percutaneous lithotripsy. Original research articles published in English language with accessibility to the full text article were analyzed for our review. RESULTS: At the end of the evaluation, we found 12 articles in English language, analyzing the effect of obesity on prone PNL outcomes. Except one study, eleven studies were evaluated in this review had a retrospective nature without randomization. Stone free status of patients was in a wide range between 49%-90% in obese patients and 41%-90% in morbid obese patients. CONCLUSION: PNL is a safe and effective treatment modality for renal stone(s) in obese and morbid obese patients. However, effect of body mass index on PNL outcomes including operation time, fluoroscopy screening time, hospitalization time, complications and stone free status are still debatable. PMID- 26945650 TI - Comparison of Anesthesia Methods in Treatment of Staghorn Kidney Stones with Percutaneous Nephrolithotomy. AB - PURPOSE: To compare the efficacy and safety of percutaneous nephrolithotomy (PNL) in the treatment of staghorn calculi (SC) under spinal anesthesia (SA) versus general anesthesia (GA). MATERIALS AND METHODS: Patients with SC who treated with PNL from 2011 to 2014 were retrospectively reviewed. In total, 100 patients were divided into 2 groups according to anesthesia type: SA (group 1, n = 47) and GA (group 2, n = 53). Demographics, perioperative parameters, and postoperative analgesic requirements were compared between the two groups. RESULTS: There was no significant difference in terms of age, sex, American Society of Anesthesiologists score, body mass index, or stone size between the two groups (P = .40, .30, .18, .20, and .50, respectively). The mean procedure times were 84.7 and 87.5 min in the SA and GA groups, respectively (P = .68). The complication rates were similar in the SA and GA groups (19.1% vs. 13.2%, respectively; P = .421). The stone-free rates were also similar in the SA and GA groups (61.7% vs. 52.8%, respectively; P = .374). No statistically significant difference was found in analgesic requirements. CONCLUSION: SA is a safe method without the risks of GA and may be used for conditions in which GA is contraindicated or in patients with concerns about GA. Our outcomes indicated that SC can be treated safely and effectively under SA. PMID- 26945651 TI - Comparison of Flexible Ureterorenoscopy and Laparoscopic Ureterolithotomy Methods for Proximal Ureteric Stones Greater Than 10 mm. AB - OBJECTIVE: To examine the outcomes and to compare the effectiveness of laparoscopic ureterolithotomy and flexible URS in patients with proximal ureteral stones greater than 10 mm in diameter. MATERIAL AND METHODS: A total of 150 patients who were performed laparoscopic ureterolithotomy and flexible URS because of uretral stones in our urology clinic between January 2010 and June 2015, were analyzed retrospectively. We constituted two groups; 70 patients who were performed laparoscopic ureterolithotomy were included in group I while flexible URS-performed 80 patients in group II. Success rates and complications of the group I and II were compared. RESULTS: Success rates were 95.7% and 90% in group I and II respectively. There was no significant difference between the groups in terms of "success-rates". No statistically and clinically significant complications occurred in both groups. CONCLUSION: Laparoscopic ureterolithotomy and flexible URS methods are effective and reliable with proper indications in treatment of proximal ureteral stones. However, when considered short operational and hospitalization times and the management of the situations that require secondary interventions, we suggest that flexible URS is a minimally invasive method and it may be the first choice in the treatment of proximal ureteral stones. PMID- 26945652 TI - Treatment of Moderate Sized Renal Pelvis Calculi: Stone Clearance Time Comparison of Extracorporeal Shock Wave Lithotripsy and Retrograde Intrarenal Surgery. AB - PURPOSE: To compare the stone clearance times in patients undergoing extracorporeal shock wave lithotripsy (SWL) or retrograde intrarenal surgery (RIRS) for single radiopaque renal pelvis stones 10-20 mm in size. The results of this study may guide urologists and patients and aid in selecting the optimal preoperative treatment. MATERIALS AND METHODS: Between January 2013 and February 2015, we conducted a retrospective study and collected data from 333 patients treated with SWL (n = 172) or RIRS (n = 161). We included successfully treated patients with a single radiopaque renal pelvis stone 10-20 mm in size to calculate stone clearance times. RESULTS: The average stone size for the SWL group was 14.62 ± 2.58 mm and 14.91 ± 2.92 mm for the RIRS group. The mean Hounsfield unit (HU) of the patients was 585.40 ± 158.39 HU in the SWL group and 567.74 ± 186.85 HU in the RIRS group. Following full fragmentation, the mean stone clearance time was 26.55 ± 9.71 days in the SWL group and 11.59 ± 7.01 days in the RIRS group (P < .001). CONCLUSION: One of the most overlooked parameters in urinary stone treatments is stone clearance. We believe this study will shed light for those who aim to conduct larger randomized prospective studies. . PMID- 26945653 TI - X-Ray Free Minimally Invasive Surgery for Urolithiasis in Pregnancy. AB - PURPOSE: Our goal was to present our experience with ultrasound guided supine or prone percutaneous nephrolithotomy in three pregnant women under spinal anesthesia. MATERIALS AND METHODS: Three pregnant women in the 16th, 20th and 28th weeks of pregnancy presented with symptomatic large renal stone in the first patient and multiple renal stones in the second and third patients which were unresponsive to conventional medical therapy. They requested a definitive stone treatment. The operations were done in November 2012, June 2014 and February 2015. Data was gathered prospectively. All steps of gaining access to the pyelocalyceal system including needle insertion, tract dilation, and Amplatz sheath placement were performed under ultrasonography guidance. Tract was dilated with a single shot technique. The first two procedures were performed in supine position and the third procedure was performed in lateral flank position. RESULTS: Two patients were stone-free postoperatively and one patient had only an asymptomatic 4 mm residual stone. They were discharged on the 2nd postoperative day and had an uneventful postoperative course. No fever, bleeding or renal colic was noticed during postoperative hospitalization. All patients delivered their fetuses at term without any abnormality reported by the examining pediatric specialist after their birth. CONCLUSION: Ultrasonography can be used as an imaging modality guiding all steps of obtaining percutaneous access in pregnant women. Supine or flank ultrasound guided percutaneous nephrolithotomy can be offered to pregnant women in whom conservative measures fail to the patients' wellbeing. PMID- 26945654 TI - The Outcome of Percutaneous Nephrolithotomy Using Intravenous Catheter for Obtaining Percutaneous Access as a Treatment for Renal Stone Disease in Children: A Pilot Study. AB - PURPOSE: Using percutaneous nephrolithotomy (PNL), it is easy to reach stones in various parts of the kidney via a single access tract. In the current study, we set out to demonstrate that the intravenous catheter is a safe way to gain renal access, and that PNL is safe in children. MATERIALS AND METHODS: We retrospectively reviewed the medical records of patients who underwent PNL as a treatment for renal stone disease at our center between September 2013 and December 2014. There were no specific exclusion criteria. We used 14 gauge intravenous catheter for renal access in all cases. RESULTS: Eleven of the 32 patients (34.4%) were female and 21 (65.6%) were male. The mean +/- SD patient age was 4.7 +/- 3.71 years (9 months-16 years). Six patients (18.7%) were infants less than 1 year of age. Fifteen of the stones (46.8%) were located in the right kidney, and 17 of the stones (53.1%) were located in the left kidney. The average stone size was 13.9 +/- 4.8 mm (range, 12-28). The average duration of operation was 69.7 +/- 10.4 minutes (range, 50-110), and the average duration of fluoroscopy was 2.21 +/- 1.06 minutes (range, 1-6). There were complications in 5 of the cases (15.6%). CONCLUSION: The access and dilatation stages are quite important. We propose that the intravenous catheter is a safe and inexpensive tool for renal access in PNL in pediatric age group patients. PMID- 26945655 TI - Association of the BsmI, ApaI, TaqI, Tru9I and FokI Polymorphisms of the Vitamin D Receptor Gene with Nephrolithiasis in the Turkish Population. AB - PURPOSE: To analyze the relationship between nephrolithiasis and vitamin D receptor (VDR) gene BsmI (rs1544410), ApaI (rs7975232), TaqI (rs731236), Tru9I (rs757343) and FokI (rs2228570) polymorphisms in a study group from the Turkish population. MATERIALS AND METHODS: Ninety-eight patients with calcium oxalate kidney stones and 70 controls were enrolled in this study. Five polymorphisms of the VDR gene were studied using the Polymerase Chain Reaction Restriction Fragment Length Polymorphism (PCR-RFLP) method. RESULTS: For all polymorphisms, genotype frequencies were in line with Hardy-Weinberg equilibrium in the patients and controls. For the BsmI polymorphism, allele frequency distribution was found to differ significantly between the patients and the controls (P < .05). The "B" allele was found to increase the risk of nephrolithiasis by approximately 1.5 fold (odds ratio = 1.55, 95% confidence interval: 1.00-2.40; P = .048). However, we did not find any statistically significant differences in the allele and genotype frequencies for the ApaI, TaqI, Tru9I and FokI polymorphisms. Proportionally, the "BAt" and "baT" haplotypes were more common than other haplotypes in the cases and controls, respectively. For the haplotypes of the BsmI and TaqI polymorphisms, the "bT" haplotype frequency was found to be common in both the patients and the controls. However, we did not find statistically significant differences between the cases and the controls for either the BsmI / ApaI / TaqI or the BsmI/TaqI haplotypes. Moreover, no relationship was identified between family history and development of stone disease. CONCLUSION: The "B" allele of the BsmI polymorphism of the VDR gene may increase stone development risk. Further investigations are needed to improve our knowledge regarding the genetic factors affecting urinary stone development. PMID- 26945656 TI - Impact of Body Habitus on Operative Difficulties during Extraperitoneal Laparoscopic Radical Prostatectomy. AB - PURPOSE: The aim of the present study was to investigate whether patients' body habitus affects the operative difficulties associated with extraperitoneal laparoscopic radical prostatectomy (LRP). Therefore, the associations between body habitus and perioperative outcomes of surgery, including bleeding, operative time, and resection margins, were evaluated. MATERIALS AND METHODS: Between August 2010 and July 2012, 40 consecutive patients with preoperative magnetic resonance imaging and abdominal X-ray examinations underwent extraperitoneal LRP for localized prostate cancer at our institution. The associations between anthropometric measurements and demographics of patients, operation duration, estimated blood loss (EBL), and resection margins were analyzed retrospectively. Multivariate analyses were performed, and P < .05 was considered significant. RESULTS: On multiple regression analysis, the view of the prostatic apex (VPA) was significantly associated with EBL (P = .02), and body mass index (BMI) was significantly associated with operative time (P = .02). On multiple logistic regression analysis, protrusion of the prostate into the bladder was significantly associated with positive resection margins (P = .04). CONCLUSION: The findings of the present study suggest that poor VPA, protrusion of the prostate into the bladder, and high BMI were related to operative difficulties in extraperitoneal LRP. If operative difficulty is predicted preoperatively, it would be better to prepare blood for transfusion and/or special instruments (e.g. flexible scope), or switch to other therapeutic procedures. PMID- 26945657 TI - Evaluation of Vitronectin Expression in Prostate Cancer and the Clinical Significance of the Association of Vitronectin Expression with Prostate Specific Antigen in Detecting Prostate Cancer. AB - PURPOSE: To detect the expression of vitronectin (VTN) in the tissues and blood serum of prostate cancer (PCa) patients, and evaluate its clinical significance and to evaluate the significance of the combined assay of VTN and prostate specific antigens (PSA) in PCa diagnosis. MATERIALS AND METHODS: To detect the expression of VTN as a potential marker for PCa diagnosis and prognosis, immunohistochemistry was performed on the tissues of 32 patients with metastatic PCa (PCaM), 34 patients with PCa without metastasis (PCa), and 41 patients with benign prostatic hyperplasia (BPH). The sera were then subjected to Western blot analysis. All cases were subsequently examined to determine the concentrations of PSA and VTN in the sera. The collected data were collated and analyzed. RESULTS: The positive expression rates of VTN in the tissues of the BPH and PCa groups (including PCa and PCaM groups) were 75.61% and 45.45%, respectively (P = .005). VTN was more highly expressed in the sera of the BPH patients (0.83 ± 0.07) than in the sera of the PCa patients (0.65 ± 0.06) (P < .05). It was also more highly expressed in the sera of the PCa patients than in the sera of the PCaM patients (0.35 ± 0.08) (P < .05). In the diagnosis of BPH and PCa, the Youden indexes of PSA detection, VTN detection, and combined detection were 0.2620, 0.3468, and 0.5635; the kappa values were 0.338, 0.304, and 0.448, respectively, and the areas under the receiver operating characteristic curve were 0.625, 0.673, and 0.703 (P < .05), respectively. CONCLUSION: VTN levels in sera may be used as a potential marker of PCa for the diagnosis and assessment of disease progression and metastasis. The combined detection of VTN and PSA in sera can be clinically applied in PCa diagnosis. . PMID- 26945658 TI - A Prospective Randomized Trial Comparing a Combined Regimen of Amikacin and Levofloxacin to Levofloxacin Alone as Prophylaxis in Transrectal Prostate Needle Biopsy. AB - PURPOSE: We investigated whether addition of amikacin to levofloxacin-based antimicrobial prophylaxis reduces febrile urinary tract infections after transrectal ultrasound-guided prostate needle biopsy (TRUSB). MATERIALS AND METHODS: A total of 447 patients undergoing TRUSB were prospectively randomized into two groups. The 230 patients in Group A were given one oral dose of levofloxacin 400 mg prior to TRUSB; the 217 patients in Group B each received the same dose of levofloxacin and one 200 mg intravenous dose of amikacin. Patients' characteristics were assessed prior to TRUSB and their symptoms were checked after the TRUSB. RESULTS: Both regimens were well tolerated with no side effects. No statistically significant difference in patients' characteristics, or in incidence of inflammation- or infection-related symptoms was seen between the two groups; nor any significant difference among those who developed fever and those who did not. Two Group A patients and one Group B patient developed febrile urinary tract infections. Accountable pathogens determined by urine and blood cultures were fluoroquinolone-resistant E.coli and extended-spectrum beta lactamase-producing E.coli. All pathogens isolated were levofloxacin-resistant, amikacin-susceptible species. CONCLUSION: Although the present study was under powered by unexpectedly low overall incidence of febrile urinary tract infections, addition of one intravenous administration of amikacin to one oral administration of levofloxacin showed no advantage compared with levofloxacin alone as antimicrobial prophylaxis in TRUSB. Strikingly, all pathogens isolated from febrile patients were sensitive to amikacin in vitro. Therefore, further understanding of amikacin's drug kinetics in the prostate is necessary to develop a more efficient drug delivery system for amikacin. PMID- 26945659 TI - Fear of Circumcision in Boys Considerably Vanishes within Ten Days of Procedure. AB - PURPOSE: To compare fear of circumcision, before, immediately after, and ten days after the operation. MATERIALS AND METHODS: This was a case-control study in which participants in the operation group consisted of children admitted for circumcision at the outpatient clinics of a hospital. The Children's Fear Scale and the Venham Picture Test were administered by face-to-face interviews. RESULTS: The sample consisted of 100 boys who were circumcised and 99 who have not been circumcised yet. Children's Fear Scale scores measured before (P = .000) and immediately after the operation (P = .000) were significantly different from scores obtained on the 10th day after the operation. Total fear scores of the Venham Picture Test of boys whose families were in the higher economic level were higher than those of boys from low-income families (P < .05). The primary reason for admission for circumcision was religious, and the reason for the remaining boys was a combination of religious and hygienic factors. The boys who came to have circumcision solely because of religious reasons were found to be less fearful compared with the boys who were brought to surgery for both religious and medical reasons (P < .05). The lowest fear scores were obtained for boys who were six years of age or older. Boys who knew what the circumcision meant were less afraid of circumcision compared with those who were unaware of the procedure. CONCLUSION: Fear from circumcision does not persist; it considerably vanishes within ten days. It seems reasonable to recommend circumcision for boys six years of age or older. Pre-operative education may help boys to overcome fear originated from circumcision. PMID- 26945660 TI - Living Unrelated Versus Related Kidney Transplantation: A 25-Year Experience with 3716 Cases. AB - PURPOSE: To evaluate the results of transplantation from living unrelated donors (LURD) versus living related donors (LRD) with a long term follow-up of 25-30 years. MATERIALS AND METHODS: From 1984 to 2015, a total of3716 kidney transplantations (411 LRDs and 3305 LURDs) were enrolled to the study. Long-term survival of grafts and patients as well as the association between relation state and patients or grafts surveillance were the outcomes. RESULTS: A total of 3716 live donor kidney transplants (LRD, n = 411; LURD, n = 3305) were carried out over this period. The mean age of donors was 28 +/- 54 years in the LURD group and 34.4 +/- 11.7 years in LRD (P < . 001), while the mean age of the recipients was 35.6 +/- 15.6 years and 27.6 +/- 10.1 years for the two groups, respectively. Donor age was the only statistically significant predictor of graft survival rate (hazard ratio = 1.021, 95% confidence interval: 1.012-1.031). Between 1984 and 2015, patient survival and graft survival improved significantly also patient survival and graft survival was similar in LURDs compared with LRDs. CONCLUSION: It seems that the outcome of LURD and LRD is comparable in terms of patient and graft survival. Therefore, transplants from LURDs may be proposed as an acceptable management for patients with end stage renal disease. PMID- 26945661 TI - Risk Factors and Types of Urinary Incontinence among Middle-Aged and Older Male and Female Primary Care Patients in Kaunas Region of Lithuania: Cross Sectional Study. AB - PURPOSE: The aims of the study were to evaluate the incidences, types of urinary incontinence (UI) and its risk factors among middle-aged and older (> 40 years) men and women visiting a general practitioner (GP). MATERIALS AND METHODS: This is a descriptive and cross-sectional comparative study using a questionnaire based survey included 172 male and female patients who consecutively visited a primary care center in Kaunas region of Lithuania. RESULTS: All 86 women (100%) and 65 men (75.58%) had symptoms of UI (P < .001). About 55% of women were classified as having stress urinary incontinence (SUI) and 60% of men urge urinary incontinence (UUI) (P < .001). The risk factors for women with SUI were: age below 60 years (odds ratio [OR] = 2.89, 95% confidence interval [CI]: 1.89 4.43; P < .001), being married (OR = 6.31, 95% CI: 2.35-16.97; P < .001), sedentary-standing job (OR = 1.492, 95% CI: 1.01-2.20; P = 0.041), arterial hypertension (OR = 2.03, 95% CI: 1.39-2.96: P < .001), diabetes mellitus (OR = 3.01, 95% CI: 1.02-8.86; P = .032), menopause (OR = 1.48, 95% CI: 1.20-1.83; P < .001) and features of past pregnancies. The UUI was associated with age over 60 years (OR in men = 2.93, 95% CI: 1.15-7.51; P = .022, in women OR = 8.76, 95% CI: 2.37-32.33; P < .001. Low health-related quality of life was the most prevalent among men with UUI (50.8%) and among women with SUI (23.3%) (P = .023). CONCLUSION: UI was common among patients aged > 40 years visiting GP and affected more women of the same age range. SUI was more prevalent among women, while more men had UUI. Age below 60, being married, pregnancy and delivery history, concomitant illnesses were significant risk factors for women' SUI and older age and menopause for UUI. The only risk factor for men' UUI was age over 60 years. PMID- 26945662 TI - Effect of Preoperative Finasteride on the Volume or Length Density of Prostate Vessels, Intraoperative, Postoperative Blood Loss during and after Monopolar Transurethral Resection of Prostate: A Dose Escalation Randomized Clinical Trial Using Stereolog Methods. AB - PURPOSE: To evaluate the effects of two preoperative treatment courses with Finasteride on intraoperative and postoperative bleeding complications and prostate blood vessel characteristics in men who underwent transurethral resection of prostate (TURP) using monopolar energy. MATERIALS AND METHODS: Men scheduled for TURP were randomized into group 1 (control n = 25, no medication), group 2 and 3 (n = 20 in each, 5 mg Finasteride daily for 2 and 4 weeks before TURP; respectively). Hematocrit level in the irrigation fluid, weight of the resected prostate chips, decreases in blood hemoglobin (Hb) level 6 and 24 hours after the operation together with volume and length density of prostate vessels using stereological methods were compared. RESULTS: The three groups were matched regarding preoperative demographic data, resection time and weight of the resected tissue. Men who received preoperative Finasteride (groups 2 and 3) had significantly lower hematocrit levels in irrigation fluid than control group (control, 0.59 +/- 0.85, group 2, 0.25 +/- 0.4, group 3, 0.175 +/- 0.16; P = .028; Power = .80). However, no statistically significant difference was found in hematocrit level in irrigation fluid between groups 2 and 3 (0.25 +/- 0.4 vs. 0.175 +/- 0.16, 95% confidence interval (CI) = -0.28-0.42; P = .68). These values were independent of the weight of the resected tissue and resection time. There were no significant differences between the three groups in the decrease in Hb 6 hours (P = .58) and 24 hours after TURP (P = .65). The stereological and histological characteristics of blood vessels in suburethral prostate tissue were similar in all three groups. CONCLUSION: A 2-week preoperative course of daily Finasteride seems sufficient to significantly reduce intraoperative blood loss; this effect was independent of the weight of the resected tissue and resection time. Neither the 2-week nor the 4-week presurgical Finasteride regimen could significantly decrease postoperative blood loss, and neither regimen induced significant changes in characteristics of prostate tissue blood vessels. PMID- 26945663 TI - Simple Renal Cysts: Prevalence, Associated Risk Factors and Follow-Up in a Health Screening Cohort. AB - PURPOSE: To investigate the prevalence of simple renal cysts in an adult health screening cohort, and to evaluate clinical characteristics, associated risk factors and the natural course. MATERIALS AND METHODS: Between April and November 2008, a thousand individuals diagnosed with simple renal cyst by ultrasonography in a check-up program were chart-reviewed for demographic-clinical characteristics and cyst features. Follow-up was done via electronic patient records. Univariate and multivariate analyses to evaluate the relationship of outcomes and correlation analysis were done to measure the degree of association between parameters. RESULTS: The prevalence was 7.7%. There were 123 cysts in 77 patients, followed for 3.5 years (mean). Individuals with cysts were older (P < .01). Prevalence rates were 2.7% in individuals younger than 40 years and 23.9% in older than 60. The cysts were predominantly (94.8%) detected in males and most (63.6%) were solitary. No relation with Body Mass Index and total cholesterol levels was found but serum creatinine values were significantly increased in individuals with cysts (P < .01). There was no difference in the diagnosis of hypertension and microscopic hematuria in patients with renal cysts, however diabetes/hyperglycemia were more common and increasing age correlated with higher number of cysts (all P < .05). Follow-up revealed that the number of cysts were increased and/or the same in 86.5%; the sizes of cysts were larger and/or the same in 78.4% of patients, while in 14% of patients the cyst disappeared. CONCLUSION: In a cohort of adults undergoing a health-screening, the prevalence of simple renal cyst was found 7.7% by ultrasonography. Renal cysts were more common in males and elders, and associated with increased levels of serum creatinine and diabetes. PMID- 26945665 TI - Bladder Agenesis Associated with Crossed Fused Renal Ectopia and Vertebral Anomalies: A Rare Entity. PMID- 26945664 TI - Successful Perineal Urethroplasty for Long Pelvic Fracture Urethral Distraction Defect (PFUDD) in a 9 Year-Old Boy. PMID- 26945666 TI - Stepwise approach for combining many sources of evidence for site-recognition in genomic sequences. AB - BACKGROUND: Recognizing the different functional parts of genes, such as promoters, translation initiation sites, donors, acceptors and stop codons, is a fundamental task of many current studies in Bioinformatics. Currently, the most successful methods use powerful classifiers, such as support vector machines with various string kernels. However, with the rapid evolution of our ability to collect genomic information, it has been shown that combining many sources of evidence is fundamental to the success of any recognition task. With the advent of next-generation sequencing, the number of available genomes is increasing very rapidly. Thus, methods for making use of such large amounts of information are needed. RESULTS: In this paper, we present a methodology for combining tens or even hundreds of different classifiers for an improved performance. Our approach can include almost a limitless number of sources of evidence. We can use the evidence for the prediction of sites in a certain species, such as human, or other species as needed. This approach can be used for any of the functional recognition tasks cited above. However, to provide the necessary focus, we have tested our approach in two functional recognition tasks: translation initiation site and stop codon recognition. We have used the entire human genome as a target and another 20 species as sources of evidence and tested our method on five different human chromosomes. The proposed method achieves better accuracy than the best state-of-the-art method both in terms of the geometric mean of the specificity and sensitivity and the area under the receiver operating characteristic and precision recall curves. Furthermore, our approach shows a more principled way for selecting the best genomes to be combined for a given recognition task. CONCLUSIONS: Our approach has proven to be a powerful tool for improving the performance of functional site recognition, and it is a useful method for combining many sources of evidence for any recognition task in Bioinformatics. The results also show that the common approach of heuristically choosing the species to be used as source of evidence can be improved because the best combinations of genomes for recognition were those not usually selected. Although the experiments were performed for translation initiation site and stop codon recognition, any other recognition task may benefit from our methodology. PMID- 26945668 TI - Recurrence of stillbirth and second trimester pregnancy loss. AB - The 3,003 women referred to the Wisconsin Stillbirth Service Program following a stillbirth or second trimester fetal death reported a total of 4,563 previous pregnancies including 180 previous second or third trimester losses for a total precurrence rate of 3.95%. The 142 women with a history of at least one previous stillbirth and/or late miscarriage differed significantly from the entire cohort with respect to timing and cause of their losses. Women experiencing multiple losses frequently had both second trimester miscarriages and stillbirths >20 weeks but did not have an increased risk of first trimester miscarriage. Recurrences were more likely to be in the second trimester (52% vs. 37%) and to have a maternal (20% vs. 11%) or placental (27% vs. 19%) cause. While fetal causes overall were less common in the group with recurrence (18% vs. 27%), the difference was due mainly to fewer common aneuploidies and other low recurrence risk conditions. Not only known recessive conditions but also "idiopathic hydrops" and multiple congenital anomalies not fitting a known syndrome were more frequent than expected, suggesting that these groups should be investigated for underlying genetic causes that might have been overlooked. Women with second trimester losses and/or a maternal or placental cause of death face significantly higher empiric risks (7-8% vs. 4% for the entire cohort) and should be counseled accordingly. Study of recurrent fetal loss can help identify high risk women who may benefit from treatment and preventive strategies in the future. PMID- 26945667 TI - Transcriptomic differences between euryhaline and stenohaline malaria vector sibling species in response to salinity stress. AB - Evolution of osmoregulatory systems is a key factor in the transition of species between fresh- and saltwater habitats. Anopheles coluzzii and Anopheles merus are stenohaline and euryhaline malaria vector mosquitoes belonging to a larger group of sibling species, the Anopheles gambiae complex, which radiated in Africa within the last 2 million years. Comparative ecological genomics of these vector species can provide insight into the mechanisms that permitted the rapid radiation of this species complex into habitats of contrasting salinity. Here, we use RNA-Seq to investigate gene expression differences between An. coluzzii and An. merus after briefly exposing both young and old larval instars of each species to either saltwater (SW) or freshwater (FW). Our study aims to identify candidate genes and pathways responsible for the greater SW tolerance of An. merus. Our results are congruent with the ability of gene induction to mediate salinity tolerance, with both species showing increasing amounts of differential gene expression between SW and FW as salt concentrations increase. Besides ion transporters such as AgAE2 that may serve as effectors for osmoregulation, we also find mitogen-activated protein kinases that may serve in a phosphorylation signalling pathway responding to salinity, and report potential cross-talk between the mosquito immune response and osmoregulation. This study provides a key step towards applying the growing molecular knowledge of these malaria vectors to improve understanding of their ecological tolerances and habitat occupancy. PMID- 26945669 TI - The reduced state of the plastoquinone pool is required for chloroplast-mediated stomatal closure in response to calcium stimulation. AB - Besides their participation in photosynthesis, leaf chloroplasts function in plant responses to stimuli, yet how they direct stimulus-induced stomatal movement remains elusive. Here, we showed that over-reduction of the plastoquinone (PQ) pool by dibromothymoquinone (DBMIB) was closely associated with stomatal closure in plants which required chloroplastic H2O2 generation in the mesophyll. External application of H2 O2 reduced the PQ pool, whereas the cell-permeable reactive oxygen species (ROS) scavenger N-acetylcysteine (NAC) reversed the DBMIB-induced over-reduction of the PQ pool and stomatal closure. Mesophyll chloroplasts are key players of extracellular Ca(2+) (Ca(2+)o)-induced stomatal closure, but when treated with either 3-(3',4'-dichlorophenyl)-1,1 dimethylurea (DCMU) or NAC they failed to facilitate Ca(2+)o-induced stomatal closure due to the inhibition of chloroplastic H2 O2 synthesis in mesophyll. Similarly, the Arabidopsis electron transfer chain-related mutants npq4-1, stn7 and cas-1 exhibited diverse responses to Ca(2+)o or DBMIB. Transcriptome analysis also demonstrated that the PQ pool signaling pathway shared common responsive genes with the H2 O2 signaling pathway. These results implicated a mechanism for chloroplast-mediated stomatal closure involving the generation of mesophyll chloroplastic H2O2 based on the reduced state of the PQ pool, which is calcium sensing receptor (CAS) and LHCII phosphorylation dependent. PMID- 26945670 TI - Impact of Low Maternal Education on Early Childhood Overweight and Obesity in Europe. AB - BACKGROUND: Comparable evidence on adiposity inequalities in early life is lacking across a range of European countries. This study investigates whether low maternal education is associated with overweight and obesity risk in children from distinct European settings during early childhood. METHODS: Prospective data of 45 413 children from 11 European cohorts were used. Children's height and weight obtained at ages 4-7 years were used to assess prevalent overweight and obesity according to the International Obesity Task Force definition. The Relative/Slope Indices of Inequality (RII/SII) were estimated within each cohort and by gender to investigate adiposity risk among children born to mothers with low education as compared to counterparts born to mothers with high education. Individual-data meta-analyses were conducted to obtain aggregate estimates and to assess heterogeneity between cohorts. RESULTS: Low maternal education yielded a substantial risk of early childhood adiposity across 11 European countries. Low maternal education yielded a mean risk ratio of 1.58 (95% confidence interval (CI) 1.34, 1.85) and a mean risk difference of 7.78% (5.34, 10.22) in early childhood overweight, respectively, measured by the RII and SII. Early childhood obesity risk by low maternal education was as substantial for all cohorts combined (RII = 2.61 (2.10, 3.23)) and (SII = 4.01% (3.14, 4.88)). Inequalities in early childhood adiposity were consistent among boys, but varied among girls in a few cohorts. CONCLUSIONS: Considerable inequalities in overweight and obesity are evident among European children in early life. Tackling early childhood adiposity is necessary to promote children's immediate health and well being and throughout the life course. PMID- 26945672 TI - In-Bead Screening of Hydroxamic Acids for the Identification of HDAC Inhibitors. AB - A one bead-one compound screening format is presented. Following solid-phase synthesis on a photolabile linker, library compounds were readily released and screened inside polymer beads. The release of screening compounds was readily controlled by varying photolysis time and light intensity. Dose-response experiments were carried out to effectively distinguish high- and low-affinity ligands. A library containing 55,800 compounds was synthesized and screened in a fluorometric assay, thereby identifying potent HDAC inhibitors with IC50 values in the nanomolar range. PMID- 26945671 TI - Structural characterization of the C-terminal coiled-coil domains of wild-type and kidney disease-associated mutants of apolipoprotein L1. AB - Trypanosomes that cause sleeping sickness endocytose apolipoprotein L1 (APOL1) containing trypanolytic factors from human serum, leading to trypanolytic death through generation of APOL1-associated lytic pores in trypanosomal membranes. The trypanosome Trypanosoma brucei rhodesiense counteracts trypanolysis by expressing the surface protein serum response-associated (SRA), which can bind APOL1 common variant G0 to block its trypanolytic activity. However, two missense variants in the C terminal predicted coiled-coil (CC) domains of human APOL1 G1 (S342G/I384M) and G2 (DeltaN388Y389) decrease or abrogate APOL1 binding to T. brucei rhodesiense SRA, thus preserving APOL1 trypanolytic activity. These evolutionarily selected APOL1 missense variants, found at a high frequency in some populations of African descent, also confer elevated risk of kidney disease. Understanding the SRA-APOL1 interaction and the role of APOL1 G1 and G2 variants in kidney disease demands structural characterization of the APOL1 CC domain. Using CD, heteronuclear NMR, and molecular dynamics (MD) simulation on structural homology models, we report here unique and dynamic solution conformations of nephropathy variants G1 and G2 as compared with the common variant G0. Conformational plasticity in G1 and G2 CC domains led to interhelical alpha1 alpha2 approximation coupled with secondary structural changes and delimited motional properties absent in the G0 CC domain. The G1 substitutions conferred local structural changes principally along helix alpha1, whereas the G2 deletion altered the structure of both helix alpha2 and helix alpha1. These dynamic features of APOL1 CC variants likely reflect their intrinsic structural properties, and should help interpret future APOL1 structural studies and define the contribution of APOL1 risk variants to kidney disease. PMID- 26945674 TI - Evaporation and dispersion of respiratory droplets from coughing. AB - Understanding how respiratory droplets become droplet nuclei and their dispersion is essential for understanding the mechanisms and control of disease transmission via droplet-borne and airborne routes. A theoretical model was developed to estimate the size of droplet nuclei and their dispersion as a function of the ambient humidity and droplet composition. The model-predicted dried droplet nuclei size was 32% of the original diameter, which agrees with the maximum residue size in the classic study by Duguid, 1946, Edinburg Med. J., 52, 335 and the validation experiment in this study, but is smaller than the 50% size predicted by Nicas et al., 2005, J. Occup. Environ. Hyg., 2, 143. The droplet nuclei size at a relative humidity of 90% (25 degrees C) could be 30% larger than the size of the same droplet at a relative humidity of less than 67.3% (25 degrees C). The trajectories of respiratory droplets in a cough jet are significantly affected by turbulence, which promotes the wide dispersion of droplets. We found that medium-sized droplets (e.g., 60 MUm) are more influenced by humidity than are smaller and larger droplets, while large droplets (>=100 MUm), whose travel is less influenced by humidity, quickly settle out of the jet. PMID- 26945673 TI - Biopsychosocial Influence on Shoulder Pain: Influence of Genetic and Psychological Combinations on Twelve-Month Postoperative Pain and Disability Outcomes. AB - OBJECTIVE: To identify novel combinations of genetic and psychological factors that predicted 12-month postoperative pain and disability outcomes following arthroscopic shoulder surgery. METHODS: A prospective presurgical cohort (n = 150) was recruited to complete validated psychological questionnaires and have their DNA collected from saliva. DNA was genotyped for a priori selected genes involved with pain modulation (ADRB2, OPRM1, AVPR1A, GCH1, and KCNS1) and inflammation (IL1B, TNF/LTA, and IL6). The outcome measures of interest were the Brief Pain Inventory and Disabilities of the Arm, Shoulder, and Hand questionnaire. Followup for the cohort was at 3, 6, and 12 months postoperatively. After controlling for age, sex, race, and preoperative status, genetic and psychological factors were entered as main effects and interaction terms in separate general linear models for predicting postoperative pain and disability outcomes. RESULTS: Seven interactions involving pain-modulatory genes were identified. Three provided strong statistical evidence for different outcomes, including KCNS1 and kinesiophobia for preoperative pain intensity, ADRB2 and depressive symptoms for postoperative course, and GCH1 and anxiety symptoms for 12-month pain-intensity outcome. Ten interactions involving inflammatory genes were identified. Three provided strong statistical evidence for the 12-month postoperative course outcome, including 2 different IL6 single nucleotide polymorphism and pain catastrophizing, and IL6 and depressive symptoms. CONCLUSION: The current study identified novel genetic and psychological interactions that can be used in future studies to further understand the development of persistent postoperative pain and investigate the effectiveness of tailored treatment. PMID- 26945675 TI - Membrane traffic during axon development. AB - Brain formation requires the establishment of complex neural circuits between a diverse array of neuronal subtypes in an intricate and ever changing microenvironment and yet with a large degree of specificity and reproducibility. In the last three decades, mounting evidence has established that neuronal development relies on the coordinated regulation of gene expression, cytoskeletal dynamics, and membrane trafficking. Membrane trafficking has been considered important in that it brings new membrane and proteins to the plasma membrane of developing neurons and because it also generates and maintains the polarized distribution of proteins into neuronal subdomains. More recently, accumulating evidence suggests that membrane trafficking may have an even more active role during development by regulating the distribution and degree of activation of a wide variety of proteins located in plasma membrane subdomains and endosomes. In this article the evidence supporting the different roles of membrane trafficking during axonal development, particularly focusing on the role of SNAREs and Rabs was reviewed. (c) 2016 Wiley Periodicals, Inc. Develop Neurobiol 76: 1185-1200, 2016. PMID- 26945676 TI - Role of myeloid early endothelial progenitor cells in bone formation and osteoclast differentiation in tissue construct based on hydroxyapatite poly(ester urethane) scaffolds. AB - Engineering of a vascularized bone construct is a highly challenging task which needs to take into account the impact of different components on the bone regeneration process. Bone repair influencing factors in such constructs range from the material properties and scaffold design, to the interaction of different cell types contributing to bone formation and remodeling or neovascularization, respectively. In this context, early endothelial progenitor cells (EPC), mononuclear cells isolated from the peripheral blood, express the endothelial marker CD31 but also a series of myeloid markers and have been shown to support the formation of vessel-like structures. These cells are also characterized by a highly adaptable phenotype influenced by other cells creating an instructive niche. The present study was designed to investigate the impact of EPC on bone formation or remodeling using a co-culture system of outgrowth endothelial cells, mature endothelial cells isolated from the peripheral blood cell cultures, and mesenchymal stem cells grown on hydroxyapatite poly(ester-urethane) scaffolds. The formation of vessel-like structures in these constructs was shown by CLSM and immunohistochemistry and further evaluated by real time RT-PCR. Osteogenic differentiation in these constructs was investigated by von Kossa, Alizarin Red, and real time PCR. Data indicated that osteogenic differentiation occurred within the constructs after 14 days of culture but without a direct influence by EPC in this process. Finally, although we observed a series of osteoclast related makers in the constructs when EPC were included, no indications for an increased osteoclast-like activity, which might lead to increased bone resorption, were observed. (c) 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1922-1932, 2016. PMID- 26945677 TI - Targeting of microRNA-199a-5p protects against pilocarpine-induced status epilepticus and seizure damage via SIRT1-p53 cascade. AB - OBJECTIVE: MicroRNAs (miRNAs) are noncoding small RNAs that control gene expression at the posttranscriptional level. Some dysregulated miRNAs have been shown to play important roles in epileptogenesis. The aim of this study was to determine if miR-199a-5p regulates seizures and seizure damage by targeting the antiapoptotic protein silent information regulator 1 (SIRT1). METHODS: Hippocampal expression levels of miR-199a-5p, SIRT1, and acetylated p53 were quantified by quantitative real-time polymerase chain reaction (RT-PCR) and Western blotting in the acute, latent, and chronic stages of epilepsy in a rat lithium-pilocarpine epilepsy model. Silencing of miR-199a-5p expression in vivo was achieved by intracerebroventricular injection of antagomirs. The effects of targeting miR-199a-5p and SIRT1 protein on seizure and epileptic damage post status epilepticus were assessed by electroencephalography (EEG) and immunohistochemistry, respectively. RESULTS: miR-199a-5p expression was up regulated, SIRT1 levels were decreased, and neuron loss and apoptosis were induced in epilepsy model rats compared with normal controls, as determined by up regulation of acetylated p53 and cleaved caspase-3 expression. In vivo knockdown of miR-199a-5p by an antagomir alleviated the seizure-like EEG findings and protected against neuron damage, in accordance with up-regulation of SIRT1 and subsequent deacetylation of p53. Furthermore, the seizure-suppressing effect of the antagomir was partly SIRT1 dependent. SIGNIFICANCE: The results of this study suggest that silencing of miR-199a-5p exerts a seizure-suppressing effect in rats, and that SIRT1 is a direct target of miR-199a-5p in the hippocampus. The effect of miR-199a-5p on seizures and seizure damage is mediated via down regulation of SIRT1. The miR-199a-5p/SIRT1 pathway may thus represent a potential target for the prevention and treatment of epilepsy and epileptic damage. PMID- 26945678 TI - Prolonged sleep increases the risk of intracerebral haemorrhage: a nationwide case-control study. AB - BACKGROUND AND PURPOSE: Although abnormal sleep duration is positively associated with increased risk for cardiovascular disease and mortality, the specific impact on intracerebral haemorrhage (ICH) risk remains unclear. The relationship between sleep duration and the risk of ICH was investigated in our study. METHODS: A nationwide, multicentre matched case-control study was performed to investigate the risk factors for haemorrhagic stroke, using patients from 33 hospitals in Korea. In all, 490 patients with ICH and 980 age- and sex-matched controls were enrolled. Detailed information regarding sleep, sociodemographic factors, lifestyle and medical history before ICH onset was obtained using qualified structured questionnaires. Sleep duration was categorized and the adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using a conditional logistic regression with 7 h as the reference duration. RESULTS: The number of subjects with long sleep duration, more than 8 h, was significantly greater in the ICH group than in the control group (>=8 h, 30.4% vs. 22.6%, P = 0.002). After controlling for relevant confounding factors, longer sleep duration was found to be independently associated with the risk of ICH in a dose-response manner (8 h, OR 1.57, 95% CI 1.00-2.47; >=9 h, OR 5.00, 95% CI 2.18-11.47). CONCLUSIONS: Our study suggested that long sleep duration is positively associated with an increased ICH risk in a dose-dependent manner. Further studies on the relationship linking long sleep duration with increased risk of ICH are required. PMID- 26945679 TI - gamma-AApeptides as a New Class of Peptidomimetics. AB - Sequence-specific peptidomimetics are molecules that mimic the structure and function of peptides and proteins. With new backbones and molecular frameworks, peptidomimetics are of considerable interest in addressing challenges encountered in chemical biology and biomedical sciences. Based on the gamma-PNA backbone, a new class of peptidomimetics - "gamma-AApeptides" were recently developed. Both linear and cyclic gamma-AApeptides can be synthesized with high efficiency. Compared with alpha-peptides, gamma-AApeptides are resistant to enzymatic degradation, and amendable to diversification with a variety of chemical groups. Moreover, they could mimic primary and secondary structure, as well as the function of peptides, and show promise in biological applications, such as the development of new agents combating bacteria, cancer, and Alzheimer's disease. A few research outcomes of gamma-AApeptides are highlighted in this Concept article, and a future perspective is also proposed. PMID- 26945680 TI - Long-term outcomes following drug-eluting stents versus bare metal stents for primary percutaneous coronary intervention: A real-world analysis of 11,181 patients from the british columbia cardiac registry. AB - BACKGROUND: Drug eluting stents (DES) are associated with reduced risk of restenosis when compared with bare metal stents (BMS). Their use in ST-elevation myocardial infarction (STEMI) is debated, owing to concerns about stent thrombosis. There are limited real-world data comparing DES versus BMS in STEMI. We conducted an observational analysis in this setting and rigorously adjusted for treatment selection bias. METHODS: We analyzed 11,181 consecutive patients with acute STEMI who received either DES or BMS during 2008-2014 in the British Columbia Cardiac Registry. We analyzed target vessel revascularization (TVR) and mortality at 2 years. RESULTS: Multivariable-adjusted, propensity-matched and inverse probability-treatment weighted analyses found DES to be associated with early and late survival up to 2 years but not TVR. However, when adjusting for measured and unmeasured confounders, instrumental variable (IV) analyses demonstrated that DES use was associated with reduced TVR up to 2 years (Delta = 6.7%, 95% CI: -10.0%, -3.4%, P < 0.001). DES use was not associated with mortality at 1 year (Delta = -2.3%, 95% CI: -5.0%, 0.4%, P = 0.100) but associated with reduced mortality at 2 years (Delta = -5.4%, 95% CI: -8.3%, 2.5%, P < 0.001). Stratified IV analyses indicated that this long-term survival benefit was largely attributable to the second generation DES. CONCLUSIONS: In this study of patients with STEMI, when adjusting for measured and unmeasured factors, DES use was associated with reduced TVR and long-term survival beyond 1 year. This long-term survival was largely attributable to the second generation DES. These real-world data are reassuring and support the use of DES for STEMI. (c) 2016 Wiley Periodicals, Inc. PMID- 26945681 TI - Episcleral cyclosporine A implants for the management of unilateral keratoconjunctivitis sicca in an 8-year-old mare. AB - An 8-year-old mare was presented for investigation of a 1-month history of blepharospasm, eyelid swelling, corneal edema, and ocular discharge of the right eye (OD). Ophthalmic examination confirmed mucopurulent ocular discharge, conjunctival hyperemia, and a dry, dull appearance to the cornea OD. Schirmer tear test results confirmed an absence of tear production OD (0 mm/min) consistent with keratoconjunctivitis sicca. Treatment with topical 0.2% cyclosporine A resulted in an improvement in clinical signs. An episcleral cyclosporine A implant was placed under standing sedation 5 days after initial presentation. Re-examination 9 days post-operatively confirmed that the mare's tear production in the right eye had improved and no further clinical signs had been observed. Topical medications were gradually discontinued. Re-examinations performed up to 12 months postsurgery showed no recurrence of clinical signs and no adverse effects of the implant. To our knowledge, this is the first report of the use of a cyclosporine A implant in the management of KCS in a horse and highlights its potential as an effective, alternative therapy in the management of KCS in horses. PMID- 26945683 TI - Childhood cancer in children with congenital anomalies in Oklahoma, 1997 to 2009. AB - BACKGROUND: Data-linkage studies have reported an association between congenital anomalies and childhood cancer. However, few studies have focused on the differences in the effect of congenital anomalies on cancer as a function of attained age. We aimed to examine associations between anomalies and childhood cancer as a function of attained age among children born in Oklahoma. METHODS: Data were obtained from the Oklahoma State Department of Health from 1997 to 2009 (n = 591,235). We linked Vital Statistics records for singleton deliveries to the Oklahoma Birth Defects Registry and the Oklahoma Central Cancer Registry using name and birth date. To assess the relation between anomalies and childhood cancer, we used Cox regression analysis allowing for a nonproportional hazards for anomalies as a function of age. RESULTS: There were 23,368 (4.0%) children with anomalies and 531 (0.1%) children with cancer. When considering 3-year age intervals, we detected an increased hazard of any childhood cancer in children with anomalies compared with those without anomalies before 1 year of age (hazard ratio, 14.1; 95% confidence interval, 8.3-23.7) and at 3 years of age (hazard ratio, 2.3; 95% confidence interval, 1.6-3.2). The increased hazard declined with increasing time since birth, with the effect diminished by 6 years of age. CONCLUSION: Our results were consistent with previous studies indicating an increased rate of childhood cancer among children with anomalies at younger ages. Furthermore, our study added a methodological refinement of assessing the effect of anomalies as a function of attained age. Birth Defects Research (Part A) 106:633-642, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26945682 TI - The Androgen Receptor Regulates PPARgamma Expression and Activity in Human Prostate Cancer Cells. AB - The peroxisome proliferator activated receptor gamma (PPARgamma) is a ligand activated transcription factor that regulates growth and differentiation within normal prostate and prostate cancers. However the factors that control PPARgamma within the prostate cancers have not been characterized. The goal of this study was to examine whether the androgen receptor (AR) regulates PPARgamma expression and function within human prostate cancer cells. qRT-PCR and Western blot analyses revealed nanomolar concentrations of the AR agonist dihydrotestosterone (DHT) decrease PPARgamma mRNA and protein within the castration-resistant, AR positive C4-2 and VCaP human prostate cancer cell lines. The AR antagonists bicalutamide and enzalutamide blocked the ability of DHT to reduce PPARgamma levels. In addition, siRNA mediated knockdown of AR increased PPARgamma protein levels and ligand-induced PPARgamma transcriptional activity within the C4-2 cell line. Furthermore, proteasome inhibitors that interfere with AR function increased the level of basal PPARgamma and prevented the DHT-mediated suppression of PPARgamma. These data suggest that AR normally functions to suppress PPARgamma expression within AR-positive prostate cancer cells. To determine whether increases in AR protein would influence PPARgamma expression and activity, we used lipofectamine-based transfections to overexpress AR within the AR-null PC-3 cells. The addition of AR to PC-3 cells did not significantly alter PPARgamma protein levels. However, the ability of the PPARgamma ligand rosiglitazone to induce activation of a PPARgamma-driven luciferase reporter and induce expression of FABP4 was suppressed in AR-positive PC-3 cells. Together, these data indicate AR serves as a key modulator of PPARgamma expression and function within prostate tumors. J. Cell. Physiol. 231: 2664-2672, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26945684 TI - Mammary analogue secretory carcinoma of parotid: Is preoperative cytological diagnosis possible? AB - Mammary analogue secretory carcinoma is a recently recognized tumor of salivary gland with characteristic t(12;15)(q13;q25) that results in ETV6-NTRK3 fusion product. Distinguishing mammary analogue secretory carcinoma from other salivary gland tumors is important. Present study highlights cytologic findings in three cases of mammary analogue secretory carcinoma of parotid which facilitate preoperative diagnosis with the aid of ancillary diagnostic techniques. Fine needle aspiration cytology of parotid was performed on three cases after clinical examination. Immunocytochemistry for mammoglobin and S100 were performed. Parotidectomy was done in all cases. The corresponding hematoxylin and eosin stained slides and blocks of all cases were studied. Molecular analysis was done in one of the cases. Cases 1 and 3 revealed uniform atypical epithelial cells arranged in branching papillary pattern with few cells in microcystic pattern. Case 2 showed atypical cells arranged mainly in loose clusters and few singly dissociated. Individual cells revealed round nuclei, vesicular chromatin, prominent nucleoli and abundant finely vacuolated cytoplasm with metachromasia prominent in May-Grunwald-Giemsa smear (case 3). Characteristic hob-nail cells covering papillae were observed in cases 1 and 3. Immunocytochemistry showed strong positivity for mammoglobin and S100 thereby confirming the diagnosis of mammary analogue secretory carcinoma preoperatively. The diagnosis was in concordance with surgical specimen. Also, characteristic ETV6-NTRK3 translocation was confirmed in case 1. Increased awareness and high index of suspicion is necessary for the upfront diagnosis, more so for the papillary variant of mammary analogue secretory carcinoma. Immunocytochemistry aids in confirming this preoperative diagnosis, based on which treatment can be planned. Diagn. Cytopathol. 2016;44:519-525. (c) 2016 Wiley Periodicals, Inc. PMID- 26945685 TI - The effects of capsaicin and capsaicinoid analogs on metabolic molecular targets in highly energetic tissues and cell types. AB - There is increasing interest in dietary chemicals that may provide benefits for pathologies such as diabetes and obesity. Capsaicinoids found in chili peppers and pepper extracts, are responsible for the "hot" or "spicy" sensation associated with these foods. Capsaicinoid consumption is also associated with enhanced metabolism, making them potentially therapeutic for metabolic disease by promoting weight loss. This review summarizes much of the current experimental evidence (ranging from basic to applied investigations) of the biochemical and molecular metabolic effects of capsaicinoids in metabolically significant cell types. Along with influencing metabolic rate, findings demonstrate capsaicinoids appear to alter molecular metabolic signaling, regulate hunger and satiety, blood metabolites, and catecholamine release. Notably, the majority of the experiments summarized herein utilized isolated supplemental or research grade capsaicinoids rather than natural food sources for experimental interventions. Additional work should be conducted using primary food sources of capsaicin to explore pharmacological, physiological, and metabolic benefits of both chronic and acute capsaicin consumption. (c) 2016 BioFactors, 42(3):229-246, 2016. PMID- 26945686 TI - Sensorimotor cortex excitability and connectivity in Alzheimer's disease: A TMS EEG Co-registration study. AB - Several studies have shown that, in spite of the fact that motor symptoms manifest late in the course of Alzheimer's disease (AD), neuropathological progression in the motor cortex parallels that in other brain areas generally considered more specific targets of the neurodegenerative process. It has been suggested that motor cortex excitability is enhanced in AD from the early stages, and that this is related to disease's severity and progression. To investigate the neurophysiological hallmarks of motor cortex functionality in early AD we combined transcranial magnetic stimulation (TMS) with electroencephalography (EEG). We demonstrated that in mild AD the sensorimotor system is hyperexcitable, despite the lack of clinically evident motor manifestations. This phenomenon causes a stronger response to stimulation in a specific time window, possibly due to locally acting reinforcing circuits, while network activity and connectivity is reduced. These changes could be interpreted as a compensatory mechanism allowing for the preservation of sensorimotor programming and execution over a long period of time, regardless of the disease's progression. Hum Brain Mapp 37:2083-2096, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26945687 TI - Metal-Oxygen Bond Ionicity as an Efficient Descriptor for Doped NiOOH Photocatalytic Activity. AB - The computational design of solid catalysts has become a very "hot" field during the last decades, especially with the recent increase in computational tool performance. However, theoretical techniques are still very time demanding because they require the consideration of many adsorption configurations of the reaction intermediates on the surface. Herein, we propose to use the metal-oxygen (M-O) bond ionicity as a descriptor for the photocatalytic activity of one of the best catalysts for the oxygen evolution reaction (OER). Ionicity is a bulk property and thus carries the advantage of being easily obtainable from a simple Bader charge analysis by using density functional theory (DFT). We will show that this criterion can be used successfully to design efficient dopants for NiOOH material. This catalyst is known to exhibit interesting photoelectrochemical properties for OER if it is doped with specific transition metals. Finally, we demonstrate that other electronic properties that relate to bulk calculation, such as oxidation states and density of states, are not alone sufficient to explain the photocatalytic activity of the material. Thus, M-O bond ionicity attracts significant interest compared with other bulk observables obtained by using DFT computations. PMID- 26945688 TI - Carboxymethylsulfonylated Ribopyrimidines: Rational Design of Ribonuclease A Inhibitors Employing Chemical Logic. AB - Hydrolysis of RNA by ribonuclease A crucially depends on the participation of the 2'-OH group as well as the positioning of the internucleotide bond at two different sites of the enzyme. Therefore, ribopyrimidines were modified with SO2CH2CO2H, an acidic functional group, which was expected to interact with the phosphate binding site. These ribonucleosides were designed to understand the influence of the 2'-OH group of these inhibitors on ribonuclease A inhibition along with the effect of the -SO2CH2CO2H group. The "down" configuration of the 2'-OH group enhanced the inhibitory properties (Ki =1.75 MUm) and also imparted important Val43 H-bonding with the furanose oxygen atom of the inhibitors. One of the most important aspects of this work is that there was no serendipitous discovery of the inhibitors. The inhibitors reported in this manuscript were obtained by design by employing chemical logic. PMID- 26945689 TI - Enviromental and risk factors for progressive supranuclear palsy. PMID- 26945690 TI - Cycling probe-based real-time PCR for the detection of Human herpesvirus 6A and B. AB - Human herpesvirus 6 (HHV-6) is classified as two distinct species: HHV-6A and B. HHV-6B infection can cause several clinical manifestations in transplant recipients including encephalitis, bone marrow suppression, and pneumonitis. In contrast to HHV-6B, the clinical features of HHV-6A infection remain largely undefined. Herein, we developed a multiplex cycling probe real-time PCR that discriminated between HHV-6A and HHV-6B. The assay was HHV-6-specific and no cross amplification was demonstrated for other herpesviruses. Moreover, the assay had a broad, linear dynamic range of detection between 1 and 10(6) copies of viral DNA. The quantification of HHV-6A DNA was suppressed by an excess amount of HHV-6B DNA (1 * 10(6) copies/tube) in the multiplex PCR assay; however, 1 * 10(6) copies/tube of HHV-6A DNA did not affect the quantification of 1 * 10(4) copies/tube of HHV-6B DNA. To determine the reliability of the assay for analysis of clinical specimens, DNAs extracted from the peripheral blood of hematopoietic stem cell transplant recipients were assayed using our multiplex real-time PCR versus the standard TaqMan PCR. Strong correlations were demonstrated between the two different assay systems for both HHV-6A (R(2) = 0.913) and HHV-6B (R(2) = 0.909). Therefore, our multiplex HHV-6 species-specific cycling probe real-time PCR is useful for evaluating the precise copy numbers of HHV-6A and B in transplant recipients. However, as HHV-6A copy numbers was affected by presence of high copies of HHV-6B DNA (1 * 10(6) copies/tube), it may be difficult to measure precise copy numbers of HHV-6A in inherited chromosomally integrated HHV 6B patient. J. Med. Virol. 88:1628-1635, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26945691 TI - Cytokines during periodontal wound healing: potential application for new therapeutic approach. AB - Regeneration of periodontal tissues is one of the main goals of periodontal therapy. However, current treatment, including surgical approach, use of membrane to allow maturation of all periodontal tissues, or use of enamel matrix derivatives, presents limitations in their indications and outcomes leading to the development of new tissue engineering strategies. Several cytokines are considered as key molecules during periodontal destruction process. However, their role during each phase of periodontal wound healing remains unclear. Control and modulation of the inflammatory response and especially, release of cytokines or activation/inhibition in a time- and spatial-controlled manner may be a potential perspective for periodontal tissue engineering. The aim of this review was to summarize the specific role of several cytokines during periodontal wound healing and the potential therapeutic interest of inflammatory modulation for periodontal regeneration especially related to the expression sequence of cytokines. PMID- 26945692 TI - A comparison of plasma levobupivacaine concentrations following transversus abdominis plane block and rectus sheath block. AB - Levobupivacaine is commonly used as the local anaesthetic of choice in peripheral nerve blocks, but its pharmacokinetics have not been fully investigated. We compared the changes in plasma concentrations of levobupivacaine following transversus abdominis plane block and rectus sheath block. Fifty woman undergoing laparoscopy were randomly allocated to receive either a transversus abdominis plane block or an rectus sheath block. In both groups, 2.5 mg.kg(-1) levobupivacaine was administered, and blood samples were obtained 15 min, 30 min, 60 min and 120 min after injection. The mean maximum plasma concentration (Cmax) and mean time to reach Cmax (Tmax) as determined by non-linear regression analysis were 1.05 MUg.ml(-1) and 32.4 min in the transversus abdominis plane group and 0.95 MUg.ml(-1) and 60.9 min in the rectus sheath group, respectively. The plasma concentration of levobupivacaine peaked earlier in the transversus abdominis plane group than in the rectus sheath group and the maximum plasma concentration depended on the dose administered but not the procedure. PMID- 26945695 TI - Onchocerciasis Presenting as a Breast Mass. PMID- 26945694 TI - Identification of Optimal Mouse Models of Systemic Sclerosis by Interspecies Comparative Genomics. AB - OBJECTIVE: Understanding the pathogenesis of systemic sclerosis (SSc) is confounded by considerable disease heterogeneity. Animal models of SSc that recapitulate distinct subsets of disease at the molecular level have not been delineated. We applied interspecies comparative analysis of genomic data from multiple mouse models of SSc and patients with SSc to determine which animal models best reflect the SSc intrinsic molecular subsets. METHODS: Gene expression measured in skin from mice with sclerodermatous graft-versus-host disease (GVHD), bleomycin-induced fibrosis, Tsk1/+ or Tsk2/+ mice was mapped to human orthologs and compared to SSc skin biopsy-derived gene expression. Transforming growth factor beta (TGFbeta) activation was assessed using a responsive signature in mice, and tumor necrosis factor receptor superfamily member 12A (TNFRSF12A) expression was measured in SSc patient and mouse skin. RESULTS: Gene expression in skin from mice with sclerodermatous GVHD and bleomycin-induced fibrosis corresponded to that in SSc patients in the inflammatory molecular subset. In contrast, Tsk2/+ mice showed gene expression corresponding to the fibroproliferative SSc subset. Enrichment of a TGFbeta-responsive signature was observed in both Tsk2/+ mice and mice with bleomycin-induced skin fibrosis. Expression of TNFRSF12A (the TWEAK receptor/fibroblast growth factor-inducible 14) was elevated in skin from patients with fibroproliferative SSc and the skin of Tsk2/+ mice. CONCLUSION: This study reveals similarities in cutaneous gene expression between distinct mouse models of SSc and specific molecular subsets of the disease. Different pathways underlie the intrinsic subsets including TGFbeta, interleukin-13 (IL-13), and IL-4. We identify a novel target, Tnfrsf12a, with elevated expression in skin from patients with fibroproliferative SSc and Tsk2/+ mice. These findings will inform mechanistic and translational preclinical studies in SSc. PMID- 26945693 TI - Interaction between inflammatory mediators and miRNAs in Helicobacter pylori infection. AB - Helicobacter pylori cause chronic inflammation favouring gastric carcinogenesis, and its eradication may prevent malignant transformation. We evaluated whether H. pylori infection and its eradication modify the expression of inflammatory mediators in patients with chronic gastritis. Furthermore, we assessed whether microRNAs modulate inflammatory pathways induced by H. pylori and identified miRNA-gene interaction networks. mRNA and protein expression of TNFA, IL6, IL1B, IL12A, IL2 and TGFBRII and miRNAs miR-103a-3p, miR-181c-5p, miR-370-3p, miR-375 and miR-223-3p were evaluated in tissue samples from 20 patients with chronic gastritis H. pylori negative (Hp-) and 31 H. pylori positive (Hp+), before and three months after bacterium eradication therapy, in comparison with a pool of Hp normal gastric mucosa. Our results showed that H. pylori infection leads to up regulation of TNFA, IL6, IL12A and IL2 and down-regulation of miRNAs. Bacterium eradication reduces the expression of TNFA and IL6 and up-regulates TGFBRII and all investigated miRNAs, except miR-223-3p. Moreover, transcriptional profiles of inflammatory mediators and miRNAs after eradication are different from the non infected group. Deregulated miRNA-mRNA interaction networks were observed in the Hp+ group before and after eradication. Therefore, miRNAs modulated cytokine expression in the presence of H. pylori and after its eradication, suggesting that miRNAs participate in the pathological process triggered by H. pylori in the gastric mucosa. PMID- 26945696 TI - Pemphigus with features of both vulgaris and foliaceus variants localized to the nose. AB - We report the case of a 74-year-old man affected by an unusual variant of pemphigus. He presented with a crusty and scaly lesion of the nose. We performed reflectance confocal microscopy and optical coherence tomography on the lesion, which suggested an unexpected diagnosis of pemphigus. Therefore, to confirm our diagnostic suspicions, we executed indirect immunofluorescence and two biopsies, one for histopathological examination and one for direct immunofluorescence. Histopathological evaluation showed acantholysis with formation of clefts in the granular and spinous layers of the epidermis. Direct immunofluorescence revealed immunoglobulin G and C3 deposit to the full thickness of the epidermis. Indirect immunofluorescence showed intercellular antibodies at a titer of 1:40 in the suprabasal epidermis. The immunoblot analysis using epidermal extract revealed the presence of circulating antibodies directed to 130- and 160-kDa antigens in the patient's serum. These two antigens were evidenced from nitrocellulose membrane with colorimetric AP systems, which highlighted the presence of autoantibodies against desmoglein (Dsg)1 and Dsg3 (sodium dodecylsulfate polyacrylamide gel electrophoresis). We also performed an enzyme-linked immunoassay. All these findings suggested that this patient's pemphigus had features of both vulgaris and foliaceus variants. PMID- 26945697 TI - Initial findings using the V8 hourglass-shaped valvuloplasty balloon for postdilatation in treating paravalvular leaks associated with transcatheter self expanding aortic valve prosthesis. AB - OBJECTIVES: The aim of this study was to assess the effect of a novel hourglass shaped balloon on reduction of paravalvular leak (PVL) in patients undergoing transcatheter aortic valve replacement (TAVR) with self-expanding prostheses. BACKGROUND: An important limitation of TAVR compared with surgical aortic valve replacement remains the higher incidence of PVL. A commonly used strategy to treat PVL is balloon postdilatation (BPD); however, the optimal technique for treating PVL after TAVR is unknown. METHODS: We examined consecutive patients with severe, symptomatic aortic stenosis who underwent TAVR with the Medtronic CoreValve followed by BPD with an InterValve V8 balloon for PVL grade >=2+. Data from echocardiographic, multidetector computed tomographic, and angiographic images were reviewed. The primary endpoint was successful reduction in PVL to grade 1+ or less as assessed by intraprocedural echocardiography. RESULTS: Eleven patients were studied (median age, 82 years; 64% female). Ten patients (91%) demonstrated successful reduction in PVL after V8 BPD. In three patients, PVL was reduced to zero or trace. PVL remained unchanged in one patient (2+). Two patients had complete heart block associated with valve deployment and received permanent pacemakers. There were no occurrences of annular injury or major adverse clinical events. CONCLUSIONS: BPD with the V8 hourglass-shaped balloon was feasible in reducing PVL from self-expanding TAVR prostheses. (c) 2016 Wiley Periodicals, Inc. PMID- 26945698 TI - Alkaline phosphatase at diagnosis of primary sclerosing cholangitis and 1 year later: evaluation of prognostic value. AB - BACKGROUND: Primary sclerosing cholangitis (PSC) is a slowly progressive liver disease. Reliable biomarkers to predict outcome are urgently needed to serve as surrogate endpoints and/or stratifiers in clinical trials. Reduction in serum alkaline phosphatase (ALP) has been proposed as prognostic surrogate marker in PSC. The aim of this study was to asses if ALP at diagnosis (T0), 1 year later (T1), and percentage change between both time points hold prognostic value, and to determine the optimal threshold. METHODS: We retrospectively collected ALP levels at T0 and T1 for patients included in a large PSC cohort. The association of ALP at T0, T1, and percentage change with the combined endpoint (PSC-related death, liver transplantation) was analysed. Predictive value was determined using C-statistics. RESULTS: A total of 366 patients were included, of whom 66 (18%) reached an endpoint: 26 (7%) PSC-related death, 40 (11%) liver transplantation. At T0 and T1, 84% used ursodeoxycholic acid. A positive association was observed between level of ALP at T0 and T1 and the hazard of reaching an endpoint, up to values around 2.5 times upper limit of normal (xULN). A larger decrease in ALP between T0 and T1 decreased the event rate. A range of thresholds (0.5-3*ULN) with about similar C-statistics was found. In this cohort, the optimal threshold was 1.3*ULN at T1. CONCLUSION: ALP can be used to discriminate between PSC patients with a good and a poor prognosis. These findings indicate that ALP can serve as stratifier, and potentially as surrogate endpoint for clinical trials in PSC. PMID- 26945699 TI - Gastric and splenic infarctions in acute pancreatitis. PMID- 26945700 TI - Effect of yeast assimilable nitrogen on the synthesis of phenolic aroma compounds by Hanseniaspora vineae strains. AB - In several grape varieties, the dominating aryl alkyl alcohols found are the volatile group of phenylpropanoid-related compounds, such as glycosylated benzyl and 2-phenylethyl alcohol, which contribute to wine with floral and fruity aromas after being hydrolysed during fermentation. Saccharomyces cerevisiae is largely recognized as the main agent in grape must fermentation, but yeast strains belonging to other genera, including Hanseniaspora, are known to predominate during the first stages of alcoholic fermentation. Although non-Saccharomyces yeast strains have a well-recognized genetic diversity, understanding of their impact on wine flavour richness is still emerging. In this study, 11 Hansenisapora vineae strains were used to ferment a chemically defined simil grape fermentation medium, resembling the nutrient composition of grape juice but devoid of grape-derived secondary metabolites. GC-MS analysis was performed to determine volatile compounds in the produced wines. Our results showed that benzyl alcohol, benzyl acetate and 2-phenylethyl acetate are significantly synthesized by H. vineae strains. Levels of these compounds found in fermentations with 11 H. vineae different strains were one or two orders of magnitude higher than those measured in fermentations with a known S. cerevisiae wine strain. The implications for winemaking in response to the negative correlation of benzyl alcohol, benzyl acetate and 2-phenylethyl acetate production with yeast assimilable nitrogen concentrations are discussed. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26945702 TI - Cu-Catalyzed Intramolecular Amidation of Unactivated C(sp(3) )-H Bonds To Synthesize N-Substituted Indolines. AB - A copper-catalyzed intramolecular amidation of unactivated C(sp(3) )-H bonds to construct indoline derivatives has been developed. Such an amidation proceeded well at primary C-H bonds preferred to secondary C-H bonds. The transformation owned a broad substrate scope. The corresponding indolines were obtained in good to excellent yields. N-Formal and other carbonyl groups were suitable and were easily deprotected and transformed into methyl or long-chained alkyl groups. Preliminary mechanistic studies suggested a radical pathway. PMID- 26945701 TI - Developing effective countermeasures against acute hydrogen sulfide intoxication: challenges and limitations. AB - Hydrogen sulfide (H2 S) is a chemical hazard in the gas and farming industry. As it is easy to manufacture from common chemicals, it has also become a method of suicide. H2 S exerts its toxicity through its high affinity with metalloproteins, such as cytochrome c oxidase and possibly via its interactions with cysteine residues of various proteins. The latter was recently proposed to acutely alter ion channels with critical implications for cardiac and brain functions. Indeed, during severe H2 S intoxication, a coma, associated with a reduction in cardiac contractility, develops within minutes or even seconds leading to death by complete electromechanical dissociation of the heart. In addition, long-term neurological deficits can develop owing to the direct toxicity of H2 S on neurons combined with the consequences of a prolonged apnea and circulatory failure. Here, we review the challenges impeding efforts to offer an effective treatment against H2 S intoxication using agents that trap free H2 S, and present novel pharmacological approaches aimed at correcting some of the most harmful consequences of H2 S intoxication. PMID- 26945703 TI - Human leukocyte antigen typing using buccal swabs as accurate and non-invasive substitute for venipuncture in children at risk for celiac disease. AB - BACKGROUND AND AIM: Human leukocyte antigen (HLA) typing is an important step in the diagnostic algorithm for celiac disease (CD) and is also used for screening purposes. Collection of blood is invasive and accompanied with emotional impact especially in children. Genetic technological progress now enables HLA typing from buccal cell samples. This study evaluated the reliability and feasibility of HLA typing for CD-associated HLA polymorphisms using buccal swabs as routine test in high-risk individuals. METHODS: Blood and buccal swabs of 77 children and adolescents with high risk for CD were prospectively collected in this cohort study. Buccal swab collection was performed either by the investigator at the outpatient clinic or by the patient or its parents at home. To evaluate the possibility of self-administration, three families performed the test at home. DNA was extracted using an adapted QIAamp method. Quantity, quality, and purity of DNA were recorded. HLA-DRB1, HLA-DQA1, and HLA-DQB1 typing was examined on buccal cell-derived and blood-derived DNA at low and, if necessary, high resolution level, using sequence-specific oligonucleotide and sequence-based typing, respectively. RESULTS: DNA isolation using buccal swabs yielded a good quality and sufficient quantity of DNA to perform HLA-DQ typing in all individuals. HLA typing results on buccal cell-derived DNA were identical to typing on blood-derived DNA, also for the self-administered samples. CONCLUSION: Introduction of the buccal swab test for HLA typing of CD risk in routine diagnostics can omit the current venipuncture and enables self-administration at home. Therefore, the buccal swab test is beneficial for individuals with a clinical suspicion for CD, as well as for screening purposes in high-risk populations. PMID- 26945704 TI - Disseminated anetoderma in a patient with nodal Epstein-Barr virus-associated classical Hodgkin lymphoma: Anetodermic form of a concurrent discordant cutaneous marginal zone lymphoma. AB - Patients with a lymphoma have an increased risk of developing a second lymphoproliferative disorder. The association of nodal Hodgkin lymphoma and primary cutaneous marginal zone lymphoma (MALT type) is exceptional, and only very few cases have been documented. Anetoderma represents a circumscribed loss or rarefication of elastic fibers. Different underlying processes may result in anetoderma, including cutaneous marginal zone lymphoma. We report a 50-year-old male patient with Epstein-Barr virus (EBV)-associated nodal Hodgkin lymphoma who presented with disseminated anetodermic skin lesions. Biopsies of the skin lesions revealed a B-cell infiltrate containing monoclonal plasma cells but without detection of EBV. The skin lesions represent an anetodermic form of primary cutaneous marginal zone lymphoma. It is the first case report of an association of anetodermic cutaneous marginal zone lymphoma and a synchronous EBV associated nodal Hodgkin lymphoma. PMID- 26945705 TI - Spindle cell hemangioma in an elderly patient: Uncommon benign vascular neoplasm. PMID- 26945707 TI - The antipsychotic story: changes in prescriptions and overdose without better safety. AB - AIMS: Morbidity and mortality from drug overdose has decreased over three decades. This is credited to safer drugs and therefore better outcomes in overdose. We aimed to investigate changing prescriptions of antipsychotic medications and associated changes in antipsychotic overdoses over a 26-year period. METHODS: All antipsychotic poisoning presentations to a tertiary referral toxicology unit between 1987 and 2012 were reviewed. Data were collected prospectively on demographics, ingestion information, clinical effects, complications and treatment. Rates of antipsychotic drug use in Australia were obtained from Australian government publications for 1990-2011 and linked to overdose admissions by postcode. RESULTS: There were 3180 antipsychotic overdoses: 1235 first generation antipsychotics, 1695 'atypical' second generation antipsychotics and 250 lithium overdoses. Over 26 years, antipsychotic overdoses increased 1.8-fold, with first generation antipsychotics decreasing to one-fifth of their peak (~80/year to 16) and second generation antipsychotics increasing to double this (~160/year), olanzapine and quetiapine accounting for 78%. All antipsychotic overdoses had a median length of stay of 18.6 h, 15.7% admitted to intensive care unit, 10.4% ventilated and 0.13% died in hospital, which was the same for first generation compared to second generation antipsychotics. There was a 2.3-fold increase in antipsychotic prescriptions over the same period; first generation antipsychotics declined whereas there was a dramatic rise in second generation antipsychotics, mainly olanzapine, quetiapine and risperidone (79%). CONCLUSION: Over 26 years there was an increase in antipsychotic prescribing associated with an increase in antipsychotic overdoses. Although the type of antipsychotics changed, the morbidity and mortality remained the same, so that antipsychotics are an increasing proportion of overdose admissions. PMID- 26945706 TI - Medication Discrepancies Associated With a Medication Reconciliation Program and Clinical Outcomes After Hospital Discharge. AB - STUDY OBJECTIVE: To identify the frequency of unintended medication discrepancies 30 days postdischarge from medicine wards with interprofessional medication reconciliation processes and clinical import. METHODS: Prospective cohort study of adults discharged between October 2013 and November 2014 from two teaching hospitals in Edmonton, Canada. The Best Possible Medication Discharge Plan (BPMDP) was prepared for all patients. Patients were called 30 days postdischarge to determine the medication discrepancy rate from the BPMDP and whether this was intentional or unintentional; three clinicians used standardized criteria to determine if the discrepancy was inconsequential. Electronic health records and patient contact were used to ascertain death, hospital readmissions, and emergency department (ED) visits at 90 days. RESULTS: Of 433 patients (mean age 64 yrs, 52% female, median discharge prescriptions 6 [interquartile range 4-9]), 168 (38.8%) had at least one unintentional medication discrepancy at 30 days (325 total discrepancies; median one [interquartile range 1-2 discrepancies per patient]). Patients with unintentional medication discrepancies were older (65.9 vs 61.9 yrs, p=0.03) with more discharge medications (7 vs 6, p=0.03). Most unintentional discrepancies (91.1%) were judged inconsequential. The presence of an unintentional medication discrepancy was not associated with 90-day readmission or death (42/167 [25.1%] vs 64/263 [24.3%], adjusted odds ratio 0.96 [95% confidence interval 0.60-1.54]) or ED visits (69 [41.3%] vs 101 [38.4%], adjusted odds ratio 1.11 [95% confidence interval 0.74-1.67]. CONCLUSION: Despite the presence of an interprofessional medication reconciliation process, over one third of patients had a medication discrepancy within 30 days of discharge, although most were inconsequential and there was no association between unintended medication discrepancies and risk of readmission, ED visit, or death 3 months after discharge. PMID- 26945709 TI - Orlistat: weight lost at cost of HIV rebound. PMID- 26945708 TI - Oligonuclear polypyridylruthenium(II) complexes: selectivity between bacteria and eukaryotic cells. AB - OBJECTIVES: The objectives of this study were to: (i) determine the in vitro activities of a series of di-, tri- and tetra-nuclear ruthenium complexes (Rubbn, Rubbn-tri and Rubbn-tetra) against a range of Gram-positive and -negative bacteria and compare the antimicrobial activities with the corresponding toxicities against eukaryotic cells; and (ii) compare MIC values with achievable in vivo serum concentrations for the least toxic ruthenium complex. METHODS: The in vitro activities were determined by MIC assays and time-kill curve experiments, while the toxicities of the ruthenium complexes were determined using the Alamar blue cytotoxicity assay. A preliminary pharmacokinetic study was undertaken to determine the Rubb12 serum concentration in mice as a function of time after administration. RESULTS: Rubb12, Rubb12-tri and Rubb12-tetra are highly active, with MIC values of 1-2 mg/L (0.5-1.5 MUM) for a range of Gram positive strains, but showed variable activities against a panel of Gram-negative bacteria. Time-kill experiments indicated that Rubb12, Rubb12-tri and Rubb12 tetra are bactericidal and kill bacteria within 3-8 h. The di-, tri- and tetra nuclear complexes were ~50 times more toxic to Gram-positive bacteria and 25 times more toxic to Gram-negative strains, classified as susceptible, than to liver and kidney cells. Preliminary pharmacokinetic experiments established that serum concentrations higher than MIC values can be obtained for Rubb12 with an administered dose of 32 mg/kg. CONCLUSIONS: The ruthenium complexes, particularly Rubb12, have potential as new antimicrobial agents. The structure of the dinuclear ruthenium complex can be readily further modified in order to increase the selectivity for bacteria over eukaryotic cells. PMID- 26945710 TI - Antibiotic prescribing for children in primary care and adherence to treatment guidelines. AB - OBJECTIVES: Antibiotic use is unnecessarily high for paediatric respiratory tract infections (RTIs) in primary care, and implementation of treatment guidelines is difficult in practice. This study aims to assess guideline adherence to antibiotic prescribing for RTIs in children and examine potential variations across Dutch general practices. METHODS: We conducted a retrospective observational study, deriving data on diagnoses and prescriptions from the electronic health records-based NIVEL Primary Care Database. Patients <18 years of age with a diagnosis of fever, ear and respiratory infections (International Classification of Primary Care codes A03, H71, R72, R75, R76, R78 and R81) during 2010-12 were included. Antibiotics were linked to episodes of illness. Two types of disease-specific outcomes were used to assess adherence to national guidelines regarding antibiotic prescribing choices. Inter-practice variability in adherence was assessed with multilevel analysis. RESULTS: Half of the episodes with RTIs with restrictive prescribing policy and 65% of episodes with pneumonia were treated with antibiotics. General practitioners prescribed antibiotics for 40% of episodes with bronchitis, even though guidelines discourage antibiotic prescribing. First-choice antibiotics were prescribed in 50%-85% of episodes with selected diseases, with lowest values for narrow-spectrum penicillins. Levels of adherence to guidelines varied widely between diagnoses and between practices. CONCLUSIONS: Most paediatric RTIs in the Netherlands continue to be treated with antibiotics conservatively. Potential aspects of concern are the inappropriate antibiotic prescribing for acute bronchitis and the underuse of some first-choice antibiotics. Continuing progress may be achieved by targeting practices with lower adherence rates to guidelines. PMID- 26945712 TI - Extensive antibiotic prescription rate among hospitalized patients in Uganda: but with frequent missed-dose days. AB - OBJECTIVES: To describe the patterns of systemic antibiotic use and missed-dose days and detail the prescription, dispensing and administration of frequently used hospital-initiated antibiotics among Ugandan inpatients. METHODS: This was a prospective cohort of consented adult inpatients admitted on the medical and gynaecological wards of the 1790 bed Mulago National Referral Hospital. RESULTS: Overall, 79% (603/762; 95% CI: 76%-82%) of inpatients received at least one antibiotic during hospitalization while 39% (300/762; 95% CI: 36%-43%) had used at least one antibiotic in the 4 weeks pre-admission; 1985 antibiotic DDDs, half administered parenterally, were consumed in 3741 inpatient-days. Two-fifths of inpatients who received at least one of the five frequently used hospital initiated antibiotics (ceftriaxone, metronidazole, ciprofloxacin, amoxicillin and azithromycin) missed at least one antibiotic dose-day (44%, 243/558). The per-day risk of missed antibiotic administration was greatest on day 1: ceftriaxone (36%, 143/398), metronidazole (27%, 67/245), ciprofloxacin (34%, 39/114) and all inpatients who missed at least one dose-day of prescribed amoxicillin and azithromycin. Most patients received fewer doses than were prescribed: ceftriaxone (74%, 273/371), ciprofloxacin (90%, 94/105) and metronidazole (97%, 222/230). Of prescribed doses, only 62% of ceftriaxone doses (1178/1895), 35% of ciprofloxacin doses (396/1130) and 27% of metronidazole doses (1043/3862) were administered. Seven percent (13/188) of patients on intravenous metronidazole and 6% (5/87) on intravenous ciprofloxacin switched to oral route. CONCLUSIONS: High rates of antibiotic use both pre-admission and during hospitalization were observed, with low parenteral/oral switch of hospital-initiated antibiotics. Underadministration of prescribed antibiotics was common, especially on the day of prescription, risking loss of efficacy and antibiotic resistance. PMID- 26945713 TI - Cobicistat versus ritonavir boosting and differences in the drug-drug interaction profiles with co-medications. AB - Nearly all HIV PIs and the integrase inhibitor elvitegravir require a pharmacokinetic enhancer in order to achieve therapeutic plasma concentrations at the desired dose and frequency. Whereas ritonavir has been the only available pharmacokinetic enhancer for more than a decade, cobicistat has recently emerged as an alternative boosting agent. Cobicistat and ritonavir are equally strong inhibitors of cytochrome P450 (CYP) 3A4 and consequently were shown to be equivalent pharmacokinetic enhancers for elvitegravir and for the PIs atazanavir and darunavir. Since cobicistat is a more selective CYP inhibitor than ritonavir and is devoid of enzyme-inducing properties, differences are expected in their interaction profiles with some co-medications. Drugs whose exposure might be altered by ritonavir but unaltered by cobicistat are drugs primarily metabolized by CYP1A2, CYP2B6, CYP2C8, CYP2C9 and CYP2C19 or drugs undergoing mainly glucuronidation. Thus, co-medications should be systematically reviewed when switching the pharmacokinetic enhancer to anticipate potential dosage adjustments. PMID- 26945711 TI - Atazanavir/ritonavir monotherapy: 96 week efficacy, safety and bone mineral density from the MODAt randomized trial. AB - OBJECTIVES: To report the 96 week results on efficacy, safety and bone mineral density (BMD) in subjects with HIV-1 that were virologically suppressed and treated with atazanavir/ritonavir monotherapy versus atazanavir/ritonavir triple therapy. METHODS: MODAt is a prospective, multicentre, open-label, non inferiority, randomized, 96 week trial (NCT01511809) comparing efficacy of atazanavir/ritonavir monotherapy versus atazanavir/ritonavir triple therapy. Treatment success was defined as no occurrence of confirmed viral rebound (two consecutive HIV-RNA >50 copies/mL) or discontinuation for any cause of the ongoing regimen. RESULTS: The 96 week treatment success was 64% in the atazanavir/ritonavir monotherapy arm and 63% in the triple-therapy arm (difference 1.3%, 95% CI: -17.5 to 20.1). In the atazanavir/ritonavir monotherapy arm, no PI- or NRTI-associated resistance mutations were observed at virological failure and all patients re-suppressed after re-intensification. In the monotherapy arm, treatment failure was more frequent in patients coinfected with hepatitis C virus [64% versus 28% (difference 35.4%, 95% CI: 3.7-67.2)]. Drug related adverse events leading to discontinuation were 3 (6%) in the atazanavir/ritonavir monotherapy arm and 11 (21.5%) in the triple-therapy arm (P = 0.041). The 96 week adjusted mean percentage change in total proximal femur (not at lumbar spine) BMD was +1.16% and -1.64% in the atazanavir/ritonavir monotherapy arm and the triple-therapy arm, respectively (P = 0.012). CONCLUSIONS: The 96 week analyses suggested that long-term efficacy of atazanavir/ritonavir monotherapy was inferior as compared with atazanavir/ritonavir triple therapy, particularly when administered in subjects coinfected with hepatitis C virus. In the atazanavir/ritonavir monotherapy arm, reintroduction of nucleosides, as needed, was always effective with no new resistance mutation; monotherapy was also associated with a lower incidence of adverse events and improvement in femur BMD. PMID- 26945714 TI - Inactivation or inhibition of AcrAB-TolC increases resistance of carbapenemase producing Enterobacteriaceae to carbapenems. AB - OBJECTIVES: The objective of this study was to study the contribution of the multidrug resistance AcrAB-TolC efflux system to carbapenem resistance in carbapenemase-producing Enterobacteriaceae and the impact of the efflux inhibitor PABN on this resistance. METHODS: Klebsiella pneumoniae, Escherichia coli, Salmonella enterica serovar Typhimurium and their corresponding AcrAB-TolC mutants, each carrying carbapenemase-carrying plasmids (pKpQIL-UK with blaKPC and pNDM-HK with blaNDM), were tested for their susceptibility to six beta-lactam antibiotics according to the BSAC agar dilution method. MICs were also determined in the presence of efflux inhibitors. The susceptibility of ertapenem in the presence of 25 and 100 mg/L PABN was also determined for 86 non-replicate clinical isolates of carbapenemase-producing Enterobacteriaceae with OXA-48-like (n = 18), IMP (n = 12), VIM (n = 16), NDM (n = 20) or KPC (n = 20) enzymes. Outer membrane protein profiles were determined with SDS-PAGE. RESULTS: The carbapenemase-producing AcrAB mutants of K. pneumoniae and E. coli and the TolC mutant of Salmonella Typhimurium had elevated resistance to carbapenem antibiotics. In Salmonella Typhimurium, the increase in carbapenem MIC correlated with the loss of OmpF. Sixty-two (72%) of the clinical isolates tested were also more resistant to ertapenem in the presence of PABN. SDS-PAGE showed that the presence of PABN affected outer membrane porin production, which was associated with the increased MIC values of ertapenem. CONCLUSIONS: The decreased susceptibility to carbapenems of carbapenemase-producing Enterobacteriaceae in the absence of AcrAB or TolC and/or in the presence of an efflux inhibitor (e.g. PABN) is likely due to the changes in porin expression (e.g. OmpF). Efflux inhibitors may not potentiate carbapenem activity, but rather could increase levels of resistance in carbapenemase-producing organisms. PMID- 26945715 TI - Who can get the next Nobel Prize in infectious diseases? AB - The aim of this paper is to deliver a perspective on future Nobel prizes by reviewing the features of Nobel prizes awarded in the infectious diseases-related (IDR) field over the last 115 years. Thirty-three out of 106 Nobel prizes (31%) in Physiology or Medicine have been awarded for IDR topics. Out of 58 Nobel laureates for IDR topics, two have been female; 67% have been medical doctors. The median age of Nobel laureates in Physiology or Medicine was found to be lower than the median age of laureates in Literature (p<0.001). Since the Second World War, US-affiliated scientists have dominated the Nobel prizes (53%); however before 1945, German scientists did so (p=0.005). The new antimicrobials received Nobel prizes until 1960; however no treatment study was awarded the Prize until the discovery of artemisinin and ivermectin, for which the Nobel Prize was awarded in 2015. Collaborative works have increasingly been appreciated. In the future, more female laureates would be expected in the IDR field. Medical graduates and scientists involved in multi-institutional and multidisciplinary collaborative efforts seem to have an advantage. PMID- 26945716 TI - Solvothermal synthesis of different phase N-TiO2 and their kinetics, isotherm and thermodynamic studies on the adsorption of methyl orange. AB - The different crystal forms of nitrogen doped-titanium oxide (N-TiO2) with different particle sizes were produced by precipitation-solvothermal method and their adsorption mechanism were also investigated. The adsorption kinetics showed that rutile N-TiO2 displayed higher adsorption capacity than anatase for methyl orange (MO) and its adsorption behavior followed the pseudo-second-order kinetics. The equilibrium adsorption rate of N-TiO2 for MO was well fitted by the Langmuir isotherm model and the adsorption process was monolayer adsorption. The adsorption capacity decreased with increasing temperature. The average correlation coefficient was beyond 97%. The thermodynamic parameters (DeltaaGm(?), DeltaaHm(?), and DeltaaSm(?)) were calculated. It was found that anatase and rutile N-TiO2 had different adsorption enthalpy and entropy. The smaller the particle size, the greater the surface area and surface energy was, then DeltaaGm(?) decreased and the standard equilibrium constant increased at the same time. The adsorption process onto different crystalline phase N-TiO2 was exothermic and non-spontaneous. PMID- 26945718 TI - Coiled-coil domain containing 42 (Ccdc42) is necessary for proper sperm development and male fertility in the mouse. AB - Spermiogenesis is the differentiation of spermatids into motile sperm consisting of a head and a tail. The head harbors a condensed elongated nucleus partially covered by the acrosome-acroplaxome complex. Defects in the acrosome-acroplaxome complex are associated with abnormalities in sperm head shaping. The head-tail coupling apparatus (HTCA), a complex structure consisting of two cylindrical microtubule-based centrioles and associated components, connects the tail or flagellum to the sperm head. Defects in the development of the HTCA cause sperm decapitation and disrupt sperm motility, two major contributors to male infertility. Here, we provide data indicating that mutations in the gene Coiled coil domain containing 42 (Ccdc42) is associated with malformation of the mouse sperm flagella. In contrast to many other flagella and motile cilia genes, Ccdc42 expression is only observed in the brain and developing sperm. Male mice homozygous for a loss-of-function Ccdc42 allele (Ccdc42(KO)) display defects in the number and location of the HTCA, lack flagellated sperm, and are sterile. The testes enriched expression of Ccdc42 and lack of other phenotypes in mutant mice make it an ideal candidate for screening cases of azoospermia in humans. PMID- 26945720 TI - Femorotibial kinematics and load patterns after total knee arthroplasty: An in vitro comparison of posterior-stabilized versus medial-stabilized design. AB - BACKGROUND: Femorotibial kinematics and contact patterns vary greatly with different total knee arthroplasty (TKA) designs. Therefore, guided motion knee systems were developed to restore natural knee kinematics and make them more predictable. The medial stabilized TKA design is supposed to replicate physiological kinematics more than the posterior-stabilized TKA system. We conducted this study to compare a newly developed medial stabilized design with a conventional posterior-stabilized design in terms of femorotibial kinematics and contact patterns in vitro. METHODS: Twelve fresh-frozen knee specimens were tested in a weight-bearing knee rig after implantation of a posterior stabilized and medial-stabilized total knee arthroplasty under a loaded squat from 20 degrees to 120 degrees of flexion. Femorotibial joint contact pressures in the medial and lateral compartments were measured by pressure sensitive films and knee kinematics were recorded by an ultrasonic 3-dimensional motion analysis system. FINDINGS: The medial stabilized design showed a reduction of medial femorotibial translation compared to posterior-stabilized design (mean 3.5mm compared to 15.7 mm, P<0.01). In the lateral compartment, both designs showed a posterior translation of the femur with flexion, but less in the medial stabilized design (mean 14.7 mm compared to 19.0mm, P<0.01). In the medial femorotibial compartment of medial stabilized design, we observed an enlarged contact area and lower peak pressure, in contrast in the lateral compartment there was a reduced contact area and an increased peak pressure. INTERPRETATION: While posterior-stabilized design enforces a medio-lateral posterior translation, the medial stabilized arthroplasty system enables a combination of a lateral translation with a medial pivot, which restores the physiological knee kinematics better. PMID- 26945719 TI - Compensatory strategies during manual wheelchair propulsion in response to weakness in individual muscle groups: A simulation study. AB - BACKGROUND: The considerable physical demand placed on the upper extremity during manual wheelchair propulsion is distributed among individual muscles. The strategy used to distribute the workload is likely influenced by the relative force-generating capacities of individual muscles, and some strategies may be associated with a higher injury risk than others. The objective of this study was to use forward dynamics simulations of manual wheelchair propulsion to identify compensatory strategies that can be used to overcome weakness in individual muscle groups and identify specific strategies that may increase injury risk. Identifying these strategies can provide rationale for the design of targeted rehabilitation programs aimed at preventing the development of pain and injury in manual wheelchair users. METHODS: Muscle-actuated forward dynamics simulations of manual wheelchair propulsion were analyzed to identify compensatory strategies in response to individual muscle group weakness using individual muscle mechanical power and stress as measures of upper extremity demand. FINDINGS: The simulation analyses found the upper extremity to be robust to weakness in any single muscle group as the remaining groups were able to compensate and restore normal propulsion mechanics. The rotator cuff muscles experienced relatively high muscle stress levels and exhibited compensatory relationships with the deltoid muscles. INTERPRETATION: These results underline the importance of strengthening the rotator cuff muscles and supporting muscles whose contributions do not increase the potential for impingement (i.e., the thoracohumeral depressors) and minimize the risk of upper extremity injury in manual wheelchair users. PMID- 26945717 TI - The analysis of novel distal Cebpa enhancers and silencers using a transcriptional model reveals the complex regulatory logic of hematopoietic lineage specification. AB - C/EBPalpha plays an instructive role in the macrophage-neutrophil cell-fate decision and its expression is necessary for neutrophil development. How Cebpa itself is regulated in the myeloid lineage is not known. We decoded the cis regulatory logic of Cebpa, and two other myeloid transcription factors, Egr1 and Egr2, using a combined experimental-computational approach. With a reporter design capable of detecting both distal enhancers and silencers, we analyzed 46 putative cis-regulatory modules (CRMs) in cells representing myeloid progenitors, and derived early macrophages or neutrophils. In addition to novel enhancers, this analysis revealed a surprisingly large number of silencers. We determined the regulatory roles of 15 potential transcriptional regulators by testing 32,768 alternative sequence-based transcriptional models against CRM activity data. This comprehensive analysis allowed us to infer the cis-regulatory logic for most of the CRMs. Silencer-mediated repression of Cebpa was found to be effected mainly by TFs expressed in non-myeloid lineages, highlighting a previously unappreciated contribution of long-distance silencing to hematopoietic lineage resolution. The repression of Cebpa by multiple factors expressed in alternative lineages suggests that hematopoietic genes are organized into densely interconnected repressive networks instead of hierarchies of mutually repressive pairs of pivotal TFs. More generally, our results demonstrate that de novo cis-regulatory dissection is feasible on a large scale with the aid of transcriptional modeling. Current address: Department of Biology, University of North Dakota, 10 Cornell Street, Stop 9019, Grand Forks, ND 58202-9019, USA. PMID- 26945721 TI - Immediate effects of modified landing pattern on a probabilistic tibial stress fracture model in runners. AB - BACKGROUND: Tibial stress fracture is a common injury in runners. This condition has been associated with increased impact loading. Since vertical loading rates are related to the landing pattern, many heelstrike runners attempt to modify their footfalls for a lower risk of tibial stress fracture. Such effect of modified landing pattern remains unknown. This study examined the immediate effects of landing pattern modification on the probability of tibial stress fracture. METHODS: Fourteen experienced heelstrike runners ran on an instrumented treadmill and they were given augmented feedback for landing pattern switch. We measured their running kinematics and kinetics during different landing patterns. Ankle joint contact force and peak tibial strains were estimated using computational models. We used an established mathematical model to determine the effect of landing pattern on stress fracture probability. FINDINGS: Heelstrike runners experienced greater impact loading immediately after landing pattern switch (P<0.004). There was an increase in the longitudinal ankle joint contact force when they landed with forefoot (P=0.003). However, there was no significant difference in both peak tibial strains and the risk of tibial stress fracture in runners with different landing patterns (P>0.986). INTERPRETATION: Immediate transitioning of the landing pattern in heelstrike runners may not offer timely protection against tibial stress fracture, despite a reduction of impact loading. Long-term effects of landing pattern switch remains unknown. PMID- 26945722 TI - Computer aided analysis of gait patterns in patients with acute anterior cruciate ligament injury. AB - BACKGROUND: Gait analysis is a useful tool to evaluate the functional status of patients with anterior cruciate ligament injury. Pattern recognition methods can be used to automatically assess walking patterns and objectively support clinical decisions. This study aimed to test a pattern recognition system for analyzing kinematic gait patterns of recently anterior cruciate ligament injured patients and for evaluating the effects of a therapeutic treatment. METHODS: Gait kinematics of seven male patients with an acute unilateral anterior cruciate ligament rupture and seven healthy males were recorded. A support vector machine was trained to distinguish the groups. Principal component analysis and recursive feature elimination were used to extract features from 3D marker trajectories. A Classifier Oriented Gait Score was defined as a measure of gait quality. Visualizations were used to allow functional interpretations of characteristic group differences. The injured group was evaluated by the system after a therapeutic treatment. The results were compared against a clinical rating of the patients' gait. FINDINGS: Cross validation yielded 100% accuracy. After the treatment the score improved significantly (P<0.01) as well as the clinical rating (P<0.05). The visualizations revealed characteristic kinematic features, which differentiated between the groups. INTERPRETATION: The results show that gait alterations in the early phase after anterior cruciate ligament injury can be detected automatically. The results of the automatic analysis are comparable with the clinical rating and support the validity of the system. The visualizations allow interpretations on discriminatory features and can facilitate the integration of the results into the diagnostic process. PMID- 26945723 TI - A Prospective Study of Biometric Stability After Scleral Buckling Surgery. AB - PURPOSE: To assess time to stabilization and factors associated with changes in biometric parameters after scleral buckling (SB). DESIGN: Prospective case series. METHODS: Seventeen eyes with primary rhegmatogenous retinal detachment (RRD) that underwent SB at the Singapore National Eye Centre were enrolled. SB surgery was performed using an encircling element and segmental buckle. Axial length (AL); anterior chamber depth (ACD), defined as the distance from the corneal epithelium to the anterior lens surface; anterior/posterior corneal curvature (K); and refraction were measured preoperatively and at week 1 and months 1, 3, 6, 9, and 12 postoperatively. Stability of each parameter was defined as the earliest time point at which there is no significant difference compared to its value at month 12. RESULTS: AL increased (26.09 +/- 1.46 to 26.51 +/- 1.96, P = .01), ACD decreased (3.84 +/- 0.47 to 3.32 +/- 0.57, P < .001), and a myopic shift of 1.04 diopters (95% CI 0.03-2.05, P = .04) occurred at month 12. Anterior/posterior K were not significantly changed from baseline. AL stabilized at month 3 while ACD and spherical equivalent (SE) stabilized at week 1. Cryotherapy was associated with greater increase in AL (P = .001) and myopic shift (P = .02). More extensive segmental buckling was associated with greater increase in AL (P = .009) and myopic shift (P = .03). CONCLUSIONS: Our study suggests that patients requiring cataract surgery after SB should have biometry performed no earlier than 3 months post SB surgery, and intraocular lens power calculation with a fourth-generation formula. A greater increase in AL and myopic shift was associated with cryotherapy and more extensive segmental buckling. PMID- 26945724 TI - Iron depletion in HCT116 cells diminishes the upregulatory effect of phenethyl isothiocyanate on heme oxygenase-1. AB - Some of the health-promoting properties of cruciferous vegetables are thought to be partly attributed to isothiocyanates. These phytochemicals can upregulate the expression of certain cytoprotective stress genes, but it is unknown if a particular nutrient is involved. Herein, the objective was to ascertain if adequate iron is needed for enabling HCT116 cells to optimally express heme oxygenase-1 (HO-1) when induced by phenethyl isothiocyanate (PEITC). PEITC increased HO-1 expression and also nuclear translocation of Nrf2, which is a transcription factor known to activate the HO-1 gene. However, in HCT116 cells that were made iron-deficient by depleting intracellular iron with deferoxamine (DFO), PEITC was less able to increase HO-1 expression and nuclear translocation of Nrf2. These suppressive effects of DFO were overcome by replenishing the iron deficient cells with the missing iron. To elucidate these findings, it was found that PEITC-induced HO-1 upregulation can be inhibited with thiol antioxidants (glutathione and N-acetylcysteine). Furthermore, NADPH oxidase inhibitors (diphenyleneiodonium and apocynin) and a superoxide scavenger (Tiron) each inhibited PEITC-induced HO-1 upregulation. In doing so, diphenyleneiodonium was the most potent and also inhibited nuclear translocation of redox-sensitive Nrf2. Collectively, the results imply that the HO-1 upregulation by PEITC involves an iron-dependent, oxidant signaling pathway. Therefore, it is concluded that ample iron is required to enable PEITC to fully upregulate HO-1 expression in HCT116 cells. As such, it is conceivable that iron-deficient individuals may not reap the full health benefits of eating PEITC-containing cruciferous vegetables that via HO-1 may help protect against multiple chronic diseases. PMID- 26945725 TI - Uterine responses to feeding soy protein isolate and treatment with 17beta estradiol differ in ovariectomized female rats. AB - There are concerns regarding reproductive toxicity from consumption of soy foods, including an increased risk of endometriosis and endometrial cancer, as a result of phytoestrogen consumption. In this study, female rats were fed AIN-93G diets made with casein (CAS) or soy protein isolate (SPI) from postnatal day (PND) 30, ovariectomized on PND 50 and infused with 5 MUg/kg/d 17beta-estradiol (E2) or vehicle. E2 increased uterine wet weight (P<0.05). RNAseq analysis revealed that E2 significantly altered expression of 1991 uterine genes (P<0.05). SPI feeding had no effect on uterine weight and altered expression of far fewer genes than E2 at 152 genes (P<0.05). Overlap between E2 and SPI genes was limited to 67 genes. Functional annotation analysis indicated significant differences in uterine biological processes affected by E2 and SPI and little evidence for recruitment of estrogen receptor (ER)alpha to the promoters of ER-responsive genes after SPI feeding. The major E2 up-regulated uterine pathways were carcinogenesis and extracellular matrix organization, whereas SPI feeding up-regulated uterine peroxisome proliferator activated receptor (PPAR) signaling and fatty acid metabolism. The combination of E2 and SPI resulted in significant regulation of 504 fewer genes relative to E2 alone. The ability of E2 to induce uterine proliferation in response to the carcinogen dimethybenz(a)anthracene (DMBA) as measured by expression of PCNA and Ki67 mRNA was suppressed by feeding SPI (P<0.05). These data suggest that SPI is a selective estrogen receptor modulator (SERM) interacting with a small sub-set of E2-regulated genes and is anti estrogenic in the presence of endogenous estrogens. PMID- 26945726 TI - Editorial. PMID- 26945727 TI - Dose-response analysis indicating time-dependent neurotoxicity caused by organic and inorganic mercury-Implications for toxic effects in the developing brain. AB - A latency period preceding neurotoxicity is a common characteristic in the dose response relationship induced by organic mercury. Latency periods have typically been observed with genotoxicants in carcinogenesis, with cancer being manifested a long time after the initiating event. These observations indicate that even a very small dose may cause extensive adverse effects later in life, so the toxicity of the genotoxic compound is dose and time-dependent. In children, methylmercury exposure during pregnancy (in utero) has been associated with delays in reaching developmental milestones (e.g., age at first walking) and decreases in intelligence, increasing in severity with increasing exposure. Ethylmercury exposure from thimerosal in some vaccines has been associated, in some studies, with autism and other neurological disorders in children. In this paper, we have examined whether dose-response data from in vitro and in vivo organic mercury toxicity studies fit the Druckrey-Kupfmuller equation c.t(n)=constant (c=exposure concentration, t=latency period), first established for genotoxic carcinogens, and whether or not irreversible effects are enhanced by time of exposure (n>=1), or else toxic effects are dose-dependent while time has only minor influence on the adverse outcome (n<1). The mode of action underlying time-dependent toxicity is irreversible binding to critical receptors causing adverse and cumulative effects. The results indicate that the Druckrey Kupfmuller equation describes well the dose-response characteristics of organic mercury induced neurotoxic effects. This amounts to a paradigm shift in chemical risk assessment of mercurial compounds and highlights that it is vital to perform toxicity testing geared to investigate time-dependent effects. PMID- 26945728 TI - Design and construction of a new human naive single-chain fragment variable antibody library, IORISS1. AB - Human monoclonal antibodies are a powerful tool with increasingly successful exploitations and the single chain fragment variable format can be considered the building block for the implementation of more complex and effective antibody based constructs. Phage display is one of the best and most efficient methods to isolate human antibodies selected from an efficient and variable phage display library. We report a method for the construction of a human naive single-chain variable fragment library, termed IORISS1. Many different sets of oligonucleotide primers as well as optimized electroporation and ligation reactions were used to generate this library of 1.2*10(9) individual clones. The key difference is the diversity of variable gene templates, which was derived from only 15 non immunized human donors. The method described here, was used to make a new human naive single-chain fragment variable phage display library that represents a valuable source of diverse antibodies that can be used as research reagents or as a starting point for the development of therapeutics. Using biopanning, we determined the ability of IORISS1 to yield antibodies. The results we obtained suggest that, by using an optimized protocol, an efficient phage antibody library can be generated. PMID- 26945729 TI - Voluntary emotion regulation in anorexia nervosa: A preliminary emotion-modulated startle investigation. AB - Emotion regulation difficulties are implicated in the development and maintenance of anorexia nervosa (AN). However, research has been limited by an almost exclusive reliance on self-report. This study is the first to use the emotion modulated startle paradigm (EMSP) to investigate emotional reactivity and voluntary emotion regulation in individuals with AN. Twenty women with AN viewed negative, positive, neutral, and food images and were asked to enhance, suppress, or maintain their emotional responses mid-way through picture presentation. Startle eyeblink magnitudes in response to startle probes administered prior, and subsequent, to regulation instructions indexed emotional reactivity and regulation, respectively. On emotional reactivity trials, startle magnitudes were greater for negative, positive, and food images, compared to neutral images. Participants had difficulty suppressing startle responses to negative and food images, as indicated by non-significant suppress-maintain comparisons. In contrast, startle responses to enhance and suppress cues during presentation of pleasant images were comparable and significantly lower than maintain cues. Findings converge with self-report data to suggest that patients with AN have difficulties with voluntary emotion regulation. The EMSP may be a promising trans diagnostic method for examining emotion regulation difficulties that underlie risk for eating disorders and other psychiatric conditions. PMID- 26945730 TI - Cerebrovascular endothelial dysfunction induced by mercury exposure at low concentrations. AB - Mercury (Hg) has many harmful vascular effects by increasing oxidative stress, inflammation and vascular/endothelial dysfunction, all of which may contribute to cerebrovascular diseases development. We aimed to explore the effects of chronic low-mercury concentration on vascular function in cerebral arteries and the mechanisms involved. Basilar arteries from control (vehicle-saline solution, im) and mercury chloride (HgCl2)-treated rats for 30 days (first dose 4.6MUg/kg, subsequent dose 0.07MUg/kg/day, im, to cover daily loss) were used. Vascular reactivity, protein expression, nitric oxide (NO) levels and superoxide anion (O2(-)) production were analyzed. HgCl2 exposure increased serotonin contraction and reduced the endothelium-dependent vasodilatation to bradykinin. After NO synthase inhibition, serotonin responses were enhanced more in control than in mercury-treated rats while bradykinin-induced relaxation was abolished. NO levels were greater in control than Hg-treated rats. Tiron and indomethacin reduced vasoconstriction and increased the bradykinin-induced relaxation only in HgCl2 treated rats. Vascular O2(-) production was greater in mercury-treated when compared to control rats. Protein expressions of endothelial NO synthase, copper/zinc (Cu/Zn), Manganese (Mn) and extracellular-superoxide dismutases were similar in cerebral arteries from both groups. Results suggest that Hg treatment increases cerebrovascular reactivity by reducing endothelial negative modulation and NO bioavailability; this effect seems to be dependent on increased reactive oxygen species and prostanoids generation. These findings show, for the first time, that brain vasculature are also affected by chronic mercury exposure and offer further evidence that even at small concentration, HgCl2 is hazardous and might be an environmental risk factor accounting for cerebral vasospasm development. PMID- 26945732 TI - Transitions. PMID- 26945731 TI - Long-term exposure to ELF-MF ameliorates cognitive deficits and attenuates tau hyperphosphorylation in 3xTg AD mice. AB - Although numerous studies have reported the influence of extremely low frequency magnetic field (ELF-MF) exposure on human health, its effects on cognitive deficits in Alzheimer's disease (AD) have remained under debate. Moreover, the influence of ELF-MF on hyperphosphorylated tau, which is one of the most common pathological hallmarks of AD, has not been reported to date. Therefore, transgenic mice (3xTg) were used in the present study. 3xTg mice, which express an APP/PS1 mutation combined with a tau (P301L) mutation and that develop cognitive deficits at 6 months of age, were subjected to ELF-MF (50Hz, 500MUT) exposure or sham exposure daily for 3 months. We discovered that ELF-MF exposure ameliorated cognitive deficits and increased synaptic proteins in 3xTg mice. The protective effects of ELF-MF exposure may have also been caused by the inhibition of apoptosis and/or decreased oxidative stress levels that were observed in the hippocampus tissues of treated mice. Furthermore, tau hyperphosphorylation was decreased in vivo because of ELF-MF exposure, and this decrease was induced by the inhibition of GSK3beta and CDK5 activities and activation of PP2Ac. We are the first to report that exposure to ELF-MF can attenuate tau phosphorylation. These findings suggest that ELF-MF exposure could act as a valid therapeutic strategy for ameliorating cognitive deficits and attenuating tau hyperphosphorylation in AD. PMID- 26945733 TI - An Enigma. PMID- 26945734 TI - Frontiers of Ocular Surface Regenerative Medicine. PMID- 26945735 TI - Macroporous natural capsules extracted from Phoenix dactylifera L. spore and their application in oral drugs delivery. AB - Macroporous natural sporopollenin exine capsules (SEC) were extracted from date palm (Phoenix dactylifera L.) and coated by natural polymer composite (carboxymethyl cellulose with epichlorohydrin). The polymer coated exine capsules (PCEC) were used in in-vitro investigations for controlled delivery of paracetamol. SEC, PCEC, and drugs loaded capsules (PCEC-PAR) were characterized by scanning electron microscope (SEM), surface area (BET), Fourier-transform infrared (FT-IR), X-ray diffraction (XRD), differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA). The length of SEC was found to be 20 20.5 MUm, and the pore sized was 50-135 nm, as measured using SEM. The studies revealed that maximum loading of the drug was at pH 6.0 (97.2%, with 50 mg mL( 1)). The results indicate that by increasing the pH from 1.4 to 7.4, the cumulative release rates of paracetamol in physiological buffer solution (PBS) is more than two times as in simulated gastric fluid (SGF). In addition, the in vitro toxicity of PCEC against Caco-2 cells was tested by the 3-[4,5 dimethylthiazole-2-yl]-2,5 diphenyltetrazolium bromide (MTT) assay, and the results revealed that PCEC are biocompatible materials. The overall results encourage further studies on the clinical use of PCEC as drug carriers. PMID- 26945736 TI - Control of biofilm-associated infections by signaling molecules and nanoparticles. AB - As the severe infections caused by resistant pathogens and biofilm embedded bacteria continue to emerge, alternative antimicrobial strategies could represent a solution. Recent studies support the development of molecular approaches (through signaling molecules) aiming to fight infections by modulating the virulence, behavior and formation of resistance structures such as biofilms. The utilization of such formulations would offer the advantage of reducing the selection of resistant isolates, since most of the proposed molecules do not interfere with the population fitness if utilized in low amounts. Despite the promising results, these therapies are delaying to be applied in the clinical context mainly because of the following: (i) limited knowledge regarding their long and medium term effect, (ii) specific properties that make most of these molecules difficult to be utilized in pharmacological formulations, (iii) low stability, (iv) difficulty to reach a target within the host body, and (v) limited availability. For reducing most of these disadvantages, nanotechnology seem to offer the best option through the development of nanostructured materials and nanoparticles able to improve the efficiency of molecular virulence modulators and novel antimicrobial compounds and to ensure their targeted delivery and controlled release. PMID- 26945737 TI - Differential proteomics reveals the hallmarks of seed development in common bean (Phaseolus vulgaris L.). AB - Common bean (Phaseolus vulgaris L.) is one of the most consumed staple foods worldwide. Little is known about the molecular mechanisms controlling seed development. This study aims to comprehensively describe proteome dynamics during seed development of common bean. A high-throughput gel-free proteomics approach (LC-MS/MS) was conducted on seeds at 10, 20, 30 and 40days after anthesis, spanning from late embryogenesis until desiccation. Of the 418 differentially accumulated proteins identified, 255 were characterized, most belonging to protein metabolism. An accumulation of proteins belonging to the MapMan functional categories of "protein", "glycolysis", "TCA", "DNA", "RNA", "cell" and "stress" were found at early seed development stages, reflecting an extensive metabolic activity. In the mid stages, accumulation of storage, signaling, starch synthesis and cell wall-related proteins stood out. In the later stages, an increase in proteins related to redox, protein degradation/modification/folding and nucleic acid metabolisms reflect that seed desiccation-resistance mechanisms were activated. Our study unveils new clues to understand the regulation of seed development mediated by post-translational modifications and maintenance of genome integrity. This knowledge enhances the understanding on seed development molecular mechanisms that may be used in the design and selection of common bean seeds with desired quality traits. SIGNIFICANCE: Common bean (P. vulgaris) is an important source of proteins and carbohydrates worldwide. Despite the agronomic and economic importance of this pulse, knowledge on common bean seed development is limited. Herein, a gel-free high throughput methodology was used to describe the proteome changes during P. vulgaris seed development. Data obtained will enhance the knowledge on the molecular mechanisms controlling this grain legume seed development and may be used in the design and selection of common bean seeds with desired quality traits. Results may be extrapolated to other pulses. PMID- 26945738 TI - Comparative proteomic study of the response to hypoxia in the muscle of oriental river prawn (Macrobrachium nipponense). AB - Adaptation to hypoxia is a complex process involving up- or down-regulation of numerous different proteins. In order to understand the molecular responses to hypoxia in crustacean muscle tissue, flow cytometry and oxidative stress analysis were used to explore the (hypoxia) physiological response on Macrobrachium nipponense. A 2D-gel-based proteomic approach was performed to compare the muscle proteome of hypoxic and normoxic M. nipponense. MALDI-TOF/TOF identified 15 and five proteins were significantly up- and down-regulated, respectively, in M. nipponense muscle under hypoxic conditions for 24h. Five spots were confirmed as hemocyanin, indicating an important role in environmental regulation. Real-time quantitative PCR confirmed that hemocyanin, heat shock protein 70, glutathione S transferases, metallothionein, phosphofructokinase, and pyruvate kinase 2 were all up-regulated by hypoxia stress. These results suggest that the cellular response to hypoxia involves regulating proteins that function in maintaining antioxidative capacity, energy levels and muscle structure. Western blotting confirmed that the well-known hypoxic stress markers hemocyanin and heat shock protein 70 were up-regulated. These results increase our understanding of hypoxia induced proteomic and transcriptional changes in M. nipponense muscle tissue. BIOLOGICAL SIGNIFICANCE: This 2-DE proteomic study investigated differentially expressed proteins in the muscle of prawns following hypoxia. Identified proteins may have roles in the response to hypoxia. These results improve our understanding of hypoxic stress in crustaceans and aquatic ecosystems. PMID- 26945739 TI - Peptidome profiling of umbilical cord plasma associated with gestational diabetes induced fetal macrosomia. AB - Fetal macrosomia, defined as a birth weight >=4000g, may affect 15-45% of newborns of women with gestational diabetes mellitus (GDM). The associations between endogenous peptides and gestational diabetes-induced macrosomia have not been investigated extensively by peptidome analysis. Here, we analyzed the umbilical cord plasma by combining ultrafiltration using molecular weight cut-off filters and liquid chromatography-tandem mass spectrometry (LC-MS/MS) to investigate potential associations of GDM with macrosomia. As macrosomic babies have increased susceptibility to obesity, diabetes and cardiovascular diseases in later life, we also aimed to identify specific biomarkers to detect these future diseases. Thirty pairs of GDM mothers and controls were randomly divided into three subgroups. We identified 235 peptides of around 1000-3000Da, originating from 115 proteins. Analyzing the cleavage sites revealed that these peptides were cleaved in regulation, which may reflect the protease activity and distribution in umbilical cord plasma. Four identified peptides, of 2471.7, 1077.2, 1446.5 and 2372.7Da, were significantly differentially expressed in the GDM macrosomia groups compared with controls, whose precursors may play a critical role in developing GDM macrosomia. We provide for the first time a validated GDM macrosomia peptidome profile and identify potential biomarkers linking the effects of macrosomia to later-life diseases. BIOLOGICAL SIGNIFICANCE: Fetal macrosomia is the predominant adverse outcome of gestational diabetes mellitus (GDM), which is a frequent medical condition during pregnancy. Till now, the detailed molecular mechanisms underlying gestational diabetes-induced macrosomia are still not elucidated. With high detection sensitivity and high throughput of peptidome technology, it is now possible to systemically identify peptides possibly involved in the umbilical cord plasma of GDM induced macrosomia cases. With LC-MS/MS based quantification, totally, we identified 235 peptides originated from 115 precursor proteins. And four peptides of 2471.7, 1077.2, 1446.5 and 2372.7Da differentially expressed between GDM cases and compared controls. A precursor protein of 1077.2Da was fibrinogen alpha chain (FGA), which was also identified in the Ai et al. [29] study with a downregulated manner in the serum samples of GDM cases. And further analysis the cleavage pattern of the identified peptides revealed that the enzymes in tissues cleaved the protein according to their rules. Thus, this quantitative peptidome approach can identify related peptides that may play a role in the gestational diabetes-induced macrosomia, and give candidate biomarkers contributing to the development of later-life diseases in macrosomic babies. PMID- 26945740 TI - The plant natriuretic peptide receptor is a guanylyl cyclase and enables cGMP dependent signaling. AB - The functional homologues of vertebrate natriuretic peptides (NPs), the plant natriuretic peptides (PNPs), are a novel class of peptidic hormones that signal via guanosine 3',5'-cyclic monophosphate (cGMP) and systemically affect plant salt and water balance and responses to biotrophic plant pathogens. Although there is increasing understanding of the complex roles of PNPs in plant responses at the systems level, little is known about the underlying signaling mechanisms. Here we report isolation and identification of a novel Leucine-Rich Repeat (LRR) protein that directly interacts with A. thaliana PNP, AtPNP-A. In vitro binding studies revealed that the Arabidopsis AtPNP-A binds specifically to the LRR protein, termed AtPNP-R1, and the active region of AtPNP-A is sufficient for the interaction to occur. Importantly, the cytosolic part of the AtPNP-R1, much like in some vertebrate NP receptors, harbors a catalytic center diagnostic for guanylyl cyclases and the recombinant AtPNP-R1 is capable of catalyzing the conversion of guanosine triphosphate to cGMP. In addition, we show that AtPNP-A causes rapid increases of cGMP levels in wild type (WT) leaf tissue while this response is significantly reduced in the atpnp-r1 mutants. AtPNP-A also causes cGMP-dependent net water uptake into WT protoplasts, and hence volume increases, whereas responses of the protoplasts from the receptor mutant are impaired. Taken together, our results suggest that the identified LRR protein is an AtPNP-A receptor essential for the PNP-dependent regulation of ion and water homeostasis in plants and that PNP- and vertebrate NP-receptors and their signaling mechanisms share surprising similarities. PMID- 26945741 TI - Moderate and Severe Inflammatory Acne Vulgaris Effectively Treated with Single Agent Therapy by a New Fixed-Dose Combination Adapalene 0.3 %/Benzoyl Peroxide 2.5 % Gel: A Randomized, Double-Blind, Parallel-Group, Controlled Study. AB - BACKGROUND: A need exists for topical treatments in managing more severe inflammatory acne. OBJECTIVES: The objectives of this study were to evaluate the efficacy and safety of adapalene 0.3 %/benzoyl peroxide 2.5 % (0.3 % A/BPO) topical gel in subjects with moderate and severe inflammatory acne. METHODS: This was a multicenter, randomized, double-blind, parallel-group study. Randomization was stratified by acne severity (50 % moderate and 50 % severe). Subjects received 0.3 % A/BPO, 0.1 % A/BPO (benchmark), or vehicle (comparator) once daily for 12 weeks. Co-primary efficacy endpoints were success rate at week 12 (the percentage of subjects rated 'clear' or 'almost clear' with at least a 2-grade improvement on Investigator's Global Assessment [IGA]) and change in inflammatory (IN) and noninflammatory (NIN) lesion counts from baseline to week 12. Secondary efficacy endpoints were percent changes in IN and NIN lesion counts. Safety endpoints were incidence of adverse events (AEs) and local tolerability signs/symptoms. RESULTS: A total of 503 subjects were randomized: 217, 217, and 69 subjects in the 0.3 % A/BPO, 0.1 % A/BPO, and vehicle groups, respectively. For success rate (subjects rated 'clear' or 'almost clear' with >=2-grade improvement in IGA), 0.3 % A/BPO was superior to vehicle, with a treatment difference of 22.7 % (33.7 vs. 11.0 %; 95 % confidence interval [CI] 12.8-32.6, p < 0.001). At week 12, 0.3 % A/BPO was superior to vehicle for mean reduction from baseline in IN (27.0 vs. 14.4) and NIN lesion counts (40.2 vs. 18.5), as well as for percentage reduction from baseline in IN (68.7 vs. 39.2 %) and NIN lesion counts (68.3 vs. 37.4 %) (all p < 0.001). Among subjects with severe inflammatory acne (IGA = 4), 0.1 % A/BPO did not reach statistical significance for success rate compared with vehicle (p = 0.443), whereas 0.3 % A/BPO demonstrated significantly greater efficacy (p = 0.029, requiring >=3-point IGA improvement). Additionally, 0.3 % A/BPO was safe and well-tolerated. CONCLUSIONS: Results of this clinical trial demonstrate the significantly greater efficacy of adapalene 0.3 % A/BPO topical gel compared with vehicle as well as a good safety profile in the treatment of moderate to severe inflammatory non-nodulocystic acne, which increases patients' treatment options. CLINICALTRIALS. GOV IDENTIFIER: NCT01880320. PMID- 26945742 TI - Natural death in the setting of autoerotic practice. AB - Deaths in an autoerotic setting are usually due to accidental asphyxia, in which the individual accidently hangs or strangles themselves while inducing hypoxia for the purpose of heightened arousal. Death occurs when the level of hypoxia causes the individual to lose consciousness and is thus unable to prevent the neck compression from becoming lethal. In some cases there is an "escape" mechanism incorporated into the set-up which may fail. In rare cases, death is not as an immediate result of the autoerotic activity and is as a result of natural causes, which may or may not be related to the process. This case demonstrates the death of a 69 year old male which has occurred in the setting of a complex autoerotic environment, not as a result of asphyxiation, but rather as a result of natural causes which is likely to have been brought about by repeated similar activity. The autopsy revealed pulmonary emboli and lower limb deep vein thrombosis. There was no other natural disease of note and no features considered typical of asphyxiation. PMID- 26945744 TI - Forensic and historical aspects of crucifixion. PMID- 26945743 TI - Gross and microscopic features of extensive subcutaneous emphysema. PMID- 26945745 TI - How useful are ultraviolet, infrared, and narrow band light sources for enhancing occult bruises in cases of assault? PMID- 26945746 TI - HealthMap: a cluster randomised trial of interactive health plans and self management support to prevent coronary heart disease in people with HIV. AB - BACKGROUND: The leading causes of morbidity and mortality for people in high income countries living with HIV are now non-AIDS malignancies, cardiovascular disease and other non-communicable diseases associated with ageing. This protocol describes the trial of HealthMap, a model of care for people with HIV (PWHIV) that includes use of an interactive shared health record and self-management support. The aims of the HealthMap trial are to evaluate engagement of PWHIV and healthcare providers with the model, and its effectiveness for reducing coronary heart disease risk, enhancing self-management, and improving mental health and quality of life of PWHIV. METHODS/DESIGN: The study is a two-arm cluster randomised trial involving HIV clinical sites in several states in Australia. Doctors will be randomised to the HealthMap model (immediate arm) or to proceed with usual care (deferred arm). People with HIV whose doctors are randomised to the immediate arm receive 1) new opportunities to discuss their health status and goals with their HIV doctor using a HealthMap shared health record; 2) access to their own health record from home; 3) access to health coaching delivered by telephone and online; and 4) access to a peer moderated online group chat programme. Data will be collected from participating PWHIV (n = 710) at baseline, 6 months, and 12 months and from participating doctors (n = 60) at baseline and 12 months. The control arm will be offered the HealthMap intervention at the end of the trial. The primary study outcomes, measured at 12 months, are 1) 10-year risk of non-fatal acute myocardial infarction or coronary heart disease death as estimated by a Framingham Heart Study risk equation; and 2) Positive and Active Engagement in Life Scale from the Health Education Impact Questionnaire (heiQ). DISCUSSION: The study will determine the viability and utility of a novel technology-supported model of care for maintaining the health and wellbeing of people with HIV. If shown to be effective, the HealthMap model may provide a generalisable, scalable and sustainable system for supporting the care needs of people with HIV, addressing issues of equity of access. TRIAL REGISTRATION: Universal Trial Number (UTN) U111111506489; ClinicalTrial.gov Id NCT02178930 submitted 29 June 2014. PMID- 26945747 TI - A comparative agreement evaluation of two subaxial cervical spine injury classification systems: the AOSpine and the Allen and Ferguson schemes. AB - PURPOSE: We performed an agreement study using two subaxial cervical spine classification systems: the AOSpine and the Allen and Ferguson (A&F) classifications. We sought to determine which scheme allows better agreement by different evaluators and by the same evaluator on different occasions. METHODS: Complete imaging studies of 65 patients with subaxial cervical spine injuries were classified by six evaluators (three spine sub-specialists and three senior orthopaedic surgery residents) using the AOSpine subaxial cervical spine classification system and the A&F scheme. The cases were displayed in a random sequence after a 6-week interval for repeat evaluation. The Kappa coefficient (kappa) was used to determine inter- and intra-observer agreement. RESULTS: Inter observer: considering the main AO injury types, the agreement was substantial for the AOSpine classification [kappa = 0.61 (0.57-0.64)]; using AO sub-types, the agreement was moderate [kappa = 0.57 (0.54-0.60)]. For the A&F classification, the agreement [kappa = 0.46 (0.42-0.49)] was significantly lower than using the AOSpine scheme. Intra-observer: the agreement was substantial considering injury types [kappa = 0.68 (0.62-0.74)] and considering sub-types [kappa = 0.62 (0.57 0.66)]. Using the A&F classification, the agreement was also substantial [kappa = 0.66 (0.61-0.71)]. No significant differences were observed between spine surgeons and orthopaedic residents in the overall inter- and intra-observer agreement, or in the inter- and intra-observer agreement of specific type of injuries. CONCLUSION: The AOSpine classification (using the four main injury types or at the sub-types level) allows a significantly better agreement than the A&F classification. The A&F scheme does not allow reliable communication between medical professionals. PMID- 26945748 TI - Is obesity associated with worse patient-reported outcomes following lumbar surgery for degenerative conditions? AB - PURPOSE: To investigate whether obesity is associated with worse patient-reported outcomes following surgery for degenerative lumbar conditions. METHODS: We evaluated consecutive patients undergoing elective lumbar laminectomy or laminectomy with fusion for degenerative lumbar conditions. The Oswestry Disability Index (ODI), EuroQol-5D (EQ-5D), Short-Form 12 (SF-12), and NASS patient satisfaction were utilized. Chi-square tests and student t test assessed the association of obesity with PROs. Multivariate regression controlled for age, sex, smoking status, anxiety, depression, revision, preoperative narcotic use, payer status, and diabetes. RESULTS: A total of 602 patients were included. All PROs improved significantly in both groups. BMI >=35 was associated with increased ODI at baseline (50.6 vs. 47.2 %, p = 0.012) and 12 months (30.5 vs. 25.7 %, p = 0.005). There was no difference in ODI change scores (21.2 vs. 19.4 %, p = 0.32). With multivariate analysis, BMI >=35 was not predictive of worse ODI at 12 months (correlation coefficient 1.23, 95 % CI -0.225 to 2.676.) There was no significant difference between groups in percentage of patients achieving the minimum clinically important difference for ODI (59.6 vs. 64 %, p = 0.46) or patient satisfaction (80.5 vs. 78.9 %, p = 0.63). CONCLUSIONS: Body mass index >=35 is associated with worse baseline and 12-month PROs, however, there was no difference in change scores across BMI groups. Controlling for important co variables, BMI greater than 35 was not an independent predictor of worse PROs at 12 months. PMID- 26945749 TI - Developing a point-of-care electronic medical record system for TB/HIV co infected patients: experiences from Lighthouse Trust, Lilongwe, Malawi. AB - BACKGROUND: Implementation of user-friendly, real-time, electronic medical records for patient management may lead to improved adherence to clinical guidelines and improved quality of patient care. We detail the systematic, iterative process that implementation partners, Lighthouse clinic and Baobab Health Trust, employed to develop and implement a point-of-care electronic medical records system in an integrated, public clinic in Malawi that serves HIV infected and tuberculosis (TB) patients. METHODS: Baobab Health Trust, the system developers, conducted a series of technical and clinical meetings with Lighthouse and Ministry of Health to determine specifications. Multiple pre-testing sessions assessed patient flow, question clarity, information sequencing, and verified compliance to national guidelines. Final components of the TB/HIV electronic medical records system include: patient demographics; anthropometric measurements; laboratory samples and results; HIV testing; WHO clinical staging; TB diagnosis; family planning; clinical review; and drug dispensing. RESULTS: Our experience suggests that an electronic medical records system can improve patient management, enhance integration of TB/HIV services, and improve provider decision making. However, despite sufficient funding and motivation, several challenges delayed system launch including: expansion of system components to include of HIV testing and counseling services; changes in the national antiretroviral treatment guidelines that required system revision; and low confidence to use the system among new healthcare workers. To ensure a more robust and agile system that met all stakeholder and user needs, our electronic medical records launch was delayed more than a year. Open communication with stakeholders, careful consideration of ongoing provider input, and a well-functioning, backup, paper-based TB registry helped ensure successful implementation and sustainability of the system. Additional, on-site, technical support provided reassurance and swift problem solving during the extended launch period. CONCLUSION: Even when system users are closely involved in the design and development of an electronic medical record system, it is critical to allow sufficient time for software development, solicitation of detailed feedback from both users and stakeholders, and iterative system revisions to successfully transition from paper to point-of-care electronic medical records. For those in low-resource settings, electronic medical records for integrated care is a possible and positive innovation. PMID- 26945750 TI - Low complication rate and an increasing incidence of surgical repair of primary indirect sliding inguinal hernia. AB - PURPOSE: The purpose of the present study was to explore the risk for complications and reoperations following open repairs for sliding groin hernias. METHOD: All primary indirect inguinal hernia repairs registered in the Swedish Hernia Register 1998-2011 were identified. Repeated and bilateral procedures were excluded. The epidemiology, the incidence of per- and postoperative complications, and the reoperation rate due to recurrences were analyzed. RESULTS: 100 240 non-repeated unilateral repairs were registered with sliding hernias in 13 132 (13.1 %) (male 14 %, female 5 %) procedures. The methods of repair for sliding and non-sliding hernias were Lichtenstein and other open anterior mesh repairs (N = 10865, 82.7 % and N = 60790, 69.8 %), endoscopic techniques (N = 136, 1.0 % and N = 4352, 5.0 %), and other techniques (N = 2131, 16.2 % and N = 21966, 25.2 %). In multivariate analyses with adjustment for gender, acute/planned surgery, reducibility, method of repair and age, sliding hernias were associated with a low but slightly increased risk for perioperative complications (hazard ratio 1.30, 95 % confidence interval 1.04-1.62, p = 0.023) and postoperative hematoma (hazard ratio 1.13, confidence interval 1.02-1.26, p = 0.019). There was no increased risk of reoperation due to recurrences. CONCLUSION: Compared to older reports, the incidence of repairs due to primary indirect sliding inguinal hernias has increased over time and it is not just a male disease. The overall results are good with low and comparable complication rates, and no increased risk of reoperations due to recurrences. PMID- 26945751 TI - Evidence-based medicine - an appropriate tool for evidence-based health policy? A case study from Norway. AB - BACKGROUND: Evidence-based policy (EBP), a concept modelled on the principles of evidence-based medicine (EBM), is widely used in different areas of policymaking. Systematic reviews (SRs) with meta-analyses gradually became the methods of choice for synthesizing research evidence about interventions and judgements about quality of evidence and strength of recommendations. Critics have argued that the relation between research evidence and service policies is weak, and that the notion of EBP rests on a misunderstanding of policy processes. Having explored EBM standards and knowledge requirements for health policy decision making, we present an empirical point of departure for discussing the relationship between EBM and EBP. METHODS: In a case study exploring the Norwegian Knowledge Centre for the Health Services (NOKC), an independent government unit, we first searched for information about the background and development of the NOKC to establish a research context. We then identified, selected and organized official NOKC publications as an empirical sample of typical top-of-the-line knowledge delivery adhering to EBM standards. Finally, we explored conclusions in this type of publication, specifically addressing their potential as policy decision tools. RESULTS: From a total sample of 151 SRs published by the NOKC in the period 2004-2013, a purposive subsample from 2012 (14 publications) advised major caution about their conclusions because of the quality or relevance of the underlying documentation. Although the case study did not include a systematic investigation of uptake and policy consequences, SRs were found to be inappropriate as universal tools for health policy decision making. CONCLUSIONS: The case study demonstrates that EBM is not necessarily suited to knowledge provision for every kind of policy decision-making. Our analysis raises the question of whether the evidence-based movement, represented here by an independent government organization, undertakes too broad a range of commissions using strategies that seem too confined. Policymaking in healthcare should be based on relevant and transparent knowledge, taking due account of the context of the intervention. However, we do not share the belief that the complex and messy nature of policy processes in general is compatible with the standards of EBM. PMID- 26945753 TI - Zika virus infection in semen: a call to action and research. PMID- 26945752 TI - Comparison between MDCK and MDCK-SIAT1 cell lines as preferred host for cell culture-based influenza vaccine production. AB - OBJECTIVES: To evaluate MDCK and MDCK-SIAT1 cell lines for their ability to produce the yield of influenza virus in different Multiplicities of Infection. RESULTS: Yields obtained for influenza virus H1N1 grown in MDCK-SIAT1 cell was almost the same as MDCK; however, H3N2 virus grown in MDCK-SIAT1 had lower viral titers in comparison with MDCK cells. The optimized MOIs to infect the cells on plates and microcarrier were selected 0.01 and 0.1 for H1N1 and 0.001 and 0.01 for H3N2, respectively. CONCLUSIONS: MDCK-SIAT1 cells may be considered as an alternative mean to manufacture cell-based flu vaccine, especially for the human strains (H1N1), due to its antigenic stability and high titer of influenza virus production. PMID- 26945754 TI - Morphometric characteristics of preantral and antral follicles and expression of factors involved in folliculogenesis in ovaries of adult baboons (Papio anubis). AB - PURPOSE: Baboons are commonly utilized as an animal model for studies of human reproduction. However, folliculogenesis in this species has not been fully documented. The aim of this study was to assess follicle morphometry and expression of essential proteins involved in folliculogenesis in baboons. METHODS: Ovaries were recovered from four adult baboons and processed for histological evaluation and immunohistochemical analyses. Follicle proportion, follicle and oocyte diameter, theca layer thickness, number of granulosa cells, and follicle density were calculated. Immunohistochemical staining was also carried out for connexin 43 (Cx43), aromatase, and zona pellucida 3 (ZP3). RESULTS: A total of 2221 follicles were counted and measured. Proportions of primordial, primary, secondary, small antral, and large antral follicles were 49, 26, 23, 1, and 1 %, respectively. The increase in follicle diameter was due not only to the increase in oocyte diameter but also to granulosa cell proliferation. Almost all antral follicles were positive for Cx43 (89.8 %), aromatase (84.8 %), and ZP3 (100 %). Most secondary follicles were positive for Cx43 (65 %) and ZP3 (64.5 %), and some primary follicles were positive only for Cx43. No primordial follicles stained positive in any of these immunohistochemical analyses. Only antral follicles showed aromatase activity. CONCLUSIONS: On the basis of these results, we can conclude that folliculogenesis in baboons appears to be similar to that in humans, and this animal therefore constitutes a valuable model. PMID- 26945755 TI - Experience of intimate partner violence among young pregnant women in urban slums of Kathmandu Valley, Nepal: a qualitative study. AB - BACKGROUND: Intimate partner violence (IPV) is an urgent public health priority. It is a neglected issue in women's health, especially in urban slums in Nepal and globally. This study was designed to better understand the IPV experienced by young pregnant women in urban slums of the Kathmandu Valley, as well as to identify their coping strategies, care and support seeking behaviours. Womens' views on ways to prevent IPV were also addressed. METHODS: 20 young pregnant women from 13 urban slums in the Kathmandu valley were recruited purposively for this qualitative study, based on pre-defined criteria. In-depth interviews were conducted and transcribed, with qualitative content analysis used to analyse the transcripts. RESULTS: 14 respondents were survivors of violence in urban slums. Their intimate partner(s) committed most of the violent acts. These young pregnant women were more likely to experience different forms of violence (psychological, physical and sexual) if they refused to have sex, gave birth to a girl, or if their husband had alcohol use disorder. The identification of foetal gender also increased the experience of physical violence at the prenatal stage. Interference from in-laws prevented further escalation of physical abuse. The most common coping strategy adopted to avoid violence among these women was to tolerate and accept the husbands' abuse because of economic dependence. Violence survivors sought informal support from their close family members. Women suggested multiple short and long term actions to reduce intimate partner violence such as female education, economic independence of young women, banning identification of foetal gender during pregnancy and establishing separate institutions within their community to handle violence against young pregnant women. CONCLUSIONS: Diversity in the design and implementation of culturally and socially acceptable interventions might be effective in addressing violence against young pregnant women in humanitarian settings such as urban slums. These include, but are not limited to, treatment of alcohol use disorder, raising men's awareness about pregnancy, addressing young women's economic vulnerability, emphasising the role of health care professionals in preventing adverse consequences resulting from gender selection technologies and working with family members of violence survivors. PMID- 26945756 TI - Influence of Fatigue Loading and Bone Turnover on Bone Strength and Pattern of Experimental Fractures of the Tibia in Mice. AB - Bone fragility depends on bone mass, structure, and material properties, including damage. The relationship between bone turnover, fatigue damage, and the pattern and location of fractures, however, remains poorly understood. We examined these factors and their integrated effects on fracture strength and patterns in tibia. Adult male mice received RANKL (2 mg/kg/day), OPG-Fc (5 mg/kg 2*/week), or vehicle (Veh) 2 days prior to fatigue loading of one tibia by in vivo axial compression, with treatments continuing up to 28 more days. One day post fatigue, crack density was similarly increased in fatigued tibiae from all treatment groups. After 28 days, the RANKL group exhibited reduced bone mass and increased crack density, resulting in reduced bone strength, while the OPG-Fc group had greater bone mass and bone strength. Injury repair altered the pattern and location of fractures created by ex vivo destructive testing, with fractures occurring more proximally and obliquely relative to non-fatigued tibia. A similar pattern was observed in both non-fatigued and fatigued tibia of RANKL. In contrast, OPG-Fc prevented this fatigue-related shift in fracture pattern by maintaining fractures more distal and transverse. Correlation analysis showed that bone strength was predominantly determined by aBMD with minor contributions from structure and intrinsic strength as measured by nanoindentation and cracks density. In contrast, fracture location was predicted equally by aBMD, crack density and intrinsic modulus. The data suggest that not only bone strength but also the fracture pattern depends on previous damage and the effects of bone turnover on bone mass and structure. These observations may be relevant to further understand the mechanisms contributing to fracture pattern in long bone with different levels of bone remodeling, including atypical femur fracture. PMID- 26945757 TI - GPS in pollen tubes: Found! PMID- 26945758 TI - Biochemical Modulation by Carbon and Nitrogen Addition in Cultures of Dictyota menstrualis (Dictyotales, Phaeophyceae) to Generate Oil-based Bioproducts. AB - Dictyota menstrualis (Hoyt) Schnetter, Horning & Weber-Peukert (Dictyotales, Phaeophyceae) was studied for the production of oil-based bioproducts and co products. Experiments were performed to evaluate the effect of carbon dioxide (CO2) concentration, under nitrogen (NO3 (-)) limiting and saturation conditions, on growth rate (GR), photosynthesis, as well as nitrate reductase (NR), carbonic anhydrase (CA), and Rubisco activities. In addition, the biochemical composition of D. menstrualis under these conditions was estimated. GR, protein content, and N content in D. menstrualis were higher in treatments containing NO3 (-), irrespective of CO2 addition. However, when CO2 was added to medium saturated with NO3 (-), values of maximum photosynthesis, Rubisco, and NR activity, as well as total soluble carbohydrates and lipids, were increased. CA activity did not vary under the different treatments. The fatty acid profile of D. menstrualis was characterized by a high content of polyunsaturated fatty acids, especially the omega-3 fatty acids, making it a possible candidate for nutraceutical use. In addition, this species presented high GR, photosynthetic rate, and fatty acid content, highlighting its economic importance and the possibility of different biotechnological applications. PMID- 26945759 TI - Fleischner recommendations for the management of subsolid pulmonary nodules: high awareness but limited conformance - a survey study. AB - OBJECTIVES: The aim of this study was to assess awareness and conformance to the Fleischner society recommendations for the management of subsolid pulmonary nodules (SSN) in clinical practice. METHODS: An online questionnaire with four imaging cases was sent to 1579 associates from the European Respiratory Society and 757 from the European Society of Thoracic Imaging. Each respondent was asked to choose from several options which one they thought was the indicated management for the nodule presented. Awareness and conformance to the Fleischner recommendations (FR) were assessed and correlated to respondents characteristics. RESULTS: In total, 119 radiologists (response rate 16.0 %) and 243 pulmonologists (response rate 16.5 %) were included. Awareness of the FR was higher in radiologists than in pulmonologists (93 % vs. 70 %, p < 0.001), as was implementation in daily practice (66 % vs. 47 %, p < 0.001). Radiologists conformed to FR in rates of 31, 69, 68, and 82 %, and pulmonologists in 12, 43, 70, and 75 % for cases 1 to 4, respectively. Overmanagement was common. Conformance in SSN management was associated with awareness, working in an academic practice, larger practice size, teaching residents, and higher SSN exposure. CONCLUSIONS: Although awareness of the Fleischner recommendations for SSN management is widespread, management choices in clinical practice show large heterogeneity. KEY POINTS: * Guideline awareness among clinicians is widespread, but conformance shows large heterogeneity. * Awareness and conformance is significantly higher among radiologists than pulmonologists. * Overmanagement is common, which may lead to avoidable financial and physical burden. PMID- 26945760 TI - Radiological and clinical predictors of long-term outcome in rotator cuff calcific tendinitis. AB - OBJECTIVES: Knowledge on the epidemiology and long-term course of rotator cuff calcific tendinitis (RCCT) is scarce. We assessed demographics, radiological characteristics, and their association with long-term outcomes in a large patient group. METHODS: Baseline demographics, radiological characteristics and treatment were recorded in 342 patients. Interobserver agreement of radiological measures was analyzed. Long-term outcome was evaluated with questionnaires (WORC, DASH). The association of baseline characteristics with outcome was assessed. RESULTS: Mean age was 49.0 (SD = 10.0), and 59.5 % were female. The dominant arm was affected in 66.0 %, and 21.3 % had bilateral disease. Calcifications were on average 18.7 mm (SD = 10.1, ICC = 0.84 (p < 0.001)) and located 10.1 mm (SD = 11.8) medially to the acromion (ICC = 0.77 (p < 0.001)). Gartner type I calcifications were found in 32.1 % (Kappa = 0.47 (p < 0.001)). After 14 years (SD = 7.1) of follow-up, median WORC was 72.5 (range, 3.0-100.0; WORC < 60 in 42 %) and median DASH 17.0 (range, 0.0-82.0). Female gender, dominant arm involvement, bilateral disease, longer duration of symptoms, and multiple calcifications were associated with inferior WORC. DASH results were similar. CONCLUSIONS: Many subjects have persisting shoulder complaints years after diagnosis, regardless of treatment. Female gender, dominant arm involvement, bilateral disease, longer duration of symptoms, and multiple calcifications were associated with inferior outcome. Radiological measures had moderate-to-good reliability and no prognostic value. KEY POINTS: * Most RCCT studies report on short-term outcome and/or small patients groups. * In this large, long-term observational study, RCCT appeared to not be self-limiting in many subjects. * Negative prognostic factors included female gender, more calcifications, dominant arm affected, and longer duration of symptoms. * Interobserver agreement of general radiological RCCT measures is moderate to good. * More rigorous diagnostics and treatment might be needed in specific RCCT cases. PMID- 26945761 TI - Multiparametric MRI in the assessment of response of rectal cancer to neoadjuvant chemoradiotherapy: A comparison of morphological, volumetric and functional MRI parameters. AB - PURPOSE: To compare morphological and functional MRI metrics and determine which ones perform best in assessing response to neoadjuvant chemoradiotherapy (CRT) in rectal cancer. MATERIALS AND METHODS: This retrospective study included 24 uniformly-treated patients with biopsy-proven rectal adenocarcinoma who underwent MRI, including diffusion-weighted (DW) and dynamic contrast-enhanced (DCE) sequences, before and after completion of CRT. On all MRI exams, two experienced readers independently measured longest and perpendicular tumour diameters, tumour volume, tumour regression grade (TRG) and tumour signal intensity ratio on T2 weighted imaging, as well as tumour volume and apparent diffusion coefficient on DW-MRI and tumour volume and transfer constant Ktrans on DCE-MRI. These metrics were correlated with histopathological percent tumour regression in the resected specimen (%TR). Inter-reader agreement was assessed using the concordance correlation coefficient (CCC). RESULTS: For both readers, post-treatment DW-MRI and DCE-MRI volumetric tumour assessments were significantly associated with %TR; DCE-MRI volumetry showed better inter-reader agreement (CCC=0.700) than DW-MRI volumetry (CCC=0.292). For one reader, mrTRG, post-treatment T2 tumour volumetry and assessments of volume change made with T2, DW-MRI and DCE-MRI were also significantly associated with %TR. CONCLUSION: Tumour volumetry on post-treatment DCE-MRI and DW-MRI correlated well with %TR, with DCE-MRI volumetry demonstrating better inter-reader agreement. KEY POINTS: * Volumetry on post-treatment DCE-/DW MRI sequences correlated well with histopathological tumour regression. * DCE-MRI volumetry demonstrated good inter-reader agreement. * Inter-reader agreement was higher for DCE-MRI volumetry than for DW-MRI volumetry. * DCE-MRI volumetry merits further investigation as a metric for evaluating treatment response. PMID- 26945762 TI - The state of the art in breast imaging using the Twente Photoacoustic Mammoscope: results from 31 measurements on malignancies. AB - OBJECTIVES: Photoacoustic mammography is potentially an ideal technique, however, the amount of patient data is limited. To further our understanding of the in vivo performance of the method and to guide further research and development, we imaged 33 breast malignancies using the research system - the Twente Photoacoustic Mammoscope (PAM). METHODS: Thirty-one patients participated in this retrospective, observational study. The study and informed consent procedure were approved by the local ethics committee. PAM uses 1,064 nm light for excitation with a planar, 588-element, 1-MHz ultrasound array for detection. Photoacoustic lesion visibility and appearance were compared with conventional imaging (x-ray mammography and ultrasonography) findings, histopathology and patient demographics. RESULTS: Of 33 malignancies 32 were visualized with high contrast and good co-localization with conventional imaging. The contrast of the detected malignancies was independent of radiographic breast density, and size estimation was reasonably good with an average 28 % deviation from histology. However, the presence of contrast areas outside the malignant region is suggestive for low specificity of the current system. Statistical analyses did not reveal any further relationship between PAM results and patient demographics nor lesion characteristics. CONCLUSIONS: The results confirm the high potential of photoacoustic mammography in future breast care. KEY POINTS: * Photoacoustic breast imaging visualizes malignancies with high imaging contrast. * Photoacoustic lesion contrast is independent of the mammographically estimated breast density. * No clear relationship exists between photoacoustic characteristics and lesion type, grade, etc. * Photoacoustic specificity to breast cancer from some cases is not yet optimal. PMID- 26945763 TI - Non-tuberculous mycobacterial lung disease: diagnosis based on computed tomography of the chest. AB - OBJECTIVES: To elucidate the accuracy and inter-observer agreement of non tuberculous mycobacterial lung disease (NTM-LD) diagnosis based on chest CT findings. METHODS: Two chest radiologists and two pulmonologists interpreted chest CTs of 66 patients with NTM-LD, 33 with pulmonary tuberculosis and 33 with non-cystic fibrosis bronchiectasis. These observers selected one of these diagnoses for each case without knowing any clinical information except age and sex. Sensitivity and specificity were calculated according to degree of observer confidence. Inter-observer agreement was assessed using Fleiss' kappa values. Multiple logistic regression was performed to elucidate which radiological features led to the correct diagnosis. RESULTS: The sensitivity of NTM-LD diagnosis was 56.4 % (95 % CI 47.9-64.7) and specificity 80.3 % (73.1-86.0). The specificity of NTM-LD diagnosis increased with confidence: 44.4 % (20.5-71.3) for possible, 77.4 % (67.4-85.0) for probable, 95.2 % (87.2-98.2) for definite (P < 0.001) diagnoses. Inter-observer agreement for NTM-LD diagnosis was moderate (kappa = 0.453). Tree-in-bud pattern (adjusted odds ratio [aOR] 6.24, P < 0.001), consolidation (aOR 1.92, P = 0.036) and atelectasis (aOR 3.73, P < 0.001) were associated with correct NTM-LD diagnoses, whereas presence of pleural effusion (aOR 0.05, P < 0.001) led to false diagnoses. CONCLUSIONS: NTM-LD diagnosis based on chest CT findings is specific but not sensitive. KEY POINTS: * Diagnosis of NTM-LD based on radiological findings showed high specificity. * Sensitivity of NTM-LD diagnosis was around 50 %. * Inter- observer agreement was moderate. * Identification of tree-in-bud pattern, consolidation and atelectasis led to correct diagnoses. PMID- 26945765 TI - Into the unknown: A review and synthesis of contemporary models involving uncertainty. AB - The current review and synthesis serves to define and contextualize fear of the unknown relative to related constructs, such as intolerance of uncertainty, and contemporary models of emotion, attachment, and neuroticism. The contemporary models appear to share a common core in underscoring the importance of responses to unknowns. A recent surge in published research has explored the transdiagnostic impact of not knowing on anxiety and related pathologies; as such, there appears to be mounting evidence for fear of the unknown as an important core transdiagnostic construct. The result is a robust foundation for transdiagnostic theoretical and empirical explorations into fearing the unknown and intolerance of uncertainty. PMID- 26945764 TI - Alterations of diffusion tensor MRI parameters in the brains of patients with Parkinson's disease compared with normal brains: possible diagnostic use. AB - OBJECTIVES: To investigate the diagnostic performance of diffusion tensor imaging in patients with Parkinson's disease (PD). METHODS: We examined a total of 126 PD patients (68 males/58 females, mean age: 62.0 +/-7.6 years) and 91 healthy controls (43 males/48 females, mean age: 59.8 +/-7.2 years). Images were acquired on a 3 Tesla magnetic resonance scanner. The Camino software was used to normalize and parcellate diffusion-weighted images into 90 cerebral regions based on the automatic anatomical labelling template. The minimum, median, and maximum values of the mean/radial/axial diffusivity/fractional anisotropy were determined. The diagnostic performance was assessed by receiver operating characteristic analysis. The associations of imaging parameters with disease severity were tested using Pearson's correlation coefficients after adjustment for disease duration. RESULTS: Compared with healthy controls, PD patients showed increased diffusivity in multiple cortical regions that extended beyond the basal ganglia. An area under curve of 85 % was identified for the maximum values of mean diffusivity in the ipsilateral middle temporal gyrus. The most significant intergroup difference was 26.8 % for the ipsilateral inferior parietal gyrus. CONCLUSION: The measurement of water diffusion from the parcellated cortex may be clinically useful for the assessment of PD patients. KEY POINTS: * Increased diffusivity was identified in multiple cortical regions of Parkinson's disease patients. * The area under the receiver operating curve was 85 % in the middle temporal gyrus. * The ipsilateral inferior parietal gyrus showed the most significant change. PMID- 26945766 TI - Comparative paleogenomics of crucifers: ancestral genomic blocks revisited. AB - A decade ago the concept of the Ancestral Crucifer Karyotype (ACK) and the definition of 24 conserved genomic blocks was presented. Subsequently, 35 cytogenetic reconstructions and/or draft genome sequences of crucifer species (members of the Brassicaceae family) have been analyzed in the context of this system; placing crucifers at the forefront of plant phylogenomics. In this review, we highlight how the ACK and genomic blocks have facilitated and guided genomic analysis of crucifers in the last 10 years and provide an update of this robust model. PMID- 26945767 TI - Efficacy of postoperative antibiotic injection in and around ventriculoperitoneal shunt in reduction of shunt infection: A randomized controlled trial. AB - OBJECTIVES: Infection is a common complication of ventriculoperitoneal (VP) shunt surgery. The incidence of shunt infection is still high despite routine administration of perioperative antibiotics. A lower incidence of shunt infection was observed when antibiotic-impregnated shunts (AIS) were used to treat hydrocephalus and a rapid cure was reported in cases of ventriculitis when antibiotics were injected into external ventricular drain (EVD). That is why we theorized that postoperative prophylactic injection of antibiotics in and around the shunt hardware would reduce the incidence of shunt infection. PATIENTS AND METHODS: A randomized controlled clinical trial where 60 patients up to one year old, diagnosed with congenital hydrocephalus and submitted to VP shunt insertion, were randomly assigned to one of 3 groups. The treatment groups received the conventional perioperative antibiotics in addition to vancomycin and gentamicin injection in the reservoir and around the peritoneal catheter either once (group A) or twice (group B), while the control group (C) received only the conventional perioperative antibiotics. Cases were followed-up for up to 1 year. RESULTS: The majority of patients were less than 1 month old. The follow-up period ranged from 2 to 12 months with a mean of 8.9 months. The mean duration of onset of infection after surgery was 30 days. Prematurity (p=0.00236), age less than one month (p<0.0001) and duration of surgery of 90 min or more (p<0.00001) were significant risk factors for postoperative shunt infection. Significantly more cases of shunt infection occurred within one month after surgery (p=0.021). The control group had significantly more cases of postoperative shunt infection than the treatment groups (p=0.0042). CONCLUSIONS: In congenital hydrocephalus patients submitted to VP shunt insertion, injection of prophylactic vancomycin and gentamicin in and around the shunt hardware significantly reduced the incidence of postoperative shunt infection. PMID- 26945768 TI - Pre-operative and post-operative cognitive deficits in patients with supratentorial meningiomas. AB - OBJECTIVES: Cognitive deficits caused by extra-axial benign brain tumors like meningiomas and the course of these deficits after surgery is not well known. The aim of the study is to assess the pre-operative and post-operative cognitive functions in patients with meningiomas in the supratentorial compartment. MATERIALS AND METHODS: In this prospective study, patients with clinico radiological diagnosis of supratentorial meningioma, operated upon and later confirmed by histopathological examination, were included. The patients were evaluated for cognitive deficits before and after surgery. The various clinical and radiological factors influencing the cognitive status were evaluated. RESULTS: A total of 57 patients were enrolled into the study. Out of 57, 22 were males and 35 were females. The frontal group had 22 patients, the parietal group had 10 patients, the temporal group had 10 patients, the occipital group had 6 patients, and the suprasellar group had 9 patients. Meningiomas, although extra axial, caused significant cognitive deficits in 42 patients (73.7%). The highest frequency of cognitive deficits is seen in the frontal and temporal group of meningiomas (90% each). Frontal meningiomas with volume greater than 35 cc and peritumoral edema greater than 40 cc caused a higher frequency of cognitive deficits. Also, patients with raised ICP had significant cognitive deficits. Postoperatively there was a significant improvement in the cognitive functions in the frontal and temporal groups. CONCLUSION: Meningiomas cause cognitive deficits in 73.7% of patients. Anatomical location of meningioma, elevated ICP, the volume of meningioma and extent of peritumoral edema significantly influence the incidence of cognitive deficits. Post-operatively, the cognitive deficits improve significantly in the frontal and temporal group. PMID- 26945769 TI - Highly expressed amino acid biosynthesis genes revealed by global gene expression analysis of Salmonella enterica serovar Enteritidis during growth in whole egg are not essential for this growth. AB - Salmonella enterica serovar Enteritidis (S. Enteritidis) is the most common cause of egg borne salmonellosis in many parts of the world. This study analyzed gene expression of this bacterium during growth in whole egg, and whether highly expressed genes were essential for the growth. High quality RNA was extracted from S. Enteritidis using a modified RNA-extraction protocol. Global gene expression during growth in whole egg was compared to growth in LB-medium using DNA array method. Twenty-six genes were significantly upregulated during growth in egg; these belonged to amino acid biosynthesis, di/oligopeptide transport system, biotin synthesis, ferrous iron transport system, and type III secretion system. Significant downregulation of 15 genes related to formate hydrogenlyase (FHL) and trehalose metabolism was observed. The results suggested that S. Enteritidis is starved for amino-acids, biotin and iron when growing in egg. However, site specific mutation of amino acid biosynthesis genes asnA (17.3 fold upregulated), asnB (18.6 fold upregulated), asnA/asnB and, serA (12.0 fold upregulated) and gdhA (3.7 fold upregulated), did not result in growth attenuation, suggesting that biosynthesis using the enzymes encoded from these genes may represent the first choice for S. Enteritidis when growing in egg, but when absent, the bacterium could use alternative ways to obtain the amino acids. PMID- 26945770 TI - Copper excess promotes propagation and induces proteomic change in root cultures of Hyoscyamus albus L. AB - Hyoscyamus albus L. seedlings respond positively to copper (Cu) excess. In the present study, to understand how roots cope with Cu excess, propagation and proteome composition in the presence of Cu were examined using a root culture system. When H. albus roots were cultured in a medium without Cu, root growth deteriorated. However, in the presence of Cu, root growth increased in a concentration-dependent manner, and vigorous lateral root development was observed at 200 MUM Cu. Cu accumulation in the roots increased with the Cu supply. Subcellular fractionation revealed that the highest amount of Cu was present in the cell wall-containing fraction, followed by the soluble fraction. However, the highest specific incorporation of Cu, in terms of fresh weight, was in the mitochondria-rich fraction. High Cu levels enhanced respiration activity. Comparative proteomic analysis revealed that proteins involved in carbohydrate metabolism, de novo protein synthesis, cell division, and ATP synthesis increased in abundance, whereas the proteasome decreased. These results indicate that Cu promotes propagation of H. albus roots through the activation of the energy supply and anabolism. Newly propagated root tissues and newly generated proteins that bind to Cu may provide space and reservoirs for deposition of additional Cu. PMID- 26945771 TI - Transient endophytic colonizations of plants improve the outcome of foliar applications of mycoinsecticides against chewing insects. AB - The current work reports how spray application of entomopathogenic fungi on alfalfa, tomato and melon plants may cause an additional Spodoptera littoralis larvae mortality due to a temporal colonization of the leaves and subsequent ingestion of those leaves by the larvae. Most entomopathogenic fungi (EF) (Ascomycota: Hypocreales) endophytes seem to colonize their host plants in a non systemic pattern, in which case at least a transient endophytic establishment of the fungus should be expected in treated areas after spray application. In this work, all strains were able to endophytically colonize roots, stems and leaves during the first 96h after inoculation. Whilst the treatment of S. littoralis larvae with a 10(8)ml(-1) conidial suspension resulted in moderate to high mortality rates for the Metarhizium brunneum EAMb 09/01-Su (41.7-50.0%) and Beauveria bassiana EABb 01/33-Su (66.7-76.6%) strains, respectively, an additive effect was detected when these larvae were also fed endophytically colonized alfalfa, tomato, and melon leaves, with mortality rates varying from 25.0% to 46.7% as a function of the host plant and total mortality rates in the combined treatment of 75-80% and 33-60% for B. bassiana and M. brunneum, respectively. Fungal outgrowth was not detected in any of the dead larvae feeding on colonized leaves, whereas traces of destruxin A were detected in 11% of the insects fed tomato discs endophytically colonized by M. brunneum. The combined effects of the fungal spray with the mortality caused by the feeding of insects on transient EF colonized leaves have to be considered to estimate the real acute impact of field sprays with entomopathogenic fungi on chewing insects. PMID- 26945772 TI - In vivo expression of genes in the entomopathogenic fungus Beauveria bassiana during infection of lepidopteran larvae. AB - The entomopathogenic fungus Beauveria bassiana (Bals.) Vuillemin is commercially available as a bio insecticide. The expression of three genes previously identified to have a role in pathogenicity in in vitro studies was validated in vivo in three lepidopteran insects infected with B. bassiana. Expression of all three genes was observed in all the tested insects starting from 48 or 72h to 10d post infection corroborating their role in pathogenicity. We suggest that it is essential to test the expression of putative pathogenicity genes both in vitro and in vivo to understand their role in different insect species. PMID- 26945773 TI - Essential oils of Nigella sativa protects Artemia from the pathogenic effect of Vibrio parahaemolyticus Dahv2. AB - The anti-Vibrio activity of essential oils (EOs) of nine medicinal plants was tested against 28 Vibrio spp. isolated from diseased Fenneropenaeus indicus. EO of Nigella sativa exhibited anti-Vibrio activity against all Vibrio spp. and greater inhibition was noted for the isolate V2 which was identified as Vibrio parahaemolyticus Dahv2. Further, EO of N. sativa effectively inhibited V. parahaemolyticus Dahv2 with an inhibition zone of 23.9mm at 101.2MUgml(-1). Moreover, EO of N. sativa revealed anti-biofilm activity at 101.2MUgml(-1) against V. parahaemolyticus Dahv2 and inhibited the growth of V. parahaemolyticus Dahv2 at 100MUgml(-1).In vivo experimental infection studies showed that the survival of Artemia spp. infected with V. parahaemolyticus Dahv2 at 1*10(3)cfuml( 1) was only 40%. However, the survival of Artemia spp. was significantly increased after challenge with 100MUgml(-1) of EO of N. sativa. EO of N. sativa showed higher anti-oxidant potential and total phenol content than other EOs tested. The anti-oxidant activity of EO of N. sativa was highly correlated to their total phenolic contents (r=0.836, P<0.05). This observation suggests that EO of N. sativa protected the Artemia spp. after experimental infection of V. parahaemolyticus Dahv2. PMID- 26945774 TI - Exon skipping creates novel splice variants of DMC1 gene in ruminants. AB - Disrupted meiotic cDNA1 (DMC1) recombinase plays a pivotal role in homology search and strand exchange reactions during meiotic homologous recombination. In the present study, full length coding sequence of DMC1 gene was sequence characterized for the first time from four ruminant species (cattle, buffalo, sheep and goat) and phylogenetic relationship of ruminant DMC1 with other eukaryotes was analyzed. DMC1 gene encodes a putative protein of 340 amino acids in cattle, sheep and buffalo and 341 amino acids in goat. A high degree of evolutionary conservation at both nucleotide and amino acid level was observed for the four ruminant orthologs. In cattle and sheep, novel alternatively spliced mRNAs with skipping of exons 7 and 8 (Transcript variant 1, TV1) were isolated in addition to the full length (FL) transcript. Novel transcript variants with partial skipping of exon 7 and complete skipping of exon 8 (Transcript variant 2, TV2) were found in sheep and goat. The presence of these variants was validated by amplifying cDNA isolated from testis tissue of ruminants using two oligonucleotides flanking the deleted region. To accurately estimate their relative proportions, real-time PCR was performed using primers specific for each variant. Expression level of DMC1-FL was significantly higher than that of TV1 in cattle and TV2 in goat (P < 0.05). Relative ratio for expression of DMC1-FL: TV1: TV2 in sheep was 6.78: 1.43: 1. In-silico analysis revealed presence of splice variants of DMC1 gene across other mammalian species underpinning the role of alternative splicing in functional innovation. PMID- 26945775 TI - Accessory (multiple) renal arteries - Differences in frequency according to population, visualizing techniques and stage of morphological development. AB - The aim of this paper is to comprehensively analyze the literature focused on frequency of the presence of the accessory renal arteries in the human body. A systematic analysis of papers has been made. With regard to ethnicity, the incidence of accessory renal arteries fluctuates from 4% in a Malaysian population to 61.5% in a Brazilian population. The frequency is lowest in eastern and southern Asia (from 4% to 18.4%). In some, not ethnically homogenous populations, wide span of occurrence of accessory renal arteries is described (e.g. American - averaging from 18% to 28.8%). A higher frequency of accessory renal arteries was observed in fetuses compared to adults. Moreover, differences in the presence and number of accessory renal arteries reported in different papers are a consequence of type of visualizing technique used in research - especially when computed tomography and anatomical dissection were compared. The increasing number of surgical interventions, especially where laparoscopic methods are concerned, underlines the importance of such knowledge especially to surgeons, interventional radiologists, nephrologists, and vascular surgeons. PMID- 26945776 TI - The 'liaisons dangereuses' between iron and antibiotics. AB - The decline in the rate of new antibiotic discovery is of growing concern, and new antibacterial strategies must now be explored. This review brings together research in two fields (metals in biology and antibiotics) in the hope that collaboration between scientists working in these two areas will lead to major advances in understanding and the development of new approaches to tackling microbial pathogens. Metals have been used as antiseptics for centuries. In this review, we focus on iron, an essential trace element that can nevertheless be toxic to bacteria. We review the many situations in which iron and antibiotics have combinatorial effects when used together. Understanding the molecular relationships between iron and antibiotics, from pure chemistry to gene reprogramming via biochemical competition, is important not only to increase basic knowledge, but also for the development of treatments against pathogens, with a view to optimizing antibiotic efficacy. PMID- 26945777 TI - Radiofrequency ablation coupled with Roux-en-Y gastric bypass: a treatment option for morbidly obese patients with Barrett's esophagus. AB - Barrett's esophagus (BE) is a premalignant condition that is associated with the development of esophageal adenocarcinoma. Risk factors that have been associated with the development of BE include male gender, Caucasian race, chronic gastroesophageal reflux disease, smoking, age >50 and obesity. The current management of BE is dependent on underlying pathological changes and treatment can range from surveillance endoscopy with daily proton pump inhibitor (PPI) therapy in the setting of intestinal metaplasia or low-grade dysplasia (LGD) to radiofrequency ablation (RFA), endoscopic mucosal resection or surgical resection in the setting of high-grade dysplasia. We report the case of a morbidly obese patient who was found to have long-segment BE with LGD during preoperative work up for weight loss surgery with Roux-en-Y gastric bypass (RYGBP). The patient underwent successful RFA for the treatment of her BE before and after her RYGBP procedure. At 5-year follow-up, there was minimal progression of BE after treatment. PMID- 26945778 TI - Obesity and peripheral arterial disease: A Mendelian Randomization analysis. AB - BACKGROUND AND AIMS: Observational studies showed that obesity is a major risk factor for peripheral arterial disease (PAD). However, conventional epidemiology studies are vulnerable to residual bias from confounding factors. We aimed to explore the causality of obesity in development of PAD using Mendelian Randomization (MR) approach. METHODS: A MR analysis was performed in 11,477 community-dwelling adults aged 40 years and above recruited from two nearby communities during 2011-2013 in Shanghai, China. We genotyped 14 body mass index (BMI) associated common variants identified and validated in East Asians. PAD was defined as ankle-to-brachial index (ABI) <0.90 or >1.40. Weighted BMI genetic risk score (GRS) was used as the Instrumental Variable (IV). RESULTS: After adjusted for confounding factors, we found that each standard deviation (SD, 2.76 points) increase in BMI-GRS was associated with 0.43 (95% confidence interval [CI]: 0.36-0.49) kg/m(2) increase in BMI (P < 0.0001) and an odds ratio (OR) for PAD of 1.17 (95% CI: 1.07-1.27; P = 0.0004). Compared with the lowest quartile of BMI-GRS, the second, third and highest quartile associated with 9%, 19% and 45% increment of PAD risk, respectively (P for trend = 0.002). In the MR analysis, we demonstrated a causal relationship between obesity and PAD (OR = 1.44 per BMI unit, 95% CI: 1.18-1.75; P = 0.0003). CONCLUSIONS: This study suggested that obesity may be causally associated with PAD after controlling for the potential intermediate factors like hypertension, dyslipidemia and hyperglycemia. PMID- 26945780 TI - Frequency of endotracheal suctioning for the prevention of respiratory morbidity in ventilated newborns. AB - BACKGROUND: Endotracheal suctioning consists of the mechanical aspiration of pulmonary secretions from the endotracheal tube (ETT) to prevent obstruction. The optimal frequency of ETT suctioning has not been defined. OBJECTIVES: To determine the effect of specific ordered frequency of ETT suctioning ('as scheduled') versus ETT suctioning only in case of indications ('as needed') and of more frequent ETT suctioning versus less frequent ETT suctioning on respiratory morbidity in ventilated newborns. SEARCH METHODS: We used the standard search strategy of the Cochrane Neonatal Review group to search the Cochrane Central Register of Controlled Trials (CENTRAL 2015, Issue 10), MEDLINE via PubMed (1966 to 31 October 2015), EMBASE (1980 to 31 October 2015), and CINAHL (1982 to 31 October 2015). We checked the reference lists of retrieved articles and contacted study authors to identify additional studies. We also searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomized controlled trials and quasi-randomized trials. SELECTION CRITERIA: Randomized, quasi-randomized, and cluster randomized controlled trials comparing different strategies regarding the frequency of ETT suctioning of newborn infants receiving ventilator support. DATA COLLECTION AND ANALYSIS: We used the standard methods of the Cochrane Neonatal Review Group. Two review authors independently extracted data and assessed the risk of bias of trials. The primary outcome was bronchopulmonary dysplasia or chronic lung disease. MAIN RESULTS: We identified one randomized controlled study recruiting 97 low birthweight infants that met the inclusion criteria. The study was conducted in the UK in 1987 and 1988. Randomized infants received ETT suctioning every six or 12 hours during the first three days of life. The quality of reporting was limited and we rated the trial at high risk of bias. Furthermore, the trial lacked adequate power. There were no statistically significant differences in any of reported outcomes: bronchopulmonary dysplasia (defined as oxygen at more than 30 days; risk ratio (RR) 0.49, 95% confidence interval (CI) 0.20 to 1.20); incidence of pneumothorax (RR 0.70, 95% CI 0.24 to 2.05); intraventricular hemorrhage (RR 1.12, 95% CI 0.44 to 2.85); neonatal death (RR 1.40, 95% CI 0.58 to 3.37); and time on ventilation (median time 39 hours in the 12-hourly group and 28 hours in the six-hourly group; RD not applicable for this outcome as mean and standard deviation were not reported). Tests for heterogeneity were not applicable as only one study was included. AUTHORS' CONCLUSIONS: There was insufficient evidence to identify the ideal frequency of ETT suctioning in ventilated neonates. Future research should focus on the effects in the very preterm newborns, that is, the most vulnerable population as concerns the risk of both lung and brain damage. Assessment should include the cases of prolonged ventilation, when more abundant, dense secretions are common. Clinical trials might include comparisons between 'as-scheduled' versus 'as needed' endotracheal suctioning, that is, based on specific indications, as well frequent versus less frequent suctioning schedules. PMID- 26945781 TI - Engineering C4 photosynthesis into C3 chassis in the synthetic biology age. AB - C4 photosynthetic plants outperform C3 plants in hot and arid climates. By concentrating carbon dioxide around Rubisco C4 plants drastically reduce photorespiration. The frequency with which plants evolved C4 photosynthesis independently challenges researchers to unravel the genetic mechanisms underlying this convergent evolutionary switch. The conversion of C3 crops, such as rice, towards C4 photosynthesis is a long-standing goal. Nevertheless, at the present time, in the age of synthetic biology, this still remains a monumental task, partially because the C4 carbon-concentrating biochemical cycle spans two cell types and thus requires specialized anatomy. Here we review the advances in understanding the molecular basis and the evolution of the C4 trait, advances in the last decades that were driven by systems biology methods. In this review we emphasise essential genetic engineering tools needed to translate our theoretical knowledge into engineering approaches. With our current molecular understanding of the biochemical C4 pathway, we propose a simplified rational engineering model exclusively built with known C4 metabolic components. Moreover, we discuss an alternative approach to the progressing international engineering attempts that would combine targeted mutagenesis and directed evolution. PMID- 26945779 TI - Comparative genomics and prediction of conditionally dispensable sequences in legume-infecting Fusarium oxysporum formae speciales facilitates identification of candidate effectors. AB - BACKGROUND: Soil-borne fungi of the Fusarium oxysporum species complex cause devastating wilt disease on many crops including legumes that supply human dietary protein needs across many parts of the globe. We present and compare draft genome assemblies for three legume-infecting formae speciales (ff. spp.): F. oxysporum f. sp. ciceris (Foc-38-1) and f. sp. pisi (Fop-37622), significant pathogens of chickpea and pea respectively, the world's second and third most important grain legumes, and lastly f. sp. medicaginis (Fom-5190a) for which we developed a model legume pathosystem utilising Medicago truncatula. RESULTS: Focusing on the identification of pathogenicity gene content, we leveraged the reference genomes of Fusarium pathogens F. oxysporum f. sp. lycopersici (tomato infecting) and F. solani (pea-infecting) and their well-characterised core and dispensable chromosomes to predict genomic organisation in the newly sequenced legume-infecting isolates. Dispensable chromosomes are not essential for growth and in Fusarium species are known to be enriched in host-specificity and pathogenicity-associated genes. Comparative genomics of the publicly available Fusarium species revealed differential patterns of sequence conservation across F. oxysporum formae speciales, with legume-pathogenic formae speciales not exhibiting greater sequence conservation between them relative to non-legume infecting formae speciales, possibly indicating the lack of a common ancestral source for legume pathogenicity. Combining predicted dispensable gene content with in planta expression in the model legume-infecting isolate, we identified small conserved regions and candidate effectors, four of which shared greatest similarity to proteins from another legume-infecting ff. spp. CONCLUSIONS: We demonstrate that distinction of core and potential dispensable genomic regions of novel F. oxysporum genomes is an effective tool to facilitate effector discovery and the identification of gene content possibly linked to host specificity. While the legume-infecting isolates didn't share large genomic regions of pathogenicity related content, smaller regions and candidate effector proteins were highly conserved, suggesting that they may play specific roles in inducing disease on legume hosts. PMID- 26945782 TI - Anion Recognition and Induced Self-Assembly of an alpha,gamma-Cyclic Peptide To Form Spherical Clusters. AB - A cyclic octapeptide composed of hydroxy-functionalized gamma-amino acids folds in a "V-shaped" conformation that allows the selective recognition of anions such as chloride, nitrate, and carbonate. The process involves the simultaneous self assembly of six peptide subunits and the recognition of four anions to form a tetrahedral structure, in which the anions are located at the corners of the resulting structure. Each anion is coordinated to three different peptides. The structure was fully characterized by several techniques, including NMR spectroscopy and X-ray diffraction, and the material was able to facilitate the transmembrane transport of chloride ions. PMID- 26945783 TI - Powerful methods for detecting introgressed regions from population genomic data. AB - Understanding the types and functions of genes that are able to cross species boundaries-and those that are not-is an important step in understanding the forces maintaining species as largely independent lineages across the remainder of the genome. With large next-generation sequencing data sets we are now able to ask whether introgression has occurred across the genome, and multiple methods have been proposed to detect the signature of such events. Here, we introduce a new summary statistic that can be used to test for introgression, RNDmin , that makes use of the minimum pairwise sequence distance between two population samples relative to divergence to an outgroup. We find that our method offers a modest increase in power over other, related tests, but that all such tests have high power to detect introgressed loci when migration is recent and strong. RNDmin is robust to variation in the mutation rate, and remains reliable even when estimates of the divergence time between sister species are inaccurate. We apply RNDmin to population genomic data from the African mosquitoes Anopheles quadriannulatus and A. arabiensis, identifying three novel candidate regions for introgression. Interestingly, one of the introgressed loci is on the X chromosome, but outside of an inversion separating these two species. Our results suggest that significant, but rare, sharing of alleles is occurring between species that diverged more than 1 million years ago, and that application of these methods to additional systems are likely to reveal similar results. PMID- 26945784 TI - Iterative h-minima-based marker-controlled watershed for cell nucleus segmentation. AB - Automated microscopy imaging systems facilitate high-throughput screening in molecular cellular biology research. The first step of these systems is cell nucleus segmentation, which has a great impact on the success of the overall system. The marker-controlled watershed is a technique commonly used by the previous studies for nucleus segmentation. These studies define their markers finding regional minima on the intensity/gradient and/or distance transform maps. They typically use the h-minima transform beforehand to suppress noise on these maps. The selection of the h value is critical; unnecessarily small values do not sufficiently suppress the noise, resulting in false and oversegmented markers, and unnecessarily large ones suppress too many pixels, causing missing and undersegmented markers. Because cell nuclei show different characteristics within an image, the same h value may not work to define correct markers for all the nuclei. To address this issue, in this work, we propose a new watershed algorithm that iteratively identifies its markers, considering a set of different h values. In each iteration, the proposed algorithm defines a set of candidates using a particular h value and selects the markers from those candidates provided that they fulfill the size requirement. Working with widefield fluorescence microscopy images, our experiments reveal that the use of multiple h values in our iterative algorithm leads to better segmentation results, compared to its counterparts. (c) 2016 International Society for Advancement of Cytometry. PMID- 26945785 TI - Reply. PMID- 26945786 TI - Retrospective success and survival rates of dental implants placed after a ridge preservation procedure. AB - AIM: Ridge preservation is any procedure that takes place at the time of, or shortly after an extraction, to minimise resorption of the ridge and maximise bone formation within the socket. The aim of this project is to investigate the outcome of implant treatment following ridge preservation and compare it to an ungrafted implant control group. METHODS AND MATERIALS: Following ethics approval, an electronic and manual search of patient records was conducted, and appropriate cases of implant placement following a ridge preservation procedure were identified. Forty-two patients with 51 implants at ridge-preserved sites were examined by one author (PA) with the following parameters assessed at each implant: pocket probing depth, bleeding on probing, presence/absence of plaque and radiographic bone loss. Clinical and radiographic findings were compared to an ungrafted implant control group and analysed by years in function. RESULTS: There was a 100% survival rate of implants in ridge-preserved sites. In the majority of cases, ridge preservation was performed in the anterior maxilla with a flap raised and the use of deproteinised bovine bone mineral and collagen membrane materials. The mean time in function was 31 (+/-24) months with a range of 2-102 months. Differences in the mean PPD, BOP, plaque index and radiographic bone loss were not statistically significant between implants at ridge-preserved or ungrafted sites. The overall success rate was around 58% for ungrafted implants and around 51% for implants in ridge-preserved sites. However, this difference was not statistically significant. CONCLUSION: In this retrospective study, implant placement at ridge-preserved sites was a predictable procedure that led to very high survival rates and similar success rates to implant placement at ungrafted sites. PMID- 26945787 TI - Graphene Oxide-Copper Nanocomposite-Coated Porous CaP Scaffold for Vascularized Bone Regeneration via Activation of Hif-1alpha. AB - Graphene has been studied for its in vitro osteoinductive capacity. However, the in vivo bone repair effects of graphene-based scaffolds remain unknown. The aqueous soluble graphene oxide-copper nanocomposites (GO-Cu) are fabricated, which are used to coat porous calcium phosphate (CaP) scaffolds for vascularized bone regeneration. The GO-Cu nanocomposites, containing crystallized CuO/Cu2 O nanoparticles of ~30 nm diameters, distribute uniformly on the surfaces of the porous scaffolds and maintain a long-term release of Cu ions. In vitro, the GO-Cu coating enhances the adhesion and osteogenic differentiation of rat bone marrow stem cells (BMSCs). It is also found that by activating the Erk1/2 signaling pathway, the GO-Cu nanocomposites upregulate the expression of Hif-1alpha in BMSCs, resulting in the secretion of VEGF and BMP-2 proteins. When transplanted into rat with critical-sized calvarial defects, the GO-Cu-coated calcium phosphate cement (CPC) scaffolds (CPC/GO-Cu) significantly promote angiogenesis and osteogenesis. Moreover, it is observed via histological sections that the GO Cu nanocomposites are phagocytosed by multinucleated giant cells. The results suggest that GO-Cu nanocomposite coatings can be utilized as an attractive strategy for vascularized bone regeneration. PMID- 26945788 TI - Associations of radiographic degeneration and pain with daily cumulative hip loading in patients with secondary hip osteoarthritis. AB - The purpose of this study was to investigate the associations of radiographic and clinical variables of hip osteoarthritis (OA) with alterations in gait and joint loading in patients with secondary hip OA. Fifty females with secondary hip OA were participated. The minimum joint space width (mJSW) of the hip as a degenerative sign and Sharp and center edge (CE) angles as morphological variables were measured radiographically. Hip joint pain was assessed using a visual analog scale. As gait variables, walking speed, range of hip motion, hip moment peak, and hip moment impulse were calculated. Daily cumulative hip loading was calculated as the hip moment impulse multiplied by the mean number of steps per day. After bivariate correlation analyses between dependent (mJSW and pain) and independent variables (age, body mass index, sharp/CE angles, steps per day, and gait variables), separate forward-backward stepwise multiple regression analyses were performed for each dependent variable. Daily cumulative hip loading in the sagittal plane (beta = 0.30, p = 0.021) and age (beta = -0.36, p = 0.007) were significantly associated with the mJSW. Walking speed (beta = -0.36, p = 0.008) and age (beta = 0.29, p = 0.031) were significantly associated with hip joint pain. Decrease in daily cumulative hip loading in the sagittal plane was associated with mJSW independently of age. Although the causal relationship was not clear, patients with hip OA reduced total exposure to hip joint loading adaptively rather than lowering the hip moment peak concerning worsening of hip degeneration. (c) 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1977-1983, 2016. PMID- 26945790 TI - The Binding Mode Prediction and Similar Ligand Potency in the Active Site of Vitamin D Receptor with QM/MM Interaction, MESP, and MD Simulation. AB - Non-secosteroidal ligands are well-known vitamin D receptor (VDR) agonists. In this study, we described a combined QM/MM to define the protein-ligand interaction energy a strong positive correlation in both QM-MM interaction energy and binding free energy against the biological activity. The molecular dynamics simulation study was performed, and specific interactions were extensively studied. The molecular docking results and surface analysis shed light on steric and electrostatic complementarities of these non-secosteroidal ligands to VDR. Finally, the drug likeness properties were also calculated and found within the acceptable range. The results show that bulky group substitutions in side chain decrease the VDR activity, whereas a small substitution increased it. Functional analyses of H393A and H301A mutations substantiate their roles in the VDR agonistic and antagonistic activities. Apart from the His393 and His301, two other amino acids in the hinge region viz. Ser233 and Arg270 acted as an electron donor/acceptor specific to the agonist in the distinct ligand potency. The results from this study disclose the binding mechanism of VDR agonists and structural modifications required to improve the selectivity. PMID- 26945789 TI - High expression of TRF2, SOX10, and CD10 in circulating tumor microemboli detected in metastatic melanoma patients. A potential impact for the assessment of disease aggressiveness. AB - Circulating tumors cells (CTCs) can be detected in the blood of metastatic melanoma patients (MMPs) both as isolated circulating tumor cells (iCTCs) and circulating tumor microemboli (CTMs), but their clinical significance remains unknown. The aim of this work was to evaluate the prognostic impact in metastatic cutaneous melanoma of CTMs and iCTCs identified by a cytomorphological approach using the isolation by size of tumor cell (ISET) method. We characterized the phenotype of CTCs using anti-PS100, anti-SOX10, anti-CD10, and anti-TRF2 antibodies. 128 MMPs and 37 control healthy individuals with benign nevi were included in this study. Results were compared to the follow-up of patients. 109/128 (85%) MMPs showed CTCs, 44/128 (34%) with 2 to 6 CTMs and 65/128 (51%) with 4 to 9 iCTCs. PS100 expression was homogeneous in iCTCs and heterogeneous in CTMs. SOX10, CD10, and TRF2 were mainly expressed in CTMs. None of the control subjects demonstrated circulating malignant tumor cells. Overall survival was significantly decreased in patients with CTMs, independently of the therapeutic strategies. In conclusion, the presence of CTMs is an independent predictor of shorter survival from the time of diagnosis of MMPs. PMID- 26945794 TI - Correction. PMID- 26945795 TI - Correction. PMID- 26945798 TI - Pd(0)-Catalyzed Dearomative Diarylation of Indoles. AB - We have developed a protocol for a Pd(0)-catalyzed dearomative syn 1,2 diarylation of indoles using readily available boroxines (dehydrated boronic acids) as coupling partners. This reaction proceeds efficiently using PtBu3 as the ligand to divergently access to fused indolines while minimizing the extent of direct Suzuki coupling. The scope of the reaction is remarkably broad and all products are obtained as single diastereomers in moderate to excellent yields. We have also compiled data which parallels the steric and electronic properties of both substrate and boroxine with the propensity to undergo the desired dearomative process over direct Suzuki coupling. PMID- 26945799 TI - A SHORT HISTORY AND CRITICAL REVIEW OF INDIVIDUAL MONITORING. AB - Soon after the discovery of X-rays and the radioactive element radium harmful radiation effects occurred, mainly in the medical field. Consequently, the radiologists, a new profession at that time, called for a limitation of radiation exposures. First proposals were to limit the exposure rate to prevent the incidence of skin erythema. It took more than two decades and there were many victims of severe radiation effects until a sound basis for radiation protection and individual monitoring was established. For external dosimetry, the film dosemeter was invented in the 1920s. This device, often combined with an ion chamber-based pencil dosemeter, dominated the systems used in personnel dosimetry until the end of the twentieth century. For internal exposure, the concept of limiting the 'body burden' was commonly used, and only in the late 1970s, the new concept of the 'effective dose equivalent' published in ICRP publication 26 allowed for a unified interpretation and, therefore, addition of the dosimetric quantities for external and internal exposures. By the end of the last century, individual monitoring had to survive an inflation of proposals for new quantities, but fortunately, it was also the time of vast developments of new technologies, methods and procedures. Later on, much room was given to highly sophisticated regulations, requirements, metrological concepts and administrative procedures. In this complex environment, the original task of individual monitoring became more and more hidden behind secondary loads. Now, like about hundred years ago, however with different motivation, once again the ultimate goal of the professional work has to be thought about by asking: Do people always know why they do what they do? Or simply: Why individual monitoring? PMID- 26945800 TI - INVESTIGATION OF THERMOLUMINESCENCE CHARACTERISTICS OF Y2O3:Er3+ NANOPHOSPHORS. AB - Thermoluminescence (TL) characteristics of Y2O3:Er3+ nanophosphor exposed to UV radiations were investigated. Combustion synthesis method was employed to synthesise the nanophosphors. The confirmation for the pure cubic phase was done by powder X-ray diffraction. The particles formed were found to have 23.19 nm size and it was calculated by the Debye-Scherrer formula for [222] plane and is in close agreement with those obtained using transmission electron microscopy analysis. scanning electron microscopy micrograph reveals porous, irregular shaped particles with large agglomeration of particles whereas Fourier transform infrared spectroscopy studies confirm the presence of organic residua OH and CO in the samples. TL characteristics of UV irradiated Y2O3:Er3+ for (1-5) mol % were investigated. All the TL glow curves show almost similar glow curves having a single broad peak at 113.26, 113.82 113.72, 113.74 and 113.72 degrees C for 1, 2, 3, 4 and 5 mol %, respectively, of Er3+ ions. The effects of heating rate were also studied and the trapping parameters, namely activation energy (E), order of kinetics (b) and frequency factor (s) were determined using Chen's peak shape method and computerised glow curve deconvolution technique suggested by Kitis for second-order kinetics. They were also discussed in detail for their possible usage in dosimetry. PMID- 26945801 TI - Transcatheter implantation of SAPIEN 3 valve in native right ventricular outflow tract for severe pulmonary regurgitation following tetralogy of fallot repair. AB - Pulmonary valve replacement (PVR) is indicated in patients with significant pulmonary regurgitation (PR), stenosis (PS), or mixed pulmonary valve disease. While once an exclusively surgical procedure, many patients can undergo transcatheter PVR (TPVR) with excellent early outcomes (Haas et al. 2013, Clin. Res. Cardiol. Off. J. German Cardiac Soc. 102:119-128; Kenny et al. 2011, J. Am. Coll. Cardiol. 58:2248-2256; Cheatham et al. Circulation 2015, 131:1960-1970). The available transcatheter options continue to expand, but the majority of cases performed in the United States involve the use of FDA approved Melody valve (Medtronic; Minneapolis, MN) or the SAPIEN (Edwards Lifesciences; Irvine, CA) family of valves. The SAPIEN 3 valve (S3) recently received FDA approval for transcatheter aortic valve replacement. We report the first S3 implantation in the pulmonary position for treatment of chronic pulmonary regurgitation and progressive right ventricular dilation in an 18 year old male with repaired Tetralogy of Fallot. (c) 2016 Wiley Periodicals, Inc. PMID- 26945802 TI - Open-angle glaucoma in the Petit Basset Griffon Vendeen. AB - OBJECTIVES: To report the prevalence and clinical characteristics of an open angle glaucoma in Petit Basset Griffon Vendeen (PBGV) dogs in the United Kingdom (UK). ANIMALS STUDIED AND METHODS: At breed society clinics extending over a 6 year period, 366 dogs of varying ages and both sexes were clinically examined for signs of glaucoma using slit-lamp biomicroscopy, indirect and direct ophthalmoscopy, tonometry, and gonioscopy. RESULTS: The prevalence of glaucoma was 10.4% (38 dogs). Clinical signs of the disease presented from 3 years of age onwards, the commonest initial feature being the elevation of intraocular pressure (IOP) in 15 dogs (39.4%). In addition to elevated IOP, another 13 dogs (34.2%) presented with other features of glaucoma, some with lens subluxation and globe enlargement and all with possible or known vision defects. In the remaining 10 dogs (26.3%), phacodonesis or lens subluxation was observed before subsequent elevation of IOP. CONCLUSIONS: High prevalence and similarity to the primary open angle glaucoma (POAG) seen in the Beagle and Elkhound breeds indicate that an open-angle glaucoma is present in the PBGV in the UK and that this disease may be genetically determined in this breed. Although increased IOP is the commonest early diagnostic feature, lens instability prior to an increase in IOP may be part of the clinical picture. PMID- 26945803 TI - Practitioner Review: On the trustworthiness of clinical practice guidelines - a systematic review of the quality of methods used to develop guidelines in child and youth mental health. AB - BACKGROUND: Numerous practice guidelines (PGs) relevant to child and youth mental health (CYMH) are available, but their quality is uncertain. We used systematic review methodology to identify the methods employed to develop PGs in CYMH and assess whether they align with international quality standards. METHODS: We used prespecified inclusion criteria to search for CYMH PGs (2009-2014) in journals of professional associations or websites of organizations who produce or house PGs. Eligible PGs and organization websites were screened to identify PG development methods. Two reviewers assessed the alignment of the PG development methods with PG quality criteria using the Appraisal of Guidelines for Research and Evaluation (AGREE II) domains and Institute of Medicine (IOM) standards. RESULTS: Five sets of eligible development methods were identified in 70 eligible PGs. Three sets adhered to all (National Institute for Health and Care Excellence; Scottish Intercollegiate Guidelines Network) or most (U.S. Preventive Services Task Force) AGREE II domains and IOM standards, and were used to develop 31.4% of PGs. The two remaining sets of development methods had important weaknesses (e.g. lack of mandatory rigorous systematic reviews, multidisciplinary development groups, or transparent conflict of interest methods) and were associated with 21.4% of PGs. No development methods could be identified in 40.0% of PGs; ineligible development methods were referenced in 7.1% of PGs. CONCLUSIONS: Up to 69% of available CYMH PGs may have been developed using methods that do not align with AGREE II quality criteria or IOM standards. The quality of available CYMH PGs needs to be assessed, and strategies designed to guide practitioners to high quality PGs and facilitate adherence by PG developers to international quality standards are needed. PMID- 26945804 TI - Comment on: The Associations Between Maternal Factors During Pregnancy and the Risk of Childhood Acute Lymphoblastic Leukemia: A Meta-Analysis. PMID- 26945806 TI - Fiber bragg grating sensor based device for simultaneous measurement of respiratory and cardiac activities. AB - This paper reports a novel optical ballistocardiography technique, which is non invasive, for the simultaneous measurement of cardiac and respiratory activities using a Fiber Bragg Grating Heart Beat Device (FBGHBD). The unique design of FBGHBD offers additional capabilities such as monitoring nascent morphology of cardiac and breathing activity, heart rate variability, heart beat rhythm, etc., which can assist in early clinical diagnosis of many conditions associated with heart and lung malfunctioning. The results obtained from the FBGHBD positioned around the pulmonic area on the chest have been evaluated against an electronic stethoscope which detects and records sound pulses originated from the cardiac activity. In order to evaluate the performance of the FBGHBD, quantitative and qualitative studies have been carried out and the results are found to be reliable and accurate, validating its potential as a standalone medical diagnostic device. The developed FBGHBD is simple in design, robust, portable, EMI proof, shock proof and non-electric in its operation which are desired features for any clinical diagnostic tool used in hospital environment. PMID- 26945805 TI - Structural connectivity of the human anterior temporal lobe: A diffusion magnetic resonance imaging study. AB - The anterior temporal lobes (ATL) have been implicated in a range of cognitive functions including auditory and visual perception, language, semantic knowledge, and social-emotional processing. However, the anatomical relationships between the ATLs and the broader cortical networks that subserve these functions have not been fully elucidated. Using diffusion tensor imaging (DTI) and probabilistic tractography, we tested the hypothesis that functional segregation of information in the ATLs is reflected by distinct patterns of structural connectivity to regions outside the ATLs. We performed a parcellation of the ATLs bilaterally based on the degree of connectivity of each voxel with eight ipsilateral target regions known to be involved in various cognitive networks. Six discrete segments within each ATL showed preferential connectivity to one of the ipsilateral target regions, via four major fiber tracts (uncinate, inferior longitudinal, middle longitudinal, and arcuate fasciculi). Two noteworthy interhemispheric differences were observed: connections between the ATL and orbito-frontal areas were stronger in the right hemisphere, while the consistency of the connection between the ATL and the inferior frontal gyrus through the arcuate fasciculus was greater in the left hemisphere. Our findings support the hypothesis that distinct regions within the ATLs have anatomical connections to different cognitive networks. Hum Brain Mapp 37:2210-2222, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26945807 TI - Theoretical Shaping of Femtosecond Laser Pulses for Molecular Photodissociation with Control Techniques Based on Ehrenfest's Dynamics and Time-Dependent Density Functional Theory. AB - The combination of nonadiabatic Ehrenfest-path molecular dynamics (EMD) based on time-dependent density functional theory (TDDFT) and quantum optimal control formalism (QOCT) was used to optimize the shape of ultra-short laser pulses to achieve photodissociation of a hydrogen molecule and the trihydrogen cation H3 (+) . This work completes a previous one [A. Castro, ChemPhysChem, 2013, 14, 1488 1495], in which the same objective was achieved by demonstrating the combination of QOCT and TDDFT for many-electron systems on static nuclear potentials. The optimization model, therefore, did not include the nuclear movement and the obtained dissociation mechanism could only be sequential: fast laser-assisted electronic excitation to nonbonding states (during which the nuclei are considered to be static), followed by field-free dissociation. Here, in contrast, the optimization was performed with the QOCT constructed on top of the full dynamic model comprised of both electrons and nuclei, as described within EMD based on TDDFT. This is the first numerical demonstration of an optimal control formalism for a hybrid quantum-classical model, that is, a molecular dynamics method. PMID- 26945808 TI - Influence of artificially-induced porosity on the compressive strength of calcium phosphate bone cements. AB - The biological and mechanical nature of calcium phosphate cements (CPC's) matches well with that of bone tissues, thus they can be considered as an appropriate environment for bone repair as bone defect fillers. The current study focuses on the experimental characterization of the mechanical properties of CPCs that are favorably used in clinical applications. Aiming on evaluation of their mechanical performance, tests in compression loading were conducted in order to determine the mechanical properties of the material under study. In this context, experimental results occurring from the above mechanical tests on porous specimens that were fabricated from three different porous additives, namely albumin, gelatin and sodium alginate, are provided, while assessment of their mechanical properties in respect to the used porous media is performed. Additionally, samples reinforced with hydroxyapatite crystals were also tested in compression and the results are compared with those of the above tested porous CPCs. The knowledge obtained allows the improvement of their biomechanical properties by controlling their structure in a micro level, and finds a way to compromise between mechanical and biological response. PMID- 26945809 TI - Mechanistic contribution of electroconductive hydroxyapatite-titanium disilicide composite on the alignment and proliferation of cells. AB - We elucidate here the mechanistic contribution of a novel electroconductive hydroxyapatite-20 wt.% titanium disilicide (HA-TiSi2) composite system in favorably modulating osteoblast functions in relation to the monolithic HA. The higher electrical conductivity of HA-TiSi2(sigmaDC ~ 67.117 +/- 3.57 S/m) in comparison to glass sample effectively guided the electroactive myoblast, leading to their significant alignment and proliferation. This favorable behavior is attributed to the formation of small electrochemical cells between HA and TiSi2phase, which produce a small electric field, directing the electroactive myoblast to migrate and grow in a particular direction. In contrast, no impact of TiSi2on osteoblast function was observed because of their inability to respond to small electric field. However, thein vitrobioactivity in simulated body fluid indicated the nucleation and growth of apatite crystals. Moreover, in the context of load-bearing capability, the presence of 20 wt.% TiSi2in HA led to increase in the fracture toughness by ~100%. This study underscores the effectiveness of HA TiSi2in favorably modulating the cellular activity, myoblast in particular. PMID- 26945810 TI - Poly (gamma-glutamic acid)/beta-TCP nanocomposites via in situ copolymerization: Preparation and characterization. AB - A series biodegradable poly (gamma-glutamic acid)/beta-tricalcium phosphate (gamma-PGA/TCP) nanocomposites were prepared which were composed of poly-gamma glutamic acid polymerized in situ with beta-tricalcium phosphate and physiochemically characterized as bone graft substitutes. The particle size via dynamic light scattering, the direct morphological characterization via transmission electron microscopy and field emission scanning electron microscope, which showed that gamma-PGA and beta-TCP were combined compactly at 80C, and the gamma-PGA/TCP nanocomposites had homogenous and nano-sized grains with narrow particle size distributions. The water uptake and retention abilities, in vitro degradation properties, cytotoxicity in the simulated medium, and protein release of these novel gamma-PGA/TCP composites were investigated. Cell proliferation in composites was nearly twice than beta-TCP when checked in vitro using MC3T3 cell line. We also envision the potential use of gamma-PGA/TCP systems in bone growth factor or orthopedic drug delivery applications in future bone tissue engineering applications. These observations suggest that the gamma-PGA/TCP are novel nanocomposites with great potential for application in the field of bone tissue engineering. PMID- 26945811 TI - The effect of fiber size and pore size on cell proliferation and infiltration in PLLA scaffolds on bone tissue engineering. AB - The scaffold microstructure has a great impact on cell functions in tissue engineering. Herein, the PLLA scaffolds with hierarchical fiber size and pore size were successfully fabricated by thermal-induced phase separation or combined thermal-induced phase separation and salt leaching methods. The PLLA scaffolds were fabricated as microfibrous scaffolds, microfibrous scaffolds with macropores (50-350 um), nanofibrous scaffolds with micropores (100 nm to 10 um), and nanofibrous scaffolds with both macropores and micropores by tailoring selective solvents for forming different fiber size and pre-sieved salts for creating controlled pore size. Among the four kinds of PLLA scaffolds, the nanofibrous scaffolds with both macropores and micropores provided a favorable microenvironment for protein adsorption, cell proliferation, and cell infiltration. The results further confirmed the significance of fiber size and pore size on the biological properties, and a scaffold with both micropores and macropores, and a nanofibrous matrix might have promising applications in bone tissue engineering. PMID- 26945812 TI - Effects of low-fat milk consumption on metabolic and atherogenic biomarkers in Korean adults with the metabolic syndrome: a randomised controlled trial. AB - BACKGROUND: Previous studies of the health effects of low-fat milk or dairy consumption on the metabolic syndrome have yielded inconsistent results. The present study aimed to investigate the effects of low-fat milk consumption on traits associated with the metabolic syndrome, as well as inflammatory and atherogenic biomarkers, in Korean adults with the metabolic syndrome. METHODS: Overweight Koreans with the metabolic syndrome (n = 58) were recruited and randomly assigned to either the low-fat milk or control group. The low-fat milk group was instructed to consume two packs of low-fat milk per day (200 mL twice daily) for 6 weeks, and the control group was instructed to maintain their habitual diet. Clinical investigations were conducted during the screening visit, on study day 0, and after 6 weeks. RESULTS: No significant differences in changes in body mass index, blood pressure, lipid profile and adiponectin levels, as well as levels of inflammatory markers, oxidative stress markers and atherogenic markers, were found between the low-fat milk and control groups. However, compared to the controls, significant favourable decreases in serum soluble vascular adhesion molecule-1 and endothelin-1 levels were found in the 12 subjects with high blood pressure and in the 18 subjects with hypertriglyceridaemia in the low-fat milk group. CONCLUSIONS: The present study did not demonstrate an overall beneficial effect of low-fat milk consumption in subjects with the metabolic syndrome. However, low-fat milk consumption may have a favourable effect on atherogenic markers in subjects with high blood pressure or hypertriglyceridaemia. PMID- 26945813 TI - Role of inflammasome genetics in susceptibility to HPV infection and cervical cancer development. AB - PROBLEM: Only a small proportion of HPV+ women develop virus-associated lesions and cervical cancer, suggesting that other factors are involved in HPV+ keratinocyte transformation. Immune response plays an important role in clearing HPV infection, and host genetic variants resulting in defective immune response have been associated with virus persistence and/or cervical cancer. Considering that genetic variations in inflammasome genes were previously associated with viral infection and cancer development, the present study investigates selected single nucleotide polymorphisms (SNPs) in inflammasome genes as a possible risk factor for HPV infection susceptibility and/or for progression to cervical cancer. PATIENTS AND METHODS: 12 SNPs in seven inflammasome-related genes (NLRP1, NLRP3, NLRP6, CARD8, IL1B, IL18, TNFAIP3) were genotyped in a Brazilian HPV+ case/control cohort (n = 246/310). Multivariate analysis was performed in case/control as well as in HPV+ women stratified by the presence or severity of histologic lesion, HPV persistence, and type of virus. RESULTS: IL1B rs1143643 was associated with protection against HPV infection in case/control analysis. NLRP1 rs11651270 plays a protection role against HPV persistence and/or oncogenesis. NLRP3 rs10754558 and IL18 rs1834481 exert a beneficial role against HPV persistence. NLRP3 rs10754558 variant resulted significantly associated with a lower risk to be infected with a high-risk HPV. CONCLUSION: Our findings for the first time demonstrated that inflammasome genetics could affect HPV/host interaction in terms of virus susceptibility as well as of virus/persistence and cervical cancer progression. J. Med. Virol. 88:1646-1651, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26945814 TI - Blind testing of cross-linking/mass spectrometry hybrid methods in CASP11. AB - Hybrid approaches combine computational methods with experimental data. The information contained in the experimental data can be leveraged to probe the structure of proteins otherwise elusive to computational methods. Compared with computational methods, the structures produced by hybrid methods exhibit some degree of experimental validation. In spite of these advantages, most hybrid methods have not yet been validated in blind tests, hampering their development. Here, we describe the first blind test of a specific cross-link based hybrid method in CASP. This blind test was coordinated by the CASP organizers and utilized a novel, high-density cross-linking/mass-spectrometry (CLMS) approach that is able to collect high-density CLMS data in a matter of days. This experimental protocol was developed in the Rappsilber laboratory. This approach exploits the chemistry of a highly reactive, photoactivatable cross-linker to produce an order of magnitude more cross-links than homobifunctional cross linkers. The Rappsilber laboratory generated experimental CLMS data based on this protocol, submitted the data to the CASP organizers which then released this data to the CASP11 prediction groups in a separate, CLMS assisted modeling experiment. We did not observe a clear improvement of assisted models, presumably because the properties of the CLMS data-uncertainty in cross-link identification and residue residue assignment, and uneven distribution over the protein-were largely unknown to the prediction groups and their approaches were not yet tailored to this kind of data. We also suggest modifications to the CLMS-CASP experiment and discuss the importance of rigorous blind testing in the development of hybrid methods. Proteins 2016; 84(Suppl 1):152-163. (c) 2016 The Authors Proteins: Structure, Function, and Bioinformatics Published by Wiley Periodicals, Inc. PMID- 26945815 TI - Microbiome alterations in HIV infection a review. AB - Recent developments in molecular techniques have allowed researchers to identify previously uncultured organisms, which has propelled a vast expansion of our knowledge regarding our commensal microbiota. Interest in the microbiome specific to HIV grew from earlier findings suggesting that bacterial translocation from the intestines is the cause of persistent immune activation despite effective viral suppression with antiretroviral therapy (ART). Studies of SIV infected primates have demonstrated that Proteobacteria preferentially translocate and that mucosal immunity can be restored with probiotics. Pathogenic SIV infection results in a massive expansion of the virome, whereas non-pathogenic SIV infection does not. Human HIV infected cohorts have been shown to have microbiota distinctive from that of HIV negative controls and efforts to restore the intestinal microbiome via probiotics have often had positive results on host markers. The microbiota of the genital tract may play a significant role in acquisition and transmission of HIV. Modification of commensal microbial communities likely represents an important therapeutic adjunct to treatment of HIV. Here we review the literature regarding human microbiome in HIV infection. PMID- 26945816 TI - Brief Report: Peripheral Osteolysis in Adults Linked to ASAH1 (Acid Ceramidase) Mutations: A New Presentation of Farber's Disease. AB - OBJECTIVE: To establish a diagnosis and provide counseling and treatment for 3 adult patients from one family presenting with peripheral osteolysis. METHODS: Following clinical and radiographic assessment, exome sequencing, targeted gene resequencing, and determination of enzyme activity in cultured fibroblasts were performed. RESULTS: The proband (age 40 years) had a history of episodic fever and pain in childhood that subsided around puberty. He and 2 of his older sisters (ages 58 and 60 years, respectively) showed adult-onset progressive shortening of fingers and toes with redundancy of the overlying skin. Radiographs showed severe osteolysis of the distal radius and ulna, carpal bones, metacarpal bones, and phalanges. Sequencing of the known genes for recessively inherited osteolysis, MMP2 and MMP14, failed to show pathogenic mutations. Exome sequencing revealed compound heterozygosity for mutations c.505T>C (p.Trp169Arg) and c.760A>G (p.Arg254Gly) in ASAH1, the gene coding for acid ceramidase. Sanger sequencing confirmed correct segregation in the family, and enzyme activity in fibroblast cultures from the patients was reduced to ~8% of that in controls, confirming a diagnosis of Farber's disease. CONCLUSION: Our findings indicate that hypomorphic mutations in ASAH1 may result in an osteoarticular phenotype with a juvenile phase resembling rheumatoid arthritis that evolves to osteolysis as the final stage in the absence of neurologic signs. This observation delineates a novel type of recessively inherited peripheral osteolysis and illustrates the long-term skeletal manifestations of acid ceramidase deficiency (Farber's disease) in what appear to be the oldest affected individuals known so far. PMID- 26945817 TI - Ameliorating effect of antioxidants and pregabalin combination in pain recurrence after ductal clearance in chronic pancreatitis: Results of a randomized, double blind, placebo-controlled trial. AB - BACKGROUND AND AIM: The aim of this study was to evaluate the effect of antioxidant-pregabalin combination on pain recurrence in patients with chronic calcific pancreatitis. METHODS: In this randomized, double-blind, placebo controlled trial, chronic calcific pancreatitis patients with pain recurrence following pancreatic ductal clearance of stones received either antioxidant pregabalin combination or matching placebo for 2 months followed by open-label antioxidants for the next 4 months in both groups. Compliance, daily pain, and adverse events were recorded weekly and at the end of study by a coordinator blinded to treatment status. Primary outcome was pain improvement (visual analog scale and Izbicki score); secondary outcomes were as follows: complete pain resolution, painful days, and adverse events. Number needed-to-treat was calculated. RESULTS: We randomized 42 and 45 patients (mean age 29.3 years) to treatment and placebo arms, respectively. Baseline characteristics, including pain scores, were similar for both groups. No patients received high-potency narcotic. At 2 months, a significant improvement in the treatment arm was observed in percent reduction of visual analog scale (-50 [-80.0; -32.1] vs -29.5 [-64.5; 0]; P = 0.01), Izbicki score (14.5 [0; 21.3] vs 30.0 [11.8; 41.3]; P = 0.001), complete pain resolution (20 [47.6%] vs 12 [26.7%]; P = 0.04), and number of painful days (10.0 [2.0; 16.0] vs 18.0 [7.0; 34.0]; P = 0.01). Needed-to-treat was 4.8. Pain reduction persisted at 6 months in the original treatment group (20.0 [15.0; 28.0] vs 36.0 [20.0; 50.0]; P = 0.006). A total of 33 patients in the treatment arm experienced mild to moderate self-limiting nausea/vomiting and drowsiness, respectively and did not require any change in study protocol. CONCLUSION: Antioxidant-pregabalin combination results in significant relief in pain recurrence after ductal clearance in narcotic naive patients with chronic calcific pancreatitis. PMID- 26945818 TI - The minimum effective concentration (MEC90 ) of ropivacaine for ultrasound-guided supraclavicular brachial plexus block. AB - The aim of this study was to determine the minimum effective concentration of ropivacaine for ultrasound-guided supraclavicular brachial plexus block. Fifty one patients undergoing arm surgery received double-injection ultrasound-guided supraclavicular block using ropivacaine 40 ml. The concentration of ropivacaine administered to each patient started at 0.225% and then depended on the response of the previous one, based on a biased coin design up-and-down sequential method. In case of failure, the ropivacaine concentration was increased by 0.025% w/v in the next subject. In the case of a successful block, the next patient was randomised to the same concentration or a concentration 0.025% w/v less. Success was defined as complete sensory blockade of the brachial plexus 30 min after the block together with pain-free surgery. The minimum effective ropivacaine concentration in 90% of subjects was 0.257% w/v (95% CI 0.241-0.280%). PMID- 26945819 TI - Thioxanthenes, chlorprothixene and flupentixol inhibit proton currents in BV2 microglial cells. AB - The thioxanthene antipsychotic drugs chlorprothixene and flupentixol have anti inflammatory and antioxidant properties. The reactive oxygen species produced by NADPH oxidase during microglia-mediated inflammatory responses cause neuronal damage, thereby contributing to various neurodegenerative diseases. Voltage-gated proton channels sustain the NADPH oxidase activity, and inhibition of the channels' activity reduces the production of reactive oxygen species. Herein, the effects of chlorprothixene and flupentixol on proton currents were investigated in BV2 microglial cells using the whole-cell patch-clamp method. Both drugs inhibited the proton currents in a concentration-dependent manner (IC50=1.7MUM and 6.6MUM, respectively). Chlorprothixene at 3MUM slightly shifted the activation voltage toward depolarization. Both the activation and the deactivation kinetics of the proton currents were slowed by chlorprothixene 1.2- and 3.5-fold, respectively. Thus, the inhibition of proton currents may be partly responsible for the antioxidant effects of thioxanthene antipsychotic drugs. PMID- 26945820 TI - Neuroprotection of taurine against reactive oxygen species is associated with inhibiting NADPH oxidases. AB - It is well established that taurine shows potent protection against glutamate induced injury to neurons in stroke. The neuroprotection may result from multiple mechanisms. Increasing evidences suggest that NADPH oxidases (Nox), the primary source of superoxide induced by N-methyl-d-aspartate (NMDA) receptor activation, are involved in the process of oxidative stress. We found that 100MUM NMDA induced oxidative stress by increasing the reactive oxygen species level, which contributed to the cell death, in vitro. Neuron cultures pretreated with 25mM taurine showed lower percentage of death cells and declined reactive oxygen species level. Moreover, taurine attenuated Nox2/Nox4 protein expression and enzyme activity and declined intracellular calcium intensity during NMDA-induced neuron injury. Additionally, taurine also showed neuroprotection against H2O2 induced injury, accompanying with Nox inhibition. So, we suppose that protection of taurine against reactive oxygen species during NMDA-induced neuron injury is associated with Nox inhibition, probably in a calcium-dependent manner. PMID- 26945821 TI - Prevention of cardiac dysfunction, kidney fibrosis and lipid metabolic alterations in l-NAME hypertensive rats by sinapic acid--Role of HMG-CoA reductase. AB - The present study was designed to evaluate the effect of sinapic acid, a bioactive phenolic acid on high blood pressure associated cardiac dysfunction, kidney fibrosis and lipid alterations in N(omega)-nitro-l-arginine methyl ester hydrochloride (l-NAME) induced hypertensive rats. Sinapic acid was administered to rats orally at a dosage of 40 mg/kg everyday for a period of 4 weeks. Sinapic acid treatment significantly decreased mean arterial pressure, left ventricular end diastolic pressure, organ weights (liver and kidney), lipid peroxidation products in tissues (liver and kidney), activities of hepatic marker enzymes and the levels of renal function markers in serum of l-NAME rats. Sinapic acid treatment also significantly increased the level of plasma nitric oxide metabolites, and enzymatic and non-enzymatic antioxidants in tissues of l-NAME rats. Tissue damage was assessed by histopathological examination. Alterations in plasma angiotensin-converting enzyme activity, level of plasma lipoproteins and tissue lipids were corrected by sinapic acid treatment in l-NAME rats. Sinapic acid treatment significantly decreased the activity of 3-hydroxy-3-methylglutaryl Coenzyme A (HMG-CoA) reductase in plasma and liver, whereas the activity of lecithin cholesterol acyl transferase was significantly increased in the plasma of hypertensive rats. Docking result showed the interaction between sinapic acid and HMG-CoA reductase. Sinapic acid has shown best ligand binding energy of -5.5 kcal/M. Moreover, in chick embryo model, sinapic acid improved vessel density on chorioallantoic membrane. These results of the present study concludes that sinapic acid acts as a protective agent against hypertension associated cardiac dysfunction, kidney fibrosis and lipid alterations. PMID- 26945823 TI - Complex Regional Pain Syndrome of the Breast and Chest Wall. PMID- 26945822 TI - Cannabinoid receptors are involved in the protective effect of a novel curcumin derivative C66 against CCl4-induced liver fibrosis. AB - Liver fibrosis is one of the major causes of morbidity and mortality worldwide and lacks efficient therapy. Recent studies suggest the curcumin protects liver from fibrosis. However, curcumin itself is in low bioavailable concentration when administered orally, and the protective mechanism remains poorly understood. The current study aimed to investigate whether a more stable derivative of curcumin, C66, protects against CCl4-inudced liver fibrosis and examine the underlying mechanism involving cannabinoid receptor (CB receptor). At a dose lower than curcumin itself, C66 displayed a superior anti-fibrotic effect. C66 significantly reduced collagen deposition, pro-inflammatory cytokine expression, and liver enzyme activities. Mechanistic study revealed that C66 treatment decreased CCl4 induced cannabinoid receptor 1 (CB1 receptor) expression and increased cannabinoid receptor 2 (CB2 receptor) expression, along with an inhibition of JNK/NF-kappaB-mediated inflammatory signaling. In conclusion, this curcumin derivative attenuates liver fibrosis likely involving a CB/JNK/NF-kappaB-mediated pathway. PMID- 26945824 TI - Pubertal exposure to ethinylestradiol promotes different effects on the morphology of the prostate of the male and female gerbil during aging. AB - In rodents, the final growth and maturation of the prostate occur at puberty, a crucial period for prostate development. The present study is a serological, morphological, morphometric, and immunohistochemical analysis of the effects of exposure to ethinylestradiol (EE) (15 ug/kg/day) during puberty (EE/PUB group) on the male ventral and female prostate in senile gerbils. In the study, male and female gerbils (Meriones unguiculatus) (42 days) received by gavage 15 MUg/kg/day of EE (a component of the contraceptive pill), diluted in 100 uL of Nujol(r) for 1 week (EE/PUB group). In the control group, males and females were not treated. Animals were killed (n = 5) after 12 months in the experimental groups. In the senile male in the EE/PUB group, we observed a reduction in testosterone levels and a decrease in the prostatic epithelial thickness, as well as in the thickness of the muscle layer. In addition, an increase in PIN multiplicity and prostatic inflammation was observed. In the senile female in the EE/PUB group, we observed increased testosterone and estradiol levels, an enhanced prostatic epithelial thickness and an increase in the thickness of the muscle layer. Immunohistochemical analysis revealed an increase in positive cells (%) for AR and PCNA in the male prostate and an increase in positive basal cells for p63 in the female prostate of the EE/PUB group. Exposure to EE during puberty resulted in an inhibitory action on the male ventral prostate and an anabolic effect on the female prostate in senile gerbils. (c) 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 477-489, 2017. PMID- 26945825 TI - Polyethylene glycol plus ascorbic acid is as effective as sodium picosulfate with magnesium citrate for bowel preparation: A randomized trial. AB - OBJECTIVE: This study was aimed to evaluate the efficacy and safety of two low volume agents, polyethylene glycol (PEG)-3350 plus ascorbic acid (PEG + Asc) and sodium picosulfate with magnesium citrate (SPMC), for bowel preparation. METHODS: We performed a prospective, endoscopist-blinded, single-center, randomized controlled trial comparing PEG + Asc with SPMC to evaluate the bowel cleansing efficacy of the two regimens using the modified Ottawa bowel preparation scale (OBPS) and the Aronchick scale. Patients' taste and overall tolerance were assessed with a questionnaire. RESULTS: In total, 200 patients were randomized to receive either PEG + Asc (n = 98) or SPMC (n = 102). Both treatments were similarly efficacious in bowel cleansing, based on the modified OBSP (PEG + Asc 4.01 +/- 2.29 vs SPMC 3.86 +/- 2.47, P = 0.62) and Aronchick scale (PEG + Asc 1.96 +/- 0.70 vs SPMC 1.89 +/- 0.70, P = 0.42). Patient-reported taste and tolerance of each regimen, as reported by the questionnaire, were significantly greater in the PEG + Asc group than in the SPMC group (P = 0.01). In terms of adverse events, dizziness was more frequently observed in the PEG + Asc group (P = 0.03), whereas nausea was more common in the SPMC group (P = 0.02). CONCLUSIONS: PEG + Asc and SPMC show similar efficacy for bowel preparation. However, patient's overall tolerance is higher in the PEG + Asc group. PMID- 26945826 TI - The human gut microbiome and its dysfunctions through the meta-omics prism. AB - The microorganisms inhabiting the human gut are abundant (10(14) cells) and diverse (approximately 500 species per individual). It is now acknowledged that the microbiota has coevolved with its host to achieve a symbiotic relationship, leading to physiological homeostasis. The gut microbiota ensures vital functions, such as food digestibility, maturation of the host immune system, and protection against pathogens. Over the last few decades, the gut microbiota has also been associated with numerous diseases, such as inflammatory bowel disease, irritable bowel syndrome, obesity, and metabolic diseases. In most of these pathologies, a microbial dysbiosis has been found, indicating shifts in the taxonomic composition of the gut microbiota and changes in its functionality. Our understanding of the influence of the gut microbiota on human health is still growing. Working with microorganisms residing in the gut is challenging since most of them are anaerobic and a vast majority (approximately 75%) are uncultivable to date. Recently, a wide range of new approaches (meta-omics) has been developed to bypass the uncultivability and reveal the intricate mechanisms that sustain gut microbial homeostasis. After a brief description of these approaches (metagenomics, metatranscriptomics, metaproteomics, and metabolomics), this review will discuss the importance of considering the gut microbiome as a structured ecosystem and the use of meta-omics to decipher dysfunctions of the gut microbiome in diseases. PMID- 26945827 TI - Lipid production from hemicellulose with Lipomyces starkeyi in a pH regulated fed batch cultivation. AB - This study investigated lipid production from the hemicellulosic fraction of birch wood by the oleaginous yeast Lipomyces starkeyi. Birch wood chips were thermochemically pretreated by hot water extraction, and the liquid phase, containing 45.1 g/l xylose as the major sugar, 13.1 g/l acetic acid and 4.7 g/l furfural, was used for cultivations of L. starkeyi CBS1807. The hydrolysate strongly inhibited yeast growth; the strain could only grow in medium containing 30% hydrolysate at pH 6. At pH 5, growth stopped already upon the addition of about 10% hydrolysate. In fed-batch cultures fed with hydrolysate or a model xylose-acetic acid mixture, co-consumption of xylose and acetic acid was observed, which resulted in a pH increase. This phenomenon was utilized to establish a pH-stat fed-batch cultivation in which, after an initial feeding, hydrolysate or model mixture was connected to the pH-regulation system of the bioreactor. Under these conditions we obtained growth and lipid production in cultures grown on either xylose or glucose during the batch phase. In cultivations fed with model mixture, a maximum lipid content of 60.5% of the cell dry weight (CDW) was obtained; however, not all xylose was consumed. When feeding hydrolysate, growth was promoted and carbon sources were completely consumed, resulting in higher CDW with maximum lipid content of 51.3%. In both cultures the lipid concentration was 8 g/l and a lipid yield of 0.1 g/g carbon source was obtained. Lipid composition was similar in all cultivations, with C18:1 and C16:0 being the most abundant fatty acids. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26945828 TI - Preventing Burnout. PMID- 26945829 TI - Case of isolated epidermolytic acanthoma: Genetic and immunohistochemical analysis. PMID- 26945830 TI - Ketamine attenuates sepsis-induced acute lung injury via regulation of HMGB1-RAGE pathways. AB - High mobility group box protein 1 (HMGB1) and receptor for the advanced glycation end product (RAGE) play important roles in the development of sepsis-induced acute lung injury (ALI). Ketamine is considered to confer protective effects on ALI during sepsis. In this study, we investigated the effects of ketamine on HMGB1-RAGE activation in a rat model of sepsis-induced ALI. ALI was induced in wild type (WT) and RAGE deficient (RAGE(-/-)) rats by cecal ligation and puncture (CLP) or HMGB1 to mimic sepsis-induced ALI. Rats were randomly divided to six groups: sham-operation+normal saline (NS, 10 mL/kg), sham-operation+ketamine (10 mg/kg), CLP/HMGB1+NS (10 mL/kg), CLP/HMGB1+ketamine (5 mg/kg), CLP/HMGB1+ketamine (7.5 mg/kg), and CLP/HMGB1+ketamine (10 mg/kg) groups. NS and ketamine were administered at 3 and 12 h after CLP/HMGB1 via intraperitoneal injection. Pathological changes of lung, inflammatory cell counts, expression of HMGB1 and RAGE, and concentrations of various inflammatory mediators in bronchoalveolar lavage fluids (BALF) and lung tissue were then assessed. Nuclear factor-kappa B (NF-kappaB) and mitogen-activated protein kinases (MAPK) signaling pathways in the lung were also evaluated. CLP/HMGB1 increased the wet to dry weight ratio and myeloperoxidase activity in lung, the number of total cells, neutrophils, and macrophages in the BALF, and inflammatory mediators in the BALF and lung tissues. Moreover, expression of HMGB1 and RAGE in lung tissues was increased after CLP. Ketamine inhibited all the above effects. It also inhibited the activation of IkappaB-alpha, NF-kappaB p65, and MAPK. Ketamine protects rats against HMGB1-RAGE activation in a rat model of sepsis-induced ALI. These effects may partially result from reductions in NF-kappaB and MAPK. PMID- 26945831 TI - Chondroprotective effects of palmatine on osteoarthritis in vivo and in vitro: A possible mechanism of inhibiting the Wnt/beta-catenin and Hedgehog signaling pathways. AB - The present study aimed to investigate the effect of palmatine (Pal) in a rabbit osteoarthritis (OA) model in vivo and rabbit interleukin-1beta (IL-1beta) stimulated chondrocytes in vitro. Appropriate concentrations of Pal were identified by the MTT assay and used to preincubate IL-1beta-induced chondrocytes, as well as an activator or inhibitor of Wnt and Hedgehog signaling pathways. Matrix metalloproteinase (MMP)-1, 3, and 13; tissue inhibitor of metalloproteinase (TIMP)-1; collagenase II; aggrecan; and the related molecules of the Wnt/beta-catenin and Hedgehog signaling pathways were investigated. Protein expression was detected by Western blot analysis and messenger RNA (mRNA) expression was examined by PCR analysis. Pal (0.3 mL, 100 mg/L) was injected into rabbit knee joints and histological examination, immunohistochemistry, and Mankin scoring of the articular cartilage were performed. Pal (10-100 mg/L) had no effect on chondrocyte viability, decreased the expression of the MMPs, and increased the synthesis of TIMP-1whereas collagenase II and aggrecan were inhibited by IL-1beta. When the activator (Licl) and inhibitor (DKK-1) of the Wnt/beta-catenin signaling pathway as well as the inhibitor (cyclopamine) of the Hedgehog signaling pathway were added, the Wnt/beta-catenin signaling pathway was less inhibited by Pal, and a similar inhibitory effect of cyclopamine on the Hedgehog signaling pathway was evident. Additionally, Pal enhanced the effect of cyclopamine. The histological examination, immunohistochemistry and Mankin scoring also demonstrated the protective effect of Pal, and the inhibition of the Wnt and Hedgehog signaling pathways by Pal. Pal may be useful in the treatment of OA, in which its effect is likely mediated via the Wnt/beta-catenin and Hedgehog signaling pathways. PMID- 26945832 TI - Interleukin 21 as a new possible player in pemphigus: Is it a suitable target? AB - Pemphigus is a rare autoimmune disease, which could be fatal without treatment. Recently, target therapy is increasingly being used in different autoimmune diseases. However, there are limited studies associated with target therapy in pemphigus. In this study, it was tried to identify the role of interleukin (IL) 21 in patients with pemphigus. Based on the available studies on the role of IL 21 associated with several cells, including T cells, B cells, natural killer (NK) cells, natural killer T (NKT) cells, mast cells as well as regulatory B cells and regulatory T cells, the possible roles of this cytokine in pemphigus were discussed in detail. It was found that IL-21 is a crucial cytokine associated with pemphigus disease, which has not been discussed in this disease yet. It is able to promote T helper (Th) 2, Th17, T follicular helper (Tfh), CD8+ cytotoxic T lymphocytes (CTLs), NK and NKT cells. It also causes the production of immunoglobulin (Ig)G in addition to the decrease of Tregs. All the mentioned alterations seem to be involved in disease progression via different signaling pathways. Inhibition of these changes must cause improvement of disease severity. By inhibition of IL-21 or its receptor, it is expected that patients with severe pemphigus experience relative and gradual improvement. This inhibition could be induced by tofacitinib, which was approved by the US Food and Drug Administration as a treatment for rheumatoid arthritis patients, or anti-IL-21 monoclonal antibody, NNC114-0006. However, more studies are needed to confirm it as a promising therapy. PMID- 26945833 TI - In vitro impact of bisphenols BPA, BPF, BPAF and 17beta-estradiol (E2) on human monocyte-derived dendritic cell generation, maturation and function. AB - Bisphenols (BPs) are widely spread pollutants that act as estrogen-like endocrine disruptors and are potentially affecting human health on a long run. We explored the effects of BPA, BPF and BPAF, on in vitro differentiation and maturation of MDDCs. Monocytes were treated with 17beta-estradiol (E2) and each BP at the beginning of their differentiation into iMDDCs. We found that 10 and 50 MUM of BPA and BPF, 10 and 30MUM of BPAF and 10 and 50 nM of E2 did not affect cell viability. However, 50 MUM of BPA and BPF, as well as 10 and 30 MUM of BPAF, significantly decreased the endocytotic capacity of iMDDCs. Both, BPA (50 MUM) and BPAF (30 MUM) decreased the expression of CD1a and increased the amount of DC SIGN molecules on iMDDCs. The E2 pre-treatment moderately decreased expression of CD80, CD86 and CD83 co-stimulatory molecules while increasing the numbers of HLA DR on mMDDCs. Only BPAF significantly influenced the expression of CD80 and CD86 (both decreased), as well as CD83 and HLA-DR molecules (both increased) on mMDDCs. In addition, BPAF modulated DC maturation signaling pathways by lowering the phosphorylation of p65 NF-kappaB (nuclear factor-kappaB) and ERK (extracellular signal regulated kinase) 1/2 proteins. Consequently, the in vitro proliferation of allogeneic T cells, stimulated with differently pre-treated iMDDCs and mMDDCs, was significantly reduced only in case of BPAF. PMID- 26945834 TI - Application of CdS quantum dots modified carbon paste electrode for monitoring the process of acetaminophen preparation. AB - In this research article, a novel, selective, and sensitive modified carbon paste electrode (CPE) using CdS quantum dots (QDs) is presented. The highly stable CdS QDs were successfully synthesized in an in situ process using Na2S2O3 as a precursor and thioglycolic acid as a catalyst and capping agent. The synthesis of CdS QDs was studied using X-ray diffraction (XRD) and transmission electron microscopy (TEM) techniques. The synthesized CdS QDs were used for preparation of a modified carbon paste electrode (CdS/CPE). The electrochemical behavior of the electrode toward p-aminophenol (PAP) and acetaminophen (Ac) was studied, and the results demonstrated that the CdS/CPE exhibited good electrocatalytic performance toward PAP and Ac oxidation. The oxidation peak potential of each analyte in the mixture was well separated. As a result, a selective and reliable method was developed for the determination of PAP and Ac simultaneously without any chemical separations. Application of the fabricated electrode for monitoring the process of Ac preparation from PAP was investigated. The obtained results show that CdS/CPE has satisfactory analytical performance; it could be a kind of attractive and promising nanomaterial-based sensor for process monitoring via the electrochemical approach. PMID- 26945835 TI - Assessment and Comparison of Vitreous Humor as an Alternative Matrix for Forensic Toxicology Screening by GC-MS. AB - Alternative specimens have been occasionally considered as substitutes for whole blood for postmortem toxicology testing. We studied the applicability of vitreous humor, and evaluated whether it would be suitable to replace (or augment) whole blood for routine drug screening. Results showed that from 51 autopsy cases, we were able to identify an aggregate of 209 findings in whole blood compared with 169 in vitreous. The total number of compounds identified was 71 for whole blood and 60 for vitreous humor. Quantitative analysis showed that whole-blood concentrations of trazodone were several fold higher than vitreous humor concentrations (1.42 +/- 0.57 vs. 0.15 +/- 0.05 mg/L, respectively) and similar results were also obtained for diazepam (0.37 +/- 0.06 vs. 0.13 +/- 0.01, respectively). For other drugs such as oxycodone, hydrocodone and doxylamine, a trend suggesting higher concentrations in vitreous humor vs. whole blood was observed; however, this was not significant. Our results are consistent with the limited work of other investigators, and suggest that vitreous humor could be an appropriate matrix for drug screening in postmortem toxicology. PMID- 26945836 TI - Abnormal distortion of aortic corevalve bioprosthesis with suicide left ventricle, aortic insufficiency, and severe mitral regurgitation during transcatheter aortic valve replacement. AB - We present a patient with critical degenerative aortic stenosis, mitral annular and aortomitral continuity calcification, and senile sigmoid septal hypertrophy who underwent transcatheter aortic valve replacement using the CoreValve bioprosthesis. Immediately after predilation of the aortic valve (18-mm balloon), the patient developed severe hypotension and dynamic left ventricular outflow tract (LVOT) obstruction with systolic anterior motion of the anterior mitral leaflet, causing severe mitral regurgitation. After deployment of a 26-mm bioprosthesis, a transesophageal echocardiogram and left ventriculogram showed that the frame of the bioprosthesis appeared distorted and underexpanded. On the mitral side of the aorta (side of the aortomitral curtain between 12:00 and 3:00, echo short axis view), we found moderate periprosthetic aortic insufficiency with worse mitral regurgitation. The left ventricle was small and hyperdynamic (ejection fraction >85%). The patient soon developed complete heart block, atrial fibrillation, and ventricular tachycardia. She was resuscitated with aggressive intravenous fluids, vasopressors, and an emergently placed atrioventricular sequential pacemaker. We postdilated the 26-mm bioprosthesis with a 22-mm Z-Med balloon and subsequently with a 25-mm balloon. Each balloon was inflated to its nominal volume and pressure and conformed the nitinol frame of the valve to the net circular shape and expected diameter. However, as soon as each balloon was deflated, the surrounding aortic root anatomy visibly recoiled and the frame returned to its smaller diameter with a distorted shape. A second 26-mm CoreValve bioprosthesis was then deployed in a "valve-in-valve" configuration. Soon after, the patient's hemodynamics improved, her clinical condition stabilized, and she completely recovered. (c) 2016 Wiley Periodicals, Inc. PMID- 26945837 TI - Nanoflower-Like Bi2 WO6 Encapsulated in ORMOSIL as a Novel Photocatalytic Antifouling and Foul-Release Coating. AB - Herein, the first multi-purpose antifouling and foul-release photocatalytic coating based on ORMOSIL thin films doped with nanoflower-like Bi2 WO6 is described. Irradiation with visible light of the new films immersed in water produces significant amounts of H2 O2 by photocatalytic oxidation of water, and allows the degradation of (bio)organic pollutants at the outer surface of the xerogel film. PMID- 26945838 TI - Studies in regard to the classification and putative toxicity of Fridericia japurensis (Arrabidaea japurensis) in Brazil. AB - Numerous plant species worldwide including Palicourea marcgravii (Rubiaceae) and Tanaecium bilabiatum (Bignoniaceae) in Brazil cause acute cardiac failure (sudden death) and are known to contain monofluoroacetate (MFA). Other Bignoniaceae species including Fridericia japurensis (Arrabidaea japurensis) are reported to cause sudden death in livestock in the Brazilian state of Roraima and are suspected to contain MFA due to the similarity of clinical signs. In this study herbarium specimens of Fridericia japurensis and field collections suspected to be F. japurensis were analyzed for MFA, and plant material from the field collections was dosed to rabbits. No MFA was detected in the herbarium specimens authoritatively identified as F. japurensis; however, MFA was detected in the field collections, which were identified as T. bilabiatum. Rabbits dosed orally with T. bilabiatum died acutely. Voucher toxic specimens initially described as F. japurensis were incorrectly identified, and the correct botanical name for this plant is T. bilabiatum (Arrabidaea bilabiata). Based on this study we conclude that there are no data to support the toxicity of F. japurensis and that the plant previously reported under this name as causing acute cardiac failure in cattle in Roraima is T. bilabiatum. This research highlights the importance of voucher specimens as part of any toxic plant investigation and corrects the literature regarding these toxic plants. PMID- 26945840 TI - An unusual pediatric presentation of guttate atrophic lesions on the trunk. PMID- 26945839 TI - A Crosstalk Between K ras (Kirsten Rat Sarcoma Viral Oncogene Homologue) and Adherence Molecular Complex Leads to Disassociation of Cells-A Possible Contribution Towards Metastasis in Colorectal Cancer. AB - Constitutive activation of mutant K ras (Kirsten rat sarcoma viral oncogene homologue) and disassembly of E-cadherin-catenin complex (E-cadherin, alpha catenin, beta-catenin, and gamma-catenin) play an important role in apoptosis, differentiation, and cell proliferation. In this study, the expression pattern of K ras and E-cadherin-catenin complex has been evaluated in normal and mutant colorectal cancer cell lines with an object to determine its impact on disassociation of cells from one another. We addressed the expression analysis of K ras with reference to its association with adherence molecules in two colorectal cancer cell lines, that is, Caco-2 (wild type K ras served as a control) and DLD1 (heterozygous mutation at codon 13) at message level by qRT-PCR and translational level by western blotting. Compared to the control Caco-2 cell lines, the K ras in DLD1 cell lines showed slightly higher values while alpha catenin showed a slight lower (1.3-folds), beta-catenin and E-cadherin showed significantly lower expression (4.2-fold decrease). It can be inferred that a possible cross talk exists between K ras and adherent junction mediated signalling. Mutation at codon 13 (G to D) leads to the overexpression of K ras and reduced expression of adherent junction complex resulting in metastasis. J. Cell. Biochem. 117: 2340-2345, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26945841 TI - Binding site of MraZ transcription factor in Mollicutes. AB - Mollicutes (mycoplasmas) feature a significant loss of known regulators of gene expression. Here, we identified the recognition site of the MraZ-family regulator of Mycoplasma gallisepticum, which is conserved in many species of different clades within class Mollicutes. The MraZ binding site is AAAGTG[T/G], in the promoter of mraZ gene it forms a series of direct repeats with a structure (AAAGTG[T/G]N3)k, where k = 3 most frequently. MraZ binds to a single repeat as an octamer complex. MraZ can also bind a single binding site or a series of repeats with different spacer lengths (2-4 nt); thus, it may play a role in the regulation of multiple operons in Mollicutes. In M. gallisepticum, MraZ acts as a transcriptional activator. The overexpression of MraZ leads to moderate filamentation of cells and the formation of aggregates, likely as a result of incomplete cytokinesis. PMID- 26945842 TI - Determination of the binding properties of the uremic toxin phenylacetic acid to human serum albumin. AB - Uremic toxins are compounds normally excreted in urine that accumulate in patients with chronic kidney disease as a result of decreased renal clearance. Phenylacetic acid (PAA) has been identified as a new protein bound uremic toxin. The purpose of this study was to investigate in vitro the interaction between PAA and human serum albumin (HSA) at physiological and pathological concentrations. We used ultrafiltration to show that there is a single high-affinity binding site for PAA on HSA, with a binding constant on the order of 3.4 * 10(4) M(-1) and a maximal stoichiometry of 1.61 mol per mole. The PAA, at the concentration reported in end-stage renal patients, was 26% bound to albumin. Fluorescent probe competition experiments demonstrated that PAA did not bind to Sudlow's site I (in subdomain IIA) and only weakly bind to Sudlow's site II (in subdomain IIIA). The PAA showed no competition with other protein-bound uremic toxins such as p-cresyl sulfate or indoxyl sulfate for binding to serum albumin. Our results provide evidence that human serum albumin can act as carrier protein for phenylacetic acid. PMID- 26945843 TI - Reduction in C-reactive protein indicates successful targeting of the IL-1/IL-6 axis resulting in improved survival in early stage multiple myeloma. AB - We report the long-term follow-up results of a phase II trial of IL-1 receptor antagonist and low-dose dexamethasone for early stage multiple myeloma (MM). Patients were eligible if they had smoldering multiple myeloma (SMM) or indolent multiple myeloma (IMM) without the need for immediate therapy. Forty seven patients were enrolled and subsequently treated with IL-1Ra; in 25/47 low-dose dexamethasone (20 mg weekly) was added. The primary endpoint was progression-free survival (PFS). In the clinical trial, three patients achieved a minor response (MR) to IL-1Ra alone; five patients a partial response (PR) and four patients an MR after addition of dexamethasone. Seven patients showed a decrease in the plasma cell labeling index (PCLI) which paralleled a decrease in the high sensitivity C-reactive protein (hs-CRP). The median PFS for the 47 patients was 1116 days (37.2 months). The median PFS for patients without (n = 22) and with (n = 25) a decrease in their baseline hs-CRP was 326 days (11 months) vs. 3139 days (104 months) respectively (P <0.0001). The median overall survival (OS) for the 47 patients was 3482 days (9.5 years). The median OS for patients without and with a decrease in their baseline hs-CRP was 2885 days (7.9 years) vs. median not reached, respectively (P = 0.001). In SMM/IMM patients at risk for progression to active myeloma, reduction in the hs-CRP indicates successful targeting of the IL 1/IL-6 axis resulting in improved PFS and OS. (Clinical Trials.gov Identifier: NCT00635154) Am. J. Hematol. 91:571-574, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26945844 TI - First insights into the genetic diversity and origin of Leishmania infantum in Mont Rolland (Thies region, Senegal). AB - Visceral leishmaniasis is not endemic in West Africa. However, high seroprevalence of Leishmania infantum infection (one of the Leishmania species that cause visceral leishmaniasis) was detected in dogs and humans in the Mont Rolland community (close to Thies, Senegal), despite the lack of reports concerning human clinical cases. Our aim was to genetically characterize this L. infantum population and identify its origin. We thus conducted seven field surveys in 25 villages of the Mont Rolland community between 2005 and 2009 and blood samples were collected from 205 dogs. Serological testing indicated that 92 dogs (44.9%) were positive for Leishmania infection. L. infantum was identified as the cause of infection. Analysis of 29 L. infantum isolates from these dogs by multilocus microsatellite typing and multilocus sequence typing indicated that this population had very limited genetic diversity, low level of heterozygosity and only seven different genotypes (79.3% of all isolates had the same genotype). Multilocus sequence typing showed that the Mont Rolland isolates clustered with strains from the Mediterranean basin and were separated from East African and Asian strains. Therefore, our data suggest a quite recent and unique introduction into Senegal of a L. infantum strain from the Mediterranean basin. PMID- 26945845 TI - Fungal empyema thoracis in cancer patients. AB - OBJECTIVES: Fungal empyema thoracis (FET) is a rare life-threatening infection. We sought to describe the clinical characteristics of FET in a large academic cancer center. METHODS: We conducted a retrospective chart review of all cancer patients who had a fungal isolate from the pleural fluid culture between 1/2005 and 8/2013. RESULTS: A total of 106 fungal isolates were identified in 97 patients. Yeasts accounted for 62% of the isolates whereas 38% were identified as molds. The most frequent pathogens were Candida spp. (58%) and Aspergillus spp. (12%). All patients with Aspergillus and 83% with Candida met criteria for proven fungal disease. Compared to the Aspergillus group, Candida FET was associated with recent abdominal or thoracic surgical procedures (44% vs. 0%, p = 0.01). Overall, 6-week mortality was high, with no significant differences between Candida and Aspergillus (31% vs. 45%, respectively [p = 0.48]). Only 1 out of 11 patients with uncommon molds died at 6 weeks, despite only 2 of them received appropriate antifungal therapy. CONCLUSIONS: Development of FET carries a high mortality in cancer patients. A history of a recent surgical procedure is a risk factor for FET due to Candida. Isolation of uncommon molds is likely to represent a contamination of the pleural fluid. PMID- 26945846 TI - The association of melioidosis with climatic factors in Darwin, Australia: A 23 year time-series analysis. AB - OBJECTIVES: Melioidosis is an often fatal disease in humans and animals and endemic in Southeast Asia and northern Australia. It is caused by the environmental bacterium Burkholderia pseudomallei. We analysed weather and climate factors preceding new melioidosis cases in Darwin and compared the time between weather event and admission to hospital for severe and average wet season rainfall. METHODS: In a time-series analysis from 1990 to 2013 we applied a boosted regression tree and a negative binomial model to investigate the association between melioidosis cases and weather events. Fitted Fourier terms controlled for long-term seasonal trends. RESULTS: We found a rise in the dew point, cloud cover, rainfall, maximum temperature and groundwater to be associated with an increased risk to acquire melioidosis. A shorter 'putative' incubation period was evident after severe rainfall events. Rainfall occurring early in the wet season was linked to more cases as was an increase in the local sea surface temperature reflecting local weather dynamics and precipitation. CONCLUSIONS: Our findings demonstrate a statistical association between frequency of recorded melioidosis cases and the nature and timing of rainfall related events and suggest a future rise in the sea surface and ambient temperature may lead to increased melioidosis. PMID- 26945847 TI - The deletion of residues 268-292 of E1 impairs the ability of HCV envelope proteins to induce pore formation. AB - We have obtained a chimeric protein containing the ectodomains of hepatitis C virus (HCV) envelope proteins but lacking the region 268-292 of E1. All its structural properties are coincident with those of the corresponding full length chimera. The deleted and entire chimeras were compared in terms of their membrane destabilizing properties. No differences were found in their ability to induce vesicle aggregation and lipid mixing but the deleted chimera showed a reduced capacity to promote leakage. The role of the deletion was also studied by obtaining HCV pseudoparticles (HCVpp). Both E1 and E2, and also the E1 deleted mutant, were incorporated into HCVpp to a similar level. However, HCVpp containing the E1 deleted protein are almost unable to infect Huh7 cells. These results point to the involvement of the region 268-292 in the formation of pores in the membrane necessary for the complete fusion of the membranes. PMID- 26945848 TI - MCMV exploits the spleen as a transfer hub for systemic dissemination upon oronasal inoculation. AB - Murine cytomegalovirus (MCMV) infection in mice is a commonly used animal model for studying human cytomegalovirus (HCMV) infections. In our previous studies, a mouse model based on an oronasal MCMV infection was set up for mimicking a natural infection, and the spleen was hypothesized to regulate viremia and virus dissemination to distal organs such as submandibular glands. Here, the role of the spleen during an MCMV infection was investigated by the comparison of intact and splenectomized Balb/c mice. Both highly passaged MCMV Smith and low passaged MCMV HaNa1 were used. Various samples were collected at 7, 14, and 21 days post inoculation (dpi) for analyses by virus isolation/titration, co-cultivation and qPCR. The results showed that for both virus strains, 1) cell-associated virus in PBMC (determined by co-cultivation) was detected in intact mice but not in splenectomized mice; 2) the mean viral DNA load in PBMC of splenectomized mice was 4.4-(HaNa1)/2.7-(Smith) fold lower at the peak viremia (7dpi) in contrast to that of intact mice; and 3) infectious virus in the submandibular glands was detected later in splenectomized mice (14dpi) than in intact mice (7dpi). Moreover, the average virus titers in submandibular glands of splenectomized mice were 10-(HaNa1)/7.9-(Smith) fold lower at 14dpi and 1.7-(HaNa1)/2.1-(Smith) fold lower at 21dpi compared with that of intact mice. Upon inoculation with MCMV Smith, infectious virus was found in the kidneys and liver of intact mice, but not in splenectomized mice. Taken together, all these data clearly demonstrate that virus dissemination to distant organs is reduced in splenectomized mice, further confirming the importance of the spleen as a viremia booming site for a natural MCMV infection. PMID- 26945849 TI - Experimental infection of European flat oyster Ostrea edulis with ostreid herpesvirus 1 microvar (OsHV-1MUvar): Mortality, viral load and detection of viral transcripts by in situ hybridization. AB - Ostreid herpesvirus 1 (OsHV-1) infections have been reported in several bivalve species. Mortality of Pacific oyster Crassostrea gigas spat has increased considerably in Europe since 2008 linked to the spread of a variant of OsHV-1 called MUvar. In the present study we demonstrated that O. edulis juveniles can be infected by OsHV-1MUvar when administered as an intramuscular injection. Mortality in the oysters injected with OsHV-1MUvar was first detected 4 days after injection and reached 25% mortality at day 10. Moreover, the high viral load observed and the detection of viral transcripts by in situ hybridization in several tissues of dying oysters suggested that OsHV-1MUvar was the cause of mortality in the O. edulis juveniles. This is therefore the first study to provide evidence about the pathogenicity of OsHV-1MUvar in a species that does not belong to the Crassostrea genus. Additionally, we present a novel method to detect OsHV-1 transcripts in infected individuals' using in situ hybridization. PMID- 26945850 TI - National, Heart, Lung, and Blood Institute support of cardiac arrhythmia research. PMID- 26945851 TI - Electrocardiographic repolarization abnormalities and increased risk of life threatening arrhythmias in children with dilated cardiomyopathy. AB - BACKGROUND: Life-threatening arrhythmia events (LTEs) occur in ~5% of children with dilated cardiomyopathy (DCM). While prolonged QRS duration has been shown to be associated with LTEs, electrocardiographic (ECG) repolarization findings have not been examined. OBJECTIVE: We sought to determine the associations between ECG repolarization abnormalities and LTEs in children with DCM. METHODS: A single center retrospective review of children with DCM was performed. LTEs were defined as documented ventricular tachycardia or fibrillation requiring medical intervention. Three pediatric cardiologists, blinded to clinical events, evaluated ECGs obtained at the time of initial referral. Kaplan-Meier survival and Cox proportional hazards analyses were used to evaluate time to LTEs. RESULTS: A total of 137 patients (mean age 7.8 +/- 6.7 years; 75(55%) male patients) with DCM (mean ejection fraction 35% +/- 16%) were included; 67 patients (49%) had a corrected JT (JTc) interval of >=340 ms, 72 (53%) had a corrected QT (QTc) interval of >=450 ms, and 41 (30%) had abnormal T waves. LTEs occurred in 15 patients at a median of 12 months (interquartile range 3-36 months) after the initial ECG. Patients with LTEs had a longer JTc interval (371 +/- 77 ms vs 342 +/- 41 ms; P = .02) and a longer QTc interval (488 +/- 96 ms vs 453 +/- 44 ms; P = .01). In survival analysis, a JTc interval of >=390 ms (hazard ratio [HR] 4.07; 95% confidence interval [CI] 1.12-14.83; P = .03), a QTc interval of >=510 ms (HR 6.95; 95% CI 1.53-31.49; P = .01), abnormal T-wave inversion (HR 11.62; 95% CI 2.75-49.00; P = .001), and ST-segment depression (HR 6.91; 95% CI 1.25-38.27; P = .03) were associated with an increased risk of LTEs, even after adjusting for QRS duration and amiodarone use. CONCLUSION: Repolarization abnormalities are common in children with DCM. Certain ECG repolarization abnormalities, such as significantly prolonged JTc and QTc intervals, may be useful in identifying patients at risk of LTEs. PMID- 26945852 TI - Congestion of mastoid mucosa and influence on middle ear pressure - Effect of retroauricular injection of adrenaline. AB - Micro-CT scanning of temporal bones has revealed numerous retroauricular microchannels, which connect the outer bone surface directly to the underlying mastoid air cells. Their structure and dimensions have suggested a separate vascular supply to the mastoid mucosa, which may play a role in middle ear (ME) pressure regulation. This role may be accomplished by changes in the mucosa congestion resulting in volumetric changes, which ultimately affect the pressure of the enclosed ME gas pocket (Boyle's law). Further, such mucosa congestion may be susceptible to alpha-adrenergic stimulation similar to the mucosa of the nose. The purpose of our study was to investigate these hypotheses by recording the ME pressure in response to adrenergic stimulation administered by retroauricular injections at the surface of the microchannels. In a group of 20 healthy adults we measured the ME pressure by tympanometry initially in the sitting position, and then in the supine position over a 5 min period with 30 s intervals. In each subject, the study included 1) a control reference experiment with no intervention, 2) a control experiment with subcutaneously retroauricular injection of 1 ml isotonic NaCl solution, and 3) a test experiment with subcutaneously retroauricular injection of 1 ml NaCl-adrenaline solution. In both control experiments the ME pressure displayed an immediate increase in response to changing body position; this pressure increase remained stable for the entire period up to five minutes. In the test experiments the ME pressure also showed an initial pressure increase, but it was followed by a distinct significant pressure decrease with a maximum after 90 s. The test group was injected with both a 5 and 10% adrenaline solution, but the responses appeared similar for the two concentrations. Subcutaneous retroauricular injection of adrenaline caused a significant pressure decrease in ME pressure compared with control ears. This may be explained by the microchannels conveying the adrenaline to the underlying mastoid mucosa, where it may result in a vascular constriction and decongestion, ultimately resulting in a ME pressure decrease. These findings suggest that the microchannels contain vascular connections to the mastoid mucosa, and that the mastoid mucosa is susceptible to vasoactive mediators, which may play a role in ME pressure regulation. Further anatomical and physiological experiments should be carried out to confirm these suggestions including pharmacological interactions with the mastoid mucosa. PMID- 26945853 TI - RNA-binding protein HuD reduces triglyceride production in pancreatic beta cells by enhancing the expression of insulin-induced gene 1. AB - Although triglyceride (TG) accumulation in the pancreas leads to beta-cell dysfunction and raises the chance to develop metabolic disorders such as type 2 diabetes (T2DM), the molecular mechanisms whereby intracellular TG levels are regulated in pancreatic beta cells have not been fully elucidated. Here, we present evidence that the RNA-binding protein HuD regulates TG production in pancreatic beta cells. Mouse insulinoma betaTC6 cells stably expressing a small hairpin RNA targeting HuD (shHuD) (betaTC6-shHuD) contained higher TG levels compared to control cells. Moreover, downregulation of HuD resulted in a decrease in insulin-induced gene 1 (INSIG1) levels but not in the levels of sterol regulatory element-binding protein 1c (SREBP1c), a key transcription factor for lipid production. We identified Insig1 mRNA as a direct target of HuD by using ribonucleoprotein immunoprecipitation (RIP) and biotin pulldown analyses. By associating with the 3'-untranslated region (3'UTR) of Insig1 mRNA, HuD promoted INSIG1 translation; accordingly, HuD downregulation reduced while ectopic HuD expression increased INSIG1 levels. We further observed that HuD downregulation facilitated the nuclear localization of SREBP1c, thereby increasing the transcriptional activity of SREBP1c and the expression of target genes involved in lipogenesis; likewise, we observed lower INSIG1 levels in the pancreatic islets of HuD-null mice. Taken together, our results indicate that HuD functions as a novel repressor of lipid synthesis in pancreatic beta cells. PMID- 26945854 TI - Notch-1 signaling activates NF-kappaB in human breast carcinoma MDA-MB-231 cells via PP2A-dependent AKT pathway. AB - Breast cancer has a high incidence in the world and is becoming a leading cause of death in female patients due to its high metastatic ability. High expression of Notch-1 and its ligand Jagged-1 correlates with poor prognosis in breast cancer. Our previous work has shown that Notch-1 signaling pathway upregulates NF kappaB transcriptional activity and induces the adhesion, migration and invasion of human breast cancer cell line MDA-MB-231. However, the role of Notch-1 in NF kappaB activation is still poorly understood. Here, we aim to understand the exact mechanism that Notch-1 regulates NF-kappaB activity. In MDA-MB-231 cells where Notch-1 is constitutively activated, the phosphorylation of p85 and AKT (Tyr308/Ser473) is upregulated, indicating PI3K/AKT pathway is activated. Notch-1 activation caused the increase of PP2A phosphorylation at Tyr307, indicating Notch-1 inhibits PP2A activity. NF-kappaB transcriptional activity was evaluated by dual-luciferase reporter assay, and the results showed that, while silencing of Notch-1, PP2A activity was upregulated and NF-kappaB activity was downregulated, whereas PP2A inhibitor okadaic acid (OA) restored NF-kappaB activity. Immunofluorescence and Western blots showed that OA treatment antagonized the decrease of p65 nuclear translocation caused by Notch-1 silencing. Moreover, OA treatment also upregulated MMP-2, MMP-9 and VEGF mRNA expression levels, indicating OA rescues Notch-1 silencing that caused low cell invasion. Taken together, our results suggest that Notch-1-activating PI3K/AKT/NF kappaB pathway is PP2A dependent; PP2A may be a potential therapeutic target in breast cancer. PMID- 26945855 TI - The polygalacturonase-inhibiting protein 4 (OsPGIP4), a potential component of the qBlsr5a locus, confers resistance to bacterial leaf streak in rice. AB - MAIN CONCLUSION: OsPGIP4 overexpression enhances resistance to bacterial leaf streak in rice. Polygalacturonase-inhibiting proteins are thought to play important roles in the innate immunity of rice against fungi. Here, we show that the chromosomal location of OsPGIP4 coincides with the major bacterial leaf streak resistance quantitative trait locus qBlsr5a on the short arm of chromosome 5. OsPGIP4 expression was up-regulated upon inoculation with the pathogen Xanthomonas oryzae pv. oryzicola strain RS105. OsPGIP4 overexpression enhanced the resistance of the susceptible rice variety Zhonghua 11 to RS105. In contrast, repressing OsPGIP4 expression resulted in an increase in disease lesions caused by RS105 in Zhonghua 11 and in Acc8558, a qBlsr5a resistance donor. More interestingly, upon inoculation, the activated expression of pathogenesis-related genes was attenuated for those genes involved in the salicylic acid pathway, while the activated expression of jasmonic acid pathway markers was increased in the overexpression lines. Our results not only provide the first report that rice PGIP could enhance resistant against a bacterial pathogen but also indicate that OsPGIP4 is a potential component of the qBlsr5a locus for bacterial leaf streak in rice. PMID- 26945856 TI - The Antirrhinum AmDEL gene enhances flavonoids accumulation and salt and drought tolerance in transgenic Arabidopsis. AB - MAIN CONCLUSION: A basic helix-loop-helix (bHLH) transcription factor gene from Antirrhinum, AmDEL , increases flavonoids accumulation and enhances salt and drought tolerance via up-regulating flavonoid biosynthesis, proline biosynthesis and ROS scavenging genes in transgenic Arabidopsis. In plants, transcriptional regulation is the most important tools for increasing flavonoid biosynthesis. The AmDEL gene, as a basic helix-loop-helix transcription factor gene from Antirrhinum, has been shown to increase flavonoids accumulation in tomato. However, its role in tolerance to abiotic stresses has not yet been investigated. In this study, the codon-optimized AmDEL gene was chemically synthesized. Subcellular localization analysis in onion epidermal cells indicated that AmDEL protein was localized to the nucleus. Expression analysis in yeast showed that the full length of AmDEL exhibited transcriptional activation. Overexpression of AmDEL significantly increased flavonoids accumulation and enhanced salt and drought tolerance in transgenic Arabidopsis plants. Real-time quantitative PCR analysis showed that overexpression of AmDEL resulted in the up-regulation of genes involved in flavonoid biosynthesis, proline biosynthesis and ROS scavenging under salt and drought stresses. Meanwhile, Western blot and enzymatic analyses showed that the activities of phenylalanine ammonia lyase, chalcone isomerase, dihydroflavonol reductase, pyrroline-5-carboxylate synthase, superoxide dismutase and peroxidase were also increased. Further components analyses indicated that the significant increase of proline and relative water content and the significant reduction of H2O2 and malonaldehyde content were observed under salt and drought stresses. In addition, the rates of electrolyte leakage and water loss were reduced in transgenic plants. These findings imply functions of AmDEL in accumulation of flavonoids and tolerance to salt and drought stresses. The AmDEL gene has the potential to be used to increase the content of valuable flavonoids and improve tolerance to abiotic stresses in plants. PMID- 26945857 TI - On the substrate specificity of the rice strigolactone biosynthesis enzyme DWARF27. AB - MAIN CONCLUSION: The beta-carotene isomerase OsDWARF27 is stereo- and double bond specific. It converts bicyclic carotenoids with at least one unsubstituted beta ionone ring. OsDWARF27 may contribute to the formation of alpha-carotene-based strigolactone-like compounds. Strigolactones (SLs) are synthesized from all-trans beta-carotene via a pathway involving the beta-carotene isomerase DWARF27, the carotenoid cleavage dioxygenases 7 and 8 (CCD7, CCD8), and cytochrome P450 enzymes from the 711 clade (MAX1 in Arabidopsis). The rice enzyme DWARF27 was shown to catalyze the reversible isomerization of all-trans- into 9-cis-beta carotene in vitro. beta-carotene occurs in different cis-isomeric forms, and plants accumulate other carotenoids, which may be substrates of DWARF27. Here, we investigated the stereo and substrate specificity of the rice enzyme DWARF27 in carotenoid-accumulating E. coli strains and in in vitro assays performed with heterologously expressed and purified enzyme. Our results suggest that OsDWARF27 is strictly double bond-specific, solely targeting the C9-C10 double bond. OsDWARF27 did not introduce a 9-cis-double bond in 13-cis- or 15-cis-beta carotene. Substrates isomerized by OsDWARF27 are bicyclic carotenoids, including beta-, alpha-carotene and beta,beta-cryptoxanthin, that contain at least one unsubstituted beta-ionone ring. Accordingly, OsDWARF27 did not produce the abscisic acid precursors 9-cis-violaxanthin or -neoxanthin from the corresponding all-trans-isomers, excluding a direct role in the formation of this carotenoid derived hormone. The conversion of all-trans-alpha-carotene yielded two different isomers, including 9'-cis-alpha-carotene that might be the precursor of strigolactones with an epsilon-ionone ring, such as the recently identified heliolactone. PMID- 26945858 TI - Profiling of acidic (amino and phenolic acids) and phenylpropanoids production in response to methyl jasmonate-induced oxidative stress in Scrophularia striata suspension cells. AB - MAIN CONCLUSION: A metabolic profiling including calculation of energy cost of amino acids biosynthesis in cultured cells of Scrophularia striata showed that methyl jasmonate-inducible oxidative stress elicited secondary metabolites formation derived from phenylalanine and tyrosine and increased energy cost for these amino acids biosynthesis. Understanding of the metabolic pathways in cell culture of Scrophularia striata, an aromatic plant species, facilitates means of production of pharmaceutical metabolites under oxidative stress. In this study, we evaluated the effects of MeJA on the S. striata metabolic pathway and the responses to oxidative stress. Exposure to methyl jasmonate (MeJA) affects plant growth, effectively induces production of reactive oxygen species (ROS) and inserts oxidative stress at the cellular level which results in alteration of primary metabolites and production of phenylepropanoid compounds. Cells treated with MeJA indicated increase in the activities of three antioxidant enzymes including superoxide dismutase (SOD), catalase (CAT), guaiacol peroxidase (GPx) as well as intracellular H2O2 and MDA contents compared with mock-treated cells. High performance liquid chromatography (HPLC)-based metabolome analysis revealed dynamic metabolic changes in oxidatively stressed S. striata cells, e.g., general phenylpropanoid pathway, phenylethanoid-glycosides, lignans, and increased energy cost of biosynthesis and accumulation of amino acids. Furthermore, principal component analysis (PCA)-derived score plots demonstrated that MeJA affects cellular metabolism in S. striata cells and significantly alters metabolite composition under MeJA-inducible oxidative stress. These observations suggest that MeJA-elicited cell suspension cultures of S. striata balanced the production of primary and secondary metabolites in coordination with ROS-scavenging system. PMID- 26945859 TI - Erratum to: Guidance for the treatment of deep vein thrombosis and pulmonary embolism. PMID- 26945860 TI - NetCapDB: measuring bioinformatics capacity development in Africa. AB - BACKGROUND: The National Institutes of Health (USA) has committed 5 years of funding to the Bioinformatics Network of the Human Heredity and Health in Africa initiative. This pan-African network aims to develop capacity for bioinformatics research, in order to provide support to human health genomics research programs ongoing on the continent. Over the 5 years of funding, it is imperative to track changes in bioinformatics capacity at the funded centres and to document how the funding has translated into capacity development during this time frame. RESULTS: The Network capacity database, NetCapDB, is a relational database that captures quantitative metrics for bioinformatics capacity, and tracks the changes in these metrics over time. A graphical user interface allows for straight-forward, browser-based data entry by users across Africa; and for visual and graph-based exploration of captured data. A reporting interface allows for semi-automated generation of standardized reports for monitoring and evaluation purposes. PMID- 26945861 TI - Evaluation of Kenya's readiness to transition from sentinel surveillance to routine HIV testing for antenatal clinic-based HIV surveillance. AB - BACKGROUND: Sentinel surveillance for HIV among women attending antenatal clinics using unlinked anonymous testing is a cornerstone of HIV surveillance in sub Saharan Africa. Increased use of routine antenatal HIV testing allows consideration of using these programmatic data rather than sentinel surveillance data for HIV surveillance. METHODS: To gauge Kenya's readiness to discontinue sentinel surveillance, we evaluated whether recommended World Health Organization standards were fulfilled by conducting data and administrative reviews of antenatal clinics that offered both routine testing and sentinel surveillance in 2010. RESULTS: The proportion of tests that were HIV-positive among women aged 15 49 years was 6.2% (95% confidence interval [CI] 4.6-7.7%] in sentinel surveillance and 6.5% (95% CI 5.1-8.0%) in routine testing. The agreement of HIV test results between sentinel surveillance and routine testing was 98.0%, but 24.1% of specimens that tested positive in sentinel surveillance were recorded as negative in routine testing. Data completeness was moderate, with HIV test results recorded for 87.8% of women who received routine testing. CONCLUSIONS: Additional preparation is required before routine antenatal HIV testing data can supplant sentinel surveillance in Kenya. As the quality of program data has markedly improved since 2010 a repeat evaluation of the use of routine antenatal HIV testing data in lieu of ANC sentinel surveillance is recommended. PMID- 26945863 TI - Restriction of HIV-1-based lentiviral vectors in adult primary marrow-derived and peripheral mobilized human CD34+ hematopoietic stem and progenitor cells occurs prior to viral DNA integration. AB - BACKGROUND: Gene therapy is currently being attempted using a number of delivery vehicles including lentiviral-based vectors. The delivery and insertion of a gene using lentiviral-based vectors involves multiple discrete steps, including reverse transcription of viral RNA into DNA, nuclear entry, integration of viral DNA into the host genome and expression of integrated genes. Transduction of murine stem cells by the murine leukemia viruses is inefficient because the expression of the integrated DNA is profoundly blocked. Transduction of human stem cells by lentivirus vectors is also inefficient, but the cause and specific part of the retroviral lifecycle where this block occurs is unknown. RESULTS: Here we demonstrate that the dominant point of restriction of an HIV-1-based lentiviral vector in adult human hematopoietic stem and progenitor cells (HSPCs) from bone marrow and also those obtained following peripheral mobilization is prior to viral DNA integration. We specifically show that restriction of HSPCs to an HIV-1-based lentiviral vector is prior to formation of nuclear DNA forms. CONCLUSIONS: Murine restriction of MLV and human cellular restriction of HIV-1 are fundamentally different. While murine restriction of MLV occurs post integration, human restriction of HIV-1 occurs before integration. PMID- 26945864 TI - An Universal packaging technique for low-drift implantable pressure sensors. AB - Monitoring bodily pressures provide valuable diagnostic and prognostic information. In particular, long-term measurement through implantable sensors is highly desirable in situations where percutaneous access can be complicated or dangerous (e.g., intracranial pressure in hydrocephalic patients). In spite of decades of progress in the fabrication of miniature solid-state pressure sensors, sensor drift has so far severely limited their application in implantable systems. In this paper, we report on a universal packaging technique for reducing the sensor drift. The described method isolates the pressure sensor from a major source of drift, i.e., contact with the aqueous surrounding environment, by encasing the sensor in a silicone-filled medical-grade polyurethane balloon. In vitro soak tests for 100 days using commercial micromachined piezoresistive pressure sensors demonstrate a stable operation with the output remaining within 1.8 cmH2O (1.3 mmHg) of a reference pressure transducer. Under similar test conditions, a non-isolated sensor fluctuates between 10 and 20 cmH2O (7.4-14.7 mmHg) of the reference, without ever settling to a stable operation regime. Implantation in Ossabow pigs demonstrate the robustness of the package and its in vivo efficacy in reducing the baseline drift. PMID- 26945862 TI - Structural and functional considerations of the cholinergic brainstem. AB - Cholinergic neurons of the brainstem have traditionally been associated with a role in wakefulness as part of the reticular activating system, but their function cannot be explained solely on the basis of their modulation of the brain state. Recent findings about their connectivity and functional heterogeneity suggest a wider role in behavior, where basal ganglia is at the center of their influence. This review focuses on recent findings that suggest an intrinsic functional organization of the cholinergic brainstem that is closely correlated with its connectivity with midbrain and forebrain circuits. Furthermore, recent evidence on the temporal structure of the activation of brainstem cholinergic neurons reveals fundamental aspects about the nature of cholinergic signaling. Consideration of the cholinergic brainstem complex in the context of wider brain circuits is critical to understand its contribution to normal behavior. PMID- 26945865 TI - Lessons learned from the design of chemical space networks and opportunities for new applications. AB - The concept of chemical space is of fundamental relevance in chemical informatics and computer-aided drug discovery. In a series of articles published in the Journal of Computer-Aided Molecular Design, principles of chemical space design were evaluated, molecular networks proposed as an alternative to conventional coordinate-based chemical reference spaces, and different types of chemical space networks (CSNs) constructed and analyzed. Central to the generation of CSNs was the way in which molecular similarity relationships were assessed and a primary focal point was the network-based representation of biologically relevant chemical space. The design and comparison of CSNs based upon alternative similarity measures can be viewed as an evolutionary path with interesting lessons learned along the way. CSN design has matured to the point that such chemical space representations can be used in practice. In this contribution, highlights from the sequence of CSN design efforts are discussed in context, providing a perspective for future practical applications. PMID- 26945866 TI - A qualitative analysis of the effect of a community-based primary health care programme on reproductive preferences and contraceptive use among the Kassena Nankana of northern Ghana. AB - BACKGROUND: In 2000, Ghana launched the Community-based Health Planning and Services (CHPS) initiative to improve access to health and family planning services. This initiative was based in part on research, known as the Navrongo Project, conducted in the Kassena-Nankana district (KND) between 1994 to 2003 which demonstrated significant impact on fertility and child mortality. This paper examines current contraceptive perceptions in communities that were exposed to the Project's service models over the 1994 to 2003 period, and the post experimental policies of the CHPS era. METHODS: Qualitative study was conducted in the KND of Ghana from June to September, 2012, by convening 8 male and 8 female FGD panels as well as 8 in-depth interviews of community leaders. Data collection was stratified by original experimental cell of the Navrongo Project to permit appraisal of social effects of contrasting experimental conditions. Inductive content analysis was performed with QSR Nvivo 10 to identify predominant themes. RESULTS: While findings show that exposure to community-based services was associated with enhanced approval of birth spacing and limitation, this view is grounded in perceptions that childhood survival has improved. Nonetheless, concerns were expressed about contraceptive side effects, prominently permanent sterility. Strategies for male outreach and community engagement originally introduced during the Navrongo Project have not been sustained with CHPS scale-up. The apparent atrophy of attention to the needs of men may explain the resistance of some males to the notion of female reproductive autonomy and the practice of some women to adopt contraception in secret. Despite this apparent programmatic dearth of male engagement, there is evidence to suggest that social impact of the original male engagement strategy persists in communities where male mobilization was combined with doorstep provision of family planning care during the Navrongo Project. CONCLUSION: Community-based services fostered attitudinal change towards family planning in a traditional sub Saharan African setting. Sustained exposure to primary health care that have improved the survival of children has made the use of contraception more acceptable. Efforts should be embedded in primary health care programmes that address concerns about child survival while also consigning sustained priority to the information needs of men. PMID- 26945867 TI - Stent-assisted coiling of intracranial aneurysms located on small vessels: midterm results with the LVIS Junior stent in 40 patients with 43 aneurysms. AB - INTRODUCTION: The Low-profile Visualized Intraluminal Support (LVIS) Junior stent is dedicated for endovascular treatment of wide-neck intracranial aneurysms located on small-diameter vessels (2-3.5 mm). This study reports midterm clinical and anatomical results of this device. METHODS: This study was approved by authors' ethical committees. A retrospective review of our prospectively maintained database identified all patients treated by this stent in three institutions. Technical issues and immediate and mid-term anatomical and clinical outcomes were evaluated. RESULTS: Forty patients (30 women/10 men, mean age of 55 years) with 43 aneurysms were identified. Mean aneurysm diameter was 5.6 mm (range, 2-13 mm). In all patients, treatment was successful and the stent could be precisely placed. There were three procedure-related complications, one stent thrombosis and two aneurysm ruptures, leading to immediate morbidity in one patient. Delayed ischemic events occurred in three patients including two transient attacks and one permanent deficit. The overall permanent morbidity rate was thus 5 %. No mortality occurred. Immediate aneurysm occlusion consisted of 36 complete occlusions (83.7 %), five neck remnants (11.6 %), and two incomplete occlusions (4.7 %). Twenty-seven patients (29 aneurysms) and 11 patients (11 aneurysms) had a 12- and 6-month angiographic follow-up, respectively. Final anatomical results included 36 complete occlusions (90 %) and four neck remnants (10 %). Two minor recanalizations were seen but did not require retreatment. Non significant intrastent stenosis occurred in 7/40 followed-up cases (17.5 %). CONCLUSION: The LVIS Junior stent appears safe and effective for endovascular treatment of wide-neck intracranial aneurysms located on small vessels. Midterm results show high rates of adequate and stable occlusion. PMID- 26945868 TI - Angiopoietin-1 and -2 as markers for disease severity in hemolytic uremic syndrome induced by enterohemorrhagic Escherichia coli. AB - BACKGROUND: Angiopoietin (Ang)-1 and -2 play important roles in maintaining vascular homeostasis. This study aimed to assess the roles of angiopoietin (Ang) 1 and -2 and to investigate the clinical significance of their serum levels in patients with hemolytic uremic syndrome (HUS) induced by enterohemorrhagic Escherichia coli (EHEC). METHODS: Twenty patients with HUS and 15 healthy controls were studied. Serum Ang-1 and Ang-2 levels were quantified using enzyme linked immunosorbent assay. The results were compared with the clinical features of HUS. RESULTS: During the HUS phase, serum Ang-1 levels were significantly decreased, whereas serum Ang-2 levels and the Ang-2/Ang-1 ratio were significantly elevated. Compared with patients without encephalopathy, serum Ang 2 levels and Ang-2/Ang-1 ratio were significantly elevated in patients with encephalopathy. Patients with HUS and serum Ang-2 levels of >7061 pg/mL or Ang2/Ang1 ratios of >2.29 were at high risk of encephalopathy. Serum Ang-1 levels were significantly decreased in patients in the pre-HUS phase compared with those in healthy controls. CONCLUSION: Disruption of homeostasis of vascular endothelial function by Ang-1 and -2 may be closely associated with the development of HUS. Serum Ang-1 and -2 levels and the Ang-2/Ang-1 ratio may be promising indicators of disease activity in HUS and the development of encephalopathy. PMID- 26945869 TI - New insights into spotty calcification and plaque rupture in acute coronary syndrome: an optical coherence tomography study. AB - Although recent optical coherence tomography (OCT) studies have focused on spotty calcification, whether there were any characteristics in the concomitant existence of calcification and plaque rupture remains unknown. The aim of the present study was to investigate the characteristics of spotty calcification in acute coronary syndrome (ACS) patients with or without plaque rupture, using OCT. This study enrolled 98 consecutive patients with ACS. OCT image acquisitions were performed in the culprit lesions, and patients were divided into the plaque rupture group (n = 38) and the non-rupture group (n = 60). The frequency of spotty calcification (p = 0.006), thin-capped fibroatheroma (p = 0.012), macrophage infiltration (p = 0.022), and the number of spotty calcification per patient (p < 0.001) were significantly higher and the largest arc and the minimum depth of spotty calcification from the luminal surface were significantly smaller in the rupture group. Moreover, in the rupture group, most of the spotty calcifications in the site nearest to the minimum lumen area were observed in the proximal portion of that site, and tended to be located near the plaque rupture. Multivariate analysis revealed that the presence of spotty calcification (OR 3.19, 95 % CI 1.12-9.76, p = 0.030) and age (OR 1.08, 95 % CI 1.02-1.14, p = 0.008) were independent predictive factors for plaque rupture. This study demonstrates the characteristics of spotty calcification in ACS patients with plaque rupture and the positional relationship between spotty calcification and plaque rupture. These detailed observations could impact on treatment strategies for the prevention of ACS. PMID- 26945870 TI - Axillo-femoral bypass steal due to subclavian artery stenosis. AB - Subclavian artery stenosis can cause a flow reversal-so-called steal-not only in the ipsilateral vertebral artery, but also in the internal mammary artery in patients with a history of coronary-artery bypass grafting. Subclavian artery stenosis is also associated with peripheral artery disease elsewhere. We report a novel finding of axillo-femoral bypass steal due to subclavian artery stenosis identified by vascular ultrasonography. PMID- 26945871 TI - Associations between retail food store exterior advertisements and community demographic and socioeconomic composition. AB - This paper examines the association between the prevalence of various types of outdoor food and beverage advertising found on the building exteriors and properties of retail food outlets and community racial/ethnic and socioeconomic composition in a nationwide sample of food outlets in the U.S. Our major finding from multivariable analysis is that food stores in low-income communities have higher prevalence of all food and beverage ads, including those for unhealthy products such as regular soda, controlling for community racial/ethnic composition and other covariates. This adds to growing research pointing to socioeconomic disparities in food and beverage marketing exposure. PMID- 26945872 TI - Quality assurance in cardiovascular CT: a practical guide. AB - Cardiovascular computed tomography (CCT) is a cutting-edge imaging technique providing important, non-invasive, diagnostic information. Concerns exist regarding radiation exposure to patient populations, but achieving optimal image quality at the lowest doses can be challenging. This guide provides practical advice about how quality can be assured in any CCT unit or radiology department. Illustrated by real-world vignettes and data analysis from our own experience, we highlight a multidisciplinary team approach to each stage of the patient journey, the effectiveness of regular dose audit overseen by a CT optimisation group, and the importance of underused systolic scanning techniques, in order to drive significant dose reduction without loss of image quality or clinical confidence. PMID- 26945873 TI - A 3-year follow-up study of the seroprevalence of antibodies to avian influenza A H5, H6, H7 and H10 viruses among the general population of Wuhan, China. PMID- 26945874 TI - Mesenchymal stem cell-induced 3D displacement field of cell-adhesion matrices with differing elasticities. AB - Cells maintain homeostasis and perform various functions by interacting mechanically with a cell-adhesive matrix. Regarding cellular differentiation, it has been found that matrix elasticity can determine the differentiation lineage of mesenchymal stem cells (MSCs). Direct quantitative measurements of the mechanical interaction between MSCs and matrix for differentiation, however, have yet to be reported. Herein, the displacement field of the cell-adhesive matrix was observed quantitatively using a digital volume correlation (DVC) method. Maximum displacement and cellular traction stress were analyzed when the MSC differentiated into a neuron-like cell or an osteoblast-like cell on a soft or hard elastic matrix, respectively. The function of non-muscle myosin II (NMM II), which plays an important role in intracellular cytoskeletal dynamics, was investigated during cellular differentiation. The mechanical interaction (maximum displacement and subjected area of the matrix) between the cell and matrix was dependent on matrix elasticity. It has also been shown that the mechanical interaction between the intracellular cytoskeleton and cell-adhesion matrix is indispensable for cellular differentiation. This work provides the first quantitative visualization of the mechanical interaction between MSCs and the cell-adhesion matrix for differentiation. PMID- 26945875 TI - Prophylactic use of anticoagulation and hemodilution for the prevention of venous thromboembolic events following meningioma surgery. AB - OBJECTIVES: Brain tumors may be associated with postoperative venous thromboembolic (VTE) events with possible devastating consequences. Meningioma has the highest incidence of postoperative VTE events among all brain tumors. Hemodilution and anticoagulation both proved efficacy in deep venous thrombosis (DVT) prophylaxis that is why we theorized that this regimen would be beneficial for VTE prophylaxis in operated intracranial meningioma patients without added risk to the patients. PATIENTS AND METHODS: A retrospective double-blinded study, where the records of consecutive intracranial meningioma patients were revised comparing the efficacy of two regimens of postoperative VTE prophylaxis. Patients were divided into 2 groups; group A was submitted to the use of compressive stockings, low-molecular weight heparin (LMWH) administration and hemodilution, while group B was submitted only to the use of compressive stockings. RESULTS: The study included 194 patients. Mean age of patients was 55 years (range from 27 to 78 years). VTE events were diagnosed in 16 patients (8.2%) all of them belonged to group B. The median time for VTE events was 12 days. Older age (P=.0001), larger size tumor (p=0.0438), delayed ambulation postoperatively (p=0.0351) as well as skull base location of meningioma (p=0.0163) were associated with higher incidence of postoperative VTE. Overall, group A patients showed more favorable outcome as compared to group B. CONCLUSION: In addition to the use of elastic stockings, we recommend starting hemodilution at the outset of surgery, LMWH administration starting 12h postoperatively as well as refraining from the use of diuretics during and after intracranial meningioma surgery till the patient became fully ambulatory to reduce the incidence of postoperative VTE events. PMID- 26945876 TI - The role of vascular endothelial growth factor and vascular endothelial growth inhibitor in clinical outcome of traumatic brain injury. AB - OBJECTIVES: Tumor necrosis factor superfamily-15 (TNFSF15) also known as vascular endothelial growth inhibitor (VEGI) is a cytokine that modulates anti angiogenesis and inflammation. Vascular endothelial growth factor (VEGF) promotes angiogenesis and vascular permeability following traumatic brain injury (TBI). The balance of VEGF and VEGI may play a key role in the maintenance of vascular and immune system homeostasis in the brain. However, the dynamic changes of circulating VEGF and VEGI after traumatic brain injury (TBI) and the correlation between plasma VEGF and plasma VEGI remains obscure. In this study, we were to investigate whether circulating VEGF and VEGI can be used as prognostic markers for patients with TBI. PATIENTS AND METHODS: A prospective clinical study was conducted in two neurosurgical intensive care units of Tianjin Medical University General Hospital and Tianjin Huanhu Hospital (Tianjin, China). 40 patients and 30 healthy controls were recruited. The recruited subjects were aged over 18 with randomized gender and GCS. 1mL of blood was withdrawn on 1, 4, 7, 14, and 21days after TBI. Blood samples were centrifuged at 3000rpm and the supernatants were used to measure VEGF and VEGI by ELISA kit. RESULTS: 1) Circulating VEGF in TBI patients was decreased on the 1st day after TBI, then climbed up on the 4th day, reaching a maximum level on the14th day after TBI, as compared to normal controls. VEGF level returned to normal level on 21th day after TBI. 2) Circulating VEGI in TBI patients was decreased on the 1st and 4th day after TBI, then climbed up on the 7th day after TBI, reaching a maximum level on 14th day after TBI, as compared to normal controls. VEGI levels declined to normal level on 21th day after TBI. 3) There was a significant positive correlation between circulating VEGF and VEGI. 4) However, TBI patients whose conditions had improved exhibited lower VEGF levels 7days after TBI when compared to TBI patients whose condition had deteriorated. Survivors exhibited higher VEGI levels 7days after TBI when compared to non-survivors. 5)TBI patients whose condition had improved exhibited higher VEGI levels when compared to TBI patients whose condition had deteriorated 21days after TBI. Patients with mild TBI exhibited higher VEGI levels than those with moderate and severe TBI 21days after TBI. 6) A lower rate of recovery and higher hospital mortality were found in patients with VEGF/VEGI ratio>=2.366 as compared to those with VEGF/VEGI ratio<2.366 7days after TBI. CONCLUSIONS: 1) VEGF level positively correlates with VEGI after TBI. 2) The elevation of VEGF exhibits an adverse effect from 4 to 14days after TBI while it has an advantageous effect from 14 to 21days after TBI. Increasing VEGI levels are beneficial in recovery after TBI. Controlling the ratio of VEGF/VEGI may benefit the clinical outcome following TBI. PMID- 26945877 TI - The incidence of dural tears after complete resection of lumbar synovial cysts and the relation to the outcome. AB - OBJECTIVE: Synovial cysts in the lumbar spine are uncommon causes of radicular pain. In cases where conservative treatment fails, surgical resection is recommended. Dural adhesions are common intraoperative findings; therefore, the removal of the cyst may sometimes result in dural tears. The frequency of dural tears is greater with synovial cysts than in other lumbar surgeries. Clinical parameters and characteristics seen on magnetic resonance imaging were assessed to investigate the correlation between the outcome after surgery of lumbar synovial cysts and dural tears. METHODS: This study was designed as a retrospective practice audit. Patient data were drawn from an electronic medical record system. Included were consecutive patients after microsurgical resection of symptomatic lumbar synovial cysts between May 2013 and November 2015. The surgical report was evaluated retrospectively regarding the extent of decompression and cyst resection as well as surgery-related complications. Pre operative magnet resonance imaging was assessed concerning the reason for compression of the neural structures, the dimension of the cyst, and the signal of the cyst content in T2 images. In a follow-up examination about four weeks after surgery, the patient satisfaction index was evaluated. RESULTS: Forty-four consecutive patients after resection of a lumbar synovial cyst met the inclusion criteria. The mean patient satisfaction index was 2.0+/-1.0. Twenty-nine patients of the 38 patients with follow-up (76.3%) with a satisfaction index of 1 or 2 were rated as favorable. One revision surgery was necessary because of a cerebrospinal fluid fistula. Furthermore, in 4 patients an incidental durotomy occurred without any symptoms after surgery. Accordingly, the rate of dural tears was 11.4%. Dural tears were significantly more common in patients with a satisfaction index of 3 or 4 (P=0.04). Sixty percent of the patients with dural tears were operated on in level L5/S1 compared to 3 patients without a dural tear (P=0.008). There was no statistically significant difference between the different patient subgroups in any other analyzed parameter. CONCLUSION: Dural tears were found significantly more often in patients without a good outcome; they appear to portend a poorer prognosis. The level L5/S1 was significantly more often affected. During surgery, it should be considered whether to remove the cyst completely and risk a dural tear, or to leave residuals of the cyst wall if otherwise a good decompression is achieved. PMID- 26945878 TI - Targeting of EMILIN-1 and EMILIN-2 to Fibrillin Microfibrils Facilitates their Incorporation into the Extracellular Matrix. AB - Elastin microfibril interface-located proteins (EMILINs) 1 and 2 belong to a family of structurally related extracellular glycoproteins with unique functions in the extracellular space, such as modulation of pro-transforming growth factor beta processing, activation of the extrinsic apoptotic pathway, and regulation of Hedgehog and Wnt ligand bioavailability. However, little is known about how EMILINs may exert their extracellular functions. We therefore investigated the spatiotemporal localization and deposition of EMILIN-1 and -2 within the extracellular space. By using immunoelectron and immunofluorescence microscopy together with biochemical extraction, we showed that EMILIN-1 and -2 are targeted to fibrillin microfibrils in the skin. In addition, during skin wound healing and in vitro matrix fiber assembly by primary dermal fibroblasts, EMILIN-1 and -2 are deposited on and coregulated with fibrillin. Analysis of wounds and mouse embryonic fibroblast cultures showed that EMILIN-1 and -2 network formation also requires the presence of fibronectin. Disruption of microfibrils in fibrillin-1 deficient mice leads to fragmentation of the EMILIN-1 and -2 networks, suggesting an involvement of EMILINs in fibrillin-related skin disorders. The addition of EMILINs to the ligand repertoire of fibrillin strengthens the concept of fibrillin microfibrils as extracellular scaffolds integrating cellular force transmission and growth factor bioactivity. PMID- 26945879 TI - Loss of CRABP-II Characterizes Human Skin Poorly Differentiated Squamous Cell Carcinomas and Favors DMBA/TPA-Induced Carcinogenesis. AB - Retinol and its derivatives play an important role in epidermal growth and differentiation and represent chemopreventive agents in nonmelanoma skin cancer. Retinoic acid binding protein II (CRABP-II) is a cytoplasmic receptor that critically regulates all-trans-retinoic acid (ATRA) trafficking. We documented the marked reduced expression of CRABP-II and its promoter methylation in human poorly differentiated squamous cell carcinomas. To investigate the role of CRABP II in skin carcinogenesis we used skin lesion induction by dimethylbenz[a]anthracene/12-O-tetradecanoyl-phorbol-13-acetate in CRABP-II knockout C57BL/6 mice. We observed earlier and more diffuse epidermal dysplasia, greater incidence and severity of tumors, reduced expression of cytokeratin 1/cytokeratin 10 and involucrin, increased proliferation, and impaired ATRA inhibition of tumor promotion compared with wild-type animals. CRABP-II transfected HaCaT, FaDu, and A431 cells showed expression of differentiation markers, retinoic acid receptor-beta/-gamma signaling, ATRA sensitivity, and suppression of EGFR/v-akt murine thymoma viral oncogene homolog 1 (AKT) pathways in a fatty acid binding protein 5/peroxisome proliferator-activated receptor beta/-delta-independent manner. The opposite was true in keratinocytes isolated from CRABP-II-knockout mice. Finally, CRABP-II accumulation induced ubiquitination-associated reduction of EGFR. Our results showed reduced CRABP-II expression in human poorly differentiated squamous cell carcinomas, and its gene deletion favored experimental skin carcinogenesis and impaired ATRA antitumor efficacy, likely modulating EGFR/AKT pathways and retinoic acid receptor-beta/ gamma signaling. Therapeutic interventions aimed at restoring CRABP-II-mediated signaling may amplify therapeutic retinoid efficacy in nonmelanoma skin cancer. PMID- 26945880 TI - Following the Rules Set by Accreditation Agencies and Governing Bodies to Maintain In-Compliance Status: Applying Critical Thinking Skills When Evaluating the Need for Change in the Clinical Laboratory. AB - Maintaining an in-compliance clinical laboratory takes continuous awareness and review of standards, regulations, and best practices. A strong quality assurance program and well informed leaders who maintain professional networks can aid in this necessary task. This article will discuss a process that laboratories can follow to interpret, understand, and comply with the rules and standards set by laboratory accreditation bodies. PMID- 26945881 TI - HGA: de novo genome assembly method for bacterial genomes using high coverage short sequencing reads. AB - BACKGROUND: Current high-throughput sequencing technologies generate large numbers of relatively short and error-prone reads, making the de novo assembly problem challenging. Although high quality assemblies can be obtained by assembling multiple paired-end libraries with both short and long insert sizes, the latter are costly to generate. Recently, GAGE-B study showed that a remarkably good assembly quality can be obtained for bacterial genomes by state of-the-art assemblers run on a single short-insert library with very high coverage. RESULTS: In this paper, we introduce a novel hierarchical genome assembly (HGA) methodology that takes further advantage of such very high coverage by independently assembling disjoint subsets of reads, combining assemblies of the subsets, and finally re-assembling the combined contigs along with the original reads. CONCLUSIONS: We empirically evaluated this methodology for 8 leading assemblers using 7 GAGE-B bacterial datasets consisting of 100 bp Illumina HiSeq and 250 bp Illumina MiSeq reads, with coverage ranging from 100x- ~200x. The results show that for all evaluated datasets and using most evaluated assemblers (that were used to assemble the disjoint subsets), HGA leads to a significant improvement in the quality of the assembly based on N50 and corrected N50 metrics. PMID- 26945882 TI - Paraesophageal parasitic thyroid protuberance: Diagnosis using endoscopic ultrasound. PMID- 26945883 TI - Activity concentration and spatial distribution of radionuclides in marine sediments close to the estuary of Shatt al-Arab/Arvand Rud River, the Gulf. AB - Tigris and Euphrates rivers both emerge in eastern Turkey and cross Syria and Iraq. They unite to Shatt al-Arab/Arvand Rud River and discharge in Arabic/Persian Gulf. The activity concentration of natural and anthropogenic radionuclides was measured during the August of 2011 in a number of surficial sediment samples collected from the seabed along an almost straight line beginning near the estuary mouth and extending seaward. The results exhibited low activity concentration levels and an almost homogeneous spatial distribution except locations where sediment of biogenic origin, poor in radionuclides, dilute their concentrations. Dose rates absorbed by reference marine biota were calculated by the ERICA Assessment Tool considering the contribution of 40 K. The results revealed a relatively low impact of 40 K mainly to species living in, on and close to the seabed. Also, statistical association of radionuclides with selected stable elements (Ca, Ba and Sr) did not indicate presence of by-products related with oil and gas exploitation and transportation activities. Moreover, a semi-empirical sedimentology model applied to reproduce seabed granulometric facies based entirely on radionuclides activity concentrations. PMID- 26945884 TI - Motor cortex and hippocampus are the two main cortical targets in LGI1-antibody encephalitis. AB - Encephalitis associated with antibodies against leucine-rich glioma-inactivated 1 (LGI1) protein is increasingly recognized as an auto-immune disorder associated with characteristic tonic-dystonic seizures. The cortical or subcortical origin of these motor events is not clear. Some patients also present with different epileptic seizures and with cognitive impairment. The frequency of these features and their timing during the natural history of this encephalitis have not been fully described. We therefore reviewed data from 34 patients harbouring antibodies against LGI1 protein (21-81 years, median age 64) referred to the French Reference Centre for Neurological Paraneoplastic Syndrome. Three types of evidence suggested tonic-dystonic seizures were of cortical origin: (i) a slow, unilateral, frontal electroencephalographic wave, of duration ~580 ms and amplitude ~71 uV, preceded the contralateral tonic-dystonic seizures in simultaneous electroencephalographic and myographic records from seven of seven patients tested; (ii) 18-Fluorodeoxyglucose imaging revealed a strong hypermetabolism in primary motor cortex, controlateral to the affected limb, during encephalitis for five patients tested, as compared with data from the same patients after remission or from 16 control subjects; and (iii) features of polymyographic records of tonic-dystonic seizure events pointed to a cortical origin. Myoclonic patterns with brief, rhythmic bursts were present in three of five patients tested and a premyoclonic potential was identified in the cortex of one patient. Initially during encephalitis, 11 of 34 patients exhibited tonic dystonic seizures (32%). Distinct epileptic syndromes were evident in 13 patients (38%). They were typically simple, focal seizures from the temporal lobe, consisting of vegetative symptoms or fear. At later stages, 22 of 32 patients displayed tonic-dystonic seizures (68%) and 29 patients presented frequent seizures (91%) including status epilepticus. Cognitive impairment, either anterograde amnesia or confusion was evident in 30 of 34 patients (88%). Brain imaging was normal in patients with isolated tonic-dystonic seizures; in patients with limbic symptoms it revealed initially a hippocampal hyperintensity in 8 of 19 patients (42%) and 17 of 24 patients (70%) at later stages. Our data suggest that the major signs of LGI1-antibody encephalitis can be linked to involvement of motor cortex and hippocampus. They occur in parallel with striatum involvement. One of these cortical targets is involved, often unilaterally at disease onset. As the encephalitis progresses, in the absence of immunomodulatory treatment, the second cortical target is affected and effects become bilateral. Progression to the second cortical target occurs with a variable delay of days to several months. PMID- 26945886 TI - Simultaneous determination of atorvastatin and valsartan in human plasma by solid based disperser liquid-liquid microextraction followed by high-performance liquid chromatography-diode array detection. AB - A simple, sensitive, and efficient method has been developed for simultaneous estimation of valsartan and atorvastatin in human plasma by combination of solid based dispersive liquid-liquid microextraction and high performance liquid chromatography-diode array detection. In the proposed method, 1,2-dibromoethane (extraction solvent) is added on a sugar cube (as a solid disperser) and it is introduced into plasma sample containing the analytes. After manual shaking and centrifugation, the resultant sedimented phase is subjected to back extraction into a small volume of sodium hydrogen carbonate solution using air-assisted liquid-liquid microextraction. Then the cloudy solution is centrifuged and the obtained aqueous phase is transferred into a microtube and analyzed by the separation system. Under the optimal conditions, extraction recoveries are obtained in the range of 81-90%. Calibration curves plotted in drug-free plasma sample are linear in the ranges of 5-5000MUgL(-1) for valsartan and 10-5000MUgL( 1) for atorvastatin with the coefficients of determination higher than 0.997. Limits of detection and quantification of the studied analytes in plasma sample are 0.30-2.6 and 1.0-8.2MUgL(-1), respectively. Intra-day (n=6) and inter-days (n=4) precisions of the method are satisfactory with relative standard deviations less than 7.4% (at three levels of 10, 500, and 2000MUgL(-1), each analyte). These data suggest that the method can be successfully applied to determine trace amounts of valsartan and atorvastatin in human plasma samples. PMID- 26945885 TI - NEK1 mutations in familial amyotrophic lateral sclerosis. PMID- 26945887 TI - Simultaneous determination of fraxin and its metabolite, fraxetin, in rat plasma by liquid chromatography-tandem mass spectrometry and its application in a pharmacokinetic study. AB - For the first time, a rapid and sensitive high-performance liquid chromatography tandem mass spectrometry (LC-MS/MS) method was developed for the simultaneous determination of fraxin and its metabolite, fraxetin, in rat plasma, using esculin as the internal standard (IS). The plasma samples were precipitated with methanol before separation on an Nova-Pak C18 column (150mm*3.9mm, 3MUm) using a mobile phase consisting of 0.1% formic acid and methanol (55:45) at a flow rate of 0.8mL/min. The analytes were detected by multiple reaction monitoring in the negative ion mode with the mass transitions at m/z 368.9-> m/z 191.9 (fraxin), m/z 206.9-> m/z 191.8 (fraxetin) and m/z 339.0-> m/z 176.9 (esculin, IS). The results demonstrated that the calibration curves for both analytes have good linearity (r>=0.995) over a concentration range of 5.00-3000ng/mL. The assay was validated according to the regulatory bioanalytical guidelines and proved acceptable. The intra- and inter-day precisions (R.S.D.%) were within 10.9% for both analytes, whereas the deviation of assay accuracies (R.E.%) ranged from -5.3 to 1.0%. The method was successfully applied to a pharmacokinetic study after a single oral dose of fraxin at 50mg/kg to rats. PMID- 26945888 TI - Exploring complex pheromone biosynthetic processes in the bumblebee male labial gland by RNA sequencing. AB - Male marking pheromones (MPs) are used by the majority of bumblebee species (Hymenoptera: Apidae), including a commercially important greenhouse pollinator, the buff-tailed bumblebee (Bombus terrestris), to attract conspecific females. MP biosynthetic processes in the cephalic part of the bumblebee male labial gland (LG) are of extraordinary complexity, involving enzymes of fatty acid and isoprenoid biosynthesis, which jointly produce more than 50 compounds. We employed a differential transcriptomic approach to identify candidate genes involved in MP biosynthesis by sequencing Bombus terrestris LG and fat body (FB) transcriptomes. We identified 12 454 abundantly expressed gene products (reads per kilobase of exon model per million mapped reads value > 1) that had significant hits in the GenBank nonredundant database. Of these, 876 were upregulated in the LG (> 4-fold difference). We identified more than 140 candidate genes potentially involved in MP biosynthesis, including esterases, fatty acid reductases, lipases, enzymes involved in limited fatty acid chain shortening, neuropeptide receptors and enzymes involved in biosynthesis of triacylglycerols, isoprenoids and fatty acids. For selected candidates, we confirmed their abundant expression in LG using quantitative real-time reverse transcription-PCR (qRT-PCR). Our study shows that the Bombus terrestris LG transcriptome reflects both fatty acid and isoprenoid MP biosynthetic processes and identifies rational gene targets for future studies to disentangle the molecular basis of MP biosynthesis. Additionally, LG and FB transcriptomes enrich the available transcriptomic resources for Bombus terrestris. PMID- 26945889 TI - NADPH oxidase 4 contributes to connective tissue growth factor expression through Smad3-dependent signaling pathway. AB - Transforming growth factor-beta (TGF-beta)/Smad signaling has been implicated in connective tissue growth factor (CTGF) expression in vascular smooth muscle cells (VSMC). Reactive oxygen species (ROS) are involved in activation of TGF-beta/Smad signaling. However, detailed mechanisms underlying the process remain unclear. In present study, we demonstrated TGF-beta1 strongly induced CTGF expression, Smad3 activation, NADPH oxidase 4 (Nox4) expression and increased ROS production in primary rat VSMC in vitro. NADPH oxidases inhibitor diphenylene iodonium (DPI) eliminated TGF-beta1-induced CTGF expression and ROS generation. In addition, small-interfering RNA (siRNA) silencing of Smad3 or Nox4 significantly suppressed TGF-beta1-mediated CTGF expression in VSMC. Furthermore, Nox4 silencing or inhibition eliminated TGF-beta1-induced Smad3 activation and interaction between Nox4 and Smad3. In vivo studies further identified a positive correlation of Nox4 levels with Smad3 activation and CTGF expression in atherosclerotic arteries of patients and animal models. These data established that a novel mechanistic link of Nox4-dependent activation of Smad3 to increased TGF-beta1-induced CTGF in the process of vascular remodeling, which suggested a new potential pathway for therapeutic interventions. PMID- 26945890 TI - Increasing age is not associated with toxicity leading to discontinuation of treatment in patients with urothelial non-muscle-invasive bladder cancer randomised to receive 3 years of maintenance bacille Calmette-Guerin: results from European Organisation for Research and Treatment of Cancer Genito-Urinary Group study 30911. AB - OBJECTIVE: To determine the relationship of age to side-effects leading to discontinuation of treatment in patients with stage Ta-T1 non-muscle-invasive bladder cancer (NMIBC) treated with maintenance bacille Calmette-Guerin (BCG). PATIENTS AND METHODS: We evaluated toxicity for 487 eligible patients with intermediate- or high-risk Ta-T1 (without carcinoma in situ) NMIBC randomised to receive 3 years of maintenance BCG therapy (247 BCG alone and 240 BCG + isoniazid) in European Organisation for Research and Treatment of Cancer Genito Urinary Group trial 30911. The percentage of patients who stopped for toxicity and the number of treatment cycles that they received were compared in four age groups, <=60, 61-70, 71-75 and >75 years, using the Mantel-Haenszel chi-square test for trend. RESULTS: The percentage of patients stopping BCG for toxicity was 17.9% in patients aged <=60 years, 21.9% in patients aged 61-70 years, 22.9% in patients aged 71-75 years, and 16.4% in patients aged >75 years (P = 0.90). For both systemic and local side-effects, there was likewise no significant difference. CONCLUSION: In patients with intermediate- and high-risk Ta-T1 NMIBC treated with BCG, no differences in toxicity as a reason for stopping treatment were detected based on patient age. PMID- 26945891 TI - Response to the "Comment on Chemical and Toxicological Investigations of a Previously Unknown Poisonous European Mushroom Tricholoma terreum". AB - Recently, Dr. Paolo Davoli and his colleagues stated that the conclusions drawn by us were misleading from a mycotoxicological perspective, as they cast doubts on the edibility of a mushroom species (Tricholoma terreum) that has been always recognized as safe. Unfortunately, they made a mistake, and seriously misinterpreted our data, which resulted in scepticism of our research. Saponaceolides B and M were tested for their stabilities heating directly on and boiling in water. It is undoubted that both saponaceolides B and M are capable of withstanding prolonged heating during cooking. PMID- 26945893 TI - Ploidy plasticity: a rapid and reversible strategy for adaptation to stress. AB - Organisms must be able to grow in a broad range of conditions found in their normal growth environment and for a species to survive, at least some cells in a population must adapt rapidly to extreme stress conditions that kill the majority of cells.Candida albicans, the most prevalent fungal pathogen of humans resides as a commensal in a broad range of niches within the human host. Growth conditions in these niches are highly variable and stresses such exposure to antifungal drugs can inhibit population growth abruptly. One of the mechanisms C. albicans uses to adapt rapidly to severe stresses is aneuploidy-a change in the total number of chromosomes such that one or more chromosomes are present in excess or are missing. Aneuploidy is quite common in wild isolates of fungi and other eukaryotic microbes. Aneuploidy can be achieved by chromosome nondisjunction during a simple mitosis, and in stress conditions it begins to appear after two mitotic divisions via a tetraploid intermediate. Aneuploidy usually resolves to euploidy (a balanced number of chromosomes), but not necessarily to diploidy. Aneuploidy of a specific chromosome can confer new phenotypes by virtue of the copy number of specific genes on that chromosome relative to the copies of other genes. Thus, it is not aneuploidy per se, but the relative copy number of specific genes that confers many tested aneuploidy associated phenotypes. Aneuploidy almost always carries a fitness cost, as cells express most proteins encoded by genes on the aneuploid chromosome in proportion to the number of DNA copies of the gene. This is thought to be due to imbalances in the stoichiometry of different components of large complexes. Despite this, fitness is a relative function-and if stress is severe and population growth has slowed considerably, then even small growth advantages of some aneuploidies can provide a selective advantage. Thus, aneuploidy appears to provide a transient solution to severe and sudden stress conditions, and may promote the appearance of more stable solutions as well. Importantly, in many clinical and environmental isolates of different fungal species aneuploidy does not appear to have a high fitness cost, and is well-tolerated. Thus, rapid changes in ploidy may provide the opportunity for rapid adaptation to stress conditions in the environment, host niches or in response to antifungal drugs. PMID- 26945894 TI - RIM15 antagonistic pleiotropy is responsible for differences in fermentation and stress response kinetics in budding yeast. AB - Different natural yeast populations have faced dissimilar selective pressures due to the heterogeneous fermentation substrates available around the world; this increases the genetic and phenotypic diversity in Saccharomyces cerevisiae In this context, we expect prominent differences between isolates when exposed to a particular condition, such as wine or sake musts. To better comprehend the mechanisms underlying niche adaptation between two S. cerevisiae isolates obtained from wine and sake fermentation processes, we evaluated fermentative and fungicide resistance phenotypes and identify the molecular origin of such adaptive variation. Multiple regions were associated with fermentation rate under different nitrogen conditions and fungicide resistance, with a single QTL co localizing in all traits. Analysis around this region identified RIM15 as the causative locus driving fungicide sensitivity, together with efficient nitrogen utilization and glycerol production in the wine strain. A null RIM15 variant confers a greater fermentation rate through the utilization of available glucose instead of its storage. However, this variant has a detrimental effect on fungicide resistance since complex sugars are not synthesized and transported into the membrane. Together, our results reveal the antagonist pleiotropic nature of a RIM15 null variant, positively affecting a series of fermentation related phenotypes, but apparently detrimental in the wild. PMID- 26945892 TI - Biological responses of osteocytic connexin 43 hemichannels to simulated microgravity. AB - Connexin 43 (Cx43) hemichannels and gap junctions in osteocytes are responsive to mechanical loading, which is important for bone formation and remodeling. However, the mechanism of these Cx43-forming channels in the process of mechanical unloading is still not very clear. In this study, unloading caused by weightlessness was simulated by using a random position machine (RPM). Osteocytic MLO-Y4 cells were subjected to 2 h of RPM treatment, and levels of Cx43 mRNA and total and cell surface expressed protein were determined by quantitative real time PCR, western blotting, and biotinylation analysis. Although mRNA was elevated by RPM, total protein level of Cx43 was not altered; however, surface biotinylated Cx43 was significantly reduced. Interestingly, RPM promoted the retention of Cx43 in the Golgi apparatus detected by co-immunofluorescence with antibodies against Cx43 and 58 K Golgi marker protein. Dye uptake assay showed that hemichannels were induced open after RPM for 2 h. Consistently, prostaglandin E2 release was increased and this increase was completely attenuated with the treatment of a Cx43 hemichannel blocking antibody. Together, this study demonstrates increased activity of Cx43 hemichannels to RPM, and active Cx43 hemichannels with prostaglandin E2 release are likely to module biological function under simulated weightless conditions. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1195-1202, 2017. PMID- 26945895 TI - Tropisetron inhibits high glucose-induced calcineurin/NFAT hypertrophic pathway in H9c2 myocardial cells. AB - OBJECTIVES: Cardiomyocyte hypertrophy is an important structural feature of diabetic cardiomyopathy. Calcineurin/nuclear factor of activated T-cell (NFAT) pathway plays a central role in the pathogenesis of cardiac hypertrophy. The purpose of this study was to investigate the effects of tropisetron, a novel calcineurin inhibitor, on high glucose (HG)-induced cardiomyocyte hypertrophy and its underlying mechanism. METHODS: H9c2 myocardial cells were treated with tropisetron or cyclosporine A 1 h before exposure to HG for 48 h. KEY FINDINGS: Exposure to HG resulted in enhanced cell size, protein content and atrial natriuretic peptide (ANP) protein expression. HG significantly increased Ca(2+) level, calcineurin expression and nuclear translocation of NFATc4. Both tropisetron and cyclosporine A markedly prevented the hypertrophic characteristic features, calcineurin overexpression and nuclear localization of NFATc4 while intracellular Ca(2+) was not affected. CONCLUSION: Our results showed that tropisetron may have protective effects against HG-induced cardiomyocyte hypertrophy. The mechanism responsible for this beneficial effect seems to be, at least in part, blockade of calcineurin/NFAT signalling pathway. PMID- 26945896 TI - HLA-C and KIR combined genotype as new response marker for HBeAg-positive chronic hepatitis B patients treated with interferon-based combination therapy. AB - Current treatment for chronic hepatitis B infection (CHB) consists of interferon based therapy. However, for unknown reasons, a large proportion of patients with CHB do not respond to this treatment. Hence, there is a pressing need to establish response markers to select patients who will benefit from therapy and to spare potential nonresponders from unnecessary side effects of antiviral therapy. Here, we assessed whether HLA-C and KIR genotypes were associated with treatment outcome for CHB. Twelve SNPs in or near the HLA-C gene were genotyped in 86 CHB patients (41 HBeAg positive; 45 HBeAg negative) treated with peginterferon alfa-2a + adefovir. Genotyping of killer immunoglobin-like receptors (KIRs) was performed by SSP-PCR. One SNP in HLA-C (rs2308557) was significantly associated with combined response in HBeAg-positive CHB patients (P = 0.003). This SNP is linked to the HLA-C group C1 or C2 classification, which controls KIR binding. The combination of KIR2DL1 with its ligand HLA-C2 was observed significantly more often in HBeAg-positive patients with a combined response (13/14) than in nonresponders (11/27, P = 0.001). Patients with the KIR2DL1/C2 genotype had significantly higher baseline ALT levels (136 vs 50 U/L, P = 0.002) than patients without this combination. Furthermore, KIR2DL1-C2 predicted response independent of HBV genotype and ALT at baseline. HLA-C and KIR genotype is strongly associated with response in HBeAg-positive CHB patients treated with interferon-based therapy. In combination with other known response markers, HLA-C/KIR genotype could enable the selection of patients more likely to respond to interferon-based therapy. PMID- 26945897 TI - Harnessing Reversible Electronic Energy Transfer: From Molecular Dyads to Molecular Machines. AB - Reversible electronic energy transfer (REET) may be instilled in bi /multichromophoric molecule-based systems, following photoexcitation, upon judicious structural integration of matched chromophores. This leads to a new set of photophysical properties for the ensemble, which can be fully characterized by steady-state and time-resolved spectroscopic methods. Herein, we take a comprehensive look at progress in the development of this type of supermolecule in the last five years, which has seen systems evolve from covalently tethered dyads to synthetic molecular machines, exemplified by two different pseudorotaxanes. Indeed, REET holds promise in the control of movement in molecular machines, their assembly/disassembly, as well as in charge separation. PMID- 26945898 TI - The Interaction of CORM-2 with Block Copolymers Containing Poly(4-vinylpyridine): Macromolecular Scaffolds for Carbon Monoxide Delivery in Biological Systems. AB - CORM-2, tricarbonyldichlororuthenium(II) dimer (Ru2 Cl4 (CO)6 ), is a common carbon monoxide releasing molecule (CORM) studied both in vitro and in vivo, but this compound possesses poor water solubility and a short half-life, which hinders its clinical development. Herein, for the first time the conjugation of CORM-2 is reported with a copolymer containing poly(4-vinylpyridine) to yield water-soluble CO-releasing polymeric nanoparticles. CORM-2 is rapidly conjugated to copolymers through pyridine groups as confirmed by inductively coupled plasma optical emission spectroscopy and infrared spectroscopy. In comparison with free CORM-2, the copolymers functionalized with CORM-2 display better water solubility and the CO release from the polymer-based CORM is slow and sustained. This study paves the way for the potential use of a copolymer encapsulating CORM-2 as a therapeutic agent. PMID- 26945899 TI - Enantioconvergent Fukuyama Cross-Coupling of Racemic Benzylic Organozinc Reagents. AB - The first enantioconvergent palladium-catalyzed Fukuyama cross-coupling of racemic benzylic organozinc reagents with thioesters has been developed. The reaction furnishes enantioenriched acyclic alpha-disubstituted ketone products in good yields and high enantioselectivities. A broad substrate scope is achieved under mild reaction conditions to prevent racemization of the potentially labile tertiary stereocenters. PMID- 26945900 TI - Interferon lambda 4 variant rs12979860 is not associated with RAV NS5A Y93H in hepatitis C virus genotype 3a. PMID- 26945901 TI - Photolytic Protein Aggregates: Versatile Materials for Controlled Release of Active Proteins. AB - Photolytic protein aggregates are developed as a facile and versatile platform for light-induced release of active proteins. The proteins modified with biotin through a photo-cleavable linker rapidly form aggregates with streptavidin and biotinylated functional molecules simply by mixing. Light irradiation releases active proteins from the aggregates in high yields, and light-induced uptake of drug-modified transferrin into living cells is successfully demonstrated. PMID- 26945902 TI - PD-L1 expression is regulated by hypoxia inducible factor in clear cell renal cell carcinoma. AB - In our study, we demonstrate that ccRCC cell lines with impaired function of pVHL to degrade HIFalpha express elevated levels of PD-L1. In vitro analysis provided evidence that both reconstitution of pVHL and silencing of HIF2alpha, but not of HIF1alpha, lead to reduced PD-L1 expression. The strong correlation of expression between the HIF2alpha-specific HIF target Glut1 and PD-L1 confirmed this finding in ccRCC cell lines and tissue. Soluble PD-L1 levels remained constant in the sera of ccRCC patients regardless of the PD-L1 expression status in their tumors. In conclusion, our data suggest PD-L1 as HIF2alpha target, which is upregulated in pVHL deficient ccRCC. The combination of PD-L1 targeting drugs with HIF inhibiting agents may be an additional option for the treatment of ccRCC. PMID- 26945903 TI - Zotarolimus compared with everolimus eluting stents-angiographic and clinical results after recanalization of true coronary chronic total occlusions. AB - OBJECTIVES: To evaluate angiographic and clinical results of ZES compared with EES after recanalization of CTOs. BACKGROUND: ZES and EES showed similar clinical results in non-CTO lesions. Whether ZES and EES are also comparable in true CTO lesions (TIMI 0 flow, duration of occlusion of more than 3 months) with a higher risk of restenosis has not been addressed so far. METHODS: 125 patients with successful CTO recanalization via antegrade or retrograde approach were included. EES were implanted in 68 patients and ZES in 57 patients. Dual antiplatelet therapy was prescribed for 12 months. Follow-up angiography was scheduled at 9 months and clinical follow-up at 12 months. The primary angiographic outcome measure was in-stent late lumen loss. Primary clinical outcome measures were target lesion revascularization rate (TLR) and major adverse cardiac events (MACE) as a composite of cardiac death, TLR and myocardial infarction not clearly attributable to a non-target vessel. RESULTS: Baseline characteristics were similar in both groups. Mean stent length was 72.8 +/- 33.0mm with EES and 70.8 +/- 31.5 mm with ZES (P = 0.72). In-stent late lumen loss was 0.50 +/- 0.71 mm for EES compared with 0.59 +/- 0.72 (P = 0.52) for ZES. There were similar rates for TLR (EES 10.3% versus ZES 10.5%, P = 0.97) and MACE (EES 10.3% versus ZES 12.3%). No definite or probable stent thrombosis occurred. Stent length but not type of stent was predictive for in-stent late loss and TLR. CONCLUSION: ZES and EES showed similar angiographic and clinical outcomes for treatment of CTOs. (c) 2016 Wiley Periodicals, Inc. PMID- 26945904 TI - Time trends in alcohol intake in early pregnancy and official recommendations in Denmark, 1998-2013. AB - INTRODUCTION: In 1999, Danish health authorities modified their recommendation to pregnant women, condoning some alcohol intake. In 2007, the recommendation was changed to one of alcohol abstention. We aimed to assess changes in average alcohol intake (drinks/week) and alcohol binge drinking in early pregnancy from 1998 to 2013 in relation to the changes in official recommendations in 1999 (condoning some intake) and 2007 (abstention). MATERIAL AND METHODS: All Danish speaking pregnant women attending routine antenatal care at the Department of Obstetrics and Gynecology, Aarhus University Hospital, Denmark, between September 1998 and June 2013 were invited to participate. During the study period, 68 395 pregnant women filled in a self-administered questionnaire at gestational week 11 (median). From 1998, questions on binge drinking included data on the number of binge episodes (>=5 drinks on a single occasion), and the timing (gestational week) of these episodes. Additional questions on binge drinking defined as >=3 drinks on a single occasion were asked separately from 2000. A question assessed the average number of alcohol-containing drinks per week the woman consumed currently at the time of filling in the questionnaire. RESULTS: From 1998 to 2013 the proportion of women reporting no alcohol intake increased from 31.2 to 83.3% (p < 0.001), the main decline occurring between 1998 and 2007. The proportion of binge drinkers decreased (p < 0.001) but remained more stable across the period. CONCLUSIONS: The decline in the proportion of pregnant women consuming alcohol occurred independently of official recommendations. Increasing national and international awareness may partly explain the changes. PMID- 26945905 TI - Papillary thyroid microcarcinoma co-exists with Hashimoto's thyroiditis: Is strain elastography still useful? AB - To study the performance of strain elastography in differentiating papillary thyroid microcarcinoma (PTMC) combined with Hashimoto's thyroiditis (HT), conventional ultrasound scan (US) and strain elastography (SE) were performed on 558 nodules smaller than 10 mm by one examiner before surgeries. Serum concentrations of thyroid peroxidase antibody (TPO-Ab) (normal range: 0-60 U/ml) were measured. Continuous variables were analyzed by independent t test. Receiver operating characteristics (ROC) curve analysis was applied to calculate the cut off values of strain ratio (SR) and elastography score (ES). The comparison of AUCs is performed by Z test. 482 nodules were diagnosed as PTMC and there were 181 nodules co-existed with HT. SR measurements were lower in PTMC co-existed with HT when comparing to those without HT. (7.292+/-6.581 vs 11.319+/-13.155, p<0.000). Taking the data from all of the 558 nodules, the best cut-off of diagnosing PTMC was SR>2.58. When taking the data from 181 PTMC with HT, the best cut-off was SR>2.10. The diagnostic value of SR>2.1 were higher than ES>3, conventional US and combining US and SE (z=3.595, 4.876, 4.420, p<0.001), but cut off of SR>2.1 did not show significant enhancement of diagnostic value compared to SR>2.58 (z=0.439, p=0.8903>0.001) in PTMC with HT. There is a negative relation between SR and titer of TPO-Ab (r=-0.650, p<0.0001). PTMC with high TPO Ab (>1000) titer presented lower SR (5.972+/-4.118 vs 8.379+/-9.172, p=0.009). Although SR measurements were lower in nodules co-existed with HT when comparing those without HT, using a regular ES and cut-off of SR measurement would not influence the diagnosing performance. SE is still very useful for diagnosing PTMC with HT. PTMC with high TPO-Ab titer might require a lower cut-off of SR. PMID- 26945907 TI - Collaboration in neuroscience: the young PI perspective. PMID- 26945906 TI - The effects of graded levels of calorie restriction: VI. Impact of short-term graded calorie restriction on transcriptomic responses of the hypothalamic hunger and circadian signaling pathways. AB - Food intake and circadian rhythms are regulated by hypothalamic neuropeptides and circulating hormones, which could mediate the anti-ageing effect of calorie restriction (CR). We tested whether these two signaling pathways mediate CR by quantifying hypothalamic transcripts of male C57BL/6 mice exposed to graded levels of CR (10 % to 40 %) for 3 months. We found that the graded CR manipulation resulted in upregulation of core circadian rhythm genes, which correlated negatively with circulating levels of leptin, insulin-like growth factor 1 (IGF-1), insulin, and tumor necrosis factor alpha (TNF-alpha). In addition, key components in the hunger signaling pathway were expressed in a manner reflecting elevated hunger at greater levels of restriction, and which also correlated negatively with circulating levels of insulin, TNF-alpha, leptin and IGF-1. Lastly, phenotypes, such as food anticipatory activity and body temperature, were associated with expression levels of both hunger genes and core clock genes. Our results suggest modulation of the hunger and circadian signaling pathways in response to altered levels of circulating hormones, that are themselves downstream of morphological changes resulting from CR treatment, may be important elements in the response to CR, driving some of the key phenotypic outcomes. PMID- 26945909 TI - Skeletal muscle regeneration via engineered tissue culture over electrospun nanofibrous chitosan/PVA scaffold. AB - Skeletal muscle tissue shows a remarkable potential in regeneration of injured tissue. However, in some of chronic and volumetric muscle damages, the native tissue is incapable to repair and remodeling the trauma. In the same condition, stem-cell therapy increased regeneration in situations of deficient muscle repair, but the major problem seems to be the lack of ability to attachment and survive of injected cells on the exact location. In this study, chitosan/poly(vinyl alcohol) nanofibrous scaffold was studied to promote cell attachment and provide mechanical support during regeneration. Scaffold was characterized using scanning electron microscope, X-ray diffraction, and tensile test. Degradation and swelling behavior of scaffold were studied for 20 days. The cell-scaffold interaction was characterized by MTT assay for 10 days and in vivo biocompatibility of scaffold in a rabbit model was evaluated. Results showed that cells had a good viability, adhesion, growth, and spread on the scaffold, which make this mat a desirable engineered muscular graft. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 1720-1727, 2016. PMID- 26945910 TI - Single institution outcomes in the first 3 years of pancreas transplantation from brain dead donors. AB - BACKGROUND: A total of 26 pancreas transplants from brain dead donors, including 21 simultaneous pancreas and kidney (SPK) transplantation procedures, have been performed at Fujita Health University Hospital since the new pancreas transplant program was initiated in August 2012. The objective of this study is to investigate the outcomes of pancreatic transplantation in our facility in first 3 years of the program. METHODS: The background characteristics of the donors and the outcomes of 26 pancreas transplant recipients were analyzed. RESULTS: The mean age of the recipients was 44.0 years, and all recipients had a long-term history of diabetes (mean: 30.2 years). In the SPK cases, the patients also had a long history of hemodialysis (mean: 6.3 years). Although the average donor age was 41.0 years and more than half of the donors were marginal donors (defined according to Kapur's criteria and Troppmann's criteria), the patient survival and pancreatic graft survival rates were 100% and 91.7%, respectively. Unfortunately, two recipients experienced graft failure due to graft thrombosis, which resulted in graft loss. CONCLUSIONS: The new pancreas transplant program at Fujita Health University has provided excellent outcomes for patients with type 1 diabetes. PMID- 26945908 TI - Suppression of IL-8-Src signalling axis by 17beta-estradiol inhibits human mesenchymal stem cells-mediated gastric cancer invasion. AB - Epidemiologic data show the incidence of gastric cancer in men is twofold higher than in women worldwide. Oestrogen is reported to have the capacity against gastric cancer development. Endogenous oestrogen reduces gastric cancer incidence in women. Cancer patients treated with oestrogens have a lower subsequent risk of gastric cancer. Accumulating studies report that bone marrow mesenchymal stem cells (BMMSCs) might contribute to the progression of gastric cancer through paracrine effect of soluble factors. Here, we further explore the effect of oestrogen on BMMSCs-mediated human gastric cancer invasive motility. We founded that HBMMSCs notably secrete interleukin-8 (IL-8) protein. Administration of IL-8 specific neutralizing antibody significantly inhibits HBMMSCs-mediated gastric cancer motility. Treatment of recombinant IL-8 soluble protein confirmed the role of IL-8 in mediating HBMMSCs-up-regulated cell motility. IL-8 up-regulates motility activity through Src signalling pathway in human gastric cancer. We further observed that 17beta -estradiol inhibit HBMMSCS-induced cell motility via suppressing activation of IL8-Src signalling in human gastric cancer cells. 17beta-estradiol inhibits IL8-up-regulated Src downstream target proteins including p-Cas, p-paxillin, p-ERK1/2, p-JNK1/2, MMP9, tPA and uPA. These results suggest that 17beta-estradiol significantly inhibits HBMMSCS-induced invasive motility through suppressing IL8-Src signalling axis in human gastric cancer cells. PMID- 26945911 TI - The novel affordable telford temporal bone holder. PMID- 26945912 TI - The effect of varicocoelectomy on the relationship of oxidative stress in peripheral and internal spermatic vein with semen parameters. AB - The aim of this prospective controlled study was to investigate the levels of reactive oxygen species (ROS), including asymmetric dimethylarginine (ADMA), oxidative stress index (OSI) and total oxidant capacity (TOC), and antioxidants with total antioxidant capacity (TAC) in peripheral and internal spermatic veins blood, the relationship of these factors with sperm parameters in the infertile varicocoele patients, and the amelioration effect of varicocoelectomy on these outcomes. Thirty-one primary infertile varicocoele patients and 31 fertile control patients evaluated for determining the levels of ADMA, TOC, OSI, superoxide dismutase (SOD), glutathione (GSH), TAC, and semen analysis. The patients' preoperative SOD, GSH and TAC levels, which were significantly lower than the controls, significantly increased postoperatively. Although SOD and GSH were significantly higher in spermatic vein compared to median cubital vein, TAC was significantly higher in median cubital vein. ADMA, TOC and OSI were significantly higher in the patient group. TOC and OSI were significantly higher in spermatic vein compared to median cubital vein. Postoperative TOC, OSI and ADMA reduced to the control levels. Total antioxidant capacity in the peripheral circulation and oxidative stress index in the internal spermatic vein could give an idea about the possible improvement in sperm count acquired by varicocoelectomy. PMID- 26945913 TI - Home tele-rehabilitation for rheumatic patients: impact and satisfaction of care analysis. AB - Introduction In this paper, we evaluated patients' perspectives on the use of a system for home tele-rehabilitation, designed for subjects with low computer literacy suffering hand impairment due to rheumatic diseases. Methods After a clinical trial assessing device effectiveness, the Psychosocial Impact of Assistive Devices Scale (PIADS), Quebec User Evaluation of Satisfaction with Assistive Technology (QUEST) and Individually Prioritised Problem Assessment (IPPA) questionnaires were administered to evaluate the system's impact on each patient's life, and the results were correlated with clinical indices. Patients were asked to continue self-administered rehabilitation with common objects. One year later, a semi-structured telephone interview gathered data on their experience. Results The system received a positive QUEST score (4.5 +/- 0.3) and a modest PIADS score (0.84 +/- 0.8) due to the small impact on adaptability and self-esteem. The IPPA (3.7 +/- 3.4) revealed improvement in the ability to perform tasks considered important, which was significantly correlated ( r = 0.60; p < 0.02) with the clinical Health Assessment Questionnaire (HAQ) index improvement. The interviews revealed a positive engagement effect, enhanced by the need to develop skills to be able to use the device (technological challenge) and by the perception of more attention by the medical staff. This may explain the significant dropout rate (80%) from the post-trial rehabilitation of the patients who used the device. Discussion The system was largely accepted by the patients. The results suggest that the need for information on their rehabilitation progress and the technological challenge deserves further study to make patients more autonomous in cases of continuous rehabilitation. PMID- 26945914 TI - Remitting seronegative symmetrical synovitis with pitting oedema syndrome with oedematous skin histopathologically characterized by granulomatous change. PMID- 26945915 TI - Mechanical and Thermal Sensory Testing in Normal Chondrodystrophoid Dogs and Dogs with Spinal Cord Injury caused by Thoracolumbar Intervertebral Disc Herniations. AB - BACKGROUND: Intervertebral disc herniation is a common cause of spinal cord injury (SCI) causing paralysis and sensory loss. Little quantitative information is available on the loss and recovery of sensation in dogs with SCI. OBJECTIVES: To determine whether quantitative sensory testing (QST) can be used to establish thermal and mechanical sensory thresholds in chrondrodystrophoid dogs and compare thresholds among normal dogs and dogs with different grades of SCI. ANIMALS: Thirty-three client-owned chondrodystrophoid dogs: 15 normal and 18 SCI dogs. METHODS: Thermal testing was performed by placing a hot (49 degrees C) and cold (5 degrees C) probe on the dorsal metatarsus and mechanical thresholds were tested using calibrated forceps to apply force to the lateral digit. Stimuli were applied until acknowledged, and response rate, latency, and force applied to response were recorded. Test-retest repeatability was determined by calculating intraclass correlation coefficients. Response rates were compared using logistic regression and thresholds were compared using Kaplan-Meier Survival curves. RESULTS: Testing was feasible with moderate repeatability. Thresholds and response rates were significantly different between normal and SCI dogs for all modalities (P < .001). When dogs were grouped by their clinical grade, each grade was significantly different from normal dogs, and cold stimuli differentiated among all grades. CONCLUSION AND CLINICAL IMPORTANCE: Sensory thresholds can be measured reliably in chondrodystrophoid dogs and are altered by SCI. The differences in sensation among neurologic grades indicate that these techniques can be used to further characterize recovery of SCI dogs. PMID- 26945916 TI - TAMIS completion proctectomy and concomitant parastomal hernia repair with transperineal mesh fixation - a video vignette. PMID- 26945917 TI - SUMOylation of KLF4 acts as a switch in transcriptional programs that control VSMC proliferation. AB - The regulation of vascular smooth muscle cell (VSMC) proliferation is an important issue due to its major implications for the prevention of pathological vascular conditions. The objective of this work was to assess the function of small ubiquitin-like modifier (SUMO)ylated Krupsilonppel-like transcription factor 4 (KLF4) in the regulation of VSMC proliferation in cultured cells and in animal models with balloon injury. We found that under basal conditions, binding of non-SUMOylated KLF4 to p300 activated p21 (p21(WAF1/CIP1))transcription, leading to VSMC growth arrest. PDGF-BB promoted the interaction between Ubc9 and KLF4 and the SUMOylation of KLF4, which in turn recruited transcriptional corepressors to the p21 promoter. The reduction in p21 enhanced VSMC proliferation. Additionally, the SUMOylated KLF4 did not affect the expression of KLF4, thereby forming a positive feedback loop enhancing cell proliferation. These results demonstrated that SUMOylated KLF4 plays an important role in cell proliferation by reversing the transactivation action of KLF4 on p21 induced with PDGF-BB. PMID- 26945918 TI - Serum models accurately predict liver-related clinical outcomes in chronic hepatitis C. AB - BACKGROUND AND AIM: This study developed liver outcome scores in chronic hepatitis C (CHC) that directly predict liver-related death, hepatocellular carcinoma (HCC), and liver decompensation. METHODS: Six hundred seventeen CHC patients were followed up for a mean of 6 years and randomized into a training set (n = 411) and a validation set (n = 206). Clinical outcomes were determined using a population-based data linkage system. RESULTS: In the training set, albumin, gamma-glutamyl transpeptidase, hyaluronic acid, age, and sex were in the final model to predict 5-year liver-related death (area under receiver operating characteristic curve [AUROC] 0.95). Two cut points (4.0 and 5.5) defined three risk groups with an incidence rate for liver-related death of 0.1%, 2%, and 13.2%, respectively (P < 0.001). Albumin, gamma-glutamyl transpeptidase, hyaluronic acid, age, and sex were used to predict 5-year liver decompensation (AUROC 0.90). A cut point of 4.5 gave a sensitivity of 94% and a specificity of 84% to predict 5-year decompensation and defined two groups with an incidence rate for decompensation of 0.2% and 5.8%, respectively (P < 0.001). Alkaline phosphatase, alpha2-macroglobulin, age, and sex were used to predict 5-year HCC occurrence (AUROC 0.95). A cut-point of eight had a sensitivity of 90% and specificity of 88% to predict 5-year HCC occurrence and defined two groups with an incidence rate for HCC of 0.2% and 5.6%, respectively (P < 0.001). Similar results were obtained using the validation set. CONCLUSIONS: All three liver outcome scores had excellent predictive accuracy and were able to stratify risk into clinical meaningful categories for CHC patients. PMID- 26945919 TI - Reply. PMID- 26945920 TI - Evaluation of two rapid screening assays for detecting hepatitis C antibodies in resource-constrained settings. AB - OBJECTIVE: To evaluate the diagnostic accuracy of the OraQuick HCV rapid antibody test from OraSure and the Multisure HCV antibody assay from MP Biomedicals. METHODS: Five seropanels from patients, intravenous drug users and blood donors with and without HCV infection were used on the two rapid immunochromatographic tests. Sensitivity, specificity and predictive values were calculated. In addition, seropanels from 10 seroconverters were used to assess early identification of HCV infection. The study was undertaken in a laboratory at Paul Ehrlich Institute in Germany. RESULTS: Panel 1 contained of 55 positive and 25 negative samples. The OraQuick HCV test had a sensitivity of 100% (95% CI: 93.5 100) and a specificity of 100% (95% CI: 86.3-100). The Multisure HCV test had a sensitivity of 100% (95% CI: 93.5-100) and a specificity of 96% (95% CI: 79.6 99.9). Panel 2 consisted of 193 pre-characterised anti-HCV-positive patient samples. The OraQuick HCV test identified 191 samples correctly and the Multisure HCV 192. The sensitivity was 99.0% (95% CI: 96.3-99.9) for the OraQuick HCV test and 99.5% (95% CI: 97.1-100) for the Multisure HCV test. Panel 3 was composed of seroconversion samples of 10 patients. The OraQuick HCV test detected all of these 10 infections while the Multisure HCV test detected six and was indeterminate on 2. Panel 4 included 53 anti-HCV negative blood samples from blood donors. Both tests correctly identified all 53. Panel 5 consisted of 26 samples of HCV/HIV co-infected patients. The sensitivity of the OraQuick HCV test was 65.2% (95% CI: 42.8-82.8) after 20 min and 73.9% (95% CI: 51.3-88.9) after 40 min of incubation. The Multisure HCV test had a sensitivity of 96.2% (95% CI: 80.4-99.9). CONCLUSION: This evaluation revealed good sensitivity for both rapid screening assays. The detection of seroconverters, however, was lower in the MutiSure HCV test. Therefore the MultiSure test should be used with hesitation in high incidence settings. The OraQuick gave HCV false-negative results in almost 25% of the HIV-positive sera. Therefore may the OraQuick be less suited in HIV prevalent areas. PMID- 26945921 TI - Effects of systemic propranolol treatment on physical growth of patients with infantile hemangiomas. AB - Propranolol has been widely used in the treatment of infantile hemangiomas since 2008. This study aimed to investigate complications of systemic propranolol therapy for infantile hemangiomas, especially its effect on infants' physical growth. In this study, propranolol was given at a dose of 2 mg/kg per day. Abnormal symptoms and growth parameters were recorded in detail during the therapy. Follow-up visits were arranged to continue at least through the age of 2 years. A total of 76 patients with complete growth parameters were enrolled into the study. Complications of propranolol were minor, and mainly included sleeping disorders, diarrhea, decrease in fasting glucose, bronchial hyperactivity and hyperkalemia. Four (5.26%) patients' growth curve dropped off more than 20 percentiles during therapy and half of them returned to normal after withdrawal of the medications. None of them suffered from underweight, wasting or stunning when medication was stopped. Systemic propranolol was proved to be a safe treatment for problematic infantile hemangiomas and did not affect the physical growth. PMID- 26945922 TI - Postmortem validation of MRI cortical volume measurements in MS. AB - Grey matter (GM) atrophy is a prominent aspect of multiple sclerosis pathology and an important outcome in studies. GM atrophy measurement requires accurate GM segmentation. Several methods are used in vivo for measuring GM volumes in MS, but assessing their validity in vivo remains challenging. In this postmortem study, we evaluated the correlation between postmortem MRI cortical volume or thickness and the cortical thickness measured on histological sections. Sixteen MS brains were scanned in situ using 3DT1-weighted MRI and these images were used to measure regional cortical volume using FSL-SIENAX, FreeSurfer, and SPM, and regional cortical thickness using FreeSurfer. Subsequently, cortical thickness was measured histologically in 5 systematically sampled cortical areas. Linear regression analyses were used to evaluate the relation between MRI regional cortical volume or thickness and histological cortical thickness to determine which postprocessing technique was most valid. After correction for multiple comparisons, we observed a significant correlation with the histological cortical thickness for FSL-SIENAX cortical volume with manual editing (std. beta = 0.345, adjusted R(2) = 0.105, P = 0.005), and FreeSurfer cortical volume with manual editing (std. beta = 0.379, adjusted R(2) = 0.129, P = 0.003). In addition, there was a significant correlation between FreeSurfer cortical thickness with manual editing and histological cortical thickness (std. beta = 0.381, adjusted R(2) = 0.130, P = 0.003). The results support the use of FSL-SIENAX and FreeSurfer in cases of severe MS pathology. Interestingly none of the methods were significant in automated mode, which supports the use of manual editing to improve the automated segmentation. Hum Brain Mapp 37:2223-2233, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26945923 TI - Adequacy of Peritoneal Dialysis in Terms of Small Solute Clearance--The Evolving Concept. PMID- 26945924 TI - Artificial Organs 2015: A Year in Review. AB - In this Editor's Review, articles published in 2015 are organized by category and briefly summarized. We aim to provide a brief reflection of the currently available worldwide knowledge that is intended to advance and better human life while providing insight for continued application of technologies and methods of organ Replacement, Recovery, and Regeneration. As the official journal of The International Federation for Artificial Organs, The International Faculty for Artificial Organs, the International Society for Rotary Blood Pumps, the International Society for Pediatric Mechanical Cardiopulmonary Support, and the Vienna International Workshop on Functional Electrical Stimulation, Artificial Organs continues in the original mission of its founders "to foster communications in the field of artificial organs on an international level." Artificial Organs continues to publish developments and clinical applications of artificial organ technologies in this broad and expanding field of organ Replacement, Recovery, and Regeneration from all over the world. We take this time also to express our gratitude to our authors for providing their work to this journal. We offer our very special thanks to our reviewers who give so generously of their time and expertise to review, critique, and especially provide meaningful suggestions to the author's work whether eventually accepted or rejected. Without these excellent and dedicated reviewers, the quality expected from such a journal could not be possible. We also express our special thanks to our Publisher, John Wiley & Sons for their expert attention and support in the production and marketing of Artificial Organs. We look forward to reporting further advances in the coming years. PMID- 26945926 TI - Allyl-isatin suppresses cell viability, induces cell cycle arrest, and promotes cell apoptosis in hepatocellular carcinoma HepG2 cells. AB - The anticancer effect of the newly synthesized isatin derivative, N-allyl-isatin (Allyl-I), was evaluated in vitro with human hepatocellular carcinoma HepG2 cells. Cell viability was detected by cell counting kit-8 (CCK8) assay. Acridine orange (AO)/ethidium bromide (EB) double staining was used to observe the cell morphology. Flow cytometry was used to assess the effects of Allyl-I on the cell cycle, apoptosis rate, and mitochondrial membrane potential (MMP). Western blot analysis was performed to detect the influence of Ally1-I on the expression of cytochrome c (cyt c), Bax, Bcl-2, and cleaved caspase-3. Allyl-I significantly inhibited HepG2 cell viability in a time- and dose-dependent manner. Allyl-I can induce cell cycle arrest in HepG2 cells at the G2/M phase. Apoptotic nuclear morphological changes were observed after AO/EB double staining. Fluorescein isothiocyanate-conjugated Annexin V (Annexin V-FITC) and propidium iodide (PI) double staining showed that the apoptotic rates significantly increased in the presence of Allyl-I. Rhodamine 123 staining indicated that Allyl-I can decrease the MMP. Allyl-I also altered the expression of mitochondrial apoptosis-related proteins. Protein levels of cyt c and cleaved caspase-3 were upregulated following Allyl-I treatment. By contrast, the Bcl-2/Bax ratio decreased. Results suggest that Allyl-I suppresses cell viability, induces cell cycle arrest, and promotes cell apoptosis in HepG2 cells. Furthermore, the induction of apoptosis might be correlated with the mitochondrial pathway. PMID- 26945927 TI - Baseline renal function of pregnant women in a geographical region with an epidemic of chronic kidney disease of unknown aetiology in Sri Lanka. PMID- 26945928 TI - Neonatal adiposity increases with rising cord blood IGF-1 levels. AB - OBJECTIVE: Infants with higher adiposity at birth may be at greater risk of developing obesity later in life. IGF-1 is important for intrauterine growth and may be a useful early life marker of adiposity, and thus later obesity risk. The aim of this study was to determine the relationship between cord blood IGF-1, neonatal anthropometrics and markers of neonatal adiposity. DESIGN, PATIENTS AND MEASUREMENTS: A cross-sectional study design was utilized to study a multiethnic cohort of full-term neonates born to healthy mothers with normal glucose tolerance at a large university hospital. Neonatal cord blood was collected after birth and assayed for IGF-1, leptin and C-peptide. Neonatal body composition was measured between 24 and 72 h of life using the method of air displacement plethysmography. RESULTS: Cord blood IGF-1 was positively and significantly associated with markers of neonatal adiposity in models adjusted for maternal age at delivery, race, maternal prepregnancy BMI, gestational age at delivery and neonatal sex: birthweight (r = 0.62, P < 0.001), leptin (r = 0.33, P = 0.018), fat mass (r = 0.52, P < 0.001) and percent body fat (r = 0.51, P < 0.001). Cord blood IGF-1 was not associated with cord blood C-peptide. CONCLUSIONS: Cord blood IGF-1 is strongly associated with all measures of neonatal adiposity suggesting that IGF-1 may be an important contributor to in utero neonatal fat accumulation. PMID- 26945930 TI - The influence of clinical and genetic factors on the development of obesity in children with type 1 diabetes. AB - The exact cause of the obesity epidemic remains unknown; however, both environmental and genetic factors are involved. People at risk of developing obesity include children with type 1 diabetes mellitus (T1DM), which in turn increases their cardiovascular disease risk. Here, we discuss the clinical and genetic factors influencing weight in patients with T1DM. In children with T1DM, the presence of obesity depends mainly on sex, metabolic control, and disease duration. However, genetic factors, including the fat mass and obesity-associated (FTO) gene, are also associated with body weight. Indeed, children with the FTO gene rs9939609 obesity-risk allele (homozygous = AA or heterozygous = AT) are predisposed to a higher body mass index and have a greater risk of being overweight or obese. However, in this review, we show that FTO gene polymorphisms only have a small effect on body weight in children, much weaker than the effect of clinical factors. The association between FTO gene polymorphisms and body weight is only statistically significant in children without severe obesity. Moreover, other genetic factors had no effect on weight in patients with T1DM, and further research involving larger populations is required to confirm the genetic basis of diabetes and obesity. Therefore, identifying the clinical features of children with T1DM, such as their initial body mass index, sex, metabolic control, and disease duration, will still have the strongest effect on reducing risk factors for cardiovascular diseases. Physicians should pay close attention to modifiable elements of these relationships, for example, metabolic control and energy and insulin intake, when caring for patients with T1DM. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26945929 TI - Efficiency of Ipratropium Bromide and Albuterol Deposition in the Lung Delivered via a Soft Mist Inhaler or Chlorofluorocarbon Metered-Dose Inhaler. AB - The propellant-free Combivent Respimat Soft Mist Inhaler (CVT-R) was developed to replace the chlorofluorocarbon-propelled Combivent metered-dose inhaler (CVT MDI). This steady-state pharmacokinetic (PK) substudy evaluated drug lung delivery efficiency, using data from two phase III safety and efficacy trials. PK parameters were obtained from well-controlled population PK analyses. Area under the plasma concentration-time curve (AUC), maximum observed plasma concentration (C(max)), and minimum observed plasma concentration (C(min)) showed systemic exposure to ipratropium bromide and albuterol delivered via the CVT-R was proportional to ex-mouthpiece delivered dose. Although the labeled dose of ipratropium bromide in the CVT-R was half that in the CVT-MDI, the systemic exposure was comparable. No PK interaction for the ipratropium bromide and albuterol Respimat drug components was demonstrated. Ipratropium bromide alone resulted in similar exposure to the combination of ipratropium bromide and albuterol. These results show that CVT-R delivers drug more efficiently to the lung than CVT-MDI. PMID- 26945931 TI - Two-dimensional-strain echocardiography in intensive care unit patients: A prospective, observational study. AB - PURPOSE: Two-dimensional-strain echocardiography (2D-strain) is a promising technique for the early detection of myocardial dysfunction. Our study was aimed to assess its feasibility in the intensive care unit (ICU). Our secondary goal was to determine if 2D-strain could predict the patient's outcome. METHODS: Conventional echocardiography and 2D-strain were performed on 64 consecutive patients admitted to our ICU. Using 2D-strain, the longitudinal deformation of the left ventricle was assessed. Feasibility of 2D-strain, diagnosis performance, and 28-day mortality prediction were determined. RESULTS: 2D-strain measurements could be performed in 77% of our patients. All 2D-strain variables related to ventricular performance were significantly impaired in the patients who died compared with those who survived. Strain global medium was the only independent echocardiographic variable predictor of 28-day mortality rate (odds ratio 0.60; 95% confidence interval 0.43-0.80, p = 0.002). CONCLUSIONS: 2D-strain measurement is feasible in ICU patients, enabling identifying early left ventricle dysfunction. Strain global medium is an independent predictor of 28-day mortality. (c) 2016 Wiley Periodicals, Inc. J Clin Ultrasound 44:368-374, 2016. PMID- 26945932 TI - Multiphase partitioning and risk assessment of endocrine-disrupting chemicals in the Pearl River, China. AB - Multiphase partitioning of endocrine-disrupting chemicals (EDCs) in the Pearl River (China) were investigated. The colloidal concentrations for 4-tert octylphenol, 4-nonylphenol, bisphenol A (BPA), and estrone (E1) were in the ranges of 0.2 ng/L to 0.8 ng/L, 23.2 ng/L to 108 ng/L, 2.3 ng/L to 97.6 ng/L, and not detectable (nd) to 0.32 ng/L, respectively; for truly dissolved concentrations, the ranges were 0.5 ng/L to 5.4 ng/L, 39 ng/L to 319 ng/L, 13.7 ng/L to 91.2 ng/L, and nd to 1.2 ng/L, respectively. Positive correlations of EDCs with colloidal organic carbon (COC) were observed. The in situ COC normalized partitioning coefficients (log KCOC ) for 4-tert-octylphenol (5.35 +/- 0.42), 4-nonylphenol (5.69 +/- 0.50), and BPA (5.51 +/- 0.77) were within the ranges reported by other studies, whereas they were 1 to 2 orders of magnitude higher than their particulate/truly dissolved phase partition coefficients (log KOCint), revealing much strong sorption of EDCs by aquatic colloids. Moreover, colloid-bound percentages of 4-tert-octylphenol, 4-nonylphenol, and BPA ranged, respectively, from 6.9% to 36.4%, from 16.7% to 63.1%, and from 3.6% to 52.4%; their estimated mass fractions were 0.29 +/- 0.21, 0.38 +/- 0.26, and 0.39 +/- 0.33, respectively. Obviously the colloid-bound fractions are significant. Furthermore, a medium risk of estrogenic effects was estimated from the truly dissolved concentrations of EDCs in the Pearl River, which was lower than the estimated high risk according to the conventionally dissolved concentrations. It is suggested that the presence of colloids be incorporated into future water quality prediction and ecological risk assessment. Environ Toxicol Chem 2016;35:2474-2482. (c) 2016 SETAC. PMID- 26945933 TI - Analysis of biostructural changes, dynamics, and interactions - Small-angle X-ray scattering to the rescue. AB - Solution small angle X-ray scattering from biological macromolecules (BioSAXS) plays an increasingly important role in biostructural research. The analysis of complex protein mixtures, dynamic equilibriums, intrinsic disorder and evolving structural processes is facilitated by SAXS data, either in stand-alone applications, or with SAXS taking a prominent role in hybrid biostructural analysis. This is not the least due to the significant advances in both hardware and software that have taken place in particular at the large-scale facilities. Here, recent developments and the future potential of BioSAXS are reviewed, exemplified by numerous examples of elegant applications to challenging systems. PMID- 26945934 TI - Transfemoral aortic valve implantation of Edwards SAPIEN 3 without predilatation. AB - OBJECTIVES: The purpose of the present study was to investigate whether transfemoral implantation of the balloon-expandable Edwards SAPIEN 3 device without prior balloon valvuloplasty is feasible. BACKGROUND: Transcatheter aortic valve implantation (TAVI) without predilatation may be advantageous and is feasible with various transcatheter heart valves. METHODS: A total of 163 consecutive patients with severe aortic stenosis undergoing transfemoral TAVI were enrolled at two sites. We assessed whether the crossing of the native aortic valve with the prosthesis without prior pre-dilation was feasible and evaluated for procedural success according to VARC-2 criteria. RESULTS: Direct implantation without pre-dilatation was feasible in 154 patients (94.5%), whereas in nine patients predilatation was required due to difficulties while crossing the native aortic valve. Procedural success was achieved in 85.6%. A large proportion of the procedural failures was mainly driven by increased post-procedural gradients >=20 mm Hg, which almost exclusively concerned the smaller prostheses sizes (23-mm 10/39 (25.6%) vs. 26-mm 5/72 (6.9%) vs. 29-mm 1/52 (1.9%); P < 0.001). Patients in the pre-ballooning group had higher calcium scores of the aortic valve (5,335 [4,421-7,807] vs. 2,893 [1,879-3,993]), more advanced age, higher transvalvular gradients, and smaller aortic valve area. CONCLUSIONS: The transfemoral implantation of the balloon-expandable SAPIEN 3 prosthesis without pre-dilatation is feasible in the majority of cases. In the presence of severe aortic valve calcification and critical aortic stenosis, however, predilatation may still be necessary. Furthermore, the significance of increased post-procedural gradients requires further verification. (c) 2016 Wiley Periodicals, Inc. PMID- 26945936 TI - RNA-Seq analysis of immune-relevant genes in Lateolabrax japonicus during Vibrio anguillarum infection. AB - Lateolabrax japonicus is one of the main marine aquatic fish species, and is popularly cultured in East Asia due to its highly commercial value. In recent years, because of large-scale and intensive farming and seawater pollution, fish diseases keep breaking out. However, systematic study on L. japonicus immunogenetics is limited due to the deficiency of deep sequencing technologies and genome backgrounds. In this study, the widely analysis at the transcriptome level for L. japonicus that infected with Vibrio anguillarum was performed. In total, 334,388,688 high quality reads were obtained in six libraries (HK-VA, HK PBS, LI-VA, LI-PBS, SP-VA and SP-PBS) and de novo assembled into 101,860 Unigenes with an average unigene length of 879 bp. Based on sequence similarity 30,142 unigenes (29.59%) were annotated in the public databases. Comparative analysis revealed, 1,202, 3034 and 3519 differentially expressed genes (DEGs) were identified in three comparisons (HK-PBS VS HK-VA, LI-PBS VS LI-VA and SP-PBS VS SP-VA). Enrichment and pathway analysis of the DEGs was also carried out to excavate the candidate genes related to immunity. In conclusion, this study identifies and evaluates dozen of potential immune related pathways and candidate genes, which are indispensable for padding genomic resources of L. japonicus, and would lay the foundation for further studying and illuminating the mechanism of host-pathogen interactions. PMID- 26945935 TI - Amino Acid Transport Associated to Cluster of Differentiation 98 Heavy Chain (CD98hc) Is at the Cross-road of Oxidative Stress and Amino Acid Availability. AB - CD98hc functions as an amino acid (AA) transporter (together with another subunit) and integrin signaling enhancer. It is overexpressed in highly proliferative cells in both physiological and pathological conditions. CD98hc deletion induces strong impairment of cell proliferation in vivo and in vitro Here, we investigate CD98hc-associated AA transport in cell survival and proliferation. By using chimeric versions of CD98hc, the two functions of the protein can be uncoupled. Although recovering the CD98hc AA transport capacity restores the in vivo and in vitro proliferation of CD98hc-null cells, reconstitution of the integrin signaling function of CD98hc is unable to restore in vitro proliferation of those cells. CD98hc-associated transporters (i.e. xCT, LAT1, and y(+)LAT2 in wild-type cells) are crucial to control reactive oxygen species and intracellular AA levels, thus sustaining cell survival and proliferation. Moreover, in CD98hc-null cells the deficiency of CD98hc/xCT cannot be compensated, leading to cell death by ferroptosis. Supplementation of culture media with beta-mercaptoethanol rescues CD98hc-deficient cell survival. Under such conditions null cells show oxidative stress and intracellular AA imbalance and, consequently, limited proliferation. CD98hc-null cells also present reduced intracellular levels of branched-chain and aromatic amino acids (BCAAs and ARO AAs, respectively) and induced expression of peptide transporter 1 (PEPT1). Interestingly, external supply of dipeptides containing BCAAs and ARO AAs rescues cell proliferation and compensates for impaired uptake of CD98hc/LAT1 and CD98hc/y(+)LAT2. Our data establish CD98hc as a master protective gene at the cross-road of redox control and AA availability, making it a relevant therapeutic target in cancer. PMID- 26945937 TI - Transcriptome profiling of grass carp (Ctenopharyngodon idellus) infected with Aeromonas hydrophila. AB - Aeromonas hydrophila is the causative pathogen of intestinal hemorrhage which has caused great economic loss in grass carp aquaculture. In order to understand the immunological response of grass carp to infection by A. hydrophila, the transcriptomic profiles of the spleens from infected and non-infected grass carp groups were obtained using HiSeqTM 2500 (Illumina). An average of 63 million clean reads per library was obtained, and approximately 80% of these genes were successfully mapped to the reference genome. A total of 1591 up-regulated and 530 down-regulated genes were identified. Eight immune-related categories involving 105 differently expressed genes were scrutinized. 16 of the differently expressed genes involving immune response were further validated by qRT-PCR. Our results provide valuable information for further analysis of the mechanisms of grass carp defense against A. hydrophila invasion. PMID- 26945938 TI - Effects of Ala-Gln feeding strategies on growth, metabolism, and crowding stress resistance of juvenile Cyprinus carpio var. Jian. AB - The present study was conducted to evaluate the effects of different L-alanyl-l glutamine (Ala-Gln) feeding strategies on the growth performance, metabolism and crowding stress resistance related parameters in juvenile Jian carp (Cyprinus carpio var. Jian) under crowded condition (80 g/L). Juvenile Jian carp (initial weight 26.1 +/- 0.6 g) were distributed into five groups which fed with graded concentrations (0% or 1.0%) of Ala-Gln for eight weeks. Control group (I, 0/0) fed with control diet (0% Ala-Gln) throughout the feeding trial. The other four groups employed different control and experimental diet feeding strategies ranging from two weeks control diet fed and two weeks experimental diet (1% Ala Gln) fed (II, 0/2) to eight weeks experimental diet fed (V, 4/4). Results revealed that Mean weight gain (MEG) under all different feeding strategies of Ala-Gln were significantly higher than that of the control group (p < 0.05), and MEG of group II (201.90%) was even higher than that of group IV (184.70%). Liver glycogen and blood total protein of groups II, III and V were significantly higher than that in groups I and IV (p < 0.05). The highest level of serum thyroxine (10.07 ng/ml), insulin-like growth factor-I (52.40 ng/ml) and insulin (9.73 MU IU/mL) were observed in group V. However, diet supplemented with Ala-Gln did not affect the levels of serum glucose, cortisol and catecholamine in fish. The mRNA expression of GR1a, GR1b and GR2 were also significantly changed in Ala Gln supplementation groups compared with control group (p < 0.05). After fish intraperitoneally injected with virulent Aeromonas hydrophila, the fish survival rates were significantly increased in all Ala-Gln supplementation groups compared with control group (p < 0.05). Results from the present experiment showed the importance of dietary supplementation of Ala-Gln in benefaction of the growth performance, metabolism and crowding stress resistance in Jian carp breeding. The optimal feeding strategy was alternatively fed with control diet and then experimental diet at an interval of two weeks for juvenile Jian carp under crowded condition. PMID- 26945939 TI - Robotic Partial Nephrectomy During Pregnancy: Case Report and Special Considerations. AB - OBJECTIVE: To report a case of robotic partial nephrectomy (RPN) during pregnancy and review the existing literature on the topic. METHODS: A 35-year-old asymptomatic pregnant woman at 20 weeks gestation was found to have a large mass in the right kidney during routine anatomic ultrasound for fetal assessment. Magnetic resonance imaging demonstrated a 7.5 cm right upper-pole solid-enhancing renal mass, concerning for malignancy, without evidence of local extension or metastases. Ultimately, after shared decision-making between the patient and her physicians, the patient elected to proceed with RPN. A multidisciplinary approach was undertaken perioperatively. Notably, coordination between high-risk maternal fetal medicine, obstetrics, anesthesia, and urology were paramount to this endeavor. RESULTS: The patient was seen and assessed by obstetrics and maternal fetal medicine preoperatively, and fetal heart tones were monitored immediately before and after surgery and every day of her hospitalization. Total operating time was 253 minutes with an estimated blood loss of 120 cc. Warm ischemia time was 36 minutes, and 70% of normal renal parenchyma was preserved. The patient's creatinine peaked at 0.81 mg/dL, and her hemoglobin nadir reached 9.6 g/dL. She was discharged on postoperative day 6 in excellent condition. Final pathology demonstrated a 6.6 cm chromophobe renal cell carcinoma with negative margins. CONCLUSION: RPN during pregnancy is feasible but requires perioperative planning, multidisciplinary coordination, and careful operative decision-making to ensure optimal safety of mother and fetus. Herein, we report the first described case of RPN for renal neoplasm during pregnancy. PMID- 26945940 TI - Gold-Catalyzed Sequential Cyclization of 1-En-3,9-Diyne Esters to Partially Hydrogenated 3H-Dicyclopenta[a,b]naphthalenes. AB - A synthetic method that relies on a gold(I)-catalyzed cycloisomerization of 1-en 3,9-diyne esters to spiro[4.4]non-2-ene-substituted 1,2-dihydronaphthalenes is described. Robust with a wide variety of substitution patterns tolerated, the reaction provides the first example of a one-step strategy to construct such novel and architecturally challenging members of the carbocycle family in good to excellent yields. A mechanism is proposed in which the sequential cycloisomerization pathway was thought to involve a gold-catalyzed 1,3-acyloxy migration/Nazarov cyclization followed by a formal [4+2] cycloaddition to give the tetracarbocyclic product. PMID- 26945941 TI - Matched analysis on orphan drug designations and approvals: cross regional analysis in the United States, the European Union, and Japan. AB - Orphan drugs have become a key area of focus in drug development for resolving unmet medical needs. The Orphan Drug Act in the USA and similar legislation in Japan, the European Union (EU), and several other countries has been enacted since 1983. This study provides a quantitative review of all orphan drug designations and approvals since the implementation of orphan drug legislation in key three regions. This study also identified and reviewed 'commonly designated' drugs across regions. Out of approximately 5000 designations, approximately 800 designations were common among the USA, EU, and/or Japan. Regional similarities, differences, and trends were identified. It is important to understand these aspects and the crucial role of orphan drug designation in global drug development. PMID- 26945942 TI - Stuck in a rut with old chemistry. PMID- 26945943 TI - Hematidrosis on the forehead following trauma: a case report. PMID- 26945944 TI - Arthroscopic Education in the 21st Century. AB - The Arthroscopy Association of North America (AANA), always with a mind to improving patient outcome, has revised it's educational course offerings to reflect changes in healthcare and education and technology. Arthroscopic and related surgeons would do well to attend the AANA Annual Meeting and Fall Course. PMID- 26945945 TI - Authors' Reply. PMID- 26945946 TI - Regarding "Outcomes After Labral Repair in Patients With Femoroacetabular Impingement and Borderline Dysplasia". PMID- 26945947 TI - Editorial Commentary: Planting a Tree to Create the Shade--Performing Quality Long-term Studies Requires Forethought. AB - Forecasting the future questions that need to be answered while collecting prospective data makes the design of long-term studies challenging. But, with the current focus in health care to report outcomes, more information will now be prospectively collected, likely providing the necessary data to more critically analyze our results with higher-level of evidence studies. PMID- 26945948 TI - Editorial Commentary: Superior Capsular Reconstruction for Irreparable Supraspinatus Tear Reveals Improved Biomechanics With a Thicker Graft Placed in 15 degrees to 45 degrees of Shoulder Abduction. AB - Biomechanical study of superior capsular reconstruction for irreparable supraspinatus tears has lower subacromial contact pressures with a thicker graft placed in 15 degrees to 45 degrees of shoulder abduction. Whether this translates to the clinical situation of massive rotator cuff insufficiency remains to be determined. PMID- 26945949 TI - Editorial Commentary: Arthroscopic Rotator Cuff Repair--Infection Rate After Rotator Cuff Repair With Arthroscopic, Open, and Mini-open Techniques. AB - In "Risk Factors for Infection After Rotator Cuff Repair," B. G. Vopat et al. report a lower rate of postoperative infection with an arthroscopic rotator cuff repair than with an open or mini-open approach. Although there were only 14 infections (infection rate of 0.77%), the reason for the preponderance of male patients, 13 of the 14 infections, needs further research to determine effective preventive strategies. PMID- 26945950 TI - Editorial Commentary: Shoulder Arthroscopy With Epinephrine Diluted Saline Irrigation Fluid. AB - The addition of epinephrine to irrigation fluid aims to improve visual clarity during shoulder arthroscopy. A potential benefit is shorter operative time. Intra articular procedures received the greatest benefit, although bleeding within the subacromial space is typically more problematic for shoulder arthroscopists. PMID- 26945951 TI - Editorial Commentary: Results of Biplanar Fluoroscopy With 3-Dimensional Analysis in Patients With Rotator Cuff Tears Challenge the Concept of Superior Translation of the Humeral Head and Must Be Interpreted With Caution. AB - Kinematic analysis of patients with rotator cuff tears shows unexpected inferior, rather than superior, translation of the humeral head. This paradox challenges conventional thought, but limitations addressed by the authors temper the results and leave the question open for future study. PMID- 26945952 TI - Editorial Commentary: Risks Versus Benefits. AB - As orthopaedic surgeons, we are constantly weighing the risks versus benefits of the procedures we may perform in our patients. The study by Werner et al. can be used to better inform our patients of the risk of undergoing arthroscopy of the elbow, allowing the orthopaedic surgeon to better weigh the risks versus benefits of the procedure. PMID- 26945953 TI - Editorial Commentary: Hip Arthroscopy Plays a Role in Painful Hip Resurfacing Arthroplasty but a Prearthroscopy Diagnosis Is Critical to Outcome. AB - Whereas hip arthroscopy plays a role in the investigation and treatment of the painful hip resurfacing arthroplasty, a diagnosis before arthroscopy is critical to improved outcome. The rate of conversion to total hip arthroplasty jumps from 7% to 37% when a pre-arthroscopy diagnosis is not known. PMID- 26945954 TI - Editorial Commentary: Think Twice, Cut Once. AB - How much of the anterior acetabulum rim needs to be resected to reduce the impingement of the pincer lesion? Hellman et al. present 3 measurements that can be performed on routine radiographs so that the surgeon can preoperatively, intraoperatively, and postoperatively measure the amount resected from the anterior acetabulum rim. PMID- 26945955 TI - Editorial Commentary: Role of Synovial Biomarkers in Patient Outcomes After Knee Arthroscopy. AB - Humans are notably poor at predicting event outcomes. In "Correlation of Synovial Fluid Biomarkers With Cartilage Pathology and Associated Outcomes in Knee Arthroscopy," Cuellar, Cuellar, Kirsch, and Strauss show that some synovial fluid biomarkers (20 were sampled for the investigation) may predict operative findings at the time of arthroscopy and patient-reported outcome measures at follow-up. Further research will clarify the role of synovial biomarkers in knee pathology and, hopefully, narrow the choices to one or two pertinent markers that can be used to improve our ability to predict outcomes from arthroscopic knee surgery. PMID- 26945956 TI - Editorial Commentary: Posterior Cruciate Ligament Reconstruction--Do Not Abandon the C-Arm Quite Yet. AB - Accurate tibial tunnel placement using the arthroscopically-assisted anatomic fovea landmark technique in transtibial posterior cruciate ligament reconstruction is possible without the use of fluoroscopic imaging. However, until a prospective, randomized controlled trial comparing the C-arm and anatomic fovea landmark techniques is completed, abandonment of the C-arm in posterior cruciate ligament reconstruction cannot be recommended. PMID- 26945957 TI - Editorial Commentary: The Promise of Platelet-Rich Plasma. AB - Platelet-rich plasma is not a panacea, but platelet-rich plasma is an effective treatment for knee osteoarthritis. PMID- 26945958 TI - Editorial Commentary: Proximal Stabilization for Recurrent Patellar Dislocation- Respect the Anatomy and Achieve Excellent Outcomes Regardless of Specific Technique. AB - In a Level IV evidence systematic review of 13 studies comparing medial patellofemoral ligament reconstruction and medial soft-tissue realignment for recurrent lateral patellar instability without osseous pathology, both techniques showed excellent outcomes with low recurrent dislocation rates (<10% for both) without significant clinical, radiographic, or instability differences between the two groups at minimum 2-year follow-up. As in all well-designed and conducted systematic reviews, the authors delicately balance study homogeneity (similar patients and surgical procedures-excluding distal osseous realignment and first-time dislocators) and heterogeneity (improved generalizability: dichotomized medial soft-tissue realignment and medial patellofemoral ligament reconstruction). PMID- 26945959 TI - Editorial Commentary: The Efficacy of Nonsteroidal Anti-inflammatory Drugs for Prophylaxis of Heterotopic Ossification in Hip Arthroscopy--Do We Treat Patients or X-rays? AB - A systematic review of 5 series comparing the incidence of heterotopic ossification after hip arthroscopy with and without nonsteroidal anti inflammatory drug prophylaxis showed a statistically significant improvement with the use of prophylaxis. PMID- 26945960 TI - Editorial Commentary: Meta-analyses Are on the Rise, but Are We Learning More? AB - The number of published meta-analyses in the arthroscopy literature is clearly on the rise. As this increase occurs, it is important to step back and refresh ourselves on the key features of meta-analyses. PMID- 26945961 TI - A mechanistic model for electrochemical nutrient recovery systems. AB - Electrochemical membrane technologies such as electrodialysis have been identified as key technologies to enable nutrient recovery from wastewater. However, current electrochemical models are focused on simpler solutions than wastewater and omit key outputs such as pH, or total cell potential. A combined physico-chemical and electrochemical model was developed which includes the mechanisms of competitive transport of ions, implicit inclusion of H(+) and OH( ), pH (including ionic activity and ion pairing), different factors contributing to total cell potential and a novel method for ion exchange membrane transport. The model outputs compare well with measurements from experiments and simulate secondary effects such as electrode reactions and current leakage. Results found that membrane, rather than boundary layer or bulk resistance was the major contributor to potential drop, and that apparent boundary layers were relatively thick (3 +/- 1 mm). Non-ideal solution effects such as ion-pairing and ionic activity had a major impact, particularly on multi-valent Ca(2+) ions, which enhances the capability of electrodialysis to recover monovalent nutrient ions such as K(+) and NH4(+). Decreased resistivity of ion exchange membranes to specific ions (for example, in this case nitrate) could also be detected. The methods here are validated using a comparatively simple synthetic solution of five ionic components, but are able to be easily scaled for a more complex solution, and are also compatible with additional mechanisms such as precipitation, fouling, and scaling. PMID- 26945962 TI - Spatiotemporal patterns and source attribution of nitrogen load in a river basin with complex pollution sources. AB - Environmental problems such as eutrophication caused by excessive nutrient discharge are global challenges. There are complex pollution sources of nitrogen (N) discharge in many river basins worldwide. Knowledge of its pollution sources and their respective load contributions is essential to developing effective N pollution control strategies. N loads from all known anthropogenic pollution sources in the Upper Huai River basin of China were simulated with the process based SWAT (Soil and Water Assessment Tool) model. The performances of SWAT driven by daily and hourly rainfall inputs were assessed and it was found that the one driven by hourly rainfall outperformed the one driven by daily rainfall in simulating both total nitrogen (TN) and ammonia nitrogen (NH4-N) loads. The hourly SWAT model was hence used to examine the spatiotemporal patterns of TN and NH4-N loads and their source attributions. TN load exhibited significant seasonal variations with the largest in summer and the smallest in spring. Despite its declining proportion of contribution downstream, crop production remained the largest contributor of TN load followed by septic tanks, concentrated animal feedlot operations (CAFOs), municipal sewage treatment plants, industries, and scattered animal feedlot operations (SAFOs). There was much less seasonal variation in NH4-N load. CAFOs remained the largest source of NH4-N load throughout the basin, while contributions from industries and municipal sewage treatment plants were more evident downstream. Our study results suggest the need to shift the focus of N load reduction from "end-of-pipe" sewage treatment to an integrated approach emphasizing stakeholder involvement and source prevention. PMID- 26945963 TI - Critical review of factors governing data quality of integrative samplers employed in environmental water monitoring. AB - Integrative sampling enables the collection of analyte mass from environmental liquids over extended timeframes from hours to months. While the incentives to complement or replace conventional, time-discrete sampling have been widely discussed, the data quality implications of employing alternative, integrative methods have not yet been systematically studied. A critical analysis of contemporary literature reports showed the data quality of integrative samplers, whether active-advection or passive-diffusion, to be governed by uncertainty in both sampling rate and analyte recovery. Derivation of two lumped parameters, representing the coefficient of accumulation (alpha) of a contaminant from an environmental fluid and the coefficient of subsequent recovery (rho) of its mass from the sampler, produced a conceptual framework for quantifying error sources in concentration data derived from accumulative samplers. Whereas the precision associated with recovery was found to be fairly consistent across eight passive diffusion and active-advection devices (averaging 5-16% relative standard deviation, RSD), active-advection samplers effectively improve precision in sampling rate (analyte uptake), as determined for two active-advection devices (2 7% average RSD) and five passive devices (12-42% average RSD). In summary, an approach is presented whereby the data quality implications of integrative sampler design can be compared, which can inform the selection, optimization, and development of sampling systems to complement the state of the art. PMID- 26945964 TI - Co-occurrence of integrase 1, antibiotic and heavy metal resistance genes in municipal wastewater treatment plants. AB - The impact of human activities on the spread and on the persistence of antibiotic resistances in the environment is still far from being understood. The natural background of resistances is influenced by human activities, and the wastewater treatment plants (WWTPs) are among the main sources of the release of antibiotic resistance into the environment. The various treatments of WWTPs provide a number of different environmental conditions potentially favoring the selection of antibiotic resistance genes (ARGs) and thereby their well-documented spread in the environment. Although the distribution of different ARGs in WWTPs has been deeply investigated, very little is known on the ecology and on the molecular mechanisms underlying the selection of specific ARGs. This study investigates the fate of diverse ARGs, heavy metal resistance genes (HMRGs) and of a mobile element (the class I integron) in three WWTPs. Abundances of the different genetic markers were correlated to each other and their relation to biotic and abiotic factors (total organic carbon, total nitrogen, prokaryotic cell abundance and its relative distribution in single cells and aggregates) influencing the microbial communities in the different treatment phases in three WWTPs, were investigated. Water samples were analyzed for the abundance of six ARGs (tetA, sulII, blaTEM, blaCTXM,ermB, and qnrS), two HMRGs (czcA and arsB), and of the class I integron (int1). The measured variables clustered in two well-defined groups, the first including tetA, ermB, qnrS and the different biotic and abiotic factors, and a second group around the genes sulII, czcA, arsB and int1. Moreover, the dynamics of sulII, HMRGs, and int1 correlated strongly. Our results suggest a potentially crucial role of HMRGs in the spread, mediated by mobile elements, of some ARGs, i.e. sulII. The possibility of a relation between heavy metal contamination and the spread of ARGs in WWTPs calls for further research to clarify the mechanisms of co-selection and their ecology, in order to implement the removal efficiency of the applied treatments. PMID- 26945965 TI - Differentiation therapy of hepatocellular carcinoma by inhibiting the activity of AKT/GSK-3beta/beta-catenin axis and TGF-beta induced EMT with sophocarpine. AB - Hepatocellular carcinoma progression is thought to be driven by cancer stem cells (CSCs). No clinical trial has, as yet, shown convincing long-term disease free survival results for the majority of patients in HCC. So it is important to discover new anti-cancer agents. In our study, we chose sophocarpine, which is derived from the foxtail-like sophora herb, for its efficacy to inhibit HCC including CSCs and potential mechanism study. Our results show that sophocarpine could not only reduce HCC cell viability, eliminate HCC and reverse hepatoma cells malignant phenotype, but also reduce the ratio of CSCs and inhibit the sphere formation of CSCs in vitro. In vivo, sophocarpine significantly displayed antitumor effects in subcutaneous xenograft HCC models and orthotopic transplantation tumor models. Further studies showed that sophocarpine could exert anti-tumor effects partly via downregulating the activity of the cancer stem cell related pathways and inhibiting EMT induced by TGF-beta. PMID- 26945966 TI - Multidisciplinary effort in treating children with hepatoblastoma in China. AB - The purpose of this study is to report the first nationwide protocol (Wuhan Protocol) developed by Chinese Children's Cancer Group and the results of multidisciplinary effort in treating hepatoblastoma. In this study, we reported the final analysis, which includes 153 hepatoblastoma patients in 13 hospitals from January 2006 to December 2013. The 6-year overall survival and event-free survival rates were 83.3 +/- 3.1% and 71.0 +/- 3.7%, respectively, in this cohort. The univariate analysis revealed that female (P = 0.027), under 5 years of age (P = 0.039), complete surgical resection (P = 0.000), no metastases (P = 0.000), and delayed surgery following neoadjuvant chemotherapy (P = 0.000) had better prognosis. In multivariate analysis, male, 5 years of age or above, stage PRETEXT III or IV, and incomplete surgical resection were among the some adverse factors contributing to poor prognosis. The preliminary results from this study showed that patients who underwent treatment following Wuhan Protocol had similar OS and EFS rates compared to those in developed countries. However, the protocol remains to be further optimized in standardizing surgical resection (including liver transplantation), refining risk stratification and risk-based chemotherapy. PMID- 26945967 TI - eIF4E-phosphorylation-mediated Sox2 upregulation promotes pancreatic tumor cell repopulation after irradiation. AB - Pancreatic cancer is a devastating disease characterized by treatment resistance and high recurrence rate. Repopulation of surviving tumor cells undergoing radiotherapy is one of the most common reasons for recurrence. Our previous studies have discovered a novel mechanism for repopulation after irradiation that activation of caspase-3 in irradiated tumor cells activates PKCdelta/p38 axis to transmit proliferation signals promoting repopulation of surviving tumor cells. Here we found Sox2 expression is up-regulated in irradiated pancreatic cancer cells, which played a major role in tumor cell repopulation after irradiation. Over-expression of Sox2 strongly enhanced the growth-stimulating effect of irradiated dying tumor cells on living tumor cells through a paracrine modality. Furthermore, we identified activated eIF4E, which is phosphorylated by MNK1, as a regulator of Sox2 expression after irradiation, and pharmacologic inhibition of eIF4E with CGP57380 and Ribavirin significantly weakened Sox2-mediated tumor cell repopulation. Finally, we showed the activation of caspase 3/PKCdelta/p38/MNK1 signal pathway in irradiated pancreatic tumor cells. Together, we showed a novel pathway regulating Sox2 expression and Sox2 may be a promising target to reduce recurrence due to repopulation of surviving tumor cells after radiotherapy. PMID- 26945968 TI - The anti-proliferative effects of type I IFN involve STAT6-mediated regulation of SP1 and BCL6. AB - Type I IFN-induced STAT6 has been shown to have anti-proliferative effects in Daudi and B cells. IFN-sensitive (DS) and IFN-resistant (DR) subclones of Daudi cells were used to study the role of STAT6 in the anti-proliferative activities. Type I IFN significantly increased STAT6 mRNA and protein expression in DS but not DR cells. STAT6 knockdown significantly reduced the sensitivity to IFN in both cell lines. The molecular targets and functional importance of IFN-activated STAT6 were performed by chromatin immunoprecipitation-on-chip (ChIP-on-chip) experiments in type I IFN-treated Daudi cells. Two target genes (Sp1 and BCL6) were selected from the ChIP-on-chip data. IFN-induced STAT6 activation led to Sp1 upregulation and BCL6 downregulation in DS cells, with only minimal effects in DR cells. siRNA inhibition of STAT6 expression resulted in decreased Sp1 and BCL6 mRNA and protein levels in both DS and DR cells. IFN treatment did not increase Sp1 and BCL6 expression in a STAT2-deficient RST2 cell line, and this effect was mitigated by plasmid overexpression of STAT2, indicating that STAT2 is important for STAT6 activation. These results suggest that STAT6 plays an important role in regulating Sp1 and BCL6 through STAT2 to exert the anti-proliferative effects of type I IFN. PMID- 26945969 TI - PCAF inhibits hepatocellular carcinoma metastasis by inhibition of epithelial mesenchymal transition by targeting Gli-1. AB - The p300-CBP-associated factor (PCAF), other than its histone acetyltransferase (HAT) activity, possesses an intrinsic ubiquitination activity that is involved in various transcriptional regulators, including the transcription factor glioma associated oncogene 1 (Gli1), a well-known regulator of epithelial-mesenchymal transition (EMT) in cancer. In present research, we detected that PCAF was down regulated in hepatocellular carcinoma (HCC) tissues compared with the adjacent non-tumor tissues and significantly associated with malignant portal vein invasion (p < 0.05) and poor survival (p < 0.05) of HCC patients. Moreover, functional study demonstrated that downregulation of PCAF facilitated tumor cell migration, invasion via EMT. Further study found that Gli1 as a direct target of PCAF induced EMT and promoted tumor metastasis and invasion. CONCLUSION: PCAF is an anti-oncogene that plays an important role in the development of HCC by suppressing HCC cell metastasis and EMT by targeting Gli1, which indicates the potential therapeutic value of PCAF for suppression of metastasis of HCC. PMID- 26945970 TI - RNA-binding protein Lin28 in cancer and immunity. AB - The highly conserved RNA-binding protein, Lin28, is involved in many biological processes, including development, reprogramming, pluripotency, and metabolism. Importantly, Lin28 functions as an oncogene, promoting tumor progression and metastasis in various human cancers. Lin28 can regulate gene expression either by directly binding to mRNAs or by blocking microRNA biogenesis, and the underlying mechanisms include Let-7-dependent and Let-7-independent modes of action. Recent evidence shows that Lin28 also plays a fundamental role in immunity. The roles of Lin28 in disease are complex and require characterization of its physiological functions in cancer and immunological contexts. Here we review emerging information on the role of Lin28 in cancer and immunity and the molecular mechanisms it uses. We discuss our present knowledge of the system and highlight remaining mysteries related to the functions of this small RNA-binding protein. This knowledge may lead to Lin28 becoming a diagnostic marker for cancer or immune-related diseases and a possible therapeutic target. PMID- 26945971 TI - Cancer development, chemoresistance, epithelial to mesenchymal transition and stem cells: A snapshot of IL-6 mediated involvement. AB - Interleukin-6 (IL-6) is a cytokine present in tumor microenvironment. Elevated level of IL-6 is associated with cancer cell proliferation, angiogenesis and metastasis through fueling STAT3, MAPK and Akt signaling. It promotes epithelial to mesenchymal transition (EMT) through altered expression of N-cadherin, vimentin, snail, twist and E-cadherin leading to cancer metastasis. IL-6 boosts mammosphere formation, self-renewal of stem cells, stemness properties of cancer cells and recruitment of mesenchymal stem cells. IL-6 is also a contributing factor for multidrug resistance in cancer due to gp130/MAPK/STAT3 mediated activation of transcription factors C/EBPbeta/delta, overexpression of p glycoprotein, EMT transition and expansion of stem cells. The in-depth investigation of IL-6 mediated cellular effects and its signaling pathway can provide the new window for future research and clinical development of IL-6 targeted therapy in cancer. Thus, an overview is delivered in this review deciphering the emerging aspect of the predominant influence of IL-6 in malignant transformation, EMT, cancer-associated stem cells and chemoresistance. PMID- 26945972 TI - The Incremental Utility of Emotion Regulation But Not Emotion Reactivity in Nonsuicidal Self-Injury. AB - This study assessed the incremental utility of emotion reactivity and emotion regulation in relation to nonsuicidal self-injury (NSSI). Participants included 379 college students aged 18-22 who completed self-report measures of emotion regulation, emotion reactivity, and NSSI. Emotion regulation was significantly related to NSSI both ignoring and controlling for reactivity, but the reverse was not true. Participants' use of NSSI for affect regulation appeared to moderate this relation. Findings support emotion regulation deficits as a target for intervention over and above heightened emotion reactivity, especially in those who use NSSI to regulate negative affect. PMID- 26945973 TI - MinR 10/20 system: Quantitative and reproducible cranial landmark setting method for MRI based on minimum initial reference points. AB - BACKGROUND: The international 10/20 system is not only a fundamental method for describing positioning for electroencephalography (EEG), but also provides intermediate cranial landmarks for the probabilistic spatial registration methods that use a reference-MRI database. However, the presence of the inion, one of the four initial reference landmarks of the international 10/20 system, is inconspicuous and can be difficult to locate on MRIs. NEW METHOD: The MinR 10/20 system utilizes only three initial reference points, the nasion (Nz) and the right and left preauricular points (AR and AL), but does not employ the inion (Iz). With the MinR 10/20 system, first the most posterior point on the occipital protuberance, IIz (Imitated Iz), is identified as an exploratory alternative to the Iz point. Next, the other landmarks are calculated according to the conventional international 10/20 system referring to these four reference points (Nz, AL, AR and IIz). RESULTS: Holistic tendencies for landmark position estimations on the heads and cortices in MNI space did not vary greatly between MinR and international 10/20 systems. COMPARISON WITH EXISTING METHODS: A comparison of MinR and international 10/20 systems applied to seventeen adult head MRIs revealed little variance in holistic tendencies for landmark position estimations on head and cortex surfaces in the MNI coordinate system. Furthermore, variability was smaller with the MinR 10/20 system than with the conventional international 10/20 system. CONCLUSIONS: The MinR 10/20 system proved to be a practical alternative to the conventional international 10/20 system in modern computational spatial analysis for scalp-based brain mapping methods. PMID- 26945974 TI - The first step for neuroimaging data analysis: DICOM to NIfTI conversion. AB - BACKGROUND: Clinical imaging data are typically stored and transferred in the DICOM format, whereas the NIfTI format has been widely adopted by scientists in the neuroimaging community. Therefore, a vital initial step in processing the data is to convert images from the complicated DICOM format to the much simpler NIfTI format. While there are a number of tools that usually handle DICOM to NIfTI conversion seamlessly, some variations can disrupt this process. NEW METHOD: We provide some insight into the challenges faced with image conversion. First, different manufacturers implement the DICOM format differently which complicates the conversion. Second, different modalities and sub-modalities may need special treatment during conversion. Lastly, the image transferring and archiving can also impact the DICOM conversion. RESULTS: We present results in several error-prone domains, including the slice order for functional imaging, phase encoding direction for distortion correction, effect of diffusion gradient direction, and effect of gantry correction for some imaging modality. COMPARISON WITH EXISTING METHODS: Conversion tools are often designed for a specific manufacturer or modality. The tools and insight we present here are aimed at different manufacturers or modalities. CONCLUSIONS: The imaging conversion is complicated by the variation of images. An understanding of the conversion basics can be helpful for identifying the source of the error. Here we provide users with simple methods for detecting and correcting problems. This also serves as an overview for developers who wish to either develop their own tools or adapt the open source tools created by the authors. PMID- 26945975 TI - Robust neuroprotective effects of intranasally delivered iNOS siRNA encapsulated in gelatin nanoparticles in the postischemic brain. AB - The therapeutic efficacy of intranasal iNOS siRNA delivery was investigated in the postischemic rat brain after encapsulating on in gelatin nanoparticles (GNPs; diameter 188.0 +/- 60.9 nm) cross-linked with 0.0667% glutaraldehyde (GA). Intranasally delivered GNPs were found in extracellular and intracellular compartments of many brain regions, including the olfactory bulb, cerebral cortex, and striatum at 1 hour after infusion and continued to be detected for days. Infarct volumes were markedly suppressed (maximal reduction to 42.1 +/- 2.6%) at 2 days after 60 minutes of middle cerebral artery occlusion (MCAO) when iNOS siRNA/GNPs were delivered at 6 hours post-MCAO. In addition, this protective effect was manifested by reductions in neurological and behavioral deficits that were sustained for 2 weeks. Therapeutic potency of iNOS siRNA/GNPs was significantly greater and sustained longer than that of bare siRNA and prolonged and efficient iNOS by iNOS siRNA/GNP is responsible for the robust neuroprotective effect. PMID- 26945976 TI - Biological analysis and imaging applications of CdSe/CdSxSe1-x/CdS core-shell magic-sized quantum dot. AB - Although colloidal magic-sized quantum dots present great promise for biological applications due to their high stability and strong luminescence, nanotoxicological analyses are scarcely reported and biomedical applications have not been demonstrated. This is the first report on biological effects of CdSe/CdSxSe1-x/CdS core-shell magic-sized quantum dot (CS-MSQD) with specific application in breast cancer cell detection. The 2-nm CS-MSQD presents a broad bandwidth emission from 450 to 750nm, low toxicity, non-immunogenicity and biocompatibility. The CS-MSQD was conjugated to a breast cancer-specific Fab antibody, and passively diffused into cells for in vitro detection of a breast cancer cell line, demonstrating to be an unprecedented tool for biomedical applications. PMID- 26945977 TI - Co-delivery of erlotinib and doxorubicin by pH-sensitive charge conversion nanocarrier for synergistic therapy. AB - Pretreatment of lung cancer cells with epidermal growth factor receptor (EGFR) inhibitor erlotinib has been recently reported that could dramatically synergize their apoptotic response to DNA damage agent doxorubicin (DOX). To translate this synergistic therapy into in vivo anticancer therapy and clinical practice, we designed a novel pH-sensitive charge conversion nanocarrier (M-HHG2C18-L) that contained erlotinib/DOX combination and produced a sequential staggered drug release for synergistic lung cancer therapy. In this study, a synthetic zwitterionic oligopeptide lipid (1,5-dioctadecyl-l-glutamyl2-histidyl hexahydrobenzoic acid, HHG2C18) was used to construct a pH-sensitive lipid bilayer (HHG2C18-L), which was subsequently applied to coat amino-functionalized mesoporous silica nanoparticles (MSN-NH2). Erlotinib and DOX were separately incorporated into HHG2C18-L and MSN-NH2 respectively to obtain pH-sensitive charge conversion erlotinib/DOX co-delivery nanoparticles (M-HHG2C18-L(E+D)). We confirmed that M-HHG2C18-L(E+D) were able to reverse surface zeta potential from negative to positive at tumor extracellular pH, thus facilitating the targeted cancer cell internalization. Furthermore, as erlotinib was sequestered in the exterior lipid bilayer and the controlled release ability of MSN-NH2, erlotinib released faster than DOX during the cellular transport. Additionally, HHG2C18-L became more positive at tumor intracellular pH and enhanced Coulombic repulsion with MSN-NH2, leading to increased sequential staggered release of erlotinib and DOX. Due to the pretreatment and time-staggered inhibition of EGFR with erlotinib and the enhanced intracellular release of DOX to the nucleus, the maximized synergistic cell killing effect was achieved. Compared to non-sensitive erlotinib/DOX co-delivery nanoparticles (M-SPC-L(E+D)) and simultaneous DRUG coadministration. M-HHG2C18-L(E+D) with sequential staggered drug release and pH sensitive charge conversional properties showed great synergistic effects in antiproliferation and apoptosis of A549 human cancer cells in vitro. The in vivo study demonstrated that M-HHG2C18-L(E+D) exhibited considerable tumor accumulation and potent suppression of tumor growth in Lewis lung carcinoma tumor bearing mice. It was also demonstrated that M-HHG2C18-L(E+D) showed no systemic toxicity and possessed distinguished effect on extending survival period. These results suggested that M-HHG2C18-L(E+D) had great potential application in cancer treatment. PMID- 26945978 TI - Analgesic potential of standardized methanol stem bark extract of Ficus platyphylla in mice: Mechanisms of action. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Extracts of the stem bark of Ficus platyphylla (FP) have been used in traditional the Nigerian medicine to treat psychoses, depression, epilepsy, pain and inflammation. Previous studies have revealed the analgesic and anti-inflammatory effects of FP in different assays including acetic acid-induced writhing, formalin-induced nociception, and albumin-induced oedema. PURPOSE/METHODS: In this study, we assessed the effects of the standardised extract of FP on hot plate nociceptive threshold and vocalisation threshold in response to electrical stimulation of the tail root in order to confirm its acclaimed analgesic properties. We also investigated the molecular mechanisms underlying these effects, with the focus on opiate receptor binding and the key enzymes of eicosanoid biosynthesis, namely cyclooxygenase (COX) and 5 lipoxygenase (5-LO). RESULTS: FP (i) increased the hot plate nociceptive threshold and vocalisation threshold. The increase in hot plate nociceptive threshold was detectable over a period of 30min whereas the increase in vocalisation threshold persisted over a period of 90min. (ii) FP showed an affinity for u opiate receptors but not for delta or kappa opiate receptors, and (iii) FP inhibited the activities of COX-2 and 5-LO but not of COX-1. CONCLUSIONS: We provided evidence supporting the use of FP in Nigerian folk medicine for the treatment of different types of pain, and identified opioid and non-opioid targets. It is interesting to note that the dual inhibition of COX-2 and 5-LO appears favourable in terms of both efficacy and side effect profile. PMID- 26945979 TI - Wound healing property of isolated compounds from Boesenbergia kingii rhizomes. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Boesenbergia kingii have been traditionally used in the treatment of inflammatory bowel disease, ulcerative colitis, aphthous ulcer, stomach discomfort, dysentery and abscess. Previously, we reported the B. kingii extract exert potential wound healing properties. Therefore the search of responsible constituents for wound healing property from these rhizomes is still relevant. AIM OF STUDY: This study was aimed to investigate for wound healing property of compounds from this plant in order to support its traditional uses. MATERIAL AND METHODS: Wound healing activities were tested using in vitro assays including cell proliferation and migration assays, collagen production and H2O2 induced oxidative stress in mouse fibroblast L929 cells. The DPPH assay was also used to determine antioxidant activity. RESULTS: Fourteen compounds from the chloroform fraction possessed potent anti-oxidant and wound healing activities. Compound 11 exhibited the most potent anti-DPPH effect (IC50=21.0uM) and also active against 0.5mMH2O2-induced oxidative stress by increasing cell survival ability up to 60.3% at 10uM. In addition, compounds 3, 8 and 14 at 10uM significantly enhanced L929 viability with 119.2%, 122.7% and 113.7%, respectively. Compounds 2, 7, 8 and 14 markedly enhanced L929 migration on day 2 up to 60-76% at 10uM, whereas 7 and 14 strongly stimulated collagen production at 75.0 and 96.7ug/ml compared to the control group (57.5ug/ml), respectively. CONCLUSION: B. kingii is responsible for wound healing property via antioxidative effect, stimulation of fibroblast proliferation and migration as well as enhancement of collagen production. PMID- 26945980 TI - Gallesia integrifolia (Spreng.) Harms: In vitro and in vivo antibacterial activities and mode of action. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Gallesia integrifolia (Phytolaccaceae) is commonly known as "pau-d'alho" in Brazil or "garlic plant" due to the strong scent of garlic peculiar to all parts of the plant. The bark decoction is used for the treatment of microbial infections among other diseases by different ethnic groups in Brazil, Peruvian Amazonians, Bolivia and Mosetene Indians. This study aimed to advance in the antibacterial activity and characterize the mode of action of the hydroethanolic extract of the inner stem bark of G. integrifolia (HEGi) using in vivo and in vitro experimental models. MATERIALS AND METHODS: The qualitative and quantitative phytochemical analyzes of HEGi were carried out using colorimetric and HPLC technique. The cytotoxic potential of HEGi was evaluated against CHO-K1 cells by Alamar blue assay and its acute toxicity was assessed by the Hippocratic screening test using Swiss-Webster mice. The antibacterial activity was evaluated by micro- dilution method against ten strains of Gram-positive and Gram-negative bacteria. The mode of action of HEGi was investigated by outer membrane permeability, nucleotide leakage and potassium efflux assays. In vivo infection model was established by using Staphylococcus aureus infection model Wistar rats. RESULTS: Qualitative phytochemical analysis of HEGi revealed the presence of saponins, alkaloids, phenolic compounds and flavonoids. Phytochemical quantification of HEGi showed that higher total phenolic (80.10+/-0.62mg GAE/g) and flavonoid (16.10+/-0.03mg RE/g) contents. HPLC fingerprint analysis revealed the presence of gallic acid, rutin, and morin. In the Alamar blue assay no cytotoxic effect of HEGi in CHO-K1 cells was observed up to 200ug/mL, and no signs or symptoms of acute toxicity were observed in mice of both sexes at higher doses of up to 2000mg/kg, p.o. HEGi demonstrated bacteriostatic effect against selected Gram positive and Gram negative bacterial pathogens. Its mode of action is associated, at least partly, with changes in the permeability of bacterial membranes, evidenced by the increased entry of hydrophobic antibiotic in Pseudomonas aeruginosa, intense K(+) efflux and nucleotides leakage in Shigella flexneri, Streptococcus pyogenes and S. aureus. HEGi attenuated the experimental blood borne S. aureus infection in rats at all the tested doses levels (10, 50 and 250mg/kg). CONCLUSION: HEGi is safe at the dose tested when used acutely, and it presented broad antibacterial effect, which support its traditional use in the treatment of bacterial infections. It contains well known important phytochemicals, recognized to be active against bacterial pathogens in vitro and might be collectively responsible for the antibacterial activity of HEGi. It is bacteriostatic in nature, with membrane perturbation being one of it mode of action. HEGi represent a potential phytotherapic antibacterial agent. PMID- 26945981 TI - Protective effect of the methanolic leaf extract of Eclipta alba (L.) Hassk. (Asteraceae) against gentamicin-induced nephrotoxicity in Sprague Dawley rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Eclipta alba, also known as Eclipta prostrata, is a weed of the family Asteraceae found in tropical and subtropical regions widely used in herbal medicine, including treatment of renal diseases. AIM OF THE STUDY: This study aims to evaluate the protective effect of the methanolic leaf extract of Eclipta alba on gentamicin-induced nephrotoxicity in rats. MATERIALS AND METHODS: Nephrotoxicity was induced in rats by subcutaneous injection of gentamicin (80mg/kg/day for seven days). Quercetin was used as a positive control. The nephroprotective activity was evaluated by determining blood urea nitrogen, serum creatinine, urinary microprotein, renal catalase and malondialdehyde levels. RESULTS: The extract protected the rat kidneys against gentamicin-induced renal tubular alterations and rises in blood urea nitrogen, serum creatinine, and microprotein levels. Lipid peroxidation and decrement in catalase levels were also ameliorated. CONCLUSION: The study revealed the protective effect of the methanolic leaf extract of E. alba and suggests that the probable mechanism for the nephroprotection by the extract may be due to its good radical scavenging activity and Fe(3+) ion-reducing ability. PMID- 26945982 TI - Chrysophyllum cainito leaves are effective against pre-clinical chronic pain models: Analysis of crude extract, fraction and isolated compounds in mice. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Chrysophyllum cainito L. (Sapotaceae), commonly known as caimito or star apple, is a neotropical tree valued for its ornamental quality and edible fruits. Besides its culinary use, the leaves are also popularly used to treat diabetes mellitus and several inflammatory diseases. AIM OF THIS STUDY: This study aimed to complement previous data obtained about the anti-hypersensitivity effects of the crude methanol extract (CME), CHCl3 fraction and isolated compounds obtained from C. cainito. MATERIALS AND METHODS: The CME, CHCl3 fraction and two isolated triterpenes identified as 3beta-Lup-20(29)-en-3 yl acetate (1) and Lup-20(29)-en-3beta-O-hexanoate (2) were evaluated regarding their effects using clinical pain models, such as post-operative, inflammatory and neuropathic pain. Acute inflammatory pain models induced by PGE2, epinephrine, LPS and CFA were also used to improve the knowledge about the mechanism of action. RESULTS: The animals treated with the CME and submitted to PGE2, epinephrine, LPS or CFA had the mechanical hypersensitivity significantly reduced. When repeatedly administered, the CME enhanced the mechanical withdrawal threshold of mice submitted to post-operative pain model, CFA-induced chronic inflammatory pain and two different models of neuropathic pain. In turn, the CHCl3 fraction presented anti-hypersensitivity effect against epinephrine- or LPS induced hypersensitivity, with a more prominent activity in both the neuropathic pain models. The compound 1 seems to present the same profile of the CHCl3, whereas compound 2 exhibited activity similar to the CME. CONCLUSIONS: This data suggests that the CME effect involves interference in the production, release or action of some chemical mediators, such as PGE2, sympathetic amines, cytokines, etc. Part of these effects was observed with the CHCl3 fraction, emphasizing the prominent inhibition of neuropathic pain. The results also demonstrated that part of the CME effects are due to the presence of the triterpenes 1 and 2, but it is important to mention that we cannot discard the effects of countless other compounds presented in the crude extract, acting in a synergic way. PMID- 26945984 TI - Long non-coding RNA GAS5 inhibited hepatitis C virus replication by binding viral NS3 protein. AB - HCV infection has a complex and dynamic process which involves a large number of viral and host factors. Long non-coding RNA GAS5 inhibits liver fibrosis and liver tumor migration and invasion. However, the contribution of GAS5 on HCV infection remains unknown. In this study, GAS5 was gradually upregulated during HCV infection in Huh7 cells. In addition, GAS5 attenuated virus replication with its 5' end sequences, as confirmed by different GAS5 truncations. Moreover, this 5' end sequences showed RNA-protein interaction with HCV NS3 protein that could act as a decoy to inhibit its functions, which contributed to the suppression of HCV replication. Finally, the innate immune responses remained low in HCV infected Huh7 cells, ruling out the possibility of GAS5 to modulate innate immunity. Thus, HCV stimulated endogenous GAS5 can suppress HCV infection by acting as HCV NS3 protein decoy, providing a potential role of GAS5 as a diagnostic or therapeutic target. PMID- 26945983 TI - Smith-Robinson Procedure with an Autologous Iliac Crest Graft and Caspar Plating: Report of 65 Patients with an Average Follow-up of 22 Years. AB - BACKGROUND: Anterior cervical discectomy and fusion with plate stabilization (ACDF+PS) is an accepted surgical procedure. We sought to evaluate the long-term clinical results of ACDF+PS with a special focus on pain, functional outcome, and adjacent segment disease. METHODS: Retrospectively, 139 patients who underwent ACDF+PS were reviewed with a standardized questionnaire including the current neurologic status, Neck Disability Index, EuroQuol-5 Dimension, Patient Satisfaction Index, Hospital Anxiety and Depression Scale, the Odom criteria, complications at the iliac crest donor side, and limitations in quality of life. RESULTS: Mean follow-up time was 22 years (range: 17-34 years). Sixty five (46.8%) patients were evaluated by completed questionnaires, and 74 (53.2%) did not participate. Forty-six patients attended a physical examination. ACDF+PS were performed at 1 level in 28 patients, at 2 levels in 29 patients, and at 3 levels in 8 patients. Fifty (83.3%) of the patients with preoperative pain remained free of pain and did not require another procedure as the result of degenerative cervical disease. The mean NDI was 14%; according to the Odom criteria 86.2% of patients reported good-to-excellent functional recovery. A total of 100% of patients were satisfied or very satisfied with their outcome and would decide to undergo ACDF+PS again. Two developed adjacent segment disease and needed a second procedure. CONCLUSIONS: ACDF+PS resulted in a significant increase in function, pain relief, and to a high degree of patient satisfaction. The rate for symptomatic adjacent segment disease was 4.5% after 20 years' follow-up. PMID- 26945985 TI - Proteomic study of benign and malignant pleural effusion. AB - BACKGROUND: Lung adenocarcinoma can easily cause malignant pleural effusion which was difficult to discriminate from benign pleural effusion. Now there was no biomarker with high sensitivity and specificity for the malignant pleural effusion. PURPOSE: This study used proteomics technology to acquire and analyze the protein profiles of the benign and malignant pleural effusion, to seek useful protein biomarkers with diagnostic value and to establish the diagnostic model. METHODS: We chose the weak cationic-exchanger magnetic bead (WCX-MB) to purify peptides in the pleural effusion, used matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) to obtain peptide expression profiles from the benign and malignant pleural effusion samples, established and validated the diagnostic model through a genetic algorithm (GA) and finally identified the most promising protein biomarker. RESULTS: A GA diagnostic model was established with spectra of 3930.9 and 2942.8 m/z in the training set including 25 malignant pleural effusion and 26 benign pleural effusion samples, yielding both 100 % sensitivity and 100 % specificity. The accuracy of diagnostic prediction was validated in the independent testing set with 58 malignant pleural effusion and 34 benign pleural effusion samples. Blind evaluation was as follows: the sensitivity was 89.6 %, specificity 88.2 %, PPV 92.8 %, NPV 83.3 % and accuracy 89.1 % in the independent testing set. The most promising peptide biomarker was identified successfully: Isoform 1 of caspase recruitment domain-containing protein 9 (CARD9), with 3930.9 m/z, was decreased in the malignant pleural effusion. CONCLUSIONS: This model is suitable to discriminate benign and malignant pleural effusion and CARD9 can be used as a new peptide biomarker. PMID- 26945986 TI - First-Line Treatments for Poor-Prognosis Metastatic Renal Cell Carcinoma: Experts' Prescribing Practices and Systematic Literature Review. AB - BACKGROUND AND OBJECTIVES: No head-to-head clinical trials are available to help physicians in the decision-making process of first-line therapy in poor-prognosis metastatic renal cell carcinoma (RCC). The objectives of our study were to identify experts' prescribing practices and to review available clinical data in first-line therapies for poor-prognosis metastatic RCC (mRCC). METHODS: Thirteen RCC experts were asked to fill in a self-administered questionnaire evaluating prescribing practices. A systematic review was performed in July 2015 in MEDLINE for clinical trials evaluating first-line strategy in poor-prognosis mRCC. RESULTS: Ten out of 13 experts completed the questionnaire (76.9%). Sunitinib was the most frequently prescribed first-line therapy (8/10; 80%). The main reason for prescribing sunitinib most frequently was the evidence of effectiveness for the majority (5/8 experts). A total of 21 articles were found suitable. Only one phase III randomized controlled trial in which all patients had a poor prognosis was retrieved. Temsirolimus increases progression-free survival and overall survival compared to IFN-alpha. Increased PFS with sunitinib in poor-prognosis patients was shown in a subgroup analysis of the pivotal trial. An expanded access trial confirmed this result. DISCUSSION: Experts tend to prefer sunitinib as first-line therapy even in poor-prognosis mRCC. In light of the systematic review, no targeted therapy appears to be more effective than another. The upcoming challenge is to discover more effective new drugs since the overall survival of poor-prognosis mRCC still remains extremely limited. PMID- 26945987 TI - Influences of gender in metabolic syndrome and its components among people living with HIV virus using antiretroviral treatment in Hawassa, southern Ethiopia. AB - BACKGROUND: Data regarding the influences of gender in metabolic syndrome (MetS) among patients using antiretroviral treatment (ART) in Ethiopia is scarce. The aim of this study was to assess the influences of gender in MetS and its components among HIV-infected patients receiving ART. METHODS: A cross-sectional study was conducted between February 2012 and April 2013. Data on demographic, clinical and anthropometric characteristics were collected from 185 HIV patients using ART. Glucose and lipid profiles were measured from overnight fast blood. The International Diabetes Federation (IDF) and United States national cholesterol education program: adult treatment (US NCEP-ATP) panel III criteria were used to define MetS. RESULT: A total number of 185 (36.8% males and 63.2% females) participants were recruited in this study. The overall prevalence of MetS was 24.3 and 17.8%, diagnosed using IDF and NCEP-ATP criteria respectively. Using IDF criteria, MetS was significantly higher in females compared to males (33.3 vs. 8.8%; p = <0.0001) respectively. Low HDL-c and central obesity were significantly higher MetS components in female compared to males (p = 0.003); and (p = <0.0001, using IDF and NCEP-ATP criteria) respectively. BMI >25 kg/m(2) was significantly associated with MetS in both IDF and NCEP-ATP criteria: unadjusted (UOR) and adjusted odds ratio (AOR) with 95% CI were 3.0 (1.3-6.5) and 3.8 (1.5 9.8); as well as 3.2 (1.4-7.4) and 3.4 (1.4-7.4) respectively. Furthermore age >40 years was significantly associated with MetS using NCEP-ATP: UOR and AOR (95% CI) were 3.1 (1.2-8.3), and 3.8 (1-13.70) respectively. CONCLUSION: Comprehensive medical care approach including with MetS components are a crucial instruments in order to minimize the risk of developing cardiovascular diseases in HIV-infected patients using ART. PMID- 26945989 TI - Floral ultrastructure of two Brazilian aquatic-epiphytic bladderworts: Utricularia cornigera Studnicka and U. nelumbifolia Gardner (Lentibulariaceae). AB - Utricularia cornigera and Utricularia nelumbifolia are giant, aquatic-epiphytic species of carnivorous bladderwort from southeastern Brazil that grow in the central 'urns' of bromeliads. Both species have large, colourful flowers. The main aim of our study is to ascertain whether the prominent floral palate of U. cornigera and U. nelumbifolia functions as an unguentarius-i.e. an organ that bears osmophores. Floral tissues of both species were investigated using light microscopy, scanning electron microscopy, transmission electron microscopy and histochemistry. Floral palates of U. cornigera and U. nelumbifolia provide clear visual signals for pollinating insects. In both species, the palate possesses diverse micro-morphology, comprising unicellular, conical to villiform papillae and multicellular, uniseriate, glandular trichomes that frequently display terminal branching. The most characteristic ultrastructural feature of these papillae was the presence of relatively large, polymorphic plastids (chromoplasts) containing many plastoglobuli. Similar plastids are known to occur in the fragrance-producing (osmophores) and oil-producing (elaiophores) tissues of several orchid species. Thus, these palate papillae may play a key role in providing the olfactory stimulus for the attraction of insect pollinators. Nectariferous trichomes were observed in the floral spurs of both species, and in U. nelumbifolia, free nectar was also recorded. The location, micro-morphology, anatomy and ultrastructure of the floral palate of the two species investigated may thus indicate that the palate functions as an unguentarius. Furthermore, the flowers of these taxa, like those of U. reniformis, have features consistent with bee pollination. PMID- 26945988 TI - A vaccine consisting of Schistosoma mansoni cathepsin B formulated in Montanide ISA 720 VG induces high level protection against murine schistosomiasis. AB - BACKGROUND: Schistosomiasis is the most important human helminth infection due to its impact on public health. The clinical manifestations are chronic and significantly decrease an individual's quality of life. Infected individuals suffer from long-term organ pathologies including fibrosis which eventually leads to organ failure. The development of a vaccine against this parasitic disease would contribute to a long-lasting decrease in disease spectrum and transmission. METHOD: Our group has chosen Schistosoma mansoni (Sm) cathepsin B, a peptidase involved in parasite feeding, as a prospective vaccine candidate. Our experimental formulation consisted of recombinant Sm-cathepsin B formulated in Montanide ISA 720 VG, a squalene based adjuvant containing a mannide mono-oleate emulsifier. Parasitological burden was assessed by determining adult worm, hepatic egg, and intestinal egg numbers in each mouse. Serum was used in ELISAs to evaluate production of antigen-specific antibodies, and isolated splenocytes were stimulated with the antigen for the analysis of cytokine secretion levels. RESULTS: The Sm-cathepsin B and Montanide formulation conferred protection against a challenge infection by significantly reducing all forms of parasitological burdens. Worm burden, hepatic egg burden and intestinal egg burden were decreased by 60%, 6%, and 56%, respectively in immunized animals compared to controls (P = 0.0002, P < 0.0001, P = 0.0009, respectively). Immunizations with the vaccine elicited robust production of Sm-cathepsin B specific antibodies (endpoint titers = 122,880). Both antigen-specific IgG1 and IgG2c titers were observed, with the former having more elevated titers. Furthermore, splenocytes isolated from the immunized animals, compared to control animals, secreted higher levels of key Th1 cytokines, IFN-gamma, IL-12, and TNF alpha, as well as the Th2 cytokines IL-5 and IL-4 when stimulated with recombinant Sm-cathepsin B. The Th17 cytokine IL-17, the chemokine CCL5, and the growth factor GM-CSF were also significantly increased in the immunized animals compared to the controls. CONCLUSION: The formulation tested in this study was able to significantly reduce all forms of parasite burden, stimulate robust production of antigen-specific antibodies, and induce a mixed Th1/Th2 response. These results highlight the potential of Sm-cathepsin B/Montanide ISA 720 VG as a vaccine candidate against schistosomiasis. PMID- 26945990 TI - Induction of reactive oxygen species and the potential role of NADPH oxidase in hyperhydricity of garlic plantlets in vitro. AB - Hyperhydricity is a physiological disorder associated with oxidative stress. Reactive oxygen species (ROS) generation in plants is initiated by various enzymatic sources, including plasma membrane-localized nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, cell wall-bound peroxidase (POD), and apoplastic polyamine oxidase (PAO). The origin of the oxidative burst associated with hyperhydricity remains unknown. To investigate the role of NADPH oxidases, POD, and PAO in ROS production and hyperhydricity, exogenous hydrogen peroxide (H2O2) and inhibitors of each ROS-producing enzyme were applied to explore the mechanism of oxidative stress induction in garlic plantlets in vitro. A concentration of 1.5 mM H2O2 increased endogenous ROS production and hyperhydricity occurrence and enhanced the activities of NADPH oxidases, POD, and PAO. During the entire treatment period, NADPH oxidase activity increased continuously, whereas POD and PAO activities exhibited a transient increase and subsequently declined. Histochemical and cytochemical visualization demonstrated that specific inhibitors of each enzyme effectively suppressed ROS accumulation. Moreover, superoxide anion generation, H2O2 content, and hyperhydric shoot frequency in H2O2-stressed plantlets decreased significantly. The NADPH oxidase inhibitor was the most effective at suppressing superoxide anion production. The results suggested that NADPH oxidases, POD, and PAO were responsible for endogenous ROS induction. NADPH oxidase activation might play a pivotal role in the oxidative burst in garlic plantlets in vitro during hyperhydricity. PMID- 26945991 TI - Recruitment to doping and help-seeking behavior of eight female AAS users. AB - BACKGROUND: Doping with anabolic androgenic steroids in sports has now developed to a widespread use of these agents among young people outside the sport. This is of major concern to the society. The purpose of the use is mainly for aesthetic reasons and is seen as a male phenomenon. But use also occurs in women where the knowledge is scarce. Our aim was to identify the pattern of doping agents in eight female cases and compare them with similar data from men. METHODS: Eight female users were recruited through Anti-Doping Hot-Line, a national telephone counseling service on doping issues during the years 1998-2004. The use was confirmed with urine doping analysis at the Doping Laboratory. The characteristic of use, co-use of narcotics/other doping agents, exercise pattern, adverse-side effects, family history and reason to begin was evaluated. RESULTS: The women used on average 1.9 different anabolic androgenic steroids and clenbuterol preparations. Ephedrine and growth hormone were co-used in five and one of the women, respectively. Three women reported co-use of narcotics (cannabis and cocaine). The average duration of anabolic agent use before contacting health care was 58 weeks (range 7-104). Side effects for anabolic androgenic steroids (n = 5) included voice changes, clitoral enlargement, body hair growth, whereas women using clenbuterol (n = 2) reported tachycardia and depression. All women except one had a man in close relationship encouraging them to begin with the doping agents. CONCLUSIONS: The use of doping agents in our eight women was different from that in male users. The women used less doping agents and were more prone to contact the health care, at an earlier stage, probably due to the adverse effects. The co-use with ephedrine, growth hormone and cannabis appeared to be in the same range as in men. This is the first study showing that a man in close relationship may motivate a woman to use anabolic agents. PMID- 26945992 TI - DNA methylation modifies the association between obesity and survival after breast cancer diagnosis. AB - Mechanisms underlying the poor breast cancer prognosis among obese women are unresolved. DNA methylation levels are linked to obesity and to breast cancer survival. We hypothesized that obesity may work in conjunction with the epigenome to alter prognosis. Using a population-based sample of women diagnosed with first primary breast cancer, we examined modification of the obesity-mortality association by DNA methylation. In-person interviews were conducted approximately 3 months after diagnosis. Weight and height were assessed [to estimate body mass index (BMI)], and blood samples collected. Promoter methylation of 13 breast cancer-related genes was assessed in archived tumor by methylation-specific PCR and Methyl Light. Global methylation in white blood cell DNA was assessed by analysis of long interspersed elements-1 (LINE-1) and with the luminometric methylation assay (LUMA). Vital status among 1308 patients (with any methylation biomarker and complete BMI assessment) was determined after approximately 15 years of follow-up (N = 194/441 deaths due to breast cancer-specific/all-cause mortality). We used Cox proportional hazards regression to estimate hazard ratios (HRs) and 95 % confidence intervals (CIs) using two-sided p values of 0.05. Breast cancer-specific mortality was higher among obese (BMI >= 30) patients with promoter methylation in APC (HR = 2.47; 95 % CI = 1.43-4.27) and TWIST1 (HR = 4.25; 95 % CI = 1.43-12.70) in breast cancer tissue. Estimates were similar, but less pronounced, for all-cause mortality. Increased all-cause (HR = 1.81; 95 % CI = 1.19-2.74) and breast cancer-specific (HR = 2.61; 95 % CI = 1.45-4.69) mortality was observed among obese patients with the lowest LUMA levels. The poor breast cancer prognosis associated with obesity may depend on methylation profiles, which warrants further investigation. PMID- 26945993 TI - Weakly coupled oscillators in a slowly varying world. AB - We extend the theory of weakly coupled oscillators to incorporate slowly varying inputs and parameters. We employ a combination of regular perturbation and an adiabatic approximation to derive equations for the phase-difference between a pair of oscillators. We apply this to the simple Hopf oscillator and then to a biophysical model. The latter represents the behavior of a neuron that is subject to slow modulation of a muscarinic current such as would occur during transient attention through cholinergic activation. Our method extends and simplifies the recent work of Kurebayashi (Physical Review Letters, 111, 214101, 2013) to include coupling. We apply the method to an all-to-all network and show that there is a waxing and waning of synchrony of modulated neurons. PMID- 26945994 TI - TNF-alpha is upregulated in T2DM patients with fracture and promotes the apoptosis of osteoblast cells in vitro in the presence of high glucose. AB - Fracture healing is regulated by proinflammatory mediators such as tumor necrosis factor-alpha (TNF-alpha), which poses influence on the balance between bone formation and remodeling. And the diabetes is thought to contribute to the delayed diabetic fracture healing. In the present study, we examined the promotion to proinflammatory cytokines and chemokines in type 2 diabetes mellitus (T2DM) patients with bone fractures, and then evaluated the promotion to TNF alpha by the high glucose treatment in human osteoblast-like MG-63 cells and the regulatory role of the promoted TNF-alpha on the MG-63 cell apoptosis. It was demonstrated that there were significantly-upregulated high-sensitivity C reactive protein (hsCRP) TNF-alpha, IL-1beta, IL-6, IFN-gamma-inducible protein 10 (IP-10) and RANTES in T2DM patients with bone fracture. And the promotion to TNF-alpha and IL-1beta was confirmed in vitro in both mRNA and protein levels in high glucose-treated MG-63 cells. And either TNF-alpha or high glucose reduced the viability of MG-63 cells, promoted apoptosis and upregulated apoptosis associated markers, such as released cytochrome c, cleaved caspase 3 and lyzed PARP. Moreover, there was a synergistic effect between TNF-alpha and high glucose. The viability reduction and the apoptosis induction of MG-63 cells were significantly higher in the group with both TNF-alpha and high glucose treatments, than in the group with singular TNF-alpha treatment. In conclusion, our study demonstrated that proinflammatory cytokines and chemokines were promoted in T2DM patients with bone fracture or in osteoblasts by the high glucose stimulation. TNF-alpha and high glucose synergistically reduced the viability and induced the apoptosis in the osteoblast-like MG-63 cells in vitro. It implies the significant regulatory role of TNF-alpha in the delayed fracture healing in T2DM. PMID- 26945995 TI - Anticoagulants used in plasma collection affect adipokine multiplexed measurements. AB - Obesity is an important health problem worldwide. Adipose tissue acts as an endocrine organ that secretes various bioactive substances, called adipokines, including pro-inflammatory biomarkers such as TNF-alpha, IL-6, leptin and C reactive protein (CRP) and anti-inflammatory molecules such as adiponectin. The deregulated production of adipokines in obesity is linked to the pathogenesis of various disease processes and monitoring their variation is critical to understand metabolic diseases. The aim of this study was to determine the plasma concentration of adipokines in healthy subjects by multiplexed measurements and the effect of anticoagulants on their levels. Plasma samples from 10 healthy donors were collected in two different anticoagulants (sodium citrate or heparin). All markers, excluding TNF-alpha, showed significantly higher concentrations in heparinized compared to citrate plasma. However, levels of adipokines in different plasma samples were highly correlated for most of these markers. We reported that different anticoagulants used in the preparation of the plasma samples affected the measurements of some adipokines. The importance of the present results in epidemiology is relevant when comparing different studies in which blood samples were collected with different anticoagulants. PMID- 26945996 TI - Interferon alpha antagonizes STAT3 and SOCS3 signaling triggered by hepatitis C virus. AB - We aimed to investigate regulation of signal transducer and activator of transcription 3 (STAT3) and suppressor of cytokine signaling 3 (SOCS3) by interferon alpha (IFN-alpha) and to analyze the relationship between STAT3 and SOCS3 during hepatitis C virus (HCV) infection. Changes in STAT3 and SOCS3 were analyzed at both mRNA and protein levels in human hepatoma cells infected with HCV (J6/JFH1). At 72h of HCV infection, STAT3 expression was decreased with sustained phosphorylation, and IFN-alpha increased such decrease and phosphorylation. HCV increased SOCS3 expression, while IFN-alpha impaired such increase, indicating different regulation of STAT3 and SOCS3 by IFN-alpha. IFN alpha-induced expression and phosphorylation of upstream kinases of the JAK/STAT pathway, Tyk2 and Jak1, were suppressed by HCV. Moreover, knockdown of STAT3 by RNA interference led to decreases in HCV RNA replication and viral protein expression, without affecting either the expression of Tyk2 and Jak1 or the SOCS3 induction in response to IFN-alpha. These results show that IFN-alpha antagonizes STAT3 and SOCS3 signaling triggered by HCV and that STAT3 regulation correlates inversely with SOCS3 induction by IFN-alpha, which may be important in better understanding the complex interplay between IFN-alpha and signal molecules during HCV infection. PMID- 26945997 TI - Modelling the relative abundance of the primary African vectors of malaria before and after the implementation of indoor, insecticide-based vector control. AB - BACKGROUND: Malaria remains a heavy burden across sub-Saharan Africa where transmission is maintained by some of the world's most efficient vectors. Indoor insecticide-based control measures have significantly reduced transmission, yet elimination remains a distant target. Knowing the relative abundance of the primary vector species can provide transmission models with much needed information to guide targeted control measures. Moreover, understanding how existing interventions are impacting on these relative abundances highlights where alternative control (e.g., larval source management) is needed. METHODS: Using the habitat suitability probabilities generated by predictive species distribution models combined with data collated from the literature, a multinomial generalized additive model was applied to produce relative abundance estimates for Anopheles arabiensis, Anopheles funestus and Anopheles gambiae/Anopheles coluzzii. Using pre- and post-intervention abundance data, estimates of the effect of indoor insecticide-based interventions on these relative abundances were made and are illustrated in post-intervention maps. RESULTS: Conditional effect plots and relative abundance maps illustrate the individual species' predicted habitat suitability and how they interact when in sympatry. Anopheles arabiensis and An. funestus show an affinity in habitat preference at the expense of An. gambiae/An. coluzzii, whereas increasing habitat suitability for An. gambiae/An. coluzzii is conversely less suitable for An. arabiensis but has little effect on An. funestus. Indoor insecticide-based interventions had a negative impact on the relative abundance of An. funestus, and a lesser effect on An. arabiensis. Indoor residual spraying had the greatest impact on the relative abundance of An. funestus, and a lesser effect on An. gambiae/An. coluzzii. Insecticide-treated bed nets reduced the relative abundance of both species equally. These results do not indicate changes in the absolute abundance of these species, which may be reduced for all species overall. CONCLUSIONS: The maps presented here highlight the interactions between the primary vector species in sub-Saharan Africa and demonstrate that An. funestus is more susceptible to certain indoor-based insecticide interventions than An. gambiae/An. coluzzii, which in turn, is more susceptible than An. arabiensis. This may provide An. arabiensis with a competitive advantage where it is found in sympatry with other more endophilic vectors, and potentially increase the need for outdoor-based vector interventions to deal with any residual transmission barring the way to malaria elimination. PMID- 26945998 TI - Vibrational studies of flexible solid polymer electrolyte based on PCL-EC incorporated with proton conducting NH4SCN. AB - A flexible solid polymer electrolyte (SPE) system based on poly(epsilon caprolactone) (PCL), a FDA approved non-toxic and biodegradable material in the effort to lower environmental impact was prepared. Ammonium thiocyanate (NH4SCN) and ethylene carbonate (EC) were incorporated as the source of charge carriers and plasticizing agent, respectively. When 50 wt.% of ethylene carbonate (EC) was added to PCL-NH4SCN system, the conductivity increased by two orders from of 3.94 * 10(-7) Scm(-1) to 3.82 * 10(-5) Scm(-1). Molecular vibrational analysis via infrared spectroscopy had been carried out to study the interaction between EC, PCL and NH4SCN. The relative percentage of free ions, ion pairs and ion aggregates was calculated quantitatively by deconvoluting the SCN(-) stretching mode (2030-2090 cm(-1)). This study provides fundamental insight on how EC influences the free ion dissociation rate and ion mobility. The findings are also in good agreement to conductivity, differential scanning calorimetry and X-ray diffraction results. High dielectric constant value (89.8) of EC had made it an effective ion dissociation agent to dissociate both ion pairs and ion aggregates, thus contributing to higher number density of free ions. The incorporation of EC had made the polymer chains more flexible in expanding amorphous domain. This will facilitate the coupling synergy between ionic motion and polymer segmental motion. Possible new pathway through EC-NH4(+) complex sites for ions to migrate with shorter distance has been anticipated. This implies an easier ion migration route from one complex site to another. PMID- 26945999 TI - Marker-less tracking of brain surface deformations by non-rigid registration integrating surface and vessel/sulci features. AB - PURPOSE: To compensate for brain shift in image-guided neurosurgery, we propose a new non-rigid registration method that integrates surface and vessel/sulci feature to noninvasively track the brain surface. METHOD: Textured brain surfaces were acquired using phase-shift three-dimensional (3D) shape measurement, which offers 2D image pixels and their corresponding 3D points directly. Measured brain surfaces were noninvasively tracked using the proposed method by minimizing a new energy function, which is a weighted combination of 3D point corresponding estimation and surface deformation constraints. Initially, the measured surfaces were divided into featured and non-featured parts using a Frangi filter. The corresponding feature/non-feature points between intraoperative brain surfaces were estimated using the closest point algorithm. Subsequently, smoothness and rigidity constraints were introduced in the energy function for a smooth surface deformation and local surface detail conservation, respectively. Our 3D shape measurement accuracy was evaluated using 20 spheres for bias and precision errors. In addition, the proposed method was evaluated based on root mean square error (RMSE) and target registration error (TRE) with five porcine brains for which deformations were produced by gravity and pushing with different displacements in both the vertical and horizontal directions. RESULTS: The minimum and maximum bias errors were 0.32 and 0.61 mm, respectively. The minimum and maximum precision errors were 0.025 and 0.30 mm, respectively. Quantitative validation with porcine brains showed that the average RMSE and TRE were 0.1 and 0.9 mm, respectively. CONCLUSION: The proposed method appeared to be advantageous in integrating vessels/sulci feature, robust to changes in deformation magnitude and integrated feature numbers, and feasible in compensating for brain shift deformation in surgeries. PMID- 26946000 TI - Arthroscopic treatment of femoroacetabular impingement shows persistent clinical improvement in the mid-term. AB - INTRODUCTION: The concept of femoroacetabular impingement (FAI) and the indication for surgical intervention have been established in the last decade. Despite promising short-term results and emerging arthroscopic techniques, it remains unclear whether patients benefit from surgical correction in the mid- to long-term and whether progressive joint degeneration can be prevented. MATERIALS AND METHODS: A retrospective study of our first 50 consecutive patients who underwent arthroscopic correction for FAI was conducted. The modified Harris hip score (mHHS) was assessed preoperatively and at final follow-up. In addition, the Western Ontario and McMaster Universities osteoarthritis index (WOMAC) and a subjective hip value (SHV) were added at final follow-up. Degenerative changes according to Kellgren and Lawrence scale and the alpha angle were analyzed preoperatively and on the most recent radiograph. RESULTS: Of a total of 50 patients, 44 (24 male, 20 female) with a mean age of 34.3 years (17-65) were available with complete follow-up. Of these 44 patients, 39 were treated with correction of the femoral offset for isolated cam deformity, 5 with additional focal pincer correction and partial labral resection. After a mean follow-up of 66.3 +/- 14.5 months the mHHS had improved significantly from 67.2 +/- 6.4 preoperatively to 86.4 +/- 13.5 (p < 0.001). The WOMAC score (converted to 0 = best/100 = worst) resulted in mean indices for the subcategories pain, stiffness and function of 11.8 +/- 16.5, 12.2 +/- 17.8 and 9.1 +/- 16.1. The SHV was reported with a mean of 77.7 +/- 21.8 % at final follow-up. The alpha angle was reduced significantly from 57.2 degrees +/- 10.1 degrees to 46.3 degrees +/- 7.4 degrees (p < 0.001). The Kellgren and Lawrence score showed a non significant trend from 2.0 +/- 0.8 preoperatively to 2.2 +/- 0.9 in the most recent radiograph (p = 0.46). 5 patients had been converted to a total hip arthroplasty a mean of 28 +/- 7.1 months postoperatively. These patients were significantly (p < 0.01) older with a mean age of 49.8 +/- 7.8 years and showed significantly higher present osteoarthritic changes with an average Kellgren and Lawrence score of 2.6 +/- 2.5 before FAI correction (p < 0.01). CONCLUSIONS: Arthroscopic correction of femoroacetabular impingement results in a persistent clinical improvement without significant progression of degenerative changes in the majority of patients. The indication for surgery should be established cautiously when degenerative changes are present. LEVEL OF EVIDENCE: Level IV, Case series with no comparison group. PMID- 26946001 TI - Bilateral sternoclavicular joint dislocation due to sternal fracture: Is it a dislocation or a separation? AB - Traumatic bilateral sternoclavicular joint dislocation is very rare injury. In shoulder girdle injuries, anterior dislocation of the sternoclavicular joint accounts for 3 % and posterior sternoclavicular joint dislocation is lesser. Previous reported cases about bilateral sternoclavicular joint dislocation were result from proximal clavicle fracture with intact connection between sternum and ribs. But, the sternoclavicular joint dislocation secondary to fracture and angulation of the sternum with intact relationship between ribs and clavicle has not been reported. Authors experienced patient who has a bilateral anterior sternoclavicular joint dislocation caused by sternum fracture and anterior angulation, but intact relationship between ribs and clavicle. We report this case with satisfactory result. PMID- 26946002 TI - Effective prevention of recurrent dislocation following primary cemented Endo MarkIII/SP2 total hip arthroplasty using a posterior lip augmentation device. AB - PURPOSE: This retrospective study was performed to determine the effectiveness of preventing recurrent dislocation following primary cemented Endo-MarkIII/SP2 total hip replacement using a posterior lip augmentation device (PLAD). METHODS: Between January 2003 and Dezember 2006, 27 PLADs were used in the treatment of recurrent hip dislocation in 27 patients who had received a cemented primary total hip arthroplasty using Endo-MarkIII/SP2 (Waldemar LINK, Hamburg, Germany) components. The mean number of dislocations prior to stabilization with this specific device was 2.6 (range 2-4, SD +/- 0.4) with a mean time to revision surgery of 10 months (IQR 13). The mean age of the patients at time of revision surgery was 81.5 years (range 70-94, SD +/- 6.9). The control group evaluating the clinical outcome using the Harris Hip Score (HHS) also received a cemented primary total hip arthroplasty using the same implants. A retrospective clinical and radiological review was carried out at a mean follow-up of 68.5 months (range 30-103, SD +/- 17.7). RESULTS: Of the 27 patients, 6 had died at the time of the latest review, with the posterior lip augmentation device still in situ and without reported further dislocation after PLAD application. In 2 of the remaining 21 patients recurrent dislocation occurred, thus a subsequent revision of respective implants had to be performed to achieve persistent joint stability. At latest follow-up no deep infection or implant loosening occurred. CONCLUSION: Surgical treatment of recurrent dislocation following primary cemented Endo MarkIII/SP2 total hip replacement using a posterior lip augmentation device is a safe and effective procedure which can lead to a secondary stabilization of the total hip arthroplasty in about 90 % of the patients. PMID- 26946003 TI - Preparation of a nitro-substituted tris(indolyl)methane modified silica in deep eutectic solvents for solid-phase extraction of organic acids. AB - A new sorbent for solid-phase extraction was synthesized by chemical immobilization of nitro-substituted tris(indolyl)methane on silica in new and green deep eutectic solvents. Elemental analysis results indicated that deep eutectic solvents could be an alternative to the traditional solvents in preparing nitro-substituted tris(indolyl)methane modified silica. Coupled with high performance liquid chromatography, the extraction performance of the sorbent was evaluated by using four organic acids as model analytes. The rebinding experiments results showed that the nitro-substituted tris(indolyl)methane modified silica sorbent had a good adsorption capacity towards the selected organic acids. Under the appropriate experimental conditions, good precision and wide linear ranges with coefficient of determination (R(2)) of higher than 0.9957 were obtained, and the limits of detection were in the range of 0.50-2.0MUgL(-1) for the organic acids tested. The developed solid-phase extraction-high performance liquid chromatography-diode array detection (SPE-HPLC-DAD) method was successfully applied for the determination of organic acids in two drinking samples with recoveries ranging from 76.7% to 110.0% and 67.7% to 104.0% for all the selected organic acids, respectively. PMID- 26946004 TI - A ratiometric fluorescent probe for aluminum ions based-on monomer/excimer conversion and its applications to real samples. AB - Excessive amount of aluminum is detrimental to growing plants or animals and people are likely to suffer from various diseases upon long-term exposure to aluminum ions. Therefore, sensitive and selective detection of trace amounts of Al(3+) in real samples is of great importance. Herein, a ratiometric fluorescent probe for detecting aluminum ions based on pyrene-1-butyric acid (Py-L-COOH) was developed, which function via monomer/excimer conversion. In the presence of Al(3+), the original monomer-state Py-L-COOH molecules coordinate with Al(3+) and form excimer, thus changing the emission wavelength from 350-400nm to 450-500nm and achieving the ratiometric detection for Al(3+). The probe responds to Al(3+) quickly and can be operable in aqueous media with a very low detection limit of 0.29uM. This system is capable of detecting Al(3+) in real samples and shows high selectivity. Furthermore, the probe exhibits low cytotoxicity and can be used in fluorescence imaging in Hela cell lines. The approach may provide an effective simple probe for aluminum ions determination with application to real samples, as well as offering insights for designing facile ratiometric fluorescent sensors. PMID- 26946005 TI - Determination of ultra-trace amounts of silver in water by differential pulse anodic stripping voltammetry using a new modified carbon paste electrode. AB - A highly sensitive and selective new procedure for the determination of silver in aqueous media was developed using a modified carbon paste electrode (MCPE) by differential pulse anodic stripping voltammetry (DPASV). The modified electrode was based on the incorporation of 2-hydroxybenzaldehyde benzoylhydrazone (2-HBBH) in the carbon paste electrode. Silver ions were preconcentrated on the modified electrode at open-circuit by complexation with the ligand and reduced to zero valent at a potential of 0V, and followed by the reoxidation of adsorbed ions onto the electrode by scanning the potential in a positive direction. The oxidation peak of Ag(I) was observed at 0.2V (versus Ag/AgCl). The analysis of Ag(I) was carried out in a cell containing the sample solution (20mL) buffered by 0.1molL(-1) K2HPO4/NaOH at pH 5.5 in aqueous solution and nitric acid (pH 1) in real water samples. The optimum conditions for the analysis of silver include a reduction potential of 0V and a pulse amplitude of 100mV, among others. The optimum carbon paste composition was found to be 14.1% (w/w) 2-HBBH, 56.2% (w/w) graphite powder and 29.7% (w/w) paraffin oil. Differential pulse anodic stripping voltammetric response was used as the analytical signal. Under the selected conditions, the voltammetric signal was proportional to the Ag(I) concentration in the range of 0.001-100MUgL(-1) with favorable limits of detection and quantification of 1.1ngL(-1) and 3.7ngL(-1) after 3min of accumulation time, respectively. By increasing the accumulation time to 10min, detection and quantification limits can be further improved up to 0.1ngL(-1) and 0.34ngL(-1), respectively. In addition, the results showed a highly reproducible procedure showing a relative standard deviation of 1.5% for 12 replicate measurements. Many coexisting metal ions were investigated and very few interferences were found on the determination of Ag(I). The proposed method was validated using certified reference estuarine waters (SLEW-3) with a relative error of -1.3% and applied to the determination of silver ions in three river water samples collected from Guadalquivir river (relative errors of +3.4%, +1.5% and -0.7%). Moreover, the method was successfully applied to the speciation analysis of total silver, free silver ions and silver nanoparticles in aqueous solutions. The results were in good agreement with those obtained by inductively coupled plasma mass spectrometry (ICP-MS). PMID- 26946006 TI - Water dispersion of magnetic nanoparticles with selective Biofunctionality for enhanced plasmonic biosensing. AB - Magnetic nanoparticles (MNPs) are widely used in biosensing, bioimaging, and drug delivery. However, high quality superparamagnetic nanoparticles with uniform size were usually synthesized by thermal decomposition using organic solvents. To be suitable for biomedical applications, a facile and efficient water dispersion of iron oxide MNPs from solvent using an innovative agent, sodium oleate (NaOL) was described. The monodispersed MNPs (4 and 15nm respectively) after transfer was biocompatible and stable at a broad temperature range (4-50 degrees C) over months. More importantly, the NaOL coating allows for surface modification with selective functionality, rendering the aqueous MNPs highly customizable for biofunctionalization. Little effect on the superparamagnetism was observed after the water dispersion. To further evaluate its practical application in biosensing, custom MNPs were prepared for specific cardiac troponin I (cTnI) detection for myocardial infarction diagnosis. Specifically, gold nanorod (GNR) biochip was probed by the MNP-captured cTnI target analyte at varying concentrations. The signal transduction of the GNR sensor is based on the localized surface plasmon resonance (LSPR). The application of the MNPs resulted in a significant enhancement of the plasmonic response of the GNRs. As such, the MNP-mediated LSPR biosenisng showed a three times lower sensitivity as compared to the direct cTnI binding without functional MNPs. Computer simulation further elucidated that the enhancement was distance dependent between the MNP and the surface of the nanorod, which corroborated with experimental results. PMID- 26946007 TI - Plutonium determination in seawater by inductively coupled plasma mass spectrometry: A review. AB - Knowing the concentration and isotopic ratio of Pu in seawater is of critical importance for assessing Pu contamination and investigating oceanic processes. In recent decades, the concentration of (239+240)Pu in seawater, particularly for surface seawater, has presented an exponential decreasing trend with time; thus determination of Pu in seawater has become a challenge nowadays. Here, we have summarized and critically discussed a variety of reported analytical methods for Pu determination in seawater sample based on inductively coupled plasma mass spectrometry (ICP-MS) analytical technique for rapid ultra-trace detection of Pu. Generally, pretreatments for seawater sample include co-precipitation, valence adjustment and chemical separation and purification procedures, all of which are comprehensively reviewed. Overall, the selected anion-exchange, extraction resins and operation condition are important for decontamination of interference from matrix elements and achieving satisfactory chemical yields. In addition, other mass spectrometric and radiometric detections are briefly addressed and compared with the focus on assessing ICP-MS. Finally, we discuss some issues and prospects in determination and application of Pu isotopes in seawater samples for future research. PMID- 26946008 TI - Measurement of pyrethroids and their environmental degradation products in fresh fruits and vegetables using a modification of the quick easy cheap effective rugged safe (QuEChERS) method. AB - Pyrethroid insecticides are used extensively in agriculture, and they, as well as their environmental degradates, may remain as residues on foods such as fruits and vegetables. Since pyrethroid degradates can be identical to the urinary markers used in human biomonitoring, it is important to understand the contribution of these degradates when studying sources of human pyrethroid exposure. We modified the widely used Quick Easy Cheap Effective Rugged Safe (QuEChERS) method to measure several current-use pyrethroids (cis/trans permethrin, cypermethrin, deltamethrin, esfenvalerate, bifenthrin, cyfluthrin, and cyhalothrin) and their environmental degradation products (3-PBA, cis/trans DCCA, 4-F-3-PBA, DBCA, and MPA) in selected fresh fruits and vegetables. Using fortified samples, we determined extraction efficiencies from: tomatoes, oranges (whole, peeled, and rind), grapes, apples, bananas (peeled and rind only), onions, lettuce, green peppers, carrots and broccoli. For a subset of these food items (apples, grapes, tomatoes, lettuce and banana peel), we also established limits of detection (MDLs) and quantitation (MQLs). Each sample was homogenized (1kg) then spiked with the target pyrethroids and their degradation products. Sub samples (15g) were extracted with acetonitrile, then salted out and partitioned with NaCl and MgSO4. The extract was divided and further cleaned using solid phase extraction (SPE) cartridges containing either graphitized non-porous carbon (pyrethroids) or C18 (degradation products). Sample analysis was via liquid chromatography/tandem mass spectrometry (LC-MS/MS). Considering the mean recoveries each of the 14 analytes in all 13 matrices: 42% of the recoveries were >=90%, 70% were >=80%, and 90% were >=70%. All MDL's were less than 100ng/kg, except 3-PBA (132ng/kg, tomato), MPA (129ng/kg, tomato), and trans-permethrin (141ng/kg, banana peel). We then applied the method to non-spiked samples (subset of 5 for which the MDLs/MQLs had been determined) collected weekly for four weeks from local supermarkets. At least one pyrethroid was present in measureable concentrations in all matrices except banana peels. In contrast, the only degradation products detected were cis/trans-DCCA, in one lettuce sample. PMID- 26946009 TI - Multi-residue methods for the determination of over four hundred pesticides in solid and liquid high sucrose content matrices by tandem mass spectrometry coupled with gas and liquid chromatograph. AB - For the first time three methods: matrix solid phase dispersion (MSPD), original and modified QuEChERS, with and without clean up step were studied in order to evaluate the extraction efficiency of various classes of pesticides from solid and liquid high sucrose content matrices. Determinations over four hundred pesticides were performed by gas and liquid chromatography with triple quadrupole mass spectrometry (GC/LC/MS/MS) using multiple reaction monitoring. The proposed methods were validated on sugar beets and their technological product beet molasses. In general, the recoveries obtained for the original QuEChERS and MSPD method were lower (<70%) than for the modified QuEChERS without clean up in sugar beet and with clean up in beet molasses. Among these methods, high extraction yields were achieved as recommended in SANCO/12571/2013, with repeatability of 4.4-19.2% and within-laboratory reproducibility of 7.1-18.4% for citrate QuEChERS, whereas greater ruggedness were observed for MSPD. The limit of quantification (LOQ) at (the lowest MRL=0.01mgkg(-1)e.g. for oxamyl()) or below (0.005mgkg(-1)) the regulatory maximum residue level for the pesticides were achieved. The expanded measurement uncertainty was not higher than 30% for all target analytes. Matrix effects were compared and observed for both matrices at both gas and liquid chromatography. The most compounds showed signal enhancement and it was compensated by using matrix-matched calibration and modified QuEChERS characterized lower matrix effects. The confirmation of suitability citrate QuEChERS optimized method was to use for routine testing of several dozen samples determination and residue of epoxiconazole and tebuconazole (both at 0.01mgkg( 1)) in the samples of beet molasses and cyfluthrin (0.06mgkg(-1)) in sugar beet were found. PMID- 26946010 TI - A facile "turn-on" fluorescent method with high sensitivity for Hg(2+) detection using magnetic Fe3O4 nanoparticles and hybridization chain reactions. AB - In this manuscript, the authors molecularly engineered a hybridization chain reactions (HCRs) based probe on magnetic Fe3O4 nanoparticles for the sensitive detection of Hg(2+). The sensing system comprised three probes: capture probe H1, report probe H2, and report probe H3. The capture probe was modified on the surface of magnetic Fe3O4 nanoparticles. The report probes were labeled with fluorescein isothiocyanate (FITC). Without Hg(2+), the report probes were stable as molecular beacons in solution. In the presence of Hg(2+), the T-rich capture probes and report probes will hybridize into double-helical DNA domains with the aid of T-Hg(2+)-T coordination chemistry. Trigged by this reaction, more molecular beacons open and form a super tandem structure. Herein, the fluorescence signal was magnified by capturing more report probes. Separating the target and captured report probes from reaction solution was benefit to decrease the background signal and interference from other metal ions. The detection limit of this method was about 0.36nM, which is much lower than the regulations of World Health Organization and U.S. Environmental Protection Agency on Hg(2+) in drink water. This proposed sensing strategy also showed favorable selectivity over other common metal ions. In addition, it has good practicability in real water samples. PMID- 26946011 TI - A ratiometric nanosensor based on conjugated polyelectrolyte-stabilized AgNPs for ultrasensitive fluorescent and colorimetric sensing of melamine. AB - A new ratiometric nanosensor is developed for selective and ultrasensitive detection of melamine based on conjugated polyelectrolyte (CPE)-stabilized silver nanoparticles (P1-AgNPs) by perfectly combining the advantages of CPE and AgNPs. P1 featuring a pi-delocalized backbone bearing pyridinyl groups can act as an excellent dual-emission fluorescent probe as well as a polymer localizer for AgNPs. In the presence of melamine, the fluorescence intensity at 386nm increases owing to the turn-on of the fluorescence of P1, whereas FL intensity at 488nm decreases due to the melamine-induced aggregation and subsequent aggregation enhanced emission quenching of P1-AgNPs, therefore leading to the ratiometric fluorescent sensing of analyte. Moreover, analyte-induced aggregation of P1-AgNPs also allows the ratiometric colorimetric measurement of melamine. Under the optimum conditions, this facile ratiometric nanosensor favors the fluorescent and colorimetric determination of melamine in liquid milk products with the detection limit as low as 0.1 and 0.45nM, respectively. PMID- 26946012 TI - Propylene carbonate quantification by its derivative 3,5-diacetyl-1,4-dihydro-2,6 lutidine. AB - Propylene carbonate (PC) is a non-toxic solvent currently used in various pharmaceutical formulations. Consequently, a simple, cost-effective and most accurate analytical method for the quantification of this optical inert solvent is of major interest. Based on a consecutive three-step reaction 3,5-diacetyl-1,4 dihydro-2,6-lutidine was obtained from PC and used for quantification by either UV and fluorescent detection. Data were compared with results from LC-ESI-MS as a reference method. After using Mandel's test for linearity assessment of the calibration curves, linear fitting was used for LC-ESI-MS and spectrofluorimetry, while a polynomial 3rd order curve fitting was used for spectrophotometry. High intra- and inter-day precision as well as high accuracy were confirmed for all three analytical methods (spectrophotometry, spectrofluorimetry and LC-ESI-MS). The comparison of all three methods was assessed using correlation coefficients and Bland-Altman plots, both showing satisfying results with a high degree of agreement. The new method confirmed its applicability for PC quantification in two formulations, namely a PC-enriched cream and polyester microimplants. This new quantification method for PC is a reliable alternative to highly sophisticated chromatographic methods. PMID- 26946013 TI - Silver speciation and characterization of nanoparticles released from plastic food containers by single particle ICPMS. AB - Silver migration from a commercial baby feeding bottle and a food box containing AgNPs, as confirmed by SEM-EDX analysis, was evaluated using food simulant solutions [i.e., water, 3% (v/v) acetic acid, and 10% and 90% (v/v) ethanol]. Silver release was investigated at temperatures in the 20-70 degrees C range using contact times of up to 10 days. Migration of silver from the food box was in all cases 2 to 3 orders of magnitude higher than that observed for the baby bottle, although the total silver content in the original box material was half of that found in the baby bottle. As expected, for both food containers, silver migration depended on both the nature of the tested solution and the applied conditions. The highest release was observed for 3% acetic acid at 70 degrees C for 2h, corresponding to 62ngdm(2) and 1887ngdm(-2) of silver for the baby bottle and the food box, respectively. Single particle-inductively coupled plasma mass spectrometry (SP-ICPMS) was used to characterise and quantify AgNPs in the food simulants extracts. Sample preparation was optimized to preserve AgNPs integrity. The experimental parameters affecting AgNPs detection, sizing and quantification by SP-ICPMS were also optimised. Analyses of water and acidic extracts revealed the presence of both dissolved silver and AgNPs. Small AgNPs (in the 18-30nm range) and particle number concentrations within the 4-1510 10(6)L(-1) range were detected, corresponding to only 0.1-8.6% of the total silver released from these materials. The only exception was AgNPs migrated into water at 40 degrees C and 70 degrees C from the food box, which accounted for as much as 34% and 69% of the total silver content, respectively. PMID- 26946014 TI - In-situ suspended aggregate microextraction of gold nanoparticles from water samples and determination by electrothermal atomic absorption spectrometry. AB - This work describes a new method for the extraction and determination of gold nanoparticles in environmental samples by means of in-situ suspended aggregate microextraction and electrothermal atomic absorption spectrometry. The method relies on the in-situ formation of a supramolecular aggregate phase through ion association between a cationic surfactant and a benzene sulfonic acid derivative. Gold nanoparticles are physically entrapped into the aggregate phase which is separated from the bulk aqueous solution by vacuum filtration on the surface of a cellulose filter in the form of a thin film. The film is removed from the filter surface and is dissociated into an acidified methanolic solution which is used for analysis. Under the optimized experimental conditions, gold nanoparticles can be efficiently extracted from water samples with recovery rates between 81.0 93.3%, precision 5.4-12.0% and detection limits as low as 75femtomolL(-1) using only 20mL of sample volume. The satisfactory analytical features of the method along with the simplicity indicate the efficiency of this new approach to adequately collect and extract gold nanoparticle species from water samples. PMID- 26946015 TI - Fluorescent carbon quantum dot hydrogels for direct determination of silver ions. AB - The paper reports for the first time the direct determination of silver ion (Ag(+)) using luminescent Carbon Quantum Dot hydrogels (CQDGs). Carbon Quantum Dots (CQDs) with different superficial moieties (passivate-CQDs with carboxylic groups, thiol-CQDs and amine-CQDs) were used to prepare hybrid gels using a low molecular weight hydrogelator (LMWG). The use of the gels results in considerable fluorescence enhancement and also markedly influences selectivity. The most selective CQDG system for Ag(+) ion detection proved to be those containing carboxylic groups onto their surface. The selectivity towards Ag(+) ions is possibly due to its flexible coordination sphere compared with other metal ions. This fluorescent sensing platform is based on the strong Ag-O interaction which can quench the photoluminescence of passivate-CQDs (p-CQDs) through charge transfer. The limit of detection (LOD) and quantification (LOQ) of the proposed method were 0.55 and 1.83ugmL(-1), respectively, being applied in river water samples. PMID- 26946017 TI - Direct determination of creatinine based on poly(ethyleneimine)/phosphotungstic acid multilayer modified electrode. AB - In this work, the direct determination of creatinine was achieved using a poly(ethyleneimine)/phosphotungstic acid multilayer modified electrode with the assistance of Copper(II) ions by cyclic voltammetry. The quantity of creatinine were determined by measuring the redox peak current of Cu(II)-creatinine complex/Cu(I)-creatinine complex. Factors affecting the response current of creatinine at the modified electrode were optimized. A linear relationship between the response current and the concentration of creatinine ranging from 0.125 to 62.5MUM was obtained with a detection limit of 0.06MUM. The proposed method was applied to determine creatinine in human urine, and satisfied results were gotten which was validated in accordance with high performance liquid chromatography. The proposed electrode provided a promising alternative in routine sensing for creatinine without enzymatic assistance. PMID- 26946018 TI - A omega-mercaptoundecylphosphonic acid chemically modified gold electrode for uranium determination in waters in presence of organic matter. AB - A chemically modified electrode (CME) on a gold surface assembled with a omega phosphonic acid terminated thiol was investigated for its capability to complex uranyl ions. The electrode, characterized by electrochemical techniques, demonstrated to be effective for the determination of uranyl at sub-MUgL(-1) level by differential pulse adsorptive stripping voltammetry (DPAdSV) in environmental waters, also in presence of humic matter and other potential chelating agents. The accuracy of the measurements was investigated employing as model probes ligands of different complexing capability (humic acids and EDTA). PMID- 26946016 TI - D-penicillamine-templated copper nanoparticles via ascorbic acid reduction as a mercury ion sensor. AB - Mercury ion is one of the most hazardous metal pollutants that can cause deleterious effects on human health and the environment even at low concentrations. It is necessary to develop new mercury detection methods with high sensitivity, specificity and rapidity. In this study, a novel and green strategy for synthesizing D-penicillamine-capped copper nanoparticles (DPA-CuNPs) was successfully established by a chemical reduction method, in which D penicillamine and ascorbic acid were used as stabilizing agent and reducing agent, respectively. The as-prepared DPA-CuNPs showed strong red fluorescence and had a large Stoke's shift (270nm). Scanning electron microscopy, transmission electron microscopy, Fourier-transform infrared spectroscopy, fluorescence spectroscopy, and ultraviolet-visible spectrophotometry were utilized to elucidate the possible fluorescence mechanism, which could be aggregation-induced emission effect. Based on the phenomenon that trace mercury ion can disperse the aggregated DPA-CuNPs, resulting in great fluorescence quench of the system, a sensitive and selective assay for mercury ion in aqueous solution with the DPA CuNPs was developed. Under optimum conditions, this assay can be applied to the quantification of Hg(2+) in the 1.0-30MUM concentration range and the detection limit (3sigma/slope) is 32nM. The method was successfully applied to determine Hg(2+) in real water samples. PMID- 26946019 TI - Microfluidic generation of magnetic-fluorescent Janus microparticles for biomolecular detection. AB - Fluorescent magnetic multifunctional microparticles were fabricated by a facile droplet microfluidic strategy. Two sodium alginate streams, one doped with Fe3O4 nanoparticles (NPs) and the other with CdSe/ZnS quantum dots, were introduced into a flow-focusing channel as a type of parallel laminar flow to form droplets containing two distinct parts. Then, at the serpentine channel, the Ca(2+) in the oil phase diffused into the droplets, causing the solidification of the droplets. Thus, the Janus microparticles with excellent magnetic/fluorescent properties formed. The flow conditions were optimized and the effects of the flow rates on magnetic/fluorescent compositions were carefully investigated. Luminescent labeling and magnetic separation were simultaneously realized with the newly designed microparticles. Moreover, spatial separation between Fe3O4 NPs and QDs prevented the interference of QDs photoluminescence by the magnetic particles. The as-prepared fluorescent magnetic Janus particles were also successfully employed for DNA assay, which demonstrated the potential of the multifunctional microbeads in biological applications. PMID- 26946020 TI - Matrix effects of calcium on high-precision sulfur isotope measurement by multiple-collector inductively coupled plasma mass spectrometry. AB - Multiple-collector inductively coupled plasma mass spectrometry (MC-ICP-MS) has been successfully applied in the rapid and high-precision measurement for sulfur isotope ratios in recent years. During the measurement, the presence of matrix elements would affect the instrumental mass bias for sulfur and these matrix induced effects have aroused a lot of researchers' interest. However, these studies have placed more weight on highlighting the necessity for their proposed correction protocols (e.g., chemical purification and matrix-matching) while less attention on the key property of the matrix element gives rise to the matrix effects. In this study, four groups of sulfate solutions, which have different concentrations of sulfur (0.05-0.60mM) but a constant sequence of atomic calcium/sulfur ratios (0.1-50), are investigated under wet (solution) and dry (desolvation) plasma conditions to make a detailed evaluation on the matrix effects from calcium on sulfur isotope measurement. Based on a series of comparative analyses, we indicated that, the matrix effects of calcium on both measured sulfur isotope ratios and detected (32)S signal intensities are dependent mainly on the absolute calcium concentration rather than its relative concentration ratio to sulfur (i.e., atomic calcium/sulfur ratio). Also, for the same group of samples, the matrix effects of calcium under dry plasma condition are much more significant than that of wet plasma. This research affords the opportunity to realize direct and relatively precise sulfur isotope measurement for evaporite gypsum, and further provides some suggestions with regard to sulfur isotope analytical protocols for sedimentary pore water. PMID- 26946021 TI - Strategies for the development of an electrochemical bioassay for TNF-alpha detection by using a non-immunoglobulin bioreceptor. AB - TNF-alpha is an inflammatory cytokine produced by the immune system. Serum TNF alpha level is elevated in some pathological states such as septic shock, graft rejection, HIV infection, neurodegenerative diseases, rheumatoid arthritis and cancer. Detecting trace amount of TNF-alpha is, also, very important for the understanding of tumor biological processes. Detection of this key biomarker is commonly achieved by use of ELISA or cytofluorimetric based methods. In this study the traditional optical detection was replaced by differential pulse voltammetry (DPV) and an affinity molecule, produced by evolutionary approaches, has been tested as capture bioreceptor. This molecule, namely a combinatorial non immunoglobulin protein (Affibody(r)) interacts with TNF-alpha selectively and was here tested in a sandwich assay format. Moreover magnetic beads were used as support for bioreceptor immobilization and screen printed carbon electrodes were used as transducers. TNF-alpha calibration curve was performed, obtaining the detection limit of 38pg/mL, the quantification range of 76-5000pg/mL and RSD%=7. Preliminary results of serum samples analysis were also reported. PMID- 26946023 TI - Advances in the analysis of iminocyclitols: Methods, sources and bioavailability. AB - Iminocyclitols are chemically and metabolically stable, naturally occurring sugar mimetics. Their biological activities make them interesting and extremely promising as both drug leads and functional food ingredients. The first iminocyclitols were discovered using preparative isolation and purification methods followed by chemical characterization using nuclear magnetic resonance spectroscopy. In addition to this classical approach, gas and liquid chromatography coupled to mass spectrometry are increasingly used; they are highly sensitive techniques capable of detecting minute amounts of analytes in a broad spectrum of sources after only minimal sample preparation. These techniques have been applied to identify new iminocyclitols in plants, microorganisms and synthetic mixtures. The separation of iminocyclitol mixtures by chromatography is particularly difficult however, as the most commonly used matrices have very low selectivity for these highly hydrophilic structurally similar molecules. This review critically summarizes recent advances in the analysis of iminocyclitols from plant sources and findings regarding their quantification in dietary supplements and foodstuffs, as well as in biological fluids and organs, from bioavailability studies. PMID- 26946022 TI - Derivatization of estrogens enhances specificity and sensitivity of analysis of human plasma and serum by liquid chromatography tandem mass spectrometry. AB - Estrogens circulate at concentrations less than 20pg/mL in men and postmenopausal women, presenting analytical challenges. Quantitation by immunoassay is unreliable at these low concentrations. Liquid chromatography tandem mass spectrometry (LC-MS/MS) offers greater specificity and sometimes greater sensitivity, but ionization of estrogens is inefficient. Introduction of charged moieties may enhance ionization, but many such derivatives of estrogens generate non-specific product ions originating from the "reagent" group. Therefore an approach generating derivatives with product ions specific to individual estrogens was sought. Estrogens were extracted from human plasma and serum using solid phase extraction and derivatized using 2-fluoro-1-methylpyridinium-p toluenesulfonate (FMP-TS). Electrospray in positive mode with multiple reaction monitoring using a QTrap 5500 mass spectrometer was used to quantify "FMP" derivatives of estrogens, following LC separation. Transitions for the FMP derivatives of estrone (E1) and estradiol (E2) were compound specific (m/z 362 >238 and m/z 364->128, respectively). The limits of detection and quantitation were 0.2pg on-column and the method was linear from 1-400pg/sample. Measures of intra- and inter-assay variability, precision and accuracy were acceptable (<20%). The derivatives were stable over 24h at 10 degrees C (7-9% degradation). Using this approach, E1 and E2, respectively were detected in human plasma and serum: pre-menopausal female serum (0.5mL) 135-473, 193-722pmol/L; male plasma (1mL) 25-111, 60-180pmol/L and post-menopausal female plasma (2mL), 22-78, 29 50pmol/L. Thus FMP derivatization, in conjunction with LC-MS/MS, is suitable for quantitative analysis of estrogens in low abundance in plasma and serum, offering advantages in specificity over immunoassay and existing MS techniques. PMID- 26946024 TI - Hypercrosslinked strong cation-exchange polymers for selective extraction of serum purine metabolites associated with gout. AB - In this study, hypercrosslinked strong cation-exchange polymer resins (HXLPP-SCX) were synthesized and employed as selective sorbents for the solid-phase extraction (SPE) of basic purine metabolites associated with gout. The HXLPP-SCX material was prepared based on hypercrosslinking reactions and sulfonated with concentrated H2SO4. This synthetic procedure is facile and efficient without using highly toxic reagent. The resulting resins were characterized in the form of monodisperse microspheres (mean diameters of 3-5MUm) with narrow pore size (2.1nm) and relatively high specific surface areas (801m(2)/g). The polymers also possess high ion-exchange capacity (IEC, 2.22mmol/g) and good adsorption and selectivity performances for basic compounds. The resins used as SPE sorbents permit the selective enrichment of three pivotal purine metabolites (hypoxanthine, xanthine and inosine) in human serum followed by HPLC analysis. Method validation including linearity range, sensitivity, accuracy and reproducibility were evaluated. This method was exemplarily applied in the analysis of serum purines in gout patients and healthy controls. The present results demonstrate a promising potential of this HXLPP-SCX material for the clinical sample pretreatment. PMID- 26946025 TI - Can matrix solid phase dispersion (MSPD) be more simplified? Application of solventless MSPD sample preparation method for GC-MS and GC-FID analysis of plant essential oil components. AB - This paper proposes and shows the analytical capabilities of a new variant of matrix solid phase dispersion (MSPD) with the solventless blending step in the chromatographic analysis of plant volatiles. The obtained results prove that the use of a solvent is redundant as the sorption ability of the octadecyl brush is sufficient for quantitative retention of volatiles from 9 plants differing in their essential oil composition. The extraction efficiency of the proposed simplified MSPD method is equivalent to the efficiency of the commonly applied variant of MSPD with the organic dispersing liquid and pressurized liquid extraction, which is a much more complex, technically advanced and highly efficient technique of plant extraction. The equivalency of these methods is confirmed by the variance analysis. The proposed solventless MSPD method is precise, accurate, and reproducible. The recovery of essential oil components estimated by the MSPD method exceeds 98%, which is satisfactory for analytical purposes. PMID- 26946026 TI - Detection of melamine in milk powders using near-infrared hyperspectral imaging combined with regression coefficient of partial least square regression model. AB - Illegal use of nitrogen-rich melamine (C3H6N6) to boost perceived protein content of food products such as milk, infant formula, frozen yogurt, pet food, biscuits, and coffee drinks has caused serious food safety problems. Conventional methods to detect melamine in foods, such as Enzyme-linked immunosorbent assay (ELISA), High-performance liquid chromatography (HPLC), and Gas chromatography-mass spectrometry (GC-MS), are sensitive but they are time-consuming, expensive, and labor-intensive. In this research, near-infrared (NIR) hyperspectral imaging technique combined with regression coefficient of partial least squares regression (PLSR) model was used to detect melamine particles in milk powders easily and quickly. NIR hyperspectral reflectance imaging data in the spectral range of 990-1700nm were acquired from melamine-milk powder mixture samples prepared at various concentrations ranging from 0.02% to 1%. PLSR models were developed to correlate the spectral data (independent variables) with melamine concentration (dependent variables) in melamine-milk powder mixture samples. PLSR models applying various pretreatment methods were used to reconstruct the two dimensional PLS images. PLS images were converted to the binary images to detect the suspected melamine pixels in milk powder. As the melamine concentration was increased, the numbers of suspected melamine pixels of binary images were also increased. These results suggested that NIR hyperspectral imaging technique and the PLSR model can be regarded as an effective tool to detect melamine particles in milk powders. PMID- 26946027 TI - A rapid method for the identification of nitrocellulose in high explosives and smokeless powders using GC-EI-MS. AB - Nitrocellulose (NC) is one of the most common ingredients in explosive mixtures, however because of its non-volatility, its detection using Gas Chromatography Electron Ionization-Mass Spectrometry (GC-EI-MS) has not been achieved until today. A rapid method for the identification of NC in bulk explosives using GC-EI MS was developed. The sample preparation is simple and takes place in a test tube, employing standard equipment of a forensics laboratory. The protocol was optimized and applied to seven, both high and low, commercial explosives, which contained the substance of interest. Moreover, three explosives in the absence of NC were tested to cross check for false positives. Fourteen different standard explosive substances that are usually found in explosive mixtures were then employed in order to monitor the effect of the method on these compounds and check for interferences. Results showed that NC was detected, by its trimethylsilyl (TMS) derivatives, in all the explosive mixtures analyzed and no false positives were observed. The proposed method showed selectivity for NC, as it had no interference coming from other ingredients of explosive mixtures. The protocol introduced offers considerable improvement in identifying the individual components of an explosive mixture and contributes in successful classification of explosives. PMID- 26946028 TI - New method for the determination of metolachlor and buprofezin in natural water using orthophthalaldehyde by thermochemically-induced fluorescence derivatization (TIFD). AB - Herbicide metolachlor (MET) and insecticide buprofezin (BUP) were determined in natural waters by means of a newly-developed, simple and sensitive thermochemically-induced fluorescence derivatization (TIFD) method. The TIFD approach is based on the thermolysis transformation of naturally non-fluorescent pesticides into fluorescent complex O-phthalaldehyde-thermoproduct(s) in water at 70 degrees C for MET and at 80 degrees C for BUP. The TIFD method was optimized with respect to the temperature, pH, complex formation kinetic and pesticides concentrations. The limit of detection (LOD=0.8ngmL(-1) for MET and 3.0ngmL(-1) for BUP) and quantification (LOQ=2.6ngmL(-1) for MET and 9.5 ngmL(-1) for BUP) values were low, and the relative standard deviation (RSD) values were small (between 1.2% and 1.8%), which indicates a good analytical sensitivity and a great repeatability of TIFD method. Recovery studies were performed on spiked well, sea and draining waters samples collected in the Niayes area by using the solid phase extraction (SPE) procedure. Satisfactory recovery results (84-118%) were obtained for the determination of MET and BUP in these natural waters. PMID- 26946029 TI - Facile electrochemical determination of tetrabromobisphenol A based on modified glassy carbon electrode. AB - In this study, surface-functionalized nitrogen-doped graphene was prepared with 1, 3, 6, 8-pyrenetetrasulfonic acid tetrasodium salt in a simple way. The characteristics of the material were demonstrated by UV-vis absorption spectra, X ray photoelectron spectroscopy, and electrochemical experiments. Then, the glassy carbon electrode was modified by the functionalized nitrogen-doped graphene and hexadecyltrimethylammonium bromide for tetrabromobisphenol A (TBBPA) determination. The oxidation current response of TBBPA was enhanced at the modified electrode and the mechanism was investigated. Upon the optimization of assay parameters, including pH value, accumulation potential and time, the oxidation current was linearly related to the concentration of TBBPA in the range of 0.01-1MUM with a detection limit of 9nM. Moreover, the modified electrode was applied to detect TBBPA in water samples with simple, low cost, and high efficiency. PMID- 26946030 TI - Use of oleic-acid functionalized nanoparticles for the magnetic solid-phase microextraction of alkylphenols in fruit juices using liquid chromatography tandem mass spectrometry. AB - Magnetic nanoparticles of cobalt ferrite with oleic acid as the surfactant (CoFe2O4/oleic acid) were used as sorbent material for the determination of alkylphenols in fruit juices. High sensitivity and specificity were achieved by liquid chromatography and detection using both diode-array (DAD) and electrospray ion trap-tandem mass spectrometry (ESI-IT-MS/MS) in the selected reaction monitoring (SRM) mode of the negative fragment ions for alkylphenols (APs) and in positive mode for ethoxylate APs (APEOs). The optimized conditions for the different variables influencing the magnetic separation procedure were: mass of magnetic nanoparticles, 50mg, juice volume, 10mL diluted to 25mL with water, pH 6, stirring for 10min at room temperature, separation with an external neodymium magnet, desorption with 3mL of methanol and orbital shaking for 5min. The enriched organic phase was evaporated and reconstituted with 100uL acetonitrile before injecting 30uL into a liquid chromatograph with a mobile phase composed of acetonitrile/0.1% (v/v) formic acid under gradient elution. Quantification limits were in the range 3.6 to 125ngmL(-1). The recoveries obtained were in the 91-119% range, with RSDs lower than 14%. The ESI-MS/MS spectra permitted the correct identification of both APs and APEOs in the fruit juice samples. PMID- 26946032 TI - Determination of cobalt in low-alloy steels using laser-induced breakdown spectroscopy combined with laser-induced fluorescence. AB - Cobalt element plays an important role for the properties of magnetism and thermology in steels. In this work, laser-induced breakdown spectroscopy combined with laser-induced fluorescence (LIBS-LIF) was studied to selectively enhance the intensities of Co lines. Two states of Co atoms were resonantly excited by a wavelength-tunable laser. LIBS-LIF with ground-state atom excitation (LIBS-LIFG) and LIBS-LIF with excited-state atom excitation (LIBS-LIFE) were compared. The results show that LIBS-LIFG has analytical performance with LoD of 0.82MUg/g, R(2) of 0.982, RMSECV of 86MUg/g, and RE of 9.27%, which are much better than conventional LIBS and LIBS-LIFE. This work provided LIBS-LIFG as a capable approach for determining trace Co element in the steel industry. PMID- 26946031 TI - Rapid, automated online SPE-LC-QTRAP-MS/MS method for the simultaneous analysis of 14 phthalate metabolites and 5 bisphenol analogues in human urine. AB - Phthalates and bisphenol A (BPA) have received special attention in recent years due to their frequent use in consumer products and potential for adverse effects on human health. BPA is being replaced with a number of alternatives, including bisphenol S, bisphenol B, bisphenol F and bisphenol AF. These bisphenol analogues have similar potential for adverse health effects, but studies on human exposure are limited. Accurate measurement of multiple contaminants is important for estimating exposure. This paper describes a sensitive and automated method for the simultaneous determination of 14 phthalate metabolites, BPA and four bisphenol analogues in urine using online solid phase extraction coupled with high-performance liquid chromatography/tandem mass spectrometry using a hybrid triple-quadrupole linear ion trap mass spectrometer (LC-QTRAP-MS/MS), requiring very little sample volume (50uL). Quantification was performed under selected reaction monitoring (SRM) mode with negative electrospray ionization. The use of SRM combined with an enhanced product ion scan within the same analysis was examined. Unequivocal identification was provided by the acquisition of three SRM transitions per compound and isotope dilution. The analytical performance of the method was evaluated in synthetic and human urine. Linearity of response over three orders of magnitude was demonstrated for all of the compounds (R(2)>0.99), with method detection limits of 0.01-0.5ng/mL and limits of reporting of 0.07 3.1ng/mL. Accuracy ranged from 93% to 113% and inter- and intra-day precision were <22%. Finally, the validated method has been successfully applied to a cohort of pregnant women to measure biomarker concentrations of phthalates and bisphenols, with median concentrations ranging from 0.3ng/mL (bisphenol S) to 18.5ng/mL (monoethyl phthalate). PMID- 26946033 TI - A non-derivative method for the quantitative analysis of isosteroidal alkaloids from Fritillaria by high performance liquid chromatography combined with charged aerosol detection. AB - A non-derivative method was developed for the qualitative and quantitative analysis of isosteroidal alkaloids from Fritillaria thunbergii. During method development the performance of two universal detectors, the charged aerosol detector (CAD) and evaporative light scattering detector (ELSD), were evaluated. The CAD was found to be 30 to 55 times more sensitive than ELSD enabling the measurement of low levels of reference compound impurities that could not be detected by ELSD. The peak area percent of the reference compound, peimisine, obtained by CAD was 50.10%, but 91.66% by ELSD showing that CAD is suitable to estimate the presence of impurities. The CAD showed good reproducibility with overall intra- and inter-day peak area RSD values of less than 1.8% and 2.7%, respectively and had a linear dynamic range of up to 4 orders of magnitude (0.06 44mg/L) for peimine and peiminine. The optimized method was used for the quantitative analysis of peimine and peiminine from F. thunbergii. PMID- 26946035 TI - Erratum to: Intraluminal measurement of papillary duct urine pH, in vivo: a pilot study in the swine kidney. PMID- 26946036 TI - Case of Barrett's adenocarcinoma with marked endoscopic morphological changes in Barrett's esophagus over a long follow-up period of 15 years. AB - The natural history of Barrett's esophagus (BE) is unclear. We herein describe a case of Barrett's adenocarcinoma (BAC) in which we could closely observe marked morphological changes in BE over a long follow-up period of 15 years. A man in his seventies received routine esophagogastroduodenoscopy (EGD) and was diagnosed as having reflux esophagitis and short-segment BE. The BE gradually became elongated, and BAC was detected 9 years following the initial EGD examination with continued administration of a proton pump inhibitor. We witnessed that BE elongated sporadically over time and mucosal breaks of reflux esophagitis were detectable several years before elongation. The patient underwent endoscopic submucosal dissection for BAC and has been monitored by EGD every year thereafter. These remarkable morphological changes may be representative of the natural history of BE and aid in deciding long-term disease management. PMID- 26946034 TI - Mechanistically Dissecting Autophagy: Insights from In Vitro Reconstitution. AB - Autophagy is a fundamental cellular mechanism responsible for bulk turnover of cytoplasmic components. It is broadly related to many cellular activities, physiological processes, and pathological conditions. Autophagy entails a spatiotemporal interaction between cytosolic factors and membranes that are remodeled to encapsulate autophagic cargo within an autophagosome. Although majority of the factors [autophagy-related gene (Atg) proteins] involved in autophagy have been identified by genetic studies, the mechanism accounting for how these factors act upon the membrane to remodel it and efficiently recruit cargo for degradation is unclear. In vitro reconstitution of several different aspects of autophagy has provided important insights into the understanding of the mechanistic details underlying autophagic membrane remodeling and cargo recruitment. Here, we highlight these efforts toward studying autophagy through in vitro approaches. PMID- 26946037 TI - Associations of body mass index with cancer incidence among populations, genders, and menopausal status: A systematic review and meta-analysis. AB - In order to further reveal the differences of association between body mass index (BMI) and cancer incidence across populations, genders, and menopausal status, we performed comprehensive meta-analysis with eligible citations. The risk ratio (RR) of incidence at 10 different cancer sites (per 5kg/m(2) increase in BMI) were quantified separately by employing generalized least-squares to estimate trends, and combined by meta-analyses. We observed significantly stronger association between increased BMI and breast cancer incidence in the Asia-Pacific group (RR 1.18:1.11-1.26) than in European-Australian (1.05:1.00-1.09) and North American group (1.06:1.03-1.08) (meta-regression p<0.05). No association between increased BMI and pancreatic cancer incidence (0.94:0.71-1.24) was shown in the Asia-Pacific group (meta-regression p<0.05), whereas positive associations were found in other two groups. A significantly higher RR in men was found for colorectal cancer in comparison with women (meta-regression p<0.05). Compared with postmenopausal women, premenopausal women displayed significantly higher RR for ovarian cancer (pre- vs. post-=1.10 vs. 1.01, meta-regression p<0.05), but lower RR for breast cancer (pre- vs. post-=0.99 vs. 1.11, meta-regression p<0.0001). Our results indicate that overweight or obesity is a strong risk factor of cancer incidence at several cancer sites. Genders, populations, and menopausal status are important factors effecting the association between obesity and cancer incidence for certain cancer types. PMID- 26946039 TI - Unprecedented Demonstration of Regioselective SE Ar Reaction giving Unsymmetrical Regioregular Oligothiophenes. AB - Aromatization of 4-cyano-3-oxotetrahydrothiophene by sulfuryl chloride gives the new building block 4-cyano-3-pyrrolidylthiophene, which forms unsymmetrical regioregular oligothiophenes with a strict alternation of the donor and acceptor groups along the conjugated system. The self-coupling reactions that form the oligomers are shown to proceed by a regioselective electrophilic aromatic substitution mechanism involving a stabilized Wheland intermediate. PMID- 26946038 TI - RNA sequencing to characterize transcriptional changes of sexual maturation and mating in the female oriental fruit fly Bactrocera dorsalis. AB - BACKGROUND: Female reproductive potential plays a significant role in the survival and stability of species, and sexual maturation and mating processes are crucial. However, our knowledge of the reproductive genes involved in sexual maturation and mating has been largely limited to model organisms. The oriental fruit fly Bactrocera dorsalis is a highly invasive agricultural pest, known to cause major economic losses; thus, it is of great value to understand the transcriptional changes involved in sexual maturation and mating processes as well as the related genes. Here, we used a high-throughput sequencing method to identify multiple genes potentially involved in sexual maturation and mating in female B. dorsalis. RESULTS: We sequenced 39,999 unique genes with an average length of 883 bp. In total, 3264 differentially expressed genes (DEGs) were detected between mature virgin and immature Bactrocera dorsalis libraries, whereas only 83 DEGs were identified between flies that had mated or were mature virgins. These DEGs were functionally annotated using the GO and KEGG pathway annotation tools. Results showed that the main GO terms associated with the DEGs from the mature virgin vs. immature groups were primarily assigned to the metabolic and developmental processes, which we focused on, whereas those from the mated vs. mature virgin group largely belonged to the response to stimulus and immune system processes. Additionally, we identified multiple DEGs during sexual maturation that are involved in reproduction, and expression pattern analysis revealed that the majority DEGs detected were highly enriched in those linked to the ovaries or fat bodies. Several mating responsive genes differentially expressed after mating were also identified, and all antimicrobial peptides detected were highly enriched in fat body and significantly up-regulated approximately 2- to 10-fold at 24 h after mating. CONCLUSION: This study supplied female reproductive genes involved in sexual maturation and the post-mating response in B. dorsalis, based on RNA-seq. Our data will facilitate molecular research related to reproduction and provide abundant target genes for effective control of this agricultural pest. PMID- 26946040 TI - Reporting of core items in hierarchical Bayesian analysis for aggregating N-of-1 trials to estimate population treatment effects is suboptimal. AB - OBJECTIVES: N-of-1 trials can be aggregated to estimate population treatment effects using hierarchical Bayesian models. It is very important to report core items in hierarchical Bayesian analysis. In this study, we assessed reporting of items in hierarchical Bayesian analysis for aggregating N-of-1 trials to estimate population treatment effects. STUDY DESIGN AND SETTING: This was a systematic literature review of aggregating N-of-1 trials by hierarchical Bayesian models to estimate population treatment effects. A comprehensive search was performed to collect eligible articles. Pilot studies, formal N-of-1 trials and reports in which the data were reanalyzed using hierarchical Bayesian methods, were included. The information of reported items related with hierarchical Bayesian analysis was extracted by two independent reviewers. The guideline "ROBUST," developed for reporting Bayesian analysis of clinical studies, was published in Journal of Clinical Epidemiology in 2005. We assessed the included reports using ROBUST criteria and 18 other important items. RESULTS: After careful screening, 11 studies were identified to be eligible for inclusion. There were three pilot studies, four formal trials, and four reports in which the data were reanalyzed using hierarchical Bayesian methods. The number of reported items in ROBUST criteria ranged from six to seven, with a median number of six. Five of eleven included articles reported all items of the ROBUST criteria. But for justification and sensitivity analysis in prior distribution items, other items were reported in all of the included articles. Software and analysis data set items were reported the most frequently in additional items excluded from the ROBUST criteria. Less than half of the studies reported the other additional items. CONCLUSION: Reporting of core items in hierarchical Bayesian analysis for aggregating N-of-1 trials to estimate population treatment effects is suboptimal. A PRISMA-like guidance on reviews of Bayesian N-of-1 trials may be required in the future. PMID- 26946041 TI - Regional circulatory distribution of novel cardiac bio-markers and their relationships with haemodynamic measurements. AB - BACKGROUND: Regional sampling may identify sites of production or removal of novel biomarkers in the circulation; their relationship to haemodynamic measurements may clarify their association with the pathophysiology of heart failure. METHODS: Samples were obtained from up to eight circulatory sites from 22 patients with left ventricular dysfunction undergoing elective cardiac catheterisation. The plasma concentrations (PC) of six biomarkers [mid-regional pro-atrial natriuretic peptide (MR-proANP), C-terminal pro-endothelin-1 (CT-proET 1), mid-regional pro-adreno-medullin (MR-proADM), high sensitivity pro-calcitonin (hsPCT), copeptin and galectin-3 (Gal-3)] were measured. RESULTS: Plasma concentrations of MR-proANP were highest in the pulmonary artery (PA) and left ventricle, suggesting myocardial production. Lower concentrations of copeptin, CT proET-1, MR-proADM and hsPCT were found in the supra-renal inferior vena cava (SRIVC) sample suggesting renal extraction. Plasma concentrations of Galectin-3 varied little by sampling site. Plasma concentrations of MR-proANP (R=0.69, P=0.002), MR-proADM (R=0.51, P=0.03), CT-proET-1 (R=0.60, P=0.009) and Copeptin (R=0.47, P<0.05) measured from PA samples correlated with PA systolic pressure. There was no relation between any measured marker and cardiac index. CONCLUSIONS: Regional sampling shows variation in the plasma concentration of various novel peptides that provides clues to sites of net production and removal. Plasma concentrations of several biomarkers were positively correlated with pulmonary artery pressure. PMID- 26946042 TI - Electrocardiographic changes in patients >= 100 years of age. PMID- 26946043 TI - Left atrial dilation in patients with heart failure and preserved ejection fraction: Insights from cardiovascular magnetic resonance. PMID- 26946046 TI - Simultaneous dynamic R2 R2', and R2* measurement using periodic pi pulse shifting multiecho asymmetric spin echo sequence moving estimation strategy: A feasibility study for lower extremity muscle. AB - PURPOSE: The purpose of this study was to demonstrate the feasibility of simultaneous dynamic R2 , R2', and R2* measurement of lower extremity muscle by means of a new method in which the periodic pi pulse shifting multiecho asymmetric spin echo (psMASE) sequence is adopted together with a moving estimation (ME) strategy. THEORY AND METHODS: The psMASE sequence is a modification of the multiecho asymmetric spin echo sequence determined by shifting the 180 degrees refocusing pulse periodically. ME strategy is introduced to improve the temporal resolution of the simultaneous dynamic measurement of R2 , R2', and R2*. Reproducibility measurements and comparison with reference methods were conducted. Furthermore, this method was tested on 10 healthy volunteers with the dynamic imaging of lower extremity muscles during a cuff occlusion release paradigm. RESULTS: Both phantom and in vivo comparisons demonstrated that psMASE-ME-based R2 and R2* had good agreement with those calculated by multiecho spin echo and gradient echo sequences. Scan-rescan tests showed good reproducibility. Moreover, muscle R2 , R2', and R2* increased obviously from rest to cuff occlusion and decreased significantly after cuff release. CONCLUSION: It is feasible to obtain high temporally resolved R2 , R2', and R2* simultaneously with the proposed psMASE-ME method. Magn Reson Med 77:766 773, 2017. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 26946044 TI - Interpreting phenotypic antibiotic tolerance and persister cells as evolution via epigenetic inheritance. AB - Epigenetic inheritance is the transmission of nongenetic material such as gene expression levels, RNA and other biomolecules from parents to offspring. There is a growing realization that such forms of inheritance can play an important role in evolution. Bacteria represent a prime example of epigenetic inheritance because a large array of cellular components is transmitted to offspring, in addition to genetic material. Interestingly, there is an extensive and growing empirical literature showing that many bacteria can form 'persister' cells that are phenotypically resistant or tolerant to antibiotics, but most of these results are not interpreted within the context of epigenetic inheritance. Instead, persister cells are usually viewed as a genetically encoded bet-hedging strategy that has evolved in response to a fluctuating environment. Here I show, using a relatively simple model, that many of these empirical findings can be more simply understood as arising from a combination of epigenetic inheritance and cellular noise. I therefore suggest that phenotypic drug tolerance in bacteria might represent one of the best-studied examples of evolution under epigenetic inheritance. PMID- 26946045 TI - Broad taxonomic characterization of Verticillium wilt resistance genes reveals an ancient origin of the tomato Ve1 immune receptor. AB - Plant-pathogenic microbes secrete effector molecules to establish themselves on their hosts, whereas plants use immune receptors to try and intercept such effectors in order to prevent pathogen colonization. The tomato cell surface localized receptor Ve1 confers race-specific resistance against race 1 strains of the soil-borne vascular wilt fungus Verticillium dahliae which secrete the Ave1 effector. Here, we describe the cloning and characterization of Ve1 homologues from tobacco (Nicotiana glutinosa), potato (Solanum tuberosum), wild eggplant (Solanum torvum) and hop (Humulus lupulus), and demonstrate that particular Ve1 homologues govern resistance against V. dahliae race 1 strains through the recognition of the Ave1 effector. Phylogenetic analysis shows that Ve1 homologues are widely distributed in land plants. Thus, our study suggests an ancient origin of the Ve1 immune receptor in the plant kingdom. PMID- 26946047 TI - pH-dependent complexation of hydroxypropyl-beta-cyclodextrin with chlorin e6: effect on solubility and aggregation in relation to photodynamic efficacy. AB - OBJECTIVES: The activity of chlorin e6 (Ce6) in photodynamic therapy of cancers is significantly reduced by its propensity to form aggregates. It was postulated that disaggregation of Ce6 could be achieved with the use of hydroxypropyl-beta cyclodextrin (HP-beta-CD) through solubility enhancement. METHODS: An initial phase solubility study of Ce6 was conducted with various concentrations of HP beta-CD at three different pH conditions, i.e. pH 3, pH 5 and pH 7. Solubility induced disaggregation of Ce6 was illustrated by fluorescence spectroscopy and singlet oxygen generation studies. Interaction between Ce6 and HP-beta-CD was further demonstrated by solid-state characterization techniques. Inclusion complex formulations were tested for improved efficacy on squamous cancer cell lines. KEY FINDINGS: Increase in Ce6 solubility was observed, especially at pH 7, indicating the formation of inclusion complex between Ce6 and HP-beta-CD. This resulted in disaggregation of Ce6 aggregates illustrated by fluorescence spectroscopy. The mode of binding was predominated by H-bonding supported by temperature-dependent binding studies and molecular simulation work. The inclusion complex demonstrated improved photodynamic efficacy through enhanced singlet oxygen generation and phototoxicity on human oral squamous carcinoma cells. CONCLUSIONS: pH-dependent complexation between Ce6- and HP-beta-CD-induced disaggregation of Ce6 aggregates and the resultant formulations facilitated improved PDT efficacy on tested cancer cell lines. PMID- 26946048 TI - Lymphomagenesis-related gene expression in B cells from sustained virological responders with occult hepatitis C virus infection. AB - The expression of activation-induced cytidine deaminase, B-aggressive lymphoma, cyclin D1 and serine/threonine kinase 15 genes, among others, is increased in B cells from patients with chronic hepatitis C virus (HCV) infection. It is unknown whether the level of expression of these genes in B cells is increased in patients with hepatitis C who have achieved a sustained virological response (SVR) but who have persistent, detectable HCV RNA, so-called occult infection. Eighty-three patients who achieved and SVR, 27 with detectable HCV and 56 without detectable HCV RNA, 28 chronic hepatitis C patients and 32 healthy controls were studied. RNA was extracted from B cells, and gene expression levels were measured by RT-PCR. Patients with chronic HCV and those who achieved an SVR (with and without persistent low-level HCV RNA) showed a statistically significant higher expression compared to healthy controls, of activation-induced cytidine deaminase (P = 0.004, P < 0.001 and P = 0.002, respectively), B-aggressive lymphoma (P < 0.001, P = 0.001 and P = 0.006) and cyclin D1 (P = 0.026, P = 0.001; P = 0.038). For activation-induced cytidine deaminase patients with an SVR and 'occult infection' had a statistically significantly higher expression level than patients with and SVR without 'occult infection' (P = 0.014). The higher expression levels found for activation-induced cytidine deaminase, together with other genes indicates that these B lymphomagenesis-related genes are upregulated following HCV therapy and this is more marked when HCV can be detected in PBMCs. PMID- 26946049 TI - Abnormalities in centrosome number in human embryos and embryonic stem cells. AB - Chromosomal abnormalities are common in human embryos. Previous studies have suggested links between centrosome number and chromosome abnormalities, but information regarding abnormalities in centrosome number in human embryos is limited. We analyzed abnormalities in centrosome number in human embryos and embryonic stem cells (hESCs). Following normal fertilization, supernumerary centrosomes were present at rates of 7.3% in two-pronucleus (2PN)-stage zygotes and 6.5% in first-cleavage zygotes. Supernumerary centrosomes were also detected in 24.4% of blastomeres from 60% of embryos derived from 2PN zygotes. Conversely, in mono- (1PN) and tri-pronucleus (3PN) zygotes, the frequency of abnormal centrosome number increased substantially at first cleavage. Rates in blastomeres of Day-3 embryos, however, were about the same between embryos derived from 1PN and 2PN zygotes, whereas abnormalities in centrosome number were higher in those from 3PN zygotes. By comparison, the rate of abnormal centrosome numbers in hESCs was 1.5-11.2%. Thus, abnormalities in centrosome number existed in human zygotes and cleaved embryos-especially those resulting from aberrant fertilization-but the frequency of such abnormalities was lower in hESCs derived from these embryos. These findings identify a source of the chromosomal instability in human embryos and hESCs, and highlight new safety issues for human assisted reproductive technology. Mol. Reprod. Dev. 83: 392-404, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26946051 TI - Hearing and vision impairment and the 5-year incidence of falls in older adults. AB - BACKGROUND: concurrent vision and hearing loss are common in older adults; however, epidemiological data on their relationship with the incidence of falls are lacking. OBJECTIVE: we assessed the association between dual sensory impairment (DSI) and incidence of falls. We examined the influence of self perceived hearing handicap and hearing aid use and risk of falls. DESIGN: a population-based, cohort study of participants followed over 5 years. SETTING: Blue Mountains, west of Sydney, Australia. SUBJECTS: one thousand four hundred and seventy-eight participants aged 55 and older at baseline were included in longitudinal analyses. METHODS: visual impairment was defined as presenting or best-corrected visual acuity less than 20/40 (better eye), and hearing impairment as average pure-tone air conduction threshold >25 dB HL (500-4,000 Hz, better ear). The shortened version of the hearing handicap inventory for the elderly was administered. Incident falls were assessed over the 12 months before each visit. Cognitive impairment was determined using the Mini-Mental State Examination. RESULTS: five-year incidence of falls was 10.4%. Participants with severe self perceived hearing handicap versus no hearing handicap had increased risk of incident falls, multivariable-adjusted OR 1.93 (95% confidence intervals, CI, 1.02-3.64). Hearing aid users versus non-users had 75% increased likelihood of incident falls. Participants with co-existing best-corrected visual impairment and mild hearing loss (>25 to <=40 dB HL) had higher odds of incident falls, OR 2.19 (95% CI 1.03-4.67). After excluding persons with cognitive impairment, this association did not persist. CONCLUSION: these epidemiological data show that DSI in older adults could significantly increase their risk of falling. PMID- 26946050 TI - Factors associated with hospital deaths in the oldest old: a cross-sectional study. AB - AIMS/OBJECTIVES: to study associations between the likelihood of hospital death with patient demographics, cause of death and co-morbidities for people aged >=85 at death who have been previously admitted (within 12 months of death) to hospital. METHODS: a cross-sectional study, using death registration data and hospital episode statistics, for 671,178 England residents who had been admitted to hospital during the 12 months before death and were aged 85 or over at death during 2008-12. The outcome variable was the likelihood of dying in hospital. Covariates included gender, age, social deprivation, care home residence, cause of death and co-morbidity. Potential associations were explored by multivariable regression analysis. RESULTS: sixty-two per cent of the sample died in hospital. The likelihood of dying in hospital varies significantly with age, cause of death, deprivation, number of emergency hospital and co-morbidities. People aged over 90 at the time of death are less likely to die in hospital than those aged 85-89 [odds ratio (OR) for aged 90-94, 0.99; 95% confidence interval (CI) 0.98 1.00, OR for aged 95 and over, 0.91; 95% CI: 0.89-0.92]. People who are care home residents at the time of death are significantly less likely to die in hospital (OR 0.34; 95% CI: 0.34-0.35). Having a mention of dementia on the death certificate was significantly associated with a reduction in the likelihood of dying in hospital (OR 0.32; 95% CI: 0.31-0.32). CONCLUSIONS: the likelihood of an older person dying in hospital is significantly associated with a number of socio demographic factors, such as age and level of deprivation. Care home residence is significantly associated with a reduction in likelihood of hospital death. PMID- 26946053 TI - Exploiting Distal Reactivity of Coumarins: A Rhodium-Catalyzed Vinylogous Asymmetric Ring-Opening Reaction. AB - While the utility of vinylogous enolates is well established in the setting of vinylogous aldol, Mannich, and Michael chemistries, literature reports concerning gamma-reactivity are scarce for other reaction classes. Presented herein is an unprecedented example of vinylogous reactivity exemplified by the rhodium catalyzed asymmetric ring-opening reaction of oxabicycles. This strategy also provides a powerful route to incorporate the biologically useful coumarin motif into the hydronapthalene scaffold. PMID- 26946052 TI - Quantitative Characterization of Configurational Space Sampled by HIV-1 Nucleocapsid Using Solution NMR, X-ray Scattering and Protein Engineering. AB - Nucleic-acid-related events in the HIV-1 replication cycle are mediated by nucleocapsid, a small protein comprising two zinc knuckles connected by a short flexible linker and flanked by disordered termini. Combining experimental NMR residual dipolar couplings, solution X-ray scattering and protein engineering with ensemble simulated annealing, we obtain a quantitative description of the configurational space sampled by the two zinc knuckles, the linker and disordered termini in the absence of nucleic acids. We first compute the conformational ensemble (with an optimal size of three members) of an engineered nucleocapsid construct lacking the N- and C-termini that satisfies the experimental restraints, and then validate this ensemble, as well as characterize the disordered termini, using the experimental data from the full-length nucleocapsid construct. The experimental and computational strategy is generally applicable to multidomain proteins. Differential flexibility within the linker results in asymmetric motion of the zinc knuckles which may explain their functionally distinct roles despite high sequence identity. One of the configurations (populated at a level of ~40 %) closely resembles that observed in various ligand bound forms, providing evidence for conformational selection and a mechanistic link between protein dynamics and function. PMID- 26946054 TI - Monthly recurrent pneumothorax. PMID- 26946055 TI - Destruction of Opportunistic Pathogens via Polymer Nanoparticle-Mediated Release of Plant-Based Antimicrobial Payloads. AB - The synthesis of antimicrobial thymol/carvacrol-loaded polythioether nanoparticles (NPs) via a one-pot, solvent-free miniemulsion thiol-ene photopolymerization process is reported. The active antimicrobial agents, thymol and carvacrol, are employed as "solvents" for the thiol-ene monomer phase in the miniemulsion to enable facile high capacity loading (~50% w/w), excellent encapsulation efficiencies (>95%), and elimination of all postpolymerization purification processes. The NPs serve as high capacity reservoirs for slow release and delivery of thymol/carvacrol-combination payloads that exhibit inhibitory and bactericidal activity (>99.9% kill efficiency at 24 h) against gram-positive and gram-negative bacteria, including both saprophytic (Bacillus subtilis ATCC 6633 and Escherichia coli ATCC 25922) and pathogenic species (E. coli ATCC 43895, Staphylococcus aureus RN6390, and Burkholderia cenocepacia K56 2). This report is among the first to demonstrate antimicrobial efficacy of essential oil-loaded nanoparticles against B. cenocepacia - an innately resistant opportunistic pathogen commonly associated with debilitating respiratory infections in cystic fibrosis. Although a model platform, these results point to promising pathways to particle-based delivery of plant-derived extracts for a range of antimicrobial applications, including active packaging materials, topical antiseptics, and innovative therapeutics. PMID- 26946056 TI - Liver X receptors and copper metabolism: New frontiers for the oxysterol receptors. PMID- 26946057 TI - BRCA1-like profile predicts benefit of tandem high dose epirubicin cyclophospamide-thiotepa in high risk breast cancer patients randomized in the WSG-AM01 trial. AB - BRCA1 is an important protein in the repair of DNA double strand breaks (DSBs), which are induced by alkylating chemotherapy. A BRCA1-like DNA copy number signature derived from tumors with a BRCA1 mutation is indicative for impaired BRCA1 function and associated with good outcome after high dose (HD) and tandem HD DSB inducing chemotherapy. We investigated whether BRCA1-like status was a predictive biomarker in the WSG AM 01 trial. WSG AM 01 randomized high-risk breast cancer patients to induction (2* epirubicin-cyclophosphamide) followed by tandem HD chemotherapy with epirubicin, cyclophosphamide and thiotepa versus dose dense chemotherapy (4* epirubicin-cyclophospamide followed by 3* cyclophosphamide methotrexate-5-fluorouracil). We generated copy number profiles for 143 tumors and classified them as being BRCA1-like or non-BRCA1-like. Twenty-six out of 143 patients were BRCA1-like. BRCA1-like status was associated with high grade and triple negative tumors. With regard to event-free-survival, the primary endpoint of the trial, patients with a BRCA1-like tumor had a hazard rate of 0.2, 95% confidence interval (CI): 0.07-0.63, p = 0.006. In the interaction analysis, the combination of BRCA1-like status and HD chemotherapy had a hazard rate of 0.19, 95% CI: 0.067-0.54, p = 0.003. Similar results were observed for overall survival. These findings suggest that BRCA1-like status is a predictor for benefit of tandem HD chemotherapy with epirubicin-thiotepa-cyclophosphamide. PMID- 26946058 TI - Neonatal acute liver failure. AB - Neonatal acute liver failure (NALF) is a rare disease about which there is little published data; however, NALF is an extremely important condition as it is distinct from acute liver failure seen in older children and adults. First, unlike acute liver failure in older patients, NALF can be diagnosed in an infant with cirrhosis. This is due to the fetal-neonatal continuum of liver disease, or the principle that neonatal liver failure may be the result of a liver disease that began in utero. Further differences exist in the mechanism of disease, diagnostic principles, and the common etiologies of NALF when compared with pediatric and adult acute liver failure. This review will address many of the distinguishing features of NALF and focus on the most common etiologies of NALF, including gestational alloimmune liver disease (GALD), the most common cause of NALF. Additionally, this review will provide insight into the pathogenesis, diagnosis, and treatment of this rare condition. Liver Transplantation 22 677-685 2016 AASLD. PMID- 26946059 TI - Distensibility and pain of the uterine cervix evaluated by novel techniques. AB - The article serves to review the literature on the human uterine cervix based on a new distension technology named functional luminal imaging probe. This technology was originally developed to study the biomechanical competence of the gastro-esophageal junction where it provides a geometric profile of the lumen during distension, which can be related to sensory data. We searched and reviewed publications on cervical distention from 2002. The functional luminal imaging probe technology has been used for studying the mechanical and mechano-sensory properties of the cervix in non-pregnant women. In early pregnant women and in term pregnant women, the technique provides geometric measurements from the whole cervical canal during distension, which changes dramatically during pregnancy. Furthermore, it has been demonstrated that the technique predicts the outcome of labor induction better than the Bishop score does. The functional luminal imaging probe technology has potential as a research tool as well as for clinical use in gynecology and obstetrics. PMID- 26946060 TI - Ecological risk assessment of ecosystem services in the Taihu Lake Basin of China from 1985 to 2020. AB - There are tremendous theoretical, methodological and policy challenges in evaluating the impact of land-use change on the degradation of ecosystem services (ES) at the regional scale. This study addresses these challenges by developing an interdisciplinary methodology based on the Procedure for Ecological Tiered Assessment of Risk (PETAR). This novel methodology integrates ecological models with a land-use change model. This study quantifies the multi-dimensional degradation risks of ES in the Taihu Lake Basin (TLB) of China from 1985 to 2020. Four key ES related to water purification, water quantity adjustment, carbon sequestration and grain production are selected. The study employs models of Denitrification-Decomposition (DNDC), Soil-Water-Atmosphere-Plant (SWAP), Biome BGC and Agro-ecological Zoning (AEZ) for assimilations. Land-use changes by 2020 were projected using a geographically weighted multinomial logit-cellular automata (GWML-CA) model. The results show that rapid land-use change has posed a great degradation risk of ES in the region in 1985-2020. Slightly less than two thirds of the basin experienced degradation of ES over the 1985-2010 period, and about 12% of the basin will continue to experience degradation until 2020. Hot spots with severe deterioration in 2010-2020 are projected to be centered around some small and less developed cities in the region. Regulating accelerated urban sprawl and population growth, reinforcing current environmental programs, and establishing monitoring systems for observing dynamics of regional ES are suggested as practical counter-measures. PMID- 26946061 TI - Comparative morphometric analysis of microglia in the spinal cord of SOD1(G93A) transgenic mouse model of amyotrophic lateral sclerosis. AB - It has long been recognized that reactive microglia undergo a series of phenotypic changes accompanying morphological transformation. However, the morphological classification of microglia has not yet been achieved. To address this issue, here we morphometrically analysed three-dimensionally reconstructed ionized calcium binding adaptor molecule 1-immunoreactive (Iba1(+) ) microglia in the ventral horn of the lumbar spinal cord of SOD1(G93A) transgenic mice, a model of amyotrophic lateral sclerosis. The hierarchical cluster analysis revealed that microglia were objectively divided into four groups: type S (named after surveillant microglia) and types R1, R2 and R3 (named after reactive microglia). For the purpose of comparative morphometry, we also analysed two pharmacological disease models using wild-type mice: 3,3'-iminodipropionitrile (IDPN)-induced axonopathy and lipopolysaccharide (LPS)-induced neuroinflammation. Type S microglia showed a typical ramified morphology of surveillant microglia, and were mostly observed in wild-type controls. Type R1 microglia were seen at the early stage of disease in SOD1(G93A) mice, and also frequently occurred in IDPN-treated mice. They exhibited small cell bodies with shorter and simple processes. Type R2 microglia were morphologically similar to type R1 microglia, but only transiently occurred in the middle stage of disease in SOD1(G93A) mice and in IDPN-treated mice. Type R3 microglia exhibited a bushy shape, and were observed in the end stage of disease in SOD1(G93A) mice and in LPS-treated mice. These findings indicate that microglia of SOD1(G93A) mice can be classified into four types, and also suggest that the phenotypic changes may be induced by the events related to axonopathy and neuroinflammation. PMID- 26946062 TI - Bacopaside I ameliorates cognitive impairment in APP/PS1 mice via immune-mediated clearance of beta-amyloid. AB - Standardized extracts of Bacopa monniera (BME) have been shown to exert a neuroprotective effect against mental diseases, such as depression, anxiety and Alzheimer's disease (AD), in chronic administration studies. However, its mechanism of action has remained unclear. In this study, we evaluated the therapeutic effect of Bacopaside I (BS-I), a major triterpenoid saponin of BME, on the cognitive impairment and neuropathology in APP/PS1 transgenic mice and explored the possible mechanism from a biological systems perspective. We found that BS-I treatment significantly ameliorated learning deficits, improved long term spatial memory, and reduced plaque load in APP/PS1 mice. We constructed BS I's therapeutic effect network by mapping the nodes onto the protein-protein interaction (PPI) network constructed according to their functional categories based on genomic and proteomic data. Because many of the top enrichment categories related to the processes of the immune system and phagocytosis were detected, we proposed that BS-I promotes amyloid clearance via the induction of a suitable degree of innate immune stimulation and phagocytosis. Our research may help to clarify the neuroprotective effect of BME and indicated that natural saponins target the immune system, which may offer new research avenues to discover novel treatments for AD. PMID- 26946063 TI - Timing of Pregnancy After Kidney Transplantation and Risk of Allograft Failure. AB - The optimal timing of pregnancy after kidney transplantation remains uncertain. We determined the risk of allograft failure among women who became pregnant within the first 3 posttransplant years. Among 21 814 women aged 15-45 years who received a first kidney-only transplant between 1990 and 2010 captured in the United States Renal Data System, n = 729 pregnancies were identified using Medicare claims. The probability of allograft failure from any cause including death (ACGL) at 1, 3, and 5 years after pregnancy was 9.6%, 25.9%, and 36.6%. In multivariate analyses, pregnancy in the first posttransplant year was associated with an increased risk of ACGL (hazard ratio [HR]: 1.18; 95% confidence interval [CI] 1.00, 1.40) and death censored graft loss (DCGL) (HR:1.25; 95% CI 1.04, 1.50), while pregnancy in the second posttransplant year was associated with an increased risk of DCGL (HR: 1.26; 95% CI 1.06, 1.50). Pregnancy in the third posttransplant year was not associated with an increased risk of ACGL or DCGL. These findings demonstrate a higher incidence of allograft failure after pregnancy than previously reported and that the increased risk of allograft failure extends to pregnancies in the second posttransplant year. PMID- 26946065 TI - Survey results on daily practice in open and laparoscopic liver resections from 27 centers participating in the second International Consensus Conference. AB - BACKGROUND: The proportions of laparoscopic approach and surgical procedures in liver resections have been unknown in clinical practice. The aim of this study is to investigate liver resections performed in select centers worldwide and analyze the ratios of laparoscopic approach, major liver resection, and left lateral sectionectomy. METHODS: A questionnaire-based survey on proportions of liver resections performed between 2008 and 2013 was conducted. The data collected from 27 respondents, which joined the conference committee of the second International Consensus Conference on Laparoscopic Liver Resection (LLR), were analyzed by the working group. RESULTS: Between 2008 and 2013, 11,712 liver resections were performed in the 27 centers. Of all of these liver resections, laparoscopic approach was selected in 32.1% (n = 3,765), whereas open approach was selected in 67.9% (n = 7,947). The ratio of laparoscopic approach taken in all left lateral sectionectomy (61.8%) is higher, compared with that of laparoscopic approach taken in all liver resections (32.1%), in all minor liver resections (35.9%), and in all major liver resections (24.8%). CONCLUSIONS: Laparoscopic approach was clinically chosen for approximately 30% of all liver resections and for more than 60% of left lateral sectionectomy in selected centers worldwide. PMID- 26946064 TI - Decellularized extracellular matrix microparticles as a vehicle for cellular delivery in a model of anastomosis healing. AB - Extracellular matrix (ECM) materials from animal and human sources have become important materials for soft tissue repair. Microparticles of ECM materials have increased surface area and exposed binding sites compared to sheet materials. Decellularized porcine peritoneum was mechanically dissociated into 200 um microparticles, seeded with fibroblasts and cultured in a low gravity rotating bioreactor. The cells avidly attached and maintained excellent viability on the microparticles. When the seeded microparticles were placed in a collagen gel, the cells quickly migrated off the microparticles and through the gel. Cells from seeded microparticles migrated to and across an in vitro anastomosis model, increasing the tensile strength of the model. Cell seeded microparticles of ECM material have potential for paracrine and cellular delivery therapies when delivered in a gel carrier. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 1728-1735, 2016. PMID- 26946067 TI - Tranexamic acid in epistaxis: a systematic review. AB - BACKGROUND: The role of tranexamic acid in the management of epistaxis remains unclear. There is uncertainty about its safety and about the contraindications for its use. We performed a systematic review of the use of systemic and topical tranexamic acid in epistaxis and a comparative review of its use in other specialties. OBJECTIVE OF REVIEW: This review assesses and summarises the existing evidence for the efficacy and safety of tranexamic acid in the management of epistaxis. TYPE OF REVIEW: Systematic review. SEARCH STRATEGY: MEDLINE and EMBASE were searched for 'epistaxis' and equivalent MESH terms, combined with the Boolean operator 'OR' and 'tranexamic acid'. The Cochrane library and society guidelines were reviewed for evidence regarding the use of tranexamic acid in other specialties. EVALUATION METHOD: All five relevant RCTs were included in the review and were evaluated according to the recommendations of the Cochrane Handbook for Systematic Reviews. RESULTS: Three RCTS pertained to spontaneous epistaxis; of these, one trial found no benefit of oral tranexamic acid in acute epistaxis, one trial found no significant benefit of topical tranexamic acid, but the largest of the trials showed significant benefit of topical tranexamic acid in acute epistaxis management. Two RCTs examined oral tranexamic acid for prophylaxis of recurrent epistaxes in patients with hereditary haemorrhagic telangiectasia; both showed significant reduction in severity and frequency. CONCLUSIONS: Tranexamic acid, as a WHO 'essential medicine', is a powerful, readily available tool, the use of which in epistaxis has been limited by uncertainty over its efficacy and its safety profile. This systematic review summarises the existing evidence and extrapolates from the wealth of data for other specialties to address the clinical question - does TXA have a role in epistaxis management? PMID- 26946066 TI - Patellofemoral Bone Marrow Lesions: Natural History and Associations With Pain and Structure. AB - OBJECTIVE: To describe the natural history of patellofemoral (PF) joint bone marrow lesions (BMLs) over 2.6 years and associations between changes in PF joint BMLs, knee pain, and knee cartilage morphology in older adults over 5 years. METHODS: A prospective population-based cohort study of men and women ages 50-80 years (mean age 63 years, n = 406) was performed. PF joint BMLs, knee cartilage volume, and cartilage defect scores (range 0-4) were measured using the Whole Organ Magnetic Resonance Imaging Score system at baseline and at 2.6 years. Knee pain was assessed by Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores at baseline and at 5 years. RESULTS: At baseline, 27% (n = 109) had PF joint BMLs; 24% of these increased (WOMAC score change of >=1) at followup, 44% persisted, 32% decreased, and 21% resolved completely. Of those without PF joint BMLs at baseline, 20% of participants developed PF joint BMLs over 2.6 years. In multivariable analyses, a change in PF joint BMLs was deleteriously associated with a change in total knee pain (beta = 0.67, 95% confidence interval [95% CI] 0.03, 1.31) and knee pain when going up/down stairs (beta = 0.24, 95% CI 0.04, 0.44) over 5 years. Baseline PF joint and tibiofemoral joint cartilage volume were protective for PF joint BMLs (relative risk [RR] 0.69, 95% CI 0.52, 0.90 for PF joint), while baseline PF joint cartilage defects were associated with an increase in PF joint BMLs (RR 1.73, 95% CI 1.38, 2.17) over 2.6 years. TF joint cartilage defects were not associated with increases in PF joint BMLs. CONCLUSION: PF joint BMLs are not static, and change is clinically relevant. PF joint cartilage morphology predicts increases in PF joint BMLs. PMID- 26946068 TI - Cultural differences in visual attention: Implications for distraction processing. AB - We investigated differences between participants of East Asian and Western descent in attention to and implicit memory for irrelevant words which participants were instructed to ignore while completing a target task (a Stroop Task in Experiment 1 and a 1-back task on pictures in Experiment 2). Implicit memory was measured using two conceptual priming tasks (category generation in Experiment 1 and general knowledge in Experiment 2). Participants of East Asian descent showed reliable implicit memory for previous distractors relative to those of Western descent with no evidence of differences on target task performance. We also found differences in a Corsi Block spatial memory task in both studies, with superior performance by the East Asian group. Our findings suggest that cultural differences in attention extend to task-irrelevant background information, and demonstrate for the first time that such information can boost performance when it becomes relevant on a subsequent task. PMID- 26946070 TI - Laparoscopic enucleation of a mesenteric cyst - a video vignette. PMID- 26946071 TI - Oxidized low-density lipoprotein antibodies/high-density lipoprotein cholesterol ratio is linked to advanced non-alcoholic fatty liver disease lean patients. AB - BACKGROUND AND AIM: A small but significant proportion of patients with normal body mass index show non-alcoholic fatty liver disease (NAFLD). Oxidized low density lipoprotein (LDL) is a powerful immunogenic molecule, which causes oxidative stress and produces antibodies (oxLDL-ab). We aimed to analyze the role of oxLDL-ab on histological features in lean-NAFLD patients. METHODS: Seventy-two biopsy-proven NAFLD patients were included. Lean patients showed body index mass of <30 kg/m(2) . Liver biopsies were assessed by one pathologist blinded to clinical data. Histological features were non-alcoholic steatohepatitis (NASH), steatosis, hepatocellular ballooning, and liver fibrosis. Metabolic and hepatic profiles were analyzed, and lipid-lowering medication was recorded. OxLDL-ab levels were measured by ELISA. OxLDL-ab-based lipid indexes analyzed: oxLDL ab/total cholesterol ratio; oxLDL-ab/LDL-c ratio; oxLDL-ab/high-density lipoprotein cholesterol (HDL-c) ratio; and oxLDL-ab/oxLDL ratio. RESULTS: Lean NAFLD patients presented 26.5% (9/34) of NASH. OxLDL-ab/HDL-c ratio (r = 0.570; n = 34; P = 0.001) correlated with NAS score and was the only variable associated with NASH in the multivariate analysis [odds ratio, OR, 1.10 (95% confidence interval, CI: 1.01-1.21); P = 0.039]. Severe steatosis was present in 41.2% (14/34) of lean-NAFLD patients. OxLDL-ab/HDL-c ratio was higher in patients with grade-III steatosis (54.9 (37.3-124.6)) than those with grade II (37.1 (20.2 71.1)) and grade I (17.7 (13.1-22.8)) (P = 0.018). Hepatocellular ballooning was present in 20.6% (7/34) of lean-NAFLD patients, and OxLDL-ab/HDL-c ratio (OR 1.03 [95% CI: 1.01-1.05]; P = 0.050) was independently associated with histological features. OxLDL-ab/HDL-c ratio was higher in patients with advanced fibrosis (39.8 (22.9-121.6) vs 17.7 (13.9-30.9); P = 0.025), increasing gradually with the fibrosis stage (P = 0.042) and remained in the final multivariate model [OR 1.05 (95% CI: 1.00-1.11); P = 0.05]. However, in obese-NAFLD patients, oxLDL/HDL-c ratio was not associated with histological features. CONCLUSIONS: Oxidized low density lipoprotein antibodies/high-density lipoprotein cholesterol ratio could represent an interesting biomarker associated with NASH, hepatocellular ballooning, and liver fibrosis, in lean patients. OxLDL-ab/HDL-c could play an important role for distinguishing patients with and without NAFLD complications. PMID- 26946069 TI - Mechanisms of Tritrichomonas foetus Pathogenicity in Cats with Insights from Venereal Trichomonosis. AB - Almost 20 years has passed since trichomonosis was first recognized as a potential cause of diarrhea in domestic cats. Despite progress in confirming disease causation, developing means for diagnosis, and identifying approaches to treatment of the infection, we still know very little about how this parasite causes diarrhea. With increasing recognition of resistance of trichomonosis to treatment with 5-nitroimidazole drugs, new treatment strategies based on an understanding of disease pathogenesis are needed. In this review, lessons learned from the pathogenesis of venereal trichomonosis in people and cattle are applied to clinical observations of trichomonosis in cats in effort to generate insight into areas where further research may be beneficial. PMID- 26946072 TI - Disassembly of the lens fiber cell nucleus to create a clear lens: The p27 descent. AB - The eye lens is unique among tissues: it is transparent, does not form tumors, and the majority of its cells degrade their organelles, including their cell nuclei. A mystery for over a century, there has been considerable recent progress in elucidating mechanisms of lens fiber cell denucleation (LFCD). In contrast to the disassembly and reassembly of the cell nucleus during mitosis, LFCD is a unidirectional process that culminates in destruction of the fiber cell nucleus. Whereas p27Kip1, the cyclin-dependent kinase inhibitor, is upregulated during formation of LFC in the outermost cortex, in the inner cortex, in the nascent organelle free zone, p27Kip1 is degraded, markedly activating cyclin-dependent kinase 1 (Cdk1). This process results in phosphorylation of nuclear Lamins, dissociation of the nuclear membrane, and entry of lysosomes that liberate DNaseIIbeta (DLAD) to cleave chromatin. Multiple cellular pathways, including the ubiquitin proteasome system and the unfolded protein response, converge on post translational regulation of p27Kip1. Mutations that impair these pathways are associated with congenital cataracts and loss of LFCD. These findings highlight new regulatory nodes in the lens and suggest that we are close to understanding this fascinating terminal differentiation process. Such knowledge may offer a new means to confront proliferative diseases including cancer. PMID- 26946073 TI - OCT angiography in the mouse: A novel evaluation method for vascular pathologies of the mouse retina. AB - PURPOSE: To investigate the application of optical coherence tomography (OCT) angiography in the retinas of healthy mice and to evaluate choroidal neovascularization (CNV) in a mouse model of laser-induced CNV. METHODS: C57BL/6J mice aged 18-25 weeks were examined using the spectral-domain optical coherence tomography device RTVue XR Avanti (Optovue, Inc, Fremont, California, USA). Blood flow in different retinal layers was detected using the split-spectrum amplitude decorrelation angiography algorithm. Fluorescein angiography (FA) images were obtained using the Heidelberg Spectralis device (Heidelberg, Germany). RESULTS: Using the RTVue XR Avanti, we were able to obtain high-quality OCT angiography images of normal vasculature in the superficial, deep capillary and choriocapillary layers in laser-treated mice and untreated controls. Whereas no blood flow was detectable in the outer retina of untreated mice, blood flow and hence neovascular vessels were found in laser-treated mice. CONCLUSIONS: OCT angiography can clearly visualize the normal vascular plexus in the different retinal layers in the mouse retina and choroid. With OCT angiography, it is possible to verify the choroidal neovascularization induced by laser treatment. Thus, OCT angiography is a helpful imaging tool for non-invasive, in vivo evaluation of laser-induced CNV in the mouse. PMID- 26946074 TI - Is Citrullination Required for the Presence of Restricted Clonotypes Reacting With Type II Collagen? Comment on the Article by Chemin et al. PMID- 26946075 TI - Brain responses reveal that infants' face discrimination is guided by statistical learning from distributional information. AB - Infants' perception of faces becomes attuned to the environment during the first year of life. However, the mechanisms that underpin perceptual narrowing for faces are only poorly understood. Considering the developmental similarities seen in perceptual narrowing for faces and speech and the role that statistical learning has been shown to play for speech, the current study examined whether and how learning from distributional information impacts face identity discrimination. We familiarized 6.5-month-old infants with exemplars of female faces taken from a morphed continuum going from one identity to another. Using event-related brain potentials (ERPs), we show that only infants who were familiarized with a bimodal frequency distribution, but not infants familiarized with a unimodal frequency distribution, discriminated between identities. These results are the first to demonstrate the influence of probabilistic information on infants' face identity discrimination, suggesting that statistical learning contributes to perceptual attunement for both faces and language. PMID- 26946076 TI - Is bevacizumab a culprit of intractable skin ulcers? PMID- 26946078 TI - Rac1 GTPase Promotes Interaction of Hematopoietic Stem/Progenitor Cell with Niche and Participates in Leukemia Initiation and Maintenance in Mouse. AB - Interaction between hematopoietic stem/progenitor cells (HSPCs) with their niche is critical for HSPC function. The interaction also plays an important role in the multistep process of leukemogenesis. Rac1 GTPase has been found to be highly expressed and activated in leukemia patients. Here, by forced expression of constitutively active form of Rac1 (Rac1-V12) in HSPCs, we demonstrate that active Rac1 promotes interaction of HSPC with niche. We then established an active Rac1 associated acute myeloid leukemia (AML) model by expression of Rac1 V12 cooperated with AML1-ETO9a (AE9a) in mouse HSPCs. Compared with AE9a alone, Rac1-V12 cooperated with AE9a (AER) drives an AML with a short latency, demonstrating that activation of Rac1 GTPase in mice promotes AML development. The mechanism of this AML promotion is by a better homing and lodging of leukemia cells in niche, which further enhancing their colony formation, quiescence and preventing leukemia cells from apoptosis. Further study showed that an inhibitor targeting activated Rac1 can increase the efficacy of chemotherapeutic agents to leukemia cells. This study provides evidence that activation of Rac1 promotes leukemia development through enhancing leukemia cells' homing and retention in niche, and suggests that inhibition of Rac1 GTPase could be an effective way of eliminating AML cells. Stem Cells 2016;34:1730-1741. PMID- 26946079 TI - Combination of two different homozygote mutations in Pompe disease. AB - Pompe disease (OMIM no 232300) is an autosomal recessive inherited metabolic disorder, caused by glycogen accumulation in the lysosome due to deficiency of the lysosomal acid 03B1-glucosidase enzyme. Here we report the case of an 8-month old girl of consanguineous Turkish parents, who was diagnosed with the infantile form of Pompe disease. Two different uncommon homozygote mutations (c.32-13 T > G homozygote and c.1856G > A homozygote) were detected. The patient had a more progressive clinical course than expected. We emphasize the rare combination of genetic mutations in this Turkish family with Pompe disease. PMID- 26946080 TI - Uncommon Kingella kingae lytic bone lesions in children. PMID- 26946077 TI - Comparison of PCSK9 Inhibitor Evolocumab vs Ezetimibe in Statin-Intolerant Patients: Design of the Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin-Intolerant Subjects 3 (GAUSS-3) Trial. AB - Statins are the accepted standard for lowering low-density lipoprotein cholesterol (LDL-C). However, 5% to 10% of statin-treated patients report intolerance, mostly due to muscle-related adverse effects. Challenges exist to objective identification of statin-intolerant patients. Evolocumab is a monoclonal antibody that binds proprotein convertase subtilisin/kexin type 9 (PCSK9), resulting in marked LDL-C reduction. We report the design of Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin-Intolerant Subjects 3 (GAUSS-3), a phase 3, multicenter, randomized, double-blind, ezetimibe controlled study to compare effectiveness of 24 weeks of evolocumab 420 mg monthly vs ezetimibe 10 mg daily in hypercholesterolemic patients unable to tolerate an effective statin dose. The study incorporates a novel atorvastatin controlled, double-blind, crossover phase to objectively identify statin intolerance. Eligible patients had LDL-C above the National Cholesterol Education Project Adult Treatment Panel III target level for the appropriate coronary heart disease risk category and were unable to tolerate >=3 statins or 2 statins (one of which was atorvastatin <=10 mg/d) or had a history of marked creatine kinase elevation accompanied by muscle symptoms while on 1 statin. This trial has 2 co primary endpoints: mean percent change from baseline in LDL-C at weeks 22 and 24 and percent change from baseline in LDL-C at week 24. Key secondary efficacy endpoints include change from baseline in LDL-C, percent of patients attaining LDL-C <70 mg/dL (1.81 mmol/L), and percent change from baseline in total cholesterol, non-high-density lipoprotein cholesterol, and apolipoprotein B. Recruitment of 511 patients was completed on November 28, 2014. PMID- 26946081 TI - Sevoflurane anesthesia induces neither contextual fear memory impairment nor alterations in local population connectivity of medial prefrontal cortex local field potentials networks in aged rats. AB - Sevoflurane has been found to increase apoptosis and pathologic markers associated with Alzheimer disease, provoking concern over their potential contribution to postoperative cognitive dysfunction. This study aimed to determine the effects of sevoflurane on contextual fear memory of aged rats and to characterize local population connectivity of local field potentials (LFPs) in medial prefrontal cortex (mPFC) of aged rats during contextual fear memory. Eighteen-month-old male SD rats were implanted with one multichannel electrode array in mPFC. The aged rats were divided into control group, sevoflurane group (1 MAC sevoflurane for 2 h) and surgical group with 1.0 MAC sevoflurane for 2 h. We then assessed the effect of the anesthesia on contextual fear memory, and alterations in the local population connectivity of mPFC LFP networks by partial directed coherence (PDC). Surgery impaired contextual fear memory and reduced local population connectivity of mPFC LFP networks in aged rats at day 1 after the surgery and anesthesia. 1 MAC Sevoflurane anesthesia induced neither contextual fear memory impairment nor alterations in local population connectivity of mPFC LFP networks in aged rats when tested 1, 7, 15 and 30 days after exposure (P > 0.05). PDC values of theta band mPFC LFPs became strongly increased during contextual fear memory at 1, 7, 15, and 30 days after anesthesia. Our results suggest that 1 MAC sevoflurane anesthesia does not induce contextual fear memory impairment in aged rats and suggest that the increased local population connectivity in theta bands LFPs of mPFC plays a role in contextual fear memory. PMID- 26946082 TI - Significance of IFN-?/IL-2 Ratio as a Circulating Diagnostic Biomarker in Extrapulmonary Tuberculosis. AB - Extrapulmonary tuberculosis (EPTB) remains a challenging diagnosis both for clinicians and microbiologists. We hypothesized that the profile of IFN-?/IL-2 ratio in clinically diagnosed cases of EPTB would be distinct from that of age- and sex-matched healthy controls. Therefore, in our study, we have assessed the ratio of serum levels of IFN-? and IL-2 in clinically diagnosed cases of EPTB to assess their potential role as diagnostic biomarkers. Sixty-nine (69) clinically confirmed EPTB cases and 69 age- and sex-matched healthy controls were included in the study. All the extrapulmonary specimens were subjected to Ziehl-Neelsen staining for acid-fast bacilli and culture on Lowenstein-Jensen (LJ) medium. Detection of serum levels of IFN-? and IL-2 was carried out using commercially available ELISA kits following manufacturers' instructions. The ratio of serum levels of IFN-? and IFN-?/IL-2 was discriminative for the diagnosis of EPTB cases (p < 0.001), although the same was not observed with IL-2 (p > 0.05). Distribution of all biomarkers significantly differed between culture-positive and culture-negative cases (p < 0.05). Among the smear-positive and smear negative ones, only IFN-? and IFN-?/IL-2 ratio could significantly differentiate (p < 0.05). Ratio of IFN-? and IL-2 rather than the individual levels was the best discriminatory biomarker with the highest area under the ROC curve. Although IFN-? and IFN-?/ IL-2 ratio could aid in the diagnosis of EPTB, IL-2 has a limited utility in the diagnosis of EPTB. Further elaborate studies to validate these results are required. PMID- 26946083 TI - Finding the right coverage: the impact of coverage and sequence quality on single nucleotide polymorphism genotyping error rates. AB - Restriction-enzyme-based sequencing methods enable the genotyping of thousands of single nucleotide polymorphism (SNP) loci in nonmodel organisms. However, in contrast to traditional genetic markers, genotyping error rates in SNPs derived from restriction-enzyme-based methods remain largely unknown. Here, we estimated genotyping error rates in SNPs genotyped with double digest RAD sequencing from Mendelian incompatibilities in known mother-offspring dyads of Hoffman's two-toed sloth (Choloepus hoffmanni) across a range of coverage and sequence quality criteria, for both reference-aligned and de novo-assembled data sets. Genotyping error rates were more sensitive to coverage than sequence quality and low coverage yielded high error rates, particularly in de novo-assembled data sets. For example, coverage >=5 yielded median genotyping error rates of >=0.03 and >=0.11 in reference-aligned and de novo-assembled data sets, respectively. Genotyping error rates declined to <=0.01 in reference-aligned data sets with a coverage >=30, but remained >=0.04 in the de novo-assembled data sets. We observed approximately 10- and 13-fold declines in the number of loci sampled in the reference-aligned and de novo-assembled data sets when coverage was increased from >=5 to >=30 at quality score >=30, respectively. Finally, we assessed the effects of genotyping coverage on a common population genetic application, parentage assignments, and showed that the proportion of incorrectly assigned maternities was relatively high at low coverage. Overall, our results suggest that the trade-off between sample size and genotyping error rates be considered prior to building sequencing libraries, reporting genotyping error rates become standard practice, and that effects of genotyping errors on inference be evaluated in restriction-enzyme-based SNP studies. PMID- 26946085 TI - Adenine nucleotide-dependent and redox-independent control of mitochondrial malate dehydrogenase activity in Arabidopsis thaliana. AB - Mitochondrial metabolism is important for sustaining cellular growth and maintenance; however, the regulatory mechanisms underlying individual processes in plant mitochondria remain largely uncharacterized. Previous redox-proteomics studies have suggested that mitochondrial malate dehydrogenase (mMDH), a key enzyme in the tricarboxylic acid (TCA) cycle and redox shuttling, is under thiol based redox regulation as a target candidate of thioredoxin (Trx). In addition, the adenine nucleotide status may be another factor controlling mitochondrial metabolism, as respiratory ATP production in mitochondria is believed to be influenced by several environmental stimuli. Using biochemical and reverse genetic approaches, we addressed the redox- and adenine nucleotide-dependent regulation of mMDH in Arabidopsis thaliana. Recombinant mMDH protein formed intramolecular disulfide bonds under oxidative conditions, but these bonds did not have a considerable effect on mMDH activity. Mitochondria-localized o-type Trx (Trx-o) did not facilitate re-reduction of oxidized mMDH. Determination of the in vivo redox state revealed that mMDH was stably present in the reduced form even in Trx-o-deficient plants. Accordingly, we concluded that mMDH is not in the class of redox-regulated enzymes. By contrast, mMDH activity was lowered by adenine nucleotides (AMP, ADP, and ATP). Each adenine nucleotide suppressed mMDH activity with different potencies and ATP exerted the largest inhibitory effect with a significantly lower K(I). Correspondingly, mMDH activity was inhibited by the increase in ATP/ADP ratio within the physiological range. These results suggest that mMDH activity is finely controlled in response to variations in mitochondrial adenine nucleotide balance. PMID- 26946084 TI - Direct effects of exercise on kynurenine metabolism in people with normal glucose tolerance or type 2 diabetes. AB - BACKGROUND: Systemic kynurenine levels are associated with resistance to stress induced depression and are modulated by exercise. Tryptophan is a precursor for serotonin and kynurenine synthesis. Kynurenine is transformed into the neuroprotective catabolite kynurenic acid by kynurenine aminotransferases (KATs). PGC-1alpha1 increases KAT mRNA and induces kynurenic acid synthesis. We tested the hypothesis that skeletal muscle PGC-1alpha1/KAT-kynurenine pathway is altered by exercise and type 2 diabetes. METHOD: Skeletal muscle and plasma from men with normal glucose tolerance (n = 12) or type 2 diabetes (n = 12) was studied at rest, after acute exercise and during recovery. Tryptophan, Kynurenine and kynurenic acid plasma concentration were measured as well as mRNA of genes related to exercise and kynurenine metabolism. RESULTS: mRNA expression of KAT1, KAT2 and PPARalpha was modestly reduced in type 2 diabetic patients. In response to exercise, mRNA expression of KAT4 decreased and PGC-1alpha1 increased in both groups. Exercise increased plasma kynurenic acid and reduced kynurenine in normal glucose tolerance and type 2 diabetic participants. Plasma tryptophan was reduced and the ratio of [kynurenic acid] * 1000/[kynurenine] increased in both groups at recovery, suggesting an improved balance between neurotoxic and neuroprotective influences. Tryptophan and kynurenine correlated with body mass index, suggesting a relationship with obesity. CONCLUSIONS: Acute exercise directly affects circulating levels of tryptophan, kynurenine and kynurenic acid, providing a potential mechanism for the anti-depressive effects of exercise. Furthermore, exercise-mediated changes in kynurenine metabolism are preserved in type 2 diabetic patients. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26946086 TI - High throughput gene complementation screening permits identification of a mammalian mitochondrial protein synthesis (rho(-)) mutant. AB - To identify nuclear DNA (nDNA) oxidative phosphorylation (OXPHOS) gene mutations using cultured cells, we have developed a complementation system based on retroviral transduction with a full length cDNA expression library and selection for OXHOS function by growth in galactose. We have used this system to transduce the Chinese hamster V79-G7 OXPHOS mutant cell line with a defect in mitochondrial protein synthesis. The complemented cells were found to have acquired the cDNA for the bS6m polypeptide of the small subunit of the mitochondrial ribosome. bS6m is a 14 kDa polypeptide located on the outside of the mitochondrial 28S ribosomal subunit and interacts with the rRNA. The V79-G7 mutant protein was found to harbor a methionine to threonine missense mutation at codon 13. The hamster bS6m null mutant could also be complemented by its orthologs from either mouse or human. bS6m protein tagged at its C-terminus by HA, His or GFP localized to the mitochondrion and was fully functional. Through site-directed mutagenesis we identified the probable RNA interacting residues of the bS6m peptide and tested the functional significance of mammalian specific C-terminal region. The N terminus of the bS6m polypeptide functionally corresponds to that of the prokaryotic small ribosomal subunit, but deletion of C-terminal residues along with the zinc ion coordinating cysteine had no functional effect. Since mitochondrial diseases can result from hundreds to thousands of different nDNA gene mutations, this one step viral complementation cloning may facilitate the molecular diagnosis of a range of nDNA mitochondrial disease mutations. This article is part of a Special Issue entitled 'EBEC 2016: 19th European Bioenergetics Conference, Riva del Garda, Italy, July 2-6, 2016', edited by Prof. Paolo Bernardi. PMID- 26946087 TI - Excitation energy transfer in Chlamydomonas reinhardtii deficient in the PSI core or the PSII core under conditions mimicking state transitions. AB - The efficient use of excitation energy in photosynthetic membranes is achieved by a dense network of pigment-protein complexes. These complexes fulfill specific functions and interact dynamically with each other in response to rapidly changing environmental conditions. Here, we studied how in the intact cells of Chlamydomonas reinhardtii (C.r.) the lack of the photosystem I (PSI) core or the photosystem II (PSII) core affects these interactions. To that end the mutants F15 and M18 (both PSI-deficient) and FUD7 (PSII-deficient) were incubated under conditions known to promote state transitions in wild-type. The intact cells were then instantly frozen to 77K and the full-spectrum time-resolved fluorescence emission of the cells was measured by means of streak camera. In the PSI deficient mutants excitation energy transfer (EET) towards light-harvesting complexes of PSI (Lhca) occurs in less than 0.5 ns, and fluorescence from Lhca decays in 3.1 ns. Decreased trapping by PSII and increased fluorescence of Lhca upon state 1 (S1)->state 2 (S2) transition appears in the F15 and less in the M18 mutant. In the PSII-deficient mutant FUD7, quenched (0.5 ns) and unquenched (2 ns) light-harvesting complexes of PSII (LHCII) are present in both states, with the quenched form more abundant in S2 than in S1. Moreover, EET of 0.4 ns from the remaining LHCII to PSI increases upon S1->S2 transition. We relate the excitation energy kinetics observed in F15, M18 and FUD7 to the remodeling of the photosynthetic apparatus in these mutants under S1 and S2 conditions. PMID- 26946089 TI - An investigation of the impact of left-censored soil contamination data on the uncertainty of descriptive statistical parameters. AB - Left-censored concentration data are frequently encountered because measuring instruments cannot detect concentrations below the instrument detection limit. For statistical analysis of left-censored data, the environmental literature mainly refers to the following methods: maximum likelihood estimator, regression on order statistics using log-normal and gamma assumption (rROS and GROS, respectively), and Kaplan-Meier. A number of simulation experiments examined the performance of these methods in terms of bias and/or mean square error. However, no matter which method is adopted, some uncertainty is introduced into outcomes because all that is known about a left-censored observation is that the concentration falls between 0 and the detection limit. The data used in the present study come from analysis of soil samples collected for a site characterization in Montreal, Canada. Employing nonparametric bootstrap, the authors quantify the uncertainty and bias in the mean and standard deviation estimates obtained by the maximum likelihood estimation (under log-normal, Weibull, and gamma distributions), rROS, GROS, and Kaplan-Meier methods. First, the authors demonstrate that the highest uncertainty is associated with the maximum likelihood estimator under log-normality and Weibull assumptions, whereas a gamma assumption leads to estimates with less uncertainty. Second, the authors show that although an increase in sample size improves the uncertainty, it reduces the bias only in the rROS, GROS, and Kaplan-Meier methods. Finally, comparing percentage uncertainty in the mean of contaminant data, the authors illustrate that adopting an inappropriate estimator results in large uncertainties. Environ Toxicol Chem 2016;35:2623-2631. (c) 2016 SETAC. PMID- 26946088 TI - Photocurrents from photosystem II in a metal oxide hybrid system: Electron transfer pathways. AB - We have investigated the nature of the photocurrent generated by Photosystem II (PSII), the water oxidizing enzyme, isolated from Thermosynechococcus elongatus, when immobilized on nanostructured titanium dioxide on an indium tin oxide electrode (TiO2/ITO). We investigated the properties of the photocurrent from PSII when immobilized as a monolayer versus multilayers, in the presence and absence of an inhibitor that binds to the site of the exchangeable quinone (QB) and in the presence and absence of exogenous mobile electron carriers (mediators). The findings indicate that electron transfer occurs from the first quinone (QA) directly to the electrode surface but that the electron transfer through the nanostructured metal oxide is the rate-limiting step. Redox mediators enhance the photocurrent by taking electrons from the nanostructured semiconductor surface to the ITO electrode surface not from PSII. This is demonstrated by photocurrent enhancement using a mediator incapable of accepting electrons from PSII. This model for electron transfer also explains anomalies reported in the literature using similar and related systems. The slow rate of the electron transfer step in the TiO2 is due to the energy level of electron injection into the semiconducting material being below the conduction band. This limits the usefulness of the present hybrid electrode. Strategies to overcome this kinetic limitation are discussed. PMID- 26946090 TI - The role of left inferior frontal cortex during audiovisual speech perception in infants. AB - In the first year of life, infants' speech perception attunes to their native language. While the behavioral changes associated with native language attunement are fairly well mapped, the underlying mechanisms and neural processes are still only poorly understood. Using fNIRS and eye tracking, the current study investigated 6-month-old infants' processing of audiovisual speech that contained matching or mismatching auditory and visual speech cues. Our results revealed that infants' speech-sensitive brain responses in inferior frontal brain regions were lateralized to the left hemisphere. Critically, our results further revealed that speech-sensitive left inferior frontal regions showed enhanced responses to matching when compared to mismatching audiovisual speech, and that infants with a preference to look at the speaker's mouth showed an enhanced left inferior frontal response to speech compared to infants with a preference to look at the speaker's eyes. These results suggest that left inferior frontal regions play a crucial role in associating information from different modalities during native language attunement, fostering the formation of multimodal phonological categories. PMID- 26946091 TI - Efficacy and safety of transcatheter aortic valve replacement in intermediate surgical risk patients: A systematic review and meta-analysis. AB - BACKGROUND: The efficacy of transcatheter aortic valve replacement (TAVR) in aortic stenosis patients at high surgical risk has been established. The data on patients with intermediate risk is not conclusive. We performed a meta-analysis of studies which compared TAVR with surgical aortic valve replacement (SAVR) in patients at intermediate surgical risk. METHODS: Several databases searched from inception to February 2015 yielded 7 eligible studies with 2,173 participants. The measured outcome of efficacy was all-cause mortality. Data on safety included stroke, permanent pacemaker implantation (PPI), aortic regurgitation (AR), vascular access complications, and major bleeding. Outcomes were pooled and relative risk (RR) was calculated with the Mantel-Haenszel method. RESULTS: There was no difference in either short-term (RR, 1.02; 95% CI: 0.63-1.63; P = 0.94; I2 = 0%) or medium to long-term all-cause mortality (RR, 0.99; 95% CI: 0.81-1.21; P = 0.91; I2 = 0%). There was increased incidence of stroke (RR, 2.96; 95% CI: 0.87-10.09; P = 0.08; I2 = 0%), AR (RR, 3.59; 95% CI: 2.13-7.19; P < 0.00001; I2 = 2%), PPI (RR, 6.53; 95% CI: 1.91-22.32; P < 0.003; I2 = 0%) and vascular access complications (RR, 3.84; 95% CI: 0.65-22.76; P < 0.14; I2 = 48%) in patients with TAVR. There was a small, albeit increased risk of major or life threatening bleeding with SAVR as compared to TAVR (RR, 1.36; 95% CI: 1.04-1.80; P < 0.03; I2 = 0%). CONCLUSIONS: In this meta-analysis we found that TAVR may be an acceptable alternative to SAVR in patients with intermediate risk for surgery. However, we must await evidence from the current large randomized trials before widespread adoption of this procedure is undertaken. (c) 2016 Wiley Periodicals, Inc. PMID- 26946092 TI - Equivalency challenge: Evaluation of Lipodox(r) as the generic equivalent for Doxil(r) in a human ovarian cancer orthotropic mouse model. AB - BACKGROUND: The objective of this study was to evaluate the in vivo growth inhibition activity and tumor distribution of Doxil(r) compared to Lipodox(r) as its generic (GLD) in human ovarian cancer orthotopic mouse model. METHODS: In the efficacy study 50 mice were randomized to: vehicle, Doxil(r) 5mg/kg or 10mg/kg, or GLD 5mg/kg or 10mg/kg for a total of three cycles with monitoring for response and toxicity with 10 mice in each arm. In the microdialysis(MD) study, 60 mice were randomized to: Doxil(r) 5mg/kg or 10mg/kg, or GLD 5mg/kg or 10mg/kg single dose (n=15 mice/arm). MD sample time points included total of 29 samples from baseline through 100h and were evaluated with a validated PaperSpray LC/MS assay. RESULTS: There was 15.7% decrease (p<0.0001) in efficacy of GLD the 5mg/kg and 21.3% decrease (p<0.0001) in efficacy of the 10mg/kg dose of GLD when compared to equivalent doses of Doxil(r). The intratumoral concentration for the GLD ranged from 1.0 to 25.5ng/mL (5mg/kg) and 2.9-35.6ng/mL (10mg/kg) compared to 2.7 42.2ng/mL (p<0.04, 5mg/kg) and 2.0-76ng/mL (p<0.02, 10mg/kg) for the Doxil(r), respectively. CONCLUSION: Significant differences in preclinical efficacy were observed between Doxil(r) and GLD. These may be due to significant pharmacodynamic effects of drug distribution and decrease uptake of GLD in tumor tissue. A prospective clinical comparison of these two products is warranted to determine equivalency. PMID- 26946094 TI - Prevalence and factors associated with cognitive deficit in women with gynecologic malignancies. AB - OBJECTIVE: Cognitive impairment has implications in counseling, treatment, and survivorship for women with gynecologic malignancies. The purpose of our study was to evaluate the prevalence and risk factors associated with cognition in women with gynecologic malignancies. METHODS: After Institutional Review Board approval, 165 women at an urban ambulatory gynecologic oncology facility were queried using a Montreal Cognitive Assessment (MoCA), Wong-Baker pain scale, neuropathy scale, Patient Health Questionnaire 9 (PHQ-9) Depression Scale, and Generalized Anxiety Disorder Scale (GAD 7). Univariate and multivariate analyses were utilized to evaluate the association of cognitive deficit with age, education, race/ethnicity, disease site, stage, treatment, pain, neuropathy, anxiety, and depression. RESULTS: The mean MoCA score for the entire cohort was 24.1 (range 13-30.) 24% of patients had MoCA scores less than 22. Low scores (<22) were associated with older age, non-white race/ethnicity, lower education level, uterine and vulvar cancers, and pain >=5 (p<0.05). There was a trend toward lower cognition scores for women treated with both chemotherapy and radiation (p=0.10). While clinically significant pain was associated with low cognition, there was no association with use of opioid pain medication and low cognition scores. CONCLUSIONS: There was a high prevalence of cognitive deficit in women with gynecologic malignancies. The association of low cognition with report of clinically significant pain, but not with use of opioid pain medications, should be further explored. Research is needed to evaluate the impact of cognitive deficits on treatment adherence and outcomes for women with gynecologic malignancies. PMID- 26946093 TI - High expression of orphan nuclear receptor NR4A1 in a subset of ovarian tumors with worse outcome. AB - OBJECTIVE: Nuclear receptors (NRs) play a vital role in the development and progression of several cancers including breast and prostate. Using TCGA data, we sought to identify critical nuclear receptors in high grade serous ovarian cancers (HGSOC) and to confirm these findings using in vitro approaches. METHODS: In silico analysis of TCGA data was performed to identify relevant NRs in HGSOC. Ovarian cancer cell lines were screened for NR expression and functional studies were performed to determine the significance of these NRs in ovarian cancers. NR expression was analyzed in ovarian cancer tissue samples using immunohistochemistry to identify correlations with histology and stage of disease. RESULTS: The NR4A family of NRs was identified as a potential driver of ovarian cancer pathogenesis. Overexpression of NR4A1 in particular correlated with worse progression free survival. Endogenous expression of NR4A1 in normal ovarian samples was relatively high compared to that of other tissue types, suggesting a unique role for this orphan receptor in the ovary. Expression of NR4A1 in HGSOC cell lines as well as in patient samples was variable. NR4A1 primarily localized to the nucleus in normal ovarian tissue while co-localization within the cytoplasm and nucleus was noted in ovarian cancer cell lines and patient tissues. CONCLUSIONS: NR4A1 is highly expressed in a subset of HGSOC samples from patients that have a worse progression free survival. Studies to target NR4A1 for therapeutic intervention should include HGSOC. PMID- 26946095 TI - Multi-material 3-D viscoelastic model of a transtibial residuum from in-vivo indentation and MRI data. AB - Although the socket is critical in a prosthetic system for a person with limb amputation, the methods of its design are largely artisanal. A roadblock for a repeatable and quantitative socket design process is the lack of predictive and patient specific biomechanical models of the residuum. This study presents the evaluation of such a model using a combined experimental-numerical approach. The model geometry and tissue boundaries are derived from magnetic resonance imaging (MRI). The soft tissue non-linear elastic and viscoelastic mechanical behavior was evaluated using inverse finite element analysis (FEA) of in-vivo indentation experiments. A custom designed robotic in-vivo indentation system was used to provide a rich experimental data set of force versus time at 18 sites across a limb. During FEA, the tissues were represented by two layers, namely the skin adipose layer and an underlying muscle-soft tissue complex. The non-linear elastic behavior was modeled using 2nd order Ogden hyperelastic formulations, and viscoelasticity was modeled using the quasi-linear theory of viscoelasticity. To determine the material parameters for each tissue, an inverse FEA based optimization routine was used that minimizes the combined mean of the squared force differences between the numerical and experimental force-time curves for indentations at 4 distinct anatomical regions on the residuum. The optimization provided the following material parameters for the skin-adipose layer: [c=5.22kPam=4.79gamma=3.57MPatau=0.32s] and for the muscle-soft tissue complex [c=5.20kPam=4.78gamma=3.47MPatau=0.34s]. These parameters were evaluated to predict the force-time curves for the remaining 14 anatomical locations. The mean percentage error (mean absolute error/ maximum experimental force) for these predictions was 7+/-3%. The mean percentage error at the 4 sites used for the optimization was 4%. PMID- 26946096 TI - Venereal diseases in Lebanon during the French mandate. PMID- 26946097 TI - WITHDRAWN: A synchronization method using heparin for the in vitro culture of Plasmodium falciparum. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 26946099 TI - Phosphoramidate-Supported Cp*Ir(III) Aminoborane H2 B=NR2 Complexes: Synthesis, Structure, and Solution Dynamics. AB - Reaction of aminoboranes H2 B=NR2 (R=iPr or Cy) with the cationic Cp*Ir(III) phosphoramidate complex [IrCp*{kappa(2) -N,O-Xyl(N)P(O)(OEt)2 }][BAr(F) 4 ] generates the aminoborane complexes [IrCp*(H){kappa(1) -N-eta(2) -HB Xyl(N)P(OBHNR2 )(OEt)2 }][BAr(F) 4 ] (R=iPr or Cy) in which coordination of a P=O bond with boron weakens the B=N multiple bond. For these complexes, solution- and solid-state, as well as DFT computational techniques, have been employed to substantiate B-N bond rotation of the coordinated aminoborane. PMID- 26946098 TI - Effect of Corilagin on the miR-21/smad7/ERK signaling pathway in a schistosomiasis-induced hepatic fibrosis mouse model. AB - This study sought to investigate the anti-fibrotic effect of Corilagin via interference with the miR-21/smad7/ERK signaling pathway in a schistosomiasis induced hepatic fibrosis mouse model. Mice were infected with Schistosoma japonicum cercaria to establish the mouse model of schistosomiasis-induced hepatic fibrosis. At four weeks after infection, the groups were given different medications. The living conditions were observed. Real-time PCR was employed to detect the mRNA levels of miR-21, smad7 and connective tissue growth factor (CTGF), and western blotting was used to examine the protein levels of smad7, CTGF, smad1, p-smad1, smad2, p-smad2, ERK1/2, p-ERK1/2 and TGF-beta receptor I. Immunohistochemistry was used to examine the expression of CTGF. Compared with the model group, increasing concentrations of Corilagin improved the quality of life, inhibited the mRNA expression of miR-21, promoted smad7 protein expression, and inhibited CTGF protein expression (p<0.05 or 0.01). Moreover, Corilagin significantly reduced the protein levels of p-smad1, p-smad2, p-ERK1/2, and TGF beta receptor I (p<0.05 or 0.01). CTGF staining in the cytoplasm was markedly decreased by Corilagin (p<0.05 or 0.01). In conclusion, Corilagin inhibited schistosomiasis-induced hepatic fibrosis via the miR21/smad7/ERK pathway in this animal model. PMID- 26946101 TI - Association of Motoric Cognitive Risk Syndrome With Brain Volumes: Results From the GAIT Study. AB - BACKGROUND: The "motoric cognitive risk" (MCR) syndrome is a newly reported predementia syndrome combining cognitive complaint and slow gait speed. We hypothesized that individuals with MCR syndrome would have lower brain volumes compared with non-MCR individuals. This study aims (i) to compare the cognitive profile of nondemented older community-dwellers with and without MCR syndrome and (ii) to examine association of global and regional brain volumes with MCR syndrome. METHODS: A total of 171 individuals (28 MCR and 143 non-MCR) were included in this cross-sectional study. Total white matter abnormalities, total white matter, total cortical and subcortical gray matters, hippocampus, motor cortex, premotor cortex, and prefrontal cortex were examined. Brain volumes were quantified from a three-dimensional T1-weighted magnetic resonance imaging using semi-automated software. Age, gender, education level, number of drugs taken daily, use of psychoactive drugs, and cognitive profile were also measured. RESULTS: The distribution of cognitively healthy individuals and those with mild cognitive impairment was not different in participants with and without MCR. Multiple logistic regression models showed that smaller volumes of total gray matter (p = .016), total cortical gray matter (p = .010), premotor cortex (p = .018), prefrontal cortex (p = .026), and dorsolateral segment of prefrontal cortex (p = .032) were associated with MCR status. The premotor cortex presented the highest mean difference for brain regional volume between MCR and non-MCR participants (p = .03). CONCLUSIONS: The findings revealed similar cognitive profile in MCR and non-MCR participants, and MCR-related smaller global and regional gray matter volumes involving premotor and prefrontal cortices, suggesting that the MCR syndrome may predict cortical neurodegenerative dementia more than subcortical dementia. PMID- 26946100 TI - Regional Hippocampal Atrophy and Higher Levels of Plasma Amyloid-Beta Are Associated With Subjective Memory Complaints in Nondemented Elderly Subjects. AB - BACKGROUND: Evidence suggests a link between the presence of subjective memory complaints (SMC) and lower volume of the hippocampus, one of the first regions to show neuropathological lesions in Alzheimer's disease. However, it remains unknown whether this pattern of hippocampal atrophy is regionally specific and whether SMC are also paralleled by changes in peripheral levels of amyloid-beta (Abeta). METHODS: The volume of hippocampal subregions and plasma Abeta levels were cross-sectionally compared between elderly individuals with (SMC(+); N = 47) and without SMC (SMC(-); N = 48). Significant volume differences in hippocampal subregions were further correlated with plasma Abeta levels and with objective memory performance. RESULTS: Individuals with SMC exhibited significantly higher Abeta1-42 concentrations and lower volumes of CA1, CA4, dentate gyrus, and molecular layer compared with SMC(-) participants. Regression analyses further showed significant associations between lower volume of the dentate gyrus and both poorer memory performance and higher plasma Abeta1-42 levels in SMC(+) participants. CONCLUSIONS: The presence of SMC, lower volumes of specific hippocampal regions, and higher plasma Abeta1-42 levels could be conditions associated with aging vulnerability. If such associations are confirmed in longitudinal studies, the combination may be markers recommending clinical follow up in nondemented older adults. PMID- 26946103 TI - Macronutrients Intake and Incident Frailty in Older Adults: A Prospective Cohort Study. AB - BACKGROUND: Only a few studies have assessed the association between protein intake and frailty incidence and have obtained inconsistent results. This study examined the association of protein and other macronutrient intake with the risk of frailty in older adults. METHODS: A prospective cohort of 1,822 community dwelling individuals aged 60 and older was recruited in 2008-2010 and followed-up through 2012. At baseline, food consumption was assessed with a validated, computerized face-to-face diet history. In 2012, individuals were contacted again to ascertain incident frailty, defined as the presence of at least three of the five Fried criteria: low physical activity, slowness, unintentional weight loss, muscle weakness, and exhaustion. Analyses were performed using logistic regression and adjusted for the main confounders, including total energy intake. RESULTS: During a mean follow-up of 3.5 years, 132 persons with incident frailty were identified. The odds ratios (95% confidence interval) of frailty across increasing quartiles of total protein were 1.00, 0.55 (0.32-0.93), 0.45 (0.26 0.78), and 0.41 (0.23-0.72); p trend: .001. The corresponding figures for animal protein intake were 1.00, 0.68 (0.40-1.17), 0.56 (0.32-0.97), and 0.48 (0.26 0.87), p trend: .011. And for intake of monounsaturated fatty acids (MUFAs), the results were 1.00, 0.66 (0.37-1.20), 0.54 (0.28-1.02), and 0.50 (0.26-0.96); p trend: .038. No association was found between intake of vegetable protein, saturated fats, long-chain omega-3 fatty acids, alpha-linolenic acid, linoleic acid, simple sugars, or polysaccharides and the risk of frailty. CONCLUSION: Intake of total protein, animal protein, and MUFAs was inversely associated with incident frailty. Promoting the intake of these nutrients might reduce frailty. PMID- 26946102 TI - Sensory Impairments and Risk of Mortality in Older Adults. AB - Background: Sensory impairments increase with age and the majority of older people will experience a sensory impairment if they live long enough. However, the relationships of hearing, visual, and olfactory impairments with mortality are not well understood. Methods: Epidemiology of Hearing Loss Study participants (n = 2,418) aged 53-97 years (mean = 69 years) were examined in 1998-2000 and hearing, visual acuity, and olfaction were measured. Participants were followed for mortality for up to 17 years (mean = 12.8 years). Cox proportional hazards models were used to assess the association between prevalent sensory impairments and the 15-year cumulative incidence of death. Results: A total of 1,099 (45.4%) of participants died during the follow-up period. In age- and sex-adjusted Cox models, the risk of mortality was higher among participants with one (hazard ratio [HR] = 1.40, 95% confidence interval [CI] = 1.19, 1.64) or two or more (HR = 2.12, 95% CI = 1.74, 2.58) sensory impairments than among participants with no sensory impairments. Olfactory impairment at baseline was significantly associated with mortality (HR = 1.28, 95% CI = 1.07, 1.52) after adjusting for age, sex, sensory comorbidities, cardiovascular risk factors and disease, cognitive impairment, frailty, subclinical atherosclerosis, and inflammatory marker levels (n = 1,745). Hearing and visual impairment were not associated with mortality after adjusting for subclinical atherosclerosis and inflammation. Conclusion: Olfactory impairment, but not hearing or visual impairment, was associated with an increased risk of mortality. These results suggest that olfactory impairment may be a marker of underlying physiologic processes or pathology that is associated with aging and reduced survival in older adults. PMID- 26946104 TI - The way in which effects are analyzed and communicated can make a difference for decision making. PMID- 26946105 TI - Effect of vital sign measurement timing on Pulmonary Embolism Severity Index (PESI) and simplified PESI 30-day mortality risk determination. PMID- 26946106 TI - Mu-Opioid (MOP) receptor mediated G-protein signaling is impaired in specific brain regions in a rat model of schizophrenia. AB - Schizophrenia is a complex mental health disorder. Clinical reports suggest that many patients with schizophrenia are less sensitive to pain than other individuals. Animal models do not interpret schizophrenia completely, but they can model a number of symptoms of the disease, including decreased pain sensitivities and increased pain thresholds of various modalities. Opioid receptors and endogenous opioid peptides have a substantial role in analgesia. In this biochemical study we investigated changes in the signaling properties of the mu-opioid (MOP) receptor in different brain regions, which are involved in the pain transmission, i.e., thalamus, olfactory bulb, prefrontal cortex and hippocampus. Our goal was to compare the transmembrane signaling mediated by MOP receptors in control rats and in a recently developed rat model of schizophrenia. Regulatory G-protein activation via MOP receptors were measured in [(35)S]GTPgammaS binding assays in the presence of a highly selective MOP receptor peptide agonist, DAMGO. It was found that the MOP receptor mediated activation of G-proteins was substantially lower in membranes prepared from the 'schizophrenic' model rats than in control animals. The potency of DAMGO to activate MOP receptor was also decreased in all brain regions studied. Taken together in our rat model of schizophrenia, MOP receptor mediated G-proteins have a reduced stimulatory activity compared to membrane preparations taken from control animals. The observed distinct changes of opioid receptor functions in different areas of the brain do not explain the augmented nociceptive threshold described in these animals. PMID- 26946107 TI - Developmental DSP4 effects on cortical Arc expression. AB - Activity Regulated Cytoskeleton Associated Protein (Arc) is an immediate early gene that is critical to brain plasticity. In this study, norepinephrine's regulation of Arc expression was examined during different stages of postnatal development. Rats were injected with N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP-4), a selective noradrenergic neurotoxin, during preadolescence (PND 0 or 13), adolescence (PND 23 or 48) or adulthood (PND 60). After each DSP4 treatment, brains were harvested later in development and Arc mRNA levels analyzed with in situ hybridization. Rats lesioned with DSP4 during preadolescence showed no differences in Arc level compared to saline treated controls. In contrast, adolescence was a time of changing Arc mRNA response to DSP4. Rats lesioned during early adolescence showed Arc expression increases, while rats lesioned during late adolescence showed dramatic Arc expression decreases. Decreases in Arc level caused by late adolescent DSP4 were similar to those found in lesioned adults. These findings highlight a qualitatively different regulation of Arc expression by norepinephrine according to developmental stage, and indicate that mature regulation is not intact until late adolescence. These data point to important developmental differences in norepinephrine's regulation of brain plasticity. These differences may underlie contrasting psychotropic responses in children and adolescents compared to adults. PMID- 26946108 TI - Intrathecal administration of rapamycin inhibits the phosphorylation of DRG Nav1.8 and attenuates STZ-induced painful diabetic neuropathy in rats. AB - The mammalian target of rapamycin (mTOR) is a key regulator of mRNA translation and protein synthesis, and it is specifically inhibited by rapamycin. In chronic pain conditions, mTOR-mediated local protein synthesis is crucial for neuronal hyperexcitability and synaptic plasticity. The tetrodotoxin-resistant (TTX-R) sodium channel Nav1.8 plays a major role in action potential initiation and propagation and cellular excitability in DRG (dorsal root ganglion) neurons. In this study, we investigated if mTOR modulates the phosphorylation of Nav1.8 that is associated with neuronal hyperexcitability and behavioral hypersensitivity in STZ-induced diabetic rats. Painful diabetic neuropathy (PDN) was induced in Sprague-Dawley rats by intraperitoneal injection with streptozotocin (STZ) at 60mg/kg. After the onset of PDN, the rats received daily intrathecal administrations of rapamycin (1MUg, 3MUg, or 10MUg/day) for 7 days; other diabetic rats received the same volumes of dimethyl sulfoxide (DMSO). Herein, we demonstrate a marked increase in protein expression of total mTOR and phospho mTOR (p-mTOR) together with the up-regulation of phosphor-Nav1.8 (p-Nav1.8) prior to the mechanical withdrawal threshold reaching a significant reduction in dorsal root ganglions (DRGs). Furthermore, the intrathecal administration of rapamycin, inhibiting the activity of mTOR, suppressed the phosphorylation of DRG Nav1.8, reduced the TTX-R current density, heightened the voltage threshold for activation and lowered the voltage threshold for inactivation and relieved mechanical hypersensitivity in diabetic rats. An intrathecal injection (i.t.) of rapamycin inhibited the phosphorylation and enhanced the functional availability of DRG Nav1.8 attenuated STZ-induced hyperalgesia. These results suggest that rapamycin is a potential therapeutic intervention for clinical PDN. PMID- 26946109 TI - The role of time in conflict-triggered control: Extending the theory of response conflict monitoring. AB - Flexible goal-directed behavior requires monitor-control networks to detect the need for behavioral adjustments and to implement the required regulations. Among event-related brain potentials related to the function of such networks is the feedback-related negativity (FRN), which is detected in trial-and-error learning tasks. Conflict monitoring theory (CMT) as one of the influential theories of such networks cannot describe the FRN. Recently, we have proposed a cost-conflict monitoring system that extends the CMT. The cost-conflict monitoring holds that the monitoring system can detect conflict signal, but the conflict is over the costs of alternative outcomes of the selected action rather than the response conflict as proposed by the CMT. In the cost-conflict monitoring, cost functions are computed based on waiting times from the response to feedback delivery and from these quantities a conflict signal is derived. Here, we present a computational realization of such cost-conflict monitor-controller network. We utilize this computational model to simulate existing human performance and ERP data of a trial-and-error learning task. The model successfully simulated the behavioral data and FRN signals under different conditions in this task. PMID- 26946110 TI - Comparison of the Effects of Telephone Suicide Prevention Help by Volunteers and Professional Paid Staff: Results from Studies in the USA and Quebec, Canada. AB - Research since the 1960s has consistently found that lay volunteers are better at helping suicidal callers than professionals. Yet, professional degrees are increasingly becoming requirements for helpline workers. In our first study, we conducted post hoc comparisons of U.S. helplines with all professional paid staff, all lay volunteers, and a mix of both, using silent monitoring and standardized assessments of 1,431 calls. The volunteer centers more often conducted risk assessments, had more empathy, were more respectful of callers, and had significantly better call outcome ratings. A second study of five Quebec suicide prevention centers used silent monitoring to compare telephone help in 1,206 calls answered by 90 volunteers and 39 paid staff. Results indicate no significant differences between the volunteers and paid employees on outcome variables. However, volunteers and paid staff with over 140 hours of call experience had significantly better outcomes. Unlike the United States, Quebec paid employees were not required to have advanced professional degrees. We conclude from these results and previous research that there is no justification for requiring that suicide prevention helpline workers be mental health professionals. In fact, the evidence to date indicates that professionals may be less effective in providing telephone help to suicidal individuals when compared to trained lay volunteers. PMID- 26946112 TI - A live, attenuated pseudorabies virus strain JS-2012 deleted for gE/gI protects against both classical and emerging strains. AB - Emerging pseudorabies virus (PRV) variant have led to pseudorabies outbreaks in Chinese pig farms. The commercially available PRV vaccine provides poor protection against the PRV variant. In this study, a gE/gI deleted PRV strain JS 2012-?gE/gI was generated from a PRV variant strain using homologous DNA recombination. Compared to the parental strain JS-2012, JS-2012-?gE/gI grew slowly and showed small plaque morphology on Vero cells. The safety and immunological efficacy of JS-2012-?gE/gI was evaluated as a vaccine candidate. JS 2012-?gE/gI was avirulent to suckling piglets, but was able to provide full protection for young piglets against challenge with both the classical virulent PRV and the emerging PRV variant. After sows were vaccinated with the gE/gI deleted strain, their suckling offspring were resistant to an otherwise lethal challenge with the classical and the variant PRVs. Piglets inoculated with JS 2012-?gE/gI did not develop PRV-specific gE-ELISA antibodies. Thus, JS-2012 ?gE/gI appears to be a promising marker vaccine candidate to control PRV variant circulating in pig farms in China. PMID- 26946114 TI - Effect of thiols enrichment on Cr(VI) photo-reduction by natural organic matter (NOM). AB - Photochemical redox transformation of Cr(VI)-NOM complexes substantially affects transport and speciation of less toxic Cr(III) in natural waters. However, the underlying mechanisms remain unclear. This study reported photochemical reactions of Cr(VI) with thiol-enriched NOM under acidic condition. More effective thiols enrichment in humic acid (HA) was observed than that in fulvic acid (FA), thereby resulting in a higher reduction capacity and faster rate of Cr(VI) photo reduction. Chemical addition of sulfide to HA formed a large number of S containing molecular formulae, which subsequently disappeared following reactions with Cr(VI) under solar irradiation. Cr(VI) photo-reduction in thiol-enriched HA consumed more S-containing formulae. Solar irradiation caused a rapid loss of the reduction capacities and thiol contents in HA and FA. All these findings can provide useful information for understanding the biogeochemical cycles of chromium and sulfur, and are also of environmental significance because they may partially account for photo-transformation of Cr(VI) when chromium enters into the aquatic environment as acidic industrial effluents. PMID- 26946111 TI - Inhibition of endoplasmic reticulum glucosidases is required for in vitro and in vivo dengue antiviral activity by the iminosugar UV-4. AB - The antiviral activity of UV-4 was previously demonstrated against dengue virus serotype 2 (DENV2) in multiple mouse models. Herein, step-wise minimal effective dose and therapeutic window of efficacy studies of UV-4B (UV-4 hydrochloride salt) were conducted in an antibody-dependent enhancement (ADE) mouse model of severe DENV2 infection in AG129 mice lacking types I and II interferon receptors. Significant survival benefit was demonstrated with 10-20 mg/kg of UV-4B administered thrice daily (TID) for seven days with initiation of treatment up to 48 h after infection. UV-4B also reduced infectious virus production in in vitro antiviral activity assays against all four DENV serotypes, including clinical isolates. A set of purified enzyme, in vitro, and in vivo studies demonstrated that inhibition of endoplasmic reticulum (ER) alpha-glucosidases and not the glycosphingolipid pathway appears to be responsible for the antiviral activity of UV-4B against DENV. Along with a comprehensive safety package, these and previously published data provided support for an Investigational New Drug (IND) filing and Phases 1 and 2 clinical trials for UV-4B with an indication of acute dengue disease. PMID- 26946113 TI - Recombinant duck enteritis viruses expressing major structural proteins of the infectious bronchitis virus provide protection against infectious bronchitis in chickens. AB - To design an alternative vaccine for control of infectious bronchitis in chickens, three recombinant duck enteritis viruses (rDEVs) expressing the N, S, or S1 protein of infectious bronchitis virus (IBV) were constructed using conventional homologous recombination methods, and were designated as rDEV-N, rDEV-S, and rDEV-S1, respectively. Chickens were divided into five vaccinated groups, which were each immunized with one of the rDEVs, covalent vaccination with rDEV-N & rDEV-S, or covalent vaccination with rDEV-N & rDEV-S1, and a control group. An antibody response against IBV was detectable and the ratio of CD4(+)/CD8(+) T-lymphocytes decreased at 7 days post-vaccination in each vaccinated group, suggesting that humoral and cellular responses were elicited in each group as early as 7 days post-immunization. After challenge with a homologous virulent IBV strain at 21 days post-immunization, vaccinated groups showed significant differences in the percentage of birds with clinical signs, as compared to the control group (p < 0.01), as the two covalent-vaccination groups and the rDEV-S group provided better protection than the rDEV-N- or rDEV-S1 vaccinated group. There was less viral shedding in the rDEV-N & rDEV-S- (2/10) and rDEV-N & rDEV-S1- (2/10) vaccinated groups than the other three vaccinated groups. Based on the clinical signs, viral shedding, and mortality rates, rDEV-N & rDEV-S1 covalent vaccination conferred better protection than use of any of the single rDEVs. PMID- 26946115 TI - Activation of peroxymonosulfate by base: Implications for the degradation of organic pollutants. AB - Increasing attention has been paid to environmentally friendly activation methods of peroxymonosulfate (PMS) in advanced oxidation processes (AOPs) for organic pollutant elimination. This work demonstrates that Base can be applied as a novel activator for PMS. The Base/PMS system, at ambient temperature, was able to degrade a variety of organic pollutants, including acid orange 7 (AO7), phenol and bisphenol A. In subsequent experiments with AO7, the decolorization rates for AO7 followed pseudo-first-order kinetics, with rate constant values ranging from 0.0006 to 0.1749 min(-1) depending on the operating parameters (initial PMS, Base, AO7 concentrations and reaction temperature). Furthermore, the mechanism for PMS activation by the Base was elucidated by radical scavenger (tert-butyl alcohol, methanol, sodium azide and p-benzoquinone) and electron spin resonance trapping studies. The results revealed that superoxide anion radical and singlet oxygen other than sulfate radical were the primary reactive oxygen species in the Base/PMS system. The findings of this study present a new pathway for PMS activation and provide useful information for the treatment of wastewater. PMID- 26946116 TI - Aluminum chloride induces neuroinflammation, loss of neuronal dendritic spine and cognition impairment in developing rat. AB - Aluminum (Al) is present in the daily life of humans, and the incidence of Al contamination increased in recent years. Long-term excessive Al intake induces neuroinflammation and cognition impairment. Neuroinflammation alter density of dendritic spine, which, in turn, influence cognition function. However, it is unknown whether increased neuroinflammation is associated with altered density of dendritic spine in Al-treated rats. In the present study, AlCl3 was orally administrated to rat at 50, 150 and 450 mg/kg for 90d. We examined the effects of AlCl3 on the cognition function, density of dendritic spine in hippocampus of CA1 and DG region and the mRNA levels of IL-1beta, IL-6, TNF-alpha, MHC II, CX3CL1 and BNDF in developing rat. These results showed exposure to AlCl3 lead to increased mRNA levels of IL-1beta, IL-6, TNF-alpha and MCH II, decreased mRNA levels of CX3CL1 and BDNF, decreased density of dendritic spine and impaired learning and memory in developing rat. Our results suggest AlCl3 can induce neuroinflammation that may result in loss of spine, and thereby leads to learning and memory deficits. PMID- 26946117 TI - Selenium and its compounds in aquatic plant Veronica anagallis-aquatica. AB - The uptake, distribution and determination of Se and its compounds in macrophyte Veronica anagallis-aquatica were investigated. V. anagallis-aquatica and sediments were sampled in years 2009-2011 and in 2013 in three Slovenian watercourses flowing through an agricultural area, where addition of Se in feedstuffs has been performed for about 25 years. Se content in sediments were up to 0.86 MUg g(-1) and in whole plant varied from 0.186 to 1.535 MUg g(-1), all on dry weight basis. Se content were measured also in different plant parts; highest content were found in roots and lowest in stems. Separation of extractable Se compounds was performed by ion exchange chromatography and for on-line detection inductively coupled plasma-mass spectrometry was used. The results showed that only approximately 24% of Se in the macrophyte was extracted using enzyme Protease XIV. Extractable Se in plant parts varied from 10.5% in roots to 29.6% in leaves. Identification of Se(IV) and Se(VI) was achieved but no Se-amino acids were detected even at highest Se content. According to our results, we assume that 25 years of Se addition in feedstuff shows minimal impact on Se content in the selected agricultural area. PMID- 26946118 TI - Evidence for the absence of visceral pain in C57BL6/N mice subjected to therapeutically relevant O3/O2-pneumoperitoneum. AB - Each different gas that is used to induce a pneumoperitoneum (PP) exhibits individual effects within the peritoneal cavity. This might include adverse effects such as pain and/or inflammatory reactions. The acute effects of ozonized oxygen (O3/O2), a highly oxidative gas mixture, after being insufflated into the peritoneal cavity are analysed in this study. Using the abdominal constriction response ('writhing') assay of chemical nociception in C57BL6/N mice, O3/O2-PP was found not to be associated with visible pain responses and did not alter the c-fos expression in the spinal cord. In addition, mRNA expression levels of the pro-inflammatory cytokines, interleukin (IL)-1beta and IL-6, were found unaltered in the spleen 2 h after insufflation. In conclusion, O3/O2-PP is free of adverse pain and does not trigger inflammatory immune responses. PMID- 26946119 TI - Use of ultrasound imaging for the diagnosis of abnormal uterine bleeding in the bonnet macaque ( Macaca radiata). AB - Ultrasound is a powerful, low-cost, non-invasive medical tool used by laboratory animal veterinarians for diagnostic imaging. Sonohysterography and transvaginal ultrasound are frequently used to assess uterine anomalies in women presenting with abnormal uterine bleeding (AUB). In the present study, we have evaluated the abdominal ultrasound of bonnet monkeys ( n = 8) showing spontaneous ovulatory ( n = 5) and anovulatory ( n = 3) AUB. The ovulatory ( n = 5) macaques showed cyclic AUB for 7-8 days. The anovulatory ( n = 3) macaques had irregular AUB with menstrual cycles of 40-45 days. The B-mode abdominal, colour Doppler and 3D ultrasound scans were performed during the proliferative phase of the menstrual cycle. Ultrasound examination revealed endometrial polyps in five macaques and endometrial hyperplasia in three animals. The width and length of endometrial polyps was around 0.5-1 cm (average 0.51 +/- 0.23 cm * 0.96 +/- 0.16 cm) with significant increase in endometrial thickness ( P < 0.0002). 3D ultrasound also showed a homogeneous mass in the uterine cavity and colour Doppler ultrasound showed increased vascularity in the endometrial polyps. Endometrial hyperplasia characteristically appeared as a thickened echogenic endometrium ( P < 0.0002). This study demonstrates the use of non-invasive ultrasound techniques in the diagnosis of AUB in macaques. PMID- 26946120 TI - Studying skin tumourigenesis and progression in immunocompetent hairless SKH1-hr mice using chronic 7,12-dimethylbenz(a)anthracene topical applications to develop a useful experimental skin cancer model. AB - Previous studies have established that 7,12-dimethylbenz(a)anthracene (DMBA) can initiate skin tumourigenesis in conventional furred mouse models by acting on hair follicle stem cells. However, further cancer progression depends on repeated applications of tumour promoter agents. This study evaluated the timeline involved in skin tumourigenesis and progression in immunocompetent hairless SKH1 hr mice with dysfunctional hair follicles using only DMBA with no additional tumour promoter agents. The results showed that topical application of 30 ug (117 nmol) of DMBA over the back and flank regions of the mouse once a week and 15 ug (58.5 nmol) twice a week produced skin tumours after 7-8 weeks. However, by week 14 a heavy benign tumour load required the mice to be euthanized. Lowering the DMBA dose to 15 ug (58.5 nmol) once a week produced tumours more slowly and allowed the mice to be studied for a longer period to week 23. This low-dose DMBA regimen yielded a high percentage of malignant tumours (58.8%) after 23 weekly applications. Additionally DMBA-treated skin showed an increase in mean epidermal thickness in comparison to untreated and acetone-treated skin. Despite the aberrant hair follicles in SKH1-hr mice, this chemically driven skin cancer model in hairless mice can serve as a suitable alternative to the ultraviolet-induced skin cancer models and can be reliably replicated as demonstrated by both the pilot and main experiments. PMID- 26946121 TI - HealthLinks randomized controlled trial: Design and baseline results. AB - Small employers, especially those in low-wage industries, frequently lack the capacity and resources to implement evidence-based health promotion interventions without support and assistance. The purpose of this paper is to (a) describe the intervention design and study protocol of the HealthLinks Trial and (b) report baseline findings. This study is a three-arm randomized controlled trial testing the impact of the HealthLinks intervention on worksites' adoption and implementation of evidence-based interventions. Group 1 will receive HealthLinks, Group 2 will receive HealthLinks plus wellness committees, and Group 3 will be a delayed control group. Seventy-eight employers are participating in the study; and 3302 employees across the worksites participated in the baseline data collection. Employers and employees will participate in follow-up surveys at one and two years after baseline to measure implementation (one year) and maintenance (two years) of HealthLinks interventions. Study outcomes will determine whether HealthLinks is an effective approach to increasing evidence-based health promotion in small, low-wage worksites and whether wellness committees are a capacity-building tool that increases HealthLinks' effectiveness. PMID- 26946122 TI - No Association between Variation in Longevity Candidate Genes and Aging-related Phenotypes in Oldest-old Danes. AB - In this study we explored the association between aging-related phenotypes previously reported to predict survival in old age and variation in 77 genes from the DNA repair pathway, 32 genes from the growth hormone 1/ insulin-like growth factor 1/insulin (GH/IGF-1/INS) signalling pathway and 16 additional genes repeatedly considered as candidates for human longevity: APOE, APOA4, APOC3, ACE, CETP, HFE, IL6, IL6R, MTHFR, TGFB1, SIRTs 1, 3, 6; and HSPAs 1A, 1L, 14. Altogether, 1,049 single nucleotide polymorphisms (SNPs) were genotyped in 1,088 oldest-old (age 92-93 years) Danes and analysed with phenotype data on physical functioning (hand grip strength), cognitive functioning (mini mental state examination and a cognitive composite score), activity of daily living and self rated health. Five SNPs showed association to one of the phenotypes; however, none of these SNPs were associated with a change in the relevant phenotype over time (7 years of follow-up) and none of the SNPs could be confirmed in a replication sample of 1,281 oldest-old Danes (age 94-100). Hence, our study does not support association between common variation in the investigated longevity candidate genes and aging-related phenotypes consistently shown to predict survival. It is possible that larger sample sizes are needed to robustly reveal associations with small effect sizes. PMID- 26946124 TI - Root spatial metabolite profiling of two genotypes of barley (Hordeum vulgare L.) reveals differences in response to short-term salt stress. AB - Barley (Hordeum vulgare L.) is the most salt-tolerant cereal crop and has excellent genetic and genomic resources. It is therefore a good model to study salt-tolerance mechanisms in cereals. We aimed to determine metabolic differences between a cultivated barley, Clipper (tolerant), and a North African landrace, Sahara (susceptible), previously shown to have contrasting root growth phenotypes in response to the early phase of salinity stress. GC-MS was used to determine spatial changes in primary metabolites in barley roots in response to salt stress, by profiling three different regions of the root: root cap/cell division zone (R1), elongation zone (R2), and maturation zone (R3). We identified 76 known metabolites, including 29 amino acids and amines, 20 organic acids and fatty acids, and 19 sugars and sugar phosphates. The maintenance of cell division and root elongation in Clipper in response to short-term salt stress was associated with the synthesis and accumulation of amino acids (i.e. proline), sugars (maltose, sucrose, xylose), and organic acids (gluconate, shikimate), indicating a potential role for these metabolic pathways in salt tolerance and the maintenance of root elongation. The processes involved in root growth adaptation and the underlying coordination of metabolic pathways appear to be controlled in a region-specific manner. This study highlights the importance of utilizing spatial profiling and will provide us with a better understanding of abiotic stress response(s) in plants at the tissue and cellular level. PMID- 26946125 TI - When one is Enough: Impaired Multisensory Integration in Cerebellar Agenesis. AB - In the last two decades, an intriguing shift in the understanding of the cerebellum has led to consider the nonmotor functions of this structure. Although various aspects of perceptual and sensory processing have been linked to the cerebellar activity, whether the cerebellum is essential for binding information from different sensory modalities remains uninvestigated. Multisensory integration (MSI) appears very early in the ontogenesis and is critical in several perceptual, cognitive, and social domains. For the first time, we investigated MSI in a rare case of cerebellar agenesis without any other associated brain malformations. To this aim, we measured reaction times (RTs) after the presentation of visual, auditory, and audiovisual stimuli. A group of neurotypical age-matched individuals was used as controls. Although we observed the typical advantage of the auditory modality relative to the visual modality in our patient, a clear impairment in MSI was found. Beyond the obvious prudence necessary for inferring definitive conclusions from this single-case picture, this finding is of interest in the light of reduced MSI abilities reported in several neurodevelopmental and psychiatric disorders-such as autism, dyslexia, and schizophrenia-in which the cerebellum has been implicated. PMID- 26946123 TI - Direct observation of local xylem embolisms induced by soil drying in intact Zea mays leaves. AB - The vulnerability of vascular plants to xylem embolism is closely related to their stable long-distance water transport, growth, and survival. Direct measurements of xylem embolism are required to understand what causes embolism and what strategies plants employ against it. In this study, synchrotron X-ray microscopy was used to non-destructively investigate both the anatomical structures of xylem vessels and embolism occurrence in the leaves of intact Zea mays (maize) plants. Xylem embolism was induced by water stress at various soil drying periods and soil water contents. X-ray images of dehydrated maize leaves showed that the ratio of gas-filled vessels to all xylem vessels increased with decreased soil water content and reached approximately 30% under severe water stress. Embolism occurred in some but not all vessels. Embolism in maize leaves was not strongly correlated with xylem diameter but was more likely to occur in the peripheral veins. The rate of embolism formation in metaxylem vessels was higher than in protoxylem vessels. This work has demonstrated that xylem embolism remains low in maize leaves under water stress and that there xylem has characteristic spatial traits of vulnerability to embolism. PMID- 26946127 TI - Nutritional n-3 PUFA Deficiency Abolishes Endocannabinoid Gating of Hippocampal Long-Term Potentiation. AB - Maternal n-3 polyunsaturated fatty acids (PUFAs), especially docosahexaenoic acid, is critical during perinatal brain development. How early postnatal n-3 PUFA deficiency impacts on hippocampal synaptic plasticity is mostly unknown. Here we compared activity-dependent plasticity at excitatory and inhibitory synapses in the CA1 region of the hippocampus in weaned pups whose mothers were fed with an n-3 PUFA-balanced or n-3 PUFA-deficient diet. Normally, endogenous cannabinoids (eCB) produced by the post-synapse dually control network activity by mediating the long-term depression of inhibitory inputs (iLTD) and positively gating NMDAR-dependent long-term potentiation (LTP) of excitatory inputs. We found that both iLTD and LTP were impaired in n-3 PUFA-deficient mice. Pharmacological dissection of the underlying mechanism revealed that impairment of NMDAR-dependent LTP was causally linked to and attributable to the ablation of eCB-mediated iLTD and associated to disinhibitory gating of excitatory synapses. The data shed new light on how n-3 PUFAs shape synaptic activity in the hippocampus and provide a new synaptic substrate to the cognitive impairments associated with perinatal n-3 deficiency. PMID- 26946126 TI - Role of Dopamine 2 Receptor in Impaired Drug-Cue Extinction in Adolescent Rats. AB - Adolescent drug users display resistance to treatment such as cue exposure therapy (CET), as well as increased liability to relapse. The basis of CET is extinction learning, which involves dopamine signaling in the medial prefrontal cortex (mPFC). This system undergoes dramatic alterations during adolescence. Therefore, we investigated extinction of a cocaine-associated cue in adolescent and adult rats. While cocaine self-administration and lever-alone extinction were not different between the two ages, we observed that cue extinction reduced cue induced reinstatement in adult but not adolescent rats. Infusion of the selective dopamine 2 receptor (D2R)-like agonist quinpirole into the infralimbic cortex (IL) of the mPFC prior to cue extinction significantly reduced cue-induced reinstatement in adolescents. This effect was replicated by acute systemic treatment with the atypical antipsychotic aripiprazole (Abilify), a partial D2R like agonist. These data suggest that adolescents may be more susceptible to relapse due to a deficit in cue extinction learning, and highlight the significance of D2R signaling in the IL for cue extinction during adolescence. These findings inspire new tactics for improving adolescent CET, with aripiprazole representing an exciting potential pharmacological adjunct for behavioral therapy. PMID- 26946130 TI - Tuning Eye-Gaze Perception by Transitory STS Inhibition. AB - Processing eye-gaze information is a key step to human social interaction. Neuroimaging studies have shown that superior temporal sulcus (STS) is highly implicated in eye-gaze perception. In autism, a lack of preference for the eyes, as well as anatomo-functional abnormalities within the STS, has been described. To date, there are no experimental data in humans showing whether it is possible to interfere with eye-gaze processing by modulating STS neural activity. Here, we measured eye-gaze perception before and after inhibitory transcranial magnetic stimulation (TMS) applied over the posterior STS (pSTS) in young healthy volunteers. Eye-gaze processing, namely overt orienting toward the eyes, was measured using eye tracking during passive visualization of social movies. Inhibition of the right pSTS led participants to look less to the eyes of characters during visualization of social movies. Such effect was specific for the eyes and was not observed after inhibition of the left pSTS nor after placebo TMS. These results indicate for the first time that interfering with the right pSTS neural activity transitorily disrupts the behavior of orienting toward the eyes and thus indirectly gaze perception, a fundamental process for human social cognition. These results could open up new perspectives in therapeutic interventions in autism. PMID- 26946131 TI - Influence of thyroid hormone therapy on the fracture rate - A claims data cohort study. AB - INTRODUCTION: It has been debated for years whether long-term thyroid hormone intake causes fractures. Not only have previous studies suffered from design limitations, they also reached contradictory conclusions. We investigated thyroid hormones (thyroxine) as a possible risk factor for fractures in a cohort of 6.7 million persons based on administrative data. METHODS: The database consists of anonymized settlement data of approximately 70 German statutory health insurances covering a time period of six years. All subjects aged 60 and above were included in the study; subjects with repeated thyroxine prescriptions were assigned to the exposure group; members without thyroxine prescriptions to the control group. Outcome was any incident fracture during a declared time period. In order to calculate fracture risk, we performed multivariate cox regression analyses to adjust for confounders. RESULTS: Of 798 770 subjects fulfilling the inclusion criteria, 11.7% took thyroxine regularly and belong to the exposure group. The final cox regression showed that subjects taking thyroxine have a 6.3% higher risk (HR 1.063; CI 1.046-1.080, p=<.0001) than members of the control group. DISCUSSION: The study supports the assumption that long term thyroxine intake leads to an increase in fracture risk among patients older than 60years. The findings have implications for long term thyroxine treatment. PMID- 26946129 TI - Retrosplenial Cortical Contributions to Anterograde and Retrograde Memory in the Monkey. AB - Primate retrosplenial cortex (RSC) is important for memory but patient neuropathologies are diffuse so its key contributions to memory remain elusive. This study provides the first causal evidence that RSC in macaque monkeys is crucial for postoperative retention of preoperatively and postoperatively acquired memories. Preoperatively, monkeys learned 300 object-in-place scene discriminations across sessions. After RSC removal, one-trial postoperative retention tests revealed significant retrograde memory loss for these 300 discriminations relative to unoperated control monkeys. Less robust evidence was found for a deficit in anterograde memory (new postoperative learning) after RSC lesions as new learning to criterion measures failed to reveal any significant learning impairment. However, after achieving >=90% learning criterion for the postoperatively presented novel 100 object-in-place scene discriminations, short term retention (i.e., measured after 24 h delay) of this well-learnt set was impaired in the RSC monkeys relative to controls. A further experiment assessed rapid "within" session acquisition of novel object-in-place scene discriminations, again confirming that new learning per se was unimpaired by bilateral RSC removal. Primate RSC contributes critically to memory by supporting normal retention of information, even when this information does not involve an autobiographical component. PMID- 26946128 TI - Cortical Structure Alterations and Social Behavior Impairment in p50-Deficient Mice. AB - Alterations in genes that regulate neurodevelopment can lead to cortical malformations, resulting in malfunction during postnatal life. The NF-kappaB pathway has a key role during neurodevelopment by regulating the maintenance of the neural progenitor cell pool and inhibiting neuronal differentiation. In this study, we evaluated whether mice lacking the NF-kappaB p50 subunit (KO) present alterations in cortical structure and associated behavioral impairment. We found that, compared with wild type (WT), KO mice at postnatal day 2 present an increase in radial glial cells, an increase in Reelin protein expression levels, in addition to an increase of specific layer thickness. Moreover, adult KO mice display abnormal columnar organization in the somatosensory cortex, a specific decrease in somatostatin- and parvalbumin-expressing interneurons, altered neurite orientation, and a decrease in Synapsin I protein levels. Concerning behavior, KO mice, in addition to an increase in locomotor and exploratory activity, display impairment in social behaviors, with a reduction in social interaction. Finally, we found that risperidone treatment decreased hyperactivity of KO mice, but had no effect on defective social interaction. Altogether, these data add complexity to a growing body of data, suggesting a link between dysregulation of the NF-kappaB pathway and neurodevelopmental disorders pathogenesis. PMID- 26946133 TI - Differences in the ectoparasite fauna between micromammals captured in natural and adjacent residential areas are better explained by sex and season than by type of habitat. AB - We compared the ectoparasite fauna in 608 micromammals (chiefly 472 wood mice Apodemus sylvaticus, 63 Algerian mice Mus spretus, and 51 greater white-toothed shrews Crocidura russula) captured in natural and adjacent residential areas in spring and autumn during three consecutive years in four areas in periurban Barcelona (NE Spain). We found little support for an association of urbanization with differences in infestation by ectoparasites. Prevalence of Rhipicephalus sp. tick in wood mice and shrews was significantly higher in residential than in natural habitats, and the opposite was found for the flea Ctenophtalmus andorrensis catalanensis in shrews. Marked differences in the prevalence of the flea Leptopsylla taschenbergi amitina in wood mice between seasons were observed in natural but not in residential habitats, probably due to enhanced flea survival probabilities in the latter. However, as a rule, males were more frequently and heavily infested than females, and the prevalence was higher in autumn than in spring. Our results suggest that the ectoparasite fauna of periurban micromammals is shaped more by other factors than by habitat modification. People living in residential areas are at risk of contact with the arthropods borne by non-commensal micromammals and the pathogens transmitted by them. PMID- 26946134 TI - Endoscopic ultrasonography in pediatric patients--Experience from a tertiary care center in India. AB - BACKGROUND AND AIMS: Although endoscopic ultrasound (EUS) is used in the management of various gastrointestinal (GI) diseases in adults, data on its role in children is limited. This study evaluated the indications, safety, and impact of EUS in children. METHODS: Records of children (<18 years age) who underwent EUS between January 2006 and September 2014 were reviewed retrospectively and analyzed. RESULTS: One hundred and twenty-one children (70 males, 51 females) aged 15.2 +/- 2.9 years (mean +/- SD) underwent 123 diagnostic (including fine needle aspiration cytology (FNAC) in 7) and 2 therapeutic EUS procedures. Conscious sedation was used in 81 procedures (65%) and general anesthesia in 44 (35%). The pancreaticobiliary system was evaluated in 114 (118 procedures), mediastinum in 5, and stomach in 2 patients. EUS diagnosed chronic pancreatitis (21 patients), pancreatic necrosis (1), splenic artery pseudoaneurysm (1), gastric varix (1), pseudocysts (3), insulinomas (2), other pancreatic masses (2), choledocholithiasis (2), choledochal cysts (2), portal biliopathy (1), esophageal leiomyoma (1), gastric neuroendocrine tumor (NET) (1), and GI stromal tumor in stomach (1). EUS-guided FNAC was positive in four of seven patients (two had tuberculosis, one pancreatic solid pseudopapillary tumor, and one gastric NET). Three patients had minor adverse events. EUS had a positive clinical impact in 43 (35.5%) patients. CONCLUSIONS: EUS is feasible and safe in children. It provides valuable information that helps in their clinical management. PMID- 26946135 TI - Modeling of Amiodarone Effect on Heart Rate Control in Critically Ill Patients with Atrial Tachyarrhythmias. AB - AIMS: Amiodarone is the gold-standard medication to control heart rate in critically ill patients with atrial tachyarrhythmias (ATs); however, effective doses and covariates influencing its efficacy remain unknown. We therefore performed pharmacodynamic modeling of heart rate reduction induced by amiodarone in these patients. METHODS AND RESULTS: This observational study included 80 consecutive severely ill patients receiving amiodarone to treat ATs. A total of 1348 time-heart rate observations with 361 amiodarone dose administrations were analyzed during a period of up to 6 days after hospital treatment initiation using a nonlinear mixed-effect model. Pretreatment with amiodarone before intensive care administration, paroxysmal versus persistent AT, catecholamine infusion, and fluid and magnesium loading were among the covariates assessed in the model. In case of paroxysmal AT in a patient not pretreated with amiodarone, a 300 mg intravenous loading dose combined with an 800 mg oral dose on the first day, followed by 800 mg/day orally for 4 days was effective in achieving a heart rate between 80 and 115 bpm within the first day, and to maintain it during the next 4 days. Corresponding doses were twice as high in patients with persistent AT. Use of intravenous magnesium (p < 0.02) and fluid loading (p < 0.02) was associated with an earlier and greater heart rate decrease, while use of dobutamine had an opposite influence (p < 0.05). CONCLUSIONS: In critically ill patients with AT, the dose of amiodarone required to control heart rate is influenced by the type of AT and by other easily measurable conditions which may allow better individualization of amiodarone dosing. PMID- 26946136 TI - Revisiting Dosing Regimen Using Pharmacokinetic/Pharmacodynamic Mathematical Modeling: Densification and Intensification of Combination Cancer Therapy. AB - Controlling effects of drugs administered in combination is particularly challenging with a densified regimen because of life-threatening hematological toxicities. We have developed a mathematical model to optimize drug dosing regimens and to redesign the dose intensification-dose escalation process, using densified cycles of combined anticancer drugs. A generic mathematical model was developed to describe the main components of the real process, including pharmacokinetics, safety and efficacy pharmacodynamics, and non-hematological toxicity risk. This model allowed for computing the distribution of the total drug amount of each drug in combination, for each escalation dose level, in order to minimize the average tumor mass for each cycle. This was achieved while complying with absolute neutrophil count clinical constraints and without exceeding a fixed risk of non-hematological dose-limiting toxicity. The innovative part of this work was the development of densifying and intensifying designs in a unified procedure. This model enabled us to determine the appropriate regimen in a pilot phase I/II study in metastatic breast patients for a 2-week-cycle treatment of docetaxel plus epirubicin doublet, and to propose a new dose-ranging process. In addition to the present application, this method can be further used to achieve optimization of any combination therapy, thus improving the efficacy versus toxicity balance of such a regimen. PMID- 26946132 TI - Inflammation, fracture and bone repair. AB - The reconstitution of lost bone is a subject that is germane to many orthopedic conditions including fractures and non-unions, infection, inflammatory arthritis, osteoporosis, osteonecrosis, metabolic bone disease, tumors, and periprosthetic particle-associated osteolysis. In this regard, the processes of acute and chronic inflammation play an integral role. Acute inflammation is initiated by endogenous or exogenous adverse stimuli, and can become chronic in nature if not resolved by normal homeostatic mechanisms. Dysregulated inflammation leads to increased bone resorption and suppressed bone formation. Crosstalk among inflammatory cells (polymorphonuclear leukocytes and cells of the monocyte macrophage-osteoclast lineage) and cells related to bone healing (cells of the mesenchymal stem cell-osteoblast lineage and vascular lineage) is essential to the formation, repair and remodeling of bone. In this review, the authors provide a comprehensive summary of the literature related to inflammation and bone repair. Special emphasis is placed on the underlying cellular and molecular mechanisms, and potential interventions that can favorably modulate the outcome of clinical conditions that involve bone repair. PMID- 26946137 TI - Comprehensive analysis and validation of contemporary survival prognosticators in Korean patients with metastatic renal cell carcinoma treated with targeted therapy: prognostic impact of pretreatment neutrophil-to-lymphocyte ratio. AB - PURPOSE: In line with the era of targeted therapy (TT), an increasing number of prognosticators are becoming available for patients with metastatic renal cell carcinoma (mRCC). Here, potential prognosticators of cancer-specific survival (CSS) were identified based on the contemporary literature and were comprehensively validated in an independent cohort of patients treated for mRCC. METHODS: Data were collected from 478 patients treated with TT for mRCC between January 1999 and July 2013 at a single institution. The analysis included 25 clinicopathological covariates that included both traditional and contemporary prognosticators. Multivariate Cox regression models were used to quantify the effect of covariates on CSS. RESULTS: Median survival from the initial diagnosis of metastasis was 24.5 (IQR, 11.5-55.7) months. There were 303 (63.4 %) cancer specific deaths, yielding a 2-year CSS rate of 62.5 %. Low Karnofsky performance status (KPS), hypercalcemia, neutrophil-to-lymphocyte ratio (NLR), the number of metastatic sites (>=2), and the presence of brain metastases were independent adverse prognosticators of CSS. The C-index of the model was 0.78. Patients with at least one adverse prognosticator demonstrated lower 2-year CSS rates compared to those with no prognosticators (53.9 vs. 70.6 %; log rank p < 0.001). CONCLUSIONS: Together with traditional prognosticators such as KPS, hypercalcemia, and the number and location of metastases, the NLR was an independent predictor of CSS in patients with mRCC treated with TT. Our findings could be useful for guiding clinical decision making including stratification of patients for TT and inclusion in clinical trials. PMID- 26946138 TI - Impact of a ketogenic diet intervention during radiotherapy on body composition: I. Initial clinical experience with six prospectively studied patients. AB - BACKGROUND: Based on promising preclinical data, ketogenic diets (KDs) have been proposed as supplementary measures for cancer patients undergoing standard-of care therapy. However, data is still scarce on the tolerability and effects of KDs on cancer patients undergoing radiotherapy (RT). Here we present six cases of patients who underwent RT and concurrently consumed a self-administered KD in our clinic within a busy community hospital setting. METHODS: All patients were followed prospectively with measurements of blood parameters, quality of life and body weight and composition using bioelectrical impedance analysis. RESULTS: No adverse diet-related side effects occurred. Two patients had no elevated ketone body levels in serum despite self-reporting compliance to the diet. There was consensus that the KD was satiating and weight loss occurred in all patients, although this was only significant in two patients. Our data indicate that weight loss was mainly due to fat mass loss with concurrent preservation of muscle mass. Overall quality of life remained fairly stable, and all subjects reported feeling good on the diet. Tumor regression occurred as expected in five patients with early stage disease; however one subject with metastatic small cell lung cancer experienced slight progression during three cycles of combined chemotherapy + KD and progressed rapidly after ending the KD. CONCLUSIONS: Our data lend support to the hypothesis that KDs administered as supportive measures during standard therapy are safe and might be helpful in preservation of muscle mass. Further studies with control groups are needed to confirm these findings and address questions regarding any putative anti-tumor effects. Based on the experience with these six cases we implemented further steps to improve issues with KD compliance and initiated a clinical study that is described in a companion paper. PMID- 26946140 TI - [Germanwings flight... the psychiatrists without word]. PMID- 26946139 TI - Automatic segmentation of myocardium at risk from contrast enhanced SSFP CMR: validation against expert readers and SPECT. AB - BACKGROUND: Efficacy of reperfusion therapy can be assessed as myocardial salvage index (MSI) by determining the size of myocardium at risk (MaR) and myocardial infarction (MI), (MSI = 1-MI/MaR). Cardiovascular magnetic resonance (CMR) can be used to assess MI by late gadolinium enhancement (LGE) and MaR by either T2 weighted imaging or contrast enhanced SSFP (CE-SSFP). Automatic segmentation algorithms have been developed and validated for MI by LGE as well as for MaR by T2-weighted imaging. There are, however, no algorithms available for CE-SSFP. Therefore, the aim of this study was to develop and validate automatic segmentation of MaR in CE-SSFP. METHODS: The automatic algorithm applies surface coil intensity correction and classifies myocardial intensities by Expectation Maximization to define a MaR region based on a priori regional criteria, and infarct region from LGE. Automatic segmentation was validated against manual delineation by expert readers in 183 patients with reperfused acute MI from two multi-center randomized clinical trials (RCT) (CHILL-MI and MITOCARE) and against myocardial perfusion SPECT in an additional set (n = 16). Endocardial and epicardial borders were manually delineated at end-diastole and end-systole. Manual delineation of MaR was used as reference and inter-observer variability was assessed for both manual delineation and automatic segmentation of MaR in a subset of patients (n = 15). MaR was expressed as percent of left ventricular mass (%LVM) and analyzed by bias (mean +/- standard deviation). Regional agreement was analyzed by Dice Similarity Coefficient (DSC) (mean +/- standard deviation). RESULTS: MaR assessed by manual and automatic segmentation were 36 +/ 10% and 37 +/- 11%LVM respectively with bias 1 +/- 6%LVM and regional agreement DSC 0.85 +/- 0.08 (n = 183). MaR assessed by SPECT and CE-SSFP automatic segmentation were 27 +/- 10%LVM and 29 +/- 7%LVM respectively with bias 2 +/- 7%LVM. Inter-observer variability was 0 +/- 3%LVM for manual delineation and -1 +/- 2%LVM for automatic segmentation. CONCLUSIONS: Automatic segmentation of MaR in CE-SSFP was validated against manual delineation in multi-center, multi-vendor studies with low bias and high regional agreement. Bias and variability was similar to inter-observer variability of manual delineation and inter-observer variability was decreased by automatic segmentation. Thus, the proposed automatic segmentation can be used to reduce subjectivity in quantification of MaR in RCT. CLINICAL TRIAL REGISTRATION: NCT01379261. NCT01374321. PMID- 26946141 TI - Tailoring implementation strategies for evidence-based recommendations using computerised clinical decision support systems: protocol for the development of the GUIDES tools. AB - BACKGROUND: A computerised clinical decision support system (CCDSS) is a technology that uses patient-specific data to provide relevant medical knowledge at the point of care. It is considered to be an important quality improvement intervention, and the implementation of CCDSS is growing substantially. However, the significant investments do not consistently result in value for money due to content, context, system and implementation issues. The Guideline Implementation with Decision Support (GUIDES) project aims to improve the impact of CCDSS through optimised implementation based on high-quality evidence-based recommendations. To achieve this, we will develop tools that address the factors that determine successful CCDSS implementation. METHODS/DESIGN: We will develop the GUIDES tools in four steps, using the methods and results of the Tailored Implementation for Chronic Diseases (TICD) project as a starting point: (1) a review of research evidence and frameworks on the determinants of implementing recommendations using CCDSS; (2) a synthesis of a comprehensive framework for the identified determinants; (3) the development of tools for use of the framework and (4) pilot testing the utility of the tools through the development of a tailored CCDSS intervention in Norway, Belgium and Finland. We selected the conservative management of knee osteoarthritis as a prototype condition for the pilot. During the process, the authors will collaborate with an international expert group to provide input and feedback on the tools. DISCUSSION: This project will provide guidance and tools on methods of identifying implementation determinants and selecting strategies to implement evidence-based recommendations through CCDSS. We will make the GUIDES tools available to CCDSS developers, implementers, researchers, funders, clinicians, managers, educators, and policymakers internationally. The tools and recommendations will be generic, which makes them scalable to a large spectrum of conditions. Ultimately, the better implementation of CCDSS may lead to better-informed decisions and improved care and patient outcomes for a wide range of conditions. PROTOCOL REGISTRATION: PROSPERO, CRD42016033738. PMID- 26946142 TI - Effect of body shape and inflammation on tooth loss in men and women. AB - OBJECTIVES: Android and gynoid adiposity is differently involved on inflammatory responses in men or women in periodontitis and tooth loss. We tested the hypothesis whether identical waist-to-hip ratios (WHR) in men and women could abolish this disparity. MATERIALS AND METHODS: Data of 2746 participants from the Study of Health in Pomerania (SHIP) were analysed. Men and women were 1:1 matched, N = 344:344, in three age strata for waist-to-hip ratio. We determined anthropometric measures, attachment loss, tooth loss and markers of systemic inflammation. RESULTS: Women matched with men by WHR had increased periodontal measures as compared to women of the general population. Nevertheless, in the matched pairs incidence risk (IRR) ratios for any tooth loss associated with elevated C-reactive protein were IRR = 2.15 (CI 1.33-3.40) and 1.04 (0.66-1.66) in men and women, respectively. Regression with tooth loss due to any cause as dependent variable showed dose dependency on C-reactive protein levels in men but not in women. The adjusted IRR associated with high C-reactive protein in men was 1.37 (CI 1.05-1.78) and 2.63 (1.58-4.38) in general and in matched subjects, respectively. CONCLUSION: Systemic inflammation was associated with tooth loss in men but not in women even in women with wide girth. Despite worsened periodontal measures and inflammation in women matched for body shape with men, these women do not lose more teeth even when they are exposed to increased markers of systemic inflammation. CLINICAL RELEVANCE: This is an attempt to disentangle the unclear relationship between obesity and periodontitis, both of them having public health relevance. PMID- 26946143 TI - Stimulation of fat storage by prostacyclin and selective agonists of prostanoid IP receptor during the maturation phase of cultured adipocytes. AB - We have previously shown that cultured adipocytes have the ability to biosynthesize prostaglandin (PG) I2 called alternatively as prostacyclin during the maturation phase by the positive regulation of gene expression of PGI synthase and the prostanoid IP receptor. To clarify how prostacyclin regulates adipogenesis, we investigated the effects of prostacyclin and the specific agonists or antagonists for the IP receptor on the storage of fats during the maturation phase of cultured adipocytes. Exogenous PGI2 and the related selective agonists for the IP receptor including MRE-269 and treprostinil rescued the storage of fats attenuated by aspirin, a cyclooxygenase inhibitor. On the other hand, selective antagonists for IP such as CAY10441 and CAY10449 were effective to suppress the accumulation of fats as GW9662, a specific antagonist for peroxisome proliferator-activated receptor (PPAR)gamma. Thus, pro-adipogenic action of prostacyclin can be explained by the action mediated through the IP receptor expressed at the maturation stage of adipocytes. Cultured adipocytes incubated with each of PGI2 and MRE-269 together with troglitazone, an activator for PPARgamma, exhibited additively higher stimulation of fats storage than with either compound alone. The combined effect of MRE-269 and troglitazone was almost abolished by co-incubation with GW9662, but not with CAY10441. Increasing concentrations of troglitazone were found to reverse the inhibitory effect of CAY10441 in a dose-dependent manner while those of MRE-269 failed to rescue adipogenesis suppressed by GW9662, indicating the critical role of the PPARgamma activation as a downstream factor for the stimulated adipogenesis through the IP receptor. Treatment of cultured adipocytes with cell permeable stable cAMP analogues or forskolin as a cAMP elevating agent partly restored the inhibitory effect of aspirin. However, excess levels of cAMP stimulated by forskolin attenuated adipogenesis. Supplementation with H-89, a cell permeable inhibitor for protein kinase A (PKA), had no effect on the promoting action of PGI2 or MRE 269 along with aspirin on the storage of fats, suggesting that the promotion of adipogenesis mediated by the IP receptor does not require the PKA activity. PMID- 26946144 TI - The effect of a number of H9C2 rat cardiomyocytes passage on repeatability of cytotoxicity study results. AB - The embryonic cardiomyocyte cell line H9C2 is commonly used in numerous in vitro studies, including cardiotoxicity analyses of new drugs. So far no results were published for studies on cell parameters variability during the cell line ageing process. For this reason the aim of the study was to evaluate the effect of a number of H9C2 rat embryonic cardiomyocytes passages on repeatability of study results for selected cytotoxicity parameters, with doxorubicin as a model toxic agent. The cultures were passaged twenty-five times. Cells from passage 1, 5, 10, 15, 20 and 25 were treated with doxorubicin for 24 h. Then drug cytotoxicity was evaluated with the MTT test and additionally the nuclear factor erythroid 2 related factor (Nrf2) gene expression was examined. The analysis of oxidative stress intensity and cell morphology was also assessed. The microscopic appearance of cells indicates that untreated cardiomyocytes morphology changes as well as sensitivity to toxic effects increases with the number of passages. Also an increase in oxidative stress in cells occurs with further passaging of cardiomyocytes. Statistical significance of differences in conducted tests results depended on doxorubicin concentration but in many cases the H9C2 line was found to be a reliable in vitro model only for the first five passages. For this reason it is important to take into consideration that further culturing of cardiomyocytes may not ensure repeatability of study results due to the culture ageing. PMID- 26946145 TI - Mutagenic and cytotoxic activities of Limonium globuliferum methanol extracts. AB - Unmonitored use of plant extractions alone or in combination with drugs may cause important health problems and toxic effects. Limonium (Plumbaginaceae) plants are known as antibacterial, anticancer and antivirus agent. But it is possible that this genus may have toxic effects. This study evaluated the mutagenic and cytotoxic effects of Limonium globuliferum (Boiss. et Heldr.) O. Kuntze (Plumbaginaceae) acetone/methanol (2:1), and methanol extracts of root, stem, and leaf. Different parts of this species were used in order to compare the mutagenic and cytotoxic effects of these parts. Ames test was carried out with S. typhimurium TA98, and TA100 strains. Strains were incubated at 37 degrees C for 72 h. MDBK cell line was used in MTT test. 10,000, 1000, 100, 10, 1 and 0.1 ug/plate concentrations of plant extracts were used in Ames test. 50, 25, 12.5, 6.25 and 3.125 ug/ml concentrations of root, stem and leaf acetone/methanol (2:1) and methanol extracts were used in MTT test. Ames test results indicated that only methanol leaf extract (10,000 ug/plate) had mutagenic activity. L. globuliferum root methanol extracts (3.125 and 6.25 ug/ml) increased the proliferation rates. Root acetone/methanol (2:1) extracts were found highly cytotoxic in all treatments. The results indicated that leaf extracts had lower cytotoxic effects than root and stem extracts. High concentrations of L. globuliferum stem and leaf methanol extracts showed cytotoxic activity in all treatment periods while low concentrations of the stem methanol extracts increased the proliferation rates. PMID- 26946147 TI - Frequency characteristics of pressure transducer kits with inserted pressure resistant extension tubes. AB - The accurate monitoring of arterial blood pressure is important for cardiovascular management. However, the frequency characteristics of pressure transducer kits are influenced by the length of the pressure-resistant tube. To date, there have been few studies addressing the frequency characteristics of pressure transducer kits with inserted pressure-resistant extension tubes (pressure-resistant extension tube (ET) circuits). In this study, we examine ET circuits from the viewpoint of the frequency characteristics of pressure transducer kits. DT4812J transducer kits (length 150 cm; Argon Medical Devices, TX, USA) were used. Three original ET circuits were prepared, with the pressure resistant tube of the DT4812J being extended with a 30-cm length of pressure resistant tube (180ET circuit), a 60-cm length of pressure-resistant tube (210ET circuit), and a 90-cm length of pressure-resistant tube (240ET circuit). Each of these circuits was evaluated as part of this study. The natural frequency of the original DT4812J circuit was 45.90 Hz while the damping coefficient was 0.160. For the 180 ET circuit, the natural frequency and damping coefficient were 36.4 Hz and 0.162, respectively. For the ET210 circuit, the natural frequency and damping coefficient were 30.3 Hz and 0.175, respectively. For the ET210 circuit, the natural frequency and damping coefficient were 25.3 Hz and 0.180, respectively. As a result of extending the circuit, it was found that the natural frequency decreased drastically, while the damping coefficient increased slightly. When the extension of a pressure transducer kit is required, we should pay careful attention to the major decrease in the natural frequency, which may influence the pressure monitoring. PMID- 26946146 TI - The effects of upper limb posture and a sub-maximal gripping task on corticospinal excitability to muscles of the forearm. AB - Variations in handgrip force influences shoulder muscle activity, and this effect is dependent upon upper limb position. Previous work suggests that neural coupling between proximal and distal muscles with changes in joint position is a possible mechanism but these studies tend to use artificially constrained postures that do not reflect activities of daily living. The purpose of this study was to examine the effects of upper limb posture on corticospinal excitability to the forearm muscles during workplace relevant arm positions. Motor evoked potentials (MEPs) were elicited in four forearm muscles via transcranial magnetic stimulation at six arm positions (45 degrees , 90 degrees and 120 degrees of humeral elevation in both the flexion and abduction planes). MEPs were delivered as stimulus-response curves (SRCs) at rest and at constant intensity during two gripping tasks. Boltzmann plateau levels were smaller for the flexor carpi radialis in flexion at 45 degrees versus 90 degrees (p=0.0008). Extensor carpi radialis had a greater plateau during flexion than abduction (p=0.0042). Corticospinal excitability to the forearm muscles were influenced by upper limb posture during both the resting and gripping conditions. This provides further evidence that upper limb movements are controlled as a whole rather than segmentally and is relevant for workplace design considerations. PMID- 26946148 TI - Perioperative risk factors and cumulative duration of "triple-low" state associated with worse 30-day mortality of cardiac valvular surgery. AB - ABSRACT: Hospital stay and mortality in high-risk patients after noncardiac surgery has been associated with a triple low anesthesia. However, the association between anesthesia-related factors and perioperative outcome after cardiac surgery remains unclear.We tested the effect of a novel triple low state: low mean arterial pressure (MAP) <65 mmHg and low bispectral index (BIS) <45 during a low target effect-site concentration (Ce) <1.5 MUg ml-1 of propofol anesthesia on postoperative duration of hospitalization and 30-day mortality in cardiac valvular patients. In this prospective observational study, univariable and multivariable logistic regression analyses were used to determine whether perioperative factors, in particular, cumulative duration of triple low state were independently associated with duration of hospitalization and 30-day mortality among patients who underwent elective valvular replacement. 489 patients were included in the final analysis. After adjusting for related covariates, cumulative duration of the triple-low state was not associated with prolonged hospitalization (multivariable odds ratio: 1.007; 95 % confidence interval 0.997-1.017; P = 0.564), but was a significant predictor of 30-day mortality (multivariable odds ratio: 1.016; 95 % confidence interval 1.002-1.031; P = 0.030). Compared to a triple-low duration of <15 min, a duration >60 min increased the 30-day mortality rate by 8 times. After adjusting for patient- and procedure-related characteristics, the cumulative duration of a triple-low state (intraoperative low MAP, low BIS, and low Ce) was associated with poorer 30-day mortality, but not with prolonged duration of hospital stay.The mortality risk was even greater when a cumulative time >60 min. PMID- 26946149 TI - Tonglian Decoction () arrests the cell cycle in S-phase by targeting the nuclear factor-kappa B signal pathway in esophageal carcinoma Eca109 cells. AB - OBJECTIVE: To investigate the anti-tumor activity and molecular mechanism of Tonglian Decoction (, TLD) on esophageal carcinoma Eca109 cells. METHODS: Eca109 cells were treated with TLD and its separated formulae, including the clearing heat and detoxification formula (Q), activating-blood and promoting-qi formula (H) and nourishing-yin and blood formula (Z). Cell proliferation was measured using the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide assay, cell morphology was observed using a microscope, the cell cycle was measured using flow cytometry and the activity of the nuclear factor-kappa B (NF kappaB) signal pathway was detected by Western blot. RESULTS: The half maximal inhibitory concentrations of TLD, Q and H were 386, 771 and 729 mg/L, respectively. TLD, Q and H significantly inhibited cell proliferation, with 69.43%, 60.84% and 61.90% of treated cells in the G phase of the cell cycle. The percentage of cells in S phase increased significantly after treatment with TLD, Q, and H compared with the control group (P<0.05), and TLD showed the strongest effect. Z had no influence on the cell cycle compared with the control group (P>0.05). Western blot detection indicated slight differences in the inhibition of the NF-kappaB pathway by the different formulae. TLD formula strongly inhibited IKKbeta, NF-kappaB, interleukin-6 and tumor necrosis factor-alpha expression compared with the control group. CONCLUSIONS: TLD inhibited Eca109 cell proliferation by arresting cells in S phase. The possible mechanism might be related to inhibiting the NF-kappaB transduction cascade. The combination of the herbs found in the three separate formulae, H, Q and Z, work synergistically in TLD to produce the inhibitory effects of TLD treatment on Eca109 proliferation. PMID- 26946150 TI - Epidemiologic features of overseas imported malaria in the People's Republic of China. AB - BACKGROUND: With the dramatic increase in international travel among Chinese people, the risk of malaria importation from malaria-endemic regions threatens the achievement of the malaria elimination goal of China. METHODS: Epidemiological investigations of all imported malaria cases were conducted in nine provinces of China from 1 Nov, 2013 to 30 Oct, 2014. Plasmodium species, spatiotemporal distribution, clinical severity, preventive measures and infection history of the imported malaria cases were analysed using descriptive statistics. RESULTS: A total of 1420 imported malaria cases were recorded during the study period, with P. falciparum (723 cases, 50.9 %) and P. vivax (629 cases, 44.3 %) being the two predominant species. Among them, 81.8 % of cases were in Chinese overseas labourers. The imported cases returned from 41 countries, mainly located in Africa (58.9 %) and Southeast Asia (39.4 %). About a quarter (25.5 %, 279/1094) of counties in the nine study provinces were affected by imported malaria cases. There were 112 cases (7.9 %) developing complicated malaria, including 12 deaths (case fatality rate: 0.8 %). Only 27.8 % of the imported cases had taken prophylactic anti-malarial drugs. While staying abroad, 27.7 % of the cases had experienced two or more episodes of malaria infection. The awareness of clinical manifestations and the capacity for malaria diagnosis were weak in private clinics and primary healthcare facilities. CONCLUSIONS: Imported malaria infections among Chinese labourers, returned from various countries, poses an increasing challenge to the malaria elimination programme in China. The risk of potential re-introduction of malaria into inland malaria-free areas of China should be urgently addressed. PMID- 26946152 TI - Evaluation of the diagnostic role of transvaginal ultrasound measurements of endometrial thickness to detect endometrial malignancy in asymptomatic postmenopausal women. AB - PURPOSE: To assess the diagnostic accuracy of endometrial thickness measurements of transvaginal ultrasound (TVUS) in asymptomatic postmenopausal women in the detection of endometrial malignancy. METHODS: A retrospective cohort study in a university hospital was undertaken with 276 consecutive asymptomatic postmenopausal women undergoing dilatation and curettage (D&C) and hysteroscopy for an incidental finding of thickened endometrium (>=4 mm) between 2003 and 2012. Different endometrial thickness cutoff values were tested on the basis of a pathologic report with carcinoma conditions (endometrial hyperplasia with atypia and endometrial carcinoma). RESULTS: The mean age of patients was 59.8 +/- 9.0 years. The mean duration of menopause was 11.2 +/- 8.9 years. The final pathology diagnoses included 107 (38.8 %) patients with polyps, 42 (15.2 %) with atrophic endometrium, 39 (14.1 %) with estrogen exposure, and 19 (6.9 %) with normal endometrium. With regard to carcinoma conditions, nine patients (3.3 %) had endometrial hyperplasia with atypia and eight patients (2.9 %) had endometrial carcinoma. The area under the ROC curve was 0.52 (95 % CI 0.44-0.57), which indicated a poor accuracy of endometrial thickness of TVUS for carcinoma conditions. CONCLUSIONS: Routine use of endometrial thickness measurement with TVUS does not seem to be an effective diagnostic tool for endometrial cancer because it has a low diagnostic performance in asymptomatic postmenopausal women. Further prospective studies are required to assess the endometrial thickness measurement with TVUS as a screening method in these women. PMID- 26946151 TI - Identification of cell-surface markers for detecting breast cancer cells in ovarian tissue. AB - PURPOSE: The safety of ovarian tissue autotransplantation in oncology patients cannot be ensured, as current tumor-detection methods compromise the ovarian tissue viability. Although non-destructive methods (for instance near-infrared fluorescence imaging) can discriminate malignant from healthy tissues while leaving the examined tissues unaffected, they require specific cell-surface tumor markers. We determined which tumor markers are suitable targets for tumor specific imaging to exclude the presence of breast cancer cells in ovarian tissue. METHODS: Immunohistochemistry was performed on formalin-fixed, paraffin embedded specimens of ten ovaries from premenopausal patients. Additionally, we screened a tissue microarray containing tumor tissue cores from 24 breast cancer patients being eligible for ovarian tissue cryopreservation. The following cell surface tumor markers were tested: E-cadherin, EMA (epithelial membrane antigen), Her2/neu (human epidermal growth factor receptor type 2), alphavbeta6 integrin, EpCAM (epithelial cell adhesion molecule), CEA (carcinoembryonic antigen), FR alpha (folate receptor-alpha), and uPAR (urokinase-type plasminogen activator receptor). For each tumor, the percentage of positive breast tumor cells was measured. RESULTS: None of the ten ovaries were positive for any of the markers tested. However, all markers (except CEA and uPAR) were present on epithelial cells of inclusion cysts. E-cadherin was present in the majority of breast tumors: >=90 % of tumor cells were positive for E-cadherin in 17 out of 24 tumors, and 100 % of tumor cells were positive in 5 out of 24 tumors. CONCLUSIONS: Of the markers tested, E-cadherin is the most suitable marker for a tumor-specific probe in ovarian tissue. Methods are required to distinguish inclusion cysts from breast tumor cells. PMID- 26946153 TI - First external quality assurance program of the Italian HLA-B*57:01 Network assessing the performance of clinical virology laboratories in HLA-B*57:01 testing. AB - BACKGROUND: Since the HLA-B*57:01 allele is strongly associated with abacavir hypersensitivity reaction, testing for the presence of HLA-B*57:01 is mandatory before administration of abacavir. While HLA-B*57:01 testing is usually provided by pharmacogenetics, genetics or blood transfusion services, clinical virology laboratories can be an optimal opportunity for HLA-B*57:01 testing since they receive blood samples for routine HIV monitoring and have the expertise for convenient and less expensive PCR-based point mutation assays. OBJECTIVES: The Italian HLA-B*57:01 Network gathers accredited clinical virology laboratories offering HLA-B*57:01 testing in Italy with the aim to share protocols, test new methods, develop and maintain external quality assurance (EQA) programs. STUDY DESIGN: A panel of 9HLA-B*57:01-positive and 16HLA-B*57:01-negative frozen blood samples were blindly distributed to 10 units including 9 clinical virology laboratories and one reference pharmacology laboratory. Each laboratory was free to use its own routine method for DNA extraction and HLA-B*57:01 testing. RESULTS: DNA was extracted by automated workstations in 6 units and by manual spin columns in 4. Eight units used the Duplicalpha Real Time HLA-B*57:01 kit by Euroclone and two units used two different PCR homemade protocols. All the 10 units correctly identified all the 25 samples. CONCLUSIONS: The first HLA-B*57:01 EQA program run in Italy showed that clinical virology units are equipped and proficient for providing HLA-B*57:01 testing by inexpensive assays easy to integrate into their routine. PMID- 26946154 TI - Pseudotumoral recto-sigmoid herpes simplex virus type 2 in an HIV-infected patient: Dramatic improvement with thalidomide. PMID- 26946155 TI - Identification of hepatitis C virus genotype 3 by a commercial assay challenged by natural polymorphisms detected in Spain from patients with diverse origins. AB - BACKGROUND: Hepatitis C virus (HCV) genotyping is crucial in clinical practise for determining the type and duration of antiviral therapy. Between 2009 and 2014, 24 (7.95%) of all HCV genotype 3 (HCV-3) cases obtained indeterminate results via the RealTime HCV Genotype II assay (Abbott) at a tertiary care center in Spain. HCV-3 is the second most common genotype worldwide. Moreover, it has been associated with a higher risk of liver disease progression and a lower response to the latest antivirals. OBJECTIVE: Given the clinical significance of accurately identifying HCV-3, we aimed to characterize the genetic diversity of the HCV 5' untranslated region (5' UTR), the target of genotyping assays, by ultradeep pyrosequencing (UDPS). STUDY DESIGN: For the 24 indeterminate samples, the 5' UTR-core was amplified and subjected to UDPS with the 454/GS-Junior platform (Roche). The genotype/subtype of each identified haplotype was assigned by phylogenetic analysis. For comparison, three additional samples correctly identified as HCV-3 by the real-time assay were also analyzed. RESULTS: HCV genotyping based on 5' UTR-core UDPS was in agreement with NS5B Sanger sequencing in all cases, confirming the absence of mixed infections and recombination events. The generated 5' UTR sequences proved the presence of one to three polymorphisms at the probe-binding site of the Abbott assay, thereby differentiating indeterminate from correctly genotyped HCV-3 samples. CONCLUSIONS: The observed naturally occurring polymorphisms provide insight into regional differences observed with genotype 3, their impact on genotyping assay performance, and potential improvement and designing options. PMID- 26946156 TI - Effects of high voltage nanosecond electric pulses on eukaryotic cells (in vitro): A systematic review. AB - For this systematic review, 203 published reports on effects of electroporation using nanosecond high-voltage electric pulses (nsEP) on eukaryotic cells (human, animal, plant) in vitro were analyzed. A field synopsis summarizes current published data in the field with respect to publication year, cell types, exposure configuration, and pulse duration. Published data were analyzed for effects observed in eight main target areas (plasma membrane, intracellular, apoptosis, calcium level and distribution, survival, nucleus, mitochondria, stress) and an additional 107 detailed outcomes. We statistically analyzed effects of nsEP with respect to three pulse duration groups: A: 1-10ns, B: 11 100ns and C: 101-999ns. The analysis confirmed that the plasma membrane is more affected with longer pulses than with short pulses, seen best in uptake of dye molecules after applying single pulses. Additionally, we have reviewed measurements of nsEP and evaluations of the electric fields to which cells were exposed in these reports, and we provide recommendations for assessing nanosecond pulsed electric field effects in electroporation studies. PMID- 26946157 TI - Substrate and electrode potential affect electrotrophic activity of inverted bioanodes. AB - Electricity-consuming microbial communities can serve as biocathodic catalysts in microbial electrochemical technologies. Initiating their functionality, however, remains a challenge. One promising approach is the polarity inversion of bioanodes. The objective of this study was to examine the impact of bioanode substrate and electrode potentials on inverted electrotrophic activity. Bioanodes derived from domestic wastewater were operated at -0.15V or +0.15V (vs. standard hydrogen electrode) with either acetate or formate as the sole carbon source. After this enrichment phase, cathodic linear sweep voltammetry and polarization revealed that formate-enriched cultures consumed almost 20 times the current ( 3.0+/-0.78mA; -100+/-26A/m(3)) than those established with acetate (-0.16+/ 0.09mA; -5.2+/-2.9A/m(3)). The enrichment electrode potential had an appreciable impact for formate, but not acetate, adapted cultures, with the +0.15V enrichment generating twice the cathodic current of the -0.15V enrichment. The total charge consumed during cathodic polarization was comparable to the charge released during subsequent anodic polarization for the formate-adapted cultures, suggesting that these communities accumulated charge or generated reduced products that could be rapidly oxidized. These findings imply that it may be possible to optimize electrotrophic activity through specific bioanodic enrichment procedures. PMID- 26946158 TI - Electroporation and lipid nanoparticles with cyanine IR-780 and flavonoids as efficient vectors to enhanced drug delivery in colon cancer. AB - Nanocarriers and electroporation (also named electropermeabilization) are convenient methods to increase drug transport. In the current study, we present an effective support of drug delivery into cancer cells, utilizing these methods. We compare the efficiency of each of them and their combination. Multifunctional solid lipid nanoparticles (SLNs) loaded with a cyanine-type IR-780 - acting as a diagnostic agent and a photosensitizer, and a flavonoid derivative - baicalein (BAI) or fisetin (FIS) as a therapeutic cargo - were fabricated via solvent diffusion method. A therapy supplemented with flavonoids may provide a more precise method to apply desirable lower drug doses and is more likely to result in lower toxicity and a decrease in tumor growth. The SLNs were stabilized with Phospholipon 90G at various concentrations; cetyl palmitate (CP) was applied as a solid matrix. The obtained nanosystems were characterized by dynamic light scattering (size along with size distribution), UV-vis (cargos encapsulation efficiency) and atomic force microscopy (morphology and shape). The obtained SLNs were used as drug carriers alone and in combination with electropermeabilization induced by millisecond pulsed electric fields of high intensity. Two cell lines were selected for the study: LoVo and CHO-K1. The viability was assessed after electroporation alone, the use of electroporation and nanoparticles, and nanoparticles or drugs alone. The intracellular accumulation of cyanine IR-780 and the impact on intracellular structure organization of cytoskeleton was visualized with confocal microscopy method with alpha-actin and beta-tubulin. In this study, the efficacy of nanoparticles with mixed cargo, additionally enhanced by electroporation, is demonstrated to act as an anticancer modality to eliminate cancer cells. PMID- 26946160 TI - Parsing Multi-omic Data to Understand Urothelial Cell Carcinoma Progression. PMID- 26946161 TI - How Active is Active Surveillance? Intensity of Followup during Active Surveillance for Prostate Cancer in the United States. AB - PURPOSE: While major prostate cancer active surveillance programs recommend repeat testing such as prostate specific antigen and prostate biopsy, to our knowledge compliance with such testing is unknown. We determined whether men in the community receive the same intensity of active surveillance testing as in prospective active surveillance protocols. MATERIALS AND METHODS: We performed a retrospective cohort study of men 66 years old or older in the SEER (Surveillance, Epidemiology and End Results)-Medicare database. These men were diagnosed with prostate cancer from 2001 to 2009, did not receive curative therapy in the year after diagnosis and underwent 1 or more post-diagnosis prostate biopsies. We used multivariable adjusted Poisson regression to determine the association of the frequency of active surveillance testing with patient demographics and clinical features. In 1,349 men with 5 years of followup we determined the proportion who underwent testing as intense as that recommended by the Sunnybrook Health Sciences Centre and PRIAS (Prostate Cancer Research International Active Surveillance) programs, including 14 or more PSA tests and 2 or more biopsies, and The Johns Hopkins program, including 10 or more prostate specific antigen tests and 4 or more biopsies. RESULTS: Among 5,192 patients undergoing active surveillance greater than 80% had 1 or more prostate specific antigen tests per year but fewer than 13% underwent biopsy beyond the first 2 years. Magnetic resonance imaging was rarely done during the study period. On multivariable analysis recent diagnosis and higher income were associated with a higher frequency of surveillance biopsy while older age and greater comorbidity were associated with fewer biopsies. African American men underwent fewer prostate specific antigen tests but a similar number of biopsies. During 5 years of active surveillance only 11.1% and 5.0% of patients met the testing standards of the Sunnybrook/PRIAS and The Johns Hopkins programs, respectively. CONCLUSIONS: In the community few elderly men receive the intensity of active surveillance testing recommended in major prospective active surveillance programs. PMID- 26946162 TI - A validated software application to measure fiber organization in soft tissue. AB - The mechanical behavior of soft connective tissue is governed by a dense network of fibrillar proteins in the extracellular matrix. Characterization of this fibrous network requires the accurate extraction of descriptive structural parameters from imaging data, including fiber dispersion and mean fiber orientation. Common methods to quantify fiber parameters include fast Fourier transforms (FFT) and structure tensors; however, information is limited on the accuracy of these methods. In this study, we compared these two methods using test images of fiber networks with varying topology. The FFT method with a band pass filter was the most accurate, with an error of [Formula: see text] in measuring mean fiber orientation and an error of [Formula: see text] in measuring fiber dispersion in the test images. The accuracy of the structure tensor method was approximately five times worse than the FFT band-pass method when measuring fiber dispersion. A free software application, FiberFit, was then developed that utilizes an FFT band-pass filter to fit fiber orientations to a semicircular von Mises distribution. FiberFit was used to measure collagen fibril organization in confocal images of bovine ligament at magnifications of [Formula: see text] and [Formula: see text]. Grayscale conversion prior to FFT analysis gave the most accurate results, with errors of [Formula: see text] for mean fiber orientation and [Formula: see text] for fiber dispersion when measuring confocal images at [Formula: see text]. By developing and validating a software application that facilitates the automated analysis of fiber organization, this study can help advance a mechanistic understanding of collagen networks and help clarify the mechanobiology of soft tissue remodeling and repair. PMID- 26946163 TI - Vitamin D and functional arterial parameters in postmenopausal women with metabolic syndrome. AB - PURPOSE: Our cross sectional study aimed to identify the relation between vitamin D level and functional arterial parameters in postmenopausal women with metabolic syndrome. MATERIAL AND METHODS: 100 postmenopausal women at age 50-65 with diagnosed metabolic syndrome were included in this study. Laboratory tests were performed to determine lipid profile, serum glucose, creatinine, C-reactive protein, serum levels of 25(OH) D, ionized calcium and urine albumin/creatinine ratio. Also non-invasive assessment of arterial function (arterial stiffness, flow-mediated dilatation and carotid artery ultrasound examinations) was performed. RESULTS: The mean vitamin D blood concentration was 47.4+/-16.9nmol/l. The prevalence of modest insufficiency and deficiency of vitamin D was 62%. Vitamin D concentration in samples assembled from January to March was significantly lower than concentration levels from September to November. No significant relationship was observed between vitamin D and endothelial function, arterial stiffness, carotid intima-media thickness. Week negative correlation was stated between mean arterial pressure and 25(OH) D concentration (p=0.04). A positive correlation was found between high density lipoprotein cholesterol and vitamin 25(OH) D (r=0.3, p<0.05). No significant difference between 25(OH) D and other lipoproteins, calcium ions, glucose, albumin/creatinine ratio and C reactive protein blood concentrations were found. CONCLUSIONS: The prevalence of vitamin D deficiency in postmenopausal women with metabolic syndrome is high. No relation was found between vitamin D levels and parameters that indicate atherosclerotic vascular lesions. Nevertheless our study revealed the relation between concentrations of vitamin D and mean blood pressure and high density lipoprotein cholesterol. PMID- 26946164 TI - CagA-positive Helicobacter pylori strain containing three EPIYA C phosphorylation sites produces increase of G cell and decrease of D cell in experimentally infected gerbils (Meriones unguiculatus). AB - PURPOSE: Human infection by Helicobacter pylori is associated with an increase in the number of gastrin-producing G cells and a concomitant decrease of somatostatin-producing D cells. However, to our knowledge, changes in G and D cell numbers in response to infection with H. pylori CagA-positive strains containing different number of EPIYA-C phosphorylation sites have not been analyzed to date. Therefore, the aim of this study was to perform a quantitative analysis of the number of G and D cells in Mongolian gerbils challenged with H. pylori strains with different numbers of EPIYA-C motifs. MATERIALS AND METHODS: Mongolian gerbils were inoculated with isogenic H. pylori strains containing one to three phosphorylation sites. Mucosal fragments were evaluated by morphometry and immunohistochemistry using primary polyclonal rabbit anti-gastrin and anti somatostatin antibodies. Positive cells were counted using an image analyzer. RESULTS: Forty-five days after infection, there was a decrease in the number of D cells and an increase in the G/D cell ratio in the group with three EPIYA-C. Six months after infection, there was a progressive and significant increase in the number of G cells and in the G/D cell ratio, with a concomitant decrease in the number of D cells, especially in the three EPIYA-C group. CONCLUSIONS: CagA positive H. pylori strains containing a large number of EPIYA-C phosphorylation sites induce a decrease in D cell number and an increase in G cell number and G/D ratio, which were correlated with the number of inflammatory cells of the lamina propria. PMID- 26946165 TI - Homo-Tandem Polymer Solar Cells with VOC >1.8 V for Efficient PV-Driven Water Splitting. AB - Efficient homo-tandem and triple-junction polymer solar cells are constructed by stacking identical subcells composed of the wide-bandgap polymer PBDTTPD, achieving power conversion efficiencies >8% paralleled by open-circuit voltages >1.8 V. The high-voltage homo-tandem is used to demonstrate PV-driven electrochemical water splitting with an estimated solar-to-hydrogen conversion efficiency of ~6%. PMID- 26946166 TI - New approach for reduction of diesel consumption by comparing different mining haulage configurations. AB - The mining operations of loading and haulage have an energy source that is highly dependent on fossil fuels. In mining companies that select trucks for haulage, this input is the main component of mining costs. How can the impact of the operational aspects on the diesel consumption of haulage operations in surface mines be assessed? There are many studies relating the consumption of fuel trucks to several variables, but a methodology that prioritizes higher-impact variables under each specific condition is not available. Generic models may not apply to all operational settings presented in the mining industry. This study aims to create a method of analysis, identification, and prioritization of variables related to fuel consumption of haul trucks in open pit mines. For this purpose, statistical analysis techniques and mathematical modelling tools using multiple linear regressions will be applied. The model is shown to be suitable because the results generate a good description of the fuel consumption behaviour. In the practical application of the method, the reduction of diesel consumption reached 10%. The implementation requires no large-scale investments or very long deadlines and can be applied to mining haulage operations in other settings. PMID- 26946167 TI - Enhanced degradation of azo dye in wastewater by pulsed discharge plasma coupled with MWCNTs-TiO2/gamma-Al2O3 composite photocatalyst. AB - In order to improve the photocatalytic performance of TiO2 in pulsed discharge plasma systems, easily recycled multi-walled carbon nanotubes (MWCNTs)-TiO2 supported on gamma-Al2O3 (MWCNTs-TiO2/gamma-Al2O3) composite photocatalyst were prepared. The morphology and physicochemical properties of the prepared catalysts were investigated using XRD, SEM, FTIR and UV-vis spectroscopy. The photocatalytic activity was evaluated by degradation of azo dye acid orange II (AO7) in wastewater under pulsed discharge plasma. The results indicate that the MWCNTs-TiO2/gamma-Al2O3 composite catalyst possesses enhanced photocatalytic activity facilitating the decomposition of AO7 compared with TiO2/gamma-Al2O3 composite in pulsed discharge plasma systems. Under pulsed discharge plasma, almost 100% AO7 is degraded by the MWCNTs-TiO2/gamma-Al2O3 composite after 60 min at optimal conditions. The degradation efficiency of AO7 is also affected by the dosage of the composite catalyst and pulsed discharge peak voltage. As the amount of MWCNTs-TiO2/gamma-Al2O3 composite and pulsed discharge peak voltage increases, the degradation efficiency of AO7 increases. The photocatalyst was implemented for 6 cycles and the degradation efficiency of AO7 remains higher than 85% under pulsed discharge plasma. Results indicate that the catalyst displays easy separation and minimal deactivation after several uses. Possible decomposition mechanisms were also investigated. MWCNTs are capable of improving the photocatalytic activity of TiO2/gamma-Al2O3 composite in pulsed discharge plasma systems primarily due to the photo-induced-electron absorption effect and the electron trap effect of MWCNTs. The results of this study establish the feasibility and potential implementation of MWCNTs-TiO2/gamma-Al2O3 composites in pulsed discharge plasma systems for the degradation of dye wastewater. PMID- 26946168 TI - Performance evaluation of powdered activated carbon for removing 28 types of antibiotics from water. AB - Currently, the occurrence and fate of antibiotics in the aquatic environment has become a very serious problem in that they can potentially and irreversibly damage the ecosystem and human health. For this reason, interest has increased in developing strategies to remove antibiotics from water. This study evaluated the performance of powdered activated carbon (PAC) in removing from water 6 representative groups of 28 antibiotics, namely Tetracyclines (TCs), Macrolides (MCs), Chloramphenicols (CPs), Penicillins (PNs), Sulfonamides (SAs) and Quinolones (QNs). Results indicate that PAC demonstrated superior adsorption capacity for all selected antibiotics. The removal efficiency was up to 99.9% in deionized water and 99.6% in surface water at the optimum conditions with PAC dosage of 20 mg/L and contact time of 120 min. According to the Freundlich model's adsorption isotherm, the values of n varied among these antibiotics and most were less than 1, suggesting that the adsorption of antibiotics onto PAC was nonlinear. Adsorption of antibiotics followed well the pseudo-second-order kinetic model (R(2) = 0.99). Analysis using the Weber-Morris model revealed that the intra-particle diffusion was not the only rate-controlling step. Overall, the findings in this study confirm that PAC is a feasible and viable option for removing antibiotics from water in terms of water quality improvement and urgent antibiotics pollution control. Further research is essential on the following subjects: (i) removing more types of antibiotics by PAC; (ii) the adsorption process; and (iii) the mechanism of the competitive adsorption existing between natural organic matters (NOMs) and antibiotics. PMID- 26946169 TI - Water activity of poultry litter: Relationship to moisture content during a grow out. AB - Poultry grown on litter floors are in contact with their own waste products. The waste material needs to be carefully managed to reduce food safety risks and to provide conditions that are comfortable and safe for the birds. Water activity (Aw) is an important thermodynamic property that has been shown to be more closely related to microbial, chemical and physical properties of natural products than moisture content. In poultry litter, Aw is relevant for understanding microbial activity; litter handling and rheological properties; and relationships between in-shed relative humidity and litter moisture content. We measured the Aw of poultry litter collected throughout a meat chicken grow-out (from fresh pine shavings bedding material to day 52) and over a range of litter moisture content (10-60%). The Aw increased non-linearly from 0.71 to 1.0, and reached a value of 0.95 when litter moisture content was only 22-33%. Accumulation of manure during the grow-out reduced Aw for the same moisture content. These results are relevant for making decisions regarding litter re-use in multiple grow-outs as well as setting targets for litter moisture content to minimise odour, microbial risks and to ensure necessary litter physical conditions are maintained during a grow-out. Methods to predict Aw in poultry litter from moisture content are proposed. PMID- 26946170 TI - Identification and role analysis of an intermediate produced by a polygenic mutant of Monascus pigments cluster in Monascus ruber M7. AB - Monascus pigments (Mps) are a group of azaphilonic secondary metabolites produced by Monascus spp. via a polyketide pathway. A mutant deleted an about 30 kb region of Mps gene cluster from Monascus ruber M7 was isolated previously, which produces a high amount of a light yellow pigment. The current study revealed that the mutant named DeltaMpigJ-R lost proximate eight genes of the Mps gene cluster in M. ruber M7 through genetic analysis at DNA and RNA levels. The produced light yellow material was identified as a benzaldehyde derivative named as 6-(4-hydroxy 2-oxopentyl)-3-methyl-2, 4-dioxocyclohexane carb-aldehyde (M7PKS-1) by FT-IR, NMR, and MS. The sodium acetate-1-(13)C feeding experiment indicated that M7PKS-1 was a product produced from polyketide pathway. Finally, the feeding of M7PKS-1 helped to induce and regain Mps production of the mutants (DeltaMpigA and DeltaMpigE) which were previously unable to biosynthesize Mps and proved that M7PKS-1 was an initial intermediate of Mps. The results in this study provide a line of action to unveil Monascus pigments biosynthesis pathway. PMID- 26946171 TI - Regulation of genes encoding cellulolytic enzymes by Pal-PacC signaling in Aspergillus nidulans. AB - Cellulosic biomass represents a valuable potential substitute for fossil-based fuels. As such, there is a strong need to develop efficient biotechnological processes for the enzymatic hydrolysis of cellulosic biomass via the optimization of cellulase production by fungi. Ambient pH is an important factor affecting the industrial production of cellulase. In the present study, we demonstrate that several Aspergillus nidulans genes encoding cellulolytic enzymes are regulated by Pal-PacC-mediated pH signaling, as evidenced by the decreased cellulase productivity of the palC mutant and pacC deletants of A. nidulans. The deletion of pacC was observed to result in delayed induction and decreased expression of the cellulase genes based on time course expression analysis. The genome-wide identification of PacC-regulated genes under cellobiose-induced conditions demonstrated that genes expressed in a PacC-dependent manner included 82 % of ClrB (a transcriptional activator of the cellulase genes)-regulated genes, including orthologs of various transporter and beta-glucosidase genes considered to be involved in cellobiose uptake or production of stronger inducer molecules. Together with the significant overlap between ClrB- and PacC-regulated genes, the results suggest that PacC-mediated regulation of the cellulase genes involves not only direct regulation by binding to their promoter regions but also indirect regulation via modulation of the expression of genes involved in ClrB-dependent transcriptional activation. Our findings are expected to contribute to the development of more efficient industrial cellulase production methods. PMID- 26946172 TI - An efficient arabinoxylan-debranching alpha-L-arabinofuranosidase of family GH62 from Aspergillus nidulans contains a secondary carbohydrate binding site. AB - An alpha-L-arabinofuranosidase of GH62 from Aspergillus nidulans FGSC A4 (AnAbf62A-m2,3) has an unusually high activity towards wheat arabinoxylan (WAX) (67 U/mg; k cat = 178/s, K m = 4.90 mg/ml) and arabinoxylooligosaccharides (AXOS) with degrees of polymerisation (DP) 3-5 (37-80 U/mg), but about 50 times lower activity for sugar beet arabinan and 4-nitrophenyl-alpha-L-arabinofuranoside. alpha-1,2- and alpha-1,3-linked arabinofuranoses are released from monosubstituted, but not from disubstituted, xylose in WAX and different AXOS as demonstrated by NMR and polysaccharide analysis by carbohydrate gel electrophoresis (PACE). Mutants of the predicted general acid (Glu(188)) and base (Asp(28)) catalysts, and the general acid pK a modulator (Asp(136)) lost 1700-, 165- and 130-fold activities for WAX. WAX, oat spelt xylan, birchwood xylan and barley beta-glucan retarded migration of AnAbf62A-m2,3 in affinity electrophoresis (AE) although the latter two are neither substrates nor inhibitors. Trp(23) and Tyr(44), situated about 30 A from the catalytic site as seen in an AnAbf62A-m2,3 homology model generated using Streptomyces thermoviolaceus SthAbf62A as template, participate in carbohydrate binding. Compared to wild-type, W23A and W23A/Y44A mutants are less retarded in AE, maintain about 70 % activity towards WAX with K i of WAX substrate inhibition increasing 4-7-folds, but lost 77-96 % activity for the AXOS. The Y44A single mutant had less effect, suggesting Trp(23) is a key determinant. AnAbf62A-m2,3 seems to apply different polysaccharide-dependent binding modes, and Trp(23) and Tyr(44) belong to a putative surface binding site which is situated at a distance of the active site and has to be occupied to achieve full activity. PMID- 26946173 TI - Modulation of primary cilia length by melanin-concentrating hormone receptor 1. AB - Melanin-concentrating hormone (MCH) receptor 1 (MCHR1) is a class A G-protein coupled receptor (GPCR). The MCH-MCHR1 system has been implicated in the regulation of feeding, emotional processing, and sleep in rodents. Recent work revealed that MCHR1 is selectively expressed in neuronal primary cilia of the central nervous system. Cilia have various chemosensory functions in many types of cell, and ciliary dysfunction is associated with ciliopathies such as polycystic kidney disease and obesity. Although dynamic modulation of neuronal cilia length is observed in obese mice, the functional interaction of neuronal ciliary GPCR and its endogenous ligand has not yet been elucidated. We report here that MCH treatment significantly reduced cilia length in hTERT-RPE1 cells (hRPE1 cells) transfected with MCHR1. Quantitative analyses indicated that MCH induced cilia shortening progressed in a dose-dependent manner with an EC50 lower than 1nM when cells were treated for 6h. Although the assembly and disassembly of primary cilia are tightly coupled to the cell cycle, cell cycle reentry was not a determinant of MCH-induced cilia shortening. We confirmed that MCH elicited receptor internalization, Ca(2+) mobilization, ERK and Akt phosphorylation, and inhibition of cyclic AMP accumulation in MCHR1-expressing hRPE1 cells. Among these diverse pathways, we revealed that Gi/o-dependent Akt phosphorylation was an important component in the initial stage of MCH-induced cilia length shortening. Furthermore, induction of fewer cilia by Kif3A siRNA treatment significantly decreased the MCH-mediated phosphorylation of Akt, indicating the functional importance of the MCHR1-Akt pathway in primary cilia. Taken together, the present data suggest that the MCH-MCHR1 axis may modulate the sensitivity of cells to external environments by controlling the cilia length. Therefore, further characterization of MCHR1 as a ciliary GPCR will provide a potential molecular mechanism to link cilia length control with obesity. PMID- 26946174 TI - PKG-1alpha mediates GATA4 transcriptional activity. AB - GATA4, a zinc-finger transcription factor, is central for cardiac development and diseases. Here we show that GATA4 transcriptional activity is mediated by cell signaling via cGMP dependent PKG-1alpha activity. Protein kinase G (PKG), a serine/tyrosine specific kinase is the major effector of cGMP signaling. We observed enhanced transcriptional activity elicited by co-expressed GATA4 and PKG 1alpha. Phosphorylation of GATA4 by PKG-1alpha was detected on serine 261 (S261), while the C-terminal activation domain of GATA4 associated with PKG-1alpha. GATA4's DNA binding activity was enhanced by PKG-1alpha via by both phosphorylation and physical association. More importantly, a number of human disease-linked GATA4 mutants exhibited impaired S261 phosphorylation, pointing to defective S261 phosphorylation in the elaboration of human heart diseases. We showed S261 phosphorylation was favored by PKG-1alpha but not by PKA, and several other kinase signaling pathways such as MAPK and PKC. Our observations demonstrate that cGMP-PKG signaling mediates transcriptional activity of GATA4 and links defective GATA4 and PKG-1alpha mutations to the development of human heart disease. PMID- 26946175 TI - Methane oxidation in heavy metal contaminated Mollic Gleysol under oxic and hypoxic conditions. AB - Soils are the largest terrestrial sink for methane (CH4). However, heavy metals may exert toxicity to soil microorganisms, including methanotrophic bacteria. We tested the effect of lead (Pb), zinc (Zn) and nickel (Ni) on CH4 oxidation (1% v/v) and dehydrogenase activity, an index of the activity of the total soil microbial community in Mollic Gleysol soil in oxic and hypoxic conditions (oxia and hypoxia, 20% and 10% v/v O2, respectively). Metals were added in doses corresponding to the amounts permitted of Pb, Zn, Ni in agricultural soils (60, 120, 35 mg kg(-1), respectively), and half and double of these doses. Relatively low metal contents and O2 status reflect the conditions of most agricultural soils of temperate regions. Methane consumption showed high tolerance to heavy metals. The effect of O2 status was stronger than that of metals. CH4 consumption was enhanced under hypoxia, where both the start and the completion of the control and contaminated treatment were faster than under oxic conditions. Dehydrogenase activity, showed higher sensitivity to the contamination (except for low Ni dose), with a stronger effect of heavy metals, than that of the O2 status. PMID- 26946176 TI - Tracking human footprints in Antarctica through passive sampling of polycyclic aromatic hydrocarbons in inland lakes. AB - Freely dissolved polycyclic aromatic hydrocarbons (PAHs) were monitored in seven inland lakes of Antarctica by a polyethylene (PE)-based passive sampling technique, with the objective of tracking human footprints. The measured concentrations of PAHs were in the range of 14-360 ng L(-1) with the highest values concentrated around the Russian Progress II Station, indicating the significance of human activities to the loading of PAHs in Antarctica. The concentrations of PAHs in the inland lakes were in the upper part of the PAHs levels in aquatic environments from remote and background regions across the globe. The composition profiles of PAHs indicated that PAHs in the inland lakes were derived mainly from local oil spills, which was corroborated by a large number of fuel spillage reports from ship and plane crash incidents in Antarctica during recent years. Clearly, local human activities, rather than long-range transport, are the dominant sources of PAH contamination to the inland lakes. Finally, the present study demonstrates the efficacy of PE-based passive samplers for investigating PAHs in the aquatic environment of Antarctica under complex field conditions. PMID- 26946177 TI - Metal(loid) distribution and Pb isotopic signatures in the urban environment of Athens, Greece. AB - Lead concentrations and isotopic compositions of contaminated urban soils and house dusts from Athens, Greece, have been determined to identify possible sources of Pb contamination and examine relationships between these two environmental media. Different soil particle sizes (<2000 MUm, <200 MUm, <100 MUm, <70 MUm, <32 MUm) and chemical fractions (total, EDTA-extractable and acetic acid-extractable (HAc)) were analyzed for their Pb content and isotopic composition. Metal(loid)s (Pb, Zn, Cu, As, Ni, Cr, Mn, Fe) are significantly enriched in the finest fraction. The Pb isotopic compositions were similar for the different soil particle size fractions and different chemical extractions. The HAc extraction proved to be a useful procedure for tracing anthropogenic Pb in urban soil. The range of (206)Pb/(207)Pb ratios (1.140-1.180) in Athens soil suggests that the Pb content represents an accumulated mixture of Pb deposited from past vehicular emissions and local natural sources. The contribution of anthropogenic Pb to total soil Pb ranged from 36% to 95%. The Pb isotopic composition of vacuum house dusts ((206)Pb/(207)Pb = 1.1.38-1.167) from Athens residents is mostly comparable to that of urban soil suggesting that exterior soil particles are transferred into homes. As a result, anthropogenic Pb in house dust from Athens urban environment principally originated from soil particles containing Pb from automobile emissions (former use of leaded gasoline). PMID- 26946178 TI - Uptake, accumulation and metabolization of the antidepressant fluoxetine by Mytilus galloprovincialis. AB - Fluoxetine, a selective serotonin re-uptake inhibitor (SSRI) antidepressant, is among the most prescribed pharmaceutical active substances worldwide. This study aimed to assess its accumulation and metabolization in the mussel Mytillus galloprovincialis, considered an excellent sentinel species for traditional and emerging pollutants. Mussels were collected from Ria Formosa Lagoon, Portugal, and exposed to a nominal concentration of fluoxetine (75 ng L(-1)) for 15 days. Approximately 1 g of whole mussel soft tissues was extracted with acetonitrile:formic acid, loaded into an Oasis MCX cartridge, and fluoxetine analysed by liquid chromatography with tandem mass spectrometry (LC-MSn). After 3 days of exposure, fluoxetine was accumulated in 70% of the samples, with a mean of 2.53 ng g(-1) dry weight (d.w.) and norfluoxetine was only detected in one sample (10%), at 3.06 ng g(-1) d.w. After 7 days of exposure, the accumulation of fluoxetine and norfluoxetine increased up to 80 and 50% respectively, and their mean accumulated levels in mussel tissues were up to 4.43 and 2.85 ng g(-1) d.w., respectively. By the end of the exposure period (15 days), both compounds were detected in 100% of the samples (mean of 9.31 and 11.65 ng g(-1) d.w., respectively). Statistical analysis revealed significant accumulation differences between the 3rd and 15th day of exposure for fluoxetine, and between the 3rd and 7th against the 15th day of exposure for norfluoxetine. These results suggest that the fluoxetine accumulated in mussel tissues is likely to be metabolised into norfluoxetine with the increase of the time of exposure, giving evidence that at these realistic environmental concentrations, toxic effects of fluoxetine in mussel tissues may occur. PMID- 26946179 TI - Formamide Synthesis through Borinic Acid Catalysed Transamidation under Mild Conditions. AB - A highly efficient and mild transamidation of amides with amines co-catalysed by borinic acid and acetic acid has been reported. A wide range of functionalised formamides was synthesized in excellent yields, including important chiral alpha amino acid derivatives, with minor racemisation being observed. Experiments suggested that the reaction rely on a cooperative catalysis involving an enhanced boron-derived Lewis acidity rather than an improved Bronsted acidity of acetic acid. PMID- 26946180 TI - Species discovery and validation in a cryptic radiation of endangered primates: coalescent-based species delimitation in Madagascar's mouse lemurs. AB - Implementation of the coalescent model in a Bayesian framework is an emerging strength in genetically based species delimitation studies. By providing an objective measure of species diagnosis, these methods represent a quantitative enhancement to the analysis of multilocus data, and complement more traditional methods based on phenotypic and ecological characteristics. Recognized as two species 20 years ago, mouse lemurs (genus Microcebus) now comprise more than 20 species, largely diagnosed from mtDNA sequence data. With each new species description, enthusiasm has been tempered with scientific scepticism. Here, we present a statistically justified and unbiased Bayesian approach towards mouse lemur species delimitation. We perform validation tests using multilocus sequence data and two methodologies: (i) reverse-jump Markov chain Monte Carlo sampling to assess the likelihood of different models defined a priori by a guide tree, and (ii) a Bayes factor delimitation test that compares different species-tree models without a guide tree. We assess the sensitivity of these methods using randomized individual assignments, which has been used in bpp studies, but not with Bayes factor delimitation tests. Our results validate previously diagnosed taxa, as well as new species hypotheses, resulting in support for three new mouse lemur species. As the challenge of multiple researchers using differing criteria to describe diversity is not unique to Microcebus, the methods used here have significant potential for clarifying diversity in other taxonomic groups. We echo previous studies in advocating that multiple lines of evidence, including use of the coalescent model, should be trusted to delimit new species. PMID- 26946181 TI - Agriculture and herbivorous waterfowl: a review of the scientific basis for improved management. AB - Swans, geese and some ducks (Anatidae) are obligate herbivores, many are important quarry species and all contribute to a variety of ecosystem services. Population growth and shifting ranges have led to increasing proximity to man and thus increasing conflicts. We review and synthesize the role of these birds as herbivores on agricultural land (cropland, rotational grassland and pasture) and other terrestrial habitats where conflict with human interests may occur. A bibliographic analysis of peer-reviewed papers (N = 359) shows that publication activity peaked in 1991-2000 in North America and 2000-2010 in Europe, and has decreased since. Taxonomic and geographical biases are obvious in research to date: Snow Goose Chen caerulescens was the most studied species (N = 98), and Canada Branta canadensis, Barnacle B. leucopsis and Brent geese B. bernicla all featured in more than 40 studies; most studies originated in northwest Europe or North America, very few have been carried out in Asia and European Russia. On the basis of nutrient/energy budgets of herbivorous waterfowl, it is evident that dense single-species crops (such as rotational grassland, early-growth cereals and root crops) and spilled grain in agricultural landscapes offer elevated energetic and nutritional intake rates of food of higher quality compared to natural or semi-natural vegetation. Hence, although affected by seasonal nutritional demands, proximity to roost, field size, disturbance levels, access to water, food depletion and snow cover, agricultural landscapes tend to offer superior foraging opportunities over natural habitats, creating potential conflict with agriculture. Herbivorous waterfowl select for high protein, soluble carbohydrate and water content, high digestibility as well as low fibre and phenolic compounds, but intake rates from grazing varied with goose body and bill morphology, creating species-specific loci for conflict. Crop damage by trampling and puddling has not been demonstrated convincingly, nor do waterfowl faeces deter grazing stock, but where consumption of crops evidently reduces yields this causes conflict with farmers. Studies show that it is difficult and expensive to assess the precise impacts of waterfowl feeding on yield loss because of other sources of variation. However, less damage has been documented from winter grazing compared to spring grazing and yield loss after spring grazing on grassland appears more pronounced than losses on cereal fields. Although yield losses at national scales are trivial, individual farmers in areas of greatest waterfowl feeding concentrations suffer disproportionately, necessitating improved solutions to conflict. Accordingly, we review the efficacy of population management, disturbance, provision of alternative feeding areas, compensation and large-scale stakeholder involvement and co-management as options for resolving conflict based on the existing literature and present a framework of management advice for the future. We conclude with an assessment of the research needs for the immediate future to inform policy development, improve management of waterfowl populations and reduce conflict with agriculture. PMID- 26946182 TI - Validation and optimization of adiabatic T1rho and T2rho for quantitative imaging of articular cartilage at 3 T. AB - PURPOSE: The aim of the present work was to validate and optimize adiabatic T1rho and T2rho mapping for in vivo measurements of articular cartilage at 3 Tesla (T). METHODS: Phantom and in vivo experiments were systematically performed on a 3T clinical system to evaluate the sequences using hyperbolic secant HS1 and HS4 pulses. R1rho and R2rho relaxation rates were studied as a function of agarose and chondroitin sulfate concentration and pulse duration. Optimal in vivo protocol was determined by imaging the articular cartilage of two volunteers and varying the sequence parameters, and successively applied in eight additional subjects. Reproducibility was assessed in phantoms and in vivo. RESULTS: Relaxation rates depended on agarose and chondroitin sulfate concentration. The sequences were able to generate relaxation time maps with pulse lengths of 8 and 6 ms for HS1 and HS4, respectively. In vivo findings were in good agreement with the phantoms. The implemented adiabatic T1rho and T2rho sequences demonstrated regional variation in relaxation time maps of femorotibial cartilage. Reproducibility in phantoms and in vivo was good to excellent for both adiabatic T1rho and T2rho . CONCLUSIONS: The findings indicate that sequences are suitable for quantitative in vivo assessment of articular cartilage at 3 T. Magn Reson Med 77:1265-1275, 2017. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 26946184 TI - Accelerated Regeneration of ATP Level after Irradiation in Human Skin Fibroblasts by Coenzyme Q10. AB - Human skin is exposed to a number of harmful agents of which the ultraviolet (UV) component of solar radiation is most important. UV-induced damages include direct DNA lesions as well as oxidative damage in DNA, proteins and lipids caused by reactive oxygen species (ROS). Being the main site of ROS generation in the cell, mitochondria are particularly affected by photostress. The resulting mitochondrial dysfunction may have negative effects on many essential cellular processes. To counteract these effects, coenzyme Q10 (CoQ10 ) is used as a potent therapeutic in a number of diseases. We analyzed the mitochondrial respiration profile, the mitochondrial membrane potential and cellular ATP level in skin fibroblasts after irradiation. We observed an accelerated regeneration of cellular ATP level, a decrease in mitochondrial dysfunction as well as a preservation of the mitochondrial membrane potential after irradiation in human skin fibroblasts by treatment with CoQ10 . We conclude that the faster regeneration of the ATP level was achieved by a preservation of mitochondrial function by the addition of CoQ10 and that the protective effect of CoQ10 is primarily mediated via its antioxidative function. We suggest also that it might be further dependent on a stimulation of DNA repair enzymes by CoQ10 . PMID- 26946183 TI - De novo analysis of transcriptome reveals genes associated with leaf abscission in sugarcane (Saccharum officinarum L.). AB - BACKGROUND: Sugarcane (Saccharum officinarum L.) is an important sugar crop which belongs to the grass family and can be used for fuel ethanol production. The growing demands for sugar and biofuel is asking for breeding a sugarcane variety that can shed their leaves during the maturity time due to the increasing cost on sugarcane harvest. RESULTS: To determine leaf abscission related genes in sugarcane, we generated 524,328,950 paired reads with RNA-Seq and profiled the transcriptome of new born leaves of leaf abscission sugarcane varieties (Q1 and T) and leaf packaging sugarcane varieties (Q2 and B). Initially, 275,018 transcripts were assembled with N50 of 1,177 bp. Next, the transcriptome was annotated by mapping them to NR, UniProtKB/Swiss-Prot, Gene Ontology and KEGG pathway databases. Further, we used TransDecoder and Trinotate to obtain the likely proteins and annotate them in terms of known proteins, protein domains, signal peptides, transmembrane regions and rRNA transcripts. Different expression analysis showed 1,202 transcripts were up regulated in leaf abscission sugarcane varieties, relatively to the leaf packaging sugarcane varieties. Functional analysis told us 62, 38 and 10 upregulated transcripts were involved in plant pathogen interaction, response to stress and abscisic acid associated pathways, respectively. The upregulation of transcripts encoding 4 disease resistance proteins (RPM1, RPP13, RGA2, and RGA4), 6 ABC transporter G family members and 16 transcription factors including WRK33 and heat stress transcription factors indicate they may be used as candidate genes for sugarcane breeding. The expression levels of transcripts were validated by qRT-PCR. In addition, we characterized 3,722 SNPs between leaf abscission and leaf packaging sugarcane plants. CONCLUSION: Our results showed leaf abscission associated genes in sugarcane during the maturity period. The output of this study provides a valuable resource for future genetic and genomic studies in sugarcane. PMID- 26946185 TI - Using models to guide field experiments: a priori predictions for the CO2 response of a nutrient- and water-limited native Eucalypt woodland. AB - The response of terrestrial ecosystems to rising atmospheric CO2 concentration (Ca ), particularly under nutrient-limited conditions, is a major uncertainty in Earth System models. The Eucalyptus Free-Air CO2 Enrichment (EucFACE) experiment, recently established in a nutrient- and water-limited woodland presents a unique opportunity to address this uncertainty, but can best do so if key model uncertainties have been identified in advance. We applied seven vegetation models, which have previously been comprehensively assessed against earlier forest FACE experiments, to simulate a priori possible outcomes from EucFACE. Our goals were to provide quantitative projections against which to evaluate data as they are collected, and to identify key measurements that should be made in the experiment to allow discrimination among alternative model assumptions in a postexperiment model intercomparison. Simulated responses of annual net primary productivity (NPP) to elevated Ca ranged from 0.5 to 25% across models. The simulated reduction of NPP during a low-rainfall year also varied widely, from 24 to 70%. Key processes where assumptions caused disagreement among models included nutrient limitations to growth; feedbacks to nutrient uptake; autotrophic respiration; and the impact of low soil moisture availability on plant processes. Knowledge of the causes of variation among models is now guiding data collection in the experiment, with the expectation that the experimental data can optimally inform future model improvements. PMID- 26946186 TI - Tattooing to "Toughen up": Tattoo experience and secretory immunoglobulin A. AB - OBJECTIVES: A costly signaling model suggests tattooing inoculates the immune system to heightened vigilance against stressors associated with soft tissue damage. We sought to investigate this "inoculation hypothesis" of tattooing as a costly honest signal of fitness. We hypothesized that the immune system habituates to the tattooing stressor in repeatedly tattooed individuals and that immune response to the stress of the tattooing process would correlate with lifetime tattoo experience. METHODS: Participants were 24 women and 5 men (aged 18-47). We measured immune function using secretory immunoglobulin A (SIgA) and cortisol (sCORT) in saliva collected before and after tattoo sessions. We measured tattoo experience as a sum of number of tattoos, lifetime hours tattooed, years since first tattoo, percent of body covered, and number of tattoo sessions. We predicted an inverse relationship between SIgA and sCORT and less SIgA immunosuppression among those with more tattoo experience. We used hierarchical multiple regression to test for a main effect of tattoo experience on post-tattoo SIgA, controlling for pretest SIgA, tattoo session duration, body mass, and the interaction between tattoo experience and test session duration. RESULTS: The regression model was significant (P = 0.006) with a large effect size (r(2) = 0.711) and significant and positive main (P = 0.03) and interaction effects (P = 0.014). CONCLUSIONS: Our data suggest that the body habituates over time to the tattooing stressor. It is possible that individuals with healthy immune systems heal faster, making them more likely to get multiple tattoos. Am. J. Hum. Biol. 28:603-609, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26946187 TI - Clinical results of ab interno trabeculotomy using the Trabectome in patients with pigmentary glaucoma compared to primary open angle glaucoma. AB - BACKGROUND: To evaluate outcomes of Trabectome on pigmentary glaucoma (PG) patients compared to matched controls with primary open angle glaucoma (POAG). DESIGN: Prospective comparison study PARTICIPANTS: A total of 101 POAG cases were matched with 101 PG cases. METHODS: Data of the patients diagnosed with PG or POAG was obtained from Trabectome Study Group Database. A one-to-one exact matching was performed between POAG and pigmentary cases based on type of surgery, baseline IOP and baseline number of glaucoma medications. IOP and number of glaucoma medications were compared between groups by Wilcoxon test. Success was defined as IOP <= 21 mmHg, at least 20% IOP reduction from baseline for two consecutive visits after 3 months and no secondary surgery. MAIN OUTCOME MEASURES: Success rate after Trabectome surgery in PG patients. RESULTS: Baseline IOP for PG is 24.4 +/- 7.7 mmHg and 24.2 +/- 7.5 mmHg for POAG (P = 1.0), while baseline number of glaucoma medications was 2.8 +/- 1.2 mmHg for PG and 2.8 +/- 1.2 mmHg for POAG (P = 1.0). Postoperative IOP values at 12 months were 17.1 +/- 5.0 for PG cases and 15.9 +/- 4.2 mmHg for POAG cases. Postoperative number of glaucoma medications at 12 month was 2.1 +/- 1.4 in PG cases and 2.4 +/- 1.3 in POAG cases. There was no statistically significant difference between groups in IOP or number of medications at any time point. Survival rate at 12 months was 92% and 86% in PG and POAG, respectively (P = 0.47). Six PG cases and nine POAG cases required secondary surgery. CONCLUSION: Trabectome provides similar outcomes to PG patients and POAG patients. PMID- 26946188 TI - TP-2Rho Is a Sensitive Solvatochromic Red-Shifted Probe for Monitoring the Interactions between CDK4 and Cyclin D. AB - Understanding the intricate steps of protein kinase regulation requires characterization of protein-protein interactions between the catalytic subunit, its regulatory partners and the substrate. Fluorescent probes are useful tools with which to study such interactions and to gain insight into their affinities and specificities. Solvatochromic probes, which display changes in their fluorescence emission in response to changes in the polarity of the medium, are particularly attractive. Here we describe conjugation of a switchable fluorescent dye, TP-2Rho, to peptide and protein derivatives of cyclin-dependent kinase 4 (CDK4) and its application to characterization of the interactions between the catalytic subunit of this kinase, its regulatory partner cyclin D1 and a peptide substrate. We demonstrate the sensitivity of TP-2Rho in relation to of those other dyes used for monitoring peptide-protein and protein-protein interactions. Moreover, we show that TP-Rho-labelled peptides can be introduced into living cells to probe endogenous CDK4/cyclin D. PMID- 26946189 TI - Three-Dimensional Graphene: A Biocompatible and Biodegradable Scaffold with Enhanced Oxygenation. AB - Owing to its high porosity, specific surface area and three-dimensional structure, three-dimensional graphene (3D-C) is a promising scaffold material for tissue engineering, regenerative medicine as well as providing a more biologically relevant platform for living organisms in vivo studies. Recently, its differentiation effects on cells growth and anti-inflammation properties have also been demonstrated. Here, we report a complete study of 3D-C as a fully adequate scaffold for tissue engineering and systematically analyze its biocompatibility and biodegradation mechanism. The metabolic activities of liver cells (HepG2 hepatocarcinoma cells) on 3D-C are studied and our findings show that cell growth on 3D-C has high cell viability (> 90%), low lactate production (reduced by 300%) and its porous structure also provides an excellent oxygenation platform. 3D-C is also biodegradable via a 2-step oxidative biodegradation process by first, disruption of domains and lift off of smaller graphitic particles from the surface of the 3D-C and subsequently, the decomposition of these graphitic flakes. In addition, the speed of the biodegradation can be tuned with pretreatment of O2 plasma. PMID- 26946190 TI - Risk of hepatocellular carcinoma after sustained virological response in Veterans with hepatitis C virus infection. AB - The long-term prognosis in terms of risk or predictors of developing hepatocellular carcinoma (HCC) among patients with sustained virological response (SVR) remains unclear. We conducted a retrospective cohort study using data from the Veterans Affairs VA hepatitis C virus (HCV) Clinical Case Registry in patients with positive HCV RNA between October 1999 and August 2009 and follow-up through December 2010. HCV treatment (interferon with or without ribavirin) and SVR (RNA test negative at least 12 weeks after the end of treatment) were determined. We used Cox's proportional hazards models to calculate hazard ratios (HRs) for potential predictors (demographic, virological, and clinical) associated with HCC development post-SVR. We identified 33,005 HCV-infected individuals who received treatment, of whom 10,817 achieved SVR. Among these patients, 100 developed new HCC during a total follow-up of 30,562 person-years for an overall incidence rate of 0.33% per year. Annual risk of HCC remained considerably high among patients with cirrhosis (1.39%) and those cured after age 64 (0.95%). Patients with diabetes (adjusted HR = 1.88; 1.21-2.91) or genotype 3 infection (adjusted HR = 1.62; 0.96-2.734) were significantly more likely to develop HCC. CONCLUSIONS: Risk of HCC after HCV cure, though considerably reduced, remains relatively high at 0.33% per year. Older age and/or presence of cirrhosis at the time of SVR are associated with a high enough risk to warrant surveillance. Diabetes is also a risk factor for post-SVR HCC. (Hepatology 2016;64:130-137). PMID- 26946193 TI - Ventricular outputs, central blood flow distribution and flow pattern through the aortic isthmus of fetuses with simple transposition of the great arteries. AB - INTRODUCTION: Our objective was to determine the impact of simple transposition of the great arteries (TGA) on fetal left ventricular (LV) and right ventricular (RV) performances and central circulatory dynamics including the aortic isthmus. MATERIAL AND METHODS: Ventricular stroke volumes were calculated as the product of the cross-sectional area of the corresponding semi-lunar valve and the flow velocity integral through these valves. Volume flow in ductus arteriosus (QDA ) was evaluated using the same technique. Flow through the lungs (QLUNGS ) was calculated by subtracting net QDA from flow in main pulmonary artery [net QDA = QDA minus retrograde ductus arteriosus (DA) diastolic flow]. Relative performance of each ventricle expressed as percentage of combined cardiac output was also indirectly assessed by the aortic isthmus systolic index (ISI) (nadir of incisura/peak systolic of the Doppler waveforms in the isthmus); the relation between ISI and QLUNGS was investigated. RESULTS: Fifty-one fetuses with TGA were compared with 74 normal controls matched for gestational age. TGA fetuses had higher QLV at T2 (58.6 +/- 9.4% vs. 43.4 +/- 5.0%, p < 0.001) and T3 (53.7 +/- 8.9% vs. 43.9 +/- 5.7%, p < 0.001). QLUNGS was higher in fetuses with TGA, in the second (50.4 +/- 16.3% vs. 39.0 +/- 16.8%, p = 0.007) and third trimesters of gestation (52.8 +/- 22.0% vs. 37.1 +/- 16.3%, p = 0.005). No difference was found between ISI values from normal and TGA groups. A significant inverse correlation was observed between ISI and QLUNGS (r = -0.55, p = 0.006). CONCLUSIONS: Central distribution of combined cardiac output of fetuses with simple TGA is characterized by a greater QLUNGS leading to a dominant LV. In prenatal TGA, changes in QLUNGS could be monitored by measuring ISI. The clinical importance of this last observation deserves further investigations. PMID- 26946192 TI - Is severe progressive liver disease caused by alpha-1-antitrypsin deficiency more common in children or adults? AB - The classical form of alpha-1-antitrypsin deficiency (A1ATD) is known to cause liver disease in children and adults, but there is relatively little information about the risk of severe, progressive liver disease and the need for liver transplantation. To better understand how newly evolving pharmacological, genetic, and cellular therapies may be targeted according to risk for progressive liver disease, we sought to determine the age distribution of A1ATD as a cause of severe liver disease, as defined by the need for liver transplantation. Using 3 US liver transplantation databases for the period 1991-2012, we found 77.2% of 1677 liver transplants with a reported diagnosis of A1ATD were adults. The peak age range was 50-64 years. Using 2 of the databases which included specific A1AT phenotypes, we found that many of these adults who undergo liver transplantation with A1ATD as the diagnosis are heterozygotes and have other potential causes of liver disease, most notably obesity and ethanol abuse. However, even when these cases are excluded and only ZZ and SZ phenotypes are considered, severe liver disease requiring transplantation is more than 2.5 times as likely in adults. The analysis also showed a markedly increased risk for males. In the pediatric group, almost all of the transplants are done in children less than 5 years of age. In conclusion, A1ATD causes progressive liver disease most commonly in adults with males in the highest risk category. In the pediatric group, children less than 5 years of age are highest in risk. These results suggest that A1ATD most commonly causes liver disease by mechanisms similar to age-dependent degenerative diseases and more rarely in children by powerful modifiers. Liver Transplantation 22 886 894 2016 AASLD. PMID- 26946191 TI - Polymorphisms in DNA repair genes, traffic-related polycyclic aromatic hydrocarbon exposure and breast cancer incidence. AB - Vehicular traffic polycyclic aromatic hydrocarbons (PAHs) have been associated with breast cancer incidence in epidemiologic studies, including our own. Because PAHs damage DNA by forming adducts and oxidative lesions, genetic polymorphisms that alter DNA repair capacity may modify associations between PAH-related exposures and breast cancer risk. Our goal was to examine the association between vehicular traffic exposure and breast cancer incidence within strata of a panel of nine biologically plausible nucleotide excision repair (NER) and base excision repair (BER) genotypes. Residential histories of 1,508 cases and 1,556 controls were assessed in the Long Island Breast Cancer Study Project between 1996 and 1997 and used to reconstruct residential traffic exposures to benzo[a]pyrene, as a proxy for traffic-related PAHs. Likelihood ratio tests from adjusted unconditional logistic regression models were used to assess multiplicative interactions. A gene-traffic interaction was evident (p = 0.04) for ERCC2 (Lys751); when comparing the upper and lower tertiles of 1995 traffic exposure estimates, the odds ratio (95% confidence interval) was 2.09 (1.13, 3.90) among women with homozygous variant alleles. Corresponding odds ratios for 1960-1990 traffic were also elevated nearly 2-3-fold for XRCC1(Arg194Trp), XRCC1(Arg399Gln) and OGG1(Ser326Cys), but formal multiplicative interaction was not evident. When DNA repair variants for ERCC2, XRCC1 and OGG1 were combined, among women with 4-6 variants, the odds ratios were 2.32 (1.22, 4.49) for 1995 traffic and 2.96 (1.06, 8.21) for 1960-1990 traffic. Our study is first to report positive associations between traffic-related PAH exposure and breast cancer incidence among women with select biologically plausible DNA repair genotypes. PMID- 26946194 TI - Relative Role of Akt, ERK and CREB in Alcohol-Induced Microglia P2X4R Receptor Expression. AB - AIMS: Previously we have demonstrated altered microglia P2X4R expression in response to alcohol and pharmacological blockade with a selective P2X4R antagonist can reverse the action, suggesting that P2X4R play a role in mediating alcohol-induced effects on microglia. In the present study, we investigated the underlying signaling mediators, which may play a role in modulating P2X4R expression in microglia cells in response to alcohol. METHODS: Embryonic stem cell-derived microglia (ESdM) cells were used to investigate the potential mechanisms involved in the regulation of P2X4R in response to alcohol. Selective P2X4R antagonist and kinase inhibitors were used to further corroborate the signal transduction pathway through which alcohol modulates P2X4R expression in microglia. RESULTS: Alcohol (100 mM) suppressed phosphorylated AKT and ERK cascades in native ESdM cells. This alcohol-induced suppression was confirmed to be P2X4R-dependent through the use of a selective P2X4R antagonist and knockdown of P2XR4 by siRNA. Alcohol increased transcriptional activity of CREB. P2X4R antagonist blocked alcohol-induced effects on CREB, suggesting a P2X4R-mediated effect. CONCLUSION: These findings provide important clues to the underlying mechanism of purinoceptors in alcohol-induced microglia immune suppression. PMID- 26946195 TI - Targeted activation of primitive neural stem cells in the mouse brain. AB - Primitive neural stem cells (pNSCs) are the earliest NSCs to appear in the developing forebrain. They persist into the adult forebrain where they can generate all cells in the neural lineage and therefore hold great potential for brain regeneration. Thus, pNSCs are an ideal population to target to promote endogenous NSC activation. pNSCs can be isolated from the periventricular region as leukaemia inhibitory factor-responsive cells, and comprise a rare population in the adult mouse brain. We hypothesized that the pup periventricular region gives rise to more clonal pNSC-derived neurospheres but that pup-derived pNSCs are otherwise comparable to adult-derived pNSCs, and can be used to identify selective markers and activators of endogenous pNSCs. We tested the self-renewal ability, differentiation capacity and gene expression profile of pup-derived pNSCs and found them each to be comparable to adult-derived pNSCs, including being GFAP(-) , nestin(mid) , Oct4(+) . Next, we used pup pNSCs to test pharmacological compounds to activate pNSCs to promote endogenous brain repair. We hypothesized that pNSCs could be activated by targeting the cell surface proteins C-Kit and ErbB2, which were enriched in pNSCs relative to definitive NSCs (dNSCs) in an in vitro screen. C-Kit and ErbB2 signalling inhibition had distinct effects on pNSCs and dNSCs in vitro, and when infused directly into the adult brain in vivo. Targeted activation of pNSCs with C-Kit and ErbB2 modulation is a valuable strategy to activate the earliest cell in the neural lineage to contribute to endogenous brain regeneration. PMID- 26946196 TI - Study on frequency of dental developmental alterations in a Mexican school-based population. AB - BACKGROUND: The aim of this study was to know the distribution of dental developmental alterations in the population requesting stomatological attention at the Admission and Diagnosis Clinic of our institution in Mexico City. MATERIAL AND METHODS: We reviewed the archives and selected those files with developmental dental alterations. Analyzed data were diagnoses, age, gender, location and number of involved teeth. RESULTS: Of the 3.522 patients reviewed, 179 (5.1%) harbored 394 developmental dental alterations. Of them, 45.2% were males and 54.8% were females with a mean age of 16.7 years. The most common were supernumeraries, dental agenesia and dilaceration. Adults were 30.7% of the patients with dental developmental alterations. In them, the most common lesions were agenesia and supernumeraries. Mesiodens was the most frequently found supernumerary teeth (14.7%). CONCLUSIONS: Our finding that 30.7% of the affected patients were adults is an undescribed and unusually high proportion of patients that have implications on planning and prognosis of their stomatological treatment. PMID- 26946197 TI - Comparison of the detection of periodontal pathogens in bacteraemia after tooth brushing by culture and molecular techniques. AB - BACKGROUND: The prevalence and amounts of periodontal pathogens detected in bacteraemia samples after tooth brushing-induced by means of four diagnostic technique, three based on culture and one in a molecular-based technique, have been compared in this study. MATERIAL AND METHODS: Blood samples were collected from thirty-six subjects with different periodontal status (17 were healthy, 10 with gingivitis and 9 with periodontitis) at baseline and 2 minutes after tooth brushing. Each sample was analyzed by three culture-based methods [direct anaerobic culturing (DAC), hemo-culture (BACTEC), and lysis-centrifugation (LC)] and one molecular-based technique [quantitative polymerase chain reaction (qPCR)]. With culture any bacterial isolate was detected and quantified, while with qPCR only Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans were detected and quantified. Descriptive analyses, ANOVA and Chi-squared tests, were performed. RESULTS: Neither BACTEC nor qPCR detected any type of bacteria in the blood samples. Only LC (2.7%) and DAC (8.3%) detected bacteraemia, although not in the same patients. Fusobacterium nucleatum was the most frequently detected bacterial species. CONCLUSIONS: The disparity in the results when the same samples were analyzed with four different microbiological detection methods highlights the need for a proper validation of the methodology to detect periodontal pathogens in bacteraemia samples, mainly when the presence of periodontal pathogens in blood samples after tooth brushing was very seldom. PMID- 26946198 TI - The wolf in sheep's clothing: Microtomographic aspects of clinically incipient radiation-related caries. AB - BACKGROUND: Radiation related caries (RRC) can cause rapid progression, with a high potential for dental destruction affecting mainly cervical and incisal areas. Unlike the injuries that occur in the conventional caries, incipient RRC present in unusual surfaces have difficult diagnosis and classification stages of cavitation. MATERIAL AND METHODS: Evaluate the radiographic patterns of demineralization of RRC by using micro-CT. Ten teeth with incipient RRC and 10 teeth with incipient conventional caries (control group) matched by anatomic teeth group and caries affected surfaces were evaluated by X-ray microtomography (micro-CT) Skyscan 1174V2 (50Kv, 1.3 megapixel, Kontich, Belgium). Teeth were placed in a standard position for micro-CT (coronal, transaxial and sagittal sections) during images acquisition. Lesions were classified according to the depth of invasion and relationship with enamel, dentin and pulp. RESULTS: RRC samples presented deeper lesions with higher involvement of enamel and dentin. Control group presented focal and superficial lesions with lower involvement of enamel and dentin. CONCLUSIONS: Incipient RRC present aggressive microtomographic patterns of demineralization when compared to conventional caries, as indicated by deep lesions, regardless of its clinically incipient aspects. PMID- 26946199 TI - Predictability of short implants ( < 10 mm) as a treatment option for the rehabilitation of atrophic maxillae. A systematic review. AB - BACKGROUND: Short implants (< 10 mm) are one of the treatment options available in cases of limited vertical bone. Although such implants are now widely used, there is controversy regarding their clinical reliability. The purpose of this paper is to evaluate the predictability of short implants as an alternative to technically more complex treatments in patients with atrophic maxillae, based on a systematic review of the literature and the analysis of the implant survival rates, changes in peri-implant bone level, and associated complications. It is postulated that short implants offer clinical results similar to those of longer implants. MATERIAL AND METHODS: A Medline-PubMed search was made covering the period between January 2004 and December 2014 (both included). Studies in English published in indexed journals, involving at least 20 implants and with a follow up period of at least 12 months were considered. A manual search in four high impact journals was also conducted. RESULTS: A total of 37 studies meeting the inclusion criteria were included in this review. 9792 implants placed in over 5000 patients were analyzed. CONCLUSIONS: Based on the results of this review, short implants are seen to offer clinical results in terms of survival, bone loss and complications similar to those of longer implants. PMID- 26946200 TI - Histopathological grading systems analysis of oral squamous cell carcinomas of young patients. AB - BACKGROUND: To analyze the clinicopathological profile of young patients (<= 40 years) with oral SCC and correlate with a control group (>= 50 years) by means of histopathological grading systems. MATERIAL AND METHODS: 14 young patients and 14 control patients were selected with similar clinical stage and tumor location. Demographic and clinical data were obtained from patient records and histological sections were evaluated according to four histopathological grading systems. Associations between categories of demographic and clinical data were performed through Chi-square test and Exact Fisher test. The survival analyzes were performed according to the Kaplan-Meier method. RESULTS: The comparison between groups showed a greater association of treatment modalities in younger patients (p=0.022), they had a higher incidence of local recurrence and regional metastasis (p=0.018) and lower disease-free survival in 5 years (p=0.069). There was no difference in 5-year overall survival among the studied groups. There was no difference in histological grading between studied groups according to the four used systems. CONCLUSIONS: This study showed that, despite tumors had similar histological grade and more therapeutic modalities were used in the young group, tumors in young patients had a higher incidence of recurrence/metastasis, showing tendency to a more aggressive behavior. PMID- 26946201 TI - Influence of different types of pulp treatment during isolation in the obtention of human dental pulp stem cells. AB - BACKGROUND: Different methods have been used in order to isolate dental pulp stem cells. The aim of this study was to study the effect of different types of pulp treatment during isolation, under 3% O2 conditions, in the time needed and the efficacy for obtaining dental pulp stem cells. MATERIAL AND METHODS: One hundred and twenty dental pulps were used to isolate dental pulp stem cells treating the pulp tissue during isolation using 9 different methods, using digestive, disgregation, or mechanical agents, or combining them. The cells were positive for CD133, Oct4, Nestin, Stro-1, CD34 markers, and negative for the hematopoietic cell marker CD-45, thus confirming the presence of mesenchymal stem cells. The efficacy of dental pulp stem cells obtention and the minimum time needed to obtain such cells comparing the 9 different methods was analyzed. RESULTS: Dental pulp stem cells were obtained from 97 of the 120 pulps used in the study, i.e. 80.8% of the cases. They were obtained with all the methods used except with mechanical fragmentation of the pulp, where no enzymatic digestion was performed. The minimum time needed to isolate dental pulp stem cells was 8 hours, digesting with 2mg/ml EDTA for 10 minutes, 4mg/ml of type I collagenase, 4mg/ml of type II dispase for 40 minutes, 13ng/ml of thermolysine for 40 minutes and sonicating the culture for one minute. CONCLUSIONS: Dental pulp stem cells were obtained in 97 cases from a series of 120 pulps. The time for obtaining dental pulp stem cells was reduced maximally, without compromising the obtention of the cells, by combining digestive, disgregation, and mechanical agents. PMID- 26946202 TI - Effect of nonsurgical periodontal treatment in patients with periodontitis and rheumatoid arthritis: A systematic review. AB - BACKGROUND: Periodontitis has been regarded as a potential risk factor for rheumatoid arthrosis (RA). A systematic review is made to determine whether nonsurgical periodontal treatment in patients with RA offers benefits in terms of the clinical activity and inflammatory markers of the disease. MATERIAL AND METHODS: A search was made of the Medline-PubMed, Cochrane, Embase and Scopus databases to identify studies on the relationship between the two disease processes, and especially on the effects of nonsurgical treatment in patients of this kind. The search was based on the following keywords: rheumatoid arthritis AND periodontitis (MeSH), rheumatoid arthritis AND periodontal treatment. RESULTS: Eight articles on the nonsurgical treatment of patients with periodontitis and RA were finally included in the study. All of them evaluated clinical (DAS28) and laboratory test activity (ESR, CRP, IL-6, TNFalpha) before and after treatment. A clear decrease in DAS28 score and ESR was recorded, while other parameters such as CRP, IL-6 and TNFalpha showed a nonsignificant tendency to decrease as a result of treatment. CONCLUSIONS: Nonsurgical treatment improved the periodontal condition of patients with periodontitis and RA, with beneficial effects upon the clinical and laboratory test parameters (DAS28 and ESR), while other inflammatory markers showed a marked tendency to decrease. However, all the studies included in the review involved small samples sizes and follow-up periods of no more than 6 months. Larger and particularly longitudinal studies are therefore needed to more firmly establish possible significant relations between the two disease processes. PMID- 26946203 TI - Histological and histomorphometric study using an ultrasonic crestal sinus grafting procedure. A multicenter case study. AB - BACKGROUND: The aim of this study was to evaluate the efficacy of a hydrodynamic ultrasonic driven transcrestal sinus grafting procedure (Intralift (r), Acteon Company, Bordeaux, France) and the use of a bovine high temperature sintered grafting material in sinus sites with less than 5 mm remaining bone height with no additional autogenous bone in order to create a sufficient recipient site for implants. MATERIAL AND METHODS: 12 patients (16 sinus) in this multicenter case study were included. Using a crestal approach, bone under the sinus was prepared with ultrasonic tips until the Schneiderian membrane was reached. With a trumpet shaped instrument, the Schneiderian membrane was elevated. In the new created subantral space a high temperature sintered bovine grafting material was introduced (Bego Oss, BEGO Implant Systems GmbH & Co. KG, Bremen, Germany). After 6 months biopsies were taken with a trephine bur and histologies were generated following histomorphometric analysis. RESULTS: The results showed new vital bone in average of 33.4% +/- 17.05%, and 43.6% +/- 16.70 of bone substitute material. No signs of abnormal inflammation were observed. CONCLUSIONS: This procedure (Intralift (r)) allows, using a bovine material with no additional autogenous bone, new bone formation in the sinus in order to allow place implant subantraly. PMID- 26946205 TI - Long-term outcomes of oral rehabilitation with dental implants in HIV-positive patients: A retrospective case series. AB - BACKGROUND: The existing information on oral rehabilitations with dental implants in VIH-positive patients is scarce and of poor quality. Moreover, no long-term follow-up studies are available. Hence, the aims of this study were to describe the long-term survival and success rates of dental implants in a group of HIV positive patients and to identify the most common postoperative complications, including peri-implant diseases. MATERIAL AND METHODS: A retrospective case series of HIV-positive subjects treated with dental implants at the School of Dentistry of the University of Barcelona (Spain) was studied. Several clinical parameters were registered, including CD4 cell count, viral load and surgical complications. Additionally, the patients were assessed for implant survival and success rates and for the prevalence of peri-implant diseases. A descriptive statistical analysis of the data was performed. RESULTS: Nine participants (57 implants) were included. The patients' median age was 42 years (IQR=13.5 years). The implant survival and success rates were 98.3% and 68.4%, respectively, with a mean follow-up of 77.5 months (SD=16.1 months). The patient-based prevalence of peri-implant mucositis and peri-implantitis were 22.2% and 44.4% respectively at the last appointment. Patients that attended regular periodontal maintenance visits had significantly less mean bone loss than non-compliant patients (1.3 mm and 3.9 mm respectively). CONCLUSIONS: Oral rehabilitation with dental implants in HIV-positive patients seems to provide satisfactory results. In order to reduce the considerably high prevalence of peri-implant diseases, strict maintenance programmes must be implemented. PMID- 26946204 TI - Non-invasive visual tools for diagnosis of oral cancer and dysplasia: A systematic review. AB - BACKGROUND: Gold standard for the diagnosis of oral dysplasia (OD) and oral squamous cell carcinoma (OSCC) and malignant lesions is the histological examination. Several adjunctive diagnostic techniques have been proposed in order to increase the sensitivity (SE) and specificity (SP) of conventional oral examination and to improve the diagnostic first level accuracy. The aim of this study is to perform a systematic review on non-invasive tools for diagnosis of OD and early OSCC. MATERIAL AND METHODS: Medline, Scopus, Web of Knowledge databases were searched, using as entry terms "oral dysplasia AND diagnosis" / "oral cancer AND diagnosis". Data extracted from each study included number of lesions evaluated, histopathological diagnosis, SE, SP, positive and negative predictive values (PPV and NPV), diagnostic accuracy (DA) and the main conclusions. RESULTS: After title and abstract scanning of 11.080 records, we selected 35 articles for full text evaluation. Most evaluated tools were autofluorescence (AF), chemiluminescence (CL), toluidine blu (TL) and chemiluminescence associated with toluidine blue (CLTB). CONCLUSIONS: There is a great inhomogeneity of the reported values and there is no significant evidence of superiority of one tool over the other. Further clinical trials with a higher level of evidence are necessary in order to assess the real usefulness visual diagnostic tools. PMID- 26946206 TI - Influence of the prosthetic arm length (palatal position) of zygomatic implants upon patient satisfaction. AB - BACKGROUND: To assess the influence of the prosthetic arm length (palatal position) of zygomatic implants upon patient comfort and stability, speech, functionality and overall satisfaction. MATERIAL AND METHODS: A retrospective clinical study was made of patients subjected to rehabilitation of atrophic maxilla with complete maxillary implant-supported fixed prostheses involving a minimum of two zygomatic implants (one on each side) in conjunction with premaxillary implants, and with 12 months of follow-up after implant loading. Subjects used a VAS to score general satisfaction, comfort and stability, speech and functionality, and the results were analyzed in relation to the prosthetic arm length of the zygomatic implants 12 months after prosthetic delivery. RESULTS: Twenty-two patients participated in the study, receiving 22 prostheses anchored on 148 implants (44 were zygomatic and 94 were conventional implants). The mean right and left prosthetic arm length was 5.9+/-2.4 mm and 6.1+/-2.7 mm, respectively, with no statistically significant differences between them (p=0.576). The mean scores referred to comfort/retention, speech, functionality and overall satisfaction were high - no correlation being found between prosthetic arm length and patient satisfaction (p=0.815). CONCLUSIONS: No relationship could be identified between prosthetic arm length (palatal position) and patient satisfaction. PMID- 26946208 TI - Randomized controlled study of a mandibular advancement appliance for the treatment of obstructive sleep apnea in children: A pilot study. AB - BACKGROUND: The current limited evidence may be suggestive that mandibular advancement appliance (MAAs) result in improvements in AHI scores, but it is not possible to conclude that MAAs are effective to treat paediatric OSA.There are significant weaknesses in the existing evidence due primarily to absence of control groups, small sample sizes, lack of randomization and short-term results. AIM: the objective of the present study was to evaluate MAAs in children with OSA. METHODS: Children presenting an apnea-hypopnea index (AHI) greater than or equal to one event per hour were considered to be apneic. This group of children with AHI greater than or equal to one was randomly divided through a draw into two subgroups: half of them in an experimental subgroup and half of them in a control subgroup. In the experimental subgroup, molds of each of these children's maxillary and mandibular arches were taken using standard molds and molding material. The control group did not use any intraoral device and did not undergo any type of treatment for OSAS. The MAAs used in this study had the aim of achieving mandibular advancement, thereby correcting the mandibular position and dental occlusion, and perhaps increasing the airway and treating OSAS. After 12 consecutive months of use of the mandibular advancement devices, polysomnography examinations using the same parameters as in the initial examinations were requested for both the experimental and the control subgroup. RESULTS: There was a decrease in AHI in the experimental group and an increase in the control group, with statistical significance. These data were used to calculate the sample size, which was 28 children in total in the groups. CONCLUSIONS: There was a decrease in AHI one year after implementing use of mandibular advancement devices, in comparison with the group that did not use these devices. PMID- 26946207 TI - Depression and anxiety disorders in a sample of facial trauma: A study from Iran. AB - BACKGROUND: Various studies have shown that such patients are susceptible to psychological problems and poor quality of life. The aim of the present study was to evaluate and compare the prevalence of depression and anxiety disorders and quality of life in a group of facial trauma. MATERIAL AND METHODS: In the present cross-sectional study Hospital Anxiety and Depression Scale (HADS) and Oral Health Impact (OHIP-14) questionnaires were used. In this study, fifty subjects were selected from the patients with maxillofacial traumas based on the judgment of the physicians, referring to hospitals in Kerman and Rafsanjan during 2012 2013. In addition, 50 patients referring to the Dental School for tooth extraction, with no maxillofacial traumas, were included. SPSS 13.5 was used for statistical analysis with two-sample t-test, Mantel-Haenszel technique, Pearson's correlation coefficient and chi-squared test. RESULTS: Seven patients with maxillofacial traumas were depressed based on HADS depression scale, with 5 other borderline cases. However, patients referring for surgery or tooth extraction only 2 were depressed and 1 patient was a borderline case. The results showed that patients with maxillofacial traumas had higher rates of depression and anxiety, with significant differences between this group and the other group (P=0.01). The results of the present study showed a significant prelateship between depression severity and confounding factors. The mean of OHIP-14 parameters were 35.51 +/-5.2 and 22.3+/-2.4 in facial trauma and dental surgery groups, respectively, with statistically significant differences (P=0.01). CONCLUSIONS: The results of the present study showed depression and anxiety disorders in patients with maxillofacial trauma. The results showed a higher rate of anxiety and anxiety in patients with maxillofacial traumas compared to the control group. PMID- 26946209 TI - Efficacy of light based detection systems for early detection of oral cancer and oral potentially malignant disorders: Systematic review. AB - BACKGROUND: Earlier detection of oral squamous cell carcinoma (OSCC) and oral potentially malignant disorders (OPMD) is essential for dental professionals to improve patient survival rates. The aim of this systematic review is to to evaluate the effectiveness of devices that utilise the principles of chemiluminescence and tissue autofluorescence as adjuncts in the detection of OSCC and OPMD. MATERIAL AND METHODS: The electronic retrieval systems and databases searched for relevant articles were PubMed [MEDLINE] and Science direct. The search was for limited articles published in English or with an English abstract and articles published during the period from January 2005 to April 2014. Clinical trials utilized ViziLite, Microlux TM/DL and Visual Enhanced Light scope (VELscope) for early detection of OPMD and OSCC. RESULTS: Twenty primary studies published satisfied our criteria for selection - 10 utilised chemiluminescence and 10 tissue autofluorescence. Senstivity of Vizilite for detecting OSCC nad OPMD ranged from 77.1 % to 100% and specificity was low that ranged from 0% to 27.8%.Most have shown that chemiluminescence increases the brightness and margins of oral mucosal white lesions and thus assist in identification of mucosal lesions not considered under Conventional visual examination. However, it preferentially detects leukoplakia and may fail to spot red patches. Clinical trials demonstrated that sensitivity of VELscope in detecting malignancy and OPMD ranged from 22 % to 100 % and specificity ranged from 16 % to 100%. Most studies concluded that VELscope can help the experienced clinician to find oral precursor malignant lesions. But it couldnot differentiate between dysplasia and benign inflammatory conditions. CONCLUSIONS: Both devices are simple, non-invasive test of the oral mucosa but are suited for clinicians with sufficient experience and training. More clinical trials in future should be conducted to establish optical imaging as an efficacious adjunct tool in early diagnosis of OSCC and OPMD. PMID- 26946210 TI - Association between susceptible genotypes to periodontitis and clinical outcomes of periodontal regenerative therapy: A systematic review. AB - BACKGROUND: The aim of this review is to systematically investigate the effect of a susceptible genotype to periodontitis with the clinical outcomes of periodontal regeneration. MATERIAL AND METHODS: Based on a focused question, an electronic search identified 155 unique citations. Three journals (Journal of Periodontology, Journal of Clinical Periodontology and Journal of Periodontal Research), references of relevant studies and review articles were hand-searched. Two independent reviewers implementing eligibility inclusion criteria selected the studies. RESULTS: Of the 155, four studies fulfilled the inclusion criteria. All studies were published between 2000 and 2004 and the samples' size was 40 to 86 patients. Polymorphisms of Interleukin-1 (IL-1) gene were included in all. Three out of four studies failed to identify an association between susceptible genotypes to periodontitis and clinical outcomes of periodontal regeneration, while one found an association. The heterogeneity and small number of studies included prevented the conduct of a meta-analysis. No studies were identified evaluating the effect of other genotypes and as a result only IL-1 genotype studies were included. CONCLUSIONS: Within the limits of the present review, no direct conclusion for the effect of a susceptible IL-1 genotype status to the clinical outcome after periodontal regeneration could be drawn. The need of more qualitative studies to explore a possible association emerges. PMID- 26946211 TI - Efficacy of amoxicillin and amoxicillin/clavulanic acid in the prevention of infection and dry socket after third molar extraction. A systematic review and meta-analysis. AB - BACKGROUND: Prophylactic use of amoxicillin and amoxicillin/clavulanic acid, although controversial, is common in routine clinical practice in third molar surgery. MATERIAL AND METHODS: Our objective was to assess the efficacy of prophylactic amoxicillin with or without clavulanic acid in reducing the incidence of dry socket and/or infection after third molar extraction. We conducted a systematic review and meta-analysis consulting electronic databases and references in retrieved articles. We included double-blind placebo-controlled randomized clinical trials published up to June 2015 investigating the efficacy of amoxicillin with or without clavulanic acid on the incidence of the aforementioned conditions after third molar extraction. Relative risks (RRs) were estimated with a generic inverse-variance approach and a random effect model using Stata/IC 13 and Review Manager Version 5.2. Stratified analysis was performed by antibiotic type. RESULTS: We included 10 papers in the qualitative review and in the quantitative synthesis (1997 extractions: 1072 in experimental groups and 925 in controls, with 27 and 74 events of dry socket and/or infection, respectively). The overall RR was 0.350 (p<0.001; 95% CI 0.214 to 0.574). We found no evidence of heterogeneity (I2=0%, p=0.470). The number needed to treat was 18 (95% CI 13 to 29). Five studies reported adverse reactions (RR=1.188, 95% CI 0.658 to 2.146, p =0.567). The RRs were 0.563 for amoxicillin (95% CI 0.295 to 1.08, p=0.082) and 0.215 for amoxicillin/clavulanic acid (95% CI 0.117 to 0.395, p<0.001). CONCLUSIONS: Prophylactic use of amoxicillin does not significantly reduce the risk of infection and/or dry socket after third molar extraction. With amoxicillin/clavulanic acid, the risk decreases significantly. Nevertheless, considering the number needed to treat, low prevalence of infection, potential adverse reactions to antibiotics and lack of serious complications in placebo groups, the routine prescription of amoxicillin with or without clavulanic acid is not justified. PMID- 26946212 TI - Past, Present, and Future of Dynamic Kidney and Liver Preservation and Resuscitation. AB - The increased demand for organs has led to the increased usage of "higher risk" kidney and liver grafts. These grafts from donation after circulatory death or expanded criteria donors are more susceptible to preservation injury and have a higher risk of unfavorable outcomes. Dynamic, instead of static, preservation could allow for organ optimization, offering a platform for viability assessment, active organ repair and resuscitation. Ex situ machine perfusion and in situ regional perfusion in the donor are emerging as potential tools to preserve and resuscitate vulnerable grafts. Preclinical findings have ignited clinical organ preservation research that investigates dynamic preservation, its various modes (continuous, preimplantation) and temperatures (hypo-, sub, or normothermic). This review outlines the current status of dynamic preservation of kidney and liver grafts and describes ongoing research and emerging clinical trials. PMID- 26946213 TI - Hyaluronan coated cerium oxide nanoparticles modulate CD44 and reactive oxygen species expression in human fibroblasts. AB - Cerium oxide nanoparticles are being widely explored for cell therapies. In this study, nanoceria was functionalized with hyaluronan (HA) using the organosilane linker, 3-aminopropyltriethoxysilane. HA-nanoceria was found to be cytocompatible and to reduce intracellular reactive oxygen species in human fibroblasts. The HA nanoceria was found to colocalize with CD44 on the surface of the cells and once internalized traffic to the lysosomes, be degraded and induce markers of autophagy. These particles were also effective in reducing the cell surface expression of CD44. Together these data suggest that HA-nanoceria is a promising drug delivery material to target CD44-expressing cells through a variety of mechanisms. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 1736-1746, 2016. PMID- 26946214 TI - Randomized controlled exploratory study comparing the usefulness of two types of metallic stents with different axial forces for the management of duodenal obstruction caused by pancreatobiliary cancer. AB - BACKGROUND: Very few studies have examined effectiveness of duodenal stent placement (DSP) for duodenal obstruction (DO) caused specifically by pancreatobiliary cancer. We compared two types of stents with different axial forces (AF) for DO with pancreatobiliary cancer. METHODS: The patients were randomly assigned to two stent groups with different AF (high AF stent, WallFlexTM: W-group or low AF stent, Niti-STM: N-group). The primary endpoint was improvement in the Gastric Outlet Obstruction Scoring System (GOOSS) score. This study was registered at UMIN000009061. RESULTS: The GOOSS scores significantly improved in both W-group (0.9 before vs. 2.7 after; P = 0.002) and N-group (1.0 before vs. 2.5 after; P = 0.001). The change in the GOOSS score after DSP did not differ significantly between the groups (P = 0.482). The median time to recurrent DO (RDO) was significantly shorter in W-group than in N-group (89 days vs. 421 days; P = 0.025). The incidence of RDO was significantly higher in W-group than in N-group (64% vs. 24%; P = 0.027). Stent kinking occurred only in W-group. CONCLUSIONS: The GOOSS scores significantly improved after DSP, but effectiveness did not differ significantly between groups. The use of stents with high AF was related to short-term stent patency, but did not influence survival time. PMID- 26946215 TI - Epidemiology of Mixed Connective Tissue Disease, 1985-2014: A Population-Based Study. AB - OBJECTIVE: To characterize the epidemiology of mixed connective tissue disease (MCTD) from 1983 to 2014. METHODS: An inception cohort of patients with incident MCTD in 1985-2014 in Olmsted County, Minnesota was identified based on comprehensive individual medical record review. Diagnosis of MCTD required fulfillment of at least 1 of the 4 widely accepted diagnostic criteria without fulfillment of classification criteria for other connective tissue diseases. Data were collected on demographic characteristics, clinical presentation, laboratory investigations, and mortality. RESULTS: A total of 50 incident cases of MCTD were identified (mean age 48.1 years and 84% were female). The annual incidence of MCTD was 1.9 per 100,000 population. Raynaud's phenomenon was the most common initial symptoms (50%), followed by arthralgia (30%) and swollen hands (16%). The diagnosis was frequently delayed with the median time from first symptom to fulfillment of criteria of 3.6 years. At fulfillment of criteria, arthralgia was the most prevalent manifestation (86%), followed by Raynaud's phenomenon (80%), swollen hands (64%), leukopenia/lymphopenia (44%), and heartburn (38%). Evolution to other connective tissue occurred infrequently with a 10-year rate of evolution of 8.5% and 6.3% for systemic lupus erythematosus and systemic sclerosis, respectively. The overall mortality was not different from the general population with a standardized mortality ratio of 1.1 (95% confidence interval 0.4-2.6). CONCLUSION: This study was the first population-based study of MCTD to provide a complete picture of epidemiology and clinical characteristics of MCTD. MCTD occurred in about 2 persons per 100,000 per year. Evolution to other connective diseases occurred infrequently and the mortality was not affected. PMID- 26946216 TI - Estimating the burden of influenza-associated hospitalizations and deaths in Central America. AB - OBJECTIVES: Our objective was to estimate the incidence of influenza-associated hospitalizations and in-hospital deaths in Central American Region. DESIGN AND SETTING: We used hospital discharge records, influenza surveillance virology data, and population projections collected from Costa Rica, El Salvador, Guatemala, Honduras, and Nicaragua to estimate influenza-associated hospitalizations and in-hospital deaths. We performed a meta-analysis of influenza-associated hospitalizations and in-hospital deaths. MAIN OUTCOME MEASURES: The highest annual incidence was observed among children aged <5 years (136 influenza-associated hospitalizations per 100 000 persons). RESULTS: Annually, 7 625-11 289 influenza-associated hospitalizations and 352-594 deaths occurred in the subregion. CONCLUSIONS: Our results suggest that a substantive number of persons are annually hospitalized because of influenza. Health officials should estimate how many illnesses could be averted through increased influenza vaccination. PMID- 26946217 TI - Comparison of efficacy of immune checkpoint inhibitors (ICIs) between younger and older patients: A systematic review and meta-analysis. AB - BACKGROUND: Immune checkpoint inhibitors (ICIs) rely on the presence of ongoing immune response to exert their antitumor effect. Little is known whether an age related decline in immune function negatively influences antitumor response and in so doing diminishes the efficacy of ICIs in elderly subjects. We performed a meta-analysis to compare the efficacy of ICIs between younger and older patients. PATIENTS AND METHODS: PubMed and the ASCO databases were searched up to September 2015. We included randomized controlled trials (RCTs) of ICIs (ipilimumab, tremelimumab, nivolumab and pembrolizumab) reporting subgroup comparison of overall survival (OS) and/or progression-free survival (PFS) based on age cutoffs. The summary hazard ratio (HR) and 95% confidence interval (CI) were calculated. RESULTS: A total of 5265 patients from nine RCTs of ICI were included. When patients are dichotomized into younger and older groups with an age cut-off of 65-70 years, ICIs improved OS in both younger (HR, 0.75; 95% CI, 0.68-0.82) and older (HR, 0.73; 95% CI, 0.62-0.87) groups. An improvement in PFS was observed in younger (HR, 0.58; 95% CI, 0.40-0.84) and older (HR, 0.77; 95% CI, 0.58-1.01) patients. Subgroup analyses according to ICI and tumor type showed a consistent survival benefit in both younger and older groups except for the subgroup of older patients treated in 4 trials of anti-programmed cell death protein-1 (PD-1) monoclonal antibody (HR, 0.86; 95% CI, 0.41-1.83). CONCLUSIONS: A benefit in OS with ICIs was significant in both younger and older patients with a cut-off age of 65-70 years. PMID- 26946218 TI - Operational Characteristics of Linear Concentration-QT Models for Assessing QTc Interval in the Thorough QT and Phase I Clinical Studies. AB - Concentration-QTc (C-QTc) analysis can be used as an alternative to the standard statistical methods in clinical QT studies. Pharmacokinetic/pharmacodynamics (PK/PD) simulations were performed to assess the operating characteristics of four C-QTc models. False negatives were 2-6% for crossover and 2-9% for parallel studies, with 12 to 60 subjects per treatment for a dose with 10-ms mean effect. All C-QTc models tested gave less than +1 ms mean bias in the DeltaDeltaQTcmax prediction. The power to exclude 10 ms was >80% across all study designs and sizes, for a dose with 3-ms mean effect. The study demonstrates that linear C-QTc models have adequate sensitivity and specificity when the simulation and data analytical models are the same. C-QTc models that incorporate time- and treatment specific terms give the least biased DeltaDeltaQTcmax predictions under scenarios of model-misspecifications and offer an advantage when applying to real clinical data where the underlying relationship is not known. PMID- 26946219 TI - European Society of Coloproctology consensus on the surgical management of intestinal failure in adults. AB - Intestinal failure (IF) is a debilitating condition of inadequate nutrition due to an anatomical and/or physiological deficit of the intestine. Surgical management of patients with acute and chronic IF requires expertise to deal with technical challenges and make correct decisions. Dedicated IF units have expertise in patient selection, operative risk assessment and multidisciplinary support such as nutritional input and interventional radiology, which dramatically improve the morbidity and mortality of this complex condition and can beneficially affect the continuing dependence on parenteral nutritional support. Currently there is little guidance to bridge the gap between general surgeons and specialist IF surgeons. Fifteen European experts took part in a consensus process to develop guidance to support surgeons in the management of patients with IF. Based on a systematic literature review, statements were prepared for a modified Delphi process. The evidence for each statement was graded using Oxford Centre for Evidence-Based Medicine Levels of Evidence. The current paper contains the statements reflecting the position and practice of leading European experts in IF encompassing the general definition of IF surgery and organization of an IF unit, strategies to prevent IF, management of acute IF, management of wound, fistula and stoma, rehabilitation, intestinal and abdominal reconstruction, criteria for referral to a specialist unit and intestinal transplantation. PMID- 26946221 TI - 24-Hour infusion of levodopa/carbidopa intestinal gel for nocturnal akinesia in advanced Parkinson's disease. PMID- 26946220 TI - Application of the TGx-28.65 transcriptomic biomarker to classify genotoxic and non-genotoxic chemicals in human TK6 cells in the presence of rat liver S9. AB - In vitro transcriptional signatures that predict toxicities can facilitate chemical screening. We previously developed a transcriptomic biomarker (known as TGx-28.65) for classifying agents as genotoxic (DNA damaging) and non-genotoxic in human lymphoblastoid TK6 cells. Because TK6 cells do not express cytochrome P450s, we confirmed accurate classification by the biomarker in cells co-exposed to 1% 5,6 benzoflavone/phenobarbital-induced rat liver S9 for metabolic activation. However, chemicals may require different types of S9 for activation. Here we investigated the response of TK6 cells to higher percentages of Aroclor-, benzoflavone/phenobarbital-, or ethanol-induced rat liver S9 to expand TGx-28.65 biomarker applicability. Transcriptional profiles were derived 3 to 4 hr following a 4 hr co-exposure of TK6 cells to test chemicals and S9. Preliminary studies established that 10% Aroclor- and 5% ethanol-induced S9 alone did not induce the TGx-28.65 biomarker genes. Seven genotoxic and two non-genotoxic chemicals (and concurrent solvent and positive controls) were then tested with one of the S9s (selected based on cell survival and micronucleus induction). Relative survival and micronucleus frequency was assessed by flow cytometry in cells 20 hr post-exposure. Genotoxic/non-genotoxic chemicals were accurately classified using the different S9s. One technical replicate of cells co-treated with dexamethasone and 10% Aroclor-induced S9 was falsely classified as genotoxic, suggesting caution in using high S9 concentrations. Even low concentrations of genotoxic chemicals (those not causing cytotoxicity) were correctly classified, demonstrating that TGx-28.65 is a sensitive biomarker of genotoxicity. A meta-analysis of datasets from 13 chemicals supports that different S9s can be used in TK6 cells, without impairing classification using the TGx-28.65 biomarker. PMID- 26946224 TI - Dual-Energy Computed Tomography-Based Molecular Imaging of Cholesterol Deposits in Achilles Tendon Xanthomatosis. PMID- 26946222 TI - Cognitive impairments following cranial irradiation can be mitigated by treatment with a tropomyosin receptor kinase B agonist. AB - Brain radiotherapy is frequently used successfully to treat brain tumors. However, radiotherapy is often associated with declines in short-term and long term memory, learning ability, and verbal fluency. We previously identified a downregulation of the brain-derived neurotrophic factor (BDNF) following cranial irradiation in experimental animals. In the present study, we investigated whether targeting the BDNF high affinity receptor, tropomysin receptor kinase B (TrkB), could mitigate radiation-induced cognitive deficits. After irradiation, chronic treatment with a small molecule TrkB agonist, 7,8-dihydroxyflavone (DHF) in mice led to enhanced activation of TrkB and its downstream targets ERK and AKT, both important factors in neuronal development. DHF treatment significantly restored spatial, contextual, and working memory, and the positive effects persisted for at least 3months after completion of the treatment. Consistent with preservation of cognitive functions, chronic DHF treatment mitigated radiation induced suppression of hippocampal neurogenesis. Spine density and major components of the excitatory synapses, including glutamate receptors and postsynaptic density protein 95 (PSD-95), were also maintained at normal levels by DHF treatment after irradiation. Taken together, our results show that chronic treatment with DHF after irradiation significantly mitigates radiation-induced cognitive defects. This is achieved most likely by preservation of hippocampal neurogenesis and synaptic plasticity. PMID- 26946225 TI - Recurrence and prognosis of patients emergently hospitalized for acute esophageal variceal bleeding: A long-term cohort study. AB - AIM: To elucidate the rates of recurrence and mortality in acute esophageal variceal bleeding and the associated risk factors. METHODS: A cohort of 174 patients emergently hospitalized for esophageal variceal bleeding was analyzed. All patients underwent endoscopic variceal ligation within 3 h of arrival. Comorbidities, vital signs, drug use, laboratory data, etiology, endoscopic findings, transfusion requirement, and follow-up endoscopy were assessed. Cox's proportional hazards model was used to estimate hazard ratios (HR). RESULTS: Rebleeding was identified in 49 patients with a mean follow-up of 18 months. The cumulative rebleeding rate at 1 month, 1 year, and 5 years was 10.2%, 30.0%, and 51.0%, respectively. In multivariate analysis, independent risk factors for rebleeding were child-Pugh class C (HR 1.94; P = 0.027), alcoholic liver cirrhosis (HR 2.32; P = 0.01), and no follow-up endoscopy (HR 13.3; P < 0.001). During the overall mean follow-up of 22 months, 69 patients died (17 due to bleeding), and the cumulative mortality rate at 1 month, 1 year, and 5 years was 12.2%, 26.6%, and 63.0%, respectively. In multivariate analysis, independent risk factors for mortality were child-Pugh class C (HR 2.91; P < 0.001), coexistence of hepatocellular carcinoma (HR 1.92; P = 0.013), and no follow-up endoscopy (HR 23.6; P < 0.001). CONCLUSION: This study revealed more than 50% cumulative rebleeding and mortality in the 5-year period after endoscopic variceal ligation for esophageal variceal bleeding in an emergency setting. Child-Pugh C, alcoholic liver cirrhosis, and no follow-up endoscopy increased the risk of rebleeding; Child-Pugh C, coexistence of hepatocellular carcinoma, and no follow-up endoscopy increased the risk of mortality. PMID- 26946226 TI - Superficial CD34-positive fibroblastic tumor: A new case from Japan. AB - A 48-year-old Japanese woman presented with a painless, slow-growing, brown nodule of 15 mm in diameter on the left thigh. She noticed the nodule a few years before the first presentation to our hospital. She underwent total resection of the nodule. On histopathological examination, a relatively well-defined tumor with infiltrative growth was located in the dermis and extended into the subcutis. The tumor was composed of spindle to polygonal cells with pleomorphic nuclei arranged in a sheet-like or fascicular pattern. Tumor cells with granular cytoplasm were also scattered. Immunohistochemical examination revealed that the tumor cells were strongly positive for CD34. The fusion transcripts of the collagen type 1 alpha 1 platelet-derived growth factor beta chain were not detected. After excluding other fibroblastic tumors through histopathological and immunohistochemical examinations, a diagnosis of superficial CD34-positive fibroblastic tumor (SCPFT) was made. SCPFT is a recently proposed fibroblastic tumor that is characterized by striking pleomorphism, granular cytoplasm, low mitotic rate and diffuse CD34 expression. Only two reports with 20 cases have been reported so far. The present case is the first that corresponds to SCPFT in Japan. PMID- 26946223 TI - Physiological changes in the pallidum in a progressive model of Parkinson's disease: Are oscillations enough? AB - Neurophysiological changes in the basal ganglia thalamo-cortical circuit associated with the development of parkinsonian motor signs remain poorly understood. Theoretical models have ranged from those emphasizing changes in mean discharge rate to increased oscillatory activity within the beta range. The present study characterized neuronal activity within and across the internal and external segments of the globus pallidus as a function of motor severity using a staged, progressively severe 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinsonism in three rhesus monkeys. An increase in coherence between neuronal pairs across the external and internal globus pallidus was present in multiple frequency bands in the parkinsonian state; both the peak frequency of oscillatory coherence and the variability were reduced in the parkinsonian state. The incidence of 8-20Hz oscillatory activity in the internal globus pallidus increased with the progression of the disease when pooling the data across the three animals; however it did not correlate with motor severity when assessed individually and increased progressively in only one of three animals. No systematic relationship between mean discharge rates or the incidence or structure of bursting activity and motor severity was observed. These data suggest that exaggerated coupling across pallidal segments contribute to the development of the parkinsonian state by inducing an exaggerated level of synchrony and loss of focusing within the basal ganglia. These data further point to the lack of a defined relationship between rate changes, the mere presence of oscillatory activity in the beta range and bursting activity in the basal ganglia to the motor signs of Parkinson's disease. PMID- 26946227 TI - Preferences regarding contemporary prenatal genetic tests among women desiring testing: implications for optimal testing strategies. AB - OBJECTIVES: To compare utilities for prenatal testing outcomes among women inclined to continue their pregnancy despite abnormal results versus those inclined to terminate and to analyze how differences affect optimal prenatal testing strategies. METHOD: Time tradeoff utilities for 23 outcomes were elicited from 281 women. We compared utilities based on termination inclination and applied them to a decision-analytic framework. RESULTS: Of participants, 46.6% indicated that they would 'definitely' or 'probably' continue their pregnancy despite results indicating an intellectual disability. These women assigned higher utilities to abnormal testing results and having a child with an intellectual disability than women who would probably or definitely terminate. Primary cell-free DNA screening had the most quality-adjusted life years for women inclined to continue their pregnancy but yielded an incremental cost effectiveness ratio (ICER) of $1 685 449. Multiple marker screening with either cell-free DNA or diagnostic testing as follow-up had an ICER of $9037. Primary diagnostic testing resulted in the most quality-adjusted life years for women inclined to terminate, with an ICER of $111 776. CONCLUSION: Women seeking testing vary in prenatal testing outcome preferences and termination inclinations in the context of results indicating an intellectual disability. How they envision utilizing prenatal testing information impacts their optimal testing strategy. (c) 2016 John Wiley & Sons, Ltd. PMID- 26946229 TI - Evaluation of Score for Neonatal Acute Physiology and Perinatal Extension II and Clinical Risk Index for Babies with additional parameters. AB - BACKGROUND: The aim of this study was to determine mortality risk by calculating Score for Neonatal Acute Physiology and Perinatal Extension II (SNAP-PE-II) and Clinical Risk Index for Babies (CRIB) score, and evaluate prediction of the effects of antenatal corticosteroid and surfactant treatment on mortality. METHODS: This multicenter study was conducted simultaneously in five different centers in four different provinces in Southern Turkey between July 2012 and July 2013. A total of 1668 inborn subjects hospitalized in the neonatal intensive care unit within the first 12 h of delivery, and meeting the selection criteria, were included in the study, and CRIB and SNAP-PE-II were used to determine mortality. RESULTS: The SNAP-PE-II scoring system was applied to all patients, and the CRIB scoring system was used for 310 newborns with gestational age <32 weeks and weighing <1500 g. Of the 1668 patients, 188 died (mortality rate, 11.3%). Cut-off was found to vary with center, which changed specificity and sensitivity of the mortality scores. SNAP-PE-II significantly predicted mortality (P < 0.05) compared with CRIB. SNAP-PE-II also successfully predicted mortality in the group receiving antenatal corticosteroid compared with the group not receiving antenatal corticosteroid. CONCLUSION: SNAP-PE-II was a significant predictor of mortality in newborns with birthweight <1500 g compared with CRIB, and assessment of antenatal corticosteroid use in conjunction with SNAP-PE-II increased the accuracy of the prediction of mortality. PMID- 26946231 TI - Young Investigator Award 2015. PMID- 26946228 TI - Lineage-Specific Early Differentiation of Human Embryonic Stem Cells Requires a G2 Cell Cycle Pause. AB - Human embryonic stem cells (hESCs) have an abbreviated G1 phase of the cell cycle that allows rapid proliferation and maintenance of pluripotency. Lengthening of G1 corresponds to loss of pluripotency during differentiation. However, precise mechanisms that link alterations in the cell cycle and early differentiation remain to be defined. We investigated initial stages of mesendodermal lineage commitment in hESCs, and observed a cell cycle pause. Transcriptome profiling identified several genes with known roles in regulation of the G2/M transition that were differentially expressed early during lineage commitment. WEE1 kinase, which blocks entry into mitosis by phosphorylating CDK1 at Y15, was the most highly expressed of these genes. Inhibition of CDK1 phosphorylation by a specific inhibitor of WEE1 restored cell cycle progression by preventing the G2 pause. Directed differentiation of hESCs revealed that cells paused during commitment to the endo- and mesodermal, but not ectodermal, lineages. Functionally, WEE1 inhibition during meso- and endodermal differentiation selectively decreased expression of definitive endodermal markers SOX17 and FOXA2. Our findings identify a novel G2 cell cycle pause that is required for endodermal differentiation and provide important new mechanistic insights into early events of lineage commitment. Stem Cells 2016;34:1765-1775. PMID- 26946232 TI - The transition to extra-uterine life by extremely preterm infants - handle with care. PMID- 26946233 TI - Skin-to-skin care, cortical activation and pain behaviour in preterm infants. PMID- 26946234 TI - Given the benefits of Kangaroo mother care, why has its routine uptake been so slow? PMID- 26946235 TI - Umbilical catheter removal and bloodstream infections: 'A case of too many antibiotics'. PMID- 26946236 TI - Currently diagnosed cases of coeliac disease are just the tip of the iceberg. PMID- 26946237 TI - Erratum. PMID- 26946238 TI - Detecting and quantifying introgression in hybridized populations: simplifying assumptions yield overconfidence and uncertainty. AB - A growing threat to the conservation of many native species worldwide is genetic introgression from non-native species. Although improved molecular genetic techniques are increasing the availability of species-diagnostic markers for many species, efficient field sampling design and reliable data interpretation require accurate estimates of uncertainty associated with the detection of non-native alleles and the quantification of introgression in native populations. Using fish populations as examples, we developed a simulation model of an age-structured population that tracks the introduction and inheritance of non-native alleles across generations by simulating stochastic mating and survival of individual fish and the resulting transmission of diagnostic markers. To simulate detection and quantification of introgression, we sampled varying combinations of n fish and m diagnostic markers to detect and quantify introgression from thousands of virtual, independent fish populations for a wide range of hybridization scenarios. Using the results of simulated sampling, we quantified the extent to which common simplifying assumptions regarding population structure and inheritance mechanisms can lead to the following: (i) overconfidence in our ability to detect non-native alleles and (ii) unrealistically narrow confidence intervals for estimates of the proportion of non-native alleles present. Under many circumstances, commonly used simplifying assumptions underestimate the probability of failing to detect ongoing introgression and the uncertainty associated with estimates of introgression by orders of magnitude. Such overconfidence in our ability to detect and quantify introgression can affect critical conservation and management decisions regarding native species undergoing or at risk of introgression from non-native species. PMID- 26946239 TI - Facilitation of bone resorption activities in synovial lavage fluid patients with mandibular condyle fractures. AB - The aim of this study was to investigate the bone resorption effect of the mediators delivered in joint cavity of patients with mandibular condyle fractures by detecting osteoclast markers using cellular biochemistry methods, and by analysing bone resorption activities via inducing osteoclast differentiation of the infiltrated cells from arthrocentesis. Sixteen joints in 10 patients with mandibular condyle fractures were evaluated. The control group consisted of synovial fluid (SF) samples from seven joints of four volunteers who had no clinical signs or symptoms involving the temporomandibular joint (TMJ) or disc displacement. We collected SF cells from all patients during therapeutic arthrocentesis. The infiltrating cells from TMJ SF were cultured, differentiated into tartrate-resistant acid phosphatase (TRAP)-positive osteoclast-like cells and examined bone resorption activities. We also investigated factors related to osteoclast induction of SF, using ELISA procedures. Osteoclast-like cells were induced from the SF cells obtained from all patients with condylar fractures. These multinucleated giant cells were positive for TRAP and actin, and had the ability to absorb dentin slices. The levels of macrophage colony-stimulating factor (M-CSF), prostaglandin E2 (PGE2), soluble form of receptor activator of nuclear factor kappa-B ligand (sRANKL) and osteoprotegerin (OPG), in SF samples from the patients, were significantly higher than in the controls. These findings indicate that bone resorption activities in SF from patients with mandibular condyle fractures were upregulated and may participate in the pathogenesis and wound healing. PMID- 26946240 TI - The outcomes of transcatheter aortic valve replacement in a cohort of patients with end-stage renal disease. AB - OBJECTIVES: To examine whether transcatheter aortic valve replacement (TAVR) is a safe and effective treatment option for aortic stenosis in patients with end stage renal disease (ESRD). BACKGROUND: Patients with ESRD undergoing surgical aortic valve replacement have an operative mortality approaching 20% and a 10 year survival of approximately 12%. We investigated whether TAVR is a more reasonable option. METHODS: This is a multicenter, retrospective study of all patients with ESRD who underwent TAVR in 8 institutions between 12/2011 and 02/2013. Demographic characteristics, mortality, major, and minor complications were evaluated. Outcomes were stratified by operative approach. RESULTS: Forty three patients with a mean age 76.2 +/- 11.0 years and a mean STS predicted risk of mortality of 15.53 +/- 8.70% underwent TAVR. Mean duration of dialysis was 45.2 +/- 52.3 months (median 29.5 months). Transfemoral (TF) TAVR was performed in 31/43 (72.1%), transapical in 11/43 (25.6%), and transaortic in 1/43 (2.3%). Operative mortality was 14.0% (6/43) with TF mortality 6.5% (2/31) and 33.3% (4/12) in non-TF patients. Six-month mortality was 11/43 (25.6%: 16.1% TF, 50.0% non-TF). Complications included stroke in 2.3% (1/43) and life-threatening or major bleeding in 14.0% (6/43). Discharge to another healthcare facility was 27.0% (10/37). Readmission within 30 days of procedure for any cause was 18.9% (7/37). CONCLUSIONS: Patients with ESRD who undergo TAVR are at high risk for mortality and complications. TAVR outcomes are comparable to but not substantially better than those with SAVR. Transfemoral TAVR seems to be at least as safe and effective as the current standard SAVR in patients undergoing aortic valve replacement. (c) 2016 Wiley Periodicals, Inc. PMID- 26946241 TI - Prevalence and genotype distribution of cytomegalovirus UL55 sequence in renal transplant recipients in north west of Iran. AB - Cytomegalovirus (CMV) is one of the most important infections in renal transplant recipients. Kidney transplant is the last hope for the patients with end stage renal diseases. Cytomegalovirus infection can threaten patients and graft survival after transplantation. Four hundred and thirty-four renal transplant recipients contributed to this study. PCR and RFLP analyses were performed in order to determine CMV viremia and its genotypes. CMV viremia was detected in 68 (15.9%) recipients. The mean post-transplantation time in our recipients was 50 months, ranging from 1 to 354 months. Viremia was detected in 31.2%, 30.7%, 17.5%, 10.2%, and 6.4% of the recipients in 0-3, 4-6, 7-12, 13-24, and more than 24 months post-transplantation, respectively. The distribution of gB1, gB2, gB3, and gB4 genotypes was detected as 26.5%, 20.5%, 17.6%, and 5.9%, respectively. Mixed genotype infection was observed in 29.4% of the recipients. Incidence of viremia was higher in the first 6 months after the transplantation compared with the later stages. Moreover, CMV gB1 and mixed genotype infection were more common in our recipients. J. Med. Virol. 88:1622-1627, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26946242 TI - Encapsulated membrane proteins: A simplified system for molecular simulation. AB - Over the past 50years there has been considerable progress in our understanding of biomolecular interactions at an atomic level. This in turn has allowed molecular simulation methods employing full atomistic modelling at ever larger scales to develop. However, some challenging areas still remain where there is either a lack of atomic resolution structures or where the simulation system is inherently complex. An area where both challenges are present is that of membranes containing membrane proteins. In this review we analyse a new practical approach to membrane protein study that offers a potential new route to high resolution structures and the possibility to simplify simulations. These new approaches collectively recognise that preservation of the interaction between the membrane protein and the lipid bilayer is often essential to maintain structure and function. The new methods preserve these interactions by producing nano-scale disc shaped particles that include bilayer and the chosen protein. Currently two approaches lead in this area: the MSP system that relies on peptides to stabilise the discs, and SMALPs where an amphipathic styrene maleic acid copolymer is used. Both methods greatly enable protein production and hence have the potential to accelerate atomic resolution structure determination as well as providing a simplified format for simulations of membrane protein dynamics. This article is part of a Special Issue entitled: Biosimulations edited by Ilpo Vattulainen and Tomasz Rog. PMID- 26946243 TI - Functionalized lipids and surfactants for specific applications. AB - Synthetic lipids and surfactants that do not exist in biological systems have been used for the last few decades in both basic and applied science. The most notable applications for synthetic lipids and surfactants are drug delivery, gene transfection, as reporting molecules, and as support for structural lipid biology. In this review, we describe the potential of the synergistic combination of computational and experimental methodologies to study the behavior of synthetic lipids and surfactants embedded in lipid membranes and liposomes. We focused on select cases in which molecular dynamics simulations were used to complement experimental studies aiming to understand the structure and properties of new compounds at the atomistic level. We also describe cases in which molecular dynamics simulations were used to design new synthetic lipids and surfactants, as well as emerging fields for the application of these compounds. This article is part of a Special Issue entitled: Biosimulations edited by Ilpo Vattulainen and Tomasz Rog. PMID- 26946245 TI - Atomic force microscopy of bacteria reveals the mechanobiology of pore forming peptide action. AB - Time-resolved AFM images revealed that the antimicrobial peptide (AMP) caerin 1.1 caused localised defects in the cell walls of lysed Klebsiella pneumoniae cells, corroborating a pore-forming mechanism of action. The defects continued to grow during the AFM experiment, in corroboration with large holes that were visualised by scanning electron microscopy. Defects in cytoplasmic membranes were visualised by cryo-EM using the same peptide concentration as in the AFM experiments. At three times the minimum inhibitory concentration of caerin, 'pores' were apparent in the outer membrane. The capsule of K. pneumoniae AJ218 was unchanged by exposure to caerin, indicating that the ionic interaction of the positively charged peptide with the negatively charged capsular polysaccharide is not a critical component of AMP interaction with K. pneumoniae AJ218 cells. Further, the presence of a capsule confers no advantage to wild-type over capsule deficient cells when exposed to the AMP caerin. PMID- 26946246 TI - Response to Letter to the Editor: the use of the term "mesenchymal stem cells" in our article is appropriate based on our laboratory study and the review of the literatures. PMID- 26946244 TI - Lipid interaction sites on channels, transporters and receptors: Recent insights from molecular dynamics simulations. AB - Lipid molecules are able to selectively interact with specific sites on integral membrane proteins, and modulate their structure and function. Identification and characterization of these sites are of importance for our understanding of the molecular basis of membrane protein function and stability, and may facilitate the design of lipid-like drug molecules. Molecular dynamics simulations provide a powerful tool for the identification of these sites, complementing advances in membrane protein structural biology and biophysics. We describe recent notable biomolecular simulation studies which have identified lipid interaction sites on a range of different membrane proteins. The sites identified in these simulation studies agree well with those identified by complementary experimental techniques. This demonstrates the power of the molecular dynamics approach in the prediction and characterization of lipid interaction sites on integral membrane proteins. This article is part of a Special Issue entitled: Biosimulations edited by Ilpo Vattulainen and Tomasz Rog. PMID- 26946247 TI - Stem cells for cartilage repair: what exactly were used for treatment, cultured adipose-derived stem cells or the unexpanded stromal vascular fraction? PMID- 26946248 TI - Clinical features and treatment of hypertriglyceridemia-induced acute pancreatitis during pregnancy: A retrospective study. AB - AIM: To analyze the features and treatment of hypertriglyceridemia-induced acute pancreatitis (HTGP) during pregnancy. METHODS: A retrospective study of 21 pregnant women diagnosed with acute pancreatitis (AP) was performed. Patients were divided into acute biliary pancreatitis (ABP), HTGP, and idiopathic groups according to etiology. RESULTS: 95% of the patients were in the third trimester of gestation. The percentage of patients with HTGP was higher than that of ABP (48% vs.14%). The percentage of severe acute pancreatitis (SAP) in the HTGP group was higher than that in the ABP group (40.0% vs.0%). The Ranson scores for moderately severe acute pancreatitis (MSAP) and SAP in the HTGP group were significantly different (2.50 +/- 0.58 vs.3.60 +/- 0.89, P < 0.05, respectively). The mean serum triglyceride (TG) levels in the MSAP and SAP HTGP groups were not significantly different (18.81 +/- 11.13 vs. 30.53 +/- 24.20 mmol/L, P > 0.05, respectively). In the HTGP group, there were five patients given plasma exchange therapy and five not. Plasmapheresis decreased the incidence of systemic inflammatory response syndrome (SIRS) from 100% to 28.6% and the TG level from 20.36 +/- 7.41 mmol/L to 5.23 +/- 3.62 mmol/L (P < 0.05). The length of hospitalization of the plasmapheresis group was shorter than that of the nonplasmapheresis group (17.3 +/- 6.7 days vs. 37.0 +/- 20.8 days). CONCLUSIONS: Plasma exchange may be safe and effectively administered for HTGP patients during pregnancy with SIRS or multiple organ dysfunction syndrome (MODS). J. Clin. Apheresis 31:571-578, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26946249 TI - Concentrations of thiocyanate and goitrin in human plasma, their precursor concentrations in brassica vegetables, and associated potential risk for hypothyroidism. AB - Brassica vegetables are common components of the diet and have beneficial as well as potentially adverse health effects. Following enzymatic breakdown, some glucosinolates in brassica vegetables produce sulforaphane, phenethyl, and indolylic isothiocyanates that possess anticarcinogenic activity. In contrast, progoitrin and indolylic glucosinolates degrade to goitrin and thiocyanate, respectively, and may decrease thyroid hormone production. Radioiodine uptake to the thyroid is inhibited by 194 MUmol of goitrin, but not by 77 MUmol of goitrin. Collards, Brussels sprouts, and some Russian kale (Brassica napus) contain sufficient goitrin to potentially decrease iodine uptake by the thyroid. However, turnip tops, commercial broccoli, broccoli rabe, and kale belonging to Brassica oleracae contain less than 10 MUmol of goitrin per 100-g serving and can be considered of minimal risk. Using sulforaphane plasma levels following glucoraphanin ingestion as a surrogate for thiocyanate plasma concentrations after indole glucosinolate ingestion, the maximum thiocyanate contribution from indole glucosinolate degradation is estimated to be 10 MUM, which is significantly lower than background plasma thiocyanate concentrations (40-69 MUM). Thiocyanate generated from consumption of indole glucosinolate can be assumed to have minimal adverse risks for thyroid health. PMID- 26946250 TI - Effectiveness of social media in reducing risk factors for noncommunicable diseases: a systematic review and meta-analysis of randomized controlled trials. AB - OBJECTIVE: The primary aim of the current study was to synthesize evidence of the effect of social media use compared with no social media use as part of interventions to reduce risk factors for noncommunicable diseases. DATA SOURCES: Databases were searched up to June 10, 2014, using medical subject headings. A secondary aim of this study was to assess the effectiveness of social media use compared with no social media use in reducing the risk factors for noncommunicable diseases, stratifying the results by the extent of bias on outcomes, by social media use alone, and by the levels of social presence and media richness. STUDY SELECTION: Sixteen trials (n=10,711 participants) met the inclusion criteria, but interventions mostly used social media with low levels of media richness and presence (e.g., discussion boards, bulletin boards). DATA SYNTHESIS: Meta-analysis of all trials showed no significant differences (standardized mean difference [SMD] -0.14; 95%CI -0.28 to 0.01), with similar findings for physical activity (SMD 0.07; 95%CI -0.25 to 0.38), body weight (SMD 0.07; 95%CI -0.17 to 0.20), and fruit and vegetable intake (SMD 0.39; 95%CI -0.11 to 0.89). Trials assessing social media interventions aimed at modifying risk factors for noncommunicable diseases showed that social media use improved the primary outcomes, but the overall quality of the included studies limits the generalizability of these findings. CONCLUSION: Further trials are warranted, especially to isolate the effect of social media use and to fully evaluate the effect of the social presence and media richness of social media platforms. PMID- 26946251 TI - Uric acid and transforming growth factor in fructose-induced production of reactive oxygen species in skeletal muscle. AB - The consumption of fructose, a major constituent of the modern diet, has raised increasing concern about the effects of fructose on health. Research suggests that excessive intake of fructose (>50 g/d) causes hyperuricemia, insulin resistance, mitochondrial dysfunction, de novo lipogenesis by the liver, and increased production of reactive oxygen species (ROS) in muscle. In a number of tissues, uric acid has been shown to stimulate the production of ROS via activation of transforming growth factor beta1 and NADPH (nicotinamide adenine dinucleotide phosphate) oxidase 4. The role of uric acid in fructose-induced production of ROS in skeletal muscle, however, has not been investigated. This review examines the evidence for fructose-induced production of ROS in skeletal muscle, highlights proposed mechanisms, and identifies gaps in current knowledge. PMID- 26946253 TI - Acute kidney injury following peripheral angiography and endovascular therapy: A systematic review of the literature. AB - INTRODUCTION: Radiographic contrast administration is a major cause of acute kidney injury (AKI), worldwide. Currently, contrast induced acute kidney injury (CI-AKI) is the third leading cause of hospital acquired renal failure in the United States. Over 50% of these cases are the result of contrast exposure during cardiac catheterization. The predictive risk factors for and clinical impact of AKI following coronary procedures have been extensively studied and documented in the literature. Similar data, however, are lacking for AKI following angiography or endovascular interventions for lower extremity peripheral artery disease (PAD). METHODS: The present review examined the published data available for AKI in patients undergoing peripheral procedures using MEDLINE searches. Specific data on number of peripheral cases, subject characteristics, hydration strategies, and AKI incidence rates was recorded. RESULTS: The systematic review resulted in 50 potentially relevant studies and ultimately 15 studies were selected for detailed analysis that included AKI incidence data on patients undergoing peripheral angiography or interventions. The summated studies included 11,311 patients and 10,316 peripheral procedures. The median incidence of AKI in the studies was 10%. The retrieved publications demonstrated significant variations in patient risk factors, definitions of AKI, and specificity of description of endovascular therapies. CONCLUSIONS: The incidence, risk factors, and outcomes related to AKI in the context of peripheral angiography or endovascular therapy remain poorly described in the literature and warrant further study in a prospective, systematic fashion. (c) 2016 Wiley Periodicals, Inc. PMID- 26946252 TI - Coconut oil consumption and cardiovascular risk factors in humans. AB - Coconut oil is being heavily promoted as a healthy oil, with benefits that include support of heart health. To assess the merits of this claim, the literature on the effect of coconut consumption on cardiovascular risk factors and outcomes in humans was reviewed. Twenty-one research papers were identified for inclusion in the review: 8 clinical trials and 13 observational studies. The majority examined the effect of coconut oil or coconut products on serum lipid profiles. Coconut oil generally raised total and low-density lipoprotein cholesterol to a greater extent than cis unsaturated plant oils, but to a lesser extent than butter. The effect of coconut consumption on the ratio of total cholesterol to high-density lipoprotein cholesterol was often not examined. Observational evidence suggests that consumption of coconut flesh or squeezed coconut in the context of traditional dietary patterns does not lead to adverse cardiovascular outcomes. However, due to large differences in dietary and lifestyle patterns, these findings cannot be applied to a typical Western diet. Overall, the weight of the evidence from intervention studies to date suggests that replacing coconut oil with cis unsaturated fats would alter blood lipid profiles in a manner consistent with a reduction in risk factors for cardiovascular disease. PMID- 26946254 TI - AC-3933, a benzodiazepine partial inverse agonist, improves memory performance in MK-801-induced amnesia mouse model. AB - AC-3933, a novel benzodiazepine receptor partial inverse agonist, is a drug candidate for cognitive disorders including Alzheimer's disease. We have previously reported that AC-3933 enhances acetylcholine release in the rat hippocampus and ameliorates scopolamine-induced memory impairment and age-related cognitive decline in both rats and mice. In this study, we further evaluated the procognitive effect of AC-3933 on memory impairment induced by MK-801, an N methyl-d-aspartate receptor antagonist, in mice. Unlike the acetylcholinesterase inhibitor donepezil and the benzodiazepine receptor inverse agonist FG-7142, oral administration of AC-3933 significantly ameliorated MK-801-induced memory impairment in the Y-maze test and in the object location test. Interestingly, the procognitive effects of AC-3933 on MK-801-induced memory impairment were not affected by the benzodiazepine receptor antagonist flumazenil, although this was not the case for the beneficial effects of AC-3933 on scopolamine-induced memory deficit. Moreover, the onset of AC-3933 ameliorating effect on scopolamine- or MK 801-induced memory impairment was different in the Y-maze test. Taken together, these results indicate that AC-3933 improves memory deficits caused by both cholinergic and glutamatergic hypofunction and suggest that the ameliorating effect of AC-3933 on MK-801-induced memory impairment is mediated by a mechanism other than inverse activation of the benzodiazepine receptor. PMID- 26946256 TI - The importance of understanding gait features in hereditary spastic paraplegia: accomplishments and next steps. PMID- 26946255 TI - CEESIt: A computational tool for the interpretation of STR mixtures. AB - In forensic DNA interpretation, the likelihood ratio (LR) is often used to convey the strength of a match. Expanding on binary and semi-continuous methods that do not use all of the quantitative data contained in an electropherogram, fully continuous methods to calculate the LR have been created. These fully continuous methods utilize all of the information captured in the electropherogram, including the peak heights. Recently, methods that calculate the distribution of the LR using semi-continuous methods have also been developed. The LR distribution has been proposed as a way of studying the robustness of the LR, which varies depending on the probabilistic model used for its calculation. For example, the LR distribution can be used to calculate the p-value, which is the probability that a randomly chosen individual results in a LR greater than the LR obtained from the person-of-interest (POI). Hence, the p-value is a statistic that is different from, but related to, the LR; and it may be interpreted as the false positive rate resulting from a binary hypothesis test between the prosecution and defense hypotheses. Here, we present CEESIt, a method that combines the twin features of a fully continuous model to calculate the LR and its distribution, conditioned on the defense hypothesis, along with an associated p-value. CEESIt incorporates dropout, noise and stutter (reverse and forward) in its calculation. As calibration data, CEESIt uses single source samples with known genotypes and calculates a LR for a specified POI on a question sample, along with the LR distribution and a p-value. The method was tested on 303 files representing 1-, 2- and 3-person samples injected using three injection times containing between 0.016 and 1 ng of template DNA. Our data allows us to evaluate changes in the LR and p-value with respect to the complexity of the sample and to facilitate discussions regarding complex DNA mixture interpretation. We observed that the amount of template DNA from the contributor impacted the LR--small LRs resulted from contributors with low template masses. Moreover, as expected, we observed a decrease of p-values as the LR increased. A p-value of 10(-9) or lower was achieved in all the cases where the LR was greater than 10(8). We tested the repeatability of CEESIt by running all samples in duplicate and found the results to be repeatable. PMID- 26946257 TI - Recent advances in salivary cancer diagnostics enabled by biosensors and bioelectronics. AB - There is a high demand for a non-invasive, rapid, and highly accurate tool for disease diagnostics. Recently, saliva based diagnostics for the detection of specific biomarkers has drawn significant attention since the sample extraction is simple, cost-effective, and precise. Compared to blood, saliva contains a similar variety of DNA, RNA, proteins, metabolites, and microbiota that can be compiled into a multiplex of cancer detection markers. The salivary diagnostic method holds great potential for early-stage cancer diagnostics without any complicated and expensive procedures. Here, we review various cancer biomarkers in saliva and compare the biomarkers efficacy with traditional diagnostics and state-of-the-art bioelectronics. We summarize biomarkers in four major groups: genomics, transcriptomics, proteomics, and metabolomics/microbiota. Representative bioelectronic systems for each group are summarized based on various stages of a cancer. Systematic study of oxidative stress establishes the relationship between macromolecules and cancer biomarkers in saliva. We also introduce the most recent examples of salivary diagnostic electronics based on nanotechnologies that can offer rapid, yet highly accurate detection of biomarkers. A concluding section highlights areas of opportunity in the further development and applications of these technologies. PMID- 26946258 TI - Graphene/graphite paste electrode incorporated with molecularly imprinted polymer nanoparticles as a novel sensor for differential pulse voltammetry determination of fluoxetine. AB - Molecularly imprinted polymer (MIP) nanoparticles including highly selective recognition sites for fluoxetine were synthesized, utilizing precipitation polymerization. Methacrylic acid and vinyl benzene were used as functional monomers. Ethylene glycol dimethacrylate was used as cross-linker agent. The obtained polymeric nanoparticles were incorporated with carbon paste electrode (CPE) in order to construct a fluoxetine selective sensor. The response of the MIP-CP electrode to fluoxetine was remarkably higher than the electrode, modified with the non-imprinted polymer, indicating the excellent efficiency of the MIP sites for target molecule recognition. It was found that the addition of a little amount of graphene, synthesized via modified hummer's method, to the MIP-CP resulted in considerable enhancement in the sensitivity of the electrode to fluoxetine. Also, the style of electrode components mixing, before carbon paste preparation, was demonstrated to be influential factor in the electrode response. Some parameters, affecting sensor response, were optimized and then a calibration curve was plotted. A dynamic linear range of 6*10(-9)-1.0*10(-7)molL(-1) was obtained. The detection limit of the sensor was calculated equal to 2.8*10( 9)molL(-1) (3Sb/m). This sensor was used successfully for fluoxetine determination in the spiked plasma samples as well as fluoxetine capsules. PMID- 26946260 TI - Cystathionine gamma lyase-hydrogen sulfide increases peroxisome proliferator activated receptor gamma activity by sulfhydration at C139 site thereby promoting glucose uptake and lipid storage in adipocytes. AB - Adipocytes express the cystathionine gamma lyase (CSE)-hydrogen sulfide (H2S) system. CSE-H2S promotes adipogenesis but ameliorates adipocyte insulin resistance. We investigated the mechanism of how CSE-H2S induces these paradoxical effects. First, we confirmed that an H2S donor or CSE overexpression promoted adipocyte differentiation. Second, we found that H2S donor inhibited but CSE inhibition increased phosphodiesterase (PDE) activity. H2S replacing isobutylmethylxanthine in the differentiation program induced adipocyte differentiation in part. Inhibiting PDE activity by H2S induced peroxisome proliferator activated receptor gamma (PPARgamma) protein and mRNA expression. Of note, H2S directly sulfhydrated PPARgamma protein. Sulfhydrated PPARgamma increased its nuclear accumulation, DNA binding activity and adipogenesis gene expression, thereby increasing glucose uptake and lipid storage, which were blocked by the desulfhydration reagent DTT. H2S induced PPARgamma sulfhydration, which was blocked by mutation of the C139 site of PPARgamma. In mice fed a high fat diet (HFD) for 4 weeks, the CSE inhibitor decreased but H2S donor increased adipocyte numbers. In obese mice fed an HFD for 13 weeks, H2S treatment increased PPARgamma sulfhydration in adipose tissues and attenuated insulin resistance but did not increase obesity. In conclusion, CSE-H2S increased PPARgamma activity by direct sulfhydration at the C139 site, thereby changing glucose into triglyceride storage in adipocytes. CSE-H2S-mediated PPARgamma activation might be a new therapeutic target for diabetes associated with obesity. PMID- 26946261 TI - Palladium-Catalyzed Arylation of Arylboronic Acids with Yagupolskii-Umemoto Reagents. AB - A Pd-catalyzed Suzuki cross-coupling of arylboronic acids with Yagupolskii Umemoto reagents was explored. In contrary to trifluoromethylations, the Pd catalyzed reaction of R-B(OH)2 and [Ar2 SCF3 ](+) [OTf](-) provided the arylation products (R-Ar) in good to high yields. The reaction confirms that the S-Ar bonds of [Ar2 SCF3 ](+) [OTf](-) can be readily cleaved in the presence of Pd complexes. The relatively electron-poor aryl groups of asymmetric [Ar(1) Ar(2) SCF3 ](+) [OTf](-) salts are more favorably transferred compared to the electron rich ones. This reaction represents the first report of utilization of [Ar2 SCF3 ](+) [OTf](-) as arylation reagents in organic synthesis. PMID- 26946262 TI - Co-cultivation of keratinocyte-human mesenchymal stem cell (hMSC) on sericin loaded electrospun nanofibrous composite scaffold (cationic gelatin/hyaluronan/chondroitin sulfate) stimulates epithelial differentiation in hMSCs: In vitro study. AB - Fortifying the scaffold with bioactive molecules and glycosaminoglycans (GAGs), is an efficient way to design new generation tissue engineered biomaterials. In this study, we evaluated the synergistic effect of electrospun nanofibrous composite scaffold (cationic gelatin/hyaluronan/chondroitin sulfate) loaded with sericin and, contact co-culture of human mesenchymal stem cells (hMSCs) keratinocytes on hMSCs' differentiation towards epithelial lineage. Cationic gelatin is prepared with one step novel synthesis process by grafting quaternary ammonium salts to the backbone of gelatin. Release kinetics studies showed that Fickian diffusion is the major release mechanism for both GAGs and sericin/gelatin. In vitro biocompatibility of the electrospun scaffold was evaluated in terms of LDH and DNA quantification assay on human foreskin fibroblast, human keratinocyte and hMSC. Significant proliferation (~ 4-6 fold) was detected after culturing all three cell on the electrospun scaffold containing sericin. After 5 days of contact co-culture, results revealed that electrospun scaffold containing sericin promote epithelial differentiation of hMSC in terms of several protein markers (keratin 14, DeltaNp63alpha and Pan cytokeratin) and gene expression of some dermal proteins (keratin 14, DeltaNp63alpha). Findings of this study will foster the progress of current skin tissue engineering scaffolds by understanding the skin regeneration and wound healing process. PMID- 26946259 TI - Lipid topogenesis--35years on. AB - Glycerophospholipids are the principal fabric of cellular membranes. The pathways by which these lipids are synthesized were elucidated mainly through the work of Kennedy and colleagues in the late 1950s and early 1960s. Subsequently, attention turned to cell biological aspects of lipids: Where in the cell are lipids synthesized? How are lipids integrated into membranes to form a bilayer? How are they sorted and transported from their site of synthesis to other cellular destinations? These topics, collectively termed 'lipid topogenesis', were the subject of a review article in 1981 by Bell, Ballas and Coleman. We now assess what has been learned about early events of lipid topogenesis, i.e. "lipid synthesis, the integration of lipids into membranes, and lipid translocation across membranes", in the 35 years since the publication of this important review. We highlight the recent elucidation of the X-ray structures of key membrane enzymes of glycerophospholipid synthesis, progress on identifying lipid scramblase proteins needed to equilibrate lipids across membranes, and new complexities in the subcellular location and membrane topology of phosphatidylinositol synthesis revealed through a comparison of two unicellular model eukaryotes. This article is part of a Special Issue entitled: The cellular lipid landscape edited by Tim P. Levine and Anant K. Menon. PMID- 26946263 TI - Glycoengineered mesenchymal stem cells as an enabling platform for two-step targeting of solid tumors. AB - Current tumor targeted drug and diagnostic delivery systems suffer from a lack of selectivity for tumor cells. Here, we propose a two-step tumor targeting strategy based on mesenchymal stem cells (MSCs), which actively traffic to tumors. We developed glycoengineering protocols to induce expression of non-natural azide groups on the surface of MSCs without affecting their viability or tumor homing properties. Glycoengineered MSCs demonstrated active tumor homing in subcutaneous and orthotopic lung and ovarian tumor models. Subsequent systemic administration of dibenzyl cyclooctyne (DBCO)-labeled fluorophores or nanoparticles to MSC pretreated mice resulted in enhanced tumor accumulation of these agents through bio-orthogonal copper-free click chemistry. Further, administration of glycoengineered MSCs along with paclitaxel-loaded DBCO-functionalized nanoparticles resulted in significant (p < 0.05) inhibition of tumor growth and improved survival (p < 0.0001) in an orthotopic metastatic ovarian tumor model. These results provide evidence for the potential of MSC-based two-step targeting strategy to improve the tumor specificity of diagnostic agents and drugs, and thus potentially improve the treatment outcomes for patients diagnosed with cancer. PMID- 26946264 TI - Bone marrow stromal cells inhibits HMGB1-mediated inflammation after stroke in type 2 diabetic rats. AB - High-mobility group box 1 (HMGB1), a ligand of receptor for advanced glycation endproducts (RAGE), functions as a proinflammatory factor. It is mainly involved in inflammatory activation and contributes to the initiation and progression of stroke. By using a model of transient middle cerebral artery occlusion (MCAo) in type 2 diabetic rats, we investigated the changes of pro-inflammation mediators, blood-brain barrier (BBB) leakage and functional outcome after stroke. Type 2 diabetic rats did not show an increased lesion volume, but exhibited significantly increased expression of HMGB1 and RAGE, BBB leakage, as well as decreased functional outcome after stroke compared with control rats. Injection of bone marrow stromal cells (BMSCs) into type 2 diabetic rats significantly reduced the expression of HMGB1 and RAGE, attenuated BBB leakage, and improved functional outcome after stroke. BMSCs-treated type 2 diabetic rats inhibited inflammation and improved functional outcome after stroke. Furthermore, in vitro data support the hypothesis that BMSCs-induced reduction of HMGB1 and RAGE in T2DM-MCAo rats contributed to attenuated inflammatory response in the ischemic brain, which may lead to the beneficial effects of BMSCs treatment. Further investigation of BMSCs treatment in type 2 diabetic stroke is warranted. PMID- 26946265 TI - Chronic stress induces persistent changes in global DNA methylation and gene expression in the medial prefrontal cortex, orbitofrontal cortex, and hippocampus. AB - Chronic stress is associated with a plethora of cognitive symptoms such as emotional dysregulation and impaired executive function that have been attributed to modifications in neuroanatomy in the orbitofrontal cortex (OFC), medial prefrontal cortex (mPFC), and hippocampus (HPC). While many studies have examined stress-induced changes in neuronal morphology, synaptic plasticity, and cellular function, there has been little investigation into persistent changes in gene expression that may be responsible for the maintenance of these changes. This study exposed adult rats to a chronic stressor and then examined changes in mRNA gene expression in the OFC, mPFC and HPC following a two-week withdrawal period. mRNA bio-sequencing results revealed sex- and region-dependent changes. Surprisingly the greatest changes in gene expression were found in the OFC, and similar to anatomical studies, analysis of gene changes with Ingenuity Pathway Analysis software demonstrated that the mPFC and OFC exhibited contrasting activation of canonical pathways and functional networks. The HPC demonstrated the largest degree of sex-dependent change in gene expression. In general, chronic stress induced persistent changes in gene expression in the three brain regions we examined and these changes could be associated with the commonly reported cognitive symptoms. The current study highlights the region- and sex dependent nature of the brain's response to chronic stress and the difficulty we face when attempting to develop treatment options. PMID- 26946266 TI - Dexras1 a unique ras-GTPase interacts with NMDA receptor activity and provides a novel dissociation between anxiety, working memory and sensory gating. AB - Dexras1 is a novel GTPase that acts at a confluence of signaling mechanisms associated with psychiatric and neurological disease including NMDA receptors, NOS1AP and nNOS. Recent work has shown that Dexras1 mediates iron trafficking and NMDA-dependent neurodegeneration but a role for Dexras1 in normal brain function or psychiatric disease has not been studied. To test for such a role, mice with germline knockout (KO) of Dexras1 were assayed for behavioral abnormalities as well as changes in NMDA receptor subunit protein expression. Because Dexras1 is up-regulated during stress or by dexamethasone treatment, we included measures associated with emotion including anxiety and depression. Baseline anxiety-like measures (open field and zero maze) were not altered, nor were depression-like behavior (tail suspension). Measures of memory function yielded mixed results, with no changes in episodic memory (novel object recognition) but a significant decrement on working memory (T-maze). Alternatively, there was an increase in pre pulse inhibition (PPI), without concomitant changes in either startle amplitude or locomotor activity. PPI data are consistent with the direction of change seen following exposure to dopamine D2 antagonists. An examination of NMDA subunit expression levels revealed an increased expression of the NR2A subunit, contrary to previous studies demonstrating down-regulation of the receptor following antipsychotic exposure (Schmitt et al., 2003) and up-regulation after exposure to isolation rearing (Turnock-Jones et al., 2009). These findings suggest a potential role for Dexras1 in modulating a selective subset of psychiatric symptoms, possibly via its interaction with NMDARs and/or other disease-related binding-partners. Furthermore, data suggest that modulating Dexras1 activity has contrasting effects on emotional, sensory and cognitive domains. PMID- 26946267 TI - Thalamic reticular nucleus in Caiman crocodilus: Relationship with the dorsal thalamus. AB - The thalamic reticular nucleus was investigated in one group of crocodilians, Caiman crocodilus. This neuronal aggregate is composed of two parts: a compact portion and a diffuse region made up of scattered cells within the forebrain bundles. In Caiman, both the lateral and medial forebrain bundles project to the telencephalon and the thalamic reticular nucleus is associated with each fiber tract. In the lateral forebrain bundle, the compact area is termed the nucleus of the dorsal peduncle (dorsal peduncular nucleus) while the diffuse part is called the perireticular area. In the medial forebrain bundle, the interstitial nucleus comprises one part of the compact area while another region without a specific neuronal label is also present. Similar to the perireticular cells of the lateral forebrain bundle, scattered cells are also present in the medial forebrain bundle. Morphological features of the thalamic reticular nucleus are revealed with stains for the following: fibers; cells; succinic acid dehydrogenase; and acetylcholinesterase. Regardless of which dorsal thalamic nucleus was injected, a localized region of the thalamic reticular nucleus contained retrogradely labeled cells and anterogradely labeled axons and terminals. This grouping was termed clusters and was felt to represent the densest interconnection between the dorsal thalamus and the reticular nucleus. Using clusters as an index of interconnections, the reticular nucleus was divided into sectors, each of which was associated with a specific dorsal thalamic nucleus. An organization similar to that found in Caiman is present in other sauropsids as well as in mammals. These data suggest that a thalamic reticular nucleus is present in all amniotes and has morphological properties similar to those described in this analysis. Lastly, a hypothesis is presented to explain how the external shape of the reticular nucleus in Caiman might be transformed into the homologous area in a representative bird and mammal. PMID- 26946268 TI - Distribution of catecholaminergic presympathetic-premotor neurons in the rat lower brainstem. AB - We previously characterized the organization of presympathetic-premotor neurons (PSPMNs), which send descending poly-synaptic projections with collaterals to skeletal muscle and the adrenal gland. Such neurons may play a role in shaping integrated adaptive responses, and many of them were found within well characterized regions of noradrenergic cell populations suggesting that some of the PSPMNs are catecholaminergic. To address this issue, we used retrograde trans synaptic tract-tracing with attenuated pseudorabies virus (PRV) recombinants combined with multi-label immunofluorescence to identify PSPMNs expressing tyrosine hydroxylase (TH). Our findings indicate that TH-immunoreactive (ir) PSPMNs are present throughout the brainstem within multiple cell populations, including the A1, C1, C2, C3, A5 and A7 cell groups along with the locus coeruleus (LC) and the nucleus subcoeruleus (SubC). The largest numbers of TH-ir PSPMNs were located within the LC and SubC. Within SubC and the A7 cell group, about 70% of TH-ir neurons were PSPMNs, which was a significantly greater fraction of neurons than in the other brain regions we examined. These findings indicate that TH-ir neurons near the pontomesencephalic junction that are distributed across the LC, SubC, and the A7 may play a prominent role in somatomotor-sympathetic integration, and that the major functional role of the A7 and SubC noradrenergic cell groups maybe in the coordination of concomitant activation of somatomotor and sympathetic outflows. These neurons may participate in mediating homeostatic adaptations that require simultaneous activation of sympathetic and somatomotor nerves in the periphery. PMID- 26946269 TI - D1 receptor-mediated inhibition of medial prefrontal cortex neurons is disrupted in adult rats exposed to amphetamine in adolescence. AB - Amphetamine (AMPH) exposure leads to changes in behavior and dopamine receptor function in the prefrontal cortex (PFC). Since dopamine plays an important role in regulating GABAergic transmission in the PFC, we investigated if AMPH exposure induces long-lasting changes in dopamine's ability to modulate inhibitory transmission in the PFC as well as whether the effects of AMPH differed depending on the age of exposure. Male Sprague-Dawley rats were given saline or 3 mg/kg AMPH (i.p.) repeatedly during adolescence or adulthood and following a withdrawal period of up to 5 weeks (Experiment 1) or up to 14 weeks (Experiment 2), they were sacrificed for in vitro whole-cell recordings in layer V/VI of the medial PFC. We found that in brain slices from either adolescent- or adult-exposed rats, there was an attenuation of dopamine-induced increases in inhibitory synaptic currents in pyramidal cells. These effects did not depend on age of exposure, were mediated at least partially by a reduced sensitivity of D1 receptors in AMPH treated rats, and were associated with an enhanced behavioral response to the drug in a separate group of rats given an AMPH challenge following the longest withdrawal period. Together, these data reveal a prolonged effect of AMPH exposure on medial PFC function that persisted for up to 14 weeks in adolescent exposed animals. These long-lasting neurophysiological changes may be a contributing mechanism to the behavioral consequences that have been observed in those with a history of amphetamine abuse. PMID- 26946271 TI - Evaluating the Potential Severity of Look-Alike, Sound-Alike Drug Substitution Errors in Children. AB - OBJECTIVE: Look-alike, sound-alike (LASA) drug name substitution errors in children may pose potentially severe consequences. Our objective was to determine the degree of potential harm pediatricians ascribe to specific ambulatory LASA drug substitution errors. METHODS: We developed a unified list of LASA pairs from published sources, removing selected drugs on the basis of preparation type (eg, injectable drugs). Using a modified Delphi method over 3 rounds, 38 practicing pediatricians estimated degree of potential harm that might occur should a patient receive the delivered drug in error and the degree of potential harm that might occur from not receiving the intended drug. RESULTS: We identified 3550 published LASA drug pairs. A total of 1834 pairs were retained for the Delphi surveys, and 608 drug pairs were retained for round 3. Final scoring demonstrated that participants were able to identify pairs where the substitutions represented high risk of harm for receiving the delivered drug in error (eg, did not receive methylphenidate/received methadone), high risk of harm for not receiving the intended drug (eg, did not receive furosemide/received fosinopril), and pairs where the potential harm was high from not receiving the intended drug and from erroneously receiving the delivered drug (eg, did not receive albuterol/received labetalol). CONCLUSIONS: Pediatricians have identified LASA drug substitutions that pose a high potential risk of harm to children. These results will allow future efforts to prioritize pediatric LASA errors that can be screened prospectively in outpatient pharmacies. PMID- 26946270 TI - Caregiver Opinion of In-Hospital Screening for Unmet Social Needs by Pediatric Residents. AB - OBJECTIVE: Child health is strongly influenced by social determinants. Little is known about the opinions of primary caregivers regarding the physicians' role in addressing social needs. Our objective was to examine caregivers' opinions about that role and any associations between those opinions, previous exposure to screening for needs by pediatric residents, and socioeconomic status (SES). METHODS: Cross-sectional survey study of caregivers of hospitalized children. The survey collected information on caregiver opinion regarding their ability to ask physicians for help with social needs, whether physicians know how to help with those needs, and whether physicians should ask about social needs. The chi square test was used to identify associations between caregiver opinions, prior screening by a resident at admission, and SES (determined by census tract median household income). RESULTS: Surveys were completed by 143 caregivers (79% participation). Most respondents agreed that they could ask their physician for help (54.5%), that their physician knows how to help (64.3%), and that physicians should ask about social needs (71.3%). Previously screened caregivers had more favorable opinions about asking for help (76.2% vs 45.5%, P < .01), whether their physician knows how to help (81.0% vs 57.4%, P = .02), and physician screening for unmet needs (85.7% vs 65.3%, P = .03). There were no SES differences in opinion. CONCLUSIONS: Caregivers have favorable opinions of the physician's role in addressing the social determinants of health, especially after being screened. Physicians should be confident in the acceptability of screening families for social needs. PMID- 26946272 TI - Decision Making in Social Context in Patients with Suicide Attempt History. AB - Decision making has been found to be altered in suicide attempters, but little is known of their performance in social contexts. Twenty-seven depressed suicide attempters (DSA), 25 nonsuicidal depressed patients (DP), and 60 healthy participants (HC) were evaluated by a decision-making task in social context. Results indicated DSA and DP obtained lower gains and invested more money with angry partners. DSA were found to invest less money than DP and HC with happy partners. DSA showed insensitivity toward rewards/punishment contingency, and they did not use the socioemotional stimuli to guide their decisions. PMID- 26946273 TI - Motivating health workers up to a limit: partial effects of performance-based financing on working environments in Nigeria. AB - BACKGROUND: In 2012, the Nigerian government launched performance-based financing (PBF) in three districts providing financial incentives to health workers based on the quantity and quality of service provision. They were given autonomy to use funds for operational costs and performance bonuses. This study aims to understand changes in perceived motivation among health workers with the introduction of PBF in Wamba district, Nigeria. METHODS: The study used a qualitative research design to compare perceptions of health workers in facilities receiving PBF payments in the pilot district of Wamba to those that were not. In-depth semi-structured interviews (n = 39) were conducted with health workers from PBF and non-PBF facilities along with managers of the PBF project. Framework analysis was used to identify patterns and variations in responses. Facility records were collated and triangulated with qualitative data. FINDINGS: Health workers receiving PBF payments reported to be 'awakened' by performance bonuses and improved working environments including routine supportive supervision and availability of essential drugs. They recounted being more punctual, hard working and proud of providing better services to their communities. In comparison, health workers in non-PBF facilities complained about the dearth of basic equipment and lack of motivating strategies. However, health workers from both sets of facilities considered there to be a severe shortage of manpower resulting in excessive workload, fatigue and general dissatisfaction. CONCLUSIONS: PBF strategies can succeed in motivating health workers by bringing about a change in incentives and working conditions. However, such programmes need to be aligned with human resource reforms including timely recruitment and appropriate distribution of health workers to prevent burn out and attrition. As people working on the frontline of constrained health systems, health workers are responsive to improved incentives and working conditions, but need more comprehensive support. PMID- 26946274 TI - Laterality strength is linked to stress reactivity in Port Jackson sharks (Heterodontus portusjacksoni). AB - Cerebral lateralization is an evolutionarily deep-rooted trait, ubiquitous among the vertebrates and present even in some invertebrates. Despite the advantages of cerebral lateralization in enhancing cognition and facilitating greater social cohesion, large within population laterality variation exists in many animal species. It is proposed that this variation is maintained due links with inter individual personality trait differences. Here we explored for lateralization in Port Jackson sharks (Heterodontus portusjacksoni) using T-maze turn and rotational swimming tasks. Additionally, we explored for a link between personality traits, boldness and stress reactivity, and cerebral lateralization. Sharks demonstrated large individual and sex biased laterality variation, with females demonstrating greater lateralization than males overall. Stress reactivity, but not boldness, was found to significantly correlate with lateralization strength. Stronger lateralized individuals were more reactive to stress. Demonstrating laterality in elasmobranchs for the first time indicates ancient evolutionary roots of vertebrate lateralization approximately 240 million years old. Greater lateralization in female elasmobranchs may be related enhancing females' ability to process multiple stimuli during mating, which could increase survivability and facilitate insemination. Despite contrasting evidence in teleost fishes, the results of this study suggest that stress reactivity, and other personality traits, may be linked to variation in lateralization. PMID- 26946275 TI - Cerebral white matter correlates of delay discounting in adolescents. AB - The adolescent brain undergoes extensive structural white matter (WM) changes. Adolescence is also a critical time period during which cognitive, emotional and social maturation occurs in transition into adulthood. Compared to adults, adolescents are generally more impulsive with increased risk-taking behaviors. The goal of this study is to examine whether adolescent impulsivity may be related to cerebral WM maturation. In 89 healthy adolescents, we assessed impulsivity using the delay discounting task, and MRI WM volumes in brain regions previously implicated in delay discounting behaviors. We found that smaller delay discounting AUC (area under the curve) was associated with larger WM volumes in orbitofrontal, dorsolateral and medial prefrontal cortices (PFC) and motor cortex. There were no significant effects of AUC on WM volumes within somatosensory brain regions. In our sample, younger age was significantly associated with greater WM volumes in orbitofrontal and dorsolateral PFC subregions. Even after accounting for age-related effects, preference for immediate rewards (or greater impulsivity) still correlated with larger WM volumes in prefrontal regions known to mediate cognitive control. Our findings lend further support to the notion that reduced brain WM maturity may limit the ability in adolescents to forgo immediate rewards leading to greater impulsivity. PMID- 26946278 TI - Weight stigma and eating behaviors. An introduction to the special issue. PMID- 26946277 TI - In-Bag Manual Extraction of Excised Myomas by Surgical Scalpel through Suprapubic Mini-Laparotomic Incision in Laparoscopic-Assisted Myomectomy. AB - STUDY OBJECTIVE: To evaluate the safety and feasibility of in-bag manual extraction for the retrieval of excised myomas through a suprapubic mini laparotomic incision in 2-port laparoscopic-assisted myomectomy. DESIGN: Retrospective comparative study (Canadian Task Force classification II-2). SETTING: Departments of obstetrics and gynecology and diagnostic pathology at a general hospital. PATIENTS: Twenty-six patients undergoing open manual extraction and 26 patients undergoing in-bag manual extraction by surgical scalpel for the retrieval of excised myomas through a suprapubic mini-laparotomic incision in 2 port laparoscopic-assisted myomectomy. INTERVENTIONS: In patients with open manual extraction, myoma tissues were directly morcellated in an uncontained setting, whereas in patients managed by in-bag manual extraction, enucleated myomas were put into a retriever bag and then were morcellated by a surgical scalpel while monitoring bag damage by the leakage of indigo carmine dye filled in a bag. The patient demographics and surgical outcome measures were compared between the 2 groups. In the initial 15 patients with in-bag manual extraction, the macroscopic myoma fragments retained in the bag were collected and removed after completion of myoma extraction. Then, the bag contents were washed with normal saline and spilled microscopic tissues salvaged by centrifugation. A histologic examination was performed for collected tissue materials to identify the microscopic myoma fragments. MEASUREMENTS AND MAIN RESULTS: In patient demographics and surgical outcomes, which include excised tissue weight, surgical duration, and estimated intraoperative blood loss, no significant differences could be identified between the 2 groups. Bag rupture as monitored by the leakage of indigo carmine dye in vivo and ex vivo was not observed. In all patients managed by in-bag manual extraction, spilled macroscopic myoma fragments were identified in the bag. Furthermore, histologic examinations of collected bag contents detected microscopic myoma tissues in 53.3% of patients. These results suggest that without closed conditions, these microscopic myoma particles, which could be difficult to completely remove even by rigorous washing of the peritoneal cavity under laparoscopic vision, might be dispersed in the peritoneal cavity and potentially form iatrogenic peritoneal parasitic myomas if they survive and grow. CONCLUSION: In-bag manual extraction of myoma tissues through a suprapubic mini-laparotomic incision by a surgical scalpel is a feasible alternative to prevent the dispersion of microscopic myoma fragments and to avoid the potential risk of spreading occult malignancy in 2-port laparoscopic-assisted myomectomy. PMID- 26946276 TI - Brief anesthesia by isoflurane alters plasma corticosterone levels distinctly in male and female rats: Implications for tissue collection methods. AB - Euthanasia by anesthetic agents is commonly performed prior to tissue collection in order to minimize pain and distress to the animal. However, depending on their mechanism of action as well as administration regimen, different methods of anesthesia may trigger an acute stress response through engaging the hypothalamic pituitary-adrenal (HPA) axis, which can impact numerous other physiological processes that the researcher may wish to examine as endpoints. We investigated the effects of the commonly used anesthetic agent isoflurane on two different endpoints related to the stress response: plasma corticosterone levels and gene expression of the glucocorticoid receptor (GR) as well as several of its regulators including FK506-binding protein 51 (Fkbp5) in the hippocampus of male and female rats. Our results indicate that brief exposure to anesthesia by isoflurane prior to decapitation can alter plasma corticosterone levels differentially in male and female rats within minutes without impacting gene expression in the hippocampus. We conclude that collection methods can influence stress-related physiological endpoints in female rats and the potential influence of even brief anesthesia as well as sex differences in response to anesthesia should be evaluated during the experimental design process and data interpretation. This finding is particularly important in light of new NIH standards regarding sex and reproducibility, and care should be taken to be certain that sex differences in endpoints of interest are not an artifact of sex differences in response to collection paradigms. PMID- 26946279 TI - Psychometric analysis of an eating behaviour questionnaire for an overweight and obese Chinese population in Singapore. AB - OBJECTIVES: Previous studies reveal that the Three-Factor Eating Questionnaire (TFEQ), which assesses eating behaviour, performs differently across population groups and cultures. We aimed to identify the factor structure that is most appropriate to capture eating behaviour in an overweight and obese Chinese population in Singapore. METHODS: TFEQ-51 was administered to 444 Chinese subjects pooled from four separate studies and scored according to various alternative versions of the TFEQ. Confirmatory factor analyses and goodness of fit indices were used to determine the most appropriate factor structure. Known group validity analyses were conducted. RESULTS: Niemeier's Disinhibition Factors and the TFEQ-R18 factor structures were found to be the most applicable in our population based on goodness of fit indices, with a x(2)/df ratio of <3, RMSEA of <= 0.6 and a CFI value of >0.9 for both. Only two of three factors (Emotional Eating and Uncontrolled Eating) of the TFEQ-R18 showed good internal consistency, while none of Niemeier's Disinhibition Factors showed good internal consistency. Known-group validity showed that Emotional Eating and Internal Disinhibition were significantly associated with higher BMI. CONCLUSION: We found that the TFEQ-R18 factor structure is the most appropriate and practical for use in measuring eating behaviour in an overweight and obese Chinese population in Singapore. PMID- 26946280 TI - Caught in the struggle with food craving: Development and validation of a new cognitive fusion measure. AB - Cognitive fusion has been related to the development and maintenance of a series of mental health difficulties. Specifically, growing research on eating psychopathology has been demonstrating the important role of cognitive fusion related to body image in these disorders. Nonetheless, cognitive fusion specifically focused on eating remained to be investigated. The current study aimed at developing and validating the Cognitive Fusion Questionnaire-Food Craving, a measure assessing the extent to which an individual is fused with food craving undesirable and disturbing thoughts and urges. This study was conducted with distinct samples comprising men and women from the student and general population. A principal component analysis was conducted to assess the scale's structure, which was further examined in a confirmatory factor analysis. The scale's reliability and validities were also analysed. Results indicated that the CFQ-FC presented a one-dimensional structure with 7 items, accounting for 66.14% of the variance. A CFA confirmed the plausibility of the measurement model, which was found to be invariant in both sexes. The CFQ-FC also revealed very good internal consistency, construct reliability, temporal stability, and convergent and divergent validity, being positively associated with similar constructs and with indicators of eating and general psychopathology. CFQ-FC also discriminated individuals with clinically significant symptoms of binge eating from participants with no symptoms. Finally, the CFQ-FC presents incremental validity over a global measure of cognitive fusion in predicting eating psychopathology, namely binge eating. The CFQ-FC is a psychometrically sound measure that allows for a brief and reliable assessment of eating-related cognitive fusion. This is a novel measure that may significantly contribute for the assessment of this specific dimension of cognitive fusion and for the understanding of its role in eating psychopathology. PMID- 26946281 TI - Microbial production of natural and non-natural flavonoids: Pathway engineering, directed evolution and systems/synthetic biology. AB - In this review, we address recent advances made in pathway engineering, directed evolution, and systems/synthetic biology approaches employed in the production and modification of flavonoids from microbial cells. The review is divided into two major parts. In the first, various metabolic engineering and system/synthetic biology approaches used for production of flavonoids and derivatives are discussed broadly. All the manipulations/engineering accomplished on the microorganisms since 2000 are described in detail along with the biosynthetic pathway enzymes, their sources, structures of the compounds, and yield of each product. In the second part of the review, post-modifications of flavonoids by four major reactions, namely glycosylations, methylations, hydroxylations and prenylations using recombinant strains are described. PMID- 26946283 TI - Antioxidant and antiapoptotic activities of Calotropis procera latex on Catfish (Clarias gariepinus) exposed to toxic 4-nonylphenol. AB - Calotropis procera L. is known as medicinal plant. The Phytochemical analyzes of its latex revealed that it possessed antioxidants, namely terpenes, phenolic compounds and cardenolides, flavonoids and saponins, while tannins, alkaloids and resin were absent in moderate to high concentration. In the present study, the role of latex of Calotropis procera as antioxidant and antiapoptotic was reported. To carry out this aim, fishes were exposed to 100 ug l(-1) 4 nonylphenol as chemical pollutant. The enzymes, superoxidase dismutase, catalase, acetlycholinstrase (AchE), glutathione s-transferase, cortisol, G6PDH) and apoptotic cells increased significantly (p<0.05) accompanied by irregular disturbance of (Na(+), K(+)) ions in the presence of 4-nonylphenol. On the other hand, these enzymes, ions, and apoptotic cells decreased normally and significantly (p<0.05) in the presence of latex. Total phenol content, total capacity antioxidant, reducing power decrease significantly (p<0.05) in the presence of 4-nonylphenol and increase normally in the presence of latex. Latex was used for the first time to protect catfish after 4-nonylphenol exposure. Our study confirms that crude latex of Calotropis procera possessed antioxidant and antiapoptotic activities against the toxicity of 4-Nonylphenol. PMID- 26946284 TI - Impact of proline application on cadmium accumulation, mineral nutrition and enzymatic antioxidant defense system of Olea europaea L. cv Chemlali exposed to cadmium stress. AB - Proline plays an important role in plant response to various environmental stresses. However, its involvement in mitigation of heavy metal stress in plants remains elusive. In this study, we examined the effectiveness of exogenous proline (10 and 20 mM) in alleviating cadmium induced inhibitory effects in young olive plants (Olea europaea L. cv. Chemlali) exposed to two Cd levels (10 and 30 mg CdCl2 kg(-1) soil). The Cd treatment induced substantial accumulation of Cd in both root and leaf tissues and a decrease in gas exchange, photosynthetic pigments contents, uptake of essential elements (Ca, Mg and K) and plant biomass. Furthermore, an elevation of antioxidant enzymes activities (superoxide dismutase, catalase, glutathione peroxydase) and proline content in association with relatively high amounts of hydrogen peroxide, thiobarbituric acid reactive substances and electrolyte leakage were observed. Interestingly, the application of exogenous proline alleviated the oxidative damage induced by Cd accumulation. In fact, Cd-stressed olive plants treated with proline showed an increase of antioxidant enzymes activities, photosynthetic activity, nutritional status, plant growth and oil content of olive fruit. Generally, it seems that proline supplementation alleviated the deleterious effects of young olive plants exposed to Cd stress. PMID- 26946282 TI - Transforming the blood glucose meter into a general healthcare meter for in vitro diagnostics in mobile health. AB - Recent advances in mobile network and smartphones have provided an enormous opportunity for transforming in vitro diagnostics (IVD) from central labs to home or other points of care (POC). A major challenge to achieving the goal is a long time and high costs associated with developing POC IVD devices in mobile Health (mHealth). Instead of developing a new POC device for every new IVD target, we and others are taking advantage of decades of research, development, engineering and continuous improvement of the blood glucose meter (BGM), including those already integrated with smartphones, and transforming the BGM into a general healthcare meter for POC IVDs of a wide range of biomarkers, therapeutic drugs and other analytical targets. In this review, we summarize methods to transduce and amplify selective binding of targets by antibodies, DNA/RNA aptamers, DNAzyme/ribozymes and protein enzymes into signals such as glucose or NADH that can be measured by commercially available BGM, making it possible to adapt many clinical assays performed in central labs, such as immunoassays, aptamer/DNAzyme assays, molecular diagnostic assays, and enzymatic activity assays onto BGM platform for quantification of non-glucose targets for a wide variety of IVDs in mHealth. PMID- 26946285 TI - Interaction between sulfur and lead in toxicity, iron plaque formation and lead accumulation in rice plant. AB - Human activities have resulted in lead and sulfur accumulation in paddy soils in parts of southern China. A combined soil-sand pot experiment was conducted to investigate the influence of S supply on iron plaque formation and Pb accumulation in rice (Oryza sativa L.) under two Pb levels (0 and 600 mg kg(-1)), combined with four S concentrations (0, 30, 60, and 120 mg kg(-1)). Results showed that S supply significantly decreased Pb accumulation in straw and grains of rice. This result may be attributed to the enhancement of Fe plaque formation, decrease of Pb availability in soil, and increase of reduced glutathione (GSH) in rice leaves. Moderate S supply (30 mg kg(-1)) significantly increased Fe plaque formation on the root surface and in the rhizosphere, whereas excessive S supply (60 and 120 mg kg(-1)) significantly decreased the amounts of iron plaque on the root surface. Sulfur supply significantly enhanced the GSH contents in leaves of rice plants under Pb treatment. With excessive S application, the rice root acted as a more effective barrier to Pb accumulation compared with iron plaque. Excessive S supply may result in a higher monosulfide toxicity and decreased iron plaque formation on the root surface during flooded conditions. However, excessive S supply could effectively decrease Pb availability in soils and reduce Pb accumulation in rice plants. PMID- 26946286 TI - Effect of subcellular distribution on nC60 uptake and transfer efficiency from Scenedesmus obliquus to Daphnia magna. AB - The potential uptake and trophic transfer ability of nanoparticles (NPs) in aquatic organisms have not been well understood yet. There has been an increasing awareness of the subcellular fate of NPs in organisms, but how the subcellular distribution of NPs subsequently affects the trophic transfer to predator remains to be answered. In the present study, the food chain from Scenedesmus obliquus to Daphnia magna was established to simulate the trophic transfer of fullerene aqueous suspension (nC60). The nC60 contaminated algae were separated into three fractions: cell wall (CW), cell organelle (CO), and cell membrane (CM) fractions, and we investigated the nC60 uptake amounts and trophic transfer efficiency to the predator through dietary exposure to algae or algal subcellular fractions. The nC60 distribution in CW fraction of S. obliquus was the highest, following by CO and CM fractions. nC60 uptake amounts in D. magna were found to be mainly relative to the NPs' distribution in CW fraction and daphnia uptake ability from CW fraction, whereas the nC60 trophic transfer efficiency (TE) were mainly in accordance with the transfer ability of NPs from the CO fraction. CW fed group possessed the highest uptake amount, followed by CO and CM fed groups, but the presence of humic acid (HA) significantly decreased the nC60 uptake from CW fed group. The CO fed groups acquired high TE values for nC60, while CM fed groups had low TE values. Moreover, even though CW fed group had a high TE value; it decreased significantly with the presence of HA. This study contributes to the understanding of fullerene NPs' dietary exposure to aquatic organisms, suggesting that NPs in different food forms are not necessarily equally trophically available to the predator. PMID- 26946287 TI - Isolation of Microsatellite Loci by Next-Generation Sequencing of the Critically Endangered Northern Bald Ibis, Geronticus eremita. AB - The Northern Bald Ibis is one of the rarest bird species, extinct in Europe for 400 years and critically endangered worldwide. The European Union-co-financed LIFE+ project "Reason for Hope - Reintroduction of the Northern Bald Ibis in Europe" aims to reintroduce the species in Europe (Germany, Austria, Italy). In order to obtain information on the genetic diversity within zoo colonies and the reintroduced population, 15 polymorphic microsatellite markers, specific for the Northern Bald Ibis, Geronticus eremita (Linnaeus, 1785), have been isolated from next-generation sequencing (Illumina MiSeq) and are described here. The microsatellite primers were tested in 30 individuals and measures of genetic variability were calculated. Values for the observed heterozygosity ranged from 0.393 to 0.867, while expected heterozygosity ranged from 0.573 to 0.718. Ten out of 15 loci were in Hardy-Weinberg equilibrium and only one showed indication for the presence of null alleles. The newly developed PCR primers can be used to examine population genetic parameters, e.g. for future conservation genetic studies of this critically endangered bird species. PMID- 26946289 TI - dbPEC: a comprehensive literature-based database for preeclampsia related genes and phenotypes. AB - Preeclampsia is one of the most common causes of fetal and maternal morbidity and mortality in the world. We built a Database for Preeclampsia (dbPEC) consisting of the clinical features, concurrent conditions, published literature and genes associated with Preeclampsia. We included gene sets associated with severity, concurrent conditions, tissue sources and networks. The published scientific literature is the primary repository for all information documenting human disease. We used semantic data mining to retrieve and extract the articles pertaining to preeclampsia-associated genes and performed manual curation. We deposited the articles, genes, preeclampsia phenotypes and other supporting information into the dbPEC. It is publicly available and freely accessible. Previously, we developed a database for preterm birth (dbPTB) using a similar approach. Using the gene sets in dbPTB, we were able to successfully analyze a genome-wide study of preterm birth including 4000 women and children. We identified important genes and pathways associated with preterm birth that were not otherwise demonstrable using genome-wide approaches. dbPEC serves not only as a resources for genes and articles associated with preeclampsia, it is a robust source of gene sets to analyze a wide range of high-throughput data for gene set enrichment analysis. Database URL: http://ptbdb.cs.brown.edu/dbpec/. PMID- 26946291 TI - Successful transfemoral aortic valve implantation through aortic stent graft after endovascular repair of abdominal aortic aneurysm. AB - The patient was a 91-year-old woman presenting with severe aortic valve stenosis. Pre-procedural computed tomography scan revealed a 45-mm abdominal aortic aneurysm (AAA). Transfemoral transcatheter aortic valve implantation (TF-TAVI) was performed after endovascular aortic repair (EVAR) of the AAA. The 23-mm Edwards Sapien XT system passed through the aortic stent graft smoothly. This is the first case report showing that successful TF-TAVI can be performed through a prior abdominal aortic stent graft. TF-TAVI after EVAR of AAA is a feasible option for patients with extremely poor access. PMID- 26946292 TI - A Pharmacovigilance Signaling System Based on FDA Regulatory Action and Post Marketing Adverse Event Reports. AB - INTRODUCTION: Many serious drug adverse events (AEs) only manifest well after regulatory approval. Therefore, the development of signaling methods to use with post-approval AE databases appears vital to comprehensively assess real-world drug safety. However, with millions of potential drug-AE pairs to analyze, the issue of focus is daunting. OBJECTIVE: Our objective was to develop a signaling platform that focuses on AEs with historically demonstrated regulatory interest and to analyze such AEs with a disproportional reporting method that offers broad signal detection and acceptable false-positive rates. METHODS: We analyzed over 1500 US FDA regulatory actions (safety communications and drug label changes) from 2008 to 2015 to construct a list of eligible signal AEs. The FDA Adverse Event Reporting System (FAERS) was used to evaluate disproportional reporting rates, constrained by minimum case counts and confidence interval limits, of these selected AEs for 109 training drugs. This step led to 45 AEs that appeared to have a low likelihood of being added to a label by FDA, so they were removed from the signal eligible list. We measured disproportional reporting for the final group of eligible AEs on a test group of 29 drugs that were not used in either the eligible list construction or the training steps. RESULTS: In a group of 29 test drugs, our model reduced the number of potential drug-AE signals from 41,834 to 97 and predicted 73 % of individual drug label changes. The model also predicted at least one AE-drug pair label change in 66 % of all the label changes for the test drugs. CONCLUSIONS: By concentrating on AE types with already demonstrated interest to FDA, we constructed a signaling system that provided focus regarding drug-AE pairs and suitable accuracy with regard to the issuance of FDA labeling changes. We suggest that focus on historical regulatory actions may increase the utility of pharmacovigilance signaling systems. PMID- 26946290 TI - Harnessing publicly available genetic data to prioritize lipid modifying therapeutic targets for prevention of coronary heart disease based on dysglycemic risk. AB - Therapeutic interventions that lower LDL-cholesterol effectively reduce the risk of coronary artery disease (CAD). However, statins, the most widely prescribed LDL-cholesterol lowering drugs, increase diabetes risk. We used genome-wide association study (GWAS) data in the public domain to investigate the relationship of LDL-C and diabetes and identify loci encoding potential drug targets for LDL-cholesterol modification without causing dysglycemia. We obtained summary-level GWAS data for LDL-C from GLGC, glycemic traits from MAGIC, diabetes from DIAGRAM and CAD from CARDIoGRAMplusC4D consortia. Mendelian randomization analyses identified a one standard deviation (SD) increase in LDL-C caused an increased risk of CAD (odds ratio [OR] 1.63 (95 % confidence interval [CI] 1.55, 1.71), which was not influenced by removing SNPs associated with diabetes. LDL C/CAD-associated SNPs showed consistent effect directions (binomial P = 6.85 * 10(-5)). Conversely, a 1-SD increase in LDL-C was causally protective of diabetes (OR 0.86; 95 % CI 0.81, 0.91), however LDL-cholesterol/diabetes-associated SNPs did not show consistent effect directions (binomial P = 0.15). HMGCR, our positive control, associated with LDL-C, CAD and a glycemic composite (derived from GWAS meta-analysis of four glycemic traits and diabetes). In contrast, PCSK9, APOB, LPA, CETP, PLG, NPC1L1 and ALDH2 were identified as "druggable" loci that alter LDL-C and risk of CAD without displaying associations with dysglycemia. In conclusion, LDL-C increases the risk of CAD and the relationship is independent of any association of LDL-C with diabetes. Loci that encode targets of emerging LDL-C lowering drugs do not associate with dysglycemia, and this provides provisional evidence that new LDL-C lowering drugs (such as PCSK9 inhibitors) may not influence risk of diabetes. PMID- 26946293 TI - Coexistence of systemic lupus erythematosus, tuberous sclerosis and aggressive natural killer-cell leukaemia: coincidence or correlated? AB - Among patients with systemic lupus erythematosus (SLE) there is an increased risk of haematological malignancies, especially non-Hodgkin lymphoma. However, the association of SLE with aggressive CD3 negative natural killer (NK)-cell leukaemia has not been reported so far. We present a case of a 39-year-old woman with SLE, aggressive NK-cell leukaemia and tuberous sclerosis complex. The prior probability of developing the combination of these three rare diseases by coincidence is extremely low (<10(-13)). Possible underlying immunological, genetic and toxic/environmental pathways are discussed. PMID- 26946294 TI - Fc gamma receptor IIIb polymorphism and systemic lupus erythematosus: association with disease susceptibility and identification of a novel FCGR3B*01 variant. AB - OBJECTIVE: The objective of this study was to evaluate the association between Fc gamma receptor IIIb polymorphism and susceptibility to systemic lupus erythematosus and clinical traits of the disease. METHODS: Genomic DNA was obtained from 303 consecutive systemic lupus erythematosus patients and 300 healthy blood donors from the southeastern region of Brazil. The polymorphic region of the FCGR3B gene was sequenced and the alleles FCGR3B*01, FCGR3B*02 and FCGR3B*03 were analyzed. RESULTS: The FCGR3B*01 allele was more frequent in systemic lupus erythematosus patients (43.1%) while the FCGR3B*02 allele prevailed among controls (63.7%) (P = 0.001). The FCGR3B*03 allele was found equally in both groups. The FCGR3B*01/*01 (20.7%) and FCGR3B*01/*02 (41.1%) genotypes were more frequent among systemic lupus erythematosus patients (P = 0.028 and P = 0.012, respectively) while the FCGR3B*02/*02 genotype was more frequent in controls (45.5%) (P < 0.001). One variant of the FCGR3B*01 allele previously described in Germany was found in only one control. A new variant of the FCGR3B*01 allele with two substitutions (A227G/G277A) was found in one control. Three variants of the FCGR3B*02 allele previously described in African Americans, Brazilians, Chinese and Japanese were found in ten 10 patients and two controls. In addition, several single nucleotide polymorphisms at non-polymorphic positions were identified in both patients and controls. CONCLUSION: Susceptibility to systemic lupus erythematosus was associated with the FCGR3B*01 allele, as well as with the FCGR3B*01/*01 and FCGR3B*01/*02 genotypes. No association was found between FCGR3B genotypes and clinical manifestations, disease severity or the presence of autoantibodies. PMID- 26946295 TI - Conscious contents as reflexive processes: Evidence from the habituation of high level cognitions. AB - Reflexes are often insuppressible, predictable, and susceptible to external control. In contrast, conscious thoughts have been regarded as whimsical, 'offline,' and shielded from external control. Recent advances suggest that conscious thoughts are more reflex-like and susceptible to external control than previously thought. In one paradigm, high-level conscious thoughts (subvocalizations) are triggered by external control, as a function of external stimuli and experimenter-induced action sets. It has been hypothesized that these conscious contents are activated involuntarily and in a reflex-like manner. If such is the case, then these activations should possess a well-known property of the reflex: habituation. Accordingly, we found that involuntary high-level cognitions (subvocalizations) habituated (i.e., were less likely to arise) after repeated stimulation. As in the case of the habituation of a reflex, this novel effect was stimulus-specific. We discuss the implications of this finding for theories about consciousness and about psychopathological phenomena involving undesired, involuntary cognitions. PMID- 26946296 TI - The Attention-Lapse and Motor Decoupling accounts of SART performance are not mutually exclusive. AB - There is an ongoing debate about the mechanisms purported to underlie performance in the Sustained-Attention-to-Response Task (SART). Whereas the Attention-Lapse account posits that SART errors result from attentional disengagement, the Motor Decoupling account proposes that SART errors result from failures to inhibit a fast, prepotent motor response, despite adequate attention to the task. That SART performance might be fully accounted for by motor decoupling is problematic for a Attention-Lapse account, and for the use of the SART as an index of attention lapses. To test whether SART performance is in fact fully accounted for by motor decoupling, I examined the relation between SART performance and attention lapses while controlling for motor decoupling. The results were clear: The SART was associated with attention lapses independently of motor decoupling. Thus, the present study suggests that both accounts are correct and that the SART is a valid measure of attention lapses. PMID- 26946298 TI - The state of child and adolescent psychiatry in Slovenia: a brief report. PMID- 26946297 TI - Intensive care unit prognostic factors in critically ill patients with advanced solid tumors: a 3-year retrospective study. AB - BACKGROUND: The objective of this study was to identify risk factors predicting prognosis of critically ill medical patients with advanced solid tumors in the intensive care unit (ICU). METHODS: We retrospectively analyzed all ICU unplanned medical admissions to the ICU of patients with advanced solid cancer in Tianjin Medical University Cancer Institute and Hospital between October 1, 2012 and March 1, 2015. Approval was obtained from the Ethical Commission of Tianjin Medical University Cancer Institute and Hospital to review and publish information from patients' records. RESULTS: One hundred and forty-one patients with full code status met the criteria for inclusion from among 813 ICU admissions. ICU mortality was 14.9 % and in-hospital mortality was 29.8 %. The major reasons for unplanned ICU admission were respiratory failure (38.3 %) and severe sepsis or septic shock (27.7 %). The ICU mortality in patients who required vasopressors, mechanical ventilation or renal replacement therapy for >24 h was 25, 25.9 and 40 %, respectively. The mean overall survival was 28.6 months. After adjusting for hypertension, type of solid cancer, intervention time, need for mechanical ventilation and Acute Physiology and Chronic Health Evaluation II score, only Sepsis-related Organ Failure Assessment (SOFA) score on day 7 of ICU treatment remained a significant predictor of ICU mortality (adjusted odds ratio 1.612, 95 % confidence interval 1.137-2.285, P = 0.007). CONCLUSIONS: We suggest broadening the criteria for ICU admission. The patients should be allowed an ICU trial consisting of unlimited ICU support, including invasive hemodynamic monitoring, mechanical ventilation and renal replacement therapy. An interdisciplinary meeting, including an ethics consultation, should be held to make end-of-life decisions if the SOFA score on day 7 shows clinical deterioration with no available therapeutic options. PMID- 26946299 TI - Asymptomatic costal exostosis with thickening in the pericardium: a case report. AB - BACKGROUND: Costal exostosis is a benign condition that sometimes requires emergent surgery because of associated hemothorax; in addition, there have been cases with malignant transformation to chondrosarcoma. Here, we describe an asymptomatic patient who underwent thoracoscopic resection for primary costal exostosis. CASE PRESENTATION: A 16-year-old male was found to have a bow-shaped shadow on a chest X-ray. Chest computed tomography revealed a rod-like mass with a soft tissue shadow adjacent to the left fifth rib. A thoracoscopic partial resection of the left fifth rib was performed. Intraoperative findings included thickening of the pericardium near the tip of the growth and erosion of the visceral pleura of the left lung. The resected specimen was diagnosed as a primary costal exostosis based on histopathological findings. CONCLUSIONS: We review the published literature on costal exostosis and discuss the surgical indications of asymptomatic cases. PMID- 26946300 TI - Health-Related Decision-Making in HIV Disease. AB - Individuals living with HIV show moderate decision-making deficits, though no prior studies have evaluated the ability to make optimal health-related decisions across the HIV healthcare continuum. Forty-three HIV+ individuals with HIV associated neurocognitive disorders (HAND+), 50 HIV+ individuals without HAND (HAND-), and 42 HIV- participants were administered two measures of health related decision-making as part of a comprehensive neuropsychological battery: (1) The Decisional Conflict Scale (DCS), and (2) The Modified UCSD Brief Assessment for Capacity to Consent (UBACC-T). Multiple regression analyses revealed that HAND was an independent predictor of both the DCS and the UBACC-T, such that the HAND+ sample evidenced significantly poorer scores relative to comparison groups. Within the HIV+ sample, poorer health-related decision-making was associated with worse performance on tests of episodic memory, risky decision making, and health literacy. Findings indicate that individuals with HAND evidence moderate deficits in effectively comprehending and evaluating various health-related choices. PMID- 26946301 TI - New Methodologies in the Molecular Monitoring of CML. AB - In chronic myeloid leukemia (CML), the BCR-ABL fusion gene is both the therapeutic target of tyrosine kinase inhibitors and the indisputable direct marker of disease burden. Thus, sensitive assays for BCR-ABL now drive therapeutic options and are good surrogates for short- and long-term outcomes. Because CML is such an ideal model, new methods are arising that should make testing in CML faster, more reliable, and reach a greater sensitivity. These methods should be able to be transferred to other hematological malignancies that have mutation markers. PMID- 26946302 TI - An advanced scheme of compressed sensing of acceleration data for telemonintoring of human gait. AB - BACKGROUND: The compressed sensing (CS) of acceleration data has been drawing increasing attention in gait telemonitoring application. In such application, there still exist some challenging issues including high energy consumption of body-worn device for acceleration data acquisition and the poor reconstruction performance due to nonsparsity of acceleration data. Thus, the novel scheme of compressive sensing of acceleration data is needed urgently for solutions that are found to these issues. METHODS: In our scheme, the sparse binary matrix is firstly designed as an optimal measurement matrix only containing a smallest number of nonzero entries. And then the block sparse Bayesian learning (BSBL) algorithm is introduced to reconstruct acceleration data with high fidelity by exploiting block sparsity. Finally, some commonly used gait classification models such as multilayer perceptron (MLP), support vector machine (SVM) and KStar are applied to further validate the feasibility of our scheme for gait telemonitoring application. RESULTS: The acceleration data were selected from open Human Activity Dataset of Southern California University (USC-HAD). The optimal sparse binary matrix (a smallest number of nonzero entries is 8) is as strong as the full optimal measurement matrix such as Gaussian random matrix. Moreover, BSBL algorithm significantly outperforms existing conventional CS reconstruction algorithms, and reaches the maximal signal-to-noise ratio value (70 dB). In comparison, MLP is best for gait classification, and it can classify upstairs and downstairs patterns with best accuracy of 95 % and seven gait patterns with maximal accuracy of 92 %, respectively. CONCLUSIONS: These results show that sparse binary matrix and BSBL algorithm are feasibly applied in compressive sensing of acceleration data to achieve the perfect compression and reconstruction performance, which has a great potential for gait telemonitoring application. PMID- 26946303 TI - Haemophilus influenzae biofilm formation in chronic otitis media with effusion. AB - Otitis media with effusion (OME) is a highly prevalent disease in children, but the exact pathogenesis and role of bacteria are still not well understood. This study aimed to investigate the presence of otopathogenic bacteria in the middle ear effusion (MEE) and adenoid of children with chronic OME (COME), and to investigate in vivo whether these bacteria, especially Haemophilus influenzae, are organized as a biofilm in the middle ear fluid. MEE and adenoid samples were collected from 21 patients with COME. Extensive bacterial culturing and genotyping was performed on all middle ear and adenoid samples. Fluorescence in situ hybridization (FISH) and confocal laser scanning microscopy (CLSM) was used to visualize possible biofilm structures for a selection of middle ear effusion samples. 34 MEE samples were collected from 21 patients of which 64.7 % were culture positive for bacteria and 47.0 % were culture positive for Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus and/or Streptococcus pneumoniae. All 21 adenoid samples were culture positive for one or more of these four otopathogens. H. influenzae (35.3 %) and S. pneumoniae (76.2 %) were the most frequently cultured bacteria in the MEE and adenoid samples, respectively. The same bacterial species was found in MEE and adenoid for 84.6 % of the patients and in 81.2 % of the cases where the same species was found in more than one site it involved the same bacterial genotype. FISH and CLSM demonstrated the presence of H. influenzae specific biofilm structures in five of the eight culture positive MEEs that were tested, but in none of the two culture negative MEEs. The findings in this study indicate that the adenoid acts as a reservoir for bacteria in MEE and confirms that biofilms, in at least half of the cases consisting of H. influenzae, are indeed present in the MEE of children with COME. Biofilms may thus play a crucial role in the pathogenesis of COME, which is important in the understanding of this disease and the development of potential future treatment options. PMID- 26946304 TI - Halitosis associated volatile sulphur compound levels in patients with laryngopharyngeal reflux. AB - Previous reports have suggested that laryngopharyngeal reflux (LPR) may cause halitosis. However, it remains unclear if LPR is a risk factor for halitosis. The aim of this study was to investigate if patients diagnosed with LPR have an increased probability of halitosis compared to a normal population. Fifty-eight patients complaining of LPR symptoms and 35 healthy subjects were included in the study. A LPR diagnosis was made using an ambulatory 24-h double pH-probe monitor, which is the gold standard diagnostic tool for LPR. Additionally, halitosis was evaluated by measuring the levels of volatile sulphur compounds using OralChromaTM and an organoleptic test score. The result of the final diagnosis of the 58 patients after the 24 h ambulatory pH monitoring was that 42 patients had LPR. Significant correlations were observed between the organoleptic test score and hydrogen sulfide (H2S) and methyl mercaptan (CH3SH) levels. These were also significantly correlated with LPR. We found a strong positive association between LPR and volatile sulphur compound levels. The H2S and CH3SH levels differed significantly between the LPR and control groups (p < 0.0001 and p < 0.0001, respectively). Halitosis was significantly associated with the occurrence and severity of LPR. The present study provides clear evidence for an association between halitosis and LPR. Halitosis has a high frequency in patients with LPR and reflux characteristics are directly related to their severity and therefore could be considered as a manifestation of LPR. PMID- 26946305 TI - Regulatory effects of anesthetics on nitric oxide. AB - Nitric oxide (NO) is a free radical gas in the biological system, which is produced by nitric oxide synthase (NOS) family. NO acts as a biological mediator and plays important roles in different systems in humans. The NO/NOS system exerts a broad spectrum of signaling functions involved in vasodilation, inflammation, oxidative stress, cardioprotection and neuroprotection. It has been demonstrated that intravenous and volatile anesthetics (such as propofol, ketamine, midazolam, isoflurane, sevoflurane, and desflurane, etc.) modulate NO production through multiple mechanisms that may influence physiological and pathophysiological processes. This review focuses on the effects of different anesthetics on NO/NOS regulation in different disease conditions. Possible cellular mechanisms and intermediate role of NO/NOS in anesthetic-mediated organ protection are also discussed. It would be interesting to clarify the impact of anesthetics on NO/NOS regulation. This review gives an overview of the effects of different anesthetics on NO/NOS regulation and function in different physiologic and pathophysiologic states. PMID- 26946306 TI - Role of single prolonged stress in acquisition of alcohol conditioned place preference in rats. AB - AIMS: Previous studies showed that exposure to certain types of stressors enhance the rewarding effects of many drugs of abuse, including alcohol; however, no systematic study has investigated the role of single prolonged stress (SPS) in acquisition of alcohol conditioned place preference (CPP). The purpose of this study was to examine whether SPS would facilitate the acquisition of alcohol CPP in rats. MAIN METHODS: Male Sprague-Dawley rats were randomly assigned to either SPS exposure condition or no exposure condition. Freezing behavior and Elevated plus maze (EPM) were employed to evaluate PTSD-like symptoms induced by SPS. Further, using unbiased procedure, CPP conditioning was conducted with alcohol (2g/kg). KEY FINDINGS: SPS significantly enhanced freezing behavior of rats, decreased percentages (%) of both time spent and number of entry into the open arms, and facilitated the acquisition of alcohol CPP without inhibiting rats' activity. SIGNIFICANCE: Our findings suggest that SPS plays an important role in alcohol dependence, and CPP paradigm with SPS may be useful for exploring the rewarding mechanism of alcohol with regard to the interaction between alcohol and post-traumatic stress disorder (PTSD). PMID- 26946307 TI - A circulating non-coding RNA panel as an early detection predictor of non-small cell lung cancer. AB - AIMS: Early non-small cell lung cancer (NSCLC) diagnosis is generally poor due to the lack of convenient and noninvasive tools. MicroRNAs (miRNAs) and the long non coding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) are non-coding RNAs, that have attracted increased attention for their use as NSCLC tumor diagnostic markers. MAIN METHODS: We constructed a serum miRNA and MALAT1 non-coding RNA panel and tested its diagnostic performance as an NSCLC biomarker. We tested the expression of 11 candidate miRNAs and MALAT1 in a training set (36 NSCLCs vs. 36 controls) by quantitative reverse transcription polymerase chain reactions. The serum non-coding RNA panel's diagnostic efficiency was tested and validated in a second validation sample set (120 NSCLCs and 71 controls) by receiver operating characteristic (ROC) curve analyses. KEY FINDINGS: In the training set, the expression of the four non-coding RNAs (miR-1254, miR-485-5p, miR-574-5p, and MALAT1) was obviously different between the NSCLC patients and healthy controls. Risk score analysis revealed that the four non-coding RNA panel can distinguish NSCLC patient samples from controls. The ROC curve results revealed areas under the curves (AUCs) of 0.861 (95% confidence interval (CI) 0.771-0.952) and 0.844 (95% CI0.778-0.910) for the training set and validation set, respectively. SIGNIFICANCE: The four non-coding RNA risk scores were also associated with NSCLC progression, and its diagnostic efficiency was relatively high for stages I/II/III. In conclusion, these data indicate that the four non coding RNA panel can serve as a convenient tool for early NSCLC diagnosis. PMID- 26946308 TI - A minireview on N-acetylcysteine: An old drug with new approaches. AB - N-acetylcysteine (NAC), a cysteine pro-drug and glutathione precursor has been used in therapeutic practices for several decades, as a mucolytic agent and for the treatment of numerous disorders including paracetamol intoxication. There is a growing interest concerning the beneficial effects of NAC against the early stages of toxicity-induced by pesticides. Nevertheless, the mechanisms underlying the therapeutic and clinical applications of NAC are not fully understood. In this review we aimed to focus on the protective effects of NAC against oxidative stress caused by pesticide in many organs. The possible mechanisms of action may be associated to its antioxidant properties. The anti-oxidative activity of NAC has been attributed to the fast reaction with free radicals as well as the restitution of reduced glutathione (GSH). PMID- 26946309 TI - Effects of IGF-1 on neural differentiation of human umbilical cord derived mesenchymal stem cells. AB - AIMS: Umbilical cord derived mesenchymal stem cells (UC-MSCs) have been demonstrated to hold the potential to be applied in the treatment of kinds of disease. In recent years, some scientists have differentiated the cells into neural progenitor cells (NPCs) successfully, providing a new cell source for neural disease therapy. However, the differentiation methods still need to be improved for the clinical studies in the future. In this study, insulin-like growth factor-1 (IGF-1) was tested to ameliorate UC-MSCs neural differentiation. MAIN METHODS: IGF-1 overexpressing UC-MSCs (UC-MSCs-IGF-1) were established through retroviral infection, and further differentiated into NPCs through neural induction. The proliferation and differentiation ability of UC-MSCs derived NPCs were evaluated respectively and the associated signaling mechanisms were further analyzed with RNA microarray, qPCR and western-blot. KEY FINDINGS: Compared with NPCs from normal UC-MSCs, the NPCs derived from UC-MSCs-IGF-1 hold better proliferation ability and more Pax6-positive cells and Nestin-positive cells. Moreover, the UC-MSCs-IGF-1 derived NPCs could differentiate into astrocyte with higher efficiency during the process of terminal differentiation in vitro. RNA microarray analysis indicated that some key genes associated with neural differentiation and NPCs proliferation were upregulated, which were also confirmed with qPCR and western-blot. Finally, NPCs from UC-MSCs-IGF-1 transfected with IGF-1-siRNA showed a decrease of proliferation ability and astrocyte differentiation. SIGNIFICANCE: This study indicated that IGF-1 could improve neural differentiation of human UC-MSCs and provided a novel strategy to enhance astrocyte differentiation of NPCs from UC-MSCs. PMID- 26946310 TI - Cryopreservation of Dog Semen in a Tris Extender with 1% or 2% Soya Bean Lecithin as a Replacement of Egg Yolk. AB - Egg yolk is usually included in extenders used for preservation of dog semen. Lecithin is an interesting animal-protein free alternative to egg yolk for semen preservation. The aim of our study was to evaluate soya bean lecithin for cryopreservation of dog semen. Five ejaculate replicates were divided in three equal parts, centrifuged and each pellet diluted with one of the three Tris-based extenders containing 20% egg yolk, 1% soya bean lecithin or 2% soya bean lecithin. Extended semen was loaded in 0.5-ml straws, cooled and diluted a second time and frozen in liquid nitrogen vapours. Sperm motility parameters (CASA), acrosome integrity (FITC-PNA/PI) and sperm membrane integrity (C-FDA) were evaluated 5 min post-thaw and after 2 and 4 h of incubation. Total motility was significantly better in the egg yolk extender than in any of the lecithin-based extender and was better in the 1% lecithin extender than in the 2% lecithin extender. Sperm membrane integrity was significantly better in the egg yolk extender than in any of the lecithin-based extenders but did not differ significantly between the 1% and 2% lecithin extenders. Acrosome integrity was significantly better in the egg yolk extender than in the 2% lecithin extender but did not differ between the egg yolk extender and the 1% lecithin extender or between the two lecithin extenders. In conclusion, egg yolk was superior to lecithin in our study. The extender with 1% lecithin preserved sperm motility better than the extender with 2% lecithin. PMID- 26946311 TI - Heat resistance in extended-spectrum beta-lactamase-producing Escherichia coli may favor environmental survival in a hospital setting. AB - Nosocomial infections caused by extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli are a major concern worldwide. There is an urgent need to identify bacterial factors promoting survival and persistence of these organisms in the nosocomial environment. Here, we describe the presence of a gene cluster, containing the Clp ATPase ClpK, within a collection of Danish ESBL-producing E. coli isolates. The cluster conferred thermoprotection upon the isolates, and thus might facilitate survival on medical devices exposed to semi-high temperatures in a hospital setting. PMID- 26946312 TI - Gynaecological Endoscopic Surgical Education and Assessment. A diploma programme in gynaecological endoscopic surgery. AB - In recent years, training and education in endoscopic surgery has been critically reviewed. Clinicians, both surgeons as gynaecologist who perform endoscopic surgery without proper training of the specific psychomotor skills are at higher risk to increased patient morbidity and mortality. Although the apprentice-tutor model has long been a successful approach for training of surgeons, recently, clinicians have recognised that endoscopic surgery requires an important training phase outside the operating theatre. The Gynaecological Endoscopic Surgical Education and Assessment programme (GESEA), recognises the necessity of this structured approach and implements two separated stages in its learning strategy. In the first stage, a skill certificate on theoretical knowledge and specific practical psychomotor skills is acquired through a high stake exam; in the second stage, a clinical programme is completed to achieve surgical competence and receive the corresponding diploma. Three diplomas can be awarded: (a) the Bachelor in Endoscopy; (b) the Minimally Invasive Gynaecological Surgeon (MIGS); and (c) the Master level. The Master level is sub-divided into two separate diplomas: the Master in Laparoscopic Pelvic Surgery and the Master in Hysteroscopy. The complexity of modern surgery has increased the demands and challenges to surgical education and the quality control. This programme is based on the best available scientific evidence and it counteracts the problem of the traditional surgical apprentice tutor model. It is seen as a major step toward standardization of endoscopic surgical training in general. PMID- 26946314 TI - Mood and anxiety disorders in patients with abnormal uterine bleeding. AB - OBJECTIVE: We aimed to investigate the prevalence of mood and anxiety disorders in patients with abnormal uterine bleeding (AUB) and the relationship between mood and anxiety disorders and AUB. METHOD: 96 consecutive patients with not yet classified AUB based on the PALM-COEIN classification and 94 volunteers were included in the study. Mood and anxiety disorders were ascertained by means of the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition/Clinical Version. RESULTS: Out of 96 patients, 55 (57.3%) met the criteria for at least one diagnosis of mood and anxiety disorder. The most common psychiatric disorders in patients with AUB were major depression (n=15, 15.6%), generalized anxiety disorder (n=18, 18.8%) and obsessive compulsive disorder (n=22, 22.9%), respectively. Compared with the control group, the prevalence of any psychiatric disorder (x(2)=43.52, p=0.000), any mood disorder (x(2)=10:37, p=0.001) and any anxiety disorder (Fisher's exact test, p=0.000) was higher in patients with AUB. The presence of any mood and anxiety disorder was an independent risk factor for AUB. CONCLUSION: Mood and anxiety disorders, particularly major depression, generalized anxiety disorder and obsessive-compulsive disorder were frequently observed in patients with AUB. PMID- 26946315 TI - Mutual Cooperation in the Formal Allyl Alcohol Nucleophilic Substitution and Hydration of Alkynes for the Construction of gamma-Substituted Ketones. AB - Mutual cooperation in the formal allyl alcohol nucleophilic substitution reaction and hydration of an alkyne has been utilized in the presence of a gold catalyst to give a series of gamma-functionalized ketones with high to excellent yields. This reaction actually involved an intramolecular O-H insertion cyclization of an alkyne to form the dihydrofuran intermediate, which was followed by the nucleophilic addition ring-opening of a dihydrofuran to give the target compound. PMID- 26946313 TI - Effect of intravenous ascorbic acid infusion on blood loss during laparoscopic myomectomy: a randomized, double-blind, placebo-controlled trial. AB - OBJECTIVE: Most interventions aimed at reducing bleeding during myomectomy lack sufficient evidence regarding their effectiveness. Recently, it was reported that intraoperative ascorbic acid administration effectively reduced blood loss during abdominal myomectomy. Therefore, this study aimed to investigate whether intravenous ascorbic acid infusion would affect intraoperative blood loss in women undergoing laparoscopic myomectomy. STUDY DESIGN: A randomized, double blind, parallel-group, placebo-controlled trial including 50 women undergoing laparoscopic myomectomy was conducted. Women with <=4 myomas, <=9cm in maximum diameter were eligible. The study:control group ratio was 1:1. Starting 30minutes before anesthesia, 2g of ascorbic acid or a placebo were administered for 2hours intraoperatively. Intraoperative blood loss, the primary endpoint, was calculated as the difference between the volume of fluids acquired from suction and that used for irrigation of the abdominal cavity during surgery using constant values. RESULTS: Among the 50 randomized women, 1 and 3 in the study and control groups, respectively, were excluded due to withdrawal of consent, cancelation of surgery, or non-measurement of the primary endpoint. The baseline and operative characteristics were similar between the study and control groups, as was the intraoperative blood loss (193+/-204mL vs. 159+/-193mL, P=0.52). In addition, the operating time (95+/-29min vs. 110+/-52min; P=0.50) and decrease in hemoglobin level after surgery (1.9+/-1.31g/dL vs. 1.4+/-1.4g/dL; P=0.24) were similar between the study and control groups. CONCLUSIONS: Intravenous ascorbic acid infusion did not reduce intraoperative blood loss in women undergoing laparoscopic myomectomy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT01715597. PMID- 26946316 TI - A pilot study of the effects of acupuncture treatment on objective and subjective gait parameters in horses. AB - OBJECTIVES: To investigate whether acupuncture can alter gait in horses as assessed by objective and subjective parameters. STUDY DESIGN: Prospective, randomized, singleblinded, crossover study. ANIMALS: Eight adult horses. METHODS: Horses were randomly assigned to a treatment (three acupuncture treatments in 8 days) or control group. Subjective and objective gait analyses were performed before and after each treatment and at 1, 3 and 7 days after the last treatment (time-points 1-9, respectively). Horses were assessed at the trot in a straight line on a hard surface and on the lunge on the left and right reins on a soft surface (conditions 1-3, respectively). After 12 weeks, groups were reversed. Objective gait analysis was performed using inertial sensors and subjective analysis by two board- certified surgeons who reviewed video-recordings. Each limb was assessed for lameness before and after treatment. Lameness and global scores were assigned using 4-point scales. Assessors were blinded to treatment status. The effects of treatment (yes/no), time (1-9) and horse under conditions 1 -3 were compared using a linear mixed-effects model and a generalized estimating equation. RESULTS: Treatment decreased hip hike difference under all conditions [condition 1: control, 6.3 +/- 6.4 mm versus treatment, -0.2 +/- 6.4 mm (p = 0.007); condition 2: control, 9.7 +/- 7.8 mm versus treatment, 2.8 +/- 7.8 mm (p = 0.032); condition 3: control, 7.3 +/- 6.3 mm versus treatment, -2.7 +/- 6.4 mm (p = 0.003)]. Other parameters also improved significantly under conditions 1 and 3. Based on subjective gait analysis, treatment decreased lameness [odds ratio (OR) 0.51, 95% confidence interval (CI) 0.34-0.78; p = 0.002] but not global (OR 0.53, 95% CI 0.24-1.10; p = 0.12) scores. CONCLUSIONS AND CLINICAL RELEVANCE: Acupuncture can change horses' gaits to a degree appreciable by objective and subjective analyses. PMID- 26946318 TI - Erratum to: Scalable temperature induced stress for the large-scale production of functionalized Bifidobacteria. PMID- 26946317 TI - Are complex DCE-MRI models supported by clinical data? AB - PURPOSE: To ascertain whether complex dynamic contrast enhanced (DCE) MRI tracer kinetic models are supported by data acquired in the clinic and to determine the consequences of limited contrast-to-noise. METHODS: Generically representative in silico and clinical (cervical cancer) DCE-MRI data were examined. Bayesian model selection evaluated support for four compartmental DCE-MRI models: the Tofts model (TM), Extended Tofts model, Compartmental Tissue Uptake model (CTUM), and Two-Compartment Exchange model. RESULTS: Complex DCE-MRI models were more sensitive to noise than simpler models with respect to both model selection and parameter estimation. Indeed, as contrast-to-noise decreased, complex DCE models became less probable and simpler models more probable. The less complex TM and CTUM were the optimal models for the DCE-MRI data acquired in the clinic. [In cervical tumors, Ktrans, Fp, and PS increased after radiotherapy (P = 0.004, 0.002, and 0.014, respectively)]. CONCLUSION: Caution is advised when considering application of complex DCE-MRI kinetic models to data acquired in the clinic. It follows that data-driven model selection is an important prerequisite to DCE-MRI analysis. Model selection is particularly important when high-order, multiparametric models are under consideration. (Parameters obtained from kinetic modeling of cervical cancer clinical DCE-MRI data showed significant changes at an early stage of radiotherapy.) Magn Reson Med 77:1329-1339, 2017. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 26946319 TI - Improving isobutanol production in metabolically engineered Escherichia coli by co-producing ethanol and modulation of pentose phosphate pathway. AB - Redox imbalance has been regarded as the key limitation for anaerobic isobutanol production in metabolically engineered Escherichia coli strains. In this work, the ethanol synthetic pathway was recruited to solve the NADH redundant problem while the pentose phosphate pathway was modulated to solve the NADPH deficient problem for anaerobic isobutanol production. Recruiting the ethanol synthetic pathway in strain AS108 decreased isobutanol yield from 0.66 to 0.29 mol/mol glucose. It was found that there was a negative correlation between aldehyde/alcohol dehydrogenase (AdhE) activity and isobutanol production. Decreasing AdhE activity increased isobutanol yield from 0.29 to 0.6 mol/mol. On the other hand, modulation of the glucose 6-phosphate dehydrogenase gene of the pentose phosphate pathway increased isobutanol yield from 0.29 to 0.41 mol/mol. Combination of these two strategies had a synergistic effect on improving isobutanol production. Isobutanol titer and yield of the best strain ZL021 were 53 mM and 0.74 mol/mol, which were 51 % and 12 % higher than the starting strain AS108, respectively. The total alcohol yield of strain ZL021 was 0.81 mol/mol, which was 23 % higher than strain AS108. PMID- 26946320 TI - Genomics of local adaptation with gene flow. AB - Gene flow is a fundamental evolutionary force in adaptation that is especially important to understand as humans are rapidly changing both the natural environment and natural levels of gene flow. Theory proposes a multifaceted role for gene flow in adaptation, but it focuses mainly on the disruptive effect that gene flow has on adaptation when selection is not strong enough to prevent the loss of locally adapted alleles. The role of gene flow in adaptation is now better understood due to the recent development of both genomic models of adaptive evolution and genomic techniques, which both point to the importance of genetic architecture in the origin and maintenance of adaptation with gene flow. In this review, we discuss three main topics on the genomics of adaptation with gene flow. First, we investigate selection on migration and gene flow. Second, we discuss the three potential sources of adaptive variation in relation to the role of gene flow in the origin of adaptation. Third, we explain how local adaptation is maintained despite gene flow: we provide a synthesis of recent genomic models of adaptation, discuss the genomic mechanisms and review empirical studies on the genomics of adaptation with gene flow. Despite predictions on the disruptive effect of gene flow in adaptation, an increasing number of studies show that gene flow can promote adaptation, that local adaptations can be maintained despite high gene flow, and that genetic architecture plays a fundamental role in the origin and maintenance of local adaptation with gene flow. PMID- 26946321 TI - High Temperature Affects Photosynthetic and Molecular Processes in Field Cultivated Vitis vinifera L. * Vitis labrusca L. AB - High-temperature stress markedly influences grape growth and development. However, how high-temperature stress response differs between controlled and field-cultivated grape is poorly understood. In this study, the effects of heat treatment on grapevines were studied for changes in photosystem II (PSII) activity and expression levels of heat-responsive genes and heat shock protein HSP21. July 31st, 2015 was considered as the post high-temperature treatment ("42 degrees C"; temperatures above 40 degrees C for a period of time each day ranging from 1-7 h) under field cultivation in our experiment. The recovery of chlorophyll fluorescence indicators and the increasing expression of heat responsive genes and the heat shock protein HSP21 suggested the development of heat tolerance in the form of acclimation in grape. Changes in various parameters of photosynthetic pigment fluorescence and of the electron transport chain (Fv/Fm, PIABS , Wk , RCQA , PhiPo , and PhiEo ) between "42 degrees C" and the 45 degrees C treatment demonstrated that the donor side, reaction center, and acceptor side of PSII were influenced by a critical high temperature. Furthermore, the difference between the two cultivation conditions studied was attributed to other environmental factors and inherent tree vigor. PMID- 26946322 TI - Few multiyear precipitation-reduction experiments find a shift in the productivity-precipitation relationship. AB - Well-defined productivity-precipitation relationships of ecosystems are needed as benchmarks for the validation of land models used for future projections. The productivity-precipitation relationship may be studied in two ways: the spatial approach relates differences in productivity to those in precipitation among sites along a precipitation gradient (the spatial fit, with a steeper slope); the temporal approach relates interannual productivity changes to variation in precipitation within sites (the temporal fits, with flatter slopes). Precipitation-reduction experiments in natural ecosystems represent a complement to the fits, because they can reduce precipitation below the natural range and are thus well suited to study potential effects of climate drying. Here, we analyse the effects of dry treatments in eleven multiyear precipitation manipulation experiments, focusing on changes in the temporal fit. We expected that structural changes in the dry treatments would occur in some experiments, thereby reducing the intercept of the temporal fit and displacing the productivity-precipitation relationship downward the spatial fit. The majority of experiments (72%) showed that dry treatments did not alter the temporal fit. This implies that current temporal fits are to be preferred over the spatial fit to benchmark land-model projections of productivity under future climate within the precipitation ranges covered by the experiments. Moreover, in two experiments, the intercept of the temporal fit unexpectedly increased due to mechanisms that reduced either water loss or nutrient loss. The expected decrease of the intercept was observed in only one experiment, and only when distinguishing between the late and the early phases of the experiment. This implies that we currently do not know at which precipitation-reduction level or at which experimental duration structural changes will start to alter ecosystem productivity. Our study highlights the need for experiments with multiple, including more extreme, dry treatments, to identify the precipitation boundaries within which the current temporal fits remain valid. PMID- 26946323 TI - Native myocardial longitudinal (T1 ) relaxation time: Regional, age, and sex associations in the healthy adult heart. AB - PURPOSE: To use magnetic resonance imaging (MRI) at two field strengths to assess healthy adults' regional myocardial noncontrast (native) T1 relaxation time distribution, and global myocardial native T1 between sexes and across age groups. MATERIALS AND METHODS: In all, 84 healthy volunteers underwent MRI at 1.5T and 3.0T. T1 maps were acquired in three left ventricular short axis slices using an optimized modified Look-Locker inversion recovery investigational prototype sequence. T1 measurements in msec were calculated from 16 regions-of interest, and a global T1 value from all evaluable segments per subject. Associations were assessed with a multivariate linear regression model. RESULTS: In total, 1297 (96.5%) segments were evaluable at 1.5T and 1263 (94.0%) segments at 3.0T. Native T1 was higher in septal than lateral myocardium (1.5T: 956.3 +/- 44.4 vs. 939.2 +/- 54.2 msec; P < 0.001; 3.0T: 1158.2 +/- 45.9 vs. 1148.9 +/- 56.9 msec; P = 0.012). Native T1 decreased with increasing age in females but not in males. Among lowest age tertile (<33 years) global native T1 was higher in females than in males at 1.5T (960.0 +/- 20.3 vs. 931.5 +/- 22.2 msec, respectively; P = 0.003) and 3.0T (1166.5 +/- 19.7 vs. 1130.2 +/- 20.6 msec; P < 0.001). No sex differences were observed in upper age tertile (>=55 years) at 1.5T (937.7 +/- 25.4 vs. 934.7 +/- 22.3 msec; P = 0.762) or 3.0T (1153.0 +/- 30.0 vs. 1132.3 +/- 23.5 msec; P = 0.056). Association of global native T1 to age (P = 0.002) and sex (P < 0.001) was independent of field strength and body size. CONCLUSION: In healthy adults, native T1 values are highest in the ventricular septum. Global native T1 was inversely associated with age in women, but not in men. J. Magn. Reson. Imaging 2016;44:541-548. PMID- 26946324 TI - Inhibition of HIV-1 Reverse Transcriptase Dimerization by Small Molecules. AB - Because HIV-1 reverse transcriptase is an enzyme whose catalytic activity depends on its heterodimeric structure, this system could be a target for inhibitors that perturb the interactions between the protein subunits, p51 and p66. We previously demonstrated that the small molecule MAS0 reduced the association of the two RT subunits and simultaneously inhibited both the polymerase and ribonuclease H activities. In this study, some analogues of MAS0 were rationally selected by docking studies and evaluated in vitro for their ability to disrupt dimeric assembly. Two inhibitors were identified with improved activity compared to MAS0. This study lays the basis for the rational design of more potent inhibitors of RT dimerization. PMID- 26946325 TI - Toll-like Receptor 9 Signaling Is Augmented in Systemic Sclerosis and Elicits Transforming Growth Factor beta-Dependent Fibroblast Activation. AB - OBJECTIVE: Although transforming growth factor beta (TGFbeta) is recognized as being a key trigger of fibroblast activation in systemic sclerosis (SSc), prominent innate immunity suggests that additional pathways contribute to disease persistence. Toll-like receptor 9 (TLR9) is implicated in autoimmunity and fibrosis; however, the expression, mechanism of action, and pathogenic role of TLR9 signaling in SSc remain uncharacterized. The aim of this study was to explore the expression, activity, and potential pathogenic role of TLR9 in the context of skin fibrosis in SSc and in mouse models of experimental fibrosis. METHODS: Expression and localization of TLR9 were evaluated in SSc skin biopsy specimens and explanted skin fibroblasts. Fibrotic responses elicited by type A CpG oligonucleotide and mitochondrial DNA (mtDNA) were examined in human skin fibroblasts by a combination of real-time quantitative polymerase chain reaction, Western blot analysis, transient transfection, immunofluorescence microscopy, and functional assays. Expression of TLR9 was examined in 2 distinct mouse models of experimental fibrosis. RESULTS: Skin biopsy specimens obtained from 2 independent cohorts of SSc patients showed up-regulation of TLR9, and myofibroblasts were the major cellular source. Moreover, SSc skin biopsy specimens showed evidence of TLR9 pathway activation. CpG induced robust TLR9-dependent fibrotic responses in explanted normal fibroblasts that could be blocked by bortezomib and were mediated through the action of endogenous TGFbeta. Mice with experimental fibrosis showed a time-dependent increase in TLR9 localized primarily to myofibroblasts in the dermis. CONCLUSION: In isolated fibroblasts, TLR9 elicits fibrotic responses mediated via endogenous TGFbeta. In patients with SSc, mtDNA and other damage-associated TLR9 ligands in the skin might trigger localized activation of TLR9 signaling, TGFbeta production, and consequent fibroblast activation. Disrupting this fibrotic process with inhibitors targeting TLR9 or its downstream signaling pathways might therefore represent a novel approach to SSc therapy. PMID- 26946326 TI - Haemorrhagic occlusive retinal vasculitis associated with intracameral vancomycin during cataract surgery. PMID- 26946327 TI - The health of Saudi youths: current challenges and future opportunities. AB - BACKGROUND: The health status of the young people is an important indicator for future health and health care needs of the next generation. In order to understand the health risk factors of Saudi youth, we analyzed data from a large national survey in the Kingdom of Saudi Arabia. METHODS: The Saudi Health Information Survey sample included 2382 youths aged 15 to 24 years old. The questionnaire included information on socio-demographic characteristics, risk factors, risky behaviors, chronic conditions, functional status, health care utilization, and anthropometric and blood pressure measurements. RESULTS: Only 45.9% of men and 48.4% of women had normal body mass index (BMI). Men were more likely than women to smoke cigarettes or shisha. The prevalence of daily consumption of at least five servings of fruits and vegetables was 6.6%. The prevalence of no or insufficient physical activity was 41.8% in men and 75.6% in women (P < 0.001). Around 40% of men and 25% of women had abnormal blood pressure. Mean BMI and prevalence of insufficient physical activity, current smoking, and hypertension washigher in 20-to 24-year-olds than younger ages. Women were more likely to report that they never use seatbelts (82.2% vs. 65.4%). CONCLUSIONS: The prevalence of modifiable risk factors and risky driving behaviors is very high among Saudi youth. If these current behaviors are not reversed during this crucial age period, the burden of disease and injuries will rise in the future. Our findings call for developing health prevention programs for youths in Saudi Arabia. PMID- 26946328 TI - Reply. PMID- 26946329 TI - Phospholipidomic Profile Variation on THP-1 Cells Exposed to Skin or Respiratory Sensitizers and Respiratory Irritant. AB - Occupational exposure to low molecular weight reactive chemicals often leads to development of allergic reactions such as allergic contact dermatitis and respiratory allergies. Further insights into the interaction of these chemicals with physiopathological relevant cellular models might provide the foundations for novel non-animal approaches to safety assessment. In this work we used the human THP-1 cell line to determine phospholipidome changes induced by the skin sensitizer 1-fluoro-2,4-dinitrobenzene (DNFB), the respiratory allergen hexamethylene diisocyanate (HDI), and the irritant methyl salicylate (MESA). We detected that these chemicals differently induce lipid peroxidation and modulate THP-1 IL-1beta, IL-12B, IL-8, CD86, and HMOX1 transcription. Decreased phosphatidylethanolamine content was detected in cells exposed to MESA, while profound alterations in the relative abundance of cardiolipin species were observed in cells exposed to DNFB. All chemicals tested induced a decrease in the relative abundance of plasmanyl phosphatidylcholine species PC (O-16:0e/18:1) and phosphatidylinositol species PI (34:1), while increasing PI (38:4). An increased abundance of oleic acid was observed in the phospholipids of cells exposed to DNFB while a decreased abundance of palmitic acid was detected in cells treated with MESA or DNFB. We conclude that both specific and common alterations at phospholipidome levels are triggered by the different chemicals, while not allowing a complete distinction between them using a Canonical Analysis of Principal Coordinates (CAP). The common effects observed at phospholipids level with all the chemicals tested might be related to unspecific cell cytotoxic mechanisms that nevertheless may contribute to the elicitation of specific immune responses. J. Cell. Physiol. 231: 2639-2651, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26946330 TI - Pediatric acute liver failure in Brazil: Is living donor liver transplantation the best choice for treatment? AB - Acute liver failure (ALF) in children is a life-threatening condition that often leads to urgent liver transplantation (LT). The aim of the present investigation was to describe the experience in Brazil in treating pediatric ALF, with an emphasis on the role of living donor liver transplantation (LDLT) in treating this condition. All children with ALF who fulfilled the criteria for an urgent LT were admitted to the intensive care unit. Patients were divided into 2 groups based on the moment of admission: before and after June 2007, when the LDLT program for ALF was started. Statistical analyses were performed to identify prognostic factors of patients with ALF. For the study, 115 children with ALF were admitted. All patients had some degree of encephalopathy. Among the patients, 26% of them required intracranial pressure monitoring (IPM), 12.8% of the patients required hemodialysis, and 79 patients underwent transplantation (50 deceased donors and 29 living donors) corresponding to 12.4% of all pediatric LTs. Only 9 children recovered without LT. The need for IPM and nonperformance of LT were related to a higher mortality. The mortality rate of patients who underwent LT was significantly lower than that of children with ALF who did not undergo a LT (48.1% versus 75%; P = 0.02). The incidences of primary nonfunction and mortality were statistically higher among deceased donor liver transplantations than LDLTs. Finally, it was verified that the overall survival rate of transplanted patients was increased after the introduction of LDLT (P = 0.02). In conclusion, ALF in children continues to be a severe and devastating condition, and a LT should be performed promptly. The introduction of LDLT could increase the survival rate of patients in Brazil. Liver Transplantation 22 1006 1013 2016 AASLD. PMID- 26946331 TI - Ductus venosus Doppler in the assessment of fetal cardiovascular health: an updated practical approach. AB - The ductus venosus has a central role in the distribution of highly oxygenated umbilical venous blood to the heart. Its waveform is related to the pressure volume changes in the cardiac atria and it is therefore important in the monitoring of any fetal condition that may affect forward cardiac function. The cardiovascular parameters that can influence forward cardiac function include afterload, myocardial performance and preload. Decreased forward flow during atrial systole (a-wave) is the most sensitive and ubiquitous finding when any of these parameters is affected. In contrast, decreased forward velocities during end-systolic relaxation (v-wave) are more specifically related to myocardial performance. The ductus venosus pulsatility index alone does not accurately reflect cardiac function, and in cases of suspected fetal cardiac dysfunction, echocardiography is required to identify the underlying mechanism. The role of ductus venosus Doppler in the assessment of fetal growth restriction, supraventricular tachycardia, fetal hydrops, complicated monochorionic twins and congenital heart disease is discussed with these considerations in mind. PMID- 26946332 TI - Unihemispheric concurrent dual-site cathodal transcranial direct current stimulation: the effects on corticospinal excitability. AB - We aimed to assess the effects of concurrent cathodal transcranial direct current stimulation (c-tDCS) of two targets in a hemisphere, termed unihemispheric concurrent dual-site cathodal tDCS (c-tDCSUHCDS ), on the size of M1 corticospinal excitability and its lasting effect. Secondary aims were to identify the mechanisms behind the efficacy of c-tDCSUHCDS and to evaluate the side effects of this new technique. Twelve healthy volunteers received 20 min c tDCS under five conditions in a random order: M1 c-tDCS, c-tDCSUHCDS of M1 dorsolateral prefrontal cortex (DLPFC), M1-primary sensory cortex (S1), M1 primary visual cortex (V1) and sham. The M1 corticospinal excitability of the first dorsal interossei muscle was assessed before, immediately after, and 30 min, 60 min and 24 h after the interventions. Short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF) were also assessed, using a paired-pulse paradigm. Compared to conventional M1 c-tDCS, corticospinal excitability significantly increased following c-tDCSUHCDS of M1-DLPFC and M1-V1 for up to 24 h (P = 0.001). Significant increases in ICF were observed following c-tDCSUHCDS of M1-DLPFC (P = 0.005) and M1-V1 (P = 0.002). Compared to baseline values, ICF and SICI increased significantly at T60 (P < 0.001) and T24 h (P < 0.001) following the concurrent c-tDCS of M1 and V1. Sham c-tDCSUHCDS did not induce any significant alteration. The corticospinal excitability increase was mainly accompanied by ICF increase, which indirectly indicates the activity of glutamergic mechanisms. The findings may help us to more fully understand the brain function and develop future motor learning studies. No significant excitability change induced by sham c-tDCSUHCDS suggests that there is no placebo effect associated with this new tDCS technique. PMID- 26946334 TI - An Emotional Stress as a Trigger for Reverse Takotsubo Cardiomyopathy: A Case Report and Literature Review. AB - BACKGROUND: Reverse Takotsubo cardiomyopathy is one of the rarest types of stress induced cardiomyopathy, which despite sharing similar pathogenic mechanisms with its more common counterpart, has different clinical manifestations, demographics, and laboratory values. CASE REPORT: We present the case of a 61-year-old woman who came to the hospital with a chief complaint of chest pain and dyspnea. She was found to have elevated troponin and severely depressed left ventricular function. Echocardiography showed normal contracting apex, with the rest of the left ventricle being hypokinetic. Cardiac catheterization revealed mild coronary artery disease and confirmed echocardiographic findings showing hyperkinetic apex and dilated base. She was discharged home on ACE inhibitor and B-blocker. A repeat echocardiogram 2 weeks after the initial presentation showed complete resolution of cardiac dysfunction. CONCLUSIONS: Reverse Takotsubo cardiomyopathy is a rare disease mimicking acute coronary syndrome. It is essential to rule out organic coronary disease prior to attributing the presentation to Takotsubo cardiomyopathy. With supportive care, the long-term prognosis is good in the vast majority of patients. PMID- 26946333 TI - Factors Associated With Major Adverse Cardiovascular Events After Liver Transplantation Among a National Sample. AB - Assessment of major adverse cardiovascular events (MACE) after liver transplantation (LT) has been limited by the lack of a multicenter study with detailed clinical information. An integrated database linking information from the University HealthSystem Consortium and the Organ Procurement and Transplant Network was analyzed using multivariate Poisson regression to assess factors associated with 30- and 90-day MACE after LT (February 2002 to December 2012). MACE was defined as myocardial infarction (MI), heart failure (HF), atrial fibrillation (AF), cardiac arrest, pulmonary embolism, and/or stroke. Of 32 810 recipients, MACE hospitalizations occurred in 8% and 11% of patients at 30 and 90 days, respectively. Recipients with MACE were older and more likely to have a history of nonalcoholic steatohepatitis (NASH), alcoholic cirrhosis, MI, HF, stroke, AF and pulmonary and chronic renal disease than those without MACE. In multivariable analysis, age >65 years (incidence rate ratio [IRR] 2.8, 95% confidence interval [95% CI] 1.8-4.4), alcoholic cirrhosis (IRR 1.6, 95% CI 1.2 2.2), NASH (IRR 1.6, 95% CI 1.1-2.4), pre-LT creatinine (IRR 1.1, 95% CI 1.04 1.2), baseline AF (IRR 6.9, 95% CI 5.0-9.6) and stroke (IRR 6.3, 95% CI 1.6-25.4) were independently associated with MACE. MACE was associated with lower 1-year survival after LT (79% vs. 88%, p < 0.0001). In a national database, MACE occurred in 11% of LT recipients and had a negative impact on survival. Pre-LT AF and stroke substantially increase the risk of MACE, highlighting potentially high risk LT candidates. PMID- 26946335 TI - Lessons from the construction of a climate change adaptation plan: A Broads wetland case study. AB - The dynamic nature of environmental change in coastal areas means that a flexible "learning by doing" management strategy has a number of advantages. This article lays out the principles of such a strategy and then assesses an actual planning and management process focused on climate change consequences for the Broads wetland on the East coast of England. The management strategy focused on the concept of ecosystem services (stocks and flows) provided by the coastal wetland and the threats and opportunities posed to the area by sea level rise and other climate change impacts. The analysis explores the process by which an adaptive management plan has been formulated and coproduced by a combination of centralized (vertical) and stakeholder social network (horizontal) arrangements. The process values where feasible the ecosystem services under threat and prioritizes response actions. Coastal management needs a careful balance between strategic requirements imposed at a national scale and local schemes that affect regional and/or local communities and social networks. These networks aided by electronic media have allowed groups to engage more rapidly and effectively with policy proposals. However, successful deliberation is conditioned by a range of context specific factors, including the type of social networks present and their relative competitive and/or complementary characteristics. The history of consultation and dialogue between official agencies and stakeholders also plays a part in contemporary deliberation processes and the success of their outcomes. Among the issues highlighted are the multiple dimensions of nature's value; the difficulty of quantifying some ecosystem service changes, especially for cultural services; and the problem of "stakeholder fatigue" complicating engagement arrangements. Integr Environ Assess Manag 2016;12:719-725. (c) 2016 SETAC. PMID- 26946336 TI - Role of intratumoral infiltrating macrophages after transarterial immunoembolization for hepatocellular carcinoma. AB - BACKGROUND: Preoperative transarterial immunoembolization (TIE) for hepatocellular carcinoma (HCC) is effective for preventing recurrence. We aimed to investigate the intratumoral and peritumoral M1 macrophage-induced immune response following TIE treatment. METHODS: We compared 13 patients treated with TIE between 2003 and 2009 (TIE group) and 13 patients treated with surgery alone during the same period of time at our institute (control group) using an immunohistological study with CD68 and CD163 antibodies. RESULTS: No significant differences in clinicopathological characteristics, except for surgical time, were observed between the two groups. The 3-year recurrence-free survival outcome of the TIE group was quite different from that of the control group (100% vs. 38.5%, P = 0.034). In the histological investigation, lytic necrosis and coagulation necrosis of the main tumor along with the presence of multinuclear giant cells were observed in 10 of the 13 patients in the TIE group. The immunohistological study showed that not only the numbers of intratumoral CD68(+) cells, but also the numbers of intratumoral and peritumoral CD8(+) cells were significantly increased in the TIE group. CONCLUSIONS: The suppression of tumor recurrence induced by preoperative TIE might be induced by intratumoral M1 macrophages that are activated by OK-432 and fibrinogen. PMID- 26946337 TI - Functional Magnetic Resonance Imaging of Working Memory and Executive Dysfunction in Systemic Lupus Erythematosus and Antiphospholipid Antibody-Positive Patients. AB - OBJECTIVE: Standardized cognitive tests and functional magnetic resonance imaging (fMRI) studies of systemic lupus erythematosus (SLE) patients demonstrate deficits in working memory and executive function. These neurobehavioral abnormalities are not well studied in antiphospholipid syndrome, which may occur independently of or together with SLE. This study compares an fMRI paradigm involving motor skills, working memory, and executive function in SLE patients without antiphospholipid antibody (aPL) (the SLE group), aPL-positive non-SLE patients (the aPL-positive group), and controls. METHODS: Brain MRI, fMRI, and standardized cognitive assessment results were obtained from 20 SLE, 20 aPL positive, and 10 healthy female subjects with no history of neuropsychiatric abnormality. RESULTS: Analysis of fMRI data showed no differences in performance across groups on bilateral motor tasks. When analysis of variance was used, significant group differences were found in 2 executive function tasks (word generation and word rhyming) and in a working memory task (N-Back). Patients positive for aPL demonstrated higher activation in bilateral frontal, temporal, and parietal cortices compared to controls during working memory and executive function tasks. SLE patients also demonstrated bilateral frontal and temporal activation during working memory and executive function tasks. CONCLUSION: Compared to controls, both aPL-positive and SLE patients had elevated cortical activation, primarily in the frontal lobes, during tasks involving working memory and executive function. These findings are consistent with cortical overactivation as a compensatory mechanism for early white matter neuropathology in these disorders. PMID- 26946339 TI - Spiradenocylindroma: an uncommon morphologic entity. PMID- 26946338 TI - Susceptibility of swine to H5 and H7 low pathogenic avian influenza viruses. AB - BACKGROUND: The ability of pigs to become infected with low pathogenic avian influenza (LPAI) viruses and then generate mammalian adaptable influenza A viruses is difficult to determine. Yet, it is an important link to understanding any relationship between LPAI virus ecology and possible epidemics among swine and/or humans. OBJECTIVES: Assess susceptibility of pigs to LPAI viruses found within the United States and their direct contact transmission potential. METHODS: Pigs were inoculated with one of ten H5 or H7 LPAI viruses selected from seven different bird species to test infectivity, virulence, pathogenesis, and potential to transmit virus to contact pigs through histological, RRT-PCR and seroconversion data. RESULTS: Although pigs were susceptible to infection with each of the LPAI viruses, no clinical disease was recognized in any pig. During the acute phase of the infection, minor pulmonary lesions were found in some pigs and one or more pigs in each group were RRT-PCR-positive in the lower respiratory tract, but no virus was detected in upper respiratory tract (negative nasal swabs). Except for one group, one or more pigs in each LPAI group developed antibody. No LPAI viruses transmitted to contact pigs. CONCLUSIONS: LPAI strains from various bird populations within the United States are capable of infecting pigs. Although adaptability and transmission of individual strains seem unlikely, the subclinical nature of the infections demonstrates the need to improve sampling and testing methods to more accurately measure incidence of LPAI virus infection in pigs, and their potential role in human-zoonotic LPAI virus dynamics. PMID- 26946340 TI - Endoscopic pilonidal sinus treatment: a prospective multicentre trial. AB - BACKGROUND: Pilonidal disease (PD) is a common inflammatory disease of the gluteal fold, resulting in recurrent acute/chronic infection at the level of the natal cleft. In this study, endoscopic pilonidal sinus treatment (EPSiT), a new endoscopic minimally invasive procedure, was evaluated for its effectiveness in treating PD. METHODS: Two hundred and fifty prospective patients with chronic PD were enrolled in a prospective multicentre study conducted at a secondary and tertiary colorectal surgery centre. The primary end-point of this study was wound healing, and the short-/long-term outcomes such as healing time, morbidity rate and recurrence rate were analysed. The secondary end-point of this study was quality of life (QoL). RESULTS: The complete wound healing rate was 94.8%, and the mean complete wound healing time was 26.7 +/- 10.4 days. The incomplete healing rate (5.2%) was significantly related to the number of external openings (P = 0.01). There was no difference in the failure rate when EPSiT was performed as the first-line treatment for PD or when it was used after unsuccessful procedures (P = n.s.). Recurrence occurred in 12 cases (5%). The QoL significantly increased from preoperative levels 15 days after the EPSiT procedure (45.3 vs 7.9; P < 0.0001). CONCLUSIONS: The EPSiT procedure is a safe and effective technique for treating PD. It provides better short- and long-term outcomes than various other techniques that are more invasive. EPSiT is a minimally invasive outpatient procedure, which is associated with a quick recovery and a good QoL outcome. PMID- 26946341 TI - Glycation in Parkinson's disease and Alzheimer's disease. AB - Glycation is a spontaneous age-dependent posttranslational modification that can impact the structure and function of several proteins. Interestingly, glycation can be detected at the periphery of Lewy bodies in the brain in Parkinson's disease. Moreover, alpha-synuclein can be glycated, at least under experimental conditions. In Alzheimer's disease, glycation of amyloid beta peptide exacerbates its toxicity and contributes to neurodegeneration. Recent studies establish diabetes mellitus as a risk factor for several neurodegenerative disorders, including Parkinson's and Alzheimer's diseases. However, the mechanisms underlying this connection remain unclear. We hypothesize that hyperglycemia might play an important role in the development of these disorders, possibly by also inducing protein glycation and thereby dysfunction, aggregation, and deposition. Here, we explore protein glycation as a common player in Parkinson's and Alzheimer's diseases and propose it may constitute a novel target for the development of strategies for neuroprotective therapeutic interventions. (c) 2016 International Parkinson and Movement Disorder Society. PMID- 26946342 TI - Memorial: Albert L. Rhoton Jr., M.D. (1932-2016). PMID- 26946344 TI - Radiation Therapy Induces Macrophages to Suppress T-Cell Responses Against Pancreatic Tumors in Mice. AB - BACKGROUND & AIMS: The role of radiation therapy in the treatment of patients with pancreatic ductal adenocarcinoma (PDA) is controversial. Randomized controlled trials investigating the efficacy of radiation therapy in patients with locally advanced unresectable PDA have reported mixed results, with effects ranging from modest benefit to worse outcomes compared with control therapies. We investigated whether radiation causes inflammatory cells to acquire an immune suppressive phenotype that limits the therapeutic effects of radiation on invasive PDAs and accelerates progression of preinvasive foci. METHODS: We investigated the effects of radiation therapy in p48(Cre);LSL-Kras(G12D) (KC) and p48(Cre);LSLKras(G12D);LSL-Trp53(R172H) (KPC) mice, as well as in C57BL/6 mice with orthotopic tumors grown from FC1242 cells derived from KPC mice. Some mice were given neutralizing antibodies against macrophage colony-stimulating factor 1 (CSF1 or MCSF) or F4/80. Pancreata were exposed to doses of radiation ranging from 2 to 12 Gy and analyzed by flow cytometry. RESULTS: Pancreata of KC mice exposed to radiation had a higher frequency of advanced pancreatic intraepithelial lesions and more foci of invasive cancer than pancreata of unexposed mice (controls); radiation reduced survival time by more than 6 months. A greater proportion of macrophages from radiation treated invasive and preinvasive pancreatic tumors had an immune-suppressive, M2-like phenotype compared with control mice. Pancreata from mice exposed to radiation had fewer CD8(+) T cells than controls, and greater numbers of CD4(+) T cells of T-helper 2 and T-regulatory cell phenotypes. Adoptive transfer of T cells from irradiated PDA to tumors of control mice accelerated tumor growth. Radiation induced production of MCSF by PDA cells. A neutralizing antibody against MCSF prevented radiation from altering the phenotype of macrophages in tumors, increasing the anti-tumor T-cell response and slowing tumor growth. CONCLUSIONS: Radiation treatment causes macrophages murine PDA to acquire an immune-suppressive phenotype and disabled T-cell-mediated anti-tumor responses. MCSF blockade negates this effect, allowing radiation to have increased efficacy in slowing tumor growth. PMID- 26946345 TI - No Association Between CEL-HYB Hybrid Allele and Chronic Pancreatitis in Asian Populations. AB - A hybrid allele between the carboxyl ester lipase gene (CEL) and its pseudogene, CELP (called CEL-HYB), generated by nonallelic homologous recombination between CEL intron 10 and CELP intron 10', was found to increase susceptibility to chronic pancreatitis in a case-control study of patients of European ancestry. We attempted to replicate this finding in 3 independent cohorts from China, Japan, and India, but failed to detect the CEL-HYB allele in any of these populations. The CEL-HYB allele might therefore be an ethnic-specific risk factor for chronic pancreatitis. An alternative hybrid allele (CEL-HYB2) was identified in all 3 Asian populations (1.7% combined carrier frequency), but was not associated with chronic pancreatitis. PMID- 26946343 TI - Infliximab Reduces Endoscopic, but Not Clinical, Recurrence of Crohn's Disease After Ileocolonic Resection. AB - BACKGROUND & AIMS: Most patients with Crohn's disease (CD) eventually require an intestinal resection. However, CD frequently recurs after resection. We performed a randomized trial to compare the ability of infliximab vs placebo to prevent CD recurrence. METHODS: We evaluated the efficacy of infliximab in preventing postoperative recurrence of CD in 297 patients at 104 sites worldwide from November 2010 through May 2012. All study patients had undergone ileocolonic resection within 45 days before randomization. Patients were randomly assigned (1:1) to groups given infliximab (5 mg/kg) or placebo every 8 weeks for 200 weeks. The primary end point was clinical recurrence, defined as a composite outcome consisting of a CD Activity Index score >200 and a >=70-point increase from baseline, and endoscopic recurrence (Rutgeerts score >=i2, determined by a central reader) or development of a new or re-draining fistula or abscess, before or at week 76. Endoscopic recurrence was a major secondary end point. RESULTS: A smaller proportion of patients in the infliximab group had a clinical recurrence before or at week 76 compared with the placebo group, but this difference was not statistically significant (12.9% vs 20.0%; absolute risk reduction [ARR] with infliximab, 7.1%; 95% confidence interval: -1.3% to 15.5%; P = .097). A significantly smaller proportion of patients in the infliximab group had endoscopic recurrence compared with the placebo group (30.6% vs 60.0%; ARR with infliximab, 29.4%; 95% confidence interval: 18.6% to 40.2%; P < .001). Additionally, a significantly smaller proportion of patients in the infliximab group had endoscopic recurrence based only on Rutgeerts scores >=i2 (22.4% vs 51.3%; ARR with infliximab, 28.9%; 95% confidence interval: 18.4% to 39.4%; P < .001). Patients previously treated with anti-tumor necrosis factor agents or those with more than 1 resection were at greater risk for clinical recurrence. The safety profile of infliximab was similar to that from previous reports. CONCLUSIONS: Infliximab is not superior to placebo in preventing clinical recurrence after CD-related resection. However, infliximab does reduce endoscopic recurrence. ClinicalTrials.gov ID NCT01190839. PMID- 26946347 TI - Erosive oral lichen planus as a sign of paraneoplastic pemphigus. PMID- 26946348 TI - Alanine aminotransferase course, serum hepatitis B virus DNA, and liver stiffness measurement for therapeutic decisions in hepatitis B e antigen-negative chronic hepatitis B. AB - AIM: To evaluate the utility of the combination of alanine aminotransferase (ALT) course, hepatitis B virus (HBV) DNA level, and liver stiffness measurement (LSM) for determining significant liver disease in hepatitis B e antigen (HBeAg) negative patients. METHODS: Three hundred and ninety nine consecutive HBeAg negative patients with HBV DNA >2000 IU/mL and documented serial measurements of ALT were enrolled to undergo LSM followed by liver biopsy. RESULTS: Using ALT <40 IU/L as a normal value, 142 patients had persistently normal ALT (PNALT), whereas 257 had persistently or intermittently elevated ALT (PIEALT) in the prior year. Among patients with HBV DNA of 2000-19 999, 20 000-199 999, and >=200 000 IU/mL, significant pathological lesions defined as the presence of moderate to severe necroinflammation and/or significant fibrosis by METAVIR scoring was present in 40%, 45%, and 71% of the PIEALT group, and 15%, 31%, and 36% of the PNALT group, respectively. In PNALT patients with HBV DNA <20 000 IU/mL, liver biopsy could be avoided in 88% when LSM <7 kPa is used as an indicator of non-significant liver histology but 12% of those who indeed had significant pathological lesions would be missed. In PIEALT patients with HBV DNA >=20 000 IU/mL, the need for liver biopsy could be reduced by 53% with a false positive rate of 14% when LSM >=7 kPa is used as a predictor of significant pathological lesions. CONCLUSION: The combination of serial ALT, viral load, and LSM appears to be a promising non invasive tool. A management algorithm for HBeAg-negative patients comprising these non-invasive measures is proposed with liver biopsy being pursued in selected cases. PMID- 26946346 TI - Anti-IgE Monoclonal Antibody (Omalizumab) in Refractory and Relapsing Eosinophilic Granulomatosis With Polyangiitis (Churg-Strauss): Data on Seventeen Patients. AB - OBJECTIVE: To describe the efficacy and safety of omalizumab, an anti-IgE monoclonal antibody, in patients with refractory and/or relapsing eosinophilic granulomatosis with polyangiitis (Churg-Strauss) (EGPA). METHODS: We conducted a nationwide retrospective study including EGPA patients who received omalizumab. Response was defined as the absence of asthma and/or sinonasal exacerbations with a prednisone dosage of <=7.5 mg/day (complete response) or >7.5 mg/day (partial response). RESULTS: Seventeen patients (median age 45 years) received omalizumab for severe steroid-dependent asthma (88%) and/or sinonasal involvement (18%). After a median follow-up of 22 months, 6 patients (35%) achieved a complete response, 5 patients (30%) achieved a partial response, and 6 patients (35%) had no improvement. The median Birmingham Vasculitis Activity Score decreased from 2.5 at baseline to 0.5 at 12 months. The median number of exacerbations per month decreased from 1 at baseline to 0 at 12 months, and the median forced expiratory volume in 1 second increased from 63% of the percent predicted at baseline to 85% of the percent predicted at 12 months. The median prednisone dosage decreased from 16 mg/day at baseline to 11 mg/day at 6 months and 9 mg/day at 12 months. Omalizumab was discontinued in 8 patients (47%) during follow-up, because of remission (12.5%), adverse event despite disease remission (12.5%), refractory disease (25%), or relapse (50%). Relapses included retrobulbar optic neuritis attributable to EGPA in 2 patients and severe asthma flare in 2 others. CONCLUSION: The results of this study suggest that omalizumab may have a corticosteroid-sparing effect in EGPA patients with asthmatic and/or sinonasal manifestations, but reducing the corticosteroid dose may also increase the risk of severe EGPA flares, which raises the question of the safety of omalizumab in patients with EGPA. PMID- 26946349 TI - Phenotypic and biomarker evaluation of zebrafish larvae as an alternative model to predict mammalian hepatotoxicity. AB - Zebrafish phenotypic assays have shown promise to assess human hepatotoxicity, though scoring of liver morphology remains subjective and difficult to standardize. Liver toxicity in zebrafish larvae at 5 days was assessed using gene expression as the biomarker approach, complementary to phenotypic analysis and analytical data on compound uptake. This approach aimed to contribute to improved hepatotoxicity prediction, with the goal of identifying biomarker(s) as a step towards the development of transgenic models for prioritization. Morphological effects of hepatotoxic compounds (acetaminophen, amiodarone, coumarin, methapyrilene and myclobutanil) and saccharin as the negative control were assessed after exposure in zebrafish larvae. The hepatotoxic compounds induced the expected zebrafish liver degeneration or changes in size, whereas saccharin did not have any phenotypic adverse effect. Analytical methods based on liquid chromatography-mass spectrometry were optimized to measure stability of selected compounds in exposure medium and internal concentration in larvae. All compounds were stable, except amiodarone for which precipitation was observed. There was a wide variation between the levels of compound in the zebrafish larvae with a higher uptake of amiodarone, methapyrilene and myclobutanil. Detection of hepatocyte markers (CP, CYP3A65, GC and TF) was accomplished by in situ hybridization of larvae to coumarin and myclobutanil and confirmed by real-time reverse transcription-quantitative polymerase chain reaction. Experiments showed decreased expression of all markers. Next, other liver-specific biomarkers (i.e. FABP10a and NR1H4) and apoptosis (i.e. CASP-3 A and TP53) or cytochrome P450 related (CYP2K19) and oxidoreductase activity-related (ZGC163022) genes, were screened. Links between basic mechanisms of liver injury and results of biomarker responses are described. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26946351 TI - Importance of high sensitivity C-reactive protein in the evaluation of wheezing in children. PMID- 26946350 TI - A Novel Therapeutic Approach Using Mesenchymal Stem Cells to Protect Against Mycobacterium abscessus. AB - Recent studies have demonstrated the therapeutic potential of mesenchymal stem cells (MSCs) for the treatment of acute inflammatory injury and bacterial pneumonia, but their therapeutic applications in mycobacterial infections have not been investigated. In this study, we demonstrated the use of MSCs as a novel therapeutic strategy against Mycobacterium abscessus (M. abscessus), which is the most drug-resistant and difficult-to-treat mycobacterial pathogen. The systemic intravenous injection of MSCs not only improved mouse survival but also enhanced bacterial clearance in the lungs and spleen. Additionally, MSCs enhanced IFN gamma, TNF-alpha, IL-6, MCP-1, nitric oxide (NO) and PGE2 production and facilitated CD4(+) /CD8(+) T cell, CD11b(high) macrophage, and monocyte recruitment in the lungs of M. abscessus-infected mice. To precisely elucidate the functions of MSCs in M. abscessus infection, an in vitro macrophage infection system was used. MSCs caused markedly increased NO production via NF-kappaB activation in M. abscessus-infected macrophages cultured in the presence of IFN gamma. Inhibiting NO or NF-kappaB signaling using specific inhibitors reduced the antimycobacterial activity of MSCs. Furthermore, the cellular crosstalk between TNF-alpha released from IFN-gamma-stimulated M. abscessus-infected macrophages and PGE2 produced by MSCs was necessary for the mycobacterial-killing activity of the macrophages. Finally, the importance of increased NO production in response to MSC administration was confirmed in the mouse M. abscessus infection model. Our results suggest that MSCs may offer a novel therapeutic strategy for treating this drug-resistant mycobacterial infection by enhancing the bacterial-killing power of macrophages. Stem Cells 2016;34:1957-1970. PMID- 26946352 TI - Infant and maternal risk factors related to necrotising enterocolitis-associated infant death in the United States. AB - AIM: To evaluate necrotising enterocolitis (NEC)-associated infant death and identify risk factors related to NEC infant death in the United States. METHODS: The United States Period Linked Birth/Infant Death data for 2010-2013 were utilised to determine risk factors associated with NEC infant death. Infant mortality rates (IMRs) were calculated and a retrospective matched case-control analysis was performed. An infant case was defined as having the International Classification of Diseases, Tenth Revision code for NEC listed on the death record. Controls were matched on birthweight and randomly selected. Conditional multivariable logistic regression models stratified by birthweight were conducted to determine risk factors for NEC infant death. RESULTS: The average annual NEC IMR was 12.5 deaths per 100 000 live births and was higher among very low birthweight (VLBW) compared to normal birthweight infants and among black compared to white infants. For VLBW infants, the multivariable analysis identified male sex, five-minute Apgar score of less than 7, and white infants born to a mother who is less than or equal to 19 years of age to be related with NEC-associated infant death. CONCLUSION: Paediatricians should be aware of the factors related to NEC-associated infant death to reduce the number of infants at greatest risk for NEC and focus on racial disparities. PMID- 26946353 TI - Estimating fish abundance and biomass from eDNA concentrations: variability among capture methods and environmental conditions. AB - Environmental DNA (eDNA) promises to ease noninvasive quantification of fish biomass or abundance, but its integration within conservation and fisheries management is currently limited by a lack of understanding of the influence of eDNA collection method and environmental conditions on eDNA concentrations in water samples. Water temperature is known to influence the metabolism of fish and consequently could strongly affect eDNA release rate. As water temperature varies in temperate regions (both seasonally and geographically), the unknown effect of water temperature on eDNA concentrations poses practical limitations on quantifying fish populations using eDNA from water samples. This study aimed to clarify how water temperature and the eDNA capture method alter the relationships between eDNA concentration and fish abundance/biomass. Water samples (1 L) were collected from 30 aquaria including triplicate of 0, 5, 10, 15 and 20 Brook Charr specimens at two different temperatures (7 degrees C and 14 degrees C). Water samples were filtered with five different types of filters. The eDNA concentration obtained by quantitative PCR (qPCR) varied significantly with fish abundance and biomass and types of filters (mixed-design ANOVA, P < 0.001). Results also show that fish released more eDNA in warm water than in cold water and that eDNA concentration better reflects fish abundance/biomass at high temperature. From a technical standpoint, higher levels of eDNA were captured with glass fibre (GF) filters than with mixed cellulose ester (MCE) filters and support the importance of adequate filters to quantify fish abundance based on the eDNA method. This study supports the importance of including water temperature in fish abundance/biomass prediction models based on eDNA. PMID- 26946354 TI - MET immunolabelling is a useful predictive tool for MET gene amplification in glioblastoma. AB - AIMS: MET gene amplification is rare in glioblastoma (GBM) and represents a potential target for MET inhibitors. An immunohistochemical screening may be useful to identify MET amplification. The aim of our study was to establish how MET immunolabelling correlates with MET amplification. METHODS: Three cohorts including 108 GBM (cohort 1, prospective), 104 GBM (cohort 2, retrospective) and 52 GBM (cohort 3, prospective) were investigated for MET expression by immunohistochemistry. MET amplification was assessed by comparative genomic hybridization on microarray (CGH-array) in all cohorts and by fluorescent in situ hybridization (FISH) in cohorts 2 and 3. Active form of MET was assessed using p MET (Y1349) immunohistochemistry. RESULTS: Diffuse MET amplification detectable by CGH-array was associated with diffuse, strong MET immunolabelling (four cases in cohort 1 and one case in cohort 2). Focal MET amplification detectable only by FISH was observed in small foci of strongly immunopositive cells in two GBM (cohort 2). In both cohorts, MET amplification was never detected in GBM devoid of strongly immunopositive cells. MET overexpression, observed in 23% of unamplified GBM, was associated with a predominant weak-to-moderate staining intensity and with necrosis (P < 0.005). p-MET was detected in all MET-amplified GBM and in perinecrotic areas of nonamplified GBM. A strong MET immunostaining intensity, at least focal and distant from necrosis, showed 100% sensitivity and 84% specificity for predicting MET amplification in cohort 3. CONCLUSIONS: MET amplification is characterized by strongly immunopositive cells. Only GBM showing strong MET immunostaining is appropriate for the assessment of MET amplification. PMID- 26946355 TI - Effect of alcohol dosage on long-term outcomes after alcohol septal ablation in patients with hypertrophic cardiomyopathy. AB - OBJECTIVES: The aim of this study is to assess the long-term effects of alcohol dosage in alcohol septal ablation (ASA) on mortality and adverse arrhythmic events (AAE). BACKGROUND: ASA can be performed to reduce left ventricular outflow tract (LVOT) obstruction in patients with hypertrophic cardiomyopathy (HCM). However, the effect of alcohol dosage on long-term outcomes is unknown. METHODS: This retrospective cohort study includes 296 HCM patients (age 60 +/- 22 years, 58% male) who underwent ASA because of symptomatic LVOT obstruction. Twenty-nine patients (9.8%) were excluded because the alcohol dosage could not be retrieved. Primary endpoints were all-cause mortality and AAE. RESULTS: During 6.3 +/- 3.7 years of follow-up, all-cause mortality and AAE rates were similar in patients who received <=2.0 mL (n = 142) and >2.0 mL (n = 121) alcohol during ASA. Age was the only independent predictor of mortality (HR 1.1 95% CI 1.0-1.1, P < 0.001). Predictors of AAE were maximum CK-MB >240 U/L (HR 3.3 95% CI 1.5-7.2, P = 0.003), and sudden cardiac death survivor (HR 5.9 95% CI 1.7-20.3, P = 0.004). There was a mild to moderate correlation between CK-MB levels and amount of alcohol (Spearman's rho 0.39, P < 0.001), cross-sectional area of the target septal branch ostium/ostia (Spearman's rho 0.19, P = 0.003), and maximum ventricular wall thickness (Spearman's rho 0.17, P = 0.006). CONCLUSIONS: Alcohol dosage appears not to have a long-term effect on mortality and AAE. A larger infarct size created by ASA increases the risk of AAE, and extended monitoring of these patients is advised. (c) 2016 Wiley Periodicals, Inc. PMID- 26946356 TI - Molecular epidemiology of rotavirus in four provinces of Angola before vaccine introduction. AB - Angola is a sub-Saharan country in southern Africa highly affected by diarrhoeal disease with limited epidemiological data regarding etiologic agents. This study was performed during 2012-2013, prior to rotavirus vaccine introduction, with the objective to detect and characterize the rotavirus strains circulating in four provinces of the country: Huambo, Luanda, Zaire, and Cabinda. A high rotavirus detection rate (35%, 117/334) was observed. G1 was the most common G-genotype (83.6%), whereas P[8] (50.9%) followed by P[6] (38.8%) were the most common P types. G1P[8] was identified as the predominant combination (50%), followed by the unusual G1P[6] (29.3%). Strains such G2P[4], G8P[6], G9P[6], and G12P[6] were also found in lower frequencies (5.2-1.7%). The P[6] strains did not cluster in the phylogenetic trees according to their geographic origin or even the corresponding G-genotype, suggesting a limited number of recent introductions and extensive reassortment events. Our results represent the first report on rotavirus genotype profiles in Angola, showing a wide circulation of the unusual genotype G1P[6], and underline the importance of RV surveillance after the vaccine introduction. J. Med. Virol. 88:1511-1520, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26946357 TI - miR-203 inhibits cell proliferation and promotes cisplatin induced cell death in tongue squamous cancer. AB - Oral squamous cell carcinoma (OSCC) is one of the most common types of the head and neck cancer. Chemo resistance of OSCC has been identified as a substantial therapeutic hurdle. In this study, we analyzed the role of miR-203 in the OSCC and its effects on cisplatin-induced cell death in an OSCC cell line, Tca8113. There was a significant decrease of miR-203 expression in OSCC samples, compared with the adjacent normal, non-cancerous tissue. After 3 days cisplatin treatment, the survived Tca8113 cells had a lower expression of miR-203 than that in the untreated control group. In contrast, PIK3CA showed an inverse expression in cancer and cisplatin survived Tca8113 cells. Transfection of Tca8113 cells with miR-203 mimics greatly reduced PIK3CA expression and Akt activation. Furthermore, miR-203 repressed PIK3CA expression through targeting the 3'UTR. Restoration of miR-203 not only suppressed cell proliferation, but also sensitized cells to cisplatin induced cell apoptosis. This effect was absent in cells that were simultaneously treated with PIK3CA RNAi. In summary, these findings suggest miR 203 plays an important role in cisplatin resistance in OSCC, and furthermore delivery of miR-203 analogs may serve as an adjuvant therapy for OSCC. PMID- 26946358 TI - The prion protein selectively binds to and modulates the content of purinergic receptor P2X4R. AB - The GPI-anchored prion protein (PrP(C)) is involved in neurodegeneration, either through misfolding in the Transmissible Spongiform Encephalopathies (TSE), or as a mediator of the neurotoxicity of peptide oligomers in Alzheimer's Disease. PrP(C) has been attributed pleiotropic functions, and appears to scaffold a variety of cell surface signaling modules, for example through its binding to several neurotransmitter receptors. Here we used transfected HEK293 cells to test for an interaction of PrP(C) with purinergic receptor P2X4R. The prion protein bound P2X4R in both overlay and co-immunoprecipitation assays, and co-localized mostly intracellularly, but occasionaly at the cell surface in confocal micrographs. Functional PrP(C):P2X4R interaction was tested by the uptake of a P2X4R-permeant compound, and by modulation of intracellular calcium. Unexpectedly, however, this interaction was traced to a selective effect of PrP(C) upon the content of co-transfected P2X4R. The results suggest a role of PrP(C) in proteostasis, dysfunctions of which may be involved in the pathogenesis of neurodegenerative diseases such as TSE and Alzheimer's Disease. PMID- 26946359 TI - Snapin mediates insulin secretory granule docking, but not trans-SNARE complex formation. AB - Secretory granule exocytosis is a tightly regulated process requiring granule targeting, tethering, priming, and membrane fusion. At the heart of this process is the SNARE complex, which drives fusion through a coiled-coil zippering effect mediated by the granule v-SNARE protein, VAMP2, and the plasma membrane t-SNAREs, SNAP-25 and syntaxin-1A. Here we demonstrate that in pancreatic beta-cells the SNAP-25 accessory protein, snapin, C-terminal H2 domain binds SNAP-25 through its N-terminal Sn-1 domain. Interestingly whilst snapin binds SNAP-25, there is only modest binding of this complex with syntaxin-1A under resting conditions. Instead synataxin-1A appears to be recruited in response to secretory stimulation. These results indicate that snapin plays a role in tethering insulin granules to the plasma membrane through coiled coil interaction of snapin with SNAP-25, with full granule fusion competency only resulting after subsequent syntaxin-1A recruitment triggered by secretory stimulation. PMID- 26946360 TI - Elucidating the richness of bacterial groups in the gut of Nicobarese tribal community - Perspective on their lifestyle transition. AB - Lifestyle and dietary habits are crucial features that can alter the gut microbiome of humans. Humans, along with their gut microbes, have coevolved in order to sustain themselves in different environments. They were able to adapt themselves to the dietary sources available in their environment. The relation between humans and their gut microbiota and the link with coevolution forms an interesting aspect of research. To understand this association, the participation of ancient communities with less exposure to urbanization is a prerequisite. The current study quantifies the richness of bacterial groups in the gut of Nicobarese. This group of population is an ethnic community of Nicobar group of islands, who have migrated from the remote to rural and urban areas. Alterations in the dominant bacterial groups in relation to their lifestyle transition were emphasized, by comparing the participants from remote, rural and urban settings. The remote cohort remains diverse and stable than the other two cohorts and had higher numbers of Bacteroidetes. Prevotella forms the dominant genus in the Bacteroidetes phylum, indicating the carbohydrate-rich diet of remote Nicobarese. Whereas, the urban cohort is dominated by Bifidobacterium group rather than the Bacteroidetes. Implications of dietary patterns, the transition to different lifestyles and their impact on the microbiota among these cohorts are discussed. PMID- 26946361 TI - Improving the reproducibility of the NAP1/B1/027 epidemic strain R20291 in the hamster model of infection. AB - Comparative analysis of the Clostridium difficile BI/NAP1/027 strain R20291 and ClosTron-derived ermB mutants in the hamster infection model are compromised by the clindamycin susceptibility of the parent. Mutants can appear more virulent. We have rectified this anomaly by genome engineering. The variant created (CRG20291) represents an ideal control strain for virulence assays of ClosTron mutants. PMID- 26946362 TI - Isolation and whole genome sequencing of a Ruminococcus-like bacterium, associated with irritable bowel syndrome. AB - In our previous studies on the intestinal microbiota in irritable bowel syndrome (IBS), we identified a bacterial phylotype with higher abundance in patients suffering from diarrhea than in healthy controls. In the present work, we have isolated in pure culture strain RT94, belonging to this phylotype, determined its whole genome sequence and performed an extensive genomic analysis and phenotypical testing. This revealed strain RT94 to be a strict anaerobe apparently belonging to a novel species with only 94% similarity in the 16S rRNA gene sequence to the closest relatives Ruminococcus torques and Ruminococcus lactaris. The G + C content of strain RT94 is 45.2 mol% and the major long-chain cellular fatty acids are C16:0, C18:0 and C14:0. The isolate is metabolically versatile but not a mucus or cellulose utilizer. It produces acetate, ethanol, succinate, lactate and formate, but very little butyrate, as end products of glucose metabolism. The mechanisms underlying the association of strain RT94 with diarrhea-type IBS are discussed. PMID- 26946364 TI - Late breaking trials of 2015 in coronary artery disease: Commentary covering ACC, EuroPCR, SCAI, TCT, ESC, and AHA. AB - The SCAI Publications Committee and Emerging Leadership Mentorship (ELM) Fellows concisely summarize and provide context on the most important coronary trials presented at large international meetings in 2015, including the MATRIX, ABSORB, and TOTAL trials. The intent is to allow quick assimilation of trial results into interventional practice, and enable busy interventional cardiologists to stay up to date. (c) 2016 Wiley Periodicals, Inc. PMID- 26946363 TI - Report of the ASFA apheresis registry on muscle specific kinase antibody positive myasthenia gravis. AB - BACKGROUND: Anti-muscle specific kinase antibody positive (MuSK Ab) myasthenia gravis (MG) patients are known to have different clinical course compared to anti acetylcholine receptor Ab positive MG patients. Therapeutic plasma exchange (TPE) has been reported to be effective; however, little is known of the response and of TPE procedural information. An ASFA Apheresis Registry was developed to analyze those data. METHODS: The study collected detailed de-identified patient data, TPE procedures, and treatment outcome/complications. Collected data was described in aggregate. RESULTS: A total of 15 MuSK Ab MG patients with exacerbation of MG symptoms, 13 females/2 males, median age 44, were investigated. Thirty TPE courses (median 5 procedures/course, total 145 procedures) were evaluated. All TPE procedures were performed with citrate anticoagulation, 1 - 1.25 plasma volume exchange in 100% fluid balance, and 90% of courses used only albumin as replacement. Calcium was added to albumin or given orally as needed. TPE was performed every other day in 55% of courses. Adverse events occurred in 3.4% of procedures. Ten patients (67%) experienced relapses within a median of 7 weeks. Objective symptoms were resolved in more than 75% of courses. Overall subjective improvement rates were 94.1%/93.3% after 3/4 TPE procedures, respectively. Thirty-one percent of patients responded poorly with minimal recovery. CONCLUSION: Overall subjective improvement was seen up to 94% of patients after one course of TPE. Some patients were poor-responders. Five TPE may be adequate for initial course with additional TPE as needed. Based upon this preliminary data, we will modify our future data collection. J. Clin. Apheresis 32:5-11, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 26946365 TI - Park characteristics, use, and physical activity: A review of studies using SOPARC (System for Observing Play and Recreation in Communities). AB - The System for Observing Play and Recreation in Communities (SOPARC) can obtain information on park users and their physical activity using momentary time sampling. We conducted a literature review of studies using the SOPARC tool to describe the observational methods of each study, and to extract public park use overall and by demographics and physical activity levels. We searched PubMed, Embase, and SPORTDiscus for full-length observational studies published in English in peer-reviewed journals through 2014. Twenty-four studies from 34 articles were included. The number of parks observed per study ranged from 3 to 50. Most studies observed parks during one season. The number of days parks were observed ranged from 1 to 16, with 16 studies observing 5 or more days. All studies included at least one weekday and all but two included at least one weekend day. Parks were observed from 1 to 14times/day, with most studies observing at least 4 times/day. All studies included both morning and afternoon observations, with one exception. There was a wide range of park users (mean 1.0 to 152.6 people/park/observation period), with typically more males than females visiting parks and older adults less than other age groups. Park user physical activity levels varied greatly across studies, with youths generally more active than adults and younger children more active than adolescents. SOPARC was adapted to numerous settings and these review results can be used to improve future studies using the tool, demonstrate ways to compare park data, and inform park promotions and programming. PMID- 26946366 TI - Developmental trajectories of physical activity during elementary school physical education. AB - OBJECTIVE: Physical education (PE) during school provides an opportunity for children to be physically active. Few empirical studies have investigated developmental trajectories and determinants of objective moderate to vigorous physical activity (MVPA) during PE classes. The purpose of this study was to examine the developmental trajectories and determinants of MVPA during PE lessons in young children (8-12years of age) in primary schools. METHODS: Students in grades 5-7 (n=1202; 51.2% girls) were recruited from 17 elementary schools from the Geneva canton in 2012-2013. The percentage of time spent in accelerometer assessed MVPA during regular PE lessons was used as a dependent variable. RESULTS: Linear mixed-model analyses revealed (a) that boys had a higher percentage of MVPA than girls, but none of the children reached the recommended activity levels (i.e., 50% of the PE class time spent in MVPA), (b) a linear decrease in the percentage of MVPA with age, (c) that higher perceived competence predicted a higher percentage of MVPA, and (d) that higher perceived competence reduced the negative linear effect of age among boys, but not among girls. CONCLUSION: The percentage of PE time spent in MVPA did not reach recommendations made by Centers for Disease Control and Prevention and decreased from 8 to 12years old both for boys and girls. Perceived competence appears crucial to reduce MVPA decline for boys, but not for girls. PMID- 26946368 TI - How do we ensure sustainable physical activity options for people with disabilities? PMID- 26946367 TI - Causal pathways linking environmental change with health behaviour change: Natural experimental study of new transport infrastructure and cycling to work. AB - BACKGROUND: Mechanisms linking changes to the environment with changes in physical activity are poorly understood. Insights into mechanisms of interventions can help strengthen causal attribution and improve understanding of divergent response patterns. We examined the causal pathways linking exposure to new transport infrastructure with changes in cycling to work. METHODS: We used baseline (2009) and follow-up (2012) data (N=469) from the Commuting and Health in Cambridge natural experimental study (Cambridge, UK). Exposure to new infrastructure in the form of the Cambridgeshire Guided Busway was defined using residential proximity. Mediators studied were changes in perceptions of the route to work, theory of planned behaviour constructs and self-reported use of the new infrastructure. Outcomes were modelled as an increase, decrease or no change in weekly cycle commuting time. We used regression analyses to identify combinations of mediators forming potential pathways between exposure and outcome. We then tested these pathways in a path model and stratified analyses by baseline level of active commuting. RESULTS: We identified changes in perceptions of the route to work, and use of the cycle path, as potential mediators. Of these potential mediators, only use of the path significantly explained (85%) the effect of the infrastructure in increasing cycling. Path use also explained a decrease in cycling among more active commuters. CONCLUSION: The findings strengthen the causal argument that changing the environment led to changes in health-related behaviour via use of the new infrastructure, but also show how some commuters may have spent less time cycling as a result. PMID- 26946369 TI - Targeted metagenomics of active microbial populations with stable-isotope probing. AB - The ability to explore microbial diversity and function has been enhanced by novel experimental and computational tools. The incorporation of stable isotopes into microbial biomass enables the recovery of labeled nucleic acids from active microorganisms, despite their initial abundance and culturability. Combining stable-isotope probing (SIP) with metagenomics provides access to genomes from microorganisms involved in metabolic processes of interest. Studies using metagenomic analysis on DNA obtained from DNA-SIP incubations can be ideal for the recovery of novel enzymes for biotechnology applications, including biodegradation, biotransformation, and biosynthesis. This chapter introduces metagenomic and DNA-SIP methodologies, highlights biotechnology-focused studies that combine these approaches, and provides perspectives on future uses of these methods as analysis tools for applied and environmental microbiology. PMID- 26946371 TI - Spinal schwannoma hemorrhage manifesting as acute paraplegia. PMID- 26946370 TI - The Listeria monocytogenes Fur-regulated virulence protein FrvA is an Fe(II) efflux P1B4 -type ATPase. AB - Listeria monocytogenes FrvA (Lmo0641) is critical for virulence in the mouse model and is an ortholog of the Bacillus subtilis Fur- and PerR-regulated Fe(II) efflux P1B4 -type ATPase PfeT. Previously, FrvA was suggested to protect against heme toxicity. Here, we demonstrate that an frvA mutant is sensitive to iron intoxication, but not to other metals. Expression of frvA is induced by high iron and this induction requires Fur. FrvA functions in vitro as a divalent cation specific ATPase most strongly activated by ferrous iron. When expressed in B. subtilis, FrvA increases resistance to iron both in wild-type and in a pfeT null strain. FrvA is a high affinity Fe(II) exporter and its induction imposes severe iron limitation in B. subtilis resulting in derepression of both Fur- and PerR regulated genes. FrvA also recognizes Co(II) and Zn(II) as substrates and can complement B. subtilis strains defective in the endogenous export systems for these cations. Building on these results, we conclude that FrvA functions in the efflux of Fe(II), and not heme during listerial infection. PMID- 26946372 TI - Can migraine aura be provoked experimentally? A systematic review of potential methods for the provocation of migraine aura. AB - Background The nature of the migraine aura and its role in migraine pathophysiology is incompletely understood. In particular, the mechanisms underlying aura initiation and the causal relation between aura and headache are unknown. The scientific investigation of aura in patients is only possible if aura can be triggered. This paper reviews potential methods for the experimental provocation of migraine aura. Methods We systematically searched PubMed for studies of experimental migraine provocation, including case reports of patients with aura and reports of the occurrence of aura following exposure to any kind of suspected trigger. Results We identified 21 provocation studies, using 13 different prospective provocation methods, and 34 case reports. In the prospective studies, aura were reported following the administration of intravenous and sublingual glyceryl trinitrate, visual stimulation, physical activity, calcitonin gene-related peptide infusion, chocolate ingestion, and the intravenous injection of insulin. In addition, carotid artery puncture has consistently been reported as a trigger of aura. Conclusions No safe and efficient method for aura provocation exists at present, but several approaches could prove useful for this purpose. PMID- 26946373 TI - High-throughput transcriptome sequencing analysis provides preliminary insights into the biotransformation mechanism of Rhodopseudomonas palustris treated with alpha-rhamnetin-3-rhamnoside. AB - BACKGROUND: The purple photosynthetic bacterium Rhodopseudomonas palustris has been widely applied to enhance the therapeutic effects of traditional Chinese medicine using novel biotransformation technology. However, comprehensive studies of the R. palustris biotransformation mechanism are rare. Therefore, investigation of the expression patterns of genes involved in metabolic pathways that are active during the biotransformation process is essential to elucidate this complicated mechanism. RESULTS: To promote further study of the biotransformation of R. palustris, we assembled all R. palustris transcripts using Trinity software and performed differential expression analysis of the resulting unigenes. A total of 9725, 7341 and 10,963 unigenes were obtained by assembling the alpha-rhamnetin-3-rhamnoside-treated R. palustris (RPB) reads, control R. palustris (RPS) reads and combined RPB&RPS reads, respectively. A total of 9971 unigenes assembled from the RPB&RPS reads were mapped to the nr, nt, Swiss-Prot, Gene Ontology (GO), Clusters of Orthologous Groups (COGs) and Kyoto Encyclopedia of Genes and Genomes (KEGG) (E-value <0.00001) databases using BLAST software. A total of 3360 unique differentially expressed genes (DEGs) in RPB versus RPS were identified, among which 922 unigenes were up-regulated and 2438 were down-regulated. The unigenes were mapped to the KEGG database, resulting in the identification of 7676 pathways among all annotated unigenes and 2586 pathways among the DEGs. Some sets of functional unigenes annotated to important metabolic pathways and environmental information processing were differentially expressed between the RPS and RPB samples, including those involved in energy metabolism (18.4% of total DEGs), carbohydrate metabolism (36.0% of total DEGs), ABC transport (6.0% of total DEGs), the two-component system (8.6% of total DEGs), cell motility (4.3% of total DEGs) and the cell cycle (1.5% of total DEGs). We also identified 19 transcripts annotated as hydrolytic enzymes and other enzymes involved in ARR catabolism in R. palustris. CONCLUSION: We present the first comparative transcriptome profiles of RPB and RPS samples to facilitate elucidation of the molecular mechanism of biotransformation in R. palustris. Furthermore, we propose two putative ARR biotransformation mechanisms in R. palustris. These analytical results represent a useful genomic resource for in-depth research into the molecular basis of biotransformation and genetic modification in R. palustris. PMID- 26946374 TI - Biocontrol activity of Paenibacillus polymyxa AC-1 against Pseudomonas syringae and its interaction with Arabidopsis thaliana. AB - Paenibacillus polymyxa AC-1 (AC-1) is a plant growth-promoting rhizobacterium (PGPR) that has been used as a soil inoculant for biocontrol of plant pathogenic fungi and to promote plant growth. In this study, we examine the effects of AC-1 on the bacterial phytopathogen Pseudomonas syringae and internal colonization of AC-1 by counting bacterial populations that colonize plants. AC-1 inhibited the growth of both P. syringae pv. tomato DC3000 (Pst) and P. syringae pv. tabaci (Pta) in a concentration-dependent manner in in vitro assays. Upon treatment of AC-1 dropping at root tip of axenically grown Arabidopsis, we found that most of the AC-1 was detected in interior of leaves of Arabidiopsis plants rather than roots after 5 days post infection, indicating systemic spreading of AC-1 occur. We examined further AC-1 colonization patterns in Arabidopsis mutants deficient in phytohormone signaling pathways. These results indicated that abscisic acid (ABA) and jasmonic acid (JA) signaling pathways positively and negatively contributed, respectively, to AC-1 colonization of leaves, whereas epiphytic accumulation of AC-1 around root tissues was not affected. This study shows that AC-1 is an effective biocontrol agent to suppress P. syringae growth, possibly owing to its colonization patterns as a leaf-inhabiting endophyte. The results showed in this work will help to expand our understanding of the mode of action of AC-1 as a biological control agent and consequently, its application in agriculture. PMID- 26946375 TI - Rare actinomycetes Nocardia caishijiensis and Pseudonocardia carboxydivorans as endophytes, their bioactivity and metabolites evaluation. AB - Two strains identified as Nocardia caishijiensis (SORS 64b) and Pseudonocardia carboxydivorans (AGLS 2) were isolated as endophytes from Sonchus oleraceus and Ageratum conyzoides respectively. The analysis of their extracts revealed them to be strongly bioactive. The N. caishijiensis extract gave an LC50 of 570 MUg/ml( 1) in the brine shrimp cytotoxicity assay and an EC50 of 0.552 MUg/ml(-1) in the DPPH antioxidant assay. Antimicrobial activity was observed against Methicillin resistant Staphlococcus aureus (MRSA) and Escherichia coli ATCC 25922 (14 mm), Klebsiella pneumoniae ATCC 706003 (13 mm), S. aureus ATCC 25923 (11 mm) and Candida tropicalis (20 mm). For the extract of P. carboxydivorans the EC50 was 0.670 MUg/ml(-1) and it was observed to be more bioactive against Bacillus subtilis DSM 10 ATCC 6051 (21 mm), C. tropicalis (20 mm), S. aureus ATCC 25923 (17 mm), MRSA (17 mm), E. coli K12 (W1130) (16 mm) and Chlorella vulgaris (10 mm). The genotoxicity testing revealed a 20 mm zone of inhibition against the polA mutant strain E. coli K-12 AB 3027 suggesting damage to the DNA and polA genes. The TLC and bioautography screening revealed a diversity of active bands of medium polar and nonpolar compounds. Metabolite analysis by HPLC-DAD via UV/vis spectral screening suggested the possibility of stenothricin and bagremycin A in the mycelium extract of N. caishijiensis respectively. In the broth and mycelium extract of P. carboxydivorans borrelidin was suggested along with alpha-pyrone. The HPLC-MS revealed bioactive long chained amide derivatives such as 7-Octadecenamide, 9, 12 octadecandienamide. This study reports the rare actinomycetes N. caishijiensis and P. carboxydivorans as endophytes and evaluates their bioactive metabolites. PMID- 26946376 TI - Biosynthesis of 3"-demethyl-gentamicin C components by genN disruption strain of Micromonospora echinospora and test their antimicrobial activities in vitro. AB - Gentamicin consists primarily of four components, which have different patterns of methylation at C-6' position. The methyl groups have a significant impact on gentamicin antimicrobial activity. Sequence analysis predicted that GenN was a methyltransferase in the gentamicin biosynthetic pathway. To study the function of genN, it was disrupted in Micromonospora echinospora. The genN disruption strains produced 3"-N-demethyl-gentamicin C complex instead of the gentamicin C complex. In this study, 3"-N-demethyl gentamicin C1a was purified from the broth of disruption strain, and its structure was elucidated using MS and NMR. Besides 3"-N-demethyl products corresponding to gentamicin C1a, C2, and C2a, two 3"-N demethyl products corresponding to gentamicin C1 were detected, which were concluded as C-6' epimers originating from decreased substrate specificity of 6' N methyltransferase. To explore the effects of 3"-N-methyl on gentamicin antimicrobial activity, antimicrobial activity of these demethyl gentamicin analogues were tested in vitro. 3"-N-Demethyl gentamicin components have identical activity with corresponding components of gentamicin. The results of bioassays showed that the 3"-N-methyl group has little impact on gentamicin activity. However, these highly bioactive compounds afforded a unique opportunity for creating new and high potent aminoglycoside antibiotics. PMID- 26946377 TI - Effect of the glycosyltransferases on the capsular polysaccharide synthesis of Streptococcus suis serotype 2. AB - Streptococcus suis serotype 2 (S. suis 2) is a serious zoonotic pathogen causing septicemia and meningitis in piglets and humans. The capsular polysaccharide (CPS) is an essential virulence factor for S. suis 2 to infect the host. The synthesis of CPS repeating units involves multiple glycosyltransferases. In this study, four genes (cps2E, cps2G, cps2J and cps2L) encoding different glycosyltransferases involved in CPS synthesis were researched in S. suis 2. Four deletion mutants (Deltacps2E, Deltacps2G, Deltacps2J and Deltacps2L) with their CPS incomplete and their sialic acid content significantly decreased were constructed in S. suis 2 SC19. All these four mutant strains showed enhanced adhesion to Hep-2 cells and increased sensitivity to phagocytosis. Flow cytometric analysis also revealed that these four mutants were more susceptible to the attack by the complement system. In a mouse model of infection, the mutant strains were rapidly cleared by the immune system, compared with the wild-type strain. In summary, this study characterized four genes (cps2E, cps2G, cps2J and cps2L) involved in CPS synthesis of S. suis 2 SC19 and it revealed that these genes were all crucial for SC19 to invade and survive in the host. PMID- 26946378 TI - Antibacterial and cytotoxic triterpenoids from the roots of Combretum racemosum. AB - A new pentacyclic triterpenoid glucoside, together with fourteen known compounds, was isolated from the roots of Combretum racemosum. Combretaceae). The structure of the new compound was established as 28-O-beta-d-glucopyranosyl 2alpha,3beta,21beta,23-tetrahydroxyolean-18-en-28-oate (1) on the basis of detailed spectroscopic data including MS, 1D, and 2D NMR. The inhibitory activity of compounds 1-15 against promyelocytic leukemia HL-60 and human erythromyeloblastoid leukemia K562 cell lines was evaluated. Compounds 11 (3-O beta-acetyl-ursolic acid), 14 (betulinic acid), and 15 (quadranoside II) exhibited significant cytotoxicity, with IC50 values of 13 to 50 MUM. Among the isolated triterpenes, compounds 1, 3 (arjungenin), 5 (terminolic acid), and 11 exhibited moderate antibacterial activity against Staphylococcus aureus, Escherichia coli and Enterococcus faecalis (MICs within a range of 64 and 256 MUg/mL). PMID- 26946379 TI - Phytochemical profiling of five medicinally active constituents across 14 Eutrema species. AB - Wasabi or Japanese horseradish (Eutrema japonicum) is both a traditional condiment and a medicinally important plant with diverse uses. Its medicinally active constituents appear to include five isothiocyanates, but their spatial variations in naturally occurring congeners are unknown. Thus, in this study we measured concentrations of these five active constituents in 20 populations of 14 species of Eutrema and one related species, Yinshania sinuata. Three to five of these constituents were detected in each of the examined species, at concentrations that varied greatly between sampled species and populations of the same species. However, two species, Eutrema tenue and Eutrema deltoideum, had higher total concentrations of the five isothiocyanates and substantially higher concentrations of one or two, than the widely cultivated E. japonicum. Thus, both of these species could be important wild resources for artificial cultivation, in addition to the currently widely cultivated E. japonicum. PMID- 26946380 TI - When Absence of Evidence Is Evidence of Absence: Rational Inferences From Absent Data. AB - Identifying patterns in the world requires noticing not only unusual occurrences, but also unusual absences. We examined how people learn from absences, manipulating the extent to which an absence is expected. People can make two types of inferences from the absence of an event: either the event is possible but has not yet occurred, or the event never occurs. A rational analysis using Bayesian inference predicts that inferences from absent data should depend on how much the absence is expected to occur, with less probable absences being more salient. We tested this prediction in two experiments in which we elicited people's judgments about patterns in the data as a function of absence salience. We found that people were able to decide that absences either were mere coincidences or were indicative of a significant pattern in the data in a manner that was consistent with predictions of a simple Bayesian model. PMID- 26946381 TI - Cocaine Self-Administration and Extinction Leads to Reduced Glial Fibrillary Acidic Protein Expression and Morphometric Features of Astrocytes in the Nucleus Accumbens Core. AB - BACKGROUND: As a more detailed picture of nervous system function emerges, diversity of astrocyte function becomes more widely appreciated. While it has been shown that cocaine experience impairs astroglial glutamate uptake and release in the nucleus accumbens (NAc), few studies have explored effects of self administration on the structure and physiology of astrocytes. We investigated the effects of extinction from daily cocaine self-administration on astrocyte characteristics including glial fibrillary acidic protein (GFAP) expression, surface area, volume, and colocalization with a synaptic marker. METHODS: Cocaine or saline self-administration and extinction were paired with GFAP Westerns, immunohistochemistry, and fluorescent imaging of NAc core astrocytes (30 saline administering and 36 cocaine-administering male Sprague Dawley rats were employed). Imaging was performed using a membrane-tagged lymphocyte protein tyrosine kinase-green fluorescent protein (Lck-GFP) driven by the GFAP promoter, coupled with synapsin I immunohistochemistry. RESULTS: GFAP expression was significantly reduced in the NAc core following cocaine self-administration and extinction. Similarly, we observed an overall smaller surface area and volume of astrocytes, as well as reduced colocalization with synapsin I, in cocaine administering animals. Cocaine-mediated reductions in synaptic contact were reversed by the beta-lactam antibiotic ceftriaxone. CONCLUSIONS: Multiple lines of investigation indicate that NAc core astrocytes exist in a hyporeactive state following cocaine self-administration and extinction. Decreased association with synaptic elements may be particularly meaningful, as cessation of chronic cocaine use is associated with changes in synaptic strength and resistance to the induction of synaptic plasticity. We hypothesize that the reduced synaptic colocalization of astrocytes represents an important maladaptive cellular response to cocaine and the mechanisms underlying relapse vulnerability. PMID- 26946383 TI - Perinatal psychiatric care needs of women who die by suicide. PMID- 26946384 TI - Mental health of migrants in low-skilled work and the families they leave behind. PMID- 26946385 TI - Freedom and equality in dignity and rights for persons with mental illness. PMID- 26946386 TI - Post-traumatic stress disorder and interleukin 6. PMID- 26946382 TI - Novel Dopamine Therapeutics for Cognitive Deficits in Schizophrenia. AB - Schizophrenia is characterized by profound cognitive deficits that are not alleviated by currently available medications. Many of these cognitive deficits involve dysfunction of the newly evolved, dorsolateral prefrontal cortex (dlPFC). The brains of patients with schizophrenia show evidence of dlPFC pyramidal cell dendritic atrophy, likely reductions in cortical dopamine, and possible changes in dopamine D1 receptors (D1R). It has been appreciated for decades that optimal levels of dopamine are essential for dlPFC working memory function, with many beneficial actions arising from D1R stimulation. D1R are concentrated on dendritic spines in the primate dlPFC, where their stimulation produces an inverted-U dose response on dlPFC neuronal firing and cognitive performance during working memory tasks. Research in both academia and the pharmaceutical industry has led to the development of selective D1 agonists, e.g., the first full D1 agonist, dihydrexidine, which at low doses improved working memory in monkeys. Dihydrexidine has begun to be tested in patients with schizophrenia or schizotypal disorder. Initial results are encouraging, but studies are limited by the pharmacokinetics of the drug. These data, however, have spurred efforts toward the discovery and development of improved or novel new compounds, including D1 agonists with better pharmacokinetics, functionally selective D1 ligands, and D1R positive allosteric modulators. One or several of these approaches should allow optimization of the beneficial effects of D1R stimulation in the dlPFC that can be translated into clinical practice. PMID- 26946387 TI - Palliative psychiatry for severe and persistent mental illness. PMID- 26946388 TI - Mental health reform in Lebanon and the Syrian crisis. PMID- 26946389 TI - Post-traumatic stress disorder and interleukin 6 - Authors' reply. PMID- 26946390 TI - Infection in people with severe mental illness. PMID- 26946391 TI - Infection in people with severe mental illness - Authors' reply. PMID- 26946392 TI - Infection in people with severe mental illness. PMID- 26946393 TI - Gisele Apter: thinking in twos and threes. PMID- 26946394 TI - Gender incongruence of childhood in the ICD-11: controversies, proposal, and rationale. AB - As part of the development of the eleventh revision of the International Classification of Diseases (ICD-11), WHO appointed a Working Group on Sexual Disorders and Sexual Health to recommend changes necessary in the classification of mental and behavioural disorders in ICD-10 that are related to sexuality and gender identity. This Personal View focuses on the Working Group's proposals to include the diagnosis gender incongruence of childhood in ICD-11 and to move gender incongruence of childhood out of the mental and behavioural disorders chapter of ICD-11. We outline the history of ICD and DSM child gender diagnoses, expert consensus, knowledge gaps, and controversies related to the diagnosis and treatment of extremely gender-variant children. We argue that retaining the gender incongruence of childhood category is justified as a basis to structure clinical care and to ensure access to appropriate services for this vulnerable population, which provides opportunities for education and informed consent, the development of standards and pathways of care to help guide clinicians and family members, and a basis for future research efforts. PMID- 26946395 TI - Health Behaviors, Mental Health, and Health Care Utilization Among Single Mothers After Welfare Reforms in the 1990s. AB - We studied the health of low-income US women affected by the largest social policy change in recent US history: the 1996 welfare reforms. Using the Behavioral Risk Factor Surveillance System (1993-2012), we performed 2 types of analysis. First, we used difference-in-difference-in-differences analyses to estimate associations between welfare reforms and health outcomes among the most affected women (single mothers aged 18-64 years in 1997; n = 219,469) compared with less affected women (married mothers, single nonmothers, and married nonmothers of the same age range in 1997; n = 2,422,265). We also used a synthetic control approach in which we constructed a more ideal control group for single mothers by weighting outcomes among the less affected groups to match pre reform outcomes among single mothers. In both specifications, the group most affected by welfare reforms (single mothers) experienced worse health outcomes than comparison groups less affected by the reforms. For example, the reforms were associated with at least a 4.0-percentage-point increase in binge drinking (95% confidence interval: 0.9, 7.0) and a 2.4-percentage-point decrease in the probability of being able to afford medical care (95% confidence interval: 0.1, 4.8) after controlling for age, educational level, and health care insurance status. Although the reforms were applauded for reducing welfare dependency, they may have adversely affected health. PMID- 26946396 TI - Invited Commentary: An Interdisciplinary Approach for Policy Evaluation. AB - Evidence-based policymaking is becoming the norm, but how do we acquire the evidence to inform policies? In their article in the present issue of the Journal, Basu et al. (Am J Epidemiol. 2016;183(6):531-538) used difference-in difference-in-differences models and a synthetic control approach to examine the effects of the 1996 welfare reforms on health outcomes among single mothers. In the present commentary, we discuss the limitations of observational studies for policy evaluation. Difference-in-differences models, from the field of economics, offer a rigorous approach to cope with those limitations. PMID- 26946397 TI - Basu et al. Respond to "Interdisciplinary Approach for Policy Evaluation". PMID- 26946399 TI - Polycistronic trypanosome mRNAs are a target for the exosome. AB - Eukaryotic cells have several mRNA quality control checkpoints to avoid the production of aberrant proteins. Intron-containing mRNAs are actively degraded by the nuclear exosome, prevented from nuclear exit and, if these systems fail, degraded by the cytoplasmic NMD machinery. Trypanosomes have only two introns. However, they process mRNAs from long polycistronic precursors by trans-splicing and polycistronic mRNA molecules frequently arise from any missed splice site. Here, we show that RNAi depletion of the trypanosome exosome, but not of the cytoplasmic 5'-3' exoribonuclease XRNA or the NMD helicase UPF1, causes accumulation of oligocistronic mRNAs. We have also revisited the localization of the trypanosome exosome by expressing eYFP-fusion proteins of the exosome subunits RRP44 and RRP6. Both proteins are significantly enriched in the nucleus. Together with published data, our data suggest a major nuclear function of the trypanosome exosome in rRNA, snoRNA and mRNA quality control. PMID- 26946400 TI - Characterization of a Fasciola gigantica protein carrying two DM9 domains reveals cellular relocalization property. AB - Even at the present age of whole-organism analysis, e.g., genomics, transcriptomics, and proteomics, the biological roles of many proteins remain unresolved. Classified among the proteins of unknown function is a family of proteins harboring repeats of the DM9 domain, a 60-75 amino acids motif first described in a small number of Drosophila melanogaster proteins. Proteins may carry two or more DM9 domains either in combination with other domains or as their sole constituent. Here we have characterized a 16.8 kDa Fasciola gigantica protein comprising two tandem repeated DM9 domains (FgDM9-1). The protein was located in the parenchyma of the immature and mature parasite and consequently it was not detected in the ES product of the parasite but only in the whole worm extract. Interestingly, extraction with SDS yielded a substantially higher amount of the protein suggesting association with insoluble cell components. In Sf9 insect cells a heterologously expressed EGFP-FgDM9-1 chimera showed cell-wide distribution but relocated to vesicle-like structures in the cytoplasm after stimulating cellular stress by bacteria, heat shock or chloroquine. These structures did not colocalize with the markers of endocytosis/phagocytosis ubiquitin, RAB7, GABARAP. The same behavior was noted for Aedes aegypti PRS1, a homologous mosquito DM9 protein as a positive control while EGFP did not exhibit such relocation in the insect cells. Cross-linking experiments on soluble recombinant FgDM9-1 indicated that the protein can undergo specific oligomerization. It is speculated that proteins carrying the DM9 domain have a role in vesicular transport in flatworms and insects. PMID- 26946401 TI - The targeted delivery of the c-Src peptide complexed with schizophyllan to macrophages inhibits polymicrobial sepsis and ulcerative colitis in mice. AB - Hyper-inflammatory responses triggered by intracellular reactive oxygen species (ROS) can lead to a variety of diseases, including sepsis and colitis. However, the regulators of this process remain poorly defined. In this study, we demonstrate that c-Src is a negative regulator of cellular ROS generation through its binding to p47phox. This molecule also competitively inhibits the NADPH oxidase complex (NOX) assembly. Furthermore, we developed the schizophyllan (SPG) c-Src SH3 peptide, which is a beta-1,3-glucan conjugated c-Src SH3-derived peptide composed of amino acids 91-108 and 121-140 of c-Src. The SPG-SH3 peptide has a significant therapeutic effect on mouse ROS-mediated inflammatory disease models, cecal-ligation-puncture-induced sepsis, and dextran sodium sulfate induced colitis. It does so by inhibiting the NOX subunit assembly and proinflammatory mediator production. Therefore, the SPG-SH3 peptide is a potential therapeutic agent for ROS-associated lethal inflammatory diseases. Our findings provide clues for the development of new peptide-base drugs that will target p47phox. PMID- 26946403 TI - Derivation of Schwann cell precursors from neural crest cells resident in bone marrow for cell therapy to improve peripheral nerve regeneration. AB - We have previously successfully enriched post-migratory neural crest cells (NCCs) from postnatal rat bone marrow (BM). These BM-NCCs possess glial and neuronal differentiating potential. Based on the neural crest origin of Schwann cells (SCs), in this study, we aimed at using a straightforward protocol to derive Schwann cell precursors (SCPs) from BM-NCCs. Several clonal subpopulations were isolated from BM-NCCs, displaying long-term proliferative capacity and maintaining the NCC identity. The BM-NCC clones could be induced to differentiate into SCs. In particular, clone N1 gave rise to a large and pure population of SCs. Clone N1-derived SCs demonstrated the myelinating capacity in their co culture with primary dorsal root ganglion (DRG) neurons. The decreased expression of NCC-markers and increased expression of SC-markers were related to the differentiation state of clone N1-derived SCs. To investigate the repair promoting effects of clone N1 on injured peripheral neurons in vitro and in vivo, on one hand, the oxygen glucose deprivation-injured DRG neurons were treated with clone N1-conditioned medium, improving the cell survival and axon growth of neurons; on the other hand, clone N1 or clone N1-derived SCs were respectively implanted to the crush sciatic nerve of rats, and clone N1 yielded the better outcome of nerve regeneration and function restoration than clone N1-derived SCs. Taken together, all the results collectively showed that clone N1 could be identified as SCPs, which might hold promise for cell therapy to improve peripheral nerve regeneration. PMID- 26946402 TI - Matrix stiffness modulates formation and activity of neuronal networks of controlled architectures. AB - The ability to construct easily in vitro networks of primary neurons organized with imposed topologies is required for neural tissue engineering as well as for the development of neuronal interfaces with desirable characteristics. However, accumulating evidence suggests that the mechanical properties of the culture matrix can modulate important neuronal functions such as growth, extension, branching and activity. Here we designed robust and reproducible laminin polylysine grid micropatterns on cell culture substrates that have similar biochemical properties but a 100-fold difference in Young's modulus to investigate the role of the matrix rigidity on the formation and activity of cortical neuronal networks. We found that cell bodies of primary cortical neurons gradually accumulate in circular islands, whereas axonal extensions spread on linear tracks to connect circular islands. Our findings indicate that migration of cortical neurons is enhanced on soft substrates, leading to a faster formation of neuronal networks. Furthermore, the pre-synaptic density was two times higher on stiff substrates and consistently the number of action potentials and miniature synaptic currents was enhanced on stiff substrates. Taken together, our results provide compelling evidence to indicate that matrix stiffness is a key parameter to modulate the growth dynamics, synaptic density and electrophysiological activity of cortical neuronal networks, thus providing useful information on scaffold design for neural tissue engineering. PMID- 26946404 TI - Terms of endearment: Bacteria meet graphene nanosurfaces. AB - Microbial multidrug resistance poses serious risks in returning the human species into the pre-antibiotic era if it remains unsolved. While conventional research approaches to combat infectious diseases have been inadequate, nanomaterials are a promising alternative for the development of sound antimicrobial countermeasures. Graphene, a two-dimensional ultra-thin nanomaterial, possesses excellent electronic and biocompatibility properties, which position it in the biotechnology forefront for diverse applications in biosensing, therapeutics, diagnostics, drug delivery and device development. Yet, several questions remain unanswered. For instance, the way these nanosurfaces interact with the microbial entities is poorly understood. The mechanistic elucidation of this interface seems critical to determine the feasibility of applications under development. Are graphene derivatives appropriate materials to design potent antimicrobial agents, vehicles or effective diagnostic microsensors? Has the partition of major microbial resistance phenotypic determinants been sufficiently investigated? Can toxicity become a limiting factor? Are we getting closer to clinical implementation? To facilitate research conducive to answer such questions, this review describes the features of the graphene-bacterial interaction. An overview on paradigms of graphene-microbial interactions is expected to shed light on the range of materials available, and identify possible applications, serving the ultimate goal to develop deeper understanding and collective conscience for the true capabilities of this nanomaterial platform. PMID- 26946405 TI - Contribution of inflammasome genetics in Plasmodium vivax malaria. AB - Recent reports showed that, in mice, symptomatic Plasmodium infection triggers NLRP3/NLRP12-dependent inflammasome formation and caspase-1 activation in monocytes. In humans, few works demonstrated that inflammasome is activated in malaria. As Plasmodiumvivax is a potent inducer of inflammatory response we hypothesised that inflammasome genetics might affect P. vivax malaria clinical presentation. For this purpose, selected SNPs in inflammasome genes were analysed among patients with symptomatic P. vivax malaria. 157 Brazilian Amazon patients with P. vivax malaria were genotyped for 10 single nucleotide polymorphisms (SNPs) in inflammasome genes NLRP1, NLRP3, AIM2, CARD8, IL1B, IL18 and MEFV. Effect of SNPs on hematologic and clinical parameters was analysed by multivariate analysis. Our data suggested an important role of NLRP1 inflammasome receptor in shaping the clinical presentation of P. vivax malaria, in term of presence of fever, anaemia and thrombocytopenia. Moreover IL1B rs1143634 resulted significantly associated to patients' parasitaemia, while IL18 rs5744256 plays a protective role against the development of anaemia. Polymorphisms in inflammasome genes could affect one or other aspects of malaria pathogenesis. Moreover, these data reveal novel aspects of P.vivax/host interaction that involved NLRP1 inflammasome. PMID- 26946406 TI - Assessment in vitro of the genotoxicity, antigenotoxicity and antioxidant of Ceratonia siliqua L. extracts in murine leukaemia cells L1210 by comet assay. AB - Genotoxicity of Ceratonia siliqua extracts, was investigated by assessing their capacity to induce nucleus DNA degradation of murine leukaemia cells L1210, using the "Comet assay". The ability of total oligomer flavonoids (TOF) and aqueous extracts to protect cell DNA against oxidative stress induced by H2O2, was performed by pre- co or post-treatment of cells with the before mentioned extracts for different periods preceding exposure to H2O2 stress. No significant genotoxic effect was detected at different exposure times, except at the lowest concentration of TOF extract (16.25 MUg/ml). It appears that extracts decreased DNA damage, induced by H2O2. Both of TOF and aqueous extracts exhibited cellular antioxidant capacity, with EC50 values of respectively <16.25 and < 35 MUg/ml, as well as, a protective capacity against lipidperoxidation inducing using L1210 cells line as a cellular model. MDA inhibition percentages reached 88.43% and 90.52% with respectively 35.5 MUg/ml of TOF extract and 70 MUg/ml of aqueous extract. Antioxidant properties of carob leaf extracts revealed by our study make a good antioxidant protection and thus a good candidate as food addition component. PMID- 26946407 TI - Opinion of the Scientific Committee on Consumer safety (SCCS) - Second revision of the opinion on carbon black, nano-form, in cosmetic products. PMID- 26946408 TI - Opinion of the Scientific Committee on Consumer Safety (SCCS) - Revision of the opinion on o-Phenylphenol, Sodium o-phenylphenate and Potassium o-phenylphenate (OPP), in cosmetic products. AB - o-Phenylphenol, Sodium o-phenylphenate, Potassium o-phenylphenate, CAS n. 90-43 7, 132-27-4, 13707-65-8 as preservatives are regulated in Annex V/7 of the Cosmetics Regulation (EC) n. 1223/2009 at a maximum concentration of 0.2% (as phenol). In February 2013, the Commission received a risk assessment submitted by the French Agency ANSM (Agence nationale de securite des medicaments et des produits de sante) which rose concerns about the use of o-Phenylphenol as preservatives in cosmetic products. In the context of the ANSM report (Evaluation du risque lie a l'utilisation de l'orthophenylphenol CAS n. 90-43-7 dans les produits cosmetiques) o-Phenylphenol has been identified as likely to be an endocrine disruptor. The report concludes that the maximum authorised concentration (currently of 0.2%) of o-Phenylphenol for use as a preservative should be revised due to low margin of safety. In January 2014, in response to a call for data on o-Phenylphenol by the Commission, Industry submitted a safety dossier in order to defend the current use of o-Phenylphenol, Sodium o phenylphenate, Potassium o-phenylphenate, CAS n. 90-43-7, 132-27-4, 13707- 65-8 as preservatives in cosmetic formulations at a maximum concentration of 0.2% (as phenol). o-Phenylphenol as preservative with a maximum concentration of 0.2% in leave-on cosmetic products is not safe. Also, in view of further exposures including noncosmetic uses (see Anses, 2014), the maximum concentration of o Phenylphenol in leave-on cosmetic products should be lowered. However, the proposed maximum use concentration of up to 0.15% by the applicant can be considered safe. The use of o-Phenylphenol as preservative with a maximum concentration of 0.2% in rinse-off cosmetic products is considered safe. Based on the information provided, no conclusions of safe use can be drawn for Sodium o phenylphenate and Potassium o-phenylphenate. In vitro data indicate an absent or very weak binding affinity of OPP to the oestrogen receptor, in line with limited stimulation of proliferation in oestrogen responsive cells. No information is available on androgenic and anti-androgenic effects of OPP in vitro. Agonistic or antagonistic effects on thyroid hormones were not observed with OPP. There might be a potential of injury to the vision system attributable to OPP. Aggregate exposure to OPP should be considered. PMID- 26946409 TI - Neonatal exposure to benzo[a]pyrene induces oxidative stress causing altered hippocampal cytomorphometry and behavior during early adolescence period of male Wistar rats. AB - Environmental neurotoxicants like benzo[a]pyrene (B[a]P) have been well documented regarding their potential to induce oxidative stress. However, neonatal exposure to B[a]P and its subsequent effect on anti-oxidant defence system and hippocampal cytomorphometry leading to behavioral changes have not been fully elucidated. We investigated the effect of acute exposure of B[a]P on five days old male Wistar pups administered with single dose of B[a]P (0.2 MUg/kg BW) through intracisternal mode. Control group was administered with vehicle i.e., DMSO and a separate group of rats without any treatment was taken as naive group. Behavioral analysis showed anxiolytic-like behavior with significant increase in time spent in open arm in elevated plus maze. Further, significant reduction in fall off time during rotarod test showing B[a]P induced locomotor hyperactivity and impaired motor co-ordination in adolescent rats. B[a]P induced behavioral changes were further associated with altered anti-oxidant defence system involving significant reduction in the total ATPase, Na(+) K(+) ATPase, Mg(2+) ATPase, GR and GPx activity with a significant elevation in the activity of catalase and GST as compared to naive and control groups. Cytomorphometry of hippocampus showed that the number of neurons and glia in B[a]P treated group were significantly reduced as compared to naive and control. Subsequent observation showed that the area and perimeter of hippocampus, hippocampal neurons and neuronal nucleus were significantly reduced in B[a]P treated group as compared to naive and control. The findings of the present study suggest that the alteration in hippocampal cytomorphometry and neuronal population associated with impaired antioxidant signaling and mood in B[a]P treated group could be an outcome of neuromorphological alteration leading to pyknotic cell death or impaired differential migration of neurons during early postnatal brain development. PMID- 26946410 TI - Lidocaine Test Increases the Success Rates of Corticosteroid Injection in Impingement Syndrome. AB - OBJECTIVE: To determine whether lidocaine test injections would increase the success rate of corticosteroid injection for treatment of impingement syndrome. METHODS: Two hundred thirty-nine patients diagnosed with impingement syndrome were allocated to the lidocaine test (LC) group (N = 139) and the subacromial (SA) group (N = 100). The LC group received 1 ml of 1% lidocaine injection into the subacromial bursa under ultrasound guidance and a second injection of the steroid solution into the subacromial bursa or glenohumeral joint according to the response. The SA group received the same amount of steroid injection into the subacromial bursa without a prior lidocaine injection. Categorical outcomes were utilized and subjects were grouped based on percentage pain relief. Clinical improvement was expressed in terms of the patient's global impression of change (PGIC) as 'not improved,' 'slightly improved,' and 'much improved. RESULTS: In the LC group, 76 of the 139 patients (54% [95 CI 46-63%]) showed '50-80% improvement' and 15 (11% [95% CI 6.6-17%]) patients showed 'more than 80% improvement' at 3 weeks after the injection. While in the SA group, 29 of the 100 patient (29% [95% CI 21-39%]) showed '50-80% improvement' and 13 (13% [95% CI 7.7 21%]) showed 'more than 80% 3 weeks after the injection (chi2 = 15.073, P = 0.001). This difference persisted at 3 months (chi2 = 8.015, P = 0.018). The chi square test of PGIC at 3 weeks also showed significant differences (P < 0.001). CONCLUSIONS: This was the first study to show that a lidocaine pre-injection increases the success rate of steroid injection in patients suspected of having impingement syndrome. PMID- 26946411 TI - Pre-Existing Chronic Pain Influences the Severity of Acute Herpes Zoster Pain-A Prospective Observational Cohort Study. AB - OBJECTIVE: . Pre-existing chronic pain has been associated with severe postoperative pain. To analyze the impact of chronic pain on non-surgical acute pain, a cohort of patients with acute herpes zoster was studied. METHODS: . Consecutive patients, who needed hospitalization because of an acute zoster infection, were characterized and compared according to their pain history. Pain intensity, pain-related function, analgesic consumption, and psychological and physiological characteristics were assessed as baseline parameters on the day of hospitalization. Pain intensity and functional restrictions were evaluated on day 1, 4, 7, and on the day of discharge. The analgesic consumption was recorded and scored for each of these days. A multivariate analysis was performed for individual predictors. RESULTS: . 59 patients were included; 25 patients (42.4%) had pre-existing chronic pain. These patients had more severe acute zoster pain on all assessment days and were more restricted in function, such as sleep quality and mobilization. There were, however, no differences in analgesic consumption. In patients without chronic pain, only the amount of analgesic consumption was associated with the severity of zoster pain. In contrast, in patients with chronic pain, the severity of the chronic pain, physical health, and the extent of neuropathic pain characteristics were associated with the intensity of zoster-related acute pain, while analgesic consumption was not. CONCLUSIONS: . Patients with chronic pain had higher intensity of zoster-related acute pain. Furthermore, they showed more pain-related dysfunction and needed longer hospitalization than patients without chronic pain. These results go along with findings for acute postoperative pain. PMID- 26946412 TI - Immunolocalisation of aromatase regulators liver kinase B1, phosphorylated AMP activated protein kinase and cAMP response element-binding protein-regulated transcription co-activators in the human testis. AB - Although oestrogens are essential for spermatogenesis and their biosynthesis is dependent on aromatase expression, the molecular mechanism of aromatase regulation is poorly understood. Our laboratory has demonstrated that liver kinase B1 (LKB1) is a negative regulator of aromatase in the breast by phosphorylating AMP-activated protein kinase (AMPK) and inhibiting the nuclear translocation of the cAMP response element-binding protein-regulated transcription co-activator (CRTC) 2. The aim of this study was to determine the location of testis-associated proteins in the LKB1-CRTC pathway. Aromatase, LKB1, phosphorylated AMPK (pAMPK) and CRTC1-3 were examined by selected immunofluorescent antibodies in testis samples from a prepubertal boy and three fertile men. Aromatase, pAMPK and LKB1 proteins were present in the seminiferous epithelium and interstitium of the testis and were expressed in a differential and developmental manner in particular cell types. The expression pattern of LKB1 was similar to that of pAMPK and inversely related to aromatase expression. CRTC1 and CRTC3 were localised in the seminiferous epithelium, whereas CRTC2 was barely detectable in testis. These results lead to the conclusion that LKB1 is involved in the molecular pathway that underpins aromatase regulation in the testis via CRTC1 and CRTC3 and may be important for the oestrogen-mediated development of germ cells. PMID- 26946413 TI - The use of carbon dioxide in gastrointestinal endoscopy. PMID- 26946414 TI - Erratum to: Soluble epoxide hydrolase inhibitor 1-trifluoromethoxyphenyl-3-(1 propionylpiperidin-4-yl) urea attenuates bleomycin-induced pulmonary fibrosis in mice. PMID- 26946415 TI - Anticoagulation in coronary intervention. AB - Percutaneous coronary intervention (PCI) induces thrombin generation and is associated with the risk of acute, subacute, or long-term ischaemic events. Therefore, intravenous anticoagulation is recommended to minimize thrombotic complications. The intensity and duration of anticoagulation needed are dependent on the clinical presentation (elective PCI for stable coronary artery disease, PCI for non-ST elevation acute coronary syndromes, or primary PCI for ST-segment elevation myocardial infarction) and procedural features. As both ischaemic and periprocedural bleeding complications are associated with acute and long-term mortality, the optimal level of anticoagulation and the best agents are a matter of debate. Despite a number of limitations and the lack of large randomized clinical trials, unfractionated heparin (UFH) is still been used in the majority of interventions. Intravenous enoxaparin, a low-molecular-weight heparin, leads to a more predictable level of anticoagulation and has been compared with UFH in patients with elective PCI and primary PCI with favourable results. The direct thrombin inhibitor bivalirudin has been studied in numerous trials and consistently shown to reduce bleeding complications when compared with UFH with or without glycoprotein IIb/IIIa inhibitors. This review will summarize the current status of anticoagulation for PCI and the results of most recent trials and give recommendations for different clinical scenarios. PMID- 26946416 TI - The spectrum of renal involvement in male patients with infertility related to excretory-system abnormalities: phenotypes, genotypes, and genetic counseling. AB - BACKGROUND: While reproductive technologies are increasingly used worldwide, epidemiologic, clinical and genetic data regarding infertile men with combined genital tract and renal abnormalities remain scarce, preventing adequate genetic counseling. METHODS: In a cohort-based study, we assessed the prevalence (1995 2014) and the clinical characteristics of renal disorders in infertile males with genital tract malformation. In a subset of 34 patients, we performed a detailed phenotype analysis of renal and genital tract disorders. RESULTS: Among the 180 patients with congenital uni- or bilateral absence of vas deferens (CU/BAVD), 45 (25 %) had a renal malformation. We also identified 14 infertile men with combined seminal vesicle (SV) and renal malformation but no CU/BAVD. Among the 34 patients with detailed clinical description, renal disease was unknown before the assessment of the infertility in 27 (79.4 %), and 7 (20.6 %) had chronic renal failure. Four main renal phenotypes were observed: solitary kidney (47 %); autosomal-dominant polycystic kidney disease (ADPKD, 0.6 %); uni- or bilateral hypoplastic kidneys (20.6 %); and a complex renal phenotype associated with a mutation of the HNF1B gene (5.8 %). Absence of SV and azoospermia were significantly associated with the presence of a solitary kidney, while dilatation of SV and necroasthenozoospermia were suggestive of ADPKD. CONCLUSION: A dominantly inherited renal disease (ADPKD or HNF1B-related nephropathy) is frequent in males with infertility and combined renal and genital tract abnormalities (26 %). A systematic renal screening should be proposed in infertile males with CU/BAVD or SV disorders. PMID- 26946417 TI - Updated genetic testing of Italian patients referred with a clinical diagnosis of primary hyperoxaluria. AB - BACKGROUND: Primary hyperoxaluria (PH) is a rare autosomal recessive disease commonly arising in childhood and presenting with nephrolithiasis, nephrocalcinosis and/or chronic renal failure. Three genes are currently known as responsible: alanine-glyoxylate aminotransferase (AGXT, PH type 1), glyoxylate reductase/hydroxypyruvate reductase (GRHPR, PH type 2), and 4-hydroxy-2 oxoglutarate aldolase (HOGA1, PH type 3). In our Centre, at the end of 2014 molecular diagnosis of PH1 had been performed in 80 patients, while one patient received a PH2 diagnosis. MATERIALS AND METHODS: Fifteen patients referred to our Centre and suspected to have PH on clinical grounds were negative for pathogenic variants in the entire coding sequence and exon-intron boundaries of the AGXT gene. Therefore, we extended the analysis to the AGXT promoter region and the GRHPR and HOGA1 genes. RESULTS: Two patients were heterozygous for two novel AGXT promoter variants (c.-647C > T, c.-424C > T) that were probably non pathogenic. One patient was homozygous for a novel HOGA1 variant of intron 2 (c.341-81delT), whose pathogenicity predicted by in silico splicing tools was not confirmed by a minigene splicing assay in COS-7 and HEK293T cells. CONCLUSION: New genetic subtypes of PH can be hypothesized in our patients, that may be caused by mutations in other gene encoding proteins of glyoxylate metabolism. Alternatively, some kind of mutations (e.g., deletions/duplications, deep intronic splicing regulatory variants) could be missed in a few cases, similarly to other genetic diseases. PMID- 26946418 TI - Use of CPAP in patients with obstructive sleep apnea admitted to the general ward: effect on length of stay and readmission rate. AB - BACKGROUND: Obstructive sleep apnea (OSA) has been associated with multiple cardiovascular comorbidities. Despite increased awareness of OSA and its treatments, the management of OSA in the hospital setting remains below expectations. METHODS: We retrospectively reviewed the demographics, clinical characteristics, and hospital course on 413 consecutive patients with a history of OSA on domiciliary CPAP therapy admitted to the general medical ward and analyzed the prevalence of CPAP use and its effect on length of stay (LOS), 30 day readmission rate, and time-to-readmission in our tertiary care teaching hospital. RESULTS: Of the 413 study participants, 264 (64.0 %) patients were receiving CPAP during their hospital admission. Patients who were receiving CPAP therapy during their hospitalization had a significantly higher body mass index (BMI) (41.4 vs. 36.8 kg/m(2), p < 0.001) and were more likely to be African American (p = 0.01) and have congestive heart failure (CHF) (42.0 vs. 31.0 %, p = 0.038) peripheral vascular disease (PVD) (26.0 vs. 15.0 %, p = 0.013), and uncomplicated diabetes mellitus (p = 0.001) than those who were not. CPAP therapy in the hospital setting did not affect LOS (4.7 vs. 4.0 days, p = 0.291), readmission rate (11.0 % for both groups), or time-to-readmission (20.8 vs. 22.3 days, p = 0.762). CONCLUSION: The majority of patients who are on domiciliary CPAP therapy were receiving CPAP therapy while admitted to the general medical ward of a tertiary care academic hospital. Presence of comorbid conditions such as obesity and certain cardiovascular diseases may have increased the likelihood of prescribing CPAP therapy while in the hospital. In-hospital CPAP therapy did not appear to significantly influence short-term outcomes such as hospital LOS, readmission rate, or time-to-readmission. PMID- 26946419 TI - Biodegradable collagen matrix implant versus mitomycin-C in trabeculectomy: five year follow-up. AB - BACKGROUND: Clinical studies comparing trabeculectomy augmented with Ologen implant (OLO) versus trabeculectomy plus mitomycin-C (MMC) show contradictory results. To obtain long-term data, we report an extended 5-year follow-up trial evaluating the safety and efficacy of OLO as adjuvant compared to low-dosage MMC in trabeculectomy. METHODS: Forty glaucoma patients (40 eyes) assigned to trabeculectomy with MMC or Ologen. PRIMARY OUTCOME: target IOP at <=21, <=17 and <=15 mmHg; complete and qualified success endpoint rates. SECONDARY OUTCOMES: visual acuity (VA), mean deviation (MD), bleb evaluation, according to Moorfields Bleb Grading System (MBGS); spectral domain OCT (SD-OCT) bleb examination; number of glaucoma medications; frequency of postoperative complications. RESULTS: The mean preoperative IOP was 26.7(+/-5.2) in MMC and 27.3(+/-6.0) in OLO eyes. Mean 60-month percentage reduction in IOP was significant in both groups [40.9 (+/ 14.2) and 42.1(+/-13.3) P = 0.01], with an endpoint value of 15.2 (+/-3.2) and 15.8 (+/-2.3) mmHg in MMC and OLO, respectively. Complete success rates at <= 21 mmHg target IOP were 65% and 70%, at <=17 mm Hg 60% and 55%, and at the <=15 mm Hg target IOP 35% and 45% in MMC and OLO, respectively. The Kaplan-Meier curves did not differ both for complete and qualified success at any target IOP, with no significant endpoint intergroup difference at <= 15 mm Hg (log-rank P = 0.595).The intergroup MBGS scores differed due to reduced central and peripheral vascularity in MMC group (P = 0.027; P = 0.041). SD-OCT analysis denied differences in bleb height between MMC vs OLO (140.5 +/- 20.3 MU vs 129.2 +/- 19.3 MU respectively; P =0.079). Mean antiglaucoma medications were significantly reduced (P < 0.0005) from 2.5 (+/-0.3) to 1.2 (+/-0.4) in MMC and from 2.6 (+/ 0.2) to 1.4 (+/-0.3) in OLO group, with no intergroup differences (P = 0.08). Six (30%) cystic thin avascular blebs without oozing were recorded in the MMC group and 2 (10%) in the OLO group, without intergroup difference (P = 0.235). CONCLUSIONS: Our extended follow-up results confirm that Ologen implant yields efficacy and long-term success rates quite similar to MMC, with at least equivalent safety. PMID- 26946420 TI - Defining and measuring adherence to cancer screening. AB - BACKGROUND: The importance of cancer screening is well-recognized, yet there is great variation in how adherence is defined and measured. This manuscript identifies measures of screening adherence and discusses how to estimate them. DISCUSSION: We begin by describing why screening adherence is of interest: to anticipate long-term outcomes, to understand differences in outcomes across settings, and to identify areas for improvement. We outline questions of interest related to adherence, including questions about uptake, currency or being up-to date, and longitudinal adherence, and then identify which measures are most appropriate for each question. Our discussion of how to select measures focuses on study inclusion criteria and outcome definitions. Finally, we describe how to estimate different measures using data from two common data sources: survey studies and surveillance studies. Estimation requires consideration of data sources, inclusion criteria, and outcome definitions. Censoring often will be present and must be accounted for. CONCLUSION: We conclude that consistent definitions and estimation of adherence to cancer screening guidelines will facilitate comparison across studies, tests, and settings, and help to elucidate areas for future research and intervention. PMID- 26946421 TI - Impact of varied center volume categories on volume-outcome relationship in children receiving ECMO for heart operations. AB - To study the volume-outcome relationship among children receiving extracorporeal membrane oxygenation (ECMO), different studies from different databases use different volume categories. The objective of this study was to evaluate if different center volume categories impact the volume-outcome relationship among children receiving ECMO for heart operations. We performed a post hoc analysis of data from an existing national database, the Pediatric Health Information System. Centers were classified into five different volume categories using different cut offs and different variables. Mortality rates were compared between the varied volume categories using a mixed effects logistic regression model after adjusting for patient- and center-level risk factors. Data collection included demographic information, baseline characteristics, pre-ECMO risk factors, operation details, patient diagnoses, and center data. In unadjusted analysis, there was a significant relationship between center volume and mortality, with low-and medium volume centers associated with higher mortality rates compared to high-volume centers in all volume categories, except the hierarchical clustering volume category. In contrast, there was no significant association between center-volume and mortality among all volume categories in adjusted analysis. We concluded that high-volume centers were not associated with improved outcomes for the majority of the categorization schemes despite using different cut-offs and different variables for volume categorization. PMID- 26946422 TI - Congenital infiltrative lipomas and retroperitoneal perirenal lipomas in a calf. AB - BACKGROUND: Congenital lipocytic tumours have rarely been reported in cattle. Lipomas are benign tumours, but infiltrative lipomas have significant health implications due to their aggressive infiltrative growth pattern. CASE PRESENTATION: A calf was born with skeletal malformations and soft tissue proliferations, primarily on the external thoracic wall. The calf was euthanized for welfare reasons and submitted for post mortem examination. Necropsy, histopathology and post mortem computed tomography scanning revealed two types of lipocytic tumours. Widespread infiltrative lipomas were present in the muscles and connective tissues along the vertebral column and diffusely invaded the external soft tissues of the right thoracic wall. The neoplastic lipocytes had invaded intervertebral spaces thus causing congenital vertebral malformations, and further invaded the vertebral canal and the bone marrow of coccygeal vertebrae. Periosteal localization of the tumour was associated with costal hyperostosis. Two large retroperitoneal lipomas enclosed the kidneys and occupied much of the abdominal space. CONCLUSION: The development of congenital bone malformation in this calf illustrates the severe consequences of the infiltrative and aggressive growth of infiltrative lipomas during foetal development. The congenital retroperitoneal lipomas occupied a large part of abdominal cavity, but did not invade the adjacent tissues. Due to their large size, perirenal lipomas should be considered in calves with distended abdomen, even in cases without other signs of tumours. PMID- 26946423 TI - Stereoselective method to quantify bupropion and its three major metabolites, hydroxybupropion, erythro-dihydrobupropion, and threo-dihydrobupropion using HPLC MS/MS. AB - Bupropion metabolites formed via oxidation and reduction exhibit pharmacological activity, but little is known regarding their stereoselective disposition. A novel stereoselective liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed to separate and quantify enantiomers of bupropion, 4 hydroxybupropion, and erythro- and threo-dihydrobupropion. Liquid-liquid extraction was implemented to extract all analytes from 50 MUL human plasma. Acetaminophen (APAP) was used as an internal standard. The analytes were separated on a Lux 3 MU Cellulose-3 250*4.6 mm column by methanol: acetonitrile: ammonium bicarbonate: ammonium hydroxide gradient elution and monitored using an ABSciex 5500 QTRAP triple-quadrupole mass spectrometer equipped with electrospray ionization probe in positive mode. Extraction efficiency for all analytes was >=70%. The stability at a single non-extracted concentration for over 48 h at ambient temperature resulted in less than 9.8% variability for all analytes. The limit of quantification (LOQ) for enantiomers of bupropion and 4-hydroxybupropion was 0.3 ng/mL, while the LOQ for enantiomers of erythro- and threo-hydrobupropion was 0.15 ng/mL. The intra-day precision and accuracy estimates for enantiomers of bupropion and its metabolites ranged from 3.4% to 15.4% and from 80.6% to 97.8%, respectively, while the inter-day precision and accuracy ranged from 6.1% to 19.9% and from 88.5% to 99.9%, respectively. The current method was successfully implemented to determine the stereoselective pharmacokinetics of bupropion and its metabolites in 3 healthy volunteers administered a single 100mg oral dose of racemic bupropion. This novel, accurate, and precise HPLC-MS/MS method should enhance further research into bupropion stereoselective metabolism and drug interactions. PMID- 26946424 TI - Determination of propofol glucuronide from hair sample by using mixed mode anion exchange cartridge and liquid chromatography tandem mass spectrometry. AB - The main objective of this study was to develop and validate a simpler and less time consuming analytical method for determination of propofol glucuronide from hair sample, by using mixed mode anion exchange cartridge and liquid chromatography-tandem mass spectrometry (LC-MS/MS). The study uses propofol glucuronide, a major metabolite of propofol, as a marker for propofol abuse. The hair sample was digested in sodium hydroxide solution and loaded in mixed-mode anion cartridge for solid phase extraction. Water and ethyl acetate were used as washing solvents to remove interfering substances from the hair sample. Consequently, 2% formic acid in ethyl acetate was employed to elute propofol glucuronide from the sorbent of mixed-mode anion cartridge, and analyzed by LC MS/MS. The method validation parameters such as selectivity, specificity, LOD, LLOQ, accuracy, precision, recovery, and matrix effect were also tested. The linearity of calibration curves showed good correlation, with correlation coefficient 0.998. The LOD and LLOQ of the propofol glucuronide were 0.2 pg/mg and 0.5 pg/mg, respectively. The intra and inter-day precision and accuracy were acceptable within 15%. The mean values of recovery and matrix effect were in the range of 91.7-98.7% and 87.5-90.3%, respectively, signifying that the sample preparation, washing and extraction procedure were efficient, and there was low significant hair matrix effect for the extraction of propofol glucuronide from hair sample on the mixed mode anion cartridge. To evaluate the suitability of method, the hair of propofol administered rat was successfully analyzed with this method. PMID- 26946425 TI - Prevalence and incidence of COPD in smokers and non-smokers: the Rotterdam Study. AB - COPD is the third leading cause of death in the world and its global burden is predicted to increase further. Even though the prevalence of COPD is well studied, only few studies examined the incidence of COPD in a prospective and standardized manner. In a prospective population-based cohort study (Rotterdam Study) enrolling subjects aged >=45, COPD was diagnosed based on a pre bronchodilator obstructive spirometry (FEV1/FVC < 0.70). In absence of an interpretable spirometry within the Rotterdam Study, cases were defined as having COPD diagnosed by a physician on the basis of clinical presentation and obstructive lung function measured by the general practitioner or respiratory physician. Incidence rates were calculated by dividing the number of incident cases by the total number of person years of subjects at risk. In this cohort of 14,619 participants, 1993 subjects with COPD were identified of whom 689 as prevalent ones and 1304 cases as incident ones. The overall incidence rate (IR) of COPD was 8.9/1000 person-years (PY); 95 % Confidence Interval (CI) 8.4-9.4. The IR was higher in males and in smokers. The proportion of female COPD participants without a history of smoking was 27.2 %, while this proportion was 7.3 % in males. The prevalence of COPD in the Rotterdam Study is 4.7 % and the overall incidence is approximately 9/1000 PY, with a higher incidence in males and in smokers. The proportion of never-smokers among female COPD cases is substantial. PMID- 26946427 TI - Trichostatin A induces a unique set of microRNAs including miR-129-5p that blocks cyclin-dependent kinase 6 expression and proliferation in H9c2 cardiac myocytes. AB - The pan-histone deacetylase inhibitor (HDACI), trichostatin A (TSA), was shown to normalize interleukin-18-induced cardiac hypertrophy in vivo and in vitro; evidently, this occurred via epigenetic mechanisms that profoundly altered cardiac gene expression (Majumdar et al. in, Physiol Genom, 43: 1392, 2011; BMC Genom, 13: 709, 2012). Here, we tested the hypothesis that TSA-induced changes in chromatin architecture also led to altered expression of microRNAs that in turn, contributed to the unique transcriptome of cardiac myocytes exposed to the HDACI. Using miRCURY LNATM Universal microRNA PCR system, we demonstrate that H9c2 cells exposed to TSA for 6 and 24 h elicited differential expression of 19 and 16 microRNAs, respectively. H9c2 cells incubated in medium-containing 100 nM of TSA elicited a rapid and robust induction of miR-129-5p. Enhanced expression of miR 129-5p was also observed in the hearts of TSA-treated mice. Induction of miR-129 5p in H9c2 cells was accompanied by reduced expression of its direct target, cyclin-dependent kinase 6 (CDK6) that is a key regulator of cell cycle. Using cell division-dependent dilution of Cell TraceTM violet measurements we showed that concomitant induction of miR-129-5p and reduced CDK6 expression were mechanistically involved in TSA-induced inhibition of proliferation of H9c2 cells. Consistent with this scenario, cells expressing an antagomiR of miR-129-5p were resistant to the anti-proliferative actions of TSA. These data indicate that although TSA treatment led to altered expression of several microRNAs, the overarching action of TSA (i.e., inhibition of cell division) in H9c2 cells was achieved via miR-129-5p. PMID- 26946426 TI - Cost-benefit analysis of the polypill in the primary prevention of myocardial infarction and stroke. AB - The primary prevention of cardiovascular disease is a public health priority. To assess the costs and benefits of a Polypill Prevention Programme using a daily 4 component polypill from age 50 in the UK, we determined the life years gained without a first myocardial infarction (MI) or stroke, together with the total service cost (or saving) and the net cost (or saving) per year of life gained without a first MI or stroke. This was estimated on the basis of a 50 % uptake and a previously published 83 % treatment adherence. The total years of life gained without a first MI or stroke in a mature programme is 990,000 each year in the UK. If the cost of the Polypill Prevention Programme were L1 per person per day, the total cost would be L4.76 bn and, given the savings (at 2014 prices) of L2.65 bn arising from the disease prevented, there would be a net cost of L2.11 bn representing a net cost per year of life gained without a first MI or stroke of L2120. The results are robust to sensitivity analyses. A national Polypill Prevention Programme would have a substantial effect in preventing MIs and strokes and be cost-effective. PMID- 26946428 TI - Spatiotemporally dissociable neural signatures for generating and updating expectation over time in children: A High Density-ERP study. AB - Temporal orienting (TO) is the allocation of attentional resources in time based on the a priori generation of temporal expectancy of relevant stimuli as well as the a posteriori updating of this expectancy as a function of both sensory-based evidence and elapsing time. These processes rely on dissociable cognitive mechanisms and neural networks. Yet, although there is evidence that TO may be a core mechanism for cognitive functioning in childhood, the developmental spatiotemporal neural dynamics of this mechanism are little understood. In this study we employed a combined approach based on the application of distributed source reconstruction on a high spatial resolution ERP data array obtained from eighteen 8- to 12-year-old children completing a TO paradigm in which both the cue (Temporal vs. Neutral) and the SOA (Short vs. Long) were manipulated. Results show both cue (N1) and SOA (CNV, Omission Detection Potential and Anterior Anticipatory Index) ERP effects, which were associated with expectancy generation and updating, respectively. Only cue-related effects were correlated with age, as revealed by a reduction of the N1 delta effect with increasing age. Our data suggest that the neural correlates underlying TO are already established at least from 8 to 12 years of age. PMID- 26946429 TI - Dependence-induced ethanol drinking and GABA neurotransmission are altered in Alk deficient mice. AB - Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase that is expressed in the brain and implicated in alcohol abuse in humans and behavioral responses to ethanol in mice. Previous studies have shown an association of human ALK with acute responses to alcohol and alcohol dependence. In addition, Alk knockout (Alk -/-) mice consume more ethanol in a binge-drinking test and show increased sensitivity to ethanol sedation. However, the function of ALK in excessive drinking following the establishment of ethanol dependence has not been examined. In this study, we tested Alk -/- mice for dependence-induced drinking using the chronic intermittent ethanol-two bottle choice drinking (CIE-2BC) protocol. We found that Alk -/- mice initially consume more ethanol prior to CIE exposure, but do not escalate ethanol consumption after exposure, suggesting that ALK may promote the escalation of drinking after ethanol dependence. To determine the mechanism(s) responsible for this behavioral phenotype we used an electrophysiological approach to examine GABA neurotransmission in the central nucleus of the amygdala (CeA), a brain region that regulates alcohol consumption and shows increased GABA signaling after chronic ethanol exposure. GABA transmission in ethanol-naive Alk -/- mice was enhanced at baseline and potentiated in response to acute ethanol application when compared to wild-type (Alk +/+) mice. Moreover, basal GABA transmission was not elevated by CIE exposure in Alk -/- mice as it was in Alk +/+ mice. These data suggest that ALK plays a role in dependence-induced drinking and the regulation of presynaptic GABA release in the CeA. PMID- 26946430 TI - Selective alterations of NMDAR function and plasticity in D1 and D2 medium spiny neurons in the nucleus accumbens shell following chronic intermittent ethanol exposure. AB - A major mouse model widely adopted in recent years to induce pronounced ethanol intake is the ethanol vapor model known as "CIE" or "Chronic Intermittent Ethanol." One critical question concerning this model is whether the rapid induction of high blood ethanol levels for such short time periods is sufficient to induce alterations in N-methyl-d-aspartate receptor (NMDAR) function which may contribute to excessive ethanol intake. In this study, we determined whether such short term intermittent ethanol exposure modulates NMDAR function as well as other prominent electrophysiological properties and the expression of plasticity in both D1 (D1+) and D2 (D1-) dopamine receptor expressing medium spiny neurons (MSNs) in the nucleus accumbens (NAc) shell. To distinguish between the two subtypes of MSNs in the NAc we treated Drd1a-TdTomato transgenic mice with CIE vapor and electrophysiological recordings were conducted 24 h after the last vapor exposure. To investigate CIE induced alterations in plasticity, long-term depression (LTD) was induced by pairing low frequency stimulation (LFS) with post synaptic depolarization. In ethanol naive mice, LFS induced synaptic depression (LTD) was apparent exclusively in D1+ MSNs. Whereas in slices prepared from CIE treated mice, LFS induced synaptic potentiation (LTP) in D1+ MSNs. Furthermore, following CIE exposure, LFS now produced LTD in D1- MSNs. We found that CIE exposure induced an increase in excitability in D1+ MSNs with no change in D1- MSNs. After CIE, we found a significant increase in spontaneous EPSCs (sEPSCs) frequency in D1+ but not D1- MSNs suggesting alterations in baseline alpha-amino 3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) mediated signaling. CIE induced changes in NMDAR function were measured using the NMDA/AMPA ratio and input-output curves of isolated NMDAR currents. We observed a significant increase in NMDAR function in D1+ MSNs and a decrease in D1- MSNs after ethanol vapor exposure. The reversal of NMDAR function may account for the CIE induced alterations in the expression of plasticity. The cell type specific alterations in excitatory signaling in the NAc shell may constitute an important neuroadaptation necessary for the expression of increased ethanol consumption induced by intermittent ethanol vapor exposure. This article is part of the Special Issue entitled 'Ionotropic glutamate receptors'. PMID- 26946431 TI - mGluR5 activation in the nucleus accumbens is not essential for sexual behavior or cross-sensitization of amphetamine responses by sexual experience. AB - Natural rewards and psychostimulants cause similar neural plasticity in the nucleus accumbens (NAc). In addition, sexual experience in male rats causes increased locomotor activity and conditioned place preference (CPP) induced by d Amphetamine (amph). The latter is dependent on a period of abstinence from sexual reward. In this study, the role of mGluR5 activation in the NAc for expression of mating and the cross-sensitizing effects of sexual experience was tested. First, intra-NAc infusions of mGluR5 antagonists MPEP (1 or 10 MUg/MUL) or MTEP (1 MUg/MUL) 15 min prior to mating during 4 daily sessions had no effect on male rat sexual behavior. Subsequently, these sexually experienced males were tested for amph-induced locomotor activity and CPP after one week of abstinence from sexual reward. In addition, sexually naive males that received MPEP, MTEP or vehicle infusions prior to 4 daily handling sessions were included. Cross-sensitization of locomotion or CPP was not prevented by NAc mGluR5 antagonism during acquisition of sexual experience. Instead, sexually naive animals that received NAc mGluR5 antagonists without mating demonstrated sensitized amph-induced locomotor responses and enhanced CPP on par with sexually experienced males. Finally, we showed that sexual experience caused prolonged down-regulation of mGluR5 protein in the NAc, dependent on abstinence from sexual behavior. Together, these findings suggest that mGluR5 activation in the NAc is not essential for the expression of mating, but that experience-induced reduction in mGluR5 protein may contribute to the cross-sensitization of amph responses by sexual experience and abstinence. PMID- 26946432 TI - Neck circumference and future cardiovascular events in a high-risk population--A prospective cohort study. AB - BACKGROUND: The distribution of adipose tissue has been evaluated in relation to cardiovascular risk factors and biochemical components of the metabolic syndrome. Neck circumference (NC) has been shown to have a strong relationship with cardiovascular disease (CVD) and may be a novel indicator of CVD. The aim of this study was to compare the incidence of CVD events in cohorts with different NC distributions, and to correlate NC with future CVD events and relative mortality. METHODS: A prospective cohort study was performed on 12,151 high-risk cardiology outpatients from 2004 until 2014. Anthropometric parameters like body mass index, NC, waist circumference, and hip circumference were measured at baseline and follow-up and compared in different cohorts with high, medium, and low NC. Fatal and non-fatal CVD events were compared in the follow-up study, and survival analysis was conducted. Independent Chi-square tests were performed to compare the incidence of CVD events and mortality among the cohorts and analyze the interactions. RESULTS: The subjects comprised of 6696 women and 5819 men who completed a mean 8.8-year follow-up. All of the participants had two or more CVD risk factors at baseline. At the end of the study, 4049 CVD events had occurred in 2304 participants. The incidence of non-fatal CVD events was 14.08, 16,65, and 25.21 % in the low-NC, medium-NC, and high-NC cohorts, respectively (p < 0.001). The all-cause mortality was 9.77, 11.93, and 19.31 %, and CVD mortality, 4.00, 6.29, and 8.01 %, respectively (p < 0.001). Compared with baseline, the number of CVD risk factors in participants had increased from 2.6, 3.0, and 3.4 to 3.5, 4.1, and 4.7 in the low-, medium-, and high-NC cohorts (34, 36, and 38 %), respectively. The event-free survival rate was 95.32, 80.15, and 75.47 %, respectively. CONCLUSIONS: A higher NC indicated a higher incidence of future fatal and non-fatal CVD events and all-cause mortality in both male and female high-risk participants. CVD risk factors increased more in the higher NC group. NC as a novel indicator of CVD showed good predictive ability for CVD events and mortality in a high-risk population. PMID- 26946433 TI - Generalized Low-Temperature Fabrication of Scalable Multi-Type Two-Dimensional Nanosheets with a Green Soft Template. AB - Two-dimensional nanosheets with high specific surface areas and fascinating physical and chemical properties have attracted tremendous interests because of their promising potentials in both fundamental research and practical applications. However, the problem of developing a universal strategy with a facile and cost-effective synthesis process for multi-type ultrathin 2 D nanostructures remains unresolved. Herein, we report a generalized low temperature fabrication of scalable multi-type 2 D nanosheets including metal hydroxides (such as Ni(OH)2, Co(OH)2, Cd(OH)2, and Mg(OH)2), metal oxides (such as ZnO and Mn3O4), and layered mixed transition-metal hydroxides (Ni-Co LDH, Ni Fe LDH, Co-Fe LDH, and Ni-Co-Fe layered ternary hydroxides) through the rational employment of a green soft-template. The synthesized crystalline inorganic nanosheets possess confined thickness, resulting in ultrahigh surface atom ratios and chemically reactive facets. Upon evaluation as electrode materials for pseudocapacitors, the Ni-Co LDH nanosheets exhibit a high specific capacitance of 1087 F g(-1) at a current density of 1 A g(-1), and excellent stability, with 103% retention after 500 cycles. This strategy is facile and scalable for the production of high-quality ultrathin crystalline inorganic nanosheets, with the possibility of extension to the preparation of other complex nanosheets. PMID- 26946434 TI - The role of 1,3-propanediol production in fermentation of glycerol by Clostridium pasteurianum. AB - Waste crude glycerol from biodiesel production can be used to produce biobutanol using Clostridium pasteurianum with the main products being n-butanol, 1,3 propanediol (PDO) and ethanol. There has been much discrepancy and mystery around the cause and effect of process parameters on the product distribution, thus a better understanding of the pathway regulation is required. This study shows that as process pH decreased, the rate of cell growth and CO2 production also decreased, resulting in slower fermentations, increased duration of butanol production and higher butanol concentrations and yields. The production rate of PDO was multi-modal and the role of PDO appears to function in redox homeostasis. The results also showed that C. pasteurianum displayed little biphasic behavior when compared to Clostridia spp. typically used in ABE fermentation due to the alternative glycolysis-independent reductive pathway of PDO production, rendering it suitable for a continuous fermentation process. PMID- 26946435 TI - A novel osmosis membrane bioreactor-membrane distillation hybrid system for wastewater treatment and reuse. AB - A novel approach was designed to simultaneously enhance nutrient removal and reduce membrane fouling for wastewater treatment using an attached growth biofilm (AGB) integrated with an osmosis membrane bioreactor (OsMBR) system for the first time. In this study, a highly charged organic compound (HEDTA(3-)) was employed as a novel draw solution in the AGB-OsMBR system to obtain a low reverse salt flux, maintain a healthy environment for the microorganisms. The AGB-OsMBR system achieved a stable water flux of 3.62L/m(2)h, high nutrient removal of 99% and less fouling during a 60-day operation. Furthermore, the high salinity of diluted draw solution could be effectively recovered by membrane distillation (MD) process with salt rejection of 99.7%. The diluted draw solution was re concentrated to its initial status (56.1mS/cm) at recovery of 9.8% after 6h. The work demonstrated that novel multi-barrier systems could produce high quality potable water from impaired streams. PMID- 26946436 TI - Beneficial changes in biomass and lipid of microalgae Anabaena variabilis facing the ultrasonic stress environment. AB - This study investigated the beneficial effects of ultrasonic treatment on the biomass, lipid and protein of the microalgae Anabaena variabilis. The microalgae after 11days cultivation (initial algae) were treated at the powers of 200, 350 and 500W for 10min and then cultured continuously for 3days (day 12-14). The power of 200W induced the highest lipid content 37.8% on day 12. The subsequent experiments tested the ultrasonic treatment times of 5, 10, 20 and 40min at 200W in the initial algae. The significantly improved lipid content 46.9% and productivity 54.2mg/L/d were obtained almost 1.46 and 1.86times more than that of the control algae respectively after 1day of continuous cultivation at 5min. The proper ultrasonic treatment showed the feasibility and high efficiency in promoting lipid accumulation without negatively influencing the biomass, fatty acid profiles and protein content. PMID- 26946437 TI - Fouling characterization and control for harvesting microalgae Arthrospira (Spirulina) maxima using a submerged, disc-type ultrafiltration membrane. AB - This study characterized the fouling of a novel circular-disc ultrafiltration membrane in a submerged bioreactor system to harvest Arthrospira maxima cells. Flux-stepping study showed that the value of critical flux was below the smallest flux tested at 28.8lm(-2)h(-1), and that the membrane was to operate above the critical flux to sustain the necessary rate of cell concentration. The membrane with similar pore size but greater pore density experienced not only lesser degree of total resistance, but also possessed smaller fraction of irreversible resistance. Membrane fouling was mainly attributed to fragmented cells rather than to soluble or extracellular polymeric substances. Furthermore, flux recovery studies demonstrated that membrane relaxation and surface cleaning could partially recover fluxes for both low (6gl(-1)) and high (40gl(-1)) cell densities, whereas backwashing could fully recover fluxes. Calculation of energy consumption and cell harvesting productivity also favoured membrane filtration with backwashing. PMID- 26946438 TI - Characterizing fluorescent dissolved organic matter in a membrane bioreactor via excitation-emission matrix combined with parallel factor analysis. AB - In this study, we successfully tracked the dynamic changes in different constitutes of bound extracellular polymeric substances (bEPS), soluble microbial products (SMP), and permeate during the operation of bench scale membrane bioreactors (MBRs) via fluorescence excitation-emission matrix (EEM) combined with parallel factor analysis (PARAFAC). Three fluorescent groups were identified, including two protein-like (tryptophan-like C1 and tyrosine-like C2) and one microbial humic-like components (C3). In bEPS, protein-like components were consistently more dominant than C3 during the MBR operation, while their relative abundance in SMP depended on aeration intensities. C1 of bEPS exhibited a linear correlation (R(2)=0.738; p<0.01) with bEPS amounts in sludge, and C2 was closely related to the stability of sludge. The protein-like components were more greatly responsible for membrane fouling. Our study suggests that EEM-PARAFAC can be a promising monitoring tool to provide further insight into process evaluation and membrane fouling during MBR operation. PMID- 26946439 TI - Evaluation of anaerobic degradation, biogas and digestate production of cereal silages using nylon-bags. AB - In this study, the degradation efficiency and the biogas and digestate production during anaerobic digestion were evaluated for the cereal silages most used to feed biogas plants. To this purpose, silages of: maize from the whole plant, maize from the ear, triticale and wheat were digested, inside of nylon bags, in laboratory scale digesters, for 75days. Overall, the test involved 288 nylon bags. After 75days of digestion, the maize ear silage shows the highest degradation efficiency (about 98%) while wheat silage the lowest (about 83%). The biogas production ranges from 438 to 852Nm(3)/t of dry matter for wheat and ear maize silage, respectively. For all the cereal silages, the degradation as well as the biogas production are faster at the beginning of the digestion time. Digestate mass, expressed as percentage of the fresh matter, ranges from 38% to 84% for wheat and maize ear silage, respectively. PMID- 26946441 TI - Modelling the PKPD of oxycodone in experimental pain - Impact of opioid receptor polymorphisms. AB - BACKGROUND: Polymorphisms in the opioid receptor genes may affect the pharmacodynamics (PD) of oxycodone and be part of the reason behind the diversity in clinical response. The aim of the analysis was to model the exposure-response profile of oxycodone for three different pain variables and search for genetic covariates. Model simulations were used to predict how population and effect-size impact the power to detect clinical significant SNPs. METHOD: The population pharmacokinetic-pharmacodynamic (PKPD) model of oral single-dosed oxycodone was based on pooled data from three published studies in healthy volunteers. Pain tolerance data from muscle pressure (n=36), visceral pressure (n=54) and skin pinch (n=34) were included. Genetic associations with 18 opioid-receptor SNPs were explored using a stepwise covariate approach. Model simulations were performed using the estimated model parameters. RESULTS: None of the selected SNPs were associated with analgesic response of oxycodone at P<0.001. Baseline response in muscle cuff pressure was associated with OPRK1 rs7016778 and rs7824175 (P<0.001). Simulations indicated that large differences in drug response between genotypes (>50% for similar population sizes) or large populations (n>200 for a 20% response difference) are necessary to identify clinical significant SNP effects due to high population variability. CONCLUSION: A population PKPD model has been developed for oral oxycodone using three different pain variables to explore impact of genetic covariates and study design. None of the selected polymorphisms were significantly associated with analgesic response of oxycodone, but an association of baseline response in muscle cuff pressure with two OPRK1 SNPs was identified. PMID- 26946440 TI - Cytokine expression in gingival and intestinal tissues of patients with periodontitis and inflammatory bowel disease: An exploratory study. AB - OBJECTIVE: To evaluate the expression of the cytokines IFN-gamma, IL-1beta, IL-4, IL-6, IL-10, IL-21, IL-22, IL-23, IL-25, IL-31, IL-33, IL-17A, IL-17F, sCD40L, and TNF-alpha in gingival tissue and intestinal mucosa of patients having both periodontitis and inflammatory bowel disease (IBD) and assess how they cluster in both tissues. METHODS: This cross-sectional study selected 28 patients with periodontitis (18 with Crohn's disease and 10 with ulcerative colitis) from the IBD gastroenterology outpatient clinic at the Pedro Ernesto University Hospital. Patients were assessed using questionnaire, medical chart check and periodontal examination. Gingival and intestinal biopsies were collected and homogenized using a cell disruptor. Cytokines expression was evaluated through multiplex technology. Cluster analysis was performed based on cytokines correlation strength and presented in dendrograms. RESULTS: Crohn's disease and ulcerative colitis patients exhibited no significant difference between them in cytokine levels (p>0.05), so they were analysed together. Significantly higher levels of IL-17A, IL-17F, IL-22, IL-25, IL-33, IL-10, and INF-gamma were found in gingival tissues in comparison with intestinal mucosa (p<0.05). In gingival tissue, cytokines formed the following clusters: IL-25/IL-10/IL-33 (r=0.775), IL-22/IL 23/IL-6 (r=0.681) and IL-6/IL-25/IL-33/IL-10 (r=0.660). In intestinal mucosa, the following clusters were formed: IL-6/IL-21/IL-10 (r=0.880), IL-17A/IL-6/IL-21/IL 10 (r=0.826), IL-I7F/IL-33/IL-25 (r=0.813) and IL-23/IL-2/IL-17A/IL-6/IL-21/IL-10 (r=0.785). CONCLUSION: Expression of IL-17A, IL-17F, IL-22, IL-25, IL-33, IL-10, and INF-gamma was significantly increased in gingival tissue in comparison with intestinal mucosa of patients with periodontitis and IBD. The cytokine clustering pattern was different in gingival and intestinal tissues. PMID- 26946442 TI - Influence of amine-modified poly(vinyl alcohol)s on vibrating-membrane nebulizer performance and lung toxicity. AB - A suitable aerosol droplet size and formulation output rate is essential for the therapy of lung diseases under application of nebulizers. The current study investigated the potential of amine-modified poly(vinyl alcohol)s as excipients for inhalation delivery. A change of conductivity (effective at <0.1mg/ml) and viscosity (effective at >0.1mg/ml) of samples that were supplemented with charge modified polymers had a significant influence on the generated droplet size (shift from ~8 to ~4 MUm) and formulation throughput rate (shift from ~0.2 to ~1.0 g/min), where polymers with a higher amine density (and molecular weight) showed an elevated activity. Biocompatibility assessment of polymers in A549 cells and an isolated lung model resulted in cell lysis and lung edema formation dependent on the type (degree of amine substitution) and dose of polymer applied. Suitable compositions and concentrations of amine-modified poly(vinyl alcohol)s were identified with respect to an optimized nebulizer performance and acceptable biocompatibility. Charge-modified polymers represent novel excipients with potential to improve inhalation therapy. PMID- 26946443 TI - The kidneys play a central role in the clearance of rhGH in rats. AB - The kidneys are thought to play an important role in the clearance of recombinant human growth hormone (rhGH), but the relative importance is not clear. Obtaining knowledge of clearance pathway is an important prerequisite for the development of new long acting growth hormone analogues targeted at treatment of patients with growth hormone disorders. The purpose of this study was to investigate the relative importance of the kidneys in the clearance of rhGH. The study employed a newly validated nephrectomy rat model and a population based pharmacokinetic approach to assess renal clearance of rhGH in non-anesthetized rats, anesthetized rats and in nephrectomized anesthetized rats. Clearance in non-anesthetized rats was 290 ml/h/kg. This was reduced to 185 ml/h/kg by anesthesia and further reduced to 18 ml/h/kg by nephrectomy. As nephrectomy was able to reduce clearance with 90%, we conclude that renal clearance plays a pivotal role in the elimination of rhGH in rats. PMID- 26946444 TI - Enantioselective Visible-Light-Induced Radical-Addition Reactions to 3-Alkylidene Indolin-2-ones. AB - The title compounds underwent a facile and high-yielding addition reaction (19 examples, 66-99% yield) with various N-(trimethylsilyl)methyl-substituted amines upon irradiation with visible light and catalysis by a metal complex. If the alkylidene substituent is non-symmetric and if the reaction is performed in the presence of a chiral hydrogen-bonding template, products are obtained with significant enantioselectivity (58-72% ee) as a mixture of diastereoisomers. Mechanistic studies suggest a closed catalytic cycle for the photoactive metal complex. However, the silyl transfer from the amine occurs not only to the product, but also to the substrate, and interferes with the desired chirality transfer. PMID- 26946445 TI - Examining an underlying mechanism between perceived stress and smoking cessation related outcomes. AB - The mediational role of negative reinforcement smoking outcome expectancies in the relation between perceived stress and (1) perceived barriers to cessation, (2) severity of problematic symptoms during past quit attempts, and (3) smoking specific experiential avoidance (AIS) was examined. Data were drawn from a baseline assessment of a larger clinical trial. Participants included 332 adult treatment-seeking smokers (47.3% female; Mage=38.45; SD=.50; age range: 18-65 years). Results indicated that perceived stress was indirectly related to perceived barriers to smoking cessation, severity of problematic symptoms during past quit attempts, and AIS through negative reinforcement outcome expectancies. These results were evident after accounting for the variance explained by gender, negative affectivity, and alternative outcome expectancies for smoking. The present findings suggest that smokers with greater perceived stress experience greater negative reinforcement smoking expectancies, which in turn, may be related to numerous processes involved in the maintenance of smoking. PMID- 26946446 TI - Trends in cigarette smoking and cessation among Medicare managed care recipients, 2005-2012. AB - OBJECTIVES: To examine recent trends in cigarette smoking among older (65 years and above) adults in the United States. METHODS: We used data from the Medicare Health Outcomes Survey dataset to estimate rates of smoking, quitting, and (re)starting from 2005 to 2012. Medicare Advantage enrollees completed mail surveys at baseline and two years later. We included subgroup analyses by sex, race, and self-rated health. RESULTS: Smoking prevalence declined slightly, with most of the decline occurring over the course of a single year (2007-2008). Rates of quitting declined slightly (meaning fewer people were quitting), and (re)starting marginally declined from 2005 to 2012. There were no substantial differences between subgroups. We did not observe any significant changes in prevalence or cessation of smoking among Medicare Advantage participants during this time. CONCLUSIONS: Smoking remains a public health problem for older adults. We did not find evidence of significant changes in smoking prevalence or cessation for older adults during the time period we examined. PMID- 26946447 TI - Cumulative contextual risk at birth in relation to adolescent substance use, conduct problems, and risky sex: General and specific predictive associations in a Finnish birth cohort. AB - BACKGROUND: Research indicates that risk factors cluster in the most vulnerable youth, increasing their susceptibility for adverse developmental outcomes. However, most studies of cumulative risk are cross-sectional or short-term longitudinal, and have been based on data from the United States or the United Kingdom. Using data from the Northern Finland Birth Cohort 1986 Study (NFBC1986), we examined cumulative contextual risk (CCR) at birth as a predictor of adolescent substance use and co-occurring conduct problems and risky sex to determine the degree to which CCR predicts specific outcomes over-and-above its effect on general problem behavior, while testing for moderation of associations by gender. METHODS: Analyses of survey data from 6963 participants of the NFBC1986 followed from the prenatal/birth period into adolescence were conducted using structural equation modeling. RESULTS: CCR had long-term positive associations with first-order substance use, conduct problems, and risky sex factors, and, in a separate analysis, with a second-order general problem behavior factor. Further analyses showed that there was a positive specific effect of CCR on risky sex, over-and-above general problem behavior, for girls only. CONCLUSIONS: This study, conducted within the Finnish context, showed that CCR at birth had long-term general and specific predictive associations with substance use and co-occurring problem behaviors in adolescence; effects on risky sex were stronger for girls. Results are consistent with the hypothesis that early exposure to CCR can have lasting adverse consequences, suggesting the need for early identification and intervention efforts for vulnerable children. PMID- 26946448 TI - Past year non-medical opioid use and abuse and PTSD diagnosis: Interactions with sex and associations with symptom clusters. AB - INTRODUCTION: Few studies have examined the associations between posttraumatic stress disorder (PTSD) and non-medical opioid use (NMOU), particularly in general U.S. METHODS: We analyzed data from wave 2 of the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), a nationally representative sample of non-institutionalized adults, to examine (1) the relationship between PTSD diagnosis with NMOU, Opioid Use Disorder diagnosis, and average monthly frequency of NMOU; and (2) the relationship between PTSD symptom clusters with NMOU, Opioid Use Disorder diagnosis, and average monthly frequency of NMOU. We also explored sex differences among these associations. RESULTS: In the adjusted model, a past year PTSD diagnosis was associated with higher odds of past year NMOU for women and men, but the association was stronger for women. In addition, PTSD was associated with higher odds of an Opioid Use Disorder diagnosis for women, but not for men. With regard to the relationship between specific symptom clusters among those with a past year PTSD diagnosis, important sex differences emerged. For women, the avoidance symptom cluster was associated with higher odds of NMOU, an Opioid Use Disorder diagnosis, and higher rate of average monthly frequency of NMOU, while for men the arousal/reactivity cluster was associated with higher odds of NMOU, an Opioid Use Disorder diagnosis, and a higher rate of average monthly frequency of NMOU. In addition, for men, the avoidance symptom cluster was associated with higher odds of an Opioid Use Disorder diagnosis, but a lower rate of average monthly frequency of NMOU. CONCLUSIONS: Results add to the literature showing an association between PTSD and NMOU and suggest that PTSD is more strongly associated with substance use for women than men. Further, results based on individual symptom clusters suggest that men and women with PTSD may be motivated to use substances for different reasons. PMID- 26946449 TI - A man with "Abdominal" pain. PMID- 26946450 TI - Effectiveness of insulin therapy in people with Type 2 diabetes in the Hoorn Diabetes Care System. AB - AIMS: To identify HbA1c trajectories after the start of insulin treatment and to identify clinically applicable predictors of the response to insulin therapy. METHODS: The study population comprised 1203 people with Type 2 diabetes included in the Hoorn Diabetes Care System (n = 9849). Inclusion criteria were: age >= 40 years; initiation of insulin during follow-up after failure to reach HbA1c levels <= 53 mmol/mol (7%) with oral glucose-lowering agents; and a follow up >= 2 years after initiating insulin. Latent class growth modelling was used to identify trajectories of HbA1c . Subjects considered to be 'off target' had HbA1c levels >= 53 mmol/mol (7.0%) during one-third or more of the follow-up time, and those considered to be 'on target' had HbA1c levels >= 53 mmol/mol (7.0%) during less than one-third of the follow-up time. RESULTS: Four HbA1c trajectories were identified. Most people (88.7%) were classified as having a stable HbA1c trajectory of ~57 mmol/mol (7.4%). Only 24.4% of the people were on target in response to insulin; this was associated with lower HbA1c levels and a higher age at the start of insulin treatment. CONCLUSIONS: Using latent class growth modelling, four HbA1c trajectories were identified. A quarter of the people starting insulin were on target. Low HbA1c levels and advanced age at the start of insulin therapy were associated with better response to insulin therapy. Initiating insulin earlier improves the likelihood of achieving and sustaining glycaemic control. PMID- 26946452 TI - Health-adjusted neuropsychological test norms based on 463 older Swedish car drivers. AB - There is a need for improved normative information in particular for older persons. The present study provides neuropsychological test norms on seven cognitive tests used in a sample representing the general older driving population, when uncontrolled and controlled for physical health. A group of 463 healthy Swedish car drivers, aged 65 to 84 years, participated in a medical and neuropsychological examination. The latter included tests of visual scanning, mental shifting, visual spatial function, memory, reaction time, selective attention, and simultaneous capacity. Hierarchical regression analyses demonstrated that, when uncontrolled for health, old age was associated with significant impairment on all seven tests. Education was associated with a significant advantage for all tests except most reaction time subtests. Women outperformed men on selective attention. Controlling for health did not consistently change the associations with education, but generally weakened those with age, indicating rises in normative scores of up to 0.36 SD (residual). In terms of variance explained, impaired health predicted on average 2.5%, age 2.9%, education 2.1% and gender 0.1%. It was concluded (1) that individual regression based predictions of expected values have the advantage of allowing control for the impact of health on normative scores in addition to the adjustment for various demographic and performance-related variables and (2) that health adjusted norms have the potential to classify functional status more accurately, to the extent that these norms diverge from norms uncontrolled for physical health. PMID- 26946451 TI - Molecular adaptation of ammonia monooxygenase during independent pH specialization in Thaumarchaeota. AB - Microbes are abundant in nature and often highly adapted to local conditions. While great progress has been made in understanding the ecological factors driving their distribution in complex environments, the underpinning molecular evolutionary mechanisms are rarely dissected. Therefore, we scrutinized the coupling of environmental and molecular adaptation in Thaumarchaeota, an abundant archaeal phylum with a key role in ammonia oxidation. These microbes are adapted to a diverse spectrum of environmental conditions, with pH being a key factor shaping their contemporary distribution and evolutionary diversification. We integrated high-throughput sequencing data spanning a broad representation of ammonia-oxidizing terrestrial lineages with codon modelling analyses, testing the hypothesis that ammonia monooxygenase subunit A (AmoA) - a highly conserved membrane protein crucial for ammonia oxidation and classical marker in microbial ecology - underwent adaptation during specialization to extreme pH environments. While purifying selection has been an important factor limiting AmoA evolution, we identified episodic shifts in selective pressure at the base of two phylogenetically distant lineages that independently adapted to acidic conditions and subsequently gained lasting ecological success. This involved nonconvergent selective mechanisms (positive selection vs. selection acting on variants fixed during an episode of relaxed selection) leading to unique sets of amino acid substitutions that remained fixed across the radiation of both acidophilic lineages, highlighting persistent adaptive value in acidic environments. Our data demonstrates distinct trajectories of AmoA evolution despite convergent phenotypic adaptation, suggesting that microbial environmental specialization can be associated with diverse signals of molecular adaptation, even for marker genes employed routinely by microbial ecologists. PMID- 26946453 TI - Is middle childhood attachment related to social functioning in young adulthood? AB - The aim of the present study (N = 69) was to examine whether middle childhood attachment, measured using the Separation Anxiety Test (Slough, Goyette & Greenberg, 1988), predicts aspects of social functioning (social initiative, prosocial orientation, social anxiety, loneliness) in young adulthood. Insecurity avoidance at age 8.5 years was, as expected, negatively related to social initiative and prosocial orientation, and was also positively related to social anxiety and loneliness at age 21 years. In addition, insecurity-avoidance contributed to developmental change in social anxiety from middle childhood to young adulthood. Contrary to our expectations, the two security scales were generally unrelated to future social functioning. Taken together, these results extend previous research by showing that insecurity-avoidance is related to social functioning also beyond childhood and adolescence, and that it contributes to developmental change in social functioning over time. The scarcity of prospective links for the attachment security scales points to the need for future studies addressing when and why attachment does not contribute to future social functioning. PMID- 26946454 TI - Bystanders' responses to offline bullying and cyberbullying: The role of empathy and normative beliefs about aggression. AB - Cyberbullying often takes place with the virtual presence or knowledge of bystanders. While we have some evidence about the determinants of bystanders' responses to offline bullying, we lack empirical studies concerning the variables that influence bystanders' responses to cyberbullying. The current study examines bystanders' responses to offline bullying and cyberbullying incidents. Two types of responses were captured: support toward the victims and the reinforcement of bullies' actions. Using data from 321 German adolescents (ages 12-18; M = 14.99; 44% girls), the association between bystanders' responses and normative beliefs about verbal aggression and cyberaggression, and affective and cognitive empathy, were tested in a path model. Both types of normative beliefs positively predicted the reinforcement of bullies, and normative belief about verbal aggression also predicted support for the victims of offline bullying. Both types of empathy predicted support in offline bullying, but only affective empathy predicted support in cyberbullying. There was no link between affective or cognitive empathy to the reinforcement of bullies. Moreover, bystanders' tendencies to respond supportively to the victim or to reinforce the bully were rather consistent in both cyber- and offline bullying, but there was no link between support and reinforcement. The findings are discussed with regard to implications for prevention and intervention efforts. PMID- 26946455 TI - Universal parent support groups for parents of adolescents: Which parents participate and why? AB - Leader-led parent support groups, offered universally to parents of adolescents, are increasingly common, yet little is known of the parents who use this support. The study presented here explored the characteristics of parents of 10- to 17 year-olds (N = 192) who had enlisted in universal support groups and their reasons for enrollment. Sociodemographic factors (parents' country of origin, educational level, long-term sick-leave or unemployment, and marital status) were compared to the general population (Statistics Sweden, 2012) and parents' psychological health and children's psychiatric symptoms were compared to a control group (the BITA study). Results showed that support group parents reported more psychosocial difficulties, such as higher frequency of long-term sick-leave or unemployment, more symptoms of anxiety and depression and more psychiatric symptoms in their children than parents in general. While about a fifth of the parents had problem-oriented (targeted) reasons for enrollment, most parents had general (universal) reasons. Thus, the universal approach does seem to reach its intended recipients. PMID- 26946456 TI - Forest understory plant and soil microbial response to an experimentally induced drought and heat-pulse event: the importance of maintaining the continuum. AB - Drought duration and intensity are expected to increase with global climate change. How changes in water availability and temperature affect the combined plant-soil-microorganism response remains uncertain. We excavated soil monoliths from a beech (Fagus sylvatica L.) forest, thus keeping the understory plant microbe communities intact, imposed an extreme climate event, consisting of drought and/or a single heat-pulse event, and followed microbial community dynamics over a time period of 28 days. During the treatment, we labeled the canopy with (13) CO2 with the goal of (i) determining the strength of plant microbe carbon linkages under control, drought, heat and heat-drought treatments and (ii) characterizing microbial groups that are tightly linked to the plant soil carbon continuum based on (13) C-labeled PLFAs. Additionally, we used 16S rRNA sequencing of bacteria from the Ah horizon to determine the short-term changes in the active microbial community. The treatments did not sever within plant transport over the experiment, and carbon sinks belowground were still active. Based on the relative distribution of labeled carbon to roots and microbial PLFAs, we determined that soil microbes appear to have a stronger carbon sink strength during environmental stress. High-throughput sequencing of the 16S rRNA revealed multiple trajectories in microbial community shifts within the different treatments. Heat in combination with drought had a clear negative effect on microbial diversity and resulted in a distinct shift in the microbial community structure that also corresponded to the lowest level of label found in the PLFAs. Hence, the strongest changes in microbial abundances occurred in the heat-drought treatment where plants were most severely affected. Our study suggests that many of the shifts in the microbial communities that we might expect from extreme environmental stress will result from the plant-soil microbial dynamics rather than from direct effects of drought and heat on soil microbes alone. PMID- 26946457 TI - Brain development during adolescence: A mixed-longitudinal investigation of cortical thickness, surface area, and volume. AB - What we know about cortical development during adolescence largely stems from analyses of cross-sectional or cohort-sequential samples, with few studies investigating brain development using a longitudinal design. Further, cortical volume is a product of two evolutionarily and genetically distinct features of the cortex - thickness and surface area, and few studies have investigated development of these three characteristics within the same sample. The current study examined maturation of cortical thickness, surface area and volume during adolescence, as well as sex differences in development, using a mixed longitudinal design. 192 MRI scans were obtained from 90 healthy (i.e., free from lifetime psychopathology) adolescents (11-20 years) at three time points (with different MRI scanners used at time 1 compared to 2 and 3). Developmental trajectories were estimated using linear mixed models. Non-linear increases were present across most of the cortex for surface area. In comparison, thickness and volume were both characterised by a combination of non-linear decreasing and increasing trajectories. While sex differences in volume and surface area were observed across time, no differences in thickness were identified. Furthermore, few regions exhibited sex differences in the cortical development. Our findings clearly illustrate that volume is a product of surface area and thickness, with each exhibiting differential patterns of development during adolescence, particularly in regions known to contribute to the development of social cognition and behavioral regulation. These findings suggest that thickness and surface area may be driven by different underlying mechanisms, with each measure potentially providing independent information about brain development. Hum Brain Mapp 37:2027-2038, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26946458 TI - The Antiadhesive Strategy in Crohn's Disease: Orally Active Mannosides to Decolonize Pathogenic Escherichia coli from the Gut. AB - Blocking the adherence of bacteria to cells is an attractive complementary approach to current antibiotic treatments, which are faced with increasing resistance. This strategy has been particularly studied in the context of urinary tract infections (UTIs), in which the adhesion of pathogenic Escherichia coli strains to uroepithelial cells is prevented by blocking the FimH adhesin expressed at the tips of bacteria organelles called fimbriae. Recently, we extended the antiadhesive concept, showing that potent FimH antagonists can block the attachment of adherent-invasive E. coli (AIEC) colonizing the intestinal mucosa of patients with Crohn's disease (CD). In this work, we designed a small library of analogues of heptyl mannoside (HM), a previously identified nanomolar FimH inhibitor, but one that displays poor antiadhesive effects in vivo. The anomeric oxygen atom was replaced by a sulfur or a methylene group to prevent hydrolysis by intestinal glycosidases, and chemical groups were attached at the end of the alkyl tail. Importantly, a lead compound was shown to reduce AIEC levels in the feces and in the colonic and ileal mucosa after oral administration (10 mg kg(-1) ) in a transgenic mouse model of CD. The compound showed a low bioavailability, preferable in this instance, thus suggesting the possibility of setting up an innovative antiadhesive therapy, based on the water-soluble and non cytotoxic FimH antagonists developed here, for the CD subpopulation in which AIEC plays a key role. PMID- 26946459 TI - Physiological and behavioral responses to routine procedures in captive common marmosets (Callithrix jacchus). AB - The effect of routine captive procedures on the welfare of species used as experimental models in biomedical research is of great interest, since stress may alter the generalization and interpretation of results. This study investigated behavioral and endocrine (fecal cortisol) reactivity patterns in common marmoset (Callithrix jacchus) adult males (N = 10) and females (N = 9) subjected to three types of routine procedures in captivity: (1) moving to a same-sized cage (P1), to a smaller cage (P2), and (2) first-time pair formation (P3). Sexually dimorphic cortisol responses were detected in animals submitted to a physical environmental stressor (cage change). Females showed an increased response throughout P1, in relation to baseline (BP) cortisol, and a trend during P2. Males increased cortisol only during P2. On the other hand, males and females showed a similar endocrine response when management involved social challenge (pair formation), with both sexes increasing cortisol levels, but females exhibited a more intense and longer-lasting cortisol increase. Males and females exhibited similar behavioral responses to cage change, except for autogrooming, with males decreasing this behavior in P1. Only females demonstrated a significantly higher increase in piloerection frequency than that of males during the pair formation phase. These endocrine and behavioral changes must be taken into account when interpreting research data that involve these types of procedures. Further studies on the impacts of routine colony management are required to devise and include protocols in official husbandry guidelines. PMID- 26946460 TI - Cytokine Signatures Associated With Early Onset, Active Lesions and Late Cicatricial Events of Retinochoroidal Commitment in Infants With Congenital Toxoplasmosis. AB - BACKGROUND: Ocular toxoplasmosis is a prominent and severe condition of high incidence in Brazil. The current study provides new insights into the immunological events that can be associated with retinochoroiditis in the setting of congenital toxoplasmosis in human infants. METHODS: Flow cytometry of intracytoplasmic cytokines in leukocyte subsets following in vitro short-term antigenic recall in infants with congenital T. gondii infection. RESULTS: Our data demonstrates that whereas neutrophils and monocytes from T. gondii-infected infants display a combination of proinflammatory and regulatory cytokine profiles, natural killer cells showed a predominantly proinflammatory profile upon in vitro T. gondii stimulation. The proinflammatory response of CD4(+) and CD8(+) T cells, characterized by the production of interferon gamma (IFN-gamma) and interleukin 17 in patients with an active retinochoroidal lesion, revealed the presence of IFN-gamma and tumor necrosis factor alpha during early and late immunological events. This specific proinflammatory pattern is associated with early events and active retinochoroidal lesion, whereas a robust monocyte-derived interleukin 10-mediated profile is observed in children with cicatricial ocular lesions. CONCLUSIONS: These findings support the existence of a progressive immunological environment concomitant with the initial, apical, and cicatricial phases in the process of retinochoroidal lesion formation in infants with congenital toxoplasmosis that may be relevant in the establishment of stage specific clinical management. PMID- 26946461 TI - Platelet-Derived S100A8/A9 and Cardiovascular Disease in Systemic Lupus Erythematosus. AB - OBJECTIVE: Levels of S100A8/A9, a proinflammatory and prothrombotic protein complex, are increased in several diseases, and high levels predispose to cardiovascular disease (CVD). Recently, platelet S100A8/A9 synthesis was described in mice and humans in relation to CVD. The aim of this study was to investigate the role of platelet S100A8/A9 in systemic lupus erythematosus (SLE), a disease with markedly increased cardiovascular morbidity, as well as the exact platelet distribution of the S100A8/A9 proteins. METHODS: The occurrence and distribution of platelet S100A8/A9 protein were detected by enzyme-linked immunosorbent assay, electron microscopy, Western blotting, and flow cytometry in healthy controls (n = 79) and in 2 individual cohorts of SLE patients (n = 148 and n = 318, respectively) and related to cardiovascular morbidity. RESULTS: We observed that human platelets expressed S100A8/A9 proteins, and that these were localized in close proximity to intracellular membranes and granules as well as on the cell surface upon activation with physiologic and pathophysiologic stimuli. Interestingly, S100A8/A9 was enriched at sites of membrane interactions, indicating a role of S100A8/A9 in cell-cell communication. S100A8/A9 levels were highly regulated by interferon-alpha, both in vivo and in vitro. Patients with SLE had increased platelet S100A8/A9 content compared with healthy individuals. Increased levels of platelet S100A8/A9 were associated with CVD, particularly myocardial infarction (odds ratio 4.8, 95% confidence interval 1.5-14.9, P = 0.032 [adjusted for age, sex, and smoking]). CONCLUSION: Platelets contain S100A8/A9 in membrane-enclosed vesicles, enabling rapid cell surface deposition upon activation. Furthermore, platelet S100A8/A9 protein levels were increased in SLE patients, particularly in those with CVD, and may be a future therapeutic target. PMID- 26946462 TI - Visual outcomes with femtosecond laser-assisted cataract surgery versus conventional cataract surgery in toric IOL insertion. AB - BACKGROUND: To evaluate the visual outcomes of femtosecond laser-assisted cataract surgery (LCS) compared with phacoemulsification cataract surgery (PCS) in patients undergoing Toric IOL insertion. DESIGN: A non-randomized, single surgeon, prospective, comparative cohort case series PARTICIPANTS: Patients undergoing LCS and PCS between January 2012 and July 2014 at a single center. METHODS: The LCS group underwent femtosecond laser pretreatment for the anterior capsulotomy and lens fragmentation. Otherwise standard phacoemulsification surgery and foldable toric intraocular lens insertion proceeded. MAIN OUTCOME MEASURES: Best corrected visual acuity (BCVA), uncorrected visual acuity (UCVA), pre and post operative cylinder and mean absolute refractive error. RESULTS: A total of 418 eyes from 323 patients were included in the study; with 95 eyes in the PCS group and 323 in the LCS group. There were 243 (75.5%) LCS eyes with a pre-operative BCVA of 20/40 or better and 54 (56.8%) in the PCS group (p < 0.001). For post-operative BCVA, 315 (97.5 %) LCS and 81 (85.3%) PCS eyes had a BCVA of 20/40 or better (p = <0.001). However, there was no significant difference for change in BCVA between the groups (mean gain in EDTRS letter 11.0 for LCS and 10.3 for PCS p = 0.64) or in MAE (mean 0.56D PCS vs 0.65D LCS p = 0.18). CONCLUSION: In patients receiving toric intraocular lenses, there is similar improvement in terms of letters gained with LCS and PCS. Overall, there is no additional benefit for patients undergoing LCS in this cohort. PMID- 26946464 TI - STAT order: Should patients with chronic liver disease be prescribed statins to prevent fibrosis progression and hepatocellular carcinoma? PMID- 26946463 TI - Contribution to the anatomical nomenclature concerning general anatomy and anatomical variations. AB - Nomenclature of the general and variant anatomy belongs to the most neglected parts of the Latin anatomical nomenclature in Terminologia Anatomica. Although many important small structures are included in Terminologia Anatomica, when describing and teaching particular anatomy of any part of the human body, the general terms are necessary, such as planes, lines and flexion grooves. Moreover, Terminologia Anatomica contains only 149 terms of variant structures, enlisted in the parentheses to differentiate them from constant ones. They are only a rather representative selection and some more should be added, both from the educational and clinical point of view. The authors present some terms, completed with their definitions or explanations concerning the general and variant anatomy to evoke broader discussion on this topic which should issue in incorporation of proposed terms (or their equivalents) into the Terminologia Anatomica. PMID- 26946466 TI - Normothermic machine perfusion reduces bile duct injury and improves biliary epithelial function in rat donor livers. AB - Bile duct injury may occur during liver procurement and transplantation, especially in livers from donation after circulatory death (DCD) donors. Normothermic machine perfusion (NMP) has been shown to reduce hepatic injury compared to static cold storage (SCS). However, it is unknown whether NMP provides better preservation of bile ducts. The aim of this study was to determine the impact of NMP on bile duct preservation in both DCD and non-DCD livers. DCD and non-DCD livers obtained from Lewis rats were preserved for 3 hours using either SCS or NMP, followed by 2 hours ex vivo reperfusion. Biomarkers of bile duct injury (gamma-glutamyltransferase and lactate dehydrogenase in bile) were lower in NMP-preserved livers compared to SCS preserved livers. Biliary bicarbonate concentration, reflecting biliary epithelial function, was 2-fold higher in NMP-preserved livers (P < 0.01). In parallel with this, the pH of the bile was significantly higher in NMP-preserved livers (7.63 +/- 0.02 and 7.74 +/- 0.05 for non-DCD and DCD livers, respectively) compared with SCS-preserved livers (7.46 +/- 0.02 and 7.49 +/- 0.04 for non-DCD and DCD livers, respectively). Scanning and transmission electron microscopy of donor extrahepatic bile ducts demonstrated significantly decreased injury of the biliary epithelium of NMP-preserved donor livers (including the loss of lateral interdigitations and mitochondrial injury). Differences between NMP and SCS were most prominent in DCD livers. Compared to conventional SCS, NMP provides superior preservation of bile duct epithelial cell function and morphology, especially in DCD donor livers. By reducing biliary injury, NMP could have an important impact on the utilization of DCD livers and outcome after transplantation. Liver Transplantation 22 994-1005 2016 AASLD. PMID- 26946465 TI - Characterization of Notch Signaling During Osteogenic Differentiation in Human Osteosarcoma Cell Line MG63. AB - Osteogenic differentiation is a multi-step process controlled by a complex molecular framework. Notch is an evolutionarily conserved intercellular signaling pathway playing a prominent role in cell fate and differentiation, although the mechanisms by which this pathway regulates osteogenesis remain controversial. This study aimed to investigate, in vitro, the involvement of Notch pathway during all the developmental stages of osteogenic differentiation in human osteosarcoma cell line MG63. Cells were cultured in basal condition (control) and in osteoinductive medium (OM). Notch inhibitors were also added in OM to block Notch pathway. During osteogenic differentiation, early (alkaline phosphatase activity and collagen type I) and late osteogenic markers (osteocalcin levels and matrix mineralization), as well as the gene expression of the main osteogenic transcription factors (Runx2, Osterix, and Dlx5) increased. Time dependent changes in the expression of specific Notch receptors were identified in OM versus control with a significant reduction in the expression of Notch1 and Notch3 receptors in the early phase of differentiation, and an increase of Notch2 and Notch4 receptors in the late phase. Among Notch nuclear target genes, Hey1 expression was significantly higher in OM than control, while Hes5 expression decreased. Osteogenic markers were reduced and Hey1 was significantly inhibited by Notch inhibitors, suggesting a role for Notch through the canonical pathway. In conclusion, Notch pathway might be involved with a dual role in osteogenesis of MG63, through the activation of Notch2, Notch4, and Hey1, inducing osteoblast differentiation and the depression of Notch1, Notch3, and Hes5, maintaining an undifferentiated status. J. Cell. Physiol. 231: 2652-2663, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26946467 TI - Importance of the geographic barriers to promote gene drift and avoid pre- and post-Columbian gene flow in Mexican native groups: Evidence from forensic STR Loci. AB - OBJECTIVE: To analyze the origin, structure, relationships, and recent admixture in Mexican Native groups based on 15 STRs commonly used in human identification. METHODS: We analyzed 39 Mexican Native population samples using STR databases based on the AmpFlSTR(r) Identifiler kit (n = 3,135), including Mexican-Mestizos (admixed), European and African populations, as reference. RESULTS: Based upon effective population size (Ne) differences, Native groups were clustered into three regions: i) Center-Southeast groups, characterized by larger Ne, migration rate (Nm), genetic diversity (He), and relative homogeneity principally in the Yucatan Peninsula; ii) Isolated southern groups from Chiapas and Oaxaca, characterized by lower Ne, Nm, and He (i.e. higher isolation and genetic differentiation); iii) North-Northwest groups, which are similar to the previous group but are characterized by generating the widest gene flow barrier in the Pre Hispanic Mexican territory, and currently by elevated admixture in some northern Native groups. Despite the relative congruence between genetic relationships with cultural, linguistic, geographic criteria, these factors do not explain the present-day population structure of Native groups, excepting in those linguistically related to the Mayan that show higher homogeneity. The Isolation by distance model was demonstrated at long distances (>1,500 km), whereas geographic isolation stands as a determining factor to avoid both non-indigenous admixture and bottleneck processes. CONCLUSIONS: Different dynamics of gene flow and drift were observed among Mexican Native groups, highlighting the geographic barriers (mountains, canyons and jungle regions) as the main factor differentiating Pre-Hispanic populations, and eventually helping to avoid Post European contact admixture and population bottleneck. Am J Phys Anthropol 160:298 316, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26946468 TI - Salivary proteins of spider mites suppress defenses in Nicotiana benthamiana and promote mite reproduction. AB - Spider mites (Tetranychidae sp.) are widely occurring arthropod pests on cultivated plants. Feeding by the two-spotted spider mite T. urticae, a generalist herbivore, induces a defense response in plants that mainly depends on the phytohormones jasmonic acid and salicylic acid (SA). On tomato (Solanum lycopersicum), however, certain genotypes of T. urticae and the specialist species T. evansi were found to suppress these defenses. This phenomenon occurs downstream of phytohormone accumulation via an unknown mechanism. We investigated if spider mites possess effector-like proteins in their saliva that can account for this defense suppression. First we performed an in silico prediction of the T. urticae and the T. evansi secretomes, and subsequently generated a short list of candidate effectors based on additional selection criteria such as life stage specific expression and salivary gland expression via whole mount in situ hybridization. We picked the top five most promising protein families and then expressed representatives in Nicotiana benthamiana using Agrobacterium tumefaciens transient expression assays to assess their effect on plant defenses. Four proteins from two families suppressed defenses downstream of the phytohormone SA. Furthermore, T. urticae performance on N. benthamiana improved in response to transient expression of three of these proteins and this improvement was similar to that of mites feeding on the tomato SA accumulation mutant nahG. Our results suggest that both generalist and specialist plant-eating mite species are sensitive to SA defenses but secrete proteins via their saliva to reduce the negative effects of these defenses. PMID- 26946469 TI - A simple, flexible and high-throughput cloning system for plant genome editing via CRISPR-Cas system. AB - CRISPR-Cas9 system is now widely used to edit a target genome in animals and plants. Cas9 protein derived from Streptococcus pyogenes (SpCas9) cleaves double stranded DNA targeted by a chimeric single-guide RNA (sgRNA). For plant genome editing, Agrobacterium-mediated T-DNA transformation has been broadly used to express Cas9 proteins and sgRNAs under the control of CaMV 35S and U6/U3 promoter, respectively. We here developed a simple and high-throughput binary vector system to clone a 19-20 bp of sgRNA, which binds to the reverse complement of a target locus, in a large T-DNA binary vector containing an SpCas9 expressing cassette. Two-step cloning procedures: (1) annealing two target-specific oligonucleotides with overhangs specific to the AarI restriction enzyme site of the binary vector; and (2) ligating the annealed oligonucleotides into the two AarI sites of the vector, facilitate the high-throughput production of the positive clones. In addition, Cas9-coding sequence and U6/U3 promoter can be easily exchanged via the Gateway(TM) system and unique EcoRI/XhoI sites on the vector, respectively. We examined the mutation ratio and patterns when we transformed these constructs into Arabidopsis thaliana and a wild tobacco, Nicotiana attenuata. Our vector system will be useful to generate targeted large scale knock-out lines of model as well as non-model plant. PMID- 26946470 TI - Effect and Mechanism of QiShenYiQi Pill on Experimental Autoimmune Myocarditis Rats. AB - BACKGROUND: To observe the effect of QiShenYiQi pill (QSYQ) on experimental autoimmune myocarditis rats, and to explore its mechanism of action. MATERIAL/METHODS: Lewis rats underwent the injection of myocardial myosin mixed with Freund's complete adjuvant were randomized into 3 groups: model, valsartan, and QSYQ groups. Rats injected with phosphate-buffered saline (PBS) mixed with Freund's complete adjuvant were used as the control group. Rats were euthanized at 4 and 8 weeks, and we weighed rat body mass, heart mass, and left ventricular mass. Myocardium sections were stained with hematoxylin and eosin (H&E) and Masson trichrome. Myocardial TGF-beta1 and CTGF protein expression was detected by immunohistochemistry, and myocardial TGF-beta1 and CTGF mRNA expression was detected by real-time qPCR. RESULTS: QSYQ reduced HMI and LVMI, as well as the histological score of hearts and CVF, which further decreased over time, and its effect was significantly greater than that of valsartan at 4 and 8 weeks. After 4 weeks, QSYQ inhibited the protein and mRNA expression of TGF-beta1 and CTGF, and its effect on lowering CTGF was significantly greater than that of valsartan. In addition, after 8 weeks, QSYQ also inhibited the protein and mRNA expression of CTGF, whereas there was no significant difference in the expression of myocardial TGF-beta1. CONCLUSIONS: This study provides evidence that QSYQ can improve cardiac remodeling of experimental autoimmune myocarditis rats. It also effectively improved the degree of myocardial fibrosis, which is related to the mechanism of regulation of TGF-beta1 CTGF. PMID- 26946471 TI - Testing against "normal" with environmental data. AB - Normal ranges are some fraction of a reference distribution deemed to represent an expected condition, typically 95%. They are frequently used as the basis for generic criteria for monitoring programs designed to test whether a sample is outside of "normal," as in reference-condition approach studies. Normal ranges are also the basis for criteria for more classic environmental effects monitoring programs designed to detect differences in mean responses between reference and exposure areas. Limits on normal ranges are estimated with error that varies depending largely on sample size. Direct comparison of a sample or a mean to estimated limits of a normal range will, with some frequency, lead to incorrect conclusions about whether a sample or a mean is inside or outside the normal range when the sample or the mean is near the limit. Those errors can have significant costs and risk implications. This article describes tests based on noncentral distributions that are appropriate for quantifying the likelihood that samples or means are outside a normal range. These noncentral tests reverse the burden of evidence (assuming that the sample or mean is at or outside normal), and thereby encourage proponents to collect more robust sample sizes that will demonstrate that the sample or mean is not at the limits or beyond the normal range. These noncentral equivalence and interval tests can be applied to uni- and multivariate responses, and to simple (e.g., upstream vs downstream) or more complex (e.g., before vs after, or upstream vs downstream) study designs. Statistical procedures for the various tests are illustrated with benthic invertebrate community data collected as part of the Regional Aquatics Monitoring Program (RAMP) in the vicinity of oil sands operations in northern Alberta, Canada. An Excel workbook with functions and calculations to carry out the various tests is provided in the online Supplemental Data. Integr Environ Assess Manag 2017;13:188-197. (c) 2016 SETAC. PMID- 26946472 TI - Liver metastases from gastric cancer represent systemic disease in comparison with those from colorectal cancer. AB - BACKGROUND: The aim of this retrospective study was to clarify the difference in behavior and outcome after initial hepatectomy between gastric cancer liver metastases (GCLM) and colorectal cancer liver metastases (CCLM). METHODS: Data for patients undergoing curative hepatectomy for liver-only metastases from colorectal cancer (n = 193) and gastric cancer (n = 26) performed at single institution with the same criteria regarding the status of liver metastases were reviewed. Post-hepatectomy recurrence pattern, re-resection for recurrence, and three different endpoints were evaluated. RESULTS: There was no significant difference between the GCLM and the CCLM in the incidence of recurrence (69% vs. 63%, P = 0.553) and recurrence-free survival (median, 15.2 months vs. 16.5 months, P = 0.230) following initial hepatectomy for liver metastases. However, the GCLM had a higher frequency of systemic unresectable recurrences than the CCLM. Time to surgical failure (median, 15.2 months vs. 39.7 months, P = 0.006) and overall survival (median, 20.1 months vs. 66.2 months, P < 0.001) were significantly shorter in the GCLM than in the CCLM. CONCLUSIONS: GCLM shows more systemic and aggressive oncological behavior than CCLM after curative hepatectomy even when metastases are confined only to the liver at the time of initial hepatectomy. PMID- 26946473 TI - Lateral Epicondylitis and Physical Exposure at Work? A Review of Prospective Studies and Meta-Analysis. AB - OBJECTIVE: In view of recent published studies, a meta-analysis was undertaken on prospective studies in order to assess any association between lateral epicondylitis and physical exposure at work. METHODS: Using the key words "lateral epicondylitis" AND "occupational" AND ("cohort" OR "longitudinal," OR "incidence") without limitations on the language or year of publication, original prospective studies were selected from 4 databases (PubMed, Scopus, Web of Science, and Base de Donnees de Sante Publique) after 2 rounds (valid design, valid association reported, and valid work exposure). Relevant associations between physical exposure at work and incident lateral epicondylitis were extracted from the articles, and a meta-risk was calculated using the generic variance approach (meta-odds ratios [meta-ORs]). RESULTS: From 2001 to 2014, 5 prospective studies were included. Among 6,922 included subjects (and 3,449 who were followed), 256 cases of incident lateral epicondylitis were diagnosed 2.5-6 years after baseline. All the published studies found a significant estimation of relative risk for a positive association between combined biomechanic exposure involving the wrist and/or elbow and incidence of lateral epicondylitis. The overall meta-OR was 2.6 (95% confidence interval 1.9-3.5), with a low heterogeneity (Q = 1.4, P > 0.05). Funnel plots and Egger's test did not suggest major publication bias. CONCLUSION: The results of this meta-analysis strongly support the hypothesis of an association between biomechanic exposure involving the wrist and/or elbow at work and incidence of lateral epicondylitis. PMID- 26946474 TI - A note comparing the welfare of Zebu cattle following three stunning-slaughter methods. AB - The objective of this study was to assess welfare of cattle during bleeding after slaughter with or without stunning. A total of 434 bulls were distributed across three slaughter treatments: penetrating captive bolt stunning followed by chest sticking (PCB, N=279), non-penetrating captive bolt stunning followed by halal slaughter (NPCB, N=67) and shechita without previous stunning (SHE, N=88). Four measures of possible consciousness and return to sensibility were recorded 20 and 60 s after bleeding as welfare indicators. They were the frequencies of responses to nostril stimulation and tongue pinch, spontaneous eye blinking, and rhythmic breathing. All responses were absent in stunned cattle at both 20 and 60 s, and in SHE cattle 7, 4, 10, and 100% of the animals presented these responses, respectively. Repeat shots were required for 46% NPCB and 2% PCB (P<0.05). The application of religious slaughter without previous stunning may result in greater risk of cattle suffering, pain and distress at slaughter. PMID- 26946475 TI - Association of single nucleotide polymorphisms in CAPN1, CAST and MB genes with meat color of Brahman and crossbreed cattle. AB - The objective of this research was to determine the association of SNPs in the candidate genes Calpain (CAPN1), Calpastatin (CAST) and Myoglobin (MB) with colorimetric parameters (L *, a *, b *, C *, hue) in a F1 population (n = 164) obtained from crossing Bos taurus * Bos indicus and Bos indicus * Bos indicus. SNPs were analyzed using PCR-RFLP and SSCP. Colorimetric measurements were performed in the muscles Longissimus thoracis et lumborum (LTL) and Semitendinosus (ST) at 7, 14 and 21 days postmortem applying the methodology CIE L* a* b*. The CAST gene showed a significant effect on the b* and hue* parameters in both muscles. MB gene showed significant association with all colorimetric parameters in both LTL and ST muscles, except with b* parameter. The CAPN1 gene did not show any significant association. These results suggest an important role of genetics in meat color variation for cattle raised under the tropic conditions. PMID- 26946476 TI - Effect of packaging atmospheres on storage quality characteristics of heavily marbled beef longissimus steaks. AB - The objective of this study was to investigate the effects of modified atmosphere packaging (MAP) systems on shelf-life and quality of beef steaks with high marbling. Four packaging types were used including 80% O2 MAP (80% O2+20% CO2), 50% O2 MAP (50% O2+30% CO2+20% N2), carbon monoxide MAP (0.4% CO+30% CO2+69.6% N2) and vacuum packaging (VP). Steaks were displayed under simulated retail conditions at 4 degrees C for 12days. Purge loss, pH, color stability, oxidative stability and microbial counts were monitored. Aerobically packaged steaks exhibited a bright-red color at the first 4days. However, discoloration and oxidation became major factors limiting their shelf-life to 8days. Compared with aerobic packaging, anaerobic packaging extended shelf-life of heavily marbled beef steaks, due to better color stability, together with lower oxidation and microbial populations. Among all packaging methods, CO-MAP had the best preservation for steaks, with more red color than other packaging types. PMID- 26946477 TI - Inhibitory effects of apple peel polyphenol extract on the formation of heterocyclic amines in pan fried beef patties. AB - The efficacy of polyphenol-rich dried apple peel extract (DAPP) to inhibit the formation of heterocyclic aromatic amines (HCAs) during frying of beef patties was assessed after DAPP was applied at 0.1, 0.15 and 0.3% (w/w) either on the surface of the patties or mixed inside the patty prior to frying. 2-Amino-3,8 dimethylimidazo[4,5f]quinoxaline (MeIQx), 2-amino-1-ethyl-6-phenylimidazo[4,5 b]pyridine (PhIP) and 2-amino-3,4,8-dimethylimidazo[4,5-f]quinoxaline (4,8 DiMeIQx) were quantified after frying. HCA concentrations decreased (p<0.05) upon both surface and mixed applications of DAPP at all of the tested doses. Surface application of 0.3% DAPP showed greater (p<0.05) inhibitory effects on HCA formation by 68% for MeIQx, 56% for 4,8-DiMeIQx and 83% for PhIP as opposed to 41%, 21% and 60% respectively, for the mixed DAPP application of 0.3%. The present study results indicate that surface application of DAPP in meat preparation prior to pan-frying can be a useful approach to minimize the formation of genotoxic HCAs in fried beef patties. PMID- 26946478 TI - Effects of soy hull pectin and insoluble fiber on physicochemical and oxidative characteristics of fresh and frozen/thawed beef patties. AB - The objective of this study was to determine the effects of pectin and insoluble fiber isolated from soy hulls on water-holding capacity (WHC), texture, color, and lipid oxidation of fresh and frozen/thawed beef patties. Beef patties were formulated with no dietary fiber (control), 1% soy hull pectin, insoluble fiber, or their mixture (1:1), respectively. The addition of soy hull pectin significantly decreased display weight loss and increased cook yield of both fresh and frozen/thawed beef patties. In addition, no significant difference in hardness between fresh and frozen/thawed beef patties was observed for all dietary fiber treatments. However, incorporation of insoluble soy hull fiber decreased color and lipid oxidation stabilities of both fresh and frozen/thawed beef patties. Our results indicate that the incorporation of soy hull pectin could be an effective non-meat ingredient to minimize water loss and hardness defects of frozen beef patties. PMID- 26946479 TI - Understanding consumers' perception of lamb meat using free word association. AB - The aims of the present study were to gather information about Brazilian consumers' perception of lamb meat and to study whether the perception is affected by the consumption frequency of this type of meat. A total of 1025 Brazilian consumers completed word association task with lamb meat. The elicited words were analyzed using inductive coding. Participants' associations with lamb meat were mainly related to sensory characteristics and hedonic attitudes and feelings, indicating that they might be the main motivations for consuming this product. Participants strongly associated lamb meat with special consumption occasions, which suggests that lack of perceived appropriateness for everyday consumption situations might be a barrier for increasing lamb meat consumption. Conceptualization of lamb meat was strongly affected by frequency of consumption of this product. Results from the present work provide a comprehensive insight on Brazilian consumers' perception of lamb meat, which can be used to develop strategies to increase its consumption and improve profitability. PMID- 26946480 TI - Esomeprazole, minocycline, metronidazole and bismuth as first-line and second line regimens for Helicobacter pylori eradication. AB - OBJECTIVE: Whether minocycline can replace tetracycline in Helicobacter pylori (H. pylori) eradication remains unclear. The aim of this study was to determine the efficacy, safety, patient compliance and risk factors of a combination regimen of esomeprazole, minocycline, metronidazole and bismuth (EMMB) for H. pylori eradication. METHODS: In this prospective single-center study, 152 patients in the first-line therapy group and 64 in the second-line therapy group received EMMB therapy (esomeprazole 20 mg twice daily, minocycline 100 mg twice daily, metronidazole 400 mg four times daily and bismuth potassium citrate 110 mg four times daily) for 14 days. The eradication outcome was assessed by (13) C urea breath test 6-12 weeks after treatment. RESULTS: EMMB therapy achieved eradication rates of 85.5% [95% confidence interval (CI) 79.6-91.4%] using intention-to-treat (ITT) analysis, 90.3% (95% CI 84.7-95.1%) using modified intention-to-treat (mITT) analysis and 92.6% (95% CI 88.1-96.3%) using per protocol (PP) analysis as the first-line therapy; and 82.8% (95% CI 71.9-90.6%), 86.9% (95% CI 77.1-95.1%) and 89.5% (95% CI 80.7-96.5%) as the second-line therapy, respectively. In the first-line group, 35.6% of the patients experienced adverse effects, 4.7% discontinued medications because of adverse effects and good compliance was achieved in 91.3%, while the results were 36.5%, 3.2% and 90.5% in the second-line therapy group. Poor compliance was identified as an independent predictor of treatment failure. CONCLUSION: The efficacy of EMMB therapy for H. pylori eradication as first-line and second-line regimens in a region with high rates of antibiotic resistance is satisfactory with relatively good patient compliance and high safety. PMID- 26946481 TI - CLAPO syndrome: case report. PMID- 26946482 TI - Tonsillectomy and inflammatory bowel disease: a meta-analysis. AB - AIM: The pathogenesis of inflammatory bowel diseases remains unclear. Genetic and environmental factors are involved. Studies of the association between tonsillectomy and inflammatory bowel disease have yielded conflicting results. METHOD: PubMed and EMBASE were searched to identify studies evaluating the association between tonsillectomy and inflammatory bowel disease [Crohn's disease (CD) and ulcerative colitis (UC)]. Odds ratios with 95% CI were calculated using a random- or fixed-effects model. The chi(2) test and I(2) test were used to assess homogeneity. Egger's test was used to evaluate publication bias. RESULTS: Thirteen observational case-control studies including 4122 patients (3035 UC/1087 CD) and 5103 controls were analysed. The summary odds ratio estimated for UC following a tonsillectomy was 0.932, 95% CI 0.819-1.062. The odds ratio for CD following a tonsillectomy was 1.194, 95% CI 0.992-1.437. Publication bias was not detected (Egger's test coefficient -3.50 to 1.55; P = 0.39). CONCLUSION: No obvious association between tonsillectomy and inflammatory bowel disease was identified in our meta-analysis. PMID- 26946483 TI - Innate immunity regulates alpha-synuclein clearance. PMID- 26946484 TI - Role of Anti-Carbamylated Protein Antibodies Compared to Anti-Citrullinated Protein Antibodies in Indigenous North Americans With Rheumatoid Arthritis, Their First-Degree Relatives, and Healthy Controls. AB - OBJECTIVE: Rheumatoid arthritis (RA) is characterized by the presence of autoantibodies, including seropositivity for rheumatoid factor (RF) and anti citrullinated protein antibodies (ACPAs). In addition, antibodies to carbamylated proteins (anti-CarP) are present in patients with RA and are associated with joint damage. This study was undertaken to assess the presence of anti-CarP antibodies in indigenous North Americans (First Nations [FN] populations) with RA compared to their at-risk first-degree relatives (FDRs) and healthy controls. METHODS: Anti-CarP IgG and ACPAs (specifically, anti-cyclic citrullinated peptide [anti-CCP] antibodies) were measured by enzyme-linked immunosorbent assay in the sera of FN patients with RA (n = 95), their unaffected FDRs (n = 109), and healthy FN controls (n = 85). Antibodies to additional citrullinated peptides were measured using a multiplex ACPA array, and the number of peptides recognized was reported as an ACPA score. Groups were compared using the chi-square test and Mann-Whitney U test. Associations between RA and seropositivity for RF, ACPAs, and anti-CarP antibodies were determined by logistic regression. RESULTS: Anti CarP antibodies were more frequent in FN patients with RA (44.3%) compared to FDRs (18.3%) and FN controls (4.7%) (both P < 0.0001 versus RA). Moreover, anti CarP antibodies were more frequent in FDRs than in FN controls (P = 0.008). The ACPA score was higher in anti-CCP-positive FN patients with RA than in anti-CCP positive FN FDRs (median score 7 [interquartile range (IQR) 7] versus median score 1 [IQR 4]; P = 0.04). The association with RA was strongest when all 3 autoantibodies (RF, anti-CCP, and anti-CarP) were present in the patients' serum (odds ratio 194, 95% confidence interval 23-1,609, P < 0.0001). CONCLUSION: Anti CarP antibodies are prevalent in FN patients with RA and also more common in their at-risk FDRs compared to healthy controls. The results indicate an association of RF, ACPAs, and anti-CarP with RA that is strongest when all 3 autoantibodies are present. These findings may provide new insights into the evolution of autoimmunity in preclinical RA. PMID- 26946486 TI - Residual symptoms and specific functional impairments in euthymic patients with bipolar disorder. AB - OBJECTIVES: The aims of the present study were to confirm the impact of residual symptoms on overall functioning in a large sample of euthymic patients with bipolar disorder in real-life conditions and to explore the relationship between residual symptoms and specific areas of functional impairment. METHODS: This was a multicenter, cross-sectional, non-interventional study of euthymic outpatients with bipolar disorder. The Functioning Assessment Short Test was used to assess overall and specific domains of functioning (autonomy, occupational functioning, cognitive functioning, financial issues, interpersonal relationships, and leisure time). Various residual symptoms were assessed (residual mood symptoms, emotional dysregulation, sleep and sexual disorders, stigma, and perceived cognitive impairment). Logistic regression was used to determine the best model of association between functional domains and residual symptoms. RESULTS: Almost half of the 468 patients included (42%) had poor overall functioning. Residual depressive symptoms appeared to have an impact on overall functioning and in nearly all areas of functioning. In addition, specific residual symptoms had significantly more negative effects on some domains of functioning in euthymic patients with bipolar disorder (residual manic symptoms and occupational stigma on autonomy, emotional inhibition on occupational functioning, residual manic symptoms on financial issues, family stigma on interpersonal relationships, and sexual function and occupational stigma on leisure time). CONCLUSIONS: Our findings highlight the importance of evaluating overall functioning in clinical practice as well as functional domains. They also indicate that some residuals symptoms in patients with bipolar disorder should be targeted in personalized treatment plans, in order to improve functioning in the domains in which the patient is most impaired. PMID- 26946485 TI - Management of erythematous skin lesions in bullous pemphigoid associated with atopic dermatitis. PMID- 26946487 TI - Effect of dietary protein sources on the small intestine microbiome of weaned piglets based on high-throughput sequencing. AB - In this study, we comprehensively investigated the effect of dietary protein sources on the gut microbiome of weaned piglets with diets comprising different protein source using High-throughput 16SrRNA gene-based Illumina Miseq. A total of 48 healthy weaned piglets were allocated randomly to four treatments with 12 piglets in each group. The weaned piglets were fed with diets containing soybean meal (SBM), cottonseed meal (CSM), SBM and CSM (SC) or fish meal (FM). The intestinal content samples were taken from five segments of the small intestine. DNA was extracted from the samples and the V3-V4 regions of the 16SrRNA gene were amplified. The microbiota of the contents of the small intestine were very complex, including more than 4000 operational taxonomic units belonging to 32 different phyla. Four bacterial populations (i.e. Firmicutes, Proteobacteria, Bacteroidetes and Acidobacteria) were the most abundant bacterial groups. The genera Lactobacillus and Clostridium were found in slightly higher proportions in the groups with added CSM compared to the other groups. The proportion of reads assigned to the genus Escherichia/Shigella was much higher in the FM group. In conclusion, dietary protein source had significant effects on the small microbiome of weaned piglets. SIGNIFICANCE AND IMPACT OF THE STUDY: Dietary protein source have the potential to affect the small intestine microbiome of weaned piglets that will have a large impact on its metabolic capabilities and intestinal health. In this study, we successfully identified the microbiomes in the contents of the small intestine in the weaned piglets that were fed different protein source diets using high-throughput sequencing. The finding provided an evidence for the option of the appropriate protein source in the actual production. PMID- 26946488 TI - 4-Aminopyridine Induced Activity Rescues Hypoexcitable Motor Neurons from Amyotrophic Lateral Sclerosis Patient-Derived Induced Pluripotent Stem Cells. AB - Despite decades of research on amyotrophic lateral sclerosis (ALS), there is only one approved drug, which minimally extends patient survival. Here, we investigated pathophysiological mechanisms underlying ALS using motor neurons (MNs) differentiated from induced pluripotent stem cells (iPSCs) derived from ALS patients carrying mutations in FUS or SOD1. Patient-derived MNs were less active and excitable compared to healthy controls, due to reduced Na(+) /K(+) ratios in both ALS groups accompanied by elevated potassium channel (FUS) and attenuated sodium channel expression levels (FUS, SOD1). ALS iPSC-derived MNs showed elevated endoplasmic reticulum stress (ER) levels and increased caspase activation. Treatment with the FDA approved drug 4-Aminopyridine (4AP) restored ion-channel imbalances, increased neuronal activity levels and decreased ER stress and caspase activation. This study provides novel pathophysiological data, including a mechanistic explanation for the observed hypoexcitability in patient derived MNs and a new therapeutic strategy to provide neuroprotection in MNs affected by ALS. Stem Cells 2016;34:1563-1575. PMID- 26946490 TI - Incidence of apparent life-threatening events and post-neonatal risk factors. AB - AIM: Even though a standard clinical definition for an apparent life-threatening event (ALTE) was established more than two decades ago, the specific International Classification of Disease (ICD) code was firstly included only in 2012. This study estimated the incidence of ALTEs in Northern Italy, together with features and risk factors. METHODS: We used the Lombardy Region Hospital Discharge Records (HDR) database to estimate the cumulative incidence for ALTE during 2002-2006 and drew up a risk profile by comparing cases with and without ALTE who were followed in infancy. RESULTS: There were 246 infants registered in the HDR with ALTE putative diagnostic codes, suggesting a cumulative incidence of 4.1 per 1000 live births in the study area. Of the 148 cases with clinical co morbidities, 31% had gastroesophageal reflux and 7% had acute respiratory infections. We analysed follow-up data from 15 ALTE cases and 1619 healthy infants and found that the significant risk factors were gastroesophageal reflux and a family history of sudden death. CONCLUSION: We established the regional incidence of ALTE and found risk factors in infants considered healthy in the first week of life and without pathological perinatal conditions. The systematic use of the specific ALTE ICD code (R68.13, ICD-10-CM) and common knowledge about ALTE diagnostic guidelines are clearly needed. PMID- 26946489 TI - Baseline features and differences in 48 week clinical outcomes in patients with gastroparesis and type 1 vs type 2 diabetes. AB - BACKGROUND: In studies of diabetic gastroparesis, patients with type 1 and type 2 diabetes mellitus (T1DM, T2DM) are often combined for analyses. We compared gastroparesis severity, healthcare utilization, psychological function, and quality of life in T1DM vs T2DM gastroparesis patients. METHODS: Questionnaire, laboratory, and scintigraphy data from patients with gastroparesis and T1DM and T2DM from seven centers of the National Institute of Diabetes and Digestive and Kidney Diseases Gastroparesis Clinical Research Consortium Registry were compared at enrollment and after 48 weeks. Multiple regression models assessed baseline and follow-up differences between diabetes subtypes. KEY RESULTS: At baseline, T1DM patients (N = 78) had slower gastric emptying, more hospitalizations, more gastric stimulator implantations, higher hemoglobin A1c (HbA1c), and more anxiety vs T2DM patients (N = 59). Independent discriminators of patients with T1DM vs T2DM included worse gastroesophageal reflux disease, less bloating, more peripheral neuropathy, and fewer comorbidities (p <= 0.05). On follow-up, gastrointestinal (GI) symptom scores decreased only in T2DM (p < 0.05), but not in T1DM patients who reported greater prokinetic, proton pump inhibitor, anxiolytic, and gastric stimulator usage over 48 weeks (p <= 0.03). Gastrointestinal symptoms at baseline and 48 weeks with both subtypes were not associated with HbA1c, peripheral neuropathy, psychological factors, or quality of life. CONCLUSIONS & INFERENCES: Baseline symptoms were similar in T1DM and T2DM patients, even though T1DM patients had worse gastric emptying delays and higher HbA1c suggesting other factors mediate symptom severity. Symptom scores at 48 weeks decreased in T2DM, but not T1DM patients, despite increased medical and surgical treatment utilization by T1DM patients. Defining causes of different outcomes in diabetic gastroparesis warrants further investigation. PMID- 26946491 TI - Enzymatic formation of carbohydrate rings catalyzed by single-walled carbon nanotubes. AB - Macrocyclic carbohydrate rings were formed via enzymatic reactions around single walled carbon nanotubes (SWNTs) as a catalyst. Cyclodextrin glucanotransferase, starch substrate and SWNTs were reacted in buffer solution to yield cyclodextrin (CD) rings wrapped around individual SWNTs. Atomic force microscopy showed the resulting complexes to be rings of 12-50 nm in diameter, which were highly soluble and dispersed in aqueous solution. They were further characterized by Raman and Fourier transform infrared spectroscopy and molecular simulation using density functional theory calculation. In the absence of SWNT, hydrogen bonding between glucose units determines the structure of maltose (the precursor of CD) and produces the curvature along the glucose chain. Wrapping SWNT along the short axis was preferred with curvature in the presence of SWNTs and with the hydrophobic interactions between the SWNTs and CD molecules. This synthetic approach may be useful for the functionalization of carbon nanotubes for development of nanostructures. PMID- 26946492 TI - Efficient production of alpha-ketoglutarate in the gdh deleted Corynebacterium glutamicum by novel double-phase pH and biotin control strategy. AB - Production of L-glutamate using a biotin-deficient strain of Corynebacterium glutamicum has a long history. The process is achieved by controlling biotin at suboptimal dose in the initial fermentation medium, meanwhile feeding NH4OH to adjust pH so that alpha-ketoglutarate (alpha-KG) can be converted to L-glutamate. In this study, we deleted glutamate dehydrogenase (gdh1 and gdh2) of C. glutamicum GKG-047, an L-glutamate overproducing strain, to produce alpha-KG that is the direct precursor of L-glutamate. Based on the method of L-glutamate fermentation, we developed a novel double-phase pH and biotin control strategy for alpha-KG production. Specifically, NH4OH was added to adjust the pH at the bacterial growth stage and NaOH was used when the cells began to produce acid; besides adding an appropriate amount of biotin in the initial medium, certain amount of additional biotin was supplemented at the middle stage of fermentation to maintain a high cell viability and promote the carbon fixation to the flux of alpha-KG production. Under this control strategy, 45.6 g/L alpha-KG accumulated after 30-h fermentation in a 7.5-L fermentor and the productivity and yield achieved were 1.52 g/L/h and 0.42 g/g, respectively. PMID- 26946494 TI - Thoracolumbar paravertebral giant ganglioneuroma and scoliosis: a case report and literature review. AB - Paravertebral ganglioneuroma and scoliosis is a rare clinical benign disease. The case we reported is about a 12-year-old girl who was hospitalized due to neoplasm with spinal deformity in the right abdomen for 1 month. Based on a careful preoperative evaluation and found no obvious surgery contraindications, the patient was treated with surgical resection of the tumor and correction of the deformity by surgery. Postoperative pathologic examination confirmed it was a ganglioneuroma. After the operation, the patient recovered well. Her spinal deformity was corrected, and she was 5 cm taller. Complete resection of ganglioneuroma following with a low recurrence rate and a good prognosis, patient does not need further chemotherapy, radiation therapy, or other treatments. All follow-up radiographic studies demonstrated no relapse of the tumor in the following 18 months. Combining this case with similar cases at home and aboard and reviewing related literature, we formed conclusions based on the manifestations, diagnosis, treatment, and prognosis of this disease and provided treatments for similar cases. PMID- 26946495 TI - Forensic analysis of tertiary-butyl alcohol (TBA) detections in a hydrocarbon rich groundwater basin. AB - Tertiary-butyl alcohol (TBA), a high-production volume (HPV) chemical, was sporadically detected in groundwater and coalbed methane (CBM) wells in southeastern Colorado's hydrocarbon-rich Raton Basin. TBA concentrations in shallow water wells averaged 75.1 MUg/L, while detections in deeper CBM wells averaged 14.4 MUg/L. The detection of TBA prompted a forensic investigation to try to identify potential sources. Historic and recent data were reviewed to determine if there was a discernable pattern of TBA occurrence. Supplemental samples from domestic water wells, monitor wells, CBM wells, surface waters, and hydraulic fracturing (HF) fluids were analyzed for TBA in conjunction with methyl tertiary-butyl ether (MTBE) and ethyl tertiary-butyl ether (ETBE), proxies for evidence of contamination from reformulated gasoline or associated oxygenates. Exploratory microbiological sampling was conducted to determine if methanotrophic organisms co-occurred with TBA in individual wells. Meaningful comparisons of historic TBA data were limited due to widely varying reporting limits. Mapping of TBA occurrence did not reveal any spatial patterns or physical associations with CBM operations or contamination plumes. Additionally, TBA was not detected in HF fluids or surface water samples. Given the widespread use of TBA in industrial and consumer products, including water well completion materials, it is likely that multiple diffuse sources exist. Exploratory data on stable isotopes, dissolved gases, and microbial profiling provide preliminary evidence that methanotrophic activity may be producing TBA from naturally occurring isobutane. Reported TBA concentrations were significantly below a conservative risk-based drinking water screening level of 8000 MUg/L derived from animal toxicity data. PMID- 26946493 TI - Loss of IkappaB kinase beta promotes myofibroblast transformation and senescence through activation of the ROS-TGFbeta autocrine loop. AB - Using forward and reverse genetics and global gene expression analyses, we explored the crosstalk between the IkappaB kinase beta (IKKbeta) and the transforming growth factor beta (TGFbeta) signaling pathways. We show that in vitro ablation of Ikkbeta in fibroblasts led to progressive ROS accumulation and TGFbeta activation, and ultimately accelerated cell migration, fibroblast myofibroblast transformation and senescence. Mechanistically, the basal IKKbeta activity was required for anti-oxidant gene expression and redox homeostasis. Lacking this activity, IKKbeta-null cells showed ROS accumulation and activation of stress-sensitive transcription factor AP-1/c-Jun. AP-1/c-Jun activation led to up-regulation of the Tgfbeta2 promoter, which in turn further potentiated intracellular ROS through the induction of NADPH oxidase (NOX). These data suggest that by blocking the autocrine amplification of a ROS-TGFbeta loop IKKbeta plays a crucial role in the prevention of fibroblast-myofibroblast transformation and senescence. PMID- 26946497 TI - Vestibular contribution to three-dimensional dynamic (allocentric) and two dimensional static (egocentric) spatial memory. PMID- 26946496 TI - Monomelic amyotrophy in cervical myelopathy associated with anterior dural sac displacement induced by neck flexion. PMID- 26946498 TI - Ophthalmoplegia heralding the onset of anti-amphiphysin related paraneoplastic stiff person syndrome. PMID- 26946500 TI - Characterization of bacterial communities in lithobionts and soil niches from Victoria Valley, Antarctica. AB - Here we provide the first exploration of microbial diversity from three distinct Victoria Valley edaphic habitats, namely lithobionts (hypoliths, endoliths) and surface soils. Using a combination of terminal restriction fragment length polymorphism (T-RFLP) analysis and 16S rRNA gene amplicon pyrosequencing we assess community structure and diversity patterns, respectively. Our analysis revealed that habitat type (endolithic versus hypolithic versus surface soils) significantly influenced bacterial community composition, even though dominant phyla such as Actinobacteria (41% of total reads) were common to all samples. Consistent with previous surveys in other Dry Valley ecosystems, we found that lithobionts were colonized by a few highly dominant phylotypes (such asGemmatimonasandLeptolyngbya). Our analyses also show that soil bacteria were more diverse and evenly distributed than initially expected based on previous evidence. In contrast to total bacteria, the distribution of Cyanobacteria was not strongly influenced by habitat type, although soil- and endolith-specific cyanobacterial lineages were found. The detection of cyanobacterial lineages in these habitats appears to be influenced by the dispersal of aquatic inocula from lacustrine communities or benthic mats which are abundant in Victoria Valley. Together, our results provide insights into the phylogenetic variation and community structure across niche habitats in Victoria Valley. PMID- 26946499 TI - Association between i.v. thrombolysis volume and door-to-needle times in acute ischemic stroke. AB - Centralization of intravenous thrombolysis (IVT) for acute ischemic stroke in high-volume centers is believed to improve the door-to-needle times (DNT), but limited data support this assumption. We examined the association between DNT and IVT volume in a large Dutch province. We identified consecutive patients treated with IVT between January 2009 and 2013. Based on annualized IVT volume, hospitals were categorized as low-volume (<= 24), medium-volume (25-49) or high-volume (>= 50). In logistic regression analysis, low-volume hospitals were used as reference category. Of 17,332 stroke patients from 11 participating hospitals, 1962 received IVT (11.3 %). We excluded 140 patients because of unknown DNT (n = 86) or in-hospital stroke (n = 54). There were two low-volume (total 101 patients), five medium-volume (747 patients) and four high-volume hospitals (974 patients). Median DNT was shorter in high-volume hospitals (30 min) than in medium-volume (42 min, p < 0.001) and low-volume hospitals (38 min, p < 0.001). Patients admitted to high-volume hospitals had a higher chance of DNT < 30 min (adjusted OR 3.13, 95 % CI 1.70-5.75), lower risk of symptomatic intracerebral hemorrhage (adjusted OR 0.39, 95 % CI 0.16-0.92), and a lower mortality risk (adjusted OR 0.45, 95 % CI 0.21-1.01), compared to low-volume centers. There was no difference in DNT between low- and medium-volume hospitals. Onset-to-needle times (ONT) did not differ between the groups. Hospitals in this Dutch province generally achieved short DNTs. Despite this overall good performance, higher IVT volumes were associated with shorter DNTs and lower complication risks. The ONT was not associated with IVT volume. PMID- 26946501 TI - Neuroimaging-Based Phenotyping of the Autism Spectrum. AB - Recent advances in neuroimaging have offered a rich array of structural and functional markers to probe the organization of regional and large-scale brain networks. The current chapter provides a brief introduction into these techniques and overviews their contribution to the understanding of autism spectrum disorder (ASD), a neurodevelopmental condition associated with atypical social cognition, language function, and repetitive behaviors/interests. While it is generally recognized that ASD relates to structural and functional network anomalies, the extent and overall pattern of reported findings have been rather heterogeneous. Indeed, while several attempts have been made to label the main neuroimaging phenotype of ASD (e.g., 'early brain overgrowth hypothesis', 'amygdala theory', 'disconnectivity hypothesis'), none of these frameworks has been without controversy. Methodological sources of inconsistent results may include differences in subject inclusion criteria, variability in image processing, and analysis methodology. However, inconsistencies may also relate to high heterogeneity across the autism spectrum itself. It, therefore, remains to be investigated whether a consistent imaging phenotype that adequately describes the entire autism spectrum can, in fact, be established. On the other hand, as previous findings clearly emphasize the value of neuroimaging in identifying atypical brain morphology, function, and connectivity, they ultimately support its high potential to identify biologically and clinically relevant endophenotypes. PMID- 26946503 TI - The Social Neuroscience of Interpersonal Emotions. AB - In our daily lives, we constantly engage in reciprocal interactions with other individuals and represent ourselves in the context of our surrounding social world. Within social interactions, humans often experience interpersonal emotions such as embarrassment, shame, guilt, or pride. How interpersonal emotions are processed on the neural systems level is of major interest for social neuroscience research. While the configuration of laboratory settings in general is constraining for emotion research, recent neuroimaging investigations came up with new approaches to implement socially interactive and immersive scenarios for the real-life investigation of interpersonal emotions. These studies could show that among other brain regions the so-called mentalizing network, which is typically involved when we represent and make sense of others' states of mind, is associated with interpersonal emotions. The anterior insula/anterior cingulate cortex network at the same time processes one's own bodily arousal during such interpersonal emotional experiences. Current research aimed to explore how we make sense of others' emotional states during social interactions and investigates the modulating factors of our emotional experiences during social interactions. Understanding how interpersonal emotions are processed on the neural systems level may yield significant implications for neuropsychiatric disorders that affect social behavior such as social anxiety disorders or autism. PMID- 26946502 TI - A Plea for Cross-species Social Neuroscience. AB - Over the past two decades, the question of how our brain makes us sensitive to the state of conspecifics and how that affects our behaviour has undergone a profound change. Twenty years ago what would now be called social neuroscience was focused on the visual processing of facial expressions and body movements in temporal lobe structures of primates (Puce and Perrett 2003). With the discovery of mirror neurons, this changed rapidly towards the modern field of social neuroscience, in which high-level vision is but one of many focuses of interest. In this essay, we will argue that for the further progress of the field, the integration of animal neuroscience and human neuroscience is paramount. We will do so, by focusing on the field of embodied social cognition. We will first show how the combination of animal and human neuroscience was critical in how the discovery of mirror neurons placed the motor system on the map of social cognition. We will then argue why an integrated cross-species approach will be pivotal to our understanding of the neural basis of emotional empathy and its link to prosocial behaviour. PMID- 26946504 TI - Airborne toluene removal for minimizing occupational health exposure by means of a trickle-bed biofilter. AB - The paper presents the experimental results on a biotrickling pilot plant, with a water scrubber as pre-treatment, finalized to the treatment of an airborne toluene stream in a working place. The air stream was characterized by a very high variability of the inlet concentrations of toluene (range: 4.35-68.20 mg Nm( 3)) with an average concentrations of 16.41 mg Nm(-3). The pilot plant has proved its effectiveness in toluene removal, along a 90-day experimentation period, in steady-state conditions. The scrubbing pre-treatment has achieved an average removal efficiency of 69.9 %, but in particular it has proven its suitability in the rough removal of the toluene peak concentrations, allowing a great stability to the following biological process. The biotrickling stage has achieved an additional average removal efficiency of 75.6 %, confirming the good biodegradability of toluene. The biofilm observation by a scanning confocal laser microscope has evidenced a biofilm thickness of 650 MUm fully penetrated by toluene degrading bacteria. Among the micro-population Pseudomonas putida resulted the dominant specie. This bacterium can therefore be considered the responsible for most of the toluene degradation. The whole experimented process has determined an average 92.7 % for toluene removal efficiency. This result meets the most stringent limits and recommendations for occupational safety, given by authoritative organizations in the USA and EU; it also meets the odorous threshold concentration of 11.1 mg Nm(-3). PMID- 26946505 TI - Exposure to occupational air pollution and cardiac function in workers of the Esfahan Steel Industry, Iran. AB - Air pollution is recognized as an important risk factor for cardiovascular disease. We investigated association of exposure to occupational air pollution and cardiac function in the workers of the steel industry. Fifty male workers of the agglomeration and coke-making parts of the Esfahan Steel Company were randomly selected (n = 50). Workers in the administrative parts were studied as controls (n = 50). Those with known history of hypertension, dyslipidemia, or diabetes, and active smokers were not included. Data of age, body mass index, employment duration, blood pressure, fasting blood sugar, and lipid profile were gathered. Echocardiography was performed to evaluate cardiac function. Left ventricular ejection fraction was lower in workers of the agglomeration/coke making parts than in controls (mean difference = 5 to 5.5 %, P < 0.001). Mild right ventricular dilatation and grade I pulmonary hypertension were present in three (12 %) workers of the coke-making part, but none of the controls (P = 0.010). According to these results, occupational air pollution exposure in workers of the steel industry is associated with left heart systolic dysfunction. Possible right heart insults due to air pollution exposure warrant further investigations. PMID- 26946506 TI - Joint acute toxicity of the herbicide butachlor and three insecticides to the terrestrial earthworm, Eisenia fetida. AB - The herbicide butachlor and three insecticides phoxim, chlorpyrifos, and lambda cyhalotrhin are widely used pesticides with different modes of action. As most previous laboratory bioassays for these pesticides have been conducted solely based on acute tests with a single compound, only limited information is available on the possible combined toxicity of these common chemicals to soil organisms. In this study, we evaluated their mixture toxicity on the terrestrial earthworm, Eisenia fetida, with binary, ternary, and quaternary mixtures. Two different types of bioassays were employed in our work, including a contact filter paper toxicity test and a soil toxicity test. Mixture toxicity effects were assessed using the additive index method. For all of the tested binary mixtures (butachlor-phoxim, butachlor-chlorpyrifos, and butachlor-lambda cyhalothrin), significant synergistic interactions were observed after 14 days in the soil toxicity assay. However, greater additive toxicity was found after 48 h in the contact toxicity bioassay. Most of the ternary and quaternary mixtures exhibited significant synergistic effects on the worms in both bioassay systems. Our findings would be helpful in assessing the ecological risk of these pesticide mixtures to soil invertebrates. The observed synergistic interactions underline the necessity to review soil quality guidelines, which are likely underestimating the adverse combined effects of these compounds. PMID- 26946507 TI - Early days of life are crucial for child survival in Gamo Gofa Zone, Southern Ethiopia: A community based study. AB - BACKGROUND: Though, Ethiopia has shown progress in the reduction of under-five mortality in the last few years, the problem of neonatal and under-five mortality are still among the highest in the world and that warrants continuous investigation of the situation for sustained interventions to maintain the reduction beyond the millennium development goals. Therefore, this study was conducted with the objective of determining the magnitude of childhood mortalities in the designated community. METHOD: A census of 11 kebeles (lowest administrative units in Ethiopia) of Arba Minch Town and 11 kebeles of Arba Minch Zuria District, which were not part of Arba Minch Demographic Surveillance System (DSS), had been done in order to identify all children (alive and dead) born between September 01, 2007 and September 30, 2014. Besides, all children born after July 01, 2009 were tracked from the data base of the Arba Minch DSS. Descriptive analyses with frequency and cross tabulation with the corresponding confidence interval and p-value were made using SPSS 16 and STATA 11. Extended Mantel-Haenszel chi-square for linear trend was also performed to assess presence of linear trend through the study period using open-Epi version 2.3. RESULT: A total of 20,161 children were included for this analysis. The overall weighted under five, infant and neonatal mortalities with their corresponding 95 % confidence intervals were: 42.76 (39.56-45.97), 33.89 (31.03-36.76) and 18.68 (16.53-20.83) per 1000 live births, respectively. Majority of neonatal deaths occurred within the first 7 days of life. Under-five mortality was found to be significantly higher among non-DSS rural kebeles, overall rural kebeles and females. CONCLUSION: Significant number of children died during their early days of life. Strengthening of maternal and child health interventions during pregnancy, during and immediately after birth are recommended in order to avert majorities of neonatal deaths. PMID- 26946508 TI - Presurgical brain mapping in epilepsy using simultaneous EEG and functional MRI at ultra-high field: feasibility and first results. AB - OBJECTIVES: The aim of this study was to demonstrate that eloquent cortex and epileptic-related hemodynamic changes can be safely and reliably detected using simultaneous electroencephalography (EEG)-functional magnetic resonance imaging (fMRI) recordings at ultra-high field (UHF) for clinical evaluation of patients with epilepsy. MATERIALS AND METHODS: Simultaneous EEG-fMRI was acquired at 7 T using an optimized setup in nine patients with lesional epilepsy. According to the localization of the lesion, mapping of eloquent cortex (language and motor) was also performed in two patients. RESULTS: Despite strong artifacts, efficient correction of intra-MRI EEG could be achieved with optimized artifact removal algorithms, allowing robust identification of interictal epileptiform discharges. Noise-sensitive topography-related analyses and electrical source localization were also performed successfully. Localization of epilepsy-related hemodynamic changes compatible with the lesion were detected in three patients and concordant with findings obtained at 3 T. Local loss of signal in specific regions, essentially due to B 1 inhomogeneities were found to depend on the geometric arrangement of EEG leads over the cap. CONCLUSION: These results demonstrate that presurgical mapping of epileptic networks and eloquent cortex is both safe and feasible at UHF, with the benefits of greater spatial resolution and higher blood oxygenation-level-dependent sensitivity compared with the more traditional field strength of 3 T. PMID- 26946509 TI - High resolution imaging of the intracranial vessel wall at 3 and 7 T using 3D fast spin echo MRI. AB - OBJECTIVES: High resolution MRI of the intracranial vessel wall provides important insights in the assessment of intracranial vascular disease. This study aims to refine high resolution 3D MRI techniques for intracranial vessel wall imaging at both 3 and 7 T using customized flip angle train design, and to explore their comparative abilities. MATERIALS AND METHODS: 11 patients with intracranial artery disease (four atherosclerotic plaques, six aneurysms and one reversible cerebral vasoconstriction syndrome) were imaged at 3 and 7 T with a 3D T 1-weighted fast-spin-echo sequence (SPACE) both pre and post Gd contrast injection. Wall to lumen contrast ratio (CRwall-lumen), contrast enhancement ratio (ER) and the sharpness of the vessel wall were quantified. Two experienced radiologists evaluated the image quality on a 0-5 scale. RESULTS: Both 3 and 7 T achieved good image quality with high resolution (nominal 0.5 mm isotropic) and whole brain coverage. The CRwall-lumen and the ER measurements were comparable (p > 0.05). The 7 T images were significantly sharper (sharpness: 2.69 +/- 0.50 vs. 1.88 +/- 0.53 mm(-1), p < 0.001) with higher image quality (reader 1 score: 3.5 +/- 1.1 vs. 2.4 +/- 1.1, p = 0.002) compared to 3 T. CONCLUSIONS: 3D T 1-weighted SPACE can be used for intracranial vessel wall evaluation at both 3 and 7 T. 7 T provides significantly better image quality and improves the confidence of diagnosis. PMID- 26946510 TI - Invasive enterococcal infections in Poland: the current epidemiological situation. AB - The aim of this study was to investigate human invasive isolates of enterococci, obtained through prospective surveillance in Poland. The consecutive enterococcal isolates were collected in 30 hospitals between May 2010 and June 2011, and studied by species identification, antimicrobial susceptibility testing and, for Enterococcus faecium by detection of markers specific for the hospital meroclone, multilocus VNTR analysis (MLVA) and multilocus sequence typing (MLST). Additionally, the genomic difference regions (GDRs) characteristic for lineage 78 were searched by PCR. Among 259 isolates, a nearly equal number of Enterococcus faecalis (n = 140; 54.1 %) and E. faecium (n = 112; 43.2 %) was found. The observed 14-day mortality rate of infected patients reached 18.1 %. All isolates were susceptible to linezolid and daptomycin. High-level aminoglycoside resistance occurred in over 50 % of isolates. Vancomycin resistance mediated by vanA or vanB was detected in 7.1 % of E. faecium; 71.4 % of isolates were multidrug resistant. E. faecium isolates ubiquitously carried molecular markers of hospital-associated meroclone (IS16, esp(Efm), intA of ICEEfm1) and multilocus sequence typing showed the domination of representatives of lineages 78 and 17/18 (52.7 % and 46.4 %, respectively). Isolates of lineage 78 were significantly enriched in all the GDRs studied. The recent spread of E. faecium from this lineage contributed to the observed increase of E. faecium in enterococcal invasive infections in hospitals in Poland. PMID- 26946511 TI - Multilocus microsatellite analysis of European and African Candida glabrata isolates. AB - This study aimed to elucidate the genetic relatedness and epidemiology of 127 clinical and environmental Candida glabrata isolates from Europe and Africa using multilocus microsatellite analysis. Each isolate was first identified using phenotypic and molecular methods and subsequently, six unlinked microsatellite loci were analyzed using automated fluorescent genotyping. Genetic relationships were estimated using the minimum-spanning tree (MStree) method. Microsatellite analyses revealed the existence of 47 different genotypes. The fungal population showed an irregular distribution owing to the over-representation of genetically different infectious haplotypes. The most common genotype was MG-9, which was frequently found in both European and African isolates. In conclusion, the data reported here emphasize the role of specific C. glabrata genotypes in human infections for at least some decades and highlight the widespread distribution of some isolates, which seem to be more able to cause disease than others. PMID- 26946512 TI - Piperine potentiates the effects of trans-resveratrol on stress-induced depressive-like behavior: involvement of monoaminergic system and cAMP-dependent pathway. AB - Stress can act as a precipitation factor in the onset of emotional disorders, particularly depression. Trans-resveratrol is a polyphenolic compound enriched in polygonum cuspidatum and has been found to exert antidepressant-like effects in our previous studies. In present study, we assessed the effects of trans resveratrol used in combination with piperine, commonly known as a bioavailability enhancer, on chronic unpredictable mild stress-induced depressive like behaviors and relevant molecular targets. Trans-resveratrol used alone reduced the immobility time of rats in the forced swimming test, with the maximal effects of trans-resveratrol around 60 % inhibition at the highest dose tested, 40 mg/kg. However, when a subthreshold dose of piperine, 2.5 mg/kg was used in combination with trans-resveratrol, the minimum effective dose of trans resveratrol in reducing the immobility time was reduced to 20 mg/kg. Further evidence from neurochemical (monoamines in the frontal cortex and the hippocampus), biochemical (monoamine oxidase, MAO activities) and molecular biological (cAMP, PKA, CREB and BDNF) assays supported the findings in the behavioral studies. These results suggest that the co-treatment strategy with trans-resveratrol and piperine might be an alternative therapy that provides efficacious protection against chronic stress. PMID- 26946513 TI - E-Health Interventions for Eating Disorders: Emerging Findings, Issues, and Opportunities. AB - This study aimed to review the emerging findings regarding E-health interventions for eating disorders and to critically discuss emerging issues as well as challenges for future research. Internet-based cognitive behavioral therapy and guided self-help have demonstrated promising results in terms of reducing eating disorder psychopathology. Emerging findings also suggest that E-health interventions reach an underserved population and improve access to care. The use of smartphone applications is becoming increasingly popular and has much potential although their clinical utility and effectiveness is presently unknown and requires investigation. Important challenges include the diagnostic process in E-health interventions, the optimization of E-health within existing health care models, and the investigation and implementation of blended care. More high quality research is needed to bring the field forward and to determine the place for E-health in our health care service delivery systems. PMID- 26946515 TI - Emergence of GII.Pg norovirus in gastroenteritis outbreaks in Victoria, Australia. AB - The ORF 1 GII.Pg genotype represents an obligatory recombinant comprising the ORF 1 GII.Pg genotype and a number of ORF 2 genotypes. The emergence, incidence, and molecular features of GII.Pg norovirus have never been considered in detail and are the subject of the current study. Over the period 2002-2013, GII.Pg norovirus was detected in 16 outbreaks in Victoria, Australia. It was first identified in 2009 and thereafter was detected at low level in each year of the study. GII.Pg norovirus outbreaks occurred in both healthcare and non-healthcare settings and could be found in individuals with a broad range of ages. The seasonality of GII.Pg norovirus outbreaks was significantly different from that of all other (non-GII.Pg) norovirus outbreaks. For the 15 GII.Pg norovirus outbreaks where ORF 2 sequencing data were available, two ORF 2 recombinant genotypes were found: GII.1 in 5 (33%) outbreaks and GII.12 in 10 (67%) outbreaks. The ORF 1 phylogenetic tree shows that the GII.Pg ORF 1 genotype fell into two distinct groups. The ORF 2 phylogenetic tree indicates that the GII.1 and GII.12 clusters each corresponded to one of the groups in the ORF 1 tree. This indicates the two recombinant forms were evolving in parallel and not one from the other. Analysis of age data indicates the GII.1 and GII.12 recombinant forms circulated in different ways in the community. J. Med. Virol. 88:1521-1528, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26946514 TI - Early goal-directed resuscitation for patients with severe sepsis and septic shock: a meta-analysis and trial sequential analysis. AB - BACKGROUND: The aim of this study was to explore whether early goal-directed therapy (EGDT) was associated with a lower mortality rate in comparison to usual care in patients with severe sepsis and septic shock. METHODS: PubMed, EMBASE, Cochrane library and a Chinese database (SinoMed) were searched systematically to identify randomized controlled trials (RCTs) comparing standard EGDT with usual care in resuscitation of patients with severe sepsis and septic shock and the search time could date back to the publication of the study by Rivers in 2001. The study selection, data extraction and methodological evaluation were performed by two investigators independently. The primary outcome was all-cause mortality. The present meta-analysis had been registered in PROSPERO (CRD42015017667). RESULTS: Our meta-analysis identified 6 studies and enrolling 4336 patients. There was no significant difference in mortality between the two groups, and the pooled odds ratio (OR) was 0.83 (95 % confident interval, CI, 0.64-1.08) with significant heterogeneity (p = 0.02, I(2) = 64%). However, the pooled OR of 3 multicenter RCTs was 1.03 (95% CI, 0.89-1.21) with no heterogeneity (p = 0.78, I(2) = 0%). The effects of EGDT on length of stay in the emergency department and intensive care unit were uncertain, and there was no effect of EGDT on hospital length of stay. There were no differences of mechanical ventilation rate and renal replacement therapy rate between the two groups, and patients in the EGDT group were more admitted in ICU than patients in the control group. During the early 6-h intervention period, patients in the EGDT group received more intravenous fluids, had a higher vasopressor usage rate, higher dobutamine usage rate and higher blood transfusion rate, than patients in the control group. Finally, there was no difference in the incidence of adverse events between the two groups, and the pooled OR was 1.06 (95%CI 0.80-1.39) with moderate heterogeneity (I(2) = 62%, p = 0.07). DISCUSSION: Our meta-analysis showed that the application of EGDT was not associated with lower mortality rate currently. However it does not mean that it is useless of EGDT in patients with sever sepsis and septic shock. On the contrary, there was no difference in mortality rate between the two groups may be due to the improvement of therapeutic strategies in these patients. And the results may be related to the different compliance rate of EGDT resuscitation bundle. CONCLUSIONS: The current evidence does not support the significant advantage of Early goal-directed therapy (EGDT) in the resuscitation of patients with severe sepsis and septic shock. PMID- 26946516 TI - Dock1 promotes the mesenchymal transition of glioma and is modulated by MiR-31. AB - AIMS: This research aimed to examine the relationship between Dock1 and miR-31 and to determine the effect of miR-31 on the mesenchymal transition and invasiveness of glioma. METHODS: Real-time PCR was used to measure the expression of miR-31 and other RNAs. The transfection was used to manipulate the expression levels of Dock1 and miR-31 in cancer cells. Western blot was used to detect the expression of Dock1 and other related proteins. Wound healing, Matrigel invasion and chemotaxis assays were performed to detect the invasion and migration of glioma cell lines. The actual binding site of miR-31 to the 3'-untranslated region of Dock1 was confirmed through luciferase assay and RNA immunoprecipitation. Methylation-specific PCR was performed to detect the methylation level of miR-31 in both glioma cell lines and tissues. RESULTS: Dock1 can promote the IL8-induced chemotaxis and mesenchymal transition of glioma cells through the NF-kappaB/Snail signalling pathway. The protein levels of Dock1 in glioma cell lines and clinical specimens were negatively correlated with miR-31 expression, and Dock1 was directly targeted by miR-31. Animal experiments showed that Dock1 downregulation and miR-31 overexpression reduced glioma cell invasion. Investigation of the underlying molecular mechanism revealed that miR-31 downregulation was attributable to the hypermethylation of the promoter region of miR-31 in glioma cells. CONCLUSION: Dock1 modulation by miR-31 plays an important function in glioma invasion both in vitro and in vivo. This study provides new insights into the invasion of glioma cells and might therefore contribute to the development of new antiglioma strategies. PMID- 26946517 TI - In vivo imaging reveals rapid astrocyte depletion and axon damage in a model of neuromyelitis optica-related pathology. AB - OBJECTIVE: Neuromyelitis optica (NMO) is an autoimmune disease of the central nervous system, which resembles multiple sclerosis (MS). NMO differs from MS, however, in the distribution and histology of neuroinflammatory lesions and shows a more aggressive clinical course. Moreover, the majority of NMO patients carry immunoglobulin G autoantibodies against aquaporin-4 (AQP4), an astrocytic water channel. Antibodies against AQP4 can damage astrocytes by complement, but NMO histopathology also shows demyelination, and - importantly-axon injury, which may determine permanent deficits following NMO relapses. The dynamics of astrocyte injury in NMO and the mechanisms by which toxicity spreads to axons are not understood. METHODS: Here, we establish in vivo imaging of the spinal cord, one of the main sites of NMO pathology, as a powerful tool to study the formation of experimental NMO-related lesions caused by human AQP4 antibodies in mice. RESULTS: We found that human AQP4 antibodies caused acute astrocyte depletion with initial oligodendrocyte survival. Within 2 hours of antibody application, we observed secondary axon injury in the form of progressive swellings. Astrocyte toxicity and axon damage were dependent on AQP4 antibody titer and complement, specifically C1q. INTERPRETATION: In vivo imaging of the spinal cord reveals the swift development of NMO-related acute axon injury after AQP4 antibody-mediated astrocyte depletion. This approach will be useful in studying the mechanisms underlying the spread of NMO pathology beyond astrocytes, as well as in evaluating potential neuroprotective interventions. Ann Neurol 2016;79:794-805. PMID- 26946518 TI - Two-Year Follow Up After Surgical Versus Percutaneous Paravalvular Leak Closure: A Non-Randomized Analysis. AB - BACKGROUND: Percutaneous closure of paravalvular leak (PVL) has emerged as an alternative treatment. Predictors of survival and procedural success are unknown. OBJECTIVES: To review our experience in the treatment of PVL and evaluate efficacy, mortality, predictors of success, and outcomes. METHODS: Retrospective review of percutaneous PVL procedures between years 2008 and 2014. Survival and results were compared with a control cohort of surgical patients. RESULTS: Percutaneous closure was attempted in 51 patients. The surgical group had 36 patients. Defects were perimitral in 67 patients (77%). Mean follow-up (FU) was 784.5 days. After propensity score analysis in-hospital mortality was higher in the surgical group (30.6% vs. 9.8%, OR 6, P 0.01). Clinical improvement was higher in the percutaneous group (71.4% vs. 36.4%, P 0.002). Multivariate analysis showed normal creatinine (OR 15, P < 0.001) as independent predictor of clinical improvement. For the composite end-point of all-cause mortality or readmission, older age (OR 10.7, P 0.001), renal failure, (OR 18, P < 0.01), poor functional class and the absence of clinical improvement (OR 3.9, P < 0.001) were related with a higher risk. There were no differences in survival free from the composite end-point according to the treatment received (surgical or percutaneous). CONCLUSION: Percutaneous PVL closure has a reasonable rate of success and low complication rates, and results compare favorably with surgical treatment. Older patients and those with poor functional class or renal failure (RF) showed a worse prognosis even after a successful closure. (c) 2016 Wiley Periodicals, Inc. PMID- 26946519 TI - MitraClip-induced systolic anterior motion complicated by pericardial effusion: A case report. AB - Systolic anterior motion (SAM) of the anterior mitral leaflet is a well reported complication of surgical mitral valve repair (MVR). In the current report, we present a case of SAM with left ventricular outflow tract obstruction (LVOTO) which occurred after transcatheter mitral valve repair (TMVR) using the MitraClip device. LVOTO was caused by the combination of protrusion of the MitraClip device into the LVOT and underfilling of the left ventricle due to pericardial effusion and atrial fibrillation. Rapid clinical resolution and marked decline in LVOT pressure gradient occurred following surgical drainage and windowing of the pericardium. We conclude that SAM and LVOTO could occur after TMVR. Seeking and addressing reversible aggravators of LVOTO including pericardial effusion is essential and could potentially make the difference between a successful procedure and a failed one. (c) 2016 Wiley Periodicals, Inc. PMID- 26946520 TI - Hemodynamic Effects, Safety, and Feasibility of Intravenous Esmolol Infusion During Takotsubo Cardiomyopathy With Left Ventricular Outflow Tract Obstruction: Results From A Multicenter Registry. AB - BACKGROUND: Left ventricular outflow tract obstruction (LVOTO) may complicate an episode of Takotsubo cardiomyopathy (TTC), potentially leading to cardiogenic shock. Beta-blockers are considered the most suitable treatment for such complication. AIM OF THE STUDY: The objective of this study was to evaluate the hemodynamic effects, safety, and feasibility of a selective beta-blocker (beta1) with a short half-life, esmolol, in subjects with a TTC episode. METHODS: Ninety six consecutive patients with TTC were enrolled in a multicenter registry. The hemodynamic and echocardiographic effects of esmolol (0.15-0.3 mg/kg/min) were analyzed in nine consecutive patients with LVOTO. Clinical course of patients, hemodynamics, days of hospitalization, LV function, and adverse events at follow up were recorded. RESULTS: Left ventricular outflow tract obstruction was present in 10 (10.4%) of 96 patients. Patients with LVOTO were older and had higher values of troponin-I at admission. LV ejection fraction at admission (36.1 +/- 8.4%) significantly improved at discharge (51.4 +/- 6.9%, P = 0.001). Among patients treated with esmolol infusion, LVOT pressure gradient before treatment was 47.6 +/- 16.6 mmHg and after 18.2 +/- 2.3 mmHg (P = 0.0091). Systolic blood pressure decreased from 123.8 +/- 29.1 to 112.6 +/- 12.7 mmHg (P = 0.1537). Mean hospital stay was 9 +/- 2 days. No adverse events were observed during hospitalization and at follow-up. CONCLUSIONS: Esmolol infusion was temporally associated with reduction in intraventricular gradient and systemic blood pressure in patients with TTC and LVOTO. Further controlled studies are warranted to confirm these preliminary findings. PMID- 26946521 TI - Editorial. PMID- 26946523 TI - Nutrition and physical activity in people with cerebral palsy: opposite sides of the same coin. PMID- 26946524 TI - Polypeptide release factors and stop codon recognition in the apicoplast and mitochondrion of Plasmodium falciparum. AB - Correct termination of protein synthesis would be a critical step in translation of organellar open reading frames (ORFs) of the apicoplast and mitochondrion of the malaria parasite. We identify release factors (RFs) responsible for recognition of the UAA and UGA stop-codons of apicoplast ORFs and the sole UAA stop-codon that terminates translation from the three mitochondrial ORFs. A single nuclear-encoded canonical RF2, PfRF2Api , localizes to the apicoplast. It has a conserved tripeptide motif (SPF) for stop-codon recognition and is sufficient for peptidyl-tRNA hydrolysis (PTH) from both UAA and UGA. Two RF family proteins are targeted to the parasite mitochondrion; a canonical RF1, PfRF1Mit , with a variant codon-recognition motif (PxN instead of the conserved RF1 PxT) is the major peptidyl-hydrolase with specific recognition of the UAA codon relevant to mitochondrial ORFs. Mutation of the N residue of the PfRF1Mit PxN motif and two other conserved residues of the codon recognition domain lowers PTH activity from pre-termination ribosomes indicating their role in codon recognition. The second RF imported by the mitochondrion is the non-canonical PfICT1 that functions as a dimer and mediates codon nonspecific peptide release. Our results help delineate a critical step in organellar translation in Plasmodium, which is an important target for anti-malarials. PMID- 26946525 TI - [Spontaneous splenic rupture as a complication of extrapulmonary tuberculosis]. PMID- 26946526 TI - [Rapid identification of Mycobacterium abscessus in cystic fibrosis patients]. PMID- 26946527 TI - Excessive sulphur accumulation and ionic storage behaviour identified in species of Acacia (Leguminosae: Mimosoideae). AB - BACKGROUND AND AIMS: Thiophores, which are typically desert gypsophytes, accumulate high (2-6 % S dry weight) sulphur concentrations and may possess unique tolerance to environmental stress factors, e.g. sulphate/metal toxicity, drought and salinity. Little is known of the prevalence of the behaviour or the associated physiological aspects. The aim of this study was to (a) determine the prevalence of thiophore behaviour in a group of Australian xerophytes; (b) identify elemental uptake/storage characteristics of these thiophores; and (c) determine whether the behaviour is constitutive or environmental. METHODS: The elemental composition of soils and the foliage of 11 species (seven genera) at a site in the Tanami Desert (NT, Australia) was compared and 13 additional Acacia species from other locations were examined for elevated calcium and sulphur concentrations and calcium-sulphur mineralization, thought to be particular to thiophores. KEY RESULTS: Acacia bivenosa DC. and 11 closely related species were identified as thiophores that can accumulate high levels of sulphur (up to 3.2 %) and calcium (up to 6.8 %), but no thiophores were identified in other genera occupying the same habitat. This behaviour was observed in several populations from diverse habitats, from samples collected over three decades. It was also observed that these thiophores featured gypsum (CaSO4.2H2O) crystal druses that completely filled cells and vascular systems in their dried phyllode tissues. CONCLUSIONS: The thiophores studied exhibit a tight coupling between sulphur and calcium uptake and storage, and apparently store these elements as inorganic salts within the cells of their foliage. Thiophore behaviour is a constitutive trait shared by closely related Acacia but is not highly prevalent within, nor exclusive to, xerophytes. Several of the newly identified thiophores occupy coastal or riparian habitats, suggesting that the evolutionary and ecophysiological explanations for this trait do not lie solely in adaptation to arid conditions or gypsiferous soils. PMID- 26946529 TI - Late-onset robust curly hair growth in a patient with BRAF-mutated metastatic melanoma responding to dabrafenib. AB - Development of curly hair has been infrequently described in association with BRAF inhibitors in clinical trials, and usually affects patients between 6 and 24 weeks of therapy. The curly hair is typically preceded by initial hair thinning or even diffuse alopecia. We report herein an occurrence of late-onset robust curly head hair growth in a patient with metastatic melanoma responding well to dabrafenib, without being preceded by hair thinning. The curly hair in our patient developed at 11 months of therapy with dabrafenib. Occurrence of late onset, robust curly hair might represent a prognostic marker of clinical response to these agents. If our hypothesis is correct, we expect more reports of late onset, robust curly hair growth with the use of this class of pharmaceuticals. Moreover, newer generations of BRAF inhibitors may expand the armory of hair care products in the future. PMID- 26946528 TI - Differences in mycorrhizal communities between Epipactis palustris, E. helleborine and its presumed sister species E. neerlandica. AB - BACKGROUND AND AIMS: In orchid species that have populations occurring in strongly contrasting habitats, mycorrhizal divergence and other habitat-specific adaptations may lead to the formation of reproductively isolated taxa and ultimately to species formation. However, little is known about the mycorrhizal communities associated with recently diverged sister taxa that occupy different habitats. METHODS: In this study, 454 amplicon pyrosequencing was used to investigate mycorrhizal communities associating with Epipactis helleborine in its typical forest habitat and with its presumed sister species E. neerlandica that almost exclusively occurs in coastal dune habitats. Samples of the phylogenetically more distant E. palustris, which co-occurred with E. neerlandica, were also included to investigate the role of habitat-specific conditions on mycorrhizal communities. RESULTS: A total of 105 operational taxonomic units (OTUs) of putative orchid mycorrhizal fungi were observed in the three studied species. The majority of these fungi were endophytic fungi of Helotiales and ectomycorrhizal fungi belonging to Thelephoraceae, Sebacinaceae and Inocybaceae. In addition, a large number of other ectomycorrhizal taxa were detected, including Cortinarius, Cenococcum, Tuber, Geopora, Wilcoxina, Meliniomyces, Hebeloma, Tricholoma, Russula and Peziza Mycorrhizal communities differed significantly between the three species, but differences were most pronounced between the forest species (E. helleborine) and the two dune slack species (E. neerlandica and E. palustris). CONCLUSION: The results clearly showed that recently diverged orchid species that occupy different habitats were characterized by significantly different mycorrhizal communities and call for more detailed experiments that aim at elucidating the contribution of habitat specific adaptations in general and mycorrhizal divergence in particular to the process of speciation in orchids. PMID- 26946531 TI - Late-onset pericardial tamponade, bilateral pleural effusions and recurrent immune monoarthritis induced by ipilimumab use for metastatic melanoma. AB - While an important agent in the contemporary anti-melanoma armamentarium, ipilimumab is associated with serious immune reactions including late immune mediated side effects. Recently, a case of late-onset acute pericarditis with tamponade was reported at 12 weeks after the last dose of ipilimumab. While polyarthralgia rheumatica has been previously documented with ipilimumab, we were not able to find any reports of recurrent monoarthritis with the use of this agent. Therefore, we present herein a unique case featuring a patient with late onset autoimmune pleuropericarditis leading to cardiac tamponade at 24 weeks post ipilimumab and recurrent late immune knee arthritis at 8 and 32 weeks, respectively. Furthermore, this late-onset toxicity seen with ipilimumab might also be expected with the PD1 inhibitors currently in clinical use. Timely diagnosis and prompt steroid use are crucial to ensure favorable clinical outcomes in these patients. PMID- 26946530 TI - A rash diagnosis: Gemcitabine-associated pseudocellulitis. AB - Gemcitabine is an antitumor agent with broad clinical application. The most common cutaneous toxicities are mild rash and pruritus; however, a severe 'pseudocellulitis' rash, which resembles infectious cellulitis in clinical presentation, has increasingly been recognized as a rare complication of this agent. Though the specific pathophysiology related to this condition is not clear, it has been observed to occur primarily in regions of significant lymphadenopathy or prior radiation exposure typically after 24-48 h following administration of gemcitabine. It is a self-limiting reaction, with most cases resolving within two to seven days of onset without any specific treatment for the rash. Treatment with gemcitabine may be safely continued in patients with this complication, though recurrence of the rash is common following repeated doses. We report a case of biopsy confirmed gemcitabine associated pseudocellulitis in a patient treated for metastatic pancreatic adenocarcinoma. Knowledge of this complication is important to avoid unwarranted hospitalizations and antibiotic use in patients treated with gemcitabine. PMID- 26946532 TI - Original Research: Generation of non-deletional hereditary persistence of fetal hemoglobin beta-globin locus yeast artificial chromosome transgenic mouse models: -175 Black HPFH and -195 Brazilian HPFH. AB - Fetal hemoglobin is a major genetic modifier of the phenotypic heterogeneity in patients with sickle cell disease and certain beta-thalassemias. Normal levels of fetal hemoglobin postnatally are approximately 1% of total hemoglobin. Patients who have hereditary persistence of fetal hemoglobin, characterized by elevated synthesis of gamma-globin in adulthood, show reduced disease pathophysiology. Hereditary persistence of fetal hemoglobin is caused by beta-globin locus deletions (deletional hereditary persistence of fetal hemoglobin) or gamma-globin gene promoter point mutations (non-deletional hereditary persistence of fetal hemoglobin). Current research has focused on elucidating the pathways involved in the maintenance/reactivation of gamma-globin in adult life. To better understand these pathways, we generated new beta-globin locus yeast artificial chromosome transgenic mice bearing the (A)gamma-globin -175 T > C or -195 C > G hereditary persistence of fetal hemoglobin mutations to model naturally occurring hereditary persistence of fetal hemoglobin. Adult -175 and -195 mutant beta-YAC mice displayed a hereditary persistence of fetal hemoglobin phenotype, as measured at the mRNA and protein levels. The molecular basis for these phenotypes was examined by chromatin immunoprecipitation of transcription factor/co-factor binding, including YY1, PAX1, TAL1, LMO2, and LDB1. In -175 HPFH versus wild-type samples, the occupancy of LMO2, TAL1 and LDB1 proteins was enriched in HPFH mice (5.8-fold, 5.2-fold and 2.7-fold, respectively), a result that concurs with a recent study in cell lines showing that these proteins form a complex with GATA-1 to mediate long-range interactions between the locus control region and the (A)gamma-globin gene. Both hereditary persistence of fetal hemoglobin mutations result in a gain of (A)gamma-globin activation, in contrast to other hereditary persistence of fetal hemoglobin mutations that result in a loss of repression. The mice provide additional tools to study gamma-globin gene expression and may reveal new targets for selectively activating fetal hemoglobin. PMID- 26946535 TI - Why We Need to Do Fewer Statistical Tests. PMID- 26946533 TI - Resveratrol attenuated TNF-alpha-induced MMP-3 expression in human nucleus pulposus cells by activating autophagy via AMPK/SIRT1 signaling pathway. AB - Resveratrol (RSV) is known to play a role of anti-TNF-alpha in a number of cell types. However, whether RSV modulates the effects of TNF-alpha on human nucleus pulposus (NP) cells is unknown. The purpose of this study is to investigate whether RSV regulates TNF-alpha-induced matrix metalloproteinase-3 (MMP-3) expression. Via quantitative real-time polymerase chain reaction (qRT-PCR) analysis, we found that MMP-3 expression induced by TNF-alpha was inhibited by RSV treatment. Depending on Western blot and qRT-PCR assay, we found that RSV induced autophagy in human NP cells, whereas inhibition of autophagy remarkably abolished the restraining role of RSV in the TNF-alpha-mediated up-regulation of MMP-3. Furthermore, RSV increased SIRT1 expression and SIRT1 knockdown significantly suppressed RSV-induced autophagy in NP cells. RSV also activated AMP-activated protein kinase (AMPK), while inhibition of AMPK notably abolished RSV-induced SIRT1 expression. Our data showed that RSV attenuated TNF-alpha induced MMP-3 expression in human NP cells by activating autophagy via AMPK/SIRT1 signaling pathway. This new finding suggested that RSV might act as a novel preventive and therapeutic role in intervertebral disc degeneration. PMID- 26946534 TI - Original Research: Sickle cell anemia and pediatric strokes: Computational fluid dynamics analysis in the middle cerebral artery. AB - Children with sickle cell anemia (SCA) have a high incidence of strokes, and transcranial Doppler (TCD) identifies at-risk patients by measuring blood velocities in large intracerebral arteries; time-averaged mean velocities greater than 200 cm/s confer high stroke risk and warrant therapeutic intervention with blood transfusions. Our objective was to use computational fluid dynamics to alter fluid and artery wall properties, to simulate scenarios causative of significantly elevated arterial blood velocities. Two-dimensional simulations were created and increasing percent stenoses were created in silico, with their locations varied among middle cerebral artery (MCA), internal carotid artery (ICA), and anterior cerebral artery (ACA). Stenoses placed in the MCA, ICA, or ACA generated local increases in velocity, but not sufficient to reach magnitudes > 200 cm/s, even up to 75% stenosis. Three-dimensional reconstructions of the MCA, ICA, and ACA from children with SCA were generated from magnetic resonance angiograms. Using finite element method, blood flow was simulated with realistic velocity waveforms to the ICA inlet. Three-dimensional reconstructions revealed an uneven, internal arterial wall surface in children with SCA and higher mean velocities in the MCA up to 145 cm/s compared to non-SCA reconstructions. There were also greater areas of flow recirculation and larger regions of low wall shear stress. Taken together, these bumps on the internal wall of the cerebral arteries could create local flow disturbances that, in aggregate, could elevate blood velocities in SCA. Identifying cellular causes of these microstructures as adhered blood cells or luminal narrowing due to endothelial hyperplasia induced by disturbed flow would provide new targets to treat children with SCA. The preliminary qualitative results provided here point out the critical role of 3D reconstruction of patient-specific vascular geometries and provide qualitative insight to complex interplay between vascular geometry and rheological properties possibly altered by SCA. PMID- 26946536 TI - Nitric oxide scavengers differentially inhibit ammonia oxidation in ammonia oxidizing archaea and bacteria. AB - Differential inhibitors are important for measuring the relative contributions of microbial groups, such as ammonia-oxidizing bacteria (AOB) and ammonia-oxidizing archaea (AOA), to biogeochemical processes in environmental samples. In particular, 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide (PTIO) represents a nitric oxide scavenger used for the specific inhibition of AOA, implicating nitric oxide as an intermediate of thaumarchaeotal ammonia oxidation. This study investigated four alternative nitric oxide scavengers for their ability to differentially inhibit AOA and AOB in comparison to PTIO. Caffeic acid, curcumin, methylene blue hydrate and trolox were tested onNitrosopumilus maritimus, two unpublished AOA representatives (AOA-6f and AOA-G6) as well as the AOB representative Nitrosomonas europaea All four scavengers inhibited ammonia oxidation by AOA at lower concentrations than for AOB. In particular, differential inhibition of AOA and AOB by caffeic acid (100 MUM) and methylene blue hydrate (3 MUM) was comparable to carboxy-PTIO (100 MUM) in pure and enrichment culture incubations. However, when added to aquarium sponge biofilm microcosms, both scavengers were unable to inhibit ammonia oxidation consistently, likely due to degradation of the inhibitors themselves. This study provides evidence that a variety of nitric oxide scavengers result in differential inhibition of ammonia oxidation in AOA and AOB, and provides support to the proposed role of nitric oxide as a key intermediate in the thaumarchaeotal ammonia oxidation pathway. PMID- 26946537 TI - Gliding motility driven by individual cell-surface movements in a multicellular filamentous bacterium Chloroflexus aggregans. AB - Chloroflexus aggregans is an unbranched multicellular filamentous bacterium having the ability of gliding motility. The filament moves straightforward at a constant rate, ~3 MUm sec(-1) on solid surface and occasionally reverses the moving direction. In this study, we successfully detected movements of glass beads on the cell-surface along long axis of the filament indicating that the cell-surface movement was the direct force for gliding. Microscopic analyses found that the cell-surface movements were confined to a cell of the filament, and each cell independently moved and reversed the direction. To understand how the cellular movements determine the moving direction of the filament, we proposed a discrete-time stochastic model; sum of the directions of the cellular movements determines the moving direction of the filament only when the filament pauses, and after moving, the filament keeps the same directional movement until all the cells pause and/or move in the opposite direction. Monte Carlo simulation of this model showed that reversal frequency of longer filaments was relatively fixed to be low, but the frequency of shorter filaments varied widely. This simulation result appropriately explained the experimental observations. This study proposed the relevant mechanism adequately describing the motility of the multicellular filament in C. aggregans. PMID- 26946538 TI - Lactobacillus acidophilus binds to MUC3 component of cultured intestinal epithelial cells with highest affinity. AB - Lactobacillus strains have been shown to adhere to the mucosal components of intestinal epithelial cells. However, established in vitro adhesion assays have several drawbacks in assessing the adhesion of new Lactobacillus strains. The present study aimed to compare the adhesion of four different Lactobacillus strains and select the most adherent microbe, based on in silico approach supported by in vitro results. The mucus-binding proteins in Lactobacillus acidophilus, L. plantarum, L. brevis and L. fermentum were identified and their capacities to interact with intestinal mucin were compared by molecular docking analysis. Lactobacillus acidophilus had the maximal affinity of binding to mucin with predicted free energy of -6.066 kcal mol(-1) Further, in vitro experimental assay of adhesion was performed to validate the in silico results. The adhesion of L. acidophilus to mucous secreting colon epithelial HT-29 MTX cells was highest at 12%, and it formed biofilm with maximum depth (Z = 84 MUm). Lactobacillus acidophilus was determined to be the most adherent strain in the study. All the Lactobacillus strains tested in this study, displayed maximum affinity of binding to MUC3 component of mucus as compared to other gastrointestinal mucins. These findings may have importance in the design of probiotics and health care management. PMID- 26946541 TI - Progress towards measles elimination in Nepal, 2007-2014. PMID- 26946542 TI - Integrated Disease Surveillance and Response in Liberia: national expert group meeting,15-19 September 2015. PMID- 26946543 TI - [Ahterosclerosis, lipdy and internal medicine]. PMID- 26946539 TI - Nut consumption and total and cause-specific mortality: results from the Golestan Cohort Study. AB - Background: A number of prospective studies have observed inverse associations between nut consumption and chronic diseases. However, these studies have predominantly been conducted in Western countries, where nut consumption tends to be more common among individuals with healthier lifestyles. It is important to examine the association in other parts of the world, and particularly among populations with different patterns of disease, socioeconomic status, lifestyles and disease risk factors. Our objective was to examine the association between nut consumption and mortality in a population whose nut consumption does not track with a healthy lifestyle. Methods: We examined the association between nut consumption and all-cause and cause-specific mortality in the 50 045 participants of the Golestan Cohort Study. Participants were aged 40 and older at baseline in 2004, and have been actively followed since that time. Dietary data were collected using a validated semi-quantitative food frequency questionnaire that was administered at baseline. Results: During 349 677 person-years of follow-up, 3981 cohort participants died, including 1732 women and 2249 men. Nut consumption was associated inversely with all-cause mortality. The pooled multivariate adjusted hazard ratios for death among participants who ate nuts, as compared with those who did not, were 0.89 [95% confidence interval (CI), 0.82-0.95] for the consumption of less than one serving of nuts per week, 0.75 (95% CI, 0.67 0.85) for one to less than three servings per week and 0.71 (95% CI, 0.58-0.86) for three or more servings per week ( P < 0.001 for trend). Among specific causes, significant inverse associations were observed between nut consumption and deaths due to cardiovascular disease, all cancers and gastrointestinal cancers. Conclusions: This study provides evidence for an inverse association between nut consumption and mortality in a developing country, where nut consumption does not track with a healthy lifestyle. Further work is needed to establish the underlying mechanisms responsible for this association. PMID- 26946540 TI - CDP-diacylglycerol synthases regulate the growth of lipid droplets and adipocyte development. AB - The expansion of lipid droplets (LDs) and the differentiation of preadipocytes are two important aspects of mammalian lipid storage. In this study, we examined the role of CDP-diacylglycerol (DAG) synthases (CDSs), encoded by CDS1 and CDS2 genes in mammals, in lipid storage. CDS enzymes catalyze the formation of CDP-DAG from phosphatidic acid (PA). Knocking down either CDS1 or CDS2 resulted in the formation of giant or supersized LDs in cultured cells. Moreover, depleting CDS1 almost completely blocked the differentiation of 3T3-L1 preadipocytes, whereas depleting CDS2 had a moderate inhibitory effect on adipocyte differentiation. The levels of many PA species were significantly increased upon knocking down CDS1 In contrast, only a small number of PA species were increased upon depleting CDS2 Importantly, the amount of PA in the endoplasmic reticulum was dramatically increased upon knocking down CDS1 or CDS2 Our results suggest that the changes in PA level and localization may underlie the formation of giant LDs as well as the block in adipogenesis in CDS-deficient cells. We have therefore identified CDS1 and CDS2 as important novel regulators of lipid storage, and these results highlight the crucial role of phospholipids in mammalian lipid storage. PMID- 26946544 TI - [Statement on new modern hypolipidemic therapy]. PMID- 26946545 TI - [Diagnostic algorithm for von Willebrand Disease (vWD) in a Mexican population]. PMID- 26946546 TI - Foreword. Overview of the workshop held and establishing of the Macedonian Association of Medical Editors in Skopje, on April 25, 2014. PMID- 26946547 TI - Editorial. PMID- 26946548 TI - Choosing wisely. PMID- 26946549 TI - Choosing wisely. PMID- 26946550 TI - Choosing wisely. PMID- 26946551 TI - [The trauma of disclosing death for physicians and residents in clinical practice]. PMID- 26946552 TI - Stimulated and non-stimulated saliva as biological material in the assessment of cotinine concentration. AB - INTRODUCTION: A biomarker of the exposure to the tobacco smoke is cotinine - a nicotine metabolite with a half-life about 16 hours. Analysis of cotinine concentration in biological material allows objective assessment of the cigarette smoking status and environmental exposure to the tobacco smoke. AIM OF THE STUDY: The aim of the study was evaluation of the influence of method of saliva collection: stimulated or non-stimulated one by chewing a paraffin cube on cotinine concentration in the saliva as well as the analysis of the obtained cotinine values depending on the status of cigarette smoking. MATERIAL AND METHODS: Survey with the use of authorial survey questionnaire and biochemical survey of saliva were conducted among 115 people aged 20-50 who reported for treatment at the Department of Conservative Dentistry with Endodontics of the Medical University of Lublin. In the examined group 66 people declared cigarette smoking, 49 reported they had never smoked cigarettes and had never tried to smoke. Cotinine concentration in the saliva was assayed with the use of Cotinine test (Calbiotech). Obtained study results were submitted to statistical analysis using Ch2 test. Statistically essential test values were those of p<0.05. While investigating the influence of age on the examined parameters Spearman correlation coefficient and the test of its relevance were employed. RESULTS: Mean cotinine concentra- tion in non-stimulated saliva in smokers was 310.36 ng/ml, in stimulated saliva 305.61 ng/ml. No statistically essential differences were stated between stimulated and non-stimulated saliva (Z=0.36, p>0.05). Cotinine concentration in non-stimulated and in stimulated saliva was increasing with age of the investigated. CONCLUSIONS: Cotinine concentration in both in stimulated and non-stimulated saliva obtains similar values. Cotinine concentration both in stimulated and non-stimulated saliva increases with age of the investigated. PMID- 26946553 TI - Effectiveness of Smoking Cessation Services in England--Clinic in Whitechapel as an example. AB - Smoking related illness and deaths are a significant problem globally. In the U.K. the government has been funding a nation-wide network of specialist clinics that provide support to smokers who want to quit since 1999. The specialist clinic in Whitechapel covers the boroughs of Tower Hamlets and the City of London. We analysed the records of 516 smokers who started their treatment with the specialist clinic in the period April 2013-March 2014. The data was analysed by ethnic group, age, sex, socio economic status, pharmacotherapy type and intervention type. Of these 516 smokers, 273 (53%) had successfully quit smoking by the end of the 7-week treatment. The results from the specialist clinic were in line with the national average of the UK in terms of self-reported quit rate (51%), although they are better than national average in terms of quit rate that has been biochemically validated. In the specialist clinic in Whitechapel, compared to the U.K. average, more people from minority ethnic groups were treated, more males than females were treated and there was a higher percentage of people who used Varenicline than NRT. The results provide useful information about the client population treated by the specialist clinic in Whitechapel, however the findings need to be understood within the context of local health geography challenges and different client mixes. PMID- 26946554 TI - Assessment of nicotine concentration in electronic nicotine delivery system (ENDS) liquids and precision of dosing to aerosol. AB - BACKGROUND: Global use of electronic nicotine delivery systems (ENDS; also called electronic cigarettes, e-cigarettes) has increased dramatically in recent years. However, due to the limited safety studies and growing concerns on the potential toxicity from long term use of ENDS, many national and international governments have employed regulatory measures to curtail its use. One of the most significant challenges regulators of ENDS encounter is the lack of quality standards to assess ENDS, e-liquid (solution used with ENDS which contain nicotine--a highly toxic and addictive substance), and amount of nicotine delivery to aerosol during ENDS use. AIM OF THE STUDY: Aims of the study were to (1) measure and compare nicotine concentration in e-liquids to values reported by manufacturers on packaging labels; (2) assess the precision of nicotine delivery from tank during aerosol formation. Methods: Nine popular Polish e-liquids (based on the market share data from October 2014) were purchased for the study. The labelled nicotine concentration for the selected e-liquids ranged between 11-25 mg/mL. All e liquids were aerosolized in the laboratory using a smoking simulation machine (Palaczbot). Each e-liquid was aerosolized in a series of 6 consecutive bouts. A single bout consisted of 15 puffs with the following puff topography: 65 mL puff volume, 2.8 sec. puff duration, and 19 sec. interpuff interval. A total of 90 puffs were generated from each e-liquid. Nicotine content in the e-liquids and the aerosol generated were determined by gas chromatography with thermionic sensitive detection (GC-TSD). RESULTS: For seven of nine analyzed e-liquids, the difference between measured and manufacturer labeled nicotine concentration was less than 10%. Nicotine dose in aerosol per bout ranged between 0.77-1.49 mg (equivalent to one-half the nicotine a smoker inhales from a single combustible cigarette). CONCLUSIONS: Our analysis showed the high consistency between the labeled and measured nicotine concentration for popular on the Polish market ENDS e-liquids. Also, our analysis demonstrates that the risk for nicotine overdose is likely minimal when ENDS are used in a similar manner as a combustible cigarette. However, due to the toxicity risk nicotine poses regulatory measures focused on safety and quality of e-liquids should continually be exercised. PMID- 26946555 TI - [Exposure to environmental tobacco smoke in pre-school children--a comparative study]. AB - The objective of the work was to compare the socioeconomic situation and the structure of tobacco use in the families of children attending preschools in Bialystok in 2004 and 2012 in terms of 3-year-olds' exposure to environmental tobacco smoke (ETS). The study involved 313 children out of 1,200 3-year-olds attending 51 pre-schools in Bialystok in 2004 (Gr I) and 273 children out of 1,100 attending 49 pre-schools in 2012 (Gr I). Information on environmental conditions and the use of tobacco in the families of the studied 3-year-olds was obtained through anonymous questionnaires filled in by their parents or caregivers. The exposure of children to ETS was evaluated using the questionnaire and by determining the cotinine/creatinine ratio in urine. The children from Gr I had better educated (p<0.001) and wealthier (p=0.005) parents, and better living conditions (p=0.008). In 47.3% of the homes of children from Gr I and 31.1% of homes of children from Gr II there was at least one smoking person (p<0.001). Both in 2004 and in 2012, fathers prevailed among the smokers, but in 2012 their number was significantly lower (p<0.001). As for mothers, 23.6% of them in Gr I and 10.3% in Gr I admitted smoking every day (p<0.001). More children from Gr I than from Gr I lived with smoking grandparents. The declared number of cigarettes smoked a day by the people living with the children was similar in both Groups The Groups did not differ significantly regarding the rules of tobacco smoke applying to the family members and guests (p=0.639). The mean cotinine/ creatinine concentration [ng/mg] in the urine of children from Gr I (60.78) was significantly higher than in those from Gr II (22.75) (p<0.001). According to the survey data, in 2012 fewer three-year-olds were exposed to ETS out of home (p<0.001). The mean cotinine/ creatinine concentrations [ng/mg] depending on the declared exposure to tobacco smoke out of home: no exposure, existing exposure, unknown exposure, were for Gr I and Gr II, respectively: 51.31 vs. 35.67; (p<0.001), 76.10 vs. 38.65; (p=0.002), 76.92 vs. 47.04; (p=0.460). In 2012, as compared to 2004, the number of smokers among young parents decreased, but despite education activities in the community, only 1/4 of homes with children had the "no smoking" rule. PMID- 26946556 TI - [Umbilical cord serum hepcidin levels and maternal smoking during pregnancy]. AB - Anemia during pregnancy is a risk factor of disturbance in pre- and postnatal child's development. Hepcidin plays the key role in iron metabolism, as protein participating in the regulation of intestinal absorption of this element and its release from macrophages, and transport across the placenta. Maternal smoking during pregnancy can result in disturbances of iron homeostasis leading to a subclinical deficiency. The depletion of maternal iron can cause fetal hypoxia condition and decreased expression of hepcidin. The aim of the study was to evaluate the effect of smoking on the levels of hepcidin and erythropoietin (as an indicator of hypoxia) and their relationships in umbilical cord blood. The research material was the umbilical cord blood of 50 newborns born in the Department of Obstetrics and Gynecology (Institute of Mother and Child in Warsaw) in the years 2013-2014. Based on an interview and determination of cotinine in the blood of mothers, newborns were divided into following groups: children of smoking mothers (n=20) and children of tobacco abstinent mothers (n=30). Hepcidin and erythropoietin concentrations were determined by enzyme immunoassay using commercial kits (DRG, Germany). It has been shown that hepcidin concentrations were significantly lower in children of smoking mothers than in the group of tobacco abstinent (37.5 ng/mL vs 45.1 ng/mL, p<0.001). However, the level of erythropoietin was higher in children of smoking mothers than in children of non smoking women (p<0.001). A negative correlation between the levels of hepcidin and erythropoietin (r = -0.41, p<0.05) and number of smoked cigarettes (r = 0.43, p<0.05) was observed. These results indicate that smoking during pregnancy significantly affects hepcidin levels in children born at term. Decrease of hepcidin concentration coexisting with high level of erythropoletin in umbilical cord blood in children of smoking pregnant women may be the cause of subclinical deficiency of iron in the newborn. PMID- 26946557 TI - [Efficacy of alcohol withdrawal syndrome therapy in patients from Independent Public Hospital for Mental Diseases in Miedzyrzecz]. AB - Consumption of alcohol is a serious social problem. Research on alcohol addicts prove that its consumption affects the physical and mental health of drinking person, his/her family and the social dimension (eg. crime, unemployment, poverty). The aim of this study was to evaluate the effectiveness of the treatment of alcohol withdrawal syndrome (AW) in patients of 2417 Unit of Treatment of Alcohol Withdrawal Syndromes of Independent Public Hospital for Mental Diseases (SPSNPCH) in Miedzyrzecz. The study was conducted in 122 of 24/7 Unit of Treatment of Alcohol Withdrawal Syndromes (SPSNPCH) treated from January to March 2015. Patients during hospitalization were subjected to intensive pharmacotherapy of AW (Stage I) and cognitive-behavioral therapy (Stage II). Of the group of 122 people starting treatment Stage I was completed by 112 patients (90%); 10 patients (8%) have been discharged at their own request. The participation in Stage II was consented only by 54 patients, of which 6 (4%) withdrew from this form of therapy. Full two-stage treatment consisting of pharmacotherapy of AWS and then psychotherapy was completed only by 48 (39%) patients. PMID- 26946558 TI - [Analysis of intoxication with novel psychoactive substance (NPS) in Pomeranian region, from January to July 2015]. AB - INTRODUCTION: During initial months of the year 2015 we observed the increase number of patients intoxicated with NPS in Poland. In our work we analysed the scale of this phenomenon in Pomeranian region. MATERIALS AND METHODS: Study was carried out on period from 1 January 2015 to 31 July 2015. Analysis was based on records derived from Electronic Poison Information Database developed and used on a daily basis on Pomeranian Centre of Toxicology (PCT), data obtained from Centre for Monitoring of Adverse Effects of Medicaments and Chemical Substances based in PCT and on information gathered from patients treated in Pomeranian Centre of Toxicology for NPS intoxication. RESULTS: Our study has shown slow, continuous rise in the number of intoxications with NPS in analysed period. The most frequent cause of intoxication were synthetic compounds. 99 cases needed treatment in Clinical Toxicology Unit due to their severe state. The youngest exposed person was 13 y.o., while the oldest was 53 y.o. Mean age was 22.5 y.o. with median 20 years. Majority of intoxications were among males (80.54%). 61.53% of all patients came from Tricity agglomeration. Ethanol was the prevalent coingestant. The most commonly used substance was generic NPS (70.59% of cases), followed by unknowns psychoactive substance (16.29% of cases), herbal mixture (16.29% of cases) and dextrometorphan (5.88% of cases). The study did not find one drug name that would be prevalent over others, with the most frequent commercial name being "Mocarz", found in 4 cases. Most dangerous substances found in NPS were PMA, PMMA, 25C-NBOMe and 251-NBOMe. There were no deaths of patients treated in PCT because of acute intoxication with NPS. PMID- 26946559 TI - [Self-medication in smoking cessation among smokers]. AB - INTRODUCTION: According to the World Health Organization defines self-medication by using OTC (over-the-counter) to treatment diseases or symptoms recognized by yourself without pay a visit to the doctor's office. Increasing availability of OTC medicines cause that Poles are more and more willing to take self-medication, even when they want to smoking cessation. The aim of the study was to investigate what nicotine replacement therapy for smoking cessation without prescription were chosen by smokers, who wanted without help to smoking cessation. MATERIALS AND METHODS: The study included 323 people (68.1% were men and 31.9% women). The average age of respondents was 49 +/-11 years. The average pack-years in the study group was 17. The research tool was the author's questionnaire, which was distributed among patients for self- fulfillment. Subjects were divided into three groups: group I up to 10 pack-years (average 7.5 pack-year), group II between-11-20 pack-years (average 15.5 pack-year), group III--between 21-35 pack year (average 28.5 pack-year). RESULTS: All subjects, at least once in their lives, bought OTC for self-medication nicotine addiction. Among the respondents in I and II group the most often chose the nicotine replacement therapy in the form of chewing gum, and in III group Cytisine tablets and pills nicotine (p<0.001). One-time purchase of OTC in group I decided 54%, in group II 47.5% and in III group 46.6% of respondents. The number of preparations used in each group was 3.1 in group I; 3.6 in group II, and 3.3 among subjects in the group III (p<0.001). 94% of respondents dissatisfied with the results of treatment ended after 1 month to self-medication. A strong self-motivation to smoking cessation was declared by 78.3% of respondents. On the other hand, Schneider test was positive in only 5% of patients. CONCLUSIONS: Smokers want to own attempt to smoking cessation by using nicotine preparations without a prescription, should be aware that self-assessment of readiness to smoking cessation is not a real preparation to quit smoking addiction. All the more should consult a doctor if subsequent attempts fail. PMID- 26946560 TI - [Family structure of smoking onset and regular smoking among adolescents in Poland]. AB - The aim of the research was to present the prevalence of the regular tobacco smoking, the age of Polish adolescents' smoking onset, as well as the trends in these behaviours in 2010-2014, and to identify the fam- ily factors related to early tobacco initiation, and regular smoking. The study was conducted in 2013/2014 as a part of the HBSC--Health Behaviour in School-aged Children: A WHO collaborative cross-national study, in a representative sample of Polish students (n=4545; 2263 boys, and 2282 girls), in three age groups, in mean age 11.6; 13.6; 15.6. The international, standard HBSC questionnaire was used. Results showed that prevalence of adolescents smoking onset, as well as regular smoking increased with age. There was no statistically significant difference comparing to HBSC study conducted in 2009/10. The important predictors of early tobacco initiation were: the male gender, living in broken or reconstructed family, and living in the rural area. Considering regular smoking, the most important risk factors were: older age (13,15 y.o.) and living with single parent or in reconstructed family. In planning the prevention strategies there is a need to take into account the family role in children and adolescents' smoking prevention, as well as how to support single parents. PMID- 26946561 TI - [The use of saliva for exposure assessments on designer drugs among adolescents]. AB - Drug use is one of the fundamental problems of the contemporary world. Due to the debilitating effects on physical and mental health and the possibility of impaired social functions, it is extremely important to assess exposure to psychoactive substances among high-risk groups. Taking into account characteristics of adolescence, one of them includes young people. To assess the exposure of young people to drugs, survey research is the most commonly use. To establish reliability of the information indicated by the students, toxicological studies could be a good manner. High-performance liquid chromatography coupled with mass spectrometry (LC-MS) is currently one of the most common techniques use for the detection and determination of psychoactive substances in biological material. In practice, an important issue in toxicological studies is the selection of a suitable biological material. Taking into account economic considerations and the method of sampling, the saliva is an increasingly used alternative material. The aim of this study was to assess the exposure of junior high school students on psychoactive substances--designer drugs, through the analysis of surveys and qualitative analysis of saliva taken from teenagers. It has been shown that surveys are a relatively quick and easy form of assessing the exposure of young people to psychoactive substances, but require verification through toxicological analysis of biological material for the presence of psychoactive substances for their reliability. Poznan secondary school students experimented with designer drugs at a similar level as respondents of nationwide survey from 2013. PMID- 26946562 TI - [Factors forming opnion on marijuana legalization in Poland among group of students from medical and technical college faculty]. AB - Marijuana is the most popular illegal drug in the world. In 2010 17.6% of polish adult population (age 15-64) and 37.3% of youth (age 17-18) declared use of marijuana at least once in their lifetime. Recent years in Poland brought back public discussion regarding decriminalization and legalization of marijuana. The main goal of the study was to reveal the opinion about legalization of marijuana in Poland among students of medical and technical faculty in correlation with chosen socio-demographic factors, college major, attitude to tobacco smoking, use of drugs and religious practice. Study included 230 students (110 from Medical University of Lodz and 120 from Technical University of Lodz). Women consisted on 56.1% of surveyed and men on 43.9%. Study used audit survey as a research method. Results. 40.4% of students considered marijuana as "soft" drug and in majority (65.7%) are convinced that it is not addictive. The main part of studied group (83%) claimed that marijuana is easily accessible in Poland. The majority of the group (38.75%) was against marijuana legalization, a little bit less (35.2%) approved its legalization in Poland and 26.1% had no opinion. Type of college faculty had not been detected as a factor influencing support for legalization. Important factors influencing positive opinion on legalization was: living in the city, tobacco smoking, socializing with legalization supporters, lack of regular religious practice, drug use. CONCLUSION. Young people's diversified opinion regarding legalization of marijuana in Poland should encourage further discussion. Educational and preventive activities within different social groups are necessary to form a conscious opinion on legalization of marijuana in Poland based on the knowledge of actual scientific facts. PMID- 26946564 TI - [Non-smokers about smokers]. AB - Although the knowledge that smoking is a health hazard is widely accessible, this addiction remains serious social problem among young generation. It poses a great challenge to therapists, economic consequences impair both national and family budgets and that is a reason why governments and publicly-founded institutions promote anti-nicotine behaviours. But still rate of young smokers is very high. Aim of work was to get a real picture of smokers seen through nonsmoker's eyes. The used questionnaire was prepared exclusively for that survey. There were 97 students of medicine that participated in the poll. The poll showed 70 of them had a negative picture of smokers. Soft personality given in to addiction was the main feature. The knowledge about compounds of tobacco smoke was very poor, much like its influence on the human body. Survey showed general need for further education in that matter during medical studies. PMID- 26946563 TI - [Conditions for use of stimulants assessed by medical university students]. AB - INTRODUCTION: The use of tobacco, alcohol and psychoactive substances in a society, also by very young consumers, currently poses a serious social problem. The representatives of medical professions are addicted, too, though the issue has not been studied well enough yet. AIM: The aim of the paper was to present data considering the, use of stimulants by students of a medical university. MATERIAL AND METHOD: The questionnaire study was carried out in the years 2014 2015 among 187 students of a medical university (147 females and 40 males), aged 20-29 years, studying dentistry and dental hygiene. After giving their consent, the students answered closed questions from a questionnaire concerning the use of tobacco, alcohol and psychoactive agents. Statistical analysis was carried out in groups of the studied subjects divided according to sex, using difference test between two proportions and Statistica v10. The studies were approved by the Bioethical Committee at the Poznan University of Medical Sciences. RESULTS: Daily tobacco smoking was declared by 5.35% of students, whereas 18.72% are occasional smokers, and 7.48% have recently refrained from smoking. As many as 94.65% of students consume alcohol, 2.14% halucynogenic agents, 1.07% ecstasy and 19.78% energy drinks. Tobacco smoking is most frequently associated with stressful situations (12.30%) or recreationally (10.16%). Alcohol consumption primarily occurred at parties (77.54%), celebrating success (60.43%), or during family gatherings (54.01%). CONCLUSIONS: Alcohol consumption is widespread among students of medical professions, and is most frequent at parties. Tobacco smoking and the use of psychoactive agents is relatively less common. Furthermore, the obtained data suggests the need for health promotion in preventing substance abuse in this population. PMID- 26946565 TI - [Frequency of oral health examinations in the group of people aged 20-54 years considering the status of cigarette smoking]. AB - BACKGROUND: Regular examinations of oral health allow dentists clinical assessment of the state of dentition and oral soft tissues in patients, early diagnosis and treatment of the diagnosed disease entity, identification of risk factors of oral diseases as well as prophylaxis and pro-health education. Aim of the study was analysis of the frequency of oral health examination in the group of people in aged 20-54 with considering sociodemographic data and the status of cigarette smoking. MATERIALS AND METHODS: Sociomedical examinations were conducted in the group of 124 people in the age of 20-54. In order to assess the status of cigarette smoking cotinine concentration in non-stimulated saliva was assayed with the use of Cotinine test (Calbiotech, USA). Statistic analysis of the obtained results was performed with the use of Chi2 and Kruskal-Wallis tests. Test values considered to be statistically significant were those of p<0.05. RESULTS: 32.76% smokers and 9.09% non-smokers had their dental appointment less frequently than once a year to have their oral health examined, whereas regular dental check-ups every six months were declared by 43.10% and 56.06% and once a year 24.14% and 34.85% respectively. In the group of smokers no correlation was stated between the frequency of their dental check-ups and their age (H=1.12, p>0.05), sex (chi2=0.09, p>0.05) and place of residence (chi2=1.66, p>0.05). In the group of non-smokers no correlations were stated between the age (H=4.39, p>0.05), sex (chi2=1.01, p>0.05), place of residence (chi2=2.40, p>0.05) and the frequency of oral health check-ups. Non smokers have their dental check-ups every six months essentially more frequently than smokers (chi2 = 10.80, p<0.01). CONCLUSIONS: Age, sex, place of residence do not influence the frequency of oral health examinations among people in the aged 20-54. Non smokers have their dental check-ups every six months essentially more frequently than smokers. PMID- 26946566 TI - [Coexistence of risky behaviors amongst group of students. Tendencies of changes between 2009-2012. Prospective studies]. AB - AIM OF STUDY: Aim of conducted studies was to asses changes in time and coexistence of improper behavior patterns among students in year 2009 and 2012. MATERIALS AND METHODS: The study included 905 students of the University of Rzeszow and Rzeszow University of Technology who have studied on medical, humanistic and science fields. Research was conducted by diagnostic sounding with usage of survey technique. In statistical elaboration squared-chi test and logical regression models were used. The study was conducted between October and December 2009 (study T1). It was repeated in 2012 among the same group of students (T2). RESULTS: Conducted in year 2009 and 2012 studies indicated that over half of surveyed students did not smoke cigarettes (T1 67.8%; T2 66.5%) and that daily smoking was declared only by 11.5% (T1) and 10.9% (T2) of asked youths. Majority of examined youth academic people drank alcohol once a month (T1 30.7%; T2 32.1%). Only 4.7% (T1) i 6.3% (T2) declared themselves as abstainers. Research pointed on significant increase of systematic drugs use (T1 0.4%; T2 1.7%). Vast majority of surveyed youths did not use legal highs in both research periods (89.3%--T2 and 91.5%--T2). There were no differences shown on the level of statistical significance in neither category (tobacco smoking, alcohol drinking, usage of drugs and legal highs). Students who smokes have bigger chance to addict themselves to alcohol, legal highs and drugs then the ones who do not smoke cigarettes. CONCLUSIONS: Conducted studies shows that tobacco smoking is a predictor of risky behaviors. Students who smoke are more exposed to addiction to alcohol, drugs and legal highs then those who reject tobacco. PMID- 26946567 TI - [The knowledge of students and teachers of selected groups about the OTC drugs containing codeine and pseudoephedrine--an alternative to "legal highs"?]. AB - BACKGROUND: Currently the youth to intoxication increasingly used drugs generally available over the counter (OTC, Over-The-Counter drug) containing psychotropic substances. The knowledge on the subject among parents and teachers is inadequate. The aim of the study is to assess the knowledge of students and teachers about OTC drugs containing codeine or pseudoephedrine and their consequences on the use and popularity of these drugs. MATERIAL AND METHODS: The study was conducted from December 2014 to March 2015 of 93 respondents. In conducting the study used research tool in the form of an anonymous questionnaire consisting of 21 questions for the students and teachers of 16 questions, the questions relate knowledge of the studied group persons on the OTC drugs containing codeine or pseudoephedrine and the effects of their use. RESULTS: Among the students participating in the study, the majority of respondents are aware that using drugs containing codeine or pseudoephedrine can be addicted to them. Higher knowledge on this subject have demonstrated high school students, but less teachers. Most of the respondents had knowledge about the health effects that result from an overdose of these drugs. Among the students most frequently reported sources of knowledge about OTC drugs containing codeine or pseudoephedrine were friends and the Internet. CONCLUSIONS: The general knowledge of high school students and teachers on the effects of OTC medications containing codeine or pseudoephedrine is not sufficient. There is a need to conduct preventive and educational action aimed at increasing knowledge among youth and adults on the health effects of these drugs. PMID- 26946568 TI - [Effects of active and passive smoking during pregnancy on the blood flow in uterine artery in third trimester of pregnancy]. AB - The aim of the study was to evaluate the influence of active and passive maternal tobacco smoking on the parameters of blood flow in the uterine arteries in the third trimester. of pregnancy. The study was performed among 96 pregnant women in a single full-term pregnancy in the third trimester of pregnancy. A questionnaire assessing the status of the concentration of nicotine and nicotine metaboliteotinine in the serum of pregnant. The plasma was extracted technique of liquid-liquid, and then performed laboratory assays using high performance liquid chromatography with spectrophotometric detection using norepinephrine as an internal standard. Based on the concentration of cotinine and interview patients were assigned to three groups: Group 1--patients smoking cigarettes during the entire pregnancy (23), group 2--patients exposed to environmental tobacco smoking (30) and a control group 3--nonsmokers and patients unexposed to passive smoking (43). In the third trimester of pregnancy blood flow in the uterine arteries was performed using "B-mode" technique with function of spectral Doppler. We analized the pulsatility index and resistance index in both uterine arteries, the presence of the indent diastolic "notch" and the scale of the uterine arteries. There were no statistically significant differences with regards to pulsatility index and index of resistance in blood flow in the uterine arteries in different groups of patients. The presence of the indent diastolic "notch" was significantly more frequent among active smokers, compared to women passively exposed to tobacco smoke and non-smoking women (39.1% vs. 20% vs. 4.6%; p = 0.012). The values in the scale of uterine arteries showed no significant difference between groups. Both active and passive smoking had no significant effect on the blood flow in uterine artery in pregnant women in the third trimester of pregnancy. PMID- 26946569 TI - Tobacco against Ebola virus disease. AB - The Ebola virus disease (EVD), formerly known as a hemorrhagic fever and discovered in 1976, is dangerous, highly infectious disease with very high mortality. There are no licensed therapeutics against EVD, although a range of medicines and therapies are currently being evaluated. During the 2014 Ebola outbreak, an experimental drug named ZMapp was administered on an emergency basis to seven patients of which five were recovered. Currently, since February 2015, ZMapp is tested in clinical trials. ZMapp is a mixture (named a cocktail) of three chimaeric monoclonal antibodies (mAbs) of IgG class, which bind to three different epitopes on Ebola surface glycoprotein (GP). ZMapp was created by systematic selection of antibodies from two other three-component cocktails--MB 003 and ZMab the components of which were produced by rapid transient expression method in tobacco species of Australian origin--Nicotiana benthamiana. The ZMapp antibodies of pharmaceutical grade are manufactured in green-house grown N.benthamiana according to the cGMP (current Good Manufacturing Practice), using RAMP platform (Rapid Antibody Manufacturing Platform) and MagnICON system, which utilizes transient expression by magnifection method using viral vectors delivered to plant tissue by a bacterium--Agrobacterium tumefaciens. The applied glycosylation mutant of N.benthamiana (delta XTFT) synthesizes human-like, biantennary N-glycans, with terminal N-acetylglucoseamine and without typical of plants, immunogenic sugar epitopes-beta1,2-linked xylose and alpha1,3-linked fucose. Due to an absence of fucose on N-glycans attached to the Fc domains, the plant-produced anti-Ebola mAbs elicited significantly stronger antibody-dependent cellular cytotoxicity (ADCC) than the analogous anti-Ebola mAbs with fucosylated (alpha1,6-linked fucose) N-glycans produced in a mammalian CHO cell line--the basic expression system for the industrial production of recombinant therapeutical glycoproteins. As far as a vaccine against Ebola virus disease is considered, so-called Ebola Immunogenic Complex (EIC) consisting of assembled molecules of a humanized IgG mAb--6D8 specific for Ebola GPI with GP1 fused to the C-terminus of the heavy chains, was obtained by transient expression in N. benthamiana. PMID- 26946570 TI - [The estimation of causal effect in observational studies]. AB - One of the frequently encountered problems in the statistical analysis of the data is the correct interpretation of the effects occurring under the influence of some kind of treatment used by the researcher or appearing without its share of action. In the first case we are dealing with an experimental study, in the second with the observational study. In the experimental study, the researcher has full control over the procedure of random allocation of cases to a group subjected to a predetermined factor and a group not exposed to the action (randomization). In the case of an observational study, also called a retrospective study there are often additional factors that modify both assigned to the same groups as well as specific actions for the test results. The article presents an example of the cause of this phenomenon and selected methods of minimizing the mentioned influence. PMID- 26946572 TI - [The role of epithelial cell rests of Hertwig's sheath in periodontal regeneration--review]. AB - Epithelial cell rests of Malassez (ERM) are the potential source of stem cells subpopulation with ability to periodontal regeneration by epithelial-mesenchymal induction. The morphology of ERM and ERM influence on root development and regeneration process was described based on the literature. PMID- 26946571 TI - [The influence of selected plants on the tobacco smoking-induced effects in the oral cavity--review]. AB - Tobacco smoking is a culprit of many pathological lesions on the oral mucosa. In this literature review we focused on various therapeutic options for tobacco induced mucosal pathologies. Many active ingredients of Aloe vera, Chamomile, Curcuma longa and Calendula show potent anti-inflammatory and regenerative activity, making plant derived drugs a reasonable option for traditional pharmaceuticals. PMID- 26946573 TI - [Periodonta disease in smokers, and the parameters of oxidative stress]. AB - Periodontal disease, periodontitis, and caries disease, are the two most common disease occurring in the mouth. They affect a large proportion of the world's population. The causes of periodontitis are varied, but the largest group are those caused by infections. The characteristic long asymptomatic period of development of periodontitis, make that patients are not aware of their condition. In-addition, it was observed that tobacco abuse affects the growth of disease and advancing disease state for periodontal diseases. Free radicals and other reactive particles are capable of destroying many cellular structures. They are produced mostly during the breathing process and the immune response or come from the environment. The evolution of living organisms ensure the proper tools to fight against reactive oxygen species after enzymatic and non-enzymatic by antioxidants. Sometimes this protection is not sufficient and the balance between antioxidants and oxidants is compromised. This condition is called oxidative stress. A number of studies looking for a link between oxidative stress, and diseases affecting human and determined that it is an important risk factor in many diseases. Evaluating the parameters of oxidative stress in the saliva allows for effective monitoring of disease progression, evaluation of the therapy and taking preventive measures in a timely manner. PMID- 26946574 TI - Hospital 'productivity' the key to savings. PMID- 26946575 TI - Expert panel engages with lively audience. PMID- 26946576 TI - CCGs' role in the future of the estate. AB - With the backdrop of a 21st century healthcare landscape where a number of previous commissioning and provider organisations now no longer exist, and other new bodies have taken their place, 'The role of the Clinical Commissioning Group in determining the future of the NHS estate' was the title of a presentation by Helen Davis, a partner in the Healthcare Advisory team at Arcadis, on the second day of this year's Healthcare Estates conference. While acknowledging the part that CCGs could have in managing and running the estate, Helen Davis felt they not only needed to be better 'geared up' with estates-related knowledge and expertise to be able to make a valuable contribution, but that effective collaboration between all providers, commissioners, and users of the healthcare estate was vital to ensure optimal use of facilities in the future. HEJ editor, Jonathan Baillie, reports. PMID- 26946577 TI - Consider fire safety at the earliest stage. PMID- 26946578 TI - Effectively maintaining high voltage switchgear. PMID- 26946579 TI - Mammoth order for Singapore project. AB - Two new hospitals in Singapore that form a new integrated healthcare hub, that feature a range of innovations in patient treatment and care, and are reportedly the country's first such healthcare facilities built together as an integrated development to complement each other's capabilities and services, were officially opened by Singapore's Prime Minister, Lee Hsien Loong, last October. Operated by Jurong Health, a public healthcare 'cluster' formed to facilitate the integration of healthcare services in the west of Singapore, the Ng Teng Fong Hospital and Jurong Community Hospital feature an extensive array of Gerflor flooring, selected, as the company explains in this article, for a combination of outstanding aesthetics, durability, safety, and hard wear. PMID- 26946580 TI - Pseudomonas - current and emerging issues. AB - Susan Pearson reports on some of the most interesting presentations at an International Biodeterioration and Biodegradation Society (IBBS) and Public Health England conference on 'Water microbiology - current and emerging issues in healthcare', held at the University of Winchester in early September. Two and a half years after the publication of the Addendum to HTM 04-01 - which gave advice on controlling and minimising the risk of morbidity and mortality due to P. aeruginosa in augmented care units - a major focus at the event was on how well the Addendum had been working for those 'at the frontline of infection control', and what improvements, if any, might be needed. PMID- 26946581 TI - Rapid microbiology - raising awareness. AB - A 'high-level overview' of some of the emerging rapid microbiology technologies designed to help healthcare engineering and infection control teams working in hospitals and other healthcare facilities more rapidly identify potentially hazardous levels of waterborne microorganisms in their water systems, enabling them to take prompt remedial action, and a look at the some of the 'pros and cons' of such testing techniques, was given by Nalco technical director, Howard Barnes, the vice-chair of the Legionella Control Association (LCA), at a recent LCA open day. HEJ editor, Jonathan Bailie, reports. PMID- 26946582 TI - Faster identification of waterborne threat. AB - The need to quickly identify and take remedial action against bacterial contamination within a hospital environment is essential for patient safety. Guidelines for the monitoring of Pseudomonas aeruginosa within hospital water systems are laid down in the HTM 04-01 Addendum, but many hospitals test more regularly as part of a water safety plan. Here, Andrew Headland, senior business manager for IDEXX Water, explains how a new testing method is allowing facility managers to detect Pseudomonas in hospital water more quickly, and deal with consequent contamination more effectively, ultimately helping to save lives. PMID- 26946583 TI - Culinary Compliations. A call becomes complicated by last night's dinner, a warm floor and a medication mishap. PMID- 26946584 TI - 5 Things Smart Managers Never Say. Effective leaders choose their words carefully. PMID- 26946585 TI - Community Paramedicine in a Rural Setting. Minnesota's approach includes free clinics and a mobile unit that travels the community. PMID- 26946586 TI - How to Make the Most of Your DISPATCH CPR INSTRUCTIONS. The makers and takers of 9-1-1 calls have a huge opportunity to help cardiac arrest victims. PMID- 26946587 TI - Cardiac Resuscitation RESEARCH REVIEW. Studies address the efficacy of continuous chest conpressions and automated cornmpression devices. PMID- 26946588 TI - Getting the Most From Your History and Physical. Done correctly, they can point you toward the right diagnosis. PMID- 26946589 TI - The ABCs of Pediatric Sepsis. Unrecognized sepsis kills kids; don't let it happen on your watch. PMID- 26946590 TI - Why You Need to SWOT Your Agency. EMS agencies have never been in more need of such analysis. PMID- 26946591 TI - What I Wish I'd Known Then, Survival tips for making it midway through your career. PMID- 26946592 TI - [ANATOMY AND BODIES: DEAD BODIES IN MUSEUMS FROM VAN RUYSCHA VON HAGENS]. AB - The aim of the conference of which we are here publishing the proceedings, held in Rome at Sapienza-University in 2013, was to valorise the specific museological heritage of Italian Universities, in relation to analogous European and non European Museums of Anatomy and Pathological Anatomy. A particular attention has been devoted to highlight the history of the origins and evolution of specific museological collections in order to focus reasons and circumstances of their foundation through the analysis of the signifcances, finctions and uses of anatomical parts or artifacts in different cultural contexts. PMID- 26946593 TI - [BODIES ARTIFACTS AND ANATOMICAL MODELS]. AB - Through three different museological approaches, diachronically arranged, the essay intends to introduce some pertinent questions related to the topic of the conference "Bodies and Anatomy: the corpses in the museums from Ruysch to Von Hagens. The first item analyzes a recent line of British museological studies, treating mainly medical British museums of the XVIII and XIX century, with intriguing developments arriving up to nowadays. A second point illustrates several aspects with regards to the donation and the arrangement of the morbid specimina Luigi Gedda collection, coming from the CSS Mendel of Rome to the Museum of Pathological Anatomy of Sapienza University of Rome. Finally, in a crossover between the previous points, it will be presented some recent studies regarding the employment of new communication technologies in the scientific and medical museology. PMID- 26946594 TI - [EMBALMING IN 19TH-20TH CENTURY LOMBARDY: PAOLO GORINI AND GIUSEPPE PARAVICINI]. AB - The Gorini Museum, later renamed Gorini Anatomical Collection, was founded in 1981 by pathologist Antonio Allegri. Many of the anatomical pieces created by scientist Paolo Gorini between 1843 and 1881 are held in the ancient chapterhouse of the Old Hospital of Lodi. These remains bear witness to Gorini's preparation skills and represent a precious historical and scientific heritage. Beyond the Gorini anatomical collection, the Museum has recently acquired the specimens prepared by Giuseppe Paravicini, a scientist and physician who developed a preservation method for educational and funerary purposes. Both the Gorini and the Paravicini specimens represent a unique opportunity to assess the evolution of preparation arts in terms of materials employed and the results achieved, and will successfully engage the general public with the world of anatomical mummies. PMID- 26946595 TI - [ANTONIO SCARPA IN HIS FIRST YEARS AT MODENA UNIVERSITY (1772-1776)]. AB - Antonio Scarpa undertakes his teacher's role at Modena University (1772) in favourable conditions for disciplines renewals in medicine and carrying out of political and administrative reforms, also affecting health professions. Besides the establishment of basic educational teachings for doctors, surgeons and midwives, the construction of the anatomical theater, the involvement of high education and intellectuals in sciences and humanities in an extensive program of renewal of higher education, the promulgation of ducal provisions aims to rule the practice of medicine, at any level. PMID- 26946596 TI - [BIRTH AND DEVELOPMENT OF THE ANATOMICAL MUSEUMS OF MODENA BETWEEN XVIII AND XIX CENTURY. THE OBSTETRIC MUSEUM, THE ANATOMICAL MUSEUM, THE ETHNOGRAPHIC ANTHROPOLOGIC MUSEUM]. AB - The interest for the study of Anatomy in Modena was particularly developed since the second half of eighteenth century, when the Duke Francesco III of Este promoted the reformation of the University and Antonio Scarpa was called from Padua to teach Anatomy. Scarpa promoted the building of the Anatomical Theatre, near the Grande Spedale, that was inaugurated in 1776. On the same year, the School of Obstetrics opened and determined the constitution of a first Cabinet or Obstetric Museum in a room next to the Theatre. After the Restoration, between 1817 and 1818, the Archduke Francesco IV of Austria Este promoted the realization of an Anatomical Museum: a big organized room in a new floor built on the Theatre. Two more rooms were added in, 1839 and a fourth one in 1853, under the direction of Paolo Gaddi. Furthermore Gaddi's interest for ethnographic studies determined the opening of the Ethnographic Anthropological Museum in 1866. PMID- 26946597 TI - PALEOPATHOLOGY OF PRE-COLUMBIAN MUMMIES AT THE MUSEUM OF ANTHROPOLOGY AND ETHNOLOGY IN FLORENCE. AB - We performed a histopathological study on the mummified tissue specimens of seven pre-Columbian mummies which arrived in Italy in the second half of the 19th century and are housed in the Section of Anthropology and Ethnology of the Museum of Natural History of the University of Florence. The results confirm that the modern techniques of pathological anatomy can be successfidly applied on mummifed tissues, so as to perform important paleopathological diagnoses. Among the results obtained from this study there is the only known complete paleopathological study of Chagas' disease (American Trypanosomiasis), comprising macroscopic, microscopic and ultrastructural data, as well as information on atherosclerosis, anthracosis, emphysema and pneumonia. PMID- 26946598 TI - ["PELVIC ABNORMALITIES" AT THE THE OSPEDALE MAGGIORE OF MILAN: HISTORY AND CURRENT EVENTS]. AB - The authors deal with the theme of the genesis and the increase of the obstetrical collection of pelvic abnormalities, i.e. the "dry" specimens stored at the Ospedale Maggiore (Major Hospital) of Milan (Italy), and of their scientific and educational values. Recently, following the restoration of the crypt of the Annunciation Church of the Ospedale Maggiore, a large space was converted, which could accommodate the pelvises collection permanently. A first step tofinally be able to introduce these extraordinary specimens not only to experts, but also to a wider audience. PMID- 26946599 TI - [DRY PREPARATIONS OF ANATOMICAL LESIONS IN PATHOLOGICAL ANATOMY MUSEUMS]. AB - Collection of pathological specimens began soon after the seminal description of autopsy by Giovan Battista Morgagni in Padoa in the second half of the 18th Century. Pathologists soon realized difficulties of preserving the form and to prevent decay caused by autolysis and attack by bacteria and parasites. The ancient procedures devoted to mummification were applied to the purpose, and a number of personal experiences were reported in the first half of the 19th century, mainly in Northern Italy and France, testifying a dedicated interest of the time in those areas. A combination of chemical fixation (with corrosive sublimate/mercuric chloride and/or tannic acid) and careful drying allowed to produce dry preparations, once very numerous in the Pathological Anatomy's Museums so much popular in the 19th and early 20th Century. In fact, it was the sole way to give visual evidence of disease and pathological processes. Only a limited number of these dry preparations are still present and visible in Pathology Museums, mainly in Universities of Northern Italy, while a few examples can be traced in the other European Country. PMID- 26946600 TI - "IN ALL ITS HIDEOUS AND APPALLING NAKEDNESS AND TRUTH": THE RECEPTION OF SOME ANATOMICAL COLLECTIONS IN GEORGIAN AND VICTORIAN ENGLAND. AB - This article explores the reception of some anatomical collections in Georgian and Victorian England. Both private medical museums and public anatomical museums reflected the central role played by anatomy in medical knowledge and education in the eighteenth and nineteenth centuries. However, because they were associated with death and sexuality, anatomical museums were both products of enlightenment science and potentially immoral loci likely to corrupt young and innocent women. But, as this article shows, the reasons behind the hostile receptions of some collections varied throughout the centuries, revealing in so doing the gradual professionalization of the medical field and growing monopoly of medical professionals over medical knowledge. PMID- 26946601 TI - MODERN BEAMS FOR ANCIENT MUMMIES COMPUTERIZED TOMOGRAPHY OF THE HOLOCENE MUMMIFIED REMAINS FROM WADI TAKARKORI (ACACUS, SOUTH-WESTERN LIBYA; MIDDLE PASTORAL). AB - The Middle Pastoral human remains from Wadi Takarkori in the Libyan Acacus mountains (Fezzan) are exceptionally preserved partial mummies ranging between 6100 and 5000 uncal years BP; this small sample represents the most ancient of its kind ever found. In this report, we present a survey of the skeletal anatomy of these mummifed corpses, based on high resolution CT-scan data, including a preliminary phenetic interpretation of their cranial morphology. PMID- 26946602 TI - JOSEPHINUM AND THE ANATOMICAL WAX MODEL COLLECTION, MEDICAL UNIVERSITY OF WIEN. AB - The collection of anatomical wax models housed at Wien Medical University's Josephinum is one of the greatest achievements initiated by Emperor Joseph II and -reflecting the reformist and revolutionary zeal of the 18th century period in which it was crafted--a remarkable benchmark of Enlightenment in Austria, spanning the divide between art and science. Originally purchased principally for teaching purposes, these artificial yet astonishingly lifelike bodies and body parts have provoked mixed reactions through the centuries, but the value of the collection with its over thousand anatomical wax models remains untouched. PMID- 26946603 TI - [POETRYAND TERATOLOGY: LORENZO MASCHERONI'S "INVITO A LESBIA CIDONIA" IN ANATOMICAL PREPARATIONS]. AB - In 1793 Lorenzo Mascheroni, appointed to the chair of Mathematics at the University of Pavia and well-known poet, wrote "L'invito di Dafni Orobiano a Lesbia Cidonia". In the poem he described the beauty of the University of Pavia and its wonders gathered in the scientific collections of the museums. From the beginning, one of the glass cases of the Museum for the History of the University of Pavia shows some of the preparations described in the Mascheroni's verses. In addition to some fossils, human teratological preparations are also exposed: they recall the verses of the poem dedicated to the description of "monstrous" preparations. However, after a detailed scientifc and historical research, the traditional association of the exposed anatomical preparations with the verses is questioned. PMID- 26946604 TI - [ANATOMICAL PREPARATIONS IN MUSEUMS A SPECIAL CATEGORY OF CULTURAL HERITAGE]. AB - The international debate on the issue of human remains in museums and on the ethical issues related to their exhibition stimulates reflection on the Italian anatomical collections and on their preparations. A definition of human remains or of anatomical preparation does not exist in the Italian legislation. The anatomical specimens in museums are protected by the laws of Cultural Heritage as part of public collections, but their status is not well defined. By their nature of human material they would in fact be considered as a special category of Cultural Heritage. Because they are part of a cadaver they can be regarded as res nullius, but since treated with special techniques they could also change their meaning and being considered a species nova. Finally, it reflects on the possibility of creating a museum in Italy composed by new anatomical preparations. The article outline the contours of a museological issue that deserves to be investigated in order to better identify the anatomical preparations and their management in museums. PMID- 26946605 TI - "PRE-COLUMBIAN MOULAGES". HUACOS, MUMMIES AND PHOTOGRAPHS IN THE INTERNATIONAL CONTROVERSY OVER PRECOLUMBIAN DISEASES, 1894-1910. AB - By the late nineteenth century an international controversy arose referred to the probable existence of certain diseases such as leprosy, syphilis and lupus in pre Columbian America. Led by the American physician Albert Sidney Ashmead (1850 1911), it brought together scholars from Europe and the Americas. In this context, certain types of Peruvian archaeological pottery and "mummies", along with series of photographs illustrating the effects of these diseases in contemporary patients, met a prominent role as comparative evidence. In this article we analyze how this type of collections were used as evidence in the debates about pathologies of the past, an issue that from a historical standpoint have received considerably little attention. PMID- 26946606 TI - [CORPSE CONSERVATION: ATTILIO MAGGIA'S PREPARATIONS]. AB - The authors analyze Attilio Maggia's method of corpse conservation. His method was based on development of formaline vapours and preservation of corpse into a hermetically closed coffin (U.S.Patent 1150688 - Aug. 17, 1915). The corpses preserved could also be hardened after the treatment, exposing them to the air. Attilio Maggia (1864-1945) treated the corpse of italian writer Giovanni Verga (1840-1922). Some Maggia's preparations were preserved into obstetrical museum at Milan University: they are lost, but some records remain (an old inventory register) and attest us the industry of this physician. PMID- 26946607 TI - [BOOSTING CITIZENS'AWARENESS: THE ANATOMICAL COLLECTIONS FOR TEACHING PAST AND PRESENT]. AB - The challenge of eight museums of the University Museum System of the University of Siena for years has been that of annually offering to Siena schools a course of learning on the themes of science. The learning workshop is articulated in a frontal lesson, followed by a visit of the class in the proponent museum to better expound the chosen theme by the teacher. The fundamental role for such a didactic proposal is sustained by the conserved collections in the museum, used in the past to facilitate the university professor in their lessons, and that continue to show a strong didactic value helping the young student to "enter" in a captivating and easy manner into the world of science. In particular, the Anatomical Museum "L. Comparini" has now organized for some years a course of learning using historical instruments, models in terracotta and wax, plastinates, and tables that consent the operator to confront, with young children, the theme of the history of anatomy and the ways and means for research, formation, and the distribution of the anatomical sciences. PMID- 26946608 TI - THE MEDICAL COLLECTIONS OF THE UNIVERSITY OF TARTU. AB - In the year 1999, a new and modern building Biomedicum was finished addressed to preclinic subjects of the Medical Faculty of the University of Tartu; the institutions of anatomy as well as pathological anatomy and forensic medicine moved there. However; no place was planned to exhibit the collections of specimens. Many of the specimens which had so far only been used for learning purposes found their place in the Old Anatomical Theatre, in the hope that this could be transformed as a museum. The medical collections of the Medical Faculty were opened up for a broader audience in October 2005. With the support of the national programme "The collections of humanities and natural sciences", the medical study specimens, models, moulages, and literature related to them in danger of being destroyed were collected from several subdivisions and buildings of the Medical Faculty. In 2012, the medical exhibition moved to the premises of Science Centre AHHAA and in the same time a specifc educational study began to be developed. PMID- 26946609 TI - THE ANATOMICAL MUSEUM PEDRO ARA. AB - The contribute is aimed to shed light on the history of the Anatomical Museum Pedro Ara since his foundation in 1878. Particularly, it describes the activity of Pedro Ara in preparing the anatomical specimens, which constitute the original collection of the Museum. PMID- 26946611 TI - [COSTE J., Writings about suffering. Medical consultation in France (1550-1825). Ceyzerieu, Champ-Vallon, 2014, pp. 274]. PMID- 26946610 TI - [GOUREVITCH D., For an archeology of Roman medicine. Paris, De Boccard, 2011. GOUREVITCH D., Limos kai loimos. A study of the Galenic plague. Paris, De Boccard, 2013]. PMID- 26946612 TI - Effectiveness of dry needling on reducing pain intensity in patients with myofascial pain syndrome: a Meta-analysis. AB - OBJECTIVE: To summarize the literature about the effectiveness of dry needling (DN) on relieving pain and increasing range of motion (ROM) in individuals with myofascial pain syndrome (MPS). METHODS: Papers published from January 2000 to January 2013 were identified through an electronic search in the databases MEDLINE, Dialnet, Cochrane Library Plus, Physiotherapy Evidence Data-base (PEDro) and Spanish Superior Council of Scientific Research (CSIC). The studies included were randomized controlled trials written in English and/or Spanish about the effectiveness of DN on pain and ROM in individuals with MPS. RESULTS: Out of 19 clinical trials that were potentially relevant, a total of 10 were included in the Meta-analysis. Regarding pain intensity reduction when measured before and immediately after the intervention, DN achieved improvement compared with the placebo treatment [d = - 0.49; 95% CI (- 3.21, 0.42)] and with the control group [d = - 9.13; 95% C (- 14.70, - 3.56)]. However, other treatments achieved better results on the same variable compared with DN, considering the measurements for pre-treatment and immediately after [d = 2.54; 95% CI (- 0.40, 5.48)], as well as the pre-treatment and after 3-4 weeks [d = 4.23; 95% CI (0.78, 7.68)]. DN showed a significantly increased ROM when measured before the intervention and immediately after, in comparison with the placebo [d = 2.00; 95% C (1.60, 2.41)]. However, other treatments achieved a significant better result regarding ROM when it was measured before the intervention and immediately after, as compared with DN [d = - 1.42; 95% CI (- 1.84, - 0.99)]. CONCLUSION: DN was less effective on decreasing pain comparing to the placebo group. Other treatments were more effective than DN on reducing pain after 3-4 weeks. However, on increasing ROM, DN was more effective comparing to that of placebo group, but less than other treatments. PMID- 26946613 TI - Effect of compound Kushen injection on T-cell subgroups and natural killer cells in patients with locally advanced non-small-cell lung cancer treated with concomitant radiochemotherapy. AB - OBJECTIVE: To observe effect of compound Kushen injection on T-cell subgroups and NK cells in patients with locally advanced non-small-cell lung cancer (NSCLC) treated with concomitant radiochemotherapy. METHODS: We randomly divided 60 patients with locally advanced NSCLC who were treated at our hospital between May 2011 and May 2013 into a treatment group and a control group by drawing. The treatment group (n = 30) received concomitant radiochemotherapy plus compound Keshen injection, and the control group (n = 30) received only radiochemotherapy. RESULTS: After treatment, levels of CD3+, CD4+, CD4+/CD8+ and CD16+/CD56+ cells had significantly increased, and CD8+ cells had significantly decreased, in the treatment group compared with both their pretreatment levels and with levels in the control group. In the control group, post-treatment levels of CD3 +, CD4 +, CD4 +/CD8 + and CD16+/CD56+ cells were not significantly changed from pretreatment levels. The two groups did not significantly differ in their rates of toxicity reactions (P> 0.05). CONCLUSION: Compound Kushen injections can increase immunologic function in patients with locally advanced non-small cell lung cancer who receive concomitant radiochemotherapy. PMID- 26946614 TI - Acupuncture-movement therapy for acute lumbar sprain: a randomized controlled clinical trial. AB - OBJECTIVE: Several studies have reported that acupuncture is effective for treatment of acute lumbar sprain, but they neglected to consider that acupuncture cannot remarkably improve lumbar activity. We performed a randomized controlled trial to evaluate the effect of acupuncture-movement therapy versus conventional acupuncture in the treatment of acute lumbar sprain. METHODS: Sixty patients were randomized into four groups: the acupuncture-movement (AM) group, sham acupuncture-movement (SAM) group, conventional acupuncture (CA) group, and physical therapy (PT) group. Patients in the AM group were treated with acupuncture at Yintang (EX-HN 3) and exercise of the lumbar region during acupuncture. Patients in the SAM group were treated with sham acupuncture at Yintang (EX-HN 3) and exercise of the lumbar region during sham acupuncture. Conventional acupuncture was performed in the CA group, and physical therapy was applied in the PT group. Each treatment lasted for 20 min. Patients were assessed before and after treatment using a visual analogue scale (VAS) and the Roland Morris Questionnaire (RMQ). RESULTS: The VAS and RMQ scores in the AM group were significantly lower after than before treatment (P < 0.01). The AM group reported lower RMQ scores in after-treatment and 24 h after treatment and lower VAS score in 24 h after treatment in comparison with those of the CA, SAM, and PT groups (P < 0.05). CONCULSION: Acupuncture-movement therapy is effective for treating acute lumbar sprain with a persistent pain-relief and remarkable improvement of lumbar activity. Movement, that is, lumbar exercise during acupuncture, enhances the effect of acupuncture. PMID- 26946615 TI - Effect of bloodletting therapy at local myofascial trigger points and acupuncture at Jiaji (EX-B 2) points on upper back myofascial pain syndrome: a randomized controlled trial. AB - OBJECTIVE: To observe the clinical efficacy of bloodletting therapy and acupuncture at Jiaji points for treating upper back myofascial pain syndrome (MPS), and compare this with lidocaine block therapy. METHODS: A total of 66 upper back MPS patients were randomly assigned to either the treatment group or the control group in a 1: 1 ratio. The treatment group (n = 33) were treated with bloodletting therapy at local myofascial trigger points and acupuncture at Jiaji (EX-B 2) points; one treatment course consisted of five, single 20-min-treatments with a 2-day break between each treatment. The control group (n = 33) were treated with a lidocaine block at trigger points; one treatment course consisted of five sessions of lidocaine block therapy with a 2-day break between each session. The simplified McGill Scale (SF-MPQ) and tenderness threshold determination were used to assess pain before and after a course of treatment. RESULTS: After the third and fifth treatment, the SF-MPQ values were significantly decreased (P < 0.01) and the tenderness thresholds were significantly increased (P < 0.01) in both groups compared with before treatment. There were no significant differences in pain assessments between the two groups after three and five treatments (P > 0.05). There were five cases with minor adverse reactions reported in the control patients, while no adverse reactions were reported in the treatment group. CONCLUSION: Bloodletting therapy at local myofascial trigger points and acupuncture at Jiaji points was effective in treating upper back MPS. Clinically, bloodletting and acupuncture therapy had the same efficacy as the lidocaine block therapy, with fewer adverse reactions. PMID- 26946616 TI - Effects of Traditional Chinese Medicine herbs for tonifying Qi and kidney, and replenishing spleen on intermittent asthma in children aged 2 to 5 years old. AB - OBJECTIVE: To evaluate the efficacy and safety of Traditional Chinese Medicine (TCM) herbs for tonifying Qi and kidney, and replenishing spleen on intermittent asthma in children aged 2 and 5 years. METHODS: A randomized, single-blind, placebo controlled trial was conducted. Children with intermittent asthma were enrolled and their baseline conditions were measured using a questionnaire. A total of 60 participants, aged 2 to 5, were randomized into either the treatment group (n = 40) or the placebo group (n = 20). The treatment group was treated with granules of TCM herbs for tonifying Qi and kidney, and replenishing spleen, and the placebo group was given placebo granules for 3 months. The number of asthma attacks was counted and TCM syndrome scores were measured at 1, 2, 3, 6, 9, and 12 months. The airway resistance and levels of eosinophil cationic protein for the two groups were observed before and after 3 months. The results were statistically analyzed. RESULTS: Compared with the placebo group, the number of asthma attacks significantly decreased in the treatment group (P < 0.05). For the treatment group, the TCM syndrome scores decreased after 1 and 2 months; there was also a significant difference in scores between the two groups (P < 0.05). The difference remained after the medicine was stopped for 9 months (P < 0.05). After the 3-month treatment, compared with the placebo group, the airway resistance decreased in the treatment group (P < 0.05). No adverse events were reported in the treatment group. CONCLUSION: The TCM herbs for tonifying Qi and kidney, and replenishing spleen reduced the number of intermittent asthma attacks, decreased the TCM syndrome scores, and reduced the airway resistance in the children aged 2 to 5. PMID- 26946617 TI - Efficacy and safety evaluation of intravenous infusion of cervus and cucumis polypeptides for treatment of avascular necrosis of the femoral head: a randomized clinical trial. AB - OBJECTIVE: To investigate the efficacy and safety of intravenous cervus and cucumis polypeptides for treating avascular necrosis of the femoral head (ANFH) in regard to pain and hip function in a randomized clinical trial. METHODS: A total of 96 subjects with ANFH who were recruited at the Orthopaedic Hospital Affiliated with Hebei United University and Qian Hai Femoral Head Hospital of Beijing were assigned by lottery to an intervention group (n = 48) or a control group (n = 48). All subjects underwent physical therapy and rehabilitation exercises. In addition, subjects in the intervention group were given intravenous infusions of cervus and cucumis polypeptides. Visual analogue scale (VAS), Harris hip score, and radiography or magnetic resonance imaging were applied to assess all subjects at the beginning of treatment and 3, 6, and 9 months afterward. All the subjects were followed up for 2 years. RESULTS: At the beginning of treatment, there were no statistically significant differences between the two groups in terms of the general condition of patients or the VAS and Harris hip scores (all P > 0.05). At 3, 6, and 9 months after treatment, however, the VAS score decreased and the Harris hip score increased in all patients, with the improvement of intervention group significantly greater than that of the control group (P < 0.05). The total effectiveness rates for the intervention and control groups were 89.58% and 70.83%, respectively, with the difference being statistically significant (P < 0.05). There was no statistically significant difference between the two groups in terms of the safety of the injections (P> 0.05). CONCLUSION: Intravenous infusion of cervus and cucumis polypeptides relieved pain and improved hip function of subjects with ANFH. Thus, the intravenous infusion of cervus and cucumis polypeptides was a safe, effective treatment for ANFH. PMID- 26946618 TI - Efficacy and safety of Yunxiangjing derived from Chinese herbal medicine administered as an enema in the management of acute radiation-induced proctitis in patients with pelvic malignancy. AB - OBJECTIVE: To assess the efficacy and safety of Yunxiangjing (YXJ), derived from Chinese herbal medicine, in the management of acute radiation-induced proctitis (ARIP) in patients with pelvic malignancy. METHODS: Forty-eight patients with grade 2 ARIP were administered YXJ as an enema (1 : 30 dilution) for 2 weeks and followed up for 2 years. All were assessed for response and ARIP grade. Quality of life (QOL) was assessed with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30. RESULTS: Of the 48 patients, six (12.5%) achieved complete remission of ARIP and 28 (58.3%) showed a decrease from grade 2 to grade 1 ARIP. No patient experienced a grade >=3 toxicity. At the end of radiotherapy, patients showed significant improvements in QOL (P < 0.05). Two years after treatment, 46 patients showed no late toxicity, with only two experiencing grade 1 late toxicity. CONCLUSION: YXJ can be used as an enema to manage acute radiation-induced proctitis in cancer patients undergoing radiotherapy. These findings suggest that YXJ enema may be an alternative treatment of ARIP. PMID- 26946619 TI - Effect of transcutaneous electrical nerve stimulation through acupoints of Pucan (BL 61) and Shenmai (BL 62) on intraocular pressure in patients with glaucoma: a randomized controlled trial. AB - OBJECTIVE: To investigate the effects of transcutaneous electrical nerve stimulation (TENS) through acupoints on the intraocular pressure (IOP) in patients with glaucoma. METHODS: A single-blinded, randomized experimental design study was conducted. Patients from the North of Taipei Ophthalmology outpatient department diagnosed with intraocular hypertension were selected and were further enrolled if they met the research subject criteria. The patients who met all criteria, and who met no exclusion criteria became the participants. Participants were randomly assigned into the treated group, wherein the TENS electrodes (Qing Ming Medical Device Co., Ltd., New Taipei City, China) were applied with direct current (DC) on the acupoints Pucan (BL 61) and Shenmai (BL 62) for 20 min. The control group received no TENS electrode treatments. Measurements of IOP were taken four times using a pneumotonometer (Clinico Co., Ltd., New Taipei City, China), before, immediately after, 30 min after, and 60 min after TENS electrode treatments. RESULTS: Eighty-two participants completed the experiment. IOP decreased more in the group treated with DC (P < 0.01) than in the control group. The IOPs were not affected by the age of the patients and their usage of medications. CONCLUSION: TENS of acupoints of Pucan (BL 61) and Shenmai (BL 62) could significantly reduce the IOP in patients with glaucoma. PMID- 26946620 TI - Effect of modified fasting therapy on body weight, fat and muscle mass, and blood chemistry in patients with obesity. AB - OBJECTIVE: The aim of this study was to investigate the effects and safety of modified fasting therapy using fermented medicinal herbs and exercise on body weight, fat and muscle mass, and blood chemistry in obese subjects. METHODS: Twenty-six patients participated in a 14-day fast, during which they ingested a supplement made from fermented medicinal herbs and carbohydrates (intake: 400-600 kcal/d). The schedule included 7 prefasting relief days and 14 days of stepwise reintroduction of food. The patients also took part in an exercise program that incorporated Qigong, weight training, and walking exercises. The efficacy of treatments was observed by assessing body fat mass and muscle mass, and alanine aminotransferase (ALT), aspartate aminotransferase (AST), cholesterol, and triglycerides in each study period. Specific symptoms or side effects were reported. RESULTS: Body weight and body fat mass both decreased significantly by (5.16 +/- 0.95) and (3.89 +/- 0.79) kg (both P < 0.05), while muscle mass decreased by an average of (0.26 +/- 0.22) kg, without statistical significance. ALT levels were significantly decreased (P < 0.05), while AST levels decreased without statistical significance (P = 0.052). The levels of total cholesterol and triglycerides were also significantly decreased (both P < 0.05). There were few adverse events except for mild dizziness, which did not affect everyday living. CONCLUSION: These results suggest that modified fasting therapy using fermented medicinal herbs and exercise could be effective and safe on obese patients. PMID- 26946621 TI - Pulse changes in patients with cervical spondylosis before and after acupuncture treatment. AB - OBJECTIVE: To study changes in pulse diagram parameters (PDP) in patients with cervical spondylosis (CS) before and after acupuncture treatment, explore the characteristics of PDP and the relationship between PDP changes and therapeutic effectiveness, and provide evidence for outcome prediction and objective evaluation of CS treatment before and after acupuncture treatment. METHODS: Patients with CS were treated with acupuncture and measured with a pulse acquisition device based on image (PADBI) before the first and after the tenth acupuncture sessions. Changes in PDP from before until after the acupuncture sessions and patient impressions were analyzed to judge the effect of acupuncture treatment for. RESULTS: The PDP values in effective patients were closer to normal values. This indicated that Qi stagnation and blood stasis of the patients was improved. The PDP changes from before to after the first acupuncture treatment were more obvious than those from before to after the tenth acupuncture treatment. This result indicates that the speed of symptom improvement decreased significantly after several acupuncture courses. Analysis of correlation between efficacy and PDP showed that the changes in PDP in five patients was abnormal, which mainly manifested as values of h1, u, p, Pp, and t1, and no significant changes or differences were increased with standard values. This indicated that the symptoms of CS were not improved in these patients. CONCLUSION: PADBI can provide evidence for outcome prediction of acupuncture treatment in patients with CS. PADBI can provide evidence for objective evaluation of acupuncture treatment of CS. PMID- 26946622 TI - Nelumbo Nucifera leaf extract attenuated pancreatic beta-cells toxicity induced by interleukin-1beta and interferon-gamma, and increased insulin secrection of pancreatic beta-cells in streptozotocin-induced diabetic rats. AB - OBJECTIVE: To evaluate the effect of Nelumbo Nucifera leaf water extract (NNLE) on insulinoma (RIN) cells induced by interleukin-1beta (IL-1beta) and interferon g (IFN-gamma), and injured pancreatic beta-cells induced by Streptozotocin (STZ) in rats. METHODS: The anti-oxidative effects of NNLE were assessed using 1,1 diphenyl-2-picryl hydrazyl (DPPH) and nitric oxide (NO) scavenging assays. The inhibitory effect of NNLE on alpha-glucosidase and DPP (dipeptidyl peptidase)-IV was measured in vitro. Pancreatic beta-cell protective and insulin secretory effects were assessed, using IL-1beta and IFN-gamma-induced rat RIN cells. STZ induced diabetic rats were treated with 50, 100, and 400 mg/kg NNLE for 4 weeks. The effects of NNLE on blood glucose (BG), body weight (BW), and lipid profiles were measured. RESULTS: NNLE inhibited DPPH, NO, alpha-glucosidase, and DPP-IV which were directly linked to the function of beta-cells. Furthermore, NNLE protected RIN cells from toxicity induced by IL-1beta and IFN-gamma, decreased NO production, and increased insulin secretion. NNLE caused a significant reduction in blood glucose, triglyceride (TG), total cholesterol (TC), blood urea nitrogen (BUN), and creatinine in STZ-induced diabetic rats. Furthermore, it significantly decreased BW loss in STZ-induced diabetic rats. CONCLUSION: Our results suggest that NNLE reduced the toxicity in insulinoma cells and increased insulin secretion in pancreatic beta-cells in STZ-induced diabetic rats. PMID- 26946623 TI - Puerarin reduces apoptosis in rat hippocampal neurons culturea in high glucose medium by modulating the p38 mitogen activated protein kinase and c-Jun N terminal kinase signaling pathways. AB - OBJECTIVE: To investigate the neuroprotective etfect of puerarin on rat hippocampal neurons cultured in high glucose medium, and to examine the role of the p38 mitogen activated protein kinase (p38 MAPK) and c-Jun N-terminal kinase (JNK) signaling pathways in this effect. METHODS: Primary cultures of hippocampal neurons were prepared from newborn Sprague Dawley rats. Neuron-specific enolase immunocytochemistry was used to identify neurons. The neurons were cultured with normal medium (control group) or with high-glucose medium (high-glucose group), and puerarin (puerarin group), a p38 MAPK inhibitor (SB239063; p38 MAPK inhibitor group) or a JNK inhibitor (SP600125; JNK inhibitor group) were added. After 72 h of treatment, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay was performed to detect apoptosis, and western blotting was used to assess protein levels of p-p38, p38, p-JNK and JNK. RESULTS: In the high glucose group, the neuronal apoptosis rate and the p-p38/p38 and p-JNK/JNK ratios were higher than in the control group. The p38 MAPK and JNK inhibitors prevented this increase in the apoptosis rate. The apoptosis rates in the puerarin group, the p38 MAPK inhibitor group and the JNK inhibitor group were significantly decreased compared with the high-glucose group. Moreover, protein levels of p-p38 and p-JNK were significantly reduced, and the p-p38/p38 and p-JNK/JNK ratios were decreased in the puerarin group compared with the high-glucose group. In addition, compared with the high-glucose group, p-p38 levels and the p-p38/p38 ratio were reduced in the p38 MAPK inhibitor group, and p-JNK levels and the p JNK/JNK ratio were decreased in the JNK inhibitor group. CONCLUSION: Puerarin attenuates neuronal apoptosis induced by high glucose by reducing the phosphorylation of p38 and JNK. PMID- 26946624 TI - Electroacupuncture alters pain-related behaviors and expression of spinal prostaglandin E2 in a rat model of neuropathic pain. AB - OBJECTIVE: To investigate the role of spinal prostaglandin E2 (PGE2) in electroacupuncture (EA) analgesia and assess the theoretical basis for selection of acupoints in the treatment of neuropathic pain. METHODS: A rat model of neuropathic pain was established. Rats were randomly divided into normal, model, sham, EA 1, EA 2, and EA 3 groups. In EA 1 group, the rats were needled at bilateral L5 Jiaji (EX-B2), Dachangshu (BL 25), Weizhong (BL 40) and Kunlun (BL 60). In EA 2 group, the rats were needled at bilateral Weizhong (BL 40) and Kunlun (BL 60). In EA 3 group, the rats were needled at bilateral L5 Jiaji (EX B2) and Dachangshu (BL 25). EA stimulation was administered once daily over 7 days. Motor function and thermal withdrawal latencies were evaluated at 1 day preoperatively and at 3, 5, and 7 days postoperatively. After 7 days of intervention, enzyme-linked immunosorbnent assay (ELISA) was used to quantify the expression of the spinal PGE2. RESULTS: Rats in the model group exhibited evident hyperalgesia in responses to thermal withdrawal latencies compared with those in the control group (P < 0.01), and EA reversed thermal withdrawal latencies (P < 0.01). The expression level of the spinal PGE2 was significantly higher in the model group than that in the control group and was reversed by EA (P < 0.01; P < 0.05). CONCLUSION: The effect of EA on neuropathic pain might alleviate the hyperalgesia state by an inhibition of local prostaglandin E2 secretion. PMID- 26946625 TI - Effect of Xinfeng capsule on nuclear factor Kappa B/tumor necrosis factor alpha and transforming growth factor beta 1/Smads pathways in rats with cardiac injuries induced by adjuvant arthritis. AB - OBJECTIVE: To investigate effects of Xinfeng capsule (XFC) on cardiac function in rats with adjuvant arthritis (AA) and explore the mechanism of these effects. METHODS: Forty-eight rats were randomly divided into normal control (NC), model control (MC), methotrexate (MTX) and XFC groups of equal size. In all groups except for the NC group, 0.1 mL Freund's complete adjuvant (FCA) was intracutaneously injected in the right rear vola pedis to induce inflammation. Drugs were applied beginning 19 days after induction of inflammation. Normal saline was administered to the NC and MC groups and 1 mg/ 100 g MTX (weekly) and 0.12 g/100 g XFC (daily) to the MTX and XFC groups, respectively. Rats were sacrificed after 30 day of treatment. Toe swelling degree (TSD), arthritis index (Al), cardiac function and expression of nuclear factor kappa B (NF-kappaB)/tumor necrosis factor alpha (TNF-alpha) and transforming growth factor beta 1 (TGF beta1)/Smads pathway proteins were measured. RESULTS: In the MC group, TSD and Al were greatly increased, while parameters of cardiac function were decreased and morphological analysis showed myocardial cell damage. Expression of TNF-alpha, NF KB, Smad2, P-Smad2, Smad4 and TGF-beta1 proteins were elevated in cardiac tissue, while Smad7 expression was decreased. TSD and Al values closely correlated to parameters of cardiac function and to levels of proteins in the NF-kappaB/TNF alpha and TGF-beta1/Smads pathways. Certain correlations were identified among TGF-beta1 and NF-KB, Smad2, P-Smad2 and Smad4. With XFC intervention, both TSD and Al were decreased and parameters of cardiac function and ultrastructure of myocardial cells improved. Expressions of NF-kappaB, Smad2, and Smad4 proteins were greatly decreased and Smad7 expression was elevated, as compared with levels in the MC and MTX groups. CONCLUSION: XFC regulates expression of proteins in the NF-KB/TNF-alpha and TGF-beta1/Smads pathways, decreases immune complex deposition in cardiac tissue and improves cardiac function in AA rats via upregulation of Smad7. PMID- 26946626 TI - Effect of Gubenfangxiao decoction on respiratory syncytial virus-induced asthma and expression of asthma susceptibility gene orosomucoid 1-like protein 3 in mice. AB - OBJECTIVE: To investigate the effect of Guben-fangxiao decoction (GBFXD) on respiratory-syncytial-virus (RSV)-induced asthma and the expression of asthma susceptibility gene, orosomucoid 1-like protein 3 (ORMDL3) in mice. METHODS: Seventy-two female BALB/c mice were randomly assigned to normal, model, GBFXD high dose, GBFXD moderate dose, GBFXD low dose and montelukast groups. An asthma model was induced via intraperitoneal injection and aerosol inhalation of ovalbumin (OVA) and repeated intranasal instillation of RSV in all mice, except those in the normal group. All treatments were administered at the first onset of asthma (within 8 weeks of model establishment) and the mice were euthanized after 28 days of treatment. The levels of transforming growth factor-beta (TGF-beta) and interleukin-6 (IL-6) in bronchoalveolar lavacie fluid (BALF) of the mice were measured and the expression of asthma susceptibility gene ORMDL3 in lung tissue was determined using real-time polymerase chain reaction (RT-PCR) and western blotting. RESULTS: Expression of ORMDL3 and levels of TGF-beta and IL-6 were significantly higher in the model group (P < 0.05, P < 0.01) compared with the normal mice. Levels of ORMDL3, TGF-beta and IL-6 were significantly lower in all three GBFXD treated groups (P < 0.05) compared with the model group. However, the levels in the GBFXD treatment groups did not differ significantly from the montelukast group. CONCLUSION: GBFXD had a therapeutic effect in this experimental model. The functional mechanism of GBFXD may involve multiple factors, including alleviation of airway inflammation, down-regulation of asthma susceptibility gene ORMDL3 and inhibition of airway remodeling. PMID- 26946627 TI - Bloodletting at Jing-well points decreases interstitial fluid flow in the thalamus of rats. AB - OBJECTIVE: To investigate the changes in the neuronal microenvironment of the middle cerebral artery (MCA) territory induced by Jing-well points bloodletting acupuncture (WPBA) and to explore the neuroprotective mechanism of WPBA in stroke. METHODS: Adult male Sprague Dawley (n = 32) rats were randomly divided into four groups of eight animals each: WPBA-thalamus group (WT), WPBA-caudate nucleus group (WC), sham-control thalamus group (ST) and sham-control caudate nucleus group (SC). Animals in the WT and WC groups received 2 uL of the extracellular tracer gadolinium-diethylene triamine pentaacetic acid (Gd-DTPA) injected into the thalamus or caudate nucleus, respectively, and 12 Jing-well points in the distal ends of the rats' digits were used for WPBA. Although 2 uL of Gd-DTPA was injected into the thalamus or caudate nucleus, respectively, for animals in the two sham groups (ST and SC), no acupuncture or bloodletting was performed. Brain extracellular space and interstitial fluid flow parameters were measured using Gd-DTPA-enhanced magnetic resonance imaging. RESULTS: The brain interstitial fluid flow speed was decreased in the thalamus after WPBA, with a significantly lower Gd-DTPA clearance rate and longer half-life of Gd-DTPA in the thalamus of treated rats than those in sham-control rats [WPBA-treated rats' clearance rate, (7.47 +/- 3.15) x 10(-5)/s (P.= 0.009); half-life, (1.52 +/- 0.13) h, P = 0.000]. By contrast, no significant changes in brain extracellular space and interstitial fluid flow parameters were detected in the caudate nucleus after WPBA (P = 0.649). In addition, no differences in the morphology of the brain extracellular space or the final distribution of the traced brain interstitial fluid were demonstrated between the WT and WC groups (P = 0.631, P = 0.970, respectively). CONCLUSION: The WPBA decreased the speed of the local thalamic ISF flow in rats, which is assumed to be a beneficial protection by down modulated the metabolic rate of the attacked neurons under stroke. PMID- 26946628 TI - Synergetic effects of aqueous extracts of Fuzi (Radix Aconiti Lateralis Preparata) and Tubeimu (Rhizoma Bolbostemmatis) on MDA-MB-231 and SKBR3 cells. AB - OBJECTIVE: To test the synergistic effects of theaqueous extract of Tubeimu (Rhizoma Bolbostemmatis) and Fuzi (Radix Aconiti Lateralis Preparata) on MDA-MB 231 and SKBR3 breast cancer cells. METHODS: A combined index was created for the effects of Tubeimu (Rhizoma Bolbostemmatis) and Fuzi (Radix Aconiti Lateralis Preparata) extracts. Cell proliferation was performed by trypan blue exclusion and 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxy-methoxyphenyl)-2-(4-sulfophenyl)-2H tetrazolium (MTS) assays. Flow cytometry was used to assess cell cycle distribution and apoptosis. Cell migration was determined by wound-healing and transwell assays. Confocal microscopy was used to detect E-cadherin and actin filaments. RESULTS: The aqueous extract from Tubeimu (Rhizoma Bolbostemmatis) and Fuzi (Radix AconitiLateralis Preparata) exerted synergetic effects on the growth of MDA-MB-231 cells and G1 phase arrest. When exposed to extracts at concentrations of 62.5 :62.5 and 62.5: 31.3 ug/mL, the combination index was 0.83 and 0.74, respectively. Interestingly, 62.5: 31.3 pg/mL of combined drugs enhanced the inhibitory effect of Tubeimu (Rhizoma Bolbostemmatis) on the migration of SKBR3 cells and reduced the stimulative effect of Fuzi (Radix Aconiti Lateralis Preparata) (P < 0.01), in which cells showed an increased expression of E-cadherin and reorganization of actin filaments (P < 0.001). 62.5:62.5 ug/mL extract also synergistically induced apoptosis of MDA-MB-231 cells (P < 0.05 and P < 0.001). Acting as the main active ingredients in the extract, tubeimoside I and acetylbenzoylaconine at 10: 10 ug/ mL and 5:2.5 ug/mL also produced inhibitory effects on the proliferation and migration of cells (P < 0.01). CONCLUSION: Tubeimu (Rhizoma Bolbostemmatis) and Fuzi (Radix Aconiti Lateralis Preparata) extracts had synergic effects on MDA-MB-231 and SKBR3 cells. PMID- 26946629 TI - Ocular myasthenia gravis accompanied by anosmia. AB - We report a case of ocular myasthenia gravis (MG) accompanied by anosmia. A 76 year-old man had idiopathic anosmia of 2-year duration. Four months before consultation, he began to have drooping in the right upper eyelid along with muscle soreness, distension, and pain in the nape. His tongue was dark-red with a thin and white coating; his pulse was wiry and slippery. According to Traditional Chinese Medicine, eyelid drooping and anosmia are the main signs of liver constraint and spleen deficiency. In Western Medicine, the diagnosis was ocular MG and idiopathic anosmia. Our patient, along with the literature, suggests that anosmia may be an early symptom before MG. MG accompanied by anosmia could be a special subtype of MG according to antibody production and symptoms. PMID- 26946630 TI - [Between life and death]. PMID- 26946631 TI - [Collaboration and coordination of birth attendants and neonatologists with special reference to documentation]. PMID- 26946632 TI - ["Wrapped in diapers...."- a brief history of the first garment]. PMID- 26946633 TI - [Cervical cancer: vaccination against cancer. Updates on vaccination and early detection]. PMID- 26946634 TI - [Homeopathy in the hospital - a serious addition or superfluous nonsense?]. PMID- 26946635 TI - [Hunger perception in breast fed infants - influence of milk components, appetite control factors and gastric emptying]. PMID- 26946636 TI - [Role of breast milk leptin in breastfeeding behavior and gastric emptying in the infant]. PMID- 26946637 TI - [Transfer of maternal stem cells to the child by breastfeeding: is the development of the infant promoted?]. PMID- 26946638 TI - [Measures to promote exclusive breastfeeding]. PMID- 26946639 TI - [NeoPAss, a interprofessional clinical management program including the family]. PMID- 26946640 TI - [Postnatal growth retardation and the possible growth improvement by individually adapted nutrition]. PMID- 26946641 TI - [Evidenced based strategies to support breastfeeding and breast milk feeding of severely ill infants]. PMID- 26946642 TI - [Anxiety in the hospital]. PMID- 26946643 TI - [What should pregnant women keep in mind about the vegetarian diet?]. PMID- 26946644 TI - ["MasterFit" Trial Day at the Witten/Herdecke University 15 January 2016]. PMID- 26946645 TI - A cautious approach to handling MABs is recommended. PMID- 26946646 TI - MABS: targeted therapy tailored to the patient's need. AB - Monoclonal antibodies (MABs) represent the window of opportunity in modern medicine. As immunology plays a vital role both in our survival and in disease development, MABs were found to be of great help in diagnosing, prognosticating and managing certain malignancies, inflammatory conditions, autoimmune as well as infectious diseases. Technological advances have enabled the production of MABs that target specific antigens linked with several disease processes. These drugs are now a component of therapy, not only for many common malignancies, including breast, colorectal, lung and pancreatic cancers, as well as lymphoma, leukaemia and multiple myeloma, but also for several inflammatory conditions such as rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis and inflammatory bowel disease. Targeted therapy has raised new questions about tailoring treatment, including cancer management, to the individual patient's needs. This would have a positive impact on the drug's effectiveness and toxicity as well as the economics of care. While targeted MABs are generally better tolerated than traditional chemotherapy, they are associated with several adverse effects, which vary from one patient to another. PMID- 26946647 TI - Safe handling and administration of MABS: the guidance. AB - While monoclonal antibodies (MABs) are not as hazardous as cytotoxic drugs, there is concern among health professionals about the potential risks and the limited evidence about this. Guidance on the safe use of MABs is mainly to be found in national documents covering all systemic anti-cancer therapies, with the only consensus guidelines specifically on MABs coming from Australia. This article therefore summarises the existing guidance relating to MABs. PMID- 26946648 TI - Use of closed-system drug transfer devices in the handling and administration of MABs. AB - There is a lack of research and consensus on the long-term risks of occupational exposure to monoclonal antibodies. There is, however, some risk to health professionals who are involved in their preparation and administration. This article discusses the use of closed-system drug transfer devices to minimise exposure, and touches on the importance of aseptic techniques, personal protective equipment, and appropriate education and training for health professionals. PMID- 26946649 TI - [TG13: THE UPDATED TOKYO'S CLINICAL RECOMMENDATIONS FOR TREATMENT OF AN ACUTE CHOLANGITIS AND CHOLECYSTITIS]. AB - Basing on analysis of the multicenter clinical investigations results, as well as meta-analysis and consensuses, the main suggestions of the updated Tokyo's clinical recommendations for the treatment of an acute cholangitis and an acute cholecystitis (TG13), diagnostic criteria and the scales of estimation for the patients' state severity, were elaborated. Indications and the drainage methods of a gallbladder were substantiated - in an acute cholecystitis, and of biliary ducts - in an acute cholangitis, as well as peculiarities of surgical treatment of an acute cholecystitis. Empirical antibacterial therapy was enlightened, taking into account the characteristics for biliary infection microorganisms and the disease severity. PMID- 26946650 TI - [MODERN VIEW ON INTENSIVE THERAPY OF GASTRO-INTESTINAL HEMORRHAGE]. AB - Basing on analysis of the treatment results in 47 patients for gastro-intestinal hemorrhage, the experience of application of a tranexamic acid in a content of infusion therapy and hemaxam per os was adduced. The data obtained witness the expediency of hemaxam application in a content of therapy on the stage of a hemorrhage letup and for the recurrence prevention. PMID- 26946651 TI - [THE TREATMENT TACTICS AND PERIOPERATIVE INTENSIVE THERAPY IN STENOSING ESOPHAGEAL DISEASES]. AB - The treatment tactics and intensive therapy in stenosing esophageal diseases for 222 patients in 2003 - 2015 yrs were analyzed. Expediency of application of the proposed treatment tactics was noted. PMID- 26946652 TI - [INTRAABDOMINAL HYPERTENSION AND RESPIRATORY DYSFUNCTION AFTER PLASTY OF THE ABDOMINAL WALL HERNIA]. AB - The impact of intraabdominal pressure on postoperative state of respiratory system after surgery for abdominal wall hernia (AWH) was analyzed. The investigation was conducted in 2013-2014 yrs in 35 patients. Perioperative state of pulmonary mechanics, the gas exchange, and the indices of a spirogram were analyzed. The postoperative period course, the rate of the respiratory insufficiency occurrence were analyzed. Respiratory insufficiency was observed, as a rule, in 24 - 48 h after hernioplasty. The AWH plasty lead to the intraabdominal pressure raising, the PaCO2-EtCO2 gradient changes, and the PaO2/FiO2 ratio as well. PMID- 26946653 TI - [PROPHYLAXIS OF AN ACUTE ADHESIVE ILEUS RECURRENCE]. AB - The results of treatment of 56 patients were studied, in whom for adhesive abdominal disease, complicated by an acute adhesive ileus (AAI), the adhesiolysis with intraabdominal introduction of antiadhesive measures, named Mezogel, Defensal were conducted, as well as in 42 patients, operated on in emergency for AAI, using a routine method. Application of videolaparoscopy gives a possibility to control the adhesive process in the early postoperative period, what is necessary for prophylaxis of the adhesive disease occurence. Application of the apparatus, we have elaborated, permitted to conduct a precisional viscerolysis due to good visualization of organs, pathologically changed and healthy tissues. Application of the procedures elaborated for prophylaxis of the AAI recurrence have promoted the reduction of risk for the AAI occurence down to 1.8%, and of disorders of the gut contents transit in terms up to 1 yr - to 3.6%. PMID- 26946654 TI - [COMBINATION OF CELLS TECHNOLOGIES AND MINSIINVASIVE SURGERY IN THE TREATMENT OF CHRONIC GASTRIC ULCER]. AB - The results of experimental and clinical use of stimulants of local reparative processes (autologous purified lipoaspirate and platelet-rich plasma) in the treatment of chronic gastric ulcer were analyzed. In the experimental part of the study the benefits of using platelet-rich plasma as donator growth factors were proved. The ability to stimulate the activity of fibroblasts and vessels formation in the young connective tissue with improving of oxygenation in ulcers and enhancing of cell proliferation, differentiation and accelerating of connective tissue maturation and healing of ulcers were demonstrated. In clinical studies the advantages of combination of standard antiulcer therapy and local endoscopic injection of platelet-rich plasma compared to only conservative therapy were shown. PMID- 26946655 TI - [DYNAMICS OF HEPATIC BLOOD FLOW IN IMMEDIATE PERIOD AFTER PREOPERATIVE EMBOLIZATION OF A PORTAL VEIN]. AB - The changes in intrahepatic blood flow, occuring after embolization of right branch (ERB) of portal vein (PV) in 42 patients, to whom a major hepatic resection was planned for focal hepatic diseases, were analyzed. Together with cessation of blood flow along the PV embolized branch, there was noted the enhancement of the volume blood flow along the PV left branch by 226% on the third day after embolization with its subsequent enhancement by 337% comparing with initial one. Enhancement of a volume blood flow along right hepatic artery (HA) by 282% was noted on the third day after ERB PV with subsequent nonsignificant reduction, and a blood flow along the left hepatic artery branch did not change essentially. The blood flow enhancement in left hepatic lobe have promoted her regeneration and increase of volume of the organ residual planned. PMID- 26946656 TI - [BILIARY COMPLICATIONS AFTER TRANSPLANTATION OF HEPATIC RIGHT LOBE FROM LIVING DONORS]. AB - Biliary complications are one of the main complications after transplantation, especially after hepatic transplantation from living donor. Of 147 patients, in whom hepatic transplantation was conducted, in 40 biliary complications have had occur, including in 29 (72.5%) - biliary leak, and in 11 (27.5%) - biliary stricture. Twelve patients were reoperated: for biliary leak - 8, and biliary stricture - 4. In 9 patients biliary leak stopped spontaneously, in 7 - a drainage under ultrasonographic control was conducted, and in 5 - endoscopic retrograde cholangiopancreaticography. In 8 patients cholangiopancreaticography was conducted for biliary stricture in 3 - transcutaneous transhepatic cholangiography. PMID- 26946658 TI - [MORPHOMETRIC FACTORS OF PROGNOSIS FOR REMOTE RECANALIZATION OF INTRACRANIAL ARTERIAL ANEURYSMS AFTER THEIR ENDOVASCULAR SURGICAL TREATMENT]. AB - The factors of the embolization stability prognostication in remote period after surgical treatment for intracranial arterial aneurysm rupture, were determined. In 34 patients in 6 - 12 mo after embolization of intracranial arterial aneurysms the angiographic control was conducted. In 18 patients (the first group) the signs of a stable embolization were revealed, and in 16 (a second group) - the aneurysm recanalization. The author considers the aneurysms noncorrect (ellipse like) form, a trustworthy dimensions of the body and volume as a risk factors for recanalization of aneurysms occurence. PMID- 26946657 TI - [TREATMENT OF A NEWBORN BABIES FOR AN ACUTE DISORDER OF THE BRAIN BLOOD CIRCULATION OF A HEMORRHAGIC TYPE]. AB - A timely and adequate application of complex of conservative and surgical measures determines at large the result of treatment of a newbor babies, suffering perinatal intracranial hematoma. The treatment includes, besides neurosurgical manipulations and operations, providing of evacuation of the blood extrused, the intracranial pressure normalization, liquorocirculation restoration, correction of hemodynamical and metabolic disorders, antiedematous, membrane-stabilizing and anticonvulsant therapy. A control of metabolic disorders, as well as especially hypoglycemia, hypocalcemia, hypomagnesemia, hypopyridoxinemia constitutes a leading moment of the treatment PMID- 26946659 TI - [APPLICATION OF VIOEOTHORACOSCOPIC PROCEDURES IN A SYNDROME OF INTRATHORACIC LYMPHADENOPATHY OF UNDETERIVIINED ORIGIN]. AB - Enhancement of rate of the intrathoracic lymphadenopathy syndrome (ILS) revealing have caused a necessity to find out the informative, secure and miniinvasive method of its diagnosis. There was established, that sensitivity, specificity and accuracy of videothoracoscopic (VTS) biopsy of intrathoracic lymph nodes (ILN) have constituted, accordingly, 96.0, 98.1 and 97.1%, and of videoassisted thoracoscopy (VATS) - 93.8, 93.6 and 93.5%. Low frequency of intraoperative and postoperative complications (accordingly 4.4 and 7.7%), small intraoperative blood loss (29 ml), short duration of operative intervention (45 min), rapid rehabilitation of patients postoperatively (10.6 days) witnesses about expediency of application of a VTS biopsy and VATS as a safe and miniinvasive procedures in ILS. PMID- 26946660 TI - [POSSIBILITIES OF THE RAOIOFREQUENCY ABLATION METHOD IN TREATMENT OF PULMONARY AND PLEURAL MALIGNANCIES]. AB - Various methods of radiofrequency ablation, using FOTEK-150 apparatus, were applied in 74 patients for pulmonary and pleural malignancies. Immediate positive effect was achieved in 92% observations, complications have occurred in 13% patients. It is expedient to use the method in patients, suffering pulmonary and pleural malignancies, when radical surgery is impossible. Radiofrequency ablation may be applied as a palliative method of treatment of pulmonary and pleural malignancies. PMID- 26946661 TI - [EFFICACY OF ALGORITHM OF ACTIONS OF ANESTHESIOLOGIST IN HARD TRACHEAL INTUBATION WHILE CONDUCTION OF ANESTHESIOLOGICAL PROCURING IN CESAREAN SECTION]. AB - Examination and treatment of 100 pregnant women, who underwent cesarean section under general anesthesia, was conducted. The hard tracheal intubation (HTI) and the failed tracheal intubation (FTI) rate in pregnant women during anesthesiological procuring of cesarean section have constituted 15 and 20%, accordingly, of them in 22.9% patients - it was prognosticated, and in 77.1% - nonprognosticated. The FTI in 5 (25%) patients coexisted with situation, when ventilation through facial mask appeared ineffective, causing lethal consequences. Application of the algorithm proposed have promoted the reduction of the failed tracheal intubation rate from 26 to 4%, and of severe complications - from 12% to 0. PMID- 26946662 TI - [OPERATIVE TREATMENT OF DIAPHRAGMATIC RELAXATION, USING WELDING OF BIOLOGICAL TISSUES]. AB - The results of examination and treatment of 17 patients for relaxation of the diaphragm were analyzed. There was proved the efficacy of application of the biological tissues welding while operative treatment of patients, using a duplicature method. While the biological welding application a reduction of the intervention total duration time was noted, and of intraoperative blood loss - by 17%, and a need for analgetic preparations - in 1.3 times. Minimal irritation impact of biological welding on parietal pleura and the pain intensity reduction was established. PMID- 26946663 TI - [TACTICS OF TREATMENT OF PATIENTS FOR ONCOLOGICAL DISEASES IN IATROGENIC INJURY OF UPPER URINARY WAYS]. AB - Results of examination and treatment of 119 patients for oncological diseases were analyzed, in whom iatrogenic injury of ureter (IIU) have occurred. Remission of oncological diseases plastic operations were performed in 48 (40.3%) patients, reconstructive - in 23 (19.3%), restoration - in 3 (2.5%); while a progress - palliative nephrostomy in 41 (34.5%) patients. In 4 (3.4%) patients dynamical observation was conducted. The method of operative treatment was selected, taking into account efficacy of treatment of oncological diseases; mechanism of IIU; level of obstruction and irreversibility of changes in wall of ureter; character of injury (one-sided, bilateral, injury of ureter of a single kidney); anatomo functional changes of upper and lower urinary ways; the patient state severity. PMID- 26946664 TI - [A SACRAL BEDSORE PLASTY, USING ROTATIONAL CUTANEO-FASCIAL GLUTEAL FLAPS]. AB - The method of rotational cutaneo-fascial plasty, applying preservation of perforating arteries in subfascial dissection with mobilization and subsequent rotation of the flaps was improved, guaranteeing preservation of blood flow from multiple perforating arteries in them. The method was successfully applied in 3 patients with a Grade IV sacral bedsores. PMID- 26946665 TI - [MORPHOLOGICAL CHANGES OF SKIN IN OPERATIVE WOUND IN SYNDROME OF OPIOID-INDUCED HYPERALGESIA]. AB - Morphological changes of skin in region of operative wound were investigated. There was established, that while application of fentanyl in high doses, using constant infusion for anesthesia in early postoperative period in children, operated for abdominal cavity tumors, the opioid-induced hyperalgesia occurrence is possible, what is accompanied by morphological changes in skin around operative wound, necrosis in centre of focus, pronounced perifocal reactive changes in a kind of significant inflammation and essential disorder of microcirculation with formation of small neural fibers on the 14th day. Pronounced fibrosis of derma, formation of big quantity of collagen fibers with edema, stratification. PMID- 26946666 TI - [APPLICATION OF BACTERIOPHAGES IN COMPLEX OF TREATMENT OF A SHOT-GUN WOUNDS OF SOFT TISSUES IN THE PATIENTS, SUFFERING MULTIPLE ALLERGY FOR ANTIBIOTICS]. AB - The results of complex therapy of the injured persons, suffering shot-gun wound of soft tissues in multiple allergy to antibiotics, using local bacteriophagotherapy, were analyzed. PMID- 26946667 TI - [EXPERIENCE OF RELAPAROTOMY APPLICATION IN SURGICAL TREATMENT OF THE ABDOMINAL CAVITY ORGANS DISEASES]. AB - During 2011 - 2014 yrs in Surgical Clinic of The First City Clinic (Poltava) a relaparotomy was performed in 127 patients. There was established, that relaparotomy constitutes the only one procedure for such life threatening states, as intraabdominal bleeding, ileus in a decompensation stage, eventration, progressing peritonitis, abdominal compartment syndrome stages III - IV. The rate of relaparotomy application after performance of urgent operative interventions is bigger than after planned operations (ratio 4:1). Individual estimation of a state and choice of optimal surgical tactics during primary and secondary operative interventions are needed to improve the results of treatment. PMID- 26946668 TI - [MORPHOLOGICAL CHANGES OF GASTRIC MUCOSA AFTER INSERTION OF INTRAGASTRIC BALLOON]. AB - Morphological changes in gastric mucosa were studied, optimal terms of bariatric operations performance after intragastric balloon (IGB) insertion were determined. Before the IGB insertion in 10 (35.7%) patients, in accordance to histological investigations, the changes in gastric mucosa were not revealed, and in 18 (64.3%) - chronic gastritis was established. In accordance to endoscopic investigation results, immediately after the IGB removal in 23 (82.1%) patients a pronounced erythematous gastropathy was noted, and in 5 (17.9%) - erosive gastropathy. While investigating the gastric mucosa biopsies in all the patients a prominent inflammatory changes were revealed, including significant edema, pronounced lymphocytic infiltration. In accordance to esophagogastroduodenoscopy data on the 14-th day of endoscopic monitoring in 6 (21.4%) patients pathological changes of gastric mucosa were not revealed, in 22 (78.6 %) - erythematous gastropathy was noted, and in accordance to histological investigation - chronic gastritis. Persistence of IGB in gastric cavity during 6 mo caused a morphological changes in gastric mucosa - a significant inflammation, what was confirmed by endoscopic and histological investigations data. The gastric mucosa structure normalization was observed in 14 days after the IGB removal, that's why a radical bariatric intervention is recommended to perform not earlier the term established. PMID- 26946669 TI - [APPLICATION OF ILEOCECAL GASTROPLASTY IN EXPERIMENT]. AB - Results of gastroplasty, using ileocecal intestinal segment in experimental animals were presented. Functional state of transplant was estimated using data of angiography, manometry, morphological investigations. In accordance to angiographic data sufficient blood supply of transplant was obtained from a. ileocolica. While manometric and roentgenologic investigations duodenal reflux into small intestine and esophagus was not revealed. Colono-small bowel reflux, determined using hydropression method, was registered in 150 - 170 mm H2O pressure. In accordance to results of morphological investigations in a large bowel reservoir the quantity of goblet cells and the mucus production have enhanced, promoting elimination of inflammation. PMID- 26946670 TI - [IMPACT OF A HEIGHTENED INTRAABDOMINAL PRESSURE ON POLYORGAN INSUFFICIENCY OCCURRENCE IN AN ACUTE PANCREATITIS]. AB - In experiment the impact of intraabdominal hypertension (IAH) on an acute pancreatitis (AP) course was studied up. The procedure of an acute experiment, using intraparenchymatose introduction of 40% solution of ethanol, was proposed. The isolated influence of IAH on target organs was investigated, as well as its impact on the simulated severe AP course. Morphological changes in pancreas, small intestine, kidneys, liver in an AP were studied up. While performing the investigation a negative impact of IAH in AP was noted, such as the polyorgan insufficiency occurence. PMID- 26946671 TI - [OBSERVATION OF AN ACUTE GANGRENOUS APPENDICITIS IN UNREDUCIBLE LEFT-SIDED INGUINAL HERNIA]. PMID- 26946672 TI - Introduction: Towards a History of the Ancient Patient's View. PMID- 26946673 TI - "This I Suffered in the Short Space of my Life". The Epitaph for Lucius Minicius Anthimianus (CIG 3272; Peek GVn 1166). AB - Herewith we present an interdisciplinary study of the metrical funerary inscription from the third century CE (CIG 3272; Peek GV 1166). This emotional Greek epitaph reports the short life (from birth to death) of the 4 year old Lucius Minicius Anthimianus. This is the first detailed study since the dissertation by Klitsch (1976). The inscription presents an ideal case for a truly interdisciplinary study of the patient-history, in that its interpretation involves the study of Greek literature and linguistics, epigraphy, social and religious history, and ancient medicine. It also offers ample opportunity to show the contradictions inherent in proposing retrospective diagnosis, without neglecting the relevant information modern medicine has to offer for the interpretation of this case history. We argue that Lucius' father was most probably a physician, that the text of the inscription stems from expert knowledge of ancient medicine and that the traditional retrospective diagnosis of this case, tuberculosis, is an untenable hypothesis. PMID- 26946674 TI - Questioning the Patient, Questioning Hippocrates: Rufus of Ephesus and the Pursuit of Knowledge. AB - Rufus of Ephesus' short treatise, Quaestiones Medicinales, the only ancient medical work that takes as its topic the dialogue between doctor and patient, has usually been seen as a procedural practical handbook serving an essentially operational purpose. In this paper I argue that the treatise, with its insistent message that doctors cannot properly understand and treat illnesses unless they supplement their own knowledge by questioning patients, and its remarkable appreciation of the singularity of each patient's experience, shows itself to be no mere handbook but a work addressing the place of questioning in the clinical encounter. I illustrate some of the differences between Rufus' conceptualisation of the relevance and use of questioning and that which can be seen in the theoretical and descriptive writings of Galen and in the Hippocratic corpus, and show how apparent resonances with some of the preoccupations of modern Western healthcare can be used judiciously to elucidate the significance of those differences. PMID- 26946675 TI - Patient Function and Physician Function in the Hippocratic Cases. AB - This chapter looks at the patient cases of the Epidemics as testimonies to the interaction between the physician and the patient. My corpus of reference is the patient cases in fifth- and early fourth-century medical texts, mostly the more elaborated examples offered by Epidemics 1 and 3. A patient case collects information from various sources: the patient's observable behavior and state; his or her account of her disease, its history and the patient's lifestyle; the contribution given by relatives and friends; and, of course, the physician with his judgment, his agenda, his terminology and didactic aims. What remains elusive and hidden is the viewpoint of the patient and his personal experience within, or under the authoritative report compiled by the physician. In this chapter, I survey key stylistic features of these reports, which I see as significant to the reconstruction of the point of view of the ill in his or her encounter with the doctor. My main aim is to extract from these texts as much as possible information about the experience of suffering and patienthood in antiquity. In my analysis I look at the text not only, and not primarily as a definitive pronouncement stemming from the physician's legislating mind, and from the material author's 'pen', nor observations from by-standers and helpers in the sick room, nor even as the plaintive cries from suffering patient, but as a composition in which all the principal actors in the drama of a sickness must contribute. PMID- 26946676 TI - Case History as Minority Report in the Hippocratic Epidemics 1. AB - Instead of being self-evident depictions of sickness, ancient medical texts were narratives created from certain points of view and for intended purposes. As a guide for the physician travelling to an unfamiliar community of people, the treatise Airs, Waters, Places anticipated "communal" conditions resulting from seasonal changes, while admitting the possibility of "personal" sickness due to individual lifestyles. Even with its geographical situatedness, Epidemics 1 continued to prioritise population narratives, subsuming sickness within the experiences of the anonymous majority whenever possible. In both its constitutions and case histories, however, patients whose conditions deviated from majority expectations were identified for forensic purposes, so that case histories functioned as minority reports rather than exemplars of how sickness behaved. Such reports guarded against surprising deviations from the rules of prognosis, which could present a threat to the physician's credibility and livelihood as a consequence. PMID- 26946677 TI - Voice Pathologies and the 'Hippocratic Triangle'. AB - Hippocratic authors frequently utilise silence, babbling, lisping and otherverbal signs to diagnose a variety of physical illnesses and predict theircourse. This chapter examines these 'voice pathologies' and evaluatestheir impact on the dialogue between patients and Hippocratic physicians. In short, Hippocratic authors treat patients' voices in two dissonant ways. On the one hand, physicians promote some form of discourse,implicitly relying on patients to report internal sensations resulting fromillnesses. On the other hand, they develop extensive techniques to diminish and downplay this reliance. As a result, Hippocratic authors treatpatients' mouths not so much as the loci of potential subjective expression, but as orifices secreting verbal discharges. They weaken the distinction between the (sonic) effluvia of the mouth and those of other bodilyoutlets, thus bringing verbal output into close conceptual proximity withother types of discharge. Words come to be scrutinised for their quantity,quality and consistency as though they were quasi-excreta of the mouth. (see text). Announce what has happened, discern what is happening and foretellwhat will happen; attend to these things. Practice two things concerningdiseases: help or do no harm. The art consists of three parts: the disease,the diseased and the physician; the physician is the servant of the art; thediseased fights against the disease with the physician (Hipp., Epid.1.5L. 2.634.6-636.4 = Kiulewein 189,24-190, 6). PMID- 26946678 TI - Galen's Anxious Patients: Lype as Anxiety Disorder. AB - Galen describes a syndrome he associates with an emotion called lype, with specific symptoms and a course that may lead to humoral imbalance, disease, and death. Lype is an emotion that encompasses distress at a loss, as the death of a close friend or the destruction of one's books by fire; but Galen also associates it with chronic worry about a future threat, and a physiology between the emotions of worry and fear (that is, 'anxiety'). Lype can cause a progressive syndrome characterised by insomnia, fever, pallor, and weight loss that can kill patients or degenerate into psychotic illness. This syndrome can be described in modern terms as an anxiety disorder. PMID- 26946679 TI - Experiencing Madness: Mental Patients in Medieval Arabo-Islamic Medicine. AB - This paper focuses on the mental patients in Arabo-Islamic Middle Ages. Patients suffering from mental illnesses generated a lot of interest for Arabo-Islamic physicians. The first objective of this study is to identify who were the mentally infirm and to compare the Arab physicians' typologies of mental patients to that of their Greek predecessors. The second part of this paper shifts the focus from theoretical descriptions to case histories and biographical sources, in order to understand how the physicians treated their mental patients, and to find out what was the social impact of this medical approach. Finally, because the special provision for the insane is a distinctive feature of the Islamic hospital, the third part of my paper examines whether the main purpose of these hospitals was the patients' confinement or their treatment. PMID- 26946680 TI - Interpretations of the Healer's Touch in the Hippocratic Corpus. AB - This paper analyses gender as an aspect of the role of touch in the relationship between doctors and patients, as represented in the Hippocratic Corpus. Touch is an essential aspect of the ancient doctor's art, but one potentially fraught with concerns over gender: while seeing, hearing, and smelling are also central to the medical encounter, touching is the act that places the greatest demands on the privacy and bodily integrity of the patient. This paper shows--perhaps counterintuitively--that, despite the multiple assertions of gender differences put forward by the authors of the Hippocratic Corpus, these authors make little distinction between touching male and female patients. At the same time, the paper argues that ancient physicians were anxious to avoid the charge that they were harming their patients when they touched them. It demonstrates that male doctors, sensitive as they were to the problems posed by their interactions with female patients, were challenged in different ways when engaging in intimate contact with male patients. PMID- 26946681 TI - Patience for the Little Patient: The Infant in Soranus' Gynaecia. AB - Despite advocating perpetual virginity and viewing childbirth as inherently injurious to female health, Soranus' attitude towards the infant in Book 2 of the Gynaecia is remarkably positive. In fact, it is only towards the infant that Soranus displays such consistently positive attitude. This compassionate approach is evident both in the content and the language employed, which is characterised by a striking occurrence of diminutives. His preference here for authorities such as Thracians and Scythians rather than illustrious ones, along with his 'language of the nursery', points to an oral, rather than literary, tradition. Soranus seems to have been the first to write so extensively on childcare; freed from the influence of any earlier tradition, he engaged in a more nuanced vision of childhood, seeing it as a 'blank slate' both physically and mentally, untouched by the faults of adulthood. While the content of Book 2 has been mined for information concerning the practicalities of child-care, it has not been evaluated in terms of its differences from the rest of the Gynaecia, which are significant. PMID- 26946682 TI - Compassion in Soranus' Gynecology and Caelius Aurelianus' On Chronic Diseases. AB - Compassion is considered an important quality for a successful physician today, but did ancient physicians display and value this emotion? How did they feel when faced with the pain and suffering of their patients? How did their patients' emotions affect their own? Many ancient physicians are not well-known for expressions of compassion in their writings; however, this seems to change in the second century AD. One medical writer who exemplifies this change is Soranus of Ephesus (c. 98-138 AD). In his Gynecology, there are a number of passages where compassion is addressed or expressed (such as the chapters on the qualities of the best midwife, the symptom of pica, childbirth, and superstition). The same points can be made of Soranus' On Chronic Diseases, preserved to some extent by the Latin version and adaptation by fifth century AD medical writer Caelius Aurelianus (see, for example, the chapters on chronic headache, mania and elephantiasis). Soranus and Caelius display compassion, understanding, and flexibility of approach when dealing with patient issues; they show themselves willing to change their medical technique when they see that it is doing more harm or discomfort than good. In Soranus and Caelius, we have an image of a physician who acknowledges and is aware of their patients' emotions, beliefs and attitudes, and who exhibits compassion for them. PMID- 26946683 TI - Galen on the Patient's Role in Pain Diagnosis: Sensation, Consensus, and Metaphor. AB - Pain might be a powerful diagnostic tool, but it is at the same time an intensely private and subjective experience that represents a formidable problem in the communication between physician and patient. Galen addresses (principally in De locis affectis) the problem of constructing a consistent and univocal terminology for different pain sensations, rejecting the system proposed earlier by Archigenes on the grounds that he relies on metaphorical descriptors which indiscriminately incorporate terms belonging to information generated by all the senses, fails to conform to patient testimony, and refers to ambiguous concepts. Galen sets himself the task of developing a system of proper or literal (kyrios) terms for pain sensations, even despite the apparent ineffability of certain sensations and laymen's imprecise self-analysis and description of their suffering. His pain vocabulary, developed through a combination of consensus between patients and physicians' expert descriptions of their own pain, promises to link terminology univocally to sensation, turning patients' testimony about their subjective experience of pain into universally applicable diagnostic guidance. PMID- 26946684 TI - The (see text) in the Praecepta: The Medical Fee and its Impact on the Patient. AB - The brief collection of deontological guidelines entitled Praecepta is one of the most important literary evidence regarding the fee of the ancient physician. This chapter focuses on three passages from the Praecepta, which offer us a wealth of information on this topic. Some technical terms used in the text, such as the term MUisigmathetaapiov, show clearly that the author intends both to provide guidelines for the ideal bedside manners and to defend the repute of the physicians from the widespread charge of greed. In some regards, the author of the Praecepta depicts medicine as a 'liberal' art: the good physician disdains monetary gain as the main goal of his service, and aims to safeguard the social status and reputation of the medical profession. On the other hand, the author of the Praecepta enlightens his readers on the bad behaviour of both charlatan physicians and bad-mannered patients. PMID- 26946685 TI - The Practical Application of Ancient Pulse-Lore and its Influence on the Patient Doctor Interaction. AB - This paper examines the effects of the emergence of pulse measurement as an essential diagnosis and prognosis method used on Graeco-Roman patients. It argues that the introduction of this diagnostic tool brought about changes to the encounter between patients and their doctors and may have also increased intimacy and patients' forthcomingness during these encounters. The paper demonstrates that the popularity and conspicuity of the practical and theoretical engagement with the pulse afforded many opportunities for the transmission of professional knowledge from doctors to patients. It argues that this transmission of knowledge was often actively encouraged by doctors for the sake of self-promotion and promotion of the medical profession as a whole. At the same time, doctors also attempted to restrict this transmission of knowledge in order to use their exclusive competence in the pulse as means for establishing their authority and superiority over patients. PMID- 26946686 TI - Images of Doctors and their Implements: A Visual Dialogue between the Patient and the Doctor. AB - Images of physicians, patients, and medical instruments were placed on Graeco Roman funerary monuments, altars and fresco paintings. These representations are examined here to determine whether there existed a standard convention by which physicians were depicted in order that the lay and possibly illiterate viewers could identify what the scene represented. Greek physicians were frequently shown with cupping vessels, midwives were seen with birthing stools, while Roman physicians were often shown with various surgical implements. It is argued that the correlation between the types of objects depicted with the medical practitioner was deliberately made by the artist to signify the nature of medicine the individual practiced, so that the viewer could identify the role the practitioner had in their society. PMID- 26946687 TI - Case Histories in Late Byzantium: Reading the Patient in John Zacharias Aktouarios' On Urines. AB - This paper provides the first analysis of case histories in the Byzantine period as they feature in the On Urines of John Zacharias Aktouarios (ca. 1275-ca. 1330). This group of clinical accounts is of special importance in that they have no counterpart in the Greek-speaking world since Galen. This study aims to illustrate various factors determining the patient's response to the physician's advice through close examination of John's clinical narratives. The first part deals with the terminology that John uses to indicate the patient's gender, age, social status, and clinical condition. The second part explores the significance of John's acquaintance with the patients, the patient's socio-economic background, and also the patient's experience in connection with the physician's professional expertise. PMID- 26946688 TI - Treatment of the Man: Galen's Preventive Medicine in the De Sanitate Tuenda. AB - Ideally in Galen's model of preventive medicine, the patient does not become a patient at all but remains a healthy person able to maintain his or her health without need of either medicines or other therapies. This chapter is divided into four sections, Galen's ideal patient; less than ideal patients; patients in old age; and patients whose nature is inclined to a bad mixture of humours, and so in need of medication. In all four categories, even those where medical recommendations such as blood-letting are recommended, Galen offers an option based on hygieine, or the art of maintaining good health. Galen's aim in de sanitate tuenda is to ensure that a well-educated person can lead a healthy life by learning what does harm and what benefits him or her. The chapter explores the extent to which the patient can really be independent of the doctor, and the interesting balance between nature and urban life which constitutes good health in Galenic thought. PMID- 26946689 TI - Literary and Documentary Evidence for Lay Medical Practice in the Roman Republic and Empire. AB - The majority of surviving ancient medical literature was written by medical practitioners and produced for the purpose of ensuring the effective diagnosis and treatment of their patients, suggesting an audience of medical professionals ranging from instructors to students. This has led historians to concentrate on the professional medical practitioner and their theories, methods and practices, rather than on lay medical practitioners, or even patients themselves. This chapter seeks to redress this imbalance, and examine the ancient literary and documentary evidence for lay medical theories, methods and practices in the Roman Republic and Empire in an attempt to reconstruct the experiences of lay medical practitioners and their patients. The Roman agricultural treatises of Cato, Varro and Columella, papyri and ostraca from Egypt, and tablets from Britain are investigated, and it is established that the individual's personal acquisition of knowledge and expertise, not only from medical professionals and works of medical literature, but also from family members and friends, and through trial and error, was considered fundamental to domestic medical practice. PMID- 26946690 TI - Aelius Aristides as Informed Patient and Physician. AB - Aelius Aristides, one of the most renowned orators of the so-called second sophistic, has often been thought of as the paradigmatic patient who surrendered his physical and psychological health to Asclepius, and spent a large part of his life in the temple of the god at Pergamum blindly following divine orders on diet and regimen. This study looks at the Hieroi Logoi as an illness narrative and argues against such a simplistic view and in favour of a more complex picture: Aristides is a far cry far from the submissive patient, who idly resided in the Pergamene Asclepieion relying exclusively on the therapeutic powers of the god and his human helpers. In fact, through a close reading of a selection of passages from the Hieroi Logoi a whole new image of Aristides emerges: the informed patient who is not only in possession of the basics of the medical discourse but who also functions as a physician of sorts, taking both his own life and the lives of others into his hands. This new type of patient, the knowledgeable patient, who is well-versed in medical matters and envisages himself as an active agent of the healing process and an equally important partner in the medical encounter, ties well with other testimonies we have about knowledgeable patients mostly to be found amongst the members of the socio political elite of the time. PMID- 26946691 TI - "It may not cure you, it may not save your life, but it will help you". AB - In the modern world, we are experiencing an epidemiological shift represented by the increasing prevalence of chronic diseases relative to that of acute diseases: more people are living longer, with more diseases, than ever before in human history. How are we to understand and to respond to this change? A study of provision of cancer treatment in Western Australia, especially among Indigenous populations, can illuminate ways in which healthcare providers and societies might better understand the treatment of chronic disease: healthcare providers should take care to appreciate patient perspectives and beliefs about disease aetiology and treatment. Consideration of treatment of disease in the ancient Graeco-Roman world supports the view that effective healing and maintenance of patient wellbeing occurs when healers communicate clearly with their patients about disease and treatment progression, and when healers are open-minded about patients' utilisation of multiple treatment modalities. PMID- 26946692 TI - Approaches to the History of Patients: From the Ancient World to Early Modern Europe. AB - This chapter looks from an early modernist's perspective at some of the major questions and methodological issues that writing the history of patients in the ancient world shares with similar work on Patientengeschichte in medieval and early modern Europe. It addresses, in particular, the problem of finding adequate sources that give access to the patients' experience of illness and medicine and highlights the potential as well as the limitations of using physicians' case histories for that purpose. It discusses the doctor-patient relationship as it emerges from these sources, and the impact of the patient's point of view on learned medical theory and practice. In conclusion, it pleads for a cautious and nuanced approach to the controversial issue of retrospective diagnosis, recommending that historians consistently ask in which contexts and in what way the application of modern diagnostic labels to pre-modern accounts of illness can truly contribute to a better historical understanding rather than distort it. PMID- 26946693 TI - [Medicine is searching for a new structural balance]. PMID- 26946694 TI - [Treatment of drugs-associated non-hereditary angioedema mediated by bradykinin]. AB - Angioedema is a deep intradermal or sub-cutaneous edema, which can be mediated by histamine, bradykinin or mixture of both components. The aims of this review are to describe the clinical approach and diagnosis of non-hereditary bradykinin mediated angioedema induced by drugs such as: angiotensin-converting inhibitor, sartan, gliptins, rapamycin or some thrombolytic reagents and renin inhibitors. Furthermore, we will discuss the drug management of these angioedema, which is mainly based on C1 inhibitor concentrate or icatibant administration. PMID- 26946695 TI - [News in angiology and hemostasis]. AB - This update describes contemporary studies of clinical relevance in angiology and hemostasis. We discuss newer developments for the treatment of haemophilia, with a focus on drugs with longer-half lives. Direct anticoagulants (DOAC: rivaroxaban, apixaban, edoxaban and dabigatran) and their approved prescription in Switzerland are summarized, with a description of antidotes that will be available in the near future. We will present new data on the utility of cancer screening at the diagnosis of idiopathic venous thromboembolism (VTE) and on the evaluation of DOAC in patients with cancer-related VTE. Finally, new studies evaluating the clinical risk-benefit of anticoagulation bridging for patients with vitamin K antagonists undergoing procedures do not support the use of such bridging in the majority of patients. PMID- 26946696 TI - [Cardiology update in 2015]. AB - The present review provides a selected choice of clinical trials and therapeutic advances in the field of cardiology in 2015. A new treatment option in heart failure will become available this year in Switzerland. In interventional cardiology, new trials have been published on the duration of dual antiplatelet therapy, the new stents with bioresorbable scaffold and the long-term results of TAVR in patients who are not surgical candidates or at high surgical risk. RegardingAF the BRIDGE trial provides new evidences to guide the management of patients during warfarin interruption for surgery. Recent publications are changing the paradigm of AF treatment by showing a major impact of the management of cardiometabolic risk factors. Finally, refined criteria for ECG interpretation in athletes have been recently proposed to reduce the burden of false-positive screening. PMID- 26946697 TI - [New developments of surgery in 2015]. AB - In this year 2015, the developments of new technologies as well as multidisciplinary management remained successfully. The implementation of enhanced rehabilitation after surgery pathways continued to expand both geographically and in various surgical specialties. The use of the vaporized intraperitoneal chemotherapy (PIPAC) showed promising results. Minimally invasive surgery was further implemented in various fields of rectal, endocrine and oesophageal surgery. PMID- 26946698 TI - [Dermatology - the key to ensure a good long term clinical response]. AB - After efficacy and safety have been used for many years to evaluate therapies and treatment success in medicine, patient reported outcomes are now increasingly being incorported in this process. This trend acknowledges that patient adherence is a prerequisit for the good long-term outcome of a treatment. In the field of dermatology, namely for psoriasis, current guidelines already recommend to base clinical decision-making on a combination of objective as well as patient reported outcomes. These parameters provide the basis for the concept of happy drug survival, building on the belief that a good quality of life reflects meaningful treatment success from the patient's point of view, motivating him to carry on with the therapy. PMID- 26946699 TI - [News in diabetology 2015]. AB - The year 2015 was punctuated by numerous events in diabetology. First, the ADA/EASD guidelines have been updated. The pharmacological panel for type 2 diabetes treatment saw the arrival of different new molecules. Two new basal insulins were also approved. Also, cardiovascular safety trials have been published regarding recent antidiabetic drugs. A new insulin pump than can be coupled with a glucosensor was released. Finally, a new unexpected complication of SGLT2 inhibitors treatment was reported, the euglycemic keto-acidosis. PMID- 26946700 TI - [Benign thyroid nodules: what support in 2015?]. AB - The thyroid nodule is a frequent and mostly benign. The purpose of this article is to review the recent literature concerning the management and follow-up for thyroid nodule, with benign after fine needle aspiration. PMID- 26946701 TI - [Geriatry]. AB - n 2015, several studies about hypertension and TAVI emphasize the importance of individualizing treatment goals in very old or vulnerable patients. The anti pneumococcal conjugate vaccine has demonstrated its effectiveness in community acquired pneumonia and the arsenal against shingles is extended by a subunit vaccine. A clinical trial confirms the ineffectiveness of testosterone supplementation in arteriosclerotic disease but not its safety. Regarding dementia, a rigorous study shows that a multimodal approach can reduce the risk of cognitive decline. The value of imaging technologies using Tau protein radiotracers is confirmed for monitoring the evolution of Alzheimer's disease and the latest studies about anti-amyloid vaccines finally demonstrate encouraging results. PMID- 26946702 TI - [Introduction in Switzerland of preimplantation genetic testing: progress or downward spiral?]. AB - The Swiss law on Assisted Reproductive Techniques (LPMA) has been modified in order to authorize preimplantation genetic diagnosis (PGD). PGD has been performed for 20 years. Switzerland is one of the last european countries where it is still prohibited. As a result, couples carrying a severe inherited disease and infertile couples with recurrent implantation failure or miscarriage have to cross the borders in order to have access to the appropriate treatments. Despite the recent popular approval to change the Constitution, the new LPMA cannot be implemented as the opponants have launched a referendum in order to obtain a more restrictive law. If they succeed, the affected couples will be left with a scientifically obsolete law that will not allow them to have access to an effective and compassionate treatment. PMID- 26946703 TI - [News in blood pressure in 2015]. AB - In this short review, we present 4 studies published in 2014-2015 which appear to important for clinicians. The results of the SPRINT trial are challenging the target systolic blood pressure (BP) to be achieved in non-diabetic hypertensive. It shows that a target BP <120 mmHg provides clear mortality and morbidity advantages over a <140 mmHg target. The PATHWAY2 and 3 studies reemphasize the important role of potassium sparing diuretics in patients with resistant hypertension and in patients with metabolic syndrome. At last the DENERHTN study conducted in France suggests that renal denervation is not dead and that additional studies are needed to position this technique in management of resistant hypertension. PMID- 26946704 TI - [Bone diseases]. AB - Calcium intake shows a small impact on bone mineral density and fracture risk. Denosumab is a more potent inhibitor of bone resorption than zoledronate. Abaloparatide, PTHrP analog, increases bone mineral density and decreases fracture incidence. Teriparatide could be delivered via a transdermic device. Romosozumab and odanacatib improve calculated bone strength. Sequential or combined treatments with denosumab and teriparatide could be of interest, but not denosumab followed by teriparatide. Fibrous dysplasia, Paget disease and hypophosphatasia are updated, as well as atypical femoral fracture and osteonecrosis of the jaw. PMID- 26946705 TI - [Emergency medicine: updates 2015]. AB - The year 2015 was marked by several publications questioning the practice of emergency medicine. The systematic administration of oxygen in STEMI patients offers no benefit. Similarly, medical expulsive therapy in patients with ureteric stones was questioned. Administration of steroids for acute radiculopathy showed only short-term, but no mid-term pain improvement. Several studies have demonstrated the benefit combining intraarterial and intravenous thrombolytic therapy for ischemic stroke. However, studies assessing optimal management strategy for patients hospitalized with community acquired pneumonia, showed conflicting results. Finally, these developments occur in the context of an aging population and increase of pre-hospital management for the elderly, raising the question of how to reduce hospital admissions in this population. PMID- 26946706 TI - [Nephrology: what's new in 2015?]. AB - Isotonic saline and buffered crystalloid solutions may carry an equivalent risk of acute kidney injury in critically ill patients. In hemodialyzed patients, highly dialyzable beta-blockers are less cardioprotective than non-dialyzable beta-blockers, cooling the dialyzate may protect their cerebral white matter and too much parenteral iron may be deleterious. A promising treatment for amyloid deposits is underway. A well tolerated treatment for hyperkalemia has emerged. Low serum magnesium and diminished phosphaturia may be associated with an increased risk of chronic kidney disease. Moderate hyponatremia should be considered as a serious public health problem. PMID- 26946707 TI - [Neurology]. AB - In 2015, cerebral stimulation becomes increasingly established in the treatment of pharmacoresistant epilepsy. Efficacy of endovascular treatment has been demonstrated for acute ischemic stroke. Deep brain stimulation at low frequency improves dysphagia and freezing of gait in Parkinson patients. Bimagrumab seems to increase muscular volume and force in patients with inclusion body myositis. In cluster-type headache, a transcutaneous vagal nerve stimulator is efficient in stopping acute attacks and also reducing their frequency. Initial steps have been undertaken towards modulating memory by stimulation of the proximal fornix. Teriflunomide is the first oral immunomodulatory drug for which efficacy has been shown in preventing conversion from clinical isolated syndrome to multiple sclerosis. PMID- 26946708 TI - [Ophthalmolgy: what's new in 2015?]. AB - Whilst imaging methods are developed allowing non-invasive analysis and quantification of corneal nerves, retinal nerve fibers and retinal vessels, the eye is considered as an open window on the nervous and vascular system. In the field of therapies, macular edema can be reduced using several drugs with different mechanisms of action and different kinetics. Artificial retina is now available in Switzerland and gene therapy continues to develop but should still be considered rather as a research tool than as a treatment. Finally, the more striking discovery of the year is probably the reversion of cataract by Lanosterol drops: towards the end of cataract surgery? PMID- 26946709 TI - [News in paediatrics]. AB - Every pediatrician will be confronted with newborns oryoung infants with skin lesions in proximity of the vertebral column. It is important not to miss a spinal dysraphism because of the risk of meningeal infection or of the possible presence of a tethered cord. A practical algorithm is presented. Non-accidental injury in young infants and toddlers is not rare but difficult to detect. Bruises and fractures are highly suspicious for non-accidental injury and should trigger specific investigations. Emergency departments and hospitals are switching from hypotonic to isotonic solutions as maintenance infusions of children. They reduce the risk of hyponatremia without increasing that of hypernatremia, and they should be used preferentially in the majority of pediatric clinical settings. PMID- 26946710 TI - [Pharmacovigilance update]. AB - The main pharmacovigilance updates in 2015are reviewed. Sofosbuvir amiodarone interaction: risk of severe bradycardia. Dasabuvir clopidogrel interaction: increased dasabuvir concentrations and potential risk of QTprolongation. SGLT2 inhibitors: risks of diabetic acidocetosis and bone fracture. Dabigatran: therapeutic drug monitoring may improve benefit-risk ratio. Ibuprofen: at higher dosage, vascular risks are comparable to coxibs. Pregabaline, gabapentine: potential for abuse and addiction. Varenicline: potentiates alcohol's effects. Codeine: contra-indicated as cough medicine under the age of twelve. Valproate: strengthened warnings on the risks of valproate use in pregnancy. Dimethylfumarate: rare observations of progressive multifocal leucoencephalopathy. Ustekinumab: rare observations of erythrodermia. PMID- 26946711 TI - [New therapeutic approaches in 2015 in pulmonary medicine]. AB - During the past year, among the many novelties in the field of pulmonary medicine, the authors chose to focus on 4 items: the positive contribution of systemic steroids on clinical improvement and length of stay in patients hospitalized for community-acquired pneumonia; the interesting results obtained with high flow oxygen, heated and humidified, in acute care and in normocapnic respiratory failure, a device which warrants further clinical testing in other indications; the now documented benefits of lung volume reduction procedures by bronchoscopy using coils in severe emphysema with hyperinflation; and the publication of new recommendations regarding pulmonary hypertension, with an emphasis on new molecules and their efficacy, on an early use of combination treatments, and on the importance of expert centres in managing these patients. PMID- 26946712 TI - [New developments in psychiatry]. AB - Three issues are discussed: i) While number of psychiatric beds has been reduced in most countries and although treatments proposed in psychiatric hospitals have evolved, they continue to be viewed as asylums implementing constraints. Considering this prevents their adequate use and leads to patients' stigmatisation, promotion of a better knowledge of contemporary hospital treatments is needed. 2) In addition, most psychiatric disorders emerging during adolescence and early adulthood, it is important to develop accessible care on university campuses. 3) While risk of weight gain and metabolic syndrome under neuroleptics or mood stabilisers is known, there is a need for the development of <> that are easy to identify. A 5% increase in weight during the first month of treatment indicates the risk for important later weight gain. PMID- 26946713 TI - [Intra-articular infiltrations in rheumatology: update]. AB - Intra-articular treatments are very useful in the daily practice of rheumatology, although their survival in the joint cavity is short and their mode of action still widely misunderstood. Corticosteroids were first used in fifty's, and are still the most widely used, despite potential local and systemic side effects. In recentyears, other molecules have been developed, especially in the treatment of osteoarthritis, but their effectiveness is controversial. Therapeutic trials were conducted with biological treatments in inflammatory arthritis, without success so far In the area of biotechnology, molecules to increase the survival of drugs into the joint are in preparation. PMID- 26946714 TI - [Novelties in Urology in 2015]. AB - This paper brings to the general practitioner some clarifications with regard to open questions - such as prostate cancer screening - and points at some disease management in different fields - such as urinary stones, overactive bladder and immunotherapy in bladder cancer. PMID- 26946715 TI - [Antiretroviral therapy: useful from prevention to HIV treatment]. AB - In 2015, the publication of important studies allowed the development of new guidelines, notably by WHO and the European AIDS ClinicalSociety (EACS), for HIV preventive treatment (pre-exposure prophylaxis), as well as for the start of antiretroviral treatment. The START and TEMPRANO studies have extended the treatment to all HIV-infected patients, irrespective of the level of immunosuppression and therefore the CD4 count. In addition, innovative screening methods, such as self-tests, are now available in all French pharmacies since 15 September 2015. The latest developments in 2015 concerning the prevention, screening, and treatment of HIV are discussed in this article and will certainly have an impact on the care of patients in Switzerland. PMID- 26946716 TI - [What is new, today, in orthopedics? Research on scoliosis...]. PMID- 26946717 TI - [To laugh]. PMID- 26946718 TI - [An antidote to the direct oral anticoagulants]. PMID- 26946719 TI - [Traumatologic miscellany and obituaries, psychiatric and literary]. PMID- 26946721 TI - [Clause of need: anti-liberal, really?]. PMID- 26946720 TI - [Duchenne muscular dystrophy and the gene of the crime: latest news from the human genome]. PMID- 26946722 TI - [Thought of the improvement and reconsitution of the theoretical sys- tem of acupuncture and moxibustion based on source, clinic and new knowledge]. PMID- 26946723 TI - [Primary effect of acupuncture and moxibustion]. AB - The primary effect is out of the conception of the psychology, which emphasizes the importance of the initial stimuli. Although the primary effect of acupuncture and moxibustion happens and is applied constantly in clinic, the conception, connotation and application of it had not been explained definitely yet. The writers attempt to explain the characteristics, theoretic significance and clinical values of the clinical primary, effect of acupuncture and moxibustion based on the conception of it so as to provide a certain of reference to the study on the clinical primary effect of acupuncture and moxibustion. PMID- 26946724 TI - [Acupuncture at Dazhui (GV 14) and Geshu (BL 17) for 39 cases of leucopenia]. PMID- 26946725 TI - [Ginger-partition moxibustion combined with glucocorticoid for thyreoitis at subacute stage: a randomizd controlled trial]. AB - OBJECTIVE: To compare the clinical effects between ginger-partition moxibustion combined with glucocorticoid and simple oral glucocorticoid for thyreoitis at subacute stage. METHODS: Eighty-one patients were randomly divided into an observation group (41 cases) and a control group (40 cases). In the observation group, ginger-partition moxibustion and hormone were applied. Moxa cones were used at local ashi points, Zusanli (ST 36), Guanyuan (CV 4) and Qihai (CV 6), six cones every point, once every other day and three times a week. Besides, 24 mg methylprednisolone tablets were adopted orally every day, and in two weeks the dose was 16 mg/d, in four weeks 8 mg/d, in six weeks 4 mg/d; all the patients were observed for 8 week. In the control group, simple methylprednisolone was prescribed orally, and the dose, the usage and treatment time were the same as those in the observation group. Erythrocyte sedimentation rate (ESR), triiodothyronine (T3), thyroxin (T4) and ultra-sensitive thyroid stimulating hormone (TSH) before and after treatment were observed in the two groups, as well as fever, the pain of thyroid gland, the regression time of swelling and adverse reaction. RESULTS: The time of thyroid gland pain relieved of the observation group was earlier than that of the control group [(3.07 +/- 0.78) days vs (3.62 +/- 0.92) days, P < 0.05]. After treatment, T3, T4 and ESR were declined apparently (all P < 0.01), and TSH was obviously increased in the two groups (both P < 0.01). After 2-week treatment, ESR in the observation group was lower than that in the control group (P < 0.05). After 4-week treatment, T3, T4, TSH and ESR in the observation group were better than those in the control group (all P < 0.05). After 8 weeks, all indices in the observation group were superior to those in the control group, without statistical significance between the two groups (all P > 0.05). The effects of the observation group in 2 weeks, 4 weeks and 8 weeks were better than those in the control group (all P < 0.05). The cured course was shorter in the observation group than that in the control group (P < 0.05). The adverse reaction rate in the observation group was lower than that in the control group [4.9% (2/41) vs 22.5% (9/40), P < 0.05]. Three months later after treatment, the cured patients were followed. There was no recrudescence in the observation group and three patients caught the disease again in the control group, but there was no statistical significance between the two groups (P > 0.05). CONCLUSION: Ginger-partition moxibustion combined with glucocorticoid achieves better effect than simple oral glucocorticoid for thyreoitis at subacute stage, and the adverse reaction is less, which presents the clinical advantages of the integration of Chinese and western medicine. PMID- 26946726 TI - [Effects of moxibustion on immune function in children with cerebral palsy]. AB - OBJECTIVE: To compare the effects between moxibustion at Guanyuan (CV 4), Shenshu (BL 23), Zusanli (ST 36) and western medication on immune function in children with cerebral palsy. METHODS: A total of 230 children with cerebral palsy were randomly divided into an observation group and a control group, 115 cases in each one. Patients in the observation group were treated with warm moxibustion at Guanyuan (CV 4), Shenshu (BL 23) and Zusanli (ST 36). Patients in the control group were treated with oral administration of pidotimod 10 mL every time. The treatment was given once a day, and 30 days were considered as one session for total 90 days. The changes of T-lymphoctyte subgroups, serum immunoglobulin and development quotient were compared 30 days, 60 days and 90 days into treatment respectively; also the occurrence rate.of disease was observed during 6-month and 12-month follow-up visit. RESULTS: The T-lymphoctyte subgroups (CD3+, CD4+, CD4+/CD8+), serum immunoglobulin (IgG, IgA) and development quotient were significantly improved 30 days, 60 days and 90 days into treatment (P < 0.01, P < 0.05). Regarding the changes of CD3+, CD4+, CD4+/CD4+, IgG, IgA and development quotient, the control group was superior to the observation group 30 days into treatment (all P < 0.05), and the control group was similar to the observation group 60 days into treatment (all P > 0.05), and the observation group was superior to the control group 90 days into treatment (all P < 0.05). There was no significant difference of CD8+ and IgM before and after treatment in two groups (all P > 0.05). The rate of adverse events was 7.0% (8/115) in the observation group, which was lower than 23.5% (27/115) in the control group (P < 0.01); during 6-month and 12-month follow-up visit, the occurrence rate of disease in the observation group was lower than that in the control group (P < 0.05). CONCLUSION: Moxibustion at Guanyuan (CV 4), Shenshu (BL 23) and Zusanli (ST 36) can improve immune function of children with cerebral palsy, which is superior to pidotimod. PMID- 26946727 TI - [Clinical efficacy of moxibustion as supplement on rheumatoid arthritis and the exploration on its mechanism]. AB - OBJECTIVE: To explore the clinical efficacy of moxibustion on rheumatoid arthritis (RA) in the patients and the impacts on the inflammatory indices. METHODS: Forty RA patients were randomized into an observation group and a control group, 20 cases in each one. In the control group, diclofenac sodium sustained release tablets were used, 0.3 g each time, twice a day; methotrexate tablets were used, 10 mg each time, once a week; folic acid was used, 5 mg each time, once a week. In the observation group, on the basis of the treatment as the control group, moxibustion was added specially on the swelling and painful joints, once a day, 15-20 min each time till: the local skin turned slightly red. The treatment was given once a day, at the interval of 1 day after every 6 treatments. In the two groups, the efficacy was observed after 30-day treatment. Before and after treatment, the rheumatoid factor (RF), high sensitivity C reactive protein (hs-CRP), erythrocyte sedimentation rate (ESR), disease activity score-28 (DAS-28) and the score of joint symptom and physical signs were observed. RESULTS: Compared with those before treatment, the levels of RF, hs CRP, ESR, DAS-28 and the symptom scale score were all reduced in the RA patients of the two groups after treatment (all P < 0.05). Compared with the control group, the levels of RF, hs-CRP, ESR, DAS-28 and the symptom scale score in the observation group were improved much apparently (all P < 0.05). The total effective rate was 85.0% (17/20) in the observation group and was 80.0% (16/20) in the control group. The total effective rate in the observation group was apparently better than that in the control group (P < 0.05). CONCLUSION: Moxibustion as supplement relieves the joint symptoms, reduces the inflammatory reactive indices and improves the clinical efficacy in the RA patients. PMID- 26946728 TI - [Control observation between mild moxibustion and TDP for obsolete collateral ligament injury of interphalangeal joints]. AB - OBJECTIVE: To compare the effects between mild moxibustion and specific electromagnetic spectrum therapy apparatus (TDP) for obsolete collateral ligament injury of interphalangeal joints. METHODS: Sixty patients were randomly divided into a mild moxibustion group and a TDP group, 30 cases in each one. In the mild moxibustion group, pure moxa sticks were used at the affected digital joints locally for 20-30 min a time. In the TDP group, TDP was applied at the affected digital joints locally for 20-30 min a time. The treatment was given once a day for two courses, and 10-day treatment was made into a course. Visual analogue scale (VAS) for pain, swelling degree of the affected digital joints before and after treatment were observed and the clinical efficacy and safety were evaluated in the two groups. RESULTS: The excellent rate was 56.7% (17/30) and the excellent and, good rate was 83.4% (25/30) in the mild moxibustion group,which were better than 36.7% (11/30) and 76.7% (23/30) in the TDP group respectively (both P < 0.01). After treatment the score of VAS and digital joints swelling degree were improved than those before treatment in the two groups (P < 0.01, P < 0.05), and the improvements of the mild moxibustion group were better than those of the TDP group (P < 0.01, P < 0.05). CONCLUSION: Mild moxibustion can apparently relieve the painful and swelling degree of obsolete collateral ligament injury of interphalangeal joints, which is superior to TDP. PMID- 26946729 TI - [Effects of "menstrual cycle-based acupuncture therapy" on IVF-ET in patients with decline in ovarian reserve]. AB - OBJECTIVE: To observe the effects of "menstrual cycle-based acupuncture therapy" on ovarian function and pregnancy results of in vitro fertilization-embryo transfer (IVF-ET) in patients with decline in ovarian reserve (DOR). METHODS: A total of 63 patients of DOR who received treatment of IVF/intracytoplasmic sperm injection (ICSI) were randomly divided into an observation group (30 cases) and a control group (33 cases). The patients in the observation group were treated with "menstrual cycle-based acupuncture therapy". The syndrome differentiation and treatment were given based on different phases of menstruation. Shiqizhui (EX-B 8) and Mingmen (GV 4) were selected during menstrual phase, Shenshu (BL 23), Geshu (BL 17), Sanyinjiao (SP 6) and Taixi (KI 3) were selected after menstruation, Qihai (CV 6), Guanyuan (CV 4), Zigong (EX-CA 1), Zusanli (ST 36) were selected during ovulatory period, Qihai (CV 6), Guanyuan (CV 4), Yanglingquan (GB 34), Taichong (LR 3) were selected before menstruation. The acupuncture was given twice a week until second menstrual cycle of oocyte retrieval. The total times of acupuncture was (15 +/- 2). After acupuncture, patients were treated with IVF-ET. The patients in the control group were treated with IVF-ET but no acupuncture. The indices of ovarian reserve function, including basic follicle-stimulating hormone (FSH), estradiol (E2), antral follicle count (AFC), number of retrieved oocytes, number of fertilization and number of high quality embryo, were compared and analyzed before and after acupuncture in the observation group. The differences of outcomes of IVF-ET, including the cycle cancellation rate, implantation rate, the clinical pregnancy rate, were compared between the two groups. RESULTS: Compared before acupuncture, the E2, AFC, number of retrieved oocytes, number of high quality embrgo and number of fertilization were all increased after acupuncture in the observation group (all P< 0. 05). Compared with the control group, levels of the E2, the number of retrieved oocytes, number of fertilization and number of high quality embryo were all increased in the observation group (all P < 0.05). Also, the implantation rate, the clinical pregnancy rate were improved (both P < 0.01) and cycle cancellation rate was reduced (P< 0.01). CONCLUSION: The "menstrual cycle based acupuncture therapy" can effectively improve the ovarian reserve function in DOR patients, leading to an improved clinical pregnancy rate of IVF-ET. PMID- 26946730 TI - [Triple acupuncture method at cervical Jiaji (EX-B 2) for cervicogenic headache: a randomized controlled trial]. AB - OBJECTIVE: To compare the efficacy difference between triple acupuncture method at cervical Jiaji (EX-B 2) and conventional acupuncture for cervicogenic headache. METHODS: A total of 66 patients were randomly divided into a triple acupuncture group and a conventional acupuncture group, 33 cases in each one. The acupoints selected in the two groups were identical, including C1 to C7 of cervical Jiaji (EX-B 2) as well as Baihui (GV 20), Qiangjian (GV 18), Naokong (GB 19), Fengchi (GB 20), Fengfu (GV 16), Tianzhu (BL 10), etc. The conven- tional acupuncture was performed at acupoints on the head in the two groups; triple acupuncture was performed at cervical Jiaji (EX-B 2) in the triple acupuncture group while perpendicular acupuncture was performed with a depth of 25 to 40 mm in the conventional acupuncture group. The treatment was given once a day. Five treatments were considered as one session and totally two sessions were required. The changes of simplified McGill scale before and after acupuncture were observed in the two groups, and the efficacy of the two groups was compared. RESULTS: After acupuncture, the simplified McGill scale was both reduced in the two groups (both P < 0.01), and there was no significant difference between the two groups after treatment (all P > 0.05). The cured and markedly effective rate was 75.8% (25/33) and the total effective rate was 93.9% (31/33) in the triple acupuncture group, which were superior to 57.6% (19/33, P < 0.01) and 84.8% (28/33, P < 0.05) in the conventional acupuncture group respectively. CONCLUSION: The efficacy of triple acupuncture method at cervical Jiaji (EX-B 2) is superior to that of conventional acupuncture for cervicogenic headache. PMID- 26946731 TI - [Short effect and adverse reaction of dog days plaster for allergic rhinitis]. AB - OBJECTIVE: To evaluate the short effect and safety of the acupoint application of dog days for allergic rhinitis. METHODS: Two hundred and forty-nine patients were randomly divided into an application group (166 cases) and a placebo group (83 cases). On the first day of the first dog days, the first day of the second of the three ten-day periods of the hot season and the first day of the last of the three ten-day periods of the hot season, acupoint application was adopted mainly at Dazhui (GV 14), Feishu (BL 13), Pishu (BL 20) and Shenshu (BL 23) in the application group. The plaster was made of Chinese herbs, including Baijiezi (semen brassicae), Xixin (asarum), Yanhusuo (corydalis tuber) and Gansui (euphorbia kansui). Buckwheat plaster without medical ingredient was used in the placebo group. The application was pasted for 2-6 h every time. On the first three days of all the three periods of dog days, treatment was used continuously. The whole period of dog days was made into one course. The changes of symptom and syndrome scores, visual analogue scale (VAS) for symptom before and after treatment and the adverse reaction with the condition disposed were observed in the two groups. RESULTS: After treatment, the symptom and syndrome scores and VAS for symptom were improved compared with those before treatment in the two groups (all P < 0.05), and the improvements of the application group were more obvious than those of the placebo group (all P < 0.05). The short effective rate of the application group was 68.1% (113/166), which was better than 48.2% (40/83) of the placebo group (P < 0.05). The adverse reaction rates were 4.2% (7/166), 2.4% (2/83) respectively, with no statistical significance between the two groups (P > 0.05). CONCLUSION: The dog days plaster achieves obvious effect with good safety for allergic rhinitis. PMID- 26946732 TI - [Effects of bloodletting pricking, cupping and surrounding acupuncture on inflammation-related indices in peripheral and local blood in patients with acute herpes zoster]. AB - OBJECTIVE: To observe the effects of bloodletting pricking, cupping and surrounding acupuncture on blood inflammation-related indices in patients with acute herpes zoster (HZ), and to explore the mechanism of pain control and treatment. METHODS: A total of 60 patients were randomly divided into an observation group and a control group, 30 cases in each one. In the observation group, the patients were treated with bloodletting pricking at herpes, followed by cupping treatment; also the surrounding acupuncture was performed at injured skin. The treatment was given once a day and once every other day after the first 3 days; totally one-week treatment was given. In the control group, the patients were treated with intravenous drip of acyclovir and oral administration of vitamin B1 and B12, once a day for total one week. The visual analogue scale (VAS) and percentages of neutrophil, lymphocyte in peripheral and local blood were observed before and after treatment in the two groups. RESULTS: After treatment, the score of VAS was significantly reduced in both groups (both P < 0.05); compared with the control group, the score of VAS and the time of pain relieve were significantly improved in the observation group (P < 0.01, P < 0.05). Compared before treatment, the percentages of lymphocyte in peripheral and local blood were reduced after treatment (both P < 0.05) and the percentages of neutrophil in local blood were increased (both P < 0.05). The lymphocyte in local blood was also reduced after treatment in the control group (P < 0.05); compared with peripheral blood in the observation group and local blood in the control group, the percentages of lymphocyte in local blood were reduced (both P < 0.05). CONCLUSION: The efficacy of bloodletting pricking, cupping and surrounding acupuncture on acute herpes zoster is positive, and it can significantly lower the number of lymphocytes in the local blood and increase the number of neutrophil, which is likely to be one of the anti-virus mechanisms. PMID- 26946733 TI - [Thirty-five cases of functional anorectal pain treated with electroacupuncture]. PMID- 26946734 TI - [Immediate effects of twirling reinforcing-reducing manipulation at head acupoints on muscle force in patients with acute ischemic stroke: a randomized controlled trial]. AB - OBJECTIVE: To observe differences of immediate effect of twirling reinforcing reducing manipulation at head acupoints on muscle force in patients with acute ischemic stroke. METHODS: A total of 126 patients who met the inclusive criteria were randomly divided into a twirling reinforcing group, a mild reinforcing reducing group and a twirling reducing group, 42 cases in each one. The lines between Baihui (GV 20) and bilateral Taiyang (EX-HN 5) were selected and treated with successive insertion of three needles. The twirling reinforcing method was used in the twirling reinforcing group, and mild reinforcing-reducing method was used in the mild reinforcing- reducing group, and twirling reducing method was used in the twirling reducing group. Each needle was manipulated for 1 min, which was repeated once every 10 min. The needles were retained for 30 min. Muscle force was evaluated immediately after treatment. RESULTS: (1) Muscle force of upper limb: after acupuncture, the muscle force of proximal and remote ends were all improved significantly in three groups (all P < 0.05), which was more obvious in proximal end (all P < 0.05). The improvement of the muscle force of proximal end in the twirling reinforcing group was superior to those in the mild reinforcing-reducing group and twirling reducing group (both P < 0.05); the differences of the muscle force of remote end were not significant among three groups (all P > 0.05). (2) Muscle force of lower limb: after acupuncture, the muscle force of proximal and remote ends was all improved significantly in the three groups (all P < 0.05). The improvement of the muscle force of proximal end was superior to that of remote end in the twirling reinforcing group and mild reinforcing-reducing group (both P < 0.05). CONCLUSION: The twirling reinforcing manipulation at head acupoints is superior to mild reinforcing-reducing and twirling reducing manipulation for muscle force in patients with acute ischemic stroke, which is more significant in proximal end of limbs. PMID- 26946735 TI - [Effects of slow twisting needle insertion and tubing needle insertion at Neiguan (PC 6) on cardiovascular function: a comparative study]. AB - OBJECTIVE: To compare the effects between slow twisting needle insertion and tubing needle insertion. METHODS: With cross-over design, 100 healthy young subjects (half male and half female) aged from 19 to 23 years were randomly divided into two groups by random digital table, 50 cases in each one. At the first stage, subjects in the group A were treated with slow twisting needle insertion while, subjects in,the group B were treated with tubing needle insertion. One week later, the procedure of second stage was performed alternately. The needle was inserted into Neiguan (PC 6) with two methods by one acupuncturist. The needle was retained for 5 min before removal. Five min before needle insertion as well as needle withdrawal and 30 min after needle withdrawal, ZXG-E automatic cardiovascular diagnostic apparatus was used to test cardiovascular function. RESULTS: At the tim of needle withdrawal, slow twisting needle insertion could improve effect work of kinetics (EWK), effective blood volume (BV) and reduce elastic expansion coefficient of blood vessel (FEK) and left ventricular spray blood impedance (VER), which was significantly different from tubing needle insertion (all P < 0.05). Thirty min after needle withdrawal, the differences of the indices of cardiovascular function between the two groups were not significant (all P > 0.05). CONCLUSION: The slow twisting needle insertion is significantly superior to tubing needle insertion on lowering vascular tension and VER, improving EWK and BV. PMID- 26946736 TI - [Operation and essence of Toutianliang manipulation by professor ZHANG Jin]. AB - Toutianliang manipulation is the most representative compound needling technique of traditional reinforcing and reducing and has the remarkable efficacy on heat syndrome with muscle and bone involved for example. Professor ZHANG Jin is one of the famous acupuncture master in China and has contributed his lifelong to the research of acupuncture manipulation techniques. He has summarized 24 single-type manipulations and has given the comprehensive explanation of the manipulations for meridian conduction, reinforcing or reducing techniques for the excess or deficiency. In the paper, Toutianliang manipulation was introduced briefly and the key operation steps had been discussed. PMID- 26946737 TI - [Electroacupuncture for 36 cases of incomplete anal incontinence after rectal prolapsed operation]. PMID- 26946738 TI - [Acupuncture at Taixi (KI 3), Taichong (LR 3) with heat-producing needling method for 26 cases of infantile enuresis]. PMID- 26946739 TI - [Bloodletting combined with medicinal cupping and moxibustion for 36 cases of insect bite dermatitis with lymphangitis]. PMID- 26946740 TI - [Effects of different moxibustion temperature on cholesterol and skin around "Shenque" (CV 8) in mice with hyperlipidemia]. AB - OBJECTIVE: To observe the effects of moxibustion with different temperatures on cholesterol and skin around "Shenque" (CV 8) in mice with acute hyperlipidemia, and to explore the correlation between moxibustion effect and transient receptor potential vanilloid 1 (TRPV1). METHODS: Eight mice among 32 mice of C57BL/6J wild type (WT) were selected into a blank group, and the remaining 24 mice were made into the acute hyperlipidemia model by injection of egg yolk. After model establishment, the mice were randomly divided into a model group, a 38 degrees C moxibustion group and a 46 degrees C moxibustion group, 8 mice in each group. The temperature was (38 +/- 1) degrees C in the 38 degrees C moxibustion group and (46 +/- 1) degrees C in the 46 degrees C moxibustion group. "Shenque" (CV 8) and "Zusanli" (ST 36) were selected in the two groups; moxibustion was given for 10 min per time, once a day for 2 times. Mice in the blank group and model group were treated with immobilization and moxibustion was not given. After treatment, the level of serum cholesterol was tested by oxidase method; the morphology of skin around "Shenque" (CV 8) was observed by HE staining; the expression of TRPV1 in skin was measured by immunohistochemistry. RESULTS: (1) Compared with the blank group, the level of serum cholesterol was increased in the model group (P < 0.001); compared with the model group, the level of serum cholesterol was reduced in the 46 degrees C moxibustion group (P < 0.001); compared with the 38 degrees C moxibustion group, the level of serum cholesterol was reduced in the 46 degrees C moxibustion group (P < 0.01). (2) There was slight change of morphology and structure in skin tissue in the 38 degrees C moxibustion group, while obvious change was observed in the 46 degrees C moxibustion group, indicating specific change. (3) The difference of the expression of TRPV1 in skin was significantly different between 46 degrees C moxibustion group and blank group, model group (both P < 0.01); it was also different from the 38 degrees C moxibustion group (P < 0.05). CONCLUSION: Moxibustion temperature is one of the important factors affecting the cholesterol and acupoint skin. The effects of moxibustion are related to TRPV1. PMID- 26946742 TI - [Ninety cases of lumbar disc herniation treated with acupuncture]. PMID- 26946741 TI - [Effects of electroacupuncture at "Neiguan" (PC 6) on sodium channel-related proteins in rats with ischemic myocardial injury]. AB - OBJECTIVE: To explore the protective mechanism of electroacupuncture (EA) at "Neiguan" (PC 6) on ischemic myocardial injury, and to explain the response patterns and characteristics of the specific effect of acupoints along meridians in sodium channel in the level of cardiac organ. METHODS: A total of 60 SPF male rats were randomly divided into a blank group, a model group, a non-acupoint group, a Neiguan group and a Lieque group, 12 cases in each one. Except the blank group, rats in the remaining group were treated with subcutaneous injection of isoprenaline to establish the model of myocardial ischemia. Rats in the Neiguan group, Lieque group and non- acupoint group were treated with EA, dilatational wave, with a frequency of 2 Hz/20 Hz. The intensity was 2-3 mA. The needles were retained for 20 min per time, once a day for consecutive 7 days. In the blank group and control group, the rats were grasped and fixed at the treating time each day. The western-blot method was used to test the expression of voltage gated sodium channel alpha subunit (Nav 1.5), protein tyrosine kinase (PTKs) and protein tyrosine phosphatase (PTPs). RESULTS: The expression of Nav 1.5 and PTKs in the model group was lower than that in the blank group (both P<0. 01); the expression in the Neiguan group and Lieque group was higher than that in the model group (all P < 0.01); the expression of Nav 1.5 and PTKs in the Neiguan group was higher than that in the Lieque group (both P < 0.01). The expression of PTPs in the model group and non-acupoint group was higher than that in the blank group (both P < 0.01); the expression of PTPs in the Neiguan group and Lieque group was significantly down-regulated, which was lower than the model group (both P < 0.01); the down-regulation in the Neiguan group was significantly different from that in the Lieque group (P < 0.05). CONCLUSION: EA at "Neiguan" (PC 6), by down-regulating the expression of PTPs, up-regulating the expression of Nav 1.5 and PTKs, is likely to achieve the aim of regulation on sodium channel activity and calcium overload, further to improve myocardial ischemia, which provides experimental basis for the theory of the specific effect of acupoints along meridians. PMID- 26946743 TI - [Ancient literature on the heat control of umbilicus fumigation method and the modern clinical research]. AB - In order to improve the clinical efficacy of the umbilicus fumigation method, the ancient literature with the heat control of umbilicus fumigation method involved is collected extensively and analyzed systematically, and the heat control, precautions and contraindications of this method are discussed. In association with the cases and the present clinical experience, the main factors to the heat control are introduced, such as preparation of doughnuts, filling quantity, size of moxa cone and numbers of moxa cones so that the clinical application of the umbilicus fumigation method can be promoted and enhanced. PMID- 26946744 TI - [Case of chronic eczema]. PMID- 26946745 TI - [Brief analysis of professor YAN Jie's academic thought on functional dyspepsia treated with acupuncture and moxibustion]. AB - The brief discussion is introduced in the paper on the academic thought of professor YAN Jie, the contemporary famous TCM doctor, on functional dyspepsia treated with acupuncture and moxibustion. Treatment based on "the three-regional acupoint selection" is applied to professor YAN's treatment for functional dyspepsia, in which, acupuncture is on Sibai (ST 2), Liangmen (ST 21) and Zusanli (ST 36), and the supplementary points are added accordingly. The academic thought is described as the combination of acupuncture and moxibustion based on strengthening healthy qi, supplemented by soothing the liver and psychological counseling. Also, an example is provided. PMID- 26946746 TI - [Professor GAO Yuchun's experience on "sequential acupuncture leads to smooth movement of qi"]. AB - Professor GAO Yuchun is considered as the key successor of GAO's academic school of acupuncture and moxibustion in Yanzhao region. Professor GAO's clinical experience of, "sequential acupuncture" is introduced in details in this article. In Professor GAO's opinions, appropriate acupuncture sequence is the key to satisfactory clinical effects during treatment. Based on different acupoints, sequential acupuncture can achieve the aim of qi following needles and needles leading qi; based on different symptoms, sequential acupuncture can regulate qi movement; based on different body positions, sequential acupuncture can harmonize qi-blood and reinforcing deficiency and reducing excess. In all, according to the differences of disease condition and constitution, based on the accurate acupoint selection and appropriate manipulation, it is essential to capture the nature of diseases and make the order of acupuncture, which can achieve the aim of regulating qi movement and reinforcing deficiency and reducing excess. PMID- 26946748 TI - [Case of blind eye disease associated with central retinal artery occlusion]. PMID- 26946747 TI - [Experience of professor LI Zhidao in the treatment of mental disorders by "regulating the heart and smoothing the liver"]. AB - The experience of Professor LI Zhidao is introduced in the treatment of mental disorders by "regulating the heart and smoothing the liver". In his experience, the basic prescription includes: penetrating needling technique from Neiguan (PC 6) to Jianshi (PC 5), Ximen (PC 4), penetrating needling technique from Qiuxu (GB 40) to Zhaohai (KI 6) and penetrating needling technique at four groups of acupoints on the gallbladder meridian [Hanyan (GB 4) to Xuanlu (GB 5) and Xuanli (GB 6), Qubin (GB 7) to Shuaigu (GB 8), Shuaigu (GB 8) to Tianchong (GB 9), Tianchong (GB 9) to Fubai (GB 10) and Touqiaoyin (GB 11)]. The manipulation with respiration involved is combined with interactive needling technique so that the patients can feel the weak needling sensation at the local acupoint regions during the treatment. In the paper, the concrete clinical cases are introduced to explain this application and the satisfactory efficacy achieved. The therapeutic method provides a new approach to the clinical treatment of mental disorders. PMID- 26946749 TI - [Transition of the blind acupuncture and massage industry and its impacts in Japan]. AB - After being introduced to Japan, the Chinese acupuncture and massage therapy has changed a lot, in which the influence aroused by the blind practitioners cannot be ignored. Through analyzing the development and the transition of the blind acupuncture and massage industry in Japan, it is found that the tube needle technique, changeable acupoints concept, technical deviation and the importance on acupoints rather than meridians are still existed commonly today, which are introduced by the blind acupuncture and massage practitioners, the special group in Japan. In the process of development, the interaction with the governmental strategy has played the essential role in the consolidation of the above features. PMID- 26946750 TI - [How to determine the qi arrival and its strength in clinical research]. AB - Qi arrival is the meridian qi response to acupuncture stimulation. Through analyzing the relevant concepts of qi arrival and summarizing the general understanding of it in clinic and on the basis of the collection of the relevant literature at home and abroad on the determination of qi arrival and its strength, the characteristics are analyzed on the present method and the method for the determination of qi arrival and its strength is discussed in terms of the results in the needling sensation scale. It is believed that the needling sensation and its strength can be used to determine whether the qi is arrived or not and its strength. The components of different types of needling sensation are much better applicable for the analysis on the characteristics and rules on the influence on qi arrival. This method is in compliance not only with the theoretic connotation of qi arrival, but also with the clinical general understanding, which lays the foundation for the analysis on the scale results. PMID- 26946751 TI - [Case of intractable trigeminal neuralgia]. PMID- 26946752 TI - [Human body meridian spatial decision support system for clinical treatment and teaching of acupuncture and moxibustion]. AB - The spatial position and distribution of human body meridian are expressed limitedly in the decision support system (DSS) of acupuncture and moxibustion at present, which leads to the failure to give the effective quantitative analysis on the spatial range and the difficulty for the decision-maker to provide a realistic spatial decision environment. Focusing on the limit spatial expression in DSS of acupuncture and moxibustion, it was proposed that on the basis of the geographic information system, in association of DSS technology, the design idea was developed on the human body meridian spatial DSS. With the 4-layer service oriented architecture adopted, the data center integrated development platform was taken as the system development environment. The hierarchical organization was done for the spatial data of human body meridian via the directory tree. The structured query language (SQL) server was used to achieve the unified management of spatial data and attribute data. The technologies of architecture, configuration and plug-in development model were integrated to achieve the data inquiry, buffer analysis and program evaluation of the human body meridian spatial DSS. The research results show that the human body meridian spatial DSS could reflect realistically the spatial characteristics of the spatial position and distribution of human body meridian and met the constantly changeable demand of users. It has the powerful spatial analysis function and assists with the scientific decision in clinical treatment and teaching of acupuncture and moxibustion. It is the new attempt to the informatization research of human body meridian. PMID- 26946753 TI - [Discussion on the industry standard: electroacupuncture therapy device]. AB - Studying the industry standard of electroacupuncture therapy device (YY 0780 2010), collaborating with the clinical practice of acupuncture and moxibustion, in view of academy and safety, the comments and suggestions are proposed on the content of the standard. The standard describes manipulation norms, terms and definitions, dianjizhen and the output energy of single pulse, etc. It is expected that these comments and suggestions can be taken in consideration in the revision of industry standard or the development of national standard so as to improve the scientific level and feasibility of the technique standard of electroacupuncture therapy device. PMID- 26946754 TI - [Electroacupuncture on the heart meridian and pericardium meridian acupoints for 29 cases of sensory disturbance after thalamic stroke]. PMID- 26946755 TI - [Characteristics on the diagnosis and treatment with acupuncture and moxibustion for the improvement of motor sensory function, urination and defecation in myelitis]. AB - The literature was analyzed on the improvement of motor sensory function, urination and defecation in myelitis treated with acupuncture and moxibustion and focused on the characteristics of the diagnosis and treatment. The literature on acupuncture and moxibustion treatment for myelitis was collected from CNKI, Wanfang, VIP and PubMed. The analysis included the characteristics of acupoint selection, methods of acupuncture and moxibustion, time of treatment, total treatment period, efficacy, follow-up, safety, etc. Totally, 26 articles were collected. The combined therapy of acupuncture and moxibustion was predominated (12/26, 46. 15%). For the motor and sensory impairment, the acupoints were mainly selected from the four limbs, the yangming meridians of hand and foot and those adjacent to the affected spinal segments and on the governor vessel as well as Jiaji (EX-B 2) points. For urinary impairment, the acupoints were selected mainly from the lower abdominal region on the conception vessel and the lumbosacral region on the bladder meridian. For the intestinal impairment, the acupoints were from the lower limb on the stomach meridian, the lower abdominal region on the conception vessel and the back points on the bladder meridian. The intervention started commonly in the first 3 months after onset. The total treatment period was in the range from 1 to 3 months. The efficacy of acupuncture and moxibustion was 69.19% to 82.56% for the improvement of motor sensory and urination, defecation function. The efficacy in follow-up was stable and the adverse reactions were not reported. It is viewed that on the basis of early diagnosis and active medication, acupuncture and moxibution achieve a certain of efficacy on the impairment of motor sensory function, urination and defecation. A clinical research is expected to further verify the efficacy. PMID- 26946756 TI - [Case of benign prostatic hyperplasia complicated with urinary retention]. PMID- 26946757 TI - [Acupoints heat-sensitive moxibustion in the application of traditional Chinese surgery]. AB - Under the guidance of meridian theory, the acupoints heat-sensitive moxibustion is a treatment method which applies moxa stick to perform mild moxibustion at heat-sensitive acupoints, which can arouse the meridian sensation transmission and promote the movement of meridian qi; consequently, the qi can be extended to the diseases. For its many advantages, such as no direct contact on skin, no injuries, no pains, fewer side effects, easy operating and moderate cost, the acupoints heat-sensitive moxibustion is widely accepted in dermatology, male urology disease, rectum and anus diseases and breast diseases. The application and research status of the acupoints heat-sensitive moxibustion in traditional Chinese surgery in recent years is reviewed, and several problems and suggestions in its clinical application and research are proposed, aiming to provide clinical basis for its further development and clinical application in traditional Chinese surgery. PMID- 26946759 TI - Changes in Cervical Lordosis and Cervicovertebral Morphology in Different Ages with the Possibility of Estimating Skeletal Maturity. AB - INTRODUCTION: During growth, proportions of craniofacial and cervical structures are changed. Craniofacial and cervicovertebral structures are morphologically and functionally connected, but their each other's influence is still unknown. OBJECTIVE: The aim of this study was to determine the changes in cervical lordosis and cervicovertebral morphology in different age periods and the possibility of estimating skeletal maturity, based on the percentage of anterior cervical vertebrae body height sum in the total anterior C2-C5 height. METHODS: The study included lateral radiographs of 120 patients of both sexes, divided into three different age groups: eight, 12-13 and 17-18 years of age. Five craniofacial and 15 cervical parameters were measured and analyzed. RESULTS: The results showed significant correlation between cervical lordosis angle and age, gender, anterior and posterior body height of C3, C4, C5, anterior C4-C5 and posterior C2-C3, C3-C4, C4-C5 intervertebral space, anterior body height of C2 C5. Overall values of all cervical body heights were more present in the total height of the spine in females, while all intervertebral spaces were more present in males. The percentage of anterior and posterior C2, C3, C4, C5 body height sum compared to total C2-C5 height increases with age. CONCLUSION: The cervical lordosis becomes more curved and vertebral bodies occupy more space in females, while intervertebral spaces occupy more in males. Skeletal maturity could be estimated following vertebral percentage distribution in the total anterior C2-C5 part. PMID- 26946758 TI - Complications in Cochlear Implantation at the Clinical Center of Vojvodina. AB - INTRODUCTION: The first modern cochlear implantation in Serbia was performed on November 26, 2002 at the Center for Cochlear Implantation of the Clinic for Ear, Nose and Throat Diseases, Clinical Center of Vojvodina. OBJECTIVE: The aim of the paper is the analysis of intraoperative and postoperative complications. Major complications include those resulting in the necessity for revision surgery, explantation, reimplantation, severe disease or even lethal outcomes. Minor complications resolve spontaneously or can be managed by conservative therapy and do not require any prolonged hospitalization of the patient. METHODS: In the 2002 2013 period, 99 patients underwent surgical procedures and 100 cochlear implants were placed. Both intraoperative and postoperative complications were analyzed in the investigated patient population. RESULTS: The analysis encompassed 99 patients, the youngest and the oldest ones being one year old and 61 years old, respectively. The complications were noticed in 11 patients, i.e. in 10.5% of 105 surgical procedures. The majority of procedures (89.5%) were not accompanied by any post-surgical complications. Unsuccessful implantation in a single-step procedure (4.04%) and transient facial nerve paralysis can be considered most frequent among our patients, whereas cochlear ossification (1.01%) and transient ataxia (2.02%) occurred rarely. Stimulation of the facial nerve (1.01%), intraoperative perilymph liquid gusher (1.01%), device failure and late infections (1.01%) were recorded extremely rarely. CONCLUSION: Complications such as electrode extrusion, skin necrosis over the implant or meningitis, which is considered the most severe postoperative complication, have not been recorded at our Center since the very beginning. Absence of postoperative meningitis in patients treated at the Center can be attributed to timely pneumococcal vaccination of children. PMID- 26946760 TI - Evaluation of Surfactant Replacement Therapy Effects--A New Potential Role of Lung Ultrasound. AB - INTRODUCTION: Previous studies suggested that effects of the surfactant administration in preterm intants with respiratory distress syndrome cannot be followed by lung ultrasound (L-US). OBJECTIVE: The aim of the paper is to evaluate the surfactant replacement therapy effects using a new, proposed grading system for L-US findings. METHODS: We report the series of 12 preterm infants with clinical and radiographic signs of respiratory distress syndrome, in whom L US examinations were performed prior to, and within the first 24 hours after surfactant administration. To evaluate the surfactant replacement therapy effects, we proposed a new grading system (1 to 6) for L-US findings at each examined lung area, based on the presence of normal finding, the amount of B lines and subpleural consolidations. RESULTS: All preterm infants had an improvement of L-US findings from one to four grades observed within the first 24 hours after surfactant administration, which has not been previously reported. The improvement of L-US findings was most commonly observed in anterior lung areas. CONCLUSION: L-US might enable an early detection of the surfactant replacement therapy effects. Further prospective studies are necessary to define the role of L-US in this field. PMID- 26946761 TI - The Burden of Gastroesophageal Reflux Disease on Patients' Daily Lives: A Cross Sectional Study Conducted in a Primary Care Setting in Serbia. AB - INTRODUCTION: Recent data from the studies conducted in the Western countries have proved that patients with gastroesophageal reflux disease have significantly impaired health-related quality of life compared to general population. OBJECTIVE: The study is aimed at evaluating the burden of reflux symptoms on patients'health-related quality of life. METHODS: The study involved 1,593 patients with diagnosed gastroesophageal reflux disease.The Serbian version of a generic self-administered Centers for Disease Control and Prevention questionnaire was used. Statistical analyses included descriptive statistics, Pearson chi-square test and a multiple regression model. RESULTS: Among all participants, 43.9% reported fair or poor health. Mean value of unhealthy days during the past 30 days was 10.4 days, physically unhealthy days 6.4 days, mentally unhealthy days 5.3 days and activity limitation days 4.3 days. Furthermore, 24.8% participants reported having >= 14 unhealthy days, 14.9% had 14 physically unhealthy days, 11.8% reported 14 mentally unhealthy days, and 9.4% had >= 14 activity limitation days. CONCLUSION: This study addressed complex relationships between reflux symptoms and patients'impaired everyday lives. PMID- 26946762 TI - Scoring System Development and Validation for Prediction Choledocholithiasis before Open Cholecystectomy. AB - INTRODUCTION: Accurate precholecystectomy detection of concurrent asymptomatic common bile duct stones (CBDS) is key in the clinical decision-making process. The standard preoperative methods used to diagnose these patients are often not accurate enough. OBJECTIVE: The aim of the study was to develop a scoring model that would predict CBDS before open cholecystectomy. METHODS: We retrospectively collected preoperative (demographic, biochemical, ultrasonographic) and intraoperative (intraoperative cholangiography) data for 313 patients at the department of General Surgery at Gornji Milanovac from 2004 to 2007. The patients were divided into a derivation (213) and a validation set (100). Univariate and multivariate regression analysis was used to determine independent predictors of CBDS. These predictors were used to develop scoring model. Various measures for the assessment of risk prediction models were determined, such as predictive ability, accuracy, the area under the receiver operating characteristic curve (AUC), calibration and clinical utility using decision curve analysis. RESULTS: In a univariate analysis, seven risk factors displayed significant correlation with CBDS. Total bilirubin, alkaline phosphatase and bile duct dilation were identified as independent predictors of choledocholithiasis. The resultant total possible score in the derivation set ranged from 7.6 to 27.9. Scoring model shows good discriminatory ability in the derivation and validation set (AUC 94.3 and 89.9%, respectively), excellent accuracy (95.5%), satisfactory calibration in the derivation set, similar Brier scores and clinical utility in decision curve analysis. CONCLUSION: Developed scoring model might successfully estimate the presence of choledocholithiasis in patients planned for elective open cholecystectomy. PMID- 26946763 TI - Assessment of the Reliability of the Serbian Version of the Sickness Impact Profile Questionnaire in Patients with Chronic Viral Hepatitis. AB - INTRODUCTION: Health-related quality of life (HRQL) of chronic patients has been researched as the ultimate goal of modern treatment of chronic diseases to improve patients'quality of life. OBJECTIVE: The objective was to assess the reliability of the Serbian version of the Sickness Impact Profile (SIP) questionnaire on the sample of patients with chronic viral hepatitis. METHODS: The research covered 102 patients with chronic hepatitis (47 type B and 55 type C). The assessment of the reliability of the SIP questionnaire was performed by testing the internal consistency of the questions by calculating the Cronbach's alpha coefficient. The factor analysis was used to assess whether the grouping of the questions within dimensions matches the distribution of the questions in the original English version of the questionnaire administered to U.S. patient population. RESULTS: The Cronbach's alpha coefficient for the entire questionnaire is 0.925, 0.869 for the physical dimension, and 0.857 for the psychosocial dimension. After running a factor analysis of the psychosocial dimension, "emotional instability" was extracted as the key factor, confirming the results of previous research. Compared with the English version of the questionnaire, the Cronbach's alpha coefficient of the Serbian version does not diverge significantly, whereas the factor analysis confirms the classification of the questionnaire into two dimensions. CONCLUSION: Our study has shown that the Serbian version of the SIP questionnaire is a reliable tool for assessing the HRQL of patients with chronic hepatitis B and C before starting treatment. PMID- 26946764 TI - Analysis of Macronutrients Intake and Body Mass Index in Preschool Children in the Western Region of the Republic of Srpska. AB - INTRODUCTION: Childhood obesity is currently considered to be one of the most prevailing and challenging public health issues in industrialized countries and some developing countries, including the Republic of Srpska. OBJECTIVE: Our objective was to determine macronutrients intake in collective diet of preschool children and to estimate the rate of obesity in this population. METHODS: Samples of food intended for preschool children diet were collected in a preschool facility in the western region of the Republic of Srpska. In daily portions, the content of proteins, fats, carbohydrates, water and mineral matter were determined using standard methods. The body mass index was determined on the basis of anthropometric measurements. RESULTS An average daily meal contained 17.5 g of fats, 19.1 g of proteins and 101.5 g of carbohydrates. The energy value was 676 Kcal. The analysis of the data from the menu showed that the number of consumed servings of fruits, vegetables, legumes, milk and dairy products was less than one portion per day. However, the amount of consumed meat and meat products exceeded one portion per day. Out of the total number of children, 10.0% were undernourished, 16.7% were overweight and 13.3% were obese. CONCLUSION: Daily portions in the preschool facility are not in accordance with the recommended dietary allowance for energy and carbohydrates intake, and the composition of meals is inadequate. Parents and caregivers should be encouraged to expose young children to a wide variety of fruit and vegetables, whole grains, low-fat dairy products, and to balance food intake with the requirements. PMID- 26946765 TI - Parental Factors Associated with Intrauterine Growth Restriction. AB - INTRODUCTION: Linear growth failure is caused by multiple factors including parental factors. OBJECTIVE: The aim of this study was to evaluate parental risk factors for intrauterine growth restriction (IUGR) on a population of Romanian newborn infants in a tertiary level maternity facility for a period of 2.5 years. METHODS: A retrospective matched case-control study was conducted in the Emergency County Hospital of Cluj-Napoca, a university hospital in North-Western Romania. The sample was selected from 4,790 infants admitted to the Neonatal Ward at 1st Gynecology Clinic between January 2012 and June 2014. RESULTS: The age of mothers was significantly lower in the IUGR group compared to controls (p = 0.041). A significantly higher percentage of mothers had hypertension in the IUGR group compared to those in the control group (p<0.05). No other significant differences were identified with regard to the investigated characteristics of mothers between IUGR infants compared to controls (p > 0.13). The age of fathers of infants with IUGR proved significantly lower compared to controls (p = 0.0278).The analysis of infants'comorbidities revealed no significant difference between groups for respiratory distress, hyperbilirubinemia, hypocalcaemia, and heart failure (p > 0.27). Intracranial hemorrhage, necrotizing enterocolitis and hypoglycemia were significantly higher in the IUGR group compared to controls. The logistic regression identified hypertension as a significant risk factor for IUGR (OR = 2.4, 95% Cl [1.3-4.5]). CONCLUSION: Although the age of the mothers and fathers proved significantly lower in the IUGR group compared to controls, only hypertension in the mothers proved significant risk factors for IUGR. PMID- 26946766 TI - Epidemiological Surveillance of Leishmaniasis in Montenegro, 1992-2013. AB - INTRODUCTION: The diseases caused by Leishmania are spread worldwide and represent a significant public health problem. OBJECTIVE: The aim of this study was to present the results of epidemiological surveillance of leishmaniasis in humans in Montenegro in the period from 1992 to 2013. METHODS: The study was planned and realized as a descriptive epidemiological study.The sample included patients of leishmaniasis in Montenegro in the period from 1992 to 2013. The health and demographic data were collected from medical records.The disease was microbiologically proven in the patients. For statistical analysis the chi2-test was used, which examined the significance of the incidence rate. RESULTS: During this period, 66 cases of leishmaniasis were identified (40 men and 26 women) aged 0 to 62 (mean 15.61 +/- 16.76 years). A visceral form of the disease was diagnosed in 65 (98%) patients, and one patient was diagnosed with cutaneous leishmaniasis. The average incidence rate for the abovementioned period is 0.48 per 100,000 inhabitants. The highest average incidence rate was identified in patients up to seven years of age (3.50 per 100,000 inhabitants). The highest average incidence rates of leishmaniasis were identified in the coastal region of Montenegro, while seasonal distribution indicates that the disease occurs throughout the year with predominance in late spring and summer. CONCLUSION: The research has shown that Montenegro is among the countries with low incidence of leishmaniasis. Nevertheless, because of leishmaniasis re-emergence in the entire Mediterranean Basin, a comprehensive research of ecological and epidemiological characteristics of leishmaniasis, including better monitoring and notification system, is required. PMID- 26946767 TI - Long-Term Treatment with Olanzapine in Hospital Conditions: Prevalence and Predictors of the Metabolic Syndrome. AB - INTRODUCTION: The risk of metabolic abnormalities is greatly increased in schizophrenic patients started on an atypical antipsychotic medication. Patients with psychiatric disorders exceed mortality ranges resulting from, among others, increased risk of cardiovascular events. Other factors contributing to the development of metabolic syndrome include prolonged duration of illness, increasing age, female sex and lifestyle factors. OBJECTIVE This cross-sectional study was taken up to assess the prevalence of the metabolic syndrome (MetS) in schizophrenic patients receiving olanzapine monotherapy for at least six months and to determine the most important risk factors associated with metabolic syndrome presence in these patients. METHODS A total of 93 long term hospitalized schizophrenic patients (71 men, 22 women), had a screening of the following: case history data, psychiatric scales, anthropometric measures, blood (fasting glucose, lipid status, C-reactive protein--CRP) and urine samples (microalbuminuria). RESULTS: Prevalence of MetS according to International Diabetes Federation criteria in our study was 34.4%. The multivariate analysis distinguished the following significant predictors of MetS presence (in order of appearance): data about diabetes mellitus in family history (p = 0.002), body mass index > 25 kg/m2 (p = 0.002), hyperlipidemia in family history (p = 0.008), and elevated CRP value (p = 0.042). CONCLUSION: High rate of MetS in patients treated with olanzapine in this study exceeds MetS prevalence in general population. Among observed parameters, our study pointed to several "high risk" predictors associated with MetS presence. Regular monitoring of cardiometabolic risk factors is highly recommended. Positive heredity distress mentioned above may direct a psychiatrist to prescribe some other drug than olanzapine in the long term treatment of schizophrenia. PMID- 26946768 TI - Prevalence of Internet Addiction among Schoolchildren in Novi Sad. AB - INTRODUCTION: Internet use has increased rapidly all over the world. Excessive Internet use tends to lead to the creation of a non-chemical addiction, most commonly known as "Internet addiction." OBJECTIVE: The aim of this study was an assessment of the prevalence of Internet use and Internet addiction among school children aged 14-18 years in the Municipality of Novi Sad, Serbia, and influence of sociodemographic variables on Internet use. METHODS: A cross-sectional study was conducted in Novi Sad among final-year students from elementary and first- and second-year students from high schools.The prevalence of Internet addiction was assessed by using Young's Diagnostic Questionnaire. RESULTS: Out of 553 participants, 62.7% were females, and the average age was 15.6 years. The sample consisted of 153 elementary school students and 400 high school students. Majority of respondents had a computer in their household. Our study showed widespread Internet use among adolescents. Facebook and YouTube were among most visited web-sites. The main purpose of Internet use was entertainment. Estimated prevalence of Internet addiction was high (18.7%), Mostly among younger adolescents (p = 0.013). CONCLUSION: Internet addiction was found in every fifth adolescent. Accessibility and availability of Internet use is constantly growing and therefore it is necessary to define more sensitive diagnostic tools for the assessment of Internet addiction and its underlying causes, in order to implement effective preventive programs. PMID- 26946769 TI - The First Telephone Line for the Psychological Support to Oncological Patients and Their Family Members in Serbia. AB - INTRODUCTION: In October of 2010, Serbian Association for Psycho-Oncology, in collaboration with the Ministry of Health of Serbia and the National Health Insurance has launched the first national telephone line for free psychological counseling and support for oncology patients and their families. OBJECTIVE: The aim of this study was to present results of the first national telephone helpline for psychological support for oncological patients and their families. METHODS The telephone line for the psychological help and support was available from 10 a.m. to 10 p.m., seven days a week and on holidays. A total of 12 previously educated psychologists were involved, with two on duty in the mornings and two in the afternoons.The basic work principles of the Line were anonymity for users (if they wished), free of charge service available to patients from all of Serbia, careful listening, emphatic reflection on anything communicated by users and adequate counselling. RESULTS: Since the beginning of the project (October 2010 up to April 2011) we received a total of 2,748 calls from across Serbia. Almost half of these calls were repeated calls, as patients asked for continuous psychological counselling. Larger percent (63.9%) of women called, when compared to men (35.4%) who used the Line. Most (52.4%) conversations were categorized as "psychological support and counseling," and as continual psychological counseling work (21.1%). CONCLUSION: The large number of calls suggests that this kind of public, free service for psychosocial and psychological support to cancer patients is necessary in Serbia. PMID- 26946770 TI - Giant Vertebrobasilar Fusiform Aneurysm as a Cerebellopontine Angle Mass. AB - INTRODUCTION: According to the literature, a fusiform aneurysm located in the cerebellopontine angle (CPA) is an extremely rare condition. CASE OUTLINE: We report a case of a 59-year-old patient with initial dizziness and left-sided sensorineural hearing loss that had gradually developed over six months. Vertebrobasilar fusiform aneurysm, with intraluminal thrombus, which was displaced to the right cerebellopontine angle, creating mass effect, was diagnosed using brain magnetic resonance imaging and magnetic resonance angiography. CONCLUSION: Atherosclerosis may be the essential factor in the pathogenesis of a fusiform aneurysm of the basilar artery, especially in elderly patients. The best treatment option is yet to be determined, but in soite of numerous previous large studies, personalized approach is probably the best. PMID- 26946771 TI - Acute Myocardial Infarction during Induction Chemotherapy for Acute MLL t(4;11) Leukemia with Lineage Switch and Extreme Leukocytosis. AB - INTRODUCTION: In patients with acute leukemias hemorrhage is the most frequent problem. Vein thrombotic events may appear rarely but arterial thromboses are exceptionally rare. We present a patient with acute leukemia and bilateral deep leg vein thrombosis who developed an acute myocardial infarction (AMI) during induction chemotherapy. The etiology and treatment of AMI in patients with acute leukemia, which is a rare occurrence, is discussed. CASE OUTLINE: In April of 2012 a 37-year-old male presented with bilateral deep leg vein thrombosis and malaise. Laboratory data were as follows: Hb 118 g/L, WBC 354 x 10(9)/L (with 91% blasts in differential leukocyte count), platelets 60x109/L. Bone marrow aspirate and immunophenotype revealed the presence of acute lymphoblastic leukemia. Cytogenetic analysis was as follows: 46,XY,t(4;11)(q21:q23) [2]/62 82,XYt(4;11)[18]. Molecular analysis showed MLL-AF4 rearrangement. The patient was on low molecular weight heparin and combined chemotherapy according to protocol HyperCVAD. On day 10 after chemotherapy he got chest pain. Three days later AMI was diagnosed (creatine kinase 66 U/L, CK-MB 13U/L, troponin 1.19 ug/L). Electrocardiogram showed the ST elevation in leads D1, D2, aVL, V5 and V6 and "micro q" in D1. On echocardiography, hypokinesia of the left ventricle and ejection fraction of 39% was found. After recovering from AMI and restoring left ventricle ejection fraction to 59%, second course of HyperCVAD was given. The control bone marrow aspirate showed 88% of blasts but with monoblastic appearance. Flow cytometry confirmed a lineage switch from lymphoblasts to monoblasts. In further course of the disease he was treated with a variety of chemotherapeutic combinations without achieving remission. Eventually, palliative chemotherapy was administered to reduce the bulk of blasts. He died five months after the initial diagnosis. CONCLUSION: AMI in young adults with acute leukemia is a very rare complication which may occur in patients with very high white blood cell count in addition with presence of a CD56 adhesion molecule and other concomitant thrombophilic factors. The treatment of AMI in patients with acute leukemias should include antiplatelet and anticoagulant therapy, even with more aggressive methods depending on patient's age and clinical risk assessment. PMID- 26946772 TI - JAK2V617F Mutation in a Patient with B-cell Chronic Lymphocytic Leukemia and Prefibrotic Primary Myelofibrosis. AB - INTRODUCTION: Secondary malignancies, particularly solid tumors, are common in patients with chronic lymphocytic leukemia (CLL), but association of myeloproliferative neoplasms and chronic lymphocytic leukemia in the same patient is very rare. CASE OUTLINE: We report of a 67-year-old man with B-cell chronic lymphoid leukemia (B-CLL) who developed primary myelofibrosis (PMF) nine years after initial diagnosis. Patient received alkylation agents and purine analogue, which can be a predisposing factor for the development of myeloproliferative neoplasms. JAK2V617F mutation was not present initially at the time of CLL diagnosis, but was found after nine years when PMF occurred, which indicates that B-CLL and PMF represent two separate clonal origin neoplasms. CONCLUSION: Pathogenic mechanisms for the development of myeloproliferative and lymphoproliferative neoplasms in the same patient are unknown. Further research is needed to determine whether these malignancies originate from two different cell clones or arise from the same pluripotent hematopoietic stem cell. PMID- 26946773 TI - Extreme Hypertriglyceridemia in an Infant with Hemophagocytic Lymphohistiocytosis and Hydroxycobalamin Deficiency. AB - INTRODUCTION: Hemophagocytic lymphohistiocytosis (HLH) is a severe hyperinflammatory condition characterized by fever, cytopenias, hepatosplenomegaly and hemophagocytosis. HLH may be primary or secondary to infection, autoimmune disease or malignancy. Hypertriglyceridemia is a common abnormality in HLH and one of the HLH-2004 diagnostic criteria. CASE OUTLINE: We present an infant with severe hypotonia and hypoproteinemic edema who also had extreme hypertriglyceridemia (21 mmol/l) and was diagnosed with HLH based on six of eight HLH-2004 criteria (fever, hepatosplenomegaly, bicytopenia, hypertriglyceridemia with hypofibrinogenemia, slL-2R > 2400 IU/ml, hemophagocytosis). The presence of IgM antibodies to Epstein-Barr virus and cytomegalovirus indicated a probable infectious trigger. The child was cured by the HLH-2004 protocol for secondary HLH (consisting of dexamethasone and cyclosporine). He was also found to have low serum hydroxycobalamin levels, promptly corrected upon hydroxycobalamin administration. CONCLUSION: The presented case history underlines the need to ascertain the presence or absence of each of the eight HLH-2004 criteria in any patient suspected to suffer from HLH. PMID- 26946774 TI - Pseudo-Bartter's Syndrome in Patients with Cystic Fibrosis: A Case Series and Review of the Literature. AB - INTRODUCTION: Pseudo-Bartter syndrome (PBS) is characterized by hyponatremic, hypochloremic metabolic alkalosis that mimics Bartter syndrome but with no pathology in the renal tubules. We present five patients with cystic fibrosis (CF) and PBS. CASES OUTLINE: Four children aged between three and five-and-one half months with previously diagnosed CF and one aged 17 months with previously undiagnosed disease, were hospitalized during the summer season, with severe dehydration, oliguria, apathy and adynamia. Additionally, one of them had an ileostomy due to meconium ileus after birth. All children were on a diet without additional salt intake. Laboratory analysis on admission showed hyponatremia (115 133 mmol/L, mean 122.4 mmol/L), high plasma renin activity (229-500 pg/ml, mean 324 pg/ml) and metabolic alkalosis (pH 7.5-7.6, mean 7.56) in all the patients, and in four of them high blood level of aldosterone (74-560 pg/ml, mean 295.9 pg/ml), hypokalemia (2.3-2.8 mmol/L, mean 2.6 mmol/L), hypochloremia (59-71 mmol/L, mean 66 mmol/L) and low urinary sodium (5-12 mmol/L, mean 9 mmol/L). After intravenous rehydration followed by additional use of sodium and chloride in mean dosis of 1.78 mmol/kg per day, all the patients made a complete recovery. With advice for additional use of salt in the mentioned amount, the patients were discharged from the hospital. CONCLUSION: PBS is one of CF complications, especially in infants and young children in situations accompanied by increased sweating and/or other causes of additional loss of sodium and chlorine. Sometimes, as was the case with one of our patients, PBS may be the initial presentation form of the disease. PMID- 26946775 TI - A Novel Frameshift Mutation of the IKBKG Gene Causing Typical Incontinentia Pigmenti. AB - INTRODUCTION: Incontinentia pigmenti (IP) is a rare X-linked dominant genodermatosis. Mutations of the IKBKG gene are responsible for IP. A deletion of exons 4-10 can be found in 80% of patients with IP. There are 69 different mutations of the IKBKG gene that have been reported. CASE OUTLINE: A proband, female patient from a family without previously diagnosed IP is reported. She had skin and dental changes typical of IP. The diagnosis was made according to updated IP criteria. Pathohistological and ultrastructural analysis of skin biopsy confirmed the diagnosis. However, the common deletion of exons 4-10 in the IKBKG gene could not be detected. Sequencing revealed the indel (deletion/insertion) mutation c.641_647delGCATGGAinsAT (p.Arg214HisfsX38) in exon 5 of the IKBKG gene. Because this mutation could not be detected in the unaffected mother of the proband, it seems to be a de novo mutation. CONCLUSION: The registered novel frameshift/KBKG mutation c.641_647delGCATGGAinsAT (p.Arg214HisfsX38) can be considered to be the cause of IP in this case. PMID- 26946776 TI - Acute Diarrhea in Children. AB - Acute diarrhea (AD) is the most frequent gastroenterological disorder, and the main cause of dehydration in childhood. It is manifested by a sudden occurrence of three or more watery or loose stools per day lasting for seven to 10 days, 14 days at most. It mainly occurs in children until five years of age and particularly in neonates in the second half-year and children until the age of three years. Its primary causes are gastrointestinal infections, viral and bacterial, and more rarely alimentary intoxications and other factors. As dehydration and negative nutritive balance are the main complications of AD, it is clear that the compensation of lost body fluids and adequate diet form the basis of the child's treatment. Other therapeutic measures, except antipyretics in high febrility, antiparasitic drugs for intestinal lambliasis, anti-amebiasis and probiotics are rarely necessary. This primarily regards uncritical use of antibiotics and intestinal antiseptics in the therapy of bacterial diarrhea.The use of antiemetics, antidiarrhetics and spasmolytics is unnecessary and potentially risky, so that it is not recommended for children with AD. PMID- 26946777 TI - Accurate Completion of Medical Report on Diagnosing Death. AB - Diagnosing death and issuing a Death Diagnosing Form (DDF) represents an activity that carries a great deal of public responsibility for medical professionals of the Emergency Medical Services (EMS) and is perpetually exposed to the control of the general public. Diagnosing death is necessary so as to confirm true, to exclude apparent death and consequentially to avoid burying a person alive, i.e. apparently dead. These expert-methodological guidelines based on the most up-to date and medically based evidence have the goal of helping the physicians of the EMS in accurately filling out a medical report on diagnosing death. If the outcome of applied cardiopulmonary resuscitation measures is negative or when the person is found dead, the physician is under obligation to diagnose death and correctly fill out the DDF. It is also recommended to perform electrocardiography (EKG) and record asystole in at least two leads. In the process of diagnostics and treatment, it is a moral obligation of each Belgrade EMS physician to apply all available achievements and knowledge of modern medicine acquired from extensive international studies, which have been indeed the major theoretical basis for the creation of these expert-methodological guidelines. Those acting differently do so in accordance with their conscience and risk professional, and even criminal sanctions. PMID- 26946778 TI - [Collaboration between Physician Emerich Lindenmayer and Architect Jan Nevole in Restoring the Sokobanja Turkish Bath]. AB - The Sokobanja Turkish bath is an exceptional example of two-section baths and quite particular in its style, structure type and technology used. It is one of the two of the same type that remained in Serbia and the only one that has retained its original function. About its construction we learn from the Vidin sanjak defter from the second half of the 16th century. In the lavish built heritage inventory, Turkish baths are quite unique secular public structures, playing a prominent role in the development of health culture. Based upon their specific function, these baths possess a special architectural expression, are often monumental, decorative and imaginative in their forms and ornamentation. Prince Milos initiated repair works of the Soko Banja baths and spa springs immediately after the settlement became a part of the Serbian Principality in 1834. When work on restoring the men's baths started, a separate room with a tub was built for Prince Milos, while the women's bath remained in ruins. In 1847, the Ministry of Interior sent Dr Emerich Lindenmayer and architect Jan Nevole, as an expert team, to assess the state of the hammam so that it could be included in the undertakings funded from the state budget. After the assessment and review of the existing issues and upon a detailed report submitted to the Ministry of Interior, complex repairs were conducted in 1850, according to Nevole's architectural design and his constant supervision. The approach implemented in the architectural renovation process was based on highly regarded principles of the time, thus preserving both the hammam's original function and its valuable architecture. PMID- 26946781 TI - Association Between Long-term Alcohol Consumption and Undercarboxylated Osteocalcin. AB - The Japanese Ministry of Health, Labour and Welfare has focused on enhancing knowldge about the association between alcohol consumption and health, such as early detection of alcohol abuse, the appropriate actions to be taken after detection, and prevention of teenage drinking. They believe that it is necessary to develop and improve the methods for early detection of alcohol-related problems in an easy and effective way. Given this context, we hypothsized that simultaneous determination of osteocalcin (OC) and undercarboxylated osteocalcin ucOC), bone metabolic markers, would facilitate research on the effects of alcohol drinking. We divided volunteers into a group of long-term drinkers (heavy drinking for 20 years or more) and a group of social drinkers (moderate and controlled drinkers), and determined blood DC, ucOC, bone-specific alkaline phosphatase (BAP), and tartrate-resistant acid phosphatase isoform 5b (TRACP-5b) levels, as bone metabolic markers, and glutamic-oxaloacetic transaminase (GOT), mitochondrial GOT (m-GOT), glutamic pyruvic transaminase (GPT), and gamma glutamyl transpeptidase (gamma-GTP) levels, as biochemical markers. In addition, we determined the levels of free and bound ethanol and methanol in urine as markers of alcohol abuse and dependence. The group of long-term drinkers showed significantly higher levels of OC and ucOC than the group of social drinkers (p < 0.01). Long-term drinkers also showed a significantly higher level of m-GOT than the social drinkers in the biochemical examinations (p < 0.01). Long-term drinkers showed a tendency to have increased free/bound ethanol and methanol levels in urine compared to social drinkers, but the differences were not statistically significant. The above results suggest that determination of the levels of OC and ucOC can provide useful information for the early detection of heavy drinkers, indicating that OC and ucOC may be used as markers for preventing alcohol dependence. PMID- 26946780 TI - [The role of CC-chemokine ligand 2 in the development of psychic dependence on methamphetamine]. AB - Addiction is described as a chronic neurological disorder associated with plasticity in the mesolimbic system. Recently, it has been suggested that neuroinflammation plays an important role in the induction of neuronal plasticity and the formation of pathogenesis in chronic neurological disorders. Therefore, we examined the role of CC-chemokine ligand 2 (CCL2), a proinflammatory chemokine, in the development of psychic dependence on methamphetamine. In mice treated with methamphetamine, CCL2 mRNA was significantly increased in prefrontal cortex and nucleus accumbens. Moreover, phosphorylated tyrosine hydroxylase serine40 (pTH Ser40) levels in the ventral tegmental area (VTA) were increased by methamphetamine. Similarly, pTH Ser40 levels in the VTA were also increased by the intracerebroventricular administration of recombinant CCL2. The increment of pTH Ser40 levels in the VTA by methamphetamine was attenuated by RS504393, a selective CC-chemokine receptor 2 (CCR2) antagonist, indicating that the increased CCL2 activates the brain reward system via CCR2 activation. In the conditioned place preference test, methamphetamine produced place preference in a dose-dependent manner, which was attenuated by RS504393. These results suggest that the activation of the brain reward system via CCL2-CCR2 pathway plays an important role in the development of psychic dependence on methamphetamine. PMID- 26946782 TI - [Development and evaluation of a therapeutic community model in Japan: Use of an encounter group method]. AB - The purpose of the present study was to develop a therapeutic community (TC) model in the Drug Addiction Rehabilitation Center (DARC), the rehabilitation facility group managed by recovered drug users in Japan, and to evaluate the effectiveness of the model. The TC model is a drug-free self-help program that is significant for its use of the peer community to facilitate social and psychological change in individuals. Although the TC model has been developed around the world in a variety of settings, its use in Japan is not well known. We introduced the therapy group with an encounter group method representing the TC model at the Kawasaki DARC, and conducted pre- and post-evaluations using the modified Self-Actualization Scale (SEAS2000). Results showed that the scores of the subscale "sobering of self-affirmation" were remarkably high among those who experienced encounter groups for six months. However, the scores of the subscale "release from biased view" declined among the users at the DARC who have experienced encounter group. for a short-term, while .the scores increased among those who have a medium-term and a long-term experience. These results suggest that the encounter group may be effective especially for the medium- and long term users in the DARC. The development of a more effective TC model is required. PMID- 26946783 TI - Alcoholic Liver Cirrhosis and Significant Risk Factors for the Development of Alcohol-related Hepatocellular Carcinoma--Japan, 2012. AB - Recent epidemiological studies showed that alcoholic liver cirrhosis (ALC) and alcohol-related hepatocellular carcinoma (HCC) continue to increase despite a gradual decrease in alcohol intake, indicating that there are other risk factors for the development of ALC and alcohol-related HCC. A nationwide survey of liver cirrhosis (LC) was undertaken by asking major hospitals in Japan to provide information on the number of patients with LC admitted in 2012 along with information related to etiology including alcohol history and other relevant demographics. Among the 1,478 ALC patients, total alcohol intake was lower in women than in men, and mean age was also lower in women. Mean age was older in the present study in 2012 compared with the data in 2008. Compared to patients without diabetes mellitus (DM), patients with DM had lower daily alcohol intake and higher mean age. The prevalence of HCC was much higher in male elderly ALC patients and also in DM patients among the younger ALC patients (65 years). DM, female sex, and age were identified as risk factors for development of ALC, and DM, male sex, and age were identified as significant risk factors for HCC in ALC. PMID- 26946784 TI - [Diagnostic accuracy for alcoholic liver disease with controlled Attenuation Parameter (CAP) measured by transient elastography for the non-invasive assessment of liver steatosis]. AB - Along with the development of interferon and therapeutic medication, the incidence of viral hepatitis constituting the largest part of liver disease decreased, and the main target in the field of liver disease is now shifting from viral hepatitis to alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) as metabolic liver disease. Although these diseases tend.to. be gathered as non-viral liver disease because the similar specific liver tissue, the natural history and etiology are considerably different between them. We need to distinguish both of them to do appropriate treatment intervention. Questioning of amount of drinking is needed, but we experience some difficult cases to understand drinking history because of a too little declaration of amount of drinking. A new ultrasonic image analyses using propagation speed in the organization of the pulse vibration wave was developed as Fibroscan by Echosens company in recent years. Fibroscan is a non-invasive test to quantify liver fibrosis as Liver Stiffness Measurement (LSM). It also detects and quantifies steatosis simultaneously using the Controlled Attenuation Parameter (CAP). CAP is a measurement of the ultrasound attenuation. We measured liver steatosis of patients using Fibroscan, and other blood tests. 63 cases of ALD, 177 cases of NAFLD, 57 cases of Virus and 271 cases of Normal were enrolled. CAP value were significantly lower in the ALD group compared with NAFLD group. (P < 0.0053, ALD 268 dB/m : NAFLD 290 dB/m) We elucidate the diagnostic accuracy of CAP using Fibroscan for ALD patients, comparing the results of them to those of virus patients and NAFLD patients. PMID- 26946785 TI - ["Unity is strength!" Eight years later]. PMID- 26946786 TI - [Swiss Society of General Internal Medicine: a new entity for a changing specialty]. PMID- 26946787 TI - [2015 Update in ambulatory general internal medicine]. AB - This article summarizes a selection of recently published clinical and public health articles of interest to primary care physicians. It touches upon the use of new oral anticoagulant in atrial fibrillation, the efficacy of baclofen for alcohol dependence, the pathogen identification in community acquired pneumonia, the accuracy of emergency room diagnosis in patients with ill-defined symptoms, the relationship between sleep and susceptibility to infection, the benefits of smoking cessation and of a new vaccine against zoster in elderly patients and finally the distribution of health literacy in Europe. PMID- 26946788 TI - [2015 highlights in hospital-based internal medicine by chief residents]. AB - The year 2015 gave us many scientific publications, among whom some will have an impact on our daily practice and some will influence our way of considering some well known diseases. Chief residents in the Service of internal medicine of the Lausanne University hospital, gathered like every year, to share their readings together in order to presentyou a small part of the many publications of 2015, which have been considered to have an impact on our future daily practice. PMID- 26946789 TI - [Internal medicine in the hospital setting]. AB - Progress in medical practice is often the result of a redefinition of pathologies and therapeutic targets. This is a natural translation of advances made in the pathophysiologic understanding of disease and clinical entities. In this manner, the use of biological agents is entering the field of cardiovascular medicine. This selective review of the literature summarizes certain studies published this year in the areas of internal, cardiovascular, pulmonary and thrombotic medicine. PMID- 26946790 TI - [2015 literature findings in general internal medicine]. AB - Benzodiazepines are associated with the risk of developing Alzheimer's disease. Systematic dosage and vitamin D substitution have no place in times of immediate post-menopause. Topical placebos challenge analgesics in the treatment of knee osteoarthritis. Palliative chemotherapy does not improve life-quality at the end of life. Restrictive transfusion thresholds entail no risk. Spirometry should always be performed before the initiation of a long-term bronchodilator therapy. Practitioners continue to overprescribe antibiotics for infections of the upper respiratory tract. Pap test may soon be replaced by HPV urinary testing. Without increasing costs, a telephone triage by the primary care physician can reduce the number of consultations. PMID- 26946791 TI - [Intelligent footwear for diabetic patients]. AB - The incidence of diabetic foot ulcerations and lower extremity amputations remains very high and inacceptable. The high risk of ulceration and consequent amputation is strongly related to difficulties to obtain foot off-loading, particularly on long term. Due to the complexity of their utilization, the available foot off-loading devices are underused both by health care providers and patients with very low therapeutic adherence. This article summarizes the foot off-loading in diabetic patients and describes the concept of intelligent footwear we developed, based on continuous measurements and permanent and automatic adaptations of the shoe insole's rigidity. PMID- 26946792 TI - [A cardiomyopathy of unusual origin]. PMID- 26946793 TI - [Is interdisciplinary health care going to make the leader fall?]. PMID- 26946795 TI - [The French government wants to end vaccination defiance]. PMID- 26946794 TI - [Response]. PMID- 26946796 TI - [Give thanks to those nurses and nurses' aides who collaborate with you]. PMID- 26946797 TI - [Hepatitis C: epidemiology and vaccination perspectives (1)]. PMID- 26946798 TI - [Hip pain and radiographic signs of arthrosis: which correlation?]. PMID- 26946799 TI - [Miscellaneous: electronic cigarettes, reproduction and terrorists]. PMID- 26946800 TI - [How will this play out in the future?]. PMID- 26946801 TI - [Words and concepts: the rigor of language to the test of science]. PMID- 26946802 TI - [Living his illness. The experience of new territories of the body]. AB - Illness as a specific experience of live, deals with a new way of living for everyone. This personal moment breaks former marks and builds new ones in every existence. These landmarks mean the discovery of unknown spatiality's intimacy. All along illness experience, because of their vulnerability, patients are especially exposed to a lot of tactlessness situations. Very often, secret territories of the self, in a way, are laying bare by tactlessness attitudes. Every medical or nursing care needs to be aware of symbolic injury risks. PMID- 26946803 TI - [Autonomy and consent to care: a socio-legal analysis]. AB - During the last decades, medical paternalism was rejected in favour of the patient's right to self-determination and, by extension, to its right to consent or refuse care offered to him. In the clinical setting, the obligation to inform user and to obtain its free and informed consent about such care is widely recognized, but rarely problematized. The aim of this paper is to analyze the construct of a consent to care and the different conceptualizations of autonomy that are part of this juridical vehicle. A socio-legal analysis was conducted through a narrative review of literature relative to nursing sciences, humanities, philosophy and bioethics, and legal sciences. Although obtaining consent is often approached as a formality, this process is situated at the intersection of an interface that is both relational and personal. This perspective requires recognition of the intersubjective process that takes place between the user and the clinician, and of the negotiating space in which they both are situated. It is finally proposed to develop further researches addressing this phenomenon, and the actor-network theories would represent a potential epistemological perspective to do so. PMID- 26946804 TI - [Franco-Ontarian parenting couples living in the Ottawa region and their perceptions regarding the usefulness of prenatal classes]. AB - In the last few years, there has been an important decrease in parents' interest and participation in prenatal classes in Canada and elsewhere in the world. Partial results were obtained on parenting couples' participation in and satisfaction with prenatal classes, from a larger study involving 103 francophone couples living in Ottawa, using'a mixed methods descriptive and longitudinal research design. This article aims to present the reasons why parents do not participate in prenatal classes and their suggestions to improve them. Several parents indicated that subjects such as pain management, birthing with a midwife, labor support from a doula, breastfeeding, and postnatal sexuality should be added to the classes. Also, they would like to have more flexible hours, more interaction during the classes, more emphasis given to expectant fathers, more access to a variety of resources and content and teaching methods that are more dynamically delivered. These research findings will provide recommendations for the delivery of prenatal education, for nurses' training in this domain, and for future research. PMID- 26946805 TI - [Underreporting of blood exposure incidents: a worrying situation among nursing students]. AB - Accidental blood exposure incidents require immediate medical evaluation, permitting early treatment, if needed, for a possible infection and enable identification of the work accident in case of HIV infectivity status. A study wax conducted with nursing students in two different years of study in order to formalize the rate of underreporting of blood exposure incidents and to determine the reasons. The results highlight that, over a period of three years of training, 52 % of blood exposure incidents have not been declared as occupational accidents. The reasons for nursing students underreporting of blood exposure incidents are related on the one hand to the negative perceptions and feelings that students have (personal fault 55 % and awkwardness 82 %) and to the fear of negatives consequences (31 %) on the evaluation of their internship in particular and on their nursing training in general. On the other hand, students tend to conform to other caregivers who themselves underestimate the risk of blood exposure incidents (22 %). The identification of these elements will help to initiate a discussion and to prepare direct actions in order to encourage reporting of blood exposure incidents by nursing students and their colleagues during internships. PMID- 26946806 TI - [Formalization of a training method to develop reflective practice and emotion skills in nursing students]. AB - CONTEXT: among health professional skills, emotion skills and reflective practice are very important. This article proposes a reflection on a training method used in a French nursing school. The method aims to develop reflective practice and emotion skills of nursing students. METHOD: the training method was experimented with fifteen students. During an individual interview, the students were invited to describe a situation loaded emotionally that they lived in clinical internship. The trainer boosted the student from a plan drawn on the base of his speech so that the student deepens his reflection. After experimentation, the trainer analysed his own practice using the method. Students' opinion and the trainer's logbook were analysed. RESULTS: the students declare to have improved their capacity for analysing, their self-knowledge and their emotional skills. They appreciated the technique and the help brought by the plan. All students expressed feelings. The analysis allowed specifying the stages, principles and foundations of the method as well as the conditions of its implementation. The transfer of the technique with the nurse trainers is described. CONCLUSION: the analysis of the training method testifies of its relevance to help nursing students to realize a reflective practice from an emotional clinical care. More research is needed to assess its effects and limitations. PMID- 26946807 TI - [Internship supervisors' perception of the management process and the quality of the clinical educational support in nursing and midwifery science in Benin]. AB - BACKGROUND: the reform of nursing education requires to focus on the quality of clinical supervision. OBJECTIVE: to identify the perception of internship supervisors of the management process and the quality of the clinical supervision of students of the National Institute Health Services (INMES). METHOD: a qualitative and quantitative descriptive cross-sectional study was conducted among the supervisors of the National Hospital and University and the Hospital of the Mother and Child Lagoon Benin. Data collected using a self-administered questionnaire was treated with EPI INFO Version 3.5.4 and according to a content analysis. RESULTS: 92 % of supervisors have not received any specific training in coaching. There is no formal and regulatory framework conducive to coaching or mentoring repository. Collaboration between INMES and internship sites is low. The supervision is not integrated in the service missions, but rather related to a contextual occasion. The daily training period is considered short for a real learning. Summative assessment tool whose criteria are non adapted is done in the absence of the student. DISCUSSION: these results demonstrate the low quality of clinical supervision. CONCLUSION: the shortcomings identified will serve as basis for improving the quality of clinical supervision. PMID- 26946808 TI - [Behind the scenes of the didactic of nursing science knowledge: role play simulation filmed for learning through "problematic situations"]. AB - INTRODUCTION: clinical simulation to teach expertise to nursing students plays an important role in nursing schools (IFSI). CONTEXT: as recommended in the training frame of reference, students must develop skills from real situations. OBJECTIVE: The objective of this study was to determine the importance of role play simulation of 'problematic situations' to boost the process of appropriation of nursing science knowledge and initiate the task of conceptualization among first year students when putting up a drip. METHOD: this contextual research used qualitative data collected from students who answered three open post-simulation questions in order to communicate how they felt faced with this learning technique. This data was compared with that of two executive tutors who used an observation grid during the simulation. RESULTS: the students' answers have shown that this learning technique offered the possibility to develop dexterity in problem solving skills, to construct new knowledge and to memorize knowledge gained from university science and nursing care. The executive tutors have observed the construction of a meta-cognitive attitude suited to the conceptualization of action. CONCLUSION: during a change in the relationship with knowledge, the executive tutors noted that students are happy to learn different types of knowledge. PMID- 26946809 TI - [Audio capture in the hybrid system of nursing training: contribution to the acquisition of knowledge for the development of professional skills]. AB - This article deals with the results of a probing study in the framework of the education and technology master of research in educational science of the university of Cergy-Pontoise. This study focuses on the use of audio capture by first year nursing students in the development of their knowledge and therefore in the development of their professional skills. By using the model of the unified theory of acceptance and use of technology (UTAUT), the results of this study have helped to identify the levers (easy-to-use digital resources, computer skilled learners, multiplicity of computer equipment of the learners) and bridles (the relative gain when using this resource, the lack of human interaction, a resource which is time consuming) in the use of audio capture. A more extensive study could focus on these bridles in order to promote the use of audio capture by learners in the hybrid system of nursing training. PMID- 26946810 TI - [THE HANOVERIAN SCHOLAR AND THE DOCTOR OF THE PEASANTS]. AB - Gottfried Wilhelm Leibniz and Bernardino Ramazzini met in Modena in autumn 1689, and made friends. Rereading their correspondence and finding other coeval documents, the author reconstructs a scientific relation forgotten by historians. They not only discussed on air pollution, artesian wells and barometric forecast, but - more generally - favored the foundation of social medicine on epidemiology. Hence the Leibnizian contribution to the European fortune of Third Hippocrates. PMID- 26946811 TI - THE MEDICI CHILDREN (FLORENCE, XVI-XVII CENTURIES): ANTHROPOLOGICAL STUDY AND PROPOSAL OF IDENTIFICATION. AB - Exploration of the Medici chapels in San Lorenzo in Florence revealed the burials of nine infantile members of the Medici family. Eight children were found in the intact tomb of the last Grand Duke Giangastone (1671- 1737). The crypt contained several small coffins collapsed to the floor or randomly spread over a raised plank, as a result of the disastrous flood of the Arno river in 1966, which partly upset the tomb and left a layer of dry mould. The children's remains, mostly skeletonised, were found inside the coffins or scattered on the floor or on the plank, probably transported by the water. Another child was exhumed from the chapel of Grand Duke Ferdinand I (1549-1609) and Cristina from Lorena (1565 1636). The infantile remains were submitted to anthropological study, which allowed to establish the number of individuals buried in the crypt, and to estimate the age at death. The anthropological results were compared with information provided by archival documents, related to members of the family who died in infantile age. An identification of the children is proposed. PMID- 26946812 TI - [PLURAL THERAPEUTIC ITINERARIES]. AB - This article addresses the strategies employed by Nahua community of Mexixo to deal with health problems. Drawing on qualitative research, it discusses the choice of plural therapeutic itineraries, including the use of informal and formal healthcare. PMID- 26946813 TI - [MEDIOEVAL HOSPITALS IN VITERBO]. AB - The article offerts a short introduction to the history of medieval hospitals in Viterbo, as descripted by the main 19th century historical local testimonies. Viterbo, as well known to the historians of Middle Age, has been an important town in medieval Italian history; its centrality in the religious way to Rome is well testified by the numerous hospitals and assistance building, some of which, along the main pilgrimage routes, still surviving and well preserved. PMID- 26946814 TI - [PLAGUE IN PALERMO IN 1575 AND SOCIAL CONTROL]. AB - The work moves from the low mortality of the plague of Palermo in 1575 - 1576 in comparison to similar outbreaks and contemporary analysis of the activity of Ingrassia, a man that the city government had wanted at his side. The extraordinary health interventions, including those to favor of the predisposition of health building to isolation, gears for a more wide-ranging than the traditional one. The isolation adopted by Ingrassia wasn't a novelty because it was already in use half a century earlier, as the Previdelli wrote. We assume that the population in crisis, hungry and out of work for the huge military expenditure of king Philip II, would have prompted the City government to use the outbreak for the purposes of <>. At the same goal always answered in the sixteenth century the establishment of the parish, created to divide the territory in order to guide and control the practice of the faith of the people. Ingrassia, a man next to political power, which in turn welded with the spiritual power in order to implement the Catholic Counter-Reformation, justified the coercive initiatives towards the population. The practice of medicine, as still happens today, is affected by the conditions of the policy, raising one of the fundamental principles of bioethics, the question ofthe independence ofthe doctor: a physician divided by the duty to represent the legitimate interests of the patient and those of political power, perhaps not always shared. It is a new interpretation of the activity of Ingrassia and his <> results than the plague. PMID- 26946815 TI - AUTOMATON AND SPONTANEOUS GENERATION: A PROBLEMATIC ASPECT IN THE ARISTOTELIAN THEORY OF REPRODUCTION. AB - In Book III of the De generatione animalium, Aristotle discusses about the problem of spontaneous generation, which will be object of interest for centuries, up to modern science. The aim of the paper is to examinate this topic trying to highlight what is the most remarkable problem in the Aristotelian theory: the ability of the matter of self-moving and self-reproducing and, connected to this, the relationship that exists in nature, in the Aristotelian biology, between a teleological based function and the presence of a necessary counterbalance in material form. In the last part of the paper the attention will also be focused on the connection between spontaneous generation and sexual reproduction, underlining, once again, the importance of the material aspects, alongside the teleological ones. PMID- 26946816 TI - [SCIENCE AND DREAMS IN THE MIDDLE AGES: IL "DE SOMNIIS" DI BOEZIO DI DACIA]. AB - Boethius of Dacia's opera "De somnis" can be defined as a brief treaty that partially follows the traditional quaestio scheme. It includes a passage that seems to copy Etienne Tempier's proposition number sixty-five, which condemns the importance attributed to astrology by many medieval authors. Boethius moves off Aristotle's "De somno et vigilia" idea of physiological dreams to assert a new kind of oneiric phenomena linked to constellations, that, according to the author, aren't divinely inspired, whereas they are to be considered as natural events. Boethius isn't the only philosopher who writes about this particular type of dream as another medieval author, Albertus Magnus, in his "Speculum Astronomiae", describes astrology and its relationship to medicine. PMID- 26946817 TI - [ETTORE BIOCCA, THE MAN AND HIS ARCHIVE (1932-2001)]. AB - Ettore Biocca's archive reflects the liveliness of scientific interests and the extreme political and social sensibility that distinguished the personality to confirin the image, still alive in the memories of those who knew him, of a free spirit, impulsive, independent; a character incapable of compromise, always ready to hear his voice everywhere warned the environment threatened or violated human rights. His archive provides interesting ideas for historical research, especially the study of Parasitology in Italy and world. PMID- 26946818 TI - GRANTING A LICENCE FOR OPENING A PHARMACY IN BOLOGNA DURING ACTIVITY OF THE BOLOGNESE ARTE DE' SPEZIALI (13TH - 18TH CENTURY). AB - The article discusses the main changes in legislation concerning granting the licenses for opening a new pharmacy in Bologna in the Middle Ages and Early Modern period. The organization of all traders, including apothecaries, was subordinated, as almost everywhere in Italy, to the Guilds. In the 2nd half of 16th century the Arte de' Speziali of Bologna came under the jurisdiction of the Collegio di Medicina, leading to disagreements between the two corporations. Giovanni Baldi, in his Notizie storiche su la farmacia bolognese (Bologna, 1955) mentioned one of these controversies, dating on the second half of 18th century. The Authors present this controversy basing on original documents from Archivio di Stato di Bologna. PMID- 26946819 TI - [THE CULT OF ST. ROCH IN CASTELLI (ABRUZZO) AND THE EARTHENWARE ANATOMICAL EX VOTO]. AB - Ex voto are devotional objects, widely used in Italy as a form of prayer or wish, or as thanksgiving for a grace received. In a broader historical perspective, votive offerings are hung in Greek, Etruscan, Roman shrines and later in churches or to show gratitude for miracles obtained, healing from illness or infirmity, or as a simple supplication and prayer. The ex voto here presented seem to be unique in the world: made of majolica, they come from the church of St. Roch in Castelli (Abruzzo). They depict breast benign and malignant lesions (mastitis, abscess, fat necrosis, inflammatory cancer, infiltrating carcinoma) in three dimensions, performing an accurate and personalized portrait of breast diseases (in some cases with the depicted name of the sick woman), showing fine details of each disease, and demonstrating accurate knowledge of the female anatomy and pathology. PMID- 26946820 TI - [THE HISTORY OF A VANISHED PHARMACY IN ROME]. AB - Starting from archive documents, the present article aims to retrace the history of a once well-known pharmacy based in S. Eustachio square, in Rome, and then commonly denominated Corsi's. Thanks to the information gathered in Roman archives, it is possible to throw light on the events related to this apothecary, whose activity, as found out, lasted since the XVIII until the first decades of the XX century, under the property of two families, first the Conti and then the Corsi. Notwithstanding its long establishment, this pharmacy seems to have suddenly vanished from the official documents registered within the archives. Nevertheless the importance of its history is actually related to some of the instruments, being part of its original inventory, and nowadays held in the collection of the Museum of History of Medicine in Rome. These specimens particularly jars and boxes, are valuable in order to describe how in the past professionals used to take care of most of the diseases. PMID- 26946821 TI - [ETHICS IN PSYCHIATRY: FROM ANTIQUITY TO THE RENAISSANCE]. AB - Ethical issues always played an important role in the historical development in psychiatry. As wll known, many ancient cultures associated mental illness with gods and divine punishments. In the first centuries of the Christian Era, mental illness is often interpreted according to demonological views and in connection with theological conceptions of sin. The article briefly examines the history of mental illness medical and cultural interpretations, focusing on medieval medicine and the treatment of psychiatric patients from Antiquity to the Early modern Period. PMID- 26946822 TI - [TO CURE THE APPARENTLY DEAD. NOSOLOGY AND MEDICAL RESUSCITATION IN ITALY(XVIII CENT.)]. AB - The first specific techniques and triages for medical resuscitation developed in the XVIII century, specifically to rescue the drowned persons. The topic of resuscitation in strictly connected to the theme of the apparent death, to the dread of the "buried alive", to the progress of forensic medicine and to the administrative and legislative policies. The contribute aims to focus on the contribution of the medical and pathologic nosology about the conception of the apparent death, read as asphyxia. PMID- 26946823 TI - [TRANSFORMATIONS OF LIFE CYCLES IN THE EVOLUTIONARY HISTORY OF TRYPANOSOMATIDAE. EXOTRANSFORMATIONS]. AB - The present review is devoted to the analysis of exotransformations of life cycles in the evolutionary history of trypanosomatids (Kinetoplastea: Trypanosomatidae). Exotransformations are treated as processes associated with the transition of a trypanosomatid to a new host. The result of these transformations comprises both the inclusion of new hosts in life cycles of parasites and also epy formation of parasitic systems de novo. It is shown that exotransformations are one of the main modi in the evolution of trypanosomatids. Different examples of exotransformations of life cycle in all the taxonomic groups of Trypanosomatidae are given. PMID- 26946824 TI - MORPHOLOGY AND ULTRASTRUCTURE OF TWO SCHISTOTAENIID CYSTICERCOIDS (CESTODA: CYCLOPHYLLIDEA) FROM THE HAEMOCOELE OF THE DRAGONFLY LARVAE. AB - Two cysticercoids, belonging to ascocercus type, namely euascocercus and multicercus, were found in haemocoele of dragonfly larvae of the genus Aeshna from the lakes of the Magadan Province. The cysticercoid of Schistotaenia srivastavai Raush, 1970 (euascocercus) is formed of the outer (exocyst) and inner (endocyst) envelopes, containing the scolex and larval strobila. The outer and inner surfaces of the exocyst are represented by the tegument covered with microvilli. The microvilli of the outer tegument are restricted by the surface layer, consisting of granular and fibrillar material, and possess different structures at different stages of post-embryonic development. The multicercus of Mircia shigini (Konyaev et Gulyaev, 2006) is able to multiply asexually by the endogenous budding. The daughters' individuals are formed in the envelope of the multicercus that represents the tegument bearing microvilli. These microvilli are also restricted by the surface layer. The morphology and development of each individual cysticercoid of the multicercus is similar to those of euascocercus. The production of a great amount of cysticercoids, and the presence of the surface layer resembling the laminated layer of Echinococcus, relates multicercus to hydatid cysts. PMID- 26946825 TI - [PARASITES OF THE COMMON ROACH (RUTILUS RUTILUS L.) UNDER THE IMPACT OF INDUSTRIAL POLLUTION OF A LAKE]. AB - The consequences of man-induced transformation of Lake Kostomukshskoe (tailings dump) related to increased mineralization and entry of highly dispersed dredge material not typical for northern lakes were studied using roach parasites as the example. It was found that the roach parasite fauna has been losing rare and scant parasite species of different taxonomic groups, mainly helminthes with an indirect life cycle. Common and dominant species of myxosporidians, monogeneans, trematodes of genera Diplostomum and Tylodelphys have been preserved. The chances of survival are higher for those parasites with direct life cycle. Also the parasite species whose larvae can actively penetrate the host have been survived. The species Ligula intestinalis, Philometra rishta, Pseudocapillaria tomentosa had reported very rare. Fish are infected with these parasites by feeding of Copepoda and oligochaetes. PMID- 26946826 TI - [GALLOGENESIS INDUCED BY ERIOPHYOIDS (ACARIFORMES: ERIOPHYOIDEA)]. AB - Eriophyoid mites are a group of phytoparasites of high economic importance due to their ability to transmit phytopathogens and cause the development of various plant malformations including galls. Chemical compounds of mite saliva injected into plant cells and the reaction of the plant cell genome play the crucial role in the gall formation process. Various triggers specific to plant DNA (e.g. exogenous phytohormones) and pathogenic microbes may be the factors inducing the gallogenesis. The process of gall formation is a complex growth reaction induced in the epidermal cells. Mechanisms of the gallogenesis induced by eriophyoids are studied very insufficiently. The analysis of the available literary data shows that malformations caused by eriophyoids on plants significantly vary in shape, topography, and longevity and may have different etiologies. Differences in the shape of a gall depend, first of all, on the mite species; plants, however, demonstrate limited number of gall types. Clarified classification of galls induced by eriophyoid mites is proposed. A gradual program for future studies is represented. PMID- 26946827 TI - [IXODID TICKS (PARASITIFORMES: IXODIDAE) FROM SMALL MAMMALS IN DEFORESTED BOREAL HABITATS IN THE NORTHERN EUROPEAN RUSSIA]. AB - Changes in the population density of two hard tick species, Ixodes (Exopalpiger) trianguliceps Birula, 1895 and Ixodes persulcatus Schulze, 1930, were examined in 1998-2001, and in 2003-2004 near Gomselga Village (Kondopoga District, 62 degrees 04' N, 33 degrees 55' E) in central Karelia. Data on the abundance of ixodid ticks and the species composition of their hosts in 4 forest sites at different stages of post-felling regeneration (secondary succession), i. e. 7-14, 12-19, 25 32, and 80-87 after logging were obtained. I. persulcatus dominated, comprising 73 % of the total tick number in samples. Regenera- tion of the forest resulted in fluctuations of the population density of two examined tick species: I. (Exopalpiger) trianguliceps (larvae 2.8-5.3; nymphs 1.5-2.2; adults 0-0.09) and I. persulcatus (larvae 4.3-10.6; nymphs 0.6-4.2). PMID- 26946828 TI - [Phenotypic Trait Variation, Principal Component, Correlation and Path Analysis of Paris polyphylla var. yunnanensis]. AB - OBJECTIVE: To investigate the phenotypic trait variation range of Paris polyphylla var. yunnanensis, and to look for phenotypic traits closely related with yield, in order to provide reference for its breeding in the future. METHODS: Wild plants of Paris polyphylla var. yunnanensis populations cultivated for three years in Xishuangbanna, Yunnan Province were chosen. The plants of Paris polyphylla var. yunnanensis were randomly labelled, its phenotypic traits were observed and analyzed by variation, principal component, correlation, variance and path analysis. RESULTS: Eleven phenotypic traits variation of the populations of Paris polyphylla var. yunnanensis were great, mainly distributed in yield, growth and genetic characteristics. Phenotypic trait of different growth years (4 - 10 years) including stem height, stem diameter, flower stem height, flower stem diameter, leaf number, leaf length and leaf width had no significant difference(P > 0. 05). The underground phenotypic traits including root weight, root length and root diameter increased significant (P <0. 05) with plant growth years. Effect of the other phenotypic traits on root weight was as follows: root diameter (0. 2550) > root growth years (0. 1183 ) > root length(0. 0202) > stem diameter(0. 0081) > stem height (0. 0044) > leaf number (0. 0025) > leaf length (0. 0018) > leaf width (0. 0004) > flower stem height (0. 0003) > flower stem diameter (0. 0001). CONCLUSION: The phenotypic traits on yield, growth and genetic characteristics have rich variations, and the phenotypic traits on the ground have no relationship with plant growth years, the plant growth years mainly affect the underground phenotypic traits. When choosing different root types, root diameter can be used as the preferred character, stem diameter as the second preferred traits when the root traits information not be easily obtained. PMID- 26946829 TI - [Study on Dry Matter Accumulation and Nutrient Uptake of Shiyao Angelica sinensis]. AB - OBJECTIVE: To study the dry matter accumulation and nutrient uptake of Shiyao Angelica sinensis, in order to provide theoretical basis for reasonable fertilization. METHODS: The aerial part(stems and leaves) and root were collected in different growth periods, and the fresh weight, dry weight and contents of nitrogen, phosphorus and potassium were measured. RESULTS: The dry matter accumulation and nutrient uptake were well fitted a Logistic equation with the increase of the number of days after sowing. In the early stage of Shiyao Angelica sinensis growth, the dry matter accumulation and nutrient uptake were very slow. Beginning in late July, the dry matter accumulation and nutrient uptake of stems and leaves sped up. Starting from the occurrence peak in August, the roots of nutrient uptake sped up. In late September, the dry matter accumulation of root reached a peak. In early October, the dry matter accumulation and nutrient uptake slowed down significantly. The middle of October was the harvest time. CONCLUSION: Some phosphorus should be applied as base fertilizer in the plantation of Shiyao Angelica sinensis, and nitrogen should be applied as top fertilizer in different growth periods. PMID- 26946830 TI - [Cooperative Protection of American Ginseng Seedlings by Applying Imidacloprid, Fludioxonil and Phoxim]. AB - OBJECTIVE: To screen out an effective method of controlling pests on American ginseng(Panax quinquefolium). METHODS: The germinating seeds of the plant from two growers in Liuba County,Shaanxi Province,were collected and potted in pest residing sandy soils indoors. Four pesticides (imidacloprid wettable powders, fludioxonil flowable concentrate for seed coating, chlorpyrifos granules and Pyrifos ? phoxim granules) in different modes and doses were applied, and their effects were assayed. RESULTS: Pests were largely enchytraeid(Enchytraeus bulbosus), root mite (Rhizoglyphus robini) and two root rot fungi(Cylindrocarpon destructans and Phytophthora cactorum), which could be transmitted by both seed and soil. The treatment of dressing or soaking seeds in mixed solution of imidacloprid 25WP and fludioxonil 2.5SD plus blending the pest-residing sandy soil with chlorpyrifos ? phoxim 5G displayed significant effects of both controlling pests and keeping stand of seedlings(P <0. 05); whereas each of the three pesticides exhibited a middle-class effect when applied alone, and chlorpyrifos l0G showed little effect when applied singly. CONCLUSION: The combined approach of seed- and soil-tteatments is able to efficiently reduce damages caused by seed- and soil-born pests, and become one optimal measure protecting seedlings,and is thus suggested to demonstrate and extend in the pests' infestation areas. PMID- 26946831 TI - [Influence of Different Growing Years on Accumulation of Flavonoids and Saponins in Astragali Radix]. AB - OBJECTIVE: To study the effects of different growing years on the accumulation of flavonoids and saponins in Astragali Radix, in order to offer evidence to determine the most appropriate harvest time. METHODS: HPLC method was developed for the determination of the contents of flavonoids and saponins. RESULTS: The contents of flavonoids and saponins in different growing years of Astragali Radix existed obvious differences, the longer growing, the content was relatively higher. CONCLUSION: With the increase of growing years, the contents of flavonoids and saponins are roughly rising year by year, the harvest time has a great influence on the accumulation of the compositions. PMID- 26946832 TI - [Potential Ecological Suitability Regionalization Analysis of Angelica sinensis Based on GIS and Fuzzy Matter Element Model]. AB - OBJECTIVE: To study the potential ecological suitability regionalization of Angelica sinensis, for protecting wild resources and selecting cultivation location and designing rational production layout. METHODS: Based on fuzzy matter element model, the relationship of fuzzy membership function between ferulic acid content and 14 ecological factors, including climate, topography and soil,were established. Then information entropy theory was used to determine the relative importance of each environmental factor, and thus to determine the most limiting habitat criteria. Finally, the probable spatial distribution of Angelica sinensis across ten provinces in Western China was determined based on GIS spatial analysis of habitat conditions. Meanwhile, the optimal index range of ecological factors was quantified. RESULTS: It was showed that the percentage of moderately and highly suitable habitats for Angelica sinensis in the study area was 9. 64%, its area was 306,768. 01 km2. The moderately and highly suitable habitats were mainly located in the southeast of Gansu ind Tibet,the north of Sichuan and the northwest of Yunnan. The results also showed that six dominant ecological factors controlling the distribution of Angelica sinensis. These six dominant features were as follows: (1) mean temperature of wettest quarter, (2) altitude, (3) precipitation of growth, (4) annual relative humidity, (5) average temperature of growth period, and (6) annual )recipitation. CONCLUSION: The habitat suitability assessment model based on GIS and fuzzy matter element model theory can accurately valuate the habitat suitability of Angelica sinensis, quantify the area of suitable habitat and analyze the spatial distribution. This informaion is of value to provide insight for choosing the most suitable cultivation sites,as well as the habitat protection zones. PMID- 26946833 TI - [Analysis of ISSR Amplification Results of Six Species in Sect. Cruciata Gaudin]. AB - OBJECTIVE: To identify and analyze the genetic relationship of four species of Gentiana (G. macrophylla, G. straminea, G. dahurica and G. crassicaulis) recorded as Gentianae Macrophyllae Radix in the Chinese Pharmacopoeia, and two other Gentiana species (G. officinalis and G. siphonantha) often used as substitutes by ISSR, in order to estimate the reasonability of G. officinalis and G. siphonantha used as substitutes from the DNA level. METHODS: Eight primers ivere screened to amplify all the samples and agarose gel electrophoresis were analyzed. NTSYSpc-2. 10E software was used to calculate similarity coefficient and draw dendrogram. Results: Nine characteristic bands were found in different species on the ISSR fingerprints and which could be used to identify five species except G. dahurica. The substitute G. officinalis firstly clustered with G. dahurica and G. siphonantha showed closer genetic relationship with G. straminea and G. dahurica. G. crassicaulis showed a far genetic relationship with the other five species. CONCLUSION: The dendrogram based on the ISSR data supports that G. officinalis and G. siphonantha can be used as substitutes of Gentianae Macrophyllae Radix. PMID- 26946834 TI - [Analytical Methods with Qualitative HPLC Fingerprint and Quantitative Measurement of Effective Components of Processed Asari Radix et Rhizoma]. AB - OBJECTIVE: In order to provide the basis for quality standard and processing principle of processed Asari Radix et Rhizoma, an HPLC fingerprint of processed Asari Radix et Rhizoma was established and the contents of methyl eugenol and asarinin were determined. METHODS: The analytical column was Agligent Tc-C18 (250 mm x 4. 6 mm, 5 um); A mixture of acetonitrile-0. 2% acetic acid solution was used as the mobile phase with gradient elution at the flow rate of 1. 0 mL/min. The wavelength was set at 285 nm and the column temperature was 30 degrees C. RESULTS: The fingerprint of processed Asari Radix et Rhizoma was established. The asarinin peak was taken as the reference peak. 22 common peaks were assigned, and two peaks were confirmed by comparing with the reference standards. The difference of components was not significant among the various processed products except ginger, honey and fried coke products, but the contents of effective constituents were different among the processed products. The retention rate of methyl eugenol in processed products was in a descending order as follows: wine > vinegar > liquorice > alkali-vinegar > fried coke > rice water system > honey > ginger > salt system > alkali. Methyl eugenol was increased 10% ~ 20% with wine processing and retained more than 95% with vinegar. The retention rate of asarinin in processed products was in declining as: rice water system > liquorice > alkali-vinegar > honey > salt system > wine > ginger > vinegar > alkali > fried coke. The processing techniques increased the content of asarinin except the alkali and fried coke products, and asarinin was increased more than 35% with rice water, alkali-vinegar or liquorice processing. CONCLUSION: The method is accurate and reliable, which can be used for the quality control of processed products of Asari Radix et Rhizoma. PMID- 26946835 TI - [Identification of Sun-dried and Sulfur-fumigated Chuanxiong Rhizoma by FTIR]. AB - OBJECTIVE: To evaluate the sulfur-fumigation effects on the chemical constituents of Chuanxiong Rhizoma. METHODS: Alcoholic and aqueous extracts of sun-dried and sulfur-fumigated Chuanxiong Rhizoma samples were analyzed by FIIR. FTIR spectra were acquired and disposed by software Omnic 8. 0, second derivative IR spectra were analyzed by software OPUS 6. 5 through smoothing and differentiation treatment to FTIR spectra, and the absorption frequencies of alcoholic and aqueous extracts of sun-dried and sulfur-fumigated Chuanxiong Rhizoma samples were assessed by using principal component analysis with software SPSS. RESULTS: There were significant differences between sun-dried and sulfur-fumigated Chuanxiong Rhizoma samples in the region ranging from 2 000 cm-1 to 750 cm-1. Some absorption peaks weakened or disappeared, and some newly emerged after the processing of sulfur-fumigation. CONCLUSION: The processing of sulfur-fumigation can influence the effective constituents of Chuanxiong Rhizoma. The established method of FTIR combined with second derivative and principal component analysis has been proved to be an effective, intuitional and rapid approach to distinguish sun-dried and sulfur-fumigated Chuanxiong Rhizoma. PMID- 26946836 TI - [HPLC Fingerprint and Active Components Determination of Polygala tenuifolia Root Bark and Root]. AB - OBJECTIVE: To compare the difference between Polygala tenuifolia root bark and root using HPLC fingerprint analysis and active components determination. METHODS: Three main characteristic components including tenuifolin, polygalaxanthone III, and 3, 6'-disinapoly sucrose in different Polygala tenuifolia samples were determined by HPLC. The fingerprint methods were optimized. Then, the similarity evaluation and multivariate statistical analysis were applied in the post-processing data analysis. RESULTS: There was a high similarity in 15 batches of Polygala tenuifolia samples and its similarity coefficient was greater than 0. 9. The Polygala tenuifolia root bark and root could be clearly separated by the cluster analysis and/or the principal component analysis due to significant differences of the contents of polygalaxanthone III and 3 ,6'-disinapoly sucrose. In addition, the result of scatter plot showed that there was a high variation of tenuifolin content among all samples. The contents range of polygalaxanthone III and 3,6'-disinapoly sucrose in root bark varied relatively slight,while the content range of polygalaxanthone III in roots varied largely. Moreover,the stacked plots suggested that it was not reasonable to evaluate the quality of Polygala tenuifolia only by a single ingredient. Conclusion:The content of 3 ,6'-disinapoly sucrose varies more largely than the other two active components in Polygala tenuifolia root bark and root. Polygala tenuifolia root bark and root should be selected for different clinical treatment to ensure the accuracy of its clinical use. PMID- 26946837 TI - [NIR Fingerprints of Different Medicinal Parts of Angelicae Sinensis Radix]. AB - OBJECTIVE: To investigate the spectrum characteristics of near-intrared dittuse retlectance spectroscopy (NIR) fingerprint of different medicinal parts of Angelicae Sinensis Radix. METHODS: 96 batches of samples were collected from 14 counties of Gansu Province and Yunnan Province. The NIR fingerprints were collected by integrated sphere. Similarity analysis and partial least square discriminant analysis(PLS-DA) were used to analyze the fingerprint. RESULTS: The average spectrum of NIR fingerprint of different medicinal parts of Angelicae Sinensis Radix showed some differences; the absorbance in characteristic absorption was in a decreasing order of body > tail > head > whole. Most NIR fingerprint similarities of different medicinal parts of Angelicae Sinensis Radix exceeded 0. 95. The established model of PLS-DA could be used to accurately classify the medicinal parts of Angelicae Sinensis Radix. The differences of NIR fingerprints of different medicinal parts of Angelicae Sinensis Radix were mainly existing in the wave number ranges of 8,443 - 8,284 cm -1, 7,003 - 6,896 cm-1, 6,102 - 5,864 cm-1, 4,847 - 4,674 cm-1, and 4,386 - 4,208 cm-1. CONCLUSION: The different medicinal parts of Angelicae Sinensis Radix have some differences in chemical components. PMID- 26946838 TI - [Identification of Moghania philippinensis and Moghania macrophylla]. AB - OBJECTIVE: To study the identification methods of Moghania philippinensis and Moghania macrophylla, and to establish a comprehensive precise discrimination method. METHODS: TLC and HPLC were applied to analyze genistein in the root of Moghania philippinensis and Moghania macrophylla. DNA barcoding establishment was based on ITS2 sequcence. RESULTS: A comprehensive differentiation method for Moghania philippinensis and Moghania macrophylla based on TLC was proposed, which was combined with HPLC for determination of genistein. The plants of Moghania philippinensis and Moghania macrophylla and their related species could be distinguished by DNA barcoding effectively. CONCLUSION: TLC and HPLC profiles of Flemingia Radix provide alternative methods of identification using chemical approach. This integrated chemical and molecular approach allows accurate comprehensive fast identification of Moghania philippinensis and Moghania macrophylla, which avoids the methods limitations on the accuracy of identification. The differentiation methods based on TLC, HPLC and DNA barcoding are simple,which provide a new scientific evidence for the identification of authenticity of Flemingia Radix. PMID- 26946839 TI - [Chemical Constituents from Sphagneticola trilobata]. AB - OBJECTIVE: To study the chemical constituents of the whole plant of Sphagneticola trilobata. METHODS: The compounds were isolated and purified by column chromatography and their structures were determined by spectroscopic techniques. RESULTS: Three lignans, two indolics and two phenolic glycosides were isolated from the whole plant of Sphagneticola trilobata and identified as syringaresinol 4-O-beta-D-glucopyranoside(1), pinoresinol-4-sulfate(2), pinoresinol-4-O-beta-D glucopyranoside(3), 1H-indole-3-carboxylic acid (4), 1H-indole-3-carbaldehyde(5), 2,6-dimethoxy-4-hydroxyphenol-1-O-beta-D-glucopyranoside (6), and 3,5-dimethoxy-4 hydroxyphenol-1-O-beta-D-glucopyranoside (7). CONCLUSION: Compounds 1 - 7 are isolated from the genus Wedelia for the first time. Compound 4 demonstrates significant inhibitory activity against alpha-glucosidase. PMID- 26946841 TI - [Chemical Constituents from Pueraria alopecuroides Ratten]. AB - OBJECTIVE: To study the chemical constituents from the ratten of Pueraria alopecuroide. METHODS: Column chromatography techniques were used for compounds separation. And their structures were elucidated by physico-chemical properties and means of spectral analysis. RESULTS: Five flavonoids were isolated from Pueraria alopecuroide and their structures were identified as: (3R)-2', 3' dihydroxy-6,7,4'-trimethoxyisoflavane(1), (3R)-8,2'-dihydroxy-7,4' dimethoxyisoflavane(2), (3S)-vestitol(3), (3R)-(-)-7,2'-dihydroxy-3',4' dimethoxyisoflavane(4), and 5,7,4'-trihydroxy-2',3'-dimethoxyisoflavanone(5). CONCLUSION: Compounds 1 5 are isolated from this plant for the first time and compound 1 is a new compound. PMID- 26946840 TI - [Low Polar Constituents from Annona squamosa Fruit Pericarp]. AB - OBJECTIVE: To study the low polar constituents from Annona squamosa fruit pericarp. METHODS: The fruit pericarp was percolated with 95% EtOH at room temperature. The extract was subjected to Silica gel chromatography and eluted with gradually more polar and EtOAc-MeOH mixtures. The part eluted range Pet EtOAc from 5:1 to 1:1 was subjected to repeated column chromatography. The constituents were identified by physicochemical property and NMR data. RESULTS: Eight constituents were isolated and identified as tricosane(1), beta sitosterol(2), succinic acid (3), annosquamosin D(4), 4alpha-hydroxy-19-nor-(E) kauran-17-oic acid(5), (E)-16beta, 17-dihydroxy-kauran-19-oic acid(6), (E) 16alpha, 17-dihydroxy-kauran-19-oic acid(7), and 16beta-hydroxy-17-acetoxy-(E) kauran-19-oic acid(8). CONCLUSION: All constituents are firstly isolated from Annona squamosa fruit pericarp except compound 6. PMID- 26946842 TI - [Extraction of miRNA from Glycyrrhiza uralensis Decoction and Its Effect on Immune Cells]. AB - OBJECTIVE: To extract microRNA(miRNA) from Glycyrrhiza uralensis(liquorice) decoction and to explore its effect on mmune cells. METHODS: With dried processed liquorice, the water decoction was prepared according to the conventional method and subsequently concentrated by rotary evaporation. The concentrated decoction was further freeze-dried by freeze dryer, and miRNAs were extracted with Plant MicroRNA Extraction Kit. The extracted miRNA was digested by DNase I and then analyzed through the agarose gell electrophoresis. The PBMC was isolated from healthy volunteers and treated respectively by liquorice water extract, glycyrrhizic acid, glycyrrhetic acid and liquorice miRNAs. After 24 hours, the cells numbers were counted, and the changes of cell morphology were observed. The expression of CD3, CD56 and HLA-DR were analyzed by flow cytometry to identify the change of cell subsets in PBMC. RESULTS: miRNAs could be extracted from the decoction of dried liquorice which further confirmed the stability of miRNAs. The in vitro culture experiment showed that,compared with the controls, PBMC treated with liquorice miRNAs appeared apparent cell aggregation and increased cell number and HLA-DR+ cells proportion. CONCLUSION: The miRNAs are successfully extracted from the freeze-dried decoction of dried liquorice. It is indicated that liquorice miRNAs have significant stimulative effects on the growth of PBMC and HLA-DR+ cells subset. PMID- 26946843 TI - [Lycium barbarum Polysaccharide Pretreatment Attenuates Cerebral Ischemic Reperfusion Injury by Inhibiting Apoptosis in Mice]. AB - OBJECTIVE: To observe the protective effects of Lycium barbarum polysaccharide(LBP) on focal cerebral ischemic reperfusion injury in mice, and to explore its mechanism. METHODS: Male mice were randomly divided into six groups: sham-operated group, middle cerebral artery occlusion(MCAO) mice group, MCAO mice treating with 4 mg/kg Nimodipine group and MCAO mice treating with 10, 20 and 40 mg/kg LBP groups. The mice were preventively administrated with LBP by intragastric administration for seven days. After 2 h of cerebral ischemia and 24 h of reperfusion, neurological scores in each group mice were estimated. Morphological changes in ischemic brain neurons were performed for HE staining. The number of apoptotic neurons was detected by Tunel staining. The Caspase-3 protein activity was measured by spectrophotometry. BAX and BCL-2 protein expressions in ischemic brains were investigated by Western blot analysis. RESULTS: Compared to the vehicle group, neurological deficit scores were significantly reduced in LBP pretreatment group(P <0.01). LBP( 10,20 and 40 mg/kg) groups relieved neuronal morphological damage respectively and also obviously attenuated the neuronal apoptosis (P <0. 05). Caspase-3 protein activity and BAX protein expression were obviously decreased(P <0. 05, P <0. 01) and BCL-2 protein expression was markedly increased(P <0. 01) in LBP pretreatment groups. CONCLUSION: LBP can protect against focal cerebral ischemic reperfusion injury in mice,the mechanism may be related with attenuating the apoptosis in ischemic brains. PMID- 26946844 TI - [Effect of Basil Polysaccharide on Histone H3K9me2 Methylation and Expression of G9a and JMJD1A in Hepatoma Cells Under Hypoxic Conditions]. AB - OBJECTIVE: To study the effect of basil polysaccharide on the expression of histone methyltransferase G9a, demethylase JMJD1A and histone H3K9me2 methylation level in hepatoma cells MHCC97H and MHCC97L under hypoxic conditions, in order to explore the regulatory effect of basil polysaccharide on the epigenetics of hepatoma cells. METHODS: Cobalt chloride(CoCl2) was used to simulate hypoxic, MHCC97H and MHCC97L hepatoma cells hypoxia model was established in vitro,and then intervened with different concantration of basil polysaccharide intervened 24 h. The expression of HIF-1alpha, G9a and JMJD1A mRNA in hepatoma cells were detected by real time fluorescent quantitative PCR. The expression of HIF-lalpha, G9a, JMJD1A protein and histone H3K9me2 methylation level was detected by Western blot method. RESULTS: Basil polysaccharide down-regulated the expression of HIF lalpha, G9a, JMJD1A mRNA and protein and histone H3K9me2 methylation level in MHCC97H cells under hypoxic condition,and down-regulated the expression of HIF lalpha mRNA and protein and histone H3K9me2 methylation level in MHCC97L cells under hypoxic condition(P <0. 05). CONCLUSION: Basil polysaccharide can regulate histone H3K9me2 methylation levels in hepatoma cells MHCC97H and MHCC97L which have different metastatic potential under hypoxic conditions. On hepatoma cell MHCC97H, the regulation of histone H3K9me2 methylation is associated with histone methyltransferase G9a and demethylase JMJDlA. In hepatoma cell MHCC97L, the regulation of histone H3K9me2 methylation was probably through other pathways. PMID- 26946845 TI - [Effect and Mechanism of Litchi Semen Effective Constituents on Insulin Resistance in Rats with Type 2 Diabetes Mellitus]. AB - OBJECTIVE: To observe the effect of Litchi Semen Effective Constituents (LSEC) on insulin resistance (IR) in rats with Type 2 Diabetes Mellitus(T2DM), and to explore its mechanism. METHOD: T2DM models in rats with IR were induced by high fat feeding combined with streptozocin, then the rats were randomly divided into four groups: model group, LSEC high-dose group (1. 87 g/kg), LSEC low-dose group(0. 47 g/kg) and rosiglitazone group(3. 87 x 10(-3) g/kg), blank group was established as control. After medication for four weeks, effects of LSEC on glucose or lipid metabolism and insulin resistance were investigated, histopathology and ultrastructure changes of pancreatic tissues were observed,Stem-loop Real-time fluorescence quantitative RT-PCR was used for evaluation of GRP78 mRNA and CHOP mRNA levels in pancreatic tissue of rats. RESULT: LSEC of high-dose group obviously improved fasting blood glucose, serum TG level and glucose tolerance in T2DM rats (P <0. 05 or P <0. 01). ISI was increased, HOMA-IR index was decreased, histopathology change of pancreatic tissue were alleviated, damaged organelle, such as endoplasmic reticulum and mitochondria were repaired in both groups of LSEC. Expression levels of GRP78 mRNA of both groups of LSEC and CHOP mRNA of high-dose group in pancreatic tissue were obviously lower than those of model group (P <0. 01). CONCLUSION: LSEC can improve glycolipid metabolism and IR, increase insulin sensitivity to cure T2DM, its effects may be attributed, at least in part, to inhibit the expression of GRP78 mRNA and CHOP mRNA. PMID- 26946846 TI - [Influence of the Compatibility of Gualou and Xiebai on Pharmacokinetics of Quercetin in Gualou]. AB - OBJECTIVE: To determine the concentration of quercetin in mouse plasma by HPLC DAD in different time after oral administration with Gualou Xiebai decoction and Gualou decoction, and to explore the influence of the compatibility of Gualou and Xiebai on pharmacokinetics of quercetin in Gualou. METHODS: The plasma sample was simply deproteinized with acetonitrile, extracted three times by aceticether, evaporated to dryness with a gentle N2 stream, dissolved with methanol and determined by HPLC. The pharmacokinetic parameters were separately calculated and compared with data processing software DAS 2. 0 and SPSS 11. 5 software. RESULTS: After oral administration with Gualou Xiebai decoction and Gualou decoction, the pharmacokinetics of quercetin in mouse plasma accorded with the two-compartment model, and t1/2alpha, t1/2beta, AUC0-t, AUC0-infinity, Cmax, tmax, Ka, K10, K12, K21, CL/F and V1/F all had significant differences(P <0. 05 or P <0. 01). CONCLUSION: Xiebai in Gualou Xiebai decoction has a remarkable effect on pharmacokinetic character of quercetin in Gualou, it can promote the absorption and distribution and reduce the elimination of quercetin, in vivo, as well as increase the bioavailability of quercetin. PMID- 26946847 TI - [HPLC Specific Fingerprint of Alcohol Extract of Andrographis paniculata]. AB - OBJECTIVE: To establish the specific fingerprint of alcohol extract of Andrographis paniculata by HPLC. METHODS: The analysis was performed on Cosmosil 5C18 -MS-II (250 mm x 4. 6 mm, 5 um) column, with gradient phase consisting of acetonitrile and water at the flow rate of 1. 0 mL/min. The UV detection wavelength was set at 225 nm, and column temperature was 30 degrees C. RESULTS: The specific fingerprint chromatogram was established and seven common peaks were identified by comparison with the reference standards and LC-MS. The relative retention times were 1. 00 (No. 1, andrographolide), 1. 04 (No. 2, deoxyandrographoside), 1. 07 (No. 3, isoandrographolide), 1. 10 (No. 4, 14-deoxy 11, 12-didehydroandrographoside), 1. 50 (No. 5, neoandrographolide), 1. 75 ( No. 6, deoxyandrographolide) and 1. 79 (No. 7, dehydroandrographolide). CONCLUSION: The method is simple and reproducible with high precision, which can provide the basis for the quality control and evaluation of alcohol extract of Andrographis paniculata and its preparations. PMID- 26946848 TI - [Investigation on Spray Drying Technology of Auricularia auricular Extract]. AB - OBJECTIVE: To investigate the feasibility of spray drying technology of Auricularia auricular extract and its optimum process. METHODS: On the basis of single factor test, with the yield of dry extract and the content of polysaccharide as indexes, orthogonal test method was used to optimize the spray drying technology on the inlet air temperature, injection speed and crude drug content. Using ultraviolet spectrophotometry, thin layer chromatography(TLC) and pharmacodynamics as indicators, extracts prepared by traditional alcohol precipitation drying process and spray drying process were compared. RESULTS: Compared with the traditional preparation method, the extract prepared by spray drying had little differences from the polysaccharide content, TLC and the function of reducing TG and TC, and its optimum technology condition were as follows: The inlet air temperature was 180 degrees C, injection speed was 10 ml/min and crude drugs content was 0. 4 g/mL. CONCLUSION: Auricularia auricular extract by spray drying technology is stable and feasible with high economic benefit. PMID- 26946849 TI - [Polypharmacy among elderly patients in Luxemburg]. AB - BACKGROUND: Since years it was suspected that a large number and possibly inappropriate medicines were prescribed to patients > 65y. OBJECTIVE: The objective of this study was the inventory of polypharmacy and the inappropriate drugs prescribed to patients of 65 years and older during the year 2008 in Luxembourg. DESIGN: For this study anonymized data were used from the data base of the medical control administration of the social security CMSS ("administration du controle medical de la securite sociale"). RESULTS: 580 general practitioners (GPs) had written 399 401 prescriptions for 58 592 patients.1080 medical specialists had written 272 197 prescriptions for 50 609 patients. Drug therapies prescribed by GPs cost 641,26 ? per patient and prescribed by medical specialists 559,12 ? per patient in 2008. Quantitative polypharmacy was prescribed to 17, 91% of patients (19, 99% to women and 14, 83% to men) by GPs. Medical specialists prescribed polypharmacy to 8,65% of patients (7,98% to women and 9,59% to men) by GPs. Among the 20 most prescribed drugs, inappropriate medicines for seniors were observed in the group of GPs as well as in the group of medical specialists. Family doctors prescribed inappropriate drugs to 13, 69% of patients and medical specialists to 5,46% of patients. In both groups lorazepam, zolpidem and lormetazepam have been identified as inappropriate active pharmaceutical ingredient (API). CONCLUSION: The pivotal role of the GPs in drug therapy of the elderly could be established. Polypharmacy as well as inappropriate drug prescriptions were more frequently observed in the group of GPs than in the group of medical specialists. Benzodiazepines and analogues are the most prescribed inappropriate medications to the elderly. PMID- 26946850 TI - [Sports in Luxembourg. The role of heart healthy sports]. AB - 30 years of organized ambulatory heart sport in Luxembourg Promoter of health sports. For more than 30 years both mortality and morbidity due to coronary artery disease (CAD) are significantly decreasing (> 70%) in the western world. This achievement is due to multiple interventions in the direct treatment of CAD and, especially, in fighting its risk factors: smoking, high blood pressure, hypercholesterolemia and physical inactivity. In 1984 the first ambulatory heart sport group (phase 3 of cardiac reeducation) was founded in Luxembourg City, followed in 1991 by a section in Esch/Alzette and in 2002 by a 3eme section in Ettelbruck. These phase 3 cardiac sport groups (= chronic phase) are organized by some committed patients working on a voluntary basis and performing a professional job. Paradoxically these phase 3 groups preceded the phases 1 and 2 (= "in hospital" and subacute) of cardiac rehabilitation. However, in a parallel way ambulatory phase 2 physical activity (PA) was started in the main hospitals in Luxembourg City (Centrum), Esch/Alzette (South) and Ettelbruck ( North). In 2002 a cornerstone study by Myers et al proved that physical fitness is the most determinant of survival both for healthy people and for cardiac patients: The better the fitness, quantified in METs, the better the prognosis and this fact is the basis for the application of sports therapy in cardiac and most other patients. An important epidemiological study published in 2012 by Lee et al in Lancet analyzed the effects of physical inactivity (PI) all over the world: 4 important diseases were studied: CAD, breast cancer, colon cancer and type 2 diabetes. The effects of PI are most pronounced in colon cancer followed by diabetes 2, breast cancer and then CAD. As a mean about 9% of all deaths -5.9 million in 57 million deaths/year worldwide- are caused by PI and for Luxembourg 12.9%. This cornerstone study can serve as rationale for physical therapy (PT) intervention in oncology, diabetes and CAD. It is noteworthy that the basic RF are more or less the same for the chronic diseases investigated in this study. Since the beginning of the new century PT has become an integral part of the strategies for cancer prevention and treatment. This option has been studied thoroughly first in breast cancer, later also in colon, prostate, and bronchial cancers etc. In primary prevention regular medium intensity training decreases the incidence of cancers by about 20-30%. For patients with proven cancers the application of PA as treatment option is more complicated compared to patients with cardiac problems since cancer patients often have to undergo surgery, then chemo- and/or irradiation therapy. All these interventions and their side effects have to be considered before applying PA. Above the physical alterations most cancer patients have to face anxiety and depression problems. PT improves the outcome between 15-25% and plays an important role in improving the psychological problems of the cancer patients. Since 10 years several oncologists in Luxembourg became interested in PA as a therapeutic option for their patients. They contacted the cardiologists and physiotherapists in charge of cardiac reeducation and progressively programs for PA in oncology were launched also in Luxembourg. Meanwhile several groups of cancer patients offer regular PT programs. In 2014 a stock concerning the different health sport activities in Luxembourg was taken by a young researcher of the Luxembourg Institute of health (LIH). 11 different associations are active; the most important and best organized are the cardiac sports groups, but there are also several oncologic, neurologic and orthopedic sports groups. A target for the coming years is to confer a robust infrastructure to all these associations following the model used by the cardiac groups. For the next year all these groups should be integrated into the Federation of Health Sports of the national Olympic Committee. PMID- 26946851 TI - [The flexibility of family medicine]. AB - We are a European academic group of family doctors and we propose a definition of flexibility in family medicine. A review of the literature shows that flexibility and complexity are emerging concepts in the field of family practice. The outcomes of a workshop at the WONCA-Europe congress in 2014 are discussed. The flexibility is a capability of the general practitioner to deal with complex clinical situations in a biomedical and societal changing world. Flexibility is framed by ethics. It could improve the quality of care, be useful against burnout and used in medical research. In conclusion, family medicine should adopt a specific definition of the flexibility describing its specificity, a useful and teachable capacity. PMID- 26946852 TI - Predisposing factors for neuropathic ulcerations in patients with diabetes. AB - OBJECTIVE: To assess the risk factors the precipitates ulcerations. MATERIAL AND METHODS: In this study a group of 100 patients were selected from November 2007 till October 2008 who were coming for treatment at the Diabetes center of Cluj Napoca, Romania for treatment. 50 cases were patients with ulcerations and 50 without any ulceration. RESULTS: Most important results were: (Age, sex type, biological parameters like HDL, total cholesterol, creatinine ESR, polyneuropathy, arteriopathy, diabetic foot type, diabetes duration). We obtained these results using different statical methods. CONCLUSION: Ulcerations in diabetic neuropathy are caused by a whole combination of several factors which should be monitored by a meticulous examination and careful follow up of diabetic patients. This in turn will be beneficiary for patients as well as economically interesting reduce the amount of money which is used to treat ulcerations. PMID- 26946853 TI - [Introduction of noninvasive prenatal testing for fetal trisomies: preliminary results and consequences on invasive samplings]. AB - Noninvasive prenatal testing (NIPT) has marked a revolution in aneuploidy screening because it allows a simple maternal blood test to detect trisomy 21, 18 and 13 in a foetus with a very high level of accuracy. After one year of NIPT utilisation with 683 samples, we analyzed retrospectively the performance of the test for 2014 : 3 positive samples (2 trisomies 21 and 1 trisomy 18) were correctly detected (100% sensitivity) and no foetal aneuploidy was missed for the pregnancies having already resulted in delivery by decembre 2014 (280 true negatif, 100% specificity). However, the additionnally available analysis of the sex chromosomes resulted in 2 erronous results: 1 uncorrect sex determination (1 male resulting in a female phenotype at birth) and 1 result suggesting a Turner syndrome was not confirmed by amniocentesis. The failure rate leading to a resampling was at 1.46% (10/683). The test used was the NIFTY of the BGI laboratory in Hong-Kong. By comparison to the year 2013, the utilisation of NIPT lead to a significant diminution of invasive samples performed by amniocentesis or choriocentesis 144 vs. 239 (- 63%). We confirmed that NIPT is a high performance tool for the screening of the main foetal aneuploidies and report that during its first year of utilisation, 63% of invasive samples collected could be avoided. The test is expensive, not reimboursed by Luxembourg social security and therefore prohibitive for a number of women and their families. PMID- 26946854 TI - Tar Heel Footprints in Health Care. John Shelburne, MD, PhD. PMID- 26946855 TI - Associations Between Practice Characteristics and Demonstration of Stage 1 Meaningful Use for the Electronic Health Record Incentive Program. AB - BACKGROUND: The Medicare and Medicaid meaningful use (MU) incentive programs promote adoption and "meaningful use" of certified electronic health records among hospitals and eligible providers in outpatient settings, with a goal of improving the quality of patient care. Despite the potential importance of MU for providers and patients, little is currently known about the practice characteristics that facilitate providers' demonstration of MU. This study examined whether selected practice characteristics were associated with providers' meeting Stage 1 MU objectives at the end of 1 year in a single large North Carolina integrated delivery system. METHODS: Our retrospective database analysis included all 702 eligible providers from 54 ambulatory care practices on the main campus of the University of North Carolina Health Care System. We assessed associations between providers' ability to meet Stage 1 MU objectives as of December 2012 and the following practice characteristics: practice specialty, size, and mix of Medicare- and Medicaid-eligible providers. RESULTS: The following practice characteristics were associated with providers' ability to meet MU objectives: primary care practices as compared to specialty practices (odds ratio [OR] = 2.49; 95% CI, 1.11-5.62), small practices as compared to medium-sized practices (OR = 0.29; 95% CI, 0.09-0.89), and the presence of only Medicare-eligible providers in the practice as compared to the presence of only Medicaid-eligible providers (OR = 6.48; 95% Cl, 1.08-38.97). LIMITATIONS: Because our sample was drawn from a single integrated delivery system, results may not be generalizable to all ambulatory practice settings. CONCLUSIONS: This study suggests that larger practices, primary care practices, and practices comprised of Medicare-eligible providers may be better able to meet MU objectives. Further research is needed to evaluate strategies that account for practice characteristics and other contextual factors in the MU implementation process. PMID- 26946856 TI - Cardiovascular Health of North Carolina Undergraduates. AB - BACKGROUND: Cardiovascular disease is highly prevalent in Eastern North Carolina (ENC). In this study, we investigated cardiometabolic risk in young adults of ENC by sampling entrant undergraduates at East Carolina University (ECU). METHODS: From June to October of 2010, 525 undergraduates were screened for elevated body mass index (BMI), blood pressure, lipids, blood glucose, inactivity, smoking, history of diabetes or hypertension, and family history of coronary disease. Participants were classified as high-risk if they had 3 or more cardiovascular risk factors or as "MetS" if they satisfied the criteria for metabolic syndrome. RESULTS: Forty-four percent of those screened had 2 or more risk factors, 12.5% had 3 or more risk factors, and 1.3% met criteria for MetS. Low levels of high density lipoprotein (27.6%), overweight status (27.2%), and inactivity (27.1%) were leading risks. Females had an increased risk of inactivity compared to males (relative risk [RR] = 1.81; 95% CI, 1.3-2.52). Blacks had a 4-fold higher risk of metabolic syndrome (RR = 4.21; 95% Cl, 1.0-18.4), and black females had a high risk for obesity (RR = 5.7; 95% CI, 2.5-13) and systolic blood pressure elevation (RR = 4.8; 95% Cl, 1.5-15). Students recognized cardiovascular disease as a valid risk to their well-being. CONCLUSION: ECU undergraduates have a high prevalence of multiple cardiovascular risk factors. High-risk and MetS students recognize cardiovascular disease as a significant health risk, but they mistakenly maintain the self-perception that they are healthy. Efforts to understand risk perception and personal strategies of risk application are needed for this population of young adults. PMID- 26946857 TI - Caring for Heroes. PMID- 26946858 TI - Utilizing Evidence to Address the Health and Health Care Needs of Veterans. AB - This issue brief focuses on opportunities to address the health needs of our nation's heroes--service members and veterans who have served the United States in the armed forces. Since the North Carolina Medical Journal (NCMJ) last examined this issue in 2008, the Veterans Affairs (VA) health care system has experienced growth in both the number of veterans served and the number of locations where services are provided. However, there has also been negative attention related to delays in care. Here we summarize the articles in this issue of the NCMJ that describe the resources available to veterans, the unique health needs of veterans, and successful examples of evidence-informed programs and policies that are being undertaken by the VA health care system to enhance care and address the concerns that have been raised about VA. Because veterans and service members receive care outside of the VA or Department of Defense health care systems and many of the programs described in this issue have promise for improving care in other health systems, as well, the topics addressed in this issue are of great importance for the entire health care community in the United States. PMID- 26946859 TI - Mental Health Among Military Personnel and Veterans. AB - This commentary describes the prevalence of mental health problems affecting military service members and veterans in North Carolina and the rest of the nation, with a special emphasis on those who served in the recent wars in Iraq and Afghanistan. Approximately 1.9 million of these veterans have become eligible for Veterans Affairs health care since 2002, and an estimated 1.16 million veterans have registered for this care. PMID- 26946860 TI - Moral Injury: An Intersection for Psychological and Spiritual Care. PMID- 26946861 TI - Health Care for North Carolina's Veterans. AB - On March 3, 1865, President Lincoln established a national soldiers' and sailors' asylum. The Veterans Health Administration (VHA) evolved from facilities established for Civil War veterans of the Union Army, and today, VHA continues to meet veterans' changing medical, surgical, and quality-of-life needs by operating America's largest integrated health system. PMID- 26946862 TI - Veterans Battling PTSD: Know the Triggers, Recognize the Symptoms. PMID- 26946863 TI - Innovative Efforts to Address Homelessness Among Veterans. AB - Ending homelessness among veterans has been a goal of the Department of Veterans Affairs for some time, and it is now becoming a reality in many communities. Unprecedented strides have been made through the rapid implementation of evidence based innovations, capacity building, and a comprehensive strategic focus on 4 goals: prevention, moving veterans into permanent housing, providing the population-tailored care and services needed to keep them housed, and providing the supports necessary to allow them to recover and be productive members of their communities. PMID- 26946864 TI - Research and Operations: Joining Forces to Improve Care for Veterans. AB - The Veterans Health Administration's move to adopt a joint operations-research perspective in promoting clinical innovation in the health care system has led to an increasing number of researchers, clinicians, and policy leaders collaborating on quality improvement activities. We describe 2 such programs, both aimed at improving care for older veterans, which were conducted by teams with both research and operations experience. We explore differences in perspectives, contributions, and roles of various team members, as well as discuss benefits and challenges of research-operations partnerships in quality improvement activities. PMID- 26946865 TI - Engaging, Supporting, and Sustaining the Invisible Partners in Care: Young Caregivers of Veterans From the Post-9/11 Era. AB - Few studies have explored the health effects of caregiving for post-9/11 veterans who have been traumatically injured, have traumatic brain injuries, or have post traumatic stress disorder. Post-9/11 veterans and their caregivers tend to be younger than veterans who served exclusively prior to 9/11. In response to the needs of caregivers, Public Law 111-163, the Caregivers and Veterans Omnibus Health Services Act of 2010, was passed, providing unprecedented support for informal caregivers of veterans. This support includes a monthly stipend and health insurance for caregivers who meet eligibility criteria. The uptake in these support services, and the resulting cost of services, has far surpassed expectations. As the Department of Veterans Affairs continues to provide caregiver support services, it is essential to determine the value and direct impact of the services provided to caregivers and veterans. PMID- 26946867 TI - Applying Regenerative Medicine to Battlefield Injuries. PMID- 26946866 TI - Rehabilitation of Combat-Related Injuries in the Veterans Administration: A Web of Support. AB - The Department of Veterans Affairs provides acute, subacute, and continuing rehabilitation for veterans using a hub-and-spoke system of hospitals and outpatient facilities. Using traumatic brain injury as an example, this commentary illustrates how this system provides interdisciplinary rehabilitative care to veterans throughout North Carolina. PMID- 26946868 TI - How Community Health Providers Can Help Patients Connect to Veterans Affairs Resources. AB - To assist the community provider in understanding and accessing Veterans Affairs (VA) resources, this commentary describes basic information regarding care of veterans. It highlights questions that may be incorporated into routine history taking, provides military culture resources, and clarifies pharmaceutical benefits. Table 2 is a quick reference guide to locate VA-based information on the Internet. PMID- 26946869 TI - New Electronic Tools for Veterans. AB - The US Department of Veterans Affairs, in partnership with the Department of Defense, has developed a host of new electronic tools designed to address the mental and behavioral health needs of military service members and veterans. These tools include online self-help programs and companion mobile apps, as well as many of the apps available through the VA App Store. This commentary provides a brief overview of these new tools and discusses some of the ways in which physicians and other medical providers in North Carolina can incorporate these tools into their work with veterans. PMID- 26946870 TI - Disease Prevention in the Veterans Health Administration. AB - The burden of chronic diseases is substantial among veterans who are seen in the Veterans Health Administration (VHA) health care system. Healthy lifestyle interventions and clinical preventive services can help veterans improve their health and well-being. The VHA's National Center for Health Promotion and Disease Prevention supports policies, programs, resources, and training for VHA. PMID- 26946871 TI - Evidence-Based Policy Making: Balancing Rigor With Real-World Health Care for Veterans and Military Personnel. AB - The US health care system is undergoing unprecedented policy transformations that will impact veterans and returning service members. Rigorous program evaluations will be crucial as policy makers make tough decisions regarding the value of new policies. Also, more partnerships between scientists and policy makers will be required to implement these designs in light of trade-offs between scientific rigor and political realities. PMID- 26946872 TI - The potential of ki67 and p53 assessment in development of individualized targeted therapy in breast cancer patients. AB - INTRODUCTION: Despite the improvement of diagnostic methods and chemotherapeutic regimens in breast cancer, overall 5-year survival significantly depends on the stage of the disease. Over expression of tumor suppressor gene p53 and the marker for cellular proliferation Ki67 in breast cancer may have prognostic significance. METHODS: We evaluated 675 patients diagnosed with breast cancer at UF Health Jacksonville between January 2000 and June 2007 with up to 5-year follow up. The aim of the study was to determine whether immunohistochemical (IHC) assessment of Ki67 and p53 may predict outcome, the 'hazard' of dying. Cox's proportional hazards models were used to control for age (< 50 vs. >= 50), race (white vs. other), lymph node group (negative vs. positive), ER (estrogen receptor) group (negative vs. positive), PR (progesterone receptor) group (negative vs. positive), and tumor type. RESULTS: When only p53 was considered in the model, the hazard of dying was significantly higher for p53 positive compared to p53 negative (HR = 1.32, 95% CI 1.02, 1.70, p = 0.036). When only ki67 was considered in the model, the hazard of dying was significantly higher for ki67 positive compared to ki67 negative (Hazard ratio = 1.64, 95% CI 1.08, 2.49, p = 0.021). Neither of the two markers, nor their interaction was significant when all variables were considered in the model. DISCUSSION: This study confirms the expression of p53 and Ki67 as strong individual indicators of patient outcome. However, when controlling for the other variables, the two markers are not independent predictors. Future studies that will include these markers might help design targeted therapy. PMID- 26946873 TI - Plexiform fibromyxoma of the gallbladder. AB - We report the unusual case of a plexiform fibromyxoma, occasionally assessed in a lithiasic gallbladder. The full thickness assessment of the gallbladder wall revealed an intra-mural, well demarked multi-nodular tumor (1 cm), consisting of a plexiform growth of spindle cells, included within a fibromyxoid stroma with a rich micro-vascular network. The tumor cells featured no nuclear atypia, nor mitotic activity. At the immunohistochemical profiling, the spindle shaped cells unequivocally featured vimentin, SMA, HHF35, collagen IV, and CD34; no cells expressed CD117, PDGFRA, CD10, desmin, GFAP, EMA, and S-100. Faint STAT6 nuclear expression was observed in isolated tumor cells. The molecular profiling did not revealed any CKIT and PDGFRA genes mutations. The uncommon site of the tumor presentation and its aberrant CD34 expression both confer to the reported case a unique place among the myxoid tumors of the gastrointestinal tract. PMID- 26946874 TI - A population of 1136 HPV DNA-HR positive women: expression of p16(INK4a)/Ki67 Dual-Stain Cytology and cytological diagnosis. Histological correlations and cytological follow up. AB - OBJECTIVE: The objectives of this study were to evaluate, in a selected HR-HPV positive population, the clinical performance of the p16/ki67 immunostaining in all the cytological diagnoses, as a reflex test of triage HPV-cytology, and assess the usefulness of p16/ki67-staining to classify CIN1 according to its risk of progression/regression in order to plan a personalized follow-up. METHODS: Our analysis was in consecutive cases of 1136 women aged 25-64 years, asymptomatic, HR-HPV DNA HC2 tested positive in a HPV-screening program, from February to December 2011. All the women had a cervical sample, in the Thin Prep, used for cytological diagnosis and for pI6/Ki67 dual- staining. Histological correlations were 442. We studied the follow-up of two years of 387 cases, especially the biological behaviour of 316 low-grade lesions. RESULTS: pI6/Ki67 dual-staining increases the VPP CIN2+ and NPV CIN2+, especially in atrophy/dystrophy, in ASC-US and LSIL. In follow-up of 387 cases, 71 CIN2+ and 316 CIN1, 69 CIN2+, after surgical treatment, had a negative follow up; two cases of CIN2 (p16/ki67-) without invasive treatments, had a spontaneous regression. Among the 316 CIN1, progression was observed in 10 women (4 pI6/Ki67 + and 6 pI6/Ki67 -); regression in 260 women (64 p16/Ki67 + and 196 p16/Ki67-); 46 women had a persistent LSIL (9 pI6/Ki67 + and 37 p16/Ki67-). It seems no significant differences in the biological behaviour in relation to the expression of the two biomarkers. CONCLUSIONS: pI6/Ki67 immunostaining increases sensitivity of cytology in some diagnostic categories. After follow up of two years, a personalized and adequate treatment does not seem still possible. Further studies and trials are required to improve the management of the cervical lesions in HPV-based screening strategies. PMID- 26946875 TI - Solitary thyroid metastasis from colon cancer: fine-needle aspiration cytology and molecular biology approach. AB - Thyroid gland is one of the most vascularized organs of the body, nevertheless clinical and surgical series report an incidence of secondary malignancies in this gland of only 3%. Colorectal carcinoma metastatic to the thyroid gland is not as uncommon as previously believed, infact the number of cases seems to be increased in recent years due to the more frequent use of fine-needle aspiration cytology (FNAC) guided by ultrasonography. Although kidney, breast and lung metastases to the thyroid are frequent, metastasis from colon cancer is clinically rare with 52 cases reported in the literature in the last 5 decades and three cases described as solitary thyroid metastasis from the colon cancer without any other visceral metastases. To the best of our knowledge, we report the fourth case of solitary, asymptomatic thyroid metastasis from colon cancer without involvement of other organs. We discuss the importance of FNAC to detect metastatazing process as a compulsory step of the diagnostic and therapeutic management algorithm, combined with a molecular biology approach. A review of the last 5 decades literature, to update the number of cases described to date, is also included. PMID- 26946876 TI - Tuberous sclerosis: histological analysis with confocal laser scanning microscope of gingival angiofibromatosis. AB - INTRODUCTION: Tuberous sclerosis (TS) is an autosomal dominant neuro-cutaneous syndrome characterized by multiple hamartomas in various organs, especially on skin and central nervous system. The most common features of TS include facial angiofibromas, hypomelanotic cutaneous macules, shagreen patches in the lumbar area, cerebral cortical tubers, sub-ependymal nodules, sub-ependymal giant cell astrocytomas, cardiac rhabdomyomas, and renal angiomyolipomas. Frequently oral manifestations such as fibrous hyperplasia, angiofibromas and dental enamel pitting are also observed. The aim of this case report was to describe the histological aspects of oral diffuse hyperplastic angiofibromatosis, never reported in the English literature and analyzed by Confocal Laser Scanning Microscope (CLSM), and to highlight the surgical implications of these aspects such as use of Diode Laser. CASE REPORT: A 14-years-old female patient with TS diagnosis came to our attention for diffuse gingival hyperplasia on the mandible. Clinical examination highlighted epidermal hamartomas on the whole body, especially on the face and scalp. Pathologic hyperplastic tissue was removed by pulsed diode laser at the power of 5-6W, and the surgical samples were sent for conventional and CLSM histopathological examination. After laser excision, wounds healed quickly without complications. At CLSM examination collagen fibres, showing intense fluorescence and with variable spatial orientation, and variably sized blood vessels were noticed suggesting the diagnosis of gingival angiofibromatosis, a still unreported finding in TS patients. CONCLUSIONS: CLSM analysis allows to highlight some unusual histopathological features of TS; diode laser is very effective for the treatment of gingival angiofibromatosis. PMID- 26946877 TI - An incidentally diagnosed epithelioid trophoblastic tumor in hysterectomy. AB - Epithelioid trophoblastic tumor is a rare non-molar gestational trophoblastic disease. A 40-year-old multiparous woman was incidentally diagnosed with epithelioid trophoblastic tumor after hysterectomy. Hysterectomy specimen revealed multiple small, tan to yellow nodules measuring 0.3-0.8 cm just below the endometrium. In the microscopic examination uniform neoplastic cells with varying cellularity were accompanied by necrotic zones and eosinophilic hyaline material. Immunohistochemically neoplastic cells were diffusely stained with CK 7, inhibin-alpha, p63, hPL, and CD146. There was no staining with beta-HCG, SMA, PLAP, or h-caldesmon. Ki-67 proliferative index was approximately 10% and cyclin E was stained in approximately 10% of the neoplastic cells. Although immunohistochemical studies are helpful in classifying gestational trophoblastic lesions, borderline values can cause diagnostic confusion between neoplastic and reactive lesions, particularly in inadequate endometrial biopsies. PMID- 26946878 TI - A new contemporary prostate cancer grading system: message to the Italian pathologists. PMID- 26946879 TI - [In ricordo di Pier-Giacomo Betta]. PMID- 26946880 TI - Interprofessional Education of Health Professionals: Social Workers Should Lead the Way. PMID- 26946881 TI - Engaging Consumer Voices in Health Care Policy: Lessons for Social Work Practice. AB - Community health centers provide comprehensive public health care in some of the most disadvantaged communities in the United States. To ensure that health centers meet the needs of their consumers, they uniquely engage them in their organizational decision-making and policy-development processes by requiring that their boards of directors encompass a 51 percent consumer majority. To understand the quality of board members' experiences, a critical ethnography was conducted using Arnstein's ladder of citizen participation and the socioecological model as a framework. The analysis identified multiple influences on the quality of participation among consumer members. Findings also confirm other research that has found that knowledge of the economic, political, and cultural factors surrounding the context of the individual health center is important to understanding meaningful participation. The experience is important to understand given the shift driven by the Patient Protection and Affordable Care Act of 2010 in health care, which emphasizes a patient-entered model of care. Social work practitioners and others in the public health arena interested in empowering consumers to have a role in the provision of services need to understand the impact of each of these areas'and the experience of this unique sample of health center board members. PMID- 26946882 TI - Parental Leave Policy as a Strategy to Improve Outcomes among Premature Infants. AB - Although gains have been made in premature birth rates among racial and ethnic minority and low socioeconomic status populations, tremendous disparities still exist in both prematurity rates and health outcomes for preterm infants. Parental involvement is known to improve health outcomes for preterm babies. However, a gap in evidence exists around whether parental involvement can help ameliorate the disparities in both short- and long-term out-comes for their preterm children. Families more likely to experience preterm birth are also less likely to have access to paid leave and thus experience significant systemic barriers to involvement, especially when their newborns are hospitalized. This article describes the research gap in this area and explores pathways by which social workers may ameliorate disparities in preterm birth outcomes through practice, policy, and research. PMID- 26946883 TI - Female Genital Mutilation Is a Violation of Reproductive Rights of Women: Implications for Health Workers. AB - Female genital mutilation (FGM) comprises all procedures that involve partial or total removal of the external female genitalia or other injury to the female genital organs for nonmedical reasons. This coercive practice is still prevalent in many parts of the world, in both developed and developing countries. However, FGM is more prevalent in African countries and some Asian countries. In this study, an attempt has been made to understand the prevalence and practice of FGM worldwide and its adverse effects on women's reproductive health. To fulfill the study objectives, the author collected evidence from various studies conducted by international agencies. Many studies found that FGM has no health benefits; is mostly carried out on girls before they reach the age of 15 years; can cause severe bleeding, infections, psychological illness, and infertility; and, most important, can have serious consequences during childbirth. The practice is mainly governed by the traditions and cultures of the communities without having any scientific or medical benefit. In conclusion, FGM is a practice that violates the human and reproductive rights of women. PMID- 26946884 TI - Impact of Death Work on Self: Existential and Emotional Challenges and Coping of Palliative Care Professionals. AB - Palliative care professionals, such as social workers, often work with death and bereavement. They need to cope with the challenges on "self" in working with death, such as coping with their own emotions and existential queries. In this study, the authors explore the impact of death work on the self of palliative care professionals and how they perceive and cope with the challenges of self in death work by conducting a qualitative study. Participants were recruited from the palliative care units of hospitals in Hong Kong. In-depth interviews were conducted with 22 palliative care professionals: five physicians, 11 nurses, and six social workers. Interviews were transcribed to text for analysis. Emotional challenges (for example, aroused emotional distress from work) and existential challenges (for example, shattered basic assumptions on life and death) were identified as key themes. Similarly, emotional coping (for example, accepting and managing personal emotions) and existential coping (for example, rebuilding and actualizing life-and-death assumptions) strategies were identified. This study enhances the understanding of how palliative care professionals perceive and cope with the challenges of death work on the self. Findings may provide insights into how training can be conducted to enhance professionals' self-competence in facing these challenges. PMID- 26946886 TI - Effectiveness of an Ongoing, Community-Based Breast Cancer Prevention Program for Korean American Women. AB - The study evaluates the effectiveness of an ongoing, community-based breast cancer prevention program offered by a local social services agency in the Washington, DC, metropolitan area. Korean American women who participated in this breast cancer prevention program were compared with those who did not participate in their knowledge, attitude, and screening behaviors. The study found that the intervention group was more knowledgeable on breast cancer and related services and reported more positive attitudes toward breast cancer screening services than the comparison group. The participants in the intervention group were also more likely to plan to receive a mammogram than those in the comparison group. However, significant differences were not observed in the two groups in their intention to receive a clinical breast examination. The study findings suggest that an ongoing, community-based breast cancer prevention program can be an effective method of addressing breast cancer prevention disparities observed among Korean American women. PMID- 26946885 TI - Traumatic Exposure History as a Risk Factor for Chronic Pain in Adult Patients with Sickle Cell Disease. AB - This article describes the impact of the integration of a licensed clinical social worker (LCSW) with expertise in behavioral health on identification of risk factors for chronic pain in a cohort of adults with sickle cell disease. Authors conducted a retrospective chart review of all visits to the adult sickle cell center during the first six months of LCSW integration. Demographics, clinical history, and LCSW notes were reviewed. Overall, 71 patients were introduced to the LCSW; 55 percent of them had chronic pain. Patients with chronic pain were older, used opioids daily, took hydroxyurea, reported higher daily pain scores, and underwent more acute care visits and hospitalizations for pain with longer stays. Fifty-eight (81 percent) patients requested concrete social work services such as transportation and housing. Thirty-two patients (55 percent) expressed a desire for mental health counseling while receiving concrete services. Twenty-two (69 percent) of these patients self-disclosed at least one traumatic experience. In fact, a statistically significant relationship between chronic pain and a history of trauma was identified (p = 0.001). Results suggest that sickle cell patients should receive clinical social work services to assess for traumatic exposures that may influence chronic pain. PMID- 26946887 TI - Using mHealth in Social Work Practice with Low-Income Hispanic Patients. PMID- 26946889 TI - Diagnostic value of the femoral vein flow pattern for the detection of an iliocaval venous obstruction. AB - OBJECTIVE: Identification of iliocaval obstructions has traditionally been difficult due to the lack of a reliable noninvasive screening technique. Although femoral vein flow patterns have been used to detect outflow obstructions, the diagnostic accuracy of indirect Doppler parameters has not yet been fully elucidated. The purpose of this study was to establish the diagnostic value of the femoral vein waveform in detecting chronic iliocaval venous lesions. METHODS: Medical records of consecutive patients with chronic venous disease classified as Clinical, Etiologic, Anatomic, and Pathophysiologic (CEAP) C3-6 between March 2011 and December 2012 were assessed retrospectively. The results of common femoral vein duplex ultrasound examinations, based on the presence or absence of respiratory variation in the femoral flow as well as its response to the Valsalva maneuver, were compared with contrast venography and intravascular ultrasound imaging of the inferior vena cava and the bilateral common and external iliac veins. Three types of flow patterns in the common femoral vein were identified with duplex ultrasound examination: phasic flow correlated with respiration, minimally phasic flow (showing some phasicity but no cessation with respiration), and monophasic flow (continuous flattened flow). In addition, three types of responses to the Valsalva maneuver were recorded: complete cessation of flow, reversal of flow, and continuation of flow. RESULTS: The study evaluated 86 patients (63 men, 23 women) with a mean age 40.3 +/- 1.5 years. Contrast venography and intravascular ultrasound imaging were used to detect venous obstructions in the inferior vena cava and the right and left iliac veins in 16.3%, 32.6%, and 80.2% of patients, respectively. When various flow parameters were evaluated, the combination of common femoral vein monophasic flow at rest and continuous flow during the Valsalva maneuver had the highest diagnostic value for iliocaval venous obstructions. The sensitivity, specificity, positive predictive value, and negative predictive value of the combination of monophasic flow at rest and unceasing forward flow during the Valsalva maneuver for the diagnosis of any degree of iliac venous obstruction were 38.1%, 100%, 100%, and 55.8%, respectively. The sensitivity and negative predictive value of these diagnostic parameters increased as the degree of obstruction increased. CONCLUSIONS: An iliocaval venous obstruction is a frequent feature of chronic venous disease. Doppler examination of the common femoral vein can be used as a screening test for iliocaval venous obstructions. The monophasic flow of the common femoral vein is a reliable diagnostic tool for the detection of possible iliac vein obstructions. PMID- 26946890 TI - Lymphatic transport in patients with chronic venous insufficiency and venous leg ulcers following sequential pneumatic compression. AB - BACKGROUND: Recent advancements in near-infrared fluorescence lymphatic imaging (NIRFLI) technology provide opportunities for non-invasive, real-time assessment of lymphatic contribution in the etiology and treatment of ulcers. The objective of this study was to assess lymphatics in subjects with venous leg ulcers using NIRFLI and to assess lymphatic impact of a single session of sequential pneumatic compression (SPC). METHODS: Following intradermal microdoses of indocyanine green (ICG) as a lymphatic contrast agent, NIRFLI was used in a pilot study to image the lymphatics of 12 subjects with active venous leg ulcers (Clinical, Etiologic, Anatomic, and Pathophysiologic [CEAP] C6). The lymphatics were imaged before and after a single session of SPC to assess impact on lymphatic function. RESULTS: Baseline imaging showed impaired lymphatic function and bilateral dermal backflow in all subjects with chronic venous insufficiency, even those without ulcer formation in the contralateral limb (C0 and C4 disease). SPC therapy caused proximal movement of ICG away from the active wound in 9 of 12 subjects, as indicated by newly recruited functional lymphatic vessels, emptying of distal lymphatic vessels, or proximal movement of extravascular fluid. Subjects with the longest duration of active ulcers had few visible lymphatic vessels, and proximal movement of ICG was not detected after SPC therapy. CONCLUSIONS: This study provides visible confirmation of lymphatic dysfunction at an early stage in the etiology of venous ulcer formation and demonstrates the potential therapeutic mechanism of SPC therapy in removing excess fluid. The ability of SPC therapy to restore fluid balance through proximal movement of lymph and interstitial fluid may explain its value in hastening venous ulcer healing. Anatomical differences between the lymphatics of longstanding and more recent venous ulcers may have important therapeutic implications. PMID- 26946891 TI - Criteria for detecting significant chronic iliac venous obstructions with duplex ultrasound. AB - OBJECTIVE: The purpose of this study was to determine the sonographic criteria for diagnosis of iliac venous outflow obstruction by assessing the correlation of this method with intravascular ultrasound (IVUS) in patients with advanced chronic venous insufficiency (CVI). METHODS: The evaluation included 15 patients (30 limbs; age, 49.4 +/- 10.7 years; 1 man) with initial CVI symptoms (Clinical class, Etiology, Anatomy, and Pathophysiology [CEAP] classification, CEAP1-2) in group I (GI) and 51 patients (102 limbs; age, 50.53 +/- 14.5 years; 6 men) with advanced CVI symptoms (CEAP3-6) in group II (GII). Patients from both groups were matched by gender, age, and race. The Venous Clinical Severity Score was considered. All patients underwent structured interviews and duplex ultrasound (DU) examination, measuring the flow phasicity, the femoral volume flows and velocities, and the velocity and obstruction ratios in the iliac vein. The reflux multisegment score was analyzed in both groups. Three independent observers evaluated individuals in GI. GII patients were submitted to IVUS, in which the area of the impaired venous segments was obtained and compared with the DU results and then grouped into three categories: obstructions <50%, obstructions between 50% and 79%, and obstructions >=80%. RESULTS: The predominant clinical severity CEAP class was C1 in 24 of 30 limbs (80%) in GI and C3 in 54 of 102 limbs (52.9%) in GII. Reflux was severe (reflux multisegment score >=3) in 3 of 30 limbs (10%) in GI and in 45 of 102 limbs (44.1%) in GII (P < .001). There was a moderately high agreement between DU and IVUS findings when they were grouped into three categories (kappa = 0.598; P < .001) and high agreement when they were grouped into two categories (obstructions <50% and >=50%; kappa = 0.784; P < .001). The best cutoff points and their correlation with IVUS were 0.9 for the velocity index (r = -0.634; P < .001), 0.7 for the flow index (r = -0.623; P < .001), 0.5 for the obstruction ratio (r = 0.750; P < .001), and 2.5 for the velocity ratio (r = 0.790; P < .001). Absence of flow phasicity was observed in 62.5% of patients with obstructions >=80%. An ultrasound algorithm was created using the measures and the described cutoff points with accuracy of 86.7% for detecting significant obstructions (>=50%) with high agreement (kappa = 0.73; P < .001). CONCLUSIONS: DU presented high agreement with IVUS for detection of obstructions >=50%. The velocity ratio in obstructions >=2.5 is the best criterion for detection of significant venous outflow obstructions in iliac veins. PMID- 26946892 TI - Relationship between development of post-thrombotic syndrome and serial ultrasound, D-dimer, and factor VIII activity after a first deep venous thrombosis. AB - OBJECTIVE: The aim of this study was to evaluate the relationship of post thrombotic syndrome (PTS) with residual vein thrombosis, deep venous reflux (DVT), D-dimer, and factor VIII (FVIII) after a first deep venous thrombosis (DVT). METHODS: There were 133 participants with objectively confirmed DVT, of whom 114 were observed for 6 months after completion of anticoagulation. Ultrasound, D-dimer, and FVIII evaluations were undertaken at 6 weeks after completion of anticoagulation and at the end of follow-up. PTS was considered present in those with a score of >=5 on the Villalta scale at either assessment. RESULTS: The cumulative incidence of PTS was 51.8%, with median duration of follow-up of 11 months. Median D-dimer and FVIII in those with PTS were significantly higher at both time points compared with those without. Similarly, residual vein thrombosis and deep venous reflux were more prevalent in those with PTS at both study assessments. On multivariable analysis, only FVIII at end of study remained significantly associated with PTS with an odds ratio of 2.83 (95% confidence interval, 1.09-7.42; P = .034). Ultrasound markers and D-dimer were not significantly associated with PTS after adjustment for age, body mass index, Charlson Index >=1, and proximal extent of DVT. CONCLUSIONS: FVIII activity at end of follow-up was independently associated with PTS, suggesting underlying activation of coagulation. PMID- 26946894 TI - Discussion. PMID- 26946893 TI - The effect of wavelength on endothermal heat-induced thrombosis incidence after endovenous laser ablation. AB - OBJECTIVE: We hypothesized that the incidence of endothermal heat-induced thrombosis (EHIT) depends on the laser wavelength used in endovenous laser ablation (EVLA) of the saphenous veins. METHODS: We identified patients undergoing EVLA in our office from 2005 to 2014 with an 810-nm (hemoglobin specific) or 1470-nm (water-specific) laser. We reviewed the records for age, sex, body mass index, Clinical, Etiologic, Anatomic, and Pathophysiologic (CEAP) class, vein diameter, vein(s) treated, adjunctive phlebectomy, energy delivered, laser pullback times, and EHIT (closure level >=3) development. The Fisher exact test and Pearson chi(2) test were used to evaluate the association between EHIT and the categoric variables. Logistic regression was used to evaluate the relationship between EHIT and the continuous variables. RESULTS: There were 1439 veins ablated in 1109 patients (769 female, 340 male). The great saphenous vein (GSV) was treated in 1332, the small saphenous vein (SSV) in 78, and both in 29 (22 procedures on accessory veins were excluded). The CEAP C class for these patients was 1 in 0, 2 in 616, 3 in 522, 4 in 150, 5 in 51, and 6 in 98, and was not recorded in 2. EHIT occurred in 76 cases (5.28%), in 73 after GSV ablation and in three after SSV ablation. The 810-nm laser was used in 1144 procedures, and EHIT developed in 69 patients (6.0%). The 1470-nm laser was used in 295 procedures, with EHIT developing in seven patients (2.4%; P = .0122 by Fisher exact test). The average energy delivered to the EHIT group (3517 +/- 1998.1 J) was higher than for the non-EHIT group (2825.1 +/- 1491.2 J; P = .0002). The average vein diameter was larger in the EHIT group (9.3 +/- 3.8 mm) than in the non-EHIT group (7.2 +/- 3.3 mm; P = .0001). EHIT occurred in 59 of 837 cases (6.6%) undergoing simultaneous stab phlebectomy compared with 17 of 525 cases (3.1%) undergoing only EVLA (P = .0049). Statistical analysis confirmed the association between EHIT and CEAP class was significant (P = .0001). No differences were seen for age, body mass index, sex, combined bilateral, and multiple or simultaneous GSV and SSV ablations between the two groups. A multivariate analysis confirmed that CEAP class, vein diameter, adjunctive phlebectomy, and laser wavelength were indeed risk factors for post-EVLA EHIT and that energy delivered and pullback time were not. CONCLUSIONS: Water-specific laser fiber wavelength (1470 nm) reduces the risk of EHIT compared with a hemoglobin-specific wavelength (810 nm). CEAP class, simultaneous phlebectomy, and vein diameter >7.5 mm are associated with increased risk of EHIT after EVLA. PMID- 26946895 TI - Radiofrequency ablation or stripping of large-diameter incompetent great saphenous varicose veins with C2 or C3 disease. AB - OBJECTIVE: The objectives of this study were to compare the results of radiofrequency ablation (RFA) and stripping for large-diameter varicose target veins for the period of 1 year, based on a composite end point; to analyze the pain severity on a digital rating scale for 7 days after RFA and stripping; and to detect the factors affecting the level of postoperative pain using the cluster analysis. METHODS: This was a multicenter retrospective cohort study. Two groups, stripping >=14 mm and RFA >=14 mm, of 129 varicose vein disease patients underwent surgical treatment in three specialized clinics. We eliminated symptomatic pathologic reflux with RFA in 64 patients and with stripping in 65 patients. In the postoperative phase, we evaluated the pain level, subcutaneous hemorrhage, and paresthesia. A composite end point with four components was used to analyze the results. These were three clinical adverse effects of the intervention (pain, hemorrhage, and paresthesia) and the technical outcome 1 year after the surgical intervention. RESULTS: The frequency of favorable outcomes was 20 (30.8%) in the stripping >=14 mm group and 61 (95.3%) in the RFA >=14 mm group (P < .0001). The odds ratio for a favorable outcome between the RFA and the stripping groups was 45.8 (95% confidence interval, 44.5-47.0). The pain clusters that were moderate were created by patients after stripping. These clusters show a link between the pain level on the one hand and an increased body mass index and large vein diameter on the other hand. CONCLUSIONS: For large-diameter veins, RFA is superior to stripping in terms of favorable outcomes according to the composite end point chosen. Significant pain after stripping was linked to a large vein diameter and excess weight or adiposis. PMID- 26946896 TI - Factors that influence perforator vein closure rates using radiofrequency ablation, laser ablation, or foam sclerotherapy. AB - OBJECTIVE: Perforator vein closure for the treatment of advanced chronic venous insufficiency has been shown to be effective using radiofrequency ablation (RFA), endovenous laser ablation (EVLA), or ultrasound-guided foam sclerotherapy (UGFS). The objective of the study was to compare these three modalities and attempt to identify factors that might predict treatment failure. METHODS: A retrospective review of a prospectively managed database of perforator vein treatments performed at a three centers within a single institution from February 2013 to July 2014. The modality for perforator closure was left to the discretion of the treating physician. A Duplex scan was performed at 2 weeks after the procedure. Standard statistical methods were used to compare subgroup characteristics. Univariate and multivariate analyses were performed using SAS v9.3. RESULTS: We performed 296 perforator ablations on 112 patients. Superficial venous reflux was appropriately treated before perforator ablation. Of the 296 procedures, 62 (21%) underwent EVLA, 93 (31%) RFA, and 141 (48%) UGFS. The indications for intervention in most patients were C5 and C6 disease (67%). At 2 weeks, closure rates were significantly lower for UGFS (57%) compared with RFA (73%; P = .05) but failed to reach significance compared with EVLA (61%; P = .09). When patients were first treated with UGFS and closure failed, thermal ablation was then successful in 85% (P = .03) of EVLA and 89% (P = .003) of RFAs as a secondary procedure, compared with initial closure rates. Systemic anticoagulation, perforator size, and presence of deep vein reflux did not affect closure rates for any modality. Factors that were predictive of failure were body mass index >50 with closure rates of only 37% for all modalities. There were five postprocedure deep venous thromboses found (5%). One patient had an isolated gastrocnemius thrombus after undergoing UGFS and the other four had focal tibial vein thrombosis without extension into the popliteal vein. CONCLUSIONS: In this study we compared EVLA, RFA, and UGFS for the treatment of incompetent perforating veins. RFA was found to be the most reliable means of perforator closure and was significantly better than UGFS. Morbid obesity (body mass index >50) predicted failure of perforator closure in all groups. Failure of UGFS as an initial treatment led to increased perforator closure when thermal ablation was used as a secondary technique. PMID- 26946897 TI - Successful venous repair and reconstruction for oncologic resections. AB - OBJECTIVE: We report our institutional experience of various venous reconstruction methods during oncologic resections, especially examining the patency of venous reconstructions and the conduits used. METHODS: All patients undergoing venous repair or reconstruction for oncologic resections between 2008 and 2014 were identified by a retrospective search of a prospectively maintained database at a single university hospital. Extent and manner of venous reconstruction and conduit or patch material were recorded. Need for intraoperative venovenous bypass or cardiopulmonary bypass was also recorded. Whereas no prescribed follow-up protocol has been instituted, patency and survival data as available were analyzed. RESULTS: During the study period, 127 patients were identified. Five patients had primary ligations, without limb loss. Of the remaining 122 patients, 77 (63%) underwent primary repairs, 23 (19%) had patch repair, and 22 (18%) had bypasses. Of these, 27 (22%) were for portal vein reconstruction during a Whipple procedure, 47 (39%) were for caval repair during caval thrombectomy in the setting of renal cell cancer, and 28 (23%) were for caval repair during resection for other abdominal malignant neoplasms. Venovenous bypass was used in 16 repairs and cardiopulmonary bypass in 10. The 1-year patency rates were 100% for primary and patch repairs and 86% for bypass graft reconstructions. Occlusions were suffered only in the prosthetic grafts group. There was no limb loss or significant long-term morbidity in patients with occluded grafts. Rate of infection was 0%, and there was no evidence of an increased infection rate in prosthetic or bioprosthetic conduits or patches. Perioperative mortality was 5.5%. CONCLUSIONS: Overall, venous reconstruction for oncologic resection can be done safely with very low complication rates and low perioperative mortality. Prosthetic grafts can be used for most reconstructions with no infections and good patency rates. PMID- 26946898 TI - Comparative study between circumferential method and laser scanner 3D method for the evaluation of arm volume in healthy subjects. AB - OBJECTIVE: Accurate and convenient measurement of upper limb volume is an important clinical tool to measure incidence of lymphedema and response to treatments. There are several methods used to evaluate arm volumes. The most commonly used methods include water displacement and circumferential method (CM), but these techniques have some limitation in use and accuracy that needs the use of a new technique for volume and swelling detection: laser scanner 3D method (LS3D). The aim of the study was to compare, in terms of intra- and interreliability, the CM and LS3D methods for the upper limb measure in a healthy subject group. METHODS: Twelve healthy adults (average age, 29 +/- 5.39 years; average weight, 63.88 +/- 7.97 kg; and average height, 168.38 +/- 7.29 cm) participated. Arm measurements were done using both CM and LS3D methods. Statistical analysis was conducted, and intra- and inter-reliability was investigated. CM and LS3D methods were also compared in terms of level of agreement. RESULTS: Both CM and LS3D methods have a high inter- and intrarater reliability and a satisfactory level of agreement, but we found a statistically significant difference in terms of volume. The laser scanner is a more accurate volume instrument, and our results shown a statistically significant difference of volumes between methods. CONCLUSIONS: Our findings provide LS3D is an innovative method of measuring the upper limb volume that could be used instead of CM. It combines precision, reproducibility, ease of use, and the ability to measure geometrical parameters and shape information of the scanned limb. PMID- 26946899 TI - In vivo evaluation of safety and performance of a nitinol venous stent in an ovine iliac venous model. AB - BACKGROUND: Obstruction of the iliocaval venous outflow tract is a common cause of acute and chronic venous symptoms. Percutaneous stenting is now frequently performed to alleviate obstruction in the central venous system. However, currently used stents were primarily designed for biliary or arterial indications and may not be optimal for use in the venous system. This study evaluated the safety and performance of a novel venous stent (NVS) designed specifically for venous applications in an in vivo venous animal model. METHODS: The study evaluated vascular response and safety of the NVS compared with the Wallstent Stent (WS; Boston Scientific, Marlborough, Mass) at baseline, 56, and 180 days in adult sheep. Four sheep received a single NVS in the iliac vein for acute evaluation, and eight underwent bilateral iliac vein stenting using a single NVS on one side and a single WS on the other for longer-term follow-up. Fluoroscopy and intravascular ultrasound imaging were performed at implantation to identify iliac vein diameters at baseline and again at 56 and 180 days. Both iliac veins from all 56-day and 180-day animals (n = 16) underwent histologic examination. Three sections from each vessel were reviewed for intimal strut coverage, luminal thickening, thrombus, and evidence of venous injury. Student t-tests were used to compare mean iliac vein diameters for the WS and the NVS. RESULTS: Stent placement of the NVS and WS was successful to within 5 mm of the preselected location in all animals. During follow-up, no clinical evidence of stent thrombosis or obstruction >50% occurred in any limb. Sections of the stented vein at 56 and 180 days exhibited complete or nearly complete endothelial cell coverage, no or minimal luminal thrombus, and virtually complete neointimal coverage of every strut. The WS and NVS both caused an increase in iliac vein diameters immediately after stenting. At 180 days, there was no difference in iliac vein diameter or the percentage change in diameter compared with diameters immediately after stenting as measured by venography and intravascular ultrasound. CONCLUSIONS: In an ovine iliac vein model, a new NVS studied to 180 days was free of thrombotic complications and significant luminal stenosis. These data support clinical evaluation of this NVS in appropriately designed human clinical trials. PMID- 26946900 TI - Lymph node content of supraclavicular and thoracodorsal-based axillary flaps for vascularized lymph node transfer. AB - OBJECTIVE: Microvascular transfer of lymph node flaps has recently gained popularity as a treatment for secondary lymphedema often occurring after axillary, groin, or pelvic lymph node dissections. This study aimed to delineate the lymph node contents and pedicle characteristics of the supraclavicular (SC) and thoracodorsal (TD)-based axillary flaps as well as to compare lymph node quantification of surgeon vs pathologist. METHODS: SC and TD flaps were dissected from fresh female cadavers. The surgeon assessed pedicle characteristics, lymph node content, and anatomy. A pathologist assessed all flaps for gross and microscopic lymph node contents. The kappa statistic was used to compare surgeon and pathologist. RESULTS: Ten SC flaps and 10 TD flaps were harvested and quantified. In comparing the SC and TD flaps, there were no statistical differences between artery diameter (3.1 vs 3.2 mm; P = .75) and vein diameter (2.8 vs 3.5 mm; P = .24). The TD flap did have a significantly longer pedicle than the SC flap (4.2 vs 3.2 cm; P = .03). The TD flap was found to be significantly heavier than the SC flap (17.0 +/- 4.8 vs 12.9 +/- 3.3 g; P = .04). Gross lymph node quantity was similar in the SC and TD flaps (2.5 +/- 1.7 vs 1.8 +/- 1.2; P = .33). There was good agreement between the surgeon and pathologist in detecting gross lymph nodes in the flaps (SC kappa = 0.87, TD kappa = 0.61). CONCLUSIONS: The SC and TD flaps have similar lymph node quantity, but the SC flap has higher lymphatic density. A surgeon's estimation of lymph node quantity is reliable and has been verified in this study by comparison to a pathologist's examination. PMID- 26946901 TI - Inferior vena cava stent grafting closure of a high-flow portacaval shunt. AB - Portacaval (PC) shunts can be of congenital or acquired types. Acquired PC shunts are usually created in patients with end-stage liver disease to manage complications associated with portal hypertension or may be part of selected adult-adult living donor liver transplantation procedures to decrease the chance of the small-for-size syndrome. The main potential complication of these acquired high-flow PC shunts is early hepatic encephalopathy. We present a case of a high flow acquired PC shunt after liver transplantation that was complicated by uncontrolled encephalopathy. This was treated by endovascular inferior vena cava stent grafting for shunt closure. PMID- 26946902 TI - Ruptured aneurysm of the external iliac vein. AB - Primary iliac venous aneurysm is an extremely rare vascular abnormality that is associated with the likelihood of rupture, embolism, and thrombosis. In this report, we describe the case of a ruptured aneurysm of the external iliac vein in a 63-year-old woman who was admitted to the emergency department and diagnosed by computed tomography. Computed tomography indicated a 4 * 5-cm ruptured aneurysm in the right external iliac vein that was surrounded by hematoma in the right side of the pelvis. The aneurysm was successfully treated by tangential aneurysmectomy and lateral venorrhaphy. PMID- 26946903 TI - Patency and clinical success 22 years after the Palma procedure. PMID- 26946904 TI - Recurrence of varicose veins after endovenous ablation of the great saphenous vein in randomized trials. AB - BACKGROUND: Recurrence of varicose veins after surgery (REVAS) for saphenous incompetence has been well described after ligation and stripping (L&S) but not after the now most frequently performed method of saphenous ablation, endovenous ablation (EVA). The purpose of this study was to define the overall incidence of REVAS as well as both the sites of reflux and the causes of REVAS through a systematic review and meta-analysis of randomized controlled trials (RCTs) for EVA. These studies have the advantage of prospectively collected data and a uniform duplex follow-up. METHODS: We searched databases (January 1, 2000 through July 1, 2014) for published RCTs evaluating EVA treatment of great saphenous vein (GSV) incompetence that employed endovenous laser ablation or radiofrequency ablation. RCTs were eliminated that (1) did not have follow-up of at least 2 years, (2) did not obtain postoperative duplex scans, (3) did not clearly report the incidence of recurrent varicosities after GSV ablation, and (4) treated the small saphenous or anterior accessory saphenous veins. RESULTS: Of the 68 studies screened, 20 RCTs that employed EVA of the GSV were identified. Eight had a follow-up of at least 2 years, but one was eliminated because of lack of information on both the site and cause of REVAS. The resultant seven RCTs provided eight comparisons (one study compared both types of EVA to a comparator arm): three used radiofrequency ablation, and five employed endovenous laser ablation. Overall recurrent varicose veins developed in 125 limbs after EVA (22%), with no difference in the incidence vs the L&S group (22%) based on the number of limbs available at the time of the development of recurrence for both groups, but this incidence is dependent on the length of follow-up after the initial treatment. The two studies with serial follow-up showed an approximate doubling of REVAS over time for both EVA and L&S. By contrast, the cause of REVAS was different between the two methods. Neovascularization occurred in only two limbs (2%) after EVA vs 18 (18%) in the L&S group. Recanalization was the most common cause of REVAS for EVA (32%; 40 of 125 limbs), followed by the development of anterior accessory saphenous vein incompetence (19%; 23 of 125 limbs). In contrast to other reports, incompetent calf perforating veins were an infrequent cause of REVAS (7%; eight of 125). CONCLUSIONS: There is no difference in the incidence of REVAS for EVA vs L&S, but the causes of REVAS are different with L&S, which has important implications for treatment. PMID- 26946905 TI - Transforming the best care into the standard for care. PMID- 26946906 TI - Left ovarian to left external iliac vein transposition for the treatment of nutcracker syndrome. AB - Nutcracker syndrome represents the constellation of symptoms caused by extrinsic compression of the left renal vein between the aorta and superior mesenteric artery, producing left renal venous outflow obstruction and, frequently, pelvic venous congestion. When severe, the syndrome is most commonly treated by surgical transposition of the left renal vein onto the inferior vena cava or by renal venous stent placement. Each of these treatment modalities is associated with significant immediate and long-term risks. This report provides the details of a simpler technique for the treatment of nutcracker syndrome by transposing the distal left ovarian to the left external iliac vein. PMID- 26946907 TI - Exploring the value of vein center accreditation to the venous specialist. AB - Whereas advancements in medicine offer potential alternatives for better treatment outcomes, these additional therapeutic options can make health care decision-making more difficult for patients, referring physicians, payers, and policy makers. In a complex and ever-changing medical world, quantifying quality care is a challenge, while the need to promote higher quality care is even more important. Many of the key developments in the field have come into common use without the opportunity for formal training for physicians already in practice, regardless of specialty background. These techniques are often learned through postgraduate educational experiences. As a result, it is likely that there is a wide range of knowledge, skill, and experience among physicians offering vein services. Given that many of these services are provided in the office, there is no hospital or institutional supervision or accreditation. In an effort to improve quality of venous care, the Intersocietal Accreditation Commission (IAC) established accreditation standards for superficial vein centers. This review discusses the process used to create the IAC Vein Center guidelines; summarizes important requirements for accreditation and their impact on quality of care; and examines the potential impact of IAC accreditation on patients, providers, and payers. PMID- 26946908 TI - Not so spectacular. PMID- 26946909 TI - Efficacy of prophylactic inferior vena caval filters in prevention of pulmonary embolism in the absence of deep venous thrombosis. AB - There is an increasing use of inferior vena caval filters (IVCFs) as prophylactic activity in the absence of a deep venous thrombosis (DVT) to prevent pulmonary embolism (PE) in high-risk patients. These devices are effective in preventing PE in the presence of lower extremity DVT, when anticoagulation is contraindicated or has failed. An electronic databases search of MEDLINE, PubMed, The Cochrane Library, and Google Scholar for relevant articles listed between January 2000 and December 2014 was performed. The review was confined to patients without a history of previous venous thromboembolism and no evidence of changes on venous duplex imaging suggestive of previous DVT. At present, the use of prophylactic IVCF is predominantly in the trauma, orthopedic, and bariatric surgical populations. Currently, no class I studies exist to support insertion of an IVCF in a patient without an established DVT or PE. However, there is a body of class II and class III evidence that would support the use of IVCFs in certain "high risk" patients who do not have a documented DVT or the occurrence of a PE. Widespread use of prophylactic IVCFs is not supported by evidence and should be discouraged. PMID- 26946910 TI - Current state of the treatment of perforating veins. AB - Perforating veins may play a role in the development of chronic venous insufficiency and ulceration. There is renewed interest in minimally invasive treatments vs historic surgical options. Current indications for treatment, technical success, and evidence for clinical efficacy are summarized. Existing recommendations include perforator closure in Clinical, Etiology, Anatomy, and Pathophysiology class 5 or class 6 disease through percutaneous thermal ablation, subfascial endoscopic perforator surgery, open surgery, or sclerotherapy. Closure rates for percutaneous thermal ablation are reported as 60% to 80% initially. More recanalization and de novo perforator formation have been reported than after thermal saphenous closure. Ultrasound-guided foam sclerotherapy has shown promise in perforator closure and wound healing, but with variable success rates. Regardless of method used, successful closure of perforators appears predictive of wound healing with minimal morbidity. However, the power and design of all studies supporting this are far from robust, and more work is needed. PMID- 26946915 TI - Comparative in vitro study of cementing techniques for implant-supported restorations. AB - STATEMENT OF PROBLEM: Various techniques are used to cement implant-supported restorations. Excess residual cement is a concern. PURPOSE: The purpose of this in vitro study was to evaluate 3 techniques for cementing implant-supported restorations. MATERIAL AND METHODS: Twelve crowns and implant-abutment complexes (IAC) were cemented with 3 techniques: technique 1, a certain amount of cement evenly placed and excess cement removed with an explorer; technique 2, a smaller amount of cement without removal of excess cement; technique 3, a resin abutment replica used for excess cement removal after using a large amount of cement. Each specimen was treated with each technique 3 times. Precementing discrepancies (predis) and postcementing discrepancies (postdis) between IACs and crowns and the postcementing linear roughness (Ra and Rz) on designated junction areas of each specimen were measured. Tensile strength of the specimens was recorded with a universal testing machine at a crosshead speed of 0.5 mm/min. Repeated measures analysis with mixed models was used for differences among the 3 cementing techniques (alpha=.05). RESULTS: Compared with techniques 1 and 2, the specimens with technique 3 showed significantly lower mean differences between postdis and predis and Ra and Rz and higher mean tensile strength (P<.05). CONCLUSIONS: The application of a resin abutment replica for the cementation of implant-supported restorations decreased the discrepancy between the restoration and abutment, reduced cement residue, and increased restoration retention. PMID- 26946917 TI - A digital approach to fabricating an abutment replica to control cement volume in a cement-retained implant prosthesis. AB - If a cement-retained implant prosthesis is placed on an abutment, excess cement should be minimized or removed to prevent periimplant inflammation. Various methods for fabricating an abutment replica have been introduced to maintain tissue health and reduce clean-up time. The purpose of this article is to present an alternative technique for fabricating an abutment replica with computer-aided design/computer-aided manufacturing (CAD/CAM) technology. PMID- 26946916 TI - Digital versus conventional impressions for fixed prosthodontics: A systematic review and meta-analysis. AB - STATEMENT OF PROBLEM: Limited evidence is available for the marginal and internal fit of fixed dental restorations fabricated with digital impressions compared with those fabricated with conventional impressions. PURPOSE: The purpose of this systematic review was to compare marginal and internal fit of fixed dental restorations fabricated with digital techniques to those fabricated using conventional impression techniques and to determine the effect of different variables on the accuracy of fit. MATERIAL AND METHODS: Medline, Cochrane, and EMBASE databases were electronically searched and enriched by hand searches. Studies evaluating the fit of fixed dental restorations fabricated with digital and conventional impression techniques were identified. Pooled data were statistically analyzed, and factors affecting the accuracy of fit were identified, and their impact on accuracy of fit outcomes were assessed. RESULTS: Dental restorations fabricated with digital impression techniques exhibited similar marginal misfit to those fabricated with conventional impression techniques (P>.05). Both marginal and internal discrepancies were greater for stone die casts, whereas digital dies produced restorations with the smallest discrepancies (P<.05). When a digital impression was used to generate stereolithographic (SLA)/polyurethane dies, misfit values were intermediate. The fabrication technique, the type of restoration, and the impression material had no effect on misfit values (P>.05), whereas die and restoration materials were statistically associated (P<.05). CONCLUSIONS: Although conclusions were based mainly on in vitro studies, the digital impression technique provided better marginal and internal fit of fixed restorations than conventional techniques did. PMID- 26946918 TI - Complete-mouth rehabilitation using a 3D printing technique and the CAD/CAM double scanning method: A clinical report. AB - According to evolving computer-aided design/computer-aided manufacturing (CAD/CAM) technology, ceramic materials such as zirconia can be used to create fixed dental prostheses for partial removable dental prostheses. Since 3D printing technology was introduced a few years ago, dental applications of this technique have gradually increased. This clinical report presents a complete mouth rehabilitation using 3D printing and the CAD/CAM double-scanning method. PMID- 26946919 TI - Convergence angles and margin widths of tooth preparations by New Zealand dental students. AB - STATEMENT OF PROBLEM: Fundamental crown preparation principles are taught and are highly regarded in dental education. Whether tooth preparations made by dental students match these principles is unclear. PURPOSE: The purpose of this retrospective study was to report the total occlusal convergence (TOC) and margin widths of crown preparations clinically prepared by New Zealand predoctoral dental students between 2013 and mid-2015. MATERIAL AND METHODS: A total of 371 stereolithography files of tooth preparations for metal ceramic crowns prepared by predoctoral dental students were extracted from the Technical Services Laboratory database at the University of Otago. The files were put through the preparation measuring software Preppr, with outputs being TOC angles in faciolingual and mesiodistal cross sections and margin widths in facial, lingual, distal, and mesial aspects. Means, standard deviations, 95% confidence intervals, and distributions using box and whisker graphs were calculated and presented. RESULTS: The majority of TOC angles fell within an acceptable range of 10 to 20 degrees; however, the angles ranged from undercuts (<0 degrees) to >60 degrees. The majority of margin widths were between 0.5 and 1 mm, while the maximum was approximately 2 mm and the minimum was 0 mm. CONCLUSIONS: Predoctoral dental students in New Zealand are able to produce literature-recommended TOC angles and margin widths for metal ceramic crowns; however, further attention and training are needed for excessive tooth preparations, mainly in the form of large TOC angles. PMID- 26946920 TI - Completely digital approach to an ovate pontic. PMID- 26946922 TI - Growth factor induced proliferation, migration, and lumen formation of rat endometrial epithelial cells in vitro. AB - Endometrial modulation is essential for the preservation of normal uterine physiology, and this modulation is driven by a number of growth factors. The present study investigated the mitogenic, motogenic, and morphogenic effects of epidermal growth factor (EGF) and hepatocyte growth factor (HGF) on rat endometrial epithelial (REE) cells. The REE cells were isolated and cultured and then characterized based on their morphology and their expression of epithelial cell markers. The MTT assay revealed that EGF and HGF induce proliferation of REE cells. Consistent with increased proliferation, we found that the cell cycle regulatory factor Cyclin D1 was also upregulated upon EGF and HGF addition. REE cell migration was prompted by EGF, as observed with the Oris Cell Migration Assay. The morphogenic impact of growth factors on REE cells was studied in a three-dimensional BD Matrigel cell culture system, wherein these growth factors also increased the frequency of lumen formation. In summary, we show that EGF and HGF have a stimulatory effect on REE cells, promoting proliferation, cell migration, and lumen formation. Our findings provide important insights that further the understanding of endometrial regeneration and its regulation. PMID- 26946923 TI - Iran, sanctions, and collaborations. PMID- 26946921 TI - Characterization and comparative analyses of transcriptomes for in vivo and in vitro produced peri-implantation conceptuses and endometria from sheep. AB - An increasing number of reports indicate that in vitro fertilization (IVF) is highly associated with long-term side effects on embryonic and postnatal development, and can sometimes result in embryonic implant failure. While high throughput gene expression analysis has been used to explore the mechanisms underlying IVF-induced side effects on embryonic development, little is known about the effects of IVF on conceptus-endometrial interactions during the peri implantation period. Using sheep as a model, we performed a comparative transcriptome analysis between in vivo (IVO; in vivo fertilized followed by further development in the uterus) and in vitro produced (IVP; IVF with further culture in the incubator) conceptuses, and the caruncular and intercaruncular areas of the ovine endometrium. We identified several genes that were differentially expressed between the IVO and IVP groups on day 17, when adhesion between the trophoblast and the uterine luminal epithelium begins in sheep. By performing Gene Ontology enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, we found that, in the conceptus, differentially expressed genes (DEGs) were associated mainly with functions relating to cell binding and the cell cycle. In the endometrial caruncular area, DEGs were involved in cell adhesion/migration and apoptosis, and in the intercaruncular area, they were significantly enriched in pathways of signal transduction and transport. Thus, these DEGs are potential candidates for further exploring the mechanism underlying IVF/IVP-induced embryonic implant failure that occurs due to a loss of interaction between the conceptus and endometrium during the peri implantation period. PMID- 26946924 TI - Pragmatic trials in critically ill children are CATCHing on. PMID- 26946926 TI - Acute myelitis due to Zika virus infection. PMID- 26946927 TI - Compensated hydrocephalus. PMID- 26946928 TI - Low forced expiratory volume in one second is associated with the history of acute coronary syndrome in patients with organic coronary stenosis. AB - BACKGROUND: Chronic obstructive pulmonary disease often coexists with cardiovascular diseases and airflow limitation has been known as a risk of cardiovascular death. However, the association between airflow limitation and the history of acute coronary syndrome (ACS) in patients with coronary stenosis remains to be determined. METHODS: Study subjects were 271 consecutive patients (age: 70.6+/-9.5 years, sex: 200 males) who underwent coronary angiography and in whom organic coronary stenosis was detected. We collected spirometric data from those patients and investigated the association of the pulmonary function and the history of ACS. We also compared the prevalence of airflow limitation of the present subjects with Japanese epidemiological data that had been previously published. RESULTS: Multivariate analysis with multiple logistic regression analysis showed that the reduced forced expiratory volume in one second (FEV1.0) less than 80% of predicted value was significantly associated with a history of ACS (odds ratio: 2.81, 95% CI: 1.27-6.20, p<0.02) independently of age, sex, body mass index, and classic coronary risk factors including smoking habit, diabetes mellitus, hypertension, and dyslipidemia. Furthermore, the airflow limitation was more prevalent in the present subjects than in the Japanese general population (25.8% vs. 10.9%, p<0.05). CONCLUSIONS: Reduced FEV1.0 is associated with a history of ACS in patients with coronary arterial stenosis irrespective of any coronary risk factors. Airflow limitation is more prevalent in patients with coronary stenosis than in the general population. PMID- 26946929 TI - A new approach to treatment of acute heart failure. AB - Conventional therapies for acute decongestion have yielded uniformly poor results in patients with acute heart failure (AHF). The failure of current strategies may be due to advanced disease in hospitalized patients, incomplete therapy, inherent limitations to existing therapy, or some combination of all three factors. Loop diuretics are the mainstay of current therapy and are in theory not ideal since while producing immediate intravascular volume reduction and relief of symptoms they activate neurohormonal forces that are deleterious to both the heart and the kidney. Ultrafiltration is an alternative to loop diuretics but has not proved advantageous in the setting of renal dysfunction, and if not carefully applied may also aggravate neurohormonal imbalance. In theory decongestive therapy for AHF should remove large volumes of fluid quickly and safely and improve symptoms, particularly dyspnea, without aggravating renal dysfunction or causing neurohormonal activation. Several studies have now suggested that the use of aquaretics such as antagonists to the V2 receptor for arginine vasopressin may be useful as adjunctive therapy in AHF, particularly when renal dysfunction and/or hyponatremia are present. These agents leverage osmotic forces to produce tissue decongestion while causing a water diuresis. They do not adversely affect renal function or neurohormonal balance. Building on the current base of knowledge about outcomes in AHF together with the only study of vasopressin antagonists as short-term monotherapy in chronic heart failure, it would be reasonable to design a trial in AHF in which the use of loop diuretics was minimized in favor of these agents. PMID- 26946925 TI - Impregnated central venous catheters for prevention of bloodstream infection in children (the CATCH trial): a randomised controlled trial. AB - BACKGROUND: Impregnated central venous catheters are recommended for adults to reduce bloodstream infections but not for children because there is not enough evidence to prove they are effective. We aimed to assess the effectiveness of any type of impregnation (antibiotic or heparin) compared with standard central venous catheters to prevent bloodstream infections in children needing intensive care. METHODS: We did a randomised controlled trial of children admitted to 14 English paediatric intensive care units. Children younger than 16 years were eligible if they were admitted or being prepared for admission to a participating paediatric intensive care unit and were expected to need a central venous catheter for 3 or more days. Children were randomly assigned (1:1:1) to receive a central venous catheter impregnated with antibiotics, a central venous catheter impregnated with heparin, or a standard central venous catheter with computer generated randomisation in blocks of three and six, stratified by method of consent, site, and envelope storage location within the site. The clinician responsible for inserting the central venous catheter was not masked to allocation, but allocation was concealed from patients, their parents, and the paediatric intensive care unit personnel responsible for their care. The primary outcome was time to first bloodstream infection between 48 h after randomisation and 48 h after central venous catheter removal with impregnated (antibiotic or heparin) versus standard central venous catheters, assessed in the intention-to treat population. Safety analyses compared central venous catheter-related adverse events in the subset of children for whom central venous catheter insertion was attempted (per-protocol population). This trial is registered with ISRCTN number, ISRCTN34884569. FINDINGS: Between Nov 25, 2010, and Nov 30, 2012, 1485 children were recruited to this study. We randomly assigned 502 children to receive standard central venous catheters, 486 to receive antibiotic-impregnated catheters, and 497 to receive heparin-impregnated catheters. Bloodstream infection occurred in 18 (4%) of those in the standard catheters group, 7 (1%) in the antibiotic-impregnated group, and 17 (3%) assigned to heparin-impregnated catheters. Primary analyses showed no effect of impregnated (antibiotic or heparin) catheters compared with standard central venous catheters (hazard ratio [HR] for time to first bloodstream infection 0.71, 95% CI 0.37-1.34). Secondary analyses showed that antibiotic central venous catheters were better than standard central venous catheters (HR 0.43, 0.20-0.96) and heparin central venous catheters (HR 0.42, 0.19-0.93), but heparin did not differ from standard central venous catheters (HR 1.04, 0.53-2.03). Clinically important and statistically significant absolute risk differences were identified only for antibiotic impregnated catheters versus standard catheters (-2.15%, 95% CI -4.09 to -0.20; number needed to treat [NNT] 47, 95% CI 25-500) and antibiotic-impregnated catheters versus heparin-impregnated catheters (-1.98%, -3.90 to -0.06, NNT 51, 26-1667). Nine children (2%) in the standard central venous catheter group, 14 (3%) in the antibiotic-impregnated group, and 8 (2%) in the heparin-impregnated group had catheter-related adverse events. 45 (8%) in the standard group, 35 (8%) antibiotic-impregnated group, and 29 (6%) in the heparin-impregnated group died during the study. INTERPRETATION: Antibiotic-impregnated central venous catheters significantly reduced the risk of bloodstream infections compared with standard and heparin central venous catheters. Widespread use of antibiotic-impregnated central venous catheters could help prevent bloodstream infections in paediatric intensive care units. FUNDING: National Institute for Health Research, UK. PMID- 26946930 TI - [Postoperative quality of life of patients with a bacterial necrotizing dermis hypodermitis or necrotizing fasciitis, a ten-year study]. AB - INTRODUCTION: Bacterial necrotizing dermis-hypodermitis and necrotizing fasciitis (BNDH-NF) are serious life-threatening soft-tissue infections. The object is to evaluate the quality of life (QOL) of patients who have been operated in our plastic surgery departement. PATIENTS AND METHODS: This is a retrospective study of cases who have been treated at Nancy University Hospital between 2005 and 2014. We analyzed the perioperative data (demographic, clinical, bacteriological), the surgical data (excision, reconstruction) and the follow up data (consequences, mortality). The quality of life was assessed by the Short Form 36 score, and the patients' satisfaction was assessed by a four-level scale. RESULTS: We analyzed 23 patients with an average age of 60 years (28-84 years). The main comorbidities were diabetes (43 %) and obesity (39 %). The average number of surgical excision was about 1.9 (1-5) and the average excised body surface area was about 5 % (1-16 %). The short-term mortality was about 17 %. The mortality rate has been statistically correlated with the surgically excised body surface area (short-term 95 days: P=0.02; and long-term: P=0.003). The statistical analysis has shown a strong relative linear relationship between number of surgical excision and the physical score of QOL (P<0.001), between number of surgical excision and mental score of QOL (P=0.032), and between age and physical score of QOL (P<=0.021). The statistical analysis has also shown a strong relative linear relationship between E. coli infections and physical score of QOL (P=0.01). The percentage of patients' satisfaction in our study was evaluated at 86 %. CONCLUSION: We have found that multiple surgical excisions, an advanced age of patients and E. coli infections have been associated with poor QOL. The mortality rate increased in relation with the importance of excised body surface. In spite of the gravity of these infections, our patients were satisfied of their treatment. PMID- 26946931 TI - A new strategy for prophylactic surgery in BRCA women: Combined mastectomy and laparoscopic salpingo-oophorectomy with immediate reconstruction by double DIEP flap. AB - BACKGROUND: Prophylactic surgery remains the most effective modality for reducing both breast and ovarian cancer rate in woman at high risk, such as BRCA1 or BRCA2. Autologous breast reconstruction with bilateral deep inferior epigastric perforator (DIEP) flap allows predictable and durable results. However, existing two-step approach separating salpingo-oophorectomy and reconstruction could even make DIEP flap impossible, or make insufflation more difficult during laparoscopy. Other authors described one-step procedure but with open laparotomy. The goal of this study was to verify the feasibility of a simultaneous procedure, including laparoscopic salpingo-oophorectomy. METHODS: We included BRCA mutation careers scheduled for simultaneous laparoscopic salpingo-oophorectomy, and bilateral breast reconstruction with DIEP flaps. The first step of the procedure was laparoscopic salpingo-oophorectomy and ports had to be strategically placed to avoid interference with the following procedure. The second step was bilateral breast reconstruction with DIEP flaps. We reviewed medical charts. Surgical procedure was analyzed for duration, revisions and surgical complications. RESULTS: During 1-year period, eight patients agreed to a simultaneous procedure. All of them were BRCA positive, mean age was 38.3years (range, 39-50), and mean BMI was 28.3kg/m(2) (range, 21-33). The mean duration of the entire procedure was 524minutes (range, 405-630) and the mean hospital stay 9.2 days (range, 8-14). There was 100% flap survival. No abdominal wall dehiscence occurred. CONCLUSION: One-step procedure for prophylactic surgery of ovarian and breast hereditary malignancies is feasible. First salpingo-oophorectomy with open laparoscopy then bilateral immediate or delayed breast reconstruction with DIEP flaps can be performed. PMID- 26946932 TI - NOD2 gene variant is a risk factor for postoperative complications in patients with Crohn's disease: A genetic association study. AB - BACKGROUND: Postoperative complications are relatively frequent in Crohn's disease (CD) and several risk factors have been identified. The influence of genetic factors, however is unknown. METHODS: CD patients who underwent CD related bowel resection were identified from the "Nancy IBD cohort." Postoperative complications were defined as intraabdominal infectious complications and non-intraabdominal infectious complications occurring within 90 days after operation. The influence of 203 single nucleotide polymorphisms on postoperative complication rates was analyzed. RESULTS: Of the 137 patients who had undergone a CD-related bowel resection in our cohort, postoperative complications occurred in 34 cases (24.8%). Postoperative intraabdominal infections occurred in 18 cases (13.1%): 12 had anastomotic leakage and 6 had intraabdominal abscesses. In multivariate analysis, current smoker status (odds ratio [OR], 2.71; 95% CI, 1.18-6.21; P = .02) and homozygosity for the risk allele (T) Nucleotide-binding Oligomerization Domain-containing protein 2 (rs5743289; NOD2; OR, 2.07 [95% CI 1.15-3.72]; P = .01) were independent risk factors of postoperative intraabdominal infectious complications. Current smoker status NOD2 homozygosity for the risk allele (T) were not associated with non intraabdominal infectious complications. CONCLUSION: Current smoker status was associated with increased risk of postoperative intraabdominal infectious complications. A novel association between the NOD2 allele and an increased risk of postoperative intraabdominal infectious complications was observed in this study. PMID- 26946933 TI - Trial application of oxygen and carbon isotope analysis in tooth enamel for identification of past-war victims for discriminating between Japanese and US soldiers. AB - Stable isotope analysis has undergone rapid development in recent years and yielded significant results in the field of forensic sciences. In particular, carbon and oxygen isotopic ratios in tooth enamel obtained from human remains can provide useful information for the crosschecking of morphological and DNA analyses and facilitate rapid on-site prescreening for the identification of remains. This study analyzes carbon and oxygen isotopic ratios in the tooth enamel of Japanese people born between 1878 and 1930, in order to obtain data for methodological differentiation of Japanese and American remains from the Second World War. The carbon and oxygen isotopic ratios in the tooth enamel of the examined Japanese individuals are compared to previously reported data for American individuals (born post WWII), and statistical analysis is conducted using a discrimination method based on a logistic regression analysis. The discrimination between the Japanese and US populations, including Alaska and Hawaii, is found to be highly accurate. Thus, the present method has potential as a discrimination technique for both populations for use in the examination of mixed remains comprising Japanese and American fallen soldiers. PMID- 26946934 TI - Fall from a car driving at high speed: A case report. AB - In cases of falls, the key issue for forensic scientists is to determine the manner of death. They must distinguish between accidental falls, suicidal falls, falls including blows and falls caused by a blow. Several strategies have been proposed in the literature to help explain injury patterns. Here, we report an original case of a man who died after jumping from a car moving at high speed. A mathematical and modeling approach was developed to reconstruct the trajectory of the body in order to understand the injury pattern and apparent discrepancy between the high speed of the car from which the victim jumped and the topography of the bone fractures, which were limited to the skull. To define the initial values of the model's parameters, a technical vehicle evaluation and several test jumps at low speed were carried out. We studied in greater detail the trajectory of three characteristic points corresponding to the dummy's center of gravity, head and right foot. Calculations were made with and without the air friction effect to show its influence. Finally, we were successful in modeling the initial trajectory of the body and the variation of its head energy over time, which were consistent with the injuries observed. PMID- 26946936 TI - Estimation of marginal costs at existing waste treatment facilities. AB - This investigation aims at providing an improved basis for assessing economic consequences of alternative Solid Waste Management (SWM) strategies for existing waste facilities. A bottom-up methodology was developed to determine marginal costs in existing facilities due to changes in the SWM system, based on the determination of average costs in such waste facilities as function of key facility and waste compositional parameters. The applicability of the method was demonstrated through a case study including two existing Waste-to-Energy (WtE) facilities, one with co-generation of heat and power (CHP) and another with only power generation (Power), affected by diversion strategies of five waste fractions (fibres, plastic, metals, organics and glass), named "target fractions". The study assumed three possible responses to waste diversion in the WtE facilities: (i) biomass was added to maintain a constant thermal load, (ii) Refused-Derived-Fuel (RDF) was included to maintain a constant thermal load, or (iii) no reaction occurred resulting in a reduced waste throughput without full utilization of the facility capacity. Results demonstrated that marginal costs of diversion from WtE were up to eleven times larger than average costs and dependent on the response in the WtE plant. Marginal cost of diversion were between 39 and 287 ? Mg(-1) target fraction when biomass was added in a CHP (from 34 to 303 ? Mg(-1) target fraction in the only Power case), between -2 and 300 ? Mg(-1) target fraction when RDF was added in a CHP (from -2 to 294 ? Mg(-1) target fraction in the only Power case) and between 40 and 303 ? Mg(-1) target fraction when no reaction happened in a CHP (from 35 to 296 ? Mg(-1) target fraction in the only Power case). Although average costs at WtE facilities were highly influenced by energy selling prices, marginal costs were not (provided a response was initiated at the WtE to keep constant the utilized thermal capacity). Failing to systematically address and include costs in existing waste facilities in decision-making may unintendedly lead to higher overall costs at societal level. To avoid misleading conclusions, economic assessment of alternative SWM solutions should not only consider potential costs associated with alternative treatment but also include marginal costs associated with existing facilities. PMID- 26946935 TI - Co-treatment of fruit and vegetable waste in sludge digesters: Chemical and spectroscopic investigation by fluorescence and Fourier transform infrared spectroscopy. AB - In a previous work co-digestion of food waste and sewage sludge was performed in a pilot apparatus reproducing operating conditions of an existing full scale digester and processing waste mixed sludge (WMS) and fruit and vegetable waste (FVW) at different organic loading rates. An analysis of the relationship among bio-methane generation, process stability and digestate phytotoxicity was conducted. In this paper we considered humification parameters and spectroscopic analysis. Humification parameters indicated a higher not humified fraction (NH) and a lower degree of humification (DH) of FVW with respect to WMS (NH=19.22 and 5.10%; DH=36.65 and 61.94% for FVW and WMS, respectively) associated with their different chemical compositions and with the stabilization process previously undergone by sludge. FVW additions seemed to be favourable from an agronomical point of view since a lower percentage of organic carbon was lost. Fourier transform infrared spectra suggested consumption of aliphatics associated with rising in bio-methane generation followed by accumulation of aliphatics and carboxylic acids when the biogas production dropped. The trend of peaks ratios can be used as an indicator of the process efficiency. Fluorescence intensity of peak B associated with tryptophan-like substances and peak D associated with humic-like substances observed on tridimensional Excitation Emission Matrix maps increased up to sample corresponding to the highest rate of biogas production. Overall spectroscopic results provided evidence of different chemical pathways of anaerobic digestion associated with increasing amount of FVW which led to different levels of biogas production. PMID- 26946937 TI - Callyptide A, a new cytotoxic peptide from the Red Sea marine sponge Callyspongia species. AB - In the course of our continuing efforts to allocate bioactive secondary metabolites from Red Sea marine invertebrates, we have investigated the sponge Callyspongia species. The cytotoxic dichloromethane fraction of the methanolic extract of the sponge afforded a new cytotoxic peptide named callyptide A (1). Its structure was determined by extensive 1D and 2D NMR (COSY, HSQC and HMBC) studies and high-resolution mass spectral determination. The configuration of the amino acids was determined by Marfey's analysis. Callyptide A was found to exhibit growth inhibitory activity when tested against different cancer cell lines. PMID- 26946938 TI - Faecal calprotectin: current usage and perceived beneficial effects of third party funding on rates of colonoscopy by Australian gastroenterologists. AB - BACKGROUND: Studies have suggested a diagnostic role for faecal calprotectin (FC) in patients with gastroenterological disorders. AIM: To investigate Australian gastroenterologists' (GE) views on FC use and to elicit factors that affect physicians' choices. METHODS: Electronic surveys were sent out to 405 consultants and 34 registrars in Australia. Respondents who answered <50% of the survey were excluded. RESULTS: In all, 140 participants provided a >50% response; 73% reported using FC in their clinical practice. Factors cited by non-users in restricting their FC use included cost (24%), availability (47%) and familiarity (18%). Even among users, 69% cited funding as a major deciding factor; 98 and 86% of FC users believed that the test is a reliable method of differentiating between inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) and assessing for mucosal healing in IBD respectively. Of non-users, 78 and 58%, respectively, would use FC to differentiate IBD from IBS and assess for mucosal healing in IBD, if FC testing was Medical Benefits Schedule (MBS) listed. Both users (79%) and non-users (68%) reported that use of FC to defer or avoid colonoscopies was likely if the test was MBS funded. CONCLUSION: Australian GE endorse the use of FC to discriminate between IBD and IBS, to check for mucosal healing in IBD and to reduce colonoscopy rates. Absence of MBS funding is an important factor contributing to the lack of usage of FC, in addition to the lack of familiarity with FC testing and availability. PMID- 26946940 TI - Solution-state conformations of natural products from chiroptical spectroscopy: the case of isocorilagin. AB - Isocorilagin, the alpha-anomer of the ellagitannin corilagin, has been frequently reported in the literature as a constituent of various plant species. Its identification is based mainly on the smaller value for the coupling constant of its anomeric proton when compared to that of corilagin. A careful investigation of the corilagin structure in both methanol and DMSO solutions using NMR, electronic and vibrational CD, and DFT and MD calculations confirmed that isocorilagin is the result of a solvent-induced conformational transition of corilagin, rather than its diastereoisomer. Corilagin changes from B1,4 and (o)S5 conformations of the beta-glucose core in DMSO-d6 to an inverted (1)C4 conformation in methanol-d4, which accounts for NMR observables attributed to the alleged alpha-anomer. This misassignment reinforces the risks of relying upon a single technique for structural elucidation and stereochemical analysis of complex natural products, especially those containing saccharide moieties. PMID- 26946939 TI - Mechanisms involved in xyloglucan catabolism by the cellulosome-producing bacterium Ruminiclostridium cellulolyticum. AB - Xyloglucan, a ubiquitous highly branched plant polysaccharide, was found to be rapidly degraded and metabolized by the cellulosome-producing bacterium Ruminiclostridium cellulolyticum. Our study shows that at least four cellulosomal enzymes displaying either endo- or exoxyloglucanase activities, achieve the extracellular degradation of xyloglucan into 4-glucosyl backbone xyloglucan oligosaccharides. The released oligosaccharides (composed of up to 9 monosaccharides) are subsequently imported by a highly specific ATP-binding cassette transporter (ABC-transporter), the expression of the corresponding genes being strongly induced by xyloglucan. This polysaccharide also triggers the synthesis of cytoplasmic beta-galactosidase, alpha-xylosidase, and beta glucosidase that act sequentially to convert the imported oligosaccharides into galactose, xylose, glucose and unexpectedly cellobiose. Thus R. cellulolyticum has developed an energy-saving strategy to metabolize this hemicellulosic polysaccharide that relies on the action of the extracellular cellulosomes, a highly specialized ABC-transporter, and cytoplasmic enzymes acting in a specific order. This strategy appears to be widespread among cellulosome-producing mesophilic bacteria which display highly similar gene clusters encoding the cytosolic enzymes and the ABC-transporter. PMID- 26946941 TI - Structure of the thermophilic l-Arabinose isomerase from Geobacillus kaustophilus reveals metal-mediated intersubunit interactions for activity and thermostability. AB - Thermophilic l-arabinose isomerase (AI), which catalyzes the interconversion of l arabinose and l-ribulose, can be used to produce d-tagatose, a sugar substitute, from d-galactose. Unlike mesophilic AIs, thermophilic AIs are highly dependent on divalent metal ions for their catalytic activity and thermostability at elevated temperatures. However, the molecular basis underlying the substrate preferences and metal requirements of multimeric AIs remains unclear. Here we report the first crystal structure of the apo and holo forms of thermophilic Geobacillus kaustophilus AI (GKAI) in hexamer form. The structures, including those of GKAI in complex with l-arabitol, and biochemical analyses revealed not only how the substrate-binding site of GKAI is formed through displacement of residues at the intersubunit interface when it is bound to Mn(2+), but also revealed the water mediated H-bonding networks that contribute to the structural integrity of GKAI during catalysis. These observations suggest metal-mediated isomerization reactions brought about by intersubunit interactions at elevated temperatures are responsible for the distinct active site features that promote the substrate specificity and thermostability of thermophilic AIs. PMID- 26946942 TI - CHNQ, a novel 2-Chloro-1,4-naphthoquinone derivative of quercetin, induces oxidative stress and autophagy both in vitro and in vivo. AB - Quercetin (Qc) shows strong antitumor effects but has limited clinical application due to poor water solubility and bioavailability. In a screening of novel semi-synthetic derivatives of Qc, 3,7-dihydroxy-2-[4-(2-chloro-1,4 naphthoquinone-3-yloxy)-3-hydroxyphenyl]-5-hydroxychromen-4-one (CHNQ) could ameliorate acetic acid induced acute colitis in vivo more efficiently than Qc. Since inflammation contributes to colorectal cancer (CRC), we have hypothesized that CHNQ may have anti-cancer effects. Using CRC cell lines HCT-116 and HT-29, we report that CHNQ was three-fold more cytotoxic than Qc along with a robust induction of apoptosis. As expected from naphthoquinones such as CHNQ, a strong induction of oxidative stress was observed. This was accompanied by reactive oxygen species (ROS) induced autophagy marked by a dramatic increase in the lipidation of LC3, decreased activation of Akt/PKB, acidic vesicle accumulation and puncta formation in HCT-116 cells treated with CHNQ. Interestingly, an incomplete autophagy was observed in HT-29 cells where CHNQ treatment led to LC3 lipidation, but not the formation of acidic vacuoles. CHNQ-induced cytotoxicity, ROS formation and autophagy were also detected in vivo in Saccharomyces cerevisiae strain RDKY3615 (WinstonS288C background). Overall, we propose that CHNQ can induce cancer cell death through the induction of oxidative stress, and may be examined further as a potential chemotherapeutic drug. PMID- 26946943 TI - Glutamine protects cardiomyocytes from hypoxia/reoxygenation injury under high glucose conditions through inhibition of the transforming growth factor-beta1 Smad3 pathway. AB - Activation of transforming growth factor-beta1 (TGF-beta1)-Smad3 pathway aggravates myocardial ischemia/reperfusion injury (IRI). We previously showed that glutamine (Gln) protects cardiomyocytes from hypoxia/reoxygenation (H/R) injury under high glucose (HG) conditions. The aim of this study was to investigate whether Gln exerts its protective effect in H/R via inhibiting TGF beta1-Smad3 pathway. In vitro, H9c2 rat cardiomyocytes were treated with Gln with HG (33 mM) and/or H/R. We also performed in vivo experiments in which we treated normal and diabetic rats with Gln or solvent control following IRI. We assessed protein levels of TGF-beta1, total Smad3, phosphorylated (p)-Smad3 and cleaved caspase-3 in H9c2 cells and rat myocardium by Western blotting. H9c2 cells treated with HG + H/R exhibited high apoptosis rates, as well as a highly activated TGF-beta1-Smad3 pathway. TGF-beta1 receptor inhibitor (SB431542) or Smad3 inhibitor (SIS3) reduced HG + H/R induced apoptosis. Similarly, Gln supplementation alleviated apoptosis and decreased p-Smad3 levels. However, Gln's protective effect was significantly weakened by TGF-beta1. Diabetic rats treated with Gln had improved hemodynamics, smaller infarct size after IRI, and a significant decrease in TGF-beta1-Smad3 pathway activation. We conclude that Gln inhibits HG + H/R induced activation of the TGF-beta1-Smad3 pathway and decreases cell apoptosis in cardiomyocytes. PMID- 26946945 TI - Commentary to "Barriers to participation in surgical randomized controlled trials in pediatric urology: A qualitative study of key stakeholder perspectives". PMID- 26946944 TI - Structural analysis of Centrolobium tomentosum seed lectin with inflammatory activity. AB - A glycosylated lectin (CTL) with specificity for mannose and glucose has been detected and purified from seeds of Centrolobium tomentosum, a legume plant from Dalbergieae tribe. It was isolated by mannose-sepharose affinity chromatography. The primary structure was determined by tandem mass spectrometry and consists of 245 amino acids, similar to other Dalbergieae lectins. CTL structures were solved from two crystal forms, a monoclinic and a tetragonal, diffracted at 2.25 and 1.9 A, respectively. The carbohydrate recognition domain (CRD), metal-binding site and glycosylation site were characterized, and the structural basis for mannose/glucose-binding was elucidated. The lectin adopts the canonical dimeric organization of legume lectins. CTL showed acute inflammatory effect in paw edema model. The protein was subjected to ligand screening (dimannosides and trimannoside) by molecular docking, and interactions were compared with similar lectins possessing the same ligand specificity. This is the first crystal structure of mannose/glucose native seed lectin with proinflammatory activity isolated from the Centrolobium genus. PMID- 26946946 TI - British Association of Paediatric Urologists consensus statement on the management of the neuropathic bladder. AB - INTRODUCTION: A large number of children with spina bifida develop a neuropathic bladder and this group of patients still forms the largest group of children who require urological management. Although there are published guidelines on the management of the neuropathic bladder, they are not specific to children. It is unsurprising, therefore, that the initial investigation, assessment and management of children with spina bifida vary considerably. The 2014 British Association of Paediatric Urologists (BAPU) meeting was devoted to the management of the neuropathic bladder. The aim was to produce a consensus on the appropriate investigation and management of a child with a neuropathic bladder. METHODS AND MATERIALS: A questionnaire was devised and the members were polled on their current practice. Six paediatric urology fellows presented an evidence-based literature review on different aspects of the neuropathic bladder. At the end of the session, the members of the organisation present were polled again using the same questions. RESULTS: The BAPU felt that the use of urodynamics in the neuropathic bladder should be selectively determined by clinical parameters. Regarding CIC, the group was evenly split between universal use or only when poor emptying was established. Oxybutinin was the first-line anticholinergic of choice. Most paediatric urologists routinely used Botox and were happy to use it repeatedly. The surgical intervention most frequently employed was determined to be an ileocystoplasty, with most surgeons deferring the need for surveillance cystoscopy until at least 10 years after surgery. CONCLUSION: It was felt that a consensus statement is not a guideline or a way to establish best practice; however, it serves as a way of surveying current practice and providing a benchmark for clinicians involved in the management of these patients. PMID- 26946947 TI - Simultaneous Detection of Tumor Cell Apoptosis Regulators Bcl-2 and Bax through a Dual-Signal-Marked Electrochemical Immunosensor. AB - B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X protein (Bax) are often used to monitor the apoptosis of tumor cells and evaluate cancer drug effect. In this work, a novel sandwich-type dual-signal-marked electrochemical biosensor was fabricated for simultaneous detection of Bcl-2 and Bax proteins. Reduced graphene oxide (RGO) layers were used as substrate to immobilize Bcl-2 and Bax antibodies for further capturing target antigens. CdSeTe@CdS quantum dots (QDs) and Ag nanoclusters (NCs) with antibody modification and mesoporous silica amplification were used as signal probes, which were proportional to the amount of Bcl-2 and Bax antigens. Mesoporous SiO2 can provide a larger surface area, more effectively charged by ethylene imine polymer or poly(diallyldimethylammonium chloride) to adsorb more probes. The Bcl-2 and Bax proteins were determined indirectly by the detection of oxidation peak currents of Cd and Ag using anodic stripping voltammetry, showing a good linear relationship in the protein concentration range from 1 ng/mL to 250 ng/mL. The detection limit of trace protein level was ~0.5 fmol. The biosensor was further introduced to investigate Bcl-2 and Bax expressions from nilotinib-treated chronic myeloid leukemia K562 cells. With the increase of drug dosage and incubation time, the up-regulation for Bax and down regulation for Bcl-2 were observed, which indicated that the apoptosis level of K562 cells could be regulated by Bcl-2 family. The ratio of Bax/Bcl-2 was further calculated for evaluation of its drug effect and apoptosis level. The limited cell amount for detection reached less than 1 * 10(3) cells, much lower than traditional methods. Furthermore, completely independent detection step and stable acid solutions containing Ag(+) and Cd(2+) for long-time storage contribute to reducing the error from the sample differences and avoiding the potential errors from the photodegradation of fluorescent probes, enzymolysis of DNA, or inactivation of enzyme during an excess experimental period. PMID- 26946948 TI - Ceftaroline fosamil treatment outcomes compared with standard of care among hospitalized patients with complicated skin and soft tissue infections. AB - AIM: Compare clinical and cost outcomes associated with ceftaroline fosamil with other commonly used antibiotics in complicated skin and soft tissue infections. METHODS: Retrospective analysis of hospital records from 2010 to 2013 in Premier's Perspective comparative database for adults with complicated skin and soft tissue infection treated with intravenous ceftaroline fosamil, vancomycin, daptomycin, linezolid or tigecycline. Length of stay, inpatient costs and mortality were compared between propensity score-matched treatment groups. RESULTS & CONCLUSION: Compared with the other commonly used antibiotics, matched patients in the ceftaroline fosamil treatment group had an equivalent (1%) or lower (compared with linezolid, 2%) in-hospital mortality rate, and significantly lower (p < 0.001) average unadjusted and regression-adjusted length of stay and inpatient costs (savings of $3398.80 compared with daptomycin). PMID- 26946949 TI - Comparative effectiveness of primary PCI versus fibrinolytic therapy for ST elevation myocardial infarction: a review of the literature. AB - AIM: To compare the effectiveness of primary percutaneous coronary intervention (pPCI) and fibrinolytic therapy (FL) for the acute management of ST elevation myocardial infarction (STEMI). METHODS: A review of guidelines and PubMed literature comparing clinical outcomes of patients with STEMI treated with pPCI or FL. RESULTS: Earlier trials reported reduced mortality and reinfarction with pPCI. Recent randomized data suggest similar outcomes for delayed pPCI compared with FL, especially in geographically remote areas. Guidelines recommend pPCI as the preferred reperfusion strategy for STEMI, if available within 120 mins of first medical contact. CONCLUSION: pPCI is the preferred treatment strategy for STEMI. However, FL with subsequent percutaneous coronary intervention remains a viable option for those in rural areas. PMID- 26946950 TI - Survival in unresectable AJCC stage I and II HCC and the effect of DEB-TACE: SEER versus tertiary cancer center cohort study. AB - AIM: To evaluate overall survival (OS) in unresectable American Joint Committee on Cancer (AJCC) stage I/II hepatocellular carcinoma (HCC) treated with drug eluting-bead transarterial chemoembolization (DEB-TACE) versus best supportive care. MATERIALS & METHODS: OS in consecutive patients with AJCC stage I/II unresectable HCC diagnosed in 2005-2010 who underwent DEB-TACE and similar patients from SEER with no surgery/radiation recommended/performed was evaluated. RESULTS: Median OS from HCC diagnosis was 28.9 months (DEB-TACE) versus 10.0 months (SEER), p < 0.0001. Median OS was 36.3 months (DEB-TACE) versus 12.0 months (SEER) in AJCC I, and 27.9 months (DEB-TACE) versus 10.0 months (SEER) in AJCC II, p < 0.0001. Significant independent prognostic factors for OS were single primary tumor, no vascular invasion, normal alpha-fetoprotein and DEB TACE. CONCLUSION: DEB-TACE in patients with unresectable AJCC stage I/II HCC was a significant independent prognostic factor for greater OS in a population-based study. PMID- 26946951 TI - Is the use of esomeprazole in gastroesophageal reflux disease a cost-effective option in Poland? AB - OBJECTIVES: To compare the cost-effectiveness of therapy of gastroesophageal reflux disease with esomeprazole and other proton pump inhibitors (PPIs) in Poland. MATERIALS & METHODS: Studies comparing esomeprazole with other PPIs in the treatment of erosive esophagitis, non-erosive reflux disease and gastroesophageal reflux disease maintenance therapy were systematically reviewed. 9 randomized clinical trials were selected, meta-analyses were conducted. Cost data derived from Polish Ministry of Health and Pharmacies in Wroclaw. RESULTS: In the treatment of erosive esophagitis esomeprazole was significantly more effective than other PPIs. Both for 4- and 8-week therapy respective incremental cost-effectiveness ratio values were acceptably low. Differences in effectiveness of non-erosive reflux disease therapy were not significant. The replacement of pantoprazole 20 mg with more effective esomeprazole 20 mg in the 6-month maintenance therapy was associated with a substantially high incremental cost effectiveness ratio. PMID- 26946952 TI - Home-based interventions for black patients with uncontrolled hypertension: a cluster randomized controlled trial. AB - AIM: Assess the comparative effectiveness of two blood pressure (BP) control interventions for black patients with uncontrolled hypertension. PATIENTS & METHODS: A total of 845 patients were enrolled in a three-arm cluster randomized trial. On admission of an eligible patient, field nurses were randomized to usual care, a basic or augmented intervention. RESULTS: Across study arms there were no significant 12 months differences in BP control rates (primary outcome) (25% usual care, 26% basic intervention, 22% augmented intervention); systolic BP (143.8 millimeters of mercury [mmHg], 146.9 mmHG, 143.9 mmHG, respectively); medication intensification (47, 43, 54%, respectively); or self-management score (18.7, 18.7, 17.9, respectively). Adjusted systolic BP dropped more than 10 mmHg from baseline to 12 months (155.5-145.4 mmHg) among all study participants. CONCLUSION: Neither the augmented nor basic intervention was more effective than usual care in improving BP control, systolic BP, medication intensification or patient self-management. Usual home care yielded substantial improvements, creating a high comparative effectiveness threshold. CLINICAL TRIAL REGISTRATION: NCT00139490. PMID- 26946956 TI - Inflammatory response of TLR4 deficient spleen macrophages (CRL 2471) to Brucella abortus S19 and an isogenic DeltamglA deletion mutant. AB - Brucellosis is a worldwide distributed zoonosis caused by members of the genus Brucella. One of them, Brucella abortus, is the etiological agent of bovine brucellosis. With the attenuated strain B. abortus S19 a vaccine is available. However, both, virulence (safety) and the ability to induce a protective B and T cell response (efficacy) have to be tested in suitable assays before successful use in the field. For this purpose, several macrophage cell lines of various origins have been used while splenic macrophages are the preferred host cells in vivo. We here characterized the in vitro response of the murine splenic macrophage cell line CRL 2471(I-13.35) to B. abortus. This cell line still depends on the presence of colony-stimulating factor 1 (CSF1) and is derived from LPS resistant (TLR4 deficient) C3H/HeJ mice. For infection the vaccine strain B. abortus S19A as well as the formerly described isogenic deletion mutant B. abortus S19A DeltamglA 3.14 were used. While numbers of viable bacteria did not differ significantly between the vaccine strain and the deletion mutant at 6h post infection, a higher bacterial load was measured in case of the mutant at 24h and 48h after infection. This was also true, when IFNgamma was used for macrophage activation. A comprehensive gene expression profile of macrophages was analysed 6 and 24h after infection by means of an RT-PCR based gene expression array. The mutant strain B. abortus S19A DeltamglA 3.14 elicited a stronger cellular response of the splenic macrophages as compared to the parental vaccine strain. This was most prominent for the pro-inflammatory cytokines IL-1alpha, IL 1beta, TNF-alpha and IL6 as well as for the chemokine ligands CXCL1, CXCL2, CXCL10, CCL2, CCL5, CCL7, CCL17 and the co-stimulatory molecules CD40 and ICAM1. While these differences were also present in IFNgamma-stimulated macrophages, an addition of IFNgamma after infection not only resulted in a dramatic increase of the translation of the afore mentioned genes but also resulted in the translation of IFNbeta1, IL12beta, MIP1alpha and beta (CCL3, CCL4), NOS2 (and SOD2) and FAS. CONCLUSION: The TLR4 deficient murine splenic macrophage cell line CRL 2471 was used for the first time for the characterization of macrophage-Brucella interaction to investigate the pre-immune phase of brucellosis in vitro. Typical pro-inflammatory cytokines and certain surface receptors were differentially induced by B. abortus S19 A and an isogenic DeltamglA deletion mutant in vitro. This model may be useful for further studies to characterize the inflammatory response of splenic macrophages to intracellular gram-negative bacteria avoiding cell responses to soluble LPS. PMID- 26946957 TI - Discovery of a Biological Mechanism of Active Transport through the Tympanic Membrane to the Middle Ear. AB - Otitis media (OM) is a common pediatric disease for which systemic antibiotics are often prescribed. While local treatment would avoid the systemic treatment side-effects, the tympanic membrane (TM) represents an impenetrable barrier unless surgically breached. We hypothesized that the TM might harbor innate biological mechanisms that could mediate trans-TM transport. We used two M13 bacteriophage display biopanning strategies to search for mediators of trans-TM transport. First, aliquots of linear phage library displaying 10(10th) 12mer peptides were applied on the TM of rats with active bacterial OM. The middle ear (ME) contents were then harvested, amplified and the preparation re-applied for additional rounds. Second, the same naive library was sequentially screened for phage exhibiting TM binding, internalization and then transit. Results revealed a novel set of peptides that transit across the TM to the ME in a time and temperature dependent manner. The peptides with highest transport capacities shared sequence similarities. Historically, the TM was viewed as an impermeable barrier. However, our studies reveal that it is possible to translocate peptide linked small particles across the TM. This is the first comprehensive biopanning for the isolation of TM transiting peptidic ligands. The identified mechanism offers a new drug delivery platform into the ME. PMID- 26946958 TI - Does Transcranial Alternating Current Stimulation Induce Cerebellum Plasticity? Feasibility, Safety and Efficacy of a Novel Electrophysiological Approach. AB - BACKGROUND: Cerebellum-brain functional connectivity can be shaped through different non-invasive neurostimulation approaches. In this study, we propose a novel approach to perturb the cerebellum-brain functional connectivity by means of transcranial alternating current stimulation (tACS). METHODS: Twenty-five healthy individuals underwent a cerebellar tACS protocol employing different frequencies (10, 50, and 300 Hz) and a sham-tACS over the right cerebellar hemisphere. We measured their after-effects on the motor evoked potential (MEP) amplitude, the cerebellum-brain inhibition (CBI), the long-latency intracortical inhibition (LICI), from the primary motor cortex of both the hemispheres. In addition, we assessed the functional adaptation to a right hand sequential tapping motor task. RESULTS: None of the participants had any side-effect. Following 50 Hz-tACS, we observed a clear contralateral CBI weakening, paralleled by a MEP increase with a better adaptation to frequency variations during the sequential tapping. The 300 Hz-tACS induced a contralateral CBI strengthening, without significant MEP and kinematic after-effects. The 10 Hz-tACS conditioning was instead ineffective. CONCLUSIONS: We may argue that tACS protocols could have interfered with the activity of CBI-sustaining Purkinje cell, affecting motor adaptation. Our safe approach seems promising in studying the cerebellum-brain functional connectivity, with possible implications in neurorehabilitative settings. PMID- 26946960 TI - Reply to Koleva-Kolarova et al. PMID- 26946959 TI - Purification of thermostable alpha-galactosidase from Irpex lacteus and its use for hydrolysis of oligosaccharides. AB - A monomeric alpha-galactosidase (ILGI) from the mushroom Irpex lacteus was purified 94.19-fold to electrophoretic homogeneity. ILGI exhibited a specific activity of 18.36 U mg(-1) and demonstrated a molecular mass of 60 kDa in sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). ILGI was optimally active at 80 degrees C and pH 5.0, and it was stable over a temperature range of 4-70 degrees C and a wide pH range of 2.0-12.0. ILGI was completely inactivated by Ag(+) and Hg(2+) ions and N-bromosuccinimide (NBS). Moreover, ILGI exhibited good resistance to proteases. Galactose acted as a noncompetitive inhibitor with Ki and Kis of 3.34 and 0.29 mM, respectively. The alpha-galactosidase presented a broad substrate specificity, which included p-nitrophenyl alpha-D galactopyranoside (pNPGal), melibiose, stachyose, and raffinose with Km values of 1.27, 3.24, 7.1, and 22.12 mM, correspondingly. ILGI exhibited efficient and complete hydrolysis to raffinose and stachyose. The aforementioned features of this enzyme suggest its potential value in food and feed industries. PMID- 26946961 TI - Role of surgery in patients with focally progressive gastrointestinal stromal tumors resistant to imatinib. AB - The benefits of surgery for focally progressive gastrointestinal stromal tumor (GIST) during imatinib therapy are still in discussion. The aim of this study was to compare the outcomes of surgical resection of progressive lesions following tyrosine kinase inhibitor (TKI) therapy (S group) or TKI therapy alone (NS group) in GIST patients. We retrospectively investigated 57 patients with focally progressive GIST during imatinib therapy who were treated in Zhongshan hospital, Fudan University. Progression-free survival (PFS) and overall survival (OS) in the S group were significantly longer than those in the NS group. Among S group, the patients with R0 resection showed longer PFS than R2 resection; however, no difference was found between these two groups. Moreover, PFS and OS were not different in the NS-S group compared with S group. On multivariate analysis, surgery is an independent prognostic factor for longer PFS and OS. Our study supports the decision of treating GIST patients who were focally resistant to imatinib with surgery resection based on its benefit. PMID- 26946963 TI - Swamp cancer: a case of human pythiosis and review of the literature. AB - Pythiosis is an infection caused by the aquatic oomycete Pythium insidiosum. Commonly known as 'swamp cancer' in veterinary pathology, pythiosis is now considered an emerging human disease associated with significant morbidity and mortality. However, because clinical information is limited, many healthcare providers, including dermatologists, are unfamiliar with this diagnosis. To increase awareness of this life-threatening infection, a case of cutaneous pythiosis is presented. We describe a middle-aged man with acute myeloid leukaemia who presented with necrotizing haemorrhagic plaques on his thighs after a weekend of freshwater boating. Histological examination of a biopsy specimen showed invasive fungal hyphae associated with dense perivascular inflammation and vessel damage. Diagnostic testing on tissue culture revealed growth of P. insidiosum. Despite multiple debridements and antifungal therapy, the patient died within 2 weeks of presentation. There are four clinical presentations reported in human pythiosis. Pythium insidiosum infection should be considered in any patient with a suggestive exposure history and fungal elements found on histological examination or in culture. Identification of the organism can be difficult, so polymerase chain reaction and serological assays can be useful in making a diagnosis. To improve clinical outcomes, early combination therapy with antifungals and surgery is needed. PMID- 26946962 TI - Melatonin Pathway and Atenolol-Related Glucose Dysregulation: Is There a Correlation? AB - Lower melatonin level, melatonin receptor gene variations, and atenolol treatment are associated with glucose dysregulation. We investigated whether atenolol related glucose and melatonin changes are correlated, and whether single nucleotide polymorphisms (SNPs) in melatonin candidate genes contribute to interindividual variation in glucose change. Hypertensive Caucasians (n = 232) from the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) study treated with atenolol for 9 weeks were studied. Urinary 6-sulfatoxymelatonin (aMT6s) was measured pre- and posttreatment and normalized to urinary creatinine. Pharmacogenetic effects on glucose change of 160 SNPs in 16 melatonin candidate genes were assessed with multiple linear regression. Atenolol was associated with increased glucose (1.8 +/- 10.1mg/dl, P = 0.02) and decreased aMT6s (-4.5 +/- 10.1 ng/mg, P < 0.0001). However, the aMT6s change was not correlated with post atenolol glucose change. SNP rs11649514 in PRKCB was associated with glucose change (P = 1.0*10(-4)). PRKCB is involved in the melatonin-insulin regulatory pathway, and may be important in mediating clinically meaningful atenolol-related hyperglycemia. PMID- 26946964 TI - 5-HT(1A) receptor antagonist improves behavior performance of delirium rats through inhibiting PI3K/Akt/mTOR activation-induced NLRP3 activity. AB - Postoperative delirium is a common complication that often results in poor outcomes in surgical and elderly patients. Accumulating evidences suggest that the pathophysiology of delirium results from multiple neurotransmitter system dysfunctions. To further clarify the effects of the selective serotonin (5-HT) (1A) antagonist WAY-100635 on the behaviors in scopolamine induced-delirium rats and to explore the molecular mechanism, in this study, we investigated the change of monoamine levels in the cerebrospinal fluid (CSF) and different brain regions using high-performance liquid chromatography and assessed the behavioral retrieval of delirium rats treated with WAY-100635. It was found that 5-hydroxy-3 indoleacetic acid (5-HIAA), 3,4-dihydroxyphenylacetic acid, and homovanillic acid concentrations in the CSF of scopolamine-induced delirium rats were significantly increased, among which 5-HIAA was also increased in hippocampus and basolateral amygdala (BLA), and 5-HT(1A) receptor was significantly higher in the hippocampuses and BLA than other brain regions. Furthermore, intrahippocampus and intra-BLA stereotactic injection of WAY-100635 improved the delirium-like behavior of rats. Mechanistically, after WAY-100635 treatment, significant reduction of IL-1beta release into CSF and NOD-like receptor family, pyrin domain containing 3 (NLRP3) expression, phosphorylated phosphatidylinositol-3-kinase (PI3K), protein kinase B (AKT), and S6K was observed. Altogether, these results suggest that delirium rats induced by scopolamine may be correlated with an increased cerebral concentration of 5-HT and dopamine neurotransmitters system; the selective 5-HT(1A) antagoniszts can reverse the delirium symptoms at some extent through tendering PI3K/Akt/mammalian target of rapamycin complex 1 (mTOR) activation-induced NLRP3 activity and then reducing IL-1beta release. PMID- 26946965 TI - Hospital survival upon discharge of ill-neonates transported by ground or air ambulance to a tertiary center. AB - OBJECTIVE: To evaluate the differences in hospital survival between modes of transport to a tertiary center in Colombia for critically ill neonates. METHODS: Observational study of seriously ill neonates transported via air or ground, who required medical care at a center providing highly complex services. Data on sociodemographic, clinical, the Transport Risk Index of Physiologic Stability (TRIPS), and mode of transport were collected. Patients were described, followed by a bivariate analysis with condition (live or dead) at time of discharge as the dependent variable. A multiple Poisson regression with robust variance model was used to adjust associations. RESULTS: A total of 176 neonates were transported by ambulance (10.22% by air) over six months. The transport distances were longer by air (median: 237.5km) than by ground (median: 11.3km). Mortality was higher among neonates transported by air (33.33%) than by ground (7.79%). No differences in survival were found between the two groups when adjusted by the multiple model. An interaction between mode of transport and distance was observed. Live hospital discharge was found to be associated with clinical severity upon admittance, birth weight, hemorrhaging during the third trimester, and serum potassium levels when admitted. CONCLUSIONS: Mode of transport was not associated with the outcome. In Colombia, access to medical services through air transport is a good option for neonates in critical condition. Further studies would determine the optimum distance (time of transportation) to obtain good clinical outcomes according type of ambulance. PMID- 26946966 TI - Comparison of two dose regimens of ibuprofen for the closure of patent ductus arteriosus in preterm newborns. AB - OBJECTIVE: To compare the efficacy of intravenous ibuprofen at high (20-10 10mg/kg/dose) and low doses (10-5-5mg/kg/dose) the closure of patent ductus arteriosus in preterm newborns. METHODS: A cohort study with historical control of newborns that received high- and low-dose intravenous ibuprofen, from 2010 to 2013 in a neonatal intensive care unit, for closure of the patent ductus arteriosus, documented by echocardiography. Secondary outcomes included the number of ibuprofen cycles, incidence of bronchopulmonary dysplasia, necrotizing enterocolitis, changes in renal function, and death. RESULTS: Seventy-seven patients received three doses of ibuprofen for the treatment of patent ductus arteriosus, with 33 receiving high-dose and 44 low-dose therapy. The ductus closed after the first cycle in 25 (56.8%) low-dose patients and in 17 (51.5%) high-dose patients (p>0.99). Sixteen patients received a second cycle of ibuprofen, and the ductus closed in 50% after low-dose and in 60% after high-dose therapy (p>0.99). Seven patients required surgery for ductus closure, 13.6% in the low-dose group and 3% in the high-dose group (p=0.22). Thirty-nine patients developed bronchopulmonary dysplasia, 50% in the low-dose group and 51.5% in the high-dose group (p>0.99). Twenty-two (50%) low-dose patients died vs. 15 (45.5%) high-dose patients (p=0.86). CONCLUSIONS: There was no difference in closure of the ductus arteriosus or occurrence of adverse effects between the two dose regimens. PMID- 26946968 TI - Genetic diversity and phylogenetic analysis of two Tunisian bivalves (Mactridae) Mactra corallina (Linnaeus, 1758) and Eastonia rugosa (Helbling, 1799) based on COI gene sequences. AB - A partial sequence of mitochondrial cytochrome c oxidase subunit I (COI) was used as a genetic marker for a genetic diversity and phylogenetic analysis (DNA barcoding) of two Mactridae species, Mactra corallina and Eastonia rugosa, collected from the Tunisian coast. These Mactridae species could be distinguished by DNA barcoding techniques and they will be considered as monophyletic clades with the Neighbor-Joining (NJ) tree. The genetic structure detected that E. rugosa presents three haplotypes with a high frequency of HER1 (0.89). However, M. corralina shared 14 haplotypes. The haplotypic diversity (H) was equal to 0.205 and 0.954, respectively, for E. rugosa and M. corallina. While the nucleotide diversity (pi) was higher for M. corallina (pi=0.0818), the mismatch distribution showed a unimodal curve for E. rugosa (a recent sudden demographic expansion) and a multimodal distribution for M. corallina (size stability). PMID- 26946967 TI - A double-blinded randomized trial on growth and feeding tolerance with Saccharomyces boulardii CNCM I-745 in formula-fed preterm infants. AB - OBJECTIVE: The use of probiotics is increasingly popular in preterm neonates, as they may prevent necrotizing enterocolitis sepsis and improve growth and feeding tolerance. There is only limited literature on Saccharomyces boulardii CNCM I-745 (S. boulardii) in preterm infants. METHOD: A prospective, randomized, case controlled trial with the probiotic S. boulardii (50mg/kg twice daily) was conducted in newborns with a gestational age of 30-37 weeks and a birth weight between 1500 and 2500g. RESULTS: 125 neonates were enrolled; 63 in the treatment and 62 in the control group. Weight gain (16.14+/-1.96 vs. 10.73+/-1.77g/kg/day, p<0.05) and formula intake at maximal enteral feeding (128.4+/-6.7 vs. 112.3+/ 7.2mL/kg/day, p<0.05) were significantly higher in the intervention group. Once enteral feeding was started, the time needed to reach full enteral feeding was significantly shorter in the probiotic group (0.4+/-0.1 vs. 1.7+/-0.5 days, p<0.05). There was no significant difference in sepsis. Necrotizing enterocolitis did not occur. No adverse effects related to S. boulardii were observed. CONCLUSION: Prophylactic supplementation of S. boulardii at a dose of 50mg/kg twice a day improved weight gain, improved feeding tolerance, and had no adverse effects in preterm infants >30 weeks old. PMID- 26946969 TI - European Network for Patient Safety and Quality of Care: PaSQ. PMID- 26946970 TI - Rattling the cage and opening the door. AB - I share with Poulin-Dubois and with Sabbagh, Koenig and Kuhlmeier the conviction that more research is needed on the mechanisms supporting selective social learning in infants and children. However, my plea is more specific: for research that tests domain-specific hypotheses about mechanism against domain-general hypotheses derived from other fields of cognitive science. Many, but not all, of these alternative hypotheses relate to domain-general mechanisms of attention. PMID- 26946971 TI - [Place of indocyanine green coupled with fluorescence imaging in research of breast cancer sentinel node]. AB - The sentinel node has a fundamental role in the management of early breast cancer. Currently, the double detection of blue and radioisotope is recommended. But in common practice, many centers use a single method. However, with a single detection, the risk of false negatives and the identification failure rate increase to a significant extent and the number of sentinel lymph node detected and removed is not enough. Furthermore, the tracers used until now show inconveniences. The purpose of this work is to present a new method of detection, using the green of indocyanine coupled with fluorescence imaging, and to compare it with the already existing methods. The method combined by fluorescence and isotopic is reliable, sure, of fast learning and could constitute a good strategy of detection. The major interest is to obtain a satisfactory number of sentinel nodes. The profit could be even more important for overweight patients. The fluorescence used alone is at the moment not possible. Wide ranging studies are necessary. The FLUOTECH, randomized study of 100 patients, comparing the isotopic method of double isotope technique and fluorescence, is underway to confirm these data. PMID- 26946972 TI - Potentiation of acid-sensing ion channel activity by peripheral group I metabotropic glutamate receptor signaling. AB - Glutamate activates peripheral group I metabotropic glutamate receptors (mGluRs) and contributes to inflammatory pain. However, it is still not clear the mechanisms are involved in group I mGluR-mediated peripheral sensitization. Herein, we report that group I mGluRs signaling sensitizes acid-sensing ion channels (ASICs) in dorsal root ganglion (DRG) neurons and contributes to acidosis-evoked pain. DHPG, a selective group I mGluR agonist, can potentiate the functional activity of ASICs, which mediated the proton-induced events. DHPG concentration-dependently increased proton-gated currents in DRG neurons. It shifted the proton concentration-response curve upwards, with a 47.3+/-7.0% increase of the maximal current response to proton. Group I mGluRs, especially mGluR5, mediated the potentiation of DHPG via an intracellular cascade. DHPG potentiation of proton-gated currents disappeared after inhibition of intracellular Gq/11 proteins, PLCbeta, PKC or PICK1 signaling. Moreover, DHPG enhanced proton-evoked membrane excitability of rat DRG neurons and increased the amplitude of the depolarization and the number of spikes induced by acid stimuli. Finally, peripherally administration of DHPG dose-dependently exacerbated nociceptive responses to intraplantar injection of acetic acid in rats. Potentiation of ASIC activity by group I mGluR signaling in rat DRG neurons revealed a novel peripheral mechanism underlying group I mGluRs involvement in hyperalgesia. PMID- 26946973 TI - Unilateral absence of pulmonary artery concomitant with chronic pulmonary thromboembolism in an adult patient. PMID- 26946974 TI - Association between the gut microbiota and diet: Fetal life, early childhood, and further life. AB - Gut microbiota establishment and further microbiota shifts are very important for maintaining host health throughout life. There are some factors, including genetics, the mother's health and diet, delivery mode, breast or formula feeding, that may influence the gut microbiota. By the end of approximately the first 3 y of life, the gut microbiota becomes an adult-like stable system. Once established, 60 to 70% of the microbiota composition remains stable throughout life, but 30 to 40% can be altered by changes in the diet and other factors such as physical activity, lifestyle, bacterial infections, and antibiotic or surgical treatment. Diet-related factors that influence the gut microbiota in people of all ages are of great interest. Nutrition may have therapeutic success in gut microbiota correction. This review describes current evidence concerning the links between gut microbiota composition and dietary patterns throughout life. PMID- 26946975 TI - Hierarchical carbon nanopetal/polypyrrole nanocomposite electrodes with brush like architecture for supercapacitors. AB - Hierarchical 3D nanocomposite electrodes with tube brush-like morphology are synthesized by electrochemically depositing polypyrrole (PPY) on carbon nanopetal (CNP) coated carbon fibers (CFs). Initially CNPs are synthesized on CF substrate by chemical vapour deposition. The CNPs synthesized on CF (CNPCF) are further used as an electrically conducting large surface area bearing template for the electropolymerization of PPY in order to fabricate CNPCF-PPY nanocomposite electrodes for supercapacitors (SCs). The CF in CNPCF-PPY nanocomposite functions as (i) a mechanical support for the CNPs, (ii) a current collector for the SC cell and also (iii) to prevent the agglomeration of CNPs within the CNPCF-PPY nanocomposite. Transmission electron microscopy and scanning electron microscopy are used to examine the surface morphology of CNPCF-PPY nanocomposites. The chemical structure of the nanocomposites is analysed by Fourier transform infrared spectroscopy. X-Ray photoelectron spectroscopy has been used to understand the chemical bonding states of the hierarchical CNPCF-PPY nanocomposites. The electrochemical properties of symmetric type CNPCF-PPY SC cells are examined by electrochemical impedance spectroscopy, cyclic voltammetry and galvanostatic charge-discharge measurements. The hierarchical CNPCF-PPY SC exhibits a maximum gravimetric capacitance of 280.4 F g(-1) and an area specific capacitance of 210.3 mF cm(-2) at a current density of 0.42 mA cm(-2). The CNPCF PPY SC cell exhibits good cycling stability of more than 5000 cycles. The present study proclaims the development of a novel lightweight SC with high-performance. PMID- 26946976 TI - Why Be Temperate: Lessons from Bacteriophage lambda. AB - Many pathogens have evolved the ability to induce latent infections of their hosts. The bacteriophage lambda is a classical model for exploring the regulation and the evolution of latency. Here, I review recent experimental studies on phage lambda that identify specific conditions promoting the evolution of lysogenic life cycles. In addition, I present specific adaptations of phage lambda that allow this virus to react plastically to variations in the environment and to reactivate its lytic life cycle. All of these different examples are discussed in the light of evolutionary epidemiology theory to disentangle the different evolutionary forces acting on temperate phages. Understanding phage lambda adaptations yield important insights into the evolution of latency in other microbes, including several life-threatening human pathogens. PMID- 26946978 TI - Microplastic as a Vector for Chemicals in the Aquatic Environment: Critical Review and Model-Supported Reinterpretation of Empirical Studies. AB - The hypothesis that 'microplastic will transfer hazardous hydrophobic organic chemicals (HOC) to marine animals' has been central to the perceived hazard and risk of plastic in the marine environment. The hypothesis is often cited and has gained momentum, turning it into paradigm status. We provide a critical evaluation of the scientific literature regarding this hypothesis. Using new calculations based on published studies, we explain the sometimes contrasting views and unify them in one interpretive framework. One explanation for the contrasting views among studies is that they test different hypotheses. When reframed in the context of the above hypothesis, the available data become consistent. We show that HOC microplastic-water partitioning can be assumed to be at equilibrium for most microplastic residing in the oceans. We calculate the fraction of total HOC sorbed by plastics to be small compared to that sorbed by other media in the ocean. We further demonstrate consistency among (a) measured HOC transfer from microplastic to organisms in the laboratory, (b) measured HOC desorption rates for polymers in artificial gut fluids (c) simulations by plastic inclusive bioaccumulation models and (d) HOC desorption rates for polymers inferred from first principles. We conclude that overall the flux of HOCs bioaccumulated from natural prey overwhelms the flux from ingested microplastic for most habitats, which implies that microplastic ingestion is not likely to increase the exposure to and thus risks of HOCs in the marine environment. PMID- 26946977 TI - Pseudomonas aeruginosa Evolutionary Adaptation and Diversification in Cystic Fibrosis Chronic Lung Infections. AB - Pseudomonas aeruginosa populations undergo a characteristic evolutionary adaptation during chronic infection of the cystic fibrosis (CF) lung, including reduced production of virulence factors, transition to a biofilm-associated lifestyle, and evolution of high-level antibiotic resistance. Populations of P. aeruginosa in chronic CF lung infections typically exhibit high phenotypic diversity, including for clinically important traits such as antibiotic resistance and toxin production, and this diversity is dynamic over time, making accurate diagnosis and treatment challenging. Population genomics studies reveal extensive genetic diversity within patients, including for transmissible strains the coexistence of highly divergent lineages acquired by patient-to-patient transmission. The inherent spatial structure and spatial heterogeneity of selection in the CF lung appears to play a key role in driving P. aeruginosa diversification. PMID- 26946979 TI - Electrical conductivity and permittivity maps of brain tissues derived from water content based on T1 -weighted acquisition. AB - PURPOSE: To develop an electrical properties tomography (EPT) technique that can provide in vivo electrical conductivity and permittivity images of biological tissue without performing complex-valued radiofrequency field measurements. THEORY AND METHODS: Electrical conductivity and permittivity images are modeled as a monotonic function of tissues' water content (W) under the principle of Maxwell's mixture theory. Water content maps are estimated from two spin-echo images having different repetition times (TRs). For the modeling functions, physically measured parameters (electrical properties, water content, and T1 ) of brain cerebrospinal fluid (CSF), gray matter, and white matter are used as landmark literature references. The formulations are validated by a developed electrolyte-protein phantom and by human brain studies at 3 Tesla (T). RESULTS: The electrical properties (EPs) of the phantom estimated by the proposed method match well with the values measured on the bench. The conductivity and permittivity maps from all experiments show uncompromised spatial resolution without boundary artifacts and higher contrast when compared with water content maps. CONCLUSIONS: Human brain and phantom EP images suggest that water content is a dominating factor in determining the electrical properties of tissues. Despite possible literature inaccuracies, the proposed method offers EP maps that can provide complementary information to current approaches, to facilitate EPT scans in clinical applications. Magn Reson Med 77:1094-1103, 2017. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 26946980 TI - Safety of Fluticasone plus Salmeterol in Asthma--Reassuring Data, but No Final Answer. PMID- 26946981 TI - Amyloid Hypothesis: Is There a Role for Antiamyloid Treatment in Late-Life Depression? AB - Antidepressants have modest efficacy in late-life depression (LLD), perhaps because various neurobiologic processes compromise frontolimbic networks required for antidepressant response. We propose that amyloid accumulation is an etiologic factor for frontolimbic compromise that predisposes to depression and increases treatment resistance in a subgroup of older adults. In patients without history of depression, amyloid accumulation during the preclinical phase of Alzheimer disease (AD) may result in the prodromal depression syndrome that precedes cognitive impairment. In patients with early-onset depression, pathophysiologic changes during recurrent episodes may promote amyloid accumulation, further compromise neurocircuitry required for antidepressant response, and increase treatment resistance during successive depressive episodes. The findings that support the amyloid hypothesis of LLD are (1) Depression is a risk factor, a prodrome, and a common behavioral manifestation of AD; (2) amyloid deposition occurs during a long predementia period when depression is prevalent; (3) patients with lifetime history of depression have significant amyloid accumulation in brain regions related to mood regulation; and (4) amyloid deposition leads to neurobiologic processes, including vascular damage, neurodegeneration, neuroinflammation, and disrupted functional connectivity, that impair networks implicated in depression. The amyloid hypothesis of LLD is timely because availability of ligands allows in vivo assessment of amyloid in the human brain, a number of antiamyloid agents are relatively safe, and there is evidence that some antidepressants may reduce amyloid production. A model of LLD introducing the role of amyloid may guide the design of studies aiming to identify novel antidepressant approaches and prevention strategies of AD. PMID- 26946983 TI - Cutaneous manifestations of IgG4-related disease (RD): A systematic review. AB - BACKGROUND: IgG4-related disease (RD) is a recently described fibroinflammatory condition with both cutaneous and systemic manifestations. To our knowledge, the cutaneous manifestations have not been well characterized or systematically investigated to date in the literature. OBJECTIVE: We sought to describe the cutaneous manifestations of IgG4-RD to guide clinical practice, aid in the diagnosis of IgG4-RD, and contribute to the creation of robust cutaneous diagnostic criteria. METHODS: A systematic search of peer-reviewed publications pertaining to cutaneous manifestations of IgG4-RD yielded 56 cases from 32 case reports and series. The clinical findings among the diagnostic categories were compared. RESULTS: Forty cases of IgG4-RD with cutaneous disease were identified. Cutaneous head and neck involvement was significantly associated with a diagnosis of IgG4-RD (P = .02). Macules and bullae were not described in any of the included cases. Among cases of systemic IgG4-RD, cutaneous head and neck involvement was most common and statistically significantly associated with the diagnosis of IgG4-RD (P = .001). LIMITATIONS: These findings are limited by reporting and publication bias of particular cases and by small sample size. CONCLUSIONS: Papules, plaques, and nodules of the head and neck appear to characterize patients with cutaneous IgG4-RD, which nevertheless usually presents with systemic manifestations. PMID- 26946982 TI - Chronic subordination stress selectively downregulates the insulin signaling pathway in liver and skeletal muscle but not in adipose tissue of male mice. AB - Chronic stress has been associated with obesity, glucose intolerance, and insulin resistance. We developed a model of chronic psychosocial stress (CPS) in which subordinate mice are vulnerable to obesity and the metabolic-like syndrome while dominant mice exhibit a healthy metabolic phenotype. Here we tested the hypothesis that the metabolic difference between subordinate and dominant mice is associated with changes in functional pathways relevant for insulin sensitivity, glucose and lipid homeostasis. Male mice were exposed to CPS for four weeks and fed either a standard diet or a high-fat diet (HFD). We first measured, by real time PCR candidate genes, in the liver, skeletal muscle, and the perigonadal white adipose tissue (pWAT). Subsequently, we used a probabilistic analysis approach to analyze different ways in which signals can be transmitted across the pathways in each tissue. Results showed that subordinate mice displayed a drastic downregulation of the insulin pathway in liver and muscle, indicative of insulin resistance, already on standard diet. Conversely, pWAT showed molecular changes suggestive of facilitated fat deposition in an otherwise insulin-sensitive tissue. The molecular changes in subordinate mice fed a standard diet were greater compared to HFD-fed controls. Finally, dominant mice maintained a substantially normal metabolic and molecular phenotype even when fed a HFD. Overall, our data demonstrate that subordination stress is a potent stimulus for the downregulation of the insulin signaling pathway in liver and muscle and a major risk factor for the development of obesity, insulin resistance, and type 2 diabetes mellitus. PMID- 26946984 TI - Immunosuppressive medication use and risk of herpes zoster (HZ) in patients with systemic lupus erythematosus (SLE): A nationwide case-control study. AB - BACKGROUND: The association between immunosuppressive medication use and herpes zoster (HZ) in patients with systemic lupus erythematosus (SLE) has not been clearly defined. OBJECTIVE: We evaluated the risk of HZ in patients with SLE treated with different immunosuppressants. METHODS: A nationwide population-based case-control study was conducted using the Taiwanese National Health Insurance Research Database. Cases (1555 patients with SLE who developed HZ) and controls (3049 age- and sex-matched patients with SLE but without HZ) were analyzed for use of various immunosuppressive medications in the preceding 3-month period, and dose-response relationships were determined. Logistic regression was performed to estimate the adjusted odds ratio for HZ development. RESULTS: Medications associated with greater HZ risk in patients with SLE included oral corticosteroids, intravenous methylprednisolone, hydroxychloroquine, oral cyclophosphamide, intravenous cyclophosphamide, azathioprine, methotrexate, and mycophenolate mofetil. Combination immunosuppressive therapy was common in patients with SLE and was associated with greatly increased HZ risk. For oral corticosteroids and hydroxychloroquine, the risk of HZ was strongly dependent on the medication dose. LIMITATIONS: This study is retrospective in nature. CONCLUSION: Recent immunosuppressive medication use is associated with increased HZ risk in patients with SLE, particularly those receiving high-dose oral corticosteroids and multiagent immunosuppressive therapy. PMID- 26946985 TI - Doxycycline for prevention of erlotinib-induced rash in patients with non-small cell lung cancer (NSCLC) after failure of first-line chemotherapy: A randomized, open-label trial. AB - BACKGROUND: Rash is a common epidermal growth factor receptor inhibitor-induced toxicity that can impair quality of life and treatment compliance. OBJECTIVE: We sought to evaluate the efficacy of doxycycline in preventing erlotinib-induced rash (folliculitis) in patients with non-small-cell lung cancer. METHODS: This open-label, randomized, prospective, phase II trial was conducted in 147 patients with locally advanced or metastatic non-small-cell lung cancer progressing after first-line chemotherapy, randomized for 4 months with erlotinib alone 150 mg/d per os (control arm) or combined with doxycycline 100 mg/d (doxycycline arm). Incidence and severity of rash, compliance, survival, and safety were assessed. RESULTS: Baseline characteristics of the 147 patients were well balanced in the intent-to-treat population. Folliculitis occurred in 71% of patients in the doxycycline arm and 81% in the control arm (P = .175). The severity of folliculitis and other skin lesions was lower in the doxycycline arm compared with the control arm. Other adverse events were reported at a similar frequency across arms. There was no significant difference in survival between treatment arms. LIMITATIONS: The open-label design of the study and the duration of the treatment with doxycycline are limitations. CONCLUSION: Doxycycline did not reduce the incidence of erlotinib-induced folliculitis, but significantly reduced its severity. PMID- 26946986 TI - Biologic therapy adherence, discontinuation, switching, and restarting among patients with psoriasis in the US Medicare population. AB - BACKGROUND: Studies indicate adherence to biologics among patients with psoriasis is low, yet little is known about their use in the Medicare population. OBJECTIVE: We sought to investigate real-world utilization patterns in a national sample of Medicare beneficiaries with psoriasis initiating infliximab, etanercept, adalimumab, or ustekinumab. METHODS: We conducted a retrospective claims analysis using 2009 through 2012 100% Medicare Chronic Condition Data Warehouse Part A, B, and D files, with 12-month follow-up after index prescription. Descriptive and multivariate analyses were used to examine rates of and factors associated with biologic adherence, discontinuation, switching, and restarting. RESULTS: We examined 2707 patients initiating adalimumab (40.0%), etanercept (37.9%), infliximab (11.7%), and ustekinumab (10.3%); during 12-month follow-up, 38% were adherent and 46% discontinued treatment, with 8% switching to another biologic and 9% later restarting biologic treatment. Being female and being ineligible for low-income subsidies were associated with increased odds of decreased adherence. Outcomes varied by index biologic. LIMITATIONS: Patient reported reasons for nonadherence or gaps in treatment are unavailable in claims data. CONCLUSION: Medicare patients initiating biologics for psoriasis had low adherence and high discontinuation rates. Further investigation into reasons for inconsistent utilization, including exploration of patient and provider decision making and barriers to more consistent treatment, is needed. PMID- 26946988 TI - Chronic paronychia treatment: Square flap technique. AB - BACKGROUND: Chronic paronychia is an inflammatory process of the periungual folds that lasts longer than 6 weeks. It manifests as hypertrophy of the proximal and lateral nailfolds, absence of cuticle, progressive retraction of the proximal nailfold, and onychodystrophy. Surgical treatment is recommended if there has been insufficient response to 6 months of appropriate medical therapies. OBJECTIVE: We describe a new surgical technique that removes the fibrotic tissue without complete excision of the proximal and lateral nailfold, minimizing nailfold retraction and recovery time. METHODS: We present a case series of 34 fingers (9 patients) treated with this new technique. RESULTS: All nailfolds healed well without complications. At the end of the follow-up, all fingers, apart from 2, were relieved of the preoperative symptoms. The length of the ungual plate was maintained in all patients, with no retraction of the nailfolds. LIMITATIONS: Follow-up period of 6 months and small sample size are limitations of this study. CONCLUSION: This surgical technique can provide an alternative treatment for chronic paronychia, with good prognosis during follow up-period and optimal cosmetic results. PMID- 26946987 TI - Psoriasiform eruptions during Kawasaki disease (KD): A distinct phenotype. AB - BACKGROUND: A psoriasis-like eruption develops in a subset of patients with Kawasaki disease (KD). OBJECTIVE: We sought to systematically compare KD associated psoriasiform eruptions with classic psoriasis and the outcomes of KD in children with and without this rash. METHODS: This was a retrospective study of 11 KD cases with a psoriasiform eruption matched 1:2 by age, gender, and ethnicity with psoriasis-only and KD-only controls. Genotyping was performed in 10 cases for a deletion of 2 late cornified envelope (LCE) genes, LCE3C_LCE3B del, associated with increased risk for pediatric-onset psoriasis. RESULTS: Similar to classic psoriasis, KD-associated eruptions were characterized clinically by well-demarcated, scaly pink plaques and histopathologically by intraepidermal neutrophils, suprabasilar keratin 16 expression, and increased Ki 67 expression. They showed less frequent diaper area involvement, more crust and serous exudate, and an enduring remission (91% vs 23% with confirmed resolution; P < .001). Frequency of LCE3C_LCE3B-del and major KD outcomes were similar between cases and controls. LIMITATIONS: The study was limited by the small number of cases, treatment variation, and availability of skin biopsy specimens. CONCLUSIONS: Although the overall clinical and histopathologic findings were similar to conventional psoriasis, this appears to be a distinct phenotype with significantly greater propensity for remission. No adverse effect on KD outcomes was noted. PMID- 26946989 TI - Associations between LGBTQ-affirmative school climate and adolescent drinking behaviors. AB - BACKGROUND: We investigated whether adolescents drank alcohol less frequently if they lived in jurisdictions with school climates that were more affirmative of lesbian, gay, bisexual, transgender, and questioning (LGBTQ) individuals. METHODS: Data from the 2010 School Health Profile survey, which measured LGBTQ school climate (e.g., percentage of schools with safe spaces and gay-straight alliances), were linked with pooled data from the 2005 and 2007 Youth Risk Behavior Survey, which measured sexual orientation identity, demographics, and alcohol use (number of drinking days, drinking days at school, and heavy episodic drinking days) in 8 jurisdictions. Two-level Poisson models tested the associations between school climate and alcohol use for each sexual-orientation subgroup. RESULTS: Living in jurisdictions with more (versus less) affirmative LGBTQ school climates was significantly associated with: fewer heavy episodic drinking days for gay/lesbian (incidence-rate ratio [IRR]=0.70; 95% confidence interval [CI]: 0.56, 0.87; p=0.001) and heterosexual (IRR=0.80; 95% CI: 0.76, 0.83; p<0.001) adolescents; and fewer drinking days at school for adolescents unsure of their sexual orientation (IRR=0.57; 95% CI: 0.35, 0.93; p=0.024). CONCLUSIONS: Fostering LGBTQ-affirmative school climates may reduce certain drinking behaviors for gay/lesbian adolescents, heterosexual adolescents, and adolescents unsure of their sexual orientation. PMID- 26946990 TI - Dose-response relationships between exercise intensity, cravings, and inhibitory control in methamphetamine dependence: An ERPs study. AB - BACKGROUND: The present study integrated behavioral and neuroelectric approaches for determining the dose-response relationships between exercise intensity and methamphetamine (MA) craving and between exercise intensity and inhibitory control in individuals with MA dependence. METHODS: Ninety-two individuals with MA dependence were randomly assigned to an exercise group (light, moderate, or vigorous intensity) or to a reading control group. The participants then completed a craving self-report at four time points: before exercise, during exercise, immediately after exercise, and 50 min after exercise. Event-related potentials were also recorded while the participants completed a standard Go/NoGo task and an MA-related Go/NoGo task approximately 20 min after exercise cessation. RESULTS: The reduction in self-reported MA craving scores of the moderate and vigorous intensity groups was greater than that of the light intensity and control groups during acute exercise as well as immediately and 50 min following exercise termination. Additionally, an inverted-U-shaped relationship between exercise intensity and inhibitory control was generally observed for the behavioral and neuroelectric indices, with the moderate intensity group exhibiting shorter Go reaction times, increased NoGo accuracy, and larger NoGo-N2 amplitudes. CONCLUSIONS: Acute exercise may provide benefits for MA-associated craving and inhibitory control in MA-dependent individuals, as revealed by behavioral and neuroelectric measures. Moderate-intensity exercise may be associated with more positive effects, providing preliminary evidence for the establishment of an exercise prescription regarding intensity for MA dependence. PMID- 26946991 TI - The male factor: Outcomes from a cluster randomized field experiment with a couples-based HIV prevention intervention in a South African township. AB - BACKGROUND: This study examined the effects of the Couples Health CoOp intervention on heavy drinking, condom use, and HIV incidence. METHODS: Thirty neighborhoods from one South African township were cluster randomized into three intervention arms: Couples Health CoOp (CHC), Women's Health CoOp/Men's Health CoOp (WHC/MHC), or a comparison arm. We recruited 290 men from informal drinking establishments who reported drinking alcohol regularly. We also recruited their main heterosexual sex partners. RESULTS: At 6-month follow-up, men in the CHC arm were less likely to report heavy drinking (OR 0.47, 95% CI: 0.25, 0.90) and were more likely to report consistent condom use during the past month (OR 2.66, 95% CI: 1.23, 5.76) than men in the comparison arm. At baseline, 26% of women and 13% of men were HIV-infected; at 6-month follow-up, 16 females and 5 males had seroconverted. HIV incidence was significantly lower among women in the CHC arm (IRR 0.22, 95% CI: 0.04, 1.01) than in the WHC/MHC arm. CONCLUSIONS: A couples based intervention focusing on intersecting risks for HIV can improve biobehavioral outcomes, underscoring the importance of engaging couples together in HIV prevention. PMID- 26946993 TI - Enhanced transparent conducting networks on plastic substrates modified with highly oxidized graphene oxide nanosheets. AB - Atomically thin and two-dimensional graphene oxide (GO) is a very fascinating material because of its functional groups, high transparency, and solution processability. Here we show that highly oxidized GO (HOGO) nanosheets serve as an effective interfacial modifier of transparent conducting films with one dimensional (1D) silver nanowires (AgNWs) and single-walled carbon nanotubes (SWCNTs). Optically transparent and small-sized GO nanosheets, with minimal sp(2) domains, were successfully fabricated by step-wise oxidation and exfoliation of graphite. We demonstrated that under-coated HOGO further decreases the sheet resistance of the SWCNT film top-coated with HOGO by increasing the contact area between the SWCNTs and HOGO nanosheets by generating hole carriers in the SWCNT as a result of charge transfer. Moreover, HOGO nanosheets with AgNWs contribute to the efficient thermal joining of AgNW networks on plastic substrates by limiting the thermal embedding of AgNWs into the plastic surface, resulting in efficient decrease of the sheet resistance. Furthermore, flexible organic photovoltaic cells with GO-modified AgNW anodes on a flexible substrate were successfully demonstrated. PMID- 26946994 TI - The face is the thing: Faces, not emotions, are responsible for chimeric perceptual asymmetry. AB - We used factor analysis to examine relationships among tasks that have previously shown right hemispheric processing asymmetries. We were interested in whether processing emotion displayed by a face constitutes a distinct perceptual process from processing other facial characteristics. Interest in this topic arose after Boles [ 1991 . Factor analysis and the cerebral hemispheres: Pilot study and parietal functions. Neuropsychologia, 29 ( 1 ), 59 - 91 ] found evidence of a common process underlying face processing and then Boles [ 1992 . Factor analysis and the cerebral hemispheres: Temporal, occipital and frontal functions. Neuropsychologia, 30 ( 11 ), 963 - 988 ] found evidence of a distinct process for the processing of the facial emotion. We used seven tasks that measured both face and non-face perception. Analysis of the asymmetries revealed measures from the five face tasks resulted in a single factor, thus failing to support the hypothesis that emotional face perception would involve a separate process from non-emotional face perception. A second factor revealed a separate process underlying enumeration, and a third factor revealed yet another process underlying line bisection. The results indicate that perceiving facial emotion results in right hemisphere processing, and faces as a whole are responsible for such processing. PMID- 26946992 TI - CSF-contacting neurons regulate locomotion by relaying mechanical stimuli to spinal circuits. AB - Throughout vertebrates, cerebrospinal fluid-contacting neurons (CSF-cNs) are ciliated cells surrounding the central canal in the ventral spinal cord. Their contribution to modulate locomotion remains undetermined. Recently, we have shown CSF-cNs modulate locomotion by directly projecting onto the locomotor central pattern generators (CPGs), but the sensory modality these cells convey to spinal circuits and their relevance to innate locomotion remain elusive. Here, we demonstrate in vivo that CSF-cNs form an intraspinal mechanosensory organ that detects spinal bending. By performing calcium imaging in moving animals, we show that CSF-cNs respond to both passive and active bending of the spinal cord. In mutants for the channel Pkd2l1, CSF-cNs lose their response to bending and animals show a selective reduction of tail beat frequency, confirming the central role of this feedback loop for optimizing locomotion. Altogether, our study reveals that CSF-cNs constitute a mechanosensory organ operating during locomotion to modulate spinal CPGs. PMID- 26946995 TI - Enhanced uptake of antibiotic resistance genes in the presence of nanoalumina. AB - Nanomaterial pollution and the spread of antibiotic resistance genes (ARGs) are global public health and environmental concerns. Whether nanomaterials could aid the transfer of ARGs released from dead bacteria into live bacteria to cause spread of ARGs is still unknown. Here, we demonstrated that nano-Al2O3 could significantly promote plasmid-mediated ARGs transformation into Gram-negative Escherichia coli strains and into Gram-positive Staphylococcus aureus; however, bulk Al2O3 did not have this effect. Under suitable conditions, 7.4 * 10(6) transformants of E. coli and 2.9 * 10(5) transformants of S. aureus were obtained from 100 ng of a pBR322-based plasmid when bacteria were treated with nano-Al2O3. Nanoparticles concentrations, plasmid concentrations, bacterial concentrations, interaction time between the nanomaterial and bacterial cells and the vortexing time affected the transformation efficiency. We also explored the mechanisms underlying this phenomenon. Using fluorescence in situ hybridization and scanning electron microscopy, we found that nano-Al2O3 damaged the cell membrane to produce pores, through which plasmid could enter bacterial cells. Results from reactive oxygen species (ROS) assays, genome-wide expression microarray profiling and quantitative real-time polymerase chain reactions suggested that intracellular ROS damaged the cell membrane, and that an SOS response promoted plasmid transformation. Our results indicated the environmental and health risk resulting from nanomaterials helping sensitive bacteria to obtain antibiotic resistance. PMID- 26946996 TI - Effects of benzalkonium chloride on histamine H1 receptor mRNA expression in nasal epithelial cells. AB - OBJECTIVE: To better understand the causes of the exacerbation of rhinitis medicamentosa (RM) induced by oxymetazoline (OMZ) or benzalkonium chloride (BKC), we examined the impact of pretreatment with OMZ or BKC on cultured human nasal epithelial cells. We also examined the effect of mometasone furoate (MF) on the cultured human nasal epithelial cells treated with OMZ or BKC. METHODS: Cells of the human nasal epithelial cell line HNEpC were treated with OMZ or BKC, and the OMZ- and BKC-induced expression of histamine H1 receptor (H1R) mRNA was assayed using real-time polymerase chain reaction. In some experiments, 1.0*10(-5)M MF was added to the HNEpC cells for 24h before treatment with OMZ or BKC. RESULTS: Treatment with OMZ slightly increased the expression level of H1R mRNA in HNEpC cells. This enhanced expression was not significantly reduced by pretreatment with MF. In contrast, treatment with BKC remarkably increased the expression level of H1R mRNA in HNEpC cells. In addition, this enhanced expression was significantly reduced by pretreatment with MF. CONCLUSION: These results suggest that the increased expression of H1R mRNA due to treatment with OMZ or BKC might be one of the factors underlying the exacerbation of symptoms in patients with RM and those complicated with allergic rhinitis. The concomitant use of a nasal steroid might reduce the exacerbation of symptoms caused by BKC, although there remains a risk of developing histamine hypersensitivity from the long-term use of a topical steroid-containing BKC. PMID- 26946998 TI - An Unusual Case of Kirschner Wire Migration in the Foot. AB - We describe a rare case, never before published, of migration of a Kirschner wire used for fusion of the proximal interphalangeal in a lesser toe in a 67-year-old female into the calcaneum. This patient presented to the orthopedic clinic 6 months after elective surgery complaining of pain in her right foot. Radiographs of the foot revealed that the Kirschner wire had migrated toward the calcaneum. Computed tomography of the right foot demonstrated the Kirschner wire within the calcaneum. PMID- 26946999 TI - Post-Traumatic Periprosthetic Tibial and Fibular Fracture After Total Ankle Arthroplasty: A Case Report. AB - Periprosthetic fractures after total ankle arthroplasty are uncommon, with most cases occurring intraoperatively. We describe a post-traumatic periprosthetic fracture of the distal tibia and fibula after total ankle arthroplasty that was treated with minimally invasive plate osteosynthesis. It is important for orthopedic surgeons not only to recognize the risk factors for postoperative periprosthetic total ankle arthroplasty fractures, but also to be familiar with the treatment options available to maximize function and minimize complications. The design of the tibial prosthesis and surgical techniques required to prepare the ankle joint for implantation are important areas of future research to limit the risk of periprosthetic fractures. PMID- 26947000 TI - Use of Cannulated Instruments to Localize the Portals in Anterior Ankle Arthroscopy: A Technique Tip. AB - The use of cannulated instruments under fluoroscopy can improve the localization of the anteromedial and posterolateral portals for use in ankle arthroscopy. This technique is valuable for the less-experienced ankle arthroscopist, in resident education, and for the experienced arthroscopist when surface anatomy palpation and visualization is less than ideal due to soft tissue edema and obesity. PMID- 26947001 TI - Isolated Acute Traumatic Subtalar Dislocations: Review of 13 Cases at a Mean Follow-Up of 6 Years and Literature Review. AB - Isolated acute traumatic subtalar dislocations are quite rare. They correspond to talotarsal dislocation, including the talonavicular and talocalcaneal joints. The purpose of the present study was to evaluate the functional and radiologic outcomes of the treatment of acute traumatic isolated subtalar dislocations. The present retrospective study included 13 patients who had sustained isolated subtalar dislocations during a 10-year period. Of the 13 cases, 10 (76.9%) were medial dislocations and 3 (23.1%) were lateral dislocations. All the patients underwent immediate closed reduction under anesthesia followed by immobilization. No open reduction was required. The mean follow-up period was 72.6 (range 24.4 to 124.8) months. The mean American Orthopaedic Foot and Ankle Society ankle hindfoot score was 80.1 of 100 (range 66 to 90). The score result was good in 69% of cases and poor in 31% of cases. The subtalar mobility was reduced for 8 (61.5%) patients and significantly affected the American Orthopaedic Foot and Ankle Society score (p = .002). Subtalar osteoarthritis was present in 6 (46.1%) cases with talonavicular osteoarthritis in 3 (23.1%) cases. No cases of avascular necrosis of the talus were noted. In accordance with the published data, the prognosis of isolated acute traumatic subtalar dislocations is favorable. Medial dislocations are more frequent than lateral dislocations. Emergent closed reduction makes it possible to remove soft tissue injuries. The risk of post traumatic subtalar osteoarthritis is significant, even without an initial subtalar lesion. A postreduction computed tomography scan will enable the diagnosis of osteochondral lesions. PMID- 26947003 TI - Stroke Impact Scale. PMID- 26947002 TI - Split Fracture of the Posteromedial Tubercle of the Talus: Case Report and Proposed Classification System. AB - We describe a rare case of a fracture of the medial tubercle of the posterior process of the talus in a 16-year-old male athlete who fell during basketball practice. The patient presented to our orthopedic clinic when pain and swelling had persisted despite 2 weeks of anti-inflammatory medication and rest. Computed tomography and magnetic resonance imaging scans revealed a fracture of the posteromedial tubercle of the talus and a small amount of retained fluid in the joint. Immobilization with a below-the-knee cast and non-weightbearing for 4 weeks, with a gradual return to full activity, was successful. At the 1-year follow-up evaluation, the patient expressed no complaints. Fracture of the posteromedial tubercle of the talus will usually result in a misdiagnosis or delayed diagnosis owing to the insidious onset of symptoms. We believe the present fracture configuration resulted from the vertical compression force that occurred on landing by posterior medial ankle impingement in plantarflexion supination, modifying the conventional concept of the posteromedial tubercle fracture. We also present a suggested classification with a flowchart diagram. PMID- 26947004 TI - A randomised trial of an intensive physiotherapy program for patients in intensive care [commentary]. PMID- 26947005 TI - Defining the polyposis/colorectal cancer phenotype associated with the Ashkenazi GREM1 duplication: counselling and management recommendations. AB - Hereditary mixed polyposis is a genetically heterogeneous, autosomal dominant condition with adenomatous, hyperplastic and juvenile polyps. We conducted a comprehensive clinical evaluation of a large Ashkenazi Jewish family with this phenotype and performed extensive genetic testing. As seen in one previous report, a 40 kb duplication upstream of GREM1 segregated with the polyposis/colon cancer phenotype in this kindred. Our study confirms the association of GREM1 with mixed polyposis and further defines the phenotype seen with this mutation. This gene should be included in the test panel for all Jewish patients with mixed polyposis and may be considered in any Ashkenazi patient with unexplained hereditary colon cancer when mutations in other hereditary colon cancer genes have been ruled out. PMID- 26947006 TI - Seismic air gun exposure during early-stage embryonic development does not negatively affect spiny lobster Jasus edwardsii larvae (Decapoda: Palinuridae). AB - Marine seismic surveys are used to explore for sub-seafloor oil and gas deposits. These surveys are conducted using air guns, which release compressed air to create intense sound impulses, which are repeated around every 8-12 seconds and can travel large distances in the water column. Considering the ubiquitous worldwide distribution of seismic surveys, the potential impact of exposure on marine invertebrates is poorly understood. In this study, egg-bearing female spiny lobsters (Jasus edwardsii) were exposed to signals from three air gun configurations, all of which exceeded sound exposure levels (SEL) of 185 dB re 1 MUPa(2) . s. Lobsters were maintained until their eggs hatched and the larvae were then counted for fecundity, assessed for abnormal morphology using measurements of larval length and width, tested for larval competency using an established activity test and measured for energy content. Overall there were no differences in the quantity or quality of hatched larvae, indicating that the condition and development of spiny lobster embryos were not adversely affected by air gun exposure. These results suggest that embryonic spiny lobster are resilient to air gun signals and highlight the caution necessary in extrapolating results from the laboratory to real world scenarios or across life history stages. PMID- 26947007 TI - Role of morphine, miR-212/132 and mu opioid receptor in the regulation of Bdnf in zebrafish embryos. AB - BACKGROUND: Morphine is one of the first-line therapies for the treatment of pain despite its secondary effects. It modifies the expression of epigenetic factors like miRNAs. In the present study, we analyzed miR-212 and miR-132 and their implication in morphine effects in the zebrafish Central Nervous System (CNS) through the regulation of Bdnf expression. METHODS: We used control and knock down zebrafish embryos to assess the effects of morphine in miRNAs 212/132 and mitotic or apoptotic cells by qPCR, immunohistochemistry and TUNEL assay, respectively. Bdnf and TrkB were studied by western blot and through a primary neuron culture. A luciferase assay was performed to confirm the binding of miRNAs 212/132 to mecp2. RESULTS: Morphine exposure decreases miR-212 but upregulates miR-132, as wells as Bdnf and TrkB, and changes the localization of proliferative cells. However, Bdnf expression was downregulated when miRNAs 212/132 and oprm1 were knocked-down. Furthermore, we proved that these miRNAs inhibit mecp2 expression by binding to its mRNA sequence. The described effects were corroborated in a primary neuron culture from zebrafish embryos. CONCLUSIONS: We propose a mechanism in which morphine alters the levels of miRNAs 212/132 increasing Bdnf expression through mecp2 inhibition. oprm1 is also directly involved in this regulation. The present work confirms a relationship between the opioid system and neurotrophins and shows a key role of miR-212 and miR-132 on morphine effects through the regulation of Bdnf pathway. GENERAL SIGNIFICANCE: miRNAs 212/132 are novel regulators of morphine effects on CNS. Oprm1 controls the normal expression of Bdnf. PMID- 26947008 TI - Hydroxytyrosol prevents chondrocyte death under oxidative stress by inducing autophagy through sirtuin 1-dependent and -independent mechanisms. AB - BACKGROUND: Hydroxytyrosol (HT), a major phenolic antioxidant found in olive oil, can afford protection from oxidative stress in several types of non-tumoral cells, including chondrocytes. Autophagy was recently identified as a protective process during osteoarthritis (OA) development and critical for survival of chondrocytes. Therefore we have investigated the possibility to modulate chondrocyte autophagy by HT treatment. METHODS: DNA damage and cell death were estimated in human C-28/I2 and primary OA chondrocytes exposed to hydrogen peroxide. Autophagic flux and mitophagy were monitored by measuring levels and location of autophagy markers through western blot, immunostaining and confocal laser microscopy. Late autophagic vacuoles were stained with monodansylcadaverine. The involvement of sirtuin 1 (SIRT-1) was evaluated by immunohistochemistry, western blot and gene silencing with specific siRNA. RESULTS: HT increases markers of autophagy and protects chondrocytes from DNA damage and cell death induced by oxidative stress. The protective effect requires the deacetylase SIRT-1, which accumulated in the nucleus following HT treatment. In fact silencing of this enzyme prevented HT from promoting the autophagic process and cell survival. Furthermore HT supports autophagy even in a SIRT-1 independent manner, by increasing p62 transcription, required for autophagic degradation of polyubiquitin-containing bodies. CONCLUSIONS: These results support the potential of HT as a chondroprotective nutraceutical compound against OA, not merely for its antioxidant ability, but as an autophagy and SIRT-1 inducer as well. GENERAL SIGNIFICANCE: HT may exert a cytoprotective action by promoting autophagy in cell types that may be damaged in degenerative diseases by oxidative and other stress stimuli. PMID- 26947010 TI - Spin rectification by orbital polarization in Bi-bilayer nanoribbons. AB - We investigate the edge states of quantum spin-Hall phase Bi(111) bilayer nano ribbons (BNRs) and their spin-rectifying effect using first-principles calculations and a non-equilibrium transport method. As low-dimensional materials, BNRs have tunable electronic properties, which are not only dependent on the edge shape, chemical passivation, or external electric fields but also governed by geometrical deformation. Depending on the passivation types, the interaction of the helical edge states in BNRs exhibits various patterns, enabling the valley engineering of the Dirac cones. In addition, the spin texture of the Dirac state is significantly tuned by edge passivation, external electric fields and geometric deformations. We demonstrate that curved BNRs can be used as the spin valves to rectify the electric currents via the edge states. Our results provide a practical way of utilizing two-dimensional topological insulator Bi bilayers for spintronic devices. PMID- 26947009 TI - The signaling pathways underlying starvation-induced upregulation of alpha mannosidase Ams1 in Saccharomyces cerevisiae. AB - BACKGROUND: Cells have evolved the mechanisms to survive nutritional shortages in the environment. In Saccharomyces cerevisiae, alpha-mannosidase Ams1 is known to play a role in catabolism of N-linked free oligosaccharides in the cytosol. Although, this enzyme is also known to be transported selectively from the cytosol to the vacuoles by autophagy, the physiological significance of this transport has not been clarified. METHODS: To elucidate the regulatory mechanism of the activity of Ams1, we assessed the enzymatic activity of the cell free extract of the wild-type and various gene disruptants under different nutritional conditions. In addition, the regulation of Ams1 at both transcription and post translation was examined. RESULTS: The activity of Ams1 was significantly increased upon the depletion of glucose in the medium. Interestingly, the activity of the enzyme was also stimulated by nitrogen starvation. Our data showed that the activity of Ams1 is regulated by the stress responsive transcriptional factors Msn2/4 through the protein kinase A and the target of rapamycin complex 1 pathways. In addition, Ams1 is post-translationally activated by Pep4-dependent processing in the vacuoles. CONCLUSION: Yeast cells monitor extracellular nutrients to regulate mannoside catabolism via the cellular signaling pathway. GENERAL SIGNIFICANCE: This study revealed that intracellular Ams1 activity is exquisitely upregulated in response to nutrient starvation by induced expression as well as by Pep4-dependent enhanced activity in the vacuoles. The signaling molecules responsible for regulation of Ams1 were also clarified. PMID- 26947011 TI - Delayed application of the anesthetic propofol contrasts the neurotoxic effects of kainate on rat organotypic spinal slice cultures. AB - Excitotoxicity due to hyperactivation of glutamate receptors is thought to underlie acute spinal injury with subsequent strong deficit in spinal network function. Devising an efficacious protocol of neuroprotection to arrest excitotoxicity might, therefore, spare a substantial number of neurons and allow later recovery. In vitro preparations of the spinal cord enable detailed measurement of spinal damage evoked by the potent glutamate analogue kainate. Any clinically-relevant neuroprotective treatment should start after the initial lesion and spare networks for at least 24h when cell damage plateaus. Using this strategy, we have observed that the gas anesthetic methoxyflurane provided strong, delayed neuroprotection. It is unclear if this beneficial effect was due to the mechanism of action by methoxyflurane, or it was the consequence of anesthetic depression. To test this hypothesis, we investigated the effect by propofol (commonly injected i.v. for general anesthesia) after kainate excitotoxicity induced on organotypic spinal slices. At 5MUM concentration, propofol significantly attenuated cell death, including neuronal losses and, especially, damage to the highly vulnerable motoneurons. The action by propofol was fully prevented when co-applied with the GABAA antagonist bicuculline, indicating that neuroprotection required intact GABAA receptor function. Although bicuculline per se was not neurotoxic, it largely enhanced the lesional effects of kainate, suggesting that GABAA receptor activity could limit excitotoxicity. Our data might offer an explanation for the beneficial clinical outcome of neurosurgery performed as soon as possible after spinal lesion: we posit that general anesthesia contributes to this outcome, regardless of the type of anesthetic used. PMID- 26947012 TI - Investigation of the identity of the nucleophile initiating the hydrolysis of phosphate esters catalyzed by dinuclear mimics of metallohydrolases. AB - di-Zinc(II) complexes of the ligands 2,6-bis((bis(2-methoxyethyl)amino)methyl)-4 methylphenol (HL1), 2,6-bis(bis(hydroxyethyl)aminomethyl)-4-methylphenol (HL2) and 2,6-bis((hydroxyethyl)(methoxyethyl)-aminomethyl)-4-methylphenol (HL3) have been prepared and characterized. The three ligands differ in their donor types, having ether donors (HL1), alkoxido donors (HL2) and both ether and alkoxido donors (HL3). These differences allowed an investigation into the role of the potential nucleophiles in the hydrolysis reaction with the phosphodiester substrate bis(2,4-dinitrophenyl)phosphate (BDNPP). In addition, the di-Mg(II) complex of ligand HL2 was prepared in order to examine the potential for Mg(II) to replace Zn(II) in these biomimetic systems. Kinetically relevant pKa values for the three di-Zn(II) complexes were determined to be 7.14 and 9.21 for [Zn2(L1)(CH3COO)2](PF6), 7.90 and 10.21 for [Zn2(L2)(CH3COO)2](BPh4) and 8.43 and 10.69 for [Zn2(L3)(CH3COO)2](BPh4). At the respective pH optima the relevant catalytic parameters are kcat=5.44(0.11)*10-5s-1 (Km=5.13(0.92) mM), 2.60(0.87)*10-4s-1 (Km=5.49(1.51) mM) and 1.53(0.27)*10-4s-1 (Km=2.14(0.50) mM) for [Zn2(L1)(CH3COO)2](PF6), [Zn2(L2)(CH3COO)2](BPh4) or [Zn2(L3)(CH3COO)2](BPh4), respectively. The di-Mg(II) complex was found to be unreactive in the hydrolysis reaction with BDNPP under the conditions employed. Computational methods using the [Zn2(L2)(CH3COO)2](BPh4) complex were used to discriminate between different possible mechanistic pathways. The DFT calculations indicate that an alkoxido-mediated pathway in the complexes formed with ligands L2 or L3 is unlikely, because it induces significant distortion of the Zn2(L) unit; a direct attack by a coordinated hydroxide is preferred in each of the three systems studied here. The calculations also revealed the important role of ligand structural rigidity. PMID- 26947013 TI - Postoperative Outcomes of Children With Tetralogy of Fallot, Pulmonary Atresia, and Major Aortopulmonary Collaterals Undergoing Reconstruction of Occluded Pulmonary Artery Branches. AB - BACKGROUND: Patients with tetralogy of Fallot, pulmonary atresia, and major aortopulmonary collaterals (TOF/PA/MAPCAs) undergoing unifocalization surgery are at risk for prolonged postoperative respiratory failure. We sought to understand whether patients undergoing reconstruction and incorporation of occluded pulmonary arterial branches were at risk for worse postoperative outcomes. METHODS: We performed a retrospective chart review to identify patients who underwent unifocalization or unifocalization revision with incorporation of occluded pulmonary artery branches. Patients with and without occluded branches were compared, with a focus on clinical outcomes. RESULTS: We studied 92 patients who underwent unifocalization procedures between 2010 and 2014, 17 (18%) of whom underwent reconstruction of occluded pulmonary artery branches. Patients with occluded vessels were more likely to require staged unifocalization procedures, although more than two thirds of this cohort eventually underwent complete intracardiac repair. Durations of mechanical ventilation, intensive care, hospital stay, and the need for early reoperation were similar between the two groups. CONCLUSIONS: Occluded pulmonary arterial branches can be safely recruited into the pulmonary vasculature in patients with TOF/PA/MAPCAs without a significant difference in postoperative outcomes compared with patients who did not have an occluded branch. Incorporation of occluded branches may also facilitate ultimate complete intracardiac repair in this complex population of patients. PMID- 26947015 TI - Piloting a quality improvement (QI) project in final year general practice trainees: setting up and evaluating the processes. AB - There is limited evidence on the effectiveness of educational initiatives designed to support and encourage training doctors to undertake quality improvement projects (QIP) at their workplace. The purpose of this study was to examine the feasibility of the RCGP proposal to implement a QIP in the final year of training. An educational intervention was designed and delivered to a group of GP trainees six months before the end of their training. This comprised facilitated small group work, web resources and guiding paperwork to structure meetings between the trainee and trainer to monitor and support the development of the project. The projects were marked and presented to a panel. The evaluation included a questionnaire to trainees, interviews with trainees and trainers and a focus group with facilitators and markers. The results suggest that the educational intervention was feasible and acceptable to GP trainees, trainers and practices. It resulted in an increase in confidence of GP trainees in understanding quality improvement methodologies and in undertaking QIP in general practices. In particularly, GP trainees highly valued the experience and leadership skills gained through engagement in change management which was viewed as advantageous for their future careers. Facilitated small group meetings and support from others in the practice were most useful resources supporting the development of QIP. PMID- 26947018 TI - Liver transplantation for hepatolithiasis: Is terminal hepatolithiasis suitable for liver transplantation? AB - Hepatolithiasis, originally as oriental cholangiohepatitis, especially prevails in Asia, but globalization and intercontinental migration have also converted the endemic disease dynamics around the world. Characterized by its high incidence of ineffective treatment and recurrence, hepatolithiasis, always, poses a therapeutic challenge to global doctors. Although the improved surgical and non surgical techniques have evolved over the past decade, incomplete clearance and recurrence of calculi are always so common and disease-related mortality from liver failure and concurrent cholangiocarcinoma still exists in the treatment of hepatolithiasis. In the late stage of hepatolithiasis, is it suitable for liver transplantation (LT)? Herein, we propose a comprehensive review and analysis of the LTx currently in potential use to treat hepatolithiasis. In our subjective opinion, and as is objective from the literatures so far, also given the strict indications, LT remains one of the definitive treatments for terminal hepatolithiasis. PMID- 26947016 TI - Topoisomerase IIalpha mediates TCF-dependent epithelial-mesenchymal transition in colon cancer. AB - Aberrant T-cell factor (TCF) transcription is implicated in the majority of colorectal cancers (CRCs). TCF transcription induces epithelial-mesenchymal transition (EMT), promoting a tumor-initiating cell (TIC) phenotype characterized by increased proliferation, multidrug resistance (MDR), invasion and metastasis. The data presented herein characterize topoisomerase IIalpha (TopoIIalpha) as a required component of TCF transcription promoting EMT. Using chromatin immunoprecipitation (ChIP) and protein co-immunoprecipitation (co-IP) studies, we show that TopoIIalpha forms protein-protein interactions with beta-catentin and TCF4 and interacts with Wnt response elements (WREs) and promoters of direct target genes of TCF transcription, including: MYC, vimentin, AXIN2 and LEF1. Moreover, both TopoIIalpha and TCF4 ChIP with the N-cadherin promoter, which is a new discovery indicating that TCF transcription may directly regulate N-cadherin expression. TopoIIalpha N-terminal ATP-competitive inhibitors, exemplified by the marine alkaloid neoamphimedine (neo), block TCF activity in vitro and in vivo. Neo effectively inhibits TopoIIalpha and TCF4 from binding WREs/promoter sites, whereas protein-protein interactions remain intact. Neo inhibition of TopoIIalpha dependent TCF transcription also correlates with significant antitumor effects in vitro and in vivo, including the reversion of EMT, the loss of TIC-mediated clonogenic colony formation, and the loss of cell motility and invasion. Interestingly, non-ATP-competitive inhibitors of TopoIIalpha, etoposide and merbarone, were ineffective at preventing TopoIIalpha-dependent TCF transcription. Thus, we propose that TopoIIalpha participation in TCF transcription may convey a mechanism of MDR to conventional TopoIIalpha inhibitors. However, our results indicate that TopoIIalpha N-terminal ATP-binding sites remain conserved and available for drug targeting. This article defines a new strategy for targeted inhibition of TCF transcription that may lead to effective therapies for the treatment of CRC and potentially other Wnt-dependent cancers. PMID- 26947017 TI - The impact of chromosomal translocation locus and fusion oncogene coding sequence in synovial sarcomagenesis. AB - Synovial sarcomas are aggressive soft-tissue malignancies that express chromosomal translocation-generated fusion genes, SS18-SSX1 or SS18-SSX2 in most cases. Here, we report a mouse sarcoma model expressing SS18-SSX1, complementing our prior model expressing SS18-SSX2. Exome sequencing identified no recurrent secondary mutations in tumors of either genotype. Most of the few mutations identified in single tumors were present in genes that were minimally or not expressed in any of the tumors. Chromosome 6, either entirely or around the fusion gene expression locus, demonstrated a copy number gain in a majority of tumors of both genotypes. Thus, by fusion oncogene coding sequence alone, SS18 SSX1 and SS18-SSX2 can each drive comparable synovial sarcomagenesis, independent from other genetic drivers. SS18-SSX1 and SS18-SSX2 tumor transcriptomes demonstrated very few consistent differences overall. In direct tumorigenesis comparisons, SS18-SSX2 was slightly more sarcomagenic than SS18-SSX1, but equivalent in its generation of biphasic histologic features. Meta-analysis of human synovial sarcoma patient series identified two tumor-gentoype-phenotype correlations that were not modeled by the mice, namely a scarcity of male hosts and biphasic histologic features among SS18-SSX2 tumors. Re-analysis of human SS18-SSX1 and SS18-SSX2 tumor transcriptomes demonstrated very few consistent differences, but highlighted increased native SSX2 expression in SS18-SSX1 tumors. This suggests that the translocated locus may drive genotype-phenotype differences more than the coding sequence of the fusion gene created. Two possible roles for native SSX2 in synovial sarcomagenesis are explored. Thus, even specific partial failures of mouse genetic modeling can be instructive to human tumor biology. PMID- 26947019 TI - Drug Delivery Vehicles Based on Albumin-Polymer Conjugates. AB - Albumin has been a popular building block to create nanoparticles for drug delivery purposes. The performance of albumin as a drug carrier can be enhanced by combining protein with polymers, which allows the design of carriers to encompass a broader spectrum of drugs while features unique to synthetic polymers such as stimuli-responsiveness are introduced. Nanoparticles based on polymer albumin hybrids can be divided into two classes: one that carries album as a bioactive surface coating and the other that uses albumin as biocompatible, although nonbioactive, building block. Nanoparticles with bioactive albumin surface coating can either be prepared by self-assembly of albumin-polymer conjugates or by postcoating of existing nanoparticles with albumin. Albumin has also been used as building block, either in its native or denatured form. Existing albumin nanoparticles are coated with polymers, which can influence the degradation of albumin or impact on the drug release. Finally, an alternative way of using albumin by denaturing the protein to generate a highly functional chain, which can be modified with polymer, has been presented. These albumin nanoparticles are designed to be extremely versatile so that they can deliver a wide variety of drugs, including traditional hydrophobic drugs, metal-based drugs and even therapeutic proteins and siRNA. PMID- 26947020 TI - New applications of wastewater analyses for assessing substance use. PMID- 26947021 TI - Sub-toxic concentrations of volatile organic compounds inhibit extracellular respiration of Escherichia coli cells grown in anodic bioelectrochemical systems. AB - Low-cost and rapid detection of volatile organic compounds (VOCs) is important for the control of water quality of used water and protection of downstream used water treatment processes. In this work, the effect of sub-toxic concentration of VOCs on the current output of Escherichia coli in bioelectrochemical systems (BES) is shown, in light of environmental sensing applications for sewage and used water networks. E. coli cells were grown on carbon felt electrodes in artificial used water, to increase sensitivity and decrease response time for detection. Extracellular electron transfer was promoted by the addition of a biocompatible redox mediator, 2-hydroxy-1,4-naphthoquinone (HNQ). Among the eight VOCs investigated, toluene is the most toxic to E. coli, with a detection limit of 50+/-2mgL(-1) and current output of 32+/-1nAmg(-1)L(-1). This work offers a straightforward route to enhance the detection of organic contaminants in used water for environmental applications. PMID- 26947022 TI - Plant and microorganisms support media for electricity generation in biological fuel cells with living hydrophytes. AB - Plant support media may impact power output in a biological fuel cell with living plants, due to the physical and biochemical processes that take place in it. A material for support medium should provide the suitable conditions for the robust microbial growth and its metabolic activity, degrading organic matter and other substances; and, transferring electrons to the anode. To consider the implementation of this type of bio-electrochemical systems in constructed wetlands, this study analyzes the electrochemical behavior of biological fuel cells with the vegetal species Phragmites australis, by using two different support media: graphite granules and a volcanic slag, commonly known as tezontle (stone as light as hair, from the Aztec or Nahuatl language). Derived from the results, both, graphite and tezontle have the potential to be used as support medium for plants and microorganisms supporting a maximum power of 26.78mW/m(2) in graphite reactors. These reactors worked under mixed control: with ohmic and kinetic resistances of the same order of magnitude. Tezontle reactors operated under kinetic control with a high activation resistance supplying 9.73mW/m(2). These performances could be improved with stronger bacterial populations in the reactor, to ensure the rapid depletion of substrate. PMID- 26947023 TI - Poldip2 negatively regulates matrix synthesis at focal adhesions. PMID- 26947024 TI - Mutations reducing replication from R-loops suppress the defects of growth, chromosome segregation and DNA supercoiling in cells lacking topoisomerase I and RNase HI activity. AB - R-loop formation occurs when the nascent RNA hybridizes with the template DNA strand behind the RNA polymerase. R-loops affect a wide range of cellular processes and their use as origins of replication was the first function attributed to them. In Escherichia coli, R-loop formation is promoted by the ATP dependent negative supercoiling activity of gyrase (gyrA and gyrB) and is inhibited by topoisomerase (topo) I (topA) relaxing transcription-induced negative supercoiling. RNase HI (rnhA) degrades the RNA moiety of R-loops. The depletion of RNase HI activity in topA null mutants was previously shown to lead to extensive DNA relaxation, due to DNA gyrase inhibition, and to severe growth and chromosome segregation defects that were partially corrected by overproducing topo III (topB). Here, DNA gyrase assays in crude cell extracts showed that the ATP-dependent activity (supercoiling) of gyrase but not its ATP-independent activity (relaxation) was inhibited in topA null cells lacking RNase HI. To characterize the cellular event(s) triggered by the absence of RNase HI, we performed a genetic screen for suppressors of the growth defect of topA rnhA null cells. Suppressors affecting genes in replication (holC2::aph and dnaT18::aph) nucleotide metabolism (dcd49::aph), RNA degradation (rne59::aph) and fimbriae synthesis (fimD22::aph) were found to reduce replication from R-loops and to restore supercoiling, thus pointing to a correlation between R-loop-dependent replication in topA rnhA mutants and the inhibition of gyrase activity and growth. Interestingly, the position of fimD on the E. coli chromosome corresponds to the site of one of the five main putative origins of replication from R-loops in rnhA null cells recently identified by next-generation sequencing, thus suggesting that the fimD22::aph mutation inactivated one of these origins. Furthermore, we show that topo III overproduction is unable to complement the growth defect of topA rnhA null mutants at low temperatures that stabilizes hyper negatively supercoiled DNA. PMID- 26947025 TI - New synergistic efficacy of combination of romiplostim and steroid in refractory immune thrombocytopenia patients. PMID- 26947026 TI - Cyclophosphamide therapy for secondary amyloidosis in a patient with juvenile idiopathic arthritis unresponsive to tumor necrosis factor alpha inhibitor therapy. PMID- 26947027 TI - Population genetic structure of Cheyletus malaccensis (Acari: Cheyletidae) in China based on mitochondrial COI and 12S rRNA genes. AB - Cheyletus malaccensis is a predatory mite widely distributed in grain storages. It has been regarded as an important biological control agent for pest mites. In this study, we investigated the population genetic structure of C. malaccensis distributed in China based on the partial regions of mitochondrial COI and 12S rRNA genes. We collected 256 individuals of C. malaccensis from stored grain in 34 sites of China. We detected 50 COI gene haplotypes and nine 12S rRNA gene haplotypes. There were three clades in the haplotype network and Bayesian and maximum parsimony phylogenetic trees based on COI sequences, and two based on 12S rRNA sequences. The clustering of haplotypes was not correlated with their geographical distributions. The analysis of molecular variance, AMOVA, indicated that the genetic differentiation between populations was relatively weak. The major genetic differentiation was found within populations. We suggest that the genetic structure of C. malaccensis observed in this study may be the result of long-term climate fluctuations and recent human disturbances. PMID- 26947029 TI - Effect of the rider position during rising trot on the horse's biomechanics (back and trunk kinematics and pressure under the saddle). AB - Knowledge about the horse-saddle-rider interaction remains limited. The aim of this study was to compare the effect of the rider's position at rising trot on the pressure distribution, spine movements, stirrups forces and locomotion of the horse. The horse's back movements were measured using IMUs fixed at the levels of thoracic (T6, T12, T16) and lumbar (L2, L5) vertebrae, the pressure distribution using a pressure mat and stirrups forces using force sensors. The horse's and rider's approximated centres of mass (COM) were calculated using 2D reflective markers. To compare both trot phases (rider seated/rider standing), three horses were trotted at the rising trot by the same rider. Means+/-SD of each parameter for sitting and standing were compared using a Student's t test (p=0.05). Stirrups forces showed two peaks of equal magnitude in every stride cycle for left and right stirrups but increased during the standing phase. Simultaneously, the pressure for the whole mat significantly increased by +3.1kPa during the sitting phase with respect to standing phase. The T12-T16 and T16-L2 angular ranges of motion (ROM) were significantly reduced (-3.2 degrees -1.2 degrees ) and the T6-T12 and L2-L5 ROM were significantly increased (+1.7 degrees +0.7 degrees ) during sitting phase compared to standing phase. During rising trot, the sitting phase does not only increase the pressure on the horse's back but also reduces the back motion under the saddle compared to the standing phase. These results give new insights into the understanding of horse-rider interactions and equine back pain management. PMID- 26947028 TI - Cellular Prion Protein Promotes Neuronal Differentiation of Adipose-Derived Stem Cells by Upregulating miRNA-124. AB - The cellular prion protein (PrP(C)) is a highly conserved glycoprotein anchored by glycosylphosphatidylinositol (GPI) to the cell surface and is also the source of pathogenic agent of scrapie prion protein (PrP(Sc)). Numerous researches have suggested putative physiological roles for PrP(C), including protection from ischemic and excitotoxic lesions, and participation in cell signaling and differentiation. Here, we demonstrated that PrP(C) positively regulates neuronal differentiation of mouse adipose-derived stem cells (ADSCs). The small C-terminal domain phosphatase 1 (SCP1) expression was knocked down by gene silencing. The mRNA expression of miRNA-124 and PrP(C) was measured with quantitative PCR. Western blot analysis was used to detect the protein levels of nestin, betaIII tubulin, and SCP1, and dual-luciferase reporter assay was performed to test the target of miRNA-124. The expression level of PrP(C) was found to increase steadily during neuron-like differentiation process, and PrP(C) knockout resulted in the reduction of neuron-like cell markers. We further showed that miRNA-124 could directly target SCP1-3'-untranslated region to decrease small C-terminal domain phosphatase 1 (SCP1) SCP1, and that miRNA-124 expression is regulated by PrP(C). Our results suggest that PrP(C) may play a key role in the neuronal differentiation of ADSC through modulating miRNA-124-SCP1 axis. To date, this is the first time strong evidence for the involvement of PrP(C) in the neuronal differentiation of ADSC is reported. PMID- 26947030 TI - Micro-computed tomography assisted distal femur metaphyseal blunt punch compression for determining trabecular bone strength in mice. AB - Shorter generation time and the power of genetic manipulation make mice an ideal model system to study bone biology as well as bone diseases. However their small size presents a challenge to perform strength measurements, particularly of the weight-bearing cancellous bone in the murine long bones. We recently developed an improved method to measure the axial compressive strength of the cancellous bone in the distal femur metaphysis in mice. Transverse micro-computed tomography image slices that are 7um thick were used to locate the position where the epiphysis-metaphysis transition occurs. This enabled the removal of the distal femur epiphysis at the exact transition point exposing the full extent of metaphyseal trabecular bone, allowing more accurate and consistent measurement of its strength. When applied to a murine model system consisting of five month old male wild-type (WT) and Ca(2+)/calmodulin dependent protein kinase kinase 2 (CaMKK2) knockout (KO) Camkk2(-/-) mice that possess recorded differences in trabecular bone volume, data collected using this method showed good correlation between bone volume fraction and strength of trabecular bone. In combination with micro-computed tomography and histology, this method will provide a comprehensive and consistent assessment of the microarchitecture and tissue strength of the cancellous bone in murine mouse models. PMID- 26947032 TI - Effects of independently altering body weight and mass on the energetic cost of a human running model. AB - The mechanisms underlying the metabolic cost of running, and legged locomotion in general, remain to be well understood. Prior experimental studies show that the metabolic cost of human running correlates well with the vertical force generated to support body weight, the mechanical work done, and changes in the effective leg stiffness. Further, previous work shows that the metabolic cost of running decreases with decreasing body weight, increases with increasing body weight and mass, and does not significantly change with changing body mass alone. In the present study, we seek to uncover the basic mechanism underlying this existing experimental data. We find that an actuated spring-mass mechanism representing the effective mechanics of human running provides a mechanistic explanation for the previously reported changes in the metabolic cost of human running if the dimensionless relative leg stiffness (effective stiffness normalized by body weight and leg length) is regulated to be constant. The model presented in this paper provides a mechanical explanation for the changes in metabolic cost due to changing body weight and mass which have been previously measured experimentally and highlights the importance of active leg stiffness regulation during human running. PMID- 26947031 TI - MUFE models can represent microdamaged regions of healthy and metastatically involved whole vertebrae identified through histology and contrast enhanced MUCT imaging. AB - Micro-damage formation within the skeleton is an important stimulant for bone remodeling, however abnormal build-up of micro-damage can lead to skeletal fragility. In this study, uCT imaging based micro finite element (MUFE) models were used to evaluate tissue level damage criteria in whole healthy and metastatically-involved vertebrae. T13-L2 spinal segments were excised from osteolytic (n=3) and healthy (n=3) female athymic rnu/rnu rats. Osteolytic metastasis was generated by intercardiac injection of HeLa cancer cells. Micro mechanical axial loading was applied to the spinal motion segments under MUCT imaging. Vertebral samples underwent BaSO4 staining and sequential calcein/fuchsin staining to identify load induced micro-damage. MUCT imaging was used generate specimen specific MUFE models of the healthy and osteolytic whole rat vertebrae. Model boundary conditions were generated through deformable image registration of loaded and unloaded scans. Elevated stresses and strains were detected in regions of micro-damage identified through histological and BaSO4 staining within healthy and osteolytic vertebral models, as compared to undamaged regions. Additionally, damaged regions of metastatic vertebrae experienced significantly higher local stresses and strains than those in the damaged regions of healthy specimens. Areas identified by BaSO4 staining, however, yielded lower levels of stress and strain in damaged and undamaged regions of healthy and metastatic vertebrae as compared to fuschin staining. The multimodal (experimental, image-based and computational) techniques used in this study demonstrated the ability of local stresses and strains computed through uFE analysis to identify trabecular micro-damage, that can be applied to biomechanical analyses of healthy and diseased whole bones. PMID- 26947033 TI - An investigation of jogging biomechanics using the full-body lumbar spine model: Model development and validation. AB - The ability of a biomechanical simulation to produce results that can translate to real-life situations is largely dependent on the physiological accuracy of the musculoskeletal model. There are a limited number of freely-available, full-body models that exist in OpenSim, and those that do exist are very limited in terms of trunk musculature and degrees of freedom in the spine. Properly modeling the motion and musculature of the trunk is necessary to most accurately estimate lower extremity and spinal loading. The objective of this study was to develop and validate a more physiologically accurate OpenSim full-body model. By building upon three previously developed OpenSim models, the full-body lumbar spine (FBLS) model, comprised of 21 segments, 30 degrees-of-freedom, and 324 musculotendon actuators, was developed. The five lumbar vertebrae were modeled as individual bodies, and coupled constraints were implemented to describe the net motion of the spine. The eight major muscle groups of the lumbar spine were modeled (rectus abdominis, external and internal obliques, erector spinae, multifidus, quadratus lumborum, psoas major, and latissimus dorsi), and many of these muscle groups were modeled as multiple fascicles allowing the large muscles to act in multiple directions. The resulting FBLS model's trunk muscle geometry, maximal isometric joint moments, and simulated muscle activations compare well to experimental data. The FBLS model will be made freely available (https://simtk.org/home/fullbodylumbar) for others to perform additional analyses and develop simulations investigating full-body dynamics and contributions of the trunk muscles to dynamic tasks. PMID- 26947035 TI - Knee osteoarthritis negatively affects the recovery step following large forward directed postural perturbations. AB - The reasons for higher fall risk of people with osteoarthritis (OA) compared to people without OA are not known. It is possible that following a loss of balance OA may negatively affect the recovery stepping response. Stepping responses have not been reported for people with knee OA. Here, we compared recovery step kinematics following laboratory-induced trip and following a large treadmill delivered perturbation simulating a trip between a group of women with and without self-reported knee OA. We hypothesized that knee OA would significantly impair recovery step kinematics compared to those of a control group. Following the laboratory-induced trip, step length and trunk flexion velocity at recovery step completion of women with OA were significantly impaired and more so for the women who fell. Following the treadmill-delivered perturbation, the recovery step kinematics of women with OA were not significantly impaired. For both perturbations, the women who fell had significantly impaired recovery step kinematics compared to those who did not fall, regardless of OA. The results are consistent with previous work on healthy middle aged and older women and suggest that the same biomechanical risk factors for trip-related falls are shared by middle age and older women regardless of the presence of knee OA. The results support the need to determine whether training protocols which have been shown to improve recovery step kinematics and reduce prospective falls by healthy older women can have similar outcomes for people with knee OA. PMID- 26947034 TI - Arterial mechanics considering the structural and mechanical contributions of ECM constituents. AB - Considering the organization and engagement behavior of different extracellular matrix (ECM) constituents in the medial and adventitial layer of the arterial wall, in this study, we proposed a new constitutive model of ECM mechanics that considers the distinct structural and mechanical contributions of medial elastin, medial collagen, and adventitial collagen, to incorporate the constituent specific fiber orientation and the sequential fiber engagement in arterial mechanics. Planar biaxial tensile testing method was used to characterize the orthotropic and hyperelastic behavior of porcine thoracic aorta. Fiber distribution functions of medial elastin, medial collagen, and adventitial collagen were incorporated into the constitutive model. Considering the sequential engagement of ECM constituents in arterial mechanics, a recruitment density function was incorporated into the model to capture the delayed engagement of adventitial collagen. A freely jointed chain model was used to capture the mechanical behavior of elastin and collagen at the fiber level. The tissue-level ECM mechanics was obtained by incorporating fiber distribution, engagement, and elastin and collagen content. The multi-scale constitutive model considering the structural and mechanical contributions of the three major ECM constituents allows us to directly incorporate information obtained from quantitative multi-photon imaging and analysis, and biochemical assay for the prediction of tissue-level mechanical response. Moreover, the model shows promises in fitting and predicting with a small set of material parameters, which has physical meanings and can be related to the structure of the ECM. PMID- 26947036 TI - Gait characterization for osteoarthritis patients using wearable gait sensors (H Gait systems). AB - The objective of this work was to investigate the possibilities of using the wearable sensors-based H-Gait system in an actual clinical trial and proposes new gait parameters for characterizing OA gait. Seven H-Gait sensors, consisting of tri-axial inertial sensors, were attached to seven lower limb body segments (pelvis, both thighs, both shanks and both feet). The acceleration and angular velocity data measured were used to estimate three-dimensional kinematic parameters of patients during level walking. Three new parameters were proposed to assess the severity of OA based on the characteristics of these joint center trajectories in addition to conventional gait spatio-temporal parameters. The experiment was conducted on ten subjects with knee OA. The kinematic results obtained (hip, knee and ankle joint angles, joint trajectory in the horizontal and sagittal planes) were compared with those from a reference healthy (control) group. As a result, the angle between the right and left knee trajectories along with that of the ankle joint trajectories were almost twice as large (21.3 degrees vs. 11.6 degrees and 14.9 degrees vs. 7.8 degrees ) compared to those of the healthy subjects. In conclusion, it was found that the ankle joints during stance abduct less to avoid adduction at the knee as the severity of OA increases and lead to more acute angles (less parallel) between the right and left knee/ankle joints in the horizontal plane. This method was capable to provide quantitative information about the gait of OA patients and has the advantage to allow for out-of-laboratory monitoring. PMID- 26947038 TI - Variations on a theme . . . do different training algorithms really make a difference? PMID- 26947039 TI - Pedicled pericardial flap for esophagorespiratory fistula: A helpful tool for a difficult problem. PMID- 26947040 TI - Ulcerative colitis -recent advance in clinical practice and basic research. PMID- 26947037 TI - Sphingolipid profile alters in retinal dystrophic P23H-1 rats and systemic FTY720 can delay retinal degeneration. AB - Retinal degeneration (RD) affects millions of people and is a major cause of ocular impairment and blindness. With a wide range of mutations and conditions leading to degeneration, targeting downstream processes is necessary for developing effective treatments. Ceramide and sphingosine-1-phosphate, a pair of bioactive sphingolipids, are involved in apoptosis and its prevention, respectively. Apoptotic cell death is a potential driver of RD, and in order to understand the mechanism of degeneration and potential treatments, we studied rhodopsin mutant RD model, P23H-1 rats. Investigating this genetic model of human RD allows us to investigate the association of sphingolipid metabolites with the degeneration of the retina in P23H-1 rats and the effects of a specific modulator of sphingolipid metabolism, FTY720. We found that P23H-1 rat retinas had altered sphingolipid profiles that, when treated with FTY720, were rebalanced closer to normal levels. FTY720-treated rats also showed protection from RD compared with their vehicle-treated littermates. Based on these data, we conclude that sphingolipid dysregulation plays a secondary role in retinal cell death, which may be common to many forms of RDs, and that the U.S. Food and Drug Administration-approved drug FTY720 or related compounds that modulate sphingolipid metabolism could potentially delay the cell death. PMID- 26947041 TI - Up-to-date medical treatment for ulcerative colitis. PMID- 26947042 TI - Front-line surgical therapy for ulcerative colitis. PMID- 26947043 TI - Diagnosis and treatment for colitis associated cancer. PMID- 26947044 TI - A study of usefulness for portal vein thrombus with edoxaban. PMID- 26947045 TI - A case report of a duodenal adenocarcinoma: a complication with Crohn's disease. AB - The prevalence of Crohn's disease (CD) in Japan is increasing, and so is the incidence of colorectal and small bowel cancers associated with CD. However, few reports have described the malignant transformation of duodenal lesions; moreover, such a diagnosis is rarely possible preoperatively. We present a case of malignant degeneration in the duodenal mucosa associated with CD. A 54-year old man had been receiving treatment for CD for more than 20 years. Seven years ago, he was diagnosed with duodenal stenosis related to CD. He was asymptomatic, and biopsy results from the proximal stricture showed inflammatory changes without malignant transformation. The lesion was then monitored during follow-up. In 2013, he underwent an endoscopy, which revealed an ulcerated, nodular mucosa, immediately proximal to a high-grade obstruction of the descending duodenum. A biopsy of the ulcer lesion confirmed a diagnosis of adenocarcinoma. The patient then underwent duodenopancreatectomy. Histopathological results from the resected duodenum confirmed a poorly differentiated adenocarcinoma that had invaded the subserosa. The patient recovered, and no recurrence has been observed. Although the duodenum can be accessed without difficulty during endoscopy, it is challenging to preoperatively diagnose malignant transformation. There are only four reported cases of duodenal cancer stemming from CD-associated stricture, and only one of them received a preoperative diagnosis of malignancy based on endoscopic biopsy results. Progressive duodenal narrowing and ulceration in patients with CD should indicate a need for careful endoscopic evaluation and biopsy in order to exclude malignant degeneration of Crohn's duodenitis. Early diagnosis of cases of CD-associated cancers is necessary. We report the features of a rare and illustrative case of duodenal adenocarcinoma in a patient with CD. PMID- 26947046 TI - A case report of a recurrent abscess secondary to fish bone penetration of the ileum. AB - A 62-year-old man with right upper abdominal swelling was admitted to our hospital. Abdominal computed tomography (CT) revealed a hepatic abscess. He was treated with percutaneous abscess drainage along with antibiotic therapy. After the treatment, the patient was discharged. However, we failed to notice a fish bone, which had been revealed in the CT scan. One year and five months later, the same patient presented with right lower abdominal pain and vomiting. Abdominal CT showed a subcutaneous abdominal abscess of the right lower abdomen, with the same fish bone penetrating out of the ileum. Accordingly, the patient was subjected to surgical abscess drainage, and the fish bone was successfully removed. The findings of this case suggest that the source of infection of the hepatic abscess should be identified, searching not only the nearby organs but also the distally located organs, including the lower gastrointestinal tract. The findings also suggest that the surgical removal of a fish bone should be considered. PMID- 26947047 TI - A case report of severe ulcerative colitis with mediastinal and subcutaneous emphysema. AB - A 17-year-old boy developed prominent mediastinal and subcutaneous emphysema while receiving treatment with 5-aminosalicylic acid (5-ASA) and oral corticosteroids for severe ulcerative colitis. We ruled out infection and initiated oral administration of tacrolimus, after which both the underlying disease and mediastinal and subcutaneous emphysema improved. However, he continued to experience repeated bouts of ulcerative colitis, so we ultimately opted for surgical intervention. Although mediastinal and subcutaneous emphysema is rare, it is one of the known extra-intestinal complications and can be particularly concerning. In this patient, mediastinal and subcutaneous emphysema might have been caused by the vulnerability of pulmonary alveolar walls to steroid medication and the increase of pulmonary alveolar pressure with abdominal pain and breath holding. Here, we report a case of inflammatory bowel disease with mediastinal and subcutaneous emphysema, along with a review of the literature. PMID- 26947048 TI - An early gastric cancer concurrent with a hyperplastic polyp in a patient confirmed negative for Helicobacter pylori. AB - A 58-year-old man was suspected of having a gastric polyp based on an upper gastrointestinal series. Esophagogastroduodenoscopy showed a gastric polyp, approximately 7mm in diameter, located at the greater curvature of the upper gastric body. Helicobacter pylori testing yielded negative results, and there was no atrophy of the gastric mucosa. Biopsy revealed a well differentiated tubular adenocarcinoma (Group 5). Endoscopic submucosal biopsies were performed, and histopathology revealed a well differentiated tubular adenocarcinoma coexisting with a hyperplastic polyp. Complete en bloc resection was performed, in accordance with the current Japanese guidelines. PMID- 26947049 TI - A case report of a common bile duct stone formed from a fish bone. AB - A 79-year-old woman was admitted for investigation of epigastric pain and jaundice. Abdominal computed tomography showed a common bile duct stone with a needle-like calcification. Endoscopic sphincterotomy was performed, and the stone was extracted from the common bile duct. After endoscopic sphincterotomy, laparoscopic cholecystectomy was performed. Pathological findings and component analysis of the stone suggested that it was formed from a fish bone. We report a rare case of a common bile duct stone formed from a fish bone. PMID- 26947050 TI - Multi-organ disseminated mucosa-associated lymphoid tissue lymphoma. AB - A 61-year-old man was admitted to our hospital with extreme weight loss. Abdominal ultrasonography revealed an 8-cm tumor of the pancreatic head. Further investigation revealed orbital, pulmonary, pancreatic, colonic, and bone marrow lesions. A histopathological examination of the pancreatic tumor specimen obtained using endoscopic ultrasound-guided fine-needle aspiration revealed mucosa-associated lymphoid tissue (MALT) lymphoma. Monoclonal rearrangement of immunoglobulin heavy chain was found in the pulmonary, pancreatic, colonic, and bone marrow lesions. We diagnosed multi-organ disseminated MALT lymphoma, with the largest lesion located in the pancreatic head. Chemo-radiation therapy resulted in complete remission. PMID- 26947051 TI - Editorial. PMID- 26947052 TI - Potential contribution of the Alzheimer's disease risk locus BIN1 to episodic memory performance in cognitively normal Type 2 diabetes elderly. AB - In recent years, several promising susceptibility loci for late-onset Alzheimer's disease (AD) were discovered, by implementing genome-wide association studies (GWAS) approach. Recent GWAS meta-analysis has demonstrated the association of 19 loci (in addition to the APOE locus) with AD in the European ancestry population at genome-wide significance level. Since Type 2 Diabetes (T2D) is a substantial risk factor for cognitive decline and dementia, the 19 single nucleotide polymorphisms (SNPs) that represent the 19 AD loci were studied for association with performance in episodic memory, a primary cognitive domain affected by AD, in a sample of 848 cognitively normal elderly Israeli Jewish T2D patients. We found a suggestive association of SNP rs6733839, located near the bridging integrator 1 (BIN1) gene, with this phenotype. Controlling for demographic (age, sex, education, disease duration and ancestry) covariates, carriers of two copies of the AD risk allele T (TT genotype) performed significantly worse (p=0.00576; p=0.00127 among Ashkenazi origin sub-sample) in episodic memory compared to carriers of the C allele (CT+CC genotypes). When including additional potential covariates (clinical and APOE genotype), results remained significant (p=0.00769; p=0.00148 among Ashkenazi). Interestingly, as validated in multiple large studies, BIN1 is one of the most established AD risk loci, with a high odds ratio. Although preliminary and require further replications, our findings support a contribution of BIN1 to individual differences in episodic memory performance among T2D patients. PMID- 26947053 TI - ADAM10 localization in temporomandibular joint disk with internal derangement: an ex vivo immunohistochemical study. AB - The purpose of this study was to determine the presence of ADAM10 in temporomandibular joint disk with internal derangement. Twenty-five paraffin blocks of displaced temporomandibular joint (TMJ) disk specimens from earlier investigations were retrieved from the archives of the University of Catania. Of these 16 had been removed from females and 9 from males; 11 with anterior disk displacement with reduction (ADDwR) and 14 with anterior disk displacement without reduction (ADDwoR). The sections were dehydrated, embedded in paraffin and cut. Then they were incubated in 0.3% H2O2/methanol and half of sections from each sample were incubated in diluted rabbit polyclonal anti-ADAM10 antibody. Then biotinylated anti-mouse/anti-rabbit IgG was applied to the sections, followed by avidin-biotin-perioxidase complex. The results were analyzed and the results were that ADAM10 was overexpressed in the posterior band of sections from patients with ADDwR compared to the other bands of both ADDwR and ADDwoR sections. Overexpression correlated with severe histopathological degeneration. We believe these results have the potential to provide insights into the pathogenesis of TMJ disk degeneration and to help design new therapeutic approaches targeting the proteolytic events that lead to tissue degeneration. Early therapeutic block of ADAM10 activity could succeed in limiting aggrecan rich matrix breakdown without affecting normal physiology. PMID- 26947054 TI - [Peripheral arterial pseudo-aneurysm in Behcet's disease: Report of two cases]. AB - Behcet's disease is a systemic vasculitis of unknown etiopathogenesis. Arterial events such as pseudo-aneurysms are rare and may be the mode of occurrence of the disease. These pseudo-aneurysms tend, regardless of size, to progress rapidly to life-threatening rupture. We report two cases of arterial pseudo-aneurysms that ruptured. Treatment consisted of surgical repair in one case and arterial ligation in the other; the postoperative course was uneventful in both cases. PMID- 26947055 TI - Split-field vs extended-field intensity-modulated radiation therapy plans for oropharyngeal cancer: Which spares the larynx? Which spares the thyroid? AB - Radiation of the low neck can be accomplished using split-field intensity modulated radiation therapy (sf-IMRT) or extended-field intensity-modulated radiation therapy (ef-IMRT). We evaluated the effect of these treatment choices on target coverage and thyroid and larynx doses. Using data from 14 patients with cancers of the oropharynx, we compared the following 3 strategies for radiating the low neck: (1) extended-field IMRT, (2) traditional split-field IMRT with an initial cord-junction block to 40Gy, followed by a full-cord block to 50Gy, and (3) split-field IMRT with a full-cord block to 50Gy. Patients were planned using each of these 3 techniques. To facilitate comparison, extended-field plans were normalized to deliver 50Gy to 95% of the neck volume. Target coverage was assessed using the dose to 95% of the neck volume (D95). Mean thyroid and larynx doses were computed. Extended-field IMRT was used as the reference arm; the mean larynx dose was 25.7 +/- 7.4Gy, and the mean thyroid dose was 28.6 +/- 2.4Gy. Split-field IMRT with 2-step blocking reduced laryngeal dose (mean larynx dose 15.2 +/- 5.1Gy) at the cost of a moderate reduction in target coverage (D95 41.4 +/- 14Gy) and much higher thyroid dose (mean thyroid dose 44.7 +/- 3.7Gy). Split field IMRT with initial full-cord block resulted in greater laryngeal sparing (mean larynx dose 14.2 +/- 5.1Gy) and only a moderately higher thyroid dose (mean thyroid dose 31 +/- 8Gy) but resulted in a significant reduction in target coverage (D95 34.4 +/- 15Gy). Extended-field IMRT comprehensively covers the low neck and achieves acceptable thyroid and laryngeal sparing. Split-field IMRT with a full-cord block reduces laryngeal doses to less than 20Gy and spares the thyroid, at the cost of substantially reduced coverage of the low neck. Traditional 2-step split-field IMRT similarly reduces the laryngeal dose but also reduces low-neck coverage and delivers very high doses to the thyroid. PMID- 26947056 TI - Attempted placental separation for suspected placenta accreta: experience may matter. PMID- 26947057 TI - Overexpression of human SOD1 in VDAC1-less yeast restores mitochondrial functionality modulating beta-barrel outer membrane protein genes. AB - Cu/Zn Superoxide Dismutase (SOD1), the most important antioxidant defense against ROS in eukaryotic cells, localizes in cytosol and intermembrane space of mitochondria (IMS). Several evidences show a SOD1 intersection with both fermentative and respiratory metabolism. The Voltage Dependent Anion Channel (VDAC) is the main pore-forming protein in the mitochondrial outer membrane (MOM), and is considered the gatekeeper of mitochondrial metabolism. Saccharomyces cerevisiae lacking VDAC1 (Deltapor1) is a very convenient model system, since it shows an impaired growth rate on non-fermentable carbon source. Transformation of Deltapor1 yeast with human SOD1 completely restores the cell growth deficit in non-fermentative conditions and re-establishes the physiological levels of ROS, as well as the mitochondrial membrane potential. No similar result was found upon yeast SOD1 overexpression. A previous report highlighted the action of SOD1 as a transcription factor. Quantitative Real-Time PCR showed that beta-barrel outer-membrane encoding-genes por2, tom40, sam50 are induced by hSOD1, but the same effect was not obtained in Deltapor1Deltapor2 yeast, indicating a crucial function for yVDAC2. Since the lack of VDAC1 in yeast can be considered a stress factor for the cell, hSOD1 could relieve it stimulating the expression of genes bringing to the recovery of the MOM function. Our results suggest a direct influence of SOD1 on VDAC. PMID- 26947058 TI - Role of cysteines in mammalian VDAC isoforms' function. AB - In this mini-review, we analyze the influence of cysteines in the structure and activity of mitochondrial outer membrane mammalian VDAC isoforms. The three VDAC isoforms show conserved sequences, similar structures and the same gene organization. The meaning of three proteins encoded in different chromosomes must thus be searched for subtle differences at the amino acid level. Among others, cysteine content is noticeable. In humans, VDAC1 has 2, VDAC2 has 9 and VDAC3 has 6 cysteines. Recent works have shown that, at variance from VDAC1, VDAC2 and VDAC3 exhibit cysteines predicted to protrude towards the intermembrane space, making them a preferred target for oxidation by ROS. Mass spectrometry in VDAC3 revealed that a disulfide bridge can be formed and other cysteine oxidations are also detectable. Both VDAC2 and VDAC3 cysteines were mutagenized to highlight their role in vitro and in complementation assays in Deltaporin1 yeast. Chemico physical techniques revealed an important function of cysteines in the structural stabilization of the pore. In conclusion, the works available on VDAC cysteines support the notion that the three proteins are paralogs with a similar pore function and slightly different, but important, ancillary biological functions. This article is part of a Special Issue entitled 'EBEC 2016: 19th European Bioenergetics Conference, Riva del Garda, Italy, July 2-6, 2016', edited by Prof. Paolo Bernardi. PMID- 26947059 TI - A Multicomponent Exercise Intervention that Reverses Frailty and Improves Cognition, Emotion, and Social Networking in the Community-Dwelling Frail Elderly: A Randomized Clinical Trial. AB - BACKGROUND: Frailty can be an important clinical target to reduce rates of disability. OBJECTIVE: To ascertain if a supervised-facility multicomponent exercise program (MEP) when performed by frail older persons can reverse frailty and improve functionality; cognitive, emotional, and social networking; as well as biological biomarkers of frailty, when compared with a controlled population that received no training. DESIGN: This is an interventional, controlled, simple randomized study. Researchers responsible for data gathering were blinded for this study. SETTING: Participants from 2 primary rural care centers (Sollana and Carcaixent) of the same health department in Spain were enrolled in the study between December 2013 and September 2014. PATIENTS: We randomized a volunteer sample of 100 men and women who were sedentary, with a gait speed lower than 0.8 meters per second and frail (met at least 3 of the frailty phenotype criteria). INTERVENTIONS: Participants were randomized to a supervised-facility MEP (n = 51, age = 79.5, SD 3.9) that included proprioception, aerobic, strength, and stretching exercises for 65 minutes, 5 days per week, 24 weeks, or to a control group (n = 49, age = 80.3, SD 3.7). The intervention was performed by 8 experienced physiotherapists or nurses. Protein-calorie and vitamin D supplementation were controlled in both groups. RESULTS: Our MEP reverses frailty (number needed to treat to recover robustness in subjects with attendance to >=50% of the training sessions was 3.2) and improves functional measurements: Barthel (trained group 91.6 SD 8.0 vs 82.0 SD 11.0 control group), Lawton and Brody (trained group 6.9 SD 0.9 vs 5.7 SD 2.0 control group), Tinetti (trained group 24.5 SD 4.4 vs 21.7 SD 4.5 control group), Short Physical Performance Battery (trained group 9.5 SD 1.8 vs 7.1 SD 2.8 control group), and physical performance test (trained group 23.5 SD 5.9 vs 16.5 SD 5.1 control group) as well as cognitive, emotional, and social networking determinations: Mini-Mental State Examination (trained group 28.9 SD 3.9 vs 25.9 SD 7.3 control group), geriatric depression scale from Yesavage (trained group 2.3 SD 2.2 vs 3.2 SD 2.0 control group), EuroQol quality-of-life scale (trained group 8.2 SD 1.6 vs 7.6 SD 1.3 control group), and Duke social support (trained group 48.5 SD 9.3 vs 41.2 SD 8.5 control group). This program is unique in that it leads to a decrease in the number of visits to primary care physician (trained group 1.3 SD 1.4 vs 2.4 SD 2.9 control group) and to a significant improvement in frailty biomarkers. CONCLUSIONS: We have designed a multicomponent exercise intervention that reverses frailty and improves cognition, emotional, and social networking in a controlled population of community-dwelling frail older adults. TRIAL REGISTRATION: ClinicalTrials.gov. Identifier: NCT02331459. PMID- 26947060 TI - Characteristics of frequent users of the emergency department in the general adult population: A systematic review of international healthcare systems. AB - OBJECTIVES: The objectives of this study were to synthesize and compare population characteristics associated with frequent emergency department (ED) use within and across healthcare systems. METHODS: A systematic review of literature published between 1950 and 2015 was conducted. Healthcare systems of included studies were categorized using the Rothgang-Wendt typology. Demographic, clinical and health service utilization characteristics of frequent ED users in the general adult population were identified within each healthcare system. Pooled estimates, stratified by healthcare system, were calculated to compare the association of each characteristic with frequent, compared to non-frequent, emergency room use. RESULTS: Twenty moderate to high quality comparative cohort studies were included. Among these, five healthcare systems were identified: National Health Insurance; Private Healthcare; National Health Service; Social Health Insurance and Etatist Social Health Insurance. Many similar characteristics were observed: in most healthcare systems, frequent ED users were more likely to be older, female, and have a mental health diagnosis. Previous hospitalizations and high primary care use (>3 visits/year) were associated with future frequent ED use in the NHIS and NHS systems. CONCLUSIONS: Observed similarities suggest that frequent ED use may not differ from one healthcare system to the next. With increasing need to develop solutions for high ED utilization world-wide, targeted efforts must be made to bolster dissemination and uptake of effective interventions across healthcare contexts. PMID- 26947061 TI - Assessing physical fitness in preschool children: Feasibility, reliability and practical recommendations for the PREFIT battery. AB - OBJECTIVES: In childhood (>6 years-old) and adolescence, fitness testing is feasible, reliable and related to later health. The purpose of this study was to examine the feasibility and reliability of a field-based fitness-test battery in preschool children. DESIGN: Repeated measures. METHODS: A total of 161 preschoolers aged 3 to 5 years participated in the study. Anthropometry, cardiorespiratory fitness, muscular strength and motor fitness were tested twice (2 weeks apart) using weight, height, waist circumference, PREFIT 20m shuttle run, handgrip strength, standing long jump, 4*10m shuttle run and one-leg stance tests, respectively. RESULTS: The main results indicated that all tests are feasible and highly reliable (mean differences, weight=0.04kg, height=0.22cm, waist circumference=-0.08cm, PREFIT 20m shuttle run=2.00 laps, handgrip strength= 0.24kg and 4*10m shuttle run=0.12s), in preschool children, except for the standing long jump test and one-leg stance test (mean differences of -7.31cm and 8.01s). After some methodological adaptations, reliability for standing long jump was improved in a replication study (i.e. from -7 to -2cm). We observed evidence of heteroscedasticity in the 4*10m shuttle run and one-leg stance tests. CONCLUSIONS: The PREFIT battery is a feasible and reliable tool to assess physical fitness in preschool children yet standing long jump has shown mixed findings and requires further studies. The one-leg stance test showed poor reliability in our study and if confirmed by future studies, its use in 3 to 5 years-old would not be recommended. Future studies should consider the mean differences provide in this study to explain the changes in test performance. PMID- 26947062 TI - A single terpene synthase is responsible for a wide variety of sesquiterpenes in Sorangium cellulosum Soce56. AB - The myxobacterium Sorangium cellulosum So ce56 is a prolific producer of volatile sesquiterpenes. The strain harbours one of the largest prokaryotic genomes (13.1 Mbp). However, it codes only for three type I terpene synthases (TSs; sce1440, sce6369, sce8552) and one type II TS (sce4636), responsible for the production of at least 17 sesquiterpenes. We report here the gene expression of TSs and biosynthesis of the TS products in E. coli. Comparison with the So ce56 volatiles allows the assignment of the terpenes to their synthesizing genes. Both, the geosmin synthase sce1440 and the previously examined (+)-eremophilene synthase sce8552 are highly specific. In contrast, Sce6369, the first characterized 10-epi cubebol synthase, is responsible for the formation of most of the So ce56 sesquiterpenes, mainly cadalanes and cubebanes. In contrast, Sce4636 does not convert FPP. Having characterized the So ce56 TSs, we screened all the 27 sequenced myxobacterial species from the NCBI and JGI-IMG databases for parent genes to predict the sesquiterpenes produced by them. PMID- 26947064 TI - Global Analysis of Cellular Protein Flux Quantifies the Selectivity of Basal Autophagy. AB - In eukaryotic cells, macroautophagy is a catabolic pathway implicated in the degradation of long-lived proteins and damaged organelles. Although it has been demonstrated that macroautophagy can selectively degrade specific targets, its contribution to the basal turnover of cellular proteins has not been quantified on proteome-wide scales. In this study, we created autophagy-deficient primary human fibroblasts and quantified the resulting changes in basal degradative flux by dynamic proteomics. Our results provide a global comparison of protein half lives between wild-type and autophagy-deficient cells. The data indicate that in quiescent fibroblasts, macroautophagy contributes to the basal turnover of a substantial fraction of the proteome at varying levels. As contrasting examples, we demonstrate that the proteasome and CCT/TRiC chaperonin are robust substrates of basal autophagy, whereas the ribosome is largely protected under basal conditions. This selectivity may establish a proteostatic feedback mechanism that stabilizes the proteasome and CCT/TRiC when autophagy is inhibited. PMID- 26947063 TI - YAP Induces Human Naive Pluripotency. AB - The human naive pluripotent stem cell (PSC) state, corresponding to a pre implantation stage of development, has been difficult to capture and sustain in vitro. We report that the Hippo pathway effector YAP is nuclearly localized in the inner cell mass of human blastocysts. Overexpression of YAP in human embryonic stem cells (ESCs) and induced PSCs (iPSCs) promotes the generation of naive PSCs. Lysophosphatidic acid (LPA) can partially substitute for YAP to generate transgene-free human naive PSCs. YAP- or LPA-induced naive PSCs have a rapid clonal growth rate, a normal karyotype, the ability to form teratomas, transcriptional similarities to human pre-implantation embryos, reduced heterochromatin levels, and other hallmarks of the naive state. YAP/LPA act in part by suppressing differentiation-inducing effects of GSK3 inhibition. CRISPR/Cas9-generated YAP(-/-) cells have an impaired ability to form colonies in naive but not primed conditions. These results uncover an unexpected role for YAP in the human naive state, with implications for early human embryology. PMID- 26947065 TI - Localized Translation of gurken/TGF-alpha mRNA during Axis Specification Is Controlled by Access to Orb/CPEB on Processing Bodies. AB - In Drosophila oocytes, gurken/TGF-alpha mRNA is essential for establishing the future embryonic axes. gurken remains translationally silent during transport from its point of synthesis in nurse cells to its final destination in the oocyte, where it associates with the edge of processing bodies. Here we show that, in nurse cells, gurken is kept translationally silent by the lack of sufficient Orb/CPEB, its translational activator. Processing bodies in nurse cells have a similar protein complement and ultrastructure to those in the oocyte, but they markedly less Orb and do not associate with gurken mRNA. Ectopic expression of Orb in nurse cells at levels similar to the wild-type oocyte dorso anterior corner at mid-oogenesis is sufficient to cause gurken mRNA to associate with processing bodies and translate prematurely. We propose that controlling the spatial distribution of translational activators is a fundamental mechanism for regulating localized translation. PMID- 26947066 TI - Dual and Opposing Roles of MicroRNA-124 in Epilepsy Are Mediated through Inflammatory and NRSF-Dependent Gene Networks. AB - Insult-provoked transformation of neuronal networks into epileptic ones involves multiple mechanisms. Intervention studies have identified both dysregulated inflammatory pathways and NRSF-mediated repression of crucial neuronal genes as contributors to epileptogenesis. However, it remains unclear how epilepsy provoking insults (e.g., prolonged seizures) induce both inflammation and NRSF and whether common mechanisms exist. We examined miR-124 as a candidate dual regulator of NRSF and inflammatory pathways. Status epilepticus (SE) led to reduced miR-124 expression via SIRT1--and, in turn, miR-124 repression--via C/EBPalpha upregulated NRSF. We tested whether augmenting miR-124 after SE would abort epileptogenesis by preventing inflammation and NRSF upregulation. SE sustaining animals developed epilepsy, but supplementing miR-124 did not modify epileptogenesis. Examining this result further, we found that synthetic miR-124 not only effectively blocked NRSF upregulation and rescued NRSF target genes, but also augmented microglia activation and inflammatory cytokines. Thus, miR-124 attenuates epileptogenesis via NRSF while promoting epilepsy via inflammation. PMID- 26947067 TI - The P72R Polymorphism of p53 Predisposes to Obesity and Metabolic Dysfunction. AB - p53 is well known for its tumor suppressor role, but this protein also has a poorly understood role in the regulation of metabolism. Human studies have implicated a common polymorphism at codon 72 of p53 in diabetic and pre-diabetic phenotypes. To understand this role, we utilized a humanized mouse model of the p53 codon 72 variants and monitored these mice following challenge with a high fat diet (HFD). Mice with the arginine 72 (R72) variant of p53 developed more severe obesity and glucose intolerance on a HFD, compared to mice with the proline 72 variant (P72). R72 mice developed insulin resistance, islet hypertrophy, increased infiltration of immune cells, and fatty liver disease. Gene expression analyses and studies with small-molecule inhibitors indicate that the p53 target genes Tnf and Npc1l1 underlie this phenotype. These results shed light on the role of p53 in obesity, metabolism, and inflammation. PMID- 26947068 TI - Plasticity between Epithelial and Mesenchymal States Unlinks EMT from Metastasis Enhancing Stem Cell Capacity. AB - Forced overexpression and/or downregulation of proteins regulating epithelial-to mesenchymal transition (EMT) has been reported to alter metastasis by changing migration and stem cell capacity of tumor cells. However, these manipulations artificially keep cells in fixed states, while in vivo cells may adapt transient and reversible states. Here, we have tested the existence and role of epithelial mesenchymal plasticity in metastasis of mammary tumors without artificially modifying EMT regulators. In these tumors, we found by intravital microscopy that the motile tumor cells have undergone EMT, while their epithelial counterparts were not migratory. Moreover, we found that epithelial-mesenchymal plasticity renders any EMT-induced stemness differences, as reported previously, irrelevant for metastatic outgrowth, because mesenchymal cells that arrive at secondary sites convert to the epithelial state within one or two divisions, thereby obtaining the same stem cell potential as their arrived epithelial counterparts. We conclude that epithelial-mesenchymal plasticity supports migration but additionally eliminates stemness-enhanced metastatic outgrowth differences. PMID- 26947069 TI - Large-Scale Profiling of Kinase Dependencies in Cancer Cell Lines. AB - One approach to identifying cancer-specific vulnerabilities and therapeutic targets is to profile genetic dependencies in cancer cell lines. Here, we describe data from a series of siRNA screens that identify the kinase genetic dependencies in 117 cancer cell lines from ten cancer types. By integrating the siRNA screen data with molecular profiling data, including exome sequencing data, we show how vulnerabilities/genetic dependencies that are associated with mutations in specific cancer driver genes can be identified. By integrating additional data sets into this analysis, including protein-protein interaction data, we also demonstrate that the genetic dependencies associated with many cancer driver genes form dense connections on functional interaction networks. We demonstrate the utility of this resource by using it to predict the drug sensitivity of genetically or histologically defined subsets of tumor cell lines, including an increased sensitivity of osteosarcoma cell lines to FGFR inhibitors and SMAD4 mutant tumor cells to mitotic inhibitors. PMID- 26947070 TI - Selective Vulnerability of Cancer Cells by Inhibition of Ca(2+) Transfer from Endoplasmic Reticulum to Mitochondria. AB - In the absence of low-level ER-to-mitochondrial Ca(2+) transfer, ATP levels fall, and AMPK-dependent, mTOR-independent autophagy is induced as an essential survival mechanism in many cell types. Here, we demonstrate that tumorigenic cancer cell lines, transformed primary human fibroblasts, and tumors in vivo respond similarly but that autophagy is insufficient for survival, and cancer cells die while their normal counterparts are spared. Cancer cell death is due to compromised bioenergetics that can be rescued with metabolic substrates or nucleotides and caused by necrosis associated with mitotic catastrophe during their proliferation. Our findings reveal an unexpected dependency on constitutive Ca(2+) transfer to mitochondria for viability of tumorigenic cells and suggest that mitochondrial Ca(2+) addiction is a feature of cancer cells. PMID- 26947071 TI - Landscape and Dynamics of Transcription Initiation in the Malaria Parasite Plasmodium falciparum. AB - A comprehensive map of transcription start sites (TSSs) across the highly AT-rich genome of P. falciparum would aid progress toward deciphering the molecular mechanisms that underlie the timely regulation of gene expression in this malaria parasite. Using high-throughput sequencing technologies, we generated a comprehensive atlas of transcription initiation events at single-nucleotide resolution during the parasite intra-erythrocytic developmental cycle. This detailed analysis of TSS usage enabled us to define architectural features of plasmodial promoters. We demonstrate that TSS selection and strength are constrained by local nucleotide composition. Furthermore, we provide evidence for coordinate and stage-specific TSS usage from distinct sites within the same transcription unit, thereby producing transcript isoforms, a subset of which are developmentally regulated. This work offers a framework for further investigations into the interactions between genomic sequences and regulatory factors governing the complex transcriptional program of this major human pathogen. PMID- 26947072 TI - Central Insulin Action Activates Kupffer Cells by Suppressing Hepatic Vagal Activation via the Nicotinic Alpha 7 Acetylcholine Receptor. AB - Central insulin action activates hepatic IL-6/STAT3 signaling, which suppresses the gene expression of hepatic gluconeogenic enzymes. The vagus nerve plays an important role in this centrally mediated hepatic response; however, the precise mechanism underlying this brain-liver interaction is unclear. Here, we present our findings that the vagus nerve suppresses hepatic IL-6/STAT3 signaling via alpha7-nicotinic acetylcholine receptors (alpha7-nAchR) on Kupffer cells, and that central insulin action activates hepatic IL-6/STAT3 signaling by suppressing vagal activity. Indeed, central insulin-mediated hepatic IL-6/STAT3 activation and gluconeogenic gene suppression were impeded in mice with hepatic vagotomy, pharmacological cholinergic blockade, or alpha7-nAchR deficiency. In high-fat diet-induced obese and insulin-resistant mice, control of the vagus nerve by central insulin action was disturbed, inducing a persistent increase of inflammatory cytokines. These findings suggest that dysregulation of the alpha7 nAchR-mediated control of Kupffer cells by central insulin action may affect the pathogenesis of chronic hepatic inflammation in obesity. PMID- 26947073 TI - Sialic Acid-Binding Immunoglobulin-like Lectin G Promotes Atherosclerosis and Liver Inflammation by Suppressing the Protective Functions of B-1 Cells. AB - Atherosclerosis is initiated and sustained by hypercholesterolemia, which results in the generation of oxidized LDL (OxLDL) and other metabolic byproducts that trigger inflammation. Specific immune responses have been shown to modulate the inflammatory response during atherogenesis. The sialic acid-binding immunoglobulin-like lectin G (Siglec-G) is a negative regulator of the functions of several immune cells, including myeloid cells and B-1 cells. Here, we show that deficiency of Siglec-G in atherosclerosis-prone mice inhibits plaque formation and diet-induced hepatic inflammation. We further demonstrate that selective deficiency of Siglec-G in B cells alone is sufficient to mediate these effects. Levels of B-1 cell-derived natural IgM with specificity for OxLDL were significantly increased in the plasma and peritoneal cavity of Siglec-G-deficient mice. Consistent with the neutralizing functions of OxLDL-specific IgM, Siglec-G deficient mice were protected from OxLDL-induced sterile inflammation. Thus, Siglec-G promotes atherosclerosis and hepatic inflammation by suppressing protective anti-inflammatory effector functions of B cells. PMID- 26947074 TI - Fibroblast Growth Factor 21 Mediates Glycemic Regulation by Hepatic JNK. AB - The cJun NH2-terminal kinase (JNK)-signaling pathway is implicated in metabolic syndrome, including dysregulated blood glucose concentration and insulin resistance. Fibroblast growth factor 21 (FGF21) is a target of the hepatic JNK signaling pathway and may contribute to the regulation of glycemia. To test the role of FGF21, we established mice with selective ablation of the Fgf21 gene in hepatocytes. FGF21 deficiency in the liver caused marked loss of FGF21 protein circulating in the blood. Moreover, the protective effects of hepatic JNK deficiency to suppress metabolic syndrome in high-fat diet-fed mice were not observed in mice with hepatocyte-specific FGF21 deficiency, including reduced blood glucose concentration and reduced intolerance to glucose and insulin. Furthermore, we show that JNK contributes to the regulation of hepatic FGF21 expression during fasting/feeding cycles. These data demonstrate that the hepatokine FGF21 is a key mediator of JNK-regulated metabolic syndrome. PMID- 26947076 TI - The Nuclear Transport Factor Kap121 Is Required for Stability of the Dam1 Complex and Mitotic Kinetochore Bi-orientation. AB - The karyopherin (Kap) family of nuclear transport factors facilitates macromolecular transport through nuclear pore complexes (NPCs). The binding of Kaps to their cargos can also regulate, both temporally and spatially, the interactions of the cargo protein with interacting partners. Here, we show that the essential yeast Kap, Kap121, binds Dam1 and Duo1, components of the microtubule (MT)-associated Dam1 complex required for linking dynamic MT ends with kinetochores (KTs). Like mutations in the Dam1 complex, loss of Kap121 function compromises the formation of normal KT-MT attachments during mitosis. We show that the stability of the Dam1 complex in vivo is dependent on its association with Kap121. Furthermore, we show that the Kap121/Duo1 complex is maintained in the presence of RanGTP but Kap121 is released by the cooperative actions of RanGTP and tubulin. We propose that Kap121 stabilizes the Dam1 complex and participates in escorting it to spindle MTs. PMID- 26947075 TI - Mutant KRas-Induced Mitochondrial Oxidative Stress in Acinar Cells Upregulates EGFR Signaling to Drive Formation of Pancreatic Precancerous Lesions. AB - The development of pancreatic cancer requires the acquisition of oncogenic KRas mutations and upregulation of growth factor signaling, but the relationship between these is not well established. Here, we show that mutant KRas alters mitochondrial metabolism in pancreatic acinar cells, resulting in increased generation of mitochondrial reactive oxygen species (mROS). Mitochondrial ROS then drives the dedifferentiation of acinar cells to a duct-like progenitor phenotype and progression to PanIN. This is mediated via the ROS-receptive kinase protein kinase D1 and the transcription factors NF-kappaB1 and NF-kappaB2, which upregulate expression of the epidermal growth factor, its ligands, and their sheddase ADAM17. In vivo, interception of KRas-mediated generation of mROS reduced the formation of pre-neoplastic lesions. Hence, our data provide insight into how oncogenic KRas interacts with growth factor signaling to induce the formation of pancreatic cancer. PMID- 26947077 TI - Context-Dependent Development of Lymphoid Stroma from Adult CD34(+) Adventitial Progenitors. AB - Despite the key role of primary and secondary lymphoid organ stroma in immunity, our understanding of the heterogeneity and ontogeny of these cells remains limited. Here, we identify a functionally distinct subset of BP3( )PDPN(+)PDGFRbeta(+)/alpha(+)CD34(+) stromal adventitial cells in both lymph nodes (LNs) and thymus that is located within the vascular niche surrounding PDPN(-)PDGFRbeta(+)/alpha(-)Esam-1(+)ITGA7(+) pericytes. CD34(+) adventitial cells developed in late embryonic thymus and in postnatal LNs and in the thymus originated, along with pericytes, from a common anlage-seeding progenitor population. Using lymphoid organ re-aggregate grafts, we demonstrate that adult CD34(+) adventitial cells are capable of differentiating into multiple lymphoid stroma-like subsets including pericyte-, FRC-, MRC-, and FDC-like cells, the development of which was lymphoid environment-dependent. These findings extend the current understanding of lymphoid mesenchymal cell heterogeneity and highlight a role of the CD34(+) adventitia as a potential ubiquitous source of lymphoid stromal precursors in postnatal tissues. PMID- 26947079 TI - CARMA3 Is a Host Factor Regulating the Balance of Inflammatory and Antiviral Responses against Viral Infection. AB - Host response to RNA virus infection is sensed by RNA sensors such as RIG-I, which induces MAVS-mediated NF-kappaB and IRF3 activation to promote inflammatory and antiviral responses, respectively. Here, we have found that CARMA3, a scaffold protein previously shown to mediate NF-kappaB activation induced by GPCR and EGFR, positively regulates MAVS-induced NF-kappaB activation. However, our data suggest that CARMA3 sequesters MAVS from forming high-molecular-weight aggregates, thereby suppressing TBK1/IRF3 activation. Interestingly, following NF kappaB activation upon virus infection, CARMA3 is targeted for proteasome dependent degradation, which releases MAVS to activate IRF3. When challenged with vesicular stomatitis virus or influenza A virus, CARMA3-deficient mice showed reduced disease symptoms compared to those of wild-type mice as a result of less inflammation and a stronger ability to clear infected virus. Altogether, our results reveal the role of CARMA3 in regulating the balance of host antiviral and pro-inflammatory responses against RNA virus infection. PMID- 26947078 TI - Multilevel Genomics-Based Taxonomy of Renal Cell Carcinoma. AB - On the basis of multidimensional and comprehensive molecular characterization (including DNA methalylation and copy number, RNA, and protein expression), we classified 894 renal cell carcinomas (RCCs) of various histologic types into nine major genomic subtypes. Site of origin within the nephron was one major determinant in the classification, reflecting differences among clear cell, chromophobe, and papillary RCC. Widespread molecular changes associated with TFE3 gene fusion or chromatin modifier genes were present within a specific subtype and spanned multiple subtypes. Differences in patient survival and in alteration of specific pathways (including hypoxia, metabolism, MAP kinase, NRF2-ARE, Hippo, immune checkpoint, and PI3K/AKT/mTOR) could further distinguish the subtypes. Immune checkpoint markers and molecular signatures of T cell infiltrates were both highest in the subtype associated with aggressive clear cell RCC. Differences between the genomic subtypes suggest that therapeutic strategies could be tailored to each RCC disease subset. PMID- 26947081 TI - Loss of a Single Mcl-1 Allele Inhibits MYC-Driven Lymphomagenesis by Sensitizing Pro-B Cells to Apoptosis. AB - MCL-1 is critical for progenitor cell survival during emergency hematopoiesis, but its role in sustaining cells undergoing transformation and in lymphomagenesis is only poorly understood. We investigated the importance of MCL-1 in the survival of B lymphoid progenitors undergoing MYC-driven transformation and its functional interactions with pro-apoptotic BIM and PUMA and the tumor suppressor p53 in lymphoma development. Loss of one Mcl-1 allele almost abrogated MYC-driven lymphoma development owing to a reduction in lymphoma initiating pre-B cells. Although loss of the p53 target PUMA had minor impact, loss of one p53 allele substantially accelerated lymphoma development when MCL-1 was limiting, most likely because p53 loss also causes defects in non-apoptotic tumor suppressive processes. Remarkably, loss of BIM restored the survival of lymphoma initiating cells and rate of tumor development. Thus, MCL-1 has a major role in lymphoma initiating pro-B cells to oppose BIM, which is upregulated in response to oncogenic stress. PMID- 26947080 TI - p73 Is Required for Multiciliogenesis and Regulates the Foxj1-Associated Gene Network. AB - We report that p73 is expressed in multiciliated cells (MCCs), is required for MCC differentiation, and directly regulates transcriptional modulators of multiciliogenesis. Loss of ciliary biogenesis provides a unifying mechanism for many phenotypes observed in p73 knockout mice including hydrocephalus; hippocampal dysgenesis; sterility; and chronic inflammation/infection of lung, middle ear, and sinus. Through p73 and p63 ChIP-seq using murine tracheal cells, we identified over 100 putative p73 target genes that regulate MCC differentiation and homeostasis. We validated Foxj1, a transcriptional regulator of multiciliogenesis, and many other cilia-associated genes as direct target genes of p73 and p63. We show p73 and p63 are co-expressed in a subset of basal cells and suggest that p73 marks these cells for MCC differentiation. In summary, p73 is essential for MCC differentiation, functions as a critical regulator of a transcriptome required for MCC differentiation, and, like p63, has an essential role in development of tissues. PMID- 26947082 TI - Motivational dynamics underlying eating regulation in young and adult female dieters: relationships with healthy eating behaviours and disordered eating symptoms. AB - OBJECTIVE: To investigate whether type of goals and motives underlying females' eating regulation are associated differentially with daily eating behaviours, dependent upon weight and age category. DESIGN: 99 late adolescent female dieters (Mage = 18.94) and 98 adult female dieters (Mage = 45.06), 23.6% of which were overweight, completed a questionnaire and a 7-day diary assessment. Descriptive analysis and path analysis were performed to investigate the research questions. MAIN OUTCOME MEASURES: Healthy eating behaviours (HEHS), drive for thinness and binge eating symptoms (EDI). RESULTS: Appearance-focused and controlled eating regulation were positively related to disordered eating symptoms throughout the week. In contrast, autonomous and health-focused eating regulation were associated positively with healthy eating behaviours and were either related negatively or unrelated to disordered eating symptoms. Mean level differences in motivation and eating behaviours emerged according to age and weight status. However, the examined structural model was similar for late adolescent and adult dieters and only few differences emerged between normal-weight and overweight dieters. CONCLUSION: Dieters' type of motivation helps to explain when eating regulation relates to healthy and disordered eating symptoms. PMID- 26947083 TI - The effectiveness of a standardised positioning tool and bedside education on the developmental positioning proficiency of NICU nurses. AB - In order to improve the developmental proficiency of neonatal intensive care unit nurses, a standardised infant positioning assessment tool and a bedside education programme were introduced to the registered nurses in a 46 bed level III neonatal intensive care unit in the western United States. A developmental positioning team collected pre-intervention positioning scores on 54 preterm infants. This was followed by a survey of the registered nurses beliefs and attitudes, the introduction of the standardised assessment tool and an informal education programme. Post-intervention positioning scores were collected on 55 preterm infants, and analysis of the data indicated there was a statistically significant change in mean positioning scores. Additionally, the registered nurses identified several barriers to the implementation of developmental positioning. This research indicates the use of a standardised infant positioning assessment tool and bedside education may be useful strategies for improving the developmental positioning proficiency of NICU nurses. PMID- 26947087 TI - Exploring diabetes management amongst immigrant Sikhs in the Greater Toronto Area: a qualitative study. AB - OBJECTIVES: This study describes the ethnocultural influences associated with managing diabetes (Type 2) in a small sample of older Sikh immigrants in Toronto, Canada. The South Asian community, which includes Sikhs, is the fastest growing immigrant population, the second largest visible minority in Canada, and is five times more likely to have diabetes than their Canadian counterparts. The relationship between culture, immigration, and management of diabetes has been recognized, but research of how these areas intersect in the Sikh community is sparse. DESIGN: Data were collected using qualitative semi-structured interviews, and participants were recruited via purposive and snowball sampling techniques. Data were analysed using constant comparative methods. RESULTS: The complexities of diabetes management are organized in this study as the (1) external (2) internal and (3) actualized experiences participants faced navigating cultural dynamics, understanding their diagnosis, and interacting with health resources. CONCLUSION: An individual's diabetes diagnosis and treatment plan interacts with layers beyond the health system which must be understood in order to provide health care that is truly an empowering resource. PMID- 26947089 TI - [Novelties in diagnostics and treatment of prostate cancer]. AB - Similarly to earlier years, a vast majority of novel findings were published on prostate cancer, which is the most common urological cancer. Clinical trials with long-term follow-up and promising observational studies were published. In this paper the author reviews the relevant novelties including the diagnostic use of magnetic resonance imaging and positron emission tomography/computed tomography as well as active surveillance, cytoreductive prostatectomy and medical treatment. PMID- 26947088 TI - [Vertigo in the Emergency Department: new bedside tests]. AB - According to international statistics, the first examination of 25% of patients with vertigo is carried out in Emergency Departments. The most important task of the examining physician is to diagnose life threatening pathologic processes. One of the most difficult otoneurological diagnostic challange in Emergency Departments is to differentiate between dangerous posterior scale stroke presenting with isolated vertigo and the benign vestibular neuritis.These two disorders can be safely differentiated using fast, non-invasive, evidence based bedside tests which have been introduced in the past few years. 35% of stroke cases mimicking vestibular neuritis (pseudoneuritis) are misdiagnosed at the Emergency Department, and 40% of these cases develop complications. During the first 48 hours, sensitivity for stroke of the new test that is based on the malfunction of the oculomotor system is better than the diffusion-weighted cranial magnetic resonance imaging. Using special test glasses each component of the new test can be made objective and repeatable. PMID- 26947090 TI - [Changes in the situation in out-of-hospital birth and the role of midwives in Hungary]. AB - The rate of homebirth decreased significantly by the 20th century, however, the practice has never disappeared. The Hungarian government issued a regulation of out-of-hospital birth in 2011, then allowed midwives to provide prenatal care for low-risk mothers in 2014. These were great steps toward the midwifery model of care. In this study the authors gathered the statistics of three licensed Hungarian out-of-hospital service providers. Despite the low number of cases, the data confirm that the rate of hospital transports in Hungary is quite similar to those found in other countries. The authors present five different studies to demonstrate that home births are just as safe as hospital births. Finally, the authors summarize a study in which hospital transports based on several criteria were analyzed. The authors conclude that in these events, fear and prejudice influences the participants on either side, harming interprofessional relationships. To improve the care given, mutually respectful communication and education of families about the option of hospital transport are key issues. PMID- 26947091 TI - [One year persistence of atorvastatin and amlodipine fixed dose combination versus atorvastatin therapy]. AB - INTRODUCTION: Hypertension and dyslipidemia are modifiable cardiovascular risk factors. In Hungary hypertension and dyslipidemia are quite frequent conditions. The patients' adherence is very important factor to reach the targets. AIM: The aim of the authors was to investigate the one-year persistence of the atorvastatin therapy and atorvastatin and amlodipine fixed dose combination. METHOD: National Health Insurance Found prescriptions database of Hungary on pharmacy claims between October 1, 2012 and September 30, 2013 was analyzed. The authors identified patients who filled prescriptions for atorvastatin and amlodipine fixed dose combination and atorvastatin prescribed for the first time. Patients did not receive similar drugs for one year before the study. To model the persistence, the apparatus of survival analysis was used, where "survival" was the time to abandon the medication. As it was available to month precision, discrete time survival analysis was applied: a generalized linear model was estimated with complementary log-log link function with the kind of drug being the only explanatory variable. RESULTS: During the trial period, atorvastatin and atorvastatin plus amlodipine fixed dose combination was started in 192,579 and 24,433 patients, respectively. One year persistence rate in patients with atorvastatin and amlodipine fixed dose combination was 43%, and 21% in patients with atorvastatin therapy. The 360-days-restricted study period, the mean duration of persistence was 221.4 (SE: 0.894) days in patients on atorvastatin and amlodipine fixed dose combination and 153.0 days (SE: 0.297) in those on atorvastatin regimen. The hazard of discontinuation was almost twofold higher during treatment with atorvastatin therapy compared with the use of the atorvastatin and amlodipine fixed dose combination (hazard ratio = 1.85, p<0.0001). CONCLUSIONS: There is a significant difference between the one-year persistence of atorvastatin therapy and atorvastatin plus amlodipine fixed dose combination. The result demonstrate that atorvastatin and amlodipine fixed dose combination is favourable to reach double goals on blood pressure and LDL cholesterol. PMID- 26947092 TI - [Forensic analysis of injuries in dentistry]. AB - INTRODUCTION: Documentation and evaluation of dental injuries in forensic medicine are rather problematic. It needs a professional work up why dental injuries are out of focus, and how the diagnosis, pattern and treatment are influenced by novel approaches of dentistry. AIM: The aims of the authors were to characterize dental injuries, to compare their own findings to literature data concerning the type and characteristics of injuries, and propose a diagnostic workflow. METHOD: Expert's reports between 2009 and 2013 at the Department of Forensic Medicine, University of Szeged were reviewed. RESULTS: Review of about 7000 reports revealed only 20 cases with dental injury, which is in contrast with literature data indicating a significantly higher frequency of dental injuries. CONCLUSIONS: Although the number of "dental cases" was low, there were several additional cases where the trauma probably affected the teeth but the injury was not documented. In future more attention is needed in forensic evaluation of the mechanism, therapeutic strategy and prognosis of dental injuries. PMID- 26947093 TI - [Effective palliative chemotherapy in a patient with collecting duct carcinoma of a unilateral kidney associated with anuria. Case report]. AB - The case of a 54-year-old woman is presented. She underwent right sided unilateral nephrectomy for metastatic bilateral renal tumour of the Bellini collecting ducts. Progression of the contralateral tumour resulted in acute complete anuric renal failure. Haemodialysis was started along with palliative gemcitabine (1000 mg/m(2))-cisplatine (70 mg/m(2)) chemotherapy. In parallel, renal function was improving and dialysis could be stopped at the end of the chemotherapy line comprising 6 cycles. Half a year later the patient was lost of uncontrolled local and pulmonary progression. The potentially nephrotoxic cisplatine chemotherapy associated to complex supportive treatment improved the renal function by controlling diffusely infiltrative tumour growth and allowed a survival benefit over one year with active household keeping capacity. PMID- 26947095 TI - [Classic pachydermodactyly. A simulator of juvenile idiopathic arthritis]. PMID- 26947096 TI - [Changes in homecare for preterm and low-birth-weight infants from 2002 to 2014]. AB - INTRODUCTION: Homecare (HC) is a service offering home medical and nursing care to the patient at home in equal quantity and quality as in the hospital. The aim of the article is to describe the changes in the HC of preterm and full-term low birth-weight infants in our department from 2002-2014. MATERIAL AND METHODS: The HC database is revised. The characteristics of the newborns and the social characteristics of the family in three consecutive time periods are analysed. A satisfaction survey of parents is also presented. RESULTS: The main changes in HC include a decrease in the weight at discharge (from 1880g in the 2002-2006 period to 1850g in the 2011-2014 period; P=.006) and at the end of HC (from 2187g to 2163g; P=.001), an increase in the duration of HC (from 10 to 11 days; P=.007) and a lower incidence of new hospitalization (from 3.4% to 1.3%; P=.019) The social characteristics of the family show a higher maternal age with more previous alive children, a family context better suited with a more appropriate housing, and an increase in exclusive breastfeeding at hospital discharge (from 25.5% to 49.0%; P<.001). The overall assessment of the program is >=7/10 in 98.8% of responses. CONCLUSIONS: The results of the HC of preterm and low-birth-weight infants have improved over time, saving approximately 10-11 days of hospitalisation, and without compromising the quality of care or reducing family satisfaction. PMID- 26947097 TI - Upper-limb stroke rehabilitation using electrode-array based functional electrical stimulation with sensing and control innovations. AB - Functional electrical stimulation (FES) has shown effectiveness in restoring upper-limb movement post-stroke when applied to assist participants' voluntary intention during repeated, motivating tasks. Recent clinical trials have used advanced controllers that precisely adjust FES to assist functional reach and grasp tasks with FES applied to three muscle groups, showing significant reduction in impairment. The system reported in this paper advances the state-of the-art by: (1) integrating an FES electrode array on the forearm to assist complex hand and wrist gestures; (2) utilising non-contact depth cameras to accurately record the arm, hand and wrist position in 3D; and (3) employing an interactive touch table to present motivating virtual reality (VR) tasks. The system also uses iterative learning control (ILC), a model-based control strategy which adjusts the applied FES based on the tracking error recorded on previous task attempts. Feasibility of the system has been evaluated in experimental trials with 2 unimpaired participants and clinical trials with 4 hemiparetic, chronic stroke participants. The stroke participants attended 17, 1 hour training sessions in which they performed functional tasks, such as button pressing using the touch table and closing a drawer. Stroke participant results show that the joint angle error norm reduced by an average of 50.3% over 6 attempts at each task when assisted by FES. PMID- 26947099 TI - A cost-utility analysis for catheter ablation of atrial fibrillation in combination with warfarin and dabigatran based on the CHADS2 score in Japan. AB - BACKGROUND: We aimed to clarify the cost-effectiveness of an expensive combination therapy for atrial fibrillation (AF) using both catheter ablation and dabigatran compared with warfarin at each CHADS2 score for patients in Japan. METHODS: A Markov model was constructed to analyze costs and quality-adjusted life years associated with AF therapeutic options with a time horizon of 10 years. The target population was 60-year-old patients with paroxysmal AF. The indication for anticoagulation was determined according to the Japanese guideline. Anticoagulation-related data were derived from the RE-LY study and the AF recurrence rate was set at 2.7% per month during the first 12 months and at 0.40% per month afterwards. Stroke risk was determined according to AF recurrence, anticoagulation, and CHADS2 score. The risks for stroke recurrence and stroke death were also considered. Costs were calculated from the healthcare payer's perspective, and only direct medical costs were included. RESULTS: Warfarin was the most preferred option for patients with a CHADS2 score of 0 from a health economics aspect. Ablation under warfarin was preferred for a CHADS2 score of 1-3, while ablation under dabigatran was preferred for a CHADS2 score >=4. The quality of life score for AF had the largest impact on the incremental cost-effectiveness ratios in the analysis between the anticoagulation arm and the anticoagulation+ablation arm for a CHADS2 score of 2. Within the range of the Japanese willingness-to-pay threshold (Y5,000,000), the ablation+warfarin arm became the best option with its probability of 81.7% for a CHADS2 score of 2; the dabigatran+ablation arm was the most preferred option with its probability of 56.1% for a CHADS2 score of 4. CONCLUSIONS: Ablation under dabigatran therapy is an expensive therapeutic option, but it might benefit patients with a low quality of life and a high CHADS2 score. PMID- 26947098 TI - Lysine-specific demethylase-1 (LSD1) is compartmentalized at nuclear chromocenters in early post-mitotic cells of the olfactory sensory neuronal lineage. AB - Mammalian olfaction depends on the development of specialized olfactory sensory neurons (OSNs) that each express one odorant receptor (OR) protein from a large family of OR genes encoded in the genome. The lysine-specific demethylase-1 (LSD1) protein removes activating H3K4 or silencing H3K9 methylation marks at gene promoters and is required for proper OR regulation. We show that LSD1 protein exhibits variable organization within nuclei of developing OSNs, and tends to consolidate into a single dominant compartment at the edges of chromocenters within nuclei of early post-mitotic cells of the mouse olfactory epithelium (MOE). Using an immortalized cell line derived from developing olfactory placode, we show that consolidation of LSD1 appears to be cell-cycle regulated, with a peak occurrence in early G1. LSD1 co-compartmentalizes with CoREST, a protein known to collaborate with LSD1 to carry out a variety of chromatin-modifying functions. We show that LSD1 compartments co-localize with 1 3 OR loci at the exclusion of most OR genes, and commonly associate with Lhx2, a transcription factor involved in OR regulation. Together, our data suggests that LSD1 is sequestered into a distinct nuclear space that might restrict a histone modifying function to a narrow developmental time window and/or range of OR gene targets. PMID- 26947100 TI - Impact of additional intracoronary nicorandil administration during fractional flow reserve measurement with intravenous adenosine 5'-triphosphate infusion. AB - BACKGROUND: Fractional flow reserve (FFR) is a useful index for determining the functional severity of epicardial coronary artery stenosis as an invasive physiological method. Although intravenous adenosine 5'-triphosphate (ATP) is generally used as a hyperemic agent for FFR measurement in Japan, there are some concerns about the variability of FFR measurement (short half-life, effect of caffeine, cyclic change). It is difficult to confirm sufficient maximum hyperemia after ATP infusion. Recent studies reported that nicorandil (NIC) could be an alternative to ATP as a hyperemic agent. METHODS: Patients who underwent FFR assessments of angiographically intermediate lesions were included. All patients were asked to refrain from caffeine-containing products more than 12hours before FFR measurements. All patients first received intravenous (IV) ATP infusion (180MUg/kg/min) for 3min to measure FFR (ATP-FFR). After additional intracoronary (IC) NIC administration (2mg/30s) during ATP infusion, FFR was measured again (NIC-FFR). To check cyclic change in FFR, we measured minimum and maximum FFR values during both ATP and NIC hyperemic phase. RESULTS: In this study, 94 patients with 94 lesions were enrolled. Mean FFR value was 0.81+/-0.10 in ATP-FFR infusion and 0.80+/-0.09 in NIC-FFR, respectively. ATP-FFR and NIC-FFR had a strong correlation on the whole (r=0.92, p<0.001). In 18 patients (19%), FFR values were significantly lower in NIC-FFR than in ATP-FFR. In one-third of those patients (6%), it was possible to change therapeutic strategy from deferral range (>0.80) to interventional range (?0.80) after NIC-FFR measurements. Cyclic change in FFR was smaller in NIC-FFR than in ATP-FFR (0.03+/-0.02 vs. 0.06+/-0.05, p<0.0001). CONCLUSION: Additional IC NIC might be useful to confirm sufficient maximum hyperemia after IV ATP infusion in daily clinical practice. Furthermore, IC NIC could reduce cyclic change in FFR; thus, physicians might find it easier to determine FFR value during the procedure. PMID- 26947101 TI - Optimal cut-off value of reverse remodeling to predict long-term outcome after cardiac resynchronization therapy in patients with ischemic cardiomyopathy. AB - BACKGROUND: Whether the optimal cut-off value of left ventricular (LV) reverse remodeling is different in patients with ischemic cardiomyopathy (ICM) vs. non ischemic cardiomyopathy (NICM) is unclear. This study aimed to clarify this value in patients with ICM and NICM. METHODS AND RESULTS: LV reverse remodeling was defined as a reduction in LV end-systolic volume (LVESV) at 6 months after cardiac resynchronization therapy (CRT). The clinical endpoint was the combination of cardiac death and first hospitalization for worsening heart failure. Ninety-one of 372 patients had ICM. Event-free survival rates did not differ between ICM and NICM groups (66.8% vs. 78.9%; p=0.12). Receiver operating characteristics analysis revealed a 9% reduction in ESV as the optimal cut-off value to predict the composite endpoint in patients with ICM and a 15% reduction in patients with NICM. Multivariate analysis revealed that reductions in ESV of >=15% and >=9% were independent predictors of the composite endpoint, as were left bundle branch block (LBBB) and B-type natriuretic peptide (BNP) at 6 months after CRT. In combination with LBBB and BNP, reduction in ESV >=9% had a higher, but not significant, C-statistics value than ESV >=15% (0.854, 95% CI 0.729-0.940 vs. 0.801, 95% CI 0.702-0.908, p=0.07). CONCLUSION: The optimal cut-off value of a reduction in LVESV was lower in patients with ICM than in patients with NICM. PMID- 26947102 TI - Effect of an intensive metabolic control lifestyle intervention in type-2 diabetes patients. AB - OBJECTIVE: To evaluate the effectiveness of an intensive lifestyle intervention on metabolic control in patients with type 2 diabetes. METHODS: 199 patients recently diagnosed with type 2 diabetes, with lack of metabolic control and overweight/obesity, were randomly assigned to intensive lifestyle intervention or collaborative educational program alone, with 6 months of follow-up. Intervention included 150min of physical activity a week to reduce body weight by 7%. Both groups received 16 sessions on behavior modification over the course of the 6 months. Measurements were taken at baseline, 3 and 6 months. Results were analyzed and compared. RESULTS: Significant weight loss was achieved by both groups, with greater loss in the intervention group. Those with lower baseline A1c appeared to benefit more from the educational program than intensive intervention over time. CONCLUSIONS: Both interventions produced positive if modest changes in metabolic control. These results suggest that, for weight loss and control of A1c, an intensive intervention may be more effective. PRACTICE IMPLICATIONS: The current study demonstrates the value of a systematic application of behavior modification and self-care techniques in the treatment of type 2 diabetes. It demonstrates the importance of intensive, all-inclusive treatment, and of attention to individual concerns. PMID- 26947103 TI - A structural investigation of ionic liquid mixtures. AB - The structures of mixtures of ionic liquids (ILs) featuring a common 1-butyl-3 methylimidazolium ([C4C1im](+)) cation but different anions have been investigated both experimentally and computationally. (1)H and (13)C NMR of the ILs and their mixtures has been performed both on the undiluted liquids and those diluted by CD2Cl2. These experiments have been complemented by quantum chemical density functional theory calculations and molecular dynamics simulations. These techniques have identified the formation of preferential interactions between H(2) of the imidazolium cation and the most strongly hydrogen bond (H-bond) accepting anion. In addition, a preference for the more weakly H-bond accepting anion to interact above the imidazolium ring through anion-pi(+) interactions has been identified. The modelling of these data has identified that the magnitude of these preferences are small, of the order of only a few kJ mol(-1), for all IL mixtures. No clustering of the anions around a specific cation could be observed, indicating that these interactions arise from the reorientation of the cation within a randomly assigned network of anions. pi(+)-pi(+) stacking of the imidazolium cations was also studied and found to be promoted by ILs with a strong H-bond accepting anion. Stacking interactions are easily disrupted by the introduction of small proportions (<50 mol%) of a weakly coordinating anion due to their propensity to form anion-pi(+) interactions. These results suggest that the formation of IL mixtures with different anions leads to subtle structural changes of much lower energy than the Coulombic ordering of ions, accounting for why most IL mixtures exhibit ideal, or nearly ideal, behaviour. PMID- 26947104 TI - Acute necrosis after Gamma Knife surgery in vestibular schwannoma leading to multiple cranial nerve palsies. AB - We discuss a rare acute complication after Gamma Knife therapy (Elekta AB, Stockholm, Sweden) in a single patient. A 52-year-old woman presented with vertigo, facial weakness and hearing loss emerging 48hours following Gamma Knife radiosurgery for a right-sided vestibular schwannoma. Neurological examination 6days after symptom onset showed right-sided facial palsy, spontaneous left beating nystagmus and pathologic head-impulse testing to the right. Pure-tone audiogram revealed right-sided sensorineural hearing loss. A diagnosis of acute vestibulocochlear and facial neuropathy was made. Brain MRI demonstrated focal contrast sparing within the schwannoma, likely related to acute radiation necrosis. Acute multiple cranial neuropathies of the cerebellopontine angle after Gamma Knife treatment should raise suspicion of acute tissue damage within the schwannoma and should result in urgent MRI. Treatment with steroids may be considered based on accompanying swelling and edema. PMID- 26947105 TI - Intestinal microbiota: From sequencing to function. PMID- 26947106 TI - Immediate facial reanimation in oncological parotid surgery with neurorrhaphy of the masseteric-thoracodorsal-facial nerve branch. AB - The extracranial facial nerve may be sacrificed together with the parotid gland during a radical parotidectomy, and immediate reconstruction of the facial nerve is essential to maintain at least part of its function. We report five patients who had had radical parotidectomy (two with postoperative radiotherapy) and immediate (n=3) or recent (n=2) reconstructions of the masseteric-thoracodorsal facial nerve branch. The first mimetic musculature movements started 6.2 (range 4 8.5) months postoperatively. At 24 months postoperatively clinical evaluation (modified House-Brackmann classification) showed grade V (n=3), grade IV (n=1), and grade III (n=1) repairs. This first clinical series of masseteric thoracodorsal-facial nerve neurorrhaphies has given encouraging results, and the technique should be considered as an option for immediate or recent reconstruction of branches of the facial nerve, particularly when its trunk is not available for proximal neurorrhaphy. PMID- 26947107 TI - Platysma flap using dual skin paddles. AB - The platysma myocutaneous flap is rarely reported as an option for reconstruction in the head and neck. In our experience it is a reliable flap that is easy to raise, has a limited risk of morbidity at the donor site, and allows for early recommencement of oral function. We report a patient with an unusually aggressive orocutaneous fistula that complicated the simple extraction of teeth. We modified the platysma flap to provide two independent skin paddles so we could reconstruct both the intraoral and cutaneous defects simultaneously with a good clinical outcome. PMID- 26947108 TI - Conjunctival chemosis: an uncommon complication after transcrestal lifting of the sinus floor. PMID- 26947109 TI - Intraorbital aspergilloma: a rare cause of orbital apex syndrome. PMID- 26947110 TI - Extraction of impacted mandibular third molars - the effect of osteotomy at two speeds on peripheral bone: a histopathological analysis. AB - The aim of this study was to find out the ideal speed for making a precise osteotomy with minimal damage to the surrounding bone. Thirty-six patients were divided into two groups (n=18 in each) depending on the speed of the handpiece used for osteotomy (slow=20000rpm and fast=40000rpm). Samples were taken from the peripheral bone and examined histologically to measure the margins of the osteotomy, the amount of debris produced, and the degree of thermal osteonecrosis. The osteotomy made with the high speed handpiece was better than that made with the low speed one on all counts. The margins in the high speed group were more or less precisely as required, with less debris and no thermal necrosis, which illustrated the efficacy of a high speed osteotomy. These findings can apply to other procedures that involve osteotomies in maxillofacial surgery. PMID- 26947111 TI - Subacute stress and chronic stress interact to decrease intestinal barrier function in rats. AB - Psychological stress increases intestinal permeability, potentially leading to low-grade inflammation and symptoms in functional gastrointestinal disorders. We assessed the effect of subacute, chronic and combined stress on intestinal barrier function and mast cell density. Male Wistar rats were allocated to four experimental groups (n = 8/group): 1/sham; 2/subacute stress (isolation and limited movement for 24 h); 3/chronic crowding stress for 14 days and 4/combined subacute and chronic stress. Jejunum and colon were collected to measure: transepithelial electrical resistance (TEER; a measure of epithelial barrier function); gene expression of tight junction molecules; mast cell density. Plasma corticosterone concentration was increased in all three stress conditions versus sham, with highest concentrations in the combined stress condition. TEER in the jejunum was decreased in all stress conditions, but was significantly lower in the combined stress condition than in the other groups. TEER in the jejunum correlated negatively with corticosterone concentration. Increased expression of claudin 1, 5 and 8, occludin and zonula occludens 1 mRNAs was detected after subacute stress in the jejunum. In contrast, colonic TEER was decreased only after combined stress, and the expression of tight junction molecules was unaltered. Increased mast cell density was observed in the chronic and combined stress condition in the colon only. In conclusion, our data show that chronic stress sensitizes the gastrointestinal tract to the effects of subacute stress on intestinal barrier function; different underlying cellular and molecular alterations are indicated in the small intestine versus the colon. PMID- 26947113 TI - Organ Donor Recovery Performed at an Organ Procurement Organization-Based Facility Is an Effective Way to Minimize Organ Recovery Costs and Increase Organ Yield. AB - BACKGROUND: A new era in organ donation with national redistricting is being proposed. With these proposals, costs of organ acquisition are estimated to more than double. Traditionally, organ recoveries occur in the donor hospital setting, incurring premium hospital expenses. The aim of the study was to determine organ recovery costs and organ yield for donor recoveries performed at an organ procurement organization (OPO) facility. STUDY DESIGN: In 2001, we established an OPO facility and in 2008 began transferring the donor expeditiously when brain death was declared. The OPO donor and hospital costs on a per donor basis were calculated. Donation after cardiac death donors cannot be transferred and were included in the hospital cost analysis. RESULTS: From January 2009 to December 2014, nine hundred and sixty-three donors originating in our OPO had organs recovered and transplanted. Seven hundred and sixty-six (79.5%) donors were transferred to the OPO facility 8.6 hours (range 0.6 to 23.6 hours) after declaration of brain death. Donor recovery cost was 51% less when donors were transferred to the OPO facility ($16,153 OPO recovery vs $33,161 hospital recovery; p < 0.0001). Organ yield was 27.5% better (3.43 organs) from OPO recovered donors vs an organ yield of 2.69 from hospital-recovered donors (p < 0.0001). Standard criteria donor organ yield from our OPO was 6% higher than the national average (3.92 vs 3.7 nationally; p = 0.012) and expanded criteria donor organ yield was 18% higher (2.2 vs 1.87 nationally; p = 0.03). CONCLUSIONS: An OPO facility for donor organ recovery increases efficiency and organ yield, reduces costs, and minimizes organ acquisition charge. As we face new considerations with broader sharing, increased efficiencies, cost. and organ use should be considered. PMID- 26947114 TI - Management of Otic and Nasopharyngeal, and Nasal Polyps in Cats and Dogs. AB - Feline inflammatory polyps are the most common nonneoplastic lesion of ear and nasopharynx in cats. Minimally invasive techniques for polyp removal, such as traction avulsion combined with curettage of the tympanic cavity and per endoscopic transtympanic traction, have been successful for long-term resolution. Feline nasal hamartomas are benign lesions of the nasopharynx, and most have a good prognosis after surgical removal. Canine aural and nasopharyngeal inflammatory polyps are rare and have a similar clinical presentation as cats with these lesions. In dogs, it is important to achieve an accurate histologic diagnosis of these masses before appropriate surgical treatment can be planned. PMID- 26947115 TI - Surgical Treatment of Laryngeal Paralysis. AB - Unilateral arytenoid lateralization is the most commonly used technique to treat laryngeal paralysis. It is important not to overabduct the arytenoid cartilage during the unilateral lateralization to minimize exposure of the rima glottides. Dogs with laryngeal paralysis treated with unilateral lateralization have a good long-term prognosis. Idiopathic polyneuropathy is the most common cause of laryngeal paralysis in dogs. PMID- 26947117 TI - Semantic processing in the left versus right cerebral hemispheres following unilateral hand contractions. AB - Unilateral hand contractions increase activation in the motor cortex of the contralateral hemisphere, providing a means to alter the relative degree of activation in the right hemisphere versus the left hemisphere through spreading activation. Prior research reported enhanced verbal creativity as measured by performance on remote associate problems in Hebrew from left-hand contractions (right-hemisphere activation). We sought to extend the previous findings to English problems and to homograph interpretation. In Experiment 1, unilateral hand contractions in fact altered performance on the English remote associates, but in the direction of improved performance following right-hand contractions and left-hemisphere activation. In Experiment 2, the probability of retrieving atypical interpretations of homographs with multiple meanings was least likely for left-hemisphere dominant strong right handers, but the hand contraction manipulation had no effect. PMID- 26947118 TI - Change Talk During Brief Motivational Intervention With Young Adult Males: Strength Matters. AB - Client change talk (CT) during motivational interviewing (MI) has been described as a predictor of change in alcohol use. We examined the predictive validity of different strength levels of CT within a brief MI session for 174 young men from the general population screened as hazardous drinkers. CT was measured using the MI Skill Code (MISC 2.1) and categorized with positive (toward change) and negative (against change) valence and 3 strength levels (1=low, 2=medium, 3=high). Analyses included linear regression models predicting drinking at 3 month follow-up, while controlling for baseline drinking. Frequency of overall negative CT (i.e., sum of -1, -2, -3) significantly predicted poorer drinking outcomes. In a multivariate model entering frequency of CT utterances at each level of strength (i.e. +1, +2, +3, -1, -2, -3), the directionality of negative strength ratings was consistently in the expected direction, but only CT-2 was statistically significant. In contrast, overall CT positive (i.e., sum of +1, +2, +3) was not a significant predictor of less alcohol use, but the multivariate model showed that the presence of CT+3 significantly predicted less drinking at 3 month follow-up. Averaged strength summary score (i.e. on the scale from -3 to +3) was a significant predictor of better outcome, while percent positive CT was not. Moderation analyses showed that young men with lower baseline readiness to change or lower alcohol problem severity had higher follow-up drinking when they expressed more CT+1 or CT+2, while the opposite pattern was observed with those reporting higher baseline readiness to change or higher alcohol problem severity. Mixed findings for varying levels of positive CT strength might explain previous studies showing poor predictive validity of positive client language in MI. Together with other studies in similar settings, these findings suggest the importance of advanced MI techniques to shape client language to soften negative change talk (also known as sustain talk) and elicit positive CT verbalized with high intensity. PMID- 26947116 TI - DNA-inorganic hybrid nanovaccine for cancer immunotherapy. AB - Cancer evolves to evade or compromise the surveillance of the immune system, and cancer immunotherapy aims to harness the immune system in order to inhibit cancer development. Unmethylated CpG dinucleotide-containing oligonucleotides (CpG), a class of potent adjuvants that activate the toll-like receptor 9 (TLR9) located in the endolysosome of many antigen-presenting cells (APCs), are promising for cancer immunotherapy. However, clinical application of synthetic CpG confronts many challenges such as suboptimal delivery into APCs, unfavorable pharmacokinetics caused by limited biostability and short in vivo half-life, and side effects associated with leaking of CpG into the systemic circulation. Here we present DNA-inorganic hybrid nanovaccines (hNVs) for efficient uptake into APCs, prolonged tumor retention, and potent immunostimulation and cancer immunotherapy. hNVs were self-assembled from concatemer CpG analogs and magnesium pyrophosphate (Mg2PPi). Mg2PPi renders hNVs resistant to nuclease degradation and thermal denaturation, both of which are demanding characteristics for effective vaccination and the storage and transportation of vaccines. Fluorophore-labeled hNVs were tracked to be efficiently internalized into the endolysosomes of APCs, where Mg2PPi was dissolved in an acidic environment and thus CpG analogs were exposed to hNVs. Internalized hNVs in APCs led to (1) elevated secretion of proinflammatory factors, and (2) elevated expression of co-stimulatory factors. Compared with molecular CpG, hNVs dramatically prolonged the tissue retention of CpG analogs and reduced splenomegaly, a common side effect of CpG. In a melanoma mouse model, two injections of hNVs significantly inhibited the tumor growth and outperformed the molecular CpG. These results suggest hNVs are promising for cancer immunotherapy. PMID- 26947122 TI - Lysosomal cell death mechanisms in aging. AB - Lysosomes are degradative organelles essential for cell homeostasis that regulate a variety of processes, from calcium signaling and nutrient responses to autophagic degradation of intracellular components. Lysosomal cell death is mediated by the lethal effects of cathepsins, which are released into the cytoplasm following lysosomal damage. This process of lysosomal membrane permeabilization and cathepsin release is observed in several physiopathological conditions and plays a role in tissue remodeling, the immune response to intracellular pathogens and neurodegenerative diseases. Many evidences indicate that aging strongly influences lysosomal activity by altering the physical and chemical properties of these organelles, rendering them more sensitive to stress. In this review we focus on how aging alters lysosomal function and increases cell sensitivity to lysosomal membrane permeabilization and lysosomal cell death, both in physiological conditions and age-related pathologies. PMID- 26947121 TI - Using Qualitative and Quantitative Assessment to Develop a Patient Safety Curriculum for Surgical Residents. AB - OBJECTIVE: The objective is to use qualitative and quantitative analysis to develop a patient safety curriculum for surgical residents. DESIGN: A prospective study of surgical residents using both quantitative and qualitative methods to craft a patient safety curriculum. Both a survey and focus groups were held before and 4 months after delivery of the patient safety curriculum. SETTING: The University of New Mexico Hospital, a tertiary academic medical center. PARTICIPANTS: General surgery residents, postgraduate years 1 to 5 RESULTS: Qualitative and quantitative analysis revealed areas that required attention and thus helped to mold the curriculum. Qualitative analysis after delivery of the curriculum showed positive changes in attitudes and normative beliefs toward patient safety. Specifically, attitudes and approach to quality improvement and teamwork showed improvement. Survey analysis did not show any significant change in resident perception of the environment during the time frame of this study. CONCLUSIONS: Using qualitative analysis to uncover attitudinal barriers to a safe patient environment can help to enhance the relevance and content of a patient safety curriculum for general surgery residents. PMID- 26947123 TI - What lysosomes actually tell us about Parkinson's disease? AB - Parkinson's disease is a common neurodegenerative disorder of unknown origin mainly characterized by the loss of neuromelanin-containing dopaminergic neurons in the substantia nigra pars compacta and the presence of intraneuronal proteinaceous inclusions called Lewy bodies. Lysosomes are dynamic organelles that degrade, in a controlled manner, cellular components delivered via the secretory, endocytic, autophagic and phagocytic membrane-trafficking pathways. Increasing amounts of evidence suggest a central role of lysosomal impairment in PD aetiology. This review provides an update on how genetic evidence support this connection and highlights how the neuropathologic and mechanistic evidence might relate to the disease process in sporadic forms of Parkinson's disease. Finally, we discuss the influence of ageing on lysosomal impairment and PD aetiology and therapeutic strategies targeting lysosomal function. PMID- 26947124 TI - Imaging of electric and magnetic fields near plasmonic nanowires. AB - Near-field imaging is a powerful tool to investigate the complex structure of light at the nanoscale. Recent advances in near-field imaging have indicated the possibility for the complete reconstruction of both electric and magnetic components of the evanescent field. Here we study the electro-magnetic field structure of surface plasmon polariton waves propagating along subwavelength gold nanowires by performing phase- and polarization-resolved near-field microscopy in collection mode. By applying the optical reciprocity theorem, we describe the signal collected by the probe as an overlap integral of the nanowire's evanescent field and the probe's response function. As a result, we find that the probe's sensitivity to the magnetic field is approximately equal to its sensitivity to the electric field. Through rigorous modeling of the nanowire mode as well as the aperture probe response function, we obtain a good agreement between experimentally measured signals and a numerical model. Our findings provide a better understanding of aperture-based near-field imaging of the nanoscopic plasmonic and photonic structures and are helpful for the interpretation of future near-field experiments. PMID- 26947126 TI - One-Pot Solvothermal Synthesis of Bi4V2O11 as A New Solar Water Oxidation Photocatalyst. AB - Bi4V2O11 was prepared via a one-pot solvothermal method and characterized via XRD, Raman, XPS, Electrochemical impedance spectroscopy. The as-prepared Bi4V2O11 sample displays excellent photocatalytic activity towards oxygen evolution under light irradiation. The hierarchical structure is in favour of the spatial separation of photogenerated electrons and holes. Furthermore, the internal polar field also plays a role in improving the charge separation. Both of the two results are responsible for excellent activity of O2 evolution. The resulting hierarchical Bi4V2O11 sample should be very promising photocatalyst for the application of photocatalytic O2 evolution in the future. PMID- 26947125 TI - The loop structure and the RNA helicase p72/DDX17 influence the processing efficiency of the mice miR-132. AB - miRNAs are small RNAs that are key regulators of gene expression in eukaryotic organisms. The processing of miRNAs is regulated by structural characteristics of the RNA and is also tightly controlled by auxiliary protein factors. Among them, RNA binding proteins play crucial roles to facilitate or inhibit miRNA maturation and can be controlled in a cell, tissue and species-specific manners or in response to environmental stimuli. In this study we dissect the molecular mechanism that promotes the overexpression of miR-132 in mice over its related, co-transcribed and co-regulated miRNA, miR-212. We have shown that the loop structure of miR-132 is a key determinant for its efficient processing in cells. We have also identified a range of RNA binding proteins that recognize the loop of miR-132 and influence both miR-132 and miR-212 processing. The DEAD box helicase p72/DDX17 was identified as a factor that facilitates the specific processing of miR-132. PMID- 26947127 TI - The p75 neurotrophin receptor augments survival signaling in the striatum of pre symptomatic Q175(WT/HD) mice. AB - Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder characterized by a constellation of motor, cognitive, and psychiatric features. Striatal medium spiny neurons, one of the most affected populations, are dependent on brain-derived neurotrophic factor (BDNF) anterogradely transported from the cortex for proper function and survival. Recent studies suggest both receptors for BDNF, TrkB and p75 neurotrophin receptor (p75), are improperly regulated in the striata of HD patients and mouse models of HD. While BDNF-TrkB signaling almost exclusively promotes survival and metabolic function, p75 signaling is able to induce survival or apoptosis depending on the available ligand and associated co-receptor. We investigated the role of p75 in the Q175 knock-in mouse model of HD by examining the levels and activation of downstream signaling molecules, and subsequently examining Hdh(+/Q175);p75(-/-) mice to determine if p75 represents a promising therapeutic target. In Hdh(+/Q175);p75(+/+) mice, we observed enhanced survival signaling as evidenced by an increase in phosphorylation and activation of Akt and the p65 subunit of NFkappaB in the striatum at 5 months of age and an increase in XIAP expression compared to Hdh(+/+);p75(+/+) mice; this increase was lost in Hdh(+/Q175);p75(-/ ) mice. Hdh(+/Q175);p75(-/-) mice also showed a decrease in Bcl-XL expression by immunoblotting compared to Hdh(+/Q175);p75(+/+) and Hdh(+/+);p75(+/+) littermates. Consistent with diminished survival signaling, DARPP-32 expression decreased both by immunoblotting and by immunohistochemistry in Hdh(+/Q175);p75( /-) mice compared to Hdh(+/+);p75(+/+), Hdh(+/Q175);p75(+/+), and Hdh(+/+);p75(-/ ) littermates. Additionally, striatal volume declined to a greater extent in Hdh(+/Q175);p75(-/-) when compared to Hdh(+/Q175);p75(+/+) littermates at 12 months, indicating a more aggressive onset of degeneration. These data suggest that p75 signaling plays an early role in augmenting pro-survival signaling in the striatum and that disruption of p75 signaling at a pre-symptomatic age may exacerbate pathologic changes in Hdh(+/Q175) mice. PMID- 26947128 TI - Hypovolemic hemorrhage induces Fos expression in the rat hypothalamus: Evidence for involvement of the lateral hypothalamus in the decompensatory phase of hemorrhage. AB - This study tested the hypothesis that the hypothalamus participates in the decompensatory phase of hemorrhage by measuring Fos immunoreactivity and by inhibiting neuronal activity in selected hypothalamic nuclei with lidocaine or cobalt chloride. Previously, we reported that inactivation of the arcuate nucleus inhibited, but did not fully prevent, the fall in arterial pressure evoked by hypotensive hemorrhage. Here, we report that hemorrhage (2.2 ml/100g body weight over 20 min) induced Fos expression in a high percentage of cells in the paraventricular, supraoptic and arcuate nuclei of the hypothalamus as shown previously. Lower densities of Fos immunoreactive cells were also found in the medial preoptic area (mPOA), anterior hypothalamus, lateral hypothalamus (LH), dorsomedial hypothalamus, ventromedial hypothalamus (VMH) and posterior hypothalamus. Bilateral injection of lidocaine (2%; 0.1 MUl or 0.3 MUl) or cobalt chloride (5mM; 0.3 MUl) into the tuberal portion of the LH immediately before hemorrhage was initiated reduced the magnitude of hemorrhagic hypotension and bradycardia significantly. Lidocaine injection into the VMH also attenuated the fall in arterial pressure and heart rate evoked by hemorrhage although inactivation of the mPOA or rostral LH was ineffective. These findings indicate that hemorrhage activates neurons throughout much of the hypothalamus and that a relatively broad area of the hypothalamus, extending from the arcuate nucleus laterally through the caudal VMH and tuberal LH, plays an important role in the decompensatory phase of hemorrhage. PMID- 26947129 TI - The neuroprotective effects and possible mechanism of action of a methanol extract from Asparagus cochinchinensis: In vitro and in vivo studies. AB - Extracts of Asparagus cochinchinensis (AC) have antitumor, anti-inflammatory, and immunostimulant effects. The neurobiological mechanisms underlying the effects of AC have not been sufficiently explored. Thus we performed in vivo and in vitro experiments to further characterize potential therapeutic effects and to clarify the underlying mechanisms. In the tail suspension test immobility time was significantly reduced after administration of AC which suggests antidepressant like activity without effect on body core temperature. Moreover, in animals pretreated with AC infarct size after occlusion of the middle cerebral artery was reduced. In vitro experiments confirmed neuroprotective effects. Total saponin obtained from AC significantly inhibited H2O2-induced cell death in cultured cortical neurons. The survival-promoting effect by AC saponins was partially blocked by inhibitors for extracellular signal-regulated kinase (ErK) and phosphoinositide 3-kinase Akt (PI3K/Akt) cascades, both of which are known as survival-promoting signaling molecules. Furthermore, phosphorylation of Scr homology-2 (SH2) domain-containing phosphatase 2 (Shp-2) was induced by AC, and the protective effect of AC was abolished by NSC87877, an inhibitor for Shp-2, suggesting an involvement of Shp-2 mediated intracellular signaling in AC saponins. Moreover, AC-induced activation of pShp-2 and ErK1/2 were blocked by NSC87877 indicating that activation of these signaling pathways was mediated by the Shp-2 signaling pathway. These effects appear to be associated with activation of the Shp-2, ErK1/2 and Akt signaling pathways. Our results suggest that AC has antidepressant-like and neuroprotective (reducing infarct size) effects and that activation of pShp-2 and pErK1/2 pathways may be involved in the effects. PMID- 26947132 TI - Life of superoxide in aprotic Li-O2 battery electrolytes: simulated solvent and counter-ion effects. AB - Li-air batteries ideally make use of oxygen from the atmosphere and metallic lithium to reversibly drive the reaction 2Li + O2<-> Li2O2. Conceptually, energy throughput is high and material use is efficient, but practically many material challenges still remain. It is of particular interest to control the electrolyte environment of superoxide (O2*(-)) to promote or hinder specific reaction mechanisms. By combining density functional theory based molecular dynamics (DFT MD) and DFT simulations we probe the bond length and the electronic properties of O2*(-) in three aprotic solvents - in the presence of Li(+) or the much larger cation alternative tetrabutylammonium (TBA(+)). Contact ion pairs, LiO2*, are favoured over solvent-separated ion pairs in all solvents, but particularly in low permittivity dimethoxyethane (DME), which makes O2*(-) more prone to further reduction. The Li(+)-O2*(-) interactions are dampened in dimethyl sulfoxide (DMSO), in relation to those in DME and propylene carbonate (PC), which is reflected by smaller changes in the electronic properties of O2*(-) in DMSO. The additive TBA(+) offers an alternative, more weakly interacting partner to O2*(-), which makes it easier to remove the unpaired electron and oxidation more feasible. In DMSO, TBA(+) has close to no effect on O2*(-), which behaves as if no cation is present. This is contrasted by a much stronger influence of TBA(+) on O2*(-) in DME - comparable to that of Li(+) in DMSO. An important future goal is to compare and rank the effects of different additives beyond TBA(+). Here, the results of DFT calculations for small-sized cluster models are in qualitative agreement with those of the DFT-MD simulations, which suggests the cluster approach to be a cost-effective alternative to the DFT-MD simulations for a more extensive comparison of additive effects in future studies. PMID- 26947130 TI - The acetyllysine reader BRD3R promotes human nuclear reprogramming and regulates mitosis. AB - It is well known that both recipient cells and donor nuclei demonstrate a mitotic advantage as observed in the traditional reprogramming with somatic cell nuclear transfer (SCNT). However, it is not known whether a specific mitotic factor plays a critical role in reprogramming. Here we identify an isoform of human bromodomain-containing 3 (BRD3), BRD3R (BRD3 with Reprogramming activity), as a reprogramming factor. BRD3R positively regulates mitosis during reprogramming, upregulates a large set of mitotic genes at early stages of reprogramming, and associates with mitotic chromatin. Interestingly, a set of the mitotic genes upregulated by BRD3R constitutes a pluripotent molecular signature. The two BRD3 isoforms display differential binding to acetylated histones. Our results suggest a molecular interpretation for the mitotic advantage in reprogramming and show that mitosis may be a driving force of reprogramming. PMID- 26947131 TI - Forgetting of long-term memory requires activation of NMDA receptors, L-type voltage-dependent Ca2+ channels, and calcineurin. AB - In the past decades, the cellular and molecular mechanisms underlying memory consolidation, reconsolidation, and extinction have been well characterized. However, the neurobiological underpinnings of forgetting processes remain to be elucidated. Here we used behavioral, pharmacological and electrophysiological approaches to explore mechanisms controlling forgetting. We found that post acquisition chronic inhibition of the N-methyl-D-aspartate receptor (NMDAR), L type voltage-dependent Ca(2+) channel (LVDCC), and protein phosphatase calcineurin (CaN), maintains long-term object location memory that otherwise would have been forgotten. We further show that NMDAR activation is necessary to induce forgetting of object recognition memory. Studying the role of NMDAR activation in the decay of the early phase of long-term potentiation (E-LTP) in the hippocampus, we found that ifenprodil infused 30 min after LTP induction in vivo blocks the decay of CA1-evoked postsynaptic plasticity, suggesting that GluN2B-containing NMDARs activation are critical to promote LTP decay. Taken together, these findings indicate that a well-regulated forgetting process, initiated by Ca(2+) influx through LVDCCs and GluN2B-NMDARs followed by CaN activation, controls the maintenance of hippocampal LTP and long-term memories over time. PMID- 26947133 TI - Conventional and innate lymphocytes response at the acute phase of HEV infection in transplanted patients. AB - OBJECTIVES: The hepatitis E virus (HEV) causes usually benign and spontaneously resolving acute hepatitis in immunocompetent individuals. In immunocompromised patients with a solid-organ transplant (SOT), chronic infections occur in about 2/3 of cases. We aimed to evaluate the immune cells implicated at the acute phase of HEV infection. METHODS: We studied the activation and memory markers on CD4, CD8, gammadelta and NK cells in 32 HEV-free control SOT patients and 23 SOT recipients, including 14 who became chronically infected. Samples from 7 immunocompetent individuals with an acute infection and 8 healthy donor samples were included for comparison. RESULTS: In acutely-infected SOT patients, NK and Vdelta2 cells, but not other gammadelta cells, had an increased expression of CD69. Based on CD45RA/CD27 markers, solid-organ recipients infected with HEV contained a larger pool of circulating naive subsets among lymphocyte Tgammadelta cells. However, these alterations of Vdelta2 cells were not associated with HEV clearance. Only the adaptive IFN-gamma responses to HEV peptides, determined by ELISpot, were associated with a favorable outcome in immunocompromised patients. CONCLUSIONS: Transplanted patients mobilized their gammadelta cells at the acute phase of infection. Their precise role in HEV infection will thus deserve further investigations as they could be specifically immunomanipulated. PMID- 26947134 TI - Controllable Heparin-Based Comb Copolymers and Their Self-assembled Nanoparticles for Gene Delivery. AB - Polysaccharide-based copolymers have attracted much attention due to their effective performances. Heparin, as a kind of polysaccharide with high negative charge densities, has attracted much attention in biomedical fields. In this work, we report a flexible way to adjust the solubility of heparin from water to oil via the introduction of tetrabutylammonium groups for further functionalization. A range of heparin-based comb copolymers with poly(poly(ethylene glycol) methyl ether methacrylate) (PPEGMEMA), poly(dimethylaminoethyl methacrylate) (PDMAEMA), or PPEGMEMA-b-PDMAEMA side chains were readily synthesized in a MeOH/dimethylsulfoxide mixture via atom transfer radical polymerization. The heparin-based polymer nanoparticles involving cationic PDMAEMA were produced due to the electrostatic interaction between the negatively charged heparin backbone and PDMAEMA grafts. Then the pDNA condensation ability, cytotoxicity, and gene transfection efficiency of the nanoparticles were characterized in comparison with the reported gene vectors. The nanoparticles were proved to be effective gene vectors with low cytotoxicity and high transfection efficiency. This study demonstrates that by adjusting the solubility of heparin, polymer graft functionalization of heparin can be readily realized for wider applications. PMID- 26947135 TI - What is the preferred number of consecutive night shifts? results from a crossover intervention study among police officers in Denmark. AB - Among police officers in Denmark, we studied (i) how many consecutive night shifts participants preferred at baseline; (ii) preferences regarding three intervention conditions (two, four, and seven consecutive night shifts followed by the same number of days off/day shifts: '2 + 2', '4 + 4', '7 + 7') at follow up; (iii) characteristics of participants preferring each of these intervention conditions. Questionnaire data from a crossover intervention study were used (baseline: n = 73; follow-up: n = 68). At baseline, 49% preferred four consecutive night shifts. At follow-up, 57% preferred '4 + 4', 26% preferred '2 + 2' and 26% preferred '7 + 7'. Participants, who preferred longer spells of night work experienced that night work was less demanding, found it easier to sleep at different times of the day, and were more frequently evening types compared with participants who preferred shorter spells of night work. The participants' preferences are likely to be influenced by their previous shift work experience. Practitioner Summary: We investigated police officers' preferences regarding the number of consecutive night shifts. The majority preferred four consecutive night shifts. Those who preferred the longer spells of night work found night work less demanding, found it easier to sleep at different times of the day, and were more frequently evening types. PMID- 26947136 TI - Stable Nuclear Transformation System for the Coccolithophorid Alga Pleurochrysis carterae. AB - Of the three dominant marine microalgal groups, dinoflagellates and diatoms can undergo genetic transformation; however, no transformation method has been established for haptophytes to date. Here, we report the first stable genetic transformation of a coccolithophore, Pleurochrysis carterae, by means of polyethylene glycol (PEG)-mediated transfer of a bacterial hygromycin B resistance gene. Together with the novel transient green fluorescent protein (GFP) expression system, this approach should facilitate further molecular-based research in this phylum. PMID- 26947137 TI - Challenges of kidney paired donation transplants involving multiple donor and recipient surgeons across Australia. AB - BACKGROUND: The Australian kidney paired donation program adopted the principles of within-chain simultaneous live donor surgery and of organ transport, with the requirement of keeping cold ischemia time (CIT) to <12 h. Whether these principles could be adhered to and what impact on transplant outcome they might have is unknown. METHODS: We evaluated the logistic challenges and outcomes of the first 100 kidney transplants performed in the Australian kidney paired donation program. RESULTS: Within 4 years, 17 donor surgeons at 12 centres were involved in 37 chain exchange surgeries. Sixteen kidneys were transplanted at the same hospital and 84 required transport to the recipient hospital. Mean (+/-SD) within chain anaesthetic induction time variability was 8 +/- 18 min and mean individual surgeon operating time was 115 +/- 44 min. In two cases, delays during donor surgery resulted in increased CIT by 1 h because of deferred transport. CIT was 2.6 +/- 0.6 h for non-shipped and 6.8 +/- 2.8 h for shipped kidneys, four kidneys had CIT of 12-14 h. Immediate allograft function was observed in 85% of recipients, with no difference between shipped and non-shipped kidneys. There were only two cases of delayed graft function requiring temporary dialysis; both had CIT <7 h. There was no difference in serum creatinine at 1 month between non shipped and shipped kidneys (105 +/- 26 versus 112 +/- 50 umol/L) and allograft survival at 1 year was 97%. CONCLUSION: The study provided a favourable audit of kidney transplant activity, despite challenges of simultaneous surgery, organ transport coordination and prolonged CIT. The decision to ship donor kidneys rather than the donor was demonstrated to be feasible and safe. PMID- 26947138 TI - Second vs. First generation drug eluting stents in multiple vessel disease and left main stenosis: Two-year follow-up of the observational, prospective, controlled, and multicenter ERACI IV registry. AB - OBJECTIVE: To compare second generation drug eluting stents (2DES) with first generation (1DES) for the treatment of patients (pts) with multiple coronary vessel disease (MVD). BACKGROUND: Although 2DES improved safety and efficacy compared to 1DES, MVD remains a challenge for percutaneous coronary interventions. METHODS: ERACI IV was a prospective, observational, and controlled study in pts with MVD including left main and treated with 2DES (Firebird 2, Microport). We included 225 pts in 15 sites from Argentina. Primary endpoint was the incidence of major adverse cardiovascular events (MACCE) defined as death, myocardial infarction (MI), cerebrovascular accident (CVA) and unplanned revascularization; and to compare with 225 pts from ERACI III study (1DES). PCI strategy was planned to treat lesions >=70% in vessels >= 2.00 mm, introducing a modified Syntax score (SS) where severe lesions in vessels < 2.0 mm and intermediate lesions were not scored. RESULTS: Baseline characteristics showed that compared to ERACI III, ERACI IV pts had higher number of diabetics (P = 0.02), previous revascularization (P = 0.007), unstable angina IIb/IIIc (P < 0.001) and three vessels/left main disease (P = 0.003). Modified SS was 22.2 +/- 11. At 2 years of follow-up ERACI IV group had significantly lower incidence of death+ MI + CVA, (P = 0.01) and MACCE (P = 0.001). MACCE rate was similar in diabetics, (5.8%) and nondiabetics (7.0%). After performing a matched propensity score, MACCE remain significantly lower in ERACI IV (P = 0.005). CONCLUSION: This registry showed that 2DES in MVD has a remarkable low incidence of MACCE in unadjusted and adjusted analysis. (c) 2016 Wiley Periodicals, Inc. PMID- 26947139 TI - Bacterial diversity and community along the succession of biological soil crusts in the Gurbantunggut Desert, Northern China. AB - Biological soil crusts (BSCs) are common and play critical roles in semi-arid and arid ecosystems. Bacteria, as an important community in BSCs, play critical roles in biochemical processes. However, how bacterial diversity and community change in different successional stages of BSCs is still unknown. We used 454 pyrosequencing of 16S rRNA to investigate the bacterial composition and community, and the relationships between bacterial composition and environmental factors were also explored. In different successional stages of BSCs, the number of bacteria operational taxonomic units (OTUs) detected in each sample ranged from 2572 to 3157. Proteobacteria, Cyanobacteria, Bacteroidetes were dominant in BSCs, followed by Firmicutes, Acidobacteria, and Actinobacteria. At the successional stages of BSCs, bacterial communities, OTU composition and their relative abundance notably differentiated, and Cyanobacteria, especially Microcoleus vaginatus, dominated algal crust and lichen crust, and were the main C-fixing bacteria in BSCs. Proteobacteria and Bacteroidetes increased with the development of BSCs. OTUs related to Planomicrobium Chinese, Desulfobulbus sp., Desulfomicrobium sp., Arthrobacter sp., and Ahhaerbacter sp. showed higher relative abundance in bare sand than other successional stages of BSCs, while relative abundance of Sphingomonas sp. Niastella sp., Pedobacter, Candidatus solobacter, and Streptophyta increased with the development of BSCs. In successional stages of BSCs, bacterial OTUs composition demonstrated strong correlations with soil nutrients, soil salts, and soil enzymes. Additionally, variation of bacterial composition led to different ecological function. In bare sand, some species were related with mineral metabolism or promoting plant growth, and in algal crust and lichen crust, C-fixing bacteria increased and accumulated C to the desert soil. In later developed stage of BSCs, bacteria related with decomposition of organic matter, such as Sphingomonas sp. Niastella sp., Pedobacter, and Candidatus solobacter increased. Therefore, bacterial community composition and their key ecological roles shifted to the development of BSCs. PMID- 26947140 TI - N-Acyl ethanolamide and eicosanoid involvement in irritant dermatitis. AB - BACKGROUND: Sodium lauryl sulfate (SLS) and ultraviolet radiation (UVR) are two commonly encountered cutaneous inflammatory stimuli. Differing histopathological and clinical features implicate involvement of alternative inflammatory pathways; bioactive lipid mediators (eicosanoids, endocannabinoids and sphingolipids) are likely candidates for regulation of the divergent inflammatory responses. OBJECTIVES: To assess comprehensively bioactive lipid involvement in SLS- and UVR induced inflammatory responses, to provide a better understanding of bioactive lipid mediator pathways in irritant inflammation. METHODS: Buttock skin from 10 healthy volunteers was treated with two minimal erythema doses of UVR (275-380 nm, peak 305 nm) or an SLS dose optimized for each individual, to produce a comparable, moderate erythema. Punch biopsies were taken 24 h postchallenge and from untreated skin, and separated into dermis and epidermis. Lipids [including 15 prostanoids, 15 hydroxy fatty acids (HFAs), nine endocannabinoids and related N-acyl ethanolamides (NAE), and 21 sphingolipids] were extracted and quantified using liquid chromatography-tandem mass spectrometry. RESULTS: Increased epidermal NAE and HFA expression was observed in response to SLS but not UVR induced low-level inflammation. Significant changes following SLS treatment included augmented levels of NAE, possessing proinflammatory and some reported anti-inflammatory properties, with 3.7-fold (P = 0.02) and threefold (P = 0.01) increased expression of palmitoyl and stearoyl ethanolamides, respectively, in addition to 1.9-fold (P = 0.02) increased expression of 12 hydroxyeicosatetraenoic acid. CONCLUSIONS: The differential bioactive lipid upregulation implicates their involvement in skin irritant responses, potentially reflecting roles in inflammatory cell recruitment and subsequent resolution of inflammation, giving scope for new treatment approaches to irritant dermatitis. PMID- 26947141 TI - Thymus medulla under construction: Time and space oddities. AB - The development of effective T-cell-based immunotherapies to treat infection, cancer, and autoimmunity should incorporate the ground rules that control differentiation of T cells in the thymus. Within the thymus, thymic epithelial cells (TECs) provide microenvironments supportive of the generation and selection of T cells that are responsive to pathogen-derived antigens, and yet tolerant to self-determinants. Defects in TEC differentiation cause syndromes that range from immunodeficiency to autoimmunity, which makes the study of TECs of fundamental and clinical importance to comprehend how immunity and tolerance are balanced. Critical to tolerance induction are medullary thymic epithelial cells (mTECs), which purge autoreactive T cells, or redirect them to a regulatory T-cell lineage. In this issue of the European Journal of Immunology, studies by Baik et al. and Mayer et al. [Eur. J. Immunol. 2016. 46: XXXX-XXXX and 46: XXXX-XXXX]) document novel spatial-temporal singularities in the lineage specification and maintenance of mTECs. While Baik et al. define a developmental checkpoint during mTEC specification in the embryo, Mayer et al. reveal that the generation and maintenance of the adult mTEC compartment is temporally controlled in vivo. The two reports described new developmentally related, but temporally distinct principles that underlie the homeostasis of the thymic medulla across life. PMID- 26947143 TI - Letter to the Editor, re: article "Factors influencing women's satisfaction with surgical abortion" by Tilles, Denny, Cansino and Creinin. PMID- 26947142 TI - Direction of attentional focus in biofeedback treatment for /r/ misarticulation. AB - BACKGROUND: Maintaining an external direction of focus during practice is reported to facilitate acquisition of non-speech motor skills, but it is not known whether these findings also apply to treatment for speech errors. This question has particular relevance for treatment incorporating visual biofeedback, where clinician cueing can direct the learner's attention either internally (i.e., to the movements of the articulators) or externally (i.e., to the visual biofeedback display). AIMS: This study addressed two objectives. First, it aimed to use single-subject experimental methods to collect additional evidence regarding the efficacy of visual-acoustic biofeedback treatment for children with /r/ misarticulation. Second, it compared the efficacy of this biofeedback intervention under two cueing conditions. In the external focus (EF) condition, participants' attention was directed exclusively to the external biofeedback display. In the internal focus (IF) condition, participants viewed a biofeedback display, but they also received articulatory cues encouraging an internal direction of attentional focus. METHODS & PROCEDURES: Nine school-aged children were pseudo-randomly assigned to receive either IF or EF cues during 8 weeks of visual-acoustic biofeedback intervention. Accuracy in /r/ production at the word level was probed in three to five pre-treatment baseline sessions and in three post-treatment maintenance sessions. Outcomes were assessed using visual inspection and calculation of effect sizes for individual treatment trajectories. In addition, a mixed logistic model was used to examine across-subjects effects including phase (pre/post-treatment), /r/ variant (treated/untreated), and focus cue condition (internal/external). OUTCOMES & RESULTS: Six out of nine participants showed sustained improvement on at least one treated /r/ variant; these six participants were evenly divided across EF and IF treatment groups. Regression results indicated that /r/ productions were significantly more likely to be rated accurate post- than pre-treatment. Internal versus external direction of focus cues was not a significant predictor of accuracy, nor did it interact significantly with other predictors. CONCLUSIONS: The results are consistent with previous literature reporting that visual-acoustic biofeedback can produce measurable treatment gains in children who have not responded to previous intervention. These findings are also in keeping with previous research suggesting that biofeedback may be sufficient to establish an external attentional focus, independent of verbal cues provided. The finding that explicit articulator placement cues were not necessary for progress in treatment has implications for intervention practices for speech-sound disorders in children. PMID- 26947144 TI - Factors influencing women's satisfaction with surgical abortion--reply. PMID- 26947145 TI - Determinants of trends in prescription opioid use in British Columbia, Canada, 2005-2013. AB - PURPOSE: To explore the determinants of total opioid consumption in a Canadian province, and to examine patterns of opioid dispensations by sex, age, and income quintile. METHODS: We used population-based administrative data on prescription drug dispensations in British Columbia (BC; population ~4 million). We apply an index-based approach to examine how changes in population exposure, type of opioids used, and intensity of use contributed to changes in total morphine equivalents dispensed per 1000 population. RESULTS: Between 2005 and 2013 in BC, opioid consumption increased by 31%, driven by longer duration of opioid therapy and by an increase in the use of stronger opioids. Consumption increased for oxycodone, hydromorphone, fentanyl, and tramadol; and declined for morphine, codeine, and other opioids. While we did not find large sex and age differences, the total level of opioid consumption was three times as high among individuals in the lowest income quintile compared to those in the highest income quintile. CONCLUSIONS: Our findings on changes in the type of opioids used and changes in intensity of use suggest that modifications to clinical management of patients on opioid therapy may be warranted. Similar drug utilization statistics, derived from drug information systems, can be reproduced in other jurisdictions to enable a better understanding of the opioid crisis. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26947146 TI - An improved anatomical MRI technique with suppression of fixative fluid artifacts for the investigation of human postmortem brain phantoms. AB - PURPOSE: Phantoms are often used to assess MR system stability in multicenter studies. Postmortem brain phantoms best replicate human brain anatomy, allowing for a combined assessment of the MR system and software chain for data analysis. However, a wash-out of fixative fluid affecting T1 values and thus T1-weighted sequences such as magnetization-prepared 180 degrees radiofrequency pulses and rapid gradient-echo (MP-RAGE) has been reported for brain phantoms, hampering their immediate use. The purpose of this study was the creation of anatomical data that provide the characteristics of conventional data while avoiding this artifact. THEORY AND METHODS: Two brain phantoms were scanned at several time points, acquiring conventional MP-RAGE data and quantitative T1 and proton density (PD) maps. Assuming a suitable cutoff value T1cut , synthetic MP-RAGE data were created from these maps, being T1-weighted for T1 > T1cut to reduce fluid signal in the sulci, but PD-weighted for T1 < T1cut for artifact suppression. RESULTS: A time-dependent artifact was observed in the T1 but not in the PD maps. The temporal stability of the synthetic data was greatly improved as compared to the conventional data. CONCLUSION: The proposed method enables anatomical imaging of postmortem brain phantoms, avoiding artifacts induced by the wash-out of fixative fluid, and thus achieving high signal stability shortly after fixation. Magn Reson Med 77:1115-1123, 2017. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 26947147 TI - Altered expression of autophagy-related genes might contribute to glucocorticoid resistance in precursor B-cell-type acute lymphoblastic leukemia. AB - OBJECTIVES: Autophagy is an evolutionarily conserved process playing an important role in tumor cell's resistance to chemotherapy. Response to glucocorticoid (GC) treatment is out of the most important prognostic factors in childhood acute lymphoblastic leukemia (ALL); however, only few data are available connecting GC response and role of autophagy. Our aim was to investigate whether altered expression of autophagy-related genes contributes to GC-resistant phenotype in GC sensitive and GC-resistant precursor B-cell-type (PBC) ALL cells. METHODS: Gene expression data were obtained from public database for 26 children diagnosed with PBC ALL either sensitive or resistant to in vitro prednisolone treatment. RESULTS: We have identified 36 autophagy-associated genes which were differently expressed, based on at least a twofold difference, GC-sensitive group as compared to GC-resistant one. Of the 36 genes, 10 were downregulated and 26 upregulated in the GC-resistant group. The average fold change values for the decreased and increased transcripts were -4.57 and 2.67, respectively. CONCLUSIONS: Our data imply that GC sensitivity might depend on the expression of several genes involved in regulation and execution of autophagy in a way that key autophagy inducers are downregulated while inhibitors of autophagy are upregulated in GC resistant cells. PMID- 26947148 TI - Papain-Catalyzed Chemoenzymatic Synthesis of Telechelic Polypeptides Using Bis(Leucine Ethyl Ester) Initiator. AB - In order to construct unique polypeptide architectures, a novel telechelic-type initiator with two leucine ethyl ester units is designed for chemoenzymatic polymerization. Glycine or alanine ethyl ester is chemoenzymatically polymerized using papain in the presence of the initiator, and the propagation occurs at each leucine ethyl ester unit to produce the telechelic polypeptide. The formation of the telechelic polypeptides is confirmed by (1) H NMR and MALDI-TOF mass spectroscopies. It is revealed by AFM observation that long nanofibrils are formed from the telechelic polyalanine, whereas a conventional linear polyalanine with a similar degree of polymerization shows granule-like structures. The telechelic polyglycine and polyalanine show the crystalline structures of Polyglycine II and antiparallel beta-sheet, respectively. It is demonstrated that this method to synthesize telechelic-type polypeptides potentially opens up a pathway to construct novel hierarchical structures by self-assembly. PMID- 26947149 TI - MtVRN2 is a Polycomb VRN2-like gene which represses the transition to flowering in the model legume Medicago truncatula. AB - Optimising the timing of flowering contributes to successful sexual reproduction and yield in agricultural plants. FLOWERING LOCUS T (FT) genes, first identified in Arabidopsis thaliana (Arabidopsis), promote flowering universally, but the upstream flowering regulatory pathways can differ markedly among plants. Flowering in the model legume, Medicago truncatula (Medicago) is accelerated by winter cold (vernalisation) followed by long day (LD) photoperiods leading to elevated expression of the floral activator, FT-like gene FTa1. However, Medicago, like some other plants, lacks the activator CONSTANS (CO) and the repressor FLOWERING LOCUS C (FLC) genes which directly regulate FT and are key to LD and vernalisation responses in Arabidopsis. Conversely, Medicago has a VERNALISATION2-LIKE VEFS-box gene (MtVRN2). In Arabidopsis AtVRN2 is a key member of a Polycomb complex involved in stable repression of Arabidopsis FLC after vernalisation. VRN2-like genes have been identified in other eudicot plants, but their function has never been reported. We show that Mtvrn2 mutants bypass the need for vernalisation for early flowering in LD conditions in Medicago. Investigation of the underlying mechanism by transcriptome analysis reveals that Mtvrn2 mutants precociously express FTa1 and other suites of genes including floral homeotic genes. Double-mutant analysis indicates that early flowering is dependent on functional FTa1. The broad significance of our study is that we have demonstrated a function for a VRN2-like VEFS gene beyond the Brassicaceae. In particular, MtVRN2 represses the transition to flowering in Medicago by regulating the onset of expression of the potent floral activator, FTa1. PMID- 26947151 TI - Global Health Cooperation: International Relations' New Frontier. AB - This issue of MEDICC Review appears in the wake of a media splash on the reopening of the Cuban and US embassies in Washington and Havana, signaling the renewal of full diplomatic relations between the two governments. Although the US embargo is still law and one of the thorniest bilateral issues remaining, the Obama administration's bold opening towards Cuba is being echoed in the chambers of Senate committees, calling for an end to the policy in place since 1962. Meanwhile, people from the United States have begun to travel to Cuba in droves, and for the first time in many years, we perceive real hope that cooperation may replace hostility-at least in the sectors that most matter to ordinary people in both nations. PMID- 26947152 TI - Latin American Medical School Class of 2015: Exclusive with Cuban-trained US Graduates. PMID- 26947150 TI - Ising Model Reprogramming of a Repeat Protein's Equilibrium Unfolding Pathway. AB - Repeat proteins are formed from units of 20-40 aa that stack together into quasi one-dimensional non-globular structures. This modular repetitive construction means that, unlike globular proteins, a repeat protein's equilibrium folding and thus thermodynamic stability can be analysed using linear Ising models. Typically, homozipper Ising models have been used. These treat the repeat protein as a series of identical interacting subunits (the repeated motifs) that couple together to form the folded protein. However, they cannot describe subunits of differing stabilities. Here we show that a more sophisticated heteropolymer Ising model can be constructed and fitted to two new helix deletion series of consensus tetratricopeptide repeat proteins (CTPRs). This analysis, showing an asymmetric spread of stability between helices within CTPR ensembles, coupled with the Ising model's predictive qualities was then used to guide reprogramming of the unfolding pathway of a variant CTPR protein. The designed behaviour was engineered by introducing destabilising mutations that increased the thermodynamic asymmetry within a CTPR ensemble. The asymmetry caused the terminal alpha-helix to thermodynamically uncouple from the rest of the protein and preferentially unfold. This produced a specific, highly populated stable intermediate with a putative dimerisation interface. As such it is the first step in designing repeat proteins with function regulated by a conformational switch. PMID- 26947153 TI - Student Opinions on Factors Influencing Tutorials at Walter Sisulu University, South Africa. AB - INTRODUCTION Problem-based learning harmonized with education in and for the community is the cornerstone of the curriculum for the undergraduate medical degree at Walter Sisulu University, Mthatha, South Africa. In tutorials, students construct knowledge and learn to work collaboratively while interacting with one another in their search for solutions to a pedagogically modeled health issue based on a patient. Problems cover students' needs defined by the learning cycle of the second year medical curriculum, organized into four learning blocks. OBJECTIVES Determine student perspectives on which factors affect tutorial group functioning and detect the reported presence of these factors in the four learning blocks comprising the second year of medical studies at Walter Sisulu University. METHODS Twenty second-year medical students were chosen by stratified random sampling and assigned to two focus groups. One group discussed factors that foster smooth functioning of the tutorial group; the other focused on factors hindering effective group work. Later, in a joint session, 17 items previously identified by both groups were selected and included in a survey given to all 97 students at the end of second year. The survey assessed presence of each item in 0, 1, 2, 3 or 4 of the learning blocks. RESULTS Survey response was 93.8%. Mean reported presence of factors that influenced tutorials in the four learning blocks was 2.71 (SD 0.31) for the social dimension, 3.02 for motivational (SD 0.02), 3.00 for cognitive (SD 0.42), and 2.22 for self-directed learning (SD 0.79). CONCLUSIONS Tutorial group performance at Walter Sisulu University is positively influenced more by motivational and cognitive factors than by social and self-directed learning factors. Social dimensions should be prioritized when training tutors and self-directed learning stressed for students. The poor productivity of extra-tutorial group discussions suggests the need for a critical evaluation of this activity. KEYWORDS Problem-based learning, problem-based curriculum, active learning, medical education, tutorial groups, South Africa. PMID- 26947154 TI - Definition of Specific Functions and Procedural Skills Required by Cuban Specialists in Intensive Care and Emergency Medicine. AB - INTRODUCTION Medical specialties' core curricula should take into account functions to be carried out, positions to be filled and populations to be served. The functions in the professional profile for specialty training of Cuban intensive care and emergency medicine specialists do not include all the activities that they actually perform in professional practice. OBJECTIVE Define the specific functions and procedural skills required of Cuban specialists in intensive care and emergency medicine. METHODS The study was conducted from April 2011 to September 2013. A three-stage methodological strategy was designed using qualitative techniques. By purposive maximum variation sampling, 82 professionals were selected. Documentary analysis and key informant criteria were used in the first stage. Two expert groups were formed in the second stage: one used various group techniques (focus group, oral and written brainstorming) and the second used a three-round Delphi method. In the final stage, a third group of experts was questioned in semistructured in-depth interviews, and a two-round Delphi method was employed to assess priorities. RESULTS Ultimately, 78 specific functions were defined: 47 (60.3%) patient care, 16 (20.5%) managerial, 6 (7.7%) teaching, and 9 (11.5%) research. Thirty-one procedural skills were identified. The specific functions and procedural skills defined relate to the profession's requirements in clinical care of the critically ill, management of patient services, teaching and research at the specialist's different occupational levels. CONCLUSIONS The specific functions and procedural skills required of intensive care and emergency medicine specialists were precisely identified by a scientific method. This product is key to improving the quality of teaching, research, administration and patient care in this specialty in Cuba. The specific functions and procedural skills identified are theoretical, practical, methodological and social contributions to inform future curricular reform and to help intensive care specialists enhance their performance in comprehensive patient care. KEYWORDS Intensive care, urgent care, emergency medicine, continuing medical education, curriculum, diagnostic techniques and procedures, medical residency, Cuba. PMID- 26947156 TI - Impact of the 1970 Reforms to Cuba's National Tuberculosis Control Program. AB - INTRODUCTION To reach the goal of eliminating tuberculosis as a public health problem in Cuba, the epidemiological evolution of the disease and of strategies designed to prevent and manage it to date must be well understood. In this context, in 1970, changes were introduced in Cuba's National Tuberculosis Control Program. OBJECTIVE Review background and evolution of Cuba's strategy for tuberculosis control, the changes implemented in the 1970 revision of the Program, and their impact on the subsequent evolution of the disease in Cuba. METHODS Published articles on the history of tuberculosis control in Cuba were reviewed, along with archival documents and medical records. Documents concerning the situation of pulmonary tuberculosis in Cuba, including measures adopted to address the disease and its extent, were selected for study, with an emphasis on the period of the Program. Interviews with key informants were conducted. RESULTS Cuba's fight against tuberculosis began in Santiago de Cuba, with the creation of a local Anti-Tuberculosis League in 1890. Strategic changes introduced by Cuba's public health sector, stressing health promotion and disease prevention, led to the 1959 creation of the Tuberculosis Department, which implemented Cuba's first National Tuberculosis Control Program in 1963. This Program was completely reorganized in 1970. The National Tuberculosis Control Program (1963) covered a network of 27 tuberculosis dispensaries, 8 sanatoriums and 24 bacteriology laboratories. Diagnosis was based on radiographic imaging criteria. Incidence was 52.6/100,000 in 1964 and reached 31.2 in 1970. The Program was updated in 1970 to include two major changes: the requirement for bacteriological confirmation of diagnosis and directly-observed outpatient treatment fully integrated into health services. By 1971, incidence was down to 17.8/100,000, and further reduced to 11.6 in 1979. The decrease is interpreted as the result of the greater specificity of microbiologic diagnosis. Tuberculosis control continued to make progress, reaching an incidence rate of 6.1/100,000 in 2012 and mortality rate of 0.3/100,000 in 2013. CONCLUSIONS Changes introduced in the National Tuberculosis Control Program in 1970 led to the successful results achieved in later decades, reducing tuberculosis incidence and mortality. These results also allowed health authorities to propose elimination of the disease in Cuba as a current objective. KEYWORDS History of medicine, tuberculosis, epidemiology, communicable disease control, public health, Cuba. PMID- 26947155 TI - Macrosomia Predictors in Infants Born to Cuban Mothers with Gestational Diabetes. AB - INTRODUCTION Fetal macrosomia is the most important complication in infants of women with diabetes, whether preconceptional or gestational. Its occurrence is related to certain maternal and fetal conditions and negatively affects maternal and perinatal outcomes. The definitive diagnosis is made at birth if a newborn weighs >4000 g. OBJECTIVE Identify which maternal and fetal conditions could be macrosomia predictors in infants born to Cuban mothers with gestational diabetes. METHODS A case-control study comprising 236 women with gestational diabetes who bore live infants (118 with macrosomia and 118 without) was conducted in the America Arias University Maternity Hospital, Havana, Cuba, during 2002-2012. The dependent variable was macrosomia (birth weight >4000 g). Independent maternal variables included body mass index at pregnancy onset, overweight or obesity at pregnancy onset, gestational age at diabetes diagnosis, pregnancy weight gain, glycemic control, triglycerides and cholesterol. Fetal variables examined included third-semester fetal abdominal circumference, estimated fetal weight at >=28 weeks (absolute and percentilized by Campbell and Wilkin, and Usher and McLean curves). Chi square was used to compare continuous variables (proportions) and the student t test (X +/- SD) for categorical variables, with significance threshold set at p <0.05. ORs and their 95% CIs were calculated. RESULTS Significant differences between cases and controls were found in most variables studied, with the exception of late gestational diabetes diagnosis, total fasting cholesterol and hypercholesterolemia. The highest OR for macrosomia were for maternal hypertriglyceridemia (OR 4.80, CI 2.34-9.84), third-trimester fetal abdominal circumference >75th percentile (OR 7.54, CI 4.04-14.06), and estimated fetal weight >90th percentile by Campbell and Wilkin curves (OR 4.75, CI 1.42 15.84) and by Usher and McLean curves (OR 8.81, CI 4.25-18.26). CONCLUSIONS Most variables assessed were predictors of macrosomia in infants of mothers with gestational diabetes. They should therefore be taken into account for future studies and for patient management. Wide confidence intervals indicate uncertainty about the magnitude of predictive power. KEYWORDS Fetal macrosomia, fetal diseases, gestational diabetes, risk factors, risk prediction, Cuba. PMID- 26947157 TI - Emergency Response to Earthquake in Chile: Experience of a Cuban Field Hospital. AB - This paper presents the author's experiences in deploying and later establishing a Cuban field hospital in response to the major earthquake that struck Chile in February 2010. It also reveals the initial difficulties the medical team faced and how collaboration with local social, medical and military partners contributed to response efficiency, and highlights the importance of Cuba's international health cooperation, especially in emergency situations. Over 254 days, Cuban health professionals had 50,048 patient encounters (outpatient visits and hospitalizations), a daily average of 197. They performed 1778 surgeries (1427 major, 80.2% of total) and accumulated valuable experience in managing a field hospital in a disaster situation. KEYWORDS Earthquake, humanitarian aid, health care, emergency response, disaster medicine, logistics, Chile, Cuba. PMID- 26947158 TI - Sentinel Surveillance Detects Low Circulation of Vibrio cholerae Serotype Inaba in Haiti, 2011-2012. AB - Over 700,000 cases of cholera were reported in Haiti between October 2010 and February 2015. In November 2011, the Cuban Medical Team serving in Haiti established a laboratory-supported sentinel surveillance system for cholera in 10 public hospitals (one in each of Haiti's 10 departments), to estimate the proportion of hospitalized patients with cholera and detect emergence of new Vibrio cholerae serotypes. Each month, the first ten stool samples collected from patients admitted with acute watery diarrhea were studied in all hospitals involved. Surveillance system findings from November 1, 2011, to October 30, 2012 showed that acute watery diarrhea was caused by V. cholerae serogroup O1 in 45.9% (210/458) of patients: Serotype Ogawa was found in 98.6% of this isolates (207/210) and serotype Inaba in 1.4% (3/210), indicating low circulation level of the latter in Haiti. Continuing laboratory sentinel surveillance of V. cholerae is needed to monitor the spread of the disease and prevent and contain outbreaks, particularly of new serotypes. It is important to ensure that these findings are systematically integrated with data available to MSPP from other surveillance sources. KEYWORDS Vibrio cholerae, serotype Inaba, serotype Ogawa, epidemiological surveillance, medical cooperation, Haiti, Cuba. PMID- 26947159 TI - Cuba's Urban Landscape Needs a Second Round of Innovation for Health. AB - Cuba's economy spiraled downward in the 1990s, reeling from the collapse of European socialism and a tightened US embargo. To mitigate the crash's drastic effects, measures were adopted that transformed our urban landscape, especially in large cities such as Havana, paradoxically linking the period to nascent health-promoting options. One of the most important was the introduction of bicycle lanes on city streets, paths daily ridden by people on the over one million bicycles imported to offset the nearly nonexistent public transport caused by fuel shortages. Second, urban gardens began to sprout up, involving urban dwellers in production of their own food, particularly vegetables. Without minimizing the impact of the crisis, these two seemingly disparate phenomena meant people were getting more exercise, consuming fewer fats and carbohydrates and more fresh vegetables. People were even breathing fresher air, with fewer CO2 belching trucks, old cars and buses on the streets and less diesel used to transport produce in from afar. PMID- 26947160 TI - Preparation and evaluation of dual-enzyme microreactor with co-immobilized trypsin and chymotrypsin. AB - The preparation of capillary microfluidic reactor with co-immobilized trypsin and chymotrypsin with the use of a low-cost commercially available enzymatic reagent (containing these proteases) as well as the evaluation of its usefulness in proteomic research were presented. The monolithic copolymer synthesized from glycidyl methacrylate (GMA) and ethylene glycol dimethacrylate (EDMA) was used as a support. Firstly, the polymerization conditions were optimized and the monolithic bed was synthesized in the fused silica capillary modified with 3 (trimethoxysilyl)propyl methacrylate (gamma-MAPS). The polymer containing epoxy groups was then modified with 1,6-diaminohexane, followed by the attachment of glutaraldehyde and immobilization of enzymes. The efficiency of the prepared monolithic Immobilized Enzyme Microreactor (MU-IMER) with regard to trypsin activity was evaluated using the low-molecular mass compound (Nalpha-benzoyl-l arginine ethyl ester, BAEE). The activities of both enzymes were investigated using a macromolecular protein (human transferrin, Tf) as a substrate. In the case of BAEE, the reaction product was separated from the substrate using the capillary liquid chromatography and the efficiency of the reaction was determined by the peak area of the substrate. The hydrolysis products of transferrin were analyzed with MALDI-TOF which allows for the verification of the prepared enzymatic system applicability in the field of proteomic research. PMID- 26947161 TI - Chemical characterization of the acid alteration of diesel fuel: Non-targeted analysis by two-dimensional gas chromatography coupled with time-of-flight mass spectrometry with tile-based Fisher ratio and combinatorial threshold determination. AB - The illicit chemical alteration of petroleum fuels is of keen interest, particularly to regulatory agencies that set fuel specifications, or taxes/credits based on those specifications. One type of alteration is the reaction of diesel fuel with concentrated sulfuric acid. Such reactions are known to subtly alter the chemical composition of the fuel, particularly the aromatic species native to the fuel. Comprehensive two-dimensional gas chromatography coupled with time-of-flight mass spectrometry (GC*GC-TOFMS) is well suited for the analysis of diesel fuel, but may provide the analyst with an overwhelming amount of data, particularly in sample-class comparison experiments comprised of many samples. Tile-based Fisher-ratio (F-ratio) analysis reduces the abundance of data in a GC*GC-TOFMS experiment to only the peaks which significantly distinguish the unaltered and acid altered sample classes. Three samples of diesel fuel from differently branded filling stations were each altered to discover chemical features, i.e., analyte peaks, which were consistently changed by the acid reaction. Using different fuels prioritizes the discovery of features likely to be robust to the variation present between fuel samples and may consequently be useful in determining whether an unknown sample has been acid altered. The subsequent analysis confirmed that aromatic species are removed by the acid alteration, with the degree of removal consistent with predicted reactivity toward electrophilic aromatic sulfonation. Additionally, we observed that alkenes and alkynes were also removed from the fuel, and that sulfur dioxide or compounds that degrade to sulfur dioxide are generated by the acid alteration. In addition to applying the previously reported tile-based F-ratio method, this report also expands null distribution analysis to algorithmically determine an F ratio threshold to confidently select only the features which are sufficiently class-distinguishing. When applied to the acid alteration of diesel fuel, the suggested per-hit F-ratio threshold was 12.4, which is predicted to maintain the false discovery rate (FDR) below 0.1%. Using this F-ratio threshold, 107 of the 3362 preliminary hits were deemed significantly changing due to the acid alteration, with the number of false positives estimated to be about 3. Validation of the F-ratio analysis was performed using an additional three fuels. PMID- 26947163 TI - Screening for total ergot alkaloids in rye flour by planar solid phase extraction fluorescence detection and mass spectrometry. AB - The analysis of ergot alkaloids is generally performed by high-performance liquid chromatography (HPLC) coupled to fluorescence detection (FLD) or mass selective detection. As for monitoring only the sum of ergot alkaloids is relevant, a fast and easy screening method for the determination of the total alkaloid content was developed using planar solid phase extraction (pSPE). Applying pSPE, recently introduced for pesticide residue analysis in fruits and vegetables (Oellig and Schwack, 2011) and tea (Oellig and Schwack, 2012), all ergot alkaloids are concentrated in a target zone followed by detection as the sum. The herein presented method includes an ammonium acetate buffered extraction step, followed by a fast liquid-liquid partitioning pre-cleaning before pSPE is performed on high-performance thin-layer chromatography (HPTLC) amino plates with a single methanol development to separate the ergot alkaloids from the remaining matrix and to collect them in a single zone. For quantitation, the native fluorescence was used after dipping the plate in n-hexane/paraffin solution for fluorescence enhancement. Limits of detection and quantitation of 0.07 and 0.24 mg/kg rye, respectively, expressed as ergocristine, were well below the currently applied quality criterion limit for rye. Near-100% recoveries were obtained at relevant spiking levels for different rye flour samples. Hence, the fast pSPE-FLD is an efficient and reliable method to screen for the total ergot alkaloid content in rye and a rapid alternative to the HPLC determination of individual alkaloids and to summing them up. HPTLC-MS additionally enables the identification of the ergot alkaloid composition by a single mass spectrum, when utilized as a fingerprint, offering an easy differentiation of Secale cornutum from different origins. PMID- 26947162 TI - Chromatographic separation of germanium and arsenic for the production of high purity (77)As. AB - A simple column chromatographic method was developed to isolate (77)As (94+/-6% (EtOH/HCl); 74+/-11 (MeOH)) from germanium for potential use in radioimmunotherapy. The separation of arsenic from germanium was based on their relative affinities for different chromatographic materials in aqueous and organic environments. Using an organic or mixed mobile phase, germanium was selectively retained on a silica gel column as germanate, while arsenic was eluted from the column as arsenate. Subsequently, enriched (76)Ge (98+/-2) was recovered for reuse by elution with aqueous solution (neutral to basic). Greater than 98% radiolabeling yield of a (77)As-trithiol was observed from methanol separated [(77)As]arsenate [17]. PMID- 26947164 TI - Problems involving the determination of the column-only band broadening in columns producing narrow and tailed peaks. AB - We have investigated which of the different existing peak variance read-out methods (including the effect of a deconvolution pre-treatment method) are most suited to eliminate the system contribution from the total observed band broadening observed in LC systems. Emphasis is put on the most demanding case, i.e., the measurement of non-retained component peaks, which typically are very narrow and tailed. The problem with such peaks is that the method that is generally considered to be the only mathematically correct method (i.e., the method of moments) leads to peak variance values that are so strongly dominated by the tail of the peak that they become highly exaggerated and practically meaningless (i.e., they are dominated by the peak width at 10 or 12sigmat, which corresponds to resolutions and peak purities that are so high they are never pursued in practice). Interestingly, filtering away the extra-column contribution from the entire peak shape using peak deconvolution (wherein not only the second order moment is corrected but also all other moments) produces corrected 4sigmat- and half height peak widths that are physically meaningful, i.e., the corrected values allow to make sufficiently accurate predictions of how the peak width at 4sigmat and at half height changes when the column length changes. This result now allows to navigate away from the classical method of moments to define the column plate height, and resort to plate heights based on the practically much more relevant 4sigmat- and 5sigmat-widths, provided theses are corrected via peak deconvolution. PMID- 26947166 TI - Thermo- and pH-responsive polymer brushes-grafted gigaporous polystyrene microspheres as a high-speed protein chromatography matrix. AB - Dual thermo- and pH-responsive chromatography has been proposed using poly(N isopropylacrylamide-co-butyl methacrylate-co-N,N-dimethylaminopropyl acrylamide) (P(NIPAM-co-BMA-co-DMAPAAM)) brushes grafted gigaporous polystyrene microspheres (GPM) as matrix. Atom transfer radical polymerization (ATRP) initiator was first coupled onto GPM through Friedel-Crafts acylation with 2-bromoisobutyryl bromide. The dual-responsive polymer brushes were then grafted onto GPM via surface initiated ATRP. The surface composition, gigaporous structure, protein adsorption and dual-responsive chromatographic properties of the matrix (GPM-P(NIPAM-co-BMA co-DMAPAAM) were characterized in detail. Results showed that GPM were successfully grafted with thermoresponsive cationic polymer brushes and that the gigaporous structure was well maintained. A column packed with GPM-P(NIPAM-co-BMA co-DMAPAAM presented low backpressure, good permeability and appreciable thermo responsibility. By changing pH of the mobile phase and temperature of the column in turn, the column can separate three model proteins at the mobile phase velocity up to 2528cmh(-1). A separation mechanism of this matrix was also proposed. All results indicate that the dual thermo- and pH-responsive chromatography matrix has great potentials in 'green' high-speed protein chromatography. PMID- 26947165 TI - Assessment of ultra high performance supercritical fluid chromatography as a separation technique for the analysis of seized drugs: Applicability to synthetic cannabinoids. AB - The recent development of modern methods for ultra high performance supercritical fluid chromatography (UHPSFC) has great potential for impacting the analysis of seized drugs. In the separation of synthetic cannabinoids the technique has the potential to produce superior resolution of positional isomers and diastereomers. To demonstrate this potential we have examined the capability of UHPSFC for the analysis of two different groups of synthetic cannabinoids. The first group was a mixture of 22 controlled synthetic cannabinoids, and the second group included JWH018 and nine of its non-controlled positional isomers The clear superiority of UHPSFC over other separation techniques was demonstrated, in that it was capable of near baseline separation of all 10 positional isomers using a chiral column. In total we examined four achiral columns, including Acquity UPC(2) Torus 2-PIC, Acquity UPC(2) Torus Diol, Acquity UPC(2) Torus DEA and Acquity UPC(2) Torus 1-AA (1.7MUm 3.0*100mm), and three chiral columns, including Acquity UPC(2) Trefoil AMY1, Acquity UPC(2) Trefoil CEL1 and Acquity UPC(2) Trefoil CEL2 (2.5MUm 3.0*150mm), using mobile phase compositions that combined carbon dioxide with methanol, acetonitrile, ethanol or isopropanol modifier gradients. Detection was performed using simultaneous PDA UV detection and quadrupole mass spectrometry. The orthogonality of UHPSFC, GC and UHPLC for the analysis of these compounds was demonstrated using principal component analysis. Overall we feel that this new technique should prove useful in the analysis and detection of seized drug samples, and will be a useful addition to the compendium of methods for drug analysis. PMID- 26947167 TI - [Infection imported virus Zika in an area settled by Aedes albopictus]. PMID- 26947168 TI - [Guillain-Barre syndrome due to Zika virus during pregnancy]. PMID- 26947169 TI - [The Zika virus out of America]. PMID- 26947170 TI - The optimal period of Ca-EDTA treatment for parthenogenetic activation of porcine oocytes during maturation culture. AB - The changes triggered by sperm-induced activation of oocytes, which are required for normal oocyte development, can be mediated by other agents, thereby inducing the parthenogenesis. In this study, we exposed porcine oocytes to 1 mM Ca-EDTA, a metal-ion chelator, at various intervals during 48 hr of in vitro maturation to determine the optimum period of Ca-EDTA treatment for parthenogenetic activation. When the oocytes were cultured with or without Ca-EDTA from 36 hr (post-12), 24 hr (post-24), 12 hr (post-36) and 0 hr (post-48) after the start of maturation culture, the blastocyst formation rates were significantly higher (P<0.05) in the post-24, post-36 and post-48 groups (3.3%, 4.0% and 2.6%, respectively) than those in the control group without treatment (0%). Furthermore, when the oocytes were cultured with Ca-EDTA for 0 hr (control), 12 hr (pre-12), 24 hr (pre-24), 36 hr (pre-36) and 48 hr (pre-48) from the start of maturation culture, the oocytes formed blastocysts only in the pre-36 and pre-48 groups (0.4% or 0.8%, respectively). Pronuclei (<66.7%) were observed only when the periods of Ca-EDTA treatment were more than 12 hr during maturation culture. In the control group, no pronuclei were detected. Our findings demonstrate that porcine immature oocytes can be parthenogenetically activated by Ca-EDTA treatment for at least 24 hr to 36 hr during maturation culture, leading to pronucleus formation followed by the formation of blastocysts. PMID- 26947171 TI - Eosinophilic granuloma with Splendore-Hoeppli material caused by Mannheimia granulomatis in a calf. AB - A large subcutaneous mass, formed on the left lower jaw of a 4-month-old Japanese Black male calf, was partially excised for histological and bacteriological examinations. Antibiotic treatment resulted in a good prognosis. Bacteria isolated from the excised material were characterized by weak hemolysis and positive reactions for catalase and oxidase, and were 99% identical to Mannheimia granulomatis strains. The presence of the leukotoxin gene product was demonstrated by polymerase chain reaction amplification. Histological examination showed that the excised material was composed of dense fibrous connective tissue with sparsely distributed eosinophilic granulomas or abscesses. These foci frequently contained Splendore-Hoeppli material with rod-shaped Gram-negative bacteria. Except for the absence of lymphangitis and the presence of basophils and mast cells, the histology of this lesion resembled that of lechiguana associated with coinfection of M. granulomatis and Dermatobia hominis. Leukotoxin was demonstrated by immunohistochemistry within Splendore-Hoeppli material and was judged to be responsible for its formation. PMID- 26947172 TI - Effectiveness of Everolimus Versus Endocrine Monotherapy or Chemotherapy Among HR+/HER2- mBC Patients With Multiple Metastatic Sites. AB - PURPOSE: This review compared the real-world effectiveness of everolimus-based therapy versus endocrine monotherapy or chemotherapy in postmenopausal hormone receptor positive (HR+)/ human epidermal growth factor receptor 2-negative (HER2 ) metastatic breast cancer (mBC) patients with multiple metastatic sites. METHODS: This retrospective chart review examined a nationwide sample of postmenopausal HR+/HER2- mBC women with >=2 non-lymph-node metastatic sites. Patients must have initiated everolimus-based therapy (monotherapy or combination therapy including everolimus), endocrine monotherapy (any endocrine agent), or chemotherapy (monotherapy or combination with another chemotherapeutic or endocrine agent) for mBC between July 1, 2012 and August 15, 2013 after nonsteroidal aromatase inhibitor failure. Progression-free survival and time on treatment were compared using Kaplan-Meier analysis and Cox proportional hazard models, adjusting for line of therapy and baseline characteristics. FINDINGS: One hundred patients received everolimus-based therapy, 79 received endocrine monotherapy, and 86 received chemotherapy. Everolimus-based therapy was associated with significantly longer progression-free survival and time on treatment than endocrine monotherapy and chemotherapy. IMPLICATIONS: Among HR+/HER2- mBC patients with multiple metastatic sites, everolimus-based therapy was associated with better real-world effectiveness than endocrine monotherapy or chemotherapy. PMID- 26947174 TI - Evaluation of a machine learning capability for a clinical decision support system to enhance antimicrobial stewardship programs. AB - OBJECTIVE: Antimicrobial stewardship programs have been shown to limit the inappropriate use of antimicrobials. Hospitals are increasingly relying on clinical decision support systems to assist in the demanding prescription reviewing process. In previous work, we have reported on an emerging clinical decision support system for antimicrobial stewardship that can learn new rules supervised by user feedback. In this paper, we report on the evaluation of this system. METHODS: The evaluated system uses a knowledge base coupled with a supervised learning module that extracts classification rules for inappropriate antimicrobial prescriptions using past recommendations for dose and dosing frequency adjustments, discontinuation of therapy, early switch from intravenous to oral therapy, and redundant antimicrobial spectrum. Over five weeks, the learning module was deployed alongside the baseline system to prospectively evaluate its ability to discover rules that complement the existing knowledge base for identifying inappropriate prescriptions of piperacillin-tazobactam, a frequently used antimicrobial. RESULTS: The antimicrobial stewardship pharmacists reviewed 374 prescriptions, of which 209 (56% of 374) were identified as inappropriate leading to 43 recommendations to optimize prescriptions. The baseline system combined with the learning module triggered alerts in 270 prescriptions with a positive predictive value of identifying inappropriate prescriptions of 74%. Of these, 240 reviewed prescriptions were identified by the alerts of the baseline system with a positive predictive value of 82% and 105 reviewed prescriptions were identified by the alerts of the learning module with a positive predictive value of 62%. The combined system triggered alerts for all 43 recommendations, resulting in a rate of actionable alerts of 16% (43 recommendations of 270 reviewed alerts); the baseline system triggered alerts for 38 interventions, resulting in a rate of actionable alerts of 16% (38 of 240 reviewed alerts); and the learning module triggered alerts for 17 interventions, resulting in a rate of actionable alerts of 16% (17 of 105 reviewed alerts). The learning module triggered alerts for every inappropriate prescription missed by the knowledge base of the baseline system (n=5). CONCLUSIONS: The learning module was able to extract clinically relevant rules for multiple types of antimicrobial alerts. The learned rules were shown to extend the knowledge base of the baseline system by identifying pharmacist interventions that were missed by the baseline system. The learned rules identified inappropriate prescribing practices that were not supported by local experts and were missing from its knowledge base. However, combining the baseline system and the learning module increased the number of false positives. PMID- 26947173 TI - The Hypoxia-inducible Factor Prolyl-Hydroxylase Inhibitor Roxadustat (FG-4592) and Warfarin in Healthy Volunteers: A Pharmacokinetic and Pharmacodynamic Drug Drug Interaction Study. AB - PURPOSE: Roxadustat is a small-molecule hypoxia-inducible factor prolyl hydroxylase inhibitor in late-stage clinical development for the treatment of anemia in patients with chronic kidney disease (CKD). Warfarin is an oral anticoagulant with a narrow therapeutic window that is often prescribed to treat coexisting cardiovascular diseases in patients with CKD. This clinical trial was designed to evaluate the effect of roxadustat on warfarin pharmacokinetic and pharmacodynamic parameters. METHODS: This open-label, single-sequence crossover study was conducted in healthy volunteers (male or female) aged 18 to 55 years with a body mass index of 18.5 to 30.0 kg/m(2). The study consisted of 2 periods separated by a minimum washout period of 14 days. After an overnight fast, volunteers received a single oral dose of 25 mg (5 * 5 mg tablets) warfarin on Day 1 of Period 1 and Day 7 of Period 2. Volunteers received oral doses of 200 mg (2 * 100 mg tablets) roxadustat on Days 1, 3, 5, 7 (concomitant with warfarin), 9, 11, 13, and 15 of Period 2. Plasma S- and R-warfarin (unbound and total concentrations) and prothrombin time were determined at multiple time points up to 216 hours postdose. Pharmacokinetic and pharmacodynamic parameters were estimated via noncompartmental methods. Tolerability was evaluated by monitoring adverse events, laboratory assays, vital signs, and 12-lead ECGs. FINDINGS: The geometric mean ratios and 90% CIs for Cmax and AUCinfinity of total and unbound S and R-warfarin (with and without roxadustat) were within the standard bioequivalence interval of 80.00% to 125.00%. Roxadustat increased the geometric mean (GM) prothrombin (PT) and international normalized ratio (INR) AUC from time zero to last measurable sample (AUCPT,last and AUCINR,last) by 24.4%. Coadministration of roxadustat and warfarin in healthy volunteers was associated with a favorable tolerability profile, with most treatment-associated adverse events mild in severity. IMPLICATIONS: Based on the lack of clinically significant pharmacokinetic interactions and the limited influence on warfarin pharmacodynamic parameters, no dose adjustment of warfarin should be required when coadministered with roxadustat. ClinicalTrials.gov identifier: NCT02252731. PMID- 26947175 TI - Satoyoshi syndrome in pregnancy. PMID- 26947177 TI - What rheumatologists should know about orofacial manifestations of autoimmune rheumatic diseases. AB - Orofacial manifestations occur frequently in rheumatic diseases and usually represent early signs of disease or of its activity that are still neglected in clinical practice. Among the autoimmune rheumatic diseases with potential for oral manifestations, rheumatoid arthritis (RA), inflammatory myopathies (IM), systemic sclerosis (SSc), systemic lupus erythematosus (SLE), relapsing polychondritis (RP) and Sjogren's syndrome (SS) can be cited. Signs and symptoms such as oral hyposalivation, xerostomia, temporomandibular joint disorders, lesions of the oral mucosa, periodontal disease, dysphagia, and dysphonia may be the first expression of these rheumatic diseases. This article reviews the main orofacial manifestations of rheumatic diseases that may be of interest to the rheumatologist for diagnosis and monitoring of autoimmune rheumatic diseases. PMID- 26947176 TI - A Preclinical Model for ERalpha-Positive Breast Cancer Points to the Epithelial Microenvironment as Determinant of Luminal Phenotype and Hormone Response. AB - Seventy-five percent of breast cancers are estrogen receptor alpha positive (ER+). Research on these tumors is hampered by lack of adequate in vivo models; cell line xenografts require non-physiological hormone supplements, and patient derived xenografts (PDXs) are hard to establish. We show that the traditional grafting of ER+ tumor cells into mammary fat pads induces TGFbeta/SLUG signaling and basal differentiation when they require low SLUG levels to grow in vivo. Grafting into the milk ducts suppresses SLUG; ER+ tumor cells develop, like their clinical counterparts, in the presence of physiological hormone levels. Intraductal ER+ PDXs are retransplantable, predictive, and appear genomically stable. The model provides opportunities for translational research and the study of physiologically relevant hormone action in breast carcinogenesis. PMID- 26947178 TI - The European Portuguese adaptation of the Fear of Pain Questionnaire. AB - In Portugal, it is estimated that chronic pain affects 36.7% of the population, constituting a multifactorial phenomenon with great impact on individual, family, community, and social levels. In the fear-avoidance model of pain, one of the most consistent consensus in the literature, the fear arises as one of the variables that can contribute to the development and maintenance of this condition. Thus, instruments for evaluating the fear of pain, as Fear of Pain Questionnaire (FPQ-III), may be useful in the conceptualization of the subjective experience of pain. Accordingly, this paper aims to describe the adaptation of FPQ-III to the European Portuguese idiom. A total of 1,094 participants (795 female; mean age=25.16, SD=7.72 years old) completed the web based questionnaire. The results point to a different factor model found in the first study of the original scale (five factors: minor pain, severe pain, medical pain, injection pain, and afflicted pain), good internal consistency (0.75 to 0.85) and good correlations (between 0.30 and 0.59) between subscales and (between 0.68 e 0.85) for the total score and subscales. Given the need to meet the various dimensions of the subjective experience of pain, the Fear of Pain Questionnaire is assumed as a useful tool that, in combination with other tools, may contribute to the evaluation and intervention procedures progressively more comprehensive and adjusted to the challenges raised with the issue of chronic pain. PMID- 26947181 TI - Hemolytic potential of miltefosine is dependent on cell concentration: Implications for in vitro cell cytotoxicity assays and pharmacokinetic data. AB - Miltefosine possesses antiparasitic, antibacterial, antifungal and antitumor activities; however, its mechanism of action is not well established. In the current work, the miltefosine concentrations required to achieve 50% hemolysis in PBS were shown to vary from 600 MUM using 5*10(9) cells/mL to ~2.9 MUM for ~5*10(6) cells/mL. This cell concentration-dependent hemolytic potential was described using an equation that included the membrane-water partition coefficient (K) and miltefosine concentrations in the cell membrane (cm) and aqueous medium (cw) as variables. The best-fit values for the 50% hemolysis data were log K=4.68, cm=110.8 mM, and cw=2.3 MUM. Hemolysis measurements in whole blood were used to determine the erythrocyte membrane-plasma partition coefficient of miltefosine (Log KM/P=1.77). Additionally, miltefosine concentration in whole blood was found to be ~86% of that in plasma. Previously reported clinical pharmacokinetics data indicate that the plasma concentration of miltefosine peaks at ~90 MUg/mL when treating visceral leishmaniasis. Using this concentration, which corresponds to ~77 MUg/mL miltefosine in whole blood, we found only 2.8% hemolysis. Significant hemolysis (5.4%) was observed only after doubling the concentration to 180 MUg/mL. Recently reported data indicate that miltefosine inhibitory concentrations in Leishmania are also dependent on cell concentration. The biophysical parameters assessed in the current study indicated that this type of response is associated with the accumulation of the drug in the cell membrane, which becomes damaged when critical drug concentrations are reached. PMID- 26947180 TI - The cardiomyocyte protein alphaT-catenin contributes to asthma through regulating pulmonary vein inflammation. AB - BACKGROUND: Recent genome-wide association studies have identified single nucleotide polymorphisms in the gene encoding the protein alphaT-catenin (CTNNA3) that correlate with both steroid-resistant atopic asthma and asthmatic exacerbations. alpha-Catenins are important mediators of cell-cell adhesion, and alphaT-catenin is predominantly expressed in cardiomyocytes. In the lung alphaT catenin appears to be exclusively expressed in cardiomyocytes surrounding the pulmonary veins (PVs), but its contribution to atopic asthma remains unknown. OBJECTIVE: We sought to understand the role of alphaT-catenin in asthma pathogenesis. METHODS: We used alphaT-catenin knockout mice and a house dust mite (HDM) extract model of atopic asthma, with assessment by means of forced oscillation, bronchoalveolar lavage, and histologic analysis. RESULTS: We found that the genetic loss of alphaT-catenin in mice largely attenuated HDM-induced airway inflammation and airway hyperresponsiveness to methacholine. Mice lacking alphaT-catenin that were exposed to HDM extract had reduced PV inflammation, specifically near the large veins surrounded by cardiac cells. The proximity of the airways to PVs correlated with the severity of airway goblet cell metaplasia, suggesting that PVs can influence the inflammatory milieu of adjacent airways. Loss of alphaT-catenin led to compensatory upregulation of alphaE-catenin, which itself has a defined anti-inflammatory function. CONCLUSION: These data mechanistically support previous clinical and genetic associations between alphaT catenin and the development of atopic asthma and suggest that PVs might have an underappreciated role in allergic airway inflammation. PMID- 26947179 TI - IL-2 consumption by highly activated CD8 T cells induces regulatory T-cell dysfunction in patients with hemophagocytic lymphohistiocytosis. AB - BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a severe inflammatory condition driven by excessive CD8(+) T-cell activation. HLH occurs as both acquired and familial hemophagocytic lymphohistiocytosis (FHL) forms. In both conditions, a sterile or infectious trigger is required for disease initiation, which then becomes self-sustaining and life-threatening. Recent studies have attributed the key distal event to excessive IFN-gamma production; however, the proximal events driving immune dysregulation have remained undefined. OBJECTIVE: We sought to investigate the role of regulatory T (Treg) cells in the pathophysiology of experimental FHL. METHODS: Because mutation in perforin is a common cause of FHL, we used an experimental FHL mouse model in which disease in perforin-deficient mice is triggered by lymphocytic choriomeningitis virus (LCMV). We assessed Treg and CD8(+) T-cell homeostasis and activation during the changing systemic conditions in the mice. In addition, human blood samples were collected and analyzed during the HLH episode. RESULTS: We found no primary Treg cell defects in perforin-deficient mice. However, Treg cell numbers collapsed after LCMV inoculation. The collapse of Treg cell numbers in LCMV-triggered perforin-deficient, but not wild-type, mice was accompanied by the combination of lower IL-2 secretion by conventional CD4(+) T cells, increased IL-2 consumption by activated CD8(+) T cells, and secretion of competitive soluble CD25. Moreover low Treg cell numbers were observed in untreated patients experiencing HLH flares. CONCLUSION: These results demonstrate that excessive CD8(+) T-cell activation rewires the IL-2 homeostatic network away from Treg cell maintenance and toward feed-forward inflammation. These results also provide a potential mechanistic pathway for the progression of infectious inflammation to persistent inflammation in patients with HLH. PMID- 26947182 TI - The Alzheimer's disease Abeta peptide binds to the anionic DMPS lipid bilayer. AB - We have applied isobaric-isothermal replica exchange molecular dynamics (REMD) and the all-atom explicit water model to study binding of Abeta10-40 peptide to the anionic DMPS bilayer. To provide comparison with a zwitterionic bilayer, we used our previous REMD simulations probing binding of the same peptide to the DMPC bilayer. Using two sets of simulations, we comparatively analyzed the equilibrium Abeta conformational ensemble, peptide-bilayer interactions, and changes in the bilayer structure induced by Abeta binding. Our results are six fold. (1) Binding to the DMPS bilayer triggers the formation of stable helix in the Abeta C-terminal, although the helix-inducing effect caused by DMPS lipids is weaker than that of DMPC. (2) Compared to the DMPC-bound Abeta monomer, the anionic bilayer weakens intrapeptide interactions, particularly, formed by charged amino acids. (3) Binding of Abeta peptide to the DMPS bilayer is primarily governed by electrostatic interactions between charged amino acids and charged lipid groups. In contrast, these interactions play minor role in Abeta binding to the DMPC bilayer. (4) Abeta peptide generally resides on the DMPS bilayer surface causing relatively minor bilayer thinning. The opposite scenario applies to Abeta binding to the DMPC bilayer. (5) In contrast to DMPC simulations, Abeta largely expels anionic lipids from its binding "footprint" forming a ring of charged amino acids mixed with charged lipid groups around the peptide. (6) Abeta binding disorders proximal DMPS lipids more strongly than their DMPC counterparts. Our simulations show that Abeta monomers fail to perturb anionic or zwitterionic bilayers across both leaflets. PMID- 26947183 TI - The oxidized phospholipid PazePC promotes permeabilization of mitochondrial membranes by Bax. AB - Mitochondria play a crucial role in programmed cell death via the intrinsic apoptotic pathway, which is tightly regulated by the B-cell CLL/lymphoma-2 (Bcl 2) protein family. Intracellular oxidative stress causes the translocation of Bax, a pro-apoptotic family member, to the mitochondrial outer membrane (MOM) where it induces membrane permeabilization. Oxidized phospholipids (OxPls) generated in the MOM during oxidative stress directly affect the onset and progression of mitochondria-mediated apoptosis. Here we use MOM-mimicking lipid vesicles doped with varying concentrations of 1-palmitoyl-2-azelaoyl-sn-glycero-3 phosphocholine (PazePC), an OxPl species known to significantly enhance Bax membrane association, to investigate three key aspects of Bax's action at the MOM: 1) induction of Bax pores in membranes without additional mediator proteins, 2) existence of a threshold OxPl concentration required for Bax-membrane action and 3) mechanism by which PazePC disturbs membrane organization to facilitate Bax penetration. Fluorescence leakage studies revealed that Bax-induced leakage, especially its rate, increased with the vesicles' PazePC content without any detectable threshold neither for OxPl nor Bax. Moreover, the leakage rate correlated with the Bax to lipid ratio and the PazePC content. Solid state NMR studies and calorimetric experiments on the lipid vesicles confirmed that OxPl incorporation disrupted the membrane's organization, enabling Bax to penetrate into the membrane. In addition, 15N cross polarization (CP) and insensitive nuclei enhanced by polarization transfer (INEPT) MAS NMR experiments using uniformly (15)N-labeled Bax revealed dynamically restricted helical segments of Bax embedded in the membrane, while highly flexible protein segments were located outside or at the membrane surface. PMID- 26947184 TI - Efficient preparation and analysis of membrane and membrane protein systems. AB - Molecular dynamics (MD) simulations have become a highly important technique to consider lipid membrane systems, and quite often they provide considerable added value to laboratory experiments. Rapid development of both software and hardware has enabled the increase of time and size scales reachable by MD simulations to match those attainable by several accurate experimental techniques. However, until recently, the quality and maturity of software tools available for building membrane models for simulations as well as analyzing the results of these simulations have seriously lagged behind. Here, we discuss the recent developments of such tools from the end-users' point of view. In particular, we review the software that can be employed to build lipid bilayers and other related structures with or without embedded membrane proteins to be employed in MD simulations. Additionally, we provide a brief critical insight into force fields and MD packages commonly used for membrane and membrane protein simulations. Finally, we list analysis tools that can be used to study the properties of membrane and membrane protein systems. In all these points we comment on the respective compatibility of the covered tools. We also share our opinion on the current state of the available software. We briefly discuss the most commonly employed tools and platforms on which new software can be built. We conclude the review by providing a few ideas and guidelines on how the development of tools can be further boosted to catch up with the rapid pace at which the field of membrane simulation progresses. This includes improving the compatibility between software tools and promoting the openness of the codes on which these applications rely. This article is part of a Special Issue entitled: Biosimulations edited by Ilpo Vattulainen and Tomasz Rog. PMID- 26947186 TI - Deracemizing organocatalyzed Michael addition reactions of 2 (arylthio)cyclobutanones with beta-nitrostyrenes. AB - Organocatalyzed Michael addition reactions of 2-(arylthio)cyclobutanones with trans-beta-nitrostyrenes have been carried out using a bifunctional thiourea primary amine catalyst, providing diastereoisomerically and enantiomerically enriched 2-alkyl-2-(arylthio)cyclobutanones having two contiguous stereocenters of which one is a chiral quaternary center. The absolute configuration of these novel adducts was assigned by X-ray diffraction analysis and a transition-state model is proposed to explain the observed stereoselectivities. PMID- 26947185 TI - Public health nutrition in the civil service (England): approaches to tackling obesity. AB - The seriousness and scale of the physical, psychological, economic and societal consequences relating to poor diets, inactivity and obesity is unprecedented. Consequently, the contextual factors underpinning the work of a nutritionist in the civil service are complex and significant; however, there are real opportunities to make a difference and help improve the health of the nation. The present paper describes the delivery of public health nutrition through two work programmes, namely action to support young people develop healthier lifestyle choices and more recently the investigation and deployment of local insights to develop action to tackle obesity. Combining the application of nutrition expertise along with broader skills and approaches has enabled the translation of research and evidence into programmes of work to better the public's health. It is evident that the appropriate evaluation of such approaches has helped to deliver engaging and practical learning opportunities for young people. Furthermore, efforts to build on local intelligence and seek collaborative development can help inform the evidence base and seek to deliver public health approaches, which resonate with how people live their lives. PMID- 26947187 TI - MR imaging of Schmorl's nodes: Imaging characteristics and epidemio-clinical relationships. AB - PURPOSE: The purpose of our prospective study was to assess the presentation of Schmorl's nodes (SN) on magnetic resonance imaging (MRI) and investigate their possible association with demographic and clinical findings. MATERIALS AND METHODS: Three hundred and thirty-three patients were prospectively included. Thirteen (3.9%) patients were excluded because of contraindication to MRI and/or Scheuermann's disease. The final study population included 320 patients. T1 weighted and short TI inversion recovery sequences were performed to assess SN prevalence, the vertebral level and their anatomical distribution in vertebra. Medical history was recorded focusing on previous diseases including degenerative, rheumatoid and neoplastic disease, and any existing spinal traumatism. Epidemiological information was also obtained, including age, gender, ethnicity, professional and sporting activity. RESULTS: The final study population included 320 patients (172 men, 148 women) with a mean age of 54 years+/-17.5 (SD) (range: 19-87 years). A total of 421 SN were found in 158/320 patients (49.4%). SN were localized in thoracic spine for 48%, in lumbar spine for 46% and cervical spine for 6%. The middle part of the thoracic vertebra was the most affected area (80%), mostly in the middle superior endplate (41%). SN were more frequently observed in manual workers who worked more than 10 years (P<0.0001) and less frequently in patients of the 30-39-year-old age group (P=0.0048). No significant associations were found with gender (P=0.17) and remarkable medical history (P=0.21). SN were less frequently observed in patients with sport activities of 1-5hours/week (P=0.04) and those with an African origin (P<0.0001). CONCLUSION: Our study suggests a potential role for ethnical and physical factors in the pathogenesis of SN. Furthers studies are mandatory to evaluate their clinical relevance, especially in patients such as Caucasian manual workers in whom SN have a high prevalence. PMID- 26947189 TI - Removal of Cr(VI) from aqueous solutions by adsorption on MnO2. AB - Adsorption of Cr(VI) on MnO2 was investigated with respect to effect of pH, temperature, ionic strength, initial Cr(VI) concentration, co-presence of different anions (HCO3(-), SO4(2-), H2PO4(-), NO3(-) and Cl(-)) and of low molecular weight natural organic materials (LMWNOM) (acetate, oxalate and citrate). The process was rapid during the first 3-5min, reaching equilibrium after one hour. Adsorption decreased with increasing pH, temperature and Cr(VI) initial concentration, and increased with increasing ionic strength. Co-presence of phosphate, sulfate, bicarbonate, citrate and oxalate hindered Cr(VI) adsorption, whereas nitrate, chloride and acetate did not exert any notable influence. The overall order of Cr(VI) adsorption suppression due to co-presence of anions and LMWNOM was H2PO4(-)>HCO3(-)>SO4(2-), and oxalate>citrate, respectively. Highest experimental equilibrium sorption capacity (0.83mgg(-1)) was obtained at 20 degrees C and pH 5.9, while lowest (0.18mgg(-1)) was noticed in the co-presence of H2PO4(-), at 20 degrees C and pH 6.9. Adsorption kinetics was successfully fitted by pseudo-second-order model. Mechanisms for both specific and non-specific adsorption are likely to be involved, while rate controlling step involved both intra-particle and film diffusion processes. Cr(VI) was strongly bound to MnO2, which makes risks of its subsequent liberation into the environment to be low. PMID- 26947188 TI - Characterization of morphology and component of struvite pellets crystallized from sludge dewatering liquor: Effects of total suspended solid and phosphate concentrations. AB - A lab-scale struvite pellet crystallization system was used to study phosphorus (P) removal and recovery from sludge dewatering liquor (SDL). Influences of total suspended solids (TSS) and phosphate concentrations on P removal as well as the size, morphology, purity, and components of struvite pellets were investigated. The increase in TSS concentration resulted in not only the decreases in phosphate removal efficiency and struvite purity but also the irregular pellet morphology and broken struvite crystals. Increasing inlet PO4-P concentration enhanced PO4-P removal, average struvite pellet diameter, purity and crystal volume growth rate. Amorphous calcium phosphate (ACP), calcite, brucite and magnesium phosphate were formed as co-precipitates with struvite. However, species and quantity of co precipitates could be variable. More calcium precipitates were easily formed at lower PO4-P concentration (48mg/L), while brucite was the main co-precipitate at higher PO4-P concentration (151mg/L). Organic compounds were involved in struvite pellets along with suspended solids during the formation of struvite. Higher TSS concentration resulted in both more species and higher contents of organic compounds in struvite pellets. Therefore, it is essential to remove suspended solids in advance so as to obtain high P-removal and harvest high-quality struvite pellets. PMID- 26947190 TI - Comment on 'The evidential value of developmental age imaging for assessing age of majority' by Cole, Annals of Human Biology, 2015. PMID- 26947195 TI - Lenalidomide in adult T-cell leukaemia-lymphoma. PMID- 26947191 TI - TFH in HIV Latency and as Sources of Replication-Competent Virus. AB - During untreated disease, HIV replication is concentrated within T follicular helper cells (TFH). Heightened permissiveness, the presence of highly infectious virions on follicular dendritic cells (FDCs), low frequencies of virus-specific cytotoxic T lymphocytes (CTLs) in B cell follicles, expansions in TFH, and TFH dysfunction, all likely promote replication in TFH. Limited data suggest that memory TFH play a role in the latent or subclinical reservoir of HIV during antiretroviral therapy (ART), potentially for many of the same reasons. A better understanding of the role of memory TFH and FDC-bound virions in promoting recrudescent viremia in the setting of ART cessation is essential. Studies that target follicular virus reservoirs are needed to determine their role in HIV latency and to suggest successful cure strategies. PMID- 26947196 TI - Does cytomegalovirus viral load in stem-cell transplant recipients matter? PMID- 26947197 TI - A new life for rituximab? PMID- 26947198 TI - A propensity to bleed. PMID- 26947199 TI - Lenalidomide in relapsed adult T-cell leukaemia-lymphoma or peripheral T-cell lymphoma (ATLL-001): a phase 1, multicentre, dose-escalation study. AB - BACKGROUND: Patients with adult T-cell leukaemia-lymphoma have few treatment options after relapse and poor survival outcomes with current therapies. We aimed to determine the maximum tolerated dose of lenalidomide, an oral immunomodulator, in Japanese patients with relapsed adult T-cell leukaemia-lymphoma and other peripheral T-cell lymphomas. METHODS: In this phase 1 study, we enrolled patients aged 20 years or older with Eastern Cooperative Oncology Group performance status 0-2, documented diagnosis of aggressive adult T-cell leukaemia-lymphoma or other peripheral T-cell lymphoma subtypes, and at least one previous antilymphoma therapy. Patients were sequentially assigned to lenalidomide 25 mg/day, days 1-21 of a 28-day cycle (cohort 1), 25 mg/day continuously (cohort 2), and 35 mg/day continuously (cohort 3) in a 3 + 3 design. The primary study endpoint was to identify the maximum tolerated dose of lenalidomide. Analyses were performed per protocol for efficacy and in the intent-to-treat patient population for safety. This completed trial is registered with ClinicalTrials.gov, number NCT01169298. FINDINGS: We enrolled 14 patients from six centres in Japan. Of 13 assessable patients (nine with adult T-cell leukaemia-lymphoma, four with other peripheral T cell lymphomas) receiving lenalidomide, dose-limiting toxic effects were reported in three patients during cycle 1 (one grade 4 thrombocytopenia [cohort 2], one grade 3 QT prolongation on electrocardiogram [cohort 3], and one grade 3 fatigue and grade 4 thrombocytopenia [cohort 3]). The maximum tolerated dose was identified as lenalidomide 25 mg/day given continuously. The most common grade 3 or worse adverse events were neutropenia (eight [62%] patients), lymphopenia (seven [54%] patients), and thrombocytopenia (four [31%] patients); myelosuppression was similar in each cohort. Serious adverse events occurred in eight (62%) patients; thrombocytopenia, which occurred in three (23%) patients, was the only serious adverse event reported in more than one patient. INTERPRETATION: We were able to determine the dose and schedule for lenalidomide treatment in previously treated patients with aggressive, adult T-cell leukaemia lymphoma. This dose will be used in a subsequent phase 2 study. FUNDING: Celgene Corporation. PMID- 26947200 TI - Cytomegalovirus viral load and mortality after haemopoietic stem cell transplantation in the era of pre-emptive therapy: a retrospective cohort study. AB - BACKGROUND: Although cytomegalovirus viral load is commonly used to guide pre emptive therapy in the post-transplantation setting, few data are available correlating viraemia with clinical endpoints. We therefore investigated the association between cytomegalovirus viral load and mortality in the first year after haemopoietic stem cell transplantation. METHODS: In this retrospective cohort study, we included patients from the Fred Hutchinson Cancer Research Center, WA, USA, who received an allogeneic haemopoietic stem cell transplantation between Jan 1, 2007, and Feb 28, 2013, were cytomegalovirus seropositive or had a seropositive donor, and underwent weekly plasma cytomegalovirus monitoring by PCR through to day 100 post-transplantation. Cox proportional hazards models were used to estimate the association of cytomegalovirus viral load at different thresholds with overall mortality by 1 year post-transplantation, adjusting for the use of pre-emptive therapy and other factors such as neutropenia, and graft-versus-host disease. FINDINGS: Of the 1037 patients initially selected for inclusion in this cohort, 87 (8%) patients were excluded because of missing cytomegalovirus testing and 24 (2%) were excluded because of their participation in cytomegalovirus prophylaxis trials. In the remaining 926 patients included in this study, the cumulative overall mortality was 30.0% (95% CI 26.9-33.0) 1 year after haemopoietic stem cell transplantation. 95 patients developed cytomegalovirus disease; death was directly attributable to cytomegalovirus disease in three (1%) of 263 patients who died in the first year after transplantation. A cytomegalovirus viral load of 250 IU/mL or greater was associated with increased risk of early (day 0-60 post-transplantation) death (adjusted hazard ratio [HR] 19.8, 95% CI 9.6-41.1). The risk was attenuated after day 60 (adjusted HR 1.8, 95% CI 1.3-2.3). Similar associations were noted for higher cytomegalovirus viral load thresholds. INTERPRETATION: Cytomegalovirus viraemia is associated with an increased risk of overall mortality in the first year after haemopoietic stem cell transplantation, independent of the use of pre emptive therapy, and with evidence of a positive dose-response relationship. These data indicate the suitability of viral load as a surrogate clinical endpoint for clinical trials for cytomegalovirus vaccines, biologics, and drugs. FUNDING: Merck and Co, National Institutes of Health. PMID- 26947203 TI - A roadmap for European research. PMID- 26947201 TI - Pharmacokinetics, safety, and efficacy of subcutaneous versus intravenous rituximab plus chemotherapy as treatment for chronic lymphocytic leukaemia (SAWYER): a phase 1b, open-label, randomised controlled non-inferiority trial. AB - BACKGROUND: Part one of the two-part SAWYER study predicted that subcutaneous rituximab 1600 mg would achieve trough serum concentrations that were non inferior to those achieved with intravenous rituximab 500 mg/m(2) in patients with chronic lymphocytic leukaemia. In part two of the study, we aimed to confirm the pharmacokinetic non-inferiority of subcutaneous rituximab, and investigate its safety and efficacy. METHODS: We did this phase 1b, open-label, randomised controlled non-inferiority study at 68 centres in 19 countries in Europe, North America, South America, and Australasia. Patients aged 18 years or older with untreated chronic lymphocytic leukaemia were randomly assigned, via an interactive voice-response system with a permuted block randomisation scheme (block size of ten), to receive subcutaneous rituximab 1600 mg or intravenous rituximab 500 mg/m(2) plus fludarabine and cyclophosphamide every 4 weeks for up to six cycles. In cycle one, all patients received intravenous rituximab 375 mg/m(2). Randomisation was stratified by Binet stage and fludarabine and cyclophosphamide administration route (oral vs intravenous). Study investigators and patients were not masked to group allocation, but allocation was concealed from the statistician, clinical scientist, and clinical pharmacologist. The primary endpoint was trough serum concentration at cycle five, with a non inferiority margin of 0.8 for the adjusted geometric mean ratio of the subcutaneous to the intravenous dose. We did the primary analysis in patients in the intention-to-treat population with complete pharmacokinetic data (pharmacokinetic population). This trial is registered with ClinicalTrials.gov, number NCT01292603, and is ongoing, although the treatment stage is now complete. FINDINGS: Between Aug 20, 2012, and June 17, 2013, we randomly assigned 176 patients to receive subcutaneous rituximab (n=88) or intravenous rituximab (n=88); 134 (76%) patients comprised the pharmacokinetic population. As of May 7, 2014, median follow-up was 13.9 months (IQR 11.9-16.0) for patients in the subcutaneous group and 14.1 months (11.6-16.5) for patients in the intravenous group. At cycle five, the geometric mean trough serum concentration in patients given subcutaneous rituximab was non-inferior to that in patients given intravenous rituximab (97.5 MUg/mL vs 61.5 MUg/mL), with an adjusted geometric mean ratio of 1.53 (90% CI 1.27-1.85). In the safety analysis, the proportion of patients reporting adverse events was similar between the subcutaneous and intravenous groups (all grades: 82 [96%] of 85 patients and 81 [91%] of 89 patients; serious adverse events: 25 [29%] and 29 [33%] patients; grade >=3: 59 [69%] and 63 [71%] patients, respectively). The most common adverse event of grade 3 or higher was neutropenia (48 [56%] patients in the subcutaneous group and 46 [52%] patients in the intravenous group); the most common serious adverse event was febrile neutropenia (n=9 [11%] and n=4 [4%], respectively). We recorded administration-related reactions in 37 (44%) patients given subcutaneous rituximab and 40 (45%) patients given the intravenous dose, with differences between administration routes for injection-site erythema (n=10 [12%] and n=0, respectively) and nausea (n=2 [2%] and n=11 [12%], respectively). More patients reported local cutaneous reactions after subcutaneous rituximab (n=36 [42%]) than after intravenous rituximab (n=2 [2%]); most of these reactions were grade 1 or 2. INTERPRETATION: When combined with fludarabine and cyclophosphamide, subcutaneous rituximab 1600 mg achieved trough serum concentrations that were pharmacokinetically non-inferior to those achieved with intravenous rituximab 500 mg/m(2), with a similar safety and efficacy profile between the two groups. Treatment with subcutaneous rituximab should allow patients with chronic lymphocytic leukaemia to receive clinical benefit from the drug via a more convenient delivery method than the intravenous route, and might also be used in combination regimens with approved and emerging oral regimens. FUNDING: F Hoffmann-La Roche. PMID- 26947202 TI - Prophylactic plasma transfusion for surgical patients with abnormal preoperative coagulation tests: a single-institution propensity-adjusted cohort study. AB - BACKGROUND: Perioperative haemorrhage negatively affects patient outcomes and results in substantial consumption of health-care resources. Plasma transfusions are often administered to address abnormal preoperative coagulation tests, with the hope to mitigate bleeding complications. We aimed to assess the associations between preoperative plasma transfusion and bleeding complications in patients with elevated international normalised ratio (INR) undergoing non-cardiac surgery. METHODS: We did an observational study in a consecutive sample of adult patients undergoing non-cardiac surgery with preoperative INR greater than or equal to 1.5. The exposure of interest was transfusion of preoperative plasma for elevated INR. The primary outcome was WHO grade 3 bleeding in the early perioperative period (from entry into the operating room until 24 h following exit from operating room). Hypotheses were tested with univariate and propensity matched analyses. We did multiple sensitivity analyses to further evaluate the robustness of study findings. FINDINGS: Between Jan 1, 2008, and Dec 31, 2011, we identified 1234 (8.4%) of 14 743 patients who had an INR of 1.5 or above and were included in this investigation. Of 1234 study participants, 139 (11%) received a preoperative plasma transfusion. WHO grade 3 bleeding occurred in 73 (53%) of 139 patients who received preoperative plasma compared with 350 (32%) of 1095 patients who did not (odds ratio [OR] 2.35, 95% CI 1.65-3.36; p<0.0001). Among the propensity-matched cohort, 65 (52%) of 125 plasma recipients had WHO grade 3 bleeding compared with 97 (40%) of 242 of those who did not receive preoperative plasma (OR 1.75, 95% CI 1.09-2.81; p=0.021). Results from multiple sensitivity analyses were qualitatively similar. INTERPRETATION: Preoperative plasma transfusion for elevated international normalised ratios was associated with an increased frequency of perioperative bleeding complications. Findings were robust in the sensitivity analyses, suggestive that more conservative management of abnormal preoperative international normalised ratios is warranted. FUNDING: Mayo Clinic, National Institutes of Health. PMID- 26947204 TI - Illness representations, knowledge and motivation to perform presymptomatic testing for late-onset genetic diseases. AB - This study addresses the relation between illness representations, knowledge and motivation to perform the presymptomatic testing (PST) of subjects at-risk for Familial Amyloydotic Polyneuropathy (FAP), Huntington's disease (HD) and Machado Joseph disease (MJD), compared with subjects at-risk for Hereditary Hemochromatosis (HH). The sample comprised a clinical group of 213 subjects at genetic risk for FAP, HD and MJD, and a comparison group of 31 subjects at genetic risk for HH, that answered three open-ended questions relating illness representations, knowledge about the disease, and motivation to perform PST. People at-risk for FAP, HD and MJD use more metaphors, make more references to the family, are more concerned with the future and feel more out of curiosity and to learn, than for HH. These subjects at-risk correspond to the profile of somatic individual or personhood, wherein the unsubjectivation of the disease can function as a coping mechanism. PMID- 26947205 TI - Complex network-based approaches to biomarker discovery. AB - Many studies on biomarker discovery have been done by analyzing mutations in DNA sequences and differences in gene expression patterns. As a new branch of the latter approach, the concept of network biomarkers has been proposed, in which expression data of small subnetworks are used as markers. Furthermore, network biomarkers have been extended to dynamical network biomarkers, in which time series expression data of subnetworks are used as markers. On the other hand, the methodologies in complex networks have also been applied to biomarker discovery. For example, various centrality measures and the concept of observability have been applied. In this article, we review these new approaches for biomarker discovery with focusing on the computational/methodological aspects. PMID- 26947206 TI - Effects of total saponins from Rhizoma Dioscoreae Nipponicae on expression of vascular endothelial growth factor and angiopoietin-2 and Tie-2 receptors in the synovium of rats with rheumatoid arthritis. AB - BACKGROUND: This study aimed to determine the effects of total saponins from Rhizoma Dioscoreae Nipponicae (TS-RDN) on the expression of vascular endothelial growth factor (VEGF) and angiopoietin (Ang)-2 and Tie-2 (endothelial tyrosine kinase receptor) receptors in the synovium of rats with rheumatoid arthritis (RA) (collagen-induced arthritis; CIA), and to examine the mechanisms of TS-RDN in alleviating RA. METHODS: The CIA rat model was established and the animals were randomly divided into control, CIA model, TS-RDN, diosgenin, and tripterygium groups. Fluorescent polymerase chain reaction was performed to detect VEGF expression in the rat knee joint synovium. Additionally, immunohistochemical assay was used to detect protein expression of Ang-2 and Tie-2 in the rat knee joint synovium. RESULTS: Expression of VEGF, Ang-2, and Tie-2 in the model group was significantly higher than in the control group (p < 0.01). After TS-RDN, tripterygium and diosgenin treatment, VEGF and Ang-2 expression was lower than in the model group (p < 0.01). However, Tie-2 expression showed no significant difference. The effects of TS-RDN on VEGF expression were more marked than those of tripterygium and diosgenin (p < 0.01). CONCLUSION: TS-RDN might reduce the expression of VEGF, Ang-2, and Tie-2 in the synovium, thus inhibiting synovial angiogenesis and playing a therapeutic role in RA. PMID- 26947207 TI - Retrohepatic cholecystitis in a human immunodeficiency virus-infected patient. PMID- 26947208 TI - Giant pleural fibrous tumour. PMID- 26947209 TI - Molecular cloning and functional analysis of chitinases in the fresh water snail, Lymnaea stagnalis. AB - Molluscan shells, consisting of calcium carbonate, are typical examples of biominerals. The small amount of organic matrices containing chitin and proteins in molluscan shells regulates calcification to produce elaborate microstructures. The shells of gastropods have a spiral shape around a central axis. The shell thickness on the internal side of the spiral becomes thinner than that on the outer side of the spiral during the growth to expand the interior space. These observations suggest that a dissolution process works as a remodeling mechanism to change shell shape in molluscan shells. To reveal the dissolution mechanism involved in the remodeling of gastropod spiral shells, we focused on chitinases in the fresh water snail Lymnaea stagnalis. Chitinase activity was observed in the acetic acid-soluble fraction of the shell and in the buffer extract from the mantle. Allosamidin, a specific inhibitor of family 18 chitinases, inhibited the chitinase activity of both fractions completely. Homology cloning and transcriptome analyses of the mantle revealed five genes (chi-I, chi-II, chi-III, chi-IV, and chi-V) encoding family 18 chitinases. All chitinases were expressed in the mantle and in other tissues suggesting that chitinases in the mantle have multiple-functions. Treatment with commercially available chitinase obtained from Trichoderma viride altered the shell microstructure of L. stagnalis. Larvae of L. stagnalis cultured in allosamidin solution had a thinner organic layer on the shell surface. These results suggest that the chitinase activities in the shell and mantle are probably associated with the shell formation process. PMID- 26947210 TI - Subjective quality of life in first-episode psychosis. A ten year follow-up study. AB - Subjective quality of life (S-QoL) is an important outcome measure in first episode psychosis (FEP). The aims of this study were to describe S-QoL development the first 10-years in FEP patients and to identify predictors of this development. METHODS: A representative sample of 272 patients with a first episode psychotic disorder was included from 1997 through 2000. At 10 year follow up 186 patients participated. QoL was measured by the Lehman's Quality of Life Interview. Linear mixed model analyses were performed to investigate longitudinal effects of baseline psychiatric symptoms and socio-economic variables and the effects of changes in the same variables on S-QoL-development. RESULTS: S-QoL improved significantly over the follow-up period. More contact with family and a better financial situation at baseline had a positive and longstanding effect on S-QoL-development, but changes in these variables were not associated with S-QoL development. Higher depressive symptoms and less daily activities at baseline both had a negative independent effect, but a positive interaction effect with time on S-QoL-development indicating that the independent negative effect diminished over time. In the change analysis, increased daily activities and a decrease in depressive symptoms were associated with a positive S-QoL development. CONCLUSIONS: Treatment of depressive symptoms and measures aimed at increasing daily activities seem important to improve S-QoL in patients with psychosis. More contact with family and a better financial situation at baseline have a long-standing effect on S-QoL-development in FEP patients. PMID- 26947211 TI - Molecular interactions between ammonium-based ionic liquids and molecular solvents: current progress and challenges. AB - In view of the spacious scope of structural information and the molecular interactions between ammonium-based ionic liquids (ILs) and molecular solvents in various applications including chemical and pharmaceutical that are crucial for all aspects of scientific community, the knowledge of the molecular mechanisms, in particular, the thermodynamic basis of the structure-breaking/making interactions as well as the packing effect of the molecular liquids is essential to understand the ion-ion and ion-solvent interactions that exist in the liquid mixtures. In this perspective, we describe how the thermodynamic parameters can be effectively used to gain valuable insights into molecular interactions between ammonium-based ILs and molecular solvents, which would be most useful in various industries. This perspective presents the thermophysical properties of pure ammonium-based ILs, then these properties of the mixtures of these ILs with other solvents, and reviews the correlation researches on the properties of these systems. Finally, this perspective also brings a brief overview on several studies accomplished in this area by various researchers. PMID- 26947212 TI - Cost-Effectiveness Evaluation of Collaborative Care for Diabetes and Depression in Primary Care. AB - INTRODUCTION: Information is limited on the cost effectiveness of strategies to improve depressive symptoms in patients with Type 2 diabetes in primary care outside of the U.S. METHODS: Using patient data from a 12-month controlled implementation trial, outcomes and healthcare costs determined through administrative database linkages were compared for a strategy of family physician notification and follow-up ("enhanced care") versus collaborative care. Two measures of effectiveness were used: depression-free days (DFDs) based on Patient Health Questionnaire, and quality-adjusted life years (QALYs) based on EQ-5D. Data were collected November 2010 to January 2013 with analyses completed in May 2015. Incremental cost-effectiveness ratios were also compared against true usual care patients. RESULTS: Among 227 patients, mean age was 58 years, 55% were female, and mean diabetes duration was 12 years. Compared with total 12-month cost per usual care patient (C$5,889), the incremental cost was C$450 for patients in enhanced care and C$1,021 for collaborative care. Both enhanced and collaborative care strategies improved outcomes compared with usual care, with incremental DFDs of 65.9 and 117.6, and incremental QALYs of 0.006 and 0.042, respectively. Compared with enhanced care, collaborative care yielded incremental cost-effectiveness ratios of C$11/DFD and C$15,861/QALY. Compared with usual care, the incremental cost-effectiveness ratios were C$7/DFD or C$76,271/QALY for enhanced care and C$9/DFD or C$24,368/QALY for collaborative care. CONCLUSIONS: In primary care patients with Type 2 diabetes who screened positive for depression, physician notification and follow-up was a clinically effective strategy compared with usual care, but investing more resources in collaborative care yielded the most cost-effective strategy. PMID- 26947213 TI - Cost Effectiveness of HIV Prevention Interventions in the U.S. AB - INTRODUCTION: The purpose of this study was to assess and compare the cost effectiveness of current HIV prevention interventions in the U.S. using a consistent, standardized methodology. METHODS: The cost effectiveness of common and emerging HIV biomedical and behavioral prevention interventions as delivered to men who have sex with men, injection drug users, and sexually active heterosexuals was estimated. Data on program costs, intervention efficacy, risk behaviors, and per contact transmission probabilities were collected from peer reviewed papers and health department reports. These data were combined with 2010 national HIV incidence and prevalence surveillance data in a Bernoulli process model to estimate the reduced annual risk of HIV transmission or acquisition associated with these interventions. The cost per prevented case of HIV and the cost per saved quality-adjusted life year were then calculated. Analyses were conducted between 2014 and 2015. RESULTS: Interventions to diagnose HIV and provide ongoing care and treatment had the lowest cost per prevented case. Among interventions targeted at specific risk groups, interventions for men who have sex with men were the most cost effective. The least cost-effective interventions typically addressed people at risk of acquiring HIV rather than those at risk of transmitting the disease. CONCLUSIONS: HIV prevention interventions targeted at high-risk populations, those associated with the care continuum, and those that reduce the transmission risk of HIV-infected people are typically the most cost effective. Decision makers can consider these results in planning an efficient allocation of HIV prevention resources. PMID- 26947214 TI - Mothers' and Clinicians' Priorities for Obesity Prevention Among Black, High-Risk Infants. AB - INTRODUCTION: Despite many recommended strategies for obesity prevention during infancy, effectively delivering recommendations to parents in clinical settings is challenging, especially among high-risk populations. This study describes and compares mothers' and clinicians' priorities for obesity prevention during infancy, to facilitate more-effective obesity prevention messaging. METHODS: A discrete choice experiment using maximum difference scaling was administered in 2013 and analyzed in 2013-2014. Twenty-nine low-income, obese mothers of infants and 30 pediatric clinicians from three urban primary care practices rated the relative importance of 16 items relevant to obesity prevention during infancy, in response to this question: Which topic would be most helpful [for new mothers] to learn about to prevent your [their] child from becoming overweight? Response options encompassed the domains of feeding, sleep, parenting (including physical activity and screen time), and maternal self-care. RESULTS: Mothers (all Medicaid enrolled and black; mean age, 27 years; mean BMI, 35 kg/m(2)) and clinicians (97% female, 87% pediatricians, 13% nurse practitioners) both highly prioritized recognizing infant satiety and hunger cues, and appropriate feeding volume. Mothers rated infant physical activity and maintaining regular routines as 3.5 times more important than clinicians did (p<0.001). Clinicians rated breastfeeding as 3.4 times more important than mothers did (p<0.001). Neither group prioritized learning about screen time or maternal self-care. CONCLUSIONS: Low-income, obese, black mothers of infants highly prioritized learning about many effective obesity prevention strategies, including recognizing hunger and satiety cues, promoting infant activity, and maintaining regular routines. Clinicians may frame preventive guidance to be responsive to these priorities. PMID- 26947215 TI - Autologous chondrocyte implantation (ACI) for cartilage defects of the knee: A guideline by the working group "Clinical Tissue Regeneration" of the German Society of Orthopaedics and Trauma (DGOU). AB - BACKGROUND: Autologous chondrocyte implantation (ACI) is an established and well accepted procedure for the treatment of localised full-thickness cartilage defects of the knee. METHODS: The present review of the working group "Clinical Tissue Regeneration" of the German Society of Orthopaedics and Trauma (DGOU) describes the biology and function of healthy articular cartilage, the present state of knowledge concerning therapeutic consequences of primary cartilage lesions and the suitable indication for ACI. RESULTS: Based on best available scientific evidence, an indication for ACI is given for symptomatic cartilage defects starting from defect sizes of more than three to four square centimetres; in the case of young and active sports patients at 2.5cm(2), while advanced degenerative joint disease needs to be considered as the most important contraindication. CONCLUSION: The present review gives a concise overview on important scientific background and the results of clinical studies and discusses the advantages and disadvantages of ACI. LEVEL OF EVIDENCE: Non-systematic Review. PMID- 26947216 TI - Telehealth by an Interprofessional Team in Patients With CKD: A Randomized Controlled Trial. AB - BACKGROUND: Telehealth and interprofessional case management are newer strategies of care within chronic disease management. We investigated whether an interprofessional team using telehealth was a feasible care delivery strategy and whether this strategy could affect health outcomes in patients with chronic kidney disease (CKD). STUDY DESIGN: Randomized clinical trial. SETTING & PARTICIPANTS: Minneapolis Veterans Affairs Health Care System (VAHCS), St. Cloud VAHCS, and affiliated clinics March 2012 to November 2013 in patients with CKD (estimated glomerular filtration rate < 60mL/min/1.73m(2)). INTERVENTIONS: Patients were randomly assigned to receive an intervention (n=451) consisting of care by an interprofessional team (nephrologist, nurse practitioner, nurses, clinical pharmacy specialist, psychologist, social worker, and dietician) using a telehealth device (touch screen computer with peripherals) or to usual care (n=150). OUTCOMES: The primary end point was a composite of death, hospitalization, emergency department visits, or admission to skilled nursing facilities, compared to usual care. RESULTS: Baseline characteristics of the overall study group: mean age, 75.1+/-8.1 (SD) years; men, 98.5%; white, 97.3%; and mean estimated glomerular filtration rate, 37+/-9mL/min/1.73m(2). Telehealth and interprofessional care were successfully implemented with meaningful engagement with the care system. One year after randomization, 208 (46.2%) patients in the intervention group versus 70 (46.7%) in the usual-care group had the primary composite outcome (HR, 0.98; 95% CI, 0.75-1.29; P=0.9). There was no difference between groups for any component of the primary outcome: all-cause mortality (HR, 1.46; 95% CI, 0.42-5.11), hospitalization (HR, 1.15; 95% CI, 0.80 1.63), emergency department visits (HR, 0.92; 95% CI, 0.68-1.24), or nursing home admission (HR, 3.07; 95% CI, 0.71-13.24). LIMITATIONS: Older population, mostly men, potentially underpowered/wide CIs. CONCLUSIONS: Telehealth by an interprofessional team is a feasible care delivery strategy in patients with CKD. There was no statistically significant evidence of superiority of this intervention on health outcomes compared to usual care. PMID- 26947218 TI - Molecular evolution of colorectal cancer: from multistep carcinogenesis to the big bang. AB - Colorectal cancer is characterized by exquisite genomic instability either in the form of microsatellite instability or chromosomal instability. Microsatellite instability is the result of mutation of mismatch repair genes or their silencing through promoter methylation as a consequence of the CpG island methylator phenotype. The molecular causes of chromosomal instability are less well characterized. Genomic instability and field cancerization lead to a high degree of intratumoral heterogeneity and determine the formation of cancer stem cells and epithelial-mesenchymal transition mediated by the TGF-beta and APC pathways. Recent analyses using integrated genomics reveal different phases of colorectal cancer evolution. An initial phase of genomic instability that yields many clones with different mutations (big bang) is followed by an important, previously not detected phase of cancer evolution that consists in the stabilization of several clones and a relatively flat outgrowth. The big bang model can best explain the coexistence of several stable clones and is compatible with the fact that the analysis of the bulk of the primary tumor yields prognostic information. PMID- 26947217 TI - Aspirin Use and Incident Cardiovascular Disease, Kidney Failure, and Death in Stable Kidney Transplant Recipients: A Post Hoc Analysis of the Folic Acid for Vascular Outcome Reduction in Transplantation (FAVORIT) Trial. AB - BACKGROUND: Cardiovascular disease (CVD) is the leading cause of death in kidney transplant recipients. Whether aspirin may reduce the risk for CVD, death, and kidney failure outcomes is uncertain. STUDY DESIGN: Post hoc cohort analysis of FAVORIT, a randomized trial examining the effect of homocysteine-lowering vitamins on CVD in kidney transplant recipients. SETTING & PARTICIPANTS: Prevalent adult kidney transplant recipients with hyperhomocysteinemia and stable kidney function from the United States, Canada, and Brazil participating in FAVORIT, with no known history of CVD. PREDICTOR: Aspirin use, with aspirin users matched to nonusers using a propensity score. OUTCOMES: Incident CVD events, kidney failure, all-cause mortality, a composite of CVD events or mortality, and a composite of kidney failure or mortality. Cox proportional hazards models with a robust variance to account for the correlation in outcomes within matched pairs were sequentially adjusted for demographic, clinical, and laboratory characteristics to assess the association between aspirin use and events. RESULTS: 981 aspirin users were matched to 981 nonusers. During a 4-year mean follow up, there were 225 CVD events, 200 deaths, 126 kidney failure events, 301 composite kidney failure or mortality events, and 324 composite CVD or mortality events. Adjusted models showed no significant difference associated with aspirin use in risk for CVD events, all-cause mortality, kidney failure, composite of kidney failure or mortality, or composite of primary CVD events or mortality (HRs of 1.20 [95% CI, 0.92-1.58], 0.92 [95% CI, 0.69-1.23], 1.19 [95% CI, 0.81-1.74], 1.03 [0.82-1.31], and 1.11 [95% CI, 0.88-1.38], respectively). LIMITATIONS: We did not examine dose or continued use of aspirin after randomization. CVD history is dependent on participant report at baseline. Aspirin use was non-randomly assigned. CONCLUSIONS: Aspirin use is not associated with reduced risk for incident CVD, all-cause mortality, or kidney failure in stable kidney transplant recipients with no history of CVD. PMID- 26947219 TI - Association between depressive symptoms and parental stress among mothers and fathers in early parenthood: A Swedish cohort study. AB - Aim To determine whether there is an association between depressive symptoms and parental stress among mothers and fathers during early parenthood in Sweden. Methods In this study, 401 mothers and 396 fathers (393 couples) were included; the Edinburgh Postnatal Depression Scale and the Sense of Coherence Scale were measured 3 months after childbirth, and the Swedish Parenthood Stress Questionnaire and the Sense of Coherence Scale after 18 months. Complete data for multivariable analysis were available for 264 mothers and 252 fathers. Results The mothers estimated greater total depressive symptoms and parental stress than the fathers did. Both the mothers and the fathers had the greatest level of stress in the sub-area 'Role restriction'. The mothers had the lowest level of stress in the sub-area 'Social isolation' and the fathers in the sub-area 'Incompetence'. The mothers perceived greater levels of stress than the fathers did in all sub-areas except for 'Social isolation', where the fathers perceived higher stress. There was an association between the parents' depressive symptoms and parental stress. The parents' own depressive symptoms at 3 months and sense of coherence and the partners' parental stress at 18 months were positively associated with the parental stress at 18 months in univariable and multivariable analyses. Conclusions Understanding the relationship between depressive symptoms and parental stress is important for health professionals so they can offer parents adequate support in early parenthood to optimize the conditions for raising a child. This knowledge should also be communicated to the parents. PMID- 26947220 TI - Identification of Structurally Diverse Antimicrobials Through Sequential Application of Pharmacophore Modeling, Virtual Screening, Molecular Docking and In Vitro Microbiological Assay. AB - Dihydrofolate reductase enzyme has been an attractive biological target for the design and development of antimicrobials. Considering this, we have attempted to identify novel dihydrofolate reductase inhibitors through our well-defined in silico and in vitro work flow. An accurate and predictive pharmacophore model comprising of one hydrogen bond acceptor, two hydrophobic and one ring aromatic was developed and utilized as a query to search the National Cancer Institute and Maybridge database leading to retrieval of various compounds which were filtered on the basis of estimated activity, fit value and Lipinski's violation. Selected hits NSC3423, KM09759, NSC391, NSC2091 and HTS00630 were subjected to docking studies which resulted into visualization of potential interaction capabilities of hits in line to pharmacophoric features. The identified hits were evaluated for in vitro antimicrobial potential, and the results revealed that among all the five hits, NSC3423 is the most potent compound with activity against E. coli, P. aeruginosa, S. aureus, B. substilis, A. niger and F. oxysporum. On the other hand, KM09759, NSC391, NSC2091 and HTS00630 showed varying degree of activities against gram-positive, gram-negative and fungal strains. PMID- 26947222 TI - Education in Professionalism: Improvisation. PMID- 26947221 TI - A Robust Emphysema Severity Measure Based on Disease Subtypes. AB - RATIONALE AND OBJECTIVES: We propose a novel single index for the quantification of emphysema severity based on an aggregation of multiple computed tomographic features evident in the lung parenchyma of smokers. Our goal was to demonstrate that this single index provides complementary information to the current standard measure of emphysema, percent emphysema (percent low attenuation areas [LAA%]), and may be superior in its association with clinically relevant outcomes. MATERIALS AND METHODS: The inputs to our algorithm were objective assessments of multiple emphysema subtypes (normal tissue; panlobular; paraseptal; and mild, moderate, and severe centrilobular emphysema). We applied dimensionality reduction techniques to the emphysema quantities to find a space that maximizes the variance of these subtypes. A single emphysema severity index was then derived from a parametrization of the reduced space, and the clinical utility of the measure was explored in a large cross-sectional cohort of 8914 subjects from the COPDGene Study. RESULTS: There was a statistically significant association between the severity index and the LAA%. Subjects with more severe chronic obstructive pulmonary disease (higher Global initiative for Obstructive Lung Disease stage) tended to have a higher computed tomography severity index. Finally, the severity index was associated with clinical outcomes such as lung function and provided a stronger association to these measures than the LAA%. CONCLUSIONS: The method provides a single clinically relevant index that can assess the severity of emphysema and that provides information that is complimentary to the more commonly used LAA%. PMID- 26947223 TI - The Impact of a Preauthorization Policy on the After-hours Utilization of Emergency Department Computed Tomography Imaging. AB - RATIONALE AND OBJECTIVES: We evaluated the effects of a streamlined emergency department (ED) policy for CT ordering, pre- and postimplementation, on the completed imaging study rates of all after-hours computed tomography (CT) studies. The study hypothesis was that a streamlined CT ordering process would increase the utilization rates of ED CT. MATERIALS AND METHODS: A prospective cohort study was used to estimate the effect of enhancing a preauthorization policy for after-hours CT studies requested through the ED, performed between January 1 and June 30, 2013, and the postimplementation period, performed between January 1 and June 30, 2014. Inclusion criteria were all CT chest, CT abdomen/pelvis, musculoskeletal, neurological, and neuroangiographic examinations performed by ED physicians on adult patients. Pre- and postintervention examination imaging study rates were compared. RESULTS: The period following implementation of the preauthorization policy was associated with a statistically significant increase in utilization for most subtypes of CT examinations (CT chest, CT abdomen/pelvis, and musculoskeletal CT studies), with the exception of neurological examinations, which showed a significant decrease. CONCLUSIONS: This study demonstrates a trend toward increased utilization of CT resources after implementation of an ED preauthorization policy with most study types showing significantly increased utilization. In the case of neurological examinations, a potential "substitution effect" was observed, whereby the rates of neuroangiographic studies showed a marked increase, offsetting the decrease in general neurological examinations performed. Departments considering implementation of preauthorization policies should weigh carefully the benefits of ED workflow efficiencies against the potential harms of increased CT use. PMID- 26947224 TI - An investigation of an outbreak of hepatitis C virus infections in a low resourced hemodialysis unit in Vietnam. AB - BACKGROUND: Hepatitis C virus (HCV) is a risk for all hemodialysis patients. Over a 2-month period in 2013, there were 11 HCV seroconversions at a satellite hemodialysis unit in Vietnam. We report the epidemiologic investigation of the transmission mode in the absence of unavailable phylogenetic analysis. METHODS: The outbreak occurred during a 2-year dynamic cohort study. All patients were tested every 2 months, and staff was tested annually for hepatitis B virus surface antigen and HCV core antigen. Cases were tested for viral genotypes to examine the genetic relationship. Direct observation of the patient care environment was performed, and infection control policy was reviewed for potential breaches. Data obtained during the cohort study were used to assess lifestyle and treatment-related risk factors for the incidence of HCV infection. RESULTS: All patients reused dialyzers and shared hemodialysis machines. One reprocessing system was used to rinse used dialyzers. The preparation area for parenteral medication and clean supplies was adjacent to the blood sample handling area and storage of reused dialyzers. HCV transmission through a shared machine was the likely mode of transmission in 1 of the 11 cases. Indirect contact transmission was the likely mode of HCV transmission for the remaining 10 cases. CONCLUSIONS: Sharing hemodialysis machines was not the main risk factor for the outbreak, which was most likely caused by environmental contamination associated with infection control breaches. The outbreak highlights the importance of providing dedicated dialyzer reprocessing systems and strict adherence to infection control precautions to prevent HCV cross-contamination. PMID- 26947225 TI - Effective photosensitization-based inactivation of Gram (-) food pathogens and molds using the chlorophyllin-chitosan complex: towards photoactive edible coatings to preserve strawberries. AB - This study is focused on the novel approaches to enhance the inactivation of the Gram (-) food pathogen Salmonella enterica and harmful molds in vitro and on the surface of strawberries using the chlorophyllin-chitosan complex. Salmonella enterica (~1 * 10(7) CFU mL(-1)) was incubated with chlorophyllin 1.5 * 10(-5) M (Chl, food additive), chitosan 0.1% (CHS, food supplement) or the chlorophyllin chitosan complex (1.5 * 10(-5) M Chl-0.1% CHS) and illuminated with visible light (lambda = 405 nm, light dose 38 J cm(-2)) in vitro. Chlorophyllin (Chl)-based photosensitization inactivated Salmonella just by 1.8 log. Chitosan (CHS) alone incubated for 2 h with Salmonella reduced viability 2.15 log, whereas photoactivated Chl-CHS diminished bacterial viability by 7 log. SEM images indicate that the Chl-CHS complex under these experimental conditions covered the entire bacterial surface. Significant cell membrane disintegration was the main lethal injury induced in Gram (-) bacteria by this treatment. Analysis of strawberry decontamination from surface-inoculated Salmonella indicated that photoactivated Chl-CHS (1.5 * 10(-5) M Chl-0.1% CHS, 30 min incubation, light dose 38 J cm(-2)) coatings diminished the pathogen population on the surface of strawberries by 2.2 log. Decontamination of strawberries from naturally distributed yeasts/molds revealed that chitosan alone reduced the population of yeasts/molds just by 0.4 log, Chl-based photosensitization just by 0.9 log, whereas photoactivated Chl-CHS coatings reduced yeasts/molds on the surface of strawberries by 1.4 log. Electron paramagnetic resonance spectroscopy confirmed that no additional photosensitization-induced free radicals have been found in the strawberry matrix. Visual quality (color, texture) of the treated strawberries was not affected either. In conclusion, photoactive Chl-CHS exhibited strong antimicrobial action against more resistant to photosensitization Gram (-) Salmonella enterica in comparison with Gram (+) bacteria in vitro. It reduced significantly the viability of strawberry surface attached yeasts/molds and inoculated Salmonella without any negative impact on the visual quality of berries. Experimental data support the idea that photoactivated Chl-CHS can be a useful tool for the future development of edible photoactive antimicrobial coatings which can preserve strawberries and prolong their shelf-life according to requirements of "clean green technology". PMID- 26947234 TI - Activation of transient receptor potential vanilloid 1 accelerates re endothelialization and inhibits neointimal formation after vascular injury. AB - OBJECTIVE: Transient receptor potential vanilloid 1 (TRPV1) is an important regulator of endothelial function, but the effects of TRPV1 on endothelial recovery and neointimal formation after vascular injury remain elusive. We tested the effects of activating TRPV1 using capsaicin on re-endothelialization and neointimal formation after wire-induced injury of the carotid artery in mice. METHODS: The human umbilical vein endothelial cells (HUVECs) were treated with the TRPV1 agonist capsaicin, its antagonist capsazepine, intracellular calcium chelator BAPTA, or mitofusin 2 (Mfn2)-specific short interfering RNA (siRNA). The migration, proliferation, mitochondrial morphology, membrane potential, and adenosine triphosphate production were measured. The carotid artery wire injury procedure was performed in male TRPV1 knockout mice and C57BL/6J wild-type (WT) mice that were then treated with or without Mfn2 siRNA. The re-endothelialization and neointimal formation were evaluated. RESULTS: Capsaicin significantly enhanced the migration and proliferation of HUVECs. Both capsazepine and BAPTA abolished capsaicin-induced migration and proliferation of HUVECs. In addition, capsaicin stimulated the formation of reticular mitochondria, augmented mitochondrial membrane potential, increased adenosine triphosphate production, and upregulated Mfn2. However, these effects were attenuated by knockdown of Mfn2 with specific siRNA. Dietary capsaicin markedly accelerated re-endothelialization and inhibited neointimal formation in WT mice but not in TRPV1 knockout mice. Moreover, Mfn2 siRNA also attenuated capsaicin-induced enhancement of endothelial recovery and suppression of neointimal hyperplasia in WT mice. CONCLUSIONS: Activation of TRPV1 with capsaicin attenuates neointimal formation by accelerating re-endothelialization through upregulation of Mfn2. PMID- 26947235 TI - A national survey of disease-specific knowledge in patients with an abdominal aortic aneurysm. AB - OBJECTIVE: Patient education is a fundamental responsibility of medical providers caring for patients with abdominal aortic aneurysms (AAA). We sought to evaluate and quantify AAA-specific knowledge in patients under AAA surveillance and in patients who have undergone AAA repair. METHODS: In 2013, 1373 patients from 6 U.S. institutions were mailed an AAA-specific quality of life and knowledge survey. Of these patients, 1008 (73%) returned completed surveys for analysis. The knowledge domain of the survey consisted of nine questions. An AAA knowledge score was calculated for each patient based on the proportion of questions answered correctly. The score was then compared according to sex, race, and education level. Surveillance and repaired patients were also compared. RESULTS: Among 1008 survey respondents, 351 were under AAA surveillance and 657 had AAA repair (endovascular repair, 414; open, 179; unknown, 64). The majority of patients (85%) reported that their "doctor's office" was their most important source of AAA information. The "Internet" and "other written materials" were each reported as the most important source of information 5% of the time with "other patients" reported 2% of the time. The mean AAA knowledge score was 47% (range 0% 100%; standard deviation, 23%) with a broad variation in percentage correct between questions. Thirty-two percent of respondents did not know that larger AAA size increases rupture risk, and 64% did not know that AAA runs in families. Only 15% of patients answered six or more of the nine questions correctly, and 23% of patients answered two or fewer questions correctly. AAA knowledge was significantly greater in men compared with women, whites compared with nonwhites, high school graduates compared with nongraduates, and surveillance compared with repaired patients. CONCLUSIONS: In a national survey of AAA-specific knowledge, patients demonstrated poor understanding of their condition. This may contribute to anxiety and uninformed decision making. The need for increased focus on education by vascular providers is a substantial unmet need. PMID- 26947236 TI - Discussion. PMID- 26947239 TI - Association of food allergy and atopic dermatitis exacerbations. AB - BACKGROUND: Atopic dermatitis (AD) and food allergy frequently coexist in children. OBJECTIVE: To examine the association between food allergy and AD. METHODS: Between 2001 and 2011, children referred to our tertiary care center underwent double-blind, placebo-controlled food challenges (DBPCFCs) for one or more suspected food allergies as part of regular care. Immediate reactions were observed and recorded by allergy nursing staff, whereas late reactions were ascertained by semistructured telephone interview 48 hours after challenge. To test to which degree specific IgE results were predictive in the outcome of DBPCFCs in children with and without (previous and current) AD, logistic regression analysis was performed. RESULTS: A total of 1186 DBPCFCs were studied. Sensitization to foods occurred significantly more often in children with previous AD. The association between specific IgE results and the outcome of DBPCFCs was significant for children with and without (previous and current) AD but stronger for children without current AD. The positivity rate of DBPCFCs in children with mild, moderate, and severe AD was 53.3%, 51.7%, and 100%, respectively. Children with AD and a history of worsening AD as their only symptom reacted as often to placebo as to challenge food. CONCLUSION: Children with current AD are more frequently asymptomatically sensitized to the foods in question than those without AD. In addition, children suspected of food allergy should be considered for testing, regardless of the severity of their AD. Our results suggest that children with exacerbation of AD in the absence of other allergic symptoms are unlikely to be food allergic. PMID- 26947237 TI - Dual antiplatelet therapy reduces stroke but increases bleeding at the time of carotid endarterectomy. AB - OBJECTIVE: Controversy persists regarding the perioperative management of clopidogrel among patients undergoing carotid endarterectomy (CEA). This study examined the effect of preoperative dual antiplatelet therapy (aspirin and clopidogrel) on in-hospital CEA outcomes. METHODS: Patients undergoing CEA in the Vascular Quality Initiative were analyzed (2003-2014). Patients on clopidogrel and aspirin (dual therapy) were compared with patients taking aspirin alone preoperatively. Study outcomes included reoperation for bleeding and thrombotic complications defined as transient ischemic attack (TIA), stroke, or myocardial infarction. Secondary outcomes were in-hospital death and composite stroke/death. Univariate and multivariable analyses assessed differences in demographics and operative factors. Propensity score-matched cohorts were derived to control for subgroup heterogeneity. RESULTS: Of 28,683 CEAs, 21,624 patients (75%) were on aspirin and 7059 (25%) were on dual therapy. Patients on dual therapy were more likely to have multiple comorbidities, including coronary artery disease (P < .001), congestive heart failure (P < .001), and diabetes (P < .001). Patients on dual therapy were also more likely to have a drain placed (P < .001) and receive protamine during CEA (P < .001). Multivariable analysis showed that dual therapy was independently associated with increased reoperation for bleeding (odds ratio [OR], 1.71; 95% confidence interval [CI], 1.20-2.42; P = .003) but was protective against TIA or stroke (OR, 0.61; 95% CI, 0.43-0.87; P = .007), stroke (OR, 0.63; 95% CI, 0.41-0.97; P = .03), and stroke/death (OR, 0.66; 95% CI, 0.44-0.98; P = .04). Propensity score matching yielded two groups of 4548 patients and showed that patients on dual therapy were more likely to require reoperation for bleeding (1.3% vs 0.7%; P = .004) but less likely to suffer TIA or stroke (0.9% vs 1.6%; P = .002), stroke (0.6% vs 1.0%; P = .04), or stroke/death (0.7% vs 1.2%; P = .03). Within the propensity score-matched groups, patients on dual therapy had increased rates of reoperation for bleeding regardless of carotid symptom status. However, asymptomatic patients on dual therapy demonstrated reduced rates of TIA or stroke (0.6% vs 1.5%; P < .001), stroke (0.4% vs 0.9%; P = .01), and composite stroke/death (0.5% vs 1.0%; P = .02). Among propensity score-matched patients with symptomatic carotid disease, these differences were not statistically significant. CONCLUSIONS: Preoperative dual antiplatelet therapy was associated with a 40% risk reduction for neurologic events but also incurred a significant increased risk of reoperation for bleeding after CEA. Given its observed overall neurologic protective effect, continued dual antiplatelet therapy throughout the perioperative period is justified. Initiating dual therapy in all patients undergoing CEA may lead to decreased neurologic complication rates. PMID- 26947240 TI - Type 1 hereditary angioedema in a 72-year-old woman. PMID- 26947241 TI - Ten Years of Theta Burst Stimulation in Humans: Established Knowledge, Unknowns and Prospects. AB - BACKGROUND/OBJECTIVES: Over the last ten years, an increasing number of authors have used the theta burst stimulation (TBS) protocol to investigate long-term potentiation (LTP) and long-term depression (LTD)-like plasticity non-invasively in the primary motor cortex (M1) in healthy humans and in patients with various types of movement disorders. We here provide a comprehensive review of the LTP/LTD-like plasticity induced by TBS in the human M1. METHODS: A workgroup of researchers expert in this research field review and discuss critically ten years of experimental evidence from TBS studies in humans and in animal models. The review also includes the discussion of studies assessing responses to TBS in patients with movement disorders. MAIN FINDINGS/DISCUSSION: We discuss experimental studies applying TBS over the M1 or in other cortical regions functionally connected to M1 in healthy subjects and in patients with various types of movement disorders. We also review experimental evidence coming from TBS studies in animals. Finally, we clarify the status of TBS as a possible new non invasive therapy aimed at improving symptoms in various neurological disorders. PMID- 26947242 TI - Thousand and one ways to quantify and compare protein abundances in label-free bottom-up proteomics. AB - How to process and analyze MS data to quantify and statistically compare protein abundances in bottom-up proteomics has been an open debate for nearly fifteen years. Two main approaches are generally used: the first is based on spectral data generated during the process of identification (e.g. peptide counting, spectral counting), while the second makes use of extracted ion currents to quantify chromatographic peaks and infer protein abundances based on peptide quantification. These two approaches actually refer to multiple methods which have been developed during the last decade, but were submitted to deep evaluations only recently. In this paper, we compiled these different methods as exhaustively as possible. We also summarized the way they address the different problems raised by bottom-up protein quantification such as normalization, the presence of shared peptides, unequal peptide measurability and missing data. This article is part of a Special Issue entitled: Plant Proteomics--a bridge between fundamental processes and crop production, edited by Dr. Hans-Peter Mock. PMID- 26947243 TI - A prominent role of PDIA6 in processing of misfolded proinsulin. AB - Despite its critical role in maintaining glucose homeostasis, surprisingly little is known about proinsulin folding in the endoplasmic reticulum. In this study we aimed to understand the chaperones involved in the maturation and degradation of proinsulin. We generated pancreatic beta cell lines expressing FLAG-tagged proinsulin. Several chaperones (including BiP, PDIA6, calnexin, calreticulin, GRP170, Erdj3 and ribophorin II) co-immunoprecipitated with proinsulin suggesting a role for these proteins in folding. To investigate the chaperones responsible for targeting misfolded proinsulin for degradation, we also created a beta cell line expressing FLAG-tagged proinsulin carrying the Akita mutation (Cys96Tyr). All chaperones found to be associated with wild type proinsulin also co immunoprecipitated with Akita proinsulin. However, one additional protein, namely P58(IPK), specifically precipitated with Akita proinsulin and approximately ten fold more PDIA6, but not other PDI family members, was bound to Akita proinsulin. The latter suggests that PDIA6 may act as a key reductase and target misfolded proinsulin to the ER-degradation pathway. The preferential association of PDIA6 to Akita proinsulin was also confirmed in another beta cell line (betaTC-6). Furthermore, for the first time, a physiologically relevant substrate for PDIA6 has been evidenced. Thus, this study has identified several chaperones/foldases that associated with wild type proinsulin and has also provided a comprehensive interactome for Akita misfolded proinsulin. PMID- 26947244 TI - Tetramer-organizing polyproline-rich peptides differ in CHO cell-expressed and plasma-derived human butyrylcholinesterase tetramers. AB - Tetrameric butyrylcholinesterase (BChE) in human plasma is the product of multiple genes, namely one BCHE gene on chromosome 3q26.1 and multiple genes that encode polyproline-rich peptides. The function of the polyproline-rich peptides is to assemble BChE into tetramers. CHO cells transfected with human BChE cDNA express BChE monomers and dimers, but only low quantities of tetramers. Our goal was to identify the polyproline-rich peptides in CHO-cell derived human BChE tetramers. CHO cell-produced human BChE tetramers were purified from serum-free culture medium. Peptides embedded in the tetramerization domain were released from BChE tetramers by boiling and identified by liquid chromatography-tandem mass spectrometry. A total of 270 proline-rich peptides were sequenced, ranging in size from 6-41 residues. The peptides originated from 60 different proteins that reside in multiple cell compartments including the nucleus, cytoplasm, and endoplasmic reticulum. No single protein was the source of the polyproline-rich peptides in CHO cell-expressed human BChE tetramers. In contrast, 70% of the tetramer-organizing peptides in plasma-derived BChE tetramers originate from lamellipodin. No protein source was identified for polyproline peptides containing up to 41 consecutive proline residues. In conclusion, the use of polyproline-rich peptides as a tetramerization motif is documented only for the cholinesterases, but is expected to serve other tetrameric proteins as well. The CHO cell data suggest that the BChE tetramer-organizing peptide can arise from a variety of proteins. PMID- 26947245 TI - Stalking influenza by vaccination with pre-fusion headless HA mini-stem. AB - Inaccuracies in prediction of circulating viral strain genotypes and the possibility of novel reassortants causing a pandemic outbreak necessitate the development of an anti-influenza vaccine with increased breadth of protection and potential for rapid production and deployment. The hemagglutinin (HA) stem is a promising target for universal influenza vaccine as stem-specific antibodies have the potential to be broadly cross-reactive towards different HA subtypes. Here, we report the design of a bacterially expressed polypeptide that mimics a H5 HA stem by protein minimization to focus the antibody response towards the HA stem. The HA mini-stem folds as a trimer mimicking the HA prefusion conformation. It is resistant to thermal/chemical stress, and it binds to conformation-specific, HA stem-directed broadly neutralizing antibodies with high affinity. Mice vaccinated with the group 1 HA mini-stems are protected from morbidity and mortality against lethal challenge by both group 1 (H5 and H1) and group 2 (H3) influenza viruses, the first report of cross-group protection. Passive transfer of immune serum demonstrates the protection is mediated by stem-specific antibodies. Furthermore, antibodies induced by these HA stems have broad HA reactivity, yet they do not have antibody-dependent enhancement activity. PMID- 26947247 TI - Soluble amyloid beta oligomers block the learning-induced increase in hippocampal sharp wave-ripple rate and impair spatial memory formation. AB - Post-learning hippocampal sharp wave-ripples (SWRs) generated during slow wave sleep are thought to play a crucial role in memory formation. While in Alzheimer's disease, abnormal hippocampal oscillations have been reported, the functional contribution of SWRs to the typically observed spatial memory impairments remains unclear. These impairments have been related to degenerative synaptic changes produced by soluble amyloid beta oligomers (Abetaos) which, surprisingly, seem to spare the SWR dynamics during routine behavior. To unravel a potential effect of Abetaos on SWRs in cognitively-challenged animals, we submitted vehicle- and Abetao-injected mice to spatial recognition memory testing. While capable of forming short-term recognition memory, Abeta mice exhibited faster forgetting, suggesting successful encoding but an inability to adequately stabilize and/or retrieve previously acquired information. Without prior cognitive requirements, similar properties of SWRs were observed in both groups. In contrast, when cognitively challenged, the post-encoding and recognition peaks in SWR occurrence observed in controls were abolished in Abeta mice, indicating impaired hippocampal processing of spatial information. These results point to a crucial involvement of SWRs in spatial memory formation and identify the Abeta-induced impairment in SWRs dynamics as a disruptive mechanism responsible for the spatial memory deficits associated with Alzheimer's disease. PMID- 26947248 TI - Two new isoquinoline alkaloids from Scolopendra subspinipes mutilans induce cell cycle arrest and apoptosis in human glioma cancer U87 cells. AB - Two new isoquinoline alkaloids 1-2 and seven known compounds 3-9 were isolated from the ethanol extract of centipede Scolopendra subspinipes mutilans L. Koch. The structures were elucidated by a combination of spectroscopic analyses including 1D and 2D NMR, and HRESIMS. Compounds 1-2 exhibited good cytotoxicity with IC50 values ranging from 1.19 to 31.28MUM against six human cancer cell lines and low cytotoxicity against human normal liver L-02 cell lines, suggesting that compounds 1-2 had high specific cytotoxicity on human cancer cell lines. Further analyses showed that compounds 1-2 inhibited U87 cells proliferation by arresting cell cycle progress at G0/G1 phase and inducing apoptosis through loss of mitochondrial membrane potential (MMP), activation of caspase 9/3 and down regulation of the Bcl-2/Bax protein ratio. The results suggest that compounds 1-2 induce apoptosis in U87 cells through the mitochondria apoptosis pathway, and they deserve further research as potential anti-glioma cancer agents. PMID- 26947246 TI - An integrative approach to investigate the respective roles of single-nucleotide variants and copy-number variants in Attention-Deficit/Hyperactivity Disorder. AB - Many studies have attempted to investigate the genetic susceptibility of Attention-Deficit/Hyperactivity Disorder (ADHD), but without much success. The present study aimed to analyze both single-nucleotide and copy-number variants contributing to the genetic architecture of ADHD. We generated exome data from 30 Brazilian trios with sporadic ADHD. We also analyzed a Brazilian sample of 503 children/adolescent controls from a High Risk Cohort Study for the Development of Childhood Psychiatric Disorders, and also previously published results of five CNV studies and one GWAS meta-analysis of ADHD involving children/adolescents. The results from the Brazilian trios showed that cases with de novo SNVs tend not to have de novo CNVs and vice-versa. Although the sample size is small, we could also see that various comorbidities are more frequent in cases with only inherited variants. Moreover, using only genes expressed in brain, we constructed two "in silico" protein-protein interaction networks, one with genes from any analysis, and other with genes with hits in two analyses. Topological and functional analyses of genes in this network uncovered genes related to synapse, cell adhesion, glutamatergic and serotoninergic pathways, both confirming findings of previous studies and capturing new genes and genetic variants in these pathways. PMID- 26947249 TI - Meroterpenoid enantiomers from Ganoderma sinensis. AB - Zizhines A-F (1-6), six pairs of new meroterpenoid enantiomers and a known meroterpenoid (7) were isolated from the fruiting bodies of Ganoderma sinensis. The structures and absolute configurations of the new substances were assigned by spectroscopic and computational methods. All the compounds apart from 7 were evaluated for their inhibition on extracellular matrix component (fibronectin) generation by using TGF-beta1-induced rat kidney tubular epithelial cells. Although none of them was found to be active in these cells, the present findings add new facets for the chemistry of Ganoderma. PMID- 26947251 TI - Removal of TcO4(-) ions from solution: materials and future outlook. AB - Technetium mainly forms during artificial nuclear fission; it exists primarily as TcO4(-) in nuclear waste, and it is among the most hazardous radiation-derived contaminants because of its long half-life (t1/2 = 2.13 * 10(5) years) and environmental mobility. The high water solubility of TcO4(-) (11.3 mol L(-1) at 20 degrees C) and its ability to readily migrate within the upper layer of the Earth's crust make it particularly hazardous. Several types of materials, namely resins, molecular complexes, layered double hydroxides, and pure inorganic and metal-organic materials, have been shown to be capable of capturing TcO4(-) (or other oxoanions) from solution. In this review, we give a brief description about the types of materials that have been used to capture TcO4(-) and closely related oxyanions so far and discuss the possibility of using metal-organic frameworks (MOFs) as next-generation ion-exchange materials for the stated application. In particular, with the advent of ultra-stable MOF materials, in conjunction with their chemical tunability, MOFs can be applied to capture these oxyanions under real-life conditions. PMID- 26947250 TI - Osteoclast-derived exosomal miR-214-3p inhibits osteoblastic bone formation. AB - Emerging evidence indicates that osteoclasts direct osteoblastic bone formation. MicroRNAs (miRNAs) have a crucial role in regulating osteoclast and osteoblast function. However, whether miRNAs mediate osteoclast-directed osteoblastic bone formation is mostly unknown. Here, we show that increased osteoclastic miR-214-3p associates with both elevated serum exosomal miR-214-3p and reduced bone formation in elderly women with fractures and in ovariectomized (OVX) mice. Osteoclast-specific miR-214-3p knock-in mice have elevated serum exosomal miR-214 3p and reduced bone formation that is rescued by osteoclast-targeted antagomir 214-3p treatment. We further demonstrate that osteoclast-derived exosomal miR-214 3p is transferred to osteoblasts to inhibit osteoblast activity in vitro and reduce bone formation in vivo. Moreover, osteoclast-targeted miR-214-3p inhibition promotes bone formation in ageing OVX mice. Collectively, our results suggest that osteoclast-derived exosomal miR-214-3p transfers to osteoblasts to inhibit bone formation. Inhibition of miR-214-3p in osteoclasts may be a strategy for treating skeletal disorders involving a reduction in bone formation. PMID- 26947253 TI - Method for the assessment of neuromuscular integrity and burrowing choice in vermiform animals. AB - BACKGROUND: The study of locomotion in vermiform animals has largely been restricted to animals crawling on agar surfaces. While this has been fruitful in the study of neuronal basis of disease and behavior, the reduced physical challenge posed by these environments has prevented these organisms from being equally successful in the study of neuromuscular diseases. Our burrowing assay allowed us to study the effects of muscular exertion on locomotion and muscle degeneration during disease (Beron et al., 2015), as well as the natural burrowing preference of diverse Caenorhabditis elegans strains (Vidal-Gadea et al., 2015). NEW METHOD: We describe a simple, rapid, and affordable set of assays to study the burrowing behavior of nematodes and other vermiform organisms which permits the titration of muscular exertion in test animals. RESULTS: We show that our burrowing assay design is versatile and can be adapted for use in widely different experimental paradigms. COMPARISON WITH EXISTING METHOD(S): Previous assays for the study of neuromuscular integrity in nematodes relied on movement through facile and homogeneous environments. The ability of modulating substrate density allows our burrowing assay to be used to separate animal populations where muscular fitness or health are not visible differentiable by standard techniques. CONCLUSION: The simplicity, versatility, and potential for greatly facilitating the study of previously challenging neuromuscular disorders makes this assay a valuable addition that overcomes many of the limitations inherent to traditional behavioral tests of vermiform locomotion. PMID- 26947252 TI - Visual tuning and metrical perception of realistic point-light dance movements. AB - Humans move to music spontaneously, and this sensorimotor coupling underlies musical rhythm perception. The present research proposed that, based on common action representation, different metrical levels as in auditory rhythms could emerge visually when observing structured dance movements. Participants watched a point-light figure performing basic steps of Swing dance cyclically in different tempi, whereby the trunk bounced vertically at every beat and the limbs moved laterally at every second beat, yielding two possible metrical periodicities. In Experiment 1, participants freely identified a tempo of the movement and tapped along. While some observers only tuned to the bounce and some only to the limbs, the majority tuned to one level or the other depending on the movement tempo, which was also associated with individuals' preferred tempo. In Experiment 2, participants reproduced the tempo of leg movements by four regular taps, and showed a slower perceived leg tempo with than without the trunk bouncing simultaneously in the stimuli. This mirrors previous findings of an auditory 'subdivision effect', suggesting the leg movements were perceived as beat while the bounce as subdivisions. Together these results support visual metrical perception of dance movements, which may employ similar action-based mechanisms to those underpinning auditory rhythm perception. PMID- 26947256 TI - Highly Selective Sensing of CO, C6H6, and C7H8 Gases by Catalytic Functionalization with Metal Nanoparticles. AB - We have fabricated multiple networked SnO2 nanowires and subsequently decorated them with uniformly distributed metal nanoparticles (NPs). The sensing tests indicated that the Pt-, Pd-, and Au-decorated SnO2 nanowires exhibited excellent sensing behavior, specifically for C7H8, C6H6, and CO gases, respectively. We discussed the associated sensing mechanisms in regard to the selective catalytic effects of metal NPs. In addition, by means of d-band theory, we explained the catalytic capabilities of each metal and proposed design principles for exploring new catalytic metals. The present study will pave the way for further development of high-selectivity sensors. PMID- 26947254 TI - Effect of emotion regulation training in patients with panic disorder: Evidenced by heart rate variability measures. AB - OBJECTIVE: We aimed to examine the effect of emotion regulation training in patients with panic disorder (PD) by measuring heart rate variability (HRV). METHODS: Forty-eight patients with PD were randomly divided into emotion regulation group (n=25) and no-regulation group (n=23). Three five-minute ECG recordings were taken in the following states: 1) baseline, 2) while subjects viewed 15 aversive pictures (active stimulus), 3) resting state after aversive pictures (post-stimulus). The emotion regulation group briefly received acceptance technique training for five minutes before performing the experimental task. Spectral analysis measures included a high-frequency (HF; 0.15-0.4 HZ) component, a low-frequency (LF; 0.04-0.15Hz) component, and an LF/HF ratio. RESULTS: The mean change in LF/HF ratio from baseline to active stimulus was significantly lower in the emotion regulation group than in the no-regulation group (emotion regulation group, 0.13; no-regulation group, 2.31; t=-2.67; P<.05). CONCLUSION: This suggests that brief emotion acceptance training could decrease aversive stimulus-induced sympathetic hyperactivity in patients with PD. PMID- 26947255 TI - Utility of pretransplant psychological measures to predict posttransplant outcomes in liver transplant patients: a systematic review. AB - OBJECTIVE: Evaluation of liver transplant (LT) candidacy involves psychosocial evaluation to ensure appropriate organ allocation. However, the utility of pre-LT psychiatric and neuropsychological factors in predicting posttransplant outcomes remains uncertain. We reviewed current evidence on the prognostic value of pre-LT psychological factors for outcomes after LT. METHOD: We conducted a systematic review of studies with adult LT recipients that investigate the relationship between pre-LT psychiatric and neuropsychological variables and posttransplant outcomes. We searched Ovid, MEDLINE, PsycINFO, EMBASE/Scopus, Cochrane Controlled trials register and Web of Science (January 1975 to May 2015) for longitudinal, peer-reviewed studies of at least 20 subjects and written in English. RESULTS: The 19 studies included in this review are heterogeneous in population, prognosis and duration of follow-up (from 20days to more than 3 years). Findings on the prognostic value of pre-LT depression or anxiety on post-LT outcomes are mixed, though depression appears to predict lower quality of life (QOL). Pre-LT suicidal thoughts in particular are associated with post-LT depression. High submissiveness may predict rejection within 20days of LT, and low conscientiousness is associated with greater nonadherence. Whereas pre-LT cognitive performance has not been shown to predict survival, poorer performance may predict poorer QOL after LT. CONCLUSION: Further studies are needed to examine this important element of LT candidacy evaluation. Studies should evaluate psychiatric factors in large samples, include systematic evaluations by mental health clinicians and explore broader neuropsychological domains in predicting posttransplant outcomes. PMID- 26947257 TI - Does the supervisor's teaching style influence the supervisee's learning prescribed techniques? AB - OBJECTIVES: This study examined the directive and non-directive supervisors' instructional styles, supervisees' interactive communications within supervision sessions as well as the relative success of supervisees' learning to apply specific techniques within psychotherapy. METHOD: The developers of Time-Limited Dynamic Psychotherapy (TLDP) provided the supervised training for 16 therapists as part of the "Vanderbilt II" psychotherapy project. Supervision sessions were rated for supervisors' adherence to TLDP content. Both supervisors and supervisee were rated for classroom interactive behaviors of "initiation" speech (e.g., introducing ideas) and "responsive" speech (e.g., amplifying the other speaker's topic). The third therapy session was targeted for discussion within supervision. Therapy sessions immediately before and after supervision were rated on TLDP adherence. RESULTS: One of the supervisors (Supervisor A) was found to use an instructional style of relatively more initiation-based speech, whereas the other (Supervisor B) used more response-based speech. Technical adherence for supervisees of Supervisor A was significantly higher than those assigned to Supervisor B. Supervisees' initiation-based speech during supervision predicted less use of TLDP techniques in the therapy session after supervision. Supervisors' interactive style was not associated with therapy adherence. CONCLUSIONS: Relatively more directive and structured supervision may influence the acquisition and use of manual-prescribed therapy techniques. PMID- 26947259 TI - Giant sigmoid diverticulum. PMID- 26947260 TI - Late breaking trials of 2015 in structural heart disease and peripheral artery disease: Commentary covering ACC, EuroPCR, SCAI, TCT, VIVA, ESC, and AHA. AB - With the large number of late breaking clinical trials presented at major meetings, it is often difficult to stay current with advances in interventional cardiology. Therefore, the SCAI Publications Committee summarizes and provides editorial commentary on the most important structural heart and peripheral artery disease late-breaking trials from 2015. (c) 2016 Wiley Periodicals, Inc. PMID- 26947258 TI - Mitochondria-targeted Triphenylamine Derivatives Activatable by Two-Photon Excitation for Triggering and Imaging Cell Apoptosis. AB - Photodynamic therapy (PDT) leads to cell death by using a combination of a photosensitizer and an external light source for the production of lethal doses of reactive oxygen species (ROS). Since a major limitation of PDT is the poor penetration of UV-visible light in tissues, there is a strong need for organic compounds whose activation is compatible with near-infrared excitation. Triphenylamines (TPAs) are fluorescent compounds, recently shown to efficiently trigger cell death upon visible light irradiation (458 nm), however outside the so-called optical/therapeutic window. Here, we report that TPAs target cytosolic organelles of living cells, mainly mitochondria, triggering a fast apoptosis upon two-photon excitation, thanks to their large two-photon absorption cross-sections in the 760-860 nm range. Direct ROS imaging in the cell context upon multiphoton excitation of TPA and three-color flow cytometric analysis showing phosphatidylserine externalization indicate that TPA photoactivation is primarily related to the mitochondrial apoptotic pathway via ROS production, although significant differences in the time courses of cell death-related events were observed, depending on the compound. TPAs represent a new class of water-soluble organic photosensitizers compatible with direct two-photon excitation, enabling simultaneous multiphoton fluorescence imaging of cell death since a concomitant subcellular TPA re-distribution occurs in apoptotic cells. PMID- 26947261 TI - Aqueous chlorhexidine (0.1%) is an effective alternative to povidone-iodine for intravitreal injection prophylaxis. PMID- 26947262 TI - Greater number of group identifications is associated with healthier behaviour in adolescents. AB - We investigated the relationship between group identification (with the family, school, and friendship groups) and adolescent health behaviour (smoking, binge drinking, and cannabis use). 1,111 students from 4 Scottish secondary (high) schools completed a questionnaire which included measures of group identification, group contact, health behaviours, and demographic variables. We found that identification with the family and school groups predicted reduced odds of substance use, whereas identification with the friend group predicted increased odds of substance use. Furthermore, the greater the number of social groups with which the participant strongly identified, the lower the odds that he/she participated in negative health behaviours. In contrast, merely having contact (rather than identifying strongly) with these groups increased the odds of participation in these behaviours. We suggest that group identification influences behaviour to the extent that it encourages adherence to group norms. PMID- 26947263 TI - Ocular solar protection in xeroderma pigmentosum: the role of untinted lenses in blocking ultraviolet radiation. PMID- 26947265 TI - On the diverse outcome of communication partner training of significant others of people with aphasia: an experimental study of six cases. AB - BACKGROUND: Communication partner training (CPT) has been shown to improve the communicative environment of people with aphasia. Interaction-focused training is one type of training that provides an individualized intervention to participants. Although shown to be effective, outcomes have mostly been evaluated in non-experimental case studies. AIMS: The aim of the controlled experimental intervention study was to evaluate an individualized approach in a CPT programme directed to significant others of people with aphasia. Specifically the effects on conversation partners' ability to support the person with aphasia in conversation and on the individuals with aphasias' perception of their functional communication were explored. METHODS & PROCEDURES: Six dyads consisting of a person with aphasia and a significant other were included in a replicated single subject design with multiple baselines across individuals. The intervention followed the interaction-focused communication training programme included in Supporting Partners of People with Aphasia in Relationships and Conversation (SPARRC). The main elements of the training consisted of supervised viewing of the couples' own video-recorded natural interaction and the formulation of individual goals for the adaptation of particular communicative strategies. Outcome was measured via blinded ratings of filmed conversational interaction obtained once a week throughout the different phases of baseline, intervention and follow-up. A rating scale to assess overall quality of conversation was used, taking into account both transfer of information and social aspects of conversation. Measures of perceived functional communication in the persons with aphasia were also collected from the individuals with aphasia and their conversation partners. OUTCOMES & RESULTS: The results were mixed, with two of the six participants showing small improvements in ability to support their partner with aphasia in conversation. Half the participants with aphasia and half the significant others reported improvements on perceived functional communication in the person with aphasia after intervention, but no changes were statistically significant. CONCLUSIONS & IMPLICATIONS: This study adds to the growing body of research concerning CPT by pinpointing the importance of careful consideration regarding set-up of training, suitability of participants and evaluation of outcome. PMID- 26947264 TI - Partially repeatable genetic basis of benthic adaptation in threespine sticklebacks. AB - The extent to which convergent adaptation to similar ecological niches occurs by a predictable genetic basis remains a fundamental question in biology. Threespine stickleback fish have undergone an adaptive radiation in which ancestral oceanic populations repeatedly colonized and adapted to freshwater habitats. In multiple lakes in British Columbia, two different freshwater ecotypes have evolved: a deep bodied benthic form adapted to forage near the lake substrate, and a narrow bodied limnetic form adapted to forage in open water. Here, we use genome-wide linkage mapping in marine * benthic F2 genetic crosses to test the extent of shared genomic regions underlying benthic adaptation in three benthic populations. We identify at least 100 Quantitative Trait Loci (QTL) harboring genes influencing skeletal morphology. The majority of QTL (57%) are unique to one cross. However, four genomic regions affecting eight craniofacial and armor phenotypes are found in all three benthic populations. We find that QTL are clustered in the genome and overlapping QTL regions are enriched for genomic signatures of natural selection. These findings suggest that benthic adaptation has occurred via both parallel and nonparallel genetic changes. PMID- 26947266 TI - Smooth-Threshold Multivariate Genetic Prediction with Unbiased Model Selection. AB - We develop a new genetic prediction method, smooth-threshold multivariate genetic prediction, using single nucleotide polymorphisms (SNPs) data in genome-wide association studies (GWASs). Our method consists of two stages. At the first stage, unlike the usual discontinuous SNP screening as used in the gene score method, our method continuously screens SNPs based on the output from standard univariate analysis for marginal association of each SNP. At the second stage, the predictive model is built by a generalized ridge regression simultaneously using the screened SNPs with SNP weight determined by the strength of marginal association. Continuous SNP screening by the smooth thresholding not only makes prediction stable but also leads to a closed form expression of generalized degrees of freedom (GDF). The GDF leads to the Stein's unbiased risk estimation (SURE), which enables data-dependent choice of optimal SNP screening cutoff without using cross-validation. Our method is very rapid because computationally expensive genome-wide scan is required only once in contrast to the penalized regression methods including lasso and elastic net. Simulation studies that mimic real GWAS data with quantitative and binary traits demonstrate that the proposed method outperforms the gene score method and genomic best linear unbiased prediction (GBLUP), and also shows comparable or sometimes improved performance with the lasso and elastic net being known to have good predictive ability but with heavy computational cost. Application to whole-genome sequencing (WGS) data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) exhibits that the proposed method shows higher predictive power than the gene score and GBLUP methods. PMID- 26947268 TI - Etiological agents of microcephaly: implications for diagnosis during the current Zika virus epidemic. PMID- 26947267 TI - Cell autonomous and nonautonomous requirements for Delltalike1 during early mouse retinal neurogenesis. AB - BACKGROUND: In the vertebrate retina, six neuronal and one glial cell class are produced from a common progenitor pool. During neurogenesis, adjacent retinal cells use Notch signaling to maintain a pool of progenitors by blocking particular cells from differentiating prematurely. In mice there are multiple Notch pathway ligands and receptors, but the role(s) of each paralogue during retinal histogenesis remains only partially defined. RESULTS: Here we analyzed the cell autonomous and nonautonomous requirements for the Deltalike1(Dll1) ligand during prenatal retinogenesis. We used the alpha-Cre driver to simultaneously delete a Dll1 conditional allele and activate the Z/EG reporter, then quantified Dll1 mutant phenotypes within and outside of this alpha-Cre GFP marked lineage. We found that Dll1 activity is required for Hes1 expression, both autonomously and nonautonomously, but were surprised that retinal ganglion cell differentiation is only blocked cell autonomously. Moreover, Dll1 does not act during cone photoreceptor neurogenesis. Finally, Dll1 mutant adult retinas contained small retinal rosettes and RGC patterning defects but were otherwise normal. CONCLUSIONS: Although Dll1 participates in bidirectional (cis + trans) Notch signaling to regulate Hes1 expression, it only acts cell autonomously (in cis) to interpret inhibitory signals from other cells that block RGC neurogenesis. Developmental Dynamics 245:631-640, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26947271 TI - Hamilton's Rule in finite populations with synergistic interactions. AB - Much debate has appeared in the literature over the generality of the inclusive fitness approach in the modeling of evolutionary behavior. Here I focus on the capacity of the inclusive fitness approach to effectively handle non-additive or synergistic interactions. I work with a binary interaction with the matrix game [abcd] and I restrict attention to transitive (homogeneous) populations with weak selective effects. First of all I observe that the construction of "higher-order" relatedness coefficients permits these synergistic interactions to be analyzed with an inclusive fitness analysis. These coefficients are an immediate generalization of Hamilton's original coefficient and can be calculated with exactly the same type of recursive equations. Secondly I observe that for models in which the population is not too large and local genetic renewal is rare (e,g, rare mutation), these higher order coefficients are not needed even with non additive interactions; in fact the synergistic interaction is entirely equivalent to a closely-related additive one. The overall conclusion is that in the study of synergistic binary social interactions (2-player games) in a finite homogeneous population with weak selection and rare genetic renewal, a standard inclusive fitness analysis is able to predict the direction of allele-frequency change. I apply this result to analyze a recent model of Allen and Nowak (2015). PMID- 26947269 TI - A bestrophin-like protein modulates the proton motive force across the thylakoid membrane in Arabidopsis. AB - During photosynthesis, photosynthetic electron transport generates a proton motive force (pmf) across the thylakoid membrane, which is used for ATP biosynthesis via ATP synthase in the chloroplast. The pmf is composed of an electric potential (DeltaPsi) and an osmotic component (DeltapH). Partitioning between these components in chloroplasts is strictly regulated in response to fluctuating environments. However, our knowledge of the molecular mechanisms that regulate pmf partitioning is limited. Here, we report a bestrophin-like protein (AtBest), which is critical for pmf partitioning. While the DeltapH component was slightly reduced in atbest, the DeltaPsi component was much greater in this mutant than in the wild type, resulting in less efficient activation of nonphotochemical quenching (NPQ) upon both illumination and a shift from low light to high light. Although no visible phenotype was observed in the atbest mutant in the greenhouse, this mutant exhibited stronger photoinhibition than the wild type when grown in the field. AtBest belongs to the bestrophin family proteins, which are believed to function as chloride (Cl- ) channels. Thus, our findings reveal an important Cl- channel required for ion transport and homeostasis across the thylakoid membrane in higher plants. These processes are essential for fine-tuning photosynthesis under fluctuating environmental conditions. PMID- 26947270 TI - Immunohistochemical evaluation of hedgehog signalling in epithelial/mesenchymal interactions in squamous cell carcinoma transformation: a pilot study. AB - Precancerous lesions have been studied because of their carcinogenic potential and their association with squamous cell carcinoma (SCC) has been reported. In the tumour microenvironment, the processes of angiogenesis and tissue remodelling are regulated by a family of proteins (Hedgehog) described as being able to modulate epithelial/mesenchymal interactions. The objective of this study was to perform a comparative study of precancerous lesions and SCCs by immunohistochemistry for the presence of Sonic, Gli2, SMO and Patched proteins, members of the Hedgehog pathway. Sixteen cases diagnosed as actinic cheilitis associated with SCC were compared to normal oral mucosa. The sections were subjected to immunohistochemistry and the positively stained cells were counted by morphometric analysis. There was a significant progressive increase in expression of all proteins of the Hedgehog pathway, both in the epithelium and in the connective tissue, when sections of normal mucosa, dysplasia and carcinoma were compared (P < 0.05). Thus, one may suggest that the Hedgehog pathway in tumour transformation influences SCC, and more studies should be conducted to expand the understanding of the role of these proteins in neoplastic transformation. PMID- 26947272 TI - Bistability analyses of CD4+ T follicular helper and regulatory cells during Helicobacter pylori infection. AB - T follicular helper (Tfh) cells are a highly plastic subset of CD4+ T cells specialized in providing B cell help and promoting inflammatory and effector responses during infectious and immune-mediate diseases. Helicobacter pylori is the dominant member of the gastric microbiota and exerts both beneficial and harmful effects on the host. Chronic inflammation in the context of H. pylori has been linked to an upregulation in T helper (Th)1 and Th17 CD4+ T cell phenotypes, controlled in part by the cytokine, interleukin-21. This study investigates the differentiation and regulation of Tfh cells, major producers of IL-21, in the immune response to H. pylori challenge. To better understand the conditions influencing the promotion and inhibition of a chronically elevated Tfh population, we used top-down and bottom-up approaches to develop computational models of Tfh and T follicular regulatory (Tfr) cell differentiation. Stability analysis was used to characterize the presence of two bi-stable steady states in the calibrated Tfh/Tfr models. Stochastic simulation was used to illustrate the ability of the parameter set to dictate two distinct behavioral patterns. Furthermore, sensitivity analysis helped identify the importance of various parameters on the establishment of Tfh and Tfr cell populations. The core network model was expanded into a more comprehensive and predictive model by including cytokine production and signaling pathways. From the expanded network, the interaction between TGFB-Induced Factor Homeobox 1 (Tgif1) and the retinoid X receptor (RXR) was displayed to exert control over the determination of the Tfh response. Model simulations predict that Tgif1 and RXR respectively induce and curtail Tfh responses. This computational hypothesis was validated experimentally by assaying Tgif1, RXR and Tfh in stomachs of mice infected with H. pylori. PMID- 26947273 TI - Measurements and micro-mechanical modelling of the response of sintered titanium foams. AB - Titanium foams of relative density in the range 0.35-0.50 are tested in quasi static compression, tension and shear. The response is ductile in compression but brittle, and weaker, in shear and tension. Virtual foam microstructures are generated by an algorithm based on Voronoi tessellation of three-dimensional space, capable of reproducing the measured size distribution of the pores in the foam. Finite Element (FE) simulations are conducted to explore the mechanical response of the material, by analysing the elasto-plastic response of a statistical volume element (SVE). The simulations correctly predict the ductile compressive response and its dependence on relative density. PMID- 26947274 TI - Migration: Wall to Wall? AB - It is no news to anyone that health transcends national borders, driven by cross border movement of vectors, populations, health professionals, climate, even policy trends. There is an increasing recognition that it is, in fact, a small world: we are affected by and affect what happens to our neighbors, whether they live around the corner or on the other side of the globe. This conception underpins the shift from the term international health to global health in policy discussions. The new terminology reflects change across several dimensions: from an approach in which there is one medicine for the developed world and another for developing countries, to an appreciation that we all have a stake in one another's wellbeing; from a primarily biomedical focus on treatment to a more multidisciplinary, population health focus taking into consideration a range of interventions to improve health and well-being, including the social and environmental determinants of health; and from a vertical bilateral-aid approach focused on specific diseases, to systems and ecological approaches addressing the complexities of health, involving multiple partnerships. PMID- 26947275 TI - Reflections on Cuban Migration. Antonio Aja PhD, University of Havana's Center for Demographic Studies. AB - Dr Aja (pronounced a-ha) himself, is a product of the ebbs and flows of Cuban migration. His father, son of Lebanese merchant immigrants to Cuba, later studied medicine and emigrated to New York. There he met Antonio's mother, a garment worker and daughter in a poor family of Cuban emigres. The young couple moved to Tampa, Florida-following a pattern of settlement for Cubans in the USA at the time-where Antonio was born in 1953. The whole family later returned to Cuba, amidst the 1950s rebellion against Batista. They stayed, but relatives are still sprinkled abroad...as they are today for many Cuban families. Dr Aja, says his own history is part of what prompted him to explore the relation of families, demography and migration, the complex subject he has studied for a quarter century. Under the broader scope of health and society, MEDICC Review editors asked Dr. Aja to share insights from his years of research and experience. PMID- 26947276 TI - Outcomes among Asylum Seekers in Atlanta, Georgia, 2003--2012. AB - INTRODUCTION Asylum seekers face a wide array of challenges, including the need for a fair and just adjudication process. In the state of Georgia, the Atlanta Asylum Network addresses the needs of such individuals by providing them physical, psychological and gynecological assessments, the results of which are presented to the courts in the asylum appeal process. OBJECTIVE As a component of the Network's program evaluation, assess outcomes among asylum seekers using its services, as well as relation of outcomes to type of service provided, the individual's geographic origin and English language proficiency. METHODS A retrospective examination was conducted of program data gathered by the Network between 2003 and 2012. Subjects included asylum seekers who received assessments by the Network during this period. The primary variable of interest was the final case outcome, defined as determination of asylum status: granted, withholding of removal, administrative closure and prosecutorial discretion, denied or voluntary departure. Outcomes were subsequently collapsed into a single positive or negative outcome variable. Positive outcomes included asylum granted, removal withheld, administrative closure and prosecutorial discretion. Negative outcomes included asylum denied and voluntary departure. We conducted bivariate and multivariate analyses, relating final case outcomes to Network services, geographic origin and English language proficiency, among the key variables. RESULTS A total of 69 of 120 asylum seekers in the study had a known final case outcome, and of those, 63.8% (44) had a positive outcome; or 37% of the total number of asylum seekers (n = 120). Among the 20 who received 2 of the 3 types of assessment (physical, psychological, gynecological), 16 (80%) received a positive case outcome. Most persons with a known final outcome came from Africa (41), where 78% (32) of cases resulted positive. Asylum seekers not proficient in English were 2.4 times more likely to have a negative case outcome. CONCLUSION Network assessment appears to result in higher rates of positive case outcomes compared to the average for asylum seekers seen in the Atlanta circuit court. Areas for programmatic improvement include systematic followup and increased community awareness of Network services, since the Network may directly impact future case outcomes by offering assessment to more asylum seekers. Access to English language instruction and legal representation for asylum claimants may also contribute to more cases with positive outcomes. KEYWORDS Refugees, United Nations High Commissioner for Refugees (UNHCR), vulnerable populations, transients and migrants, human rights, human rights abuses, torture, PTSD, USA. PMID- 26947277 TI - Environmental, Nutrition and Health Issues in a US Refugee Resettlement Community. AB - INTRODUCTION In 2012, North Carolina ranked in the top ten states in refugee resettlement, with central Guilford County one of the most diverse in the southeast. OBJECTIVE Examine the local resettlement environmental, nutrition and health barriers and needs of refugees in Guilford County, as perceived by individuals providing services to them. METHODS Participants (n = 40) included: medical and social service providers, educators, faith-based volunteers, resettlement agency caseworkers and liaisons to a variety of refugee communities. Guided semistructured interviews were audio-recorded and transcribed verbatim. Themes were identified using deductive content analysis and categorized by frequency of reporting by participants. RESULTS Perceptions were consistent across participants regarding a diverse local refugee population. Resettlement housing was observed to be in poor condition, located in areas of poverty with transportation barriers. However, refugees rarely relocated, due to strong community relationships and support. Perceived dietary risks included: difficulties budgeting and maintaining food assistance, hoarding food, high consumption of sodas and sweets, misperceptions regarding US products (e.g., perceived need for infant formula), and limited health knowledge. Respondents observed that most refugees preferred "fresh" foods, and had strong agricultural skills but lacked green space. Major barriers to health care reported were: poverty, short duration of initial Medicaid coverage, and language (both lack of interpretation services and translated materials). Providers consistently observed type 2 diabetes, weight gain and dental problems across refugee groups. CONCLUSIONS Direct service providers' experiences and observations working with a diverse resettlement population provide unique insight into consistent barriers to achieving good health that confront refugees. While refugees face many barriers, groups often have impressive strengths, such as agricultural skills, on which to focus. KEYWORDS Refugees, emigration, immigration, minority health, health care disparities, diet, environment, USA. PMID- 26947278 TI - HIV-1 Genetic Variability in Cuba and Implications for Transmission and Clinical Progression. AB - INTRODUCTION Serological and molecular HIV-1 studies in Cuba have shown very low prevalence of seropositivity, but an increasing genetic diversity attributable to introduction of many HIV-1 variants from different areas, exchange of such variants among HIV-positive people with several coinciding routes of infection and other epidemiologic risk factors in the seropositive population. The high HIV 1 genetic variability observed in Cuba has possible implications for transmission and clinical progression. OBJECTIVE Study genetic variability for the HIV-1 env, gag and pol structural genes in Cuba; determine the prevalence of B and non-B subtypes according to epidemiologic and behavioral variables and determine whether a relationship exists between genetic variability and transmissibility, and between genetic variability and clinical disease progression in people living with HIV/AIDS. METHODS Using two molecular assays (heteroduplex mobility assay and nucleic acid sequencing), structural genes were characterized in 590 people with HIV-1 (480 men and 110 women), accounting for 3.4% of seropositive individuals in Cuba as of December 31, 2013. Nonrandom sampling, proportional to HIV prevalence by province, was conducted. Relationships between molecular results and viral factors, host characteristics, and patients' clinical, epidemiologic and behavioral variables were studied for molecular epidemiology, transmission, and progression analyses. RESULTS Molecular analysis of the three HIV-1 structural genes classified 297 samples as subtype B (50.3%), 269 as non-B subtypes (45.6%) and 24 were not typeable. Subtype B prevailed overall and in men, mainly in those who have sex with men. Non-B subtypes were prevalent in women and heterosexual men, showing multiple circulating variants and recombinant forms. Sexual transmission was the predominant form of infection for all. B and non-B subtypes were encountered throughout Cuba. No association was found between subtypes and transmission or clinical progression, although the proportion of deaths was higher for subtype B. Among those who died during the study period, there were no differences between subtypes in the mean time from HIV or AIDS diagnosis to death. CONCLUSIONS Our results suggest that B and non-B HIV-1 subtypes found in Cuba do not differ in transmissibility and in clinical disease progression. KEYWORDS HIV-1, AIDS, molecular epidemiology, transmissibility, clinical progression, subtypes, circulating recombinant forms, pathogenesis, Cuba. PMID- 26947280 TI - Early Signs of Atherogenesis in Adolescents in a Havana Family Medicine Catchment Area. AB - INTRODUCTION Atherosclerosis is the common underlying cause of cardiovascular diseases; the leading cause of morbidity and mortality globally. It is a major contributor to disability and poorer quality of life and is costly to health systems, individuals, families and society. Early signs of atherogenesis are manifestations of atherosclerosis and known atherogenic risk factors occurring at young ages and detectable by health professionals. Early detection of such signs in children and adolescents enables actions to prevent short- and long-term complications. OBJECTIVE Detect early signs of atherogenesis in adolescents in Family Doctor-and-Nurse Office No. 13 of the Raul Gomez Garcia Polyclinic in Havana's 10 de Octubre Municipality. METHODS An observational, cross-sectional descriptive study was conducted: the universe consisted of 110 adolescents and, once exclusion criteria were applied, the sample was made up of 96 adolescents in the office's geographical catchment area. Variables included sociodemographic data; measurements from physical and anthropometric examinations (weight, height, body mass index, waist circumference, blood pressure, presence of acanthosis nigricans); maternal history of diabetes mellitus and hypertension, smoking during pregnancy; birth weight and duration of exclusive breastfeeding; lifestyle (physical activity, dietary habits by frequency of consumption of fruits and vegetables, salt intake, and smoking); and a history of atherogenic risk factors and atherosclerotic diseases (hypertension, diabetes mellitus, heart disease, cerebrovascular disease, peripheral arterial disease and chronic kidney disease) in adolescents and their families. The number of early signs of atherogenesis was determined. Descriptive statistics and a chi-square test, with significance threshold set at p = 0.05, were used to examine differences by sex and age. RESULTS A total of 62.5% of participating adolescents were female and the same percent of the total were in early adolescence. Prevalent risk factors were poor dietary habits (81.3%), passive smoking (54.2%) and sedentary lifestyle (45.8%). The latter was more frequent among female and adolescents aged 10-14 years. Prehypertension and active smoking were prevalent during late adolescence. Hypertension was the disease most often found in family history (91.7%). All adolescents had at least one early sign of atherogenesis, and 72.9% had >=3 signs, noted especially in female participants. CONCLUSIONS The high prevalence of >=3 early signs of atherogenesis in this study suggests the need to initiate primary prevention before onset of adolescence, and even prior to birth, using a gender perspective, to conduct educational interventions designed to change the risk factors highlighted in the study and reduce cardiovascular risk in adolescents. KEYWORDS Adolescents, adolescent health, atherosclerosis, atherogenesis, arterial occlusive diseases, early detection of disease, risk factors, Cuba. PMID- 26947279 TI - Safety and Immunogenicity of Cuban Antipneumococcal Conjugate Vaccine PCV7-TT in Healthy Adults. AB - INTRODUCTION Pneumococcal infections are a major cause of morbidity and mortality and are associated with considerable economic burden on health systems. To prevent pneumococcal infections, 7-valent conjugate vaccines have been available for over a decade; more recently, 10- and 13-valent conjugate vaccines have been formulated, which are more immunogenic than vaccines with capsular polysaccharides only. In Cuba, a new vaccine candidate has been developed, PCV7 TT, a conjugate of tetanus toxoid with antigens of seven of the serotypes of Streptococcus pneumoniae with highest circulation in Cuba and in the world: 1, 5, 6B, 14, 18C, 19F and 23F. OBJECTIVE Assess the safety of the vaccine candidate PCV7-TT in healthy adults and conduct a preliminary assessment of its immunogenicity. METHODS A phase I, double-blind clinical trial was performed at the National Toxicology Center in Havana, Cuba. Healthy male volunteers aged 18 35 years were randomly assigned to two groups: 20 received the vaccine candidate PCV7-TT and 20 the polyvalent antipneumococcal vaccine PNEUMO-23 used as control, each in a single intramuscular dose. To assess safety, the occurrence of adverse events was monitored for 30 days following inoculation. To explore immunogenicity, concentrations of serotype-specific antibodies was quantified before and 30 days after inoculation, as well titers of opsonophagocytic antibodies. (National Clinical Trial Registry RPCEC00000133) RESULTS Local adverse events were pain, redness, induration, increased sensitivity to touch, and warmth in the injection area. Pain was registered in 70% of individuals who received PCV7-TT and in 75% of those vaccinated with PNEUMO-23. Reported systemic adverse events were general malaise, headache and drowsiness. All adverse events appeared in the first 72 hours post inoculation and lasted no longer than 3 days. One event was reported that was classified as severe in intensity and serious in consequences, but it was unrelated to vaccination appendicitis in one individual inoculated with the control vaccine. Before vaccination, all participants but one had antibody concentrations =0.20 ug/ml against the vaccine strains; after vaccination 100% of individuals were positive and the concentrations of antibodies increased in previously positive volunteers. Some individuals had opsonophagocytic antibodies against serotypes 1, 14, 19F and 23F before vaccination, with highest concentrations against serotypes 14 and 19F. After vaccination, the percent of individuals with opsonophagocytic titers >1:8 for all serotypes in the vaccine was >50% in both groups. CONCLUSIONS A single dose of candidate vaccine PCV7-TT was safe when used in healthy adults. Preliminary results showed that it was able to activate an immune response against the serotypes of Streptococcus pneumoniae used. KEYWORDS Invasive pneumococcal diseases, pneumococcal vaccines, conjugate vaccines, immunization, randomized clinical trial, safety, Cuba. PMID- 26947281 TI - A Woman-centered Educational Program for Primary Prevention of Lung Cancer in a Cuban Municipality, 2012--2013. AB - Lung cancer educational programs seek the involvement of different groups in efforts to promote healthier habits and lifestyles. Women are primary agents for targeting prevention actions because of their ability to foster healthy lifestyles within their families. The purpose of this study was to develop a woman-centered educational program to strengthen knowledge and promote responsible behavior aimed at primary prevention of lung cancer. Based on identified learning needs in 133 female participants concerning lung cancer self care, healthy habits and communication skills about self care, a ten-workshop series was designed and validated by specialists and users. Before intervention, 82% of participants were highly aware of smoking-related harm, but only 26% were highly aware of healthy environmental management practices at home and 14% were knowledgeable about self care. Differences in both awareness and practice of health-promoting behaviors were observed by the end of the training: those highly aware of smoking-related harm rose to 86.5%, and those highly aware of environmental management and self care increased to 66.2% and 83.5%, respectively. The proportions reporting acceptable levels of environmental management and self-care practices increased to 86.5% (from 0%) and 91% (from 3.8%), respectively. One year later, a positive impact on families was confirmed, predominantly on children. We conclude that such a woman-centered educational program can increase awareness and promote healthy behaviors aimed at lung cancer prevention. Women's ability to communicate and share lessons learned within their families should be considered in designing community health education programs. KEYWORDS Lung cancer, health education, disease prevention, primary prevention, health promotion, Cuba. PMID- 26947282 TI - The Debate in Cuba's Scientific Community on Sudden Cardiac Death. AB - Sudden cardiac death poses a challenge to modern medicine because of its high incidence, the unexpected and dramatic nature of the event, and years of potential life lost. What's more, despite modest decreases in global mortality attributed to cardiovascular diseases, incidence of sudden cardiac death has not declined. Cuba, like most of the Americas, suffers from knowledge gaps that hamper adequate strategies to address sudden cardiac death as a population health problem. We suggest that a generally accepted operational definition of sudden cardiac death be agreed upon, and a national registry developed that recognizes this cause of death on death certificates. These two actions will enable Cuba's public health authorities to assess the extent of the problem and to design intervention strategies for the population with intermediate and lower cardiovascular risk, the group in which most cases occur. KEYWORDS Sudden cardiac death, cardiovascular disease, sudden death, sudden cardiac arrest, risk reduction, prevention and control, Cuba. PMID- 26947283 TI - When Politics Trumps Health: Undocumented Latino Immigrants and US Health Care. PMID- 26947284 TI - Under the Cover of Night: Abortion Across Borders. AB - Jessica and Robert* had a three-year-old son and were excited about their second child, a daughter. When Jessica was 21 weeks pregnant, the routine ultrasound was normal. At 26 weeks, she was in a minor car accident and her obstetrician referred her for a specialized ultrasound, concerned about the baby's heart. This was how Jessica and Robert discovered that their daughter had a serious heart defect. After meeting with a perinatologist, a genetics counselor and a pediatric cardiologist, they realized the prognosis was dire. After birth, their daughter would need urgent open-heart surgery, and would need two more surgeries in her first year of life. If she survived long enough, her only real chance would be a heart transplant. They cried, they raged, and then they turned to the Internet. They felt the only way they could protect their daughter from a lifetime of suffering was to terminate the pregnancy. When they arrived at our clinic in New Mexico, they looked beaten down, fragile. "I feel like we snuck across state borders under the cover of night," Jessica told us, "but what choice did we have?" PMID- 26947285 TI - Management of the calving pen is a crucial factor for paratuberculosis control in large dairy herds. AB - Improvement of hygiene and herd management to reduce the contact of calves with adult cow feces to prevent new infections is one of the basic strategies to manage paratuberculosis-affected dairy herds. Control programs should recommend an evidence-based selection of factors that demonstrably reduce the transmission of the infectious agent and decrease the prevalence of infected cattle to improve acceptance and implementation of the recommended measures among farmers. This study aimed to assess the influence of several management measures on control success in a longitudinal study in 28 large dairy herds with a median size of 415 cows in Thuringia, Germany. The cumulative incidence of cows shedding Mycobacterium avium ssp. paratuberculosis (MAP) per year was determined by individual fecal culture of all cows during 5 consecutive years. Relevant management practices as well as herd size, milk yield, and purchase of cattle were recorded by on-farm risk assessment. Mean holding time of MAP shedders within the herd was calculated from individual data of each shedding cow. Using multiple regression models, separate calving pens for shedders and disinfection of the pen after use were identified as significant risk factors that reduced the cumulative incidence of MAP shedders per year on the herd level. The results provide evidence that, in addition to other factors, calving hygiene and management of the calving pens are crucial for paratuberculosis control, particularly in large dairy herds. Considered together with the outcome from other studies, these results might be important to weight various risk factors and to avoid overburdening and overwhelming farmers and keeping them committed. PMID- 26947286 TI - Influence of the molecular weight of carboxymethylcellulose on properties and stability of whey protein-stabilized oil-in-water emulsions. AB - The influence of the molecular weight (Mw; 270, 750, and 2,500 kDa) and concentration of carboxymethylcellulose (CMC) on the stability and properties of whey protein isolate (WPI)-stabilized oil-in-water emulsions were assessed by measuring zeta-potential, droplet size, apparent viscosity, protein surface coverage, and creaming stability. Emulsions were prepared to contain 5% oil, 0.5% WPI, and 0 to 0.5% CMC at pH 7. After emulsification, pH was adjusted to 5.2. In the absence of CMC, the WPI-stabilized emulsion was unstable to droplet flocculation and coalescence due to the relatively low droplet charge. Emulsions stabilized by mixed WPI-CMC had improved surface properties as well as reduced droplet flocculation, as indicated by increased negative charges and protein surface coverage as well as smaller droplet size. Increased viscosity due to nonadsorbed CMC also contributed to increased stability at high CMC concentration. The high-Mw CMC was more effective in enhancing surface properties and providing better stability against creaming compared with lower-Mw CMC. Maximum stability was achieved with mixed WPI-CMC stabilized emulsion containing 0.08% CMC 2,500 kDa. PMID- 26947287 TI - Randomized noninferiority study evaluating the efficacy of a postmilking teat disinfectant for the prevention of naturally occurring intramammary infections. AB - The objective of this study was to complete a positive-control, natural exposure, noninferiority design field study to test the efficacy of a novel glycolic acid based postmilking teat disinfectant as compared with a previously proven iodine based postmilking teat disinfectant (positive control). The primary outcome of interest was the effect of treatment on incidence of new intramammary infections. Secondary outcomes included the effect of treatment on prevalence of infection, somatic cell count, and teat condition. After blocking by parity, approximately 300 early- to mid-lactation cows on a large Wisconsin dairy farm were randomly assigned to 1 of 2 groups. For a 12-wk period between May and August 2014, the 2 groups were dipped after each milking with either the experimental (EX) or positive control (PC) product. Individual quarters were sampled to establish bacteriological infection status at the beginning of the study, and every 2 wk thereafter, by use of a 2-stage process evaluating somatic cell count (SCC), and then culturing milk samples only when SCC exceeded a parity-specific threshold. Teat condition scoring was completed at the beginning of the study and on wk 4, 8, and 12. Mixed logistic regression was used to evaluate the effect of treatment on dichotomous outcome measures including the odds of acquiring a new infection during a given 2-wk sampling interval (incidence), the odds for presence of infection at sampling (prevalence), and odds for a normal teat skin condition score. Mixed linear regression was used to evaluate the effect of treatment on somatic cell count. For the noninferiority analysis, the upper bound of the 95% confidence interval for the difference in new infection rate between the 2 treatments (EX - PC), had to be to the left of the critical value d (0.035) to conclude that EX was noninferior relative to PC with respect to risk for new infections. Results showed that the incidence of new infections was not different for quarters dipped with EX (3.2%) as compared with PC (4.2%). Similarly, the prevalence of infection tended to be lower for quarters dipped with EX (3.92%) as compared with PC (5.03%). No overall difference was found between treatments when evaluating somatic cell count measures and teat condition scores. Because the upper bound of the 95% confidence interval of the new IMI rate difference was smaller than the predefined noninferiority limit, it was concluded that the experimental product was not inferior compared with the positive control. As such, the glycolic acid-based teat disinfectant evaluated in this study can be considered an effective postmilking teat disinfectant, as well as safe, in so far as the product was not irritating to teat skin and did not negatively affect skin condition measures, as compared with the positive control group. PMID- 26947288 TI - The influence of casein haplotype on quality, coagulation, and yield traits of milk from Italian Holstein cows. AB - The aim of this work was to investigate the effect of casein haplotype (CSN1S1, CSN2, and CSN3) on quality, coagulation, and yield traits of milk from Italian Holstein cows. The casein haplotype was determined by isoelectric focusing; milk clotting properties were determined by using a mechanical lacto-dynamographic instrument; and the yields of pressed and pasta filata cheeses were expressed as kilograms of cheese per 100kg of milk processed. Statistical analysis showed a significant effect of the casein haplotype. In particular, BB-A(1)A(1)-AA milk showed the highest fat content (4.01g/100g), whereas BB-A(2)A(2)-BB milk had a higher protein content, the best coagulation characteristics, and the highest yields in pressed and pasta filata cheeses, and, consequently, better ability to retain fat and protein in the curd. The results of this study suggest that knowledge of milk protein polymorphisms not only allows the production of milk with specific qualitative and quantitative characteristics, but it could also be used as a specific marker within a breed to identify milk suitable for cheesemaking, which confers an economical advantage for dairy producers. PMID- 26947289 TI - Effect of different scenarios for selective dry-cow therapy on udder health, antimicrobial usage, and economics. AB - The goal of dry-cow therapy (DCT) is to reduce the prevalence of intramammary infections (IMI) by eliminating existing IMI at drying off and preventing new IMI from occurring during the dry period. Due to public health concerns, however, preventive use of antimicrobials has become questionable. In this study, we evaluated the effects of 8 scenarios for selecting animals for DCT, taking into account variation in parity and cow-level somatic cell count (SCC) at drying off. The aim of this study was to evaluate udder health, antimicrobial usage, and economics at the herd level when using different scenarios for selecting cows for DCT. To enable calculation and comparison of the effects of different scenarios to select cows for DCT in an "average" herd, we created an example herd, with a virtual herd size of 100 dairy cows to be calving during a year. Udder health, antimicrobial usage, and economics were evaluated during the dry period and the first 100 d in lactation, the period during which the greatest effect of DCT is expected. This leads to an estimated 13,551 cow-days at risk during a year in a 100-cow dairy herd. In addition to a blanket DCT (BDCT) scenario, we developed 7 scenarios to select cows for DCT based on SCC. The scenarios covered a range of possible approaches to select low-SCC cows for DCT, all based on cow-level SCC thresholds on the last milk recording before drying off. The incidence rate of clinical mastitis in the example herd varied from 11.6 to 14.5 cases of clinical mastitis per 10,000 cow-days at risk in the different scenarios, and the prevalence of subclinical mastitis varied from 38.8% in scenario 1 (BDCT) to 48.3% in scenario 8. Total antimicrobial usage for DCT and clinical mastitis treatment varied over the scenarios from 1.27 (scenario 8) to 3.15 animal daily dosages (BDCT), leading to a maximum reduction in antimicrobial usage of 60% for scenario 8 compared with BDCT. The total costs for each of the scenarios showed little variation, varying from ?4,893 for scenario 5 to ?5,383 for scenario 8. The effect of selective DCT compared with BDCT on udder health, antimicrobial usage, and economics is influenced by the SCC criteria used to select cows for DCT. Scenario 2 resulted in the lowest increases in clinical and subclinical mastitis compared with BDCT. The greatest reduction in antimicrobial usage was achieved under scenario 8. From an economic perspective, lowest costs were achieved with scenario 5. Drying off dairy cows with antimicrobials has an effect on udder health, antimicrobial usage, and economics. PMID- 26947290 TI - Identifying the ideal profile of French yogurts for different clusters of consumers. AB - Identifying the sensory properties that affect consumer preferences for food products is an important feature of product development. Different methods, such as external preference mapping or partial least squares regression, are used to establish relationships between sensory data and consumer preferences and to identify sensory attributes that drive consumer preferences, by highlighting optimum products. Plain French yogurts were evaluated by a sensory profiling method performed by 12 trained judges. In parallel, 180 consumers were asked to score their overall liking and complete a cognitive restraint questionnaire. After hierarchical cluster analysis on the liking scores, preference mapping using a quadratic regression model was performed. Five clusters of consumers were identified as a function of different preference patterns. Contrary to our expectations, fat levels were not discriminating. For each cluster, the results of preference mapping enabled the identification of optimum products. A comparison of the 5 sensory profiles revealed numerous differences between key sensory attributes. For example, one consumer cluster had a strong preference for products perceived as very thick, grainy, but with a less flowing texture, less sticky, whey presence and color, in contrast to other clusters. In addition, each segment of consumers was characterized according to the results of the cognitive restraint questionnaire. PMID- 26947291 TI - Identification of fimbrial subunits in the genome of Trueperella pyogenes and association between serum antibodies against fimbrial proteins and uterine conditions in dairy cows. AB - Understanding the role of fimbrial subunits during bacterial adherence and the host's immunological response against anchorage proteins is critical for the development of strategies to prevent pathogens from thriving. The objectives of the present study were to locate fimbria-related proteins in the genome of Trueperella pyogenes (CP007519), define their importance for bacterial adherence, and evaluate the association between serum antibodies against fimbrial subunits and uterine health in dairy cows. Using a BLASTp search through the GenBank database, 4 putative clusters for fimbrial assembly were identified in the genome of T. pyogenes, namely FimA, FimC, FimE, and the novel major fimbriae FimJ. The fimbrial proteins FimA, FimC, FimE, and surface-anchored protein (SAP) were cloned into the pET 26b (+) vector, expressed in Escherichia coli BL21, and purified using affinity chromatography. Serum antibodies against FimA, FimC, FimE, and SAP were determined by ELISA on d 260+/-3 of gestation and at 2+/-1 and 35+/-3 d in milk (DIM) to assess the relationship between antigenicity against fimbrial proteins and parameters of uterine health. Antibodies against FimC and FimE were greater both pre- and postpartum in cows from which T. pyogenes was recovered by uterine flushing at 35+/-3 DIM, whereas T. pyogenes infection was not associated with differences in serum concentrations of FimA and SAP antibodies. Likewise, concentrations of FimC antibodies were consistently greater in cows diagnosed with clinical endometritis at 35+/-3 DIM compared with healthy counterparts. These results suggest that fimbrial proteins evaluated in the present study, particularly FimC and FimE, are important for maintenance of T. pyogenes in the uterus postpartum and development of uterine diseases in dairy cattle. Additional research is warranted to elucidate the mechanisms by which each fimbrial subunit contributes to the establishment of uterine diseases, evaluate its effect on fertility responses, and assess its relevance as a target for vaccine development. PMID- 26947293 TI - Effect of pulsation rest phase duration on teat end congestion. AB - The objective of this study was to quantify the effect of d-phase (rest phase) duration of pulsation on the teat canal cross-sectional area during the period of peak milk flow from bovine teats. A secondary objective was to test if the effect of d-phase duration on teat canal cross-sectional area was influenced by milking system vacuum level, milking phase (b-phase) duration, and liner overpressure. During the d-phase of the pulsation cycle, liner compression facilitates venous flow and removal of fluids accumulated in teat-end tissues. It was hypothesized that a short-duration d-phase would result in congestion of teat-end tissue and a corresponding reduction in the cross-sectional area of the teat canal. A quarter milking device, designed and built at the Milking Research and Instruction Laboratory at the University of Wisconsin-Madison, was used to implement an experiment to test this hypothesis. Pulsator rate and ratios were adjusted to achieve 7 levels of d-phase duration: 50, 100, 150, 175, 200, 250, and 300ms. These 7 d-phase durations were applied during one milking session and were repeated for 2 vacuum levels (40 and 50kPa), 2 milking phase durations (575 and 775ms), and 2 levels of liner overpressure (9.8 and 18kPa). We observed a significant reduction in the estimated cross-sectional area of the teat canal with d-phase durations of 50 and 100ms when compared with d-phase durations of 150, 175, 225, 250, and 300ms. No significant difference was found in the estimated cross-sectional area of the teat canal for d-phase durations from 150 to 300ms. No significant interaction was observed between the effect of d-phase and b-phase durations, vacuum level, or liner overpressure. PMID- 26947292 TI - Improving the performance of dairy cattle with a xylanase-rich exogenous enzyme preparation. AB - The objective of this experiment was to examine effects of adding 2 exogenous fibrolytic enzymes (EFE) to the total mixed ration (TMR) on the performance of lactating dairy cows (experiment 1) and the kinetics of ruminal degradation of the diet (experiment 2). Twelve EFE had been screened in a series of in vitro assays that identified the most potent EFE and their optimal doses for increasing the digestibility of bermudagrass. In experiment 1, 66 Holstein cows (21+/-5 d in milk) were grouped by previous milk production and parity (45 multiparous and 21 primiparous) and assigned randomly to 1 of the following 3 treatments: (1) control (CON, untreated), (2) Xylanase Plus [2A, 1mL/kg of TMR dry matter (DM); Dyadic International, Jupiter, FL], and (3) a 75:25 (vol/vol) mixture of Cellulase Plus and Xylanase Plus EFE (3A, 3.4mL/kg of TMR DM; Dyadic International). The EFE were sprayed twice daily onto a TMR (10% bermudagrass silage, 35% corn silage, 5% alfalfa-orchardgrass hay mixture, and 50% concentrates; DM basis) and fed for a 14-d training and covariate period and a 70 d measurement period. Experiment 2 aimed to examine the in situ DM ruminal degradability and ruminal fermentation measurements of the diets fed in experiment 1. Three ruminally fistulated lactating Holstein cows were assigned to the diets. The experiment had a 3*3 Latin square design with 23-d periods. In experiment 1, application of 2A increased intakes (kg/d) of DM (23.5 vs. 22.6), organic matter (21.9 vs. 20.9), and crude protein (3.9 vs. 3.7) and tended to increase yields (kg/d) of fat-corrected milk (41.8 vs. 40.7) and milk fat (1.48 vs. 1.44). In particular, 2A increased milk yield (kg/d) during wk 3 (41.2 vs. 39.8, tendency), 6 (41.9 vs. 40.1), and 7 (42.1 vs. 40.4), whereas 3A increased milk yield (kg/d) during wk 6 (41.5 vs. 40.1, tendency), 8 (41.8 vs. 40.0), and 9 (40.9 vs. 39.5, tendency). In experiment 2, EFE treatment did not affect ruminal DM degradation kinetics or ruminal pH, ammonia-N, and volatile fatty acid concentration. Application of 2A to the bermudagrass-based TMR increased DM intake and milk production, implying that this EFE could be used to increase the performance of lactating dairy cows fed diets containing up to 10% bermudagrass. PMID- 26947294 TI - Influence of milk urea concentration on fractional urea disappearance rate from milk to blood plasma in dairy cows. AB - The relationship between milk urea nitrogen (MUN; mg of N/dL) and urinary N excretion is affected, among others, by diurnal dynamics in MUN, which in turn is largely influenced by feed intake pattern and characteristics of urea transfer from blood plasma to milk and vice versa. This study aimed to obtain insight in urea transfer characteristics within the mammary gland and from the mammary gland to blood plasma in dairy cows at various concentrations of plasma urea nitrogen (PUN; mg of N/dL) and MUN. Urea transfer from milk to blood plasma and urea transfer within the mammary gland itself was evaluated in a 4*4 Latin square design using 4 lactating multiparous Holstein-Friesian cows (milk production of 39.8+/-4.70kg/d and 90+/-3.9 d in milk). Treatments consisted of 4 primed continuous intravenous urea infusions of 0, 5, 10, and 15g of urea/h. Boluses of [(15)N(15)N]urea were injected in cistern milk at 20, 60, and 100 min before the 1700h milking. Milk was collected in portions of approximately 2 L at the 1700h milking. Milk samples were analyzed for urea and enrichment of (15)N-urea. Results from one cow were discarded because of leakage of milk from the teats after injection of boluses of [(15)N(15)N]urea. Increasing urea infusion rate linearly increased PUN from 11.4 (0g of urea/h) to 25.9mg/dL (15g of urea/h) and MUN from 10.3 (0g of urea/h) to 23.5 (15g of urea/h) mg of N/dL. The percentage of injected [(15)N(15)N]urea recovered from milk at the time of injection was not affected by urea infusion rate and varied between 65.1 and 73.0%, indicating that a substantial portion of injected [(15)N(15)N]urea was not accounted for by collected milk. The estimated fractional disappearance rate of (15)N-urea from milk to blood (Kurea; per hour) linearly increased from 0.429 (0g of urea/h) to 0.641 per hour (15g of urea/h). Cistern injected [(15)N(15)N]urea diffused within 20 min after injection toward alveoli milk. Calculations with the average Kurea estimated in this study show that 89% of an initial difference between PUN and MUN will have disappeared after 4 h. In conclusion, urea disappearance from milk in the mammary gland is substantial, as well as the intramammary urea exchange between cistern, duct, and alveoli milk. However, results have to be interpreted with caution given the lack of full recovery of dosed (15)N urea at time of injection. Information on Kurea is useful to quantify the effects of diurnal variation in PUN on MUN, which enhances the utility of MUN as an indicator for N excretion in urine. PMID- 26947295 TI - Propionate induces mRNA expression of gluconeogenic genes in bovine calf hepatocytes. AB - Hepatocytes monolayers from neonatal calves were used to determine the responses of the cytosolic phosphoenolpyruvate carboxykinase (PCK1) mRNA expression to propionate and direct hormonal cues including cyclic AMP (cAMP), dexamethasone, and insulin. The responses of other key gluconeogenic genes, including mitochondrial phosphoenolpyruvate carboxykinase (PCK2), pyruvate carboxylase (PC), and glucose-6-phosphotase (G6PC), were also measured. Expression of PCK1 was linearly induced with increasing propionate concentrations in media and 2.5 mM propionate increased PCK1 mRNA at 3 and 6h of incubation; however, the induction disappeared at 12 and 24 h. The induction of PCK1 mRNA by propionate was mimicked by 1 mM cAMP, or in combination with 5 uM dexamethasone, but not by dexamethasone alone. The induction of PCK1 mRNA by propionate or cAMP was eliminated by addition of 100 nM insulin. Additionally, expression of PCK2 and PC mRNA was also induced by propionate in a concentration-dependent manner. Consistent with PCK1, propionate-stimulated PCK2 and PC mRNA expression was inhibited by insulin. Expression of G6PC mRNA was neither affected by propionate nor cAMP, dexamethasone, insulin, or their combinations. These findings demonstrate that propionate can directly regulate its own metabolism in bovine calf hepatocytes through upregulation of PCK1, PCK2, and PC mRNA expression. PMID- 26947296 TI - The potential of Fourier transform infrared spectroscopy of milk samples to predict energy intake and efficiency in dairy cows. AB - Knowledge of animal-level and herd-level energy intake, energy balance, and feed efficiency affect day-to-day herd management strategies; information on these traits at an individual animal level is also useful in animal breeding programs. A paucity of data (especially at the individual cow level), of feed intake in particular, hinders the inclusion of such attributes in herd management decision support tools and breeding programs. Dairy producers have access to an individual cow milk sample at least once daily during lactation, and consequently any low cost phenotyping strategy should consider exploiting measureable properties in this biological sample, reflecting the physiological status and performance of the cow. Infrared spectroscopy is the study of the interaction of an electromagnetic wave with matter and it is used globally to predict milk quality parameters on routinely acquired individual cow milk samples and bulk tank samples. Thus, exploiting infrared spectroscopy in next-generation phenotyping will ensure potentially rapid application globally with a negligible additional implementation cost as the infrastructure already exists. Fourier-transform infrared spectroscopy (FTIRS) analysis is already used to predict milk fat and protein concentrations, the ratio of which has been proposed as an indicator of energy balance. Milk FTIRS is also able to predict the concentration of various fatty acids in milk, the composition of which is known to change when body tissue is mobilized; that is, when the cow is in negative energy balance. Energy balance is mathematically very similar to residual energy intake (REI), a suggested measure of feed efficiency. Therefore, the prediction of energy intake, energy balance, and feed efficiency (i.e., REI) from milk FTIRS seems logical. In fact, the accuracy of predicting (i.e., correlation between predicted and actual values; root mean square error in parentheses) energy intake, energy balance, and REI from milk FTIRS in dairy cows was 0.88 (20.0MJ), 0.78 (18.6MJ), and 0.63 (22.0MJ), respectively, based on cross-validation. These studies, however, are limited to results from one research group based on data from 2 contrasting production systems in the United Kingdom and Ireland and would need to be replicated, especially in a range of production systems because the prediction equations are not accurate when the variability used in validation is not represented in the calibration data set. Heritable genetic variation exists for all predicted traits. Phenotypic differences in energy intake also exists among animals stratified based on genetic merit for energy intake predicted from milk FTIRS, substantiating the usefulness of such FTIR-predicted phenotypes not only for day-to-day herd management, but also as part of a breeding strategy to improve cow performance. PMID- 26947297 TI - Citrus-derived oil inhibits Staphylococcus aureus growth and alters its interactions with bovine mammary cells. AB - This experiment examined the effects of cold-pressed, terpeneless citrus-derived oil (CDO) on growth of Staphylococcus aureus, which a major cause of contagious bovine mastitis, and invasion of bovine mammary cells (MAC-T). To determine minimum inhibitory concentration, we used the broth dilution method, using CDO concentrations range from 0.0125 to 0.4% with 2-fold dilutions. Growth inhibition was examined by adding 0.00, 0.05, 0.025, 0.0125, and 0.00625% CDO to 10(5) cfu/mL S. aureus in nutrient broth and enumerating colonies after serial dilution. In a 96-well plate, S. aureus (10(7) cfu/mL) was allowed to form a biofilm, treated with 0, 0.025, 0.5, or 1% CDO, and then was measured using a spectrophotometer. Cytotoxic effect on immortalized MAC-T cells was also examined at various concentrations of CDO using a 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide assay. We observed that the minimum inhibitory concentration of CDO to inhibit the growth of S. aureus in vitro was 0.025% CDO. A time kill curve for CDO action on S. aureus over 4h was generated. The CDO completely eliminated S. aureus after 3h of incubation at a concentration of 0.25%, or after 2h of incubation at concentrations of 0.05%. It was also observed that CDO had no effect on preformed biofilms except at a concentration of 0.05%, in which a significant reduction in the measured absorbance was noted. In addition, the association and invasion of S. aureus to MAC-T cells were significantly inhibited after 1h of treatment with CDO. Citrus-derived oil was also able to increase cellular proliferation of MAC-T cells at concentrations up 0.05% and had no effect at a concentration of 0.1% after 1 h. Our data suggests that CDO should be considered for further research as a preventive and therapeutic against bovine mastitis. PMID- 26947298 TI - Short communication: Flavor and flavor stability of cheese, rennet, and acid wheys. AB - Dried whey ingredients are valuable food ingredients but potential whey sources are underutilized. Previous work has established flavor and flavor stability differences in Cheddar and Mozzarella wheys, but little work has compared these whey sources to acid or rennet wheys. The objective of this study was to characterize and compare flavor and flavor stability among cheese, rennet, and acid wheys. Full-fat and fat-free Cheddar, rennet and acid casein, cottage cheese, and Greek yogurt fluid wheys were manufactured in triplicate. Wheys were fat separated and pasteurized followed by compositional analyses and storage at 4 degrees C for 48 h. Volatile compound analysis and descriptive sensory analysis were evaluated on all liquid wheys initially and after 24 and 48 h. Greek yogurt whey contained almost no true protein nitrogen (0.02% wt/vol) whereas other wheys contained 0.58%+/-0.4% (wt/vol) true protein nitrogen. Solids and fat content were not different between wheys, with the exception of Greek yogurt whey, which was also lower in solids content than the other wheys (5.6 vs. 6.5% wt/vol, respectively). Fresh wheys displayed sweet aromatic and cooked milk flavors. Cheddar wheys were distinguished by diacetyl/buttery flavors, and acid wheys (acid casein, cottage cheese, and Greek yogurt) by sour aromatic flavor. Acid casein whey had a distinct soapy flavor, and acid and Greek yogurt wheys had distinct potato flavor. Both cultured acid wheys contained acetaldehyde flavor. Cardboard flavor increased and sweet aromatic and buttery flavors decreased with storage in all wheys. Volatile compound profiles were also distinct among wheys and changed with storage, consistent with sensory results. Lipid oxidation aldehydes increased in all wheys with storage time. Fat-free Cheddar was more stable than full-fat Cheddar over 48h of storage. Uncultured rennet casein whey was the most stable whey, as exhibited by the lowest increase in lipid oxidation products over time. These results provide baseline information for the viability of processing underutilized wheys into value-added ingredients. PMID- 26947299 TI - Increasing linseed supply in dairy cow diets based on hay or corn silage: Effect on enteric methane emission, rumen microbial fermentation, and digestion. AB - We investigated the effects of increasing extruded linseed supply in diets based on hay (H; experiment 1) or corn silage (CS; experiment 2) on enteric methane (CH4) emission, rumen microbial and fermentation parameters, and rumen and total tract digestibility. In each experiment, 4 lactating Holstein cows fitted with cannulas at the rumen and proximal duodenum were used in a 4*4 Latin square design (28-d periods). Cows were fed ad libitum a diet [50:50 and 60:40 forage:concentrate on a dry matter (DM) basis for experiments 1 and 2, respectively] without supplementation (H0, CS0) or supplemented with extruded linseed at 5% (H5, CS5), 10% (H10, CS10), and 15% (H15, CS15) of dietary DM (i.e., 1.8, 3.6 and 5.4% total fatty acids added, respectively). All measurements were carried out during the last 8 d of each period. Linseed supply linearly decreased daily CH4 emission in cows fed H diets (from 486 to 289g/d for H0 to H15, on average) and CS diets (from 354 to 207g/d for CS0 to CS15, on average). The average decrease in CH4 per kilogram of DM intake was, respectively, -7, -15, and -38% for H5, H10, H15 compared with the H0 diet, and -4, -8, and -34% for CS5, CS10, and CS15 compared with the CS0 diet. The same dose-response effect was observed on CH4 emission in percent of gross energy intake, per kilogram of nutrient digested, and per kilogram of 4% fat- and 3.3% protein-corrected milk (FPCM) in both experiments. Changes in the composition of rumen volatile fatty acids in response to increasing linseed supply resulted in a moderate or marked linear decrease in acetate:propionate ratio for H or CS diets, respectively. The depressive effect of linseed on total protozoa concentration was linear for H diets (-15 to -40%, on average, for H5 to H15 compared with H0) and quadratic for CS diets (-17 to -83%, on average, for CS5 to CS15 compared with CS0). Concentration of methanogens was similar among H or CS diets. The energetic benefits from the decreased CH4 emission with linseed supply in diets based on hay or corn silage did not improve digestibility or milk yield. Milk efficiency (kg of FPCM/kg of DM intake) was improved with linseed supply up to H10 in H diets and was unchanged in CS diets. Lower CH4 enteric emission from dairy cows fed linseed helps limit the environmental footprint of ruminant livestock. PMID- 26947300 TI - Short communication: The effect of an exogenous enzyme with amylolytic activity on gas production and in vitro rumen starch degradability of small and large particles of corn or barley meals. AB - The objective of this study was to evaluate the effect of exogenous amylase supplementation on gas production and on in vitro rumen starch degradability (IVSD) of different sized particles of corn and barley meals (Cm and Bm, respectively). An aqueous liquid amylase formulation from Bacillus licheniformis was tested at 3 enzyme doses (EnzD; 0, 300 and 1,500 kilo novo units/kg of dry matter) on small (<750 um) and large (>=750 um) particle size (PS) of Cm and Bm. Data were analyzed according to a randomized complete block design with a factorial arrangement of treatments; the main tested effects were PS, EnzD, and their interaction. Fermentation run entered in the model as random effect. The mixed rumen fluid was collected from 2 rumen-fistulated Holstein dry dairy cows fed at maintenance (forage:concentrate ratio of 80:20; 12% crude protein; 55% amylase-treated neutral detergent fiber). Small particles of both Cm and Bm had a greater rate of fermentation and shorter lag time than large particles. The rate of starch degradation was greater for small than for large particles of Bm, being 0.187 and 0.125 1/h, respectively. Conversely, the rate of starch degradation of Cm averaged 0.063 1/h and was similar among treatments. Enzyme supplementation tended to reduce lag time and to increase rate of fermentation for both PS of Cm and Bm, with a more pronounced effect for small PS. A limited EnzD effect was measured for IVSD data and rate of starch degradation; PS influenced fermentation parameters and the magnitude of starch degradation more than EnzD. Supplementation with exogenous amylase influenced the rumen fermentation pattern of small and large PS of Cm and Bm, even if the effect of the enzyme supplementation differed according to the PS of cereal meals. PMID- 26947301 TI - Economic comparison of common treatment protocols and J5 vaccination for clinical mastitis in dairy herds using optimized culling decisions. AB - This study used an existing dynamic optimization model to compare costs of common treatment protocols and J5 vaccination for clinical mastitis in US dairy herds. Clinical mastitis is an infection of the mammary gland causing major economic losses in dairy herds due to reduced milk production, reduced conception, and increased risk of mortality and culling for infected cows. Treatment protocols were developed to reflect common practices in dairy herds. These included targeted therapy following pathogen identification, and therapy without pathogen identification using a broad-spectrum antimicrobial or treating with the cheapest treatment option. The cost-benefit of J5 vaccination was also estimated. Effects of treatment were accounted for as changes in treatment costs, milk loss due to mastitis, milk discarded due to treatment, and mortality. Following ineffective treatments, secondary decisions included extending the current treatment, alternative treatment, discontinuing treatment, and pathogen identification followed by recommended treatment. Average net returns for treatment protocols and vaccination were generated using an existing dynamic programming model. This model incorporates cow and pathogen characteristics to optimize management decisions to treat, inseminate, or cull cows. Of the treatment protocols where 100% of cows received recommended treatment, pathogen-specific identification followed by recommended therapy yielded the highest average net returns per cow per year. Out of all treatment scenarios, the highest net returns were achieved with selecting the cheapest treatment option and discontinuing treatment, or alternate treatment with a similar spectrum therapy; however, this may not account for the full consequences of giving nonrecommended therapies to cows with clinical mastitis. Vaccination increased average net returns in all scenarios. PMID- 26947302 TI - Effect of stage of lactation on the immune competence of goat mammary gland. AB - The present research was undertaken to evaluate the effect of stage of lactation on immune competence of the goat mammary gland. The prevalence and etiology of intramammary infections and cytokine pattern were studied in individual caprine milk during lactation. A total of 1,200 caprine milk samples were collected during early, mid, and late lactation (less than 40 d, from 110 to 130 d, and more than 200 d in lactation, respectively) and analyzed for milk quality, bacterial cell load, and cytokine pattern. Contagious and environmental pathogens associated with intramammary infection were isolated from caprine milk. Nutritional components of caprine milk were affected by stage of lactation; fat, protein, casein, and whey protein increased along with lactation due to the lowest milk yield. Lactose content showed an opposite trend, with a reduced percentage passing from early to late lactation. The impaired rheological properties detected in early and late lactation milk were associated with a modification of milk quality. An impairment of microbial quality was detected at the end of lactation as a consequence of a major susceptibility of mammary gland to infections. The percentage of bacteriologically positive caprine milk samples was 44% throughout lactation. The incidence of bacteria associated with intramammary infection was different according to the stage of lactation with a major prevalence of Staphylococcus aureus, Enterobacteriaceae, Staphylococcus hyicus, and Streptococcus uberis in early lactation milk, Staphylococcus chromogenes, Streptococcus bovis, and Staphylococcus epidermidis in mid lactation, and Pseudomonas aeruginosa and Staphylococcus caprae in late lactation milk. The higher values of IL-1beta, tumor necrosis factor-alpha, and IL-6 were ascribed to the major prevalence of Staphylococcus aureus at the beginning of lactation, whereas a higher level of IL-10 was detected in mid-lactation caprine milk and correlated with Staphylococcus chromogenes. Monitoring the cytokine pattern in milk helps to understand the immune status of the mammary gland, its ability to cope with bacteria, and the evolution of infections. PMID- 26947303 TI - Factors associated with ovarian structures and intrauterine fluid in the postpartum period in dairy cows. AB - The objective was to examine risk factors for the interval to resumption of ovarian cyclicity (ROC), multiple ovulations (MCL), ovarian follicular cysts (OC), and presence of intrauterine fluid (IUF) at 22 to 28 [visit (V) 1] and 36 to 42 (V2) days in milk (DIM) in dairy cows. The study was conducted retrospectively by evaluating records from 1,155 Holstein cows from 3 herds. Ovaries and uteri were examined at V1 and V2 by transrectal ultrasonography to determine ovarian structures and IUF. Based on the odds ratio, multiparous cows were more likely to have ROC at V1 by a factor of 1.79 compared with primiparous cows. The likelihood of ROC at V1 was lower in cows with higher milk production, in cows with retained fetal membranes (RFM) or cows with IUF at V1 by factors of 0.98 (for each kg of milk increased), 0.52, and 0.61, respectively. Based on the odds ratio, cows diagnosed with IUF at V2 were 2.85 times more likely to have attained ROC at V2. Multiparous cows and cows that delivered twins were 2.73 and 2.16 times, respectively, more likely to have MCL at V1, whereas cows with RFM were 0.38 times less likely to have MCL at V1. The likelihood of MCL at V2 was higher in cows with MCL and OC at V1 by factors of 2.67 and 1.91, respectively. Multiparous cows were 8.51 times more likely to have OC at V1 than primiparous cows. Higher producing cows were more likely to have OC at V2 by a factor of 1.04 compared with lower producing cows. Parity, stillbirth, RFM, and ROC at V1 were all identified as risk factors for IUF at V1. Cows with RFM and delivering twins were more likely to be diagnosed with IUF at V2 by a factor of 3.43 and 4.07, respectively. In summary, parity, twinning, RFM, metritis, IUF, and milk production were all associated with altered ovarian structures, and the presence of IUF was related to parity, twinning, RFM, and ROC in postpartum dairy cows. PMID- 26947304 TI - Genome-wide association of coagulation properties, curd firmness modeling, protein percentage, and acidity in milk from Brown Swiss cows. AB - Cheese production is increasing in many countries, and a desire toward genetic selection for milk coagulation properties in dairy cattle breeding exists. However, measurements of individual cheesemaking properties are hampered by high costs and labor, whereas traditional single-point milk coagulation properties (MCP) are sometimes criticized. Nevertheless, new modeling of the entire curd firmness and syneresis process (CFt equation) offers new insight into the cheesemaking process. Moreover, identification of genomic regions regulating milk cheesemaking properties might enhance direct selection of individuals in breeding programs based on cheese ability rather than related milk components. Therefore, the objective of this study was to perform genome-wide association studies to identify genomic regions linked to traditional MCP and new CFt parameters, milk acidity (pH), and milk protein percentage. Milk and DNA samples from 1,043 Italian Brown Swiss cows were used. Milk pH and 3 MCP traits were grouped together to represent the MCP set. Four CFt equation parameters, 2 derived traits, and protein percentage were considered as the second group of traits (CFt set). Animals were genotyped with the Illumina SNP50 BeadChip v.2 (Illumina Inc., San Diego, CA). Multitrait animal models were used to estimate variance components. For genome-wide association studies, the genome-wide association using mixed model and regression-genomic control approach was used. In total, 106 significant marker traits associations and 66 single nucleotide polymorphisms were identified on 12 chromosomes (1, 6, 9, 11, 13, 15, 16, 19, 20, 23, 26, and 28). Sharp peaks were detected at 84 to 88 Mbp on Bos taurus autosome (BTA) 6, with a peak at 87.4 Mbp in the region harboring the casein genes. Evidence of quantitative trait loci at 82.6 and 88.4 Mbp on the same chromosome was found. All chromosomes but BTA6, BTA11, and BTA28 were associated with only one trait. Only BTA6 was in common between MCP and CFt sets. The new CFt traits reinforced the support of MCP signals and provided with additional information on genomic regions that might be involved in regulation of the coagulation process of bovine milk. PMID- 26947305 TI - Novel methods to study the effect of protein content and dissolution temperature on the solubility of milk protein concentrate: Focused beam reflectance and ultrasonic flaw detector-based methods. AB - Processing, storage, dissolution conditions, and the composition of milk protein concentrates (MPC) affect the solubility of high-protein dairy powders. Increasing the storage temperature and time decrease the solubility of MPC and milk protein isolates (MPI). The MPC and MPI are popular ingredients in high protein food products and have a variety of protein contents. In addition, the dissolution temperature has been shown to affect the solubility of the powders. This study focused on determining how protein content and dissolution temperature affect the solubility of MPC and MPI. For this study, 11 powders were obtained from a commercial manufacturer. The powders were classified as A, B, C, and D, and they had a mean protein content of 85, 87, 88, and 90%, respectively. A 5% (wt/wt) concentration of powder was dissolved in water at 40 and 48 degrees C. The solubility of the MPC and MPI samples were characterized using an ultrasonic flaw detector (UFD) and focused beam reflectance measurement (FBRM). The UFD and FBRM data were collected every 15 and 10 s, respectively, for 1,800 s. At both dissolution temperatures, the UFD and FBRM data showed that the solubility decreased as the protein content increased. Powders A and B were found to be more soluble because they had a lower relative velocity standard deviation, high area under the attenuation curve, high peak height, and low peak time. With the FBRM, the fine and medium particle count decreased and large particle count increased as the protein content increased. Powders dissolved at 48 degrees C typically had a lower relative velocity standard deviation, higher area under the attenuation curve, higher peak height, and lower peak time than the powders dissolved at 40 degrees C. The FBRM showed that powders dissolved at 48 degrees C reached a stable counts before the powders dissolved at 40 degrees C. Overall, the study showed that increasing the protein content led to a reduction in solubility and increasing the dissolution temperature improved the solubility of the powders. PMID- 26947306 TI - Characterization of the liver X receptor-dependent regulatory mechanism of goat stearoyl-coenzyme A desaturase 1 gene by linoleic acid. AB - Stearoyl-coenzyme A desaturase 1 (SCD1) is a key enzyme in the biosynthesis of palmitoleic and oleic acid. Although the transcriptional regulatory mechanism of SCD1 via polyunsaturated fatty acids (PUFA) has been extensively explored in nonruminants, the existence of such mechanism in ruminant mammary gland remains unknown. In this study, we used goat genomic DNA to clone and sequence a 1,713-bp fragment of the SCD1 5' flanking region. Deletion assays revealed a core region of the promoter located between -415 and -109 bp upstream of the transcription start site, and contained the highly conserved PUFA response region. An intact PUFA response region was required for the basal transcriptional activity of SCD1. Linoleic acid reduced endogenous expression of SCD1 and sterol regulatory element binding factor-1 (SREBF1) in goat mammary epithelial cells. Further analysis indicated that both the sterol response element (SRE) and the nuclear factor Y (NF-Y) binding site in the SCD1 promoter were responsible for the inhibition effect by linoleic acid, whereas the effect was abrogated once NF-Y was deleted. In addition, SRE and NF-Y were partly responsible for the transcriptional activation induced via the liver X receptor agonist T 4506585 (Sigma-Aldrich, St. Louis, MO). When goat mammary epithelial cells were cultured with linoleic acid, addition of T 4506585 markedly increased SCD1 transcription in controls, but had no effect on cells with a deleted SRE promoter. These results demonstrated that linoleic acid can regulate SCD1 expression at the transcriptional level through SRE and NF-Y in a liver X receptor-dependent fashion in the goat mammary gland. PMID- 26947308 TI - Effect of maternal heat stress during the dry period on growth and metabolism of calves. AB - Preliminary studies suggest that maternal heat stress (HS) during late gestation exerts carryover effects on a calf's insulin response after weaning, but a comprehensive evaluation of how maternal HS affects calf intake, growth, and metabolic response from birth to weaning is lacking. Our objective was to evaluate the effects of maternal HS during the dry period on dry matter intake, growth, and metabolism from birth to weaning. After birth, 20 heifers born to either HS (n=10) or cooled (CL, n=10) dry cows were immediately separated from their dams and fed 3.8 L of colostrum from a common pool within 4h of birth. All heifers were managed identically and weaned at 49 d of age (DOA). Calf starter intake was recorded daily, and body weight was assessed at birth and every 2 wk from birth to 56 DOA. Blood samples were collected twice a week until 56 DOA to assess hematocrit and concentrations of insulin and metabolites. To evaluate metabolic responses to maternal HS, a glucose tolerance test, insulin, and epinephrine challenge were performed on 3 consecutive days for all heifers at 8, 29, and 57 DOA. Maternal HS during the dry period did not affect heifer birth weight. Compared with HS, CL calves consumed more starter (0.53 vs. 0.34kg/d) from birth to 56 DOA and were heavier (71.7 vs. 61.4kg) at 56 DOA. Relative to HS calves, CL calves tended to have higher hematocrit (27.4 vs. 24.7%). No differences were found between treatments in plasma concentrations of insulin and glucose, but HS calves had higher nonesterified fatty acids and beta hydroxybutyrate concentrations after 32 DOA. Compared with CL, HS calves had a faster glucose clearance after a glucose tolerance test and a slower insulin clearance after an insulin challenge. In conclusion, maternal HS during late gestation reduces calf starter intake and growth, alters blood metabolite profile, and increases noninsulin-dependent glucose uptake. PMID- 26947307 TI - Spleen tyrosine kinase regulates mammary epithelial cell proliferation in mammary glands of dairy cows. AB - Spleen tyrosine kinase (SYK) is a nonreceptor tyrosine kinase that has been considered a hematopoietic cell-specific signal transducer involved in cell proliferation and differentiation. However, the role of SYK in normal mammary gland is still poorly understood. Here we show that SYK is expressed in mammary glands of dairy cows. Expression of SYK was higher in dry period mammary tissues than in lactating mammary tissues. Knockdown and overexpression of SYK affected dairy cow mammary epithelial cell proliferation as well as the expression of signal molecules involved in proliferation, including protein kinase B (PKB, also known as AKT1), p42/44 mitogen-activated protein kinase (MAPK), and signal transducer and activator of transcription 5 (STAT5). Dual-luciferase reporter assay showed that SYK increased the transcriptional activity of the AKT1 promoter, and cis-elements within the AKT1 promoter region from -439 to -84 bp mediated this regulation. These results suggest that SYK affects mammary epithelial cell proliferation by activating AKT1 at the transcriptional level in mammary glands of dairy cows, which is important for the mammary remodeling process in dry cows as well as for increasing persistency of lactation in lactating cows. PMID- 26947309 TI - The effect of storage temperature and duration on the microbial quality of bulk tank milk. AB - The dairy industry in Ireland is currently undergoing a period of expansion and, as a result, it is anticipated that milk may be stored in bulk tanks on-farm for periods greater than 48 h. The objective of this study was to investigate the effects of storage temperature and duration on microbial quality of bulk tank milk when fresh milk is added to the bulk tank twice daily. Bulk tank milk stored at 3 temperatures was sampled at 24-h intervals during storage periods of 0 to 96 h. Bulk tank milk samples were analyzed for total bacterial count (TBC), psychrotrophic bacterial count (PBC), laboratory pasteurization count (LPC), psychrotrophic-thermoduric bacterial count (PBC-LPC), proteolytic bacterial count, lipolytic bacterial count, presumptive Bacillus cereus, sulfite-reducing Clostridia (SRC), and SCC. The bulk tank milk temperature was set at each of 3 temperatures (2 degrees C, 4 degrees C, and 6 degrees C) in each of 3 tanks on 2 occasions during two 6-wk periods. Period 1 was undertaken in August and September, when all cows were in mid lactation, and period 2 was undertaken in October and November, when all cows were in late lactation. None of the bulk tank bacterial counts except the proteolytic count were affected by lactation period. The proteolytic bacterial count was greater in period 2 than in period 1. The TBC and PBC of milk stored at 6 degrees C increased as storage duration increased. The TBC did not increase with increasing storage duration when milk was stored at 2 degrees C or 4 degrees C but the PBC of milk stored at 4 degrees C increased significantly between 0 and 96 h. The numbers of proteolytic and lipolytic bacteria, LPC, or PBC-LPC in bulk tank milk were not affected by temperature or duration of storage. Presumptive B. cereus were detected in 10% of all bulk tank milk samples taken over the two 6-wk periods, with similar proportions observed in both. In bulk tank milk samples, a greater incidence of SRC was observed in period 2 (20%) compared with period 1 (3%). Milk produced on-farm with minimal bacterial contamination can be successfully stored at 2 degrees C and 4 degrees C for up to 96h with little effect on its microbial quality. PMID- 26947310 TI - Single motherhood and neonatal and infant mortality in Sierra Leone, Burkina Faso and Burundi. AB - BACKGROUND: Childhood mortality is a stubborn problem and remains highest in Sub Saharan Africa (SSA). Existing research on childhood mortality in SSA indicate that most of the childhood deaths are from preventable causes such as diarrhoea, pneumonia, measles, malaria, HIV and underlying malnutrition, acute respiratory infections, whooping cough, tuberculosis, bronchopneumonia, dirty feeding bottles and utensils, inadequate disposal of household refuse and poor storage of drinking water. However, insufficient attention has been given to maternal marital status and childhood mortality relationships. Understanding the implications of maternal marital status for childhood mortality can add to our knowledge of the correlates of neonatal and infant mortality and furnish insights to support the design and delivery of interventions to address the problem. OBJECTIVE: To document and examine the extent to which the association between neonatal and infant mortality varies between single and ever-married mothers in Sierra Leone, Burkina Faso, and Burundi. A single mother is defined in this study as a woman who has either lived with a partner, married before, widowed, separated during the survey periods and has given at least one life birth. Ever married woman is woman who has been married at least once in their lives although their current marital status may not be married. STUDY DESIGN: Data for this study were drawn from the latest Demographic and Health Surveys (DHS) in Burkina Faso, Sierra Leone and Burundi. The selected datasets came from 2010 Burkina Faso DHS (BFDHS), 2008 Sierra Leone DHS (SLDHS) and 2010 Burundi DHS (EDSB II). METHODS: The relevant data for this study (women age 15-49 years who had at least one live birth within the five years preceding the survey) were extracted from the whole dataset of each country (Burkinabe (n = 17,087), Sierra Leonean (n = 7374) and Burundian (n = 9389). Univariate and multivariate statistical analyses were used to assess the association between neonatal and infant mortality and maternal marital status. All data were analysed using STATA Version 11. RESULTS: The multivariate logistic regression analyses yielded significantly increased risk of neonatal and infant mortality among single mothers. CONCLUSIONS: Neonates and infants of single mothers are at increased risk of neonatal and infant mortality compared to those of ever-married women. PMID- 26947311 TI - Problems with cigarette smoking and attitudes towards the ban of smoking in Shantou, China. AB - OBJECTIVES: To investigate the extent of cigarette smoking, knowledge of health hazards and attitudes towards the ban of smoking in Shantou, China, as causes for failure to control smoking. STUDY DESIGN: Environmental monitoring and population survey. METHODS: Particulate matter (PM2.5) measurements were conducted in randomly selected public places (restaurants, non-alcoholic drink shops and internet bars) and exposure-related health hazards were evaluated. University students and adult citizens were randomly selected to determine their extent of cigarette smoking, knowledge of health hazards and attitude towards the ban of smoking in public places. The collected data were used to evaluate possible causes and solutions to the smoking problem. RESULTS: From PM2.5 measurements, the average indoor to outdoor concentrations in non-smoking restaurants were 33.4 vs. 30.6 MUg/m(3), P > 0.05; average indoor of smoking restaurants was 350.0% higher, P < 0.05; internet bars was 395.7% higher, P < 0.05; and non-alcoholic drink shops was 650.2% higher, P > 0.001. From our survey of 1100 university students: 1) 17.5% and 7.5% were active male and female smokers, respectively; and 2) 57.5% of students would accept a smoke-ban policy. From 502 adult citizens: 1) 27.5% were active male smokers; 2) Approximately 40 and 60% had inadequate knowledge of health hazards from smoking and second-hand smoke exposure; and 3) >90% of them would accept a smoke-ban policy. CONCLUSIONS: Our data indicate that failure to ban smoking was not caused by resistance from smokers but inadequate (national and local) government effort to educate the public and to enforce existing policy. The data suggest that development of a citizen-based approach, in collaboration with willing officials, may be highly successful in the control of cigarette smoking in China. PMID- 26947312 TI - Active commuting reduces sociodemographic differences in adherence to recommendations derived from leisure-time physical activity among Brazilian adults. AB - OBJECTIVE: To investigate the consequences of including active commuting, compared with the leisure domain only, in the prevalence and sociodemographic factors associated with attending the physical activity recommendations, in Brazilian adults. STUDY DESIGN: Population-based cross-sectional study. METHOD: Adults between 20 and 59 years of age (n = 1720) were face-to-face interviewed from September 2009 to January 2010. Sociodemographic indicators and leisure-time and commuting physical activity were assessed by a validated questionnaire. Poisson regression was used to estimate crude and adjusted prevalence ratio (PR) and 95% confidence interval (95% CI). RESULTS: The prevalence of adherence to recommendations when only leisure-time physical activity was considered was 15.5% (95% CI: 13.6; 17.4) and was associated with men (PR: 1.57, 95% CI: 1.25; 1.96), adults without a partner (PR: 1.38 95% CI: 1.05; 1.81) and higher educational level and income. The prevalence of adherence to physical activity recommendations after the combination of leisure-time and commuting was 29.1% (95% CI: 26.5; 31.6). Percentages differences in favor of men, white adults and those with higher educational level and income were no longer significant after the inclusion of active commuting. CONCLUSION: The inclusion of active commuting expands the percentage of adults who achieved the health-related physical activity recommendations and reduced important sociodemographic differences derived from the analysis of leisure-time physical activity alone. Public health strategies should consider the different domains of physical activity in the monitoring and promotion of a more active lifestyle. PMID- 26947314 TI - Combination Therapy of Denosumab and Calcitriol for a Renal Transplant Recipient with Severe Bone Loss due to Therapy-Resistant Hyperparathyroidism. AB - Denosumab (DMAb), a complete human type monoclonal antibody directed against the receptor activator of nuclear factor-kappaB ligand, has gained attention as a novel treatment for osteoporosis. However, its efficacy in patients with chronic kidney disease (CKD) remains unclear. We describe a 64-year-old man with severe bone loss and persistent secondary hyperparathyroidism (SHPT) after renal transplantation, whose condition failed to respond to conventional pharmacologic or surgical interventions. He underwent parathyroidectomy with left forearm autograft of crushed tiny parathyroid gland (PTG) particles. However, the autografted PTGs became swollen and caused persistent SHPT in spite of two additional parathyroidectomies of the left forearm. A single subcutaneous administration of DMAb induced hypocalcemia, which was corrected by calcium supplementation and high-dose calcitriol. Eventually, combination therapy with DMAb and calcitriol led to a decline in the patient's elevated serum parathyroid hormone levels, normalization of laboratory markers of bone metabolism, and improvement in bone mineral density in a short period of time. To the best of our knowledge, this is the first case report of severe bone loss with persistent SHPT in a renal transplant recipient effectively treated with the combination therapy of DMAb and vitamin D (VD). Although DMAb itself exerts no direct effects on PTGs, the DMAb treatment improved the patient's bone loss. In addition, administration of DMAb allowed for high-dose VD therapy which ultimately controlled SHPT and prevented DMAb-induced hypocalcemia. Therefore, this combination therapy might be a reasonable therapeutic strategy to reverse severe bone loss due to therapy-resistant SHPT in patients with CKD. PMID- 26947315 TI - Treadmill Training with Virtual Reality Improves Gait, Balance, and Muscle Strength in Children with Cerebral Palsy. AB - Independent walking is an important goal of clinical and community-based rehabilitation for children with cerebral palsy (CP). Virtual reality-based rehabilitation therapy is effective in motivating children with CP. This study investigated the effects of treadmill training with virtual reality on gait, balance, muscular strength, and gross motor function in children with CP. Eighteen children with spastic CP were randomly divided into the virtual reality treadmill training (VRTT) group (9 subjects, mean age, 10.2 years) and treadmill training (TT) group (9 subjects, mean age, 9.4 years). The groups performed their respective programs as well as conventional physical therapy 3 times/week for 8 weeks. Muscle strength was assessed using a digitalized manual muscle tester. Gross motor function was assessed using the Gross Motor Functional Measure (GMFM). Balance was assessed using the Pediatric Balance Scale (PBS). Gait speed was assessed using the 10-meter walk test (10MWT), and gait endurance was assessed using the 2-minute walk test (2MWT). After training, gait and balance was improved in the VRTT compared to the TT group (P < 0.05). Muscular strength was significantly greater in the VRTT group than the TT group, except for right hamstring strength. The improvements in GMFM (standing) and PBS scores were greater in the VRTT group than the TT group (P < 0.05). Furthermore, the VRTT group showed the higher values of 10MWT and 2MWT compared to the TT group (P < 0.05). In conclusion, VRTT programs are effective for improving gait, balance, muscular strength, and gross motor function in children with CP. PMID- 26947313 TI - Strategies for delivery of HIV test results in population-based HIV seroprevalence surveys: a review of the evidence. AB - OBJECTIVES: Many population-based demographic surveys assess local and national HIV prevalence in developing countries through home-based HIV testing and counselling (HBHTC), but results are rarely returned to participants. This review gathered evidence on the feasibility and best practices of providing HIV test results during such surveys by reviewing population-based surveys that provided test results. STUDY DESIGN: Literature review. METHODS: This review was conducted as part of a broader literature review related to HBHTC. We present results from population-based HIV seroprevalence surveys conducted between January 1984 and June 2013. RESULTS: We identified eighteen population-based surveys describing uptake of results when testing or results were offered in the home, four of which compare home uptake to facility-based testing. All were from Sub-Saharan Africa. More people tested and received results in HBHTC compared to facility-based testing. Uptake of test results (72%) and the percentage of the population tested (59%) was highest when testing and the provision of results were provided in the home compared to the provision of results elsewhere (41% uptake; 37% population coverage), as well as mobile/facility-based testing and the provision of results (15% uptake; 13% population coverage). Providing results the same day as testing in HBHTC produces higher uptake (97% uptake; 74% population coverage) than delayed results. CONCLUSIONS: Inclusion of home testing and provision of HIV results to participants in national population-based surveys in Sub-Saharan Africa is possible and should be prioritized. The timing and location of testing and the provision of results during HBHTC as part of population-based surveys affects uptake of testing and population coverage. PMID- 26947316 TI - Organisation of Prostate Cancer Services in the English National Health Service. AB - AIMS: The National Prostate Cancer Audit (NPCA) started in April 2013 with the aim of assessing the process of care and its outcomes in men diagnosed with prostate cancer in England and Wales. One of the key aims of the audit was to assess the configuration and availability of specialist prostate cancer services in England. MATERIALS AND METHODS: In 2014, the NPCA undertook an organisational survey of all 143 acute National Health Service (NHS) Trusts and 48 specialist multidisciplinary team (MDT) hubs cross England. Questionnaires established the availability and location of core diagnostic, treatment and patient-centred support services for the management of non-metastatic prostate cancer in addition to specific diagnostic and treatment procedures that reflect the continuing evolution of prostate cancer management, such as high-intensity focused ultrasound (HIFU) and stereotactic body radiotherapy. RESULTS: The survey received a 100% response rate. The results showed considerable geographical variation with respect to the availability of core treatment modalities, the size of the target population and catchment areas served by specialist MDT hubs, as well as in the uptake of additional procedures and services. Specifically there are gaps in the availability of core radiotherapy procedures; high dose rate and low dose rate brachytherapy are available in 44% and 75% of specialist MDTs, respectively. By comparison, there seems to be a relative 'over-penetration' of surgical innovation, with 67% of specialist MDTs providing robotic-assisted laparoscopic prostatectomy and 21% HIFU. There is also evidence of increased centralisation of core surgical procedures and regional inequity in the availability of surgical innovation across England. CONCLUSIONS: The organisational survey of the NPCA has provided a comprehensive assessment of the structure and function of specialist MDTs in England and the availability of prostate cancer procedures and services. As part of the prospective audit, the NPCA will assess the effect of the availability of prostate cancer services on access regionally and subsequent outcomes of care according to evidence-based guidelines. PMID- 26947317 TI - Ultra high temperature gasification of municipal wastewater primary biosolids in a rotary kiln reactor for the production of synthesis gas. AB - Primary Fine-Sieved Solids (PFSS) are produced from wastewater by the use of micro-sieves, in place of primary clarification. Biosolids is considered as a nuisance product, however, it contains significant amounts of energy, which can be utilized by biological (anaerobic digestion) or thermal (combustion or gasification) processes. In the present study, an semi-industrial scale UHT rotary kiln gasifier, operating with electric energy, was employed for the gasification of PFSS (at 17% moisture content), collected from a municipal wastewater treatment plant. Two gasification temperatures (950 and 1050 degrees C) had been tested, with minimal differences, with respect to syngas yield. The system appears to reach steady state after about 30-40 min from start up. The composition of the syngas at near steady state was measured approximately as 62.4% H2, 30.0% CO, 2.4% CH4 and 3.4% CO2, plus 1.8% unidentified gases. The potential for electric energy production from the syngas produced is theoretically greater than the electric energy required for gasification. Theoretically, approximately 3.8 MJ/kg PFSS of net electric energy may be produced. However, based on the measured electric energy consumption, and assuming that all the syngas produced is used for electric energy production, addition of excess electric energy (about 0.43 MJ/kg PFSS) is required to break even. The latter is probably due to heat losses to the environment, during the heating process. With the improvement of energy efficiency, the process can be self sustained, form the energy point of view. PMID- 26947318 TI - Degradation of olive mill wastewater by the induced extracellular ligninolytic enzymes of two wood-rot fungi. AB - Olive mill wastewater (OMWW) is a major problem in olive oil - producing countries, due to its high organic load and concentration in phenols that are toxic for marine life, plants and soil microorganisms. In the present study, two mushroom species were tested in regard to their OMWW's oxidative capacity, Pleurotus citrinopileatus LGAM 28684 and Irpex lacteus LGAM 238. OMWW (25% v/v) degradation was investigated for several culture conditions, namely pH, agitation speed, nitrogen-based supplements and their concentration. The selected values were pH 6, agitation rate 150 rpm, 30 g L-1 corn steep liquor as nitrogen source for P. citrinopileatus and 20 g L-1 diammonium tartrate for I. lacteus. The two strains performed well in cultures supplemented with OMWW, generating very high titers of oxidative enzymes and achieving more than 90% color and phenols reduction within a 24 days cultivation period. In addition, the amount of glucans present in the fungal biomass was assessed. Hence, P. citrinopileatus and I. lacteus appear as potent degraders of OMWW with the ability to use the effluent as a substrate for the production of biotechnologically important enzymes and valuable fungal glucans. PMID- 26947319 TI - Analytical strategies to assess the functional metabolome of vitamin E. AB - After more than 90 years from its discovery and thousands of papers published, the physiological roles of vitamin E (tocopherols and tocotrienols) are still not fully clarified. In the last few decades, the enzymatic metabolism of this vitamin has represented a stimulating subject of research. Its elucidation has opened up new horizons to the interpretation of the biological function of that class of molecules. The identification of specific properties for some of the physiological metabolites and the definition of advanced analytical techniques to assess the human metabolome of this vitamin in vivo, have paved the way to a series of hypotheses on the functional implications that this metabolism may have far beyond its catabolic role. The present review collects the available information on the most relevant analytical strategies employed to assess the status and metabolism of vitamin E in humans as well as in other model systems. A particular focus is dedicated to the analytical methods used to measure vitamin E metabolites, and particularly long-chain metabolites, in biological fluids and tissues. Preliminary information on a new LC-APCI-MS/MS method to measure these metabolites in human serum is reported. PMID- 26947321 TI - Food, hunger, health, and climate change. PMID- 26947320 TI - High-dose-rate interstitial brachytherapy in oral cancer-Its impact on quality of life. AB - PURPOSE: The aim of the study was to assess the impact of high-dose-rate (HDR) interstitial brachytherapy on quality of life (QOL) in oral cancer. METHODS AND MATERIALS: Thirty-two patients of oral cancer treated at our institute from January 2010 to December 2014 with radical radiotherapy (external beam radiotherapy + brachytherapy) were included for analysis; 30 patients received external beam radiotherapy (50-54 Gy) and HDR brachytherapy boost (18-24.5 Gy); 2 patients received radical HDR brachytherapy (31.5 Gy). Quality of life (QOL) was assessed by Telugu, Hindi, and English versions of EORTC Quality of Life Core-30 and EORTC Quality of Life Head and Neck Module (QLQ H&N35) before treatment, at 3 months, 6 months, 1 year, and 2 years after treatment. RESULTS: Of the 32 patients, 2 patients died and 1 patient progressed on followup; 2 patients were re-irradiation cases. On excluding these cases, 27 patients were available for analysis. The followup duration was 6-55 months. At the time of analysis, 91% (29) patients were disease free, 3% (1) progressed, and 6% (2) died. At the end of 2 years, none of the QLQ-C30 functional scores fell below the baseline. Pain, swallowing, sensory, speech, social contact, and social eating worsened at 3 months but improved over 2 years (p < 0.001). Sexuality and financial status showed delayed improvement (p < 0.001). Among the head and neck parameters, dry mouth and sticky saliva were significant determinants of QOL with delayed improvement (p < 0.001). The impact of age, sex, and tumor stage and on QOL was analyzed. Women reported a poorer QOL for physical and emotional parameters, social eating, weight loss, and fatigue. Tumor stage significantly affected QOL, with early stages showing a better QOL. CONCLUSIONS: Almost all patients regained normal function after treatment and reported an excellent QOL at 2 years. However, tumor stage significantly affected the QOL. PMID- 26947322 TI - Global and regional health effects of future food production under climate change: a modelling study. AB - BACKGROUND: One of the most important consequences of climate change could be its effects on agriculture. Although much research has focused on questions of food security, less has been devoted to assessing the wider health impacts of future changes in agricultural production. In this modelling study, we estimate excess mortality attributable to agriculturally mediated changes in dietary and weight related risk factors by cause of death for 155 world regions in the year 2050. METHODS: For this modelling study, we linked a detailed agricultural modelling framework, the International Model for Policy Analysis of Agricultural Commodities and Trade (IMPACT), to a comparative risk assessment of changes in fruit and vegetable consumption, red meat consumption, and bodyweight for deaths from coronary heart disease, stroke, cancer, and an aggregate of other causes. We calculated the change in the number of deaths attributable to climate-related changes in weight and diets for the combination of four emissions pathways (a high emissions pathway, two medium emissions pathways, and a low emissions pathway) and three socioeconomic pathways (sustainable development, middle of the road, and more fragmented development), which each included six scenarios with variable climatic inputs. FINDINGS: The model projects that by 2050, climate change will lead to per-person reductions of 3.2% (SD 0.4%) in global food availability, 4.0% (0.7%) in fruit and vegetable consumption, and 0.7% (0.1%) in red meat consumption. These changes will be associated with 529,000 climate related deaths worldwide (95% CI 314,000-736,000), representing a 28% (95% CI 26 33) reduction in the number of deaths that would be avoided because of changes in dietary and weight-related risk factors between 2010 and 2050. Twice as many climate-related deaths were associated with reductions in fruit and vegetable consumption than with climate-related increases in the prevalence of underweight, and most climate-related deaths were projected to occur in south and east Asia. Adoption of climate-stabilisation pathways would reduce the number of climate related deaths by 29-71%, depending on their stringency. INTERPRETATION: The health effects of climate change from changes in dietary and weight-related risk factors could be substantial, and exceed other climate-related health impacts that have been estimated. Climate change mitigation could prevent many climate related deaths. Strengthening of public health programmes aimed at preventing and treating diet and weight-related risk factors could be a suitable climate change adaptation strategy. FUNDING: Oxford Martin Programme on the Future of Food. PMID- 26947323 TI - [An atypical form of ocular involvement in cat scratch disease]. PMID- 26947324 TI - [HIV-associated conjunctivo-palpebral Kaposi's sarcoma: A case report]. PMID- 26947325 TI - A huge corneoscleral cyst. PMID- 26947326 TI - [Melanoma associated retinopathy: A case report]. PMID- 26947327 TI - Polyglutamine Fibrils: New Insights into Antiparallel beta-Sheet Conformational Preference and Side Chain Structure. AB - Understanding the structure of polyglutamine (polyQ) amyloid-like fibril aggregates is crucial to gaining insights into the etiology of at least ten neurodegenerative disorders, including Huntington's disease. Here, we determine the structure of D2Q10K2 (Q10) fibrils using ultraviolet resonance Raman (UVRR) spectroscopy and molecular dynamics (MD). Using UVRR, we determine the fibril peptide backbone Psi and glutamine (Gln) side chain chi3 dihedral angles. We find that most of the fibril peptide bonds adopt antiparallel beta-sheet conformations; however, a small population of peptide bonds exist in parallel beta-sheet structures. Using MD, we simulate three different potential fibril structural models that consist of either beta-strands or beta-hairpins. Comparing the experimentally measured Psi and chi3 angle distributions to those obtained from the MD simulated models, we conclude that the basic structural motif of Q10 fibrils is an extended beta-strand structure. Importantly, we determine from our MD simulations that Q10 fibril antiparallel beta-sheets are thermodynamically more stable than parallel beta-sheets. This accounts for why polyQ fibrils preferentially adopt antiparallel beta-sheet conformations instead of in-register parallel beta-sheets like most amyloidogenic peptides. In addition, we directly determine, for the first time, the structures of Gln side chains. Our structural data give new insights into the role that the Gln side chains play in the stabilization of polyQ fibrils. Finally, our work demonstrates the synergistic power and utility of combining UVRR measurements and MD modeling to determine the structure of amyloid-like fibrils. PMID- 26947328 TI - Metformin for chemoprevention of metachronous colorectal adenoma or polyps in post-polypectomy patients without diabetes: a multicentre double-blind, placebo controlled, randomised phase 3 trial. AB - BACKGROUND: The prevalence of, and mortality from, colorectal cancer is increasing worldwide, and new strategies for prevention are needed to reduce the burden of this disease. The oral diabetes medicine metformin might have chemopreventive effects against cancer, including colorectal cancer. However, no clinical trial data exist for the use of metformin for colorectal cancer chemoprevention. Therefore, we devised a 1-year clinical trial to assess the safety and chemopreventive effects of metformin on sporadic colorectal cancer (assessed by adenoma and polyp recurrence) in patients with a high risk of adenoma recurrence. METHODS: This trial was a multicentre, double-blind, placebo controlled, randomised phase 3 trial. Non-diabetic adult patients who had previously had single or multiple colorectal adenomas or polyps resected by endoscopy were enrolled into the study from five hospitals in Japan. Eligible patients were randomly assigned (1:1) to receive oral metformin (250 mg daily) or identical placebo tablets by a stratified computer-based randomisation method, with stratification by institute, age, sex, and body-mass index. All patients, endoscopists, doctors, and investigators were masked to drug allocation until the end of the trial. After 1 year of administration of metformin or placebo, colonoscopies were done to assess the co-primary endpoints: the number and prevalence of adenomas or polyps. Our analysis included all participants who underwent random allocation, according to the intention-to-treat principle. This trial is registered with University Hospital Medical Information Network (UMIN), number UMIN000006254. FINDINGS: Between Sept 1, 2011, and Dec 30, 2014, 498 patients who had had single or multiple colorectal adenomas resected by endoscopy were enrolled into the study. After exclusions for ineligibility, 151 patients underwent randomisation: 79 were assigned to the metformin group and 72 to the placebo group. 71 patients in the metformin group and 62 in the placebo group underwent 1-year follow-up colonoscopy. The prevalence of total polyps (hyperplastic polyps plus adenomas) and of adenomas in the metformin group was significantly lower than that in the placebo group (total polyps: metformin group 27 [38.0%; 95% CI 26.7-49.3] of 71 patients, placebo group 35 [56.5%; 95% CI 44.1 68.8] of 62; p=0.034, risk ratio [RR] 0.67 [95% CI 0.47-0.97]; adenomas: metformin group 22 [30.6%; 95% CI 19.9-41.2] of 71 patients, placebo group 32 [51.6%; 95% CI 39.2-64.1] of 62; p=0.016, RR 0.60 [95% CI 0.39-0.92]). The median number of polyps was zero (IQR 0-1) in the metformin group and one (0-1) in the placebo group (p=0.041). The median number of adenomas was zero (0-1) in the metformin group and zero (0-1) in the placebo group (p=0.037). 15 (11%) of patients had adverse events, all of which were grade 1. We recorded no serious adverse events during the 1-year trial. INTERPRETATION: The administration of low dose metformin for 1 year to patients without diabetes was safe. Low-dose metformin reduced the prevalence and number of metachronous adenomas or polyps after polypectomy. Metformin has a potential role in the chemoprevention of colorectal cancer. However, further large, long-term trials are needed to provide definitive conclusions. FUNDING: Ministry of Health, Labour and Welfare, Japan. PMID- 26947329 TI - Palbociclib: efficacious but predictive biomarkers still needed. PMID- 26947330 TI - Metformin for cancer prevention: a reason for optimism. PMID- 26947331 TI - Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. AB - BACKGROUND: In the PALOMA-3 study, the combination of the CDK4 and CDK6 inhibitor palbociclib and fulvestrant was associated with significant improvements in progression-free survival compared with fulvestrant plus placebo in patients with metastatic breast cancer. Identification of patients most suitable for the addition of palbociclib to endocrine therapy after tumour recurrence is crucial for treatment optimisation in metastatic breast cancer. We aimed to confirm our earlier findings with this extended follow-up and show our results for subgroup and biomarker analyses. METHODS: In this multicentre, double-blind, randomised phase 3 study, women aged 18 years or older with hormone-receptor-positive, HER2 negative metastatic breast cancer that had progressed on previous endocrine therapy were stratified by sensitivity to previous hormonal therapy, menopausal status, and presence of visceral metastasis at 144 centres in 17 countries. Eligible patients-ie, any menopausal status, Eastern Cooperative Oncology Group performance status 0-1, measurable disease or bone disease only, and disease relapse or progression after previous endocrine therapy for advanced disease during treatment or within 12 months of completion of adjuvant therapy-were randomly assigned (2:1) via a centralised interactive web-based and voice-based randomisation system to receive oral palbociclib (125 mg daily for 3 weeks followed by a week off over 28-day cycles) plus 500 mg fulvestrant (intramuscular injection on days 1 and 15 of cycle 1; then on day 1 of subsequent 28-day cycles) or placebo plus fulvestrant. The primary endpoint was investigator-assessed progression-free survival. Analysis was by intention to treat. We also assessed endocrine therapy resistance by clinical parameters, quantitative hormone receptor expression, and tumour PIK3CA mutational status in circulating DNA at baseline. This study is registered with ClinicalTrials.gov, NCT01942135. FINDINGS: Between Oct 7, 2013, and Aug 26, 2014, 521 patients were randomly assigned, 347 to fulvestrant plus palbociclib and 174 to fulvestrant plus placebo. Study enrolment is closed and overall survival follow-up is in progress. By March 16, 2015, 259 progression-free-survival events had occurred (145 in the fulvestrant plus palbociclib group and 114 in the fulvestrant plus placebo group); median follow-up was 8.9 months (IQR 8.7-9.2). Median progression-free survival was 9.5 months (95% CI 9.2-11.0) in the fulvestrant plus palbociclib group and 4.6 months (3.5-5.6) in the fulvestrant plus placebo group (hazard ratio 0.46, 95% CI 0.36-0.59, p<0.0001). Grade 3 or 4 adverse events occurred in 251 (73%) of 345 patients in the fulvestrant plus palbociclib group and 38 (22%) of 172 patients in the fulvestrant plus placebo group. The most common grade 3 or 4 adverse events were neutropenia (223 [65%] in the fulvestrant plus palbociclib group and one [1%] in the fulvestrant plus placebo group), anaemia (ten [3%] and three [2%]), and leucopenia (95 [28%] and two [1%]). Serious adverse events (all causalities) occurred in 44 patients (13%) of 345 in the fulvestrant plus palbociclib group and 30 (17%) of 172 patients in the fulvestrant plus placebo group. PIK3CA mutation was detected in the plasma DNA of 129 (33%) of 395 patients for whom these data were available. Neither PIK3CA status nor hormone receptor expression level significantly affected treatment response. INTERPRETATION: Fulvestrant plus palbociclib was associated with significant and consistent improvement in progression-free survival compared with fulvestrant plus placebo, irrespective of the degree of endocrine resistance, hormone receptor expression level, and PIK3CA mutational status. The combination could be considered as a therapeutic option for patients with recurrent hormone-receptor positive, HER2-negative metastatic breast cancer that has progressed on previous endocrine therapy. FUNDING: Pfizer. PMID- 26947332 TI - Rosiglitazone attenuates inflammation and CA3 neuronal loss following traumatic brain injury in rats. AB - Rosiglitazone, a potent peroxisome proliferator-activated receptor (PPAR)-gamma agonist, has been shown to confer neuroprotective effects in stroke and spinal cord injury, but its role in the traumatic brain injury (TBI) is still controversial. Using a controlled cortical impact model in rats, the current study was designed to determine the effects of rosiglitazone treatment (6 mg/kg at 5 min, 6 h and 24 h post injury) upon inflammation and histological outcome at 21 d after TBI. In addition, the effects of rosiglitazone upon inflammatory cytokine transcription, vestibulomotor behavior and spatial memory function were determined at earlier time points (24 h, 1-5 d, 14-20 d post injury, respectively). Compared with the vehicle-treated group, rosiglitazone treatment suppressed production of TNFalpha at 24 h after TBI, attenuated activation of microglia/macrophages and increased survival of CA3 neurons but had no effect on lesion volume at 21 d after TBI. Rosiglitazone-treated animals had improved performance on beam balance testing, but there was no difference in spatial memory function as determined by Morris water maze. In summary, this study indicates that rosiglitazone treatment in the first 24 h after TBI has limited anti-inflammatory and neuroprotective effects in rat traumatic injury. Further study using an alternative dosage paradigm and more sensitive behavioral testing may be warranted. PMID- 26947333 TI - Type 1 5'-deiodinase activity is inhibited by oxidative stress and restored by alpha-lipoic acid in HepG2 cells. AB - 3,3',5-triiodothyronine (T3) is largely generated from thyroxine (T4) by the catalysis of deiodinases in peripheral tissues. Emerging evidences have indicated its broad participation in regulating various metabolic process via protecting tissues from oxidative stress and improving cellular antioxidant capacity. However, the potential correlation between the oxidative stress and conversion of T4 to T3 is still unclear. In the present study, the effects of T3 and T4 on redox homeostasis in HepG2 cells pre-treated with H2O2 was investigated. It revealed that T3 significantly rescued the apoptotic cell death, consistent with an upregulation of cell antioxidant ability and reduction of ROS accumulation while T4 did not. Afterwards, we examined the enzyme activity and mRNA expression of type 1 5'-deiodianse (DIO1), T3 and rT3 level and found that H2O2 reduced both DIO1 activity and expression in a dose-dependent manner, which consequently declined T3 and rT3 generation. Alpha-lipoic acid (LA) treatment notably restored DIO1 activity, T3 and rT3 level, as well as transcriptional abnormalities of inflammation-associated genes. It suggests that oxidative stress may reduce DIO1 activity by an indirect way like activating cellular inflammatory responses. All these results indicate that the oxidative stress downregulates the conversion of T4 to T3 through DIO1 function in HepG2 cells. PMID- 26947334 TI - Copper-catalyzed radical reactions of 2-azido-N-arylacrylamides with 1 (trifluoromethyl)-1,2-benziodoxole and 1-azidyl-1,2-benziodoxole. AB - The reactions of 2-azido-N-arylacrylamides with trifluoromethyl radicals and azidyl radicals were investigated by using Togni's reagent and Zhdankin's reagent as the source of these radicals. Under the catalysis of CuI, Togni's reagent was firstly converted into the trifluoromethyl radical, which then reacted with 2 azido-N-arylacrylamides to afford the corresponding alpha (arylaminocarbonyl)iminyl radicals. The cyclization of the iminyl radicals delivered quinoxalin-2(1H)-one products in moderate yields. A similar reaction took place between 2-azido-N-arylacrylamides and the azidyl radical. In the latter cases, the reaction produced 3-azidomethyl and 3-cyano-subsituted quinoxalin-2(1H)-ones. This study not only helps elucidate the factors influencing the cyclization of alpha-(arylaminocarbonyl)iminyl radicals, but also provides a new approach towards quinoxalin-2-ones. PMID- 26947335 TI - Abnormal white matter integrity as a structural endophenotype for bipolar disorder. AB - BACKGROUND: Several lines of evidence suggest that bipolar disorder (BD) is associated with white matter (WM) pathology. Investigation of unaffected first degree relatives of BD patients may help to distinguish structural biomarkers of genetic risk without the confounding effects of burden of illness, medication or clinical state. In the present study, we applied tract-based spatial statistics to study WM changes in patients with BD, unaffected siblings and controls. METHOD: A total of 27 euthymic patients with BD type I, 20 unaffected siblings of bipolar patients and 29 healthy controls who did not have any current or past diagnosis of Axis I psychiatric disorders were enrolled in the study. RESULTS: Fractional anisotropy (FA) was significantly lower in BD patients than in the control group in the corpus callosum, fornix, bilateral superior longitudinal fasciculus, inferior longitudinal fasciculus, inferior fronto-occipital fasciculus, anterior thalamic radiation, posterior thalamic radiation, cingulum, uncinate fasciculus, superior corona radiata, anterior corona radiata and left external capsule. In region-of-interest (ROI) analyses, we found that both unaffected siblings and bipolar patients had significantly reduced FA in the left posterior thalamic radiation, the left sagittal stratum, and the fornix compared with healthy controls. Average FA for unaffected siblings was intermediate between the healthy controls and bipolar patients within these ROIs. CONCLUSIONS: Decreased FA in the fornix, left posterior thalamic radiation and left sagittal stratum in both bipolar patients and unaffected siblings may represent a potential structural endophenotype or a trait-based marker for BD. PMID- 26947336 TI - Nanocrystalline SSZ-39 zeolite as an efficient catalyst for the methanol-to olefin (MTO) process. AB - The synthesis of nanosized SSZ-39 zeolite has been achieved using a high silica FAU zeolite as the Si and Al source and tetraethylphosphonium (TEP) cations as OSDAs. The obtained SSZ-39 material shows a remarkably high catalyst lifetime compared to conventional SSZ-13 and SSZ-39 materials. PMID- 26947337 TI - Higher Adherence to the Australian Dietary Guidelines Is Associated with Better Mental Health Status among Australian Adult First-Time Mothers. AB - BACKGROUND: Mental health disorders are a leading cause of disability worldwide, including in first-time mothers. Understanding the associations between diet and depressive symptoms could assist in improving mental health status in this group. OBJECTIVE: Our aim was to determine the association between diet quality, fruit, vegetable, and fish consumption and depressive symptoms in first-time mothers aged 19 to 45 years. DESIGN: We analyzed cross-sectional, baseline data (3 months postpartum) from the Melbourne InFANT (Infant Feeding, Activity, and Nutrition Trial) Extend Program. PARTICIPANTS/SETTING: Participants were first-time Australian mothers aged 19 to 45 years from the Geelong and Melbourne regions of Victoria, Australia (n=457). MAIN OUTCOME MEASURES: A self-administered, 137-item food frequency questionnaire assessed dietary intake over the past year. Adherence to the 2013 Australian Dietary Guidelines was assessed using the Dietary Guideline Index as a measure of diet quality. Depressive symptoms were determined using the Center for Epidemiologic Studies Depression Scale. STATISTICAL ANALYSIS PERFORMED: Relationships between diet quality, fruit, vegetable, and fish intake and depressive symptoms were investigated using linear regression adjusted for relevant covariates (age, smoking status, sleep quality, education, physical activity status, and body mass index). RESULTS: Better diet quality, as indicated by a higher score on the Dietary Guideline Index, was associated with lower depressive symptoms after adjusting for relevant covariates (beta=-.034; 95% CI -.056 to -0.012). There were no other associations between dietary intake and depressive symptoms. CONCLUSIONS: Adherence to the Australian Dietary Guidelines was associated with better mental health status among first time mothers. Further research, including longitudinal and intervention studies, are required to determine causality between dietary intake and depressive symptoms, which might help inform future public health nutrition programs for this target group. PMID- 26947338 TI - The Effects of Increased Protein Intake on Fullness: A Meta-Analysis and Its Limitations. AB - BACKGROUND: Higher protein intake has been implicated in weight management because of its appetitive properties. However, the effects of protein intake on appetitive sensations such as fullness have not been systematically assessed. Meta-analysis is a useful technique to evaluate evidence of an intervention's effect on testable outcomes, but it also has important limitations. OBJECTIVE: The primary aim of this study was to synthesize the available evidence on the effect of protein intake on fullness using a quantitative meta-analysis and a secondary directional analysis using the vote-counting procedure. A tertiary aim was to address limitations of meta-analyses as they pertain to findings from this meta-analysis. DESIGN: We searched multiple databases for interventional studies that evaluated the effect of increased protein intake on fullness ratings. Inclusion criteria for both analyses were as follows: healthy human participants, preload studies that utilized intact dietary protein, delivery of protein load orally, and studies reporting fullness as an outcome. For the meta-analysis, an additional criterion was that the studies also needed to report 2- to 4-hour area under the curve value for fullness. RESULTS: Five studies met all criteria for the meta-analysis. Twenty-eight studies met all criteria for the directional analysis. The meta-analysis indicated higher protein preloads have a greater effect on fullness than lower protein preloads (overall effect estimate: 2,435.74 mm.240 min, (95% CI 1,375.18 to 3,496.31 mm.240 min; P<0.0001). The directional analysis also revealed a positive effect on fullness with higher protein preloads (P<0.01). Many related scientifically rigorous studies were excluded from the analysis because analytical criteria required a narrowly focused research question. CONCLUSIONS: The present analyses show that higher protein preloads increase fullness ratings more than lower protein preloads under tightly defined conditions. Extrapolation of findings to common conditions outside the specified criteria of this analysis must be made cautiously, as must speculation about the influence of fullness sensations on ingestive behavior, body weight, and various health outcomes. PMID- 26947339 TI - Use of external orthotic helmet therapy in positional plagiocephaly. AB - Positional plagiocephaly is the most common type of cranial asymmetry affecting infants. We aimed to investigate the effectiveness of helmet therapy compared to no helmet therapy in treating positional plagiocephaly in infants under the age of 1year. This retrospective review was conducted in an Australian paediatric hospital and included 171 patients recruited from outpatient clinics. Only 30 patients had positional plagiocephaly scores recorded at first and final consultations while 39 patients had diagonal measurements recorded at both visits. The mean age was 7.38months at initial consultation with a mean follow-up duration of 5.85months. Those who had helmet therapy had a significantly greater reduction in diagonal difference than those who did not use helmets (p=0.011). Therefore, there may be a role for helmet therapy in the treatment of severe positional plagiocephaly. PMID- 26947340 TI - Hypofractionated stereotactic radiosurgery for treatment of cerebral arteriovenous malformations: outcome analysis with use of the modified arteriovenous malformation scoring system. AB - Radiosurgery has long been an accepted modality for definitive treatment of cerebral arteriovenous malformations (AVM). Efforts to improve the therapeutic ratio for this indication include use of staged volume procedures and hypofractionation. This study reviews our experience with a cohort of patients treated with hypofractionated radiosurgery. Over a 3year period, 38 patients harboring 39 cerebral AVM were treated with hypofractionated stereotactic radiotherapy. Seventeen of these patients presented due to hemorrhage, four were asymptomatic unruptured lesions and the remainder were symptomatic unruptured lesions. The median AVM volume was 11.43 cc and median modified Radiosurgery Based Arteriovenous Malformation Score (mRBAS) was 2.02. The median follow-up was 7.32years. Four patients harboring four AVM were lost to follow-up before a result could be ascertained leaving 35 AVM for analysis. Excellent outcomes (AVM obliteration without new deficits) occurred in 17 of 34 (50%) patients and in 18 of 35 (51%) AVM treated. AVM obliteration was seen in 26 of 35 (74%) lesions treated. Two patients died during the follow-up period (6%). A poor result (major deficit without obliteration) was seen in one patient. Of 19 patients harboring AVM with mRBAS >2.0, an excellent outcome was achieved in eight (42%). Hypofractionation for cerebral AVM can result in satisfactory obliteration rates, but with risk of significant complications commensurate with mRBAS. Further study of this technique will be needed to ascertain the degree of incremental improvement, if any, over other radiosurgery treatment methods. PMID- 26947341 TI - Normalization of coagulopathy is associated with improved outcome after isolated traumatic brain injury. AB - Acute traumatic coagulopathy (ATC) has been reported in the setting of isolated traumatic brain injury (iTBI) and is associated with poor outcomes. We aimed to evaluate the effectiveness of procoagulant agents administered to patients with ATC and iTBI during resuscitation, hypothesizing that timely normalization of coagulopathy may be associated with a decrease in mortality. A retrospective review of the Alfred Hospital trauma registry, Australia, was conducted and patients with iTBI (head Abbreviated Injury Score [AIS] ?3 and all other body AIS <3) and coagulopathy (international normalized ratio ?1.3) were selected for analysis. Data on procoagulant agents used (fresh frozen plasma, platelets, cryoprecipitate, prothrombin complex concentrates, tranexamic acid, vitamin K) were extracted. Among patients who had achieved normalization of INR or survived beyond 24hours and were not taking oral anticoagulants, the association of normalization of INR and death at hospital discharge was analyzed using multivariable logistic regression analysis. There were 157 patients with ATC of whom 68 (43.3%) received procoagulant products within 24hours of presentation. The median time to delivery of first products was 182.5 (interquartile range [IQR] 115-375) minutes, and following administration of coagulants, time to normalization of INR was 605 (IQR 274-1146) minutes. Normalization of INR was independently associated with significantly lower mortality (adjusted odds ratio 0.10; 95% confidence interval 0.03-0.38). Normalization of INR was associated with improved mortality in patients with ATC in the setting of iTBI. As there was a substantial time lag between delivery of products and eventual normalization of coagulation, specific management of coagulopathy should be implemented as early as possible. PMID- 26947342 TI - Endovascular therapy including thrombectomy for acute ischemic stroke: A systematic review and meta-analysis with trial sequential analysis. AB - One of the primary strategies for the management of acute ischemic stroke is intravenous (IV) thrombolysis with tissue plasminogen activator (t-PA). Over the past decade, endovascular therapies such as the use of stent retrievers to perform mechanical thrombectomy have been found to improve functional outcomes compared to t-PA alone. We aimed to reassess the functional outcomes and complications of IV thrombolysis with and without endovascular treatment for acute ischemic stroke using conventional meta-analysis and trial sequential analysis. Pooled relative risks (RR) and 95% confidence intervals (CI) were calculated for the effect of IV thrombolysis with and without endovascular therapy on functional outcome, mortality and symptomatic intracranial hemorrhage (SICH). Trial sequential analysis was done to strengthen the meta-analysis. We analyzed six randomized controlled trials involving 1943 patients. Patients who received IV thrombolysis with endovascular treatment showed significantly higher rates of excellent functional outcomes (modified Rankin Scale [mRS] 0-1) (RR, 1.75 [95% CI, 1.29-2.39]) compared to those who received IV thrombolysis alone. A similar association was seen for good functional outcomes (mRS 0-2) (RR, 1.56 [95% CI, 1.24-1.96]). Trial sequential analysis demonstrated endovascular treatment increased the RR of a good functional outcome by at least 30% compared to IV thrombolysis alone. There was no significant difference in all-cause mortality for mechanical thrombectomy compared to IV thrombolysis alone or the incidence of SICH at 3month follow-up. Endovascular treatment is more likely to result in a better functional outcome for patients compared to IV thrombolysis alone for acute ischemic stroke. PMID- 26947348 TI - Protective effects of Urtica dioica seed extract in aflatoxicosis: histopathological and biochemical findings. AB - The ameliorative potential and antioxidant capacity of an extract of Urtica dioica seeds (UDS) was investigated using histopathological changes in liver and kidney, measuring serum marker enzymes, antioxidant defence systems and lipid peroxidation (malondialdehyde (MDA)) content in various tissues of broilers exposed to aflatoxin (AF). A total of 32 broilers were divided randomly into 4 groups: control, UDS extract-treated, AF-treated and AF+UDS extract-treated. Broilers in control and UDS extract-treated groups were fed on a diet without AF. The AF-treated group and AF+UDS extract-treated groups were treated with an estimated 1 mg total AF/kg feed. The AF+UDS extract groups received in addition 30 ml UDS extract/kg diet for 21 d. The AF-treated group had significantly decreased body weight gain when compared to the other groups. Biochemical analysis showed a small increase in the concentrations of serum aspartate aminotransferase, alanine aminotransferase, gamma glutamyl transpeptidase and lactate dehydrogenase in the AF-treated group compared to that of the control group, whereas concentrations of these enzymes were decreased in the AF+UDS group compared to that of the AF-treated group. Administration of supplementary UDS extract helped restore the AF-induced increase in MDA and reduced the antioxidant system towards normality, particularly in the liver, brain, kidney and heart. Hepatorenal protection by UDS extracts was further supported by the almost normal histology in AF+UDS extract-treated group as compared to the degenerative changes in the AF-treated broilers. It was concluded that UDS extract has a protective hepatorenal effect in broilers affected by aflatoxicosis, probably acting by promoting the antioxidative defence systems. PMID- 26947349 TI - Advanced Interfere Treatment of Diabetic Cardiomyopathy Rats by aFGF-Loaded Heparin-Modified Microbubbles and UTMD Technique. AB - This study aims to investigate the preclinical performance and mechanism of a novel strategy of aFGF-loaded heparin-modified microbubbles (aFGF-HMB) combined with ultrasound-targeted microbubble destruction (UTMD) technique for diabetic cardiomyopathy (DCM) prevention. Type 1 diabetic rats were induced by streptozotocin. Twelve weeks after intervention, indexes from transthoracic echocardiography and cardiac catheterization showed that the left ventricular function in the aFGF-HMB/UTMD group was significantly improved compared with diabetes control (DM). From Picrosirius Red staining and TUNEL staining, the aFGF HMB/UTMD group showed significant difference from the other groups. The cardiac collagen volume fraction (CVF) and myocardial cell apoptosis index (AI) in aFGF HMB/UTMD group decreased to 7.2 % and 7.11 % respectively, compared with the DM group (CVF = 24.5 % and AI =20.3 % respectively). The results of myocardial microvascular density (MCD) also proved the strongest inhibition of aFGF-HMB/UTMD group on DCM progress. CD31 staining of aFGF-HMB/UTMD group reached 22 n/hrp, much higher than that of DM group (9 n/hrp). These results confirmed that the abnormalities including left ventricular dysfunction, myocardial fibrosis, cardiomyocytes apoptosis and microvascular rarefaction could be suppressed by twice weekly aFGF treatments for 12 consecutive weeks (free aFGF or aFGF-HMB+/ UTMD), with the strongest improvements observed in the aFGF-HMB/UTMD group (P < 0.05 vs free aFGF or aFGF-HMB). Western blot analyses of heart tissue further revealed the highest aFGF, anti-apoptosis protein (Bcl-2), VEGF-C, pAkt, pFoxo-3a levels and strongest reduction in pro-apoptosis proteins (Bax) level in aFGF HMB/UTMD group. Overall, aFGF-HMB combined with UTMD technique might be developed as an effective strategy to prevent DCM in future clinical therapy. PMID- 26947351 TI - Optimization of a UDP-glucuronosyltransferase assay for trout liver S9 fractions: activity enhancement by alamethicin, a pore-forming peptide. AB - 1. An existing assay for UDP-glucuronosyltransferase (UGT) activity in trout liver microsomes was optimized using trout liver S9 fractions. Individual experiments were conducted to determine the time dependence of UGT activity as well as optimal levels of S9 protein, uridine 5'-diphosphoglucuronic acid (UDPGA), substrate (p-nitrophenol) and alamethicin, a pore-forming agent added to eliminate latency. 2. Addition of Mg2+ (to 1 mM) or bovine serum albumin (BSA; to 2% w/v) had variable effects on activity, but these effects were minor. Eliminating alamethicin from the system resulted in very low levels of activity. A portion of this activity could be recovered by adding Triton X-100 or Brij 58; however, the optimal concentration range for either detergent was very narrow. 3. When expressed on a pmol/min/g liver basis, UGT activities determined using this updated assay were substantially higher than those reported previously for uninduced trout. 4. These results clearly demonstrate the advantages of using alamethicin for the removal of latency in UGT activity studies with trout and may have broad implications for the study of UGTs in other fish species. PMID- 26947350 TI - Histological subtype of renal cell carcinoma significantly affects survival in the era of partial nephrectomy. AB - OBJECTIVES: To analyze whether the histological subtype of renal cell carcinoma (RCC) affects survival after surgical resection in contemporary patients, and if so, whether prognostic significance differs according to the type of surgical resection or tumor stage. MATERIALS AND METHODS: From 2006 to 2014, 2,237 patients underwent surgical resection (25% radical nephrectomy and 75% partial nephrectomy [PN]) for nonmetastatic RCC at a tertiary referral center. Estimated survival function curves and Cox regression models evaluated the effect of histological subtype on recurrence-free survival (RFS) and overall survival (OS). Interaction analyses tested whether the effect of histological subtype depends on the type of surgical resection or tumor stage. RESULTS: Patients with RCC stage T2 or lower and those with low-grade conventional clear cell, papillary or chromophobe RCC of any stage had 5-year RFS probabilities>90%. Patients with clear cell papillary RCC stage T3 or greater had predicted 5-year RFS of 81%. However, 5-year OS probabilities were>94% for clear cell papillary RCC of any stage. High-grade conventional clear cell and papillary RCC stage T2 or lower, low-grade conventional clear cell and chromophobe RCC of any stage conferred 5 year OS probabilities of >93%. Unclassified RCC demonstrated the lowest OS probabilities at any stage. In multivariable analyses, histological subtype affected RFS (P<0.0001) and OS (P = 0.026) following surgical resection, with no differences in this association for radical nephrectomy vs. PN (RFS, P = 0.2; OS, P = 0.4), and across pathologic stages (RFS, P = 0.1; OS, P = 0.3). Compared with low-grade conventional clear cell RCC, chromophobe (hazard ratio [HR] = 0.72, 95% CI: 0.30-1.75) and papillary RCC (HR = 0.30, 95% CI: 0.09-0.97) conferred lower risk of recurrence. Chromophobe (HR = 0.67, 95% CI: 0.30-1.52) and clear cell papillary RCC (HR = 0.91, 95% CI: 0.12-6.78) conferred the lowest risk of all cause mortality. CONCLUSIONS: In the era of PN for RCC, histological subtype remained a significant predictor of survival, regardless of type of surgical resection or tumor stage. PMID- 26947352 TI - Construction of a multipurpose photochemical reactor with on-line spectrophotometric detection. AB - A versatile photoreactor was built for studying homogeneous and heterogeneous photochemical reactions using fiber-optic devices. The reactor was designed to allow simultaneous photochemical initiation and online spectrophotometric monitoring of the reaction using independently controlled excitation and detection lamps. The system consists of a CCD spectrophotometer, a thermostated sample holder, two light sources, and standard 1.00 * 1.00 cm (or possibly smaller) fluorescence cuvettes, all coupled with fiber optic cables. The device can be used as a photoreactor, a diode-array spectrophotometer and also as a spectrofluorimeter. The reactor can be used in flow-through operation modes. Performance tests of the instrument are reported here with a number of known photochemical systems. PMID- 26947353 TI - Toll-like receptor 2 of tongue sole Cynoglossus semilaevis: Signaling pathway and involvement in bacterial infection. AB - Toll-like receptor (TLR) 2 is a member of the TLR family that plays a pivotal role in innate immunity. In mammals, TLR2 is known to recognize specific microbial structures and trigger MyD88-dependent signaling to induce various cytokine responses. In this study, we examined the expression and function of the tongue sole Cynoglossus semilaevis TLR2, CsTLR2. CsTLR2 is composed of 898 amino acid residues and shares 25.6%-27.3% overall sequence identities with known teleost TLR2. CsTLR2 is a transmembrane protein with a toll/interleukin-1 receptor domain and eight leucine-rich repeats. Expression of CsTLR2 occurred in multiple tissues and was upregulated during bacterial infection. Stimulation of the CsTLR2 pathway led to enhanced expression of MyD88-dependent signaling molecules. Recombinant CsTLR2 (rCsTLR2) corresponding to the extracellular region was able to bind to a wide range of bacteria. Under both in vitro and in vivo conditions, rCsTLR2 significantly reduced bacterial infection. These observations add new insights into the signaling and function of teleost TLR2. PMID- 26947354 TI - Effect of Electrothermal Treatment on Nerve Tissue Within the Triangular Fibrocartilage Complex, Scapholunate, and Lunotriquetral Interosseous Ligaments. AB - PURPOSE: To evaluate the effect of thermal treatment on neural tissue in the triangular fibrocartilage complex (TFCC), scapholunate interosseous ligament (SLIL), and lunotriquetral interosseous ligament (LTIL). METHODS: The intact TFCC, SLIL, and LTIL were harvested from cadaveric specimens and treated with a radiofrequency probe as would be performed intraoperatively. Slides were stained using a triple-stain technique for neurotrophin receptor p75, pan-neuronal marker protein gene product 9.5 (PGP 9.5), and 4',6-diamidino-2-phenylindole for neural identification. Five TFCC, 5 SLIL, and 4 LTIL specimens were imaged with fluorescence microscopy. Imaging software was used to measure fluorescence signals and compare thermally treated areas with adjacent untreated areas. A paired t test was used to compare treated versus untreated areas. P < .05 was considered significant. RESULTS: For the TFCC, a mean of 94.9% +/- 2.7% of PGP 9.5-positive neural tissue was ablated within a mean area of 11.7 +/- 2.5 mm(2) (P = .02). For the SLIL treated from the radiocarpal surface, 97.4% +/- 1.0% was ablated to a mean depth of 2.4 +/- 0.3 mm from the surface and a mean horizontal spread of 3.4 +/- 0.5 mm (P = .01). For the LTIL, 96.0% +/- 1.5% was ablated to a mean depth of 1.7 +/- 0.7 mm and a mean horizontal spread of 2.6 +/- 1.0 mm (P = .02). Differences in the presence of neural tissue between treated areas and adjacent untreated areas were statistically significant for all specimens. CONCLUSIONS: Our study confirms elimination of neuronal markers after thermal treatment of the TFCC, SLIL, and LTIL in cadaveric specimens. This effect penetrates below the surface to innervated collagen tissue that is left structurally intact after treatment. CLINICAL RELEVANCE: Electrothermal treatment as commonly performed to treat symptomatic SLIL, LTIL, and TFCC tears eliminates neuronal tissue in treated areas and may function to relieve pain through a denervation effect. PMID- 26947355 TI - [A nasal congenital malformation not published in the literature: About 5 cases]. AB - AIM OF STUDY: Five cases of the same congenital malformation of the nose, affecting the nasal dorsum and the supra-tip, were supported in our university plastic surgery center. This malformation has not been described in the literature known to the authors. The aim of this study is to analyze this nasal deformity. PATIENTS AND METHODS: Five children presented this congenital deformity between 1994 and 2014. The patients were examined and the malformation precisely described. Genetic and histological examinations were carried on. The diagnosis and treatment of this pathology were discussed. RESULTS: This malformation associated 4 anomalies: hypertrophy of soft tissue of the dorsum located in the middle third of the nasal bridge, deformed alar cartilages turned back downward and outside, advanced support default and median skin brand similar to a scar. These patients showed no other abnormalities of the midline or respiratory disorders. No genetic disorder was found for these five patients, and no histological arguments were found. Three patients were operated, one until adulthood with a satisfying cosmetic result. CONCLUSION: Bibliographic research has not allowed us to make an accurate diagnosis of this malformation that appears to be non-syndromic and to have a genetic origin. Our therapeutic approach became more clear and it now seems legitimate to propose early excision of fat mass to prevent alar deformations, associated with a cortico-cancellous graft, which in our experience grows with age, to support the tip. PMID- 26947356 TI - Therapeutic plasma exchange for hypertriglyceridemia induced pancreatitis: A rapid and practical approach. AB - OBJECTIVES: Acute hypertriglyceridemia induced pancreatitis (HTP) presents with a more severe clinical course compared to other etiologies of pancreatitis. Therapeutic plasma exchange (TPE) is a potential treatment option for lowering plasma triglycerides and possibly decreasing morbidity and mortality. However, clinical data regarding its effectiveness are limited. METHODS: We retrospectively examined the clinical data and outcomes of 13 consecutive episodes of HTP in which TPE was employed to reduce plasma triglycerides during a 15-month period. RESULTS: The TPE was initiated at a median of 19 hours from the time of presentation. We performed 1.2-1.5 volume TPEs with 5% albumin as the replacement fluid. After only one TPE procedure, the mean plasma triglycerides values decreased from 2993 mg/dl to 487 mg/dl with a reduction of 84%. All 13 patients survived with a mean length of hospital stay of 9.5 days. There were no complications related to TPE. CONCLUSIONS: One TPE procedure is an effective method for reducing plasma triglycerides and possibly decreases the length of hospital stay in patients admitted with HTP. PMID- 26947357 TI - Triangular lattice exciton model. AB - We present a minimalistic equilateral triangular lattice model showing explicitly that the two-dimensional hydrogen model for excitons breaks down for excitons in semiconducting monolayer transition-metal dichalcogenides due to lattice effects and that these excitons are neither Wannier nor Frenkel excitons but rather span an intermediate regime. The model is formulated on sparse form in direct space, allowing it to be solved with great computational efficiency. PMID- 26947358 TI - In vivo corrosion behaviour of magnesium alloy in association with surrounding tissue response in rats. AB - Biodegradable magnesium (Mg) alloys are the most promising candidates for osteosynthesis devices. However, their in vivo corrosion behaviour has not been fully elucidated. The aim of this study was to clarify the influence of the physiological environment surrounding Mg alloys on their corrosion behaviour. A Mg-1.0Al alloy with a fine-grained structure was formed into plates using titanium (Ti) as a control. These plates were implanted into the subperiosteum in the head, subcutaneous tissue of the back, and in the muscle of the femur of rats for 1, 2 and 4 weeks. The volumes of the remaining Mg alloy and of the insoluble salt deposition and gas cavities around the Mg alloy were determined by microtomography, and the volume losses were calculated. Then, the tissue response around the plates in each implantation site was examined histopathologically, and its relation to the respective volume loss was analyzed. These analyses determined that the Mg alloy was corroded fastest in the head, at an intermediate level in the back, and slowest in the femur. The insoluble salt deposition at the Mg alloy surface had no influence on the volume loss. Gas cavities formed around the Mg alloy at all implantation sites and decreased after 4 weeks. Histopathological examination revealed that the Mg alloy exhibited good biocompatibility, as was seen with Ti. In addition, vascularized fibrous capsules formed around the plates and became mature with time. Notably, the volume loss in the different anatomical locations correlated with capsule thickness. Together, our results suggest that, to facilitate the successful clinical application of Mg alloys, it will be necessary to further comprehend their interactions with specific in vivo environments. PMID- 26947359 TI - Surface Structures of the Human Vestibular Sensory Regions. AB - The hair bundles and other surface organelles of the human vestibular sensory regions have been studied with SEM and TEM. The material was taken from individuals of different ages, from the fetal period to old age. The hair bundles have a remarkably mature appearance in fetuses three to four months old. Each hair bundle consists of one kinocilium and of many stereocilia of different length. Some hair bundles are shorter than the majority. There are indications that these short hair bundles, which are especially numerous at the edges of the maculae, belong to type II sensory cells. In old individuals, laminated inclusions are often seen in the cytoplasm close to the cuticular plate. Each supporting cell is equipped with microvilli and a solitary kinocilium in the fetal period. In adults these microvilli are shorter and more scanty, and the kinocilium is usually missing. PMID- 26947360 TI - Distribution of Macromolecular Tracer Particles (Thorotrast(R)) in the Cochlea. An Electron Microscopic Study in Guinea Pig: Part I. The organ of Corti, the basilar membrane and the tympanic covering layer. AB - Thorotrast(R) containing thorium dioxide particles with diameters of around 100 A was introduced in perilymph or endolymph using various methods and concentrations. The location of the tracer particles in the cochleas was determined using the transmission electron microscope. Injection of tracer into the cerebrospinal fluid (CSF) was considered to be the least unphysiological way to bring the tracer to the cochlea, and therefore most of the experiments were performed in that way. The distribution of tracer was very dependent on the mode of injection and the concentration of tracer in the cochlea. With very high concentrations it appeared that every kind of cell had a capacity of phagocytizing. No significant tracer uptake was noted in the cells of the organ of Corti after direct injection of small amounts of tracer in the cochlear duct. After tracer administration in the cerebrospinal fluid, the tracer rapidly reached the scala tympani. The tympanic border cells contained large numbers of tracer particles, while lesser amounts were found in the homogenous parts of the basilar membrane. No tracer was seen in the cells of the organ of Corti. After perfusion of the cochlear perilymph, some tracer was seen in the cells of the organ of Corti. The limited passage of tracer to the organ of Corti was not regarded as proof of free communication between perilymph and cortilymph. Glycerol administration to the animals did not change the propagation of tracer in the cochlea. After injection of tracer into dead animals, tracer inclusions could be seen in the tympanic border cells, indicating the possibility of a cell phagocytizing ability, also some time after death. PMID- 26947361 TI - The Tympanic Covering Layer. An Electron Microscopic Study in Guinea Pig. AB - The tympanic covering layer in guinea pig was studied with transmission and scanning electron microscopy. The tympanic border cells looked like bipolar ganglion cells with long processes. There was often a kinocilium on the cell body. The cells were rather similar structurally but their arrangement varied in the different coils. In the basal coil the cells were lying close together and oriented strictly longitudinally. In the upper coils both longitudinally and radially oriented cells were seen. There were fewer cells in the apical coils and the perilymphatic space between the cells, as well as the area of contact between the perilymph and the basilar membrane, became larger. On every level in the cochlea the tympanic covering layer was thinnest under the tunnel of Corti. The significance of the appearance of the cells and their arrangement are discussed. The tissue on the lower side of the basilar membrane is called the tympanic lamella or the tympanic covering layer and its cells have been called tympanic border cells, basilar membrane cells or cells of the tympanic covering layer. They are of mesothelial origin and were already noticed by Claudius (1856), Hensen (1863), Boettcher (1869) and Retzius (1884). Little interest was paid to them until Iurato (1962) described their submicroscopic anatomy in detail in his investigations of the rat's inner ear. In the studies of the cochlea using tracer substance it has been observed that these cells in the guinea pig have a high phagocytic ability (Angelborg & Engstrom, 1973; Angelborg, in press). Further studies of the tympanic border cells showed some new features in their anatomy which had not been described earlier. In this investigation their ultrastructure in guinea pig will be presented. PMID- 26947362 TI - Scanning Electron Microscopy of the Inner Structure of the Organ of Corti and its Neural Pathways. AB - Scanning electron microscopy has been used by the author since 1968 and has become an important tool in the study of inner ear structures. By the combination of good preparation and microdissection, light and electron microscopy, we can better visualize the structure of the normal and pathologically altered organ of Corti and also the vestibular sensory regions. In the present publication it is shown that good preparation permits a study of the inner of the organ of Corti and also of the neural pathways not only in the organ of Corti but also in the osseous spiral lamina and in the modiolus. PMID- 26947363 TI - Impact of an emergency medicine pharmacist on antibiotic dosing adjustment. AB - OBJECTIVE: Overall medication-related errors in the emergency department (ED) are 13.5 times more likely to occur in the absence of an emergency medicine pharmacist (EMP). Although the effectiveness of pharmacist-driven renal dosing adjustment has been studied in the intensive care unit, data are lacking in the ED setting. The aim of our study was to evaluate the appropriateness of antibiotic dosing when an EMP is physically present in the ED compared to when absent. METHODS: This was a retrospective cohort study of patients treated in a level I trauma center with 75 adult and 12 pediatric beds and an annual census of 90000 patients. The study period was from March 1 to September 30, 2014. An EMP was physically present in the ED from 11:00 to 01:30 and absent from 01:31 to 10:59. Male and female patients 18years and older were considered for inclusion if cefazolin, cefepime, ciprofloxacin, piperacillin-tazobactam, or vancomycin was ordered. The primary outcome was the composite rate of correct antibiotic dose and frequency. Statistics included a multivariable logistic regression using age, sex, presence of EMP, and creatinine clearance as independent predictors of correct antibiotic use. RESULTS: A total 210 cases were randomly chosen for evaluation, half during times when EMPs were present and half when they were absent. There were 130 males (62%) with an overall mean age of 54+/-18years. Overall, 178 (85%) of 210 of the antibiotic orders were appropriate, with 95% appropriate when an EMP was present compared to 74% when an EMP was absent (odds ratio, 6.9; 95% confidence interval, 2.5-18.8). In a logistic regression model, antibiotic appropriateness was independently associated with the presence of the EMP and creatinine clearance. CONCLUSION: Antibiotics that require renal and/or weight dosing adjustment are 6.5 times more likely to be appropriate in the ED when an EMP is present. Prevalence of antibiotic dosing error is related to both the presence of EMPs and the degree of renal impairment. PMID- 26947364 TI - COHgb levels predict the long-term development of acute myocardial infarction in CO poisoning. AB - BACKGROUND: There are several studies evaluating the cardiac effects of carbon monoxide (CO) poisoning during the acute period; however, the number of studies evaluating the long-term cardiac effects is limited. OBJECTIVE: The present study aimed to evaluate the effects of blood carboxyhemoglobin (COHb) levels, elevated due to CO poisoning on the long-term development of acute myocardial infarction (AMI). METHODS: This cross-sectional cohort study included a total of 1013 consecutive patients who presented to the emergency department (ED) due to CO poisoning, between January 2005 and December 2007. The diagnosis of CO poisoning was made according to the medical history and a COHb level of greater than 5%. In terms of AMI development, the patients were followed up for an average of 56 months. RESULTS: At the end of follow-up, 100 (10%) of 1013 patients experienced AMI. Carboxyhemoglobin levels at the time of poisoning were higher among those who were diagnosed with AMI compared to those who were not (55%+/-6% vs 30%+/-7%; P<.001). Using a multivariate Cox proportional hazards model with forward stepwise method, age, COHb level, CO exposure time, and smoking remained associated with an increased risk of AMI after adjustment for the variables found to be statistically significant in a univariate analysis. According to a receiver operating characteristic curve analysis, the optimal cutoff value of COHb used to predict the development of AMI was found to be greater than 45%, with 98% sensitivity and 94.1% specificity. CONCLUSION: In patients presenting to the ED with CO poisoning, COHb levels can be helpful for risk stratification in the long term development of AMI. PMID- 26947365 TI - Are paramedics able to confirm endotracheal tube placement using ultrasonography? PMID- 26947366 TI - Straight back syndrome manifesting as acute myocardial infarction. PMID- 26947367 TI - Hemodynamic challenges in traumatic subarachnoid hemorrhage complicated by cerebral vasospasm. PMID- 26947368 TI - Combination of chest compressions and interposed abdominal compressions in a swine model of ventricular fibrillation. AB - PURPOSE: The aim of this study was to investigate the effects of the combination of chest compressions and interposed abdominal compressions (IAC-CPR) in a swine model of ventricular fibrillation (VF). METHODS: Twenty healthy female Landrace Large White pigs were the study subjects. At the end of the eighth minute of VF, animals in the control group (Group A) received chest compressions at a rate of 100/min, while animals in the experimental group received chest compressions and simultaneous interposed abdominal compressions (CC-IAC - Group B), both at a rate of 100/min. The primary end point of the experiment was return of spontaneous circulation (ROSC). Secondary outcomes were 48-h survival rate and 48-h neurologic outcome. RESULTS: Six animals (60%) from Group A and 9 animals (90%) from Group B achieved ROSC (P=.121). There was a statistically significant difference in systolic aortic pressure, mean aortic pressure, right atrial pressures, and end-tidal carbon dioxide (ETCO2) between the two groups during the first cycle of CPR, while during the second cycle, diastolic aortic pressure was significantly higher in Group B. Coronary perfusion pressure (CPP) values in group B were significantly higher compared with those in Group A during the first and second cycle of CPR. Neurologic examination was statistically significantly better in Group B (75.00+/-10.00 vs. 90.00+/-10.00, P=.037). CONCLUSION: ROSC did not differ statistically significant in the IAC-CPR compared to the CPR group only, while CPP was significantly higher in IAC-CPR-treated animals. PMID- 26947369 TI - Fuchs syndrome: A rare and unique variant of Stevens-Johnson Syndrome. PMID- 26947370 TI - Characteristics of heroin-dependent patients seeking asthma care in the ED. AB - BACKGROUND: Limited data suggest that heroin worsens asthma severity, but little is known about heroin-dependent patients who seek emergency department (ED) care for asthma. OBJECTIVES: To describe what heroin-dependent patients know about their asthma and how they use health care resources. METHODS: A prospective study of heroin-dependent patients seeking care for "asthma" at an urban ED with 130000 annual visits was conducted. Eligible subjects were English-speaking heroin dependent adults seeking care for mild to moderate asthma symptoms. A closed format survey instrument to assess opioid use, asthma knowledge, and health care use was developed by content experts, piloted for study performance, revised, and then administered to eligible patients prior to ED discharge. Descriptive analysis was done. RESULTS: Thirty subjects participated. Mean age was 47.5 years; 21 (70%) were male. Most used heroin several times weekly. Intranasal was the most common route (93%). Almost half (47%) stated that their asthma was diagnosed in the ED, 13% by a primary care physician, 13% by a lung specialist, and 27% did not know how diagnosed. The ED was used as the primary source for asthma medications in 73% cases; 43% used the ED for breathing issues at least once per month. Most subjects (77%) felt that heroin worsened their asthma symptoms. Only 7 (23%) also abused prescription opioids, and only 7 (23%) knew about prescription naloxone. CONCLUSION: Patients with heroin dependence frequently use the ED for their health care needs related to asthma. Most do not have other health care providers, most have limited health literacy, and all would benefit from referral to a primary care provider and substance abuse resources. PMID- 26947371 TI - Comparison of two chest compression techniques when using CBRN-PPE: a randomized crossover manikin trial. PMID- 26947372 TI - High-flow nasal cannula oxygen supply as treatment in hypercapnic respiratory failure. PMID- 26947373 TI - A new route to life in patients with circulatory shock: intraosseous route. PMID- 26947374 TI - Heart stopping honey-not just Turkish honey. PMID- 26947375 TI - Posterior reversible encephalopathy syndrome after bevacizumab treatment presenting to the ED as chest pain and headache. PMID- 26947376 TI - Influence of caudal traction of ipsilateral arm on ultrasound image for supraclavicular central venous catheterization. AB - BACKGROUND: The first step for successful ultrasound (US)-guided subclavian vein (SCV) catheterization using a supraclavicular approach is to obtain a good longitudinal image of SCV for in-plane needle placement. We evaluated the efficacy of caudal traction of ipsilateral arm on the exposure of the SCV. METHODS: We enrolled 20 infants, 20 children, and 20 adults undergoing general anesthesia. After tracheal intubation, US probe was applied as the supraclavicular approach, and the longitudinal US image of SCV was obtained in 3 different ipsilateral arm positions: neutral, caudal traction, and abduction. The length of puncturable SCV, the diameter of SCV, and the available angle for needle insertion in 3 different arm positions were analyzed. RESULTS: In all patients, the length of puncturable SCV and the available angle for needle insertion were significantly increased after caudal traction (35.6% +/- 27.1% and 25.0% +/- 19.3%, respectively) and decreased after the abduction (36.6% +/- 22.9% and 29.5% +/- 23.8%, respectively) compared to neutral position. The diameter of SCV was not changed after applying the caudal traction in infants and children. However, in adults, the caudal traction slightly increased the diameter of SCV (P = .012). CONCLUSION: The caudal traction of ipsilateral arm toward to the knee improves the longitudinal US view of SCV for the supraclavicular approach, without reducing its size. Proper caudal traction of the arm might ensure the high success rate with safe needle insertion technique. Abduction should be avoided during US-guided supraclavicular SCV catheterization. PMID- 26947377 TI - Failure of outpatient antibiotics among patients hospitalized for acute bacterial skin infections: What is the clinical relevance? AB - BACKGROUND: Infectious Diseases Society of America guidelines recommend that patients hospitalized for acute bacterial skin infections after failure of outpatient antibiotic therapy be managed as "severe" infections; however, the clinical relevance of apparent failure of outpatient therapy is not clear. METHODS: This was a secondary analysis of a multicenter, retrospective cohort of adults and children hospitalized for cellulitis, abscess, or wound infection. We compared clinical features, laboratory and microbiology findings, antibiotic treatment, and outcomes among patients who received outpatient antibiotics prior to admission and those who did not. RESULTS: Of 533 patients, 179 (34%) received outpatient antibiotics prior to admission. Compared with those who did not, patients who received antibiotics prior to admission less frequently had fever (18% vs 26%, P=.04) and leukocytosis (33% vs 51%, P<.001). In the 202 cases where a microorganism was identified, Staphylococcus aureus was more common among those who received antibiotics prior to admission (75% vs 58%, P=.02), particularly methicillin-resistant S aureus (41% vs 27%, P=.049), whereas aerobic gram negative bacilli were less common (3% vs 13%, P=.03). After hospitalization, clinical failure occurred with similar frequency between the 2 groups (12% vs 11%, P=.73). CONCLUSIONS: Patients hospitalized with skin infections after apparently failing outpatient therapy had clinical features suggestive of less severe infection and similar outcomes compared with patients who did not receive antibiotics prior to admission. Our results suggest that inpatient treatment for patients not responding to outpatient therapy should focus on methicillin resistant S aureus, not gram-negative pathogens. PMID- 26947379 TI - Recent emergence of photon upconversion based on triplet energy migration in molecular assemblies. AB - An emerging field of triplet energy migration-based photon upconversion (TEM-UC) is reviewed. Highly efficient photon upconversion has been realized in a wide range of chromophore assemblies, such as non-solvent liquids, ionic liquids, amorphous solids, gels, supramolecular assemblies, molecular crystals, and metal organic frameworks (MOFs). The control over their assembly structures allows for unexpected air-stability and maximum upconversion quantum yield at weak solar irradiance that has never been achieved by the conventional molecular diffusion based mechanism. The introduction of the "self-assembly" concept offers a new perspective in photon upconversion research and triplet exciton science, which show promise for numerous applications ranging from solar energy conversion to chemical biology. PMID- 26947378 TI - [Atrioventricular septal defect in an adult patient: There are 'clefts' and clefts]. AB - In this report, we present the case of an adult male with severe mitral regurgitation due to an atrioventricular septal defect. Anatomical assessment by two- and three-dimensional transesophageal echocardiography was essential for detailed morphological characterization and surgical planning. The different features of a 'cleft' in an atrioventricular septal defect compared to an anterior leaflet cleft in an otherwise normal mitral valve are here discussed. PMID- 26947380 TI - Nonketotic Hyperglycinemia of Infants in Taiwan. AB - BACKGROUND: Nonketotic hyperglycinemia (NKH) is a rare, inherited disease, with very poor outcome. It is difficult to confirm the diagnosis due to nonspecific presentations and rapid progression. The incidence was reported in a few countries. We report the clinical and genetic features of typical neonatal NKH with novel splicing mutation, c.1058+3A>C, in the intron 7 of the glycine decarboxylase (GLDC) gene. Furthermore, this study aimed to delineate the estimated incidence and clinical characteristics of NKH in the Taiwanese population. METHODS: Reports of Health Promotion Administration, Ministry of Health and Welfare of Taiwan, during the period from 2000 to 2013; the Human Gene Mutation Database; and literature regarding NKH in Taiwan were reviewed. Demographic information, age of onset, clinical characteristics, genetic analysis, electroencephalography examinations, and outcome of the patients were analyzed. RESULTS: The estimated incidence of NKH in the Taiwanese population was 7.2 cases per 1,000,000 live births. Among the 12 cases reported in Taiwan, more than 90% were of neonatal type. Fifty-five percent of affected patients died within 5 years, and all survivors had severe neurologic outcomes. Only three infants underwent genetic analysis during the study period. Two neonatal NKH infants had mutation in the GLDC gene, and the other one, who had late-onset NKH, had mutation in the glutaredoxin 5 gene. CONCLUSION: Compared with other countries, the estimated incidence of NKH was relatively rare in the Taiwanese population. It is important to characterize all index cases at the genetic level. With more awareness of NKH, increased knowledge of gene mutation, and improvement of diagnostic tools, NKH can be diagnosed more accurately. PMID- 26947381 TI - Active tissue stiffness modulation controls valve interstitial cell phenotype and osteogenic potential in 3D culture. AB - Calcific aortic valve disease (CAVD) progression is a highly dynamic process whereby normally fibroblastic valve interstitial cells (VIC) undergo osteogenic differentiation, maladaptive extracellular matrix (ECM) composition, structural remodeling, and tissue matrix stiffening. However, how VIC with different phenotypes dynamically affect matrix properties and how the altered matrix further affects VIC phenotypes in response to physiological and pathological conditions have not yet been determined. In this study, we develop 3D hydrogels with tunable matrix stiffness to investigate the dynamic interplay between VIC phenotypes and matrix biomechanics. We find that VIC populated within hydrogels with valve leaflet like stiffness differentiate towards myofibroblasts in osteogenic media, but surprisingly undergo osteogenic differentiation when cultured within lower initial stiffness hydrogels. VIC differentiation progressively stiffens the hydrogel microenvironment, which further upregulates both early and late osteogenic markers. These findings identify a dynamic positive feedback loop that governs acceleration of VIC calcification. Temporal stiffening of pathologically lower stiffness matrix back to normal level, or blocking the mechanosensitive RhoA/ROCK signaling pathway, delays the osteogenic differentiation process. Therefore, direct ECM biomechanical modulation can affect VIC phenotypes towards and against osteogenic differentiation in 3D culture. These findings highlight the importance of the homeostatic maintenance of matrix stiffness to restrict pathological VIC differentiation. STATEMENT OF SIGNIFICANCE: We implement 3D hydrogels with tunable matrix stiffness to investigate the dynamic interaction between valve interstitial cells (VIC, major cell population in heart valve) and matrix biomechanics. This work focuses on how human VIC responses to changing 3D culture environments. Our findings identify a dynamic positive feedback loop that governs acceleration of VIC calcification, which is the hallmark of calcific aortic valve disease. Temporal stiffening of pathologically lower stiffness matrix back to normal level, or blocking the mechanosensitive signaling pathway, delays VIC osteogenic differentiation. Our findings provide an improved understanding of VIC-matrix interactions to aid in interpretation of VIC calcification studies in vitro and suggest that ECM disruption resulting in local tissue stiffness decreases may promote calcific aortic valve disease. PMID- 26947383 TI - Transcatheter Closure of Large Coronary Fistulae via a Transradial Sheathless Approach. PMID- 26947382 TI - Biophysical characterization of small molecule antiviral-loaded nanolipogels for HIV-1 chemoprophylaxis and topical mucosal application. AB - Nanocarriers are versatile vehicles for drug delivery, and emerging as platforms to formulate and deliver multiple classes of antiretroviral (ARV) drugs in a single system. Here we describe the fabrication of hydrogel-core and lipid-shell nanoparticles (nanolipogels) for the controlled loading and topical, vaginal delivery of maraviroc (MVC) and tenofovir disoproxil fumarate (TDF), two ARV drugs with different mechanisms of action that are used in the treatment of HIV. The nanolipogel platform was used to successfully formulate MVC and TDF, which produced ARV drug-loaded nanolipogels that were characterized for their physical properties and antiviral activity against HIV-1 BaL in cell culture. We also show that administration of these drug carriers topically to the vaginal mucosa in a murine model leads to antiviral activity against HIV-1 BaL in cervicovaginal lavages. Our results suggest that nanolipogel carriers are promising for the encapsulation and delivery of hydrophilic small molecule ARV drugs, and may expand the nanocarrier systems being investigated for HIV prevention or treatment. STATEMENT OF SIGNIFICANCE: Topical, mucosal intervention of HIV is a leading strategy in the efforts to curb the spread of viral infection. A significant research thrust in the field has been to characterize different dosage forms for formulation of physicochemically diverse antiretroviral drugs. Nanocarriers have been used to formulate and deliver small molecule and protein drugs for a range of applications, including ARV drugs for HIV treatment. The broad significance of our work includes evaluation of lipid-shell, hydrogel-core nanoparticles for formulation and topical, vaginal delivery of two water-soluble antiretroviral drugs. We have characterized these nanocarriers for their physical properties and their biological activity against HIV-1 infection in vitro, and demonstrated the ability to deliver drug-loaded nanocarriers in vivo. PMID- 26947385 TI - To Define Is to Limit: Is That Good or Bad When it Comes to Chest Pain? PMID- 26947384 TI - Sex Difference in Chest Pain After Implantation of Newer Generation Coronary Drug Eluting Stents: A Patient-Level Pooled Analysis From the TWENTE and DUTCH PEERS Trials. AB - OBJECTIVES: This study sought to assess sex differences in chest pain after percutaneous coronary intervention (PCI) with newer generation drug-eluting stents (DES). BACKGROUND: Sex-based data on chest pain after PCI with DES are scarce. METHODS: The authors performed a patient-level pooled analysis of the TWENTE and DUTCH PEERS randomized trials, in which patients were treated with newer generation permanent polymer-coated DES. At 1 and 2 years, clinical follow up was available in 99.8% and patient-reported chest pain data in 94.1% and 93.6%, respectively. RESULTS: Among all 3,202 patients, the 871 (27.2%) women were older (67.5 +/- 10.2 years vs. 62.8 +/- 10.6 years; p < 0.001) and had more cardiovascular risk factors: diabetes (24.2% vs. 17.8%; p < 0.001), hypertension (63.6% vs. 51.6%; p < 0.001), and positive family history (54.5% vs. 50.1%; p = 0.03). At 1- and 2-year follow-up, women reported more clinically relevant chest pain (16.3% vs. 10.5%; p < 0.001, and 17.2% vs. 11.1%; p < 0.001, respectively). Multivariate analysis demonstrated that female sex independently predicted clinically relevant chest pain at 1- and 2-year follow-up both during daily activities and at minimum physical exertion/at rest (1 year adjusted odds ratio [OR]: 1.7; 95% confidence interval [CI]: 1.2 to 2.4; p = 0.002; and adjusted OR: 1.8; 95% CI: 1.3 to 2.5; p < 0.001; 2-year adjusted OR: 1.8; 95% CI: 1.3 to 2.6; p < 0.001; and adjusted OR: 1.7; 95% CI: 1.3 to 2.3; p = 0.001). Nevertheless, the 2-year rates of death, myocardial infarction, revascularization, stent thrombosis, and various composite clinical endpoints were similar for both sexes. CONCLUSIONS: Although the incidence of adverse cardiovascular events was low and similar for both sexes, women showed a statistically significantly higher prevalence of clinically relevant chest pain, which might be largely related to mechanisms other than epicardial coronary obstruction. PMID- 26947386 TI - Angioseal-Assisted Closure of Iatrogenic Refractory Femoral Arterial Pseudoaneurysm: A Novel Technique. PMID- 26947388 TI - Chronic Total Occlusion PCI: Is This the Ultimate Test of the Importance of Complete Revascularization? PMID- 26947387 TI - Successful Recanalization of Native Coronary Chronic Total Occlusion Is Not Associated With Improved Long-Term Survival. AB - OBJECTIVES: The purpose of this study was to evaluate long-term clinical outcomes after drug-eluting stent-supported percutaneous coronary intervention (PCI) for native coronary total occlusion (CTO). BACKGROUND: The benefit of successful recanalization of CTO on prognosis remains uncertain. METHODS: Between March 2003 and May 2014, 1,173 consecutive patients with CTO of native coronary vessels requiring PCI were enrolled. Drug-eluting stent implantation was performed in all successful procedures (1,004 patients, 85.6%). RESULTS: During a median follow-up of 4.6 years, the adjusted risks of all-cause mortality (hazard ratio [HR]: 1.04; 95% confidence interval [CI]: 0.53 to 2.04; p = 0.92) and the composite of death or myocardial infarction (HR: 1.05; 95% CI: 0.56 to 1.94; p = 0.89) were found to be comparable between patients with successful and failed CTO-PCI, whereas the adjusted risk of target vessel revascularization (HR: 0.15; 95% CI: 0.10 to 0.25; p < 0.001) and coronary artery bypass grafting (HR: 0.02; 95% CI: 0.006 to 0.06, p < 0.001) was significantly higher in patients with failed CTO-PCI. Among patients (n = 879) in whom complete revascularization for non-CTO vessels was performed, the risk of death or the composite of death or myocardial infarction were not found to differ between patients who underwent successful recanalization of the remaining CTO and patients who did not. This finding was consistent regardless of whether the patient had a multivessel disease including CTO or only had a single CTO disease. CONCLUSIONS: Successful CTO-PCI compared with failed PCI was not associated with a lesser risk for mortality. However, successful CTO PCI was associated with significantly less subsequent coronary artery bypass grafting. PMID- 26947389 TI - A Novel Wire-Assisted Technique for Closing Large Atrial Septal Defects: New Concepts of Closure Mechanism. PMID- 26947390 TI - SmMYC2a and SmMYC2b played similar but irreplaceable roles in regulating the biosynthesis of tanshinones and phenolic acids in Salvia miltiorrhiza. AB - Salvia miltiorrhiza Bunge, which contains tanshinones and phenolic acids as major classes of bioactive components, is one of the most widely used herbs in traditional Chinese medicine. Production of tanshinones and phenolic acids is enhanced by methyl jasmonate (MeJA). Transcription factor MYC2 is the switch of jasmontes signaling in plants. Here, we focused on two novel JA-inducible genes in S. miltiorrhiza, designated as SmMYC2a and SmMYC2b, which were localized in the nucleus. SmMYC2a and SmMYC2b were also discovered to interact with SmJAZ1 and SmJAZ2, implying that the two MYC2s might function as direct targets of JAZ proteins. Ectopic RNA interference (RNAi)-mediated knockdown experiments suggested that SmMYC2a/b affected multiple genes in tanshinone and phenolic acid biosynthetic pathway. Besides, the accumulation of tanshinones and phenolic acids was impaired by the loss of function in SmMYC2a/b. Meanwhile, SmMYC2a could bind with an E-box motif within SmHCT6 and SmCYP98A14 promoters, while SmMYC2b bound with an E-box motif within SmCYP98A14 promoter, through which the regulation of phenolic acid biosynthetic pathway might achieve. Together, these results suggest that SmMYC2a and SmMYC2b are JAZ-interacting transcription factors that positively regulate the biosynthesis of tanshinones and Sal B with similar but irreplaceable effects. PMID- 26947393 TI - Nuclear Factor Erythroid-2 Like 1 (NFE2L1): Structure, function and regulation. AB - Nrf1 (also referred to as NFE2L1) is a member of the CNC-bZIP family of transcription factors that are characterized by a highly conserved CNC-domain, and a basic-leucine zipper domain required for dimerization and DNA binding. Nrf1 is ubiquitously expressed across tissue and cell types as various isoforms, and is induced by stress signals from a broad spectrum of stimuli. Evidence indicates that Nrf1 plays an important role in regulating a range of cellular functions including oxidative stress response, differentiation, inflammatory response, metabolism, and maintaining proteostasis. Thus, Nrf1 has been implicated in the pathogenesis of various disease processes including cancer development, and degenerative and metabolic disorders. This review summarizes our current understanding of Nrf1 and the molecular mechanism underlying its regulation and action in different cellular functions. PMID- 26947392 TI - HHV-8-unrelated primary effusion-like lymphoma associated with clonal loss of inherited chromosomally-integrated human herpesvirus-6A from the telomere of chromosome 19q. AB - Primary effusion lymphomas (PEL) are associated with human herpesvirus-8 (HHV-8) and usually occur in immunocompromised individuals. However, there are numerous reports of HHV-8-unrelated PEL-like lymphomas with unknown aetiology. Here we characterize an HHV-8-unrelated PEL-like lymphoma in an elderly woman who was negative for human immunodeficiency viruses 1 and 2, and hepatitis B and C. The woman was, however, a carrier of an inherited-chromosomally-integrated human herpesvirus-6A (iciHHV-6A) genome in one 19q telomere. The iciHHV-6A genome was complete in blood DNA, encoding a full set of protein-coding genes. Interestingly, the entire iciHHV-6A genome was absent from the HHV-8-unrelated PEL-like lymphoma cells despite retention of both copies of chromosome 19. The somatic loss of the 19q-iciHHV-6A genome occurred very early during lymphoma development and we propose it occurred via telomere-loop formation and excision to release a circular viral genome that was subsequently lost. Whether release of the HHV-6A genome from the telomere contributed to lymphomagenesis, or was coincidental, remains unclear but this event may have deregulated the expression of HHV-6A or 19q genes or else disrupted telomere function. To establish the frequency and importance of iciHHV-6 loss from telomeres, the HHV-6 copy number should be assessed in tumours that arise in iciHHV-6 carriers. PMID- 26947391 TI - Evidence for Tautomerisation of Glutamine in BLUF Blue Light Receptors by Vibrational Spectroscopy and Computational Chemistry. AB - BLUF (blue light sensor using flavin) domains regulate the activity of various enzymatic effector domains in bacteria and euglenids. BLUF features a unique photoactivation through restructuring of the hydrogen-bonding network as opposed to a redox reaction or an isomerization of the chromophore. A conserved glutamine residue close to the flavin chromophore plays a central role in the light response, but the underlying modification is still unclear. We labelled this glutamine with (15)N in two representative BLUF domains and performed time resolved infrared double difference spectroscopy. The assignment of the signals was conducted by extensive quantum chemical calculations on large models with 187 atoms reproducing the UV-vis and infrared signatures of BLUF photoactivation. In the dark state, the comparatively low frequency of 1,667 cm(-1) is assigned to the glutamine C=O accepting a hydrogen bond from tyrosine. In the light state, the signature of a tautomerised glutamine was extracted with the C=N stretch at ~1,691 cm(-1) exhibiting the characteristic strong downshift by (15)N labelling. Moreover, an indirect isotope effect on the flavin C4=O stretch was found. We conclude that photoactivation of the BLUF receptor does not only involve a rearrangement of hydrogen bonds but includes a change in covalent bonds of the protein. PMID- 26947394 TI - Conserved sequences in the current strains of HIV-1 subtype A in Russia are effectively targeted by artificial RNAi in vitro. AB - Highly active antiretroviral therapy has greatly reduced the morbidity and mortality of AIDS. However, many of the antiretroviral drugs are toxic with long term use, and all currently used anti-HIV agents generate drug-resistant mutants. Therefore, there is a great need for new approaches to AIDS therapy. RNAi is a powerful means of inhibiting HIV-1 production in human cells. We propose to use RNAi for gene therapy of HIV/AIDS. Previously we identified a number of new biologically active siRNAs targeting several moderately conserved regions in HIV 1 transcripts. Here we analyze the heterogeneity of nucleotide sequences in three RNAi targets in sequences encoding the reverse transcriptase and integrase domains of current isolates of HIV-1 subtype A in Russia. These data were used to generate genetic constructs expressing short hairpin RNAs 28-30-bp in length that could be processed in cells into siRNAs. After transfection of the constructs we observed siRNAs that efficiently attacked the selected targets. We expect that targeting several viral genes important for HIV-1 reproduction will help overcome the problem of viral adaptation and will prevent the appearance of RNAi escape mutants in current virus strains, an important feature of gene therapy of HIV/AIDS. PMID- 26947395 TI - Full-scale computation for all the thermoelectric property parameters of half Heusler compounds. AB - The thermoelectric performance of materials relies substantially on the band structures that determine the electronic and phononic transports, while the transport behaviors compete and counter-act for the power factor PF and figure-of merit ZT. These issues make a full-scale computation of the whole set of thermoelectric parameters particularly attractive, while a calculation scheme of the electronic and phononic contributions to thermal conductivity remains yet challenging. In this work, we present a full-scale computation scheme based on the first-principles calculations by choosing a set of doped half-Heusler compounds as examples for illustration. The electronic structure is computed using the WIEN2k code and the carrier relaxation times for electrons and holes are calculated using the Bardeen and Shockley's deformation potential (DP) theory. The finite-temperature electronic transport is evaluated within the framework of Boltzmann transport theory. In sequence, the density functional perturbation combined with the quasi-harmonic approximation and the Klemens' equation is implemented for calculating the lattice thermal conductivity of carrier-doped thermoelectric materials such as Ti-doped NbFeSb compounds without losing a generality. The calculated results show good agreement with experimental data. The present methodology represents an effective and powerful approach to calculate the whole set of thermoelectric properties for thermoelectric materials. PMID- 26947397 TI - Scalable chromatography-based purification of virus-like particle carrier for epitope based influenza A vaccine produced in Escherichia coli. AB - Virus-like particles (VLPs) are promising molecular structures for the design and construction of novel vaccines, diagnostic tools, and gene therapy vectors. Size, oligomer assembly and repetitiveness of epitopes are optimal features to induce strong immune responses. Several VLP-based vaccines are currently licensed and commercialized, and many vaccine candidates are now under preclinical and clinical studies. In recent years, the development of genetically engineered recombinant VLPs has accelerated the need for new, improved downstream processes. In particular, a rapid low cost purification process has been identified as a remaining key challenge in manufacturing process development. In the present study we set up a size-exclusion chromatography-based, scalable purification protocol for the purification of a VLP-based influenza A vaccine produced in Escherichia coli. Recombinant VLPs derived from the RNA bacteriophage MS2 displaying an epitope from the ectodomain of Matrix 2 protein from influenza A virus were produced and purified. The 3 steps purification protocol uses a recently developed multimodal size-exclusion chromatography medium (CaptoTM Core 700) in combination with detergent extraction and size-exclusion polishing to reach a 89% VLP purity with a 19% yield. The combination of this downstream strategy following production in E. coli would be suited for production of VLP based veterinary vaccines targeting livestock and companion animals where large amounts of doses must be produced at an affordable price. PMID- 26947398 TI - Development of pan-phlebovirus RT-PCR assay. AB - This study reports the pan-phlebovirus assay capable of detecting both sandfly/mosquito- and tick-borne phleboviruses. Sensitivity and specificity of the assay was verified using a panel of arboviruses. The RT-PCR assay is simple and sensitive, and thus well suited for screening of field samples. PMID- 26947400 TI - Transition Metal-Oxide Free Perovskite Solar Cells Enabled by a New Organic Charge Transport Layer. AB - Various electron and hole transport layers have been used to develop high efficiency perovskite solar cells. To achieve low-temperature solution processing of perovskite solar cells, organic n-type materials are employed to replace the metal oxide electron transport layer (ETL). Although PCBM (phenyl-C61-butyric acid methyl ester) has been widely used for this application, its morphological instability in films (i.e., aggregation) is detrimental. Herein, we demonstrate the synthesis of a new fullerene derivative (isobenzofulvene-C60-epoxide, IBF-Ep) that serves as an electron transporting material for methylammonium mixed lead halide-based perovskite (CH3NH3PbI(3-x)Cl(x)) solar cells, both in the normal and inverted device configurations. We demonstrate that IBF-Ep has superior morphological stability compared to the conventional acceptor, PCBM. IBF-Ep provides higher photovoltaic device performance as compared to PCBM (6.9% vs 2.5% in the normal and 9.0% vs 5.3% in the inverted device configuration). Moreover, IBF-Ep devices show superior tolerance to high humidity (90%) in air. By reaching power conversion efficiencies up to 9.0% for the inverted devices with IBF-Ep as the ETL, we demonstrate the potential of this new material as an alternative to metal oxides for perovskite solar cells processed in air. PMID- 26947399 TI - A rapid and quantitative assay for measuring neutralizing antibodies of Coxsackievirus B3. AB - Coxsackievirus B3 (CVB3) infection has been found to account for an increasing proportion cases of hand, foot and mouth disease (HFMD) in recent epidemiology studies. CVB3 is a single stranded, non-enveloped RNA virus and the infection can cause prominent health threat to pre-school children. Here, by taking approaches of reverse genetics, we established a single-round infection system for CVB3. The pseudovirus was produced by sequential transfection of CVB3 capsid expresser plasmid and CVB3 replicon RNA bearing firefly luciferase as a reporter. The CVB3 pseudovirus system was used for quantifying neutralizing antibody (NtAb) levels of 720 human serum samples and showed superior specificity and sensitivity comparing traditional cytopathic effect (CPE) assay. Furthermore, we compared the seroprevalence of CVB3 NtAbs in pre-school children and healthy adults, and found that only 11.94% of pre-school children were NtAbs positive which suggested that most children were naive to CVB3 infection; while there is much higher positive rate in adults (60%) indicating that most adults have experienced CVB3 infection during childhood. This rapid and quantitative assay greatly facilitates evaluating the level of NtAbs against CVB3 in populations and will help to advance CVB3 vaccine development. PMID- 26947401 TI - Audit of emergent and urgent surgery for acutely ill pediatric patients: is access timely? AB - There is a paucity of literature about wait times for urgent/emergent surgeries in Canada. Delays and performance of non-emergent operations overnight increase morbidity and mortality. The study aim was to determine patterns of delays and performance of less-emergent surgery overnight. METHODS: A retrospective analysis (June 2011-December 2013) of emergent/urgent surgeries was conducted using the ORSOS database (prospective patient and operative data). Surgeries were classified: class 1, 2A, 2B, and 3: target times of 1, 6, 24 and 72h. In hours (IH)=7:45AM-3:30PM, M-F; others were out of hours (OOH) and overnight =2300-0700. RESULTS: There were 4668 operations: class 1 (5.8%), 2A (29.1%), 2B (42.1%), and 3(23%). For class 1, 2A, 2B, and 3 surgeries, mean in-room times were 2, 4.7, 15.4, and 54h respectively; 59.2% (class 1), 81.9% (class 2A), 81.2% (class 2B) and 74.4%(class 3) were performed in target. OOH occurred for 73.2% (class 1), 71.5%(class 2A), 54.7% (class 2B), and 27.7% (class 3). There were 37 class 2B and 3 surgeries overnight. There was a significant increase surgeries IH: 41.8% to 49.6%. CONCLUSION: The majority of urgent/emergent surgery occurred OOH and the most unstable patients are least likely to have their operation within target. LEVEL OF EVIDENCE: 4. PMID- 26947396 TI - Data publication with the structural biology data grid supports live analysis. AB - Access to experimental X-ray diffraction image data is fundamental for validation and reproduction of macromolecular models and indispensable for development of structural biology processing methods. Here, we established a diffraction data publication and dissemination system, Structural Biology Data Grid (SBDG; data.sbgrid.org), to preserve primary experimental data sets that support scientific publications. Data sets are accessible to researchers through a community driven data grid, which facilitates global data access. Our analysis of a pilot collection of crystallographic data sets demonstrates that the information archived by SBDG is sufficient to reprocess data to statistics that meet or exceed the quality of the original published structures. SBDG has extended its services to the entire community and is used to develop support for other types of biomedical data sets. It is anticipated that access to the experimental data sets will enhance the paradigm shift in the community towards a much more dynamic body of continuously improving data analysis. PMID- 26947402 TI - Use of covered self-expandable stents for benign colorectal disorders in children. AB - PURPOSE: There is a lack of experience with covered self-expandable stents for benign colorectal disorders in children. METHODS: Five children (4M, 1F) with a median age of 5years (range, 6months-9years) who underwent treatment with covered self-expandable plastic (SEPSs) or self-expandable metal stents (SEMSs) for a benign colorectal condition between April 2005 and November 2013 were recruited to this retrospective study. Etiologies included: anastomotic stricture with (n=1) or without (n=3) simultaneous enterocutaneous fistula, as well as an anastomotic leak associated with enterocutaneous fistula (n=1). All children suffered from either Hirschsprung's disease (n=3) or total colonic aganglionosis (Zuelzer-Wilson syndrome) (n=2). RESULTS: Median duration of individual stent placement was 23days (range, 1-87days). In all cases up to five different stents were placed over time. At follow-up two patients were successfully treated without further intervention. In another patient the anastomotic stricture resolved fully, but a coexisting enterocutaneous fistula persisted. Overall, three patients did not improve completely following stenting and required definite surgery. Stent-related problems were noted in all cases. There was one perforation of the colon at stent insertion. Further complications consisted of stent dislocation (n=4), obstruction (n=1), formation of granulation tissue (n=1), ulceration (n=1) and discomfort (n=3). CONCLUSIONS: Covered self expandable stents enrich the armamentarium of interventions for benign colorectal disorders in children including anastomotic strictures and intestinal leaks. A stent can be applied either as an emergency procedure (bridge to surgery) or as an adjuvant treatment further to endoscopy and dilatation. Postinterventional problems are frequent but there is a potential for temporary or definite improvement following stent insertion. PMID- 26947409 TI - Can we tell what patients die of? Does it matter? PMID- 26947403 TI - Intestinal epithelial cell injury is rescued by hydrogen sulfide. AB - BACKGROUND/PURPOSE: Oxidative stress is implicated in the pathogenesis of necrotizing enterocolitis (NEC). Hydrogen sulfide (H2S) has been reported to have a protective function against oxidative stress in the gut. We hypothesize that administration of H2S can help decrease intestinal epithelial cell injury in vitro. METHODS: Intestinal epithelial cells (IEC-18) were treated with 200MUM hydrogen peroxide (H2O2) for 21h. At 21h sodium hydrosulfide (NaHS), an H2S donor, was administered as a rescue treatment at two different concentrations: 0.1mM and 0.2mM. At 24h, cell viability was measured using a colorimetric assay (MTT). Oxidative stress was studied by glutathione peroxidase (GPx) activity and thiobarbituric acid reactive substances (TBARS). IL-6 and TNFalpha levels were tested to study inflammation. Data were presented as mean+/-SD and compared using one-way ANOVA with Bonferroni post-test. RESULTS: Compared to control, H2O2 treated IEC-18 had reduced viability (p<0.01), lower GPx activity (p<0.01), higher TBARS levels (p<0.01), and increased IL6 and TNFalpha (p<0.001). Compared to H2O2-treated IEC-18, treatment with 0.2mM NaHS rescued viability (p<0.01), increased GPx activity (p<0.05), and reduced TBARS (p<0.01), IL6 and TNFalpha (p<0.001). CONCLUSIONS: H2S successfully rescues epithelial cell damage induced by oxidative stress in vitro. This indicates that H2S could be a potential pharmacological intervention in conditions like NEC. PMID- 26947410 TI - Choices, consequences and cost: low-value treatments and intensive care medicine. PMID- 26947411 TI - Incidence and mortality of postoperative sepsis in New South Wales, Australia, 2002-2009. AB - OBJECTIVE: To describe the incidence and mortality of postoperative sepsis in New South Wales, Australia. DESIGN, SETTING AND PARTICIPANTS: A retrospective study of adult elective surgical admissions (n = 229 918) in 82 public acute care hospitals in NSW, 2002-2009. MAIN OUTCOME MEASURES: Changes in the incidence rate of post-operative sepsis and sepsis-related mortality. RESULTS: Although the mortality rate among patients with sepsis decreased from 26.9% in 2002 to 20.2% in 2009 (P = 0.006 for adjusted trend), the incidence rate of sepsis increased from 12.7 to 15.8 per 1000 admissions (adjusted rate ratio [RR], 1.23; 95% CI, 1.06-1.42). Thus, the incidence rate of sepsis-related deaths remained unchanged (3.4 v 3.2 per 1000 admissions; adjusted RR, 0.90; 95% CI, 0.67-1.22), as did deaths from sepsis as a proportion of all elective surgical deaths (P = 0.96 for adjusted trend). The incidence rate of infections without a specified organism identified increased; was twice the rate of gram-positive infections (8.5 v 4.1 per 1000 admissions, P < 0.001); and was three times the rate of gram-negative infections (8.5 v 2.7 per 1000 admissions, P < 0.001). Also, compared with patients with gram-positive infections, patients with an unspecified infection were more likely to die (adjusted RR, 1.33; 95% CI, 1.13-1.57), but patients with gram-negative infections and mixed infections had a similar likelihood of death from their infection. CONCLUSION: Over 8 years, the mortality from postoperative sepsis decreased, but its incidence rate increased, resulting in a lack of improvement in the incidence rate of sepsis-related deaths. The increasing incidence of postoperative sepsis and the poor record of identification of causative organisms remain a significant public health challenge. PMID- 26947412 TI - Calorie delivery and clinical outcomes in the critically ill: a systematic review and meta-analysis. AB - OBJECTIVES: To determine the effect of calorie delivery on hospital mortality among critically ill adults receiving enteral nutrition (EN). Secondary outcomes included the effect of calorie delivery on intensive care unit and hospital length of stay (LOS), duration of mechanical ventilation (MV) and incidence of new-onset pneumonia. METHODS: We identified randomised clinical trials of EN, with or without supplemental parenteral nutrition (PN), involving adult ICU patients for whom mortality data were available, and when there was a significant difference in calorie supplementation between intervention arms (P < 0.05). We searched English language electronic databases (1946-2014), bibliographies of nutrition society guidelines and high-impact nutrition and critical care journals. We calculated summary odds ratio (OR) estimates and 95% confidence intervals using a random effects estimator, and used meta-regression to assess the effect on mortality of average calories delivered. RESULTS: Of 1545 articles identified, 16 eligible studies involving 3473 patients were included. Five studies involved supplemental PN. Mean calorie delivery ranged from 126 kcal/day (SD, 115 kcal/day) to 2086 kcal/day (SD, 460 kcal/day). Mortality was 26.0% in the lower calorie delivery group and 26.5% in the higher calorie delivery group. There was no effect of increased calorie delivery on mortality (OR, 1.02; 95% CI , 0.85-1.24; P = 0.27; I2 = 16.3%). ICU and hospital LOS and incidence of newonset pneumonia did not differ between groups. Duration of MV was decreased with lower calorie delivery (weighted mean difference, 2.92 days; 95% CI, -4.49 to -1.35 days; P < 0.001; I2 = 14.7%). Meta-regression analysis did not show an overall effect on mortality of average calories delivered (P = 0.73; I2 = 40.8%). CONCLUSION: Delivery of increased calories via the enteral route, with or without supplemental PN, was not associated with a survival benefit. PMID- 26947413 TI - The ANZROD model: better benchmarking of ICU outcomes and detection of outliers. AB - OBJECTIVE: To compare the impact of the 2013 Australian and New Zealand Risk of Death (ANZROD) model and the 2002 Acute Physiology and Chronic Health Evaluation (APACHE) III-j model as risk-adjustment tools for benchmarking performance and detecting outliers in Australian and New Zealand intensive care units. METHODS: Data were extracted from the Australian and New Zealand Intensive Care Society Adult Patient Database for all ICUs that contributed data between 1 January 2010 and 31 December 2013. Annual standardised mortality ratios (SMRs) were calculated for ICUs using the ANZROD and APACHE III-j models. They were plotted on funnel plots separately for each hospital type, with ICUs above the upper 99.8% control limit considered as potential outliers with worse performance than their peer group. Overdispersion parameters were estimated for both models. Overall fit was assessed using the Akaike information criterion (AIC) and Bayesian information criterion (BIC). Outlier association with mortality was assessed using a logistic regression model. RESULTS: The ANZROD model identified more outliers than the APACHE III-j model during the study period. The numbers of outliers in rural, metropolitan, tertiary and private hospitals identified by the ANZROD model were 3, 2, 6 and 6, respectively; and those identified by the APACHE III-j model were 2, 0, 1 and 1, respectively. The degree of overdispersion was less for the ANZROD model compared with the APACHE III-j model in each year. The ANZROD model showed better overall fit to the data, with smaller AIC and BIC values than the APACHE III-j model. Outlier ICUs identified using the ANZROD model were more strongly associated with increased mortality. CONCLUSION: The ANZROD model reduces variability in SMRs due to casemix, as measured by overdispersion, and facilitates more consistent identification of true outlier ICUs, compared with the APACHE III-j model. PMID- 26947414 TI - Palliative ICU beds for potential organ donors: an effective use of resources based on quality-adjusted life-years gained. AB - OBJECTIVE: To evaluate whether the admission of a palliative patient to the intensive care unit for end-of-life care and consideration of organ donation provides an equivalent net benefit in quality-adjusted life-years (QALYs) compared with the admission of a non-palliative patient for active management. DESIGN: Relevant publications from the period 1995-2015 were reviewed to estimate the mean QALYs gained from ICU admission of a critically ill patient and mean QALYs gained from transplantation of solid organs from an organ donor. Australian audit data were used to estimate the likelihood of a palliative patient admitted to the ICU progressing to organ donation. We calculated probabilities of each outcome and developed an algorithm to illustrate possible pathways for a patient who may progress to organ donation. RESULTS: A non-palliative ICU admission provides to the patient about 1.0 QALY per ICU bed-day. An ICU bed provided to a patient admitted to the ICU for palliation and consideration of organ donation results in 7.3 QALYs gained for the community per ICU bed-day. CONCLUSION: The admission of a dying patient to the ICU when organ donation may be possible is of considerable community benefit, yielding an average of over seven times the QALYs per ICU bed-day compared with the average benefit for ICU patients expected to survive. When it is possible to offer end-of-life care in the ICU, it should not be denied on the basis of concerns about lack of benefit or inappropriate use of resources. PMID- 26947415 TI - Insurance status and mortality in critically ill patients. AB - OBJECTIVE: The association between insurance status and outcome in critically ill patients is uncertain. We aimed to determine if there was an independent relationship between the presence or absence of compensable insurance status and mortality, after admission to the intensive care unit. METHODS: We performed a retrospective cohort study in five public hospitals in Victoria, comprising adult patients admitted to the ICU between 2007 and 2012. We obtained data on demographics, severity of illness, chronic health status, insurance category, length of stay (LOS) and mortality. We matched socio-economic indices (collected from the Australian Bureau of Statistics) to postcodes. The primary outcome measured was in-hospital mortality. Secondary outcomes were ICU mortality, and ICU and hospital LOS, measured in days. RESULTS: We studied 33 306 patients. Compensable patients comprised 21.2% of the study population (7046). Personal private insurance accounted for 13.4% (4451) and Transport Accident Commission insurance for 5.1% (1701) of compensable patients. Unadjusted in-hospital mortality was higher in publicly insured patients (13.4% v 10.6%, P < 0.0001). After adjusting for age, severity of illness, diagnosis and socio-economic status, being a compensable patient in a public hospital ICU was independently associated with a reduction in mortality (odds ratio, 0.73; 95% CI, 0.65-0.80; P < 0.001). CONCLUSIONS: Among ICU patients treated in public hospitals in Victoria, being a compensable patient appears to be independently associated with a reduction in mortality. Further studies are needed to confirm and validate these findings elsewhere in Australia. PMID- 26947417 TI - Gone fishing in a fluid trial. AB - OBJECTIVE: To maximise the yield of existing data by assessing the effect on mortality of being born under the zodiac sign Pisces in a trial of intravenous (IV) fluids. DESIGN, SETTING AND PARTICIPANTS: A retrospective observational study, with no predefined hypothesis or statistical analysis plan, of 26 Scandinavian intensive care units between 2009 and 2011. Patients aged 18 years or older with severe sepsis and in need of fluid resuscitation, randomised in the Scandinavian Starch for Severe Sepsis/ Septic Shock (6S) trial. MAIN OUTCOME MEASURE: Ninety-day mortality. RESULTS: We included all 798 randomised patients in our study; 70 (9%) were born under the sign of Pisces. The primary outcome (death within 90 days after randomisation) occurred in 25 patients (35.7%) in the Pisces group, compared with 348 patients (48%) in the non-Pisces group (relative risk, 0.75; 95% CI, 0.54-1.03; one-sided P = 0.03). CONCLUSIONS: In a multicentre randomised clinical trial of IV fluids, being born under the sign of Pisces was associated with a decreased risk of death. Our study shows that with convenient use of statistics and an enticing explanatory hypothesis, it is possible to achieve significant findings in post-hoc analyses of data from large trials. PMID- 26947416 TI - Validation of a classification system for causes of death in critical care: an assessment of inter-rater reliability. AB - OBJECTIVE: Trials in critical care have previously used unvalidated systems to classify cause of death. We aimed to provide initial validation of a method to classify cause of death in intensive care unit patients. DESIGN, SETTING AND PARTICIPANTS: One hundred case scenarios of patients who died in an ICU were presented online to raters, who were asked to select a proximate and an underlying cause of death for each, using the ICU Deaths Classification and Reason (ICU-DECLARE) system. We evaluated two methods of categorising proximate cause of death (designated Lists A and B) and one method of categorising underlying cause of death. Raters were ICU specialists and research coordinators from Australia, New Zealand and the United Kingdom. MAIN OUTCOME MEASURES: Inter rater reliability, as measured by the Fleiss multirater kappa, and the median proportion of raters choosing the most likely diagnosis (defined as the most popular classification choice in each case). RESULTS: Across all raters and cases, for proximate cause of death List A, kappa was 0.54 (95% CI, 0.49-0.60), and for proximate cause of death List B, kappa was 0.58 (95% CI, 0.53-0.63). For the underlying cause of death, kappa was 0.48 (95% CI, 0.44-0.53). The median proportion of raters choosing the most likely diagnosis for proximate cause of death, List A, was 77.5% (interquartile range [IQR], 60.0%-93.8%), and the median proportion choosing the most likely diagnosis for proximate cause of death, List B, was 82.5% (IQR, 60.0%-92.5%). The median proportion choosing the most likely diagnosis for underlying cause was 65.0% (IQR, 50.0%-81.3%). Kappa and median agreement were similar between countries. ICU specialists showed higher kappa and median agreement than research coordinators. CONCLUSIONS: The ICU-DECLARE system allowed ICU doctors to classify the proximate cause of death of patients who died in the ICU with substantial reliability. PMID- 26947418 TI - Use of neostigmine for acute colonic pseudo-obstruction in a patient receiving dexmedetomidine. PMID- 26947419 TI - The case for legislation: explicit rather than implicit rationing (who gets into the ICU and who doesn't). PMID- 26947420 TI - Using heterogeneity in the population structure of U.S. swine farms to compare transmission models for porcine epidemic diarrhoea. AB - In 2013, U.S. swine producers were confronted with the disruptive emergence of porcine epidemic diarrhoea (PED). Movement of animals among farms is hypothesised to have played a role in the spread of PED among farms. Via this or other mechanisms, the rate of spread may also depend on the geographic density of farms and climate. To evaluate such effects on a large scale, we analyse state-level counts of outbreaks with variables describing the distribution of farm sizes and types, aggregate flows of animals among farms, and an index of climate. Our first main finding is that it is possible for a correlation analysis to be sensitive to transmission model parameters. This finding is based on a global sensitivity analysis of correlations on simulated data that included a biased and noisy observation model based on the available PED data. Our second main finding is that flows are significantly associated with the reports of PED outbreaks. This finding is based on correlations of pairwise relationships and regression modeling of total and weekly outbreak counts. These findings illustrate how variation in population structure may be employed along with observational data to improve understanding of disease spread. PMID- 26947422 TI - Rebuttal: Coronary perforation: The solution is right on the table. PMID- 26947421 TI - Strong invaders are strong defenders - implications for the resistance of invaded communities. AB - Many ecosystems receive a steady stream of non-native species. How biotic resistance develops over time in these ecosystems will depend on how established invaders contribute to subsequent resistance. If invasion success and defence capacity (i.e. contribution to resistance) are correlated, then community resistance should increase as species accumulate. If successful invaders also cause most impact (through replacing native species with low defence capacity) then the effect will be even stronger. If successful invaders instead have weak defence capacity or even facilitative attributes, then resistance should decrease with time, as proposed by the invasional meltdown hypothesis. We analysed 1157 introductions of freshwater fish in Swedish lakes and found that species' invasion success was positively correlated with their defence capacity and impact, suggesting that these communities will develop stronger resistance over time. These insights can be used to identify scenarios where invading species are expected to cause large impact. PMID- 26947423 TI - Inhibition of para-Hydroxyphenylpyruvate Dioxygenase by Analogues of the Herbicide Nitisinone As a Strategy to Decrease Homogentisic Acid Levels, the Causative Agent of Alkaptonuria. AB - Alkaptonuria (AKU) is a rare multisystem metabolic disease caused by deficient activity of homogentisate 1,2-dioxygenase (HGD), which leads to the accumulation of homogentisic acid (HGA). Currently, there is no treatment for AKU. The sole drug with some beneficial effects is the herbicide nitisinone (1), an inhibitor of p-hydroxyphenylpyruvate dioxygenase (4-HPPD). 1 has been used as a life-saving drug in infants with type I tyrosinemia despite severe side effects due to the buildup of tyrosine. Four clinical trials of nitisinone to treat AKU have shown that 1 consistently decreases HGA levels, but also caused the accumulation of tyrosine in blood serum. Moreover, the human preclinical toxicological data for 1 are incomplete. In this work, we performed pharmacodynamics and toxicological evaluations of 1, providing the first report of LD50 values in human cells. Intracellular tyrosinemia was also evaluated. Three additional 4-HPPD inhibitors with a more favorable profile than that of 1 in terms of IC50, LD50, and tyrosine accumulation were also identified among commercially available compounds. These may be promising starting points for the development of new therapeutic strategies for the treatment of AKU. PMID- 26947424 TI - Differential visceral blood flow in the hyperdynamic circulation of patients with liver cirrhosis. AB - BACKGROUND: With advancing liver disease and the development of portal hypertension, there are major alterations in somatic and visceral blood flow. Using phase-contrast magnetic resonance angiography, we characterised alterations in blood flow within the hepatic, splanchnic and extra-splanchnic circulations of patients with established liver cirrhosis. AIM: To compare blood flow in splanchnic and extra-splanchnic circulations in patients with varying degrees of cirrhosis and healthy controls. METHODS: In a single-centre prospective study, 21 healthy volunteers and 19 patients with established liver disease (Child's stage B and C) underwent electrocardiogram-gated phase-contrast-enhanced 3T magnetic resonance angiography of the aorta, hepatic artery, portal vein, superior mesenteric artery, and the renal and common carotid arteries. RESULTS: In comparison to healthy volunteers, resting blood flow in the descending thoracic aorta was increased by 43% in patients with liver disease (4.31 +/- 1.47 vs. 3.31 +/- 0.80 L/min, P = 0.011). While portal vein flow was similar (0.83 +/- 0.38 vs. 0.77 +/- 0.35 L/min, P = 0.649), hepatic artery flow doubled (0.50 +/- 0.46 vs. 0.25 +/- 0.15 L/min, P = 0.021) and consequently total liver blood flow increased by 30% (1.33 +/- 0.84 vs. 1.027 +/- 0.5 L/min, P = 0.043). In patients with liver disease, superior mesenteric artery flow was threefold higher (0.65 +/- 0.35 vs. 0.22 +/- 0.13 L/min, P < 0.001), while total renal blood flow was reduced by 40% (0.37 +/- 0.14 vs. 0.62 +/- 0.22 L/min, P < 0.001) and total carotid blood flow unchanged (0.62 +/- 0.20 vs. 0.65 +/- 0.13 L/min, P = 0.315). CONCLUSIONS: Rather than a generalised systemic hyperdynamic circulation, liver disease is associated with dysregulated splanchnic vasodilatation and portosystemic shunting that, while inducing a high cardiac output, causes compensatory extra-splanchnic vasoconstriction - the 'splanchnic steal' phenomenon. These circulatory disturbances may underlie many of the manifestations of advanced liver disease. PMID- 26947425 TI - Haematogone hyperplasia in copper deficiency. PMID- 26947426 TI - Oral morphosyntactic competence as a predictor of reading comprehension in children with specific language impairment. AB - BACKGROUND: Children with a diagnosis of specific language impairment (SLI) present impaired oral comprehension. According to the simple view of reading, general amodal linguistic capacity accounts for both oral and reading comprehension. Considering this, we should expect SLI children to display a reading comprehension deficit. However, previous research regarding the association between reading disorders and SLI has yielded inconsistent results. AIMS: To study the influence of prior oral comprehension competence over reading comprehension during the first years of reading acquisition of bilingual Catalan Spanish children with SLI (ages 7-8). METHODS & PROCEDURES: We assessed groups of bilingual Catalan-Spanish SLI and matched control children at ages 7 and 8 with standardized reading comprehension tasks including grammatical structures, sentence and text comprehension. Early oral competence and prior non-verbal intelligence were also measured and introduced into regression analyses with the participants' reading results in order to state the relation between the comprehension of oral and written material. OUTCOMES & RESULTS: Although we found no significant differences between the scores of our two participant groups in the reading tasks, data regarding their early oral competence, but not non-verbal intelligence measures, significantly influence their reading outcome. CONCLUSIONS & IMPLICATIONS: The results extend our knowledge regarding the course of literacy acquisition of children with SLI and provide evidence in support of the theories that assume common linguistic processes to be responsible for both oral and reading comprehension. PMID- 26947427 TI - Profiling the U.S. Sick Leave Landscape: Presenteeism among Females. AB - OBJECTIVE: To profile the sick leave landscape in the United States. DATA SOURCES: The 2011 Leave Supplement of the American Time Use Survey. STUDY DESIGN: Bivariate and multivariate analyses to identify (i) employees without sick pay coverage and (ii) employees who attend work sick. PRINCIPAL FINDINGS: Sixty-five percent of full-time employees have sick pay coverage. Coverage rates are below 20 percent for employees with hourly wages below $10, part-time employees, and employees in the hospitality and leisure industry. CONCLUSION: Each week, up to 3 million U.S. employees go to work sick. Females, low-income earners, and those aged 25 to 34 years have a significantly elevated risk of presenteeism behavior. PMID- 26947429 TI - Thermal taster status: Evidence of cross-modal integration. AB - Thermal taster status refers to the finding that, in some individuals, thermal stimulation of the tongue elicits a phantom taste. Little is known regarding the mechanism for this, it is hypothesised to be a result of cross-wiring between gustatory and trigeminal nerves whose receptors co-innervate papillae on the tongue. To address this, we use functional magnetic resonance imaging to perform the first study of whether the cortical response to gustatory-trigeminal samples is altered with thermal taster status. We study the response to cold (6 degrees C) gustatory (sweet) samples at varying levels of trigeminal stimulation elicited by CO2 (no CO2 , low CO2 , high CO2 ) in thermal taster (TT) and thermal non taster (TnT) groups, and evaluate associated behavioural measures. Behaviourally, the TT group perceived gustatory and trigeminal stimuli significantly more intense than TnTs, and were significantly more discriminating of CO2 level. fMRI data revealed elevated cortical activation to the no CO2 sample for the TT group compared to TnT group in taste, oral somatosensory and reward areas. In TnTs, a significant positive modulation in cortical response with increasing level of CO2 was found across taste, somatosensory and reward areas. In contrast, in TTs, a reduced positive modulation with increasing level of CO2 was found in somatosensory areas (SI, SII), whilst a significant negative modulation was found in taste (anterior insula) and reward (ACC) areas. This difference in cortical response to trigeminal stimuli supports cross-modal integration in TTs, with gustatory and trigeminal nerves highly stimulated by cold gustatory samples due to their intertwined nature. Hum Brain Mapp 37:2263-2275, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26947430 TI - Erratum. PMID- 26947428 TI - Preoperative NLR and PLR in the middle or lower ESCC patients with radical operation. AB - Neutrophil lymphocyte ratio (NLR) and platelet lymphocyte ratio (PLR) had been analysed in many kind of tumours, but its role of predict the oesophageal squamous cell carcinoma (ESCC) patients' prognosis was not reach a consensus. Relationship between NLR, PLR and ESCC located in the middle or lower segment was evaluated. 317 patients with ESCC who underwent attempted curative oesophagectomy were analysed in this study. 157 and 98 patients had elevated NLR and PLR respectively (NLR >3.3 and PLR >150). The median overall survival time (OS) and disease-free survival (DFS) was 34.1 and 19.2 months respectively. Multivariate analysis found PLR >150 (P = 0.018, HR 1.426, 95%CI 1.063-1.912) accompanied by male, lymphatic metastases, tumour size more than 3 cm, tumour located at middle segment and poor differentiation were associated with significantly worse DFS. Meanwhile, gender, lymphatic metastases, tumour location and differentiation along with PLR >150 (P = 0.003, HR 1.595, 95% CI 1.172-2.170) and NLR>3.3 (P = 0.039, HR 1.367, 95% CI 1.015-1.840) were all independent prognostic factors for OS. Preoperative NLR and PLR might be used as predictive factors in patients with ESCC. For DFS, elevated PLR compared to NLR may have an advantage to indicate poor prognosis. PMID- 26947432 TI - Endoscopic ultrasound-guided fine-needle aspiration for diagnosis of Burkitt's lymphoma in the pancreas of a 3 year old. PMID- 26947433 TI - Noninvasive Diagnosis of Bladder Outlet Obstruction in Patients with Lower Urinary Tract Symptoms Using Ultrasound Decorrelation Analysis. AB - PURPOSE: We developed a noninvasive method to diagnose bladder outlet obstruction. An ultrasound based decorrelation method was applied in male patients with lower urinary tract symptoms. MATERIALS AND METHODS: In 60 patients ultrasound data were acquired transperineally while they were voiding while sitting. Each patient also underwent a standard invasive pressure flow study. RESULTS: High frequent sequential ultrasound images were successfully recorded during voiding in 45 patients. The decorrelation (decrease in correlation) between subsequent ultrasound images was higher in patients with bladder outlet obstruction than in unobstructed patients and healthy volunteers. ROC analysis resulted in an AUC of 0.96, 95% specificity and 88% sensitivity. A linear relationship was fitted to the decorrelation values as a function of the degree of obstruction represented by the bladder outlet obstruction index, measured in the separate pressure flow studies. CONCLUSIONS: It is possible to noninvasively diagnose bladder outlet obstruction using the ultrasound decorrelation technique. PMID- 26947434 TI - Testicular Biopsy for Fertility Preservation in Prepubertal Boys with Cancer: Identifying Preferences for Procedure and Reactions to Disclosure Practices. AB - PURPOSE: Fertility preservation options are limited in prepubertal boys with cancer. Worldwide there has been growing interest in testicular tissue cryopreservation as a promising experimental strategy to address future infertility. We measured and compared parent, male cancer survivor and provider willingness to accept the risk of testicular biopsy among prepubertal boys with cancer, and identified reactions to disclosure practices. MATERIALS AND METHODS: We conducted a multicenter study that included 153 parents of prepubertal boys with cancer, 77 male survivors of childhood cancer and 30 oncology providers. The threshold technique was used to measure subject relative willingness to accept risk of testicular biopsy under 4 different aspects of care, ie chance of infertility, complications from biopsy, development of technology to use tissue and tissue storage cost. A total of 47 in-depth interviews were conducted to identify reactions to disclosure practices. RESULTS: A total of 52 survivors (67%), 22 providers (73%) and 110 parents (72%) selected to have testicular biopsy (vs no biopsy). Median minimum infertility risk to make biopsy worthwhile varied from 25% to 30% among the 3 respondent groups. Interviews revealed that some providers would not offer biopsy in cases of greater perceived risk than benefit, that parents preferred having information regardless of risk of infertility and that nondisclosure elicited adverse feelings from some parents. CONCLUSIONS: Parents, survivors and providers were willing to accept risk of prepubertal testicular biopsy. Parental/survivor desire for information and provider decision not to disclose suggest that barriers to information delivery need to be addressed. PMID- 26947435 TI - Obstetric and gynecologic malpractice claims in Saudi Arabia: Incidence and cause. AB - INTRODUCTION: The occurrence of a bad outcome, injury or death of a patient during treatment increases the chance of malpractice litigation, increases legal responsibility and leads to increased fees for malpractice insurance. Physicians practicing obstetrics and gynecology face among the highest risks of malpractice litigation, and such litigation has led to an increase in the practice of defensive medicine and has made this specialty less appealing. Previous clinical data from Saudi Arabia have shown that more malpractice litigation concerns claims in obstetrics and gynecology than claims in any other field of medicine. OBJECTIVE: To identify the main causes of obstetrics and gynecology (OBGYN) professional liability claims in Saudi Arabia to have a better understanding and management of risks. METHODS: All OBGYN claims opened in Saudi Arabia between 2008 and 2013 were analyzed to identify the most common causes of claims. The results of these claims and the times until a final judgment made were also analyzed. RESULTS: Out of a total of 463 malpractice claims that were closed during the study period, 114 (24.6%) claims were in obstetrics and gynecology, and 92 (80.7%) of these claims concerned complications related to delivery room events. The most common causes of obstetric malpractice litigation were shoulder dystocia (brachial plexus injury) and fetal distress (hypoxic ischemic encephalopathy). Urinary system injury was the most common cause of gynecology cases. Most cases were decided in favor of the defendants with the exception of cases for which maternal and/or fetal death was the cause of litigation; nearly all of those cases were decided against the defendants. CONCLUSION: Obstetricians face a high risk of malpractice claims in Saudi Arabia, although most claims do not end in payments to plaintiffs. However, the effects of such claims on obstetric care should not be underestimated. Adherence to standards of care and careful documentation may decrease litigation and the number of indefensible malpractice claims. PMID- 26947436 TI - Primary Urinary Bladder Angiosarcoma with Osteoclast-Like Multinucleated Giant Cells: A Case Report and Literature Review. AB - BACKGROUND: Angiosarcoma is a fatal and aggressive mesenchymal tumor. It occurs in skin, breast, and parenchymal organs. It rarely arises primarily in the urinary bladder. Only 13 cases of primary urinary bladder angiosarcoma have been reported in the English literature. CASE REPORT: The patient was a 68-year-old man who presented to the Emergency Department with inability to void. Computed tomography of the abdomen and pelvis showed a urinary bladder mass. Surgical excision of the mass was performed. Pathological examination results were consistent with angiosarcoma. In addition to the unusual location of this tumor, the pathology was different from the previously reported cases in that this case was rich with osteoclast-like multinucleated giant cells. CONCLUSIONS: The pathological diagnosis of primary urinary bladder angiosarcoma is challenging. Histological patterns and immunophenotypes are variable. Here, we review all reported cases of primary urinary bladder angiosarcoma, highlight the clinical and morphological features of this malignant neoplasm, and report a unique case of primary urinary bladder angiosarcoma with osteoclast-like multinucleated giant cells. PMID- 26947438 TI - Biosimilars: Rationale and current regulatory landscape. AB - OBJECTIVES: To discuss current terminology and the regulatory standards and processes involved in the development of biosimilars. METHODS: An Internet-based literature search through April 2015 was performed for information related to biosimilars in chronic inflammatory disorders. Keywords were as follows: biosimilar, development, manufacturing, characterization, structural, functional, preclinical, clinical, immunogenicity, rheumatoid arthritis, juvenile idiopathic arthritis, psoriasis, psoriatic arthritis, Crohn's disease, ulcerative colitis, and ankylosing spondylitis. The European Medicines Agency (EMA) and US Food and Drug Administration (FDA) websites were searched for guidelines and information related to biosimilars. RESULTS: Biosimilars are products that are highly similar to the reference product regarding quality, biological activity, safety, and efficacy. Biosimilars are biological products and not generic drugs and, thus, do not follow the same regulatory pathways as generic molecules. Rigorous early stage structural, functional, and analytical testing, followed by nonclinical and clinical analyses comparing a biosimilar with its reference product, are required to demonstrate biosimilarity in regulatory markets worldwide. CONCLUSIONS: The addition of biosimilars to the market has the potential to improve access to biologic therapies. Many regulatory agencies have enacted stringent pathways, which must be followed for a biosimilar to be labeled and approved as such; following the pathways will help protect and maintain the integrity, quality, and safety of the biosimilar product. PMID- 26947439 TI - Treatment of tophaceous gout: When medication is not enough. AB - OBJECTIVES: To review the literature concerning surgical intervention of tophaeceous gout and propose clinical circumstances for when it may be considered. INTRODUCTION: Tophi develop in approximately 12-35% of patients with gout. Tophaceous disease is usually preventable given the availability of effective urate lowering therapies (ULT) including allopurinol, febuxostat, probenecid, lesinurad, and pegloticase. Despite medical therapy, there remains a subset of patients who develop significant complications of tophi including infection, ulceration, and entrapment neuropathy. Tophi in close proximity to joints can cause joint instability, severely limited range of motion, and significant functional impairment. For the rare circumstance when a tophus is causing an urgent complication or if a patient has a contraindication to all available ULTs, surgery may be an appropriate option. This review summarizes the published experience with surgical interventions for tophaceous gout and offers recommendations for its consideration. METHODS: Using Medline and Google Scholar, all available series of surgery for tophaceous gout were reviewed. RESULTS: Overall, 7 published surgical series were identified. In all, 6 of these 7 series were published between 2002 and 2014. The reported outcomes of surgical interventions for tophaceous gout were generally positive without major post surgical complications. CONCLUSION: Although medical therapy with ULTs should be the first-line approach to tophaceous gout, surgery should be considered for the rare patient with impending or severe, debilitating complications including infections, entrapment neuropathy or those at risk for permanent joint destruction. In these selected clinical circumstances, surgical intervention for tophaceous gout may be appropriate. PMID- 26947437 TI - Spatial organization of acute myocardial ischemia. AB - INTRODUCTION: Myocardial ischemia is a pathological condition initiated by supply and demand imbalance of the blood to the heart. Previous studies suggest that ischemia originates in the subendocardium, i.e., that nontransmural ischemia is limited to the subendocardium. By contrast, we hypothesized that acute myocardial ischemia is not limited to the subendocardium and sought to document its spatial distribution in an animal preparation. The goal of these experiments was to investigate the spatial organization of ischemia and its relationship to the resulting shifts in ST segment potentials during short episodes of acute ischemia. METHODS: We conducted acute ischemia studies in open-chest canines (N=19) and swines (N=10), which entailed creating carefully controlled ischemia using demand, supply or complete occlusion ischemia protocols and recording intramyocardial and epicardial potentials. Elevation of the potentials at 40% of the ST segment between the J-point and the peak of the T-wave (ST40%) provided the metric for local ischemia. The threshold for ischemic ST segment elevations was defined as two standard deviations away from the baseline values. RESULTS: The relative frequency of occurrence of acute ischemia was higher in the subendocardium (78% for canines and 94% for swines) and the mid-wall (87% for canines and 97% for swines) in comparison with the subepicardium (30% for canines and 22% for swines). In addition, acute ischemia was seen arising throughout the myocardium (distributed pattern) in 87% of the canine and 94% of the swine episodes. Alternately, acute ischemia was seen originating only in the subendocardium (subendocardial pattern) in 13% of the canine episodes and 6% of the swine episodes (p<0.05). CONCLUSIONS: Our findings suggest that the spatial distribution of acute ischemia is a complex phenomenon arising throughout the myocardial wall and is not limited to the subendocardium. PMID- 26947440 TI - Development of biosimilars. AB - OBJECTIVE: To provide an overview of the underlying scientific principles and standards for developing a biosimilar product. METHODS: An Internet-based literature search through June 2015 was performed for information related to biosimilar manufacturing and development, including a review of regulatory guidelines and requirements. RESULTS: Biologics, both biosimilars and their corresponding reference products, are complex molecules produced by biotechnology in living systems. The development of biologics involves multiple levels of intricate, highly controlled manufacturing processes, combined with pre-clinical structural, functional, and biological assessments, as well as clinical efficacy and safety, including immunogenicity, analyses. In addition, to ensure a high degree of similarity, a biosimilar must undergo a comparability exercise at every step of its development, as outlined by regulatory agencies, to demonstrate that potential differences from the reference product are not clinically meaningful with regard to quality, safety, and efficacy [European Medicines Agency (EMA)] or safety, purity, and potency [US Food and Drug Administration (FDA)]. At the foundation of the biosimilar development process lays the establishment of a high degree of structural similarity with its reference product. State-of-the-art technologies must be employed to demonstrate a high degree of structural and functional similarity. Finally, clinical pharmacokinetic and pharmacodynamic as well as clinical efficacy and safety similarity must be confirmed between biosimilar and originator. Regulators, including the FDA and the EMA consider the totality of the evidence from this comprehensive step-wise comparative similarity exercise in its determination of biosimilarity for licensing. CONCLUSIONS: The rigorous and highly regulated processes required to develop a biosimilar have been designed as such to establish a high degree of biosimilarity with a reference product in terms of the structural, functional, biological, and clinical attributes. PMID- 26947441 TI - Direct Detection of Fe(II) in Extracellular Polymeric Substances (EPS) at the Mineral-Microbe Interface in Bacterial Pyrite Leaching. AB - We herein investigated the mechanisms underlying the contact leaching process in pyrite bioleaching by Acidithiobacillus ferrooxidans using scanning transmission X-ray microscopy (STXM)-based C and Fe near edge X-ray absorption fine structure (NEXAFS) analyses. The C NEXAFS analysis directly showed that attached A. ferrooxidans produces polysaccharide-abundant extracellular polymeric substances (EPS) at the cell-pyrite interface. Furthermore, by combining the C and Fe NEXAFS results, we detected significant amounts of Fe(II), in addition to Fe(III), in the interfacial EPS at the cell-pyrite interface. A probable explanation for the Fe(II) in detected EPS is the leaching of Fe(II) from the pyrite. The detection of Fe(II) also indicates that Fe(III) resulting from pyrite oxidation may effectively function as an oxidizing agent for pyrite at the cell-pyrite interface. Thus, our results imply that a key role of Fe(III) in EPS, in addition to its previously described role in the electrostatic attachment of the cell to pyrite, is enhancing pyrite dissolution. PMID- 26947442 TI - Morphological, Physiological, and Taxonomic Characterization of Actinobacterial Isolates Living as Endophytes of Cacao Pods and Cacao Seeds. AB - Vascular plants are commonly colonized by endophytic actinobacteria. However, very little is known about the relationship between these microorganisms and cacao fruits. In order to determine the physiological and taxonomic relationships between the members of this community, actinobacteria were isolated from cacao fruits and seeds. Among the 49 isolates recovered, 11 morphologically distinct isolates were selected for further characterization. Sequencing of the 16S rRNA gene allowed the partition of the selected isolates into three phylogenetic clades. Most of the selected endophytic isolates belonged to the Streptomyces violaceusniger clade. Physiological characterization was carried out and a similarity index was used to cluster the isolates. However, clustering based on physiological properties did not match phylogenetic lineages. Isolates were also characterized for traits commonly associated with plant growth-promoting bacteria, including antibiosis and auxin biosynthesis. All isolates exhibited resistance to geldanamycin, whereas only two isolates were shown to produce this antibiotic. Endophytes were inoculated on radish seedlings and most isolates were found to possess plant growth-promoting abilities. These endophytic actinobacteria inhibited the growth of various plant pathogenic fungi and/or bacteria. The present study showed that S. violaceusniger clade members represent a significant part of the actinobacterial community living as endophytes in cacao fruits and seeds. While several members of this clade are known to be geldanamycin producers and efficient biocontrol agents of plant diseases, we herein established the endophytic lifestyle of some of these microorganisms, demonstrating their potential as plant health agents. PMID- 26947443 TI - Sulfur Fertilization Changes the Community Structure of Rice Root-, and Soil- Associated Bacteria. AB - Under paddy field conditions, biological sulfur oxidation occurs in the oxidized surface soil layer and rhizosphere, in which oxygen leaks from the aerenchyma system of rice plants. In the present study, we examined community shifts in sulfur-oxidizing bacteria associated with the oxidized surface soil layer and rice roots under different sulfur fertilization conditions based on the 16S ribosomal RNA (rRNA) gene in order to explore the existence of oligotrophic sulfur-oxidizing bacteria in the paddy rice ecosystem. Rice plants were grown in pots with no fertilization (control) or CaCO3 or CaSO4 fertilization. A principal coordinates analysis (PCoA) showed that CaSO4 fertilization markedly affected bacterial communities associated with rice roots and soil, whereas no significant differences were observed in plant growth among the fertilizer treatments examined. In rice roots, the relative abundance of Acidobacteria, Alphaproteobacteria, Gammaproteobacteria, and TM7 was significantly higher in CaSO4-fertilized pots than in control pots. Alphaproteobacteria, Bradyrhizobiaceae, and Methylocystaceae members were significantly more abundant in CaSO4-fertilized roots than in control roots. On the other hand, the abundance of Actinobacteria and Proteobacteria was lower in CaSO4-fertilized soil than in control soil. These results indicate that the bacteria associated with rice roots and soil responded to the sulfur amendment, suggesting that more diverse bacteria are involved in sulfur oxidation in the rice paddy ecosystem than previously considered. PMID- 26947444 TI - Benchmarking the mARC performance - treatment time and dosimetric linearity. AB - PURPOSE: The mARC technique is a hybrid rotational IMRT modality operating in "burst mode". While it is generally assumed that it will be slower than VMAT, the real limits of operation have not been defined so far. We here present the first systematic study of the technical limits on mARC treatment. METHODS: The following scenarios are considered: 18, 30, 36 or 45 arclets per rotation (spacing between 20 degrees and 8 degrees ), flat and flattening-filter-free (FFF) energy, arclet width 4 degrees or 2 degrees , from 1 MU/arclet to 1000 MU/plan. All scenarios are irradiated, treatment times are measured and treatment parameters reported. Dose linearity was assessed by point dose measurements of the 18 arclet plans with 1-30 MU per arclet. RESULTS: Minimum treatment times (no MLC movement, few MUs) depend strongly on the number of arclets per rotation (1minute for 18 arclets to 1:50min for 45 arclets), and rise linearly with MU/arclets after a given cut-off value depending on scenario, arclet width and available maximum dose rate. MLC movement adds up to 2minutes of treatment time, but generally less (ca. 45seconds in realistic plans). The rules by which irradiation parameters are selected by the firmware can be partly discovered. The choice of dose rate is most clearly defined. For the flat 6 MV energy, the highest available dose rate (300 MU/min) is always applied. For FFF 7 MV dose rate is reduced for arclets with few MUs, so that an arclet is irradiated in no less than 0.3 s. Only for the case of 1 MU/arclet can this constraint not be met (the technical limit on the dose rate if 500 MU/min for FFF 7 MV). In this case, dosimetric linearity is reduced. In all other instances, deviations from linearity at low MU remain below 2%. CONCLUSIONS: Treatment times of down to 90seconds are technically achievable for treatment with FFF beams using up to 36 arclets per rotation (arclet spacing every 10 degrees ) for up to 900 MU/plan, comparable to VMAT treatment times. The values provided here are meant to serve as a reference for the design of mARC plans (choice of arclets spacing etc.) and as minimum times against which the performance of different treatment planning systems can be evaluated. PMID- 26947447 TI - Influence of Food Intake on 2-D Shear Wave Elastography Assessment of Liver Stiffness in Healthy Subjects. AB - Transient elastography and Acoustic Radiation Force Impulse imaging are useful non-invasive methods for liver stiffness estimation, although both are influenced by food intake. The aim of the work described here was to identify liver stiffness variation after a standardized meal using 2-D shear wave elastography. Liver stiffness was estimated in 31 apparently healthy subjects, under fasting conditions and after a standardized meal (20, 40, 60, 80, 100 and 120 min after food intake). In most of the cases, liver stiffness values increased between 20 and 40 min after the meal (p < 0.05) and then significantly decreased between 60 and 80 min (p < 0.05). At 120 min after food intake, liver stiffness values were significantly lower compared with liver stiffness values under fasting conditions (p < 0.05). Gender, but not body mass index, had an important role in liver stiffness variation after food intake (p < 0.01). In conclusion, to avoid the influence of food intake on liver stiffness estimation, 2-D shear wave elastography should be performed only under fasting conditions. PMID- 26947445 TI - Identifying Clinically Significant Prostate Cancers using 3-D In Vivo Acoustic Radiation Force Impulse Imaging with Whole-Mount Histology Validation. AB - Overly aggressive prostate cancer (PCa) treatment adversely affects patients and places an unnecessary burden on our health care system. The inability to identify and grade clinically significant PCa lesions is a factor contributing to excessively aggressive PCa treatment, such as radical prostatectomy, instead of more focal, prostate-sparing procedures such as cryotherapy and high-dose radiation therapy. We have performed 3-D in vivo B-mode and acoustic radiation force impulse (ARFI) imaging using a mechanically rotated, side-fire endorectal imaging array to identify regions suspicious for PCa in 29 patients being treated with radical prostatectomies for biopsy-confirmed PCa. Whole-mount histopathology analyses were performed to identify regions of clinically significant/insignificant PCa lesions, atrophy and benign prostatic hyperplasia. Regions of suspicion for PCa were reader-identified in ARFI images based on boundary delineation, contrast, texture and location. These regions of suspicion were compared with histopathology identified lesions using a nearest-neighbor regional localization approach. Of all clinically significant lesions identified on histopathology, 71.4% were also identified using ARFI imaging, including 79.3% of posterior and 33.3% of anterior lesions. Among the ARFI-identified lesions, 79.3% corresponded to clinically significant PCa lesions, with these lesions having higher indices of suspicion than clinically insignificant PCa. ARFI imaging had greater sensitivity for posterior versus anterior lesions because of greater displacement signal-to-noise ratio and finer spatial sampling. Atrophy and benign prostatic hyperplasia can cause appreciable prostate anatomy distortion and heterogeneity that confounds ARFI PCa lesion identification; however, in general, ARFI regions of suspicion did not coincide with these benign pathologies. PMID- 26947446 TI - Assistant role of bioelectrode on methanogenic reactor under ammonia stress. AB - To assess the role of abiotic/biotic electrode and electric field for enhancing methanogenesis under ammonia stress, three sets were conducted, i.e. R1 (titanium electrode+closed circuit), R2 (graphite felt+closed circuit), R3 (graphite felt+open circuit). Volatile fatty acids (VFAs) degradation and methane generation were gradually inhibited in all reactors when elevating NH4(+)-N to 4g/L; nevertheless, butyrate and propionate degradation rates in R2 and R3 were enhanced by 10-70% as compared to R1. Under the extremely high stress of NH4(+)-N (6g/L), insignificant difference was found among three tests and the methanogenesis were seriously hampered. Under ammonium stress, abundance of Methanobacterium significantly increased without electricity stimulation, however, acetoclastic Methanosaeta was found to survive and even increase in R2. Furthermore, Methanosaeta was enriched on graphite felt biofilm as compared to the suspended sludge, indicating the assistant role of bioelectrode for the methanogenesis under ammonium stress. PMID- 26947448 TI - Safety of a picosecond laser with diffractive lens array (DLA) in the treatment of Fitzpatrick skin types IV to VI: A retrospective review. AB - BACKGROUND: Laser therapy in patients with skin of color is associated with an increased rate of complications. The 755-nm picosecond laser with the diffractive lens array (DLA) has been used for the treatment of scars, striae, and rejuvenation. By delivering high energy to focused areas, the DLA minimizes complications. OBJECTIVE: This study explores the adverse events associated with treatment with the 755-nm picosecond laser with DLA in individuals with Fitzpatrick skin type IV to VI. METHOD: A retrospective chart review of patients treated with the 755-nm picosecond laser with DLA with a standardized spot size of 6 mm, fluence of 0.71 J/cm(2), and pulse width of 750 to 850 picoseconds was performed. Standard clinical photographs were obtained before treatment and at follow-up. Treatment sites were assessed for dyspigmentation, erythema, edema, and herpetic lesions. RESULTS: A total of 56 patients with Fitzpatrick skin type IV to VI, atrophic and hypertrophic scars, and pigmented lesions or striae were included. Ten patients (17.9%) were lost to follow-up. Transient adverse events, most commonly erythema and hyperpigmentation, were reported after therapy; these resolved in all cases. LIMITATIONS: Retrospective design is a limitation. CONCLUSION: The 755-nm picosecond laser with the DLA device may be a safe therapeutic alternative for unwanted scars, pigmented lesions, and striae in patients with skin of color. PMID- 26947449 TI - Comparison of 3 type VII collagen (C7) assays for serologic diagnosis of epidermolysis bullosa acquisita (EBA). AB - BACKGROUND: Serologic diagnosis of epidermolysis bullosa acquisita (EBA) relies on the detection of circulating autoantibodies to type VII collagen (C7). OBJECTIVE: We sought to compare the diagnostic performances of a commercialized enzyme-linked immunosorbent assay (ELISA) using C7 noncollagenous (NC) domains (C7-NC1/NC2 ELISA) and indirect immunofluorescence (IIF) biochip test on NC1-C7 expressing transfected cells (IIFT), with a full-length-C7 ELISA developed in our laboratory. METHODS: C7-NC1/NC2 ELISA, IIFT, and full-length-C7 ELISA were run on 77 nonselected consecutive EBA sera. RESULTS: C7-NC1/NC2 ELISA, IIFT, and full length-C7 ELISA were positive, respectively, for: 30%, 27%, and 65% of the 77 sera; 43%, 32%, and 80% of 44 sera labeling the salt-split-skin (SSS) floor (F) by IIF (SSS/F(+)); 9%, 22%, and 47% of 32 SSS/F(-) sera; 28%, 28%, and 58% of classic EBA; 41%, 41%, and 82% of inflammatory EBA; and 18%, 0%, and 55% of mucous-membrane-predominant EBA. Significant differences for all sera were found between: the 2 ELISAs for the 77 sera, SSS/F(+) and SSS/F(-) sera, and IIFT versus full-length-C7 ELISA. LIMITATIONS: The retrospective design was a limitation. CONCLUSION: C7-NC1/NC2 ELISA and IIFT sensitivities for serologic diagnoses of EBA were low. Full-length-C7 ELISA was significantly more sensitive and could serve as a reference test. PMID- 26947450 TI - Reduction in nevus biopsies in patients monitored by total body photography. AB - BACKGROUND: Total body photography (TBP) can facilitate identification of new and changing lesions. By confirming that particular nevi are stable, TBP may reduce nevus biopsies. OBJECTIVES: We sought to determine the number and rate of nevus biopsies before and after TBP, and the factors associated with increased biopsy rate during monitoring by TBP. METHODS: We reviewed records of all patients in 2 pigmented lesion clinics (PLCs) who received TBP and had 2 or more follow-up visits over a period of 2 years or longer. RESULTS: Before PLCs and TBP, the mean number of nevus biopsies per patient was 5.92 (589 patients) at a mean rate of 1.62 per year (160 patients). After TBP in PLCs, the same patients averaged 1.56 biopsies at a mean rate of 0.34 per year (P < 2 * 10(-16)). The entire cohort (926 patients) averaged similarly low post-TBP biopsy rates of less than 0.2 per year and per visit. Biopsy rates after TBP were positively correlated with decreased age, male gender, and family history of melanoma, but not nevus number. LIMITATIONS: Some information was not available for some patients. CONCLUSIONS: Patients at risk for melanoma experienced a 3.8-fold reduction in nevus biopsies after TBP. Younger male patients with family history of melanoma had higher biopsy rates after TBP. PMID- 26947451 TI - Strategies to manage refractory endometrium: state of the art in 2016. AB - The endometrium is one of a number of factors involved in achieving optimal outcomes after assisted reproductive treatment. Owing to its "passive" growth following adequate ovarian stimulation, it has received virtually no attention. Only when either endometrial thickness or ultrasonographic pattern seem inadequate have different strategies been assessed to try to improve it, especially in those cases where it seems difficult or impossible to make it grow. The objective of this review is to summarize the different strategies that have been investigated in patients with inadequate endometrium, to attempt to provide solid evidence of therapies that may be beneficial and to move away from empirism. A review of the existing literature was performed by searching MEDLINE, EMBASE, Cochrane library and Web of Science for publications in English related to refractory endometrium. Most current treatments are based on anecdotal cases and not on solid data, although worldwide many doctors and patients use them. In conclusion, this review found that it is not easy to provide a pragmatic, evidence-based approach to help physicians and patients confused by the available data on how to improve a poor endometrium. Honest balanced information provided to our patients is the best that we can do. PMID- 26947452 TI - Knowledge of, and treatment strategies for, endometriosis among general practitioners. AB - Endometriosis is the most common benign gynaecological disorder. The general practitioner (GP) plays an important role in identifying women at early stages of the disease. This study was conducted to acquire information about awareness and knowledge of endometriosis among Dutch GPs, and clinical strategies taken. A total of 101 GPs completed a questionnaire either by email or at a local education meeting. The GPs annually encounter 2.8 women they suspect of having endometriosis. The estimated time to diagnosis was 65.7 months (39.1 months patient delay and 26.6 months doctors delay); 56.7% of GPs primarily refer to a gynaecologist for consultation or diagnostic tests. The GPs answered on average 16.6 out of 28 knowledge questions correctly. Seventy-six out of 87 GPs stated that they needed further education. The results of this study indicate that if a GP considers endometriosis as a diagnosis, adequate action is undertaken. As only limited numbers of women with endometriosis are encountered in their practice, GPs do not recognize immediately the symptoms that may be caused by endometriosis, leading to diagnostic delay. Our findings may help to set up teaching programmes and awareness strategies for first-line medical professionals to enhance timely diagnosis and treatment of endometriosis. PMID- 26947453 TI - Anti-osteoclastogenic activity of isoliquiritigenin via inhibition of NF-kappaB dependent autophagic pathway. AB - Previous studies, including those from our laboratory, have demonstrated that the natural flavonoid isoliquiritigenin (ISL) is a promising agent for bone destructive diseases. However, the mechanisms underlying its anti osteoclastogenic effects are still far from clear. Here, we evaluated the potential alterations of autophagy and nuclear factor-kappaB (NF-kappaB) during anti-osteoclastogenic effects by ISL in vitro and in vivo. We observed that ISL inhibited the receptor activator of nuclear factor-kappaB ligand (RANKL)-induced osteoclastogenesis and suppressed autophagic microtubule-associated protein light chain 3 (LC3)-II and Beclin 1 accumulation. ISL treatment resulted in the interruption of several specific features for autophagy in osteoclast precursors, including acidic vesicular organelle formation, LC3-II accumulation, and appearance of autophagic vacuoles. The RANKL-stimulated expression levels of autophagy-related genes and proteins also diminished in ISL-treated osteoclast precursors. The reactivation of autophagy by rapamycin almost reversed the ISL elicited anti-osteoclastogenic effects. Interestingly, ISL inhibited the RANKL stimulated NF-kappaB expression and nuclear translocation, whereas the NF-kappaB inhibitor Bay 11-7082 markedly suppressed the RANKL-induced autophagic activation. Consistent with the in vitro results, the administration of ISL could attenuate osteoclastogenic cathepsin K, autophagic LC3, and NF-kappaB expression to protect against inflammatory calvarial bone erosion in vivo. Our findings highlight the inhibition of NF-kappaB-dependent autophagy as an important mechanism of ISL-mediated anti-osteoclastogenic activity. PMID- 26947455 TI - Characterization of novel cytochrome P450 2E1 knockout rat model generated by CRISPR/Cas9. AB - A bacterial CRISPR-associated protein-9 nuclease (CRISPR/Cas9) from Streptococcus pyogenes has generated considerable excitement as a new tool to edit the targeted genome. Cytochrome P450 (CYP) 2E1 not only plays an important role in the xenobiotic metabolism and chemical toxicity, but also is involved in many kinds of diseases, such as alcoholic liver diseases and diabetes. Despite its importance, few animal models are used to predict CYP2E1 properties in physiology, pathology, as well as carcinogen activation. To establish a novel model for investigating the functions of CYP2E1 in vivo, this study has successfully generated the Cyp2e1 knockout (KO) rat model without detectable off target effects using CRISPR/Cas9 system. The Cyp2e1 KO rats were viable and fertile and did not display any obvious physiological abnormities. The absent expression of CYP2E1 in KO rats also resulted in inactive behaviors in the metabolism of CYP2E1 substrates. The Cyp2e1 KO rats as a novel and available rodent animal model provide a powerful tool for the study of CYP2E1 in the chemical metabolism, toxicity, carcinogenicity, and its core factor in drug-drug interactions. PMID- 26947454 TI - Oroxyloside prevents dextran sulfate sodium-induced experimental colitis in mice by inhibiting NF-kappaB pathway through PPARgamma activation. AB - Oroxyloside, as a metabolite of oroxylin A, may harbor various beneficial bioactivities which have rarely been reported in the previous studies. Here we established the dextran sulfate sodium (DSS)-induced experimental colitis and evaluated the anti-inflammatory effect of oroxyloside in vivo. As a result, oroxyloside attenuated DSS-induced body weight loss, colon length shortening and colonic pathological damage. Furthermore, oroxyloside inhibited inflammatory cell infiltration and decreased myeloperoxidase (MPO) and inducible nitric oxide synthase (iNOS) activities as well. The production of pro-inflammatory cytokines in serum and colon was also significantly reduced by oroxyloside. We unraveled the underlying mechanisms that oroxyloside inhibited NF-kappaB pathway by activating Peroxisome Proliferator-Activated Receptor gamma (PPARgamma) to attenuate DSS-induced colitis. Moreover, we investigated the anti-inflammatory effect and mechanisms of oroxyloside in the mouse macrophage cell line RAW264.7 and bone marrow derived macrophages (BMDM). Oroxyloside decreased several LPS induced inflammatory cytokines, including IL-1beta, IL-6 and TNF-alpha in RAW264.7 and BMDM. We also found that oroxyloside inhibited LPS-induced activation of NF-kappaB signaling pathway via activating PPARgamma in RAW 264.7 and BMDM. Docking study showed that oroxyloside could bind with PPARgamma. GW9662, the inhibitor of PPARgamma, and PPARgamma siRNA transfection blocked the effect of oroxyloside on PPARgamma activation. Our study suggested that oroxyloside prevented DSS-induced colitis by inhibiting NF-kappaB pathway through PPARgamma activation. Therefore, oroxyloside may be a promising and effective agent for inflammatory bowel disease (IBD). PMID- 26947456 TI - Comparing the epidemiology of hospital-acquired methicillin-resistant Staphylococcus aureus clone groups in Alberta, Canada. AB - Patients with methicillin-resistant Staphylococcus aureus (MRSA) clones, which were traditionally seen in the community setting (USA400/CMRSA7 and USA300/CMRSA10), are often identified as hospital-acquired (HA) infections using Infection Prevention and Control (IPC) surveillance definitions. This study examined the demographics and healthcare risk factors of patients with HA-MRSA to help understand if community MRSA clones are from a source internal or external to the hospital setting. Despite USA300/CMRSA10 being the predominant clone in Alberta, hospital clones (USA100/CMRSA2) still dominated in the acute care setting. In the Alberta hospitalized population, patients with USA400/CMRSA7 and USA300/CMRSA10 clones were significantly younger, had fewer comorbidities, and a greater proportion had none or ambulatory care-only healthcare exposure. These findings suggest that there are two distinct populations of HA-MRSA patients, and the patients with USA400/CMRSA7 and USA300/CMRSA10 clones identified in hospital more greatly resemble patients affected by those clones in the community. It is possible that epidemiological assessment overidentifies HA acquisition of MRSA in patients unscreened for MRSA on admission to acute care. PMID- 26947458 TI - Plasma ionization under simulated ambient Mars conditions for quantification of methane by mass spectrometry. AB - Ambient ionization techniques enable ion production in the native sample environment for mass spectrometry, without a need for sample preparation or separation. These techniques provide superior advantages over conventional ionization methods and are well developed and investigated for various analytical applications. However, employing ambient ionization techniques for in situ extra terrestrial chemical analysis requires these techniques to be designed and developed according to the ambient conditions of extra-terrestrial environments, which substantially differ from the ambient conditions of Earth. Here, we report a plasma ionization source produced under simulated ambient Mars conditions for mass spectrometry. The plasma ionization source was coupled to a quadrupole mass spectrometer, and quantitative and qualitative analyses of trace amounts of methane, as an analyte of interest in Mars discovery missions, were demonstrated. The miniature plasma source was operational at a net power as low as ~1.7 W in the pressure range of 4-16 Torr. A detection limit as low as ~0.15 ppm (v/v) at 16 Torr for methane was demonstrated. PMID- 26947457 TI - Four new carbazole alkaloids from Murraya koenigii that display anti-inflammatory and anti-microbial activities. AB - In our present study, four new, designated as murrayakonine A-D (), along with 18 known carbazole alkaloids were isolated from CHCl3 : MeOH (1 : 1) crude extracts of the stems and leaves of Murraya koenigii (Linn.) Spreng. The structures of the all isolated compounds were characterized by analysis of HR-ESI-MS and NMR (1D and 2D spectroscopy) results, and comparison of their data with the literature data. For the first time, all the isolates were evaluated for their anti inflammatory activities, using both in vitro and in vivo experiments, against the key inflammatory mediators TNF-alpha and IL-6. The new compound murrayakonine A (), O-methylmurrayamine A () and mukolidine () were proven to be the most active, efficiently inhibiting TNF-alpha and IL-6 release in a dose-dependent manner and showing decreased LPS induced TNF-alpha and IL-6 production in human PBMCs. Furthermore, all the isolates were screened for their antimicrobial potential, and the compounds girinimbine () (IC50 3.4 MUM) and 1-hydroxy-7-methoxy-8-(3 methylbut-2-en-1-yl)-9H-carbazole-3-carbaldehyde () (IC50 10.9 MUM) displayed potent inhibitory effects against Bacillus cereus. Furthermore, compounds murrayamine J () (IC50 11.7 MUM) and koenimbine () (IC50 17.0 MUM) were active against Staphylococcus aureus. However, none of the compounds were found to be active against Escherichia coli or Candida albicans. PMID- 26947459 TI - Cyclization and unsaturation rather than isomerisation of side chains govern the selective antibacterial activity of cationic-amphiphilic polymers. AB - Membrane-active agents represent a promising alternative to overcome antibiotic resistance. Here, we report cationic-amphiphilic polymers with variations in the side chain architecture such as cyclization, isomerization and unsaturation that resulted in potent antibacterial activity and low mammalian cell toxicity with a membrane-active mode of action. PMID- 26947461 TI - Allergen Immunotherapy for Atopic Dermatitis: Is There Room for Debate? PMID- 26947460 TI - Exposure and Health Effects of Fungi on Humans. AB - Fungi are ubiquitous microorganisms that are present in outdoor and indoor environments. Previous research has found relationships between environmental fungal exposures and human health effects. We reviewed recent articles focused on fungal exposure and dampness as risk factors for respiratory disease development, symptoms, and hypersensitivity. In particular, we reviewed the evidence suggesting that early exposure to dampness or fungi is associated with the development of asthma and increased asthma morbidity. Although outdoor exposure to high concentrations of spores can cause health effects such as asthma attacks in association with thunderstorms, most people appear to be relatively unaffected unless they are sensitized to specific genera. Indoor exposure and dampness, however, appears to be associated with an increased risk of developing asthma in young children and asthma morbidity in individuals who have asthma. These are important issues because they provide a rationale for interventions that might be considered for homes and buildings in which there is increased fungal exposure. In addition to rhinitis and asthma, fungus exposure is associated with a number of other illnesses including allergic bronchopulmonary mycoses, allergic fungal sinusitis, and hypersensitivity pneumonitis. Additional research is necessary to establish causality and evaluate interventions for fungal- and dampness-related health effects. PMID- 26947462 TI - The use of metaphyseal sleeves in revision total knee arthroplasty. AB - BACKGROUND: Bone loss in revision total knee arthroplasty is common. Various reconstruction options are available. The purpose of our study is to report on one such reconstruction option, titanium metaphyseal sleeves. METHODS: We describe a series of 45 patients (46 knees) who underwent revision total knee arthroplasty and were treated with a porous metaphyseal sleeve between August 2000 and September 2009 at two centers. Patients were followed for a minimum of four years, and at final follow-up, 40 patients (40 knees) were available for review. Patients were evaluated using The Knee Society's Knee Scoring System at each follow-up. Radiographs (standing anteroposterior, lateral, and sunrise views) were taken at six weeks, three months, and final evaluations. RESULTS: Mean Knee Society Scores increased from 36 (range 10 to 69) pre-operatively to 90 (range 38 to 100) at final follow-up. Mean alignment on final radiographic evaluation was 5 degrees (range 3 degrees to 8 degrees valgus). Mean pre operative alignment was 6 degrees (range 15 degrees varus to 18 degrees valgus). Mean range of motion was 125 degrees (range 80 degrees to 140 degrees ) pre-operatively and 115 degrees (range 95 degrees to 130 degrees ) postoperatively. One device failed to achieve ingrowth and was revised at two years. All other knees were radiographically stable and ingrown. CONCLUSIONS: Metaphyseal sleeves provide an alternative for bone loss reconstruction in revision total knee arthroplasty. LEVEL OF EVIDENCE: III. PMID- 26947463 TI - Outcomes following impaction bone grafting for treatment of unstable osteochondritis dissecans. AB - BACKGROUND: Many methods have been proposed to treat unstable osteochondritis dissecans (OCD). Our purpose is to report outcomes in a cohort of patients undergoing impaction bone grafting for treatment of knee OCD. METHODS: Patients undergoing impaction bone grafting for knee OCD between 1998 and 2011 were contacted and stratified into (a) those who have undergone subsequent surgery on the affected knee and (b) those who have not had revision surgery performed on the affected knee since the impaction bone grafting procedure. For those not undergoing another procedure, physical examination, radiographs, MRI, and functional outcomes (SF12, Tegner, Activity Rating Scale, and IKDC) were obtained. RESULTS: Of nine patients (10 knees) undergoing the procedure, seven (eight knees) were available for follow-up. Three had revision surgery. One had debridement due to surface overgrowth and had no symptoms 43months following debridement, while two had osteochondral allograft and autograft procedures at three and 10years after initial surgery, respectively. Four patients did not require a revision surgical procedure at average follow-up of 55.4months (range, 21-116months). All had complete MRI fill of the cartilaginous defect with less than 50% of surface irregularity and redeveloped the tidemark and a heterogeneous cartilaginous surface. Follow-up Tegner, ARS, and SF12-PCS averaged 6.8, 67.5, and 56.6, respectively. All four had good/excellent IKDC results. CONCLUSION: Impaction bone grafting can reliably restore osteocartilaginous defect produced by OCD and is a readily available and less-expensive option in treating OCD lesions. Further investigation is necessary to determine the long-term durability of the results. Level IV - Case series. PMID- 26947464 TI - Reducing Phthalate, Paraben, and Phenol Exposure from Personal Care Products in Adolescent Girls: Findings from the HERMOSA Intervention Study. AB - BACKGROUND: Personal care products are a source of exposure to potentially endocrine-disrupting chemicals such as phthalates, parabens, triclosan, and benzophenone-3 (BP-3) for adolescent girls. METHODS: We enrolled 100 Latina girls in a youth-led, community-based participatory research intervention study to determine whether using personal care products whose labels stated they did not contain these chemicals for 3 days could lower urinary concentrations. Pre- and postintervention urine samples were analyzed for phthalate metabolites, parabens, triclosan, and BP-3 using high-performance liquid chromatography/tandem mass spectrometry. RESULTS: Urinary concentrations of mono-ethyl phthalate (MEP) decreased by 27.4% (95% CI: -39.3, -13.2) on average over the 3-day intervention; no significant changes were seen in urinary concentrations of mono-n-butyl phthalate (MnBP) and mono-isobutyl phthalate (MiBP). Methyl and propyl paraben concentrations decreased by 43.9% (95% CI: -61.3, -18.8) and 45.4% (95% CI: 63.7, -17.9), respectively. Unexpectedly, concentrations of ethyl and butyl paraben concentrations increased, although concentrations were low overall and not detected in almost half the samples. Triclosan concentrations decreased by 35.7% (95% CI: -53.3, -11.6), and BP-3 concentrations decreased by 36.0% (95% CI: -51.0, -16.4). DISCUSSION: This study demonstrates that techniques available to consumers, such as choosing personal care products that are labeled to be free of phthalates, parabens, triclosan, and BP-3, can reduce personal exposure to possible endocrine-disrupting chemicals. Involving youth in the design and implementation of the study was key to recruitment, retention, compliance, and acceptability of the intervention. CITATION: Harley KG, Kogut K, Madrigal DS, Cardenas M, Vera IA, Meza-Alfaro G, She J, Gavin Q, Zahedi R, Bradman A, Eskenazi B, Parra KL. 2016. Reducing phthalate, paraben, and phenol exposure from personal care products in adolescent girls: findings from the HERMOSA Intervention Study. Environ Health Perspect 124:1600-1607; http://dx.doi.org/10.1289/ehp.1510514. PMID- 26947494 TI - Sphingosine 1-phosphate receptor 1 agonists: a patent review (2013-2015). AB - INTRODUCTION: The sphingosine-1-phosphate (S1P) regulates diverse biological functions including cell proliferation, endothelial cell chemotaxis, angiogenesis, immune cell trafficking, mitogenesis, heart rate. The first-in class S1P1,3-5-R pan-agonist fingolimod (FTY720) was approved by the FDA and EMEA for the treatment of relapsing-remitting multiple sclerosis, though the most common adverse effect is bradycardia which occurs in the early stage of treatment and resolves within the first 24 h despite continuing treatment. The underlying mechanism of the cardiovascular effects is the activation of G-protein-gated inwardly rectifying potassium (GIRK) channel by the S1P1-R. Several second generation S1P1-R agonists with distinct selectivity, pharmacokinetics and safety profile from FTY720 are under development for the treatment of autoimmune and chronic inflammatory diseases. AREAS COVERED: This review provides a summary of the patent literature from 2013 up to November 2015 on the S1P1-R agonist molecules and their relevant biological/pharmacological properties. EXPERT OPINION: The molecules reviewed are S1P1-R agonists with a promising clinical outlook in particular in inflammation and autoimmune diseases. Clinical and preclinical studies of second generation S1P1-R agonists have been generating interesting results and may finally provide pharmacological agents with improved therapeutic profile than FTY720, particularly in terms of cardiovascular and pulmonary liabilities. PMID- 26947495 TI - Safety of classical swine fever virus vaccine strain LOM in pregnant sows and their offspring. AB - The present study aimed to evaluate the safety of the classical swine fever virus (CSFV) vaccine strain LOM in pregnant sows. Pregnant sows with free CSFV antibody were inoculated with a commercial LOM vaccine during early pregnancy (day 38; n=3) or mid-pregnancy (days 49-59; n=11). In pregnant sows vaccinated during the early stages of gestation, abortion (day 109) was observed in one case, with two stillbirths and seven mummified fetuses. The viability of live-born piglets was 34.9% in sows vaccinated during mid-pregnancy compared with 81.8% in the control group. Post-mortem examination of the organs of the sows and piglets did not reveal any pathological lesions caused by CSFV; however, CSFV RNA was detected in the organs of several vaccinated sows and their litters. The LOM strain was transmitted from sows with free CSFV antibody to their fetus, but did not appear to induce immune tolerance in the offspring from vaccinated pregnant sows. Side effects were not observed in pregnant sows with antibody to the LOM strain: transmission from sow to their litters and stillbirth or mummified fetuses. The LOM strain may induce sterile immunity and provide rapid, long-lasting, and complete protection against CSFV; however, it should be contraindicated in pregnant sows due to potential adverse effects in pregnant sows with free CSFV antibody. PMID- 26947496 TI - Quality vaccines for all people: Report on the 16th annual general meeting of the Developing Countries Vaccine Manufacturers' Network, 05-07th October 2015, Bangkok, Thailand. AB - The Developing Countries Vaccine Manufacturers Network (DCVMN) assembled high profile leaders from global health organisations and vaccine manufactures for its 16th Annual General Meeting to work towards a common goal: providing quality vaccines for all people. Vaccines contribute to a healthy community and robust health system; the Ebola outbreak has raised awareness of the threat and damage one single infectious disease can make, and it is clear that the world was not prepared. However, more research to better understand emerging infectious agents might lead to suitable vaccines which help prevent future outbreaks. DCVMN members presented their progress in developing novel vaccines against Dengue, HPV, Chikungunya, Cholera, cell-based influenza and other vaccines, demonstrating the commitment towards eliminating and eradicating preventable diseases worldwide through global collaboration and technology transfer. The successful introduction of novel Sabin-IPV and Oral Cholera vaccine in China and Korea respectively in 2015 was highlighted. In order to achieve global immunisation, local authorities and community leaders play an important role in the decision-making in vaccine introduction and uptake, based on the ability of vaccines to protect vaccinated people and protect non-vaccinated in the community through herd immunity. Reducing the risk of vaccine shortages can also be achieved by increasing regulatory convergence at regional and international levels. Combatting preventable diseases remains challenging, and collective efforts for improving multi-centre clinical trials, creating regional vaccine security strategies, fostering developing vaccine markets and procurement, and building trust in vaccines were discussed. PMID- 26947497 TI - Human papillomavirus vaccine series completion: Qualitative information from providers within an integrated healthcare organization. AB - OBJECTIVE: This qualitative study aimed to identify doctors' and nurses' perceptions of patient-, provider-, and system-level factors associated with human papillomavirus (HPV) vaccine completion that may be targets for intervention. METHODS: We analyzed data from 61 qualitative interviews with pediatricians, family medicine physicians, and immunization nurses at medical centers that had the highest and lowest HPV vaccine completion rates within the same health care system. RESULTS: In both groups, almost all providers reported strong support for the HPV vaccine. In detailing how they talk to parents and patients about the vaccine, more of the providers working at higher completion centers described using effective communication techniques, including engaging parents and patients in two-way conversation and demonstrating awareness of cultural and practical barriers to completion that families may face. Providers at higher completion centers were also more likely to depict a local medical culture supportive of and committed to HPV vaccine completion, with greater levels of proactivity and teamwork. In contrast, providers working at lower completion medical centers described a lack of proactivity, and the strategies they suggested to improve HPV vaccine completion tended to be approaches that someone other than medical providers would implement. The comments made by these providers sometimes reflected a level of negativity and judgment absent from the comments of providers at higher completion centers. CONCLUSION: Interventions to improve HPV vaccination completion rates should address both individual- and system-level factors. Improving communication skills, encouraging a supportive medical culture, and addressing resource issues is likely to improve vaccine adherence. PMID- 26947498 TI - Do selective immunisation against tuberculosis and hepatitis B reach the targeted populations? A nationwide register-based study evaluating the recommendations in the Norwegian Childhood Immunisation Programme. AB - BACKGROUND: Selective immunisation is an alternative to universal vaccination if children at increased risk of disease can be identified. Within the Norwegian Childhood Immunisation Programme, BCG vaccine against tuberculosis and vaccine against hepatitis B virus (HBV) are offered only to children with parents from countries with high burden of the respective disease. We wanted to study whether this selective immunisation policy reaches the targeted groups. METHODS: The study population was identified through the Norwegian Central Population Registry and consisted of all children born in Norway 2007-2010 and residing in Norway until their second birthday, in total 240,484 children. Information on vaccinations from the Norwegian Immunisation Registry, and on parental country of birth from Statistics Norway, was linked to the population registry by personal identifiers. The coverage of BCG and HBV vaccine was compared with the coverage of vaccines in the universal programme. RESULTS: Among the study population, 16.1% and 15.9% belonged to the target groups for BCG and HBV vaccine, respectively. Among children in the BCG target group the BCG vaccine coverage was lower than the coverage of pertussis and measles vaccine (83.6% vs. 98.6% and 92.3%, respectively). Likewise, the HBV vaccine coverage was lower than the coverage of pertussis and measles vaccine in the HBV target group (90.0% vs. 98.6% and 92.3%, respectively). The coverage of the targeted vaccines was highest among children with parents from South Asia and Sub-Saharan Africa. The coverage of vaccines in the universal programme was similar in targeted and non-targeted groups. CONCLUSIONS: Children targeted by selective vaccination had lower coverage of the target vaccines than of vaccines in the universal programme, indicating that selective vaccination is challenging. Improved routines for identifying eligible children and delivering the target vaccines are needed. Universal vaccination of all children with these vaccines could be considered. PMID- 26947499 TI - Rabies transmission risks during peripartum--Two cases and a review of the literature. AB - We report two cases of probable rabies in near-term/at-term pregnant women in sub Saharan Africa and Asia. One baby was delivered by caesarean section and the other one vaginally. Both received post-exposure prophylaxis (PEP), including RIG and vaccine and both are alive and healthy, at 9 and 24 months, respectively. We found 14 other published cases of infants born from rabid mothers. One confirmed case of rabies transmission occurred. The other children born from rabid mothers, with or without caesarean section, did not acquire rabies, and were still healthy at the time of reporting, with or without post-exposure prophylaxis. Mother-to child transmission of rabies is possible, but rare, because rabies virus is not present in blood and exposure of the baby's mucosa to maternal infectious fluids and tissue seems limited. A conservative approach should however, be adopted, and rabies PEP, including RIG, be administered as soon as possible to babies born from probably rabid mothers. Whether cesarean-section clearly provides prevention remains unclear. Rabies can be prevented in pregnant women by PEP administration. Rabies cell-culture vaccines are safe and effective and can be administered to pregnant and lactating women, as well as newborns. Efforts must focus on raising rabies awareness in the general population, as well as in healthcare workers. PMID- 26947511 TI - Strategies toward optimization of the metabolism of a series of serotonin-4 partial agonists: investigation of azetidines as piperidine isosteres. AB - 1.The first generation 5HT-4 partial agonist, 4-{4-[4-Tetrahydrofuran-3-yloxy) benzo[d]isoxazol-3-yloxymethyl]-piperidin-1-ylmethyl}-tetrahydropyran-4-ol, PF 4995274 (TBPT), was metabolized to N-dealkylated (M1) and an unusual, cyclized oxazolidine (M2) metabolites. M1 and M2 demonstrated pharmacological activity at 5HT receptor subtypes warranting further investigation into their dispositional properties in humans; M2 was a minor component in vitro but was the pre-dominant metabolite identified in human plasma. 2.To shift metabolism away from the piperidine ring of TBPT, a series of heterocyclic replacements were designed, synthesized, and profiled. Groups including azetidines, pyrrolidines, as well as functionalized piperidines were evaluated with the goal of identifying an alternative group that maintained the desired potency, functional activity, and reduced turnover in human hepatocytes. 3.Activities of 4-substituted piperidines or pyrrolidine analogs at the pharmacological target were not significantly altered, but the same metabolic pathways of N-dealkylation and oxazolidine formation were still observed. Altering these to bridged ring systems lowered oxazolidine metabolite formation, but not N-dealkylation. 4.The effort concluded with identification of azetidines as second-generation 5HT4 partial agonists. These were neither metabolized via N-dealkylation nor converted to cyclized oxazolidine metabolites rather oxidized on the isoxazole ring. The use of azetidine as a replacement for aliphatic aza-heterocyclic rings in drug design to alter drug metabolism and pharmacology is discussed. PMID- 26947510 TI - Effect of l-Arginine in One Patient with Peroxisome Biogenesis Disorder due to PEX12 Deficiency. AB - Peroxisome biogenesis disorders (PBD) are a heterogeneous group of disorders due to PEX genes mutations, with a broad clinical spectrum comprising severe neonatal disease to mild presentation. Recently, Berendse et al reported an improvement of peroxisomal functions with l-arginine supplementation in fibroblasts with specific mutations of PEX1, PEX6, and PEX12. We report the first treatment by l arginine in a patient homozygous for the specific PEX12 mutation shown to be l arginine responsive in fibroblasts. We described the effect of l-arginine on biochemical (decrease of some plasma peroxisomal parameters) and neurophysiological (improvement of deafness) parameters. Some subjective clinical effects have also been observed (no more sialorrhea, behavior improvement). More studies are needed to assess the efficacy of l-arginine in some PBD patients with specific mutations. PMID- 26947509 TI - ace-3 plays an important role in phoxim resistance in Caenorhabditis elegans. AB - Organophosphorus and carbamate are widely used in agricultural production. Caenorhabditis elegans is a model organism that is widely used in various toxicology studies. To understand the effects of two types of commonly used pesticides, phoxim (organophosphorus) and carbaryl (carbamate), we determined the activities of acetylcholinesterases (AChEs) and detected the expression of four ace genes by RT-qPCR in C. elegans following treatment with these pesticides. The results showed that phoxim and carbaryl could reduce acetylcholinesterase activities and up-regulate the ace-3 mRNA expression levels. We also detected the toxic effects of these pesticides on the ace-3 deletion mutant dc-2, and found that some characteristics, including LC50, development, movement, reproduction and lifespan, were reduced in the dc-2 mutant. However, the toxic effects of carbaryl were weaker than those of phoxim. Carbaryl treatment did not significantly affect the LC50, movement ability or lifespan. Interestingly, body and brood size increased with carbaryl treatment at low concentrations. These data showed that both phoxim and carbaryl could inhibit AChE but that the ace-3 was necessary for phoxim detoxification. The LC50 of phoxim and carbaryl in wild type N2 and the ace-3 deletion mutant dc-2. **Higher significant differences (P < 0.01). PMID- 26947512 TI - Novel Epigenetic Markers on Chromosome 21 for Noninvasive Prenatal Testing of Fetal Trisomy 21. AB - Until now, fetal placenta-specific epigenetic markers for noninvasive prenatal testing of fetal trisomy 21 (T21) have been identified based only on differences in tissue-specific epigenetic characteristics between placenta and maternal blood, but these characteristics have not been validated in T21 placenta. We aimed to discover novel epigenetic markers on chromosome 21 that show a hypermethylated pattern in fetal placenta compared with blood, regardless of the presence of T21. We performed a high-resolution tiling array analysis of chromosome 21 using the methylated-CpG binding domain protein-based method. We identified 93 epigenetic regions that showed fetal placenta-specific differential methylation patterns; among these, three regions showed fetal placenta-specific methylation patterns in T21 placenta samples. The methylation patterns of these three regions in the array were confirmed by bisulfite direct sequencing. The three regions were detectable in first-trimester maternal plasma. Moreover, a combination of their methylation ratio achieved high diagnostic accuracy for noninvasive prenatal testing of fetal T21 by further statistical analysis. These three novel regions with fetal placenta-specific differential methylation patterns on chromosome 21 were identified irrespective of the presence of T21. Our findings suggest that epigenetic characteristics of markers according to the presence or absence of T21 should be considered in the development of noninvasive prenatal testing of fetal T21 using fetal placenta-specific epigenetic markers. PMID- 26947513 TI - Somatic Mutations of PI3K in Early and Advanced Gallbladder Cancer: Additional Options for an Orphan Cancer. AB - Gallbladder cancer (GBC) is the second-leading cause of death from malignant tumors in Chilean women. The phosphatidylinositol 3-kinase (PI3K) pathway is involved in proliferation, cell survival, and growth. We investigated mutations in exons 9 and 20 of the PI3K gene in GBC. Mutations in exons 9 (E542K, E545G, E545K) and 20 (H1047L and H1047R) of PI3K were determined by direct sequencing in 130 cases of GBC. The patient group consisted of 110 women and 20 men, and mutations were found in 22 cases (16.9%). Of these, 14 cases had mutations in exon 9 (63.6%) (E542K, 64%; E545K, 29%; and E545G, 7%) and 8 in exon 20 (37.4%; H1047L, 50%; H1047R, 50%). No differences were noted in the frequency and type of mutations analyzed by sex, age, or histologic features. We observed mutations in 22% of the early-stage GBC and 14.6% of the advanced cases. In this series of GBC, 17% of cases were noted as having mutations in either exons 9 or 20 of PI3K. These results suggest that therapeutic testing of inhibitors of the PI3K/AKT pathway may be of benefit in advanced GBC patients. PMID- 26947515 TI - Using the GVB Ansatz to develop ensemble DFT method for describing multiple strongly correlated electron pairs. AB - Ensemble density functional theory (DFT) furnishes a rigorous theoretical framework for describing the non-dynamic electron correlation arising from (near) degeneracy of several electronic configurations. Ensemble DFT naturally leads to fractional occupation numbers (FONs) for several Kohn-Sham (KS) orbitals, which thereby become variational parameters of the methodology. The currently available implementation of ensemble DFT in the form of the spin-restricted ensemble referenced KS (REKS) method was originally designed for systems with only two fractionally occupied KS orbitals, which was sufficient to accurately describe dissociation of a single chemical bond or the singlet ground state of biradicaloid species. To extend applicability of the method to systems with several dissociating bonds or to polyradical species, more fractionally occupied orbitals must be included in the ensemble description. Here we investigate a possibility of developing the extended REKS methodology with the help of the generalized valence bond (GVB) wavefunction theory. The use of GVB enables one to derive a simple and physically transparent energy expression depending explicitly on the FONs of several KS orbitals. In this way, a version of the REKS method with four electrons in four fractionally occupied orbitals is derived and its accuracy in the calculation of various types of strongly correlated molecules is investigated. We propose a possible scheme to ameliorate the partial size inconsistency that results from perfect spin-pairing. We conjecture that perfect pairing natural orbital (NO) functionals of reduced density matrix functional theory (RDMFT) should also display partial size-inconsistency. PMID- 26947514 TI - Preemptive Pharmacogenomic Testing for Precision Medicine: A Comprehensive Analysis of Five Actionable Pharmacogenomic Genes Using Next-Generation DNA Sequencing and a Customized CYP2D6 Genotyping Cascade. AB - Significant barriers, such as lack of professional guidelines, specialized training for interpretation of pharmacogenomics (PGx) data, and insufficient evidence to support clinical utility, prevent preemptive PGx testing from being widely clinically implemented. The current study, as a pilot project for the Right Drug, Right Dose, Right Time-Using Genomic Data to Individualize Treatment Protocol, was designed to evaluate the impact of preemptive PGx and to optimize the workflow in the clinic setting. We used an 84-gene next-generation sequencing panel that included SLCO1B1, CYP2C19, CYP2C9, and VKORC1 together with a custom designed CYP2D6 testing cascade to genotype the 1013 subjects in laboratories approved by the Clinical Laboratory Improvement Act. Actionable PGx variants were placed in patient's electronic medical records where integrated clinical decision support rules alert providers when a relevant medication is ordered. The fraction of this cohort carrying actionable PGx variant(s) in individual genes ranged from 30% (SLCO1B1) to 79% (CYP2D6). When considering all five genes together, 99% of the subjects carried an actionable PGx variant(s) in at least one gene. Our study provides evidence in favor of preemptive PGx testing by identifying the risk of a variant being present in the population we studied. PMID- 26947516 TI - E2F1 transcription factor and its impact on growth factor and cytokine signaling. AB - E2F1 is a transcription factor involved in cell cycle regulation and apoptosis. The transactivation capacity of E2F1 is regulated by pRb. In its hypophosphorylated form, pRb binds and inactivates DNA binding and transactivating functions of E2F1. The growth factor stimulation of cells leads to activation of CDKs (cyclin dependent kinases), which in turn phosphorylate Rb and hyperphosphorylated Rb is released from E2F1 or E2F1/DP complex, and free E2F1 can induce transcription of several genes involved in cell cycle entry, induction or inhibition of apoptosis. Thus, growth factors and cytokines generally utilize E2F1 to direct cells to either fate. Furthermore, E2F1 regulates expressions of various cytokines and growth factor receptors, establishing positive or negative feedback mechanisms. This review focuses on the relationship between E2F1 transcription factor and cytokines (IL-1, IL-2, IL-3, IL-6, TGF-beta, G-CSF, LIF), growth factors (EGF, KGF, VEGF, IGF, FGF, PDGF, HGF, NGF), and interferons (IFN-alpha, IFN-beta and IFN-gamma). PMID- 26947517 TI - A ruthenium(ii) based photosensitizer and transferrin complexes enhance photo physical properties, cell uptake, and photodynamic therapy safety and efficacy. AB - Metal-based photosensitizers are of interest as their absorption and chemical binding properties can be modified via the use of different ligands. Ru(2+) based photosensitizers are known to be effective photodynamic therapy (PDT) agents against bacteria, whereas use for oncological indications in vivo has not been demonstrated with the same level of evidence. We present data showing that premixing the Ru(2+)-complex TLD1433 with transferrin increases the molar extinction coefficient, including longer activation wavelengths, reduces photobleaching rates, and reduces the toxicity of the complex improving overall PDT efficacy. As the transferrin receptor is upregulated in most malignancies, premixing the Ru(2+) complex with transferrin converts the active pharmaceutical ingredient TLD1433 into a drug of potentially considerable clinical utility. PMID- 26947518 TI - Stimulating forebrain communications: Slow sinusoidal electric fields over frontal cortices dynamically modulate hippocampal activity and cortico hippocampal interplay during slow-wave states. AB - Slow-wave states are characterized by the most global physiological phenomenon in the mammalian brain, the large-amplitude slow oscillation (SO; ~1Hz) composed of alternating states of activity (ON/UP states) and silence (OFF/DOWN states) at the network and single cell levels. The SO is cortically generated and appears as a traveling wave that can propagate across the cortical surface and can invade the hippocampus. This cortical rhythm is thought to be imperative for sleep dependent memory consolidation, potentially through increased interactions with the hippocampus. The SO is correlated with learning and its presumed enhancement via slow rhythmic electrical field stimulation improves subsequent mnemonic performance. However, the mechanism by which such field stimulation influences the dynamics of ongoing cortico-hippocampal communication is unknown. Here we show - using multi-site recordings in urethane-anesthetized rats - that sinusoidal electrical field stimulation applied to the frontal region of the cerebral cortex creates a platform for improved cortico-hippocampal communication. Moderate-intensity field stimulation entrained hippocampal slow activity (likely by way of the temporoammonic pathway) and also increased sharp wave ripples, the signature memory replay events of the hippocampus, and further increased cortical spindles. Following cessation of high-intensity stimulation, SO interactions in the cortical-to-hippocampal direction were reduced, while the reversed hippocampal-to-cortical communication at both SO and gamma bandwidths was enhanced. Taken together, these findings suggest that cortical field stimulation may function to boost memory consolidation by strengthening cortico hippocampal and hippocampo-cortical interplay at multiple nested frequencies in an intensity-dependent fashion. PMID- 26947519 TI - Lines of Baillarger in vivo and ex vivo: Myelin contrast across lamina at 7T MRI and histology. AB - The human cerebral cortex is characterized by a number of features that are not uniformly distributed, such as the presence of multiple cytoarchitectonic elements and of myelinated layers running tangentially to the cortex surface. The presence and absence of these features are the basis of the parcellation of the cerebral cortex in several areas. A number of areas show myelin increases localized within the cortex, e.g., the stria of Gennari located in layer IV of the primary visual cortex. Sub-millimeter MRI can resolve myelin variations across the human cortex and may allow in vivo parcellation of these brain areas. Here, we image within-area myelination. We modified a T1-weighted (T1-w) MPRAGE sequence to enhance myelin visualization within the cortex. First, we acquired images from an ex vivo sample, and compared MRI laminar profiles from calcarine (corresponding to primary visual cortex) and extra-calcarine areas with histology sections from the same locations. Laminar profiles between myelin stained sections and the T1-w images were similar both in calcarine as well as extra calcarine cortex. In calcarine cortex, the profile reveals the stria of Gennari. In extra-calcarine cortex, a similar profile exists which we suggest corresponds to the lines of Baillarger. Next, we adapted the same sequence to image within area myelination in vivo. Also in in vivo data, we discriminated similar laminar profiles in calcarine and extra-calcarine cortex, extending into parietal and frontal lobes. We argue that this myelin pattern outside the calcarine cortex represents the lines of Baillarger. PMID- 26947520 TI - Methods for assessing high frequency hearing loss in every-day listening situations. PMID- 26947521 TI - Circadian Rhythms, Sleep, and Disorders of Aging. AB - Sleep-wake cycles are known to be disrupted in people with neurodegenerative disorders. These findings are now supported by data from animal models for some of these disorders, raising the question of whether the disrupted sleep/circadian regulation contributes to the loss of neural function. As circadian rhythms and sleep consolidation also break down with normal aging, changes in these may be part of what makes aging a risk factor for disorders like Alzheimer's disease (AD). Mechanisms underlying the connection between circadian/sleep dysregulation and neurodegeneration remain unclear, but several recent studies provide interesting possibilities. While mechanistic analysis is under way, it is worth considering treatment of circadian/sleep disruption as a means to alleviate symptoms of neurodegenerative disorders. PMID- 26947524 TI - Procalcitonin in critically ill patients: time to change guidelines and antibiotic use in practice. PMID- 26947522 TI - Apolipoprotein L1 and Kidney Disease in African Americans. AB - Genetic variants in the Apolipoprotein L1 (APOL1) gene cause high rates of kidney disease in African Americans. These variants, found only in individuals with recent African ancestry, confer enhanced innate immunity against African trypanosomes. Although they are among the most powerful disease-causing common variants discovered to date, we are just beginning to understand how they promote kidney injury. Since APOL1 is present in only a few primate species, much of our current knowledge has come from natural experiments in humans and in vitro studies while awaiting the development of transgenic animal models. Understanding more about the function of ApoL1 and how the high-risk variants behave differently from other ApoL1 molecules is a high priority in kidney disease research. PMID- 26947523 TI - Efficacy and safety of procalcitonin guidance in reducing the duration of antibiotic treatment in critically ill patients: a randomised, controlled, open label trial. AB - BACKGROUND: In critically ill patients, antibiotic therapy is of great importance but long duration of treatment is associated with the development of antimicrobial resistance. Procalcitonin is a marker used to guide antibacterial therapy and reduce its duration, but data about safety of this reduction are scarce. We assessed the efficacy and safety of procalcitonin-guided antibiotic treatment in patients in intensive care units (ICUs) in a health-care system with a comparatively low use of antibiotics. METHODS: We did a prospective, multicentre, randomised, controlled, open-label intervention trial in 15 hospitals in the Netherlands. Critically ill patients aged at least 18 years, admitted to the ICU, and who received their first dose of antibiotics no longer than 24 h before inclusion in the study for an assumed or proven infection were eligible to participate. Patients who received antibiotics for presumed infection were randomly assigned (1:1), using a computer-generated list, and stratified (according to treatment centre, whether infection was acquired before or during ICU stay, and dependent on severity of infection [ie, sepsis, severe sepsis, or septic shock]) to receive either procalcitonin-guided or standard-of-care antibiotic discontinuation. Both patients and investigators were aware of group assignment. In the procalcitonin-guided group, a non-binding advice to discontinue antibiotics was provided if procalcitonin concentration had decreased by 80% or more of its peak value or to 0.5 MUg/L or lower. In the standard-of care group, patients were treated according to local antibiotic protocols. Primary endpoints were antibiotic daily defined doses and duration of antibiotic treatment. All analyses were done by intention to treat. Mortality analyses were completed for all patients (intention to treat) and for patients in whom antibiotics were stopped while being on the ICU (per-protocol analysis). Safety endpoints were reinstitution of antibiotics and recurrent inflammation measured by C-reactive protein concentrations and they were measured in the population adhering to the stopping rules (per-protocol analysis). The study is registered with ClinicalTrials.gov, number NCT01139489, and was completed in August, 2014. FINDINGS: Between Sept 18, 2009, and July 1, 2013, 1575 of the 4507 patients assessed for eligibility were randomly assigned to the procalcitonin-guided group (761) or to standard-of-care (785). In 538 patients (71%) in the procalcitonin guided group antibiotics were discontinued in the ICU. Median consumption of antibiotics was 7.5 daily defined doses (IQR 4.0-12.7) in the procalcitonin guided group versus 9.3 daily defined doses (5.0-16.6) in the standard-of-care group (between-group absolute difference 2.69, 95% CI 1.26-4.12, p<0.0001). Median duration of treatment was 5 days (3-9) in the procalcitonin-guided group and 7 days (4-11) in the standard-of-care group (between-group absolute difference 1.22, 0.65-1.78, p<0.0001). Mortality at 28 days was 149 (20%) of 761 patients in the procalcitonin-guided group and 196 (25%) of 785 patients in the standard-of-care group (between-group absolute difference 5.4%, 95% CI 1.2-9.5, p=0.0122) according to the intention-to-treat analysis, and 107 (20%) of 538 patients in the procalcitonin-guided group versus 121 (27%) of 457 patients in the standard-of-care group (between-group absolute difference 6.6%, 1.3-11.9, p=0.0154) in the per-protocol analysis. 1-year mortality in the per-protocol analysis was 191 (36%) of 538 patients in the procalcitonin-guided and 196 (43%) of 457 patients in the standard-of-care groups (between-group absolute difference 7.4, 1.3-13.8, p=0.0188). INTERPRETATION: Procalcitonin guidance stimulates reduction of duration of treatment and daily defined doses in critically ill patients with a presumed bacterial infection. This reduction was associated with a significant decrease in mortality. Procalcitonin concentrations might help physicians in deciding whether or not the presumed infection is truly bacterial, leading to more adequate diagnosis and treatment, the cornerstones of antibiotic stewardship. FUNDING: Thermo Fisher Scientific. PMID- 26947526 TI - Hemolysis following red cell concentrate transfusion in severe trauma patients. PMID- 26947525 TI - Sarcoidosis associated with psoriasis: 2 disease entities, one pathogenic pathway. PMID- 26947527 TI - Implications of renal artery anatomy for endovascular repair using fenestrated, branched, or parallel stent graft techniques. AB - OBJECTIVE: This study evaluated renal artery (RA) and accessory renal artery (ARA) anatomy and implications for endovascular repair using fenestrated, branched, or parallel (chimney, snorkel, and periscope) stent graft techniques. METHODS: We analyzed the digital computed tomography angiograms of 520 consecutive patients treated by open or fenestrated endovascular repair for complex abdominal aortic aneurysms (2000-2012). RA/ARA anatomy was assessed using diameter, length, angles, and kidney perfusion based on analysis of estimated volumetric kidney parenchyma. Endovascular suitability was determined by RA diameter >=4 mm, length to RA bifurcation >=13 mm, and preservation of >75% of a single kidney or >60% of two kidneys by volumetric kidney parenchyma analysis. RESULTS: There were 222 juxtarenal (43%), 241 suprarenal (46%), and 57 type IV thoracoabdominal aortic aneurysms (11%), Analysis of 1009 RAs and 177 ARAs showed endovascular incorporation was possible in 884 RAs (88%) and 30 ARAs (17%) using the proposed criteria. One or more factors rendered RA incorporation unsuitable in 97 patients (19%), including early bifurcation in 45 (9%), small diameter in 28 (5%), or inability to preserve kidney parenchyma in 28 (5%). Other anatomic issues were present in 170 patients (33%) that would increase technical difficulty to RA incorporation using transfemoral access, including excessive downward angulation in 125 (24%), high-grade stenosis in 51 (10%), or prior renal stents in 11 (2%). CONCLUSIONS: Independent of the endovascular technique that is selected to treat a complex abdominal aortic aneurysm, one of five patients has anatomic limitations to endovascular incorporation. In these patients, open repair may provide the best alterative to maximize RA patency and preserve renal function. PMID- 26947529 TI - [The Relationship Between Burnout Symptoms and Work Satisfaction Among Child Welfare Workers in Residential Care]. AB - Working in residential care is associated with high demands and high stress. As a result, employees may develop symptoms of burnout. These symptoms lead to absence from work and have a negative effect on the continuity and quality of the residential care. Until now, little is known about burnout risks in child welfare workers, although children and adolescents are especially dependent on continuous relationships and healthy caregivers. A better understanding of the relationship between burnout symptoms and work satisfaction may help to identify starting points for prevention and intervention. The present study assessed symptoms of burnout in a sample of 319 social education workers in residential care in Switzerland using the burnout-screening-scales (BOSS). Work satisfaction was assessed with a newly developed questionnaire based on concepts of trauma sensitive care. The questionnaire was tested for reliability and factorial validity in the present study. In order to estimate the relationship between burnout symptoms and work satisfaction, correlations and relative risks were calculated. Almost one fifth (18 %) of the sample showed a risk of burnout. The principal component analysis of the questionnaire on work satisfaction revealed four factors: support by superiors, participation and transparency; communication and support within the team; gratification in the work; and institutional structures and resources. All four factors as well as the total score showed significant correlations with burnout symptoms. Among employees with a comparably lower work satisfaction, the risk of burnout was 5.4 times higher than among employees with a comparably higher work satisfaction. It is discussed how work satisfaction could be promoted and how, as a result, the quality and continuity of care for the children and adolescents could be improved. PMID- 26947530 TI - [Assessment of Social-Communicative Behaviour Problems and Expression of Emotions in Three- to Six-Year Old Children in Nursery School and Kindergarten]. AB - Developmental support and promotion of children with behavioural disorders received little attention in nursery school and kindergarten in the last years. Parents expect that their children exhibiting psychosocial deficits or problems in social-communicative competence will also get support by the said educational institutions. This requires a preliminary, but reliable and economic monitoring, estimation and evaluation of selected behaviour patterns. Therefore, we developed and validated a scale to rate social-communicative behaviour problems and expression of emotions. Factor analysis suggested two factors which corresponded to the intended measurement object and the defined taxonomy of behavioural problems (scale 1: mainly internalized behaviour; scale 2: externalized behaviour). Both internal consistency and split-half reliability proved to be good. High convergent criterion validity was found for scale 1 and still substantial, although lower, for scale 2. The rating is simple and can be performed within ten and scored within five minutes. The result is a reliable indicator for a step-by-step approach to recommend an expanded specific psycho diagnostics, so that therapeutic interventions as well as prevention programmes for vulnerable children and appropriate social training programmes can start timely. PMID- 26947531 TI - ["Kids' Skills" by Ben Furman - Description and Research Review]. AB - The article describes the programme "Kids' Skills" by the Finnish psychiatrist Ben Furman. "Kids' Skills" was developed to address behavioural issues in children. It is based on the assumption that children's behavioural problems should not be pathologized, but can instead be corrected by learning a corresponding skill. The programme is characterised by its focus on strengths and its humorous and playful approach. The 15 steps of "Kids' Skills" are intended to identify the specific skill, help generate a learning process and continue motivating the child. The authors describe the steps of the programme using a case study. They also address the limited number of existing studies, which have included a telephone and an online survey of practitioners using the programme, as well as case studies. The results of these studies are discussed with regard to their basis in evidence and practical relevance. Continuing research is recommended and possible implementations are suggested. PMID- 26947535 TI - Secular Trends in Preeclampsia Incidence and Outcomes in a Large Canada Database: A Longitudinal Study Over 24 Years. AB - BACKGROUND: The incidence of preeclampsia is increasing, but effects on women and infants are unclear. We measured the incidence of preeclampsia over time in a large Canadian population, and assessed trends in maternal and infant morbidity and mortality. METHODS: We carried out a population-based study of 1,901,376 linked hospital discharge abstracts for all deliveries in the province of Quebec, Canada from 1989 through 2012. We computed the annual incidence of preeclampsia, and used log binomial models to determine associations with severe morbidity and mortality for preeclamptic vs nonpreeclamptic pregnancies. Main outcomes included maternal, fetal, and infant mortality, admission to intensive care, intubation, preterm delivery, growth restriction, cesarean delivery, transfusion, and severe medical complications. RESULTS: The incidence of preeclampsia increased from 26.4 per 1000 deliveries in 1989 to 50.6 in 2012. Maternal, fetal, and infant mortality decreased with time for preeclamptic but not for nonpreeclamptic pregnancies. By 2007-2012, risk for women with preeclampsia had declined for most maternal morbidities, except acute renal failure, which increased relative to no preeclampsia (risk ratio, 21.5; 95% confidence interval, 16.9-27.3). Risk of infant morbidity also decreased, but this coincided with an increase in the excess number of intubations and admissions for intensive care for preeclampsia relative to no preeclampsia. CONCLUSIONS: The incidence of preeclampsia increased during the study, but with little effect on the risk of maternal and infant morbidity and mortality. For most outcomes, the risk decreased relative to no preeclampsia, with more aggressive medical management over time. PMID- 26947537 TI - A Case of Kounis Type I in a Young Woman With Samter's Triad. AB - Kounis syndrome is defined as an acute coronary syndrome triggered by allergic or hypersensitivity reactions resulting in mast cell and platelet activation. Numerous causes have been described, including various drugs, medical conditions, and environmental exposures. Samter's triad consists of nasal polyps, asthma, and aspirin (or nonsteroidal anti-inflammatory drug) sensitivity. We describe a case of Kounis type I in a young woman with Samter's triad who presented with cardiac arrest on 3 occasions. Ergonovine provocation testing established the diagnosis of coronary vasospasm. The patient has derived significant benefit from calcium channel blockers. PMID- 26947536 TI - Significantly Greater Progression of Intima-Media Thickness of the Carotid Artery in Japanese American Men Than in White Men: The ERA JUMP Study. AB - BACKGROUND: Although a westernized lifestyle was associated with increased coronary heart disease (CHD), morbidity, and mortality in first- and second generation Japanese Americans, CHD mortality was reported to be lower in this population than in whites. The risk profile of CHD for third- and fourth generation Japanese Americans is not known. We compared the progression of carotid intima-media thickness (CIMT) between third- or fourth-generation Japanese Americans and whites. METHODS: Population-based samples of 473 men (Japanese Americans, 227; whites, 246) aged 40-49 years at baseline and free of clinical cardiovascular disease were examined for CIMT at baseline (2004-2007) and follow-up (2007-2013). CIMT was determined centrally at the University of Pittsburgh, Pittsburgh, Pennsylvania. Analysis of covariance was used to compare annualized progression of CIMT between Japanese Americans and whites, adjusting for cardiovascular risk factors and baseline CIMT. RESULTS: Progression of CIMT was significantly greater in Japanese Americans than in whites both before and after adjusting for covariates: mean, 14.4 MUm/y; 95% confidence interval [CI],12.3-16.4 vs 9.8 MUm/y; 95% CI, 7.8-11.7; P < 0.05 and 15.1 MUm/y; 95% CI, 13.1-17.1 vs 9.1 MUm/y; 95% CI, 7.2-11.0; P < 0.05, respectively. Age, total cholesterol/high-density lipoprotein cholesterol, and diabetes in Japanese Americans and age, hypertension, and lipid medication in whites were significantly associated with progression of CIMT. CONCLUSIONS: The significantly greater progression of CIMT in Japanese Americans than in whites might suggest a higher future burden of CHD in Japanese Americans than in whites. The current study identifies Japanese Americans as an important target group for prevention of CHD. Future research assessing carotid plaque in addition to CIMT is warranted. PMID- 26947539 TI - The Economic Evaluation of Surgical Interventions. PMID- 26947538 TI - Neutrophil Gelatinase-Associated Lipocalin (NGAL) is Associated with Symptomatic Carotid Atherosclerosis and Drives Pro-inflammatory State In Vitro. AB - OBJECTIVE: Neutrophil gelatinase-associated lipocalin (NGAL), a protein found in activated neutrophils, is expressed in kidney tubule cells in response to noxious stimuli, and is thus recognized as a marker of acute kidney injury. Recent studies have suggested that NGAL could also have pathophysiological importance in cardiovascular diseases. The aim of the present study was to examine NGAL expression in human carotid endarterectomy tissues ex vivo as well as the effects of NGAL in the main cell types involved in atherogenesis, namely in human macrophages, endothelial cells, and smooth muscle cells in vitro. METHODS: NGAL protein was analyzed in human endarterectomy samples from patients with asymptomatic and symptomatic carotid stenosis by immunofluorescence, and NGAL mRNA expression was detected using RealTime-PCR. Human monocyte derived macrophages (MDM), human coronary artery smooth muscle cells (HCASMC), and human umbilical vein endothelial cells (HUVEC) were treated with recombinant human (rh) NGAL at different concentrations. Interleukin (IL)-6, IL-8, and monocyte chemo attractant protein-1 (MCP-1) were determined by specific enzyme linked immunosorbent assays (ELISAs) in culture supernatants of such treated cells. RESULTS: Expression of NGAL protein was demonstrated by macrophages, smooth muscle cells, and endothelial cells in human carotid atherosclerotic tissue. NGAL mRNA expression was detected at a higher rate in atherosclerotic tissue of patients with symptomatic carotid stenosis (in 70%; n = 19) compared with asymptomatic patients (in 37%; n = 20, p < .001). Treatment of MDM, HCASMC, and HUVEC with rhNGAL led to a significant (p < 0.05) and concentration dependent increase of pro-inflammatory cytokines IL-6, IL-8, and MCP-1 in all cell types analyzed. CONCLUSION: By induction of pro-inflammatory mediators in human macrophages, smooth muscle cells and endothelial cells, NGAL, which is predominantly expressed in atherosclerotic plaques of symptomatic patients, could be involved in creating the local and systemic pro-inflammatory environment characteristic for atherosclerosis. PMID- 26947540 TI - Peeling Away Better Than Fishing Around Later! PMID- 26947542 TI - Upper Extremity Ischemia as a "Warning Shot" of Cerebellar Infarction. PMID- 26947541 TI - Systematic Review of the Growth Rates and Influencing Factors in Thoracic Aortic Aneurysms. AB - OBJECTIVE/BACKGROUND: The growth rates of thoracic aortic aneurysms (TAAs) and factors influencing their expansion are poorly understood. This study aimed to review systematically published literature describing TAA expansion and examine factors that may be associated with this. METHODS: A comprehensive search of MEDLINE and Embase databases was performed until 30 April 2015. Studies describing rates of TAA growth were identified and systematically reviewed. Outcomes of interest were TAA growth rates and associated factors. Study quality was assessed using Scottish Intercollegiate Guidelines Network quality checklists for cohort studies. RESULTS: Eleven publications, involving 1383 patients, met the eligibility criteria and were included in the review. Included studies were generally low in quality. Aneurysm measurement and growth-rate estimation techniques were inconsistently reported. Mean growth rates for all TAAs ranged from 0.2 to 4.2 mm/year. Mean growth rates for ascending and aortic arch aneurysms ranged from 0.2 to 2.8 mm/year, while those for descending and thoracoabdominal aneurysms ranged from 1.9 to 3.4 mm/year in studies reporting according to anatomical location. Large aneurysm size, distal aneurysm locations, presence of Marfan's syndrome, and bicuspid aortic valve were consistently associated with accelerated TAA growth. Presence of chronic dissection and chronic obstructive pulmonary disorder were also implicated as risk factors for faster TAA growth. Associations between medical comorbidity and aneurysm expansion were conflicting. Previous aortic surgery and anticoagulants were reported to have a protective effect on aneurysm growth in two studies. CONCLUSION: There is a shortfall in the understanding of TAA expansion rates. Existing studies are heterogeneous in methodology and reported outcomes. Identified unifying themes suggest that TAAs grow at a slow rate with large presenting diameter, distal aneurysm, and history of bicuspid aortic valve or Marfan's syndrome serving as main risk factors for accelerated aneurysm growth. High-quality studies with a standardised approach to TAA growth assessment are required. PMID- 26947543 TI - Topical vs Intravenous Tranexamic Acid in Reducing Blood Loss After Bilateral Total Knee Arthroplasty: A Prospective Study. AB - BACKGROUND: Total knee arthroplasty (TKA) results in substantial postoperative blood loss with increased morbidity. Despite various studies proving the efficacy of tranexamic acid (TXA), no consensus exists on the routes of administration. METHODS: Seventy consecutive patients with knee arthritis undergoing simultaneous bilateral TKA, who were eligible and fulfilled the criteria, were taken up for this study. They were randomly allocated by a computer-generated random number table, either to receive intravenous TXA (IVTXA; group 1) or topical TXA (TTXA; group 2) in a prospective, double-blinded study. The primary outcome measures were total blood loss and total drain output. The secondary outcome measures were number of blood units transfused and clinical and functional outcomes as evaluated by the Knee Society Score, Western Ontario and McMaster Universities Arthritis Index score, visual analog score, and wound score. RESULTS: Both groups were similar in age, sex, and body mass index, and no statistical significance was observed. There was statistically significant difference between IVTXA and TTXA groups in mean postoperative total blood loss (P < .001), postoperative hemoglobin (P < .001) with a higher drop of hemoglobin in the former, total drain output (P < .001), and allogeneic blood transfusion (P < .001). No complication was observed in either group. Significant difference was observed in the Western Ontario and McMaster Universities Arthritis Index score at 12 weeks and 6 months (P = .015 and .007) and Knee Society Score at 6 and 12 months (P = .050 and .045, respectively). However, no significant difference was found at 6 weeks. CONCLUSION: TTXA is better than IVTXA in reducing blood loss and clinical outcome after simultaneous bilateral TKA. PMID- 26947544 TI - Alkylsulfuric acid ionic liquids: a promising class of strongly acidic room temperature ionic liquids. AB - Strongly acidic (pKa ~ -3.5) room-temperature ionic liquids (ILs) with -OSO3H functionalized cations are introduced. The strong acidity, easy synthesis, and better physical properties of these R-OSO3H ILs make them excellent alternatives to the well-known sulfonic acid (R-SO3H) ILs, especially in the domain of metal processing. PMID- 26947545 TI - A pseudoencephalitis presentation of a pediatric non-intentional intoxication. AB - We report a case of a pseudo encephalitis presentation of pediatric intoxication Case report - a 7 year-old girl was admitted to our pediatric emergency unit after she developed sudden agitation, visual and tactile hallucinations. She was febrile (38.3 degrees C). She had not experienced any recent head trauma, infection or toxic ingestion; she did not take any medication for ADD. Her physical exam revealed tachycardia, normal pupils, reflexes and normal plantar responses. Laboratory investigations (complete blood count, basic metabolic panel, plasma lactate level, ammonia level) produced normal results. Lumbar puncture and computed tomography of the brain were normal. A serum and urine drug screening (benzodiazepines, barbiturates, cocaine, cannabis, amphetamines, methadone, ethanol) was negative. An electroencephalogram, performed during an episode of hallucinations, was compatible with benzodiazepine intoxication. A larger toxic detection by liquid chromatography/diode array detector (LC-DAD) detected promethazine and its metabolites. Symptoms lasted 20 h and she finally said she drank syrup from an over-the-counter cough suppressant medication. Comments - Anticholinergic syndrome is not well recognized or evoked in children presenting hallucinations. Promethazine is still present in several over-the counter medications, alone or in combination with acetaminophen, carbocisteine or opiates. CONCLUSION: Medications containing promethazine should not be prescribed in children. Such intoxication can mimic encephalitis. PMID- 26947546 TI - Mutations in BRAT1 cause autosomal recessive progressive encephalopathy: Report of a Spanish patient. AB - We describe a 4-year-old male child born to non-consanguineous Spanish parents with progressive encephalopathy (PE), microcephaly, and hypertonia. Whole exome sequencing revealed compound heterozygous BRAT1 mutations [c.1564G > A (p.Glu522Lys) and c.638dup (p.Val214Glyfs*189)]. Homozygous and compound heterozygous BRAT1 mutations have been described in patients with lethal neonatal rigidity and multifocal seizure syndrome (MIM# 614498). The seven previously described patients suffered from uncontrolled seizures, and all of those patients died in their first months of life. BRAT1 acts as a regulator of cellular proliferation and migration and is required for mitochondrial function. The loss of these functions may explain the cerebral atrophy observed in this case of PE. This case highlights the extraordinary potential of next generation technologies for the diagnosis of rare genetic diseases, including PE. Making a prompt diagnosis of PE is important for genetic counseling and disease management. PMID- 26947547 TI - The first report of Brucella suis biovar 1 isolation in human in Turkey. AB - BACKGROUND: Brucella melitensis and B. abortus are the species generally isolated from human samples in Turkey. Several studies have also demonstrated the presence of antibodies against B. canis. CASE REPORT AND STUDY: Brucella spp. was isolated from blood culture from a 35-year-old male with clinical signs and symptoms of acute meningitis, including fever lasting for 1 week. Multiplex PCR demonstrated B. suis, and biochemical features indicated biovar 1. CONCLUSIONS: This report is the first emphasizing that B. suis should be considered among the causes of brucellosis in Turkey. PMID- 26947548 TI - Validity and reliability assessment of the Compliance with Standard Precautions Scale Arabic version in Saudi nursing students. AB - Strict compliance with standard precautions (SPs) is warranted to ensure the safety of patients in healthcare facilities. Nursing students (NSs), who are regarded as nurses in training, potentially play a role in cross-contamination in the hospital. NSs are also at high risk of acquiring infections in cases of ineffective compliance with SPs. Thus, an assessment of NSs' compliance with SPs should be conducted on a regular basis, which necessitates a valid and reliable tool. This study was conducted to assess the validity and reliability of the Compliance with Standard Precautions Scale Arabic version (CSPS-A) in Saudi NSs. A convenient sample of 230 respondents (158 NSs and 72 staff nurses) was included in this descriptive, cross-sectional study. The CSPS English version was translated into the Arabic language following a recommended guideline from cross cultural adaptation and translation instruments. The Cronbach's alpha, the intraclass correlation coefficient (ICC) of the test-retest scores, and the item total correlations (ITC) were computed to establish the reliability. Content validity and construct validity by the known-groups method and hypothesis testing method were performed. The CSPS-A exhibited good internal consistency and reliability (Cronbach's alpha, 0.89; ICC, 0.88; ITCs, 0.325-0.728). A satisfactory content and construct validity was also reported. The CSPS-A is a valid and reliable tool that can measure the compliance to SPs among NSs in Saudi Arabia. PMID- 26947549 TI - Relationship between phosphorylation of sperm-specific antigen and prognosis of lung adenocarcinoma. AB - Lung cancer is generally considered as a highly malignant cancer. A major challenge for the management of lung adenocarcinoma patients is to predict the clinical course of the disease after resection. We analyzed the different levels of phosphorylation of proteins in lung adenocarcinoma tissues between a poor prognosis (PP) group, in which six patients exhibited recurrence within five years after surgery, and a good prognosis (GP) group, in which seven patients did not exhibit recurrence within five years after surgery. We found that phosphorylation at Ser92 of the sperm-specific antigen 2 (SSFA2) [phospho SSFA2(pS92)] was stimulated in the PP group. Using samples from a total of 46 patients, we investigated the utility of phospho-SSFA2(pS92) to discriminate patients of GP and PP groups, with multiple reaction monitoring (MRM) mass spectrometry. Consequently, we confirmed that the PP group had significantly elevated phospho-SSFA2(pS92) levels. Additionally, no expression of SSFA2 recognized in the normal lung tissues. From these results, we demonstrate that phospho-SSFA2 (pS92) is related to the prognosis of early resected lung adenocarcinomas. Therefore, we suggest that phosphorylation of this protein indicates its role as a potential biomarker and new therapeutic target. BIOLOGICAL SIGNIFICANCE: Lung adenocarcinoma patients often experience a high rate of recurrence after surgery. It is important to discover biomarkers for prognostic prediction and therapeutic targets for treatment of early-stage lung adenocarcinoma. In this study, using tissue samples obtained from patients with lung adenocarcinoma that had been stored for five years at -80 degrees C, we identified 13 unique phosphorylated peptides, which were differentially expressed between poor and good prognosis groups. We confirmed that phosphorylation at Ser92 of the sperm-specific antigen 2 (SSFA2)[phospho-SSFA2 (pS92)], was related to poor prognosis. Our study demonstrates that prognostic prediction of early stage lung adenocarcinoma is possible, and suggests new therapeutic targets for its treatment. PMID- 26947551 TI - Proteomics for the authentication of fish species. AB - Assessment of seafood authenticity and origin, mainly in the case of processed products (fillets, sticks, baby food) represents the crucial point to prevent fraudulent deceptions thus guaranteeing market transparency and consumers health. The most dangerous practice that jeopardies fish safety is intentional or unintentional mislabeling, originating from the substitution of valuable fish species with inferior ones. Conventional analytical methods for fish authentication are becoming inadequate to comply with the strict regulations issued by the European Union and with the increase of mislabeling due to the introduction on the market of new fish species and market globalization. This evidence prompts the development of high-throughput approaches suitable to identify unambiguous biomarkers of authenticity and screen a large number of samples with minimal time consumption. Proteomics provides suitable and powerful tools to investigate main aspects of food quality and safety and has given an important contribution in the field of biomarkers discovery applied to food authentication. This report describes the most relevant methods developed to assess fish identity and offers a perspective on their potential in the evaluation of fish quality and safety thus depicting the key role of proteomics in the authentication of fish species and processed products. BIOLOGICAL SIGNIFICANCE: The assessment of fishery products authenticity is a main issue in the control quality process as deceptive practices could imply severe health risks. Proteomics based methods could significantly contribute to detect falsification and frauds, thus becoming a reliable operative first-line testing resource in food authentication. PMID- 26947550 TI - PlantPReS: A database for plant proteome response to stress. AB - About 75% of plant yield potential has been estimated to be lost to environmental stresses, even in developed agricultures. To facilitate the biotechnological improvement of crop productivity, genes and proteins that control crop adaptation to a wide range of environments will need to be identified. Due to the challenges faced in text/data mining, there is a large gap between the data available to researchers and the hundreds of published plant stress proteomics articles. Plant stress proteome database (PlantPReS; www.proteome.ir) is an open online proteomic database, which currently (as of October 2015) comprises >20,413 entries from 456 manually curated articles, and contains >10,600 unique stress responsive proteins. Since every aspect of the experiments, including protein name, accession number, plant type, tissue, stress types, organelles, and developmental stage has been digitized, experimental data can be rapidly accessed and integrated. Furthermore, PlantPReS enables researchers to perform multiple analyses on the database using the filtration mode, and the results of each query indicate a series of proteins for which a set of selected criteria is met. The query results can be displayed in either text or graphical format. SIGNIFICANCE: The promise of text and data mining to facilitate and enhance research fundamentally has not yet been achieved, mainly because great numbers of stress associated proteins are not deposited in databases. PlantPReS is a valuable database for the vast majority of researchers working in proteomics and plant stress areas. It has a user-friendly interface with a number of useful features, including a search engine, analysis tools, gene ontology, a function for cross referencing useful external databases, and the expression pattern of stress associated proteins. PMID- 26947552 TI - TMT-based quantitative proteomics analyses reveal novel defense mechanisms of Brassica napus against the devastating necrotrophic pathogen Sclerotinia sclerotiorum. AB - The white mould disease, caused by Sclerotinia sclerotiorum, is one of the most important diseases in the vital oil crop Brassica napus. Nevertheless, the defense mechanisms of B. napus against S. sclerotiorum are poorly understood. In this study, we performed comparative quantitative proteomics analyses to reveal B. napus defense mechanisms against S. sclerotiorum. The proteomes of B. napus leaves inoculated with S. sclerotiorum wild-type strain 1980 and nonpathogenic mutant strain Ep-1PB as well as empty agar plug as the control were analyzed using TMT label-based quantitative analysis technique. A total of 79, 299 and 173 proteins consistently differentially expressed between Ep-1PB- and mock inoculated leaves, 1980- and mock-inoculated leaves, as well as 1980- and Ep-1PB inoculated leaves, respectively, were identified. The differential expression of 12 selected proteins was confirmed by qRT-PCR analyses. The Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and protein-protein interaction prediction analyses revealed that redox homeostasis, lipid signaling, calcium signaling, histone and DNA methylation-mediated transcription regulation and defense-related proteins such as defensin and defensin-like proteins and cyanate lyase, contribute to defense against S. sclerotiorum. Our results provide new insights into molecular mechanisms that may be involved in defense responses of B. napus to S. sclerotiorum. SIGNIFICANCE: The Sclerotinia white mould disease is one of the most important diseases in the significant oil crop Brassica napus. Nevertheless, the defense mechanisms of B. napus against S. sclerotiorum are still largely unknown to date. In this study, we addressed this issue by performing TMT label-based comparative quantitative analyses of the proteomes of B. napus leaves inoculated with S. sclerotiorum wild-type strain 1980 and nonpathogenic mutant strain Ep-1PB as well as empty agar plug as the control. Through comparative analyses on 79, 299, and 173 proteins that are consistently differentially expressed in between Ep-1PB-inoculated and the control leaves, 1980-inoculated and the control leaves, as well as 1980-inoculated and Ep-1PB inoculated leaves, respectively, we revealed that redox homeostasis, lipid signaling, calcium signaling, histone and DNA methylation-mediated transcription regulation and defense-related proteins such as defensin and defensin-like proteins as well as cyanate lyase, contribute to B. napus defenses against S. sclerotiorum. Notably, the potential role of lipid signaling, calcium signaling, histone and DNA methylation-mediated transcription regulation and cyanate lyase in B. napus defense against S. sclerotiorum are not reported previously but rather unveiled for the first time in this study. The current study represents the most extensive analysis of the protein profile of B. napus in response to S. sclerotiorum inoculation and includes for the first time the results from comparison between plants inoculated with the wild-type strain and a nonpathogenic mutant strain of S. sclerotiorum. Collectively, our results provide new insights into the molecular mechanisms of interactions between B. napus and S. sclerotiorum. PMID- 26947554 TI - Global proteome analysis in plants by means of peptide libraries and applications. AB - Like in animals plant proteins are differently expressed by organ with, for instance, few high abundance species such as RuBisCO in leaves colonizing the analytical space. Contrary to animals, a very large number of plant proteins are present at particularly low concentrations and in the presence of an excessive amount of polysaccharides and other natural polymers. This situation renders the functional investigations particularly challenging since the understanding of plant expression and interaction commences with the particularly laborious proteome deciphering. This fact impacts the investigations on protein differential biosynthesis in response to various stresses of physical, chemical and biological nature. This review updates the technical situation of global protein analysis while making a point on profiling changes resulting from external aggressions throughout recently published data. Within this context the importance of the combinatorial peptide ligand library methodology as an approach for facilitating the differential expression analysis is highlighted. BIOLOGICAL SIGNIFICANCE: The present review covers in extenso the latest progresses made in plant proteomics analyses with the use of the combinatorial peptide ligand library (CPLL) methodology. It well documents the ability of the CPLL technology in greatly extending the coverage of such proteomes, particularly in regard to the discovery and identification of low-abundance proteins, whose signal is obscured not only by the high-abundance species, as typically occurring in animal proteomics, but also by the overwhelming presence of plant polymers, such as polysaccharides, polyphenols, fibers and the like. The review covers the proteomics analysis aspect of modifications contingent upon plant stresses of physical, chemical and biological nature, as well as the discovery of hidden allergens on fruits and vegetable and their undiscovered proteomes. A sure conclusion can be made: no matter what mass spectrometry experts say, pre fractionation in plant proteomics is a must and among such tools CPLLs appear to exert a major role in plant proteome discoveries. PMID- 26947553 TI - iTRAQ-based quantitative proteomic analysis of cultivated Pseudostellaria heterophylla and its wild-type. AB - Pseudostellaria heterophylla is an important traditional Chinese herbal medicine with vast clinical consumption because of its positive effects. To date, changes in the metabolite composition of P. heterophylla have been well documented; however, the molecular differences between cultivated P. heterophylla and its wild-type are still unknown. The aim of this study was to investigate differences in cultivated and wild P. heterophylla. Due to the lack of a genomic database, we used high-throughput transcriptomic and proteomic technologies to identify proteins in the herb. Isobaric tags for relative and absolute quantification (iTRAQ) MS/MS were used to detect statistically significant changes between cultivated and wild P. heterophylla. We detected 3775 proteins; 332 showed differential accumulations across two different ecotypes of P. heterophylla. 71 significant differential expressions of proteins were selected based on GO annotations, KEGG, STRING analysis, and expression level. Quantitative real-time PCR analysis confirmed the authenticity and accuracy of the proteomic analysis. The results indicated that the carbohydrate and cellular amino acid metabolisms in cultivated P. heterophylla were weaker than those in its wild-type; seven important proteins were found to regulate sucrose and amino acids. This will provide the basic information for exploring the cause of differences in secondary metabolites in different ecotypes of P. heterophylla and the protein mechanism of its quality formation. BIOLOGICAL SIGNIFICANCE: This study combined a transcriptome, proteome, and metabolism approach for analyzing differentially expressed proteins of cultivated and wild P. heterophylla and established the relationship between significantly differentially expressed proteins and differential chemical components in non-model plants. The results of proteomic analysis provide the basic information for exploring the quality forming process, which will demonstrate, and provide guidance for, the study of effective constituents of P. heterophylla and its quality formation mechanism. PMID- 26947555 TI - Successful treatment of osteonecrosis-induced fractured mandible with teriparatide therapy: A case report. AB - INTRODUCTION: The management of medication-related osteonecrosis of the jaw (MRONJ) is controversial. To date, there is no established treatment for cases of advanced stage 3 MRONJ osteoporosis in elderly patients. PRESENTATION: An 87-year old osteoporotic woman with osteonecrosis-induced left mandible fracture related to minodronate therapy was referred to us for treatment. She had a vertebral compression fracture concurrently and had started subcutaneous injection of teriparatide. After 18 months of treatment with teriparatide the pathological mandible fracture was healed and functional recovery of the occlusion was obtained by complete dentures. DISCUSSION: Teriparatide may have a powerful anabolic effect on bone, and promote bone regeneration against pathologic mandible fracture induced by MRONJ. CONCLUSION: Based upon these findings, teriparatide might be beneficial for advanced stage 3 MRONJ osteoporosis in elderly patients. PMID- 26947556 TI - Multifunctional poly(beta-amino ester) hydrogel microparticles in periodontal in situ forming drug delivery systems. AB - In situ forming implants (ISIs) formed from poly(lactic-co-glycolic acid) (PLGA) have been commercialized for local drug delivery to treat periodontitis, but drug release from these bulk materials is typically subject to an initial burst. In addition, PLGA has inferior material properties for the dynamic mechanical environment of gingival tissue. In this work, poly(beta-amino ester) (PBAE) hydrogel microparticles were incorporated into a PLGA matrix to provide several new functions: mechanical support, porosity, space-filling, and controlled co delivery of antimicrobial and osteogenic drugs. First, the effects of PBAE microparticles on ISI architecture and material properties throughout degradation were investigated. Second, the influence of PBAE microparticles on drug release kinetics was quantified. Over a 15 d period, ISIs containing PBAE microparticles possessed greater porosity, ranging from 42-80%, compared to controls, which ranged from 24-54% (p < 0.001), and these ISIs also developed significantly greater accessible volume to simulated cell-sized spheres after 5 d or more of degradation (p < 0.001). PBAE-containing ISIs possessed a more uniform microarchitecture, which preserved mechanical resilience after cyclical loading (p < 0.001), and the materials swelled to fill the injected space, which significantly increased interfacial strength in an artificial periodontal pocket (p < 0.0001). PBAE microparticles eliminated the burst of freely-mixed simvastatin compared to 36% burst from controls (p < 0.0001), and high-dose doxycycline release was prolonged from 2 d to 7 d by pre-loading drug into the microparticles. PBAE-containing PLGA ISIs are more effective space-filling scaffolds and offer improved release kinetics compared to existing ISIs used to treat periodontitis. PMID- 26947557 TI - Systematic Review of All-Arthroscopic Versus Mini-Open Repair of Rotator Cuff Tears: A Meta-Analysis. AB - The objective of this study was to compare outcomes in patients with rotator cuff tears undergoing all-arthroscopic versus mini-open rotator cuff repair. A systematic review and meta-analysis of outcomes of all-arthroscopic repair versus mini-open repair in patients with rotator cuff repair was conducted. Studies meeting the inclusion criteria were screened and included from systematic literature search for electronic databases including Medline, Embase, Cochrane CENTRAL, and CINAHL library was conducted from 1969 and 2015. A total of 18 comparative studies including 4 randomized clinical trials (RCTs) were included. Pooled results indicate that there was no difference in the functional outcomes, range of motion, visual analog scale (VAS) score, and short-form 36 (SF-36) subscales. However, Constant-Murley functional score was found to be significantly better in patients with mini-open repair. However, the results of the review should be interpreted with caution due to small size and small number of studies contributing to analysis in some of the outcomes. All-arthroscopic and mini-open repair surgical techniques for the management of rotator cuff repair are associated with similar outcomes and can be used interchangeably based on the patient and rotator tear characteristics. PMID- 26947558 TI - In-situ Observation of Cross-Sectional Microstructural Changes and Stress Distributions in Fracturing TiN Thin Film during Nanoindentation. AB - Load-displacement curves measured during indentation experiments on thin films depend on non-homogeneous intrinsic film microstructure and residual stress gradients as well as on their changes during indenter penetration into the material. To date, microstructural changes and local stress concentrations resulting in plastic deformation and fracture were quantified exclusively using numerical models which suffer from poor knowledge of size dependent material properties and the unknown intrinsic gradients. Here, we report the first in-situ characterization of microstructural changes and multi-axial stress distributions in a wedge-indented 9 MUm thick nanocrystalline TiN film volume performed using synchrotron cross-sectional X-ray nanodiffraction. During the indentation, needle like TiN crystallites are tilted up to 15 degrees away from the indenter axis in the imprint area and strongly anisotropic diffraction peak broadening indicates strain variation within the X-ray nanoprobe caused by gradients of giant compressive stresses. The morphology of the multiaxial stress distributions with local concentrations up to -16.5 GPa correlate well with the observed fracture modes. The crack growth is influenced decisively by the film microstructure, especially by the micro- and nano-scopic interfaces. This novel experimental approach offers the capability to interpret indentation response and indenter imprint morphology of small graded nanostructured features. PMID- 26947559 TI - Subcortical cytoskeleton periodicity throughout the nervous system. AB - Superresolution fluorescence microscopy recently revealed a ~190 nm periodic cytoskeleton lattice consisting of actin, spectrin, and other proteins underneath the membrane of cultured hippocampal neurons. Whether the periodic cytoskeleton lattice is a structural feature of all neurons and how it is modified when axons are ensheathed by myelin forming glial cells is not known. Here, STED nanoscopy is used to demonstrate that this structure is a commonplace of virtually all neuron types in vitro. To check how the subcortical meshwork is modified during myelination, we studied sciatic nerve fibers from adult mice. Periodicity of both actin and spectrin was uncovered at the internodes, indicating no substantial differences between unmyelinated and myelinated axons. Remarkably, the actin/spectrin pattern was also detected in glial cells such as cultured oligodendrocyte precursor cells. Altogether our work shows that the periodic subcortical cytoskeletal meshwork is a fundamental characteristic of cells in the nervous system and is not a distinctive feature of neurons, as previously thought. PMID- 26947560 TI - Characterization of urinary metabolites as biomarkers of colistin-induced nephrotoxicity in rats by a liquid chromatography/mass spectrometry-based metabolomics approach. AB - Colistin is a polypeptide antibiotic that effectively treats infections caused by multidrug-resistant Gram-negative bacteria, but its clinical use is limited due to nephrotoxicity. The purpose of the present study was to identify biomarkers of colistin-induced nephrotoxicity and to further characterize the mechanisms underlying this process by analyzing urinary metabolites using untargeted metabolomic approach. Rats receiving intraperitoneal administration of colistin sodium methanesulfonate (CMS) (25 or 50mg/kg) exhibited histopathological changes in the kidney and increased blood urea nitrogen levels. Additionally, the levels of phenylalanine, tryptophan, and tyrosine in the urine of the CMS-treated group were significantly higher than those of the control group, suggesting that colistin caused proximal tubular damage. Urinary acetylcarnitine and butyrylcarnitine levels also increased after CMS treatment, but the levels of purine metabolites and metabolites related to the tricarboxylic acid cycle were reduced. The most significant increase in the CMS-treated groups was observed in creatine levels. CMS-induced selective nephrotoxicity may be attributed to relatively high tissue concentrations of colistin in the kidney. Taken together, our results indicate that high levels of colistin in the kidney caused perturbations in the tricarboxylic acid cycle, amino acid metabolism, creatine metabolism, and purine metabolism and ultimately led to kidney injury. PMID- 26947562 TI - Seeking a geochemical identifier for authigenic carbonate. AB - Authigenic carbonate was recently invoked as a third major global carbon sink in addition to primary marine carbonate and organic carbon. Distinguishing the two carbonate sinks is fundamental to our understanding of Earth's carbon cycle and its role in regulating the evolution of atmospheric oxygen. Here, using microscale geochemical measurements of carbonates in Early Triassic strata, we show that the growth of authigenic carbonate follows a different trajectory from primary marine carbonate in a cross-plot of uranium concentration and carbon isotope composition. Thus, a combination of the two geochemical variables is able to distinguish between the two carbonate sinks. The temporal distribution of authigenic carbonates in the Early Triassic strata suggests that the increase in the extent of carbonate authigenesis acted as a negative feedback to the elevated atmospheric CO2 concentration. PMID- 26947563 TI - Tuning the size and magnetic properties of ZnxCo1-xFe2O4 nanocrystallites. AB - Magnetically soft zinc-substituted cobalt ferrite ZnxCo1-xFe2O4 (x = 0.4, 0.5 and 0.6) nanocrystallites were successfully synthesized from cheap, abundant materials, using a mild, scalable hydrothermal route. The partial substitution of zinc by cobalt was generally observed to reduce the resulting crystallite sizes and the saturation magnetization. Post-synthesis annealing proved to be an efficient way of inducing crystallite growth to a certain limit, thereby improving the magnetic properties. In the annealing experiments crystallite growth was observed to be extremely dependent on the annealing atmosphere, with the size increasing from dynamic vacuum, to air, argon and helium. As prepared crystallite sizes were found to be between 4.74(1) nm and 5.90(1) nm. Heat treatment caused the growth to increase to anywhere between 7.9 nm and 21.7 nm. The largest crystallite sizes, 35.2(1) nm to 44.9(1) nm, were reached by compaction of the powders prior to heating. The largest magnetizations were generally observed in the largest samples containing the least amount of zinc. The highest observed saturation magnetization was 80.49(1) emu g(-1) measured for a sample with 35.2(1) nm sized crystallites of the composition Zn0.35Co0.66Fe1.99O4. PMID- 26947561 TI - Increasing TRPV4 expression restores flow-induced dilation impaired in mesenteric arteries with aging. AB - The flow-stimulated intracellular Ca(2+) concentration ([Ca(2+)]i) rise in endothelial cells is an important early event leading to flow-induced blood vessel dilation. Transient receptor potential vanilloid subtype 4 (TRPV4), a Ca(2+)-permeable cation channel, facilitates the flow-stimulated [Ca(2+)]i rise. To determine whether TRPV4 is involved in age-related flow-induced blood vessel dilation impairment, we measured blood vessel diameter and nitric oxide (NO) levels and performed Ca(2+) imaging, immunoblotting, and immunostaining assays in rats. We found that the flow-induced and TRPV4 activator 4alpha-PDD-induced dilation of mesenteric arteries from aged rats were significantly decreased compared with those from young rats. The flow- or 4alpha-PDD-induced [Ca(2+)]i rise was also markedly reduced in primary cultured mesenteric artery endothelial cells (MAECs) from aged rats. Immunoblotting and immunostaining results showed an age-related decrease of TRPV4 expression levels in MAECs. Additionally, the 4alpha-PDD-induced NO production was significantly reduced in aged MAECs. Compared with lentiviral GFP-treated aged rats, lentiviral vector delivery of TRPV4 increased TRPV4 expression level in aged MAECs and restored the flow- and 4alpha-PDD-induced vessel dilation in aged mesenteric arteries. We concluded that impaired TRPV4-mediated Ca(2+) signaling causes endothelial dysfunction and that TRPV4 is a potential target for clinical treatment of age-related vascular system diseases. PMID- 26947565 TI - What changes a manuscript from just another one to an important contribution in aquatic toxicology: Points that increase the chances of work getting published in Aquatic Toxicology-and being rewarded. PMID- 26947564 TI - HCV evolutionary genetics of SVR versus virologic failure assessed from the vaniprevir phase III registration trials. AB - In the phase III registration studies conducted in Japan, Japanese HCV gt1 patients administered vaniprevir 300 mg twice daily plus pegylated interferon/ribavirin for 12 or 24 weeks achieved SVR24 rates of 83.7-84.5% among treatment-naive patients, and 92.0-96.2% and 61.9% among breakthrough/relapsers or null-responders to prior interferon based therapy. As evidenced by direct sequencing, patients who did not achieve SVR24 principally failed due to treatment-emerging mutations at D168 or in a few cases R155. In this work, additional sequence analysis was conducted to address whether there were baseline polymorphisms associated with failure, evaluate the persistence of resistant virus among treatment failures, and assess for evidence of second site co evolution with R155 or D168 mutations. To accomplish this, clonal sequencing (up to 40 clones per sample) was conducted on baseline, failure, and follow-up samples from all 38 patients among the vaniprevir treatment arms who met virologic failure criteria (37 gt1b, 1 gt1a, herein referred to as virologic failures) and baseline samples from 41 vaniprevir-treated SVR24 patients (all gt1b) selected among the three studies. SVR24 and virologic failure patients showed similar distributions of baseline polymorphisms previously associated with failure to one or more protease inhibitors. Furthermore, there was no evidence for baseline polymorphisms or a genetic signature across the NS3 protease domain specific to virologic failure patients, and which distinguishes them from baseline SVR24 sequences beyond a chance distribution. 24 of 32 virologic failures for whom baseline, failure, and follow-up samples were available showed reduced prevalence of the resistant virus first observed at the time of failure during the protocol-defined follow-up period of 24 weeks. Finally, pairwise analysis using either alignment or phylogenetic based methodologies provided no evidence for second site evolution with either the R155 or D168 mutations attributed to failure. This work supports and extends earlier findings based upon direct sequencing that attributed virologic failure to vaniprevir in the Phase III studies solely to the emergence of R155 or D168 mutations, with no apparent influence by other residues within the NS3 protease domain on treatment outcome. CLINICALTRIALS. GOVIDENTIFIERS: NCT01370642, NCT01405937, NCT01405560. PMID- 26947566 TI - Structural Insights into the Processing of Nucleobase-Modified Nucleotides by DNA Polymerases. AB - The DNA polymerase-catalyzed incorporation of modified nucleotides is employed in many biological technologies of prime importance, such as next-generation sequencing, nucleic acid-based diagnostics, transcription analysis, and aptamer selection by systematic enrichment of ligands by exponential amplification (SELEX). Recent studies have shown that 2'-deoxynucleoside triphosphates (dNTPs) that are functionalized with modifications at the nucleobase such as dyes, affinity tags, spin and redox labels, or even oligonucleotides are substrates for DNA polymerases, even if modifications of high steric demand are used. The position at which the modification is introduced in the nucleotide has been identified as crucial for retaining substrate activity for DNA polymerases. Modifications are usually attached at the C5 position of pyrimidines and the C7 position of 7-deazapurines. Furthermore, it has been shown that the nature of the modification may impact the efficiency of incorporation of a modified nucleotide into the nascent DNA strand by a DNA polymerase. This Account places functional data obtained in studies of the incorporation of modified nucleotides by DNA polymerases in the context of recently obtained structural data. Crystal structure analysis of a Thermus aquaticus (Taq) DNA polymerase variant (namely, KlenTaq DNA polymerase) in ternary complex with primer-template DNA and several modified nucleotides provided the first structural insights into how nucleobase modified triphosphates are tolerated. We found that bulky modifications are processed by KlenTaq DNA polymerase as a result of cavities in the protein that enable the modification to extend outside the active site. In addition, we found that the enzyme is able to adapt to different modifications in a flexible manner and adopts different amino acid side-chain conformations at the active site depending on the nature of the nucleotide modification. Different "strategies" (i.e., hydrogen bonding, cation-pi interactions) enable the protein to stabilize the respective protein-substrate complex without significantly changing the overall structure of the complex. Interestingly, it was also discovered that a modified nucleotide may be more efficiently processed by KlenTaq DNA polymerase when the 3'-primer terminus is also a modified nucleotide instead of a nonmodified natural one. Indeed, the modifications of two modified nucleotides at adjacent positions can interact with each other (i.e., by pi-pi interactions) and thereby stabilize the enzyme-substrate complex, resulting in more efficient transformation. Several studies have indicated that archeal DNA polymerases belonging to sequence family B are better suited for the incorporation of nucleobase-modified nucleotides than enzymes from family A. However, significantly less structural data are available for family B DNA polymerases. In order to gain insights into the preference for modified substrates by members of family B, we succeeded in obtaining binary structures of 9 degrees N and KOD DNA polymerases bound to primer-template DNA. We found that the major groove of the archeal family B DNA polymerases is better accessible than in family A DNA polymerases. This might explain the observed superiority of family B DNA polymerases in polymerizing nucleotides that bear bulky modifications located in the major groove, such as modification at C5 of pyrimidines and C7 of 7 deazapurines. Overall, this Account summarizes our recent findings providing structural insight into the mechanism by which modified nucleotides are processed by DNA polymerases. It provides guidelines for the design of modified nucleotides, thus supporting future efforts based on the acceptance of modified nucleotides by DNA polymerases. PMID- 26947567 TI - Early Formation of Serum Advanced Glycation End-Products in Children with Type 1 Diabetes Mellitus: Relationship with Glycemic Control. AB - OBJECTIVES: To quantify serum advanced glycation end-products (AGEs) at the onset of type 1 diabetes mellitus and to determine their potential usefulness as retrospective indicators of glycemic balance. STUDY DESIGN: Carboxymethyllysine (CML) and pentosidine concentrations were determined by liquid chromatography tandem mass spectrometry in 3 groups of children with type 1 diabetes mellitus: group (Gr) 1, subjects included at disease onset (n = 36); Gr2, subjects with diabetes of 5 years duration (n = 48); Gr3, subjects with diabetes of 10 years duration and in control subjects (n = 33). Hemoglobin A1c (HbA1c) values were recorded over the entire course of treatment for assessing long-term glycemic balance. RESULTS: Serum AGE concentrations were increased in all groups of subjects with diabetes compared with control subjects, but were highest in Gr1 (for CML: 0.155, 0.306, 0.219, and 0.224 mmol/mol Lys in control, Gr1, Gr2, and Gr3 subjects, respectively; for pentosidine: 312, 492, 365, and 403 nmol/mol Lys, respectively). AGE concentrations were closely correlated with HbA1c values (r = 0.78 for CML; r = 0.49 for pentosidine). In Gr2 and Gr3, the overall glycemic balance estimated by average HbA1c values was positively correlated with CML and pentosidine concentrations, especially in the first year of follow-up. CONCLUSION: Our results indicate that AGE concentrations are elevated in serum at the time of diabetes mellitus diagnosis, suggesting that the deleterious role of AGEs in the development of long-term complications should be taken into account even at the initial stages of the disease. Moreover, in some circumstances, AGEs could serve as surrogate markers of HbA1c for monitoring glycemic control. PMID- 26947569 TI - Incidence Trends and Mortality from Childhood Venous Thromboembolism: A Population-Based Cohort Study. AB - OBJECTIVE: To determine the incidence, incidence trend, and mortality of venous thromboembolism (VTE) in a general pediatric population during an 11-year period. STUDY DESIGN: The administrative health care databases of the province of Quebec, Canada were used to identify all children (ages 1-17 years inclusive) diagnosed with incident VTE between January 1, 1994 and December 31, 2004. The incidence rate and trend over the 11-year study period were then analyzed. RESULTS: In total, 487 incident cases of pediatric VTE were documented. The age-standardized incidence rate was 0.29 VTE per 10 000 person-years (95% CI 0.26-0.31). Girls had a statistically significant higher incidence rate (per 10 000 person-years) than boys, 0.37 and 0.21 per 10 000 person-years, respectively, with an incidence rate ratio comparing females with males, adjusted for age group of 1.75 (95% CI 1.46 2.10). Trend analysis illustrated no statistically significant change in the age standardized incidence rates. Overall all-cause mortality was 11.4 per 1000 children-years (95% CI 8.1-16.1). CONCLUSIONS: Pediatric VTE is frequent, although its incidence is stable over time and all-cause mortality is lower than previously reported. Future studies that address possible sex and age group differences in the incidence of pediatric VTE are needed to help determine effective primary thromboprophylaxis strategies in children at high risk for VTE. PMID- 26947568 TI - A Randomized Controlled Trial of an Outpatient Protocol for Transitioning Children from Tube to Oral Feeding: No Need for Amitriptyline. AB - OBJECTIVE: To assess the role of amitriptyline in the effectiveness of an outpatient protocol for weaning medically complicated children from tube to oral feeding. STUDY DESIGN: Twenty-one children seen in multidisciplinary outpatient feeding teams across 4 sites were recruited to a randomized placebo-controlled trial of a 6-month outpatient treatment protocol with behavioral, oral-motor, nutrition, and medication components. RESULTS: All of the children who completed the 6-month program (73%) were weaned to receive only oral feeding, regardless of group assignment. The transition from tube to oral feeding resulted in decreases in body mass index percentile and pain, some improvements in quality of life, and no statistically significant changes in cost. CONCLUSIONS: Amitriptyline is not a key component of this otherwise effective outpatient, interdisciplinary protocol for weaning children from tube to oral feeding. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01206478. PMID- 26947570 TI - Active Video Games in Schools and Effects on Physical Activity and Health: A Systematic Review. AB - OBJECTIVE: To assess the quality of evidence for the effects of school active video game (AVG) use on physical activity and health outcomes. STUDY DESIGN: Online databases (ERIC, PsycINFO, PubMed, SPORTDiscus, and Web of Science) and gray literature were searched. Inclusion criteria were the use of AVGs in school settings as an intervention; assessment of at least 1 health or physical activity outcome; and comparison of outcomes with either a control group or comparison phase. Studies featuring AVGs within complex interventions were excluded. Study quality was assessed using the Effective Public Health Practice Project tool. RESULTS: Twenty-two reports were identified: 11 assessed physical activity outcomes only, 5 assessed motor skill outcomes only, and 6 assessed both physical activity and health outcomes. Nine out of 14 studies found greater physical activity in AVG sessions compared with controls; mostly assessed by objective measures in school time only. Motor skills were found to improve with AVGs vs controls in all studies but not compared with other motor skill interventions. Effects of AVGs on body composition were mixed. Study quality was low in 16 studies and moderate in the remaining 6, with insufficient detail given on blinding, participation rates, and confounding variables. CONCLUSIONS: There is currently insufficient evidence to recommend AVGs as efficacious health interventions within schools. Higher quality AVG research utilizing randomized controlled trial designs, larger sample sizes, and validated activity measurements beyond the school day is needed. PMID- 26947572 TI - Second magnetization peak effect, vortex dynamics, and flux pinning in 112-type superconductor Ca0.8La0.2Fe(1-x)CoxAs2. AB - Investigation of vortex pinning and its relaxation is of great importance for both basic physics and technological applications in the field of superconductivity. We report a great improvement of superconducting properties in the recently discovered 112-type superconductors (Ca, La)FeAs2 through Co co doping. High critical current density Js(5 K) > 2(*)10(6) A/cm(2) is obtained and pronounced second peak effect is observed in magnetization hysteresis loops. Both the dynamic and static relaxation studies result in comparable and sizable relaxation rates S or Q, indicating a fast vortex creep. The second magnetization peak (SMP) is found to be strongly associated with a crossover from elastic to plastic vortex creep. Above the crossover, plastic vortex creep governs the vortex dynamics in a wide range of temperatures and fields. A good scaling behavior of the normalized pinning force density fp by formula fp = h(p)(1-h)(q) ((p) = 1.44, q = 1.66, h = 0.44) is revealed, which demonstrates an important contribution from core normal point-like pinning sites. To better understand the SMP phenomenon, we discuss the related physical scenario as well as the affecting factors in the SMP occurrence. PMID- 26947573 TI - Temporal dynamics of biotic and abiotic drivers of litter decomposition. AB - Climate, litter quality and decomposers drive litter decomposition. However, little is known about whether their relative contribution changes at different decomposition stages. To fill this gap, we evaluated the relative importance of leaf litter polyphenols, decomposer communities and soil moisture for litter C and N loss at different stages throughout the decomposition process. Although both microbial and nematode communities regulated litter C and N loss in the early decomposition stages, soil moisture and legacy effects of initial differences in litter quality played a major role in the late stages of the process. Our results provide strong evidence for substantial shifts in how biotic and abiotic factors control litter C and N dynamics during decomposition. Taking into account such temporal dynamics will increase the predictive power of decomposition models that are currently limited by a single-pool approach applying control variables uniformly to the entire decay process. PMID- 26947574 TI - Reducing the availability of food to control feral pigeons: changes in population size and composition. AB - BACKGROUND: As feeding by humans is one of the main food resources to pigeons (Columba livia), there is general agreement that public education that aims to reduce the food base may be the most feasible way to reduce pigeon abundance. However, except for the classic example of Basel, the method has rarely been tested or implemented. We provide results from a 1 year study in the city of Barcelona where we tested the effect of public education on pigeon population abundance and composition. RESULTS: The quantity of food provided by people to pigeons was significantly reduced during the study. Feral pigeon density was reduced by 40% in the two experimental districts, but no variation was detected in the control district. Detailed analyses in one of the districts showed that the reduction was mainly related to the reduction in food availability but not to culling. Pigeons captured at the end of the experiment were larger than at the start of the study, but body condition was reduced. CONCLUSION: Results show the effectiveness of public information to manage feral pigeon populations in a large city, and that control operations can exert important selection pressure on the population, leading to changes in population composition. (c) 2016 Society of Chemical Industry. PMID- 26947575 TI - Redox Polypharmacology as an Emerging Strategy to Combat Malarial Parasites. AB - 3-Benzylmenadiones are potent antimalarial agents that are thought to act through their 3-benzoylmenadione metabolites as redox cyclers of two essential targets: the NADPH-dependent glutathione reductases (GRs) of Plasmodium-parasitized erythrocytes and methemoglobin. Their physicochemical properties were characterized in a coupled assay using both targets and modeled with QSPR predictive tools built in house. The substitution pattern of the west/east aromatic parts that controls the oxidant character of the electrophore was highlighted and accurately predicted by QSPR models. The effects centered on the benz(o)yl chain, induced by drug bioactivation, markedly influenced the oxidant character of the reduced species through a large anodic shift of the redox potentials that correlated with the redox cycling of both targets in the coupled assay. Our approach demonstrates that the antimalarial activity of 3 benz(o)ylmenadiones results from a subtle interplay between bioactivation, fine tuned redox properties, and interactions with crucial targets of P. falciparum. Plasmodione and its analogues give emphasis to redox polypharmacology, which constitutes an innovative approach to antimalarial therapy. PMID- 26947576 TI - Dividing the pie: differential dung pat size utilization by sympatric Haematobia irritans and Musca autumnalis. AB - Horn flies [Haematobia irritans (Diptera: Muscidae) (L.)] and face flies [Musca autumnalis (Diptera: Muscidae) De Geer] use the same larval resource, but their interactions are poorly studied. Dung pats (n = 350) were core sampled in the summers of 2012 and 2013 from irrigated pastures in Pomona, California, U.S.A. (34 degrees 03'N, 117 degrees 48'W) and held for face fly and horn fly emergence. Surface areas and estimated weights were recorded for each whole pat. Almost half (42.0%) of the pat cores yielded neither fly, 29.7% yielded horn flies only, 12.9% yielded face flies only and 15.4% yielded both flies. Of the fly-positive pats, surface area and mass were larger for face fly-occupied pats, whereas horn fly-occupied pats were smaller. Pats shared by the two species were intermediate. Horn flies per positive core were unaffected by the absence/presence of face flies, but half as many face flies emerged when pats were co-inhabited by horn flies. Face flies inhabited larger pats, which might better resist heating and drying, to which they are susceptible; horn flies inhabited a broad pat size range. Horn fly tolerance of lower dung moisture probably allows horn flies to colonize and survive in a wide range of pats in dry areas like southern California. PMID- 26947577 TI - Present and future of molecular monitoring in chronic myeloid leukaemia. AB - Currently, physicians treating chronic myeloid leukaemia (CML) patients can rely on a wide spectrum of therapeutic options: the best use of such options is essential to achieve excellent clinical outcomes and, possibly, treatment-free remission (TFR). To accomplish this, proper integration of expert clinical and laboratory monitoring of CML patients is fundamental. Molecular response (MR) monitoring of patients at defined time points has emerged as an important success factor for optimal disease management and BCR-ABL1 kinase domain mutation screening is useful to guide therapeutic reassessment in patients who do not achieve optimal responses to tyrosine kinase inhibitor therapy. Deeper MRs might be associated with improved long-term survival outcomes. More importantly, they are considered a gateway to TFR. In molecular biology, novel procedures and technologies are continually being developed. More sophisticated molecular tools and automated analytical solutions are emerging as CML treatment endpoints and expectations become more and more ambitious. Here we provide a critical overview of current and novel methodologies, present their strengths and pitfalls and discuss what their present and future role might be. PMID- 26947578 TI - Co- and Post-Translational Protein Folding in the ER. AB - The biophysical rules that govern folding of small, single-domain proteins in dilute solutions are now quite well understood. The mechanisms underlying co translational folding of multidomain and membrane-spanning proteins in complex cellular environments are often less clear. The endoplasmic reticulum (ER) produces a plethora of membrane and secretory proteins, which must fold and assemble correctly before ER exit - if these processes fail, misfolded species accumulate in the ER or are degraded. The ER differs from other cellular organelles in terms of the physicochemical environment and the variety of ER specific protein modifications. Here, we review chaperone-assisted co- and post translational folding and assembly in the ER and underline the influence of protein modifications on these processes. We emphasize how method development has helped advance the field by allowing researchers to monitor the progression of folding as it occurs inside living cells, while at the same time probing the intricate relationship between protein modifications during folding. PMID- 26947579 TI - Effect of delayed reinforcement on skill acquisition during discrete-trial instruction: Implications for treatmen-integrity errors in academic settings. AB - We used an adapted alternating treatments design to compare skill acquisition during discrete-trial instruction using immediate reinforcement, delayed reinforcement with immediate praise, and delayed reinforcement for 2 children with autism spectrum disorder. Participants acquired the skills taught with immediate reinforcement; however, delayed reinforcement decreased the efficiency and effectiveness of discrete-trial instruction. We discuss the importance of evaluating the influence of treatment-integrity errors on skill acquisition during discrete-trial instruction. PMID- 26947580 TI - Using habit reversal to decrease filled pauses in public speaking. AB - This study evaluated the effectiveness of simplified habit reversal in reducing filled pauses that occur during public speaking. Filled pauses consist of "uh," "um," or "er"; clicking sounds; and misuse of the word "like." After baseline, participants received habit reversal training that consisted of awareness training and competing response training. During postintervention assessments, all 6 participants exhibited an immediate decrease in filled pauses. PMID- 26947581 TI - The (1) H NMR spectrum of pyrazole in a nematic phase. AB - The experimental (1) H nuclear magnetic resonance (NMR) spectrum of 1H-pyrazole was recorded in thermotropic nematic liquid crystal N-(p-ethoxybenzylidene)-p butylaniline (EBBA) within the temperature range of 299-308 K. Two of three observable dipolar DHH -couplings appeared to be equal at each temperature because of fast prototropic tautomerism. Analysis of the Saupe orientational order parameters using fixed geometry determined by computations and experimental dipolar couplings results in a situation in which the molecular orientation relative to the magnetic field (and the liquid crystal director) can be described exceptionally by a single parameter. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26947582 TI - Editorial (Thematic Issue: Embryonic Signaling Pathways as Potential Targets for the Treatment of Rhabdomyosarcoma). PMID- 26947583 TI - Individualised mindfulness-based stress reduction for head and neck cancer patients undergoing radiotherapy of curative intent: a descriptive pilot study. AB - People with head and neck cancer (HNC) experience elevated symptom toxicity and co-morbidity as a result of treatment, which is associated with poorer psychosocial and quality-of-life (QoL) outcomes. This Phase I study examined whether an individualised mindfulness-based stress reduction (IMBSR) programme could be successfully used with HNC patients undergoing curative treatment. Primary aims were to explore feasibility, compliance, acceptability and fidelity. Secondary aims were to determine whether (1) participation in the intervention was associated with changes in post-intervention mindfulness and (2) post intervention mindfulness was associated with post-intervention distress and QoL. Nineteen HNC patients participated in a seven-session IMBSR programme with pre- and post-test outcome measures of psychological distress, depression, anxiety and QoL. Primary aims were assessed by therapists or participants. Mindfulness, distress and QoL were assessed using self-report questionnaires at pre- and post intervention. Longer time spent meditating daily was associated with higher post intervention mindfulness. After controlling for pre-intervention mindfulness, there was an association between higher post-intervention mindfulness and lower psychological distress and higher total, social and emotional QoL. This study offers important preliminary evidence than an IMBSR intervention can be administered to HNC patients during active cancer treatment. A randomised controlled trial is warranted to confirm these findings. PMID- 26947585 TI - Audit of paediatric residents' medical records. AB - BACKGROUND: The quality of the information contained in a medical record is dependent on the knowledge and skills of the doctor. The auditing of medical records is one of the items included in the competency evaluation of residents at the Department of Pediatrics, Prince of Songkla University (PSU), Thailand. OBJECTIVES: To determine the percentages of 'not met' and 'not acceptable' charts written by residents, which parts of the residents' writing required improvement and associated factors. METHODS: The charts of four newly admitted cases at each ward were selected non-randomly by attending staff for bi-weekly audit. The audit form comprised 15 components, with each component scored as 'met' or 'not met'. Medical records with more than two 'not met' items were categorised as 'not acceptable'. RESULTS: From September 2012 to October 2013, a total 506 in-patient medical records written by PSU paediatric residents were reviewed. The components identified as having the highest rates of 'not acceptable' completion were 'initial investigations' (5.3%), 'summary of investigations' (4.5%) and 'progression of clinical conditions' (4.3%). The reasons for a 'not acceptable' evaluation were 'incomplete documentation' (65.0%), 'lack of follow-up' (26.7%) and 'incorrect clinical reasoning' (8.3%). Using logistic regression analysis, the charts of patients from the chronic illness wards were found to be most significantly associated with the 'not acceptable' rating. Residents need skills and knowledge when completing patient records CONCLUSIONS: Residents need skills and knowledge when completing patient records, and attending staff should be aware that it is their responsibility to ensure that residents complete documentation fully and correctly. PMID- 26947586 TI - Mutation in the caveolin-3 gene causes asymmetrical distal myopathy. AB - Mutations in the gene encoding caveolin-3 (CAV3) can cause a broad spectrum of clinical phenotypes, including limb girdle muscular dystrophy, rippling muscle disease, distal myopathy (MD), idiopathic persistent elevation of serum creatine kinase and cardiomyopathy. MD is a relatively rare subtype of caveolinopathy. Here, we report a sporadic case of a middle-aged female Chinese patient with MD in which a CAV3 mutation was identical to that previously reported in cases of rippling muscle disease. T1-weighted enhanced skeletal muscle MRI of the lower limbs showed an abnormal signal in the distal and proximal muscles. A muscle biopsy revealed moderate dystrophic changes, and immunohistochemical staining showed reduced CAV-3 expression in the plasmalemma. Genetic analysis revealed a heterozygous c.136G > A (p.Ala46Thr) CAV3 mutation that appeared to be de novo because it was absent from the patient's parents. This study suggested that the CAV3 c.136G > A (p.Ala46Thr) mutation can cause MD as well as different phenotypes in different individuals, suggesting that additional unknown loci must affect the disease phenotypes. PMID- 26947584 TI - Negative and interactive effects of sex, aging, and alcohol abuse on gray matter morphometry. AB - Chronic alcohol use is associated with declines in gray matter (GM) volume, as is the normal aging process. Less apparent, however, is how the interaction between aging and heavy alcohol use affects changes in GM across the lifespan. There is some evidence that women are more vulnerable to the negative effects of alcohol use on GM than men. In the current study, we examined whether localized GM was related to measures of alcohol use disorder (e.g., AUDIT score) in a large sample (N = 436) of participants, ages 18-55 years, with a range of disease severity, using both voxel-based morphometry (VBM) and surface-based morphometry (SBM). We also explored whether GM associations with alcohol use disorder (AUD) severity are moderated by sex and age. Results showed significant negative associations between AUD severity and GM volume throughout temporal, parietal, frontal, and occipital lobes. Women showed more negative effects of alcohol use than men for cortical thickness in left orbitofrontal cortex, but evidence for increased vulnerability based on sex was limited overall. Similarly, a specific age by alcohol use interaction was observed for volume of right insula, but other regional or global interactions were not statistically supported. However, significant negative associations between heavy alcohol use and GM volumes were observed as early as 18-25 years. These findings support that alcohol has deleterious effects on global and regional GM above and beyond age, and, of particular importance, that regional associations emerge in early adulthood. Hum Brain Mapp 37:2276-2292, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26947588 TI - Proteomic identification of predictive tissue biomarkers of sensitive to neoadjuvant chemotherapy in squamous cervical cancer. AB - AIMS: The regimens of neoadjuvant chemotherapy (NAC) in squamous cervical cancer (SCC) frequently use cisplatin combined with paclitaxel. Unfortunately, some cervical cancers show resistance to the principal chemotherapeutic agents in the treatment, decreasing the effectiveness of this therapy. The objective of this study was to search for predictive markers of response to NAC in patients with SCC. MAIN METHODS: Two-dimensional gel electrophoresis (2-DE) accompanied by matrix-assisted laser desorption ionization time-of-flight tandem mass spectrometry (MALDI-TOF-MS) was used to analyze and identify differentially expressed proteins in ten cases of advanced cervical cancer patients receiving cisplatin-based NAC. Each of these patients received more than two cycles of NAC. Cell proliferation rate in cisplatin resistant human cervical cancer cell Hela/DDP and its parent cell Hela after treatment with Hsp70 inhibitor and/or cisplatin were tested by MTT assay. KEY FINDINGS: Twelve protein spots changed in abundance, quantitative comparison of spot volumes showed that seven protein spots were up-regulated and five spots were down-regulated in the NAC non responders compared to the NAC responders. These proteins are involved in various cellular processes essential for cell metabolism, migration and apoptotic signal transduction. The high-fold changes proteins of stathmin1, Hsp70 and pyruvate kinase isoform M2 were validated by Western blot analysis. Over-expression of Hsp70 inhibits the efficacy of cisplatin. Hsp70 inhibitor enhanced the sensitivity to cisplatin in both Hela and Hela/DDP cells. SIGNIFICANCE: The study found many candidate proteins involved in chemotherapy resistance/sensitivity, among them Hsp70 might be potential biomarkers to predict the efficacy of chemotherapy for SCC patients. PMID- 26947587 TI - Mechanisms of echinochrome potency in modulating diabetic complications in liver. AB - BACKGROUND: Diabetes mellitus is one of the most public metabolic disorders. It is mainly classified into type 1 and type 2. Echinochrome is a pigment from sea urchins that has antioxidant, anti-microbial, anti-inflammatory and chelating abilities. AIMS: The present study aimed to investigate the anti-diabetic mechanisms of echinochrome pigment in streptozotocin-induced diabetic rats. MAIN METHODS: Thirty six male Wistar albino rats were divided into two main groups, type 1 diabetes and type 2 diabetes groups. Each group was divided into 3 subgroups (6 rats/subgroup); control, diabetic and echinochrome groups. Diabetic model was induced by a single dose of streptozotocin (60mg/kg, i.p) for type 1 diabetes and by a high fat diet for 4weeks before the injection with streptozotocin (30mg/kg, i.p) for type 2 diabetes. Diabetic groups were treated orally with echinochrome extract (1mg/kg body weight in 10% DMSO) daily for 4weeks. KEY FINDINGS: Echinochrome groups showed a reduction in the concentrations of glucose, MDA and the activities of arginase, AST, ALT, ALP and GGT. While it caused general increase in the levels of insulin, TB, DB, IB, NO and the activities of G6PD, GST, GPx, SOD and GSH. The histopathological investigation showed partial restoration of pancreatic islet cells and clear improvement in the hepatic architecture. SIGNIFICANCE: The suggested mechanism of Ech action in the reduction of diabetic complications in liver involved two pathways; through the hypoglycemic activity and the antioxidant role of Ech. PMID- 26947589 TI - Modulation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) mediated apoptosis by Helicobacter pylori in immune pathogenesis of gastric mucosal damage. AB - Helicobacter pylori infection is associated with chronic gastritis, peptic ulcer, gastric carcinoma, and gastric mucosa-associated lymphoid tissue lymphomas. Apoptosis induced by microbial infections is implicated in the pathogenesis of H. pylori infection. Enhanced gastric epithelial cell apoptosis during H. pylori infection was suggested to play an important role in the pathogenesis of chronic gastritis and gastric pathology. In addition to directly triggering apoptosis, H. pylori induces sensitivity to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis in gastric epithelial cells. Human gastric epithelial cells sensitized to H. pylori confer susceptibility to TRAIL-mediated apoptosis via modulation of death-receptor signaling. The induction of TRAIL sensitivity by H. pylori is dependent upon the activation of caspase-8 and its downstream pathway. H. pylori induces caspase-8 activation via enhanced assembly of the TRAIL death-inducing signaling complex through downregulation of cellular FLICE-inhibitory protein. Moreover, H. pylori infection induces infiltration of T lymphocytes and triggers inflammation to augment apoptosis. In H. pylori infection, significant increases in CCR6+ CD3+ T cell infiltration in the gastric mucosa was observed, and the CCR6 ligand, CCL20 chemokine, was selectively expressed in inflamed gastric tissues. These mechanisms initiate chemokine mediated T lymphocyte trafficking into inflamed epithelium and induce mucosal injury during Helicobacter infection. This article will review recent findings on the interactions of H. pylori with host-epithelial signaling pathways and events involved in the initiation of gastric pathology, including gastric inflammation and mucosal damage. PMID- 26947590 TI - Characterization of a novel qepA3 variant in Enterobacter aerogenes. AB - Five isolates harboring qepA were studied by polymerase chain reaction (PCR) amplification and relevant methods. One was determined to be a novel qepA3 from Enterobacter aerogenes, and four involved three qepA1 and one qepA2 determinants from Escherichia coli; the qepA3 changed five amino acids. These results characterized genetic structures A, B, C, D, and E. PMID- 26947592 TI - Effects of chronic amiodarone treatment on rat testis. AB - Amiodarone is a potent agent used to treat tachyarrhythmias, which are especially refractory to other medications, in both adults and children. Although widely used as an antiarrhythmic drug, amiodarone causes many serious adverse effects that limit its use. This study investigated the possible morphological and apoptotic effects of amiodarone on rat testes. Amiodarone was administered to male Sprague-Dawley rats at doses of 20 or 200mg/kg/day for 14 days. A histopathological examination of testicular tissue revealed the presence of inflammatory cells in the seminiferous tubule lumen together with swelling and vacuolization in the cytoplasm of some spermatogonia; these effects occured in a dose-dependent manner. Immunohistochemical staining showed evidence of apoptosis, including caspase-3, caspase-9, Bax and increased DNA fragmentation was detected via a terminal deoxynucleotidyl transferase dUTP nick-end labeling assay. In conclusion, the results show that chronic amiodarone treatment causes dose dependent degenerative and apoptotic effects on rat testes. PMID- 26947591 TI - Use of Ozone to Treat Ileostomy Dermatitis in an Experimental Rat Model. AB - BACKGROUND: Dermatitis associated with ileostomy is an important problem that affects many people, especially children. The aim of this study was to investigate the therapeutic effects of ozone on dermatitis due to ileostomy, and to develop an alternative treatment option. MATERIAL/METHODS: A total of 28 rats were divided into 4 groups: control, ileostomy, ozone, and zinc oxide. Ileostomy was performed in all rats except the control group. After a 1-week waiting time, the ozone group was administered ozone therapy and the zinc oxide group was administered zinc oxide cream locally once a day for a total of 7 days. All rats were sacrificed at the end of this period. The efficacy of treatment was examined by biochemical, histopathological, and immunohistochemical parameters. The levels of malondialdehyde (MDA), total glutathione (tGSH), total antioxidant capacity (TAC), and total oxidant status (TOS) were measured from tissue. Vascular endothelial growth factor (VEGF) and proliferating cell nuclear antigen (PCNA) were examined immunohistochemically. RESULTS: Dermatitis occurred pathologically in all rats that underwent ileostomy surgery. The lowest dermatitis score was in the ozone treatment group (p<0.05). Ileostomy dermatitis caused increased levels of MDA and TOS. Ozone treatment resulted in reduced MDA and TOS levels, while the levels of tGSH and TAC were increased (p<0.05). Both VEGF and PCNA immunostaining were augmented in the ozone treatment group (p<0.05). CONCLUSIONS: Local ozone application may be a good alternative compared to the conventional treatment methods for the prevention of skin lesions that develop after ileostomy. PMID- 26947593 TI - Preoperative biomedical risk and depressive symptoms are differently associated with reduced health-related quality of life in patients 1year after cardiac surgery. AB - OBJECTIVE: To examine whether preoperative biomedical risk and depressive symptoms were associated with physical and mental components of health-related quality of life (HRQoL) in patients 1year after cardiac surgery. METHOD: Seventy five patients completed a psychological evaluation, including the Center for Epidemiological Study of Depression scale, the 12-item Short-Form Physical Component Scale (SF-12-PCS) and Mental Component Scale (SF-12-MCS), the Instrumental Activities of Daily Living questionnaire for depressive symptoms and HRQoL, respectively, before surgery and at 1-year follow-up. RESULTS: Preoperative depressive symptoms predicted the SF-12-PCS (beta=-.22, P<.05) and SF-12-MCS (beta=-.30, P<.04) scores in patients 1year after cardiac surgery, whereas the European System for Cardiac Operative Risk Evaluation was associated with SF-12-PCS (beta=-.28, P<.02), but not SF-12-MCS (beta=.01, P=.97) scores postoperatively. CONCLUSIONS: The current findings showed that preoperative depressive symptoms are associated with poor physical and mental components of HRQoL, whereas high biomedical risk predicts reduced physical, but not mental, functioning in patients postoperatively. This study suggests that a preoperative assessment of depressive symptoms in addition to the evaluation of common biomedical risk factors is essential to anticipate which patients are likely to show poor HRQoL after cardiac surgery. PMID- 26947595 TI - Involvement of Angiotensin II Type 1 and 2 Receptors in Gelatinase Regulation in Human Carotid Atheroma in vitro. AB - AIM: Matrix metalloproteinases (MMPs), angiotensin II (AII) and its receptors are implicated in atherosclerotic plaque instability, however the roles of the two receptor subtypes, ATR1 and ATR2, in MMP regulation remain uncertain. In this study, we investigated the effect of ATR1 and ATR2 blockade on the expression and activity of MMP-2, MMP-3 and MMP-9, in human carotid atheroma. METHODS: Atheroma samples (n=36) were obtained from patients undergoing carotid endarterectomy. The effects of ATR1 (irbesartan), ATR2 (PD123319) and combined ATR1 and ATR2 blockade on the expression and activity of the MMPs and the expression of tissue inhibitors of metalloproteinases (TIMPs) were investigated in explant culture experiments. Paired atheroma samples were incubated with the intervention or media control for 4 days. Protein levels (MMP-2, MMP-3, MMP-9, TIMP-1, TIMP-2, TIMP-4, ATR1 and ATR2) were determined by ELISA. Overall gelatinase activity and specific activation were measured by chromogenic activity assays and zymography, respectively. RESULTS: ATR1 blockade, but not ATR2 blockade significantly reduced TIMP-1, TIMP-2 and TIMP-4 expression in atheroma supernatant. Combined ATR1 and ATR2 blockade significantly reduced MMP-2, MMP-3 and MMP-9 expression. MMP-2 and MMP-9 relative activation, and overall MMP-9 catalytic capacity were significantly increased by ATR1 blockade. CONCLUSIONS: Our findings suggest that ATR1 blockade reduces TIMP expression and increases gelatinase activity in human carotid atheroma. PMID- 26947594 TI - Long-acting insulin analog detemir displays reduced effects on adipocyte differentiation of human subcutaneous and visceral adipose stem cells. AB - BACKGROUND AND AIMS: Since treatment with insulin detemir results in a lower weight gain compared to human insulin, we investigated whether detemir is associated with lower ability to promote adipogenesis and/or lipogenesis in human adipose stem cells (ASC). METHODS AND RESULTS: Human ASC isolated from both the subcutaneous and visceral adipose tissues were differentiated for 30 days in the presence of human insulin or insulin detemir. Nile Red and Oil-Red-O staining were used to quantify the rate of ASC conversion to adipocytes and lipid accumulation, respectively. mRNA expression levels of early genes, including Fos and Cebpb, as well as of lipogenic and adipogenic genes, were measured at various phases of differentiation by qRT-PCR. Activation of insulin signaling was assessed by immunoblotting. ASC isolated from subcutaneous and visceral adipose tissue were less differentiated when exposed to insulin detemir compared to human insulin, showing lower rates of adipocyte conversion, reduced triglyceride accumulation, and impaired expression of late-phase adipocyte marker genes, such as Pparg2, Slc2a4, Adipoq, and Cidec. However, no differences in activation of insulin receptor, Akt and Erk and induction of the early genes Fos and Cebpb were observed between insulin detemir and human insulin. CONCLUSION: Insulin detemir displays reduced induction of the Pparg2 adipocyte master gene and diminished effects on adipocyte differentiation and lipogenesis in human subcutaneous and visceral ASC, in spite of normal activation of proximal insulin signaling reactions. These characteristics of insulin detemir may be of potential relevance to its weight-sparing effects observed in the clinical setting. PMID- 26947596 TI - Beneficial Effects of Exercise-Based Cardiac Rehabilitation on High-Density Lipoprotein-Mediated Cholesterol Efflux Capacity in Patients with Acute Coronary Syndrome. AB - AIM: Recent studies reported that low high-density lipoprotein (HDL)-mediated cholesterol efflux capacity rather than low HDL cholesterol (HDL-C) is strongly associated with the increased risk for coronary artery disease. It remains unclear whether exercised-based cardiac rehabilitation (CR) can increase HDL cholesterol efflux capacity. METHOD: This study is a retrospective analysis of stored serum from patients with acute coronary syndrome (ACS) who participated in outpatient CR program following successful percutaneous coronary intervention. We employed a cell-based cholesterol efflux system including the incubation of (3)H cholesterol labeled macrophages with apolipoprotein B-depleted serum at the onset or early phase of ACS and at 6-month follow-up periods in 57 male and 11 female patients with ACS. Cardiopulmonary exercise tests were performed at the beginning and end of CR program. RESULT: Fifty-seven patients completed the CR program. Compared with patients who dropped out from CR program (non-CR group), CR participants showed marked amelioration in serum lipid levels, increased efflux capacity, and improved exercise capacity. Spearman's rank correlation coefficient analysis revealed that the percent increases of efflux capacity were significantly associated with the percent increases in HDL-C (rho=0.598, p<0.0001) and apolipoprotein A1 (rho=0.508, p<0.0001), whereas no association between increases in efflux capacity and increases in cardiopulmonary fitness was observed. Increases in cholesterol efflux capacity were not seen in patients who continued smoking and those who did not achieve all risk factor targets and higher exercise tolerance. CONCLUSION: CR can markedly increase both HDL-C and HDL cholesterol efflux capacity. These results suggest that CR is a very useful therapy for reverse cholesterol transport and secondary prevention. PMID- 26947598 TI - Analysis of Gut Microbiota in Coronary Artery Disease Patients: a Possible Link between Gut Microbiota and Coronary Artery Disease. AB - AIM: Recent studies have suggested that metabolic disorders such as obesity and type 2 diabetes are associated with gut microbiota. The association between atherosclerosis and gut microbiota has also been attracting increased attention. Our aim was to specify a characteristic trend of gut microbiota in coronary artery disease (CAD). METHODS: This study included 39 CAD patients, 30 age- and sex-matched no-CAD controls (Ctrls) with coronary risk factors and 50 healthy volunteers (HVs) without coronary risk factors. Bacterial DNA was extracted from their fecal samples and analyzed by terminal restriction fragment length polymorphism. RESULTS: A characteristic change of gut microbiota was observed in CAD patients, where the order Lactobacillales was increased (CAD, Ctrl vs. HV; 13.6%+/-12.0%, 6.2%+/-7.7% vs. 4.1%+/-5.9%; p<0.001) and the phylum Bacteroidetes (Bacteroides+Prevotella) was decreased (CAD, Ctrl vs. HV;35.5%+/-11.6%, 43.9%+/ 11.2% vs. 47.4%+/-11.5%; p<0.001). The CAD group was over-represented in enterotype "others" (III), compared with the Ctrl or HV group (p<0.001, chi squared test), although we could not deny the possibility that some drugs affect the gut flora types. CONCLUSIONS: Although this study had some limitations, we demonstrated that the incidence of CAD was linked with an alteration of gut microbiota. A prospective study is desired to clarify a causal relationship between CAD and gut microbiota. PMID- 26947597 TI - Trans-Resveratrol Enhances the Anticoagulant Activity of Warfarin in a Mouse Model. AB - AIM: Resveratrol is a popular ingredient in dietary supplements. Some patients concomitantly use dietary supplements and medicines in Japan. In the present study, we determined whether trans-resveratrol and melinjo (Gnetum gnemon L.) seed extract (MSE), which contains resveratrol dimers, interacted with drugs using a mouse model. METHODS: Male C57BL/6J mice were fed experimental diets containing 0.005%, 0.05%, or 0.5% (w/w) trans-resveratrol or MSE for 1 or 12 weeks. The expression of liver cytochrome P-450 (CYP) mRNA and activity of liver microsomal CYP were measured. To determine the influence of resveratrol or MSE on drug efficacy, the anticoagulant activity of warfarin was examined in mice that were fed diets containing trans-resveratrol or MSE for 12 weeks. RESULTS: When the mice were fed experimental diets for 1 week, none of the doses of trans resveratrol and MSE affected body weight, liver weight, or plasma AST and ALT levels. Trans-resveratrol also did not affect CYP1A1, CYP1A2, CYP2C, or CYP3A activities. In contrast, 0.5% MSE slightly increased CYP1A1 activity. When the mice were fed experimental diets for 12 weeks, 0.05% trans-resveratrol increased CYP1A1, CYP2C, and CYP3A activities, whereas 0.5% MSE suppressed CYP3A activity. Under these conditions, 0.5% trans-resveratrol enhanced the anticoagulant activity of warfarin, although CYP2C activity increased. However, MSE did not affect the anticoagulant activity of warfarin. CONCLUSION: The 0.05% trans resveratrol did not interact with warfarin in a mouse model, whereas 0.5% trans resveratrol may have enhanced the anticoagulant activity of warfarin. PMID- 26947599 TI - Visceral Adiposity is Preferentially Associated with Vascular Stiffness Rather than Thickness in Men with Type 2 Diabetes. AB - AIM: Visceral fat accumulation is known to underlie the clustering of cardiovascular risk factors. However, it is not completely understood how visceral fat accumulation influences the development of cardiovascular disease. In this study, we investigated the clinical impact of visceral adiposity on vascular stiffness and thickness in patients with type 2 diabetes (T2D). METHODS: One hundred and sixty-one patients with T2D, including 92 men and 69 women, were included in this cross-sectional study. Visceral fat area (VFA) and subcutaneous fat area (SFA) were measured by dual bioelectrical impedance analysis. Stiffness parameter beta and intima-media thickness (IMT) of the common carotid artery were measured by ultrasonography. RESULTS: The mean age and duration of diabetes in the study population were 61 years and 13.9 years, respectively. In men, VFA and waist circumference (WC) were positively correlated with stiffness parameter beta, whereas body mass index (BMI), WC, and SFA were negatively correlated with IMT. In contrast, in women, none of the obesity-related indices were significantly correlated with stiffness parameter beta or IMT. In multiple regression analyses, VFA as well as WC, BMI, and SFA were independently associated with stiffness parameter beta after adjustment for age and other potential confounders in men but not in women. None of the obesity-related indices were independently associated with IMT for either sex. CONCLUSION: In men with T2D, visceral adiposity is associated with carotid arterial stiffness but not thickness. PMID- 26947600 TI - Impact of Serum Uric Acid Levels on Coronary Plaque Stability Evaluated Using Integrated Backscatter Intravascular Ultrasound in Patients with Coronary Artery Disease. AB - AIM: Because the prevalence of hyperuricemia is lower in females than in males, the association between hyperuricemia and cardiovascular disease has been frequently reported in females. Increased serum uric acid levels are associated with the presence of cardiovascular risk factors such as hypertension, renal dysfunction, insulin resistance, and metabolic syndrome. However, it is controversial whether hyperuricemia is an independent risk factor for coronary artery disease in both the genders. The purpose of this study was to investigate the relationship between serum uric acid levels and coronary plaque components assessed using integrated backscatter intravascular ultrasound (IB-IVUS) in males and females. METHODS: In total, 385 patients (298 males and 87 females) who underwent percutaneous coronary intervention using IB-IVUS were divided into three groups in each gender according to their serum uric acid levels. We characterized tissue from coronary plaques in culprit lesions. RESULTS: Serum uric acid levels significantly correlated with percent lipid volume (r=0.37) and inversely correlated with percent fibrous volume (r=-0.35). Multivariate analysis showed that the uric acid level was independently associated with lipid-rich plaques (odds ratio 2.43, 95%, confidence interval 1.75-3.47). The prevalence of lipid-rich plaques increased with increasing uric acid levels in both genders. CONCLUSION: Increased serum uric acid levels were associated with larger lipid content plaques in both genders. PMID- 26947601 TI - Characteristics and Vascular Complications of Familial Hypercholesterolemia in Korea. AB - Familial hypercholesterolemia (FH) is presently an important health issue worldwide. This condition shows phenotypic and genetic variations among affected people, and clinical and genetic data on FH are critical for effective diagnosis and management. Korean FH patients have relatively low levels of cholesterol and prevalence of xanthoma than patients from other countries, as determined by previous studies. The best predictive value of low-density lipoprotein cholesterol (LDL-C) for pathogenic mutations is suggested as 225 mg/dL. Many known and novel mutations on LDLR and some on APOB or PCSK9 have been identified in one-third of clinically diagnosed probands, and their locations on genes varied. Coronary artery disease was reported in 28% Korean FH patients, and traditional cardiovascular risk factors were associated with this complication. Aortic valve changes were also prevalent. However, the achievement rate of LDL-C target using lipid-lowering therapy is not satisfactory and is only 21%-44%. A further expanded registry and additional analysis may provide a more useful clinical tool for the diagnosis and treatment of Korean FH patients. PMID- 26947603 TI - Which Way for Waterproofing? PMID- 26947602 TI - Exploratory Decision-Tree Modeling of Data from the Randomized REACTT Trial of Tadalafil Versus Placebo to Predict Recovery of Erectile Function After Bilateral Nerve-Sparing Radical Prostatectomy. AB - BACKGROUND: Understanding predictors for the recovery of erectile function (EF) after nerve-sparing radical prostatectomy (nsRP) might help clinicians and patients in preoperative counseling and expectation management of EF rehabilitation strategies. OBJECTIVE: To describe the effect of potential predictors on EF recovery after nsRP by post hoc decision-tree modeling of data from A Study of Tadalafil After Radical Prostatectomy (REACTT). DESIGN, SETTING, AND PARTICIPANTS: Randomized double-blind double-dummy placebo-controlled trial in 423 men aged <68 yr with adenocarcinoma of the prostate (Gleason <=7, normal preoperative EF) who underwent nsRP at 50 centers from nine European countries and Canada. INTERVENTION: Postsurgery 1:1:1 randomization to 9-mo double-blind treatment with tadalafil 5mg once a day (OaD), tadalafil 20mg on demand, or placebo, followed by a 6-wk drug-free-washout, and a 3-mo open-label tadalafil OaD treatment. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Three decision-tree models, using the International Index of Erectile Function-Erectile Function (IIEF-EF) domain score at the end of double-blind treatment, washout, and open label treatment as response variable. Each model evaluated the association between potential predictors: presurgery IIEF domain and IIEF single-item scores, surgical approach, nerve-sparing score (NSS), and postsurgery randomized treatment group. RESULTS AND LIMITATIONS: The first decision-tree model (n=422, intention-to-treat population) identified high presurgery sexual desire (IIEF item 12: >=3.5 and <3.5) as the key predictor for IIEF-EF at the end of double blind treatment (mean IIEF-EF: 14.9 and 11.1), followed by high confidence to get and maintain an erection (IIEF item 15: >=3.5 and <3.5; IIEF-EF: 15.4 and 7.1). For patients meeting these criteria, additional non-IIEF-related predictors included robot-assisted laparoscopic surgery (yes or no; IIEF-EF: 19.3 and 12.6), quality of nerve sparing (NSS: <2.5 and >=2.5; IIEF-EF: 14.3 and 10.5), and treatment with tadalafil OaD (yes and no; IIEF-EF: 17.6 and 14.3). Additional analyses after washout and open-label treatment identified high presurgery intercourse satisfaction as the key predictor. CONCLUSIONS: Exploratory decision tree analyses identified high presurgery sexual desire, confidence, and intercourse satisfaction as key predictors for EF recovery. Patients meeting these criteria might benefit the most from conserving surgery and early postsurgery EF rehabilitation. Strategies for improving EF after surgery should be discussed preoperatively with all patients; this information may support expectation management for functional recovery on an individual patient level. PATIENT SUMMARY: Understanding how patient characteristics and different treatment options affect the recovery of erectile function (EF) after radical surgery for prostate cancer might help physicians select the optimal treatment for their patients. This analysis of data from a clinical trial suggested that high presurgery sexual desire, sexual confidence, and intercourse satisfaction are key factors predicting EF recovery. Patients meeting these criteria might benefit the most from conserving surgery (robot-assisted surgery, perfect nerve sparing) and postsurgery medical rehabilitation of EF. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01026818. PMID- 26947604 TI - Re: Daniel M. Geynisman. Anti-programmed Cell Death Protein 1 (PD-1) Antibody Nivolumab Leads to a Dramatic and Rapid Response in Papillary Renal Cell Carcinoma with Sarcomatoid and Rhabdoid Features. Eur Urol 2015;68:912-4. PMID- 26947605 TI - Reply to Francesco Piva, Matteo Santoni, Marina Scarpelli, et al's Letter to the Editor re: Daniel M. Geynisman. Anti-programmed Cell Death Protein 1 (PD-1) Antibody Nivolumab Leads to a Dramatic and Rapid Response in Papillary Renal Cell Carcinoma with Sarcomatoid and Rhabdoid Features. Eur Urol 2015;68:912-4. PMID- 26947606 TI - Design and synthesis of novel 5-aminosalicylate (5-ASA)-4-thiazolinone hybrid derivatives with promising antiproliferative activity. AB - Two privileged pharmacophores were assembled in one molecular frame involving 5 aminosalicylate and 4-thiazolinones that can be found in different stereochemical features. The compounds were fully characterized and evaluated for antiproliferative activity against four human cancer cell lines and some are equipotent to doxorubicin with lower cytotoxicity to normal cells. The most interesting finding relates to compound 10, which shows an IC50 value of 70nM against MCF-7 cells, while the IC50 against human fibroblasts is 10MUM. The results of this study indicate that the new compounds are optimal anti-cancer leading compounds and merit further studies to optimize their structure, detect their biotargets and in vivo activity. PMID- 26947607 TI - Pterostilbene-O-acetamidoalkylbenzylamines derivatives as novel dual inhibitors of cholinesterase with anti-beta-amyloid aggregation and antioxidant properties for the treatment of Alzheimer's disease. AB - A series of pterostilbene-O-acetamidoalkylbenzylamines were designed, synthesized and evaluated as dual inhibitors of AChE and BuChE. To further explore the multifunctional properties of the new derivatives, their antioxidant activities and inhibitory effects on self-induced Abeta1-42 aggregation and HuAChE-induced Abeta1-40 aggregation were also tested. The results showed that most of these compounds could effectively inhibit AChE and BuChE. Particularly, compound 21d exhibited the best AChE inhibitory activity (IC50=0.06 MUM) and good inhibition of BuChE (IC50=28.04 MUM). Both the inhibition kinetic analysis and molecular modeling study revealed that these compounds showed mixed-type inhibition, binding simultaneously to the CAS and PAS of AChE. In addition to cholinesterase inhibitory activities, these compounds showed different levels of antioxidant activity. However, the inhibitory activities against self-induced and HuAChE induced Abeta aggregation of these new derivatives were unsatisfied. Taking into account the results of the biological evaluation, further modifications will be designed in order to increase the potency on the different targets. The results displayed in this Letter can be a new starting point for further development of multifunctional agents for Alzheimer's disease. PMID- 26947608 TI - Synthesis and evaluation of antifungal activity of C21-steroidal derivatives. AB - The antifungal activities of eleven C21-steroidal compounds isolated from Cynanchum wilfordii, together with thirty-six derivatives of caudatin and qingyangshengenin were evaluated on Sclerotinia sclerotiorum and other five fungal strains by the mycelium growth rate method. Four derivatives 1k, 1y, 10d, and 10j exhibited much stronger inhibitions on growth of S. sclerotiorum with IC50 values of 0.0084, 0.0049, 0.0053, and 0.0034 MUM, respectively. PMID- 26947609 TI - Synthesis and biological evaluation of novel 6,7-dihydro-5H cyclopenta[d]pyrimidine and 5,6,7,8-tetrahydroquinazoline derivatives as sigma-1 (sigma1) receptor antagonists for the treatment of pain. AB - The synthesis and biological evaluation of new series of 6,7-dihydro-5H cyclopenta[d]pyrimidine and 5,6,7,8-tetrahydroquinazoline derivatives as selective sigma-1 receptor (sigma1R) antagonists are reported. The receptor affinities of new compounds were evaluated in vitro in sigma1 and sigma2 receptor binding assays. The structure-active relationship study leads us to the most promising compound: 2-(4-chlorophenyl)-4-(3-(4-methylpiperidin-1-yl)propoxy) 5,6,7,8-tetra-hydroquinazoline (33). Compound 33 has exerted nanomolar affinity for sigma1R (Kisigma1=15.6 nM) and high sigma1/sigma2 selectivity (Kisigma2 >2000 nM), and identified to be a sigma1R antagonist. In animal model, compound 33 exhibited dose dependent anti-nociceptive effects in the formalin test. These results suggest that compound 33 could be a potent analgesic for pain treatment. PMID- 26947610 TI - Streptococcus pneumoniae: a rare pathogen in epidural abscess. PMID- 26947611 TI - Prior authorization for child and adolescent psychiatric patients deemed to be in need of inpatient admission. PMID- 26947612 TI - Prediction of en-route complications during interfacility transport by outcome predictive scores in ED. AB - OBJECTIVE: The objective was to determine the accuracy of the outcome predictive scores (Modified Early Warning Score [MEWS]; Hypotension, Low Oxygen Saturation, Low Temperature, Abnormal ECG, Loss of Independence [HOTEL] score; and Simple Clinical Score [SCS]) in predicting en-route complications during interfacility transport (IFT) in emergency department. DESIGN: This was a retrospective cohort study. METHODS: All IFT cases by ambulances with either nurse-led or physician led escort, occurring between 1 January 2011 and 31 December 2012, were included. Obstetric and pediatric cases (age < 18 years) were excluded. The condition of patients was quantified by using the predictive scores (MEWS, HOTEL, and SCS) at triage station and on ambulance departure. The accuracy of predictive scores was compared by the receiver operating characteristic (ROC) curves. RESULTS: A total of 659 cases were included. Seventeen cases had en-route complications (2.6%). The complication rate in physician-escorted transport (2.2%) was similar to that in nurse-escorted transport (2.6%). None of the 57 intubated cases had en-route complications. The area under the ROC curve for MEWS was 0.662 (triage) and 0.479 (departure). The accuracy of MEWS at triage was better than that at departure (P = .049). The area under the ROC curve for HOTEL was 0.613 (triage) and 0.597 (departure), and that for SCS was 0.6 (triage) and 0.568 (departure). In general, the predictive scores at triage were better than those on departure. CONCLUSION: None of the scores had good accuracy in prediction of en-route complications during IFT. MEWS at triage was among the best one already but was not ideal. PMID- 26947614 TI - Challenging Already Established Statements on the Therapy of Renal Angiomiolypoma. PMID- 26947613 TI - A longitudinal study of placental perfusion using dynamic contrast enhanced magnetic resonance imaging in murine pregnancy. AB - INTRODUCTION: To evaluate changes in placental perfusion with advancing gestation in normal murine pregnancy using dynamic contrast enhanced magnetic resonance imaging (DCE-MRI). METHODS: Seven timed-pregnant CD-1 mice underwent DCE-MRI scanning longitudinally on gestational days (GD) 13, 15 and 17. Placentas were segmented into high (HPZ) and low perfusion zones (LPZ) using tissue similarity mapping. Blood perfusion of the respective regions and the whole placenta was quantified using the steepest slope method. The diameter of the maternal central canal (CC) was also measured. RESULTS: An increase in perfusion was observed between GD13 and GD17 in the overall placenta (p = 0.04) and in the HPZ (p = 0.02). Although perfusion in the LPZ showed a slight increasing trend, it was not significant (p = 0.07). Perfusion, in units of ml/min/100 ml, in the overall placenta and the HPZ was respectively 61.2 +/- 31.2 and 106.2 +/- 56.3 at GD13 (n = 19 placentas); 90.3 +/- 43.7 and 139 +/- 55.4 at GD15 (n = 20); and 104.9 +/- 76.1 and 172.2 +/- 85.6 at GD17 (n = 14). The size of the CC increased with advancing gestation (p < 0.05). DISCUSSION: Using longitudinal DCE-MRI, the gestational age-dependent perfusion change in the normal murine placenta and in its regional compartments was quantified. In mid and late gestations, placental constituent regions differ significantly in their perfusion rates. The CC diameter also showed increase with advancing gestation, which may be playing an important role toward the gestational age-dependent increase in placental perfusion. PMID- 26947615 TI - Modulation of Folding Internal Friction by Local and Global Barrier Heights. AB - Recent experiments have revealed an unexpected deviation from a first power dependence of protein relaxation times on solvent viscosity, an effect that has been attributed to "internal friction". One clear source of internal friction in protein dynamics is the isomerization of dihedral angles. A key outstanding question is whether the global folding barrier height influences the measured internal friction, based on the observation that the folding rates of fast folding proteins, with smaller folding free energy barriers, tend to exhibit larger internal friction. Here, by studying two alanine-based peptides, we find that systematic variation of global folding barrier heights has little effect on the internal friction for folding rates. On the other hand, increasing local torsion angle barriers leads to increased internal friction, which is consistent with solvent memory effects being the origin of the viscosity dependence. Thus, it appears that local torsion transitions determine the viscosity dependence of the diffusion coefficient on the global coordinate and, in turn, internal friction effects on the folding rate. PMID- 26947616 TI - Next steps for antimicrobial stewardship. PMID- 26947617 TI - Current evidence on hospital antimicrobial stewardship objectives: a systematic review and meta-analysis. AB - BACKGROUND: Antimicrobial stewardship is advocated to improve the quality of antimicrobial use. We did a systematic review and meta-analysis to assess whether antimicrobial stewardship objectives had any effects in hospitals and long-term care facilities on four predefined patients' outcomes: clinical outcomes, adverse events, costs, and bacterial resistance rates. METHODS: We identified 14 stewardship objectives and did a separate systematic search for articles relating to each one in Embase, Ovid MEDLINE, and PubMed. Studies were included if they reported data on any of the four predefined outcomes in patients in whom the specific antimicrobial stewardship objective was assessed and compared the findings in patients in whom the objective was or was not met. We used a random effects model to calculate relative risk reductions with relative risks and 95% CIs. FINDINGS: We identified 145 unique studies with data on nine stewardship objectives. Overall, the quality of evidence was generally low and heterogeneity between studies was mostly moderate to high. For the objectives empirical therapy according to guidelines, de-escalation of therapy, switch from intravenous to oral treatment, therapeutic drug monitoring, use of a list of restricted antibiotics, and bedside consultation the overall evidence showed significant benefits for one or more of the four outcomes. Guideline-adherent empirical therapy was associated with a relative risk reduction for mortality of 35% (relative risk 0.65, 95% CI 0.54-0.80, p<0.0001) and for de-escalation of 56% (0.44, 0.30-0.66, p<0.0001). Evidence of effects was less clear for adjusting therapy according to renal function, discontinuing therapy based on lack of clinical or microbiological evidence of infection, and having a local antibiotic guide. We found no reports for the remaining five stewardship objectives or for long-term care facilities. INTERPRETATION: Our findings of beneficial effects on outcomes with nine antimicrobial stewardship objectives suggest they can guide stewardship teams in their efforts to improve the quality of antibiotic use in hospitals. FUNDING: Dutch Working Party on Antibiotic Policy and Netherlands National Institute for Public Health and the Environment. PMID- 26947619 TI - Exploiting temporal predictability: Event-related potential correlates of task supportive temporal cue processing in auditory distraction. AB - The human cognitive system has various functions to enhance performance in tasks requiring responses to stimuli. When potentially occurring stimuli are known, we can establish selective attention sets and ignore task-irrelevant events while attending task-relevant ones. When the stimulation is temporally structured, we can rely on constant temporal relationships between stimulus events to prepare for the task-relevant moments. Most distraction paradigms feature task-irrelevant events which are followed by task-relevant ones within a constant interval, and distraction is induced by randomly replacing some of the standard task-irrelevant events. The constant time interval transforms irrelevant events to task supportive temporal cues, which are integrated into the task-behavior by the participants. The present study investigated whether distracters could be utilized as temporal cues to support task-related processing in a continuous auditory stimulation paradigm. A continuous tone featuring short and long gaps, and pitch glides was presented. Participants performed a gap duration discrimination task, while ignoring glides. Glides could be presented frequently or rarely. In the informative condition, 80% of the glides predicted the presentation time of the forthcoming gap (400ms), while in the uninformative condition, the occurrence of gaps and glides was independent. Rare glides elicited an enhanced N1, mismatch negativity, and P3 event-related potentials in both informative and uninformative conditions. In informative conditions glides were followed by a contingent negative variation; and rare informative glides elicited an N2b, suggesting that despite triggering distraction-related processes, distracters could be integrated into the task-behavior, and could be utilized as task-supportive cues. PMID- 26947618 TI - MicroRNA-204 suppresses epileptiform discharges through regulating TrkB-ERK1/2 CREB signaling in cultured hippocampal neurons. AB - MicroRNAs (miRs) have been increasingly recognized as post-transcriptional regulators involved in the pathogenesis of epilepsy. Extensive evidence suggests that inhibition of tropomyosin related kinase type B (TrkB) signaling limits epileptogenesis. It has been reported that miR-204 directly targeted and downregulated TrkB protein in a variety of cancers to suppress tumorigenesis, but its effect on epileptogenesis is unknown. Here we showed that miR-204 was downregulated in cultured hippocampal neurons following status epilepticus (SE) induced by Mg(2+)-free treatment. Overexpression of miR-204 using a transfection technique negatively regulated the expression of TrkB mRNA. Insight into the downstream signaling pathway activated by TrkB may provide valuable clues to the underlying mechanisms of epileptogenesis. Biochemical measures revealed activation of phospholipase Cgamma1 (PLCgamma1), extracellular signal-regulated kinase1/2 (ERK1/2) and cAMP response-element binding protein (CREB) signaling molecules in the Mg(2+)-free model in hippocampal neurons, of which ERK1/2-CREB but not PLCgamma1 signaling pathway was able to be inhibited by miR-204. Epileptiform discharges assessed using whole-cell current-clamp techniques were suppressed by miR-204 in cultured hippocampus neurons of SE. These results suggest that miR-204 exerts an antiepileptogenic effect in the Mg(2+)-free model in hippocampal neurons through regulating TrkB and downstream ERK1/2-CREB signaling pathway. PMID- 26947620 TI - Oxidation of ion channels in the aging nervous system. AB - Ion channels are integral membrane proteins that allow passive diffusion of ions across membranes. In neurons and in other excitable cells, the harmonious coordination between the numerous types of ion channels shape and propagate electrical signals. Increased accumulation of reactive oxidative species (ROS), and subsequent oxidation of proteins, including ion channels, is a hallmark feature of aging and may contribute to cell failure as a result. In this review we discuss the effects of ROS on three major types of ion channels of the central nervous system, namely the potassium (K(+)), calcium (Ca(2+)) and sodium (Na(+)) channels. We examine two general mechanisms through which ROS affect ion channels: via direct oxidation of specific residues and via indirect interference of pathways that regulate the channels. The overall status of the present studies indicates that the interaction of ion channels with ROS is multimodal and pervasive in the central nervous system and likely constitutes a general mechanism of aging susceptibility. PMID- 26947621 TI - Drug therapy in the prevention of failure of the Fontan circulation: a systematic review. AB - BACKGROUND: The Fontan circulation is the optimal treatment for patients with univentricular hearts. These patients are at high risk of circulatory failure. There is no consensus on the optimal drug treatment for the prevention of failure of the Fontan circulation. The aim of this systematic review was to provide an overview of evidence for drug therapy used in the prevention of Fontan circulatory failure. METHODS: We searched the Embase database for articles that reported drug therapy in Fontan patients. Studies published between 1997 and 2014 were included if efficacy or safety of medication was assessed, drug therapy aimed to prevent or treat failure of the Fontan circulation, and if the full text was available. Case reports were excluded. RESULTS: A total of nine studies were included with a total of 267 Fontan patients; four studies evaluated the medication sildenafil, one iloprost, three bosentan, and one enalapril. Among all, two sildenafil studies reported improvement in exercise capacity, one in exercise haemodynamics, and one in ventricular performance. In the largest study of bosentan, an increase in exercise capacity was found. Enalapril did not result in improvements. CONCLUSION: The studies analysed in this review suggest that bosentan, sildenafil, and iloprost may improve exercise capacity at the short term. Given the limitations of the studies, more, larger, placebo-controlled studies with longer follow-up periods are needed to better understand which drug therapies are effective in the prevention of failure of the Fontan circulation. PMID- 26947622 TI - Water-oil Janus emulsions: microfluidic synthesis and morphology design. AB - In this work we developed a facile method to prepare water-oil Janus emulsions in situ with tunable morphologies by using a double-bore capillary microfluidic device. In addition, by combining the theory model and our liquids' properties, we propose a method to design the morphology of water-oil Janus emulsions. To systematically research Janus morphologies we combined the theory model and the fluids' properties. Under the model guidance, we carefully selected the liquids system where only the interfacial tension between the water phase and the continuous phase changed while keeping the other two interfacial tensions unchanged. Thus we could adjust the Janus morphology by changing the surfactant mass fraction in the continuous phase. In addition, with the double-bore capillary, we prepared water-oil Janus emulsions with a large flow ratio range. By adjusting the flow ratio and the surfactant mass fraction, we successfully prepared Janus emulsions with gradual morphology changes, which would be meaningful in fields that have a high demand for morphology designing of amphiphilic Janus particles. PMID- 26947623 TI - A sensitive fluorescent sensor for the detection of endogenous hydroxyl radicals in living cells and bacteria and direct imaging with respect to its ecotoxicity in living zebra fish. AB - We have synthesized a novel fluorescent probe, , which shown a high potential for imaging of endogenous OH in living cells and various types of bacteria. In addition, it is an excellent sensor for in vivo imaging of OH generated following treatment with TiO2NPs in zebra fish. PMID- 26947625 TI - The electrophysiology of spinocerebellar ataxias. AB - Spinocerebellar Ataxias (SCAs) are a group of autosomal dominantly inherited neurodegenerative diseases, involving the cerebellum and the brainstem. Genetic testing is the most important method of diagnosis. Nowadays, nearly 40 types of SCAs have been identified by genetic analysis. Peripheral nerve impairment is common in SCAs: electrophysiological examination of SCA1, SCA2 and SCA3 usually shows sensorimotor and sensory neuropathy, while pure motor neuropathy is more rare, being seen only in SCA2. The abnormal VEP of SCA1, SCA2 and SCA3 include prolonged P100 latencies and reduced P100 amplitudes. Abnormal BAEP involves prolonged interpeak latency of I-III and III-V. Abnormal SEP usually show absent P40 wave and prolonged P40 latency. The abnormal MEP usually shows prolonged central motor conduction time or absent responses. SCA2 is not associated with gaze-evoked nystagmus and dysmetric saccades. SCA3 usually presents as saccadic intrusions and oscillations. Whether peripheral nerves are involved in SCA6 is uncertain; although abnormal electrophysiology has been reported, neuropathological examinations have not found degenerative changes or reductions in the number of neurons in the anterior horns and/or dorsal root ganglia in SCA6. It is therefore hypothesized that this might be a displayed feature of axonopathy. The clinical presentation of most cases of SCA6 includes spontaneous and positional downbeat nystagmus, and perverted head-shaking nystagmus. Opinion about peripheral nerve involvement in SCA7 varies between authors. Losing P100 is a predominant feature of SCA7, while III and IV/V wave absence is common in SCA17. Electrophysiological study of other types is currently limited, requiring large-scale studies for confirmation. Similar and overlapping clinical features make it difficult to differentiate each type. Electrophysiological testing can therefore play an important role in helping to identify the common phenotypes of SCAs, and determine the extent and progression of disease. PMID- 26947624 TI - Association between driving pressure and development of postoperative pulmonary complications in patients undergoing mechanical ventilation for general anaesthesia: a meta-analysis of individual patient data. AB - BACKGROUND: Protective mechanical ventilation strategies using low tidal volume or high levels of positive end-expiratory pressure (PEEP) improve outcomes for patients who have had surgery. The role of the driving pressure, which is the difference between the plateau pressure and the level of positive end-expiratory pressure is not known. We investigated the association of tidal volume, the level of PEEP, and driving pressure during intraoperative ventilation with the development of postoperative pulmonary complications. METHODS: We did a meta analysis of individual patient data from randomised controlled trials of protective ventilation during general anesthaesia for surgery published up to July 30, 2015. The main outcome was development of postoperative pulmonary complications (postoperative lung injury, pulmonary infection, or barotrauma). FINDINGS: We included data from 17 randomised controlled trials, including 2250 patients. Multivariate analysis suggested that driving pressure was associated with the development of postoperative pulmonary complications (odds ratio [OR] for one unit increase of driving pressure 1.16, 95% CI 1.13-1.19; p<0.0001), whereas we detected no association for tidal volume (1.05, 0.98-1.13; p=0.179). PEEP did not have a large enough effect in univariate analysis to warrant inclusion in the multivariate analysis. In a mediator analysis, driving pressure was the only significant mediator of the effects of protective ventilation on development of pulmonary complications (p=0.027). In two studies that compared low with high PEEP during low tidal volume ventilation, an increase in the level of PEEP that resulted in an increase in driving pressure was associated with more postoperative pulmonary complications (OR 3.11, 95% CI 1.39-6.96; p=0.006). INTERPRETATION: In patients having surgery, intraoperative high driving pressure and changes in the level of PEEP that result in an increase of driving pressure are associated with more postoperative pulmonary complications. However, a randomised controlled trial comparing ventilation based on driving pressure with usual care is needed to confirm these findings. FUNDING: None. PMID- 26947626 TI - [Effusive pericarditis: clinical and etiological aspects in Lome]. AB - OBJECTIVE: to describe the course and the etiologic, prognostic, and therapeutic aspects of effusive pericarditis (EP) in Togo. MATERIAL ANDMETHODS: Prospective and longitudinal study conducted at the cardiology department of Sylvanus Olympio Teaching Hospital of Lome from February 1, 2011, to January 31, 2014, of patients hospitalized for EP, confirmed by Doppler echocardiography. RESULTS: The study included 38 patients. The hospital incidence rate of EP was 2.0%. The mean age was 42.5 +/- 14.9 years (range: 16 to 73 years) with a sex ratio of 0.7. Exertional dyspnea, poor general condition, chest pain, and fever were the main symptoms. Pericardial effusion was abundant in 24 patients (63%). The Koch bacillus was identified on direct examination in five patients (13%) and only from sputum. HIV serology was positive in 18 patients (47%). Pericardial fluid was collected from 24 patients (63%). Pathology examinations of pericardial tissue found nonspecific inflammation in 5 patients and pericardial tuberculosis in 7. The causes of EP were: tuberculous (55%), idiopathic (16%), bacterial (8%), HIV-related (5%), uremic (5%), neoplastic (5%), lupus (3%), and rheumatic (3%). CONCLUSION: EFP is a frequent, serious, even deadly disease in Africa because of the HIV-AIDS pandemic. Treatment depends on the cause, most often tuberculosis. PMID- 26947667 TI - Sugar beet molasses as an ingredient to enhance the nutritional and functional properties of gluten-free cookies. AB - Sugar beet molasses is a raw material with high potential to be a functional ingredient in baked goods. This paper investigated the nutritional and functional properties of gluten-free cookies enriched with sugar beet molasses. At all enrichment levels and forms tested (liquid and dry), the addition of beet molasses improved the micronutrient pattern and antioxidative status of gluten free cookies. The cookies prepared with molasses were significantly higher in potassium, magnesium, calcium, iron, betaine, total phenolics and DPPH radical scavenging abilities. Molasses contributed to wider spectra of phenolic compounds. The dominating phenolic compounds in the molasses-enriched cookies were catechin, ferulic, syringic and vanillic acid. Molasses also contributed to the presence of p-hydroxybenzoic acid in the cookies. Addition of molasses increased the content of hydroxymethyfurfural in the cookies, but not above values commonly reported for this product type. Molasses addition improved the overall acceptance of gluten-free cookies up to 30% enrichment level. PMID- 26947668 TI - Watermelon extract reduces blood pressure but does not change sympathovagal balance in prehypertensive and hypertensive subjects. AB - Previous studies have shown that watermelon extract reduces blood pressure through vasodilation. However, those studies have not verified whether sympathetic nervous activity is influenced by watermelon extract. This study aimed to evaluate the effect of supplementation with watermelon extract for 6 weeks on blood pressure and sympathovagal balance of prehypertensive and hypertensive individuals. Forty volunteers participated in a randomized, double blind, experimental and placebo-controlled study. They consumed 6 g of watermelon extract daily (n = 20; age 48.7 +/- 1.9 years, 10 men) or a placebo (n = 20; age 47.4 +/- 1.2 years, 11 men) for 6 weeks. Blood pressure and cardiac autonomic modulation were measured. Watermelon extract promoted a significant reduction in systolic (137.8 +/- 3.9 to 126.0 +/- 4.0 mmHg, p < 0.0001) and diastolic (79.2 +/ 2.2 to 72.3 +/- 2.0 mmHg, p < 0.001) blood pressure, but showed no differences compared to the placebo group. This significant reduction in blood pressure occurred without a significant change in sympathovagal balance from the beginning (1.7 +/- 0.1) to the end of the study (1.7 +/- 0.4). In conclusion, supplementation with watermelon extract reduces systolic and diastolic blood pressure in prehypertensive and hypertensive individuals, but does not alter the cardiac autonomic modulation of these individuals. PMID- 26947669 TI - Impact of the number of veins repaired in short-term digital replantation survival rate. AB - BACKGROUND: Venous congestion/insufficiency plays a major role in failure of finger replantation. Despite acceptable salvage rates with postoperative anticoagulation or leeching, operative technique remains the most important predictor of success. However, there are no indications in the literature on the benefit of anastomosing single versus multiple veins. METHODS: A retrospective review of finger amputations from 2011 to 2013 was conducted. The analyzed endpoint was the finger survival rate at discharge depending on the number of veins repaired: multiple veins (group 1), only one vein (group 2), or no veins (group 3). Proportions were compared using v2 tests/Fisher's exact tests; p-value <0.05 was considered significant. RESULTS: Seventy-two patients with complete digital amputation were operated including 101 fingers. Twenty-seven fingers (26.7%) failed before hospital discharge, with 78% of failures due to venous complications versus 22% with an arterial etiology. Group 2 had 15 replantation failures due to venous causes as opposed to only one from group 1, representing a 1.27-fold (95% confidence interval (CI): 0.99, 1.34) increased relative risk of failure (p = 0.032). Similarly, five fingers from group 3 suffered venous complications, resulting in a 1.49-fold (95% CI: 1.02, 1.73) increased likelihood of failure in comparison to group 1 (p = 0.008). No significant difference was observed between having only one vein repaired versus none (RR: 1.1792, 95% CI: 0.83, 2.10, p = 0.502). CONCLUSION: Efforts toward favoring two-vein repair lead to better survival of the replanted fingers. More cases need to be analyzed before formulating conclusions on specific levels of amputation with regard to venous anastomoses. PMID- 26947670 TI - Microvascular free flaps are a safe and suitable training procedure during structured plastic surgery residency: A comparative cohort study with 391 patients. AB - BACKGROUND: Microvascular free flaps have become a reliable standard procedure. Due to increasing microsurgical experience in teaching hospitals, residents are getting acquainted with performing free flap surgeries earlier in their training. However, economic considerations and safety regulations contradict adequate teaching. A validation of procedures for residency training is necessary to reduce the existing concerns. METHODS: This retrospective, comparative cohort study was designed to investigate whether free flaps are a safe residency training procedure. In addition, the aim was to establish standards for microsurgical training. Between 2008 and 2011, 391 patients were included who underwent reconstructive surgery with free flaps, under the supervision of either an experienced microsurgeon (cohort 1) or a resident in training (cohort 2). Patient demographics, interventional characteristics, as well as outcome parameters were attributed for comparative analysis. RESULTS: The comparison of both cohorts revealed a significant difference for defect cause (p < 0.01) and defect localization (p < 0.001). Free flaps for breast reconstruction were more frequently used in cohort 1, and ALT flaps were more used in cohort 2 (p < 0.001). The length of hospital stay was significantly reduced in cohort 1 (p < 0.001). No significant differences for major postoperative complications were identified. CONCLUSION: With respect to standardized environmental conditions and risk stratification, microvascular free flaps can be applied as a safe training procedure during residency. Adequate teaching conditions require a sufficient case load and a high level of expertise of the teacher. The resident's experience and skills as well as the institutional infrastructure and expertise require consideration. LEVEL OF EVIDENCE: III. PMID- 26947671 TI - Extending the limits of reconstructive microsurgery in elderly patients. AB - BACKGROUND: Population aging strongly affects the demographic development of industrialized countries. While microsurgical procedures were initially believed to be only feasible in patients of younger age because of the duration of the surgical procedure and the higher risk of vascular insufficiency due to age related comorbidities, it has become evident that these procedures are beneficial even for patients at an advanced age. METHODS: We retrospectively investigated microsurgical procedures in a patient cohort (n = 25 with 27 free flaps) with a minimum age of 78 years with regard to patients' characteristics, flap survival, and postoperative surgical and medical complications. RESULTS: Median age was 81 years (IQR 6). Most defects were located in the head and neck region. The mean operation time was 384 min (standard deviation (SD) 131). Flap failure was observed in three cases (11%). The median length of hospital stay was 17 days (interquartile range (IQR) 8). The mean ASA score was 2.48. Patients' age and ASA group did not correlate. The mortality rate was 4%. Postoperative surgical complications were observed in 11 cases (41%), while 19 patients (70%) showed one or more medical complications. Higher ASA classes tended to show more postoperative complications. However, neither age nor operating time nor ASA status showed significant influence on the occurrence of postoperative medical or surgical complications. CONCLUSION: There is growing demand for structural and functional restoration using free tissue transfer in an aging population. If there are no alternative treatment options available promising similar structural and functional preservation, free tissue transfer is justifiably in very old patients despite a potentially increased flap failure. As such, free tissue transfer is used as a curative treatment concept aiming at a maximum of patients' independence and early ambulation. Occurrence of complications can be diminished by adequate patient selection and thorough perioperative care. PMID- 26947672 TI - The use of contralateral free extended latissimus dorsi myocutaneous flap for a tertiary failed breast reconstruction: Is it still an option? AB - BACKGROUND: Unsuccessful breast reconstruction management represents a complex challenge for the plastic surgeon. Although these events rarely occur, many patients are not suitable candidates for conventional flaps, because of either previous donor-site surgery or lack of sufficient tissue. METHODS: In this study, a contralateral free latissimus dorsi musculocutaneous flap (CL-LDMF) was planned for correction of major lesions in the anterior chest wall. Twelve patients underwent secondary/tertiary breast reconstruction with CL-LDMF with a customized shape (horizontal, oblique, or "fleur-de-lis") depending on the amount of tissue necessary. The technique was indicated in patients with large thoracic defects who lacked a donor site and had undergone previous unsuccessful pedicled LDMF. RESULTS: The mean follow-up time was 42.5 months (range: 18-72 months). Five local complications occurred in four of the 12 patients. Dorsal dehiscence was observed in one, local wound infection in one, small partial CL-LDMF necrosis in one, and dorsal seroma in one patient. All cases of complications were limited and treated with a conservative approach except for one implant extrusion 4 months after reconstruction. No total flap loss was reported. All patients achieved a satisfactory thoracic and breast reconstruction. CONCLUSION: The results of this study demonstrate that free CL-LDMF is a reliable technique and should be considered in selected cases of tertiary reconstructions. The majority of complications were immediate, minor, and comparable to other reconstructive techniques. We believe that in selected patients, especially those who do not have available donor-site areas, free CL-LDMF is advantageous and should be part of the armamentarium of all plastic surgeons who deal with tertiary breast reconstructions. PMID- 26947690 TI - Sound bite-based medicine muddies the waters. PMID- 26947673 TI - Planning digital artery perforators using color Doppler ultrasonography: A preliminary report. AB - Digital artery perforator (DAP) flaps have been applied for the coverage of finger soft tissue defects. Although an advantage of this method is that there is no scarification of the digital arteries, it is difficult to identify the location of the perforators during intraoperative elevation of the DAP flap. In this study, anatomically reliable locations of DAPs were confirmed using color Doppler ultrasonography (US) in healthy volunteers. A successful case using an adiposal-only DAP flap for the coverage of a released digital nerve using preoperative DAP mapping with color Doppler US is also described. A total of 40 digital arteries in 20 fingers of the right hands of five healthy volunteers (mean age: 32.2 years old) were evaluated. The DAPs were identified using color flow imaging based on the beat of the digital artery in the short axial view. In total, 133 perforators were detected, 76 (an average of 3.8 per finger) arising from the radial digital artery and 57 (an average of 2.9 per finger) arising from ulnar digital artery. Sixty-three perforators (an average of 3.2 per finger) in the middle phalanges and 70 (an average of 3.5 per finger) in the proximal phalanges were found. Overall, an average of 1.7 perforators from each digital artery was detected in the proximal or middle phalanges. Moreover, at least one DAP per phalanx was reliably confirmed using color Doppler US. Preoperative knowledge of DAP mapping could make elevating the DAP flap easier and safer. PMID- 26947691 TI - Well-being in wounds inventory (WOWI): development of a valid and reliable measure of well-being in patients with wounds. AB - OBJECTIVE: Physical and psychosocial deficits have been reported in people living with chronic wounds. While the negative impact of these factors on an individual's quality of life (QoL) is well documented, there has been little research into the well-being of those living with chronic wounds, despite recent calls for increased attention to this related, yet distinct construct. This paper introduces the Well-being in Wounds Inventory (WOWI) and provides support for the WOWI as a valid and reliable measure of well-being in patients living with chronic wounds. METHOD: A draft questionnaire was administered to a convenience sample of individuals with chronic wounds (n=85) and the resulting data subject to factor analysis in order to refine the structure of the questionnaire. The reliability, validity and responsiveness of the resulting questionnaire were then tested by administration to a second sample of individuals with wounds (n=49). Socio-demographic data, issues affecting patient well-being and well-being factors, such as, emotions; perceived coping skills; social support; personal control; hope for the future, were measured. RESULTS: Results confirmed the WOWI as a reliable and valid measure of well-being. Items loaded onto two subscales, 'personal resources' and 'wound worries'. Analysis revealed the WOWI to be highly feasible measure of well-being, with good test-retest reliability and responsiveness to changes in health status. CONCLUSION: The current study highlights the importance of assessing well-being factors in individuals living with chronic wounds. It introduces the WOWI as a valid and reliable measure of well-being in chronic wound patients. The authors recommend health-care practitioners take account of well-being as part of a holistic treatment plan in order to maximise patient outcomes. DECLARATION OF INTEREST: This project was funded by Urgo Medical. The authors have no conflict of interest to declare. PMID- 26947692 TI - The importance of hydration in wound healing: reinvigorating the clinical perspective. AB - Balancing skin hydration levels is important as any disruption in skin integrity will result in disturbance of the dermal water balance. The discovery that a moist environment actively supports the healing response when compared with a dry environment highlights the importance of water and good hydration levels for optimal healing. The benefits of 'wet' or 'hyper-hydrated' wound healing appear similar to those offered by moist over a dry environment. This suggests that the presence of free water may not be detrimental to healing, but any adverse effects of wound fluid on tissues is more likely related to the biological components contained within chronic wound exudate, for example elevated protease levels. Appropriate dressings applied to wounds must not only be able to absorb the exudate, but also retain this excess fluid together with its protease solutes, while concurrently preventing desiccation. This is particularly important in the case of chronic wounds where peri-wound skin barrier properties are compromised and there is increased permeation across the injured skin. This review discusses the importance of appropriate levels of hydration in skin, with a particular focus on the need for optimal hydration levels for effective healing. Declaration of interest: This paper was supported by Paul Hartmann Ltd. The authors have provided consultative services to Paul Hartmann Ltd. PMID- 26947693 TI - A next-generation antimicrobial wound dressing: a real-life clinical evaluation in the UK and Ireland. AB - OBJECTIVE: To assess the effectiveness of a new, next-generation antimicrobial dressing (NGAD; AQUACEL Ag+ EXTRA dressing) in managing wound exudate, infection and biofilm, and facilitating progression toward healing. METHOD: Clinicians from the UK and Ireland selected stalled or deteriorating wounds that were considered to be compromised by infection and/or biofilm. Only the primary dressing was replaced by the NGAD, for up to 4 weeks or as deemed clinically appropriate; otherwise, standard protocols of care were used. Evaluation forms captured the baseline and final assessment characteristics of wound status, exudate levels, skin health, wound bed appearance, signs of infection and biofilm, and wound dimensions. RESULTS: In all, 29 wounds were suitable for inclusion in the final analysis. Following the NGAD evaluation, wound statuses were shifted from stagnant/deteriorating to mainly improved, exudate levels were shifted from moderate/high to moderate/low, and skin health was improved in 20 wounds (69%). Wound bed tissue types were shifted from largely suspected biofilm/sloughy tissue (76%) to largely granulation tissue (53%). All signs of clinical infection were reduced in average frequency, with biofilm suspicion falling from 76% to 45% of the cases. The median management period with the NGAD was 4.5 weeks, after which 26 wounds (90%) became smaller in size and 10 wounds (34%) completely healed. CONCLUSION: This real-life clinical evaluation of the NGAD suggests that its successful management of exudate, infection and biofilm is generally accompanied by notable improvements in wound health and size, and in some cases, complete healing. DECLARATION OF INTEREST: The authors are all employed by ConvaTec Ltd. but have no other conflict of interest to declare. Dressings were provided to the clinicians free of charge. PMID- 26947694 TI - A multi-centre clinical evaluation of reactive oxygen topical wound gel in 114 wounds. AB - OBJECTIVE: This article reports the outcomes of the use of Surgihoney RO (SHRO), topical wound dressing in a multi-centre, international setting. The aims were to explore the clinical effects of SHRO, including a reduction in bacterial load and biofilm and improvement in healing in a variety of challenging non-healing and clinically infected wounds. METHOD: This was a non-comparative evaluation, where both acute and chronic wounds with established delayed healing were treated with the dressing. Clinicians prospectively recorded wound improvement or deterioration, level of wound exudate, presence of pain, and presence of slough and necrosis. Analysis of this data provided information on clinical performance of the dressing. Semi-quantitative culture to assess bacterial bioburden was performed where possible. RESULTS: We recruited 104 patients, mean age 61 years old, with 114 wounds. The mean duration of wounds before treatment was 3.7 months and the mean duration of treatment was 25.7 days. During treatment 24 wounds (21%) healed and the remaining 90 (79%) wounds improved following application of the dressing. No deterioration in any wound was observed. A reduction in patient pain, level of wound exudate and in devitalised tissue were consistently reported. These positive improvements in wound progress were reflected in the wound cultures that showed a reduction in bacterial load in 39 out of the 40 swabs taken. There were two adverse events recorded: a stinging sensation following application of the dressing was experienced by 2 patients, and 2 elderly patients died of causes unrelated to the dressing or to the chronic wound. These patients' wounds and their response to SHRO have been included in the analysis. CONCLUSION: SHRO was well tolerated and shows great promise as an effective potent topical antimicrobial in the healing of challenging wounds. DECLARATION OF INTEREST: Matthew Dryden has become a shareholder in Matoke Holdings, the manufacturer of Surgihoney RO, since the completion of this study. Keith Cutting is a consultant to Matoke Holdings. PMID- 26947695 TI - Epidermal skin grafting in patients with complex wounds: a case series. AB - OBJECTIVE: Complex wounds are often difficult to close and sometimes require a split-thickness skin graft (STSG). However, epidermal skin grafts, which contain only an epidermal layer of skin, are a viable option for wound coverage in these challenging wounds. We report our experience using an automated epidermal harvesting tool to harvest epidermal skin grafts for the treatment of complex wounds. METHOD: Epidermal skin grafts were harvested from the patient's thigh, which was first washed with isopropyl alcohol. After harvesting, they were transferred to the recipient site using a film dressing. A bolster dressing using gauze and a self-adherent wrap held the grafts in place. RESULTS: We selected 34 patients with wounds that had been present from several weeks to over a year. Prior treatments, included skin substitutes, alginate dressings, Unna Boot, and collagen dressings. There were 17 female and 17 male patients with a mean age of 67.1 years (range: 37-103). Wound types were: traumatic wounds, diabetic foot ulcers, venous stasis ulcers, pressure ulcers, and surgical wounds. Patient comorbidities included hypertension, diabetes, congestive heart failure, and osteoarthritis. Mean epithelialisation rate at the recipient site was 7.0 weeks (range: 1-35 weeks). Wound complications included drainage, hypergranulation, and oedema. At follow-up 82.4% (28/34) of wounds were healed, 2.9% (1/34) wounds showed improved healing, 11.8% (4/34) of wounds did not heal, and 2.9% (1/34) were lost to follow-up. All donor sites healed without complications. CONCLUSION: In our cohort, use of epidermal skin grafts in conjunction with bolster dressings resulted in full closure or wound improvement of a majority of patients. Epidermal grafting provides another treatment option to physicians when only the epidermal layer is needed. DECLARATION OF INTEREST: Dr. Bhatia is a consultant for KCI, an Acelity company. PMID- 26947696 TI - Negative pressure wound therapy versus standard wound care on quality of life: a systematic review. AB - OBJECTIVE: Negative pressure wound therapy (NPWT) is a widely accepted treatment modality for open or infected wounds. Premature ending of NPWT occasionally occurs due to negative effects on the quality of life (QoL), however, the actual impact on QoL is unknown. The aim of this review is to analyse the effect of NPWT versus standard wound care (SWC) on QoL when used for the treatment of open or infected wounds. METHOD: A systematic literature search in a range of databases (PubMed, CINAHL, Medline, Web of Science, Science Direct Freedom Collection, SwetsWise, PSYCArticles and Infrotrac Custom Journals) using the following search terms; 'standard wound care', 'wound dressing', 'dressing', 'treatment', OR 'negative pressure wound therapy [MESH]', OR 'vacuum assisted closure' AND 'quality of life [MESH]', 'patient-satisfaction', OR 'experiences' was performed. Methodological quality was assessed using the methodological index for non randomised studies (MINORS) checklist. RESULTS: There were 42 studies identified, five matched the inclusion criteria: two randomised clinical trials (RCTs), one clinical comparative study, one exploratory prospective cohort study and one quasi experimental pilot study. Median MINORS-score was 75% (58%-96%). There were seven different questionnaires used to measure QoL or a subsidiary outcome. QoL in the NPWT group was lower in the first week, though no difference in QoL was observed thereafter. CONCLUSION: This systematic review observed that QoL improved at the end of therapy independent of which therapy was used. NPWT led to a lower QoL during the first week of treatment, possible due to aniexty, after which a similar or better QoL was reported when compared with SWC. It could be suggested that NPWT might be associated with increased anxiety. DECLARATION OF INTEREST: All authors of this publication have received no financial support or have personal interests conflicting with the objectivity of this manuscript. PMID- 26947697 TI - Effect of a wound cleansing solution on wound bed preparation and inflammation in chronic wounds: a single-blind RCT. AB - OBJECTIVE: Research into surfactant solutions for the debridement of chronic wounds suggests that surfactants may support wound bed preparation (WBP) in chronic wounds, however their efficacy has not been evaluated in randomised controlled trials (RCTs). Our aim was to assess the clinical efficacy of a propylbetaine-polihexanide (PP) solution versus normal saline (NS) solution in WBP, assessing inflammatory signs and wound size reduction in patients with pressure ulcers (PUs) or vascular leg ulcers. METHOD: In a single-blinded randomised controlled trial (RCT) patients were randomly allocated to two groups and treated with either propylbetaine-polihexanide (PP) solution (Prontosan) or NS. Wounds were assessed using the Bates-Jensen wound assessment tool (BWAT). Assessments took place at inclusion (T0), day 7 (T1), day 14 (T2), day 21 (T3), and day 28 (T4). Outcomes were analysed using a two-tailed Student's t-test. RESULTS: A total of 289 patients were included. Both groups had similar demographics, clinical status, and wound characteristics. Data analysis showed statistically significant differences between T0 and T4 for the following outcomes: BWAT total score, p=0.0248; BWAT score for inflammatory items, p=0.03; BWAT scores for wound size reduction (p=0.049) and granulation tissue improvement (p=0.043), all in favour of PP. The assessment of pain did not show any significant difference between the two groups. CONCLUSION: The study results showed significantly higher efficacy of the PP solution versus NS solution, in reducing inflammatory signs and accelerating the healing of vascular leg ulcers and PUs. This evidence supports the update of protocols for the care of chronic wounds. DECLARATION OF INTEREST: The authors have no conflict of interest regarding this research. This is an investigator initiated trial. B. Braun Milano SpA kindly provided the material under investigation for both treatment groups, and paid the Ethics Committees' application fees in all participating centres. PMID- 26947698 TI - Letters--Response to call to action: the proposed National Formulary for Wound Care. PMID- 26947699 TI - Letter in response to Investigating staff knowledge of safeguarding and pressure ulcers in care homes. PMID- 26947700 TI - Letter in response to Investigating staff knowledge of safeguarding and pressure ulcers in care homes. PMID- 26947701 TI - Intrauterine Contraception. AB - Currently, there are only two basic types of intrauterine devices (IUDs): copper and hormonal. However, other types of IUDs are under development, some of which are in clinical trials around the world. Continued development has focused on increasing efficacy, longer duration of use, and noncontraceptive benefits. This review discusses currently available intrauterine contraceptives, such as the Cu380A IUD and levonorgestrel-releasing intrauterine systems; novel intrauterine contraceptives that are available in select parts of the world including the intrauterine ball, low-dose copper products, frameless devices, and intrauterine delivery systems impregnated with noncontraceptive medication; and novel products currently in development. PMID- 26947702 TI - Contraception Counseling in the Digital Age. AB - The digital age has revolutionized how providers and patients seek medical information and access care. The Internet, flush with online forums and other social media networks, has replaced services once provided by medical libraries. Meanwhile, downloadable apps help patients remember medications, choose treatments, and remotely access face-to-face physician encounters. Unfortunately, technology comes at a price. Reputable, data-driven sites exist alongside sites riddled with inaccuracies. The lack of peer review means that discredited ideas and therapies can resurface in the blogosphere, "going viral" and influencing the thoughts of hapless users. The Internet never forgets. Online media and digital technology pose unique challenges to family planning providers. The "net" offers a private environment to address sexual and reproductive health issues. Patients, especially adolescents, may prefer the anonymity of technology-based sources to consulting physicians or other community providers, but they may receive inaccurate information or information that fails to consider the psychosocial context of reproductive behavior. Family planning providers must become familiar with reputable technology-based options to ensure that family planning care remains accurate, accessible, and relevant in the ever-changing digital age. PMID- 26947704 TI - The O, OH and OOH-assisted selective coupling of methanol on Au-Ag(111). AB - Using density functional theory (DFT) calculations, we performed a thorough theoretical investigation on the catalytic mechanism of oxidative self-coupling of methanol with molecular oxygen on Au-Ag catalysts. It is found that molecular oxygen can be activated via a hydroperoxyl (OOH) intermediate by taking a hydrogen atom from co-adsorbed methanol with an energy barrier of 0.51 eV, which is actually the rate determining step for the overall reaction. The O, OH and OOH oxidant formation proceeds via two channels of I and II with low barriers. We demonstrated that the oxidative coupling of methanol by OOH, atomic oxygen, and hydroxyl is much more favorable than the total oxidation of methanol, and is responsible for the high selectivity of Au-Ag catalysts in methanol oxidation. The revealed activation mechanism provides an efficient pathway for optimizing the selective coupling of methanol with dioxygen. PMID- 26947703 TI - Beyond the Condom: Frontiers in Male Contraception. AB - Nearly half of all pregnancies worldwide are unplanned, despite numerous contraceptive options available. No new contraceptive method has been developed for men since the invention of condom. Nevertheless, more than 25% of contraception worldwide relies on male methods. Therefore, novel effective methods of male contraception are of interest. Herein we review the physiologic basis for both male hormonal and nonhormonal methods of contraception. We review the history of male hormonal contraception development, current hormonal agents in development, as well as the potential risks and benefits of male hormonal contraception options for men. Nonhormonal methods reviewed will include both pharmacological and mechanical approaches in development, with specific focus on methods which inhibit the testicular retinoic acid synthesis and action. Multiple hormonal and nonhormonal methods of male contraception are in the drug development pathway, with the hope that a reversible, reliable, safe method of male contraception will be available to couples in the not too distant future. PMID- 26947705 TI - Toxicity evaluation of copper oxide bulk and nanoparticles in Nile tilapia, Oreochromis niloticus, using hematological, bioaccumulation and histological biomarkers. AB - The increased industrial applications of nanoparticles (NPs) augment the possibility of their deposition into aquatic ecosystems and threatening the aquatic life. So, this study aimed to provide a comparable toxicological effects of nano-CuO and bulk CuO on a common freshwater fish, Oreochromis niloticus. Fish were exposed to two selected doses (1/10 and 1/20 of the LC50/96 h) of both nano /bulk CuO for 30 days. Based on the studied hematological parameters (RBCs count, hemoglobin content and hematocrit%), the two selected concentrations of CuO in their nano- and bulk sizes were found to induce significant decrease in all studied parameters. But, nano-CuO-treated fish showed the maximum decrease in all recorded parameters among the all studied groups especially at the low concentration of 1/20 LC50/96 h. Hematological status was also confirmed using the calculated blood indices (MCV, MHC and MCHC). In case of bulk CuO-treated groups, the significant decrease in the studied hematological parameters was not followed by any change in MCV and MCH (normocytic anemia), while fish that exposed to NPs showed a significant increase in all calculated blood parameters reflecting erythrocytes swelling which is related to the intracellular osmotic disorders (macrocytic anemia). Regarding metal bioaccumulation factor, the results showed that CuO NPs had more efficiency to internalize fish tissues (liver, kidneys, gills, skin and muscle). The accumulation pattern of Cu metal was ensured by histopathological investigation of liver, kidneys and gills. The histopathological analysis revealed various alterations that varied between adaptation responses and permanent tissue damage. PMID- 26947706 TI - Molecular endocrine changes of Gh/Igf1 axis in gilthead sea bream (Sparus aurata L.) exposed to different environmental salinities during larvae to post-larvae stages. AB - The influence of acclimation of the euryhaline gilthead sea bream (Sparus aurata) larvae/post-larvae to brackish water on growth, energetic contents, and mRNA levels of selected hormones and growth-regulating hypothalamic neurohormones was assessed. Specimens from 49 days post-hatching were acclimated during 28 days to two different environmental salinities: 38 and 20 psu (as brackish water). Both groups were then transferred to 38 psu and acclimated for an additional week. Early juveniles were sampled after 28 days of acclimation to both salinities and one week after transfer to 38 psu. Pituitary adenylate cyclase-activating peptide (adcyap1; pacap), somatostatin-I (sst1), growth hormone (gh1), insulin-like growth factor-I (igf1), and prolactin (prl) mRNA expression were all studied by QPCR. Post-larvae acclimated to 20 psu showed better growth performance and body energetic content than post-larvae maintained at 38 psu. prl, adcyap1, and igf1 mRNA expression levels increased in 20-psu-acclimated post-larvae but decreased upon transfer to 38 psu. GH1 expression did not show significant changes under both experimental conditions. Our results suggested an enhanced general performance for post-larvae in brackish water, supported by the actions of adcyap1, igf1, and prl. PMID- 26947708 TI - Anion triggered metallogels: demetalation and crystal growth inside the gel matrix and improvement in viscoelastic properties using Au-NPs. AB - Progelator complex Zn-TRPA-2 undergoes Cl(-) triggered gelation to afford ZTP2G, while Zn-TRPA-2 capped Au-NPs under similar conditions gave another gel GNZTP2G which also represents a rare nano-composite metallogel. When Zn-TRPA-2 was triggered by Cl(-) and NO3(-) simultaneously, crystals of demetalated species NA TRPA-2 grew inside the ZTP2G matrix. Interestingly, GNZTP2G exhibits superior viscoelastic properties over ZTP2G. PMID- 26947709 TI - Phylogenetic study of the genus Kudoa (Myxozoa: Multivalvulida) with a description of Kudoa rayformis sp. nov. from the trunk muscle of Pacific sierra Scomberomorus sierra. AB - Kudoa rayformis n. sp. (Myxozoa; Multivalvulida) was observed in the trunk muscle of Pacific sierra Scomberomorus sierra caught off the coast of Tonosi, Panama. The species formed pseudocysts in myofibers and infection was subclinical. The myxospores possessed four polar capsules and spore valves, one of which had a distinct filamentous extension. This unique morphological characteristic of the myxospore validated this as a new species of Kudoa. Genetically, K. rayformis n. sp. is closest to K. inornata, with 98% and 91% similarity in 18S and 28S rDNA, respectively, but its spore shape was clearly distinct. The 18S rDNA and concatenated sequences from K. rayformis were used in molecular phylogenetic analyses of kudoids to examine the congruence of phylogeny with infection site tropism, spore morphology and cyst/pseudocyst formation. The results demonstrated that the phenotypic traits were correlated with the phylogeny of Kudoidae, and that the biological features of K. rayformis originated from the ancient Kudoidae as exhibited by the non-specific infection site tropism and the ability to infect muscle and form pseudocysts. PMID- 26947711 TI - Reply. PMID- 26947710 TI - Multilocus phylogeny and phylogenomics of Eriochrysis P. Beauv. (Poaceae Andropogoneae): Taxonomic implications and evidence of interspecific hybridization. AB - Species delimitation is a vital issue concerning evolutionary biology and conservation of biodiversity. However, it is a challenging task for several reasons, including the low interspecies variability of markers currently used in phylogenetic reconstructions and the occurrence of reticulate evolution and polyploidy in many lineages of flowering plants. The first phylogeny of the grass genus Eriochrysis is presented here, focusing on the New World species, in order to examine its relationships to other genera of the subtribe Saccharinae/tribe Andropogoneae and to define the circumscriptions of its taxonomically complicated species. Molecular cloning and sequencing of five regions of four low-copy nuclear genes (apo1, d8, ep2-ex7 and ep2-ex8, kn1) were performed, as well as complete plastome sequencing. Trees were reconstructed using maximum parsimony, maximum likelihood, and Bayesian inference analyses. The present phylogenetic analyses indicate that Eriochrysis is monophyletic and the Old World E. pallida is sister to the New World species. Subtribe Saccharinae is polyphyletic, as is the genus Eulalia. Based on nuclear and plastome sequences plus morphology, we define the circumscriptions of the New World species of Eriochrysis: E. laxa is distinct from E. warmingiana, and E. villosa is distinct from E. cayennensis. Natural hybrids occur between E. laxa and E. villosa. The hybrids are probably tetraploids, based on the number of paralogues in the nuclear gene trees. This is the first record of a polyploid taxon in the genus Eriochrysis. Some incongruities between nuclear genes and plastome analyses were detected and are potentially caused by incomplete lineage sorting and/or ancient hybridization. The set of low-copy nuclear genes used in this study seems to be sufficient to resolve phylogenetic relationships and define the circumscriptions of other species complexes in the grass family and relatives, even in the presence of polyploidy and reticulate evolution. Complete plastome sequencing is also a promising tool for phylogenetic inference. PMID- 26947712 TI - Pulmonary Artery Catheter Use During Cardiac Surgery in the United States, 2010 to 2014. AB - OBJECTIVES: To examine patterns of use of pulmonary artery catheters in a large cohort of patients undergoing cardiac surgery. DESIGN: A retrospective study with univariate and multivariate logistic regression to identify independent predictors for the utilization of pulmonary artery catheters. SETTING: University, small, medium and large community hospitals participating in the National Anesthesia Clinical Outcomes Registry. PARTICIPANTS: A total of 116,333 patients undergoing pulmonary artery catheter placement during cardiac surgery in the National Anesthesia Clinical Outcomes Registry from the Anesthesia Quality Institute. MEASUREMENTS AND MAIN RESULTS: Age older than 50 years, American Society of Anesthesiologists classification of 3 or higher, case duration of longer than 6 hours, and presence of a resident physician or certified nurse anesthetist were associated with increased likelihood of pulmonary artery catheter (PAC) placement. Age<18 years, or presence of a board-certified anesthesiologist, were associated with a decreased likelihood of catheter placement. The use of PACs has increased from 2010 to 2014. The presence of a PAC did not alter the risk of cardiac arrest intraoperatively. A nonsignificant decrease in mortality was associated with catheter placement. Transfusion was 75% less likely in the PAC cohort than in the control group. CONCLUSIONS: Pulmonary artery catheter use remains a mainstay of cardiac anesthesia practice. No significant change in the incidence of intraoperative death was noted, but patients with a PAC were less likely to have blood transfused. PMID- 26947713 TI - Sepsis After Cardiac Surgery: From Pathophysiology to Management. PMID- 26947714 TI - Echocardiographic Confirmation of Coronary Blood Flow. PMID- 26947707 TI - Protective and pro-inflammatory roles of intestinal bacteria. AB - The intestinal mucosal surface in all vertebrates is exposed to enormous numbers of microorganisms that include bacteria, archaea, fungi and viruses. Coexistence of the host with the gut microbiota represents an active and mutually beneficial relationship that helps to shape the mucosal and systemic immune systems of both mammals and teleosts (ray-finned fish). Due to the potential for enteric microorganisms to invade intestinal tissue and induce local and/or systemic inflammation, the mucosal immune system has developed a number of protective mechanisms that allow the host to mount an appropriate immune response to invading bacteria, while limiting bystander tissue injury associated with these immune responses. Failure to properly regulate mucosal immunity is thought to be responsible for the development of chronic intestinal inflammation. The objective of this review is to present our current understanding of the role that intestinal bacteria play in vertebrate health and disease. While our primary focus will be humans and mice, we also present the new and exciting comparative studies being performed in zebrafish to model host-microbe interactions. PMID- 26947715 TI - Data Interpretation on the Use of Double-Lumen Tube (DLT) Versus Bronchial Blocker (BB) for One-Lung Ventilation. PMID- 26947716 TI - Left Atrial Appendage and Echocardiography. PMID- 26947717 TI - Assessing Coronary Sinus Blood Flow to Assess Coronary Artery Patency. PMID- 26947718 TI - Fighting neuropathic pain with botulinum toxin A. PMID- 26947719 TI - Safety and efficacy of repeated injections of botulinum toxin A in peripheral neuropathic pain (BOTNEP): a randomised, double-blind, placebo-controlled trial. AB - BACKGROUND: Data from previous studies suggest that botulinum toxin A has analgesic effects against peripheral neuropathic pain, but the quality of the evidence is low. We aimed to assess the safety and efficacy of repeated administrations of botulinum toxin A in patients with neuropathic pain. METHODS: We did a randomised, double-blind, placebo-controlled trial at two outpatient clinics in France (Clinical Pain Centre, Ambroise Pare Hospital, APHP, Boulogne Billancourt, and Neurological Centre, Hopital Dupuytren, Limoges) and one in Brazil (Neurological Department, Hospital das Clinicas da FMUSP, Sao Paulo). Patients aged 18-85 years with peripheral neuropathic pain were randomly assigned (1:1) by block randomisation, according to a centralised schedule, to receive two subcutaneous administrations of botulinum toxin A (up to 300 units) or placebo, 12 weeks apart. All patients and investigators were masked to treatment assignment. The primary outcome was the efficacy of botulinum toxin A versus placebo, measured as the change from baseline in self-reported mean weekly pain intensity over the course of 24 weeks from the first administration. The primary efficacy analysis was a mixed-model repeated-measures analysis in the intention to-treat population. This trial is registered with ClinicalTrials.gov, NCT01251211. FINDINGS: Between Oct 2, 2010, and Aug 2, 2013, 152 patients were enrolled, of whom 68 were randomly assigned (34 per group), and 66 (37 [56%] men) were included in the primary analysis (34 in the botulinum toxin A group and 32 in the placebo group). Botulinum toxin A reduced pain intensity over 24 weeks compared with placebo (adjusted effect estimate -0.77, 95% CI -0.95 to -0.59; p<0.0001). Pain on injection was the only adverse effect reported, and occurred in 19 (56%) participants in the botulinum toxin A group and 17 (53%) of those in the placebo group (p=1.0). Severe pain was experienced by ten (29%) participants in the botulinum toxin A group and 11 (34%) in the placebo group (p=0.8). INTERPRETATION: Two administrations of botulinum toxin A, each of which comprised several injections, have a sustained analgesic effect against peripheral neuropathic pain. Several factors, such as the presence of allodynia and a limited thermal deficit, may be useful in predicting treatment response and should be investigated further. FUNDING: Institut National de la Sante et de la Recherche Medicale (INSERM) and Fondation CNP (France). PMID- 26947721 TI - The presence of spontaneous portosystemic shunts increases the risk of complications after transjugular intrahepatic portosystemic shunt (TIPS) placement. AB - PURPOSE: The goal of this study was to identify clinical and imaging variables that are associated with an unfavorable outcome during the 30 days following transjugular intrahepatic portosystemic shunt (TIPS) placement. MATERIAL AND METHODS: Fifty-four consecutive patients with liver cirrhosis (Child-Pugh 6-13, Model for End-stage Liver Disease 7-26) underwent TIPS placement for refractory ascites (n=25), recurrent or uncontrolled variceal bleeding (n=23) or both (n=6). Clinical, biological and imaging variables including type of stent (covered n=40; bare-stent n=14), presence of spontaneous portosystemic shunt (n=31), and variations in portosystemic pressure gradient were recorded. Early severe complication was defined as the occurrence of overt hepatic encephalopathy or death within the 30days following TIPS placement. RESULTS: Sixteen patients (30%) presented with early severe complication after TIPS placement. Child-Pugh score was independently associated with complication (HR=1.52, P<0.001). Among the imaging variables, opacification of spontaneous portosystemic shunt during TIPS placement but before its creation was associated with an increased risk of early complication (P=0.04). The other imaging variables were not associated with occurrence of complication. CONCLUSION: Identification of spontaneous portosystemic shunt during TIPS placement reflects the presence of varices and is associated with an increased risk of early severe complication. PMID- 26947720 TI - Peripheral hypertrophic neuropathy due to leprosy: Ultrasound and MR imaging findings. PMID- 26947722 TI - Endovascular management of hepatic arterial injury during TIPS placement. PMID- 26947723 TI - Unusual late discovery of interrupted aortic arch by ultrasonography and three dimensional MDCT. PMID- 26947724 TI - Gamma Knife Surgery for Metastatic Brain Tumors from Gynecologic Cancer: Time for What Saves Time, Grants Time, and Is Tested By Time? PMID- 26947725 TI - Primary Intracranial Extra-Axial Anaplastic Ependymomas. AB - BACKGROUND: Ependymomas are usually located in the ventricular system or in the central canal of the spinal cord; intracranial extra-axial ependymomas (IEAEs) are rare. To date, only 17 cases of IEAEs have been reported. CASE DESCRIPTION: We report 2 cases with 3 IEAEs (anaplastic) that were initially misdiagnosed. In Case 1 (47-year-old male), the para-falcine lesion was initially refractory to radiosurgery and gross total resection (GTR) was required due to relentless growth. The lesion had adhered to the falx and was well demarcated from the surrounding cortex. It was then correctly diagnosed as an anaplastic ependymoma on the basis of histopathology, and the patient received radiotherapy. No recurrence was observed after the 53-month follow-up. In Case 2 (30-year-old male), 2 IEAEs underwent staged surgeries and were identified as extra-axial lesions without connection to the ventricular system. Near total resection (NTR) and GTR were achieved in the right temporal and right occipital lesions, respectively, but the patient declined radiotherapy. The residual tumor after NTR regrew rapidly, and aggressive resection was performed followed by radiotherapy. No further recurrence was observed after 28 months. The previous 17 cases were male predominant (76.5%) without correct preoperative diagnoses; no recurrence was observed after total resection in the 9 patients reported in the literature. CONCLUSIONS: IEAEs are rare and have a wide spectrum of clinical and radiological phenotypes. Preoperative diagnosis is difficult. Favorable outcomes for IEAEs can be achieved by GTR plus radiotherapy. Multiple IEAEs benefit from tailored staged surgical resection plus radiotherapy. PMID- 26947726 TI - Static FET-PET and MR Imaging in Anaplastic Gliomas (WHO III). AB - OBJECTIVE: O-(2-[18F]-fluoroethyl)-L-tyrosine-positron emission tomography (FET PET) imaging is an additional tool for tumor grading and surgery planning. Up to now, not much is known about FET-PET imaging in anaplastic gliomas. Our objective was to assess the FET uptake in anaplastic gliomas, compared with magnetic resonance imaging (MRI), histopathologic markers, and its prognostic value. PATIENTS AND METHODS: Forty-six patients (27 males/19 females) with an anaplastic glioma (WHO III) who received MRI and FET-PET imaging before surgery were retrospectively analyzed. Tumor volume was calculated in MRI and FET-PET imaging using a tumor-to-background ratio (TBR), and maximum FET uptake (TBRmax) was calculated. Overall survival (OS) and histopathologic markers (isocitrate dehydrogenase 1/2-mutation, oligodendrial differentiation, and Ki67 proliferation index) were assessed. Univariate and multivariate analysis was performed for OS. RESULTS: In univariate analysis a significant correlation of TBRmax to OS was observed (P = 0.031). Tumor volume in FET-PET imaging (TBR > 2.0) (P = 0.028) showed a higher correlation to OS than the volume of the contrast-enhancing tumor part (P = 0.031). The highest correlation was observed for intersection of volume TBR > 1.3 and the volume of the contrast-enhancing tumor part (P = 0.005); fluid attenuated inversion recovery volume showed no significant correlation to OS (P = 0.401) in the univariate analysis. Anaplastic glioma with oligodendrial differentiation showed significantly higher TBRmax values (P = 0.029), while no significant difference was observed for isocitrate hydrogenase 1/2-mutation (P = 0.752). CONCLUSION: Static FET-PET provides significant prognostic information in anaplastic gliomas, which adds to the value of MRI, supporting the use of both modalities preoperatively to assess individual risks and estimate prognosis. Definition of the histopathologic subtype using static FET-PET remains challenging. PMID- 26947727 TI - Appraisal of the Quality of Neurosurgery Clinical Practice Guidelines. AB - OBJECTIVE: The rate of neurosurgery guidelines publications was compared over time with all other specialties. Neurosurgical guidelines and quality of supporting evidence were then analyzed and compared by subspecialty. METHODS: The authors first performed a PubMed search for "Neurosurgery" and "Guidelines." This was then compared against searches performed for each specialty of the American Board of Medical Specialties. The second analysis was an inventory of all neurosurgery guidelines published by the Agency for Healthcare Research and Quality Guidelines clearinghouse. All Class I evidence and Level 1 recommendations were compared for different subspecialty topics. RESULTS: When examined from 1970-2010, the rate of increase in publication of neurosurgery guidelines was about one third of all specialties combined (P < 0.0001). However, when only looking at the past 5 years the publication rate of neurosurgery guidelines has converged upon that for all specialties. The second analysis identified 49 published guidelines for assessment. There were 2733 studies cited as supporting evidence, with only 243 of these papers considered the highest class of evidence (8.9%). These papers were used to generate 697 recommendations, of which 170 (24.4%) were considered "Level 1" recommendations. CONCLUSION: Although initially lagging, the publication of neurosurgical guidelines has recently increased at a rate comparable with that of other specialties. However, the quality of the evidence cited consists of a relatively low number of high quality studies from which guidelines are created. Wider implications of this must be considered when defining and measuring quality of clinical performance in neurosurgery. PMID- 26947728 TI - Mythological and Prehistorical Origins of Neurosurgery. AB - Mythology has a cultural appeal, and the description of some neurosurgical procedures in the Hindu, Greek, Egyptian, and Chinese mythology has a bearing to the origins of our professions. The traces to some of our modern-day practices also can be linked back to the ancient prehistoric eras of the Siberian, Persian, and the Andean region. In this historical perspective, we briefly dwell into individual accounts through the prism of different cultures to highlight the development of neurosurgery in mythology and prehistoric era. PMID- 26947729 TI - Intrathecal CGS-26303 Pretreatment Attenuates Spinal Nerve Ligation-Induced Neuropathic Pain in the Spinal Cord. AB - BACKGROUND: Matrix metalloproteinase (MMPs) and endothelin-1 may prove to be important in the generation of pain induced by inflammation and nerve lesion. This study aimed to investigate the relationship between endothelin receptors and MMPs. METHODS: Male Sprague-Dawley rats (250-300 g) were divided into 5 groups: a normal (control) group; an L5 spinal nerve ligation (SNL) group; a CGS-26303 IT + L5 SNL group; a BQ-123 IT + L5 SNL group; and a BQ-788 IT + L5 SNL group. The expression of glial fibrillary acidic protein, endothelin-A receptor (ETAR), endothelin-B receptor, MMP-2, and MMP-9 in the ipsilateral L5 dorsal root ganglion (DRG) and the activation of microglia and astrocytes in the L5 spinal dorsal horn (SDH) were quantified by immunofluorescence and Western blotting. RESULTS: Intrathecal pretreatment with CGS-26303 significantly attenuated the hyperalgesic and mechanical responses induced by SNL for 4 days, whereas BQ-123 administration alleviated the hyperalgesia only for 3 hours and mechanical allodynia for only 1 hour. Pretreatment with CGS-26303 significantly down regulated the glial fibrillary acidic protein, ET-A, MMP-2, and MMP-9 expressions in DRG and their effect lasted for 6 hours, 1 day, 7 days, and 1 day, respectively. By immunofluorescence and Western blotting, there was colocalization of ETAR and MMP-9 in the DRG neurons, whereas MMP-2 was expressed in DRG satellite cells. Furthermore, CGS-26303 treatment also reduced SNL-induced microglia and astrocyte activation on the SDH for 7 days. CONCLUSIONS: In this study, CGS-26303 can attenuate SNL-induced neuropathic pain by down-regulating MMP-9, MMP-2, and ETAR expressions in the DRG and by glia cell activation in the SDH. PMID- 26947730 TI - Using Tailored Videos to Teach Inhaler Technique to Children With Asthma: Results From a School Nurse-Led Pilot Study. AB - Our purpose was to test whether a tailored inhaler technique video intervention: (1) could be feasibly implemented by school nurses and (2) improve the inhaler technique of children with asthma. METHODS: School nurses recruited a convenience sample of 25 children with asthma (ages 7-17) and assessed their inhaler technique. Children then watched a tailored video that provided: (1) step-by-step feedback on which steps (out of 8) they performed correctly, (2) praise for correctly-performed steps, and (3) statements about why incorrectly-performed steps are important. Nurses reassessed the child's inhaler technique immediately after watching the video and again 1month later. Non-parametric Wilcoxon signed rank tests were calculated to assess whether children's technique significantly improved from baseline to post-video and baseline to 1-month follow-up. A focus group with the school nurses was conducted post-intervention to discuss feasibility issues. RESULTS: Children's inhaler technique improved by 1.2 steps (with spacer; p=0.03) and 2.7 steps (without spacer; p<0.01) from baseline to post-video. These improvements were maintained at 1-month follow-up. School nurses believed the intervention was feasible to implement and met an important educational need. CONCLUSIONS: A school nurse-led tailored video intervention is feasible to implement and a promising method for improving children's inhaler technique. PMID- 26947731 TI - Comparison of intramedullary fibular allograft with locking compression plate versus shoulder hemi-arthroplasty for repair of osteoporotic four-part proximal humerus fracture: Consecutive, prospective, controlled, and comparative study. AB - OBJECTIVES: To compare the outcomes of intramedullary fibular allograft (IFA) with locking compression plates (LCPs) versus shoulder hemi-arthroplasty (HA) in osteoporotic four-part proximal humeral fracture (PHF). METHODS: Between January 2010 and December 2012, totally 60 cases with osteoporotic four-part PHF were enrolled in this study and were randomly separated into IFA and LCPs group and HA group (n=30). Additionally, surgery indexes for patients in the two groups, such as Constant-Murley score (CMS), the Disability of Arm, Shoulder and Hand (DASH) score, individual subject evaluation of the outcomes, plain X-ray, and computer tomography (CT) scanning were evaluated and compared. RESULTS: CMS, DASH score, activities of daily living (ADL), and range of motion (ROM) were statistically higher in the IFA and LCPs group than those in the HA group at the last follow up, whereas the pain were obviously lower than that in the HA group. Besides, patients in the IFA and LCPs group had higher abduction, external rotation with elbow, strength, and satisfactory rating compared with HA group at the last follow-up. However, one case developed avascular necrosis (AVN), one case encountered screw perforation, and one case experienced varus displacement in the IFA and LCPs group, while there were 2, 4, and 2 cases suffered from superficial infection, shoulder stiffness, tuberosity migration in the HA group, respectively. CONCLUSION: IFA with LCP have an advantage in functional outcomes than shoulder HA. LEVEL OF EVIDENCE: Level II. Prospective cohort study. PMID- 26947732 TI - Distal radius fracture malunion: Importance of managing injuries of the distal radio-ulnar joint. AB - BACKGROUND: Distal radius malunion is a major complication of distal radius fractures, reported in 0 to 33% of cases. Corrective osteotomy to restore normal anatomy usually provides improved function and significant pain relief. We report the outcomes in a case-series with special attention to the potential influence of the initial management. MATERIAL AND METHODS: This single-centre retrospective study included 12 patients with a mean age of 35years (range, 14-60years) who were managed by different surgeons. There were 8 extra-articular fractures, including 3 with volar angulation, 2 anterior marginal fractures, and 2 intra articular T-shaped fractures; the dominant side was involved in 7/12 patients. Initial fracture management was with an anterior plate in 2 patients, Kapandji intra-focal pinning in 5 patients, plate and pin fixation in 2 patients, and non operative reduction in 3 patients. The malunion was anterior in 10 patients, including 2 with intra-articular malunion, and posterior in 2 patients. Corrective osteotomy of the radius was performed in all 12 patients between 2005 and 2012. In 11/12 patients, mean time from fracture to osteotomy was 168days (range, 45-180days). The defect was filled using an iliac bone graft in 7 patients and a bone substitute in 4 patients. No procedures on the distal radio ulnar joint were performed. RESULTS: All 12 patients were evaluated 24months after the corrective osteotomy. They showed gains in ranges not only of flexion/extension, but also of pronation/supination. All patients reported improved wrist function. The flexion/extension arc increased by 40 degrees (+21 degrees of flexion and +19 degrees of extension) and the pronation/supination arc by 46 degrees (+13 degrees of pronation and +15 degrees of supination). Mean visual analogue scale score for pain was 1.7 (range, 0-3). Complications recorded within 2years after corrective osteotomy were complex regional pain syndrome type I (n=1), radio-carpal osteoarthritis (n=3), and restricted supination due to incongruity of the distal radio-ulnar joint surfaces (n=3). This last abnormality should therefore receive careful attention during the management of distal radius malunion. DISCUSSION: In our case-series study, 3 (25%) patients required revision surgery for persistent loss of supination. The main error in these patients was failure to perform a complementary procedure on the distal radio-ulnar joint despite postoperative joint incongruity. This finding and data from a literature review warrant a high level of awareness that distal radio-ulnar joint congruity governs the outcome of corrective osteotomy for distal radius malunion. PMID- 26947733 TI - Ectopic bone formation with joint impingement after posterior lumbar fusion with rhBMP-2. AB - Recombinant human bone morphogenetic protein-2 (rhBMP-2) was recently licensed for local administration during posterior lumbar fusion. In this indication, considerable uncertainty remains about the nature and mechanisms of the many adverse effects of rhBMP-2, such as ectopic bone formation. We report a case of ectopic bone formation with impingement on a facet joint and incapacitating low back pain after minimally invasive transforaminal L5-S1 interbody fusion with local application of rhBMP-2 (InductOs((r))). Revision surgery was eventually performed to alleviate the symptoms by removing the ectopic bone. Caution is in order regarding the use of rhBMP-2 during posterior lumbar fusion. Every effort should be made to minimise the risk of complications. PMID- 26947734 TI - Clinical results of endoscopic treatment without repair for partial thickness gluteal tears. AB - INTRODUCTION: Various surgical treatments have been proposed for greater trochanteric pain syndrome (GTPS) related to gluteal tendinopathy with partial thickness tears. The clinical results of endoscopic debridement without repair of these gluteal tears are not well known. The objectives of this study were to determine if this procedure leads to: (1) reduction of pain, (2) functional improvement, (3) patient satisfaction (on scale of 0 to 10). HYPOTHESIS: Endoscopic treatment without tendon repair provides short-term pain relief in patients with GTPS due to partial thickness gluteal tears. MATERIAL AND METHODS: Seventeen patients (16 women, 1 man) with GTPS due to partial thickness gluteal tears that was present for at least 6 months and was refractory to conservative treatment were included in the analysis. The average age at the time of the procedure was 53.5years (17-71). Pain was evaluated with a visual analogue scale (VAS). Functional outcomes were defined using the Harris Hip Score and the UCLA activity score. Satisfaction was evaluated using a VAS and Odom's criteria. RESULTS: The average follow-up was 37.6months (12-48). The average preoperative and follow-up values were respectively: (1) Pain: 7.2+/-1.1 (5-9) versus 3.3+/ 1.9 (1-7) (P<0.001), (2) Harris score: 53.5+/-8.4 (36-68) versus 79.8+/-14.7 (45 96) (P<0.001). Seven patients (41.2%) were able to resume sports activities. The average satisfaction score for the surgery was 6.2+/-2.4 (0-9) at follow-up. Five patients had a poor outcome at the review: four still had pain and one had recurrence of the lateral snapping hip. CONCLUSION: Endoscopic treatment without repair of partial thickness gluteal tears is a treatment option with modest clinical results for GTPS patients refractory to conservative treatment. LEVEL OF EVIDENCE: IV, retrospective study. PMID- 26947736 TI - [Fulminant Clostridium difficile colitis]. PMID- 26947735 TI - Men in the spotlight: A rare case of penile squamous carcinoma associated with human papillomavirus (HPV) infection in a patient with ulcerative colitis (UC). PMID- 26947737 TI - African media coverage of tobacco industry corporate social responsibility initiatives. AB - Guidelines for implementing the World Health Organization's Framework Convention on Tobacco Control (FCTC) recommend prohibiting tobacco industry corporate social responsibility (CSR) initiatives, but few African countries have done so. We examined African media coverage of tobacco industry CSR initiatives to understand whether and how such initiatives were presented to the public and policymakers. We searched two online media databases (Lexis Nexis and Access World News) for all news items published from 1998 to 2013, coding retrieved items through a collaborative, iterative process. We analysed the volume, type, provenance, slant and content of coverage, including the presence of tobacco control or tobacco interest themes. We found 288 news items; most were news stories published in print newspapers. The majority of news stories relied solely on tobacco industry representatives as news sources, and portrayed tobacco industry CSR positively. When public health voices and tobacco control themes were included, news items were less likely to have a positive slant. This suggests that there is a foundation on which to build media advocacy efforts. Drawing links between implementing the FCTC and prohibiting or curtailing tobacco industry CSR programmes may result in more public dialogue in the media about the negative impacts of tobacco company CSR initiatives. PMID- 26947738 TI - Bitargeted microemulsions based on coix seed ingredients for enhanced hepatic tumor delivery and synergistic therapy. AB - A hepatic tumor bitargeted microemulsions drug delivery system using coix seed oil and coix seed polysaccharide (CP) acting as anticancer components, as well as functional excipients, was developed for enhanced tumor-specific accumulation by CP-mediated enhancement on passive tumor targeting and modification of galactose stearate (tumor-targeted ligand). In the physicochemical characteristics studies, galactose stearate-modified coix seed multicomponent microemulsions containing 30% CP (w%) (Gal-C-MEs) had a well-defined spherical shape with a small size (47.63 +/- 1.41 nm), a narrow polydispersity index (PDI, 0.101 +/- 0.002), and a nearly neutral surface charge (-4.37 +/- 1.76 mV). The half-maximal inhibitory concentration (IC50) of Gal-C-MEs against HepG2 cells was 70.2 MUg/mL, which decreased by 1.8-fold in comparison with that of coix seed multicomponent microemulsions (C-MEs). The fluorescence intensity of fluorescein isothiocyanate (FITC)-loaded Gal-C-MEs (FITC-Gal-C-MEs) internalized by HepG2 cells was 1.8-fold higher than that of FITC-loaded C-MEs (FIT C-C-MEs), but the cellular uptake of the latter became reduce by 1.6-fold when the weight ratio of CP decreased up to 10%. In the cell apoptosis studies, C-MEs (containing 30% CP) did not show a significant difference with Gal-C-MEs, but exhibited 3.3-fold and 1.5-fold increase relative to C-MEs containing 10% CP and 20% CP, respectively. In the in vivo tumor targeting studies, Cy5-loaded Gal-C-MEs (Cy5-Gal-C-MEs), notably distributed in the tumor sites and still found even at 48 h post-administration, displayed the strongest capability of tumor tissue accumulation and retention among all the test groups. Most importantly, Gal-C-MEs had stronger inhibition of tumor growth, prolonged survival time and more effectively tumor cell apoptosis induction in comparison with C-MEs containing different amounts of CP, which further confirmed that a certain amount of CP and tumor-targeted ligand were of great importance to potent anticancer efficacy. The aforementioned results suggested that Gal-C-MEs presented promising potential as a highly effective and safe anticancer drug delivery system for enhanced liver cancer delivery. PMID- 26947739 TI - Tautomerization of 2,6-lutidines in the presence of B(C6F5)3 using catecholborane as a precatalyst. AB - 2,6-Lutidine and its derivatives in the presence of B(C6F5)3 undergo tautomerization to yield the corresponding enamine.B(C6F5)3 adducts when catecholborane is applied as a precatalyst. This reaction provides a straightforward way for benzylic C-H borylation of lutidines. PMID- 26947741 TI - Radiographic Signs of Femoroacetabular Impingement Are Associated With Decreased Pelvic Incidence. AB - PURPOSE: To investigate the relation between cam, acetabular version, and pelvic incidence. METHODS: This was a retrospective analysis of 65 patients with symptomatic hip pain and radiographic signs of femoroacetabular impingement (FAI). Twenty-seven patients were used as a control. All patients received a CT scan of the pelvis that included the sacral endplate. Alpha angle, acetabular version, and pelvic incidence (PI) were measured on 2D CT. Patients were then assigned to 1 of 4 groups: control, cam (alpha angle > 55 degrees , version > 15 degrees ), retroverted (alpha angle < 55 degrees , version < 15 degrees ), or mixed (alpha angle > 55 degrees , version < 15 degrees ). RESULTS: The PI in mixed-type FAI was 46.7 degrees +/- 3.7 degrees , which showed a statistically significant decrease from the PI of the control group, 56.1 degrees +/- 4.4 degrees (P = .01). The PI for cam-only deformity was 50.8 degrees +/- 4.6 degrees , and the PI for retroverted-only deformity was 51.0 degrees +/- 4.6 degrees . Neither was statistically different from the control. CONCLUSIONS: This study suggests that mixed-type FAI may develop as a response to decreased PI. This result is consistent with previous reports showing decreased PI associated with cam and retroversion deformities. Although the cause of FAI remains controversial, the potential impact of sagittal balance of the pelvis, and specifically, decreased PI, should not be ignored. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 26947740 TI - Whole genome sequencing identifies a novel species of the genus Capnocytophaga isolated from dog and cat bite wounds in humans. AB - C. canimorsus and C. cynodegmi are dog and cat commensals which can be transmitted to humans via bites or scratches and can cause sepsis, meningitis, endocarditis, and eye- or wound infections. Recently an additional Capnocytophaga species was identified as part of the oral flora of healthy dogs and was given the name "C. canis". We previously identified a Capnocytophaga isolate that could not be typed with available diagnostic tests including MALDI-TOF, 16S rRNA sequencing or species-specific PCR. This strain and 21 other Capnocytophaga spp isolated in Sweden from clinical blood- or wound-cultures were subjected to whole genome sequencing using the Illumina platform. Phylogenetic analysis revealed that the previously non-typable isolate belongs to the putative new species "C. canis". Since this strain was isolated from a wound it also shows that members of "C. canis" have the potential to be pathogenic. In addition, our phylogenetic analysis uncovered an additional species of Capnocytophaga, which can be transmitted from dogs and cats to humans, suggesting a speciation within the Capnocytophaga family that has not been observed before. We propose the name of "C. stomatis" for this putative novel species. PMID- 26947742 TI - A Comparison of Supine and Lateral Decubitus Positions for Hip Arthroscopy: A Systematic Review of Outcomes and Complications. AB - PURPOSE: This systematic review examines outcomes and risk profiles of the hip arthroscopy in the supine versus lateral decubitus positions to elucidate any superiority of one approach over the other. METHODS: Three databases (Embase, PubMed, and Medline) were searched for studies that addressed hip arthroscopy performed in either position, and were subsequently screened by two reviewers with data abstracted in duplicate. RESULTS: Similar outcomes were observed. Supine studies showed a greater mean postoperative improvement for modified Harris hip score (33.74), visual analog scale (-3.99), nonarthritic hip score (29.61), Harris hip score (35.73), and hip outcome score (31.4). Lateral decubitus studies showed greater improvement using the Western Ontario and McMaster University Osteoarthritis (14.76) score. Supine studies reported more neuropraxic injuries (2.06% v 0.47%), labral penetration (0.65% v 0%), and heterotopic ossification (0.21% v 0%). Lateral decubitus studies reported more fluid extravasation (0.21% v 0.05%) and missed loose bodies (0.08% v 0.01%). Similar rates of revision (1.8% lateral, 1.4% supine) and conversion to open procedures (2.6% in lateral, 2.0% in supine) were also identified. CONCLUSIONS: Because of quality of evidence, direct comparisons are currently limited; however, the supine position is associated with more neuropraxic injuries, labral penetration, and heterotopic ossification, whereas lateral decubitus has increased risk of fluid extravasation and missed loose bodies. At this time, no evidence exists to establish superiority of one position. LEVEL OF EVIDENCE: Level IV, systematic review of Level II, III, and IV studies. PMID- 26947749 TI - Orientation dependent tribological behavior of TiN coatings. AB - The preferred growth direction of cathodic arc physical vapor deposition-produced TiN coatings changes from (1 1 1) to (2 2 0) with high voltage pulsed bias application in the presence of Ar gas. In this study, tribological properties of these coatings were investigated via reciprocating wear tests against an inert counterbody for observing the role of orientation on tribological properties. Friction coefficients and wear of (2 2 0) oriented coatings were observed to be significantly lower compared to (1 1 1) oriented coatings. Micro-Raman investigations of the wear debris formed during tribotest revealed clear differences between (1 1 1) and (2 2 0) oriented films. Wear debris obtained from (2 2 0) oriented coatings consisted of nc TiO2 phases (anatase and rutile) whereas (1 1 1) oriented coatings produced amorphous Ti oxides. This behavior is attributed to the orientation dependent oxidation kinetics of the coatings as verified with isothermal oxidation tests. A mechanism for improved tribological behavior is proposed based on the obtained results. PMID- 26947748 TI - Spatial distribution and source apportionment of PFASs in surface sediments from five lake regions, China. AB - Perfluoroalkyl substances (PFASs) have been found in environment globally. However, studies on PFAS occurrence in sediments of lakes or reservoirs remain relatively scarce. In this study, two hundred and sixty-two surface sediment samples were collected from forty-eight lakes and two reservoirs all over China. Average PFAS concentrations in surface sediments from each lake or reservoir varied from 0.086 ng/g dw to 5.79 ng/g dw with an average of 1.15 ng/g dw. Among five lake regions, average PFAS concentrations for the lakes from Eastern Plain Region were the highest. Perfluorooctanoic acid, perfluoroundecanoic acid and perfluorooctane sulfonic acid (PFOS) were the predominant PFASs in surface sediments. The significant positive correlations between PFAS concentrations and total organic carbon, total nitrogen and total phosphorus contents in sediments revealed the influences of sedimentary characteristics on PFAS occurrence. A two dimensional hierarchical cluster analysis heat map was depicted to analyze the possible origins of sediments and individual PFAS. The food-packaging, textile, electroplating, firefighting and semiconductor industry emission sources and the precious metals and coating industry emission sources were identified as the main sources by two receptor models, with contributions of 77.7 and 22.3% to the total concentrations of C4-C14- perfluoroalkyl carboxylic acids and PFOS, respectively. PMID- 26947750 TI - Lactate and combined parameters for triaging sepsis patients into intensive care facilities. AB - PURPOSE: To find predictors of intensive care unit (ICU) requirement within the first 48 hours in newly diagnosed sepsis patients presenting at the emergency department. MATERIALS AND METHODS: Analysis of a prospective observational cohort was performed. We recruited new sepsis patients at the emergency department, and collected baseline characteristics and parameters. Variables were compared between patients: those that required ICU within 48 hours and those that did not. Multivariate analysis was performed to identify independent predictors. RESULTS: Out of 719 patients enrolled, 275 were confirmed to have sepsis. There were 107 patients (39%) that required ICU admission within 48 hours. Independent predictors for ICU requirement were: lower body temperature (P = .019), initial lactate (P = .02), 2-hour lactate clearance (P = .035), and the Sequential Organ Failure Assessment (SOFA) score without cardiovascular component (SOFA no CVS) (P < .001). The optimal cutoff values for the two strongest predictors were: SOFA no CVS >=5 (adjusted OR, 5.3; 95% CI, 1.9-14.7) and initial lactate >=1.9 mmol/L (adjusted OR, 3.3; 95% CI, 1.2-8.9). We also proposed a combined "LACTIC score" with higher predictive ability. CONCLUSIONS: We suggested a way to predict ICU requirement in sepsis patients and proposed a combined score that might be better than individual parameters. Further validation should be performed before using them clinically. PMID- 26947752 TI - Response to "Comment on "Conformational analysis of small organic molecules using NOE and RDC data: A discussion of strychnine and alpha-methylene-gamma butyrolactone" by I.A. Khodov, M.G. Kiselev, V.V. Klochkov, S.V. Efimov [http://dx.doi.org/10.1016/j.jmr.2016.02.009]" - Or Life is about compromises. PMID- 26947753 TI - Slow-moving and far-travelled dense pyroclastic flows during the Peach Spring super-eruption. AB - Explosive volcanic super-eruptions of several hundred cubic kilometres or more generate long run-out pyroclastic density currents the dynamics of which are poorly understood and controversial. Deposits of one such event in the southwestern USA, the 18.8 Ma Peach Spring Tuff, were formed by pyroclastic flows that travelled >170 km from the eruptive centre and entrained blocks up to ~ 70 90 cm diameter from the substrates along the flow paths. Here we combine these data with new experimental results to show that the flow's base had high-particle concentration and relatively modest speeds of ~ 5-20 m s(-1), fed by an eruption discharging magma at rates up to ~ 10(7)-10(8) m(3) s(-1) for a minimum of 2.5-10 h. We conclude that sustained high-eruption discharge and long-lived high-pore pressure in dense granular dispersion can be more important than large initial velocity and turbulent transport with dilute suspension in promoting long pyroclastic flow distance. PMID- 26947751 TI - Influence of aging on the quantity and quality of human cardiac stem cells. AB - Advanced age affects various tissue-specific stem cells and decreases their regenerative ability. We therefore examined whether aging affected the quantity and quality of cardiac stem cells using cells obtained from 26 patients of various ages (from 2 to 83 years old). We collected fresh right atria and cultured cardiosphere-derived cells (CDCs), which are a type of cardiac stem cell. Then we investigated growth rate, senescence, DNA damage, and the growth factor production of CDCs. All samples yielded a sufficient number of CDCs for experiments and the cellular growth rate was not obviously associated with age. The expression of senescence-associated b-galactosidase and the DNA damage marker, gH2AX, showed a slightly higher trend in CDCs from older patients (>= 65 years). The expression of VEGF, HGF, IGF-1, SDF-1, and TGF-b varied among samples, and the expression of these beneficial factors did not decrease with age. An in vitro angiogenesis assay also showed that the angiogenic potency of CDCs was not impaired, even in those from older patients. Our data suggest that the impact of age on the quantity and quality of CDCs is quite limited. These findings have important clinical implications for autologous stem cell transplantation in elderly patients. PMID- 26947754 TI - Photo-induced transformation process at gold clusters-semiconductor interface: Implications for the complexity of gold clusters-based photocatalysis. AB - The recent thrust in utilizing atomically precise organic ligands protected gold clusters (Au clusters) as photosensitizer coupled with semiconductors for nano catalysts has led to the claims of improved efficiency in photocatalysis. Nonetheless, the influence of photo-stability of organic ligands protected-Au clusters at the Au/semiconductor interface on the photocatalytic properties remains rather elusive. Taking Au clusters-TiO2 composites as a prototype, we for the first time demonstrate the photo-induced transformation of small molecular like Au clusters to larger metallic Au nanoparticles under different illumination conditions, which leads to the diverse photocatalytic reaction mechanism. This transformation process undergoes a diffusion/aggregation mechanism accompanied with the onslaught of Au clusters by active oxygen species and holes resulting from photo-excited TiO2 and Au clusters. However, such Au clusters aggregation can be efficiently inhibited by tuning reaction conditions. This work would trigger rational structural design and fine condition control of organic ligands protected-metal clusters-semiconductor composites for diverse photocatalytic applications with long-term photo-stability. PMID- 26947757 TI - Platinum complexes bearing normal and mesoionic N-heterocyclic carbene based pincer ligands: syntheses, structures, and photo-functional attributes. AB - Platinum complexes featuring pyridine bis-N-heterocyclic-imidazol-2-ylidene/ mesoionic-triazol-5-ylidene donors as pincer ligands and chloro (-Cl), acetonitrile (-NCCH3) or cyano (-CN) groups as auxiliary ligands are prepared as highly strained organometallic phosphors. X-ray structures of four of these complexes confirm a distorted square planar geometry, where the pincer ligand and its mesityl wingtips occur in a twisted conformation to each other. Electrochemical and photophysical characterization have been carried out and the experimental results are interpreted with the aid of density functional theory calculations. Emission responses of complexes under exposure to different vapors and mechanical shear are reported. Notably, the platinum complex featuring pyridine bis-imidazol-2-ylidene and a weakly donating acetonitrile auxiliary ligand exhibited strong aquachromic and mechanochromic emission responses, showing color changes from sky blue to green or yellow-green. PMID- 26947756 TI - The identification of metabolic disturbances in the prefrontal cortex of the chronic restraint stress rat model of depression. AB - Major depressive disorder, with serious impairment in cognitive and social functioning, is a complex psychiatric disorder characterized by pervasive and persistent low mood and a loss of interest or pleasure. However, the underlying molecular mechanisms of depression remain largely unknown. In this study, we used a non-targeted metabolomics approach based on gas chromatography-mass spectrometry of the prefrontal cortex in chronic restraint stress (CRS)-treated rats. CRS was induced in the stress group by restraining rats in a plastic restrainer for 6h every day. This stress paradigm continued for 21 days. Body weight measurement and behavior tests were applied, including the sucrose preference test for anhedonia, the forced swimming test for despair-like behavior, and open field test and the elevated plus-maze to test for anxiety-like behaviors in rats after CRS. Differentially expressed metabolites associated with CRS-treated rats were identified by combining multivariate and univariate statistical analysis and corrected for multiple testing using the Benjamini Hochberg procedure. A heat map of differential metabolites was constructed using Matlab. Ingenuity Pathways Analysis was applied to identify the predicted pathways and biological functions relevant to the bio-molecules of interest. Our findings showed that CRS induces depression-like behaviors and not anxiety-like behaviors. Thirty-six metabolites were identified as potential depression biomarkers involved in amino acid metabolism, energy metabolism and lipid metabolism, as well as a disturbance in neurotransmitters. Consequently, this study provides useful insights into the molecular mechanisms of depression. PMID- 26947755 TI - The medial preoptic area modulates cocaine-induced locomotion in male rats. AB - Cocaine-induced locomotion is mediated by dopamine in the nucleus accumbens (NAc). Recent evidence indicates that the medial preoptic area (mPOA), a region in the rostral hypothalamus, modulates cocaine-induced dopamine in the NAc. Specifically, rats with lesions of the mPOA experienced a greater increase in dopamine following cocaine administration than rats with sham lesions. Whether the mPOA similarly influences cocaine-induced locomotion is not known. Here we examined whether radiofrequency or neurotoxic lesions of the mPOA in male rats influence changes in locomotion that follow cocaine administration. Locomotion was measured following cocaine administration in male rats with neurotoxic, radiofrequency, or sham lesions of the mPOA. Results indicate that bilateral lesions of the mPOA facilitated cocaine-induced locomotion. This facilitation was independent of lesion type, as increased locomotion was observed with either approach. These findings support a role for the mPOA as an integral region in the processing of cocaine-induced behavioral response, in this case locomotor activity. PMID- 26947758 TI - Peptidomics of Peptic Digest of Selected Potato Tuber Proteins: Post Translational Modifications and Limited Cleavage Specificity. AB - Bioinformatic tools are useful in predicting bioactive peptides from food proteins. This study was focused on using bioinformatics and peptidomics to evaluate the specificity of peptide release and post-translational modifications (PTMs) in a peptic digest of potato protein isolate. Peptides in the protein hydrolysate were identified by LC-MS/MS and subsequently aligned to their parent potato tuber proteins. Five major proteins were selected for further analysis, namely, lipoxygenase, alpha-1,4-glucan phosphorylase, annexin, patatin, and polyubiquitin, based on protein coverage, abundance, confidence levels, and function. Comparison of the in silico peptide profile generated with ExPASy PeptideCutter and experimental peptidomics data revealed several differences. The experimental peptic cleavage sites were found to vary in number and specificity from PeptideCutter predictions. Average peptide chain length was also found to be higher than predicted with hexapeptides as the smallest detected peptides. Moreover, PTMs, particularly Met oxidation and Glu/Asp deamidation, were observed in some peptides, and these were unaccounted for during in silico analysis. PTMs can be formed during aging of potato tubers, or as a result of processing conditions during protein isolation and hydrolysis. The findings provide insights on the limitations of current bioinformatics tools for predicting bioactive peptide release from proteins, and on the existence of structural modifications that can alter the peptide bioactivity and functionality. PMID- 26947759 TI - Behavioral Analysis of Dopaminergic Activation in Zebrafish and Rats Reveals Similar Phenotypes. AB - Zebrafish is emerging as a complement to mammals in behavioral studies; however, there is a lack of comparative studies with rodents and humans to establish the zebrafish as a predictive translational model. Here we present a detailed phenotype evaluation of zebrafish larvae, measuring 300-3000 variables and analyzing them using multivariate analysis to identify the most important ones for further evaluations. The dopamine agonist apomorphine has previously been shown to have a complex U-shaped dose-response relationship in the variable distance traveled. In this study, we focused on breaking down distance traveled into more detailed behavioral phenotypes for both zebrafish and rats and identified in the multivariate analysis low and high dose phenotypes with characteristic behavioral features. Further analysis of single parameters also identified an increased activity at the lowest concentration indicative of a U shaped dose-response. Apomorphine increased the distance of each swim movement (bout) at both high and low doses, but the underlying behavior of this increase is different; at high dose, both bout duration and frequency increased whereas bout max speed was higher at low dose. Larvae also displayed differences in place preference. The low dose phenotype spent more time in the center, indicative of an anxiolytic effect, while the high-dose phenotype had a wall preference. These dose-dependent effects corroborated findings in a parallel rat study and previous observations in humans. The translational value of pharmacological zebrafish studies was further evaluated by comparing the amino acid sequence of the dopamine receptors (D1-D4), between zebrafish, rats and humans. Humans and zebrafish share 100% of the amino acids in the binding site for D1 and D3 whereas D2 and D4 receptors share 85-95%. Molecular modeling of dopamine D2 and D4 receptors indicated that nonconserved amino acids have limited influence on important ligand-receptor interactions. PMID- 26947760 TI - Development and Evaluation of a Novel Drug Delivery: Pluronics/SDS Mixed Micelle Loaded With Myricetin In Vitro and In Vivo. AB - This study is to prepare and evaluate Pluronics-modified mixed micelle (MM) to deliver polyphenolic myricetin (MYR) across the blood-brain barrier. MYR has been proven to be an effective anticancer agent against glioblastoma cells in our previous studies. However, the poor solubility of MYR limits its access to the brain. In this study, the feasibility of preparing lipid-based MM that combined sodium dodecyl sulphate (SDS) with Pluronic F68 (F68) and Labrasol was investigated. Furthermore, the nonionic surfactant coating technology for the protection of MYR against oxidation, and its attainment in oral bioavailability, was examined. On account of the altered biomaterial properties of F68/SDS modified lipid-based micelles, myricetin-loaded mixed micelles (MYR-MMs) were prepared by solvent-evaporation method to self-assembly into MMs. The average size of MYR-MMs was 96.3 nm, with negatively charged potential and spherical in shape. The drug loading of MYR-MMs was high with the increased grafting ratio, the more prolonged drug release profile, and more effective killing glioblastoma cells in vitro. Moreover, MYR-MMs showed a higher preference for the brain than free MYR alone, suggesting the novel MMs loaded with MYR could promote absorption and increase relative bioavailability. Taken together, the F68/SDS-modified and Labrasol-modified lipid-based micelles may provide a promising method to deliver polyphenolic compounds across the brain to treat brain tumor. PMID- 26947764 TI - Influence of cyclosporine A on glomerular growth and the effect of mizoribine and losartan on cyclosporine nephrotoxicity in young rats. AB - The aim of this study was to evaluate the influence of cyclosporine A (CsA) on glomerular growth and the effect of mizoribine (MZR) and losartan (LSAR) on CsA induced nephropathy in young rats. Six-week-old male Sprague-Dawley rats maintained on a low salt diet were given CsA (15 mg/kg), CsA and LSRT (30 mg/kg/day), CsA and MZR (5 mg/kg), or a combination of CsA, LSRT, and MZR for 4 and 7 weeks (two experiments) and compared with control group (olive oil treated). Histopathology and glomerular size, inflammatory and fibrotic factors were studied. The score of acute CsA toxicity significantly decreased in the CsA + MZR group compared to the CsA group (p < 0.01). MZR and MZR + LSRT reduced tubulointerstitial fibrosis and TGF-beta1 mRNA expression at 7 weeks. Osteopontin (OPN) mRNA expression was decreased at 7 weeks in MZR + LSRT (p < 0.01). Glomerular area decreased CsA group and recovered in MZR (p < 0.01) and MZR + LSRT (p < 0.01) at 7 weeks. This study demonstrated that MZR and LSRT had suppressive effects on inflammatory process in chronic CsA nephropathy and led to improvement of tubular damage, tubulointerstitial fibrosis and arteriolopathy by down regulation of OPN and TGF-beta1 and glomerular size contraction. PMID- 26947765 TI - Production of highly bioactive resveratrol analogues pterostilbene and piceatannol in metabolically engineered grapevine cell cultures. AB - Grapevine stilbenes, particularly trans-resveratrol, have a demonstrated pharmacological activity. Other natural stilbenes derived from resveratrol such as pterostilbene or piceatannol, display higher oral bioavailability and bioactivity than the parent compound, but are far less abundant in natural sources. Thus, to efficiently obtain these bioactive resveratrol derivatives, there is a need to develop new bioproduction systems. Grapevine cell cultures are able to produce large amounts of easily recoverable extracellular resveratrol when elicited with methylated cyclodextrins and methyl jasmonate. We devised this system as an interesting starting point of a metabolic engineering-based strategy to produce resveratrol derivatives using resveratrol-converting enzymes. Constitutive expression of either Vitis vinifera resveratrol O-methyltransferase (VvROMT) or human cytochrome P450 hydroxylase 1B1 (HsCYP1B1) led to pterostilbene or piceatannol, respectively, after the engineered cell cultures were treated with the aforementioned elicitors. Functionality of both gene products was first assessed in planta by Nicotiana benthamiana agroinfiltration assays, in which tobacco cells transiently expressed stilbene synthase and VvROMT or HsCYP1B1. Grapevine cell cultures transformed with VvROMT produced pterostilbene, which was detected in both intra- and extracellular compartments, at a level of micrograms per litre. Grapevine cell cultures transformed with HsCYP1B1 produced about 20 mg/L culture of piceatannol, displaying a sevenfold increase in relation to wild type cultures, and reaching an extracellular distribution of up to 45% of total production. The results obtained demonstrate the feasibility of this novel system for the bioproduction of natural and more bioactive resveratrol derivatives and suggest new ways for the improvement of production yields. PMID- 26947766 TI - The new liver allocation score for transplantation is validated and improved transplant survival benefit in Germany but not in the United Kingdom. AB - Prognostic models for the prediction of 90-day mortality after transplantation with pretransplant donor and recipient variables are needed to calculate transplant benefit. Transplants in adult recipients in Germany (Hannover, n = 770; Kiel, n = 234) and the United Kingdom (Birmingham, n = 829) were used for prognostic model design and validation in separate training and validation cohorts. The survival benefit of transplantation was estimated by subtracting the observed posttransplant 90-day mortality from the expected 90-day mortality without transplantation determined by the Model for End-Stage Liver Disease (MELD) score. A prognostic model called the liver allocation score (LivAS) was derived using a randomized sample from Hannover using pretransplant donor and recipient variables. This model could be validated in the German training and validation cohorts (area under the receiver operating characteristic curve [AUROC] > 0.70) but not in the English cohort (AUROC, 0.58). Although 90-day mortality rates after transplantation were 13.7% in Hannover, 12.1% in Kiel, and 8.3% in Birmingham, the calculated 90-day survival benefits of transplantation were 6.8% in Hannover, 7.8% in Kiel, and 2.8% in Birmingham. Deployment of the LivAS for limiting allocation to donor and recipient combinations with likely 90 day survival as indicated by pretransplant LivAS values below the cutoff value would have increased the survival benefit to 12.9% in the German cohorts, whereas this would have decreased the benefit in England to 1.3%. The English and German cohorts revealed significant differences in 21 of 28 pretransplant variables. In conclusion, the LivAS could be validated in Germany and may improve German allocation policies leading to greater survival benefits, whereas validation failed in England due to profound differences in the selection criteria for liver transplantation. This study suggests the need for national prognostic models. Even though the German centers had higher rates of 90-day mortality, estimated survival benefits were greater. Liver Transplantation 22 743-756 2016 AASLD. PMID- 26947767 TI - Albumin Nanoparticles for Brain Delivery: A Comparison of Chemical versus Thermal Methods and in vivo Behavior. AB - Human serum albumin nanoparticles (NPs) have gained considerable attention owing to their high loading capacity for various drugs and the fact that they are well tolerated. The aim of this work was to investigate two different methods to produce NPs without the use of organic solvents and to obtain useful drug delivery systems to cross the blood-brain barrier. NPs were obtained by coacervation, using both chemical and thermal cross-linking processes. They were developed and optimized to target brain tissues after parenteral administration in healthy rats. Furthermore, their distribution, cellular uptake, and fate were investigated in vivo after intracerebral injection in healthy rats. The toxicity of the developed carriers was estimated by behavioral tests. All NPs were chemically and physically characterized by dynamic light scattering, transmission electron microscopy, and high-performance liquid chromatography coupled with diode array and fluorimetric detectors. Their distribution and fate in the brain were evaluated by fluorescence microscopy. NPs were observed to be located in different brain tissues depending on the mode of injection, and did not induce an inflammatory response. Behavioral tests demonstrated no locomotor, explorative, or cognitive function impairment induced by the NPs. PMID- 26947768 TI - Repeated significance tests of linear combinations of sensitivity and specificity of a diagnostic biomarker. AB - A sequential design is proposed to test whether the accuracy of a binary diagnostic biomarker meets the minimal level of acceptance. The accuracy of a binary diagnostic biomarker is a linear combination of the marker's sensitivity and specificity. The objective of the sequential method is to minimize the maximum expected sample size under the null hypothesis that the marker's accuracy is below the minimal level of acceptance. The exact results of two-stage designs based on Youden's index and efficiency indicate that the maximum expected sample sizes are smaller than the sample sizes of the fixed designs. Exact methods are also developed for estimation, confidence interval and p-value concerning the proposed accuracy index upon termination of the sequential testing. Published 2016. This article is a U.S. Government work and is in the public domain in the USA. PMID- 26947769 TI - Post-transplantation cyclophosphamide versus conventional graft-versus-host disease prophylaxis in mismatched unrelated donor haematopoietic cell transplantation. AB - Post-transplantation cyclophosphamide (PTCy) is an effective strategy to prevent graft-versus-host disease (GVHD) after haploidentical haematopoietic cell transplantation (HCT). We determined the efficacy of PTCy-based GVHD prophylaxis in human leucocyte antigen (HLA)-mismatched unrelated donor (MMUD) HCT. We analysed 113 adult patients with high-risk haematological malignancies who underwent one-antigen MMUD transplantation between 2009 and 2013. Of these, 41 patients received PTCy, tacrolimus and mycophenolate mofetil (MMF) for GVHD prophylaxis; 72 patients received conventional prophylaxis with anti-thymocyte globulin, tacrolimus and methotrexate. Graft source was primarily bone marrow (83% PTCy vs. 63% conventional group). Incidence of grade II-IV (37% vs. 36%, P = 0.8) and grade III-IV (17% vs. 12%, P = 0.5) acute GVHD was similar at day 100. However, the incidence of grade II-IV acute GVHD by day 30 was significantly lower in the PTCy group (0% vs. 15%, P = 0.01). Median time to neutrophil (18 days vs. 12 days, P < 0.001) and platelet (25.5 days vs. 18 days, P = 0.05) engraftment was prolonged in PTCy group. Rates of graft failure, chronic GVHD, 2 year non-relapse mortality, relapse, progression-free survival or overall survival were similar. Our results demonstrate that PTCy, tacrolimus and MMF for GVHD prophylaxis is safe and produced similar results as conventional prophylaxis in patients with one antigen HLA-MMUD HCT. PMID- 26947770 TI - Influence of initial insulin dosage on blood glucose dynamics of children and adolescents with newly diagnosed type 1 diabetes mellitus. AB - OBJECTIVE: To investigate the effect of initial insulin dosage on blood glucose (BG) dynamics, beta-cell protection, and oxidative stress in type 1 diabetes mellitus. METHODS: Sixty newly diagnosed type 1 diabetes mellitus patients were randomly assigned to continuous subcutaneous insulin infusions of 0.6 +/- 0.2 IU/kg/d (group 1), 1.0 +/- 0.2 IU/kg/d (group 2), or 1.4 +/- 0.2 IU/kg/d (group 3) for 3 wk. BG was monitored continuously for the first 10 d and the last 2 d of wk 2 and 3. A total of 24-hour urinary 8-iso-PGF2alpha was assayed on days 8, 9, and 10. The occurrence and duration of the honeymoon period were recorded. Fasting C-peptide and glycosylated hemoglobin (HbA1c) were assayed after 1, 6, and 12 months of insulin treatment. RESULTS: BG decreased to the target range by the end of wk 3 (group 1), wk 2 (group 2), or wk 1 (group 3). The actual insulin dosage over the 3 wk, frequency of hypoglycemia on wk 1 and 2, and median BG at the end of wk 1 differed significantly, but not 8-iso-PGF2alpha and the honeymoon period in the three groups. No severe hypoglycemia event was observed in any patient, but there was significant difference in the first occurrence of hypoglycemia. CONCLUSIONS: Differences in initial insulin dosage produced different BG dynamics in wk 1, equivalent BG dynamics on wk 2 and 3, but had no influence on short- and long-term BG control and honeymoon phase. The wide range of initial insulin dosage could be chosen if guided by BG monitoring. PMID- 26947771 TI - Impact of fraction unbound, CYP3A, and CYP2D6 in vivo activities, and other potential covariates to the clearance of tramadol enantiomers in patients with neuropathic pain. AB - The pharmacokinetics of tramadol is characterized by a large interindividual variability, which is partially attributed to polymorphic CYP2D6 metabolism. The contribution of CYP3A, CYP2B6, fraction unbound, and other potential covariates remains unknown. This study aimed to investigate the contribution of in vivo activities of cytochrome P450 (CYP) 2D6 and 3A as well as other potential covariates (CYP2B6 genotype to the SNP g.15631G>T, fraction unbound, age, body weight, creatinine clearance) to the enantioselective pharmacokinetics of tramadol. Thirty patients with neuropathic pain and phenotyped as CYP2D6 extensive metabolizers were treated with a single oral dose of 100 mg tramadol. Multiple linear regressions were performed to determine the contribution of CYP activities and other potential covariates to the clearance of tramadol enantiomers. The apparent total clearances were 44.9 (19.1-102-2) L/h and 55.2 (14.8-126.0) L/h for (+)- and (-)-tramadol, respectively [data presented as median (minimum-maximum)]. Between 79 and 83% of the overall variation in apparent clearance of tramadol enantiomers was explained by fraction unbound, CYP2D6, and CYP3A in vivo activities and body weight. Fraction unbound explained 47 and 41% of the variation in clearance of (+)-tramadol and (-)-tramadol, respectively. Individually, CYP2D6 and CYP3A activities were shown to have moderate contribution on clearance of tramadol enantiomers (11-16% and 11-18%, respectively). In conclusion, factors affecting fraction unbound of drugs (such as hyperglycemia or co-administration of drugs highly bound to plasma proteins) should be monitored, because this parameter dominates the elimination of tramadol enantiomers. PMID- 26947773 TI - Effects of fenugreek seed extract supplementation on growth performance, nutrient digestibility, diarrhoea scores, blood profiles, faecal microflora and faecal noxious gas emission in weanling piglets. AB - This study was conducted to evaluate the effect of dietary fenugreek seed extract (FSE) on growth performance, apparent total tract digestibility (ATTD), diarrhoea scores, blood profiles, faecal microflora and faecal gas emission in weanling pigs. A total of 135 weanling pigs [(Yorkshire * Landrace) * Duroc] with an average BW of (7.96 +/- 1.03 kg; 28 days of age) were used in a 42-day study. Piglets were randomly allotted to three experimental diets with nine replicate pens and five pigs per pen. Dietary treatments were as follows: CON, basal diet; FSE1, basal diet + 0.1% FSE; FSE2, basal diet + 0.2% FSE. Pigs were fed with phase 1 (0-14 days) and phase 2 (14-42 days) diets in the form of mash. Average daily gain (ADG) was linearly increased (p = 0.031) by FSE supplementation compared with CON diet during days 0-14. From days 14-42, FSE2 diet had increased ADG and growth efficiency (G/F) compared with the CON diet (p = 0.014 and 0.026 respectively). Moreover, ADG and G/F were increased by FSE supplementation during days 0-42 (linear, p = 0.037 and 0.014 respectively). Energy digestibility was higher (linear, p = 0.030) by FSE supplementation at 6 weeks. On day 42, dietary supplementation of FSE linearly increased red blood cells (RBC) and immunoglobulin G (IgG) concentration (p = 0.042 and 0.038 respectively). Piglets fed FSE2 diet had higher (linear, p = 0.025) serum high-density lipoprotein cholesterol (HDL-C) concentration compared with those fed CON diet. However, piglets fed FSE2 diet had linearly reduced faecal ammonia (NH3 ) and hydrogen sulphide (H2 S) gas emission compared with those fed the CON diet (p = 0.018 and 0.010 respectively). In conclusion, FSE supplementation increased the performance and reduced faecal gas emission in weanling pigs. PMID- 26947772 TI - Structural characterization of NRAS isoform 5. AB - It was recently discovered that the NRAS isoform 5 (20 amino acids) is expressed in melanoma and results in a more aggressive cell phenotype. This novel isoform is responsible for increased phosphorylation of downstream targets such as AKT, MEK, and ERK as well as increased cellular proliferation. This structure report describes the NMR solution structure of NRAS isoform 5 to be used as a starting point to understand its biophysical interactions. The isoform is highly flexible in aqueous solution, but forms a helix-turn-coil structure in the presence of trifluoroethanol as determined by NMR and CD spectroscopy. PMID- 26947774 TI - Early radiation-induced liver toxicities are associated with poor survival in patients with advanced hepatocellular carcinoma. AB - AIM: Little is known about the impact of radiotherapy associated early hepatic toxicities. This study is to investigate the risk factors and outcome of early radiation-induced liver disease (early-RILD) in patients with hepatocellular carcinoma. METHODS: One hundred patients with advanced hepatocellular carcinoma receiving hepatic radiotherapy were included in this retrospective analysis. All had no evidence of intrahepatic tumor progression within 3 months after initiating radiotherapy. The toxicities were graded according to the Common Terminology Criteria for adverse events version 4.0. Early-RILD was defined as any detectable events of RILD occurring during or within 2 weeks after the ending of radiotherapy. Patient- and radiotherapy-related data, and several staging/scoring parameters were retrieved for analysis. Logistic regression analysis was used to find risk factors for early-RILD. Cox regression model was performed to explore prognosticators for survival. RESULTS: Child-Turcotte-Pugh (CTP) score >5 was the predictor for early-RILD (odds ratio 5.38, P = 0.004). The incidence of early-RILD in patients with CTP scores 6/7 and 5 was 34% and 13.2%, respectively. Early-RILD and a Cancer of the Liver Italian Program (CLIP) score > 2 were the two prognostic factors associated with inferior overall survival (hazard ratio 2.79, P = 0.04; hazard ratio = 3.79, P = 0.04, respectively). The median overall survival for patients with early-RILD was 3.5 months compared with 12.7 months in those without this event. CONCLUSION: The occurrence of early-RILD is associated with high mortality. A CTP score >5 is the most informative factor predicting early-RILD. PMID- 26947775 TI - A formulation of the foundations of genetics and evolution. AB - This paper proposes a formulation of theories of the foundations of genetics and evolution that can be used to mathematically simulate phenotype expression, reproduction, mutation, and natural selection. It will be shown that Mendelian inheritance can be mathematically simulated with expressions involving matrices and that these expressions can also simulate phenomena that are modifications to Mendel's basic principles, like alleles that give rise to quantitative effects and traits that are the expression of multiple alleles and/or multiple genetic loci. PMID- 26947777 TI - Immune-Regulatory Mechanisms of Classical and Experimental Multiple Sclerosis Drugs: A Special Focus on Helminth-Derived Treatments. AB - Multiple sclerosis (MS) is the most prevalent autoimmune disease affecting the central nervous system (CNS). Its pathophysiology is centered on neuron myelin sheath destruction in a manner largely dependent upon CD4+/CD8+ T-cell autoreactivity against myelin antigens, inducing Th1/Th17 pathogenic responses with the resulting production of free radicals and soluble mediators that exhibit the effector mechanisms of neurodegeneration. The immune response responsible for this disease is complex and challenges modern medicine. Consequently, many experimental therapies have been proposed in addition to the classical array of immunoregulatory/ immunosuppressive drugs that are normally used to treat MS. In this review, we will describe the effects and mechanisms of action of widely used disease-modifying MS drugs as well as those of select treatments that are currently in the experimental phase. Special emphasis is placed on helminth derived immunoregulators, as some of them have shown promising results. Additionally, we will compare the mechanisms of action of both the MS drugs and the helminth-derived treatments to discuss the potential importance of some signaling pathways in the control of MS. PMID- 26947776 TI - Current Advances in Developing Inhibitors of Bacterial Multidrug Efflux Pumps. AB - Antimicrobial resistance represents a significant challenge to future healthcare provision. An acronym ESKAPEE has been derived from the names of the organisms recognised as the major threats although there are a number of other organisms, notably Neisseria gonorrhoeae, that have become equally challenging to treat in the clinic. These pathogens are characterised by the ability to rapidly develop and/or acquire resistance mechanisms in response to exposure to different antimicrobial agents. A key part of the armoury of these pathogens is a series of efflux pumps, which effectively exclude or reduce the intracellular concentration of a large number of antibiotics, making the pathogens significantly more resistant. These efflux pumps are the topic of considerable interest, both from the perspective of basic understanding of efflux pump function, and its role in drug resistance but also as targets for the development of novel adjunct therapies. The necessity to overcome antimicrobial resistance has encouraged investigations into the characterisation of resistance-modifying efflux pump inhibitors to block the mechanisms of drug extrusion, thereby restoring antibacterial susceptibility and returning existing antibiotics into the clinic. A greater understanding of drug recognition and transport by multidrug efflux pumps is needed to develop clinically useful inhibitors, given the breadth of molecules that can be effluxed by these systems. This review discusses different bacterial EPIs originating from both natural source and chemical synthesis and examines the challenges to designing successful EPIs that can be useful against multidrug resistant bacteria. PMID- 26947779 TI - Chiropteran influenza viruses: flu from bats or a relic from the past? AB - The identification of influenza A-like genomic sequences in bats suggests the existence of distinct lineages of chiropteran influenza viruses in South and Central America. These viruses share similarities with conventional influenza A viruses but lack the canonical receptor-binding property and neuraminidase function. The inability to isolate infectious bat influenza viruses impeded further studies, however, reverse genetic analysis provided new insights into the molecular biology of these viruses. In this review, we highlight the recent developments in the field of the newly discovered bat-derived influenza A-like viruses. We also discuss whether bats are a neglected natural reservoir of influenza viruses, the risk associated with bat influenza viruses for humans and whether these viruses originate from the pool of avian IAV or vice versa. PMID- 26947780 TI - Utilizing Big Data for Public Health. PMID- 26947778 TI - Scalp Hematoma Characteristics Associated With Intracranial Injury in Pediatric Minor Head Injury. AB - OBJECTIVES: Minor head trauma accounts for a significant proportion of pediatric emergency department (ED) visits. In children younger than 24 months, scalp hematomas are thought to be associated with the presence of intracranial injury (ICI). We investigated which scalp hematoma characteristics were associated with increased odds of ICI in children less than 17 years who presented to the ED following minor head injury and whether an underlying linear skull fracture may explain this relationship. METHODS: This was a secondary analysis of 3,866 patients enrolled in the Canadian Assessment of Tomography of Childhood Head Injury (CATCH) study. Information about scalp hematoma presence (yes/no), location (frontal, temporal/parietal, occipital), and size (small and localized, large and boggy) was collected by emergency physicians using a structured data collection form. ICI was defined as the presence of an acute brain lesion on computed tomography. Logistic regression analyses were adjusted for age, sex, dangerous injury mechanism, irritability on examination, suspected open or depressed skull fracture, and clinical signs of basal skull fracture. RESULTS: ICI was present in 159 (4.1%) patients. The presence of a scalp hematoma (n = 1,189) in any location was associated with significantly greater odds of ICI (odds ratio [OR] = 4.4, 95% confidence interval [CI] = 3.06 to 6.02), particularly for those located in temporal/parietal (OR = 6.0, 95% CI = 3.9 to 9.3) and occipital regions (OR = 5.6, 95% CI = 3.5 to 8.9). Both small and localized and large and boggy hematomas were significantly associated with ICI, although larger hematomas conferred larger odds (OR = 9.9, 95% CI = 6.3 to 15.5). Although the presence of a scalp hematoma was associated with greater odds of ICI in all age groups, odds were greatest in children aged 0 to 6 months (OR = 13.5, 95% CI = 1.5 to 119.3). Linear skull fractures were present in 156 (4.0%) patients. Of the 111 patients with scalp hematoma and ICI, 57 (51%) patients had a linear skull fracture and 54 (49%) did not. The association between scalp hematoma and ICI attenuated but remained significant after excluding patients with linear skull fracture (OR = 3.3, 95% CI = 2.1 to 5.1). CONCLUSIONS: Large and boggy and nonfrontal scalp hematomas had the strongest association with the presence of ICI in this large pediatric cohort. Although children 0 to 6 months of age were at highest odds, the presence of a scalp hematoma also independently increased the odds of ICI in older children and adolescents. The presence of a linear skull fracture only partially explained this relation, indicating that ruling out a skull fracture beneath a hematoma does not obviate the risk of intracranial pathology. PMID- 26947781 TI - Modern management of intracranial aneurysms. PMID- 26947782 TI - Retractorless surgery for intracranial aneurysms. AB - Microsurgical clipping of intracranial aneurysms often requires access to the subarachnoid space deep in the brain. In the past, fixed retractors have been used to maintain the surgical corridor. However, studies have shown that fixed retraction leads to brain injuries. Here we present strategies to replace conventional fixed retractor blades with dynamic retraction so that the brain is no longer under constant pressure. We show that dynamic retraction without fixed retractors, when combined with optimal patient position and neuroprotective anesthetics, can provide the surgeon with adequate visualization of aneurysms and the patient with excellent surgical outcomes. PMID- 26947783 TI - The role of extra- and intracranial bypass in the treatment of complex aneurysms. AB - The availability of flow diverters and new endovascular techniques has greatly reduced the need and indications for bypass surgery. Nevertheless, there are situations where a bypass is the best option for a complex cerebrovascular problem. Generally, typical indications are giant aneurysms with a wide neck and/or partially calcified aneurysms with main branches or perforating arteries arising directly from the sac or from the neck itself, or fusiform aneurysms, partially calcified aneurysms. In this paper we discuss the following issues as they apply to the modern use of bypass techniques. In case of fusiform aneurysms involving the proximal bifurcations of the media or the internal carotid artery combined and coordinated evaluations and efforts by a team which includes neurosurgeons and endovascular specialists is essential. Treatment with bypass alone may not be sufficient and the combination of one or more bypasses with an endovascular treatment of occlusion, partial aneurysm embolization or flow diversion may be the best strategy. Addressing complex and fusiform aneurysm surgery requires a problem solving attitude and in this lies both the challenging and the fun side of this surgery. PMID- 26947784 TI - Minimally invasive pedicle-based non-fusion stabilization of the lumbar spine. PMID- 26947785 TI - Evidence-based review of epidural adhesiolysis is misleading. PMID- 26947786 TI - Double circle of the base: the unique variation of the circle of Willis anatomy. PMID- 26947787 TI - Misdiagnosed atypical Lemierre's Syndrome: what a neurosurgeon has to know. PMID- 26947788 TI - Benign thoracic dumbbell tumor can be removed through hemilaminectomy and facetectomy without spinal reconstruction. PMID- 26947789 TI - Long-term clinical and functional impact of biliopancreatic diversion on type 2 diabetes in morbidly and non-morbidly obese patients. AB - SETTING: Obesity surgery has been proposed as a treatment option for diabetic patients with body mass index (BMI)<35 kg/m(2), but the efficacy of metabolic surgery has not been conclusively determined. OBJECTIVES: To evaluate the long term metabolic outcome of non-morbidly obese (NMO) patients with type 2 diabetes (T2D) after biliopancreatic diversion (BPD). MATERIAL AND METHODS: Two groups of T2D patients with different degree of obesity (NMO, 17 cases, BMI 25-35 kg/m(2); and morbidly obese [MO], 13 cases, BMI>35 kg/m(2)) were studied before and at 1 and 5 years after BPD in a university hospital setting. Insulin secretion was assessed by acute insulin response (AIR) to intravenous glucose and by insulinogenic index (IGI). RESULTS: In all MO patients, T2D was remitted or controlled (1 case) at 1 year and results were maintained at 5 years; AIR (MUU/mL) and IGI (MUU/mg) improved (P<.001) at 1 year (from .1+/-3.1 to 18.52+/ 21.9, and from 6.0+/-8.5 to 9.1+/-22.8, respectively) with a further increase (to 24.8+/-25.5 and to 14.3+/-13.8, respectively) at 5 years. Within the NMO group, T2D was remitted in 1/17 and controlled in 14/17 patients at 1 year, and in 2/17 and in 4/17 patients at 5 years, respectively; AIR (MUU/mL) and IGI (MUU/mg) remained unchanged throughout the postoperative period (from .31+/-9.26 to 1.5+/ 2.8 at 1 yr and to .4+/-3.29 at 5 yr for AIR, and from 2.2+/-4.9 to 1.3+/-9.0 at 1 yr and to 2.3+/-3.3 at 5 yr for IGI). CONCLUSIONS: After BPD, restoration of beta-cell secretion/production plays a pivotal role in determining postoperative T2D remission. PMID- 26947790 TI - Roux-en-Y gastric bypass 10 year follow-up: the found population. PMID- 26947791 TI - An optimized multivitamin supplement lowers the number of vitamin and mineral deficiencies three years after Roux-en-Y gastric bypass: a cohort study. AB - BACKGROUND: Vitamin and mineral deficiencies are common after Roux-en-Y gastric bypass (RYGB) surgery. In particular, inadequate serum concentrations of ferritin and vitamin B12 have been found in 11% and 23% (respectively) of patients using a standard multivitamin supplement (sMVS) 1 year after RYGB. OBJECTIVE: To evaluate the effectiveness and safety of Weight Loss Surgery (WLS) Forte(r) (a pharmaceutical-grade, optimized multivitamin supplement) compared with an sMVS and a control group (nonuser) 3 years after RYGB. SETTING: General hospital specialized in bariatric surgery. METHODS: A follow-up cohort study of a triple blind randomized, controlled clinical trial. RESULTS: At baseline 148 patients were enrolled (74 [50%] in the sMVS group and 74 [50%] in the WLS Forte group). After a mean follow-up of 36 months, 11 (7%) patients were lost to follow-up, of whom 2 were secondary to death. At the end of the study, 11 (17%) patients in the WLS Forte and 17 (24%) in the sMVS group stopped using a supplement. In addition, 64 (47%) patients were using WLS Forte and 45 (33%) patients a sMVS. Patient characteristics and follow-up length were comparable between the groups. Significantly more patients were diagnosed with anemia (16% versus 3% [P = .021]), a ferritin deficiency (14% versus 3% [P = .043]), and a zinc deficiency (8% versus 0% [P = .033]) in the sMVS group compared with WLS Forte. Five patients developed a vitamin B12 deficiency while using WLS Forte, versus 15 of sMVS users (P = .001). No adverse events occurred that were related to supplement use. CONCLUSION: At 3 years postoperative of RYGB, an optimized multivitamin supplement (WLS Forte) was more effective in reducing anemia and ferritin, vitamin B12, and zinc deficiencies compared with a standard supplement and control. PMID- 26947792 TI - Comment on: A beta-cell pancreatic dysfunction participates in the hyperglycemic peaks observed after gastric bypass surgery of obese patients. PMID- 26947794 TI - Divorcing Strain Classification from Species Names. AB - Confusion about strain classification and nomenclature permeates modern microbiology. Although taxonomists have traditionally acted as gatekeepers of order, the numbers of, and speed at which, new strains are identified has outpaced the opportunity for professional classification for many lineages. Furthermore, the growth of bioinformatics and database-fueled investigations have placed metadata curation in the hands of researchers with little taxonomic experience. Here I describe practical challenges facing modern microbial taxonomy, provide an overview of complexities of classification for environmentally ubiquitous taxa like Pseudomonas syringae, and emphasize that classification can be independent of nomenclature. A move toward implementation of relational classification schemes based on inherent properties of whole genomes could provide sorely needed continuity in how strains are referenced across manuscripts and data sets. PMID- 26947793 TI - Reply to comment on "Comparison between circular-and linear-stapled gastrojejunostomy in laparoscopic Roux-en-Y gastric bypass-a cohort from the Scandinavian Obesity Registry". PMID- 26947795 TI - Pulse palpation is an effective method for population-based screening to exclude peripheral arterial disease. AB - OBJECTIVE: There is a strong association between peripheral arterial disease (PAD) and future cardiovascular events. Therefore, intensive atherosclerotic risk factor reduction is recommended for people with PAD, and early detection is essential. This study assessed whether systematic pedal pulse palpation is an effective screening method for PAD in population-based screening programs. METHODS: As part of a randomized screening project, The Viborg Vascular Screening trial, 18,681 men (mean age, 69.3 years; range, 65-74 years) participated in a screening program, which included bilateral pulse palpation and ankle-brachial index (ABI) measurement. PAD was defined as ABI <=0.9 or >=1.4. Analysis was conducted on sensitivity, specificity, positive predictive value, and negative predictive value for PAD and for the number of pedal pulses. RESULTS: PAD was present in 2215 participants (12.1%). The pedal pulse palpation test was set to be positive for having PAD if one or more pulses were missing. Sensitivity was 71.7% and specificity was 72.3%. No palpable pulses were associated with a 50% chance of ABI-verified PAD or with a false finding. Four palpable pulses were associated with 5% false-negative PAD cases. CONCLUSIONS: Pedal pulse palpation is was shown to be a reliable initial screening tool for PAD in population-based programs but only when four pedal pulses were present. Therefore, ABI measurement should routinely be measured in patients with fewer than four palpable pedal pulses so cardiovascular preventive actions can be initiated if PAD is confirmed. PMID- 26947796 TI - Reducing Adverse Effects During Drug Development: The Example of Lesogaberan and Paresthesia. AB - PURPOSE: Lesogaberan, a gamma-aminobutyric acid (GABA)B receptor agonist, was developed for the treatment of gastroesophageal reflux disease in patients with a partial response to proton pump inhibitor therapy. A high prevalence of paresthesia was observed in healthy individuals after dosing with lesogaberan in early-phase clinical trials. The aim of this review was to gain further insight into paresthesia caused by lesogaberan by summarizing the relevant preclinical and clinical data. METHODS: This study was a narrative review of the literature and unpublished data. FINDINGS: The occurrence of paresthesia may depend on the route or rate of drug administration; several studies were conducted to test this hypothesis, and formulations were developed to minimize the occurrence of paresthesia. Phase I clinical studies showed that, in healthy individuals, paresthesia occurred soon after administration of lesogaberan in a dose-dependent manner regardless of the route of administration. The occurrence of paresthesia could be decreased by fractionating the dose or reducing the rate of administration. These findings suggest that the initial rate of absorption plays an important part in the development of paresthesia. Modified-release formulations minimize the occurrence of paresthesia while retaining the anti reflux activity of the drug, as measured by esophageal pH and the number of transient lower esophageal sphincter relaxations. IMPLICATIONS: The development of lesogaberan was halted because the effect on gastroesophageal reflux disease symptoms observed in Phase II studies was not considered clinically meaningful in the target patient population. Nevertheless, it is an example of successful formulation development designed to minimize the occurrence of a compound's adverse effect while retaining its pharmacodynamic action. PMID- 26947797 TI - Opportunity Cost and Policy: A Utilization Review of Self-monitoring of Blood Glucose in Manitoba, Canada. AB - PURPOSE: Recently, there has been a re-evaluation of the frequency, benefits, and costs associated with self-monitoring of blood glucose (SMBG). Based on little evidence of the benefit of frequent SMBG in patients with diabetes not using insulin, new guidelines and test strip limit policies have been suggested and implemented in various Canadian jurisdictions to promote a more selective practice of SMBG. The objective of this study was to assess the overall utilization and cost associated with test strips and lancets for SMBG in Manitoba from 2000 to 2013 as well as to explore the policy implications of the implementation of test strip quantity limits and its impact on overall and government costs. METHODS: An analysis of prescription claims for blood glucose test strips (BGTSs) and lancets for all patients with diabetes in Manitoba from 2000 to 2013 was conducted. In each year, patients were stratified into 4 mutually exclusive hierarchical groups according to most intensive diabetes treatment. Test strip and lancet utilization and cost were assessed for each group in each year, and the potential cost savings associated with implementation of a BGTS limit policy was projected using autoregressive integrated moving average models. FINDINGS: In the year 2000, 8 million test strips were dispensed in Manitoba, increasing by 170% to 21.7 million test strips in 2013. Insulin users accounted for the majority of test strip use. However, based on potential implementation of test strip limit policies, 95% of the reduction of test strip use is predicted to occur in the groups not using insulin. Based on current trends, the 5-year predicted additional cost associated with not implementing a test strip limit policy similar to that implemented in other Canadian provinces was estimated to be a total of $12.35 million. IMPLICATIONS: Implementation of the guideline-based policy limits is predicted to produce considerable savings, with 95% of potential savings occurring in patients not using insulin. There is, therefore, a significant opportunity cost associated with not implementing a policy to reduce BGTS utilization by patients with diabetes in Manitoba. Based on the lack of evidence to suggest significant outcome improvements with long-term frequent SMBG by patients not using insulin, more selective use of test strips for SMBG could allow for significant cost savings that could be redirected to other programs and interventions for the growing population of patients with diabetes in Manitoba. PMID- 26947798 TI - The Developing Microbiome of the Preterm Infant. AB - PURPOSE: To determine the importance of the neonatal microbiome in intestinal and overall health. METHOD: A review of existing literature. FINDINGS AND IMPLICATIONS: The microbiome is increasingly understood to have a significant role in health and disease. However, the microbiome of the preterm infant is unique, with simple microbial communities exposed to a consistent diet in a regulated environment, and development from naive to stable under the influence of the neonatal intensive care unit. This early microbiome encounters a still developing host and thus has the potential to program fundamental pathways with implications for neonatal and later outcomes. PMID- 26947799 TI - Poor Outcomes After Emergency Department Discharge of the Elderly: A Case-Control Study. AB - STUDY OBJECTIVE: The emergency department (ED) is an inherently high-risk setting. Our objective is to identify the factors associated with the combined poor outcome of either death or an ICU admission shortly after ED discharge in older adults. METHODS: We conducted chart review of 600 ED visit records among adults older than 65 years that resulted in discharge from any of 13 hospitals within an integrated health system in 2009 to 2010. We randomly chose 300 patients who experienced the combined outcome within 7 days of discharge and matched case patients to controls who did not experience the outcome. Two emergency physicians blinded to the outcome reviewed the records and identified whether a number of characteristics were present. Predictors of the outcome were identified with conditional logistic regression. RESULTS: Of 1,442,594 ED visits to Kaiser Permanente Southern California in 2009 to 2010, 300 unique cases and 300 unique control records were randomly abstracted. Characteristics associated with the combined poor outcome included cognitive impairment (adjusted odds ratio [AOR] 2.10; 95% confidence interval [CI] 1.19 to 3.56), disposition plan change (AOR 2.71; 95% CI 1.50 to 4.89), systolic blood pressure less than 120 mm Hg (AOR 1.48; 95% CI 1.00 to 2.20), and pulse rate greater than 90 beats/min (AOR 1.66; 95% CI 1.02 to 2.71). CONCLUSION: We found that older patients discharged from the ED with a change in disposition from "admit" to "discharge," cognitive impairment, systolic blood pressure less than 120 mm Hg, and pulse rate greater than 90 beats/min were at increased risk of death or ICU admission shortly after discharge. Increased awareness of these high-risk characteristics may improve ED disposition decisionmaking. PMID- 26947800 TI - Effectiveness of EDACS Versus ADAPT Accelerated Diagnostic Pathways for Chest Pain: A Pragmatic Randomized Controlled Trial Embedded Within Practice. AB - STUDY OBJECTIVE: A 2-hour accelerated diagnostic pathway based on the Thrombolysis in Myocardial Infarction score, ECG, and troponin measures (ADAPT ADP) increased early discharge of patients with suspected acute myocardial infarction presenting to the emergency department compared with standard care (from 11% to 19.3%). Observational studies suggest that an accelerated diagnostic pathway using the Emergency Department Assessment of Chest Pain Score (EDACS-ADP) may further increase this proportion. This trial tests for the existence and size of any beneficial effect of using the EDACS-ADP in routine clinical care. METHODS: This was a pragmatic randomized controlled trial of adults with suspected acute myocardial infarction, comparing the ADAPT-ADP and the EDACS-ADP. The primary outcome was the proportion of patients discharged to outpatient care within 6 hours of attendance, without subsequent major adverse cardiac event within 30 days. RESULTS: Five hundred fifty-eight patients were recruited, 279 in each arm. Sixty-six patients (11.8%) had a major adverse cardiac event within 30 days (ADAPT-ADP 29; EDACS-ADP 37); 11.1% more patients (95% confidence interval 2.8% to 19.4%) were identified as low risk in EDACS-ADP (41.6%) than in ADAPT-ADP (30.5%). No low-risk patients had a major adverse cardiac event within 30 days (0.0% [0.0% to 1.9%]). There was no difference in the primary outcome of proportion discharged within 6 hours (EDACS-ADP 32.3%; ADAPT-ADP 34.4%; difference -2.1% [-10.3% to 6.0%], P=.65). CONCLUSION: There was no difference in the proportion of patients discharged early despite more patients being classified as low risk by the EDACS-ADP than the ADAPT-ADP. Both accelerated diagnostic pathways are effective strategies for chest pain assessment and resulted in an increased rate of early discharges compared with previously reported rates. PMID- 26947801 TI - Risk Factors for Persistent Frequent Emergency Department Use in Medicare Beneficiaries. AB - STUDY OBJECTIVE: We examine factors associated with persistent frequent emergency department (ED) use during a 2-year period among Medicare beneficiaries. METHODS: We conducted a retrospective, claims-based analysis of fee-for-service Medicare beneficiaries, using the Chronic Condition Data Warehouse's random 20% sample files. We used multinomial logistic regression models to compare frequent ED use (defined as 4 or more ED visits per year) with infrequent use (1 to 3 visits per year), non-ED use, and death in 2010 as a function of sociodemographic, primary care, clinical characteristics, and 2009 ED use. RESULTS: Approximately 1.1% of Medicare beneficiaries were persistent frequent ED users, defined as experiencing frequent ED use in 2009 and 2010 consecutively. Of the 3.3% of Medicare beneficiaries who were frequent ED users in 2009, 34.3% were frequent ED users, 19.4% were non-ED users, 39.0% were infrequent ED users, and 7.4% died in 2010. Frequent ED use in 2009 was highly associated with frequent ED use in 2010 (relative risk ratio 35.2; 95% confidence interval 34.5 to 35.8). Younger age, Medicaid status, and mental illness were also strong predictors of frequent ED use. The probability of frequent ED use in 2010 was 3.4% for the total sample, but was 19.4% for beneficiaries who were frequent users in 2009 and 49.0% for beneficiaries in the youngest age group who had mental illness, Medicaid, and frequent ED use in 2009. CONCLUSION: Efforts to curtail frequent ED use in Medicare should focus on disabled, socially vulnerable beneficiaries. PMID- 26947802 TI - Salicylic acid degradation by advanced oxidation processes. Coupling of solar photoelectro-Fenton and solar heterogeneous photocatalysis. AB - A 3.0 L solar flow plant with a Pt/air-diffusion (anode/cathode) cell, a solar photoreactor and a photocatalytic photoreactor filled with TiO2-coated glass spheres has been utilized to couple solar photoelectro-Fenton (SPEF) and solar heterogeneous photocatalysis (SPC) for treating a 165mgL(-1) salicylic acid solution of pH 3.0. Organics were destroyed by OH radicals formed on the TiO2 photocatalyst and at the Pt anode during water oxidation and in the bulk from Fenton's reaction between added Fe(2+) and cathodically generated H2O2, along with the photolytic action of sunlight. Poor salicylic acid removal and mineralization were attained using SPC, anodic oxidation with electrogenerated H2O2 (AO-H2O2) and coupled AO-H2O2-SPC. The electro-Fenton process accelerated the substrate decay, but with low mineralization by the formation of byproducts that are hardly destroyed by OH. The mineralization was strongly increased by SPEF due to the photolysis of products by sunlight, being enhanced by coupled SPEF-SPC due to the additional oxidation by OH at the TiO2 surface. The effect of current density on the performance of both processes was examined. The most potent SPEF-SPC process at 150mAcm(-2) yielded 87% mineralization and 13% current efficiency after consuming 6.0AhL(-1). Maleic, fumaric and oxalic acids detected as final carboxylic acids were completely removed by SPEF and SPEF-SPC. PMID- 26947803 TI - On the capacity of ozonation to remove antimicrobial compounds, resistant bacteria and toxicity from urban wastewater effluents. AB - The degradation of erythromycin (ERY) and ethylparaben (EtP) in urban wastewater effluents at low concentration level during ozonation was investigated under different experimental conditions. Both substrates were rapidly eliminated within 2min at low ozone dose of 0.3mgL-1 and the experimental data were well fitted in the pseudo-first-order kinetic model. The ratio of HO- and O3-exposure (Rct) at the inherent pH was found to be 1.9*10-8. The degradation of ERY and EtP was pronounced at pH 8 compared to acidic pH conditions, while the degradation rate of both substrates was found to be matrix-depended. It was also shown that both O3- and HO-mediated pathways are involved in the degradation of EtP, whereas the saturated-rich structure of ERY renders it O3-recalcitrant. Under the optimum O3 dose, the BrO3- concentration was found to be lower than 10MUgL-1. Five and fifteen transformation products were elucidated during ERY and EtP oxidation, respectively. The root and shoot inhibition can be attributed to the oxidation products formed upon dissolved effluent organic matter transformation. Escherichia coli harbouring resistance to ERY survived ozonation better than EtP resistant E. coli. However, neither ERY- nor EtP-resistant E. coli were detected after 15min of ozonation. PMID- 26947804 TI - Identification of polypropylene glycols and polyethylene glycol carboxylates in flowback and produced water from hydraulic fracturing. AB - The purpose of the study was to separate and identify the unknown surfactants present in flowback and produced water from oil and gas wells in the Denver Julesburg Basin (Niobrara Formation) in Weld County, Colorado, USA. Weld County has been drilled extensively during the last five years for oil and gas between 7000-8000 feet below land-surface. Polypropylene glycols (PPGs) and polyethylene glycols carboxylates (PEG-Cs) were found for the first time in these flowback and produced water samples. These ethoxylated surfactants may be used as friction reducers, clay stabilizers, and surfactants. Ultrahigh-performance liquid chromatography/quadrupole-time-of-flight mass spectrometry (UHPLC/QTOF-MS) was used to separate and identify the different classes of PPGs, PEG-Cs, and their isomers. The Kendrick mass scale was applied along with mass spectrometry/mass spectrometry (MS-MS) with accurate mass for rapid and unequivocal identification. The PPGs and their isomers occur at the ppm concentration range and may be useful as "fingerprints" of hydraulic-fracturing. Comparing these detections to the compounds used in the fracturing process from FracFocus 3.0 (https://fracfocus.org), it appears that both PPGs and polyethylene glycols (PEGs) are commonly named as additives, but the PEG-Cs have not been reported. The PEG-Cs may be trace impurities or degradation products of PEGs. PMID- 26947805 TI - High-Performance Chemical Isotope Labeling Liquid Chromatography-Mass Spectrometry for Profiling the Metabolomic Reprogramming Elicited by Ammonium Limitation in Yeast. AB - Information about how yeast metabolism is rewired in response to internal and external cues can inform the development of metabolic engineering strategies for food, fuel, and chemical production in this organism. We report a new metabolomics workflow for the characterization of such metabolic rewiring. The workflow combines efficient cell lysis without using chemicals that may interfere with downstream sample analysis and differential chemical isotope labeling liquid chromatography mass spectrometry (CIL LC-MS) for in-depth yeast metabolome profiling. Using (12)C- and (13)C-dansylation (Dns) labeling to analyze the amine/phenol submetabolome, we detected and quantified a total of 5719 peak pairs or metabolites. Among them, 120 metabolites were positively identified using a library of 275 Dns-metabolite standards, and 2980 metabolites were putatively identified based on accurate mass matches to metabolome databases. We also applied (12)C- and (13)C-dimethylaminophenacyl (DmPA) labeling to profile the carboxylic acid submetabolome and detected over 2286 peak pairs, from which 33 metabolites were positively identified using a library of 188 DmPA-metabolite standards, and 1595 metabolites were putatively identified. Using this workflow for metabolomic profiling of cells challenged by ammonium limitation revealed unexpected links between ammonium assimilation and pantothenate accumulation that might be amenable to engineering for better acetyl-CoA production in yeast. We anticipate that efforts to improve other schemes of metabolic engineering will benefit from application of this workflow to multiple cell types. PMID- 26947806 TI - Ciprofloxacin mediates cancer stem cell phenotypes in lung cancer cells through caveolin-1-dependent mechanism. AB - Cancer stem cells (CSCs), a subpopulation of cancer cells with high aggressive behaviors, have been identified in many types of cancer including lung cancer as one of the key mediators driving cancer progression and metastasis. Here, we have reported for the first time that ciprofloxacin (CIP), a widely used anti microbial drug, has a potentiating effect on CSC-like features in human non-small cell lung cancer (NSCLC) cells. CIP treatment promoted CSC-like phenotypes, including enhanced anchorage-independent growth and spheroid formation. The known lung CSC markers: CD133, CD44, ABCG2 and ALDH1A1 were found to be significantly increased, while the factors involving in epithelial to mesenchymal transition (EMT): Slug and Snail, were depleted. Also, self-renewal transcription factors Oct-4 and Nanog were found to be up-regulated in CIP-treated cells. The treatment of CIP on CSC-rich populations obtained from secondary spheroids resulted in the further increase of CSC markers. In addition, we have proven that the mechanistic insight of the CIP induced stemness is through Caveolin-1 (Cav-1)-dependent mechanism. The specific suppression of Cav-1 by stably transfected Cav-1 shRNA plasmid dramatically reduced the effect of CIP on CSC markers as well as the CIP induced spheroid formation ability. Cav-1 was shown to activate protein kinase B (Akt) and extracellular signal-regulated kinase (ERK) pathways in CSC-rich population; however, such an effect was rarely found in the main lung cancer cells population. These findings reveal a novel effect of CIP in positively regulating CSCs in lung cancer cells via the activation of Cav-1, Akt and ERK, and may provoke the awareness of appropriate therapeutic strategy in cancer patients. PMID- 26947807 TI - Barrier cream based on CeO2 nanoparticles grafted polymer as an active compound against the penetration of organophosphates. AB - Due to their small size, nanoparticles possess unique properties. Cerium oxide nanoparticles have been already studied for their capacity to adsorb and neutralize toxic compounds including organophosphates. By covalently grafting these nanoparticles to a thickening polymer, their potential aggregation resulting in a loss of surface area and their potential toxicity are avoided. Indeed, copolymers easily form gels in water at neutral pH thanks to low interactions occurring between polymeric chains; thus, gels can be spread on membrane supports to afford protective barriers. However, as we demonstrated previously, a formulation step of these hydride nanoparticle-polymeric compounds is necessary to overcome the cracking of the coating during drying. This work reports the impact of many factors on the efficiency of a new active Topical Skin Protectant (aTSP) including: (1) the presence of CeO2 nanoparticles in the protective coating and their amount, (2) their grafting to a perfluorocarbon thickening polymer and (3) the formulation of the CeO2 nanoparticle-grafted polymer. The combination of all the benefit parameters led to a very effective new aTSP against paraoxon penetration. The major in vitro diffusion studies were performed in Franz-type diffusion cells on two artificial membranes (silicone and Strat-M) and final validation on ex vivo human skin. The comparison of 24 h exposure between membrane results indicated a difference in the behavior between the two artificial supports and the biological model; Strat-M membranes seeming closer to human skin results. Therefore, positive results regarding occlusive conditions should be confirmed with human skin. PMID- 26947808 TI - Analysis of Ferrous on Ten-Eleven Translocation Activity and Epigenetic Modifications of Early Mouse Embryos by Fluorescence Microscopy. AB - Iron is an essential trace element that plays important roles in the cellular function of all organs and systems. However, the function of Fe(II) in mammalian embryo development is unknown. In this study, we investigated the role of Fe(II) during preimplantation embryo development. Depletion of Fe(II) using thiosemicarbazone-24 (TSC24), a specific Fe(II) chelator, rescued quenching of the Fe(II)-sensitive fluorophore phen green-SK. After in vitro fertilization, TSC24 significantly reduced the cleavage rate as well as blastocyst formation. The hatch rate of blastocysts was also reduced with 1 pM TSC24 treatment (20.25+/ 1.86 versus 42.28+/-12.96%, p<0.05). Blastocysts were cultured in leukemia inhibitory factor-free mouse embryonic stem cell culture medium with or without TSC24, and those with depleted Fe(II) displayed delayed attachment and lost the ability to induce embryoid body formation. To further explore the mechanism of Fe(II) in embryo development, we assessed the expression of 5 hydroxymethylcytosine (5hmC) and OCT4 in the pronuclear and blastocyst stages, respectively. We observed that Fe(II) reduced 5hmC and OCT4 expression, which could be explained by low ten-eleven translocation (TET) enzyme activity induced by TSC24 treatment. These findings demonstrate that Fe(II) is required for mammalian embryo development and that it facilitates the process via regulation of TET activity. PMID- 26947809 TI - Dock 'n roll: folding of a silk-inspired polypeptide into an amyloid-like beta solenoid. AB - Polypeptides containing the motif ((GA)mGX)n occur in silk and have a strong tendency to self-assemble. For example, polypeptides containing (GAGAGAGX)n, where X = G or H have been observed to form filaments; similar sequences but with X = Q have been used in the design of coat proteins (capsids) for artificial viruses. The structure of the (GAGAGAGX)m filaments has been proposed to be a stack of peptides in a beta roll structure with the hydrophobic side chains pointing outwards (hydrophobic shell). Another possible configuration, a beta roll or beta solenoid structure which has its hydrophobic side chains buried inside (hydrophobic core) was, however, overlooked. We perform ground state analysis as well as atomic-level molecular dynamics simulations, both on single molecules and on two-molecule stacks of the silk-inspired sequence (GAGAGAGQ)10, to decide whether the hydrophobic core or the hydrophobic shell configuration is the most stable one. We find that a stack of two hydrophobic core molecules is energetically more favorable than a stack of two hydrophobic shell molecules. A shell molecule initially placed in a perfect beta roll structure tends to rotate its strands, breaking in-plane hydrogen bonds and forming out-of-plane hydrogen bonds, while a core molecule stays in the beta roll structure. The hydrophobic shell structure has type II' beta turns whereas the core configuration has type II beta turns; only the latter secondary structure agrees well with solid-state NMR experiments on a similar sequence (GA)15. We also observe that the core stack has a higher number of intra-molecular hydrogen bonds and a higher number of hydrogen bonds between stack and water than the shell stack. Hence, we conclude that the hydrophobic core configuration is the most likely structure. In the stacked state, each peptide has more intra-molecular hydrogen bonds than a single folded molecule, which suggests that stacking provides the extra stability needed for molecules to reach the folded state. PMID- 26947811 TI - Posterior mandibular widening secondary to advancement sagittal split osteotomy: A retrospective study. AB - INTRODUCTION: Patients sometimes spontaneously report a modification of the width of their lower face after an advancement bilateral sagittal split osteotomy (ABSSO). The main goal of our study was to assess the variation of the bigonial distance (BGD) before and after ABSSO in a group of patients. The second goal was to look for a possible relation between the variation of BGD and the amount of mandibular advancement. MATERIALS AND METHODS: We conducted a retrospective radiological study on patients who underwent an isolated ABSSO (Obwegeser-Dal Pont II type osteotomy) for a class II malocclusion in our department over a 26 months period. The measures were made on standardized frontal and lateral teleradiographies taken before, one day and one year postoperatively. RESULTS: Fifty patients (36 females, 14 males; mean age: 24) could be included. BGD was significantly increased one day (+9.8mm, P<10(-3)) and one year after surgery (+4mm, P<10(-3)). There was no relation between the amount of mandibular advancement and the increase of BGD. DISCUSSION: Our results suggest that ABSSO is responsible for posterior mandibular enlargement which must be taken into account during the aesthetic preoperative assessment. Further studies are mandatory to identify the risk factors for this phenomenon. PMID- 26947810 TI - [Head and neck localizations of hydatid cyst: A series of 17 cases]. AB - INTRODUCTION: Head and neck localizations of hydatid cyst are very rare (1% of human cases) even in countries where echinococcosis is endemic (human sites). Our objective was to report the epidemiological, and clinical characteristics and the management of head and neck localizations of hydatid cyst. MATERIALS AND METHODS: A retrospective descriptive study of 17 cases of head and neck hydatid cysts taken in charge in our department between 2000 and 2014 was conducted. RESULTS: The mean age was 35 years. Male were slightly predominant (sex ratio: 1.12). Eighty-eight percent of the patients had regular contact with dogs and 53% were of rural origin. The soft tissues of the head and neck were involved in six patients, the parotid gland in 6 patients, the thyroid in 4 patients and the submaxillary gland in one patient. Complete surgical resection of the lesions was systematically done. Hydatid disease was confirmed in all the cases by histology. The outcome was uneventful in all the patients with a mean follow-up of 2 years. CONCLUSION: Given the lack of recommendations for the surgical treatment of head and neck hydatid cysts, we advocate a total resection of the affected organ if there is no functional risk. Otherwise, an excision of the cyst and of the surrounding tissues combined with an abundant washing-out of the residual cavity must be done, especially in case of intraoperative breaking of the cyst. PMID- 26947813 TI - Translating gastric cancer genomics into targeted therapies. AB - Gastric cancer is a common disease with limited treatment options and a poor prognosis. Many gastric cancers harbour potentially actionable targets, including over-expression and mutations in tyrosine kinase pathways. Agents have been developed against these targets with varying success- in particular, the use of trastuzumab in HER2-overexpressing gastric cancers has resulted in overall survival benefits. Gastric cancers also have high levels of somatic mutations, making them candidates for immunotherapy; early work in this field has been promising. Recent advances in whole genome and multi-platform sequencing have driven the development of molecular classification systems, which may in turn guide the selection of patients for targeted treatment. Moving forward, challenges will include the development of appropriate biomarkers to predict responses to targeted therapy, and the application of new molecular classifications into trial development and clinical practice. PMID- 26947814 TI - How does our increased understanding of the role of inflammation and innate immunity in acne impact treatment approaches? AB - A supplement article recently published in the Journal of the European Academy of Dermatology and Venereology by Dreno et al., members of the Global Alliance to Improve Outcomes in Acne group, summarized the data for the emerging concept that inflammation in general and the innate immune system specifically play a central role in the pathogenesis of acne. This review, entitled "Understanding innate immunity and inflammation in acne: implications for management", also discusses the impact of different treatment options on the innate immune response and inflammation. The aim of the present summary is to provide a synopsis of the key points made in the paper, from the members of the Global Alliance, as relevant to the main article within this supplement: "Recent advances in the use of adapalene 0.1%/benzoyl peroxide 2.5% to treat acne patients with moderate to severe acne". PMID- 26947812 TI - Mucositis in head and neck cancer patients treated with radiotherapy and systemic therapies: Literature review and consensus statements. AB - BACKGROUND: Oral mucositis (OM) due to radiotherapy and systemic therapies in head and neck cancer treatment represents a major problem causing a wide spectrum of clinical signs and symptoms. This adverse event may reduce quality of life, resulting from debilitating oral pain, bleeding, dysphagia, infections, impairment of food intake, high rate of hospitalization and may interfere with the delivery of programmed treatment plans, ultimately jeopardizing patient outcome. Globally, there is a lack of evidence on effective measures for the prevention and treatment of OM, and only scant uniform conclusions and recommendations can be derived from the existing literature and guidelines. A multidisciplinary team of Italian head and neck cancer experts met in Milan 17-18 February 2013 with the aim of reaching consensus on prophylaxis and management of mucositis. The results of the literature review and the statements that achieved consensus are reported and discussed in this paper. MATERIAL AND METHODS: The Delphi Appropriateness Method was used as a structured communication method for achieving consensus. Subsequently, external expert reviewers evaluated the conclusions carefully according to their area of expertise. RESULTS: This paper presents 13 clusters of statements on prophylaxis and treatment of mucositis that achieved consensus. CONCLUSIONS: OM represents a very stressful situation for head and neck cancer patients submitted to chemo-radiation or exclusive radiation treatment. A multidisciplinary approach is mandatory, but there is still no gold standard protocol that is prominently better than others. PMID- 26947815 TI - Recent advances in the use of adapalene 0.1%/benzoyl peroxide 2.5% to treat patients with moderate to severe acne. AB - The central role of inflammation in acne is now more clearly understood. Adapalene, a third-generation topical retinoid, down-regulates toll-like receptor 2 expression and inhibits activator protein-1 activity. In a fixed-dose combination, adapalene and benzoyl peroxide (BPO) act synergistically on inflammatory patterns through regulation of innate immunity. In addition to reducing inflammatory and non-inflammatory lesions, adapalene/BPO helps prevent lesion and microcomedone formation. The combination of a topical retinoid and antimicrobial agent remains the preferred approach for almost all patients with acne. In cases of more severe disease, there is a clinical benefit in combining adapalene/BPO with an oral antibiotic for 12 weeks. Most recently, adapalene/BPO plus doxycycline 200 mg was found to be highly effective when compared with isotretinoin in the treatment of patients with severe acne with nodules. Long term maintenance therapy is needed for most patients. Retinoids are the preferred agents, with BPO added in patients with more severe disease if needed. Adapalene is anticomedogenic, reduces comedones and has anti-inflammatory properties, while BPO is a unique antimicrobial agent not shown to induce microbial resistance after more than 50 years of use. Maintenance therapy for 6 months with adapalene/BPO prevents relapse among patients with severe acne and continues to reduce disease symptoms. PMID- 26947850 TI - Profile of black woman in Senegal with breast cancer. AB - To describe the profile of Senegalese black women with breast cancer. This is a retrospective and prospective study of patients receiving care for breast cancer in the breast diseases department of the Aristide Le Dantec Teaching Hospital in Dakar from 2010 through June 2014. 188 women patients met the inclusion criteria. Their mean age at diagnosis was 43.3 years. The age of onset of the first menses was early (<12 years) in 7 patients (4.9%). More than two thirds of the women (71.6%) were premenopausal at diagnosis. At least one pregnancy was reported by 161 women (86.1%) and 96.3 had given birth. Mean age at first pregnancy was 19.47 years, and 85.9% had had their first pregnancy before the age of 30. Similarly, 133 (87.3%) had breastfed, for a mean duration of 18.36 months. In our country, breast cancer occurs in young women, who had their first menses after 12 years, are premenopausal, had their first pregnancy before the age of 30, and breastfed for several months. These data suggest that further study of this profile is needed but that the testing policy must change drastically, to start much earlier than 50 years. PMID- 26947851 TI - Factors influencing clinicians' perceptions of interruptions as disturbing or non disturbing: A qualitative study. AB - OBJECTIVE: Emergency departments consist of multiple systems requiring interaction with one another while still being able to operate independently, creating frequent interruptions in the clinical workflow. Most research on interruptions in health care settings has focused on the relationship between interruptions and negative outcomes. However, there are indications that not all interruptions are negatively perceived by those being interrupted. Therefore, this study aimed to explore factors that influence when a clinician perceives interruptions as non-disturbing or disturbing in an emergency department context. METHOD: Explorative design based on interviews with 10 physicians and 10 registered nurses at two Swedish emergency departments. Data were analyzed using qualitative content analysis. RESULT: Factors influencing whether emergency department clinicians perceived interruptions as non-disturbing or disturbing were identified: clinician's constitution, external factors of influence and the nature of the interrupted task. The clinicians' perceptions were related to a complex of attributes inherent in these three factors at the time of the interruption. Thus, the same type of interruption could be perceived as either non-disturbing or disturbing contingent on the surrounding circumstances in which the event occurred. CONCLUSION: Emergency department clinicians' perceptions of interruptions as non-disturbing or disturbing were related to the character of identified influencing factors. PMID- 26947871 TI - [How Reliable are Meta-Analyses? An Appraisal Using the Example of Magnesium Tocolysis]. AB - INTRODUCTION: Crowther et al. 3 analysed the effectivity of magnesium tocolysis in preventing preterm birth. They conclude that there is no evidence for protection. In its latest guidelines, based on this Cochrane analysis, the German Association of Gynaecology and Obstetrics (DGGG) does not recommend any more the use of magnesium for tocolysis. Magnesium tocolysis is said neither to delay nor to prevent preterm birth. Moreover, magnesium could be responsible for increased mortality in infants. These conclusions are mostly based on the research of Mittendorf et al. 4. In a Cochrane study from 2014, which in principal was identical to the study mentioned above 3, Crowther et al. 6 confirm the previous findings and conclusions. METHOD: Having successfully applied magnesium tocolysis for many years, these surprising conclusions led us to review the soundness of the publications mentioned above. Combining the practical experience of many years with the results of a comprehensive literature retrieval, we finally contrasted this knowledge with the findings of the aforementioned publications that caused the DGGG to withdraw the recommendation for magnesium. RESULTS: To draw binding consequences from a meta-analysis is possible only when stringent quality guidelines are observed. The studies that were included in the Cochrane review of Crowther et al. 3 are very heterogeneous and are not suitable for concluding on poor or even lacking effectiveness of magnesium tocolysis. Furthermore, the cases of infant deaths, as stated by Mittendorf et al. 4, are very unlikely caused by magnesium. CONCLUSION: When including studies in a meta analysis special attention has to be given to the relevance and unbiased selection of studies. To prevent any misjudgment, a thorough knowledge of the included studies seems essentiell. There is not sufficient evidence to withdraw the recommendation for applying magnesium tocolysis as a preventive measure to prevent preterm birth. In the sense of evidence-based medicine, long-standing, scientifically proven therapeutic success should be incorporated into the meta analysis as well. PMID- 26947872 TI - Understanding the complexation of Eu(3+) with three diglycolamide-functionalized calix[4]arenes: spectroscopic and DFT studies. AB - Complexation of Eu(3+) with three diglycolamide-functionalized calix[4]arene (C4DGA) ligands was investigated by UV-Vis and luminescence spectroscopy measurements in acetonitrile medium. The complexation thermodynamics was studied by micro-calorimetry while structural information was obtained from DFT calculations. PMID- 26947873 TI - Cognitive Models as Bridge between Brain and Behavior. AB - How can disparate neural and behavioral measures be integrated? Turner and colleagues propose joint modeling as a solution. Joint modeling mutually constrains the interpretation of brain and behavioral measures by exploiting their covariation structure. Simultaneous estimation allows for more accurate prediction than would be possible by considering these measures in isolation. PMID- 26947874 TI - Additional N-glycosylation in the N-terminal region of recombinant human alpha-1 antitrypsin enhances the circulatory half-life in Sprague-Dawley rats. AB - Glycosylation affects the circulatory half-lives of therapeutic proteins. However, the effects of an additional N-glycosylation in the unstructured region or the loop region of alpha-1 antitrypsin (A1AT) on the circulatory half-life of the protein are largely unknown. In this study, we investigated the role of an additional N-glycosylation site (Q4N/D6T, Q9N, D12N/S14T, A70N, G148T, R178N, or V212N) to the three naturally occurring N-glycosylation sites in human A1AT. A single-dose (445 MUg/kg) pharmacokinetic study using male Sprague-Dawley rats showed that, among the seven recombinant A1AT (rA1AT) mutants, Q9N and D12N/S14T showed the highest serum concentration and area under the curve values, as well as similar circulatory half-lives that were 2.2-fold higher than plasma-derived A1AT and 1.7-fold higher than wild-type rA1AT. We further characterized the Q9N mutant regarding the N-glycan profile, sialic acid content, protease inhibitory activity, and protein stability. The results indicate that an additional N glycosylation in the flexible N-terminal region increases the circulatory half life of rA1AT without altering its protease inhibitory activity. Our study provides novel insight into the use of rA1AT for the treatment of emphysema with an increased injection interval relative to the clinically used plasma-derived A1AT. PMID- 26947875 TI - Prognostic Value of SMAD4 in Pancreatic Cancer: A Meta-Analysis. AB - PURPOSE: The prognostic value of SMAD4 in pancreatic cancer has been evaluated in several studies. However, the conclusions remain controversial. Therefore, we aimed to evaluate the association between SMAD4 expression and the outcome of pancreatic cancer patients by performing a meta-analysis. METHODS: We systematically searched for relevant studies evaluating the relationship between SMAD4 expression and the outcome of pancreatic cancer patients until May 2015. A meta-analysis was performed using STATA 12.0, and pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were used to estimate the strength of the association between SMAD4 expression and the prognosis of pancreatic cancer patients. RESULTS: The analysis included 1762 patients from 14 studies, with 1401 patients from 11 studies and 927 patients from 8 studies included in the univariate and multivariate analyses, respectively. Loss of SMAD4 expression was found to be significantly correlated with poor overall survival, with the combined HR (95% CI) of 1.20 (1.03-1.40). After adjusting for potential confounders using the Cox regression model, the pooled HR (95% CI) was 1.88 (1.31 2.70). In subgroup analysis, study region, number of patients, follow-up duration, and cutoff value were found to affect the significance of the association between loss of SMAD4 expression and poor prognosis. In addition, there was no evidence of publication bias, as suggested by Begg's and Egger's test. CONCLUSIONS: Loss of SMAD4 was associated with poor survival and was a negative prognostic indicator in patients with pancreatic cancer. PMID- 26947876 TI - Early Prediction and Evaluation of Breast Cancer Response to Neoadjuvant Chemotherapy Using Quantitative DCE-MRI. AB - The purpose is to compare quantitative dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) metrics with imaging tumor size for early prediction of breast cancer response to neoadjuvant chemotherapy (NACT) and evaluation of residual cancer burden (RCB). Twenty-eight patients with 29 primary breast tumors underwent DCE-MRI exams before, after one cycle of, at midpoint of, and after NACT. MRI tumor size in the longest diameter (LD) was measured according to the RECIST (Response Evaluation Criteria In Solid Tumors) guidelines. Pharmacokinetic analyses of DCE-MRI data were performed with the standard Tofts and Shutter-Speed models (TM and SSM). After one NACT cycle the percent changes of DCE-MRI parameters K(trans) (contrast agent plasma/interstitium transfer rate constant), ve (extravascular and extracellular volume fraction), kep (intravasation rate constant), and SSM-unique taui (mean intracellular water lifetime) are good to excellent early predictors of pathologic complete response (pCR) vs. non-pCR, with univariate logistic regression C statistics value in the range of 0.804 to 0.967. ve values after one cycle and at NACT midpoint are also good predictors of response, with C ranging 0.845 to 0.897. However, RECIST LD changes are poor predictors with C = 0.609 and 0.673, respectively. Post-NACT K(trans), taui, and RECIST LD show statistically significant (P < .05) correlations with RCB. The performances of TM and SSM analyses for early prediction of response and RCB evaluation are comparable. In conclusion, quantitative DCE-MRI parameters are superior to imaging tumor size for early prediction of therapy response. Both TM and SSM analyses are effective for therapy response evaluation. However, the taui parameter derived only with SSM analysis allows the unique opportunity to potentially quantify therapy-induced changes in tumor energetic metabolism. PMID- 26947878 TI - MiR-200a Suppresses the Proliferation and Metastasis in Pancreatic Ductal Adenocarcinoma through Downregulation of DEK Gene. AB - MiR-200a has been reported to be able to suppress the epithelial-mesenchymal transition process in pancreatic cancer stem cells, suggesting that miR-200a could suppress the metastasis of pancreatic ductal adenocarcinoma (PDAC). However, its role in proliferation and metastasis of PDAC and the underlying mechanism by which miR-200a works in PDAC have not been elucidated. In our study, we for the first time identified that DEK gene is a direct downstream target of miR-200a. It was found that overexpression of miR-200a decreased DEK expression, suppressing the proliferation, migration, and invasion of PDAC cells. Meanwhile, knockdown of miR-200a can increase DEK level, promoting the proliferation, migration, and invasion of PDAC cells. Our study demonstrated that miR-200a suppresses the metastasis in pancreatic PDAC through downregulation of DEK, suggesting that miR-200a may be used as a novel potential marker in prediction of metastasis of PDAC. PMID- 26947877 TI - Assessment of Hyperthermic Intraperitoneal Chemotherapy to Eradicate Intraperitoneal Free Cancer Cells. AB - OBJECTIVE: To assess the effect of hyperthermic intraperitoneal chemotherapy (HIPEC) to eradicate intraperitoneal free cancer cells and to explore the feasibility of cytological cure for peritoneal carcinomatosis (PC). METHODS: The peritoneal lavage fluid (or ascites) from 50 PC patients was collected before and after intraoperative HIPEC, respectively, for conventional cytology test, and conventional and real-time quantitative reverse transcript polymerase chain reaction detecting carcinoembryonic antigen (CEA) mRNA and cytokeratin-20 (CK20) mRNA. The blood samples 3 days before and 7 days after intraoperative HIPEC were also collected for detecting the serum tumor markers, including CEA, carbohydrate antigen (CA) 125, and CA19-9. RESULTS: The positive rate of conventional cytology test before HIPEC versus after HIPEC was100.0% versus 22.0% (P = .000). The positive rates of CEA mRNA and CK20 mRNA before HIPEC versus after HIPEC were 100.0% versus 86.0% (P = .012) and 100.0% versus 96.0% (P = .495), respectively. Moreover, after HIPEC, 18 (36.0%) patients had a decline in CEA mRNA (P = .000), and 17 (34.0%) patients had a decline in CK20 mRNA (P = .000). The positive rates of serum CEA, CA125, and CA199 before HIPEC versus after HIPEC were 52.0% versus 28.0% (P = .014), 52.0% versus 44.0% (P = .423), and 40.0% versus 28.0% (P = .205), respectively. CONCLUSION: HIPEC could effectively eradicate intraperitoneal free cancer cells and partially achieve cytological cure for PC. PMID- 26947879 TI - Anti-Programmed Cell Death (PD)-1 Immunotherapy for Malignant Tumor: A Systematic Review and Meta-Analysis. AB - This systematic review and meta-analysis evaluated anti-programmed cell death (PD)-1 immunotherapy (nivolumab or pembrolizumab) for overall efficacy, safety, and effective dose relative to standard chemotherapy or other conventional drugs in the treatment of malignant tumors. We searched the following databases, PubMed, Medline, Embase, Cochrane, Wangfang Data, Weipu, and China National Knowledge Infrastructure, and the reference lists of the selected articles for randomized controlled trials (RCTs) of anti-PD-1 therapies in humans. The outcome measures were overall survival, treatment response, and adverse events. Only four randomized controlled trials met our inclusion criteria. Three of these evaluated responses to nivolumab, whereas one tested pembrolizumab. The result of our analysis suggested that nivolumab may improve the overall response rate in treating melanoma relative to chemotherapy and has few associated adverse events. Similarly, in metastatic melanoma patients, nivolumab had a significant advantage over dacarbazine in terms of 1-year survival, progression-free survival, and objective response rate. Regarding dose levels of nivolumab for patients with metastatic renal cell carcinoma, the outcomes in response to 2 and 10 mg/kg were similar, but both had significant advantages over 0.3 mg/kg. In addition, pembrolizumab showed similar outcomes in response to 2- and 10-mg/kg treatment. Anti-PD-1 immunotherapy appears to be safe and effective for patients with melanoma or metastatic renal cell carcinoma. Our meta-analysis is limited, but additional clinical trials are warranted to verify this preliminary evidence of positive outcomes and before anti-PD-1 therapy can be recommended for routine clinical use. PMID- 26947880 TI - Monitoring Prostate Tumor Growth in an Orthotopic Mouse Model Using Three Dimensional Ultrasound Imaging Technique. AB - Prostate cancer (CaP) is the most commonly diagnosed and the second leading cause of death from cancer in males in USA. Prostate orthotopic mouse model has been widely used to study human CaP in preclinical settings. Measurement of changes in tumor size obtained from noninvasive diagnostic images is a standard method for monitoring responses to anticancer modalities. This article reports for the first time the usage of a three-dimensional (3D) ultrasound system equipped with photoacoustic (PA) imaging in monitoring longitudinal prostate tumor growth in a PC-3 orthotopic NODSCID mouse model (n = 8). Two-dimensional and 3D modes of ultrasound show great ability in accurately depicting the size and shape of prostate tumors. PA function on two-dimensional and 3D images showed average oxygen saturation and average hemoglobin concentration of the tumor. Results showed a good fit in representative exponential tumor growth curves (n = 3; r(2) = 0.948, 0.955, and 0.953, respectively) and a good correlation of tumor volume measurements performed in vivo with autopsy (n = 8, r = 0.95, P < .001). The application of 3D ultrasound imaging proved to be a useful imaging modality in monitoring tumor growth in an orthotopic mouse model, with advantages such as high contrast, uncomplicated protocols, economical equipment, and nonharmfulness to animals. PA mode also enabled display of blood oxygenation surrounding the tumor and tumor vasculature and angiogenesis, making 3D ultrasound imaging an ideal tool for preclinical cancer research. PMID- 26947881 TI - Preclinical Data on Efficacy of 10 Drug-Radiation Combinations: Evaluations, Concerns, and Recommendations. AB - BACKGROUND: Clinical testing of new therapeutic interventions requires comprehensive, high-quality preclinical data. Concerns regarding quality of preclinical data have been raised in recent reports. This report examines the data on the interaction of 10 drugs with radiation and provides recommendations for improving the quality, reproducibility, and utility of future studies. The drugs were AZD6244, bortezomib, 17-DMAG, erlotinib, gefitinib, lapatinib, oxaliplatin/Lipoxal, sunitinib (Pfizer, Corporate headquarters, New York, NY), thalidomide, and vorinostat. METHODS: In vitro and in vivo data were tabulated from 125 published papers, including methods, radiation and drug doses, schedules of administration, assays, measures of interaction, presentation and interpretation of data, dosimetry, and conclusions. RESULTS: In many instances, the studies contained inadequate or unclear information that would hamper efforts to replicate or intercompare the studies, and that weakened the evidence for designing and conducting clinical trials. The published reports on these drugs showed mixed results on enhancement of radiation response, except for sunitinib, which was ineffective. CONCLUSIONS: There is a need for improved experimental design, execution, and reporting of preclinical testing of agents that are candidates for clinical use in combination with radiation. A checklist is provided for authors and reviewers to ensure that preclinical studies of drug radiation combinations meet standards of design, execution, and interpretation, and report necessary information to ensure high quality and reproducibility of studies. Improved design, execution, common measures of enhancement, and consistent interpretation of preclinical studies of drug-radiation interactions will provide rational guidance for prioritizing drugs for clinical radiotherapy trials and for the design of such trials. PMID- 26947882 TI - The Role of NG2 Proteoglycan in Glioma. AB - Neuron glia antigen-2 ((NG2), also known as chondroitin sulphate proteoglycan 4, or melanoma-associated chondroitin sulfate proteoglycan) is a type-1 membrane protein expressed by many central nervous system (CNS) cells during development and differentiation and plays a critical role in proliferation and angiogenesis. 'NG2' often references either the protein itself or the highly proliferative and undifferentiated glial cells expressing high levels of NG2 protein. NG2 glia represent the fourth major type of neuroglia in the mammalian nervous system and are classified as oligodendrocyte progenitor cells by virtue of their committed oligodendrocyte generation in developing and adult brain. Here, we discuss NG2 glial cells as well as NG2 protein and its expression and role with regards to CNS neoplasms as well as its potential as a therapeutic target for treating childhood CNS cancers. PMID- 26947883 TI - PD-L1 Expression and Survival among Patients with Advanced Non-Small Cell Lung Cancer Treated with Chemotherapy. AB - BACKGROUND: Recent clinical trial results have suggested that programmed cell death ligand 1 (PD-L1) expression measured by immunohistochemistry may predict response to anti-programmed cell death 1 (PD-1) therapy. Results on the association between PD-L1 expression and survival among patients with advanced non-small cell lung cancer (NSCLC) treated with chemotherapy are inconsistent. MATERIAL AND METHODS: We evaluated the relationship between PD-L1 expression and overall survival (OS) among 204 patients with advanced NSCLC treated at Aarhus University Hospital, Aarhus, Denmark, from 2007 to 2012. PD-L1 expression was measured using a prototype immunohistochemistry assay with the anti-PD-L1 22C3 antibody (Merck). PD-L1 strong positivity and weak positivity were defined to be traceable to the clinical trial version of the assay. RESULTS: Twenty-five percent of patients had PD-L1 strong-positive tumors, and 50% had PD-L1 weak positive tumors. No statistically significant association was found between PD-L1 expression and survival; adjusted hazard ratio of 1.34 (95% confidence interval, 0.88-2.03; median OS, 9.0 months) for the PD-L1 strong-positive group and 1.07 (0.74-1.55; median OS, 9.8 months) for the PD-L1 weak-positive group compared with the PD-L1-negative group (median OS, 7.5 months). No association was seen between PD-L1 expression and OS when PD-L1 expression levels were stratified by median or tertiles. CONCLUSIONS: In concordance with previous studies, we found PD-L1 measured by immunohistochemistry to be frequently expressed in patients with advanced NSCLC. However, PD-L1 expression is not a strong prognostic marker in patients with advanced NSCLC treated with chemotherapy. PMID- 26947884 TI - Droxinostat, a Histone Deacetylase Inhibitor, Induces Apoptosis in Hepatocellular Carcinoma Cell Lines via Activation of the Mitochondrial Pathway and Downregulation of FLIP. AB - BACKGROUND: The current chemotherapeutic outcomes for hepatocellular carcinoma (HCC) are not encouraging, and long-term survival of this patient group remains poor. Recent studies have demonstrated the utility of histone deacetylase inhibitors that can disrupt cell proliferation and survival in HCC management. However, the effects of droxinostat, a type of histone deacetylase inhibitor, on HCC remain to be established. METHODS: The effects of droxinostat on HCC cell lines SMMC-7721 and HepG2 were investigated. Histone acetylation and apoptosis modulating proteins were assessed via Western blot. Proliferation was examined with 3-(4, 5 dimetyl-2-thiazolyl)-2, 5-diphenyl 2H-tetrazolium bromide, cell proliferation, and real-time cell viability assays, and apoptosis with flow cytometry. RESULTS: Droxinostat inhibited proliferation and colony formation of the HCC cell lines examined. Hepatoma cell death was induced through activation of the mitochondrial apoptotic pathway and downregulation of FLIP expression. Droxinostat suppressed histone deacetylase (HDAC) 3 expression and promoted acetylation of histones H3 and H4. Knockdown of HDAC3 induced hepatoma cell apoptosis and histone H3 and H4 acetylation. CONCLUSIONS: Droxinostat suppresses HDAC3 expression and induces histone acetylation and HCC cell death through activation of the mitochondrial apoptotic pathway and downregulation of FLIP, supporting its potential application in the treatment of HCC. PMID- 26947885 TI - Scaffold-Free Coculture Spheroids of Human Colonic Adenocarcinoma Cells and Normal Colonic Fibroblasts Promote Tumorigenicity in Nude Mice. AB - The aim of this study was to form a scaffold-free coculture spheroid model of colonic adenocarcinoma cells (CACs) and normal colonic fibroblasts (NCFs) and to use the spheroids to investigate the role of NCFs in the tumorigenicity of CACs in nude mice. We analysed three-dimensional (3D) scaffold-free coculture spheroids of CACs and NCFs. CAC Matrigel invasion assays and tumorigenicity assays in nude mice were performed to examine the effect of NCFs on CAC invasive behaviour and tumorigenicity in 3D spheroids. We investigated the expression pattern of fibroblast activation protein-alpha (FAP-alpha) by immunohistochemical staining. CAC monocultures did not form densely-packed 3D spheroids, whereas cocultured CACs and NCFs formed 3D spheroids. The 3D coculture spheroids seeded on a Matrigel extracellular matrix showed higher CAC invasiveness compared to CACs alone or CACs and NCFs in suspension. 3D spheroids injected into nude mice generated more and faster-growing tumors compared to CACs alone or mixed suspensions consisting of CACs and NCFs. FAP-alpha was expressed in NCFs-CACs cocultures and xenograft tumors, whereas monocultures of NCFs or CACs were negative for FAP-alpha expression. Our findings provide evidence that the interaction between CACs and NCFs is essential for the tumorigenicity of cancer cells as well as for tumor propagation. PMID- 26947886 TI - Leptin promotes apoptosis and inhibits autophagy of chondrocytes through upregulating lysyl oxidase-like 3 during osteoarthritis pathogenesis. AB - OBJECTIVE: Leptin has been found highly expressed in human osteoarthritis. We aimed to explore the possible effects and mechanisms of leptin on the apoptosis and autophagy of chondrocytes during osteoarthritis pathogenesis. METHODS: Gene expression profile from osteoarthritis affected and preserved cartilage were downloaded from NCBI's Gene Expression Omnibus database (GSE57218). Lysyl oxidase like 3 (LOXL3) mRNA expression in cartilage tissues and leptin concentration in joint synovial fluid (SF) was measured in samples from 45 osteoarthritis patients and 25 healthy donors by real-time PCR and radioimmunoassay, respectively. Rat osteoarthritis model was induced by anterior cruciate ligament transection (ACLT). The expression of apoptosis regulators and autophagy markers were detected by Western blot. Cell survival and cell apoptosis were identified by CCK 8 and flow cytometry, respectively. RESULTS: Re-analysis on GSE57218 indicated that LOXL3 mRNA was upregulated in osteoarthritis affected cartilage. LOXL3 mRNA was upregulated in osteoarthritis patients, which was positively correlated with SF leptin concentration. Similar results were obtained in rat osteoarthritis model. Moreover, ACLT surgery led to a significant increase in the protein levels of cleaved caspase 3, and a notable decrease in the protein levels of Bcl-2, LC3 II/LC3 I and Beclin1. Silencing of LOXL3 in ACLT and leptin treated primary chondrocytes significantly inhibited cell apoptosis, and promoted cell proliferation and autophagy. Moreover, overexpression of LOXL3 remarkably inhibited autophagy of chondrocytes via activating mTORC1. CONCLUSIONS: LOXL3, a downstream of leptin, stimulated the apoptosis, but inhibited the autophagy of chondrocytes. LOXL3 is a potential therapy target for osteoarthritis. PMID- 26947888 TI - Risk factors for complications following immediate tissue expander based breast reconstruction in Taiwanese population. AB - BACKGROUND/PURPOSE: Breast cancer patients in Asia show considerable disparities from Caucasian patients, such as younger age of onset and lower rates of smoking, obesity, and diabetes. Findings of prior studies regarding risk factors associated with complications in tissue expander may not hold for Asian populations, since most of these studies involved Caucasian patients. In this study, we surveyed risk factors in the Taiwanese population, providing additional evidence about the important differences and discuss the implications for clinical practice. METHODS: Patients who underwent immediate, two-stage, tissue expander breast reconstruction from December 2008 to August 2014 in the National Taiwan University Hospital, Taipei, Taiwan were included. Follow-up observations of all patients were conducted until December 2014. Complications occurring during the tissue expander stage were evaluated. Multivariate regression modeling was used to identify risk factors for complications. RESULTS: A total of 246 consecutive, immediate, smooth round tissue expander placements were performed for breast reconstruction. The most common complication was skin necrosis (4.9%), followed by wound dehiscence (4.1%). In the multivariate model, body mass index (BMI) >= 24 kg/m2 was the only risk factor that reached statistical significance (odds ratio: 2.41, 95% confidence interval: 1.17-4.96). CONCLUSION: We provided evidence that racial disparities have an impact on the risk factors for complications associated with tissue expander breast reconstruction. BMI>=24 kg/m2 was the only risk factor significantly associated with complications. Clinically, BMI>=24 kg/m2, rather than the standard definition of obesity (BMI > 30 kg/m2), may be a more suitable cutoff point for risk in patients of Asian ethnicity. PMID- 26947887 TI - Serum lipoprotein(a) levels and diabetic nephropathy among Japanese patients with type 2 diabetes mellitus. AB - AIMS: We aimed to evaluate the association between serum lipoprotein(a) [Lp(a)] levels and diabetic nephropathy among Japanese patients with type 2 diabetes mellitus. METHODS: This study included 581 patients with type 2 diabetes mellitus. Serum Lp(a) levels were divided into four groups; the cut-off points were at the 30th, 60th, and 90th percentile values on the basis of the distribution for all subjects. Diabetic nephropathy was defined as present when the urinary albumin-creatinine ratio was >=33.9mg/mmol creatinine and/or the estimated glomerular filtration rate was <30ml/min/1.72m(2). Adjustment was made for age, sex, body mass index, hemoglobin A1c, duration of diabetes mellitus, current drinking, current smoking, hypertension, dyslipidemia, coronary heart disease, and stroke. RESULTS: Higher serum Lp(a) levels were significantly associated with a higher prevalence of diabetic nephropathy: the adjusted odds ratios (95% confidence intervals) for diabetic nephropathy in relation to serum Lp(a) levels of <=6, 7-15, 16-38, and >=39mg/dl were 1.00 (reference), 2.74 (1.08 7.00), 3.31 (1.28-8.54), and 4.80 (1.57-14.60), respectively (P for trend=0.004). CONCLUSIONS: The results suggest that serum Lp(a) levels may be positively associated with diabetic nephropathy among Japanese patients with type 2 diabetes mellitus. PMID- 26947890 TI - Achiral flexible liquid crystal trimers exhibiting chiral conglomerates. AB - Chiral conglomerates of domains with opposite handedness have attracted much attention from researchers. We prepared a homologous series of achiral liquid crystal trimers in which two phenylpyrimidine units and one biphenyl unit were connected via flexible methylene spacers. We investigated their phase transition behaviour. Some trimers possessing odd-numbered spacers were found to exhibit a nematic phase and a dark chiral conglomerate phase possessing a layered structure. The chiral characteristics were confirmed by uncrossing the polarizers in opposite directions. The layer spacing detected using X-ray diffraction was about 80% of the molecular length. The structure-property relations indicate that intermolecular interactions cause a conformational change in the trimers possessing flexible odd-numbered methylene spacers to form helical conformers with axial chirality, which might induce chiral segregation and layer deformation to drive the chiral conglomerates. PMID- 26947889 TI - The Remote Food Photography Method Accurately Estimates Dry Powdered Foods-The Source of Calories for Many Infants. AB - BACKGROUND: Infant formula is a major source of nutrition for infants, with more than half of all infants in the United States consuming infant formula exclusively or in combination with breast milk. The energy in infant powdered formula is derived from the powder and not the water, making it necessary to develop methods that can accurately estimate the amount of powder used before reconstitution. OBJECTIVE: Our aim was to assess the use of the Remote Food Photography Method to accurately estimate the weight of infant powdered formula before reconstitution among the standard serving sizes. METHODS: For each serving size (1 scoop, 2 scoops, 3 scoops, and 4 scoops), a set of seven test bottles and photographs were prepared as follow: recommended gram weight of powdered formula of the respective serving size by the manufacturer; three bottles and photographs containing 15%, 10%, and 5% less powdered formula than recommended; and three bottles and photographs containing 5%, 10%, and 15% more powdered formula than recommended (n=28). Ratio estimates of the test photographs as compared to standard photographs were obtained using standard Remote Food Photography Method analysis procedures. The ratio estimates and the US Department of Agriculture data tables were used to generate food and nutrient information to provide the Remote Food Photography Method estimates. STATISTICAL ANALYSES PERFORMED: Equivalence testing using the two one-sided t tests approach was used to determine equivalence between the actual gram weights and the Remote Food Photography Method estimated weights for all samples, within each serving size, and within underprepared and overprepared bottles. RESULTS: For all bottles, the gram weights estimated by the Remote Food Photography Method were within 5% equivalence bounds with a slight underestimation of 0.05 g (90% CI -0.49 to 0.40; P<0.001) and mean percent error ranging between 0.32% and 1.58% among the four serving sizes. CONCLUSIONS: The maximum observed mean error was an overestimation of 1.58% of powdered formula by the Remote Food Photography Method under controlled laboratory conditions, indicating that the Remote Food Photography Method accurately estimated infant powdered formula. PMID- 26947891 TI - Kelly procedure for exstrophy or epispadias patients: Anatomical description of the pudendal neurovasculature. AB - INTRODUCTION: Adequate penile length in males with bladder exstrophy or epispadias is a major challenge. Kelly previously described a surgical technique of a single stage reconstruction for patients with exstrophy or epispadias that potentially achieves significant penile lengthening by completely detaching the insertion of the corpora cavernosa from the ischiopubic rami. However, because of the possibility of damage to the pudendal neurovascular supply that may lead to partial or complete penile loss, this technique has not gained popularity. The aim of this study is to describe the surgical anatomic relationship of the pudendal neurovascular bundle (NVB) to the ischiopubic rami and to determine a safer approach to dissection during the Kelly procedure. METHODS: We performed meticulous dissection in three formalin-fixed and one fresh adult male cadavers to demonstrate the anatomical relationships between the pudendal neurovascular supply of the penis and the cavernosal insertion to the ischiopubic ramus. RESULTS AND DISCUSSION: We demonstrated the relationships and distance between the NVB and the area of separation between the crus and the ischiopubic ramus at the level of the periosteum. The insertion of the crus to the ischiopubic ramus is inferior lateral, whereas the NVB lies at a superior medial position. This anatomical relationship is best visualized when the dissection is carried out starting from the distal portion of the NVB and proceeding proximally. This area of the periosteum is avascular and the NVB can be preserved safely as long as the dissection is conducted at that subperiosteal level. Based on this cadaver dissection study, we suppose that detaching the corporal cavernosa from the pubic bones at the subperiosteal level allows for a safe distance to be maintained from the pudendal nerve at all times. We believe that if a surgeon performs the dissection inferiorly and laterally, the corpora cavernosa can be safely detached from the ischiopubic ramus and injury to the pudendal vessels and nerve can be avoided. However, it must be noted that there are limitations to applying the results from this study of normal, adult cadavers to the anatomy of children and adolescents with exstrophy or epispadias, who form the largest proportion of patients who are candidates for this procedure. CONCLUSION: This anatomical study demonstrates the relationship between the pudendal NVB, the crus, and the ischiopubic ramus. We demonstrated how the separation of the crus from the ischiopubic periosteum might be performed more safely. PMID- 26947892 TI - TGFbeta-2 signaling is essential for osteoblast migration and differentiation during fracture healing in medaka fish. AB - TGFbeta is known as a canonical coupling factor based on its effects on bone formation and bone resorption. There are 3 different isoforms of it related to bone metabolism in mammals. TGFbeta function in vivo is complicated, and each isoform shows a different function. Since TGFbetas are secreted during inflammation accompanied by the release of latent TGFbeta from inside of the bones where they are stored in the extracellular matrix, TGFbeta function is potentially related to fracture healing. Although a few reports examined the TGFbeta expression during fracture healing, the function of TGFbeta in this process is poorly understood. To investigate TGFbeta function during fracture healing in vivo, we used the fracture healing model of the medaka fish, which enabled us to observe the behavior and function of living cells in response to a bone-specific injury. RNA in-situ hybridization analysis showed that only tgfbeta 2 of the 4 TGFbeta isoforms in medaka was expressed in the bone-forming region. To examine the TGFbeta-2 function for bone formation by osteoblasts, we used a medaka transgenic line, Tg (type X collagen: GFP); and the results revealed that type X collagen-positive immature osteoblasts migrated to the fracture site and differentiated to osterix-positive osteoblasts. However, only a few type X collagen-positive osteoblasts exhibited BrdU incorporation after the fracture. Then we inhibited TGFbeta signaling by using a chemical TGFbeta receptor kinase inhibitor (SB431542), and demonstrated that inhibition of TGFbeta strongly impaired osteoblast migration and differentiation. In addition, this TGFbeta inhibitor reduced the RANKL expression and caused a delay of osteoclast differentiation. Our findings thus demonstrated that TGFbeta-2 functioned specifically during fracture healing to stimulate the migration of osteoblasts as well as the differentiation of osteoblasts and osteoclasts. PMID- 26947894 TI - Comment on "Piriformis muscle syndrome: Diagnostic criteria and treatment of a monocentric series of 250 patients" by F. Michel et al. PMID- 26947895 TI - Osteoarthritis guidelines: Barriers to implementation and solutions. AB - Osteoarthritis (OA) is a leading cause of disability worldwide. Clinical practice guidelines (CPGs) have been developed to facilitate improved OA management. Scientific communities worldwide have proposed CPGs for OA treatment. Despite the number of highly prominent guidelines available and their remarkable consistency, their uptake has been suboptimal. Possibly because of the multitude of barriers related to the implementation of CPGs. For example, different guidelines show contradictions, some lack evidence, and they lack a hierarchy or tools to facilitate their translation and application. Also, the guidelines do not acknowledge the effect of comorbidities on choosing the treatments. Finally, poor integration of multidisciplinary services within and across healthcare settings is a major barrier to the effective implementation of management guidelines. Here we describe the main problems related to the OA guidelines and some solutions so as to offer some guidance on the elaboration of future CPGs and their implementation in primary care. PMID- 26947893 TI - The effects of proteasome inhibitors on bone remodeling in multiple myeloma. AB - Bone disease is a characteristic feature of multiple myeloma, a malignant plasma cell dyscrasia. In patients with multiple myeloma, the normal process of bone remodeling is dysregulated by aberrant bone marrow plasma cells, resulting in increased bone resorption, prevention of new bone formation, and consequent bone destruction. The ubiquitin-proteasome system, which is hyperactive in patients with multiple myeloma, controls the catabolism of several proteins that regulate bone remodeling. Clinical studies have reported that treatment with the first-in class proteasome inhibitor bortezomib reduces bone resorption and increases bone formation and bone mineral density in patients with multiple myeloma. Since the introduction of bortezomib in 2003, several next-generation proteasome inhibitors have also been used clinically, including carfilzomib, oprozomib, ixazomib, and delanzomib. This review summarizes the available preclinical and clinical evidence regarding the effect of proteasome inhibitors on bone remodeling in multiple myeloma. PMID- 26947897 TI - [Intestinal microbiota and ageing: A new intervention route?]. AB - Intestinal microbiota (IM) has continued to be the subject in all types of studies and publications. More is known on its different components and functions, as well as the changes that take place in IM through the life cycle, and the role of the factors involved in these changes. The aim of this review is to update the relationship between IM and aging. The presentation in 4 sections: (i)main factors of the human ageing process, underlining those related with gut changes; (ii)conceptual meaning of words like microbiota and other related terms; (iii)to comment on the most current findings as regards the changes in IM that occur in the ageing process, whether arising from the physiology or from disease situations, or other factors (environment, diet, drugs, etc.), and the health consequences of these changes, and (iv)possibilities of different active positive interventions, with emphasis on diet measures. PMID- 26947896 TI - Humoral deficiency in three paediatric patients with genetic diseases. AB - BACKGROUND: Primary immunodeficiencies (PID) represent a heterogeneous group of genetic disorders characterised by poor or absent function in one or more components of the immune system. Humoral or antibody immunodeficiencies are the most common form of PID, of which common variable immunodeficiency (CVID) is the most frequent symptomatic form. CVID is usually characterised by hypogammaglobulinaemia with poor antibody specificity, and an increased susceptibility to infections, autoimmunity and lymphoproliferation. Fewer than 10% of CVID patients have a known monogenic basis. Several chromosomal abnormalities (chromosome 18q-syndrome, monosomy 22, trisomy 8 and trisomy 21) are currently identified as causes of hypogammaglobulinaemia, and can manifest with recurrent infections and mimic CVID. METHODS: Review of clinical charts and laboratory results of paediatric patients followed in the outpatient clinic of PID with a diagnosis of genetic disease and humoral immunodeficiency. RESULTS: Three patients with different genetic diseases (19p13.3 deletion, a ring 18 chromosome and Kabuki syndrome), were identified. During follow-up, they developed signs and symptoms suggestive of humoral deficiency mimicking CVID, despite which immunoglobulin levels were quantified with considerable delay with respect to symptoms onset, and specific management was subsequently delayed. CONCLUSIONS: Patients with genetic abnormalities and recurrent infections should be evaluated for hypogammaglobulinaemia. An early diagnosis of humoral deficiency can allow treatment optimisation to prevent complications and sequelae. PMID- 26947898 TI - Linkages between public and non-government sectors in healthcare: A case study from Uttar Pradesh, India. AB - Effective utilisation of collaborative non-governmental organisation (NGO)-public health system linkages in pluralistic health systems of developing countries can substantially improve equity and quality of services. This study explores level and types of linkages between public health sector and NGOs in Uttar Pradesh (UP), an underprivileged state of India, using a social science model for the first time. It also identifies gaps and challenges for effective linkage. Two NGOs were selected as case studies. Data collection included semi-structured in depth interviews with senior staff and review of records and reporting formats. Formal linkages of NGOs with the public health system related to registration, participation in district level meetings, workforce linkages and sharing information on government-supported programmes. Challenges included limited data sharing, participation in planning and limited monitoring of regulatory compliances. Linkage between public health system and NGOs in UP was moderate, marked by frequent interaction and some reciprocity in information and resource flows, but weak participation in policy and planning. The type of linkage could be described as 'complementarity', entailing information and resource sharing but not joint action. Stronger linkage is required for sustained and systematic collaboration, with joint planning, implementation and evaluation. PMID- 26947899 TI - Ring-opening metathesis polymerization of 1,2-disubstituted cyclopropenes. AB - The ring-opening metathesis polymerization (ROMP) of 1,2-disubstituted cyclopropenes (CPs) has been explored for the first time using Grubbs 3rd generation catalyst. A range of 1,2-CPs yielded polymers with controllable MWs and low dispersitities, and allowed the synthesis of block copolymers, absent from secondary metathesis. However, there existed a competing intramolecular termination pathway for these monomers, limiting the timescale for their ROMP to stay living. PMID- 26947900 TI - Ethnopharmacological survey on medicinal plants used in herbal drinks among the traditional communities of Pakistan. AB - ETHNOPHARMACOLOGICAL RELEVANCE: There is very limited information regarding medicinal plants used by traditional healers in Pakistan, for treating wide ranging diseases. Current study provides significant ethnopharmacological information, both qualitative and quantitative on medical plants in Pakistan and the pharmacological importance of herbal drinks, especially in the discovery of new drugs. MATERIALS AND METHODS: The current ethnomedicinal field study was conducted from various traditional communities of Pakistan to document usage of medicinal plants as herbal drinks. Data was collected through field interviews from local people and using semi-structured questionnaires. Data was analyzed using quantitative indices such as UV (use value), RFC (Relative frequency of citation), and FL (Fidelity level). RESULTS: The present study recorded 217 plant species belonging to 174 genera and 69 families used in herbal drinks preparations. Major herbal preparations include decoctions, infusions and juice. According to use reports, significant species were Aloe vera, Artemisia fragrans, Allium cepa, Senegalia catechu, Alternanthera sessilis, Malva ludwigii, Arnebia benthamii, Cichorium intybus, Coccinia grandis, Dalbergia sissoo. Major ailment treated with herbal drinks include heartburn, fever, diarrhea, hypertension, and others. Use value (UV) varies from 0.23 to 0.02, with Mentha arvensis (0.23) having the highest value of UV followed by Mentha longifolia (0.22), Plantago lanceolate (0.19), Achillea millefolium (0.18), Coriandrum sativum (0.18), Justicia adhatoda and Malva sylvestris (0.17). Values of RFC varies from 0.28 to 0.09 while Fidelity level (FL) among plants varies from 37.5 to 100. Alternanthera sessilis, Oxytropis lapponica, Millettia pinnata and Salvia bucharica had the highest FL value (100). CONCLUSION: The use of medicinal plants is prevalent in traditional communities of Pakistan. Different herbal preparations are in common practice including various herbal drinks a common tradition and much favoured herbal preparation in terms of its results and regarded as reciprocal to modern drugs. Therefore, suggesting further pharmacological, phytochemical evaluation for essential metabolites and chemical constituents. PMID- 26947901 TI - Synergistic cytotoxic effects of combined delta-tocotrienol and jerantinine B on human brain and colon cancers. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The genus Tabernaemontana has widespread distribution throughout tropical and subtropical parts of the world, i.e. Africa, Asia and America which has long been used for treatments of different disease conditions including tumours, wounds, syphilis, stomach ache and headache. Some Tabernaemontana species are used for treatment of piles, spleen and abdominal tumours in India. In particular, the leaf of Tabernaemontana corymbosa is used for treatment of tumours in Bangladesh. Parts of the plant or whole plants are used as decoctions, steam bath, powder and ointments. AIM OF STUDY: The present study was undertaken to study the mechanism of apoptosis induction in human glioblastoma (U87MG) and colorectal adenocarcinoma (HT-29) cancer cells by a novel indole alkaloid, jerantinine B isolated from T. corymbosa, delta tocotrienol and the combined low-dose treatments of delta-tocotrienol with IC20 dose of jerantinine B. MATERIALS AND METHODS: Cell viability, isobologram and combinational index (CI) analyses were used to determine the pharmacological interaction between combined treatments based on the IC50 values obtained. Fluorescence and histochemical staining techniques as well as comet assay were used for evaluating the morphological changes and DNA damage pattern, respectively. The effects of treatments on microtubules, caspase activity and cell death were determined using immunofluorescence technique, caspase colorimetric and neutral red uptake assays, respectively. RESULTS: Jerantinine B, delta-tocotrienol and combined low-dose treatments induced a dose-dependent growth inhibition against U87MG and HT-29 cells selectively with less toxicity acted towards the normal MRC5 cells. Synergistic growth inhibition observed with CI values of 0.85 and 0.77 for U87MG and HT-29 cells, resulting in up to 2-fold and 3.8-fold dose reduction of delta-tocotrienol and jerantinine B, respectively. U87MG and HT-29 cells exhibited morphological features of apoptosis and double stranded DNA breaks. Individual and combined treatments induced caspase 8 and 3 activities and cell death independent of caspase activation on U87MG and HT-29 cells. An increased caspase 9 activity was also evident on U87MG and HT-29 treated with combined treatments and HT-29 cells treated with jerantinine B. Jerantinine B and combined low-dose treatments with delta-tocotrienol undoubtedly disrupted the microtubule networks. CONCLUSION: The present study demonstrated the mechanism for cytotoxic potency of delta-tocotrienol and jerantinine B against U87MG and HT-29 cells. Furthermore, combined low-dose treatments induced concurrent synergistic inhibition of cancer cell growth with concomitant dose reduction thus minimizing toxicity to normal cells and improving potency of delta tocotrienol and jerantinine B. PMID- 26947902 TI - Bioassay-guided isolation of wound healing active compounds from Echium species growing in Turkey. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The roots and root barks of Echium sp. have been used to treat ulcers, burns and wounds in traditional Turkish medicine. AIM OF THE STUDY: On the basis of them traditional use and literature references, four Echium species were selected for evaluation of them wound healing potential. Isolation of active component(s) from the active extracts through the bioassay guided fractionation procedures. MATERIAL AND METHODS: In vivo the wound healing activity of the plants was evaluated by linear incision experimental models. The chloroform extract of Echium italicum L. was fractionated by successive chromatographic techniques. Wound healing activity of each fraction was investigated following the bioassay-guided fractionation procedures. Moreover, the tissue samples of isolated compounds were examined histopathologically. The healing potential was comparatively assessed with a reference ointment Madecassol(r), which contains 1% extract of Centella asiatica. RESULTS: Significant wound healing activity was observed from the ointment prepared with ethanol extract at 1% concentration. The ethanol root extract treated in groups of animals showed a significant increase (37.38%, 40.97% and 35.29% separately for E. italicum L, Echium vulgare L. and Echium angustifolium Miller) wound tensile strength in the incision wound model. Subfractions showed significant but reduced wound healing activity on in vivo wound models. Shikonin derivatives "Acetylshikonin", "Deoxyshikonin" and "2-methyl-n butyrylshikonin+Isovalerylshikonin", were isolated and determined as active components of active final subfraction from E. italicum L. roots. The results of histopathological examination supported the outcome of linear incision wound models. CONCLUSION: The experimental study revealed that Echium species display remarkable wound healing activity. PMID- 26947903 TI - Large variations in ocular dimensions in a multiethnic population with similar genetic background. AB - We aimed to describe the ethnic variations in ocular dimensions among three ethnic groups with similar genetic ancestry from mainland of China. We included 2119 ethnic Bai, 2202 ethnic Yi and 2183 ethnic Han adults aged 50 years or older in the study. Ocular dimensions including axial length (AL), anterior chamber depth (ACD), vitreous chamber depth (VCD) and lens thickness (LT) were measured using A-scan ultrasonography. Bai Chinese had longer ALs (P < 0.001), deeper ACDs (P < 0.001) but shallower VCDs (P < 0.001) compared with the other two ethnic groups. There were no ethnic variations in LTs. Diabetes was associated with shallower ACDs and this association was stronger in Bai Chinese compared with Yi or Han Chinese (P for interaction = 0.02). Thicker lenses were associated with younger age (P = 0.04), male gender (P < 0.001), smoking history (P = 0.01), alcohol intake (P = 0.03), the presence of cataract (P < 0.001), and the presence of diabetes (P < 0.001). There were significant differences in ocular dimensions among different ethnic groups with small differences in genetics but large variations in cultures and lifestyles. PMID- 26947910 TI - [Which place for point-of-care screening tests in the diagnosis of hepatitis C infection among drug users?]. AB - Hepatitis C is a severe disease, which often evolves into chronicity and for which there is no vaccine available. Therefore its screening is essential, especially among drug users who are the main reservoir of the hepatitis C virus (HCV). Current guidelines for screening are based on the detection of total anti HCV antibodies (Ab) by means of third generation EIA. This test is performed in a laboratory from a venous sample. Alternative methods have been recently developed, including point-of-care tests (POCT) that offer many advantages. Their excellent diagnostic performance, their quick results and their ease of use by a large number of professionals are arguments in favor of widespread use of these tests. The expected benefits of the use of POCT are individual (better knowledge of HCV status, better access to care and treatment) but also collective (reduction of morbidity and mortality related to HCV and its cost in terms of public health) Because of their clinical interest, POCT should be refunded as well as the currently recommended screening test. In order to optimize their ease of use, POCT use should be integrated into an organized screening and hepatology follow-up system. PMID- 26947911 TI - [Cutaneous myiasis of the scalp: An exceptional case in the emergency department]. PMID- 26947912 TI - A covalent and cleavable antibody-DNA conjugation strategy for sensitive protein detection via immuno-PCR. AB - Immuno-PCR combines specific antibody-based protein detection with the sensitivity of PCR-based quantification through the use of antibody-DNA conjugates. The production of such conjugates depends on the availability of quick and efficient conjugation strategies for the two biomolecules. Here, we present an approach to produce cleavable antibody-DNA conjugates, employing the fast kinetics of the inverse electron-demand Diels-Alder reaction between tetrazine and trans-cyclooctene (TCO). Our strategy consists of three steps. First, antibodies are functionalized with chemically cleavable NHS-s-s-tetrazine. Subsequently, double-stranded DNA is functionalized with TCO by enzymatic addition of N3-dATP and coupling to trans-Cyclooctene-PEG12-Dibenzocyclooctyne (TCO-PEG12-DBCO). Finally, conjugates are quickly and efficiently obtained by mixing the functionalized antibodies and dsDNA at low molar ratios of 1:2. In addition, introduction of a chemically cleavable disulphide linker facilitates release and sensitive detection of the dsDNA after immuno-staining. We show specific and sensitive protein detection in immuno-PCR for human epidermal stem cell markers, ITGA6 and ITGB1, and the differentiation marker Transglutaminase 1 (TGM1). We anticipate that the production of chemically cleavable antibody-DNA conjugates will provide a solid basis for the development of multiplexed immuno PCR experiments and immuno-sequencing methodologies. PMID- 26947913 TI - Making the invisible visible: a qualitative study of the values, attitudes and norms of radiologists relating to radiation safety. AB - Some shortcomings regarding safety have emerged in inspections by the Swedish Radiation Safety Authority of Swedish radiology departments which perform 5.4 million radiological examinations and 100 000 nuclear scans annually. To ensure safety in the healthcare system and to build a strong environment of radiation protection for patients (and for employees) there must be a strong culture of safety. To understand an organization's behaviour, decisions and actions it is important to study its cultural values. The aims of this study were to discuss how values, attitudes and norms affect radiologists' decisions as well as how they influence the implementation of various radiation protection measures. To investigate this, focus group interviews and in-depth individual interviews were performed in a sample from a number of radiology departments at hospitals in Sweden. The results show that the core value was derived from the patients' perspective with the focus on the knowledge that he or she has come to the healthcare system for a particular reason: to discover disease or, in the best case, to be declared healthy. The majority attitudes were based on experiences associated with aspects that the radiologist could not influence. This often concerns increased pressure on radiology investigations from clinics in the various operational units. Under the concept of norms, the radiologists in the study requested that the development of regulations and guidelines should be connected to issues of justification for various radiological queries. PMID- 26947914 TI - Non-coding RNA LINC00473 mediates decidualization of human endometrial stromal cells in response to cAMP signaling. AB - Decidualization is an essential step in the establishment of pregnancy. However, the functional contributions of long intergenic noncoding RNAs (LincRNAs) to decidualization have not been explored. To explore the regulation and role of LincRNAs during human decidualization, human endometrial stromal cells (HESCs) are induced to undergo in vitro decidualization by treating with estradiol 17beta, db-cAMP and medroxyprogesterone acetate. LINC00473 (LINC473) expression is highly induced in HESCs after decidual stimulus. We found that cAMP-PKA pathway regulates the expression of LINC473 through IL-11-mediated STAT3 phosphorylation. RNA interference-mediated down-regulation of LINC473 inhibits in vitro decidualization. These results suggested that LINC473 might be functionally required for human decidualization. This is the first report demonstrating the presence of LincRNA during human decidualization. PMID- 26947915 TI - The effect of white light on normal and malignant murine melanocytes: A link between opsins, clock genes, and melanogenesis. AB - The skin possesses a photosensitive system comprised of opsins whose function is not fully understood, and clock genes which exert an important regulatory role in skin biology. Here, we evaluated the presence of opsins in normal (Melan-a cells) and malignant (B16-F10 cells) murine melanocytes. Both cell lines express Opn2, Opn4--for the first time reported in these cell types--as well as S-opsin. OPN4 protein was found in a small area capping the cell nuclei of B16-F10 cells kept in constant dark (DD); twenty-four hours after the white light pulse (WLP), OPN4 was found in the cell membrane. Despite the fact that B16-F10 cells expressed less Opn2 and Opn4 than Melan-a cells, our data indicate that the malignant melanocytes exhibited increased photoresponsiveness. The clock gene machinery is also severely downregulated in B16-F10 cells as compared to Melan-a cells. Per1, Per2, and Bmal1 expression increased in B16-F10 cells in response to WLP. Although no response in clock gene expression to WLP was observed in Melan-a cells, gene correlational data suggest a minor effect of WLP. In contrast to opsins and clock genes, melanogenesis is significantly upregulated in malignant melanocytes in comparison to Melan-a cells. Tyrosinase expression increased after WLP only in B16-F10 cells; however no increase in melanin content after WLP was seen in either cell line. Our findings may prove useful in the treatment and the development of new pharmacological approaches of depigmentation diseases and skin cancer. PMID- 26947916 TI - Large-area graphene-based nanofiltration membranes by shear alignment of discotic nematic liquid crystals of graphene oxide. AB - Graphene-based membranes demonstrating ultrafast water transport, precise molecular sieving of gas and solvated molecules shows great promise as novel separation platforms; however, scale-up of these membranes to large-areas remains an unresolved problem. Here we demonstrate that the discotic nematic phase of graphene oxide (GO) can be shear aligned to form highly ordered, continuous, thin films of multi-layered GO on a support membrane by an industrially adaptable method to produce large-area membranes (13 * 14 cm(2)) in <5 s. Pressure driven transport data demonstrate high retention (>90%) for charged and uncharged organic probe molecules with a hydrated radius above 5 A as well as modest (30 40%) retention of monovalent and divalent salts. The highly ordered graphene sheets in the plane of the membrane make organized channels and enhance the permeability (71 +/- 5 l m(-2) hr(-1) bar(-1) for 150 +/- 15 nm thick membranes). PMID- 26947917 TI - Significance of ACADM mutations identified through newborn screening of MCAD deficiency in Japan. AB - BACKGROUND: Since the first case was detected in 2000, there has been a remarkable increase in Japanese patients diagnosed with medium-chain acyl-CoA dehydrogenase (MCAD) deficiency. Genetic analysis has revealed a spectrum of mutations that is quite different from those observed in Caucasian populations. In 2014, Japan initiated nationwide newborn screening (NBS) for MCAD using tandem mass spectrometry (MS/MS). It is an urgent issue to assess the risk of acute metabolic decompensation from the respective novel mutations found thus far. METHODS: To evaluate the pathogenic effect of each mutation, we established a eukaryotic cell expression system and prepared 11 mutant proteins identified in five symptomatic patients and eight MS/MS-NBS-positive newborns, as well as two common Caucasian mutations, p.K329E (c.985G>A) and p.Y67H (c.157C>T) for comparison. RESULTS: The expression of four mutant proteins (p.Q45R, p.P92L, p.P128X and p.Y397N) were severely impaired, whereas the others expressed normally, as did p.K329E and p.Y67H. Based on their dehydrogenase activities toward n-octanoyl-CoA, we determined three mutations (p.R53C, p.R281S and p.G362E) to be disease-causing, two mutations having (p.R17H and p.M274V) to be of marginal risk, and two mutations (p.K271E and p.I416T) as benign. Their allele specific activities were as a whole in accordance with those estimated from the results of measurement in peripheral blood mononuclear cells. CONCLUSION: As most of the mutations detected in the Japanese population are unique, prudent genetic and enzymatic analysis is essential to precisely evaluate the latent risk of clinical onset for screening-positive newborns. PMID- 26947918 TI - Morphometric analysis of gray matter integrity in individuals with early-treated phenylketonuria. AB - The most widely-reported neurologic finding in individuals with early-treated phenylketonuria (PKU) is abnormality in the white matter of the brain. In contrast, much less is known regarding the impact of PKU on cortical gray matter (GM) structures. Presently, we applied advanced morphometric methods to the analysis of high-resolution structural MRI images from a sample of 19 individuals with early-treated PKU and an age- and gender-matched comparison group of 22 healthy individuals without PKU. Data analysis revealed decreased GM volume in parietal cortex for the PKU group compared with the non-PKU group. A similar trend was observed for occipital GM volume. There was no evidence of group related differences in frontal or temporal GM volume. Within the PKU group, we also found a significant relationship between blood phenylalanine levels and GM volume for select posterior cortical sub-regions. Taken together with previous research on white matter and gray matter abnormalities in PKU, the present findings point to the posterior cortices as the primary site of neurostructural changes related to early-treated PKU. PMID- 26947919 TI - Mitochondrial selectivity and remarkable photocytotoxicity of a ferrocenyl neodymium(III) complex of terpyridine and curcumin in cancer cells. AB - A series of four novel neodymium(iii) complexes of the formulation [Nd(R-tpy)(O O)(NO3)2] (), where R-tpy is 4'-phenyl-2,2':6',2''-terpyridine (Ph-tpy; , ) and 4'-ferrocenyl-2,2':6',2''-terpyridine (Fc-tpy; , ); O-O is the conjugate base of acetylacetone (Hacac; , ) or curcumin (Hcurc; , ), are synthesized and characterized. The single crystal structure of shows that the complex is a discrete mononuclear species with the Nd(iii) centre in a nine coordinate environment provided by a set of O6N3 donor atoms. Complexes and having the simple acac ligand are prepared as control compounds. Complex , possessing an appended ferrocenyl (Fc) and the curcumin moiety, is remarkably photocytotoxic to HeLa and MCF-7 cancer cells in visible light giving respective IC50 values of 0.7 MUM and 2.1 MUM while being significantly less toxic to MCF-10A normal cells (IC50 = 34 MUM) and in the dark (IC50 > 50 MUM). The phenyl appended complex , lacking a ferrocenyl moiety, is significantly less toxic to both the cell lines when compared with . Complexes and , lacking the photoactive curcumin moiety, do not show any apparent toxicity both in light and in the dark. The cell death is apoptotic in nature and is mediated by the light-induced formation of reactive oxygen species (ROS). Fluorescence imaging experiment with HeLa cells reveals mitochondrial accumulation of complex within 4 h of incubation. The complexes bind to calf thymus (ct) DNA with moderate affinity giving Kb values in the range of 10(4)-10(5) M(-1). The curcumin complexes and cleave plasmid supercoiled DNA to its nicked circular form in visible light via(1)O2 and OH pathways. The presence of the ferrocenyl moiety is likely to be responsible for the enhanced cellular uptake and photocytotoxicity of complex . Thus, the mitochondria targeting complex , being remarkably cytotoxic in light but non-toxic in the dark and to normal cells, is a potential candidate for photochemotherapeutic applications. PMID- 26947920 TI - Chlorination of Betacyanins in Several Hypochlorous Acid Systems. AB - This study presents a comparative evaluation of chlorination of betanin, betanidin, and neobetanin exposed to sodium hypochlorite and myeloperoxidase (MPO)/H2O2/Cl(-) systems. For betanin/betanidin, the chlorination takes place at the aglycone unit, but for neobetanin, no chlorinated products in the reaction mixtures can be detected. In the RP-HPLC system, monochloro-betanin/-betanidin were eluted earlier than their corresponding nonchlorinated substrates. An influence of Cl(-) concentration on betanin/betanidin chlorination efficiency in sodium hypochlorite and MPO systems was investigated. At pH 3-5, the yields of formed monochloro-betanin/-betanidin decrease dramatically at higher Cl(-) concentrations, indicating that generated Cl2 is not the chlorinating agent in the presence of sodium hypochlorite. The intriguing low activity of Cl2 in betanin/betanidin chlorination compared to HOCl and/or Cl2O can be explained by a special position of the attack by molecules of HOCl and/or Cl2O. In the MPO/H2O2/Cl(-) system, the highest efficiency of monochloro-betanin/-betanidin generation is observed at pH 5. PMID- 26947921 TI - Characterization of Therapeutic Monoclonal Antibodies at the Subunit-Level using Middle-Down 193 nm Ultraviolet Photodissociation. AB - Monoclonal antibodies (mAbs) are a rapidly advancing class of therapeutic glycoproteins that possess wide clinical utility owing to their biocompatibility, high antigen specificity, and targeted immune stimulation. These therapeutic properties depend greatly on the composition of the immunoglobulin G (IgG) structure, both in terms of primary sequence and post-translational modifications (PTMs); however, large-scale production in cell culture often results in heterogeneous mixtures that can profoundly affect clinical safety and efficacy. This places a high demand on analytical methods that afford comprehensive structural characterization of mAbs to ensure their stringent quality control. Here we report the use of targeted middle-down 193 nm ultraviolet photodissociation (UVPD) to provide detailed primary sequence analysis and PTM site localization of therapeutic monoclonal antibody subunits (~25 kDa) generated upon digestion with recombinant immunoglobulin G-degrading enzyme of Streptococcus pyogenes (IdeS) followed by chemical reduction. Under optimal conditions, targeted UVPD resulted in approximately 60% overall coverage of the IgG sequence, in addition to unambiguous glycosylation site localization and extensive coverage of the antigen-binding complementarity determining regions (CDRs) in a single LC-MS/MS experiment. Combining UVPD and ETD data afforded even deeper sequencing and greater overall characterization of IgG subunits. Overall, this targeted UVPD approach represents a promising new strategy for the comprehensive characterization of antibody-based therapeutics. PMID- 26947925 TI - Integrated coastal management: Lessons learned to address new challenges. PMID- 26947926 TI - Oil-material fractionation in Gulf deep water horizontal intrusion layer: Field data analysis with chemodynamic fate model for Macondo 252 oil spill. AB - Among the discoveries of the Deepwater Horizon blowout was the so-called "sub surface plume"; herein termed the "oil-trapping layer". Hydrocarbons were found positioned at ~1100-1300m with thickness ~100-150m and moving horizontally to the SW in a vertically stratified layer at the junction of the cold abyssal water and the permanent thermocline. This study focuses on its formation process and fate of the hydrocarbons within. The originality of this work to the field is two fold, first it provides a conceptual framework which places layer origin in the context of a horizontal "intrusion" from the near-field, vertical, blow-out plume and second, it offers a theoretical model for the hydrocarbon chemicals within the horizontal layer as it moves far-afield. The model quantifies the oil material fractionation process for the soluble and fine particle. The classical Box model, retrofitted with an internal gradient, the "G-Box", allows an approach that includes turbulent eddy diffusion coupled with droplet rise velocity and reactive decay to produce a simple, explicit, transparent, algebraic model with few parameters for the fate of the individual fractions. Computations show the soluble and smallest liquid droplets moving very slowly vertically through the layer appearing within the trapping layer at low concentration with high persistence. The larger droplets move-through this trapping zone quickly, attain high concentrations, and eventually form the sea surface slick. It impacts the field of oil spill engineering science by providing the conceptual idea and the algorithms for projecting the quantities and fractions of oil-material in a deep water, horizontal marine current being dispersed and moving far afield. In the field of oil spill modeling this work extends the current generation near-field plume source models to the far-field. The theory portrays the layer as an efficient oil-material trap. The model-forecasted concentration profiles for alkanes and aromatics against the available field data support the proposed theory and the resulting model. PMID- 26947924 TI - Genome-wide characterization and analysis of bZIP transcription factor gene family related to abiotic stress in cassava. AB - The basic leucine zipper (bZIP) transcription factor family plays crucial roles in various aspects of biological processes. Currently, no information is available regarding the bZIP family in the important tropical crop cassava. Herein, 77 bZIP genes were identified from cassava. Evolutionary analysis indicated that MebZIPs could be divided into 10 subfamilies, which was further supported by conserved motif and gene structure analyses. Global expression analysis suggested that MebZIPs showed similar or distinct expression patterns in different tissues between cultivated variety and wild subspecies. Transcriptome analysis of three cassava genotypes revealed that many MebZIP genes were activated by drought in the root of W14 subspecies, indicating the involvement of these genes in the strong resistance of cassava to drought. Expression analysis of selected MebZIP genes in response to osmotic, salt, cold, ABA, and H2O2 suggested that they might participate in distinct signaling pathways. Our systematic analysis of MebZIPs reveals constitutive, tissue-specific and abiotic stress-responsive candidate MebZIP genes for further functional characterization in planta, yields new insights into transcriptional regulation of MebZIP genes, and lays a foundation for understanding of bZIP-mediated abiotic stress response. PMID- 26947927 TI - Historical record of lead accumulation and source in the tidal flat of Haizhou Bay, Yellow Sea: Insights from lead isotopes. AB - In order to investigate the historical records of lead contamination and source in coastal region of Haizhou Bay, Yellow Sea, a sediment core was collected from tidal flat, dated by (210)Pb and (137)Cs. Lead and its stable isotopic ratios were determined. The profiles of enrichment factor (EF) and Pb isotope ratios showed increasing trend upward throughout the core, correlating closely with the experience of a rapid economic and industrial development of the catchment. According to Pb isotopic ratios, coal combustion emission mainly contributed to the Pb burden in sediments. Based on end-member model, coal combustion emission dominated anthropogenic Pb sources in recent decades contributing from 48% to 67% in sediment. And the contribution of leaded gasoline was lower than 20%. A stable increase of coal combustion source was found in sediment core, while the contribution of leaded gasoline had declined recently, with the phase-out of leaded gasoline in China. PMID- 26947928 TI - Combination Therapy using Co-encapsulated Resveratrol and Paclitaxel in Liposomes for Drug Resistance Reversal in Breast Cancer Cells in vivo. AB - Multidrug resistance (MDR) is a major impediment to cancer treatment. A promising strategy for treating MDR is the joint delivery of combined anticancer agents to tumor cells in a single nanocarrier. Here, for the first time, Resveratrol (Res) was co-encapsulated with paclitaxel (PTX) in a PEGylated liposome to construct a carrier-delivered form of combination therapy for drug-resistant tumors. The composite liposome had an average diameter of 50 nm with encapsulated efficiencies of above 50%. The studies demonstrated that the composite liposome could generate potent cytotoxicity against the drug-resistant MCF-7/Adr tumor cells in vitro and enhance the bioavailability and the tumor-retention of the drugs in vivo. Moreover, systemic therapy with the composite liposome effectively inhibited drug-resistant tumor in mice (p < 0.01), without any notable increase in the toxicity. These results suggested that the co-delivery of Res and a cytotoxic agent in a nanocarrier may potentially improve the treatment of drug resistant tumors. PMID- 26947930 TI - The elephant man and other physical abnormalities. PMID- 26947929 TI - Tissue factor deficiency increases alveolar hemorrhage and death in influenza A virus-infected mice. AB - Essentials H1N1 Influenza A virus (IAV) infection is a hemostatic challenge for the lung. Tissue factor (TF) on lung epithelial cells maintains lung hemostasis after IAV infection. Reduced TF-dependent activation of coagulation leads to alveolar hemorrhage. Anticoagulation might increase the risk for hemorrhages into the lung during severe IAV infection. SUMMARY: Background Influenza A virus (IAV) infection is a common respiratory tract infection that causes considerable morbidity and mortality worldwide. Objective To investigate the effect of genetic deficiency of tissue factor (TF) in a mouse model of IAV infection. Methods Wild type mice, low-TF (LTF) mice and mice with the TF gene deleted in different cell types were infected with a mouse-adapted A/Puerto Rico/8/34 H1N1 strain of IAV. TF expression was measured in the lungs, and bronchoalveolar lavage fluid (BALF) was collected to measure extracellular vesicle TF, activation of coagulation, alveolar hemorrhage, and inflammation. Results IAV infection of wild-type mice increased lung TF expression, activation of coagulation and inflammation in BALF, but also led to alveolar hemorrhage. LTF mice and mice with selective deficiency of TF in lung epithelial cells had low basal levels of TF and failed to increase TF expression after infection; these two strains of mice had more alveolar hemorrhage and death than controls. In contrast, deletion of TF in either myeloid cells or endothelial cells and hematopoietic cells did not increase alveolar hemorrhage or death after IAV infection. These results indicate that TF expression in the lung, particularly in epithelial cells, is required to maintain alveolar hemostasis after IAV infection. Conclusion Our study indicates that TF dependent activation of coagulation is required to limit alveolar hemorrhage and death after IAV infection. PMID- 26947932 TI - RUNX1 amplification in AML with myelodysplasia-related changes and ring 21 chromosomes. AB - Ring 21 is an unstable structural abnormality of chromosome 21 that can lead to RUNX1 gene amplification. We present a unique case with a carrier patient of a constitutional ring chromosome 21 (partial monosomy and trisomy 21) with dysmorphic features and congenital malformations phenotype, who developed acute myeloid leukaemia with myelodysplasia-related changes and two ring 21 chromosomes with RUNX1 amplification. The patient's constitutional ring 21 chromosome showed alterations in tumour suppressor genes, and oncogenes, but not in RUNX1. RUNX1 gene expression at acute myeloid leukaemia diagnosis, showed no upregulation, so other genes may also be the genetic amplification targets in this patient. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26947931 TI - Proteomics study reveals that the dysregulation of focal adhesion and ribosome contribute to early pregnancy loss. AB - PURPOSE: Early pregnancy loss (EPL) affects 50-70% pregnant women in first trimester. The precise molecular mechanisms underlying EPL are far from being fully understood. Therefore, we aim to identify the molecular signaling pathways relating to EPL. EXPERIMENTAL DESIGN: We performed proteomics and bioinformatics analysis of the placental villi in women who have undergone EPL and in normal pregnant women. The proteomics data were validated by Western blot analysis. RESULTS: We identified a total of 5952 proteins in placental villi, of which 588 proteins were differentially expressed in the EPL women. Bioinformatics analysis revealed that these differentially expressed proteins participated in a variety of signaling pathways, including the focal adhesion pathway and ribosome pathway. Moreover, results of the Western blot confirmed that Desmin, Lamin A/C, MMP-9, and histone H4 were upregulated in EPL and the Lamin C/ Lamin A ratio decreased obviously in EPL. These proteins could be associated with the pathophysiology of EPL. The data have been deposited to the ProteomeXchange with identifier PXD002391. CONCLUSION AND CLINICAL RELEVANCE: Our study demonstrated that the focal adhesion pathway and ribosome pathway are involved in EPL, and these findings might contribute to unveil the pathophysiology of EPL. PMID- 26947934 TI - A Facile Method for the Synthesis of Binary Tungsten Iodides. AB - The preparation of tungsten iodides in large quantities is a challenge because these compounds are not accessible using an easy synthesis method. A new, remarkably efficient route is based on a halide exchange reaction between WCl6 and SiI4. The reaction proceeds at moderate temperatures in a closed glass vessel. The new compounds W3I12 (W3I8 ?2 I2) and W3I9 (W3I8 ?1/2I2) containing the novel [W3I8] cluster are formed at 120 and 150 degrees C, and remain stable in air. W3I12 is an excellent starting material for the synthesis of other metal rich tungsten iodides. At increasing temperature these trinuclear clusters undergo self-reduction until an octahedral tungsten cluster is formed in W6I12 . The synthesis, structure, and an analysis of the bonding of compounds containing this new trinuclear tungsten cluster are presented. PMID- 26947933 TI - PnPP-19, a spider toxin peptide, induces peripheral antinociception through opioid and cannabinoid receptors and inhibition of neutral endopeptidase. AB - BACKGROUND AND PURPOSE: The synthetic peptide PnPP-19 has been studied as a new drug candidate to treat erectile dysfunction. However, PnTx2-6, the spider toxin from which the peptide was designed, induces hyperalgesia. Therefore, we intended to investigate the role of PnPP-19 in the nociceptive pathway. EXPERIMENTAL APPROACH: Nociceptive thresholds were measured by paw pressure test. PnPP-19 was administered intraplantarly alone or with selective cannabinoid or opioid receptor antagonists. The hydrolysis of PnPP-19 by neutral endopeptidase (NEP) (EC 3.4.24.11), an enzyme that cleaves enkephalin, was monitored by HPLC and the cleavage sites were deduced by LC-MS. Inhibition by PnPP-19 and Leu-enkephalin of NEP enzyme activity was determined spectrofluorimetrically. KEY RESULTS: PnPP-19 (5, 10 and 20 MUg per paw) induced peripheral antinociception in rats. Specific antagonists of MU opioid receptors (clocinnamox), delta opioid receptors (naltrindole) and CB1 receptors (AM251) partly inhibited the antinociceptive effect of PnPP-19. Inhibition of fatty acid amide hydrolase by MAFP or of anandamide uptake by VDM11 enhanced PnPP-19-induced antinociception. NEP cleaved PnPP-19 only after a long incubation, and Ki values of 35.6 +/- 1.4 and 14.6 +/- 0.44 MUmol.L(-1) were determined for PnPP-19 and Leu-enkephalin respectively as inhibitors of NEP activity. CONCLUSIONS AND IMPLICATIONS: Antinociception induced by PnPP-19 appears to involve the inhibition of NEP and activation of CB1, MU and delta opioid receptors. Our data provide a greater understanding of the antinociceptive effects of PnPP-19. This peptide could be useful as a new antinociceptive drug candidate. PMID- 26947935 TI - Behaviour in a standardized assay, but not metabolic or growth rate, predicts behavioural variation in an adult aquatic top predator Esox lucius in the wild. AB - This study tested for links among behaviour, state and life-history variables as predicted by the pace-of-life hypothesis in adult pike Esox lucius. First, a standardized open-field behavioural assay was developed to assess individual behaviour of wild-captured adult E. lucius. Behaviour within the standardized assay predicted swimming behaviour in the lake, providing an ecological validation of the assay. There was no relationship between standardized behaviour and any of the life-history and state variables, including metabolism, body condition, juvenile growth rate and adult growth rate in contrast to predictions from the pace-of-life hypothesis. This study demonstrates that it is possible to assess ecologically relevant behavioural variation in a large-bodied top predator using a standard open-field assay, but it is noteworthy that this standardized behaviour is not systematically related to standard metabolism or growth. PMID- 26947937 TI - Hospital-assisted home care after early discharge from a Swedish neonatal intensive care unit was safe and readmissions were rare. AB - AIM: It is common in Sweden to discharge infants early from a neonatal intensive care unit (NICU) and provide hospital-assisted neonatal home care (HANHC), as an alternative to hospital care, for infants with a persisting need for specialised care. This study assessed the safety of HANHC by reviewing hospital readmissions. METHODS: We retrospectively reviewed the files of all 1410 infants enrolled in HANHC at the NICU at Sachs' Children's Hospital, Stockholm, from 2002 to 2011 up until hospital readmission or their discharge from HANHC. Each readmitted infant was matched to the next HANHC infant who was not readmitted. Predictors and reasons for readmission were investigated in a retrospective nested case-control study. RESULTS: We readmitted 74 (5.2%) of the 1410 infants in HANHC. Extremely preterm infants, born at less than 28 weeks, were readmitted more frequently than other infants, with an odds ratio of 6.07 (range 2.06-17.8). The most common symptoms were respiratory symptoms (55%), and viral respiratory tract infections were the most common reason (28%) for readmission. CONCLUSION: HANHC was safe for the vast majority of infants (94.8%). Extremely preterm birth was identified as a predictor for hospital readmission. Further studies investigating the safety of HANHC in other settings would be valuable. PMID- 26947936 TI - Spa47 is an oligomerization-activated type three secretion system (T3SS) ATPase from Shigella flexneri. AB - Gram-negative pathogens often use conserved type three secretion systems (T3SS) for virulence. The Shigella type three secretion apparatus (T3SA) penetrates the host cell membrane and provides a unidirectional conduit for injection of effectors into host cells. The protein Spa47 localizes to the base of the apparatus and is speculated to be an ATPase that provides the energy for T3SA formation and secretion. Here, we developed an expression and purification protocol, producing active Spa47 and providing the first direct evidence that Spa47 is a bona fide ATPase. Additionally, size exclusion chromatography and analytical ultracentrifugation identified multiple oligomeric species of Spa47 with the largest greater than 8 fold more active for ATP hydrolysis than the monomer. An ATPase inactive Spa47 point mutant was then engineered by targeting a conserved Lysine within the predicted Walker A motif of Spa47. Interestingly, the mutant maintained a similar oligomerization pattern as active Spa47, but was unable to restore invasion phenotype when used to complement a spa47 null S. flexneri strain. Together, these results identify Spa47 as a Shigella T3SS ATPase and suggest that its activity is linked to oligomerization, perhaps as a regulatory mechanism as seen in some related pathogens. Additionally, Spa47 catalyzed ATP hydrolysis appears to be essential for host cell invasion, providing a strong platform for additional studies dissecting its role in virulence and providing an attractive target for anti-infective agents. PMID- 26947944 TI - Effect of statin and aspirin use on toxicity and pathological complete response rate of neo-adjuvant chemoradiation for rectal cancer. AB - AIM: To retrospectively evaluate the potential impact of statin and aspirin use on acute toxicity and pathological complete response (pCR) rate in rectal cancer patients receiving neo-adjuvant long-course radiation therapy (LCRT) with concurrent chemotherapy. METHODS: A retrospective review was performed of all patients undergoing neo-adjuvant LCRT for rectal adenocarcinoma at the Regional Cancer Treatment Service between 1 September 2007 and 1 June 2011. Data obtained include demographic details; date and radiological TNM stage at diagnosis; medication taken at time of RT; toxicity during LCRT; and surgical histology to determine if a pCR was obtained following LCRT. RESULTS: Neo-adjuvant LCRT was administered to 142 patients for rectal cancer during this period; concurrent chemotherapy was omitted in 13 due to significant comorbidities. TNM stage was 2 or 3 radiologically at diagnosis in 127 (89.4%) of patients. At the time of LCRT, 23% were taking a statin and 25% were taking aspirin. Of 135 assessable patients, 34 (13%) achieved a pCR at surgery. On logistic regression, pCR was not significantly associated with the use of chemotherapy, statins, aspirin, other NSAIDs, T-stage or N-stage. There was no significant correlation between statin or aspirin use with bladder or rectal toxicity. Actuarial time to maximum rectal toxicity was not different in statin users or nonusers. CONCLUSION: In contrast to other larger retrospective series, this study did not find improvements in toxicity or pCR rate through statin or aspirin use in rectal cancer patients undergoing LCRT. Their potential benefits in this setting would be best studied prospectively in a large randomized trial. PMID- 26947945 TI - Selective chemical genetic inhibition of protein kinase C epsilon reduces ethanol consumption in mice. AB - Reducing expression or inhibiting translocation of protein kinase C epsilon (PKCepsilon) prolongs ethanol intoxication and decreases ethanol consumption in mice. However, we do not know if this phenotype is due to reduced PKCepsilon kinase activity or to impairment of kinase-independent functions. In this study, we used a chemical-genetic strategy to determine whether a potent and highly selective inhibitor of PKCepsilon catalytic activity reduces ethanol consumption. We generated ATP analog-specific PKCepsilon (AS-PKCepsilon) knock-in mice harboring a point mutation in the ATP binding site of PKCepsilon that renders the mutant kinase highly sensitive to inhibition by 1-tert-butyl-3-naphthalen-1 ylpyrazolo[3,4-d]pyrimidin-4-amine (1-NA-PP1). Systemically administered 1-NA-PP1 readily crossed the blood brain barrier and inhibited PKCepsilon-mediated phosphorylation. 1-NA-PP1 reversibly reduced ethanol consumption by AS-PKCepsilon mice but not by wild type mice lacking the AS-PKCepsilon mutation. These results support the development of inhibitors of PKCepsilon catalytic activity as a strategy to reduce ethanol consumption, and they demonstrate that the AS- PKCepsilon mouse is a useful tool to study the role of PKCepsilon in behavior. PMID- 26947947 TI - Comparison of immediate postoperative pain in implant-based breast reconstructions. AB - BACKGROUND: Implant-based techniques represent the most common form of breast reconstruction. However, substantial postoperative pain has been associated with implant-based breast reconstruction. OBJECTIVE: The objective of this study is to evaluate immediate postoperative pain in implant-based breast reconstruction. METHODS: We reviewed 378 patients who underwent implant-based reconstruction between January 2004 and December 2012. Each patient's visual analog scale (VAS) score, pain medication, and patient-controlled analgesia (PCA) attempts were used to assess in-hospital postoperative pain. We evaluated timing of reconstruction post mastectomy, tissue expander (TE) designed fill volume, TE initial fill volume, and single-stage immediate implant (II) versus TE reconstruction. RESULTS: No significant differences in pain parameters were noted between the immediate and delayed postmastectomy reconstruction cohorts. TEs with larger (>300 cc) designed volumes required significantly more narcotic use (p = 0.02) and PCA attempts (p < 0.01). Narcotic use was higher in the larger (>250-cc) TE initial fill group starting on postoperative day 2, but overall differences in VAS score and PCA attempts were not significant. Morphine equivalence (p < 0.01) and non-opioid oral analgesic use (average p = 0.03) of the TE cohort were significantly higher than those of the II cohort. CONCLUSION: Patients undergoing TE-based implant reconstruction show greater analgesic use than those with single stage II-based reconstruction. This may indicate a higher immediate postoperative pain in TE procedures than in II procedures. Furthermore, higher initial fill and designed volume of TE require more morphine equivalence postoperatively. These findings may warrant further preoperative discussion for better pain management and patient satisfaction. PMID- 26947946 TI - Differential regulation of the phosphorylation of Trimethyl-lysine27 histone H3 at serine 28 in distinct populations of striatal projection neurons. AB - Phosphorylation of histone H3 (H3) on serine 28 (S28) at genomic regions marked by trimethylation of lysine 27 (H3K27me3) often correlates with increased expression of genes normally repressed by Polycomb group proteins (PcG). We show that amphetamine, an addictive psychostimulant, and haloperidol, a typical antipsychotic drug, increase the phosphorylation of H3 at S28 and that this effect occurs in the context of H3K27me3. The increases in H3K27me3S28p occur in distinct populations of projection neurons located in the striatum, the major component of the basal ganglia. Genetic inactivation of the protein phosphatase-1 inhibitor, dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32), reduces the phosphorylation of H3K27me3S28 produced by amphetamine and haloperidol. In contrast, knockout of the mitogen- and stress activated kinase 1 (MSK1), which is implicated in the phosphorylation of histone H3, decreases the effect of amphetamine, but not that of haloperidol. Chromatin immunoprecipitation analysis shows that amphetamine and haloperidol increase the phosphorylation of H3K27me3S28 at the promoter regions of Atf3, Npas4 and Lipg, three genes repressed by PcG. These results identify H3K27me3S28p as a potential mediator of the effects exerted by amphetamine and haloperidol, and suggest that these drugs may act by re-activating PcG repressed target genes. PMID- 26947948 TI - Nonpharmacological Correction of Hypersympatheticotonia in Patients with Chronic Coronary Insufficiency and Severe Left Ventricular Dysfunction. AB - BACKGROUND: Control of sympathetic hyperactivity is pivotal for treatment of heart failure (HF) in patients with coronary artery disease (CAD). Our earlier studies demonstrated that the auricular pulsed electrical stimulation of the vagus nerve (VNS) beneficially affected condition of CAD patients with HF. The aim of our study was to evaluate changes in heart rate (HR) and the levels of heat shock proteins in peripheral blood lymphocytes in patients with CAD in the course of VNS. METHODS: The study comprised 70 individuals aged 50-68 years with chronic coronary insufficiency, severe left ventricular dysfunction, and NYHA functional class (FC) III-IV HF. Main group included 63 patients who received VNS course (group 1). Control patients (n = 7) received sham therapy (group 2). RESULTS: According to the results of 6-minute walk test and 24-hour ECG monitoring, administration of VNS improved clinical condition of 58 of 63 patients, decreased HF FC, and attenuated HR. Clinical condition in sham therapy group did not change. Immunoenzyme method demonstrated that hsp70 and hsp60 contents in peripheral blood lymphocyte lysate increased by 58% and 48% (P < 0.05), respectively, in patients who initially had HR < 80 bpm. The hsp70 level significantly increased and hsp60 level remained unchanged in patients with initial HR > 80 bpm. CONCLUSIONS: Correction of autonomous nervous status by VNS attenuated HR and improved functional state of the heart in CAD patients. Cardiotropic effect of VNS was the most pronounced in patients with preserved endogenous stress-limiting systems associated with hsp60 and/or hsp70. PMID- 26947949 TI - Factors Associated with Attendance after Referral to a Pediatric Weight Management Program. AB - OBJECTIVE: To evaluate factors affecting attendance or nonattendance at an initial interprofessional pediatric weight management visit after referral. We hypothesized that increased severity of obesity, farther distance from the program, lower education level of the primary caregiver, public insurance or no insurance, and lower socioeconomic status would all decrease likelihood of attending initial visit after referral. STUDY DESIGN: We examined referral and visit data over 4 years and 5 months. We used geocoding and multivariable logistic regression to analyze links between attendance and demographic factors, baseline body mass index, insurance type, and distance from patients' homes to the program site. RESULTS: Over the study period, 41.2% of the 4783 children referred to the pediatric weight management clinic attended at least 1 visit. A total of 4086 children were included in the full analyses. Factors associated with attendance were female sex, higher body mass index severity class, private health insurance, residence in areas with higher median income, and residence in areas with a higher prevalence of high school completion. CONCLUSIONS: The current project expands our understanding of factors linked to children's attendance at an initial pediatric weight management visit. Despite limitations including missing data, results have important implications for pediatric weight management clinics, referring providers, and policymakers to target populations with low attendance and optimize use of these evidence-based programs. PMID- 26947950 TI - Janeway Lesion: A Forgotten Entity. PMID- 26947951 TI - The Association Between Unhealthy Lifestyle Behaviors and the Prevalence of Chronic Kidney Disease (CKD) in Middle-Aged and Older Men. AB - BACKGROUND: This cross-sectional study evaluated the association between unhealthy lifestyle behaviors and the prevalence of chronic kidney disease (CKD) in middle-aged and older men. METHODS: The subjects included 445 men without a history of cardiovascular disease, stroke, or dialysis treatment, who were not taking medications. Unhealthy lifestyle behaviors were evaluated using a standardized self-administered questionnaire and were defined as follows: 1) lack of habitual moderate exercise, 2) lack of daily physical activity, 3) slow walking speed, 4) fast eating speed, 5) late-night dinner, 6) bedtime snacking, and 7) skipping breakfast. The participants were divided into four categories, which were classified into quartile distributions based on the number of unhealthy lifestyle behaviors (0-1, 2, 3, and >=4 unhealthy behaviors). RESULTS: According to a multivariate analysis, the odds ratio (OR) for CKD (defined as estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m(2) and/or proteinuria) was found to be significantly higher in the >=4 group than in the 0 1 group (OR 4.67; 95% confidence interval [CI], 1.51-14.40). Moreover, subjects' lack of habitual moderate exercise (OR 3.06; 95% CI, 1.13-8.32) and presence of late-night dinner (OR 2.84; 95% CI, 1.40-5.75) and bedtime snacking behaviors (OR 2.87; 95% CI, 1.27-6.45) were found to be significantly associated with the prevalence of CKD. CONCLUSIONS: These results suggest that an accumulation of unhealthy lifestyle behaviors, especially those related to lack of habitual moderate exercise and presence of late-night dinner and bedtime snacking may be associated with the prevalence of CKD. PMID- 26947952 TI - Evaluating the Impact of Criminalizing Drunk Driving on Road-Traffic Injuries in Guangzhou, China: A Time-Series Study. AB - BACKGROUND: Road-traffic injury (RTI) is a major public-health concern worldwide. However, the effectiveness of laws criminalizing drunk driving on the improvement of road safety in China is not known. METHODS: We collected daily aggregate data on RTIs from the Guangzhou First-Aid Service Command Center from 2009 to 2012. We performed an interrupted time-series analysis to evaluate the change in daily RTIs before (January 1, 2009, to April 30, 2011) and after (May 1, 2011, to December 31, 2012) the criminalization of drunk driving. We evaluated the impact of the intervention on RTIs using the overdispersed generalized additive model after adjusting for temporal trends, seasonality, day of the week, and holidays. Daytime/Nighttime RTIs, alcoholism, and non-traffic injuries were analyzed as comparison groups using the same model. RESULTS: From January 1, 2009, to December 31, 2012, we identified a total of 54 887 RTIs. The standardized daily number of RTIs was almost stable in the pre-intervention period but decreased gradually in the post-intervention period. After the intervention, the standardized daily RTIs decreased 9.6% (95% confidence interval [CI], 6.5% 12.8%). There were similar decreases for the daily daytime and nighttime RTIs. In contrast, the standardized daily cases of alcoholism increased 38.8% (95% CI, 35.1%-42.4%), and daily non-traffic injuries increased 3.6% (95% CI, 1.4%-5.8%). CONCLUSIONS: This time-series study provides scientific evidence suggesting that the criminalization of drunk driving from May 1, 2011, may have led to moderate reductions in RTIs in Guangzhou, China. PMID- 26947953 TI - Global Strategies for the Prevention and Control of Infectious Diseases and Non Communicable Diseases. AB - This article on global health reviews the environment surrounding health strategies and plans, as well as lessons learned from the first 15 years of the 21st century, followed by a discussion on the quest for a new paradigm for disease control efforts and challenges and opportunities for Japan. PMID- 26947955 TI - Non-Fatal Injury in Thailand From 2005 to 2013: Incidence Trends and Links to Alcohol Consumption Patterns in the Thai Cohort Study. AB - BACKGROUND: We analyzed population-based injury trends and the association between injury and alcohol consumption patterns in Thailand, a middle-income country undergoing rapid social change. METHODS: A nationwide cohort of 42 785 Thai adult Open University students, who were aged 15 to 87 years at enrolment, participated in cross-sectional assessments at baseline (2005) and 8 years later (2013). Incident non-fatal traffic and non-traffic injuries were recorded. Alcohol consumption patterns were categorized as follows: non-drinkers, occasional light drinkers, occasional heavy drinkers, regular drinkers, and ex drinkers. Logistic regression was used to assess associations in 2005 and 2013 between injuries and alcohol consumption. We adjusted odds ratios (ORs) for socio demographic factors, stress, health behaviors, and risk-taking behaviors. RESULTS: Incidence estimates in 2013 were standardized to the age structure of 2005: the standardized rates were 10% (95% confidence interval [CI], 9.32-9.89) for participants with at least one non-traffic injury and 5% (95% CI, 4.86-5.29) for those with at least one traffic injury. Both standardized incidences for non traffic and traffic injuries were significantly lower than corresponding rates in 2005 (20% and 6%, respectively). Alcohol consumption was significantly associated with non-traffic injury in 2005, but the association disappeared in 2013. For example, non-traffic injury was associated with regular drinking (adjusted OR 1.17; 95% CI, 1.01-1.40) in 2005, but not in 2013 (adjusted OR 0.89; 95% CI, 0.73 1.10). In both survey years, traffic injury was not associated with occasional heavy drinking when adjusted for health and risk-taking behavior. CONCLUSIONS: We examined non-fatal injury and the health-risk transition in Thailand in 2005 and 2013. Our data revealed decreases in alcohol consumption and non-fatal injury in the Thai Cohort between 2005 and 2013. Alcohol-related injury in Thailand today could be amenable to preventive intervention. PMID- 26947954 TI - Relationship of Having Hobbies and a Purpose in Life With Mortality, Activities of Daily Living, and Instrumental Activities of Daily Living Among Community Dwelling Elderly Adults. AB - BACKGROUND: This study's aim was to clarify the relationship of having hobbies and a purpose in life (PIL; in Japanese, ikigai) with mortality and a decline in the activities of daily living (ADL) and instrumental ADL (IADL) among the community-dwelling elderly. METHODS: Prospective observational data from residents aged >=65 years who were at increased risk for death (n = 1853) and developing a decline in ADL (n = 1254) and IADL (n = 1162) were analyzed. Cox proportional hazard models were used for mortality analysis of data from February 2011 to November 2014. ADL and IADL were evaluated using the Barthel Index and the Tokyo Metropolitan Institute of Gerontology Index of Competence, respectively. ADL and IADL were assessed at baseline and follow-up and were evaluated using logistic regression models. Fully adjusted models included terms for age, gender, BMI, income, alcohol intake, smoking history, number of chronic diseases, cognitive function, and depression. RESULTS: During the follow-up of eligible participants, 248 had died, 119 saw a decline in ADL, and 178 saw a decline in IADL. In fully adjusted models, having neither hobbies nor PIL was significantly associated with an increased risk of mortality (hazard ratio 2.08; 95% confidence interval [CI], 1.47-2.94), decline in ADL (odds ratio 2.74; 95% CI, 1.44-5.21), and decline in IADL (odds ratio 1.89; 95% CI, 1.01-3.55) compared to having both hobbies and PIL. CONCLUSIONS: Although effect modifications by cognitive functioning and depression cannot be ruled out, our findings suggest that having hobbies and PIL may extend not only longevity, but also healthy life expectancy among community-dwelling older adults. PMID- 26947957 TI - [Nursing Workforce Characteristics and Control of Diabetes Mellitus in Primary Care: a Multilevel Analysis]. AB - OBJECTIVE: Nurse activity is determined by the characteristics of nursing staff. The objective was to determine the impact of Primary Health Care (PHC) nursing workforce characteristics on the control of Diabetes Mellitus (DM) in adults. METHODS: Cross-sectional analytical study. Administrative and clinical registries and questionnaire PES-Nursing Work Index from PHC nurses. Participants 44.214 diabetic patients in two health zones within the Community of Madrid, North-West Zone (NWZ) with higher socioeconomic situation and South-West Zone (SWZ) with lower socioeconomic situation, and their 507 reference nurses. Analyses were performed to multivariate multilevel logistic regression models. PRIMARY OUTCOME MEASURE: Poor DM control (figures equal or higher than 7% HbA1c). RESULTS: The prevalence of poor DM control was 40.1% [CI95%: 38.2-42.1]. There was a risk of 25% more of poor control if the patient changed centre and of 27% if changed of doctor-nurse pair. In the multilevel multivariate regression models: in SWZ increasing the ratio of patients over 65 years per nurse increased the poor control (OR=1.00008 [CI95%:1.00006-1.001]); and higher proportion of patients whose Hb1Ac was not measured at the centre contributed to poor DM control (OR=5.1 [CI95%:1.6-15.6]). In two models for health zone, the economic immigration condition increased poor control, in SWZ (OR=1.3 [CI95%:1.03-1.7]); and in NWZ (OR=1.29 [CI95%:1.03-1.6]). CONCLUSIONS: Higher 65 years old patients ratio per nurse, economic immigration condition and a higher proportion of patients whose Hb1Ac was not measured contribute to worse DM control. PMID- 26947956 TI - Risk of Lung Cancer in Workers Exposed to Benzidine and/or Beta-Naphthylamine: A Systematic Review and Meta-Analysis. AB - Benzidine (BZ) and beta-naphthylamine (BNA) have been classified as definite human carcinogens for bladder cancer by the International Agency for Research on Cancer. However, the epidemiological evidence for an association between exposure to BZ and/or BNA and lung cancer has been inconclusive. We conducted a systematic review and meta-analysis to determine the risk for lung cancer among workers exposed to BZ/BNA. A systematic literature search was conducted to identify studies that had reported occupational BZ/BNA exposure and the outcome of interest (lung cancer death and/or incidence). Meta-analyses were performed using random effects models to combine standardized mortality ratios (SMRs) or standardized incidence ratios (SIRs). We identified 23 retrospective cohort studies including 1745 cases of lung cancer; only one study reported smoking adjusted lung cancer risk. A significantly increased lung cancer risk (pooled SMR/SIR 1.28; 95% CI, 1.14-1.43) was observed by combining all studies, with significant heterogeneity among studies (I(2) = 64.1%, P < 0.001). Effect estimates were higher for studies with direct BZ/BNA exposure (ie, dyestuff and manufacturing industries) (pooled SMR/SIR 1.58; 95% CI, 1.31-1.89), and studies that identified BZ/BNA-associated bladder cancer with SMR/SIR >=4.7 (pooled SMR/SIR 1.68; 95% CI, 1.35-2.09). Effect estimates were similar for studies with and without concomitant occupational exposure to chromium, asbestos, arsenic, or bis(chloromethyl) ether. The cumulative meta-analysis showed that the evidence of association between occupational BZ/BNA exposure and lung cancer has been stable since 1995. Although the results of this meta-analysis have the potential for confounding by smoking and heterogeneity, our findings suggest that a finding of lung cancer following occupational BZ/BNA exposure should be considered to be a potential occupational disease. PMID- 26947958 TI - Critical Roles of EGFR Family Members in Breast Cancer and Breast Cancer Stem Cells: Targets for Therapy. AB - The roles of the epidermal growth factor receptor (EGFR) signaling pathway in various cancers including breast, bladder, brain, colorectal, esophageal, gastric, head and neck, hepatocellular, lung, neuroblastoma, ovarian, pancreatic, prostate, renal and other cancers have been keenly investigated since the 1980's. While the receptors and many downstream signaling molecules have been identified and characterized, there is still much to learn about this pathway and how its deregulation can lead to cancer and how it may be differentially regulated in various cell types. Multiple inhibitors to EGFR family members have been developed and many are in clinical use. Current research often focuses on their roles and other associated pathways in cancer stem cells (CSCs), identifying sites where therapeutic resistance may develop and the mechanisms by which microRNAs (miRs) and other RNAs regulate this pathway. This review will focus on recent advances in these fields with a specific focus on breast cancer and breast CSCs. Relatively novel areas of investigation, such as treatments for other diseases (e.g., diabetes, metabolism, and intestinal parasites), have provided new information about therapeutic resistance and CSCs. PMID- 26947959 TI - Synthesis, structural characterization, docking, lipophilicity and cytotoxicity of 1-[(1R)-1-(6-fluoro-1,3-benzothiazol-2-yl)ethyl]-3-alkyl carbamates, novel acetylcholinesterase and butyrylcholinesterase pseudo-irreversible inhibitors. AB - In the current study, sixteen novel derivatives of (R)-1-(6-fluorobenzo[d]thiazol 2-yl)ethanamine were synthesized as acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors. Chemical structures together with purity of the synthesized compounds were substantiated by IR, (1)H, (13)C, (19)F NMR, high resolution mass spectrometry and elemental analysis. The optical activities were confirmed by optical rotation measurements. The synthesized compounds were evaluated for their AChE and BChE inhibitory activities. In addition, the cytotoxicity of the most active compounds was investigated against human cell lines employing XTT tetrazolium salt reduction assay and xCELLigence system allowing a label-free assessment of the cells proliferation. Our results demonstrated that the inhibitory mechanism was confirmed to be pseudo irreversible, in line with previous studies on carbamates. Compounds indicated as 3b, 3d, 3l and 3n showed the best AChE inhibitory activity of all the evaluated compounds and were up to tenfold more potent than standard drug rivastigmine. The binding mode was determined using state-of-the-art covalent docking and scoring methodology. The obtained data clearly demonstrated that 3b, 3d, 3l and 3n benzothiazole carbamates possess high inhibitory activity against AChE and BChE and concurrently negligible cytotoxicity. In conclusion, our results indicate, that these derivatives could be promising in an effective therapeutic intervention for Alzheimer's disease. PMID- 26947960 TI - Impact of novel histopathological factors on the outcomes of liver surgery for colorectal cancer metastases. AB - INTRODUCTION: We evaluated the impacts of a series of novel histopathological factors on clinical-surgical outcomes and survival of patients who underwent surgery for colorectal cancer liver metastasis, with and without neoadjuvant chemotherapy. MATERIALS AND METHODS: A prospective database including 150 consecutive patients who underwent 183 hepatic resections for metastatic colorectal cancer was evaluated. Among them, 74 (49.3%) received neoadjuvant chemotherapy before surgery. The histopathological factors studied were: a) microsatellitosis, b) type and pattern of tumour growth, c) nuclear grade and the number of mitoses/mm(2), d) perilesional pseudocapsule, e) intratumoural fibrosis, f) lesion cellularity, g) hypoxic-angiogenic perilesional growth pattern, and h) the tumour normal interface. RESULTS: Three or more metastatic lesions, R1 resection margins, and <50% tumour necrosis were prognostic factors for a worse OS, but only the former was confirmed to be an independent prognostic factor in the multivariate analysis. Furthermore, tumour fibrosis <40% and cellularity >10% were predictive of a worse neoadjuvant therapy response, but these findings were not confirmed in the multivariate analysis. Finally, tumour necrosis <50%, cellularity >10%, and TNI >0.5 mm were prognostic factors for a worse DFS and AS in the univariate but not in the multivariate analysis. CONCLUSIONS: Several factors seem to influence the outcomes of surgery for colorectal cancer liver metastasis, especially the number of the lesions, the margins of resection, the percentage of necrosis and fibrosis, as well as the cellularity and the TNI. PMID- 26947961 TI - Mesh versus acellular dermal matrix in immediate implant-based breast reconstruction - A prospective randomized trial. AB - BACKGROUND: Comparative studies on the use of meshes and acellular dermal matrices (ADM) in implant-based breast reconstruction (IBBR) have not yet been performed. METHODS: This prospective, randomized, controlled, multicenter pilot study was performed at four Austrian breast cancer centers. Fifty patients with oncologic or prophylactic indication for mastectomy and IBBR were randomized to immediate IBBR with either an ADM (Protexa((r))) or a titanized mesh (TiLOOP((r)) Bra). Complications, failed reconstruction, cosmetic outcome, patients' quality of life and the thickness of the overlying tissue were recorded immediately postoperatively and 3 and 6 months after surgery. RESULTS: 48 patients participated in the study (Protexa((r)) group: 23; TiLOOP((r)) Bra group: 25 patients). The overall complication rate was 31.25% with similar rates in both groups (Protexa((r)) group: 9 versus TiLOOP((r)) Bra group: 6; p = 0.188). There was a higher incidence of severe complications leading to failed reconstructions with implant loss in the Protexa((r)) group than in the TiLOOP((r)) Bra group (7 versus 2; p < 0.0001). An inverted T-incision technique led to significantly more complications and reconstructive failure with Protexa((r)) (p = 0.037, p = 0.012, respectively). There were no significant differences in patients' satisfaction with cosmetic results (p = 0.632), but surgeons and external specialists graded significantly better outcomes with TiLOOP((r)) Bra (p = 0.034, p = 0.032). CONCLUSION: This pilot study showed use of TiLOOP((r)) Bra or Protexa((r)) in IBBR is feasible leading to good cosmetic outcomes and high patient satisfaction. To validate the higher failure rates in the Protexa((r)) group, data from a larger trial are required. NCT02562170. PMID- 26947963 TI - Evaluation of glioblastomas and lymphomas with whole-brain CT perfusion: Comparison between a delay-invariant singular-value decomposition algorithm and a Patlak plot. AB - OBJECTIVE: Correction of contrast leakage is recommended when enhancing lesions during perfusion analysis. The purpose of this study was to assess the diagnostic performance of computed tomography perfusion (CTP) with a delay-invariant singular-value decomposition algorithm (SVD+) and a Patlak plot in differentiating glioblastomas from lymphomas. MATERIALS AND METHODS: This prospective study included 17 adult patients (12 men and 5 women) with pathologically proven glioblastomas (n=10) and lymphomas (n=7). CTP data were analyzed using SVD+ and a Patlak plot. The relative tumor blood volume and flow compared to contralateral normal-appearing gray matter (rCBV and rCBF derived from SVD+, and rBV and rFlow derived from the Patlak plot) were used to differentiate between glioblastomas and lymphomas. The Mann-Whitney U test and receiver operating characteristic (ROC) analyses were used for statistical analysis. RESULTS: Glioblastomas showed significantly higher rFlow (3.05+/-0.49, mean+/-standard deviation) than lymphomas (1.56+/-0.53; P<0.05). There were no statistically significant differences between glioblastomas and lymphomas in rBV (2.52+/-1.57 vs. 1.03+/-0.51; P>0.05), rCBF (1.38+/-0.41 vs. 1.29+/-0.47; P>0.05), or rCBV (1.78+/-0.47 vs. 1.87+/-0.66; P>0.05). ROC analysis showed the best diagnostic performance with rFlow (Az=0.871), followed by rBV (Az=0.771), rCBF (Az=0.614), and rCBV (Az=0.529). CONCLUSION: CTP analysis with a Patlak plot was helpful in differentiating between glioblastomas and lymphomas, but CTP analysis with SVD+ was not. PMID- 26947962 TI - Outcomes of pelvic exenteration for locally advanced primary rectal cancer: Overall survival and quality of life. AB - INTRODUCTION: Radical surgery with pelvic exenteration offers the only potential for cure in patients with locally advanced primary rectal cancer. This study describes the clinical and patient-reported quality of life outcomes over 12 months for patients having pelvic exenteration for locally advanced primary rectal cancer at a specialised centre for pelvic exenteration. METHODS: Clinical data of consecutive patients undergoing pelvic exenteration for locally advanced primary rectal cancer and patient-reported outcomes were collected at baseline, hospital discharge and at 1, 3, 6, 9 and 12 months. Patient-reported outcomes included cancer-specific quality of life (QoL) and physical and mental health status. Quality of life trajectories were modelled over the 12 months from the date of surgery using linear mixed models. RESULTS: 104 patients with locally advanced rectal cancer underwent pelvic exenteration at Royal Prince Alfred Hospital, Sydney, between December 1994 and October 2014. Complete soft tissue exenteration was performed in 38%. A clear margin was obtained in 86% with a 62% overall five-year survival. QoL outcome questionnaires were completed by 62% of patient cohort. The average FACT-C score returned to pre-surgery QoL by 2 months after surgery, and the average QoL continued to increase slowly over the 12 months. CONCLUSION: Our results support an aggressive approach to advanced primary rectal cancer and lend weight to the oncological role of pelvic exenteration for this group of patients. Quality of life improves rapidly after pelvic exenteration for locally advanced primary rectal cancer and continues to improve over the first year. PMID- 26947965 TI - Effects of Oscillatory Shear on the Orientation of the Inverse Bicontinuous Cubic Phase in a Nonionic Surfactant/Water System. AB - The bicontinuous inverse cubic phase (V2 phase) formed in amphiphilic systems consists of bilayer networks with a long-range order. We have investigated effects of oscillatory shear on the orientation of the V2 phase with space group Ia3d formed in a nonionic surfactant (C12E2)/water system by using simultaneous measurements of rheology/small-angle X-ray scattering. It is shown that grain refining occurs by applying the large amplitude oscillatory shear (LAOS) with a strain amplitude (gamma0) of ~20, which gives the ratio of the loss modulus (G") to the storage modulus (G') (G"/G' = tan delta) of ~100. On the other hand, orientation of the cubic lattice occurs when the small amplitude (gamma0 ~ 0.0004) oscillatory shear (SAOS) in the linear regime is applied to the sample just after the LAOS. Interestingly, the orientation is strongly enhanced by the "medium amplitude" (gamma0 ~ 0.05) oscillatory shear ("MAOS") after the SAOS. When the MAOS is applied before applying the LAOS, orientation to a particular direction is not observed, indicating that the grain refining process by the LAOS is necessary for the orientation during the MAOS. The results of additional experiments show that the shear sequence "LAOS-MAOS" is effective for the orientation of the cubic lattice. When the LAOS and MAOS are applied to the sample alternatively, grain refining and orientation occur during the LAOS and MAOS, respectively, indicating reversibility of the orientation. It is shown that (i) the degree of the orientation is dependent on gamma0 and the frequency (omega) of the MAOS and (ii) relatively higher orientation can be obtained for the combination of gamma0 and omega, which gives tan delta = 2-3. The lattice constant does not change throughout all the shearing processes and is equal to that before shearing within the experimental errors, indicating that the shear melting does not occur. These results suggest a possibility to control the orientation of the cubic lattice only by changing the conditions of oscillatory shear without using the epitaxial transition from other anisotropic phases, such as the hexagonal and lamellar phases. PMID- 26947964 TI - Efficacy and safety of sarolaner (SimparicaTM) against fleas on dogs presented as veterinary patients in the United States. AB - The efficacy and safety of a novel isoxazoline parasiticide, sarolaner (SimparicaTM), for the control of fleas on dogs was evaluated in a randomized, controlled clinical study conducted in 19 general veterinary practices throughout the United States. Four hundred and seventy nine (479) dogs from 293 households were enrolled. Each household was randomly assigned to treatment with either sarolaner oral tablets (SimparicaTM, Zoetis) at the proposed label dose or an approved comparator product at the label dose (spinosad, Comfortis((r)), Elanco). Dogs were dosed by their owners at home on Day 0 and on approximately Days 30 and 60. Dogs were examined at the clinics for general health, flea and tick infestation, and clinical signs of flea allergy dermatitis (FAD) at the initial visit and Days 14, 30, 60 and 90. Blood was collected for clinical pathology at screening and Day 90. Sarolaner was well-accepted by dogs with the majority of flavored chewable tablets (91.5%) accepted free choice, by hand or in food. Geometric mean live flea counts were reduced by >99% at the first time measured (14 days) after initiation of treatment and continued to reduce through the study. Treatment success (proportion of dogs with >=90% reduction in fleas) for the sarolaner-treated dogs was superior to that for spinosad-treated dogs at Days 14 and 30 and non-inferior on Days 60 and 90 (P<=0.025) The rapid reduction in flea infestations resulted in a similar rapid resolution of the clinical signs associated with FAD. Sarolaner chewable tablets were well tolerated with no treatment related adverse reactions. Most of the clinical signs reported were consistent with allergies and dermatitis or sporadic occurrences of conditions commonly observed in the general dog population. A wide variety of concomitant medications, including many commercially available heartworm preventatives and other anthelmintic drugs, were administered to study dogs and all were well tolerated. Sarolaner administered orally to provide a minimum dosage of 2.0mg/kg (range 2-4mg/kg) once monthly for three consecutive treatments was safe and effective in the treatment and prevention of natural infestations of fleas and resulted in a substantial improvement of clinical signs associated with FAD. PMID- 26947966 TI - Validation of a robust PCR-based assay for quantifying fragile X CGG repeats. AB - BACKGROUND: Sizing of FMR1 trinucleotide repeats in the clinical laboratory requires the use of capillary sequencer by PCR, or by a labor intensive measurement using Southern blot method. Our aim was to validate an accurate and robust PCR assay for quantification of CGG repeats. METHODS: We performed an analytical and clinical validation of a new PCR-based method that utilizes a low cost capillary electrophoresis instrument and the FragilEaseTM reagent kit. First, analytical performance was demonstrated on 12 Coriell reference samples comprising normal through full mutations. Subsequently, a cohort of 112 archived clinical DNA samples, enriched for premutation and full mutations, was analyzed. RESULTS: All samples were amplified successfully. Quantification of repeat numbers was interpreted by the use of standards with known repeats. Twenty-five full-mutation samples were successfully amplified with the largest allele size measured at 1380 repeats. The repeat numbers from the new assay were concordant with those obtained with the reference method. The intra-assay (CV<2.5%) and inter-assay imprecision was within 1 CGG repeat. CONCLUSION: This new PCR-based method is reproducible and capable of identifying all Fragile X alleles. It is an accurate and robust method that facilitates Fragile X testing in a broader spectrum of clinical laboratories. PMID- 26947967 TI - A fatty acid profiling method using liquid chromatography-high resolution mass spectrometry for improvement of assisted reproductive technology. AB - BACKGROUND: Liquid chromatography-high resolution mass spectrometry (LC-HRMS) can be useful to improve in vitro fertilization (IVF). This study aims to find out an association between embryonic growth and embryonic uptake of free fatty acid (FFA) from culture media by using LC-HRMS. METHODS: Embryos (n=55) from 15 couples undergoing IVF were studied. An embryo was cultivated for up to 6 days in a 20 MUl-medium drop under mineral oil, and classified by a morphological grading system into the good-growth group (n=32; good quality blastocysts) and the poor growth group (n=23; non-blastocysts). The control study was set up without embryo. Extracted ion chromatogram of FFAs was collected in negative-ion mode for each medium sample obtained after use. RESULTS: The percent change from control to sample in mass area for docosahexaenoic acid showed a decrease in the good growth group than that in the poor-growth group (p<0.05). Decrease in %change of docosahexaenoic acid might indicate proper embryonic growth. Similar but insignificant change was observed for other essential FFAs, but not for non essential FFAs. CONCLUSION: The proposed metabolomic approach using LC-HRMS might be a powerful tool for non-invasive evaluation of embryonic growth. PMID- 26947968 TI - Cystatin C standardization decreases assay variation and improves assessment of glomerular filtration rate. AB - BACKGROUND: Cystatin C is increasingly used in glomerular filtration rate (GFR) estimation equations. The dependence of cystatin C results upon the analytical method has been a major source of controversy. METHODS: Cystatin C was measured with non-standardized turbidimetric Roche Generation 1 and standardized nephelometric Siemens assays in 3666 and additionally with standardized Roche Generation 2 and Siemens in 567 blood samples of the Berlin Initiative Study. Cystatin C-based GFR was assessed with CKD-EPIcys (Chronic Kidney Disease Epidemiology) and CAPA (Caucasian, Asian, Pediatric, Adult) equations and the impact of the assays on GFR estimation was determined. Equation performance compared to measured GFR was evaluated. RESULTS: Concordance of Roche Gen2 and Siemens was high with median difference of 0.003 +/- 0.13 mg/L (limits of agreement: -0.12 to 0.12) and Passing Bablok correlation was essentially perfect. Roche Gen1 assay showed worse concordance with Siemens: median difference was 0.08 +/- 0.13 mg/L (limits of agreement: -0.18 to 0.34) and correlation was inferior. Mean difference (+/- SD) of estimated GFRCKD-EPIcys was 0 +/- 4 mL/min/1.73 m(2) for Gen2 and Siemens compared to -5 +/- 8 with Gen1. Performance of GFR estimating equations was not influenced by the choice of Siemens or Gen2 assays. CONCLUSIONS: Standardization of Roche Gen2 assay improved accuracy of cystatin C measurement compared to Siemens. It suggests only negligible method bias and results in equal performance of both assays when estimating GFR indicating that successful calibration has led to major progress in cystatin C analysis. PMID- 26947969 TI - The antibiotic cefepime interferes with amino acid analysis by ion-exchange chromatography. PMID- 26947970 TI - Mechanical spectroscopy of retina explants at the protein level employing nanostructured scaffolds. AB - Development of neuronal tissue, such as folding of the brain, and formation of the fovea centralis in the human retina are intimately connected with the mechanical properties of the underlying cells and the extracellular matrix. In particular for neuronal tissue as complex as the vertebrate retina, mechanical properties are still a matter of debate due to their relation to numerous diseases as well as surgery, where the tension of the retina can result in tissue detachment during cutting. However, measuring the elasticity of adult retina wholemounts is difficult and until now only the mechanical properties at the surface have been characterized with micrometer resolution. Many processes, however, such as pathological changes prone to cause tissue rupture and detachment, respectively, are reflected in variations of retina elasticity at smaller length scales at the protein level. In the present work we demonstrate that freely oscillating cantilevers composed of nanostructured TiO2 scaffolds can be employed to study the frequency-dependent mechanical response of adult mammalian retina explants at the nanoscale. Constituting highly versatile scaffolds with strong tissue attachment for long-term organotypic culture atop, these scaffolds perform damped vibrations as fingerprints of the mechanical tissue properties that are derived using finite element calculations. Since the tissue adheres to the nanostructures via constitutive proteins on the photoreceptor side of the retina, the latter are stretched and compressed during vibration of the underlying scaffold. Probing mechanical response of individual proteins within the tissue, the proposed mechanical spectroscopy approach opens the way for studying tissue mechanics, diseases and the effect of drugs at the protein level. PMID- 26947971 TI - CAEP 2015 Academic Symposium: Leadership within the emergency medicine academic community and beyond. AB - OBJECTIVES: A panel of emergency medicine (EM) leaders endeavoured to define the key elements of leadership and its models, as well as to formulate consensus recommendations to build and strengthen academic leadership in the Canadian EM community in the areas of mentorship, education, and resources. METHODS: The expert panel comprised EM leaders from across Canada and met regularly by teleconference over the course of 9 months. From the breadth of backgrounds and experience, as well as a literature review and the development of a leadership video series, broad themes for recommendations around the building and strengthening of EM leadership were presented at the CAEP 2015 Academic Symposium held in Edmonton, Alberta. Feedback from the attendees (about 80 emergency physicians interested in leadership) was sought. Subsequently, draft recommendations were developed by the panel through attendee feedback, further review of the leadership video series, and expert opinion. The recommendations were distributed to the CAEP Academic Section for further feedback and updated by consensus of the expert panel. RESULTS: The methods informed the panel who framed recommendations around four themes: 1) leadership preparation and training, 2) self-reflection/emotional intelligence, 3) academic leadership skills, and 4) gender balance in academic EM leadership. The recommendations aimed to support and nurture the next generation of academic EM leaders in Canada and included leadership mentors, availability of formal educational courses/programs in leadership, self-directed education of aspiring leaders, creation of a Canadian subgroup with the AACEM/SAEM Chair Development Program, and gender balance in leadership roles. CONCLUSIONS: These recommendations serve as a roadmap for all EM leaders (and aspiring leaders) to build on their success, inspire their colleagues, and foster the next generation of Canadian EM academic leaders. PMID- 26947972 TI - Universal statistical fluctuations in thermodynamics and kinetics of single molecular recognition. AB - We investigated the main universal statistical distributions of single molecular recognition. The distributions of the single molecule binding free energy spectrum or density of states were characterized in the ligand-receptor binding energy landscape. The analytical results are consistent with the microscopic molecular simulations. The free energy distribution of different binding modes or states for a single molecule ligand receptor pair is approximately Gaussian near the mean and exponential at the tail. The equilibrium constant of single molecule binding is log-normal distributed near the mean and power law distributed near the tail. Additionally, we found that the kinetics distribution of single molecule ligand binding can be characterized by log-normal around the mean and power law distribution near the tail. This distribution is caused by exploration of the underlying inhomogeneous free energy landscape. Different ligand-receptor binding complexes have the same universal form of distribution but differ in parameters. PMID- 26947973 TI - p38alpha MAPK Regulates Lineage Commitment and OPG Synthesis of Bone Marrow Stromal Cells to Prevent Bone Loss under Physiological and Pathological Conditions. AB - Bone marrow-derived mesenchymal stromal cells (BM-MSCs) are capable of differentiating into osteoblasts, chondrocytes, and adipocytes. Skewed differentiation of BM-MSCs contributes to the pathogenesis of osteoporosis. Yet how BM-MSC lineage commitment is regulated remains unclear. We show that ablation of p38alpha in Prx1+ BM-MSCs produced osteoporotic phenotypes, growth plate defects, and increased bone marrow fat, secondary to biased BM-MSC differentiation from osteoblast/chondrocyte to adipocyte and increased osteoclastogenesis and bone resorption. p38alpha regulates BM-MSC osteogenic commitment through TAK1-NF-kappaB signaling and osteoclastogenesis through osteoprotegerin (OPG) production by BM-MSCs. Estrogen activates p38alpha to maintain OPG expression in BM-MSCs to preserve the bone. Ablation of p38alpha in BM-MSCs positive for Dermo1, a later BM-MSC marker, only affected osteogenic differentiation. Thus, p38alpha mitogen-activated protein kinase (MAPK) in Prx1+ BM-MSCs acts to preserve the bone by promoting osteogenic lineage commitment and sustaining OPG production. This study thus unravels previously unidentified roles for p38alpha MAPK in skeletal development and bone remodeling. PMID- 26947974 TI - Activation of GLP-1 Receptor Promotes Bone Marrow Stromal Cell Osteogenic Differentiation through beta-Catenin. AB - Glucagon-like peptide 1 (GLP-1) plays an important role in regulating bone remodeling, and GLP-1 receptor agonist shows a positive relationship with osteoblast activity. However, GLP-1 receptor is not found in osteoblast, and the mechanism of GLP-1 receptor agonist on regulating bone remodeling is unclear. Here, we show that the GLP-1 receptor agonist exendin-4 (Ex-4) promoted bone formation and increased bone mass and quality in a rat unloading-induced bone loss model. These functions were accompanied by an increase in osteoblast number and serum bone formation markers, while the adipocyte number was decreased. Furthermore, GLP-1 receptor was detected in bone marrow stromal cells (BMSCs), but not in osteoblast. Activation of GLP-1 receptor by Ex-4 promoted the osteogenic differentiation and inhibited BMSC adipogenic differentiation through regulating PKA/beta-catenin and PKA/PI3K/AKT/GSK3beta signaling. These findings reveal that GLP-1 receptor regulates BMSC osteogenic differentiation and provide a molecular basis for therapeutic potential of GLP-1 against osteoporosis. PMID- 26947975 TI - OSKM Induce Extraembryonic Endoderm Stem Cells in Parallel to Induced Pluripotent Stem Cells. AB - The reprogramming factors OCT4, SOX2, KLF4, and MYC (OSKM) can reactivate the pluripotency network in terminally differentiated cells, but also regulate expression of non-pluripotency genes in other contexts, such as the mouse primitive endoderm. The primitive endoderm is an extraembryonic lineage established in parallel to the pluripotent epiblast in the blastocyst, and is the progenitor pool for extraembryonic endoderm stem (XEN) cells. We show that OSKM induce expression of endodermal genes, leading to formation of induced XEN (iXEN) cells, which possess key properties of blastocyst-derived XEN cells, including morphology, transcription profile, self-renewal, and multipotency. Our data show that iXEN cells arise in parallel to induced pluripotent stem cells, indicating that OSKM drive cells to two distinct cell fates during reprogramming. PMID- 26947976 TI - A Serial shRNA Screen for Roadblocks to Reprogramming Identifies the Protein Modifier SUMO2. AB - The generation of induced pluripotent stem cells (iPSCs) from differentiated cells following forced expression of OCT4, KLF4, SOX2, and C-MYC (OKSM) is slow and inefficient, suggesting that transcription factors have to overcome somatic barriers that resist cell fate change. Here, we performed an unbiased serial shRNA enrichment screen to identify potent repressors of somatic cell reprogramming into iPSCs. This effort uncovered the protein modifier SUMO2 as one of the strongest roadblocks to iPSC formation. Depletion of SUMO2 both enhances and accelerates reprogramming, yielding transgene-independent, chimera-competent iPSCs after as little as 38 hr of OKSM expression. We further show that the SUMO2 pathway acts independently of exogenous C-MYC expression and in parallel with small-molecule enhancers of reprogramming. Importantly, suppression of SUMO2 also promotes the generation of human iPSCs. Together, our results reveal sumoylation as a crucial post-transcriptional mechanism that resists the acquisition of pluripotency from fibroblasts using defined factors. PMID- 26947977 TI - Naive Pluripotent Stem Cells Derived Directly from Isolated Cells of the Human Inner Cell Mass. AB - Conventional generation of stem cells from human blastocysts produces a developmentally advanced, or primed, stage of pluripotency. In vitro resetting to a more naive phenotype has been reported. However, whether the reset culture conditions of selective kinase inhibition can enable capture of naive epiblast cells directly from the embryo has not been determined. Here, we show that in these specific conditions individual inner cell mass cells grow into colonies that may then be expanded over multiple passages while retaining a diploid karyotype and naive properties. The cells express hallmark naive pluripotency factors and additionally display features of mitochondrial respiration, global gene expression, and genome-wide hypomethylation distinct from primed cells. They transition through primed pluripotency into somatic lineage differentiation. Collectively these attributes suggest classification as human naive embryonic stem cells. Human counterparts of canonical mouse embryonic stem cells would argue for conservation in the phased progression of pluripotency in mammals. PMID- 26947978 TI - Active range of motion outcomes after reconstruction of burned wrist and hand deformities. AB - This works aim is to evaluate the efficacy of skin grafts and flaps in reconstruction of post-burn hand and wrist deformities. A prospective study of 57 burn contractures of the wrist and dorsum of the hand was performed. Flaps were used only if there was a non-vascularized structure after contracture release, otherwise a skin graft was used. Active range of motion (ROM) was used to assess hand function. The extension deformity cohort uniformly underwent skin graft following contracture release with a mean improvement of 71 degrees (p<0.0001). The flexion deformity cohort was treated with either skin grafts (8 patients) or flaps (9 patients) with a mean improvement of 44 degrees (p<0.0001). Skin grafts suffice for dorsal hand contractures to restore functional wrist ROM. For flexion contractures, flaps were more likely for contractures >6 months. Early release of burn contracture is advisable to avoid deep structure contracture. PMID- 26947979 TI - The contributions of allergic sensitization and respiratory pathogens to asthma inception. AB - Of the chronic diseases affecting grade-school children, asthma is the most common and accounts for the greatest number of school days missed. Moreover, it can influence family dynamics and function in other ways, and unfortunately, it can also be associated with mortality, particularly in the inner-city environments of the United States. Thus understanding factors that lead to its development in early life is essential in developing strategies aimed at primary prevention. Two risk factors that have been identified by a number of investigators include the development of allergic sensitization and wheezing respiratory tract illnesses caused by viruses and bacteria, either alone or in combination. Both of these factors appear to exert their influences within the first few years of life, such that asthma becomes established before the child enters grade school at age 5 to 6 years. Therefore, because both allergic sensitization and viral and bacterial illnesses can occur in children who do not have asthma, it is paramount to identify genetic and environmental factors that activate, interact with, and/or direct the immune system and components of the respiratory tract along pathways that allow asthma to become established and expressed clinically. PMID- 26947980 TI - Leveraging gene-environment interactions and endotypes for asthma gene discovery. AB - Asthma is a heterogeneous clinical syndrome that includes subtypes of disease with different underlying causes and disease mechanisms. Asthma is caused by a complex interaction between genes and environmental exposures; early-life exposures in particular play an important role. Asthma is also heritable, and a number of susceptibility variants have been discovered in genome-wide association studies, although the known risk alleles explain only a small proportion of the heritability. In this review, we present evidence supporting the hypothesis that focusing on more specific asthma phenotypes, such as childhood asthma with severe exacerbations, and on relevant exposures that are involved in gene-environment interactions (GEIs), such as rhinovirus infections, will improve detection of asthma genes and our understanding of the underlying mechanisms. We will discuss the challenges of considering GEIs and the advantages of studying responses to asthma-associated exposures in clinical birth cohorts, as well as in cell models of GEIs, to dissect the context-specific nature of genotypic risks, to prioritize variants in genome-wide association studies, and to identify pathways involved in pathogenesis in subgroups of patients. We propose that such approaches, in spite of their many challenges, present great opportunities for better understanding of asthma pathogenesis and heterogeneity and, ultimately, for improving prevention and treatment of disease. PMID- 26947981 TI - Microbes and asthma: Opportunities for intervention. AB - The worldwide incidence and prevalence of asthma continues to increase. Asthma is now understood as an umbrella term for different phenotypes or endotypes, which arise through different pathophysiologic pathways. Understanding the many factors contributing to development of the disease is important for the identification of novel therapeutic targets for the treatment of certain asthma phenotypes. The hygiene hypothesis has been formulated to explain the increasing prevalence of allergic disease, including asthma. This hypothesis postulates that decreased exposure at a young age to certain infectious agents as a result of improved hygiene, increased antibiotic use and vaccination, and changes in lifestyle and dietary habits is associated with changes in the immune system, which predispose subjects to allergy. Many microbes, during their coevolution with human subjects, developed mechanisms to manipulate the human immune system and to increase their chances of survival. Improving models of asthma, as well as choosing adequate end points in clinical trials, will lead to a more complete understanding of the underlying mechanisms, thus providing an opportunity to devise primary and secondary interventions at the same time as identifying new molecular targets for treatment. This article reports the discussion and conclusion of a workshop under the auspices of the Netherlands Lung Foundation to extend our understanding of how modulation of the immune system by bacterial, parasitic, and viral infections might affect the development of asthma and to map out future lines of investigation. PMID- 26947983 TI - Hematopoietic prostaglandin D synthase: Linking pathogenic effector CD4(+) T(H)2 cells to proeosinophilic inflammation in patients with gastrointestinal allergic disorders. PMID- 26947984 TI - Cost-effectiveness analysis of peginterferon beta-1a compared with interferon beta-1a and glatiramer acetate in the treatment of relapsing-remitting multiple sclerosis in the United States. AB - Objective Peginterferon beta-1a 125 mcg, administered subcutaneously (SC) every 2 weeks, a new disease-modifying therapy (DMT) for relapsing-remitting multiple sclerosis (RRMS), was approved by the US Food and Drug Administration in 2014. This study assesses the cost-effectiveness of peginterferon beta-1a vs interferon beta-1a (44 mcg SC 3 times per week) and glatiramer acetate (20 mg SC once-daily) in the treatment of RRMS from the perspective of a US payer over 10 years. Methods A Markov cohort economic model was developed for this analysis. The model predicts disability progression, occurrence of relapses and other adverse events and translates them into quality-adjusted life years (QALYs) and costs. Natural history data were obtained from the placebo arm of the ADVANCE trial of peginterferon beta-1a, the London Ontario (Canada) database and a large population-based MS survey. Comparative efficacy of each DMT vs placebo was obtained from a network meta-analysis. Costs (in 2014 US dollars) were sourced from public databases and literature. Clinical and economic outcomes were discounted at 3% per year. Results Over 10 years, peginterferon beta-1a was dominant (i.e., more effective and less costly), with cost-savings of $22,070 and additional 0.06 QALYs when compared with interferon beta-1a 44 mcg and with cost savings of $19,163 and 0.07 QALYs gained when compared with glatiramer acetate 20 mg. Results were most sensitive to variations in the treatment effect of each DMT, treatment acquisition costs of each DMT and the time horizon. Probabilistic sensitivity analyses indicated that peginterferon beta-1a remains dominant in >90% of 5,000 replications compared with either DMTs. Conclusion This analysis suggests that long-term treatment with peginterferon beta-1a improves clinical outcomes at reduced costs compared with interferon beta-1a 44 mcg and glatiramer acetate 20 mg and should be a valuable addition to managed care formularies for treating patients with RRMS. PMID- 26947985 TI - Survey on Trypanosoma spp. infection of dogs in Gabon and its epidemiological implications for sleeping sickness. AB - This survey screened native dogs (Canis familiaris) in Gabon (Africa) for trypanosome infection. A total of 376 apparently healthy dogs, divided into two populations, were examined. The first group included 252 semi-domesticated dogs inhabiting 16 villages of the Ogooue-Ivindo Province, a rural inland area in northeast Gabon, and the second group 124 dogs belonging to protection companies or families from Libreville (n = 113) and Port-Gentil (n = 11), in the coastal area of Gabon. Both study areas include active or former foci of sleeping sickness in Gabon. Molecular testing (polymerase chain reaction) was performed on blood samples from dogs in both groups. All dogs were negative for T. congolense ("savanna type" and "forest type"). Eighteen dogs (4.7%), however, tested positive for T. brucei s.l.: 3% (8/252) were from the Ogooue-Ivindo Province, and 8% (10/124) from the coastal area. These animals may be potential reservoirs of the parasite T. brucei gambiense, responsible for human African trypanosomiasis. This hypothesis, as well as the role of the dog as a sentinel of human infection by T. brucei gambiense, should be investigated in further studies. PMID- 26947986 TI - [Kidney and hemoglobinopathy]. AB - Sickle-cell disease (SCD), one of the most common severe monogenic disorders into the world, is associated with an increased frequency of chronic kidney disease. SCD is caused by a point mutation in the gene encoding beta globin gene which leads to the formation of hemoglobin S that polymerises after deoxygenation. HbS polymerisation is associated with erythrocyte rigidity and vaso-occlusive episodes that play a central role into SCD pathogenesis. The spectrum of renal diseases during SCD is broad and includes various renal manifestations which become more apparent with increasing age. Underlying pathophysiological processes involved in sickle cell nephropathy are multifactorial but endothelial dysfunction related to chronic hemolysis is a key factor contributing to renal involvement. Our review focuses on the pathogenesis and on the spectrum of renal manifestations occurring in SCD patients. PMID- 26947988 TI - Attachment issues: kinetochore transformations and spindle checkpoint silencing. AB - Cell division culminates in the segregation of duplicated chromosomes in opposite directions prior to cellular fission. This process is guarded by the spindle assembly checkpoint (SAC), which prevents the anaphase of cell division until stable connections between spindle microtubules and the kinetochores of all chromosomes are established. The anaphase inhibitor is generated at unattached kinetochores and inhibitor production is prevented when microtubules are captured. Understanding the molecular changes in the kinetochore that are evoked by microtubule attachments is crucial for understanding the mechanisms of SAC signaling and silencing. Here, we highlight the most recent findings on these events, pinpoint some remaining mysteries, and argue for incorporating holistic views of kinetochore dynamics in order to understand SAC silencing. PMID- 26947989 TI - Growth, development, puberty and adult height of patients with congenital multiple pituitary hormone deficiencies. AB - OBJECTIVE: Congenital MPHD is a rare condition caused by mutations in pituitary transcription factors genes: PROP1, POU1F1 (PIT1), HESX1, LHX3, LHX4. DESIGN: We evaluated in a retrospective study the effects on growth and development in 29 patients with congenital MPHD (cMPHD), during hGH replacement therapy alone and combined with sex hormones. Twenty nine patients with cMPHD were included and diagnosed, treated and followed in our clinic from diagnosis to adult age. Measurements on growth and development were taken by the same medical team. RESULTS: Mean birth weight of 21/29 neonates was 3126 +/- 536 g. Mean birth length of 7/29 neonates was 48.7 +/- 2 cm. Neuromotor development was normal or slightly delayed. Mean age at referral was 9.5 +/- 7 years (m), 6.7 +/- 3.5 years (f) (p=0.17). Height (SDS) before treatment was -2.8 +/- 1.0 (m), -2.8 +/- 1.0 (f) (p=0.99). Mean age at initiation of hGH treatment was 9.9 +/- 6.7 years (m), 10.3 +/- 4.2 years (f) (p=0.85). Mean age at initiation of sex hormone treatment was 17.0 +/- 3.5 years (m), 17.1 +/- 2.3 years (f) (p=0.88). Penile and testicular sizes were below normal before and after treatment. Head circumference (SD) was -1.9 +/- 0.9 before and -0.6 +/- 1.8 at end of treatment (p<0.001). Adult height (SDS) reached -1.1 +/- 0.6 (p<0.001) for both males and females. CONCLUSION: Despite the multiple pituitary hormone deficiencies including hGH, children with congenital MPHD present with a better auxological development than children with congenital IGHD or congenital IGF-1 deficiency. These findings may be due to irregular and incomplete hormone deficiencies increasing with progressive age and late initiation of puberty. PMID- 26947998 TI - [Propensity Score and Long-Term Survival Results after Open versus Endovascular Treatment of Abdominal Aortic Aneurysm]. AB - Background: There are not many publications on the long-term results of surgical treatment for abdominal aortic aneurysm (AAA) comparing open repair (OR) and endovascular aneurysm repair (EVAR). Method: Using a propensity score (PS), we matched cohorts which were eligible for both types of treatment and underwent an elective surgical procedure for infrarenal AAA between 2002 and 2008. The endpoint of the study was long-term survival without re-intervention. Results: From a total of 442 patients treated from 2002 to 2008, we identified 140 patients of whom 72 received a tube graft and 68 were treated by EVAR. Median observation time was 5 years (0.04-10.3). Mortality was zero in the EVAR group and 1 % in the OR group, with cumulative survival after 5 and 10 years being 82 (79 %) in the OR group and 80 (58 %) in the EVAR group. Three patients (4 %) out of 72 with open surgery and 23 patients (34 %) from the EVAR group had to undergo a repeat surgery. Conclusion: Both procedures are safe methods to eliminate aneurysms. However, the high rate of re-interventions or conversions in the EVAR group has to be considered in the selection of treatment. PMID- 26948000 TI - Four coordination polymers derived from a one-pot reaction and their controlled synthesis. AB - Four different Co(ii) coordination polymers have been built by two flexible ligands 4,4'-dicarboxydiphenyl sulfone (4,4'-sdb) and 1,4-bis((1H-imidazol-1 yl)methyl) benzene (BMB) in a one-pot solvothermal reaction. The structures of and are new, and and have been reported. The crystal structures of were obtained, namely [Co(4,4'-sdb)(BMB)]n (), {[Co2(4,4'-sdb)2(BMB)].2H2O}n (), and [Co3(4,4' sdb)2(DMF)(H2O)3]n (), but was confirmed by PXRD. Both and are 2D layered structures with sql topology and their point symbol is {4(4).6(2)}. These complexes have been characterized by single crystal X-ray diffraction, infrared spectroscopy, thermogravimetry, elemental analysis, and powder X-ray diffraction measurements. By changing the synthesis conditions, four different Co(ii) coordination polymers can be obtained respectively. PMID- 26947999 TI - [Management Competence in Leading Positions in Clinical Surgery - What Does a Surgeon Need to Know?] AB - Background: Surgeons, more than other specialists, are required to combine high medical expertise with management competence. This is due to changing environments, new demands with respect to quality, the ongoing discussion on increased performance in the context of questionable target agreements, an increasing tendency of university hospitals and other departments and clinics to recruit leading personnel in medicine with management competence, but also to the understanding of one's own role and surgeons' distinguished public reputation. Aim: This narrative review describes the changing environments for surgeons in leading positions in hospitals and provides an overview on the practical use of management skills in surgery. In addition, it advises on how to acquire management competence and presents an educational concept appropriate for surgeons in leading positions. Key points: 1. The management of new challenges in the healthcare system - also in clinical surgery - requires management skills, which are indispensable for a surgeon in a leading position. 2. Management skills in surgery comprise aspects such as communication ability, social competence, cooperation and leadership skills, knowledge on business administration aspects and legal certainty. 3. The necessary knowledge can be acquired in courses leading to a certificate (e.g. "MHM(r) Medical Hospital Manager") or by earning a "Master of Business Administration" (MBA). Conclusion: Management competence is essential in leading positions in clinical surgery today. The use of these skills is challenging in daily practice. Successfully applied, management competence not only guarantees comprehensive patient care and leadership of employees, but also provides satisfaction in leading positions of a surgical department. PMID- 26948001 TI - Interobserver variability of an open-source software for tear meniscus height measurement. AB - PURPOSE: Different values of the lower tear meniscus height (TMH) can be obtained depending on the method and technique of measurement employed. The aim of this study was to analyse the interobserver variability of a method for measuring TMH by using an open source software. MATERIAL AND METHODS: On a group of 176 subjects, two videos of the central lower tear meniscus, first under slit-lamp illumination and ten minutes later under Tearscope illumination, were generated by a digital camera attached to a slit-lamp. Images were extracted from each video by a masked observer. Two further observers measured in a masked and randomized order the TMH in each illumination method by using an open source software based on Java (NIH ImageJ). TMH was measured from the lower lid to the upper limit of the tear meniscus for both slit-lamp (TMH-SL) and Tearscope (TMH Tc) illumination methods. Subsequently, in different order, observers assigned a four-grading and a healthy/abnormal subjective classification to each central meniscus. RESULTS: No significant differences were found between the TMH measurements obtained by both investigators in slit-lamp or Tearscope image datasets (t-test; both p>=0.136). When comparing TMH measurements stratified by grade, only interobserver significant differences were observed for grades 3 and 4 with silt-lamp (t-test; both p<=0.009). Significant differences on TMH results between subjective subgroups were observed for both illumination techniques (ANOVA, all p<=0.045). CONCLUSION: This study showed a useful tool to objectively measure TMH by photography. PMID- 26948002 TI - The Pythian Left Atrium: Predicting LV Reverse Remodeling and Cardiovascular Events in New-Onset Dilated Cardiomyopathy. PMID- 26948003 TI - Brachialis syndrome: a rare consequence of patient positioning causing postoperative median neuropathy. AB - BACKGROUND: Poor positioning of patients can result in devastating permanent neurologic deficits. We describe a previously unreported cause of median nerve compression that we have termed the brachialis syndrome, associated with patient positioning that results in permanent median nerve damage. METHODS: We identified this condition affecting 6 median nerves. All patients underwent surgical decompression of the proximal median nerve at the level of the antecubital fossa. RESULTS: Five patients presented with symptoms of median nerve compression; 6 affected median nerves manifested brachialis syndrome after a lengthy index surgery. Every patient had a similar presentation characterized by a mixed sensory and motor deficit. Average time to symptom presentation postoperatively was 1 hour. Two patients had delayed time to decompression, one of 25 days and one of 92 days. In the additional patients, the average time to decompression was 19.7 hours. At median nerve decompression, the brachialis was found to have varying degrees of muscle necrosis. In the patients whose decompression was delayed, there was only partial neurologic recovery at follow-up to 1 year. In the patients expeditiously decompressed, full neurologic recovery occurred in 1 to 14 days. CONCLUSIONS: This is the first description of the brachialis syndrome. During surgery, arms were placed into full extension, compressing the brachialis against the trochlea. The brachialis reliably developed necrosis, resulting in swelling, compressing the median nerve against the lacertus fibrosus. Two patients with delayed decompression had poor neurologic outcomes. This supports modification of patient positioning, postoperative vigilance, and timely surgical management of brachialis syndrome. PMID- 26948004 TI - Delayed administration of recombinant human parathyroid hormone improves early biomechanical strength in a rat rotator cuff repair model. AB - BACKGROUND: Despite advances in intraoperative techniques, rotator cuff repairs frequently do not heal. Recombinant human parathyroid hormone (rhPTH) has been shown to improve healing at the tendon-to-bone interface in an established acute rat rotator cuff repair model. We hypothesized that administration of rhPTH beginning on postoperative day 7 would result in improved early load to failure after acute rotator cuff repair in an established rat model. METHODS: Acute rotator cuff repairs were performed in 108 male Sprague-Dawley rats. Fifty-four rats received daily injections of rhPTH beginning on postoperative day 7 until euthanasia or a maximum of 12 weeks postoperatively. The remaining 54 rats received no injections and served as the control group. Animals were euthanized at 2 and 16 weeks postoperatively and evaluated by gross inspection, biomechanical testing, and histologic analysis. RESULTS: At 2 weeks postoperatively, rats treated with rhPTH demonstrated significantly higher load to failure than controls (10.9 vs. 5.2 N; P = .003). No difference in load to failure was found between the 2 groups at 16 weeks postoperatively, although control repairs more frequently failed at the tendon-to-bone interface (45.5% vs. 22.7%; P = .111). Blood vessel density appeared equivalent between the 2 groups at both time points, but increased intracellular and extracellular vascular endothelial growth factor expression was noted in the rhPTH-treated group at 2 weeks. CONCLUSIONS: Delayed daily administration of rhPTH resulted in increased early load to failure and equivalent blood vessel density in an acute rotator cuff repair model. PMID- 26948005 TI - Glenoid version and its relationship to glenohumeral instability and labral tears. AB - BACKGROUND: Evidence suggests a relationship between glenoid retroversion and posterior instability, but no literature exists comparing glenoid version referencing the scapular body versus the endosteal vault. This study evaluated glenoid version and its relationship to unidirectional instability and labral tears. METHODS: Glenoid version in patients with unidirectional instability or labral tears was measured with magnetic resonance imaging by either the Friedman method or the Poon and Ting method. Analyses of variance followed by independent t tests were used to compare 3 groups: anterior instability or labral tears (anterior pathology group, n = 33); posterior instability or labral tears (posterior pathology group, n = 34); and stable controls (n = 30). The referencing error for 2-dimensional axial images was evaluated for variance by imaging facility. Interobserver and intraobserver reliability scores were calculated. RESULTS: With the Friedman method, the posterior pathology group (-9 degrees ) was more retroverted than the control group (-4 degrees ) (P = .0005) and the anterior pathology group (-5 degrees ) (P = .0104) but there was no difference between the control group and anterior pathology group (P = .38). The referencing error in the sagittal plane averaged 23 degrees and varied by facility (P = .0365). The coronal-plane error averaged 1 degrees and did not vary by facility (P = .7180). Intraclass correlation coefficient scores showed good to excellent intrarater and inter-rater reliability. CONCLUSION: The posterior pathology group had 5 degrees more retroversion than controls using the Friedman method. Glenoid version using the Poon and Ting method or the Friedman method did not predict anterior instability or labral tears. Axial magnetic resonance images were constructed with a referencing error in the sagittal plane that varied by magnetic resonance imaging facility and has implications for improving 2-dimensional axial imaging protocols. PMID- 26948006 TI - Loose glenoid components in revision shoulder arthroplasty: is there an association with positive cultures? AB - BACKGROUND: Glenoid loosening is one of the most common causes of total shoulder failure. High rates of positive cultures of Propionibacterium and coagulase negative staphylococcus have been found among shoulders having surgical revision for glenoid loosening. This study reviewed the culture results in a series of surgical revisions for failed total shoulder arthroplasty to determine the relationship between glenoid loosening and positive cultures. METHODS: The medical records of 221 patients without obvious evidence of infection who underwent revision total shoulder arthroplasty were reviewed to examine the association between the security of fixation of the glenoid component and the results of cultures obtained at revision surgery. RESULTS: Of the revised shoulders, 53% had positive cultures; 153 of the shoulders (69%) had a loose glenoid component, whereas 68 (31%) had secure glenoid component fixation. Of the 153 loose glenoid components, 82 (54%) had at least 1 positive culture and 44 (29%) had 2 or more positive cultures of the same microorganism. Similarly, of the 68 secure glenoid components, 35 (51%) had at least 1 positive culture (P = .77) and 14 (21%) had 2 or more positive cultures of the same microorganism (P = .25). Explanted glenoid components that were loose had a higher rate of culture positivity (56% [24/43]) in comparison to explanted glenoid components that were well fixed (13% [1/8]) (P = .05). CONCLUSION: Propionibacterium and coagulase negative staphylococcus are commonly recovered in revision shoulder arthroplasty, whether or not the glenoid components are loose. PMID- 26948007 TI - Effect of zero magnetic field on cardiovascular system and microcirculation. AB - The effects of zero magnetic field conditions on cardiovascular system of healthy adults have been studied. In order to generate zero magnetic field, the facility for magnetic fields modeling "ARFA" has been used. Parameters of the capillary blood flow, blood pressure, and the electrocardiogram (ECG) monitoring were measured during the study. All subjects were tested twice: in zero magnetic field and, for comparison, in sham condition. The obtained results during 60 minutes of zero magnetic field exposure demonstrate a clear effect on cardiovascular system and microcirculation. The results of our experiments can be used in studies of long-term stay in hypo-magnetic conditions during interplanetary missions. PMID- 26948009 TI - Advanced nutrient root-feeding system for conveyor-type cylindrical plant growth facilities for microgravity. AB - A compact and reliable automatic method for plant nutrition supply is needed to monitor and control space-based plant production systems. The authors of this study have designed a nutrient root-feeding system that minimizes and regulates nutrient and water supply without loss of crop yields in a space greenhouse. The system involves an ion-exchange fibrous artificial soil (AS) BIONA-V3(TM) as the root-inhabited medium; a pack with slow-release fertilizer as the main source of nitrogen, phosphorus, and potassium; and a cartridge with granular mineral-rich ionite (GMRI) as a source of calcium, magnesium, sulfur, and iron. A controller equipped with an electrical conductivity meter controls the solution flow and concentration of the solution in the mixing tank at specified values. Experiments showed that the fibrous AS-stabilized pH of the substrate solution within the range of 6.0-6.6 is favorable to the majority of crops. The experimental data confirmed that this technique allowed solution preparation for crops in space greenhouses by means of pumping water through the cartridge and minimization of the AS stock onboard the space vehicle. PMID- 26948008 TI - A priming dose of protons alters the early cardiac cellular and molecular response to (56)Fe irradiation. AB - PURPOSE: Recent evidence suggests that the heart may be injured by ionizing radiation at lower doses than was previously thought. This raises concerns about the cardiovascular risks from exposure to radiation during space travel. Since space travel is associated with exposure to both protons from solar particle events and heavy ions from galactic cosmic rays, we here examined the effects of a "priming" dose of protons on the cardiac cellular and molecular response to a "challenge" dose of (56)Fe in a mouse model. METHODS: Male C57BL/6 mice at 10 weeks of age were exposed to sham-irradiation, 0.1 Gy of protons (150 MeV), 0.5 Gy of (56)Fe (600 MeV/n), or 0.1 Gy of protons 24 hours prior to 0.5 Gy of (56)Fe. Hearts were obtained at 7 days post-irradiation and western-blots were used to determine protein markers of cardiac remodeling, inflammatory infiltration, and cell death. RESULTS: Exposure to (56)Fe caused an increase in expression of alpha-smooth muscle cell actin, collagen type III, the inflammatory cell markers mast cell tryptase, CD2 and CD68, the endothelial glycoprotein thrombomodulin, and cleaved caspase 3. Of all proteins investigated, protons at a dose of 0.1 Gy induced a small increase only in cleaved caspase 3 levels. On the other hand, exposure to protons 24 hours before (56)Fe prevented all of the responses to (56)Fe. CONCLUSIONS: This study shows that a low dose of protons may prime the heart to respond differently to a subsequent challenge dose of heavy ions. Further investigation is required to identify responses at additional time points, consequences for cardiac function, threshold dose levels, and mechanisms by which a proton priming dose may alter the response to heavy ions. PMID- 26948010 TI - Monte Carlo simulations for the space radiation superconducting shield project (SR2S). AB - Astronauts on deep-space long-duration missions will be exposed for long time to galactic cosmic rays (GCR) and Solar Particle Events (SPE). The exposure to space radiation could lead to both acute and late effects in the crew members and well defined countermeasures do not exist nowadays. The simplest solution given by optimized passive shielding is not able to reduce the dose deposited by GCRs below the actual dose limits, therefore other solutions, such as active shielding employing superconducting magnetic fields, are under study. In the framework of the EU FP7 SR2S Project - Space Radiation Superconducting Shield--a toroidal magnetic system based on MgB2 superconductors has been analyzed through detailed Monte Carlo simulations using Geant4 interface GRAS. Spacecraft and magnets were modeled together with a simplified mechanical structure supporting the coils. Radiation transport through magnetic fields and materials was simulated for a deep-space mission scenario, considering for the first time the effect of secondary particles produced in the passage of space radiation through the active shielding and spacecraft structures. When modeling the structures supporting the active shielding systems and the habitat, the radiation protection efficiency of the magnetic field is severely decreasing compared to the one reported in previous studies, when only the magnetic field was modeled around the crew. This is due to the large production of secondary radiation taking place in the material surrounding the habitat. PMID- 26948011 TI - Oxygen dependency of germinating Brassica seeds. AB - Establishing plants in space, Moon or Mars requires adaptation to altered conditions, including reduced pressure and composition of atmospheres. To determine the oxygen requirements for seed germination, we imbibed Brassica rapa seeds under varying oxygen concentrations and profiled the transcription patterns of genes related to early metabolism such as starch degradation, glycolysis, and fermentation. We also analyzed the activity of lactate dehydrogenase (LDH) and alcohol dehydrogenase (ADH), and measured starch degradation. Partial oxygen pressure (pO2) greater than 10% resulted in normal germination (i.e., protrusion of radicle about 18 hours after imbibition) but lower pO2 delayed and reduced germination. Imbibition in an oxygen-free atmosphere for three days resulted in no germination but subsequent transfer to air initiated germination in 75% of the seeds and the root growth rate was transiently greater than in roots germinated under ambient pO2. In hypoxic seeds soluble sugars degraded faster but the content of starch after 24 h was higher than at ambient oxygen. Transcription of genes related to starch degradation, alpha-amylase (AMY) and Sucrose Synthase (SUS), was higher under ambient O2 than under hypoxia. Glycolysis and fermentation pathway-related genes, glucose phosphate isomerase (GPI), 6 phosphofructokinase (PFK), fructose 1,6-bisphosphate aldolase (ALD), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), pyruvate decarboxylase (PDC), LDH, and ADH, were induced by low pO2. The activity of LDH and ADH was the highest in anoxic seeds. Germination under low O2 conditions initiated ethanolic fermentation. Therefore, sufficient oxygen availability is important for germination before photosynthesis provides necessary oxygen and the determination of an oxygen carrying capacity is important for uniform growth in space conditions. PMID- 26948013 TI - Reference field specification and preliminary beam selection strategy for accelerator-based GCR simulation. AB - The galactic cosmic ray (GCR) simulator at the NASA Space Radiation Laboratory (NSRL) is intended to deliver the broad spectrum of particles and energies encountered in deep space to biological targets in a controlled laboratory setting. In this work, certain aspects of simulating the GCR environment in the laboratory are discussed. Reference field specification and beam selection strategies at NSRL are the main focus, but the analysis presented herein may be modified for other facilities and possible biological considerations. First, comparisons are made between direct simulation of the external, free space GCR field and simulation of the induced tissue field behind shielding. It is found that upper energy constraints at NSRL limit the ability to simulate the external, free space field directly (i.e. shielding placed in the beam line in front of a biological target and exposed to a free space spectrum). Second, variation in the induced tissue field associated with shielding configuration and solar activity is addressed. It is found that the observed variation is likely within the uncertainty associated with representing any GCR reference field with discrete ion beams in the laboratory, given current facility constraints. A single reference field for deep space missions is subsequently identified. Third, a preliminary approach for selecting beams at NSRL to simulate the designated reference field is presented. This approach is not a final design for the GCR simulator, but rather a single step within a broader design strategy. It is shown that the beam selection methodology is tied directly to the reference environment, allows facility constraints to be incorporated, and may be adjusted to account for additional constraints imposed by biological or animal care considerations. The major biology questions are not addressed herein but are discussed in a companion paper published in the present issue of this journal. Drawbacks of the proposed methodology are discussed and weighed against alternative simulation strategies. PMID- 26948014 TI - Reed warblers migrating through Portugal: climatic influence on stopover ecology over the last decade. AB - The arrival and breeding dates of small migrant birds have advanced throughout Europe. This study evaluates the hypothesis of a faster migration along the migratory route, which should lead to a decrease in stopover duration in staging areas over the last decades. Several climatic predictors were analysed as proxies to understand the stopover ecology of reed warbler Acrocephalus scirpaceus migrating through Central Portugal. The minimum stopover duration of migratory reed warblers decreased significantly over the last decade during both the spring and autumn migrations. Warmer conditions en route should increase food availability, increasing the body condition of departing birds and the quality of departing sites en route to Portugal, such that migrants will reduce the stopover duration at Portuguese reedbeds. PMID- 26948012 TI - Galactic cosmic ray simulation at the NASA Space Radiation Laboratory. AB - Most accelerator-based space radiation experiments have been performed with single ion beams at fixed energies. However, the space radiation environment consists of a wide variety of ion species with a continuous range of energies. Due to recent developments in beam switching technology implemented at the NASA Space Radiation Laboratory (NSRL) at Brookhaven National Laboratory (BNL), it is now possible to rapidly switch ion species and energies, allowing for the possibility to more realistically simulate the actual radiation environment found in space. The present paper discusses a variety of issues related to implementation of galactic cosmic ray (GCR) simulation at NSRL, especially for experiments in radiobiology. Advantages and disadvantages of different approaches to developing a GCR simulator are presented. In addition, issues common to both GCR simulation and single beam experiments are compared to issues unique to GCR simulation studies. A set of conclusions is presented as well as a discussion of the technical implementation of GCR simulation. PMID- 26948017 TI - Simultaneous removal of third molars and completion of a sagittal split osteotomy: effects of age and presence of third molars. AB - OBJETIVES: The risk of removal of third molars (M3) during a sagittal split osteotomy (SSO) is controversial. The purpose of this study was to review our experience with removal of mandibular M3 during versus before SSO. STUDY DESIGN: A chart and radiographic review was completed in all patients who underwent an SSO from April 2010 until September 2014. The presence or absence of M3, degree of impaction, age, sex, and occurrence of bad splits were noted. The variables were analyzed using the Pearson chi(2), ANOVA, and Fisher's exact tests set to a significance of 5%. RESULTS: For the 215 patients, the mean age was 23.28 years with an increase in the incidence of bad splits in older patients (P = .013). Sixty-six (30.70%) of them had at least 1 M3 present at the time of surgery. There were 6 (2.79%) bad splits. Paradoxically, looking at the occurrence of bad splits and presence of third molar, when the data were analyzed by the number of patients undergoing the procedure, there was slight evidence of a difference (P = .073), but when the data were analyzed by the surgical site, there was a statistically significant association (P = .05). CONCLUSION: The discrepancy between the 2 ways of analyzing the data may be related to there being double the number of observations when analyzed by surgical site and thus the analysis being more powerful. PMID- 26948018 TI - Sera and salivary matrix metalloproteinases are elevated in patients with vesiculoerosive disease: a pilot study. AB - BACKGROUND: Oral vesiculoerosive (VE) diseases, such as lichen planus and mucous membrane pemphigoid, are immune-mediated pathoses. Matrix metalloproteinase (MMP) 2 and MMP-9 are elevated in oral lesional biopsy specimens of patients with VE disease. However, the systemic levels and activity of MMP-2 and MMP-9 in this patient population are poorly understood. We performed a pilot study to determine whether the levels and activity of MMP-2 and MMP-9 are elevated in the sera and saliva of patients with VE disease. STUDY DESIGN: We recruited patients with VE disease (n = 10) and healthy controls (n = 19). We collected sera and saliva and performed enzyme-linked immunosorbent assays to measure MMP levels. We used gelatin zymography and Biotrak assays to determine enzyme activity. Data were analyzed using the Mann-Whitney test. RESULTS: There was no difference in the activity of either MMP in the sera or saliva of patients with VE disease compared with controls. Significantly, MMP-2 levels were elevated in the sera of patients with VE disease (P < .0001), whereas MMP-9 was elevated in their saliva (P = .003). CONCLUSIONS: MMP-2 is elevated in the sera of patients with VE disease, and MMP-9 is increased in their saliva. Therefore, these enzymes may be potential markers of disease or therapeutic targets. PMID- 26948019 TI - Bilateral sagittal split surgery is not a predictable treatment for temporomandibular dysfunction in patients with retrognathia. AB - OBJECTIVE: A prospective study to clarify the impact of forward bilateral sagittal split osteotomy (BSSO) on temporomandibular dysfunction (TMD). STUDY DESIGN: We examined and interviewed patients with BSSO before and at 1 year after surgery to evaluate the changes in TMD symptoms. A well-known TMD index, which incorporated two complementary subindices-the objective functional Helkimo dysfunction index (Di) and the subjective symptomatic anamnestic index (Ai)-was used. Patients with a forward movement of the mandible and osteosynthesis with titanic miniplates were included. RESULTS: Forty patients (26 females and 14 males, mean age of study population 36.9 years) retrognathia completed the study. There was no change in TMD symptoms in 24 patients (60%), as measured by the Di, and 26 (65%), as measured by the Ai. Twelve patients improved (30%), according to the Di scores and 10 (25%) according to the Ai scores. Four patients had more TMD symptoms at follow-up (10%), as measured by both Di and Ai. CONCLUSIONS: Surgery for orthognathia is a predictable treatment for improving aesthetics and occlusion but less predictable for alleviating TMD symptoms in patients with retrognathia. TMD symptoms should therefore be treated independently. PMID- 26948020 TI - Odontogenic myxoma with diffuse calcifications: a case report and review of a rare histologic feature. AB - Calcifications have been rarely reported in odontogenic myxoma. We describe here an additional case and review all reported cases. A 45-year-old female patient presented with a gingival swelling around a mobile mandibular left second molar. Radiographic investigation revealed a large multilocular radiolucent lesion of the posterior mandible. Microscopic examination revealed an odontogenic myxoma with numerous newly formed trabeculae of bone or cementum-like material present throughout the specimen, reminiscent of those seen in fibro-osseous lesions of the jaws. After total excision, regular follow-up of the patient showed gradual healing of the surgical defect. To our knowledge, only a few documented cases of odontogenic myxoma with calcifications have been reported in the literature. This histopathologic finding is rare but should not lead to the misdiagnosis of a central odontogenic fibroma, cemento-ossifying fibroma, fibro-osseous lesion, or low-grade osteosarcoma. PMID- 26948021 TI - Early and late physical and psychosocial effects of primary surgery in patients with oral and oropharyngeal cancers: a systematic review. AB - The purpose of this systematic review is to explore early and late physical and psychosocial effects of primary surgery for oral and oropharyngeal cancers and to investigate the factors that influence these effects. PubMed, Cinahl, and PsycInfo were searched for studies concerning patients diagnosed with oral and oropharyngeal cancers and treated with primary surgery and which followed the treatment trajectory from time of diagnosis to 10 years after surgery; these studies reported the quantitative assessments and qualitative experiences of the patient's physical and psychosocial well-being. Of the 438 articles accessed, 20 qualified for inclusion, of which 16 and 4 were quantitative and qualitative articles, respectively, and mainly quality-of-life assessments. Time of measurement ranged from time of diagnosis to 9 years after the surgical procedure. The total number of patients included in this review was 3386; of these, 1996 were treated by surgery alone and 1390 with combined surgery and adjuvant radiation therapy and/or chemotherapy. The studies showed that because of the nature of their disease, patients are negatively affected by the different types of surgical treatment for oral and oropharyngeal cancers, with both early and late interrelated effects, and by the side effects of adjuvant therapy. PMID- 26948022 TI - Three-dimensional effects of pterygomaxillary disconnection during surgically assisted rapid palatal expansion: a cadaveric study. AB - OBJECTIVE: The aim of this study was to investigate the influence of pterygomaxillary disconnection on the transversal expansion of the maxilla. STUDY DESIGN: Fifteen cadaver heads were used for surgically assisted rapid palatal expansion (SARPE), which was carried out twice on the same heads-with and without pterygoid disconnection. The maxillae were expanded by 10 mm by using a rapid palatal expander. Study models before and after both SARPE techniques were made and scanned by an oral scanner for virtual analysis by software. RESULTS: Performing pterygomaxillary disconnection during SARPE led to a decrease in the deviation between the incisor regions from 5.42 +/- 1.13 mm to 4.05 +/- 1.12 mm (P = .002) and an increase in the distance between second premolar regions from 2.63 +/- 1.64 mm to 4.07 +/- 2.01 mm (P = .040). CONCLUSIONS: SARPE without pterygomaxillary disconnection led to a V-shaped transverse expansion of the maxilla, whereas osteotomy of the pterygoid plates led to a parallel transverse expansion. PMID- 26948023 TI - Isostructural solid-solid phase transition in monolayers of soft core-shell particles at fluid interfaces: structure and mechanics. AB - We have studied the complete two-dimensional phase diagram of a core-shell microgel-laden fluid interface by synchronizing its compression with the deposition of the interfacial monolayer. Applying a new protocol, different positions on the substrate correspond to different values of the monolayer surface pressure and specific area. Analyzing the microstructure of the deposited monolayers, we discovered an isostructural solid-solid phase transition between two crystalline phases with the same hexagonal symmetry, but with two different lattice constants. The two phases corresponded to shell-shell and core-core inter particle contacts, respectively; with increasing surface pressure the former mechanically failed enabling the particle cores to come into contact. In the phase-transition region, clusters of particles in core-core contacts nucleate, melting the surrounding shell-shell crystal, until the whole monolayer moves into the second phase. We furthermore measured the interfacial rheology of the monolayers as a function of the surface pressure using an interfacial microdisk rheometer. The interfaces always showed a strong elastic response, with a dip in the shear elastic modulus in correspondence with the melting of the shell-shell phase, followed by a steep increase upon the formation of a percolating network of the core-core contacts. These results demonstrate that the core-shell nature of the particles leads to a rich mechanical and structural behavior that can be externally tuned by compressing the interface, indicating new routes for applications, e.g. in surface patterning or emulsion stabilization. PMID- 26948024 TI - Diabetes Attitudes, Wishes and Needs Second Study (DAWN2): Understanding Diabetes Related Psychosocial Outcomes for Canadians with Diabetes. AB - OBJECTIVES: DAWN2 assessed the psychosocial impact of diabetes on persons with diabetes (PWDs), family members and healthcare professionals (HCPs) across 17 countries. This article reports on the Canadian cohort of PWDs. METHODS: PWDs completed online, validated self-report scales assessing quality of life (QOL), self-management, beliefs, social support and priorities for improving diabetes care. Analyses used unweighted data. RESULTS: Of 500 participants (80 type 1, 420 type 2) positive self-reported QOL was common (64.6%) and likely depression less common (12.8%). Diabetes distress, however, was identified by almost half of PWDs with type 1 diabetes, and one-quarter of PWDs with type 2 (47.5% vs. 25.7% type 2; p<0.001). Numerous life areas were negatively impacted, particularly finances, work and emotional well-being for those with type 1 diabetes (p<0.001 vs. type 2). Most PWDs reported support from family, friends and HCPs, but few reported being asked by HCPs how diabetes affected their lives. Most PWDs participated in (type 1, 90.0%; type 2, 85.7%) and valued (type 1, 84.7%; type 2, 78.1%) diabetes education. Few PWDs relied on community supports (type 1, 17.5%; type 2, 26.9%), and discrimination was not uncommon for those with type 1 (33.8% vs. 12.4% for type 2; p<0.001). CONCLUSIONS: PWDs experience psychological challenges that should be addressed within diabetes management services. PMID- 26948027 TI - Electron trapping on Fe(3+) sites in photodoped ZnO colloidal nanocrystals. AB - The effects of photodoping on the electronic structure of Fe(3+)-doped ZnO colloidal nanocrystals are presented. We observe disappearance of the spectroscopic signatures attributed to both substitutional Fe(3+) and interstitial Fe(3+) in the ZnO host as a function of photodoping time, which precede the appearance of the well-known localized surface plasmon resonance from conduction band electrons in ZnO nanocrystals. These results suggest that the oxidation state of Fe(3+) defects can be reversibly switched in ZnO nanocrystals. PMID- 26948026 TI - Utility of a consultation on hereditary kidney diseases: A different approach based on the family tree. PMID- 26948025 TI - Engrailed-2 might play an anti-oncogenic role in clear-cell renal cell carcinoma. AB - Our preliminary study indicated that Engrailed-2 (EN2) is downregulated but also ectopically expressed in clear-cell renal cell carcinoma (CCRCC), and the absence of EN2 expression was associated with poor histological grade. However, the specific roles of EN2 in CCRCC have yet to be elucidated. In the present study, we examined the effects of inhibiting EN2 expression by human renal tubular epithelial cells (HK-2) and overexpressing EN2 by human clear-cell renal cells (786-O). Results showed that EN2 inhibition accelerated HK-2 cell proliferation, shortened the cell cycle, reduced apoptosis, and acted more invasively. By contrast, EN2 overexpression in 786-O cells decelerated the proliferative ability of 786-O, increased the percentage of cell apoptosis, and weakened the invasive ability. Overall, the results demonstrated that EN2 might play an anti-oncogenic role in oncogenesis and development of CCRCC, thereby maintaining the normal growth of human renal tubular epithelial cells. PMID- 26948028 TI - The promise of Mama Kits: Perceptions of in-kind goods as incentives for facility deliveries in Uganda. AB - There is growing interest in the use of incentives to increase the utilisation of maternal health services globally, including the use of in-kind goods. As part of the Saving Mothers, Giving Life (SMGL) programme, pregnant women in three districts in Uganda were incentivised to deliver in a facility by the promise of 'Mama Kits' - clean delivery kits augmented with goods for newborns. We collected and analysed qualitative data from 18 focus groups (130 women) who had a recent home (N = 9) or facility delivery (N = 9 groups) to understand their overall perceptions of the SMGL programme, and, in particular, the Mama Kit. There was a high level of awareness of Mama Kits among women who delivered in a health facility and a moderate awareness among women who delivered at home. When available, kits positively affected women's perceptions of facility delivery because they associated availability of kits with affordability of care. When not available, women's perceptions of their actual or expected delivery experience were negatively affected. When well implemented, in-kind goods can be important complements in broader efforts to incentivise facility delivery. Inconsistent implementation and an underestimation of their influence on care-seeking can undermine efforts to reduce maternal mortality and morbidity. PMID- 26948029 TI - Quantitative feature extraction from the Chinese hamster ovary bioprocess bibliome using a novel meta-analysis workflow. AB - The scientific literature concerning Chinese hamster ovary (CHO) cells grows annually due to the importance of CHO cells in industrial bioprocessing of therapeutics. In an effort to start to catalogue the breadth of CHO phenotypes, or phenome, we present the CHO bibliome. This bibliographic compilation covers all published CHO cell studies from 1995 to 2015, and each study is classified by the types of phenotypic and bioprocess data contained therein. Using data from selected studies, we also present a quantitative meta-analysis of bioprocess characteristics across diverse culture conditions, yielding novel insights and addressing the validity of long held assumptions. Specifically, we show that bioprocess titers can be predicted using indicator variables derived from viable cell density, viability, and culture duration. We further identified a positive correlation between the cumulative viable cell density (VCD) and final titer, irrespective of cell line, media, and other bioprocess parameters. In addition, growth rate was negatively correlated with performance attributes, such as VCD and titer. In summary, despite assumptions that technical diversity among studies and opaque publication practices can limit research re-use in this field, we show that the statistical analysis of diverse legacy bioprocess data can provide insight into bioprocessing capabilities of CHO cell lines used in industry. The CHO bibliome can be accessed at http://lewislab.ucsd.edu/cho-bibliome/. PMID- 26948031 TI - Early toxicity of hypofractionated radiotherapy for prostate cancer. AB - BACKGROUND: Hypofractionated accelerated radiotherapy (HART) is now a feasible option for prostate cancer treatment apropos toxicity, biochemical control and shortening of treatment. The aim of this study was to investigate hypofractionated schedules in the treatment of patients with localized prostate cancer. PATIENTS AND METHODS: Between 2011-2014, 158 patients were treated using the RapidArc technique with IGRT. The target volume for low risk patients was the prostate alone with a prescribed dose of 20x3.0 Gy (EQD2=77 Gy). Targets volumes for intermediate and high risk patients were prostate and two thirds of the seminal vesicles with a prescribed dose 21-22x3.0/2.1 Gy (EQD2=81/45.4 84.9/47.5). Based on radiobiological modelling of early toxicity, we used four fractions per week in the low risk group and four fractions in odd weeks and three fractions in even weeks in intermediate and high risk groups. The RTOG/EORTC toxicity scale was used. RESULTS: Early genitourinary (GU) toxicity was observed for grades 0, 1, 2, 3 and 4 in 73 (46%), 60 (38%), 22 (14%), 0 and 3 (2%), respectively; early gastrointestinal (GI) toxicity was recorded for grades 0, 1, 2 and 3 in 119 (75%), 37 (23%), and 2 (1%) patients, respectively. CONCLUSION: A combination of moderate hypofractionation, number of fractions per week adapted to target volume and precise dose delivery technique with image guidance appears safe with low early toxicity. Longer follow up is needed to assess late toxicity and tumor control probability. PMID- 26948032 TI - Longitudinal, circumferential and radial systolic left ventricular function in patients with heart failure and preserved ejection fraction. AB - INTRODUCTION: Heart failure with preserved left ventricular ejection fraction (HFPEF) is an epidemiologically serious disease. Noninvasive diagnosis of HFPEF remains challenging. The current diagnosis is based on evidence of diastolic dysfunction, albeit systolic dysfunction is also present but not included in the diagnostic algorithm. The aim of this study was to analyze the longitudinal (long), circumferential (circ) and radial (rad) component of systolic left ventricular (LV) function in patients with exertional dyspnea of unexplained etiology and normal left ventricular ejection fraction (LVEF). METHODS: One hundred and twenty-two patients with exertional dyspnea of unexplained etiology and normal LVEF and 21 healthy controls, underwent echocardiography examination at rest and at the end of symptom-limited exercise. We analysed the longitudinal, circumferential and radial deformation of myocardium using two dimensional speckle tracking echocardiography in all subjects. RESULTS: Patients with exertional dyspnea and preserved LVEF were divided into group A1 (46 patients meeting the criteria for the diagnosis HFPEF) and group A2 (76 patients without HFPEF). Group A1 had significantly worse longitudinal and circumferential systolic LV function than group A2. Subjects in group A1 compared to group A2 showed significantly different strain rates during atrial contraction (SR A), circ and ratio of peak early trans-mitral flow velocity (E) and strain rate E wave (E / SR E) circ. Multivariate logistic regression analysis showed that the SR parameter A circ is an independent predictor of HFPEF (odds ratio 0.550, 95% confidence interval: 0.370 - 0.817, P value 0.003). CONCLUSION: Longitudinal and circumferential LV deformation was significantly more impaired in patients with HFPEF than in patients with exertional dyspnea without HFPEF. In patients with exertional dyspnea and normal LVEF, the value of SRA circ appears to be a significant and independent predictor of HFPEF. This parameter may, in the future complement the diagnostic algorithm for HFPEF. PMID- 26948033 TI - MicroRNA-377 Mediates Cardiomyocyte Apoptosis Induced by Cyclosporin A. AB - Cyclosporin A (CsA) is a potent immunosuppressant that has wide clinical applications for autoimmune disorders and prevention of rejection in organ transplantation. However, its liver, kidney, and heart toxicity has limited its use. In this study, we investigated the mechanism by which CsA induced cardiomyocyte apoptosis. Through microarray analysis, we found that the expression of microRNA (miR)-377 was regulated by CsA. Ectopic overexpression of miR-377 led to increased apoptosis in cardiomyocytes, as evidenced by an increased number of apoptotic cells, increased levels of proapoptotic proteins, decreased levels of antiapoptotic proteins, and elevated caspase pathway activity. We also found that miR-377 was required for CsA-induced apoptosis, because inhibition of miR-377 expression markedly reduced the ability of CsA to induce cardiomyocyte apoptosis. In addition, we identified XIAP and NRP2 as direct targets for miR-377. The expression levels of these 2 antiapoptotic proteins were negatively regulated by miR-377, as well as by CsA both in vitro and in vivo. Our data suggested that CsA induced cardiomyocyte apoptosis through the miR-377-XIAP/NRP2 axis. PMID- 26948034 TI - An Echocardiographic Illustration of the Dock's Murmur in a Patient With Wellens Syndrome. PMID- 26948036 TI - Does Lichen Planus Cause Increased Carotid Intima-Media Thickness and Impaired Endothelial Function? AB - BACKGROUND: Lichen planus (LP) has been associated with cardiovascular disease (CVD) risk factors, but there are no studies on the association between LP and subclinical atherosclerosis. We investigated the presence of subclinical atherosclerosis in patients with LP not known to have CVD using carotid intima media thickness (CIMT) and flow-mediated dilatation (FMD). METHODS: The study included 30 patients with LP and 30 controls. High-resolution ultrasonography was used to assess CIMT and FMD. Participants' biochemical parameters, body mass index (BMI), and waist circumference were recorded in both groups. RESULTS: FMD was significantly lower (7.45% +/- 3.63% vs 11.01% +/- 5.34%; P = 0.004) and CIMT was higher (0.8 mm [range, 0.7-0.9 mm] vs 0.6 mm [0.4-0.6 mm]; P < 0.001) in the LP group compared with the control group. After adjustment for age, sex, BMI, high-density lipoprotein cholesterol levels, and C-reactive protein levels, the presence of LP was associated with impairment of FMD (beta = -0.441; 95% CI, 9.336 to -0.321; P = 0.037) and an increase in CIMT (beta = 0.459; 95% CI, 0.057 to -0.351; P = 0.008). CONCLUSIONS: Reduced FMD and increased CIMT levels are sensitive indicators of target-organ damage and display increased risk for cardiovascular morbidity and mortality. Our study found that patients with LP showed a tendency toward impaired levels of FMD and increased CIMT. LP may be a novel predictor of early vascular dysfunction and structural changes. PMID- 26948037 TI - Quality of Care for Transcatheter Aortic Valve Implantation: Development of Canadian Cardiovascular Society Quality Indicators. AB - Transcatheter aortic valve implantation (TAVI) is a relatively new procedure to treat aortic stenosis in patients at high surgical risk, and it is becoming increasingly available in Canada. Variation exists in the clinical care, program coordination, evaluation, and funding across provinces and centres. As a part of the Canadian Cardiovascular Society (CCS) quality initiative, the TAVI Quality Indicator (QI) Working Group was established in 2014 to develop a set of indicators to measure quality of care for Canadians undergoing TAVI for aortic stenosis. The TAVI QI Working Group is composed of expert clinical and government agency representatives. The group developed consensus agreements for the selection of the first iteration of measurable structure, process, and outcome indicators reflective of the quality of care for patients undergoing TAVI. The objectives of the project are to develop quality indicators with the eventual goal of standardizing TAVI quality reports across Canada and to support local and national quality assurance, as well as engage multiple stakeholders to build a national strategy for the evaluation of quality of care. PMID- 26948038 TI - Successful Single-Stage Operation for Loeys-Dietz Syndrome With Critical Coarctation of the Descending Aorta in a Young Adult. AB - Patients with critical coarctation of the aorta complicated with Loeys-Dietz syndrome are extremely rare. We report a successful single-stage operation involving critical coarctation of the descending aorta with a bicuspid aortic valve, aneurysmal aortic root, and ascending aorta in a 19-year-old man. The patient was genetically evaluated and a novel heterozygous TGFBR2 mutation was detected. PMID- 26948035 TI - Sirtuins, Cell Senescence, and Vascular Aging. AB - The sirtuins (SIRTs) constitute a class of proteins with nicotinamide adenine dinucleotide-dependent deacetylase or adenosine diphosphate-ribosyltransferase activity. Seven SIRT family members have been identified in mammals, from SIRT1, the best studied for its role in vascular aging, to SIRT7. SIRT1 and SIRT2 are localized in the nucleus and cytoplasm. SIRT3, SIRT4, and SIRT5 are mitochondrial, and SIRT6 and SIRT7 are nuclear. Extensive studies have clearly revealed that SIRT proteins regulate diverse cell functions and responses to stressors. Vascular aging involves the aging process (senescence) of endothelial and vascular smooth muscle cells. Two types of cell senescence have been identified: (1) replicative senescence with telomere attrition; and (2) stress induced premature senescence without telomere involvement. Both types of senescence induce vascular cell growth arrest and loss of vascular homeostasis, and contribute to the initiation and progression of cardiovascular diseases. Previous mechanistic studies have revealed in detail that SIRT1, SIRT3, and SIRT6 show protective functions against vascular aging, and definite vascular function of other SIRTs is under investigation. Thus, direct SIRT modulation and nicotinamide adenine dinucleotide stimulation of SIRT are promising candidates for cardiovascular disease therapy. A small number of pilot studies have been conducted to assess SIRT modulation in humans. These clinical studies have not yet provided convincing evidence that SIRT proteins alleviate morbidity and mortality in patients with cardiovascular diseases. The outcomes of multiple ongoing clinical trials are awaited to define the efficacy of SIRT modulators and SIRT activators in cardiovascular diseases, along with the potential adverse effects of chronic SIRT modulation. PMID- 26948039 TI - Understanding Vascular Diseases: Lessons From Premature Aging Syndromes. AB - Early human mummies examined recently by computed tomography demonstrated a high prevalence of vascular calcification, a pathognomonic sign of atherosclerosis, which was correlated with estimated age at death. Early populations had little exposure to modern-day metabolic risk factors: these observations thus suggest that humans have an inherent age-dependent predisposition to atherosclerosis. Premature aging syndromes are extremely rare genetic disorders that exhibit clinical phenotypes resembling accelerated aging, including severe atherosclerosis, but those phenotypes are usually segmental. Controversy persists, therefore, regarding the extent to which the molecular mechanisms underlying premature aging syndromes overlap with those of physiological aging. Hutchinson-Gilford progeria syndrome (HGPS) and Werner syndrome are well characterized premature aging syndromes. HGPS is caused by gain-of-function mutations in the LMNA gene, which result in the accumulation of a mutant nuclear protein, called "progerin," at the nuclear rim. In contrast, loss-of-function mutations in Werner syndrome ATP-dependent helicase (WRN) lead to Werner syndrome. Mesenchymal stem cells (MSCs), which can differentiate into vascular cells to maintain vascular homeostasis in response to injury, are severely affected in these syndromes. Mechanistically, either aberrant expression of progerin or loss of WRN protein in MSCs alters heterochromatin structure, resulting in premature senescence and exhaustion of functional MSCs in premature aging syndromes. Surprisingly, vascular cells and MSCs in elderly healthy individuals have shown progerin expression and decreased expression levels of WRN, respectively. Studying these rare genetic disorders could thus provide valuable insights into age-related vascular diseases that occur in the general population. PMID- 26948041 TI - Chernobyl and Fukushima-where are we now? PMID- 26948040 TI - Structure of Main Protease from Human Coronavirus NL63: Insights for Wide Spectrum Anti-Coronavirus Drug Design. AB - First identified in The Netherlands in 2004, human coronavirus NL63 (HCoV-NL63) was found to cause worldwide infections. Patients infected by HCoV-NL63 are typically young children with upper and lower respiratory tract infection, presenting with symptoms including croup, bronchiolitis, and pneumonia. Unfortunately, there are currently no effective antiviral therapy to contain HCoV NL63 infection. CoV genomes encode an integral viral component, main protease (M(pro)), which is essential for viral replication through proteolytic processing of RNA replicase machinery. Due to the sequence and structural conservation among all CoVs, M(pro) has been recognized as an attractive molecular target for rational anti-CoV drug design. Here we present the crystal structure of HCoV-NL63 M(pro) in complex with a Michael acceptor inhibitor N3. Structural analysis, consistent with biochemical inhibition results, reveals the molecular mechanism of enzyme inhibition at the highly conservative substrate-recognition pocket. We show such molecular target remains unchanged across 30 clinical isolates of HCoV NL63 strains. Through comparative study with M(pro)s from other human CoVs (including the deadly SARS-CoV and MERS-CoV) and their related zoonotic CoVs, our structure of HCoV-NL63 M(pro) provides critical insight into rational development of wide spectrum antiviral therapeutics to treat infections caused by human CoVs. PMID- 26948042 TI - Aldo-keto Reductase Family 1 Member B 10 Mediates Liver Cancer Cell Proliferation through Sphingosine-1-Phosphate. AB - AKR1B10 is involved in hepatocarcinogenesis via modulation of fatty acid and lipid synthesis. AKR1B10 inhibition results in apoptosis of tumor cells whose lipids, especially phospholipids, were decreased by over 50%, suggesting involvement of phospholipids like sphingosine-1-phosphate (S1P) in AKR1B10's oncogenic function. Using a co-culture system, we found that co-culture of QSG 7701 (human hepatocyte) with HepG2 (hepatoma cell line) increases QSG-7701's proliferation, in which AKR1B10-S1P signaling plays a pivotal role. Consistent with previous findings, AKR1B10 mRNA and protein levels were higher in primary hepatocellular carcinoma (PHC) tissues than in peri-tumor tissues. Interestingly, the level of S1P was also higher in PHC tissues than in peri-tumor tissues. After analyzing the correlation between AKR1B10 mRNA expression in PHC tissues and the clinical data, we found that AKR1B10 mRNA expression was associated with serum alpha-fetoprotein (AFP), tumor-node-metastasis (TNM) stage, and lymph node metastasis, but not with other clinicopathologic variables. A higher AKR1B10 mRNA expression level is related to a shorter DFS (disease free survival) and OS (overall survival), serving as an independent predictor of DFS and OS in PHC patients with surgical resection. PMID- 26948043 TI - Designing high-performance layered thermoelectric materials through orbital engineering. AB - Thermoelectric technology, which possesses potential application in recycling industrial waste heat as energy, calls for novel high-performance materials. The systematic exploration of novel thermoelectric materials with excellent electronic transport properties is severely hindered by limited insight into the underlying bonding orbitals of atomic structures. Here we propose a simple yet successful strategy to discover and design high-performance layered thermoelectric materials through minimizing the crystal field splitting energy of orbitals to realize high orbital degeneracy. The approach naturally leads to design maps for optimizing the thermoelectric power factor through forming solid solutions and biaxial strain. Using this approach, we predict a series of potential thermoelectric candidates from layered CaAl2Si2-type Zintl compounds. Several of them contain nontoxic, low-cost and earth-abundant elements. Moreover, the approach can be extended to several other non-cubic materials, thereby substantially accelerating the screening and design of new thermoelectric materials. PMID- 26948044 TI - Phytoplankton IF-FISH: Species-specific labeling of cellular proteins by immunofluorescence (IF) with simultaneous species identification by fluorescence immunohybridization (FISH). AB - Phytoplankton rarely occur as unialgal populations. Therefore, to study species specific protein expression, indicative of physiological status in natural populations, methods are needed that will both assay for a protein of interest and identify the species expressing it. Here we describe a protocol for IF-FISH, a dual labeling procedure using immunofluorescence (IF) labeling of a protein of interest followed by fluorescence in situ hybridization (FISH) to identify the species expressing that protein. The protocol was developed to monitor expression of the cell cycle marker proliferating cell nuclear antigen (PCNA) in the red tide dinoflagellate, Karenia brevis, using a large subunit (LSU) rRNA probe to identify K. brevis in a mixed population of morphologically similar Karenia species. We present this protocol as proof of concept that IF-FISH can be successfully applied to phytoplankton cells. This method is widely applicable for the analysis of single-cell protein expression of any protein of interest within phytoplankton communities. PMID- 26948045 TI - A rapid and accurate quantification method for real-time dynamic analysis of cellular lipids during microalgal fermentation processes in Chlorella protothecoides with low field nuclear magnetic resonance. AB - The rapid and real-time lipid determination can provide valuable information on process regulation and optimization in the algal lipid mass production. In this study, a rapid, accurate and precise quantification method of in vivo cellular lipids of Chlorella protothecoides using low field nuclear magnetic resonance (LF NMR) was newly developed. LF-NMR was extremely sensitive to the algal lipids with the limits of the detection (LOD) of 0.0026g and 0.32g/L in dry lipid samples and algal broth, respectively, as well as limits of quantification (LOQ) of 0.0093g and 1.18g/L. Moreover, the LF-NMR signal was specifically proportional to the cellular lipids of C. protothecoides, thus the superior regression curves existing in a wide detection range from 0.02 to 0.42g for dry lipids and from 1.12 to 8.97gL(-1) of lipid concentration for in vivo lipid quantification were obtained with all R(2) higher than 0.99, irrespective of the lipid content and fatty acids profile variations. The accuracy of this novel method was further verified to be reliable by comparing lipid quantification results to those obtained by GC-MS. And the relative standard deviation (RSD) of LF-NMR results were smaller than 2%, suggesting the precision of this method. Finally, this method was successfully used in the on-line lipid monitoring during the algal lipid fermentation processes, making it possible for better understanding of the lipid accumulation mechanism and dynamic bioprocess control. PMID- 26948046 TI - [Spironolactone versus placebo, bisoprolol and doxazosin to determine the optimal treatment for drug-resistant hypertension]. PMID- 26948047 TI - [Lipschutz ulcer: Presentation of 2 cases]. PMID- 26948048 TI - [Interval cancer, screening, and risk markers in breast tumours]. PMID- 26948049 TI - Hydrodealkoxylation reactions of silyl ligands at platinum: reactivity of SiH3 and SiH2Me complexes. AB - The platinum(ii) complex [Pt(H)2(dcpe)] (; dcpe = 1,2 bis(dicyclohexylphosphino)ethane) reacts with an excess of the dialkoxymethylsilanes (HSiMe(OR)2; R = Me, Et) to give the bis(silyl) complex [Pt(SiH2Me)2(dcpe)] () and trialkoxymethylsilanes by hydrodealkoxylation reactions. These rearrangements of the silyl ligands involve Si-O bond activations. The exchange of the alkoxy moieties against silicon-bound hydrogen atoms occurs stepwise. The intermediate complexes [Pt(H){SiMe(OEt)2}(dcpe)] (), [Pt{SiMe(OEt)2}2(dcpe)] (), [Pt{SiHMe(OEt)}2(dcpe)] () and [Pt{SiHMe(OMe)}2(dcpe)] () were detected. Treatment of the complex with an excess of dichloromethylsilane yields the bis(silyl) complex [Pt(SiMeCl2)2(dcpe)] (). The hydrido silyl complex [Pt(H)(SiMeCl2)(dcpe)] () was identified as an intermediate. The reactions of the complexes [Pt(SiH3)2(dcpe)] () and [Pt(SiH2Me)2(dcpe)] () with iodomethane lead to a transfer of the SiH3 and SiH2Me ligands. Methylsilane and dimethylsilane, respectively, as well as the platinum diiodo complex [Pt(I)2(dcpe)] () were identified as main products. PMID- 26948050 TI - Characterization of a Glycoside Hydrolase Family 27 alpha-Galactosidase from Pontibacter Reveals Its Novel Salt-Protease Tolerance and Transglycosylation Activity. AB - alpha-Galactosidases are of great interest in various applications. A glycoside hydrolase family 27 alpha-galactosidase was cloned from Pontibacter sp. harbored in a saline soil and expressed in Escherichia coli. The purified recombinant enzyme (rAgaAHJ8) was little or not affected by 3.5-30.0% (w/v) NaCl, 10.0-100.0 mM Pb(CH3COO)2, 10.0-60.0 mM ZnSO4, or 8.3-100.0 mg mL(-1) trypsin and by most metal ions and chemical reagents at 1.0 and 10.0 mM concentrations. The degree of synergy on enzymatic degradation of locust bean gum and guar gum by an endomannanase and rAgaAHJ8 was 1.22-1.54. In the presence of trypsin, the amount of reducing sugars released from soybean milk treated by rAgaAHJ8 was approximately 3.8-fold compared with that treated by a commercial alpha galactosidase. rAgaAHJ8 showed transglycosylation activity when using sucrose, raffinose, and 3-methyl-1-butanol as the acceptors. Furthermore, potential factors for salt adaptation of the enzyme were presumed. PMID- 26948051 TI - Peptide-Induced AIEgen Self-Assembly: A New Strategy to Realize Highly Sensitive Fluorescent Light-Up Probes. AB - Fluorescent light-up probes with aggregation-induced emission (AIE) characteristics have recently attracted great research interest due to their intelligent fluorescence activation mechanism and excellent photobleaching resistance. In this work, we report a new, simple, and generic strategy to design and prepare highly sensitive AIE fluorescent light-up bioprobe through facile incorporation of a self-assembling peptide sequence GFFY between the recognition element and the AIE luminogen (AIEgen). After the bioprobes respond to the targets, the peptide GFFY is capable of inducing the ordered self-assembly of AIEgens, yielding close and tight intermolecular steric interactions to restrict the intramolecular motions of AIEgens for excellent signal output. Using two proof-of-concepts, we have demonstrated that self-assembling peptide incorporating AIE light-up probes show much higher sensitivity in sensing the corresponding targets in both solutions and cancer cells as compared to those without GFFY induced self-assembly. Taking the probe TPE-GFFYK(DVEDEE-Ac), for example, a detection limit as low as 0.54 pM can be achieved for TPE-GFFYK(DVEDEE Ac) in caspase-3 detection, which is much lower than that of TPE-K(DVED-Ac) (3.50 pM). This study may inspire new insights into the design of advanced fluorescent molecular probes. PMID- 26948053 TI - NECAB3 Promotes Activation of Hypoxia-inducible factor-1 during Normoxia and Enhances Tumourigenicity of Cancer Cells. AB - Unlike most cells, cancer cells activate hypoxia inducible factor-1 (HIF-1) to use glycolysis even at normal oxygen levels, or normoxia. Therefore, HIF-1 is an attractive target in cancer therapy. However, the regulation of HIF-1 during normoxia is not well characterised, although Mint3 was recently found to activate HIF-1 in cancer cells and macrophages by suppressing the HIF-1 inhibitor, factor inhibiting HIF-1 (FIH-1). In this study, we analysed Mint3-binding proteins to investigate the mechanism by which Mint3 regulates HIF-1. Yeast two-hybrid screening using Mint3 as bait identified N-terminal EF-hand calcium binding protein 3 (NECAB3) as a novel factor regulating HIF-1 activity via Mint3. NECAB3 bound to the phosphotyrosine-binding domain of Mint3, formed a ternary complex with Mint3 and FIH-1, and co-localised with Mint3 at the Golgi apparatus. Depletion of NECAB3 decreased the expression of HIF-1 target genes and reduced glycolysis in normoxic cancer cells. NECAB3 mutants that binds Mint3 but lacks an intact monooxygenase domain also inhibited HIF-1 activation. Inhibition of NECAB3 in cancer cells by either expressing shRNAs or generating a dominant negative mutant reduced tumourigenicity. Taken together, the data indicate that NECAB3 is a promising new target for cancer therapy. PMID- 26948054 TI - Achieving the Benefits of a High-Potassium, Paleolithic Diet, Without the Toxicity. AB - The average US dietary intake of K(+) is well below the current recommended nutritional requirements. This deficiency is even more striking when comparing our current intake with that of our ancestors, who consumed large amounts of dietary K(+). K(+) deficiency has been implicated in many diseases including cardiovascular disease, kidney stones, and osteoporosis. Importantly, dietary supplementation of K(+) has favorable effects on reducing blood pressure, decreasing the risk of stroke, improving bone health, and reducing the risk of nephrolithiasis. For this comprehensive review, we scanned the literature using PubMed and MEDLINE using the following search terms: potassium intake, renal potassium excretion, and prevention of hyperkalemia. Articles were selected for inclusion if they represented primary data or review articles published between 1980 and 2015 in high-impact journals. The normal kidney has the capacity to tightly regulate K(+) homoeostasis. We discuss new findings with respect to sensing mechanisms by which the kidney maintains K(+) homeostasis in the gastrointestinal tract and distal tubule. There are widely prescribed hypertensive medications that cause hyperkalemia and thus require dietary K(+) restriction. We conclude by discussing newly approved drugs capable of binding K(+) in the gastrointestinal tract and speculate that this new pharmacology might allow diet liberalization in patients at risk for hyperkalemia, affording them the numerous benefits of a K(+)-rich diet. PMID- 26948055 TI - Sharing self-related information is associated with intrinsic functional connectivity of cortical midline brain regions. AB - Human beings are social animals and they vary in the degree to which they share information about themselves with others. Although brain networks involved in self-related cognition have been identified, especially via the use of resting state experiments, the neural circuitry underlying individual differences in the sharing of self-related information is currently unknown. Therefore, we investigated the intrinsic functional organization of the brain with respect to participants' degree of self-related information sharing using resting state functional magnetic resonance imaging and self-reported social media use. We conducted seed-based correlation analyses in cortical midline regions previously shown in meta-analyses to be involved in self-referential cognition: the medial prefrontal cortex (MPFC), central precuneus (CP), and caudal anterior cingulate cortex (CACC). We examined whether and how functional connectivity between these regions and the rest of the brain was associated with participants' degree of self-related information sharing. Analyses revealed associations between the MPFC and right dorsolateral prefrontal cortex (DLPFC), as well as the CP with the right DLPFC, the left lateral orbitofrontal cortex and left anterior temporal pole. These findings extend our present knowledge of functional brain connectivity, specifically demonstrating how the brain's intrinsic functional organization relates to individual differences in the sharing of self-related information. PMID- 26948056 TI - A three-dimensional finite element analysis of the sports mouthguard. AB - BACKGROUND/AIM: The aim of this study was to evaluate the compressive and tensile stresses on dentin and enamel in five different situations: no mouthguard and mouthguards from 1 mm thickness up to 4 mm thickness, using finite element analysis. MATERIALS AND METHODS: A three-dimensional geometry of an upper right central incisor was obtained from a computed tomography and transformed into a mesh separating enamel from dentin. A mouthguard was created covering the buccal surface of the enamel in different thicknesses, and a rubber ball with a velocity of 5 m s(-1) was made as the impact object. RESULTS: The maximum principal stress and the minimal principal stress were evaluated in all situations on dentin and enamel. Both maximum and minimal stress on enamel had the greatest value on the control situation (no mouthguard), and their value decreased as the mouthguard thickness increased. The reduction ranged from 66.62% to 85.5% for compressive stress and from 9.76% to 33.37% for tensile stress on enamel. The results for dentin were similar among the situations with or without mouthguards. CONCLUSION: The mouthguard had beneficial effect considering the stresses on enamel, and between the mouthguard thickness of 3 and 4 mm, there was minimum difference. PMID- 26948057 TI - Obesity and vitamin D deficiency: is there an association? PMID- 26948058 TI - Platelet clinical proteomics: Facts, challenges, and future perspectives. AB - In recent years, proteomics has been applied to platelet clinical research. Platelets are small enucleated cells that play a fundamental role in hemostasis. In a pathological context, unwanted platelet activation is related to various diseases, primarily thrombosis, but also cancer metastasis, inflammation, immunity, and neurodegenerative diseases. The absence of a nucleus is one of the reasons why proteomics can be considered an ideal analytical tool for platelet research. Indeed, platelet proteomics has allowed the identification of many novel signaling proteins and receptors, several of which are being pursued as potential therapeutic targets. Encouraged by this success, several research groups have recently initiated clinical proteomics studies covering diseases where platelets are involved in some way, such as coronary artery disease, storage pool diseases, uremia, cystic fibrosis, and Alzheimer disease. The goal was to identify platelet biomarkers and drug targets that can help to improve the treatment/diagnosis of the disease and provide further mechanistic evidences of the role platelets play in the pathology. The present article will comment on the recent progress of clinical proteomics in the context of platelet research, challenges, and perspectives for the future ahead. PMID- 26948059 TI - Occult recurrence of monomorphic epitheliotropic intestinal T-cell lymphoma and the role of MATK gene expression in diagnosis. AB - Monomorphic epitheliotropic intestinal T-cell lymphomas (MEITL), formerly Type II enteropathy-associated T-cell lymphomas (EATL), are rare peripheral T-cell lymphomas. They are associated with poor survival outcomes, in part because of their late diagnosis. Although MEITLs may be reliably diagnosed based on histological and immunophenotypic findings, overlaps with other NK/T and T-cell lymphomas may confound the diagnosis. The distinctive high-level nuclear staining of the novel marker Megakaryocyte-associated tyrosine kinase (MATK) in MEITLs is an invaluable tool in distinguishing MEITL from classical EATL and other NK/T or T-cell lymphomas. 18-Fluorine-2-fluorodeoxyglucose positron emission tomography (18 F-FDG PET) has been shown to be a useful tool in the staging and follow-up of aggressive lymphomas. Herein, we describe an unusual case of occult hepatic recurrence of MEITL that was non-avid on 18 F-FDG PET, in which diagnosis was confirmed based on the expression of MATK in tumour cells. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26948060 TI - The meanings of theorizing. PMID- 26948061 TI - Theorizing--for what? PMID- 26948062 TI - What conception of the theoretical does 'theorizing' presuppose? Comment on Richard Swedberg's 'Before theory comes theorizing or how to make social science more interesting'. PMID- 26948063 TI - Theorizing resistance. PMID- 26948064 TI - The pragmatist wave of theory construction. PMID- 26948065 TI - Reply to the commentators. PMID- 26948066 TI - The moral economy of austerity: analysing UK welfare reform. AB - This paper notes the contemporary emergence of 'morality' in both sociological argument and political rhetoric, and analyses its significance in relation to ongoing UK welfare reforms. It revisits the idea of 'moral economy' and identifies two strands in its contemporary application; that all economies depend on an internal moral schema, and that some external moral evaluation is desirable. UK welfare reform is analysed as an example of the former, with reference to three distinct orientations advanced in the work of Freeden (1996), Laclau (2014), and Lockwood (1996). In this light, the paper then considers challenges to the reform agenda, drawn from third sector and other public sources. It outlines the forms of argument present in these challenges, based respectively on rationality, legality, and morality, which together provide a basis for evaluation of the welfare reforms and for an alternative 'moral economy'. PMID- 26948068 TI - Morphology of congenital portosystemic shunts involving the left colic vein in dogs and cats. AB - OBJECTIVE: To describe the anatomy of congenital portosystemic shunts involving the left colic vein in dogs and cats. METHODS: Retrospective review of a consecutive series of dogs and cats managed for congenital portosystemic shunts. For inclusion a shunt involving the left colic vein with recorded intraoperative mesenteric portovenography or computed tomography angiography along with direct gross surgical observations at the time of surgery was required. RESULTS: Six dogs and three cats met the inclusion criteria. All cases had a shunt which involved a distended left colic vein. The final communication with a systemic vein was variable; in seven cases (five dogs, two cats) it was via the caudal vena cava, in one cat it was via the common iliac vein and in the remaining dog it was via the internal iliac vein. In addition, two cats showed caudal vena cava duplication. CLINICAL SIGNIFICANCE: The morphology of this shunt type appeared to be a result of an abnormal communication between either the left colic vein or the cranial rectal vein and a pelvic systemic vein (caudal vena cava, common iliac vein or internal iliac vein). This information may help with surgical planning in cases undergoing shunt closure surgery. PMID- 26948067 TI - Light-Activated Hypoxia-Responsive Nanocarriers for Enhanced Anticancer Therapy. AB - A light-activated hypoxia-responsive conjugated polymer-based nanocarrier is developed for efficiently producing singlet oxygen ((1) O2 ) and inducing hypoxia to promote release of its cargoes in tumor cells, leading to enhanced antitumor efficacy. This dual-responsive nanocarrier provides an innovative design guideline for enhancing traditional photodynamic therapeutic efficacy integrated with a controlled drug-release modality. PMID- 26948070 TI - Free fatty acid suppositories are as effective as docusate sodium and sorbitol enemas in treating constipation in children. AB - AIM: A well-documented, clinically proven per rectum treatment for childhood constipation is needed. This phase two clinical trial evaluated the efficacy of suppositories containing free fatty acids (FFA) compared with Klyx docusate sodium and sorbitol enemas. METHODS: A randomised, controlled, single-blind study was undertaken on 77 children aged between one and 17 who presented to an emergency department in Iceland and were diagnosed with constipation. In stage one, 23 patients were randomised to receive lower dose FFA suppositories or Klyx (n = 33). In stage two, 21 different patients were randomised to receive higher dose suppositories and compared with the same Klyx control subjects. RESULTS: The suppositories were effective at bowel emptying in 39% of the group who received the lower FFA doses and 81% of the group receiving higher doses, compared with 88% in the Klyx control group. Symptom relief was obtained in 30% of the group receiving the lower doses and 71% of the group receiving the higher doses, compared with 73% in the control group. CONCLUSION: The higher dose FFA suppositories were as effective as the Klyx enemas with regard to bowel emptying and symptom relief and might provide an important and less invasive alternative for childhood constipation. PMID- 26948069 TI - Rotameric preferences of a protein spin label at edge-strand beta-sheet sites. AB - Protein spin labeling to yield the nitroxide-based R1 side chain is a powerful method to measure protein dynamics and structure by electron spin resonance. However, R1 measurements are complicated by the flexibility of the side chain. While analysis approaches for solvent-exposed alpha-helical environment have been developed to partially account for flexibility, similar work in beta-sheets is lacking. The goal of this study is to provide the first essential steps for understanding the conformational preferences of R1 within edge beta-strands using X-ray crystallography and double electron electron resonance (DEER) distance measurements. Crystal structures yielded seven rotamers for a non-hydrogen-bonded site and three rotamers for a hydrogen-bonded site. The observed rotamers indicate contextual differences in R1 conformational preferences compared to other solvent-exposed environments. For the DEER measurements, each strand site was paired with the same alpha-helical site elsewhere on the protein. The most probable distance observed by DEER is rationalized based on the rotamers observed in the crystal structure. Additionally, the appropriateness of common molecular modeling methods that account for R1 conformational preferences are assessed for the beta-sheet environment. These results show that interpretation of R1 behavior in beta-sheets is difficult and indicate further development is needed for these computational methods to correctly relate DEER distances to protein structure at edge beta-strand sites. PMID- 26948071 TI - Multi-tasking uncovers right spatial neglect and extinction in chronic left hemisphere stroke patients. AB - Unilateral Spatial Neglect, the most dramatic manifestation of contralesional space unawareness, is a highly heterogeneous syndrome. The presence of neglect is related to core spatially lateralized deficits, but its severity is also modulated by several domain-general factors (such as alertness or sustained attention) and by task demands. We previously showed that a computer-based dual task paradigm exploiting both lateralized and non-lateralized factors (i.e., attentional load/multitasking) better captures this complex scenario and exacerbates deficits for the contralesional space after right hemisphere damage. Here we asked whether multitasking would reveal contralesional spatial disorders in chronic left-hemisphere damaged (LHD) stroke patients, a population in which impaired spatial processing is thought to be uncommon. Ten consecutive LHD patients with no signs of right-sided neglect at standard neuropsychological testing performed a computerized spatial monitoring task with and without concurrent secondary tasks (i.e., multitasking). Severe contralesional (right) space unawareness emerged in most patients under attentional load in both the visual and auditory modalities. Multitasking affected the detection of contralesional stimuli both when presented concurrently with an ipsilesional one (i.e., extinction for bilateral targets) and when presented in isolation (i.e., left neglect for right-sided targets). No spatial bias emerged in a control group of healthy elderly participants, who performed at ceiling, as well as in a second control group composed of patients with Mild Cognitive Impairment. We conclude that the pathological spatial asymmetry in LHD patients cannot be attributed to a global reduction of cognitive resources but it is the consequence of unilateral brain damage. Clinical and theoretical implications of the load-dependent lack of awareness for contralesional hemispace following LHD are discussed. PMID- 26948073 TI - Simultaneous optimization of limited sampling points for pharmacokinetic analysis of amrubicin and amrubicinol in cancer patients. AB - AIM: Limited sampling points for both amrubicin (AMR) and its active metabolite amrubicinol (AMR-OH) were simultaneously optimized using Akaike's information criterion (AIC) calculated by pharmacokinetic modeling. METHODS: In this pharmacokinetic study, 40 mg/m(2) of AMR was administered as a 5-min infusion on three consecutive days to 21 Japanese lung cancer patients. Blood samples were taken at 0, 0.08, 0.25, 0.5, 1, 2, 4, 8 and 24 h after drug infusion, and AMR and AMR-OH concentrations in plasma were quantitated using a high-performance liquid chromatography. The pharmacokinetic profile of AMR was characterized using a three-compartment model and that of AMR-OH using a one-compartment model following a first-order absorption process. These pharmacokinetic profiles were then integrated into one pharmacokinetic model for simultaneous fitting of AMR and AMR-OH. After fitting to the pharmacokinetic model, 65 combinations of four sampling points from the concentration profiles were evaluated for their AICs. Stepwise regression analysis was applied to select the sampling points for AMR and AMR-OH to predict the area under the concentration-time curves (AUCs) at best. RESULTS: Of the three combinations that yielded favorable AIC values, 0.25, 2, 4 and 8 h yielded the best AUC prediction for both AMR (R(2) = 0.977) and AMR OH (R(2) = 0.886). The prediction error for AUC was less than 15%. CONCLUSION: The optimal limited sampling points of AMR and AMR-OH after AMR infusion were found to be 0.25, 2, 4 and 8 h, enabling less frequent blood sampling in further expanded pharmacokinetic studies for both AMR and AMR-OH. PMID- 26948072 TI - Neuroanatomical substrates of executive functions: Beyond prefrontal structures. AB - Executive functions are often considered lynchpin "frontal lobe tasks", despite accumulating evidence that a broad network of anterior and posterior brain structures supports them. Using a latent variable modelling approach, we assessed whether prefrontal grey matter volumes independently predict executive function performance when statistically differentiated from global atrophy and individual non-frontal lobar volume contributions. We further examined whether fronto parietal white matter microstructure underlies and independently contributes to executive functions. We developed a latent variable model to decompose lobar grey matter volumes into a global grey matter factor and specific lobar volumes (i.e. prefrontal, parietal, temporal, occipital) that were independent of global grey matter. We then added mean fractional anisotropy (FA) for the superior longitudinal fasciculus (dorsal portion), corpus callosum, and cingulum bundle (dorsal portion) to models that included grey matter volumes related to cognitive variables in previous analyses. Results suggested that the 2-factor model (shifting/inhibition, updating/working memory) plus an information processing speed factor best explained our executive function data in a sample of 202 community dwelling older adults, and was selected as the base measurement model for further analyses. Global grey matter was related to the executive function and speed variables in all four lobar models, but independent contributions of the frontal lobes were not significant. In contrast, when assessing the effect of white matter microstructure, cingulum FA made significant independent contributions to all three executive function and speed variables and corpus callosum FA was independently related to shifting/inhibition and speed. Findings from the current study indicate that while prefrontal grey matter volumes are significantly associated with cognitive neuroscience measures of shifting/inhibition and working memory in healthy older adults, they do not independently predict executive function when statistically isolated from global atrophy and individual non-frontal lobar volume contributions. In contrast, better microstructure of fronto-parietal white matter, namely the corpus callosum and cingulum, continued to predict executive functions after accounting for global grey matter atrophy. These findings contribute to a growing literature suggesting that prefrontal contributions to executive functions cannot be viewed in isolation from more distributed grey and white matter effects in a healthy older adult cohort. PMID- 26948074 TI - Pediatric anesthesiology fellow education: is a simulation-based boot camp feasible and valuable? AB - BACKGROUND: Pediatric anesthesiologists must manage crises in neonates and children with timely responses and limited margin for error. Teaching the range of relevant skills during a 12-month fellowship is challenging. An experiential simulation-based curriculum can augment acquisition of knowledge and skills. OBJECTIVES: To develop a simulation-based boot camp (BC) for novice pediatric anesthesiology fellows and assess learner perceptions of BC activities. We hypothesize that BC is feasible, not too basic, and well received by fellows. METHODS: Skills stations, team-based in situ simulations, and group discussions of complex cases were designed. Stations were evaluated by anonymous survey; fellows rated usefulness in improving knowledge, self-confidence, technical skill, and clinical performance using a Likert scale (1 strongly disagree to 5 strongly agree). They were also asked if stations were too basic or too short. Median and interquartile range (IQR) data were calculated and noted as median (IQR). RESULTS: Fellows reported the difficult airway station and simulated scenarios improved knowledge, self-confidence, technical skill, and clinical performance. They disagreed that stations were too basic or too short with exception of the difficult airway session, which was too short [4 (4-3)]. Fellows believed the central line station improved knowledge [4 (4-3)], technical skills [4 (4-4)], self-confidence [4 (4-3)], and clinical performance [4 (4-3)]; scores trended toward neutral likely because the station was perceived as too basic [3.5 (4-3)]. An interactive session on epinephrine and intraosseous lines was valued. Complicated case discussion was of educational value [4 (5-4)], the varied opinions of faculty were helpful [4 (5-4)], and the session was neither too basic [2 (2-2)] nor too short [2 (2-2)]. CONCLUSION: A simulation-based BC for pediatric anesthesiology fellows was feasible, perceived to improve confidence, knowledge, technical skills, and clinical performance, and was not too basic. PMID- 26948075 TI - Sera of patients with infantile eosinophilic gastroenteritis showed a specific increase in both thymic stromal lymphopoietin and IL-33 levels. PMID- 26948076 TI - A mild topical steroid leads to progressive anti-inflammatory effects in the skin of patients with moderate-to-severe atopic dermatitis. AB - BACKGROUND: Topical glucocorticosteroids are considered an efficient treatment option for atopic dermatitis (AD), but a global assessment of glucocorticosteroid responses on key disease circuits upon weeks to months of treatment is currently lacking. OBJECTIVE: We sought to assess short (4 weeks) and long-term (16 weeks) application of topical glucocorticosteroids on AD skin and define response biomarkers. METHODS: The effects of triamcinolone acetonide cream 0.025% were assessed based on gene expression and immunohistochemistry studies at baseline, 4 weeks, and 16 weeks in biopsy specimens from 15 patients with moderate-to-severe AD. RESULTS: At 16 weeks, only 3 patients were clinical responders (by using SCORAD50 criteria), but 6 patients qualified as responders based on histologic criteria. Baseline characteristics indicated more severe disease in nonresponders. While 3 of 15 patients experienced only transient benefit after 4 weeks, others showed progressive improvements toward 16 weeks. Topical glucocorticosteroid use in patients with AD resulted in improvements of the AD genomic signature of 25.6% at 4 weeks and 71.8% at 16 weeks, respectively, and even 123.9% in the histologic responder group. Cytokines (IL-12p40, IL-13, IL-22, CCL17, CCL18, peptidase inhibitor 3 [PI3]/elafin, and S100As) showed consistent decreases from baseline toward 16 weeks with corresponding improvements in epidermal disease hallmarks (keratin 16 and loricrin) in lesional skin from responders (P < .05). Nonresponders largely showed lesser/nonsignificant reductions in key inflammatory and barrier markers (keratin 16, IL-13, IL-22, CCL17, CCL18, PI3/elafin, S100As, and loricrin). The combination of IL-21 and IFN gamma baseline expression closely predicted individual clinical glucocorticosteroid responses at 16 weeks of treatment. CONCLUSION: Our study indicates that even low-potency glucocorticosteroids can broadly affect immune and barrier responses in patients with moderate-to-severe AD, associating higher baseline severity with increased steroid resistance in patients with AD. PMID- 26948078 TI - Chronic mucocutaneous candidiasis associated with an SH2 domain gain-of-function mutation that enhances STAT1 phosphorylation. PMID- 26948077 TI - Diminution of signal transducer and activator of transcription 3 signaling inhibits vascular permeability and anaphylaxis. AB - BACKGROUND: During IgE-mediated immediate hypersensitivity reactions, vascular endothelial cells permeabilize in response to mast cell mediators. We have demonstrated previously that patients and mice with signal transducer and activator of transcription 3 (STAT3) mutations (autosomal dominant hyper-IgE syndrome [AD-HIES]) are partially protected from anaphylaxis. OBJECTIVES: We sought to study the mechanism by which STAT3 contributes to anaphylaxis and determine whether small-molecule inhibition of STAT3 can prevent anaphylaxis. METHODS: Using unaffected and STAT3-inhibited or genetic loss-of-function samples, we performed histamine skin prick tests, investigated the contribution of STAT3 to animal models of anaphylaxis, and measured endothelial cell permeability, gene and protein expression, and histamine receptor-mediated signaling. RESULTS: Although mouse mast cell degranulation was minimally affected by STAT3 blockade, mast cell mediator-induced anaphylaxis was blunted in Stat3 mutant mice with AD-HIES and in wild-type mice subjected to small-molecule STAT3 inhibition. Histamine skin prick test responses were diminished in patients with AD-HIES. Human umbilical vein endothelial cells derived from patients with AD HIES or treated with a STAT3 inhibitor did not signal properly through Src or cause appropriate dissolution of the adherens junctions made up of the proteins vascular endothelial-cadherin and beta-catenin. Furthermore, we found that diminished STAT3 target microRNA17-92 expression in human umbilical vein endothelial cells from patients with AD-HIES is associated with increased phosphatase and tensin homolog (PTEN) expression, which inhibits Src, and increased E2F transcription factor 1 expression, which regulates beta-catenin cellular dynamics. CONCLUSIONS: These data demonstrate that STAT3-dependent transcriptional activity regulates critical components for the architecture and functional dynamics of endothelial junctions, thus permitting vascular permeability. PMID- 26948079 TI - A novel splenic B1 regulatory cell subset suppresses allergic disease through phosphatidylinositol 3-kinase-Akt pathway activation. AB - BACKGROUND: IL-10-producing regulatory B (B10) cells potently suppress allergic diseases, such as contact hypersensitivity (CHS). Splenic B10 cells share overlapping phenotypic markers with CD5+ B1 B cells, CD1dhiCD21+CD23- marginal zone (MZ) B cells, and CD1dhiCD21+CD23+ T2-MZ precursor B cells but do not exclusively belong to either subset. OBJECTIVE: In this study we investigated the signaling mechanisms and a novel phenotypic parameter of B10 cells. METHOD: We performed microarray analysis comparing IL-10+ and IL-10- B cells. B cell specific phosphatase and tensin homolog (PTEN)-deficient mice, which exhibit aberrant activation of the phosphatidylinositol 3-kinase (PI3K)-Akt pathway in B cells, were examined. RESULTS: Microarray analysis revealed that the PI3K-Akt pathway is important for IL-10 production in B cells. PI3K-Akt pathway inhibitors reduced B10 cell numbers in vitro. B10 cell numbers were significantly increased in B cell-specific PTEN-deficient mice. The CHS response was significantly diminished in PTEN-deficient mice. Unexpectedly, splenic B10 cells in these mice were found within the B1 B-cell subset but not within the MZ B-cell subset. In wild-type mice not only MZ B10 cells but also B1-B10 cells were identified in the spleen. In addition, these 2 B10 cell subsets were predominantly found within the CD9+CD80+ B-cell fraction. CONCLUSION: A novel splenic B1 regulatory cell subset (B1-B10 cells) was identified. Our findings show that the PI3K-Akt pathway in B cells is critical for B10 cell development and CHS response and that CD9/CD80 coexpression is a novel phenotypic parameter for both MZ-B10 and B1-B10 cells. PMID- 26948080 TI - Marginal and internal fit of pressed ceramic crowns made from conventional and computer-aided design and computer-aided manufacturing wax patterns: An in vitro comparison. AB - STATEMENT OF PROBLEM: To our knowledge, no studies have evaluated the influence of the wax fabrication technique on the internal adaptation and marginal accuracy of pressed ceramic single crowns. PURPOSE: The purpose of this in vitro study was to compare the marginal and internal fit of a lithium disilicate crown fabricated either from conventional waxing or from a subtractive milled wax pattern. MATERIAL AND METHODS: Ten silicone impressions were made for a maxillary canine prepared to receive a complete crown. Two pressed lithium disilicate glass ceramic copings were made on the die poured from each impression. The first was from a conventional wax pattern and the second from milled wax blocks. The replica technique was used to measure the fit by scanning electron microscope at *80 magnification. Collected data were analyzed with the paired Student t test for the marginal and wall fit. For the occlusal fit, the difference in scores did not follow a normal distribution, and the Wilcoxon signed ranks test was used (alpha=.05). RESULTS: The mean values +SD were 170.3 +/-50.7 MUm for the marginal fit and 130.3 +/-21.6 MUm for the internal fit with the conventional technique. For the computer-aided design and computer-aided manufacturing (CAD-CAM) technique, they were 105.1 +/-39.6 MUm and 98.1 +/-26.1 MUm. Statistical significance was found for the marginal and internal fit (P<.05). The occlusal fit median and interval interquartile scores were 305.0 MUm (269.9 to 334.4) for conventional fabrication and 199.0 MUm (141.5 to 269.9) for subtractive manufacturing. The differences were not statistically significant (P>.05). CONCLUSIONS: The subtractive CAD-CAM waxing technique resulted in the improved fit of a pressed lithium disilicate crown by decreasing the marginal discrepancies and internal adaptation. PMID- 26948081 TI - Effect of screw-access channels on the fracture resistance of 3 types of ceramic implant-supported crowns. AB - STATEMENT OF PROBLEM: Access channels for retrieving ceramic implant-supported screw-retained crowns may decrease their fracture resistance. PURPOSE: The purpose of this in vitro study was to evaluate the effect of screw-access channels on 3 types of ceramic implant-supported crowns. MATERIAL AND METHODS: Sixty computer-aided designed and computer-aided manufactured (CAD-CAM) ceramic implant-supported screw-retained maxillary premolar crowns were fabricated, 30 with an occlusal screw-access channel and 30 without access channels. Each group was further divided into the following 3 subgroups of 10 specimens each: monolithic zirconia, veneered zirconia, and lithium disilicate. Identical milled titanium implant abutments were fabricated. Crowns were fabricated with standardized thicknesses and subjected to cyclic loading until failure occurred. Data analysis was performed using 1-way analysis of variance test of significance followed by Tukey honest significant difference (HSD) test (alpha=.05). RESULTS: No significant differences in fracture resistance were found between access channel groups and corresponding groups without access channels (P>.05). Among the subgroups, monolithic zirconia recorded the highest fatigue failure mean load values (2047.8 +/-83.2 N for crowns with access channels and 2028.7 +/-104.5 N for crowns without access channels), which was significantly higher (P<.05) than values for the lithium disilicate group (605.4 +/-37.9 N for crowns with access channels and 615.3 +/-76.6 N for crowns without access channels) and the veneered zirconia group (411 +/-34.4 N for crowns with access channels and 461.2 +/-72.7 N for crowns without access channels), which recorded the lowest fatigue failure load mean values. CONCLUSIONS: Screw-access channels did not affect the fatigue failure load of monolithic zirconia, monolithic lithium disilicate, or veneered zirconia ceramic crowns. Monolithic zirconia crowns recorded significantly higher fatigue failure load among the 3 types of crowns tested. PMID- 26948082 TI - Assessment of reliability of CAD-CAM tooth-colored implant custom abutments. AB - STATEMENT OF PROBLEM: Information is lacking about the fatigue resistance of computer-aided design and computer-aided manufacturing (CAD-CAM) tooth-colored implant custom abutment materials. PURPOSE: The purpose of this in vitro study was to investigate the reliability of different types of CAD-CAM tooth-colored implant custom abutments. MATERIAL AND METHODS: Zirconia (Lava Plus), lithium disilicate (IPS e.max CAD), and resin-based composite (Lava Ultimate) abutments were fabricated using CAD-CAM technology and bonded to machined titanium-6 aluminum-4 vanadium (Ti-6Al-4V) alloy inserts for conical connection implants (NobelReplace Conical Connection RP 4.3*10 mm; Nobel Biocare). Three groups (n=19) were assessed: group ZR, CAD-CAM zirconia/Ti-6Al-4V bonded abutments; group RC, CAD-CAM resin-based composite/Ti-6Al-4V bonded abutments; and group LD, CAD-CAM lithium disilicate/Ti-6Al-4V bonded abutments. Fifty-seven implant abutments were secured to implants and embedded in autopolymerizing acrylic resin according to ISO standard 14801. Static failure load (n=5) and fatigue failure load (n=14) were tested. Weibull cumulative damage analysis was used to calculate step-stress reliability at 150-N and 200-N loads with 2-sided 90% confidence limits. Representative fractured specimens were examined using stereomicroscopy and scanning electron microscopy to observe fracture patterns. RESULTS: Weibull plots revealed beta values of 2.59 for group ZR, 0.30 for group RC, and 0.58 for group LD, indicating a wear-out or cumulative fatigue pattern for group ZR and load as the failure accelerating factor for groups RC and LD. Fractographic observation disclosed that failures initiated in the interproximal area where the lingual tensile stresses meet the compressive facial stresses for the early failure specimens. Plastic deformation of titanium inserts with fracture was observed for zirconia abutments in fatigue resistance testing. CONCLUSIONS: Significantly higher reliability was found in group ZR, and no significant differences in reliability were determined between groups RC and LD. Differences were found in the failure characteristics of group ZR between static and fatigue loading. PMID- 26948083 TI - FAD104, a Regulator of Adipogenesis and Osteogenesis, Interacts with the C Terminal Region of STAT3 and Represses Malignant Transformation of Melanoma Cells. AB - Anchorage-independent growth is one of the defining characteristics of cancer cells. Many oncogenes and tumor suppressor genes are involved in regulating this type of growth. Factor for adipocyte differentiation 104 gene (fad104) is a regulator of adipogenesis and osteogenesis. Previously, we reported that fad104 suppressed metastasis as well as invasion of melanoma cells. However, it is unclear whether fad104 is involved in malignant transformation, which is associated with metastasis. In this study, we revealed that fad104 negatively regulated the colony forming activity of melanoma cells. The presence of the N terminal region of FAD104 was required for the regulation of malignant transformation of melanoma cells. In addition, the deletion mutant of FAD104 that contained the N-terminal region and transmembrane domain interacted with signal transducer and activator of transcription 3 (STAT3) and suppressed STAT3 activity. However, the deletion mutant of FAD104 lacking the N-terminal region did not influence the interaction with STAT3 or suppress the STAT3 activity. Moreover, FAD104 interacted with the C-terminal region of STAT3. In summary, we demonstrated that fad104 suppressed anchorage-independent growth of melanoma cells, and that the N-terminal region of FAD104 is essential for inhibiting malignant transformation and STAT3 activity. PMID- 26948084 TI - Assessment of Drug-Drug Interaction between Warfarin and Aprepitant and Its Effects on PT-INR of Patients Receiving Anticancer Chemotherapy. AB - Aprepitant is a known inducer of CYP2C9, the main warfarin-metabolizing enzyme. Consequently, co-administration of these two drugs may result in reduction of the anticoagulation activity of warfarin. However, the nature and degree of time dependent changes in prothrombin time international normalized ratio (PT-INR) after aprepitant and warfarin co-treatment in patients receiving anticancer chemotherapy has not been elucidated. We retrospectively examined the changes in warfarin dose, PT-INR, and warfarin sensitivity index (WSI; average of PT-INR value/average of daily warfarin dose) during four weeks, i.e., one week before and three weeks after aprepitant administration. The mean and standard deviation values of WSI for one week before and one, two, and three weeks after the beginning of aprepitant administration were 0.51+/-0.22 (1.00, n=34), 0.74+/-0.30 (1.53+/-0.59, n=30), 0.38+/-0.15 (0.82+/-0.22, n=28), and 0.46+/-0.29 (0.87+/ 0.23, n=24), respectively. Values in parentheses represent relative changes versus WSI of one week before and number of subjects. Although the mean value of WSI significantly increased one week after aprepitant administration compared to that at one week before the administration, it in turn significantly decreased two weeks after compared to one week before (paired t-test, p<0.05 after Bonferoni correction). In patients taking warfarin, PT-INR should be carefully monitored for at least two weeks after the beginning of aprepitant administration because it may fluctuate with both aprepitant and chemotherapy during this period. PMID- 26948085 TI - Hyperoside induces both autophagy and apoptosis in non-small cell lung cancer cells in vitro. AB - AIM: Hyperoside (quercetin-3-O-beta-D-galactopyranoside) is a flavonol glycoside found in plants of the genera Hypericum and Crataegus, which exhibits anticancer, anti-oxidant, and anti-inflammatory activities. In this study we investigated whether autophagy was involved in the anticancer mechanisms of hyperoside in human non-small cell lung cancer cells in vitro. METHODS: Human non-small cell lung cancer cell line A549 was tested, and human bronchial epithelial cell line BEAS-2B was used for comparison. The expression of LC3-II, apoptotic and signaling proteins was measured using Western blotting. Autophagosomes were observed with MDC staining, LC3 immunocytochemistry, and GFP-LC3 fusion protein techniques. Cell viability was assessed using MTT assay. RESULTS: Hyperoside (0.5, 1, 2 mmol/L) dose-dependently increased the expression of LC3-II and autophagosome numbers in A549 cells, but had no such effects in BEAS-2B cells. Moreover, hyperoside dose-dependently inhibited the phosphorylation of Akt, mTOR, p70S6K and 4E-BP1, but increased the phosphorylation of ERK1/2 in A549 cells. Insulin (200 nmol/L) markedly enhanced the phosphorylation of Akt and decreased LC3-II expression in A549 cells, which were reversed by pretreatment with hyperoside, whereas the MEK1/2 inhibitor U0126 (20 MUmol/L) did not blocked hyperoside-induced LC3-II expression. Finally, hyperoside dose-dependently suppressed the cell viability and induced apoptosis in A549 cells, which were significantly attenuated by pretreatment with the autophagy inhibitor 3 methyladenine (2.5 mmol/L). CONCLUSION: Hyperoside induces both autophagy and apoptosis in human non-small cell lung cancer cells in vitro. The autophagy is induced through inhibiting the Akt/mTOR/p70S6K signal pathways, which contributes to anticancer actions of hyperoside. PMID- 26948086 TI - Pretreatment with low-dose gadolinium chloride attenuates myocardial ischemia/reperfusion injury in rats. AB - AIM: We have shown that low-dose gadolinium chloride (GdCl3) abolishes arachidonic acid (AA)-induced increase of cytoplasmic Ca(2+), which is known to play a crucial role in myocardial ischemia/reperfusion (I/R) injury. The present study sought to determine whether low-dose GdCl3 pretreatment protected rat myocardium against I/R injury in vitro and in vivo. METHODS: Cultured neonatal rat ventricular myocytes (NRVMs) were treated with GdCl3 or nifedipine, followed by exposure to anoxia/reoxygenation (A/R). Cell apoptosis was detected; the levels of related signaling molecules were assessed. SD rats were intravenously injected with GdCl3 or nifedipine. Thirty min after the administration the rats were subjected to LAD coronary artery ligation followed by reperfusion. Infarction size, the release of serum myocardial injury markers and AA were measured; cell apoptosis and related molecules were assessed. RESULTS: In A/R treated NRVMs, pretreatment with GdCl3 (2.5, 5, 10 MUmol/L) dose-dependently inhibited caspase-3 activation, death receptor-related molecules DR5/Fas/FADD/caspase-8 expression, cytochrome c release, AA release and sustained cytoplasmic Ca(2+) increases induced by exogenous AA. In I/R-treated rats, pre administration of GdCl3 (10 mg/kg) significantly reduced the infarct size, and the serum levels of CK-MB, cardiac troponin-I, LDH and AA. Pre-administration of GdCl3 also significantly decreased the number of apoptotic cells, caspase-3 activity, death receptor-related molecules (DR5/Fas/FADD) expression and cytochrome c release in heart tissues. The positive control drug nifedipine produced comparable cardioprotective effects in vitro and in vivo. CONCLUSION: Pretreatment with low-dose GdCl3 significantly attenuates I/R-induced myocardial apoptosis in rats by suppressing activation of both death receptor and mitochondria-mediated pathways. PMID- 26948087 TI - Valvular performance and aortic regurgitation following transcatheter aortic valve replacement using Edwards valve versus CoreValve for severe aortic stenosis: A Meta-analysis. AB - OBJECTIVES: To compare incidence of aortic regurgitation (AR), paravalvular AR and valvular performance with Doppler hemodynamic parameters following transcatheter aortic valve replacement (TAVR) with Edwards valve (EV) versus CoreValve (CV). Currently, there are scarce data on post-TAVR echocardiographic outcomes comparing EV and CV. METHODS: PubMed and the Cochrane Center Register of Controlled Trials were searched through May 2015. Twenty studies (n=11,244) comparing TAVR procedure that used EV (n=6445) and CV (n=4799) were included. End points were post-TAVR moderate to severe AR and paravalvular AR, effective orifice area (EOA), mean trans-aortic pressure gradient (MPG), peak trans-aortic pressure gradient (PPG) and left ventricular ejection fraction (LVEF). The mean difference (MD) or relative risk (RR) with 95% confidence interval (CI) was computed and p<0.05 was considered as a level of significance. RESULTS: Moderate to severe AR and paravalvular AR were significantly lower in EV group (RR: 0.57, CI: 0.52-0.63, p<0.00001 and RR: 0.40, CI: 0.25-0.63, p<0.0001 respectively) compared to CV group. EOA and PPG were not significantly different between EV and CV groups. MPG was significantly lower among patients in CV group (MD: 1.08, CI: 0.05-2.10, p=0.04). LVEF was significantly higher in patients in EV group (MD: 2.26, CI: 0.77-3.74, p=0.03). CONCLUSIONS: This study showed CV is associated with higher incidence of post-TAVR moderate to severe paravalvular AR. Echocardiographic valvular performance measures (MPG, LVEF) showed minimal but significant difference, which may not be clinically significant. PMID- 26948088 TI - Current state of clinical end-points assessment in transplant: Key points. AB - Solid organ transplantation is the treatment of choice for patients with end stage organ disease. However, organ transplantation can stress the cardiovascular system and decrease immune surveillance, leading to early mortality and graft loss due to multiple underlying comorbidities. Clinical end-points in transplant include death and graft failure. Thus, generating accurate predictive models through regression models is crucial to test for definitive clinical post transplantation end-points. Survival predictive models should assemble efficient surrogate markers or prognostic factors to generate a minimal set of variables derived from a proper modeling strategy through regression models. However, a few critical points should be considered when reporting survival analyses and regression models to achieve proper discrimination and calibration of the predictive models. Additionally, population-based risk scores may underestimate risk prediction in transplant. The application of predictive models in these patients should therefore incorporate both classical and non-classical risk factors, as well as community-based health indicators and transplant-specific factors to quantify the outcomes in terms of survival properly. This review focuses on assessment of clinical end-points in transplant through regression models by combining predictive and surrogate variables, and considering key points in these analyses to accurately predict definitive end-points, which could aid clinicians in decision making. PMID- 26948090 TI - Verification of absorbed dose rates in reference beta radiation fields: Measurements with an extrapolation chamber and radiochromic film. AB - Beta Secondary Standard 2 (BSS 2) provides beta radiation fields with certified values of absorbed dose to tissue and the derived operational radiation protection quantities. As part of the quality assurance, the reliability of the CDTN BSS2 system was verified through measurements in the 90Sr/90Y and 85Kr beta radiation fields. Absorbed dose rates and their angular variation were measured with a 23392 model PTW extrapolation chamber and with Gafchromic radiochromic films on a PMMA slab phantom. The feasibility of using both methods was analyzed. PMID- 26948091 TI - Assessment of Weight Bias Among Pediatric Nurses and Clinical Support Staff Toward Obese Patients and Their Caregivers. AB - The increasing burden of obesity is prevalent in the pediatric populations. Pediatric nurses are spending increasing amounts of time and effort caring for obese patients however no prior studies have explored how nurses perceive obese patients. The purpose of this study is to identify weight bias in pediatric nurses (RNs) and clinical support staff (CSS) working in a pediatric hospital setting. A convenience sample of RNs and CSS from an urban, pediatric hospital were surveyed using the Nurses' Attitudes toward Obesity and Obese Patients Scale (NATOOPS), which consists of 6 patient-care factors with an additional factor added to assess bias towards the patient's caregiver. Mean factor scores >=50 indicated bias. Data were summarized using descriptive statistics and means were compared using independent t tests. Multivariate logistic regression models were used to determine the association between putative risk factors and weight bias. RNs and CSS (N=308) demonstrated weight bias toward obese patient characteristics (mean=61.9) and perceived controllability of obesity (mean=65.8). CSS felt negatively about their supportive roles in caring for obese patients (mean=52.5). Respondent weight status and professional title resulted in variability of biased attitudes. Race, employment status, number of obese patients cared for daily, and department were predictive of biased attitudes. Weight biased attitudes toward obese pediatric patients and their caregivers were found among RNs and CSS. Future qualitative research will assist in the understanding the factors that cause nurse weight bias. PMID- 26948092 TI - Transperineal prostate biopsy with ECHO-MRI fusion. Biopsee system. Initial experience. AB - OBJECTIVE: The aim of this study is to present our initial experience with the stereotactic echo-MRI fusion system for diagnosing prostate cancer. MATERIAL AND METHODS: Between September 2014 and January 2015, we performed 50 prostate biopsies using the stereotactic echo-MRI fusion system. The 3-Tesla multiparameter MR images were superimposed using this image fusion system on 3D echo images obtained with the Biopsee system for the exact locating of areas suspected of prostate cancer. The lesions were classified using the Prostate Imaging Report and Date System. RESULTS: We assessed a total of 50 patients, with a mean age of 63 years (range, 45-79), a mean prostate-specific antigen level of 8 ng/mL (range, 1.9-20) and a mean prostate volume of 52mL (range, 12-118). Prostate cancer was diagnosed in 69% of the patients and intraepithelial neoplasia in 6%. The results of the biopsy were negative for 24% of the patients. The results of the biopsy and MRI were in agreement for 62% of the patients; however, 46% also had a tumour outside of the suspicious lesion. We diagnosed 46% anterior tumours and 33% apical tumours. One patient had a haematuria, another had a haematoma and a third had acute urine retention. CONCLUSIONS: Multiparametric prostatic MRI helps identify prostate lesions suggestive of cancer. The Biopsee echo-MRI fusion system provides for guided biopsy and increases the diagnostic performance, reducing the false negatives of classical biopsies and increasing the diagnosis of anterior tumours. Transperineal access minimises the risk of prostatic infection and sepsis. PMID- 26948093 TI - [Crusted scabies: A review]. AB - Crusted scabies is a rare and severe form of infestation by Sarcoptes scabies var. hominis. It is characterized by profuse hyperkeratosis containing over 4000 mites per gram of skin, with treatment being long and difficult. The condition is both direct and indirectly contagious. It has a central role in epidemic cycles of scabies, the incidence of which is on the rise in economically stable countries. Recent discoveries concerning the biology of mites, the pathophysiology of hyperkeratosis and the key role of IL-17 in this severe form open up new therapeutic perspectives. PMID- 26948094 TI - Effects of feed access after hatch and inclusion of fish oil and medium chain fatty acids in a pre-starter diet on broiler chicken growth performance and humoral immunity. AB - Delayed feed and water access is known to impair growth performance of day old broiler chickens. Although effects of feed access on growth performance and immune function of broilers have been examined before, effects of dietary composition and its potential interaction with feed access are hardly investigated. This experiment aimed to determine whether moment of first feed and water access after hatch and pre-starter composition (0 to 7 days) affect growth rate and humoral immune function in broiler chickens. Direct fed chickens received feed and water directly after placement in the grow-out facility, whilst delayed fed chickens only after 48 h. Direct and delayed fed chickens received a control pre-starter diet, or a diet containing medium chain fatty acids (MCFA) or fish oil. At 21 days, chickens were immunized by injection of sheep red blood cells. The mortality rate depended on an interaction between feed access and pre starter composition (P=0.014). Chickens with direct feed access fed the control pre-starter diet had a higher risk for mortality than chickens with delayed feed access fed the control pre-starter diet (16.4% v. 4.2%) whereas the other treatment groups were in-between. BW gain and feed intake till 25 days in direct fed chickens were higher compared with delayed fed chickens, whilst gain to feed ratio was lower. Within the direct fed chickens, the control pre-starter diet resulted in the highest BW at 28 days and the MCFA pre-starter diet the lowest (Delta=2.4%), whereas this was opposite for delayed fed chickens (Delta=3.0%; P=0.033). Provision of MCFA resulted in a 4.6% higher BW gain and a higher gain to feed ratio compared with other pre-starter diets, but only during the period it was provided (2 to 7 days). Minor treatment effects were found for humoral immune response by measuring immunoglobulins, agglutination titers, interferon gamma (IFN- gamma ), and complement activity. Concluding, current inclusion levels of fish oil (5 g/kg) and MCFA (30 g/kg) in the pre-starter diet appear to have limited (carryover) effects on growth and development, as well as on humoral immune function. PMID- 26948095 TI - Extremely strong bipolar optical interactions in paired graphene nanoribbons. AB - Graphene is an excellent multi-functional platform for electrons, photons, and phonons due to exceptional electronic, photonic, and thermal properties. When combining its extraordinary mechanical characteristics with optical properties, graphene-based nanostructures can serve as an appealing platform for optomechanical applications at the nanoscale. Here, we demonstrate, using full wave simulations, the emergence of extremely strong bipolar optical forces, or, optical binding and anti-binding, between a pair of coupled graphene nanoribbons, due to the remarkable confinement and enhancement of optical fields arising from the large effective mode indices. In particular, the binding and anti-binding forces, which are about two orders of magnitude stronger than that in metamaterials and high-Q resonators, can be tailored by selective excitation of either the even or the odd optical modes, achievable by tuning the relative phase of the lightwaves propagating along the two ribbons. Based on the coupled mode theory, we derive analytical formulae for the bipolar optical forces, which agree well with the numerical results. The attractive optical binding force F(y)(b) and the repulsive anti-binding force F(y)(a) exhibit a remarkably different dependence on the gap distance g between the nanoribbons and the Fermi energy E(F), in the forms of F(y)(b) ? 1/?(g3E(F)) and F(y)(a) ? 1/E(F)(2). With E(F) dynamically tunable by bias voltage, the bipolar forces may provide a flexible handle for active control of the nanoscale optomechanical effects, and also, might be significant for optoelectronic and optothermal applications as well. PMID- 26948096 TI - Expression of insulin-like growth factor II mRNA binding protein 3 (IMP3) in enchondroma and chondrosarcoma. AB - Atypical cartilaginous tumor and enchondroma are similar in histopathologic aspects. Although the clinical course, radiologic and pathologic examinations enable distinction in most cases, difficulties are still encountered by the pathologists. There is no known biomarker to help make a distinction between benign and malignant cartilaginous tumors. Insulin-like growth factor II mRNA binding protein (IMP3) is a member of an oncofetal family of proteins that is expressed in different human malignancies and rapidly emerging as a prognostic and diagnostic marker in surgical pathology. In this study, IMP3 expression was examined by immunohistochemistry in 36 enchondromas and 42 chondrosarcomas of different histologic grades. The results showed that all 36 cases of enchondroma were negative for IMP3, while it was overexpressed in 15 of 42 chondrosarcomas (36%) (P<0.01). Significant higher levels of IMP3 were detected in grade III chondrosarcomas (6 of 7; 85.7%) when compared to low-grade tumors (6 of 19; 31.5% in grade II and 3 of 16; 18.7% in Atypical Cartilaginous Tumor). We proved statistically significant difference in IMP3 expression between enchondromas and ACTs (P=0.025). Our study clearly demonstrated differentiation-dependent expression of IMP3 in chondrosarcoma, and suggests IMP3 as a novel marker for differentiating problematic cases of enchondroma from well-differentiated chondrosarcomas. To our knowledge, this study is the first study to clarify expression of IMP-3 in chondromas and chondrosarcomas. PMID- 26948097 TI - Utilizing global data to estimate analytical performance on the Sigma scale: A global comparative analysis of methods, instruments, and manufacturers through external quality assurance and proficiency testing programs. AB - OBJECTIVE: To assess the analytical performance of instruments and methods through external quality assessment and proficiency testing data on the Sigma scale. DESIGN AND METHODS: A representative report from five different EQA/PT programs around the world (2 US, 1 Canadian, 1 UK, and 1 Australasian) was accessed. The instrument group standard deviations were used as surrogate estimates of instrument imprecision. Performance specifications from the US CLIA proficiency testing criteria were used to establish a common quality goal. Then Sigma-metrics were calculated to grade the analytical performance. RESULTS: Different methods have different Sigma-metrics for each analyte reviewed. Summary Sigma-metrics estimate the percentage of the chemistry analytes that are expected to perform above Five Sigma, which is where optimized QC design can be implemented. The range of performance varies from 37% to 88%, exhibiting significant differentiation between instruments and manufacturers. Median Sigmas for the different manufacturers in three analytes (albumin, glucose, sodium) showed significant differentiation. CONCLUSIONS: Chemistry tests are not commodities. Quality varies significantly from manufacturer to manufacturer, instrument to instrument, and method to method. The Sigma-assessments from multiple EQA/PT programs provide more insight into the performance of methods and instruments than any single program by itself. It is possible to produce a ranking of performance by manufacturer, instrument and individual method. Laboratories seeking optimal instrumentation would do well to consult this data as part of their decision-making process. To confirm that these assessments are stable and reliable, a longer term study should be conducted that examines more results over a longer time period. PMID- 26948098 TI - Pediatric reference data of serum lipids and prevalence of dyslipidemia: Results from a population-based cohort in Germany. AB - BACKGROUND: Serum lipid concentrations are thought to be risk factors for the development of cardiovascular disease. The present study aims to investigate the prevalence of dyslipidemia and provide sex- and age-related reference values for triglycerides, total cholesterol, LDL and HDL cholesterol as well as apolipoproteins A1 and B by using modern analytical approaches. MATERIALS AND METHODS: Venous blood and anthropometric data were collected from 2571 subjects of the LIFE Child study, aged between 0.5 and 16years. Age- and gender-related reference intervals (3rd and 97th percentiles) were established by using Cole's LMS method. RESULTS: Serum concentrations of TC, LDL-C, TG and ApoB were higher in girls than in boys. In girls TC reached peak levels two years earlier than in boys. Triglyceride levels initially declined until the school age. Until early adolescence there was a steady increase. The LDL-C concentrations in girls and boys followed similar patterns to that of TC. Up to the age of 8years, a continuous increase in HDL levels for both sexes was found. Due to the strong correlation between HDL-C and ApoA1 (r=0.87) or rather between LDL-C and ApoB (r=0.93), the respective percentiles showed very similar patterns. Dyslipidemia prevalence were as follows: increased TC 7.8%, increased LDL 6.1%, increased TG 0 9years 22.1%, increased TG 10-16years 11.7%, and decreased HDL 8.0%. CONCLUSION: Age- and sex-related trends for all parameters are similar to those of the German KIGGS study. With the exception of HDL cholesterol, the prevalence of dyslipidemias in the German LIFE Child cohort are similar to the US-American prevalence. PMID- 26948099 TI - Real-Time Observation of Antimicrobial Polycation Effects on Escherichia coli: Adapting the Carpet Model for Membrane Disruption to Quaternary Copolyoxetanes. AB - Real-time atomic force microscopy (AFM) was used for analyzing effects of the antimicrobial polycation copolyoxetane P[(C12)-(ME2Ox)-50/50], C12-50 on the membrane of a model bacterium, Escherichia coli (ATCC# 35218). AFM imaging showed cell membrane changes with increasing C12-50 concentration and time including nanopore formation and bulges associated with outer bacterial membrane disruption. A macroscale bactericidal concentration study for C12-50 showed a 4 log kill at 15 MUg/mL with conditions paralleling imaging (1 h, 1x PBS, physiological pH, 25 degrees C). The dramatic changes from the control image to 1 h after introducing 15 MUg/mL C12-50 are therefore reasonably attributed to cell death. At the highest concentration (60 MUg/mL) further cell membrane disruption results in leakage of cytoplasm driven by detergent-like action. The sequence of processes for initial membrane disruption by the synthetic polycation C12-50 follows the carpet model posited for antimicrobial peptides (AMPs). However, the nanoscale details are distinctly different as C12-50 is a synthetic, water-soluble copolycation that is best modeled as a random coil. In a complementary AFM study, chemical force microscopy shows that incubating cells with C12-50 decreased the hydrophobicity across the entire cell surface at an early stage. This finding provides additional evidence indicating that C12-50 polycations initially bind with the cell membrane in a carpet-like fashion. Taken together, real time AFM imaging elucidates the mechanism of antimicrobial action for copolyoxetane C12-50 at the single cell level. In future work this approach will provide important insights into structure-property relationships and improved antimicrobial effectiveness for synthetic amphiphilic polycations. PMID- 26948100 TI - Modifiers of stress related to timing of diagnosis in parents of children with complex congenital heart disease. AB - OBJECTIVE: Prenatal diagnosis of congenital heart disease (CHD) reportedly increases parental stress compared with postnatal diagnosis. We investigated the association of timing of diagnosis with parental stress and modifiers of this relationship. METHODS: We enrolled parents with a fetus/infant diagnosed prenatally (Group 1) or postnatally (Group 2) with CHD requiring intervention prior to newborn discharge. Parents completed a Basic Symptom Inventory (BSI) - at diagnosis, birth, and follow-up. Adjusted mixed effects regression models compared scores. RESULTS: The BSI was completed by 105 families (Group 1, n = 60 and Group 2, n = 45). On regression modeling, anxiety and global stress were lower in Group 1 (effect size -0.19 to -0.62) at diagnosis and birth though not at follow-up. When stratified by gender, Group 1 scores for anxiety and stress were primarily lower in fathers. Within Group 1, mothers scored higher in all domains and later gestational age at diagnosis was associated with higher anxiety and stress. CONCLUSIONS: Contrary to prior reports, parents of prenatally diagnosed infants with CHD had lower anxiety and stress than those diagnosed postnatally after adjusting for severity. Identifying those most vulnerable and modifiable risk factors will allow us to appropriately target psychosocial services for families with a CHD diagnosis. PMID- 26948101 TI - [Evaluation of stool microscopy and culture to assist the diagnosis of pulmonary tuberculosis in a tuberculosis endemic country]. AB - OBJECTIVE: the aim of this study is to evaluate the performance of stool microscopy and culture in the diagnosis of pulmonary tuberculosis (PTB). MATERIAL AND METHOD: In resource-limited settings, PTB is mainly diagnosed in sputum by microscopy methods. In patients unable to provide sputum, invasive procedures are necessary to obtain alternative respiratory tract specimens. Because Mycobacterium tuberculosis complex (MTC) organisms are known to survive in gastric fluid, we hypothesized that swallowed MTC organisms would be detectable in stool samples. We compared the presence of MTC organisms in sputum and stool specimens collected at the same time from the same patients. RESULTS: We included samples routinely submitted to our laboratory of microbiological diagnosis from patients with suspected PTB. In addition, a stool specimen was collected within 24 h of the sputum collection or gastric aspirate. In the 57 patients included, sputum microcopy and culture confirmed respectively 9 (21%) and 15 (26%) cases. Stool samples made it possible to confirm 9 cases by microscopy and 5 cases by culture. The sensitivity of microscopy was 60% and that of culture 33%. Sputum analysis was negative for one HIV-infected patient, but the stool sample was positive and permitted the diagnosis of PTB. CONCLUSION: This study proves that despite the low sensitivity of stool cultures it can be an alternative or additional interesting sample for the diagnosis of PTB in patients who have difficulty expectorating. PMID- 26948102 TI - An acidic sphingomyelinase Type C activity from Mycobacterium tuberculosis. AB - Sphingomyelinases (SMases) catalyze the hydrolysis of sphingomyelin to ceramide and phosphorylcholine. Sphingolipids are recognized as diverse and dynamic regulators of a multitude of cellular processes mediating cell cycle control, differentiation, stress response, cell migration, adhesion, and apoptosis. Bacterial SMases are virulence factors for several species of pathogens. Whole cell extracts of Mycobacterium tuberculosis strains H37Rv and CDC1551 were assayed using [N-methyl-(14)C]-sphingomyelin as substrate. Acidic Zn(2+) dependent SMase activity was identified in both strains. Peak SMase activity was observed at pH 5.5. Interestingly, overall SMase activity levels from CDC1551 extracts are approximately 1/3 of those of H37Rv. The presence of exogenous SMase produced by M. tuberculosis during infection may interfere with the normal host inflammatory response thus allowing the establishment of infection and disease development. This Type C activity is different from previously identified M. tuberculosis SMases. Defining the biochemical characteristics of M. tuberculosis SMases helps to elucidate the roles that these enzymes play during infection and disease. PMID- 26948105 TI - Adult tonsillectomy: postoperative pain depends on indications. AB - INTRODUCTION: Intense pain is one of the most important postoperative complaints after tonsillectomy. It is often described by patients as comparable to the pain that accompanies an acute tonsillitis. Although recurrent tonsillitis is the most frequent indication for surgery, many tonsillectomies are performed due to other indications and these patients may be unfamiliar with such pain. OBJECTIVE: To verify whether individuals with recurrent tonsillitis experience different post tonsillectomy pain intensity than those with other indications for surgery, with no history of episodes of acute tonsillitis. METHODS: A total of 61 tonsillectomies were performed under general anesthesia, using a potassium titanyl phosphate (KTP) laser (to eliminate the potential influence on the study results of forceful dissection of fibrotic tonsils in patients with history of recurrent tonsillitis) and multiple ligations of blood vessels within the tonsillar beds. The patients received 37.5mg Tramadoli hydrochloridum+325mg Paracetamol tablets for 10 days. Postoperative variables included the duration of hospital stay, postoperative hemorrhage and readmission rate. The patients reported pain intensity on consecutive days, pain duration, weight loss on postoperative day 10, character, intensity and duration of swallowing difficulties, and the need for additional doses of painkillers. Healing was also assessed. Capsular nerve fibers were histologically examined in the resected tonsils by immunostainings for general and sensory markers. RESULTS: Indications for the surgery were: recurrent acute tonsillitis (34 patients), no history of recurrent tonsillitis: focus tonsil (20) and intense malodour (7). Pain intensity on postoperative days 3-4 and incidence of readmissions due to dehydration were significantly higher in the group with no history of recurrent tonsillitis. No significant differences in relative densities of protein gene product (PGP) 9.5- and calcitonin gene-related peptide (CGRP)-immunoreactive nerve fibers were observed. CONCLUSION: Patients with recurrent tonsillitis qualified for tonsillectomy reported lower pain intensity than those without recurrent tonsillitis and the pain scores were unrelated to nerve fibers density. PMID- 26948106 TI - Relapsing polychondritis in Singapore: a case series and review of literature. AB - INTRODUCTION: This study aimed to describe the clinical presentation, treatment and outcome of patients with relapsing polychondritis (RP) who were seen at a large tertiary-care academic medical institution in Singapore. METHODS: The medical records of all patients diagnosed with RP at the Department of Rheumatology and Immunology, Singapore General Hospital, Singapore, between 2005 and 2013 were reviewed. The diagnosis of RP was made using the modified McAdam criteria. RESULTS: Ten patients were diagnosed with RP during the study period. Among these patients, five fulfilled the modified McAdam criteria and five were probable cases of RP. The most common clinical presentations were auricular chondritis (n = 9), episcleritis or scleritis (n = 5), and large airway involvement (n = 3). All of the patients received prednisolone. Five patients developed haematological disorders. Patients with both RP and haematological disorders had a longer duration of RP symptoms prior to diagnosis, compared to patients with RP who did not develop haematological disorders (average duration of symptoms 14.7 months vs. 4.2 months). CONCLUSION: The high frequency of patients with haematological malignancies in this series was unexpected. Myelodysplastic syndrome has been reported, but other haematological malignancies are rarely associated with RP. As the association between haematological malignancies and RP is currently unclear, the threshold for haematological/lymphoproliferative screening should be lowered in patients with RP. PMID- 26948103 TI - Racial-ethnic differences in all-cause and HIV mortality, Florida, 2000-2011. AB - PURPOSE: We compared all-cause and human immunodeficiency virus (HIV) mortality in a population-based, HIV-infected cohort. METHODS: Using records of people diagnosed with HIV during 2000-2009 from the Florida Enhanced HIV-acquired immunodeficiency syndrome (AIDS) Reporting System, we conducted a proportional hazards analysis for all-cause mortality and a competing risk analysis for HIV mortality through 2011 controlling for individual-level factors, neighborhood poverty, and rural-urban status and stratifying by concurrent AIDS status (AIDS within 3 months of HIV diagnosis). RESULTS: Of 59,880 HIV-infected people, 32.2% had concurrent AIDS and 19.3% died. Adjusting for period of diagnosis, age group, sex, country of birth, HIV transmission mode, area-level poverty, and rural-urban status, non-Hispanic black (NHB) and Hispanic people had an elevated adjusted hazards ratio (aHR) for HIV mortality relative to non-Hispanic whites (NHB concurrent AIDS: aHR 1.34, 95% confidence interval [CI], 1.23-1.47; NHB without concurrent AIDS: aHR 1.41, 95% CI 1.26-1.57; Hispanic concurrent AIDS: aHR 1.18, 95% CI 1.05-1.32; Hispanic without concurrent AIDS: aHR 1.18, 95% CI 1.03-1.36). CONCLUSIONS: Considering competing causes of death, NHB and Hispanic people had a higher risk of HIV mortality even among those without concurrent AIDS, indicating a need to identify and address barriers to HIV care in these populations. PMID- 26948107 TI - The long and short of cephalomedullary nails in the treatment of osteoporotic pertrochanteric fracture. AB - INTRODUCTION: Pertrochanteric fractures after low-energy trauma are common among osteoporotic patients. Although the use of intramedullary devices to treat such fractures is becoming increasingly popular, there is a paucity of data comparing the outcomes of the use of short cephalomedullary nails (SCN) with the use of long cephalomedullary nails (LCN). This study aimed to compare the outcomes of treatment using LCN with treatment using SCN for patients with osteoporotic pertrochanteric fractures. METHODS: A retrospective review of 64 patients with osteoporotic pertrochanteric fractures who were treated with either LCN or SCN and had a minimum follow-up of one year was performed. Primary outcome measures include complications, revision surgeries and union rates. Secondary outcome measures include duration of surgery, estimated blood loss, length of hospital stay, and ambulatory and mortality status at one year. RESULTS: There was no significant difference in the clinical and functional outcomes of the patients who were treated with LCN and those who were treated with SCN. However, there was a higher incidence of heterotopic ossification in the latter group, and a slightly greater average estimated blood loss and duration of surgery in the former group. Patients treated with LCN tended to be more osteoporotic. CONCLUSION: Our study found no significant difference in terms of complications, revision surgeries, union rates and ambulatory status between the patients who were treated with LCN and those who were treated with SCN. Both LCN and SCN provided safe and reliable outcomes in the treatment of osteoporotic pertrochanteric fractures. PMID- 26948108 TI - Linking pyrolysis and anaerobic digestion (Py-AD) for the conversion of lignocellulosic biomass. AB - Biogas is a mixture of CO2 and CH4 produced by a consortia of Bacteria and Archeae operating in anaerobic digestion (AD) plants. Biogas can be burnt as such in engines to produce electricity and heat or upgraded into biomethane. Biomethane is a drop-in fuel that can be injected in the natural gas grid or utilised as a transport fuel. While a wide array of biomass feedstock can be degraded into biogas, unconverted lignin, hemicellulose and cellulose end up in the co-product digestate leaving a large portion of chemical energy unutilised. Pyrolysis (Py) transforms in a single step and without chemical reagents the lignocellulose matrix into gaseous (syngas), liquid (bio-oil, pyrolysis oil) and solid (biochar) fractions for the development of renewable fuels and materials. The Py route applied downstream to AD is actively investigated in order to valorise the solid digestate presently destined only for soil applications. Coupling Py upstream to AD is an emerging field of research aimed at expanding the feedstock towards biologically recalcitrant substrates (wood, paper, sludge). The biomethanation potential was demonstrated for gaseous (H2/CO) and water soluble pyrolysis products, while the influence of insoluble pyrolytic lignin remains fairly unexplored. Biochar can promote the production of biomethane by acting as a support for microorganism colonisation, conductor for direct interspecies electron transfer, sorbent for hydrophobic inhibitors, and reactant for in situ biogas upgrading. Enhancing the advantages (carbon source) over the side effects (toxicity) of Py fractions represents the main challenge of Py-AD. This can be addressed by increasing the selectivity of the thermochemical process or improving the ecological flexibility of mixed bacterial consortia towards chemically complex environments. PMID- 26948109 TI - Magnetic resonance imaging-guided attenuation correction in whole-body PET/MRI using a sorted atlas approach. AB - Quantitative whole-body PET/MR imaging is challenged by the lack of accurate and robust strategies for attenuation correction. In this work, a new pseudo-CT generation approach, referred to as sorted atlas pseudo-CT (SAP), is proposed for accurate extraction of bones and estimation of lung attenuation properties. This approach improves the Gaussian process regression (GPR) kernel proposed by Hofmann et al. which relies on the information provided by a co-registered atlas (CT and MRI) using a GPR kernel to predict the distribution of attenuation coefficients. Our approach uses two separate GPR kernels for lung and non-lung tissues. For non-lung tissues, the co-registered atlas dataset was sorted on the basis of local normalized cross-correlation similarity to the target MR image to select the most similar image in the atlas for each voxel. For lung tissue, the lung volume was incorporated in the GPR kernel taking advantage of the correlation between lung volume and corresponding attenuation properties to predict the attenuation coefficients of the lung. In the presence of pathological tissues in the lungs, the lesions are segmented on PET images corrected for attenuation using MRI-derived three-class attenuation map followed by assignment of soft-tissue attenuation coefficient. The proposed algorithm was compared to other techniques reported in the literature including Hofmann's approach and the three-class attenuation correction technique implemented on the Philips Ingenuity TF PET/MR where CT-based attenuation correction served as reference. Fourteen patients with head and neck cancer undergoing PET/CT and PET/MR examinations were used for quantitative analysis. SUV measurements were performed on 12 normal uptake regions as well as high uptake malignant regions. Moreover, a number of similarity measures were used to evaluate the accuracy of extracted bones. The Dice similarity metric revealed that the extracted bone improved from 0.58 +/- 0.09 to 0.65 +/- 0.07 when using the SAP technique compared to Hofmann's approach. This enabled to reduce the SUVmean bias in bony structures for the SAP approach to -1.7 +/- 4.8% as compared to -7.3 +/- 6.0% and -27.4 +/- 10.1% when using Hofmann's approach and the three-class attenuation map, respectively. Likewise, the three-class attenuation map produces a relative absolute error of 21.7 +/- 11.8% in the lungs. This was reduced on average to 15.8 +/- 8.6% and 8.0 +/- 3.8% when using Hofmann's and SAP techniques, respectively. The SAP technique resulted in better overall PET quantification accuracy than both Hofmann's and the three-class approaches owing to the more accurate extraction of bones and better prediction of lung attenuation coefficients. Further improvement of the technique and reduction of the computational time are still required. PMID- 26948110 TI - Directional wavelet based features for colonic polyp classification. AB - In this work, various wavelet based methods like the discrete wavelet transform, the dual-tree complex wavelet transform, the Gabor wavelet transform, curvelets, contourlets and shearlets are applied for the automated classification of colonic polyps. The methods are tested on 8 HD-endoscopic image databases, where each database is acquired using different imaging modalities (Pentax's i-Scan technology combined with or without staining the mucosa), 2 NBI high magnification databases and one database with chromoscopy high-magnification images. To evaluate the suitability of the wavelet based methods with respect to the classification of colonic polyps, the classification performances of 3 wavelet transforms and the more recent curvelets, contourlets and shearlets are compared using a common framework. Wavelet transforms were already often and successfully applied to the classification of colonic polyps, whereas curvelets, contourlets and shearlets have not been used for this purpose so far. We apply different feature extraction techniques to extract the information of the subbands of the wavelet based methods. Most of the in total 25 approaches were already published in different texture classification contexts. Thus, the aim is also to assess and compare their classification performance using a common framework. Three of the 25 approaches are novel. These three approaches extract Weibull features from the subbands of curvelets, contourlets and shearlets. Additionally, 5 state-of-the-art non wavelet based methods are applied to our databases so that we can compare their results with those of the wavelet based methods. It turned out that extracting Weibull distribution parameters from the subband coefficients generally leads to high classification results, especially for the dual-tree complex wavelet transform, the Gabor wavelet transform and the Shearlet transform. These three wavelet based transforms in combination with Weibull features even outperform the state-of-the-art methods on most of the databases. We will also show that the Weibull distribution is better suited to model the subband coefficient distribution than other commonly used probability distributions like the Gaussian distribution and the generalized Gaussian distribution. So this work gives a reasonable summary of wavelet based methods for colonic polyp classification and the huge amount of endoscopic polyp databases used for our experiments assures a high significance of the achieved results. PMID- 26948117 TI - Intra-operative radiation therapy (IORT) in recurrent head and neck cancer. PMID- 26948118 TI - Delay-dependent guaranteed-cost control based on combination of Smith predictor and equivalent-input-disturbance approach. AB - This paper presents a new system configuration and a design method to improve control performance for a system with an input time delay and disturbances. The equivalent-input-disturbance approach is extended to handle a time-delay system. It is combined with the Smith predictor to reject disturbances. A delay-dependent stability condition is devised in terms of a matrix inequality by using the free weighting matrix approach. The gain of the observer is designed by applying the cone complementary linearization method to the matrix inequality. A numerical example demonstrates the validity of the method. PMID- 26948119 TI - Role of crystal size on swing-effect and adsorption induced structure transition of ZIF-8. AB - The flexibility and structure transition behaviour of ZIF-8 in a series of samples with different particle size has been studied using a combination of high resolution N2 gas adsorption isotherms and, for the first time, a broad in situ PXRD and Rietveld analysis. During the stepped adsorption process, large particles showed a narrow adsorption/desorption pressure range with a shorter equilibrium time due to lower kinetic hindrance, deriving from higher amount of active sites. In situ PXRD showed that both the rotation of imidazole ring and a bend in the methyl group led to the gate opening of ZIF-8. PMID- 26948121 TI - Reconsolidation and update of morphine-associated contextual memory in mice. AB - Drug addiction can be viewed as a pathological memory that is constantly retrieved and reconsolidated. Since drug abuse takes place in different contexts, it could be considered that reconsolidation plays a role in memory updating. There is consistent evidence supporting the role of reconsolidation in the strength and maintenance of contextual memories induced by drugs of abuse. However, this role is not well established in memory update. The purpose of the current study was to assess the reconsolidation process over memory update. C57BL6 mice were subjected to a morphine-induced, conditioned place preference (CPP) paradigm. Based on CPP results, animals were divided into distinct experimental groups, according to the contextual characteristics of the re exposure and a second CPP Test. Re-exposure in the original context was important for memory maintenance and re-exposure under discrete contextual changes resulted in memory updating, although original memory was maintained. Interestingly, cycloheximide, an inhibitor of protein synthesis, had different outcomes in our protocol. When the re-exposure was done under discrete contextual changes, cycloheximide treatment just after re-exposure blocked memory updating, without changes in memory maintenance. When re-exposure was done under the original context, only two subsequent cycloheximide injections (3 and 6h) disrupted later CPP expression. Considering the temporal window of protein synthesis in consolidation and reconsolidation, these findings suggest that re-exposure, according to the contextual characteristics in our protocol, could trigger both phenomena. Furthermore, when new information is present on retrieval, reconsolidation plays a pivotal role in memory updating. PMID- 26948120 TI - The neural encoding of cocaine-induced devaluation in the ventral pallidum. AB - Cocaine experience affects motivation structures such as the nucleus accumbens (NAc) and its major output target, the ventral pallidum (VP). Previous studies demonstrated that both NAc activity and hedonic responses change reliably as a taste cue comes to predict cocaine availability. Here we extended this investigation to examine drug-experience induced changes in hedonic encoding in the VP. VP activity was first characterized in adult male Sprague-Dawley rats in response to intraoral infusions of palatable saccharin and unpalatable quinine solutions. Next, rats received 7 daily pairings of saccharin that predicted either a cocaine (20mg/kg, ip) or saline injection. Finally, the responses to saccharin and quinine were again assessed. Of 109 units recorded in 11 rats that received saccharin-cocaine pairings, 71% of responsive units significantly reduced firing rate during saccharin infusions and 64% increased firing rate during quinine exposure. However, as saccharin came to predict cocaine, and elicited aversive taste reactivity, VP responses changed to resemble quinine. After conditioning, 70% of saccharin-responsive units increased firing rate. Most units that encoded the palatable taste (predominantly reduced firing rate) were located in the anterior VP, while most units that were responsive to aversive tastes were located in the posterior VP. This study reveals an anatomical complexity to the nature of hedonic encoding in the VP. PMID- 26948123 TI - Proteomic insights into the functional basis for the response regulator DrRRA of Deinococcus radiodurans. AB - Purpose To investigate the function basis of the recently discovered response regulator, drRRA (DNA damage response regulator A) in Deinococcus radiodurans, we compared the proteomic profile of the radiation-sensitive drRRA mutant with that of wild-type strain under both non-stress and gamma radiation treatment. Materials and methods Total proteins of D. radiodurans cells were subjected to two-dimension electrophoresis. Protein spots in 2-Dimension gels were silver stained and scanned. Spots that changed significantly in expression levels were selected for mass spectrometry analysis. Seven genes encoding representative proteins were knocked out for stress resistance analysis. Results A total of 52 proteins displayed significant expression level changes at least 1.5-fold in the mutant relative to wild-type strain under non-stress conditions, with 31 repressed and 21 induced proteins, which might affect the cell response of D. radiodurans to gamma radiation. The proteins were distributed into functional groups including stress response, metabolism, and function unknown. Disruptions of several altered proteins including DRA0259 (Catalase E) and DR1538 (Osmotically inducible protein C), reduced the antioxidant activity of D. radiodurans. Conclusion Combined with our previous result of transcriptional profile, we further confirmed that inactivation of DrRRA affects the expression of various stress response systems. PMID- 26948122 TI - Mini-review: Prediction errors, attention and associative learning. AB - Most modern theories of associative learning emphasize a critical role for prediction error (PE, the difference between received and expected events). One class of theories, exemplified by the Rescorla-Wagner (1972) model, asserts that PE determines the effectiveness of the reinforcer or unconditioned stimulus (US): surprising reinforcers are more effective than expected ones. A second class, represented by the Pearce-Hall (1980) model, argues that PE determines the associability of conditioned stimuli (CSs), the rate at which they may enter into new learning: the surprising delivery or omission of a reinforcer enhances subsequent processing of the CSs that were present when PE was induced. In this mini-review we describe evidence, mostly from our laboratory, for PE-induced changes in the associability of both CSs and USs, and the brain systems involved in the coding, storage and retrieval of these altered associability values. This evidence favors a number of modifications to behavioral models of how PE influences event processing, and suggests the involvement of widespread brain systems in animals' responses to PE. PMID- 26948124 TI - When will French smokers be concerned by varenicline's benefit-to-risk ratio? PMID- 26948126 TI - Comparison of Biofilm Formation between Methicillin-Resistant and Methicillin Susceptible Isolates of Staphylococcus aureus. AB - BACKGROUND: The aim of this study was to compare the biofilm formation and the prevalence of biofilm-associated genes between the isolates of methicillin resistant (MRSA) and methicillin-susceptible (MSSA) Staphylococcus aureus. METHODS: In total, 209 S. aureus isolates were collected. The antibiotic susceptibility test was conducted using nine antibiotics according to the guidelines of Clinical and Laboratory Standards Institute. Phenotypic biofilm formation was performed with microtiter plate assay. The polymerase chain reaction was employed to detect icaA, icaD, icaB, icaC, clfA, clfB, fnbA, fnbB, fib, cna, eno, ebps, bbp, mecA, and SCCmec types as well as agr group genes with specific primers. RESULTS: Sixty-four (30.62%) isolates were resistant to methicillin, and 54 (83%) MRSA harbored SCCmec III. Furthermore, 122 (58.3%) isolates belonged to agr group I. Twenty-six (36.1%) MRSA and 42 (28.9%) MSSA isolates were strong biofilm producers (no significant difference). The prevalence of icaA, icaD, icaB, and icaC genes in MSSA isolates was 71, 41, 76, and 72%, respectively. The frequency of clfA, clfB, fnbA, fnbB, fib, cna, eno, ebps, and bbp in MSSA was 100, 100, 56, 46, 74, 54, 78, 11, and 1%, respectively. However, in MRSA isolates, the frequency was 97, 97, 64, 51, 76, 56, 79, and 12% with no track of bbp, respectively. CONCLUSION: Statistical difference between MSSA and MRSA regarding biofilm formation and the frequency of all biofilm encoding genes was not significant. The majority of the S. aureus isolates harbored clfA, clfB, eno, fib, icaA, and icaD genes. PMID- 26948125 TI - Components of Metabolic Syndrome and the Risk of Disability among the Elderly Population. AB - The direct relationship between metabolic syndrome (MetS) and function disability has not been established. The aim of the present study was to investigate the relationship between MetS and functional disability in the elderly. This retrospective observational study included 1,778 participants aged 60-84 years from the National Health and Nutrition Examination Survey (1999-2002). Impairments in activities of daily living (ADL), instrumental activities of daily living (IADL), leisure and social activities (LSA), lower extremity mobility (LEM), and general physical activities (GPA) were assessed. Additionally, the associations between the features of MetS and disability were evaluated. MetS was associated with a high prevalence of functional dependence in ADL, IADL, LSA, LEM, and GPA. After adjusting for potential confounders, a high number of MetS components was found to be associated with increased disability (P = 0.002). Additionally, associations were observed between MetS components, including abdominal obesity and high triglycerides levels, and functional dependence in ADL, IADL, LSA, LEM, and GPA (all, P < 0.05). A linear increase in disability might be associated with the number of MetS components in an elderly population. Additionally, MetS abnormalities, particularly abdominal obesity and high triglycerides levels, might be highly predictive of functional dependence in the elderly. PMID- 26948127 TI - The natural process of congenital nasolacrimal duct obstruction and effect of lacrimal sac massage. AB - This study aimed to examine the rate of symptomatic improvement of congenital nasolacrimal duct obstruction (CNLDO) in infants treated with conservative management within the first year of age. Other purpose of the study is to emphasize the relationship between spontaneous resolution time and effective lacrimal sac massage. Thirty-one infants were diagnosed to have CNLDO by an ophthalmologist prior to 3 months of age. In this study, 36 eyes of 31 patients were included with CNLDO. The patients were divided into two groups. Group 1 (28 eyes of 24 patients) was consisted of the patients who were applied effective lacrimal sac massage regularly during the follow-up period, and patients whose parents did not apply a regular lacrimal passage regularly were accepted as group 2 (8 eyes of 7 patients). Thirty-three eyes of 31 patients (18 rights and 15 left) successfully resolved with only conservative management (91.6 %). In these thirty-three eyes, one eye (3 %) resolved between 0 and 3 months, fourteen eyes (42.5 %) resolved between 4 and 6 months, eleven eyes (33.3 %) resolved between 7 and 9 months, and seven eyes (21.2 %) resolved between 10 and 12 months. CNLDO was resolved in 27 (96.2 %) of 28 eyes in group 1, and in group 2, six eyes (77.7 %) had resolvement. This difference was statistically significant (p = 0.001). The mean age of resolution was 6.8 +/- 1.88 months in group 1, 10.3 +/- 1.5 months in group 2 (p < 0.001). In light of our study, we believe that conservative management of CNLDO is highly successful. Our study provided a possible objective explanation for the efficacy of lacrimal sac massage. Emphasizing the importance of the massage to parents and describing in detail can reduce the risk of unnecessary surgical interventions. PMID- 26948128 TI - Rotamerism-driven large magnitude host-guest binding change in a crown ether derivatized pyridinium-phenolate series. AB - Two TICTOID-based pyridinium-phenolates bearing a crown ether macrocycle have been designed for the complexation of a potassium cation. The nucleophilicity of the intraannular phenolate -O(-) function can be strongly modulated by biaryl twisting. Such a structure/electronic transduction effect gives rise to a host guest binding change by more than two orders of magnitude. PMID- 26948130 TI - Medial Protrusio Technique in Cementless Total Hip Arthroplasty for Developmental Dysplasia of the Hip: A Prospective 6- to 9-Year Follow-Up of 43 Consecutive Patients. AB - BACKGROUND: The medial protrusio technique may be used during total hip arthroplasty (THA) on patients with developmental dysplasia. However, studies have yet to determine whether a cementless cup can be sufficiently stable to withstand loading forces. This study aimed to assess the clinical and radiographic outcomes of this technique. Furthermore, we sought to determine the relationship between the rate of medial protrusion and the incidence of cup loosening. METHODS: Thirty-nine patients (43 hips) underwent cementless THA between April 2006 and March 2009 by using the medial protrusio technique. These patients participated in a 6- to 9-year follow-up. Their clinical and radiographic data were gathered prospectively. RESULTS: The average Harris Hip Score improved from 43.1 +/- 15.4 points preoperatively to 91.9 +/- 12.8 points at the final follow-up (P < .001). The mean height of hip center and the distance of hip center medialization were 2.4 +/- 0.6 and 2.5 +/- 0.9 cm, respectively. The rate of medial protrusion and the rate of cup coverage were 42.1 +/- 12.4% and 96.8 +/- 5.1%, respectively. The rate of medial protrusion ranged from 18.3% to 58.3% in 38 hips (group A) and from 61.3% to 68.9% in 5 hips (group B). None of the cups in group A loosened or failed, 2 failures occurred in group B (0% vs 40.0%; P = .011). CONCLUSIONS: Developmental dysplasia was treated through THA using the medial protrusio technique, which easily achieves a sufficient superolateral host bony coverage of the cup and promotes socket reconstruction at the true acetabulum. The rate of medial protrusion of <60% may be necessary to obtain excellent clinical and radiographic midterm results. PMID- 26948129 TI - Microglial P2Y12 is necessary for synaptic plasticity in mouse visual cortex. AB - Microglia are the resident immune cells of the brain. Increasingly, they are recognized as important mediators of normal neurophysiology, particularly during early development. Here we demonstrate that microglia are critical for ocular dominance plasticity. During the visual critical period, closure of one eye elicits changes in the structure and function of connections underlying binocular responses of neurons in the visual cortex. We find that microglia respond to monocular deprivation during the critical period, altering their morphology, motility and phagocytic behaviour as well as interactions with synapses. To explore the underlying mechanism, we focused on the P2Y12 purinergic receptor, which is selectively expressed in non-activated microglia and mediates process motility during early injury responses. We find that disrupting this receptor alters the microglial response to monocular deprivation and abrogates ocular dominance plasticity. These results suggest that microglia actively contribute to experience-dependent plasticity in the adolescent brain. PMID- 26948131 TI - Risk of Contamination in Assembled vs Disassembled Instruments in Hip Arthroplasty Surgery. AB - BACKGROUND: Periprosthetic joint infection (PJI) is one of the most common causes of revision total hip arthroplasty (THA) and associated with higher costs, prolonged pain, and worse clinical outcomes. Many factors have been linked to increased infection rates, one being the operative equipment and instrumentation used during the surgical procedure. With few arthroplasty instruments designed for complete disassembly and increasingly complex instrument designs, this study seeks to understand the effect that instrument disassembly plays on infection using disassembled and assembled standard femoral broach handles (BHs). METHODS: Two BHs, not designed for disassembly, were modified and then contaminated in the disassembled state with Geobacillus stearothermophilus vegetative-form bacteria and spores. Using both flash and standard sterilization cycles, the BHs were steam sterilized in the disassembled or assembled state and then analyzed for remaining bacteria and spores. RESULTS: At all target locations after either a flash sterilization cycle or a standard sterilization cycle, complete eradication of both the vegetative-form and spore-form of G stearothermophilus was achieved. CONCLUSION: This study demonstrates that adequate decontamination of the tested BHs can be achieved after steam sterilization in either the disassembled or assembled state, without an increased risk of infection transmission. PMID- 26948132 TI - In Reply to Ismaili. PMID- 26948133 TI - External beam radiation therapy for small cell carcinoma of the bladder. PMID- 26948134 TI - Posttreatment FDG-PET-CT response is predictive of tumor progression and survival in anal carcinoma. AB - PURPOSE: We hypothesize that posttreatment F-18 fluorodeoxyglucose positron emission tomography-computed tomography (FDG PET-CT) metabolic response predicts clinical outcomes in patients with anal cancer treated with chemoradiation. METHODS AND MATERIALS: This was a single-institution retrospective review of 148 patients treated definitively for anal squamous cell carcinoma between 2005 and 2012. All patients were followed with posttreatment PET-CT scans and clinical examinations. Progression-free survival (PFS), cause-specific survival, and overall survival (OS) estimates were calculated using the Kaplan-Meier method. RESULTS: The median follow-up was 34 months (range, 5-89 months). Pretreatment PET was successful in detecting the primary tumor in 140 cases (95%). Computed tomography (CT) alone was able to detect primary tumors in 78 of 122 patients who had pretreatment CT scans (64%). Inguinal or pelvic lymph nodes were FDG avid in 68 patients, with only 41 of these patients having enlarged lymph nodes by CT criteria (60.3%). Initial posttreatment PET-CT was obtained on average 12.7 +/- 4.3 weeks after the last day of radiation (range, 5-25 weeks). Overall complete metabolic response (CR) on initial PET-CT was found in 82 patients (58%). Partial metabolic response was noted in 52 (36.9%) and progression in 7 patients (5%). Only 12/82 patients (14.6%) with a FDG-PET CR eventually recurred. The negative predictive value of a PET-CT scan performed between 13 and 25 weeks posttreatment was 92.9%. The 2-year PFS for patients with CR versus non-CR was 89.8% and 69.2%, respectively (P = .004). The 2-year OS for CR versus non-CR patients was 94.8% and 79.3% (P = .036). CONCLUSIONS: Complete metabolic response on posttreatment FDG PET-CT is highly predictive of increased PFS and OS in patients treated with chemoradiation for anal carcinoma. In addition to close clinical surveillance, we recommend obtaining posttreatment PET-CT scans >12 weeks following definitive treatment for anal cancer. PMID- 26948135 TI - Is high-intensity interval training more effective on improving cardiometabolic risk and aerobic capacity than other forms of exercise in overweight and obese youth? A meta-analysis. AB - BACKGROUND: The scientific interest in high-intensity interval training (HIIT) has greatly increased during recent years. OBJECTIVE: The objective of this meta analysis was to determine the effectiveness of HIIT interventions on cardio metabolic risk factors and aerobic capacity in overweight and obese youth, in comparison with other forms of exercise. DATA SOURCES: A computerized search was made using seven databases. STUDY ELIGIBILITY CRITERIA: The analysis was restricted to studies that examined the effect of HIIT interventions on cardio metabolic and/or aerobic capacity in pediatric obesity (6-17 years old). PARTICIPANTS AND INTERVENTIONS: Nine studies using HIIT interventions were selected (n = 274). STUDY APPRAISAL AND SYNTHESIS METHODS: Standarized mean difference (SMD) and 95% confidence intervals were calculated. The DerSimonian Laird approach was used. RESULTS: HIIT interventions (4-12 week duration) produced larger decreases in systolic blood pressure (SMD = 0.39; -3.63 mmHg) and greater increases in maximum oxygen uptake (SMD = 0.59; 1.92 ml/kg/min) than other forms of exercise. Also, type of comparison exercise group and duration of study were moderators. CONCLUSIONS: HIIT could be considered a more effective and time-efficient intervention for improving blood pressure and aerobic capacity levels in obese youth in comparison to other types of exercise. (c) 2016 World Obesity. PMID- 26948136 TI - Temporal relationships between awakening cortisol and psychosocial variables in inpatients with anorexia nervosa - A time series approach. AB - OBJECTIVE: The aim of the study was to investigate the characteristics of the awakening salivary cortisol in patients with anorexia nervosa (AN) using a time series design. We included ten AN inpatients, six with a very low BMI (high symptom severity, HSS group) and four patients with less severe symptoms (low symptom severity, LSS group). METHODS: Patients collected salivary cortisol daily upon awakening. The number of collected saliva samples varied across patients between n=65 and n=229 (due to the different lengths of their inpatient stay). In addition, before retiring, the patients answered questions daily on the handheld regarding disorder-related psychosocial variables. The analysis of cortisol and diary data was conducted by using a time series approach. RESULTS: Time series showed that the awakening cortisol of the AN patients was elevated as compared to a control group. Cortisol measurements of patients with LSS essentially fluctuated in a stationary manner around a constant mean. The series of patients with HSS were generally less stable; four HSS patients showed a non-stationary cortisol awakening series. Antipsychotic medication did not change awakening cortisol in a specific way. The lagged dependencies between cortisol and depressive feelings became significant for four patients. Here, higher cortisol values were temporally associated with higher values of depressive feelings. CONCLUSIONS: Upon awakening, the cortisol of all AN patients was in the standard range but elevated as compared to healthy controls. Patients with HSS appeared to show less stable awakening cortisol time series compared to patients with LSS. PMID- 26948137 TI - Hair cortisol concentrations in relation to ill-being and well-being in healthy young and old females. AB - Hair cortisol concentration (HCC) provides a retrospective measure of long-term (i.e. over a period of months) cortisol secretion and has been shown to be elevated in relation to chronic stress conditions. However associations in healthy participants with subjective ill-being are less clear and associations with well-being have not been explored. The current study examined HCC in relation to independent comprehensive measures of ill-being (stress, depression, anxiety) and well-being (subjective happiness, life satisfaction, psychological well-being) in healthy young and old females (mean+/-SD: 19.5+/-2.2years and 78.6+/-6.7years respectively, total N=115). The data supported evidence of increased total cortisol secretion with increased age. No association between ill being and HCC was found in either the young or older group of participants. A positive association between HCC and well-being was found in the older participant group which was independent of ill-being and potential confounds. These findings do not support associations between HCC and ill-being in healthy young or old females. However the results suggest that HCC is able to distinguish levels of well-being in healthy older females. PMID- 26948138 TI - Neglected chronic disease: The WHO framework on non-communicable diseases and implications for the global poor. AB - The current global framework on noncommunicable disease (NCD), as exemplified by the WHO Action Plan of 2012, neglects the needs of the global poor. The current framework is rooted in an outdated pseudo-evolutionary theory of epidemiologic transition, which weds NCDs to modernity, and relies on global aggregate data. It is oriented around a simplistic causal model of behaviour, risk and disease, which implicitly locates 'risk' within individuals, conveniently drawing attention away from important global drivers of the NCD epidemic. In fact, the epidemiologic realities of the bottom billion reveal a burden of neglected chronic diseases that are associated with 'alternative' environmental and infectious risks that are largely structurally determined. In addition, the vertical orientation of the framework fails to centralise health systems and delivery issues that are essential to chronic disease prevention and treatment. A new framework oriented around a global health equity perspective would be able to correct some of the failures of the current model by bringing the needs of the global poor to the forefront, and centralising health systems and delivery. In addition, core social science concepts such as Bordieu's habitus may be useful to re-conceptualising strategies that may address both behavioural and structural determinants of health. PMID- 26948139 TI - Erionite-Na upon heating: dehydration dynamics and exchangeable cations mobility. AB - Erionite is a fibrous zeolite significantly more tumorigenic than crocidolite asbestos upon inhalation. In recent years, several papers have been published aimed at characterizing from the crystal-chemical point of view erionite fibres. As their toxicity has been ascribed to Fe acquired within the human body, studies aimed at characterizing the iron topochemistry have also been published, suggesting a possible important role played by the ionic exchange properties and cations mobility of this zeolite on developing carcinogenicity. Here we report the analysis results of the thermal behaviour of erionite-Na, which has been found to deviate significantly from that of erionite-K. This result is in contrast with the current scientific view that differences in weighted ionic potential, Si/Al ratio and size of exchangeable cations result in significantly different thermal behaviours, all those parameters being nearly identical or very similar in both species. The different mobility of the extraframework cations observed in erionite samples with dissimilar chemistry is of particular interest within the frame of the hypothesis that their biological activity could depend, apart from surface interactions, also on bulk effects. PMID- 26948140 TI - Bio-oil production and removal of organic load by microalga Scenedesmus sp. using culture medium contaminated with different sugars, cheese whey and whey permeate. AB - The objective of this study was to evaluate the bio-oil production and the organic load removal using the microalga Scenedesmus sp. The cultivation was carried out in reactors with a total volume of 3 L and 0.7 vvm aeration, with illumination in photoperiods of 12 h light/12 h dark for 12 days. The following sugar concentrations were tested: 2.5, 5.0 and 10 g/L of glucose, lactose, fructose and galactose with 10% inoculum volume. After experiments were performed with cheese whey in natura and cheese whey permeate with different lactose concentrations (1.5, 2.5, 3.5 and 5.0 g/L). In these experiments the inoculum concentrations were 10, 15, 20 and 30% (v/v). The results showed that this microalga was effective for the production of lipids when it was cultivated in medium with cheese whey in natura with 2.5 g/L of lactose and 20% inoculum (v/v). Using cheese whey in natura at the concentration of 3.5 g/L of lactose and 30% (v/v) of inoculum obtained 77.9% of TOC removal and 38.447 mg of TOC removed/mg oil produced. It was also observed that when there is increased production of bio oil, there is less removal of organic matter. The addition of glucose, fructose or galactose in the medium did not enhance the production of bio-oil by Scenedesmus sp. when compared to lactose, but increased the organic matter removal. PMID- 26948141 TI - Prevalence of Osteoporosis in Women in Buenos Aires Based on Bone Mineral Density at the Lumbar Spine and Femur. AB - The aim of the study was to report values for osteoporosis (OP) prevalence in Buenos Aires. Bone mineral density (BMD) at different skeletal sites was measured from November 2012 to July 2014. Participants were recruited through a newspaper advertisement inviting women at least 50 yr of age to receive free BMD measurement. After signing an informed consent form, 5448 women living in Buenos Aires and surrounding districts were studied. Lumbar spine (L1-L4), femur neck, and total hip BMDs were measured (Lunar Prodigy, software version 12.3 GE, Madison, WI, USA). OP was defined as a T-score <=-2.5 at the lumbar spine or the femoral neck. Results showed that 1021 out of 5448 studied subjects (18.7%) had OP at the lumbar spine or the femoral neck. Comparison of age of the population sample with reference data for the general population showed a moderate (+0.6%) increase in prevalence. Prevalence of OP was low, up to the age of 70 yr when based on femoral neck BMD only. Conversely, the prevalence of OP at the lumbar spine, which was reportedly high in women up to the age of 70 yr, tended to level off over that age. The results of the total femur only added a slight (+0.7%) nonsignificant increase to the OP prevalence. A total 346,500 out of 1,853,000 women aged 50+ yr in Buenos Aires had OP at the lumbar spine or femoral neck, whereas only 163,500 had OP at the upper femur, reducing the number by 53%. The present study assessed OP prevalence in the most densely populated urban area in Argentina. The results are similar to those reported for Caucasian populations in the United States and Canada. As measurement of only the BMD of femoral neck overlooks the diagnosis in half of the women, future studies should include measurement of the lumbar spine in combination with the femoral neck for a more accurate estimation of OP prevalence. PMID- 26948142 TI - Compact Feeding Network for Array Radiations of Spoof Surface Plasmon Polaritons. AB - We propose a splitter feeding network for array radiations of spoof surface plasmon polaritons (SPPs), which are guided by ultrathin corrugated metallic strips. Based on the coupled mode theory, SPP fields along a single waveguide in a certain frequency range can be readily coupled into two adjacent branch waveguides with the same propagation constants. We propose to load U-shaped particles anti-symmetrically at the ends of such two branch waveguides, showing a high integration degree of the feeding network. By controlling linear phase modulations produced by the U-shaped particle chain, we demonstrate theoretically and experimentally that the SPP fields based on bound modes can be efficiently radiated to far fields in broadside direction. The proposed method shows that the symmetry of electromagnetic field modes can be exploited to the SPP transmission network, providing potential solutions to compact power dividers and combiners for microwave and optical devices and systems. PMID- 26948143 TI - In vitro activities of five antifungal agents against 199 clinical and environmental isolates of Aspergillus flavus, an opportunistic fungal pathogen. AB - Aspergillus flavus is the second leading cause of invasive and non-invasive aspergillosis, as well as the most common cause of fungal sinusitis, cutaneous infections, and endophthalmitis in tropical countries. Since resistance to antifungal agents has been observed in patients, susceptibility testing is helpful in defining the activity spectrum of antifungals and determining the appropriate drug for treatment. A collection of 199 clinical and environmental strains of Aspergillus flavus consisted of clinical (n=171) and environmental (n=28) were verified by DNA sequencing of the partial b-tubulin gene. MICs of amphotericin B, itraconazole, voriconazole, posaconazole, and MEC of caspofungin were determined in accordance with the Clinical and Laboratory Standards Institute M38-A2 document. Caspofungin, followed by posaconazole, exhibited the lowest minimum inhibitory concentrations (MIC). All isolates had caspofungin MEC90 (0.063MUg/ml) lower than the epidemiologic cutoff values, and 3.5% of the isolates had amphotericin B MIC higher than the epidemiologic cutoff values. However, their clinical effectiveness in the treatment of A. flavus infection remains to be determined. PMID- 26948145 TI - Interactive dose shaping part 1: a new paradigm for IMRT treatment planning. AB - In this work we present a novel treatment planning technique called interactive dose shaping (IDS) to be employed for the optimization of intensity modulated radiation therapy (IMRT). IDS does not rely on a Newton-based optimization algorithm which is driven by an objective function formed of dose volume constraints on pre-segmented volumes of interest (VOIs). Our new planning technique allows for direct, interactive adaptation of localized planning features. This is realized by a dose modification and recovery (DMR) planning engine which implements a two-step approach: firstly, the desired localized plan adaptation is imposed on the current plan (modification) while secondly inevitable, undesired disturbances of the dose pattern elsewhere are compensated for automatically by the recovery module. Together with an ultra-fast dose update calculation method the DMR engine has been implemented in a newly designed 3D therapy planning system Dynaplan enabling true real-time interactive therapy planning. Here we present the underlying strategy and algorithms of the DMR based planning concept. The functionality of the IDS planning approach is demonstrated for a phantom geometry of clinical resolution and size. PMID- 26948146 TI - Proteomic profiling of eccrine sweat reveals its potential as a diagnostic biofluid for active tuberculosis. AB - PURPOSE: Excessive sweating is a common symptom of the disease and an unexplored biofluid for TB diagnosis; we conducted a proof-of-concept study to identify potential diagnostic biomarkers of active TB in eccrine sweat. EXPERIMENTAL DESIGN: We performed a global proteomic profile of eccrine sweat sampled from patients with active pulmonary TB, other lung diseases (non-TB disease), and healthy controls. A comparison of proteomics between Active-TB, Non-TB, and Healthy Controls was done in search for potential biomarkers of active TB. RESULTS: Sweat specimens were pooled from 32 active TB patients, 27 patients with non-TB diseases, and 24 apparently healthy controls, all were negative for HIV. Over 100 unique proteins were identified in the eccrine sweat of all three groups. Twenty-six proteins were exclusively detected in the sweat of patients with active TB while the remaining detected proteins overlapped between three groups. Gene ontology evaluation indicated that the proteins detected uniquely in sweat of active TB patients were involved in immune response and auxiliary protein transport. Gene products for cellular components (e.g. ribosomes) were detected only in active TB patients. Data are available via ProteomeXchange with identifier PXD003224. CONCLUSIONS AND CLINICAL RELEVANCE: Proteomics of sweat from active TB patients is a viable approach for biomarker identification, which could be used to develop a nonsputum-based test for detection of active TB. PMID- 26948148 TI - Hydrogen evolution catalyzed by a cobalt complex containing an asymmetric Schiff base ligand. AB - A cobalt(iii) complex containing an asymmetric Schiff-base ligand has been found to be active for proton reduction. Catalysis occurs at -1.2 V vs. Fc(+)/Fc (0.56 V vs. NHE), resulting in an overpotential of 350 mV. Additionally, the complex is active with a turnover frequency of 420 s(-1). An enhancement in activity is observed upon addition of water. PMID- 26948147 TI - General Bioluminescence Resonance Energy Transfer Homogeneous Immunoassay for Small Molecules Based on Quantum Dots. AB - Here, we describe a general bioluminescence resonance energy transfer (BRET) homogeneous immunoassay based on quantum dots (QDs) as the acceptor and Renilla luciferase (Rluc) as the donor (QD-BRET) for the determination of small molecules. The ratio of the donor-acceptor that could produce energy transfer varied in the presence of different concentrations of free enrofloxacin (ENR), an important small molecule in food safety. The calculated Forster distance (R0) was 7.86 nm. Under optimized conditions, the half-maximal inhibitory concentration (IC50) for ENR was less than 1 ng/mL and the linear range covered 4 orders of magnitude (0.023 to 25.60 ng/mL). The cross-reactivities (CRs) of seven representative fluoroquinolones (FQs) were similar to the data obtained by an enzyme-linked immunosorbent assay (ELISA). The average intra- and interassay recoveries from spiked milk of were 79.8-118.0%, and the relative standard deviations (RSDs) were less than 10%, meeting the requirement of residue detection, which was a satisfactory result. Furthermore, we compared the influence of different luciferase substrates on the performance of the assay. Considering sensitivity and stability, coelenterazine-h was the most appropriate substrate. The results from this study will enable better-informed decisions on the choice of Rluc substrate for QD-BRET systems. For the future, the QD-BRET immunosensor could easily be extended to other small molecules and thus represents a versatile strategy in food safety, the environment, clinical diagnosis, and other fields. PMID- 26948149 TI - Comparative evaluation of custom and standard boil and bite (self-adapted) mouthguards and their effect on the functioning of the oral cavity. AB - BACKGROUND: Mouthguards provide an effective preventive method against the effects of injuries sustained during sports activities, in particular cycling, football, basketball, skiing or hockey. However, when placed in the oral cavity, they can induce disorders in basic physiological functions. AIM: The objective of this clinical study was to compare the effects of various custom mouthguards with generally available standard boil and bite mouthguards on the functions of the oral cavity. MATERIAL AND METHODS: A total of a 168 mouthguards (five custom and three standard boil and bite mouthguards) were assessed in a questionnaire-based survey. Their negative effects on the integrity of mucosa, speech, breathing, salivary flow and taste as well as in terms of inducing gag reflex, tooth clenching and temporomandibular joint complaints were compared. RESULTS: Porida mouthguard was reported to have the most adverse effects on oral functions. In the majority of the respondents, the remaining mouthguards did not have any adverse effects on the stomatognathic system functions. CONCLUSIONS: Mouthguards do not significantly disturb basic functions of the stomatognathic system. Standard Porida mouthguards were shown to have the most unfavourable effect on oral functions. PMID- 26948151 TI - Intracerebroventricular D-galactose administration impairs memory and alters activity and expression of acetylcholinesterase in the rat. AB - Tissue accumulation of galactose is a hallmark in classical galactosemia. Cognitive deficit is a symptom of this disease which is poorly understood. The aim of this study was to investigate the effects of intracerebroventricular administration of galactose on memory (inhibitory avoidance and novel object recognition tasks) of adult rats. We also investigated the effects of galactose on acetylcholinesterase (AChE) activity, immunocontent and gene expression in hippocampus and cerebral cortex. Wistar rats received a single injection of galactose (4mM) or saline (control). For behavioral parameters, galactose was injected 1h or 24h previously to the testing. For biochemical assessment, animals were decapitated 1h, 3h or 24h after galactose or saline injection; hippocampus and cerebral cortex were dissected. Results showed that galactose impairs the memory formation process in aversive memory (inhibitory avoidance task) and recognition memory (novel object recognition task) in rats. The activity of AChE was increased, whereas the gene expression of this enzyme was decreased in hippocampus, but not in cerebral cortex. These findings suggest that these changes in AChE may, at least in part, to lead to memory impairment caused by galactose. Taken together, our results can help understand the etiopathology of classical galactosemia. PMID- 26948150 TI - Evaluation of cellular immunological responses in mono- and polymorphic clinical forms of post-kala-azar dermal leishmaniasis in India. AB - Post-kala-azar dermal leishmaniasis (PKDL) is a chronic dermal complication that occurs usually after recovery from visceral leishmaniasis (VL). The disease manifests into macular, papular and/or nodular clinical types with mono- or polymorphic presentations. Here, we investigated differences in immunological response between these two distinct clinical forms in Indian PKDL patients. Peripheral blood mononuclear cells of PKDL and naive individuals were exposed in vitro to total soluble Leishmania antigen (TSLA). The proliferation index was evaluated using an enzyme-linked immunosorbent assay (ELISA)-based lymphoproliferative assay. Cytokines and granzyme B levels were determined by cytometric bead array. Parasite load in tissue biopsy samples of PKDL was quantified by quantitative polymerase chain reaction (qPCR). The proportion of different lymphoid subsets in peripheral blood and the activated T cell population were estimated using flow cytometry. The study demonstrated heightened cellular immune responses in the polymorphic PKDL group compared to the naive group. The polymorphic group showed significantly higher lymphoproliferation, increased cytokines and granzyme B levels upon TSLA stimulation, and a raised proportion of circulating natural killer (NK) T cells against naive controls. Furthermore, the polymorphic group showed a significantly elevated proportion of activated CD4(+) and CD8(+) T cells upon in-vitro TSLA stimulation. Thus, the polymorphic variants showed pronounced cellular immunity while the monomorphic form demonstrated a comparatively lower cellular response. Additionally, the elevated level of both activated CD4(+) and CD8(+) T cells, coupled with high granzyme B secretion upon in-vitro TSLA stimulation, indicated the role of cytotoxic cells in resistance to L. donovani infection in polymorphic PKDL. PMID- 26948152 TI - Early life adversities or high fat diet intake reduce cognitive function and alter BDNF signaling in adult rats: Interplay of these factors changes these effects. AB - Environmental factors, like early exposure to stressors or high caloric diets, can alter the early programming of central nervous system, leading to long-term effects on cognitive function, increased vulnerability to cognitive decline and development of psychopathologies later in life. The interaction between these factors and their combined effects on brain structure and function are still not completely understood. In this study, we evaluated long-term effects of social isolation in the prepubertal period, with or without chronic high fat diet access, on memory and on neurochemical markers in the prefrontal cortex of rats. We observed that early social isolation led to impairment in short-term and working memory in adulthood, and to reductions of Na(+),K(+)-ATPase activity and the immunocontent of phospho-AKT, in prefrontal cortex. Chronic exposure to a high fat diet impaired short-term memory (object recognition), and decreased BDNF levels in that same brain area. Remarkably, the association of social isolation with chronic high fat diet rescued the memory impairment on the object recognition test, as well as the changes in BDNF levels, Na(+),K(+)-ATPase activity, MAPK, AKT and phospho-AKT to levels similar to the control-chow group. In summary, these findings showed that a brief social isolation period and access to a high fat diet during a sensitive developmental period might cause memory deficits in adulthood. On the other hand, the interplay between isolation and high fat diet access caused a different brain programming, preventing some of the effects observed when these factors are separately applied. PMID- 26948155 TI - Corrigendum: Active layers of high-performance lead zirconate titanate at temperatures compatible with silicon nano- and microelectronic devices. PMID- 26948153 TI - Development of human white matter fiber pathways: From newborn to adult ages. AB - Major long-range white matter pathways (cingulum, fornix, uncinate fasciculus [UF], inferior fronto-occipital fasciculus [IFOF], inferior longitudinal fasciculus [ILF], thalamocortical [TC], and corpus callosal [CC] pathways) were identified in eighty-three healthy humans ranging from newborn to adult ages. We tracked developmental changes using high-angular resolution diffusion MR tractography. Fractional anisotropy (FA), apparent diffusion coefficient, number, length, and volume were measured in pathways in each subject. Newborns had fewer, and more sparse, pathways than those of the older subjects. FA, number, length, and volume of pathways gradually increased with age and reached a plateau between 3 and 5 years of age. Data were further analyzed by normalizing with mean adult values as well as with each subject's whole brain values. Comparing subjects of 3 years old and under to those over 3 years old, the studied pathways showed differential growth patterns. The CC, bilateral cingulum, bilateral TC, and the left IFOF pathways showed significant growth both in volume and length, while the bilateral fornix, bilateral ILF and bilateral UF showed significant growth only in volume. The TC and CC took similar growth patterns with the whole brain. FA values of the cingulum and IFOF, and the length of ILF showed leftward asymmetry. The fornix, ILF and UF occupied decreased space compared to the whole brain during development with higher FA values, likely corresponding to extensive maturation of the pathways compared to the mean whole brain maturation. We believe that the outcome of this study will provide an important database for future reference. PMID- 26948154 TI - Traumatic axonal injury: Relationships between lesions in the early phase and diffusion tensor imaging parameters in the chronic phase of traumatic brain injury. AB - This prospective study of traumatic brain injury (TBI) patients investigates fractional anisotropy (FA) from chronic diffusion tensor imaging (DTI) in areas corresponding to persistent and transient traumatic axonal injury (TAI) lesions detected in clinical MRI from the early phase. Thirty-eight patients (mean 24.7 [range 13-63] years of age) with moderate-to-severe TBI and 42 age- and sex matched healthy controls were included. Patients underwent 1.5-T clinical MRI in the early phase (median 7 days), including fluid-attenuated inversion recovery (FLAIR) and T2* gradient echo (T2*GRE) sequences. TAI lesions from the early phase were characterized as nonhemorrhagic or microhemorrhagic. In the chronic phase (median 3 years), patients and controls were imaged at 3 T with FLAIR, T2*GRE, T1, and DTI sequences. TAI lesions were classified as transient or persistent. The FLAIR/T2*GRE images from the early phase were linearly registered to the FA images from the chronic phase and lesions manually segmented on the FA registered FLAIR/T2*GRE images. For regions of interest (ROIs) from both nonhemorrhagic and microhemorrhagic lesion, we found a significant linear trend of lower mean FA from ROIs in healthy controls to ROIs in patients without either nonhemorrhagic or microhemorrhagic lesions and further to transient and finally persistent lesion ROIs (P < 0.001). Histogram analyses showed lower FA in persistent compared with transient nonhemorrhagic lesion ROIs (P < 0.001), but this was not found in microhemorrhagic lesion ROIs (P = 0.08-0.55). The demonstrated linear trend of lower FA values from healthy controls to persistent lesion ROIs was found in both nonhemorrhagic and microhemorrhagic lesions and indicates a gradual increasing disruption of the microstructure. Lower FA values in persistent compared with transient lesions were found only in nonhemorrhagic lesions. Thus, clinical MRI techniques are able to depict important aspects of white matter pathology across the stages of TBI. (c) 2016 Wiley Periodicals, Inc. PMID- 26948156 TI - A Metal-Organic Framework with a Pore Size/Shape Suitable for Strong Binding and Close Packing of Methane. AB - Much effort has been devoted to develop new porous structures for methane storage. We report a new porous coordination framework showing exceptional methane uptakes (e.g. 263 v/v at 298 K and 65 bar) and adsorption enthalpies (21.6 kJ mol(-1)) as high as current record holders functionalized by open metal sites. Computational simulations demonstrated that the hierarchical pore structure consisting of single-wall nanocages has suitable sizes/shapes and organic binding sites to enforce not only strong host-methane and methane-methane interactions but also dense packing of methane molecules. PMID- 26948157 TI - Construction of a Graphene/Au-Nanoparticles/Cucurbit[7]uril-Based Sensor for Pb(2+) Sensing. AB - The development of highly sensitive and selective methods for the detection of lead ion (Pb(2+)) is of great scientific importance. In this work, we develop a new surface-enhanced Raman scattering (SERS)-based sensor for the selective trace measurement of Pb(2+). The SERS-based sensor is assembled from gold nanoparticles (AuNPs) and graphene using cucurbit[7]uril (CB[7]) as a precise molecular glue and a local SERS reporter. Upon the addition of Pb(2+), CB[7] forms stronger complexes with Pb(2+) and desorbs from AuNPs, resulting in a sensitive "turn-off" of SERS signals. This SERS-based assay shows a limit of detection (LOD) of 0.3 nm and a linear detection range from 1 nm to 0.3 MUm for Pb(2+). The feasibility of the assay is further demonstrated by probing Pb(2+) in real water samples. This SERS-based analytical method is highly sensitive and selective, and therefore holds promising applications in environmental analysis. PMID- 26948158 TI - Evolutionary analysis of iron (Fe) acquisition system in Marchantia polymorpha. AB - To acquire appropriate iron (Fe), vascular plants have developed two unique strategies, the reduction-based strategy I of nongraminaceous plants for Fe(2+) and the chelation-based strategy II of graminaceous plants for Fe(3+) . However, the mechanism of Fe uptake in bryophytes, the earliest diverging branch of land plants and dominant in gametophyte generation is less clear. Fe isotope fractionation analysis demonstrated that the liverwort Marchantia polymorpha uses reduction-based Fe acquisition. Enhanced activities of ferric chelate reductase and proton ATPase were detected under Fe-deficient conditions. However, M. polymorpha did not show mugineic acid family phytosiderophores, the key components of strategy II, or the precursor nicotianamine. Five ZIP (ZRT/IRT-like protein) homologs were identified and speculated to be involved in Fe uptake in M. polymorpha. MpZIP3 knockdown conferred reduced growth under Fe-deficient conditions, and MpZIP3 overexpression increased Fe content under excess Fe. Thus, a nonvascular liverwort, M. polymorpha, uses strategy I for Fe acquisition. This system may have been acquired in the common ancestor of land plants and coopted from the gametophyte to sporophyte generation in the evolution of land plants. PMID- 26948159 TI - Back to basics. PMID- 26948160 TI - Brain mechanisms that underlie the effects of motivational audiovisual stimuli on psychophysiological responses during exercise. AB - Motivational audiovisual stimuli such as music and video have been widely used in the realm of exercise and sport as a means by which to increase situational motivation and enhance performance. The present study addressed the mechanisms that underlie the effects of motivational stimuli on psychophysiological responses and exercise performance. Twenty-two participants completed fatiguing isometric handgrip-squeezing tasks under two experimental conditions (motivational audiovisual condition and neutral audiovisual condition) and a control condition. Electrical activity in the brain and working muscles was analyzed by use of electroencephalography and electromyography, respectively. Participants were asked to squeeze the dynamometer maximally for 30s. A single item motivation scale was administered after each squeeze. Results indicated that task performance and situational motivational were superior under the influence of motivational stimuli when compared to the other two conditions (~20% and ~25%, respectively). The motivational stimulus downregulated the predominance of low frequency waves (theta) in the right frontal regions of the cortex (F8), and upregulated high-frequency waves (beta) in the central areas (C3 and C4). It is suggested that motivational sensory cues serve to readjust electrical activity in the brain; a mechanism by which the detrimental effects of fatigue on the efferent control of working muscles is ameliorated. PMID- 26948162 TI - Efficiency of the male effect with photostimulated bucks does not depend on their familiarity with goats. AB - In ewes, the ovulatory response of females exposed to familiar rams is lower than the response of those exposed to novel ones. In goats, males rendered sexually active by exposure to long days are more efficient to induce ovulation in seasonal anestrous females than untreated males. Two experiments were conducted to determine 1) whether male goats remain familiar to females after 45days of separation; and 2) whether photostimulated males are able to stimulate the sexual activity of females, independently of their familiarity with them. In Experiment 1, three groups of goats (n=10 goats per group) were put in contact with males (n=2 per group) during 10days in November (familiarization period). These males were called familiar males. After 15, 30 and 45days of separation from the males, females of each group were exposed to familiar or novel males during 10min. In each test, goats in contact with novel males displayed more distress bleats, escapes, head butts, and sniffing than those in contact with familiar males (P<0.05). In Experiment 2, we used sexually inactive (n=4 control males), and sexually active males (n=4 photostimulated males). In February, two groups of goats (n=50 each) were put in contact with control or photostimulated males (n=2 each) during 10days ("familiar" control or photostimulated male, respectively). After 45days of separation from the males, both groups of females were further divided into two groups (n=25 goats per group). In April, two groups were re exposed to "familiar" control or "familiar" photostimulated males (n=2 per group), whereas the other two groups were exposed to "novel" control or "novel" photostimulated males (n=2 per group). The photostimulated males displayed a higher level of sexual behavior than the controls. The proportion of goats that ovulated and displayed estrus was higher when exposed to the photostimulated males than when exposed to control ones (>=80% vs. 0%; P<0.05). These proportions did not differ between groups exposed to familiar or novel photostimulated males (P>0.05). We concluded that after 45days of separation, males are still familiar to females. The photostimulated males are able to induce the sexual activity of seasonally anestrous goats independently of their familiarity with them. PMID- 26948161 TI - Short-term effects of chewing gum on satiety and afternoon snack intake in healthy weight and obese women. AB - Afternoon snacking contributes significantly to total energy intake. Strategies to enhance the satiety value of lunch and reduce afternoon snacking are of interest for body weight management. To assess whether between-meal gum chewing would enhance the satiety response to a fixed lunch meal; and assess the role of cholecystokinin (CCK) as a potential mediator of the response in non-obese healthy weight and obese women. Fifty unrestrained obese (n=25) and non-obese healthy weight (n=25) women participated in a two-arm cross-over study assessing multiple (15min per hour*3h) gum chewing (GUM) occurrences or no gum (Control) on subjective ratings of satiety, subsequent sweet and salty snack intake, CCK and general metabolic responses. GUM compared to Control resulted in significant suppression of hunger, desire to eat and prospective consumption (p<0.05). Total snack energy intake was reduced ~9.3% by GUM, but not significantly different from Control (p=0.08). However, overall carbohydrate intake was reduced by GUM (p=0.03). This was consistent with a reduction in snacks characterized as high carbohydrate, low fat (p=0.02). BMI specific effects indicated GUM reduced pretzel intake in obese women (p=0.05) and Oreo cookie intake in healthy weight women (p=0.03) 3h after lunch. Metabolic responses and CCK did not differ between experimental conditions. Chewing gum intermittently post-lunch enhances perceptions of satiety and may have important implications in reducing afternoon high carbohydrate-snack intake. PMID- 26948163 TI - Gastrointestinal: Pyogenic granuloma of the duodenum. PMID- 26948164 TI - Posterosuperior rotator cuff repair by an independent double-row technique. Technical note and radiological and clinical results. AB - The present study reports an original independent double-row technique for arthroscopic posterosuperior rotator cuff repair. Clinical and ultrasound results were assessed at 6-month follow-up in a single-center series of 78 patients with a mean age of 57years. Constant score improved from 55 to 73 (P<0.05). Seven patients (9%) had re-tear: 6 tendon avulsions from the bone and 1 tear at the myotendinous junction. This repair technique provided a high rate of tendon healing on the bone, with a lower rate of complications than with traditional double-row repair techniques. LEVEL OF EVIDENCE: II. PMID- 26948165 TI - Primary Amyloidosis Discovered During Pregnancy. PMID- 26948166 TI - Creation of a second submucosal tunnel enabled successful per-oral endoscopic myotomy (POEM). PMID- 26948167 TI - Pedicled posterior pericardial repair of tracheoesophageal fistula after chemoradiotherapy for esophageal cancer. PMID- 26948168 TI - Epidemiology of central sleep apnoea in heart failure. AB - Central sleep apnoea occurs in about a third of patients with reduced systolic heart failure and is a marker of increased mortality. Such patients usually are older males with advanced heart failure (i.e., high pulmonary wedge pressure), often in atrial fibrillation, with evidence of hyperventilation (i.e., low PaCO2) in the absence of hypoxemia. Characteristically, ventilation waxes and wanes in a sinusoidal pattern, with mild hypoxemia, occurring in the lighter levels of sleep usually when supine. Snoring may also occur in central sleep apnoea, often at the peak of hyperventilation, sometimes contributing to the confusion or overlap with obstructive sleep apnoea. Central sleep apnoea is associated with orthopnoea, paroxysmal nocturnal dyspnoea and an oscillatory respiratory pattern with an incremental cardiopulmonary exercise study. Importantly, heart failure therapies (e.g., afterload reduction, diuresis, pacemakers, transplantation) attenuate central sleep apnoea. Night to night variability in severity of central sleep apnoea may occur with changes in patients' posture during sleep (less severe when sleeping on-side or upright). PMID- 26948169 TI - Effective mRNA Inhibition in PANC-1 Cells in Vitro Mediated via an mPEG-SeSe-PEI Delivery System. AB - RNA interference (RNAi)-mediated gene therapy is a promising approach to cure various diseases. However, developing an effective, safe, specific RNAi delivery system remains a major challenge. In this study, a novel redox-responsive polyetherimide (PEI)-based nanovector, mPEG-SeSe-PEI, was developed and its efficacy evaluated. We prepared three mPEG-SeSe-PEI vector candidates for small interfering glyceraldehyde-3-phosphate dehydrogenase (siGADPH) and determined their physiochemical properties and transfection efficiency using flow cytometry and PEG11.6-SeSe-PEI polymer. We investigated the silencing efficacy of GADPH mRNA expression in PANC-1 cells and observed that PEG11.6-SeSe-PEI/siGADPH (N/P ratio=10) polyplexes possessed the appropriate size and zeta-potential and exhibited excellent in vitro gene silencing effects with the least cytotoxicity in PANC-1 cells. In conclusion, we present PEG11.6-SeSe-PEI as a potential therapeutic gene delivery system for small interfering RNA (siRNA). PMID- 26948170 TI - Updraft gasification of poultry litter at farm-scale--A case study. AB - Farm and animal wastes are increasingly being investigated for thermochemical conversion, such as gasification, due to the urgent necessity of finding new waste treatment options. We report on an investigation of the use of a farm scale, auto-thermal gasification system for the production of a heating gas using poultry litter (PL) as a feedstock. The gasification process was robust and reliable. The PL's ash melting temperature was 639 degrees C, therefore the reactor temperature was kept around this value. As a result of the low reactor temperature the process performance parameters were low, with a cold gas efficiency (CGE) of 0.26 and a carbon conversion efficiency (CCE) of 0.44. The calorific value of the clean product gas was 3.39 MJ m(-3)N (LHV). The tar was collected as an emulsion containing 87 wt.% water and the extracted organic compounds were identified. The residual char exceeds thresholds for Zn and Cu to obtain European biochar certification; however, has potential to be classified as a pyrogenic carbonaceous material (PCM), which resembles a high nutrient biochar. PMID- 26948171 TI - Traumatic globe dislocation into the paranasal sinuses: Literature review and treatment guidelines. AB - Traumatic globe dislocation into the paranasal sinuses is rare. Only 24 cases have been reported in the English-language literature indexed in PUBMED. This form of injury frequently occurs as a result of high-energy blunt trauma mainly associated to traffic accidents. Traumatic globe dislocation into the paranasal sinuses can be explained by the mechanism of blowout fracture when strong blunt trauma forces are applied to the globe fracturing the thin orbital walls and displacing the eyeball. Medical and surgical management of severe globe displacement is still controversial. However, the majority of researchers agreed that the globe should be replaced into the orbital cavity as soon as possible. The present study aims to describe a case of traumatic globe dislocation into the maxillary sinus suggesting treatment guidelines based on English-language literature from 1971 to 2015. PMID- 26948172 TI - Maxillary expansion and maxillomandibular expansion for adult OSA: A systematic review and meta-analysis. AB - OBJECTIVE: This study sought to systematically review the international literature for articles evaluating maxillary expansion and maxillomandibular expansion as treatments for obstructive sleep apnea (OSA) in adults and to perform a meta-analysis. DATA SOURCES: Nine databases (including MEDLINE/PubMed). REVIEW METHODS: Searches were performed through January 8, 2016. The PRISMA statement was followed. RESULTS: Eight adult studies (39 patients) reported polysomnography and/or sleepiness outcomes. Six studies reported outcomes for maxillary expansion (36 patients), and the apnea-hypopnea index (AHI) decreased from a mean (M) +/- standard deviation (SD) of 24.3 +/- 27.5 [95% CI 15.3, 33.3] to 9.9 +/- 13.7 [95% CI 5.4, 14.4] events/hr (relative reduction: 59.3%). Maxillary expansion improved lowest oxygen saturation (LSAT) from a M +/- SD of 84.3 +/- 8.1% [95% CI 81.7, 87.0] to 86.9 +/- 5.6% [95% CI 85.1, 88.7]. Maxillomandibular expansion was reported in two studies (3 patients) and AHI decreased from a M +/- SD of 47.53 +/- 29.81 [95% CI -26.5 to 121.5] to 10.7 +/- 3.2 [95% CI 2.8, 18.6] events/hr (relative reduction: 77.5%). Maxillomandibular expansion improved LSAT from a M +/- SD of 76.7 +/- 14.5% [95% CI 40.7, 112.7] to 89.3 +/- 3.1 [95% CI 81.6, 97]. CONCLUSION: The current literature demonstrates that maxillary expansion can improve and maxillomandibular expansion can possibly improve AHI and LSAT in adults; however, given the paucity of studies, these remain open for additional research efforts. PMID- 26948173 TI - Sentinel node biopsy versus elective neck dissection. Which is more cost effective? A prospective observational study. AB - OBJECTIVE: The aim of this prospective not randomized observational study was to determine the costs and outcomes of sentinel lymph node biopsy (SNB) vs elective neck dissection (END) among patients with early oral squamous cell carcinoma (OSCC). MATERIALS AND METHODS: Seventy-three consecutive patients were divided according to neck staging method. Patients took the decision themselves after receiving detailed information of both suggested treatment tools. False negative (FN) and negative predictive value (NPV) were assessed. Log-rank test was used to compare disease-free survival (DFS) and overall survival (OS). Only direct costs were analysed. Cost information derived from volumes for hospital stay, surgery and neck outcome were obtained from an internal database of tertiary health care center. RESULTS: Thirty-two patients underwent SNB and 41 underwent an END (levels I-III). Average follow-up time was 48.2 months (range 7-80). Five neck recurrences were recorded in the SNB group (range 11-21). Seven neck recurrences occurred in the END group (range 9-16). No significant differences were found in DFS or OS. True negative patients in SNB group incurred in 42% less costs than END group. FN regardless of radiotherapy, was also lower in the SNB group. However, pN+ patients generated 23% more costs in the SNB group. CONCLUSION: In this not randomized observational study with an average follow-up period of 48.2 months, SNB appear to confer less cost than END, with similar prognosis. PMID- 26948174 TI - Orbital floor reconstruction using a tensor fascia lata sling after total maxillectomy. AB - PURPOSE: Reconstruction after total maxillectomy with extensive orbital floor defects poses a significant challenge for the reconstruction. The aim of this study is to present the outcomes of orbital floor reconstruction using tensor fascia lata slings after total maxillectomy and to compare these results to orbital floor reconstruction using alloplastic implants. METHOD: This was a retrospective analysis of 19 consecutive patients who underwent tumor resection with orbital floor removal for malignancies. Reconstructions were performed using either tensor fascia lata slings (Group A) or alloplastic implants (Group B). The early and late postoperative outcomes such as wound infection, plate exposure, ectropion, diplopia, and enophthalmos, were analyzed and compared between the two groups. RESULTS: Patients in group A had significantly less wound complication than in group B (p < 0.05). In group A, there were no early or late wound complications after the operation. However, in group B, five patients had infection, the plate was exposed in eight of fourteen patients, and three patients had enophthalmos. Eight patients in group B underwent reoperation to correct their complications. CONCLUSIONS: Reconstruction of the orbital floor with a tensor fascia lata sling offers reliable support to the globe and prevents the ophthalmic complications associated with loss of orbital support. PMID- 26948175 TI - Effect of Patellar Resurfacing on Patellofemoral Crepitus in Posterior-Stabilized Total Knee Arthroplasty. AB - BACKGROUND: Patellofemoral crepitus (PC) is a complication of total knee arthroplasty (TKA). Although patellar resurfacing (PR) directly influences the kinematics of the patellofemoral joint, the influence of PR on PC is unclear. The purpose of this study was to investigate the influence of PR on the incidence of PC. METHODS: This study included 84 knees from 69 patients who underwent TKA using the Vanguard Complete Total Knee System, with or without PR (n = 42 each). Clinical evaluation of the incidence of PC; Knee Society Score; and radiographic measurements of patellar tilt, patellar distance, patellar shift, Insall-Salvati ratio, patellar flexion, femorotibial angle; and rotation of the femoral component was performed. Parameters were evaluated preoperatively and at postoperative months 2, 6, 12, and 24. Logistic regression analysis was conducted to investigate the effect of PR on the risk of PC. RESULTS: The incidence of PC was significantly higher in the non-PR group than the PR group (33.3% vs 4.8%). The knees of the PR group displayed a significantly increased patellar tilt, medially shifted patella, and decreased patella flexion angle compared with those of the non-PR group. There were no significant differences in the other radiographic parameters or Knee Society Score. The absence of PR was associated with a much higher risk of PC (odds ratio, 10.37; 95% confidence interval, 2.18 10.37). CONCLUSION: PR may decrease the incidence of PC by increasing the patellar tilt and medial shift and positioning the patella more closely parallel to the femur. PR is recommended during TKA with this prosthesis. PMID- 26948176 TI - The Economic Impact of Periprosthetic Infections After Total Hip Arthroplasty at a Specialized Tertiary-Care Center. AB - BACKGROUND: Periprosthetic infections after total hip arthroplasty represent an increased risk for patient morbidity and mortality, and an increased economic burden. The purpose of this study was to compare a group of patients who had periprosthetic infections after total hip arthroplasty to a matched group of patients who underwent primary total hip arthroplasty in terms of the associated costs, length of hospitalization, and number of readmissions (within 1 year). METHODS: Between 2007 and 2011, 16 consecutive infected patients were matched to 32 noninfected patients (1:2 ratio). RESULTS: The mean episode cost, length of hospitalization, and median readmissions was significantly higher in the infected group when compared to the matched cohort: $88,623 vs $25,659, 7.6 vs 3.29 days, and 2 vs 0, respectively. CONCLUSION: Periprosthetic infections after THA resulted in an increased episode cost by approximately 3-fold, mean hospitalization period 2-fold, and led to a higher median number of readmissions. PMID- 26948177 TI - Acute interstitial nephritis induced by proton-pump inhibitor: Uncommon indication of antireflux surgery. PMID- 26948178 TI - Sofosbuvir antiviral therapy in HCV patients with severe renal failure. PMID- 26948179 TI - An update on the management of acute esophageal variceal bleeding. AB - The mortality rate in acute variceal haemorrhage remains high (around 15%). Treatment is based on the combined use of vasoactive drugs, endoscopic band ligation, and prophylactic antibiotics. Effective resuscitation (haemostasis, volume management) is essential to prevent complications. Treatment failure is best managed by transjugular intrahepatic portosystemic shunt (TIPS). Balloon tamponade or specifically designed covered oesophageal stents can be used as a bridge to definitive therapy in unstable patients. Early, pre-emptive TIPS should be the first choice in patients at high risk of treatment failure (Child-Pugh B with active bleeding or Child-Pugh C<14). This article reviews the most recent advances in the management of variceal bleeding and discusses the recent recommendations of the Baveno VI consensus conference. PMID- 26948180 TI - Characteristics of US Adults Who Have Positive and Negative Perceptions of Doctors of Chiropractic and Chiropractic Care. AB - OBJECTIVE: The purpose of this study was to compare characteristics, likelihood to use, and actual use of chiropractic care for US survey respondents with positive and negative perceptions of doctors of chiropractic (DCs) and chiropractic care. METHODS: From a 2015 nationally representative survey of 5422 adults (response rate, 29%), we used respondents' answers to identify those with positive and negative perceptions of DCs or chiropractic care. We used the chi(2) test to compare other survey responses for these groups. RESULTS: Positive perceptions of DCs were more common than those for chiropractic care, whereas negative perceptions of chiropractic care were more common than those for DCs. Respondents with negative perceptions of DCs or chiropractic care were less likely to know whether chiropractic care was covered by their insurance, more likely to want to see a medical doctor first if they were experiencing neck or back pain, less likely to indicate that they would see a DC for neck or back pain, and less likely to have ever seen a DC as a patient, particularly in the recent past. Positive perceptions of chiropractic care and negative perceptions of DCs appear to have greater influence on DC utilization rates than their converses. CONCLUSION: We found that US adults generally perceive DCs in a positive manner but that a relatively high proportion has negative perceptions of chiropractic care, particularly the costs and number of visits required by such care. Characteristics of respondents with positive and negative perceptions were similar, but those with positive perceptions were more likely to plan to use-and to have already received-chiropractic care. PMID- 26948181 TI - Effect of feed consumption levels on growth performance and carcass composition during the force-feeding period in foie gras production of male Mule ducks. AB - In order to avoid excess feed consumption during the force-feeding period in foie gras production, a dose-response experiment with seven feed consumption levels (450, 540, 630, 720, 810, 900, 990 g/day per bird) was conducted to evaluate the effects of feed consumption levels on growth performance and carcass composition of male Mule ducks from 91 to 102 days of age. One-day-old Mule ducklings (sterile and artificial hybrid of male Albatre Muscovy duck and female Pekin duck were fed a two-phase commercial diets for ad libitum intake from hatching to 91 days of age, followed by graded feeding levels of a corn diet by force-feeding from 91 to 102 days of age. Fifty-six 91-day-old male Mule ducks with similar BW were randomly assigned to seven treatments, with eight birds per treatment. Birds were housed in individual pens. At 102 days of age, final BW was measured and BW gain and feed conversion ratio of ducks from each treatment were calculated from day 91 to 102, and then all ducks were slaughtered to evaluate the yields of skin with subcutaneous fat, abdominal fat, breast meat (including pectoralis major and pectoralis minor), leg meat (including thigh and drum stick), and liver. Significant differences in BW gain, total liver weight and liver relative weight were observed among the treatments (P<0.001). According to the broken-line regression analysis, the optimal feed consumption levels of male Mule ducks from 91 to 102 days of age for maximum BW gain, total liver weight and liver relative weight were 217, 227 and 216 g feed/kg BW0.75.per day, respectively. PMID- 26948182 TI - Conducting polymer based electrochemical biosensors. AB - Conducting polymer (CP)-based electrochemical biosensors have gained great attention as such biosensor platforms are easy and cost-effective to fabricate, and provide a direct electrical readout for the presence of biological analytes with high sensitivity and selectivity. CP materials themselves are both sensing elements and transducers of the biological recognition event at the same time, simplifying sensor designs. This review summarizes the advances in electrochemical biosensors based on CPs. Recognition probe immobilisation techniques, transduction mechanisms and detection of various target biomolecules have been discussed in detail. Efforts to miniaturize CP-based electrochemical biosensors and fabrication of sensor arrays are also briefly reviewed. PMID- 26948183 TI - Twelve-month discontinuation of etonogestrel implant in an outpatient pediatric setting. AB - OBJECTIVE: The etonogestrel (ENG) contraceptive implant is the most effective reversible contraceptive method. Uptake remains limited in adolescents, a population at high risk for unintended pregnancy. The objectives of this study were to determine the 12-month discontinuation rate of the ENG implant among adolescents in an outpatient setting and to characterize risk factors for discontinuation. STUDY DESIGN: A retrospective chart review identified adolescent females aged 12 to 22years who received the ENG implant in one pediatric institution between January 1, 2011, and April 15, 2014. Patients were categorized into ENG discontinuers (removed prior to 12months) and ENG continuers (continued for >=12months). Associations between demographic, clinical and postplacement characteristics with ENG discontinuation category were assessed with t tests, chi(2)/Fisher's Exact Tests and backwards stepwise logistic regression. RESULTS: Of the 750 patients who had an ENG implant inserted, 77 (10.3%) had the device removed prior to 12months of use. The mean length of implant use for those who discontinued was 7.5months. Problematic bleeding was the most commonly cited reason for discontinuation. Older age at time of insertion, history of pregnancy and >=1 medical visit for implant concerns (not including removal) were independently predictive (p<.01) of method discontinuation. CONCLUSION: The vast majority of adolescents continued the ENG implant at 12months, making it an excellent contraceptive choice for adolescents within the outpatient pediatric setting. Greater efforts should be made to increase its use by pediatric providers. IMPLICATIONS: The ENG implant is an excellent contraceptive option for adolescents in the outpatient pediatric setting. PMID- 26948184 TI - A randomized controlled trial evaluating same-day mifepristone and misoprostol compared to misoprostol alone for cervical preparation prior to second-trimester surgical abortion. AB - OBJECTIVE: We evaluated initial cervical dilation with the addition of oral mifepristone to vaginal misoprostol as cervical preparation for same-daysecond trimester dilation and evacuation (D&E). STUDY DESIGN: Women desiring abortion between gestational ages 14weeks 0days and 19weeks 6days were randomized to 200 mg mifepristone or identical placebo immediately followed by 400-mcg misoprostol vaginally 4-6h prior to D&E. Primary outcome was cervical dilation assessed by largest Hegar dilator passed without resistance. Secondary outcomes included total procedure time and participant and provider perceptions. We had 90% power to detect a 2-mm change in initial cervical dilation with a mean of 10mm (SD=3.0mm), requiring 48 participants in each arm. RESULTS: Of 100 women enrolled, 96 were randomized and completed the study. Age, race, gestational age (mean 17.4weeks, SD=1.3) and parity did not significantly differ. Mean initial Hegar dilation measurements were 11.7 and 10.9mm in the mifepristone and placebo groups, respectively, with difference of 0.8 [95% CI=-0.4, 2.0mm]. We found total procedure times of 11.8 and 13.0min, respectively (difference of 1.2min [95% CI= 2.4, 4.8min]. Participant and provider perceptions did not differ. All 96 procedures were completed without hemorrhage, cervical laceration or other observed complications. CONCLUSION: The addition of mifepristone to vaginal misoprostol did not provide a significant increase in cervical dilation compared to misoprostol alone as cervical preparation 4-6h prior to D&E at 14weeks through 19weeks 6days. IMPLICATIONS: Adding mifepristone for a short interval (4-6h) did not improve cervical preparation with misoprostol prior to D&E at 14-19weeks. Future studies should evaluate alternative timing intervals of medications for this purpose. PMID- 26948185 TI - Impact evaluation of the Urban Health Initiative in urban Uttar Pradesh, India. AB - OBJECTIVES: The Urban Health Initiative (UHI) was initiated in 2009 with the goal of increasing family planning (FP) use among the poor in urban areas of Uttar Pradesh, India. The Measurement, Learning & Evaluation project (MLE) was tasked with rigorous impact evaluation of the UHI. This paper presents the impact evaluation findings of the UHI program. STUDY DESIGN: The MLE design includes a longitudinal sample of women and health facilities with baseline (2010) and endline (2014) data collection in six cities in Uttar Pradesh, India. At baseline, samples representative of women in each city were selected with oversampling of the poor. Eighty-four percent of women interviewed at baseline were reinterviewed 4 years later at endline. The longitudinal data support a within/fixed-effects approach to identification of program impact on changes in modern FP use. RESULTS: Impact evaluation results show significant effects of exposure to both demand and supply side program activities. In particular, women exposed to brochures (marginal effect: 6.96, p<.001), billboards/posters/wall hangings (marginal effect: 2.09, p<.05), and FP on the television (marginal effect: 2.46, p<.001) were significantly more likely to be using a modern method at endline. In addition, we found borderline significance for being exposed to a community health worker (marginal effect: 1.66, p<.10) and living close to an improved public and private supply environment where UHI undertook activities (marginal effects and p values: 2.48, p<.05 and 1.56, p<.10, respectively). CONCLUSIONS: UHI program activities were designed to complement the Government of India's strategies aimed at ensuring access to and provision of FP to urban poor populations. The effective demand- and supply-side strategies of the UHI program are therefore likely to be sustainable and scalable to other urban areas in India. IMPLICATIONS STATEMENT: Findings from this study are important for designing sustainable and scalable FP strategies for urban India where increases in FP use will be relevant for meeting international FP targets. PMID- 26948186 TI - Silicon Nitride Bioceramics Induce Chemically Driven Lysis in Porphyromonas gingivalis. AB - Organisms of Gram-negative phylum bacteroidetes, Porphyromonas gingivalis, underwent lysis on polished surfaces of silicon nitride (Si3N4) bioceramics. The antibacterial activity of Si3N4 was mainly the result of chemically driven principles. The lytic activity, although not osmotic in nature, was related to the peculiar pH-dependent surface chemistry of Si3N4. A buffering effect via the formation of ammonium ions (NH4(+)) (and their modifications) was experimentally observed by pH microscopy. Lysis was confirmed by conventional fluorescence spectroscopy, and the bacteria's metabolism was traced with the aid of in situ Raman microprobe spectroscopy. This latter technique revealed the formation of peroxynitrite within the bacterium itself. Degradation of the bacteria's nucleic acid, drastic reduction in phenilalanine, and reduction of lipid concentration were observed due to short-term exposure (6 days) to Si3N4. Altering the surface chemistry of Si3N4 by either chemical etching or thermal oxidation influenced peroxynitrite formation and affected bacteria metabolism in different ways. Exploiting the peculiar surface chemistry of Si3N4 bioceramics could be helpful in counteracting Porphyromonas gingivalis in an alkaline pH environment. PMID- 26948187 TI - Knee Donor Site Morbidity Following Harvest of Medial Femoral Trochlea Osteochondral Flaps for Carpal Reconstruction. AB - PURPOSE: This study examines donor site morbidity associated with the medial femoral trochlea (MFT) when used as a donor site for vascularized osteochondral flaps for reconstruction of challenging carpal defects such as proximal pole scaphoid nonunion and advanced Kienbock disease. METHODS: The retrospective study population included all patients who had undergone MFT flap harvest for scaphoid or lunate reconstruction. Chart review, patient questionnaires, and validated knee function assessment tools were used: International Knee Documentation Committee Subjective Knee Form scores ranged from 0 (maximal disability) to 100 (no disability). Western Ontario and McMaster Universities osteoarthritis index scores ranged from 0% (no disability) to 100% (maximal disability). Magnetic resonance imaging and radiographs were obtained on the donor knee on the majority of patients. RESULTS: Questionnaire response rate was 79% (45 of 57 patients). Average patient age was 35 +/- 11 years (range, 19-70 years). Average postoperative follow-up was 27 +/- 17 months (range, 9-108 months). The indication for MFT flap reconstruction was scaphoid nonunion in 30 patients and Kienbock disease in 15 patients. All 45 patients had a stable knee on examination. Magnetic resonance and radiographic imaging obtained on 35 patients exhibited no pathological changes. Average duration of postoperative pain was 56 +/- 59 days (range, 0-360 days); average duration until patients reported the knee returning to normal was 90 +/- 60 days (range, 14-360 days). Forty-three of 44 patients would have the same surgery again if needed; overall satisfaction with the surgery was rated as 5 +/- 1 (range, 2-5) on a scale from 0 (no satisfaction) to 5 (maximal satisfaction). Average International Knee Documentation Committee score was 96 +/- 9 (range, 56.3-100) and the average Western Ontario and McMaster Universities score was 6% +/- 16% (range, 0%-68%). CONCLUSIONS: Medial femoral trochlea osteochondral flap harvest results in minimal donor site morbidity in the majority of patients. Symptoms are time limited. Intermediate-term follow-up demonstrates excellent results in subjective outcome measures. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 26948189 TI - Prognosis of spontaneous hemorrhagic stroke in people under 55 in Senegal, a developing country in Africa: a series of 53 cases. AB - Strokes occur increasingly frequently in people aged 55 years or younger and present a problem of management and therefore of prognosis. The objective of this study was to determine the prognostic factors associated with hemorrhagic stroke in this population in Senegal. This retrospective study concerns 53 patients aged 16 to 55 years, hospitalized for hemorrhage stroke in the neurological department of Fann Teaching Hospital during 2010. The patients' mean age was 42.1 years (16 to 55 years) and the sex ratio 1.30 in favor of women. Hypertension was found in 62% of the patients, and 11% had a history of stroke. Hemiplegia was observed in 76%, associated more or less with impairment of consciousness (43%) and language (38%). Intraparenchymal hematomas were principally supratentorial (78%); only 15% were subtentorial (10% cerebellar and 5% in the brainstem). During the acute phase of hemorrhage, glycemic levels were high among one third of the patients. The mortality rate in our series was 43% and was highest among those of impaired consciousness and abnormal glycemic, cholesterol, and creatinemia levels. Neuropsychological sequelae occurred in 47% of all patients, including 83% of the survivors. Hemorrhagic stroke in people aged 55 years or younger is a public health problem. In view of the high mortality rate, effective control requires prevention of its risk factors and increased awareness of the danger of these factors and of the warning signs of stroke. PMID- 26948190 TI - [Isolation and restraint: practices by the team and ethical practice]. PMID- 26948188 TI - Brain-imaging studies of treatment-resistant schizophrenia: a systematic review. AB - Around 30% of patients with schizophrenia show an inadequate response to antipsychotics-ie, treatment resistance. Neuroimaging studies can help to uncover the underlying neurobiological reasons for such resistance and identify these patients earlier. Additionally, studies examining the effect of clozapine on the brain can help to identify aspects of clozapine that make it uniquely effective in patients with treatment resistance. We did a systematic search of PubMed between Jan 1, 1980, and April 13, 2015, to identify all neuroimaging studies that examined treatment-resistant patients or longitudinally assessed the effects of clozapine treatment. We identified 330 articles, of which 61 met the inclusion criteria. Replicated differences between treatment-resistant and treatment responsive patients include reductions in grey matter and perfusion of frontotemporal regions, and increases in white matter and basal ganglia perfusion, with effect sizes ranging from 0.4 to greater than 1. Clozapine treatment led to reductions in caudate nucleus volume in three separate studies. The available evidence supports the hypothesis that some of the neurobiological changes seen in treatment-resistant schizophrenia lie along a continuum with treatment-responsive schizophrenia, whereas other differences are categorical in nature and have potential to be used as biomarkers. However, further replication is needed, and for neuroimaging findings to be clinically translatable, future studies need to focus on a-priori hypotheses and be adequately powered. PMID- 26948191 TI - [Psychiatric care behind bars]. PMID- 26948192 TI - [The long road for psychiatric care in prisons]. AB - From the 19th century to the present day, the history of psychiatry in prisons has evolved considerably. In parallel with successive laws, codes and articles, psychiatry has gained in structure. From the "medical prison", mental health consultations in every detention centre, the regional medico-psychological services, to today's specially equipped hospital units (UHSA), prisoners receive both preventive care as well as curative treatment. PMID- 26948193 TI - [Pathway of a patient within a healthcare unit]. AB - Care in prison must be based as much as possible on the model used for the general population. The system of psychiatric care in prisons comprises three levels of provision. The presentation of the pathway of a young patient with severe mental disorders shows the possibilities and the difficulties involved in caring within a healthcare unit. PMID- 26948194 TI - [Psychopathology of violence in prisons]. AB - The issue of violence in prisons concerns the people detained there, the conditions of the imprisonment and the relations which are established between the prisoners and the guards. The deprivation of liberty in prison, by suppressing desire, stirs up violence. Security contingency measures are not sufficient to control aggressive urges. Violence in prison stems from the internal regulations, the architecture of the building, the organisation of the surveillance and from the psychopathological dynamics of the deprivations resulting from being locked up. PMID- 26948195 TI - [Health and justice coordination in prisons]. AB - The question of health-justice coordination has been present since the law of 18th January 1994. Since then, professional relations between prison staff and health carers have been regularly questioned in terms of their aims. The texts structuring this interinstitutional health-justice coordination constitutes a framework which the various professionals must appropriate and implement by drawing on specific knowledge and skills. It is an invitation to work together around the same population, on their respective and different missions. The implementation of a structured therapeutic group with sex offenders constitutes a positive experience. PMID- 26948196 TI - [The UHSA, an improvement in the care provision]. AB - Established by the law on the orientation and programming of justice of September 2002, the specially equipped hospital unit (UHSA) provides psychiatric treatment with full medical care to prisoners, in direct cooperation with the prison. In this specific social context, can the organisation of the care and the structure itself represent a lasting solution? PMID- 26948198 TI - ["We are free to choose the institutions which we visit"]. AB - The role of the Controller General of Places of Deprivation of Liberty (CGLPL) is to ensure the proper management of future prisoners and the guarantee of their fundamental rights. This role concerns the legal framework of measures as well as the conditions of their application and the environment of the person entering a detention centre, a prison or a specially equipped hospital unit (UHSA), for prisoners with psychiatric conditions. Interview with Adeline Hazan, a CGLPL since July 2014. PMID- 26948197 TI - [Prisoners in units for difficult patients]. AB - Prisoners, on remand or convicted, can be placed for a variable amount of time in a unit for difficult patients if their pathological mental state so requires. For the most part, their therapeutic care does not depend on their status as prisoner. The treatments provided are those indicated for their psychological pathologies and their potential or known dangerousness. However, some administrative measures make a distinction between their treatment and that of non-prisoner patients placed in these secure psychiatric units. PMID- 26948199 TI - [2/6 Edouard Zarifian]. PMID- 26948202 TI - Statins and myocardial infarction: Type, dose, and administration time: Does it matter? AB - Patients with ST-elevation myocardial infarction (STEMI) constitute a vulnerable group that demands the careful assessment and application of all the up-to-date clinical and experimental knowledge, with final aim, the improvement of their prognosis. Statins are an indispensable part of the primary and secondary prevention of coronary artery disease (CAD), not only due to their strong hypolipidemic effect, but also due to their numerous pleiotropic properties that play an important role in the treatment of CAD, especially when the more vulnerable group of STEMI patients is addressed. Nevertheless, there are still issues that require further discussion and clarification, such as the type of statin, the dose of the regimen, the administration time, and the treatment duration. PMID- 26948204 TI - Major trauma guidance. PMID- 26948203 TI - Effects of body mass index or dosage on gastrointestinal disorders associated with extended-release metformin in type 2 diabetes: Sub-analysis of a Phase IV open-label trial in Chinese patients. AB - AIM: To determine whether gastrointestinal (GI) tolerability of metformin monotherapy varies according to baseline BMI or at doses >1500mg/day in patients newly diagnosed with type 2 diabetes. METHODS: We performed a sub-analysis of the safety population from a prospective, multicenter, Phase IV open-label study in which 371 Chinese patients with type 2 diabetes received extended-release metformin monotherapy for 16 weeks. The incidence, severity and duration of GI adverse events (AEs) were compared between normal-weight (BMI<25kg/m(2), n=155) and overweight/obese (BMI>=25kg/m(2), n=216) patients. The primary objective was to determine whether baseline BMI affect the incidence, severity and duration of GI AEs, using Fisher's exact test and Student's t-test. Secondary objectives were to compare these factors according to final metformin dose (<=1500mg/day versus 2000mg/day). RESULTS: The proportion of patients who reported >=1 GI AE did not differ significantly between BMI groups (25.2% of the normal-weight group versus 21.3% of the overweight/obese group; p=0.3840). Patients who reported GI AEs in the two BMI groups experienced similar GI AE severity (p=0.5410), mean duration (p=0.3572) and duration distribution (p=0.1347). There was no significant difference in GI AE severity and duration between metformin dosage groups (<=1500mg/day versus 2000mg/day). CONCLUSIONS: Newly-diagnosed Chinese type 2 diabetes patients of normal weight are no more likely than overweight/obese patients to suffer from increased incidence rates, severity or duration of GI AEs when treated with first-line extended-release metformin monotherapy. Doses of 2000mg/day did not increase the severity or duration of GI AEs. PMID- 26948205 TI - Three tests under scrutiny to speed up sepsis diagnosis. PMID- 26948206 TI - Call for all NHS 111 staff to be clinicians after death of boy with sepsis. PMID- 26948209 TI - Second air ambulance up and running. PMID- 26948207 TI - Science committee calls on government to build Zika virus evidence base. PMID- 26948210 TI - Major trauma care standards emphasise role of nurses. PMID- 26948211 TI - Testing out new services to cut hospital attendances. PMID- 26948212 TI - Simple solution, radical change. PMID- 26948219 TI - All set for a challenge. PMID- 26948222 TI - Transfusion delays and mortality. PMID- 26948223 TI - Weekend emergency admissions. PMID- 26948224 TI - Consent to HIV testing. PMID- 26948225 TI - Improving patient flow: role of the orthopaedic discharge sister. AB - Timely and well-planned discharge improves the patient's experience, contributes to patient safety and reduces the length of hospital stays. The role of orthopaedic discharge sister was developed at James Cook University Hospital in 2007 to provide safe, timely and efficient discharge for patients from the trauma and theatre centre, and to improve patient experience and flow. This article gives an overview of the role and describes how the sister works with colleagues to plan patient discharges from pre-assessment and emergency department admission through their hospital stay until their departure. PMID- 26948226 TI - How emergency department staff perceive acute nurse practitioners. AB - Over the past few years, emergency nursing has introduced new roles to allow nurses to practise at advanced levels. The well established emergency nurse practitioner role, which focuses on patients with minor illnesses and injuries, is being expanded and remodelled, partly to fill the gap created by the decline in the number of emergency medicine doctors. One emergency department in Scotland has introduced an extended nursing role called the acute nurse practitioner, which enables nurses to work at an extended level in the majors area of the department. This article discusses findings from a study that examined a range of healthcare clinicians' perceptions of this newly established service. Findings suggest that the service is received positively by colleagues and patients, but also highlight a number of issues that need to be addressed to enhance the service and support implementation in other emergency departments. PMID- 26948227 TI - Achilles tendon rupture in atypical patient populations. AB - Rupture of the Achilles tendon is a significant injury, and the likelihood of a good recovery is directly associated with early diagnosis and appropriate referral. Such injuries are commonly assessed and identified by practitioners working in 'minors' areas of emergency departments or urgent care settings. The literature frequently describes rupture of the Achilles tendon as 'typically sport-related' affecting 'middle-aged weekend warriors', but this aetiology accounts for only about 70% of such injuries. Factors such as the natural ageing process, obesity and use of some commonly prescribed medications, can increase the risk of developing a tendinopathy and subsequent rupture, often from a seemingly insignificant incident. However, research suggests that injuries in this patient population are more likely be missed on first examination. This article describes risk factors that should alert clinicians to the possibility of Achilles tendon rupture in 'atypical' patient populations. PMID- 26948228 TI - Finding my niche. PMID- 26948236 TI - Vascular closure devices for femoral arterial puncture site haemostasis. AB - BACKGROUND: Vascular closure devices (VCDs) are widely used to achieve haemostasis after procedures requiring percutaneous common femoral artery (CFA) puncture. There is no consensus regarding the benefits of VCDs, including potential reduction in procedure time, length of hospital stay or time to patient ambulation. No robust evidence exists that VCDs reduce the incidence of puncture site complications compared with haemostasis achieved through extrinsic (manual or mechanical) compression. OBJECTIVES: To determine the efficacy and safety of VCDs versus traditional methods of extrinsic compression in achieving haemostasis after retrograde and antegrade percutaneous arterial puncture of the CFA. SEARCH METHODS: The Cochrane Vascular Trials Search Co-ordinator searched the Specialised Register (April 2015) and the Cochrane Central Register of Controlled Trials (CENTRAL) (2015, Issue 3). Clinical trials databases were searched for details of ongoing or unpublished studies. References of articles retrieved by electronic searches were searched for additional citations. SELECTION CRITERIA: We included randomised and quasi-randomised controlled trials in which people undergoing a diagnostic or interventional procedure via percutaneous CFA puncture were randomised to one type of VCD versus extrinsic compression or another type of VCD. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data and assessed the methodological quality of trials. We resolved disagreements by discussion with the third author. We performed meta-analyses when heterogeneity (I(2)) was < 90%. The primary efficacy outcomes were time to haemostasis and time to mobilisation (mean difference (MD) and 95% confidence interval (CI)). The primary safety outcome was a major adverse event (mortality and vascular injury requiring repair) (odds ratio (OR) and 95% CI). Secondary outcomes included adverse events. MAIN RESULTS: We included 52 studies (19,192 participants) in the review. We found studies comparing VCDs with extrinsic compression (sheath size <= 9 Fr), different VCDs with each other after endovascular (EVAR) and percutaneous EVAR procedures and VCDs with surgical closure after open exposure of the artery (sheath size >= 10 Fr). For primary outcomes, we assigned the quality of evidence according to GRADE (Grades of Recommendation, Assessment, Development and Evaluation) criteria as low because of serious imprecision and for secondary outcomes as moderate for precision, consistency and directness.For time to haemostasis, studies comparing collagen-based VCDs and extrinsic compression were too heterogenous to be combined. However, both metal clip-based (MD -14.81 minutes, 95% CI -16.98 to -12.63 minutes; five studies; 1665 participants) and suture-based VCDs (MD -14.58 minutes, 95% CI -16.85 to -12.32 minutes; seven studies; 1664 participants) were associated with reduced time to haemostasis when compared with extrinsic compression.For time to mobilisation, studies comparing collagen-, metal clip- and suture-based devices with extrinsic compression were too heterogeneous to be combined. No deaths were reported in the studies comparing collagen-based, metal clip-based or suture-based VCDs with extrinsic compression. For vascular injury requiring repair, meta-analyses demonstrated that neither collagen (OR 2.81, 95% CI 0.47 to 16.79; six studies; 5731 participants) nor metal clip-based VCDs (OR 0.49, 95% CI 0.03 to 7.95; three studies; 783 participants) were more effective than extrinsic compression. No cases of vascular injury required repair in the study testing suture-based VCD with extrinsic compression.Investigators reported no differences in the incidence of infection between collagen-based (OR 2.14, 95% CI 0.88 to 5.22; nine studies; 7616 participants) or suture-based VCDs (OR 1.66, 95% CI 0.22 to 12.71; three studies; 750 participants) and extrinsic compression. No cases of infection were observed in studies testing suture-based VCD versus extrinsic compression. The incidence of groin haematoma was lower with collagen-based VCDs than with extrinsic compression (OR 0.46, 95% CI 0.40 to 0.54; 25 studies; 10,247 participants), but no difference was evident when metal clip-based (OR 0.79, 95% CI 0.46 to 1.34; four studies; 1523 participants) or suture-based VCDs (OR 0.65, 95% CI 0.41 to 1.02; six studies; 1350 participants) were compared with extrinsic compression. The incidence of pseudoaneurysm was lower with collagen-based devices than with extrinsic compression (OR 0.74, 95% CI 0.55 to 0.99; 21 studies; 9342 participants), but no difference was noted when metal clip-based (OR 0.76, 95% CI 0.20 to 2.89; six studies; 1966 participants) or suture-based VCDs (OR 0.79, 95% CI 0.25 to 2.53; six studies; 1527 participants) were compared with extrinsic compression. For other adverse events, researchers reported no differences between collagen-based, clip-based or suture-based VCDs and extrinsic compression.Limited data were obtained when VCDs were compared with each other. Results of one study showed that metal clip-based VCDs were associated with shorter time to haemostasis (MD -2.24 minutes, 95% CI -2.54 to -1.94 minutes; 469 participants) and shorter time to mobilisation (MD -0.30 hours, 95% CI -0.59 to 0.01 hours; 469 participants) than suture-based devices. Few studies measured (major) adverse events, and those that did found no cases or no differences between VCDs.Percutaneous EVAR procedures revealed no differences in time to haemostasis (MD -3.20 minutes, 95% CI -10.23 to 3.83 minutes; one study; 101 participants), time to mobilisation (MD 1.00 hours, 95% CI -2.20 to 4.20 hours; one study; 101 participants) or major adverse events between PerClose and ProGlide. When compared with sutures after open exposure, VCD was associated with shorter time to haemostasis (MD -11.58 minutes, 95% CI -18.85 to -4.31 minutes; one study; 151 participants) but no difference in time to mobilisation (MD -2.50 hours, 95% CI -7.21 to 2.21 hours; one study; 151 participants) or incidence of major adverse events. AUTHORS' CONCLUSIONS: For time to haemostasis, studies comparing collagen-based VCDs and extrinsic compression were too heterogeneous to be combined. However, both metal clip-based and suture-based VCDs were associated with reduced time to haemostasis when compared with extrinsic compression. For time to mobilisation, studies comparing VCDs with extrinsic compression were too heterogeneous to be combined. No difference was demonstrated in the incidence of vascular injury or mortality when VCDs were compared with extrinsic compression. No difference was demonstrated in the efficacy or safety of VCDs with different mechanisms of action. Further work is necessary to evaluate the efficacy of devices currently in use and to compare these with one other and extrinsic compression with respect to clearly defined outcome measures. PMID- 26948237 TI - Antimicrobial peptide melittin against Xanthomonas oryzae pv. oryzae, the bacterial leaf blight pathogen in rice. AB - Xanthomonas oryzae pv. oryzae is a destructive bacterial disease of rice, and the development of an environmentally safe bactericide is urgently needed. Antimicrobial peptides, as antibacterial sources, may play important roles in bactericide development. In the present study, we found that the antimicrobial peptide melittin had the desired antibacterial activity against X. oryzae pv. oryzae. The antibacterial mechanism was investigated by examining its effects on cell membranes, energy metabolism, and nucleic acid, and protein synthesis. The antibacterial effects arose from its ability to interact with the bacterial cell wall and disrupt the cytoplasmic membrane by making holes and channels, resulting in the leakage of the cytoplasmic content. Additionally, melittin is able to permeabilize bacterial membranes and reach the cytoplasm, indicating that there are multiple mechanisms of antimicrobial action. DNA/RNA binding assay suggests that melittin may inhibit macromolecular biosynthesis by binding intracellular targets, such as DNA or RNA, and that those two modes eventually lead to bacterial cell death. Melittin can inhibit X. oryzae pv. oryzae from spreading, alleviating the disease symptoms, which indicated that melittin may have potential applications in plant protection. PMID- 26948238 TI - Management of post-traumatic bone defects of the tibia using vascularised fibular graft combined with Ilizarov external fixator. AB - INTRODUCTION: Post-traumatic bone defects of the tibia present a difficult reconstructive challenge. Various methods of reconstruction are available, such as allografts, vascularised fibular graft (either free or pedicled) and bone transport technique. PATIENTS AND METHODS: Fourteen patients with an average age of 34.1 years at operation (range, 12-65) with post-traumatic bony defects of the tibia were selected for reconstruction with vascularised fibular graft combined with Ilizarov external fixation. There were 12 male and two female. The size of the bony gap was 10.4 cm (range, 7-13) and the average length of the fibula used was 16.4 cm (range, 14-21). RESULTS: The mean follow up period was 20.4 months (range, 10-37). All patients had bony union at both proximal and distal ends of the fibula primarily except one patient that required secondary iliac bone graft at the distal end of the fibula to obtain union. The average time for bone healing was 3.9 months (range, 3-9). The average time spent in Ilizarov frame was 5.9 months (range, 5-11). Unprotected full weight-bearing was achieved within an average of 7.3 months (range, 6-12). CONCLUSION: Vascularised fibular bone graft combined with an Ilizarov frame is a successful approach to safely and effectively reconstruct bone defects of the tibia. It has the advantages of vascularised fibular bone grafts together with the biomechanical advantages of Ilizarov frame that allows weight bearing to start almost immediately after surgery. This leads to a good outcome regarding the union and function. PMID- 26948239 TI - A novel method to correctly place the fasciotomy incision for decompression of the anterior and peroneal compartments of the leg. AB - Incorrectly placed fasciotomy incisions can lead to catastrophic complications in compartment syndrome. Two distinctly different techniques are widely practiced to decompress the anterior and peroneal compartments. In one technique the anterior compartment is decompressed directly, and then the peroneal via the inter muscular septum, avoiding the peroneal perforators. The second technique relies on surface anatomy landmarks to place the skin incision immediately over the inter-muscular septum, and then the respective fascial envelopes are incised separately. A study in healthy active volunteers was conducted to explore the feasibility of a new technique for the placing the incision very accurately over the inter-muscular septum and so avoiding perforator vessels. Hypothesis The inter-muscular septum can be reliably identified using hand-held ultrasound, and confirmed with MRI. METHODS: Fourteen healthy active volunteers underwent hand held ultrasound to identify the antero-lateral inter-muscular septum in the left lower limb, which was then marked using cod liver oil capsules. The positions of the anterior, septal and peroneal perforators were then identified using hand held Doppler, and marked in the same way. MRI was then used to measure the relationship between the surface land marks, the septum (compared to its US position), and the relationship of the perforators themselves. RESULTS: Hand held ultrasound was successful in identifying the position of the inter-muscular septum in healthy volunteers, as confirmed on MRI scanning. The position and number of peroneal and anterior perforators proved very variable. Direct decompression of the anterior compartment would result in the loss of all anterior perforators in all subjects. Decompression with the skin incision over the inter-muscular septum would not jeopardise any peroneal muscular perforators. CONCLUSION: This new technique enables decompression both the anterior and peroneal compartments through an accurately placed incision, sparing the greatest number of perforators. Two brief case histories in which the technique was used are presented. PMID- 26948240 TI - Trackable life: Data, sequence, and organism in movement ecology. AB - Over the past decade an increasing number of ecologists have begun to frame their work as a contribution to the emerging research field of movement ecology. This field's primary object of research is the movement track, which is usually operationalized as a series of discrete "steps and stops" that represent a portion of an animal's "lifetime track." Its practitioners understand their field as dependent on recent technical advances in tracking organisms and analyzing their movements. By making movement their primary object of research, rather than simply an expression of deeper biological phenomena, movement ecologists are able to generalize across the movement patterns of a wide variety of species and to draw on statistical techniques developed to model the movements of non-living things. Although it can trace its roots back to a long tradition of statistical models of movement, the field relies heavily on metaphors from genomics; in particular, movement tracks have been seen as similar to DNA sequences. Though this has helped movement ecology consolidate around a shared understanding of movement, the field may need to broaden its understanding of movement beyond the sequence if it is to realize its potential to address urgent concerns such as biodiversity loss. PMID- 26948241 TI - Nanoparticle puzzles and research opportunities that go beyond state of the art. AB - We present an overview of current progress and research challenges in the field of nanoparticle assembly, touching on the following topics: (1) historical perspective; (2) consideration of what is a nanoparticle; (3) contrast between nanoparticle self-assembly and top-down construction; (4) opportunities for nanoparticles with more intelligent sub-structures; (5) opportunities for nanoparticle systems cued to interact subtly in space and time. In this personal and subjective account, certain holy grails for nanoparticle science and technology are identified. PMID- 26948242 TI - Differential proteomic analysis of outer membrane enriched extracts of Bacteroides fragilis grown under bile salts stress. AB - Bacteroides fragilis is the most commonly isolated anaerobic bacteria from infectious processes. Several virulence traits contribute to the pathogenic nature of this bacterium, including the ability to tolerate the high concentrations of bile found in the gastrointestinal tract (GIT). The activity of bile salts is similar to detergents and may lead to membrane permeabilization and cell death. Modulation of outer membrane proteins (OMPs) is considered a crucial event to bile salts resistance. The primary objective of the current work was to identify B. fragilis proteins associated with the stress induced by high concentration of bile salts. The outer membrane of B. fragilis strain 638R was isolated after growth either in the presence of 2% conjugated bile salts or without bile salts. The membrane fractions were separated on SDS-PAGE and analyzed by ESI-Q/TOF tandem mass spectrometry. A total of 37 proteins were identified; among them nine were found to be expressed exclusively in the absence of bile salts whereas eight proteins were expressed only in the presence of bile salts. These proteins are related to cellular functions such as transport through membrane, nutrient uptake, and protein-protein interactions. This study demonstrates the alteration of OMPs composition in B. fragilis during bile salts stress resistance and adaptation to environmental changes. Proteomics of OMPs was also shown to be a useful approach in the identification of new targets for functional analyses. PMID- 26948243 TI - A Prospective Comparison of Clinical, Radiographic, and Intraoperative Features of Hallux Rigidus: Long-Term Follow-Up and Analysis. AB - Forty-seven patients (50 feet) underwent surgical intervention for symptomatic hallux rigidus from February 1998 to April 1999. Thirty-eight patients (41 feet) returned at 1 year for a follow-up evaluation. Of these 38 patients, 20 (21 feet) returned for the 15-year follow-up evaluation. Subjective evaluations were performed using the modified American Orthopaedic Foot and Ankle Surgery hallux metatarsophalangeal-interphalangeal 100-point scale. Long-term postoperative objective physical examination and radiographic analysis were performed. These data were compared with the preoperative and short-term follow-up data. The subjective evaluation showed a statistically significant differing over the long term, with a mean increase of 27.6 points. The results of the physical examination and radiographic measurements were mixed. The long-term dorsal range of motion was not significant across surgery type. Radiographically, the procedure types resulted in similar changes, suggesting that neither joint preservation nor joint destructive procedures were more stable over time. Plantar transposition of the capital fragment, offsetting the longitudinal shortening of the first metatarsal, was not significant, confirming the short-term findings. For this patient population, the long-term results of surgical intervention for hallux rigidus, regardless of procedure type, provided subjective patient improvement but no statistically significant increase in first metatarsophalangeal joint function or dorsal range of motion. PMID- 26948244 TI - [An historic case of mandibular ameloblastoma]. PMID- 26948245 TI - Late-onset neutropenia after rituximab in ANCA-associated vasculitis. AB - BACKGROUND: Rituximab (RTX) is being used increasingly in anti-neutrophil cytoplasmatic antibody (ANCA)-associated vasculitis (AAV). Late-onset neutropenia (LON) and risks of infections have been observed following RTX therapy in rheumatological diseases including granulomatosis with polyangiitis (GPA) but data on microscopic polyangiitis (MPA) are lacking. METHOD: We studied the occurrence of LON in 59 AAV (47 GPA/12 MPA) patients treated with RTX. Patient charts were retrospectively reviewed for the occurrence of LON and clinical data were extracted and included in the analysis. RESULTS: Seven of the total 59 patients (11.9%) developed LON after a median time of 86 days (range 56-168 days) since their latest RTX treatment. Of these seven LON patients, 5/47 (10.6%) had a diagnosis of GPA and 2/12 (16.7%) of MPA. Three of the patients developed LON after the first RTX treatment and four had received repeated courses. Five LON patients developed infectious symptoms. Six of the patients were hospitalized. Retreatment with RTX was given in three cases without further LON episodes. CONCLUSIONS: LON is a potentially severe side-effect of RTX occurring in both GPA and MPA and may develop after both single and repeated treatment courses. As infections are commonly seen, the condition requires an increased awareness. No predisposing factors for LON were identified. PMID- 26948246 TI - The prevalence of diffuse idiopathic skeletal hyperostosis in Japan - the first report of measurement by CT and review of the literature. AB - BACKGROUND: Diffuse idiopathic skeletal hyperostosis (DISH) is prone to be accompanied by a spinal column fracture which is resistant to conservative therapy. This major characteristic of DISH is not recognized adequately by physicians, because the disease's detailed pathological condition has not yet been investigated. Therefore, the purposes of this study were to investigate the prevalence of DISH using computed tomography (CT), and to validate the reliability of CT interpretation. METHODS: Subjects were 558 patients (300 male and 258 female) who underwent both CT of chest to pelvis and x-ray of chest and abdomen from August 2011 to July 2012 at any department other than orthopedic surgery in our institution. The definition of DISH based on x-ray as well as CT was the presence of consecutive fused vertebral bodies according to Resnick's criteria. The prevalence of DISH based on both modalities was calculated in all subjects. For 107 subjects extracted at random, intra- (Cohen kappa) and inter observer error (Fleiss kappa) were calculated and the levels of fused segments were investigated. RESULTS: Ninety-eight of 558 subjects (17.6%) were diagnosed as DISH by x-ray, and 152 (27.2%) by CT. Among males, 70 of 300 subjects (23.3%) were diagnosed by x-ray, and 116 (38.7%) by CT. Among females, 28 of 258 subjects (10.9%) were diagnosed by x-ray and 36 (14.0%) by CT. The levels of fused segments were presented from thoracic spine to lumbar spine, especially the middle and lower thoracic spine. Cohen kappa of x-ray was 0.587, and that of CT was 0.825. Fleiss kappa of x-ray was 0.552, and that of CT was 0.643. CONCLUSIONS: The prevalence of DISH based on CT was 27.1%, which was higher than that of x-ray. In addition, intra- and inter-observer error by review of CT was less than that of x-ray. CT evaluation would be a better method for precise understanding of the state of DISH. PMID- 26948248 TI - Characterizing microscale aluminum composite layer properties on silicon solar cells with hybrid 3D scanning force measurements. AB - This article presents a novel technique to estimate the mechanical properties of the aluminum composite layer on silicon solar cells by using a hybrid 3 dimensional laser scanning force measurement (3-D LSFM) system. The 3-D LSFM system measures the material properties of sub-layers constituting a solar cell. This measurement is critical for realizing high-efficient ultra-thin solar cells. The screen-printed aluminum layer, which significantly affects the bowing phenomenon, is separated from the complete solar cell by removing the silicon (Si) layer with deep reactive ion etching. An elastic modulus of ~15.1 GPa and a yield strength of ~35.0 MPa for the aluminum (Al) composite layer were obtained by the 3-D LSFM system. In experiments performed for 6-inch Si solar cells, the bowing distances decreased from 12.02 to 1.18 mm while the Si layer thicknesses increased from 90 to 190 MUm. These results are in excellent agreement with the theoretical predictions for ultra-thin Si thickness (90 MUm) based on the obtained Al composite layer properties. PMID- 26948247 TI - Excellent Long-term Breast Preservation Rate After Accelerated Partial Breast Irradiation Using a Balloon Device. AB - BACKGROUND: Accelerated partial breast irradiation (APBI) using a balloon device has been well tolerated. A recent retrospective population-based study showed an increase in the rate of subsequent mastectomy for patients who undergo APBI compared with whole breast radiation therapy. Our aim was to analyze the long term results of patients treated with APBI at our institution to determine the salvage mastectomy and locoregional recurrence rates and cosmesis outcomes. MATERIALS AND METHODS: After institutional review board approval, we conducted a retrospective review of 111 patients treated from June 2003 to October 2014 at our institution for early-stage breast cancer using a balloon device. After lumpectomy and nodal staging, the patients underwent APBI with high-dose rate iridium-192 brachytherapy. A computed tomography-based 3-dimensional plan was created, and a dose of 34 Gy in 10 fractions was given twice daily, 6 hours apart, over 5 days. Follow-up examinations were performed 2 to 3 times annually by either a surgeon and/or a radiation oncologist. Annual mammograms were obtained. The patients included postmenopausal women with node-negative early stage invasive ductal carcinoma with a tumor size < 3 cm (n = 93) or ductal carcinoma in situ (n = 18). Cosmesis was evaluated using the Harvard criteria, as excellent, good, fair, or poor. RESULTS: At a median follow-up period of 66 months (range, 1-139 months) after completing treatment, with a minimum of 5 years of follow-up data for 62 patients (55.9%), the incidence of ipsilateral breast tumor recurrence (IBTR) was 2.7% (n = 3) and the incidence of ipsilateral axilla nodal recurrence was 1.8% (n = 2). The ipsilateral breast preservation rate was 97.3%. The salvage mastectomy rate was 2.7% (n = 3), and the 5-year salvage mastectomy-free rate was 98.7% (95% confidence interval, 91.0%-99.8%). No distant failure developed, and no breast cancer-related deaths occurred. The 5 year overall survival rate was 91.7% (95% confidence interval, 83.2%-96.0%), and the 10-year breast cancer-specific survival rate was 100%. Of the 3 cases of IBTR, 2 were estrogen receptor negative (P = .076). The mean interval to IBTR was 78.7 +/- 27.5 months from treatment completion. A significant association was noted between African-American ethnicity and IBTR (P = .0398). Excellent to good cosmesis was observed in 98.1% of the patients. The maximum skin dose (mean value) for patients with excellent, good, and fair cosmesis was 302.2 Gy, 315.4 Gy, and 372.5 Gy (88.9%, 92.7%, and 109.5% of the prescription dose), respectively. The maximum skin dose was < 340 Gy (100% of the prescribed dose) in 69.9% of patients with excellent to good cosmesis. CONCLUSION: The long-term follow-up data of patients receiving APBI with a balloon device showed a low salvage mastectomy rate with durable long-term breast preservation. Excellent local control with good cosmesis was noted in these postmenopausal patients treated with APBI. PMID- 26948249 TI - An acido- and photochromic molecular device that mimics triode action. AB - The photo-controlled shift of pH titration curves, describing the acidochromic behaviour of a spiropyran switch network, was harnessed for the realisation of a molecular triode. The intricate network can be correctly interpreted with respect to the pH dependence of the main involved species. PMID- 26948250 TI - Humans choose representatives who enforce cooperation in social dilemmas through extortion. AB - Social dilemmas force players to balance between personal and collective gain. In many dilemmas, such as elected governments negotiating climate-change mitigation measures, the decisions are made not by individual players but by their representatives. However, the behaviour of representatives in social dilemmas has not been investigated experimentally. Here inspired by the negotiations for greenhouse-gas emissions reductions, we experimentally study a collective-risk social dilemma that involves representatives deciding on behalf of their fellow group members. Representatives can be re-elected or voted out after each consecutive collective-risk game. Selfish players are preferentially elected and are hence found most frequently in the 'representatives' treatment. Across all treatments, we identify the selfish players as extortioners. As predicted by our mathematical model, their steadfast strategies enforce cooperation from fair players who finally compensate almost completely the deficit caused by the extortionate co-players. Everybody gains, but the extortionate representatives and their groups gain the most. PMID- 26948251 TI - Predicting difficult laryngoscopy using ultrasound measurement of distance from skin to epiglottis. AB - BACKGROUND: Unpredicted difficult intubation can have severe consequences, and it is a significant source of morbidity and mortality. Although recent studies indicate that specific ultrasonography (US) measurements may be predictors of difficult laryngoscopy, their use is still limited, and its quantification is missing. The purpose of this prospective observational study is to evaluate the use of US-measured distance from skin to epiglottis (DSE) for difficult laryngoscopy prediction. METHODS: In a double-blind study, standard preintubation, screening tests, and DSE were obtained from 74 adult patients requiring endotracheal intubation. The relationship between difficult laryngoscopy and DSE was evaluated using a t test. A comparative analysis of its predictive performance with common clinical preintubation screening tests was performed using bootstrapping. RESULTS: We found that increasing DSE is strongly associated with difficult laryngoscopy (P < .001, 2-sided t test). We showed that a cutoff value of 27.5 mm was able to predict difficult laryngoscopy with an accuracy of 74.3%, a sensitivity of 64.7%, and a specificity of 77.1%. CONCLUSIONS: Our work demonstrates that the DSE can be effectively used to predict difficult laryngoscopy. Moreover, combining DSE with the modified Mallampati score in a decision tree significantly improves the predictive power over either test alone. PMID- 26948252 TI - Addition of indapamide to frusemide increases natriuresis and creatinine clearance, but not diuresis, in fluid overloaded ICU patients. AB - BACKGROUND: Fluid and sodium overload are a common problem in critically ill patients. Frusemide may result in diuresis in excess of natriuresis. The addition of indapamide may achieve a greater natriuresis, and also circumvent some of the problems associated with frusemide. The objective of this study was to examine the effect of adding indapamide to frusemide on diuresis, natriuresis, creatinine clearance and serum electrolytes. METHODS: Fluid overloaded ICU patients were randomised to either intravenous frusemide (Group F) or intravenous frusemide and enteral indapamide (Group F + I). Comprehensive exclusion criteria were applied to address confounders. 24 hour urine was analysed for electrolytes and creatinine. Serum electrolytes were measured before and 24 hours after administration of diuretics. RESULTS: Forty patients (20 in each group) were included in the study. The groups were similar in their baseline characteristics. Over the 24 h study period, patients in Group F + I, had a larger natriuresis (P = 0.01), chloride loss (P = 0.01) and kaliuresis (P = 0.047). Patients in Group F + I also had a greater 24 hour urinary creatinine clearance (P = 0.01). The 24 hour urine volume and fluid balance was similar between the groups. Patients in Group F had an increase in serum sodium (P = 0.04), while patients in Group F + I had a decrease in both serum chloride (P = 0.01) and peripheral oedema (P < 0.001) during the study duration. CONCLUSION: In fluid overloaded ICU patients, addition of indapamide to frusemide led to a greater natriuresis and creatinine clearance. Such a strategy might be utilised in optimising sodium balance in ICU patients. PMID- 26948253 TI - Effect of theophylline on ventilator-induced diaphragmatic dysfunction. AB - PURPOSE: To evaluate the effect of theophylline in patients with ventilator induced diaphragmatic dysfunction (VIDD). MATERIALS AND METHODS: Patients who required mechanical ventilation at least 72 hours, met the criteria for a spontaneous breathing trial, and had evidence of VIDD by ultrasonography were included in the study. RESULTS: Of the 40 patients, 21 received theophylline and 19 did not. Clinical characteristics were similar in the 2 groups. Assessment of VIDD showed no between-group differences in baseline diaphragmatic excursion (DE) of both hemidiaphragms. Changes in DE from baseline to 72 hours (DeltaDE) were significantly higher in the theophylline group than in the nontheophylline group in the right (3.5 +/- 4.5 mm vs 0.4 +/- 2.1 mm; P = .004) and left (3.2 +/- 5.1 mm vs 0.1 +/- 4.0 mm; P = .03) hemidiaphragms and in the total DE of both diaphragms (6.9 +/- 9.1 mm vs 0.5 +/- 5.7 mm; P = .02). In the theophylline group, theophylline was effective for the diaphragms with VIDD, whereas it was not effective for the diaphragms without VIDD. DeltaDE in the right (rs = -0.49, P = .006) hemidiaphragm and total Delta DE in both diaphragms (rs = -0.46, P = .01) correlated negatively with weaning time. CONCLUSIONS: Theophylline significantly improved diaphragmatic movements in patients with VIDD. Our results warrant a larger study to determine whether theophylline use has benefits during weaning from mechanical ventilation. PMID- 26948254 TI - Evaluation of the effect on patient parameters of not monitoring gastric residual volume in intensive care patients on a mechanical ventilator receiving enteral feeding: A randomized clinical trial. AB - PURPOSE: This study aimed to evaluate the effects of not measuring gastric residual volume (GRV) in intensive care patients on a mechanical ventilator and receiving enteral feeding on the feeding intolerance, gastroesophageal reflux (GER) risk, and nutritional adequacy. METHODS: This randomized clinical study was performed in 2 medical intensive care units of 2 university hospitals in Ankara, Turkey. The patients were randomized into 2 groups. In the group with GRV monitoring, GRV was measured 3 times a day, and the GRV threshold was accepted as 250 mL. In addition, 24-hour pH monitoring was used in this group to assess the risk of GER. In the group without GRV monitoring, GRV was not measured. The patients were followed-up for 5 days. RESULTS: The feeding targets were reached more quickly in the group without GRV monitoring (n = 26) with no increase in the complication rate (P < .05). No significant relationship was found between GRV and GER in the group with GRV monitoring (n = 25) (P > .05). CONCLUSION: The discrepancies in GRV measurement make it unreliable for monitoring feeding intolerance and GER. The use of GRV measurements may therefore be discontinued as part of the standard care protocol in medical intensive care units. PMID- 26948255 TI - Detection of SENV Virus in Healthy, Hepatitis B- and Hepatitis C-Infected Individuals in Yazd Province, Iran. AB - BACKGROUND: SEN virus (SENV) is the latest virus proposed as a cause of unknown hepatitis cases. Among nine detected genotypes of the virus, genotypes D and H are more frequent in hepatitis cases of unknown origin. The aim of this study was to determine the frequency of SENV-D and SENV-H genotypes in the sera of healthy individuals and hepatitis B and C patients. METHODS: Totally, 200 serum samples from healthy individuals as well as 50 hepatitis B and 50 hepatitis C patients were collected. Anti-HCV (hepatitis C virus), anti-human immunodeficiency virus, hepatitis B surface antigen and anti-HBV (hepatitis B virus) core antigen were detected, and serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured. Viral DNA was subjected to nested PCR. Fisher's exact and unpaired ANOVA tests were used for statistical analyses. RESULTS: SENV was detected in 90%, 66%, and 46% of the healthy individuals HBV and HCV-positive individuals, respectively. The frequency of SENV and its two genotypes were significantly lower in hepatitis B and hepatitis C patients (P<0.01). Also, the frequency of SENV-H was higher than SENV-D in all studied groups. In SENV positive HBV patients, the level of ALT and AST enzymes were significantly less than SENV-negative patients (P<0.05). It was the same for SENV-H-negative and positive cases. CONCLUSIONS: The levels of liver enzymes were significantly lower in HBV patients co-infected with SENV compared to HBV patients (P<0.05), indicating a positive impact of the virus in liver pathology by decreasing liver damage and thus decreasing the liver enzymes. PMID- 26948256 TI - Experiences of Being Heterozygous for Fabry Disease: a Qualitative Study. AB - Little is known about the experiences of women with Fabry disease. The aim of this study was to explore women's experiences of being heterozygous for Fabry disease. We used an explorative qualitative study design and selected ten Norwegian women who were known heterozygous for Fabry disease to participate. We conducted in-depth semi-structured interviews and analyzed the interviews using inductive thematic analysis. We found that learning about one's heterozygous status may be devastating for some. However, for most of the participants, heterozygous status, as well as doctors' acceptance of symptoms in women heterozygous for Fabry disease, provided an explanation and relief. Although many women did not consider themselves ill, they wished to be acknowledged as more than "just carriers." The participants were grateful for enzyme replacement therapy, although it had its burdens regarding time, planning, and absences from school or work. Women with Fabry disease felt that the lack of knowledge among healthcare professionals about Fabry disease was frustrating and worrisome. These findings suggest that healthcare professionals should acknowledge the different ways women react to their diagnosis, and be aware of the personal costs of receiving treatment. PMID- 26948258 TI - Framing post-pandemic preparedness: Comparing eight European plans. AB - Framing has previously been studied in the field of pandemic preparedness and global health governance and influenza pandemics have usually been framed in terms of security and evidence-based medicine on a global scale. This paper is based on the pandemic preparedness plans, published after 2009, from eight European countries. We study how pandemic preparedness is framed and how pandemic influenza in general is narrated in the plans. All plans contain references to 'uncertainty', 'pandemic phases', 'risk management', 'vulnerability' and 'surveillance'. These themes were all framed differently in the studied plans. The preparedness plans in the member states diverge in ways that will challenge the ambition of the European Union to make the pandemic preparedness plans interoperable and to co-ordinate the member states during future pandemics. PMID- 26948257 TI - Systematic review and meta-analysis of internet-delivered interventions providing personalized feedback for weight loss in overweight and obese adults. AB - BACKGROUND: Obesity levels continue to rise annually. Face-to-face weight loss consultations have previously identified mixed effectiveness and face high demand with limited resources. Therefore, alternative interventions, such as internet delivered interventions, warrant further investigation. The aim was to assess whether internet-delivered weight loss interventions providing personalized feedback were more effective for weight loss in overweight and obese adults in comparison with control groups receiving no personalized feedback. METHOD: Nine databases were searched, and 12 studies were identified that met all inclusion criteria. RESULTS: Meta-analysis, identified participants receiving personalized feedback via internet-delivered interventions, had 2.13 kg mean difference (SMD) greater weight loss (and BMI change, waist circumference change and 5% weight loss) in comparison with control groups providing no personalized feedback. This was also true for results at 3 and 6-month time points but not for studies where interventions lasted >=12 months. CONCLUSION: This suggests that personalized feedback may be an important behaviour change technique (BCT) to incorporate within internet-delivered weight loss interventions. However, meta-analysis results revealed no differences between internet-delivered weight loss interventions with personalized feedback and control interventions >=12 months. Further investigation into longer term internet-delivered interventions is required to examine how weight loss could be maintained. Future research examining which BCTs are most effective for internet-delivered weight loss interventions is suggested. PMID- 26948259 TI - Clinical Evaluation of Red Eyes in Pediatric Patients. AB - Patients with the primary symptom of a red eye are commonly seen in pediatric primary care clinics. The differential diagnoses of a red eye are broad, but with a succinct history and physical examination, the diagnosis can be readily identified in many patients. Identifying conditions that threaten vision and understanding the urgency of referral to an ophthalmologist is paramount. Some systemic diseases such as leukemia, sarcoidosis, and juvenile idiopathic arthritis can present with the chief symptom of a red eye. Finally, trauma, ranging from mild to severe, often precipitates an office visit with a red eye, and thus understanding the signs that raise concern for a ruptured globe is essential. In the primary care setting, with a focused history, a few simple examination techniques, and an appreciation of the differential diagnosis, one can feel confident in managing patients with acute red eyes. PMID- 26948260 TI - Improved Estimation of Ultrasound Thermal Strain Using Pulse Inversion Harmonic Imaging. AB - Thermal (temporal) strain imaging (TSI) is being developed to detect the lipid rich core of atherosclerotic plaques and presence of fatty liver disease. However, the effects of ultrasonic clutter on TSI have not been considered. In this study, we evaluated whether pulse inversion harmonic imaging (PIHI) could be used to improve estimates of thermal (temporal) strain. Using mixed castor oil gelatin phantoms of different concentrations and artificially introduced clutter, we found that PIHI improved the signal-to-noise ratio of TSI by an average of 213% or 52.1% relative to 3.3- and 6.6-MHz imaging, respectively. In a phantom constructed using human liposuction fat in the presence of clutter, the contrast to-noise ratio was degraded by 35.1% for PIHI compared with 62.4% and 43.7% for 3.3- and 6.6-MHz imaging, respectively. These findings were further validated using an ex vivo carotid endarterectomy sample. PIHI can be used to improve estimates of thermal (temporal) strain in the presence of clutter. PMID- 26948261 TI - Diagnostic phylogenetics reveals a new Porcine circovirus 2 cluster. AB - Porcine circovirus 2 (PCV2) was prevalent in swine in the United States before PCV2-associated disease (PCVAD) appeared in 2006. Limited nucleotide sequencing of open reading frame 2 (ORF2) encoding capsid, the only structural protein, revealed the presence of two genotypes, PCV2a and PCV2b. Later, PCV2c and mutant PCV2b, or PCV2d, were also described. However, extensive PCV2 ORF2 sequence databases in veterinary diagnostic laboratories have not been analyzed systematically to determine the genetic diversity of field isolates. Here, we interrogated >1100 PCV2 ORF2 nucleotide sequences to assess population diversity and genetic variation. We detected a novel PCV2 genotype that is substantially different, primarily in ORF2, from all known PCV2. Notably, ORF2 contains a unique carboxyl terminal amino acid insertion resulting in a 238 amino acid ORF2. All other PCV2 ORF2 proteins are 233 or 234 aa in length. Phylogenetic analysis indicates that it is more ancient than other PCV2 genotypes. The findings demonstrate the value of analyzing routine diagnostic laboratory sequence databases in population genetic analyses of animal pathogens. PMID- 26948262 TI - Identification of amino acid residues of the coat protein of Sri Lankan cassava mosaic virus affecting symptom production and viral titer in Nicotiana benthamiana. AB - Sri Lankan cassava mosaic virus (SLCMV) is bipartite begomovirus infecting cassava in India and Sri Lanka. Interestingly, the DNA-A component of the SLCMV alone is able to infect Nicotiana benthamiana causing symptoms of upward leaf rolling and stunting. One of the differences between monopartite and bipartite begomoviruses is the requirement of Coat Protein (CP) for infectivity; CP being essential for the former, but dispensable in the latter. This investigation was aimed to determine the importance of CP in the infectivity of the bipartite SLCMV, behaving as a monopartite virus in N. benthamiana. We tested CP-null mutants, single amino acid replacement mutants and double, triple and quadruple combinations of the above in SLCMV DNA-A, for infectivity, symptom development and viral DNA accumulation in N. benthamiana. While CP-null mutants were non infectious, a majority of the single amino acid replacement mutants and their combinations retained infectivity, some with attenuated symptoms and reduced viral titers. Some of the combined mutations restored the attenuated symptoms to wild type levels. Some of the mutations were predicted to cause changes in the secondary structure of the CP, which roughly correlated with the attenuation of symptoms and the reduction in viral titers. PMID- 26948263 TI - A high-throughput screening system targeting the nuclear export pathway via the third nuclear export signal of influenza A virus nucleoprotein. AB - Two classes of antiviral drugs, M2 channel inhibitors and neuraminidase (NA) inhibitors, are currently approved for the treatment of influenza; however, the development of resistance against these agents limits their efficacy. Therefore, the identification of new targets and the development of new antiviral drugs against influenza are urgently needed. The third nuclear export signal (NES3) of nucleoprotein (NP) is the most important for viral replication among seven NESs encoded by four viral proteins, NP, M1, NS1, and NS2. NP-NES3 is critical for the nuclear export of NP, and targeting NP-NES3 is therefore a promising strategy that may lead to the development of antiviral drugs. However, a high-throughput screening (HTS) system to identify inhibitors of NP nuclear export has not been established. Here, we developed a novel HTS system to evaluate the inhibitory effects of compounds on the nuclear export pathway mediated by NP-NES3 using a MDCK cell line stably expressing NP-NES3 fused to a green fluorescent protein from aequorea coerulescens (AcGFP-NP-NES3) and a cell imaging analyzer. This HTS system was used to screen a 9600-compound library, leading to the identification of several hit compounds with inhibitory activity against the nuclear export of AcGFP-NP-NES3. The present HTS system provides a useful strategy for the identification of inhibitors targeting the nuclear export of NP via its NES3 sequence. PMID- 26948264 TI - Common Emergencies in Rabbits, Guinea Pigs, and Chinchillas. AB - Rabbits, guinea pigs, and chinchillas are some of the more common exotic pets seen in emergency clinics. They frequently present with acute illnesses that are the result of several chronic conditions, most related to inadequate diet and husbandry. This article reviews the diagnosis and treatment of some of the more common acute illnesses. It also discusses the predisposing factors that culminate in acute presentations, so that emergency providers can recognize and be mindful of underlying causes of disease before treatment of acute illnesses. PMID- 26948265 TI - Preparing the Small Animal Hospital for Avian and Exotic Animal Emergencies. AB - Small animal veterinary hospitals will have exotic animal emergencies. Preparing the hospital space, equipment, and staff will provide optimal exotic animal emergency medicine and care. A well-gathered history can be more valuable in exotic pet medicine than most diagnostics. A gentle, well-planned approach, combined with common sense and focused observational skills, is necessary for avian and exotic patients. PMID- 26948266 TI - Emergencies and Critical Care of Commonly Kept Fowl. AB - Fowl are birds belonging to one of the 2 biological orders, the game fowl or land fowl (Galliformes) and the waterfowl (Anseriformes). Studies of anatomic and molecular similarities suggest these two groups are close evolutionary relatives. Multiple fowl species have a long history of domestication. Fowl are considered food-producing animals in most countries and clinicians should follow legislation regarding reportable diseases and antibiotic use, even if they are pets. This article reviews aspects of emergency care for most commonly kept fowl, including triage, patient assessment, diagnostic procedures, supportive care, short-term hospitalization, and common emergency presentations. PMID- 26948267 TI - Common Emergencies in Pet Birds. AB - Treating avian emergencies can be a challenging task. Pet birds often mask signs of illness until they are critically ill and require quick initiation of supportive care with minimal handling to stabilize them. This article introduces the clinician to common avian emergency presentations and details initial therapeutics and diagnostics that can be readily performed in the small-animal emergency room. Common disease presentations covered include respiratory and extrarespiratory causes of dyspnea, gastrointestinal signs, reproductive disease, neurologic disorders, trauma, and toxin exposure. The duration and severity of the avian patient's disease and the clinician's initiation of appropriate therapy often determines clinical outcome. PMID- 26948268 TI - Wildlife Emergency and Critical Care. AB - Wildlife patients often present as emergencies. For veterinarians who do not typically treat wildlife, it is important to be able to stabilize and determine the underlying cause of the animal's signs. This article discusses initial assessment, stabilization, and treatment of common emergency presentations in wild birds, reptiles, and mammals. PMID- 26948270 TI - [A pleural effusion of unusual cause]. PMID- 26948271 TI - [Differential diagnosis of aortitis]. AB - Aortitis are mainly described in inflammatory disorders such as Takayasu arteritis, giant cell arteritis or Behcet's disease. Aortitis is sometimes qualified as idiopathic. However, differential diagnoses must be searched since they need specific interventions. Infectious aortitis should be ruled out first as its rapid evolution and short-term poor prognosis makes it a therapeutic emergency. Furthermore, rarer differential diagnoses should be known as they require specific care that might sometimes differ from the treatment of inflammatory aortitis, such as retroperitoneal fibrosis mostly idiopathic but also secondary to neoplasia or malignant hemopathies. IgG4 related disease, Erdheim-Chester disease and inflammatory abdominal aortic aneurysm due to atherosclerosis are other differential diagnoses to mention in the presence of aortitis in order to adapt patients' care consequently. PMID- 26948273 TI - A sandwich-type electrochemical immunosensor based on the biotin- streptavidin biotin structure for detection of human immunoglobulin G. AB - A sandwich-type immunosensor is designed and fabricated to detect the human immunoglobulin G (HIgG) using polyaniline and tin dioxide functionalized graphene (GS-SnO2-PAN) as the platform and biotin-functionalized amination magnetic nanoparticles composite (B-Fe3O4@APTES) as the label. GS-SnO2-PAN is used as the sensing agent to capture the primary anti-HIgG (Ab1) and SnO2 reduces the stack of GS. The B-Fe3O4@APTES with a large surface area and excellent biocompatibility captures second antibody (Ab2) efficiently based on the highly selective recognition of streptavidin to biotinylated antibody. The B-Fe3O4@APTES has better electro-catalytic activity in the reduction of hydrogen peroxide (H2O2) and the "biotin-streptavidin-biotin" (B-SA-B) strategy leads to signal amplification. Under optimal conditions, the immunosensor has a wide sensitivity range from 1 pg/L to 10 ng/L and low detection limit of 0.33 pg/L (S/N = 3) for HIgG. The immunosensor has high sensitivity, fast assay rate, as well as good reproducibility, specificity, and stability especially in the quantitative detection of biomolecules in serum samples. PMID- 26948272 TI - Insulin Resistance in Human iPS Cells Reduces Mitochondrial Size and Function. AB - Insulin resistance, a critical component of type 2 diabetes (T2D), precedes and predicts T2D onset. T2D is also associated with mitochondrial dysfunction. To define the cause-effect relationship between insulin resistance and mitochondrial dysfunction, we compared mitochondrial metabolism in induced pluripotent stem cells (iPSC) from 5 healthy individuals and 4 patients with genetic insulin resistance due to insulin receptor mutations. Insulin-resistant iPSC had increased mitochondrial number and decreased mitochondrial size. Mitochondrial oxidative function was impaired, with decreased citrate synthase activity and spare respiratory capacity. Simultaneously, expression of multiple glycolytic enzymes was decreased, while lactate production increased 80%. These perturbations were accompanied by an increase in ADP/ATP ratio and 3-fold increase in AMPK activity, indicating energetic stress. Insulin-resistant iPSC also showed reduced catalase activity and increased susceptibility to oxidative stress. Thus, insulin resistance can lead to mitochondrial dysfunction with reduced mitochondrial size, oxidative activity, and energy production. PMID- 26948274 TI - Interactive dose shaping part 2: proof of concept study for six prostate patients. AB - Recently we introduced interactive dose shaping (IDS) as a new IMRT planning strategy. This planning concept is based on a hierarchical sequence of local dose modification and recovery operations. The purpose of this work is to provide a feasibility study for the IDS planning strategy based on a small set of six prostate patients. The IDS planning paradigm aims to perform interactive local dose adaptations of an IMRT plan without compromising already established valuable dose features in real-time. Various IDS tools were developed in our in house treatment planning software Dynaplan and were utilized to create IMRT treatment plans for six patients with an adeno-carcinoma of the prostate. The sequenced IDS treatment plans were compared to conventionally optimized clinically approved plans (9 beams, co-planar). For each patient, several IDS plans were created, with different trade-offs between organ sparing and target coverage. The reference dose distributions were imported into Dynaplan. For each patient, the IDS treatment plan with a similar or better trade-off between target coverage and OAR sparing was selected for plan evaluation, guided by a physician. For this initial study we were able to generate treatment plans for prostate geometries in 15-45 min. Individual local dose adaptations could be performed in less than one second. The average differences compared to the reference plans were for the mean dose: 0.0 Gy (boost) and 1.2 Gy (PTV), for D98% : -1.1 Gy and for D2% : 1.1 Gy (both target volumes). The dose-volume quality indicators were well below the Quantec constraints. However, we also observed limitations of our currently implemented approach. Most prominent was an increase of the non-tumor integral dose by 16.4% on average, demonstrating that further developments of our planning strategy are required. PMID- 26948275 TI - Physiological regulation of Syntrichia caninervis Mitt. in different microhabitats during periods of snow in the Gurbantunggut Desert, northwestern China. AB - Moss crusts, the most advanced stage of biological soil crust (BSC) development, play important roles in BSC biomass and soil surface stabilization. They usually survive freeze-thaw cycles and remain active during periods of extremely low temperatures. We selected Syntrichia caninervis Mitt., the dominant moss crust species, to study physiological characteristics in winter in three different microhabitats (under the canopy of living shrubs, under dead shrubs, and in exposed areas) in the Gurbantunggut Desert of northwestern China. The results show that soluble sugar content and antioxidant enzyme activity were significantly higher when heavy snow covered the ground in midwinter, than in early winter and late winter. Soluble protein content was highest in mosses in BSCs under shrub canopies. In contrast, antioxidant enzyme activity was at its maximum in BSCs of exposed areas. Our results indicate that moss crusts have the potential to effectively survive rapid environmental change during winter by an increase in osmoregulatory substances and by increased antioxidant enzymes activity. Mosses in BSCs in exposed areas showed the highest antioxidant enzyme activity, in direct contrast to that of mosses in BSCs growing under canopies of both dead and living shrubs. This may indicate that plants of S. caninervis growing in exposed conditions are better adapted to harsh environmental conditions than plants growing in more sheltered habitats. PMID- 26948276 TI - Synthesis, structure, and physical properties of new rare earth ferrocenoylacetonates. AB - New ferrocenoylacetonate complexes of several rare earth elements, [Ln(fca)3(bpy)].MeC6H5 (Ln = Pr (), Eu (), Gd (), Tb (), Dy (), Ho (), Y (); bpy 2,2'-bipyridine; Hfca - FcCOCH2COMe) as well as scandium ferrocenoylacetonate [Sc(fca)3].0.5MeC6H5 (), were synthesized and characterized by single crystal X ray diffraction analysis. In the crystal lattice of the isostructural complexes , two [Ln(fca)3(bpy)] molecules form a pair due to stacking interactions between the bpy ligands. The Ln(3+) ions are coordinated in a square antiprism geometry with a coordination number of 8. The Sc(3+) ions in complex are coordinated in an octahedral geometry. Thermolysis of complexes was studied under air and argon atmospheres; in the first case, it affords perovskites LnFeO3 as one of the products. Complexes display single-molecule magnet properties, and the effective relaxation barrier for the Dy complex , was found to be Deltaeff/kB = 241 K, which is one of the highest values obtained for a mononuclear beta-diketonate lanthanide complex. PMID- 26948277 TI - Use of Multiple Peptide-Based SERS Probes Binding to Different Epitopes on a Protein Biomarker To Improve Detection Sensitivity. AB - We propose an analytical strategy to improve the sensitivity for detecting a protein biomarker through signal multiplication by manipulating multiple peptide based surface-enhanced Raman scattering (SERS) probes to bind the biomarker. Protective antigen (PA) was used as an Anthrax biomarker in this study. For this purpose, five small peptides selective to various PA epitopes with different binding affinities were chosen and peptide-conjugated Au nanoparticle (AuNP) SERS probes were individually prepared using each peptide. Initially, five different SERS probes were separately used to detect PA and the sensitivities were compared. Next, the possibility of enhancing sensitivity by employing multiple SERS probes was examined. Rather than applying the probes simultaneously, which would induce competitive binding, each probe was added sequentially and an optimal probe-addition sequence was determined to provide maximal sensitivity. Finally, PA samples at seven different concentrations were measured with the optimal sequence. The limit of detection (LOD) was 0.1 aM, and the enhancement was more effective at lower PA concentrations. The proposed scheme can be further applicable to detect other protein biomarkers to diagnose various diseases. PMID- 26948278 TI - Red blood cell abnormalities and the pathogenesis of anemia in end-stage renal disease. AB - Anemia is the most common hematologic complication in end-stage renal disease (ESRD). It is ascribed to decreased erythropoietin production, shortened red blood cell (RBC) lifespan, and inflammation. Uremic toxins severely affect RBC lifespan; however, the implicated molecular pathways are poorly understood. Moreover, current management of anemia in ESRD is controversial due to the "anemia paradox" phenomenon, which underlines the need for a more individualized approach to therapy. RBCs imprint the adverse effects of uremic, inflammatory, and oxidative stresses in a context of structural and functional deterioration that is associated with RBC removal signaling and morbidity risk. RBCs circulate in hostile plasma by raising elegant homeostatic defenses. Variability in primary defect, co-morbidity, and therapeutic approaches add complexity to the pathophysiological background of the anemic ESRD patient. Several blood components have been suggested as biomarkers of anemia-related morbidity and mortality risk in ESRD. However, a holistic view of blood cell and plasma modifications through integrated omics approaches and high-throughput studies might assist the development of new diagnostic tests and therapies that will target the underlying pathophysiologic processes of ESRD anemia. PMID- 26948280 TI - Prenatal diagnosis of trisomy 21, 18 and 13 by quantitative pyrosequencing of segmental duplications. AB - Chromosomal aberration mostly occurs in chromosomes 21, 18 and 13, with an incidence approximately 1 out of 160 live births in humans, therefore making prenatal diagnosis necessary in clinics. Current methods have drawbacks such as time consuming, high cost, complicated operations and low sensitivity. In this paper, a novel method for rapid and accurate prenatal diagnosis of aneuploidy is proposed based on pyrosequencing, which quantitatively detects the peak height ratio (PHR) of different bases of segmental duplication. A direct polymerase chain reaction (PCR) approach was undertaken, where a small volume of amniotic fluid was used as the starting material without DNA extraction. Single-stranded DNA was prepared from PCR products and subsequently analyzed using pyrosequencing. The PHR between target and reference chromosome of 2.2 for euploid and 3:2 for a trisomy fetus were used as reference. The reference intervals and z scores were calculated for discrimination of aneuploidy. A total of 132 samples were collected, within trisomy 21 (n = 11), trisomy 18 (n = 3), trisomy 13 (n = 2), and unaffected controls (n = 116). A set of six segmental duplications were chosen for analysis. This method had consistent results with karyotyping analysis, a correct diagnosis with 100% sensitivity and 99.9% specificity. PMID- 26948281 TI - Staphylococcus aureus induces TGF-beta1 and bFGF expression through the activation of AP-1 and NF-kappaB transcription factors in bovine mammary gland fibroblasts. AB - Staphylococcus aureus is a common Gram-positive pathogen that causes bovine mastitis, a persistent infection of the bovine mammary gland. To better understand the importance of bovine mammary fibroblasts (BMFBs) and the roles of the TLR-NF-kappaB and TLR-AP-1 signaling pathways in the regulation of S. aureus associated mastitis and mammary fibosis, BMFBs cultured in vitro were stimulated with different concentrations of heat-inactivated S. aureus to analyze the gene and protein expression of toll-like receptor 2 (TLR2), toll-like receptor 4 (TLR4), transforming growth factor beta 1 (TGF-beta1), basic fibroblast growth factor (bFGF) as well as the protein expression of nuclear factor-kappa B (NF kappaB) and activation protein-1 (AP-1) by means of quantitative polymerase chain reaction (qPCR) and western blotting, respectively. Specific NF-kappaB and AP-1 inhibitors were also used to investigate their effects on the regulation of TGF beta1 and bFGF expression. The results indicated that, in addition to increasing mRNA and protein expression of TLR2 and TLR4, S. aureus could also upregulate TGF beta1 and bFGF mRNA expression and secretion through the activation of NF-kappaB and AP-1. The increase in TGF-beta1 and bFGF expression was shown to be inhibited by AP-1- and NF-kappaB-specific inhibitors. Taken together, S. aureus induces TGF beta1 and bFGF expression through the activation of AP-1 and NF-kappaB in BMFBs. This information offers new potential targets for the treatment of bovine mammary fibrosis. PMID- 26948282 TI - Sensory symptoms in Parkinson's disease: Clinical features, pathophysiology, and treatment. AB - Parkinson's disease (PD) is one of the most common forms of neurodegenerative disease in the elderly population and is typically manifested by motor symptoms and nonmotor symptoms and signs. Nonmotor symptoms, such as sensory symptoms, have been regarded as the significant features of this disease. These symptoms often occur in early stages of PD and influence quality of life. However, researchers suggest that the sensory symptoms of PD are frequently unrecognized by clinicians and remain untreated. The disorders include pain, olfactory disturbance, and visual dysfunction input on the underlying sensory abnormality. This Review focuses on the clinical features, pathophysiological mechanisms, and treatment strategies for sensory symptoms of PD from both clinical studies and basic research, providing a comprehensive overview of the sensory symptoms in PD. (c) 2016 Wiley Periodicals, Inc. PMID- 26948279 TI - Identification of quantitative trait loci and candidate genes for an anxiolytic like response to ethanol in BXD recombinant inbred strains. AB - Genetic differences in acute behavioral responses to ethanol contribute to the susceptibility to alcohol use disorder and the reduction of anxiety is a commonly reported motive underlying ethanol consumption among alcoholics. Therefore, we studied the genetic variance in anxiolytic-like responses to ethanol across the BXD recombinant inbred (RI) mouse panel using the light-dark transition model of anxiety. Strain-mean genetic mapping and a mixed-model quantitative trait loci (QTL) analysis replicated several previously published QTL for locomotor activity and identified several novel anxiety-related loci. Significant loci included a chromosome 11 saline anxiety-like QTL (Salanq1) and a chromosome 12 locus (Etanq1) influencing the anxiolytic-like response to ethanol. Etanq1 was successfully validated by studies with BXD advanced intercross strains and fine mapped to a region comprising less than 3.5 Mb. Through integration of genome wide mRNA expression profiles of the mesocorticolimbic reward circuit (prefrontal cortex, nucleus accumbens and ventral midbrain) across the BXD RI panel, we identified high priority candidate genes within Etanq1, the strongest of which was Ninein (Nin), a Gsk3beta-interacting protein that is highly expressed in the brain. PMID- 26948283 TI - 3D Binder-free MoSe2 Nanosheets/Carbon Cloth Electrodes for Efficient and Stable Hydrogen Evolution Prepared by Simple Electrophoresis Deposition Strategy. AB - We successfully developed a simple electrophoretic deposition (EPD) method to decorate the MoSe2 nanosheets on the carbon fiber surface of carbon cloth (MoSe2/CC). With this process, MoSe2 nanosheets can be uniformly and tightly deposited on this flexible conductor to form a 3D binder-free electrode for hydrogen evolution reaction (HER). The film thickness can also be controlled by the EPD time. Directly used as binder-free electrodes for hydrogen evolution reaction, the as-prepared 3D MoSe2/CC samples exhibit excellent catalytic activity in an acidic electrolyte (21 mA/cm(2) at an over-potential of 250 mV). Variation of MoSe2 nanosheets film thickness in the electrodes could affect the catalytic activity, and it was found that the MoSe2/CC sample prepared with 60 min EPD time shows the highest HER activity amongst these different thickness samples. Moreover, stability tests though long-term potential cycles (no degradation after 1000 continuous potential cycles) and extended electrolysis confirm the exceptional durability of the catalyst. This development offers us an attractive and active 3D electrode for electrochemical water splitting. PMID- 26948284 TI - Cardiovascular Safety of Oral p-Synephrine (Bitter Orange) in Healthy Subjects: A Randomized Placebo-Controlled Cross-over Clinical Trial. AB - Bitter orange (Citrus aurantium) extract and its primary protoalkaloid p synephrine are widely consumed in combination with multiple herbal ingredients for weight management and sports performance. p-Synephrine is also present in juices and foods derived from a variety of Citrus species. Questions exist regarding the safety of p-synephrine because of structural similarities with other biogenic amines. This study assessed the cardiovascular (stimulatory) effects of bitter orange extract (49-mg p-synephrine) given to 18 healthy subjects (nine men and nine women) in a double-blinded, placebo-controlled cross over study. Heart rates, blood pressures, and electrocardiograms were determined at baseline, 30, 60, 90 min, 2, 4 , 6, and 8 h. Blood samples were drawn at baseline, 2 h and 8 h for serum chemistries, blood cell counts, and p-synephrine and caffeine levels. No significant changes occurred in electrocardiograms, heart rates, systolic blood pressure, blood chemistries, or blood cell counts at any time point in either control or p-synephrine treated group. A small (4.5 mmHg) decrease in diastolic blood pressure occurred in the p-synephrine treated group at 60 min. No adverse effects were reported. Caffeine ingestion varied markedly among the participants. p-Synephrine does not act as a stimulant at the dose used. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26948285 TI - Poly(phenylene) and m-Terphenyl as Powerful Protecting Groups for the Preparation of Stable Organic Hydroxides. AB - Four benzimidazolium hydroxide compounds, in which the C2-position is attached to a phenyl group possessing hydrogen, bromine, methyl groups, or phenyl groups at the ortho positions, are prepared and investigated for stability in a quantitative alkaline stability test. The differences between the stability of the various protecting groups in caustic solutions are rationalized on the basis of their crystal structures and DFT calculations. The highest stability was observed for the m-terphenyl-protected benzimidazolium, showing a half-life in 3 M NaOD/CD3OD/D2O at 80 degrees C of 3240 h. A high-molecular-weight polymer analogue of this model compound is prepared that exhibits excellent mechanical properties, high ionic conductivity and ion-exchange capacity, as well as remarkable hydroxide stability in alkaline solutions: only 5% degradation after 168 h in 2 M KOH at 80 degrees C. This is the most stable hydroxide-conducting benzimidazolium polymer to date. PMID- 26948286 TI - Response to, "On the origins of the linear no-threshold (LNT) dogma by means of untruths, artful dodges and blind faith.". AB - It is not true that successive groups of researchers from academia and research institutions-scientists who served on panels of the US National Academy of Sciences (NAS)-were duped into supporting a linear no-threshold model (LNT) by the opinions expressed in the genetic panel section of the 1956 "BEAR I" report. Successor reports had their own views of the LNT model, relying on mouse and human data, not fruit fly data. Nor was the 1956 report biased and corrupted, as has been charged in an article by Edward J. Calabrese in this journal. With or without BEAR I, the LNT model would likely have been accepted in the US for radiation protection purposes in the 1950's. PMID- 26948287 TI - The risk of allowing blood donation from men having sex with men after a temporary deferral: predictions versus reality. AB - BACKGROUND: In most industrialized countries, men who had sex with men (MSM) are permanently deferred from blood donation. Some countries have adopted a temporary deferral after the MSM behavior, thus avoiding donations made during the window period of human immunodeficiency virus (HIV) infection. However, one concern with this approach is the possible increase in the number of HIV-positive donations obtained from unknowingly infected, abstinent MSM; such donations might inadvertently be made available for transfusion, a risk that was previously estimated through mathematical modeling. STUDY DESIGN AND METHODS: Model predictions were compared to the actual donor rate of HIV in three countries that went from a permanent to a temporary deferral: Australia, the United Kingdom, and Canada. RESULTS: Depending on the model, a temporary deferral should have increased the rate of HIV in the male donor pool by 73% to more than 3400%. In reality, the very low baseline rate of HIV before the change in these three countries (22 cases/year) remained unchanged 2 years after the revised policy (16 cases/year). CONCLUSION: These observations strongly suggest that a temporary deferral for MSM incurs zero risk to recipients, at least in jurisdictions where HIV epidemiology is comparable to that of countries where the change happened. PMID- 26948288 TI - Is it time to define minimally clinically important differences for patient reported outcome measures used in alcohol brief intervention studies? PMID- 26948289 TI - Abiotic and biotic interactions determine whether increased colonization is beneficial or detrimental to metapopulation management. AB - Increasing the colonization rate of metapopulations can improve persistence, but can also increase exposure to threats. To make good decisions, managers must understand whether increased colonization is beneficial or detrimental to metapopulation persistence. While a number of studies have examined interactions between metapopulations, colonization, and threats, they have assumed that threat dynamics respond linearly to changes in colonization. Here, we determined when to increase colonization while explicitly accounting for non-linear dependencies between a metapopulation and its threats. We developed patch occupancy metapopulation models for species susceptible to abiotic, generalist, and specialist threats and modeled the total derivative of the equilibrium proportion of patches occupied by each metapopulation with respect to the colonization rate. By using the total derivative, we developed a rule for determining when to increase metapopulation colonization. This rule was applied to a simulated metapopulation where the dynamics of each threat responded to increased colonization following a power function. Before modifying colonization, we show that managers must understand: (1) whether a metapopulation is susceptible to a threat; (2) the type of threat acting on a metapopulation; (3) which component of threat dynamics might depend on colonization, and; (4) the likely response of a threat-dependent variable to changes in colonization. The sensitivity of management decisions to these interactions increases uncertainty in conservation planning decisions. PMID- 26948291 TI - Double Filtration Plasmapheresis in the Treatment of Antineutrophil Cytoplasmic Autoantibody Associated Vasculitis With Severe Renal Failure: A Preliminary Study of 15 Patients. AB - Our aim was to investigate the clinical efficacy of double filtration plasmapheresis (DFPP) in the treatment of antineutrophil cytoplasmic autoantibody (ANCA) associated vasculitis (AAV) with severe renal involvement. Fifteen AAV patients who had severe renal failure (median SCr 5.6(IQR 5.2-9.0) mg/dL) and needed initial renal replacement therapy (RRT) were treated with DFPP and immunosuppressive therapy. Two plasma volumes were processed during each DFPP session. The changes of serum ANCA and renal function were investigated. After the DFPP treatment for three to five sessions, serum MPO-ANCA level decreased from 250.0 +/- 86.9 RU/mL to 70.5 +/- 64.7RU/mL (P = 0.00), with a median reduction rate of 67.6%. Eleven patients (73.3%) no longer needed from RRT 3 months after DFPP treatment, while another four patients remained on dialysis. During the follow up for median 10 (IQR 6-24) months, SCr level decreased to normal in one patient, one patient progressed into ESRD. The 1 year renal survival rate was 62.9%. Five (33.3%) patients were complicated with pulmonary infection. DFPP combined with immunosuppressive therapy could increase the renal recovery rate through rapidly decreasing serum ANCA levels for AAV patients with severe renal failure, but its clinical efficacy and impact on long-term renal survival require further studies. PMID- 26948290 TI - Power calculations and placebo effect for future clinical trials in progressive supranuclear palsy. AB - BACKGROUND: Two recent randomized, placebo-controlled trials of putative disease modifying agents (davunetide, tideglusib) in progressive supranuclear palsy (PSP) failed to show efficacy, but generated data relevant for future trials. METHODS: We provide sample size calculations based on data collected in 187 PSP patients assigned to placebo in these trials. A placebo effect was calculated. RESULTS: The total PSP-Rating Scale required the least number of patients per group (N = 51) to detect a 50% change in the 1-year progression and 39 when including patients with <= 5 years disease duration. The Schwab and England Activities of Daily Living required 70 patients per group and was highly correlated with the PSP-Rating Scale. A placebo effect was not detected in these scales. CONCLUSIONS: We propose the 1-year PSP-Rating Scale score change as the single primary readout in clinical neuroprotective or disease-modifying trials. The Schwab and England Activities of Daily Living could be used as a secondary outcome. (c) 2016 International Parkinson and Movement Disorder Society. PMID- 26948292 TI - Validating endpoints for therapeutic trials in fecal incontinence. AB - BACKGROUND: A 50% or greater reduction in the frequency of fecal incontinence (FI) recorded with daily bowel diaries is the primary endpoint in clinical trials of FI. Whether this difference is clinically important is unknown. The relationship between FI symptoms recorded with daily and weekly instruments is unknown. The contribution of psychological factors to quality of life (QOL) in FI is unclear. METHODS: Fecal incontinence severity was assessed with daily bowel diaries and periodic questionnaires (fecal incontinence severity score [FISS], FIQOL, 36-Item Short Form Health Survey [SF-36], and hospital anxiety and depression scales) for 4 weeks before and during double-blind randomization to placebo or clonidine in 44 women with FI. The reduction in FI frequency was compared to the minimal clinically important difference (MCID) computed from the FISS. Endpoints of FI were compared between daily and weekly diaries. KEY RESULTS: The FISS exceeded the MCID in 75% and 83% of patients in whom the FI frequency declined by 50-74% and >=75% respectively. Parameters of FI measured with daily and weekly instruments were significantly correlated. The daily parameters explained 71% of the inter-patient variation in the FISS. The SF-36 health scores, rather than the FISS rating, explained a majority of the inter subject variation in FIQOL. CONCLUSIONS & INFERENCES: Most patients who report a >=50% reduction in FI frequency experience a clinically important improvement. Weekly questionnaires accurately assess the severity of FI. Self-reported physical and mental health explained a greater proportion of the variance in FIQOL than FI symptom severity. PMID- 26948293 TI - Perfluoroalkylated substances (PFASs) and legacy persistent organic pollutants (POPs) in halibut and shrimp from coastal areas in the far north of Norway: Small survey of important dietary foodstuffs for coastal communities. AB - Halibut (Hippoglossus hippoglossus) and shrimps (Pandalus borealis) are regular foodstuffs for communities in northern Norway and important species for the coastal fishing industry. This is the first study to present a comprehensive overview of the contaminant status of these species, with emphasis on unregulated perfluoroalkylated substances (PFAS). The contaminant concentrations were low and within tolerable levels for human dietary exposure. Median Sigmapolychlorinated biphenyls (PCB) were 4.9 and 2.5ng/g ww for halibut and unpeeled shrimps, respectively. Concentrations of perfluorooctane sulfonate (PFOS) - the most abundant PFASs - were 0.9 and 2.7ng/g ww in halibut and shrimp, respectively. The halibut fillets were dominated by PCBs, which contributed to 50% of the total POPs load, followed by SigmaDDTs; 26% and PFASs (18%), whereas shrimps were dominated by PFASs (74%). SigmaPBDEs (polybrominated diphenyl ethers) contributed to 1-4% of the total POP load. Local sources are not contributing significantly to the contaminant burden in these species. PMID- 26948295 TI - Expression of androgen-producing enzyme genes and testosterone concentration in Angus and Nellore heifers with high and low ovarian follicle count. AB - Follicle population is important when animals are used in assisted reproductive programs. Bos indicus animals have more follicles per follicular wave than Bos taurus animals. On the other hand, B taurus animals present better fertility when compared with B indicus animals. Androgens are positively related with the number of antral follicles; moreover, they increase growth factor expression in granulose cells and oocytes. Experimentation was designed to compare testosterone concentration in plasma, and follicular fluid and androgen enzymes mRNA expression (CYP11A1, CYP17A1, 3BHSD, and 17BHSD) in follicles from Angus and Nellore heifers. Heifers were assigned into two groups according to the number of follicles: low and high follicle count groups. Increased testosterone concentration was measured in both plasma and follicular fluid of Angus heifers. However, there was no difference within groups. Expression of CYP11A1 gene was higher in follicles from Angus heifers; however, there was no difference within groups. Expression of CYP17A1, 3BHSD, and 17BHSD genes was higher in follicles from Nellore heifers, and expression of CYP17A1 and 3BHSD genes was also higher in HFC groups from both breeds. It was found that Nellore heifers have more antral follicles than Angus heifers. Testosterone concentration was higher in Angus heifers; this increase could be associated with the increased mRNA expression of CYP11A1. Increased expression of androgen-producing enzyme genes (CYP17A1, 3BHSD, and 17BHSD) was detected in Nellore heifers. It can be suggested that testosterone is acting through different mechanisms to increase follicle development in Nellore and improve fertility in Angus heifers. PMID- 26948294 TI - Phylogeny of Symbiodinium populations in zoantharians of the northern Persian Gulf. AB - Zoantharians of the Persian Gulf (PG) experience periods of anomalous high temperature, irradiance and desiccation. Their survival largely relies on the symbiotic relationship with single celled dinoflagellates of the genus Symbiodinium. However, the phylogeny of symbionts of zoantharians has not been investigated in the region. In this study, the second internal transcribed spacer region of ribosomal DNA (ITS2) was used to recognize in hospite populations of Symbiodinium in Palythoa aff. mutuki, Palythoa tuberculosa and Zoanthus sansibaricus colonies from Hengam, Kish, Larak, and Qeshm Islands, in the PG. The results showed subclade D1-4 and a variant of A1, were the most prevalent subclades of Symbiodinium. Predominance of stress tolerant subclade D1-4 and putatively radiation tolerant variant of A1 of Symbiodinium in zoantharian species might suggest an adaptation strategy to the extreme physical environment of the PG. PMID- 26948296 TI - Effect of antifreeze glycoprotein 8 supplementation during vitrification on the developmental competence of bovine oocytes. AB - The purpose of this study was to investigate the effect of antifreeze glycoprotein 8 (AFGP8) supplementation during vitrification on the survival, fertilization, and embryonic development of bovine oocytes and the underlying molecular mechanism(s). Survival, fertilization, early embryonic development, apoptosis, DNA double-strand breaks, reactive oxygen species levels, meiotic cytoskeleton assembly, chromosome alignment, and energy status of mitochondria were measured in the present experiments. Compared with that in the nonsupplemented group; survival, monospermy, blastocyst formation rates, and blastomere counts were significantly higher in the AFGP8-supplemented animals. Oocytes of the latter group also presented fewer double-strand breaks and lower cathepsin B and caspase activities. Rates of normal spindle organization and chromosome alignment, actin filament impairment, and mitochondrial distribution were significantly higher in the AFGP8-supplemented group. In addition, intracellular reactive oxygen species levels significantly decreased in the AFGP8 supplemented groups, maintaining a higher DeltaPsim than that in the nonsupplemented group. Taken together, these results indicated that supplementation with AFGP8 during vitrification has a protective effect on bovine oocytes against chilling injury. PMID- 26948297 TI - Incidence of mammary tumors in the canine population living in the Veneto region (Northeastern Italy): Risk factors and similarities to human breast cancer. AB - Although mammary gland tumors (MT) are the most-common type of tumor in intact female dogs, there is little information about their incidence in dog population. Data on MT in female dogs was retrieved from the Animal Tumor registry of dogs and cats of Venice and Vicenza provinces during 2005-2013 and was analyzed to visualize crude incidence rates by breed and across age categories. Overall, 2744 mammary tumors were reported accounting for 54% of all tumors in female dogs. The annual incidence rate (IR) was 250 cases per 100,000 dogs. The most frequent malignant tumors were complex carcinomas, consisting of both epithelial and myoepithelial tissues (IR=71.89), and simple carcinomas (IR=62.59). The MT incidence rate increased through the study period; particularly in the last 4 years, and malignant neoplasms occurred more frequently (70%) than the benign counterparts (30%). Seventy-four percent of tumors were diagnosed in intact females, and the mean age at diagnosis was significantly higher for spayed dogs than for intact ones. MT were less frequent in dogs younger than 6 years and increased up to approximately 60% for ages between 8 and 13 years. The purebred dogs had a higher probability to have a malignant neoplasm than mixed-breed dogs, particularly in dogs younger than 7 years, and the Samoyed, Dobermann, Schnauzer and Yorkshire Terrier breeds were more inclined to develop malignant MT. The incidence of MT in dogs is increasing, and IRs are comparable to that in women. The epidemiological similarities between dogs and women support the validity of canine MT as a model for human breast cancer. PMID- 26948298 TI - Interspecies spread of Staphylococcus aureus clones among companion animals and human close contacts in a veterinary teaching hospital. A cross-sectional study in Greece. AB - Staphylococcus aureus and methicillin-resistant S. aureus (MRSA) prevalence among companion animals and veterinary personnel (VP) was investigated. Strains' molecular characteristics were evaluated in order to assess S. aureus transmission. Specimens (224) from colonized and infected sites of 102 animals (92 dogs, 10 cats) and 18 VP were collected during 2012 and 2013. Antibiotic susceptibility was performed by the disk diffusion method and Etest. mecA, mecC, tst (toxic shock syndrome toxin) and lukF/lukS-PV (Panton-Valentine leukocidin, PVL) genes were investigated by PCR. Genotypes were identified by Multi Locus Sequence Typing (MLST), Staphylococcal Cassette Chromosome mec (SCCmec), accessory gene regulator group (agr), spa and Pulsed Field Gel Electrophoresis (PFGE). S. aureus prevalence among pets and VP was 36.3% (37/102) and 38.9% (7/18), respectively. Younger companion animals, those living in rural areas, having a disease upon admission or Coagulase-negative staphylococci co-carriage showed significantly higher prevalence of S. aureus isolation (p<0.05). Twenty six pets and five VP carried PVL-positive S. aureus. In total, 60 S. aureus strains were recovered (53 from pets, seven from VP) of which 16 were MRSA (26.7%), 12 mecA- and four mecC-positive. MRSA showed higher resistance rates against other antimicrobials as compared to methicillin-susceptible ones. Strains were classified by MLST in 13 STs, with the predominance of ST80 and ST15. In MRSA, SCCmec types II, IV and XI were identified. The most frequent spa types were t5559 and t7558. Fifty-six strains were classified into 15 PFGE types. Comparison of genetic markers shows that identical or very similar strains disseminate among animals and VP. Companion animals harbor PVL-positive clones constituting a possible source for transmission to humans. PMID- 26948299 TI - Current Topics on Salvage Thoracic Surgery in Patients with Primary Lung Cancer. AB - Salvage primary tumor resection is sometimes considered for isolated local failures after definitive chemoradiation, urgent matters, such as hemoptysis (palliative intent), and in cases judged to be contraindicated for chemotherapy or definite radiation due to severe comorbidities, despite an initial clinical diagnosis of stage III or IV disease. However, salvage surgery is generally considered to be technically more difficult, with a potentially higher morbidity. This review discusses the current topics on salvage thoracic surgery such as the definition of salvage surgery and its outcome, and future perspectives. PMID- 26948300 TI - Predictors of metastasis to lymph nodes posterior to the right recurrent laryngeal nerve in differentiated thyroid carcinoma: A prospective study. AB - OBJECTIVES: To study the clinicopathological characteristics and the risk factors of lymph nodes posterior to the right recurrent laryngeal nerve (LN-prRLN) metastasis in differentiated thyroid carcinoma; and to identify the indication for LN-prRLN dissection. METHODS: We treated 145 patients with differentiated thyroid carcinoma with appropriate surgical intervention. The specimens were examined by the pathologists. The right paratracheal lymph nodes were divided into two groups: anterior or posterior to right recurrent laryngeal nerve (VIa or VIp compartment, respectively). We recorded the clinical characteristics, histopathological features of the primary tumors, and lymph node metastasis of the patients. The results were statistically analyzed. RESULTS: There were 85 patients (58.6%) with central lymph node metastasis, of whom 61 (42.1%) had metastasis in VIa compartment; 16 patients (11.0%) had VIp subdistrict metastasis; and 25 patients had lateral lymph node metastasis. Multiplicity, larger tumor (>=1 cm), and coexistence of central lymph node metastasis, VIa compartment metastasis, and lateral lymph node metastasis were all significantly related with LN-prRLN metastasis, while sex, age, location of the tumor, and extrathyroid extension of the tumor showed no significant relation (p > 0.05). CONCLUSION: The incidence of LN-prRLN metastasis was lower than other central lymph nodes, as well as lymph nodes anterior to right recurrent laryngeal nerve. When there were multiple foci of tumors, or the tumor was larger than 1 cm, or central or lateral LN metastasis was indicated by preoperative ultrasound or confirmed by intraoperative frozen sections, it is strongly recommended that exploration and dissection of the LN-prRLN should only be performed by experienced surgeons. PMID- 26948301 TI - Dysplasia, not malignancy, present in a 41-year-old colonic interposition flap. PMID- 26948302 TI - How transient alterations of organelles in mammalian cells submitted to electric field may explain some aspects of gene electrotransfer process. AB - Electric pulses can be used to transiently permeabilize the cell plasma membrane. This method is nowadays employed as a safe and efficient means to deliver therapeutic molecules into target cells and tissues. Despite the large bulk of literature on this topic, there is a lack of knowledge about the mechanism(s) of molecule delivery. The behavior of the cells both while the field is on and after its application is indeed not well described. Questions about cell organelle alterations remain unanswered. We report here evidence for a number of ultrastructural alterations in mammalian cells exposed to electric pulses. Specifically, CHO cells were subjected to trains of 10 pulses lasting 5ms using an electric field of 800V/cm, i.e. under conditions leading both to membrane permeabilization, gene transfer and expression. Cells were observed to undergo morphological alterations of the mitochondria and nucleus. These modifications, detected in the minutes following pulse delivery, were transient. They may have direct consequences on molecule delivery and therefore may explain various aspects of the mechanisms of DNA electrotransfer. PMID- 26948303 TI - [Management of avoidable acute transfers from an intermediate care geriatric facility to acute hospitals: critical aspects of an intervention protocol]. AB - OBJECTIVE: The unplanned transfers (UT) from post-acute intermediate care facilities, are associated with adverse outcomes for patients, and a significant cost to the system. We present a practical protocol and the design of an intervention study aimed at reducing avoidable UT from a geriatric post-acute rehabilitation setting to acute care hospitals. PATIENTS AND METHODS: A quasi experimental non randomized study. The intervention consists in: 1) protocol for early detection of symptoms in order to conduct a pro-active management of decompensation; 2) an advanced care planning structured protocol for the acute decompensations. We will compare the intervention group with a parallel and a historical cohort for demographic, functional, cognitive, comorbidity and social variables. OUTCOME: number of UT to acute care hospitals. DISCUSSION: This is a quasi-experimental study, focused on everyday care practice that intends to assess the impact of multi-disciplinary and multi-factorial intervention to reduce UT from a post-acute rehabilitation unit. We expect that the project results will be useful for future randomized and controlled studies. PMID- 26948304 TI - Tranexamic Acid for Prevention PPH: a Promising Drug But Today Only a Promising Drug. PMID- 26948305 TI - Oral Contraceptive Use and Prevalence of Self-Reported Glaucoma or Ocular Hypertension in the United States. AB - PURPOSE: To investigate the association between oral contraceptive (OC) use and glaucoma prevalence in the United States. DESIGN: Cross-sectional study. PARTICIPANTS: A total of 3406 female participants, aged 40 years or older, from the 2005 to 2008 National Health and Nutrition Examination Survey, who reported a presence or absence of glaucoma or ocular hypertension completed both the vision and the reproductive health questionnaires and underwent eye examinations. METHODS: Multivariate regression analysis was used to assess the correlation between OC use and self-reported glaucoma or ocular hypertension (n = 231 cases), controlling for potential confounders, including age, ethnicity, systemic comorbidities such as hypertension and stroke, ocular diseases such as cataract and diabetic retinopathy, and reproductive health factors, including age at menopause, age at menarche, history of hormone replacement therapy, and gynecological surgical history. MAIN OUTCOME MEASURES: The outcome variable was self-reported glaucoma or ocular hypertension. RESULTS: After adjusting for confounders, those with >=3 years of OC use had greater odds (odds ratio, 1.94; 95% confidence interval, 1.22-3.07) of self-reported glaucoma or ocular hypertension. Other factors associated with higher glaucoma or ocular hypertension prevalence included older age, African American race, and later age at menarche. CONCLUSIONS: Oral contraceptive use may be associated with increased risk of self-reported glaucoma or ocular hypertension. PMID- 26948306 TI - Glaucoma Patient Treatment Preferences. PMID- 26948308 TI - Director orientations in lyotropic liquid crystals: diffusion MRI mapping of the Saupe order tensor. AB - The macroscopic physical properties of a liquid crystalline material depend on both the properties of the individual crystallites and the details of their spatial arrangement. We propose a diffusion MRI method to estimate the director orientations of a lyotropic liquid crystal as a spatially resolved field of Saupe order tensors. The method relies on varying the shape of the diffusion-encoding tensor to disentangle the effects of voxel-scale director orientational order and the local diffusion anisotropy of the solvent. Proof-of-concept experiments are performed on water in lamellar and reverse hexagonal liquid crystalline systems with intricate patterns of director orientations. PMID- 26948307 TI - ISOLD: A New Highly Sensitive Interleukin Score for Intraocular Lymphoma Diagnosis. PMID- 26948309 TI - Reversible Interactions of Proteins with Mixed Shell Polymeric Micelles: Tuning the Surface Hydrophobic/Hydrophilic Balance toward Efficient Artificial Chaperones. AB - Molecular chaperones can elegantly fine-tune its hydrophobic/hydrophilic balance to assist a broad spectrum of nascent polypeptide chains to fold properly. Such precious property is difficult to be achieved by chaperone mimicking materials due to limited control of their surface characteristics that dictate interactions with unfolded protein intermediates. Mixed shell polymeric micelles (MSPMs), which consist of two kinds of dissimilar polymeric chains in the micellar shell, offer a convenient way to fine-tune surface properties of polymeric nanoparticles. In the current work, we have fabricated ca. 30 kinds of MSPMs with finely tunable hydrophilic/hydrophobic surface properties. We investigated the respective roles of thermosensitive and hydrophilic polymeric chains in the thermodenaturation protection of proteins down to the molecular structure. Although the three kinds of thermosensitive polymers investigated herein can form collapsed hydrophobic domains on the micellar surface, we found distinct capability to capture and release unfolded protein intermediates, due to their respective affinity for proteins. Meanwhile, in terms of the hydrophilic polymeric chains in the micellar shell, poly(ethylene glycol) (PEG) excels in assisting unfolded protein intermediates to refold properly via interacting with the refolding intermediates, resulting in enhanced chaperone efficiency. However, another hydrophilic polymer-poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC) severely deteriorates the chaperone efficiency of MSPMs, due to its protein resistant properties. Judicious combination of thermosensitive and hydrophilic chains in the micellar shell lead to MSPM-based artificial chaperones with optimal efficacy. PMID- 26948310 TI - 4-Phenylbutyric acid regulates CCl4-induced acute hepatic dyslipidemia in a mouse model: A mechanism-based PK/PD study. AB - Endoplasmic reticulum (ER) stress and associated protein aggregation are closely associated with human diseases, including alterations in hepatic lipid metabolism. Inhibition of ER stress can have a significant effect on the prevention of hepatic dyslipidemia. Here, we studied the role of 4-phenylbutyric acid (4-PBA), a chemical chaperone, on ER stress-induced hepatic lipid accumulation. We studied ER stress induction following CCl4 exposure and delineated mechanisms of the CCl4-induced ER stress response in liver tissue from mice. CCl4 affected the formation of disulfide bonds through excessive hyper oxidation of protein disulfide isomerase (PDI). Increased complex formation between PDI and its client proteins persisted in CCl4-exposed samples. Conversely, 4-PBA inhibited ER stress via secretion of apolipoprotein B and prevention of hepatic lipid accumulation. We also studied the mechanism-based pharmacokinetic and pharmacodynamic profiles and identified the ER stress-related proteins GRP78 and CHOP, along with plasma apolipoprotein B and triglyceride levels, as novel biomarkers of ER stress-induced hepatic lipid accumulation. ER stress and its clinical relevance for therapeutic approaches were well correlated with the activity of the ER stress regulator 4-PBA, which may be a promising drug candidate for the treatment of hepatic lipid accumulation, such as hepatic steatosis. PMID- 26948312 TI - The interaction between histamine H1 receptor and MU- opioid receptor in scratching behavior in ICR mice. AB - In this study, we examined the interaction between histamine H1 receptor and MU opioid receptor in scratching behavior in ICR mice. Both histamine and morphine caused scratching and simultaneous injection of histamine and morphine had an additive effect. Chlorpheniramine and naloxone inhibited histamine-induced scratching behavior. These two drugs also inhibited morphine-induced scratching behavior. Simultaneous injection of chlorpheniramine and naloxone caused a significant inhibition of histamine-induced scratching compared with separate injections. The same findings were also noted for morphine-induced scratching. These results strongly indicate a close relationship between histamine H1 receptor and MU-opioid receptor in scratching behavior in ICR mice. PMID- 26948313 TI - Pharmacology of novel intraocular pressure-lowering targets that enhance conventional outflow facility: Pitfalls, promises and what lies ahead? AB - Intraocular pressure (IOP) lowering drugs that are approved for the treatment of glaucoma and ocular hypertension have limited activity on increasing aqueous humor movement through the trabecular meshwork and Schlemm's canal (TM/SC). The TM/SC complex is considered the conventional outflow pathway and is a primary site of increased resistance to aqueous humor outflow in glaucoma. Novel mechanisms that enhance conventional outflow have shown promise in IOP reduction via modulation of several pathways including Rho kinase, nitric oxide/soluble guanylate cyclase/cGMP, adenosine A1, prostaglandin EP4/cAMP, and potassium channels. The clinical translatability of these pharmacological modulators based on pre-clinical efficacy models is currently being explored. In addition, identification of pathways from GWAS and other studies involving transgenic rodent models with elevated/reduced IOP phenotypes have begun to yield additional insights into IOP regulation and serve as a source for the next generation of IOP lowering targets. Lastly, improvements in drug delivery technologies to enable sustained IOP reduction are also discussed. PMID- 26948314 TI - Involvement of opioid receptors in the systemic and peripheral antinociceptive actions of montelukast in the animal models of pain. AB - This study aimed to investigate the involvement of opioid receptors in the systemic and peripheral antinociceptive activities of montelukast in different animal models of pain. Rats and mice were injected with montelukast to produce analgesia. The formalin and acetic acid-induced writhing tests were used to assess the nociceptive activity. The results showed that i.p. administration of montelukast (0.3-10mg/kg) dose-dependently reduced flinching behavior in both the first and second phases of formalin test with mean ED50 of 0.55 and 5.31mg/kg, respectively. Also, intraplantar administration of montelukast (3-30MUg/paw) produced antinociception against the two phases of formalin assay in a dose dependent way with mean ED30 of 2.92 and 8.11MUg/paw, respectively. Furthermore, pre-treatment with naloxone (a non-selective opioid receptor antagonist) significantly inhibited both the systemic and also peripheral antinociceptive actions of montelukast in formalin test. In writhing test, the results showed that intraperitoneal administration of montelukast (3-10mg/kg) significantly reduced the writhe number induced by acetic acid in mice. Moreover, co administration of non-effective doses of montelukast (0.3 and 1mg/kg; i.p.) and morphine (0.25mg/kg; i.p.) significantly decreased the writhes number induced by acetic acid. Also, this effect was naloxone-reversible. These findings suggest that the systemic and peripheral antinociception produced by montelukast were mediated through the opioid receptors in central and peripheral nervous systems. Moreover, combination of montelukast and morphine could be noted as a new strategy for pain relief. PMID- 26948315 TI - Treatment for neovascular age related macular degeneration: The state of the art. AB - With the introduction in the clinical practice of drugs inhibiting vascular endothelial growth factor (VEGF) the visual outcomes of patients with neovascular age related macular degeneration (AMD) dramatically improved. Since 2006 repeated intravitreal injections of anti-VEGF became the standard of care for the treatment of neovascular AMD. This review provides an overview of available data form clinical trials supporting the use of anti-VEGF molecules for the treatment of this condition. Several questions remain open, in particular the regimen of treatment, the frequency of injection, the safety of the different drugs, and the poor response to the treatment in some cases. Therefore, new agents and alternative delivery are currently under evaluation. PMID- 26948311 TI - Targeting the complement system for the management of retinal inflammatory and degenerative diseases. AB - The retina, an immune privileged tissue, has specialized immune defense mechanisms against noxious insults that may exist in diseases such as age-related macular degeneration (AMD), diabetic retinopathy (DR), uveoretinitis and glaucoma. The defense system consists of retinal innate immune cells (including microglia, perivascular macrophages, and a small population of dendritic cells) and the complement system. Under normal aging conditions, retinal innate immune cells and the complement system undergo a low-grade activation (parainflammation) which is important for retinal homeostasis. In disease states such as AMD and DR, the parainflammatory response is dysregulated and develops into detrimental chronic inflammation. Complement activation in the retina is an important part of chronic inflammation and may contribute to retinal pathology in these disease states. Here, we review the evidence that supports the role of uncontrolled or dysregulated complement activation in various retinal degenerative and angiogenic conditions. We also discuss current strategies that are used to develop complement-based therapies for retinal diseases such as AMD. The potential benefits of complement inhibition in DR, uveoretinitis and glaucoma are also discussed, as well as the need for further research to better understand the mechanisms of complement-mediated retinal damage in these disease states. PMID- 26948316 TI - Effects of baclofen and raclopride on reinstatement of cocaine self administration in the rat. AB - At present there is no satisfactory treatment against relapse of drug-seeking behavior. Relapse can be modeled in laboratory animals using reinstatement procedures, whereby previously extinguished self-administration for a drug is reinstated by different factors, such as exposure to cues or drug priming. It is thought that activation of gamma-aminobutyric acid (GABA) B receptor complexes could represent a promising approach to pharmacotherapy for diminishing relapse potential with drugs possessing reinforcing properties. The effects of baclofen (a prototypic GABAB receptor agonist) on cue-induced cocaine reinstatement were evaluated in the rat with or without a priming injection of cocaine. The effects of raclopride (an antagonist of dopamine D2 receptors) were also evaluated. Cue induced reinstatement under vehicle resulted in a significant increase in the number of presses on the active lever, as compared with extinction lever responding. This effect was accentuated in rats receiving a priming injection of cocaine (cocaine-plus-cue-induced reinstatement). Baclofen, at doses without effects on food-motivated operant behavior (2.5 and 5mg/kg i.p.), dose dependently decreased the number of active lever presses during cue-induced reinstatement. Baclofen had slightly weaker effects on cocaine-plus-cue-induced reinstatement. Raclopride (0.08 and 0.15 mg/kg s.c.) had similar effects against cue-induced reinstatement although it failed to inhibit cocaine-plus-cue-induced reinstatement at the lower dose. Baclofen dose-dependently and selectively decreased reinstatement of cocaine self-administration. The data obtained provide support for the potential anti-craving efficacy of baclofen in the treatment of cocaine drug-seeking. PMID- 26948319 TI - History and pre-history of optotypes: From Alcor and Mizar to the ETDRS optotype. PMID- 26948318 TI - Salidroside-regulated lipid metabolism with down-regulation of miR-370 in type 2 diabetic mice. AB - Salidroside is known for its pharmacological properties and in particular its antioxidation effects. In recent years, it has been recognized that salidroside plays an important role in treating diabetes. Accumulated evidence suggests that microRNAs may be involved in diabetic lipid disorders. We investigated how salidroside regulates lipid metabolism through miR-370 in vivo and in vitro. After 4 weeks of a high-fat diet, and intraperitoneal injection of streptozotocin (100mg/kg), type 2 diabetes was induced in male C56BL/6J mice. After 4 weeks, mice with fasting blood glucose levels above 7.8mmol/l were divided into five groups: those with diabetes mellitus, and those treated with 40mg/kg, 80mg/kg, and 160mg/kg salidroside, and metformin (480mg/kg), for a further 4 weeks. The hypoglycemic effects of salidroside were consistently demonstrated when measuring fasting blood glucose levels, observing insulin-sensitizing effects, and testing oral glucose tolerance. In addition to this, the expressions of miR-370, and related lipid protein expression in primary hepatocytes, were examined in primary type 2 diabetic mice. The present study has shown that the expression levels of miR-370, SREBP-1 and FAS-1 were significantly elevated in the liver of type 2 diabetic mice. In contrast, the elevated expression levels were reversed by salidroside. The addition of salidroside attenuated the effect of miR-370, and reduced the expression of these lipid metabolism proteins in primary hepatocytes. These findings demonstrate that salidroside can directly decrease the expression of miR-370 in type 2 diabetic mice, and particularly in primary hepatocytes, affecting lipid metabolism in the liver. PMID- 26948317 TI - Antithrombotic activities of ferulic acid via intracellular cyclic nucleotide signaling. AB - Ferulic acid (FA) produces protective effects against cardiovascular dysfunctions. However, the mechanisms of FA is still not known. Here we examined the antithrombotic effects of FA and its potential mechanisms. Anticoagulation assays and platelet aggregation was evaluated in vitro and in vivo. Thromboxane B2 (TXB2), cyclic adenosine monophosphate(cAMP), and cyclic guanosine monophosphate (cGMP) was determined using enzyme immunoassay kits. Nitric oxide (NO) production was measured using the Griess reaction. Protein expression was detected by Western blotting analysis. Oral administration of FA prevented death caused by pulmonary thrombosis and prolonged the tail bleeding and clotting time in mice,while, it did not alter the coagulation parameters, including the activated partial thromboplastin time (APTT), prothrombin time (PT), and thrombin time (TT). In addition, FA (50-200 uM) dose-dependently inhibited platelet aggregation induced by various platelet agonists, including adenosine diphosphate (ADP), thrombin, collagen, arachidonic acid (AA), and U46619. Further, FA attenuated intracellular Ca(2)(+) mobilization and TXB2 production induced by the platelet agonists. FA increased the levels of cAMP and cGMP and phosphorylated vasodilator-stimulated phosphoprotein (VASP) while decreased phospho-MAPK (mitogen-activated protein kinase) and phosphodiesterase (PDE) in washed rat platelets, VASP is a substrate of cyclic nucleotide and PDE is an enzyme family responsible for hydrolysis of cAMP/cGMP. These results suggest that antithrombotic activities of FA may be regulated by inhibition of platelet aggregation, rather than through inhibiting the release of thromboplastin or formation of thrombin. The mechanism of this action may involve activation of cAMP and cGMP signaling. PMID- 26948320 TI - Artifacts Affecting Musculoskeletal Magnetic Resonance Imaging: Their Origins and Solutions. AB - Among articles within the radiology literature, few present the manifestations of magnetic resonance imaging artifacts in a clinically oriented manner. Recognizing such artifacts is imperative given the increasing clinical use of magnetic resonance imaging and the emphasis by the American Board of Radiology on practical physics applications. The purpose of this article is to present magnetic resonance physics principles visually and conceptually in the context of common musculoskeletal radiology artifacts and their solutions, described using nonmathematical explanations. PMID- 26948321 TI - [Diagnostic, therapeutic, and prognostic aspects of typhoid intestinal perforations in Dapaong, Togo]. AB - PURPOSE: This study's aim is to describe the diagnostic, therapeutic, and prognostic aspects of typhoid intestinal perforations (TIP) at the Dapaong regional hospital (Togo). MATERIAL AND METHODS: This retrospective study covered all patients with such perforations seen and managed in the Dapaong regional hospital's general surgery department during the 3-year period of 2009-2011. RESULTS: There were 110 patients with TIP during the study period, and they accounted for 67.9% of the patients treated for generalized peritonitis (162 cases). Their mean age was 10.2 years. The sex-ratio was 1.4. A single perforation was present for 69 patients (62.7%) and multiple perforations for the other 41 (37.3%). Sixty (54.5%) patients underwent simple closure, 36 (32.8%) had an ileal resection and enteroanastomosis, and 14 (12.7%) had loop or double barrelled ileostomy. The postoperative course was complicated in 26 cases (23.6%), most often by surgical site infection, seen in 19 patients (17.3%). Overall, 23 patients died during the postoperative period, for a mortality rate of 20.9%. CONCLUSION: Typhoid intestinal perforations are the most common cause of generalized peritonitis at the Dapaong regional hospital. Most patients have only a single perforation, which is repaired by excision-suture. Their morbidity and mortality rate are high. PMID- 26948322 TI - Pasture intake and milk production of dairy cows rotationally grazing on multi species swards. AB - Increasing plant species diversity has been proposed as a means for enhancing annual pasture productivity and decreasing seasonal variability of pasture production facing more frequent drought scenarios due to climate change. Few studies have examined how botanical complexity of sown swards affects cow performance. A 2-year experiment was conducted to determine how sward botanical complexity, from a monoculture of ryegrass to multi-species swards (MSS) (grasses legumes-forb), affect pasture chemical composition and nutritive value, pasture dry matter (DM) intake, milk production and milk solids production of grazing dairy cows. Five sward species: perennial ryegrass (L as Lolium), white clover and red clover (both referred to as T as Trifolium because they were always sown together), chicory (C as Cichorium) and tall fescue (F as Festuca) were assigned to four grazing treatments by combining one (L), three (LT), four (LTC) or five (LTCF) species. Hereafter, the LT swards are called mixed swards as a single combination of ryegrass and clovers, whereas LTC and LTCF swards are called MSS as a combination of at least four species from three botanical families. The experimental area (8.7 ha) was divided into four block replicates with a mineral nitrogen fertilisation of 75 kg N/ha per year for each treatment. In total, 13 grazing rotations were carried out by applying the same grazing calendar and the same pasture allowance of 19 kg DM/cow per day above 4 cm for all treatments. Clover represented 20% of DM for mixed and MSS swards; chicory represented 30% of DM for MSS and tall fescue represented 10% of DM for LTCF swards. Higher milk production (+1.1 kg/day) and milk solids production (+0.08 kg/day) were observed for mixed swards than for ryegrass swards. Pasture nutritive value and pasture DM intake were unaffected by the inclusion of clover. Pasture DM, organic matter and NDF concentrations were lower for MSS than for mixed swards. Higher milk production (+0.8 kg/day), milk solids production (+0.04 kg/day) and pasture DM intake (+1.5 kg DM/day) were observed for MSS than for mixed swards. These positive effects of MSS were observed for all seasons, but particularly during summer where chicory proportion was the highest. In conclusion, advantages of grazing MSS on cow performance were due to the cumulative effect of improved pasture nutritive value and increased pasture DM intake that raised milk production and milk solids production. PMID- 26948323 TI - Developments in SPR Fragment Screening. AB - INTRODUCTION: Fragment-based approaches have played an increasing role alongside high-throughput screening in drug discovery for 15 years. The label-free biosensor technology based on surface plasmon resonance (SPR) is now sensitive and informative enough to serve during primary screens and validation steps. AREAS COVERED: In this review, the authors discuss the role of SPR in fragment screening. After a brief description of the underlying principles of the technique and main device developments, they evaluate the advantages and adaptations of SPR for fragment-based drug discovery. SPR can also be applied to challenging targets such as membrane receptors and enzymes. EXPERT OPINION: The high-level of immobilization of the protein target and its stability are key points for a relevant screening that can be optimized using oriented immobilized proteins and regenerable sensors. Furthermore, to decrease the rate of false negatives, a selectivity test may be performed in parallel on the main target bearing the binding site mutated or blocked with a low-off-rate ligand. Fragment based drug design, integrated in a rational workflow led by SPR, will thus have a predominant role for the next wave of drug discovery which could be greatly enhanced by new improvements in SPR devices. PMID- 26948324 TI - Progress in Drug Treatment of Cerebral Edema. AB - Cerebral edema causes intracranial hypertension (ICH) which leads to severe outcome of patients in the clinical setting. Effective anti-edema therapy may significantly decrease the mortality in a variety of neurological conditions. At present drug treatment is a cornerstone in the management of cerebral edema. Osmotherapy has been the mainstay of pharmacologic therapy. Mannitol and hypertonic saline (HS) are the most commonly used osmotic agents. The relative safety and efficacy of HS and mannitol in the treatment of cerebral edema and reduction of enhanced ICP have been demonstrated in the past decades. Apart from its osmotic force, HS exerts anti-edema effects partly through inhibition of Na(+)-K(+)-2Cl(-) Cotransporter-1 (NKCC1) and aquaporin 4 (AQP4) expression in astrocytes. Melatonin may also reduce brain edema and exert neuroprotective effect on several central nervous system diseases through inhibition of inflammatory response. The inhibitors of Na/H exchanger, NKCC and AQP4 may attenuate brain edema formation through inhibition of excessive transportation of ion and water from blood into the cerebral tissue. In this review we survey some of the most recent findings in the drug treatment of brain edema focusing on the use of osmotherapy, melatonin and inhibitors of ion cotransporters and water channels. A better understanding of the molecular mechanism of these agents would help to improve in the clinical management of patients with brain edema. PMID- 26948327 TI - Individualized CT Angiography Protocols for the Evaluation of the Aorta: A Feasibility Study. AB - PURPOSE: Ionizing radiation and iodinated contrast media are potential drawbacks to repetitive follow-up CT angiography in current practice. The aim of the present study was to optimize radiation dose and contrast agent volume by using individualized CT angiography protocols. MATERIALS AND METHODS: Eighty consecutive patients referred for CT angiography of the whole aorta were prospectively evaluated. Patients were divided into groups of patients with a body mass index (BMI) < 28 kg/m(2) (group 1; n = 50) and those with a BMI >= 28 kg/m(2) (group 2; n = 30). A control group consisted of 50 consecutive patients who were retrospectively evaluated. CT angiography parameters on a second generation dual-source scanner were 128 * 0.6-mm collimation, pitch of 0.9, rotation time of 0.33 seconds, tube voltages of 80/100/120 kVp (group 1/group 2/control), reference tube current of 400 mA, and image reconstruction at 1 mm/0.8-mm slice thickness (kernels, B30f [control] and I30f/strength 3 [groups 1/2]). The control group received 120 mL of contrast agent (300 mgI/mL) at 4.8 mL/s; groups 1 and 2 received 44 mL and 53 mL at 3.3 mL/s and 4 mL/s, respectively. Effective dose was evaluated for each patient. Image quality was determined by qualitative image analysis at the levels of the thoracic, abdominal, and pelvic aorta as nondiagnostic, diagnostic, good, or excellent, and quantitative image analysis was performed, including attenuation values and contrast-to-noise ratio (CNR). RESULTS: Mean effective radiation dose values for CT angiography of the aorta were 3.7 mSv +/- 0.7 in group 1, 6.7 mSv +/- 1.4 in group 2, and 8.7 mSv +/- 1.9 in the control group (P < .001). Mean attenuation values and CNR levels were 334 HU +/- 66 and 16 +/- 8, respectively, in group 1, 277 HU +/- 56 and 14 +/- 5 in group 2, and 305 HU +/- 77 and 11 +/- 4 in the control group. CONCLUSIONS: Iterative reconstruction algorithms resulted in 23% 57% less radiation in combination with 55%-63% less contrast agent volume compared with standard CT protocols. PMID- 26948326 TI - The Role of Repeat Administration of Adventitial Delivery of Lentivirus-shRNA Vegf-A in Arteriovenous Fistula to Prevent Venous Stenosis Formation. AB - PURPOSE: To determine if a second dose of a lentivirus mediated small hairpin RNA that inhibits Vegf-A gene expression (LV-shRNA-Vegf-A) can improve lumen vessel area (LVA) of the outflow vein of an arteriovenous fistula (AVF) and decrease venous neointimal hyperplasia. MATERIALS AND METHODS: Chronic kidney disease was created in C57BL/6 mice; 28 days later, an AVF was created by connecting the right carotid artery to the ipsilateral jugular vein. Immediately after AVF creation, 5 * 10(6) plaque-forming units of LV-shRNA-Vegf-A or control shRNA was administered to the adventitia of the outflow vein, and a second dose of the same treatment was administered 14 days later. Animals were sacrificed at 21 days, 28 days, and 42 days after AVF creation for reverse transcription polymerase chain reaction and histomorphometric analyses. RESULTS: By day 21, there was a 125% increase in the average LVA (day 21, P = .11), with a decrease in cell proliferation (day 21, P = .0079; day 28, P = .28; day 42, P = .5), decrease in alpha-smooth muscle cell actin staining (day 21, P < .0001; day 28, P < .05; day 42, P = .59), and decrease in hypoxic stress (day 21, P < .001; day 28, P = .28; day 42, P = .46) in LV versus control shRNA vessels. CONCLUSIONS: A second dose of LV-shRNA-Vegf-A administration results in a moderate improvement in LVA at day 21. PMID- 26948328 TI - Assessing the Risk of Hemorrhagic Complication following Transjugular Liver Biopsy in Bone Marrow Transplantation Recipients. AB - PURPOSE: To determine if recipients of bone marrow transplants (BMTs) are at increased risk of hemorrhagic complications following transjugular liver biopsy (TJLB). MATERIALS AND METHODS: TJLBs in BMT and non-BMT patients between January 2007 and July 2014 were reviewed. Patient demographic and pre- and postprocedural laboratory data were reviewed. Mean platelet count and International Normalized Ratio were 174,300 * 10(3)/uL +/- 107.3 (standard deviation) and 1.2 +/- 0.4, respectively, for BMT recipients, compared with 88,100 * 10(3)/uL +/- 70.9 and 1.2 +/- 0.5, respectively, for non-BMT. Patients in whom hemoglobin level decreased by > 1 g/dL and/or required transfusion within 15 days of TJLB were reviewed to determine the presence of a biopsy-related hemorrhagic complication. RESULTS: A total of 1,600 TJLBs in 1,120 patients were analyzed. Of these, 183 TJLBs in 159 BMT recipients and 1,417 TJLBs in 961 patients non-BMT patients were performed. Thirteen TJLBs were complicated by hemorrhage: five in BMT (2.9%) and eight in the non-BMT cohorts (0.6%; P < .01). Preprocedural platelet counts were within normal range (57-268 * 10(3)/uL) in all but one patient (8 * 10(3)/uL). BMT recipients had an odds ratio of 4.9 (95% confidence interval, 1.25-17.3) for post-TJLB bleeding/hemorrhage compared with those without BMTs (P < .01). CONCLUSIONS: TJLB continues to be a safe procedure in the vast majority of patients. However, hemorrhagic complications occurred at a rate of 2.9% in BMT recipients, compared with 0.6% in patients without BMTs, and therefore caution should be exercised when performing TJLB in this group. PMID- 26948329 TI - Types of Research Bias Encountered in IR. AB - Bias is a systemic error in studies that leads to inaccurate deductions. Relevant biases in the field of IR and interventional oncology were identified after reviewing articles published in the Journal of Vascular and Interventional Radiology and CardioVascular and Interventional Radiology. Biases cited in these articles were divided into three categories: preinterventional (health care access, participation, referral, and sample biases), periinterventional (contamination, investigator, and operator biases), and postinterventional (guarantee-time, lead time, loss to follow-up, recall, and reporting biases). PMID- 26948338 TI - IdealKnock: A framework for efficiently identifying knockout strategies leading to targeted overproduction. AB - In recent years, computer aided redesigning methods based on genome-scale metabolic network models (GEMs) have played important roles in metabolic engineering studies; however, most of these methods are hindered by intractable computing times. In particular, methods that predict knockout strategies leading to overproduction of desired biochemical are generally unable to do high level prediction because the computational time will increase exponentially. In this study, we propose a new framework named IdealKnock, which is able to efficiently evaluate potentials of the production for different biochemical in a system by merely knocking out pathways. In addition, it is also capable of searching knockout strategies when combined with the OptKnock or OptGene framework. Furthermore, unlike other methods, IdealKnock suggests a series of mutants with targeted overproduction, which enables researchers to select the one of greatest interest for experimental validation. By testing the overproduction of a large number of native metabolites, IdealKnock showed its advantage in successfully breaking through the limitation of maximum knockout number in reasonable time and suggesting knockout strategies with better performance than other methods. In addition, gene-reaction relationship is well considered in the proposed framework. PMID- 26948339 TI - Phenotypes of intimate partner violence among women experiencing infertility in Kano, Northwest Nigeria. AB - OBJECTIVE: To determine the prevalence of and risk factors for intimate partner violence (IPV) among women attending a large urban fertility clinic in Kano, Nigeria. METHODS: Interviewers administered questionnaires to a cross-section of women attending an infertility clinic in Northwest Nigeria, regarding their experience of IPV and associated factors. RESULTS: In total, 373 individuals were interviewed. Of the individuals interviewed, 134 (35.9%; 95% confidence Interval [CI] 31.1%-41.0%) had experienced at least one form of IPV in the preceding year. Of the 134 patients who had encountered violence, 126 (94.0%), 111 (82.8%), 47 (35.1%), and 25 (18.7%) had experienced psychological, sexual, verbal, and physical forms of violence, respectively. Of the affected individuals, 34 (25.4%) experienced multiple forms of violence, with spouses being the main perpetrators. A lack of formal education (adjusted odds ratio [OR] 2.21; 95%CI 1.21-7.43), employment in the informal sector (OR 2.01; 95%C: 1.02-4.52), and having an unemployed spouse (OR 1.56; 95%CI 1.02-3.15) or one with low level of education (OR 2.32; 95%CI 1.87-4.21) were independently associated with IPV. CONCLUSION: In this setting, women who were infertile experienced a high incidence of IPV. Women presenting at fertility clinics should be screened for IPV and provided with links to appropriate support services. PMID- 26948330 TI - Association of FTO and near MC4R variants with obesity measures in urban and rural dwelling Sri Lankans. AB - OBJECTIVES: To investigate the association between the fat mass and obesity related (FTO) gene rs9939609 and near melanocortin-4-receptor (MC4R) gene rs17782313 polymorphisms with obesity measures and metabolic parameters in urban and rural dwelling Sri Lankans. METHODS: 535 subjects (60.9% female) from the general adult population (ages 18-70 years) representative of both urban (28.4%) and rural areas of residence were recruited by multi-stage random sampling. Body mass index (BMI), waist circumference (WC) and waist-to-hip ratio (WHR) was obtained by standard methods. DNA extracted from whole blood was genotyped using real-time PCR. RESULTS: The FTO risk genotypes (AA+AT) were associated with higher BMI (p=0.03) and WC (p=0.05) measures as well as categorical obesity (BMI >=27.5kgm-2 definition) (OR 1.69 95% CI 1.11-2.56, p=0.01). The near MC4R risk genotypes (CC+CT) were associated with greater BMI (p=0.03) as well as categorical obesity (BMI >=25kgm-2 definition) (OR 1.57 95% CI 1.11-2.22, p=0.01). In addition the MC4R risk genotype carriers (CC+CT) had significantly higher fasting blood sugar (FBS) levels compared to the 'TT' genotype carriers independent of BMI (p=0.05). Urban living was associated with significantly greater BMI values for FTO risk genotypes compared to rural living (p=0.02). CONCLUSIONS: FTO and near MC4R variants are associated with obesity measures in Sri Lankan populations whilst urban living accentuates the obesogenic effect of the FTO polymorphism. PMID- 26948340 TI - Prevalence of repeat pregnancies and associated factors among teenagers in KwaZulu-Natal, South Africa. AB - OBJECTIVE: To determine the prevalence of repeat teenage pregnancy and the interval between first/most recent and repeat pregnancies, as well as to evaluate the sexual/reproductive health characteristics of teenagers with repeat pregnancies. METHODS: A prospective observational study was undertaken at a hospital in KwaZulu-Natal, South Africa, between May and September 2013. Teenagers aged 13-19years who were pregnant, had recently delivered, or had terminated a pregnancy were enrolled. A questionnaire was used to obtain data. RESULTS: Among 341 participants, 281 (82.4%) were seen for a first pregnancy and 60 (17.6%) for a repeat pregnancy. The interval between first/most recent and repeat pregnancies was 24months or lower in 45 (75.0%) of repeat pregnancy participants. Only 58 (17.0%) participants had previously used contraception (54 [93.1%] of whom stopped within 12months) and 28 (8.2%) had used emergency contraception. More participants with repeat pregnancy than with first pregnancy had a positive HIV status (18 [30.0%] vs 26 [9.3%]; P<0.001), more than one sexual partner in the past 12months (21 [35.0%] vs 35 [12.5%]; P<0.001), and a partner at least 5years older (38 [63.3%] vs 128 [45.6%]; P<0.001). CONCLUSION: High repeat pregnancy rates, low contraception use, and high HIV prevalence among teenagers in South Africa is worrying. Focused interventions targeting teenagers following their first pregnancy need to be urgently implemented. PMID- 26948341 TI - Transperineal ultrasonography for measuring cervical length during preterm labor. PMID- 26948343 TI - Dynamic of expression and localization of cannabinoid-degrading enzymes FAAH and MGLL in relation to CB1 during meiotic maturation of human oocytes. AB - The endogenous cannabinoid system has been characterized in some female reproductive organs but little is known about the expression and localization pattern of cannabinoid-degrading enzymes in relation to the CB1 cannabinoid receptor in human oocytes. In this study, we focus on the investigation of the presence and differential distribution of fatty acid amide hydrolase (FAAH) and monoglyceride lipase (MGLL) in relation to CB1 during the maturation of human oocytes. We used a total of 290 human oocytes not suitable for in vitro fertilization/intracytoplasmic sperm injection (ICSI): germinal-vesicle (GV) and metaphase-I (MI) stages and metaphase-II (MII) oocytes that had not developed into an embryo after ICSI. Cannabinoid-degrading enzymes and the cannabinoid CB1 receptor were present in human oocytes. Specifically, FAAH was detected in the periphery of the oocyte from the GV to MI stage and co-localized with CB1. Later, by the MII stage, FAAH was spread within the oocyte, whereas MGLL immunostaining was homogeneous across the oocyte at all stages of maturation and only overlapped with CB1 at the GV stage. This coordinated redistribution of cannabinoid system proteins suggests a role for this system in the maturation of the female gamete. PMID- 26948344 TI - Continuum modeling of hydrodynamic particle-particle interactions in microfluidic high-concentration suspensions. AB - A continuum model is established for numerical studies of hydrodynamic particle particle interactions in microfluidic high-concentration suspensions. A suspension of microparticles placed in a microfluidic channel and influenced by an external force, is described by a continuous particle-concentration field coupled to the continuity and Navier-Stokes equation for the solution. The hydrodynamic interactions are accounted for through the concentration dependence of the suspension viscosity, of the single-particle mobility, and of the momentum transfer from the particles to the suspension. The model is applied on a magnetophoretic and an acoustophoretic system, respectively, and based on the results, we illustrate three main points: (1) for relative particle-to-fluid volume fractions greater than 0.01, the hydrodynamic interaction effects become important through a decreased particle mobility and an increased suspension viscosity. (2) At these high particle concentrations, particle-induced flow rolls occur, which can lead to significant deviations of the advective particle transport relative to that of dilute suspensions. (3) Which interaction mechanism that dominates, depends on the specific flow geometry and the specific external force acting on the particles. PMID- 26948345 TI - Epidemiology. AB - More than 250,000 new cases of primary malignant brain tumors are diagnosed annually worldwide, 77% of which are gliomas. A small proportion of gliomas are caused by the inheritance of rare high-penetrance genetic variants or high-dose radiation. Since 2009, inherited genetic variants in 10 regions near eight different genes have been consistently associated with glioma risk via genome wide association studies. Most of these variants increase glioma risk by 20-40%, but two have higher relative risks. One on chromosome 8 increases risk of IDH mutated gliomas sixfold and another that affects TP53 function confers a 2.5-fold increased risk of glioma. Functions of some of the other risk variants are known or suspected, but future research will determine functions of other risk loci. Recent progress also has been made in defining subgroups of glioma based on acquired alterations within tumors. Allergy history has been consistently associated with reduced glioma risk, though the mechanisms have not yet been clarified. Future studies will need to be large enough so that environmental and constitutive genetic risk factors can be examined within molecularly defined, etiologically homogeneous subgroups. PMID- 26948346 TI - Presenting signs and symptoms in brain tumors. AB - Focal symptoms and signs occurring during brain tumor clinical presentation are dependent on a number of factors. Location and rate of growth are the most critical, followed by overall lesion size and nature, whether infiltrating or causing the displacement of neural structures, but also the presence or extent of associated pathology, including edema, hemorrhage, vascular compromise, and cerebrospinal fluid obstruction. Mechanisms of presenting symptomatology can be divided into tumor and peritumoral factors. Tumor factors include histology, for example, in that seizures are common in patients with certain low-grade gliomas. Peritumoral factors, including regional hypoxia and ionic changes in the peritumoral zone, may influence neuronal activity and extracellular glutamate may be associated with neuronal hyperexcitability. Blood-brain barrier breakdown may predispose to seizure and localized neuronal dysfunction. Finally, signs and symptoms in brain tumors can be generalized, associated with increased intracranial brain pressure, but can also be localized, based on the involvement of the major structures of the central nervous system. PMID- 26948347 TI - Neuroimaging. AB - Imaging is integral to the management of patients with brain tumors. Conventional structural imaging provides exquisite anatomic detail but remains limited in the evaluation of molecular characteristics of intracranial neoplasms. Quantitative and physiologic biomarkers derived from advanced imaging techniques have been increasingly utilized as problem-solving tools to identify glioma grade and assess response to therapy. This chapter provides a comprehensive overview of the imaging strategies used in the clinical assessment of patients with gliomas and describes how novel imaging biomarkers have the potential to improve patient management. PMID- 26948348 TI - Surgical approaches for the gliomas. AB - Neurosurgical intervention remains the first step in effective glioma management. Mounting evidence suggests that cytoreduction for low- and high-grade gliomas is associated with a survival benefit. Beyond conventional neurosurgical principles, an array of techniques have been refined in recent years to maximize the effect of the neurosurgical oncologist and facilitate the impact of subsequent adjuvant therapy. With intraoperative mapping techniques, aggressive microsurgical resection can be safely pursued even when tumors occupy essential functional pathways. Other adjunct techniques, such as intraoperative magnetic resonance imaging, intraoperative ultrasonography, and fluorescence-guided surgery, can be valuable tools to safely reduce the tumor burden of low- and high-grade gliomas. Taken together, this collection of surgical strategies has pushed glioma extent of resection towards the level of cellular resolution. PMID- 26948349 TI - Histologic classification of gliomas. AB - Gliomas form a heterogeneous group of tumors of the central nervous system (CNS) and are traditionally classified based on histologic type and malignancy grade. Most gliomas, the diffuse gliomas, show extensive infiltration in the CNS parenchyma. Diffuse gliomas can be further typed as astrocytic, oligodendroglial, or rare mixed oligodendroglial-astrocytic of World Health Organization (WHO) grade II (low grade), III (anaplastic), or IV (glioblastoma). Other gliomas generally have a more circumscribed growth pattern, with pilocytic astrocytomas (WHO grade I) and ependymal tumors (WHO grade I, II, or III) as the most frequent representatives. This chapter provides an overview of the histology of all glial neoplasms listed in the WHO 2016 classification, including the less frequent "nondiffuse" gliomas and mixed neuronal-glial tumors. For multiple decades the histologic diagnosis of these tumors formed a useful basis for assessment of prognosis and therapeutic management. However, it is now fully clear that information on the molecular underpinnings often allows for a more robust classification of (glial) neoplasms. Indeed, in the WHO 2016 classification, histologic and molecular findings are integrated in the definition of several gliomas. As such, this chapter and Chapter 6 are highly interrelated and neither should be considered in isolation. PMID- 26948350 TI - Molecular classification of gliomas. AB - The identification of distinct genetic and epigenetic profiles in different types of gliomas has revealed novel diagnostic, prognostic, and predictive molecular biomarkers for refinement of glioma classification and improved prediction of therapy response and outcome. Therefore, the new (2016) World Health Organization (WHO) classification of tumors of the central nervous system breaks with the traditional principle of diagnosis based on histologic criteria only and incorporates molecular markers. This will involve a multilayered approach combining histologic features and molecular information in an "integrated diagnosis". We review the current state of diagnostic molecular markers for gliomas, focusing on isocitrate dehydrogenase 1 or 2 (IDH1/IDH2) gene mutation, alpha-thalassemia/mental retardation syndrome X-linked (ATRX) gene mutation, 1p/19q co-deletion and telomerase reverse transcriptase (TERT) promoter mutation in adult tumors, as well as v-raf murine sarcoma viral oncogene homolog B1 (BRAF) and H3 histone family 3A (H3F3A) aberrations in pediatric gliomas. We also outline prognostic and predictive molecular markers, including O6-methylguanine DNA methyltransferase (MGMT) promoter methylation, and discuss the potential clinical relevance of biologic glioblastoma subtypes defined by integration of multiomics data. Commonly used methods for individual marker detection as well as novel large-scale DNA methylation profiling and next-generation sequencing approaches are discussed. Finally, we illustrate how advances in molecular diagnostics affect novel strategies of targeted therapy, thereby raising new challenges and identifying new leads for personalized treatment of glioma patients. PMID- 26948351 TI - Next-generation molecular diagnostics. AB - The classification of brain tumors is based on the time-honored tradition of histologic examination, coupled with clinicopathologic correlation, and is based on the fundamental importance of microscopic morphologic interpretation. Supplementation by immunohistochemical markers is of substantial value to distinguish related entities and to confirm morphologic impressions. The use of techniques such as fluorescent in situ hybridization (FISH) is also critical in specific situations. However, with these practices, it is clear that the use of state-of-the-art molecular techniques has great promise to add to classification to (1) reduce the subjectivity inherent in interobserver discordance, particularly with specific entities; and (2) elucidate the biologic diversity of entities that are not resolvable by routine methods. In this chapter, we discuss these possibilities, focusing on several tumor types affecting the central nervous system, including diffuse glioma and ependymoma. PMID- 26948352 TI - Principles of radiation therapy. AB - Although resection remains the mainstay in the treatment of gliomas, microscopically complete resection of most central nervous system tumors remains challenging, and is, in fact, rarely accomplished. Considering their invasive nature, gross total resections to clearly negative margins often do or would require removal or transection of functional brain, with likely serious neurologic deficits. Consequently, radiotherapy has emerged as an indispensable component of therapy. It is delivered primarily by external-beam radiotherapy or brachytherapy techniques. Herein, we present the biologic principles, techniques, and applications of radiotherapy in glioma treatment today. PMID- 26948353 TI - Principles of pharmacotherapy. AB - This chapter will review the challenges in pharmacotherapy in primary brain tumors that include the presence of the blood-brain barrier, a blood-tumor barrier, active drug efflux pumps, and high plasma protein binding of agents. The approaches to improve the delivery of drugs to the brain will be discussed. Often the management of brain tumors involves the use of corticosteroids and enzyme inducing antiseizure medications that can have significant drug interactions that may impact the efficacy or toxicity of drugs used to treat these patients. Various techniques used to assess drug distribution to the brain will be reviewed. PMID- 26948354 TI - Principles of immunotherapy. AB - Gliomas are the most common primary brain tumors of the central nervous system, and carry a grim prognosis. Novel approaches utilizing the immune system as adjuvant therapy are quickly emerging as viable and effective options. Immunotherapeutic strategies being investigated to treat glioblastoma include: vaccination therapy targeted against either specific tumor antigens or whole tumor lysate, adoptive cellular therapy with cytotoxic T lymphocytes, chimeric antigen receptors and bi-specific T-cell engaging antibodies allowing circumvention of major histocompatibility complex restriction, aptamer therapy with aims for more efficient target delivery, and checkpoint blockade in order to release the tumor-mediated inhibition of the immune system. Given the heterogeneity of glioblastoma and its ability to gain mutations throughout the disease course, multifaceted treatment strategies utilizing multiple forms of immunotherapy in combination with conventional therapy will be most likely to succeed moving forward. PMID- 26948355 TI - Experimental therapies: gene therapies and oncolytic viruses. AB - Glioblastoma is the most common and aggressive primary brain tumor in adults. Over the past three decades, the overall survival time has only improved by a few months, therefore novel alternative treatment modalities are needed to improve clinical management strategies. Such strategies should ultimately extend patient survival. At present, the extensive insight into the molecular biology of gliomas, as well as into genetic engineering techniques, has led to better decision processes when it comes to modifying the genome to accommodate suicide genes, cytokine genes, and tumor suppressor genes that may kill cancer cells, and boost the host defensive immune system against neoantigenic cytoplasmic and nuclear targets. Both nonreplicative viral vectors and replicating oncolytic viruses have been developed for brain cancer treatment. Stem cells, microRNAs, nanoparticles, and viruses have also been designed. These have been armed with transgenes or peptides, and have been used both in laboratory-based experiments as well as in clinical trials, with the aim of improving selective killing of malignant glioma cells while sparing normal brain tissue. This chapter reviews the current status of gene therapies for malignant gliomas and highlights the most promising viral and cell-based strategies under development. PMID- 26948356 TI - Complications of glioma surgery. AB - Even with current advances in adjunctive therapies, including radiation, chemotherapy, and various clinical trials of gene therapy and immunotherapy, surgical resection remains one of the most effective treatment for intra-axial gliomas. Survival in these patients has been shown to be related to the extent of resection. In some cases, it can provide cures of long-term remission; in others, it can provide disease control when combined with the above adjunctive treatments. However, surgical resection carries its own risks and complications. These complications can be broadly divided into neurologic, regional, and systemic, including direct cortical and vascular injury, surgical wound complications, and postsurgical medical complications. Certain patient characteristics, including Karnofsky performance status score (KPS) and pathology of the tumor, have been shown to have an impact on the risk of postsurgical complications. Advancement in preoperative and intraoperative adjunct technology such as cortical mapping and navigation has improved the surgeon's ability to safely and maximally resect the tumors. It is therefore important to understand the perioperative complications after craniotomy and tumor resection and factors affecting morbidity and mortality in order for surgeons to optimally select and counsel patients who will benefit the most from surgical resection. This chapter will focus on the complications associated with craniotomy for intrinsic glioma and ways of avoiding these events. PMID- 26948357 TI - Complications from radiotherapy. AB - Radiotherapy (RT) of the brain is associated with significant stigma in the neuro oncology community. This is primarily because of the potentially severe complications with which it may be associated. These complications, especially in subacute and latent settings, are often unpredictable, potentially progressive, and irreversible. The onset of complications may start from the first fraction of 2 Gy, continuing over several months after end of RT with persistent drowsiness and apathy. It may also extend over many years with progressive onset of neurocognitive impairments such as memory decline, and diminished focus/attention. For long-term survivors, such as young patients irradiated for a favorable low-grade glioma, quality of life can be seriously impacted by RT. It is essential, as in the pediatric field, to propose patient-specific regimens from the very outset of therapy. The use of molecular biomarkers to better predict survival, control of comorbidities along with judicious use of medications such as steroids and antiepileptics, improved targeting with the help of modern imaging and RT techniques, modulation of the dose, and fractionation aimed at limiting integral dose to the healthy brain all have the potential to minimize treatment-related complications while maintaining the therapeutic efficacy for which RT is known. Sparing "radiosensitive" areas such as hippocampi could have a modest but measurable impact with regard to cognitive preservation, an effect that can possibly be enhanced when used in conjunction with memantine and/or donepezil. PMID- 26948358 TI - Complications from pharmacotherapy. AB - The pharmacotherapy management of cancers of the nervous system has significant overlap with systemic solid cancers that may utilize similar drugs or agents. There is however a unique aspect related to central nervous system (CNS) cancers where therapies directed against a malignant process may have enhanced toxicities or toxicities unique to the CNS. In addition, many agents used to treat CNS malignancies have unique CNS toxicities that may require a specific intervention. This chapter attempts to review conventional and biologic therapies utilized for CNS malignancies and characterize expected and, if known, unique toxicities. PMID- 26948359 TI - Vascular complications in glioma patients. AB - Vascular complications in patients with glioma most commonly include venous and arterial thromboembolism; however, treatment-induced vasculopathies are also problematic, especially in long-term survivors. The interactions between treatment such as radiation and chemotherapy, the coagulation cascade, endothelium, and regulators of angiogenesis are complex, drive glioma growth and invasion, and create common management problems in the clinic. We review the incidence of thrombotic complications in glioma, the biology of the coagulome as related to glioma progression, prevention and treatment of thrombosis, the role of anticoagulants as anticancer therapy, and vascular complications such as ischemic stroke and intracranial bleeding. The coagulation cascade is intimately involved in cancer-related thrombosis, glioma progression, and vascular complications of glioma therapy. Tissue factor is the principal initiator of coagulation and is upregulated in a glioma subtype-specific fashion. Short-term (perioperative) antithrombotic prophylaxis is effective, but long-term anticoagulation, although attractive, is not routinely indicated. Most patients with symptomatic venous thromboembolism can be safely anticoagulated, including those on anti-vascular endothelial growth factor therapeutics such as bevacizumab. Initial therapy should include low-molecular-weight heparin, and protracted anticoagulant treatment, perhaps indefinitely, is indicated. Many complex interactions resulting in vessel wall injury can lead to ischemic stroke, intracranial and intratumoral hemorrhage, and long-term sequelae such as cognitive impairment. PMID- 26948362 TI - Psycho-oncology. AB - Psycho-oncologic care for glioma patients has two important aspects. First, clinical decision making regarding treatment of the tumor should reflect a sound balance between quality and quantity of life. Second, supportive care should be targeted at the symptoms that are most detrimental to perceived quality of life (QOL) of glioma patients, and of their informal caregivers. In this chapter we will first focus on the definition of QOL and the ways of measuring this adequately in clinical trials, and then discuss the impact of the disease itself, and of established and experimental treatment modalities on perceived QOL. Subsequently, we will discuss frequently occurring symptoms that have an impact on the perceived QOL of glioma patients and their caregivers. This will include what is known about the efficacy of symptomatic treatment and maintaining or improving QOL in both patients and caregivers, followed by recommendations for future directions of clinical care and research. PMID- 26948361 TI - Rehabilitation of patients with glioma. AB - Disabling sequelae occur in a majority of patients diagnosed with brain tumor, including glioma, such as cognitive deficits, weakness, and visual perceptual changes. Often, multiple impairments are present concurrently. Healthcare staff must be aware of the "biographic disruption" the patient with glioma has experienced. While prognostic considerations factor into rehabilitation goals and expectations, regardless of prognosis the treatment team must offer cohesive support, facilitating hope, function, and quality of life. Awareness of family and caregiver concerns plays an important role in the overall care. Inpatient rehabilitation, especially after surgical resection, has been shown to result in functional improvement and homegoing rates on a par with individuals with other neurologic conditions, such as stroke or traumatic brain injury. Community integration comprises a significant element of life satisfaction, as has been shown in childhood glioma survivors. Employment is often affected by the glioma diagnosis, but may be ameliorated, when appropriate, by addressing modifiable factors such as depression, fatigue, or sleep disturbance, or by workplace accommodations. Further research is needed into many facets of rehabilitation in the setting of glioma, including establishing better care models for consistently identifying and addressing functional limitations in this population, measuring outcomes of various levels of rehabilitation care, identifying optimal physical activity strategies, delineating the long-term effects of rehabilitation interventions, and exploring impact of rehabilitation interventions on caregiver burden. The effective elements of cognitive rehabilitation, including transition of cognitive strategies to everyday living, need to be better defined. PMID- 26948363 TI - Palliative care at the end-of-life in glioma patients. AB - The end-of-life (EOL) phase of patients with a glioma starts when symptom prevalence increases and antitumor treatment is no longer effective. During the EOL phase, care is primarily aimed at reducing symptom burden while maintaining quality of life as long as possible without inappropriate prolongation of life. Palliative care during the EOL phase also involves complex medical decisions for the prevention and relief of suffering. We discuss the prevalence and treatment of the most common EOL symptoms, decision making in the EOL phase, the organization of EOL care, and the role of the patient's caregiver. Treating disease-specific symptoms, such as impaired consciousness, seizures, focal neurologic deficits and cognitive disturbances, is a major concern during the EOL phase, as these symptoms may interfere with EOL decision making. Advance care planning is aimed at reaching consensus about possible EOL decisions between all participants, respecting the values of patients and their informal caregivers. In order to prevent the possibility that the patient becomes incompetent to make informed decisions, we recommend initiating EOL conversations at a relatively early stage in the disease course. PMID- 26948364 TI - Pilocytic astrocytomas. AB - Pilocytic astrocytoma (PA) is the most common pediatric brain tumor in children. PAs are a distinct histologic and biologic subset of glioma that have a slow growth rate and may even spontaneously regress. These tumors tend to arise in the cerebellum and chiasmatic/hypothalamic region, but can also occur in other regions of the central nervous system. Dissemination is uncommon, but may occur in newly diagnosed PAs. Alterations in the Ras/RAF/mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway (Ras/ERK) have been discovered in a majority of PAs, with KIAA1549-BRAF fusions being the most commonly identified alteration. Children with neurofibromatosis 1 are predisposed to developing PAs, primarily within the optic pathway. When required, treatment consists of surgery, chemotherapy, and/or radiation, although new molecular agents targeting the Ras/ERK and related signaling pathways are promising new approaches. The 10-year survival rates are greater than 90% in pediatric patients; however, they are poorer in adults. Tumors that are amenable to complete resection (i.e., cerebellum and cortex) have the best overall survival. PMID- 26948365 TI - Astrocytic gliomas WHO grades II and III. AB - World Health Organization grades II and III lower-grade astrocytomas are a challenging area in neuro-oncology. One the one hand, for proper diagnosis, the analysis of molecular factors, especially mutation status of isocitrate dehydrogenase and 1p/19q status in the tumor status needs to be done in addition to classical neuropathology. Further, the high clinical and prognostic value of a maximal safe resection requires a profound knowledge of presurgical diagnosis and surgical as well as imaging techniques to ensure optimal outcome for patients. Also medical treatment may be more intensive than previously believed, with randomized trials providing evidence for a benefit in overall survival by combined chemoradiation versus radiation alone. A critical problem concerns the considerable undesirable effects of therapeutic interventions on long-term health related quality of life, cognitive and functional outcome as well as future developments in this still difficult disease that will need to be addressed in future trials. PMID- 26948360 TI - Epilepsy and brain tumors. AB - Seizures are common in patients with brain tumors, and epilepsy can significantly impact patient quality of life. Therefore, a thorough understanding of rates and predictors of seizures, and the likelihood of seizure freedom after resection, is critical in the treatment of brain tumors. Among all tumor types, seizures are most common with glioneuronal tumors (70-80%), particularly in patients with frontotemporal or insular lesions. Seizures are also common in individuals with glioma, with the highest rates of epilepsy (60-75%) observed in patients with low grade gliomas located in superficial cortical or insular regions. Approximately 20-50% of patients with meningioma and 20-35% of those with brain metastases also suffer from seizures. After tumor resection, approximately 60-90% are rendered seizure-free, with most favorable seizure outcomes seen in individuals with glioneuronal tumors. Gross total resection, earlier surgical therapy, and a lack of generalized seizures are common predictors of a favorable seizure outcome. With regard to anticonvulsant medication selection, evidence-based guidelines for the treatment of focal epilepsy should be followed, and individual patient factors should also be considered, including patient age, sex, organ dysfunction, comorbidity, or cotherapy. As concomitant chemotherapy commonly forms an essential part of glioma treatment, enzyme-inducing anticonvulsants should be avoided when possible. Seizure freedom is the ultimate goal in the treatment of brain tumor patients with epilepsy, given the adverse effects of seizures on quality of life. PMID- 26948366 TI - Low-grade and anaplastic oligodendroglioma. AB - Anaplastic oligodendrogliomas have long attracted interest because of their sensitivity to chemotherapy, in particular in the subset of 1p/19q co-deleted tumors. Recent molecular studies have shown that all 1p/19q co-deleted tumors have IDH mutations and most of them also have TERT mutations. Because of the presence of similar typical genetic alterations in astrocytoma and glioblastoma, the current trend is to diagnose these tumors on the basis of their molecular profile. Further long-term follow-up analysis of both EORTC and RTOG randomized studies on (neo)adjuvant procarbazine, lomustine, vincristine (PCV) chemotherapy have shown that adjuvant chemotherapy indeed improves outcome, and this is now standard of care. It is also equally clear that benefit to PCV chemotherapy is not limited to the 1p/19q co-deleted cases; potential other predictive factors are IDH mutations and MGMT promoter methylation. Moreover, a recent RTOG study on low-grade glioma also noted an improved outcome after adjuvant PCV chemotherapy, thus making (PCV) chemotherapy now standard of care for all 1p/19q co-deleted tumors regardless of grade. It remains unclear whether temozolomide provides the same survival benefit, as no data from well-designed clinical trials on adjuvant temozolomide in this tumor type are available. Another question that remains is whether one can safely leave out radiotherapy as part of initial treatment to avoid cognitive side-effects of radiotherapy. The current data suggest that delaying radiotherapy and treatment with chemotherapy only may be detrimental for overall survival. PMID- 26948367 TI - Glioblastoma. AB - Glioblastoma is the most common and aggressive primary brain tumor in adults. Defining histopathologic features are necrosis and endothelial proliferation, resulting in the assignment of grade IV, the highest grade in the World Health Organization (WHO) classification of brain tumors. The classic clinical term "secondary glioblastoma" refers to a minority of glioblastomas that evolve from previously diagnosed WHO grade II or grade III gliomas. Specific point mutations of the genes encoding isocitrate dehydrogenase (IDH) 1 or 2 appear to define molecularly these tumors that are associated with younger age and more favorable outcome; the vast majority of glioblastomas are IDH wild-type. Typical molecular changes in glioblastoma include mutations in genes regulating receptor tyrosine kinase (RTK)/rat sarcoma (RAS)/phosphoinositide 3-kinase (PI3K), p53, and retinoblastoma protein (RB) signaling. Standard treatment of glioblastoma includes surgery, radiotherapy, and alkylating chemotherapy. Promoter methylation of the gene encoding the DNA repair protein, O(6)-methylguanyl DNA methyltransferase (MGMT), predicts benefit from alkylating chemotherapy with temozolomide and guides choice of first-line treatment in elderly patients. Current developments focus on targeting the molecular characteristics that drive the malignant phenotype, including altered signal transduction and angiogenesis, and more recently, various approaches of immunotherapy. PMID- 26948368 TI - Rare glial tumors. AB - This chapter describes the epidemiology, pathology, molecular characteristics, clinical and neuroimaging features, treatment, outcome, and prognostic factors of the rare glial tumors. This category includes subependymal giant cell astrocytoma, pleomorphic xanthoastrocytoma, astroblastoma, chordoid glioma of the third ventricle, angiocentric glioma, ganglioglioma, desmoplastic infantile astrocytoma and ganglioma, dysembryoplastic neuroepithelial tumor, papillary glioneuronal tumor, and rosette-forming glioneuronal tumor of the fourth ventricle. Many of these tumors, in particular glioneuronal tumors, prevail in children and young adults, are characterized by pharmacoresistant seizures, and have an indolent course, and long survival following surgical resection. Radiotherapy and chemotherapy are reserved for recurrent and/or aggressive forms. New molecular alterations are increasingly recognized. PMID- 26948370 TI - Preface. PMID- 26948369 TI - Ependymoma: a heterogeneous tumor of uncertain origin and limited therapeutic options. AB - Ependymomas are tumors that typically occur with an age-based site preference, with adults harboring supratentorial and spinal tumors and pediatric tumors being mainly in the posterior fossa. Despite their similar histologic appearance, the prognosis varies significantly by age and tumor location, with a better prognosis in increasing age. The mainstay of treatment remains surgical excision with or without radiation therapy as the tumor biology is poorly understood and chemotherapy is generally considered to be ineffective. More recently, molecular biology data have increased our understanding of the genetic and epigenetic changes that drive these tumors, but still it will take a lot of effort to find effective chemotherapeutic regimens. Currently, we are trying to define a subset of tumors, for which radiation therapy can be avoided. PMID- 26948371 TI - Foreword. PMID- 26948372 TI - Clinical management of the uraemic syndrome in chronic kidney disease. AB - The clinical picture of the uraemic syndrome is a complex amalgam of accelerated ageing and organ dysfunction, which progress in parallel to chronic kidney disease. The uraemic syndrome is associated with cardiovascular disease, metabolic bone disease, inflammation, protein energy wasting, intestinal dysbiosis, anaemia, and neurological and endocrine dysfunction. In this Review, we summarise specific, modern management options for the uraemic syndrome in chronic kidney disease. Although large randomised controlled trials are scarce, based on data from randomised controlled trials and observational studies, as well as pathophysiological reasoning, a therapeutic algorithm can be developed for this complex and multifactorial condition, with interventions targeting several modifiable factors simultaneously. PMID- 26948374 TI - Emergence of a novel bovine spongiform encephalopathy (BSE) prion from an atypical H-type BSE. AB - The H-type of atypical bovine spongiform encephalopathy (H-BSE) was serially passaged in bovinized transgenic (TgBoPrP) mice. At the fourth passage, most challenged mice showed a typical H-BSE phenotype with incubation periods of 223 +/- 7.8 days. However, a different phenotype of BSE prion with shorter incubation periods of 109 +/- 4 days emerged in a minor subset of the inoculated mice. The latter showed distinct clinical signs, brain pathology, and abnormal prion protein profiles as compared to H-BSE and other known BSE strains in mice. This novel prion was transmitted intracerebrally to cattle, with incubation periods of 14.8 +/- 1.5 months, with phenotypes that differed from those of other bovine prion strains. These data suggest that intraspecies transmission of H-BSE in cattle allows the emergence of a novel BSE strain. Therefore, the continuation of feed ban programs may be necessary to exclude the recycling of H-BSE prions, which appear to arise spontaneously, in livestock. Such measures should help to reduce the risks from both novel and known strains of BSE. PMID- 26948373 TI - Complex Antigens Drive Permissive Clonal Selection in Germinal Centers. AB - Germinal center (GC) B cells evolve toward increased affinity by a Darwinian process that has been studied primarily in genetically restricted, hapten specific responses. We explored the population dynamics of genetically diverse GC responses to two complex antigens-Bacillus anthracis protective antigen and influenza hemagglutinin-in which B cells competed both intra- and interclonally for distinct epitopes. Preferred VH rearrangements among antigen-binding, naive B cells were similarly abundant in early GCs but, unlike responses to haptens, clonal diversity increased in GC B cells as early "winners" were replaced by rarer, high-affinity clones. Despite affinity maturation, inter- and intraclonal avidities varied greatly, and half of GC B cells did not bind the immunogen but nonetheless exhibited biased VH use, V(D)J mutation, and clonal expansion comparable to antigen-binding cells. GC reactions to complex antigens permit a range of specificities and affinities, with potential advantages for broad protection. PMID- 26948375 TI - Decreased IL-10(+) regulatory B cells (Bregs) in lupus nephritis patients. AB - OBJECTIVES: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by B cell-dependent autoantibody production. Recently, a new B-cell subset was discovered that has a regulatory capacity. The aim of this study was to analyse regulatory B cells (Bregs) in SLE patients. METHOD: Peripheral mononuclear blood cells (PBMCs) of 34 SLE patients fulfilling the American College of Rheumatology (ACR) criteria for SLE and 21 healthy controls (HC) were included. PBMCs were stained for CD19, CD24, and CD38 and analysed by flow cytometry. In vitro stimulated PBMCs with CpG and restimulated with phorbol 12 myristate 13-acetate (PMA) and ionomycin were investigated for IL-10(+) Bregs . RESULTS: The percentages of circulating CD19(+)CD24(hi)CD38(hi) cells in HC were not different those in from SLE patients. The percentages of IL-10(+) Bregs were significantly decreased in SLE patients, in particular those with lupus nephritis (LN), compared to HC. The proportion was independent of disease activity. CONCLUSIONS: This is the first study to demonstrate a decrease in IL-10-producing B cells in LN patients compared to HC, reflecting an impaired regulatory function. PMID- 26948377 TI - Efficient multi-click approach to well-defined two-faced octasilsesquioxanes: the first perfect Janus nanocube. AB - The preparation of the first structurally well-defined Janus nanocube showing two chemically distinct opposed faces is described. The synthetic approach is based on a highly efficient and symmetry-controlled CuAAC functionalization of an octa azido cubic silsesquioxane with a conformationally constrained tetra-alkyne with an appropriate spatial orientation of the triple bonds. PMID- 26948376 TI - Longitudinal Assessment of Effort-Reward Imbalance and Job Strain Across Pregnancy: A Preliminary Study. AB - OBJECTIVES: To assess longitudinal changes in occupational effort-reward imbalance (ERI) and demand-control (DC) scores across pregnancy and examine associations with blood pressure (BP) during pregnancy. METHODS: A pilot repeated measures survey was administered four times to a sample of working women across pregnancy using the ERI and DC instruments. Demographic data and blood pressure measurements were collected at each interval. Growth mixture modeling was used to examine trajectories of change in occupational characteristics. Associations with BP were examined using repeated-measures linear regression models. RESULTS: ERI model components (effort, reward, and overcommitment) all declined across pregnancy while job control remained stable. Increasing ERI trajectory was associated with higher systolic BP (b = 8.8; p < 0.001) as was high overcommitment; declining ERI also showed a lesser association with higher BP. Associations between DC trajectories and BP were much smaller, and non significant once controlled for overcommitment. CONCLUSIONS: Self-assessed efforts, rewards, and overcommitment at work decline across pregnancy in our participants, while job control remains stable. Replication in a more diverse pregnant working population is warranted to confirm these results. These preliminary data suggest that further investigation into the factors that may be linked with improved work psychosocial climate during pregnancy may be useful in order to improve pregnancy outcomes. PMID- 26948378 TI - The First Report of a 290-bp Deletion in beta-Globin Gene in the South of Iran. AB - BACKGROUND: beta-thalassemia is one of the most widespread disease in the world, including Iran. In this study, we reported, for the first time, a 290-bp beta globin gene deletion in the south of Iran. METHODS: Four individuals from three unrelated families with Arabic ethnic background were studied in Khuzestan Province. Red blood cell indices and hemoglobin analysis were carried out according to the standard methods. Genomic DNA was obtained from peripheral blood cells by salting out procedures. beta-globin gene amplification, multiplex ligation-dependent probe amplification (MLPA) and DNA sequencing were performed. RESULTS: The PCR followed by sequencing and MLPA test of the beta-globin gene confirmed the presence of a 290-bp deletion in the heterozygous form, along with 88C>A mutation. All the individuals had elevated hemoglobin A2 and normal fetal hemoglobin levels. CONCLUSIONS: This mutation causes beta0-thalassemia and can be highly useful for prenatal diagnosis in compound heterozygous condition with different beta-globin gene mutations. PMID- 26948379 TI - Increased amyloidogenic APP processing in APOE E4-negative individuals with cerebral beta-amyloidosis. AB - Increased APP (amyloid precursor protein) processing causes beta-amyloid (Abeta) accumulation in autosomal dominant Alzheimer's disease (AD), but it is unclear if it also affects sporadic Abeta accumulation. We tested healthy controls and patients with mild cognitive symptoms (N=331) in the BioFINDER study, using cerebrospinal fluid (CSF) Abeta40 as a surrogate for amyloidogenic APP processing. We find that levels of brain Abeta fibrils (measured by 18F flutemetamol PET) are independently associated with high CSF Abeta40 (P<0.001) and APOE E4 (P<0.001). The association between CSF Abeta40 and brain Abeta is stronger in APOE E4-negative than in positive people (P=0.0080). The results are similar for CSF Abeta38 and for a combination of CSF Abeta38 and CSF Abeta40. In conclusion, sporadic Abeta accumulation may be partly associated with increased amyloidogenic APP production, especially in APOE E4-negative subjects. The risk for sporadic AD may consequently depend on increased Abeta production, in addition to decreased Abeta clearance. PMID- 26948380 TI - Gender counts: A systematic review of evaluations of gender-integrated health interventions in low- and middle-income countries. AB - As a result of new global priorities, there is a growing need for high-quality evaluations of gender-integrated health programmes. This systematic review examined 99 peer-reviewed articles on evaluations of gender-integrated (accommodating and transformative) health programmes with regard to their theory of change (ToC), study design, gender integration in data collection, analysis, and gender measures used. Half of the evaluations explicitly described a ToC or conceptual framework (n = 50) that guided strategies for their interventions. Over half (61%) of the evaluations used quantitative methods exclusively; 11% used qualitative methods exclusively; and 28% used mixed methods. Qualitative methods were not commonly detailed. Evaluations of transformative interventions were less likely than those of accommodating interventions to employ randomised control trials. Two-thirds of the reviewed evaluations reported including at least one specific gender-related outcome (n = 18 accommodating, n = 44 transformative). To strengthen evaluations of gender-integrated programmes, we recommend use of ToCs, explicitly including gender in the ToC, use of gender sensitive measures, mixed-method designs, in-depth descriptions of qualitative methods, and attention to gender-related factors in data collection logistics. We also recommend further research to develop valid and reliable gender measures that are globally relevant. PMID- 26948381 TI - Effects of thermoresponsivity and softness on skin penetration and cellular uptake of polyglycerol-based nanogels. AB - Nanogels are water soluble cross-linked polymer networks with nanometer size dimensions that can be designed to incorporate different types of compounds and are promising carrier systems for drugs and biological molecules. In this study, the interactions of thermoresponsive nanogels (tNGs) with the human skin barrier and underlying epidermis cells were investigated with the aim of using such macromolecules to improve dermal and transdermal drug delivery. The investigated tNGs were made of acrylated dendritic polyglycerol, as water soluble cross linker, and of oligo ethylene glycol methacrylate (OEGMA) as subunit conferring thermoresponsive properties. tNGs with different polymer transition temperatures were tagged with Rhodamine B (RhdB) and analyzed for their physicochemical properties. We found that tNGs with cloud point temperatures (Tcps) of 38 degrees C (tNG-RhdB-T38) lost softness (measured by PeakForce quantitative nanomechanics, QNM) and aggregated to bigger sized particles (measured as increase of particle average size by dynamic light scattering, DLS) when temperature changed from 15 to 37 degrees C. On the contrary, at the same conditions, tNGs with higher Tcps (tNG-RhdB-T55) did not show any significant changes of these characteristics. Applied on excised human skin, both tNGs penetrated deep in the stratum corneum (SC). Small amounts of tNGs were detected also in cells of the viable epidermis. Interestingly, whereas tNG softness correlated with higher penetration in SC, a better cellular uptake was observed for the thermoresponsive tNG-RhdB-T38. We conclude that soft nanocarriers possess a high SC penetration ability and that thermoresponsive nanogels are attractive carrier systems for the targeting of drugs to epidermis cells. PMID- 26948382 TI - A designed recombinant fusion protein for targeted delivery of siRNA to the mouse brain. AB - RNA interference represents a novel therapeutic approach to modulate several neurodegenerative disease-related genes. However, exogenous delivery of siRNA restricts their transport into different tissues and specifically into the brain mainly due to its large size and the presence of the blood-brain barrier (BBB). To overcome these challenges, we developed here a strategy wherein a peptide known to target specific gangliosides was fused to a double-stranded RNA binding protein to deliver siRNA to the brain parenchyma. The designed fusion protein designated as TARBP-BTP consists of a double-stranded RNA-binding domain (dsRBD) of human Trans Activation response element (TAR) RNA Binding Protein (TARBP2) fused to a brain targeting peptide that binds to monosialoganglioside GM1. Conformation-specific binding of TARBP2 domain to siRNA led to the formation of homogenous serum-stable complex with targeting potential. Further, uptake of the complex in Neuro-2a, IMR32 and HepG2 cells analyzed by confocal microscopy and fluorescence activated cell sorting, revealed selective requirement of GM1 for entry. Remarkably, systemic delivery of the fluorescently labeled complex (TARBP BTP:siRNA) in AlphabetaPP-PS1 mouse model of Alzheimer's disease (AD) led to distinctive localization in the cerebral hemisphere. Further, the delivery of siRNA mediated by TARBP-BTP led to significant knockdown of BACE1 in the brain, in both AlphabetaPP-PS1 mice and wild type C57BL/6. The study establishes the growing importance of fusion proteins in delivering therapeutic siRNA to brain tissues. PMID- 26948383 TI - Brachial neuritis or Parsonage-Turner syndrome: A problem of liability. A presentation of 3 cases. AB - Neuralgic amyotrophy, brachial neuritis or Parsonage-Turner syndrome is a rare neuromuscular involvement of unknown aetiology. When it onsets in connection with a health care act, such as childbirth or surgery, a malpractice argument is often used as a cause of adverse outcome, usually due to an incorrect position of the patient on the operating table, a circumstance which directly involves the anesthesia area. Three cases are presented of Parsonage-Turner syndrome following very different surgery, with different results as regards prognosis. A review and discussion of bibliography is presented on the possibility that such circumstances are the subject of malpractice claims. Special emphasis is placed on the most currently accepted aetiopathogenic theories, and the relationship of this syndrome with the surgical act as a determining medico-legal aspect. Valuation parameters are proposed. PMID- 26948384 TI - Characteristics of particulate and non-particulate corticosteroids. Indications for their use in chronic pain treatments. AB - Corticosteroids been used frequently in pain treatments since the middle of last century (1952). Due to a review of the complications as a result of their application in epidural injections, the United States of America Food and Drug Administration (FDA) issued an "alert controversy" requesting that a warning label should be added to injectable corticosteroids, where risks must be described (loss of sight, brain damage, paralysis and death) when administering by this route. It must be mentioned that there are different types of corticosteroids with diverse characteristics, which as a result, may produce different side-effects. Due to the aforementioned developments, the controversies that have arisen, and the lack of well-conducted studies on the use of steroids in epidural injections, we must begin by reviewing their indications in different pain conditions. PMID- 26948385 TI - Effect of Training and Level of External Auditory Feedback on the Singing Voice: Pitch Inaccuracy. AB - BACKGROUND: One of the most important aspects of singing is the control of fundamental frequency. OBJECTIVES: The effects on pitch inaccuracy, defined as the distance in cents in equally tempered tuning between the reference note and the sung note, of the following conditions were evaluated: (1) level of external feedback, (2) tempo (slow or fast), (3) articulation (legato or staccato), (4) tessitura (low, medium, or high), and (5) semi-phrase direction (ascending or descending). METHODS: The subjects were 10 nonprofessional singers and 10 classically trained professional or semi-professional singers (10 men and 10 women). Subjects sang one octave and a fifth arpeggi with three different levels of external auditory feedback, two tempi, and two articulations (legato or staccato). RESULTS: It was observed that inaccuracy was greatest in the descending semi-phrase arpeggi produced at a fast tempo and with a staccato articulation, especially for nonprofessional singers. The magnitude of inaccuracy was also relatively large in the high tessitura relative to the low and the medium tessitura for such singers. Contrary to predictions, when external auditory feedback was strongly attenuated by the hearing protectors, nonprofessional singers showed greater pitch accuracy than in the other external feedback conditions. This finding indicates the importance of internal auditory feedback in pitch control. CONCLUSIONS: With an increase in training, the singer's pitch inaccuracy decreases. PMID- 26948386 TI - Characterization of a new unshielded diode for small field dosimetry under flattening filter free beams. AB - PURPOSE: To characterize the performance of a new unshielded silicon diode (Razor IBA) for dose measurements in small flattening filter free beams. METHODS: The Razor has an active volume of 0.6 mm in diameter and 20 um in length. The detector response stability in measured dose, dose rate, dose per pulse, and dark current were evaluated. The detector response in square fields (0.6-5.0 cm) was determined using PDD curves, axial beam profiles and output ratios. The performances were compared to that of the previously available SFD-IBA and PFD IBA diodes. RESULTS AND DISCUSSION: The Razor short term stability relative to the SFD was much improved (<+/-0.1% after 1.2 kGy). The linearity was <+/-1% (0.05-30 Gy range) and the dose rate dependence was <+/-0.5% (4-24 Gy/min range). The dose per pulse dependence was <+/-0.7% (0.08-0.21 cGy/pulse range). The PDDs measured with Razor and PFD differed <1%. A larger dark current was observed with increase in dose (0.0025 pA/Gy) compared to the SFD (0.0002 pA/Gy). This characteristic is attributed to an increased concentration of recombination centers. The beam profile showed good agreement with the SFD. Penumbra differences were <+/-0.3 mm relative to PFD, with a slight overestimation of the tails (<1%), due to the absence of diode shielding. Output ratios were in good agreement for fields up to 5 * 5 cm(2) (<1%). CONCLUSIONS: The Razor diode has the same spatial resolution and performance reliability as its predecessor (SFD), but exhibits the additional advantage of improved stability. These features make the Razor diode detector a good candidate for small field dosimetry. PMID- 26948387 TI - Data and methods to assess occupational exposure to personnel involved in cardiac catheterization procedures. AB - PURPOSE: To provide normalized scatter exposure data and methods for reliable estimation of cumulative effective dose and eye-lens equivalent dose to personnel involved in fluoroscopically guided cardiac catheterization (FGCC) procedures. METHODS: An anthropomorphic phantom was placed supine on the table of a modern digital C-arm angiographic system and 17 different fluoroscopic projections commonly employed during FGCC procedures were represented. Scatter exposure rates at the waist and eye level were measured for varying exposure parameters and position in the operating room. The effect of beam field size, patient size, use of radioprotective garments and small variations in projection angulation and table height on scatter radiation was investigated. RESULTS: Apart from the position and use of radio-protective garments, radiation burden to operators during fluoroscopic guidance was found to remarkably depend beam field size (>45% reduction if a 10 * 10 cm(2) instead of 15 * 15 cm(2) fluoroscopy beam is used) and patient size (>25% increased scatter for obese patients). In contrast, the variation of measured scatter exposure from a given projection was found to be <10% when the source to skin distance was altered by +/-10 cm or beam angulation of a specific projection was altered by +/-10 degrees . CONCLUSION: Presented scatter exposure data charts and methods allow for prospective and retrospective estimation of effective dose and eye-lens equivalent dose to personnel involved in any FGCC procedure. Projection specific maps of scatter exposure produced may enhance familiarization of involved medical staff to good radiation protection practice and optimization of working habits in the cardiac catheterization lab. PMID- 26948388 TI - Innate lymphoid cells as novel regulators of obesity and its-associated metabolic dysfunction. AB - The increased prevalence of obesity worldwide has been accompanied by increases in risk and rates of obesity-associated metabolic dysfunctions, such as insulin resistance. The chronic, low-grade inflammatory condition of obesity highlights the pathophysiological link between the immune system and the metabolic system, which has yet to be fully understood. Recent studies of obesity have started to uncover potential regulatory roles for the innate lymphoid cells (ILCs), which under normal conditions serve to regulate development of lymphoid tissue and function of the mucosal immune system. The ILCs are a newly identified immune cell population with complicated composition and subsequently diverse and dynamic functions. Studies to determine the distribution profile of the various ILCs in adipose tissue provide intriguing clues as to their regulatory capacity in obesity and its associated metabolic dysfunctions. Here, we review the recent findings supporting a role for ILCs as regulators of obesity or its associated insulin resistance, and discuss the potential underlying molecular mechanism as well as its promise as a therapeutic target for clinical applications. (c) 2016 World Obesity. PMID- 26948389 TI - Formation and Geological Sequestration of Uranium Nanoparticles in Deep Granitic Aquifer. AB - The stimulation of bacterial activities that convert hexavalent uranium, U(VI), to tetravalent uranium, U(IV), appears to be feasible for cost-effective remediation of contaminated aquifers. However, U(VI) reduction typically results in the precipitation of U(IV) particles less than 5 nanometers in diameter, except for environmental conditions enriched with iron. Because these tiny particles are mobile and susceptible to oxidative dissolution after the termination of nutrient injection, in situ bioremediation remains to be impractical. Here we show that U(IV) nanoparticles of coffinite (U(SiO4)1 x(OH)4x) formed in fracture-filling calcium carbonate in a granitic aquifer. In situ U-Pb isotope dating demonstrates that U(IV) nanoparticles have been sequestered in the calcium carbonate for at least 1 million years. As the microbiologically induced precipitation of calcium carbonate in aquifer systems worldwide is extremely common, we anticipate simultaneous stimulation of microbial activities for precipitation reactions of calcium carbonate and U(IV) nanoparticles, which leads to long-term sequestration of uranium and other radionuclides in contaminated aquifers and deep geological repositories. PMID- 26948390 TI - Coronary Obstruction During Transcatheter Aortic Valve Replacement: Related to Calcification or Thrombus? PMID- 26948391 TI - Ischemic Heart Disease and Acute Cardiac Care 2015: A Selection of Topical Issues. PMID- 26948392 TI - Bayes' Syndrome. PMID- 26948393 TI - Coronary Obstruction During Transcatheter Aortic Valve Replacement: Related to Calcification or Thrombus? Response. PMID- 26948394 TI - A pilot study of gestational diabetes mellitus not controlled by diet alone: First-line medical treatment with myoinositol may limit the need for insulin. AB - AIM: This study assessed whether myoinositol might be a first-line medical treatment for gestational diabetes mellitus (GDM). METHODS: For 12 months, women with GDM not controlled by diet (n=32) were prospectively treated with myoinositol 1200mg and folic acid 400MUg/day, while consecutive women (n=28) with insulin-requiring GDM treated during the previous year at our centre constituted the control group. Baseline characteristics and care were similar in both groups. RESULTS: Insulin was required in eight women (25%) in the myoinositol group who, compared with the 24 who did not need insulin, were older (37+/-5 vs. 32+/-5 years, respectively; P=0.018) and had a larger percentage of high self-monitored glucose values (45+/-8% vs. 32+/-14%; P<0.0001) during the week prior to the introduction of myoinositol treatment. All of the women had similar pregnancy outcomes regardless of their GDM management, although less labour induction was required in the myoinositol group (OR: 0.22 [0.07-0.65]), which had no side effects. CONCLUSION: This pilot study suggests that myoinositol may be a safe first-line medical treatment for uncontrolled GDM. PMID- 26948396 TI - Re: Christopher J.D. Wallis, Refik Saskin, Richard Choo, et al. Surgery Versus Radiotherapy for Clinically-localized Prostate Cancer: A Systematic Review and Meta-analysis. Eur Urol 2016;70:21-30. PMID- 26948395 TI - TMPRSS2-ERG in Blood and Docetaxel Resistance in Metastatic Castration-resistant Prostate Cancer. AB - : TMPRSS2-ERG rearrangement is a genetic alteration exclusive to prostate cancer, associated with taxane resistance in preclinical models. Its detection in blood samples of metastatic resistant prostate cancer (mCRPC) patients may indicate the presence of circulating tumour cells with this genetic alteration and may predict taxane resistance. To test this hypothesis, we evaluated TMPRSS2-ERG expression using quantitative reverse transcription polymerase chain reaction in peripheral blood mononuclear cells and tumour tissue from mCPRC patients treated with taxanes. We examined peripheral blood mononuclear cells from 24 healthy controls, 50 patients treated with docetaxel, and 22 with cabazitaxel. TMPRSS2-ERG was detected in 0%, 16%, and 22.7% of them, respectively. In docetaxel-treated patients TMPRSS2-ERG detection correlated with lower prostatic-specific antigen (PSA) response rate (12.5% vs 68.3%, p=0.005), PSA-progression-free survival (PFS; 3.1 mo vs 7.5 mo, p<0.001), clinical/radiological-PFS (3.1 mo vs 8.2 mo, p<0.001), and it was independently associated with PSA-PFS (hazard ratio 3.7; p=0.009) and clinical/radiological-PFS (hazard ratio 6.3; p<0.001). Moreover, TMPRSS2-ERG also predicted low PSA-PFS to cabazitaxel. At progression, a switch from negative to positive TMPRSS2-ERG was observed in 41% of patients with undetected TMPRSS2-ERG at the baseline sample. Tissue TMPRSS2-ERG expression correlated with lower PSA-PFS (p=0.02) to docetaxel. Our findings support the potential role of TMPRSS2-ERG detection as a biomarker to tailor treatment strategies. PATIENT SUMMARY: Taxanes are the most active chemotherapy agents in metastatic resistant prostate cancer. However, not all patients respond to this therapy. In the present study we show that the detection of TMPRSS2-ERG in blood from metastatic resistant prostate cancer patients predicts resistance to docetaxel and it may be useful to select treatment and to avoid possible toxicities in refractory patients. PMID- 26948398 TI - Towards an integrated understanding of the therapeutic utility of exclusive enteral nutrition in the treatment of Crohn's disease. AB - Crohn's disease (CD) is a chronic disease characterized by episodic and disabling inflammation of the gastrointestinal tract in genetically susceptible individuals. The incidence and prevalence of CD is rising rapidly across the world emphasising that disease risk is also influenced by environmental and lifestyle factors, as well as the microbial community resident in the gut. Childhood-onset CD is associated with an aggressive disease course that can adversely impact patient growth and development. There is no cure for CD however new onset and recurrent cases of paediatric CD are often responsive to exclusive enteral nutrition (EEN) treatment. EEN treatment involves the exclusive consumption of an elemental or polymeric formula for several weeks and it is well established as a primary intervention strategy. EEN treatments typically achieve remission rates of over 80% and importantly they are associated with a high rate of mucosal healing, far superior to steroids, which is prognostic of improved long-term health outcomes. Furthermore, they are safe, have few side effects, and improve nutritional status and linear growth. Surprisingly, despite the utility of EEN our understanding of the host-microbe-diet interactions that underpin clinical remission and mucosal healing are limited. Here, we review the current state of knowledge and propose that the induction of autophagy, in addition to modulation of the microbiota and coordinated effects on inflammation and epithelial cell biology, may be critical for the therapeutic effects associated with EEN. A better understanding of EEN treatment will provide new opportunities to restore gut homeostasis and prolong periods of remission, as well as provide new insights into the factors that trigger and perhaps prevent CD. PMID- 26948397 TI - Overall Survival in Patients with Localized Prostate Cancer in the US Veterans Health Administration: Is PIVOT Generalizable? AB - A better understanding of overall survival among patients with clinically localized prostate cancer (PCa) in the US Veterans Health Administration (VHA) is critical to inform PCa treatment decisions, especially in light of data from the Prostate Intervention Versus Observation Trial (PIVOT). We sought to describe patterns of survival for all patients with clinically localized PCa treated by the VHA. We created an analytic cohort of 35 954 patients with clinically localized PCa diagnosed from 1995 to 2001, approximating the PIVOT inclusion criteria (age of diagnosis <=75 yr and clinical stage T2 or lower). Mean patient age was 65.9 yr, and median follow-up was 161 mo. Overall, 22.5% of patients were treated with surgery, 16.6% were treated with radiotherapy, and 23.1% were treated with androgen deprivation. Median survival of the entire cohort was 14 yr (25th, 75th percentiles, range: 7.9-20 yr). Among patients who received treatment with curative intent, median survival was 17.9 yr following surgery and 12.9 yr following radiotherapy. One-third of patients died within 10 yr of diagnosis compared with nearly half of the participants in PIVOT. This finding sounds a note of caution when generalizing the mortality data from PIVOT to VHA patients and those in the community. PATIENT SUMMARY: More than one-third of patients diagnosed with clinically localized prostate cancer treated through the US Veterans Health Administration from 1995 to 2001 died within 10 yr of their diagnosis. Caution should be used when generalizing the estimates of competing mortality data from PIVOT. PMID- 26948399 TI - In vivo quantification of the shear modulus of the human Achilles tendon during passive loading using shear wave dispersion analysis. AB - The shear wave velocity dispersion was analyzed in the Achilles tendon (AT) during passive dorsiflexion using a phase velocity method in order to obtain the tendon shear modulus (C 55). Based on this analysis, the aims of the present study were (i) to assess the reproducibility of the shear modulus for different ankle angles, (ii) to assess the effect of the probe locations, and (iii) to compare results with elasticity values obtained with the supersonic shear imaging (SSI) technique. The AT shear modulus (C 55) consistently increased with the ankle dorsiflexion (N = 10, p < 0.05). Furthermore, the technique showed a very good reproducibility (all standard error of the mean values <10.7 kPa and all coefficient of variation (CV) values ? 0.05%). In addition, independently from the ankle dorsiflexion, the shear modulus was significantly higher in the proximal location compared to the more distal one. The shear modulus provided by SSI was always lower than C55 and the difference increased with the ankle dorsiflexion. However, shear modulus values provided by both methods were highly correlated (R = 0.84), indicating that the conventional shear wave elastography technique (SSI technique) can be used to compare tendon mechanical properties across populations. Future studies should determine the clinical relevance of the shear wave dispersion analysis, for instance in the case of tendinopathy or tendon tear. PMID- 26948400 TI - Timing of food intake is associated with weight loss evolution in severe obese patients after bariatric surgery. AB - BACKGROUND: Recent research has demonstrated a relationship between the timing of food intake and weight loss in humans. However, whether the meal timing can be associated with weight loss in patients treated with bariatric surgery is unknown. OBJECTIVE: To evaluate the role of food-timing in the evolution of weight loss in a sample of 270 patients that underwent bariatric surgery with a follow-up of 6 years. METHODS: Participants (79% women; age [mean +/- SD]: 52 +/- 11 years; BMI: 46.5 +/- 6.0 kg/m2) were classified according their weight loss response patterns after bariatric surgery: good weight-loss-responders (67.8%), primarily poor weight-loss-responders (10.8%) or secondarily poor weight-loss responders (21.4%). Then, they were grouped in early-eaters and late-eaters, according to the timing of the main meal (before or after 15:00 h). Obesity and biochemical parameters, energy and macronutrients intake, energy expenditure, sleep duration, and chronotype were studied. RESULTS: The percentage of late eaters (after 15:00 h) was significantly higher in the primarily poor weight-loss responders (~70%) than in both secondarily poor weight-loss-responders (~42%) and good weight-loss-responders (~37%) (p = 0.011). Consistently, primarily poor weight-loss-responders had lunch later as compared to good and secondarily poor weight-loss-responders (p = 0.034). Age, gender and type of surgery were not determining. Surprisingly, obesity-related variables, biochemical parameters, pre surgical total energy expenditure, sleep duration, chronotype, calorie intake and macronutrients distribution, were similar among groups. CONCLUSIONS: Weight loss effectiveness after bariatric surgery is related to the timing of the main meal. Our preliminary results suggest that the timing of food intake is important for weight regulation and that eating at the right time may be a relevant factor to consider in weight loss therapy even after bariatric surgery. PMID- 26948401 TI - The flesh ethanolic extract of Hylocereus polyrhizus exerts anti-inflammatory effects and prevents murine colitis. AB - BACKGROUND & AIMS: IBD is a chronic disorder of the gastrointestinal tract characterized by mucosal inflammation and epithelial damage. Biologic therapy has significantly improved the course of the disease but there are still a high percentage of patients that do not respond to current therapies. We aim to determine the effects of the flesh ethanolic extract of Hylocereus polyrhizus (EH) in a mice model of colitis induced by TNBS. METHODS: Balb/c mice received TNBS (175 mg/kg, 100 MUl, i.r.) and six and thirty hours later were administered with EH (1 g/kg, i.p.). Mice were weighted daily and after sacrificing (2 and 4 days after TNBS) we analyzed mucosal histology, myeloperoxidase activity (MPO), the expression of pro-inflammatory molecules (qPCR) and NF-kappaB and Ikappabeta alpha protein levels. The chemical characterization of the EH was determined by LC-MS/MS. RESULTS: The administration of EH to TNBS-treated mice prevented (P < 0.05) the loss of body weight and significantly reduced in the colon: a) histological damage score, b) MPO enzymatic activity c) the expression of pro inflammatory molecules and d) Ikappabeta-alpha degradation and nuclear NF kappabeta protein levels. The LC-MS analysis detected metabolites such as polyphenols and fatty acids. CONCLUSION: Systemic administration of the ethanolic extract of H. polyrhizus exerts an anti-inflammatory effect and prevents murine colitis induced by TNBS. PMID- 26948402 TI - Effectiveness of the SYSTEM 1E Liquid Chemical Sterilant Processing System for reprocessing duodenoscopes. AB - BACKGROUND: A troubling number of health care-acquired infection outbreaks and transmission events, some involving highly resistant microbial pathogens and resulting in serious patient outcomes, have been traced to reusable, high-level disinfected duodenoscopes in the United States. The Food and Drug Administration (FDA) requested a study be conducted to verify liquid chemical sterilization efficacy of SYSTEM 1E((r)) Liquid Chemical Sterilant Processing System (STERIS Corporation, Mentor, OH) with varied duodenoscope designs under especially arduous conditions. Here, we describe the system's performance under worst case SYSTEM 1E((r)) processing conditions. METHODS: The test protocol challenged the system's performance by running a fractional cycle to evaluate reduction of recoverable test spores from heavily contaminated endoscopes, including all channels and each distal tip, under worst case SYSTEM 1E((r)) processing conditions. RESULTS: All devices were successfully liquid chemically sterilized, showing greater than a 6 log10 reduction of Geobacillus stearothermophilus spores at every inoculation site of each duodenoscope tested, in less than half the exposure time of the standard cycle. CONCLUSIONS: The successful outcome of the additional efficacy testing reported here indicates that the SYSTEM 1E((r)) is an effective low-temperature liquid chemical sterilization method for duodenoscopes and other critical and semicritical devices. It offers a fast, safe, convenient processing alternative while providing the assurance of a system expressly tested and cleared to achieve liquid chemical sterilization of specific validated duodenoscope models. PMID- 26948403 TI - Antioxidant Properties and Flavonoid Profile in Leaves of Calabrian Lavandula multifida L., an Autochthon Plant of Mediterranean Southern Regions. AB - Lavandula multifida is a rare short-lived plant characteristic of Mediterranean basin able to survive in hot and arid climatic conditions on poorly evolved limestone soils. In this work, we characterize the enzymatic antioxidant system and phenolic composition, as well as the antioxidant properties of L. multifida fresh leaves. Enzymatic patterns show high level of peroxidases, ascorbate peroxidase, and dehydroascorbate reductase activities, when compared with L. angustifolia. The same trend is evident in total carotenoids, ascorbic acid, and reduced glutathione, and in the total antioxidant capacity assay. Moreover, RP DAD-HPLC analyses of EtOH extract, obtained from fresh leaves, reveal main components, carvacrol, vitexin, and 7- or 8-glucoside derivatives of hypolaetin, scutellarein, luteolin, isoscutellarein, apigenin, and chrysoeriol. The analysis of this autochthon plant depicted a series of strategies adopted by L. multifida to survive in its stressful natural habitat and richness in health-promoting compounds that can be a resource for the preservation of this variety in dangerous of extinction. PMID- 26948404 TI - Catalytic Isomerization of Biomass-Derived Aldoses: A Review. AB - Selected aldohexoses (D-glucose, D-mannose, and D-galactose) and aldopentoses (D xylose, L-arabinose, and D-ribose) are readily available components of biopolymers. Isomerization reactions of these substances are very attractive as carbon-efficient processes to broaden the portfolio of abundant monosaccharides. This review focuses on the chemocatalytic isomerization of aldoses into the corresponding ketoses as well as epimerization of aldoses at C2. Recent advances in the fields of catalysis by bases and Lewis acids are considered. The emphasis is laid on newly uncovered catalytic systems and mechanisms of carbohydrate transformations. PMID- 26948405 TI - Covalent immobilization of metal-organic frameworks onto the surface of nylon--a new approach to the functionalization and coloration of textiles. AB - The prevention of refractory organic pollution caused by conventional dyeing and the development of new fabrics with various functions are two issues to be solved urgently in the field of textile fabrication. Here, we report a new environmentally friendly route for the simultaneous coloration and functionalization of textiles by the covalent immobilization of a metal-organic framework, Cr-based MIL-101(Cr), onto the surfaces of nylon fabrics by co-graft polymerization with 2-hydroxyethyl acrylate initiated by gamma-ray irradiation. The Cr(III) clusters color the nylon fabric, and the color intensity varies with the MIL-101 content, providing a "green" textile coloration method that is different from conventional dyeing processes. An X-ray diffraction (XRD) analysis shows that the nanoporous structure of the original MIL-101 particles is retained during radiation-induced graft polymerization. Numerous nanopores are introduced onto the surface of the nylon fabric, which demonstrated better sustained-release of-aroma performance versus pristine nylon fabric in tests. The modified fabrics exhibit laundering durability, with MIL-101 nanoparticles intact on the nylon surface after 30 h of dry cleaning. PMID- 26948406 TI - In Vivo Lighted Fluorescence via Fenton Reaction: Approach for Imaging of Hydrogen Peroxide in Living Systems. AB - By virtue of its high sensitivity and rapidity, Fenton reaction has been demonstrated as a powerful tool for in vitro biochemical analysis; however, in vivo applications of Fenton reaction still remain to be exploited. Herein, we report, for the first time, the design, formation and testing of Fenton reaction for in vivo fluorescence imaging of hydrogen peroxide (H2O2). To realize in vivo fluorescence imaging of H2O2 via Fenton reaction, a functional nanosphere, Fc@MSN FDNA/PTAD, is fabricated from mesoporous silica nanoparticle (MSN), a Fenton reagent of ferrocene (Fc), ROX-labeled DNA (FDNA), and a cationic perylene derivative (PTAD). The ferrocene molecules are locked in the pore entrances of MSN, and exterior of MSN is covalently immobilized with FDNA. As a key part, PTAD acts as not only the gatekeeper of MSN but also the efficient quencher of ROX. H2O2 can permeate into the nanosphere and react with ferrocene to product hydroxyl radical (.OH) via Fenton reaction, which cleaves FDNA to detach ROX from PTAD, thus in turn, lights the ROX fluorescence. Under physiological condition, H2O2 can be determined from 5.0 nM to 1.0 MUM with a detection limit of 2.4 nM. Because of the rapid kinetics of Fenton reaction and high specificity for H2O2, the proposed method meets the requirement for real applications. The feasibility of Fc@MSN-FDNA/PTAD for in vivo applications is demonstrated for fluorescence imaging of exogenous and endogenous H2O2 in cells and mice. We expect that this work will not only contribute to the H2O2-releated studies but also open up a new way to exploit in vivo Fenton reaction for biochemical research. PMID- 26948407 TI - Development of 3,5-Dinitrobenzylsulfanyl-1,3,4-oxadiazoles and Thiadiazoles as Selective Antitubercular Agents Active Against Replicating and Nonreplicating Mycobacterium tuberculosis. AB - Herein, we report the discovery and structure-activity relationships of 5 substituted-2-[(3,5-dinitrobenzyl)sulfanyl]-1,3,4-oxadiazoles and 1,3,4 thiadiazoles as a new class of antituberculosis agents. The majority of these compounds exhibited outstanding in vitro activity against Mycobacterium tuberculosis CNCTC My 331/88 and six multidrug-resistant clinically isolated strains of M. tuberculosis, with minimum inhibitory concentration values as low as 0.03 MUM (0.011-0.026 MUg/mL). The investigated compounds had a highly selective antimycobacterial effect because they showed no activity against the other bacteria or fungi tested in this study. Furthermore, the investigated compounds exhibited low in vitro toxicities in four proliferating mammalian cell lines and in isolated primary human hepatocytes. Several in vitro genotoxicity assays indicated that the selected compounds have no mutagenic activity. The oxadiazole and thiadiazole derivatives with the most favorable activity/toxicity profiles also showed potency comparable to that of rifampicin against the nonreplicating streptomycin-starved M. tuberculosis 18b-Lux strain, and therefore, these derivatives, are of particular interest. PMID- 26948408 TI - Simple blood-feeding method for live imaging of gut tube remodeling in regenerating planarians. AB - Live cell imaging is a powerful technique to study cellular dynamics in vivo during animal development and regeneration. However, few live imaging methods have been reported for studying planarian regeneration. Here, we developed a simple method for steady visualization of gut tube remodeling during regeneration of a living freshwater planarian, Dugesia japonica. When planarians were fed blood several times, gut branches were well-visualized in living intact animals under normal bright-field illumination. Interestingly, tail fragments derived from these colored planarians enabled successive observation of the processes of the formation of a single anterior gut branch in the prepharyngeal region from the preexisting two posterior gut branches in the same living animals during head regeneration. Furthermore, we combined this method and RNA interference (RNAi) and thereby showed that a D. japonica raf-related gene (DjrafA) and mek-related gene (DjmekA) we identified both play a major role in the activation of extracellular signal-regulated kinase (ERK) signaling during planarian regeneration, as indicated by their RNAi-induced defects on gut tube remodeling in a time-saving initial screening using blood-feeding without immunohistochemical detection of the gut. Thus, this blood-feeding method is useful for live imaging of gut tube remodeling, and provides an advance for the field of regeneration study in planarians. PMID- 26948409 TI - Adverse Effects of Plant Food Supplements and Plants Consumed as Food: Results from the Poisons Centres-Based PlantLIBRA Study. AB - Plant food supplements (PFS) are products of increasing popularity and wide spread distribution. Nevertheless, information about their risks is limited. To fill this gap, a poisons centres-based study was performed as part of the EU project PlantLIBRA. Multicentre retrospective review of data from selected European and Brazilian poisons centres, involving human cases of adverse effects due to plants consumed as food or as ingredients of food supplements recorded between 2006 and 2010. Ten poisons centres provided a total of 75 cases. In 57 cases (76%) a PFS was involved; in 18 (24%) a plant was ingested as food. The 10 most frequently reported plants were Valeriana officinalis, Camellia sinensis, Paullinia cupana, Melissa officinalis, Passiflora incarnata, Mentha piperita, Glycyrrhiza glabra, Ilex paraguariensis, Panax ginseng, and Citrus aurantium. The most frequently observed clinical effects were neurotoxicity and gastro intestinal symptoms. Most cases showed a benign clinical course; however, five cases were severe. PFS-related adverse effects seem to be relatively infrequent issues for poisons centres. Most cases showed mild symptoms. Nevertheless, the occurrence of some severe adverse effects and the increasing popularity of PFS require continuous active surveillance, and further research is warranted. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26948411 TI - Integrated Onco-Palliative Care Associated With Prolonged Survival Compared to Standard Care for Patients With Advanced Lung Cancer: A Retrospective Review. AB - CONTEXT: Lung cancer is the leading cause of cancer-related death in the U.S. A large randomized controlled trial in advanced lung cancer found a survival advantage with an early palliative care (EPC) intervention compared to standard oncologic care. OBJECTIVES: We performed retrospective analysis of our partially integrated onco-palliative care lung cancer clinic to evaluate overall survival and resource utilization. METHODS: All outpatients with advanced lung cancer cared for within our institution from 2007 to 2011 were identified. Overall survival, clinical trial participation, hospice enrollment and length of stay, and chemotherapy utilization were calculated for patients treated with EPC and compared to standard oncologic care. RESULTS: Two hundred seven patients with advanced lung cancer were identified; 82 received EPC. EPC patients had a survival advantage (11.9 vs. 10.1 months, P = 0.031), were more likely to participate in clinical trials (29% vs. 19%, P = 0.014), and median hospice length of stay was longer (38.5 vs. 24 days, P = 0.032). No difference in chemotherapy utilization or hospice enrollment was seen between the groups. CONCLUSION: EPC in advanced lung cancer was associated with a nearly two-month survival advantage compared to standard oncologic care. This finding provides supportive evidence to previously published reports of survival benefit with EPC intervention. Clinical trial participation rates in advanced lung cancer are lacking, and we found more frequent clinical trial participation in the early PC group. No differences were seen in chemotherapy utilization or hospice enrollment. EPC patients' longer hospice length of stay did not compromise survival. PMID- 26948410 TI - On the morphology of antennular sensory and attachment organs in cypris larvae of the deep-sea vent/seep barnacles, Ashinkailepas and Neoverruca. AB - Barnacle cypris larvae show high morphological variation in the organs used in search of and attaching to a substratum. This variation may represent adaptation to the habitat of the species. Here, we studied SEM level morphologies of cypris antennular sensory and attachment organs in a deep-sea vent endemic species (Neoverruca sp.) and a vent/seep inhabiting species (Ashinkailepas seepiophila). We compare them with three species from other environments. The antennular morphologies of Neoverruca sp. and A. seepiophila were similar, which is consistent with recent molecular studies showing a close relationship of the two species. The setation pattern of the antennules was very conservative among species from various environments. In contrast, striking differences were observed in the structure of the attachment organ (the third antennular segment). Neoverruca sp. and A. seepiophila had no velum or a skirt surrounding the attachment disc on the third segment, while other cirripede cyprids almost always have either of these structures. In addition, both cyprids of A. seepiophila and Neoverruca sp. had the attachment disc angled toward the substratum, whereas it faces distally in cyprids from hard bottom inhabiting barnacles. We suggest that both velum/skirt and the angle of the attachment disc play an important role, when the antennules are contacting the substratum during surface exploration. Differences in attachment organ structures may be highly adaptive, enabling cirripede species to enter new habitats during evolution. PMID- 26948412 TI - An accuracy measurement method for star trackers based on direct astronomic observation. AB - Star tracker is one of the most promising optical attitude measurement devices and it is widely used in spacecraft for its high accuracy. However, how to realize and verify such an accuracy remains a crucial but unsolved issue until now. The authenticity of the accuracy measurement method of a star tracker will eventually determine the satellite performance. A new and robust accuracy measurement method for a star tracker based on the direct astronomical observation is proposed here. In comparison with the conventional method with simulated stars, this method utilizes real navigation stars as observation targets which makes the measurement results more authoritative and authentic. Transformations between different coordinate systems are conducted on the account of the precision movements of the Earth, and the error curves of directional vectors are obtained along the three axes. Based on error analysis and accuracy definitions, a three-axis accuracy evaluation criterion has been proposed in this paper, which could determine pointing and rolling accuracy of a star tracker directly. Experimental measurements confirm that this method is effective and convenient to implement. Such a measurement environment is close to the in-orbit conditions and it can satisfy the stringent requirement for high-accuracy star trackers. PMID- 26948413 TI - Catalytic Hypervalent Iodine Promoters Lead to Styrene Dimerization and the Formation of Tri- and Tetrasubstituted Cyclobutanes. AB - Reported herein is that the use of catalytic quantities of hypervalent iodine reagents (phenyliodine diacetate or Dess-Martin periodinane) allows the rapid and stereoselective formation of cyclobutanes under very mild reaction conditions. The presence of a fluorinated solvent is essential for the success of these reactions which form unsymmetrical tri- and tetrasubstituted cyclobutanes through a heterodimerization process involving two different alkenes. PMID- 26948414 TI - Fragrance allergy could be missed without patch testing with 26 individual fragrance allergens. AB - BACKGROUND: In 2003, the EU Cosmetics Directive stated that 26 fragrance substances must be listed on the cosmetic product ingredient labels. Not all of these 26 fragrance substances are detected by the usual screening markers comprising fragrance mix I, fragrance mix II, and Myroxylon pereirae. OBJECTIVES: To evaluate the usefulness of testing with the 26 individual fragrance substances in addition to the standard fragrance screening markers. MATERIALS AND METHODS: Three hundred and twelve consecutive patients were patch tested with our baseline series and the 26 specific fragrance substances required to be declared on cosmetic product ingredient labels in accordance with the EU Cosmetics Directive. RESULTS: Positive reactions to at least either one of the 26 individual fragrance substances or the usual fragrance screening markers were seen in 84 of 312 patients (26.9%). Fifteen of these 84 patients (17.8%) reacted negatively to the fragrance screening markers. The most common individual fragrance allergens were cinnamyl alcohol (11.2%), cinnamal (9%), and hydroxycitronellal (3.8%). Sixty-two of 312 patients (19.8%) had at least one positive reaction to the fragrance screening markers. CONCLUSION: Additional patch testing with the 26 individual fragrance allergens, or with the commonest fragrance allergens identified within these 26, should be performed to optimize the detection of fragrance allergy. Cinnamyl alcohol and cinnamal are important fragrance allergens in Thailand. PMID- 26948415 TI - Occupational contact allergy to sodium cocoamphopropionate in a hand cleanser. PMID- 26948416 TI - The many faces of coconut oil derivatives: occupational hand dermatitis caused by a liquid soap containing cocamidopropylamine oxide. PMID- 26948417 TI - Facial allergic contact dermatitis without hand involvement caused by disposable latex gloves. PMID- 26948418 TI - Severe reaction to emtricitabine and lamiduvine: evidence of cross-reactivity. PMID- 26948419 TI - Toxic dermatitis caused by ammonium nitrate released by a cold pack. PMID- 26948420 TI - Should Evernia furfuracea be included in a baseline screening series of contact allergens? PMID- 26948421 TI - Is it time for a more ambitious research agenda for decreasing alcohol-related harm among young adults? PMID- 26948422 TI - Induction of Colonic M Cells during Intestinal Inflammation. AB - Intestinal M (microfold) cells are specialized epithelial cells overlying lymphoid tissues in the small intestine. Unlike common enterocytes, M cells lack an organized apical brush border, and are able to transcytose microparticles across the mucosal barrier to underlying antigen-presenting cells. We found that in both the dextran sodium sulfate and Citrobacter rodentium models of colitis, significantly increased numbers of Peyer's patch (PP) phenotype M cells were induced at the peak of inflammation in colonic epithelium, often accompanied by loosely organized lamina propria infiltrates. PP type M cells are thought to be dependent on cytokines, including tumor necrosis factor (TNF)-alpha and receptor activator of nuclear factor kappa-B ligand; these cytokines were also found to be induced in the inflamed tissues. The induction of M cells was abrogated by anti TNF-alpha blockade, suggesting that anti-TNF-alpha therapies may have similar effects in clinical settings, although the functional consequences are not clear. Our results suggest that inflammatory cytokine-induced PP type M cells may be a useful correlate of chronic intestinal inflammation. PMID- 26948425 TI - The metabolism of the non-proteinogenic amino acid beta-N-methylamino-L-alanine (BMAA) in the cyanobacterium Synechocystis PCC6803. AB - The neurotoxic amino acid beta-N-methylamino-L-alanine (BMAA) is produced by cyanobacteria under nitrogen starvation conditions and its metabolism is closely associated with cellular nitrogen control. Very little is known regarding the metabolism or biosynthesis of this amino acid in the producing organisms and current knowledge is limited to the spontaneous formation of carbamate adducts in the presence of aqueous carbon dioxide, the rapid removal of free cellular BMAA upon the addition of ammonia to nitrogen-starved cyanobacterial cultures, and the link between cellular nitrogen status and BMAA synthesis. Data presented here show that exogenous BMAA is readily metabolised by cyanobacteria during which, the primary amino group is rapidly transferred to other cellular amino acids. Furthermore, data suggest that BMAA is metabolised in cyanobacteria via a reversible transamination reaction. This study presents novel data on BMAA metabolism in cyanobacteria and provides the first proposed biosynthetic precursor to BMAA biosynthesis in cyanobacteria. PMID- 26948423 TI - TNF-alpha Modulation of Intestinal Tight Junction Permeability Is Mediated by NIK/IKK-alpha Axis Activation of the Canonical NF-kappaB Pathway. AB - Tumor necrosis factor (TNF)-alpha, a key mediator of intestinal inflammation, causes an increase in intestinal epithelial tight junction (TJ) permeability by activating myosin light chain kinase (MLCK; official name MYLK3) gene. However, the precise signaling cascades that mediate the TNF-alpha-induced activation of MLCK gene and increase in TJ permeability remain unclear. Our aims were to delineate the upstream signaling mechanisms that regulate the TNF-alpha modulation of intestinal TJ barrier function with the use of in vitro and in vivo intestinal epithelial model systems. TNF-alpha caused a rapid activation of both canonical and noncanonical NF-kappaB pathway. NF-kappaB-inducing kinase (NIK) and mitogen-activated protein kinase kinase-1 (MEKK-1) were activated in response to TNF-alpha. NIK mediated the TNF-alpha activation of inhibitory kappaB kinase (IKK)-alpha, and MEKK1 mediated the activation of IKK complex, including IKK beta. NIK/IKK-alpha axis regulated the activation of both NF-kappaB p50/p65 and RelB/p52 pathways. Surprisingly, the siRNA induced knockdown of NIK, but not MEKK 1, prevented the TNF-alpha activation of both NF-kappaB p50/p65 and RelB/p52 and the increase in intestinal TJ permeability. Moreover, NIK/IKK-alpha/NF-kappaB p50/p65 axis mediated the TNF-alpha-induced MLCK gene activation and the subsequent MLCK increase in intestinal TJ permeability. In conclusion, our data show that NIK/IKK-alpha/regulates the activation of NF-kappaB p50/p65 and plays an integral role in the TNF-alpha-induced activation of MLCK gene and increase in intestinal TJ permeability. PMID- 26948424 TI - Myocardial Galectin-3 Expression Is Associated with Remodeling of the Pressure Overloaded Heart and May Delay the Hypertrophic Response without Affecting Survival, Dysfunction, and Cardiac Fibrosis. AB - The beta-galactoside-binding animal lectin galectin-3 is predominantly expressed by activated macrophages and is a promising biomarker for patients with heart failure. Galectin-3 regulates inflammatory and fibrotic responses; however, its role in cardiac remodeling remains unclear. We hypothesized that galectin-3 may be up-regulated in the pressure-overloaded myocardium and regulate hypertrophy and fibrosis. In normal mouse myocardium, galectin-3 was constitutively expressed in macrophages and was localized in atrial but not ventricular cardiomyocytes. In a mouse model of transverse aortic constriction, galectin-3 expression was markedly up-regulated in the pressure-overloaded myocardium. Early up-regulation of galectin-3 was localized in subpopulations of macrophages and myofibroblasts; however, after 7 to 28 days of transverse aortic constriction, a subset of cardiomyocytes in fibrotic areas contained large amounts of galectin-3. In vitro, cytokine stimulation suppressed galectin-3 synthesis by macrophages and cardiac fibroblasts. Correlation studies revealed that cardiomyocyte- but not macrophage specific galectin-3 localization was associated with adverse remodeling and dysfunction. Galectin-3 knockout mice exhibited accelerated cardiac hypertrophy after 7 days of pressure overload, whereas female galectin-3 knockouts had delayed dilation after 28 days of transverse aortic constriction. However, galectin-3 loss did not affect survival, systolic and diastolic dysfunction, cardiac fibrosis, and cardiomyocyte hypertrophy in the pressure-overloaded heart. Despite its potential role as a prognostic biomarker, galectin-3 is not a critical modulator of cardiac fibrosis but may delay the hypertrophic response. PMID- 26948426 TI - Cyanobacteria biennal dynamic in a volcanic mesotrophic lake in central Italy: Strategies to prevent dangerous human exposures to cyanotoxins. AB - Vico Lake, a volcanic meso-eutrophic lake in Central Italy, whose water is used for drinking and recreational activities, experienced the presence of the microcystins (MC) producing cyanobacterium Planktothrix rubescens. In order to assess the human health risks and to provide the local health authorities with a scientific basis for planning tailored monitoring activities, we studied P. rubescens ecology and toxicity for two years. P. rubescens generally dominated the phytoplankton community, alternating with Limnothrix redekei, potentially toxic. P. rubescens was distributed throughout the water column during winter; in summer it produced intense blooms where drinking water is collected (-20 m); here MC were detected all year round (0.5-5 MUg/L), with implications for drinking water quality. In surface waters, MC posed no risk for recreational activities in summer, while in winter surface blooms and foams (containing up to 56 MUg MC/L) can represent a risk for people and children practicing water sports and for animals consuming raw water. Total phosphorus, phosphate and inorganic nitrogen were not relevant to predict densities nor toxicity; however, a strong correlation between P. rubescens density and aminopeptidase ectoenzymatic activity, an enzyme involved in protein degradation, suggested a role of organic nitrogen for this species. The fraction of potentially toxic population, determined both as mcyB(+)/16SrDNA (10-100%) and as the MC/mcyB(+) cells (0.03 0.79 pg MC/cell), was much more variable than usually observed for P. rubescens. Differently from other Italian and European lakes, the correlation between cell density or the mcyB(+) cells and MC explained only ~50 and 30% of MC variability, respectively: for Vico Lake, monitoring only cell or the mcyB(+) cell density is not sufficient to predict MC concentrations, and consequently to protect population health. Finally, during a winter bloom one site has been sampled weekly, showing that monthly sampling during such a phase could greatly underestimate the 'hazard'. Our results highlight the need to adopt a stepwise monitoring activity, considering the lake and the cyanobacteria specific features. This activity should be complemented with communication to the public and involvement of stakeholders. PMID- 26948427 TI - Post-Transplant Lymphoproliferative Disorder in Kidney Transplant Recipients: A Single-Center Experience in Japan. AB - Post-transplant lymphoproliferative disorder is a serious complication of solid organ transplantation; however, few large studies have been performed in Asian institutions. We review our single-center experience with post-transplant lymphoproliferative disorder patients in Japan. We retrospectively evaluated patients with post-transplant lymphoproliferative disorder following kidney transplantation between January 1985 and December 2013. The patients were divided into early-onset post-transplant lymphoproliferative disorder (<1 year) and late onset post-transplant lymphoproliferative disorder (>=1 year) groups. Thirteen patients had the disorder, an incidence rate of 0.75% (13/1730). Early-onset post transplant lymphoproliferative disorder (N = 3) had not occurred for the last two decades. In the late-onset group (N = 10), the median time of onset was 108.7 months. The Kaplan-Meier 10-year overall survival rates were 76.9% and 95.4% in patients with and without the disorder, respectively (P = 0.0001). Post transplant lymphoproliferative disorder significantly affected transplant recipients' mortality. Late-onset occurred even > 10 years after transplantation; therefore, long-term monitoring of patients is needed. PMID- 26948428 TI - Access and latency to first antipsychotic treatment in Italian patients with schizophrenia and other schizophrenic spectrum disorders across different epochs. AB - BACKGROUND: The duration of untreated illness (DUI) is a measure to express the latency to first psychopharmacological treatment: it differs among psychiatric disorders, being influenced by several illness-intrinsic and environmental factors. The present study aimed to assess differences in DUI and related variables in patients with schizophrenia (SKZ) versus other schizophrenic spectrum disorders (SSDs) across different epochs. METHODS: 101 SKZ or SSD patients were assessed with respect to DUI and related variables through clinical interview and questionnaire. RESULTS: Patients with SKZ showed earlier ages of onset, first diagnosis and first antipsychotic treatment compared with patients with other SSDs (F = 11.02, p < 0.001; F = 12.68, p < 0.001; F = 13.74, p < 0.001, respectively) who showed an earlier access to benzodiazepines than SKZ patients (F = 6.547; p < 0.05). Dividing the total sample by the epoch of onset (before 1978; between 1978-2000; after 2000) showed a significantly later age of onset in patients with onset within the two most recent epochs (F = 7.46; p < 0.001) and a reduced DUI across epochs (from 144 to 41 to 20 months, on average; F = 11.78, p < 0.001). CONCLUSION: Schizophrenic patients showed earlier onset and longer DUI compared with patients with other SSDs. Data on the total sample showed a later age of onset and a reduced DUI across epochs. PMID- 26948429 TI - Anatomic abnormalities are common potential explanations of manometric esophagogastric junction outflow obstruction. AB - BACKGROUND: Esophagogastric junction outflow obstruction (EGJOO) is an esophageal motility diagnosis associated with a myriad of conditions. The frequency of EGJOO attributed to anatomic causes compared to idiopathic causes is uncertain. Our study aims to identify the frequency of EGJOO and to compare these two groups. METHODS: We conducted a case-control study of high-resolution manometry (HRM) studies with a diagnosis of EGJOO performed at a single academic center. EGJOO cases were classified as anatomic (if any potential anatomic cause was identified) or idiopathic. Clinical and manometric characteristics of idiopathic EGJOO were compared with anatomic EGJOO cases. KEY RESULTS: Criteria for EGJOO were met in 11% of HRM studies. Ancillary studies revealed 21/32 EGJOO cases had potential anatomic causes with a hiatal hernia noted in 15/21 cases of anatomic EGJOO. Idiopathic EGJOO cases met Chicago Classification criteria for hypercontractile esophagus with greater frequency than anatomic cases (p = 0.01). The mean distal contractile integral was significantly greater for idiopathic cases compared to anatomic cases (p = 0.003). Treatments used for EGJOO were varied and usually successful in alleviating symptoms. Patients with anatomic EGJOO related to a hiatal hernia who underwent an antireflux operation did not develop dysphagia postoperatively. CONCLUSIONS & INFERENCES: EGJOO is a frequently encountered manometric diagnosis, commonly associated with anatomic abnormalities potentially explaining the EGJOO. These findings support current recommendations to pursue ancillary diagnostics to investigate cases of unexplained EGJOO. Cases of idiopathic EGJOO are more likely to have hypercontractility on HRM, possibly suggesting a primary esophageal motility disorder. PMID- 26948430 TI - Influence of atmospheric pressure low-temperature plasma treatment on the shear bond strength between zirconia and resin cement. AB - PURPOSE: Zirconia exhibits excellent strength and high biocompatibility in technological applications and it is has therefore been investigated for clinical applications and research. Before setting prostheses, a crown prosthesis inner surface is sandblasted with alumina to remove contaminants and form small cavities. This alumina sandblasting causes stress-induced phase transition of zirconia. Atmospheric-pressure low-temperature plasma has been applied in the dental industry, particularly for adhesives, as a surface treatment to activate the surface energy and remove contaminants. The purpose of this study was to examine the influence of atmospheric-pressure low-temperature plasma treatment on the shear bond strength between zirconia and adhesive resin cement. METHODS: The surface treatment method was classified into three groups: untreated (Cont group), alumina sandblast treatment (Sb group), and atmospheric-pressure low temperature plasma treatment (Ps group). Adhesive resin cement was applied to stainless steel and bonded to zirconia. Shear adhesion tests were performed after complete hardening of the cement. Multiple comparisons were performed using a one way analysis of variance and the Bonferroni method. X-ray diffractometry was used to examine the change in zirconia crystal structure. RESULTS: Statistically significant differences were noted between the control and Sb groups and between the control and Ps groups. In contrast, no statistically significant differences were noted for the Ps and Sb bond strength. Atmospheric-pressure low-temperature plasma treatment did not affect the zirconia crystal structure. CONCLUSIONS: Atmospheric-pressure low-temperature plasma treatment improves the bonding strength of adhesive resin cement as effectively as alumina sandblasting, and does not alter the zirconia crystal structure. PMID- 26948431 TI - Body Mass Index, the Most Widely Used But Also Widely Criticized Index: Would a Criterion Standard Measure of Total Body Fat Be a Better Predictor of Cardiovascular Disease Mortality? AB - OBJECTIVES: To examine whether an accurate measure (using a criterion standard method) of total body fat would be a better predictor of cardiovascular disease (CVD) mortality than body mass index (BMI). PARTICIPANTS AND METHODS: A total of 60,335 participants were examined between January 1, 1979, and December 31, 2003, and then followed-up for a mean follow-up period of 15.2 years. Body mass index was estimated using standard procedures. Body composition indices (ie, body fat percentage [BF%], fat mass index [FMI], fat-free mass [FFM], and FFM index [FFMI]) were derived from either skinfold thicknesses or hydrostatic weighing. For exact comparisons, the indices studied were categorized identically using sex specific percentiles. RESULTS: Compared with a medium BMI, a very high BMI was associated with a hazard ratio (HR) of 2.7 (95% CI, 2.1-3.3) for CVD mortality, which was a stronger association than for BF% or FMI (ie, HR, 1.6; 95% CI, 1.3 1.9 and HR, 2.2; 95% CI, 1.8-2.7, respectively). Compared with a medium FFMI, a very high FFMI was associated with an HR of 2.2 (95% CI, 1.7-2.7) for CVD mortality, with these estimates being markedly smaller for FFM (ie, HR, 1.2; 95% CI, 0.9-1.6). When the analyses were restricted only to the sample assessed with hydrostatic weighing (N=29,959, 51.7%), the results were similar, with even slightly larger differences in favor of BMI (ie, HR, 3.0; 95% CI, 2.2-4.0) compared with BF% and FMI (ie, HR, 1.5; 95% CI, 1.2-1.9 and HR, 2.1; 95% CI, 1.6 2.7, respectively). We estimated Harrell's c-index as an indicator of discriminating/predictive ability of these models and observed that the c-index for models including BMI was significantly higher than that for models including BF% or FMI (P<.005 for all). CONCLUSION: The simple and inexpensive measure of BMI can be as clinically important as, or even more than, total adiposity measures assessed using accurate, complex, and expensive methods. Physiological explanations for these findings are discussed. PMID- 26948432 TI - Zika virus and Guillain-Barre syndrome: another viral cause to add to the list. PMID- 26948434 TI - Chronic pancreatitis. AB - Chronic pancreatitis describes a wide spectrum of fibro-inflammatory disorders of the exocrine pancreas that includes calcifying, obstructive, and steroid responsive forms. Use of the term chronic pancreatitis without qualification generally refers to calcifying chronic pancreatitis. Epidemiology is poorly defined, but incidence worldwide seems to be on the rise. Smoking, drinking alcohol, and genetic predisposition are the major risk factors for chronic calcifying pancreatitis. In this Seminar, we discuss the clinical features, diagnosis, and management of chronic calcifying pancreatitis, focusing on pain management, the role of endoscopic and surgical intervention, and the use of pancreatic enzyme-replacement therapy. Management of patients is often challenging and necessitates a multidisciplinary approach. PMID- 26948433 TI - Guillain-Barre Syndrome outbreak associated with Zika virus infection in French Polynesia: a case-control study. AB - BACKGROUND: Between October, 2013, and April, 2014, French Polynesia experienced the largest Zika virus outbreak ever described at that time. During the same period, an increase in Guillain-Barre syndrome was reported, suggesting a possible association between Zika virus and Guillain-Barre syndrome. We aimed to assess the role of Zika virus and dengue virus infection in developing Guillain Barre syndrome. METHODS: In this case-control study, cases were patients with Guillain-Barre syndrome diagnosed at the Centre Hospitalier de Polynesie Francaise (Papeete, Tahiti, French Polynesia) during the outbreak period. Controls were age-matched, sex-matched, and residence-matched patients who presented at the hospital with a non-febrile illness (control group 1; n=98) and age-matched patients with acute Zika virus disease and no neurological symptoms (control group 2; n=70). Virological investigations included RT-PCR for Zika virus, and both microsphere immunofluorescent and seroneutralisation assays for Zika virus and dengue virus. Anti-glycolipid reactivity was studied in patients with Guillain-Barre syndrome using both ELISA and combinatorial microarrays. FINDINGS: 42 patients were diagnosed with Guillain-Barre syndrome during the study period. 41 (98%) patients with Guillain-Barre syndrome had anti-Zika virus IgM or IgG, and all (100%) had neutralising antibodies against Zika virus compared with 54 (56%) of 98 in control group 1 (p<0.0001). 39 (93%) patients with Guillain-Barre syndrome had Zika virus IgM and 37 (88%) had experienced a transient illness in a median of 6 days (IQR 4-10) before the onset of neurological symptoms, suggesting recent Zika virus infection. Patients with Guillain-Barre syndrome had electrophysiological findings compatible with acute motor axonal neuropathy (AMAN) type, and had rapid evolution of disease (median duration of the installation and plateau phases was 6 [IQR 4-9] and 4 days [3 10], respectively). 12 (29%) patients required respiratory assistance. No patients died. Anti-glycolipid antibody activity was found in 13 (31%) patients, and notably against GA1 in eight (19%) patients, by ELISA and 19 (46%) of 41 by glycoarray at admission. The typical AMAN-associated anti-ganglioside antibodies were rarely present. Past dengue virus history did not differ significantly between patients with Guillain-Barre syndrome and those in the two control groups (95%, 89%, and 83%, respectively). INTERPRETATION: This is the first study providing evidence for Zika virus infection causing Guillain-Barre syndrome. Because Zika virus is spreading rapidly across the Americas, at risk countries need to prepare for adequate intensive care beds capacity to manage patients with Guillain-Barre syndrome. FUNDING: Labex Integrative Biology of Emerging Infectious Diseases, EU 7th framework program PREDEMICS. and Wellcome Trust. PMID- 26948435 TI - Guillain-Barre syndrome. AB - Guillain-Barre syndrome is the most common and most severe acute paralytic neuropathy, with about 100,000 people developing the disorder every year worldwide. Under the umbrella term of Guillain-Barre syndrome are several recognisable variants with distinct clinical and pathological features. The severe, generalised manifestation of Guillain-Barre syndrome with respiratory failure affects 20-30% of cases. Treatment with intravenous immunoglobulin or plasma exchange is the optimal management approach, alongside supportive care. Understanding of the infectious triggers and immunological and pathological mechanisms has advanced substantially in the past 10 years, and is guiding clinical trials investigating new treatments. Investigators of large, worldwide, collaborative studies of the spectrum of Guillain-Barre syndrome are accruing data for clinical and biological databases to inform the development of outcome predictors and disease biomarkers. Such studies are transforming the clinical and scientific landscape of acute autoimmune neuropathies. PMID- 26948436 TI - Surgical Outcome in Hemodialysis Patients with Active-Phase Infective Endocarditis. AB - PURPOSE: The aim of this study was to elucidate the characteristics of chronic hemodialysis (HD) patients requiring surgery during the active phase of infective endocarditis (IE). METHODS: From December 2004 to July 2015, 58 patients underwent surgery in our institute for active IE. Seven patients had been on HD for 1-15 years. Their preoperative profiles and surgical outcomes were compared to those of the other 51 patients (non-HD group). RESULTS: The predominant causative microorganisms in the HD group were Staphylococcus spp, particularly methicillin-resistant Staphylococcus aureus (MRSA), whereas Streptococcus spp were predominant in the non-HD group. Prosthetic dysfunction (stuck valve after mechanical and structural valve dysfunction following bioprosthetic valve replacement), complete atrioventricular (AV) block, and annular abscess formation were more frequent in the HD group. In-hospital mortality was higher in the HD group (29% vs. 6%, p = 0.044). Actuarial survival in the HD and non-HD groups was 43% vs. 87% at 5 years and 43% vs. 76% at 10 years (p = 0.007). CONCLUSIONS: Early and long term outcomes in patients with chronic HD were poor. Compared to other patients, chronic HD patients undergoing valve surgery during active IE had higher incidences of MRSA infection, annular abscess formation, postoperative valve dysfunction, and postoperative complete AV block. PMID- 26948437 TI - Synthetic Evolution of Metabolic Productivity Using Biosensors. AB - Synthetic biology has progressed to the point where genes that encode whole metabolic pathways and even genomes can be manufactured and brought to life. This impressive ability to synthesise and assemble DNA is not yet matched by an ability to predictively engineer biology. These difficulties exist because biological systems are often overwhelmingly complex, having evolved to facilitate growth and survival rather than specific engineering objectives such as the optimisation of biochemical production. A promising and revolutionary solution to this problem is to harness the process of evolution to create microbial strains with desired properties. The tools of systems biology can then be applied to understand the principles of biological design, bringing synthetic biology closer to becoming a predictive engineering discipline. PMID- 26948438 TI - Checking the Biocompatibility of Plant-Derived Metallic Nanoparticles: Molecular Perspectives. AB - Understanding the biocompatibility of metallic nanoparticles (MNPs) is pivotal for biomedical applications. The biocompatibility of plant-derived MNPs has been mostly attributed to capped plant molecules. This claim seems to be straightforward but lacks conclusive evidence. The capped phytochemicals and the metallic core might have decisive and individual roles in imparting the overall biocompatibility. Whether capped phytochemicals really make sense in diminishing the toxicity effect of the otherwise naked or metallic core needs further analysis. Here, we readdress the biocompatibility of plant-derived MNPs with references to contemporary cellular assays, different reactants for green synthesis, possible epigenetic involvement, and nanobiocompatibility at the molecular level. Finally, we discuss relevant in vivo studies and large-scale production issues. PMID- 26948439 TI - CNS-accessible Inhibitor of Glucosylceramide Synthase for Substrate Reduction Therapy of Neuronopathic Gaucher Disease. AB - Gaucher disease (GD) is caused by a deficiency of glucocerebrosidase and the consequent lysosomal accumulation of unmetabolized glycolipid substrates. Enzyme replacement therapy adequately manages the visceral manifestations of nonneuronopathic type-1 Gaucher patients, but not the brain disease in neuronopathic types 2 and 3 GD. Substrate reduction therapy through inhibition of glucosylceramide synthase (GCS) has also been shown to effectively treat the visceral disease. Here, we evaluated the efficacy of a novel small molecule inhibitor of GCS with central nervous system (CNS) access (Genz-682452) to treat the brain disease. Treatment of the conduritol beta epoxide-induced mouse model of neuronopathic GD with Genz-682452 reduced the accumulation of liver and brain glycolipids (>70% and >20% respectively), extent of gliosis, and severity of ataxia. In the genetic 4L;C* mouse model, Genz-682452 reduced the levels of substrate in the brain by >40%, the extent of gliosis, and paresis. Importantly, Genz-682452-treated 4L;C* mice also exhibited an ~30% increase in lifespan. Together, these data indicate that an orally available antagonist of GCS that has CNS access is effective at attenuating several of the neuropathologic and behavioral manifestations associated with mouse models of neuronopathic GD. Therefore, Genz-682452 holds promise as a potential therapeutic approach for patients with type-3 GD. PMID- 26948440 TI - Recombinant AAV Integration Is Not Associated With Hepatic Genotoxicity in Nonhuman Primates and Patients. AB - Recombinant adeno-associated viral vectors (rAAV) currently constitute a real therapeutic strategy for the sustained correction of diverse genetic conditions. Though a wealth of preclinical and clinical studies have been conducted with rAAV, the oncogenic potential of these vectors is still controversial, particularly when considering liver-directed gene therapy. Few preclinical studies and the recent discovery of incomplete wild-type AAV2 genomes integrated in human hepatocellular carcinoma biopsies have raised concerns on rAAV safety. In the present study, we have characterized the integration of both complete and partial rAAV2/5 genomes in nonhuman primate tissues and clinical liver biopsies from a trial aimed to treat acute intermittent porphyria. We applied a new multiplex linear amplification-mediated polymerase chain reaction (PCR) assay capable of detecting integration events that are originated throughout the rAAV genome. The integration rate was low both in nonhuman primates and patient's samples. Importantly, no integration clusters or events were found in genes previously reported to link rAAV integration with hepatocellular carcinoma development, thus showing the absence of genotoxicity of a systemically administered rAAV2/5 in a large animal model and in the clinical context. PMID- 26948441 TI - Determination for multiple mycotoxins in agricultural products using HPLC-MS/MS via a multiple antibody immunoaffinity column. AB - Mycotoxins usually found in agricultural products such as peanut, corn, and wheat, are a serious threat to human health and their detection requires multiplexed and sensitive analysis methods. Herein, a simultaneous determination for aflatoxin B1, B2, G1, G2, ochratoxin A, zearalanone and T-2 toxin was investigated using high performance liquid chromatography coupled with tandem mass spectrometry in a single run via a home-made multiple immunoaffinity column. Four monoclonal antibodies were produced in our lab against aflatoxins, ochratoxin A, zearalanone and T-2 toxin, respectively, then combined as a pool and bound to Sepharose-4B for affinity chromatography. Seven mycotoxins were effectively extracted from the agricultural product samples by using acetonitrile/water/acetic acid (80:19:1, v/v/v) Then, the extraction was cleanup by multiple immunoaffinity column. This method demonstrated a considerable linear range of 0.30-25, 0.12-20, 0.30-20, 0.12-20, 0.60-30, 0.30-25, and 1.2-40MUgkg( 1)and lower limits of detection at 0.1, 0.04, 0.1, 0.04, 0.2, 0.1 and 0.4MUgkg( 1) for AFB1, AFB2, AFG1, AFG2, OTA, ZEN and T-2, respectively, in comparison with previously reported methods, as well as excellent recoveries. The mIAC capacity for AFB1, AFB2, AFG1, AFG2, OTA, ZEN, and T-2 were 187, 181, 153, 151, 105, 130, 88ng, respectively. It was found that all of the 7 mycotoxins were present in 90 agricultural product samples. The proposed method meets the requirements for rapid sample preparation and highly sensitive identification of multiple mycotoxins in agricultural product and food safety. This method provides a promising alternative with high throughput and high sensitivity for rapid analysis of seven mycotoxins in the monitoring of food safety. PMID- 26948442 TI - Recovery of agricultural nutrients from biorefineries. AB - This review lays the foundation for why nutrient recovery must be a key consideration in design and operation of biorefineries and comprehensively reviews technologies that can be used to recover an array of nitrogen, phosphorus, and/or potassium-rich products of relevance to agricultural applications. Recovery of these products using combinations of physical, chemical, and biological operations will promote sustainability at biorefineries by converting low-value biomass (particularly waste material) into a portfolio of higher-value products. These products can include a natural partnering of traditional biorefinery outputs such as biofuels and chemicals together with nutrient-rich fertilizers. Nutrient recovery not only adds an additional marketable biorefinery product, but also avoids the negative consequences of eutrophication, and helps to close anthropogenic nutrient cycles, thereby providing an alternative to current unsustainable approaches to fertilizer production, which are energy-intensive and reliant on nonrenewable natural resource extraction. PMID- 26948443 TI - Importance of monitoring and treatment of failed maturation in radiocephalic arteriovenous fistula in predialysis: Role of ultrasound. AB - The aim of the study was to analyse outcomes of AVF-RC in predialysis stage in which a clinical and radiological follow up of its maturation had been done and primary failure had been treated. MATERIAL AND METHODS: We studied 127 RC-AVF in 117 predialysis patients. All cases had a preoperative map. The RC-AVF was considered mature if it had a brachial artery flow >=500ml/min and a cephalic vein diameter of >=4mm. Primary failure was treated radiologically or surgically depending on the type of lesion. Fifty-eight patients started dialysis at the time of the study. RESULTS: In 106 RC-AVF without thrombosis, 72 (68%) were mature and 34 (32%) were immature. A total of 97% of the immature had at least one lesion, and the most common site was the post-anastomotic vein. Lesions were found in 31% of mature RC-AVF, and 18% of patients required treatment. Radiological treatment was the most frequent for maturation failure. After 6 months, primary and secondary patency were 59% and 78%, while after 12 months they were 48% and 77%, respectively. The 80% of patients started dialysis with a distal AVF (76% RC-AVF and 4% ulnar basilic). None of the patients with treated immature RC-AVF started dialysis with CVC, while 78% of the patients started with said AVF. CONCLUSION: Ultrasonography for monitoring maturation provides advantages over clinical monitoring. With our management of RC-AVF in predialysis, 80% of patients start dialysis with an adequate distal AVF. PMID- 26948444 TI - Endocytosis of the tachykinin neuropeptide, neurokinin B, in astrocytes and its role in cellular copper uptake. AB - The tachykinin neuropeptide, neurokinin B (NKB), belongs to a family of peptides having diverse roles in the brain. NKB, along with several other tachykinins, has been identified as a copper-binding peptide, however the physiological relevance of the binding is unclear. Previously, NKB was shown to limit the ability of copper to enter astrocytes and disrupt calcium homeostasis and it was thought that the peptide was sequestering the metal extracellularly. Here we use a fluorescein-labelled NKB peptide (F-NKB) to show that NKB is not retained extracellularly, but is endocytosed within 10-20min after addition to the cell media. The endocytosis is not inhibited when NKB is delivered as a copper complex, [CuII(F-NKB)2]. Endocytosis of NKB can increase intracellular copper. Comparison to cells cultured in copper-free buffer indicated that apo-NKB can facilitate uptake of copper found in normal culture media. To achieve this NKB must compete with a variety of copper proteins, and we show that NKB can successfully compete with copper-binding peptides derived from the prion protein, itself associated with Cu(II) and Zn(II) metabolism. We suggest a mechanism of receptor mediated endocytosis to account for the observations. PMID- 26948445 TI - Comment on: Abnormal calcium, 25(OH) vitamin D, and parathyroid hormone after biliopancreatic diversion; correction through elongation of the common tract and reduction of the gastric pouch. PMID- 26948446 TI - Roux-en-Y gastric bypass 10-year follow-up: the found population. AB - BACKGROUND: The long-term durability of Roux-en-Y gastric bypass (RYGB) remains ill-defined in the American population secondary to poor follow-up after bariatric surgery. OBJECTIVES: This study evaluated the population lost to follow up to better define the long-term durability of RYGB for weight loss and co morbidity amelioration. METHODS: All patients (n = 1087) undergoing RYGB at a single institution between 1985 and 2004 were evaluated. Univariate differences in preoperative co-morbidities, postoperative complications, annual weight loss, and 10-year co-morbidities were analyzed to compare outcomes between patients with routine follow-up and those without. Using electronic medical record review for all encounters at our academic medical center and telephone survey, we obtained data for patients lost to follow-up. RESULTS: Among 1087 RYGB patients, 151 (14%) had consistent 10-year follow-up in our prospectively collected database, with yearly clinic visits beyond 2 years postoperatively. Electronic medical record review and telephone survey data were collected on an additional 500 (46%) patients, resulting in 60% of patients having 10-year follow-up after RYGB. There was no statistical difference in any preoperative or postoperative variables between the 2 groups. We found no difference in co-morbidity prevalence preoperatively or at 10 years between groups. Examination of percent excess body mass index lost at yearly intervals revealed no difference between the groups at each interval up to 10 years (P = .36). CONCLUSION: We found no difference in 10 year outcomes, including weight loss and co-morbidity reduction, between patients with routine clinic visits and those lost to follow-up. These 10-year data address the gap in knowledge resulting from poor long-term follow-up after bariatric surgery. PMID- 26948447 TI - Bariatric surgery reduces urinary albumin excretion in diabetic nephropathy: a systematic review and meta-analysis. AB - BACKGROUND: Bariatric surgery is found to prevent type 2 diabetes, improve glycemic control, and decrease long-term incidence of microvascular and macrovascular complications in obese persons. However, its effect on urinary albumin excretion (UAE) in patients with diabetic nephropathy (DN) is still unknown. This is a systematic review and meta-analysis of observational studies on bariatric surgery and change in UAE in patients with diabetes. OBJECTIVE: To explore whether there is improvement in UAE after bariatric surgery. METHODS: We comprehensively searched the databases of MEDLINE, Embase, and Cochrane. The inclusion criteria were published studies evaluating effects of bariatric surgery in patients with DN at baseline. The primary outcome was the pre- and postbariatric surgery UAE as characterized by urinary albumin-to-creatinine ratio and albuminuria. A meta-analysis comparing pre- and postsurgery UAE was performed. RESULTS: From 65 full-text articles, 15 observational studies met our inclusion criteria, and 11 studies were included in the meta-analysis based on the random effects model. There was a significant reduction in urinary albumin-to creatinine ratio after bariatric surgery with a mean difference of -6.60 mg/g of creatinine (95% CI -9.19 to -4.02; P<.001). There was also a reduction in albuminuria with a mean difference of -55.76 mg/24 hours (95% CI -92.11 to 19.41; P<.001) after bariatric surgery. CONCLUSION: Bariatric surgery significantly decreases urinary albumin excretion in DN. However, studies comparing bariatric surgery and conventional or intensive care of diabetes on UAE outcome should be done. PMID- 26948448 TI - A comparison of 30-day versus 90-day proton pump inhibitor therapy in prevention of marginal ulcers after laparoscopic Roux-en-Y gastric bypass. AB - BACKGROUND: Marginal ulceration is one of the most common complications after laparoscopic Roux-en-Y gastric bypass (LRYGB) surgery. Proton pump inhibitors (PPIs) are commonly administered to decrease the incidence of marginal ulcer development. OBJECTIVE: We examine the differential impact of employing a 30-day versus 90-day postoperative PPI regimen on the development of marginal ulceration after LRYGB. SETTING: University hospital. METHODS: A retrospective cohort design was used to study all patients undergoing LRYGB at a single, high-volume bariatric center in Hamilton, Ontario, Canada. Three years previously, the duration of postoperative PPI administration was increased at our center from 30 to 90 days. Diagnosis of marginal ulceration was confirmed by upper endoscopy in patients presenting with epigastric pain and a clinical history suggestive of marginal ulceration. A chi(2) test of independence was performed to examine incidence of marginal ulceration and PPI duration. RESULTS: A total of 1016 patients underwent LRYGB at our center between January 2009 and January 2013. No differences in baseline characteristics were observed between groups. Of the 1016 patients followed, 614 received 30 days of PPI therapy and 402 received 90 days of PPI therapy. The incidence of marginal ulceration after LRYGB decreased significantly (P<.05) among patients receiving daily PPI for 90 days (n = 26, 6.5%) compared with those receiving PPI for 30 days (n = 76, 12.4%). CONCLUSION: This study suggests a significant benefit to longer duration prophylactic PPI administration after gastric bypass surgery to minimize the risk of symptomatic marginal ulceration. PMID- 26948449 TI - Repair of major lymphatic duct injury during laparoscopic sleeve gastrectomy. PMID- 26948450 TI - Perioperative noninvasive ventilation in obese patients: a qualitative review and meta-analysis. AB - BACKGROUND: Perioperative noninvasive ventilation (NIV) has been proposed to reduce postoperative morbidity and improve perioperative outcomes in patients undergoing general anesthesia. Whether it is advantageous to apply NIV just before and after general anesthesia in obese patients has not been yet established. OBJECTIVES: To perform a qualitative review and meta-analysis to assess the effectiveness and tolerability of perioperative NIV in obese patients. METHODS: All studies in English language performed in clinical setting that compared the application of NIV with standard care just before and after induction of general anesthesia in obese adults (body mass index [BMI]>=35 kg/m(2)) were included. Data on oxygenation, respiratory function, complications, and outcomes were extracted. RESULTS: Twenty-nine articles were selected and used in the qualitative review. Eleven studies including 768 patients were used for subsequent meta-analyses. Compared with standard preoxygenation, NIV was associated with a significant improvement in oxygenation (P<.0001) before tracheal intubation. Benefits in oxygenation (P<.0001), clearance of carbon dioxide (P<.0001), and pulmonary function testing (P<.0001) after general anesthesia were observed with NIV compared with standard care. Postoperatively, NIV was associated with a decreased risk of respiratory complications (relative risk [RR] = .33; 95% confidence interval [CI] .16-.66; P = .002), but not of reintubation after tracheal extubation (RR = .41; 95% CI .09-1.82]; P = .3657) and unplanned intensive care unit admission (RR = .43; 95% CI .16-1.15; P = .0937). NIV-related complications in obese patients were mainly due to intolerance and ranged from 7% to 28% of cases. NIV-related anastomotic leakage and adverse events were not reported. CONCLUSIONS: Results from this review and meta-analysis suggest that NIV is well tolerated and effective in improving perioperative care in obese patients. The application of NIV before and after general anesthesia should be considered and promoted in relevant cases. PMID- 26948451 TI - Comparison of safety between 1-stage and 2-stage surgery: from laparoscopic adjustable gastric banding to laparoscopic sleeve gastrectomy. AB - BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) is becoming increasingly popular. With significant failure rates for laparoscopic adjustable gastric banding (LAGB), conversion to LSG is an attractive consideration for maintenance of target percentage excess weight loss (%EWL). Conversions can be successfully achieved in either 1-stage (OS) or 2-stage (TS) surgery. OBJECTIVES: We intend to examine safety between OS and TS surgery and determine features indicative for OS surgery. SETTING: Records were audited from the database of a private surgical practice located in Perth, Western Australia. METHODS: We analyzed 86 patients in a prospective observational study over a 3-year time frame (38 OS, 48 TS). The primary outcome was perioperative events, graded using the Clavien-Dindo classification system. Secondary outcomes included any preoperative, intraoperative, and postoperative events. RESULTS: Surgical complications were similar between OS and TS groups. Grades of complications were not significantly different. No difference was found in procedural normality between cohorts (P = .95). More adhesions were present in the TS group compared with the OS group after accounting for adjustments (P = .05). Patient demographic characteristics were not different between groups, with the exception of body mass index (BMI). There were no staple line leaks within the OS group; 2 leaks occurred in the TS group. CONCLUSION: OS surgery appears as safe as TS surgery provided surgeons carefully assess patient eligibility. We recommend the following features for ideal OS candidacy: no previous band complications, minimal peritoneal adhesions under laparoscopy, minimal co-morbidities, and a lower BMI at entry into conversion. PMID- 26948452 TI - Response to M. Deitel. PMID- 26948453 TI - Predictive factors of biliary complications after bariatric surgery. AB - BACKGROUND: Obesity and rapid weight loss are risk factors for gallstone development. Bariatric surgery and significant postoperative weight loss are associated with postoperative biliary complications. OBJECTIVE: We aim to identify predictive factors of biliary complications after bariatric surgery. SETTING: University hospital. METHODS: After Institutional Review Board approval, charts at a single institution were reviewed to identify patients with biliary complications after bariatric surgery from 2005 to 2012. Data collected included baseline patients demographic characteristics, perioperative parameters, and postoperative biliary complications. Parameters were analyzed using paired and unpaired Student t test for continuous variables and chi2 test for categorical variables. Univariate and multivariate analyses were used to assess risk factors for complications after bariatric surgery. All tests were 2 tailed; results with P<.05 were considered statistically significant. RESULTS: One hundred thirty eight (3.6%) of 3765 patients who underwent bariatric surgery developed postoperative biliary complications. Mean time from surgery to biliary complication was 1.8+/-1.4 years. Complications included acute cholecystitis (18.1%), chronic cholecystitis (70.2%), acute pancreatitis (9.4%), choledocholithiasis (5.7%), and jaundice (2.8%). Interventions were laparoscopic (n = 134, 97.0%) and open (n = 1, .7%) cholecystectomy. Forty patients (28.9%) had known cholelithiasis before surgery. There were no mortalities. Univariate analysis identified female gender, age>50, cholelithiasis at time of bariatric procedure, and Roux-en-Y gastric bypass independent of excess weight loss as predictive factors of biliary complications. Multivariate analysis confirmed advanced age as an independent predictive factor. CONCLUSION: The results of our study suggest that patients of advanced age are at higher risk of biliary complications. However, the indications for prophylactic cholecystectomy at time of bariatric surgery remain unclear. PMID- 26948454 TI - Generation of spin in single cholesterol molecules on gold. AB - Compact islands of cholesterol on Au(111) were investigated with scanning tunneling microscopy at ~5 K. Single molecules have been switched among several states, three of which exhibit a sharp spectroscopic feature at the Fermi level. This feature signals the presence of a localized spin and suggests that the molecule may be controllably switched between paramagnetic and diamagnetic states. PMID- 26948456 TI - [World Kidney Day 2016: Averting the legacy of kidney disease. Focus on childhood]. PMID- 26948455 TI - The elevation of intraocular pressure is associated with apoptosis and increased immunoreactivity for nitric oxide synthase in rat retina whereas the effectiveness of retina derived relaxing factor is unaffected. AB - Glaucoma is a progressive ocular disease that stands in the upper rank for the cause of blindness in worldwide. In the present study, we aimed to elucidate the possible disturbances occurred in the layers of retina due to an increase in intraocular pressure (IOP) and to verify the effectiveness of retina derived relaxing factor, i.e., RRF in this pathologic condition. The increase in IOP was induced by cauterization of the three of episcleral veins simultaneously in rats. After 8 weeks period, the retinas excised from the vein cauterized eyes were evaluated for the possible histopathological and ultrastructural alterations as well as for the relaxing effects on isolated bovine retinal and rat mesenteric arteries, in comparison with the retinas obtained from contralateral sham operated eyes. In the retinas of IOP-elevated eyes, profound morphological deteriorations were determined in the ganglion and outer nuclear cell layers which were associated with an increased number of TUNEL positive cells in the ganglion and inner nuclear cell layers. Increased immunohistochemical stainings for three isoforms of nitric oxide synthase (NOS) were defined in almost all layers of the retinas of IOP-elevated eyes, in which eNOS was abundant particularly in the inner plexiform and ganglion cell layers. An irregular basal folding of retinal pigment epithelium (RPE) and an increased inter lamellar space of photoreceptor cell layer furtherly characterized the prominent degeneration of those layers in the retinas of IOP-elevated eyes. On the other hand, the relaxing effects of the retina obtained from IOP-elevated eyes were determined to be unchanged on the retinal and mesenteric arteries precontracted either with prostaglandin F2alpha (PGF2alpha, 30 MUM) or potassium chloride (K(+), 100 mM), when compared with the relaxations of control retina obtained from contralateral sham-operated eyes. Overall, these findings suggested that the elevation of IOP induces prominent structural changes in rat retina particularly in the ganglion and inner layers that is associated with marked apoptosis and increased immunoreactivity for NOS, while the functional effectiveness of retina derived relaxing factor, i.e., RRF is unaffected. PMID- 26948457 TI - Application of sepsis calculator in newborns with suspected infection. AB - OBJECTIVE: To compare actual antibiotic use to the stratification based on the sepsis calculator in newborns with suspected early onset sepsis (EOS). To investigate differences in EOS risk and vital signs between newborns that received early (<12 h) versus late antibiotics (>=12 h of life). METHODS: Newborns born >=34 weeks gestation in 2014 treated with antibiotics started within 72 h after birth were included. We calculated the risk per 1000 live births and retrospectively assigned each newborn to one of four recommended categories using the sepsis calculator. RESULTS: There were 2094 newborns, 111 (5.3%) received antibiotics and 108 newborns were included. The incidence of culture-proven EOS was 0.096%. In 57 newborns, the advice of the sepsis calculator was not to start antibiotic therapy. Antibiotic treatment was started early in 66 (61%) and late in 42 (39%) newborns. In the "late treatment" group, clinical condition deteriorated, including two newborns with culture-proven EOS. Tachypnea and respiratory distress were significantly more present. CONCLUSION: Antibiotic use could be reduced by more than 50%. Newborns with initial low sepsis risk score clinically deteriorated beyond 12 h of life. Continuous good clinical observation remains very important. Prospective validation is necessary to evaluate the safety of this approach. PMID- 26948459 TI - Our Lady of the Big Eyes of Lugo. PMID- 26948460 TI - Interest of a drug and therapeutics committee for the operation of a hospital in a developing country: Dapaong, Togo. AB - The department of pharmacy of the Regional Hospital of Dapaong is responsible for delivery of health products. We sought to assess the department's avoidable costs to optimize the hospital's drug policies and thereby improve patient care. This cost-forecasting study is intended to convince the hospital staff of the utility of setting up a drug and therapeutics committee and more particularly of developing a drug handbook for use within the public health institutions of the Savanna region. This prospective study seeks to improve the efficiency, quality, and availability of medicines by listing the references currently available at the Regional Hospital to demonstrate the percentage of duplicates and to show the references currently unavailable via "lost" sales. A retrospective study then estimated the loss of income from sales due to expired drugs. Our studies indicate that optimized management of the pharmacy would result in a potential gain of 14,914,397 FCFA, that is, 22,770 ?. This significant savings could be used to improve the quality of care and promote quality assurance at the CHRD. The elimination of duplicates would allow the purchase of currently unavailable pharmaceutical classes (12,369,701 FCFA, that is, 18,885 ? for reinvestment), and multidisciplinary collaboration with prescribers could reduce the losses associated with expired drugs (2,544,696 FCFA, or 3,885 ?). These changes would improve the matching of the drugs prescribed at the CHRD and those delivered by the pharmacy. PMID- 26948458 TI - Genetic systems for a new approach to risk of progression of diabetic retinopathy. AB - OBJECTIVE: To evaluate the risk of progression of diabetic retinopathy (DR) using new strategies to obtain genetic information in type 2 diabetes (T2D) based on interfering ribonucleic acid (RNA). MATERIAL AND METHODS: A prospective multicentre case-control study of 132 participants was distributed into: T2D with (+DR) or without (-DR) (T2DG; n=77), and a control group (CG; n=55). After an eye examination and personal interview, tears were collected for molecular analysis (expression of microRNAs [miRNAs] (miRCURY TM ARN Isolation Kit, Qiagen)]. Libraries, 137 vs. 140bp (GeneMapper, Applied Biosystems), were obtained in 18 samples (T2DG+DR=6; T2DG-DR=6; CG=6) by performing next-generation sequencing (NGS). SPSS 15.0 statistical program was used to perform data analysis. RESULTS: The mean age was 67+/-12 years in the T2DG vs. 55+/-21 years in the CG. Distribution men/women: 25/30 in T2DG vs. 51/28 in CG. A family history of DM, diet compliance, smoking, drinking and exercise, showed significant differences between groups (P<.001). A 20-25 microlitre sample of tears contained a mean of 9.42+/-3.30 ng/mL of purified ARN, with significant differences between T2DG/CG (P=.002) and T2DG+RD/CG (P=.004). Tear expression of miARNs in T2DG directly correlated with age/obesity/T2D duration (P<.05), and indirectly with visual acuity (P<.05). A total of 14 miRNAs related to the presence, pathogenic mechanisms and risk factors for the progression of diabetic retinopathy, were identified. CONCLUSIONS: We propose to use tears as a source of genetic information for DM. Specific miRNAs involved in DR development and/or progression can be used as molecular biomarkers, and based on these, for developing future biotherapies. PMID- 26948461 TI - Individual Differences in Personality Masculinity-Femininity: Examining the Effects of Genes, Environment, and Prenatal Hormone Transfer. AB - Males and females score differently on some personality traits, but the underlying etiology of these differences is not well understood. This study examined genetic, environmental, and prenatal hormonal influences on individual differences in personality masculinity-femininity (M-F). We used Big-Five personality inventory data of 9,520 Swedish twins (aged 27 to 54) to create a bipolar M-F personality scale. Using biometrical twin modeling, we estimated the influence of genetic and environmental factors on individual differences in a M-F personality score. Furthermore, we tested whether prenatal hormone transfer may influence individuals' M-F scores by comparing the scores of twins with a same sex versus those with an opposite-sex co-twin. On average, males scored 1.09 standard deviations higher than females on the created M-F scale. Around a third of the variation in M-F personality score was attributable to genetic factors, while family environmental factors had no influence. Males and females from opposite-sex pairs scored significantly more masculine (both approximately 0.1 SD) than those from same-sex pairs. In conclusion, genetic influences explain part of the individual differences in personality M-F, and hormone transfer from the male to the female twin during pregnancy may increase the level of masculinization in females. Additional well-powered studies are needed to clarify this association and determine the underlying mechanisms in both sexes. PMID- 26948462 TI - Intrauterine systems: a frameless future? AB - INTRODUCTION: Intrauterine devices (IUD) are viewed as important contraceptive methodologies to prevent unintended pregnancy. AREAS COVERED: This expert opinion examines the place of frameless devices for use in young women in order to minimize side effect, improve patient comfort and maximize continuation of use to help reduce unintended pregnancies. EXPERT OPINION: Frameless designed IUDs have the ability to be used in both small and large uterine cavities of varied shapes and can significantly reduce abnormal bleeding, pain, embedment and expulsion and likely account for higher continuation rates than that seen with framed IUDs. PMID- 26948464 TI - Trend of Nutritional Support in Preterm Infants. AB - Without appropriate nutritional support, preterm infants fail to grow after birth and have malnutrition. The main reason for delayed feeding is fear of immaturity of gastrointestinal function. The principles of nutritional practice should be as follows: (1) minimal early initiation of enteral feeding with breast milk (0.5-1 mL/h) to start on Day 1 if possible and gradual increase as tolerated; (2) early aggressive parenteral nutrition as soon as possible; (3) provision of lipids at rates that will meet the additional energy needs of about 2-3 g/kg/d; and (4) attempt to increase enteral feeding rather than parenteral nutrition. PMID- 26948465 TI - Acute Pain and Analgesic Requirements After Pulmonary Endarterectomy With Deep Hypothermic Circulatory Arrest. AB - OBJECTIVES: To assess postoperative pain intensity and the analgesic requirements in the postoperative period in patients undergoing sternotomy for pulmonary endarterectomy involving deep hypothermic circulatory arrest. DESIGN: Retrospective cohort study. SETTING: Single-center hospital study. PARTICIPANTS: Patients 18 years and older undergoing sternotomy for cardiac surgery between August 2012 and August 2014. INTERVENTIONS: No modification to usual clinical practice. MEASUREMENTS AND MAIN RESULTS: Intraoperative opioid and steroid administration, referral to the chronic pain unit, intensive care unit pain scores, and analgesic administration in the first 48 hours after the admission to the intensive care unit were recorded. Postoperative pain was evaluated by means of a categoric verbal scale from no pain (0) to severe pain (3); this is the routine analgesic scale used in the authors' intensive care unit. A total of 200 consecutive patients undergoing pulmonary endarterectomy (PEA group) were included in the study. No patient in the PEA group received morphine during surgery. The mean (standard deviation) postoperative pain intensity score at 24 hours was 0.30 (0.54) in the PEA group. Postoperative morphine was administered in 39% of patients. No PEA patient was referred to the chronic pain unit after hospital discharge. CONCLUSION: The total analgesic requirements and pain score of patients undergoing sternotomy for pulmonary endarterectomy with deep hypothermic circulatory arrest seemed to be low. PMID- 26948466 TI - Protamine Administration Via the Ascending Aorta May Prevent Cardiopulmonary Instability. AB - OBJECTIVE: The method of protamine administration may influence adverse reactions. The authors investigated the effects of 3 different methods of protamine administration on cardiopulmonary function. DESIGN: Prospective, randomized clinical study. SETTING: Single university hospital. PARTICIPANTS: Human volunteer patients. INTERVENTIONS: Ninety-five patients undergoing cardiac surgery were randomized prospectively into 3 groups. Group central vein control (CVC) and group central vein (CV) received protamine via a central vein over 10 minutes and 2 minutes, respectively. Group ascending aorta (AA) received protamine via the ascending aorta over 2 minutes. Hemodynamic parameters were assessed at 7 intraoperative time points, and pulmonary parameters were assessed at 4 intraoperative time points. MEASUREMENTS AND MAIN RESULTS: The groups were similar regarding preoperative demographics, intraoperative care, and baseline cardiopulmonary function. However, both the CVC and CV groups exhibited decreased blood pressure and impaired pulmonary oxygenation after protamine administration; these changes were not observed in the AA group. Within-group changes in mean arterial blood pressure after protamine administration were significant in the AA group (mean increase 6.5 mmHg; p = 0.01) but not in the CVC (mean decrease 3.1 mmHg, p = 0.13) or CV (mean decrease 4.3 mmHg, p = 0.14) groups. Within-group changes in arterial oxygenation after protamine administration were significant in the CVC (mean decrease 85 mmHg; p<0.001) and CV (mean decrease 47 mmHg; p = 0.009) groups but not in the AA group (mean decrease 8 mmHg; p = 0.82). CONCLUSIONS: The results indicated that administration of protamine via the ascending aorta may be the preferred route. The potential ability of administering protamine via the ascending aorta to prevent cardiopulmonary instability in patients undergoing cardiac surgery deserves further clinical investigation. PMID- 26948476 TI - The effect of prone positioning with surgical bolsters on liver blood flow in healthy volunteers. AB - This study sought to identify changes in hepatic flood flow and cardiac output during prone positioning on surgical bolsters in awake volunteers, and was prompted by a local incident of significant hepatic dysfunction following surgery in the prone position. Cardiac output was determined using the non-invasive Penaz technique, and plasma disappearance rate of indocyanine green (ICG-PDR) was measured as a surrogate maker for hepatic blood flow along with serum hepatic enzyme assays. Measurements were made after one hour in supine, prone and returned supine positions. Ten volunteers completed the study. There were significant changes in the disappearance rate of indocyanine green, which decreased this from mean (SD) 31.1 (9.70) supine to 19.6 (4.37)%.min prone, respectively (p = 0.02), increasing on return to the supine position to 24.6 (5.54)%.min (p = 0.019). Cardiac output was also significantly reduced when changing from the supine to the prone position, from mean (SD) 4.7 (1.0 to 3.5 (1.1) (l.min(-1) ), respectively (p = 0.002). We demonstrated an acute and reversible change in both hepatocellular function and cardiac output associated with the prone position. PMID- 26948477 TI - Large-scale nanoelectromechanical switches based on directly deposited nanocrystalline graphene on insulating substrates. AB - The direct growth of graphene on insulating substrate is highly desirable for the commercial scale integration of graphene due to the potential lower cost and better process control. We report a simple, direct deposition of nanocrystalline graphene (NCG) on insulating substrates via catalyst-free plasma-enhanced chemical vapor deposition at relatively low temperature of ~800 degrees C. The parametric study of the process conditions that we conducted reveals the deposition mechanism and allows us to grow high quality films. Based on such film, we demonstrate the fabrication of a large-scale array of nanoelectromechanical (NEM) switches using regular thin film process techniques, with no transfer required. Thanks to ultra-low thickness, good uniformity, and high Young's modulus of ~0.86 TPa, NCG is considered as a promising material for high performance NEM devices. The high performance is highlighted for the NCG switches, e.g. low pull-in voltage <3 V, reversible operations, minimal leakage current of ~1 pA, and high on/off ratio of ~10(5). PMID- 26948478 TI - Foreword. PMID- 26948468 TI - Prostate cancer - evidence of exercise and nutrition trial (PrEvENT): study protocol for a randomised controlled feasibility trial. AB - BACKGROUND: A growing body of observational evidence suggests that nutritional and physical activity interventions are associated with beneficial outcomes for men with prostate cancer, including brisk walking, lycopene intake, increased fruit and vegetable intake and reduced dairy consumption. However, randomised controlled trial data are limited. The 'Prostate Cancer: Evidence of Exercise and Nutrition Trial' investigates the feasibility of recruiting and randomising men diagnosed with localised prostate cancer and eligible for radical prostatectomy to interventions that modify nutrition and physical activity. The primary outcomes are randomisation rates and adherence to the interventions at 6 months following randomisation. The secondary outcomes are intervention tolerability, trial retention, change in prostate specific antigen level, change in diet, change in general physical activity levels, insulin-like growth factor levels, and a range of related outcomes, including quality of life measures. METHODS/DESIGN: The trial is factorial, randomising men to both a physical activity (brisk walking or control) and nutritional (lycopene supplementation or increased fruit and vegetables with reduced dairy consumption or control) intervention. The trial has two phases: men are enrolled into a cohort study prior to radical prostatectomy, and then consented after radical prostatectomy into a randomised controlled trial. Data are collected at four time points (cohort baseline, true trial baseline and 3 and 6 months post-randomisation). DISCUSSION: The Prostate Cancer: Evidence of Exercise and Nutrition Trial aims to determine whether men with localised prostate cancer who are scheduled for radical prostatectomy can be recruited into a cohort and subsequently randomised to a 6-month nutrition and physical activity intervention trial. If successful, this feasibility trial will inform a larger trial to investigate whether this population will gain clinical benefit from long-term nutritional and physical activity interventions post-surgery. Prostate Cancer: Evidence of Exercise and Nutrition Trial (PrEvENT) is registered on the ISRCTN registry, ref number ISRCTN99048944. Date of registration 17 November 2014. PMID- 26948480 TI - The Abbott RealTime MTB assay and the Cepheid GeneXpert assay show comparable performance for the detection of Mycobacterium tuberculosis in sputum specimens. AB - OBJECTIVES: To evaluate the performance of the newly developed technology Abbott RealTime MTB assay (RealTime MTB assay) for the detection of Mycobacterium tuberculosis in sputum specimens and to compare its performance with that of the Cepheid GeneXpert assay. METHODS: Sputum specimens were collected from 270 subjects suspected to have tuberculosis (TB). Smear microscopy, culture, identification, RealTime MTB, and GeneXpert assays were performed according to standard protocols. Accuracy measures of the method evaluated were determined using solid culture as the reference standard. RESULTS: The RealTime MTB assay showed similar positive detection rates as the GeneXpert assay in smear-positive, culture-positive, and smear/culture-negative groups; no significant differences were found in these groups between the two assays. The RealTime MTB assay demonstrated a sensitivity of 100% and a specificity of 84.4%; the GeneXpert assay had a sensitivity of 96.9% and specificity of 89.6%. After the resolution of discordant results by PCR-based molecular method, the sensitivities and specificities of the RealTime MTB and GeneXpert assays were 100% vs. 97% and 90.0% vs. 95.6%, respectively; no significant difference in sensitivity or specificity was found between the RealTime MTB and GeneXpert assays. CONCLUSIONS: This study demonstrated that the Abbott RealTime MTB and Cepheid GeneXpert assays have similar sensitivity and specificity. The Abbott RealTime MTB assay is a highly promising method for the diagnosis of TB. PMID- 26948479 TI - The platelet-to-lymphocyte ratio, superior to the neutrophil-to-lymphocyte ratio, correlates with hepatitis C virus infection. AB - OBJECTIVES: The platelet-to-lymphocyte ratio (PLR) and neutrophil-to-lymphocyte ratio (NLR) have been studied widely in cancer diseases. However, their correlation with hepatitis C virus (HCV) infection is unknown. The aim of this study was to investigate the correlation of PLR and NLR with disease severity in patients with HCV-related liver disease and the virological response in chronic hepatitis C (CHC) patients. METHODS: The clinical data of 120 HCV-infected patients and 40 healthy controls were analyzed. The clinical data of 24 CHC patients who had been followed up regularly were collected for the following time points: before treatment (week 0) and weeks 4, 48, and 72 during treatment. These data were also analyzed. All data were collected from the database of the hospital patient electronic medical record system. RESULTS: The HCV-related cirrhosis group and HCV-related hepatocellular carcinoma group were found to have lower PLRs (61+/-31 and 51+/-23) than the healthy controls (115+/-23). The PLR of the HCV cleared group (154+/-85) was significantly higher than that of the HCV untreated group and HCV uncleared group (90+/-28 and 88+/-40, respectively). Receiver operating characteristics curve analysis for the PLR showed an area under the curve of 0.772 (95% confidence interval 0.674-0.869, p<0.000); for NLR, the area under the curve was 0.612 (95% confidence interval 0.495-0.730, p=0.063). Furthermore, an increasing PLR in CHC patients indicated a good virological response, and a stable PLR or a downward trend in PLR could predict no rapid virological response being achieved by week 4, and even no sustained virological response by week 72. CONCLUSIONS: The PLR is closely related to disease severity in patients with HCV-related liver disease and to the virological response in CHC patients. Dynamic continuous monitoring of the PLR will contribute to disease surveillance, with an increasing tendency predicting a good virological response. PMID- 26948481 TI - Actinomycosis resembling liver tumor with multiple metastasis. PMID- 26948482 TI - Erratum to: Safety and efficacy of dual direct-acting antiviral therapy (daclatasvir and asunaprevir) for chronic hepatitis C virus genotype 1 infection in patients on hemodialysis. PMID- 26948483 TI - The developmental course of suicidal ideation in first-episode psychosis. PMID- 26948484 TI - Trajectories of suicidal ideation in patients with first-episode psychosis: secondary analysis of data from the OPUS trial. AB - BACKGROUND: Heterogeneity in suicidal ideation over time in patients with first episode psychosis is expected, but prototypical trajectories of this have not yet been established. We aimed to identify trajectories of suicidal ideation over a 3 year period and to examine how these trajectories relate to subsequent suicidality. METHODS: We used longitudinal data from the prospective 10-year follow-up OPUS trial of young Danish patients with first-episode psychosis. Participants were recruited between January, 1998, and December, 2000, from all inpatient and outpatient mental health services in Copenhagen and Aarhus County, were aged between 18 and 45 years, and had a diagnosis in the schizophrenia spectrum. Randomisation was done by a computer-generated randomisation list, stratified in alternating blocks for five centres. In Aarhus, a secretary drew lots when the researcher phoned her. Patients were randomly assigned to a treatment group (modified assertive community treatment) or a control group (standard treatment at community mental health centres) and assessed at treatment initiation, and after 1, 2, 5, and 10 years. We included all patients' data on suicidal ideation from the first three assessments in a latent growth mixture modelling analysis to empirically identify trajectories of suicidal ideation. Multivariable logistic regression analyses were applied to estimate associations between trajectories and subsequent suicidality. This trial is registered with ClinicalTrials.gov, number NCT00157313. FINDINGS: Three trajectories for suicidal ideation were identified in 521 patients. 317 of 521 members (61%) of the largest trajectory, low-decreasing, consisted of patients who initially reported suicidal ideation once-to-a-few-times in the past year followed by a decrease in suicidal ideation. 172 of 521 (33%) members of the frequent-stable trajectory reported suicidal ideation sometimes-to-frequently at the first assessment and remained stable over time. Finally, 32 of 521 (6%) members of the frequent-increasing trajectory reported frequent suicidal ideation initially followed by worsening. Compared with the low-decreasing class, the risk of persistent suicidal ideation was higher for patients in the frequent-stable and frequent-increasing classes at 5 years (Odds ratio=4.5, 95% CI 2.50-8.02 and 4.7, 1.55-14.24 respectively) and at 10 years (4.2, 2.42-7.13 and 3.2, 1.20-8.70 respectively). Also the risk of suicide attempt at 5 years was higher for patients in the frequent-stable (2.8, 1.07-7.43) and frequent-increasing classes (6.6, 1.69-25.54) compared with the low-decreasing class. There was no difference in suicide rate at 5 or 10 years between trajectories. INTERPRETATION: Because up to 40% of patients experienced frequent suicidal ideations that persisted or increased during the first years of treatment, our findings warrant special focus on suicidal issues as an integral part of treatment along with treatment to target psychotic symptoms. FUNDING: The Danish Council for Independent Research (Medical Sciences), Trygfonden, The Mental Health Services of the Capital Region of Denmark, The Danish Ministry of Health, The Danish Ministry of Social Affairs, the Psychiatry and Social Service Department in Central Denmark Region, and The Lundbeck Foundation. PMID- 26948485 TI - Risk factors for fatal and nonfatal reactions to subcutaneous immunotherapy: National surveillance study on allergen immunotherapy (2008-2013). AB - BACKGROUND: In 2008, an annual surveillance study of systemic reactions (SRs) from subcutaneous immunotherapy (SCIT) injections was initiated in North America. OBJECTIVE: To define the incidence of SRs to SCIT. METHODS: From 2008 to 2013, 27% to 51% of American Academy of Allergy, Asthma, and Immunology and American College of Asthma, Allergy, and Immunology members completed an annual survey of SCIT-related SRs of varying severity. From 2012 to 2013, data were collected regarding SRs with off-label sublingual immunotherapy (SLIT), selection of patients with asthma for SCIT, and strategies for dose adjustment during pollen seasons. RESULTS: From 2008 to 2013, data were gathered on 28.9 million injection visits, including 344,480 patients for 2012 to 2013. Since 2008, a total of 2 confirmed fatalities were directly reported that occurred under the care of allergists. Two additional fatalities occurred under the care of nonallergists. The rate of SRs from SCIT remained stable, occurring in 1.9% of patients, with 0.08% and 0.02% experiencing grade 3 and 4 SRs. SRs occurred in 1.4% of patients receiving off-label SLIT, including 0.03% with grade 3 SRs. There were no SLIT related grade 4 SRs or fatalities. Practices that never administered SCIT in patients with uncontrolled asthma (Asthma Control Test score <20) had significantly fewer grade 3 and 4 SRs (odds ratio, 0.7; 95% confidence interval, 0.5-1.0, and odds ratio, 0.3; 95% confidence interval, 0.1-0.8, respectively). Lowering doses during pollen seasons for patients with highly positive skin tests reduced SRs of all severity grades (P < .05). CONCLUSIONS: SCIT-related fatality rates may be decreasing, but continued vigilance regarding modifiable risk factors, including careful patient selection, is needed. Dose adjustment during pollen seasons for highly sensitive patients may reduce risks. Potential risk for SRs from off-label SLIT exists. PMID- 26948486 TI - Intercalation-assisted longitudinal unzipping of carbon nanotubes for green and scalable synthesis of graphene nanoribbons. AB - We have demonstrated an effective intercalation of multi-walled carbon nanotubes (MWCNTs) for the green and scalable synthesis of graphene nanoribbons (GNRs) using an intercalation-assisted longitudinal unzipping of MWCNTs. The key step is to introduce an intercalation treatment of raw MWCNTs with KNO3 and H2SO4, making it promising to decrease the strong van der Waals attractions in the MWCNTs bundles and between the coaxial graphene walls of CNTs. Systematic micro Raman, X ray photoelectron spectroscopy (XPS), and X-ray diffraction (XRD) characterizations suggest that potassium, nitrate, and sulfate ions play an important role in the CNT intertube and intratube intercalations during the pretreatment. Detailed scanning electron microscopy (SEM), transmission electron microscopy, XRD, and micro Raman characterizations indicate that the developed methodology possesses the ability to synthesis GNRs effectively with an improved CNT concentration in H2SO4 of 10 mg/ml at 70 degrees C, which is amenable to industrial-scale production because of the decreased amount of strong acid. Our work provides a scientific understanding how to enhance the GNR formation by accelerating the CNT longitudinal unzipping via suitable molecular intercalation. PMID- 26948487 TI - Post-occlusive reactive hyperaemia (POHR) in systemic sclerosis: very early disease (VEDOSS) represents a separate entity compared to established disease. AB - OBJECTIVES: Vascular involvement is a key feature of systemic sclerosis (SSc). Vascular changes are central to the pathogenesis of the disease and the assessment of vascular involvement has a prognostic value. This assessment therefore has a pivotal role in the management of SSc patients. The aim of our study was to evaluate post-occlusive reactive hyperaemia (PORH) in consecutive SSc patients and to test whether a PORH test might be a useful tool for the early diagnosis of SSc. METHOD: Between April 2011 and April 2015, 60 consecutive SSc patients (mean age 56 +/- 15 years, females:males = 18:1) were enrolled in the study. The patients were divided into those with full-blown SSc (n = 50) and those with very early diagnosis of SSc (VEDOSS) (n = 10) according to the literature. Laser speckle contrast analysis (LASCA) was used to assess PORH. RESULTS: A statistically significant difference was detected in the post ischaemic hyperaemic peak flow between VEDOSS and established SSc (424% vs. 137%, p = 0.0011). PORH peak flow decreased according to the capillaroscopic pattern (early = 419%, active = 163%, late = 145%, p = 0.0027). Moreover, a correlation between capillary density and peak flow was revealed (rho = 0.33, p < 0.01). CONCLUSIONS: These data show a different pattern of vascular involvement in VEDOSS compared to established disease that mirrors capillaroscopic changes. Functional features of very early and established disease seem to be the physiological counterpart of abnormalities detected by capillaroscopy. The POHR test might be a useful aid for further characterization of vascular involvement in SSc. In particular, blunted POHR might prove a tool to separate pre-clinical from full-blown SSc. PMID- 26948488 TI - Copper-catalyzed oxidative coupling between quinazoline 3-oxides and unactivated aldehydes: an efficient approach to functionalized quinazolines. AB - A copper-catalyzed oxidative coupling between quinazoline 3-oxides and unactivated aldehydes was described. The reaction worked well for both aliphatic and aromatic aldehydes and produced not only the direct oxidative coupling ketones but also cyclic hydroxamic esters derived from quinazolines. PMID- 26948490 TI - Raman chemical imaging of the rhizosphere bacterium Pantoea sp. YR343 and its co culture with Arabidopsis thaliana. AB - Chemical imaging of plant-bacteria co-cultures makes it possible to characterize bacterial populations and behaviors and their interactions with proximal organisms, under conditions closest to the environment in the rhizosphere. Here Raman micro-spectroscopy and confocal Raman imaging are used as minimally invasive probes to study the rhizosphere bacterial isolate, Pantoea sp. YR343, and its co-culture with model plant Arabidopsis thaliana by combining enhanced Raman spectroscopies with electron microscopy and principal component analysis (PCA). The presence of carotenoid pigments in the wild type Pantoea sp. YR343 was characterized using resonance Raman scattering, which was also used to confirm successful disruption of the crtB gene in an engineered carotenoid mutant strain. Other components of the Pantoea sp. YR343 cells were imaged in the presence of resonantly enhanced pigments using a combination of surface enhanced Raman imaging and PCA. Pantoea sp. YR343 cells decorated with Ag colloid synthesized ex situ gave spectra dominated by carotenoid scattering, whereas colloids synthesized in situ produced spectral signatures characteristic of flavins in the cell membrane. Scanning electron microscopy (SEM) of whole cells and transmission electron microscopy (TEM) images of thinly sliced cross-sections were used to assess structural integrity of the coated cells and to establish the origin of spectral signatures based on the position of Ag nanoparticles in the cells. Raman imaging was also used to characterize senescent green Arabidopsis thaliana plant roots inoculated with Pantoea sp. YR343, and PCA was used to distinguish spectral contributions from plant and bacterial cells, thereby establishing the potential of Raman imaging to visualize the distribution of rhizobacteria on plant roots. PMID- 26948489 TI - HOT mutation screening in human glioblastomas. AB - AIMS: Somatic mutations in IDH1 and IDH2 are described in glioblastomas (GBMs). Mutant IDH1 and IDH2 reduce alpha-KG to D-2HG which accumulates, and is proposed to promote tumorigenesis. HOT catalyzes the conversion of gamma-hydroxybutyrate to succinic semialdehyde in a reaction that produces D-2HG. Since increased HOT enzyme activity could lead to an accumulation of D-2HG, coupled with the fact that only a minority of GBMs carry IDH1/2 mutations and 2HG accumulation has recently been described in IDH wild-type tumors, we analyzed a set of GBM samples for mutations in the HOT gene. MATERIALS & METHODS: We screened 42 human GBM samples for mutations in HOT. RESULTS: No mutations in HOT were identified in the 42 GBM samples screened. CONCLUSION: Mutations in the coding regions of HOT do not occur at an appreciable frequency in GBM. PMID- 26948491 TI - Summer rainfall over the southwestern Tibetan Plateau controlled by deep convection over the Indian subcontinent. AB - Despite the importance of precipitation and moisture transport over the Tibetan Plateau for glacier mass balance, river runoff and local ecology, changes in these quantities remain highly uncertain and poorly understood. Here we use observational data and model simulations to explore the close relationship between summer rainfall variability over the southwestern Tibetan Plateau (SWTP) and that over central-eastern India (CEI), which exists despite the separation of these two regions by the Himalayas. We show that this relationship is maintained primarily by 'up-and-over' moisture transport, in which hydrometeors and moisture are lifted by convective storms over CEI and the Himalayan foothills and then swept over the SWTP by the mid-tropospheric circulation, rather than by upslope flow over the Himalayas. Sensitivity simulations confirm the importance of up-and over transport at event scales, and an objective storm classification indicates that this pathway accounts for approximately half of total summer rainfall over the SWTP. PMID- 26948492 TI - Means and ENDS - e-cigarettes, the Framework Convention on Tobacco Control, and global health diplomacy in action. AB - E-cigarettes are a new and disruptive element in global health diplomacy (GHD) and policy-making. This is an ethnographic account of how e-cigarettes and other Electronic Nicotine Delivery Systems (ENDS) were tackled at the 6th Conference of the Parties to the World Health Organization's Framework Convention on Tobacco Control. It demonstrates how uncertainty about ENDS and differences of opinion are currently so great that 'agreeing to disagree' as a consensus position and 'strategic use of time' were the principles that ensured effective GHD in this case. Observers representing accredited non-governmental organisations were active in briefing and lobbying country delegates not to spend too much time debating an issue for which insufficient evidence exists, and for which countries were unlikely to reach a consensus on a specific regulatory approach or universally applicable regulatory measures. Equally, the work of Costa Rica in preparing and re-negotiating the draft decision, and the work of the relevant Committee Chair in managing the discussion, contributed to effectively reining in lengthy statements from Parties and focusing on points of consensus. As well as summarising the debate itself and analysing the issues surrounding it, this account offers an example of GHD working effectively in a situation of epistemic uncertainty. PMID- 26948493 TI - The Use of Magnetic Resonance Spectroscopy in the Evaluation of Pediatric Patients With Seizures. AB - BACKGROUND: The objective was to determine if it is useful to routinely add magnetic resonance spectroscopy (MRS) to magnetic resonance imaging (MRI) in the evaluation of seizure in the pediatric patient. Specifically, how often does MRS contribute information to conventional MRI? METHODS: A retrospective search, over a period of 3 years, of patients <18 years of age who underwent both MRI and MRS as part of the evaluation of seizures yielded a total of 233 cases in 216 patients. The medical records were reviewed to determine how many patients carried a diagnosis relevant to seizures. The MRIs and MRSs were reviewed by two neuroradiologists and an MR physicist/spectroscopist who determined by consensus in how many cases MRS contributed information regarding management, diagnosis, or prognosis, in addition to the findings on MRI alone. RESULTS: In 100 of 233 cases (43%), MRS contributed information additional to MRI. In 40 cases, MRS contributed information relevant to patient management by prompting an evaluation for an underlying inborn error of metabolism. MRS contributed information relevant to diagnosis in 24 of 100 cases (e.g., neoplasm versus dysplasia). MRS contributed information relevant to prognosis in 36 cases (e.g., hypoxic-ischemic injury). MRS added more information in cases where the patients had a diagnosis relevant to seizure before imaging. Interestingly, in 25 cases where the MRI was normal, MRS was found to be abnormal, which prompted evaluation for an inborn error of metabolism. CONCLUSIONS: These results suggest that MRS is a useful evaluation tool in addition to MRI for children undergoing imaging for the evaluation of seizures. PMID- 26948494 TI - Tiny RNA with great effects: miR-155 in alcoholic liver disease. PMID- 26948496 TI - Direct acting antivirals for decompensated cirrhosis. Efficacy and safety are now established. PMID- 26948495 TI - Constitutive androstane receptor (Car)-driven regeneration protects liver from failure following tissue loss. AB - BACKGROUND & AIMS: Liver can recover following resection. If tissue loss is too excessive, however, liver failure will develop as is known from the small-for size-syndrome (SFSS). The molecular processes underlying liver failure are ill understood. Here, we explored the role and the clinical potential of Nr1i3 (constitutive androstane receptor, Car) in liver failure following hepatectomy. METHODS: Activators of Car, various hepatectomies, Car(-/-) mice, humanized CAR mice, human tissue and ex vivo liver slice cultures were used to study Car in the SFSS. Pathways downstream of Car were investigated by in vivo siRNA knockdown. RESULTS: Excessive tissue loss causing liver failure is associated with deficient induction of Car. Reactivation of Car by an agonist normalizes all features associated with experimental SFSS. The beneficial effects of Car activation are relayed through Foxm1, an essential promoter of the hepatocyte cell cycle. Deficiency in the CAR-FOXM1 axis likewise is evident in human SFSS. Activation of human CAR mitigates SFSS in humanized CAR mice and improves the culture of human liver slices. CONCLUSIONS: Impaired hepatic Car-Foxm1 signaling provides a first molecular characterization of liver that fails to recover after tissue loss. Our findings place deficient regeneration as a principal cause behind the SFSS and suggest CAR agonists may bear clinical potential against liver failure. LAY SUMMARY: The unique regenerative capacity of liver has its natural limits. Following tissue loss that is too excessive, such as through extended resection in the clinic, liver failure may develop. This is known as small-for-size syndrome (SFSS) and represents the most frequent cause of death due to liver surgery. Here we show that deficient induction of the protein Car, a central regulator of liver function and growth, is a cause of liver failure following extended resection; reactivation of Car through pharmacological means is sufficient to prevent or rescue the SFSS. PMID- 26948497 TI - Understanding collective agency in bioethics. AB - Bioethicists tend to focus on the individual as the relevant moral subject. Yet, in highly complex and socially differentiated healthcare systems a number of social groups, each committed to a common cause, are involved in medical decisions and sometimes even try to influence bioethical discourses according to their own agenda. We argue that the significance of these collective actors is unjustifiably neglected in bioethics. The growing influence of collective actors in the fields of biopolitics and bioethics leads us to pursue the question as to how collective moral claims can be characterized and justified. We pay particular attention to elaborating the circumstances under which collective actors can claim 'collective agency.' Specifically, we develop four normative-practical criteria for collective agency in order to determine the conditions that must be given to reasonably speak of 'collective autonomy'. For this purpose, we analyze patient organizations and families, which represent two quite different kinds of groups and can both be conceived as collective actors of high relevance for bioethical practice. Finally, we discuss some practical implications and explain why the existence of a shared practice of trust is of immediate normative relevance in this respect. PMID- 26948498 TI - Prognostic impact of the site of portal vein invasion in patients with surgically resected perihilar cholangiocarcinoma. AB - BACKGROUND: The aim of this study was to determine the impact of the site of portal vein invasion on survival after hepatectomy for perihilar cholangiocarcinoma. METHODS: This study classified 168 patients undergoing resection for perihilar cholangiocarcinoma histologically as without portal vein resection or tumor invasion to the portal vein (PV0), with tumor invasion to unilateral branches of the portal vein (PVt3), or with tumor invasion to the main portal vein or its bilateral branches, or to unilateral second-order biliary radicals with contralateral portal vein involvement (PVt4). Patients in PVt4 were subclassified into the A-M group (cancer invasion limited to the tunica adventitia or media) or the I group (cancer invasion reaching the tunica intima). RESULTS: Of the patients, 121 were in PV0, 21 were in PVt3, and 26 were in PVt4. There was no difference in survival between the PV0 and PVt3 groups (P = .267). The PVt4 group had a worse prognosis than the PVt3 group (P = .046). In addition, the A-M (n = 19) and I subgroups (n = 7) of PVt4 had worse prognoses than the PV0 or PVt3 groups (P = .005 and < .001, respectively). All patients in the I subgroup of PVt4 died within 9 months after resection. On multivariate analysis, PVt4 (P = .029) was identified as an independent prognostic factor. CONCLUSIONS: In perihilar cholangiocarcinoma, postoperative survival was no different between patients with and without ipsilateral portal vein invasion, although patients with tumor invasion to the main or contralateral branches of the portal vein, especially with tunica intima invasion, had extremely poor prognoses. PMID- 26948500 TI - Intensive alcohol consumption by adolescents in Southern Spain: The importance of friendship. AB - BACKGROUND: There has been an increase in intensive alcohol drinking by Spanish adolescents since the 1990s, especially among the females, but there has been limited exploration of this phenomenon. The objective of this study was to analyse the discourses of Spanish adolescents on their drinking behaviour at contextual, relational, and personal levels. METHODS: A qualitative study was undertaken in 96 adolescents aged between 14 and 17 years who had experienced at least one intensive drinking episode during the previous year. They lived with family members and were not offenders or at risk of social exclusion. Participants were recruited at educational centres and youth centres in two provinces in southern Spain. Ten focus groups and 30 in-depth individual interviews were conducted. A summative content analysis was performed. RESULTS: Intensive alcohol drinking was widely practiced in this study population. Consolidation of this practice was influenced by cultural, interpersonal and personal dimensions. Consumption in public spaces emerged as a key influential factor, especially the botellon, a collective space-time in which Spanish adolescents socialize and become initiated into intensive alcohol consumption. Besides the facilitating elements of the social and cultural setting, the results also evidence the effects of interpersonal relationships within the peer group, which offer a series of approaches to risk and protective practices. In these adolescents, the main reason for engaging in alcohol drinking was to enhance their social relationships, which acted as a mechanism to normalize intensive alcohol consumption. CONCLUSIONS: Policies to reduce the harm caused to adolescents by intensive alcohol drinking need to take account of the contextual, relational and personal dimensions of this practice. The discourses of these adolescents from Southern Spain point to a potential role for the peer group in harm reduction strategies. PMID- 26948499 TI - The laparoscopic Glissonian approach is safe and efficient when compared with standard laparoscopic liver resection: Results of an observational study over 7 years. AB - OBJECTIVE: This study compares the Glissonian approach with the standard approach to laparoscopic liver resection for safety and efficacy. BACKGROUND: The standard laparoscopic approach to anatomic liver resection is the dissection of the elements of the Glissonian pedicle below the hilar plate. In contrast, the Glissonian approach identifies the intrahepatic pedicles by tentative clamping. Concerns have been raised about the safety of the Glissonian approach in laparoscopic liver surgery. The study was performed to examine the initial 7 years of experience in a single center with regard to safety and efficacy. METHODS: All consecutive patients undergoing laparoscopic liver resections from April 2007 to April 2014 at a single referral center for liver tumors were included. An observational comparison was performed between Glissonian and standard laparoscopic liver resections performed by the same team but during different eras. The primary endpoint was safety of the procedures as assessed by the recently published comprehensive complication index. Secondary endpoints were parameters of surgical efficacy, such as operating time, blood loss, blood transfusion, conversion rate, duration of hospitalization, and pathologic margin of the specimen. RESULTS: Between 2007 and 2014, 234 resections were performed laparoscopically at our institution, 120 using the conventional approach and 114 using the Glissonian approach. There was no difference in age, sex, tumor types, or comorbidities between the groups. The number of major liver resections was greater in the Glissonian group, yet there were fewer complications in the Glissonian group compared with the standard group (P < .05). Operative time was greater and more transfusions were given in the standard group; in addition, more patients had positive margins (P < .01). Overall hospital stay was less in the Glissonian group. CONCLUSIONS: In the 7-year experience of a single center, the Glissonian approach is not less safe and may seems to offer advantages when compared with the standard laparoscopic approach. PMID- 26948502 TI - Social behavior, interaction appraisals, and suicidal ideation in schizophrenia: The dangers of being alone. AB - Despite the increasing attention to social appraisals in suicide risk, the interpersonal correlates of suicidal thoughts and behavior in schizophrenia are not well understood. Ecological momentary assessment could reveal whether dysfunctional social appraisals and behavior are evident in people with schizophrenia with suicidal ideation. A total of 93 outpatients with diagnoses of schizophrenia with (n=18, 19%) and without (N=75; 81%) suicidal ideation participated in one week of intensive daily monitoring via mobile devices, generating real-time reports on the quantity of social interactions and appraisals about them, as well as information concerning concurrent affect and symptoms. The presence of suicidal ideation was not associated with the quantity of social interactions or time spent alone, but it was associated with the anticipation of being alone as well as greater negative and lower positive affect when alone. Despite this aversive experience of being alone, people with suicidal ideation reported negative appraisals about the value of recent and potential social interactions. These findings suggest that suicidal ideation in schizophrenia may not be associated with the quantity of social interactions, but with negative expectations about the quality of social interactions coupled with an aversive experience of being alone. Cognitive therapy interventions that address negative expectations and pleasure about social interactions, especially when alone, may reduce suicidal ideation. PMID- 26948501 TI - Do police arrestees substitute legal highs for other drugs? AB - BACKGROUND: Some commentators have suggested legal highs (LH) might reduce existing illegal drug use and contribute to lower drug-related harm. However, no studies have specifically investigated substitution between LH and other drugs. AIMS: To explore the extent to which police detainees substitute LH for illegal drugs. METHOD: A total of 848 detainees at four central police stations were interviewed about their drug and LH use. Detainees were asked what impact their LH use had on their other drug use (i.e., 'no change', 'more', 'less' or 'stopped'). The detainees were placed into four groups: (i) no LH use; (ii) LH use and 'no change' in drug use; (iii) LH use and 'more' drug use; (iv) LH use and 'less' or 'stopped' drug use. Demographics and levels of drug use in the past month were compared between groups. RESULTS: Ninety-six percent of the LH using detainees had used synthetic cannabinoids (SC), and, of those who reported substituting a drug, 94% had substituted (natural) cannabis. Overall, 54% of the detainee sample had not used SC, 34% had used SC but not changed their cannabis use, 9% had used SC and used 'less' or 'stopped' cannabis use, and 3% had used SC and used 'more' cannabis. The SC users were more likely to have recently been in drug treatment. All those who used SC had higher cannabis consumption regardless of substitution behaviour. The SC users who used 'more' cannabis also used more methamphetamine and ecstasy. CONCLUSION: Twenty percent of those who used SC and cannabis reported reducing or stopping their cannabis use while 6% increased their cannabis use, suggesting a modest overall reduction in cannabis use. Further research is required to quantify the magnitude of substitution changes, the impact on drug-related harm, and extent to which substitution occurs for other LH and other populations. PMID- 26948509 TI - Zr-doped TiO2 supported on delaminated clay materials for solar photocatalytic treatment of emerging pollutants. AB - Solar light-active Zr-doped TiO2 nanoparticles were successfully immobilized on delaminated clay materials by a one-step sol-gel route. Fixing the amount of TiO2 at 65wt.%, this work studies the influence of Zr loading (up to 2%) on the photocatalytic activity of the resulting Zr-doped TiO2/clay materials. The structural characterization demonstrates that all samples were formed by a delaminated clay with nanostructured anatase assembled on its surface. The Zr dopant was successfully incorporated into the anatase lattice, resulting in a slight deformation of the anatase crystal and the reduction of the band gap. These materials exhibit high surface area with a disordered mesoporous structure formed by TiO2 particles (15-20nm) supported on a delaminated clay. They were tested in the solar photodegradation of antipyrine, usually used as an analgesic drug and selected as an example of emerging pollutant. High degradation rates have been obtained at low antipyrine concentrations and high solar irradiation intensities with the Zr-doped TiO2/clay catalyst, more effective than the undoped one. This work demonstrates the potential application of the synthesis method for preparing novel and efficient solar-light photocatalysts based on metal-doped anatase and a delaminated clay. PMID- 26948504 TI - [Epidemiological aspects of cutaneous mycosis of HIV-infected patients in the National Referral Center of Burkina Faso, West Africa]. AB - AIM: Our study aimed to analyze the epidemiological aspects of cutaneous mycosis in people living with human immunodeficiency virus (PLHIV). MATERIALS AND METHODS: This is a descriptive study of 382 patients living with HIV. Following an investigation into the risk factors, mycological samples have been performed. Each sample underwent direct examination and cultivation for the identification of fungal species. The Blastese test is used for the identification of Candida albicans. RESULTS: One hundred and six (106) of the 382 people living with human immunodeficiency virus undergo a mycological collection of which 76 gave a positive result. The overall prevalence of cutaneous mycosis was 19.9 %. It was significantly higher in women and in patients who had a CD4 count <=500/mm3. C. albicans and Trichophyton rubrum were the most isolated species with 22.4 and 19.8 % of all fungal species isolated, respectively. CONCLUSION: Cutaneous mycoses are common among people living with human immunodeficiency virus and whose CD4 count <= 500/mm(3). PMID- 26948503 TI - Morphometric analysis of the cerebral expression of ATP-binding cassette transporter protein ABCB1 in chronic schizophrenia: Circumscribed deficits in the habenula. AB - There is increasing evidence that microvascular abnormalities and malfunction of the blood-brain barrier (BBB) significantly contribute to schizophrenia pathophysiology. The ATP-binding cassette transporter ABCB1 is an important molecular component of the intact BBB, which has been implicated in a number of neurodegenerative and psychiatric disorders, including schizophrenia. However, the regional and cellular expression of ABCB1 in schizophrenia is yet unexplored. Therefore, we studied ABCB1 protein expression immunohistochemically in twelve human post-mortem brain regions known to play a role in schizophrenia, in 13 patients with schizophrenia and nine controls. In ten out of twelve brain regions under study, no significant differences were found with regard to the numerical density of ABCB1-expressing capillaries between all patients with schizophrenia and control cases. The left and right habenular complex, however, showed significantly reduced capillary densities in schizophrenia patients. In addition, we found a significantly reduced density of ABCB1-expressing neurons in the left habenula. Reduced ABCB1 expression in habenular capillaries might contribute to increased brain levels of proinflammatory cytokines in patients with schizophrenia, while decreased expression of this protein in a subpopulation of medial habenular neurons (which are probably purinergic) might be related to abnormalities of purines and their receptors found in this disease. PMID- 26948510 TI - Distribution, mass inventories, and ecological risk assessment of legacy and emerging contaminants in sediments from the Pearl River Estuary in China. AB - This study focused on comparing the occurrences and environmental toxic risks for diverse priority and emerging contaminants (>100 chemicals) in the sediments from the Pearl River Estuary (PRE, China). The most predominant compounds were cationic surfactants, organophosphate flame retardants (e.g., triisobutylphosphate), and polycyclic aromatic hydrocarbons (PAHs), accounting for >75% of the total mass inventory (~330 metric tons). Wastewater discharges seem to be one of the main sources of pollution in the area, as the highest concentrations (>1000ngg-1 for some chemicals) were reported in the upper part of the PRE (near Guangzhou city) and Macau. Highest levels of ultraviolet (UV) filters, however, were observed in recreational areas, revealing the importance of direct sources (e.g., outdoor activities). An environmental risk assessment showed that PAHs and dichlorodiphenyl dichloroethylene had the highest hazard quotient (HQ) values (up to 233). Nonylphenol, a metabolite from nonionic surfactant, and two UV filters (2-ethyl-hexyl-4-trimethoxycinnamate and 4 methylbenzylidene camphor) also posed a significant threat to benthic species (HQ>1). Further research through the realization of monitoring campaigns and toxicity tests is encouraged, as the exposure of the resident aquatic organisms and human population to these and other emerging chemicals is expected to increase over the years. PMID- 26948511 TI - Cauda equina syndrome secondary to lumbar disc herniation: Surgical delay and its relationship with prognosis. AB - OBJECTIVE: To determine whether surgical treatment delayed for more than 48 hours in patients with cauda equina syndrome (CES) influenced the clinical outcome. MATERIAL AND METHODS: A retrospective study of 18 patients treated in our hospital from March 2000 to January 2012, after presenting with CES. The pre- and post-operative clinical status was determined: existence of back pain and/or sciatica, sensory disturbance in the perineum, sensory and motor deficits in the lower extremities, and the degree of sphincter incontinence (complete or incomplete CES). A clinical assessment was performed using the Oswestry disability index. RESULTS: As regards the onset of symptoms, 44% (8 of 18) of patients were treated at an early stage (within 48 hours). None of the patients with complete CES operated in the early stage had urinary incontinence, and also had greater motor recovery. Of the 5 patients with complete CES who underwent delayed surgery, 3 showed residual urinary incontinence. A mean of 12.55 was obtained on the Oswestry disability index scale at the end of follow-up. CONCLUSION: Although no statistically significant difference was found in our study, we observed greater motor and sphincter recovery in patients who were operated on within 48 hours. PMID- 26948512 TI - [Bone metastases relapse after cementoplasty: Case report and discussion about the combination of radiotherapy and cementoplasty]. AB - Interventional radiology techniques - vertebroplasty, kyphoplasty and vertebroplasty - are part of the therapeutic arsenal in oncology. They are not, however, antitumoural by themselves. A combination of these techniques with an antitumoral treatment is thus required. We present the case of a patient with a spinal metastasis who received antitumor vertebroplasty without additional treatment. The follow-up has found a tumour development around the cement. This case illustrates the need for a complementary antitumor treatment following a consolidative procedure. Many combinations of treatment and techniques have been published; however, no study reached a sufficient proof of efficiency for any combination to be recommended. Prospective trials are needed to guide clinicians. PMID- 26948516 TI - Detection of a Novel Bovine Astrovirus in a Cow with Encephalitis. AB - Encephalitis can be caused by several infectious agents, including bacteria, fungi, parasites and viruses. In many cases, the causative agent cannot be identified, because the pathogens are unknown or detection methods are not routinely available. In our case, a 15-month-old cow developed central nervous disorders and died within 6 days after the onset of clinical signs. The histopathology revealed an acute encephalitis, predominantly in the brain stem, and a ganglionitis of the trigeminal ganglion with massive neuronal necroses in both the brain and the ganglion. However, a relevant panel of bacterial and viral infections of cattle could be routinely excluded. Therefore, a brain sample from the cow was analysed using a metagenomics approach with next-generation sequencing. A novel bovine astrovirus (BoAstV-BH89/14) could be identified using the analysis pipeline RIEMS, and the finding could be confirmed with a specific BoAstV RT-qPCR. The genome of the bovine astrovirus (BoAstV), belonging to the family Astroviridae in the genus Mamastrovirus, has a length of 6478 bp. Sequence identities between 71% to a sheep astrovirus and 69% to two recently described bovine astroviruses from the USA and Switzerland were ascertained. The latter were also connected to encephalitis cases in cattle. Like these, the new virus described here was detected in different brain sections using the specific BoAstV RT-qPCR and fluorescent in situ hybridization. In conclusion, while astroviruses so far were mainly found in relation to gastroenteritis in animals and humans, recently detected astrovirus infections were also related to encephalitis. PMID- 26948513 TI - Improved spatial regression analysis of diffusion tensor imaging for lesion detection during longitudinal progression of multiple sclerosis in individual subjects. AB - Subject-specific longitudinal DTI study is vital for investigation of pathological changes of lesions and disease evolution. Spatial Regression Analysis of Diffusion tensor imaging (SPREAD) is a non-parametric permutation based statistical framework that combines spatial regression and resampling techniques to achieve effective detection of localized longitudinal diffusion changes within the whole brain at individual level without a priori hypotheses. However, boundary blurring and dislocation limit its sensitivity, especially towards detecting lesions of irregular shapes. In the present study, we propose an improved SPREAD (dubbed improved SPREAD, or iSPREAD) method by incorporating a three-dimensional (3D) nonlinear anisotropic diffusion filtering method, which provides edge-preserving image smoothing through a nonlinear scale space approach. The statistical inference based on iSPREAD was evaluated and compared with the original SPREAD method using both simulated and in vivo human brain data. Results demonstrated that the sensitivity and accuracy of the SPREAD method has been improved substantially by adapting nonlinear anisotropic filtering. iSPREAD identifies subject-specific longitudinal changes in the brain with improved sensitivity, accuracy, and enhanced statistical power, especially when the spatial correlation is heterogeneous among neighboring image pixels in DTI. PMID- 26948514 TI - Antistaphylococcal activity and metabolite profiling of manuka honey (Leptospermum scoparium L.) after in vitro simulated digestion. AB - The antistaphylococcal activity against methicillin-susceptible and -resistant Staphylococcus aureus and the metabolite profiling of manuka honey (MH) were investigated before and after in vitro simulated gastric (GD) and gastroduodenal (GDD) digestions. Undigested manuka honey showed antibacterial activity against all the tested strains, the GD sample showed no activity against S. aureus, and the GDD honey showed an antistaphylococcal activity, which was slightly reduced in comparison with the undigested sample. To explain these results, methylglyoxal (MGO), to which most of the antibacterial activity of MH is ascribed, was subjected to in vitro simulated GD and GDD. After digestion, MGO showed antibacterial activity at concentrations definitively higher than those registered in digested MH samples. These results showed that the antistaphylococcal activity registered after digestion cannot be ascribed to MGO. Thus metabolite analysis, carried out using an explorative untargeted NMR-based approach and a targeted RP-HPLC-PAD-ESI-MSn analysis focused on bio-active substances, was used to highlight the chemical modifications occurring from digestion. The results showed that (1) the level of MGO decreases and (2) the content of aromatic compounds, such as leptosin and methyl syringate, markers of manuka honey, was stable under gastric and gastroduodenal conditions, whereas (3) the levels of acetic and lactic acids increase in particular after gastroduodenal digestion, being 1.5 and 2.8 times higher in GDD-MH than in UND-MH, respectively. Overall, the results obtained from chemical analysis provide at least a partial explanation of the registered antibacterial activity observed after gastroduodenal digestion. PMID- 26948505 TI - Controllable chaos in hybrid electro-optomechanical systems. AB - We investigate the nonlinear dynamics of a hybrid electro-optomechanical system (EOMS) that allows us to realize the controllable opto-mechanical nonlinearity by driving the microwave LC resonator with a tunable electric field. A controllable optical chaos is realized even without changing the optical pumping. The threshold and lifetime of the chaos could be optimized by adjusting the strength, frequency, or phase of the electric field. This study provides a method of manipulating optical chaos with an electric field. It may offer the prospect of exploring the controllable chaos in on-chip optoelectronic devices and its applications in secret communication. PMID- 26948515 TI - Herbicidal and Cytotoxic Constituents from Aralia armata (Wall.) Seem. AB - Two new triterpenoids, 3beta-hydroxyoleana-11,13(18)-diene-28,30-dioic acid (1) and 3-oxooleana-11,13(18)-diene-28,30-dioic acid (2), one novel triterpenoid glycoside, 3beta-O-(6'-O-methyl-beta-D-glucuronopyranosyl)oleana-11,13(18)-dien 28-oic acid (3) along with six known compounds (4 - 9) were isolated from the stem bark of Aralia armata (Wall.) Seem. Their structures were elucidated through extensive spectroscopic methods. The herbicidal activities of these compounds against Bidens pilosa L., an invasive weed in P. R. China, were evaluated. Compounds 3, 5, and 6 exhibited more significant herbicidal activities on B. pilosa than the positive-control pendimethalin. Their possible use as herbicidal chemicals or model compounds deserved more attention. The effects of compounds 1 9 on Spodoptera litura cultured cell line Sl-1 cell proliferation and its morphology were also evaluated. The results indicated that compounds 1 - 5 affected Sl-1 cell proliferation. Compound 3 showed more obvious proliferation inhibition activities on Sl-1 cell than the positive-control rotenone. With regard to the effect on morphology, compound 2 significantly changed Sl-1 cell, resulting in cell blebbing and vacuole forming. Triterpenoids aremedicinally and agriculturally important, and cytotoxicity of the three new compounds 1 - 3 deserved further studies. PMID- 26948517 TI - Genetic scores of smoking behaviour in a Chinese population. AB - This study sought to structure a genetic score for smoking behaviour in a Chinese population. Single-nucleotide polymorphisms (SNPs) from genome-wide association studies (GWAS) were evaluated in a community-representative sample (N = 3,553) of Beijing, China. The candidate SNPs were tested in four genetic models (dominance model, recessive model, heterogeneous codominant model and additive model), and 7 SNPs were selected to structure a genetic score. A total of 3,553 participants (1,477 males and 2,076 females) completed the survey. Using the unweighted score, we found that participants with a high genetic score had a 34% higher risk of trying smoking and a 43% higher risk of SI at <= 18 years of age after adjusting for age, gender, education, occupation, ethnicity, body mass index (BMI) and sports activity time. The unweighted genetic scores were chosen to best extrapolate and understand these results. Importantly, genetic score was significantly associated with smoking behaviour (smoking status and SI at <= 18 years of age). These results have the potential to guide relevant health education for individuals with high genetic scores and promote the process of smoking control to improve the health of the population. PMID- 26948518 TI - Mental health of children with vision impairment at 11 years of age. AB - AIM: The purpose of the study was to compare the risk of psychiatric disturbance among sighted and vision-impaired children aged 11 years. METHOD: Scores from the parent and teacher versions of the Strengths and Difficulties Questionnaire (SDQ) were used to compare sighted children with: vision-impaired children; vision impaired children with no other reported disabilities or special educational needs; and children with vision impairment and additional disabilities or special educational needs. Logistic regression was used to measure the associations between the independent variables and SDQ scores, and to test for significance of the observed differences. RESULTS: Both parents and teachers scored vision impaired children significantly higher on the SDQ compared with sighted children (p<=0.000) and a significantly higher proportion of the vision-impaired children had SDQ scores in the abnormal range (p<=0.000). Children with vision impairment and other disabilities or special educational needs were rated as being at greatest risk of psychiatric disorder by both parents (30%) and teachers (22%). INTERPRETATION: Vision impairment among children as young as 11 years of age is associated with an increased risk of psychiatric disorder. PMID- 26948519 TI - Ginger for Prevention of Antituberculosis-induced Gastrointestinal Adverse Reactions Including Hepatotoxicity: A Randomized Pilot Clinical Trial. AB - In this study, the potential benefits of ginger in preventing antituberculosis drug-induced gastrointestinal adverse reactions including hepatotoxicity have been evaluated in patients with tuberculosis. Patients in the ginger and placebo groups (30 patients in each group) received either 500 mg ginger (Zintoma)((r)) or placebo one-half hour before each daily dose of antituberculosis drugs for 4 weeks. Patients' gastrointestinal complaints (nausea, vomiting, dyspepsia, and abdominal pain) and antituberculosis drug-induced hepatotoxicity were recorded during the study period. In this cohort, nausea was the most common antituberculosis drug-induced gastrointestinal adverse reactions. Forty eight (80%) patients experienced nausea. Nausea was more common in the placebo than the ginger group [27 (90%) vs 21 (70%), respectively, p = 0.05]. During the study period, 16 (26.7%) patients experienced antituberculosis drug-induced hepatotoxicity. Patients in the ginger group experienced less, but not statistically significant, antituberculosis drug-induced hepatotoxicity than the placebo group (16.7% vs 36.7%, respectively, p = 0.07). In conclusion, ginger may be a potential option for prevention of antituberculosis drug-induced gastrointestinal adverse reactions including hepatotoxicity. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26948520 TI - The head morphology of Clambidae and its implications for the phylogeny of Scirtoidea (Coleoptera: Polyphaga). AB - External and internal structures of the head of adults of Clambus are described and illustrated in detail. The results are compared with structural features found in the clambid genus Calyptomerus, in representatives of other scirtoid families, and also in species of other coleopteran suborders, notably Myxophaga. The results tentatively support the monophyly of Scirtoidea and a close relationship between Clambidae and Eucinetidae is suggested by one shared derived feature of the mandible, a long and slender apical tooth with a serrate edge. The monophyly of Clambidae is very strongly supported and Acalyptomerus is probably the sistergroup of a clade Calyptomerus + Clambinae. Potential scirtoid autapomorphies are the loss of the dorsal tentorial arms, a bulging gula, a strongly transverse labrum, and a ridge separating the mediostipes from the lacinia. However, all these features are homoplasious. The monophyly of Clambidae is supported by modifications of the head capsule which is strongly flattened and broadened, by a deep clypeofrontal incision enabling vertical antennal movements, and a series of antennal features. Synapomorphies of Clambinae + Calyptomerus (Clambidae excluding Acalyptomerus) are the conglobate body form with the ventral side of the head capsule in contact with the mesocoxae, and compound eyes integrated in the contour of the head. The completely subdivided eye is an autapomorphy of Clambus. An entire series of features is shared by Clambidae (or Scirtoidea) and Myxophaga. Most of them are apomorphies that apparently evolved independently in both groups. However, the presence of well-developed maxillary and labial glands is arguably a retained groundplan feature of Coleoptera, with parallel loss in Archostemata, Adephaga and various groups of Polyphaga. PMID- 26948521 TI - Prenatal exposure to di-n-butyl phthalate (DBP) differentially alters androgen cascade in undeformed versus hypospadiac male rat offspring. AB - This study was to compare the alterations of androgen cascades in di-n-butyl phthalate (DBP)-exposed male offspring without hypospadias (undeformed) versus those with hypospadias. To induce hypospadias in male offspring, pregnant rats received DBP via oral gavage at a dose of 750mg/kg BW/day during gestational days 14-18. The mRNA expression levels of genes downstream of the androgen signaling pathway, such as androgen receptor (AR) and Srd5a2, in testes of undeformed rat pups were similar to those in controls; in hypospadiac rat pups these levels were significantly lower than those of control pups. In contrast, both undeformed and hypospadiac rats had decreased serum testosterone levels, reduced mRNA expression of key enzymes in the androgen synthetic pathway in the testes, and ablated genes of developmental pathways, such as Shh, Bmp4, Fgf8, Fgf10 and Fgfr2, in the genital tubercle (GT) as compared to those in DBP-unexposed controls, albeit hypospadiac rats had a more severe decrement than those of undeformed rats. Although other possibilities cannot be excluded, our findings suggest that the relatively normal levels of testosterone-AR-Srd5a2 may contribute to the resistance to DBP toxicity in undeformed rats. In conclusion, our results showed a potential correlation between decreased testosterone levels, reduced mRNA expression of AR and Srd5a2 and the occurrence of hypospadias in male rat offspring prenatally exposed to DBP. PMID- 26948522 TI - Structure-Activity Studies of Cysteine-Rich alpha-Conotoxins that Inhibit High Voltage-Activated Calcium Channels via GABA(B) Receptor Activation Reveal a Minimal Functional Motif. AB - alpha-Conotoxins are disulfide-rich peptides that target nicotinic acetylcholine receptors. Recently we identified several alpha-conotoxins that also modulate voltage-gated calcium channels by acting as G protein-coupled GABA(B) receptor (GABA(B)R) agonists. These alpha-conotoxins are promising drug leads for the treatment of chronic pain. To elucidate the diversity of alpha-conotoxins that act through this mechanism, we synthesized and characterized a set of peptides with homology to alpha-conotoxins known to inhibit high voltage-activated calcium channels via GABA(B)R activation. Remarkably, all disulfide isomers of the active alpha-conotoxins Pu1.2 and Pn1.2, and the previously studied Vc1.1 showed similar levels of biological activity. Structure determination by NMR spectroscopy helped us identify a simplified biologically active eight residue peptide motif containing a single disulfide bond that is an excellent lead molecule for developing a new generation of analgesic peptide drugs. PMID- 26948525 TI - Influence of Islam and the globalized alcohol industry on drinking in Muslim countries. PMID- 26948528 TI - Influence and Impact of Cognitive Trajectories on Outcome in Patients Undergoing Radical Cystectomy: An Observational Study. AB - OBJECTIVE: To evaluate cognitive trajectories after radical cystectomy and their impact on surgical outcomes, including urinary continence. MATERIALS AND METHODS: Ninety patients received cognitive testing using the Mini Mental State Examination before open radical cystectomy as well as 3 days and 2 weeks after surgery. Based on the Mini Mental State Examination changes >=3 points between the three time points, five cognitive trajectories emerged (stable cognition, persistent or transient deterioration, or persistent or transient improvement). Surgical outcomes were assessed 90 days, 6 months, and 1 year postoperatively. RESULTS: Mean age was 67.9 +/- 9.3 years (range 40-88 years). Sixty-six patients (73.3%) had stable cognition, 9 patients (10.0%) had persistent deterioration and 7 patients (7.8%) had transient deterioration, 5 patients (5.6%) had persistent improvement and 3 patients (3.3%) had transient improvement. An impaired preoperative cognition was the only significant risk factor of short-term cognitive deterioration (odds ratio adjusted for age and sex 9.4, 95% confidence interval 1.6-56.5, P = .014). Cognition showed no associations with 1-year mortality, 90-day complication rate, cancer progression, or duration of in hospital stay. Patients with transient or persistent cognitive deterioration had an increased risk for nighttime incontinence (odds ratio adjusted for age and sex 5.1, 95% confidence interval 1.1-22.4, P = .032). CONCLUSION: In this study, the majority of patients showed stable cognition after major abdominopelvic surgery. Cognitive deterioration occurred in a small subgroup of patients, and an impaired preoperative cognition was the only significant risk factor. Postoperative cognitive deterioration was associated with nighttime incontinence. PMID- 26948526 TI - Current Practice Patterns Among Members of the American Urological Association for Male Genitourinary Lichen Sclerosus. AB - OBJECTIVE: To determine the practice patterns of urologists who treat male genitourinary lichen sclerosus (MGU-LS) via a national web-based survey distributed to American Urological Association members. METHODS: A 20-question survey was collected from a random sample of American Urological Association members. Respondents answered questions on their practice patterns for MGU-LS diagnosis, treatment of symptomatic urethral stricture disease, surveillance, and follow-up. RESULTS: In total, 309 urologists completed the survey. The majority of respondents reported practicing more than 20+ years (37.5%) within an academic (31.7%) or group practice (31.1%) setting. The majority of respondents saw 3-5 men with MGU-LS per year (32.7%). The most common locations of MGU-LS involvement included the glans penis (66.2%), foreskin (26.3%), and/or the urethra (5.8%). Respondent first-line treatment for urethral stricture disease was direct visual internal urethrotomy (26.6%) and second-line treatment was referral to subspecialist (38.4%). After controlling for the number of patients evaluated with MGU-LS per year, those with reconstructive training were more likely to perform a primary urethroplasty for men with symptomatic urethral stricture disease (adjusted odds ratio 13.1, 95% confidence interval 5.1-33.8, P < .001). They were also more likely to counsel men on the associated penile cancer risks (adjusted odds ratio 4.6, 95% confidence interval 1.7-12.5, P < .01). CONCLUSION: Reconstructive urologists evaluate the most number of patients with MGU-LS and are more likely to perform primary urethroplasty for urethral stricture disease. Men with MGU-LS should be referred to a reconstructive urologist to understand the full gamut of treatment options. PMID- 26948527 TI - Effect of Tadalafil on Prevention of Urethral Stricture After Urethral Injury: An Experimental Study. AB - OBJECTIVE: To evaluate the preventive effect of phosphodiesterase type 5 inhibitor (tadalafil) on the formation of urethral stricture after urethral injury. MATERIALS AND METHODS: A total of 28, 4-month-old male New Zealand rabbits were included and divided into 3 groups. Group 1 was a sham group with 8 rabbits that underwent only urethroscopy. Group 2 was a nontreatment group with 10 rabbits that underwent urethral electrocoagulation without any treatment. Group 3 was the treatment group with 10 rabbits that underwent urethral electrocoagulation with systemic tadalafil treatment. After 30 days of follow-up, urethroscopy and retrograde urethrography were performed to evaluate the morphological changes in the urethra. The urethra tissues were examined with standard light microscopy by a histologist, and apoptosis was evaluated by the terminal dUTP nick end-labeling assay. RESULTS: Urethral diameters in group 1, group 2, and group 3 were 9.14 +/- 0.73 mm, 3.52 +/- 1.2 mm, and 7.68 +/- 1.14 mm, respectively. The differences in urethral diameters were statistically significant between groups (P < .01). Collagen deposition in submucosal connective tissue was significantly less in the tadalafil group vs the nontreatment group. The numbers of apoptotic cells in submucosal connective tissue were also quantitatively higher in urethral stricture groups compared to the sham group. CONCLUSION: Tadalafil treatment had a protective effect against the formation of urethral stricture in rabbit model. This treatment can be a promising opportunity for urethral stricture and must be supported by clinical studies. PMID- 26948531 TI - A Case of Copper Deficiency-Induced Pancytopenia With Maintenance Hemodialysis Outpatient Treated With Polaprezinc. PMID- 26948529 TI - Open Partial Nephrectomy for Wilms' Tumor in a Cross-fused Pelvic Ectopic Kidney. AB - Wilms' tumor is the most common pediatric solid renal tumor. Cross-fused renal ectopia is a rare congenital anomaly in which the left and right kidneys become fused and fail to ascend from the pelvis and abdomen. We report a case of a 5 year-old girl that underwent open partial nephrectomy on a cross-fused ectopic kidney, "pancake kidney," after incidental discovery of a solid renal mass found to be a Wilms' tumor. Thorough review of the literature shows that this combination of Wilms' tumor in the setting of cross-fused renal ectopia has only been reported twice previously. PMID- 26948523 TI - Intravascular optical imaging of high-risk plaques in vivo by targeting macrophage mannose receptors. AB - Macrophages mediate atheroma expansion and disruption, and denote high-risk arterial plaques. Therefore, they are substantially gaining importance as a diagnostic imaging target for the detection of rupture-prone plaques. Here, we developed an injectable near-infrared fluorescence (NIRF) probe by chemically conjugating thiolated glycol chitosan with cholesteryl chloroformate, NIRF dye (cyanine 5.5 or 7), and maleimide-polyethylene glycol-mannose as mannose receptor binding ligands to specifically target a subset of macrophages abundant in high risk plaques. This probe showed high affinity to mannose receptors, low toxicity, and allowed the direct visualization of plaque macrophages in murine carotid atheroma. After the scale-up of the MMR-NIRF probe, the administration of the probe facilitated in vivo intravascular imaging of plaque inflammation in coronary-sized vessels of atheromatous rabbits using a custom-built dual-modal optical coherence tomography (OCT)-NIRF catheter-based imaging system. This novel imaging approach represents a potential imaging strategy enabling the identification of high-risk plaques in vivo and holds promise for future clinical implications. PMID- 26948534 TI - From genetic associations to functional studies in multiple sclerosis. AB - Genetic screens steadily reveal more loci that show robust associations to complex human diseases, including multiple sclerosis (MS). Although some of the identified genetic variants are easily interpreted into a biological function, most of the genetic associations are frequently challenging to interpret. Underlying these difficulties is the fact that chip-based assays typically detect single nucleotide polymorphisms (SNPs) representative of a stretch of DNA containing many genomic variants in linkage disequilibrium. Furthermore, a large proportion of the SNPs with strongest association to MS are located in regions of the DNA that do not directly code for proteins. Here we discuss challenges faced by MS researchers to follow up the large-scale genetic screens that have been published over the past years in search of functional consequences of the identified MS-associated SNPs. We discuss experimental design, tools and methods that may provide the much-needed biological insights in both disease etiology and disease manifestations. PMID- 26948530 TI - Robot-assisted Versus Standard Laparoscopy for Simple Prostatectomy: Multicenter Comparative Outcomes. AB - OBJECTIVE: To report a comparative analysis of laparoscopic simple prostatectomy (LSP) vs robot-assisted simple prostatectomy (RASP). PATIENTS AND METHODS: Consecutive cases of LSP and RASP done between 2003 and 2014 at 3 participating institutions were included in this retrospective analysis. The effectiveness of the two procedures was determined by performing a paired analysis of main functional and surgical outcomes. A multivariate analysis was also conducted to determine the factors predictive of "trifecta" outcome (combination of International Prostate Symptom Score <8, Qmax > 15 mL/second, and no perioperative complications). RESULTS: A total of 319 patients underwent minimally invasive simple prostatectomy at the participating institutions over the study period. Total prostate volume was larger in the RASP group (median 118.5 mL vs 109 mL, P = .02). Median estimated blood loss tended to be higher for LSP (300 mL vs 350 mL, P = .07). There was no difference in terms of catheterization time (P = .3) and hospital stay (P = .42). A higher rate of overall postoperative complications was recorded in the RASP group (17.7% vs 5.3%), but rate of major complications was not significantly different between the two techniques (2.3 vs 2.1, P = .6). Subjective and objective parameters significantly improved for both LSP and RASP. On multivariable analysis, only two factors were associated with likelihood of obtaining a favorable (trifecta) outcome: age (odds ratio: 0.94; P = .03) and body mass index (odds ratio: 0.84; P = .03). CONCLUSION: Both LSP and RASP can be regarded as safe and effective minimally invasive surgical treatments for bladder outlet obstruction due to large prostate glands. PMID- 26948535 TI - Presence of type 1 diabetes in women with polycystic ovary syndrome: Does it have any impact on anti-Mullerian hormone concentrations? PMID- 26948537 TI - Selectively enhanced photocurrent generation in twisted bilayer graphene with van Hove singularity. AB - Graphene with ultra-high carrier mobility and ultra-short photoresponse time has shown remarkable potential in ultrafast photodetection. However, the broad and weak optical absorption (~ 2.3%) of monolayer graphene hinders its practical application in photodetectors with high responsivity and selectivity. Here we demonstrate that twisted bilayer graphene, a stack of two graphene monolayers with an interlayer twist angle, exhibits a strong light-matter interaction and selectively enhanced photocurrent generation. Such enhancement is attributed to the emergence of unique twist-angle-dependent van Hove singularities, which are directly revealed by spatially resolved angle-resolved photoemission spectroscopy. When the energy interval between the van Hove singularities of the conduction and valance bands matches the energy of incident photons, the photocurrent generated can be significantly enhanced (up to ~ 80 times with the integration of plasmonic structures in our devices). These results provide valuable insight for designing graphene photodetectors with enhanced sensitivity for variable wavelength. PMID- 26948532 TI - Total elbow arthroplasty for the treatment of distal humeral fractures. AB - OBJECTIVE: To report the clinical-functional outcomes of the treatment of humeral distal fractures with a total elbow prosthesis. MATERIAL AND METHODS: This retrospective study was performed in two surgical centres. A total of 23patients were included, with a mean age of 79years, and of which 21 were women. The inclusion criteria were: patients with humeral distal fractures, operated on using a Coonrad-Morrey prosthesis, and with a follow-up of more than one year. According to AO classification, 15fractures were type C3, 7 C2 and 1 A2. All patients were operated on without de-insertion of the extensor mechanism. The mean follow-up was 40 months. RESULTS: Flexor-extension was 123-17 degrees , with a total mobility arc of 106 degrees (80% of the contralateral side). Pain, according to a visual analogue scale was 1. The Mayo Elbow Performance Index (MEPI) was 83 points. Excellent results were obtained in 8 patients, good in 13, medium in 1, and poor in 1. The mean DASH (disability) score was 24 points. CONCLUSION: Treatment of humeral distal fractures with total elbow arthroplasty could be a good treatment option, but indications must be limited to patients with complex fractures, poor bone quality, with osteoporosis and low functional demands. In younger patients, the use is limited to serious cases where there is no other treatment option. LEVEL OF EVIDENCE: Level of Evidence IV. PMID- 26948538 TI - Trophoblastic-like transdifferentiation: A key to oncogenesis. AB - The epigenetic plasticity of cancer stem-like cells allows them to reprogram multifaceted properties. Being determined by an oncogene driving force, the reprogrammed properties are suitable for extensive, non-homeostatic clone expansion rather than controlled tissue generation. They belong to physiological phenotypes, under strict control in normal cells but illicitly expressed in malignant cells. Comparing the embryo nidation implemented by trophoblast with tumor progression, it clearly appears that trophoblastic and cancerous cells share strongly similar behavior and logistical properties, likely making the trophoblastic phenotype a core component of the malignant phenotype. By reprogramming it, malignant cells acquire a coordinated set of functions very efficient for survival, protection, expansion and migration. This phenotype seems to have not yet been experimentally studied in depth as to its contribution to oncogenesis. We suggest opening a specific field of research on malignant cells and host tissue receptivity, guided by the relationship between nidation and tumor implantation. PMID- 26948533 TI - Identification of the active site of human mitochondrial malonyl-coenzyme a decarboxylase: A combined computational study. AB - Malonyl-CoA decarboxylase (MCD) can control the level of malonyl-CoA in cell through the decarboxylation of malonyl-CoA to acetyl-CoA, and plays an essential role in regulating fatty acid metabolism, thus it is a potential target for drug discovery. However, the interactions of MCD with CoA derivatives are not well understood owing to unavailable crystal structure with a complete occupancy in the active site. To identify the active site of MCD, molecular docking and molecular dynamics simulations were performed to explore the interactions of human mitochondrial MCD (HmMCD) and CoA derivatives. The findings reveal that the active site of HmMCD indeed resides in the prominent groove which resembles that of CurA. However, the binding modes are slightly different from the one observed in CurA due to the occupancy of the side chain of Lys183 from the N-terminal helical domain instead of the adenine ring of CoA. The residues 300 - 305 play an essential role in maintaining the stability of complex mainly through hydrogen bond interactions with the pyrophosphate moiety of acetyl-CoA. Principle component analysis elucidates the conformational distribution and dominant concerted motions of HmMCD. MM_PBSA calculations present the crucial residues and the major driving force responsible for the binding of acetyl-CoA. These results provide useful information for understanding the interactions of HmMCD with CoA derivatives. Proteins 2016; 84:792-802. (c) 2016 Wiley Periodicals, Inc. PMID- 26948524 TI - TGF-beta1-induced transcription factor networks in Langerhans cell development and maintenance. AB - Langerhans cells (LC) represent a specialized subset of evolutionarily conserved dendritic cells (DC) that populate stratified epithelial tissues, which are essential for the induction of skin and mucosal immunity and tolerance, including allergy. Transforming growth factor-beta1 (TGF-beta1) has been confirmed to be a predominant factor involved in LC development. Despite great advances in the understanding of LC ontogeny and diverse replenishment patterns, the underlying molecular mechanisms remain elusive. This review focuses on the recent discoveries in TGF-beta1-mediated LC development and maintenance, with special attention to the involved transcription factors and related regulators. PMID- 26948536 TI - Artificially reared mice exhibit anxiety-like behavior in adulthood. AB - It is important to establish experimental animal techniques that are applicable to the newborn and infant phases for nutrition and pharmacological studies. Breeding technology using the artificial suckling method without breast milk is very effective for the study of newborn nutrition. Using this method, we separated newborn mice from dams within 48 h of birth and provided them with artificial milk. We evaluated mouse anxiety levels after early postnatal maternal separation. Artificially reared mice were subjected to elevated plus-maze tests to assess emotional behavior at 9 weeks of age. Artificially reared mice showed a significantly lower frequency of entries and dipping into the open arms of the maze compared with dam-reared mice. This result indicates that the anxiety level of artificially reared mice was higher than that of dam-reared mice. Moreover, the concentration of monoamines in the brain was determined after the behavioral experiment. The hippocampal norepinephrine, serotonin, and 5-hydroxyindoleacetic acid levels in the artificially reared mice were significantly higher than those of the dam-reared mice. These results suggest that maternal-offspring interactions are extremely important for the emotional development of newborn infants during the lactation period. In future studies, it is necessary to consider the environmental factors and conditions that minimize the influence of artificial rearing on emotional behavior. PMID- 26948544 TI - A detailed assignment of NEXAFS resonances of imidazolium based ionic liquids. AB - In Near Edge X-Ray Absorption Fine Structure (NEXAFS) spectroscopy X-Ray photons are used to excite tightly bound core electrons to low-lying unoccupied orbitals of the system. This technique offers insight into the electronic structure of the system as well as useful structural information. In this work, we apply NEXAFS to two kinds of imidazolium based ionic liquids ([C(n)C1im](+)[NTf2](-) and [C4C1im](+)[I](-)). A combination of measurements and quantum chemical calculations of C K and N K NEXAFS resonances is presented. The simulations, based on the transition potential density functional theory method (TP-DFT), reproduce all characteristic features observed by the experiment. Furthermore, a detailed assignment of resonance features to excitation centers (carbon or nitrogen atoms) leads to a consistent interpretation of the spectra. PMID- 26948540 TI - Synthesis and mechanistic aspects of 2-anilinonicotinyl-pyrazolo[1,5-a]pyrimidine conjugates that regulate cell proliferation in MCF-7 cells via estrogen signaling. AB - A series of anilinonicotinyl linked pyrazolo[1,5-a]pyrimidine conjugates (6a-x) were synthesized and evaluated for their antiproliferative activity. Some of these conjugates exhibited promising cytotoxic effects in the MCF-7 cell line and among these 6a and 6c exhibited significant effects, apart from G2/M cell cycle arrest. Interestingly they showed profound effects on cyclin D1, Bcl-2 and survivin proteins that regulate breast cancer cell proliferation. Moreover, ER alpha protein expression was studied to understand regulatory role of these conjugates on estrogen activity in estrogen positive breast cancer cells like MCF 7 and compounds 6a and 6c reduced their activity. PMID- 26948541 TI - Copper-catalyzed three-component synthesis of aminonaphthoquinone-sulfonylamidine conjugates and in vitro evaluation of their antiproliferative activity. AB - A series of aminonaphthoquinone-sulfonylamidine conjugates were synthesized via a copper-catalyzed three-component reaction of N-propargyl aminonaphthoquinone, sulfonyl azides and various amines. Majority of the compounds exhibited promising antiproliferative potential when evaluated against a panel of four cancer cell lines. Docking experiments of representative compounds indicated that the conjugates can occupy the ATP-binding pocket of topoisomerase-II enzyme. PMID- 26948545 TI - Loss of Ca(2+)-permeable AMPA receptors in synapses of tonic firing substantia gelatinosa neurons in the chronic constriction injury model of neuropathic pain. AB - Synapses transmitting nociceptive information in the spinal dorsal horn undergo enduring changes following peripheral nerve injury. Indeed, such injury alters the expression of the GluA2 subunit of glutamatergic AMPA receptors (AMPARs) in the substantia gelatinosa and this predicts altered channel conductance and calcium permeability, leading to an altered function of excitatory synapses. We therefore investigated the functional properties of synaptic AMPA receptors in rat substantia gelatinosa neurons following 10-20d chronic constriction injury (CCI) of the sciatic nerve; a model of neuropathic pain. We measured their single channel conductance and sensitivity to a blocker of calcium permeable AMPA receptors (CP-AMPARs), IEM1460 (50MUM). In putative inhibitory, tonic firing neurons, CCI reduced the average single-channel conductance of synaptic AMPAR from 14.4+/-3.5pS (n=12) to 9.2+/-1.0pS (n=10, p<0.05). IEM1460 also more effectively antagonized evoked, spontaneous and miniature EPSCs in tonic neurons from sham operated animals than in those from animals that had been subjected to CCI. By contrast, CCI did not change the effectiveness of IEM1460 in delay firing neurons although average single channel conductance was increased from 7.6+/ 1.2pS (n=11) to 12.2+/-1.5pS (n=10, p<0.01). CCI thus elicits plastic changes in a specific set of glutamatergic synapses of substantia gelatinosa due to subunit recomposition and loss of GluA2-lacking CP-AMPAR. These insights reveal a molecular mechanism of nerve injury acting at synapses of inhibitory neurons to reduce their drive and therefore inhibitory tone in the spinal cord, therefore contributing to the central sensitization associated with neuropathic pain. PMID- 26948539 TI - BDNF acting in the hypothalamus induces acute pressor responses under permissive control of angiotensin II. AB - Brain-derived neurotrophic factor (BDNF) expression increases in the paraventricular nucleus of the hypothalamus (PVN) during hypertensive stimuli including stress and hyperosmolarity, but its role in PVN cardiovascular regulatory mechanisms is unclear. Chronic BDNF overexpression in the PVN has been shown to elevate sympathetic tone and blood pressure in part by modulating central angiotensin (Ang) II mechanisms. However, the cardiovascular effects of short-term increases in PVN levels of BDNF and the mechanisms governing them are unknown. Therefore, we investigated whether acute BDNF microinjections into the PVN of conscious and anesthetized Sprague-Dawley rats induce blood pressure elevations and whether Ang II signaling is involved in these hypertensive responses. In conscious rats, unilateral BDNF (12.5ng) microinjections into the PVN increased mean arterial pressure (MAP) by 27+/-1mmHg (P<0.001 vs vehicle), which was significantly attenuated by intracerebroventricular infusion of the Ang II-type-1 receptor (AT1R) antagonist losartan and by ganglionic blockade with intravenous hexamethonium infusion. In anesthetized rats, unilateral PVN microinjection of BDNF increased MAP by 31+/-4mmHg (P<0.001 vs vehicle), which was prevented by PVN microinjection pretreatments with the high-affinity BDNF receptor TrkB antagonist ANA-12, losartan, the angiotensin converting enzyme inhibitor lisinopril, or by intravenous hexamethonium. Additional experiments in hypothalamic samples including the PVN revealed that BDNF-induced TrkB receptor phosphorylation was prevented by ANA-12 and losartan pretreatments. Collectively, these data indicate that BDNF acting within the PVN acutely raises blood pressure under permissive control of Ang II-AT1R mechanisms and therefore may play an important role in mediating acute pressor responses to hypertensive stimuli. PMID- 26948542 TI - Prevalence of impaired fasting glucose and type 1 and 2 diabetes mellitus in a large nationwide working population in Spain. AB - INTRODUCTION: To report the prevalence of impaired fasting glucose (IFG), undiagnosed and diagnosed diabetes, and their association to occupational categories in a representative sample of working population in Spain. MATERIALS AND METHODS: A cross-sectional study of workers who attended routine medical check-ups from January 2007 to December 2007. A structured questionnaire was completed, and physical examinations and routine serum biochemical tests were performed. IFG was defined as fasting glucose levels ranging from 100 to 125 mg/dl with no diagnosis of T1DM or T2DM; T1DM was defined as previous diagnosis of T1DM; and T2DM as previous diagnosis of T2DM, treatment with oral antidiabetic drugs or insulin or fasting glucose levels >=126 mg/dl, according to ADA criteria. RESULTS: Of the 371,997 participants (median age 35 [interquartile range 29-44] years), 72.4% were male. Raw prevalence rates (95% CI) of IFG, undiagnosed (UKDM), and previously known type 2 (KDM2) and type 1 (KDM1) diabetes were 10.4% (10.3-10.5%), 1.3% (1.2-1.3%), 1.1% (1.1-1.2%), and 0.3% (0.3-0.3%), respectively. With the exception of KDM1, prevalence of these conditions increased with age and was greater among manual/blue-collar workers (12.1%, 1.5%, 1.3% and 0.3%, respectively) as compared to non-manual/white-collar workers (7.3%, 0.8%, 0.8% and 0.3%, respectively). Age- and sex-adjusted prevalence rates of IFG, UKDM and KDM2 were 13.1%, 2.0% and 2.4%, respectively. DISCUSSION: In this sample of Spanish working population, impaired glycemic profiles were common. Prevalence rates of IFG and T2DM were high among blue-collar workers (except for T1DM). These data emphasize the need for earlier structured preventive schemes. PMID- 26948547 TI - La Palabre: A New Schema for Global Health. AB - The Ebola virus epidemic in West Africa has led to a paradigm shift in the way the global community responds to outbreaks of disease. This new paradigm places even greater emphasis on collaboration in global health. The palabre, the traditional African practice of mediation and decision-making in the public sphere, offers a schema from which to view current and future global health engagement. This process of dialogue and exchange has many applications to global health exemplified recently by the West African Disaster Preparedness Initiative (WADPI), a follow-on activity to the Operation United Assistance (OUA) Ebola Response effort. WADPI, utilizing the structure of a palabre, seeks to catalyze and synergize constructive collaboration to set a foundation for disaster response in West Africa for years to come. (Disaster Med Public Health Preparedness. 2016;10:541-543). PMID- 26948546 TI - Blood glucose and lipid concentrations after overload are not associated with the risk of alcohol relapse. AB - AIMS: There is evidence for the functioning of feedback between alcohol consumption and fat (positive) and carbohydrate (negative) intake. We tried to verify the hypothesis that blood glucose and lipid concentration in a fasting state and after loading may affect the risk of relapse in alcohol-dependent male patients during withdrawal therapy. METHODS: Blood glucose, total cholesterol (TC) and triglycerides (TG) were determined at the beginning of the study, and again after 4 weeks and 6 months of observation in 54 alcohol-dependent male patients treated against drinking relapse. Glucose concentration was checked after fasting and 2h after loading with a 75 g water solution of glucose, and blood lipids were determined on an empty stomach and 5h after butter loading (0.5 g of butter per kilogram of body mass). RESULTS: Patients who relapsed compared to subjects who remained abstinent during the 6-month observation did not differ significantly in relation to blood glucose, TC or TG blood concentrations, either in a fasting state or after loading. Patients with an initial above-median increase in TG blood concentration after butter loading (>38%) before the beginning of the study, and who smoked cigarettes with a greater content of nicotine and tar, preferred vodka and had lower values of aminotransferases. CONCLUSION: Fasting and postprandial blood glucose, TC and TG concentrations had no relationship with the outcome of anti-relapse treatment. However, they presented some associations with the pathomechanism of addiction to nicotine. PMID- 26948548 TI - Comparison of Anatomic Double- and Single-Bundle Techniques for Anterior Cruciate Ligament Reconstruction Using Hamstring Tendon Autografts: A Prospective Randomized Study With 5-Year Clinical and Radiographic Follow-up. AB - BACKGROUND: The aim of this prospective randomized study was to compare the outcomes of the anatomic double-bundle (DB) and anatomic single-bundle (SB) techniques 5 years after anterior cruciate ligament (ACL) reconstruction. Since more effective restoration of rotational laxity is considered the main advantage of the DB technique, the pivot-shift test was the primary outcome variable of the study. HYPOTHESIS: Double-bundle ACL reconstruction will result in a better outcome in terms of the pivot-shift test. STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: A total of 105 patients (33 women, 72 men; median age, 27 years; range, 18-52 years) were randomized and underwent ACL reconstruction (DB group, n = 53; SB group, n = 52). All reconstructions were performed anatomically by identifying the ACL footprints, using the anteromedial portal for the femoral tunnel drilling, and utilizing interference screw for tibial and femoral fixation. A single blinded observer examined the patients preoperatively and at follow-up (median, 64 months; range, 55-75 months). Multiple subjective and objective clinical evaluation tests and radiographic assessments of osteoarthritis (OA) were performed using the Ahlback, Kellgren Lawrence, and Fairbank grading systems at 6 weeks postoperatively and at the final follow-up evaluation. RESULTS: Preoperatively, no differences were found between the study groups, apart from the preinjury Tegner activity level, which was lower in the DB group (SB: mean, 7.8 [range, 3-9]; DB: mean, 7.3 [range, 0 9]; P = .02). Eighty-seven patients (83%) were available for examination at the 5 year follow-up. Statistical differences could not be found between the groups in terms of the pivot-shift test, KT-1000 arthrometer laxity measurements, manual Lachman test, single-legged-hop test, square-hop test, range of motion, Lysholm knee scoring scale, Tegner activity scale, or Knee injury and Osteoarthritis Outcome Score. Correspondingly, no differences were found between the groups regarding the presence of OA at follow-up. However, a significant increase of OA was found within the DB group at the 5-year follow-up. Both groups improved at follow-up compared with the preoperative assessment in terms of the laxity tests, hop tests, and scoring scales. CONCLUSION: At the 5-year follow-up of an unselected group of patients, anatomic DB reconstruction was not superior to anatomic SB reconstruction in terms of the pivot-shift test. PMID- 26948552 TI - Skin Diseases Affecting High-Level Competition Sailors: Descriptive Study Carried Out During the 2012 AG2R Transatlantic Boat Race. AB - OBJECTIVES: The primary objective of this study was to identify skin disorders encountered in a population of sport sailors. Unlike merchant mariners and fishermen, there is sparse literature on this maritime population. Secondary objectives were to uncover on-board conditions that may contribute to dermatological problems in this population. METHODS: We conducted a prospective study during the 2012 AG2R transatlantic race. Sixteen two-man crews participated in this race, all using the same model of sailboat (Beneteau Figaro 2). Clinical examinations were conducted, photographs taken, and questionnaires containing 34 questions were handed out before departure and on arrival, 22 to 24 days later. RESULTS: Twenty-eight of 32 skippers (88%) participated in departure data collection, and 18 (56%) completed data collection on arrival. The average age of sailors was 34 years (SD = 8). Compared with skin diseases documented on departure, there was an increased amount of folliculitis on the buttocks, fungal infections, and hyperkeratosis of the hands on arrival. Furthermore, several new skin problems were found postrace: skin scaling, skin erosions on the buttocks, dyshidrosis, thermal burns, and sunburns. The use of protective gear and sunscreen was common, but on-board hygiene was poor with infrequent bathing and clothing changes. CONCLUSIONS: Skin conditions are nearly universal in this maritime population. Further assessments are needed to know if long-term use of protective gear; improved hygiene; use of barrier creams; and proper on-board care of fungal infections, wounds, and burns could reduce the number and severity of skin problems encountered in sport sailors. PMID- 26948556 TI - Primary Care in Extreme Environments: Medical Clinic Utilization at Antarctic Stations, 2013-2014. AB - OBJECTIVES: The unique challenges posed by the Antarctic environment include both physiological and psychological stressors to the individual as well as the limited onsite medical capabilities available to address them. This report compares medical clinic utilization among 3 US Antarctic stations to identify differences in diagnostic frequency and utilization of clinic resources under current medical prescreening regimes for summer and winter seasons. METHODS: Clinic data from 3 Antarctic locations (McMurdo Station, Amundsen-Scott South Pole Station, and Palmer Station) for the 2013-2014 Antarctic year were reviewed for patient encounter frequency by season, and provider-assigned visit diagnostic category. Differences between relative diagnosis frequencies among stations were analyzed, and per-capita clinic utilization was compared. RESULTS: The McMurdo clinic recorded 1555 patient encounters, with South Pole Station reporting 744 and Palmer with 128 encounters over the year. The most frequent reasons for clinic visits were orthopedic and dermatologic, with increased visits at McMurdo for respiratory illness and at the more remote locations for neurologic complaints and insomnia. Altitude-related visits were reported only at McMurdo and South Pole stations. CONCLUSIONS: The clinic volume predictably correlated with station population. Insomnia and headache complaints, reported only at the South Pole Station, are likely associated with the increased elevation at that site, although they could be attributable to psychological stress from the isolated environment. Although the majority of cases could not be prevented with current screening, we suggest several changes to the current concept of operations that may decrease medical utilization and provide significant improvements to health care delivery on the ice. PMID- 26948551 TI - Is Postevent Intravenous Hydration an Appropriate Service at Endurance Competitions? PMID- 26948557 TI - Risk Determinants of Acute Mountain Sickness and Summit Success on a 6-Day Ascent of Mount Kilimanjaro (5895 m). AB - OBJECTIVE: The aims of this study were to assess incidence of acute mountain sickness (AMS) and summit success on a 6-day ascent profile of Mt. Kilimanjaro and evaluate potential risk factors for these outcomes. METHODS: All trekkers through a single Australian tour company between August 2012 and July 2014 were included. Participants ascended via the Rongai route and attempted the summit on day 6. Daily assessments were made using the self-reported Lake Louise score (LLS) questionnaire. Two different AMS diagnostic criteria (LLS >= 3 and LLS >= 5) were used for data analysis. Risk factors for development of AMS and summit success were analyzed. RESULTS: Over the 24-month period a total of 175 participants undertook the trek. Incidence of AMS was 52.6% (LLS >= 3) and 22.9% (LLS >= 5). Summit success was 88%. Age, sex, body mass index, and acetazolamide use were not associated with risk of AMS development. Age >= 40 years (P = .0002) and female sex (P = .0004) were both significantly associated with reduced summit success rate. CONCLUSIONS: Our cohort found a lower incidence of AMS and better summit success on a 6-day ascent of Mt Kilimanjaro than previously described in other groups on 4- and 5-day ascents. Female sex and age >= 40 years both predicted failure to summit, but did not increase risk of developing AMS. AMS is a common cause of morbidity on Mt. Kilimanjaro, and although the risk can be mitigated by a slower ascent, there is an ongoing need for education of individual trekkers, tour companies, and local authorities. PMID- 26948555 TI - Medical Knowledge and Preparedness of Climbers on Colorado's 14,000-Foot Peaks. AB - OBJECTIVE: To assess the medical knowledge and preparedness of mountain climbers on Colorado's 14,000-foot peaks and to compare differences in knowledge and preparedness based on demographics, training, and difficulty of the climb. METHODS: Mountain climbers from 11 14,000-foot peaks in Colorado were surveyed at the time of summiting. These peaks represented every major mountain range and class of difficulty in Colorado. Marijuana use and demographic information including age, gender, state of residence, and income level was collected in the survey. In addition, participants were scored on medical knowledge and preparedness using a novel assessment tool. Scores were then compared and statistically analyzed. RESULTS: Mountain climbers scored 2.84 +/- 1.25 and 3.92 +/- 1.20 out of 6.00 on medical knowledge and preparedness, respectively. Medical training was shown to be the only significant predictor of medical knowledge, whereas age, race, income, and group status were all shown to be significant predictors of preparedness. It was shown that 9.4% of participants were using marijuana. Only 25% of individuals climbing class 3 mountains elected to wear helmets. CONCLUSIONS: Most mountain climbers had no formal wilderness medicine training and did worse on the medical knowledge assessment than those who did have training. Consistent with previous studies, participants performed poorly on the medical knowledge assessment. As such, ways to improve wilderness medical knowledge among outdoor recreationalists should be sought. The low rate of helmet use on Colorado's technical peaks represents an important area for education and injury prevention. PMID- 26948543 TI - Exercise Training Normalizes Timing of Left Ventricular Untwist Rate, but Not Peak Untwist Rate, in Individuals with Type 2 Diabetes and Diastolic Dysfunction: A Pilot Study. AB - BACKGROUND: There is limited information regarding the role of left ventricular (LV) twist and the effect of exercise in type 2 diabetes (T2D). The aim of this study was to compare LV twist parameters in patients with T2D versus healthy control subjects and the effects of high-intensity interval exercise (HIIE) and moderate-intensity exercise (MIE) on LV twist in patients with T2D with diastolic dysfunction. METHODS: This study, which included both prospective and retrospective components, included 47 patients with T2D and diastolic dysfunction and 37 healthy individuals. Patients with T2D were randomized to HIIE (4 * 4 min at 90%-95% of maximal heart rate, three times a week, 120 min/wk; n = 24) or MIE (210 min/wk; n = 23) for 12 weeks and examined with echocardiography (LV twist by speckle-tracking method) at baseline and posttest. The control subjects received no intervention and were matched according to age, gender, and body mass index to those completing the intervention. RESULTS: In total, 37 subjects completed 12 weeks of MIE (n = 17) or HIIE (n = 20). LV peak untwist rate (UTR) was similar in patients with T2D and control subjects (P ? .05). At baseline, LV peak UTR, relative to total diastolic period, occurred 5.8 percentage points later in patients with T2D compared with control subjects (P = .004). Time to peak UTR was shortened by 6.5 percentage points (P = .002) and 7.7 percentage points (P < .001) after MIE and HIIE, respectively. Time to peak UTR was similar to that in control subjects after exercise interventions. CONCLUSIONS: In patients with T2D and diastolic dysfunction, LV peak UTR was similar, but time to peak LV UTR was delayed compared with control subjects. Twelve weeks of endurance exercise normalized the timing of UTR. PMID- 26948558 TI - A New Proposal for Management of Severe Frostbite in the Austere Environment. AB - Despite advances in outdoor clothing and medical management of frostbite, individuals still experience catastrophic amputations. This is a particular risk for those in austere environments, due to resource limitations and delayed definitive treatment. The emerging best therapies for severe frostbite are thrombolytics and iloprost. However, they must be started within 24 hours after rewarming for recombinant tissue plasminogen activator (rt-PA) and within 48 hours for iloprost. Evacuation of individuals experiencing frostbite from remote environments within 24 to 48 hours is often impossible. To date, use of these agents has been confined to hospitals, thus depriving most individuals in the austere environment of the best treatment. We propose that thrombolytics and iloprost be considered for field treatment to maximize chances for recovery and reduce amputations. Given the small but potentially serious risk of complications, rt-PA should only be used for grade 4 frostbite where amputation is inevitable, and within 24 hours of rewarming. Prostacyclin has less risk and can be used for grades 2 to 4 frostbite within 48 hours of rewarming. Until more field experience is reported with these agents, their use should probably be restricted to experienced physicians. Other modalities, such as local nerve blocks and improving oxygenation at high altitude may also be considered. We submit that it remains possible to improve frostbite outcomes despite delayed evacuation using resource-limited treatment strategies. We present 2 cases of frostbite treated with rt-PA at K2 basecamp to illustrate feasibility and important considerations. PMID- 26948559 TI - Portable Prehospital Methods to Treat Near-Hypothermic Shivering Cold Casualties. AB - OBJECTIVE: To compare the effectiveness of a single-layered polyethylene survival bag (P), a single-layered polyethylene survival bag with a hot drink (P+HD), a multi-layered metalized plastic sheeting survival bag (MPS: Blizzard Survival), and a multi-layered MPS survival bag with 4 large chemical heat pads (MPS+HP: Blizzard Heat) to treat cold casualties. METHODS: Portable cold casualty treatment methods were compared by examining core and skin temperature, metabolic heat production, and thermal comfort during a 3-hour, 0 degrees C cold air exposure in 7 shivering, near-hypothermic men (35.4 degrees C). The hot drink (70 degrees C, ~400 ml, ~28 kJ) was consumed at 0, 1, and 2 hours during the cold air exposure. RESULTS: During the cold air exposure, core rewarming and thermal comfort were similar on all trials (P = .45 and P = .36, respectively). However, skin temperature was higher (10%-13%; P < .001; large effect sizes d > 2.7) and metabolic heat production lower (15%-39%; P < .05; large effect sizes d > .9) on MPS and MPS+HP than P and P+HD. The addition of heat pads further lowered metabolic heat production by 15% (MPS+HP vs MPS; P = .05; large effect size d = .9). The addition of the hot drink to polyethylene survival bag did not increase skin temperature or lower metabolic heat production. CONCLUSIONS: Near hypothermic cold casualties are rewarmed with less peripheral cold stress and shivering thermogenesis using a multi-layered MPS survival bag compared with a polyethylene survival bag. Prehospital rewarming is further aided by large chemical heat pads but not by hot drinks. PMID- 26948553 TI - Avalanche Fatalities in the United States: A Change in Demographics. AB - OBJECTIVE: To describe demographic patterns in avalanche fatalities in the United States during the past 6 decades according to geographic location and preavalanche activity. METHODS: The Colorado Avalanche Information Center currently manages the National Avalanche Accident Dataset. This dataset describes deidentified avalanche fatalities beginning in 1951. Covariates included age, sex, month, state of occurrence, and preavalanche activity. Both absolute and proportional avalanche fatalities were calculated by year and by each covariate. A linear regression model was used to trend the proportion of avalanche fatalities stratified by covariate. RESULTS: There were 925 recorded avalanche fatalities in the United States between 1951 and 2013. There were an average of 15 +/- 11 fatalities/y (mean +/- SD; range, 0 to 40 fatalities/y). The mean (+/- SD) age was 29 +/- 6.6 years (range, 6-67 years), and 86% were men. Total avalanche fatalities have increased linearly (R(2) = 0.68). Despite the highest number of total deaths in Colorado (n = 253), the proportion of avalanche fatalities in Colorado decreased (-5% deaths/decade; P = .01). Snowmobilers are now the largest group among fatalities and accounted for 23% of deaths (n = 213). The proportion of snowmobile fatalities has increased (+7% deaths/decade; P < .01), as has the proportion of snowboarder fatalities (+2% deaths/decade; P < .01). CONCLUSIONS: Avalanche fatalities have increased. This is most likely related to an overall rise in backcountry utilization. Fatalities have increased among snowmobilers and snowboarders. Despite a rise in backcountry utilization, avalanche fatalities in Colorado are decreasing. A strategy of focused training and education aimed toward at-risk groups could result in lower avalanche fatalities. PMID- 26948554 TI - Estimating the Burden of Snakebite on Public Hospitals in KwaZulu Natal, South Africa. AB - OBJECTIVE: We propose a formula as a means to estimate the number and incidence of snakebites treated per annum in KwaZulu Natal (KZN), South Africa. METHODS: Using an unvalidated formula that includes an antivenom ratio, we crudely estimated the total number of snakebite presentations in KZN. Using antivenom supply data from the central pharmacy, we stratified a sample of 6 hospitals that were surveyed to establish an antivenom ratio, that is, the total number of patients receiving antivenom to the total number of snakebite presentations at hospitals. The antivenom ratio and the average number of antivenom vials for treated snakebites were incorporated into a formula to crudely estimate the number of snakebite presentations. This was then applied to all public hospitals and districts in the region. RESULTS: Seventy-eight percent of public hospitals were included. The mean antivenom ratio derived from the sample hospitals indicated that 12% (95% CI, 10-14%) of snakebite presentations received antivenom. We estimated an annual total of 1680 (95% CI, 1193-2357) snakebite presentations to hospitals. Two thirds of cases (1109 of 1680) were in the low lying subtropical coastal region. Few cases were in the higher, cooler regions of KZN (87 of 1680) or the metropolitan city of Durban (93 of 1680). The overall incidence for KZN was 16/100,000. The estimated cost of snakebite in KZN was between $1,156,930 and $2,827,848. CONCLUSIONS: We propose an alternative method to estimate the annual number of snakebite presentations to hospitals. PMID- 26948560 TI - A Novel Application for Cognitive Evaluation in Mountain Ultramarathons: Olfactory Assessment. AB - OBJECTIVE: Olfactory function, a cognitive impairment biomarker, was evaluated in mountain ultramarathon (MUM) runners during the Tor des Geants race (332.5 km with an overall altitude gain of 24,000 m; altitude range 330-3296 m above the sea). METHODS: An Odor Identification Test was administered before (T0; n = 53), at 148.7 kms (T1; n = 32) and after the race (T2; n = 28). The effect of dehydration and sleep deprivation on olfactory function was assessed. Olfactory function was also assessed in non-MUM athletes and sedentary controls (C) at rest. RESULTS: A majority of the athletes completed the olfactory test at all time intervals. Olfactory function decreased throughout the race (T0: 13.8 +/- 1.9, T1: 13.7 +/- 1.6, T2: 13.1 +/- 1.8; T0 vs T2 P = .01). There was no relationship with race time or sleep deprivation on the sense of smell throughout the competition. However, there was a combined effect with decreased olfaction during the second half of the race, while a poor relationship was seen between olfaction and total body water at midterm (T1: rs = -0.427; P = .019), but not at baseline or after the race. MUM athletes had similar olfactory scores to C (13.8 +/- 1.9 vs 13.7 +/- 1.4) and non-MUM (13.8 +/- 1.9 vs 13.9 +/- 1.6) athletes. CONCLUSIONS: This pilot study showed the feasibility of olfactory evaluation as a minimally invasive cognitive impairment assessment. The test can be used in logistically difficult environments, adding scientific value to this promising method. Although olfaction decreased after prolonged physical activity, further studies are warranted to make the relationship between cognition and external factors (eg, sleep deprivation, dehydration) more clear. PMID- 26948563 TI - Juvenile gorilla smile, framed by vegetation. PMID- 26948562 TI - Outbreaks of Gastrointestinal Disease Among Rafters. PMID- 26948561 TI - Poisoning by Herbs and Plants: Rapid Toxidromic Classification and Diagnosis. AB - The American Association of Poison Control Centers has continued to report approximately 50,000 telephone calls or 8% of incoming calls annually related to plant exposures, mostly in children. Although the frequency of plant ingestions in children is related to the presence of popular species in households, adolescents may experiment with hallucinogenic plants; and trekkers and foragers may misidentify poisonous plants as edible. Since plant exposures have continued at a constant rate, the objectives of this review were (1) to review the epidemiology of plant poisonings; and (2) to propose a rapid toxidromic classification system for highly toxic plant ingestions for field use by first responders in comparison to current classification systems. Internet search engines were queried to identify and select peer-reviewed articles on plant poisonings using the key words in order to classify plant poisonings into four specific toxidromes: cardiotoxic, neurotoxic, cytotoxic, and gastrointestinal hepatotoxic. A simple toxidromic classification system of plant poisonings may permit rapid diagnoses of highly toxic versus less toxic and nontoxic plant ingestions both in households and outdoors; direct earlier management of potentially serious poisonings; and reduce costly inpatient evaluations for inconsequential plant ingestions. The current textbook classification schemes for plant poisonings were complex in comparison to the rapid classification system; and were based on chemical nomenclatures and pharmacological effects, and not on clearly presenting toxidromes. Validation of the rapid toxidromic classification system as compared to existing chemical classification systems for plant poisonings will require future adoption and implementation of the toxidromic system by its intended users. PMID- 26948564 TI - Long-term survival after lung transplantation among cystic fibrosis patients: Moving away from mere palliation. PMID- 26948573 TI - Major correlates of male height: A study of 105 countries. AB - The purpose of this study is to explore the main correlates of male height in 105 countries in Europe & overseas, Asia, North Africa and Oceania. Actual data on male height are compared with the average consumption of 28 protein sources (FAOSTAT, 1993-2009) and seven socioeconomic indicators (according to the World Bank, the CIA World Factbook and the United Nations). This comparison identified three fundamental types of diets based on rice, wheat and milk, respectively. The consumption of rice dominates in tropical Asia, where it is accompanied by very low total protein and energy intake, and one of the shortest statures in the world (~162-168cm). Wheat prevails in Muslim countries in North Africa and the Near East, which is where we also observe the highest plant protein consumption in the world and moderately tall statures that do not exceed 174cm. In taller nations, the intake of protein and energy no longer fundamentally rises, but the consumption of plant proteins markedly decreases at the expense of animal proteins, especially those from dairy. Their highest consumption rates can be found in Northern and Central Europe, with the global peak of male height in the Netherlands (184cm). In general, when only the complete data from 72 countries were considered, the consumption of protein from the five most correlated foods (r=0.85) and the human development index (r=0.84) are most strongly associated with tall statures. A notable finding is the low consumption of the most correlated proteins in Muslim oil superpowers and highly developed countries of East Asia, which could explain their lagging behind Europe in terms of physical stature. PMID- 26948575 TI - A description of spinal fatigue strength. AB - Understanding fatigue failure of the spine is important to establish dynamic loading limits for occupational health and safety. In this study experimental data were combined with published data to develop a description of the predictive parameters for spinal fatigue failure. 41 lumbar functional spinal units (FSUs) from cadaveric spines (age 49.0 +/- 11.9 yr) where cyclically loaded. Three different levels of sinusoidal axial compression (0-3 kN, 0-2kN or 1-3kN) were applied for 300,000 cycles. Further, published data consisted of 70 thoracic and lumbar FSUs loaded in axial compression for 5000 cycles. Cyclic forces ranged from lower peaks (Fmin) of 0.7-1kN to upper peaks (Fmax) of 1.2-7.1 kN. Based on Wohler analysis, a fatigue model was developed accounting for three parameters: I) specimen-specific scaling based on the endplate area, II) specimen-specific strength dependency on age or bone mineral density, III) load-specific correction factors based on Fmax and Fmin. The most predictive model was achieved for a combination of Fmax, endplate area and bone mineral density; this model explained 61% of variation (p<0.001). A model including Fmax, endplate area and age explained only 28% of variation (p<0.001). Inclusion of a load-specific correction factor did not significantly improve model prediction of fatigue failure. This analysis presents the basis for the prediction of specimen-specific fatigue failure of the lumbar spine, provided the endplate area and bone mineral density can be derived. PMID- 26948574 TI - A computational framework for particle and whole cell tracking applied to a real biological dataset. AB - Cell tracking is becoming increasingly important in cell biology as it provides a valuable tool for analysing experimental data and hence furthering our understanding of dynamic cellular phenomena. The advent of high-throughput, high resolution microscopy and imaging techniques means that a wealth of large data is routinely generated in many laboratories. Due to the sheer magnitude of the data involved manual tracking is often cumbersome and the development of computer algorithms for automated cell tracking is thus highly desirable. In this work, we describe two approaches for automated cell tracking. Firstly, we consider particle tracking. We propose a few segmentation techniques for the detection of cells migrating in a non-uniform background, centroids of the segmented cells are then calculated and linked from frame to frame via a nearest-neighbour approach. Secondly, we consider the problem of whole cell tracking in which one wishes to reconstruct in time whole cell morphologies. Our approach is based on fitting a mathematical model to the experimental imaging data with the goal being that the physics encoded in the model is reflected in the reconstructed data. The resulting mathematical problem involves the optimal control of a phase-field formulation of a geometric evolution law. Efficient approximation of this challenging optimal control problem is achieved via advanced numerical methods for the solution of semilinear parabolic partial differential equations (PDEs) coupled with parallelisation and adaptive resolution techniques. Along with a detailed description of our algorithms, a number of simulation results are reported on. We focus on illustrating the effectivity of our approaches by applying the algorithms to the tracking of migrating cells in a dataset which reflects many of the challenges typically encountered in microscopy data. PMID- 26948577 TI - Pancreatic neuroendocrine tumor mimicking a malignant intraductal papillary mucinous neoplasm. PMID- 26948576 TI - Mechanical assessment of arterial dissection in health and disease: Advancements and challenges. AB - Arterial dissection involves a complex series of coupled biomechanical events. The past two decades have witnessed great advances in the understanding of the intrinsic mechanism for dissection initiation, and hence in the development of novel therapeutic strategies for surgical repair. This is due in part to the profound advancements in characterizing emerging behaviors of dissection using state-of-the-art tools in experimental and computational biomechanics. In addition, researchers have identified the important role of the microstructure in determining the tissue's fracture modality during dissection propagation. In this review article, we highlight a variety of approaches in terms of biomechanical measurements, computational modeling and histological/microstructural analysis used to characterize a dissection that propagates in healthy and diseased arteries. Notable findings with quantitative mechanical data are reviewed. We conclude by discussing some unsolved problems that are of interest for future research. PMID- 26948579 TI - Multifunctional electrocatalytic hybrid carbon nanocables with highly active edges on their walls. AB - Graphene sheets exhibit fast heterogeneous electron transfer at the edges while at the basal plane the electron transfer is much slower. Carbon nanotubes (CNTs) represent fascinating quasi-1-dimensional materials due to their electronic and mechanical properties which enable the formation of (unlike graphene) robust, flexible and well defined three dimensional structures. Because CNTs are created from "rolled up" graphene sheets, exposing mostly inactive walls, they generally exhibit poor electrochemical properties. In contrast, graphene sheets can exhibit fast electron transfer rates but are often prone to "restacking" which hinders their true electrochemical potential. Here we obviate this problem by partial unzipping of CNTs, where their inner core creates nanocables with high electrical conductivity while the outer unzipped graphene layers full of edges and defects act as highly electroactive materials. Metallic nanoparticles are introduced into graphene oxide/CNT hybrid structures (GOCNT), so they do catalyze reactions which are not catalyzed by carbon. We show that in combination with trace metal doping, these nanocables act as efficient electrocatalysts towards oxidation of biomarkers and energy related applications, such as hydrogen evolution reaction. Such hybrid graphene/CNT/metallic nanoparticles present universal well-structured catalysts which should find wide applications in electrochemical devices. GOCNTs rich in oxygenated groups show much promise in pollution management, thus their adsorption behaviour was investigated to establish their ability to remove harmful heavy-metal pollutants. The results show an increasing trend in the concentration of oxygen functional groups, directly correlated with the GOCNT adsorption capacity. PMID- 26948578 TI - Validation of local review for the identification of contributory factors and potentially avoidable perinatal deaths. AB - BACKGROUND: Reporting on perinatal mortality commenced 2006 in New Zealand through the Perinatal and Maternal Mortality Review Committee (PMMRC). Following review of international models, a process was developed for use in local review to identify contributory factors and potentially avoidable perinatal deaths. Local review of 720 perinatal deaths in 2009 found contributory factors in 24% of deaths and 14% to be potentially avoidable. AIMS: To validate the process of local review for identification of contributory factors and potentially avoidable perinatal deaths. MATERIAL AND METHODS: Records of 48 perinatal deaths were reviewed by an independent multidisciplinary panel using the same methodology as local review to determine agreement between local and independent review for identification of contributory factors and potentially avoidable perinatal death. RESULTS: Independent review found contributory factors in 54% of deaths compared to 40% by local review. Independent review identified eight deaths and local review identified one death with contributory factors not identified by the other review. Kappa statistic for agreement for identifying contributory factors was substantial [0.63 (0.42, 0.84)]. Independent review found 42% of deaths potentially avoidable compared to 23% by local review. Independent review identified 10 deaths and local review identified one death not identified by the other review. Kappa statistic for agreement for identifying potentially avoidable deaths was moderate [0.50 (0.26, 0.73)]. CONCLUSIONS: This study provides validation of local review for identification of contributory factors in perinatal death. The higher proportion of potentially avoidable perinatal deaths identified by independent review compared to local review requires further exploration. PMID- 26948582 TI - Identification of bitter compounds in whole wheat bread crumb. AB - Consumer acceptability of whole wheat foods is challenged by negative bitter flavour attributes. In this study, bitter compounds in whole wheat bread crumb were investigated. Utilising sensory-guided multi-dimensional fractionation techniques, the compounds with the highest bitterness intensity in the crumb were purified and identified by LC-MS-ToF and NMR techniques. The main bitter compounds were reported to be L-tryptophan, Wessely-Moser isomers apigenin-6-C galactoside-8-C-arabinoside & apigenin-6-C-arabinoside-8-C-galactoside, and 9,12,13-trihydroxy-trans-10-octadecenoic acid (pinellic acid). Sensory recombination experiments of the bitter compounds formulated at the concentrations determined in expectorated saliva after bread mastication indicated pinellic acid had the greatest contribution to the bitterness perception of the crumb. Quantitative analysis of pinellic acid in the raw flour was reported to be inherently low compared to bread; the concentration increased more than 30-fold after flour hydration and baking. PMID- 26948584 TI - In vitro liberation of carotenoids from spinach and Asia salads after different domestic kitchen procedures. AB - Green-leafy vegetables are rich in nutritionally important constituents including carotenoids. Their potential health benefits depend among others on their liberation from the plant matrix. The aim of the present study was to evaluate the effect of particle size and heat treatments on lutein and beta-carotene liberation from spinach and Asia salads by applying an in vitro digestion protocol and UHPLC analysis. Reduction of particle size resulted in a three- to fourfold increase in liberation of lutein and beta-carotene when comparing whole leaf and puree preparations of spinach. However, this positive effect was shown to be nullified by the severe heat impact during stir-frying of minced spinach, showing that domestic treatments need to be chosen carefully to maximise carotenoid liberation. Steaming significantly improved lutein liberation from Asia salads, but had no or a negative effect in spinach samples, possibly due to differences in liberation or degradation between the two plant matrices. PMID- 26948581 TI - Determination of D-glucaric acid and/or D-glucaro-1,4-lacton in different apple varieties through hydrophilic interaction chromatography. AB - d-Glucaric acid (GA) derivatives exhibit anti-cancerogenic properties in vivo in apples, but quantitative information about these derivatives is limited. Hydrophilic interaction-based HPLC with ultraviolet detection or mass spectrometry was developed to quantify GA and/or D-glucaro-1,4-lacton (1,4-GL) in apples. Although the formation of 1,4-GL from GA could be the prerequisite to exert biological effects in vivo, only a small portion of GA (<5%) was identified and converted to 1,4-GL in the rat stomach. The 1,4-GL content in apples ranged from 0.3 mg/g to 0.9 mg/g, and this amount can substantiate health claims associated with apples. The amount of 1,4-GL was 1.5 times higher in Gala and the ratio of 1,4-GL to GA was lower in Green Delicious apples than those in the other varieties. Our findings suggested that the variety and maturity of apples at harvest are factors that determine 1,4-GL content. PMID- 26948583 TI - Edible seaweed as future functional food: Identification of alpha-glucosidase inhibitors by combined use of high-resolution alpha-glucosidase inhibition profiling and HPLC-HRMS-SPE-NMR. AB - Crude chloroform, ethanol and acetone extracts of nineteen seaweed species were screened for their antioxidant and alpha-glucosidase inhibitory activity. Samples showing more than 60% alpha-glucosidase inhibitory activity, at a concentration of 1 mg/ml, were furthermore investigated using high-resolution alpha-glucosidase inhibition profiling combined with high-performance liquid chromatography-high resolution mass spectrometry-solid-phase extraction-nuclear magnetic resonance spectroscopy (HR-bioassay/HPLC-HRMS-SPE-NMR). The results showed Ascophyllum nodosum and Fucus vesicolosus to be rich in antioxidants, equaling a Trolox equivalent antioxidant capacity of 135 and 108 mM Troloxmg(-1) extract, respectively. HR-bioassay/HPLC-HRMS-SPE-NMR showed the alpha-glucosidase inhibitory activity of A. nodosum, F. vesoculosus, Laminaria digitata, Laminaria japonica and Undaria pinnatifida to be caused by phlorotannins as well as fatty acids - with oleic acid, linoleic acid and eicosapentaenoic acid being the most potent with IC50 values of 0.069, 0.075 and 0.10 mM, respectively, and showing a mixed-type inhibition mode. PMID- 26948580 TI - A single dose of the gamma-secretase inhibitor semagacestat alters the cerebrospinal fluid peptidome in humans. AB - BACKGROUND: In Alzheimer's disease, beta-amyloid peptides in the brain aggregate into toxic oligomers and plaques, a process which is associated with neuronal degeneration, memory loss, and cognitive decline. One therapeutic strategy is to decrease the production of potentially toxic beta-amyloid species by the use of inhibitors or modulators of the enzymes that produce beta-amyloid from amyloid precursor protein (APP). The failures of several such drug candidates by lack of effect or undesired side-effects underscore the importance to monitor the drug effects in the brain on a molecular level. Here we evaluate if peptidomic analysis in cerebrospinal fluid (CSF) can be used for this purpose. METHODS: Fifteen human healthy volunteers, divided into three groups, received a single dose of placebo or either 140 mg or 280 mg of the gamma-secretase inhibitor semagacestat (LY450139). Endogenous peptides in CSF, sampled prior to administration of the drug and at six subsequent time points, were analyzed by liquid chromatography coupled to mass spectrometry, using isobaric labeling based on the tandem mass tag approach for relative quantification. RESULTS: Out of 302 reproducibly detected peptides, 11 were affected by the treatment. Among these, one was derived from APP and one from amyloid precursor-like protein 1. Nine peptides were derived from proteins that may not be gamma-secretase substrates per se, but that are regulated in a gamma-secretase-dependent manner. CONCLUSIONS: These results indicate that a CSF peptidomic approach may be a valuable tool both to verify target engagement and to identify other pharmacodynamic effects of the drug. Data are available via ProteomeXchange with identifier PXD003075. TRIAL REGISTRATION: NCT00765115 , registered 30/09/2008. PMID- 26948585 TI - Identification of meat products by shotgun spectral matching. AB - A new method, based on shotgun spectral matching of peptide tandem mass spectra, was successfully applied to the identification of different food species. The method was demonstrated to work on raw as well as processed samples from 16 mammalian and 10 bird species by counting spectral matches to spectral libraries in a reference database with one spectral library per species. A phylogenetic tree could also be constructed directly from the spectra. Nearly all samples could be correctly identified at the species level, and 100% at the genus level. The method does not use any genomic information and unlike targeted methods, no prior knowledge of genetic variation within a genus or species is necessary. PMID- 26948592 TI - Relationship between the elemental composition of grapeyards and bioactive compounds in the Cabernet Sauvignon grapes Vitis vinifera harvested in Mexico. AB - The red grape Vitis vinifera is an important source of phenolic compounds, which can prevent disease if included as a part of a diet. The levels of these compounds in grapes have been associated with various environmental factors, such as climate, soil composition, and biotic stress. The purpose of this study was to determine the relationship between the elemental compositions of the soil and the grapes and the presence of bioactive compounds, such as catechin, epicatechin, piceid and resveratrol. Ethanol-based extracts of red grapes were used to quantify total and individual phenolic compounds by HPLC. It was observed that the elemental compositions of the soil and the grapes were related to their locations within different wine-producing regions. A principal component analysis showed a relationship between high metal content (Sr, Mn, Si and Pb) and higher concentrations of antioxidants in the grapes. PMID- 26948586 TI - Electrochemical assay of the antioxidant ascorbyl palmitate in mixed medium. AB - Electrooxidation of ascorbyl palmitate (AP) over gold screen-printed electrode (AuSPE) and gold nanoparticles modified graphite (AuNPs/gr) was examined in mixed water-alcohol medium. Voltammetric and amperometric studies showed that: (i) AP oxidation on the AuSPE proceeds at higher potential than on AuNPs/gr; (ii) the current density on AuNPs/gr was 2.4 times higher than on AuSPE; (iii) the linear dynamic range for AuNPs/gr doubled that for AuSPE. At the optimal for AuNPs/gr operating potential (250 mV) the following operational parameters were determined: sensitivity 1.627 +/- 0.138 MUA mM(-1) mm(-2); linearity up to 500 MUM; LOD=5.8 MUM. Quantification of the AP content in a real sample - stabilised flaxseed oil, was performed. PMID- 26948589 TI - The effects of cooking on wire and stone barbecue at different cooking levels on the formation of heterocyclic aromatic amines and polycyclic aromatic hydrocarbons in beef steak. AB - The effects of type of barbecue (wire and stone) and cooking levels (rare, medium, well-done and very well-done) on the formation of heterocyclic aromatic amines (HCAs) and polycyclic aromatic hydrocarbons (PAHs) in beef steak were investigated. Varying levels of IQx (up to 0.29 ng/g), IQ (up to 0.93 ng/g), MeIQx (up to 0.08 ng/g), MeIQ (up to 0.75 ng/g), 7,8-DiMeIQx (up to 0.08 ng/g), 4,8-DiMeIQx (up to 4.95 ng/g), PhIP (up to 6.24 ng/g) and AalphaC (up to 0.20 ng/g) were determined, while MeAalphaC was not detected. The total HCA amounts in wire barbecued samples were higher than stone barbecued samples. Total HCA contents of the samples ranged between nd and 13.52 ng/g. In terms of PAHs, varying levels of BaA (up to 0.34 ng/g), Chry (up to 0.28 ng/g), BbF (up to 0.39 ng/g), BkF (up to 0.90 ng/g), BaP (up to 0.29 ng/g) and Bghip (up to 0.43 ng/g) were determined, while DahA and IncdP were not detected. The total PAH amounts in stone barbecued samples were higher than those of wire barbecued samples. Total PAH amounts of the samples ranged between nd and 2.63 ng/g. PMID- 26948594 TI - The effect of frying on glycidyl esters content in palm oil. AB - The changes in palm oil, as affected by frying temperature, and content of the glycidyl esters (GEs) were studied. Potato chips were fried intermittently in palm oil, which was heated for 8 h daily over five consecutive days. Frying was conducted at three frying temperatures: 150, 165 and 180 degrees C. Thermo oxidative alterations of the oil were measured by acid and anisidine values, changes in fatty acid composition, total polar components, polar fraction composition and colour components formation. Content of GE was measured by liquid chromatography-mass spectrometry. Results showed that amount of products of hydrolysis, oxidation and polymerization (excluding decrease of degree of unsaturation) increased significantly as a function of frying temperature and time. Between GEs of fatty acids the most abundant were esters of palmitic and oleic acids. With increasing temperature and frying time, the content of GE decreased. The extent of GE decrease was correlated with degree of oil degradation. PMID- 26948588 TI - Fruit composition diversity in land races and modern pepino (Solanum muricatum) varieties and wild related species. AB - Pepino (Solanum muricatum) fruits from 15 accessions of cultivated pepino as well as six accessions from wild relatives were evaluated for contents in dry matter, protein, beta-carotene, chlorophylls and seven minerals. Several-fold differences among accessions were found for most traits. Average values obtained were similar to those of melon and cucumber, but the phenolic contents were much higher. Wild species had significantly higher average contents for all traits vs. the cultivated pepino accessions. And, the comparisons among the cultivated pepino varieties showed that the modern varieties were more uniform in composition, and they possessed significantly lower concentrations of protein, P, K, and Zn than local land races. Most of the significant correlations among composition traits were positive. Our studies show that regular consumption of pepino fruits could make a significant contribution to the recommended daily intake of P, K, Fe and Cu as well as to the average daily intake of phenolics. Furthermore, the higher values for most nutrients measured in the wild species and in the local land races indicate that new pepino varieties with improved fruit contents in nutrient and bioactive compounds can be developed. PMID- 26948595 TI - Highlighting metabolic indicators of olive oil during storage by the AComDim method. AB - Lipid oxidation during olive oil storage induces changes in the metabolite content of the oil, which can be measured using so-called quality indices. High values indicate poor quality oils that should be labeled accordingly or removed from the market. Based on quality indices measured over two years for two olive oils, the AComDim method was used to highlight the influence of five factors (olive oil type, oxygen, light, temperature and storage time) on oxidative stability during storage. To identify the significant factors, two full factorial experimental designs were built, each containing four of the five factors examined. The results showed that all five factors, as well as some two-factor interactions, were significant. Phenols and hydroperoxides were identified as being the most sensitive to these factors, and potential markers for the ageing of olive oil. PMID- 26948591 TI - Ultra-sensitive biosensor based on genetically engineered acetylcholinesterase immobilized in poly (vinyl alcohol)/Fe-Ni alloy nanocomposite for phosmet detection in olive oil. AB - An ultra-sensitive screen-printed biosensor was successfully developed for phosmet detection in olive oil, based on a genetically-engineered acetylcholinesterase (AChE) immobilized in a azide-unit water-pendant polyvinyl alcohol (PVA-AWP)/Fe-Ni alloy nanocomposite. Fe-Ni not only allowed amplifying the response current but also lowering the applied potential from 80 mV to 30 mV vs Ag/AgCl. The biosensor showed a very good analytical performance for phosmet detection, with a detection limit of 0.1 nM. This detection limit is lower than the allowable concentrations set by international regulations. In addition to the good reproducibility, operational and storage stability, the developed biosensor was successfully used for the determination of phosmet in olive oil samples without any laborious pre-treatment. The phosmet recovery rate was about 96% after a simple liquid-liquid extraction. PMID- 26948593 TI - Isotopic and elemental characterisation of Slovenian apple juice according to geographical origin: Preliminary results. AB - This study examined the applicability of stable isotope and multi-element data for determining the geographical origin of fresh apple juices. Samples included three apple cultivars (Idared, Golden Delicious and Topaz) harvested in 2011 and 2012 from five different geographical regions of Slovenia. Regional discrimination of the juice samples was most successful when using linear discriminant analysis (LDA) and taking into account the following parameters: delta(2)H and delta(18)O content of juice water; delta(15)N and delta(13)C content of the pulp, (D/H)I and (D/H)II in ethanol and the concentration of S, Cl, Fe, Cu, Zn and Sr. Overall prediction ability was 83.9%. The factors that best distinguished the different types of cultivar were the delta(2)H and delta(18)O content of fruit juice water; the delta(13)C and (D/H)I content of ethanol; and the concentration of S, Mg, K, Cu, and Ti. Prediction ability, taking into account all ten parameters, was 75.8%. PMID- 26948590 TI - Norsesquiterpenoids and triterpenoids from strawberry cv. Falandi. AB - Falandi is a common strawberry (Fragaria * ananassa Duch.) cultivar in southern China. Further study of the chemical constituents in Falandi fruit led to the isolation of nine norsesquiterpenoids and three triterpenoids. Falandioside D (1) and falandins A (2) and B (3) were new norsesquiterpenoids, and the others excluding tormentic acid (11) were found in strawberry for the first time. Compounds 1 and 11 exhibited potent alpha-glucosidase inhibitory activity with the half maximal inhibitory concentration (IC50) values of 565.0 and 27.4 MUM in comparison to acarbose (619.9 MUM). Compounds 3, 7 (blumenol C glucoside), and 11 showed cytotoxicity against human nasopharyngeal carcinoma cell line CNE1 with the IC50 values of 57.6, 56.4, and 36.0 MUM, respectively. Among new compounds, 1 showed 2,2'-azinobis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS) radical cation scavenging capacity (IC50=36.2 MUM). These results suggested that non-phenolic constituents were also involved in the antidiabetic, antitumour, and antioxidant effects of strawberry fruit. PMID- 26948596 TI - Physical and antimicrobial properties of anise oil loaded nanoemulsions on the survival of foodborne pathogens. AB - The purpose of this research was to investigate antimicrobial effects of nano emulsions of anise oil (AO) on the survival of common food borne pathogens, Listeria monocytogenes and Escherichia coli O157:H7. Series of emulsions containing different level of anise oil as potential antimicrobial delivery systems were prepared. Antimicrobial activities of bulk anise oil and its emulsions (coarse and nano) was tested by the minimum inhibitory concentration and time kill assay. Our results showed that bulk anise oil reduced the population of E. coli O157:H7 and L. monocytogenes by 1.48 and 0.47 log cfu/ml respectively after 6 h of contact time. However, under the same condition anise oil nanoemulsion (AO75) reduced E. coli O157:H7 and L. monocytogenes count by 2.51 and 1.64 log cfu/ml, respectively. Physicochemical and microbial analyses indicated that both nano and coarse emulsions of anise oil showed better and long term physicochemical stability and antimicrobial activity compared to bulk anise oil. PMID- 26948603 TI - Effect of ultrafiltration process on physico-chemical, rheological, microstructure and thermal properties of syrups from male and female date palm saps. AB - This study investigates the effect of the ultrafiltration process on physicochemical, rheological, microstructure and thermal properties of syrups from male and female date palm sap. All the studied syrups switched from pseudoplastic rheological behaviour (n=0.783) to Newtonian behaviour (n~1) from 10 to 50 degrees C respectively and present similar thermal profiles. Results revealed that the ultrafiltration process significantly affects the rheological behaviour of the male and female syrups. These differences on rheological properties are attributed to the variation of chemical composition between sap and sap permeate syrups. Furthermore, the effect of temperature on viscosity of the syrups was investigated during heating and cooling processes at the same shear rate (50s(-1)). This study provides idea of the stability of the syrup by evaluating the area between heating and cooling curves. Actually, the syrup prepared from male sap permeate is the most stable between the four studied syrups. PMID- 26948599 TI - A label-free fluorescent aptasensor for selective and sensitive detection of streptomycin in milk and blood serum. AB - Sensitive and fast detection of antibiotic residues in animal derived foods and blood serum is of great interest. In this study a fluorescent aptasensor was designed for selective and sensitive detection of streptomycin (STR) based on Exonuclease III (Exo III), SYBR Gold and aptamer complimentary strand. In the absence of STR, the fluorescence intensity is weak. Upon addition of STR, the aptamer binds to its target, leading to release of complementary strand from aptamer and more protection against Exo III function. Following addition of SYBR Gold, a strong fluorescence intensity is obtained. This aptasensor showed a high selectivity toward STR with a limit of detection (LOD) as low as 54.5 nM. The validity of the procedure and applicability of the aptasensor were successfully assessed by detection of STR in a spiked milk and blood serum without interference from the sample matrix. PMID- 26948598 TI - The thermal aggregation of ovalbumin as large particles decreases its allergenicity for egg allergic patients and in a murine model. AB - Most egg-allergic children can tolerate extensively cooked eggs. Ovalbumin, a major allergen in egg whites, is prone to aggregate upon heating. This study compares ovalbumin's allergenicity when it is aggregated as large particles to ovalbumin in its native form. Immunoglobulins (Ig)-binding and the degranulation capacities of native and aggregated ovalbumin were measured with sera from egg allergic children and from mice sensitized to native or aggregated ovalbumin. The influence of ovalbumin structure on Ig production upon sensitization and elicitation potency by challenge was also studied. We showed that heat aggregation of ovalbumin as large particles enhances IgG production and promotes IgG2a production (a shift toward the T helper 1 profile). Aggregated ovalbumin displayed lower Ig-binding and basophil-activation capacities for sera from both allergic patients and mice. This work illustrates the links between ovalbumin structure after heating and allergenicity potential using parameters from both the sensitization and elicitation phases of the allergic reaction. PMID- 26948601 TI - Production of glutinous rice flour from broken rice via ultrasonic assisted extraction of amylose. AB - In this study, a modified aqueous leaching method by complex formation of amylose with glycerol was employed for reducing the amylose content of starch in broken white rice to less than 2%, so that the resulting starch can be classified to that of glutinous rice flour. By employing ultrasonication in alkaline condition, extraction of amylose could be performed by washing at lower temperature in shorter time compared to the existing aqueous leaching method. The effects of glycerol concentration, alkali concentration, ultrasonication and treatment time on the amylose content of the treated starch were systematically investigated. Under optimum condition, amylose content of broken white rice starch can be reduced from 27.27% to 1.43% with a yield of 80.42%. The changes in the physicochemical properties of the rice flour before and after treatment were studied. PMID- 26948600 TI - Mechanism evaluation of the interactions between flavonoids and bovine serum albumin based on multi-spectroscopy, molecular docking and Q-TOF HR-MS analyses. AB - The mechanism of interactions between a flavonoid glycoside (linarin) and 6 flavonoids with various hydroxyl and methoxyl substituents (luteolin, apigenin, acacetin, tricin, 5,3',4'-trihydroxy-6,7-dimethoxyflavone, and 5,7,4'-trihydroxy 6,3',5'-trimethoxyflavone) and bovine serum albumin (BSA) were investigated by multi-spectroscopy, molecular docking, and quadrupole (Q)-time of flight (TOF) high resolution (HR) mass spectrometry (MS). Fluorescence spectra and molecular docking predicted that each of the flavonoids had only one probable binding site inside the hydrophobic cleft of BSA. The binding constants appeared to correlate positively with the number of hydroxyl groups, and negatively with the number of methoxyl groups. In addition, hydroxyls on ring B bound more easily with BSA than those on ring A. The change in conformation of BSA after binding suggested that the quenching mechanism was static quenching combined with nonradiative energy transfer. The results of Q-TOF HR-MS were consistent with fluorescence quenching and molecular docking. PMID- 26948587 TI - Quantification of megastigmatrienone, a potential contributor to tobacco aroma in spirits. AB - A SPME-GC-MS method was adapted and validated in order to quantify 5 megastigmatrienones and related odorous compounds from oak wood: guaiacol, cis whisky lactone, trans-whisky lactone, gamma-nonalactone, eugenol, vanillin, and acetovanillone in a single run. The five megastigmatrienone isomers (tabanones) were quantified, for the first time, in Cognac, Armagnac and rum, as contributors to tobacco-like aromas. Spirits aged in oak barrels contain higher amounts, but megastigmatrienones are also present in freshly-distilled spirits. Statistical analysis revealed that freshly-distilled and barrel-aged spirits were differentiated by their megastigma-4,7E,9-trien-3-one levels. The Armagnac and Cognac samples were distinguished by their concentrations of the megastigma 4,6Z,8E-trien-3-one isomer. PMID- 26948602 TI - Fractionation of sheep cheese whey by a scalable method to sequentially isolate bioactive proteins. AB - This study reports a procedure for the simultaneous purification of glyco(caseino)macropeptide, immunoglobulin, lactoperoxidase, lactoferrin, alpha lactalbumin and beta-lactoglobulin from sheep cheese sweet whey, an under utilized by-product of cheese manufacture generated by an emerging sheep dairy industry in New Zealand. These proteins have recognized value in the nutrition, biomedical and health-promoting supplements industries. A sequential fractionation procedure using economical anion and cation exchange chromatography on HiTrap resins was evaluated. The whey protein fractionation is performed under mild conditions, requires only the adjustment of pH between ion exchange chromatography steps, does not require buffer exchange and uses minimal amounts of chemicals. The purity of the whey protein fractions generated were analyzed by reversed phase-high performance liquid chromatography and the identity of the proteins was confirmed by mass spectrometry. This scalable procedure demonstrates that several proteins of recognized value can be fractionated in reasonable yield and purity from sheep cheese whey in one streamlined process. PMID- 26948606 TI - Antioxidant and ACE-inhibitory activities of hemp (Cannabis sativa L.) protein hydrolysates produced by the proteases AFP, HT, Pro-G, actinidin and zingibain. AB - Hemp protein isolates (HPIs) were hydrolysed by proteases (AFP, HT, ProG, actinidin and zingibain). The enzymatic hydrolysis of HPIs was evaluated through the degree of hydrolysis and SDS-PAGE profiles. The bioactive properties of the resultant hydrolysates (HPHs) were accessed through ORAC, DPPH scavenging and ACE inhibitory activities. The physical properties of the resultant HPHs were evaluated for their particle sizes, zeta potential and surface hydrophobicity. HT had the highest rate of caseinolytic activity at the lowest concentration (0.1 mg mL(-1)) compared to other proteases that required concentration of 100 mg mL(-1) to achieve their maximum rate of caseinolytic activity. This led to the highest degree of hydrolysis of HPIs by HT in the SDS-PAGE profiles. Among all proteases and substrates, HT resulted in the highest bioactivities (ORAC, DPPH scavenging and ACE-inhibitory activities) generated from alkali extracted HPI in the shortest time (2 h) compared to the other protease preparations. PMID- 26948608 TI - Abscisic acid and pyrabactin improve vitamin C contents in raspberries. AB - Abscisic acid (ABA) is a plant growth regulator with roles in senescence, fruit ripening and environmental stress responses. ABA and pyrabactin (a non photosensitive ABA agonist) effects on red raspberry (Rubus idaeus L.) fruit development (including ripening) were studied, with a focus on vitamin and antioxidant composition. Application of ABA and/or pyrabactin just after fruit set did not affect the temporal pattern of fruit development and ripening; neither provitamin A (carotenoids) nor vitamin E contents were modified. In contrast, ABA and pyrabactin altered the vitamin C redox state at early stages of fruit development and more than doubled vitamin C contents at the end of fruit ripening. These were partially explained by changes in ascorbate oxidation and recycling. Therefore, ABA and pyrabactin applications may be used to increase vitamin C content of ripe fruits, increasing fruit quality and value. However, treatments containing pyrabactin-combined with ABA or alone-diminished protein content, thus partially limiting its potential applicability. PMID- 26948605 TI - Building global models for fat and total protein content in raw milk based on historical spectroscopic data in the visible and short-wave near infrared range. AB - A large set of fresh cow milk samples collected from many suppliers over a large geographical area in Russia during a year has been analyzed by optical spectroscopy in the range 400-1100 nm in accordance with previously developed scatter-based technique. The global (i.e. resistant to seasonal, genetic, regional and other variations of the milk composition) models for fat and total protein content, which were built using partial least-squares (PLS) regression, exhibit satisfactory prediction performances enabling their practical application in the dairy. The root mean-square errors of prediction (RMSEP) were 0.09 and 0.10 for fat and total protein content, respectively. The issues of raw milk analysis and multivariate modelling based on the historical spectroscopic data have been considered and approaches to the creation of global models and their transfer between the instruments have been proposed. Availability of global models should significantly facilitate the dissemination of optical spectroscopic methods for the laboratory and in-line quantitative milk analysis. PMID- 26948597 TI - Physical and oxidative stability of fish oil-in-water emulsions stabilized with fish protein hydrolysates. AB - The emulsifying and antioxidant properties of fish protein hydrolysates (FPH) for the physical and oxidative stabilization of 5% (by weight) fish oil-in-water emulsions were investigated. Muscle proteins from sardine (Sardina pilchardus) and small-spotted catshark (Scyliorhinus canicula) were hydrolyzed to degrees of hydrolysis (DH) of 3-4-5-6% with subtilisin. Sardine hydrolysates with low DH, 3% and 4%, presented the most effective peptides to physically stabilize emulsions with smaller droplet size. This implied more protein adsorbed at the interface to act as physical barrier against prooxidants. This fact might also be responsible for the higher oxidative stability of these emulsions, as shown by their lowest peroxide value and concentration of volatiles such as 1-penten-3-one and 1-penten 3-ol. Among the hydrolysates prepared from small-spotted catshark only the hydrolysate with DH 3% yielded a physically stable emulsion with low concentration of unsaturated aldehydes. These results show the potential of FPH as alternative protein emulsifiers for the production of oxidatively stable fish oil-in-water emulsions. PMID- 26948607 TI - Natural oxygenation of Champagne wine during ageing on lees: A metabolomics picture of hormesis. AB - The oxygenation of Champagne wine after 4 and 6 years of aging on lees in bottle was investigated by FTICR-MS and UPLC-Q-TOF-MS. Three levels of permeability were considered for the stoppers, ranging from 0.2 to 1.8 mg/L/year of oxygen transfer rate. Our results confirmed a good repeatability of ultra-high resolution FTICR MS, both in terms of m/z and coefficient of variation of peak intensities among biological replicates. Vintages appeared to be the most discriminated features, and metabolite annotations suggested that the oldest wines (2006) were characterized by a higher sensitivity towards oxygenation. Within each vintage, the oxygenation mechanisms appeared to be different for low and high ingresses of oxygen, in agreement with the hormesis character of wine oxygenation. In the particular case of single variety wines and for a given level of stopper permeability, our results also showed that variety discrimination could be easily achieved among wines. PMID- 26948610 TI - Chemical composition and health effects of Tartary buckwheat. AB - Tartary buckwheat (Fagopyrum tataricum) contains a range of nutrients including bioactive carbohydrates and proteins, polyphenols, phytosterols, vitamins, carotenoids, and minerals. The unique composition of Tartary buckwheat contributes to their various health benefits such as anti-oxidative, anti-cancer, anti-hypertension, anti-diabetic, cholesterol-lowering, and cognition-improving. Compared with the more widely cultivated and utilised common buckwheat (F. esculentum), Tartary buckwheat tends to contain higher amounts of certain bioactive components such as rutin, therefore, showing higher efficiency in preventing/treating various disorders. This review summarises the current knowledge of the chemical composition of Tartary buckwheat, and their bio functions as studied by both in vitro and in vivo models. Tartary buckwheat can be further developed as a sustainable crop for functional food production to improve human health. PMID- 26948609 TI - Characterization of the nanoscale structure of milk fat. AB - The nanoscale structure of milk fat (MF) crystal networks is extensively described for the first time through the characterization of milk fat-crystalline nanoplatelets (MF-CNPs). Removing oil by washing with cold isobutanol and breaking-down crystal aggregates by controlled homogenization allowed for the extraction and visualization of individual MF-CNPs that are mainly composed of high melting triacylglycerols (TAGs). By image analysis, the length and width of MF-CNPs were measured (600 nm * 200 nm-900 nm * 300 nm). Using small-angle X-ray scattering (SAXS), crystalline domain size, (i.e., thickness of MF-CNPs), was determined (27 nm (d001)). Through interpretation of ultra-small-angle X-ray scattering (USAXS) patterns of MF using Unified Fit and Guinier-Porod models, structural properties of MF-CNPs (smooth surfaces) and MF-CNP aggregations were characterized (RLCA aggregation of MF-CNPs to form larger structures that present diffused surfaces). Elucidation of MF-CNPs provides a new dimension of analysis for describing MF crystal networks and opens-up opportunities for modifying MF properties through nanoengineering. PMID- 26948604 TI - In-line electrochemical reagent generation coupled to a flow injection biamperometric system for the determination of sulfite in beverage samples. AB - This work reports an in-line electrochemical reagent generation coupled to a flow injection biamperometric procedure for the determination of SO3(2-). The method was based on a redox reaction between the I3(-) and SO3(2-) ions, after the diffusion of SO2 through a gas diffusion chamber. Under optimum experimental conditions, a linear response ranging from 1.0 to 12.0 mg L(-1) (R=0.9999 and n=7), a detection and quantification limit estimated at 0.26 and 0.86 mg L(-1), respectively, a standard deviation relative of 0.4% (n=10) for a reference solution of 4.0 mg L(-1) SO3(2-) and sampling throughput for 40 determinations per hour were achieved. Addition and recovery tests with juice and wine samples were performed resulting in a range between 92% and 110%. There were no significant differences at a 95% confidence level in the analysis of eight samples when comparing the new method with a reference procedure. PMID- 26948612 TI - Characterization of Coffea arabica monofloral honey from Espirito Santo, Brazil. AB - In this study, samples of coffee honey produced in Espirito Santo State, Brazil, were characterized based on their melissopalynology, physicochemical and nutritional properties, and mineral and caffeine contents. The caffeine content in the nectar from coffee flowers was measured by high performance liquid chromatography (HPLC). Blends of honey were obtained from three Coffea arabica crops, each with 10 colonies of Africanized Apis mellifera. All honey samples contained monofloral (75-78%) pollen belonging to C. arabica. Physicochemical parameters (total acidity, pH, moisture, dry matter, ash, and qualitative hydroxymethylfurfural) were within the approved limits established by EU legislation. Coffee honey contains high levels of ascorbic acid (294.68 mg kg( 1)) and low amounts of total flavonoids (3.51 +/- 0.18 mg QE kg(-1)). The most abundant minerals were potassium and calcium (962.59 +/- 154.3 and 343.75 +/- 25.56 mg kg(-1), respectively). The caffeine content in coffee nectar (1.64 mg kg(-1)) was approximately 8-fold lower than that in honey (12.02 +/- 0.81 mg kg( 1)). PMID- 26948611 TI - Degradation of bifenthrin and pirimiphos-methyl residues in stored wheat grains (Triticum aestivum L.) by ozonation. AB - Pesticide insecticides are used on wheat grains in storage units but their efficiency is hindered by persistent residues in the grains. Therefore, this study aims to evaluate the effectiveness of ozone (O3) gas treatment on the degradation of residual bifenthrin and pirimiphos-methyl insecticides commonly used in storage wheat grains, as well as to evaluate degradation of their by products. The residues of bifenthrin decreased after 180 min of exposure in a concentration of 60 MUmol/mol (a 37.5 +/- 7.4% reduction) with 20% moisture content and 0.9 water activity. On the other hand, under the same experimental conditions, the pirimiphos-methyl residues significantly decreased in the wheat grains (71.1 +/- 8.6%) after 30 min of exposure. After O3 gas treatment, three by products of pirimiphos-methyl (m/z=306.1) containing different molecular mass to charge ratios (m/z=278.1, 301.1 and 319.2) were identified by LC-MS. O3 is a strong oxidizer that has shown the potential to reduce pesticide residues in stored grain in order to ensure food quality and safety. PMID- 26948613 TI - In vitro anti-inflammatory and antioxidant activities and protein quality of high hydrostatic pressure treated squids (Todarodes pacificus). AB - This study investigated the in vitro anti-inflammatory and antioxidant properties, protein quality, and other related characteristics obtained by the single-cycle and two-cycle high hydrostatic pressure (HHP at 200, 400 and 600 MPa) treatment of squids (Todarodes pacificus). The soluble protein nitrogen content and in vitro protein digestibility increased significantly (p<0.05) after all HHP treatments, and the two-cycle 600 MPa HHP treatments yielded the highest values, 7.59% and 84.42%, respectively. The estimated protein efficiency ratios, and antioxidant and anti-inflammatory properties of squids significantly increased by all HHP treatments. (1)H nuclear magnetic resonance (NMR) showed that the main spectral changes associated to the anti-inflammatory properties of proteins following HHP treatment were in the range of 3.00-3.19 and 3.60-3.79 ppm. This indicates that the HHP treatments modified the protein and functional properties of squids and gave the relevant chemical shifts in NMR signals, either migrated or disappeared. PMID- 26948614 TI - Gelation of wheat arabinoxylans in the presence of Cu(+2) and in aqueous mixtures with cereal beta-glucans. AB - The effect of copper ions (0.63-0.16 mM) on the rheological behavior of arabinoxylan (AX) aqueous solutions was investigated. Moreover, the influence of beta-glucan addition (BG, 0.5-3% w/v) on the gelation of mixed AX/BG solutions with and without addition of the peroxidase/H2O2 was examined. Generally, gels formed with inclusion of transition metal-ions differed from those obtained by adding peroxidase/H2O2. Copper ions induced viscosity increase of the AX solutions and form stronger thermoreversible gels with increasing ion concentration; optimal gelation was at 15 degrees C. For added beta-glucan at levels >1%, the lower the concentration and the higher the molecular weight of beta-glucan, the weaker the gelling ability of the mixed AX/BG system treated with peroxidase/H2O2. The polysaccharide-ratio affected both the gelling rate and the network melting temperature, with the beta-glucan itself giving the strongest network. Calorimetry provided evidence for existence of beta-glucan ordered domains in the mixed gel structures of AX/BG1, indicative of phase separation events. PMID- 26948615 TI - Effects of chitosan combined with nisin treatment on storage quality of large yellow croaker (Pseudosciaena crocea). AB - Effects of chitosan combined with different concentrations of nisin on quality enhancement of large yellow croaker (Pseudosciaena crocea) stored at 4 degrees C were evaluated for 8 days. Changes in sensory score and volatile spoilage products, total viable counts (TVC), and physiochemical indexes including weight loss, colour, pH, total volatile basic nitrogen (TVB-N), and K-value were examined. Results demonstrated that nisin-treated samples presented better quality preservation effects than chitosan alone. 1% chitosan combined with 0.6% nisin presented optimal quality enhancement effects, such as moisture loss control, volatile spoilage inhibition, TVB-N reduction, TVC growth control, and colour and sensory acceptability maintenance. Therefore, chitosan combined with nisin is promising in large yellow croaker shelf life extension. PMID- 26948616 TI - A new synthesis, characterization and application chelating resin for determination of some trace metals in honey samples by FAAS. AB - In this study, we developed a simple and rapid solid phase extraction (SPE) method for the separation/preconcentration and determination of some trace metals by flame atomic absorption spectrometry (FAAS). A new chelating resin, poly [2-(4 methoxyphenylamino)-2-oxoethyl methacrylate-co-divinylbenzene-co-2-acrylamido-2 methyl-1-propanesulfonic acid] (MPAEMA-co-DVB-co-AMPS), was synthesized and characterized. This chelating resin was used as a new adsorbent material for determination of Cd(II), Co(II), Cr(III), Cu(II), Fe(III), Mn(II), Pb(II), and Zn(II) ions. The parameters influential on the determination of this trace metals were examined. Under the optimum conditions, the detection limits (DL) of the method for trace metals were found to be (3s) in the range of 0.9-2.2 MUg L(-1) (n=21), the preconcentration factor was calculated as 200 and the relative standard deviation was obtained achieved as ?2% for n=11. The method was performed for the determination of trace metals in some honey samples and standard reference materials. PMID- 26948617 TI - Effect of irrigation regime on perceived astringency and proanthocyanidin composition of skins and seeds of Vitis vinifera L. cv. Syrah grapes under semiarid conditions. AB - In this work, the effect of water availability on astringency of seed and skin extracts of Vitis vinifera cv. Syrah berries under the typical semiarid conditions of Greece was investigated. Moreover, astringency was assessed in relation to proanthocyanidin composition. For this purpose, three irrigation treatments were applied starting at berry set through harvest of 2011 and 2012: full irrigation (FI) at 100% of crop evapotranspiration, deficit irrigation (DI) at 50% and non-irrigated (NI). FI skin and seed extracts were perceived significantly more astringent than NI. Total phenol, total tannin, (+)-catechin, (-)-epicatechin and procyanidin C1 concentrations were positively correlated with astringency. Positive correlations were also obtained among astringency and average degree of polymerization and proportion of the extension units of shorter tannins while astringency of larger tannins was correlated with the proportion of terminal units. On the contrary, total anthocyanin and epigallocatechin contents were negatively correlated with astringency. PMID- 26948619 TI - Retrogradation behavior of corn starch treated with 1,4-alpha-glucan branching enzyme. AB - The retrogradation behavior of corn starch treated with 1,4-alpha-glucan branching enzyme (GBE) was investigated using rheometry, pulsed nuclear magnetic resonance (PNMR), differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FTIR). Dynamic time sweep analysis confirmed that the storage modulus (G') of corn starch stored at 4 degrees C decreased with increasing GBE treatment time. PNMR analysis demonstrated that the transverse relaxation times (T2) of corn starches treated with GBE were higher than that of control during the storage at 4 degrees C. DSC results demonstrated that the retrogradation enthalpy (DeltaHr) of corn starch was reduced by 22.3% after GBE treatment for 10h. Avrami equation analysis showed that GBE treatment reduced the rate of starch retrogradation. FTIR analysis revealed that GBE treatment led to a decrease in hydrogen bonds within the starch. Overall, these results demonstrate that both short- and long-term retrogradation of corn starch were retarded by GBE treatment. PMID- 26948618 TI - Comparative nutritional compositions and proteomics analysis of transgenic Xa21 rice seeds compared to conventional rice. AB - Transgenic rice expressing the Xa21 gene have enhanced resistant to most devastating bacterial blight diseases caused by Xanthomonas oryzae pv. oryzae (Xoo). However, identification of unintended modifications, owing to the genetic modification, is an important aspect of transgenic crop safety assessment. In this study, the nutritional compositions of seeds from transgenic rice plants expressing the Xa21 gene were compared against non-transgenic rice seeds. In addition, to detect any changes in protein translation levels as a result of Xa21 gene expression, rice seed proteome analyses were also performed by two dimensional gel electrophoresis. No significant differences were found in the nutritional compositions (proximate components, amino acids, minerals, vitamins and anti-nutrients) of the transgenic and non-transgenic rice seeds. Although gel electrophoresis identified 11 proteins that were differentially expressed between the transgenic and non-transgenic seed, only one of these (with a 20-fold up regulation in the transgenic seed) shows nutrient reservoir activity. No new toxins or allergens were detected in the transgenic seeds. PMID- 26948620 TI - Olive oil sensory defects classification with data fusion of instrumental techniques and multivariate analysis (PLS-DA). AB - Three instrumental techniques, headspace-mass spectrometry (HS-MS), mid-infrared spectroscopy (MIR) and UV-visible spectrophotometry (UV-vis), have been combined to classify virgin olive oil samples based on the presence or absence of sensory defects. The reference sensory values were provided by an official taste panel. Different data fusion strategies were studied to improve the discrimination capability compared to using each instrumental technique individually. A general model was applied to discriminate high-quality non-defective olive oils (extra virgin) and the lowest-quality olive oils considered non-edible (lampante). A specific identification of key off-flavours, such as musty, winey, fusty and rancid, was also studied. The data fusion of the three techniques improved the classification results in most of the cases. Low-level data fusion was the best strategy to discriminate musty, winey and fusty defects, using HS-MS, MIR and UV vis, and the rancid defect using only HS-MS and MIR. The mid-level data fusion approach using partial least squares-discriminant analysis (PLS-DA) scores was found to be the best strategy for defective vs non-defective and edible vs non edible oil discrimination. However, the data fusion did not sufficiently improve the results obtained by a single technique (HS-MS) to classify non-defective classes. These results indicate that instrumental data fusion can be useful for the identification of sensory defects in virgin olive oils. PMID- 26948621 TI - Changes of microstructure characteristics and intermolecular interactions of preserved egg white gel during pickling. AB - Changes in gel microstructure characteristics and in intermolecular interactions of preserved egg whites during pickling were investigated. Spin-spin relaxation times of preserved egg whites significantly decreased in the first 8 days and remained unchanged after the 16th day. SEM images revealed a three-dimensional gel network, interwoven with a loose linear fibrous mesh structure. The protein gel mesh structure became more regular, smaller, and compacted with pickling time. Free sulfhydryl contents in the egg whites increased significantly, while total sulfhydryl contents dramatically decreased during pickling. The primary intermolecular forces in the preserved egg white gels were ionic and disulfide bonds. Secondary forces included hydrophobic interaction and relatively few hydrogen bonds. During the first 8 days, the proportion of ionic bonds sharply decreased, and that of disulfide bonds increased over the first 24 days. PMID- 26948622 TI - Encapsulation of omega-3 fatty acids in nanoemulsion-based delivery systems fabricated from natural emulsifiers: Sunflower phospholipids. AB - Nanoemulsions have considerable potential for encapsulating and delivering omega 3 fatty acids, but they are typically fabricated from synthetic surfactants. This study shows that fish oil-in-water nanoemulsions can be formed from sunflower phospholipids, which have advantages for food applications because they have low allergenicity and do not come from genetically modified organisms. Nanoemulsions containing small droplets (d<150 nm) could be produced using microfluidization, by optimizing phospholipid type and concentration, with the smallest droplets being formed at high phosphatidylcholine levels and at surfactant-to-oil ratios exceeding unity. The physical stability of the nanoemulsions was mainly attributed to electrostatic repulsion, with droplet aggregation occurring at low pH values (low charge magnitude) and at high ionic strengths (electrostatic screening). These results suggest that sunflower phospholipids may be a viable natural emulsifier to deliver omega-3 fatty acids into food and beverage products. PMID- 26948623 TI - Stability of glucosinolates and glucosinolate degradation products during storage of boiled white cabbage. AB - The aim of the study was to investigate the effect of storage on the contents of glucosinolates (GLS) and their degradation products in a boiled white cabbage. A 24h storage at 4 degrees C resulted in a decrease in GLS content (20-40%, depending on the cooking time applied) in the edible parts. The most significant losses were observed for sinigrin (20-45%), and the least for glucobrassicin (12 32%). Storage had a diversified effect on GLS breakdown products (indole-3 acetonitrile, indole-3-carbinol, ascorbigen and 3,3'-diindolylmethane released from glucobrassicin and 4-methylsulfinylbutanenitrile released from glucoiberin) in the boiled cabbage. The increase in the content of indole-3-acetonitrile, especially considerable within the first 24h of storage (and a simultaneous decrease in glucobrassicin) clearly indicates that degradation of GLS may occur during storage or cooling to 4 degrees C. PMID- 26948624 TI - Encapsulation of CO2 into amorphous alpha-cyclodextrin powder at different moisture contents - Part 1: Encapsulation capacity and stability of inclusion complexes. AB - This study investigated the effects of water-induced crystallization of amorphous alpha-cyclodextrin (alpha-CD) powder on CO2 encapsulation at 0.4-1.6 MPa pressure for 1-72 h through the addition of water (to reach to 13, 15 and 17% wet basis, w.b.) into amorphous alpha-CD powder prior to the encapsulation. The results showed that the alpha-CD encapsulation capacity was over 1 mol CO2/mol alpha-CD after pressurizing for longer than 48 h. The encapsulated CO2 concentration by the addition of water was considerably higher (p<0.05) than that of amorphous alpha-CD powder (5.51% MC, w.b.) without an addition of water and that of crystalline alpha-CD powders under the same MC and encapsulation conditions. A comparison of CO2 release properties (75% relative humidity, 25 degrees C) from complexed powders prepared from amorphous and crystalline alpha-CD powders under the same conditions is also presented. PMID- 26948625 TI - Evaluation of nutritional profiles of starch and dry matter from early potato varieties and its estimated glycemic impact. AB - To identify healthier potatoes with respect to starch profiles, fourteen early varieties were evaluated for their dietary fiber, total starch, rapidly digestible (RDS), slowly digestible (SDS), and resistant (RS) starch for nutrition and with regard to estimated glycemic index (eGI) and glycemic load (eGL). While all these profiles were highly dependent on the potato variety, eleven out of fourteen varieties were classified as low GL foods (p<0.05). A strong positive correlation was observed with eGI and RDS (r=0.975-1.00, 0.96 1.00 and 0.962-0.997 for uncooked, cooked and retrograded varieties, respectively), whereas a strong negative correlation was observed between eGI and RS (r=-0.985 to -0.998, -0.96 to -1.00 and -0.983 to -0.999 for uncooked, cooked and retrograded varieties respectively, p<0.05). For the cultivars examined, the present study identified RDS and RS as major starch factors contributing to eGI. PMID- 26948626 TI - In silico and in vitro analyses of the angiotensin-I converting enzyme inhibitory activity of hydrolysates generated from crude barley (Hordeum vulgare) protein concentrates. AB - Angiotensin-I-converting enzyme (ACE-I) plays a key role in control of hypertension, and type-2 diabetes mellitus, which frequently co-exist. Our current work utilised in silico methodologies and peptide databases as tools for predicting release of ACE-I inhibitory peptides from barley proteins. Papain was the enzyme of choice, based on in silico analysis, for experimental hydrolysis of barley protein concentrate, which was performed at the enzyme's optimum conditions (60 degrees C, pH 6.0) for 24 h. The generated hydrolysate was subjected to molecular weight cut-off (MWCO) filtration, following which the non ultrafiltered hydrolysate (NUFH), and the generated 3 kDa and 10 kDa MWCO filtrates were assessed for their in vitro ACE-I inhibitory activities. The 3 kDa filtrate (1 mg/ml), that demonstrated highest ACE-I inhibitory activity of 70.37%, was characterised in terms of its peptidic composition using mass spectrometry and 1882 peptides derived from 61 barley proteins were identified, amongst which 15 peptides were selected for chemical synthesis based on their predicted ACE-I inhibitory properties. Of the synthesized peptides, FQLPKF and GFPTLKIF were most potent, demonstrating ACE-I IC50 values of 28.2 MUM and 41.2 MUM respectively. PMID- 26948627 TI - Development of a fast DNA extraction method for sea food and marine species identification. AB - The authentication of food components is one of the key issues in food safety. Similarly taxonomy, population and conservation genetics as well as food web structure analysis, also rely on genetic analyses including the DNA barcoding technology. In this scenario we developed a fast DNA extraction method without any purification step from fresh and processed seafood, suitable for any PCR analysis. The protocol allows the fast DNA amplification from any sample, including fresh, stored and processed seafood and from any waste of industrial fish processing, independently of the sample storage method. Therefore, this procedure is particularly suitable for the fast processing of samples and to carry out investigations for the authentication of seafood by means of DNA analysis. PMID- 26948628 TI - Use of cyclodextrins to recover catechin and epicatechin from red grape pomace. AB - The capacity of cyclodextrins (CDs) to extract phenolic compounds from grape pomace was evaluated and compared with that of ethanol/water or aqueous extraction. The extraction method (stirring and ultrasound), temperature and time were also studied. Total phenolic compounds (TPC) and antioxidant activity were measured, and HPLC analysis was used to identify the phenolic compounds. The extracts obtained using the ethanol/water mixture presented the highest TPC content and antioxidant activity, followed by those obtained using CD solutions. The addition of CDs to the extractant agent had a selective effect on the extraction of catechin and epicatechin. The yield of catechin and epicatechin by using aqueous solutions of CDs was similar to that obtained using organic solvents as ethanol. PMID- 26948629 TI - A novel extraction method for beta-carotene and other carotenoids in fruit juices using air-assisted, low-density solvent-based liquid-liquid microextraction and solidified floating organic droplets. AB - Green extraction using air-assisted, low-density solvent-based liquid-liquid microextraction and solidified floating organic droplets (AA-LDS-LLME-SFOD) prior to spectrophotometry was successfully applied for quantitation of carotenoids in fruit juices. Under optimal conditions, beta-carotene could be quantified with a linear response up to a concentration of 60 MUg mL(-1). The procedure was performed in a microcentrifuge tube with 40 MUL of 1-dodecanol as the extraction solvent and a 1.0 mL juice sample containing 8% NaCl under seven extraction cycles of air pumping by syringe. This method was validated based on linearity (0.2-30 MUg mL(-1), R(2) 0.998), limit of detection (0.04 MUg mL(-1)) and limit of quantification (0.13 MUg mL(-1)). The precision, expressed as the relative standard deviation (RSD) of the calibration curve slope (n=12), for inter-day and intra-day analysis was 4.85% and 7.92%, respectively. Recovery of beta-carotene was in the range of 93.6-101.5%. The newly proposed method is simple, rapid and environmentally friendly, particularly as a useful screening test for food analysis. PMID- 26948631 TI - Recovery of protein from green leaves: Overview of crucial steps for utilisation. AB - Plant leaves are a major potential source of novel food proteins. Till now, leaf protein extraction methods mainly focus on the extraction of soluble proteins, like rubisco protein, leaving more than half of all protein unextracted. Here, we report on the total protein extraction from sugar beet leaves (Beta vulgaris L.) by a traditional thermal extraction method consisting of mechanical pressing, heating to 50 degrees C and centrifugation. The resulting streams (i.e. supernatant, green-protein pellet and fibrous pulp) were characterised in terms of composition, physical structure and processing options. The protein distributed almost equally over the supernatant, pellet and pulp. This shows that thermal precipitation is an unselective process with respect to fractionation between soluble (rubisco) and insoluble (other) proteins. About 6% of the total protein could be extracted as pure rubisco (90% purity) from the supernatant. Surfactants commonly used for protein solubilisation could hardly re-dissolve the precipitated proteins in the pellet phase, which suggested that irreversible association was induced between the co-precipitated proteins and cell debris. Thus, the extraction of this protein will require prevention of their co precipitation, and should take place in the original juice solution. PMID- 26948632 TI - Evaluation on oxidative stability of walnut beverage emulsions. AB - Walnut beverage emulsions were prepared with walnut kernels, mixed nonionic emulsifiers and xanthan gum. The effects of food antioxidants on the physical stability and lipid oxidation of walnut beverage emulsions were investigated. The results showed that tea polyphenols could not only increase the droplet size of the emulsions, but also enhance physical stability during the thermal storage at 62 +/- 1 degrees C. However, water-dispersed oil-soluble vitamin E and enzymatically modified isoquercitrin obviously decreased the physical stability of the emulsion system during the thermal storage. BHT and natural antioxidant extract had scarcely influenced on the physical stability of walnut beverage emulsions. Tea polyphenols and BHT could significantly retard lipid oxidation in walnut beverage emulsions against thermal and UV light exposure during the storage. Vitamin E exhibited the prooxidant effect during the thermal storage and the antioxidant attribute during UV light exposure. Other food antioxidants had no significant effect on retarding lipid oxidation during thermal or light storage. PMID- 26948630 TI - Application of pH-zone refining hydrostatic countercurrent chromatography (hCCC) for the recovery of antioxidant phenolics and the isolation of alkaloids from Siberian barberry herb. AB - The development of a fast hCCC method tailored to recover phenolics of Siberian barberry (Berberis sibirica, Berberidaceae) responsible for the observed strong antioxidant activity was performed. Initially, the optimization of extraction procedure was evaluated based on the antiradical potential assessment (DPPH and Folin-Ciocalteu assays). 100 degrees C methanol ASE extract exhibited the highest antiradical activity (IC50=60 +/- 4 MUg/mL), and a significant TPC (159 +/- 2 mgGAE/g). Thorough determination of phenolic content by UHPLC-DAD-ESI( )HRMS revealed the presence of 10 phenolics as major constituents, and several groups of alkaloids. pH-zone refining hCCC was chosen as the most promising method for the extract's fractionation due to the ionizable character of its constituents. For this purpose a MtBE-H2O (1:1) system with 10mM TEA and HCl was applied leading to a phenolic fraction, free of alkaloids, with higher antioxidant capacity (IC50=25 MUg/mL, TPC=178 mg GAE/g). Additionally, fractionation of alkaloids was achieved resulting isolation of pharmacologically important alkaloids: magnoflorine and berberine. PMID- 26948633 TI - Changes in antioxidant and antiinflammatory activity of black bean (Phaseolus vulgaris L.) protein isolates due to germination and enzymatic digestion. AB - Germination is an inexpensive process to improve the nutritional properties of legumes. The effect of germinating black bean seeds on the production of cotyledon protein hydrolysates (CPH) with antioxidant and antiinflammatory activities was analyzed in this research. After simulated enzymatic digestion, the oxygen radical absorbance capacity (ORAC) of CPH obtained from germinated black beans was lower than that observed for raw cotyledons. There were no significant differences among CPH cellular antioxidant activities (CAA), except for the high CAA of the 120 min hydrolysate obtained from one day germinated black bean cotyledons. The most significant changes due to germination and enzymatic hydrolysis were observed for the inhibition of nitric oxide (NO) production in macrophages. The NO synthesis inhibition observed for raw CPH was reduced after simulated gastrointestinal digestion but for germinated samples the inhibition was doubled. Peptides derived from cell wall proteins produced during germination could be responsible of antiinflammatory activity. PMID- 26948634 TI - Spectroscopy analysis of phenolic and sugar patterns in a food grade chestnut tannin. AB - Tannin of chestnut (Castanea sativa Mill.) wood, commonly used in winemaking was characterised with a spectroscopy qualitative approach that revealed its phenolic composition: several vibrational diagnostic bands assigned using the Attenuated Total Reflectance-Infrared Spectroscopy, and fragmentation patterns obtained using the Laser-Desorption-Ionization Time-of-Flight technique evidenced polygalloylglucose, e.g. castalagin/vescalagin-like structures as the most representative molecules, together with sugar moieties. The implication of these findings on winemaking application and the potential influence of the chemical structure on the sensory properties of wine are discussed. PMID- 26948635 TI - Mushroom (Agaricus bisporus) polyphenoloxidase inhibited by apigenin: Multi spectroscopic analyses and computational docking simulation. AB - It has been revealed that some polyphenols can prevent enzymatic browning caused by polyphenoloxidase (PPO). Apigenin, widely distributed in many fruits and vegetables, is an important bioactive flavonoid compound. In this study, apigenin exhibited a strong inhibitory activity against PPO, and some reagents had synergistic effect with apigenin on inhibiting PPO. Apigenin inhibited PPO activity reversibly in a mixed-type manner. The fact that inactivation rate constant (k) of PPO increased while activation energy (Ea) and thermodynamic parameters (DeltaG, DeltaH and DeltaS) decreased indicated that the thermosensitivity and stability of PPO decreased. The conformational changes of PPO were revealed by fluorescence emission spectra and circular dichroism. Atomic force microscopy observation suggested that the dimension of PPO molecules was larger after interacting with apigenin. Moreover, computational docking simulation indicated that apigenin bound to PPO and inserted into the hydrophobic cavity of PPO to interact with some amino acid residues. PMID- 26948636 TI - Impact of wine production on the fractionation of copper and iron in Chardonnay wine: Implications for oxygen consumption. AB - Copper and iron in wine can influence oxidative, reductive and colloidal stability. The current study utilises a solid phase extraction technique to fractionate these metals into hydrophobic, cationic and residual forms, with quantification by ICP-OES. The impact of aspects of wine production on the metal fractions was examined, along with the relationship between metal fractions and oxygen decay rates. Addition of copper and iron to juice, followed by fermentation, favoured an increase in all of their respective metal fractions in the wine, with the largest increase observed for the cationic form of iron. Bentonite fining of the protein-containing wines led to a significant reduction in the cationic fraction of copper and an increase in the cationic form of iron. Total copper correlated more closely with oxygen consumption in the wine compared to total iron, and the residual and cationic forms of copper provided the largest contribution to this impact. PMID- 26948637 TI - The lager yeast Saccharomyces pastorianus removes and transforms Fusarium trichothecene mycotoxins during fermentation of brewer's wort. AB - An investigation was conducted to determine the fate of deoxynivalenol, deoxynivalenol-3-glucoside, HT-2 toxin and T-2 toxin, during a four-day fermentation with the lager yeast Saccharomyces pastorianus. The influence of excessive mycotoxin concentrations on yeast growth, productivity and viability were also assessed. Mycotoxins were dosed at varying concentrations to 11.5 degrees Plato wort. Analysis of yeast revealed that presence of the toxins even at concentrations up to 10,000 MUg/L had little or no effect on sugar utilisation, alcohol production, pH, yeast growth or cell viability. Of the dosed toxin amounts 9-34% were removed by the end of fermentation, due to physical binding and/or biotransformation by yeast. Deoxynivalenol-3-glucoside was not reverted to its toxic precursor during fermentation. Processing of full-scan liquid chromatography-quadrupole time-of-flight-mass spectrometry (LC-QTOF-MS) data with MetaboLynx and subsequent LC-QTOF-MS/MS measurements resulted in annotation of several putative metabolites. De(acetylation), glucosylation and sulfonation were the main metabolic pathways activated. PMID- 26948638 TI - Oenological characteristics, amino acids and volatile profiles of Hongqu rice wines during pottery storage: Effects of high hydrostatic pressure processing. AB - Hongqu rice wines were subjected to high hydrostatic pressure (HHP) treatments of 200 MPa and 550 MPa at 25 degrees C for 30 min and effects on wine quality during pottery storage were examined. HHP treatment can significantly (p<0.05) decrease the content of fusel-like alcohols and maintain the concentration of lactones in these wines. After 18 months of storage, the HHP-treated wines exhibited a more rapid decrease in total sugars (9.3-15.3%), lower free amino acid content (e.g. lysine content decreased by 45.0-84.5%), and higher ketone content (e.g. 6- and 14-fold increase for 2-nonanone). These changes could be attributed to the occurrence of Maillard and oxidation reactions. The wines treated at 550 MPa for 30 min developed about twice as rapidly during pottery storage than untreated wines based on principal component analysis. After only 6 months, treated wines had a volatile composition and an organoleptic quality similar to that of untreated wines stored in pottery for 18 months. PMID- 26948640 TI - Unsupervised pattern recognition methods in ciders profiling based on GCE voltammetric signals. AB - This work presents a complete methodology of distinguishing between different brands of cider and ageing degrees, based on voltammetric signals, utilizing dedicated data preprocessing procedures and unsupervised multivariate analysis. It was demonstrated that voltammograms recorded on glassy carbon electrode in Britton-Robinson buffer at pH 2 are reproducible for each brand. By application of clustering algorithms and principal component analysis visible homogenous clusters were obtained. Advanced signal processing strategy which included automatic baseline correction, interval scaling and continuous wavelet transform with dedicated mother wavelet, was a key step in the correct recognition of the objects. The results show that voltammetry combined with optimized univariate and multivariate data processing is a sufficient tool to distinguish between ciders from various brands and to evaluate their freshness. PMID- 26948639 TI - Modeling and optimization of red currants vacuum drying process by response surface methodology (RSM). AB - Fresh red currants were dried by vacuum drying process under different drying conditions. Box-Behnken experimental design with response surface methodology was used for optimization of drying process in terms of physical (moisture content, water activity, total color change, firmness and rehydratation power) and chemical (total phenols, total flavonoids, monomeric anthocyanins and ascorbic acid content and antioxidant activity) properties of dried samples. Temperature (48-78 degrees C), pressure (30-330 mbar) and drying time (8-16 h) were investigated as independent variables. Experimental results were fitted to a second-order polynomial model where regression analysis and analysis of variance were used to determine model fitness and optimal drying conditions. The optimal conditions of simultaneously optimized responses were temperature of 70.2 degrees C, pressure of 39 mbar and drying time of 8 h. It could be concluded that vacuum drying provides samples with good physico-chemical properties, similar to lyophilized sample and better than conventionally dried sample. PMID- 26948641 TI - Transition of phenolics and cyanogenic glycosides from apricot and cherry fruit kernels into liqueur. AB - Popular liqueurs made from apricot/cherry pits were evaluated in terms of their phenolic composition and occurrence of cyanogenic glycosides (CGG). Analyses consisted of detailed phenolic and cyanogenic profiles of cherry and apricot seeds as well as beverages prepared from crushed kernels. Phenolic groups and cyanogenic glycosides were analyzed with the aid of high-performance liquid chromatography (HPLC) and mass spectrophotometry (MS). Lower levels of cyanogenic glycosides and phenolics have been quantified in liqueurs compared to fruit kernels. During fruit pits steeping in the alcohol, the phenolics/cyanogenic glycosides ratio increased and at the end of beverage manufacturing process higher levels of total analyzed phenolics were detected compared to cyanogenic glycosides (apricot liqueur: 38.79 MUg CGG per ml and 50.57 MUg phenolics per ml; cherry liqueur 16.08 MUg CGG per ml and 27.73 MUg phenolics per ml). Although higher levels of phenolics are characteristic for liqueurs made from apricot and cherry pits these beverages nevertheless contain considerable amounts of cyanogenic glycosides. PMID- 26948642 TI - Chemical composition and antioxidant capacity of different anatomical parts of pear (Pyrus communis L.). AB - Sugar, organic acid, triterpenoid and phenolic composition as well as antioxidant capacity of different anatomical parts of pear were studied. Fruits and leaves of 'Radana' pear (Pyrus communis L.) were used. The results showed great quantitative differences in the composition of the pear pulp, peel, leaves and seeds. Fructose was the major sugar in pulp, seeds and peel (227.46, 45.36 and 67.49 g/kg dry mass [DM], respectively), while sorbitol was predominant in leaves (40.66 g/kg DM). Malic acid was the major organic acid, followed by citric and shikimic acids. The highest concentration of triterpenoids (3460.5 MUg/g DM) was determined in pear peel, and ursolic acid was predominant. Leaves were characterized by the highest amount of phenolics (5326.7 mg/100 g DM) and the highest DPPH and FRAP values (2027.9 and 3539.6 MUmol TE/100 g DM, respectively). Pear leaves and seeds may be selected as potential sources of phytochemicals. PMID- 26948643 TI - A novel method to quantify the activity of alcohol acetyltransferase Using a SnO2 based sensor of electronic nose. AB - Alcohol acetyltransferase (AATFase) extensively catalyzes the reactions of alcohols to acetic esters in microorganisms and plants. In this work, a novel method has been proposed to quantify the activity of AATFase using a SnO2-based sensor of electronic nose, which was determined on the basis of its higher sensitivity to the reducing alcohol than the oxidizing ester. The maximum value of the first-derivative of the signals from the SnO2-based sensor was therein found to be an eigenvalue of isoamyl alcohol concentration. Quadratic polynomial regression perfectly fitted the correlation between the eigenvalue and the isoamyl alcohol concentration. The method was used to determine the AATFase activity in this type of reaction by calculating the conversion rate of isoamyl alcohol. The proposed method has been successfully applied to determine the AATFase activity of a cider yeast strain. Compared with GC-MS, the method shows promises with ideal recovery and low cost. PMID- 26948644 TI - Citrinin mycotoxin recognition and removal by naked magnetic nanoparticles. AB - Citrinin is a nephrotoxic mycotoxin which can be synthesized by Monascus mold during the fermentation process in foods. Monascus, generally described as red mold, is a red-pigmented filamentous fungus attracting a great interest for the production of natural dyes and cholesterol-lowering statins. We individuated a specie of Monascus producing high amount of natural dyes. However, this high pigmentation was correlated with the production of citrinin. Peculiar magnetic nanoparticles, synthesized in-house and called "Surface Active Maghemite Nanoparticles" (SAMNs), are proposed as an efficient and reliable mean for citrinin removal from Monascus treated foods. The nanomaterial efficiency for citrinin binding was proved on Monascus suspensions, and SAMN@citrinin complex was characterized by Mossbauer spectroscopy and magnetization measurements, showing that SAMNs resulted structurally and magnetically well conserved after citrinin binding. SAMNs are excellent and stable magnetic nano-carrier for toxin removal, which can be applied in food industry. PMID- 26948645 TI - Dry heat treatment affects wheat bran surface properties and hydration kinetics. AB - Heat stabilization of wheat bran aims at inactivation of enzymes which may cause rancidity and processability issues. Such treatments may however cause additional unanticipated phenomena which may affect wheat bran technological properties. In this work, the impact of toasting on wheat bran hydration capacity and hydration kinetics was studied. Hydration properties were assessed using the Enslin-Neff and drainage centrifugation water retention capacity methods, thermogravimetric analysis and contact angle goniometry, next to more traditional methods. While equilibrium hydration properties of bran were not affected by the heat treatment, the rate at which the heat treated bran hydrated was, however, very significantly reduced compared to the untreated bran. This phenomenon was found to originate from the formation of a lipid coating during the treatment rendering the bran surface hydrophobic. These insights help to understand and partially account for the modified processability of heat treated bran in food applications. PMID- 26948646 TI - Rapid screening and identification of phenolic antioxidants in Hydrocotyle sibthorpioides Lam. by UPLC-ESI-MS/MS. AB - The aim of the study was to identify the phenolic compounds present in Hydrocotyle sibthorpioides (HS), Centella asiatica (CA) and Amaranthus viridis (AV) extracts and investigate their respective antioxidant activities. Herein, an ultra-high pressure liquid chromatography-mass spectrometer (UPLC-MS/MS) analytical method has been developed for the separation, and systematic characterization of the phenolic compounds in HS, CA and AV extracts and was compared along with ten standard phenolic compounds. Additionally, in vitro antioxidant activity of the phenolic compounds was also determined. The HS extract revealed excellent antioxidant activity such as 1,1-diphenyl-2 picrylhydrazyl radical scavenging activity (IC50=19.7 +/- 1.2 MUg/mL), total reduction capability (0.169 +/- 0.003 at 100 MUg/mL), nitric oxide radical scavenging activity (IC50=39.33 +/- 3.2 MUg/mL), metal chelating activity (IC50=56.51 +/- 3.6 MUg/mL) and inhibition of lipid peroxidation (IC50=12.34 +/- 2.3 MUg/mL) as compared to CA and AV extracts. Furthermore, catechin, epicatechin, quercetin and chlorogenic acid were found to be the major components responsible for the antioxidant activity of the HS extract as evidenced from UPLC MS/MS. Taken together, this study demonstrates the promising antioxidant properties of the HS extract, which can further be utilized in various pharmaceutical, food, and agricultural applications. PMID- 26948647 TI - Highly branched dextrin prepared from high-amylose maize starch using waxy rice branching enzyme (WRBE). AB - Branching enzyme (BE, EC 2.4.1.18) was isolated from the developing waxy rice endosperm and used to prepare a highly branched dextrin based on high-amylose maize starch (HAMS) as a substrate. The molecular mass of the starch initially degraded quickly from 2.5 * 10(7) to 4.1 * 10(5)Da, and then stabilized, with a minimal increase during the BE treatment. The resultant branched dextrin had a narrow size distribution, with a mean molecular weight of 5.1 * 10(5)Da and a polydispersity index (PI) of 1.567. The results of high-performance anion exchange chromatography indicated that the degree of polymerization (DP) of the branched chains ranged from 3 to 27; approximately 75.26% of these chains were short (DP<10). These findings suggest that the isolated BE can cleave long chains into oligosaccharides, subsequently transferring oligosaccharides into highly branched dextrins with a narrow size distribution and short side chains. PMID- 26948648 TI - Effect of methyl jasmonate application to grapevine leaves on grape amino acid content. AB - Over the last few years, considerable attention has been paid to the application of elicitors to vineyard. However, research about the effect of elicitors on grape amino acid content is scarce. Therefore, the aim of this study was to evaluate the influence of foliar application of methyl jasmonate on must amino acid content. Results revealed that total amino acid content was not modified by the application of methyl jasmonate. However, the individual content of certain amino acids was increased as consequence of methyl jasmonate foliar application, i.e., histidine, serine, tryptophan, phenylalanine, tyrosine, asparagine, methionine, and lysine. Among them, phenylalanine content was considerably increased; this amino acid is precursor of phenolic and aromatic compounds. In conclusion, foliar application of methyl jasmonate improved must nitrogen composition. This finding suggests that methyl jasmonate treatment might be conducive to obtain wines of higher quality since must amino acid composition could affect the wine volatile composition and the fermentation kinetics. PMID- 26948649 TI - Melanin and humic acid-like polymer complex from olive mill waste waters. Part I. Isolation and characterization. AB - A water soluble humic acid and melanin-like polymer complex (OMWW-ASP) was isolated from olive mill waste waters (OMWW) by ammonium sulfate fractionation to be used as natural additive in food preparations. The dark polymer complex was further characterized by a variety of biochemical, physicochemical and spectroscopic techniques. OMWW-ASP is composed mainly of proteins associated with polyphenols and carbohydrates and the distribution of its relative molecular size was determined between about 5 and 190 kDa. SDS-PAGE shows the presence of a well separated protein band of 21.3 kDa and a low molecular weight peptide. The OMWW ASP complex exhibits a monotonically increasing UV-Vis absorption spectrum and it contains stable radicals. Antioxidant activity measurements reveal the ability of the OMWW protein fraction to scavenge both the cationic 2,2'-azino-bis-(3 ethylbenzothiazoline-6-sulfonic acid) (ABTS(+)) radical, as well as the stable nitroxide free radical 4-hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPOL). PMID- 26948650 TI - Ripening and storage conditions of Chetoui and Arbequina olives: Part I. Effect on olive oils volatiles profile. AB - The distinctive aroma of virgin olive oil is mainly attributed to its volatile profile including components responsible for positive attributes and others for sensory defects resulting from chemical oxidation and exogenous enzymes. For this reason, the evolution of volatile compounds from Chetoui and Arbequina virgin olive oils during olive ripening and storage (at 4 and 25 degrees C during 4 weeks) was investigated. The profile of volatile phenols during olive storage was also studied. Quantitative differences in the volatile compounds during olive storage at 4 and 25 degrees C according to olive cultivar was determined. Concerning the volatile phenols, the Arbequina olives were the most affected by high storage temperature, as the formation of these compounds, especially 4-ethyl and 4-vinyl derivatives of phenol and guaiacol were more noticeable in Arbequina oils extracted from stored fruits at 25 degrees C. PMID- 26948651 TI - Inhibition of spleen tyrosine kinase (syk) suppresses renal fibrosis through anti inflammatory effects and down regulation of the MAPK-p38 pathway. AB - Renal fibrosis results from an excessive accumulation of extracellular matrix that occurs in most types of chronic kidney disease. Among the many fibrogenic factors that regulate renal fibrotic processes, transforming growth factor-beta1 (TGF-beta1) and inflammation after injury play critical roles. Spleen tyrosine kinase (Syk) is important for signaling processes implicated in autoimmune, inflammatory, and allergic diseases. We examined the effects of Syk inhibition on renal fibrosis in vivo and on TGF-beta1-induced renal fibroblast activation in vitro. A unilateral ureteral obstruction (UUO) model was induced in male B6 mice. Mice with UUO were administered a Syk inhibitor or saline intraperitoneally 1 day before UUO surgery and daily thereafter. Both kidneys were harvested 7 days after surgery for further analysis. For the in vitro experiments, NRK-49F rat fibroblasts were pre-incubated with a Syk inhibitor before TGF-beta1 stimulation. The inhibitory effects of Syk inhibition on signaling pathways down-stream of TGF beta1 were analyzed. In the UUO mouse model, administration of a Syk inhibitor attenuated extracellular matrix protein deposition and expression of alpha-smooth muscle actin, type I collagen, and fibronectin in a dose-dependent manner. In addition, macrophage infiltration in UUO kidney was reduced by Syk inhibition. Pre-incubation of NRK-49F cells with a Syk inhibitor suppressed TGF-beta1-induced myofibroblast activation. Furthermore, inhibitory effects of Syk inhibition on TGF-beta1-mediated myofibroblast activation were associated with down-regulation of MAPK-p38. These results suggest that Syk inhibition reduces tubulointerstitial fibrosis in UUO mice and inhibits TGF-beta1-induced kidney myofibroblast activation. Syk inhibition could have therapeutic potential for the treatment of renal tubulointerstitial fibrosis. PMID- 26948652 TI - Prognostic value of metabolic tumour volume and total lesion glycolysis in 18F FDG PET/CT scans in locally advanced breast cancer staging. AB - OBJECTIVE: To determine whether metabolic tumour volume (MTV) and total lesion glycolysis (TLG) are able to predict recurrence risk in locally advanced breast cancer (LABC) patients. MATERIAL AND METHODS: Retrospective study of LABC patients who undertook neoadjuvant, local and adjuvant treatment and follow up. A 18F-FDG PET/CT study for initial staging was performed analysing in this study different metabolic parameters (MTV, TLG, SUVmax and SUVmed) both in the primary tumour (T) as well as in axillary nodes (N) and whole-body (WB). RESULTS: Forty females were included between January 2010-2011; follow up until January 2015 was completed. The average follow-up was 46 months. Twenty percent presented recurrence: local disease (n=2) and distant metastasis (n=6); 3 patients died (38% of the patients which recurred and 7.5% from the total). SUVmax, MTV and TLG, in T, N and WB, were higher in those patients with recurrence. The MTV and TLG parameters in the tumour (T) were related to the recurrence rate (P=.020 and P=.028, respectively); whereas SUVmax in the lymph nodes (N) was significantly related (P=.008) to the recurrence rate. The best cut-off points to predict recurrence where: MTV T >=19.3cm3, TLG T>=74.4g and SUVmax N>=13.8, being 10-12 times more likely to recidivate when these thresholds where exceeded. Tumour grade was the only clinical-pathological variable which was related to recurrence probability (p=.035). CONCLUSIONS: In this study of LABC patients the metabolic parameters which have a better relationship with recurrence rate are: MTV and TLG in the primary tumour, SUVmax in the regional lymph node disease and whole-body PET data. PMID- 26948653 TI - Literature Review of Benign Mullerian Papilloma Contrasted With Vaginal Rhabdomyosarcoma. AB - STUDY OBJECTIVES: Benign mullerian papillomas of the genital tract are rare and, hence, can be mistaken for vaginal rhabdomyosarcoma on initial clinical review. This review of the literature will consolidate the previous cases of mullerian papilloma reported and looks for clues to differentiate the 2 entities. DESIGN AND SETTING: We provide a case report and literature review, with patients from a pediatric adolescent gynecology clinic in a tertiary center. METHODS: We conducted a search of English-language publications from 1951 (the first case report) until January 2014 by using the search words "Mullerian papilloma" and "prepubertal bleeding." References from previous published reports were also obtained for completeness. MAIN OUTCOME: Literature review of benign mullerian papilloma. RESULTS: Since 1951, 56 cases of mullerian papilloma were reported, including 4 cases at our institution. Comorbid conditions were found in 31.5% of cases (with 3 cases associated with mesenchymal tumors). The average length of time from onset of symptoms (primarily vaginal bleeding) to diagnosis was 6.7 months (range, 1 day to 3 years), with only 1 case diagnosed incidentally. Median age of presentation was 5 years (range, 1 day to 52 years). Most cases were localized and resected with ease. Histology reveals complex papillary lesions without cytologic atypia. CONCLUSION: Benign mullerian papilloma is distinguished from the more significant diagnosis of vaginal rhabdomyosarcoma by initial length of vaginal bleeding at presentation, lack of vaginal wall extension, ease of resection, and histopathology. This is compared with vaginal rhabdomyosarcoma which commonly exhibits both localized and distant spread. PMID- 26948654 TI - Identifying the Assembly Configuration and Fluorescence Spectra of Nanoscale Zinc Tetraphenylporphyrin Aggregates with Scanning Tunneling Microscopy. AB - ZnTPP (Zinc-Tetraphenylporphyrin) is one of the most common nanostructured materials, having high stability and excellent optoelectronic properties. In this paper, the fluorescence features of self-assembled ZnTPP monomers and aggregates on Au(111) surface are investigated in detail on the nanometer scale with scanning tunneling microscopy (STM). The formation of ZnTPP dimers is found in thick layers of a layer-by-layer molecular assembly on Au substrate with its specific molecular arrangement well characterized. Tip-induced luminescence shows a red shift from tilted dimers comparing with the behavior from monomers, which can be attributed to the change of vibrational states due to the intermolecular interaction and the increasing dielectric effect. The nanoscale configuration dependence of electroluminescence is demonstrated to provide a powerful tool aiding the design of functional molecular photoelectric devices. PMID- 26948659 TI - Renal diseases in patients with rheumatoid arthritis. PMID- 26948661 TI - A novel dual-emission fluorescent probe for the simultaneous detection of H2S and GSH. AB - A novel chlorinated coumarin-malononitrile fluorescent probe with three potential reaction sites, which exhibited highly selective, rapid response, low detection limit, and was capable of the simultaneous detection of H2S (lambdaex/em = 515/564 nm) and GSH (lambdaex/em = 430/517 nm), was first proposed. The probe was successfully applied to dual-channel imaging H2S and GSH in MCF-7 cells. PMID- 26948660 TI - Proteomic profiling identifies the inorganic pyrophosphatase (PPA1) protein as a potential biomarker of metastasis in laryngeal squamous cell carcinoma. AB - Relapse and metastasis are the main causes of unfavorable outcome in head and neck cancers. Whereas, understanding of the molecular background of these processes is far from being complete. Therefore, in this study we aimed to identify potential biomarker candidates of relapse and metastasis in laryngeal squamous cell carcinoma (LSCC) by combining the 2D electrophoresis based protein screen and immunohistochemical analysis of candidate proteins. We screened three groups of LSCC cell lines derived from primary tumors, recurrent tumors and metastases and identified seven proteins that differed significantly in relative abundance between the analyzed groups. Among the identified proteins were the heat shock proteins HSP60 and HSP70 that were significantly downregulated both in recurrences- and metastases-derived cell lines but not in primary tumor-derived cell lines. Moreover, we identified significant upregulation of the annexin V, calreticulin and the inorganic pyrophosphatase (PPA1) exclusively in the metastases-derived cell lines. As these upregulated proteins could potentially become novel biomarkers of metastasis, we have compared their abundance in primary tumor LSCC N(0) cases, primary tumor LSCC N(+) cases as well as in LSCC metastases N(+). Our results show an intense increase of cytoplasmic PPA1 abundance in the N(+) (p = 0.000042) compared to the N(0) group. In summary, we show a group of proteins deregulated in recurrences and metastases of LSCC. Moreover, we suggest the PPA1 protein as a potential new biomarker for metastasis in this cancer. PMID- 26948663 TI - Rapid fabrication of functionalized plates for peptides, glycopeptides and protein purification and mass spectrometry analysis. AB - A rapid and simple approach for fabricating a disposable functionalized membrane on matrix-assisted laser desorption ionization (MALDI) targets, glass, or plastic substrates, without using complex mechanical protocols or chemical reactions, was developed for sample enrichment and mass spectrometry analysis. By coating functionalized-silica particles on a polydimethylsiloxane (PDMS)-coated plate, these particles can form a monolayer of materials on the PDMS membrane for sample handling without peeling off. An octadecyl(C18)-functionalized plate was fabricated by coating porous C18-silica particles on a PDMS-coated plate. The C18 particle-coated PDMS plate (CP plate) has better sensitivity than C18 tips and magnetic nanoparticles, along with a higher sample recovery (64.3 +/- 4.9%) compared to the C18 tip method, when analyzing trace amounts of 5 fm BSA digest samples. The CP plate shows significantly higher urea/SDS removal efficiency on the cell lysate proteome compared to C18 tips. The capacity of the C18 spot (~2.8 mm in diameter) on the CP plate was ~10 MUg of BSA digests. A hydrophilic particle-coated PDMS plate was also fabricated and successfully used for glycopeptide enrichment and matrix-assisted laser desorption ionization time-of flight mass spectrometry (MALDI-TOF MS) analysis. PMID- 26948662 TI - Development and internal validation of a multivariable prediction model for biochemical failure after whole-gland salvage iodine-125 prostate brachytherapy for recurrent prostate cancer. AB - BACKGROUND: Localized recurrent prostate cancer after primary radiotherapy can be curatively treated using salvage iodine-125 ((125)I) brachytherapy. Selection is hampered by a lack of predictive factors for cancer control. This study aims to develop and internally validate a prognostic model for biochemical failure (BF) after salvage (125)I brachytherapy. METHODS AND MATERIALS: Whole-gland salvage (125)I brachytherapy patients were treated between 1993 and 2010 in two radiotherapy centers in the Netherlands. Multivariable Cox regression was performed to assess the predictive value of clinical parameters related to BF (Phoenix-definition [prostate-specific antigen [PSA]-nadir + 2.0 ng/mL]). Missing data were handled by multiple imputation. The model's discriminatory ability was assessed with Harrell's C-statistic. Internal validation was performed using bootstrap resampling (2000 data sets). Goodness-of-fit was evaluated with calibration plots. All analyses were performed using the recently published TRIPOD (Transparent reporting of a multivariable prediction model for individual prognosis or diagnosis) statement. RESULTS: After median followup of 74 months (range 5-138), 43 of a total 62 patients developed BF. In multivariable analysis, disease-free survival interval (DFSI) after primary therapy and pre-salvage prostate-specific antigen doubling time (PSADT) were predictors of BF: corrected hazard ratio (HR) 0.99 (95% confidence interval 0.97-0.999; p = 0.04) and 0.94 (95% confidence interval 0.89-0.99; p = 0.03), both for a 1-month increase (optimism-adjusted C-statistic 0.70). Calibration was accurate up to 36 months. Of patients with PSADT >30 months and DFSI >60 months, 36-month biochemical disease-free survival was >75%. Every 12-month increase in DFSI will allow 3 month decrease in PSADT while maintaining the same biochemical recurrence-free rates. CONCLUSIONS: We have presented results from a cohort of patients undergoing salvage (125)I-brachytherapy. Our data show that better selection of patients is possible with the DFSI and PSADT. PMID- 26948664 TI - The world is confounded: a comment on Williams and Rhodes (2016). PMID- 26948665 TI - Inhibition of multispecies biofilms by a fluoride-releasing dental prosthesis copolymer. AB - OBJECTIVES: This study aimed to develop a new mixed-species acidogenic biofilm model and use it to assess the antimicrobial properties of a novel fluoride releasing copolymer. METHODS: Stubs composed of a copolymer of methyl methacrylate (MMA) and 2-hydroxyethyl methacrylate (HEMA) with polymethyl methacrylate (PMMA) were produced by chemically-activated free radical polymerization. A fluoride-releasing copolymer was developed by incorporating sodium fluoride in place of a portion of the PMMA. Samples were mounted in polysulfone Modified Robbins Devices (MRDs) and were optimized for single- and mixed-species biofilm formation by Candida albicans, Lactobacillus casei and Streptococcus mutans. RESULTS: Fluoride release was sustained for at least 48h in flowing conditions. Fluoride did not affect the colonization and biofilm growth of any of the microorganisms in monocultures. However, in mixed-species biofilms, cell densities of all three species were reduced approximately ten-fold (p<0.05) on the fluoridated material compared with the non-fluoridated copolymer. CONCLUSIONS: These data demonstrate that intermicrobial interactions in mixed species acidogenic biofilms are sensitive to fluoride, and that the inclusion of fluoride in a denture lining copolymer reduces the formation of polymicrobial biofilms. CLINICAL SIGNIFICANCE: The growth of acidogenic microorganisms on denture materials is associated with denture stomatitis and dental caries on surrounding teeth. A fluoride-releasing copolymer that inhibits acidogenic mixed species biofilms, such as the material described in this study, has the potential to control these diseases by limiting biofilm growth. PMID- 26948666 TI - Melatonin modulates monochromatic light-induced GHRH expression in the hypothalamus and GH secretion in chicks. AB - To study the mechanism by which monochromatic lights affect the growth of broilers, a total of 192 newly hatched broilers, including the intact, sham operated and pinealectomy groups, were exposed to white light (WL), red light (RL), green light (GL) and blue light (BL) using a light-emitting diode (LED) system for 2 weeks. The results showed that the GHRH-ir neurons were distributed in the infundibular nucleus (IN) of the chick hypothalamus. The mRNA and protein levels of GHRH in the hypothalamus and the plasma GH concentrations in the chicks exposed to GL were increased by 6.83-31.36%, 8.71-34.52% and 6.76-9.19% compared to those in the chicks exposed to WL (P=0.022-0.001), RL (P=0.002-0.000) and BL (P=0.290-0.017) in the intact group, respectively. The plasma melatonin concentrations showed a positive correlation with the expression of GHRH (r=0.960) and the plasma GH concentrations (r=0.993) after the various monochromatic light treatments. After pinealectomy, however, these parameters decreased and there were no significant differences between GL and the other monochromatic light treatments. These findings suggest that melatonin plays a critical role in GL illumination-enhanced GHRH expression in the hypothalamus and plasma GH concentrations in young broilers. PMID- 26948667 TI - Pilot-scale testing of a leachbed for anaerobic digestion of livestock residues on-farm. AB - A leachbed is a relatively simple anaerobic digester suitable for high-solids residues and on-farm applications. However, performance characteristics and optimal configuration of leachbeds are not well-understood. In this study, two 200 L pilot-scale leachbeds fed with spent straw bedding from pigs/swine (methane potential, B0 = 195-218 L CH4 kg(-1) VS fed) were used to assess the effects of leachate recirculation mode (trickling vs. flood-and-drain) on the digestion performance. Results showed comparable substrate solubilisation extents (30-45% of total chemical oxygen demand fed) and methane conversion (50% of the B0) for the trickling and flood-and-drain modes, indicating that digestion performance was insensitive to the mode of leachate flow. However, the flood-and-drain leachbed mobilised more particulates into the leachate than the trickling leachbed, an undesirable outcome, because these particulates were mostly non biodegradable. Inoculation with solid residues from a previous leachbed (inoculum to-substrate ratio of 0.22 on a VS basis) hastened the leachbed start-up, but methane recovery remained at 50% of the B0 regardless of the leachate recirculation mode. Post-digestion testing indicated that the leachbeds may have been limited by microbial activity/inhibition. The high residual methane potential of leachate from the trickling (residual Bo = 732 +/- 7 L CH4 kg(-1) VS fed) and flood-and-drain leachbeds (582 +/- 8 L CH4 kg(-1) VS fed) indicated an opportunity for further processing of leachate via a separate methanogenic step. Overall, a trickling leachbed appeared to be more favourable than the flood-and drain leachbed for treating spent bedding at farm-scale due to easier operation. PMID- 26948668 TI - Comparison of the bacterial composition of two commercial composts with different physicochemical, stability and maturity properties. AB - Previously, two municipal solid waste commercial composts (MSW1 and MSW2) were characterized. Although sharing the same type of raw material, most of their physicochemical, stability and maturity properties differed. The present study aimed to characterize them at a microbiological level, and to infer on possible relationships between the composts properties and the structure of their bacterial communities. Both the 16S rRNA gene-based PCR-DGGE profiling and 454 pyrosequencing technology showed that the structure of the bacterial communities of these composts was distinct. The bacterial community of MSW1 was more diverse than that of MSW2. Multivariate analyses revealed that the high electrical conductivity, Cu content as well as the low phytotoxity of compost MSW1, when compared to MSW2, contributed most to shape its bacterial community structure. Indeed, high abundance of halophilic (Halomonadaceae and Brevibacteriaceae) and metal resistant organisms (Brevibacteriaceae and Bacillaceae) were found in MSW1. In addition, Pseudonocardiaceae, Streptomycetaceae, Bacillaceae, and Brevibacteriaceae may have contributed to the high humic-like acids content and low phytotoxicity of MSW1. In contrast, the high organic matter content and the high density of the cultivable fungi population were the parameters most correlated with the structure of the bacterial community of compost MSW2, dominated by Corynebacteriaceae and mainly Aerococcaceae, taxonomic groups not commonly found in composts. PMID- 26948670 TI - Radiographic progression in patients with ankylosing spondylitis according to tumor necrosis factor blocker exposure: Observation Study of Korean Spondyloarthropathy Registry (OSKAR) data. AB - OBJECTIVE: To evaluate the influence of tumor necrosis factor (TNF) blocker on the radiographic progression in ankylosing spondylitis (AS) patients. METHODS: A total of 610 patients were recruited. We stratified two groups (TNF blocker naive and exposure patients). After then, we analyzed the radiographic spinal progression. Univariable and multivariable analyses were performed to identify predictors associated with radiographic progression, which was assessed by the modified Stokes AS Spinal Score (mSASSS). As this was an observational study, the patients were not randomized to the treatment arm. Therefore, propensity score matching was also done with age, gender, and the baseline CRP. The generalized estimating equation model was performed in the post-matched samples. Potential confounders were included in the model. RESULTS: Agreements between the two readers were excellent. Of the 610 patients with AS, 341 patients did not have any exposure to TNF blocker. The radiographic progression (mean+/-SEM) was not significantly different between groups (4.73+/-1.01, and 6.14+/-2.00, P=0.54) in spite of adjusting for confounding factors (age, gender, disease duration, smoking, CRP level, NSAID intake, and baseline mSASSS). Propensity score matching was done to confirm the effect of TNF blockers on radiographic progression. Even after adjusting for the TNF blocker exposure, the result still remained not significant with an OR for progression while taking TNF blocker of 0.69 (P=0.41; 95% CI: 0.29-1.63). CONCLUSION: Our registry data showed that TNF blocker failed to affect the radiographic progression over 5 years in AS patients. PMID- 26948669 TI - Metacognitive impairment in active cocaine use disorder is associated with individual differences in brain structure. AB - Dysfunctional self-awareness has been posited as a key feature of drug addiction, contributing to compromised control over addictive behaviors. In the present investigation, we showed that, compared with healthy controls (n=13) and even individuals with remitted cocaine use disorder (n=14), individuals with active cocaine use disorder (n=8) exhibited deficits in basic metacognition, defined as a weaker link between objective performance and self-reported confidence of performance on a visuo-perceptual accuracy task. This metacognitive deficit was accompanied by gray matter volume decreases, also most pronounced in individuals with active cocaine use disorder, in the rostral anterior cingulate cortex, a region necessary for this function in health. Our results thus provide a direct unbiased measurement - not relying on long-term memory or multifaceted choice behavior - of metacognition deficits in drug addiction, which are further mapped onto structural deficits in a brain region that subserves metacognitive accuracy in health and self-awareness in drug addiction. Impairments of metacognition could provide a basic mechanism underlying the higher-order self-awareness deficits in addiction, particularly among recent, active users. PMID- 26948672 TI - Design of a polarization-insensitive superconducting nanowire single photon detector with high detection efficiency. AB - Superconducting nanowire single photon detectors (SNSPDs) deliver superior performance over their competitors in the near-infrared regime. However, these detectors have an intrinsic polarization dependence on the incident wave because of their one-dimensional meander structure. In this paper, we propose an approach to eliminate the polarization sensitivity of SNSPDs by using near-field optics to increase the absorption of SNSPDs under transverse magnetic (TM) illumination. In addition, an optical cavity is added to our SNSPD to obtain nearly perfect absorption of the incident wave. Numerical simulations show that the maximum absorption of a designed SNSPD can reach 96% at 1550 nm, and indicate that the absorption difference between transverse electric (TE) and TM polarization is less than 0.5% across a wavelength window of 300 nm. Our work provides the first demonstration of the possibility of designing a polarization-insensitive and highly efficient SNSPD without performing device symmetry improvements. PMID- 26948671 TI - Robotic assisted laparoscopic partial nephrectomy using contrast-enhanced ultrasound scan to map renal blood flow. AB - OBJECTIVE: The paper describes novel real-time 'in situ mapping' and 'sequential occlusion angiography' to facilitate selective ischaemia robotic partial nephrectomy (RPN) using intraoperative contrast enhanced ultrasound scan (CEUS). MATERIALS AND METHODS: Data were collected and assessed for 60 patients (61 tumours) between 2009 and 2013. 31 (50.8%) tumours underwent 'Global Ischaemia', 27 (44.3%) underwent 'Selective Ischaemia' and 3 (4.9%) were removed 'Off Clamp Zero Ischaemia'. Demographics, operative variables, complications, renal pathology and outcomes were assessed. RESULTS: Median PADUA score was 9 (range 7 10). The mean warm ischaemia time in selective ischaemia was less and statistically significant than in global ischaemia (17.1 and 21.4, respectively). Mean operative time was 163 min. Postoperative complications (n = 10) included three (5%) Clavien grade 3 or above. Malignancy was demonstrated in 47 (77%) with negative margin in 43 (91.5%) and positive margin in four (8.5%). Long-term decrease in eGFR post selective ischaemia robotic partial nephrectomy was less compared with global ischaemia (four and eight, respectively) but not statistically significant. CONCLUSIONS: This technique is safe, feasible and cost effective with comparable perioperative outcomes. The technical aspects elucidate the role of intraoperative CEUS to facilitate and ascertain selective ischaemia. Further work is required to demonstrate long-term oncological outcomes. (c) 2016 The Authors. The International Journal of Medical Robotics and Computer Assisted Surgery published by John Wiley & Sons, Ltd. PMID- 26948674 TI - A numerical model for multiple detector energy dispersive X-ray spectroscopy in the transmission electron microscope. AB - Here we report a numerical approach to model a four quadrant energy dispersive X ray spectrometer in the transmission electron microscope. The model includes detector geometries, specimen position and absorption, shadowing by the holder, and filtering by the Be carrier. We show that this comprehensive model accurately predicts absolute counts and intensity ratios as a function of specimen tilt and position. We directly compare the model to experimental results acquired with a FEI Super-X EDS four quadrant detector. The contribution from each detector to the sum is investigated. The program and source code can be downloaded from https://github.com/subangstrom/superAngle. PMID- 26948675 TI - [Early cardiovascular changes in young people with normal and normal-high blood pressure]. AB - INTRODUCTION: Increased cardiac mass, as well as reduced arterial distensibility, are well recognised independent cardiovascular risk factors. OBJECTIVE: The aim of this study was to determine the existence of early structural and/or functional alterations of the left ventricle (LV) and the aortic root in young people with optimal (O), normal (N) or normal-high (HN) blood pressure (BP). MATERIAL AND METHODS: BP was recorded, and LV mass (LVM), LV function, and aortic distensibility (AD) were evaluated by echocardiogram in medical students. RESULTS: The study included 754 students (271 males; 20.47+/-1.35 years old). According to their BP, 54% were classified as O, 32% N, and 14% HN. LVM index was higher in N (30.9+/-0.44g/m(2.7)), and HN (31.26+/-0.73g/m(2.7)) than O (28.39+/ 0.29g/m(2.7), P<.01). Corrected mean ventricular shortening was similar between O (99.8+/-0.8%) and N (99.2+/-1.1%, ns), but smaller in HN (95.4+/-1.9%, P<.05). The e'/a' ratio used to evaluate LV diastolic function, was higher in O (2.18+/ 0.03) compared to HN (2.03+/-0.06, P<.03). AD was lower in HN (1.41+/ 0.05mmHg/cm(3)/m(2)) compared to N (1.22+/-0.02mmHg/cm(3)/m(2), P<.01) and O (1.14+/-0.01mmHg/cm(3)/m(2), P<.01). CONCLUSIONS: Those young individuals with an N and HN BP showed an increased LVM index with decreased LV function and AD; evidence that would probably allow us to early identify non-hypertensive subjects with an increased cardiovascular risk. PMID- 26948673 TI - Management patterns of patients with cerebral metastases who underwent multiple stereotactic radiosurgeries. AB - With escalating focus on cost containment, there is increasing scrutiny on the practice of multiple stereotactic radiosurgeries (SRSs) for patients with cerebral metastases distant to the initial tumor site. Our goal was to determine the survival patterns of patients with cerebral metastasis who underwent multiple SRSs. We retrospectively analyzed survival outcomes of 801 patients with 3683 cerebral metastases from primary breast, colorectal, lung, melanoma and renal histologies consecutively treated at the University of California, San Diego/San Diego Gamma Knife Center (UCSD/SDGKC), comparing the survival pattern of patients who underwent a single (n = 643) versus multiple SRS(s) (n = 158) for subsequent cerebral metastases. Findings were recapitulated in an independent cohort of 2472 patients, with 26,629 brain metastases treated with SRS at the Katsuta Hospital Mito GammaHouse (KHMGH). For the UCSD/SDGKC cohort, no significant difference in median survival was found for patients undergoing 1, 2, 3, or >=4 SRS(s) (median survival of 167, 202, 129, and 127 days, respectively). Median intervals between treatments consistently ranged 140-178 days irrespective of the number of SRS(s) (interquartile range 60-300; p = 0.25). Patients who underwent >1 SRSs tend to be younger, with systemic disease control, harbor lower cumulative tumor volume but increased number of metastases, and have primary melanoma (p < 0.001, <0.001, <0.001, 0.02, and 0.009, respectively). Comparable results were found in the KHMGH cohort. Using an independent validation study design, we demonstrated comparable overall survival between judiciously selected patients who underwent a single or multiple SRS(s). PMID- 26948676 TI - Fibrodysplasia ossificans progressiva. A case report and focus on the BMP signaling pathway. AB - Fibrodysplasia ossificans progressiva is a very rare heritable disease characterized by a progressive heterotopic endochondal ossification, occurring in the first decade of life, and leading thereafter to a severe ankylosis of the spine, limbs and jaw, with a progressive and severe functional disability. To date the cause of the disease remains unknown and no medical treatment has been proved efficient. It has recently been shown that a recurrent mutation in activation domain of the activin-receptor IA (ACVR1), a BMP receptor, could lead to an abnormal signalling pathway of BMP-4 and contribute to the occurrence of the devastating lesions characteristic of the disease. PMID- 26948677 TI - Aluminum adjuvants of vaccines injected into the muscle: Normal fate, pathology and associated disease. AB - Aluminum oxyhydroxide (Alhydrogel((r))) is a nano-crystalline compound forming aggregates that has been introduced in vaccine for its immunologic adjuvant effect in 1926. It is the most commonly used adjuvant in human and veterinary vaccines but mechanisms by which it stimulates immune responses remain ill defined. Although generally well tolerated on the short term, it has been suspected to occasionally cause delayed neurologic problems in susceptible individuals. In particular, the long-term persistence of aluminic granuloma also termed macrophagic myofasciitis is associated with chronic arthromyalgias and fatigue and cognitive dysfunction. Safety concerns largely depend on the long biopersistence time inherent to this adjuvant, which may be related to its quick withdrawal from the interstitial fluid by avid cellular uptake; and the capacity of adjuvant particles to migrate and slowly accumulate in lymphoid organs and the brain, a phenomenon documented in animal models and resulting from MCP1/CCL2 dependant translocation of adjuvant-loaded monocyte-lineage cells (Trojan horse phenomenon). These novel insights strongly suggest that serious re-evaluation of long-term aluminum adjuvant phamacokinetics and safety should be carried out. PMID- 26948678 TI - A machine learning approach to the accurate prediction of multi-leaf collimator positional errors. AB - Discrepancies between planned and delivered movements of multi-leaf collimators (MLCs) are an important source of errors in dose distributions during radiotherapy. In this work we used machine learning techniques to train models to predict these discrepancies, assessed the accuracy of the model predictions, and examined the impact these errors have on quality assurance (QA) procedures and dosimetry. Predictive leaf motion parameters for the models were calculated from the plan files, such as leaf position and velocity, whether the leaf was moving towards or away from the isocenter of the MLC, and many others. Differences in positions between synchronized DICOM-RT planning files and DynaLog files reported during QA delivery were used as a target response for training of the models. The final model is capable of predicting MLC positions during delivery to a high degree of accuracy. For moving MLC leaves, predicted positions were shown to be significantly closer to delivered positions than were planned positions. By incorporating predicted positions into dose calculations in the TPS, increases were shown in gamma passing rates against measured dose distributions recorded during QA delivery. For instance, head and neck plans with 1%/2 mm gamma criteria had an average increase in passing rate of 4.17% (SD = 1.54%). This indicates that the inclusion of predictions during dose calculation leads to a more realistic representation of plan delivery. To assess impact on the patient, dose volumetric histograms (DVH) using delivered positions were calculated for comparison with planned and predicted DVHs. In all cases, predicted dose volumetric parameters were in closer agreement to the delivered parameters than were the planned parameters, particularly for organs at risk on the periphery of the treatment area. By incorporating the predicted positions into the TPS, the treatment planner is given a more realistic view of the dose distribution as it will truly be delivered to the patient. PMID- 26948679 TI - Radiocesium distribution and fluxes in the typical Cryptomeria japonica forest at the late stage after the accident at Fukushima Dai-Ichi Nuclear Power Plant. AB - The Fukushima-derived radiocesium distribution in the typical Japanese cedar (Cryptomeria japonica D. Don) forest ecosystem was determined. In four years after the Fukushima accident, about 74% of the total radiocesium inventory was localized in soil, 20% was in the litter, and only 6% was associated with the aboveground biomass. Most of the radiocesium that was initially intercepted by the tree canopies has been already transported to the ground surface. The importance of the processes for removal of radiocesium from the tree canopies decreased in the order litterfall > throughfall >> stemflow. Within the tree compartments, the largest radiocesium activity fraction, about 46%, was observed in old foliage, which indicates that the process of removal of the initial deposit from the tree crowns has not yet completed. The aggregate soil-to-wood transfer factor was 1.1?10-3 m2 kg-1 d.w., which is close to the geometric means of transfer factors recommended by IAEA for other coniferous tree species. Further studies in Fukushima forest are necessary to assess the variation of this parameter under various soil-landscape conditions. Presence of the residues of the initial deposits does not allow to obtain the accurate values of the annual radiocesium fluxes in the ecosystem. Based on the conservative assumptions, the ranges of the fluxes were estimated. Analysis of the flux structures shows that up to percents of the total radiocesium activity in the ecosystem may be involved into biogenic cycling. PMID- 26948680 TI - An on-chip model for investigating the interaction between neurons and cancer cells. AB - Emerging evidence suggests that there is extensive interaction between neurons and cancer cells. However, few model systems have been developed to investigate nerve-cancer cell interaction in vitro. Herein, a high-throughput microfluidic compartmentalized chip is developed to examine the interaction between neurons and cancer cells. The nerve bundles appear to provide a biophysical support for cancer cells and guide their directional migration. The cancers that have high levels of perineural invasion in clinical observations exhibit greater migration along neurites in the on-chip model. The on-chip model allows the screening of compounds which inhibit cancer cell migration along neurites in vitro. The interruption of neurites, the pharmacological blockade of nerve-cancer signaling, effectively attenuates the migration of cancer cells along neurites. This on-chip model provides a useful platform to investigate the dynamic interaction between cancer cells and neurons and can dramatically broaden the chemical space in screening neuron-related drugs for cancers. PMID- 26948681 TI - How I diagnose and manage ventilator-associated tracheobronchitis. PMID- 26948682 TI - Comparison of the Composition and Antimicrobial Activities of the Essential Oils of Green Branches and Leaves of Egyptian Navel Orange (Citrus sinensis (L.) Osbeck var. malesy). AB - The essential oils isolated from the leaves and green branches of the Egyptian navel orange trees were analyzed by GC and GC/MS. A total of 33 and 24 compounds were identified from the oils of the leaves and branches accounting for 96.0% and 97.9%, respectively, of the total detected constituents. The major ones were sabinene (36.5; 33.0%), terpinen-4-ol (8.2; 6.2%), delta-3-carene (7.0; 9.4%), limonene (6.8; 18.7%), trans-ocimene (6.7; 6.1%), and beta-myrcene (4.5; 4.4%). The antimicrobial activities of both oils were evaluated using the agar-well diffusion method toward three representatives for each of Gram-positive bacteria, Gram-negative bacteria, and fungi. The oil of leaves was more effective as antimicrobial agent than that of the branches. Streptococcus pyogenes, Staphylococcus aureus, Salmonella typhimurium, and Aspergillus fumigatus were the most sensitive bacteria and fungi by the leaves oil. PMID- 26948683 TI - Performance of the 1 mg dexamethasone suppression test in patients with severe obesity. AB - OBJECTIVE: To analyze the performance of the 1 mg dexamethasone suppression test (DST) in patients with obesity. Special attention was paid to the influence of interfering medication on DST. METHODS: In this prospective cohort study (Mannheim Obesity Study), patients with obesity were evaluated before bariatric surgery. For evaluation of hypercortisolism, a 1 mg dexamethasone-suppression test (DST) in all subjects was performed. Medication was assessed for possible interference. RESULTS: Two hundred seventy-eight patients with a mean age of 42.3 years (68.8% women) and a mean BMI of 47.9 +/- 8.4 kg/m(2) were screened. Insufficient suppression of cortisol after DST was found in 24 patients (8.6%). In two patients hypercortisolism was confirmed. The specificity for DST was calculated at 92.0%. Only CYP3A4 inducers (n = 22, 7.9%) and estrogen therapy (n = 17, 6.1%) were significantly associated with falsely elevated cortisol after DST. Regression analysis excluded any interrelation between DST and anthropometry. CONCLUSIONS: Low prevalence of hypercortisolism (0.7 or <1.8%) was found. Specificity of DST in this cohort typically screened for hypercortisolism was 92.0% (<= 50 nmol/L). DST should be avoided in patients taking CYP3A4 inducers or estrogen therapy, due to their significant interaction. In summary, the 1 mg DST is an adequate test for screening for hypercortisolism even in patients with extreme obesity. PMID- 26948685 TI - Moving from health disparities to health inequities - and why it matters. PMID- 26948684 TI - Fabrication of BiOBrxI(1-x) photocatalysts with tunable visible light catalytic activity by modulating band structures. AB - A series of BiOBrxI(1-x) solid solutions were explored as novel visible light sensitive photocatalysts. These BiOBrxI(1-x) solid-solution photocatalysts grew into two-dimensional nanoplates with exposed (001) facets and possessed continuously modulated band gaps from 2.87 to 1.89 eV by decreasing the Br/I ratio. The photocatalytic activities of these samples were measured, and the samples exhibited visible light-driven activities for the degradation of Rhodamine B (RhB). In particular, BiOBr0.8I0.2 exhibited the highest activity for the degradation of RhB. This result could be attributed to the balance between the effective light absorption and adequate redox potential. Additionally, investigations into the photocatalytic mechanism showed that the photodegradation of RhB over BiOBr0.8I0.2 solid-solution photocatalysts involved direct holes oxidation, in which the reaction that dominated during photocatalysis was determined by the potential of the valence band. Furthermore, a high stability in the photocatalytic activity of BiOBr0.8I0.2 was demonstrated by the cycling photocatalytic experiment and long-term irradiation, which might offer opportunities for its practical application as a catalyst. PMID- 26948686 TI - Stereoselective Construction of beta-Mannopyranosides by Anomeric O-Alkylation: Synthesis of the Trisaccharide Core of N-linked Glycans. AB - A new and efficient approach for direct and stereoselective synthesis of beta mannopyranosides by anomeric O-alkylation has been developed. This anomeric O alkylation of mannopyranose-derived lactols is proposed to occur under synergistic control of a kinetic anomeric effect and metal chelation. The presence of a conformationally flexible C6 oxygen atom in the sugar-derived lactol donors is required for this anomeric O-alkylation to be efficient, probably because of its chelation with cesium ion. In contrast, the presence of a C2 oxygen atom plays a minor role. This glycosylation method has been successfully utilized for the synthesis of the trisaccharide core of complex N linked glycans. PMID- 26948687 TI - Identification and characterization of DC-SIGN-binding glycoproteins in allergenic foods. AB - BACKGROUND: DC-SIGN (dendritic cell-specific intercellular adhesion molecule-3 grabbing nonintegrin) is a C-type lectin receptor expressed on macrophages and dendritic cells. DC-SIGN has high affinity for fucosylated glycans in several plant glycoproteins and pathogens. DC-SIGN is thought to be crucial for the development of allergic sensitization. However, the precise role of DC-SIGN in food allergy pathogenesis is not yet understood. OBJECTIVE: We sought to characterize DC-SIGN-binding glycoproteins in a panel of allergenic and non allergenic foods. METHODS: Fluorescent-labeled peanut and soy extracts were used to test protein binding to human monocyte-derived dendritic cells (DCs) by flow cytometry. DC-SIGN-blocking assays were performed by incubating DCs with food extracts followed by staining with anti-DC-SIGN antibody. Using a DC-SIGN-Fc chimera, food extracts were tested for binding by ELISA and autoradiography. IgE immunoblotting was performed with pooled sera from food-allergic subjects. DC activation and maturation were assessed by flow cytometry. RESULTS AND CONCLUSIONS: We demonstrate that peanut agglutinin, a minor peanut allergen, is a novel ligand for DC-SIGN. Peanut agglutinin activates DCs to induce the expression of costimulatory molecules in vitro. We present a comprehensive report on the characterization of DC-SIGN-binding proteins in common allergenic foods such as peanut, soy, tree nuts, egg, and milk. Foods that rarely induce allergy, such as pine nuts, chickpea, and corn, showed no binding to DC-SIGN. Several DC SIGN-binding proteins show reactivity in serum IgE immunoblots. We have also identified novel non-IgE-binding proteins that interact with DC-SIGN; these proteins may be important for regulating immune responses to these foods. PMID- 26948688 TI - Synthesis of Arylazide- and Diazirine-Containing CrAsH-EDT2 Photoaffinity Probes. AB - Two photo-crosslinking biarsenical (CrAsH-EDT2 )-modified probes were synthesized that are expected to be useful tools for tetracysteine-labeled proteins to facilitate the co-affinity purification of their DNA binding sequences and interacting proteins. In addition, improvements for the synthesis of CrAsH-EDT2 and N(1) -(4-azido-2-nitrophenyl)hexane-1,6-diamine are reported. Both photoprobes effectively entered HeLa cells (and the nucleus) and were dependent on the tetracysteine motif in recombinant DMRT1 (doublesex and Mab3-related transcription factor) to induce fluorescence, suggesting that their crosslinking abilities can be exploited for the identification of nucleic acids and proteins associated with a protein of interest. PMID- 26948689 TI - Gun-shot injuries in UK military casualties - Features associated with wound severity. AB - INTRODUCTION: Surgical treatment of high-energy gun-shot wounds (GSWs) to the extremities is challenging. Recent surgical doctrine states that wound tracts from high-energy GSWs should be laid open, however the experience from previous conflicts suggests that some of these injuries can be managed more conservatively. The aim of this study is to firstly characterise the GSW injuries sustained by UK forces, and secondly test the hypothesis that the likely severity of GSWs can be predicted by features of the wound. METHODS: The UK Military trauma registry was searched for cases injured by GSW in the five years between 01 January 2009 and 31 December 2013: only UK personnel were included. Clinical notes and radiographs were then reviewed. Features associated with energy transfer in extremity wounds in survivors were further examined with number of wound debridements used as a surrogate marker of wound severity. RESULTS: There were 450 cases who met the inclusion criteria. 96 (21%) were fatally injured, with 354 (79%) surviving their injuries. Casualties in the fatality group had a median New Injury Severity Score (NISS) of 75 (IQR 75-75), while the median NISS of the survivors was 12 (IQR 4-48) with 10 survivors having a NISS of 75. In survivors the limbs were most commonly injured (56%). 'Through and through' wounds, where the bullet passes intact through the body, were strongly associated with less requirement for debridement (p<0.0001). When a bullet fragmented there was a significant association with a requirement for a greater number of wound debridements (p=0.0002), as there was if a bullet fractured a bone (p=0.0006). CONCLUSIONS: More complex wounds, as indicated by the requirement for repeated debridements, are associated with injuries where the bullet does not pass straight through the body, or where a bone is fractured. Gunshot wounds should be assessed according to the likely energy transferred, extremity wounds without features of high energy transfer do not require extensive exploration. PMID- 26948691 TI - Tocotrienol and cancer metastasis. AB - Tumor metastasis involves some of the most complex and dynamic processes in cancer, often leading to poor quality of life and inevitable death. The search for therapeutic compounds and treatment strategies to prevent and/or manage metastasis is the ultimate challenge to fight cancer. In the past two decades, research focus on vitamin E has had a shift from saturated tocopherols to unsaturated tocotrienols (T3). Despite sharing structural similarities with tocopherols, T3 strive to gain scientific prominence due to their anti-cancer effects. Recent studies have shed some light on the anti-metastatic properties of T3. In this review, the roles of T3 in each step of the metastatic process are discussed. During the invasion process, signaling pathways that regulate the extracellular matrix and tumor cell motility have been reported to be modulated by T3. Although studies on T3 and tumor cell migration are fairly limited, they were shown to play a vital role in the suppression of angiogenesis. Furthermore, the anti-inflammatory effect of T3 could be highly promising in the regulation of tumor microenvironment, which is crucial in supporting tumor growth in distant organs. PMID- 26948690 TI - Retrospective analysis of case series of patients with vascular war injury treated in a district hospital. AB - INTRODUCTION: As the Syrian civil war continues, medical care of the injured remains a priority for health facilities receiving casualties. Ziv Medical Centre, the closest hospital in Israel to the Syrian border, has received 500 casualties since February 2013. Seventeen of these patients had vascular injuries. This research reports the care of these seventeen patients and explores the challenges of treatment in patients with little antecedent clinical history and improvised initial care that may be complicated by delay to definitive care, sepsis and limb ischaemia. METHOD: Electronic and paper patient records were examined. Descriptive case series data are presented. RESULTS: Fifteen of the 17 patients were male. The mean age was 20 years (range 8-30 years). Causes of injury included gunshot wounds (4 patients), shrapnel (multi-fragment) injury (12 patients), and 1 patient was run over and dragged behind a car. The time from injury to transfer to definitive care ranged from 5h to 7 days (mean 43 h). All but one patient had associated non-vascular multiple-trauma. Thirteen patients presented with limb ischaemia. Four patients had arterio-venous fistula (AVF) or pseudoaneurysm. There were 5 upper and 10 lower limb major vascular injuries. Three patients had neck vessel injuries. All patients were investigated with CT angiography and underwent surgical or endovascular intervention. In 12 patients, 4 vessels were debrided and re-anastomosed and 13 vessels bypassed. Endovascular repair was performed in 4 patients. After initial revascularisation, 4 patients went on to amputation. There were no deaths. CONCLUSIONS: The injuries treated are heterogeneous, and reflect the range of high energy vascular trauma expected in conflict. The broad range of vascular solutions required to optimise outcomes, in particular, limb salvage, in turn, reflect the challenges of dealing with such injuries, especially within the context of sepsis, ischaemia and delay. As war continues, there is a pressing need to address the needs of patients with high energy injuries in austere environments where there is a dearth of health resources and where definitive care may be days away. PMID- 26948693 TI - Estimating under- and over-reporting of drinking in national surveys of alcohol consumption: identification of consistent biases across four English-speaking countries. AB - BACKGROUND AND AIMS: Questions about drinking 'yesterday' have been used to correct under-reporting of typical alcohol consumption in surveys. We use this method to explore patterns of over- and under-reporting of drinking quantity and frequency by population subgroups in four countries. DESIGN: Multivariate linear regression analyses comparing estimates of typical quantity and frequency of alcohol consumption with and without adjustments using the yesterday method. SETTING AND PARTICIPANTS: Survey respondents in Australia (n = 26 648), Canada (n = 43 371), USA (n = 7969) and England (n = 8610). MEASUREMENTS: Estimates of typical drinking quantities and frequencies over the past year plus quantity of alcohol consumed the previous day. FINDINGS: Typical frequency was underestimated by less frequent drinkers in each country. For example, after adjustment for design effects and age, Australian males self-reporting drinking 'less than once a month' were estimated to have in fact drunk an average of 14.70 (+/- 0.59) days in the past year compared with the standard assumption of 6 days (t = 50.5, P < 0.001). Drinking quantity 'yesterday' was not significantly different overall from self-reported typical quantities during the past year in Canada, the United States and England, but slightly lower in Australia (e.g. 2.66 versus 3.04 drinks, t = 20.4, P < 0.01 for women). CONCLUSIONS: People who describe themselves as less frequent drinkers appear to under-report their drinking frequency substantially, but country and subgroup-specific corrections can be estimated. Detailed questions using the yesterday method can help correct under reporting of quantity of drinking. PMID- 26948692 TI - Tumour angiogenesis as a chemo-mechanical surface instability. AB - The hypoxic conditions within avascular solid tumours may trigger the secretion of chemical factors, which diffuse to the nearby vasculature and promote the formation of new vessels eventually joining the tumour. Mathematical models of this process, known as tumour angiogenesis, have mainly investigated the formation of the new capillary networks using reaction-diffusion equations. Since angiogenesis involves the growth dynamics of the endothelial cells sprouting, we propose in this work an alternative mechanistic approach, developing a surface growth model for studying capillary formation and network dynamics. The model takes into account the proliferation of endothelial cells on the pre-existing capillary surface, coupled with the bulk diffusion of the vascular endothelial growth factor (VEGF). The thermo-dynamical consistency is imposed by means of interfacial and bulk balance laws. Finite element simulations show that both the morphology and the dynamics of the sprouting vessels are controlled by the bulk diffusion of VEGF and the chemo-mechanical and geometric properties at the capillary interface. Similarly to dendritic growth processes, we suggest that the emergence of tree-like vessel structures during tumour angiogenesis may result from the free boundary instability driven by competition between chemical and mechanical phenomena occurring at different length-scales. PMID- 26948695 TI - Laryngeal dysplasia: a prospective cohort study of 70 patients. PMID- 26948694 TI - Racial disparity in survival of patients with uterine serous carcinoma: Changes in clinical characteristics, patterns of care and outcomes over time from 1988 to 2011. AB - OBJECTIVES: To determine if the disparities in the outcome between white (W) and African American (AA) patients with uterine serous carcinoma (USC) have changed over time. METHODS: Women with USC were identified using the SEER database from 1988 to 2011 (N=7667). Years of the study were divided into three periods (1988 1997, 1998-2004 and 2005-2011). Overall (OS) and disease-specific survivals (DSS) was estimated. RESULTS: Over the three time periods, African American patients continued to be younger and less likely to have cancer directed surgery and extensive lymphadenectomy when compared to white patients. In multivariable analysis adjusting for age, race, marital status, stage, cancer-directed surgery, extent of lymphadenectomy, adjuvant radiation, and geographic location, AA was significantly associated with worse DSS and OS in the three time periods compared to white race. African American patients were 29% (95% CI 1.03-1.62, p=0.027) in 1988-1997, 40% in 1998-2004 (95% CI 1.21-1.63, p<0.0001) and 34% in 2005-2011 (95% CI 1.13-1.59, p=0.0008) more likely to die from uterine cancer compared to their white counterparts. A slight improvement in the difference in OS over time was noted comparing African American and white patients. African American patients were 46% (95% CI 1.23-1.73, p<0.0001) in 1988-1997, 39% in 1998-2004 (95% CI 1.23-1.56, p<0.0001) and 26% in 2005-2011 (95% CI 1.10-1.45, p<0.0001) more likely to die from any cause compared to their white counterparts. CONCLUSIONS: Significant improvement in outcome was noted in both racial groups over time. However, African American patients continued to have worse outcome than white patients over time. PMID- 26948696 TI - Protein side chain conformation predictions with an MMGBSA energy function. AB - The prediction of protein side chain conformations from backbone coordinates is an important task in structural biology, with applications in structure prediction and protein design. It is a difficult problem due to its combinatorial nature. We study the performance of an "MMGBSA" energy function, implemented in our protein design program Proteus, which combines molecular mechanics terms, a Generalized Born and Surface Area (GBSA) solvent model, with approximations that make the model pairwise additive. Proteus is not a competitor to specialized side chain prediction programs due to its cost, but it allows protein design applications, where side chain prediction is an important step and MMGBSA an effective energy model. We predict the side chain conformations for 18 proteins. The side chains are first predicted individually, with the rest of the protein in its crystallographic conformation. Next, all side chains are predicted together. The contributions of individual energy terms are evaluated and various parameterizations are compared. We find that the GB and SA terms, with an appropriate choice of the dielectric constant and surface energy coefficients, are beneficial for single side chain predictions. For the prediction of all side chains, however, errors due to the pairwise additive approximation overcome the improvement brought by these terms. We also show the crucial contribution of side chain minimization to alleviate the rigid rotamer approximation. Even without GB and SA terms, we obtain accuracies comparable to SCWRL4, a specialized side chain prediction program. In particular, we obtain a better RMSD than SCWRL4 for core residues (at a higher cost), despite our simpler rotamer library. Proteins 2016; 84:803-819. (c) 2016 Wiley Periodicals, Inc. PMID- 26948698 TI - Excluding acute aortic dissection: The need for a reliable biomarker. PMID- 26948697 TI - A randomized controlled pilot trial to improve advance care planning for LVAD patients and their surrogates. AB - OBJECTIVES: To examine feasibility, acceptability and preliminary effects of an advance care planning (ACP) intervention, SPIRIT-HF, in LVAD patients and their surrogates. BACKGROUND: LVADs may improve HF symptoms but they are not curative. Thus, ACP is needed to prepare patients and surrogates for end-of-life (EOL) decision-making. METHODS: Bridge to transplant and destination therapy LVAD patient-surrogate dyads were randomized to either SPIRIT-HF or usual care. Percentages of eligible dyads who were enrolled and completed the study determined feasibility. Analysis of interviews with SPIRIT dyads determined acceptability. Group comparisons of dyad congruence, patient's decisional conflict, and surrogate's decision-making confidence determined preliminary effects. RESULTS: Of 38 eligible dyads, 29 (76%) were enrolled, randomized, and completed the study. The 14 intervention dyads characterized SPIRIT-HF as beneficial. All dyads demonstrated improvement in outcomes. However, SPIRIT-HF dyads tended toward greater congruence on patient EOL treatment goals. CONCLUSIONS: SPIRIT-HF is feasible and acceptable. Results will inform future trials. PMID- 26948699 TI - Etiology of Sudden Cardiac Arrest in Patients with Epilepsy: Experience of Tertiary Referral Hospital in Sapporo City, Japan. AB - It has been reported that epilepsy patients had higher risk of sudden death than that of the general population. However, in Japan, there is very little literature on the observational research conducted on sudden fatal events in epilepsy. We performed a single-center, retrospective study on all the out-of hospital cardiac arrest (OHCA) patients treated in our emergency department between 2007 and 2013. Among the OHCA patients, we extracted those with a history of epilepsy and then analyzed the characteristics of the fatal events and the background of epilepsy. From 1,823 OHCA patients, a total of 10 cases were enrolled in our study. The median age was 34 years at the time of the incident [9 52 years; interquartile range (IQR), 24-45]. We determined that half of our cases resulted from external causes of death such as drowning and suffocation and the other half were classified as sudden unexpected death in epilepsy (SUDEP). In addition, asphyxia was implicated as the cause in eight cases. Only the two near drowning patients were immediately resuscitated, but the remaining eight patients died. The median age of first onset of epilepsy was 12 years (0.5-30; IQR, 3-21), and the median disease duration was 25 years (4-38; IQR, 6-32). Patients with active epilepsy accounted for half of our series and they were undergoing poly anti-epileptic drug therapy. The fatal events related to epilepsy tended to occur in the younger adult by external causes. An appropriate therapeutic intervention and a thorough observation were needed for its prevention. PMID- 26948700 TI - Invasive Evaluations for Epilepsy Surgery: A Review of the Literature. AB - Invasive evaluations play important roles in identifying epileptogenic zones and functional areas in patients with intractable focal epilepsy. This article reviews the usefulness, methods, and limitations of invasive evaluations for epilepsy surgery. Invasive evaluations include various types of intracranial electrodes such as stereotactically implanted intracranial depth electrodes (stereo-EEG), chronic subdural electrodes, and intraoperative electrocorticography. Scalp EEG is distorted by the skull, meninges, and skin. On the other hand, intracranial electrodes provide spatial information with higher resolution than scalp electrodes, thereby enabling further delineation of epileptogenic zones and mapping of functional areas with electrical stimulation. In addition, intracranial electrodes record a wide frequency range of electrical activity, which is not possible with scalp electrodes. The very slow potentials in ictal recordings, known as ictal direct current (DC) shifts and ictal/interictal high frequency oscillations, such as ripples (100-200 Hz) and fast ripples (200-500 Hz), have been correlated with the ictal onset zone and are a sensitive and specific marker for epileptogenicity. Furthermore, several studies reported that the electrical stimulation of epileptogenic zones elicited enhanced cortical evoked potentials, abnormal delayed or repetitive responses, and fast ripples. These responses may assist in the delineation of the epileptogenic cortex as a potential new marker. There are definite risks of complications associated with the use of intracranial electrodes. However, when an invasive evaluation is selected based on careful consideration of the risks and benefits, it provides useful information for establishing a strategy for epilepsy surgery. PMID- 26948701 TI - Surgical and Endovascular Treatment for Spinal Arteriovenous Malformations. AB - Spinal arteriovenous malformation (AVM) is a broad term that constitutes diverse vascular pathologies. To date, various classification schemes for spinal AVM have been proposed in literature, which helped neurosurgeons understand the pathophysiology of the disease and determine an optimal treatment strategy. To discuss indications and results of surgical and endovascular interventions for spinal AVM, this article refers to the following classification proposed by Anson and Spetzler in 1992: type I, dural arteriovenous fistula (AVF); type II, glomus intramedullary AVM; type III, juvenile malformations; and type IV, perimedullary AVF. In general, complete obliteration of the fistula is a key for better outcome in type I dural and type IV perimedullary AVFs. On the other hand, in type II glomus and type III juvenile malformations, functional preservation, instead of pursuing angiographical cure, is the main goal of the treatment. In such cases, reduction of the shunt flow can alleviate clinical symptoms. Proper management of spinal AVM should start with neurological examination and understanding of angioarchitectures, which provide critical information that guides the indication and modality of intervention. Finally, close collaboration of the microsurgical and endovascular teams are mandatory for successful treatment. PMID- 26948702 TI - Catch-bond mechanism of the bacterial adhesin FimH. AB - Ligand-receptor interactions that are reinforced by mechanical stress, so-called catch-bonds, play a major role in cell-cell adhesion. They critically contribute to widespread urinary tract infections by pathogenic Escherichia coli strains. These pathogens attach to host epithelia via the adhesin FimH, a two-domain protein at the tip of type I pili recognizing terminal mannoses on epithelial glycoproteins. Here we establish peptide-complemented FimH as a model system for fimbrial FimH function. We reveal a three-state mechanism of FimH catch-bond formation based on crystal structures of all states, kinetic analysis of ligand interaction and molecular dynamics simulations. In the absence of tensile force, the FimH pilin domain allosterically accelerates spontaneous ligand dissociation from the FimH lectin domain by 100,000-fold, resulting in weak affinity. Separation of the FimH domains under stress abolishes allosteric interplay and increases the affinity of the lectin domain. Cell tracking demonstrates that rapid ligand dissociation from FimH supports motility of piliated E. coli on mannosylated surfaces in the absence of shear force. PMID- 26948703 TI - Healthcare coverage for undocumented migrants in Spain: Regional differences after Royal Decree Law 16/2012. AB - The economic crisis has prompted the debate on how to regulate health coverage of undocumented migrants in publicly funded healthcare systems. Spain, as one of the most heavily affected countries in Europe, can be considered a case of particular interest. In 2012 the Spanish Government issued a Royal Decree Law (RDL 16/2012) which revoked their previous full right to public healthcare coverage, now limited for some exceptions. However, the Spanish National Health System is highly decentralized, and this Central Government decree had to be implemented by the Regional Health Authorities. Our aim is to compare regional policies regarding entitlement to healthcare for undocumented migrants after RDL 16/2012 in the 17 Autonomous Regions by performing an exhaustive review of the regional health policy regulations published after the enactment of RDL 16/2012. Our analysis shows that many Regions adopted legal, legislative and administrative actions to void or limit its effects, while others applied it as intended, resulting in huge differences in healthcare coverage for irregular migrants among Spanish Regions. The unequal implementation of this Law constitutes a paradigmatic example of the complexity of nation-wide regulation of controversial key issues in decentralized health systems. In addition, our results highlight that within-country differences in access and/or entitlement can be as relevant as those reported among-country when there is healthcare decentralization. PMID- 26948705 TI - New technique for bloodless surgery to the scalp. PMID- 26948704 TI - Cross-border healthcare directive: Assessing stakeholders' perspectives in Poland and Portugal. AB - Within the context of the EU, a succession of rulings from the European Court of Justice addressed the gap of specific healthcare legislation. These rulings shook the member states assumption of health provision autonomy and led the European Commission to produce a specific directive concerning cross-border healthcare. In spite of different viewpoints of member states, including Poland and Portugal, the directive was approved and expected to be implemented by October 2013. The objective of this study was to analyse stakeholders' perspective towards the directive, unveiling the factors that supported a different viewpoint, and to identify challenges and assess the expected impact associated with the directive implementation on Poland and Portugal, using the WHO health systems conceptual framework. Information was collected through a literature review, identifying potential stakeholders. Primary qualitative analysis was conducted through the dissemination of open-ended questionnaires. Content and critical analysis was performed considering the available literature intertwined with the WHO health systems conceptual framework. The directive appears to be positive regarding patient rights, increased transparency, and potential to set new information technologies and healthcare networks. However, it also seems to potentially generate access inequalities between home and foreign patients, and increase healthcare costs due to the short-term investments needed. PMID- 26948706 TI - Giant ameloblastoma. PMID- 26948707 TI - Specific electrical capacitance and voltage breakdown as a function of temperature for different planar lipid bilayers. AB - The breakdown voltage and specific electrical capacitance of planar lipid bilayers formed from lipids isolated from the membrane of archaeon Aeropyrum pernix K1 as a function of temperature were studied and compared with data obtained previously in MD simulation studies. Temperature dependence of breakdown voltage and specific electrical capacitance was measured also for dipalmitoylphosphatidylcholine (DPPC) bilayers and bilayers formed from mixture of diphytanoylphosphocholine (DPhPC) and DPPC in ratio 80:20. The breakdown voltage of archaeal lipids planar lipid bilayers is more or less constant until 50 degrees C, while at higher temperatures a considerable drop is observed, which is in line with the results from MD simulations. The breakdown voltage of DPPC planar lipid bilayer at melting temperature is considerably higher than in the gel phase. Specific electrical capacitance of planar lipid bilayers formed from archaeal lipids is approximately constant for temperatures up to 40 degrees C and then gradually decreases. The difference with MD simulation predictions is discussed. Specific electrical capacitance of DPPC planar lipid bilayers in fluid phase is 1.75 times larger than that of the gel phase and it follows intermediated phases before phase transition. Increase in specific electrical capacitance while approaching melting point of DPPC is visible also for DPhPC:DPPC mixture. PMID- 26948709 TI - Atrial flutter in myotonic dystrophy type 1: Patient characteristics and clinical outcome. AB - The prevalence and the incidence of atrial flutter in patients with myotonic dystrophy type 1 (DM1) and the most appropriate strategies for its management are unknown. We retrospectively included in the DM1 Heart Registry 929 adult patients with DM1 admitted to our Institutions between January 2000 and September 2013. We selected patients presenting with atrial flutter and analysed data relative to the occurrence of arterial thromboembolism, severe bradyarrhythmias and atrial flutter recurrences. Atrial flutter was present in 79 of the 929 patients included in our Registry, representing a 8.5% prevalence. Patients with atrial flutter were older, had a higher muscular disability rating scale score and had higher prevalence of other cardiac manifestations of DM1. Sixty patients presented with a first episode of atrial flutter, representing a 4.6% incidence. Severe bradyarrhythmias requiring permanent pacing were present in 4 patients (6.7%). Over a 53 +/- 28 months mean follow-up duration, 2 patients (3.3%) had ischaemic stroke and 12 (20%) had atrial flutter recurrences. Patients who underwent radiofrequency ablation were more frequently free of atrial flutter recurrence than other patients (95 vs. 61%; HR = 0.17; P = 0.04). Atrial flutter is a common manifestation of DM1, potentially complicated by arterial thromboembolism or severe bradyarrhythmias. Radiofrequency catheter ablation is associated with a lower risk for recurrences. PMID- 26948708 TI - 212th ENMC International Workshop: Animal models of congenital muscular dystrophies, Naarden, The Netherlands, 29-31 May 2015. PMID- 26948710 TI - The Dutch patients' perspective on oculopharyngeal muscular dystrophy: A questionnaire study on fatigue, pain and impairments. AB - Research on oculopharyngeal muscular dystrophy focuses mainly on genetic and pathophysiological aspects. Clinically, oculopharyngeal muscular dystrophy is often considered as a disease with a relatively mild initial disease course with no or only mild functional disabilities. However the occurrence of fatigue, pain and functional impairments other than dysphagia has never been studied systematically. The aim of this study is therefore to assess the prevalence of fatigue, pain, and functional limitations, and the social participation and psychological well-being of oculopharyngeal muscular dystrophy patients. We performed a questionnaire study on fatigue, pain, functional impairments, social participation and psychological distress in 35 genetically confirmed oculopharyngeal muscular dystrophy patients with an average disease duration of 11.6 years. We showed that 19 (54%) of the patients experienced severe fatigue and also 19 (54%) experienced pain. Limitations in daily life activities and social participation were detected in 33 (94%) of the patients. Many patients reported pelvic girdle weakness and limitations in ambulation. Fatigue severity was related to functional impairments, while pain and disease duration were not. Psychological distress was not different from healthy adults. In conclusion, fatigue and pain are present among approximately half of the patients, and almost all patients are impaired in daily life activities, social participation and ambulation. These data should be taken into account in symptomatic management of oculopharyngeal muscular dystrophy. PMID- 26948711 TI - TRPV4 related scapuloperoneal spinal muscular atrophy: Report of an Italian family and review of the literature. AB - Scapuloperoneal spinal muscular atrophy (SPSMA) is a rare autosomal dominant disorder caused by heterozygous mutations in the transient receptor potential cation channel (TRPV4) gene, characterized by progressive scapuloperoneal atrophy and weakness. Additional features, such as vocal cord paralysis, scoliosis and/or arthrogryposis, are likely to occur. We report the first Italian family with SPSMA, harboring the c.806G>A mutation in TRPV4 gene (p. R269H). The pattern of expression was variable: the father showed a mild muscular involvement, while the son presented at birth skeletal dysplasia and a progressive course. We reinforce the concept that the disease can be more severe in the following generations. The disorder should be considered in scapuloperoneal syndromes with autosomal dominant inheritance and a neurogenic pattern. The presence of skeletal deformities strongly supports this suspicion. An early diagnosis of SPSMA may be crucial in order to prevent the more severe congenital form. PMID- 26948712 TI - The Impact of Adipose Tissue on Insulin Resistance in Acromegaly. AB - Adipose tissue (AT) is recognized as key contributor to the systemic insulin resistance and overt diabetes seen in metabolic syndrome. Acromegaly is a disease characterized by excessive secretion of growth hormone (GH) and insulin-like growth factor I (IGF-I). GH is known both for its action on AT and for its detrimental effect on glucose metabolism and insulin signaling. In active acromegaly, while body fat deports are diminished, insulin resistance is increased. Early studies have demonstrated defects in insulin action, both at the hepatic and extrahepatic (i.e., muscle and fat) levels, in active disease. This review discusses recent data suggesting that AT inflammation, altered AT distribution, and impaired adipogenesis are potential mechanisms contributing to systemic insulin resistance in acromegaly. PMID- 26948713 TI - Treatment with monoclonal antibodies and pregnancy in women with systemic inflammatory diseases: A special situation. PMID- 26948714 TI - Diagnostic categorization according to the First International Workshop on Ocular Sarcoidosis (FIWOS) criteria in a series of 11 patients. AB - OBJECTIVE: Categorization of patients diagnosed with ocular sarcoidosis during the period 2009-2014. METHODS: The medical records of patients with ocular sarcoidosis were reviewed and variables were collected to categorize the patients according to the criteria of the FIWOS. RESULTS: We found 11 patients, 7 women and 4 men, with sarcoid uveitis; the median age was 58 years. Bilateral panuveitis was the most common pattern (54.5%), followed by chronic anterior uveitis (27.2%). The diagnosis of sarcoidosis was definitive in 4 patients (36.3%), presumed in 5 (45.4%), probable in 1 (9%) and possible in 1 (9%). CONCLUSIONS: Ocular sarcoidosis was diagnosed in more than half of the patients who had no confirmatory biopsy. Bilateral panuveitis and chronic anterior uveitis were the patterns most frequently observed. PMID- 26948716 TI - Decomposition of the fluoroethylene carbonate additive and the glue effect of lithium fluoride products for the solid electrolyte interphase: an ab initio study. AB - Additives in the electrolyte solution of lithium-ion batteries (LIBs) have a large impact on the performance of the solid electrolyte interphase (SEI) that forms on the anode and is a key to the stability and durability of LIBs. We theoretically investigated effects of fluoroethylene carbonate (FEC), a representative additive, that has recently attracted considerable attention for the enhancement of cycling stability of silicon electrodes and the improvement of reversibility of sodium-ion batteries. First, we intensively examined the reductive decompositions by ring-opening, hydrogen fluoride (HF) elimination to form a vinylene carbonate (VC) additive and intermolecular chemical reactions of FEC in the ethylene carbonate (EC) electrolyte, by using density functional theory (DFT) based molecular dynamics and the blue-moon ensemble technique for the free energy profile. The results show that the most plausible product of the FEC reductive decomposition is lithium fluoride (LiF), and that the reactivity of FEC to anion radicals is found to be inert compared to the VC additive. We also investigated the effects of the generated LiF on the SEI by using two model systems; (1) LiF molecules distributed in a model aggregate of organic SEI film components (SFCs) and (2) a LiF aggregate interfaced with the SFC aggregate. DFT calculations of the former system show that F atoms form strong bindings with the Li atoms of multiple organic SFC molecules and play as a joint connecting them. In the latter interface system, the LiF aggregate adsorbs the organic SFCs through the F-Li bindings. These results suggest that LiF moieties play the role of glue in the organic SFC within the SEI film. We also examined the interface structure between a LiF aggregate and a lithiated silicon anode, and found that they are strongly bound. This strong binding is likely to be related to the effectiveness of the FEC additive in the electrolyte for the silicon anode. PMID- 26948715 TI - Inhibition of the classical pathway of the complement system by saliva of Amblyomma cajennense (Acari: Ixodidae). AB - Inhibition of the complement system during and after haematophagy is of utmost importance for tick success in feeding and tick development. The role of such inhibition is to minimise damage to the intestinal epithelium as well as avoiding inflammation and opsonisation of salivary molecules at the bite site. Despite its importance, the salivary anti-complement activity has been characterised only in species belonging to the Ixodes ricinus complex which saliva is able to inhibit the alternative and lectin pathways. Little is known about this activity in other species of the Ixodidae family. Thus, the aim of this study was to describe the inhibition of the classical pathway of the complement system by the saliva of Amblyomma cajennense at different stages of the haematophagy. The A. cajennense saliva and salivary gland extract (SGE) were able to inhibit the complement classical pathway through haemolytic assays with higher activity observed when saliva was used. The anti-complement activity is present in the salivary glands of starving females and also in females throughout the whole feeding process, with significant higher activity soon after tick detachment. The SGE activity from both females fed on mice or horses had no significant correlation (p > 0.05) with tick body weight. The pH found in the intestinal lumen of A. cajennense was 8.04 +/- 0.08 and haemolytic assays performed at pH 8.0 showed activation of the classical pathway similarly to what occurs at pH 7.4. Consequently, inhibition could be necessary to protect the tick enterocytes. Indeed, the inhibition observed by SGE was higher in pH 8.0 in comparison to pH 7.4 reinforcing the role of saliva in protecting the intestinal cells. Further studies should be carried out in order to identify the inhibitor molecule and characterise its inhibition mechanism. PMID- 26948717 TI - Nonlinear spectral and lifetime management in upconversion nanoparticles by controlling energy distribution. AB - Optical tuning of lanthanide-doped upconversion nanoparticles has attracted considerable attention over the past decade because this development allows the advance of new frontiers in energy conversion, materials science, and biological imaging. Here we present a rational approach to manipulating the spectral profile and lifetime of lanthanide emission in upconversion nanoparticles by tailoring their nonlinear optical properties. We demonstrate that the incorporation of energy distributors, such as surface defects or an extra amount of dopants, into a rare-earth-based host lattice alters the decay behavior of excited sensitizers, thus markedly improving the emitters' sensitivity to excitation power. This work provides insight into mechanistic understanding of upconversion phenomena in nanoparticles and also enables exciting new opportunities of using these nanomaterials for photonic applications. PMID- 26948718 TI - Sonographic assessment of fetal occiput position during labor for the prediction of labor dystocia and perinatal outcomes. AB - OBJECTIVES: To evaluate the effect of the occiput posterior (OP) position on dystocia and perinatal outcomes. METHODS: This was a prospective cohort study of 162 primiparous women. We performed intrapartum sonography, and fetal occiput positions were recorded. The relationships between the position of the occiput and the course of labor and perinatal outcomes were investigated. Statistical analysis was performed using SAS 9.2. RESULTS: Fifty-six of 162 fetuses were found to be in the OP position during the first stage of labor. Eight (80.0%) of 10 fetuses in the OP position during the second stage were among the 56 that were in OP position during the first stage. The rate of cesarean sections performed in the OP position group during the first stage was significantly higher than the rate in the non-OP position group (37.5% versus 8.5%, p < 0.0001). The duration of the second stage of labor was longer and neonatal complications occurred more frequently in the OP position group during the second stage than in the non-OP position group (77.9 +/- 33.4 min versus 52.2 +/- 26.6 min, p = 0.0104; 50.0% versus 17.2%, p = 0.0118). CONCLUSIONS: The OP position may be a useful predicator for labor dystocia that can lead to poor neonatal outcomes. PMID- 26948719 TI - C-Terminal Modification of Fully Unprotected Peptide Hydrazides via in Situ Generation of Isocyanates. AB - A method for chemo- and regioselective conjugation of nucleophiles to fully unprotected peptides and proteins via in situ generation of C-terminal isocyanates is reported. Oxidation of C-terminal peptide hydrazides in aqueous media followed by Curtius rearrangement of acyl azides reliably generates isocyanates, which react with a variety of external nucleophiles, such as hydrazines, hydrazides, aromatic thiols, and hydroxylamines. Multiple peptides and a 53 kDa protein hydrazide were conjugated to different nucleophiles using this reaction. PMID- 26948720 TI - Knowledge, attitudes, and practices regarding travel health among Muscat International Airport travelers in Oman: Identifying the gaps and addressing the challenges. AB - Although the majority of travel-associated communicable diseases can be prevented, the public health burden of these diseases remains significant. Relatively little is known about how travelers know and perceive the health risks associated with travel and how they utilize preventive measures before and while traveling abroad. This study was conducted to determine the level of the knowledge, attitudes, and practices (KAP) of Muscat International Airport travelers about travel health in order to assess the knowledge gap and the need for travel health services in Oman. A cross-sectional study was conducted over a period of 1week using a self-administered questionnaire. The overall level of knowledge about vaccine-preventable diseases, food safety, and preventive measures against insect bites of the participants was inadequate. The practice concerning preventive travel health measures, such as the use of specific immunizations and antimalarial prophylaxis, was very limited, and influenced by some personal and travel-related factors. The inadequate level of travelers' knowledge and poor utilization of travel medicine services highlights the need for the provisions of specialized travel medicine services at the national level and to develop educational materials promoting the importance of pre-travel health advice. PMID- 26948722 TI - Unions call for better health support of pupils at school. AB - Urgent action is needed to protect the health needs of children and young people in schools, it is claimed. PMID- 26948721 TI - Celebrating our silver jubilee. AB - Not everyone knows early on what job they would like to end up doing, but for some nurses there was only ever one option and it was just the specialty that needed to be worked out. Someone who fits into that category is Karen Brombley, nurse consultant in palliative care, who has achieved the seemingly rare feat of combining a senior nursing role with remaining in clinical practice. Karen, who works at the pioneering hospice Helen and Douglas House, is the first candidate for our new careers series which I hope you will find inspirational. PMID- 26948723 TI - Computer-based child abuse alert system to be launched. AB - An online child protection information system intended to alert nurses and doctors in emergency departments is to be introduced in 2015. PMID- 26948724 TI - Institute founded to support the health visitor profession. AB - An organisation to ensure health visitors have access to the latest public health research and practice materials so they can offer the best advice to families has been launched. PMID- 26948725 TI - Student voice: First lessons. AB - I will never forget the day that I upset a child for the first time. I was a first-year nursing student and asked by the staff nurse to take a child's temperature. Off I went, delighted that I was to be of some use on the ward. PMID- 26948726 TI - Assessment of comorbidity in lung cancer: How, why, and in whom? PMID- 26948727 TI - Mind God's mind: History, development, and teaching. AB - We dispute the target article that belief in Big Gods facilitated development of large societies and suggest that the direction of causality might be inverted. We also suggest that plain theory of mind (ToM), although necessary, is not sufficient to conceive Big Gods. Grasp of other aspects of the mind is required. However, this theory is useful for the teaching of religion. PMID- 26948728 TI - Even "Bigger Gods" developed amongst the pastoralist followers of Moses and Mohammed: Consistent with uncertainty and disadvantage, but not prosocality. AB - The gods of monotheistic religions, which began amongst pastoralists and defeated exiles, are closer to Big Gods than those associated with ancient city-based polities. The development of Big Gods is contingent upon a need to reduce uncertainty and negative feelings in combination with a relatively high level of prosociality, rather than a need to induce or assess prosociality. PMID- 26948729 TI - Awe: A direct pathway from extravagant displays to prosociality. AB - Whereas Norenzayan et al. describe extravagant displays as a reliable means of belief transmission, this commentary reviews three emerging hypotheses about a direct connection between the awe elicited by extravagant displays and prosocial behaviour. If some of these hypotheses are correct, extravagant displays enhanced prosociality even among nonbelievers. Methodological suggestions are made for future experimental research on the awe-prosociality pathway. PMID- 26948730 TI - Big Gods: Extended prosociality or group binding? AB - Big Gods are described as having a "prosocial" effect. However, this conflates parochialism (group cohesion) with cooperation extended to strangers or out-group members. An examination of the cited experimental studies indicates that religion is actually associated with increased within-group parochialism, rather than extended or universal prosociality, and that the same general mechanisms underlie both religious and secular effects. PMID- 26948731 TI - Recognizing religion's dark side: Religious ritual increases antisociality and hinders self-control. AB - The target article develops an account of religious prosociality that is driven by increases in self-control. We suggest this account is incomplete. Although religion might increase prosociality to the in-group, it decreases it to the much larger out-group. Rituals, for example, lead to out-group derogation. We also challenge the link between religion and improved self-control, offering evidence that religion hinders self-control. PMID- 26948732 TI - Cultural evolution and prosociality: Widening the hypothesis space. AB - Norenzayan et al. suggest that Big Gods can be replaced by Big Governments. We examine forms of social and self-monitoring and ritual practice that emerged in Classical China, heterarchical societies like those that emerged in pre-Columbian Mesoamerica, and the contemporary Zapatista movement of Chiapas, and we recommend widening the hypothesis space to include these alternative forms of social organization. PMID- 26948733 TI - Authoritarian and benevolent god representations and the two sides of prosociality. AB - The Big Gods model focuses on belief in an authoritarian God as a psychological mechanism that inhibits antisocial behavior and facilitates the formation of tight, cohesive groups. Recent empirical evidence suggests, however, that belief in a benevolent God is more likely to inspire helping and inclusivity. Both kinds of beliefs are necessary to explain the development of large-scale societies. PMID- 26948734 TI - Hell of a theory. AB - The theory of group-selected Big God religions is a master narrative of cultural evolution. The evidence is a positive manifold of correlated assumptions and variables. Although provocative, the theory is overly elastic. Its critical ingredient - belief in Big Gods - is neither necessary nor sufficient to account for in-group prosociality and discipline. Four specific issues illustrate this elasticity. PMID- 26948735 TI - Let us be careful with the evidence on mentalizing, cognitive biases, and religious beliefs. AB - Norenzayan et al.'s theoretical synthesis is highly plausible and commendable. However, the empirical evidence for the arguments on mentalizing, cognitive biases, and religious belief is currently not as strong as the writers suggest. Although certainly abundant and compelling, this evidence is indirect, contradictory, and weak and must be acknowledged as such. More direct studies are needed to support the theory. PMID- 26948736 TI - Are gods and good governments culturally and psychologically interchangeable? AB - Cognitive by-product theorists maintain that standard cognitive development facilitates the acquisition of religion. Citing secularization, Norenzayan et al. qualify that theory, proposing that gods and good governments are psychologically and culturally interchangeable. That contention, though, occasions questions about the psychological dynamics involved, about what qualifies as religiosity, and about asymmetries between gods and good governments in the face of catastrophes. PMID- 26948737 TI - Moralizing religions: Prosocial or a privilege of wealth? AB - Today's major religions are moralizing religions that encourage material sacrifice for spiritual rewards. A key issue is whether moralizing religions gradually evolved over several millennia to enable cooperation among genetic strangers in the spiraling competition between increasingly large groups occupying Eurasia's middle latitudes, or whether they emerged only with the onset of the Axial Age, about 2,500 years ago, as societal wealth increased to allow privileging long-term goals over immediate needs. PMID- 26948738 TI - Religion promotes a love for thy neighbour: But how big is the neighbourhood? AB - The term prosocial has often been taken to mean nice or neighbourly, but many acts that further in-group interests are hostile and aggressive towards out groups. According to Norenzayan et al., religion's ability to foster social cohesion within religious groups has been a key factor in the human transition to complex societies. But what are the prospects for nonparochial "religious prosociality"? PMID- 26948739 TI - Self-control, cultural animals, and Big Gods. AB - As Norenzayan et al. cogently argue, religions that proliferated most successfully did so because they facilitated prosociality and cooperation in large-scale, anonymous groups. One important way that religion promotes cooperation may be through improving self-control. In this comment, we cover some potential obstacles to implementing self-control and how religion can overcome them. PMID- 26948740 TI - Moralizing gods revisited. AB - Six ideas explaining the existence of moralizing gods are mentioned, and I discuss the words prosocial and antisocial. PMID- 26948741 TI - Divorcing the puzzles: When group identities foster in-group cooperation. AB - We argue that general social psychological mechanisms (e.g., common group identity) can account for prosocial behavior and cooperative norms without the need for punishing Big Gods. Moreover, prosocial religions often do not prevent conflict within their religious groups. Hence, we doubt whether Big Gods and prosocial religions are more effective than alternative identities in enhancing high-level cooperation. PMID- 26948742 TI - Coerced coordination, not cooperation. AB - Norenzayan et al. propose that Big God (BG) religions are large-group cooperative enterprises that promote internal harmony and higher fertility, resulting in "mutually beneficial exchanges" for those involved. We examine the possible distributions of costs and benefits within BG religions and propose that they are, instead, successful coordinating mechanisms that rely on intragroup competition and exploitation between the classes and sexes. PMID- 26948743 TI - Credibility, credulity, and redistribution. AB - After raising some doubts for cultural group selection as an explanation of prosocial religiosity, we propose an alternative that views it as a "greenbeard effect." We combine the dynamic constraints on the evolution of greenbeard effects with Iannaccone's (1994) account of strict sects. Our model shows that certain social conditions may foster credulity and prosociality. PMID- 26948744 TI - The functions of ritual in social groups. AB - Ritual cognition builds upon social learning biases that may have become specialized for affiliation within social groups. The adaptive problems of group living required a means of identifying group members, ensuring commitment to the group, facilitating cooperation, and maintaining group cohesion. We discuss how ritual serves these social functions. PMID- 26948745 TI - Clarity and causality needed in claims about Big Gods. AB - We welcome Norenzayan et al.'s claim that the prosocial effects of beliefs in supernatural agents extend beyond Big Gods. To date, however, supporting evidence has focused on the Abrahamic Big God, making generalisations difficult. We discuss a recent study that highlights the need for clarity about the causal path by which supernatural beliefs affect the evolution of big societies. PMID- 26948746 TI - Explaining the success of karmic religions. AB - One of the central claims of Norenzayan et al.'s article is that supernatural monitoring and intergroup competition have facilitated the rise of large-scale prosocial religions. Although the authors outline in detail how social instincts that govern supernatural monitoring are honed by cultural evolution and have given rise to Big Gods, they do not provide a clear explanation for the success of karmic religions. Therefore, to test the real scope of their model, Norenzayan et al. need to seriously engage with questions concerning the evolution of karmic prosocial religions. PMID- 26948747 TI - Parochial prosocial religions: Historical and contemporary evidence for a cultural evolutionary process. AB - In our response to the 27 commentaries, we refine the theoretical claims, clarify several misconceptions of our framework, and explore substantial disagreements. In doing so, we (1) show that our framework accommodates multiple historical scenarios; (2) debate the historical evidence, particularly about "pre-Axial" religions; (3) offer important details about cultural evolutionary theory; (4) clarify the term prosociality; and (4) discuss proximal mechanisms. We review many interesting extensions, amplifications, and qualifications of our approach made by the commentators. PMID- 26948748 TI - The prosocial benefits of seeing purpose in life events: A case of cultural selection in action? AB - Norenzayan et al. propose that religious beliefs with incidental prosocial effects propagated via a long-term process of cultural evolution. Applying their model, I explore a possible candidate target of cultural selection: the teleological view - often culturally elaborated as a belief in karma or fate - that life events occur to punish or reward individuals' moral behavior. PMID- 26948749 TI - Prosociality and religion: History and experimentation. AB - Norenzayan et al. are praised for choosing to deal with significant questions in the understanding of religion. They are then criticized for refusing to define religion and for relying on problematic theoretical concepts. The authors discuss Abrahamic religions as the best-known prosocial religions, but the evidence shows that the case does not fit their conceptual framework. Finally, an extension of the authors' ideas about the meaning of priming effects is proposed. PMID- 26948750 TI - Memes and the evolution of religion: We need memetics, too. AB - In their analysis, Norenzayan et al. completely ignore memetics, which, unlike other theories, treats memes as replicators and looks to memetic as well as genetic advantage. Now that memes are evolving ever faster, genetic advantage is less relevant. So when religious and secular values are at odds, we need a memetic analysis to understand what is going on. PMID- 26948751 TI - Projecting WEIRD features on ancient religions. AB - The proposed narrative relies on an anachronistic projection of current religions onto prehistorical and historical cultures that were not concerned with prosocial morality or with public statement of belief. Prosocial morality appeared in wealthier post-Axial environments. Public demonstrations of belief are possible and advantageous when religious diversity starts interacting with coalitional recruitment dynamics in large-scale societies, a typical feature of modern, so called WEIRD societies. PMID- 26948752 TI - Why would anyone want to believe in Big Gods? AB - We suggest an alternative explanation for the emergence of Big Gods that places less emphasis on the role of cognitive tendencies and selection of prosocial cultural variants. Instead, we argue that the fundamental motivation to reduce uncertainty and increase long-term predictability provides a better account for the rise of Big moralizing Gods in a complex and heavily regulated social environment. PMID- 26948753 TI - A developmental perspective on the cultural evolution of prosocial religious beliefs. AB - Norenzayan et al. argue that prosocial religion develops through cultural evolution. Surprisingly, they give little attention to developmental accounts of prosocial religious beliefs. A consideration of the developmental literature supports some, but not all, of the authors' conclusions. PMID- 26948754 TI - Monotheism versus an innate bias towards mentalizing. AB - Norenzayan et al.'s account for the spread of monotheistic "Big God" religions sees these religions originating as by-products of innate cognitive biases. These biases produce polytheistic rather than monotheistic systems, however, and so do not explain the origin of monotheism. Accounts where monotheism arises from polytheism (for political reasons, for example) appear better able to explain the spread of monotheism. PMID- 26948755 TI - Readiness-to-change as a moderator of a web-based brief intervention for marijuana among students identified by health center screening. AB - INTRODUCTION: Electronic screening and brief intervention has been identified as a low cost strategy to address marijuana use among students, however there is little known about who may be most responsive to this intervention approach. This study examined whether readiness-to-change moderated the influence of a web-based intervention on frequency of use at 3-month outcomes. METHODS: One-hundred twenty three students who smoked marijuana at least monthly were identified by screening in a student health center. Baseline and 3-month outcome assessments were conducted on-line. Participants were randomly assigned to either eCHECKUP TO GO marijuana or a control condition after completing marijuana measures and the Readiness-to-Change Questionnaire (RTCQ). Negative binomial regression analyses were conducted to examine whether the effect of the intervention on marijuana use at 3-month outcomes was moderated by the Action and Problem Recognition dimensions of the RTCQ, adjusting for baseline use. RESULTS: Analyses showed a significant Intervention * Action interaction. Probing of interaction effects showed that among those with high scores on the Action scale participants in the intervention group reported significantly fewer days of use than those in the control condition at follow-up (IRR=0.53, 95%CI: 0.94, 2.08). The Problem Recognition dimension did not moderate the influence of the intervention on outcomes. CONCLUSION: These results suggest that this eSBI may bolster change efforts among students who have begun taking steps toward changing their marijuana use. PMID- 26948756 TI - White matter development and tobacco smoking in young adults: A systematic review with recommendations for future research. AB - BACKGROUND: Adolescence and young adulthood are critical vulnerability periods for initiation of tobacco smoking. White matter development is ongoing during this time and may be influenced by exposure to nicotine. Synthesis of findings from diffusion tensor imaging (DTI) studies of adolescent and young adult smokers may be helpful in understanding the relationship between neurodevelopment and initiation and progression of tobacco-use behaviors and in guiding further research. METHODS: A systematic literature review was conducted to identify DTI studies comparing adolescent and young adult (mean age <30 years) smokers versus nonsmokers. A total of 5 studies meeting inclusion criteria were identified. Primary study findings are reviewed and discussed within the context of neurodevelopment and in relation to findings from adult studies. Directions for further research are also discussed. RESULTS: All identified studies reported increases in fractional anisotropy (FA) among adolescent/young adult smokers in comparison to non-smokers. Increased FA was most frequently reported in regions of the corpus callosum (genu, body and spenium), internal capsule and superior longitudinal fasciculus. CONCLUSIONS: Findings of increased FA among adolescent/young adult smokers are contrary to those from most adult studies and thus raise the possibility of differential effects of nicotine on white matter across the lifespan. Further research including multiple time points is needed to test this hypothesis. Other areas warranting further research include DTI studies of e-cigarette use and studies incorporating measures of pubertal stage. PMID- 26948757 TI - Depression, posttraumatic stress, and alcohol misuse in young adult veterans: The transdiagnostic role of distress tolerance. AB - BACKGROUND: Alcohol misuse is common among young adult veterans, and is commonly associated with depression and posttraumatic stress disorder (PTSD). In fact, rates of comorbid depression, PTSD, and problem drinking are high in this population. Although distress tolerance, the capacity to experience and withstand negative psychological states, has been examined as a potential transdiagnostic factor that accounts for the development of mental health disorders, problem drinking, and the comorbidity between these presenting concerns, its role has not been evaluated in a veteran population. METHODS: Young adult veterans were recruited for an online survey related to alcohol use. Participants (n=783) completed self-report measures of alcohol use, depression and PTSD symptoms, and distress tolerance. Mediation models were conducted to examine whether distress tolerance mediated the relationship between (1) probable PTSD, (2) probable depression, and (3) comorbid probable PTSD and depression with alcohol misuse. Moderated mediation models were conducted to examine gender as a moderator. RESULTS: Significant bivariate associations were observed among mental health symptoms, distress tolerance, and alcohol misuse. Distress tolerance significantly mediated the relationship between probable depression and PTSD (both alone and in combination) and alcohol misuse. Evidence of moderated mediation was present for probable PTSD and probable comorbid PTSD and depression, such that the indirect effect was stronger among males. CONCLUSIONS: These results suggest that distress tolerance may be a transdiagnostic factor explaining the comorbidity of depression and PTSD with alcohol misuse in young adult veterans. These findings may inform screening and intervention efforts with this high-risk population. PMID- 26948758 TI - Nodal metastases in thyroid cancer: prognostic implications and management. AB - The significance of cervical lymph node metastases in differentiated thyroid cancer has been controversial and continues to evolve. Current staging systems consider nodal metastases to confer a poorer prognosis, particularly in older patients. Increasingly, the literature suggests that characteristics of the metastatic lymph nodes such as size and number are also prognostic. There is a growing trend toward less aggressive treatment of low-volume nodal disease. The aim of this review is to summarize the current literature and discuss prognostic and management implications of lymph node metastases in differentiated thyroid cancer. PMID- 26948759 TI - Enhanced performance for the analysis of prostaglandins and thromboxanes by liquid chromatography-tandem mass spectrometry using a new atmospheric pressure ionization source. AB - Eicosanoids, including prostaglandins and thromboxanes are lipid mediators synthetized from polyunsaturated fatty acids. They play an important role in cell signaling and are often reported as inflammatory markers. LC-MS/MS is the technique of choice for the analysis of these compounds, often in combination with advanced sample preparation techniques. Here we report a head to head comparison between an electrospray ionization source (ESI) and a new atmospheric pressure ionization source (UniSpray). The performance of both interfaces was evaluated in various matrices such as human plasma, pig colon and mouse colon. The UniSpray source shows an increase in method sensitivity up to a factor 5. Equivalent to better linearity and repeatability on various matrices as well as an increase in signal intensity were observed in comparison to ESI. PMID- 26948760 TI - Direct determination of lignin peroxidase released from Phanerochaete chrysosporium by in-capillary enzyme assay using micellar electrokinetic chromatography. AB - Here we describe the application of an in-capillary enzyme assay using micellar electrokinetic chromatography (MEKC) in the determination of enzyme activity in a crude culture medium containing lignin peroxidase released from Phanerochaete chrysosporium (P. chrysosporium). The method consists of a plug-plug reaction between lignin peroxidase and its substrate, veratryl alcohol, the separation of the product, veratraldehyde, from the other components including the enzyme and the culture medium, and the determination of the enzyme activity from the peak area of veratraldehyde produced by the plug-plug reaction. This method is more sensitive than conventional spectrophotometry since the background originates from the enzyme and the culture medium can be removed via MEKC separation. Veratraldehyde was separated at -10kV in a background electrolyte containing 50mM tartrate buffer (pH 2.5) and 50mM sodium dodecyl sulfate (SDS) after a plug-plug reaction in the capillary for 5min. The calibration curve of veratraldehyde was linear up to 4pmol (500MUM) with a limit to quantification of 0.026pmol (3.2MUM) (SN=10). The activity of lignin peroxidase was directly measured from the peak area of veratraldehyde. The activity of lignin peroxidase released from P. chrysosporium into the medium for 7 days was successfully determined to be 3.40UL(-1). PMID- 26948761 TI - Nucleic acid separations using superficially porous silica particles. AB - Ion pair reverse-phase liquid chromatography has been widely employed for nucleic acid separations. A wide range of alternative stationary phases have been utilised in conjunction with ion pair reverse-phase chromatography, including totally porous particles, non-porous particles, macroporous particles and monolithic stationary phases. In this study we have utilised superficially porous silica particles in conjunction with ion pair reverse-phase liquid chromatography for the analysis of nucleic acids. We have investigated a range of different pore sizes and phases for the analysis of a diverse range of nucleic acids including oligonucleotides, oligoribonucleotides, phosphorothioate oligonucleotides and high molecular weight dsDNA and RNA. The pore size of the superficially porous silica particles was shown to significantly affect the resolution of the nucleic acids. Optimum separations of small oligonucleotides such as those generated in RNase mapping experiments were obtained with 80A pore sizes and can readily be interfaced with mass spectrometry analysis. Improved resolution of larger oligonucleotides (>19mers) was observed with pore sizes of 150A. The optimum resolution for larger dsDNA/RNA molecules was achieved using superficially porous silica particles with pore sizes of 400A. Furthermore, we have utilised 150A pore size solid-core particles to separate typical impurities of a fully phosphorothioated oligonucleotide, which are often generated in the synthesis of this important class of therapeutic oligonucleotide. PMID- 26948762 TI - Pressurized liquid extraction-gas chromatography-mass spectrometry for confirming the photo-induced generation of dioxin-like derivatives and other cosmetic preservative photoproducts on artificial skin. AB - The stability and photochemical transformations of cosmetic preservatives in topical applications exposed to UV-light is a serious but poorly understood problem. In this study, a high throughput extraction and selective method based on pressurized liquid extraction (PLE) coupled to gas chromatography-mass spectrometry (GC-MS) was validated and applied to investigate the photochemical transformation of the antioxidant butylated hydroxytoluene (BHT), as well as the antimicrobials triclosan (TCS) and phenyl benzoate (PhBz) in an artificial skin model. Two sets of photodegradation experiments were performed: (i) UV Irradiation (8W, 254nm) of artificial skin directly spiked with the target preservatives, and (ii) UV-irradiation of artificial skin after the application of a cosmetic cream fortified with the target compounds. After irradiation, PLE was used to isolate the target preservatives and their transformation products. The follow-up of the photodegradation kinetics of the parent preservatives, the identification of the arising by-products, and the monitorization of their kinetic profiles was performed by GC-MS. The photochemical transformation of triclosan into 2,8-dichloro-dibenzo-p-dioxin (2,8-DCDD) and other dioxin-like photoproducts has been confirmed in this work. Furthermore, seven BHT photoproducts, and three benzophenones as PhBz by-products, have been also identified. These findings reveal the first evidences of cosmetic ingredients phototransformation into unwanted photoproducts on an artificial skin model. PMID- 26948763 TI - Determinants of protein elution rates from preparative ion-exchange adsorbents. AB - The rate processes involved in elution in preparative chromatography can affect both peak resolution and hence selectivity as well as practical factors such as facility fit. These processes depend on the physical structure of the adsorbent particles, the amount of bound solute, the solution conditions for operation or some combination of these factors. Ion-exchange adsorbents modified with covalently attached or grafted polymer layers have become widely used in preparative chromatography. Their often easily accessible microstructures offer substantial binding capacities for biomolecules, but elution has sometimes been observed to be undesirably slow. In order to determine which physicochemical phenomena control elution behavior, commercially available cellulosic, dextran grafted and unmodified agarose materials were characterized here by their elution profiles at various conditions, including different degrees of loading. Elution data were analyzed under the assumption of purely diffusion-limited control, including the role of pore structure properties such as porosity and tortuosity. In general, effective elution rates decreased with the reduction of accessible pore volume, but differences among different proteins indicated the roles of additional factors. Additional measurements and analysis, including the use of confocal laser scanning microscopy to observe elution within single chromatographic particles, indicated the importance of protein association within the particle during elution. The use of protein stabilizing agents was explored in systems presenting atypical elution behavior, and l-arginine and disaccharide excipients were shown to alleviate the effects for one protein, lysozyme, in the presence of sodium chloride. Incorporation of these excipients into eluent buffer gave rise to faster elution and significantly lower pool volumes in elution from polymer-modified adsorbents. PMID- 26948764 TI - Silver and gold nanoparticle separation using asymmetrical flow-field flow fractionation: Influence of run conditions and of particle and membrane charges. AB - Flow-Field Flow Fractionation (Flow-FFF), coupled with online detection systems is one of the most promising tools available for the separation and quantification of engineered nanoparticles (ENPs) in complex matrices. To correctly relate the retention of nanoparticles in the Flow-FFF-channel to the particle size, ideal separation conditions must be met. This requires optimization of the parameters that influence the separation behavior. The aim of this study was therefore to systematically investigate and evaluate the influence of parameters such as the carrier liquid, the cross flow, and the membrane material, on the separation behavior of two metallic ENPs. For this purpose the retention, recovery, and separation efficiency of sterically stabilized silver nanoparticles (AgNPs) and electrostatically stabilized gold nanoparticles (AuNPs), which represent two materials widely used in investigations on environmental fate and ecotoxicology, were investigated against a parameter matrix of three different cross-flow densities, four representative carrier solutions, and two membrane materials. The use of a complex mixture of buffers, ionic and non-ionic surfactants (FL-70 solution) together with a medium cross flow density provided an acceptable compromise in peak quality and recovery for both types of ENPs. However, these separation conditions do not represent a perfect match for both particle types at the same time (maximized recovery at maximized retention). It could be shown that the behavior of particles within Flow-FFF channels cannot be predicted or explained purely in terms of electrostatic interactions. Particles were irreversibly lost under conditions where the measured zeta potentials suggested that there should have been sufficient electrostatic repulsion to ensure stabilization of the particles in the Flow-FFF channel resulting in good recoveries. The wide variations that we observed in ENP behavior under different conditions, together with the different behavior that has been reported in published literature for the same NPs under similar conditions, indicate a need for improvement in the membrane materials used for Flow-FFF analysis of NPs. This research has shown that careful adjustment of separation conditions can result in acceptable, but not ideal, separation conditions for two fundamentally different stabilized materials, and that it may not be possible to separate a set of different particles under ideal conditions for each particle type. This therefore needs to be taking into account in method development and when interpreting FFF results from complex samples. PMID- 26948765 TI - Effects of sodium selenite on c-Jun N-terminal kinase signalling pathway induced by oxidative stress in human chondrocytes and c-Jun N-terminal kinase expression in patients with Kashin-Beck disease, an endemic osteoarthritis. AB - The c-Jun N-terminal kinases (JNK) are members of the mitogen-activated protein kinase family and are activated by environmental stress. Se plays an important role in the biological pathways by forming selenoprotein. Selenoproteins have been shown to exhibit a variety of biological functions including antioxidant functions and maintaining cellular redox balance, and compromise of such important proteins would lead to oxidative stress and apoptosis. We examined the expression levels of JNK in Kashin-Beck disease (KBD) patients, tested the potential protective effects of sodium selenite on tert-butyl hydroperoxide (tBHP)-induced oxidative injury and apoptosis in human chondrocytes as well as its underlying mechanism in this study. We produced an oxidative damage model induced by tBHP in C28/I2 human chondrocytes to test the essential anti-apoptosis effects of Se in vitro. The results indicated that the expression level of phosphorylated JNK was significantly increased in KBD patients. Cell apoptosis was increased and molecule expressions of the JNK signalling pathway were activated in the tBHP-injured chondrocytes. Na2SeO3 protected against tBHP induced oxidative stress and apoptosis in cells by increasing cell viability, reducing reactive oxygen species generation, increasing Glutathione peroxidase (GPx) activity and down-regulating the JNK pathway. These results demonstrate that apoptosis induced by tBHP in chondrocytes might be mediated via up regulation of the JNK pathway; Na2SeO3 has an effect of anti-apoptosis by down regulating the JNK signalling pathway. PMID- 26948766 TI - Warfarin Anticoagulation and Spontaneous Pectoral Haematomas. AB - Warfarin is the oldest and most commonly used anticoagulant in the outpatient setting. Major bleeding events remain as the most life threatening complication of this medication. Bleeding into enclosed structures and body cavities can be fatal in acute scenarios or cause continuous exsanguination if left unnoticed. Pectoral haematomas are an unusual presentation of bleeding diathesis, and are also seldom reported in the literature. We present three cases of patients with development of spontaneous pectoral haematoma during therapy with warfarin alone or with heparin bridging in the treatment of atrial fibrillation and thromboembolism. PMID- 26948767 TI - Wire Externalisation for Left Ventricular Lead Placement in Cardiac Resynchronisation Therapy: A Step-by-step Guide. PMID- 26948768 TI - Clinical Challenges in Catecholaminergic Polymorphic Ventricular Tachycardia. AB - Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inheritable cardiac disorder associated with exercise- and stress-induced sudden death in young individuals. Although important steps forward have been made in the comprehension and treatment of this disease, several aspects remain unclear. Firstly, from an epidemiological standpoint the actual prevalence of CPVT is still unknown and possibly underestimated. In addition, the diagnostic process remains very challenging and can be supported by genetic analysis in only about half of the cases. Finally, up to one third of CPVT patients continue to present complex arrhythmias despite beta blocker treatment; the role of newer therapeutic options, such as flecainide and left cardiac sympathetic denervation, needs to be further elucidated. All these points constitute challenges for the cardiologist in the management of CPVT patients and fuel research into new diagnostic, prognostic and therapeutic approaches. PMID- 26948769 TI - Chimeric spider silk proteins mediated by intein result in artificial hybrid silks. AB - Hybrid silks hold a great potential as specific biomaterials due to its controlled mechanical properties. To produce fibers with tunable properties, here we firstly made chimeric proteins in vitro, called W2C4CT and W2C8CT, with ligation of MaSp repetitive modules (C) with AcSp modules (W) by intein trans splicing technology from smaller precursors without final yield reduction. Intein mediated chimeric proteins form fibers at a low concentration of 0.4 mg/mL in 50 mM K3 PO4 pH 7.5 just drawn by hand. Hybrid fibers show smoother surface, and also have stronger chemical resistance as compared with fibers from W2CT (W fibers) and mixture of W2CT/C8CT (MHF8 fibers). Fibers from chimeric protein W2C4CT (HFH4) have improved mechanical properties than W fibers; however, with more C modules W2C8CT fibers (HFH8) properties decreased, indicates the length proportion of various modules is very important and should be optimized for fibers with specific properties. Generally, hybrid silks generated via chimeric proteins, which can be simplified by intein trans splicing, has greater potential to produce fibers with tunable properties. Our research shows that intein mediated directional protein ligation is a novel way to make large chimeric spider silk proteins and hybrid silks. (c) 2016 Wiley Periodicals, Inc. Biopolymers 105: 385-392, 2016. PMID- 26948770 TI - A New Year's resolution: Better patient outcomes after cataract surgery. PMID- 26948771 TI - Peripheral iridectomy for atraumatic haptic externalization in large eyes having anterior sclerotomy for glued intraocular lens. AB - We describe a simple technique of vitrector-assisted peripheral iridectomy performed along the base of the scleral flap and beneath a corneal mark at the 180-degree axis for atraumatic haptic externalization in large eyes having glued intrascleral haptic fixation of an intraocular lens (IOL). Anterior sclerotomy is often performed in large eyes, which shifts the IOL plane anteriorly, often leading to peripheral iris damage during the anterior sclerotomy or haptic externalization. The vitrector-assisted peripheral iridectomy helps to prevent iatrogenic iris tissue damage during the surgical procedure. FINANCIAL DISCLOSURE: Neither author has a financial or proprietary interest in any material or method mentioned. PMID- 26948772 TI - Laser-assisted marking for toric intraocular lens alignment. AB - We describe a technique of 3-dimensional spectral-domain optical coherence tomography-controlled laser-assisted corneal marking for toric intraocular lens implantation. To facilitate accurate alignment, the technique creates 2 perpendicular intrastromal incisions (width 0.75 mm) using an image-guided femtosecond laser. This was performed in a case series comprising 10 eyes of 10 patients. No posterior corneal perforation or epithelial alterations occurred. The incisions were plainly visible under the operating microscope, and no optical phenomena were reported 6 weeks after surgery. Laser-assisted marking can be performed safely and has the potential to enable precise axis marking. FINANCIAL DISCLOSURE: Dr. Dick is a paid consultant to Abbott Medical Optics, Inc. Dr. Schultz has no financial or proprietary interest in any material or method mentioned. PMID- 26948773 TI - Results of topography-guided laser in situ keratomileusis custom ablation treatment with a refractive excimer laser. AB - PURPOSE: To evaluate the safety and effectiveness of topography-guided custom ablation treatment (T-CAT) to correct myopia and myopic astigmatism with laser in situ keratomileusis (LASIK). SETTING: Nine clinical sites in the USA. DESIGN: Prospective observational nonrandomized unmasked study. METHODS: The study comprised patients aged 18 to 65 years old with myopia or myopic astigmatism with a manifest refraction spherical equivalent (MRSE) up to -9.0 diopters (D) and astigmatism of 6.0 D or less. Patients with previous refractive surgery or abnormal topography were excluded. Corneal topographies were obtained using the Allegro Topolyzer, and laser treatment was delivered with the Allegretto Wave Eye Q excimer laser system. Visual outcomes were evaluated postoperatively at 1 day, 1 week, and 1, 3, 6, 9, and 12 months. RESULTS: The clinical trial enrolled 212 patients (249 eyes). The T-CAT procedure significantly reduced the MRSE and cylinder, with stability of outcomes evident from 3 to 12 months after surgery. Compared with the preoperative corrected distance visual acuity (CDVA), the postoperative uncorrected distance visual acuity (UDVA) improved by 1 line or more in 30% of eyes and the postoperative UDVA was at least as good as the preoperative CDVA in 90% of eyes. Most visual symptoms improved after T-CAT. There were no significant treatment-related adverse events or loss of vision. CONCLUSION: The T-CAT procedure performed with the diagnostic device and the refractive excimer laser system safely and effectively achieved predictable refractive outcomes and reduced visual symptoms with stable results through 12 months. FINANCIAL DISCLOSURE: Dr. Stulting is a paid consultant to Alcon Laboratories, Inc., and was a medical monitor for the U.S. Food and Drug Administration (FDA) clinical trial. Dr. Fant is president of Clinical Research Consultants, Inc. (CRC), the clinical and regulatory consulting group that sponsored the FDA clinical trial. Dr. Fant and CRC were supported by Alcon Laboratories, Inc. PMID- 26948774 TI - Long-term outcomes of cataract surgery: 15-year results of a prospective study. AB - PURPOSE: To describe the change over a 15-year period in corrected distance visual acuity (CDVA), subjective visual function, and neodymium:YAG (Nd:YAG) frequency after cataract surgery. SETTING: Eye Clinic, Norrlands University Hospital, Umea, Sweden. DESIGN: Prospective longitudinal population-based cohort study. METHODS: Patients who had cataract surgery during a 1-year period, 15 years previously (1997 to 1998), were included. All patients answered the same Visual Function-14 (VF-14) questionnaire preoperatively, 4 months postoperatively, and 5, 10, and 15 years after surgery. Most patients (88%; 168/190; 74% of survivors) also had an ocular examination. The CDVA was measured with logMAR charts. RESULTS: The study included 190 patients (83% of survivors). Fifteen years after surgery, the median CDVA in the operated eye had deteriorated from 20/20 postoperatively to 20/25 (P = .0001). Sixty percent of the patients had worsening of CDVA of less than 0.1 logMAR units compared with postoperatively. Fifty-four percent (103/190) had no deterioration in subjective visual function (VF-14), and 79% (150/190) had 10 points of decline or less. Previous Nd:YAG laser capsulotomy was more common in those younger than 65 years at surgery (49% versus 25%) (P = .002). CONCLUSIONS: The study confirms the effectiveness of cataract extraction, offering good long-term visual rehabilitation for the majority of the patients. The most common comorbidity causing large functional loss 15 years after surgery was age-related macular degeneration. Fifteen years after surgery, one half of the patients younger than 65 years at surgery had not required a posterior Nd:YAG laser capsulotomy. FINANCIAL DISCLOSURE: The author has no financial or proprietary interest in any method or material mentioned. PMID- 26948775 TI - Comparison of sutured versus sutureless scleral-fixated intraocular lenses. AB - PURPOSE: To compare the intermediate-term anatomic and visual results of scleral fixated intraocular lens (IOL) implantation using 4-point suture fixation or transscleral sutureless fixation. SETTING: Tertiary referral eye care center in South India. DESIGN: Retrospective case series. METHODS: Medical records of consecutive patients who had scleral-fixated IOL surgery from January 1, 2010, to March 31, 2014, with more than 1 year of follow-up were retrospectively analyzed. Indication for scleral-fixated IOL implantation was aphakia after cataract extraction or trauma. The surgical technique was based on individual surgeon preference. The uncorrected distance visual acuity (UDVA), previous surgery, type of trauma, surgical technique, and complications were analyzed. RESULTS: One hundred nine cases were analyzed. The mean follow-up was 18.9 months +/- 8.7 (SD). The majority of eyes experienced an improvement in UDVA after surgery; 93 eyes (86%) had a Snellen equivalent corrected distance visual acuity of 6/12 or better. The baseline characteristics and final visual outcomes in the sutured scleral-fixated IOL group (n = 52) and sutureless scleral-fixated IOL group (n = 59) were comparable. Patients with previous trauma (n = 52) were predominantly men and were significantly younger than those in the cataract group. The visual and refractive outcomes were comparable between eyes with previous trauma and eyes with previous cataract surgery. Transient cystoid macular edema was the most common complication (12%); retinal detachment occurred in 5 cases (4.5%). CONCLUSIONS: Scleral-fixated IOLs provided excellent visual rehabilitation of aphakic eyes without capsular support. The sutured technique and sutureless technique appear to be equally good in eyes with aphakia after cataract surgery or trauma. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 26948776 TI - Long-term changes in intraocular lens position and corneal curvature after cataract surgery and their effect on refraction. AB - PURPOSE: To evaluate the role of intraocular lens (IOL) position shift and changes in corneal curvature on long-term refractive shift after cataract surgery. SETTING: Rotterdam Ophthalmic Institute, Rotterdam, the Netherlands. DESIGN: Prospective cohort study. METHODS: Patients who had routine cataract surgery with implantation of a hydrophobic acrylic 1-piece IOL (Acrysof SA60AT) in the capsular bag were enrolled. Measurements were performed preoperatively and 1 month, 3 months, and 1 year postoperatively. Refraction was measured with the ARK-530A autorefractor. The IOL position and corneal curvature were measured with the Lenstar LS-900 biometer. The refractive effect of changes in IOL position and corneal curvature was calculated with a Gaussian optics-based thin-lens formula and correlated with the measured refractive shift. RESULTS: The study group comprised 59 eyes of 59 patients. The median measured absolute refractive change was 0.25 diopter (D). The IOL position showed a statistically significant mean posterior shift of 0.033 mm +/- 0.060 (SD) between 1 month and 1 year postoperatively (P < .01), of which the median calculated absolute refractive effect was 0.05 D. This did not correlate with the measured refractive shift (Pearson r = 0.10, P = .46). Natural fluctuations in corneal curvature caused a median calculated absolute refractive effect of 0.17 D, which correlated well with the measured refractive shift (Pearson r = .55, P < .001). CONCLUSIONS: Long term changes in refraction after cataract surgery resulted from natural fluctuations in corneal curvature rather than from IOL position shift. These fluctuations limit the accuracy with which the refractive outcome can be planned. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 26948777 TI - Influence of the effective lens position, as predicted by axial length and keratometry, on the near add power of multifocal intraocular lenses. AB - PURPOSE: To calculate the near focal distance of different multifocal intraocular lenses (IOLs) as a function of the 2 parameters that are measured before cataract surgery; that is, axial length (AL) and refractive corneal power (keratometry [K]). SETTING: GB Bietti Foundation IRCCS, Rome, Italy. DESIGN: Noninterventional theoretical study. METHODS: The IOL power for emmetropia was first calculated in an eye model with the AL ranging from 20 to 30 mm and K from 38 to 48 diopters (D). Then, the predicted myopic refraction for any given IOL add power (from +1.5 to +4.0 D) was calculated, and from this value the near focal distance was obtained. Calculations were also performed for the average eye (K = 43.81 D; AL = 23.65 mm). RESULTS: The near focal distance increased with increasing values of K and AL for each near power add. The near focal distance ranged between 53 cm and 72 cm (21 inches and 28 inches) for a multifocal IOL with +2.50 D, between 44 cm and 60 cm (17 inches and 24 inches) for a multifocal IOL with +3.00 D add, and between 33 cm and 44 cm (13 inches and 18 inches) for a multifocal IOL with +4.00 D add. In the average eye, the near focal distance ranges between 36 cm (near add power = 4.00 D) and 99 cm (near add power = 1.5 D). CONCLUSIONS: Longer eyes with steeper corneas showed the longest near focal distance and could experience more difficulties in focusing near objects after surgery. The opposite was true for short hyperopic eyes. FINANCIAL DISCLOSURE: Dr. Hoffer receives licensing fees for the commercial use of the registered trademark Hoffer from all biometry manufacturers using the Hoffer Q formula to ensure that it is programmed correctly and book royalties from Slack, Inc., for the textbook IOL Power. None of the authors has a financial or proprietary interest in any material or method mentioned. PMID- 26948778 TI - Biometry measurements using a new large-coherence-length swept-source optical coherence tomographer. AB - PURPOSE: To evaluate the repeatability and reproducibility of the measurements obtained with the Argos, a new biometer with swept-source optical coherence tomography (SS-OCT), and to compare them with the results obtained with the IOLMaster 500 (partial-coherence interferometry [PCI]) and the Lenstar LS 900 (optical low-coherence reflectometry [OLCR]) biometers. SETTING: Private practice, Lynwood, California, USA. DESIGN: Prospective observational study. METHODS: All measurements were performed with the SS-OCT tomographer, the PCI biometer, and the OLCR biometer. RESULTS: Eyes (n = 107) were measured to evaluate the axial length (AL), central corneal thickness (CCT), aqueous depth, anterior chamber depth (ACD), lens thickness, pupil size, corneal diameter, and anterior corneal radius of curvature (RAV). Repeatability and reproducibility of the SS-OCT measurements showed comparable values and a low variation rate, with an interset mean difference of 0.01 mm for AL, 0.01 mm for CCT, 0.01 mm for aqueous depth and ACD, 0.03 mm for lens thickness, 0.10 mm for pupil size, 0.14 mm for corneal diameter, and 0.02 mm for RAV. The SS-OCT device correctly measured the AL in 96% of the cases compared with 79% for the OLCR device and 77% for the PCI device. Comparisons between the PCI device and SS-OCT device were 0.01 +/- 0.05 mm for AL, -0.17 +/- 0.20 mm for ACD, and -0.01 +/- 0.05 mm for RAV. Comparison between the OLCR device and the SS-OCT device was 0.01 +/- 0.06 mm for AL, 0.08 +/- 0.15 mm for ACD, 0.00 +/- 0.05 mm for RAV, 0.00 +/- 0.01 mm for CCT, 0.07 +/- 0.14 mm for aqueous depth, -0.23 +/- 0.22 mm for lens thickness, -0.29 +/- 0.53 mm for pupil size, and -0.34 +/- 0.76 mm for corneal diameter. CONCLUSION: Axial length measurements with the new SS-OCT biometer were comparable to the PCI and OLCR measurements with a higher AL acquisition rate. FINANCIAL DISCLOSURE: Dr. Shammas is a consultant to Movu, Inc. Drs. Ortiz, Kim, and Chong have proprietary interest in the new technology. PMID- 26948779 TI - Multicenter study of optical low-coherence interferometry and partial-coherence interferometry optical biometers with patients from the United States and China. AB - PURPOSE: To evaluate the agreement between the measurements provided by a new optical biometer, the Aladdin, based on optical low-coherence interferometry (OLCI), and those provided by the most commonly used optical biometer (IOLMaster 500), based on partial-coherence interferometry (PCI). SETTING: Multicenter clinical trial. DESIGN: Prospective evaluation of diagnostic test. METHODS: In this study, 2 samples of adult patients were enrolled, 1 in the United States and the other in China. The U.S. group included a sample of consecutive patients scheduled for cataract surgery. The China group included a sample of healthy subjects with no cataracts. In both cases, only 1 eye of each patient was analyzed. Axial length (AL), corneal power (in diopters [D]) (K), anterior chamber depth (ACD) (corneal epithelium to lens), and corneal astigmatism were measured. All values were analyzed using a paired t test, the Pearson product moment correlation coefficient (r), and Bland-Altman plots. RESULTS: In the U.S. and China groups, the OLCI mean AL values did not show a statistically significant difference from PCI values and showed excellent agreement and correlation. On the contrary, OLCI measured a lower mean K (-0.14 D) and a deeper ACD measurements (U.S. +0.16 mm and China +0.05 mm). These differences were statistically significant (P < .0001). Vector analysis did not show a statistically significant difference in astigmatism measurements. CONCLUSIONS: Agreement between OLCI and PCI was good. However, the small but statistically significant differences in K and ACD measurements make constant optimization necessary when calculating the intraocular lens power using theoretical formulas. FINANCIAL DISCLOSURE: Dr. Hoffer licenses the registered trademark name Hoffer to Carl Zeiss-Meditec (PCI), Haag-Streit (Lenstar), Movu (Argos), Oculus (Pentacam, AXL), Nidek (AL-Scan), Tomey (OA-2000), Topcon EU Visia Imaging (Aladdin), Ziemer (Galilei G6), and all A-scan biometer manufacturers. Dr. Shammas licenses his formulas to Carl Zeiss-Meditec (PCI), Haag-Streit (Lenstar), Nidek (AL-Scan), and Topcon EU (Visia Imaging) (Aladdin). None of the other authors has a financial or proprietary interest in any material or method mentioned. PMID- 26948780 TI - Measurement agreement between a new biometer based on partial coherence interferometry and a validated biometer based on optical low-coherence reflectometry. AB - PURPOSE: To evaluate the agreement of ocular measurements obtained with a new optical biometer (AL-Scan) and a previously validated optical biometer (Lenstar). SETTING: Eye Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China. DESIGN: Prospective observational cross-sectional study. METHODS: For a comprehensive comparison between the partial coherence interferometry (PCI) device and the optical low-coherence reflectometry (OLCR) device, the axial length (AL), central corneal thickness (CCT), anterior chamber depth (ACD), aqueous depth, mean keratometry (K), astigmatism, white-to-white (WTW), and pupil diameter were measured 3 times per device in eyes with cataract. The sequence of the device was in random order. The mean values were compared and 95% limits of agreement (LoA) were assessed. RESULTS: Ninety-two eyes of 92 cataract patients were included. Bland-Altman analysis showed excellent agreement between the PCI device and the OLCR device for AL, CCT, ACD and aqueous depth measurements with narrow 95% LoA (-0.05 to 0.06 mm, -13.39 to 15.61 MUm, -0.11 to 0.10 mm, and 0.12 to 0.10 mm, respectively), and the P values were more than 0.05. The mean K, astigmatism, and WTW values provided by the PCI device were in good agreement with the OLCR device, although statistically significant differences were detected. A major difference was observed in the pupil diameter measurement, with a 95% LoA of -0.73 to 1.21 mm. CONCLUSIONS: The PCI device biometer provided ocular measurements similar to those provided by the OLCR device for most parameters, especially for AL, CCT, and ACD. The pupil diameter values obtained with the PCI device were in poor agreement with the OLCR device, and these measurements should be interpreted with necessary adjustment. FINANCIAL DISCLOSURE: None of the authors has a proprietary or financial interest in any material or method mentioned. PMID- 26948781 TI - Repeatability and agreement in optical biometry of a new swept-source optical coherence tomography-based biometer versus partial coherence interferometry and optical low-coherence reflectometry. AB - PURPOSE: To estimate the repeatability of biometric parameters obtained with a new swept-source biometer and to compare the agreement with that of partial coherence interferometry (PCI) and optical low-coherence reflectometry (OLCR). SETTING: Department of Ophthalmology, Helios Hospital Erfurt, Erfurt, Julius Maximilians University, Wurzburg, and Philipps University, Marburg, Germany. DESIGN: Prospective comparative multicenter clinical study. METHODS: Biometry was taken with the use of 3 different biometers: the IOLMaster 700 swept-source biometer, the PCI-based IOLMaster 500, and the OCLR-based Lenstar LS 900. Axial length (AL), anterior chamber depth (ACD), and spherical equivalent (SE) were compared between swept-source and PCI biometry and central corneal thickness (CCT) and lens thickness (LT) between swept-source and OLCR biometry. The repeatability of swept-source biometry was evaluated on the basis of 3 measurements captured for each patient. RESULTS: One hundred twenty cataract eyes were included in the study. The mean difference between swept-source and PCI biometry for AL, ACD, and SE measurements was 4 MUm +/- 25 (SD), 17 +/- 122 MUm, and -0.001 +/- 0.19 diopter (D), respectively. The mean difference between swept source and OLCR biometry for LT and CCT measurements was 21 +/- 122 MUm and 0.15 +/- 4.51 MUm, respectively. Differences between swept-source biometry and the other devices distributed around zero without statistical significance. The standard deviation of repeatability for AL, ACD, LT, CCT, and SE was 8.8 MUm, 9.8 MUm, 2.3 MUm, 19.5 MUm, and 0.1 D, respectively. CONCLUSIONS: Swept-source biometry showed high repeatability performance for all biometric parameters. The agreement of AL, ACD, and SE between swept-source and PCI biometry as well as that of LT and CCT between swept-source and OLCR biometry was excellent. It remains to be validated whether high repeatability shown by swept-source biometry will result in better postoperative refractive outcomes. FINANCIAL DISCLOSURE: Drs. Blum and Sekundo are members of the Scientific Advisory Board of Carl Zeiss Meditec AG. Drs. Peter and Buhren are employees of Carl Zeiss Meditec AG. PMID- 26948782 TI - Influence factors of estimation errors for total corneal astigmatism using keratometric astigmatism in patients before cataract surgery. AB - PURPOSE: To evaluate the influence factors of the estimation errors for total corneal astigmatism using keratometric astigmatism in patients preparing for cataract surgery. SETTING: EYE and ENT Hospital of Fudan University, Shanghai, China. DESIGN: Prospective observational study. METHODS: Eyes of patients preparing for cataract surgery were measured with Pentacam Scheimpflug imaging device. Keratometric astigmatism was obtained using the anterior corneal surface measurement and the keratometric index (1.3375) while neglecting the posterior corneal surface measurement. The Scheimpflug-measured total corneal astigmatism was derived by vector analysis of the astigmatism on both corneal surfaces. RESULTS: The study comprised 374 eyes of 374 patients 45 to 84 years old. The mean absolute error in magnitude and mean absolute error in angle comparing keratometric astigmatism with Scheimpflug-derived astigmatism was 0.18 +/- 0.14 diopter (D) and 7.7 +/- 11.0 degrees, respectively. The mean magnitude of the error vector was 0.24 +/- 0.14 D. The error in magnitude was significantly larger in eyes with against-the-rule anterior astigmatism, while error in angle was larger in eyes with with-the-rule and oblique anterior astigmatism. Multiple regressions showed that 4 predictors (difference in anterior-posterior astigmatism axis, magnitude of posterior astigmatism, magnitude of keratometric astigmatism, and axial length [AL]) were significantly associated with the absolute error in magnitude. Predictors including the difference in the anterior posterior astigmatism axis, magnitude of posterior astigmatism, magnitude of keratometric astigmatism, and age were significantly associated with the absolute error in angle and magnitude of the error vector. CONCLUSIONS: Neglecting posterior corneal astigmatism yielded significant estimation errors in total corneal astigmatism in patients preparing for cataract surgery. Estimation errors were significantly influenced by the difference in the anterior -posterior astigmatism axis, magnitude of posterior astigmatism, keratometric astigmatism, AL, and age. FINANCIAL DISCLOSURE: None of the authors has any conflicts of interest to disclose. PMID- 26948783 TI - Comparison of very-high-frequency ultrasound and spectral-domain optical coherence tomography corneal and epithelial thickness maps. AB - PURPOSE: To compare corneal thickness and epithelial thickness measurements in maps obtained using the RTVue spectral domain optical coherence tomography (SD OCT) system and the Artemis 2 immersion arc-scanning very-high-frequency ultrasound (VHF-US) system. SETTING: Department of Ophthalmology, Columbia University Medical Center, New York, New York, USA. DESIGN: Comparative study. METHODS: Eyes of normal volunteers were scanned with the SD-OCT system followed by the VHF-US system and then again by the SD-OCT system. On each map, the minimum corneal thickness and mean values of corneal thickness and epithelial thickness in the 3.0 mm radius zone and in 0.5 mm wide concentric annuli of up to a 3.0 mm radius around the corneal vertex were determined. RESULTS: Both eyes of 12 normal volunteers were scanned. The corneal thickness values from both devices were highly correlated (R > 0.96); in the 3.0 mm radius zone, they were not statistically significantly different. There was no statistically significant change in epithelial thickness or corneal thickness in SD-OCT measurements taken before versus after immersion US. Although highly correlated (R > 0.76), the SD OCT epithelial thickness values were systematically thinner (1.7 +/- 2.1 MUm) than the VHF-US measurements in the 3.0 mm radius zone (P < .01). CONCLUSIONS: The corneal thickness measurements in the 3.0 mm radius zone in normal eyes were equivalent between the 2 systems. Although correlated, the VHF-US epithelial thickness measurements were systemically thicker than the SD-OCT values. FINANCIAL DISCLOSURES: Drs. Silverman and Reinstein have a commercial interest in Arcscan, Inc. Dr. Reinstein is a consultant to Carl Zeiss Meditec. None of the other authors has a financial or proprietary interest in any material or method presented. PMID- 26948784 TI - Nonpenetrating femtosecond laser intrastromal astigmatic keratotomy in eyes having cataract surgery. AB - PURPOSE: To describe the effect of femtosecond laser intrastromal astigmatic keratotomy (AK) performed during cataract surgery. SETTING: Moorfields Eye Hospital, London, United Kingdom. DESIGN: Prospective case series. METHODS: This study comprised patients having laser cataract surgery with concurrent astigmatism management by intrastromal AK. All eyes had greater than 0.7 corneal diopter (D) cylinder. An intrastromal AK nomogram with 8.0 mm diameter paired symmetric limbal centered arcs was used. Corneal keratometry was measured preoperatively and 1 month postoperatively using a KR8100PA topographer autorefractor. Astigmatic analyses were performed using the Alpins method considering 3 vectors-target induced astigmatism (TIA), surgically induced astigmatism (SIA) and difference vector (DV)-and calculation of coupling measures. RESULTS: In all, 196 eyes of 133 patients were analyzed. The mean TIA (equivalent to preoperative corneal cylinder) was 1.21 D +/- 0.42 (SD) (range 0.75 to 2.64 D) and the mean SIA was 0.74 DC +/- 0.40 (range 0.00 to 2.86). The mean difference vector was 0.74 +/- 0.38 D (range 0.00 to 2.25 D). The mean correction index was 0.63 +/- 0.32 (range 0.00 to 1.93), indicating that the mean astigmatism correction was 63%. Fourteen eyes (7.1%) and 7 eyes (3.6%) had an astigmatism correction of greater than 100% and greater than 120%, respectively. Overall 0%, 48.5%, and 51.5% of eyes had 0.50 D or less, 1.0 D or less, or greater than 1.0 D, respectively, preoperatively compared with 32.1%, 85.7%, and 14.3%, postoperatively. There were no cases of corneal endothelial perforation or inadvertent placement within the visual axis. CONCLUSIONS: The intrastromal AKs were easily programmed as an integral part of laser-assisted cataract surgery without additional cost, significantly reduced corneal cylinder, and appeared to be safe through 1 month of follow-up. FINANCIAL DISCLOSURE: Dr. Day was supported by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology. Dr. Stevens has been a consultant to Optimedica Inc., now part of Abbott Medical Optics. PMID- 26948785 TI - Effect of a multimedia-assisted informed consent procedure on the information gain, satisfaction, and anxiety of cataract surgery patients. AB - PURPOSE: To assess whether a multimedia-assisted preoperative informed consent procedure has an effect on patients' knowledge concerning cataract surgery, satisfaction with the informed consent process, and reduction in anxiety levels. SETTING: Hietzing Hospital, Vienna, Austria. DESIGN: Prospective randomized controlled clinical trial. METHODS: Patients participated in an informed consent procedure for age-related cataract surgery that included the standard approach only (reading the information brochure and having a standardized face-to-face discussion) or supplemented with a computer-animated video. The main outcome was information retention assessed by a questionnaire. Further outcome measures used were the State-Trait Anxiety Inventory, the Visual Function-14 score, and an assessment of satisfaction. RESULTS: The study included 123 patients (64 in standard-only group; 59 in computer-animated video group). Both groups scored well on the questionnaire; however, patients who watched the video performed better (82% retention versus 72%) (P = .002). Scores tended to decrease with increasing age (r = -0.25, P = .005); however, this decrease was smaller in the group that watched the video. Both groups had elevated anxiety levels (means in video group: anxiety concerning the current situation [S-anxiety] = 63.8 +/- 9.6 [SD], general tendency toward anxiety [T-anxiety] = 65.5 +/- 7.9; means in control group: S-anxiety = 61.9 +/- 10.3, T-anxiety = 66.2 +/- 7.8). CONCLUSIONS: A high level of information retention was achieved using an informed consent procedure consisting of an information brochure and a standardized face-to-face discussion. A further increase in information retention was achieved, even with increasing patient age, by adding a multimedia presentation. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 26948786 TI - Paired-eye comparison of corneal endothelial cell counts after unilateral iris claw phakic intraocular lens implantation. AB - PURPOSE: To compare the corneal endothelial cell density (ECD) after unilateral iris-claw phakic intraocular lens (pIOL) implantation. SETTING: Instituto de Microcirugia Ocular, Barcelona, Spain. DESIGN: Retrospective interventional nonrandomized paired-eye comparison. METHODS: Patients who had pIOL implantation in 1 eye and corneal refractive surgery (Group 1) or no surgery in the fellow eye (Group 2) between 1998 and 2010 were included. The main outcome measures were central corneal ECD and the percentage of corneal endothelial cell loss. Secondary outcome measures were uncorrected distance visual acuity, corrected distance visual acuity, manifest refraction, and complications. Outcome measures were analyzed 1, 5, and 10 years postoperatively. RESULTS: Both groups comprised 29 patients. Ten years after surgery, the mean endothelial cell loss was 6.41% +/ 8.02% (SD) (Group 1, iris-claw pIOLs), 5.59% +/- 5.98% (Group 1, corneal refractive surgery), 7.84% +/- 6.83% (Group 2, iris-claw pIOLs), and 6.74% +/- 3.97% (Group 2, no surgery). No significant endothelial cell loss was observed after pIOL implantation or corneal refractive surgery at any timepoint (P > .05). No significant differences were observed in the percentage of endothelial cell loss between the groups (P > .05). CONCLUSIONS: Iris-claw pIOL implantation did not produce significant corneal endothelial cell loss up to 10 years after surgery compared with corneal refractive surgery and unoperated eyes when strict inclusion criteria were met. FINANCIAL DISCLOSURE: Dr. Guell is a consultant to Ophtec BV and Carl Zeiss Meditec AG. No other author has a financial or proprietary interest in any material or method mentioned. PMID- 26948787 TI - Changes in ocular biomechanics after femtosecond laser creation of a laser in situ keratomileusis flap. AB - PURPOSE: To evaluate ocular biomechanical parameters with the Corvis ST, a noncontact tonometer combined with an ultra-high-speed Scheimpflug camera, before and after creation of a femtosecond laser-created laser in situ keratomileusis (LASIK) flap. SETTING: Private practice, Siena, Italy. DESIGN: Prospective consecutive study. METHODS: Right eyes of patients having LASIK were assessed with the dynamic Scheimpflug camera before and after femtosecond laser (LDV Z4) flap creation but before mechanical flap lifting. RESULTS: Twenty-eight eyes of 28 patients were evaluated. Before flap creation, the mean values on the dynamic Scheimpflug camera were intraocular pressure (IOP), 15.04 mm Hg +/- 3.99 (SD); central pachymetry, 550.8 +/- 101.0 MUm; applanation 1 length, 1.721 +/- 0.134 mm; applanation 2 length, 1.674 +/- 0.287 mm; applanation 1 velocity, 0.126 +/- 0.031 m/s; and deflection amplitude, 1.039 +/- 0.141 mm. After flap creation, the mean values were IOP, 16.10 +/- 3.11 mm Hg (95% confidence interval [CI], 0.44 1.78; P < .05); central pachymetry, 561.8 +/- 35.9 MUm (95% CI, -28.9 to 50.9; P = .21); applanation 1 length, 1.789 +/- 0.1492 mm (95% CI, 0.003-0.134; P < .05); applanation 2 length, 1.759 +/- 0.259 mm (95% CI, -0.005 to 0.173; P = .08); applanation 1 velocity, 0.136 +/- 0.022 m/s (95% CI, 0.001-0.017; P < .05); and deflection amplitude, 1.029 +/- 0.151 mm (95% CI: -0.043 to 0.025; P = .34). CONCLUSION: The dynamic Scheimpflug camera showed changes in biomechanical properties after femtosecond creation of a LASIK flap as indicated by an increased applanation 1 length and applanation 1 velocity. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 26948788 TI - Effect of endocyclophotocoagulation on refractive outcomes in angle-closure eyes after phacoemulsification and posterior chamber intraocular lens implantation. AB - PURPOSE: To compare postoperative refractive outcomes in angle-closure eyes having phacoemulsification and intraocular lens (IOL) implantation with or without endocyclophotocoagulation (ECP). SETTING: Single tertiary-level ophthalmology practice. DESIGN: Retrospective comparative study. METHODS: Primary angle-closure suspect (PACS), primary angle-closure (PAC), or primary angle closure glaucoma (PACG) eyes that had phacoemulsification and IOL implantation with or without ECP from 2012 to 2014 were studied. Clinical data collected included axial length (AL), minimum and maximum keratometry (K) values, corneal powers, anterior chamber depth (ACD), corneal white-to-white (WTW), implanted IOL power, and postoperative manifest refraction. The Holladay 1 formula was used for IOL calculations. Primary and secondary outcome measures were the mean absolute error (MAE) and mean arithmetic error, respectively. RESULTS: Sixty-eight eyes with ECP and 71 eyes without ECP were included. There were no statistically significant differences between the 2 groups in age, sex, eye side, ethnicity, AL, minimum or maximum keratometry values, ACD, WTW, or implanted IOL power. The MAE was lower in the non-ECP group (0.47 +/- 0.32D versus 0.62 +/- 0.43D; P = .0285). The mean arithmetic error showed a more myopic result in the ECP group ( 0.54 +/- 0.53D versus -0.26 +/- 0.52D; P = .0017). CONCLUSION: In this study, patients with PACS, PAC, or PACG having phacoemulsification and IOL implantation with ECP had decreased predictability of the postoperative refraction and a small myopic shift compared with those without ECP. FINANCIAL DISCLOSURE: Dr. Ahmed is a consultant to Alcon, Advanced Medical Optics, Bausch & Lomb, and Carl Zeiss. None of the other authors has a proprietary or financial interest in any material or method mentioned. PMID- 26948789 TI - In vitro optical quality comparison of 2 trifocal intraocular lenses and 1 progressive multifocal intraocular lens. AB - PURPOSE: To evaluate the optical quality of 3 multifocal intraocular lenses (IOLs): the Mini Well Ready progressive multifocal aspheric IOL, the AT LISA trifocal diffractive IOL, and the Finevision full diffractive trifocal IOL. SETTING: University of Valencia, Valencia, Spain. DESIGN: Experimental study. METHODS: An instrument designed for measuring real-time modulation transfer function (MTF) and IOL power was used to measure the optical quality of each IOL for 3.0 mm and 4.5 mm apertures. This instrument measures both sagittal and tangential MTFs. The optical quality of each IOL was evaluated with the MTF, through-focus MTF, defocus tolerance, Strehl ratio MTF, and relative percentage of light in each focus. These metrics were evaluated at best focus for each IOL. RESULTS: Through-focus graphs corresponding to trifocal IOLs showed 3 mean peaks. Nevertheless, the progressive multifocal aspheric IOL showed 2 main areas, 1 corresponding to distance vision focus and the other including both intermediate and near vision foci. CONCLUSIONS: The results obtained in the present study suggest that the progressive multifocal aspheric IOL might be considered for cataract surgery. FINANCIAL DISCLOSURE: None of the authors has a financial or proprietary interest in any method or material mentioned. PMID- 26948790 TI - Light scattering, straylight, and optical quality in hydrophobic acrylic intraocular lenses with subsurface nanoglistenings. AB - PURPOSE: To evaluate forward light scattering and straylight in single-piece hydrophobic acrylic intraocular lenses (IOLs) (Acrysof) removed from cadaver eyes and design- and power-matched controls, as well as the effect of subsurface nanoglistenings on other optical quality and performance indicators. SETTING: John A. Moran Eye Center, University of Utah, Salt Lake City, Utah, USA. DESIGN: Experimental study. METHODS: Seventeen single-piece IOLs (11 blue light filtering; 6 without blue-light filter) with subsurface nanoglistenings were removed from cadaver eyes. The Complete Angle Scatter Instrument scatterometer was used to measure the forward-scattered light; straylight values at various angles were calculated. The modulation transfer function (MTF) and Badal images were also obtained. Backscatter was measured with a Scheimpflug camera (EAS-1000) and light transmittance with a spectrophotometer (Lambda 35 UV-VIS) to confirm findings in previous studies. RESULTS: The mean straylight values at a scattered angle of 10 degrees were 1.06 +/- 0.23 log(s) for blue light-filtering IOLs, 0.97 +/- 0.28 log(s) for IOLs without a blue-light filter, and 0.22 +/- 0.22 log(s) for controls. The MTF and Badal image contrast of IOLs removed from cadaver eyes were similar to control values (no subsurface nanoglistenings). Backscatter was significantly higher in IOLs from cadaver eyes, although light transmittance was similar to that of controls. CONCLUSION: Straylight in hydrophobic IOLs resulting from subsurface nanoglistenings was well below the value of straylight hindrance and would not cause noticeable visual impairments. FINANCIAL DISCLOSURE: Dr. Das is an employee of Alcon Laboratories, Inc. The Complete Angle Instrument scatterometer was developed by Dr. Stover at the Scatterworks, Inc. Neither of the other authors has a financial or proprietary interest in any method or material mentioned. PMID- 26948791 TI - Experimental anterior chamber maintenance in active versus passive phacoemulsification fluidics systems. AB - PURPOSE: To evaluate the ability of phacoemulsifiers with active versus passive infusion fluidics control systems to maintain target intraocular pressures (IOPs) under varying flow conditions. SETTING: Alcon Research, Ltd., Lake Forest, California, USA. DESIGN: Experimental study. METHODS: An acrylic test chamber was used to model the anterior chamber of the eye. Two passive (gravity-based) systems were tested using bottle heights yielding infusion pressures of 41, 75, and 109 cm of water under zero-flow conditions. One actively controlled system was tested using equivalent target IOPs of 30, 55, and 80 mm Hg. Test chamber IOPs were measured at aspiration flow rates of 15, 30, 45, and 60 cc/min. RESULTS: The measured flow rates were similar between fluidics systems across the range of intended aspiration flow rates. All systems achieved the desired target IOPs under zero-flow conditions. After activation of aspiration flow, however, measured IOPs decreased from target IOPs for the 2 passive systems. Each 15 cc/min increase in the aspiration flow rate produced a pressure drop of 14.0 to 16.2 mm Hg or 9.3 to 14.2 mm Hg, depending on the system. Measured IOPs in the actively controlled system closely matched the targeted IOPs across all tested aspiration flow rates, deviating from targets by no more than 4.3 mm Hg. CONCLUSIONS: All phacoemulsification aspiration infusion fluidics systems achieved target IOPs under zero-flow conditions. Only the actively controlled system maintained target IOPs across a range of aspiration flow rates. These experimental findings suggest that anterior chamber stability might be better in the clinical setting using an actively controlled system. FINANCIAL DISCLOSURE: Dr. Dimalanta is an employee of Alcon Research, Ltd. Dr. Miller is an investigator and speaker for and a consultant to Alcon Laboratories, Inc. Dr. Nicoli has no financial or proprietary interest in any material or method mentioned. PMID- 26948792 TI - Metaanalysis of intraocular lens power calculation after laser refractive surgery in myopic eyes. AB - To evaluate the accuracy of intraocular lens (IOL) power calculation methods after laser refractive surgery in myopic eyes, a comprehensive literature search was carried out for retrospective case series studies with data on post-myopic laser surgery IOL power calculations published from January 2000 to May 2014. A metaanalysis of the 9 identified studies was performed using odds ratios in percentage of prediction error within +/-0.5 or 1.0 diopter (D) of the target refraction. Compared with the Haigis-L method, the clinical history method, corneal bypass method, and Feiz-Mannis method were associated with lower odds of predication; the Masket method showed higher odds. The subgroup data showed significantly better performance of the Shammas no-history method with the Shammas post-LASIK formula than the Haigis-L method in predication error. The Masket method and the Shammas no-history method with the Shammas post-LASIK formula without historical data had more prediction accuracy than the Haigis-L method. The clinical history method, Feiz-Mannis method, and corneal bypass method, which required historical data, were less accurate in their predictions. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 26948793 TI - Direct oral anticoagulant drugs (DOAC). PMID- 26948794 TI - Refractory acute angle-closure glaucoma with retinal ischemia: January consultation #1. PMID- 26948795 TI - January consultation #2. PMID- 26948796 TI - January consultation #3. PMID- 26948797 TI - January consultation #4. PMID- 26948798 TI - January consultation #5. PMID- 26948799 TI - January consultation #6. PMID- 26948800 TI - January consultation #7. PMID- 26948801 TI - DILIrank: the largest reference drug list ranked by the risk for developing drug induced liver injury in humans. PMID- 26948802 TI - Entrepreneurial patent management in pharmaceutical startups. AB - Startups fill an increasingly important role as innovators in the pharmaceutical industry, and patenting is typically central to their success. This article aims to explore patent management in pharmaceutical startups. The results show that startups need to deal with several challenges related to patenting and an 'entrepreneurial' approach to patent management is called for. Resource constraints, venture capital provision, exits and other conditions and events must be readily considered in the patent management process to build a successful pharmaceutical venture, something that could benefit the pharmaceutical industry as a whole. PMID- 26948803 TI - Targeting and Imaging of Cancer Cells via Monosaccharide-Imprinted Fluorescent Nanoparticles. AB - The recognition of cancer cells is a key for cancer diagnosis and therapy, but the specificity highly relies on the use of biorecognition molecules particularly antibodies. Because biorecognition molecules suffer from some apparent disadvantages, such as hard to prepare and poor storage stability, novel alternatives that can overcome these disadvantages are highly important. Here we present monosaccharide-imprinted fluorescent nanoparticles (NPs) for targeting and imaging of cancer cells. The molecularly imprinted polymer (MIP) probe was fluorescein isothiocyanate (FITC) doped silica NPs with a shell imprinted with sialic acid, fucose or mannose as the template. The monosaccharide-imprinted NPs exhibited high specificity toward the target monosaccharides. As the template monosaccharides used are over-expressed on cancer cells, these monosaccharide imprinted NPs allowed for specific targeting cancer cells over normal cells. Fluorescence imaging of human hepatoma carcinoma cells (HepG-2) over normal hepatic cells (L-02) and mammary cancer cells (MCF-7) over normal mammary epithelial cells (MCF-10A) by these NPs was demonstrated. As the imprinting approach employed herein is generally applicable and highly efficient, monosaccharide-imprinted NPs can be promising probes for targeting cancer cells. PMID- 26948812 TI - Chiroptical switching caused by crystalline/liquid crystalline phase transition of a chiral bowl-shaped molecule. AB - The liquid crystal of a chiral bowl-shaped molecule having a central-phosphorus atom and long alkyl chains was developed. The DSC and XRD analyses suggested the formation of columnar liquid crystals of both the enantiopure and racemic compounds. The condensed phase of the enantiopure compound in a thin film exhibited a significant signal in CD spectra, which was switched by a reversible phase transition between the crystalline and liquid crystalline states. PMID- 26948811 TI - Antisynthetase syndrome after acute massive inhalation of wood and paint dust. PMID- 26948813 TI - Driving Innovation in Radiology: A Trainee Perspective on the 37th Annual Intersociety Summer Conference. PMID- 26948814 TI - Evolutionary genetics: Haunted by the past--modern consequences of Neanderthal DNA. PMID- 26948816 TI - Microbial genetics: CRISPR memories of RNA. PMID- 26948817 TI - Gene regulation: A gene-centric analysis of transcriptional cascades. PMID- 26948815 TI - Enhancers as non-coding RNA transcription units: recent insights and future perspectives. AB - Networks of regulatory enhancers dictate distinct cell identities and cellular responses to diverse signals by instructing precise spatiotemporal patterns of gene expression. However, 35 years after their discovery, enhancer functions and mechanisms remain incompletely understood. Intriguingly, recent evidence suggests that many, if not all, functional enhancers are themselves transcription units, generating non-coding enhancer RNAs. This observation provides a fundamental insight into the inter-regulation between enhancers and promoters, which can both act as transcription units; it also raises crucial questions regarding the potential biological roles of the enhancer transcription process and non-coding enhancer RNAs. Here, we review research progress in this field and discuss several important, unresolved questions regarding the roles and mechanisms of enhancers in gene regulation. PMID- 26948818 TI - Mitchochondrial replacement therapy: the IOM report and its aftermath. PMID- 26948819 TI - Improving the moisturizing properties of collagen film by surface grafting of chondroitin sulfate for corneal tissue engineering. AB - Cornea disease is the second cause of blindness and keratoplasty is the most commonly performed option for visual rehabilitation of patients with corneal blindness. However, the clinical treatment has been drastically limited due to a severe shortage of high-quality donor corneas. Although collagen film with outstanding biocompatibility has promising application in corneal tissue engineering, the moisturizing properties of collagen-based materials must be further improved to satisfy the requirements of clinical applications. This paper describes a novel collagen-based film with high moisture capacity reinforced by surface grafting of chondroitin sulfate. The collagen-chondroitin sulfate (abbreviated as Col-CS) film was analyzed by Fourier transform infrared spectroscopy and X-ray photoelectron spectroscopy and its hydrophilic property, moisture retention, optical property, and mechanical performance had been tested. The moisture-retaining capacity is found to be improved with the introduction of chondroitin sulfate, and the Col-CS membrane performs better mechanical properties than the collagen film. Moreover, the modified film proves excellent biocompatibility for the proliferation of human corneal epithelial cells in vitro. This Col-CS film with good moisturizing properties can reduce the risk of xerophthalmia and is expected to increase the implant success rate in clinic patients with corneal defects. PMID- 26948820 TI - Should predictive scores based on vital signs be used in the same way as those based on laboratory data? A hypothesis generating retrospective evaluation of in hospital mortality by four different scoring systems. AB - BACKGROUND: few studies have compared the discrimination of predictive scores of in-hospital mortality that used vital signs with those using laboratory results in different patient populations. METHODS: a hypothesis generating retrospective observational cohort study. A score that only used vital signs was compared with three other scores that used laboratory changes in 44,985 medical and 20,432 surgical patients. RESULTS: the discrimination of the score based only on vital signs was highest for the prediction of in-hospital death within 24h. In contrast the, albeit lower, discrimination of scores based only on laboratory data remained constant for the prediction of death up to 30 days after hospital admission. Moreover, the discrimination of scores based only on laboratory data was higher in surgical than in medical patients. CONCLUSION: in acutely ill medical patients a vital sign based score appears to predict mortality within 24h better than scores using laboratory data. This may be because in acutely ill patients vital sign changes indicate how well a patient is responding to a current insult. In contrast, for patients without acute illness laboratory data may be a more valuable indication of the patient's capacity to respond to insults in the future. PMID- 26948821 TI - Prognostication of out-of-hospital cardiac arrest patients by 3-min end-tidal capnometry level in emergency department. AB - OBJECTIVE: To evaluate the role of initial ETCO2 value in prognostication of OHCA patients in an Asian-Chinese cohort. DESIGN: Prospective cohort study. SETTING: Emergency departments of two regional hospitals in a cluster of Hong Kong. PATIENTS: Patients were recruited prospectively from the local cardiac arrest registry from July 2012 to June 2013. Patients of non traumatic OHCA aged >=18 years old were included. Patients of OHCA presented with postmortem changes, those who decided for Do Not Resuscitate (DNR), regained pulse before arrival, or those without proper documentation of ETCO2 would be excluded. OUTCOME: Primary outcome was return of spontaneous circulation (ROSC). RESULTS: A 3-min ETCO2 >10mmHg was a predictor of ROSC with OR 18.16 (95% CI 4.79-51.32, p<0.001). The diagnostic accuracy of 3-min ETCO2 >10mmHg to predict ROSC: sensitivity was 0.95 (95% CI 0.89-0.98) while the specificity was 0.27 (95% CI 0.21-0.33). Positive predictive value was 0.40 (95% CI 0.34-0.46) while negative predictive value (NPV) was 0.92 (95% CI 0.82-0.97). Area under ROC curve of 3-min ETCO2 predicting ROSC was 0.80 (95% CI 0.71-0.91). CONCLUSIONS: A 3-min ETCO2 <=10mmHg was associated with poor prognosis and low chance of ROSC. Low ETCO2 level may have a role to reduce prolonged medically futile resuscitation. PMID- 26948822 TI - ECPR: Are we ready for primetime? PMID- 26948824 TI - Evidence for a delay in diagnosis of Wilms' tumour in the UK compared with Germany: implications for primary care for children. AB - The UK has a longstanding system of general practice which provides the vast majority of primary care, including that for children. It acts as a 'gatekeeper' to more specialist care. Parents may also use accident and emergency departments as their first point of medical contact for their children. Outcomes in the UK for many conditions in children appear to be worse than in comparable European countries where there is direct access to care by paediatricians. We have therefore looked at pathways to diagnosis and compared outcomes in the childhood kidney cancer, Wilms' tumour, which has been treated in the UK and Germany within the same clinical trial for over a decade. We find that Wilms' tumours are significantly larger in volume and have a more advanced tumour stage at diagnosis in the UK compared to Germany. There is a small (~3%) difference in event free and overall survival between the two countries. Our data suggest that the system of primary care for children in the UK is less likely to result in the incidental finding of an abdominal mass in a child with no or vague symptoms. This may be a reason for the poorer outcome. PMID- 26948823 TI - The UK Paediatric Familial Hypercholesterolaemia Register: preliminary data. AB - BACKGROUND: The National Institute for Health and Care Excellence 2008 guidelines on the treatment and management of familial hypercholesterolaemia (FH) recommend that children with FH should be considered for statin treatment by the age of 10 years. The Paediatric FH Register was established in 2012 to collect baseline and long-term follow-up data on all children with FH in the UK. METHODS: Paediatricians and adult lipidologists have been invited to enter baseline data on any child with a clinical diagnosis of FH using an electronic capture record. RESULTS: Baseline data is on 232 children (50% boys, 80% Caucasian), with an untreated mean (SD) total cholesterol of 7.61 (1.48) mmol/L and low-density lipoprotein cholesterol (LDL-C) of 5.67 (1.46) mmol/L. Overall 111/232 (47.8%) of the children were on statins. Children over the age of 10 years at the most recent follow-up were twice as likely to be on statin treatment than those under 10 years (57.6% (102/177) vs 23.1% (9/39), p=0.00009). In both age groups, those subsequently on statin treatment had significantly higher diagnostic total and LDL-C (overall 6.01 (1.46) mmol/L vs 5.31 (1.37) mmol/L, p=0.00007), and had stronger evidence of a family history of early coronary heart disease (CHD) in parent or first-degree relative (overall 28.4% vs 19.0%, p=0.09). In statin treated children LDL-C level was reduced by 35% (2.07 (1.38) mmol/L) compared with a reduction of 5.5% (0.29 (0.87) mmol/L), p=0.0001 in those not treated. None of those on statin had measured plasma levels of creatine kinase, alanine aminotransferase and AST indicative of statin toxicity (ie, >2.5 times the upper limit of the normal range). CONCLUSIONS: The data indicates that treatment decisions in children with FH are appropriately based on a stronger family history of CHD and higher LDL-C. PMID- 26948825 TI - Editorial overview: Nucleic acids and their protein complexes. PMID- 26948826 TI - Call for quality epilepsy neuroimaging-An illustrative case of missed epileptic substrate. PMID- 26948827 TI - [Gestational diabetes mellitus]. AB - While the prevalence of gestational diabetes mellitus (GDM) was estimated between 5 and 10% in 2010, the application of new thresholds recommended by IADPSG and adopted in 2010 by CNGOF seems to significantly increase the number of patients affected by this pathology. A prospective single-center French study estimated in 2014 the prevalence of gestational diabetes at 14% with these criteria, making it one of the most frequent complications during pregnancy. However, to date, there is no published study using these criteria to show a benefit to the health of women and children. If a diagnosis of GDM or type 2 diabetes during pregnancy is definitively an important risk factor for maternal as well as newborn and child complications, it is probably not the case for moderate hyperglycemia discovered during pregnancy. PMID- 26948828 TI - Downregulation of human paraoxonase 1 (PON1) by organophosphate pesticides in HepG2 cells. AB - Paraoxonase 1 (PON1) is a calcium-dependent esterase synthesized primarily in the liver and secreted into the plasma where it is associated with high-density lipoproteins (HDL). PON1 hydrolyzes and detoxifies some toxic metabolites of organophosphorus compounds (OPs) such as methyl parathion and chlorpyrifos. Thus, PON1 activity and expression levels are important for determining susceptibility against OPs poisoning. Some studies have demonstrated that OPs can modulate gene expression through interactions with nuclear receptors. In this study, we evaluated the effects of methyl parathion and chlorpyrifos on the modulation of PON1 in Human Hepatocellular Carcinoma (HepG2) cells by real-time PCR, PON1 activity assay, and western blot. The results showed that the treatments with methyl parathion and chlorpyrifos decreased PON1 mRNA and immunoreactive protein and increased inflammatory cytokines in HepG2 cells. The effects of methyl parathion and chlorpyrifos on the downregulation of PON1 gene expression in HepG2 cells may provide evidence of OPs cytotoxicity related to oxidative stress and an inflammatory response. A decrease in the expression of the PON1 gene may increase the susceptibility to OPs intoxication and the risk of diseases related to inflammation and oxidative stress. (c) 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 490-500, 2017. PMID- 26948829 TI - Absence of Exceptional Points in Square Waveguide Arrays with Apparently Balanced Gain and Loss. AB - The concept of parity-time (PT) symmetry in the field of optics has been intensively explored. This study shows the absence of exceptional points in a three-dimensional system composed of a square waveguide array with diagonally balanced gain/loss distribution. More specifically, we show that an array of four coupled waveguides supports eight fundamental propagation supermodes, four of which are singlet, and the other two pairs are double degenerated. It is found that the singlet states follow the routine PT phase transition; however, the double-degenerated modes never coalesce as the gain/loss-to-coupling strength level varies, showing no actual PT symmetry-derived behavior. This is evident in the phase rigidity which does not approach zero. The absence of exceptional points is ascribed to the coupling of non-symmetric supermodes formed in the diagonal waveguide pairs. Our results suggest comprehensive interplay between the mode pattern symmetry, the lattice symmetry, and the PT-symmetry, which should be carefully considered in PT-phenomena design in waveguide arrays. PMID- 26948830 TI - Determination of the effective dose of a novel oral formulation of sarolaner (SimparicaTM) for the treatment and month-long control of fleas and ticks on dogs. AB - Three laboratory studies were conducted to determine the appropriate dose of sarolaner, a novel isoxazoline, for the treatment and month-long control of infestations of fleas and ticks on dogs. In the first study, dogs were treated orally with sarolaner suspension formulations at 1.25, 2.5 or 5.0mg/kg, and infested with Dermacentor reticulatus, Rhipicephalus sanguineus ticks and with Ctenocephalides felis felis (cat flea) prior to treatment and then weekly for up to 8 weeks. Fleas and ticks were counted 48h after treatment and after each subsequent infestation at 24h for fleas and 48h for ticks. The lowest dose of sarolaner (1.25mg/kg) provided 100% efficacy against fleas from treatment through Day 35 and 98.4% at Day 56. This dose of sarolaner resulted in 99.7-100% control of both species of ticks through Day 28. In Study 2, dogs were dosed orally with placebo or sarolaner suspension formulations at 0.625, 1.25 or 2.5mg/kg and infested with Ixodes scapularis prior to treatment and weekly for 6 weeks, Amblyomma americanum (pretreatment and Day 26), Dermacentor variabilis (Day 33) and A. maculatum (Day 41). Ixodes scapularis was the most susceptible; the lowest dose (0.625mg/kg) providing>95% efficacy through Day 43. Efficacy against D. variabilis on Day 35 was>95% at 1.25 and 2.5mg/kg, whereas the 0.625mg/kg dose gave only 61.4% efficacy. Amblyomma spp. were the least susceptible ticks; efficacy of the 1.25mg/kg dose at Day 28 for A. americanum was markedly lower (88.5%) than achieved for D. reticulatus (100%) at Day 28 and also lower than for D. variabilis at Day 35 (96.2%). In Study 3, dogs were dosed orally with placebo or sarolaner in the proposed commercial tablet (SimparicaTM) at 1.0, 2.0 or 4.0mg/kg, and infested with A. maculatum, one of the ticks determined to be dose limiting, prior to treatment and then weekly for 5 weeks. All doses gave 100% control of the existing infestation. The two highest dosages resulted in >93% control of subsequent challenges for 5 weeks. There was no significant improvement in efficacy provided by the 4.0 mg/kg dose over the 2.0mg/kg dose (P>0.05) at any time point. The 2.0mg/kg dose was superior to the 1.0mg/kg on Day 14 (P=0.0086) and as efficacy for 1.0mg/kg declined below 90% at Day 28, a single 1mg/kg dose would not provide a full month of tick control. Thus, 2.0mg/kg was selected as the sarolaner dose rate to provide flea and tick control for at least one month following a single oral treatment. PMID- 26948831 TI - A HHV-8 positive, HIV negative multicentric Castleman disease treated with R-CEOP chemotherapy and valganciclovir combination. AB - Multicentric Castleman disease (MCD) is a lymphoproliferative disorder characterized by systemic symptoms like recurrent lymphadenopathy, fever and hepatosplenomegaly. Human herpes virus 8 (HHV-8) can be associated with MCD whether the patient is infected with human immunodeficiency virus (HIV) or not. A 59-year-old male patient presented with fatigue, drowsiness and enlarged lymph nodes. Thoracic and abdominal computed tomography showed enlarged mediastinal, axillary, paracardiac, paraaortic, celiac, mesenteric, obturator and inguinal lymph nodes concomitant with enlarged liver and spleen. Cervical lymph node biopsy revealed HHV-8 positive plasma cell MCD. The patient's tests were negative for HIV. R-CEOP (rituximab, cyclophosphamide, etoposide, vincristin, prednisolone) and valganciclovir treatments were started simultaneously. After sixth cycle of R-CEOP, the patient achieved unconfirmed complete remission. Rituximab combined with CEOP protocol and antiviral therapy against HHV-8 might be an effective therapeutic approach without a considerable side effect for HHV-8 positive HIV-negative MCD patients. PMID- 26948832 TI - Rat-bite fever complicated by vertebral osteomyelitis: A case report. AB - Rat-bite fever (RBF) is a challenging diagnosis transmitted by the bite of the rats. We present the first reported case of RBF complicated by vertebral osteomyelitis. It is important to consider performing the MRI to differentiate vertebral osteomyelitis from simple back pain to determine the appropriate duration of antibiotic therapy. PMID- 26948833 TI - Biologically effective dose in fractionated molecular radiotherapy--application to treatment of neuroblastoma with (131)I-mIBG. AB - In this work, the biologically effective dose (BED) is investigated for fractionated molecular radiotherapy (MRT). A formula for the Lea-Catcheside G factor is derived which takes the possibility of combinations of sub-lethal damage due to radiation from different administrations of activity into account. In contrast to the previous formula, the new G-factor has an explicit dependence on the time interval between administrations. The BED of tumour and liver is analysed in MRT of neuroblastoma with (131)I-mIBG, following a common two administration protocol with a mass-based activity prescription. A BED analysis is also made for modified schedules, when due to local regulations there is a maximum permitted activity for each administration. Modifications include both the simplistic approach of delivering this maximum permitted activity in each of the two administrations, and also the introduction of additional administrations while maintaining the protocol-prescribed total activity. For the cases studied with additional (i.e. more than two) administrations, BED of tumour and liver decreases at most 12% and 29%, respectively. The decrease in BED of the tumour is however modest compared to the two-administration schedule using the maximum permitted activity, where the decrease compared to the original schedule is 47%. PMID- 26948835 TI - Estimated GFR Trajectories of People Entering CKD Stage 4 and Subsequent Kidney Disease Outcomes and Mortality. AB - BACKGROUND: Estimated glomerular filtration rate (eGFR) trajectories of people entering chronic kidney disease (CKD) stage 4 and their associations with subsequent kidney disease outcomes or death are not known. STUDY DESIGN: Longitudinal observational cohort study. SETTING & PARTICIPANTS: 26,246 patients in the Veterans Affairs Healthcare System who entered CKD stage 4 in fiscal year 2008 followed up until October 2013. FACTORS: 5-year eGFR trajectories, demographic and health characteristics. OUTCOMES: Composite kidney disease outcome of kidney failure, dialysis therapy or transplantation, and death. RESULTS: Latent class group modeling and functional characterization suggest the presence of 3 distinct trajectory classes: class 1 (72%), consistent slow decline with absolute eGFR change of -2.45 (IQR, -3.89 to -1.16) mL/min/1.73m(2) per year; class 2 (18%), consistent fast decline and eGFR change of -8.60 (IQR, 11.29 to -6.66) mL/min/1.73m(2) per year; and class 3 (10%), early nondecline and late fast decline with eGFR change of -0.4mL/min/1.73m(2) per year in years 1 to 3 and -7.98 and -21.36mL/min/1.73m(2) per year in years 4 and 5, respectively. During 4.34 years of follow-up, 9,809 (37%) patients had the composite kidney disease outcome and 14,550 (55%) patients died. Compared to the referent group (trajectory class 1), HRs for 1-year risk for composite kidney disease outcome for trajectory classes 2 and 3 were 1.13 (95% CI, 1.05-1.22) and 0.67 (95% CI, 0.59-0.75), whereas HRs for 1-year risk for death for classes 2 and 3 were 1.17 (95% CI, 1.10-1.28) and 1.29 (95% CI, 1.18-1.42), respectively. The 1-year risk for composite kidney disease outcome was 32% and was 42% more likely than the risk for death in trajectory classes 1 and 2, respectively, whereas the risk for death was 67% more likely than the risk for composite kidney disease outcome in trajectory class 3. LIMITATIONS: Inclusion criteria and mostly male participants limit generalizability of study results. CONCLUSIONS: We characterized 3 different eGFR trajectory classes of people entering CKD stage 4. Our results suggest that the pattern of eGFR trajectory informs the risk for kidney disease outcomes and death. PMID- 26948834 TI - Clinical Use of the Urine Biomarker [TIMP-2] * [IGFBP7] for Acute Kidney Injury Risk Assessment. AB - Acute kidney injury (AKI) is a serious complication, commonly occurring in the critically ill population, with devastating short- and long-term consequences. Despite standardization of the definition and staging of AKI, early recognition remains challenging given that serum creatinine level is a marker, albeit imperfect, of kidney function and not kidney injury. Furthermore, the delay in increase in serum creatinine level after loss of glomerular filtration also prevents timely detection of decreased kidney function in patients with AKI. During the past decade, numerous clinical investigations have evaluated the utility of several biomarkers in the early diagnosis and risk stratification of AKI. In 2014, the US Food and Drug Administration approved the marketing of a test based on the combination of urine concentrations of tissue inhibitor of metalloproteinase 2 and insulin-like growth factor binding protein 7 ([TIMP-2] * [IGFBP7]) to determine whether certain critically ill patients are at risk for developing moderate to severe AKI. The optimal role of this biomarker in the diagnosis, management, and prognosis of AKI in different clinical settings requires further clarification. In this perspective, we summarize the biological actions of these 2 cell-cycle arrest biomarkers and present important considerations regarding the clinical application, interpretation, and limitations of this novel test for the early detection of AKI. PMID- 26948836 TI - Tribological characteristics of few-layer graphene over Ni grain and interface boundaries. AB - The tribological properties of metal-supported few-layered graphene depend strongly on the grain topology of the metal substrate. Inhomogeneous distribution of graphene layers at such regions led to variable landscapes with distinguishable roughness. This discrepancy in morphology significantly affects the frictional and wetting characteristics of the FLG system. We discretely measured friction characteristics of FLG covering grains and interfacial grain boundaries of polycrystalline Ni metal substrate via an atomic force microscopy (AFM) probe. The friction coefficient of FLG covered at interfacial grain boundaries is found to be lower than that on grains in vacuum (at 10(-5) Torr pressure) and similar results were obtained in air condition. Sliding history with AFM cantilever, static and dynamic pull-in and pull-off adhesion forces were addressed in the course of friction measurements to explain the role of the out of-plane deformation of graphene layer(s). Finite element simulations showed good agreement with experiments and led to a rationalization of the observations. Thus, with interfacial grain boundaries the FLG tribology can be effectively tuned. PMID- 26948837 TI - [Clinical outcome after discontinuation of infliximab in patients with ulcerative colitis in deep remission]. AB - INTRODUCTION: Infliximab (IFX) is effective in treating ulcerative colitis (UC) and in achieving mucosal healing (MH). Little is known about the role of mucosal healing (MH) in the subsequent evolution of the disease and the consequences of discontinuing treatment. AIMS: To evaluate the characteristics and evolution of patients with UC treated with IFX who discontinued treatment after disease remission. METHODS: Observational, prospective study of patients with moderate to severe UC, corticosteroid-resistant/corticosteroid-dependent, naive to anti-TNF. IFX administration regimen: 5 mg/kg at 0-2-6 weeks and every 8 weeks thereafter until week 54. In patients achieving MH, IFX was discontinued and the patients were followed-up for at least 20 months. Clinical remission (CR): mayo score <2; Clinical response: decrease in mayo score of 3 points; MH: mayo score 0-1; Deep remission: patient with CR and MH. RESULTS: Of the 21 patients enrolled, 19 completed the study (colectomy, n = 1; non-responder, n = 1). Mean age: 47.8 years. UC: severe (n = 13) and moderate (n = 6); most patients (n = 11) were steroid-resistant; 57.8% received combined treatment with immunosuppressants, and 31.5% intensified treatment. Week 54: 16 patients (84.2%) showed clinical response, 13 (68.4%) showed CR, and 12 (63.2%) deep remission. Of these, 6 (25%) presented a new episode of UC, and in 3 (25%) IFX was restarted within 12 weeks of discontinuation, with all patients responding. Of the total sample, 91.7% remained IFX-free at week 8, and 75% at week 12, with no remission during follow up. None of the patients required hospitalization or surgery. CONCLUSIONS: Half of patients with deep remission of UC with IFX therapy presented a new episode after treatment discontinuation, and in 25% IFX therapy was restarted. PMID- 26948838 TI - Efficacy and safety of vedolizumab in the treatment of ulcerative colitis. AB - Integrins play a crucial role in the development and maintenance of the inflammatory process in patients with inflammatory bowel disease. Vedolizumab is a humanized monoclonal antibody with a predominantly gastrointestinal effect. It specifically inhibits leukocyte integrin alpha4beta7, thus preventing its interaction with mucosal vascular addressin cell adhesion molecule 1(MAdCAM-1), which is involved in the migration of lymphocytes from the blood stream to the intestinal tissue. Vedolizumab is indicated in the treatment of moderate to severe active Crohn's disease and ulcerative colitis in adult patients with poor response, loss of response, or intolerance to conventional treatment or to tumour necrosis factor alpha (TNF-alpha) antagonists. This review presents the most relevant clinical outcomes of vedolizumab in the treatment of patients with ulcerative colitis. PMID- 26948841 TI - Low Voltage Transmission Electron Microscopy of Graphene. PMID- 26948844 TI - RGD-mimic polyamidoamine-montmorillonite composites with tunable stiffness as scaffolds for bone tissue-engineering applications. AB - This paper reports on the development of montmorillonite (MMT)-reinforced hydrogels, based on a peptidomimetic polyamidoamine carrying guanidine pendants (AGMA1), as substrates for the osteo-induction of osteoblast precursor cells. AGMA1 hydrogels of various degrees of crosslinking responded favourably to MMT reinforcement, giving rise to composite hydrogels with shear storage modulus G', when fully swollen in water, up to 200 kPa, i.e. 20 times higher than the virgin hydrogels and of the same order or higher than other hydrogel-based composites proposed for orthopaedic applications. This significant improvement was ascribed to the effective interpenetration between the polymer matrix and the inorganic filler. AGMA1-MMT hydrogels, when evaluated as scaffolds for the osteogenic differentiation of mouse calvaria-derived pre-osteoblastic MC3T3-E1 cells, proved able to support cell adhesion and proliferation and clearly induced differentiation towards the osteoblastic phenotype, as indicated by different markers. In addition, AGMA1-MMT hydrogels proved completely degradable in aqueous media at pH 7.4 and did not provide any evidence of cytotoxicity. The experimental evidence suggests that AGMA1-MMT composites definitely warrant potential as scaffolds for osteoblast culture and bone grafts. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26948845 TI - Antifungal activity, kinetics and molecular mechanism of action of garlic oil against Candida albicans. AB - The antifungal activity, kinetics, and molecular mechanism of action of garlic oil against Candida albicans were investigated in this study using multiple methods. Using the poisoned food technique, we determined that the minimum inhibitory concentration of garlic oil was 0.35 MUg/mL. Observation by transmission electron microscopy indicated that garlic oil could penetrate the cellular membrane of C. albicans as well as the membranes of organelles such as the mitochondria, resulting in organelle destruction and ultimately cell death. RNA sequencing analysis showed that garlic oil induced differential expression of critical genes including those involved in oxidation-reduction processes, pathogenesis, and cellular response to drugs and starvation. Moreover, the differentially expressed genes were mainly clustered in 19 KEGG pathways, representing vital cellular processes such as oxidative phosphorylation, the spliceosome, the cell cycle, and protein processing in the endoplasmic reticulum. In addition, four upregulated proteins selected after two-dimensional fluorescence difference in gel electrophoresis (2D-DIGE) analysis were identified with high probability by mass spectrometry as putative cytoplasmic adenylate kinase, pyruvate decarboxylase, hexokinase, and heat shock proteins. This is suggestive of a C. albicans stress responses to garlic oil treatment. On the other hand, a large number of proteins were downregulated, leading to significant disruption of the normal metabolism and physical functions of C. albicans. PMID- 26948846 TI - Is there a difference between various presentations of valproate for cognitive outcome after in utero exposure? PMID- 26948847 TI - Clobazam-induced pedal edema: "An unrecognized side effect of a common antiepileptic drug". PMID- 26948848 TI - L-Arginine-Triggered Self-Assembly of CeO2 Nanosheaths on Palladium Nanoparticles in Water. AB - Pd@CeO2 core-shell nanostructures with a tunable Pd core size, shape, and nanostructure as well as a tunable CeO2 sheath thickness were obtained by a biomolecule-assisted method. The synthetic process is simple and green, as it involves only the heating of a mixture of Ce(NO3 )3 , l-arginine, and preformed Pd seeds in water without additives. Importantly, the synthesis is free of thiol groups and halide ions, thus providing a possible solution to the problem of secondary pollution by Pd nanoparticles in the sheath-coating process. The Pd/CeO2 nanostructures can be composited well with gamma-Al2 O3 to create a heterogeneous catalyst. In subsequent tests of catalytic NO reduction by CO, Pd@CeO2 /Al2 O3 samples based on Pd cubes (6, 10, and 18 nm), Pd octahedra (6 nm), and Pd cuboctahedra (9 nm) as well as a simply loaded Pd cube (6 nm)-CeO2 /Al2 O3 sample were used as catalysts to investigate the effects of the Pd core size and shape and the hybrid nanostructure on the catalytic performance. PMID- 26948849 TI - An increased prevalence of self-reported allergic rhinitis in major Chinese cities from 2005 to 2011. AB - BACKGROUND: The prevalence of allergic rhinitis (AR) has increased worldwide in recent decades. This study was conducted to investigate the prevalence of self reported AR and profiles of AR-related comorbidities in the adult population of China over time. METHODS: This study surveyed residents of 18 major cities in mainland China. Telephone interviews were conducted with study participants after sampling target telephone numbers by random digit dialing. The questions asked during telephone interviews were based on those included in validated questionnaires and focused on topics regarding AR, nonallergic rhinitis (NAR), acute/chronic rhinosinusitis (ARS/CRS), asthma, and atopic dermatitis (AD). RESULTS: During 2011, a total of 47 216 telephone interviews were conducted, and the overall response rate was 77.5%. When compared with the AR prevalence in 11 cities surveyed in 2005, there was a significant increase in self-reported adult AR in eight of those cities (P < 0.01). In 2011, the standardized prevalence of self-reported adult AR in the 18 cities was 17.6%. The concentration of SO2 was positively correlated with the prevalence of AR (r = 0.504, P = 0.033). A multiple regression model showed that the absolute change in household yearly income was significantly associated with the change in the prevalence of AR (R(2) = 0.68), after adjusting for PM10 , SO2 , NO2, temperature, and humidity. The overall prevalences of NAR, ARS, CRS, asthma, and AD in the general population were 16.4%, 5.4%, 2.1%, 5.8%, and 14%, respectively. CONCLUSION: During a 6-year period, there was a significant increase in the prevalence of self-reported AR in the general Chinese adult population. The incidence of AR being accompanied by rhinosinusitis, asthma, or AD was significantly higher among individuals having self-reported AR compared with the general population. PMID- 26948850 TI - A Prospective Investigation of Prenatal Mood and Childbirth Perceptions in an Ethnically Diverse, Low-Income Sample. AB - INTRODUCTION: Few studies have examined prenatal mood as a means to identify women at risk for negative childbirth experiences. We explore associations between prenatal mood and birth perceptions in a socioeconomically diverse, American sample. METHODS: We conducted a prospective study of 136 predominantly low-income and ethnic minority women of mixed parity. Prenatal measures of perceived stress, pregnancy-related anxiety, and depressive symptoms were used to predict maternal perceptions of birth experiences 1 month postpartum, using the childbirth experience questionnaire (CEQ; 1). RESULTS: After adjusting for sociodemographic variables and mode of delivery, higher third-trimester stress predicted worse CEQ total scores. This association was predominantly explained by two CEQ domains: own capacity (e.g., feelings of control and capability), and perceived safety. Pregnancy-related anxiety and depressive symptoms correlated with perceived stress, though neither independently predicted birth experience. An unplanned cesarean delivery was associated with a worse CEQ total score. Vaginal delivery predicted greater perceived safety. Altogether, sociodemographic covariates, mode of delivery, and prenatal mood accounted for 35 percent of the variance in birth experience (p < 0.001). DISCUSSION: Our finding that prenatal stress explains a significant and likely clinically meaningful proportion of the variance in birth experience suggests that women perceive and recall their birth experiences through a lens that is partially determined by preexisting personal circumstances and emotional reserves. Since childbirth perceptions have implications for maternal and child health, patient satisfaction, and health care expenditures, these findings warrant consideration of prenatal stress screening to target intervention for women at risk for negative birth experiences. PMID- 26948851 TI - Correction to Mercury Isotope Study of Sources and Exposure Pathways of Methylmercury in Estuarine Food Webs in the Northeastern U.S. PMID- 26948852 TI - Co-crystal formation based on structural matching. AB - A co-crystal is defined as a single crystalline structure composed of two or more components with no proton transfer which are solid at room temperature. Our group has come up with the following rationale selection of co-formers for initial co crystal screening: 1) selection of co-formers with the highest potential for hydrogen bonding with the API and 2) selection of co-formers with diversity of secondary structural characteristics. We demonstrate the feasibility of this technique with a Novartis drug candidate A. In the first tier, 20 co-formers were screened and two hits were identified. By examining the two co-formers, which worked from the first round, a second round of screening was undertaken with more focused chemical matter. Nineteen co-crystal formers closely related to the two hits in the first screen were screened in the second tier. From this screen five hits were identified. All the hits were compared for their physical and chemical stability and dissolution profile. Based on the comparison 4-aminobenzoic co crystal was chosen for in-vivo comparison with the free form. The co-crystal had 12 times higher exposure than the free form thus overcoming the solubility limited exposure. PMID- 26948853 TI - New IVIVE method for the prediction of total human clearance and relative elimination pathway contributions from in vitro hepatocyte and microsome data. AB - Total human clearance is a key determinant for the pharmacokinetic behavior of drug candidates. Our group recently introduced the Extended Clearance Model (ECM) as an accurate in vitro-in vivo extrapolation (IVIVE) method for the prediction of hepatic clearance. Yet, knowledge about relative elimination pathway contributions is needed in order to predict the total human clearance of drug candidates. In the present work, a training set of 18 drug compounds was used to describe the affiliations between in vitro sinusoidal uptake clearance and the fractional contributions of hepatic (metabolic and biliary) or renal clearance to overall in vivo elimination. By means of these quantitative relationships and using a validation set of 10 diverse drug molecules covering different (sub)classes of the Extended Clearance Concept Classification System (ECCCS), the relative contributions of elimination pathways were calculated and demonstrated to well correlate with human reference data. Likewise, ECM- and pathway-based predictions of total clearances from both data sets demonstrated a strong correlation with the observed clinical values with 26 out of 28 compounds within a three-fold deviation. Hence, total human clearance and relative contributions of elimination pathways were successfully predicted by the presented method using solely hepatocyte and microsome in vitro data. PMID- 26948854 TI - Bioregulators of stem and progenitor cells in preservation solution reduce cold ischemia-reperfusion injury of isolated rat livers. AB - The effects of bioregulators of stem and progenitor cells (BSPC) of fetal tissue cytosol on rat liver during 24h hypothermic storage (HS) and following normothermic reperfusion (NR) were investigated. It was shown that BSPC presence in the preservation medium stabilized pro-oxidant-antioxidant balance impaired in liver after HS and NR, prevented the uncoupling of mitochondrial oxidative phosphorylation and ATP level decline. These consequences led to significant improvement of hepatic morphological integrity and functional state. Powerful protective effect of BSPC on liver at sub-zero temperatures can serve as basis for new approaches to extend safe time for organ preservation and foster understanding of pathways of stem and progenitor cell paracrine action. (c) 2016 BioFactors, 42(3):287-295, 2016. PMID- 26948855 TI - Experimental and theoretical thermal equations of state of MgSiO3 post-perovskite at multi-megabar pressures. AB - The MgSiO3 post-perovskite phase is the most abundant silicate phase in a super Earth's mantle, although it only exists within the Earth's lowermost mantle. In this study, we established the thermal equation of state (EoS) of the MgSiO3 post perovskite phase, which were determined by using both laser-heated diamond anvil cell and density-functional theoretical techniques, within a multi-megabar pressure range, corresponding to the conditions of a super-Earth's mantle. The Keane and AP2 EoS models were adopted for the first time to extract meaningful physical properties. The experimentally determined Gruneisen parameter, which is one of the thermal EoS parameters, and its volume dependence were found to be consistent with their theoretically obtained values. This reduced the previously reported discrepancy observed between experiment and theory. Both the experimental and theoretical EoS were also found to be in very good agreement for volumes at pressures and temperatures of up to 300 GPa and 5000 K, respectively. Our newly developed EoS should be applicable to a super-Earth's mantle, as well as the Earth's core-mantle boundary region. PMID- 26948857 TI - A Preliminary Examination of Facts Up Front: Survey Results from Primary Shoppers and At-Risk Segments. PMID- 26948856 TI - Buprenorphine + naloxone plus naltrexone for the treatment of cocaine dependence: the Cocaine Use Reduction with Buprenorphine (CURB) study. AB - AIMS: To examine the safety and effectiveness of buprenorphine + naloxone sublingual tablets (BUP, as Suboxone((r)) ) provided after administration of extended-release injectable naltrexone (XR-NTX, as Vivitrol((r)) ) to reduce cocaine use in participants who met DSM-IV criteria for cocaine dependence and past or current opioid dependence or abuse. METHODS: This multi-centered, double blind, placebo-controlled study, conducted under the auspices of the National Drug Abuse Treatment Clinical Trials Network, randomly assigned 302 participants at sites in California, Oregon, Washington, Colorado, Texas, Georgia, Ohio, New York and Washington DC, USA to one of three conditions provided with XR-NTX: 4 mg/day BUP (BUP4, n = 100), 16 mg/day BUP (BUP16, n = 100, or no buprenorphine (placebo; PLB, n = 102). Participants received pharmacotherapy for 8 weeks, with three clinic visits per week. Cognitive behavioral therapy was provided weekly. Follow-up assessments occurred at 1 and 3 months post-intervention. The planned primary outcome was urine drug screen (UDS)-corrected, self-reported cocaine use during the last 4 weeks of treatment. Planned secondary analyses assessed cocaine use by UDS, medication adherence, retention and adverse events. RESULTS: No group differences were found between groups for the primary outcome (BUP4 versus PLB, P = 0.262; BUP16 versus PLB, P = 0.185). Longitudinal analysis of UDS data during the evaluation period using generalized linear mixed equations found a statistically significant difference between BUP16 and PLB [P = 0.022, odds ratio (OR) = 1.71] but not for BUP4 (P = 0.105, OR = 1.05). No secondary outcome differences across groups were found for adherence, retention or adverse events. CONCLUSIONS: Buprenorphine + naloxone, used in combination with naltrexone, may be associated with reductions in cocaine use among people who meet DSM-IV criteria for cocaine dependence and past or current opioid dependence or abuse. PMID- 26948858 TI - Cognitive benefits of memantine in Alzheimer's 5XFAD model mice decline during advanced disease stages. AB - Memantine, a noncompetitive NMDA receptor antagonist with neuroprotective properties, has been used for the treatment of Alzheimer's disease (AD). Administration of memantine to various transgenic AD mice has been reported to improve cognitive deficits, very often completely back to normal wild-type control levels. However, such great benefits of memantine in preclinical studies do not translate into clinical results of this drug, showing only marginal and transient efficacy in moderate to severe AD. To further address in vivo efficacy, we compared the effects of memantine at different disease stages in 5XFAD mice, one of the rapid-onset and most aggressive amyloid models. Specifically, we administered memantine once daily for 30 days to 5XFAD mice, which showed moderate (6-7 months of age) and robust (12-15 months) beta-amyloid (Abeta) accumulation. Treatments with memantine (10mg/kg, i.p.) reversed memory impairments in the younger 5XFAD mice, as tested by the contextual fear conditioning and spontaneous alternation Y-maze paradigms. Memantine had no effects on soluble Abeta oligomer or total Abeta42 levels in 5XFAD mouse brains. In contrast, subchronic treatments with memantine showed no behavioral benefits in the older 5XFAD group, which exhibited more profound memory deficits concomitant with highly increased concentrations of Abeta as compared with those of the younger 5XFAD group. Since subchronic memantine at the higher dose (30 mg/kg) impaired memory performances in wild-type controls, we further tested acute administration of 50mg/kg memantine, which was reported to enhance hippocampal adult neurogenesis and memory function. However, this treatment also failed to rescue memory deficits in 12-15-month-old 5XFAD mice. Collectively, our results demonstrate that cognitive benefits of memantine independent of Abeta reductions were no longer observed in the 5XFAD Alzheimer mouse model during advanced stages, which may be reflective of the limited efficacy of memantine in clinical settings. PMID- 26948859 TI - Valproic acid ameliorates olfactory dysfunction in APP/PS1 transgenic mice of Alzheimer's disease: Ameliorations from the olfactory epithelium to the olfactory bulb. AB - Olfactory dysfunction is a common and early symptom of many neurodegenerative diseases, particularly of Alzheimer's disease (AD) and mild cognitive impairment, pointing to the progression to dementia. Recent studies have revealed that valproic acid (VPA) has neuroprotective effects in rodent models of AD. In this study, we investigated the effects of VPA on olfactory dysfunction of APP/PS1 double transgenic mouse models of AD. After continuous treatment with a 100mg/kg daily dose of VPA for 3 months, APP/PS1 mice showed improved olfactory performances. In agreement with the behavioral findings, VPA treatment reduced amyloid beta (Abeta) burden in the olfactory epithelium (OE) of transgenic mice. And, VPA increased epithelial thickness of the olfactory mucosa through decreased cell apoptosis and increased cell proliferation. In the olfactory bulb (OB), VPA administration also reduced senile plaques and levels of soluble and insoluble Abeta42 peptides. Besides, VPA promoted the increase of mitral cells and decrease of neurofilament immunostaining. In hence, VPA treatment completely improved the olfactory performances and prevented degenerative changes of the OE and OB. Our study raises the possibility of AD diagnosis by OE biopsy. Moreover, VPA may provide a novel therapeutic strategy for the treatment of olfactory dysfunction in AD patients. PMID- 26948860 TI - Risk Factors for Development of Chronic Kidney Disease in Cats. AB - BACKGROUND: Identification of risk factors for development of chronic kidney disease (CKD) in cats may aid in its earlier detection. HYPOTHESIS/OBJECTIVES: Evaluation of clinical and questionnaire data will identify risk factors for development of azotemic CKD in cats. ANIMALS: One hundred and forty-eight client owned geriatric (>9 years) cats. METHODS: Cats were recruited into the study and followed longitudinally for a variable time. Owners were asked to complete a questionnaire regarding their pet at enrollment. Additional data regarding dental disease were obtained when available by development of a dental categorization system. Variables were explored in univariable and multivariable Cox regression models. RESULTS: In the final multivariable Cox regression model, annual/frequent vaccination (P value, .003; hazard ratio, 5.68; 95% confidence interval, 1.83 17.64), moderate dental disease (P value, .008; hazard ratio, 13.83; 95% confidence interval, 2.01-94.99), and severe dental disease (P value, .001; hazard ratio, 35.35; 95% confidence interval, 4.31-289.73) predicted development of azotemic CKD. CONCLUSION: Our study suggests independent associations between both vaccination frequency and severity of dental disease and development of CKD. Further studies to explore the pathophysiological mechanism of renal injury for these risk factors are warranted. PMID- 26948861 TI - Seminal Fluid and Mate Choice: New Predictions. AB - Recent evidence shows that seminal fluid can affect females and offspring independently of fertilisation in species lacking conventional 'nuptial gifts'. We argue that a hypothesis from paternal investment systems - that selection can favour changing female preferences that maximise both sperm-borne and seminal fluid-borne benefits - could therefore apply much more broadly. PMID- 26948862 TI - Ceftazidime-Avibactam: A Novel Cephalosporin/beta-Lactamase Inhibitor Combination for the Treatment of Resistant Gram-negative Organisms. AB - PURPOSE: Multidrug-resistant gram-negative bacterial infections have emerged as a major threat in hospitalized patients. Treatment options are often inadequate and, as a result, these infections are associated with high mortality. A cephalosporin and a novel synthetic non-beta-lactam, beta-lactamase inhibitor, ceftazidime-avibactam, is approved for the treatment of serious infections caused by resistant gram-negative bacteria. This article reviews the spectrum of activity, clinical pharmacology, pharmacodynamic and pharmacokinetic properties, clinical efficacy and tolerability, and dosing and administration of ceftazidime avibactam. METHODS: Searches of MEDLINE and International Pharmaceutical Abstracts from 1980 to September 2015 were conducted by using the search terms ceftazidime, avibactam, and ceftazidime-avibactam. Abstracts from Infectious Disease Week (2014-2015), the Interscience Conference on Antimicrobial Agents and Chemotherapy (2014-2015), and the European Congress of Clinical Microbiology and Infectious Diseases were also searched. FINDINGS: Ceftazidime, a third-generation cephalosporin, when combined with avibactam has a significant improvement in its activity against beta-lactamase-producing gram-negative pathogens, including extended-spectrum beta-lactamases, AmpC beta-lactamases, Klebsiella pneumoniae carbapenemase-producing Enterobacteriaceae, and multidrug-resistant Pseudomonas aeruginosa. Data from 2 Phase II and 1 Phase III clinical trial are available. In the Phase II trial of patients with complicated intra-abdominal infections, ceftazidime-avibactam produced clinical cure rates comparable to meropenem (91.2% vs 93.4%). Similarly, patients receiving ceftazidime-avibactam in a Phase II study of complicated urinary tract infections had clinical and microbiologic response rates similar to those receiving imipenem-cilastatin (70.4% and 71.4% microbiologic success rates, respectively). A Phase III trial compared ceftazidime-avibactam to best available therapy for the treatment of ceftazidime resistant organisms. Clinical response and microbiological response for ceftazidime-avibactam versus best available therapy was comparable (90.9% and 91.2% clinical response, respectively); (81.8% and 63.5% microbiological response, respectively). IMPLICATIONS: Currently, ceftazidime-avibactam is approved for the indications of complicated intra-abdominal infections (with metronidazole) and complicated urinary tract infections. Clinical trials published to date on this antimicrobial agent have shown its excellent safety and tolerability. This new combination agent has a role, but its use should be limited to patients without other treatment options in the empiric and documented treatment of multidrug-resistant gram-negative organisms. Further investigation is needed in patients with carbapenemase-producing Enterobacteriaceae and multidrug-resistant P aeruginosa who have bacteremia or nosocomial or ventilator associated pneumonia. It is imperative that ceftazidime-avibactam be used in a responsible manner so that its effectiveness can be retained. PMID- 26948863 TI - Sentinel lymph node biopsy for head and neck mucosal cancers - an update on the current evidence. AB - Regional metastases are a prominent feature of mucosal-associated head and neck squamous cell carcinomas and are an important prognostic factor. Sentinel lymph node biopsy (SLNB) is one modality that has potential to add to the accuracy of neck staging, although it is currently not used as widely in the head and neck as it is in other areas such as breast cancer. We review the efficacy of SLNB in head and neck mucosal squamous cell carcinomas and provide an overview of current practice and include details of technical advances. PMID- 26948864 TI - Ischemic Lesion Formation in Solitary Tract Nuclei During Central Sleep Apnea With Heart Failure. PMID- 26948865 TI - Ischemic Lesion Formation in Solitary Tract Nuclei During Central Sleep Apnea With Heart Failure - Reply - Adaptive Servo-Ventilation Therapy for Patients With Chronic Heart Failure in a Confirmatory, Multicenter, Randomized, Controlled Study. PMID- 26948866 TI - Ischemic Lesion Formation in Solitary Tract Nuclei During Central Sleep Apnea With Heart Failure - Reply. PMID- 26948867 TI - High Fibrinogen Plus Low Plasminogen Levels Predict Poor Post-Surgical Survival in Patients With Chronic Thromboembolic Pulmonary Hypertension. PMID- 26948870 TI - Paramedics' involvement in planned home birth: A one-year case study. AB - OBJECTIVE: to report findings from a study performed prior to the introduction of publicly funded home birth programmes in Victoria, Australia, that investigated the incidence of planned home births attended by paramedics and explored the clinical support they provided as well as the implications for education and practice. METHODS: retrospective data previously collected via an in-field electronic patient care record (VACIS((r))) was provided by a state-wide ambulance service. Cases were identified via a comprehensive filter, manually screened and analysed using SPSS version 19. RESULTS: over a 12-month period paramedics attended 26 intended home births. Eight women were transported in labour, most for failure to progress. Three called the ambulance service and their pre-organised midwife simultaneously. Paramedics were required for a range of complications including post partum haemorrhage, perineal tears and neonatal resuscitation. Procedures performed for mothers included IV therapy and administering pain relief. For infants, paramedics performed intermittent positive pressure ventilation, endotracheal intubation and external cardiac compression. Of the 23 women transferred to hospital, 22 were transported to hospital within 32minutes. CONCLUSIONS: findings highlight that paramedics can provide clinical support, as well as efficient transportation, during perinatal emergencies at planned home births. Cooperative collaboration between ambulance services, privately practising midwives and maternity services to develop guidelines for emergency clinical support and transportation service may minimise risk associated with planned home births. This could also lead to opportunities for interprofessional education between midwives and paramedics. PMID- 26948869 TI - The HMGB1 protein induces a metabolic type of tumour cell death by blocking aerobic respiration. AB - The high-mobility group box 1 (HMGB1) protein has a central role in immunological antitumour defense. Here we show that natural killer cell-derived HMGB1 directly eliminates cancer cells by triggering metabolic cell death. HMGB1 allosterically inhibits the tetrameric pyruvate kinase isoform M2, thus blocking glucose-driven aerobic respiration. This results in a rapid metabolic shift forcing cells to rely solely on glycolysis for the maintenance of energy production. Cancer cells can acquire resistance to HMGB1 by increasing glycolysis using the dimeric form of PKM2, and employing glutaminolysis. Consistently, we observe an increase in the expression of a key enzyme of glutaminolysis, malic enzyme 1, in advanced colon cancer. Moreover, pharmaceutical inhibition of glutaminolysis sensitizes tumour cells to HMGB1 providing a basis for a therapeutic strategy for treating cancer. PMID- 26948871 TI - Risk and fear in the lived experience of birth without a midwife. AB - PURPOSE: the broad aim of this study was to examine the lived-experience of women who birth without a midwife or other health-care professional in the United Kingdom; the specific purpose of this paper is to examine risk discourse as experienced by these women. RESEARCH DESIGN: reflective lifeworld research, a phenomenological approach was used in this study based on the philosophical writings of Husserl, Merleau-Ponty and Gadamer (Dahlberg et al., 2008). 10 in depth interviews were conducted with women who had birthed without a midwife or other health-care professional present, interviews were transcribed and hermeneutically analysed. FINDINGS: women's lived-experiences of the maternity services in this study suggest a pervading mood of fear which finds voice in manipulative risk discourse and midwifery behaviours that can result in women avoiding maternity care. Fear based 'risk-talk' is used as a scare tactic to coerce women into particular choices; if women do not comply they are labelled 'risk-takers' and can become ostracised by the maternity care system. KEY CONCLUSIONS: risk discourse and its emphasis on mortality and morbidity raises awareness of death and creates important existential concerns for women which are unaddressed by health-care professionals. This can lead to a loss of trust in health-care professionals and women sourcing positive support and a salutogenic approach to childbirth from outside the system. IMPLICATIONS FOR PRACTICE: health care professionals need to become aware of and address manipulative and coercive attitudes in risk discourse. PMID- 26948872 TI - Impact of substitution among generic drugs on persistence and adherence: A retrospective claims data study from 2 Local Healthcare Units in the Lombardy Region of Italy. AB - BACKGROUND: The use of generics, equivalent but less expensive drugs, is an important opportunity to reduce healthcare expenditure. METHODS: The purpose of this study was to investigate the effect of substitution between unbranded generics on persistence and adherence to therapy in two Italian Local Health Units (ASL) in real-world clinical practice in 5 therapeutic areas using tracing drugs. Substitution of generic drugs is any change in the name of the manufacturer of the generic drug. The therapeutic areas were: diabetes (metformin); hypertension (amlodipine); dyslipidemia (simvastatin); psychiatry (sertraline); cardiology (propafenone); osteoporosis (alendronate). The retrospective analysis was carried out on the administrative databases of two Local Healthcare Units (ASL - Azienda sanitaria locale Bergamo (BG) and Pavia (PV)) in the Lombardy Region of Italy. The correlation between persistence and adherence with the different cohorts of generic substitution frequency within each therapeutic area was then calculated. RESULTS: According to the inclusion criteria, 23,773 patients were evaluated. Patients were observed for a period of 36 months starting from the first drug delivery (index date). The median age of the overall population was above 61 years in all therapeutic areas. The generic drug substitution occurred in 61.5% of patients (BG: 57.6% and PV: 65.4% respectively); Hypertension was the therapeutic area with the highest percentage of patients with substitutions. Patients' adherence, evaluated by the Medical Possession Rate (MPR) and persistence to the treatment decreases with the increase in the frequency of generic substitutions. This observation was confirmed by a statistically significant negative correlation (p-value of <0.001) between the adherence and persistence and the number of generic substitutions in each therapeutic area and Local Healthcare Units (ASL). DISCUSSION: Adherence is one of the pillars of the patient's health management in the control and prevention of progression of the disease. Several factors, such as ageing, comorbidities, and polypharmacy, may affect adherence and influence the outcome of treatments. These results are in line with studies supporting the possibility that the change of package appearance each time a new prescription is dispensed may create confusion and ultimately reduce patients' adherence. Clinicians and decision makers should consider the impact of frequent generic substitutions on persistence and adherence, which may influence efficacy and/or safety. PMID- 26948873 TI - Identification of a Peptidergic Pathway Critical to Satiety Responses in Drosophila. AB - Although several neural pathways have been implicated in feeding behaviors in mammals [1-7], it remains unclear how the brain coordinates feeding motivations to maintain a constant body weight (BW). Here, we identified a neuropeptide pathway important for the satiety and BW control in Drosophila. Silencing of myoinhibitory peptide (MIP) neurons significantly increased BW through augmented food intake and fat storage. Likewise, the loss-of-function mutation of mip also increased feeding and BW. Suppressing the MIP pathway induced satiated flies to behave like starved ones, with elevated sensitivity toward food. Conversely, activating MIP neurons greatly decreased food intake and BW and markedly blunted the sensitivity of starved flies toward food. Upon terminating the activation protocol of MIP neurons, the decreased BW reverts rapidly to the normal level through a strong feeding rebound, indicating the switch-like role of MIP pathway in feeding. Surprisingly, the MIP-mediated BW decrease occurred independently of sex peptide receptor (SPR), the only known receptor for MIP, suggesting the presence of a yet-unknown MIP receptor. Together, our results reveal a novel anorexigenic pathway that controls satiety in Drosophila and provide a new avenue to study how the brain actively maintains a constant BW. PMID- 26948874 TI - The Conserved VPS-50 Protein Functions in Dense-Core Vesicle Maturation and Acidification and Controls Animal Behavior. AB - The modification of behavior in response to experience is crucial for animals to adapt to environmental changes. Although factors such as neuropeptides and hormones are known to function in the switch between alternative behavioral states, the mechanisms by which these factors transduce, store, retrieve, and integrate environmental signals to regulate behavior are poorly understood. The rate of locomotion of the nematode Caenorhabditis elegans depends on both current and past food availability. Specifically, C. elegans slows its locomotion when it encounters food, and animals in a food-deprived state slow even more than animals in a well-fed state. The slowing responses of well-fed and food-deprived animals in the presence of food represent distinct behavioral states, as they are controlled by different sets of genes, neurotransmitters, and neurons. Here we describe an evolutionarily conserved C. elegans protein, VPS-50, that is required for animals to assume the well-fed behavioral state. Both VPS-50 and its murine homolog mVPS50 are expressed in neurons, are associated with synaptic and dense core vesicles, and control vesicle acidification and hence synaptic function, likely through regulation of the assembly of the V-ATPase complex. We propose that dense-core vesicle acidification controlled by the evolutionarily conserved protein VPS-50/mVPS50 affects behavioral state by modulating neuropeptide levels and presynaptic neuronal function in both C. elegans and mammals. PMID- 26948875 TI - The Initiator Methionine tRNA Drives Secretion of Type II Collagen from Stromal Fibroblasts to Promote Tumor Growth and Angiogenesis. AB - Expression of the initiator methionine tRNA (tRNAi(Met)) is deregulated in cancer. Despite this fact, it is not currently known how tRNAi(Met) expression levels influence tumor progression. We have found that tRNAi(Met) expression is increased in carcinoma-associated fibroblasts, implicating deregulated expression of tRNAi(Met) in the tumor stroma as a possible contributor to tumor progression. To investigate how elevated stromal tRNAi(Met) contributes to tumor progression, we generated a mouse expressing additional copies of the tRNAi(Met) gene (2+tRNAi(Met) mouse). Growth and vascularization of subcutaneous tumor allografts was enhanced in 2+tRNAi(Met) mice compared with wild-type littermate controls. Extracellular matrix (ECM) deposited by fibroblasts from 2+tRNAi(Met) mice supported enhanced endothelial cell and fibroblast migration. SILAC mass spectrometry indicated that elevated expression of tRNAi(Met) significantly increased synthesis and secretion of certain types of collagen, in particular type II collagen. Suppression of type II collagen opposed the ability of tRNAi(Met)-overexpressing fibroblasts to deposit pro-migratory ECM. We used the prolyl hydroxylase inhibitor ethyl-3,4-dihydroxybenzoate (DHB) to determine whether collagen synthesis contributes to the tRNAi(Met)-driven pro-tumorigenic stroma in vivo. DHB had no effect on the growth of syngeneic allografts in wild type mice but opposed the ability of 2+tRNAi(Met) mice to support increased angiogenesis and tumor growth. Finally, collagen II expression predicts poor prognosis in high-grade serous ovarian carcinoma. Taken together, these data indicate that increased tRNAi(Met) levels contribute to tumor progression by enhancing the ability of stromal fibroblasts to synthesize and secrete a type II collagen-rich ECM that supports endothelial cell migration and angiogenesis. PMID- 26948876 TI - Kinesin-Binding Protein Controls Microtubule Dynamics and Cargo Trafficking by Regulating Kinesin Motor Activity. AB - Kinesin motor proteins play a fundamental role for normal neuronal development by controlling intracellular cargo transport and microtubule (MT) cytoskeleton organization. Regulating kinesin activity is important to ensure their proper functioning, and their misregulation often leads to severe human neurological disorders. Homozygous nonsense mutations in kinesin-binding protein (KBP)/KIAA1279 cause the neurological disorder Goldberg-Shprintzen syndrome (GOSHS), which is characterized by intellectual disability, microcephaly, and axonal neuropathy. Here, we show that KBP regulates kinesin activity by interacting with the motor domains of a specific subset of kinesins to prevent their association with the MT cytoskeleton. The KBP-interacting kinesins include cargo-transporting motors such as kinesin-3/KIF1A and MT-depolymerizing motor kinesin-8/KIF18A. We found that KBP blocks KIF1A/UNC-104-mediated synaptic vesicle transport in cultured hippocampal neurons and in C. elegans PVD sensory neurons. In contrast, depletion of KBP results in the accumulation of KIF1A motors and synaptic vesicles in the axonal growth cone. We also show that KBP regulates neuronal MT dynamics by controlling KIF18A activity. Our data suggest that KBP functions as a kinesin inhibitor that modulates MT-based cargo motility and depolymerizing activity of a subset of kinesin motors. We propose that misregulation of KBP-controlled kinesin motors may represent the underlying molecular mechanism that contributes to the neuropathological defects observed in GOSHS patients. PMID- 26948877 TI - Neural Summation in the Hawkmoth Visual System Extends the Limits of Vision in Dim Light. AB - Most of the world's animals are active in dim light and depend on good vision for the tasks of daily life. Many have evolved visual adaptations that permit a performance superior to that of manmade imaging devices [1]. In insects, a major model visual system, nocturnal species show impressive visual abilities ranging from flight control [2, 3], to color discrimination [4, 5], to navigation using visual landmarks [6-8] or dim celestial compass cues [9, 10]. In addition to optical adaptations that improve their sensitivity in dim light [11], neural summation of light in space and time-which enhances the coarser and slower features of the scene at the expense of noisier finer and faster features-has been suggested to improve sensitivity in theoretical [12-14], anatomical [15-17], and behavioral [18-20] studies. How these summation strategies function neurally is, however, presently unknown. Here, we quantified spatial and temporal summation in the motion vision pathway of a nocturnal hawkmoth. We show that spatial and temporal summation combine supralinearly to substantially increase contrast sensitivity and visual information rate over four decades of light intensity, enabling hawkmoths to see at light levels 100 times dimmer than without summation. Our results reveal how visual motion is calculated neurally in dim light and how spatial and temporal summation improve sensitivity while simultaneously maximizing spatial and temporal resolution, thus extending models of insect motion vision derived predominantly from diurnal flies. Moreover, the summation strategies we have revealed may benefit manmade vision systems optimized for variable light levels [21]. PMID- 26948878 TI - A Causal Gene for Seed Dormancy on Wheat Chromosome 4A Encodes a MAP Kinase Kinase. AB - Seed germination under the appropriate environmental conditions is important both for plant species survival and for successful agriculture. Seed dormancy, which controls germination time, is one of the adaptation mechanisms and domestication traits [1]. Seed dormancy is generally defined as the absence of germination of a viable seed under conditions that are favorable for germination [2]. The seed dormancy of cultivated plants has generally been reduced during domestication [3]. Bread wheat (Triticum aestivum L.) is one of the most widely grown crops in the world. Weak dormancy may be an advantage for the productivity due to uniform emergence and a disadvantage for the risks of pre-harvest sprouting (PHS), which decreases grain quality and yield [4]. A number of quantitative trait loci (QTLs) controlling natural variation of seed dormancy have been identified on various chromosomes [5]. A major QTL for seed dormancy has been consistently detected on chromosome 4A [6-13]. The QTL was designated as a major gene, Phs1, which could be precisely mapped within a 2.6 cM region [14]. Here, we identified a mitogen activated protein kinase kinase 3 (MKK3) gene (designated TaMKK3-A) by a map based approach as a candidate gene for the seed dormancy locus Phs1 on chromosome 4A in bread wheat. Complementation analysis showed that transformation of a dormant wheat cultivar with the TaMKK3-A allele from a nondormant cultivar clearly reduced seed dormancy. Cultivars differing in dormancy had a single nonsynonymous amino acid substitution in the kinase domain of the predicted MKK3 protein sequence, which may be associated with the length of seed dormancy. PMID- 26948880 TI - Mitogen-Activated Protein Kinase Kinase 3 Regulates Seed Dormancy in Barley. AB - Seed dormancy has fundamental importance in plant survival and crop production; however, the mechanisms regulating dormancy remain unclear [1-3]. Seed dormancy levels generally decrease during domestication to ensure that crops successfully germinate in the field. However, reduction of seed dormancy can cause devastating losses in cereals like wheat (Triticum aestivum L.) and barley (Hordeum vulgare L.) due to pre-harvest sprouting, the germination of mature seed (grain) on the mother plant when rain occurs before harvest. Understanding the mechanisms of dormancy can facilitate breeding of crop varieties with the appropriate levels of seed dormancy [4-8]. Barley is a model crop [9, 10] and has two major seed dormancy quantitative trait loci (QTLs), SD1 and SD2, on chromosome 5H [11-19]. We detected a QTL designated Qsd2-AK at SD2 as the single major determinant explaining the difference in seed dormancy between the dormant cultivar "Azumamugi" (Az) and the non-dormant cultivar "Kanto Nakate Gold" (KNG). Using map-based cloning, we identified the causal gene for Qsd2-AK as Mitogen-activated Protein Kinase Kinase 3 (MKK3). The dormant Az allele of MKK3 is recessive; the N260T substitution in this allele decreases MKK3 kinase activity and appears to be causal for Qsd2-AK. The N260T substitution occurred in the immediate ancestor allele of the dormant allele, and the established dormant allele became prevalent in barley cultivars grown in East Asia, where the rainy season and harvest season often overlap. Our findings show fine-tuning of seed dormancy during domestication and provide key information for improving pre-harvest sprouting tolerance in barley and wheat. PMID- 26948879 TI - The Mother Centriole Appendage Protein Cenexin Modulates Lumen Formation through Spindle Orientation. AB - Establishing apical-basal polarity is instrumental in the functional shaping of a solitary lumen within an acinus. By exploiting micropatterned slides, wound healing assays, and three-dimensional culture systems, we identified a mother centriole subdistal appendage protein, cenexin, as a critical player in symmetric lumen expansion through the control of microtubule organization. In this regard, cenexin was required for both centrosome positioning in interphase cells and proper spindle orientation during mitosis. In contrast, the essential mother centriole distal appendage protein CEP164 did not play a role in either process, demonstrating the specificity of subdistal appendages for these events. Importantly, upon closer examination we found that cenexin depletion decreased astral microtubule length, disrupted astral microtubule minus-end organization, and increased levels of the polarity protein NuMA at the cell cortex. Interestingly, spindle misorientation and NuMA mislocalization were reversed by treatment with a low dose of the microtubule-stabilizing agent paclitaxel. Taken together, these results suggest that cenexin modulates microtubule organization and stability to mediate spindle orientation. PMID- 26948881 TI - Behavioral and Neural Mechanisms of Overgeneralization in Anxiety. AB - Overgeneralization of dangerous stimuli is a possible etiological account for anxiety disorders, yet the underlying behavioral and neural origins remain vague. Specifically, it is unclear whether this is a choice behavior in an unsafe environment ("better safe than sorry") or also a fundamental change in how the stimulus is perceived. We show that anxiety patients have wider generalization for loss-conditioned tone when compared to controls and do so even in a safe context that requires a different behavioral policy. Moreover, patients overgeneralized for gain-conditioned tone as well. Imaging (fMRI) revealed that in anxiety only, activations during conditioning in the dACC and the putamen were correlated with later overgeneralization of loss and gain, respectively, whereas valence distinction in the amygdala and hippocampus during conditioning mediated the difference between loss and gain generalization. During generalization itself, neural discrimination based on multivoxel patterns in auditory cortex and amygdala revealed specific stimulus-related plasticity. Our results suggest that overgeneralization in anxiety has perceptual origins and involves affective modulation of stimulus representations in primary cortices and amygdala. PMID- 26948882 TI - Genetic Exchange among Bdelloid Rotifers Is More Likely Due to Horizontal Gene Transfer Than to Meiotic Sex. AB - Although strict asexuality is supposed to be an evolutionary dead end, morphological, cytogenetic, and genomic data suggest that bdelloid rotifers, a clade of microscopic animals, have persisted and diversified for more than 60 Myr in an ameiotic fashion. Moreover, the genome of bdelloids of the genus Adineta comprises 8%-10% of genes of putative non-metazoan origin, indicating that horizontal gene transfers are frequent within this group and suggesting that this mechanism may also promote genetic exchanges among bdelloids as well. To test this hypothesis, we used five independent sequence markers to study the genetic diversity of 576 Adineta vaga individuals from a park in Belgium. Haplowebs and GMYC analyses revealed the existence of six species among our sampled A. vaga individuals, with strong evidence of both intra- and interspecific recombination. Comparison of genomic regions of three allele-sharing individuals further revealed signatures of genetic exchanges scattered among regions evolving asexually. Our findings suggest that bdelloids evolve asexually but exchange DNA horizontally both within and between species. PMID- 26948883 TI - Learning and Recognition of a Non-conscious Sequence of Events in Human Primary Visual Cortex. AB - Human primary visual cortex (V1) has long been associated with learning simple low-level visual discriminations [1] and is classically considered outside of neural systems that support high-level cognitive behavior in contexts that differ from the original conditions of learning, such as recognition memory [2, 3]. Here, we used a novel fMRI-based dichoptic masking protocol-designed to induce activity in V1, without modulation from visual awareness-to test whether human V1 is implicated in human observers rapidly learning and then later (15-20 min) recognizing a non-conscious and complex (second-order) visuospatial sequence. Learning was associated with a change in V1 activity, as part of a temporo occipital and basal ganglia network, which is at variance with the cortico cerebellar network identified in prior studies of "implicit" sequence learning that involved motor responses and visible stimuli (e.g., [4]). Recognition memory was associated with V1 activity, as part of a temporo-occipital network involving the hippocampus, under conditions that were not imputable to mechanisms associated with conscious retrieval. Notably, the V1 responses during learning and recognition separately predicted non-conscious recognition memory, and functional coupling between V1 and the hippocampus was enhanced for old retrieval cues. The results provide a basis for novel hypotheses about the signals that can drive recognition memory, because these data (1) identify human V1 with a memory network that can code complex associative serial visuospatial information and support later non-conscious recognition memory-guided behavior (cf. [5]) and (2) align with mouse models of experience-dependent V1 plasticity in learning and memory [6]. PMID- 26948884 TI - Continuous positive airway pressure: Physiology and comparison of devices. AB - Nasal continuous positive airway pressure (CPAP) is increasingly used for respiratory support in preterm babies at birth and after extubation from mechanical ventilation. Various CPAP devices are available for use that can be broadly grouped into continuous flow and variable flow. There are potential physiologic differences between these CPAP systems and the choice of a CPAP device is too often guided by individual expertise and experience rather than by evidence. When interpreting the evidence clinicians should take into account the pressure generation sources, nasal interface, and the factors affecting the delivery of pressure, such as mouth position and respiratory drive. With increasing use of these devices, better monitoring techniques are required to assess the efficacy and early recognition of babies who are failing and in need of escalated support. PMID- 26948885 TI - Duration of continuous positive airway pressure in premature infants. AB - Continuous positive airway pressure (CPAP) has been used for respiratory support in premature infants for more than 40 years and is now a cornerstone of modern neonatal care. Clinical research on CPAP has primarily focused on understanding which devices and pressure sources best implement this therapy. In contrast, less research has examined the optimal duration over which CPAP is administered. We review this aspect of CPAP therapy. PMID- 26948886 TI - Treatment of Severe Alcoholic Hepatitis. AB - Alcoholic hepatitis (AH) is a syndrome of jaundice and liver failure that occurs in a minority of heavy consumers of alcohol. The diagnosis usually is based on a history of heavy alcohol use, findings from blood tests, and exclusion of other liver diseases by blood and imaging analyses. Liver biopsy specimens, usually collected via the transjugular route, should be analyzed to confirm a diagnosis of AH in patients with an atypical history or presentation. The optimal treatment for patients with severe AH is prednisolone, possibly in combination with N acetyl cysteine. At present, only short-term increases in survival can be expected-no treatment has been found to increase patient survival beyond 3 months. Abstinence is essential for long-term survival. New treatment options, including liver transplantation, are being tested in trials and results eagerly are awaited. PMID- 26948887 TI - Changes in the Intestinal Microbiome and Alcoholic and Nonalcoholic Liver Diseases: Causes or Effects? AB - The prevalence of fatty liver diseases is increasing rapidly worldwide; after treatment of hepatitis C virus infection becomes more widespread, fatty liver diseases are likely to become the most prevalent liver disorders. Although fatty liver diseases are associated with alcohol, obesity, and the metabolic syndrome, their mechanisms of pathogenesis are not clear. The development and progression of fatty liver, alcoholic, and nonalcoholic liver disease (NAFLD) all appear to be influenced by the composition of the microbiota. The intestinal microbiota have been shown to affect precirrhotic and cirrhotic stages of liver diseases, which could lead to new strategies for their diagnosis, treatment, and study. We review differences and similarities in the cirrhotic and precirrhotic stages of NAFLD and alcoholic liver disease. Differences have been observed in these stages of alcohol-associated disease in patients who continue to drink compared with those who stop, with respect to the composition and function of the intestinal microbiota and intestinal integrity. NAFLD and the intestinal microbiota also differ between patients with and without diabetes. We also discuss the potential of microbial therapy for patients with NAFLD and ALD. PMID- 26948888 TI - Mentoring: A Necessary But Not Sufficient Ingredient for Enhancing Success. PMID- 26948889 TI - A New Population of Parvocellular Oxytocin Neurons Controlling Magnocellular Neuron Activity and Inflammatory Pain Processing. AB - Oxytocin (OT) is a neuropeptide elaborated by the hypothalamic paraventricular (PVN) and supraoptic (SON) nuclei. Magnocellular OT neurons of these nuclei innervate numerous forebrain regions and release OT into the blood from the posterior pituitary. The PVN also harbors parvocellular OT cells that project to the brainstem and spinal cord, but their function has not been directly assessed. Here, we identified a subset of approximately 30 parvocellular OT neurons, with collateral projections onto magnocellular OT neurons and neurons of deep layers of the spinal cord. Evoked OT release from these OT neurons suppresses nociception and promotes analgesia in an animal model of inflammatory pain. Our findings identify a new population of OT neurons that modulates nociception in a two tier process: (1) directly by release of OT from axons onto sensory spinal cord neurons and inhibiting their activity and (2) indirectly by stimulating OT release from SON neurons into the periphery. PMID- 26948890 TI - Cerebellar Transcriptome Profiles of ATXN1 Transgenic Mice Reveal SCA1 Disease Progression and Protection Pathways. AB - SCA1, a fatal neurodegenerative disorder, is caused by a CAG expansion encoding a polyglutamine stretch in the protein ATXN1. We used RNA sequencing to profile cerebellar gene expression in Pcp2-ATXN1[82Q] mice with ataxia and progressive pathology and Pcp2-ATXN1[30Q]D776 animals having ataxia in absence of Purkinje cell progressive pathology. Weighted Gene Coexpression Network Analysis of the cerebellar expression data revealed two gene networks that significantly correlated with disease and have an expression profile correlating with disease progression in ATXN1[82Q] Purkinje cells. The Magenta Module provides a signature of suppressed transcriptional programs reflecting disease progression in Purkinje cells, while the Lt Yellow Module reflects transcriptional programs activated in response to disease in Purkinje cells as well as other cerebellar cell types. Furthermore, we found that upregulation of cholecystokinin (Cck) and subsequent interaction with the Cck1 receptor likely underlies the lack of progressive Purkinje cell pathology in Pcp2-ATXN1[30Q]D776 mice. PMID- 26948891 TI - The Complete Genome Sequences, Unique Mutational Spectra, and Developmental Potency of Adult Neurons Revealed by Cloning. AB - Somatic mutation in neurons is linked to neurologic disease and implicated in cell-type diversification. However, the origin, extent, and patterns of genomic mutation in neurons remain unknown. We established a nuclear transfer method to clonally amplify the genomes of neurons from adult mice for whole-genome sequencing. Comprehensive mutation detection and independent validation revealed that individual neurons harbor ~100 unique mutations from all classes but lack recurrent rearrangements. Most neurons contain at least one gene-disrupting mutation and rare (0-2) mobile element insertions. The frequency and gene bias of neuronal mutations differ from other lineages, potentially due to novel mechanisms governing postmitotic mutation. Fertile mice were cloned from several neurons, establishing the compatibility of mutated adult neuronal genomes with reprogramming to pluripotency and development. PMID- 26948893 TI - Thalamocortical Projections onto Behaviorally Relevant Neurons Exhibit Plasticity during Adult Motor Learning. AB - Layer 5 neurons of the neocortex receive direct and relatively strong input from the thalamus. However, the intralaminar distribution of these inputs and their capacity for plasticity in adult animals are largely unknown. In slices of the primary motor cortex (M1), we simultaneously recorded from pairs of corticospinal neurons associated with control of distinct motor outputs: distal forelimb versus proximal forelimb. Activation of ChR2-expressing thalamocortical afferents in M1 before motor learning produced equivalent responses in monosynaptic excitation of neurons controlling the distal and proximal forelimb, suggesting balanced thalamic input at baseline. Following skilled grasp training, however, thalamocortical input shifted to bias activation of corticospinal neurons associated with control of the distal forelimb. This increase was associated with a cell-specific increase in mEPSC amplitude but not presynaptic release probability. These findings demonstrate distinct and highly segregated plasticity of thalamocortical projections during adult learning. PMID- 26948892 TI - Memory-Relevant Mushroom Body Output Synapses Are Cholinergic. AB - Memories are stored in the fan-out fan-in neural architectures of the mammalian cerebellum and hippocampus and the insect mushroom bodies. However, whereas key plasticity occurs at glutamatergic synapses in mammals, the neurochemistry of the memory-storing mushroom body Kenyon cell output synapses is unknown. Here we demonstrate a role for acetylcholine (ACh) in Drosophila. Kenyon cells express the ACh-processing proteins ChAT and VAChT, and reducing their expression impairs learned olfactory-driven behavior. Local ACh application, or direct Kenyon cell activation, evokes activity in mushroom body output neurons (MBONs). MBON activation depends on VAChT expression in Kenyon cells and is blocked by ACh receptor antagonism. Furthermore, reducing nicotinic ACh receptor subunit expression in MBONs compromises odor-evoked activation and redirects odor-driven behavior. Lastly, peptidergic corelease enhances ACh-evoked responses in MBONs, suggesting an interaction between the fast- and slow-acting transmitters. Therefore, olfactory memories in Drosophila are likely stored as plasticity of cholinergic synapses. PMID- 26948894 TI - Cognitive Neurostimulation: Learning to Volitionally Sustain Ventral Tegmental Area Activation. AB - Activation of the ventral tegmental area (VTA) and mesolimbic networks is essential to motivation, performance, and learning. Humans routinely attempt to motivate themselves, with unclear efficacy or impact on VTA networks. Using fMRI, we found untrained participants' motivational strategies failed to consistently activate VTA. After real-time VTA neurofeedback training, however, participants volitionally induced VTA activation without external aids, relative to baseline, Pre-test, and control groups. VTA self-activation was accompanied by increased mesolimbic network connectivity. Among two comparison groups (no neurofeedback, false neurofeedback) and an alternate neurofeedback group (nucleus accumbens), none sustained activation in target regions of interest nor increased VTA functional connectivity. The results comprise two novel demonstrations: learning and generalization after VTA neurofeedback training and the ability to sustain VTA activation without external reward or reward cues. These findings suggest theoretical alignment of ideas about motivation and midbrain physiology and the potential for generalizable interventions to improve performance and learning. PMID- 26948895 TI - Two Anatomically and Computationally Distinct Learning Signals Predict Changes to Stimulus-Outcome Associations in Hippocampus. AB - Complex cognitive processes require sophisticated local processing but also interactions between distant brain regions. It is therefore critical to be able to study distant interactions between local computations and the neural representations they act on. Here we report two anatomically and computationally distinct learning signals in lateral orbitofrontal cortex (lOFC) and the dopaminergic ventral midbrain (VM) that predict trial-by-trial changes to a basic internal model in hippocampus. To measure local computations during learning and their interaction with neural representations, we coupled computational fMRI with trial-by-trial fMRI suppression. We find that suppression in a medial temporal lobe network changes trial-by-trial in proportion to stimulus-outcome associations. During interleaved choice trials, we identify learning signals that relate to outcome type in lOFC and to reward value in VM. These intervening choice feedback signals predicted the subsequent change to hippocampal suppression, suggesting a convergence of signals that update the flexible representation of stimulus-outcome associations. PMID- 26948896 TI - NMDA Receptors Multiplicatively Scale Visual Signals and Enhance Directional Motion Discrimination in Retinal Ganglion Cells. AB - Postsynaptic responses in many CNS neurons are typically small and variable, often making it difficult to distinguish physiologically relevant signals from background noise. To extract salient information, neurons are thought to integrate multiple synaptic inputs and/or selectively amplify specific synaptic activation patterns. Here, we present evidence for a third strategy: directionally selective ganglion cells (DSGCs) in the mouse retina multiplicatively scale visual signals via a mechanism that requires both nonlinear NMDA receptor (NMDAR) conductances in DSGC dendrites and directionally tuned inhibition provided by the upstream retinal circuitry. Postsynaptic multiplication enables DSGCs to discriminate visual motion more accurately in noisy visual conditions without compromising directional tuning. These findings demonstrate a novel role for NMDARs in synaptic processing and provide new insights into how synaptic and network features interact to accomplish physiologically relevant neural computations. PMID- 26948897 TI - Hydrogen-atom attack on phenol and toluene is ortho-directed. AB - The reaction of H + phenol and H/D + toluene has been studied in a supersonic expansion after electric discharge. The (1 + 1') resonance-enhanced multiphoton ionization (REMPI) spectra of the reaction products, at m/z = parent + 1, or parent + 2 amu, were measured by scanning the first (resonance) laser. The resulting spectra are highly structured. Ionization energies were measured by scanning the second (ionization) laser, while the first laser was tuned to a specific transition. Theoretical calculations, benchmarked to the well-studied H + benzene -> cyclohexadienyl radical reaction, were performed. The spectrum arising from the reaction of H + phenol is attributed solely to the ortho-hydroxy cyclohexadienyl radical, which was found in two conformers (syn and anti). Similarly, the reaction of H/D + toluene formed solely the ortho isomer. The preference for the ortho isomer at 100-200 K in the molecular beam is attributed to kinetic, not thermodynamic effects, caused by an entrance channel barrier that is ~5 kJ mol(-1) lower for ortho than for other isomers. Based on these results, we predict that the reaction of H + phenol and H + toluene should still favour the ortho isomer under elevated temperature conditions in the early stages of combustion (200-400 degrees C). PMID- 26948898 TI - A Co2+-selective and chirality-sensitive supermolecular metallohydrogel with a nanofiber network skeleton. AB - This paper introduces a new metallohydrogel precursor that offers a peculiar gelation response to Co(2+) at pH 7-8. It is notable that the stability of this metallohydrogel is significantly dependent on its enantiomeric purity. In addition to the expected multi-stimuli responsive properties, including thixotropy, as well as re-assembly properties on adding HCl, this metallohydrogel possesses excellent self-healing behavior, which is uncommon in low-molecular weight gelators. Electron microscopy (EM) studies revealed that the cryodried remains of this gel presented as well an organized three dimensional (3D) network of fibrils. This interesting metallohydrogel shows potential for developing new soft materials with drug delivery and catalysis properties. PMID- 26948899 TI - Pregnancy outcomes in severe polyhydramnios: no increase in risk in patients needing amnioreduction for maternal pain or respiratory distress. AB - INTRODUCTION: Polyhydramnios is a common complication of fetal malformations and has been described to have high risk of pregnancy complications such as prematurity and placental abruption. In a subgroup of women severe polyhydramnios may lead to maternal dyspnea or untreatable pain, and amnioreduction is the procedure indicated to relieve those symptoms. There is a lack of information concerning the increase in the risk for the pregnancy when the procedure is indicated. Therefore, this study sought to evaluate the risk of complications in pregnancies with severe polyhydramnios that needed amnioreduction in relation to the basal risk for the pregnancy of having polyhydramnios without the need for the procedure. MATERIALS AND METHODS: Patients with singleton pregnancies and severe polyhydramnios followed in our fetal medicine center were evaluated retrospectively. Pregnancy complications (prematurity rate, fetal death, premature rupture of membranes, placental abruption and chorioamnionitis) were studied in the group of patients needing the procedure and their risk was compared to the risk of having a pregnancy with severe polyhydramnios but with no need for the procedure. RESULTS: One hundred and thirty-five patients were evaluated. Forty-four patients (32.6%) needed amnioreduction. There was no increase in the risk of having complications when the procedure was needed OR = 1.4 (CI 0.46-1.26). CONCLUSION: Amnioreduction performed to relieve maternal symptoms did not statistically increase the risk of pregnancy complications with severe polyhydramnios in single pregnancies. PMID- 26948900 TI - Macrocyclization of Unprotected Peptide Isocyanates. AB - A chemistry for the facile two-component macrocyclization of unprotected peptide isocyanates is described. Starting from peptides containing two glutamic acid gamma-hydrazide residues, isocyanates can be readily accessed and cyclized with hydrazides of dicarboxylic acids. The choice of a nucleophilic linker allows for the facile modulation of biochemical properties of a macrocyclic peptide. Four cyclic NYAD-1 analogues were synthesized using the described method and displayed a range of biological activities. PMID- 26948901 TI - Cytokine modulation of human blood viscosity from vivax malaria patients. AB - Malaria is a major infectious disease in several countries and is caused by protozoa of the genus Plasmodium. In vivax malaria patients, inflammatory processes occur, as well as changes in cytokines and blood flow. The present study analyzed the cytokine modulation of blood viscosity from patients infected with Plasmodium vivax (P. vivax). Blood samples were collected from 42 non infected individuals (control group) and 37 individuals infected with P. vivax. The IL-2, IL-4, IL-6, IL-10, TNFalpha, TGF-beta and IL-17 cytokine concentrations in the serum were assessed, and the blood rheological properties were determined. The analysis of blood viscosity for shear rates revealed that the blood viscosity of the infected patients was significantly greater than that of the non-infected individuals. The viscosity of the blood was greater in the infected individuals than in the non-infected subjects. The serum from individuals with P. vivax infections exhibited higher IFN-gamma and IL-17 concentrations and lower TGF-beta levels. Incubation of the blood from infected individuals with IL-17 or IL-17 associated with IFN-gamma reduced the viscosity to rates equivalent to the blood from non-infected individuals. Independently of cytokine modulation, no correlation was found between the parasitemia and blood viscosity of the infected patients. These data suggest that the alterations of blood viscosity are relevant as an auxiliary tool for the clinical diagnosis of disease. In malaria, erythrocytes are more sensitive to osmotic shock, and the reduction of viscosity by IL-17 may be related to a possible immunomodulator agent during infection. PMID- 26948902 TI - Genetic variability of Echinococcus granulosus complex in various geographical populations of Iran inferred by mitochondrial DNA sequences. AB - To investigate the genetic variability and population structure of Echinococcus granulosus complex, 79 isolates were sequenced from different host species covering human, dog, camel, goat, sheep and cattle as of various geographical sub populations of Iran (Northwestern, Northern, and Southeastern). In addition, 36 sequences of other geographical populations (Western, Southeastern and Central Iran), were directly retrieved from GenBank database for the mitochondrial cytochrome c oxidase subunit 1 (cox1) gene. The confirmed isolates were grouped as G1 genotype (n=92), G6 genotype (n=14), G3 genotype (n=8) and G2 genotype (n=1). 50 unique haplotypes were identified based on the analyzed sequences of cox1. A parsimonious network of the sequence haplotypes displayed star-like features in the overall population containing IR23 (22: 19.1%) as the most common haplotype. According to the analysis of molecular variance (AMOVA) test, the high value of haplotype diversity of E. granulosus complex was shown the total genetic variability within populations while nucleotide diversity was low in all populations. Neutrality indices of the cox1 (Tajima's D and Fu's Fs tests) were shown negative values in Western-Northwestern, Northern and Southeastern populations which indicating significant divergence from neutrality and positive but not significant in Central isolates. A pairwise fixation index (Fst) as a degree of gene flow was generally low value for all populations (0.00647 0.15198). The statistically Fst values indicate that Echinococcus sensu stricto (genotype G1-G3) populations are not genetically well differentiated in various geographical regions of Iran. To appraise the hypothetical evolutionary scenario, further study is needed to analyze concatenated mitogenomes and as well a panel of single locus nuclear markers should be considered in wider areas of Iran and neighboring countries. PMID- 26948918 TI - Primary epidermoid carcinoma of the lacrimal sac. PMID- 26948919 TI - Quality of life in patients with metastatic breast cancer treated with metronomic chemotherapy. AB - AIM: The objective of the study was to detect changes in quality of life (QoL) in metastatic breast cancer patients treated with metronomic chemotherapy with daily low doses of cyclophosphamide and celecoxib. MATERIAL & METHODS: Patients included in a Phase II trial, treated with metronomic cyclophosphamide and celecoxib were included in the QoL study. Assessment of QoL was carried out every 2 months by the Functional Assessment of Cancer Therapy Breast (FACT-B) questionnaire, Brief Pain Inventory and Eastern Cooperative Oncologic Group scale. Data were analyzed at three time points: baseline (BL); middle of treatment (MT); and end of treatment (ET). RESULTS: A total of 20 patients were included. All patients were heavily pretreated. Treatment showed a good and safe therapeutic profile. With FACT-B questionnaire, no significant differences were observed during the response period (BL-MT). However, a significant increase was observed in the Emotional well-being and Additional concerns axes, when the last time point was included in the analysis (BL-MT-ET). A significant decrease in the proportion of patients with pain was found when comparing BL with ET (p = 0.046). The assessment with Eastern Cooperative Oncologic Group scale showed that 26.7% (4/15) of the patients improved their functional status and 40% (6/15) showed no changes, while 33.3% (5/10) worsened it. CONCLUSION: Patients treated metronomically for several months did not worsen their QoL. A high proportion of patients showed improvement or no changes and there were less patients with pain at the end of the treatment. PMID- 26948920 TI - HIV/AIDS: trends in the Middle East and North Africa region. AB - OBJECTIVES: To give an overview of the HIV epidemic in the Middle East and North Africa (MENA) region. METHODS: Articles on the MENA region were reviewed. RESULTS: The MENA region comprises a geographically defined group of countries including both high-income, well-developed nations and low- and middle-income countries. While the annual number of new HIV infections in Sub-Saharan Africa has declined by 33% since 2005, new HIV infections in the MENA region have increased by 31% since 2001, which is the highest increase among all regions in the world. Moreover, the number of AIDS-related deaths in 2013 was estimated to be 15000, representing a 66% increase since 2005. However, the current prevalence of 0.1% is still among the lowest rates globally. There is substantial heterogeneity in HIV epidemic dynamics across MENA, and different risk contexts are present throughout the region. Despite unfavorable conditions, many countries in the region have put significant effort into scaling up their response to this growing epidemic, while in others the response to HIV is proving slower due to denial, stigma, and reluctance to address sensitive issues. CONCLUSIONS: The HIV epidemic in the MENA region is still at a controllable level, and this opportunity should not be missed. PMID- 26948921 TI - Antimyeloperoxidase antibody is a biomarker for progression of diabetic retinopathy. AB - AIM: To study the correlation between serum antimyeloperoxidase (MPO) antibody levels with severity of diabetic retinopathy (DR). METHODS: Study subjects included 60 consecutive cases of type 2 diabetes mellitus (DM): no diabetic retinopathy (NODR, n=20); nonproliferative DR (NPDR, n=20); proliferative DR (PDR, n=20) and 20 healthy controls. Best corrected visual acuity (BCVA) was measured on logMAR scale. Serum anti-MPO antibody levels were evaluated using ELISA IgG kit. Serum urea and creatinine was measured using standard protocol. Data were analysed statistically. RESULTS: Mean serum anti-MPO antibody (RU/ml) was 16.94 +/- 4.85 in controls, 17.66 +/- 4.78 in NODR, 21.51 +/- 5.27 in NPDR and 37.27 +/- 11.92 in PDR groups. On ANOVA, significant difference in visual acuity was found among the study groups (F=73.46, p<0.001). Serum anti-MPO antibody was correlated significantly with decrease in visual acuity (F=48.40, p<0.001), increase in serum urea (F=128.13, p<0.001) and creatinine (F=77.10, p<0.001). CONCLUSION: Increase in serum anti-MPO antibody levels correlate with increased severity of DR. Serum anti-MPO antibody may be a noteworthy biochemical marker for progression of retinopathy from nonproliferative to proliferative stage. PMID- 26948922 TI - Non-viable sperm in the ejaculate: Lethal escorts for contemporary viable sperm. AB - Non-viable sperm ("dead sperm") are present in variable numbers in mammalian ejaculates and their number increase substantially when semen is stored, particularly cryopreserved. This review comparatively highlights, with experimental data in porcine, the role-played by non-viable sperm in the outcome of semen used in assisted reproductive technologies. As well, the review discusses our current understanding of their origin and the pathways involved when their large numbers negative influence the functional lifespan of contemporary viable sperm to eventually cause irreversible dysfunction that reduces their fertility potential and their ability to develop healthy embryos. Finally, it highlights procedures currently available to mitigate these harmful effects. PMID- 26948923 TI - Effects of oxidised dietary fish oil and high-dose vitamin E supplementation on growth performance, feed utilisation and antioxidant defence enzyme activities of juvenile large yellow croaker (Larmichthys crocea). AB - This study was conducted to elucidate the effects of oxidised dietary lipids and high-dose vitamin E (VE) on growth performance and immune responses of large yellow croaker. Juvenile fish (initial average body weight of 7.82 (sem 0.68) g) were fed diets containing either fresh fish oil (fresh diet, peroxide value (POV)=1.72 mEq/kg) or fish oil oxidised to varying degrees (oxidised diets, POV=28.29-104.21 mEq/kg), with or without supplementary 600 mg VE/kg diet, for 10 weeks in floating cages. Growth was significantly lower and feed intake (g/100 g body weight per d) was higher in fish fed the oxidised diet. Supplementation with VE increased the growth of fish fed the oxidised diets, but significantly decreased the growth of fish fed the fresh diet. Hepatosomatic index increased with increasing dietary POV and decreased with VE supplementation. Hepatic catalase activity, superoxide dismutase (SOD) activity and malondialdehyde content were significantly higher in fish fed the oxidised diets, and these values decreased significantly following VE supplementation. However, hepatic SOD activity was enhanced by VE supplementation in fish fed the fresh diet. Air exposure mortality was significantly increased by dietary POV, and this effect was inhibited by VE supplementation. These results suggest that dietary oxidised fish oil could stimulate the activities of antioxidant defence enzymes in stressed large yellow croaker. High-dose VE supplementation can alleviate oxidative stress of large yellow croaker fed oxidised fish oil, but can exert deleterious effects on fish in the absence of oxidative stress. PMID- 26948924 TI - Challenges for the new Cancer Drugs Fund. PMID- 26948925 TI - Weekly dose-dense chemotherapy for ovarian cancer. PMID- 26948926 TI - Molecular subgroups of pancreatic cancer. PMID- 26948927 TI - Multicentre study on inflammatory skin diseases from The International Confocal Working Group: specific confocal microscopy features and an algorithmic method of diagnosis. AB - BACKGROUND: The real value of reflectance confocal microscopy (RCM) for the evaluation of inflammatory skin conditions remains unclear. A project on RCM for inflammatory skin diseases involving international centres was designed by a coordinating centre and executed under the supervision of the International Confocal Working Group. OBJECTIVES: To identify specific confocal features useful for distinction between the three main groups of superficial inflammatory skin diseases. METHODS: Nineteen different RCM features were evaluated in a total of 155 lesions, diagnosed as spongiotic (45), interface (52) or psoriasiform (58) dermatitis, collected by a consortium of 19 different centres. RESULTS: Univariate and multivariate analysis identified RCM descriptors for the three main superficial inflammatory disease groups. Later, a multivariate method was employed to define a scoring system to be applied on an algorithmic method of analysis for fast clinical application. CONCLUSIONS: Our preliminary evaluation supports the use of RCM for the identification of confocal patterns consistent with the major features of the diagnostic groups of inflammatory skin diseases. Moreover, an efficient multivariate method for clinical in vivo RCM diagnosis using a tree decision diagram has been established. PMID- 26948929 TI - Quantification of natural killer cell polarization and visualization of synaptic granule externalization by imaging flow cytometry. AB - Defining immunological mechanisms underlying NK cell biology is crucial for the treatment and prevention of immune deficiency and malignancy. The limited availability of human biological specimens presents a challenge to the study of human immunobiology. The use of high throughput, multi-parametric assays will not only aid in the definition and diagnosis of complex human immune disorders affecting NK cell function but also advance NK cell biology through population based assessment of molecular signaling. In an effort to garner the most information from limited numbers of human cells, we designed a quantitative method to study NK cell function using imaging flow cytometry (IFC), which combines multiparametric flow cytometry and fluorescence microscopy. Specifically, we developed IFC as a tool to measure polarization and secretion of lytic granules at the immunological synapse formed between an NK cell and a susceptible target. We have further validated our approach through quantitative comparison with high-resolution confocal microscopy. We show that IFC can be used as a quantitative, high throughput measure of NK cell biological function possessing greater dimensionality than standard flow cytometry. PMID- 26948930 TI - Shaping the spectrum - From autoinflammation to autoimmunity. AB - Historically, autoimmune-inflammatory disorders were subdivided into autoinflammatory vs. autoimmune diseases. About a decade ago, an immunological continuum was proposed, placing "classical" autoinflammatory disorders, characterized by systemic inflammation in the absence of high-titer autoantibodies or autoreactive T lymphocytes, at the one end, and autoimmune disorders at the other end. We provide an overview of recent developments and observations, filling in some of the gaps and showing strong interconnections between innate and adaptive immune mechanisms, indicating that disorders from both ends of the immunological spectrum indeed share key pathomechanisms. We focus on three exemplary disorders: i) systemic juvenile idiopathic arthritis representing "classical" autoinflammatory disorders; ii) psoriasis, a mixed pattern disease; and iii) systemic lupus erythematosus, a prototypical autoimmune disease. We summarize scientific observations suggesting that, depending on disease stages and/or duration, individualized treatment targeting innate or adaptive immune mechanisms in disorders from either end of the immunological spectrum may control disease activity. PMID- 26948928 TI - Transcriptional and post-transcriptional regulation of NK cell development and function. AB - Natural killer (NK) cells are specialized innate lymphoid cells that survey against viral infections and malignancy. Numerous advances have improved our understanding of the molecular mechanisms that control NK cell development and function over the past decade. These include both studies on the regulatory effects of transcription factors and translational repression via microRNAs. In this review, we summarize our current knowledge of DNA-binding transcription factors that regulate gene expression and thereby orchestrate NK cell development and activation, with an emphasis on recent discoveries. Additionally, we highlight our understanding of how RNA-binding microRNAs fine tune the NK cell molecular program. We also underscore the large number of open questions in the field that are now being addressed using new technological approaches and genetically engineered model organisms. Ultimately, a deeper understanding of the basic molecular biology of NK cells will facilitate new strategies to manipulate NK cells for the treatment of human disease. PMID- 26948931 TI - Can Psoriasis Produce Irreversible Alopecia? PMID- 26948932 TI - Annular Elastolytic Giant Cell Granuloma in Sun-Protected Sites Responds to Dapsone. PMID- 26948933 TI - Transport in serial spinful multiple-dot systems: The role of electron-electron interactions and coherences. AB - Quantum dots are nanoscopic systems, where carriers are confined in all three spatial directions. Such nanoscopic systems are suitable for fundamental studies of quantum mechanics and are candidates for applications such as quantum information processing. It was also proposed that linear arrangements of quantum dots could be used as quantum cascade laser. In this work we study the impact of electron-electron interactions on transport in a spinful serial triple quantum dot system weakly coupled to two leads. We find that due to electron-electron scattering processes the transport is enabled beyond the common single-particle transmission channels. This shows that the scenario in the serial quantum dots intrinsically deviates from layered structures such as quantum cascade lasers, where the presence of well-defined single-particle resonances between neighboring levels are crucial for device operation. Additionally, we check the validity of the Pauli master equation by comparing it with the first-order von Neumann approach. Here we demonstrate that coherences are of relevance if the energy spacing of the eigenstates is smaller than the lead transition rate multiplied by h. PMID- 26948937 TI - Anakinra for the treatment of familial Mediterranean fever-associated spondyloarthritis. PMID- 26948938 TI - Toward the stereochemical assignment and synthesis of hemicalide: DP4f GIAO-NMR analysis and synthesis of a reassigned C16-C28 subunit. AB - Using the DP4f GIAO-NMR method, the stereochemistry of hemicalide was computationally analysed, resulting in a reassignment at C18 as supported by improved NMR shift correlations with a model C13-C25 fragment 23. An advanced C16 C28 subunit 6 of this potent anticancer agent was then synthesised with the revised 18,19-syn relationship. PMID- 26948939 TI - Regional differences in the coverage and uptake of bariatric-metabolic surgery: A focus on type 2 diabetes. AB - BACKGROUND: There is high-quality evidence that bariatric-metabolic surgery (BMS) generates positive health outcomes in patients with obesity and type 2 diabetes (T2D). OBJECTIVES: To understand the regional variations in the coverage and uptake of BMS, with a focus on T2D. SETTING: An Australian diabetes research institute. METHODS: A survey was conducted via a questionnaires sent to national leaders in BMS. The respondents provide their nations' BMS annual numbers, general and any T2D-specific indications for surgery, and source of surgical funding. The total population and adult diabetes prevalence (age 20-70 yr) of the countries were used to model the uptake of BMS for those with T2D. RESULTS: Data were provided from 22 countries, representing approximately 75% of BMS procedures performed in 2014. BMS uptake varied from 885 per million total population per year in Belgium to 2 per million per year in Japan. The estimated proportion of eligible individuals with diabetes treated annually varied from 1.9% in The Netherlands to<.01% in China and Japan. Few countries treat>1% of estimated eligible patients annually. Of 22 countries, 19 have national guidelines for BMS, and all incorporate BMI in the selection criteria. Several countries have specific criteria for patients with T2D. CONCLUSION: Results indicated that BMS has a negligible impact on the global burden of T2D. The low uptake indicates that BMS has not become an established treatment for T2D and emphasizes the need to define when it should be recommended as a standard of care. BMS needs to be integrated into the clinical pathways for managing T2D. PMID- 26948940 TI - Metabolic surgery in morbidly obese patients with type 1 diabetes. PMID- 26948941 TI - Bile acids synthesis decreases after laparoscopic sleeve gastrectomy. AB - BACKGROUND: Bariatric surgery is the most effective treatment alternative in morbid obesity. The mechanisms contributing to these benefits remain poorly understood. Bile acids (BAs) are mediators of different regulatory functions in glucose and cholesterol homeostasis and energy expenditure. Recent evidence suggests that BAs are critically important for the beneficial effects of sleeve gastrectomy (SG). OBJECTIVES: The aim of this study was to evaluate the effect of SG on BA synthesis. SETTING: University Hospital. Santiago, Chile. METHODS: Obese patients were evaluated before and after SG (1, 3, 6, and 12 months). BA synthesis was evaluated through the serum marker, 7 alpha-hydroxy-4-cholesten-3 one (C4). Primary and secondary BA and C4 were determined by high performance liquid chromatography coupled with tandem mass spectrometry detection (HPLC MS/MS). RESULTS: From June 2013 to January 2014, 19 patients (age 37.6+/-7.8 years; BMI 35.8+/-3.5 kg/m(2); 79% female) were included in this study. Mean weight loss at 1, 3, 6, and 12 months was 11.3, 17.5, 23.6, and 25.4 kg, respectively, equivalent to 11.8, 18.6, 24.8, and 26.9 of total body water percentage (%TBW) (P<.0001), respectively and 43.2, 68.2, 91, and 98.8 of percentage of excess weight loss (%EWL), respectively (P<.001). Serum C4 levels at baseline, 1, 3, 6, and 12 months were 23.4+/-21.1, 4.9+/-8.2, 8.7+/-12.1, 13.8+/-12.9, and 18.8+/-16.8 ng/mL (P<.0001), respectively. Fibroblast growth factor 19 (FGF19) levels at baseline, 1, 3, 6, and 12 months were 71+/-33.3, 130.5+/-66.2, 117.8+/-57.2, 134.6+/-91.7, and 124.3+/-85.9 pg/mL (P = .019), respectively. CONCLUSION: Serum levels of C4 decrease after SG, indicating a reduction in the synthesis of BA. FGF19 may play a role in decreasing BA synthesis. Further studies are necessary to characterize the effect of bariatric surgery on BA homeostasis. PMID- 26948942 TI - Weight loss surgery improves quality of life in pediatric patients with osteogenesis imperfecta. AB - BACKGROUND: Osteogenesis imperfecta (OI) is an inherited disorder, which causes brittle bones resulting in recurrent fractures. The associated poor mobility of children with OI increases susceptibility to obesity, and obesity further dramatically limits mobility and increases fracture risk. OBJECTIVES: The aim of this report is to describe outcomes of weight loss surgery (WLS) in 2 adolescents with severe obesity and OI. SETTING: Two University Hospitals (in the United Kingdom and in the United States). METHODS: Two cases of OI treated with WLS were identified. Pre- and postoperative anthropometric and biochemical data and clinical course were reviewed. RESULTS: In these 2 cases, preoperative Body Mass Index (BMI) values were 38 and 46 kg/m2. Following laparoscopic sleeve gastrectomy (LSG), BMI decreased by 55% and 60% by 26 and 24 months, respectively. There were no surgical complications, and both patients experienced improvement in their mobility and ability to perform activities of daily living. CONCLUSION: WLS effectively treated severe obesity in 2 OI patients and substantially improved mobility and quality of life, theoretically reducing fracture risk. PMID- 26948943 TI - Primary care physician decision making regarding severe obesity treatment and bariatric surgery: a qualitative study. AB - BACKGROUND: Less than 1% of severely obese US adults undergo bariatric surgery annually. It is critical to understand the factors that contribute to its utilization. OBJECTIVES: To understand how primary care physicians (PCPs) make decisions regarding severe obesity treatment and bariatric surgery referral. SETTING: Focus groups with PCPs practicing in small, medium, and large cities in Wisconsin. METHODS: PCPs were asked to discuss prioritization of treatment for a severely obese patient with multiple co-morbidities and considerations regarding bariatric surgery referral. Focus group sessions were analyzed by using a directed approach to content analysis. A taxonomy of consensus codes was developed. Code summaries were created and representative quotes identified. RESULTS: Sixteen PCPs participated in 3 focus groups. Four treatment prioritization approaches were identified: (1) treat the disease that is easiest to address; (2) treat the disease that is perceived as the most dangerous; (3) let the patient set the agenda; and (4) address obesity first because it is the common denominator underlying other co-morbid conditions. Only the latter approach placed emphasis on obesity treatment. Five factors made PCPs hesitate to refer patients for bariatric surgery: (1) wanting to "do no harm"; (2) questioning the long-term effectiveness of bariatric surgery; (3) limited knowledge about bariatric surgery; (4) not wanting to recommend bariatric surgery too early; and (5) not knowing if insurance would cover bariatric surgery. CONCLUSION: Decision making by PCPs for severely obese patients seems to underprioritize obesity treatment and overestimate bariatric surgery risks. This could be addressed with PCP education and improvements in communication between PCPs and bariatric surgeons. PMID- 26948944 TI - Long-term outcomes of laparoscopic sleeve gastrectomy: a Lebanese center experience. AB - BACKGROUND: Long-term data of laparoscopic sleeve gastrectomy (LSG) are still scarce in the Middle East. OBJECTIVES: The aim of this study was to assess the efficacy and safety at 5 years and beyond. SETTING: Tertiary referral hospital between April 2007 and March 2015. METHODS: A retrospective review of 76 patients who underwent LSG at the senior author's institution between April 2007 and March 2010. RESULTS: Mean preoperative body mass index (BMI) was 42.8+/-7.1 kg/m2. Follow-up rates were 90.4%, 86.3%, and 77.8% at 5, 6, and 7 years, respectively. Percentage of excess weight loss (%EWL) was 69.8%+/-28.7% at 5 years, 70.6%+/ 32.7% at 6 years, and 76.6%+/-21.2% at 7 years, respectively. Mean total weight loss was 26.5%+/-8.7%, 24.9%+/-8.8%, and 26.6%+/-6.0% at 5, 6, and 7 years, respectively. %EWL at 5-years was significantly higher for patients with a preoperative BMI<45 kg/m2 (83.1% versus 46.3%, P<.0001). LSG improved or resolved diabetes, hypertension, and asthma in 87.5%, 68%, and 81.7% of patients, respectively. New onset gastroesophageal acid reflux disease developed in 21.2% of patients. Long-term complications included hiatal hernias necessitating repair (1.4%), incisional hernias (2.7%), and symptomatic gallstones (9.6%), as well as depression necessitating admission (4.1%). CONCLUSION: In the present patient population, LSG resulted in satisfactory %EWL and co-morbidity resolution after 5 years. The results were excellent for patients with a BMI<45 kg/m2. De novo acid reflux symptoms developed in 1 of 5 patients. Cholelithiasis necessitating cholecystectomy was the most common long-term complication. PMID- 26948945 TI - American Society for Metabolic and Bariatric Surgery position statement on vagal blocking therapy for obesity. PMID- 26948946 TI - Preparation and characterization of magnetic thermosensitive fluorouracil micelles. AB - In this study, we synthesized P(NIPAM-co-DMAM)-b-PLA polymers with free radical polymerization and ring-opening addition polymerization, and immediately assembled 'dextran magnetic layered double hydroxide fluorouracil' (DMF) magnetic particles into the core of the amphiphilic polymer micelles with synchronous hydration and dialysis, to generate a magnetic thermosensitive fluorouracil drug delivery system. The basic properties of the micelle particles, such as the core shell-type structure, size, and zeta potential, were studied with (1)H-NMR, FTIR, TEM, TGA, laser nanoparticle size analysis, and other characterization techniques. The thermosensitivity of the micelles was investigated by measuring parameters such as the lower critical solution temperature (LCST) and the relationship between the particle size variation and temperature. The drug release curves for the micelles at different temperatures were constructed with a dialysis method. The LCST of the triblock polymers was 42 degrees C. The particle sizes of the blank micelles and DMF-loaded micelles were 493.6 +/- 1.8 nm and 464.9 +/- 4.1 nm, respectively, at 25 degrees C. When the temperature was higher than LSCT, a contraction phase change in the micelle structure occurred, a significant characteristic of the core-shell-type structure, and reversible phase transition phenomena. The release behavior of the drug-loaded micelles showed obvious variations with temperature. Therefore, the magnetic thermosensitive fluorouracil drug delivery system has a good magnetic response and excellent temperature controlled release characteristics, so it can be used as a drug delivery system in magnetically and thermally targeted chemotherapy for tumors. PMID- 26948947 TI - Polydatin attenuates AGEs-induced upregulation of fibronectin and ICAM-1 in rat glomerular mesangial cells and db/db diabetic mice kidneys by inhibiting the activation of the SphK1-S1P signaling pathway. AB - We previously demonstrated that activation of sphingosine kinase 1 (SphK1)- sphingosine 1- phosphate (S1P) signaling pathway by high glucose (HG) plays a pivotal role in increasing the expression of fibronectin (FN), an important fibrotic component, by promoting the DNA-binding activity of transcription factor activator protein 1 (AP-1) in glomerular mesangial cells (GMCs) under diabetic conditions. As a multi-target anti-oxidative drug, polydatin (PD) has been shown to have renoprotective effects on experimental diabetes. However, whether PD could resist diabetic nephropathy (DN) by regulating SphK1-S1P signaling pathway needs further investigation. Here, we found that PD significantly reversed the upregulated FN and ICAM-1 expression in GMCs exposed to AGEs. Simultaneously, PD dose-dependently inhibited SphK1 levels at the protein expression and kinase activity and attenuated S1P production under AGEs treatment conditions. In addition, PD reduced SphK activity in GMCs transfected with wild-type SphK(WT) plasmid and significantly suppressed SphK1-mediated increase of FN and ICAM-1 levels under normal conditions. Furthermore, we found that the AGEs-induced upregulation of phosphorylation of c-Jun at Ser63 and Ser73 and c-Fos at Ser32, DNA-binding activity and transcriptional activity of AP-1 were blocked by PD. In comparison with db/db model group, PD treatment suppressed SphK1 levels (mRNA, protein expression, and activity) and S1P production, reversed the upregulation of FN, ICAM-1, c-Jun, and c-Fos in the kidney tissues of diabetic mice, and finally ameliorated renal injury in db/db mice. These findings suggested that the downregulation of SphK1-S1P signaling pathway is probably a novel mechanism by which PD suppressed AGEs-induced FN and ICAM-1 expression and improved renal dysfunction of diabetic models. PMID- 26948948 TI - Extensive metabolic disorders are present in APC(min) tumorigenesis mice. AB - Wnt signaling plays essential role in mesenchymal stem cell (MSC) differentiation. Activation of Wnt signaling suppresses adipogenesis, but promotes osteogenesis in MSC. Adenomatous polyposis coli (APC) is a negative regulator of beta-catenin and Wnt signaling activity. The mutation of APC gene leads to the activation of Wnt signaling and is responsible for tumorigenesis in APC(min) mouse; however, very few studies focused on its metabolic abnormalities. The present study reports a widespread metabolic disorder phenotype in APC(min) mice. The old APC(min) mice have decreased body weight and impaired adipogenesis, but severe hyperlipidemia, which mimic the phenotypes of Familial Adenomatous Polyposis (FAP), an inherited disease also caused by APC gene mutation in human. We found that the expression of lipid metabolism and free fat acids (FA) use genes in the white adipose tissue (WAT) of the APC(min) mice is much lower than those of control. The changed gene expression pattern may lead to the disability of circulatory lipid transportation and storage at WAT. Moreover, the APC(min) mice could not maintain the core body temperature in cold condition. PET-CT determination revealed that the BAT of APC(min) mice has significantly impaired ability to take up (18)FDG from the blood. Morphological studies identified that the brown adipocytes of APC(min) mice were filled with lipid droplets but fewer mitochondria. These results matched with the findings of impaired BAT function in APC(min) mice. Collectively, our study explores a new mechanism that explains abnormal metabolism in APC(min) mice and provides insights into studying the metabolic disorders of FAP patients. PMID- 26948949 TI - Synergistic role of beta-catenin1 and 2 in ovarian differentiation and maintenance of female pathway in Nile tilapia. AB - Two beta-catenin (beta-cat) genes exist in teleosts but little is known about their expression and function in ovarian development. We identified beta-cat1 and beta-cat2 from the Nile tilapia. beta-cat1 and beta-cat2 displayed a similar expression pattern in the ovary during development, and were mainly expressed in the oogonia and oocytes. In luciferase assays, beta-cat1 activated the TOPFlash reporter dose-dependently, whereas beta-cat2 failed to do so. Cotransfection of beta-cat1 and beta-cat2 synergistically enhanced the expression of the reporter. A specific interaction between beta-cat1 and beta-cat2 was also observed in a mammalian two-hybrid assay. Furthermore, tilapia recombinant Dkk1, an inhibitor of the beta-cat pathway, decreased beta-cat1 and beta-cat2, while increased sox9, dmrt1, cyp11b2 and foxl2 expression in the in vitro cultured tilapia ovary, which could be abolished by simultaneous treatment with Bio, an agonist of beta-cat. Consistently, beta-cat1 or beta-cat2 knockdown in XX fish by TALENs caused the retardation of ovarian differentiation and masculinization, as reflected by the upregulation of dmrt1, cyp11b2, sox9, and serum 11-KT level. On the contrary, serum E2 level was unchanged even though foxl2 transcription was upregulated. These data suggestes that both beta-cat1 and beta-cat2 are important members and play synergistic roles in the canonical Wnt signal pathway in fish. Independent of Foxl2-leading estrogen pathway, they might be involved in ovarian differentiation and repression of the male pathway gene expression in tilapia. PMID- 26948951 TI - Melatonin attenuates 60 Co gamma-ray-induced hematopoietic, immunological and gastrointestinal injuries in C57BL/6 male mice. AB - Protection of hematopoietic, immunological, and gastrointestinal injuries from deleterious effects of ionizing radiation is prime rational for developing radioprotector. The objective of this study, therefore, was to evaluate the radioprotective potential of melatonin against damaging effects of radiation induced hematopoietic, immunological, and gastrointestinal injuries in mice. C57BL/6 male mice were intraperitoneally administered with melatonin (50-150 mg/kg) 30 min prior to whole-body radiation exposure of 5 and 7.5 Gy using 60 Co teletherapy unit. Thirty-day survival against 7.5 Gy was monitored. Melatonin (100 mg/kg) pretreatment showed 100% survival against 7.5 Gy radiation dose. Melatonin pretreatment expanded femoral HPSCs, and inhibited spleenocyte DNA strands breaks and apoptosis in irradiated mice. At this time, it also protected radiation-induced loss of T cell sub-populations in spleen. In addition, melatonin pretreatment enhanced crypts regeneration and increased villi number and length in irradiated mice. Translocation of gut bacteria to spleen, liver and kidney were controlled in irradiated mice pretreated with melatonin. Radiation induced gastrointestinal DNA strand breaks, lipid peroxidation, and expression of proapoptotic-p53, Bax, and antiapoptotic-Bcl-xL proteins were reversed in melatonin pretreated mice. This increase of Bcl-xL was associated with the decrease of Bax/Bcl-xL ratio. ABTS and DPPH radical assays revealed that melatonin treatment alleviated total antioxidant capacity in hematopoietic and gastrointestinal tissues. Present study demonstrated that melatonin pretreatment was able to prevent hematopoietic, immunological, and gastrointestinal radiation induced injury, therefore, overcoming lethality in mice. These results suggest potential of melatonin in developing radioprotector for protection of bone marrow, spleen, and gastrointestine in planned radiation exposure scenarios including radiotherapy. (c) 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 501 518, 2017. PMID- 26948950 TI - Up-regulation of SNCA gene expression: implications to synucleinopathies. AB - Synucleinopathies are a group of neurodegenerative diseases that share a common pathological lesion of intracellular protein inclusions largely composed by aggregates of alpha-synuclein protein. Accumulating evidence, including genome wide association studies, has implicated alpha-synuclein (SNCA) gene in the etiology of synucleinopathies. However, the precise variants within SNCA gene that contribute to the sporadic forms of Parkinson's disease (PD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA), and other synucleinopathies and their molecular mechanisms of action remain elusive. It has been suggested that SNCA expression levels are critical for the development of these diseases. Here, we review several model systems that have been developed to advance the understanding of the role of SNCA expression levels in the etiology of synucleinopathies. We also describe different molecular mechanisms that regulate SNCA gene expression and discuss possible strategies for SNCA down-regulation as means for therapeutic approaches. Finally, we highlight some examples that underscore the relationships between the genetic association findings and the regulatory mechanisms of SNCA expression, which suggest that genetic variability in SNCA locus is directly responsible, at least in part, to the changes in gene expression and explain the reported associations of SNCA with synucleinopathies. Future studies utilizing induced pluripotent stem cells (iPSCs)-derived neuronal lines and genome editing by CRISPR/Cas9, will allow us to validate, characterize, and manipulate the effects of particular cis-genetic variants on SNCA expression. Moreover, this model system will enable us to compare different neuronal and glial lineages involved in synucleinopathies representing an attractive strategy to elucidate-common and specific-SNCA-genetic variants, regulatory mechanisms, and vulnerable expression levels underlying synucleinopathy spectrum disorders. This forthcoming knowledge will support the development of precision medicine for synucleinopathies. PMID- 26948952 TI - Human cytosolic sulfotransferase SULT1C4 mediates the sulfation of doxorubicin and epirubicin. AB - Doxorubicin, an anthracycline, has been reported to be excreted in sulfate conjugated form. The current study aimed to identify the human cytosolic sulfotransferase(s) (SULT(s)) that is(are) capable of sulfating doxorubicin and its analog epirubicin, and to verify whether sulfation of doxorubicin and epirubicin may occur under metabolic conditions. A systematic analysis of thirteen known human SULTs, previously cloned, expressed, and purified, revealed SULT1C4 as the only human SULT capable of sulfating doxorubicin and epirubicin. Cultured HepG2 human hepatoma cells and Caco-2 human colon carcinoma cells were labeled with [(35)S]sulfate in the presence of different concentrations of doxorubicin or epirubicin. Analysis of spent labeling media showed the generation and release of [(35)S]sulfated doxorubicin and epirubicin by HepG2 cells and Caco 2 cells. Reverse transcription-polymerase chain reaction (RT-PCR) analysis revealed the expression of SULT1C4 in both HepG2 cells and Caco-2 cells. These results provided a molecular basis underlying the previous finding that sulfate conjugated doxorubicin was excreted in the urine of patients treated with doxorubicin. PMID- 26948953 TI - Biodistribution and pharmacokinetics of the (99m)Tc labeled human elastase inhibitor, elafin, in rats. AB - Elafin is a potent reversible inhibitor of the pro-inflammatory proteases leukocyte elastase and protease 3. It is currently in clinical development for the use in postoperative inflammatory diseases. We investigated the pharmacokinetics of (99m)Tc-labeled elafin ((99m)Tc-Elafin) in blood and individual organs in rat after bolus intravenous injection using the single photon emission tomography (SPECT). (99m)Tc-Elafin predominantly accumulated in the kidney reaching a maximum of 8.5% +/- 0.1% of the injected dose per gram (ID/g) at 5 min post injection (p.i) and decreased only slowly during 24 h. In contrast, the initially high radio activity recorded in the other organs rapidly decreased parallel to the radioactivity detected in blood. The blood kinetics fits to a two compartment kinetics model. The radio activity in the dissected kidney was 4.98 +/- 1.24%ID/g 24 h p.i, while in other organs, including the brain, no accumulation of (99m)Tc-Elafin was detected. At this time point 30% of the detected radioactivity in the kidney was identified to be not metabolized (99m)Tc-Elafin. In conclusion, the blood and organ-specific kinetic data provide a basis for planning of adequate dosing regimens and the high accumulation of intact elafin in the kidney favors clinical developments targeting inflammatory kidney diseases, such as chronic allograft nephropathy after kidney transplantation. PMID- 26948954 TI - Cardiorespiratory fitness estimation in free-living using wearable sensors. AB - OBJECTIVE: In this paper we propose artificial intelligence methods to estimate cardiorespiratory fitness (CRF) in free-living using wearable sensor data. METHODS: Our methods rely on a computational framework able to contextualize heart rate (HR) in free-living, and use context-specific HR as predictor of CRF without need for laboratory tests. In particular, we propose three estimation steps. Initially, we recognize activity primitives using accelerometer and location data. Using topic models, we group activity primitives and derive activities composites. We subsequently rank activity composites, and analyze the relation between ranked activity composites and CRF across individuals. Finally, HR data in specific activity primitives and composites is used as predictor in a hierarchical Bayesian regression model to estimate CRF level from the participant's habitual behavior in free-living. RESULTS: We show that by combining activity primitives and activity composites the proposed framework can adapt to the user and context, and outperforms other CRF estimation models, reducing estimation error between 10.3% and 22.6% on a study population of 46 participants. CONCLUSIONS: Our investigation showed that HR can be contextualized in free-living using activity primitives and activity composites and robust CRF estimation in free-living is feasible. PMID- 26948955 TI - Mechanical insights into ribosomal progression overcoming RNA G-quadruplex from periodical translation suppression in cells. AB - G-quadruplexes formed on DNA and RNA can be roadblocks to movement of polymerases and ribosome on template nucleotides. Although folding and unfolding processes of the G-quadruplexes are deliberately studied in vitro, how the mechanical and physical properties of the G-quadruplexes affect intracellular biological systems is still unclear. In this study, mRNAs with G-quadruplex forming sequences located either in the 5' untranslated region (UTR) or in the open reading frame (ORF) were constructed to evaluate positional effects of the G-quadruplex on translation suppression in cells. Periodic fluctuation of translation suppression was observed at every three nucleotides within the ORF but not within the 5' UTR. The results suggested that difference in motion of ribosome at the 5' UTR and the ORF determined the ability of the G-quadruplex structure to act as a roadblock to translation in cells and provided mechanical insights into ribosomal progression to overcome the roadblock. PMID- 26948956 TI - Mental health and itch in burns patients: Potential associations. AB - The purpose of this study was to investigate the relationship between mental health and self-reported itch in patients with burns across a 6 month time period and to test the hypothesis that poorer mental health outcomes are associated with increased severity of itch. METHOD: A quantitative study with three time points for data collection was conducted. Participants (232) completed assessments at 1 month, 3 months, and 6 months after burn injury. The Patient and Observer Scar Assessment Scale (POSAS) was used to report itch and the Short Form Health Survey (SF-36) provided an assessment of mental health across time. Only data from the itch and mental health subscales were used in the analysis. To analyze the data a quantile regression model was used. RESULTS: Mental health is significantly associated with itch after adjusting for variation in itch over time (p=0.001). The regression coefficient indicates that as mental health increases by one unit, itch decreases by 0.03. Of importance, the relationship remained significant after adjusting for total burn surface area (p<0.001). CONCLUSION: These findings suggest there is a relationship between mental health and itch. Given the powerful impact itch can have on an individual's wellbeing health professionals can begin to further investigate itch from a bio-psychosocial perspective. Further research to investigate causal relationships between mental health and itch is important. PMID- 26948957 TI - Application of the cultured epidermal autograft "JACE((r)") for treatment of severe burns: Results of a 6-year multicenter surveillance in Japan. AB - BACKGROUND: In the 1970s, Green et al. developed a method that involved culturing keratinocyte sheets and used for treatment of burns. Since then, the take rate of cultured epidermal autograft (CEA) onto fascia, granulation tissue, or allografts has been extensively reported, while that on an artificial dermis in a large case series is not. Moreover, the contribution of CEA to patient survival has not been analyzed in a multicenter study. METHODS: We conducted a 6-year multicenter surveillance on the application of the CEA "JACE((r)") for treatment of burns >30% total body surface area (TBSA) across 118 Japanese hospitals. This surveillance included 216 patients and 718 graft sites for efficacy analysis. The CEA take rate at 4 weeks after grafting was evaluated, and safety was monitored until 52 weeks. In addition, the survival curve obtained in this study and the data obtained from the Tokyo Burn Unit Association (TBUA) were compared. RESULTS: The mean CEA take rates at week 4 were 66% (sites) and 68% (patients), and the rate on the artificial dermis was 65% for 226 sites. CEA application combined with wide split-thickness auto or patch autograft increased the CEA take rate. On comparison with the data obtained from the TBUA, which included data on individuals with burns of the same severity, CEA application was found to contribute to patient survival until 7 weeks after burn. CONCLUSIONS: We reported the take rate of CEA based on a 6-year multicenter surveillance. From our results, we found that the application of CEA is a useful treatment for the patients with extensive burns. PMID- 26948958 TI - Pituitary adenylate cyclase-activating polypeptide type 1 receptor signaling evokes long-lasting nociceptive behaviors through the activation of spinal astrocytes in mice. AB - Intrathecal (i.t.) administration of pituitary adenylate cyclase-activating polypeptide (PACAP) induces long-lasting nociceptive behaviors for more than 60 min in mice, while the involvement of PACAP type1 receptor (PAC1-R) has not been clarified yet. The present study investigated signaling mechanisms of the PACAP induced prolonged nociceptive behaviors. Single i.t. injection of a selective PAC1-R agonist, maxadilan (Max), mimicked nociceptive behaviors in a dose dependent manner similar to PACAP. Pre- or post-treatment of a selective PAC1-R antagonist, max.d.4, significantly inhibited the nociceptive behaviors by PACAP or Max. Coadministration of a protein kinase A inhibitor, Rp-8-Br-cAMPS, a mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase inhibitor, PD98059 or a c-Jun N-terminal kinase (JNK) inhibitor, SP600125, significantly inhibited the nociceptive behaviors by Max. Immunohistochemistry and immunoblotting analysis revealed that spinal administration of Max-induced ERK phosphorylation and JNK phosphorylation, and also augmented an astrocyte marker, glial fibrillary acidic protein in mouse spinal cord. Furthermore, an astroglial toxin, l-alpha-aminoadipate, significantly attenuated the development of the nociceptive behaviors and ERK phosphorylation by Max. These results suggest that the activation of spinal PAC1-R induces long-lasting nociception through the interaction of neurons and astrocytes. PMID- 26948960 TI - Long-term financing needs for HIV control in sub-Saharan Africa in 2015-2050: a modelling study. AB - OBJECTIVES: To estimate the present value of current and future funding needed for HIV treatment and prevention in 9 sub-Saharan African (SSA) countries that account for 70% of HIV burden in Africa under different scenarios of intervention scale-up. To analyse the gaps between current expenditures and funding obligation, and discuss the policy implications of future financing needs. DESIGN: We used the Goals module from Spectrum, and applied the most up-to-date cost and coverage data to provide a range of estimates for future financing obligations. The four different scale-up scenarios vary by treatment initiation threshold and service coverage level. We compared the model projections to current domestic and international financial sources available in selected SSA countries. RESULTS: In the 9 SSA countries, the estimated resources required for HIV prevention and treatment in 2015-2050 range from US$98 billion to maintain current coverage levels for treatment and prevention with eligibility for treatment initiation at CD4 count of <500/mm(3) to US$261 billion if treatment were to be extended to all HIV-positive individuals and prevention scaled up. With the addition of new funding obligations for HIV--which arise implicitly through commitment to achieve higher than current treatment coverage levels- overall financial obligations (sum of debt levels and the present value of the stock of future HIV funding obligations) would rise substantially. CONCLUSIONS: Investing upfront in scale-up of HIV services to achieve high coverage levels will reduce HIV incidence, prevention and future treatment expenditures by realising long-term preventive effects of ART to reduce HIV transmission. Future obligations are too substantial for most SSA countries to be met from domestic sources alone. New sources of funding, in addition to domestic sources, include innovative financing. Debt sustainability for sustained HIV response is an urgent imperative for affected countries and donors. PMID- 26948961 TI - The influence of masked hypertension on the right ventricle: is everything really masked? AB - We sought to investigate right ventricular (RV) structure, function, and mechanics in subjects with masked hypertension (MH), normotensive, and sustained hypertensive patients. This cross-sectional study included 186 untreated subjects who underwent 24-hour ambulatory blood pressure (BP) monitoring and complete two dimensional echocardiographic (2DE) examination including multilayer strain analysis. MH was diagnosed if clinic BP was normal (<140/90 mm Hg) and 24-hour BP was increased (>=130/80 mm Hg). Global and free-wall RV longitudinal strains were significantly lower in MH and sustained hypertensive patients comparing with controls. Systolic and early diastolic RV strain rates were lower, whereas late diastolic strain rate was higher, among patients with MH and sustained hypertension than in control group. Endocardial and midmyocardial RV strains were also significantly lower in MH and hypertensive patients. There was no difference between MH and subjects with sustained hypertension. RV structure, function, and deformation are significantly changed in subjects with MH and sustained hypertension. PMID- 26948962 TI - Effects of aerobic dance training on blood pressure in individuals with uncontrolled hypertension on two antihypertensive drugs: a randomized clinical trial. AB - There is a dearth of reports on possible additive blood pressure (BP)-reducing effect of aerobic exercise on antihypertensive drug in humans. This study investigated the additive BP-reducing effect of aerobic exercise on BP in individuals with uncontrolled hypertension. In this 12-week double-blind study, 120 new-diagnosed individuals with mild-to-moderate hypertension were randomized to receive coamilozide + 5/10 mg of amlodipine + aerobic dance or coamilozide + 5/10 mg of amlodipine alone. Forty-five and 43 participants in exercise and control groups, respectively, completed the 12-week intervention. Addition of aerobic exercise to antihypertensive drug therapy significantly reduced systolic BP (7.1 mm Hg [95% confidence interval: 5.0, 9.3]; P < .001) and diastolic BP (1.7 mm Hg [95% confidence interval: 0.4, 3.0]; P = .009) at 12 weeks. BP control rate differed significantly between exercise (53.9%) and control (35.3%) groups, P < .001. Postintervention, proportion of participants in exercise group who had their number of antihypertensive drug reduced to one (20.3%) differed from that in control group (11.1%); (chi(2) = 11.0; P = .001). Combination of aerobic dance and antihypertensive drugs reduces number of antihypertensive drugs needed to achieve BP control and enhances BP control in individuals with hypertension on two antihypertensive drugs. PMID- 26948963 TI - Terminal groups control self-assembly of amphiphilic block copolymers in solution. AB - The terminal groups of amphiphilic block copolymers are shown to control macromolecular self-assembly in aqueous solutions, in the micellar/lamellar region of the phase diagram. At the same concentration and using the same self assembly conditions, dramatic differences are observed in polymer hydration and the resulting nano-/microstructure for two series of polymers with identical block chemistry and hydrophilic-lipophilic balance (HLB). This suggests a strong contribution from end groups to the hydration as the initial step of the self assembly process, and could be conveniently used to guide the particle morphology and size. Additionally, for polymers with those head groups which drive vesicular structures, differences in membrane organization affect their physical properties, such as permeability. PMID- 26948964 TI - [Decrease in toxicity and therapeutic effect of zoledronic acid in combination therapy with different antioxidant extracts]. AB - BACKGROUND: Zoledronic acid is used in the treatment of cancer-related diseases, although its use has been associated with avascular osteonecrosis. AIMS: To determine the possible protective effect of a range of antioxidant substances against the inhibition of human prostate epithelial cell growth (PNT2) and transgenic adenocarcinoma mouse prostate tumour cells (TRAMP-C1), in treatments combining zoledronic acid and ionising radiation (IR). MATERIAL AND METHOD: Cell survival is studied via cell viability assays (MTT) for 2 cell lines in isolated and combined treatments with zoledronic acid and/or IR, as well as the effect of adding 3 antioxidant substances. RESULTS: Zoledronic acid displays a significant cytotoxic effect over PNT2 and TRAMP-C1 cells (P<.001). The administration of antioxidants together with the zoledronic acid shows a protective effect for normal prostate cells, yet not so for prostate tumour cells. However, the administration of rosmarinic acid and apigenin in treatments combined with zoledronic acid provides a protective effect from the harmful effects of applying ionizing radiation, not only for normal PNT2 cells, but also for tumour cells. CONCLUSION: The use of antioxidant substances decreases the cytotoxic effect of zoledronic acid over non-tumour cells, and as such could be used in benign diseases. Furthermore, in the combined treatment using ionising radiation, these antioxidants also produced a protective effect in tumour cells, thus reducing the therapeutic effect sought by combining the treatment with radiation. PMID- 26948965 TI - Nanoparticle Cookies Derived from Metal-Organic Frameworks: Controlled Synthesis and Application in Anode Materials for Lithium-Ion Batteries. AB - The capacity of anode materials plays a critical role in the performance of lithium-ion batteries. Using the nanocrystals of oxygen-free metal-organic framework ZIF-67 as precursor, a one-step calcination approach toward the controlled synthesis of CoO nanoparticle cookies with excellent anodic performances is developed in this work. The CoO nanoparticle cookies feature highly porous structure composed of small CoO nanoparticles (~12 nm in diameter) and nitrogen-rich graphitic carbon matrix (~18 at% in nitrogen content). Benefiting from such unique structure, the CoO nanoparticle cookies are capable of delivering superior specific capacity and cycling stability (1383 mA h g(-1) after 200 runs at 100 mA g(-1) ) over those of CoO and graphite. PMID- 26948966 TI - Association of prenatal antibiotics with foetal size and cord blood leptin and adiponectin. AB - BACKGROUND: Early postnatal antibiotic use has been shown to promote excess weight gain, but it is unclear whether intrauterine exposure to antibiotics is associated with foetal growth and adiposity. The objective of this study was to examine associations of antibiotic prescription in each trimester of pregnancy with foetal size and adipokine levels at birth. METHODS: In 2128 pregnant women from the pre-birth Project Viva cohort, from electronic medical records, we estimated antibiotic prescribing by timing during pregnancy. Outcomes were sex specific birth weight-for-gestational-age z-score (BW/GA-z) and levels of umbilical cord leptin and adiponectin. We used linear regression models adjusted for maternal age, pre-pregnancy body mass index, parity, race/ethnicity, education, smoking during pregnancy, household income and child sex and additionally adjusted cord blood leptin and adiponectin models for gestation length. RESULTS: Of the 2128 women in our sample, 643 (30.2%) were prescribed with oral antibiotics during pregnancy. Mean (standard deviation) BW/GA-z was 0.17 (0.97), cord blood leptin was 9.0 ng mL-1 (6.6) and cord blood adiponectin was 28.8 ng mL-1 (6.8). Overall, antibiotic prescription in pregnancy was associated with lower BW/GA-z [multivariable adjusted beta -0.11; 95% confidence interval {CI} -0.20, -0.01]. In trimester-specific analyses, only second trimester antibiotic prescription was associated with lower BW/GA-z (beta -0.23; 95% CI -0.37, -0.08). Overall, antibiotic prescription in pregnancy was not associated with cord blood leptin or adiponectin levels. However, in trimester specific analyses, third trimester antibiotic prescription was associated with higher cord blood leptin (beta 2.28 ng mL-1 ; 95% CI 0.38, 4.17). CONCLUSIONS: Antibiotics in mid-pregnancy were associated with lower birth weight for gestational age, whereas third trimester antibiotics were associated with higher cord blood leptin. PMID- 26948967 TI - Re-refinement of 4g4a: room-temperature X-ray diffraction study of cisplatin and its binding to His15 of HEWL after 14 months chemical exposure in the presence of DMSO. AB - A re-refinement of 4g4a, the room-temperature X-ray diffraction study of cisplatin and its binding to His15 of HEWL after 14 months chemical exposure in the presence of DMSO is published as an addendum to Tanley et al. [(2012), Acta Cryst. F68, 1300-1306]. This example illustrates the benefits of sharing raw diffraction images, as well as structure factors and molecular coordinates, as the diffraction resolution of the study is now much improved at 1.70 A. PMID- 26948968 TI - Immobilizing photogenerated electrons from graphitic carbon nitride for an improved visible-light photocatalytic activity. AB - Reducing the recombination probability of photogenerated electrons and holes is pivotal in enhancing the photocatalytic ability of graphitic carbon nitride (g C3N4). Speeding the departure of photogenerated electrons is the most commonly used method of achieving this. To the best of our knowledge, there is no report on suppressing the recombination of photogenerated electron-hole pairs by immobilizing the electrons with ester functional groups. Here, for the first time the mesoporous g-C3N4 (mpg-C3N4) was integrated with polymethyl methacrylate, a polymer abundant in ester groups, which showed a photocatalytic activity unexpectedly higher than that of the original mpg-C3N4 under visible-light irradiation. Experimental observations, along with theoretical calculations, clarified that the impressive photocatalytic ability of the as-modified mpg-C3N4 was mainly derived from the immobilization of photogenerated electrons via an electron-gripping effect imposed by the ester groups in the polymethyl methacrylate. This novel strategy might also be applied in improving the photocatalytic performance of other semiconductors. PMID- 26948969 TI - The geochemistry model of the surface sediment determined by using ED-XRF technique: a case study of the Boka Kotorska bay, Adriatic Sea. AB - The spatial distribution of major oxides (Na2O, K2O, SiO2, Al2O3, Fe2O3, CaO, MgO, MnO, TiO2, P2O5) and numerous elements (Cr, Co, Ni, Cu, Zn, As, Se, Pb, Sn, Sb, Ba, Sr, Br, Rb, Zr, Mo, Cs, Y, V, Ga, La, U, Th, Nb, W, Sc, Ge, Gd, Yb, Hf, and Ce) was determined by using energy dispersive X-ray fluorescence spectrometry on the basis of previously measured organic matter and carbonates. The optimal measuring variables for the investigated oxides and elements were determined by using five standard reference materials. The carbonated sediment type can be determined on the basis of the highest Sr, Sc, La, Nb, Hf, and Yb concentrations followed with the lowest concentrations of the remaining elements and the negative Ce anomaly. The complexity of the obtained data was also examined by principal component analysis (PCA) and cluster analysis (CA) in the identifying geochemical composition of the surface sediment. Boka Kotorska bay's geographical position, orographical configuration, and hydrographic characteristics influence the geochemistry model of the surface sediment, quite different from the open sea. PMID- 26948970 TI - Mobilisation processes responsible for iron and manganese contamination of groundwater in Central Adriatic Italy. AB - Iron and manganese are two of the most common contaminants that exceed the threshold imposed by international and national legislation. When these contamination occurs in groundwater, the use of the water resource is forbidden for any purposes. Several studies investigated these two metals in groundwater, but research focused in the Central Adriatic area are still lacking. Thus, the objective of this study is to identify the origin of Fe and Mn contamination in groundwater and the hydrogeochemical processes that can enrich aquifers with these metals. This work is based on hydrogeochemical and multivariate statistical analysis of analytical results undertaken on soils and groundwater. Fe and Mn contamination are widespread in the alluvial aquifers, and their distribution is regulated by local conditions (i.e. long residence time, presence of peat or organic-rich fine sediments or anthropic pollution) that control redox processes in the aquifers and favour the mobilisation of these two metals in groundwater. The concentration of iron and manganese identified within soil indicates that the latter are a concrete source of the two metals. Anthropic impact on Fe and Mn contamination of groundwater is not related to agricultural activities, but on the contrary, the contribution of hydrocarbons (e.g. spills) is evident. PMID- 26948971 TI - A method for heavy metal exposure risk assessment to migratory herbivorous birds and identification of priority pollutants/areas in wetlands. AB - Wetlands are important habitats for migratory birds but have been degraded by many anthropogenic factors including heavy metal contamination. Birds inhabiting wetlands are exposed to pollutants. In this study, a method for exposure risk assessment of migratory herbivorous birds and identification of priority pollutants/areas was developed and employed in East Dongting Lake wetland (EDT). Four heavy metals (Cr, Cu, Pb, and Cd) in sedge and soil samples from ten lesser white-fronted goose (Anser erythropus) habitats in EDT were investigated. Results showed that negative effect of Cr and Pb on lesser white-fronted goose may occur while the concentrations of Cu and Cd are considered to be relatively safe. Prioritize threats were decreased in the following sequence: Cr > Pb > Cu > Cd. Cr and Pb were considered to be the priority pollutants. Spatial interpolation based on geostatistical methods showed that Spring Breeze Lake should draw much attention. Furthermore, regions with high hazard index were identified to be priority areas of EDT for risk management. PMID- 26948972 TI - Genetic effects on sleep/wake variation of seizures. AB - OBJECTIVE: There is a complex bidirectional relationship between sleep and epilepsy. Sleep/wake timing of seizures has been investigated for several individual seizure types and syndromes, but few large-scale studies of the timing of seizures exist in people with varied epilepsy types. In addition, the genetic contributions to seizure timing have not been well studied. METHODS: Sleep/wake timing of seizures was determined for 1,395 subjects in 546 families enrolled in the Epilepsy Phenome/Genome Project (EPGP). We examined seizure timing among subjects with different epilepsy types, seizure types, epilepsy syndromes, and localization. We also examined the familial aggregation of sleep/wake occurrence of seizures. RESULTS: Seizures in nonacquired focal epilepsy (NAFE) were more likely to occur during sleep than seizures in generalized epilepsy (GE), for both convulsive (odds ratio [OR] 5.2, 95% confidence interval [CI] 3.59-7.52) and nonconvulsive seizures (OR 4.2, 95% CI 2.48-7.21). Seizures occurring within 1 h of awakening were more likely to occur in patients with GE than with NAFE for both convulsive (OR 2.3, 95% CI 1.54-3.39) and nonconvulsive (OR 1.7, 95% CI 1.04 2.66) seizures. Frontal onset seizures were more likely than temporal onset seizures to occur during sleep. Sleep/wake timing of seizures in first-degree relatives predicted timing of seizures in the proband. SIGNIFICANCE: We found that sleep/wake timing of seizures is associated with both epilepsy syndrome and seizure type. In addition, we provide the first evidence for a genetic contribution to sleep/wake timing of seizures in a large group of individuals with common epilepsy syndromes. PMID- 26948973 TI - Conversion of Dinitrogen into Acetonitrile under Ambient Conditions. AB - About 20% of the ammonia production is used as the chemical feedstock for nitrogen-containing chemicals. However, while synthetic nitrogen fixation at ambient conditions has had some groundbreaking contributions in recent years, progress for the direct conversion of N2 into organic products remains limited and catalytic reactions are unknown. Herein, the rhenium-mediated synthesis of acetonitrile using dinitrogen and ethyl triflate is presented. A synthetic cycle in three reaction steps with high individual isolated yields and recovery of the rhenium pincer starting complex is shown. The cycle comprises alkylation of a nitride that arises from N2 splitting and subsequent imido ligand centered oxidation to nitrile via a 1-azavinylidene (ketimido) intermediate. Different synthetic strategies for intra- and intermolecular imido ligand oxidation and associated metal reduction were evaluated that rely on simple proton, electron, and hydrogen-atom transfer steps. PMID- 26948974 TI - Human basophil chemotaxis and activation are regulated via the histamine H4 receptor. AB - BACKGROUND: IgE-mediated cross-linking of FcepsilonRI results in the release of mediators stored in basophil granules, such as histamine and proteases, and in the de novo synthesis of sulfidoleukotrienes. OBJECTIVE: In this study, we investigated the role of the histamine receptors, in particular that of the histamine H4 receptor (H4R), in modulating human basophil function. METHODS: The mRNA expression of the histamine receptors was measured by real-time PCR. Migration of basophils was assessed using the modified Boyden chamber technique. The expression levels of CD63 and CD203c on the cell surface and the sulfidoleukotriene release were determined by flow cytometry and ELISA, respectively. RESULTS: We could show that highly purified basophils express the H1R, H2R, and H4R but not the H3R mRNA. Human basophils expressed higher H4R mRNA levels as compared to the expression levels of the H1R (P < 0.01). Histamine and the H4R agonist ST-1006 initiated active migration of basophils (P < 0.001). A significant reduction in FcepsilonRI cross-linking-mediated surface expression of CD63 and CD203c was observed on basophils after pre-incubation with histamine or the specific H4R agonist ST-1006 (P < 0.01). The synthesis and release of sulfidoleukotrienes from basophils after activation with different stimuli, by FcepsilonRI cross-linking or by stimulation with hymenoptera venom allergens, were significantly reduced by histamine or the H4R agonist ST-1006 (P < 0.05 0.001). CONCLUSION: These data imply that the H4R regulates IgE-dependent processes in human basophils and provides a novel function of the H4R preventing an overwhelming immune reaction by engagement of a negative feedback loop. PMID- 26948975 TI - Oral Health Disparities: Let the Voice of PHNs Be Heard. PMID- 26948976 TI - Quantification of low levels of amorphous content in crystalline celecoxib using dynamic vapor sorption (DVS). AB - A minor amount of amorphous phase, especially present on the surface of crystalline pharmaceutical actives, can have a significant impact on their processing and performance. Despite the presence of sophisticated analytical tools, detection and quantification of low levels of amorphous content pose significant challenges owing to issues of sensitivity, suitability, limit of detection and limit of quantitation. Current study encompasses the quantification of amorphous content in the crystalline form of celecoxib (CLB) using a dynamic vapor sorption (DVS) based method. Water, used as the solvent probe, achieved equilibration within a very short period of time (i.e. 6h) due to hydrophobic nature of CLB, thus allowing development of a rapid quantification method. The study included optimization of instrument and sample related parameters for the development of an analytical method. The calibration curve for amorphous CLB in crystalline CLB was prepared in the concentration range of 0-10% w/w. The analytical method was validated for linearity, range, accuracy and precision. The method for quantification was found to be linear with R(2) value of 0.999, rapid and sensitive for quantification of low levels of amorphous CLB content. It was able to detect the presence of amorphous phase in a predominantly crystalline phase at concentrations as low as 0.3% w/w. The limit of quantitation was found to be 0.9% w/w. Moreover, the influence of mechanical processing on the amorphous content in crystalline CLB was also investigated. PMID- 26948977 TI - Dermal quercetin smartCrystals(r): Formulation development, antioxidant activity and cellular safety. AB - Flavonoids are natural plant pigments, which possess high antioxidative and antiradical activities. However, their poor water solubility led to a limited bioavailability. To overcome this major hurdle, quercetin nanocrystals were produced implementing smartCrystals(r) technology. This process combines bead milling and subsequent high-pressure homogenization at relatively low pressure (300bar). To test the possibility to develop a dermal formulation from quercetin smartCrystals(r), quercetin nanosuspensions were admixed to Lutrol(r) F127 and hydroxythylcellulose nonionic gels. The physicochemical properties (morphology, size and charge), saturation solubility, dissolution velocity and the antioxidant properties (DPPH assay) as well as the cellular interaction of the produced quercetin smartCrystals(r) were studied and compared to crude quercetin powder. Quercetin smartCrystals(r) showed a strong increase in the saturation solubility and the dissolution velocity (7.6 fold). SmartCrystals(r) loaded or not into gels proved to be physically stable over a period of three months at 25 degrees C. Interestingly, in vitro DPPH assay confirmed the preservation of quercetin antioxidative properties after nanonization. In parallel, the nanocrystalline form did not display cellular toxicity, even at high concentration (50MUg/ml), as assayed on an epithelial cell line (VERO cells). In addition, the nanocrystalline form confirmed a protective activity for VERO cells against hydrogen peroxide induced toxicity in vitro. This new formulation presents a promising approach to deliver quercetin efficiently to skin in well-tolerated formulations. PMID- 26948978 TI - Simultaneous expression and transportation of insulin by supramolecular polysaccharide nanocluster. AB - Drug/gene transportation systems with stimuli-responsive release behaviors are becoming research hotspots in biochemical and biomedical fields. In this work, a glucose-responsive supramolecular nanocluster was successfully constructed by the intermolecular complexation of phenylboronic acid modified beta-cyclodextrin with adamantane modified polyethylenimine, which could be used as a biocompatible carrier for insulin and pCMV3-C-GFPSpark-Ins DNA which could express insulin co delivery. Benefiting from the response capability of phenylboronic acid moiety toward glucose, the encapsulated insulin could be specifically released and the corresponding targeted DNA could efficiently express insulin in HepG2 cell, accompanied by the high-level insulin release in vitro. Our results demonstrate that the simultaneous insulin drug delivery and insulin gene transfection in a controlled mode may have great potential in the clinical diabetes treatments. PMID- 26948979 TI - 'Maybe they should regulate them quite strictly until they know the true dangers': a focus group study exploring UK adolescents' views on e-cigarette regulation. AB - BACKGROUND AND AIMS: Regulation of electronic cigarettes has moved to the top of the addiction policy agenda, as demonstrated by the recent focus across the United Kingdom on introducing age-of-sale restrictions. However, the views of those affected by such regulation remain largely unexplored. This paper presents the first detailed qualitative exploration of adolescents' perceptions of existing, and opinions about potential e-cigarette regulation. METHODS: Sixteen focus groups, including a total of 83 teenagers between the ages of 14 and 17 years, were conducted in deprived, mixed and affluent urban areas in Scotland and England between November 2014 and February 2015. Transcripts were imported into Nivivo 10, coded thematically and analysed. RESULTS: Participants critically considered existing evidence and competing interests in regulatory debates and demonstrated sophisticated understanding of the advantages and disadvantages of regulation. They overwhelmingly supported strong e-cigarette regulation and endorsed restrictions on sales to minors, marketing and e-cigarette use in public places. Concern about potential health harms of e-cigarette use and marketing increasing the acceptability of vaping and smoking led these adolescents to support regulation. CONCLUSIONS: In focus group discussions, a sample of UK adolescents exposed to particular communications about e-cigarettes supported strict regulation of e-cigarettes, including banning sales to minors and use in indoor public areas. PMID- 26948980 TI - Associations between obstructive lung disease and symptoms of obstructive sleep apnoea in a general population. AB - OBJECTIVES: To examine the prevalence of self-reported symptoms of obstructive sleep apnoea (OSA) in relation to asthma, respiratory symptoms and pulmonary function. A secondary objective was to determine how sex impacted these relationships. METHODS: A random sample of all adults aged 47-48 and 71-73 years living in Bergen, Norway, were invited. Participants (3506, 69%) underwent spirometry testing and completed a questionnaire on sleep, respiratory symptoms and past medical history. OSA was defined by positive answers to questions on snoring, breathing cessations and daytime sleepiness. Current asthma was defined by ever having received a physician's diagnosis of asthma and current use of anti asthma medication. Logistic regression analyses, including interaction analyses between sex and the different explanatory variables, were used to examine associations between OSA and current asthma, pre- and post-bronchodilator pulmonary function tests, smoking habits and respiratory symptoms. All models were adjusted for age, sex, waist-hip ratio and smoking. RESULTS: OSA was more prevalent in the middle-aged compared to the elderly (6.2% vs 3.6%), and in subjects reporting respiratory symptoms. 4.8% had OSA and 6.1% had current asthma. Current asthma and the lowest quartile of post-bronchodilator FVC were significantly associated with OSA with ORs of 2.5 (1.5, 4.2) and 1.7 (1.1, 2.7), respectively. In interaction analyses, women with post-bronchodilator FEV1 /FVC < 0.7 had an increased risk of OSA [OR of 4.1 (1.7, 9.7)] compared to women with a FEV1 /FVC >= 0.7. CONCLUSIONS: Current asthma was associated with increased risk of OSA. Women with chronic airflow limitation, but not men, had increased risk of OSA. PMID- 26948981 TI - Hormetic and anti-inflammatory properties of oxidized phospholipids. AB - Oxidized phospholipids are generally recognized as deleterious factors involved in disease pathogenesis. This review summarizes the data suggesting that under certain biological conditions the opposite is correct, namely that OxPLs can also induce protective effects. Examples that are discussed in the review include upregulation of antioxidant genes, inhibition of inflammatory signaling pathways through Nrf2-dependent and -independent mechanisms, antagonism of Toll-like receptors, immuno-modulating and immuno-suppressive action of OxPLs in adaptive immunity and autoimmune disease, activation of PPARs known for their anti inflammatory action, as well as protective action against lung edema in acute lung inflammation. The data support the notion that oxidation of phospholipids provides a negative feedback preventing damage to host tissues due to uncontrolled inflammation and oxidative stress. PMID- 26948982 TI - Rapid recovery of photosynthetic rate following soil water deficit and re watering in cotton plants (Gossypium herbaceum L.) is related to the stability of the photosystems. AB - The responses of gas exchange, chlorophyll fluorescence and the anti-oxidative system of cotton leaves were studied during water deficit and recovery. The results show that water deficit led to a reversible reduction in the photosynthetic rate. This reduction was mainly accompanied by stomatal limitation. The activity of photosystem II (PSII) and photosystem I (PSI) was relatively stable during water deficit and recovery. Water deficit caused an enhanced production of reactive oxygen species (ROS) and increased lipid peroxidation. Proline accumulation and the anti-oxidative enzymes such as superoxide dismutase (SOD), ascorbate peroxidase (APX) and peroxidase (POD), along with the antioxidant ascorbate (AsA), increased during water deficit. On re watering, the ROS generation rate, anti-oxidative enzymes activities and the extent of the lipid peroxidation returned to near control values. Overall, rapid recovery of the photosynthetic rate is related to the stability of the photosystems which appears to be a critical mechanism allowing cotton plants to withstand and survive drought environments. PMID- 26948983 TI - Variability in the carbon isotope composition of individual amino acids in plant proteins from different sources: 1 Leaves. AB - The natural carbon isotope composition of individual amino acids from plant leaf proteins has been measured to establish potential sources of variability. The plant leaves studied, taken from a range of plant groups (forbs, trees, grasses, and freshwater aquatic plants), showed no significant influence of either season or environment (water and light availability) on their Deltadelta(13)C values. Plant groups did, however, differ in carbon isotope composition, although no consistent differences were identified at the species level. A discriminant analysis model was constructed which allowed leaves from (1) nettles, (2) Pooideae, (3) other Poales, (4) trees and (5) freshwater higher plants to be distinguished from each other on the basis of their natural abundance (13)C/(12)C ratios of individual amino acids. Differences in carbon isotope composition are known to be retained, to some extent, in the tissues of their consumers, and hence an understanding of compound-specific variation in (13)C/(12)C fractional abundance in plants has the potential to provide dietary insights of value in archaeological and ecological studies. PMID- 26948984 TI - Creating a cultural analysis tool for the implementation of Ontario's civil mental health laws. AB - Ethno-racial people with mental health disabilities experience multiple inequities and differential outcomes when interacting with Ontario's civil mental health laws. Given the increasing multi-racial population in Ontario, there is a need to develop mechanisms to address these intersecting issues. Other countries that have created evaluative tools for mental health legislation include the United Kingdom and Australia. Australia's Rights Analysis Tool, the United Kingdom's Race Equality Impact Assessment, the Scottish Recovery Tool, and the World Health Organization's Mental Health and Human Rights checklist are examples of evaluative tools developed for mental health legislation. Such a tool does not exist in Canada, let alone in Ontario specifically. Thus, this study developed a Cultural Analysis Tool (CAT) consisting of specific and meaningful thematic questions that can be used by practitioners when addressing issues of culture and equity for ethno-racial people with mental health disabilities interacting with Ontario's civil mental health laws. It is hoped that the CAT, and the research underlying its development, will enable practitioners to critically question whether cultural and intersecting concerns are being appropriately addressed within an ethno-racial client's case and, furthermore, how equitable outcomes can be achieved. This article describes and analyzes the methodology, research and qualitative data used to develop the CAT. It then presents and examines the CAT itself. The qualitative data was drawn from thirty-five semi-structured interviews with seven members of each of the following groups: (1) ethno-racial people with mental health disabilities including in-patients and ex-patients, (2) lawyers who practice in the area of mental health law, (3) health care professionals including psychiatrists, nurses and social workers, (4) service providers such as front-line case workers at mental health agencies and (5) adjudicators, government advisors and academics. After an analysis of these data, the CAT's questions were refined through an expert review (involving the qualitative technique of member-checking) using three focus groups comprised of ethno-racial people with mental health disabilities, mental health lawyers and service providers and health care professionals. PMID- 26948985 TI - Silent Cerebral Embolism After Catheter Ablation for Atrial Fibrillation - Unresolved Issue or Too Much Concern? PMID- 26948986 TI - Implantation Site Does Matter for Defibrillation Threshold. PMID- 26948987 TI - High-performance thermoelectric nanocomposites from nanocrystal building blocks. AB - The efficient conversion between thermal and electrical energy by means of durable, silent and scalable solid-state thermoelectric devices has been a long standing goal. While nanocrystalline materials have already led to substantially higher thermoelectric efficiencies, further improvements are expected to arise from precise chemical engineering of nanoscale building blocks and interfaces. Here we present a simple and versatile bottom-up strategy based on the assembly of colloidal nanocrystals to produce consolidated yet nanostructured thermoelectric materials. In the case study on the PbS-Ag system, Ag nanodomains not only contribute to block phonon propagation, but also provide electrons to the PbS host semiconductor and reduce the PbS intergrain energy barriers for charge transport. Thus, PbS-Ag nanocomposites exhibit reduced thermal conductivities and higher charge carrier concentrations and mobilities than PbS nanomaterial. Such improvements of the material transport properties provide thermoelectric figures of merit up to 1.7 at 850 K. PMID- 26948988 TI - Complementary clinical effects of red complex bacteria on generalized periodontitis in a caucasian population. AB - OBJECTIVES: To relate five periodontopathogenic bacteria, including the red complex, to the severity, extent, and inflammation of the periodontal lesion in Caucasian patients with generalized aggressive and chronic periodontitis and to explore whether tobacco use is associated with a specific bacterial profile. MATERIALS AND METHODS: A cross-sectional and analytic study was conducted in patients with aggressive and chronic periodontitis. Data were gathered on socio demographic and periodontal variables, and RH-PCR was used to determine subgingival bacterial profile. Linear and logistic regression analyses were performed. RESULTS: The study included 60 patients with aggressive and 123 with chronic periodontitis. Total red complex bacteria count was higher in aggressive periodontitis, mainly due to T. denticola (P = 0.015). In both periodontitis types, models showed an association between T. forsythia count and probing depth (B = 0.157, P = 0.030) and between T. denticola count and higher bleeding scores (B = 2.371, P = 0.027). Smoking did not affect the red complex bacteria count in either disease. CONCLUSIONS: The prevalence of red complex bacteria was similar between aggressive and chronic periodontitis, but their count was higher in the former. In both diseases, T. forsythia was associated with greater severity and T. denticola with more severe bleeding. Tobacco smoking was not associated with the presence of red complex bacteria in either disease. PMID- 26948989 TI - Harmonic reduction of Direct Torque Control of six-phase induction motor. AB - In this paper, a new switching method in Direct Torque Control (DTC) of a six phase induction machine for reduction of current harmonics is introduced. Selecting a suitable vector in each sampling period is an ordinal method in the ST-DTC drive of a six-phase induction machine. The six-phase induction machine has 64 voltage vectors and divided further into four groups. In the proposed DTC method, the suitable voltage vectors are selected from two vector groups. By a suitable selection of two vectors in each sampling period, the harmonic amplitude is decreased more, in and various comparison to that of the ST-DTC drive. The harmonics loss is greater reduced, while the electromechanical energy is decreased with switching loss showing a little increase. Spectrum analysis of the phase current in the standard and new switching table DTC of the six-phase induction machine and determination for the amplitude of each harmonics is proposed in this paper. The proposed method has a less sampling time in comparison to the ordinary method. The Harmonic analyses of the current in the low and high speed shows the performance of the presented method. The simplicity of the proposed method and its implementation without any extra hardware is other advantages of the proposed method. The simulation and experimental results show the preference of the proposed method. PMID- 26948990 TI - Serum beta-Trace Protein and beta2-Microglobulin as Predictors of ESRD, Mortality, and Cardiovascular Disease in Adults With CKD in the Chronic Renal Insufficiency Cohort (CRIC) Study. AB - BACKGROUND: Serum beta-trace protein (BTP) and beta2-microglobulin (B2M) are independently associated with end-stage renal disease (ESRD) and mortality in the general population and high-risk groups with diabetes or advanced chronic kidney disease (CKD). Less is known about their associations with outcomes and predictive ability in adults with moderate CKD. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 3,613 adults from the CRIC (Chronic Renal Insufficiency Cohort) Study (45% women; mean age, 57.9 years; 41.0% non-Hispanic black; 51.9% with diabetes). PREDICTORS: BTP and B2M levels with a reciprocal transformation to reflect their associations with filtration, creatinine-based estimated glomerular filtration rate (eGFRcr), measured GFR, and a 4-marker composite score combining BTP, B2M, creatinine, and cystatin C levels. Predictors were standardized as z scores for comparisons across filtration markers. OUTCOMES: ESRD, all-cause mortality, and new-onset cardiovascular disease. RESULTS: During a 6-year median follow-up, 755 (21%) participants developed ESRD, 653 died, and 292 developed new-onset cardiovascular disease. BTP, B2M, and the 4 marker composite score were independent predictors of ESRD and all-cause mortality, and B2M and the 4-marker composite score of cardiovascular events, after multivariable adjustment. These associations were stronger than those observed for eGFRcr (P vs eGFRcr<=0.02). The 4-marker composite score led to improvements in C statistic and 2.5-year risk reclassification beyond eGFRcr for all outcomes. LIMITATIONS: Filtration markers measured at one time point; measured GFR available in subset of cohort. CONCLUSIONS: BTP and B2M levels may contribute additional risk information beyond eGFRcr, and the use of multiple markers may improve risk prediction beyond this well-established marker of kidney function among persons with moderate CKD. PMID- 26948992 TI - High prevalence of W1282x mutation in cystic fibrosis patients from Karachay Cherkessia. AB - Cystic fibrosis (CF; OMIM #219700) is a common autosomal recessive disease. The spectrum and frequency of CFTR mutations vary significantly in different populations and ethnic groups. A genetic epidemiological study was conducted in the indigenous ethnic group of people known as the Karachais. They live in the Republic of Karachay-Cherkessia, which lies in the northwest of Russia's North Caucasus region. Karachai's are Turkic-speaking and consist of 194 thousand people (approximately 40% of the population of the Republic). Molecular genetic analysis was performed in 10 unrelated Karachai families with CF patients from three districts in the Republic. A high frequency of W1282X mutation was found (18 of 20 mutant alleles): eight patients were homozygous for the W1282X mutation, and two were compound heterozygous (the second alleles were R1066C and R709X). Analysis for 13 common CF mutations in the sample of 142 healthy Karachais identified two 1677delTA and two W1282X mutation carriers. Thus, the most common CFTR mutation, F508del, was not detected among the CF patients or in healthy Karachais. The most frequent mutation among Karachai patients is W1282X (90%). Its frequency in healthy Karachais is approximately 0.007. Haplotype analysis using the CFTR intragene DNA markers IVS1CA, IVS6aGATT, IVS8CA and IVS17bCA showed that the origins of the W1282X mutation in Karachay-Cherkessia and the Eastern European part of Russia are different. PMID- 26948994 TI - A Phantom Study and a Retrospective Clinical Analysis to Investigate the Impact of a New Image Processing Technology on Radiation Dose and Image Quality during Hepatic Embolization. AB - PURPOSE: To investigate changes in radiation dose and image quality using phantoms and hepatic embolization procedures performed with a new image processing technology (ClarityIQ) for a single-plane flat-detector-based interventional fluoroscopy system. MATERIALS AND METHODS: Phantom study was performed using acrylic sheets simulating different patient sizes. Air kerma rates (AKRs) were compared for different fluoroscopy modes and magnification modes without and with ClarityIQ. Repeat hepatic embolization procedures performed on the same lobe of the liver in the same patient by the same interventional radiologist between January 2013 and July 2014 without and with ClarityIQ were evaluated retrospectively. This included treatment of 33 hepatic lobes in 26 patients. Cumulative air kerma (CAK), kerma-area product (KAP), and factors affecting radiation dose were extracted from study metadata and compared. Blinded randomized image quality review was performed on arteriograms using a five-point scale. RESULTS: The phantom study revealed a significantly lower AKR (P < .005) with ClarityIQ. Repeated-measures analysis revealed a significant effect of ClarityIQ (P <= .001) on CAK and KAP, with reductions ranging between 9% and 85% (median, 67%) and between 5% and 89% (median, 75%), respectively, on a case-by-case basis. Mean reductions in CAK and KAP were 279 mGy and 134,030 mGy.cm(2), respectively. Image quality review scores were significantly lower (P <= .001) with ClarityIQ, effecting visualization of tumor vasculature and appearance of noise texture. CONCLUSIONS: ClarityIQ resulted in radiation dose reduction in the phantom study and in the hepatic embolization procedures, but with a decrease in subjective perceptions of image quality. PMID- 26948995 TI - Exploring photochemistry of p-bromophenylsulfonyl, p-tolylsulfonyl and methylsulfonyl azides by ultrafast UV-pump-IR-probe spectroscopy and computations. AB - The photochemistry of p-bromophenylsulfonyl azide (BsN3), p-tolylsulfonyl azide (TsN3) and methylsulfonyl azide (MsN3) was studied by femtosecond time-resolved infrared spectroscopy with CH2Cl2 and CCl4 as solvents along with quantum chemical calculations. The photolysis of these azides after 267 nm light excitation leads to the population of each respective azide S1 excited state. Decay of the S1 excited state gives rise to singlet nitrene formation. In the case of BsN3, the decay was found to correlate with the formation of a pseudo Curtius photoproduct (PCP) BrC6H4NSO2. Transient electronic ground states of the three azides on their way to singlet nitrenes and PCPs were shown by locating the corresponding transition states on the potential energy surfaces. The lifetime of singlet (1)(BsN) and (1)(TsN) nitrenes is tau(S) = ~20 ps in CH2Cl2 and ~700 ps in CCl4. Singlet (1)(MsN) was not detected. Due to fast intersystem crossing (ISC), singlet nitrenes are converted into the triplet spin isomers lying lower in energy, the formation time constants being equal to the corresponding singlet nitrene lifetime. The formation of (3)(MsN) was shown and the formation time constant in CH2Cl2 was found to be tau(ISC) = 34 +/- 3 ps. Internal conversion of the S1 excited state to the ground state of the azide was low (Phi ~ 0.15) for BsN3 and TsN3 and was not found in the case of MsN3. PMID- 26948993 TI - Satellite Cell Heterogeneity in Skeletal Muscle Homeostasis. AB - The cellular turnover required for skeletal muscle maintenance and repair is mediated by resident stem cells, also termed satellite cells. Satellite cells normally reside in a quiescent state, intermittently entering the cell cycle to fuse with neighboring myofibers and replenish the stem cell pool. However, the mechanisms by which satellite cells maintain the precise balance between self renewal and differentiation necessary for long-term homeostasis remain unclear. Recent work has supported a previously unappreciated heterogeneity in the satellite cell compartment that may underlie the observed variability in cell fate and function. In this review, we examine the work supporting this notion as well as the potential governing principles, developmental origins, and principal determinants of satellite cell heterogeneity. PMID- 26948996 TI - Fibrocyte and T cell interactions promote disease pathogenesis in rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is a systemic autoimmune disease. We previously identified a circulating cell population, fibrocytes, which is activated early in disease. As RA is characterized by the formation of autoantibodies and autoreactive T cells, which often precede symptom onset, the objective of these studies was to characterize fibrocyte activation in the context of T cell activation. Multidimensional flow cytometry was used to characterize the activation status of peripheral blood (PB) fibrocytes and T cells derived from RA patients with different levels of disease activity. Compared to healthy controls, fibrocytes from RA patients exhibited increased activation, denoted as elevated levels of phosphorylation of STAT3 and NF-kappaB. RA patients had higher numbers of circulating activated Th17 cells and Tregs compared with healthy controls, Th17 cell numbers being higher in patients with moderate to high disease activity. Additionally, increased numbers of FOXP3+ RORgammat+ double positive CD4+ T cells were observed in RA patients with more severe disease. Our data confirm that circulating fibrocytes are expanded in RA and that there is a direct correlation between the increase in number of activated fibrocytes and increased number of CD4+ T cells. Moreover, our data suggest that interactions between circulating fibrocytes and activated T cells may promote disease activity. Specifically, we provide in vitro evidence that mouse-derived CD4+ T cells produce GM-CSF which induces fibrocyte proliferation. In turn, activated fibrocytes produce IL-6, promoting Th17 polarization. PMID- 26948998 TI - Basal cell carcinomata: Risk factors for incomplete excision and results of re excision. AB - INTRODUCTION: Re-excision of incompletely excised basal cell carcinomas (BCCs) can be unsatisfactory in the absence of residual tumours. Recommended guidelines do suggest re-excision as a treatment modality; however, its value has been questioned due to low or variable residual tumour presence. We analysed the incomplete excision and re-excision rates and the presence of residual tumours over an 18-month period in a single unit. METHOD: Using pathology results and case notes, 2586 primary excisions of BCCs in 1717 patients were reviewed. RESULTS: The incomplete excision rate was reported to be 7.1% (184/2586). Excision of a lesion by multiple excision lesion procedure was associated with a higher rate of incomplete excision when compared to single lesion excision procedure (61.5% vs. 38.5%). Of the incompletely excised BCCs, 33.6% (62/184) were re-excised, of which 62.9% (39/62) had residual tumours. Although the figures are small, most anatomical sites examined had a residual tumour presence >50%. CONCLUSION: After evaluating each patient individually, considering the high residual tumour rate, re-excision of an incompletely excised BCC would be a worthwhile procedure. PMID- 26948999 TI - Painful thumb carpometacarpal joint osteoarthritis: Results of a novel treatment approach. AB - BACKGROUND: Pain reduction as well as preservation and improvement in range of motion remain the main aims in the treatment of thumb carpometacarpal (CMC) osteoarthritis (OA). We performed a retrospective outcome analysis of patients with symptomatic stage II-III thumb CMC joint arthritis treated with denervation, joint lavage and capsular imbrication. METHODS: 73 patients with stage II to III OA of the thumb CMC-joint underwent the described technique. A total of 42 patients complied with follow-up assessment and were included in this study. Mean follow-up was 41.2 (range 12-81) months. RESULTS: Mean operative time was 28.4 (+/-6.5) minutes. The follow-up assessments showed a significant decrease in pain (preoperative Numerical Rating Scale (NRS): 7.5 - postoperative NRS: 1.1) (p < 0.0001) and a significant improvement in function of the thumb (preoperative DASH Score: 46.8; Cooney-Wrist-Score: 35.4; Krimmer-Wrist-Score: 38.3 - postoperative DASH-Score: 18.1; Cooney-Wrist-Score: 73.7; Krimmer-Wrist-Score: 80.0) (p < 0.0001). CONCLUSION: The findings of our study indicate that the presented treatment approach could be a good alternative to more invasive surgical options in patients with stage II-III CMC OA of the thumb, without impairing more invasive surgical options like trapeziectomy or arthroplasty for the future. PMID- 26948997 TI - Obstacles and opportunities for targeting the effector T cell response in type 1 diabetes. AB - Autoreactive lymphocytes display a programmed set of characteristic effector functions and phenotypic markers that, in combination with antigen-specific profiling, provide a detailed picture of the adaptive immune response in Type 1 diabetes (T1D). The CD4+ T cell effector compartment (referred to as "Teff" in this article) has been extensively analyzed, particularly because the HLA genes most strongly associated with T1D are MHC class II alleles that form restriction elements for CD4+ T cell recognition. This "guilt by association" can now be revisited in terms of specific immune mechanisms and specific forms of T cell recognition that are displayed by Teff found in subjects with T1D. In this review, we describe properties of Teff that correlate with T1D, and discuss several characteristics that advance our understanding of disease persistence and progression. Focusing on functional disease-associated immunological pathways within these Teff suggests a rationale for next-generation clinical trials with targeted interventions. Indeed, immune modulation therapies in T1D that do not address these properties of Teff are unlikely to achieve durable clinical response. PMID- 26949000 TI - Coloured cornea replacements with anti-infective properties: expanding the safe use of silver nanoparticles in regenerative medicine. AB - Despite the broad anti-microbial and anti-inflammatory properties of silver nanoparticles (AgNPs), their use in bioengineered corneal replacements or bandage contact lenses has been hindered due to their intense yellow coloration. In this communication, we report the development of a new strategy to pre-stabilize and incorporate AgNPs with different colours into collagen matrices for fabrication of corneal implants and lenses, and assessed their in vitro and in vivo activity. PMID- 26949001 TI - Invasive fungal diseases in patients with acute lymphoid leukemia. AB - Invasive fungal disease (IFD) represents an important complication in patients with acute lymphoid leukemia (ALL). The objectives of this study were to determine the prevalence of IFD in ALL patients with neutropenia, identify factors associated with IFD, and estimate the impact of IFD on the outcome. All patients with ALL who developed febrile neutropenia from 1987 to 2013 were evaluated. Cases of IFD were classified as proven or probable. Factors associated with IFD were evaluated by comparing episodes with and without a diagnosis of IFD. Among 350 episodes of febrile neutropenia, 31 IFDs were diagnosed (8.8%). Prolonged neutropenia was the only factor associated with IFD caused by yeasts. Factors associated with IFD caused by molds by multivariate analysis were the period after 2008, receipt of allogeneic transplant, relapsed ALL and prolonged neutropenia. Patients in relapse should receive induction chemotherapy in rooms with HEPA filter and receive antifungal prophylaxis. PMID- 26949002 TI - Probe-based confocal laser endomicroscopy for the differential diagnosis of gastric tubular adenoma and intestinal metaplasia in a patient with severe atrophic pangastritis. PMID- 26949003 TI - FDA-Approved Anti-Obesity Drugs in the United States. AB - Obesity is a growing health problem in our society and its treatment has been challenging. In recent decades, several anti-obesity drugs have been withdrawn from the market because of reported and documented adverse effects. After years of interruption, the US Food and Drug Administration (FDA) has recently approved multiple new anti-obesity drugs. The majority of these medications are taken orally, and only one is administered subcutaneously. In this article, we review the efficacy, adverse effects, and mechanism of action of all 5 FDA-approved drugs. PMID- 26949004 TI - Biomimetic Synthesis of Moschamine-Related Indole Alkaloids via Iron-Catalyzed Selectively Oxidative Radical Coupling. AB - An iron-catalyzed oxidative radical coupling reaction was developed to selectively construct indolofuran or bisphenolic indole cores, which exist in two types of moschamine-related indole alkaloids. Both (+)-decursivine and 4,4"-bis(N feruloyl)serotonin were biomimetically synthesized by using coupling reactions. The proposed reassignment of the structure of montamine as 4,4"-bis(N feruloyl)serotonin was excluded. PMID- 26949013 TI - Left Atrial Function Is Impaired in Some Patients With Stroke of Undetermined Etiology: Potential Implications for Evaluation and Therapy. AB - INTRODUCTION AND OBJECTIVES: Stroke etiology remains undetermined in up to 30% of cases. Paroxysmal atrial fibrillation is found in 20% to 28% of patients with stroke initially classified as being of undetermined etiology. The aim of our study was to analyze left atrial function in ischemic stroke patients to identify patterns associated with cardioembolic etiology and to determine whether the patterns identified can be found in individuals initially classified as having a stroke of undetermined etiology. METHODS: We studied a cohort of in-hospital ischemic stroke patients referred for transthoracic echocardiography. Treating neurologists determined stroke etiology based on the TOAST classification. Left atrial contractile function was assessed using 2-dimensional echocardiography to determine their ejection fraction and speckle tracking to measure left atrial strain rate: a-wave. Left atrial function was compared between stroke etiology subgroups and healthy controls. RESULTS: Ninety-seven patients (aged 67+/-15 years) with ischemic stroke (16.5% large-artery atherosclerosis, 15.5% small vessel occlusion, 11.3% cardioembolic, 5.1% other determined etiology, 51.1% undetermined etiology) and 10 healthy volunteers (aged 63+/-7 years) were included. Left atrial ejection fraction was significantly decreased only in patients with stroke of cardioembolic and undetermined etiology compared with the control group (31.5+/-17.2%, 40.2+/-17.1%, and 59.1+/-8.4%, respectively; P=.004). The left atrial strain rate was significantly lower in patients with stroke caused by cardioembolic or undetermined etiology, or large-artery atherosclerosis compared with controls (-0.86+/-0.49, -1.31+/-0.56, -1.5+/-0.47, 2.37+/-1.18, respectively; P<.001). CONCLUSIONS: Patients with stroke of undetermined etiology with left atrial function (ejection fraction and strain) similar to that of cardioembolic stroke patients may be misclassified and could potentially benefit from prolonged electrocardiography monitoring. Left atrial function analysis (ejection fraction and strain) might help to identify potential cardioembolic sources in patients with stroke of undetermined etiology. PMID- 26949014 TI - Bioresorbable Vascular Scaffold for the Treatment of Coronary Bifurcation Lesions: Immediate Results and 1-year Follow-up. AB - INTRODUCTION AND OBJECTIVES: The treatment of coronary lesions with a bioresorbable vascular scaffold has been shown to be effective. However there is little information about its use in bifurcations. The aim of this study was to analyze the safety and efficacy of the bioresorbable scaffold in the treatment of coronary bifurcation lesions. METHODS: From January 2012 to January 2015, we used a bioresorbable vascular scaffold to treat 194 patients with 230 bifurcation lesions. The scaffold geometry was examined by intracoronary imaging techniques in 145 bifurcations (65%). In all, 78% of the bifurcations were evaluated angiographically during follow-up (computed tomography angiography in 138 and coronary angiography in 41). RESULTS: The most common clinical presentation was acute coronary syndrome (81%). The most frequent type of bifurcation was 1,1,1 (34%). A simple approach was the chosen strategy in 221 bifurcations (96%). In 90 of these lesions, the side branch was postdilated through the cells of the platform and, in 3 cases, strut fractures were observed in optical coherence tomography. Procedural success was achieved in all patients. There was 1 case of subacute thrombosis and 1 sudden cardiac death during the first month. The duration of angiographic follow-up was 7.3+/-1.6 months and that of clinical follow-up, 14+/-6 months. Twelve (5%) restenoses were documented and revascularized. During follow-up, 2 patients (1%) had an infarction in another territory and another 2 patients (1%) died; the remaining patients had a symptom free follow-up. The incidence of thrombosis was 1.3%. CONCLUSIONS: Treatment of bifurcation coronary lesions using a provisional approach is feasible and safe, with a low rate of adverse events. PMID- 26949015 TI - Three new triterpenoid saponins from the roots of Ardisia crenata and their cytotoxic activities. AB - Three new triterpenoid saponins, ardisicrenoside O (1), ardisicrenoside P (2) and ardisicrenoside Q (3) together with three known compounds, 3beta,16alpha dihydroxy-30-methoxy-28, 30-epoxy-olean-12-en, cyclamiretin A 3-O-beta-d glucopyranosyl-(1->2) -alpha-l-arabinopyranoside and cyclamiretin A 3-O-beta-d glucopyranosyl-(1->4) -alpha-l-arabinopyranoside were isolated from the roots of Ardisia crenata Sims. Their structures were determined by one- and two dimensional NMR techniques, including HSQC, HMBC and TOCSY experiments, as well as acid hydrolysis and GC analysis. All isolates were evaluated for the cytotoxic activities on two human cancer cell lines and compounds 3, 5 and 6 showed significant cytotoxicity. PMID- 26948991 TI - Estimated GFR and the Effect of Intensive Blood Pressure Lowering After Acute Intracerebral Hemorrhage. AB - BACKGROUND: The kidney-brain interaction has been a topic of growing interest. Past studies of the effect of kidney function on intracerebral hemorrhage (ICH) outcomes have yielded inconsistent findings. Although the second, main phase of the Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT2) suggests the effectiveness of early intensive blood pressure (BP) lowering in improving functional recovery after ICH, the balance of potential benefits and harms of this treatment in those with decreased kidney function remains uncertain. STUDY DESIGN: Secondary analysis of INTERACT2, which randomly assigned patients with ICH with elevated systolic BP (SBP) to intensive (target SBP<140mmHg) or contemporaneous guideline-based (target SBP<180mmHg) BP management. SETTING & PARTICIPANTS: 2,823 patients from 144 clinical hospitals in 21 countries. PREDICTORS: Admission estimated glomerular filtration rates (eGFRs) of patients were categorized into 3 groups based on the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) creatinine equation: normal or high, mildly decreased, and moderately to severely decreased (>90, 60-90, and <60mL/min/1.73m(2), respectively). OUTCOMES: The effect of admission eGFR on the primary outcome of death or major disability at 90 days (defined as modified Rankin Scale scores of 3-6) was analyzed using a multivariable logistic regression model. Potential effect modification of intensive BP lowering treatment by admission eGFR was assessed by interaction terms. RESULTS: Of 2,623 included participants, 912 (35%) and 280 (11%) had mildly and moderately/severely decreased eGFRs, respectively. Patients with moderately/severely decreased eGFRs had the greatest risk for death or major disability at 90 days (adjusted OR, 1.82; 95% CI, 1.28-2.61). Effects of early intensive BP lowering were consistent across different eGFRs (P=0.5 for homogeneity). LIMITATIONS: Generalizability issues arising from a clinical trial population. CONCLUSIONS: Decreased eGFR predicts poor outcome in acute ICH. Early intensive BP lowering provides similar treatment effects in patients with ICH with decreased eGFRs. PMID- 26949016 TI - Evaluation of acute ischemia in pre-procedure ECG predicts myocardial salvage after primary PCI in STEMI patients with symptoms >12hours. AB - BACKGROUND: Primary percutaneous coronary intervention (pPCI) is recommended in patients with ST Elevation Myocardial Infarction (STEMI) and symptom duration <12hours. However, a considerable amount of myocardium might still be salvaged in STEMI patients with symptom durations >12hours (late-presenters). The Anderson Wilkin's score (AW-score) estimates the acuteness of myocardial ischemia from the electrocardiogram (ECG) in STEMI patients. We hypothesized that the AW-score is superior to symptom duration in identifying substantial salvage potential in late presenters. METHODS: The AW-score (range 1-4) was obtained from the pre-pPCI ECG in 55 late-presenters and symptoms 12-72 hours. Myocardial perfusion imaging was performed to assess area at risk before pPCI and after 30days to assess myocardial salvage index (MSI). We correlated both the AW-score and pain-to balloon with MSI and determined the salvage potential (MSI) according to AW-score >=3 (acute ischemia) and AW-score <3 (late ischemia). RESULTS: Late-presenters had median MSI 53% (inter quartile range (IQR) 27-89). The AW-score strongly correlated with MSI (beta=0.60, R(2)=0.36, p<0.0001), while pain-to-balloon time did not (beta=-0.21, R(2)=0.04, p=0.14). Patients with AW-score >=3 (n=16) compared to those with AW-score <3 (n=27) had significant larger MSI (82.7% vs 41.5%, p=0.014). MSI>median was observed in 79% in patients with AW-score >=3 vs 32% in patients with AW-score <3 (adjusted OR 6.74 [95% CI 1.35-33.69], p=0.02). CONCLUSION: AW-score was strongly associated with myocardial salvage while pain to-balloon time was not. STEMI patients with symptom duration between 12 -72hours and AW-score >=3 achieved substantial salvage after pPCI. PMID- 26949017 TI - Fatigue failure of reverse shoulder humeral tray components of a single design. AB - BACKGROUND: Modularity in shoulder arthroplasty provides surgical flexibility and facilitates less-complex revision surgery. Modular designs must fit in the glenohumeral joint space, necessitating minimal thickness and careful material selection. The potential for fatigue fracture is higher, and fatigue fracture has been experienced by patients. The purpose of this study was to determine the impact of geometry and materials used for modular humeral trays from a single manufacturer. METHODS: We consecutively retrieved 8 humeral trays of nearly identical designs: 4 Ti-6Al-4V (Ti) and 4 CoCrMo (CoCr). Optical microscopy and scanning electron microscopy were used, along with metallurgical techniques. Finite element and fatigue analyses of the stresses at the humeral tray taper informed observation interpretation. RESULTS: Two Ti devices were revised for in vivo fracture. Scanning electron microscopy showed cracking in the other 2 Ti trays and no evidence of cracking in the CoCr components. A geometric difference in the CoCr devices resulted in a 25% decreased stress under simulated activities of daily living. Accounting for the tray material properties, the fatigue failure envelope ranged from 1000 to 1 million cycles for Ti and from 30,000 to >10 million cycles for CoCr. CONCLUSIONS: All Ti humeral tray retrievals fractured in vivo or were cracked at the taper fillet. No CoCr retrievals showed signs of cracking. Finite element and fatigue analyses predict a 10-fold lifetime increase for the CoCr devices compared with the Ti devices. This study shows that fatigue failure is possible for some reverse shoulder components and is likely exacerbated by fillet radius, tray thickness, and material choice. PMID- 26949018 TI - A novel IL-10-producing innate lymphoid cells (ILC10) in a contact hypersensitivity mouse model. AB - The immunoregulatory cytokine Interleukin 10 (IL-10) protein is produced by various cells during the course of inflammatory disorders. Mainly, it downregulates pro-inflammatory cytokines, antigen presentation, and helper T cell activation. In this study, we show that the ratio of IL-10-producing cells was significantly increased in lineage negative (i.e., not T, B, or leukocyte cell lineages) cells than in lineage positive cells in lymphoid and peripheral tissues. We further observed that IL-10-producing innate lymphoid cells (ILCs), here called firstly ILC10, were increased in number in oxazolone-induced contact hypersensitivity (CHS) mice. In detail, IL-10-producing lineage negative cells were elevated in the axillary, inguinal lymph node, and ear tissues of CHS mice. Notably, the cells expressed classical ILC marker proteins such as CD45, CD127, and Sca-1. Altogether, our findings suggest for the first time that ILC10s are present in various physiological settings and could be involved in numerous immune responses as regulatory cells. [BMB Reports 2016; 49(5): 293-296]. PMID- 26949020 TI - Gene repressive mechanisms in the mouse brain involved in memory formation. AB - Gene regulation in the brain is essential for long-term plasticity and memory formation. Despite this established notion, the quantitative translational map in the brain during memory formation has not been reported. To systematically probe the changes in protein synthesis during memory formation, our recent study exploited ribosome profiling using the mouse hippocampal tissues at multiple time points after a learning event. Analysis of the resulting database revealed novel types of gene regulation after learning. First, the translation of a group of genes was rapidly suppressed without change in mRNA levels. At later time points, the expression of another group of genes was downregulated through reduction in mRNA levels. This reduction was predicted to be downstream of inhibition of ESR1 (Estrogen Receptor 1) signaling. Overexpressing Nrsn1, one of the genes whose translation was suppressed, or activating ESR1 by injecting an agonist interfered with memory formation, suggesting the functional importance of these findings. Moreover, the translation of genes encoding the translational machineries was found to be suppressed, among other genes in the mouse hippocampus. Together, this unbiased approach has revealed previously unidentified characteristics of gene regulation in the brain and highlighted the importance of repressive controls. [BMB Reports 2016; 49(4): 199-200]. PMID- 26949019 TI - SETDB1 mediated FosB expression increases the cell proliferation rate during anticancer drug therapy. AB - The efficacy of anticancer drugs depends on a variety of signaling pathways, which can be positively or negatively regulated. In this study, we show that SETDB1 HMTase is down-regulated at the transcriptional level by several anticancer drugs, due to its inherent instability. Using RNA sequence analysis, we identified FosB as being regulated by SETDB1 during anticancer drug therapy. FosB expression was increased by treatment with doxorubicin, taxol and siSETDB1. Moreover, FosB was associated with an increased rate of proliferation. Combinatory transfection of siFosB and siSETDB1 was slightly increased compared to transfection of siFosB. Furthermore, FosB was regulated by multiple kinase pathways. ChIP analysis showed that SETDB1 and H3K9me3 interact with a specific region of the FosB promoter. These results suggest that SETDB1- mediated FosB expression is a common molecular phenomenon, and might be a novel pathway responsible for the increase in cell proliferation that frequently occurs during anticancer drug therapy. [BMB Reports 2016; 49(4): 238-243]. PMID- 26949021 TI - Spot the difference: Solving the puzzle of hidden pictures in the lizard genome for identification of regeneration factors. AB - All living things share some common life processes, such as growth and reproduction, and have the ability to respond to their environment. However, each type of organism has its own specialized way of managing biological events. Genetic sequences determine phenotypic and physiological traits. Based on genetic information, comparative genomics has been used to delineate the differences and similarities between various genomes, and significant progress has been made in understanding regenerative biology by comparing the genomes of a variety of lower animal models of regeneration, such as planaria, zebra fish, and newts. However, the genome of lizards has been relatively ignored until recently, even though lizards have been studied as an excellent amniote model of tissue regeneration. Very recently, whole genome sequences of lizards have been uncovered, and several attempts have been made to find regeneration factors based on genetic information. In this article, recent advances in comparative analysis of the lizard genome are introduced, and their biological implications and putative applications for regenerative medicine and stem cell biology are discussed. [BMB Reports 2016; 49(5): 249-254]. PMID- 26949022 TI - Identification of a neural pathway governing satiety in Drosophila. AB - Satiety cues a feeding animal to cease further ingestion of food, thus protecting it from excessive energy gain. Impaired control of satiety is often associated with feeding-related disorders such as obesity. In our recent study, we reported the identification of a neural pathway that expresses the myoinhibitory peptide (MIP), critical for satiety responses in Drosophila. Targeted silencing of MIP neuron activity strikingly increased the body weight (BW) through elevated food intake. Similarly, genetic disruption of the gene encoding MIP also elevated feeding and BW. Suppressing the MIP pathway behaviorally transformed the satiated flies to feed similar to the starved ones, with augmented sensitivity to food. Conversely, temporal activation of MIP neuron markedly reduced the food intake and BW, and blunted the sensitivity of the starved flies to food as if they have been satiated. Shortly after termination of MIP neuron activation, the reduced BW reverted to the normal level along with a strong feeding rebound. Together our results reveal the switch-like role of the MIP pathway in feeding regulation by controlling satiety. [BMB Reports 2016; 49(3): 137-138]. PMID- 26949023 TI - History, research and practice of forensic anthropology in Thailand. AB - Forensic anthropology is an increasingly developing discipline born about a century ago in the United States with the objective to contribute the knowledge of bone biology and physical anthropology to the emerging needs of the court of law. The development of research in biological and forensic anthropology has made rapid progress worldwide in the past few years, however, in most countries--with the exception of the United States--forensic anthropology work is still considered within the duties of the forensic pathologist. This paper attempts to summarise the history and development of forensic anthropology in Thailand by providing information on past and current research and practice that can help forensic practitioners to apply existing methods in forensic cases and mass disasters. It is hoped that the lessons learned from the tsunami catastrophe and the emerging need for positive identification in medicolegal settings will lead to rapid advances in education, training and professional engagement of anthropologists from the forensic departments and the law enforcement agencies in Thailand. PMID- 26949024 TI - Light inhibition of fumarase in Arabidopsis leaves is phytochrome A-dependent and mediated by calcium. AB - Inhibition of fumarase activity in the light has been studied in Arabidopsis in relation to the involvement of phytochrome. Using knockout phytochrome mutants, we observed that the main regulator of FUM1 gene transcription, encoding the mitochondrial form of fumarase, is phytochrome A. The active form of phytochrome A suppressed FUM1 expression, while the expression of the FUM2 gene encoding the cytosolic form of fumarase was unaffected both in darkness and in light. The nuclear concentration of Ca(2+) was modulated by red and far-red light. We suggest that the signal transduction mechanism operates via Ca(2+) activation of expression of the gene encoding the transcription factor PIF3, which binds to promoters of phytochrome-regulated genes and inhibits FUM1 expression. PMID- 26949025 TI - Genome-wide identification, characterization and expression analysis of calmodulin-like (CML) proteins in tomato (Solanum lycopersicum). AB - Calcium (Ca(2+)) has emerged as a significant secondary messenger that regulates the activities of hormonal and environmental signals that are associated with biotic and abiotic stresses. Ca(2+) binding proteins typically contain a Ca(2+) binding EF-hand (a helix-loop-helix structure) motif. In this study, tomato genes encoding calmodulin-like (CML) proteins that possess EF-hand motifs and no other identifiable functional domains were analyzed. Using genome analysis and BLAST searches in database, 52 CML genes were identified in tomato. Comprehensive analyses, including evolutionary relationships, gene structures, chromosomal locations, functional annotations, and gene duplications, were performed. Distribution mapping exhibited that 52 SlCML proteins containing different intron/exon patterns were unevenly distributed among ten chromosomes. In addition, 24 SlCML proteins were predicted as segmentally duplicated. Conserved motifs, promoter cis-regulatory elements, organ-based expression patterns and expression analyses indicated the potential responsiveness of SlCML proteins to abiotic stresses and phytohormones. These results illustrate the complexity of the CML gene family and indicate a potential vital role for these molecules in tomato growth and development as Ca(2+) signal transducers. PMID- 26949026 TI - Predominantly night-time feeding and maternal glycaemic levels during pregnancy. AB - Little is known about the influence of meal timing and energy consumption patterns throughout the day on glucose regulation during pregnancy. We examined the association of maternal feeding patterns with glycaemic levels among lean and overweight pregnant women. In a prospective cohort study in Singapore, maternal 24-h dietary recalls, fasting glucose (FG) and 2-h postprandial glucose (2HPPG) concentrations were measured at 26-28 weeks of gestation. Women (n 985) were classified into lean (BMI<23 kg/m2) or overweight (BMI>=23 kg/m2) groups. They were further categorised as predominantly daytime (pDT) or predominantly night time (pNT) feeders according to consumption of greater proportion of energy content from 07.00 to 18.59 hours or from 19.00 to 06.59 hours, respectively. On stratification by weight status, lean pNT feeders were found to have higher FG than lean pDT feeders (4.36 (sd 0.38) v. 4.22 (sd 0.35) mmol/l; P=0.002); however, such differences were not observed between overweight pDT and pNT feeders (4.49 (sd 0.60) v. 4.46 (sd 0.45) mmol/l; P=0.717). Using multiple linear regression with confounder adjustment, pNT feeding was associated with higher FG in the lean group (beta=0.16 mmol/l; 95 % CI 0.05, 0.26; P=0.003) but not in the overweight group (beta=0.02 mmol/l; 95 % CI -0.17, 0.20; P=0.879). No significant association was found between maternal feeding pattern and 2HPPG in both the lean and the overweight groups. In conclusion, pNT feeding was associated with higher FG concentration in lean but not in overweight pregnant women, suggesting that there may be an adiposity-dependent effect of maternal feeding patterns on glucose tolerance during pregnancy. PMID- 26949027 TI - Zika virus: high infectious viral load in semen, a new sexually transmitted pathogen? PMID- 26949028 TI - Dengue during pregnancy and adverse fetal outcomes: a systematic review and meta analysis. AB - BACKGROUND: Little is known about the possible adverse effects of dengue infection during pregnancy on fetal outcomes. In this systematic review and meta analysis we aimed to estimate the increase in risk of four adverse fetal outcomes in women who had dengue infection during pregnancy. METHODS: For this systematic review and meta-analysis, we searched Medline, Embase, Global Health Library, and Scopus for articles published before Aug 1, 2015. We included original studies that reported any fetal outcomes for pregnant women who had dengue infection during the gestational period. Case-control, cohort, and cross-sectional studies and unselected case series were eligible for inclusion. We excluded case reports, ecological studies, reviews, in-vitro studies, and studies without data for pregnancy outcomes. We independently screened titles and abstracts to select papers for inclusion and scored the quality of those included in meta-analyses. For each study, we recorded study design, year of publication, study location, period of study, and authors and we extracted data for population characteristics such as the number of pregnancies, dengue diagnostic information, and the frequency of outcomes. We investigated four adverse fetal outcomes: stillbirth, miscarriage, preterm birth, and low birthweight. We estimated the increase in risk of these adverse fetal outcomes by use of Mantel-Haenszel methods. We assessed heterogeneity of odds ratios (OR) with the I(2) statistic. FINDINGS: We identified 278 non-duplicate records, of which 107 full-text articles were screened for eligibility. 16 studies were eligible for inclusion in the systematic review and eight were eligible for the meta-analyses, which included 6071 pregnant women, 292 of whom were exposed to dengue during pregnancy. For miscarriage, the OR was 3.51 (95% CI 1.15-10.77, I(2)=0.0%, p=0.765) for women with dengue infection during pregnancy compared with those without. We did not do a meta-analysis for stillbirth because this outcome was investigated in only one study with a comparison group; we calculated the crude relative risk to be 6.7 (95% CI 2.1-21.3) in women with symptomatic dengue compared with women without dengue. Preterm birth and low birthweight were the most common adverse pregnancy outcomes. The OR for the association with dengue was 1.71 (95% CI 1.06-2.76, I(2)=56.1%, p=0.058) for preterm birth and 1.41 (95% CI 0.90-2.21, I(2)=0.0%, p=0.543) for low birthweight. INTERPRETATION: Evidence suggests that symptomatic dengue during pregnancy might be associated with fetal adverse outcomes. If confirmed, it would be important to monitor pregnancies during which dengue is diagnosed and to consider pregnant women in dengue control policies. FUNDING: National Council for Scientific and Technological Development (CNPq). PMID- 26949029 TI - What are the true consequences of dengue during pregnancy? PMID- 26949030 TI - In vivo confocal microscopy efficacy assessment of daylight photodynamic therapy in actinic keratosis patients. AB - BACKGROUND: Reflectance confocal microscopy (RCM) is a noninvasive diagnostic technique with an acceptable sensitivity and specificity for actinic keratosis (AK). OBJECTIVES: We evaluated efficacy of daylight photodynamic therapy (DL-PDT) in patients with AK using a new RCM atypia scoring system. MATERIALS AND METHODS: All patients with AK lesions (Grade I-II) were included in our study (2012-15). Baseline clinical, dermoscopy and RCM evaluations were followed by DL-PDT. In the first follow-up, clinical examination, dermoscopy and RCM imaging of the treated area were carried out. Atypia scoring and cell size measurements were used to compare before and after RCM images. RESULTS: From 40 lesions (20 patients with mean age of 75.5 years), complete resolution and partial response of the actinic damage was detected in 80% and 17.5% of lesions, respectively. No cellular atypia was seen in the follow-up RCM images of 57.5% of lesions (n = 23), while in 40% of lesions (n = 16) minimal changes to the honeycomb pattern of the epidermis were seen in the follow-up RCM images (atypia score 1). Only one lesion showed minimal or no clinical response, and a persistent moderate amount of atypia in RCM. Furthermore, atypia score and mean cell size decreased significantly in the follow-up DL-PDT RCM images (P < 0.001, P = 0.001, respectively). CONCLUSIONS: RCM features of actinic damage at cellular level have been shown to correlate well with the results of a clinical assessment of AK lesions. This study confirms that in vivo RCM technology might be an additional technique to monitor the efficacy of DL-PDT for AK. PMID- 26949031 TI - Grand Challenges--Management of municipal solid waste. PMID- 26949032 TI - Primary cervical intramedullary synovial sarcoma: a longitudinal observation. PMID- 26949033 TI - Persistent axial neck pain after cervical disc arthroplasty: a radiographic analysis. AB - BACKGROUND CONTEXT: There is very little literature examining optimal radiographic parameters for placement of cervical disc arthroplasty (CDA), nor is there substantial evidence evaluating the relationship between persistent postoperative neck pain and radiographic outcomes. PURPOSE: We set out to perform a single-center evaluation of the radiographic outcomes, including associated complications, of CDA. DESIGN: This is a retrospective review. PATIENT SAMPLE: Two hundred eighty-five consecutive patients undergoing CDA were included in the review. OUTCOME MEASURES: The outcome measures were radiological parameters (preoperative facet arthrosis, disc height, CDA placement in sagittal and coronal planes, heterotopic ossification [HO] formation, etc.) and patient outcomes (persistent pain, recurrent pain, new-onset pain, etc.). METHODS: We performed a retrospective review of all patients from a single military tertiary medical center from August 2008 to August 2012 undergoing CDA. Preoperative, immediate postoperative, and final follow-up films were evaluated. The clinical outcomes and complications associated with the procedure were also examined. RESULTS: The average radiographic follow-up was 13.5 months and the rate of persistent axial neck pain was 17.2%. For patients with persistent neck pain, the rate of HO formation per level studied was 22.6%, whereas the rate was significantly lower for patients without neck pain (11.7%, p=.03). There was no significant association between the severity of HO and the presence of neck pain. Patients with a preoperative diagnosis of cervicalgia, compared to those without cervicalgia, were significantly more likely to experience continued neck pain postoperatively (28.6% vs. 13.1%, p=.01). There were no differences in preoperative facet arthrosis, pre- or postoperative disc height, segmental range of motion, or placement of the device relative to the posterior edge of the vertebral body.However, patients with implants more centered between the uncovertebral joints were more likely to experience posterior neck pain (p=.03). CONCLUSIONS: We found that posterior axial neck pain is relatively frequent after CDA, and patients with persistent neck pain were significantly more likely to have preoperative cervicalgia and develop HO postoperatively. We also found that patients with implants that were placed off-centered were less likely to also complain of neck pain, although the reasons for this finding remain unclear. PMID- 26949034 TI - Circumferential intradural meningioma of the thoracic spinal cord. AB - BACKGROUND AND CONTEXT: There are very few reported cases of a meningioma circumferentially surrounding the spinal cord. To date, this entity has only been described at the conus medullaris and in the cervical cord. Herewith, the authors describe a case of an intradural extramedullary meningioma that completely encircled the thoracic spinal cord. CASE REPORT: A 40-year-old woman with progressive numbness of the lower limbs and spasticity of gait following a fall presented to our hospital. Magnetic resonance imaging of the spine demonstrated an abnormality at T6-T7 completely encircling the spinal cord. The patient underwent a T6-T8 laminectomy and subtotal resection of the intradural partially calcified lesion. Resection of the anterolateral portion was not feasible. Histology revealed psammomatous meningioma (WHO Grade 1). The patient recovered well and was discharged with improved gait but some residual numbness of her feet and right hemithorax. CONCLUSION: This is the first reported case of an intradural extramedullary meningioma completely encircling the thoracic spinal cord. Achieving complete resection of this circumferential meningioma was not possible via a posterior approach. The optimum management of this condition is unknown; clearly, achieving symptomatic relief with adequate cord decompression is paramount; however, the long-term outcome and risk of recurrence in these cases, given their rarity and the difficulties in achieving complete resection, is unknown. PMID- 26949035 TI - Atypical appearance of a schwannoma in the thoracic spine mimicking meningioma. PMID- 26949036 TI - Comparison of the Frequency of Sudden Cardiovascular Deaths in Young Competitive Athletes Versus Nonathletes: Should We Really Screen Only Athletes? AB - The issue of sudden death in young athletes and consideration for the most practical and optimal strategy to identify those genetic and/or congenital heart diseases responsible for these tragic events continues to be debated. However, proponents of broad-based and mandatory national preparticipation screening, including with 12-lead electrocardiograms have confined the focus to a relatively small segment of the youthful population who choose to engage in competitive athletic programs at the high school, college, and elite-professional level. Therefore, lost in this discussion of preparticipation screening of athletes is that the larger population of young people not involved in competitive sports (and, therefore, a priori are excluded from systematic screening) who nevertheless may die suddenly of the same cardiovascular diseases as athletes. To substantiate this hypothesis, we accessed the forensic Hennepin County, Minnesota registry in which cardiovascular sudden deaths were 8-fold more common in nonathletes (n = 24) than athletes (n = 3) and threefold more frequent in terms of incidence. The most common diseases responsible for sudden death were hypertrophic cardiomyopathy (n = 6) and arrhythmogenic right ventricular cardiomyopathy (n = 4). These data raise ethical considerations inherent in limiting systematic screening for unsuspected genetic and/or congenital heart disease to competitive athletes. PMID- 26949037 TI - Relation of Muscle Mass and Fat Mass to Cardiovascular Disease Mortality. AB - We evaluated the relation between components of body composition and mortality in patients with cardiovascular disease (CVD). Dual x-ray absorptiometry body composition data from the National Health and Nutrition Examination Survey 1999 to 2004 was linked to total and CVD mortality data 1999 to 2006 in 6,451 patients with CVD. Kaplan-Meier survival analysis for the end points of total and CVD mortality was plotted by quartiles of muscle mass, fat mass, and categories of body mass index (BMI). Subjects were stratified into 4 groups (low muscle/low fat mass, low muscle/high fat mass, high muscle/low fat mass, and high muscle/high fat mass). Adjusted Cox proportional hazards regression determined hazard ratios for total and CVD mortality. Rates of cardiovascular/total mortality were lower in higher quartiles of muscle mass, fat mass, and higher categories of BMI (p <0.001). The high muscle/low fat mass group had a lower risk of CVD and total mortality (risk-adjusted hazard ratios of 0.32, 95% confidence interval 0.14 to 0.73 and 0.38, 95% confidence interval 0.22 to 0.68, for CVD and total mortality, respectively). Thus, increasing fat mass, muscle mass, and BMI were all correlated with improved survival. The specific subgroup of high muscle and low fat mass had the lowest mortality risk compared with other body composition subtypes. This suggests the importance of body composition assessment in the prediction of cardiovascular and total mortality in patients with CVD. PMID- 26949038 TI - Temozolomide-perillyl alcohol conjugate induced reactive oxygen species accumulation contributes to its cytotoxicity against non-small cell lung cancer. AB - Temozolomide-perillyl alcohol conjugate (TMZ - POH), a novel temozolomide analog, was reported to play a cytotoxic role in triple-negative breast cancer and TMZ resistant gliomas. In a current study we had demonstrated how TMZ - POH also exhibited its cytotoxicity against non-small cell lung cancer (NSCLC), the most common type of lung cancer, as evidence from cell/tumor proliferation inhibition, G2/M arrest, DNA damage and mitochondrial apoptosis. Importantly, TMZ - POH's cytotoxicity is closely related to reactive oxygen species (ROS) accumulation because it can be reversed by two ROS scavengers, catalase (CAT) and N-acetyl-L cysteine (NAC). TMZ - POH induces mitochondrial transmembrane potential (MTP) decrease and ROS accumulation, in turn activates mitogen-activated protein kinase (MAPKs) signaling and mitochondrial apoptosis, and then exerts its cytotoxicity, thus proposing TMZ - POH as a potential therapeutic candidate for NSCLC. PMID- 26949040 TI - Adaptation in CRISPR-Cas Systems. AB - Clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR associated (Cas) proteins constitute an adaptive immune system in prokaryotes. The system preserves memories of prior infections by integrating short segments of foreign DNA, termed spacers, into the CRISPR array in a process termed adaptation. During the past 3 years, significant progress has been made on the genetic requirements and molecular mechanisms of adaptation. Here we review these recent advances, with a focus on the experimental approaches that have been developed, the insights they generated, and a proposed mechanism for self- versus non-self-discrimination during the process of spacer selection. We further describe the regulation of adaptation and the protein players involved in this fascinating process that allows bacteria and archaea to harbor adaptive immunity. PMID- 26949041 TI - Modulation of spinal inhibitory reflexes depends on the frequency of transcutaneous electrical nerve stimulation in spastic stroke survivors. AB - Neurophysiological studies in healthy subjects suggest that increased spinal inhibitory reflexes from the tibialis anterior (TA) muscle to the soleus (SOL) muscle might contribute to decreased spasticity. While 50 Hz is an effective frequency for transcutaneous electrical nerve stimulation (TENS) in healthy subjects, in stroke survivors, the effects of TENS on spinal reflex circuits and its appropriate frequency are not well known. We examined the effects of different frequencies of TENS on spinal inhibitory reflexes from the TA to SOL muscle in stroke survivors. Twenty chronic stroke survivors with ankle plantar flexor spasticity received 50-, 100-, or 200-Hz TENS over the deep peroneal nerve (DPN) of the affected lower limb for 30 min. Before and immediately after TENS, reciprocal Ia inhibition (RI) and presynaptic inhibition of the SOL alpha motor neuron (D1 inhibition) were assessed by adjusting the unconditioned H-reflex amplitude. Furthermore, during TENS, the time courses of spinal excitability and spinal inhibitory reflexes were assessed via the H-reflex, RI, and D1 inhibition. None of the TENS protocols affected mean RI, whereas D1 inhibition improved significantly following 200-Hz TENS. In a time-series comparison during TENS, repeated stimulation did not produce significant changes in the H-reflex, RI, or D1 inhibition regardless of frequency. These results suggest that the frequency dependent effect of TENS on spinal reflexes only becomes apparent when RI and D1 inhibition are measured by adjusting the amplitude of the unconditioned H-reflex. However, 200-Hz TENS led to plasticity of synaptic transmission from the antagonist to spastic muscles in stroke survivors. PMID- 26949039 TI - System-Wide Modulation of HECT E3 Ligases with Selective Ubiquitin Variant Probes. AB - HECT-family E3 ligases ubiquitinate protein substrates to control virtually every eukaryotic process and are misregulated in numerous diseases. Nonetheless, understanding of HECT E3s is limited by a paucity of selective and potent modulators. To overcome this challenge, we systematically developed ubiquitin variants (UbVs) that inhibit or activate HECT E3s. Structural analysis of 6 HECT UbV complexes revealed UbV inhibitors hijacking the E2-binding site and activators occupying a ubiquitin-binding exosite. Furthermore, UbVs unearthed distinct regulation mechanisms among NEDD4 subfamily HECTs and proved useful for modulating therapeutically relevant targets of HECT E3s in cells and intestinal organoids, and in a genetic screen that identified a role for NEDD4L in regulating cell migration. Our work demonstrates versatility of UbVs for modulating activity across an E3 family, defines mechanisms and provides a toolkit for probing functions of HECT E3s, and establishes a general strategy for systematic development of modulators targeting families of signaling proteins. PMID- 26949045 TI - Donor-acceptor co-assembled supramolecular nanofibers with high and well-balanced ambipolar charge transport properties under ambient conditions. AB - Single-bundle nanofiber based OFETs were fabricated from co-assembled supramolecular nanofibers which comprise TCAT and PDI-13, using a simple gelation method. The co-assembled supramolecular nanoarchitecture was fully characterized by means of optical microscopy, TEM, SEM, 2D-GIWAXS and so on. The devices exhibited typical ambipolar charge transport characteristics with very well balanced hole and electron mobilities as well as high photoresponsivity under ambient conditions. PMID- 26949046 TI - Detection of Lung Cancer through Metabolic Changes Measured in Blood Plasma. AB - INTRODUCTION: Low-dose computed tomography, the currently used tool for lung cancer screening, is characterized by a high rate of false-positive results. Accumulating evidence has shown that cancer cell metabolism differs from that of normal cells. Therefore, this study aims to evaluate whether the metabolic phenotype of blood plasma allows detection of lung cancer. METHODS: The proton nuclear magnetic resonance spectrum of plasma is divided into 110 integration regions, representing the metabolic phenotype. These integration regions reflect the relative metabolite concentrations and were used to train a classification model in discriminating between 233 patients with lung cancer and 226 controls. The validity of the model was examined by classifying an independent cohort of 98 patients with lung cancer and 89 controls. RESULTS: The model makes it possible to correctly classify 78% of patients with lung cancer and 92% of controls, with an area under the curve of 0.88. Important moreover is the fact that the model is convincing, which is demonstrated by validation in the independent cohort with a sensitivity of 71%, a specificity of 81%, and an area under the curve of 0.84. Patients with lung cancer have increased glucose and decreased lactate and phospholipid levels. The limited number of patients in the subgroups and their heterogeneous nature do not (yet) enable differentiation between histological subtypes and tumor stages. CONCLUSIONS: Metabolic phenotyping of plasma allows detection of lung cancer, even in an early stage. Increased glucose and decreased lactate levels are pointing to an increased gluconeogenesis and are in accordance with recently published findings. Furthermore, decreased phospholipid levels confirm the enhanced membrane synthesis. PMID- 26949047 TI - EPEC: a cocktail of virulence. AB - Genomics studies are prompting a re-evaluation of the diversity of Escherichia coli pathovars and how this diversity corresponds to virulence. PMID- 26949048 TI - Viral evolution: One giant leap for Cas-kind. PMID- 26949050 TI - Effects of power variation on cycle performance during simulated hilly time trials. AB - It has previously been shown that cyclists are unable to maintain a constant power output during cycle time-trials on hilly courses. The purpose of the present study is therefore to quantify these effects of power variation using a mathematical model of cycling performance. A hypothetical cyclist (body mass: 70 kg, bicycle mass: 10 kg) was studied using a mathematical model of cycling, which included the effects of acceleration. Performance was modelled over three hypothetical 40-km courses, comprising repeated 2.5-km sections of uphill and downhill with gradients of 1%, 3%, and 6%, respectively. Amplitude (5-15%) and distance (0.31-20.00 km) of variation were modelled over a range of mean power outputs (200-600 W) and compared to sustaining a constant power. Power variation was typically detrimental to performance; these effects were augmented as the amplitude of variation and severity of gradient increased. Varying power every 1.25 km was most detrimental to performance; at a mean power of 200 W, performance was impaired by 43.90 s (+/-15% variation, 6% gradient). However at the steepest gradients, the effect of power variation was relatively independent of the distance of variation. In contrast, varying power in parallel with changes in gradient improved performance by 188.89 s (+/-15% variation, 6% gradient) at 200 W. The present data demonstrate that during hilly time-trials, power variation that does not occur in parallel with changes in gradient is detrimental to performance, especially at steeper gradients. These adverse effects are substantially larger than those previously observed during flat, windless time trials. PMID- 26949051 TI - Concerns regarding "2015 ACR/ACC/AHA/AATS/ACEP/ASNC/NASCI/SAEM/SCCT/SCMR/SCPC/SNMMI/STR/STS: Appropriate Utilization of Cardiovascular Imaging in Emergency Department Patients with Chest Pain". PMID- 26949049 TI - Metabolic crosstalk between host and pathogen: sensing, adapting and competing. AB - Our understanding of bacterial pathogenesis is dominated by the cell biology of the host-pathogen interaction. However, the majority of metabolites that are used in prokaryotic and eukaryotic physiology and signalling are chemically similar or identical. Therefore, the metabolic crosstalk between pathogens and host cells may be as important as the interactions between bacterial effector proteins and their host targets. In this Review we focus on host-pathogen interactions at the metabolic level: chemical signalling events that enable pathogens to sense anatomical location and the local physiology of the host; microbial metabolic pathways that are dedicated to circumvent host immune mechanisms; and a few metabolites as central points of competition between the host and bacterial pathogens. PMID- 26949052 TI - A novel PI3K/AKT signaling axis mediates Nectin-4-induced gallbladder cancer cell proliferation, metastasis and tumor growth. AB - Nectin-4 is a Ca(2+)-independent immunoglobulin-like cell adhesion molecule which has diverse functions in cell-cell adhesion via homophilic and heterophilic interactions. Cell-cell adhesive processes are central to cell polarization, differentiation, proliferation, survival and movement. Here we report that Nectin 4 is substantially overexpressed in gallbladder cancer (GBC), the most common biliary tract malignancy with a high risk of local tumor spread and invasion. Further, Nectin-4 high expression in GBC patients was associated with pathologic T stage and lymph node metastasis status, and the expression level of the downstream target Rac1 and poor prognoses were also correlated with Nectin-4. Ectopic expression of Nectin-4 promoted GBC cell growth, motility and tumor growth in a mouse model. The depletion of Nectin-4 inhibited GBC cell proliferation and migration both in cell culture and in mice. Our data suggest that activation of the PI3K/AKT pathway was involved in the oncogenic function of Nectin-4 to activate Rac1 in GBC. Inhibition of PI3K/AKT with LY294002 and/or Rac1 with NSC23766 impaired Nectin-4-mediated GBC cell proliferation and motility. We hypothesize that Nectin-4 is critical for GBC progression via PI3K/AKT pathway activation of Rac1. Nectin-4 may be a novel prognostic factor and therapeutic target in GBC patients. PMID- 26949053 TI - Development of a combined pretreatment and hydrolysis strategy of rice straw for the production of bioethanol and biopolymer. AB - The present study highlights the development of a combined pretreatment and hydrolysis strategy of rice straw for the production of bioethanol and biopolymer (poly-3-hydroxybutyrate). Maximum reducing sugar yield was 0.374g/g. The hydrolyzate is devoid of major fermentation inhibitors like furfural and organic acids and can be used for fermentation without any detoxification. Fermentation of the non-detoxified hydrolyzate with Saccharomyces cerevisiae yielded 1.48% of ethanol with a fermentation efficiency of 61.25% and with Comamonas sp. yielded 35.86% of poly-3-hydroxybutyrate without any nutrient supplementation. Characterization of native, control as well as the residue left out after combined pretreatment and hydrolysis of RS by scanning electron microscopy and X ray diffraction showed difference. Compositional analysis revealed that the residue contains lignin and hemicellulose as the major component indicating that major portion of cellulose were hydrolyzed in this strategy. PMID- 26949054 TI - Influence of abscisic acid on growth, biomass and lipid yield of Scenedesmus quadricauda under nitrogen starved condition. AB - Scenedesmus quadricauda, accumulated more lipid but with a drastic reduction in biomass yield during nitrogen starvation. Abscisic acid (ABA) being a stress responsible hormone, its effect on growth and biomass with sustainable lipid yield during nitrogen depletion was studied. The result revealed that the ABA level shoots up at 24h (27.21pmol/L) during the onset of nitrogen starvation followed by a sharp decline. The external supplemented ABA showed a positive effect on growth pattern (38*10(6)cells/ml) at a lower concentration. The dry biomass yield is also increasing up to 2.1 fold compared to nitrogen deficient S. quadricauda. The lipid content sustains in 1 and 2MUM concentration of ABA under nitrogen-deficient condition. The fatty acid composition of ABA treated S. quadricauda cultures with respect to nitrogen-starved cells showed 11.17% increment in saturated fatty acid content, the desired lipid composition for biofuel application. PMID- 26949055 TI - A novel sono-assisted acid pretreatment of chili post harvest residue for bioethanol production. AB - The objective of the present study was to develop a sono-assisted acid pretreatment strategy for the effective removal of lignin and hemicelluloses and to improve the sugar yield from chili post harvest residue. Operational parameters that affect the pretreatment efficiency were studied and optimized. Inhibitor analysis of the hydrolyzate revealed that major fermentation inhibitors like furfural, hydroxymethyl furfural and organic acids like citric acid, succinic acid and propionic acid were absent. Changes in structural properties of the biomass were studied in relation to the pretreatment process using scanning electron microscopy (SEM), X-ray diffraction (XRD) and Fourier Transform Infrared (FTIR) analysis, and the changes in chemical composition was also monitored. The biomass pretreated with the optimized novel method yielded 0.465g/g of reducing sugars on enzymatic hydrolysis. Fermentation of the non-detoxified hydrolysate yielded 2.14% of bioethanol with a fermentation efficiency of 71.03%. PMID- 26949056 TI - Staphylococcus aureus-derived lipoteichoic acid induces temporary T-cell paralysis independent of Toll-like receptor 2. AB - BACKGROUND: The interplay between microbes and surface organs, such as the skin, shapes a complex immune system with several checks and balances. The first-line defense is mediated by innate immune pathways leading to inflammation. In the second phase specific T cells invade the infected organ, amplifying inflammation and defense. Consecutively, termination of inflammation is crucial to avoid chronic inflammation triggered by microbes, such as in patients with atopic dermatitis. OBJECTIVE: We aimed to elucidate how the Staphylococcus aureus derived cell-wall component lipoteichoic acid (LTA) governs the second phase of immune responses when high concentrations of LTA access T cells directly through disrupted skin. METHODS: We analyzed the direct exposure of T cells to LTA in vitro. For in vivo analyses, we used fluorescein isothiocyanate contact hypersensitivity and ovalbumin-induced dermatitis as models for TH2-mediated cutaneous inflammation. RESULTS: We observed that LTA potently suppressed T lymphocyte activation in a Toll-like receptor 2-independent manner. LTA-exposed T cells did not proliferate and did not produce cytokines. Importantly, these T cells remained completely viable and were responsive to consecutive activation signals on subsequent removal of LTA. Thus LTA exposure resulted in temporary functional T-cell paralysis. In vivo experiments revealed that T-cell cytokine production and cutaneous recall responses were significantly suppressed by LTA. CONCLUSION: We identified a new mechanism through which bacterial compounds directly but temporarily modulate adaptive immune responses. PMID- 26949057 TI - Circulating innate lymphoid cells are differentially regulated in allergic and nonallergic subjects. PMID- 26949058 TI - Inflammatory endotypes of chronic rhinosinusitis based on cluster analysis of biomarkers. AB - BACKGROUND: Current phenotyping of chronic rhinosinusitis (CRS) into chronic rhinosinusitis with nasal polyps (CRSwNP) and chronic rhinosinusitis without nasal polyps (CRSsNP) might not adequately reflect the pathophysiologic diversity within patients with CRS. OBJECTIVE: We sought to identify inflammatory endotypes of CRS. Therefore we aimed to cluster patients with CRS based solely on immune markers in a phenotype-free approach. Secondarily, we aimed to match clusters to phenotypes. METHODS: In this multicenter case-control study patients with CRS and control subjects underwent surgery, and tissue was analyzed for IL-5, IFN-gamma, IL-17A, TNF-alpha, IL-22, IL-1beta, IL-6, IL-8, eosinophilic cationic protein, myeloperoxidase, TGF-beta1, IgE, Staphylococcus aureus enterotoxin-specific IgE, and albumin. We used partition-based clustering. RESULTS: Clustering of 173 cases resulted in 10 clusters, of which 4 clusters with low or undetectable IL-5, eosinophilic cationic protein, IgE, and albumin concentrations, and 6 clusters with high concentrations of those markers. The group of IL-5-negative clusters, 3 clusters clinically resembled a predominant chronic rhinosinusitis without nasal polyps (CRSsNP) phenotype without increased asthma prevalence, and 1 cluster had a TH17 profile and had mixed CRSsNP/CRSwNP. The IL-5-positive clusters were divided into a group with moderate IL-5 concentrations, a mixed CRSsNP/CRSwNP and increased asthma phenotype, and a group with high IL-5 levels, an almost exclusive nasal polyp phenotype with strongly increased asthma prevalence. In the latter group, 2 clusters demonstrated the highest concentrations of IgE and asthma prevalence, with all samples expressing Staphylococcus aureus enterotoxin specific IgE. CONCLUSION: Distinct CRS clusters with diverse inflammatory mechanisms largely correlated with phenotypes and further differentiated them and provided a more accurate description of the inflammatory mechanisms involved than phenotype information only. PMID- 26949059 TI - Tumor-suppressive functions of long-chain acyl-CoA synthetase 4 in gastric cancer. AB - Long chain acyl CoA synthetase 4 (ACSL4) is a key enzyme in fatty acid metabolism with marked preference for arachidonic acid (AA). Recent reports have implicated its crucial roles in tumorigenesis. However in gastric cancer (GC), the expression and function of ACSL4 remain unclear. In the present study, we identified ACSL4 as a potential tumor suppressor in GC. The ACSL4 expression in GC samples was evaluated by real-time PCR and immunohistochemistry. The results indicated that the mRNA and protein levels of ACSL4 were frequently downregulated in cancer tissues compared with the adjacent non-cancerous mucosa control tissues. Cell-based functional assays exhibited that ectopic expression of ACSL4 inhibits cell growth, colony formation and cell migration, whereas ACSL4 knockdown enhanced these effects. In a nude mice model, ACSL4 knockdown also promoted subcutaneous xenografts' growth in vivo. Moreover, western blot analysis revealed that ACSL4 expression had a significant effect on FAK and P21 protein level. These findings suggest that ACSL4 plays a tumor-suppressive role and could be a potential therapeutic target in GC. PMID- 26949060 TI - Association between cerebral small vessel diseases and mild parkinsonian signs in the elderly with vascular risk factors. AB - INTRODUCTION: The aim of this study was to examine the association between mild parkinsonian signs (MPS), cerebral small-vessel disease (SVD), and total SVD burden in patients with vascular risk factors. METHODS: We performed a cross sectional study among 268 patients with vascular risk factors but without parkinsonism or dementia (71.0 +/- 7.8 years, 63% male). MPS was evaluated via Unified Parkinson's Disease Rating Scale Part III. Brain MRI was used to determine SVD (cerebral microbleeds [CMBs], lacunar infarctions [LIs], and white matter hyperintensities [WMH]). The presence of each SVD feature was indicated by the total SVD score. Logistic regression analyses were performed adjusting for age, sex, history of stroke, hypertension, diabetes mellitus, and dyslipidemia. RESULTS: In a multivariate analysis, we found that the presence of CMBs, deep CMBs, mixed (in the basal ganglia and thalamus) LIs, periventricular hyperintensities (PVH), and deep WMH (DWMH), and total SVD score were significantly associated with MPS, whereas strictly lobar CMBs and other LIs (in strictly basal ganglia or strictly thalamus) were not. We also found a significant association between mixed LIs, PVH, DWMH and total SVD score and gait/balance function, between PVH and rigidity, and between mixed LIs and bradykinesia. Among elderly participants (>=73years), the association of total SVD score, deep CMBs, mixed LIs, and PVH, with MPS remained significant. CONCLUSION: Our results provide additional evidence that SVD including CMBs, and especially total SVD burden, might be a surrogate marker for MPS and support the contribution of hypertensive microangiopathy as the underlying etiology. PMID- 26949061 TI - Neutralizing Monoclonal Antibodies against Disparate Epitopes on Ricin Toxin's Enzymatic Subunit Interfere with Intracellular Toxin Transport. AB - Ricin is a member of the A-B family of bacterial and plant toxins that exploit retrograde trafficking to the Golgi apparatus and endoplasmic reticulum (ER) as a means to deliver their cytotoxic enzymatic subunits into the cytoplasm of mammalian cells. In this study we demonstrate that R70 and SyH7, two well characterized monoclonal antibodies (mAbs) directed against distinct epitopes on the surface of ricin's enzymatic subunit (RTA), interfere with toxin transport from the plasma membrane to the trans Golgi network. Toxin-mAb complexes formed on the cell surface delayed ricin's egress from EEA-1(+) and Rab7(+) vesicles and enhanced toxin accumulation in LAMP-1(+) vesicles, suggesting the complexes were destined for degradation in lysosomes. Three other RTA-specific neutralizing mAbs against different epitopes were similar to R70 and SyH7 in terms of their effects on ricin retrograde transport. We conclude that interference with toxin retrograde transport may be a hallmark of toxin-neutralizing antibodies directed against disparate epitopes on RTA. PMID- 26949062 TI - Upper Extremity Runoff: Pearls and Pitfalls in Computed Tomography Angiography and Magnetic Resonance Angiography. AB - Upper extremity vasculature can be affected by various traumatic and nontraumatic pathologies; however, the evaluation of these arteries can be challenging for the radiologists as well as for the clinicians. After an accurate history and clinical examination, imaging plays a vital role in the diagnosis and treatment planning of these patients. Depending on the urgency and the indication, upper extremity arteries may be evaluated by ultrasonography with color Doppler, computed tomography (CT), magnetic resonance imaging (MRI), or digital subtraction angiography. This review article discusses relevant imaging anatomy of the upper extremity arteries, presents CT and MRI protocols, briefly describes the state-of-the-art CT and MRI of various pathologies affecting the upper extremity arteries, and summarizes the important pearls needed for busy practicing radiologist. PMID- 26949063 TI - Pseudoangiomatous Stromal Hyperplasia of the Breast: Multimodality Review With Pathologic Correlation. AB - Pseudoangiomatous stromal hyperplasia (PASH) is a rare benign breast condition. PASH is thought to be hormonally responsive, and it is usually identified in premenopausal and perimenopausal women. PASH may also be seen in postmenopausal woman on hormone replacement therapy (HRT). Approximately 53% of patients with PASH present with abnormalities on screening mammography, and 44% of patients with PASH present with palpable abnormalities. On imaging studies, PASH appears similar to fibroadenomas. On mammography, PASH is usually seen as a noncalcified, circumscribed mass. On ultrasound, PASH often appears as an oval, circumscribed, hypoechoic mass. On magnetic resonance imaging, PASH usually has progressive (Type 1) enhancement, and high-signal slit-like spaces may be seen on T2-weighted and short tau inversion recovery (STIR) images. The slit-like spaces correspond to empty clefts within acellular hyalinized stroma on histopathology. PASH may be mistaken for a low-grade angiosarcoma on pathologic examination. While angiosarcoma has true vascular spaces, PASH has a network of pseudoangiomatous slit-like clefts. Women with biopsy-proven PASH usually undergo follow-up imaging. Surgical excision may be considered for larger lesions and in women at an increased risk for developing breast cancer. In the future, additional studies are needed to provide definitive data regarding appropriate management and long term outcomes for women with PASH. PASH has become increasingly recognized, but the literature regarding the imaging features of PASH is scarce. This paper reviews the imaging and pathologic features of PASH and some processes that may simulate PASH are discussed. Features of PASH on mammography, ultrasound, MRI, and nuclear medicine studies are discussed with pathologic correlation. PMID- 26949064 TI - Effect of clofibrate on fatty acid metabolism in the kidney of puromycin-induced nephrotic rats. AB - BACKGROUND: Proteinuria plays an essential role in the progression of tubulointerstitial damage, which causes end-stage renal disease. An increased load of fatty acids bound to albumin reabsorbed into proximal tubular epithelial cells (PTECs) contributes to tubulointerstitial damage. Fibrates, agonists of peroxisome proliferator-activated receptor alpha (PPARalpha), have renoprotective effects against proteinuria whereas the effects of these compounds on fatty acid metabolism in the kidney are still unknown. Therefore, the present study examined whether the renoprotective effects of clofibrate were associated with improvement of fatty acid metabolism in puromycin aminonucleoside (PAN)-induced nephrotic rats. METHODS: Rats were allocated to the control, PAN or clofibrate-treated PAN group. Biochemical parameters, renal injury and changes in fatty acid metabolism were studied on day14. RESULTS: PAN increased proteinuria, lipid accumulation in PTECs, excretions of N-acetyl-beta-D-glucosaminidase (NAG) and 8 hydroxydeoxyguanosine (8OHdG) and the area of caspase 3-positive tubular cells. It decreased renal expressions of medium-chain acyl-CoA dehydrogenase (MCAD), cytochrome P450 (CYP)4A, peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) and estrogen-related receptor alpha (ERRalpha) without change of the expression of PPARalpha. Clofibrate reduced proteinuria, lipid accumulation, NAG excretion and the area of caspase 3-positive tubular cells. However, albumin excretion was not reduced and 8OHdG excretion was increased. Clofibrate minimized changes in MCAD, CYP4A, PGC-1alpha and ERRalpha expressions with increased PPARalpha, very long-chain acyl-CoA dehydrogenase (VLCAD) and long-chain acyl-CoA dehydrogenase (LCAD) expressions. CONCLUSION: Clofibrate is protective against renal lipotoxicity in PAN nephrosis. This study indicates that clofibrate has renoprotective effects through maintaining fatty acid metabolism in the kidney of PAN-induced nephrotic rats. PMID- 26949065 TI - The relationship between balance confidence and control in individuals with Parkinson's disease. AB - INTRODUCTION: A broad range of subjective and objective assessments have been used to assess balance confidence and balance control in persons with Parkinson's disease (PD). However, little is known about the relationship between self perceived balance confidence and actual balance control in PD. The purpose of this investigation was to determine the relationship between self-perceived balance confidence and objectively measured static/dynamic balance control abilities. METHODS: Forty-four individuals with PD participated in the study. Patients were stratified into 2 groups based on the modified Hoehn and Yahr (H&Y) disability score: early stage, H&Y <= 2.0 and moderate stage, H&Y >= 2.5. All participants completed the activities-specific balance confidence (ABC) scale and performed standing balance and gait initiation tasks to assess static and dynamic balance control. The center of pressure (COP) sway (CE95%Sway) during static balance and the peak distance between the projections of the COP and the center of mass (COM) in the transverse plane (COPCOM) during gait initiation were calculated. Pearson correlation analyses were conducted relating the ABC score and CE95%Sway and COPCOM. RESULTS: For early stage PD, there was a moderate correlation between ABC score and CE95%Sway (r = -0.56, R(2) = 0.32, p = 0.002), while no significant correlation was found between ABC score and COPCOM (r = 0.24, R(2) = 0.06, p = 0.227). For moderate stage PD, there was a moderate correlation between ABC score and COPCOM (r = 0.49, R(2) = 0.24, p = 0.044), while no correlation was found between ABC score and CE95%Sway (r = -0.19, R(2) = 0.04, p = 0.478). CONCLUSION: Individuals with different disease severities showed different relationships between balance confidence and actual static/dynamic balance control. PMID- 26949068 TI - Long-standing air-leak after valve lung volume reduction necessitating lobectomy. PMID- 26949069 TI - [The role of atherogenic dyslipidaemia in clinical practice guidelines]. AB - BACKGROUND AND OBJECTIVE: Atherogenic dyslipidaemia is underdiagnosed, undertreated, and under-controlled. The aim of the present study was to assess the positioning of clinical guidelines as regards atherogenic dyslipidaemia. MATERIAL AND METHOD: The major clinical guidelines of scientific societies or official agencies issued between January 1, 2012 and March 31, 2015 were collected from the MEDLINE database. High-density lipoprotein (HDL) cholesterol, triglycerides, atherogenic dyslipidaemia, non-HDL cholesterol, and apolipoprotein (apo) B were gathered from the 10 selected guidelines, and it was assessed whether these parameters were considered a cardiovascular risk factor, a therapeutic target, or proposed a pharmacological strategy. RESULTS: American guidelines, except the National Lipid Association (NLA), do not consider HDL cholesterol and triglycerides in cardiovascular prevention. The NLA emphasises the relevance of atherogenic dyslipidaemia. The Canadian guidelines introduced non-HDL cholesterol and ApoB as alternative targets, and proposes non-statin treatment in the presence of low HDL cholesterol and hypertriglyceridaemia. The International Atherosclerosis Society (IAS) and National Institute for Health and Care Excellence (NICE) guidelines promote the importance of non-HDL cholesterol. European, Brazilian and Japanese guidelines highlight HDL cholesterol and triglycerides, but with the limitation that the main evidence comes from sub analysis of clinical studies. CONCLUSIONS: The clinical guidelines analysed do not consider, or unconvincingly address, the importance of atherogenic dyslipidaemia. PMID- 26949070 TI - [Epidemiology of diabetes mellitus in South America: The experience of Colombia]. AB - According to the International Diabetes Federation, 8.3% of the world population suffers from diabetes mellitus, and it is expected that the number of individuals with the disease will increase to over 592 million. In South and Central America, it is estimated that the increase in the number of cases diagnosed in the period from 2013 to 2035 will be 59.8% (from 24 to 38.5 millions). According to the World Health Organisation, the prevalence of fasting hyperglycaemia in the region of the Americas in 2014 was 9.3% in men and 8.1% in women. The countries with the highest prevalence of diabetes mellitus in adults >=18years were: Guyana, Surinam, Chile, and Argentina. In Colombia, the prevalence of type 2 diabetes mellitus is variable, depending on the population range assessed and the diagnostic criteria used. PMID- 26949072 TI - A graphene superficial layer for the advanced electroforming process. AB - Advances in electroplating technology facilitate the progress of modern electronic devices, including computers, microprocessors and other microelectronic devices. Metal layers with high electrical and thermal conductivities are essential for high speed and high power devices. In this paper, we report an effective route to fabricate free-standing metal films using graphene as a superficial layer in the electroforming process. Chemical vapor deposition (CVD) graphene grown on a Cu foil was used as a template, which provides high electrical conductivity and low adhesive force with the template, thus enabling an effective electroforming process. The required force for delamination of the electroplated Cu layer from graphene is more than one order smaller than the force required for removing graphene from the Cu foil. We also demonstrated that the electroformed free-standing Cu thin films could be utilized for patterning microstructures and incorporated onto a flexible substrate for LEDs. This innovative process could be beneficial for the advancement of flexible electronics and optoelectronics, which require a wide range of mechanical and physical properties. PMID- 26949073 TI - PROTEOMICS Reviews 2016--Part 2. PMID- 26949071 TI - [Delphi consensus on management of dyslipidaemia in patients with impaired glucose metabolism: Diana study]. AB - OBJECTIVES: The aim of the present study was to develop a multidisciplinary consensus based on the Delphi system to establish clinical recommendations for the management of dyslipidaemia when hyperglycaemia is present, and the relevant factors that should be taken into consideration when prescribing and monitoring treatment with statins. METHODS: The questionnaire developed by the scientific committee included four blocks of questions about dyslipidaemia in patients with impaired glucose metabolism. The results of the first two blocks are presented here: a) management of dyslipidaemia; b) relevant factors that should be taken into consideration when prescribing and monitoring treatment with statins. RESULTS: Among the 497 experts who participated in the study, an agreement of over 90% was attained for recommending screening for dyslipidaemia in patients with diabetes or pre-diabetes and/or cardiovascular disease or a family history and/or abdominal obesity and/or hypertension. There was a high degree of agreement that a statin is the lipid-lowering treatment of choice, and that it should be switched when side effects develop. Also, the choice of statin and dose should be made according to baseline LDL cholesterol levels, the target to achieve, and the possible drug-drug interactions. CONCLUSIONS: The screening of dyslipidaemia is primarily conducted in patients with cardiovascular disease, or any major cardiovascular risk factor. When prescribing a statin, physicians mainly focus on the ability to reduce LDL cholesterol and the risk of drug interactions. PMID- 26949076 TI - Development of an infusion bioreactor for the accelerated preparation of decellularized skeletal muscle scaffolds. AB - The implantation of decellularized tissue has shown effectiveness as a strategy for the treatment of volumetric muscle loss (VML) injuries. The preparation of decellularized tissue typically relies on the diffusion driven removal of cellular debris. For bulky tissues like muscle, the process can be lengthy, which introduces opportunities for both tissue contamination and degradation of key ECM molecules. In this study we report on the accelerated preparation of decellularized skeletal muscle (DSM) scaffolds using a infusion system and examine scaffold performance for the repair of VML injuries. The preparation of DSM scaffolds using infusion was dramatically accelerated. As the infusion rate (1% SDS) was increased from 0.1 to 1 and 10ml/hr, the time needed to remove intracellular myoglobin and actin decreased from a maximum of 140 +/- 3hrs to 45 +/- 3hrs and 10 +/- 2hrs respectively. Although infusion appeared to remove cellular debris more aggressively, it did not significantly decrease the collagen or glycosaminoglycan composition of DSM samples when compared to un-infused controls. Infusion prepared DSM samples retained the aligned network structure and mechanical integrity of control samples. Infusion prepared DSM samples supported the attachment and in-vitro proliferation of myoblast cells and was well tolerated by the host when examined in-vivo. (c) 2016 American Institute of Chemical Engineers Biotechnol. Prog., 32:745-755, 2016. PMID- 26949077 TI - Novel Slide-Ring Material/Natural Rubber Composites with High Damping Property. AB - A novel class of polymers called "slide-ring" (SR) materials with slideable junctions were used for high damping composites for the first time. The SR acts as the high damping phase dispersed in the natural rubber (NR) matrix, and epoxidized natural rubber (ENR) acts as the compatibilizer. The morphological, structural, and mechanical properties of the composites were investigated by atomic force microscope (AFM), transmission electron microscope (TEM), dynamic mechanical thermal analyzer (DMTA), rubber processing analyzer (RPA), and tensile tester. AFM and TEM results showed that the SR phase was uniformly dispersed in the composites, in a small size that is a function of ENR. DMTA and RPA results showed that the damping factor of the composites is much higher than that of NR, especially at room temperatures. Stretch hysteresis was used to study the energy dissipation of the composites at large strains. The results showed that SR and ENR can significantly improve the dissipation efficiency at strains lower than 200% strain. Wide-angle X-ray diffraction was used to study the strain-induced crystallization of the composites. The results indicated that the impact of the SR on the crystallization of NR is mitigated by the insulating effect of ENR. PMID- 26949078 TI - Capture efficiency of dynamic pH junction focusing in capillary electrophoresis. AB - Dynamic pH junction is one of the techniques used to overcome the issue of poor concentration sensitivity in CE. By introducing a long sample plug in the capillary and focusing the target molecules at the pH boundary between the sample plug and background electrolyte, this focusing technique can achieve a detection limit that is one to two orders of magnitude better than conventional CE. For quantification purposes, the capturing efficiency of the injected molecules should be scrutinized. Focusing of all target molecules inside the sample plug is desired to ensure good linearity across the whole dynamic range. To test the theoretical prediction with a real experiment, nicotine is used as the test molecule for two types of dynamic pH junctions. The first one is with acidic background electrolyte, and can accommodate both optical detection methods and positive-ion mode mass spectrometric detection, while the other is suitable for optical detection only due to the use of basic separation background electrolyte. With a theoretical simulation study, it is demonstrated that, for either of these dynamic pH junctions, focusing of at least 95% of target molecule injected into the capillary was easily achievable. More importantly, a longer sample plug could generate a high percentage of molecules captured by dynamic pH junction focusing. Sharp, symmetrical peaks and good linearity for calibration curve can be obtained. Real samples with complex matrixes were also used to demonstrate that nicotine can be selectively focused and quantified using CE-MS. PMID- 26949079 TI - Dienamine Activation of Diazoenals: Application to the Direct Synthesis of Functionalized 1,4-Oxazines. AB - A novel rhodium-catalyzed dienamine activation of diazoenals resulted in a new class of gamma-functionalized donor-acceptor dienamines. The synthetic utility of these dienamines has been demonstrated in a cooperative rhodium(II)/Bronsted acid and gold(I)-catalyzed direct [3+3] annulation of enaldiazo ketones with N propargyl anilines, thus leading to highly substituted enal-functionalized 1,4 oxazines. The reaction is proposed to involve dienamine activation through the diacceptor rhodium enalcarbenoid NH-insertion and a gold-catalyzed intramolecular site-selective 6-exo-dig heterocyclization. The methodology was applied to the efficient synthesis of structurally complex [1,4]oxazino[4,3-a]quinolone, which is present in the antibacterial agent PNU-286607. PMID- 26949080 TI - Long-drawn-out story. PMID- 26949081 TI - Peculiarities of insight: Clinical implications of self-representations. PMID- 26949082 TI - What history tells us XL. The success story of the expression 'genome editing'. PMID- 26949083 TI - Phase variation of Opa proteins of Neisseria meningitidis and the effects of bacterial transformation. AB - Opa proteins are major proteins involved in meningococcal colonization of the nasopharynx and immune interactions. Opa proteins undergo phase variation (PV) due to the presence of the 5'-CTCTT-3' coding repeat (CR) sequence. The dynamics of PV of meningococcal Opa proteins is unknown. Opa PV, including the effect of transformation on PV, was assessed using a panel of Opa-deficient strains of Neisseria meningitidis. Analysis of Opa expression from UK disease-causing isolates was undertaken. Different opa genes demonstrated variable rates of PV, between 6.4 * 10(-4) and 6.9 * 10(-3) per cell per generation. opa genes with a longer CR tract had a higher rate of PV (r(2) = 0.77, p = 0.1212). Bacterial transformation resulted in a 180-fold increase in PV rate. The majority of opa genes in UK disease isolates (315/463, 68.0%) were in the 'on' phase, suggesting the importance of Opa proteins during invasive disease. These data provide valuable information for the first time regarding meningococcal Opa PV. The presence of Opa PV in meningococcal populations and high expression of Opa among invasive strains likely indicates the importance of this protein in bacterial colonization in the human nasopharynx. These findings have potential implications for development of vaccines derived from meningococcal outer membranes. PMID- 26949084 TI - Male function for ensuring pollination and reproductive success in Berberis lycium Royle: A novel mechanism. AB - In Berberis lycium anthers on alternate stamens dehisce, thus prolonging the male function so that pollination is affected and reproduction is ensured. The large pollen sac of each bithecous anther after the appearance of longitudinal dehiscence slit moves away from the filament while remaining attached at the tip of the connective and then orients in such a way that pollen-laden surface faces the stigma. No pollen is available to receptive stigma as pollen grains remain stuck to the anther sac. They do not get dispersed even by wind. Pollination and consequently reproduction is ensured through the intervention of insect, which does not affect pollen transfer to the stigma directly but by touching the base of the staminal filament while foraging nectar secreted by nectaries at the base of corolla, thus leading to staminal movement. This makes the dehisced anthers stick to the stigma and deposit pollen there. PMID- 26949085 TI - A putative Type IIS restriction endonuclease GeoICI from Geobacillus sp.--A robust, thermostable alternative to mezophilic prototype BbvI. AB - Screening of extreme environments in search for novel microorganisms may lead to the discovery of robust enzymes with either new substrate specificities or thermostable equivalents of those already found in mesophiles, better suited for biotechnology applications. Isolates from Iceland geysers' biofilms, exposed to a broad range of temperatures, from ambient to close to water boiling point, were analysed for the presence of DNA-interacting proteins, including restriction endonucleases (REases). GeoICI, a member of atypical Type IIS REases, is the most thermostable isoschizomer of the prototype BbvI, recognizing/cleaving 5' GCAGC(N8/12)-3'DNA sequences. As opposed to the unstable prototype, which cleaves DNA at 30 degrees C, GeoICI is highly active at elevated temperatures, up to 73 degrees C and over a very wide salt concentration range. Recognition/cleavage sites were determined by: (i) digestion of plasmid and bacteriophage lambda DNA (Lambda); (ii) cleavage of custom PCR substrates, (iii) run-off sequencing of GeoICI cleavage products and (iv) shotgun cloning and sequencing of Lambda DNA fragmented with GeoICI. Geobacillus sp. genomic DNA was PCR-screened for the presence of other specialized REases-MTases and as a result, another putative REase- MTase, GeoICII, related to the Thermus sp. family of bifunctional REases methyltransferases (MTases) was detected. PMID- 26949086 TI - Environmental fluctuations do not select for increased variation or population based resistance in Escherichia coli. AB - Little is known about the mechanisms that enable organisms to cope with unpredictable environments. To address this issue, we used replicate populations of Escherichia coli selected under complex, randomly changing environments. Under four novel stresses that had no known correlation with the selection environments, individual cells of the selected populations had significantly lower lag and greater yield compared to the controls. More importantly, there were no outliers in terms of growth, thus ruling out the evolution of population based resistance. We also assayed the standing phenotypic variation of the selected populations, in terms of their growth on 94 different substrates. Contrary to expectations, there was no increase in the standing variation of the selected populations, nor was there any significant divergence from the ancestors. This suggested that the greater fitness in novel environments is brought about by selection at the level of the individuals, which restricts the suite of traits that can potentially evolve through this mechanism. Given that day-to-day climatic variability of the world is rising, these results have potential public health implications. Our results also underline the need for a very different kind of theoretical approach to study the effects of fluctuating environments. PMID- 26949088 TI - Laser stimulation of the acupoint 'Zusanli' (ST.36) on the radiopharmaceutical biodistribution in Wistar rats. AB - Laser used to stimulate acupoints is called laser acupuncture (LA). It is generally believed that similar clinical responses to manual acupuncture can be achieved. Here we analysed the effects of the laser (904 nm) at the 'Zusanli' acupoint (ST.36) of the stomach meridian on the biodistribution of the radiopharmaceutical Na(99m)TcO4. Wistar rats were divided into control (CG) and experimental groups (EG). The EG were exposed daily to the laser (904 nm) at ST.36 with 1 joule/min (40 mW/cm(2)) for 1 min. The animals of the CG were not exposed to laser at all. On the 8th day after LA, the animals were sedated and Na(99m)TcO4 was administered. After 10 min, the animals were all sacrificed and the organs removed. The radioactivity was counted in each organ to calculate the percentage of radioactivity of the injected dose per gram (%ATI/ g). Comparison of the %ATI/g in EG and CG was performed by Mann-Whitney test. The %ATI/g was significantly increased in the thyroid due to the stimulation of the ST.36 by laser. It is possible to conclude that the stimulation of ST.36 does lead to biological phenomena that interfere with the metabolism of the thyroid. PMID- 26949087 TI - Identification of EhTIF-IA: The putative E. histolytica orthologue of the human ribosomal RNA transcription initiation factor-IA. AB - Initiation of rDNA transcription requires the assembly of a specific multi protein complex at the rDNA promoter containing the RNA Pol I with auxiliary factors. One of these factors is known as Rrn3P in yeast and Transcription Initiation Factor IA (TIF-IA) in mammals. Rrn3p/TIF-IA serves as a bridge between RNA Pol I and the pre-initiation complex at the promoter. It is phosphorylated at multiple sites and is involved in regulation of rDNA transcription in a growth dependent manner. In the early branching parasitic protist Entamoeba histolytica, the rRNA genes are present exclusively on circular extra chromosomal plasmids. The protein factors involved in regulation of rDNA transcription in E. histolytica are not known. We have identified the E. histolytica equivalent of TIF-1A (EhTIF-IA) by homology search within the database and was further cloned and expressed. Immuno-localization studies showed that EhTIF-IA co-localized partially with fibrillarin in the peripherally localized nucleolus. EhTIF-IA was shown to interact with the RNA Pol I-specific subunit RPA12 both in vivo and in vitro. Mass spectroscopy data identified RNA Pol I-specific subunits and other nucleolar proteins to be the interacting partners of EhTIF-IA. Our study demonstrates for the first time a conserved putative RNA Pol I transcription factor TIF-IA in E. histolytica. PMID- 26949089 TI - Zinc finger protein 521 overexpression increased transcript levels of Fndc5 in mouse embryonic stem cells. AB - Zinc finger protein 521 is highly expressed in brain, neural stem cells and early progenitors of the human hematopoietic cells. Zfp521 triggers the cascade of neurogenesis in mouse embryonic stem cells through inducing expression of the early neuroectodermal genes Sox1, Sox3 and Pax6. Fndc5, a precursor of Irisin has inducing effects on the expression level of brain derived neurotrophic factor in hippocampus. Therefore, it is most likely that Fndc5 may play an important role in neural differentiation. To exhibit whether the expression of this protein is under regulation with Zfp521, we overexpressed Zfp521 in a stable transformants of mESCs expressing EGFP under control of Fndc5 promoter. Increased expression of Zfp521 enhanced transcription levels of both EGFP and endogenous Fndc5. This result was confirmed by overexpression the aforementioned vectors in HEK cells and indicated that Zfp521 functions upstream of Fndc5 expression. It is most likely that Zfp521 may act through the binding to its response element on Fndc5 core promoter. Therefore it is concluding that an enhanced expression of Fndc5 in neural progenitor cells is stimulated by Zfp521 overexpression in these cells. PMID- 26949090 TI - MiR-128b is down-regulated in gastric cancer and negatively regulates tumour cell viability by targeting PDK1/Akt/NF-kappaB axis. AB - Gastric cancer (GC) is the fourth most prevalent type of cancer worldwide, which is usually caused by the interaction between environmental and genetic factors, or epigenetic aspects. Referring to the non-coding RNAs, miR-128b has been reported to be associated with many tumour cases, and exerts distinct functions in different types of cancers. However, the function of miR-128b in GC onset and progression largely remains unknown. In the present study, we found that miR-128b expression was down-regulated in tissues from 18 GC patients and 3 carcinoma cell lines. In turn, over-expression of miR-128b suppressed GC cell proliferation, invasion and promoted apoptosis. Moreover, miR-128b was predicted to bind the 3'UTR of PDK1 gene using bioinformatic target-screening tools. Accordingly, ectopic expression of miR-128b inhibited the PDK1 expression at both transcriptional and post-transcriptional levels, and furthermore, the expression of gene tailed by the 3'UTR of PDK1 gene was significantly decreased in a dualluciferase reporter assay, suggesting that PDK1 was a direct target of miR 128b in GC cells. In the conditon of miR- 128b over-expression, we also observed spontaneous inactivation of the Akt/NF-kappaB signalling, implying PDK1 was a potential regulator of this pathway. In conclusion, our study shed some novel light on miR-128b-PDK1/Akt/NF-kappaB axis on GC progression. PMID- 26949091 TI - Cystathionine-gamma-lyase gene silencing with siRNA in monocytes/ macrophages attenuates inflammation in cecal ligation and puncture-induced sepsis in the mouse. AB - Hydrogen sulphide is an endogenous inflammatory mediator produced by cystathionine-gamma-lyase (CSE) in macrophages. To determine the role of H2S and macrophages in sepsis, we used small interference RNA (siRNA) to target the CSE gene and investigated its effect in a mouse model of sepsis. Cecal ligation puncture (CLP)-induced sepsis is characterized by increased levels of myeloperoxidase (MPO) activity, morphological changes in liver and pro inflammatory cytokines and chemokines in the liver and lung. SiRNA treatment attenuated inflammation in the liver and lungs of mice following CLP-induced sepsis. Liver MPO activity increased in CLP-induced sepsis and treatment with siRNA significantly reduced this. Similarly, lung MPO activity increased following induction of sepsis with CLP while siRNA treatment significantly reduced MPO activity. Liver and lung cytokine and chemokine levels in CLP-induced sepsis reduced following treatment with siRNA. These findings show a crucial pro inflammatory role for H2S synthesized by CSE in macrophages in sepsis and suggest CSE gene silencing with siRNA as a potential therapeutic approach for this condition. PMID- 26949092 TI - Do prion protein gene polymorphisms induce apoptosis in non-mammals? AB - Genetic variations such as single nucleotide polymorphisms (SNPs) in prion protein coding gene, Prnp, greatly affect susceptibility to prion diseases in mammals. Here, the coding region of Prnp was screened for polymorphisms in redeared turtle, Trachemys scripta. Four polymorphisms, L203V, N205I, V225A and M237V, were common in 15 out of 30 turtles; in one sample, three SNPs, L203V, N205I and M237V, and in the remaining 14 samples, only L203V and N205I polymorphisms, were investigated. Besides, C658T, C664T, C670A and C823A SNPs were silent mutations. To elucidate the relationship between the SNPs and apoptosis, TUNEL assays and active caspase-3 immunodetection techniques in brain sections of the polymorphic samples were performed. The results revealed that TUNEL-positive cells and active caspase-3-positive cells in the turtles with four polymorphisms were significantly increased compared with those of the turtles with two polymorphisms (P less than 0.01 and P less than 0.05, respectively). In conclusion, this study provides preliminary information about the possible relationship between SNPs within the Prnp locus and apoptosis in a non-mammalian species, Trachemys scripta, in which prion disease has never been reported. PMID- 26949093 TI - Identification and validation of a virus-inducible ta-siRNA-generating TAS4 locus in tomato. AB - Trans-acting small interfering RNAs (ta-siRNAs) are a class of endogenous small RNA, associated with posttranscriptional gene silencing. Their biogenesis requires an initial microRNA (miRNA)-mediated cleavage of precursor RNA. Around 20 different ta-siRNA-producing loci (TASs), whose sequences are conserved, are reported in plants. In tomato, two TAS gene families have been identified, which are found to target auxin response factor gene and bacterial spot disease resistance protein Bs4 gene. Using high-throughput computational and experimental approach, we identified a new locus-producing ta-siRNA in tomato. We have also identified the putative miRNA regulating the production of ta-siRNA from this locus. The ta-siRNAs generated from TAS4 were up-regulated upon infection with a DNA virus. The potential targets of ta-siRNAs were predicted to be variety of proteins including MYB transcription factors and cell cycle regulators for some of the ta-siRNAs produced. PMID- 26949094 TI - Transcriptome analysis of stem wood of Nothapodytes nimmoniana (Graham) Mabb. identifies genes associated with biosynthesis of camptothecin, an anti carcinogenic molecule. AB - Camptothecin (CPT), a monoterpene indole alkaloid, is a potent inhibitor of DNA topoisomerase I and has applications in treating ovarian, small lung and refractory ovarian cancers. Stem wood tissue of Nothapodytes nimmoniana (Graham) Mabb. (family Icacinaceae) is one of the richest sources of CPT. Since there is no genomic or transcriptome data available for the species, the present work sequenced and analysed transcriptome of stem wood tissue on an Illumina platform. From a total of 77,55,978 reads, 9,187 transcripts were assembled with an average length of 255 bp. Functional annotation and categorization of these assembled transcripts unraveled the transcriptome architecture and also a total of 13 genes associated with CPT biosynthetic pathway were identified in the stem wood tissue. Four genes of the pathway were cloned to full length by RACE to validate the transcriptome data. Expression analysis of 13 genes associated with CPT biosynthetic pathway in 11 different tissues vis-a-vis CPT content analysis suggested an important role of NnPG10H, NnPSLS and NnPSTR genes in the biosynthesis of CPT. These results indicated that CPT might be synthesized in the leaves and then perhaps exported to stem wood tissue for storage. PMID- 26949095 TI - In silico dissection of Type VII Secretion System components across bacteria: New directions towards functional characterization. AB - Type VII Secretion System (T7SS) is one of the factors involved in virulence of Mycobacterium tuberculosis H37Rv. Numerous research efforts have been made in the last decade towards characterizing the components of this secretion system. An extensive genome-wide analysis through compilation of isolated information is required to obtain a global view of diverse characteristics and pathogenicity related aspects of this machinery. The present study suggests that differences in structural components (of T7SS) between Actinobacteria and Firmicutes, observed earlier in a few organisms, is indeed a global trend. A few hitherto uncharacterized T7SS-like clusters have been identified in the pathogenic bacteria Enterococcus faecalis, Saccharomonospora viridis, Streptococcus equi, Streptococcus gordonii and Streptococcus sanguinis. Experimental verification of these clusters can shed lights on their role in bacterial pathogenesis. Similarly, verification of the identified variants of T7SS clusters consisting additional membrane components may help in unraveling new mechanism of protein translocation through T7SS. A database of various components of T7SS has been developed to facilitate easy access and interpretation of T7SS related data. PMID- 26949096 TI - Finding clues to the riddle of sex determination in zebrafish. AB - How sex is determined has been one of the most intriguing puzzles in biology since antiquity. Although a fundamental process in most metazoans, there seems to be myriad of ways in which sex can be determined - from genetic to environmental sex determination. This variation is limited mainly to upstream triggers with the core of sex determination pathway being conserved. Zebrafish has gained prominence as a vertebrate model system to study development and disease. However, very little is known about its primary sex determination mechanism. Here we review our current understanding of the sex determination in zebrafish. Zebrafish lack identifiable heteromorphic sex chromosomes and sex is determined by multiple genes, with some influence from the environment. Recently, chromosome 4 has been identified as sex chromosome along with few sex-linked loci on chromosomes 5 and 16. The identities of candidate sex-linked genes, however, have remained elusive. Sex in zebrafish is also influenced by the number of meiotic oocytes in the juvenile ovary, which appear to instruct retention of the ovarian fate. The mechanism and identity of this instructive signal remain unknown. We hypothesize that sex in zebrafish is a culmination of combinatorial effects of the genome, germ cells and the environment with inputs from epigenetic factors translating the biological meaning of this interaction. PMID- 26949098 TI - Topoisomerase IB of Deinococcus radiodurans resolves guanine quadruplex DNA structures in vitro. PMID- 26949097 TI - Human regeneration: An achievable goal or a dream? AB - The main objective of regenerative medicine is to replenish cells or tissues or even to restore different body parts that are lost or damaged due to disease, injury and aging. Several avenues have been explored over many decades to address the fascinating problem of regeneration at the cell, tissue and organ levels. Here we discuss some of the primary approaches adopted by researchers in the context of enhancing the regenerating ability of mammals. Natural regeneration can occur in different animal species, and the underlying mechanism is highly relevant to regenerative medicine-based intervention. Significant progress has been achieved in understanding the endogenous regeneration in urodeles and fishes with the hope that they could help to reach our goal of designing future strategies for human regeneration. PMID- 26949099 TI - Behavior of vascular resistance undergoing various pressure insufflation and perfusion on decellularized lungs. AB - Bioengineering of functional lung tissue by using whole lung scaffolds has been proposed as a potential alternative for patients awaiting lung transplant. Previous studies have demonstrated that vascular resistance (Rv) could be altered to optimize the process of obtaining suitable lung scaffolds. Therefore, this work was aimed at determining how lung inflation (tracheal pressure) and perfusion (pulmonary arterial pressure) affect vascular resistance. This study was carried out using the lungs excised from 5 healthy male Sprague-Dawley rats. The trachea was cannulated and connected to a continuous positive airway pressure (CPAP) device to provide a tracheal pressure ranging from 0 to 15cmH2O. The pulmonary artery was cannulated and connected to a controlled perfusion system with continuous pressure (gravimetric level) ranging from 5 to 30cmH2O. Effective Rv was calculated by ratio of pulmonary artery pressure (PPA) by pulmonary artery flow (V'PA). Rv in the decellularized lungs scaffolds decreased at increasing V'PA, stabilizing at a pulmonary arterial pressure greater than 20cmH2O. On the other hand, CPAP had no influence on vascular resistance in the lung scaffolds after being subjected to pulmonary artery pressure of 5cmH2O. In conclusion, compared to positive airway pressure, arterial lung pressure markedly influences the mechanics of vascular resistance in decellularized lungs. PMID- 26949101 TI - Exploration of the validity of the two-dimensional sagittal plane assumption in modeling the standing long jump. AB - Most previous standing long jump studies have been based on the assumption of two dimensional sagittal plane motion with bilateral symmetry. The purpose of this study was to investigate the validity of this assumption. Standing long jump trials were collected using six adult male participants. Each participant stood with a foot on each of two force plates and performed eight standing long jumps for maximal distance. Inverse dynamics analyses were performed for two dimensional (2D) and three-dimensional (3D) models, and joint moments, powers, and work values were compared. The differences between these models with respect to the validity of the common planar jumping assumption were analyzed. Good agreement was observed between 2D and 3D methods for the lower body, with minimal differences in sagittal plane moments, power, and work for the ankle, knee, and lower back. There were significant, but relatively small differences in the sagittal plane kinematics and kinetics at the hip. For the upper body, the results contradicted the sagittal plane assumption in that significant moments and power were generated about the abduction/adduction axis of the shoulder and a similar amount of work was performed about both abduction/adduction and flexion/extension axes of the shoulder. The elbow also showed significant differences in power and work. These results indicate that an assumption of planar motion should be sufficient for many studies of the standing long jump that only examine lower body movement. However, for studies that include upper body motion, diagnosing injury risk, or investigating gender differences, a 3D model may be more appropriate. PMID- 26949100 TI - Effective modulus of the human intervertebral disc and its effect on vertebral bone stress. AB - The mechanism of vertebral wedge fractures remains unclear and may relate to typical variations in the mechanical behavior of the intervertebral disc. To gain insight, we tested 16 individual whole discs (between levels T8 and L5) from nine cadavers (mean+/-SD: 66+/-16 years), loaded in compression at different rates (0.05-20.0% strain/s), to measure a homogenized "effective" linear elastic modulus of the entire disc. The measured effective modulus, and average disc height, were then input and varied parametrically in micro-CT-based finite element models (60-MUm element size, up to 80 million elements each) of six T9 human vertebrae that were virtually loaded to 3 degrees of moderate forward flexion via a homogenized disc. Across all specimens and loading rates, the measured effective modulus of the disc ranged from 5.8 to 42.7MPa and was significantly higher for higher rates of loading (p<0.002); average disc height ranged from 2.9 to 9.3mm. The parametric finite element analysis indicated that, as disc modulus increased and disc height decreased across these ranges, the vertebral bone stresses increased but their spatial distribution was largely unchanged: most of the highest stresses occurred in the central trabecular bone and endplates, and not anteriorly. Taken together with the literature, our findings suggest that the effective modulus of the human intervertebral disc should rarely exceed 100MPa and that typical variations in disc effective modulus (and less so, height) minimally influence the spatial distribution but can appreciably influence the magnitude of stress within the vertebral body. PMID- 26949102 TI - The Use of Kits in the Analysis of Tissue Lipids Requires Validation. AB - The ready availability and ease of use of kits for the measurement of serum lipids has greatly facilitated these measurements. In many cases it would be convenient to use these kits in the determination of lipid concentrations in tissues. The successful application of serum kits in tissue analysis requires that two important issues be considered. First, the solvent system for the extraction of the lipids and the solvent used for analysis by the kit must be compatible with the reactions in the kit. Second, the concentration range in the analyzed solution must be within the range for which the kit is used. We report here that lipids in liver and adipose tissues may be significantly underestimated by the use of some kits. We recommend that the use of kits for tissue analysis of lipids be validated for the specific analysis. PMID- 26949103 TI - One-Pot Synthesis of Arylketones from Aromatic Acids via Palladium-Catalyzed Suzuki Coupling. AB - A palladium-catalyzed one-pot procedure for the synthesis of aryl ketones has been developed. Triazine esters when coupled with aryl boronic acids provided aryl ketones in moderate to excellent yields (up to 95%) in the presence of 1 mol % Pd(PPh3)2Cl2 for 30 min. PMID- 26949105 TI - Comparison of the biological effects of exogenous and endogenous 1,25 dihydroxyvitamin D3 on the mature osteoblast cell line MLO-A5. AB - Clinical and animal data indicate that serum 25-hydroxyvitamin D3 (25D) exerts an anabolic effect on bone while serum 1alpha,25-dihydroxyvitamin D3 (1,25D) stimulates bone mineral loss, although the mechanism responsible for these divergent actions is unknown. Biological effects of 25D on bone cells are dependent on the local conversion to 1,25D by the 25-hydroxyvitamin D-1alpha hydroxylase enzyme, CYP27B1. Therefore, identification of possible differential activities of locally produced and exogenously supplied 1,25D in bone is likely to be informative for guiding optimal administration of vitamin D supplements for bone health. The mature osteoblastic cell line MLO-A5 expresses both the vitamin D receptor (Vdr) and Cyp27b1, and therefore is a suitable model for comparing the activities of 1,25D arising from these sources. Biologically, exogenous and endogenous sources of 1,25D have similar effects on proliferation, mineralisation and induction of a range of genes by MLO-A5 osteoblasts under osteogenic conditions although endogenous 1,25D levels are markedly lower than exogenous levels. Significant differences of pharmacokinetics and pharmacodynamics of 1,25D are evident between these two sources particularly in terms of modulating gene expression for Cyp24a1 and other genes largely expressed by embedded osteoblasts/osteocytes suggesting that endogenously synthesised 1,25D is more efficiently utilised by the differentiating osteoblast. PMID- 26949104 TI - 1,25(OH)2D3 inhibits oxidative stress and monocyte adhesion by mediating the upregulation of GCLC and GSH in endothelial cells treated with acetoacetate (ketosis). AB - BACKGROUND: There is a significantly higher incidence of cardiovascular disease (CVD) among type 1 diabetic (T1D) patients than among non-diabetic subjects. T1D is associated with hyperketonemia, a condition with elevated blood levels of ketones, in addition to hyperglycemia. The biochemical mechanism by which vitamin D (VD) may reduce the risk of CVD is not known. This study examines whether VD can be beneficial in reducing hyperketonemia (acetoacetate, AA) induced oxidative stress in endothelial cells. METHODS: HUVEC were pretreated with 1,25(OH)2D3, and later exposed to the ketone body acetoacetate. RESULTS: The increases in ROS production, ICAM-1 expression, MCP-1 secretion, and monocyte adhesion in HUVEC treated with AA were significantly reduced following treatment with 1,25(OH)2D3. Interestingly, an increase in glutathione (GSH) levels was also observed with 1,25(OH)2D3 in ketone treated cells. The effects of 1,25(OH)2D3 on GSH, ROS, and monocyte-endothelial adhesion were prevented in GCLC knockdown HUVEC. This suggests that 1,25(OH)2D3 inhibits ROS, MCP-1, ICAM-1, and adherence of monocytes mediated by the upregulation of GCLC and GSH. CONCLUSION: This study provides evidence for the biochemical mechanism through which VD supplementation may reduce the excess monocyte adhesion to endothelium and inflammation associated with T1D. PMID- 26949106 TI - The semiology of psychogenic nonepileptic seizures revisited: Can video alone predict the diagnosis? Preliminary data from a prospective feasibility study. AB - OBJECTIVE: To investigate if, when, and to what extent visual information contained in a video-recorded event allows experienced epileptologists to predict the diagnosis of psychogenic nonepileptic seizures (PNES) without the aid of electroencephalography (EEG). METHODS: Five neurologists actively practicing in epilepsy centers in Italy and the United States were asked to review 23 videos capturing representative events of 21 unselected consecutive patients admitted for long-term video-EEG monitoring (VEM). Four raters were blind to EEG and clinical information; one rater was not. They were requested to (1) rate the videos for quality and content; (2) choose among four diagnoses: (a) epileptic seizures (ES); (b) PNES; (c) Other nonepileptic seizures (NES; (syncope, movement disorder, migraine, etc.); (d) "Cannot Say"; and (3) explain in their own words the main reasons leading to the diagnosis of choice. RESULTS: All raters predicted the diagnosis correctly in 7 of 23 videos (all ES or PNES) (30.4%), whereas all raters failed in 5 of 23 cases (three Other NES, one PNES, one Cannot Say) (21.7%). The conditions that facilitate, and those that interfere with, a confident diagnosis were predictable. Degree of accuracy among raters was not uniform and was consistently better in three raters. Two among the four blind raters were as accurate as the rater who was not blinded. Interrater agreement was "moderate" (k = 0.52) for the overall group; "moderate" for ES (k = 0.53); "substantial" for PNES (k = 0.63); "fair" for Other NES (k = 0.21)-similar to the results obtained in a previous study evaluating the reliability of combined video EEG. SIGNIFICANCE: In about one third of cases, a confident diagnosis of PNES/ES can be established on clinical grounds based on video data alone. Our results benefit all affected patients, particularly those with no access to video-EEG monitoring units. PMID- 26949107 TI - Simultaneous multislice imaging in dynamic cardiac MRI at 7T using parallel transmission. AB - PURPOSE: Cardiac MRI at 7T suffers from contrast heterogeneity that can be mitigated with parallel transmission (pTX) and, when performed during breath hold, from a limited number of slices that can be multiplied with multiband (MB) radiofrequency pulses by simultaneous excitation of multiple slices (SMS). The goal of this study was to apply both approaches simultaneously. METHODS: Using a 16-channel transmit/receive body coil, pTX SMS was applied with/without CAIPIRINHA with a modified gradient echo cine sequence. Different calibration schemes were investigated for the slice-GRAPPA reconstruction kernels as a function of the cardiac cycle. RESULTS: Excellent slice separation for MB = 2 was achieved with CAIPIRINHA, with slice leakage values below 3% for 99% of all voxels. A critical finding of this study was the variation of the MB leakage factor in the heart by as much as 30% throughout the cardiac cycle, which was reduced greatly when reconstruction kernels were calibrated on multiple cardiac phases. Acceptable results were still obtained when applying further acceleration with MB = 3 in combination with in-plane GRAPPA. In one case, two-spoke pulses were compared with one-spoke pulses, resulting as expected in improved homogeneity. CONCLUSION: pTX SMS imaging at 7T can address contrast heterogeneity while allowing larger slice coverage in cardiac MRI performed under breath-hold. Magn Reson Med 77:1010-1020, 2017. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 26949108 TI - Dynamic secondary degeneration in the spinal cord and ventral root after a focal cerebral infarction among hypertensive rats. AB - Cerebral infarction can cause secondary damage to nonischemic brain regions. However, whether this phenomenon will appear in central nervous system regions outside the brain remains unclear. Here we investigated pathological changes in the spinal cord and ventral root after ischemic stroke. All rats exhibited apparent neurological deficits post-MCAO, which improved gradually but could still be detected 12-weeks. Neuronal filaments in the corticospinal tract (CST) and neurons in the ventral horn were significantly declined in the contralateral cervical and lumbar enlargement 1-week post-MCAO. These decreases remained stable until 12-weeks, accompanied by progressively increased glial activation in the ventral horn. Axonal degeneration and structural derangement were evident in the contralateral cervical and lumbar ventral root 1-week post-MCAO; these changes spontaneously attenuated over time, but abnormalities could still be observed 12 weeks. The number of neural fibers in the contralateral CST and neurons in the contralateral ventral horn were positively correlated with neurological scores 12 weeks post-MCAO. Additionally, GFAP(+)cell density in the contralateral CST and ventral horn was negatively correlated with neurological scores. Our results suggest that cerebral infarction can elicit secondary degeneration in the cervical and lumbar spinal cord, as well as the projecting ventral root, which may hamper functional recovery after stroke. PMID- 26949109 TI - Canine cutaneous neosporosis in Brazil. AB - The clinical signs of infection in dogs with Neospora caninum are usually associated with neurological disorders and are seen in young dogs. In this brief case report we observed multifocal ulcerative and exudative skin nodules on the neck and pelvic limbs of a 10-year-old cocker spaniel dog. Infection with N. caninum was diagnosed on the basis of cytology and examination of skin tissues by PCR. The dog initially responded to treatment with clindamycin and then relapsed; the dog died. Infection with N. caninum may have been due in part to immune suppression due to hyperadrenocorticism; which either allowed for the development of a primary infection or reactivation of a latent infection by N. caninum with the occurrence of skin lesions. PMID- 26949111 TI - Pre-invasive lung adenocarcinoma lesions on CT. PMID- 26949110 TI - Predictors of pregnancy and live-birth in couples with unexplained infertility after ovarian stimulation-intrauterine insemination. AB - OBJECTIVE: To identify baseline characteristics of couples that are likely to predict conception, clinical pregnancy, and live birth after up to four cycles of ovarian stimulation with IUI in couples with unexplained infertility. DESIGN: Secondary analyses of data from a prospective, randomized, multicenter clinical trial investigating pregnancy, live birth, and multiple pregnancy rates after ovarian stimulation-IUI with clomiphene citrate, letrozole, or gonadotropins. SETTING: Outpatient clinical units. PATIENT(S): Nine-hundred couples with unexplained infertility who participated in the Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation clinical trial. INTERVENTION(S): As part of the clinical trial, treatment was randomized equally to one of three arms and continued for up to four cycles or until pregnancy was achieved. MAIN OUTCOME MEASURE(S): Conception, clinical pregnancy, and live-birth rates. RESULT(S): In a multivariable logistic regression analysis, after adjustment for other covariates, age, waist circumference, income level, duration of infertility, and a history of prior pregnancy loss were significantly associated with at least one pregnancy outcome. Other baseline demographic and lifestyle characteristics including smoking, alcohol use, and serum levels of antimullerian hormone were not significantly associated with pregnancy outcomes. CONCLUSION(S): While age and duration of infertility were significant predictors of all pregnancy outcomes, many other baseline characteristics were not. The identification of level of income as a significant predictor of outcomes independent of race and education may reflect differences in the underlying etiologies of unexplained infertility or could reveal disparities in access to fertility and/or obstetrical care. CLINICAL TRIAL REGISTRATION: NCT01044862. PMID- 26949112 TI - Resolving uncertainty in the spatial relationships between passive benzene exposure and risk of non-Hodgkin lymphoma. AB - BACKGROUND: Benzene is a known occupational carcinogen associated with increased risk of hematologic cancers, but the relationships between quantity of passive benzene exposure through residential proximity to toxic release sites, duration of exposure, lag time from exposure to cancer development, and lymphoma risk remain unclear. METHODS: We collected release data through the Environmental Protection Agency's Toxics Release Inventory (TRI) from 1989 to 2003, which included location of benzene release sites, years when release occurred, and amount of release. We also collected data on incident cases of non-Hodgkin lymphoma (NHL) from the Georgia Comprehensive Cancer Registry (GCCR) for the years 1999-2008. We constructed distance-decay surrogate exposure metrics and Poisson and negative binomial regression models of NHL incidence to quantify associations between passive exposure to benzene and NHL risk and examined the impact of amount, duration of exposure, and lag time on cancer development. Akaike's information criteria (AIC) were used to determine the scaling factors for benzene dispersion and exposure periods that best predicted NHL risk. RESULTS: Using a range of scaling factors and exposure periods, we found that increased levels of passive benzene exposure were associated with higher risk of NHL. The best fitting model, with a scaling factor of 4 kilometers (km) and exposure period of 1989-1993, showed that higher exposure levels were associated with increased NHL risk (Level 4 (1.1-160kilograms (kg)) vs. Level 1: risk ratio 1.56 [1.44-1.68], Level 5 (>160kg) vs. Level 1: 1.60 [1.48-1.74]). CONCLUSIONS: Higher levels of passive benzene exposure are associated with increased NHL risk across various lag periods. Additional epidemiological studies are needed to refine these models and better quantify the expected total passive benzene exposure in areas surrounding release sites. PMID- 26949113 TI - Prokaryotic expression of the chicken xanthine oxidase (XOD) subunit and its localization in liver and kidney. AB - Xanthine oxidase (XOD) is the members of the molybdenum hydroxylase flavoprotein family and it plays a vital role in the body's purine catabolism. In this study, we cloned the XOD 37kDa subunit protein by using RT-PCR and pMD-18-T clone vector based on the total RNA extracted from chicken liver. The cloning XOD subunit protein gene was ligated into the pET-32a to construct the recombinant plasmid pET-XOD. After the pET-XOD expression vector was transformed into host cells Rosetta (DE3), the recombinant XOD subunit proteins (54.8kDa) were successfully induced by isopropy1 beta-d-thiogalactoside (IPTG). Rabbit antiserums were produced by using the purification of the recombinant XOD subunit protein as antigen. The titer of the antiserum was more than 1:102,400 determined by using ELISA. The result of Western blot demonstrated that the antiserum could specifically recognize the chicken liver XOD. Immunohistochemistry and immunofluorescence showed that the XOD mainly presented in the cytoplasm of chicken hepatocytes and proximal tubular epithelial cells. Our results indicated that the XOD subunit protein polyclonal antibody prepared by this method could be used for the further researches of the biological function of the XOD in the chicken. PMID- 26949114 TI - Residual visual function in a man with a large subfoveal outer retinal tubulation in late-onset Stargardt disease. PMID- 26949115 TI - Uhthoff's phenomenon as the first manifestation of multiple sclerosis in an adult male. PMID- 26949116 TI - Onset of neuromyelitis optica in the elderly. PMID- 26949117 TI - Five-year follow-up of bilateral choroidal neovascularization secondary to optic nerve head drusen treated with ranibizumab in a nine-year-old girl. PMID- 26949118 TI - Alcohol and Sedative-Hypnotic Withdrawal Catatonia: Two Case Reports, Systematic Literature Review, and Suggestion of a Potential Relationship With Alcohol Withdrawal Delirium. AB - BACKGROUND: Withdrawal from alcohol and sedative-hypnotics can be complicated by seizures, hallucinations, or delirium. Withdrawal catatonia is another, less commonly discussed complication that clinicians should appreciate. METHODS: We present a case of alcohol withdrawal catatonia and a case of benzodiazepine withdrawal catatonia and offer a systematic review of previous cases of alcohol or sedative-hypnotic withdrawal catatonia. We outline clinical features that suggest a potential link between withdrawal catatonia and withdrawal delirium. RESULTS: We identified 26 cases of withdrawal catatonia in the literature-all principally with catatonic stupor-with an average age of 56 years (range: 27-92) and balanced prevalence between sexes. Withdrawal catatonia tends to occur only after chronic use of alcohol or sedative-hypnotic agents with a typical onset of 3-7 days after discontinuation and duration of 3-10 days. Withdrawal catatonia is responsive to benzodiazepines or electroconvulsive therapy. Features that suggest a parallel between withdrawal catatonia and withdrawal delirium include time course, neurobiologic convergence, efficacy of benzodiazepines and electroconvulsive therapy, typical absence of abnormal electroencephalographic findings, and phenotypic classification suggested by a recent literature in sleep medicine. CONCLUSION: Alcohol and sedative-hypnotic withdrawal may present with catatonia or catatonic features. The clinical and neurobiologic convergence between withdrawal catatonia and withdrawal delirium deserves further attention. In view of these similarities, we propose that withdrawal delirium may represent excited catatonia: these new viewpoints may serve as a substrate for a better understanding of the delirium-catatonia spectrum. PMID- 26949120 TI - Identification of Diabetic Retinopathy and Ungradable Image Rate with Ultrawide Field Imaging in a National Teleophthalmology Program. AB - PURPOSE: To compare diabetic retinopathy (DR) identification and ungradable image rates between nonmydriatic ultrawide field (UWF) imaging and nonmydriatic multifield fundus photography (NMFP) in a large multistate population-based DR teleophthalmology program. DESIGN: Multiple-site, nonrandomized, consecutive, cross-sectional, retrospective, uncontrolled imaging device evaluation. PARTICIPANTS: Thirty-five thousand fifty-two eyes (17 526 patients) imaged using NMFP and 16 218 eyes (8109 patients) imaged using UWF imaging. METHODS: All patients undergoing Joslin Vision Network (JVN) imaging with either NMFP or UWF imaging from May 1, 2014, through August 30, 2015, within the Indian Health Service-JVN program, which serves American Indian and Alaska Native communities at 97 sites across 25 states, were evaluated. All retinal images were graded using a standardized validated protocol in a centralized reading center. MAIN OUTCOME MEASURES: Ungradable rate for DR and diabetic macular edema (DME). RESULTS: The ungradable rate per patient for DR and DME was significantly lower with UWF imaging compared with NMFP (DR, 2.8% vs. 26.9% [P < 0.0001]; DME, 3.8% vs. 26.2% [P < 0.0001]). Identification of eyes with either DR or referable DR (moderate nonproliferative DR or DME or worse) was increased using UWF imaging from 11.7% to 24.2% (P < 0.0001) and from 6.2% to 13.6% (P < 0.0001), respectively. In eyes with DR imaged with UWF imaging (n = 3926 eyes of 2402 patients), the presence of predominantly peripheral lesions suggested a more severe level of DR in 7.2% of eyes (9.6% of patients). CONCLUSIONS: In a large, widely distributed DR ocular telehealth program, as compared with NMFP, nonmydriatic UWF imaging reduced the number of ungradable eyes by 81%, increased the identification of DR nearly 2-fold, and identified peripheral lesions suggesting more severe DR in almost 10% of patients, thus demonstrating significant benefits of this imaging method for large DR teleophthalmology programs. PMID- 26949119 TI - Structural and Functional Progression in the Early Manifest Glaucoma Trial. AB - PURPOSE: To elucidate the temporal relationship between detection of glaucomatous optic disc progression, as assessed by fundus photography, and visual field progression. DESIGN: Prospective, randomized, longitudinal trial. PARTICIPANTS: Three hundred six study eyes with manifest glaucoma with field loss and 192 fellow eyes without any field defect at the start of the trial, from a total of 249 subjects included in the Early Manifest Glaucoma Trial (EMGT), were assessed. METHODS: Evaluation of visual field progression and optic disc progression during an 8-year follow-up period. Three graders independently assessed optic disc progression in optic disc photographs. Visual field progression was assessed using glaucoma change probability maps and the EMGT progression criterion. MAIN OUTCOME MEASURES: Time to detection of visual field progression and optic disc progression. RESULTS: Among study eyes with manifest glaucoma, progression was detected in the visual field first in 163 eyes (52%) and in the optic disc first in 39 eyes (12%); in 1 eye (0%), it was found simultaneously with both methods. Among fellow eyes with normal fields, progression was detected in the visual field first in 28 eyes (15%) and in the optic disc first in 34 eyes (18%); in 1 eye (1%), it occurred simultaneously. CONCLUSIONS: In eyes with manifest glaucoma, progression in the visual field was detected first more than 4 times as often as progression in the optic disc. Among fellow eyes without visual field loss at baseline, progression was detected first as frequently in the optic disc as in the visual field. PMID- 26949121 TI - Intravitreal Tissue Plasminogen Activator, Ranibizumab, and Gas Injection for Submacular Hemorrhage in Polypoidal Choroidal Vasculopathy. AB - PURPOSE: To investigate the efficacy of intravitreal injection of recombinant tissue plasminogen activator (rt-PA), ranibizumab, and gas without vitrectomy for submacular hemorrhage. DESIGN: Prospective, interventional, consecutive case series. PARTICIPANTS: Twenty consecutive patients (20 eyes) with submacular hemorrhage secondary to exudative age-related macular degeneration (AMD) or polypoidal choroidal vasculopathy (PCV). METHODS: Ranibizumab, rt-PA (25 MUg/0.05 ml), and 100% perfluoropropane (0.3 ml) were injected intravitreally, followed by 2-day prone positioning. MAIN OUTCOME MEASURES: The primary outcome measure was best-corrected visual acuity (BCVA) 6 months after treatment. Secondary outcome measures included central retinal thickness (CRT), central pigment epithelial detachment (PED) thickness, central ellipsoid zone, recurrence rate, and complications. RESULTS: Underlying disease was exudative AMD in 1 eye and PCV in 19 eyes. Submacular hemorrhage ranged in size from 2 to 31 disc diameters. Complete displacement of submacular hemorrhage was achieved in 17 eyes (85%), and partial displacement was achieved in 3 eyes (15%). Snellen BCVA improved from 20/139 before treatment to 20/65 at 6 months (P = 0.0061). Mean change in Early Treatment Diabetic Retinopathy Study score from baseline was +13 letters (P = 0.0040). Mean CRT decreased from 599 MUm before treatment to 208 MUm at 6 months (P < 0.0001), and central PED thickness decreased from 188 to 88 MUm (P = 0.0140). Three eyes developed vitreous hemorrhage, and 1 eye developed retinal detachment; all were treated surgically, and Snellen BCVA improved at 6 months (P = 0.0012). Recurrence was observed in 10 eyes (50%) within 6 months, but visual acuity was preserved with intravitreal injection of anti-vascular endothelial growth factor (VEGF) pro re nata (PRN). The factors that affect BCVA at 6 months after treatment were pre- and posttreatment central ellipsoid zone (P = 0.0366 and P = 0.0424), pretreatment BCVA (P = 0.0015), and pre- and posttreatment central PED thickness (P = 0.0046, P = 0.0021). CONCLUSIONS: Subretinal hemorrhage treatment by intravitreal injection of rt-PA, ranibizumab, and gas is useful to achieve hemorrhage displacement and lesion improvement. To preserve visual acuity, early detection of posttreatment recurrence and intravitreal anti VEGF injection PRN are necessary. PMID- 26949122 TI - Rule learning enhances structural plasticity of long-range axons in frontal cortex. AB - Rules encompass cue-action-outcome associations used to guide decisions and strategies in a specific context. Subregions of the frontal cortex including the orbitofrontal cortex (OFC) and dorsomedial prefrontal cortex (dmPFC) are implicated in rule learning, although changes in structural connectivity underlying rule learning are poorly understood. We imaged OFC axonal projections to dmPFC during training in a multiple choice foraging task and used a reinforcement learning model to quantify explore-exploit strategy use and prediction error magnitude. Here we show that rule training, but not experience of reward alone, enhances OFC bouton plasticity. Baseline bouton density and gains during training correlate with rule exploitation, while bouton loss correlates with exploration and scales with the magnitude of experienced prediction errors. We conclude that rule learning sculpts frontal cortex interconnectivity and adjusts a thermostat for the explore-exploit balance. PMID- 26949123 TI - Disruption of blood-brain barrier integrity in postmortem alcoholic brain: preclinical evidence of TLR4 involvement from a binge-like drinking model. AB - Inflammatory cytokines and reactive oxygen species are reported to be involved in blood-brain barrier (BBB) disruption. Because there is evidence that ethanol (EtOH) induces release of free radicals, cytokines and inflammatory mediators we examined BBB integrity and matrix metalloproteinase (MMP) activity in postmortem human alcoholic brain and investigated the role of TLR4 signaling in BBB permeability in TLR4-knockout mice under a binge-like EtOH drinking protocol. Immunohistochemical studies showed reduced immunoreactivity of the basal lamina protein, collagen-IV and of the tight junction protein, claudin-5 in dorsolateral prefrontal cortex of alcoholics. There was also increased MMP-9 activity and expression of phosphorylated ERK1/2 and p-38. Greater number of CD45+ IR cells were observed associated with an enhanced neuroinflammatory response reflected by increased GFAP and Iba-1 immunostaining. To further explore effects of high EtOH consumption on BBB integrity we studied TLR4-knockout mice exposed to the drinking in the dark paradigm. Repetitive EtOH exposure in wild-type mice decreased hippocampal expression of laminin and collagen-IV and increased IgG immunoreactivity, indicating IgG extravasation. Western blot analysis also revealed increased MyD88 and p-ERK1/2 levels. None of these changes was observed in TLR4-knockout mice. Collectively, these findings indicate that chronic EtOH increases degradation of tight junctions and extracellular matrix in postmortem human brain and induces a neuroinflammatory response associated with activation of ERK1/2 and p-38 and greater MMP-9 activity. The EtOH-induced effects on BBB impairment are not evident in the hippocampus of TLR4-knockout mice, suggesting the involvement of TLR4 signaling in the underlying mechanism leading to BBB disruption in mice. PMID- 26949124 TI - Esophageal Stricture Prevention after Endoscopic Submucosal Dissection. AB - Advances in diagnostic modalities and improvement in surveillance programs for Barrett esophagus has resulted in an increase in the incidence of superficial esophageal cancers (SECs). SEC, due to their limited metastatic potential, are amenable to non-invasive treatment modalities. Endoscopic ultrasound, endoscopic mucosal resection, and endoscopic submucosal dissection (ESD) are some of the new modalities that gastroenterologists have used over the last decade to diagnose and treat SEC. However, esophageal stricture (ES) is a very common complication and a major cause of morbidity post-ESD. In the past few years, there has been a tremendous effort to reduce the incidence of ES among patients undergoing ESD. Steroids have shown the most consistent results over time with minimal complications although the preferred mode of delivery is debatable, with both systemic and local therapy having pros and cons for specific subgroups of patients. Newer modalities such as esophageal stents, autologous cell sheet transplantation, polyglycolic acid, and tranilast have shown promising results but the depth of experience with these methods is still limited. We have summarized case reports, prospective single center studies, and randomized controlled trials describing the various methods intended to reduce the incidence of ES after ESD. Indications, techniques, outcomes, limitations, and reported complications are discussed. PMID- 26949126 TI - A decade of research on Incontinence-Associated Dermatitis (IAD): Evidence, knowledge gaps and next steps. AB - BACKGROUND: Incontinence-Associated Dermatitis (IAD) is one of the clinical manifestations of Moisture- Associated Skin Damage (MASD). IAD is a common problem in aged patients with fecal and/or urinary incontinence. AIM: Update about IAD terminology, etiology, epidemiology, observation, prevention, and treatment. METHODS: Integrative review. RESULTS: The lack of an ICD-10 code and an internationally validated and standardized method for IAD data collection contribute to a variation in epidemiological data. Frequent episodes of incontinence (especially fecal), occlusive containment products, poor skin condition, reduced mobility, diminished cognitive awareness, inability to perform personal hygiene, pain, pyrexia, certain medications (antibiotics, immunosuppressants), poor nutritional status, and critical illness are associated with IAD. Correctly diagnosing IAD and distinguish it from pressure ulcers is difficult. Even though the clinical presentation of partial thickness pressure ulcers and IAD is similar, the underlying etiologic factors differ. However, incontinence and IAD were found to be risk factors for pressure ulcer development. IAD management should essentially focus on skin cleansing to remove dirt, debris and microorganisms; skin moisturization to repair or augment the skin's barrier; and the application of a skin barrier product to prevent skin breakdown by providing an impermeable or semi-permeable barrier on the skin. The body of evidence is still limited, but growing since the last decade. CONCLUSION: Incontinence causes disruptions of the skin barrier function and leads to superficial skin damage. Macerated skin and superficial skin changes due to incontinence are associated with pressure ulcer development. Skin maceration, chemical irritation, and physical irritation should be targeted to effectively prevent and treat IAD. PMID- 26949125 TI - MicroRNA-548j functions as a metastasis promoter in human breast cancer by targeting Tensin1. AB - MicroRNAs (miRNAs) are single-stranded, small non-coding RNA molecules that participate in important biological processes. Although the functions of many miRNAs in breast cancer metastasis have been established, the role of others remains to be characterized. To identify additional miRNAs involved in metastasis, we performed a genetic screen by transducing a Lenti-miRTM virus library into MCF-7 cells. Using transwell invasion assays we identified human miR 548j as an invasion-inducing miRNA. The endogenous levels of miR-548j expression in breast cancer cell lines were shown to correlate with invasiveness. Moreover, miR-548j was shown to stimulate breast cancer cell invasion and metastasis in vitro and in vivo, but had no effect on proliferation. Next, using a series of in vitro and in vivo experiments, we found that Tensin1 served as a direct and functional target of miR-548j. Both miR-548j and Tensin1 modulated the activation of Cdc42 to regulate cell invasion and siCdc42 or the selective Cdc42 inhibitor ML141 suppressed the pathway of miR-548j-mediated cell invasion. Furthermore, a strong correlation between miR-548j, Tensin1, metastasis and survival was observed using two sets of clinical breast cancer samples. Our findings demonstrate that miR-548j functions as a metastasis-promoting miRNA to regulate breast cancer cell invasion and metastasis by targeting Tensin1 and activating Cdc42, suggesting a potential therapeutic application in breast cancer. PMID- 26949127 TI - Analyses of pressure ulcer point prevalence at the first skin assessment in a Portuguese hospital. AB - AIM: To analyze the first pressure ulcer risk and skin assessment records of hospitalized adult patients in medical and surgical areas of Aveiro Hospital during 2012 in association with their demographic and clinical characteristics. MATERIAL AND METHODS: Retrospective cohort analysis of electronic health record database from 7132 adult patients admitted to medical and surgical areas in a Portuguese hospital during 2012. The presence of (at least) one pressure ulcer at the first skin assessment in inpatient setting was associated with age, gender, type of admission, specialty units, length of stay, patient discharge and ICD-9 diagnosis. RESULTS: Point prevalence of participants with pressure ulcer category/stage I-IV of 7.9% at the first skin assessment in inpatient setting. A total of 1455 pressure ulcers were documented, most of them category/stage I. The heels and the sacrum/coccyx were the most problematic areas. Participants with pressure ulcer commonly had two or more pressure ulcers. CONCLUSIONS: The point prevalence of participants with pressure ulcer of our study was similar international literature. The presence of a pressure ulcer at the first skin assessment could be an important measure of frailty and the participants with pressure ulcer commonly had more than one documented pressure ulcer. Advanced age or lower Braden Scale scores or Emergency Service admission were relevant variables for the presence of (at least) one pressure ulcer at the first skin assessment in inpatient setting as well as respiratory, infectious or genitourinary system diseases. PMID- 26949128 TI - Molecular degradation of D35 and K77 sensitizers when exposed to temperatures exceeding 100 degrees C investigated by photoelectron spectroscopy. AB - Degradation of the materials in dye-sensitized solar cells at elevated temperatures is critical for use in real applications. Both during fabrication of the solar cell and under real working conditions the solar cells will be exposed to heat. In this work, mesoporous TiO2 electrodes sensitized with the dyes D35 and K77 were subject to heat-treatment and the effects of this were thereafter investigated by photoelectron spectroscopy. For D35 it was found that heat treatment changes the binding configuration inducing an increased interaction between the sulfur of the linker unit and the TiO2 surface. The interaction resulting from the change in binding configuration also affects the position of the HOMO level, where a shift of +0.2 eV is observed when heated to 200 degrees C. For K77, parts of the thiocyanate units are detached and the nitrogen atom leaves the electrode whereas sulfur remains on the surface in various forms of sulfurous oxides. The total dye coverage of K77 gets reduced by heat-treatment. The HOMO level gets progressively less pronounced due to a loss of HOMO level electrons as a consequence of the lower dye coverage when heat-treated, which leads to a lower excitation rate and lower efficiency. The results are discussed in the context of performance for dye-sensitized solar cells. PMID- 26949129 TI - Correlation between hyoid bone position and airway dimensions in Chinese adolescents by cone beam computed tomography analysis. AB - This study aimed to investigate the correlation between upper airway dimensions and hyoid bone position in Chinese adolescents based on cone beam computed tomography (CBCT) images. CBCT images from a total of 254 study subjects were included. The upper airway and hyoid bone parameters were measured by Materialism's interactive medical image control system (MIMICS) v.16.01 (Materialise, Leuven, Belgium). The airway dimensions were evaluated in terms of volume, cross-sectional area (CSA), mean CSA, length, anteroposterior dimension of the cross-section (AP), lateral dimension of the cross-section (LAT), and LAT/AP ratio. The hyoid bone position was evaluated using eight linear parameters and two angular parameters. Facial characteristics were evaluated using three linear parameters and three angular parameters. Most hyoid bone position parameters (especially the distance between the hyoid bone and hard palate) were significantly associated with most airway dimension parameters. Significant correlations were also observed between the different facial characteristic parameters and hyoid bone position parameters. Most airway dimension parameters showed significant correlations with linear facial parameters, but they displayed significant correlations with only a few angular facial parameters. These findings provide an understanding of the static relationship between the hyoid bone position and airway dimensions, which may serve as a reference for surgeons before orthodontic or orthognathic surgery. PMID- 26949130 TI - Perovskites at the nanoscale: from fundamentals to applications. PMID- 26949131 TI - Peihua Luo, Meili Lin, Meihua Lin, Yiyu Chen, Bo Yang, Qiaojun He, Function of retinoid acid receptor a and p21 in all-trans-retinoic acid-induced acute T lymphoblastic leukemia apoptosis. July 2009;50(7):1183-1189. http://dx/doi.org/10.1080/10428190902934936. PMID- 26949132 TI - The male ejaculate as inhibitor of female remating in two tephritid flies. AB - The inhibition of female receptivity after copulation is usually related to the quality of the first mating. Males are able to modulate female receptivity through various mechanisms. Among these is the transfer of the ejaculate composed mainly by sperm and accessory gland proteins (AGPs). Here we used the South American fruit fly Anastrepha fraterculus (where AGP injections inhibit female receptivity) and the Mexican fruit fly Anastrepha ludens (where injection of AGPs failed to inhibit receptivity) as study organisms to test which mechanisms are used by males to prevent remating. In both species, neither the act of copulation without ejaculate transfer nor sperm stored inhibited female receptivity. Moreover, using multiply mated sterile and wild males in Mex flies we showed that the number of sperm stored by females varied according to male fertility status and number of previous matings, while female remating did not. We suggest female receptivity in both flies is inhibited by the mechanical and/or physiological effect of the full ejaculate. This finding brings us closer to understanding the mechanisms through which female receptivity can be modulated. PMID- 26949133 TI - Photoactivated Chromophore for Moderate to Severe Infectious Keratitis as an Adjunct Therapy: A Randomized Controlled Trial. AB - PURPOSE: To evaluate the efficacy of photoactivated chromophore for infectious keratitis (PACK-CXL) in the treatment of patients with moderate to severe infectious keratitis as adjunct therapy to the topical medication treatment. DESIGN: Randomized clinical trial. METHODS: Thirty eyes from 30 patients with moderate to severe infectious keratitis were randomized to receive either standard treatment plus PACK-CXL (n = 15) or standard treatment alone (control group, n = 15). The primary outcome was the sizes of stromal infiltrates measured on slit-lamp photographs 30 days after treatment. The secondary outcomes were the sizes of epithelial defects, the complication rates, and best pinhole-corrected visual acuity (BPVA). RESULTS: The median (interquartile range [IQR]) sizes of stromal infiltrates at day 30 were 5.0 mm(2) (0-23.0 mm(2)) in the PACK-CXL group and 10.6 mm(2) (1.1-16.3 mm(2)) in the control group (median difference 0, 95% CI -7.0 to 0, P = .66). The median (IQR) sizes of epithelial defects were 0.7 mm(2) (0-6.3 mm(2)) and 4.6 mm(2) (0-10.2 mm(2)) in the PACK-CXL group and control group, respectively (median difference -3.0, 95% CI -0.8 to 0, P = .41). The complication rates and BPVA after treatment were comparable between groups. CONCLUSIONS: Standard treatment combined with PACK-CXL did not provide any advantageous effect over standard treatment alone in moderate to severe infectious keratitis over a 30-day period. PMID- 26949134 TI - Volume-Rendered Optical Coherence Tomography of Retinal Vein Occlusion Pilot Study. AB - PURPOSE: To investigate the retinal vascular findings and associated cystoid edema in the central macula of eyes with retinal vein occlusion using volume rendered angiographic and structural optical coherence tomography. STUDY DESIGN: Observational case series. METHODS: In this retrospective study 12 eyes of 12 consecutive patients, 3 with branch and 9 with central retinal vein occlusion, were imaged in 27 sessions with optical coherence tomography (OCT) using split spectrum amplitude decorrelation. The structural OCT data were segmented for cystoid spaces and integrated into the angiographic data for subsequent volume rendering. The inner and deep vascular plexus were analyzed in relation to cystoid macular edema with retention of depth information. RESULTS: Retinal vascular flow abnormalities were demonstrated by flow voids with abnormal vascular morphology in the inner vascular layer and varying flow loss in the deep vascular plexus. Areas of cystoid edema were associated with topographically co localizing flow voids in the deep vascular layer. Treatment with intravitreous anti-vascular endothelial growth factor injections resulted in resolution of edema but no change in flow patterns in either the inner or deep plexus. Recurrence of edema happened in the same areas of altered inner and absent deep vascular plexus flow signal. CONCLUSIONS: Cystoid macular edema in retinal vein occlusion occurred in relation to altered inner plexus and absent deep vascular plexus flow. This pattern of cystoid fluid accumulation is similar to that seen in diabetic retinopathy and may represent an important underlying pathophysiologic foundation for cystoid macular edema in retinal vascular diseases. PMID- 26949135 TI - Corneal Hysteresis and Progressive Retinal Nerve Fiber Layer Loss in Glaucoma. AB - PURPOSE: To investigate the relationship between corneal hysteresis (CH) and progressive retinal nerve fiber layer (RNFL) loss in a cohort of patients with glaucoma followed prospectively over time. DESIGN: Prospective observational cohort study. METHODS: One hundred and eighty-six eyes of 133 patients with glaucoma were followed for an average of 3.8 +/- 0.8 years, with a median of 9 visits during follow-up. The CH measurements were acquired using the Ocular Response Analyzer (Reichert Instruments, Depew, New York, USA) and RNFL measurements were obtained at each follow up visit using spectral-domain optical coherence tomography (SDOCT). Random-coefficient models were used to investigate the relationship between baseline CH, central corneal thickness (CCT), average intraocular pressure (IOP), and rates of RNFL loss during follow-up, while adjusting for potentially confounding factors. RESULTS: Average baseline RNFL thickness was 76.4 +/- 18.1 MUm and average baseline CH was 9.2 +/- 1.8 mm Hg. CH had a significant effect on rates of RNFL progression. In the univariable model, including only CH as a predictive factor along with time and their interaction, each 1 mm Hg lower CH was associated with a 0.13 MUm/year faster rate of RNFL decline (P = .011). A similar relationship between low CH and faster rates of RNFL loss was found using a multivariable model accounting for age, race, average IOP, and CCT (P = .015). CONCLUSIONS: Lower CH was significantly associated with faster rates of RNFL loss over time. The prospective longitudinal design of this study provides further evidence that CH is an important factor to be considered in the assessment of the risk of progression in patients with glaucoma. PMID- 26949136 TI - On-road Driving Performance of Patients With Bilateral Moderate and Advanced Glaucoma. AB - PURPOSE: To compare on-road driving performance of patients with moderate or advanced glaucoma to controls and evaluate factors associated with unsafe driving. DESIGN: Case-control pilot study. METHODS: A consecutive sample of 21 patients with bilateral moderate or advanced glaucoma from Washington University, St Louis, Missouri and 38 community-dwelling controls were enrolled. Participants, aged 55-90 years, underwent a comprehensive clinical evaluation by a trained occupational therapist and an on-road driving evaluation by a masked driver rehabilitation specialist. Overall driving performance of pass vs marginal/fail and number of wheel and/or brake interventions were recorded. RESULTS: Fifty-two percent of glaucoma participants scored a marginal/fail compared to 21% of controls (odds ratio [OR], 4.1; 95% CI, 1.30-13.14; P = .02). Glaucoma participants had a higher risk of wheel interventions than controls (OR, 4.67; 95% CI, 1.03-21.17; P = .046). There were no differences detected between glaucoma participants who scored a pass vs marginal/fail for visual field mean deviation of the better (P = .62) or worse (P = .88) eye, binocular distance (P = .15) or near (P = .23) visual acuity, contrast sensitivity (P = .28), or glare (P = .88). However, glaucoma participants with a marginal/fail score performed worse on Trail Making Tests A (P = .03) and B (P = .05), right-sided Jamar grip strength (P = .02), Rapid Pace Walk (P = .03), Braking Response Time (P = .03), and identifying traffic signs (P = .05). CONCLUSIONS: Patients with bilateral moderate or advanced glaucoma are at risk for unsafe driving-particularly those with impairments on psychometric and mobility tests. A comprehensive clinical assessment and on-road driving evaluation is recommended to effectively evaluate driving safety of these patients. PMID- 26949138 TI - Revision shoulder arthroplasty from resurfacing to non-cemented short-stem reverse prosthesis. AB - OBJECTIVE: To assess the surgical parameters and the clinical and radiological outcomes of revisions of resurfacing shoulder arthroplasty to non-cemented short stem reverse total shoulder arthroplasty. MATERIAL AND METHODS: A total of 23 revisions from resurfacing shoulder arthroplasty to reverse total shoulder arthroplasty were performed. The mean age was 70.3+/-11.95 years. The patients included 82.6% (19/23) revised for cuff failure; 13.04% (3/23) cuff failure and aseptic loosening, and 4.35% (1/23) peri-prosthetic fracture. The need for humeral osteotomy or structural allograft, operation length, blood loss, blood transfusions and intraoperative fractures were recorded. Minimum follow-up 25 months. RESULTS: No humeral osteotomy or humeral structural allograft was required, and 2/23 (8.69%) required allograft for glenoid reconstruction. The mean operation time was 113.35+/-21.30minutes. Intra-operative blood loss was 374+/-245.09 mls. Blood transfusion was required in one case. Intra-operative fracture occurred in 1 case. The Constant score improved from 17.32 to 59.78 (age/sex adjusted, 84). Overall satisfaction improved from 1.37 to 8.04. The range of motion increased 79.57 degrees in forward elevation; 72.88 degrees in abduction; 38.06 degrees in internal rotation; and 13.57 degrees in external rotation. There was no evidence of radiolucency, subsidence, or bone resorption. CONCLUSION: Revisions of resurfacing implants to non-cemented short-stem reverse prosthesis show good clinical and radiological outcomes, with minimal intra operative complexities. LEVEL OF EVIDENCE: IV, case series. PMID- 26949139 TI - Morphometrical analysis of preantral follicular survival of VEGF-treated bovine ovarian cortex tissue following xenotransplantation in an immune deficient mouse model. AB - The increasing number of cancer survivors the past decades, has sparked the need for fertility preservation strategies. Due to predominantly ethical constraints, human research material is scarce. A bovine in vitro model is a valuable alternative. Therefore, the following objectives were defined: 1) to xeno-graft bovine ovarian cortex tissue in immune deficient mice as a study-model for female fertility preservation strategies; 2) to stereologically quantify vascularization in Vascular Endothelial Growth Factor (VEGF)-treated and non-treated tissue; 3) to study preantral follicular survival in situ, after xenotransplantation. Bovine ovarian tissue strips were incubated with or without VEGF prior to grafting into female, neutered BALB/c-nu mice (n=16). Non-transplanted cortical tissue was used as a control. At time zero (control), two (2 weeks) and four (4 weeks) weeks after transplantation, grafts were retrieved and assessed by von Willebrand Factor and caspase-3 immunostaining. Data were analyzed using a linear mixed model. In the VEGF+ grafts, 31% of the follicles were considered 'alive' 2 weeks after transplantation, compared to only 17% in the VEGF- grafts (P<0.05). However, no difference could be detected 4 weeks after transplantation (P=0.76) with less follicles being considered 'alive' after transplantation (22%), compared to the control (47.5%) (P<0.05). Finally, the vascular surface density was significantly less in the grafts, irrespective of the transplantation period or the use of VEGF. Although the transplantation process overall negatively influenced the number of viable follicles and vascular density, VEGF exposure prior to transplantation can favor follicle survival during a 2 weeks transplantation period. PMID- 26949140 TI - Effect of different light sources on reproductive anatomy and physiology of Japanese quail (Coturnix coturnix japonica). AB - Artificial lights are essential for controlling the reproductive tract development of birds during puberty and therefore influence reproductive quality. The aim of this study was to evaluate the effect of different light sources on reproductive anatomic and physiological characteristics of female Japanese quail (Coturnix coturnix japonica). A total of 270 birds from one day of age were housed in a masonry shed divided into six rooms with light isolation. Each room was equipped with a different type of light bulb and contained seven cages with five birds in each. The light bulbs tested were: incandescent; compact fluorescent; and light-emitting diode (LED) in the colors white, blue, red and green. The experimental design was completely randomized with six treatments and seven replications of individual birds each. The anatomic and physiological condition of the birds was evaluated at four, eight and 12 weeks of age. The white LED bulb advanced (P<0.05) the sexual maturity by one week, resulted (P<0.05) in higher live weights and greater weight and relative percentage of ovarian stroma, oviduct and ovarian tissue at eight weeks of age. Higher plasma concentrations of estradiol and lipids were also observed (P<0.05) at eight weeks under the white LED bulb. At 12 weeks of age, the magnum and isthmus folding characteristics were better (P<0.05) with the red LED bulb. In conclusion, the photostimulation with the white LED bulb was more efficient at activating the reproductive cycle, hastening the onset of sexual maturity and increasing the development of reproductive organs after puberty. PMID- 26949141 TI - Functional properties and fatty acids profile of different beans varieties. AB - Dried seeds of four varieties of Phaseolus vulgaris, three of Vigna unguiculata ssp. unguiculata and two of Vigna angularis grown and marketed in Italy, Mexico, India, Japan, Ghana and Ivory Coast were analysed for fatty acids content. In oils from seeds of P. vulgaris, the main fatty acids were linolenic (34.7-41.5%) and linoleic (30.7-40.3%), followed by palmitic (10.7-16.8%). The first three aforementioned fatty acids in the lipid fraction of V. unguiculata varieties were 28.4, 28.7 and 26.2%, respectively; while in V. angularis varieties, main fatty acids were linoleic (36.4-39.1%) and palmitic (26.9-33.3%), followed by linolenic (17.9-22.2%). Statistical analyses indicate that botanical species play a rule in bean fatty acids distribution, while the same was not verified for geographical origin. Furthermore, the atherogenic index (AI) and the thrombogenic index (TI) were investigated for health and nutritional information. The results showed that these wide spread legumes have functional features to human health. PMID- 26949142 TI - Neurodevelopmental outcomes of tracheoesophageal fistulas. AB - PURPOSE: The purpose of this study was to perform a retrospective review of tracheoesophageal fistula (TEF) patients who followed up in a state-sponsored program to assess neurodevelopmental outcomes. METHODS: Records were reviewed retrospectively of children who underwent TEF repair between August 2001 and June 2014. Children discharged from the neonatal intensive care unit were referred to the state-sponsored Developmental Tracking Infant Progress Statewide (TIPS) program. We reviewed TIPS assessments performed before age 24months and noted referral for early school intervention services. Poor outcomes were defined as scores of "failure" on the screening assessment or referral for enrollment in early intervention services by 24months. Children with TEF were compared with case-matched nonsyndromic children of similar gestational age and birth weight. RESULTS: Seventy-eight children underwent TEF repair. Thirty-eight followed up with TIPS. Survival was 93.6%. Predictors of hospital survival were Waterston classification (p=0.001), birth weight (p=0.027), and ventilator days (p=0.013). LOS was the only significant predictor of referral for early intervention services (p=0.0092) in multivariate analysis. There was a borderline significant difference in referral rate between children with TEF and controls. 52.6% of TEF patients were referred, while 34.2% of controls were referred (p=0.071). CONCLUSION: More than half of TEF patients experience neurodevelopmental delays requiring referral for early intervention (53%). PMID- 26949143 TI - A stitch in time saves nine: suture technique does not affect intestinal growth in a young, growing animal model. AB - BACKGROUND: Although this issue remains unexamined, pediatric surgeons commonly use simple interrupted suture for bowel anastomosis, as it is thought to improve intestinal growth postoperatively compared to continuous running suture. However, effects on intestinal growth are unclear. We compared intestinal growth using different anastomotic techniques during the postoperative period in young rats. METHODS: Young, growing rats underwent small bowel transection and anastomosis using either simple interrupted or continuous running technique. At 7-weeks postoperatively after a four-fold growth, the anastomotic site was resected. Diameters and burst pressures were measured. RESULTS: Thirteen rats underwent anastomosis with simple interrupted technique and sixteen with continuous running method. No differences were found in body weight at first (102.46 vs 109.75g) or second operations (413.85 vs 430.63g). Neither the diameters (0.69 vs 0.79cm) nor burst pressures were statistically different, although the calculated circumference was smaller in the simple interrupted group (2.18 vs 2.59cm; p=0.03). No ruptures occurred at the anastomotic line. CONCLUSIONS: This pilot study is the first to compare continuous running to simple interrupted intestinal anastomosis in a pediatric model and showed no difference in growth. Adopting continuous running techniques for bowel anastomosis in young children may lead to faster operative time without affecting intestinal growth. PMID- 26949144 TI - Laparoscopic-assisted transanal pull-through (LATP) versus complete transanal pull-through (CTP) in the surgical management of Hirschsprung's disease. AB - BACKGROUND: It is unclear whether laparoscopic-assisted transanal pull-through (LATP) or complete transanal pull-through (CTP) is superior for the surgical management of Hirschsprung's disease. We compared outcomes between approaches. METHODS: We retrospectively reviewed patients with Hirschsprung's disease who underwent LATP or CTP at our centre between 1995 and 2014. Patients were matched based on age, birth weight, and level of aganglionosis. A systematic literature review and meta-analysis were also performed. RESULTS: From our data, LATP (n=24) took significantly longer than CTP (n=12; 3.9+/-1.1 vs. 2.6+/-0.6h, p=0.001). There was no difference in length of stay or incidence of postoperative complications. A literature search identified 17 published studies, of which 2 were comparative. Our pooled analysis of comparative studies including our results showed that operative time was significantly longer for the LATP group (OR 1.59, 95% CI 1.21-1.96, p<0.001). There was no significant difference in major complications (OR 1.75, 95% CI 0.76-4.04, p=0.19) or length of stay (OR 0.33, 95% CI -0.41 to 1.08, p=0.38). CONCLUSION: Clinical outcomes are comparable between LATP and CTP. CTP offers shorter operative time without the need for laparoscopic instruments. PMID- 26949145 TI - Chest radiograph after fluoroscopic guided line placement: No longer necessary. AB - PURPOSE: Historically, a chest radiograph was obtained after central line placement in the operating room. Recent retrospective studies have questioned the need for this radiograph. The prevailing current practice at our center is to order chest radiograph only for symptomatic patients. This study examines the outcomes of selective chest radiography after fluoroscopic guided central line placement. METHODS: After obtaining institutional review board approval, a single institution retrospective chart review of patients undergoing central venous catheter placement by the pediatric surgery or interventional radiology service between January 2010 and July 2014 was performed. Outcome measures included CXR within 24h of catheter placement, reason for chest radiograph, complication, and complication requiring intervention. RESULTS: In the study population 622 catheters were placed under fluoroscopy. A chest radiograph was performed in 118 (19%) patients within 24h of the line placement with 25 (4%) of these patients being symptomatic in the recovery room. One patient required chest tube for shortness of breath and pleural effusion. Four symptomatic patients (0.6%) were found to have a pneumothorax, none of which required chest tube placement. There were no re-operations because of mal-position of the catheter. In the 504 patients with no postoperative chest x-ray, there were no adverse outcomes. At our institution the current average charge of a chest radiograph is $283, thus we produced savings of $142,632 for the study period without adverse events. CONCLUSION: After placement of central venous catheter under fluoroscopic guidance, a chest radiograph is unlikely to be helpful in an asymptomatic patient. PMID- 26949146 TI - Acute oesophageal necrosis (black oesophagus). AB - A 54-year-old man was admitted to hospital after being found unconscious in his home. He had a history of alcoholism, multiple drug addictions, and type I diabetes mellitus. At admission, he had hyperglycaemia (550 mg/dL) with glucosuria and ketone bodies in the urine, along with septic shock refractory to bilateral alveolar infiltrates and severe respiratory failure. The patient died 24 hours post admission due to multiple organ failure, with diabetic ketoacidosis decompensated by possible respiratory infection in a patient with polytoxicomania. The autopsy confirmed the presence of acute bilateral bronchopneumonia, chronic pancreatitis, severe hepatic steatosis, and generalized congestive changes. At the oesophagus, acute oesophageal necrosis was evident. PMID- 26949147 TI - Spontaneous intramural esophageal dissection: an unusual onset of eosinophilic esophagitis. AB - A 35-year-old man, with a history of rhinitis, eczema and a dubious achalasia was admitted due to chest pain and sialorrhea. Upper endoscopy showed a little hole and a narrowing of the distal esophagus. A CT-scan with oral contrast exposed a discontinuity of the lumen of the middle third of the esophagus and a dissection of submucosal space 16 cm long. The patient recovered after parenteral nutrition. After four months, an esophageal endoscopic showed transient whitish exudates, longitudinal furrows and esophageal lacerations. The biopsies illustrated significant eosinophilic inflammation, eosinophilic microabscesses and basal cell hyperplasia. PMID- 26949150 TI - Swimming and cycling do not cause positive effects on bone mineral density: a systematic review. AB - Osteoporosis is considered a common metabolic bone disease and its prevalence is increasing worldwide. In this context, physical activity has been used as a non pharmacological tool for prevention and auxiliary treatment of this disease. The aim of this systematic review was to evaluate the effects of cycling and swimming practice on bone mineral density (BMD). This research was conducted in accordance with the recommendations outlined by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. The studies were consulted in the period from 2004 to 2014, through major electronic databases: PubMed(r), SciELO(r) and LILACS(r). Ten studies evaluated the effects of cycling on BMD, and the results showed that nine studies have linked the practice of professional cycling with low levels of BMD. Another 18 studies have reported that swimming has no positive effects on bone mass. We conclude that cycling and swimming do not cause positive effects on BMD; thus, these are not the most suitable exercises for prevention and treatment of osteoporosis. PMID- 26949151 TI - Substitutions of red meat, poultry and fish and risk of myocardial infarction. AB - Red meat has been suggested to be adversely associated with risk of myocardial infarction (MI), but previous studies have rarely taken replacement foods into consideration. We aimed to investigate optimal substitutions between and within the food groups of red meat, poultry and fish for MI prevention. We followed up 55 171 women and men aged 50-64 years with no known history of MI at recruitment. Diet was assessed by a validated 192-item FFQ at baseline. Adjusted Cox proportional hazard models were used to calculate hazard ratios (HR) and 95 % CI for specified food substitutions of 150 g/week. During a median follow-up time of 13.6 years, we identified 656 female and 1694 male cases. Among women, the HR for replacing red meat with fatty fish was 0.76 (95 % CI 0.64, 0.89), whereas the HR for replacing red meat with lean fish was 1.00 (95 % CI 0.89, 1.14). Similarly, replacing poultry with fatty but not lean fish was inversely associated with MI: the HR was 0.81 (95 % CI 0.67, 0.98) for fatty fish and was 1.08 (95 % CI 0.92, 1.27) for lean fish. The HR for replacing lean with fatty fish was 0.75 (95 % CI 0.60, 0.94). Replacing processed with unprocessed red meat was not associated with MI. Among men, a similar pattern was found, although the associations were not statistically significant. This study suggests that replacing red meat, poultry or lean fish with fatty fish is associated with a lower risk of MI. PMID- 26949152 TI - Neuropsychological consequences of sleep disturbance in children with epilepsy. AB - A growing body of research reveals strong relationships between sleep disturbance, sleep architecture, and neuropsychological functioning in children. Children with epilepsy experience numerous neuropsychological comorbidities, including cognitive deficiencies and emotional/behavioral difficulties; thus, it is reasonable to consider the moderating role of sleep in this population. This review summarizes findings involving the prevalence and characteristics of sleep problems often experienced by children with epilepsy. The complex and bidirectional relationship between sleep and seizure frequency is discussed. Research pertaining to the relationship between sleep disturbance and daytime cognition as well as behavior reveals a substantial association between these variables. Clinically relevant practices related to the assessment and treatment of sleep-related complications are reviewed, and directions for further research involving intervention and assessment are also reviewed. PMID- 26949153 TI - Sudden unexpected death in Parkinson's disease: Perspectives on what we have learned about sudden unexpected death in epilepsy (SUDEP). PMID- 26949154 TI - Analgesic opioid use in a health-insured epilepsy population during 2012. AB - RATIONALE: Analgesic opioid use has increased dramatically in the general population. Although opioid analgesics are not indicated for the treatment of epilepsy, frequent opioid use has been reported in the epilepsy population. It is not clear whether comorbid disorders and/or epilepsy-associated injuries due to seizures foster opioid use. Our primary objective was to compare the prevalence of analgesic opioid use in an insured patient population with epilepsy to a matched control population without epilepsy. After observing increased frequency of opioid use in people with epilepsy compared with matched controls, we assessed the contribution of age, gender, pain diagnosis, and psychiatric illness as possible drivers regarding the use of opioids. METHODS: Health insurance claims and membership data from nine United States (U.S.) health plans for the year 2012 were analyzed. Individuals with epilepsy (n=10,271) were match-paired at a 1:2 ratio to individuals without epilepsy (n=20,542) within each health plan using propensity scores derived from age group, gender, and insurance type. Matched comparison groups had 53% females and 47% males with an average age of 34 years for the group with epilepsy and 33 years for controls. Each matched comparison group included 66% of individuals with commercial insurance, 30% with Medicaid insurance, and 4% with Medicare coverage. Based on prescriptions filled at least once during 2012, prevalence of analgesic opioid use was determined. The percentages of individuals with diagnosis for specific pain conditions and those with psychiatric diagnoses were also determined for the two comparison groups. RESULTS: Analgesic opioids were used by 26% of individuals in the group with epilepsy vs. 18% of matched controls (p<0.001). Compared with matched controls, the group with epilepsy had a significantly higher percentage of individuals with all 16 pain conditions examined: joint pain or stiffness (16% vs. 11%), abdominal pain (14% vs. 9%), headache (14% vs. 5%), pain in limb (12% vs. 7%), chest pain (11% vs. 6%), sprain of different parts (9% vs. 7%), sinusitis (9% vs. 7%), migraine (8% vs. 2%), lumbago (8% vs. 6%), backache (6% vs. 4%), cervicalgia (6% vs. 3%), fracture (5% vs. 3%), fibromyalgia (4% vs. 3%), chronic pain (3% vs. 1%), sciatica (1.4% vs. 1%), and jaw pain (0.4% vs. 0.1%) (all p<0.001). The prevalence of pain diagnosis was 51% in the group with epilepsy and 39% in the matched control group (p<0.0001). The prevalence of 'psychiatric diagnoses' was 27% in the group with epilepsy and 12% in the matched control group (p<0.0001). CONCLUSION: The prevalences of analgesic opioid use, psychiatric diagnoses, and 16 pain conditions were significantly higher in the patient population with epilepsy than in the control population without epilepsy. Our study also showed how opioid use rate varied by gender, age category, and depression. The reasons for the greater prevalence of opioid use in people with epilepsy are unclear. It seems that increased pain prevalence is an important driver for the higher frequency of opioid use in people with epilepsy. Psychiatric illness and other factors also appear to contribute. Further analysis including more detailed clinical information that cannot be obtained through claims data alone will be required to provide more insight into opioid use in people with epilepsy. If opioid use is higher in people with epilepsy as our results suggest, physicians managing patients with epilepsy need to pay special attention to safe opioid prescribing habits in order to prevent adverse outcomes such as abuse, addiction, diversion, misuse, and overdose. PMID- 26949155 TI - Electroencephalographic patterns during sleep in children with chromosome 15q11.2 13.1 duplications (Dup15q). AB - Our objective was to define the EEG features during sleep of children with neurodevelopmental disorders due to copy number gains of 15q11-q13 (Dup15q). We retrospectively reviewed continuous EEG recordings of 42 children with Dup15q (mean age: eight years, 32 with idic15), and data collected included background activity, interictal epileptiform discharges, sleep organization, and ictal activity. Three patterns were recognized: Pattern 1: Alpha-delta sleep was noted in 14 children (33%), not associated with any clinical changes. Pattern 2: Electrical status epilepticus in sleep was noted in 15 children (35%), all diagnosed with treatmentresistant epilepsy. Thirteen of the 15 children had clinical seizures. Pattern 3: Frequent bursts of high amplitude bifrontal predominant, paroxysmal fast activity (12-15 Hz) during non-REM sleep was noted in 15 children (35%). All 15 children had treatment-resistant epilepsy. This is the first report of electroencephalographic patterns during sleep of children with Dup15q reporting alpha-delta rhythms, CSWS, and high amplitude fast frequencies. Alpha-delta rhythms are described in children with dysautonomia and/or mood disorders and CSWS in children with developmental regression. The significance of these findings in cognitive function and epilepsy for the children in our cohort needs to be determined with follow-up studies. PMID- 26949156 TI - Video-ambulatory EEG in a secondary care center: A retrospective evaluation of utility in the diagnosis of epileptic and nonepileptic seizures. AB - The development and optimization of protocols using simultaneous video recording alongside long-term electroencephalography (EEG), such as ambulatory EEG (AEEG), expanded the range of available techniques for the investigation of paroxysmal clinical events. In particular, video-AEEG has received increasing attention over the last few years because of its potential to further improve diagnostic utility in the differential diagnosis between epileptic and nonepileptic seizures. We retrospectively evaluated 88 video-AEEG studies in order to assess the diagnostic utility of video-AEEG in 87 patients consecutively referred to a neurophysiology department. Typical clinical events occurred during 55 studies (62.5%). In 26 of these, at least one event was also clearly seen on video recording, contributing to a confident diagnosis. Clinical events were classified according to three diagnostic categories: epileptic seizures (6 studies, 6.8%), physiologic nonepileptic events (13 studies, 14.8%), or psychogenic nonepileptic seizures (36 studies, 40.9%). Of the studies with an event not recorded on video, a confident diagnosis could be reached in 55.2% of cases. The main reason for unsuccessful video recording was failure to activate the camcorder by the patient or carer. We found an overall diagnostic utility of 67.0%, which confirms the findings of previous reports evaluating the diagnostic yield of AEEG. Implementation of video AEEG protocols in a secondary care center appears to have high diagnostic utility, particularly for patients with psychogenic nonepileptic seizures. Our findings prompt further research into the potential applications of video-AEEG, in consideration of important implications for successful patient management and healthcare resource allocation. PMID- 26949159 TI - End-of-life care in critical care: moving forward to enhance patient and family experiences. PMID- 26949157 TI - The modularity and dynamicity of miRNA-mRNA interactions in high-grade serous ovarian carcinomas and the prognostic implication. AB - Ovarian carcinoma is the fifth-leading cause of cancer death among women in the United States. Major reasons for this persistent mortality include the poor understanding of the underlying biology and a lack of reliable biomarkers. Previous studies have shown that aberrantly expressed MicroRNAs (miRNAs) are involved in carcinogenesis and tumor progression by post-transcriptionally regulating gene expression. However, the interference of miRNAs in tumorigenesis is quite complicated and far from being fully understood. In this work, by an integrative analysis of mRNA expression, miRNA expression and clinical data published by The Cancer Genome Atlas (TCGA), we studied the modularity and dynamicity of miRNA-mRNA interactions and the prognostic implications in high grade serous ovarian carcinomas. With the top transcriptional correlations (Bonferroni-adjusted p-value<0.01) as inputs, we identified five miRNA-mRNA module pairs (MPs), each of which included one positive-connection (correlation) module and one negative-connection (correlation) module. The number of miRNAs or mRNAs in each module varied from 3 to 7 or from 2 to 873. Among the four major negative-connection modules, three fit well with the widely accepted miRNA mediated post-transcriptional regulation theory. These modules were enriched with the genes relevant to cell cycle and immune response. Moreover, we proposed two novel algorithms to reveal the group or sample specific dynamic regulations between these two RNA classes. The obtained miRNA-mRNA dynamic network contains 3350 interactions captured across different cancer progression stages or tumor grades. We found that those dynamic interactions tended to concentrate on a few miRNAs (e.g. miRNA-936), and were more likely present on the miRNA-mRNA pairs outside the discovered modules. In addition, we also pinpointed a robust prognostic signature consisting of 56 modular protein-coding genes, whose co expression patterns were predictive for the survival time of ovarian cancer patients in multiple independent cohorts. PMID- 26949158 TI - Staphylococcus aureus and chronic folliculocentric pustuloses of the scalp - cause or association? PMID- 26949160 TI - Tending to everyday and BIG conversations in teaching and practice. PMID- 26949161 TI - Arginine-rich ionic complementary peptides as potential drug carriers: Impact of peptide sequence on size, shape and cell specificity. AB - Ionic complementary peptides have shown potential in delivering hydrophobic anticancer drugs. In this study, a series of four ionic complementary peptides, EAR16-II, EAR8-II, EAR8-IIa and ELR8-IIa, is derived from the most studied ionic complementary peptide EAK16-II. The purpose is to investigate the impact of peptide sequence on nanostructure formation, delivery efficacy and cell specificity of the peptide-drug complex. We show that the peptide length has a pronounced impact on the morphology of peptide complex with the anticancer drug ellipticine (EPT), and the amino acid arrangement affects the complex size. Cytotoxicity studies show that the complexes are effective at inhibiting the growth of A549 lung cancer cells and EAR16-II-EPT is the most effective. Interestingly, the complexes formulated with EAR16-II and EAR8-II become less active against MCF-7 breast cancer cells, but more hemolytic than the other two complexes. This work provides essential information to optimize self-assembling peptide-based drug delivery for cancer therapy. PMID- 26949162 TI - Biocompatibility assessment of fibrous nanomaterials in mammalian embryos. AB - Currently there is a growing interest in the use of nanotechnology in reproductive medicine and reproductive biology. However, their toxic effects on mammalian embryos remain poorly understood. In this work, we evaluate the biocompatibility of two fibrous nanomaterials (NMs): cotton cellulose nanofibers (CNF) and carboxylated multiwalled carbon nanotubes (MWCNT-COOH), by performing an investigation of the embryonic development, gene expression (biomarkers focused on cell stress, apoptosis and totipotency) and in situ apoptosis in bovine embryos. Exposure to NMs did not interfere in preimplantation development or in the incidence of apoptosis in the bovine embryo, but they did affect the gene expression. The results presented are important for an understanding of the toxicity of cotton CNF and MWCNT-COOH on mammalian embryos. To our knowledge, we report the first evaluation of biocompatibility between these NMs on preimplantation embryos, which may open a new window for reproductive biomedical applications. PMID- 26949164 TI - Iron oxide nanoparticles as magnetic relaxation switching (MRSw) sensors: Current applications in nanomedicine. AB - Since pioneering work in the early 60s on the development of enzyme electrodes the field of sensors has evolved to different sophisticated technological platforms. Still, for biomedical applications, there are key requirements to meet in order to get fast, low-cost, real-time data acquisition, multiplexed and automatic biosensors. Nano-based sensors are one of the most promising healthcare applications of nanotechnology, and prone to be one of the first to become a reality. From all nanosensors strategies developed, Magnetic Relaxation Switches (MRSw) assays combine several features which are attractive for nanomedical applications such as safe biocompatibility of magnetic nanoparticles, increased sensitivity/specificity measurements, possibility to detect analytes in opaque samples (unresponsive to light-based interferences) and the use of homogeneous setting assay. This review aims at presenting the ongoing progress of MRSw technology and its most important applications in clinical medicine. PMID- 26949137 TI - Serious Asthma Events with Fluticasone plus Salmeterol versus Fluticasone Alone. AB - BACKGROUND: The safe and appropriate use of long-acting beta-agonists (LABAs) for the treatment of asthma has been widely debated. In two large clinical trials, investigators found a potential risk of serious asthma-related events associated with LABAs. This study was designed to evaluate the risk of administering the LABA salmeterol in combination with an inhaled glucocorticoid, fluticasone propionate. METHODS: In this multicenter, randomized, double-blind trial, adolescent and adult patients (age, >=12 years) with persistent asthma were assigned to receive either fluticasone with salmeterol or fluticasone alone for 26 weeks. All the patients had a history of a severe asthma exacerbation in the year before randomization but not during the previous month. Patients were excluded from the trial if they had a history of life-threatening or unstable asthma. The primary safety end point was the first serious asthma-related event (death, endotracheal intubation, or hospitalization). Noninferiority of fluticasone-salmeterol to fluticasone alone was defined as an upper boundary of the 95% confidence interval for the risk of the primary safety end point of less than 2.0. The efficacy end point was the first severe asthma exacerbation. RESULTS: Of 11,679 patients who were enrolled, 67 had 74 serious asthma-related events, with 36 events in 34 patients in the fluticasone-salmeterol group and 38 events in 33 patients in the fluticasone-only group. The hazard ratio for a serious asthma-related event in the fluticasone-salmeterol group was 1.03 (95% confidence interval [CI], 0.64 to 1.66), and noninferiority was achieved (P=0.003). There were no asthma-related deaths; 2 patients in the fluticasone only group underwent asthma-related intubation. The risk of a severe asthma exacerbation was 21% lower in the fluticasone-salmeterol group than in the fluticasone-only group (hazard ratio, 0.79; 95% CI, 0.70 to 0.89), with at least one severe asthma exacerbation occurring in 480 of 5834 patients (8%) in the fluticasone-salmeterol group, as compared with 597 of 5845 patients (10%) in the fluticasone-only group (P<0.001). CONCLUSIONS: Patients who received salmeterol in a fixed-dose combination with fluticasone did not have a significantly higher risk of serious asthma-related events than did those who received fluticasone alone. Patients receiving fluticasone-salmeterol had fewer severe asthma exacerbations than did those in the fluticasone-only group. (AUSTRI ClinicalTrials.gov number, NCT01475721.). PMID- 26949163 TI - Liposome-mediated delivery of the p21 activated kinase-1 (PAK-1) inhibitor IPA-3 limits prostate tumor growth in vivo. AB - P21 activated kinases-1 (PAK-1) is implicated in various diseases. It is inhibited by the small molecule 'inhibitor targeting PAK1 activation-3' (IPA-3), which is highly specific but metabolically unstable. To address this limitation we encapsulated IPA-3 in sterically stabilized liposomes (SSL). SSL-IPA-3 averaged 139nm in diameter, polydispersity index (PDI) of 0.05, and a zeta potential of -28.1, neither of which changed over 14days; however, the PDI increased to 0.139. Analysis of liposomal IPA-3 levels demonstrated good stability, with 70% of IPA-3 remaining after 7days. SSL-IPA-3 inhibited prostate cancer cell growth in vitro with comparable efficacy to free IPA-3. Excitingly, only a 2day/week dose of SSL-IPA-3 was needed to inhibit the growth of prostate xenografts in vivo, while a similar dose of free IPA-3 was ineffective. These data demonstrate the development and clinical utility of a novel liposomal formulation for the treatment of prostate cancer. PMID- 26949165 TI - Rational engineering of single-chain polypeptides into protein-only, BBB-targeted nanoparticles. AB - A single chain polypeptide containing the low density lipoprotein receptor (LDLR) ligand Seq-1 with blood-brain barrier (BBB) crossing activity has been successfully modified by conventional genetic engineering to self-assemble into stable protein-only nanoparticles of 30nm. The nanoparticulate presentation dramatically enhances in vitro, LDLR-dependent cell penetrability compared to the parental monomeric version, but the assembled protein does not show any enhanced brain targeting upon systemic administration. While the presentation of protein drugs in form of nanoparticles is in general advantageous regarding correct biodistribution, this principle might not apply to brain targeting that is hampered by particular bio-physical barriers. Irrespective of this fact, which is highly relevant to the nanomedicine of central nervous system, engineering the cationic character of defined protein stretches is revealed here as a promising and generic approach to promote the controlled oligomerization of biologically active protein species as still functional, regular nanoparticles. PMID- 26949167 TI - Electron transporting organic materials with an exceptional large scale homeotropic molecular orientation. AB - An electron transporting anthraquinone derivative demonstrated a stable large scale homeotropic alignment on an open substrate surface, which substantially improved its charge carrier mobility. The electron mobility (MU(E)) increased by two orders of magnitude from 3.2 * 10(-4) cm(2) V(-1) s(-1) for the film without alignment to 1.2 * 10(-2) cm(2) V(-1) s(-1) for the homeotropically aligned film. A distinct enhancement in the UV absorption spectra of the films around the short wavelength range was observed to be associated with the molecular alignments. These alignments are less sensitive to the substrate under test. The anchoring force of the columnar stacks appears to be related to the nature of the material associated with the strong interaction between the molecules and substrate interface. PMID- 26949168 TI - Dural arteriovenous fistula at the foramen magnum: Report of a case and clinical anatomical review. AB - Arterial supply and venous drainage at the foramen magnum is variable. Two main forms of clinical presentation, intracranial and spinal, can be differentiated when a dural arteriovenous fistula (DAVF) is found at this level. We describe a case of a 68-year-old patient with a progressive paraparesis, diagnosed of dural arteriovenous fistula located at the posterior lip of foramen magnum. We review, in this setting, the vascular radiological anatomy of those fistulas and its important correlation with neurologic clinical symptoms. PMID- 26949166 TI - Investigation of the cause of geographic disparities in IDEXX ELISA sensitivity in serum samples from Mycobacterium bovis-infected cattle. AB - Accurately identifying Mycobacterium bovis-infected cattle is critical for bovine tuberculosis prevention and control. One method for identifying infected cattle is an ELISA developed by IDEXX laboratories, which detects antibodies to two M. bovis proteins, MPB70 and MPB83. The assay's sensitivity varies by geographic region, with sensitivities of 77%, 45%, and 9% in bovine serum samples from the United Kingdom (n = 126), the United States (n = 146), and Mexico (n = 128), respectively. We hypothesized that geographically-biased sequence variation in mpb70 and mpb83, or in the genes that regulate their expression (sigK and rskA), may explain these differing sensitivities. This hypothesis was tested by comparing the sequences of these four genes in 455 M. bovis strains isolated from cattle in the aforementioned countries. For each gene, a single, common sequence was identified in most genomes of the M. bovis strains collected in all three countries. Twelve of the 455 strains were isolated from infected cattle for which the IDEXX ELISA was also performed. Five of the seven ELISA-positive genomes and three of the five ELISA-negative genomes contained the most common sequence of all four genes. Thus, sequence variation in mpb70, mpb83, sigK, and rskA does not explain the geographic disparities in IDEXX ELISA sensitivity. PMID- 26949169 TI - [Author's response to article "Intrathoracic migration of a ventriculoperitoneal shunt catheter: A case report" by Y. Sanchez-Medina et al]. PMID- 26949171 TI - A Systematic Review of the Prognostic Role of Hematologic Scoring Systems in Patients With Renal Cell Carcinoma Undergoing Nephrectomy With Curative Intent. AB - The objective is to evaluate the prognostic benefit of the Glasgow Prognostic Score (GPS), neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), and Prognostic Nutrition Index (PNI) in patients with localized renal cell carcinoma undergoing nephrectomy with curative intent. Embase and MEDLINE databases were searched for all publications before April 2015. Duplicates were excluded, and inclusion/exclusion criteria were applied to all abstracts; of those remaining, full articles were obtained and inclusion/exclusion criteria were again applied, and the remaining articles were included and critically appraised. Eight articles were included in this review. Three articles were included for GPS. Outcomes included recurrence-free survival, cancer-specific survival (CSS), and overall survival (OS). All articles demonstrated better prognosis associated with a lower GPS on multivariate analysis: 1-year recurrence free survival hazard ratio (HR), 7.0 (P = .001); CSS HR, 6.7 to 8.6 (P < .001); and OS HR 4.2 (P < .001). Four articles were included for NLR. All articles demonstrated elevated NLR to be associated with a poorer prognosis. Two articles demonstrated elevated NLR to be associated with a lower progression-free survival. One article demonstrated elevated NLR to be associated with a lower CSS (HR, 1.02, P = .009), and 2 articles demonstrated elevated NLR to be associated with a lower OS (HR, 1.02-1.6). No articles were included for PLR, and only 1 article was identified for PNI. There may be a role for modified GPS and NLR in patients with renal cell carcinoma undergoing nephrectomy with curative intent. Evidence for PLR and PNI is minimal. PMID- 26949170 TI - Documenting stress in caregivers of transplantation patients: initial evidence of HPA dysregulation. AB - There is growing evidence linking caregiver stress with an increased risk for morbidity and mortality. While the emotional and practical burden experienced by caregivers is well established, the physiological changes that may affect the caregiver's health are less understood. This study sought to compare self reported stress, anxiety and depression along with neuroendocrine and immune markers of stress among adult caregivers of allogeneic hematopoietic stem cell transplantation patients during the acute transplant recovery period to matched non-caregivers controls. Biomarkers and self-reported data were collected at three points during the patient's HSCT: (1) before transplant, (2) after initial transplantation discharge (+/-7 days) and (3) 6 weeks after initial transplantation discharge. Mixed linear modeling was used to examine differences by group and time. Twenty-one caregivers and 20 controls completed all study procedures. The majority of caregivers were female (57% or 57.1%) and married (95.2%), with a mean age of 52 +/- 11.4 years. Caregiver perceived stress, anxiety and depression scores were significantly higher than controls (p < 0.001) with effect sizes (ES) ranging from 1.37 to 1.80 and they did not change over time (p > 0.05) for either group. Caregivers had significantly lower serum cortisol levels than controls at both discharge (p = 0.013; ES = 0.81) and 6 weeks after discharge (p = 0.028; ES = 0.72) but exhibited no significant relationship between self-reported stress and serum cortisol. In addition, caregivers showed a significant inverse relationship between stress and epinephrine levels (r(s)=-0.654, p = 0.021). These findings support the evidence of the caregiving experience being stressful. The counter-intuitive relationship between cortisol and epinephrine might suggest dysregulation of the HPA axis and central nervous system but additional research on the physiological impact of caregiving is warranted. PMID- 26949176 TI - Quiet eye predicts goaltender success in deflected ice hockey shots. AB - In interceptive timing tasks, long quiet eye (QE) durations at the release point, along with early tracking on the object, allow performers to couple their actions to the kinematics of their opponent and regulate their movements based on emergent information from the object's trajectory. We used a mobile eye tracker to record the QE of eight university-level ice hockey goaltenders of an equivalent skill level as they responded to shots that deflected off a board placed to their left or right, resulting in a trajectory with low predictability. QE behaviour was assessed using logistic regression and magnitude-based inference. We found that when QE onset occurred later in the shot (950 +/- 580 ms, mean +/- SD) there was an increase in the proportion of goals allowed (41% vs. 22%) compared to when QE onset occurred earlier. A shorter QE duration (1260 +/- 630 ms) predicted a large increase in the proportion of goals scored (38% vs. 14%). More saves occurred when QE duration (2074 +/- 47 ms) was longer. An earlier QE offset (2004 +/- 66 ms) also resulted in a large increase in the number of goals allowed (37% vs. 11%) compared to a later offset (2132 +/- 41 ms). Since an early, sustained QE duration contributed to a higher percentage of saves, it is important that coaches develop practice activities that challenge the goaltender's ability to fixate the puck early, as well as sustain a long QE fixation on the puck until after it is released from the stick. PMID- 26949178 TI - Renal fibrosis: PDGF-D in renal fibrosis. PMID- 26949179 TI - Glomerular disease: Novel candidate genes implicated in FSGS. PMID- 26949177 TI - Biologics for the treatment of autoimmune renal diseases. AB - Biological therapeutics (biologics) that target autoimmune responses and inflammatory injury pathways have a marked beneficial impact on the management of many chronic diseases, including rheumatoid arthritis, psoriasis, inflammatory bowel disease, and ankylosing spondylitis. Accumulating data suggest that a growing number of renal diseases result from autoimmune injury - including lupus nephritis, IgA nephropathy, anti-neutrophil cytoplasmic antibody-associated glomerulonephritis, autoimmune (formerly idiopathic) membranous nephropathy, anti glomerular basement membrane glomerulonephritis, and C3 nephropathy - and one can speculate that biologics might also be applicable to these diseases. As many autoimmune renal diseases are relatively uncommon, with long natural histories and diverse outcomes, clinical trials that aim to validate potentially useful biologics are difficult to design and/or perform. Some excellent consortia are undertaking cohort studies and clinical trials, but more multicentre international collaborations are needed to advance the introduction of new biologics to patients with autoimmune renal disorders. This Review discusses the key molecules that direct injurious inflammation and the biologics that are available to modulate them. The opportunities and challenges for the introduction of relevant biologics into treatment protocols for autoimmune renal diseases are also discussed. PMID- 26949181 TI - Intrathecal rimantadine induces motor, proprioceptive, and nociceptive blockades in rats. AB - The purpose of the experiment was to evaluate the local anesthetic effect of rimantadine in spinal anesthesia. Rimantadine in a dose-dependent fashion was constructed after intrathecally injecting the rats with four different doses. The potency and duration of rimantadine were compared with that of the local anesthetic lidocaine at producing spinal motor, nociceptive, and proprioceptive blockades. We demonstrated that intrathecal rimantadine dose-dependently produced spinal motor, nociceptive, and proprioceptive blockades. On the 50% effective dose (ED50) basis, the ranks of potencies at inducing spinal motor, nociceptive, and proprioceptive blockades was lidocaine>rimantadine (P<0.01). Rimantadine exhibited more nociceptive block (ED50) than motor block (P<0.05). At equi anesthetic doses (ED25, ED50, and ED75), the spinal block duration produced by rimantadine was longer than that produced by lidocaine (P<0.01). Furthermore, rimantadine (26.52MUmol/kg) prolonged the nociceptive nerve block more than the motor block (P<0.001). Our preclinical data showed that rimantadine, with a more sensory-selective action over motor block, was less potent than lidocaine. Rimantadine produced longer duration in spinal anesthesia when compared with lidocaine. PMID- 26949182 TI - Changes in autophagy in rats after spinal cord injury and the effect of hyperbaric oxygen on autophagy. AB - The purpose of this study was to explore the effects of Hyperbaric oxygen (HBO) on the autophagic changes after induction of spinal cord injury (SCI) in rats. A total of 75 rats were randomly divided into the sham-operated group, the spinal cord injury group, and the SCI+HBO group. We found that at 7 d and 14 d after surgery, the BBB scores were higher in the SCI+HBO group in comparison to the SCI group. The expression of Beclin-1 and LC3II was upregulated in the SCI and SCI+HBO groups after SCI. Fluorescently stained Beclin-1 and LC3II proteins were barely detectable in the sham group. In contrast, Beclin-l and LC3II expression was observed in neurons and glial cells from the SCI and SCI+HBO groups. Beclin-1 and LC3II expression appeared at 6h after SCI. At each time point, Beclin-1 and LC3II expression was significantly higher in the SCI+HBO group compared to the SCI group. These results suggest that autophagy is activated in rats after SCI and sustained over a period of time. HBO treatment enhances autophagy expression in rats after SCI and accelerates cell repair rate, which may represent one of the mechanisms of action of HBO in the treatment of SCI. PMID- 26949183 TI - Identification of novel GLUT inhibitors. AB - The compound class of 1H-pyrazolo[3,4-d]pyrimidines was identified using HTS as very potent inhibitors of facilitated glucose transporter 1 (GLUT1). Extensive structure-activity relationship studies (SAR) of each ring system of the molecular framework was established revealing essential structural motives (i.e., ortho-methoxy substituted benzene, piperazine and pyrimidine). The selectivity against GLUT2 was excellent and initial in vitro and in vivo pharmacokinetic (PK) studies are encouraging. PMID- 26949184 TI - Spinal Inhibitory Interneuron Diversity Delineates Variant Motor Microcircuits. AB - Animals generate movement by engaging spinal circuits that direct precise sequences of muscle contraction, but the identity and organizational logic of local interneurons that lie at the core of these circuits remain unresolved. Here, we show that V1 interneurons, a major inhibitory population that controls motor output, fractionate into highly diverse subsets on the basis of the expression of 19 transcription factors. Transcriptionally defined V1 subsets exhibit distinct physiological signatures and highly structured spatial distributions with mediolateral and dorsoventral positional biases. These positional distinctions constrain patterns of input from sensory and motor neurons and, as such, suggest that interneuron position is a determinant of microcircuit organization. Moreover, V1 diversity indicates that different inhibitory microcircuits exist for motor pools controlling hip, ankle, and foot muscles, revealing a variable circuit architecture for interneurons that control limb movement. PMID- 26949185 TI - BOK Is a Non-canonical BCL-2 Family Effector of Apoptosis Regulated by ER Associated Degradation. AB - The mitochondrial pathway of apoptosis is initiated by mitochondrial outer membrane permeabilization (MOMP). The BCL-2 family effectors BAX and BAK are thought to be absolutely required for this process. Here, we report that BCL-2 ovarian killer (BOK) is a bona fide yet unconventional effector of MOMP that can trigger apoptosis in the absence of both BAX and BAK. However, unlike the canonical effectors, BOK appears to be constitutively active and unresponsive to antagonistic effects of the antiapoptotic BCL-2 proteins. Rather, BOK is controlled at the level of protein stability by components of the endoplasmic reticulum (ER)-associated degradation pathway. BOK is ubiquitylated by the AMFR/gp78 E3 ubiquitin ligase complex and targeted for proteasomal degradation in a VCP/p97-dependent manner, which allows survival of the cell. When proteasome function, VCP, or gp78 activity is compromised, BOK is stabilized to induce MOMP and apoptosis independently of other BCL-2 proteins. PMID- 26949187 TI - Bayesian Sparse Regression Analysis Documents the Diversity of Spinal Inhibitory Interneurons. AB - Documenting the extent of cellular diversity is a critical step in defining the functional organization of tissues and organs. To infer cell-type diversity from partial or incomplete transcription factor expression data, we devised a sparse Bayesian framework that is able to handle estimation uncertainty and can incorporate diverse cellular characteristics to optimize experimental design. Focusing on spinal V1 inhibitory interneurons, for which the spatial expression of 19 transcription factors has been mapped, we infer the existence of ~50 candidate V1 neuronal types, many of which localize in compact spatial domains in the ventral spinal cord. We have validated the existence of inferred cell types by direct experimental measurement, establishing this Bayesian framework as an effective platform for cell-type characterization in the nervous system and elsewhere. PMID- 26949188 TI - Comparing the effects of MSCs and CD34+ cell therapy in a rat model of myocardial infarction. AB - Stem cell therapy is considered as a promising approach in the treatment of myocardial infarction (MI). This study was designed as a comparison of human umbilical cord blood (HUCB)-derived CD34+ and HUCB-derived MSCs for the repair of cardiac tissue by induction of the angiogenesis. Forty-eight male rats were randomized into four groups: sham-operated group, MI group, MSCs-treated group, and CD34+ cells-treated group. After 4 weeks, the rats were sacrificed. All sections from left ventricles of all groups were subjected to hematoxylin & eosin, Masson's trichrome, and immunohistochemical stains (CD133, CD44, and alpha smooth muscle actin). RNA was extracted for gene expression of the angiogenic markers. A significant reduction of the infarct size and the amplitude of T-wave in the CD34+ cells-treated group when compared with the MSCs-treated group were determined. Histologically, the MI group showed scar tissue, congested blood capillaries around the infarcted area, some necrotic cells, and inflammatory cells. Administration of either MSCs or CD34+ cells had a therapeutic potential to induce regenerative changes in the myocardium with better results in CD34+cells-treated group. Quantitative RT-PCR analysis revealed a significant increase in the expression of vascular endothelial growth factor (VEGF), VEGFR-2, Ang-1, and Tie-2 and a significant decreased expression of Ang-2 in stem cells transplanted groups when compared with the noncell transplanted hearts. A significant increase of VEGF, VEGFR-2, Ang-1, and Tie-2 expression in the group receiving CD34+ cells than those receiving MSCs was found. Finally, there was an upregulation of both human VEGF and human hypoxia-inducible factor 1alpha in the infarcted hearts treated by CD34+ cells than that treated by MSCs. We first revealed a superior efficacy of CD34+ cells when compared with MSCs in induction of regenerative changes in the MI model. Both cell therapies may repair the damaged heart tissue primarily by secretion of proangiogenic factors that induce the angiogenesis and activate the angiogenesis signaling pathway. (c) 2016 IUBMB Life, 68(5):343-354, 2016. PMID- 26949186 TI - Maturation Pathway from Germline to Broad HIV-1 Neutralizer of a CD4-Mimic Antibody. AB - Antibodies with ontogenies from VH1-2 or VH1-46-germline genes dominate the broadly neutralizing response against the CD4-binding site (CD4bs) on HIV-1. Here, we define with longitudinal sampling from time-of-infection the development of a VH1-46-derived antibody lineage that matured to neutralize 90% of HIV-1 isolates. Structures of lineage antibodies CH235 (week 41 from time-of-infection, 18% breadth), CH235.9 (week 152, 77%), and CH235.12 (week 323, 90%) demonstrated the maturing epitope to focus on the conformationally invariant portion of the CD4bs. Similarities between CH235 lineage and five unrelated CD4bs lineages in epitope focusing, length-of-time to develop breadth, and extraordinary level of somatic hypermutation suggested commonalities in maturation among all CD4bs antibodies. Fortunately, the required CH235-lineage hypermutation appeared substantially guided by the intrinsic mutability of the VH1-46 gene, which closely resembled VH1-2. We integrated our CH235-lineage findings with a second broadly neutralizing lineage and HIV-1 co-evolution to suggest a vaccination strategy for inducing both lineages. PMID- 26949189 TI - What is known about community pharmacy supply of naloxone? A scoping review. AB - There is growing evidence that expanded supply of take-home naloxone to prevent opioid overdose deaths is needed. Potential routes for expansion of naloxone provision include through community pharmacies. The aim of this scoping review is to establish what is known about community pharmacy supply of naloxone, in light of unique challenges and opportunities present in pharmacy settings. A scoping review methodology was employed using the six stage iterative process advocated by Arksey and O'Malley (2005) and Levac et al. (2010). Searches used key words and terms such as 'naloxone'; 'overdose prevention/drug overdose/opiate overdose'; 'community/retail pharmacy'; 'pharmacist/pharmacy/community pharmacy/pharmaceutical services'; 'professional practice/role'; 'community care'; attitude of health personnel'; 'training/supply/cost'. Appropriate search terms were selected for each database. After initial exploratory searches, comprehensive searches were conducted with Cochrane Database of Systematic Reviews, Medline, Medline in Process, Embase, PsycINFO and CINAHL. Eligibility criteria centered on whether studies broadly described supply of naloxone in community pharmacy or had content relating to community pharmacy supply. The search identified 95 articles, of which 16 were related to pharmacy supply of naloxone. Five themes were presented after initial review of the data and consultation with the project Expert Group, and are; 'Pharmacists Perceptions of Naloxone: Facilitators and Barriers', 'Patient Populations: Identification and Recruitment', 'Supply Systems and Cost', 'Legal Issues', and 'Training of Pharmacists and Community Pharmacy Naloxone Recipients'. Findings from this scoping review suggest that community pharmacy based supply of take-home naloxone warrants the community pharmacy based route for distribution of take home naloxone provision warrants further consideration and development. Existing strengths include a range of established supply models, and training curricula, few direct concerns regarding legal liability of pharmacists in the supply of naloxone (once legal supply systems have been established) and the wide range of potential identifiable patient populations, which include pain patients that may not be in contact with existing naloxone supply programmes. PMID- 26949190 TI - Legal harvest and illegal trade: Trends, challenges, and options in khat production in Ethiopia. AB - The production of khat in Ethiopia has boomed over the last two decades, making the country the world's leading source. Khat is now one of Ethiopia's largest crops by area of cultivation, the country's second largest export earner, and an essential source of income for millions of Ethiopian farmers. Consumption has also spread from the traditional khat heartlands in the eastern and southern regions of Ethiopia to most major cities. This steady growth in production and use has unfolded under negligible government support or regulation. Meanwhile, khat, which releases a stimulant when chewed, is considered an illicit drug in an increasing number of countries. Drawing on government data on khat production, trade, and seizures as well as research on the political, socioeconomic, and development effects of plant-based illicit narcotics industries, this commentary identifies possible considerations and scenarios for Ethiopia as the country begins to manage rising khat production, domestic consumption, and criminalization abroad. Deeply embedded in social and cultural practices and a major source of government and agricultural revenue, Ethiopian policymakers have few enviable choices. Criminalization abroad raises a small but not insignificant possibility that previously nonexistent linkages between khat and transnational organized crime and trafficking networks will emerge. Likewise, more stringent regulation of khat in Ethiopia could merge with lingering political cleavages and anti-government sentiments, exacerbating low-level domestic conflicts. PMID- 26949191 TI - The identification of age-associated cancer markers by an integrative analysis of dynamic DNA methylation changes. AB - As one of the most widely studied epigenetic modifications, DNA methylation has an important influence on human traits and cancers. Dynamic variations in DNA methylation have been reported in malignant neoplasm and aging; however, the mechanisms remain poorly understood. By constructing an age-associated and cancer related weighted network (ACWN) based on the correlation of the methylation level and the protein-protein interaction, we found that DNA methylation changes associated with age were closely related to the occurrence of cancer. Additional analysis of 102 module genes mined from the ACWN revealed discrimination based on two main patterns. One pattern involved methylation levels that increased with aging and were higher in cancer patients compared with normal controls (HH pattern). The other pattern involved methylation levels that decreased with aging and were lower in cancer compared with normal (LL pattern). Upon incorporation with gene expression levels, 25 genes were filtered based on negative regulation by DNA methylation. These genes were regarded as potential cancer risk markers that were influenced by age in the process of carcinogenesis. Our results will facilitate further studies regarding the impact of the epigenetic effects of aging on diseases and will aid in the development of tailored cancer preventive strategies. PMID- 26949192 TI - Bullous pemphigoid and primary biliary cirrhosis, an infrequent association: A case report. PMID- 26949193 TI - Rapunzel syndrome: A rare cause of abdominal pain. PMID- 26949194 TI - Multiple and synchronous squamous cell carcinoma of the esophagus in a young woman: An example of early and rapid carcinogenesis? PMID- 26949195 TI - Risk factors for the development of postoperative pneumonia after cardiac surgery. AB - OBJECTIVE: Identify risk factors that determine pneumonia development in patients who have undergone cardiac surgery. METHODS: Prospective study of a single cohort in a postoperative intensive care unit at a tertiary care center, encompassing all patients undergoing cardiac surgery from January to July 2014. RESULTS: 31 postoperative pneumonia cases were enrolled out of 211 patients (14.6%). The following independent risk factors were identified: hypertension (OR: 3.94, p=0.01), chronic renal failure (OR: 13.67, p=0.02), reintubation (OR: 22.29, p=0.001) and extubation after 6h (OR: 15.81, p=0.005). CONCLUSIONS: Main determinants for pneumonia after surgery were hypertension, chronic renal failure, extubation after 6h and reintubation. PMID- 26949198 TI - Energy and protein deficits throughout hospitalization in patients admitted with a traumatic brain injury. AB - BACKGROUND AND AIMS: Patients with traumatic brain injury (TBI) experience considerable energy and protein deficits in the intensive care unit (ICU) and these are associated with adverse outcomes. However, nutrition delivery after ICU discharge during ward-based care, particularly from oral diet, has not been measured. This study aimed to quantify energy and protein delivery and deficits over the entire hospitalization for critically ill TBI patients. METHODS: Consecutively admitted adult patients with a moderate-severe TBI (Glasgow Coma Scale 3-12) over 12 months were eligible. Observational data on energy and protein delivered from all routes were collected until hospital discharge or day 90 and compared to dietician prescriptions. Oral intake was quantified using weighed food records on three pre-specified days each week. Data are mean (SD) unless indicated. Cumulative deficit is the mean absolute difference between intake and estimated requirements. RESULTS: Thirty-seven patients [45.3 (15.8) years; 87% male; median APACHE II 18 (IQR: 14-22)] were studied for 1512 days. Median duration of ICU and ward-based stay was 13.4 (IQR: 6.4-17.9) and 19.9 (9.6 32.0) days, respectively. Over the entire hospitalization patients had a cumulative deficit of 18,242 (16,642) kcal and 1315 (1028) g protein. Energy and protein intakes were less in ICU than the ward (1798 (800) vs 1980 (915) kcal/day, p = 0.015; 79 (47) vs 89 (41) g/day protein, p = 0.001). Energy deficits were almost two-fold greater in patients exclusively receiving nutrition orally than tube-fed (806 (616) vs 445 (567) kcal/day, p = 0.016) while protein deficits were similar (40 (5) vs 37 (6) g/day, p = 0.616). Primary reasons for interruptions to enteral and oral nutrition were fasting for surgery/procedures and patient-related reasons, respectively. CONCLUSIONS: Patients admitted to ICU with a TBI have energy and protein deficits that persist after ICU discharge, leading to considerable shortfalls over the entire hospitalization. Patients ingesting nutrition orally are at particular risk of energy deficit. PMID- 26949197 TI - Extra-coronary calcification (aortic valve calcification, mitral annular calcification, aortic valve ring calcification and thoracic aortic calcification) in HIV seropositive and seronegative men: Multicenter AIDS Cohort Study. AB - INTRODUCTION: Previous studies have demonstrated an association between HIV infection and coronary artery disease (CAD); little is known about potential associations between HIV infection and extra-coronary calcification (ECC). METHODS: We analyzed 621 HIV infected (HIV+) and 384 HIV uninfected (HIV-) men from the Multicenter AIDS Cohort Study who underwent non-contrast computed tomography (CT) from 2010-2013. Agatston scores were calculated for mitral annular calcification (MAC), aortic valve calcification (AVC), aortic valve ring calcification (AVRC), and thoracic aortic calcification (TAC). The associations between HIV infection and the presence of each type of ECC (score > 0) were evaluated by multivariable logistic regression. We also evaluated the association of ECC with inflammatory biomarker levels and coronary plaque morphology. RESULTS: Among HIV+ and HIV- men, the age-standardized prevalences were 15% for TAC (HIV+ 14%/HIV- 16%), 10% for AVC (HIV+ 11%/HIV- 8%), 24% for AVRC (HIV+ 23% HIV- 24%), and 5% for MAC (HIV+ 7%/HIV- 3%). After adjustment, HIV+ men had 3 fold greater odds of MAC compared to HIV- men (OR = 3.2, 95% CI: 1.5-6.7), and almost twice the odds of AVC (1.8, 1.1-2.9). HIV serostatus was not associated with TAC or AVRC. AVRC was associated with higher Il-6 and sCD163 levels. TAC was associated with higher ICAM-1, TNF-alpha RII, and Il-6 levels. AVC and AVRC calcification were associated with presence of non-calcified plaque in HIV+ but not HIV- men. CONCLUSION: HIV infection is an independent predictor of MAC and AVC. Whether these calcifications predict mortality in HIV+ patients deserves further investigation. PMID- 26949199 TI - A magnetic-dependent protein corona of tailor-made superparamagnetic iron oxides alters their biological behaviors. AB - In recent years, it is becoming increasingly evident that once nanoparticles come into contact with biological fluids, a protein corona surely forms and critically affects the biological behaviors of nanoparticles. Herein, we investigate whether the formation of protein corona on the surface of superparamagnetic iron oxides (SPIOs) is influenced by static magnetic field. Under static magnetic field, there is no obvious variation in the total amount of protein adsorption, but the proportion of adsorbed proteins significantly changes. Noticeably, certain proteins including apolipoproteins, complement system proteins and acute phase proteins, increase in the protein corona of SPIOs in the magnetic field. More importantly, the magnetic-dependent protein corona of SPIOs enhances the cellular uptake of SPIOs into the normal cell line (3T3 cells) and tumor cell line (HepG2 cells), due to increased adsorption of apolipoprotein. In addition, SPIOs with the magnetic-dependent protein corona cause high cytotoxicity to 3T3 cells and HepG2 cells. This work discloses that superparamagnetism as a key feature of SPIOs affects the composition of protein corona to a large extent, which further alters the biological behaviors of SPIOs. PMID- 26949200 TI - A glycoproteomic approach to identify novel glycomarkers for cancer stem cells. AB - Most cancers consist of heterogeneous populations of cells with substantial differences in tumorigenicity. Cells that possess self-renewal and tumor initiating properties are often called cancer stem cells (CSCs). Since CSCs underlie tumor recurrence and metastasis and are resistant to current anti-cancer therapies, novel therapeutic strategies to efficiently target this subset of cells are needed. Aberrant glycosylation is one of the hallmarks of cancer. Many cancer-associated glycans have been reported to be involved in tumor progression and metastasis, and are used as tumor markers. Over the past several years, we have identified characteristic glycans on CSCs by utilizing recent advances in glycoproteomic technologies. In this review, we would like to summarize a series of our recent studies and discuss possible applications of glycomarkers for CSCs. PMID- 26949201 TI - Soil gross nitrogen transformations along the Northeast China Transect (NECT) and their response to simulated rainfall events. AB - Climate changes are predicted to increase extreme rainfall events in semiarid and arid region in Northern Hemisphere. Nutrient cycles will be affected by the precipitation changes but so far only very little is known how soil N transformations may respond. Here we investigated gross soil N transformation rates and their response to simulated rainfall events across Northeast China Transect (NECT). The results showed that gross N mineralisation rate, nitrification rate and nitrification to mineralisation ratio significantly increased as the humidity index decreased along NECT, resulting in NO3(-) as the predominant inorganic N form. These characteristics could increase the risk of NO3(-) losses but at the same time reduce the risk of N losses via volatilization in the semiarid and arid region. The soil-plant ecosystems have developed effective N conservation strategies in the long term with respect to the prevailing climate in arid region. However, compared to humid soils more dramatic changes of soil N transformation rates are likely to occur in arid soils, after sudden soil moisture increases. Soil N conservation mechanisms in arid regions were drastically affected when the heavy rainfall frequently occurred. Arid ecosystems are expected to be more vulnerable than humid ecosystems in response to extreme rainfall events. PMID- 26949202 TI - Astaxanthin preparation by fermentation of esters from Haematococcus pluvialis algal extracts with Stenotrophomonas species. AB - Natural astaxanthin (Ax) is an additive that is widely used because of its beneficial biochemical functions. However, the methods used to produce free Ax have drawbacks. Chemical saponification methods produce several by-products, and lipase-catalyzed hydrolysis methods are not cost effective. In this study, a bacterial strain of Stenotrophomonas sp. was selected to enzymatically catalyze the saponification of Ax esters to produce free all-trans-Ax. Through single factor experiments and a Box-Behnken design, the optimal fermentation conditions were determined as follows: a seed culture age of 37.79 h, an inoculum concentration of 5.92%, and an initial broth pH of 6.80. Under these conditions, a fermentation curve was drawn, and the optimal fermentation time was shown to be 60 h. At 60 h, the degradation rate of the Ax esters was 98.08%, and the yield of free all-trans-Ax was 50.130 MUg/mL. (c) 2016 American Institute of Chemical Engineers Biotechnol. Prog., 32:649-656, 2016. PMID- 26949203 TI - Outcomes of exertional rhabdomyolysis following high-intensity resistance training. AB - BACKGROUND: High-intensity resistance training (HIRT) programmes are increasingly popular amongst personal trainers and those attending gymnasiums. We report the experience of exertional rhabdomyolysis (ER) at two tertiary hospitals in Melbourne, Australia. AIMS: To compare the clinical outcomes of ER with other causes of rhabdomyolysis. METHODS: Retrospective cross-sectional study of patients presenting with a serum creatine kinase (CK) of greater than 25 000 units/L from 1 September 2013 to 31 August 2014 at two tertiary referral hospitals in Melbourne, Australia. Records were examined to identify care measures implemented during hospital stay, clinical outcomes during admission and on subsequent follow up. RESULTS: Thirty four cases of rhabdomyolysis with a CK of greater than 25 000 units/L (normal range: 20-180 units/L) were identified during the 12-month study period. Twelve of the 34 cases (35%) had ER with 10 of 12 related to HIRT. No acute kidney injury, intensive care admission or death were seen among those with ER. All cases were managed conservatively, with 11 admitted and 9 receiving intravenous fluids only. In contrast, patients with rhabdomyolysis from other causes experienced significantly higher rates of intensive care admission (64%, P = 0.0002), acute kidney injury (82%, P = 0.0001) and death (27%, P = 0.069). CONCLUSION: ER resulting from HIRT appears to have a benign course compared with rhabdomyolysis of other aetiologies in patients with a serum CK greater than 25 000 units/L. Conservative management of ER appears to be adequate, although this requires confirmation in future prospective studies. PMID- 26949204 TI - Comparative studies on group III sigma-hole and pi-hole interactions. AB - The sigma-hole of M2 H6 (M = Al, Ga, In) and pi-hole of MH3 (M = Al, Ga, In) were discovered and analyzed, the bimolecular complexes M2 H6 ...NH3 and MH3 ...N2 P2 F4 (M = Al, Ga, In) were constructed to carry out comparative studies on the group III sigma-hole interactions and pi-hole interactions. The two types of interactions are all partial-covalent interactions; the pi-hole interactions are stronger than sigma-hole interactions. The electrostatic energy is the largest contribution for forming the sigma-hole and pi-hole interaction, the polarization energy is also an important factor to form the M...N interaction. The electrostatic energy contributions to the interaction energy of the sigma-hole interactions are somewhat greater than those of the pi-hole interactions. However, the polarization contributions for the pi-hole interactions are somewhat greater than those for the sigma-hole interactions. PMID- 26949205 TI - Introduction: Pain, Trauma, and Philia in Middle English Literature. PMID- 26949207 TI - Cultural Trauma and Christian Identity in the Late Medieval Heroic Epic, The Siege of Jerusalem. AB - This essay examines scenes of violence in the late medieval poem The Siege of Jerusalem in order to reveal the ways in which trauma is used as the grounds upon which Christian/Jewish difference is established. In particular, I argue that this poem serves as an example of a widespread element in Christian chivalric identity, namely the need to manage the repetitive invocation of Christ's crucifixion (ritually repeated through liturgical and poetic invocation) as a means of asserting both the bodily and psychic integrity of the Christian subject in contrast to the violently abjected figure of the Jewish body. The failure of The Siege protagonist, Wespasian, to navigate the cultural trauma of the crucifixion is contrasted to the successful management of trauma by the martial hero, Tancred, in Tasso's epic, Gerusalemme Liberata, illustrating the range of imaginative possibilities for understanding trauma in pre-modern war literature. PMID- 26949206 TI - Wearing Your Heart on Your Face: Reading Lovesickness and the Suicidal Impulse in Chaucer. AB - Geoffrey Chaucer frequently depicts the emotions of his characters via the outward physical signs of the body, and he often does so using a discourse that draws on Galenic theories. A striking example of Chaucer's medicalized descriptions of emotion is his adaptation of the suicidal impulse associated with lovesickness. Chaucer reconstructs this motif in "The Knight's Tale" and The Book of the Duchess by altering his sources (Boccaccio, and Froissart and Machaut) to anatomize the emotional body of the suffering knight. Through the medicalized language of bodily health describing emotional upheavals, other characters and the reader are prompted to feel with and begin to understand and appropriately respond to the suffering individual. This reading shows Chaucer using moments of embodied emotional examination to teach his audience how to read, interpret, and respond to literature. PMID- 26949208 TI - On the Unruly Power of Pain in Middle English Drama. AB - Late medieval culture tends to value pain highly and positively. Accordingly, much medievalist scholarship links pain with fear and emphasizes their usefulness in the period's philosophy, literature, visual art, and drama. Yet, key moments in The York Play of the Crucifixion, The Second Shepherds' Play, and The Tretise of Miraclis Pleyinge trouble the significance of pain and its relationships with punishment and performance; these works admit the unreliability of pain and fear, even as they harness the formidable power pain holds throughout Middle English literature. This essay analyzes passages from all three texts to demonstrate their deep skepticism about the signifying power of pain alongside their abiding investments in pain's utility. I argue that these texts ultimately challenge Middle English drama's dominant discourses of patriarchy and empire by way of their representations of pain. PMID- 26949209 TI - Lydgate's Danse Macabre and the Trauma of the Hundred Years War. AB - This essay argues that the foundational traumatic lacuna behind John Lydgate's Danse Macabre is the social agon between those who wage the Hundred Years War and those who fight in it. Drawing from the insights of trauma theory to discuss the poem's form, the essay uncovers Lydgate's persistent concern with the damage caused by the war and the concomitant political unrest it causes. It argues further that Lydgate theorized this agon using the emergent genre of tragedy, which is beginning to be practiced anew in late-medieval England. Tragic discourse is riven by concerns about the efficacy of human action and the radical contingency of fortune, creating a crisis of agency that can be used as a form of political critique. Ultimately, Lydgate blends the genre of tragedy with the mirror for princes and estates satire genres to argue that, while everyone must eventually dance with death, during war some estates lead the dance. PMID- 26949210 TI - Transculturation of Madness: The Double Origin of Lu Xun's "Diary of a Madman". AB - Over the years scholars have examined the allegorical features of the depiction of madness in Lu Xun's "Diary of a Madman," yet to date little research has taken into consideration the intercultural angle embedded in the narrative's intersection of three cultures, namely Russian, Japanese and Chinese. This paper traces the European-Japanese-Sino route of modern neologisms of madness to explore the introduction of such neologisms into the modern Chinese language and how it corresponds with changing patterns of knowledge and power. I use my study of transculturation on the macro scale to frame a reexamination of the lexicon in "Diary of a Madman." I focus especially on kuangren and pohaikuang, the two key words employed by Lu Xun, to see how they contribute to the ambiguity in his attitude towards the power struggle between the East and the West, the old and the new. PMID- 26949211 TI - Metaphors Unto Themselves: Mental Illness Poetics in Contemporary Chinese Poetry. AB - Recently, proponents of the critical medical humanities have recommended a more discerning view of the ways in which genres and forms "speak" to and for illness, looking specifically at cultural and historical dimensions and cultural specificities of idioms of distress rather than at transhistorical and transcultural approaches. These two claims for a genre-specific critique and, in this case, a cross-cultural approach, ground my reading of the work of Chinese poets Guo Lusheng (Indexfinger; b. 1948) and Wen Jie (b. 1963), diagnosed with schizophrenia and clinical depression, respectively. The study uncovers a lyrical voice that takes shape in the poets' illness-related content, but also in the formal aspects of the Chinese poetic tradition. I argue that the delight of writing poetry lies less in the attempt to express a subjective experience than in finding the devices and forms that integrate an individual experience into a collective form of "illness poetics." PMID- 26949212 TI - Dismemberment and the Attempt at Re-membering in R. D. Laing's The Bird of Paradise. AB - Despite renewed interest in the radical psychiatrist R. D. Laing (1927-1989), his The Bird of Paradise (1967), published in a single volume with The Politics of Experience, has received scant scholarly attention. Characterized largely as odd, it has even been read as a sign that Laing, deeply sympathetic to the mad, had himself gone crazy. Eschewing biographical criticism, I focus rather on the problem of assigning Bird to a genre (and the significance of this difficulty). Finding the capacious prose poem genre the most appropriate category, I take Bird seriously as a complex literary text, offer an overview of it, relate it to Politics and 1960s counterculture, and attend to Laing's ambivalent attitude towards writing. Bird, I argue, represents an attempt-albeit an ultimately unsuccessful one-at overcoming what Laing understands as alienated self-division ("dismemberment") through a reaching towards wholeness (a "re-membering" of the self). PMID- 26949214 TI - Magnetic reduced graphene oxide functionalized with beta-cyclodextrin as magnetic solid-phase extraction adsorbents for the determination of phytohormones in tomatoes coupled with high performance liquid chromatography. AB - A beta-cyclodextrin (beta-CD) functionalized magnetic reduced graphene oxide composite (Fe3O4/RGO@beta-CD) has been prepared and its application as a selective adsorbent for the determination of the two naphthalene-derived phytohormones (1-naphthalene acetic acid (NAA) and 2-naphthoxyacetic acid (2 NOA)) has been investigated. Magnetic reduced graphene oxide composite (Fe3O4/RGO) was first synthesized via in situ chemical precipitation method and then beta-CD was applied to further functionalize the resultant Fe3O4/RGO composite. The as-prepared Fe3O4/RGO@beta-CD was characterized by Fourier transform infrared spectrometry (FT-IR), X-ray diffraction (XRD) and vibrating sample magnetometer (VSM). Compared with Fe3O4/RGO, the as-prepared Fe3O4/RGO@beta-CD showed better molecular selectivity and higher extraction efficiency for NAA and 2-NOA by dint of the size complementarity brought by the introduction of beta-CD. Response surface methodology (RSM), a multivariate experimental design technique, was used to optimize experimental parameters affecting the extraction efficiency in detail. Under the optimal conditions, good performance data was obtained. The calibration curves were linear over the concentration ranging from 2 to 600 ngg(-1) with correlation coefficients (R(2)) between 0.9995 and 0.9997 for all the analytes. The limits of detection (LODs) were 0.67 ngg(-1) for both NAA and 2-NOA. The intra- and inter-day relative standard deviations (RSDs) were less than 6.02% and 7.34%, respectively. The recoveries ranged from 91.45% to 95.89%. Taken together, the proposed method was an efficient pretreatment and enrichment procedure and could be successfully applied for selective extraction and determination of naphthalene-derived phytormones in complex matrices. PMID- 26949215 TI - A water resistant solid-phase microextraction fiber with high selectivity prepared by a metal organic framework with perfluorinated pores. AB - A novel solid-phase microextraction (SPME) fiber was fabricated by the construction of fluorous metal organic frameworks (FMOF) and a polyimide (PI) composite strategy. As an auxiliary material, PI was expected to help FMOF particles form well-knit film on the surface of stainless steel wire and reinforce the coating, and FMOF was expected to afford a special structure to absorb, extract and enrich. Furthermore, it was explored for the headspace SPME (HS-SPME) of six volatile aromatic compounds (VACs) from water samples followed by gas chromatographic (GC) separation with flame ionization detection. Under the optimized conditions, the fiber afforded wide linear ranges (1-1000 MUgL(-1)), low detection limits (0.15-0.9 MUgL(-1)) and acceptable repeatability (<4.6%) and reproducibility (<7.3%). The FMOF@PI coated fiber not only offered large enhancement factors for benzene (1227) but also exhibited high extraction selectivity for benzene to other benzene homologues, hydrocarbons and phenols; for example, the extraction ratio of benzene to toluene, n-hexane and phenol could be as high as 10.2, 64.1 and 32.3, respectively. Moreover, the FMOF@PI coated fiber afforded good thermal, water and organic solvent stabilities, and a long lifetime (over 200 times). The developed method was successfully applied to the determination of VACs in wastewater samples. PMID- 26949216 TI - Predicting the Sorption of Aromatic Acids to Noncarbonized and Carbonized Sorbents. AB - Approaches based on the octanol-water partition coefficient are commonly used to describe sorption of neutral organic compounds in environmental systems, but they are not suitable for organic acids, which can dissociate to form anions. We here investigate the applicability of an alternative approach based on the pH dependent distribution ratio (DOW) to describe sorption of aromatic acids to sorbents representing different degrees of carbonization. Sorption isotherms for four structurally similar acids ((2,4-dichlorophenoxy)acetic acid (2,4-D), 4 chloro-2-15 methylphenoxy)acetic acid (MCPA), 4-(2,4-dichlorophenoxy)butanoic16 acid (2,4-DB), and 5-chloro-2-(2,4-dichlorophenoxy)phenol (triclosan)) were measured for 15 sorbents: fresh and carbonized wood shavings, pig manure, sewage sludge, carbon nanotubes, and activated carbon. Dissociation greatly affected the sorption of all acids. Sorption coefficients measured in the high pH range indicated that sorption of the anions ranged over several orders of magnitude and should not be neglected. Sorption trends for all sorbates and carbonized sorbents could be very well described by a single regression equation that included DOW of the sorbate and the specific surface area of the sorbent (R(2) > 0.89). PMID- 26949217 TI - Mutant Tau knock-in mice display frontotemporal dementia relevant behaviour and histopathology. AB - Models of Tau pathology related to frontotemporal dementia (FTD) are essential to determine underlying neurodegenerative pathologies and resulting tauopathy relevant behavioural changes. However, existing models are often limited in their translational value due to Tau overexpression, and the frequent occurrence of motor deficits which prevent comprehensive behavioural assessments. In order to address these limitations, a forebrain-specific (CaMKIIalpha promoter), human mutated Tau (hTauP301L+R406W) knock-in mouse was generated out of the previously characterised PLB1Triple mouse, and named PLB2Tau. After confirmation of an additional hTau species (~60kDa) in forebrain samples, we identified age dependent progressive Tau phosphorylation which coincided with the emergence of FTD relevant behavioural traits. In line with the non-cognitive symptomatology of FTD, PLB2Tau mice demonstrated early emerging (~6months) phenotypes of heightened anxiety in the elevated plus maze, depressive/apathetic behaviour in a sucrose preference test and generally reduced exploratory activity in the absence of motor impairments. Investigations of cognitive performance indicated prominent dysfunctions in semantic memory, as assessed by social transmission of food preference, and in behavioural flexibility during spatial reversal learning in a home cage corner-learning task. Spatial learning was only mildly affected and task-specific, with impairments at 12months of age in the corner learning but not in the water maze task. Electroencephalographic (EEG) investigations indicated a vigilance-stage specific loss of alpha power during wakefulness at both parietal and prefrontal recording sites, and site-specific EEG changes during non-rapid eye movement sleep (prefrontal) and rapid eye movement sleep (parietal). Further investigation of hippocampal electrophysiology conducted in slice preparations indicated a modest reduction in efficacy of synaptic transmission in the absence of altered synaptic plasticity. Together, our data demonstrate that the transgenic PLB2Tau mouse model presents with a striking behavioural and physiological face validity relevant for FTD, driven by the low level expression of mutant FTD hTau. PMID- 26949218 TI - Soluble prion protein and its N-terminal fragment prevent impairment of synaptic plasticity by Abeta oligomers: Implications for novel therapeutic strategy in Alzheimer's disease. AB - The pathogenic process in Alzheimer's disease (AD) appears to be closely linked to the neurotoxic action of amyloid-beta (Abeta) oligomers. Recent studies have shown that these oligomers bind with high affinity to the membrane-anchored cellular prion protein (PrP(C)). It has also been proposed that this binding might mediate some of the toxic effects of the oligomers. Here, we show that the soluble (membrane anchor-free) recombinant human prion protein (rPrP) and its N terminal fragment N1 block Abeta oligomers-induced inhibition of long-term potentiation (LTP) in hippocampal slices, an important surrogate marker of cognitive deficit associated with AD. rPrP and N1 are also strikingly potent inhibitors of Abeta cytotoxicity in primary hippocampal neurons. Furthermore, experiments using hippocampal slices and neurons from wild-type and PrP(C) null mice (as well as rat neurons in which PrP(C) expression was greatly reduced by gene silencing) indicate that, in contrast to the impairment of synaptic plasticity by Abeta oligomers, the cytotoxic effects of these oligomers, and the inhibition of these effects by rPrP and N1, are independent of the presence of endogenous PrP(C). This suggests fundamentally different mechanisms by which soluble rPrP and its fragments inhibit these two toxic responses to Abeta. Overall, these findings provide strong support to recent suggestions that PrP based compounds may offer new avenues for pharmacological intervention in AD. PMID- 26949219 TI - Mechanism of the Ferrocyanide-Iodate-Sulfite Oscillatory Chemical Reaction. AB - Existing models of the ferrocyanide-iodate-sulfite (FIS) reaction seek to replicate the oscillatory pH behavior that occurs in open systems. These models exhibit significant differences in the amplitudes and waveforms of the concentration oscillations of such intermediates as I(-), I3(-), and Fe(CN)6(3-) under identical conditions and do not include several experimentally found intermediates. Here we report measurements of sulfite concentrations during an oscillatory cycle. Knowing the correct concentration of sulfite over the course of a period is important because sulfite is the main component that determines the buffer capacity, the pH extrema, and the amount of oxidizer (iodate) required for the transition to low pH. On the basis of this new result and recent experimental findings on the rate laws and intermediates of component processes taken from the literature, we propose a mass action kinetics model that attempts to faithfully represent the chemistry of the FIS reaction. This new comprehensive mechanism reproduces the pH oscillations and the periodic behavior in [Fe(CN)6(3 )], [I3(-)], [I(-)], and [SO3(2-)]T with characteristics similar to those seen in experiments in both CSTR and semibatch arrangements. The parameter ranges at which stationary and oscillatory behavior is exhibited also show good agreement with those of the experiments. PMID- 26949220 TI - Impact of an ICU EEG monitoring pathway on timeliness of therapeutic intervention and electrographic seizure termination. AB - OBJECTIVES: We aimed to determine whether implementation of a structured multidisciplinary electroencephalography (EEG) monitoring pathway improved the timeliness of administration of antiseizure medication in response to electrographic seizures in encephalopathic critically ill children. METHODS: A multidisciplinary team developed a pathway to standardize EEG monitoring and seizure management in encephalopathic critically ill children, aiming to decrease the time from electrographic seizure onset to antiseizure medication administration. Data were collected to inform the team of improvement opportunities, which were then provided by an institutional pathway, staff education, and streamlined communication. Measurements were obtained before and after pathway implementation to assess for improvement. RESULTS: We collected data on 41 patients before and 21 after pathway implementation. There were no differences between the baseline and pathway groups in demographic characteristics, acute encephalopathy etiologies, or antiseizure medications utilized. The median duration [interquartile range, IQR] from seizure onset to antiseizure medication administration was shorter for patients treated with the pathway (64 min [50, 101]) compared to patients treated prior to pathway implementation (139 min [71, 189]; p = 0.0006). The median [IQR] interval from seizure onset to antiseizure medication order was shorter for the pathway group (31 min [20, 49]) than the baseline group (71 min [33, 131]; p = 0.003). The median [IQR] interval from antiseizure medication order to administration was shorter for the pathway group (30 min [19, 40]) than the baseline group (40 min [17, 68]) (p = 0.047). Seizure termination was more likely to occur following initial antiseizure medication administration in the pathway than baseline group (67% vs. 27%, p = 0.002). SIGNIFICANCE: Implementation of the pathway resulted in a significant reduction in the duration between electrographic seizure onset and antiseizure medication administration, and a significant increase in the rate of electrographic seizure termination following an initial antiseizure medication. Further study is needed to determine whether these changes are associated with improved outcomes. PMID- 26949221 TI - Model-based reconstruction for real-time phase-contrast flow MRI: Improved spatiotemporal accuracy. AB - PURPOSE: To develop a model-based reconstruction technique for real-time phase contrast flow MRI with improved spatiotemporal accuracy in comparison to methods using phase differences of two separately reconstructed images with differential flow encodings. METHODS: The proposed method jointly computes a common image, a phase-contrast map, and a set of coil sensitivities from every pair of flow compensated and flow-encoded datasets obtained by highly undersampled radial FLASH. Real-time acquisitions with five and seven radial spokes per image resulted in 25.6 and 35.7 ms measuring time per phase-contrast map, respectively. The signal model for phase-contrast flow MRI requires the solution of a nonlinear inverse problem, which is accomplished by an iteratively regularized Gauss-Newton method. Aspects of regularization and scaling are discussed. The model-based reconstruction was validated for a numerical and experimental flow phantom and applied to real-time phase-contrast MRI of the human aorta for 10 healthy subjects and 2 patients. RESULTS: Under all conditions, and compared with a previously developed real-time flow MRI method, the proposed method yields quantitatively accurate phase-contrast maps (i.e., flow velocities) with improved spatial acuity, reduced phase noise and reduced streaking artifacts. CONCLUSION: This novel model-based reconstruction technique may become a new tool for clinical flow MRI in real time. Magn Reson Med 77:1082-1093, 2017. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 26949222 TI - A systematic method to identify modulation of transcriptional regulation via chromatin activity reveals regulatory network during mESC differentiation. AB - Chromatin regulators (CRs) are crucial for connecting the chromatin level and transcriptome level by modulating chromatin structures, establishing, and maintaining epigenetic modifications. We present a systematic method to identify MOdulation of transcriptional regulation via CHromatin Activity (MOCHA) from gene expression data and demonstrate its advantage in associating CRs to their chromatin localization and understand CRs' function. We first re-construct the CRs modulation network by integrating the correlation and conditional correlation concepts. Then we quantify the chromatin activity as hidden variable in network by integrating the upstream and downstream information. We applied MOCHA to systematically explore the interplay of CRs, TFs, and target genes in mouse embryonic stem cells (ESC). As a result, MOCHA identified 420 chromatin regulators with modulation preference, including Pou5f1 and Eed. We found that BAF complex, NuRD complex, and polycomb-group proteins, regulate the delicate balance between pluripotency and differentiation by modulating key TFs including Klf4, Tcf3, and Max; NuRD complex members Mbd3 and Hdac1 may modulate Klf4 to achieve its dual functional roles in pluripotent and differentiation stages;Imprinted gene H19 and Igf2 are modulated by DNA methylation, histone acetylation, and insulator CTCF. Finally, we analyzed CR's combinational modulation pattern by constructing a CR-CR interaction network. PMID- 26949223 TI - Diagnosis and Management of Rhinosinusitis: Highlights from the 2015 Practice Parameter. AB - Rhinosinusitis is a commonly diagnosed disease in the USA. Rhinosinusitis is classified as acute, recurrent, or chronic (with or without nasal polyps). While acute rhinosinusitis is diagnosed by history and physical examination, chronic rhinosinusitis and recurrent acute rhinosinusitis are diagnosed based on symptoms and the presence of disease on either a sinus CT scan and/or endoscopy. Management of uncomplicated acute rhinosinusitis includes analgesics, saline irrigation, and/or intranasal steroids. Antibiotics and intranasal steroids are recommended for acute bacterial rhinosinusitis. Intranasal and oral steroids with antibiotics are recommended to treat chronic rhinosinusitis although the evidence for antibiotics is weak. Biologics such as omalizumab and mepolizumab are being investigated for the treatment of chronic rhinosinusitis with nasal polyps. Surgery may be indicated in management of refractory chronic rhinosinusitis and rarely for acute bacterial rhinosinusitis. This review discusses highlights of the updated 2014 practice parameter and up-to-date evidence from other literature sources. PMID- 26949225 TI - Neocortical neurogenesis and the etiology of autism spectrum disorder. AB - Researchers have now identified many highly penetrant genetic risk factors for autism spectrum disorder (ASD). Some of these genes encode synaptic proteins, lending support to the hypothesis that ASD is a disorder of synaptic homeostasis. Less attention, however, has been paid to the genetic risk factors that converge on events that precede synaptogenesis, including the proliferation of neural progenitor cells and the migration of neurons to the appropriate layers of the developing neocortex. Here I review this evidence, focusing on studies of mutant mouse phenotypes, human postmortem data, systems biological analyses, and non genetic risk factors. These findings highlight embryonic neurogenesis as a potentially important locus of pathology in ASD. In some instances, this pathology may be driven by alterations in chromatin biology and canonical Wnt signaling, which in turn affect fundamental cellular processes such as cell-cycle length and cell migration. This view of ASD suggests the need for a better understanding of the relationship between variation in neuron number, laminar composition, and the neural circuitry most relevant to the disorder. PMID- 26949226 TI - Mature granule cells of the dentate gyrus--Passive bystanders or principal performers in hippocampal function? AB - The dentate gyrus is the main entrance of highly processed information to the hippocampus which derives from associative cortices and it is one of the few privileged areas in the brain where adult neurogenesis occurs. This creates the unique situation that neurons of diverse maturation stages are part of one neuronal network at any given point in life. While recently adult-born cells have a low induction threshold for long-term potentiation several studies suggest that following maturation granule cells are poorly excitable and they exhibit reduced Hebbian synaptic plasticity to an extent that it was even suggested that they functionally retire. Here, we review the functional properties of mature granule cells and discuss how plasticity of intrinsic excitability and alterations in excitation-inhibition balance might impact on their role in hippocampal information processing. PMID- 26949227 TI - Nanocellulose 3, 5-Dimethylphenylcarbamate Derivative Coated Chiral Stationary Phase: Preparation and Enantioseparation Performance. AB - Nanocrystalline cellulose (NCC) with high surface area and high ordered crystalline structure was prepared from microcrystalline cellulose (MCC) under the hydrolysis of sodium hypochlorite. NCC was further reacted with 3,5 dimethylphenyl isocyanate to obtain the nanocellulose derivative, and then coated successfully on the surface of silica gel to a prepared NCC-coated chiral stationary phase (CSP) as a new kind of chiral separation material. Similarly, MCC derivative-coated CSP was also prepared as contrast. The chiral separation performance of NCC-based CSP was evaluated and compared with MCC-based CSP by high-performance liquid chromatography. Moreover, the effects of the alcohol modifiers, mobile phase additives, and flow rates on chiral separations were investigated in detail. The results showed that 10 chiral compounds were separated on NCC-based CSP with better peak shape and higher column efficiency than MCC-based CSP, which confirmed that NCC-based CSP was a promising packing material for the resolution of chiral compounds.Chirality 28:376-381, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26949228 TI - Hemolymphangioma in the posterior mediastinum: a case report and literature review. AB - Hemolymphangioma of the thorax is a very rare benign tumor. There were only three reports of this disease until 2016. Herein, we report a case of hemolymphangioma of the thorax with pleural effusion. A 57-year-old woman had been admitted to hospital. Computed tomography also demonstrated a heterogenous mass in the posterior mediastinum and suspected invasion to the artery. Surgery was performed. The mediastinal tumor was soft. The pathological diagnosis was a hemolymphangioma of the posterior mediastinum. Her postoperative course was uneventful and she was discharged on the fifth day after surgery. Major symptoms are chest tightness and short of breath due to the tumor and pleural effusion. However, we experienced a case of hemolymphangioma of the thorax with pleural effusion. This disease is a very rare entity, but should be considered when patients have mass and pleural effusion in the thorax. PMID- 26949224 TI - Social dysfunction after pediatric traumatic brain injury: A translational perspective. AB - Social dysfunction is common after traumatic brain injury (TBI), contributing to reduced quality of life for survivors. Factors which influence the development or persistence of social deficits after injury remain poorly understood, particularly in the context of ongoing brain maturation during childhood and adolescence. Aberrant social interactions have recently been modeled in adult and juvenile rodents after experimental TBI, providing an opportunity to gain new insights into the underlying neurobiology of these behaviors. Here, we review our current understanding of social dysfunction in both humans and rodent models of TBI, with a focus on brain injuries acquired during early development. Modulators of social outcomes are discussed, including injury-related and environmental risk and resilience factors. Disruption of social brain network connectivity and aberrant neuroendocrine function are identified as potential mechanisms of social impairments after pediatric TBI. Throughout, we highlight the overlap and disparities between outcome measures and findings from clinical and experimental approaches, and explore the translational potential of future research to prevent or ameliorate social dysfunction after childhood TBI. PMID- 26949229 TI - Lasing in silicon-organic hybrid waveguides. AB - Silicon photonics enables large-scale photonic-electronic integration by leveraging highly developed fabrication processes from the microelectronics industry. However, while a rich portfolio of devices has already been demonstrated on the silicon platform, on-chip light sources still remain a key challenge since the indirect bandgap of the material inhibits efficient photon emission and thus impedes lasing. Here we demonstrate a class of infrared lasers that can be fabricated on the silicon-on-insulator (SOI) integration platform. The lasers are based on the silicon-organic hybrid (SOH) integration concept and combine nanophotonic SOI waveguides with dye-doped organic cladding materials that provide optical gain. We demonstrate pulsed room-temperature lasing with on chip peak output powers of up to 1.1 W at a wavelength of 1,310 nm. The SOH approach enables efficient mass-production of silicon photonic light sources emitting in the near infrared and offers the possibility of tuning the emission wavelength over a wide range by proper choice of dye materials and resonator geometry. PMID- 26949230 TI - Does multiple paternity influence offspring disease resistance? AB - It has been suggested that polyandry allows females to increase offspring genetic diversity and reduce the prevalence and susceptibility of their offspring to infectious diseases. We tested this hypothesis in wild-derived house mice (Mus musculus) by experimentally infecting the offspring from 15 single- and 15 multiple-sired litters with two different strains of a mouse pathogen (Salmonella Typhimurium) and compared their ability to control infection. We found a high variation in individual infection resistance (measured with pathogen loads) and significant differences among families, suggesting genetic effects on Salmonella resistance, but we found no difference in prevalence or infection resistance between single- vs. multiple-sired litters. We found a significant sex difference in infection resistance, but surprisingly, males were more resistant to infection than females. Also, infection resistance was correlated with weight loss during infection, although only for females, indicating that susceptibility to infection had more harmful health consequences for females than for males. To our knowledge, our findings provide the first evidence for sex-dependent resistance to Salmonella infection in house mice. Our results do not support the hypothesis that multiple-sired litters are more likely to survive infection than single sired litters; however, as we explain, additional studies are required before ruling out this hypothesis. PMID- 26949231 TI - Dormancy release and flowering time in Ziziphus jujuba Mill., a "direct flowering" fruit tree, has a facultative requirement for chilling. AB - In deciduous fruit trees, the effect of chilling on flowering has mostly been investigated in the "indirect flowering" group, characterized by a period of rest between flower bud formation and blooming. In the present study, we explored the effects of chilling and chilling deprivation on the flowering of Ziziphus jujuba, a temperate deciduous fruit tree belonging to the "direct flowering" group, in which flower bud differentiation, blooming and fruit development occur after dormancy release, during a single growing season. Dormancy release, vegetative growth and flowering time in Z. jujuba cv. Ben-Li were assessed following several treatments of chilling. Chilling treatments quantitatively decreased the timing of vegetative bud dormancy release, thereby accelerating flowering, but had no effect on the time from dormancy release to flowering. Trees grown at a constant temperature of 25 degrees C, without chilling, broke dormancy and flowered, indicating the facultative character of chilling in this species. We measured the expression of Z. jujuba LFY and AP1 homologues (ZjLFY and ZjAP1). Chilling decreased ZjLFY expression in dormant vegetative buds but had no effect on ZjAP1expression, which reached peak expression before dormancy release and at anthesis. In conclusion, chilling is not obligatory for dormancy release of Z. jujuba cv. Ben-Li vegetative buds. However, the exposure to chilling during dormancy does accelerate vegetative bud dormancy release and flowering. PMID- 26949232 TI - What are the Main Physical Functioning Factors Associated With Falls Among Older People With Different Perceived Fall Risk? AB - BACKGROUND AND PURPOSE: Fall risk perceptions may influence the judgement over physical and functional competencies to avoid falls. However, few studies have explored the physical functioning characteristics associated with falls among older people with low perceived fall risk. This study aimed to identify the prevalence of falls and physical functioning factors associated with falling among community-dwelling older adults with low and high perceived fall risk. METHODS: We conducted a cross-sectional population based study with 773 community dwelling elders. Perceived fall risk was investigated using Falls Efficacy Scale International. We considered fallers those who reported at least one fall in the previous 12 months. Physical functioning measures used were grip strength, usual gait speed, sit-to-stand test, five step test, timed up and go test, one-legged stance test, anterior and lateral functional reach test. RESULTS: At least one fall was reported by 103 (30%) participants with low perceived fall risk and by 196 (46%) participants with high perceived fall risk. The odds of falling were lower among those with greater grip strength and with a greater stance time in one-legged test, and the odds of falling among elders with high perceived fall risk were higher among those who took more time in performing the five step test. DISCUSSION: We believe that our results highlight the need of not neglecting the risk of falls among active older adults with low perceived fall risk, particularly in those elders that show reduced stability in a small base of support and a lower leg strength. In addition, we suggest that elders with high perceived fall risk should be assessed using anticipatory postural adjustment tests. Particularly, our results may help physiotherapists to identify eligible elders with different perceptions of fall risk for tailored interventions aimed at reducing falls. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26949233 TI - Treatment needs and predictive capacity of explanatory variables of oral disease in young athletes with an intellectual disability in Europe and Eurasia. AB - AIM: To evaluate the oral condition and treatment needs of young athletes with intellectual disability (ID) from 53 countries of Europe and Eurasia who participated in the Special Olympics European Games held in Antwerp, October 2014. METHODS: A cross- sectional study was undertaken with data collected through standardised procedures from consenting athletes under 21 years of age. Oral hygiene habits, reports of oral pain and presence of gingival signs, sealants, untreated caries and missing teeth were recorded. STATISTICS: Data analysis was performed in SPSS to produce descriptive statistics and explanatory variables for untreated decay, and gingival signs of disease were tested with Multilevel Generalized Linear Mixed Models. RESULTS: Five hundred three athletes participated in this study (mean age 17 yrs). Untreated decay was recorded in 33.4% of the participants and 38.7% of them had signs of gingival disease. Absence of untreated decay was associated with lower chances of gingival signs, while absence of sealants was related with higher chances of untreated decay. CONCLUSIONS: There is consistent evidence of persistent need for increased promotion of oral health, as well as preventive and restorative treatment in young athletes with ID in Europe and Eurasia. Due to the limited predictive capacity of the studied variables for oral disease, further studies including other related factors are needed. PMID- 26949234 TI - Evaluation of shear bond strength, penetration ability, microleakage and remineralisation capacity of glass ionomer-based fissure sealants. AB - AIM: The aim of this study was to evaluate the bond strength, penetration ability, microleakage, and remineralisation capacity of glass ionomer-based fissure sealant materials. MATERIALS AND METHODS: In this study, three glass ionomer-based fissure sealants were evaluated (Fuji Triage, Fuji VII EP, and GCP Glass Seal). A dye-penetration test was performed to evaluate microleakage under a stereomicroscope. The materials were applied to occlusal tooth surfaces, and bucco-lingual sections (1 mm width) were assessed to evaluate the penetration ability. Shear bond strength of tested materials was assessed using a universal testing machine. Finally, the remineralisation capacities of the materials were evaluated with EDS. RESULTS: The Fuji Triage exhibited the lowest microleakage and unfilled area proportion (p<0.05). The highest shear bond strength was calculated with Fuji VII EP (p<0.05). The fluoride content for all treatment groups was significantly different when remineralisation values were compared to demineralisation (p<0.05). CONCLUSION: Both the Fuji Triage and Fuji VII EP yielded compatible and satisfactory results and all fissure sealants used in this study are sufficient as anti-caries agents. PMID- 26949235 TI - Endodontic treatment of trauma-induced necrotic immature teeth using a tricalcium silicate-based bioactive cement. A report of 3 cases with 24-month follow-up. AB - BACKGROUND: Pulp necrosis is the second most common complication after traumatic dental injuries and occurs mostly within the first 6-24 months of follow-up period, depending on the type of dental trauma. CASE REPORT: Three cases with endodontic treatment scenarios of trauma-induced necrosis in immature permanent anterior teeth. All cases were treated by full canal obturation with Biodentine (Septodont, Saint Maur des Fosses, France) and documented for a follow-up period of 24 months. CONCLUSION: Copious irrigation of the root canal, minimal mechanical preparation, use of calcium hydroxide for a short period of time and complete obturation of these immature teeth with a bioactive cement with superior mechanical properties such as Biodentine were the prominent reasons attributed to the success of these three cases. PMID- 26949236 TI - Prediction model of regional orthodontic workforce needs, using Greece as an example. AB - AIM: To develop a theoretical aepidemiological model for the prediction of orthodontic workforce needs, based on regional orthodontic treatment need. MATERIALS AND METHODS: Data were collected for the number of children between the ages of 8-11 years attending primary schools in Greece, within each regional division. Treatment need of the children was estimated using the Index of Orthodontic Treatment Need (IOTN). Demographics of practicing orthodontists in Greece were also collected. Based on the distribution of orthodontists and the number of children per region who would potentially receive orthodontic treatment (IOTN 3-5), the presence and distribution of orthodontic manpower was evaluated. RESULTS: Overall orthodontic manpower is sufficient for Greece's needs with an excess of 55 orthodontists. Distribution however is not uniform, and this ranges from a large underrepresentation of orthodontists in the Ionian Islands (47% of those required) to an overrepresentation in the Attica region (183% of those required). CONCLUSION: Based on the present theoretical model, Greece has an adequate overall orthodontic workforce for coverage of the population needs, but with large regional variations indicating that some regions have a surplus while others a shortage of orthodontists. The present model seems suitable for the calculation of regional orthodontic workforce coverage of a population. PMID- 26949237 TI - Prevalence of occlusal traits and orthodontic treatment need in 14 year-old adolescents in Northeast Italy. AB - AIM: Studies on prevalence of malocclusion support the planning and provision of public dental services. The aim of the study was to assess the prevalence of malocclusion and occlusal traits in adolescents aged 14 years from public secondary schools in the area of Health District n.15 - Veneto region, Italy. MATERIALS AND METHODS: STUDY DESIGN: Cross-sectional survey. METHODS: Out of a randomly selected sample of 1187 subjects, 444 adolescents (55% males, 45% females) were evaluated in the school settings according to the criteria adopted by Brunelle et al. [1996]. Alginate impressions were then taken for 380 students together with a wax bite. The occlusal traits of the cast were analysed and IOTN was established. RESULTS: The most common occlusal traits measured on casts were overjet >3 mm (48%), overbite >3 mm (39%), midline misalignment (32%), crowding (30%), 99% of the sample showed at least one occlusal trait. Class I molar relationship prevailed (75.5%) and the prevalence of molar asymmetries was 21.9%. The prevalence of anterior and posterior crossbite and open bite was significantly higher in females, while the mean values of overjet and overbite were higher in males. The distribution of IOTN in the study population showed that only 49.5% had no or little need of treatment, and more than one third (35.8%) were assigned a 4 or 5 score. STATISTICS: Descriptive statistics are expressed as a percentage (+/- confidence interval) or mean +/- standard deviation, according to the nature of the variable. CONCLUSIONS: These outcomes indicate a high prevalence of the aforementioned occlusal traits and also a high need for orthodontic treatment among adolescents in Northeast Italy. PMID- 26949238 TI - Anterior open-bite and sucking habits in Italian preschool children. AB - AIM: To evaluate the consequences of prolonged sucking habits on the development of the orofacial complex in deciduous dentition. MATERIALS AND METHODS: A cross sectional study was carried out involving 235 preschool children. A questionnaire for children parents and clinical examinations were carried out by calibrated blinded examiners. The chi-square test and the T-Student test were used for statistical analysis. RESULTS: The prevalence of non-nutritive sucking habits (NNSH) in the sample was 74%. Anterior open-bite (AOB) was detected in 18%, and it was significantly related to non-nutritive sucking habits, bottle-feeding (only in the 3-year-old group) and persistent use of pacifier (p<0.05). CONCLUSIONS: NNSH and type of feeding were important contributing factors in the development of anterior open-bite in deciduous dentition. PMID- 26949239 TI - Evaluation of masseter muscle in different vertical skeletal patterns in growing patients. AB - AIM: The present study aimed to evaluate the relationship between masseter size, maxillary intermolar width and craniofacial vertical skeletal pattern. MATERIALS AND METHODS: STUDY DESIGN: The study followed a prospective longitudinal design and enrolled 61 subjects (30 males and 31 females), 9-14 years of age (mean age 11.5) at 2-3 CVM stage. The participants were divided into three groups based on their vertical skeletal pattern which was estimated using the Frankfurt mandibular plane angle: low-angle group (L-A), normal-angle group (N-A), high angle group (H-A). An additional gender-based distinction was made. Maxillary intermolar width was measured on the maxillary cast of each patient by means of an electronic caliper; masseter volume was estimated by using magnetic resonance (MR) and masseter thickness was measured by means of ultrasonography (US). The US registrations were performed during the relaxation state (RS) and the maximum voluntary contraction (MVC) of the muscle. The indipendent samples T- test was used for sex comparisons; the analysis of variance test (ANOVA) was used to evaluate the differences between the three groups in males and females, and the Pearson r correlation coefficient was employed to assess the correlation between maxillary intermolar width and masseter volume. RESULTS AND CONCLUSION: Maxillary intermolar width, masseter volume and thickness showed significant gender differences; all the tested variables decreased significantly according to the facial vertical pattern, with greater values in females, especially in low- and normal-angle subjects; maxillary intermolar width and masseter volume showed significant correlations, higher in females. PMID- 26949240 TI - Clinical evaluation of specific oral and salivary findings of coeliac disease in eastern Turkish paediatric patients. AB - AIM: The aim of this study was to evaluate enamel defects (EDs), recurrent aphthous stomatitis (RAS) and salivary findings in Eastern Turkish children with coeliac disease (CD), and to compare the results with healthy children. MATERIALS AND METHODS: STUDY DESIGN: 70 children (35 CD patients and 35 healthy patients) aged between 5 to 15 years were included in this study. Intraoral examination was performed; saliva specimens were collected for analysis. Oral health conditions, tooth brushing frequency, saliva pH level, flow rate and buffering capacity were recorded. Kruskal-Wallis test was used for comparison of DMFT and dft index. Chi squared test was used for the data of oral health status. The significance level was set at p = 0.05. RESULTS: EDs were seen in 54.3% (19 patients) of the CD patients and more frequently than the controls (p < 0.05). Regarding RAS, 31.4% (11 patients) of the CD patients and none of control group had aphthous ulcers (p < 0.05). Salivary flow rate and buffering capacity were lower in CD patients (p < 0.05). CONCLUSION: The oral examination could be a significant contribution to the detection of CD. Especially paediatric dentists can play an important role in the early diagnosis and may help paediatricians about CD. PMID- 26949241 TI - A survey of oral and dental health in children on home parenteral nutrition. AB - AIM: To determine oral and dental problems in children who are receiving long term intravenous nutrition at home. MATERIALS AND METHODS: DESIGN: Children who had been at home on parenteral nutrition (PN) for a period of at least 3 months were recruited from the intestinal failure clinic database of a large tertiary nutrition centre. The parents were contacted by email, face to face or telephone and asked to fill in a questionnaire. Information about the PN, enteral nutrition, type of feeding in infancy, weaning, dental and oral problems was collected. Results A total of 35 patients were identified, of which 28 participated in the study. The age of the children ranged from 1-18 years with a median age of 5.5 years. The average duration of PN administration was 4.3 years. Just over half were also orally fed and three quarters had a history of breast and/or bottle feeding in infancy. Around 60% of children reported oral problems including teeth staining (29%), gum infections (11%), teeth decay and delayed dentition (16%). 68% regularly visited the dentist at 2-12 monthly intervals. CONCLUSION: In comparison to the general UK paediatric population, oral and dental problems occurred less commonly in our study group of children on HPN, unlike adult patients on intravenous nutrition where poor oral health was much more prominent compared to the general public. However the overall prevalence was similar in the adult and paediatric age group receiving long-term HPN highlighting the need for specific health advice in this patient group. PMID- 26949242 TI - MicroCT study on the enamel mineral density of primary molars. AB - AIM: The aim of this study is to report on the mineral density of the enamel of primary molars related to the age of the child and to compare the mineral density of sound and carious enamel in those molars. MATERIALS AND METHODS: This study included 23 children and 41 extracted primary molars. The primary molars of 21 children met all of the inclusion criteria, and these were studied and scanned using microCT. The teeth were embedded in Impregum (3M ESPE) and stored in a solution of tap water with thymol crystals. Sixteen primary molars from 7 children were used to compare the mineral density in sound and carious areas, and 13 primary molars from 11 children were used for the comparison between mineral density and time in situ. RESULTS: A statistically significant difference (31%) was found between the mineral density in carious enamel and sound enamel (p = 0.0006). In addition, a significant relationship was observed between the mineral density of sound enamel and the time the teeth had been in situ (r = 0.698). We also found two teeth with radiolucencies in the dentin with the enamel clinically showing only a non-cavitated carious lesion in the enamel. No significant differences were found between the mean mineral density in sound enamel surfaces and unaffected areas in surfaces of molars with enamel caries (p = 0.4373). CONCLUSION: Local and general differences in enamel mineralisation are presented. Post-eruptive maturation seems to be present not only in permanent teeth but also in primary molars. Carious enamel has significantly less mineral density than clinically sound enamel. PMID- 26949243 TI - Comparative study of dental anomalies assessed with panoramic radiographs of Down syndrome and non-Down syndrome patients. AB - AIM: The aim of this study was to compare the prevalence of dental anomalies from panoramic radiographs of age-matched individuals with and without Down Syndrome (DS). MATERIALS AND METHODS: STUDY DESIGN: This is a retrospective cross sectional study. A group of 41 patients (19 female and 22 male) with Down Syndrome (DS), mean age 10.6 +/- 1.4 and a control group of 42 non- DS patients (26 female and 16 male), mean age 11.1 +/- 1.3 were studied. METHODS: This study examined the medical history and a panoramic radiograph of each patient. The dental anomalies studied were agenesis of permanent teeth (except third molars), size and shape maxillary lateral anomalies and maxillary canine eruption path anomalies. STATISTICS: The groups were compared using Mann-Whitney and Wilcoxon non-parametric tests (p<0.05). Rho Spearman correlation coefficient was applied for associations. Results Agenesis of one permanent tooth was found in 73.17% of DS subjects and two or more permanent teeth in more than 50% (p<0.001). Maxillary lateral incisor was the most frequently absent tooth followed by mandibular second premolar, mandibular lateral incisor, maxillary second premolar and mandibular central incisor. No significant differences were detected between maxilla and mandible on either side. No differences in gender were observed. Significant differences were found for size and shape anomalies of maxillary lateral incisors, as well as for canine eruption anomalies (p<0.05). No gender differences were observed for either variable. No association was found between these two variables in the DS group. CONCLUSIONS: More dental anomalies were present in the DS group than in the control group, which implied that DS patients need periodical dental and orthodontic supervision so as to prevent or control subsequent oral problems. PMID- 26949244 TI - Association between salivary level of infection with Streptococcus mutans/Lactobacilli and caries-risk factors in mothers. AB - AIM: Understanding factors in mothers associated with high and low salivary levels of Streptococcus mutans and Lactobacilli is an important strategy for early childhood caries prevention. Aim of the study was to identify the association between salivary levels of Streptococcus mutans/Lactobacillus and potential caries risk factors in mothers. MATERIALS AND METHODS: Cross-sectional design used a voluntary sample of 300 mothers of young children. Close-ended questions and observations were used to identify mothers' potential caries risk factors. The presence of Streptococcus mutans and Lactobacilli was determined using the CRT bacteria test (Ivoclar Vivadent). All collected information was converted into frequency and proportion describing the prevalence factor in correlation with Streptococcus mutans and Lactobacilli cariogenic bacteria levels of infection. Results Sample participants showed a high caries risk based on socioeconomic, behavioural and clinical factors. RESULTS: also showed high levels (>105) of Streptococcus mutans and Lactobacilli infections among 28% of mothers. Three factors were significantly associated with Streptococcus mutans infection: level of education, past caries experiences, and observable dental plaque, whereas, a fourth factor, frequency of daily tooth brushing, was associated to Lactobacilli infection. CONCLUSION: This study showed that easily collectible informations such as maternal level of education, frequency of daily tooth brushing and past clinical factors tend to be associated with high level of Streptococcus mutans and Lactobacilli infections in caregivers. PMID- 26949245 TI - Prevalence and aetiology of Molar-Incisor Hypomineralisation among children aged 8-10 years in Tirana, Albania. AB - AIM: Molar incisor hypomineralisation (MIH) describes the clinical appearance of enamel hypomineralisation of systemic origin affecting one or more permanent first molars (PFMs) that are frequently associated with affected incisors. The aim of this study was to investigate the prevalence and aetiology of MIH in children living in Tirana, Albania. MATERIALS AND METHODS: DESIGN: The study was conducted at the Department of Paediatric and Preventive Dentistry, Faculty of Dental Medicine, and Tirana Dental Public Health Service. A total of 1,575 school children aged 8-10 years were examined by 7 calibrated examiners (dentists) (kappa: 0.86). The Weerheijm criteria were used for the diagnosis of demarcated opacities, post-eruption breakdown, atypical restorations, and extracted PFMs due to MIH. RESULTS: Prevalence of MIH was found to be 14% (n=227). In the 227 children with MIH, tooth 36 was the most affected PFM, and tooth 46 the least affected. Tooth 21 was the most affected incisor and tooth 32 the least affected incisor by MIH. MIH(+) children had significanly more childhood diseases in the first 3 years of life (p=0.006). Among the children who used antibiotics, MIH(+) cases were 1.41 (1.06-1.87) times higher than in children who did not usedantibiotics, MIH(-) cases. CONCLUSION: MIH was found to be common among 8-10 year-old Tirana children. PMID- 26949246 TI - Oral manifestations of gastrointestinal diseases in children. Part 1: General introduction. AB - BACKGROUND: Alterations of the oral cavity are common in children: 22% of children aged less than 4 years and 44% of those aged more than 12 develop dental erosion, 9-95% of children in Europe and in North America develop gingivitis, with adolescents showing a prevalence of more than 60% (Linee guida - Ministero della Salute 2013). Alterations within the oral cavity can be the first sign of systemic diseases and may thus allow for an early diagnosis and treatment. In particular, being the oral cavity a part of the gastrointestinal system, oral alterations can be an expression of a gastrointestinal disease. CONCLUSION: A prompt recognition of sYstemic diseases through a careful examination of the oral cavity could allow the child to have appropriate investigations and to be managed in a timely fashion. PMID- 26949247 TI - Mapping body-building potential. AB - Experiments in mice shed new light on an elusive population of embryonic cells called neuromesodermal progenitors. PMID- 26949248 TI - Molecular mechanism of activation-triggered subunit exchange in Ca(2+)/calmodulin dependent protein kinase II. AB - Activation triggers the exchange of subunits in Ca(2+)/calmodulin-dependent protein kinase II (CaMKII), an oligomeric enzyme that is critical for learning, memory, and cardiac function. The mechanism by which subunit exchange occurs remains elusive. We show that the human CaMKII holoenzyme exists in dodecameric and tetradecameric forms, and that the calmodulin (CaM)-binding element of CaMKII can bind to the hub of the holoenzyme and destabilize it to release dimers. The structures of CaMKII from two distantly diverged organisms suggest that the CaM binding element of activated CaMKII acts as a wedge by docking at intersubunit interfaces in the hub. This converts the hub into a spiral form that can release or gain CaMKII dimers. Our data reveal a three-way competition for the CaM binding element, whereby phosphorylation biases it towards the hub interface, away from the kinase domain and calmodulin, thus unlocking the ability of activated CaMKII holoenzymes to exchange dimers with unactivated ones. PMID- 26949249 TI - Midbrain dopamine neurons compute inferred and cached value prediction errors in a common framework. AB - Midbrain dopamine neurons have been proposed to signal reward prediction errors as defined in temporal difference (TD) learning algorithms. While these models have been extremely powerful in interpreting dopamine activity, they typically do not use value derived through inference in computing errors. This is important because much real world behavior - and thus many opportunities for error-driven learning - is based on such predictions. Here, we show that error-signaling rat dopamine neurons respond to the inferred, model-based value of cues that have not been paired with reward and do so in the same framework as they track the putative cached value of cues previously paired with reward. This suggests that dopamine neurons access a wider variety of information than contemplated by standard TD models and that, while their firing conforms to predictions of TD models in some cases, they may not be restricted to signaling errors from TD predictions. PMID- 26949250 TI - Epigenomic landscapes of retinal rods and cones. AB - Rod and cone photoreceptors are highly similar in many respects but they have important functional and molecular differences. Here, we investigate genome-wide patterns of DNA methylation and chromatin accessibility in mouse rods and cones and correlate differences in these features with gene expression, histone marks, transcription factor binding, and DNA sequence motifs. Loss of NR2E3 in rods shifts their epigenomes to a more cone-like state. The data further reveal wide differences in DNA methylation between retinal photoreceptors and brain neurons. Surprisingly, we also find a substantial fraction of DNA hypo-methylated regions in adult rods that are not in active chromatin. Many of these regions exhibit hallmarks of regulatory regions that were active earlier in neuronal development, suggesting that these regions could remain undermethylated due to the highly compact chromatin in mature rods. This work defines the epigenomic landscapes of rods and cones, revealing features relevant to photoreceptor development and function. PMID- 26949252 TI - Further support for aneuploidy tolerance in wild yeast and effects of dosage compensation on gene copy-number evolution. AB - In our prior work by Hose et al., we performed a genome-sequencing survey and reported that aneuploidy was frequently observed in wild strains of S. cerevisiae. We also profiled transcriptome abundance in naturally aneuploid isolates compared to isogenic euploid controls and found that 10-30% of amplified genes, depending on the strain and affected chromosome, show lower-than-expected expression compared to gene copy number. In Hose et al., we argued that this gene group is enriched for genes subject to one or more modes of dosage compensation, where mRNA abundance is decreased in response to higher dosage of that gene. A recent manuscript by Torres et al. refutes our prior work. Here, we provide a response to Torres et al., along with additional analysis and controls to support our original conclusions. We maintain that aneuploidy is well tolerated in the wild strains of S. cerevisiae that we studied and that the group of genes enriched for those subject to dosage compensation show unique evolutionary signatures. PMID- 26949251 TI - The cell proliferation antigen Ki-67 organises heterochromatin. AB - Antigen Ki-67 is a nuclear protein expressed in proliferating mammalian cells. It is widely used in cancer histopathology but its functions remain unclear. Here, we show that Ki-67 controls heterochromatin organisation. Altering Ki-67 expression levels did not significantly affect cell proliferation in vivo. Ki-67 mutant mice developed normally and cells lacking Ki-67 proliferated efficiently. Conversely, upregulation of Ki-67 expression in differentiated tissues did not prevent cell cycle arrest. Ki-67 interactors included proteins involved in nucleolar processes and chromatin regulators. Ki-67 depletion disrupted nucleologenesis but did not inhibit pre-rRNA processing. In contrast, it altered gene expression. Ki-67 silencing also had wide-ranging effects on chromatin organisation, disrupting heterochromatin compaction and long-range genomic interactions. Trimethylation of histone H3K9 and H4K20 was relocalised within the nucleus. Finally, overexpression of human or Xenopus Ki-67 induced ectopic heterochromatin formation. Altogether, our results suggest that Ki-67 expression in proliferating cells spatially organises heterochromatin, thereby controlling gene expression. PMID- 26949253 TI - Changing our minds about changes of mind. AB - Two theories that attempt to explain why we sometimes reverse a decision shortly after making it may both be correct. PMID- 26949254 TI - Neural signatures of perceptual inference. AB - Generative models, such as predictive coding, posit that perception results from a combination of sensory input and prior prediction, each weighted by its precision (inverse variance), with incongruence between these termed prediction error (deviation from prediction) or surprise (negative log probability of the sensory input). However, direct evidence for such a system, and the physiological basis of its computations, is lacking. Using an auditory stimulus whose pitch value changed according to specific rules, we controlled and separated the three key computational variables underlying perception, and discovered, using direct recordings from human auditory cortex, that surprise due to prediction violations is encoded by local field potential oscillations in the gamma band (>30 Hz), changes to predictions in the beta band (12-30 Hz), and that the precision of predictions appears to quantitatively relate to alpha band oscillations (8-12 Hz). These results confirm oscillatory codes for critical aspects of generative models of perception. PMID- 26949255 TI - No current evidence for widespread dosage compensation in S. cerevisiae. AB - Previous studies of laboratory strains of budding yeast had shown that when gene copy number is altered experimentally, RNA levels generally scale accordingly. This is true when the copy number of individual genes or entire chromosomes is altered. In a recent study, Hose et al. (2015) reported that this tight correlation between gene copy number and RNA levels is not observed in recently isolated wild Saccharomyces cerevisiae variants. To understand the origins of this proposed difference in gene expression regulation between natural variants and laboratory strains of S. cerevisiae, we evaluated the karyotype and gene expression studies performed by Hose et al. on wild S. cerevisiae strains. In contrast to the results of Hose et al., our reexamination of their data revealed a tight correlation between gene copy number and gene expression. We conclude that widespread dosage compensation occurs neither in laboratory strains nor in natural variants of S. cerevisiae. PMID- 26949256 TI - SOX2 O-GlcNAcylation alters its protein-protein interactions and genomic occupancy to modulate gene expression in pluripotent cells. AB - The transcription factor SOX2 is central in establishing and maintaining pluripotency. The processes that modulate SOX2 activity to promote pluripotency are not well understood. Here, we show SOX2 is O-GlcNAc modified in its transactivation domain during reprogramming and in mouse embryonic stem cells (mESCs). Upon induction of differentiation SOX2 O-GlcNAcylation at serine 248 is decreased. Replacing wild type with an O-GlcNAc-deficient SOX2 (S248A) increases reprogramming efficiency. ESCs with O-GlcNAc-deficient SOX2 exhibit alterations in gene expression. This change correlates with altered protein-protein interactions and genomic occupancy of the O-GlcNAc-deficient SOX2 compared to wild type. In addition, SOX2 O-GlcNAcylation impairs the SOX2-PARP1 interaction, which has been shown to regulate ESC self-renewal. These findings show that SOX2 activity is modulated by O-GlcNAc, and provide a novel regulatory mechanism for this crucial pluripotency transcription factor. PMID- 26949257 TI - Sleep-active neuron specification and sleep induction require FLP-11 neuropeptides to systemically induce sleep. AB - Sleep is an essential behavioral state. It is induced by conserved sleep-active neurons that express GABA. However, little is known about how sleep neuron function is determined and how sleep neurons change physiology and behavior systemically. Here, we investigated sleep in Caenorhabditis elegans, which is induced by the single sleep-active neuron RIS. We found that the transcription factor LIM-6, which specifies GABAergic function, in parallel determines sleep neuron function through the expression of APTF-1, which specifies the expression of FLP-11 neuropeptides. Surprisingly FLP-11, and not GABA, is the major component that determines the sleep-promoting function of RIS. FLP-11 is constantly expressed in RIS. At sleep onset RIS depolarizes and releases FLP-11 to induce a systemic sleep state. PMID- 26949258 TI - Acquisition of exogenous haem is essential for tick reproduction. AB - Haem and iron homeostasis in most eukaryotic cells is based on a balanced flux between haem biosynthesis and haem oxygenase-mediated degradation. Unlike most eukaryotes, ticks possess an incomplete haem biosynthetic pathway and, together with other (non-haematophagous) mites, lack a gene encoding haem oxygenase. We demonstrated, by membrane feeding, that ticks do not acquire bioavailable iron from haemoglobin-derived haem. However, ticks require dietary haemoglobin as an exogenous source of haem since, feeding with haemoglobin-depleted serum led to aborted embryogenesis. Supplementation of serum with haemoglobin fully restored egg fertility. Surprisingly, haemoglobin could be completely substituted by serum proteins for the provision of amino-acids in vitellogenesis. Acquired haem is distributed by haemolymph carrier protein(s) and sequestered by vitellins in the developing oocytes. This work extends, substantially, current knowledge of haem auxotrophy in ticks and underscores the importance of haem and iron metabolism as rational targets for anti-tick interventions. PMID- 26949259 TI - Cryo-EM single particle analysis with the Volta phase plate. AB - We present a method for in-focus data acquisition with a phase plate that enables near-atomic resolution single particle reconstructions. Accurate focusing is the determining factor for obtaining high quality data. A double-area focusing strategy was implemented in order to achieve the required precision. With this approach we obtained a 3.2 A resolution reconstruction of the Thermoplasma acidophilum 20S proteasome. The phase plate matches or slightly exceeds the performance of the conventional defocus approach. Spherical aberration becomes a limiting factor for achieving resolutions below 3 A with in-focus phase plate images. The phase plate could enable single particle analysis of challenging samples in terms of small size, heterogeneity and flexibility that are difficult to solve by the conventional defocus approach. PMID- 26949261 TI - Potential barriers to pursuing a career in academic dermatology. PMID- 26949260 TI - Urine phyto-oestrogen metabolites are not significantly associated with risk of type 2 diabetes: the Singapore Chinese health study. AB - We evaluated the relationship between urine concentrations of phyto-oestrogens (isoflavones and lignans) and risk of incident type 2 diabetes in middle-aged and elderly Chinese residing in Singapore. Urine metabolites of isoflavones and lignans were assayed by HPLC among 564 diabetes cases and 564 matched controls in a case-control study nested within the Singapore Chinese Health Study cohort. Participants were free of diagnosed diabetes, CVD and cancer at morning urine collections during 1999-2004. Cases were participants who reported to have physician-diagnosed diabetes at follow-up visits during 2006-2010, whereas controls were randomly selected among those who remained free of diabetes and were matched to the index cases by age, sex, dialect group and date of urine collection. Conditional logistic regression models were used to calculate OR and 95 % CI with adjustment for potential confounders. The mean age of the participants at the time of urine collection was 59.8 years, and the average interval between urine collection and diabetes diagnosis was 4.0 years. The multivariate-adjusted OR for diabetes were 1.00 (reference), 0.76 (95 % CI 0.52, 1.11), 0.78 (95 % CI 0.53, 1.14) and 0.79 (95 % CI 0.54, 1.15) across quartiles of urine isoflavones (P for trend=0.54), and were 1.00 (reference), 0.87 (95 % CI 0.60, 1.27), 1.10 (95 % CI 0.77, 1.56) and 0.93 (95 % CI 0.63, 1.37) for lignans (P for trend=0.93). The results were similar in men and women, as well as for individual metabolites of isoflavones (genistein, daidzein, glycitin and equol) or lignans (enterodiol and enterolactone). The present study did not find a significant association between urine phyto-oestrogen metabolites and risk of type 2 diabetes in Chinese adults. PMID- 26949262 TI - Low insulin resistance after surgery predicts poor GH suppression one year after complete resection for acromegaly: a retrospective study. AB - Remission of acromegaly is defined as a nadir in GH <1.0 ng/mL during a 75-g oral glucose tolerance test (75gOGTT) and insulin-like growth factor-1 (IGF-1) normalization. Recently, a lower cut-off value for GH nadir (<0.4 ng/mL) has been proposed. We retrospectively evaluated the prevalence and clinical characteristics of postoperative cases with normalized IGF-1 levels and a GH nadir of 0.4-1.0 ng/mL one year after complete resection of GH-secreting pituitary adenoma (GHoma). We included 110 cases of acromegaly with complete adenoma resection, no preoperative treatment, preoperative glycosylated hemoglobin <6.5%, preoperative basal plasma glucose <126 mg/dL, GH nadir <1.0 ng/mL during a 75gOGTT, and normalized IGF-1 at the first postoperative year evaluation, whereupon patients were divided into two groups: control (GH nadir <0.4 ng/mL) and high GH (GH nadir >0.4 ng/mL). Clinical parameters, including measures of insulin secretion and resistance, were compared between groups. The high GH group included 10 patients (9.1%) and had a lesser level of insulin resistance immediately following surgery and at the first postoperative year evaluation. On single regression analysis, insulin resistance immediately following surgery was predictive of and correlated with the GH nadir at the first postoperative year evaluation. The GH nadir at the first postoperative year evaluation may be insufficient in patients with normalized IGF-1 with low insulin resistance immediately following complete resection of GHoma. Careful evaluation is needed to assess remission in such patients. PMID- 26949263 TI - Drug Development for Hypertension: Do We Need Another Antihypertensive Agent for Resistant Hypertension? AB - The prevalence of resistant hypertension is seemingly much lower than had been reported in early studies. Recent analyses suggest that <5 % of treated hypertensive patients remain uncontrolled if fully adherent to an optimized antihypertensive treatment. However, these patients do have increased cardiovascular risk and need effective therapeutic approaches. Drug development is a high-risk, complex, lengthy, and very expensive process. In this article, we discuss the factors that should be considered in the process of developing a new agent for treatment of resistant hypertension. PMID- 26949264 TI - No Time to Waste: in Support of Aggressive and Immediate Management of Hypertension. AB - Untreated and uncontrolled hypertension (HTN) presents a major public health burden in the USA and worldwide. Despite the known risk for increased cardiovascular (CV) morbidity and mortality, blood pressure remains untreated and uncontrolled at alarming rates of between 20 and 40 % in patients with known HTN. Further, while cumulative evidence indicates that early onset of antihypertensive effect improves CV outcomes, the time to blood pressure (BP) control remains long. The objective of hypertension management cannot be simply to achieve and maintain the goal BP, but to do so quickly to improve short-term and long-term CV outcomes. In this review, we will (1) describe the magnitude of uncontrolled HTN, (2) identify the factors that contribute to uncontrolled BP in patients with the diagnosis of HTN, and (3) explore the rationale for and benefits of aggressive and immediate control of HTN. PMID- 26949265 TI - Recent social conditions affect boldness repeatability in individual sticklebacks. AB - Animal personalities are ubiquitous across the animal kingdom and have been shown both to influence individual behaviour in the social context and to be affected by it. However, little attention has been paid to possible carryover effects of social conditions on personality expression, especially when individuals are alone. Here we investigated how the recent social context affected the boldness and repeatability of three-spined sticklebacks, Gasterosteus aculeatus, during individual assays. We housed fish either solitarily, solitarily part of the time or socially in groups of four, and subjected them twice to a risk-taking task. The social conditions had a large effect on boldness repeatability, with fish housed solitarily before the trials showing much higher behavioural repeatability than fish housed socially, for which repeatability was not significant. Social conditions also had a temporal effect on the boldness of the fish, with only fish housed solitarily taking more risks during the first than the second trial. These results show that recent social conditions can thus affect the short-term repeatability of behaviour and obfuscate the expression of personality even in later contexts when individuals are alone. This finding highlights the need to consider social housing conditions when designing personality studies and emphasizes the important link between animal personality and the social context by showing the potential role of social carryover effects. PMID- 26949266 TI - Measuring the robustness of network community structure using assortativity. AB - The existence of discrete social clusters, or 'communities', is a common feature of social networks in human and nonhuman animals. The level of such community structure in networks is typically measured using an index of modularity, Q. While modularity quantifies the degree to which individuals associate within versus between social communities and provides a useful measure of structure in the social network, it assumes that the network has been well sampled. However, animal social network data is typically subject to sampling errors. In particular, the associations among individuals are often not sampled equally, and animal social network studies are often based on a relatively small set of observations. Here, we extend an existing framework for bootstrapping network metrics to provide a method for assessing the robustness of community assignment in social networks using a metric we call community assortativity (rcom). We use simulations to demonstrate that modularity can reliably detect the transition from random to structured associations in networks that differ in size and number of communities, while community assortativity accurately measures the level of confidence based on the detectability of associations. We then demonstrate the use of these metrics using three publicly available data sets of avian social networks. We suggest that by explicitly addressing the known limitations in sampling animal social network, this approach will facilitate more rigorous analyses of population-level structural patterns across social systems. PMID- 26949267 TI - Responding to Changes in HIV Policy: Updating and Enhancing the Families Matter! Curriculum. AB - OBJECTIVES: The past decade has seen changes in US HIV policy in sub-Saharan Africa in response to a new Administration and far-reaching technical, scientific and programmatic developments. These include: dramatically increased access to life-saving ART and related services; the roll-out of voluntary medical male circumcision; and growing sensitivity to gender-based violence, including child sexual abuse, and to its role in increasing vulnerability to HIV. The Families Matter! Program (FMP) is an intervention for parents and caregivers of 9-12 year olds that promotes effective parent-child communication about sexuality and sexual risk reduction. FMP was adapted from a US evidence-based intervention in 2003-4 and is now implemented in eight African countries. In 2012-13, the FMP curriculum was updated and enhanced to respond to new US Government priorities. METHODS: Enhancements to the curriculum drew on the results of Violence Against Children surveys, on a review of existing literature, on feedback from the field on the existing curriculum, and on stories written by young people across Africa for scriptwriting competitions. RESULTS: We updated FMP with scientific content and stronger linkages to services. We also intensified our focus on structural determinants of risk. This contextualisation of sexual risk-taking within structural constraints led us to place greater emphasis on gendered vulnerability and the diverse pressures children face, and to intensify our situation-based pedagogical approach, drawing on the authentic youth-authored narratives. CONCLUSION: We describe these changes as an illustration of and source of insight into much-needed programmatic adaptation in response to evolving HIV policy. PMID- 26949268 TI - Three-dimensional computational fluid dynamics modeling of particle uptake by an occupational air sampler using manually-scaled and adaptive grids. AB - This work presents fluid flow and particle trajectory simulation studies to determine the aspiration efficiency of a horizontally oriented occupational air sampler using computational fluid dynamics (CFD). Grid adaption and manual scaling of the grids were applied to two sampler prototypes based on a 37-mm cassette. The standard k-epsilon model was used to simulate the turbulent air flow and a second order streamline-upwind discretization scheme was used to stabilize convective terms of the Navier-Stokes equations. Successively scaled grids for each configuration were created manually and by means of grid adaption using the velocity gradient in the main flow direction. Solutions were verified to assess iterative convergence, grid independence and monotonic convergence. Particle aspiration efficiencies determined for both prototype samplers were undistinguishable, indicating that the porous filter does not play a noticeable role in particle aspiration. Results conclude that grid adaption is a powerful tool that allows to refine specific regions that require lots of detail and therefore better resolve flow detail. It was verified that adaptive grids provided a higher number of locations with monotonic convergence than the manual grids and required the least computational effort. PMID- 26949269 TI - Health Insurance and Risk of Divorce: Does Having Your Own Insurance Matter? AB - Most American adults under 65 obtain health insurance through their employers or their spouses' employers. The absence of a universal healthcare system in the United States puts Americans at considerable risk for losing their coverage when transitioning out of jobs or marriages. Scholars have found evidence of reduced job mobility among individuals who are dependent on their employers for healthcare coverage. This paper finds similar relationships between insurance and divorce. I apply the hazard model to married individuals in the longitudinal Survey of Income Program Participation (N=17,388) and find lower divorce rates among people who are insured through their partners' plans without alternative sources of their own. Furthermore, I find gender differences in the relationship between healthcare coverage and divorce rates: insurance dependent women have lower rates of divorce than men in similar situations. These findings draw attention to the importance of considering family processes when debating and evaluating health policies. PMID- 26949270 TI - Integral-valued polynomials over sets of algebraic integers of bounded degree. AB - Let K be a number field of degree n with ring of integers [Formula: see text]. By means of a criterion of Gilmer for polynomially dense subsets of the ring of integers of a number field, we show that, if [Formula: see text] maps every element of [Formula: see text] of degree n to an algebraic integer, then [Formula: see text] is integral-valued over [Formula: see text], that is, [Formula: see text]. A similar property holds if we consider the set of all algebraic integers of degree n and a polynomial [Formula: see text]: if [Formula: see text] is integral over [Formula: see text] for every algebraic integer alpha of degree n, then [Formula: see text] is integral over [Formula: see text] for every algebraic integer beta of degree smaller than n. This second result is established by proving that the integral closure of the ring of polynomials in [Formula: see text] which are integer-valued over the set of matrices [Formula: see text] is equal to the ring of integral-valued polynomials over the set of algebraic integers of degree equal to n. PMID- 26949271 TI - Homodimeric Protein-Polymer Conjugates via the Tetrazine-trans-Cyclooctene Ligation. AB - Tetrazine end-functionalized telechelic polymers were synthesized by controlled radical polymerization (CRP) and employed to generate T4 Lysozyme homodimers. Mutant T4 Lysozyme (V131C), containing a single surface-exposed cysteine, was modified with a protein-reactive trans-cyclooctene (T4L-TCO). Reversible addition fragmentation chain transfer (RAFT) polymerization yielded poly(N isopropylacrylamide) (pNIPAAm) with a number average molecular weight (Mn by 1H NMR) of 2.0 kDa and a dispersity (D by GPC) of 1.05. pNIPAAm was then modified at both ends by post-polymerization with 6-methyl tetrazine. For comparison, 2.0 kDa bis-tetrazine poly(ethylene glycol) (PEG) and 2.0 kDa bis-maleimide pNIPAAm were synthesized. Ligation of T4L-TCO to bis-tetrazine pNIPAAm or bis-tetrazine PEG resulted in protein homodimer in 38% yield and 37% yield, respectively, after only 1 hour, whereas bis-maleimide pNIPAAm resulted in only 5% yield of dimer after 24 h. This work illustrates the advantage of employing tetrazine ligation over maleimide thiol-ene chemistry for the synthesis of protein homodimer conjugates. PMID- 26949272 TI - Social Networks and Externalities from Gift Exchange: Evidence from A Field Experiment. AB - This paper asks whether gift exchange generates externalities for people outside of the bilateral relationship between the gift giver and recipient, and whether the nature of this relationship is affected by social networks. We examine this question in the context of a field experiment in urban Chinese hospital outpatient clinics. We first show that when patients give a small gift, doctors reciprocate with better service and a fewer unnecessary prescriptions of antibiotics. We then show that gift giving creates externalities for third parties. If two patients, A and B are perceived as unrelated, B receives worse care when A gives a gift. However, if A identifies B as a friend, then both A and B benefit from A's gift giving. Hence, we show that gift giving can create positive or negative externalities, depending on the giver's social distance to the third party. PMID- 26949273 TI - Mercury and antimony in wastewater: fate and treatment. AB - It is important to understand the fate of Hg and Sb within the wastewater treatment process so as to examine potential treatment options and to ensure compliance with regulatory standards. The fate of Hg and Sb was investigated for an activated sludge process treatment works in the UK. Relatively high crude values (Hg 0.092 MUg/L, Sb 1.73 MUg/L) were observed at the works, whilst low removal rates within the primary (Hg 52.2 %, Sb 16.3 %) and secondary treatment stages (Hg 29.5 %, Sb -28.9 %) resulted in final effluent concentrations of 0.031 MUg/L for Hg and 2.04 MUg/L for Sb. Removal of Hg was positively correlated with suspended solids (SS) and chemical oxygen demand (COD) removal, whilst Sb was negatively correlated. Elevated final effluent Sb concentrations compared with crude values were postulated and were suggested to result from Sb present in returned sludge liquors. Kepner Tregoe (KT) analysis was applied to identify suitable treatment technologies. For Hg, chemical techniques (specifically precipitation) were found to be the most suitable whilst for Sb, adsorption (using granulated ferric hydroxide) was deemed most appropriate. Operational solutions, such as lengthening hydraulic retention time, and treatment technologies deployed on sludge liquors were also reviewed but were not feasible for implementation at the works. PMID- 26949274 TI - Using communication to manage uncertainty about cervical cancer screening guideline adherence among Appalachian women. AB - Changes to the United States Preventive Services Task Force (USPSTF) recommendations for cervical cancer preventive services have led to patient confusion, especially in medically underserved populations. We investigated how patient uncertainty concerning cervical cancer screening guidelines is appraised and managed through communication with healthcare providers by conducting in depth, face-to-face interviews with 24 adult women between the ages of 24 and 65 (m = 41, SD = 14) living in Appalachia Kentucky. In general, participants expressed a high degree of uncertainty about the updated cervical cancer screening guidelines and appraised this uncertainty as both a danger and an opportunity. Communication with healthcare providers served both to exacerbate and to mitigate patient uncertainty. The study identifies how health care providers may use the change in USPSTF guidelines as a 'teachable moment' to productively counsel patients on the importance of timely screening, the typical progression of certain types of high-risk HPV infection to cervical cancer, and the importance of follow-up care. PMID- 26949275 TI - (Dis)similarity in Impulsivity and Marital Satisfaction: A Comparison of Volatility, Compatibility, and Incompatibility Hypotheses. AB - Impulsivity is negatively associated with relationship satisfaction, but whether relationship functioning is harmed or helped when both partners are high in impulsivity is unclear. The influence of impulsivity might be exacerbated (the Volatility Hypothesis) or reversed (the Compatibility Hypothesis). Alternatively, discrepancies in impulsivity might be particularly problematic (the Incompatibility Hypothesis). Behavioral and self-report measures of impulsivity were collected from a community sample of couples. Mixed effect polynomial regressions with response surface analysis provide evidence in favor of both the Compatibility Hypothesis and the Incompatibility Hypothesis, but not the Volatility Hypothesis. Mediation analyses suggest results for satisfaction are driven by perceptions of the partner's negative behavior and responsiveness. Implications for the study of both impulsivity and relationship functioning are discussed. PMID- 26949276 TI - Forcing your luck: Goal-striving behavior in chance situations. AB - Previous research suggests that desired end-states (i.e., goals) initiate a set of motivational processes supporting goal-attainment. For example, motivational intensity (e.g., effort investment) increases as distance to the goal decreases. The present studies investigate whether this goal-gradient can also be observed in chance determined situations, situations in which there is a desired end-state (i.e., winning) but in which increased effort investment does not support goal attainment. Three studies provide consistent evidence for the goal-gradient in chance determined situations. We show that participants (in the lab and in a TV game show) invest more effort into goal-directed behavior the closer they get to the end of the game. The moderation of expectancy and value was, however, modest. Interestingly, participants' self-reports suggest that their dynamic changes in behavior were unintentional and perceived as non-instrumental. Findings are related to theories of goal pursuit and illusory control, and contrasted to the principle of resource conservation, according to which such behavior should not occur. PMID- 26949277 TI - Autonomy support and diastolic blood pressure: Long term effects and conflict navigation in romantic relationships. AB - Perceiving autonomy support-or encouragement to be oneself-from a romantic partner or other close relationship partners has been shown to yield a variety of psychological health benefits, but it is less clear how perceiving autonomy support from partners is linked to physical health. In two studies we examine the associations between receiving autonomy support in romantic relationships and diastolic blood pressure, an important indicator of cardiovascular health. Results of a longitudinal study found support for a model in which autonomy supportive romantic relationships are linked with lower diastolic blood pressure. Whereas Study 1 showed general longitudinal effects, Study 2 revealed the importance of receiving autonomy support from partners during times of conflict. Implications of the findings will be discussed in the context of self determination theory. PMID- 26949278 TI - Manifestation of neuronal ceroid lipofuscinosis in Australian Merino sheep: observations on altered behaviour and growth. AB - Neuronal ceroid lipofuscinoses (NCL) is an inherited neurodegenerative disorder in children. Presently there is no effective treatment and the disorder is lethal. NCL occur in a variety of non-human species including sheep, which are recognised as valuable large animal models for NCL. This experiment investigated the progressive postural, behavioural and liveweight changes in NCL-affected lambs, to establish practical, non-invasive biomarkers of disease progression for future preclinical trials in a CLN6 Merino sheep model. A flock of eight lambs at pasture was studied, with the observer blind to the disorder status. Three genotypes were compared: homozygous affected NCL; n = 4), clinically normal heterozygous (Carrier; n = 2) and homozygous normal (non-carrier control (Normal); n = 2). Direct observation during daylight and continuous accelerometer measurements over 72 h were used to quantify lamb posture and behaviour in 11 sessions between 26-60 weeks of age, conducted at 3-5 week intervals. There was a Genotype (G) * Age (A) interaction (P = 0.001) for liveweight of the lambs in the experiment, with NCL, Carrier and Normal lambs gaining 11.8, 16.5 and 23.4 kg, respectively, between 26 and 60 weeks of age. G*A interactions were also found for walking behaviour (means for NCL, Carrier and Normal genotype groups at 26 and 60 weeks, were 1.7 and 7.9%, 3.3 and 3.1%, and 2.5 and 1.9% of observations, P = 0.008) and a composite variable of key behaviours identified in the principal components analysis (P < 0.001), with mean values for NCL lambs increasing three fold compared to non-affected lambs as age increased. Similarly, NCL lambs became less responsive to visual and auditory stimuli as they aged. Mean responsiveness scores (out of 3) to visual stimuli for the NCL, Carrier and Normal genotypes at 26 and 60 weeks of age were 2.7 and 1.4, 2.8 and 2.9, and 3.0 and 3.0, respectively (G * A, P < 0.001). Changes in response to auditory stimuli were similar to visual stimuli. NCL lambs took more (P = 0.015) steps per 24 h than Carrier and Normal genotype lambs, but there was no G * A interaction. At 26 and 60 weeks of age respectively, NCL lambs took 2724 and 4121 steps per 24 h, compared to Carrier (1708 and 3105 steps) and Normal genotype lambs (2109 and 3506 steps). NCL lambs also performed less (P = 0.018) grazing behaviour than Carrier and Normal genotype lambs (66.5, 72.3 and 72.5% of observations for NCL, Carrier and Normal lambs, respectively). A number of behavioural changes identified in the experiment could form the basis for a protocol for monitoring and evaluation of disease progression. PMID- 26949279 TI - Model-based optimal design of experiments - semidefinite and nonlinear programming formulations. AB - We use mathematical programming tools, such as Semidefinite Programming (SDP) and Nonlinear Programming (NLP)-based formulations to find optimal designs for models used in chemistry and chemical engineering. In particular, we employ local design based setups in linear models and a Bayesian setup in nonlinear models to find optimal designs. In the latter case, Gaussian Quadrature Formulas (GQFs) are used to evaluate the optimality criterion averaged over the prior distribution for the model parameters. Mathematical programming techniques are then applied to solve the optimization problems. Because such methods require the design space be discretized, we also evaluate the impact of the discretization scheme on the generated design. We demonstrate the techniques for finding D-, A- and E-optimal designs using design problems in biochemical engineering and show the method can also be directly applied to tackle additional issues, such as heteroscedasticity in the model. Our results show that the NLP formulation produces highly efficient D-optimal designs but is computationally less efficient than that required for the SDP formulation. The efficiencies of the generated designs from the two methods are generally very close and so we recommend the SDP formulation in practice. PMID- 26949280 TI - Changes in negative urgency, positive urgency, and sensation seeking across adolescence. AB - The development and potential co-development of traits related to impulsivity and sensation seeking across adolescence has garnered substantial attention within the extant literature. Some prior research suggests that facets show distinct patterns of change across adolescence and that intraindividual changes in these traits may be unrelated. However, the extant literature is somewhat hampered by measurement issues and inconsistent findings. Using an accelerated longitudinal design in a sample of adolescents (n = 1018; ages 11-16), changes in negative urgency, positive urgency, and sensation seeking were examined. The three facets showed similar trajectories across time (i.e., increasing during early adolescence before leveling off). Across all facets, there was strong evidence of correlated change, suggesting these traits are, developmentally, strongly related phenomena. PMID- 26949282 TI - Trends in Substance Use Among 6th- to 10th-Grade Students From 1998 to 2010: Findings From a National Probability Study. AB - Of the handful of national studies tracking trends in adolescent substance use in the United States, only the Health Behavior in School-Aged Children (HBSC) study collects data from 6th through 10th graders. The purpose of this study was to examine trends from 1998 to 2010 (four time points) in the prevalence of tobacco, alcohol, and marijuana use among 6th through 10th graders. Differences in trends by grade, gender, and race/ethnicity were examined for each substance use behavior, with a primary focus on trends for sixth and seventh graders. Overall, there were significant declines in tobacco, alcohol, and marijuana use from 1998 to 2010. The declines were largest for the younger grades, which suggest promise for future declines among high school students as these cohorts age into high school. PMID- 26949281 TI - Protein Stabilization and Enzyme Activation in Ionic Liquids: Specific Ion Effects. AB - There are still debates on whether the hydration of ions perturbs the water structure, and what is the degree of such disturbance; therefore, the origin of Hofmeister effect on protein stabilization continues being questioned. For this reason, it is suggested to use the 'specific ion effect' instead of other misleading terms such as Hofmeister effect, Hofmeister series, lyotropic effect, and lyotropic series. In this review, we firstly discuss the controversial aspect of inorganic ion effects on water structures, and several possible contributors to the specific ion effect of protein stability. Due to recent overwhelming attraction of ionic liquids (ILs) as benign solvents in many enzymatic reactions, we further evaluate the structural properties and molecular-level interactions in neat ILs and their aqueous solutions. Next, we systematically compare the specific ion effects of ILs on enzyme stability and activity, and conclude that (a) the specificity of many enzymatic systems in diluted aqueous IL solutions is roughly in line with the traditional Hofmeister series albeit some exceptions; (b) however, the specificity follows a different track in concentrated or neat ILs because other factors (such as hydrogen-bond basicity, nucelophilicity, and hydrophobicity, etc) are playing leading roles. In addition, we demonstrate some examples of biocatalytic reactions in IL systems that are guided by the empirical specificity rule. PMID- 26949283 TI - Letter to the Editor: Probabilistic population forecasts for informed decision making. AB - Demographic forecasts are inherently uncertain. Nevertheless, an appropriate description of this uncertainty is a key underpinning of informed decision making. In recent decades various methods have been developed to describe the uncertainty of future populations and their structures, but the uptake of such tools amongst the practitioners of official population statistics has been lagging behind. In this letter we revisit the arguments for the practical uses of uncertainty assessments in official population forecasts, and address their implications for decision making. We discuss essential challenges, both for the forecasters and forecast users, and make recommendations for the official statistics community. PMID- 26949284 TI - Addressing Antibiotic Abuse in China: An Experimental Audit Study. AB - China has high rates of antibiotic abuse and antibiotic resistance but the causes are still a matter for debate. Strong physician financial incentives to prescribe are likely to be an important cause. However, patient demand (or physician beliefs about patient demand) is often cited and may also play a role. We use an audit study to examine the effect of removing financial incentives, and to try to separate out the effects of patient demand. We implement a number of different experimental treatments designed to try to rule out other possible explanations for our findings. Together, our results suggest that financial incentives are the main driver of antibiotic abuse in China, at least in the young and healthy population we draw on in our study. PMID- 26949285 TI - Reducing the land use of EU pork production: where there's swill, there's a way. AB - Livestock production occupies approximately 75% of agricultural land, consumes 35% of the world's grain, and produces 14.5% of anthropogenic greenhouse gas emissions. With demand for meat and dairy products forecast to increase 60% by 2050, there is a pressing need to reduce the footprint of livestock farming. Food wastes have a long history as a source of environmentally benign animal feed, but their inclusion in feed is currently banned in the EU because of disease control concerns. A number of East Asian states have in the last 20 years, however, introduced regulated, centralised systems for safely recycling food wastes into animal feed. This study quantifies the land use savings that could be realised by changing EU legislation to promote the use of food wastes as animal feed and reviews the policy, public, and industry barriers to the use of food waste as feed. Our results suggest that the application of existing technologies could reduce the land use of EU pork (20% of world production) by one fifth, potentially saving 1.8 million hectares of agricultural land. While swill presents a low-cost, low-impact animal feed, widespread adoption would require efforts to address consumer and farmer concerns over food safety and disease control. PMID- 26949286 TI - Classroom Quality at Pre-kindergarten and Kindergarten and Children's Social Skills and Behavior Problems. AB - Focusing on the continuity in the quality of classroom environments as children transition from preschool into elementary school, this study examined the associations between classroom quality in pre-kindergarten and kindergarten and children's social skills and behavior problems in kindergarten and first grade. Participants included 1175 ethnically-diverse children (43% African American) living in low-wealth rural communities of the US. Results indicated that children who experienced higher levels of emotional and organizational classroom quality in both pre-kindergarten and kindergarten demonstrated better social skills and fewer behavior problems in both kindergarten and first grade comparing to children who did not experience higher classroom quality. The examination of the first grade results indicated that the emotional and organizational quality of pre-kindergarten classrooms was the strongest predictor of children's first grade social skills and behavior problems. The study results are discussed from theoretical, practical, and policy perspectives. PMID- 26949287 TI - Do children need reminders on the Day-Night task, or simply some way to prevent them from responding too quickly? AB - We previously reported better performance on the Day-Night task when a ditty was chanted between stimulus presentation and when children could respond (Diamond, Kirkham, & Amso, 2002). Here we investigated competing hypotheses about why the ditty helps. Does it help because it imposes a brief waiting time (the child waits while the ditty is chanted before responding)? Or, does the ditty help because of its content, providing information helpful to performing the task? One third of the 72 children (age 4) were tested with the ditty previously used which reminds them: "Think about the answer; don't tell me." Another 24 children were tested with a ditty with no task-relevant content: "I hope you have a nice time; I like you." One-third received the standard condition. Performance in both ditty conditions was comparable and better than in the standard condition. That indicates that a factor common to both ditties (that chanting them took time, allowing the prepotent response to subside and the more-considered answer to reach response threshold) likely accounts for their benefit. Whether a ditty reminded children what to do or not did not affect the results. The challenge of the Day-Night task for preschoolers is not its working memory demands but the need to inhibit a dominant response, making a different response instead. PMID- 26949288 TI - Reducing the Misinformation Effect Through Initial Testing: Take Two Tests and Recall Me in the Morning? AB - Initial retrieval of an event can reduce people's susceptibility to misinformation. We explored whether protective effects of initial testing could be obtained on final free recall and source-monitoring tests. After studying six household scenes (e.g., a bathroom), participants attempted to recall items from the scenes zero, one, or two times. Immediately or after a 48-hour delay, non presented items (e.g., soap and toothbrush) were exposed zero, one, or four times through a social contagion manipulation in which participants reviewed sets of recall tests ostensibly provided by other participants. A protective effect of testing emerged on a final free recall test following the delay and on a final source-memory test regardless of delay. Taking two initial tests did not increase these protective effects. Determining whether initial testing will have protective (versus harmful) effects on memory has important practical implications for interviewing eyewitnesses. PMID- 26949289 TI - Denoising Magnetic Resonance Images Using Collaborative Non-Local Means. AB - Noise artifacts in magnetic resonance (MR) images increase the complexity of image processing workflows and decrease the reliability of inferences drawn from the images. It is thus often desirable to remove such artifacts beforehand for more robust and effective quantitative analysis. It is important to preserve the integrity of relevant image information while removing noise in MR images. A variety of approaches have been developed for this purpose, and the non-local means (NLM) filter has been shown to be able to achieve state-of-the-art denoising performance. For effective denoising, NLM relies heavily on the existence of repeating structural patterns, which however might not always be present within a single image. This is especially true when one considers the fact that the human brain is complex and contains a lot of unique structures. In this paper we propose to leverage the repeating structures from multiple images to collaboratively denoise an image. The underlying assumption is that it is more likely to find repeating structures from multiple scans than from a single scan. Specifically, to denoise a target image, multiple images, which may be acquired from different subjects, are spatially aligned to the target image, and an NLM like block matching is performed on these aligned images with the target image as the reference. This will significantly increase the number of matching structures and thus boost the denoising performance. Experiments on both synthetic and real data show that the proposed approach, collaborative non-local means (CNLM), outperforms the classic NLM and yields results with markedly improved structural details. PMID- 26949290 TI - The Effect of Task-Irrelevant Fearful-Face Distractor on Working Memory Processing in Mild Cognitive Impairment versus Healthy Controls: An Exploratory fMRI Study in Female Participants. AB - In mild cognitive impairment (MCI), a risk state for Alzheimer's disease, patients have objective cognitive deficits with relatively preserved functioning. fMRI studies have identified anomalies during working memory (WM) processing in individuals with MCI. The effect of task-irrelevant emotional face distractor on WM processing in MCI remains unclear. We aim to explore the impact of fearful face task-irrelevant distractor on WM processing in MCI using fMRI. Hypothesis. Compared to healthy controls (HC), MCI patients will show significantly higher BOLD signal in a priori identified regions of interest (ROIs) during a WM task with a task-irrelevant emotional face distractor. Methods. 9 right-handed female participants with MCI and 12 matched HC performed a WM task with standardized task-irrelevant fearful versus neutral face distractors randomized and counterbalanced across WM trials. MRI images were acquired during the WM task and BOLD signal was analyzed using statistical parametric mapping (SPM) to identify signal patterns during the task response phase. Results. Task-irrelevant fearful face distractor resulted in higher activation in the amygdala, anterior cingulate, and frontal areas, in MCI participants compared to HC. Conclusions. This exploratory study suggests altered WM processing as a result of fearful-face distractor in MCI. PMID- 26949292 TI - Preparedness to Respond to the Ever-increasing Cancer Cases. PMID- 26949291 TI - Activation of Melanocortin Receptors MC 1 and MC 5 Attenuates Retinal Damage in Experimental Diabetic Retinopathy. AB - We hypothesize that melanocortin receptors (MC) could activate tissue protective circuit in a model of streptozotocin- (STZ-) induced diabetic retinopathy (DR) in mice. At 12-16 weeks after diabetes induction, fluorescein angiography (FAG) revealed an approximate incidence of 80% microvascular changes, typical of DR, in the animals, without signs of vascular leakage. Occludin progressively decreased in the retina of mice developing retinopathy. qPCR of murine retina revealed expression of two MC receptors, Mc1r and Mc5r. The intravitreal injection (5 MUL) of the selective MC1 small molecule agonist BMS-470539 (33 MUmol) and the MC5 peptidomimetic agonist PG-901 (7.32 nM) elicited significant protection with regular course and caliber of retinal vessels, as quantified at weeks 12 and 16 after diabetes induction. Mouse retina homogenate settings indicated an augmented release of IL-1alpha, IL-1beta, IL-6, MIP-1alpha, MIP-2alpha, MIP-3alpha, and VEGF from diabetic compared to nondiabetic mice. Application of PG20N or AGRP and MC5 and MC1 antagonist, respectively, augmented the release of cytokines, while the agonists BMS-470539 and PG-901 almost restored normal pattern of these mediators back to nondiabetic values. Similar changes were quantified with respect to Ki-67 staining. Finally, application of MC3-MC4 agonist/antagonists resulted to be inactive with respect to all parameters under assessment. PMID- 26949293 TI - Adherence to Healthcare Waste Management Guidelines among Nurses and Waste Handlers in Thika Sub-county- Kenya. AB - BACKGROUND: Despite the set guidelines on Healthcare Waste Management in Kenya, mixing of different categories of waste, crude dumping and poor incineration are still a common phenomenon in public health facilities in Thika Subcounty, Kenya. Thika Subcounty generates 560 Kilograms of healthcare waste daily, which is risk to the many patients (admission rate of 26%). This may pose a potential environmental risk and be a source of disease diffusion. This research explored the adherence to healthcare waste management waste guidelines in health care facilities among the nurses and waste handlers. METHODS: This was a cross sectional survey in which mixed methods were applied. A census and proportionate random sampling method were used. Quantitative data was analyzed using Statistical Package for Social Science (SPSS) version 20.0, while qualitative data was analyzed manually into themes. RESULTS: Full adherence to the seven waste disposal guidelines was low (16.3%). Knowledge on waste segregation, waste separation then disposal and means of transports were statistically significant in relation to adherence. The type of incinerator and burning status, protection maintenance and supply of adequate waste bins were also important to adherence level. CONCLUSION: Adherence level was low (16.3%,) and insignificantly different among nurses and waste handlers. From this finding, compliance remains a key challenge. Strategies targeted at contextualizing waste regulations and guidelines into local settings are necessary and important. Policy makers may design and implement standard incinerators across all the health facilities. This study is not exhaustive; therefore, it is necessary to carry out a study linking poor treatment and disposal of clinical waste to purported health outcomes in Kenya. PMID- 26949294 TI - Routine Iron Supplementation and Anaemia by Third Trimester in a Nigerian Hospital. AB - BACKGROUND: Anaemia in pregnancy is associated with adverse maternal and fetal outcome. Unfortunately, in developing countries its prevalence has continued to rise. To improve the situation, iron supplement is routinely prescribed during pregnancy. We therefore examine the impact of the intervention as being currently practised in our clinical setting. METHODS: In total, 255 prenatal clinic attendees who had more than 8 weeks of prescribed iron supplements were sampled. Data was obtained on their socio-demographic features, haemoglobin concentration at booking, compliance with iron supplements and third trimester haemoglobin value. RESULTS: Observed iron supplementation compliance rate was 184(72.2%). There was a significant drop in mean haemoglobin (Hb) concentration between the two time points (booking Hb: 32.56+/-2.99; third trimester Hb: 31.67+/-3.01; mean diff: 0.89+/-3.04; t = 4.673; 95% CI= 0.52-1.27; p= <0.001). Anaemia increased from 132(51.8%) to 150(58.8%) by the third trimester. Increase in anaemia occurred in both iron-compliant and non-compliant groups. Non-compliance however had higher odds of predicting anaemia by the third trimester (OR: 1.83; 95% CI: 1.03-3.26; p: 0.04). CONCLUSION: Although iron supplementation is still a good intervention in developing countries, it is not sufficient to reduce overall prevalence of anaemia by the third trimester. There is a need to look beyond the approach and reinforce the importance of better feeding practices, food fortification and reduced frequency of pregnancies. PMID- 26949295 TI - Prevalence of Disability and Associated Factors among Registered Leprosy Patients in All Africa Tb and Leprosy Rehabilitation and Training Centre (ALERT), Addis Ababa, Ethiopia. AB - BACKGROUND: Delay in leprosy diagnosis and treatment causes disabilities due to nerve damage, immunological reactions and bacillary infiltration. Leprosy disability leads not only to physical dysfunction and activity limitation but also disrupts social interaction of affected individuals by creating stigma and discrimination. This study was aimed at assessing leprosy disability status in patients registered at All African TB and Leprosy Rehabilitation and Training Centre. METHODS: Medical records of leprosy patients registered from September 11, 2010 to September 10, 2013 G.C were reviewed. Prevalence of disability calculated, bivariate and multiple logistic regressions were used to determine crude and adjusted odds ratios with 95% confidence interval. RESULTS: The overall prevalence of disability was found to be 65.9% from all categories of patients (40.2% Grade I and 25.7% Grade II). The Prevalence among the new category was 62.8% (39.1% Grade 1 and 23.7% Grade 2). Those ageed above 30 years, with duration of symptoms 6-12 months and above 24 months, with sensory loss, nerve damage and reversal reaction were more likely to develop disability. CONCLUSION: In this study the prevalence of disability, both Grade I and II, is very high. Disability was associated with age, duration of symptom, sensory loss, signs of nerve damage and reversal reaction. These risk factors indicate the existence of delay in diagnosis and treatment of leprosy cases. Therefore, the national leprosy control program should investigate leprosy case detection and diagnosis system in the country and work on improving early case detection and prevention of disability. PMID- 26949296 TI - What Factors are Responsible for Higher Prevalence of HIV Infection among Urban Women than Rural Women in Tanzania? AB - BACKGROUND: Tanzania is the country hit the hardest by the HIV epidemic in Sub Saharan Africa. The present study was carried out to examine the factors of HIV infection among women who lived in an urban area in Tanzania. METHODS: The Tanzania HIV/AIDS and Malaria Indicator Survey (2011-12) data was used. The sample size for urban and rural women who had been tested for HIV and ever had sex was 2227 and 6210 respectively. Bivariate and multivariate logistic regression analyses were used. RESULTS: The present study found that rural women were significantly less likely to be HIV-infected compared to urban women (OR = 0.612, p<0.00). About 10% urban women were HIV-infected whereas 5.8% women in rural areas were HIV positive. Women who had more than five sex partners were significantly four times more likely to be HIV-infected as compared to women who had one sex partner (OR = 4.49, p<0.00). CONCLUSION: The results of this study suggest that less-educated women, women belonging to poor or poorer quintile, women spending nights outside and women having more than one sex partner were significantly more likely to have HIV infection among urban women as compared to rural women. There is an urgent need for a short and effective program to control the HIV epidemic in urban areas of Tanzania especially for less-educated urban women. PMID- 26949297 TI - Effects of Training on Knowledge, Attitude and Practices of Malaria Prevention and Control among Community Role Model Care Givers in South Western Nigeria. AB - BACKGROUND: Malaria is endemic in Nigeria, with significant records of mortality and morbidity. Adequate community involvement is central to a successful implementation of malaria control programs. This study assessed the effects of a training programme on knowledge of malaria prevention and control among community role model care givers. METHODS: A descriptive cross sectional study of a pre-and post-test design method was conducted among 400 eligible community members in Osun State. Training was given in the form of organized lectures, health education and practical demonstration sessions. Scores of pre-test and post-test conducted after four months interval were compared. Multistage sampling method was adopted in selecting study participants, while data was analyzed using the SPSS software version 17.0. RESULTS: Mean age was 43.8 (+/-1.4) years. Average knowledge score of cause, transmission, risk factors and consequences, awareness of common symptoms and preventive practices improved during post-training test when compared with pr-training test. The overall descriptive mean knowledge score in pre-test and post-test were 2.1 and 3.5 respectively out of an average maximum score of 5.0, giving an increment of 66.7%. Role model care givers with formal education were twice and three times more likely to know about disease 'transmission' (OR 1.9, 95%CI 0.11-0.19, p=0.002) and 'consequences' (OR 2.9, 95%CI 0.25-0.65, p=0.040) respectively compared to those without formal education. CONCLUSION: Training on malaria improved the knowledge of malaria prevention and control among role model community care givers towards a successful implementation of malaria control programmes. PMID- 26949298 TI - How Effective is the Treatment of Locally Advanced and Metastatic Breast Cancer in Developing Centres?: A Retrospective Review. AB - BACKGROUND: The use of chemotherapy in advanced metastatic breast cancer remains a subject of controversy. The thought of MicKinnon et al (early 1950s) that the course of breast cancer was unaffected by chemotherapy has been refuted by results of treatment in the developed countries. The poor result of treatment in developing centres still compares with prechemotherapy era. Consequently, The McKinnon's thought may still lurk. We compared the survival of chemotherapy treated with chemotherapy untreated cancer of breast patients. METHOD: Records of breast cancer patients who presented and died between January 2010 and May 2014 were reviewed. The primary outcome was overall survival. Records of patients that received chemotherapy with or without other tumor directed specific therapy were compared with records of patients who did not receive any tumor directed therapy. RESULT: Thirty-one patients received chemotherapy while 25 patients did not. All were females, more than 90% were of the patients had advanced or metastatic disease. Treatments were not biologically directed and treatment plans were largely compromised and suboptimal. The overall mean survival was 19.2 +/-9.2 months, and the median duration was 17.5 months(range 6-44months). The overall survival was not statistically different between the two groups (p= 0.230, unequal variance assumed). The objective of using neoadjuvant chemotherapy for fungating lesions was not achieved. CONCLUSION: In advanced and metastatic breast cancer, outcomes of patients who receive suboptimal regimen of cytotoxic chemotherapy do not differ from chemotherapy untreated patients. PMID- 26949299 TI - Risk Factors Associated with Invasive Cervical Carcinoma among Women Attending Jimma University Specialized Hospital, Southwest Ethiopia: A Case Control Study. AB - BACKGROUND: Cervical cancer is a more serious public health problem than other cancers in women in Sub-Saharan Africa in general and in Ethiopia in particular. Thus, this study assessed risk factors related to invasive cervical carcinomas in southwestern Ethiopia. METHODS: Unmatched case control study was conducted in Jimma University Specialized Hospital from April 1 to September 30, 2010. The study consisted of 60 cases (women who had cervical cancers based on histopathologic examination) and 120 controls (women with no cervical cancers). Semi-structured questionnaire was utilized for data collection. Vaginal examinations often visualized with speculum insertions were done for both cases and controls. Punch cervical biopsies were then performed for the suspected cases at Jimma University Hospital that serves about 15 million people in a catchment radius of 250 kms. Data were analyzed using SPSS version 13.0 software. Univariate and multivariate analyes were done to describe and identify independent predictors of cervical cancer. RESULTS: The mean ages of cases and controls were 47.7 (SD=10.8) and 35.5 (SD =10.5) years respectively. Older women (40-59 years), (OR= 4.7; 95%CI= 2.3-9.6), more than one husband (OR= 2.0; 95%CI=1.0-3.9), as well as more than one wife in lifetime, (OR= 3.0; 95% CI= 1.5 5.9), women who had more than 4 children, (OR =10.3, 95% CI= 3.6-29.0), and age greater than 25 years at first full term delivery, (OR= 8.8; 95% CI= 3.5-22.0) were statistically significant and the latter two were independently associated with invasive cervical cancer. Only 7(11.7 %) of cases and 58(48.3%) of controls ever heard of cervical cancers; however, 2(3.3%) of cases and 7(5.8%) of controls had ever had history of papaneocolous (pap) smear tests done. CONCLUSION: Poor knowledge on cervical cancer was observed that required more work to be done to increase knowledge of mothers on cervical cancer and on associated risk factors. Behavioral communication activities and establishment of cervical cancer screening programs for the young could help reduce the advancement of cervical cancer particularly among the less knowledgeable, older and grand multiparous women in our parts of the world. PMID- 26949300 TI - The Role of Empowerment in the Association between a Woman's Educational Status and Infant Mortality in Ethiopia: Secondary Analysis of Demographic and Health Surveys. AB - BACKGROUND: Socioeconomic status at national, sub-national, household, and individual levels explains a significant portion of variation in infant mortality. Women's education is among the major determinants of infant mortality. The mechanism through which a woman's own educational status, over her husband's as well as household characteristics, influences infant mortality has not been well studied in developing countries. The objective of this study was to explore the role of woman's empowerment and household wealth in the association between a woman's educational status and infant mortality. METHODS: The association between a woman's educational status and infant death, and the role of woman's empowerment and household wealth in this relationship, were examined among married women in Ethiopia through a secondary, serial cross-sectional analysis utilizing data on birth history of married women from three rounds of the Ethiopian Demographic and Health Survey. Univariate, bivariate, and multivariate analyses were conducted to examine the association between woman's education and infant death, and the possible mediation or moderation roles of woman empowerment and household wealth. RESULTS: Female education and empowerment were inversely associated with infant death. The results indicated mediation by empowerment in the education-infant death association, and effect modification by household wealth. Both empowerment and education had strongest inverse association with infant death among women from the richest households. CONCLUSION: The findings suggest an important role of female empowerment in the education-infant death relation, and the complexity of these factors according to household wealth. Woman empowerment programs may prove effective as a shorter term intervention in reducing infant mortality. PMID- 26949301 TI - Mobile Learning in Medical Education: Review. AB - In the past several years, mobile learning made rapid inroads into the provision of medical education. There are significant advantages associated with mobile learning. These include high access, low cost, more situated and contextual learning, convenience for the learner, continuous communication and interaction between learner and tutor and between learner and other learners, and the ability to self-assess themselves while learning. Like any other form of medical pedagogy, mobile learning has its downsides. Disadvantages of mobile learning include: inadequate technology, a risk of distraction from learning by using a device that can be used for multiple purposes, and the potential for breakdown in barriers between personal usage of the mobile device and professional or educational use. Despite these caveats, there is no question but that mobile learning offers much potential. In the future, it is likely that the strategy of mobile first, whereby providers of e-learning think of the user experience on a mobile first, will result in learners who increasingly expect that all e-learning provision will work seamlessly on a mobile device. PMID- 26949302 TI - Oral Pemphigus Vulgaris: Case Report. AB - BACKGROUND: Pemphigus is a potentially life threatening autoimmune disease that causes blisters and erosions of the skin and the mucous membrane. The epithelial lesions are a result of auto-antibodies that react with desmosomal glycoproteins that are present on the cell surface of the keratinocyte. The autoimmune reaction against these glycoproteins causes a loss of cell to cell adhesion, resulting in the formation of intraepithelial bullae. Eighty to ninety percent of patients with pemphigus vulgaris develop oral lesions and in 60% of cases oral lesions are the first sign. Timely recognition and therapy of oral lesion is critical as it may prevent skin involvement. If treatment is instituted during this time, the disease is easier to control and the chance for an early remission of the disorder is enhanced. CASE DETAILS: This case report describes the case of a patient who complained of ulcers of the mouth and difficulty in swallowing since 20 days, who was diagnosed as having Pemphigus vulgaris. Due to early diagnosis, lower doses of medication for a shorter period of time could control the disease. CONCLUSION: Dental professionals must be sufficiently familiar with the clinical manifestations of pemphigus vulgaris to ensure early diagnosis and treatment which in turn determines the prognosis and course of the disease. PMID- 26949303 TI - Plasmacytoma of the Breast: A Report of a Rare Disease. AB - BACKGROUND: Extramedullary plasma cells tumours are rare. Much more rarer is their occurance in the breast tissue. Our aim is to report a single case of this very rare lesion (at least from an African perspective) that we incidentally diagnosed histopathologically as a primary extramedullary lesion in a 53 year old woman. CASE DETAILS: Clinical records of a 53 year old postmenopausal woman was referred from a secondary health centre to our clinic with a three weeks' history of right breast lump were reviewed. There was no associated pain, nipple discharge, weight loss or systemic symptoms nor was there a previous history of trauma or surgery to the breast. On examination: two discrete lumps measuring 3x2 and 2 x 1.5cm in the upper medial quadrant of the right breast were identified. The lumps were firm, irregular in shape, not attached to the skin or underlying tissues. Tentative diagnosis of adenocarcinoma of the breast was made, with a differential as fat necrosis. A wide excision biopsy was done four days later for histology, after an inconclusive cytological examination of smear of which the result revealed plasmacytosis. The liver function test, Plasma proteins electrophoresis, electrolytes, urea, creatinine, bicarbonate and pelvic X-rays, and abdomino-pelvic ultrasonography were normal. Bence Jones proteins were negative in urine. Histology of bone marrow aspirate revealed scanty plasma cells. RESULTS: She received 20mg dexamethasone, 20mg adramycin, and 2mg vincristine intravenously and 200mg of alloperinol daily by mouth for three days before leaving by the 4th treatment day against medical advice for personal reasons. CONCLUSION: This rare lesion should sometimes be considered as a differential diagnosis of a breast lump, as it does not differ from the common lesions clinically, especially in older women. PMID- 26949304 TI - Vaginal Leech Infestation: A Rare Cause of Hypovolumic Shock In Postmenopausal Woman. AB - BACKGROUND: Human leech infestation is a disease of the poor who live in rural areas and use water contaminated with leeches. Like any other body orifices, vagina can also be infested by leech when females use contaminated water for bathing and/or douching. Although this condition is very rare in postmenopausal women, it causes morbidities and mortalities. CASE DETAILS: A 70 year old Para X (all alive) abortion I mother, postmenopausal for the last 20 years, presented with vaginal bleeding of 3 weeks duration to Gimbie Adventist Hospital, Western Ethiopia. On examination, she had deranged vital signs and there was a dark moving worm attached to the cervical os. She was admitted with the diagnosis of hypovolumic shock and severe anemia secondary to postmenopausal vaginal bleeding. After the patient was stabilized with intravenous crystalloids, the leech was removed from the vagina. She was then transfused with two units of whole blood and discharged with good condition on the 3(rd) post procedure day with ferrous sulphate. CONCLUSION: Vaginal leech infestation in postmenopausal woman can cause hypovolumic shock and severe anemia. Therefore, in order to decrease morbidities from failure or delay in making the diagnosis, health care providers should consider the possibility of vaginal leech infestation in postmenopausal woman from rural areas and those who use river water for drinking, bathing and/or douching and presented with vaginal bleeding. In addition, the importance of using clean water and improving access to safe water should be emphasized. PMID- 26949305 TI - Leiomyoma Arising from Mullerian Remnant, Mimicking Ovarian Tumor in a Woman with MRKH Syndrome and Unilateral Renal Agenesis. AB - BACKGROUND: Leiomyoma with secondary changes arising from Mullerian remnant may mimic ovarian tumor in women with Mayer-Rockitansky-Kuster-Hauser (MRKH) syndrome in patients with pelvic mass and urologic abnormalities. CASE DETAIL: The patient was a 40 years old known case of MRKH, presented with lower abdominal pain and swelling for over one year. On physical examination, large pelvic mass (about 15cm by 10cm) was found and a diagnosis of ovarian tumor was made by imaging which also showed absent right kidney. Finally, the mass was found to be a big leiomyoma with areas of hyaline, edematous and cystic degenerations. CONCLUSION: Although leiomyoma arising from rudimentary Mullerian bulb is a rare condition, it should be considered in differential diagnosis of pelvic mass in patients with MRKH. Possibility of urologic abnormalities should also be considered in these patients and appropriate work up per local context should be made. PMID- 26949306 TI - Congenital Antithrombin Deficiency in a Pregnant Woman with Right Atrium Thrombosis. AB - BACKGROUND: One of the rare causes of venous thromboembolism in pregnancy is antithrombin III deficiency. Antithrombin III deficiency is estimated to carry a 30% risk of venous thrombotic complication during each pregnancy and postpartum. CASE DETAILS: We present thea case of a A 21-year-old pregnant woman (Para 1+) with a history of large atrial septal defect repair at our hospital (Imam Ali Hospital, 2 May 2014). The patient, with unknown history of antithrombin III deficiency, was admitted at our emergency center with dyspnea and chest pain for the rule out of tamponade. She presented with a right atrial thrombosis in the second trimester of pregnancy despite the use of therapeutic doses of heparin and warfarin in the postoperative period as thromboembolic prophylaxis. The risk of warfarin emberyopaty led to termination of pregnancy, and successful redo-cardiac surgery outcome was achieved with the combined use of therapeutic anticoagulation and regular plasma-derived antithrombin concentrate infusions to normalize her antithrombin levels. CONCLUSION: She recovered from the operation uneventfully, and wad discharged in the 12(th) postoperative day. In the 6(th) month of follow up, antithrombin III increased to 70% in more stable level and transethoracic echocardiography showed no recurrence of right atrial thrombus formation. This case leads to further debate regarding whether full anticoagulation should be a worthy preventive measure for venous thromboembolic prophylaxis after an open heart surgery complicated by pregnancy in a women with inherited antithrombin III deficiency. This point may become more relevant as further experience is gained with the use of recombinant human antithrombin in known cases during open cardiac surgery. PMID- 26949309 TI - Sharing Clinical Trial Data: A Proposal from the International Committee of Medical Journal Editors. PMID- 26949310 TI - Validation of The 3-Question Headache Screen in The Diagnosis of Migraine in Nigeria. AB - BACKGROUND: Migraine is a chronic episodic disorder that is still under-diagnosed and undertreated. A rapid diagnostic method is desirable so that treatment can be initiated early. We compared the 3-question headache screen with the International Headache Society (IHS) criteria in the diagnosis of migraine among Nigerians. METHODS: Using a multi-stage sampling technique, 1513 respondents were screened for migraine using both the IHS criteria and the 3-question headache screen. A statistical comparison of the two diagnostic methods was then done by determination of kappa coefficient, sensitivity and specificity. RESULTS: The prevalence of migraine obtained using the IHS criteria was 9.6% (95% CI, 8.1% 11.1%) while it was 8.3% (95% CI, 8.1%-8.5%) with the use of the 3-question headache screen. There was a good agreement between the IHS criteria and the 3 question headache screen (k=0.68, p<0.001). The 3-question headache screen had a sensitivity of 66.2% (95% CI, 58.5%-73.9%), specificity of 97.8% (95% CI, 97.0% 98.6%), positive predictive value of 76.2% (95% CI, 68.8%-83.6%) and a negative predictive value of 96.5% (95% CI, 95.5%-97.5%). CONCLUSION: The 3-question headache screen is sensitive and specific in making a rapid diagnosis of migraine among Nigerians. Its use is thus encouraged so that appropriate management of the condition can be initiated early in order to reduce associated disability. PMID- 26949311 TI - Epidemiology and Outcomes of Hospitalized Burn Patients in Gaza Strip: A Descriptive Study. AB - BACKGROUND: Burns are serious health problems and leading causes of mortality and morbidity in the Eastern Mediterranean Region. This study aimed to overview the epidemiological profile and to present outcomes among hospitalized burn patients in AL Alamy burn center in Gaza. METHODS: This was a cross-sectional retrospective study of medical records of hospitalized patients from July 2013 to June 2014. Descriptive analysis for studied variables was applied and P <= 0.05 considered statistically significant. RESULTS: One humdred eighty nime admissions, 60.8% were males and 63% were under 10 years old. Burn patients in the age range between 19-40 years represented 25.9%. Most common burn injuries were accidental (86.2%), located at home (88.9%), caused by scald (66.1%) and by fire flame (23.8%). On admission, the majority of cases presented with second degree burn (45.5%) or mixed burn (38.6%). The mean TBSA was 11.86 (SD +/- 10.78) ranging from 1% to 75% whereas, the mean hospital length of stay was 11.45 (SD +/ 12.60) ranging from 1 to 115 days. Total in hospital mortality rate was 2.1% and length of stay was significantly associated with TBSA (P < 0.001). CONCLUSION: Young children below 10 years seem to be at a higher risk for burn injuries. A significant improvement in burn patients care is observed and practiced and in hospital mortality rate is better compared to neighbouring countries. Preventive programs focusing on safety measures, especially for mothers working in the home, should be implemented urgently to save our children. PMID- 26949312 TI - Dried Blood Spot Test for HIV Exposed Infants and Children and Their Anti-Retro Viral Treatment Status in Selected Hospitals in Ethiopia. AB - BACKGROUND: Infants and children living with HIV receive antiretroviral treatment often late, are exposed to opportunistic infection and quickly develop AIDS. Few hospitals are providing ART service after Dried Blood Spot (DBS)test.The objective of this study is to assess the status of infants and children linked to ART. METHODS: Descriptive cross-sectional study was conducted in hospitals. Data of 138 infants and children exposed to HIV were collected from registration books and data bases from 2009 to 2011. Data were analyzed using SPSS version 16. Chi squared test and p-value were computed. In-depth interviews were conducted with key informants. RESULT: Ninety-eight (71%) infants and children exposed to HIV were diagnosed for HIV infection of which 68(69.4%) initiated ART. Twenty four (35.3%) initiated ART one month after HIV screening results. Thirty-three (50.0%) and 23(35.3%) infants and children dropped from and adhered to ART respectively. Eleven (16.2%) of them who initiated ART died within the study period. HIV infection status (p-value=0.003), dropping from ART (p-value=0.002) and death after ART initiation (p-value=0.010) showed significance with mothers' PMTCT service status. CONCLUSION: Seven in ten HIV-exposed infants and children were diagnosed with HIV, and almost all of them initiated ART. The overall turnaround time was 10 days. Based up on mothers' PMTCT service status, there was a significant difference among HIV-exposed infants and children in acquiring HIV infection from mothers during pregnancy (p-value=0.003) and dropping from ART (p value=0.010). There were challenges in sample collection and transportation. Early HIV screening during pregnancy and PMTCT service should be strengthened. PMID- 26949313 TI - Immunological Response of Hiv-Infected Children to Highly Active Antiretoviral Therapy at Gondar University Hospital, North-Western Ethiopia. AB - BACKGROUND: The effectiveness of highly active antiretroviral therapy (HAART) in children has not been well studied specially in developing countries where the burden of HIV is high. This study was aimed to assess the immunologic response of HIV-infected children to HAART at Pediatric ART Clinic Gondar University Hospital. METHODS: Institution based cross-sectional study was conducted at the Pediatric ART Clinic Gondar University Hospital from March 01-April 30, 2014. The study included 283 HIV-infected children who were on HAART for 6 months and above. Medical records of HIV-infected children were reviewed using pre-tested questionnaire. CD4 count/percent was collected every 6 months retrospectively. For all statistical significance tests, the cut-off value was p<0.05. Poison Regression was used for further analysis. RESULTS: The mean age of children was 6.9 years with a standard deviation of 3.4 years. The median CD4 count/percent was 232/13%, 450/21%, 540/25% and 608/27% at the time of initiation, 6, 12 and 18 months of ART, respectively. HAART initiated at higher CD4 count, good adherence and HIV status disclosure were found to have positive effects for immunological response. CONCLUSION: The study revealed that there was good Immunological response to ART, and that the maximum response was in the 1(st) 6 months of ART. Low CD4 count at initiation, undisclosed HIV status and lack of good adherence were found to cause low immunological response to HAART. PMID- 26949314 TI - Macrosomic Births in a Tertiary Public Hospital: A Survey of Maternal Characteristics and Fetal Outcome. AB - BACKGROUND: Macrosomic fetuses are high risk with their delivery process being associated with potential risk to both mother and baby The aim of this study is to determine the incidence of macrosomic births and the associated maternal characteristics and to ascertain the fetal outcome. METHODS: It was a retrospective survey of maternal characteristics and pregnancy outcome of macrosomic births. Comparison was made with the next selected normal birth weight delivery during the study period. RESULTS: There were 8607 deliveries during the period (3 years) reviewed. Of this, 306 were macrosomic deliveries, a frequency of 3.6%. The mean weight for macrosomic babies was 4.23kg (range 4.01 - 5.62kg). There was a higher mean maternal weight and gestational age of mothers with macrosomic deliveries compared to mothers in the control group, (85.87 +/- 19.39kg vs 74.92 +/- 19.11kg P<0.01; and 41.51+/-1.46 vs 39.02+/-1.29, P<0.001). Caesarean delivery was significantly associated with macrosomic births compared to controls, p<0.0001, odds ratio 3.977. Also, asphyxia and shoulder dystocia occurred more in macrosomic babies, 10.4% vs 2.9% and 2.28% vs 0.65%, P<0.001. The majority of the asphyxiated babies amongst macroomic births were following vagina delivery compared to caesarean delivery, (65.6% vs 34.4%) p= 0.001. There were 3 cases of still birth in the macrosomic deliveries, but no maternal deaths were encountered. CONCLUSION: Macrosomic births could be tragic. Although delivery outcome seems better with a caesarean section, good fetal outcome can only be assured on the premise of astute labour and delivery management. PMID- 26949315 TI - Aetiologies and Short-term Outcomes of Acute Kidney Injury in a Tertiary Centre in Southwest Nigeria. AB - BACKGROUND: Acute kidney injury (AKI) has become a global health problem and is associated with increased morbidity, mortality and overall health expenditure. Information on the epidemiology and outcomes of AKI will help to audit practice and advocate for policies that will reduce this burden. This study determined aetiologies, short term outcomes and their predictors in AKI patients in a tertiary hospital in Southwest Nigeria. METHODS: This was an 18-month retrospective study that involved 91 patients with AKI. The socio-demographic information, aetiology, severity and the treatment given to patients were recorded. Outcomes and their predictors were determined using multivariate analysis. P value < 0.05 was taken as statistically significant. RESULTS: The mean age of the study population was 45.12 +/-20.67 years. Common causes of AKI were sepsis in 50(54.9%), hypovolaemia in 23(25.3%), cardiac failure in 7(7.7%) and eclampsia in 6(6.6%). Fifty-seven (62.6%) presented with stage 3. Thirty-one (34.1%) had haemodialysis. Forty-eight (52.7%) had complete renal recovery, 35(38.5%) died and 3(3.3%) left against medical advice while five (5.5%) were referred to other hospitals. Stage 3 AKI (Adjusted odd ratio: 6.79, confidence interval: 1.21:38.04, p = 0.029) and age >= 65 years (Adjusted odd ratio: 4.14, confidence interval: 1.32-13.04, p = 0.015) were significant predictors of mortality in AKI patients. CONCLUSION: Sepsis and hypovolaemia were the commonest causes of AKI. The associated mortality is still high and factors associated with mortality were late presentation and older age. Early presentation, treatment and making haemodialysis affordable are key to improving AKI outcomes. PMID- 26949316 TI - Delivery Site Preferences and Associated Factors among Married Women of Child Bearing Age in Bench Maji Zone, Ethiopia. AB - BACKGROUND: Efforts to reduce maternal mortality and morbidity must address societal and cultural factors that affect women's health and their access to services. There was no research conducted previously on delivery site preferences and associated factors among married women of child bearing age in the study area. The aim of this study was to assess the delivery site preferences and associated factors among women of child bearing age in Bench Maji Zone, Southwest Ethiopia. METHODS: A community based cross sectional quantitative study design supplemented by qualitative data was conducted from April 20 to May 20, 2013. Simple random sampling to select kebeles and systematic random sampling to contact eligible woman were used. Data was collected using structured questionnaire. Data was analyzed by using SPSS version 16. Logistic regressions analysis was employed to identify potential predictor variables. Odds ratio with 95% confidence interval was used to assess the association of variables. P-value less than 5% was used to declare significant association. RESULTS: Three hundred five (61.9%) of the mothers gave birth at home. Three Hundred ninety six (78.7%) of them had Ante natal care. The preference of facility delivery was 412(88.3%). Age of women, mothers' educational level, and place of delivery of the last baby, perception of mothers about pregnancy and health care workers significantly affected delivery site preference. CONCLUSION: Most of the women attended Ante natal care. However, only some had actually delivered at health facilities to their last pregnancy. Community members should get health education to reduce misconceptions on delivering in health facility. PMID- 26949317 TI - Safety and Analgesic Properties of Ethanolic Extracts of Toddalia Asiatica (L) Lam. (Rutaceae) Used for Central and Peripheral Pain Management Among the East African Ethnic Communities. AB - BACKGROUND: Although herbs are often perceived as "natural" and therefore safe, many different side effects have been reported. Additionally, there is limited scientific evidence to establish the safety and efficacy of most herbal products. The aim of this study was to evaluate the biochemical and haematological effects of Toddaliaasiatica (L) Lam. (Rutaceae) (T. asiatica (L.) in albino Wistar rats. MATERIALS AND METHODS: The phytochemicals present in the plant were determined. The analgesic activity was determined using the hot plate technique. The whole blood with anticoagulant was used for assay of the haematological parameters using the COULTERAc*T5diff AL Hematology Analyzer (Fullerton, CA, USA). The biochemical parameters determined with HumaLyzer 2000, a semi-automatic, microprocessor-controlled photometer fromchem-labs, Nairobi. RESULTS: The effect of extract on serum biochemical parameters after 14 days treatment with the crude ethanolic extract of T. asiatica (L.) revealed significant difference in the Cholesterol (P = 0.041), alanine transaminase (P = 0.007), gamma-glutamyl transferase (P = 0.045). There was no significance in the alkaline phosphatase (ALP), aspartate transaminase (AST) levels compared to the untreated controls. Peripheral blood films (PBFs) of the treated animals were performed and stained with leishman's stain. Major morphological changes were observed including anisocytosis, burr cells, anisochromia, hypochromia and reactive lymphocytes among others. CONCLUSION: The crude extract of T. asiatica (L.) showed better analgesic effect (28.2+/-13.16) than Acetylsalicylate used as control (4+/-0.31). The potential of T. asiatica (L.) asananalgesic was remarkable. However, the crude extract of T. asiatica (L.) induced nephrotoxicity and liver enzymes modulation and elevated total cholesterol in the test organisms compared to the untreated negative controls. PMID- 26949318 TI - Treatment Outcomes of Tuberculosis Patients at Debre Berhan Hospital, Amhara Region, Northern Ethiopia. AB - BACKGROUND: Directly observed treatment remains one of the most widely-accepted global health interventions for tuberculosis. Tuberculosis treatment outcome is one of the performance indicators of the programme set by World Health Organization. Therefore, evaluating the treatment success rate of Debre Berhan Hospital was mandatory to show the achievement and to indicate where the hospital is against the World Health Organization target. METHODS: A register based cross sectional study covering the period of January 2009 to December 2013 was employed. All clients with complete records of the treatment outcome were included in the study. A checklist was prepared to extract data from patient charts. Data were entered into Epi-info version 3.2.2andanalyzed using SPSS version 16 for windows. RESULTS: Between January 2009 and December 2013, a total of 1280 tuberculosis cases that had complete records on treatment outcome were included in the analysis. Four in five (79.4%) of the patients had favorable treatment outcome; 15.8% were cured and 63.5%completed their treatment. There was a continuous increment of treatment success rate from 2010 to 2013 in the area and the treatment success rate in the year 2013 was 84.4%. CONCLUSION: Despite the recent improvements in treatment success rate, treatment completed and defaulting rate, further efforts should be made by responsible bodies to identify and improve possible promoting factors for successful tuberculosis treatment outcome. PMID- 26949319 TI - Institution Based Prospective Cross-Sectional Study on Patterns of Neonatal Morbidity at Gondar University Hospital Neonatal Unit, North-West Ethiopia. AB - BACKGROUND: Every year, millions of babies are born and a large proportion of them are being admitted to hospital for various indications. This study was conducted to identify the general characteristics, disease spectrum and common causes of Neonatal morbidity and mortality at Gondar University Hospital, Neonatal Unit. METHODS: Institution based prospective cross-sectional study was conducted at Gondar University Hospital (GUH), Neonatal Unit, from January 1(st) to March 31(st), 2014. The study included 325 newborns who were admitted to the unit during the study period. The neonates were followed up using structured checklist and neonatal parameters like Neonatal sex, place of delivery, address, length of stay, gestational age, diagnosis and discharge conditions were transcribed into an electronic database for all observations. The primary outcome measures were death and cause of death. RESULTS: A total of 325 neonates were admitted during the study period. Of these, 75.1%, 23.1%, 1.2% and 0.6% were discharged improved, died, discharged with same condition and disappeared, respectively. Ten variables were found to have significant statistical associations with neonatal mortality after adjusting for demographic covariates: Prematurity (p < 0.001), Meningitis (p <0.001), Hemorrhagic Diseases (P <0.001), Hyaline Membrane Disease (P<0.001), Neonatal Sepsis (p <0.05), Meningitis (<0.05), Perinatal Asphyxia (p <0.05), Neonatal Seizure (p <0.05), Home delivery (p <0.05) and Meconium Aspiration (p <0.05). CONCLUSION: Our study showed that the common causes of neonatal mortality are almost similar with the previous evidences (problems of prematurity, Asphyxia and Sepsis). PMID- 26949320 TI - A Brodie's Abscess of Femoral Neck Mimicking Osteoid Osteoma: Diagnostic Approach and Management Strategy. AB - BACKGROUND: Brodie's abscess usually presents as a diagnostic dilemma resulting in a diagnostic delay. It mimics various benign and malignant conditions both clinically and radiologically. CASE DETAILS: This report describes a case of a 14 year old boy who presented with a clinical and radiological picture of osteoid osteoma of proximal femur but found to have a brodie's abscess on histology and culture. CONCLUSION: It describes the clinical spectrum of subacute osteomyelitis, its unusual MRI features and the importance of obtaining a histological diagnosis before definitive treatment. PMID- 26949321 TI - Retained Fractured Fragment of A Central Venous Catheter: A Minimally Invasive Approach to Safe Retrieval. AB - BACKGROUND: Complication following fracture of a central venous catheter can be catastrophic to both the patient and the attending doctor. Catheter fracture has been attributed to several factors namely prolong mechanical force acting on the catheter, and forceful removal or insertion of the catheter. CASE DETAILS: In the present case, the fracture was suspected during the process of removal. The tip of the catheter was notably missing, and an emergency chest radiograph confirmed our diagnosis of a retained fracture of central venous catheter. The retained portion was removed by the interventional radiologist using an endovascular loop snare and delivered through a femoral vein venotomy performed by the surgeon. CONCLUSION: Endovascular approach to retrieval of retained fractured catheters has helped tremendously to reduce associated morbidity and the need for major surgery. The role of surgery has become limited to instances of failed endovascular retrieval and in remote geographical locations devoid of such specialty. PMID- 26949322 TI - Hydrometrocolpos Presenting as a Huge Abdominal Swelling and Obstructive Uropathy in a 4 Day Old Newborn: A Diagnostic Challenge. AB - BACKGROUND: Abdominal swelling is an uncommon presentation in newborn babies. A combination of huge abdominal swelling, obstructive uropathy and imperforate hymen in newborns has not been reported in the medical literature. CASE DETAILS: We report a 4 days old newborn with a rare presentation of hydrometrocolpos which posed a diagnostic challenge and consequently resulted in delays in diagnosis and treatment. CONCLUSION: Hydrometrocolpos should be considered as a differential diagnosis in neonates who present with huge abdominal swelling. PMID- 26949323 TI - Do Infant Temperament Characteristics Predict Core Academic Abilities in Preschool-Aged Children? AB - Examined relationships between temperament, measured via parent report at 4 months and structures laboratory observations at 12 months of age, and a school readiness battery administered at about 4 years of age (N=31). Scores on the School Readiness Assessment of the Bracken Basic Concept Scale (BBCS) were related to infant Positive Affectivity/Surgency (PAS), with infants described as demonstrating higher levels of PAS at 4 months of age later demonstrating greater school readiness in the domains of color, letter, and number skills. Regulatory Capacity/Orienting (RCO) at 4 months also predicted color skills, with more regulated infants demonstrating superior pre-academic functioning in this area. Analyses involving laboratory observations of temperament provided additional information concerning the importance of infant Positive Affectivity/Surgency, predictive of overall letter skills and overall school-readiness scores later in childhood. Results are discussed in the context of implications for theory and research, as well as early education settings. PMID- 26949324 TI - Survey of Obstetrics and Gynecology Residents Regarding Pneumococcal Vaccination in Pregnancy: Education, Knowledge, and Barriers to Vaccination. AB - OBJECTIVE: The 23-valent pneumococcal vaccine is recommended for adults over 65 years of age and younger adults with certain medical conditions. The Centers for Disease Control and Prevention (CDC) state insufficient evidence to recommend routine pneumococcal vaccination during pregnancy, but the vaccine is indicated for pregnant women with certain medical conditions. We designed this project to gauge obstetrics and gynecology (OB/GYN) resident knowledge of maternal pneumococcal vaccination. METHODS: We administered a 22-question survey to OB/GYN residents about maternal pneumococcal vaccination. We performed descriptive analysis for each question. RESULTS: 238 OB/GYN residents responded. Overall, 69.3% of residents reported receiving vaccination education and 86.0% reported having ready access to vaccine guidelines and safety data. Most residents knew that asplenia (78.2%), pulmonary disease (77.3%), and HIV/AIDS (69.4%) are indications for vaccination but less knew that cardiovascular disease (45.0%), diabetes (35.8%), asthma (42.8%), nephrotic syndrome (19.7%), and renal failure (33.6%) are also indications for vaccination. CONCLUSION: OB/GYN residents are taught about vaccines and have ready access to vaccine guidelines and safety data. However, knowledge of indications for pneumococcal vaccination in pregnancy is lacking. Likely, the opportunity to vaccinate at-risk pregnant patients is being missed. PMID- 26949325 TI - THE USE OF GLUTAMATE MODULATING DRUGS IN OBSESSIVE COMPULSIVE DISORDER. PMID- 26949326 TI - NEUROBIOLOGICAL EVIDENCE SUPPORTING GLUTAMATE'S ROLE IN PEDIATRIC OBSESSIVE COMPULSIVE DISORDER. PMID- 26949327 TI - Integrating developmental theory and methodology: Using derivatives to articulate change theories, models, and inferences. AB - Matching theories about growth, development, and change to appropriate statistical models can present a challenge, which can result in misuse, misinterpretation, and underutilization of different analytical approaches. We discuss the use of derivatives --- the change of a construct with respect to changes in another construct. Derivatives provide a common language linking developmental theory and statistical methods. Conceptualizing change in terms of derivatives allows precise translation of theory into method and highlights commonly overlooked models of change. A wide variety of models can be understood in terms of the level, velocity and acceleration of constructs: the 0th, 1st, and 2nd derivatives, respectively. We introduce the language of derivatives, and highlight the conceptually differing questions that can be addressed in developmental studies. A substantive example is presented to demonstrate how common and unfamiliar statistical methodology can be understood as addressing relations between differing pairs of derivatives. PMID- 26949328 TI - Factors Associated with Adoption and Adoption Intentions of Nonparental Caregivers. AB - Data from the 2011-2012 National Survey of Children's Health and the 2013 National Survey of Children in Nonparental Care were used to fit a multinomial logistic model comparing three groups to those who never considered adoption: those who ever considered, but are not currently planning adoption; those planning adoption; and those who adopted. Adoption may be more likely when the caregiver is a nonkin foster parent, a foster care agency was involved, and/or financial assistance is available. Those with plans to adopt but who have not adopted may face adoption barriers such as extreme poverty, lower education and being unmarried. PMID- 26949329 TI - Antibacterial Activity of Alanine-Derived Gemini Quaternary Ammonium Compounds. AB - The antibacterial activity of alanine-derived gemini quaternary ammonium salts (chlorides and bromides) with various spacer and alkyl chain lengths was investigated. The studied compounds exhibited a strong bactericidal effect, especially bromides with 10 and 12 carbon alkyl chains and 3 carbon spacer groups (TMPAL-10 Br and TMPAL-12 Br), with a short contact time. Both salts dislodged biofilms of Pseudomonas aeruginosa and Staphylococcus epidermidis, and were lethal to adherent cells of S. epidermidis. Bromide with 2 carbon spacer groups and 12 carbon alkyl chains (TMEAL-12 Br) effectively reduced microbial adhesion by coating polystyrene and silicone surfaces. The results obtained suggest that, after further studies, gemini QAS might be considered as antimicrobial agents in medicine or industry. PMID- 26949330 TI - A Linear Diffusion Model of Adsorption Kinetics at Fluid/Fluid Interfaces. AB - The paper presents a new model for kinetically controlled adsorption at the fluid/fluid interface. The main purpose of the presented approach is to relate easy to estimate bulk surfactant concentration with Gibbs surface excess. Two adsorption isotherms are involved in the new model development: Frumkin and Szyszkowski isotherms. Additionally the Johannsen time profile of concentration in the adsorption layer is assumed and estimated in the model derivation. The proposed approach assumes the near interface, adsorptive layer which is described based on Fick's transient diffusion law. The solution to the model contains the estimation of effective diffusivities with adsorptive layer thickness as well. The experimental results of toluene/water + sodium dodecyl sulfate are presented and used for model verification. PMID- 26949331 TI - Itaconic Acid Based Surfactants: I. Synthesis and Characterization of Sodium n Octyl Sulfoitaconate Diester Anionic Surfactant. AB - A novel itaconate-based surfactant, namely sodium n-octyl sulfoitaconate diester (SOSID), has been synthesized from itaconic acid (IA) and n-octanol by sulfonation and esterification reaction processes. The effects of reaction temperature, reaction time, molar ratios of n-octanol to IA and the catalyst dosage on the esterification were investigated. The chemical structure of the surfactants SOSID was characterized by means of LC-MS and confirmed by FT-IR and 1H NMR spectroscopy. The surface tension gamma and the critical micelle concentration (CMC) were determined as 25.02 mN/m and 4.0 * 10-4 mol/L by using surface tensiometer at 20 degrees C. Further investigations showed that SOSID possess excellent wetting, emulsifying and lime soap dispersing properties. PMID- 26949332 TI - Forward-in-Time, Spatially Explicit Modeling Software to Simulate Genetic Lineages Under Selection. AB - SELECTOR is a software package for studying the evolution of multiallelic genes under balancing or positive selection while simulating complex evolutionary scenarios that integrate demographic growth and migration in a spatially explicit population framework. Parameters can be varied both in space and time to account for geographical, environmental, and cultural heterogeneity. SELECTOR can be used within an approximate Bayesian computation estimation framework. We first describe the principles of SELECTOR and validate the algorithms by comparing its outputs for simple models with theoretical expectations. Then, we show how it can be used to investigate genetic differentiation of loci under balancing selection in interconnected demes with spatially heterogeneous gene flow. We identify situations in which balancing selection reduces genetic differentiation between population groups compared with neutrality and explain conflicting outcomes observed for human leukocyte antigen loci. These results and three previously published applications demonstrate that SELECTOR is efficient and robust for building insight into human settlement history and evolution. PMID- 26949333 TI - Preliminary In Vivo Evaluation of a Hybrid Armored Vascular Graft Combining Electrospinning and Additive Manufacturing Techniques. AB - In this study, we tested in vivo effectiveness of a previously developed poly-l lactide/poly-epsilon-caprolactone armored vascular graft releasing heparin. This bioprosthesis was designed in order to overcome the main drawbacks of tissue engineered vascular grafts, mainly concerning poor mechanical properties, thrombogenicity, and endothelialization. The bioprosthesis was successfully implanted in an aortic vascular reconstruction model in rabbits. All grafts implanted were patent at four weeks postoperatively and have been adequately populated by endogenous cells without signs of thrombosis or structural failure and with no need of antiplatelet therapy. The results of this preliminary study might warrant for further larger controlled in vivo studies to further confirm these findings. PMID- 26949335 TI - Operative Myocardial Protection in Patients with Left Ventricular Hypertrophy: The Role of Systemic Hypothermia. AB - OBJECTIVES: Myocardial hypertrophy represents a great challenge in cardiac surgery. Several strategies have been described to protect the hypertrophied myocardium during cardiopulmonary bypass, and aortic clamping, yet the ideal strategy has not been identified. This study investigates the use of moderate systemic hypothermia (MSH) as an adjuvant method to protect the hypertrophied myocardium in patients undergoing aortic valve replacement (AVR). METHODS: Twenty eight patients undergoing AVR were divided into two groups, (Group I) received continuous cold 5-8 degrees C retrograde blood cardioplegia (CRBC) and their body temperature was cooled down to 23-26 degrees C. (Group II) also received CRBC but their body temperature was kept at 32-34 degrees C. RESULTS: No operative morality (30 days) was noted in both groups. Postoperative reduction in ejection fraction (EF) was seen in nine patients of group I and in twelve patients of group II (P < 0.05). The need for multiple inotropes was more in group II (eight patients) than in group I (two patients) (P < 0.001). IABP was needed in three patients of group II and non in group I (P < 0.01). CONCLUSION: Moderate systemic hypothermia might have a role in protecting hypertrophied myocardium in patients undergoing AVR. PMID- 26949336 TI - Intra-Aortic Balloon Pump Entrapment in a Nonatherosclerotic Common Iliac Artery. AB - Use of an intra-aortic balloon pump (IABP) is helpful for maintaining hemodynamic stability in patients with low cardiac output and compromised left ventricular function undergoing coronary artery bypass grafting. Although the incidence of complications has decreased significantly as experience with the device has increased, IABP use still carries a risk of complications. The most common complication is limb ischemia, mainly as a result of IABP entrapment and thromboembolism. Here we report a case of IABP entrapment in a nonatherosclerotic common iliac artery where forced removal caused fracture of the catheter. PMID- 26949334 TI - Membrane Contact Sites: Complex Zones for Membrane Association and Lipid Exchange. AB - Lipid transport between membranes within cells involves vesicle and protein carriers, but as agents of nonvesicular lipid transfer, the role of membrane contact sites has received increasing attention. As zones for lipid metabolism and exchange, various membrane contact sites mediate direct associations between different organelles. In particular, membrane contact sites linking the plasma membrane (PM) and the endoplasmic reticulum (ER) represent important regulators of lipid and ion transfer. In yeast, cortical ER is stapled to the PM through membrane-tethering proteins, which establish a direct connection between the membranes. In this review, we consider passive and facilitated models for lipid transfer at PM-ER contact sites. Besides the tethering proteins, we examine the roles of an additional repertoire of lipid and protein regulators that prime and propagate PM-ER membrane association. We conclude that instead of being simple mediators of membrane association, regulatory components of membrane contact sites have complex and multilayered functions. PMID- 26949337 TI - Prevalence and Predisposing Factors of Atrial Fibrillation in a Multi-Ethnic Society: The Impact of Racial Differences in Bahrain. AB - BACKGROUND: The prevalence and epidemiological data of atrial fibrillation (AF) among multi-ethnic populations is less well studied worldwide. AIM: Evaluation of the prevalence and predisposing factors of AF in patients who were admitted to acute medical emergencies (ER) in Bahrain over the period of one year. METHODS: Two hundred and fifty three patients with onset of AF were studied. The mean difference of biochemical data and clinical characteristics between Middle Eastern (ME) and sub continental (SC) patients was evaluated. The odds ratio of different predisposing factors for the development of clinical events in AF patients was assessed using multiple logistic regression analysis. RESULTS: Out of 7,450 patients that were admitted to ER over one year, 253 had AF based on twelve leads Electrocardiogram (ECG), with prevalence of 3.4%. In the whole study, the mean age was 59.45 +/- 18.27 years, with 164 (65%) male. There were 150 ME patients (59%), and 107 (41%) SC, 55 (22%) were Indian (IND) and 48 (19%) were South Asian (SA). In the whole study clinical presentation was of 48% for palpitation, pulmonary edema was of 14%, angina pectoris on rest of 12%, 10% had embolic phenomena, 6% had dizziness, and 7% were asymptomatic. The odds ratio of different variables for occurrence of clinical events in the study was positive of 2.2 for history of hypertension, 1.8 for sickle cell disease, 1.2 for high body mass index (BMI) >30, 1.1 for mitral valve disease. The ME patients, compared with SC, were older, had significantly higher body mass index, higher history of rheumatic valve disease, sickle cell disease with high level of uric acid and lower hemoglobin. The history of hypertension, DM and smoking was higher among the SC patients. The rate of thyroid disease was equal in both groups. CONCLUSION: The prevalence of atrial fibrillation was 3.4% with male predominance of 65%. Patients of sub continental origin were younger with a significantly high history of hypertension and ischemic heart disease. The patients of Middle Eastern origin had significantly high rate of rheumatic heart disease, and sickle cell disease. The history of hypertension was the most important independent clinical predictor of adverse events in patients presented with AF. PMID- 26949339 TI - Type A Aortic Dissection Presenting with Acute Lower Extremity Vascular Insufficiency in the Absence of Chest Pain. AB - We report a case of a 53 year-old man with a history of hypertension presenting with acute left lower extremity parasthesias and pulselessness initially presumed to be secondary to arterial thrombosis or embolism. Work-up included a transthoracic echocardiogram which revealed an aortic dissection at the level of the aortic root extending to the visualized portions of the descending aorta. Type A aortic dissections are relatively rare, with the vast majority of patients presenting with chest pain. Timely diagnosis of Type A aortic dissections are critical as to facilitate rapid surgical repair. To our knowledge, this is the first report of a painless Type A aortic dissection presenting with isolated lower extremity vascular insufficiency and demonstrates the potential role of transthoracic echocardiography as a rapid, non-invasive bedside modality in visualizing Type A aortic dissections. PMID- 26949338 TI - Pulsed and Tissue Doppler Echocardiographic Changes in Hypertensive Crisis with and without End Organ Damage. AB - BACKGROUND: Hypertensive crisis (HC) is a common medical emergency associated with acute rise in arterial blood pressure that leads to end-organ damage (EOD). Therefore, it is imperative to find markers that may help in the prediction of EOD in acute hypertensive crisis. AIM: To assess the clinical presentations on admission; echocardiographic changes of pulsed and tissue Doppler changes in EOD patients compared with no EOD; and the risk of developing end organ damage for clinical and biochemical variables in hypertension crisis. MATERIAL AND METHODS: The data of 241 patients with hypertensive crisis with systolic blood pressure (SBP) of >180 mmHg or diastolic blood pressure (DBP) >120 mmHg were extracted from patients files. Patients divided into hypertensive emergency (HE) with EOD, n = 62 and hypertensive urgency (HU) without EOD, n = 179. LV hypertrophy on ECG, echo parameters for wall thickness, left Ventricular mass index (LVMI), Body mass index (BMI), pulse Doppler ratio of early filling velocity E wave to late A wave (E/A) and ratio of E wave velocity to tissue Doppler Em to E wave (E/Em) were evaluated. Serum creatinine, hemoglobin, age, gender, body mass Index (BMI), history of diabetes mellitus, smoking, hypertension, stroke and hyperlipidemia were recorded. Multiple logistic regression analysis was applied for risk prediction of end organ damage of clinical variables. RESULTS: Patients with HE compared with HU were significantly older, with a significantly higher SBP on admission, high BMI and LVMI. Further there were significantly higher E/A ratio on Doppler echo and higher E/Em ratio on tissue Doppler echocardiogram. Multiple regression analysis with adjustment for age and sex shows positive predictive value with odds ratio of SBP on admission >220 mmHg of 1.98, serum creatinine > 120 ug/L of 1.43, older age > 60 year of 1.304, obesity (BMI >= 30) of 1.9, male gender of 2.26 and left ventricle hypertrophy on ECG of 1.92. The hemoglobin level, history of smoking, hyperlipidemia and DM were with no significant predictive value. The pulsed Doppler E/A ratio was >=1.6, E/Em > 15, LVMI > 125 gm/m(2) in patients with EOD compared with those without. CONCLUSION: In patients presented with hypertensive crisis, the echo indices of E/A ratio and E/Em ratio of tissue Doppler are significantly higher in patients with hypertensive emergency compared to hypertensive urgency. The left ventricle hypertrophy on ECG, high LV mass index of >125 gm/m(2), BMI > 30, old age > 60 year, male gender and history of hypertension and stroke were positive predictors of poor outcome and end organ damage. PMID- 26949340 TI - Dobutamine Stress Echocardiography for the Bedside Assessment of Viability Following a Motor Vehicle Accident and Subsequent Myocardial Infarction: A Case Report. AB - The authors describe a case of a critically ill patient presenting after motor vehicle trauma complicated by anterior myocardial infarction and cardiogenic shock. Assessment of myocardial viability in the territory of a critically stenosed left anterior descending artery (LAD) was necessary to determine the optimal management strategy. Bedside dobutamine stress echocardiography (DSE) demonstrated viability in the LAD territory and the patient underwent uncomplicated single-vessel bypass surgery with subsequent improvement in left ventricular function. This case illustrates the utility of bedside DSE to assess myocardial viability in patients for whom other non-invasive modalities are not feasible. PMID- 26949342 TI - Estrogen Receptor Alpha (ESR1) Single-Nucleotide Polymorphisms (SNPs) Affect Malignant Melanoma Susceptibility and Disease Course. AB - The incidence of malignant melanoma in the developed world is continuously increasing. We conducted a case-control study in order to evaluate the association between each of the four estrogen receptor alpha polymorphisms (ESR1 single-nucleotide polymorphisms [SNPs] +2464C/T, -4576A/C, +1619A/G, and +6362C/T) and malignant melanoma susceptibility and disease course. The study population consisted of 205 Caucasian patients who were diagnosed as having malignant melanoma and 208 healthy Caucasian controls. Through DNA genotyping, we identified a SNP-dependent malignant melanoma susceptibility as well as a SNP dependent effect on the course of disease and response to therapy. PMID- 26949341 TI - A Simple Model to Study Tau Pathology. AB - Tau proteins play a role in the stabilization of microtubules, but in pathological conditions, tauopathies, tau is modified by phosphorylation and can aggregate into aberrant aggregates. These aggregates could be toxic to cells, and different cell models have been used to test for compounds that might prevent these tau modifications. Here, we have used a cell model involving the overexpression of human tau in human embryonic kidney 293 cells. In human embryonic kidney 293 cells expressing tau in a stable manner, we have been able to replicate the phosphorylation of intracellular tau. This intracellular tau increases its own level of phosphorylation and aggregates, likely due to the regulatory effect of some growth factors on specific tau kinases such as GSK3. In these conditions, a change in secreted tau was observed. Reversal of phosphorylation and aggregation of tau was found by the use of lithium, a GSK3 inhibitor. Thus, we propose this as a simple cell model to study tau pathology in nonneuronal cells due to their viability and ease to work with. PMID- 26949343 TI - The VA Point-of-Care Precision Oncology Program: Balancing Access with Rapid Learning in Molecular Cancer Medicine. AB - The Department of Veterans Affairs (VA) recognized the need to balance patient centered care with responsible creation of generalizable knowledge on the effectiveness of molecular medicine tools. Embracing the principles of the rapid learning health-care system, a new clinical program called the Precision Oncology Program (POP) was created in New England. The POP integrates generalized knowledge about molecular medicine in cancer with a database of observations from previously treated veterans. The program assures access to modern genomic oncology practice in the veterans affairs (VA), removes disparities of access across the VA network of clinical centers, disseminates the products of learning that are generalizable to non-VA settings, and systematically presents opportunities for patients to participate in clinical trials of targeted therapeutics. PMID- 26949345 TI - A Case of Cystic Adventitial Degeneration of the Left Popliteal Artery Diagnosed by Intravascular Ultrasound. AB - An 87-year-old male was admitted with intermittent claudication of the left calf. We performed lower extremity angiography, which revealed stenosis of the left popliteal artery. Intravascular ultrasound (IVUS) image correctly identified the cystic appearance of visualized extravascular hypodensity, causing extrinsic compression of the lumen. We diagnosed the condition as cystic adventitial degeneration (CAD) of the popliteal artery. We operated a resection of a cyst with the artery and replaced the autovein graft (saphenous vein). After surgery, the patient was free of symptoms. CAD is a rare disease; thus, our IVUS findings may provide unique diagnostic clues in patients with CAD. PMID- 26949344 TI - Imaging Biomarkers in Immunotherapy. AB - Immune-based therapies have been in use for decades but recent work with immune checkpoint inhibitors has now changed the landscape of cancer treatment as a whole. While these advances are encouraging, clinicians still do not have a consistent biomarker they can rely on that can accurately select patients or monitor response. Molecular imaging technology provides a noninvasive mechanism to evaluate tumors and may be an ideal candidate for these purposes. This review provides an overview of the mechanism of action of varied immunotherapies and the current strategies for monitoring patients with imaging. We then describe some of the key researches in the preclinical and clinical literature on the current uses of molecular imaging of the immune system and cancer. PMID- 26949346 TI - Pathology of Idiopathic Interstitial Pneumonias. AB - The updated classification of idiopathic interstitial pneumonias (IIPs) in 2013 by American Thoracic Society/European Respiratory Society included several important revisions to the categories described in the 2002 classification. In the updated classification, lymphoid interstitial pneumonia (LIP) was moved from major to rare IIPs, pleuroparenchymal fibroelastosis (PPFE) was newly included in the rare IIPs, acute fibrinous and organizing pneumonia (AFOP) and interstitial pneumonias with a bronchiolocentric distribution are recognized as rare histologic patterns, and unclassifiable IIP (UCIP) was classified as an IIP. However, recent reports indicate the areas of concern that may require further evaluation. Here, we describe the histopathologic features of the updated IIPs and their rare histologic patterns and also point out some of the issues to be considered in this context. PMID- 26949347 TI - A Rare Occurrence of Simultaneous Venous and Arterial Thromboembolic Events - Lower Limb Deep Venous Thrombosis and Pulmonary Thromboembolism as Initial Presentation in Acute Promyelocytic Leukemia. AB - The development of acute myeloid leukemia has been attributed to various factors, including hereditary, radiation, drugs, and certain occupational exposures. The association between malignancy and venous thromboembolism events is well established. Here, we present a case of a 70-year-old Indian man who had presented with arterial and venous thrombosis, and the patient was later diagnosed with acute promyelocytic leukemia (APL). In our case, the patient presented with right lower limb deep venous thrombosis and pulmonary thromboembolism four months prior to the diagnosis of APL. Although thromboembolic event subsequent to the diagnosis of malignancy, and especially during the chemotherapy has been widely reported, this prior presentation with simultaneous occurrence of both venous and arterial thromboembolism has rarely been reported. We take this opportunity to state the significance of a complete medical evaluation in cases of recurrent or unusual thrombotic events. PMID- 26949348 TI - Continuous Glucose Monitoring in Patients with Abnormal Glucose Tolerance during Pregnancy: A Case Series. AB - Abnormal glucose tolerance during pregnancy is associated with perinatal complications. We used continuous glucose monitoring (CGM) in pregnant women with glucose intolerance to achieve better glycemic control and to evaluate the maternal glucose fluctuations. We also used CGM in women without glucose intolerance (the control cases). Furthermore, the standard deviation (SD) and mean amplitude of glycemic excursions (MAGE) were calculated for each case. For the control cases, the glucose levels were tightly controlled within a very narrow range; however, the SD and MAGE values in pregnant women with glucose intolerance were relativity high, suggesting postprandial hyperglycemia. Our results demonstrate that pregnant women with glucose intolerance exhibited greater glucose fluctuations compared with the control cases. The use of CGM may help to improve our understanding of glycemic patterns and may have beneficial effects on perinatal glycemic control, such as the detection of postprandial hyperglycemia in pregnant women. PMID- 26949349 TI - Endothelial-to-mesenchymal transition contributes to the myofibroblast population in proliferative diabetic retinopathy. PMID- 26949350 TI - Validation of the existing modified screening criteria for detection of all cases of Retinopathy of Prematurity in preterm babies - 11 year study from a governorate referral hospital in Oman. AB - PURPOSE: To study appropriateness of our modified screening criteria for detection of all cases of Retinopathy of Prematurity (ROP) among preterm babies. METHOD: Retrospective observational cohort study among preterm neonates who underwent ROP screening as per set protocol for 11 years at Nizwa Hospital, Al Dhakilya Governorate, Oman. We screened all babies with gestational age ?32 weeks or BW ? 1500 g. Preterm babies >32 weeks of GA or BW > 1500 g with unstable clinical course believed to be at high risk by the attending neonatologist also were screened. RESULTS: During the study period 528 babies were screened for ROP of which 76 babies were excluded due to death, associated congenital ocular malformation and loss for follow-up either due to transfer to other institution or defaulting. Thus 452 babies were included in the final analysis. Incidence of ROP was 46.4% of which 27.9% had mild ROP, 11.3% had severe ROP which regressed and 7.3% had severe ROP who were treated. The incidence of ROP among infants with GA < 26 wks, 26-28 wks, 29-30 wks, 31-32 wks and above 32 weeks was 100.0%, 80.0%, 59.3%, 34.4% and 19.4% respectively. 56 babies of this cohort belonged to Extended (modified) criteria group. Among these 12 babies had ROP out of which 9 had mild ROP and 3 had severe ROP. Among cases with severe ROP, two cases regressed spontaneously and one case needed treatment. Multivariate analysis using stepwise regression model showed statistically significant association of GA and BW to development of ROP. We would have missed few babies with ROP if we had followed other criteria. CONCLUSION: Our modified screening criteria seem to be appropriate as no infant with severe ROP was missed during the study period. Incidence of severe ROP among babies in the extended criteria group (5.4%) is low but significant compared to lower gestational age. We plan to formulate a scoring system following all risk factor analysis to enable us to optimize the number of infants screened. Detection of all babies with ROP is important as they need long term follow-up for the timely detection and management of associated ocular comorbidities. PMID- 26949351 TI - Choroidal thickness profile in Retinitis Pigmentosa - Correlation with outer retinal structures. AB - PURPOSE: To compare the choroidal thickness (CT) of subjects with Retinitis Pigmentosa (RP) with age-matched healthy subjects and to correlate the visual acuity with retinal parameters including central macular thickness (CMT), inner segment/outer segment junction (IS/OS junction) integrity, external limiting membrane (ELM) integrity and choroidal thickness in subjects with RP. METHODS: Eighty-eight eyes (69 patients) with typical RP and 188 eyes of 104 healthy subjects were enrolled between September 2012 and January 2013. All subjects underwent a comprehensive ocular examination including choroidal imaging using enhanced depth imaging with spectral domain optical coherence tomography. Outcome measures were CT difference between RP and age-matched healthy subjects; and correlation of various factors such CMT, IS/OS junction integrity, ELM integrity, and CT with visual acuity. RESULTS: Among RP subjects, mean age was 31.39 +/- 13.4 years with a mean BCVA of 0.99 +/- 0.94 logMAR. Mean spherical equivalent was -0.6 +/- 1.6D. Mean CMT was 148.48 +/- 119 MUm. Mean subfoveal CT was 296.9 +/- 72 MUm. Mean IS/OS and ELM integrity was 42.2 +/- 46.6% and 43.75 +/- 45.7%, respectively. The mean age was 40.0 +/- 13.5 years with a mean spherical equivalent of 0.18 +/- 0.6D for the normal age-matched healthy group. Mean subfoveal CT was 283.1 +/- 47.8 MUm. CT at various locations in patients of various ages in the RP group did not show any statistical significant difference (P = ?0.05) in comparison with age-matched healthy subjects. On multivariate regression, ELM percentage integrity had the strongest association with best corrected visual acuity, followed by IS/OS junction percentage integrity. Subfoveal choroidal thickness had very weak correlation with visual acuity as well other retinal parameters. There was a significant difference in the outer retinal structure integrity (p = 0.002) and CMT (p = 0.02) between the eyes with good (?20/200) and poor vision (<20/200), but not in subfoveal choroidal thickness (p = 0.3). CONCLUSIONS: Our study results did not show any significant difference in choroidal thickness between subjects with RP and age-matched healthy subjects. Choroidal thickness correlated better with the age but not with the vision or outer retinal structures in eyes with RP. Outer retinal structure integrity and CMT had a better correlation with visual acuity. PMID- 26949352 TI - Systemic steroids as an aid to the management of Idiopathic Polypoidal Choroidal Vasculopathy (IPCV): A descriptive analysis. AB - PURPOSE: To determine the role of systemic steroids in improving visual acuity, preventing recurrence and hastening pigment epithelial detachment resolution in IPCV patients. METHODS: Retrospective computer assisted comparative case series of consecutive patients with documented IPCV who did and did not receive systemic steroids as part of their treatment regimen between 2007 and 2012. Patients who had systemic contraindication to steroid therapy were excluded from the steroid arm. Data collected included demographics, the best corrected visual acuity, details of the ocular and systemic exam, the treatment offered, the follow-up period and the final visual and anatomic outcomes. Outcome measures included the final BCVA, the time to resolution of the associated pigment epithelial detachment (PED, if present), the recurrence rate and the associated side effects, if any. Appropriate statistical analysis was done. Statistical significance: p < 0.05. RESULTS: 14 patients (14 eyes) had received systemic steroids in the stated period; these were compared with 26 consecutive patients (26 eyes) who did not. Mean age: 59.24 vs 62.38 years (A vs B). Mean baseline BCVA: 1.86 +/- 1.24 logMAR vs 2.12 +/- 1.48 logMAR (A vs B). 8 females in Group A and 14 in Group B. 11 patients in group A and 19 in group B had associated systemic hypertension. Therapy consisted of laser photocoagulation, anti-vascular endothelial growth factor therapy, photodynamic therapy or a combination of these. Mean follow-up: 43.21 +/- 11.32 months (Group A) vs 48.24 +/- 9.75 months (Group B). BCVA at three months was significantly better (0.84 +/- 0.74 logMAR vs 1.16 +/- 0.89 (p = 0.039). Final BCVA: 0.86 +/- 0.78 logMAR (Group A) vs 1.29 +/- 0.92 (Group B, p = 0.042). 7 patients in group A and 12 in Group B had a recurrence (insignificant difference). 1 patient in Group A and 7 in Group B had unresolved disease (persistent PED) at the end of follow-up (OR: 4.60; 95% CI 1.7 11.10). CONCLUSION: Steroids appear to improve visual acuity and accelerate the resolution of the PEDs in patients with IPCV and large PEDs, but do not seem to influence recurrence. PMID- 26949353 TI - A control-matched comparison of flap off and flap on laser-assisted subepithelial keratectomy (LASEK) for the treatment of myopia and myopic astigmatism. AB - PURPOSE: To compare the visual and refractive outcomes of flap off and flap on, Laser Assisted Subepithelial Keratectomy (LASEK) for low to moderate myopia. METHODS: A prospective non-randomized control-matched study was conducted in which 53 patients underwent LASEK for the treatment of low to moderate myopia and myopic astigmatism. Right eye of each patient had the flap removed (flap off) while in the left eye the flap was recapped (flap on). Equal number (N = 53) of flap on was matched with flap off having preoperative manifest refraction spherical equivalent within +/-0.75 Diopters (D). Primary outcome variables included uncorrected visual acuity (UCVA), best spectacle-corrected visual acuity (BSCVA) and manifest refraction. RESULTS: Preoperatively, the mean spherical equivalent (SE) was -3.59 +/- 1.46 D for flap off and -3.67 +/- 1.51 D for flap on (p = 0.779). The mean preoperative sphere was -3.32 +/- 1.58 D for flap off group and -3.36 +/- 1.61 D for flap on group (p = 0.338) whereas, the mean preoperative cylinder was -0.55 +/- 0.70 D and -0.63 +/- 0.68 D for flap removal and flap preservation groups respectively (p = 0.576). Postoperatively, the mean LogMAR UCVA was -0.035 +/- 0.079 for flap off and -0.043 +/- 0.085 for flap on. The percentages of eyes that had UCVA of 20/40 or better were 98.1% for flap off group and 100% for flap on group (p = 0.317). Mean postoperative SE was 0.00 +/- 0.19 D for flap off group and -0.03 +/- 0.43 D for flap on group. In flap removal group, 100% eyes were within +/-0.50 D of the intended correction while in flap preservation group, 92.5% and 100% eyes were within +/-0.50 D and +/-1.00 D of the intended correction, respectively. Mean postoperative LogMAR BSCVA was -0.013 +/- 0.044 for flap removal group and -0.016 +/- 0.049 for flap preservation group (p = 0.727). CONCLUSIONS: The differences in the visual and refractive results between flap preservation and flap removal groups were not clinically significant. Both procedures seemed safe and effective for the treatment of myopia and myopic astigmatism. PMID- 26949354 TI - The applicability of correction factor for corneal thickness on non-contact tonometer measured intraocular pressure in LASIK treated eyes. AB - PURPOSE: To determine the applicability of central corneal thickness (CCT) based correction factor for non-contact tonometer (NCT) measured intraocular pressure (IOP) readings. METHOD: A prospective, non-randomized study involved 346 eyes of 173 consecutive patients with age ?21 years undergoing laser-assisted in situ keratomileusis (LASIK) for myopia and/or myopic astigmatism. The CCT and IOP were measured before and after the LASIK procedure. The IOP pre and post-LASIK was compared after applying the correction factor for CCT. Patients not completing the 3 month postoperative follow-up were excluded. RESULTS: The median spherical equivalent before undergoing LASIK was -4.25D (inter-quartile range, -3.25D). The mean preoperative CCT was 536.82 +/- 33.71 MUm which reduced to 477.55 +/- 39.3 MUm (p < 0.01) post-LASIK. The mean IOP reduced from a preoperative value of 14.6 +/- 2.32 mmHg to 10.64 +/- 2.45 mmHg postoperatively (p < 0.01). On applying correction for the corneal thickness, the pre and postoperative IOP was 15.14 +/- 2.8 mmHg and 15.37 +/- 2.65 mmHg (p = 0.06) respectively with a strong positive correlation (r = 0.7, p < 0.01). Three hundred eyes (86.7%) had an absolute difference in IOP of less than 3.0 mmHg post-CCT correction which is within the retest variability of NCT. Only 46 eyes (13.3%) had an absolute difference of more than 3.0 mmHg. CONCLUSION: The modified Ehler's correction algorithm used in this study can be effectively applied in the normal IOP range in a majority of patients. PMID- 26949355 TI - Corneal and conjunctival sensitivity in rosacea patients. AB - PURPOSE: To assess corneal and conjunctival sensitivity in rosacea patients. METHODS: A total of 55 patients with rosacea and 37 control subjects participated in the study. Corneal and conjunctival sensitivity was determined by Cochet Bonnet esthesiometer. Subjective symptoms of ocular dryness were evaluated using Ocular Surface Disease Index (OSDI). Schirmer's I test (ST), tear breakup time (tBUT) and ocular surface staining with fluorescein were carried out to measure objective signs. RESULTS: The mean corneal and conjunctival sensitivity did not differ significantly between rosacea patients and controls (all p > 0.05). Schirmer's I test and tBUT were significantly reduced (p = 0.004 for OD and p < 0.001 for OS) and grade of ocular surface staining was significantly high (p = 0.018 for OD and p = 0.038 for OS) in rosacea patients. Corneal and conjunctival sensitivity did not show significant correlation with ST, tBUT, ocular surface staining (Oxford Schema), duration of rosacea and OSDI score. CONCLUSIONS: Corneal and conjunctival sensitivity did not change significantly in rosacea. PMID- 26949356 TI - The combination of phacoemulsification surgery and intravitreal triamcinolone injection in patients with cataract and diabetic macular edema. AB - PURPOSE: To assess the safety and efficiency of combined phacoemulsification (PHACO) surgery and intravitreal triamcinolone (IVTA) injection with or without macular grid laser photocoagulation in patients with cataract and diabetic macular edema. MATERIAL AND METHODS: This prospective study included 41 eyes of 36 diabetic patients with cataract and coexisting clinically significant macular edema (CSME). After PHACO and IVTA injection eyes were divided into two groups: the laser and IVTA group (Group 1) and only IVTA group (Group 2). Preoperative and postoperative best corrected visual acuity (BCVA), central macular thickness (CMT), and intraocular pressure (IOP) were recorded. Paired sample t-test was used to compare data in the groups and C square test for qualitative variables. RESULTS: Postoperative BCVA was significantly higher than the initial BCVA during the follow-up period in both groups (p < 0.01). The BCVA 6 months after surgery was significantly higher in group 1 than in group 2 (p < 0.01). There was no statistically significant difference in IOP between two groups preoperatively and postoperatively during the follow-up period (p > 0.05). There was no statistically significant difference between both groups in mean CMT preoperatively and 2nd week, 2nd month and 3rd month after surgery (p > 0.05). The mean CMT 6 months after surgery was statistically significantly lower in group 1 than in group 2 (p < 0.01). CONCLUSIONS: PHACO surgery combined with IVTA injection improves BCVA and provides a decrease in CMT in diabetic patients with CSME. Additional macular grid laser photocoagulation after surgery helps to preserve this improvement in BCVA and decrease in CMT. PMID- 26949357 TI - Ocular manifestation of Ichthyosis. AB - PURPOSE: Ichthyosis is a rare dermato-ocular disease. This study evaluates the presenting ocular signs, symptoms, complications and prognosis of ichthyosis in a case series from Saudi Arabia. METHODS: A retrospective chart review was performed for 11 patients with ichthyosis who presented to King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia, over the last 20 years. RESULTS: The most common presenting ocular diagnosis was ectropion of both the lids. Two patients developed corneal perforation with poor prognosis. Most of the patients underwent skin grafting to repair eyelid ectropion. The visual prognosis was excellent because timely surgical interventions were performed. Hence the rate of corneal complications such as perforation was low. CONCLUSION: The most ocular presentation of ichthyosis is ectropion of both the upper and lower lids. Despite good visual prognosis, there were some devastating corneal complications such as perforation with unpredictable outcomes. PMID- 26949358 TI - Age, gender and refractive error association with intraocular pressure in healthy Saudi participants: A cross-sectional study. AB - PURPOSE: To determine the distribution of intraocular pressure (IOP) and its association with age, gender and refractive error in non-glaucomatous Saudi participants. DESIGN: Hospital-based cross-sectional observational study during Vision Day Screening Program. PARTICIPANTS: 458 participants living in the Al Khobar, Saudi Arabia. METHODS: Recruited participants (aged 20 years or over) underwent a comprehensive questionnaire and ocular examination, including measurement of IOP with Perkins hand-held applanation tonometry and autorefraction. MAIN OUTCOME MEASURES: The distribution of IOP of either of the eyes (right or left eye by randomization) and associations with age, gender and refractive error. RESULTS: Median IOP was 15.0 (range: 6-28) mmHg in the total population. There is no significant difference between the overall IOP of male participants, median 15 (range: 6-28) mmHg and female participants, median 16 (range: 6-28) mmHg (p = 0.180). No statistically significant difference in IOP in relation to age comparing 20-45 years group to 46-69 years group was documented (p = 0.751). There was no statistically significant relationship between refractive error category and IOP (p = 0.405). Ocular hypertension with IOP > 21 mmHg was found in 8.7% of the participants. CONCLUSION: Variation in IOP by gender, age group and type of refractive error was not statistically significant. The observations need confirmation by study with larger sample representing Saudi population. PMID- 26949359 TI - Corneal xanthogranuloma in association with multiple endocrine neoplasia 1: A clinicopathologic case report and review of the literature. AB - Juvenile xanthogranuloma (JXG) is a benign inflammatory condition of uncertain pathogenesis. It is characterized by skin and ocular involvement - typically in the iris - in children. It has been reported in older age groups and has been also observed to involve other ocular structures such as the cornea and conjunctiva. In this case report, we are presenting an extensive right eye corneal lesion in a 43-year old male which showed the typical histopathological feature of JXG and in association with multiple endocrine neoplasia (type 1). Similar cases in the English-language literature have been also reviewed. PMID- 26949360 TI - Macular infarction and traumatic optic neuropathy following blunt ocular trauma. AB - Macular infarction is a visually disabling condition caused by a variety of reasons. It has rarely been described in association with blunt ocular trauma. We describe the case of a young healthy male who sustained injury with a bull's leg and presented with severe visual loss owing to macular infarction and traumatic optic neuropathy. This report of an angiographically documented macular infarct secondary to ocular contusion highlights an additional feature in the spectrum of ocular findings following blunt trauma that might lead to a severe and permanent affliction of vision. PMID- 26949361 TI - Extracting a large live freely floating cysticercosis cyst from the anterior chamber of the eye using visco expression technique: A case report. AB - Ocular involvement by cysticercosis is uncommon and rare in the anterior chamber. It can give rise to iridocyclitis which can be potentially blinding to the patient. The management is usually surgical. We report a case of 18-year-old girl with large cysticercosis cyst in the anterior chamber. The cyst was removed intact by viscoexpression technique from the anterior chamber of the eye and the patient achieved visual acuity of 6/9 post-operatively. PMID- 26949362 TI - Peripheral retinal ischemia in a young Indian woman with neurofibromatosis type 1. AB - Neurofibromatosis type 1 (NF-1) is an autosomal dominantly inherited disease characterized by cafe-au-lait spots, neurofibromas, axillary freckling, Lisch nodules of iris, gliomas and various systemic vascular ischemic manifestations mainly in the aorta, brain and kidney. Retinal vascular manifestations in patients with NF-1 are usually representative of retinal capillary hemangiomatosis. Few cases of NF-1 with retinal vascular occlusive disease have been described. We describe a young Indian woman with NF-1 with unilateral peripheral retinal ischemia but no vascular abnormality at the posterior pole. PMID- 26949364 TI - Valsalva retinopathy with double ring sign: Laser membranotomy for twin bleeds. AB - This report describes the case of a 27-year-old lady who presented with sudden decrease in vision in the right eye for one week. She was suffering from constipation and had a history of straining while passing stools. She was found to have two large sub-internal limiting membrane haemorrhages with the classical double ring sign, which were drained using laser membranotomy, following which her vision rapidly improved. This case of two sub-internal limiting membrane haemorrhages is reported for its rarity and also highlights the usefulness of laser hyaloidotomy or membranotomy in large haemorrhages of recent onset. The literature was also reviewed to discuss the other treatment options in brief. PMID- 26949363 TI - Combined cataract phacoemulsification and aniridia endocapsular rings implantation in a patient with bilateral congenital aniridia and cataract: A case report. AB - The objective of this article was to determine the long-term outcome of surgical treatment in a patient with bilateral congenital aniridia and congenital cataracts. The patient was treated by cataract removal and implantation of a single piece IOL in both eyes. Two aniridia rings were also implanted in the capsular bag. The best-corrected visual acuity (BCVA), intraocular pressure (IOP), stability of the intraocular lens (IOL) and subjective glare reduction were measured for two years after the surgery. After 10 months, the IOP in the left eye had increased to 26 mmHg despite the fact that anti-glaucoma medication was added. Therefore, the patient was scheduled for an Ahmed valve implantation. These results suggest that good visual outcomes can be achieved in patients with bilateral congenital aniridia and cataracts. Nevertheless, the IOPs must be continuously monitored, and glaucoma screening performed to prevent further complications. PMID- 26949365 TI - Endogenous bacterial endophthalmitis masquerading as an intraocular tumor. AB - A 40-year-old female patient referred for a possible intraocular tumor was found to have an endogenous bacterial endophthalmitis in her right eye. Fundus examination revealed an amelanotic dome shaped choroidal mass and an exudative retinal detachment. Enhanced Depth Imaging-Optical Coherence Tomography (EDI OCT), fundus autofluorescence (FAF) and ultrasounds were suggestive of a possible choroidal melanoma. A multimodal imaging approach and a thorough anamnesis were instrumental in establishing the correct diagnosis. PMID- 26949366 TI - Secondary implantation of implantable collamer lens (ICL) for correction of anisometropic hyperopia in a 3-year-old pseudophakic child. AB - We report the first case of secondary implantation of implantable collamer lens (ICL) for correction of anisometropic hyperopia in a 3-year-old pseudophakic child. The ICL implantation was considered in our patient due to parental noncompliance for contact lens and spectacles use for one year. In terms of efficacy, the preoperative refractive error of +7.00-1.75 diopter (D) reduced to +1.00-1.75 D. The uncorrected distance visual acuity (UDVA) significantly improved from 20/400 (preoperatively) to 20/50 (postoperatively). In terms of safety, after an uneventful implantation surgery, the ICL was well tolerated, and remained well centered, with no serious postoperative complications encountered over a 22-month follow-up. PMID- 26949367 TI - Unilateral phthiriasis palpebrarum infestation in a child during occlusion therapy for amblyopia: Case report. AB - An 8-year-old mentally retarded boy is brought to the hospital because of itching and burning at his right eye for 10 days. He was on full time right eye occlusion therapy for left amblyopia. Slit lamp examination revealed nits and adult lice anchored to the eyelashes in his occluded eye. Eyelashes and all detected lice and nits were mechanically trimmed, and sent for parasitological examination, which confirmed the diagnosis. Upon familial evaluation for additional infestation, the father was also found to have genital phthiriasis pubis and received appropriate treatment. While phthiriasis palpebrarum in children may signify sexual abuse, a detailed investigation by a child psychiatrist was performed and revealed no sign of abuse. Since the infestation was at only on occluded eye, the most possible explanation for the transmission was evaluated as the misusage of the adhesive patch in our case. In conclusion, sexual abuse should be excluded in children with phthiriasis palpebrarum and parents of amblyopic children on occlusion therapy should be warned about the importance of the hygiene of the patching in order to avoid any kind of infection and infestation. PMID- 26949368 TI - Diagnosis of reverse Implantable Collamer Lens (ICL) orientation on Anterior Segment Optical Coherence Tomography (ASOCT). PMID- 26949369 TI - Cytocompatibility of direct water synthesized cadmium selenide quantum dots in colo-205 cells. AB - Cadmium selenide quantum dots (CdSe QDs), inorganic semiconducting nanocrystals, are alluring increased attraction due to their highly refined chemistry, availability, and super tunable optical properties suitable for many applications in different research areas, such as photovoltaics, light-emitting devices, environmental sciences, and nanomedicine. Specifically, they are being widely used in bio-imaging in contrast to organic dyes due to their high brightness and improved photo-stability, and their ability to tune their absorption and emission spectra upon changing the crystal size. The production of CdSe QDs is mostly assisted by trioctylphosphine oxide compound, which acts as solvent or solubilizing agent and renders the QDs soluble in organic compounds (such as toluene, chloroform, and hexane) that are highly toxic. To circumvent the toxicity-related factor in CdSe QDs, we report the synthesis of CdSe QDs capped with thioglycolic acid (TGA) in an aqueous medium, and their biocompatibility in colo-205 cancer cells. In this study, the [Cd2+]/[TGA] ratio was adjusted to 11:1 and the Se concentration (10 and 15 mM) was monitored in order to evaluate its influence on the optical properties and cytocompatibility. QDs resulted to be quite stable in water (after purification) and RPMI cell medium and no precipitation was observed for long contact times, making them appealing for in vitro experiments. The spectroscopy analysis, advanced electron microscopy, and X ray diffractometry studies indicate that the final products were successfully formed exhibiting an improved optical response. Colo-205 cells being exposed to different concentrations of TGA-capped CdSe QDs for 12, 24, and 48 h with doses ranging from 0.5 to 2.0 mM show high tolerance reaching cell viabilities as high as 93 %. No evidence of cellular apoptotic pathways was observed as pointed out by our Annexin V assays at higher concentrations. Moreover, confocal microscopy analysis conducted to evaluate the intracellular uptake of TGA-CdSe QDs reveal that the TGA-CdSe QDs were uniformly distributed within the cytosolic side of cell membranes. Our results also suggest that under controlled conditions, direct water-soluble TGA-CdSe QDs can be potentially employed for bio-imaging colo-205 cancer cells with minimal adverse effects. PMID- 26949370 TI - Concise Synthesis of Tetrazole-keto-piperazines by Two Consecutive Ugi Reactions. PMID- 26949375 TI - Recurrent venous thrombosis in an adequately anticoagulated patient with pemphigus vulgaris. AB - BACKGROUND: Several autoimmune skin disorders are characterised by an increased risk of thrombosis, with bollous pemphigoid carrying a higher risk than pemphigus vulgaris (PV). We describe the case of a middle aged gentleman who developed recurrent venous thromboembolism despite adequate oral anticoagulation during very active PV that required escalation of treatment to bring the disease under control. CASE PRESENTATION: In May 2014 a 49 year gentleman was admitted for widespread mucocutaneous blistering diagnosed as PV by histology and immunofluorescence. After 6 weeks of treatment with systemic steroids and azathioprine the patient developed pulmonary emboli and started oral anticoagulation with warfarin. In late September, the patient re-presented with a severe flare of PV and a recurrent deep vein thrombosis despite oral anticoagulation within therapeutic range. Warfarin was changed to subcutaneous low molecular heparin in therapeutic dose while treatment for pemphigus was escalated: first azathioprine was switched to mycophenolate mofetil and the steroids dose increased; then due to poor response, intravenous immunoglobulins were given for three courses and finally he received four infusions of Rituximab that induced sustained remission. In April 2015 the dose of mycophenolate was decreased but anticoagulation was continued until the beginning of July 2015 to ensure that decreasing immune suppression did not allow the emergence of another flare with attendant thrombotic risk. CONCLUSION: The case highlights the risk of thrombosis and re-thrombosis in aggressive PV and demands further clinical research in this area to assess the need for thromboprophylaxis in aggressive bollous skin disease. PMID- 26949373 TI - Knowledge and attitudes of health professionals towards pressure ulcers at a rehabilitation hospital: a cross-sectional study. AB - BACKGROUND: Pressure ulcers are common conditions among hospitalized patients and impose substantial burden on patients and their caregivers. To assess the knowledge and attitudes of health professionals towards PUs prevention. METHODS: A cross-sectional study was performed in the rehabilitation hospital at King Fahad Medical City, Riyadh, Saudi Arabia in 2014. The study population consisted of nurses, physical therapists, occupational therapists, and physical medicine rehabilitation physicians who have a minimum of at least one year of clinical practice. The survey that was created for use in this study consisted of demographic characteristics, Pressure Ulcers Knowledge Test and Staff Attitude Scale. RESULTS: The survey was completed by 105 participants of the 120 total eligible staff. The mean knowledge score of correct answers from all participants was 34.1 +/- 4.8 (71.5 %). Only 77(73.3 %) participants had a mean knowledge score of >= 70 %. The mean attitude score was 30.5 (56.5 %). The study revealed that age and profession factors had a significant relationship with participants' mean knowledge of PUs prevention (P < 0.001), (P < 0.001) respectively. Moreover, 101 (98.1 %) participants are concerned about PUs prevention in their practices. While, 11 (10.7 %) of participants believe that PUs prevention is a time consuming procedure. CONCLUSIONS: The present study assessed the current knowledge and attitudes of health professionals regarding PUs prevention in an acute rehabilitation hospital. The majority of participants had an average level of knowledge and exhibited unsatisfactory attitudes towards PUs prevention. Increased health professionals awareness may improve their attitudes towards PUs prevention. PMID- 26949377 TI - Efficient Transition Probability Computation for Continuous-Time Branching Processes via Compressed Sensing. AB - Branching processes are a class of continuous-time Markov chains (CTMCs) with ubiquitous applications. A general difficulty in statistical inference under partially observed CTMC models arises in computing transition probabilities when the discrete state space is large or uncountable. Classical methods such as matrix exponentiation are infeasible for large or countably infinite state spaces, and sampling-based alternatives are computationally intensive, requiring integration over all possible hidden events. Recent work has successfully applied generating function techniques to computing transition probabilities for linear multi-type branching processes. While these techniques often require significantly fewer computations than matrix exponentiation, they also become prohibitive in applications with large populations. We propose a compressed sensing framework that significantly accelerates the generating function method, decreasing computational cost up to a logarithmic factor by only assuming the probability mass of transitions is sparse. We demonstrate accurate and efficient transition probability computations in branching process models for blood cell formation and evolution of self-replicating transposable elements in bacterial genomes. PMID- 26949376 TI - Multiple Measures of Fixation on Social Content in Infancy: Evidence for a Single Social Cognitive Construct? AB - The preference of infants to fixate on social information in a stimulus is well known. We examine how this preference manifests across a series of free-viewing tasks using different stimulus types. Participants were thirty typically developing infants. We measured eye movements when viewing isolated faces, faces alongside objects in a grid, and faces naturally presented in photographed scenes. In each task, infants fixated social content for longer than nonsocial content. Social preference scores representing distribution of fixation to social versus general image content were highly correlated and thus combined into a single composite measure, which was independent of demographic and behavioral measures. We infer that multiple eye-tracking tasks can be used to generate a composite measure of social preference in infancy. This approach may prove useful in the early characterization of developmental disabilities. PMID- 26949372 TI - High use of over-the-counter analgesic; possible warnings of reduced quality of life in adolescents - a qualitative study. AB - BACKGROUND: Use of over-the-counter analgesics among adolescents has increased markedly. High consumption of over-the-counter analgesics among adolescents is associated with frequent pain, lower self-esteem, reduced sleep, lower educational ambition, binge drinking, higher caffeine consumption, and part-time employment. Knowledge about life experiences of adolescents who frequently use over-the-counter analgesics may be useful to prevent health problems. The purpose of the study was to increase knowledge about adolescents who suffer from frequent pain and have a high consumption of over-the-counter analgesics. METHODS: A qualitative study, employing one-on-one, in-depth interviews using a thematic interview guide. Data were collected in Norway in 2013-2014. Three boys and sixteen girls; aged 14-16 years, who continuously consumed over-the-counter analgesics were recruited from ten high schools in urban and suburban districts. Candidate participants were excluded if they were medically diagnosed with an acute or chronic illness, requiring extended use of over-the-counter analgesics within the last year. The interviews were taped, transcribed and analysed as text according to Kvale's three contexts of interpretation: self-understanding, common sense and theory. RESULTS: All participants disclosed unresolved physical and psychosocial distress characterized as pain. Frequent pain from various body parts made everyday life challenging. Methods of pain self-appraisal and over-the counter analgesics use often mimicked maternal patterns. Participants reported being raised under unpredictable circumstances that contributed to long lasting family conflicts and peer-group problems. Participants wanted to feel appreciated and to be socially and academically successful. However, pain reduced their ability to manage everyday life, hampered experienced possibilities for success, and made social settings difficult. CONCLUSIONS: Childhood experiences influence how adolescents experience pain and use over-the-counter analgesics. Coping with difficult situations or attempting to mask symptoms with over-the-counter analgesics can perpetuate and amplify underlying problems. High consumption of over-the-counter analgesics and frequent pain may be warning signs of adolescents with possible health threatening conditions and reduced quality of life. These adolescent might be in need of support from school nurses and General Practitioners. This study identifies new perspectives that may lead to novel approaches to identify, guide, and support adolescents with frequent pain and high consumption of over-the-counter analgesics. PMID- 26949374 TI - Lipopolysaccharide-induced inflammation or unilateral ureteral obstruction yielded multiple types of glycosylated Lipocalin 2. AB - BACKGROUND: The amount of urinary glycoprotein lipocalin 2 (LCN2) has been known to increase after kidney injury because of failed reabsorption by the proximal tubules or direct secretion from injured tissues. However, the relationship between urinary tract obstruction and the isoform diversity of LCN2 has not been examined. METHODS: The urinary levels of LCN2 isoforms were examined in male mice after an intraperitoneal injection of lipopolysaccharide (LPS) or in a mouse model of unilateral ureter obstruction (UUO). The LCN2 levels in sera, bladder urine, renal pelvic urine, and tissue samples were also analyzed. Endo- and exoglycosidases were used to investigate the different N-glycan patterns of LCN2. RESULTS: Two isoforms of urinary LCN2 with different molecular weights were identified in an immunoblotting analysis, and the levels of both isoforms were increased 6 h after LPS administration. The primary LCN2 isoform was the lower molecular weight 22-kDa isoform, which was detected in the serum, urine, liver and kidney. In contrast, the 24-kDa LCN2 isoform was detected only in urine. In the UUO experiments, the levels of the 24-kDa LCN2 were increased in the bladder urine but not in the urine accumulated in the renal pelvis due to UUO. The 22-kDa LCN2 was identified in the renal pelvic urine from UUO mice. The peptide-N glycosidase F digestion of the two urinary LCN2 isoforms generated a single protein. Moreover, the two urinary LCN2 proteins were sensitive to neuraminidase and resistant to endoglycosidase H (Endo H). The LCN2 in the serum, lung and kidney was resistant to Endo H, as observed in urine, whereas the LCN2 in the liver and the ureter were degraded by this enzyme. CONCLUSIONS: These results suggest that the difference in the molecular weights of the LCN2 proteins was due to their N-glycan structure. The high molecular weight LCN2 in urine could be detected after the inflammatory response to LPS and UUO. Furthermore, the sensitivity to Endo H identified the presence of two types of carbohydrate moieties, depending on the tissue in which the LCN2 was produced. These findings are useful for widening the clinical applicability of urinary LCN2 analyses. PMID- 26949378 TI - Protein intake during training sessions has no effect on performance and recovery during a strenuous training camp for elite cyclists. AB - BACKGROUND: Training camps for top-class endurance athletes place high physiological demands on the body. Focus on optimizing recovery between training sessions is necessary to minimize the risk of injuries and improve adaptations to the training stimuli. Carbohydrate supplementation during sessions is generally accepted as being beneficial to aid performance and recovery, whereas the effect of protein supplementation and timing is less well understood. We studied the effects of protein ingestion during training sessions on performance and recovery of elite cyclists during a strenuous training camp. METHODS: In a randomized, double-blinded study, 18 elite cyclists consumed either a whey protein hydrolysate-carbohydrate beverage (PRO-CHO, 14 g protein/h and 69 g CHO/h) or an isocaloric carbohydrate beverage (CHO, 84 g/h) during each training session for six days (25-29 h cycling in total). Diet and training were standardized and supervised. The diet was energy balanced and contained 1.7 g protein/kg/day. A 10 s peak power test and a 5-min all-out performance test were conducted before and after the first training session and repeated at day 6 of the camp. Blood and saliva samples were collected in the morning after overnight fasting during the week and analyzed for biochemical markers of muscle damage, stress, and immune function. RESULTS: In both groups, 5-min all-out performance was reduced after the first training session and at day 6 compared to before the first training session, with no difference between groups. Peak power in the sprint test did not change significantly between tests or between groups. In addition, changes in markers for muscle damage, stress, and immune function were not significantly influenced by treatment. CONCLUSIONS: Intake of protein combined with carbohydrate during cycling at a training camp for top cyclists did not result in marked performance benefits compared to intake of carbohydrates when a recovery drink containing adequate protein and carbohydrate was ingested immediately after each training session in both groups. These findings suggest that the addition of protein to a carbohydrate supplement consumed during exercise does not improve recovery or performance in elite cyclists despite high demands of daily exhaustive sessions during a one-week training camp. PMID- 26949379 TI - Gold Nanosphere Gated Mesoporous Silica Nanoparticle Responsive to Near-Infrared Light and Redox Potential as a Theranostic Platform for Cancer Therapy. AB - A gold/mesoporous silica hybrid nanoparticle (GoMe), which possesses the best of both conventional gold nanoparticles and mesoporous silica nanoparticles, such as excellent photothermal converting ability as well as high drug loading capacity and triggerable drug release, has been developed. In contrast to gold nanorod and other heat generating gold nanoparticles, GoMe is photothermal stable and can be repetitively activated through NIR irradiation. Doxorubicin loaded GoMe (DOX@GoMe) is sensitive to both NIR irradiation and intracellularly elevated redox potential. DOX@GoMe coupled with NIR irradiation exhibits a synergistic effect of photothermal therapy and chemotherapy in killing cancer cells. Furthermore, 64Cu-labeled GoMe can successfully detect the existence of clinically relevant spontaneous lung tumors in a urethane-induced lung cancer mouse model through PET imaging. Altogether, GoMe can be utilized as an effective theranostic platform for cancer therapy. PMID- 26949381 TI - Developing a model for understanding patient collection of observations of daily living: A qualitative meta-synthesis of the Project HealthDesign Program. AB - We conducted a meta-synthesis of five different studies that developed, tested, and implemented new technologies for the purpose of collecting Observations of Daily Living (ODL). From this synthesis, we developed a model to explain user motivation as it relates to ODL collection. We describe this model that includes six factors that motivate patients' collection of ODL data: usability, illness experience, relevance of ODLs, information technology infrastructure, degree of burden, and emotional activation. We show how these factors can act as barriers or facilitators to the collection of ODL data and how interacting with care professionals and sharing ODL data may also influence ODL collection, health related awareness, and behavior change. The model we developed and used to explain ODL collection can be helpful to researchers and designers who study and develop new, personal health technologies to empower people to improve their health. PMID- 26949380 TI - What is Xenohormesis? AB - Polyphenols such as resveratrol and quercetin, which are produced by stressed plants, activate sirtuin enzymes and extend the lifespan of fungi and animals, ostensibly by mimicking the beneficial effects of caloric restriction. This observation raises an interesting question: Why should foreign molecules that are non-nutritive and seemingly unrelated to any endogenous molecule modulate the same biochemical pathways that mediate the response to an energy deficit? A possible explanation is that the sirtuin enzymes have evolved to respond to plant stress molecules as indicators of an impending deterioration of the environment. This idea has become known as the Xenohormesis Hypothesis, the name stemming from a combination of the prefix xeno-(for stranger) with hormesis (a protective response induced by mild stress). Here we review the evidence for xenohormesis in a broader context, taking into account the diverse spectrum of phytochemicals to which animals are exposed. We also consider alternative hypotheses that may explain some of the beneficial effects of plant-based foods. We suggest that xenohormesis, defined as an adaptive response in the physiology of an organism to molecular cues that are neither nutritive nor direct stressors, most likely occurs at some level. Whether this can fully or partially account for the beneficial effects of resveratrol and other phytochemicals remains to be seen. However, there is already sufficient cause to re-evaluate the relationship between complex organisms, including humans and their food. PMID- 26949382 TI - Polymorphisms of the PPAR-gamma (rs1801282) and Its Coactivator (rs8192673) Have a Minor Effect on Markers of Carotid Atherosclerosis in Patients with Type 2 Diabetes Mellitus. AB - Background. The present study was designed to clarify whether common single nucleotide polymorphisms (SNPs) of the Peroxisome Proliferator-Activated Receptor gamma (PPAR-gamma) gene (rs1801282) and the Peroxisome Proliferator-Activated Receptor-gamma Coactivator-1 (PGC-1alpha) gene (rs8192673) are associated with markers of carotid and coronary atherosclerosis in Caucasians with type 2 diabetes mellitus (T2DM). Patients and Methods. 595 T2DM subjects and 200 control subjects were enrolled in the cross-sectional study. Markers of carotid atherosclerosis were assessed ultrasonographically. In 215 out of 595 subjects with T2DM, a coronary computed tomography angiography (CCTA) was performed for diagnostic purposes. Genotyping of either rs1801282 or rs8192673 was performed using KASPar assays. Results. In our study, we demonstrated an effect of the rs1801282 on markers of carotid atherosclerosis (presence of plaques) in Caucasians with T2DM in univariate and in multivariable linear regression analyses. Finally, we did not demonstrate any association between either rs1801282 or rs8192673 and markers of coronary atherosclerosis. Conclusions. In our study, we demonstrated a minor effect of the rs1801282 on markers of carotid atherosclerosis (presence of plaques) in Caucasians with T2DM. Moreover, we demonstrated a minor effect of the rs8192673 on CIMT progression in the 3.8-year follow-up in Caucasians with T2DM. PMID- 26949383 TI - Experimental Matching of Instances to Heuristics for Constraint Satisfaction Problems. AB - Constraint satisfaction problems are of special interest for the artificial intelligence and operations research community due to their many applications. Although heuristics involved in solving these problems have largely been studied in the past, little is known about the relation between instances and the respective performance of the heuristics used to solve them. This paper focuses on both the exploration of the instance space to identify relations between instances and good performing heuristics and how to use such relations to improve the search. Firstly, the document describes a methodology to explore the instance space of constraint satisfaction problems and evaluate the corresponding performance of six variable ordering heuristics for such instances in order to find regions on the instance space where some heuristics outperform the others. Analyzing such regions favors the understanding of how these heuristics work and contribute to their improvement. Secondly, we use the information gathered from the first stage to predict the most suitable heuristic to use according to the features of the instance currently being solved. This approach proved to be competitive when compared against the heuristics applied in isolation on both randomly generated and structured instances of constraint satisfaction problems. PMID- 26949384 TI - Foreign Bodies Ingestion in Children: Experience of 61 Cases in a Pediatric Gastroenterology Unit from Romania. AB - The ingestion of foreign bodies is a worldwide pediatric pathology. We assessed the clinical, endoscopic, and therapeutic aspects of this condition in a pediatric gastroenterology unit. We reviewed 61 patients (median age of 3.25 +/- 4.7 years). The most frequently ingested objects were coins (26.23%), unidentified metal objects (13.11%), bones (8.19%), batteries, and buttons (6.55%). The clinical features we encountered included abdominal pain (55.73%), vomiting (34.42%), and asymptomatic children (29.5%). Routine X-ray examination enabled finding the foreign body in 42 of the cases. An esophagogastroduodenoscopy was performed within 24-72 hours. 25 cases resulted in a negative endoscopy (40.98%), 19 objects (31.14%) were removed using a polypectomy snare, and extraction failure occurred in 17 patients (27.86%). 28 foreign bodies were passed without incidents; in 14 cases, the swallowed objects were never found. In one case, a battery was stuck in the esophageal folds and led to tracheal-esophageal fistula and bronchopneumonia and later to esophageal stenosis. We report a large proportion of foreign bodies that could not be identified or removed due to lack of early endoscopy and poor technical settings. Batteries and sharp objects lead to severe complications and preschool-age children are at high risk for such events. PMID- 26949385 TI - Neutrophil-to-Lymphocyte Ratio Predicts Early Mortality in Patients with HBV Related Decompensated Cirrhosis. AB - Background. The neutrophil-to-lymphocyte ratio (NLR) is an inflammation index that has been shown to independently predict poor clinical outcomes. We aimed to evaluate the clinical value of NLR in the prediction of 30-day mortality in patients with HBV-related decompensated cirrhosis (HBV-DeCi). Methods. This was a retrospective cohort study that included 148 patients with HBV-DeCi. Results. An elevated NLR was associated with increased severity of liver disease and mortality within 30 days. Multivariate analysis suggested that NLR, similar to the model for end-stage liver disease (MELD) score, is an additional independent predictor of 30-day mortality (P < 0.01). Conclusion. Our results suggest that a high NLR can be considered a new independent biomarker for predicting 30-day mortality in patients with HBV-DeCi. PMID- 26949387 TI - Interaction of XRCC1 Arg399Gln Polymorphism and Alcohol Consumption Influences Susceptibility of Esophageal Cancer. AB - Background. To explore the correlation between the Arg399Gln polymorphism and susceptibility to esophageal cancer in Korean and Han Chinese individuals in Harbin, China, and its potential interaction with alcohol consumption. Methods. This prospective study included 203 patients with esophageal squamous cell carcinoma; 88 were of Korean descent and 115 were of Han Chinese descent. A group of healthy controls included 105 participants of Korean descent and 105 of Han Chinese descent. Genotyping of the Arg399Gln locus of XRCC1 was performed by PCR RFLP. Results. The allelic and genotypic frequencies were not significantly different between individuals with esophageal cancer and controls or between individuals of Korean and Han Chinese descent (P > 0.05). However, when individuals with the wild-type Arg/Arg genotype also consumed alcohol, the risk of esophageal cancer was lower (OR = 3.539; 95% CI = 2.039-6.142; P < 0.05). Conclusions. The XRCC1 Arg399Gln polymorphism does not appear to be associated with esophageal cancer in individuals of Korean or Han Chinese descent in Harbin, China. However, alcohol consumption may decrease the risk of esophageal cancer in persons with the wild-type genotype. PMID- 26949386 TI - Outcome of the Pediatric Patients with Portal Cavernoma: The Retrospective Study for 10 Years Focusing on Recurrent Variceal Bleeding. AB - Background. Portal cavernoma (PC) is the most critical condition with risk or variceal hemorrhage in pediatric patients. We retrospectively investigated the patients with PC focusing on the predictors for recurrent variceal bleeding. Methods. Between July 2003 and June 2013, we retrospectively enrolled all consecutive patients admitted to our department with a diagnosis of PC without abdominal malignancy or liver cirrhosis. The primary endpoint of this observational study was recurrent variceal bleeding. Independent predictors of recurrent variceal bleeding were identified using the logistic regression model. Results. A total of 157 patients were enrolled in the study. During the follow-up period, 24 patients exhibited onset of recurrent variceal bleeding. Acute variceal bleeding was subjected to conservative symptomatic treatment and emergency endoscopic sclerotherapy. Surgical procedure selection was based on the severity of vascular dilation and collateral circulation. Multivariate logistic regression analysis demonstrated that the presence of ascites, collateral circulation, and portal venous pressure were independent prognostic factors of recurrent variceal bleeding for patients with portal cavernoma. Conclusions. The presence of ascites, collateral circulation, and portal venous pressure evaluation are important and could predict the postsurgical recurrent variceal bleeding in patients with portal cavernoma. PMID- 26949388 TI - Retracted: Technique of Intravesical Laparoscopy for Ureteric Reimplantation to Treat VUR. AB - [This retracts the article DOI: 10.1155/2008/937231.]. PMID- 26949390 TI - Efficacy of Continuous S(+)-Ketamine Infusion for Postoperative Pain Control: A Randomized Placebo-Controlled Trial. AB - Aim. A double-blind, randomized, placebo-controlled trial was designed to evaluate the efficacy of continuous intraoperative infusion of S(+)-ketamine under intravenous anesthesia with target-controlled infusion of remifentanil and propofol for postoperative pain control. Methods. Forty-eight patients undergoing laparoscopic cholecystectomy were assigned to receive continuous S(+)-ketamine infusion at a rate of 0.3 mg.kg(-1).h(-1) (n = 24, intervention group) or an equivalent volume of saline at the same rate (n = 24, placebo group). The same target-controlled intravenous anesthesia was induced in both groups. Pain was assessed using a 0 to 10 verbal numeric rating scale during the first 12 postoperative hours. Pain scores and morphine consumption were recorded in the postanesthesia care unit (PACU) and at 4 and 12 hours after surgery. Results. Pain scores were lower in the intervention group at all time points. Morphine consumption did not differ significantly between groups during PACU stay, but it was significantly lower in the intervention group at each time point after PACU discharge (P = 0.0061). At 12 hours after surgery, cumulative morphine consumption was also lower in the intervention group (5.200 +/- 2.707) than in the placebo group (7.525 +/- 1.872). Conclusions. Continuous S(+)-ketamine infusion during laparoscopic cholecystectomy under target-controlled intravenous anesthesia provided better postoperative pain control than placebo, reducing morphine requirement. Trial Registration. This trial is registered with ClinicalTrials.gov NCT02421913. PMID- 26949391 TI - Gun Access and Safety Practices among Older Adults. AB - Background. Given high rates of gun ownership among older adults, geriatric providers can assess firearm safety practices using a "5 Ls" approach: Locked; Loaded; Little children; feeling Low; and Learned owner. This study describes gun access and the "5 Ls" among US older adults. Methods. Data on the "5 Ls" from the Second Injury Control and Risk Survey (ICARIS-2), a national telephone survey conducted by the Centers for Disease Control and Prevention, were analyzed. Weighted variables were used to generate national estimates regarding prevalence of gun ownership and associated gun safety among older adults (>=55 years). Results. Of 2939 older adults, 39% (95% CI 37%-42%) reported >=1 gun stored at home. Among those with guns at home, 21% (95% CI 18-24%) stored guns loaded and unlocked; 9.2% (95% CI 6.6-12%) had >=1 child in household; 5.1% (95% CI 3.5 6.8%) reported past-year suicidal ideation and 3.6% (95% CI 2.1-5.2%) reported history of a suicide attempt; and 55% (95% CI 51-59%) stated that >=1 adult had attended firearm safety workshop. Conclusion. Some older adults may be at elevated risk of firearm injury because of storage practices, suicidal thoughts, or limited safety training. Future work should assess effective approaches to reduce the risk of gun-related injuries among older adults. PMID- 26949392 TI - Correlation between Trichomonas vaginalis and Concurrency: An Ecological Study. AB - Objective. There is a large variation in the prevalence of Trichomonas vaginalis (TV) between different countries and between racial groups within countries. Sexual partner concurrency may play a role. We investigate the correlation between the prevalence of sexual partner concurrency and TV prevalence. Methods. Spearman's correlation to assess relationship between TV prevalence in women and point prevalence of concurrency in men in (1) 11 countries with comparable data (concurrency data from WHO Survey and TV prevalence data from Global Burden of Disease estimates) and (2) three racial groups in the United States (Add Health Study). Results. The prevalence of TV and concurrency was positively correlated in the international (rho = 0.84, P = 0.001) and USA study (rho = 1.0, P < 0.001). Conclusion. Prospective longitudinal studies that include measures of partner behavior are required to definitively establish the role of concurrency in the spread of TV. PMID- 26949393 TI - Arsenic and Lead Uptake by Vegetable Crops Grown on Historically Contaminated Orchard Soils. AB - Transfer of Pb and As into vegetables grown in orchard soils historically contaminated by Pb arsenate pesticides was measured in the greenhouse. Lettuce, carrots, green beans and tomatoes were grown on soils containing a range of total Pb (16.5-915 mg/kg) and As (6.9-211 mg/kg) concentrations. The vegetables were acid-digested and analyzed for total Pb and As using ICP-mass spectrometry. Vegetable contamination was dependent on soil total Pb and As content, pH, and vegetable species. Arsenic concentrations were highest in lettuce and green beans, lower in carrots, and much lower in tomato fruit. Transfer of Pb into lettuce and beans was generally lower than that of As, and Pb and As were strongly excluded from tomato fruit. Soil metal concentrations as high as 400 mg/kg Pb and 100 mg/kg As produced vegetables with concentrations of Pb and As below the limits of international health standards. PMID- 26949389 TI - Improving Patient Safety through Simulation Training in Anesthesiology: Where Are We? AB - There have been colossal technological advances in the use of simulation in anesthesiology in the past 2 decades. Over the years, the use of simulation has gone from low fidelity to high fidelity models that mimic human responses in a startlingly realistic manner, extremely life-like mannequin that breathes, generates E.K.G, and has pulses, heart sounds, and an airway that can be programmed for different degrees of obstruction. Simulation in anesthesiology is no longer a research fascination but an integral part of resident education and one of ACGME requirements for resident graduation. Simulation training has been objectively shown to increase the skill-set of anesthesiologists. Anesthesiology is leading the movement in patient safety. It is rational to assume a relationship between simulation training and patient safety. Nevertheless there has not been a demonstrable improvement in patient outcomes with simulation training. Larger prospective studies that evaluate the improvement in patient outcomes are needed to justify the integration of simulation training in resident education but ample number of studies in the past 5 years do show a definite benefit of using simulation in anesthesiology training. This paper gives a brief overview of the history and evolution of use of simulation in anesthesiology and highlights some of the more recent studies that have advanced simulation-based training. PMID- 26949394 TI - Does the Degree of Hepatocellular Carcinoma Tumor Necrosis following Transarterial Chemoembolization Impact Patient Survival? AB - Purpose. The association between transarterial chemoembolization- (TACE-) induced HCC tumor necrosis measured by the modified Response Evaluation Criteria In Solid Tumors (mRECIST) and patient survival is poorly defined. We hypothesize that survival will be superior in HCC patients with increased TACE-induced tumor necrosis. Materials and Methods. TACE interventions were retrospectively reviewed. Tumor response was quantified via dichotomized (responders and nonresponders) and the four defined mRECIST categories. Results. Median survival following TACE was significantly greater in responders compared to nonresponders (20.8 months versus 14.9 months, p = 0.011). Survival outcomes also significantly varied among the four mRECIST categories (p = 0.0003): complete, 21.4 months; partial, 20.8; stable, 16.8; and progressive, 7.73. Only progressive disease demonstrated significantly worse survival when compared to complete response. Multivariable analysis showed that progressive disease, increasing total tumor diameter, and non-Child-Pugh class A were independent predictors of post-TACE mortality. Conclusions. Both dichotomized (responders and nonresponders) and the four defined mRECIST responses to TACE in patients with HCC were predictive of survival. The main driver of the survival analysis was poor survival in the progressive disease group. Surprisingly, there was small nonsignificant survival benefit between complete, partial, and stable disease groups. These findings may inform HCC treatment decisions following first TACE. PMID- 26949395 TI - Haploidentical Hematopoietic Stem Cell Transplantation: Expanding the Horizon for Hematologic Disorders. AB - Despite the advent of targeted therapies and novel agents, allogeneic hematopoietic stem cell transplantation remains the only curative modality in the management of hematologic disorders. The necessity to find an HLA-matched related donor is a major obstacle that compromises the widespread application and development of this field. Matched unrelated donors and umbilical cord blood have emerged as alternative sources of donor stem cells; however, the cost of maintaining donor registries and cord blood banks is very high and even impractical in developing countries. Almost every patient has an HLA haploidentical relative in the family, meaning that haploidentical donors are potential sources of stem cells, especially in situations where cord blood or matched unrelated donors are not easily available. Due to the high rates of graft failure and graft-versus-host disease, haploidentical transplant was not considered a feasible option up until the late 20th century, when strategies such as "megadose stem cell infusions" and posttransplantation immunosuppression with cyclophosphamide showed the ability to overcome the HLA disparity barrier and significantly improve the rates of engraftment and reduce the incidence and severity of graft-versus-host disease. Newer technologies of graft manipulation have also yielded the same effects in addition to preserving the antileukemic cells in the donor graft. PMID- 26949396 TI - Influence of Oxidative Stress on Stored Platelets. AB - Platelet storage and its availability for transfusion are limited to 5-6 days. Oxidative stress (OS) is one of the causes for reduced efficacy and shelf-life of platelets. The studies on platelet storage have focused on improving the storage conditions by altering platelet storage solutions, temperature, and materials. Nevertheless, the role of OS on platelet survival during storage is still unclear. Hence, this study was conducted to investigate the influence of storage on platelets. Platelets were stored for 12 days at 22 degrees C. OS markers such as aggregation, superoxides, reactive oxygen species, glucose, pH, lipid peroxidation, protein oxidation, and antioxidant enzymes were assessed. OS increased during storage as indicated by increments in aggregation, superoxides, pH, conjugate dienes, and superoxide dismutase and decrements in glucose and catalase. Thus, platelets could endure OS till 6 days during storage, due to the antioxidant defense system. An evident increase in OS was observed from day 8 of storage, which can diminish the platelet efficacy. The present study provides an insight into the gradual changes occurring during platelet storage. This lays the foundation towards new possibilities of employing various antioxidants as additives in storage solutions. PMID- 26949397 TI - Joint Degradation in a Monkey Model of Collagen-Induced Arthritis: Role of Cathepsin K Based on Biochemical Markers and Histological Evaluation. AB - The role of cathepsin K in joint degradation in a model of collagen-induced arthritis (CIA) in cynomolgus monkey was examined using biochemical markers and histology. Joint swelling, urinary C-telopeptide of type II collagen (CTX-II), deoxypyridinoline (DPD), and N- and C-telopeptides of type I collagen (NTX and CTX-I, resp.) were analyzed. Immunohistochemistry of type II collagen, cathepsin K, and CTX-II were performed using joints. Joint swelling reached peak on day 42 and continued at this level. The CTX-II level peaked on day 28 and declined thereafter, while CTX-I, NTX, and DPD reached plateau on day 43. Joint swelling was positively correlated with CTX-II increases on days 20 and 42/43, with increases in CTX-I and NTX/Cr on days 42/43 and 84, and with DPD increases throughout the study period. Intense cathepsin K staining was observed in osteoclasts and in articular cartilage and synovial tissue in arthritic joints. CTX-II was present in the superficial layer of articular cartilage in CIA monkeys. Evidence from biochemical markers suggests that matrix degradation in the CIA model starts with degradation of cartilage, rather than bone resorption. Cathepsin K expressed in osteoclasts, articular cartilage, and synovial tissue may contribute to degradation of cartilage. PMID- 26949400 TI - Adult Stem Cells in Tissue Maintenance and Regeneration. PMID- 26949398 TI - Secretome of Olfactory Mucosa Mesenchymal Stem Cell, a Multiple Potential Stem Cell. AB - Nasal olfactory mucosa mesenchymal stem cells (OM-MSCs) have the ability to promote regeneration in the nervous system in vivo. Moreover, with view to the potential for clinical application, OM-MSCs have the advantage of being easily accessible from patients and transplantable in an autologous manner, thus eliminating immune rejection and contentious ethical issues. So far, most studies have been focused on the role of OM-MSCs in central nervous system replacement. However, the secreted proteomics of OM-MSCs have not been reported yet. Here, proteins secreted by OM-MSCs cultured in serum-free conditions were separated on SDS-PAGE and identified by LC-MS/MS. As a result, a total of 274 secreted proteins were identified. These molecules are known to be important in neurotrophy, angiogenesis, cell growth, differentiation, and apoptosis, and inflammation which were highly correlated with the repair of central nervous system. The proteomic profiling of the OM-MSCs secretome might provide new insights into their nature in the neural recovery. However, proteomic analysis for clinical biomarkers of OM-MSCs needs to be further studied. PMID- 26949401 TI - Highly Synchronized Expression of Lineage-Specific Genes during In Vitro Hepatic Differentiation of Human Pluripotent Stem Cell Lines. AB - Human pluripotent stem cells- (hPSCs-) derived hepatocytes have the potential to replace many hepatic models in drug discovery and provide a cell source for regenerative medicine applications. However, the generation of fully functional hPSC-derived hepatocytes is still a challenge. Towards gaining better understanding of the differentiation and maturation process, we employed a standardized protocol to differentiate six hPSC lines into hepatocytes and investigated the synchronicity of the hPSC lines by applying RT-qPCR to assess the expression of lineage-specific genes (OCT4, NANOG, T, SOX17, CXCR4, CER1, HHEX, TBX3, PROX1, HNF6, AFP, HNF4a, KRT18, ALB, AAT, and CYP3A4) which serve as markers for different stages during liver development. The data was evaluated using correlation and clustering analysis, demonstrating that the expression of these markers is highly synchronized and correlated well across all cell lines. The analysis also revealed a distribution of the markers in groups reflecting the developmental stages of hepatocytes. Functional analysis of the differentiated cells further confirmed their hepatic phenotype. Taken together, these results demonstrate, on the molecular level, the highly synchronized differentiation pattern across multiple hPSC lines. Moreover, this study provides additional understanding for future efforts to improve the functionality of hPSC-derived hepatocytes and thereby increase the value of related models. PMID- 26949402 TI - Effects of Human Umbilical Cord Mesenchymal Stem Cells on Human Trophoblast Cell Functions In Vitro. AB - Trophoblast cell dysfunction is involved in many disorders during pregnancy such as preeclampsia and intrauterine growth restriction. Few treatments exist, however, that target improving trophoblast cell function. Human umbilical cord mesenchymal stem cells (hUCMSCs) are capable of self-renewing, can undergo multilineage differentiation, and have homing abilities; in addition, they have immunomodulatory effects and paracrine properties and thus are a prospective source for cell therapy. To identify whether hUCMSCs can regulate trophoblast cell functions, we treated trophoblast cells with hUCMSC supernatant or cocultured them with hUCMSCs. Both treatments remarkably enhanced the migration and invasion abilities of trophoblast cells and upregulated their proliferation ability. At a certain concentration, hUCMSCs also modulated hCG, PIGF, and sEndoglin levels in the trophoblast culture medium. Thus, hUCMSCs have a positive effect on trophoblast cellular functions, which may provide a new avenue for treatment of placenta-related diseases during pregnancy. PMID- 26949404 TI - Clinical Effect and Mechanism of Yisui Shengxue Granules in Thalassemia Patients with Mild, Moderate, or Severe Anemia. AB - Yisui Shengxue granules, which is a Chinese traditional medicine, can increase hemoglobin, red blood cells, and Ret of thalassemia patients with mild, moderate, and severe anemia and thus relieve clinical anemia symptoms. Studies on mechanism found that Yisui Shengxue granules can increase the proliferation ability of hematopoietic stem cells. Emodin promoted colony forming of hematopoietic stem cells. Yisui Shengxue granules can increase the activity of GSH-PX in bone marrow blood and decreased the severity of inclusion bodies on the cytomembrane of RBCs. YSSXG attenuated anemia symptoms in patients with thalassemia mostly by increasing the proliferation of hematopoietic stem cells and decreasing the hemolysis of RBCs. PMID- 26949403 TI - Do epinephrine auto-injectors have an unsuitable needle length in children and adolescents at risk for anaphylaxis from food allergy? AB - BACKGROUND: Food allergy is the most common cause of anaphylaxis in children. Intramuscular delivery of epinephrine auto-injectors (EAI) is the standard of care for the treatment of anaphylaxis. We examined if children and adolescents at risk of anaphylaxis weighing 15-30 kg and >30 kg would receive epinephrine into the intramuscular space with the currently available EAI in North America and Europe. METHODS: The distance from skin to muscle (STMD) and skin to bone (STBD) on the mid third anterolateral area of the right thigh was measured by ultrasound applying either high pressure (max) or slight pressure (min) in 102 children weighing 15-30 kg (group 1) and 100 children and adolescents, weighing more than 30 kg (group 2). RESULTS: Using a high pressure EAI (HPEAI), Epipen Jr((r)) and Auvi-Q((r))/Allerject((r)) 0.15 mg, 11/102 (11 %) children in group 1 and 38/102 (38 %) using another HPEAI, Jext((r)), had a STMDmax that showed a risk of intraosseous injection. There was a 1 % risk of subcutaneous injection with these devices. There was no risk of intraosseous injection using a low pressure EAI (LPEAI), Emerade((r)). In group 2, the risk of intraosseous injection using a HPEAI was 3 % and no risk using a LPEAI. However, the risk of subcutaneous injection using HPEAI was 9 % and using LPEAI was 2 %. CONCLUSION: There is a risk of intraosseous injection using HPEAI (Epipen((r))/Epipen Jr((r)), Auvi Q((r))/Allerject((r)) and especially Jext((r))) in children at risk of anaphylaxis. There was also a risk of subcutaneous injection using the currently available HPEAI in children and adolescents. PMID- 26949405 TI - Naoxintong Protects Primary Neurons from Oxygen-Glucose Deprivation/Reoxygenation Induced Injury through PI3K-Akt Signaling Pathway. AB - Naoxintong capsule (NXT), developed from Buyang Huanwu Decoction, has shown the neuroprotective effects in cerebrovascular diseases, but the neuroprotection mechanisms of NXT on ischemia/reperfusion injured neurons have not yet been well known. In this study, we established the oxygen-glucose deprivation/reoxygenation (OGD/R) induced neurons injury model and treat the neurons with cerebrospinal fluid containing NXT (BNC) to investigate the effects of NXT on OGD/R induced neurons injury and potential mechanisms. BNC improved neuron viability and decreased apoptotic rate induced by OGD/R. BNC attenuated OGD/R induced cytosolic and mitochondrial Ca(2+) overload, ROS generation, intracellular NO levels and nNOS mRNA increase, and cytochrome-c release when compared with OGD/R group. BNC significantly inhibited both mPTP opening and DeltaPsim depolarization. BNC increased Bcl-2 expression and decreased Bax expression, upregulated the Bcl 2/Bax ratio, downregulated caspase-3 mRNA and caspase-9 mRNA expression, and decreased cleaved caspase-3 expression and caspase-3 activity. BNC increased phosphorylation of Akt following OGD/R, while LY294002 attenuated BNC induced increase of phosphorylated Akt expression. Our study demonstrated that NXT protected primary neurons from OGD/R induced injury by inhibiting calcium overload and ROS generation, protecting mitochondria, and inhibiting mitochondrial apoptotic pathway which was mediated partially by PI3K-Akt signaling pathway activation. PMID- 26949407 TI - White-nose syndrome survivors do not exhibit frequent arousals associated with Pseudogymnoascus destructans infection. AB - BACKGROUND: White-nose syndrome (WNS) has devastated bat populations in North America, with millions of bats dead. WNS is associated with physiological changes in hibernating bats, leading to increased arousals from hibernation and premature consumption of fat reserves. However, there is evidence of surviving populations of little brown myotis (Myotis lucifugus) close to where the fungus was first detected nearly ten years ago. RESULTS: We examined the hibernation patterns of a surviving population of little brown myotis and compared them to patterns in populations before the arrival of WNS and populations at the peak of WNS mortality. Despite infection with Pseudogymnoascus destructans, the causative fungal agent, the remnant population displayed less frequent arousals from torpor and lower torpid body temperatures than bats that died from WNS during the peak of mortality. The hibernation patterns of the remnant population resembled pre WNS patterns with some modifications. CONCLUSIONS: These data show that remnant populations of little brown myotis do not experience the increase in periodic arousals from hibernation typified by bats dying from WNS, despite the presence of the fungal pathogen on their skin. These patterns may reflect the use of colder hibernacula microclimates by WNS survivors, and/or may reflect differences in how these bats respond to the disease. PMID- 26949399 TI - Low Density Lipoprotein Receptor Related Proteins as Regulators of Neural Stem and Progenitor Cell Function. AB - The central nervous system (CNS) is a highly organised structure. Many signalling systems work in concert to ensure that neural stem cells are appropriately directed to generate progenitor cells, which in turn mature into functional cell types including projection neurons, interneurons, astrocytes, and oligodendrocytes. Herein we explore the role of the low density lipoprotein (LDL) receptor family, in particular family members LRP1 and LRP2, in regulating the behaviour of neural stem and progenitor cells during development and adulthood. The ability of LRP1 and LRP2 to bind a diverse and extensive range of ligands, regulate ligand endocytosis, recruit nonreceptor tyrosine kinases for direct signal transduction and signal in conjunction with other receptors, enables them to modulate many crucial neural cell functions. PMID- 26949408 TI - Workplace bullying and general health status among the nursing staff of Greek public hospitals. AB - BACKGROUND: The arduous emotional and physical nurses' work, the gradual nursing staff cutbacks and the lack of recognition that nurses feel regarding their skills and overall capabilities are some of the factors that act of bullying between nursing staff and management, between nurses and patients/families or even among nurses themselves. Workplace bullying has physical and psychological effects on worker-victims and, by extension, patients themselves. The purpose of this study was to investigate the relationship between the phenomenon of workplace bullying and general health status among the nursing staff of Greek public hospitals. METHODS: A cross-sectional study was conducted on a convenience sample of 841 members of the nursing staff working in five major hospitals of the 1st Regional Health Authority of Attica, located in Athens. The response rate was 84.1 %. The respondents completed the Negative Acts Questionnaire (NAQ) and the General Health Questionnaire (GHQ-12) and also their demographic characteristics. The appropriate permissions were obtained by the Hospitals' Ethics Committees and the questionnaire's authors. Data were collected from March to July 2013. Data analysis was performed with IBM SPSS 21.0 and included t test, chi (2) test and regression analysis. The two-tailed significance level was set <=0.05. RESULTS: 30.2 % of the respondents reported that they had been psychologically harassed in their workplaces during the preceding 6 months. Statistical analysis revealed that relative to other respondents, respondents who had received support from their families and friends enjoyed better health but respondents who perceived their work environments more negatively because of work-related bullying suffered from worse general health. CONCLUSIONS: Workplace bullying among nursing staff is a major concern in Greece. Support systems play a crucial role in addressing the negative effects of bullying and they should be taken into account when designing prevention and troubleshooting policies about bullying. PMID- 26949409 TI - Sensory cognitive abnormalities of pain in autism spectrum disorder: a case control study. AB - BACKGROUND: The Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) recently included sensory processing abnormalities in the diagnostic criteria for individuals with autism spectrum disorder (ASD). However, there is no standard method for evaluating sensory abnormalities in individuals with ASD. METHODS: Fifteen individuals with ASD and 15 age- and sex-matched controls were enrolled in this study. We compared objective pain sensitivity by measuring the pain detection threshold and pain tolerance to three different stimuli (electricity, heat, and cold). Then, we compared both subjective pain sensitivity, assessed by the visual analog scale (VAS), and quality of pain, assessed by the short-form McGill Pain Questionnaire (SF-MPQ), to determine the maximum tolerable pain intensities of each stimulation. RESULTS: The pain detection threshold and pain tolerance of individuals with ASD were not impaired, indicating that there were no differences in the somatic perception of pain between groups. However, individuals with ASD were hyposensitive to subjective pain intensity compared to controls (VAS; electrical: p = 0.044, cold: p = 0.011, heat: p = 0.042) and hyposensitive to affective aspects of pain sensitivity (SF MPQ; electrical: p = 0.0071, cold: p = 0.042). CONCLUSIONS: Our results suggest that the cognitive pathways for pain processing are impaired in ASD and, furthermore, that our methodology can be used to assess pain sensitivity in individuals with ASD. Further investigations into sensory abnormalities in individuals with ASD are needed to clarify the pathophysiologic processes that may alter sensory processing in this disorder. PMID- 26949411 TI - Computer Vision Based Automatic Extraction and Thickness Measurement of Deep Cervical Flexor from Ultrasonic Images. AB - Deep Cervical Flexor (DCF) muscles are important in monitoring and controlling neck pain. While ultrasonographic analysis is useful in this area, it has intrinsic subjectivity problem. In this paper, we propose automatic DCF extractor/analyzer software based on computer vision. One of the major difficulties in developing such an automatic analyzer is to detect important organs and their boundaries under very low brightness contrast environment. Our fuzzy sigma binarization process is one of the answers for that problem. Another difficulty is to compensate information loss that happened during such image processing procedures. Many morphologically motivated image processing algorithms are applied for that purpose. The proposed method is verified as successful in extracting DCFs and measuring thicknesses in experiment using two hundred 800 * 600 DICOM ultrasonography images with 98.5% extraction rate. Also, the thickness of DCFs automatically measured by this software has small difference (less than 0.3 cm) for 89.8% of extracted DCFs. PMID- 26949410 TI - The Adeno-Associated Virus Genome Packaging Puzzle. PMID- 26949412 TI - Wavelet Based Method for Congestive Heart Failure Recognition by Three Confirmation Functions. AB - An investigation of the electrocardiogram (ECG) signals and arrhythmia characterization by wavelet energy is proposed. This study employs a wavelet based feature extraction method for congestive heart failure (CHF) obtained from the percentage energy (PE) of terminal wavelet packet transform (WPT) subsignals. In addition, the average framing percentage energy (AFE) technique is proposed, termed WAFE. A new classification method is introduced by three confirmation functions. The confirmation methods are based on three concepts: percentage root mean square difference error (PRD), logarithmic difference signal ratio (LDSR), and correlation coefficient (CC). The proposed method showed to be a potential effective discriminator in recognizing such clinical syndrome. ECG signals taken from MIT-BIH arrhythmia dataset and other databases are utilized to analyze different arrhythmias and normal ECGs. Several known methods were studied for comparison. The best recognition rate selection obtained was for WAFE. The recognition performance was accomplished as 92.60% accurate. The Receiver Operating Characteristic curve as a common tool for evaluating the diagnostic accuracy was illustrated, which indicated that the tests are reliable. The performance of the presented system was investigated in additive white Gaussian noise (AWGN) environment, where the recognition rate was 81.48% for 5 dB. PMID- 26949413 TI - Directed evolution of a fungal beta-glucosidase in Saccharomyces cerevisiae. AB - BACKGROUND: beta-glucosidases (BGLs) catalyze the hydrolysis of soluble cellodextrins to glucose and are a critical component of cellulase systems. In order to engineer Saccharomyces cerevisiae for the production of ethanol from cellulosic biomass, a BGL tailored to industrial bioconversions is needed. RESULTS: We applied a directed evolution strategy to a glycosyl hydrolase family 3 (GH3) BGL from Aspergillus niger (BGL1) by expressing a library of mutated bgl1 genes in S. cerevisiae and used a two-step functional screen to identify improved enzymes. Twelve BGL variants that supported growth of S. cerevisiae on cellobiose and showed increased activity on the synthetic substrate p-nitrophenyl-beta-D glucopyranoside were identified and characterized. By performing kinetic experiments, we found that a Tyr -> Cys substitution at position 305 of BGL1 dramatically reduced transglycosidation activity that causes inhibition of the hydrolytic reaction at high substrate concentrations. Targeted mutagenesis demonstrated that the position 305 residue is critical in GH3 BGLs and likely determines the extent to which transglycosidation reactions occur. We also found that a substitution at Gln(140) reduced the inhibitory effect of glucose and could be combined with the Y305C substitution to produce a BGL with decreased sensitivity to both the product and substrate. Using the crystal structure of a GH3 BGL from A. aculeatus, we mapped a group of beneficial mutations to the beta/alpha domain of the molecule and postulate that this region modulates activity through subunit interactions. Six BGL variants were identified with substitutions in the MFalpha pre-sequence that was used to mediate secretion of the protein. Substitutions at Pro(21) or Val(22) of the MFalpha pre-sequence could produce up to a twofold increase in supernatant hydrolase activity and provides evidence that expression and/or secretion was an additional factor limiting hydrolytic activity. CONCLUSIONS: Using directed evolution on BGL1, we identified a key residue that controls hydrolytic and transglycosidation reactions in GH3 BGLs. We also found that several beneficial mutations could be combined and increased the hydrolytic activity for both synthetic and natural substrates. PMID- 26949414 TI - Life cycle impacts of ethanol production from spruce wood chips under high gravity conditions. AB - BACKGROUND: Development of more sustainable biofuel production processes is ongoing, and technology to run these processes at a high dry matter content, also called high-gravity conditions, is one option. This paper presents the results of a life cycle assessment (LCA) of such a technology currently in development for the production of bio-ethanol from spruce wood chips. RESULTS: The cradle-to-gate LCA used lab results from a set of 30 experiments (or process configurations) in which the main process variable was the detoxification strategy applied to the pretreated feedstock material. The results of the assessment show that a process configuration, in which washing of the pretreated slurry is the detoxification strategy, leads to the lowest environmental impact of the process. Enzyme production and use are the main contributors to the environmental impact in all process configurations, and strategies to significantly reduce this contribution are enzyme recycling and on-site enzyme production. Furthermore, a strong linear correlation between the ethanol yield of a configuration and its environmental impact is demonstrated, and the selected environmental impacts show a very strong cross-correlation ([Formula: see text] in all cases) which may be used to reduce the number of impact categories considered from four to one (in this case, global warming potential). Lastly, a comparison with results of an LCA of ethanol production under high-gravity conditions using wheat straw shows that the environmental performance does not significantly differ when using spruce wood chips. For this comparison, it is shown that eutrophication potential also needs to be considered due to the fertilizer use in wheat cultivation. CONCLUSIONS: The LCA points out the environmental hotspots in the ethanol production process, and thus provides input to the further development of the high-gravity technology. Reducing the number of impact categories based only on cross-correlations should be done with caution. Knowledge of the analyzed system provides further input to the choice of impact categories. PMID- 26949415 TI - Robust normalization protocols for multiplexed fluorescence bioimage analysis. AB - study of mapping and interaction of co-localized proteins at a sub-cellular level is important for understanding complex biological phenomena. One of the recent techniques to map co-localized proteins is to use the standard immuno fluorescence microscopy in a cyclic manner (Nat Biotechnol 24:1270-8, 2006; Proc Natl Acad Sci 110:11982-7, 2013). Unfortunately, these techniques suffer from variability in intensity and positioning of signals from protein markers within a run and across different runs. Therefore, it is necessary to standardize protocols for preprocessing of the multiplexed bioimaging (MBI) data from multiple runs to a comparable scale before any further analysis can be performed on the data. In this paper, we compare various normalization protocols and propose on the basis of the obtained results, a robust normalization technique that produces consistent results on the MBI data collected from different runs using the Toponome Imaging System (TIS). Normalization results produced by the proposed method on a sample TIS data set for colorectal cancer patients were ranked favorably by two pathologists and two biologists. We show that the proposed method produces higher between class Kullback-Leibler (KL) divergence and lower within class KL divergence on a distribution of cell phenotypes from colorectal cancer and histologically normal samples. PMID- 26949416 TI - Gait and Lower Limb Observation of Paediatrics (GALLOP): development of a consensus based paediatric podiatry and physiotherapy standardised recording proforma. AB - BACKGROUND: Paediatric gait and lower limb assessments are frequently undertaken in podiatry and physiotherapy clinical practice and this is a growing area of expertise within Australia. No concise paediatric standardised recording proforma exists to assist clinicians in clinical practice. The aim of this study was to develop a gait and lower limb standardised recording proforma guided by the literature and consensus, for assessment of the paediatric foot and lower limb in children aged 0-18 years. METHOD: Expert Australian podiatrists and physiotherapists were invited to participate in a three round Delphi survey panel using the online Qualtrics((c)) survey platform. The first round of the survey consisted of open-ended questions on paediatric gait and lower limb assessment developed from existing templates and a literature search of standardised lower limb assessment methods. Rounds two and three consisted of statements developed from the first round responses. Questions and statements were included in the final proforma if 70 % or more of the participants indicated consensus or agreement with the assessment method and if there was support within the literature for paediatric age-specific normative data with acceptable reliability of outcome measures. RESULTS: There were 17 of the 21 (81 %) participants who completed three rounds of the survey. Consensus was achieved for 41 statements in Round one, 54 statements achieved agreement in two subsequent rounds. Participants agreed on 95 statements relating to birth history, developmental history, hip measurement, rotation of the lower limb, ankle range of motion, foot posture, balance and gait. Assessments with acceptable validity and reliability were included within the final Gait and Lower Limb Observation of Paediatrics (GALLOP) proforma. CONCLUSION: The GALLOP proforma is a consensus based, systematic and standardised way to collect information and outcome measures in paediatric lower limb assessment. This standardised recording proforma will assist professions to collect information in a standardised format based on best evidence assessment methods whilst aiding consistency in communication between health professionals. PMID- 26949417 TI - Bioalerts: a python library for the derivation of structural alerts from bioactivity and toxicity data sets. AB - BACKGROUND: Assessing compound toxicity at early stages of the drug discovery process is a crucial task to dismiss drug candidates likely to fail in clinical trials. Screening drug candidates against structural alerts, i.e. chemical fragments associated to a toxicological response prior or after being metabolized (bioactivation), has proved a valuable approach for this task. During the last decades, diverse algorithms have been proposed for the automatic derivation of structural alerts from categorical toxicity data sets. RESULTS AND CONCLUSIONS: Here, the python library bioalerts is presented, which comprises functionalities for the automatic derivation of structural alerts from categorical (dichotomous), e.g. toxic/non-toxic, and continuous bioactivity data sets, e.g. [Formula: see text] or [Formula: see text] values. The library bioalerts relies on the RDKit implementation of the circular Morgan fingerprint algorithm to compute chemical substructures, which are derived by considering radial atom neighbourhoods of increasing bond radius. In addition to the derivation of structural alerts, bioalerts provides functionalities for the calculation of unhashed (keyed) Morgan fingerprints, which can be used in predictive bioactivity modelling with the advantage of allowing for a chemically meaningful deconvolution of the chemical space. Finally, bioalerts provides functionalities for the easy visualization of the derived structural alerts. PMID- 26949418 TI - Associations between fish consumption and metabolic syndrome. A large cross sectional study from the Norwegian Tromso Study: Tromso 4. AB - BACKGROUND: Fish consumption may prevent or improve metabolic health. The aim of this study was to identify associations between fish consumption, both fatty and lean, and metabolic syndrome and its components. METHODS: Associations between fish consumption and metabolic syndrome and its components were studied in a large sample from a Norwegian population (N = 23,907), using cross-sectional data from the Tromso 4 survey (1994-1995). Metabolic syndrome was defined using the JIS definition, and dietary data was collected using food frequency questionnaires (FFQ). Blood samples were taken for biochemical assessments, and anthropometric and blood pressure measurements were carried out according to standard protocols. RESULTS: In this sample from an adult population (aged 26-70 years, mean age 44 years, SD 11.69, 48 % men), a higher fish consumption (>=1/week) was associated with a healthier lipid profile with increased HDL-C and decreased TG. Participants aged 60-70 years consuming fish once a week or more had significantly lower risk of having MetS, compared to those consuming fish less than once a week (OR 0.64, CI 0.45-0.91). When investigating fatty and lean fish separately, only lean fish consumption was associated with a reduced the risk of having MetS. Participants aged 60-70 years consuming lean fish once a week or more, had lower risk of having MetS compared to those consuming lean fish less than once a week (OR 0.65, CI 0.48-0.87). No association was found for consumption of fatty fish, or for lean fish in the age groups <45 or 45-59 years. CONCLUSIONS: These results indicates that fatty and lean fish consumption influences MetS risk differently, possibly also related to age. However, further investigation is needed to establish how various fish consumption may influence MetS and its components, particularly when stratified by fatty and lean fish. PMID- 26949421 TI - Improved initialisation of model-based clustering using Gaussian hierarchical partitions. AB - Initialisation of the EM algorithm in model-based clustering is often crucial. Various starting points in the parameter space often lead to different local maxima of the likelihood function and, so to different clustering partitions. Among the several approaches available in the literature, model-based agglomerative hierarchical clustering is used to provide initial partitions in the popular mclust R package. This choice is computationally convenient and often yields good clustering partitions. However, in certain circumstances, poor initial partitions may cause the EM algorithm to converge to a local maximum of the likelihood function. We propose several simple and fast refinements based on data transformations and illustrate them through data examples. PMID- 26949419 TI - Usefulness of circulating E-selectin to early detection of the atherosclerotic process in the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). AB - BACKGROUND: This cross-sectional analysis evaluated whether determination of E selectin concentrations could identify deterioration of cardiometabolic risk profile or subclinical atherosclerosis in individuals at low-to-moderate risk included in The Brazilian Longitudinal Study of Adult Health-ELSA-Brasil. METHODS: A sample of 984 individuals from ELSA-Brasil (35-54 years) without cardiovascular disease or diabetes was stratified according to E-selectin tertiles. Traditional risk factors, inflammatory markers and categories of coronary artery calcium (CAC) scores were evaluated across the tertiles by ANOVA or Chi-squared test. In linear regression models, associations of E-selectin levels with insulin resistance index, adjusted for age, sex and adiposity were tested. RESULTS: The mean age of the participants was 45.8 (SD 4.9) years and 55 % were women. Mean values of age, anthropometric data, biochemical variables and inflammatory status increased across E-selectin tertiles. Also, a gradual deterioration of the cardiometabolic profile was reflected by increments in frequencies (95 % CI) of BMI >= 25 kg/m(2) [53.7 % (48.5-58.8), 61.0 % (56.1 66.5) and 64.2 % (59.0-69.4), p = 0.019], hypertension [18.0 % (14.1-22.8), 19.8 % (15.4-24.6) and 24.8 % (20.4-29.9), p = 0.048], pre-diabetes [62.5 % (57.4 68.3), 63.1 % (58.4-69.6) and 73.8 % (68.8-78.3), p = 0.003] and hypertriglyceridemia [22.4 % (17.9-27.2), 27.3 % (22.5-32.8) and 33.4 % (28.3 38.5), p = 0.013]. Insulinemia and HOMA-IR were independently associated with E selectin concentration. A greater proportion of individuals with CAC scores different from zero was found in the third tertile when compared with the first and second tertiles (16.1 versus 11 %, p = 0.04, respectively). CONCLUSIONS: Direct associations of E-selectin with traditional risk factors slightly above their normal ranges, components of the metabolic syndrome, insulin resistance and presence of CAC suggest that this biomarker may indicate an initial atherogenic process. PMID- 26949420 TI - The Contribution of Advanced Glycation End product (AGE) accumulation to the decline in motor function. AB - Diminishing motor function is commonly observed in the elderly population and is associated with a wide range of adverse health consequences. Advanced Glycation End products (AGE's) may contribute to age-related decline in the function of cells and tissues in normal ageing. Although the negative effect of AGE's on the biomechanical properties of musculoskeletal tissues and the central nervous system have been previously described, the evidence regarding the effect on motor function is fragmented, and a systematic review on this topic is lacking. Therefore, a systematic review was conducted from a total of eight studies describing AGE's related to physical functioning, physical performance, and musculoskeletal outcome which reveals a positive association between high AGE's levels and declined walking abilities, inferior ADL, decreased muscle properties (strength, power and mass) and increased physical frailty. Elevated AGE's levels might be an indication to initiate (early) treatment such as dietary advice, muscle strengthening exercises, and functional training to maintain physical functions. Further longitudinal observational and controlled trial studies are necessary to investigate a causal relationship, and to what extent, high AGE's levels are a contributing risk factor and potential biomarker for a decline in motor function as a component of the ageing process. PMID- 26949422 TI - A subset of low-grade B cell lymphomas with a follicular growth pattern but without a BCL2 translocation shows features suggestive of nodal marginal zone lymphoma. AB - In our consultation practice, it was noted that many cases that were considered to represent follicular lymphoma (FL) without a BCL2 translocation were ultimately classified as nodal marginal zone lymphoma (NMZL). This study set out to define recurrent morphological features of these cases. Thirty-three low-grade B cell lymphomas without a BCL2 rearrangement were studied for recurrent morphological features. These features were then applied on 20 randomly selected cases to verify if these criteria are able to distinguish between lymphomas with and without a BCL2 rearrangement, assigning them to one of five categories ranging from "certain FL" to "certain NMZL." Highly recurrent morphological features were noted in the lymphomas without a BCL2 rearrangement, which were strongly overlapping with the morphological features of NMZL. All six cases that were assigned to the category of certainly FL or most likely FL indeed harbored a BCL2 rearrangement, whereas all 12 cases assigned to the category of most likely NMZL or certain NMZL had no BCL2 break. Of the two cases in the ambiguous category, one had received a final diagnosis of FL and the other of NMZL. This study raises the hypothesis that a subset of low-grade B cell lymphomas with a follicular growth pattern but without a BCL2 translocation actually represents NMZL. This is at present difficult to prove, because no gold standard is available to differentiate between NMZL and FL without a BCL2 rearrangement, so further investigations are needed. PMID- 26949423 TI - New developments in the pathology of malignant lymphoma. A review of the literature published from September 2015-December 2015. PMID- 26949424 TI - MSRE-HTPrimer: a high-throughput and genome-wide primer design pipeline optimized for epigenetic research. AB - BACKGROUND: Methylation-sensitive restriction enzymes-polymerase chain reaction (MSRE-PCR) has been used in epigenetic research to identify genome-wide and gene specific DNA methylation. Currently, epigenome-wide discovery studies provide many candidate regions for which the MSREqPCR approach can be very effective to confirm the findings. MSREqPCR provides high multiplexing capabilities also when starting with limited amount of DNA-like cfDNA to validate many targets in a time and cost-effective manner. Multiplex design is challenging and cumbersome to define specific primers in an effective manner, and no suitable software tools are freely available for high-throughput primer design in a time-effective manner and to automatically annotate the resulting primers with known SNPs, CpG, repeats, and RefSeq genes. Therefore a robust, powerful, high-throughput, optimized, and methylation-specific primer design tool with great accuracy will be very useful. RESULTS: We have developed a novel pipeline, called MSRE HTPrimer, to design MSRE-PCR and genomic PCR primers pairs in a very efficient manner and with high success rate. First, our pipeline designs all possible PCR primer pairs and oligos, followed by filtering for SNPs loci and repeat regions. Next, each primer pair is annotated with the number of cut sites in primers and amplicons, upstream and downstream genes, and CpG islands loci. Finally, MSRE HTPrimer selects resulting primer pairs for all target sequences based on a custom quality matrix defined by the user. MSRE-HTPrimer produces a table for all resulting primer pairs as well as a custom track in GTF file format for each target sequence to visualize it in UCSC genome browser. CONCLUSIONS: MSRE HTPrimer, based on Primer3, is a high-throughput pipeline and has no limitation on the number and size of target sequences for primer design and provides full flexibility to customize it for specific requirements. It is a standalone web based pipeline, which is fully configured within a virtual machine and thus can be readily used without any configuration. We have experimentally validated primer pairs designed by our pipeline and shown a very high success rate of primer pairs: out of 190 primer pairs, 71 % could be successfully validated. The MSRE-HTPrimer software is freely available from http://sourceforge.net/p/msrehtprimer/wiki/Virtual_Machine/ as a virtual machine. PMID- 26949425 TI - Assessment of Scientific Reasoning: the Effects of Task Context, Data, and Design on Student Reasoning in Control of Variables. AB - Scientific reasoning is an important component under the cognitive strand of the 21st century skills and is highly emphasized in the new science education standards. This study focuses on the assessment of student reasoning in control of variables (COV), which is a core sub-skill of scientific reasoning. The main research question is to investigate the extent to which the existence of experimental data in questions impacts student reasoning and performance. This study also explores the effects of task contexts on student reasoning as well as students' abilities to distinguish between testability and causal influences of variables in COV experiments. Data were collected with students from both USA and China. Students received randomly one of two test versions, one with experimental data and one without. The results show that students from both populations (1) perform better when experimental data are not provided, (2) perform better in physics contexts than in real-life contexts, and (3) students have a tendency to equate non-influential variables to non-testable variables. In addition, based on the analysis of both quantitative and qualitative data, a possible progression of developmental levels of student reasoning in control of variables is proposed, which can be used to inform future development of assessment and instruction. PMID- 26949426 TI - Teachers and Teaching: Speech Production Accommodations Due to Changes in the Acoustic Environment. AB - School teachers have an elevated risk of voice problems due to the vocal demands in the workplace. This manuscript presents the results of three studies investigating teachers' voice use at work. In the first study, 57 teachers were observed for 2 weeks (waking hours) to compare how they used their voice in the school environment and in non-school environments. In a second study, 45 participants performed a short vocal task in two different rooms: a variable acoustic room and an anechoic chamber. Subjects were taken back and forth between the two rooms. Each time they entered the variable acoustics room, the reverberation time and/or the background noise condition had been modified. In this latter study, subjects responded to questions about their vocal comfort and their perception of changes in the acoustic environment. In a third study, 20 untrained vocalists performed a simple vocal task in the following conditions: with and without background babble and with and without transparent plexiglass shields to increase the first reflection. Relationships were examined between [1] the results for the room acoustic parameters; [2] the subjects' perception of the room; and [3] the recorded speech acoustic. Several differences between male and female subjects were found; some of those differences held for each room condition (at school vs. not at school, reverberation level, noise level, and early reflection). PMID- 26949428 TI - Effectiveness of Ventricular Intrinsic Preference (VIPTM) and Ventricular AutoCapture (VAC) algorithms in pacemaker patients: Results of the validate study. AB - BACKGROUND: Several past clinical studies have demonstrated that frequent and unnecessary right ventricular pacing in patients with sick sinus syndrome and compromised atrio-ventricular conduction (AVC) produces long-term adverse effects. The safety and efficacy of two pacemaker algorithms, Ventricular Intrinsic PreferenceTM (VIP) and Ventricular AutoCapture (VAC), were evaluated in a multi-center study in pacemaker patients. METHODS: We evaluated 80 patients across 10 centers in India. Patients were enrolled within 15 days of dual chamber pacemaker (DDDR) implantation, and within 45 days thereafter were classified to either a compromised AVC (cAVC) arm or an intact AVC (iAVC) arm based on intrinsic paced/sensed (AV/PV) delays. In each arm, patients were then randomized (1:1) into the following groups: VIP OFF and VAC OFF (Control group; CG), or VIP ON and VAC ON (Treatment Group; TG). Subsequently, the AV/PV delays in the CG groups were mandatorily programmed at 180/150 ms, and to up to 350 ms in the TG groups. The percentage of right ventricular pacing (%RVp) evaluated at 12-month post-implantation follow-ups were compared between the two groups in each arm. Additionally, in-clinic time required for collecting device data was compared between patients programmed with the automated AutoCapture algorithm activated (VAC ON) vs. the manually programmed method (VAC OFF). RESULTS: Patients randomized to the TG with the VIP algorithm activated exhibited a significantly lower %RVp at 12 months than those in the CG in both the cAVC arm (39+/-41% vs. 97+/-3%; p=0.0004) and the iAVC arm (15+/-25% vs. 68+/-39%; p=0.0067). In-clinic time required to collect device data was less in patients with the VAC algorithm activated. No device-related adverse events were reported during the year-long study period. CONCLUSIONS: In our study cohort, the use of the VIP algorithm significantly reduced the %RVp, while the VAC algorithm reduced in-clinic time needed to collect device data. PMID- 26949430 TI - Clinical implication of monitoring rivaroxaban and apixaban by using anti-factor Xa assay in patients with non-valvular atrial fibrillation. AB - BACKGROUND: Although patients taking non-vitamin K antagonist oral anticoagulants (NOACs) do not require routine coagulation monitoring, high-risk patients require monitoring to assess pharmacodynamics. METHODS: We measured (1) anti-factor Xa activity (AXA), using chromogenic assay with the HemosIL Liquid Heparin kit, (2) prothrombin time (PT), and (3) activated partial thromboplastin time (aPTT) in 188 blood samples from 70 patients with non-valvular atrial fibrillation, of whom 36 received rivaroxaban once daily and 34 received apixaban twice daily. RESULTS: After the rivaroxaban therapy, AXA ranged from 0 to 3.65 IU/mL; PT, from 9.6 to 44.5 s; and APTT, from 19.3 to 69.7 s. After the apixaban therapy, AXA ranged from 0.02 to 3.18 IU/mL; PT, from 10.2 to 20.8 s; and APTT, from 21.8 to 59.8 s. At peak time, the AXA of patients who received rivaroxaban and apixaban were almost the same (2.08+/-0.91 IU/mL vs. 1.71+/-0.57 IU/mL), but the PT and APTT of patients who received rivaroxaban were more prolonged than those of patients who received apixaban (18.1+/-5.6 s vs. 13.8+/-0.9 s, p<0.001 and 40.9+/-7.3 s vs. 35.5+/-7.5 s, p<0.01, respectively). At trough time, the AXA and PT of patients who received rivaroxaban were respectively lower and shorter than those of patients who received apixaban (0.28+/-0.31 IU/mL vs. 1.04+/-0.72 IU/mL, p<0.001 and 11.9+/-2.0 s vs. 13.7+/-2.4 s, p<0.01, respectively), but the APTT of patients who received rivaroxaban and apixaban did not significantly differ (32.3+/-4.3 s vs. 34.3+/-3.8 s). CONCLUSIONS: Measurement of AXA might be useful to assess the pharmacodynamics of high-risk patients, such as high age, low body weight, and/or low renal function, and to assess the intensity of anticoagulation by using different methods of administration, such as crushed tablet via the nasogastric tube. PMID- 26949429 TI - Impact of esophageal temperature monitoring guided atrial fibrillation ablation on preventing asymptomatic excessive transmural injury. AB - BACKGROUND: Even with the use of a reduced energy setting (20-25 W), excessive transmural injury (ETI) following catheter ablation of atrial fibrillation (AF) is reported to develop in 10% of patients. However, the incidence of ETI depends on the pulmonary vein isolation (PVI) method and its esophageal temperature monitor setting. Data comparing the incidence of ETI following AF ablation with and without esophageal temperature monitoring (ETM) are still lacking. METHODS: This study was comprised of 160 patients with AF (54% paroxysmal, mean: 24.0+/ 2.9 kg/m(2)). Eighty patients underwent ablation accompanied by ETM. The primary endpoint was defined as the occurrence of ETI assessed by endoscopy within 5 d after the AF ablation. The secondary endpoint was defined as AF recurrence after a single procedure. If the esophageal temperature probe registered >39 degrees C, the radiofrequency (RF) application was stopped immediately. RF applications could be performed in a point-by-point manner for a maximum of 20 s and 20 W. ETI was defined as any injury that resulted from AF ablation, including esophageal injury or periesophageal nerve injury (peri-ENI). RESULTS: The incidence of esophageal injury was significantly lower in patients whose AF ablation included ETM compared with patients without ETM (0 [0%] vs. 6 [7.5%], p=0.028), but not the incidence of peri-ENI (2 [2.5%] vs. 3 [3.8%], p=1.0). AF recurrence 12 months after the procedure was similar between the groups (20 [25%] in the ETM group vs. 19 [24%] in the non-ETM group, p=1.00). CONCLUSIONS: Catheter ablation using ETM may reduce the incidence of esophageal injury without increasing the incidence of AF recurrence but not the incidence of peri-ENI. PMID- 26949431 TI - Measurement of diffuse ventricular fibrosis with myocardial T1 in patients with atrial fibrillation. AB - BACKGROUND: Atrial fibrillation (AF) is associated with cardiac fibrosis, which can now be measured noninvasively using T1-mapping with cardiac magnetic resonance imaging (CMRI). This study aimed to assess the impact of AF on ventricular T1 at the time of CMRI. METHODS: Subjects with AF scheduled for AF ablation underwent CMRI with standard electrocardiography gating and breath-hold protocols on a 1.5 T scanner with post-contrast ventricular T1 recorded from 6 regions of interest at the mid-ventricle. Baseline demographic, clinical, and imaging characteristics were examined using univariate and multivariable linear regression modeling for an association with myocardial T1. RESULTS: One hundred fifty-seven patients were studied (32% women; median age, 61 years [interquartile range {IQR}, 55-67], 50% persistent AF [episodes>7 days or requiring electrical or pharmacologic cardioversion], 30% in AF at the time of the CMRI). The median global T1 was 404 ms (IQR, 381-428). AF at the time of CMRI was associated with a 4.4% shorter T1 (p=0.000) compared to sinus rhythm when adjusted for age, sex, persistent AF, body mass index, congestive heart failure, and renal dysfunction (estimated glomerular filtration rate<60). A post-hoc multivariate model adjusted for heart rate suggested that heart rate elevation (p=0.009) contributes to the reduction in T1 observed in patients with AF at the time of CMRI. No association between ventricular T1 and AF recurrence after ablation was demonstrated. CONCLUSION: AF at the time of CMRI was associated with lower post-contrast ventricular T1 compared with sinus rhythm. This effect was at least partly due to elevated heart rate. T1 was not associated with the recurrence of AF after ablation. PMID- 26949432 TI - Development of an alert system for subjects with paroxysmal atrial fibrillation. AB - BACKGROUND: Knowledge of the onset of atrial fibrillation (AF) episodes in patients with paroxysmal atrial fibrillation (PAF) will enable them to better manage this condition. Current advances in mobile technology allow RR interval data to be obtained in real time. An analysis technique using RR interval data is presented with a view to alert a subject before a PAF episode. METHOD: The method is based on a time series of standard deviation and 0.99 quantile values of the spectral entropy, constructed from RR data. The RR data are taken from three time periods. The first time period has no occurrences of AF for 45 min to either side of the time period. The second time period just precedes an AF attack. Both of these are of thirty minutes duration. The third time period of approximately 5 min follows the second, and is when AF occurs. RESULTS: Twenty-two PAF subjects were studied and in all cases there was a steady increase in the values of these indices as the onset of the AF attack approached. CONCLUSION: This method of analysis of RR interval data shows potential use to alert a PAF subject before the onset of an AF episode. PMID- 26949427 TI - 2015 HRS/EHRA/APHRS/SOLAECE expert consensus statement on optimal implantable cardioverter-defibrillator programming and testing. PMID- 26949433 TI - Efficacy of bilateral thoracoscopic sympathectomy in a patient with catecholaminergic polymorphic ventricular tachycardia. AB - A 27-year-old woman with frequent implantable cardioverter defibrillator (ICD) shocks related to catecholaminergic polymorphic ventricular tachycardia (VT) experienced aborted sudden death due to incessant polymorphic VT despite the administration of beta-blockers, verapamil, and flecainide. Catheter ablation failed to suppress the polymorphic VT. Based on the temporary efficacy of the local anesthetic administered at the left and right cervical sympathetic nerves to suppress VT under an isoproterenol infusion, stepwise, bilateral thoracoscopic sympathectomy was performed. Postoperatively, no further VT or syncopal episodes were documented under ICD telemetry. Bilateral thoracoscopic sympathectomy may be an alternative for patients with drug-refractory catecholaminergic polymorphic VT. PMID- 26949434 TI - An appropriate shock of the wearable cardioverter-defibrillator in an outpatient setting. AB - The wearable cardioverter-defibrillator (WCD) represents an alternative clinical approach to prevent sudden cardiac death as a bridge to therapy when making a final decision regarding the need for an implantable cardioverter defibrillator (ICD), especially in patients who are in the so-called gray zone according to ICD guidelines. Although the WCD system was introduced in Japan in April 2014, data regarding its usage and experience are limited. We report the first case of appropriate shock therapy using the WCD in an outpatient setting in Japan. We describe the case of a 22-year-old-woman who received the first case of successful appropriate WCD shock therapy in an outpatient setting in Japan. PMID- 26949435 TI - An overlap of Brugada syndrome and arrhythmogenic right ventricular cardiomyopathy/dysplasia. AB - Overlapping characteristics of Brugada syndrome (BrS) and arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) have been reported in recent studies, but little is known about the overlapping disease state of BrS and ARVC/D. A 36-year-old man, hospitalized at our institution for syncope, presented with this overlapping disease state. The electrocardiogram showed spontaneous coved-type ST-segment elevation, and ventricular fibrillation was induced by right ventricular outflow tract stimulation in an electrophysiological study. BrS was subsequently diagnosed; additionally, the presence of epsilon-like waves and right ventricular structural abnormalities met with the 2010 revised task force criteria for ARVC/D. After careful investigation for both BrS and ARVC/D, an implantable cardioverter defibrillator was inserted in the patient. This case revealed 2 important clinical findings: (1) BrS and ARVC/D clinical features can coexist in a single patient, and EPS might be useful for determining the phenotype of overlapping disease (e.g., BrS-like or ARVC/D-like). (2) An overlapping disease state of BrS and ARVC/D can change phenotypically during its clinical course. Therefore, careful examination and attentive follow-up are required for patients with BrS or ARVC/D. PMID- 26949436 TI - Takotsubo syndrome and polymorphic ventricular tachycardia: The chicken or the egg. PMID- 26949437 TI - Rejoinder. PMID- 26949438 TI - Estimating Population Size Using the Network Scale Up Method. AB - We develop methods for estimating the size of hard-to-reach populations from data collected using network-based questions on standard surveys. Such data arise by asking respondents how many people they know in a specific group (e.g. people named Michael, intravenous drug users). The Network Scale up Method (NSUM) is a tool for producing population size estimates using these indirect measures of respondents' networks. Killworth et al. (1998a,b) proposed maximum likelihood estimators of population size for a fixed effects model in which respondents' degrees or personal network sizes are treated as fixed. We extend this by treating personal network sizes as random effects, yielding principled statements of uncertainty. This allows us to generalize the model to account for variation in people's propensity to know people in particular subgroups (barrier effects), such as their tendency to know people like themselves, as well as their lack of awareness of or reluctance to acknowledge their contacts' group memberships (transmission bias). NSUM estimates also suffer from recall bias, in which respondents tend to underestimate the number of members of larger groups that they know, and conversely for smaller groups. We propose a data-driven adjustment method to deal with this. Our methods perform well in simulation studies, generating improved estimates and calibrated uncertainty intervals, as well as in back estimates of real sample data. We apply them to data from a study of HIV/AIDS prevalence in Curitiba, Brazil. Our results show that when transmission bias is present, external information about its likely extent can greatly improve the estimates. The methods are implemented in the NSUM R package. PMID- 26949439 TI - Photophysical Analysis of the Formation of Organic-Inorganic Trihalide Perovskite Films: Identification and Characterization of Crystal Nucleation and Growth. AB - In this work we demonstrate that the different processes occurring during hybrid organic-inorganic lead iodide perovskite film formation can be identified and analyzed by a combined in situ analysis of their photophysical and structural properties. Our observations indicate that this approach permits unambiguously identifying the crystal nucleation and growth regimes that lead to the final material having a cubic crystallographic phase, which stabilizes to the well known tetragonal phase upon cooling to room temperature. Strong correlation between the dynamic and static photoemission results and the temperature dependent X-ray diffraction data allows us to provide a description and to establish an approximate time scale for each one of the stages and their evolution. The combined characterization approach herein explored yields key information about the kinetics of the process, such as the link between the evolution of the defect density during film formation, revealed by a fluctuating photoluminescence quantum yield, and the gradual changes observed in the PbI2 related precursor structure. PMID- 26949440 TI - Ethical Issues in the Management of Renal Cell Carcinoma. PMID- 26949441 TI - On the Theory of Evolution Versus the Concept of Evolution: Three Observations. AB - Here we address three misconceptions stated by Rice et al. in their observations of our article Paz-y-Mino and Espinosa (Evo Edu Outreach 2:655-675, 2009), published in this journal. The five authors titled their note "The Theory of Evolution is Not an Explanation for the Origin of Life." First, we argue that it is fallacious to believe that because the formulation of the theory of evolution, as conceived in the 1800s, did not include an explanation for the origin of life, nor of the universe, the concept of evolution would not allow us to hypothesize the possible beginnings of life and its connections to the cosmos. Not only Stanley Miller's experiments of 1953 led scientists to envision a continuum from the inorganic world to the origin and diversification of life, but also Darwin's own writings of 1871. Second, to dismiss the notion of Rice et al. that evolution does not provide explanations concerning the universe or the cosmos, we identify compelling scientific discussions on the topics: Zaikowski et al. (Evo Edu Outreach 1:65-73, 2008), Krauss (Evo Edu Outreach 3:193-197, 2010), Pereto et al. (Orig Life Evol Biosph 39:395-406, 2009) and Follmann and Brownson (Naturwissenschaften 96:1265-1292, 2009). Third, although we acknowledge that the term Darwinism may not be inclusive of all new discoveries in evolution, and also that creationists and Intelligent Designers hijack the term to portray evolution as ideology, we demonstrate that there is no statistical evidence suggesting that the word Darwinism interferes with public acceptance of evolution, nor does the inclusion of the origin of life or the universe within the concept of evolution. We examine the epistemological and empirical distinction between the theory of evolution and the concept of evolution and conclude that, although the distinction is important, it should not compromise scientific logic. PMID- 26949442 TI - Educators of Prospective Teachers Hesitate to Embrace Evolution Due to Deficient Understanding of Science/Evolution and High Religiosity. AB - Acceptance of evolution by educators of prospective teachers remains superficially studied despite their role in having mentored schoolteachers whose weak support of evolution is known. Here, we contrast the views of New England educators of prospective teachers (n=62; 87% Ph. D./doctorate holders in 32 specializations) with those of the general faculty (n=244; 93% Ph.D./doctorate holders in 40 disciplines), both members of 35 colleges and universities, and with college students (n=827; subsample of the 35 institutions) who were polled on: (1) the controversy evolution vs. creationism vs. intelligent design (ID), (2) their understanding of how science/evolution works, and (3) their religiosity. The educators held intermediate positions in respect to the general faculty and the students: 94% of the general faculty, 75% of the educators, and 63% of the students said they accepted evolution openly; and 82% of the general faculty, 71% of the educators, and 58% of the students thought that evolution is definitely true. Only 3% of the general faculty in comparison to 19% of the educators and 24% of the students thought that evolution and creationism are in harmony. Although 93% of the general faculty, educators, and students knew that evolution relies on common ancestry, 26% of the general faculty, 45% of the educators, and 35% of the students did not know that humans are apes. Remarkably, 15% of the general faculty, 32% of the educators, and 35% of the students believed, incorrectly, that the origin of the human mind cannot be explained by evolution; and 30% of the general faculty, 59% of the educators, and 75% of the students were Lamarckian (=believed in inheritance of acquired traits). For science education: 96% of the general faculty, 86% of the educators, and 71% of the students supported the exclusive teaching of evolution, while 4% of the general faculty, 14% of the educators, and 29% of the students favored equal time to evolution, creationism and ID; note that 92% of the general faculty, 82% of the educators, and 50% of the students perceived ID as either not scientific and proposed to counter evolution based on false claims or as religious doctrine consistent with creationism. The general faculty was the most knowledgeable about science/evolution and the least religious (science index, SI=2.49; evolution index, EI= 2.49; and religiosity index, RI=0.49); the educators reached lower science/evolution but higher religiosity indexes than the general faculty (SI=1.96, EI=1.96, and RI=0.83); and the students were the least knowledgeable about science/ evolution and the most religious (SI=1.80, EI=1.60, and RI=0.89). Understanding of science and evolution were inversely correlated with level of religiosity, and understanding of evolution increased with increasing science literacy. Interestingly, ~36% of the general faculty, educators and students considered religion to be very important in their lives, and 17% of the general faculty, 34% of the educators, and 28% of the students said they prayed daily. Assessing the perception of evolution by educators of prospective teachers vs. the general faculty and the students of New England, one of the historically most progressive regions in the U.S., is crucial for determining the magnitude of the impact of creationism and ID on attitudes toward science, reason, and education in science. PMID- 26949443 TI - Social Support Among Substance Using Women with Criminal Justice Involvement. AB - Social support types (abstinence, appraisal, belonging, tangible) were analyzed among a sample of women with criminal justice involvement and substance use disorders (n = 200). Hierarchical linear regression was conducted to examine social support types in relation to changes in abstinence self-efficacy while controlling for incarceration histories. Only abstinence social support and tangible social support predicted significant increases in abstinence self efficacy, with tangible support accounting for more variance in the analytic model. Findings suggest women with criminal justice involvement who have substance use disorders have basic needs that if met would have an indirect effect on their recovery. Implications for treatment and research are discussed. PMID- 26949444 TI - Crispr-mediated Gene Targeting of Human Induced Pluripotent Stem Cells. AB - CRISPR/Cas9 nuclease systems can create double-stranded DNA breaks at specific sequences to efficiently and precisely disrupt, excise, mutate, insert, or replace genes. However, human embryonic stem or induced pluripotent stem cells (iPSCs) are more difficult to transfect and less resilient to DNA damage than immortalized tumor cell lines. Here, we describe an optimized protocol for genome engineering of human iPSCs using a simple transient transfection of plasmids and/or single-stranded oligonucleotides. With this protocol, we achieve transfection efficiencies greater than 60%, with gene disruption efficiencies from 1-25% and gene insertion/replacement efficiencies from 0.5-10% without any further selection or enrichment steps. We also describe how to design and assess optimal sgRNA target sites and donor targeting vectors; cloning individual iPSC by single cell FACS sorting, and genotyping successfully edited cells. PMID- 26949446 TI - Interplay between Oxidative Stress and Metabolism in Signalling and Disease. PMID- 26949447 TI - Exercise, Free Radical Metabolism, and Aging: Cellular and Molecular Processes. PMID- 26949449 TI - Neurodegeneration, Neurogenesis, and Oxidative Stress 2015. PMID- 26949445 TI - Lipids and Oxidative Stress Associated with Ethanol-Induced Neurological Damage. AB - The excessive intake of alcohol is a serious public health problem, especially given the severe damage provoked by chronic or prenatal exposure to alcohol that affects many physiological processes, such as memory, motor function, and cognitive abilities. This damage is related to the ethanol oxidation in the brain. The metabolism of ethanol to acetaldehyde and then to acetate is associated with the production of reactive oxygen species that accentuate the oxidative state of cells. This metabolism of ethanol can induce the oxidation of the fatty acids in phospholipids, and the bioactive aldehydes produced are known to be associated with neurotoxicity and neurodegeneration. As such, here we will review the role of lipids in the neuronal damage induced by ethanol-related oxidative stress and the role that lipids play in the related compensatory or defense mechanisms. PMID- 26949450 TI - Oxidative Stress in Metabolic Disorders: Pathogenesis, Prevention, and Therapeutics. PMID- 26949451 TI - New Bone Formation in Tuberculous-Infected Vertebral Body Defect after Administration of Bone Marrow Stromal Cells in Rabbit Model. AB - STUDY DESIGN: Preliminary experimental study using a rabbit spondylitis model. PURPOSE: To observe the ossification in a micro-environment containing live Mycobacterium tuberculosis transplanted with bone marrow stromal cells (BMSCs) in rabbits. OVERVIEW OF LITERATURE: BMSCs differentiate to osteoblasts and then osteocytes during ossification. Mycobacterium tuberculosis does not affect BMSC growth in vitro. METHODS: Six rabbits were divided into two groups of three rabbits. One group was positive for spondylitis tuberculosis by culture, polymerase chain reaction (PCR), and histopathologically. The other group was positive by PCR and histopathologically. Both groups were treated using BMSC transplantation and anti-tuberculosis drugs. After 6 weeks, ossification was evaluated by enumerating the number of osteoblasts, osteocytes, and lesion level of calcium. RESULTS: Mean number of osteoblasts was 207.00+/-31.00 in the first group and 220.33+/-73.46 in the second group. Mean number of intra-lesions osteocytes was in the first and second group was 18.33+/-30.04 and 31.00+/-26.87, respectively. Mean calcium level in the first group and second group was 2.94%+/ 0.89% and 2.51%+/-0.13%, respectively. Total ossification score in the first and second group was 31.00 and 25.67, respectively. CONCLUSIONS: Mycobacterium tuberculosis provides support for new bone formation by stimulating intra-lesion calcium metabolism. The microscopic environment containing live Mycobacterium tuberculosis enhances ossification. PMID- 26949452 TI - Simple and Economical Method to Create Thoracolumbar Burst Fracture in a Calf Spine Model. AB - STUDY DESIGN: Calf spine model study. PURPOSE: To describe a technique of creating thoracolumbar burst fractures in calf spine model by low weight drop weight. OVERVIEW OF LITERATURE: Burst fractures are one of the commonest types of thoracolumbar fractures and their treatment is controversial. Biomechanical studies aid in the decision of treatment of these fractures. A simple method of creation of burst fractures would help these biomechanical studies. METHODS: Ten specimens of thoracolumbar spines harvested from 6-8 week old calves were weakened at the target vertebra by standardized osteotomy cuts. Burst fractures were created by dropping a 5-kg of weight from a height of 1.2 m using an in house device. An accelerometer attached to the weight measured the acceleration at the point of impact. RESULTS: Average weight and bone mineral density of the specimens was 390 g and 0.67 g/cm(2), respectively. Computed tomography scan analysis of the fractures revealed McCormack grade 2 and grade 3 fractures in 5 and 3 specimens, respectively, Dennis type 2B in 4, type 2A burst fractures in 5 specimens and fracture dislocation in 1 specimen, AO type A3.1.1 in 4 specimens, type A3.2.2 in 4 and type A3.3.3 in 2 specimens. Vertical laminar split fracture was seen in 6 specimens. Average acceleration and energy at impact was 9.04 m/sec and 54.24 Nm, respectively. CONCLUSIONS: We describe a technique to create thoracolumbar burst fractures in calf spine by a drop weight method using a device that is simple to operate and easy to construct. The method is consistent and produces fractures similar to those occurring naturally, and can be considered as an alternative method for creating burst fractures in biomechanical studies. PMID- 26949448 TI - Isosteviol Sensitizes sarcKATP Channels towards Pinacidil and Potentiates Mitochondrial Uncoupling of Diazoxide in Guinea Pig Ventricular Myocytes. AB - KATP channel is an important mediator or factor in physiological and pathological metabolic pathway. Activation of KATP channel has been identified to be a critical step in the cardioprotective mechanism against IR injury. On the other hand, desensitization of the channel to its opener or the metabolic ligand ATP in pathological conditions, like cardiac hypertrophy, would decrease the adaption of myocardium to metabolic stress and is a disadvantage for drug therapy. Isosteviol, obtained by acid hydrolysis of stevioside, has been demonstrated to play a cardioprotective role against diseases of cardiovascular system, like anti IR injury, antihypertension, antihyperglycemia, and so forth. The present study investigated the effect of isosteviol (STV) on sarcKATP channel current induced by pinacidil and mitochondrial flavoprotein oxidation induced by diazoxide. Our results showed that preincubating cells with STV not only increased the current amplitude and activating rate of sarcKATP channels induced by pinacidil but also potentiated diazoxide-elicited oxidation of flavoprotein in mitochondria. PMID- 26949453 TI - Correlation of Vitamin D and Body Mass Index with Modic Changes in Patients with Non-Specific Low Back Pain in a Sub-Tropical Asian Population. AB - STUDY DESIGN: Cross-sectional study by non-probability consecutive sampling. PURPOSE: The objective of this study was to assess body mass index (BMI) and investigate vitamin D levels in patients with low back pain (LBP) and study a possible relationship with myopathy-related symptoms and Modic changes. OVERVIEW OF LITERATURE: LBP is a multifactorial problem and the search for its patho anatomical causes is ongoing. Modic changes seem to be a cause of back pain but the pathological mechanisms underlying this are not completely defined. Hypovitaminosis D and obesity have also been shown to cause chronic musculoskeletal pain. The relationship between vitamin D deficiency and BMI with Modic changes has not been studied in detail. METHODS: Three hundred and sixteen patients with chronic LBP was selected for the study by non-probability consecutive sampling. The study was conducted over a period of 12 months from January 2014 to December 2014 at St. John's Medical College, Banglore. Questionnaires were provided to the participants and demographic information, symptoms, weight and height were recorded from the study subjects. BMI was calculated. Serum vitamin D level was assessed and Modic changes studied on magnetic resonance imaging. Correlations between vitamin D, BMI and Modic changes were studied using correlation coefficients and odds ratios obtained from logistic regression. RESULTS: Two hundred and fifty-six out of 316 patients (80%) had low vitamin D. 83% of patients with BMI>25 kg/m(2) had low vitamin D levels as compared to 69% with BMI<25 kg/m(2). Statistically significant correlation coefficients were found between vitamin D levels, BMI and Modic changes. Significant association was found between low vitamin D levels and Modic changes (odds ratio 1.75). CONCLUSIONS: Vitamin D deficiency and obesity have significant relations with LBP. Low vitamin D levels is associated with Modic changes but whether they represent a subgroup of patients whose low backpain is associated with low vitamin D needs to be further evaluated. PMID- 26949454 TI - Cervical Footprint Anthropometry in Indian Population: Implications on Design of Artificial Disc Replacement Devices. AB - STUDY DESIGN: Cross-sectional study. PURPOSE: To accurately measure the dimensions of cervical endplates based on computed tomography (CT) scans in Indian population and assess accuracy of match with currently available cervical disc prostheses. OVERVIEW OF LITERATURE: The dimensions of currently available cervical disc replacement implants are based on early published geometrical measurements of vertebrae endplates for Caucasian population. To author's knowledge, similar study has not been published for patients from Indian subcontinent. METHODS: CT scans of cervical spine of patients from Indian subcontinent were collected and reviewed. Seventy patients (54 men and 16 women; aged 18-56 years with average of 37 years) who underwent CT scans of cervical spine were included in study. 3D CT scans of sub axial cervical spine (C3 to C7) were analyzed. The anterior-posterior (AP) and central mediolateral (CML) dimensions of superior and inferior endplates from C3 to C7 were measured using digital measuring system. RESULTS: A total of 560 endplates of 70 patients were included in the study. The AP diameter of cervical endplates ranged from 0.87 to 2.47 cm. The CML diameters ranged from 0.84 to 2.98 cm. For levels C3/C4 and C4/C5 for AP dimension Prestige-LP (90.5%) and Prodisc-C (89%) discs showed higher percentage of matching than Discover discs (58.5%). For CML diameter, Prestige-LP (69.5%), Prodisc-C (70%) and Discover (39.5%) discs showed almost similar matching with measured endplates. For levels C5/C6 and C6/C7 for AP dimension, Prestige-LP (67.25%), Prodisc-C (49.35%) and Discover (51.5%) discs showed similar matching. For CML diameter Prestige-LP (32%), Prodisc-C (27.5%) and Discover (42.2%) discs showed poor matching with measured endplates. CONCLUSIONS: This study indicates need for redesign of cervical disc prostheses to match Indian patients. The collected anthropometric dimensions from this study may be used to design and develop indigenous artificial total disc replacement prosthesis and even cervical cages in India. With the present study being a small pilot study, the authors recommend anthropometric CT measurements in larger number of Indian patients in order to validate footprint dimensions for designing better-matched prosthesis. PMID- 26949455 TI - Lumbar Interspinous Process Fixation and Fusion with Stand-Alone Interlaminar Lumbar Instrumented Fusion Implant in Patients with Degenerative Spondylolisthesis Undergoing Decompression for Spinal Stenosis. AB - STUDY DESIGN: Prospective cohort study. PURPOSE: To assess the ability of a stand alone lumbar interspinous implant (interspinous/interlaminar lumbar instrumented fusion, ILIF) associated with bone grafting to promote posterior spine fusion in degenerative spondylolisthesis (DS) with vertebral instability. OVERVIEW OF LITERATURE: A few studies, using bilateral laminotomy (BL) or bilateral decompression by unilateral laminotomy (BDUL), found satisfactory results in stenotic patients with decompression alone, but others reported increased olisthesis, or subsequent need for fusion in DS with or without dynamic instability. METHODS: Twenty-five patients with Grade I DS, leg pain and chronic low back pain underwent BL or BDUL and ILIF implant. Olisthesis was 13% to 21%. Follow-up evaluations were performed at 4 to 12 months up to 25 to 44 months (mean, 34.4). Outcome measures were numerical rating scale (NRS) for back and leg pain, Oswestry disability index (ODI) and short-form 36 health survey (SF-36) of body pain and function. RESULTS: Fusion occurred in 21 patients (84%). None had increased olisthesis or instability postoperatively. Four types of fusion were identified. In Type I, the posterior part of the spinous processes were fused. In Type II, fusion extended to the base of the processes. In Type III, bone was present also around the polyetheretherketone plate of ILIF. In Type IV, even the facet joints were fused. The mean NRS score for back and leg pain decreased by 64% and 80%, respectively. The mean ODI score was decreased by 52%. SF-36 bodily pain and physical function mean scores increased by 53% and 58%, respectively. Computed tomography revealed failed fusion in four patients, all of whom still had vertebral instability postoperatively. CONCLUSIONS: Stand-alone ILIF with interspinous bone grafting promotes vertebral fusion in most patients with lumbar stenosis and unstable Grade I DS undergoing BL or BDUL. PMID- 26949457 TI - Juxtafacet Spinal Synovial Cysts. AB - STUDY DESIGN: This was a retrospective study. PURPOSE: To study the surgical outcome of synovial cysts of the lumbar spine through posterior laminectomy in combination with transpedicular screw fixation. OVERVIEW OF LITERATURE: Synovial cysts of the lumbar spine contribute significantly to narrowing of the spinal canal and lateral thecal sac and nerve root compression. Cysts form as a result of arthrotic disruption of the facet joint, leading to degenerative spondylolisthesis in up to 40% of patients. METHODS: Retrospective data from 6 patients, treated during the period of March 2007 to February 2011, were analyzed. All preoperative and postoperative manifestations, extension/flexion radiographs, magnetic resonance imaging, and computed tomography records were reviewed. All underwent surgery for synovial cysts with excision and decompression combined with posterior fixation. The result of surgery was evaluated with Macnab's classification. An excellent or good outcome was considered as satisfactory. Japanese Orthopedic Association Scale was used for evaluation of back pain. RESULTS: All patients included in this study had excellent outcomes as regarding to improvement of all preoperative manifestations and returning to normal daily activities. Only 2 cases developed postoperative transient cerebro-spinal fluid leak and were treated conservatively and improved during the follow up period. CONCLUSIONS: Although this study included a small number of cases and we could not have statistically significant results, the good outcome of decompression of synovial cysts combined with posterior fixation and fusion encouraged us to recommend this approach for patients with juxtafacet synovial cysts. PMID- 26949456 TI - Feasibility Study of Free-Hand Technique for Pedicle Screw Insertion at C7 without Fluoroscopy-Guidance. AB - STUDY DESIGN: Retrospective interventional study. PURPOSE: To introduce a free hand pedicle screw (PS) insertion technique without fluoroscopic guidance in the C7 vertebra and evaluate the procedure's feasibility and radiologic outcomes. OVERVIEW OF LITERATURE: Although PS insertion at C7 has been recognized as a critical procedure in posterior cervical fusion surgery, conventional techniques for C7 PS have several limitations. METHODS: Thirty two patients (64 screws) who underwent PS insertion in C7 with the novel technique were included in this study. Postoperative clinical and radiological outcomes were evaluated. Special attention was paid to the presence of any problems in the screw position including cortical breaches of the PS and encroachment of the PS into the spinal canal or the vertebral foramen. This novel technique for PS insertion in C7 without fluoroscopy guidance had three key elements. First, the ideal PS entry point was chosen near the C6-7 facet joint using preoperative images. Second, the convergent angle distance was measured at axial computed tomography (CT) imaging, which defined the distance between the tip of C7 spinous process and the extended line passing through the pedicle axis from the ideal entry point. Third, the cranial-caudal angle distance was measured in sagittal CT images, which defined the distance between the tip of the C7 spinous process and the extended line passing through the pedicle axis. RESULTS: Cortical breach on postoperative CT images was observed in three screws. All violated only the lateral wall of the affected pedicle. The breached screws occurred in the initial five cases. Postoperative neurologic deterioration was not observed in any patient, regardless of cortical breaching. CONCLUSIONS: The novel technique successfully allows for C7 PS to be placed and is associated with a low rate of cortical breach. PMID- 26949458 TI - Transforaminal Lumbar Interbody Fusion for Management of Recurrent Lumbar Disc Herniation. AB - STUDY DESIGN: Retrospective study. PURPOSE: To study the surgical outcome of transforaminal lumbar interbody fusion (TLIF) combined with trans-pedicular screws fixation for management of selected cases of recurrent lumbar disc herniation. OVERVIEW OF LITERATURE: Recurrent lumbar disc herniation is a major cause of surgical failure, occurring in 5%-11% of cases. The optimal technique for treatment is controversial. Some authors believe that repeated simple discectomy is the treatment of choice, but approach-related complications can be considerable. Other surgeons prefer more removal of posterior elements (as lamina and facet joints) with posterior fusion. METHODS: The study included 15 patients who presented with symptomatic recurrent lumbar disc herniation who underwent reoperation through posterior trans-pedicular screws and TLIF in our department from April 2008 to May 2010, with a 24-month follow-up. Japanese Orthopedic Association Scale (JOA) was used for low back pain. The results of surgery were also evaluated with the MacNab classification. RESULTS: The mean JOA score showed significant improvement, increasing from 9.5 before surgery to 24.0 at the end of follow-up (p<0.001). Clinical outcome was excellent in 7 patients (46% of cases), good in 6 patients (40%) and fair in only 2 patients (14%). There was a significant difference (p<0.05) between patients presenting with recurrent disc at the ipsilateral side and those at the contralateral side. CONCLUSIONS: In spite of the small number of patients and the short follow-up period, the good clinical and radiological outcome achieved in this study encourage the belief that TLIF is an effective option for the treatment of selected cases of recurrent lumbar disc herniation. PMID- 26949460 TI - Sensitivity of Pyramidal Signs in Patients with Cervical Spondylotic Myelopathy. AB - STUDY DESIGN: This was a retrospective study. PURPOSE: The purpose of this study was to study the relationship between prevalence of pyramidal signs and the severity of cervical myelopathy. The study is focused on patients having increased signal intensity in T2-weighted magnetic resonance imaging. OVERVIEW OF LITERATURE: Cervical spondylotic myelopathy is the most common cause of spinal cord dysfunction in elderly population. It is the consequence of spondylotic changes leading to cervical cord injury with resulting clinical deficits. Diagnosis in such patients is made based on clinical and radiographic features. A patient must have both symptoms and signs consistent with cervical cord injury as well as radiographic evidence of damage to spondylotic cord. METHODS: Forty-six patients with complaint of cervical spondylotic myelopathy with increased signal intensity in T2-weighted magnetic resonance imaging were included in the study. The neurological finding of the patients was reviewed for the presence of pyramidal signs. The prevalence of each pyramidal sign was calculated and correlated to severity of cervical myelopathy. The motor function scores of the upper and lower extremities for cervical myelopathy set by the Japanese Orthopedic Association (motor Japanese Orthopaedic Association score, m-JOA) scores were used to assess severity of myelopathy. RESULTS: The most prevalent signs were hyperreflexia (89.1%), Hoffmann reflex (80.4%), Babiniski sign (56.5%), and ankle clonus (39.1%). Babiniski sign, ankle clonus, and Hoffmann reflex showed significant association with the lower m-JOA score. CONCLUSIONS: In patients with cervical myelopathy, hyperreflexia exhibited highest sensitivity whereas ankle clonus demonstrated lowest sensitivity. The prevalence of the pyramidal signs is correlated with increasing severity of myelopathy. PMID- 26949459 TI - Comparison with Magnetic Resonance Three-Dimensional Sequence for Lumbar Nerve Root with Intervertebral Foramen. AB - STUDY DESIGN: Prospective study based on magnetic resonance (MR) imaging of the lumbar spinal root of the intervertebral foramen. PURPOSE: This study was to compare MR three-dimensional (3D) sequences for the evaluation of the lumbar spinal root of the intervertebral foramen. OVERVIEW OF LITERATURE: The diagnosis of spinal disorders by MR imaging is commonly performed using two-dimensional T1- and T2-weighted images, whereas 3D MR images can be used for acquiring further detailed data using thin slices with multi-planar reconstruction. METHODS: On twenty healthy volunteers, we investigated the contrast-to-noise ratio (CNR) of the lumbar spinal root of the intervertebral foramen with a 3D balanced sequence. The sequences used were the fast imaging employing steady state acquisition and the coherent oscillatory state acquisition for the manipulation of image contrast (COSMIC). COSMIC can be used with or without fat suppression (FS). We compared these sequence to determine the optimized visualization sequence for the lumbar spinal root of the intervertebral foramen. RESULTS: For the CNR between the nerve root and the peripheral tissue, these were no significant differences between the sequences at the entry of foramen. There was a significant difference and the highest CNR was seen with COSMIC-FS for the intra- and extra-foramen. CONCLUSIONS: In this study, the findings suggest that the COSMIC-FS sequences should be used for the internal or external foramen for spinal root disorders. PMID- 26949461 TI - Reliable Magnetic Resonance Imaging Based Grading System for Cervical Intervertebral Disc Degeneration. AB - STUDY DESIGN: Observational. PURPOSE: To develop a simple and comprehensive grading system for cervical discs that precisely, consistently and meaningfully presents radiologic and morphologic data. OVERVIEW OF LITERATURE: The Thompson grading system is commonly used to classify the severity of degenerative lumbar discs on magnetic resonance imaging (MRI). Inherent differences in the morphological and physiological characteristics of cervical discs have hindered development of precise classification systems. Other grading systems have been developed for degenerating cervical discs, but their versatility and feasibility in the clinical setting is suboptimal. METHODS: MRIs of 46 human cervical discs were de-identified and displayed in PowerPoint format. Each slide depicted a single disc with a normal (grade 0) disc displayed in the top right corner for reference. The presentation was given to 25 physicians comprising attending spine surgeons, spine fellows, orthopaedic residents, and two attending musculoskeletal radiologists. The grading system included Grade 0 (normal height compared to C2 3, mid cleft still visible), grade 1 (dark disc, normal height), grade 2 (collapsed disc, few osteophytes), and grade 3 (collapsed disc, many osteophytes). The ease of use of the system was gauged in the participants and the interobserver reliability was calculated. RESULTS: The intraclass correlation coefficient for interobserver reliability was 0.87, and 0.94 for intraobserver reliability, indicating excellent reliability. Ninety-five percent and 85 percent of the clinicians judged the grading system to be clinically feasible and useful in daily practice, respectively. CONCLUSIONS: The grading system is easy to use, has excellent reliability, and can be used for precise and consistent clinician communication. PMID- 26949462 TI - Decompression without Fusion for Low-Grade Degenerative Spondylolisthesis. AB - STUDY DESIGN: Retrospective series. PURPOSE: Assess results of decompression-only surgery for low-grade degenerative spondylolisthesis with consideration of instability. OVERVIEW OF LITERATURE: There is no consensus on whether fusion or decompression-only surgery leads to better outcomes for patients with low-grade degenerative spondylolisthesis. Current trends support fusion but many studies are flawed due to over-generalization without consideration of radiological instability and their variable presentations and natural history. METHODS: Patients with surgically treated degenerative spondylolisthesis from 1990-2013 were included. Clinical and radiological instability measures were included. Any residual or recurrence of symptoms, revision surgery performed and functional outcome scores including the numerical global rate of change scale, visual analogue scale, and modified Barthel index were measured. Follow-up periods for patients were divided into short-term (<5 years), mid-term (5-10 years) and long term (>10 years). RESULTS: A total of 64 patients were recruited. Mechanical low back pain was noted in 48 patients and most (85.4%) had relief of back pain postoperatively. Radiological instability was noted in 4 subjects by flexion extension radiographs and 12 subjects with prone traction radiographs by increased disc height and reduction of olisthesis and slip angle. From the results of the short-term, mid-term and long-term follow-up, reoperation only occurred within the first 5-year follow-up period. All functional scores improved from preoperative to postoperative 1-year follow-up. CONCLUSIONS: Decompression only for low-grade degenerative spondylolisthesis has good long-term results despite instability. Further higher-level studies should be performed on this patient group with radiological instability to suggest the superior surgical option. PMID- 26949463 TI - Efficacy of Titanium Mesh Cages for Anterior Column Reconstruction after Thoracolumbar Corpectomy. AB - STUDY DESIGN: This retrospective study was conducted to determine the safety and efficacy of titanium cage reconstruction and anterior plating after thoracolumbar corpectomy. PURPOSE: To study the clinical and radiological outcome of anterior column reconstruction after thoracolumbar corpectomy. OVERVIEW OF LITERATURE: Anterior column reconstruction aims to optimize neural decompression with adequate stabilization. METHODS: A series of 16 patients underwent reconstruction after thoracolumbar corpectomy to treat injury due to trauma (n=10), tuberculosis (n=3), and tumor (n=3). The average duration of follow-up was 18 months (range, 8 58 months). The degree of kyphosis, construct height, and the subsidence of the cage in relation to the vertebral endplates were measured. The approach was thoracoabdominal in 10 cases and retroperitoneal in 6 cases. RESULTS: Four patients were neurologically intact with Frankel grade E on admission, and all remained intact postoperatively. Of the 6 patients with Frankel grade D, all fully recovered full motor and sensory functions. Of the 6 patients with Frankel grade C, three improved one grade and the other three improved two grades. The mean height of the vertebra before surgery was 41 mm and the mean construct height immediately after surgery and at follow-up was 47 mm and 44 mm, respectively. Solid fusion was observed in all patients. The sagittal alignment of the fractured segment was restored immediately after surgery as a significant decrease in the local kyphotic angle. CONCLUSIONS: Anterior instrumentation is an effective and safe treatment for thoracolumbar instability with satisfactory clinical and radiological outcomes. PMID- 26949464 TI - Comparison of Posterior Lumbar Interbody Fusion and Posterolateral Lumbar Fusion in Monosegmental Vacuum Phenomenon within an Intervertebral Disc. AB - STUDY DESIGN: Retrospective. PURPOSE: To compare the clinical and radiological outcomes of posterolateral lumbar interbody fusion (PLIF) and posterolateral lumbar fusion (PLF) in monosegmental vacuum phenomenon within an intervertebral disc. OVERVIEW OF LITERATURE: The vacuum phenomenon within an intervertebral disc is a serious form of degenerative disease that destabilizes the intervertebral body. Outcomes of PLIF and PLF in monosegmental vacuum phenomenon are unclear. METHODS: Monosegmental instrumented PLIF and PLF was performed on 84 degenerative lumbar disease patients with monosegmental vacuum phenomenon (PLIF, n=38; PLF, n=46). Minimum follow-up was 24 months. Clinical outcomes of leg and back pain were assessed using visual analogue scales for leg pain (LVAS) and back pain (BVAS), and the Oswestry disability index (ODI). The radiographic outcome was the estimated bony union rate. RESULTS: LVAS, BVAS, and ODI improved in both groups. There was no significant difference in the degree of these improvements between PLIF and PLF patients (p>0.05). Radiological union rate was 91.1% in PLIF group and 89.4% in PLF group at postoperative 24 months (p>0.05). CONCLUSIONS: No significant differences in clinical results and union rates were found between PLIF and PLF patients. Selection of the operation technique will reflect the surgeon's preferences and patient condition. PMID- 26949465 TI - Minimally Invasive Spinal Stabilization Using Fluoroscopic-Guided Percutaneous Screws as a Form of Palliative Surgery in Patients with Spinal Metastasis. AB - STUDY DESIGN: Prospective cohort study. PURPOSE: To report the outcome of 50 patients with spinal metastases treated with minimally invasive stabilization (MISt) using fluoroscopic guided percutaneous pedicle screws with/without minimally invasive decompression. OVERVIEW OF LITERATURE: The advent of minimally invasive percutaneous pedicle screw stabilization system has revolutionized the treatment of spinal metastasis. METHODS: Between 2008 and 2013, 50 cases of spinal metastasis with pathological fracture(s) with/without neurology deficit were treated by MISt at our institution. The patients were assessed by Tomita score, pain score, operation time, blood loss, neurological recovery, time to ambulation and survival. RESULTS: The mean Tomita score was 6.3+/-2.4. Thirty seven patients (74.0%) required minimally invasive decompression in addition to MISt. The mean operating time was 2.3+/-0.5 hours for MISt alone and 3.4+/-1.2 hours for MISt with decompression. Mean blood loss for MISt alone and MISt with decompression was 0.4+/-0.2 L and 1.7+/-0.9 L, respectively. MISt provided a statistically significant reduction in visual analog scale pain score with mean preoperative score of 7.9+/-1.4 that was significantly decreased to 2.5+/-1.2 postoperatively (p=0.000). For patients with neurological deficit, 70% displayed improvement of one Frankel grade and 5% had an improvement of 2 Frankel grades. No patient was bed-ridden postoperatively, with the average time to ambulation of 3.4+/-1.8 days. The mean overall survival time was 11.3 months (range, 2-51 months). Those with a Tomita score <8 survived significantly longer than those a Tomita score >=8 with a mean survival of 14.1+/-12.5 months and 6.8+/-4.9 months, respectively (p=0.019). There were no surgical complications, except one case of implant failure. CONCLUSIONS: MISt is an acceptable treatment option for spinal metastatic patients, providing good relief of instability back pain with no major complications. PMID- 26949466 TI - Percutaneous Transpedicular Fixation: Technical tips and Pitfalls of Sextant and Pathfinder Systems. AB - STUDY DESIGN: The efficacy of the operative techniques, possible benefits as well as pitfalls and limitations of the techniques are discussed. Potential drawbacks are also detected. PURPOSE: This study aims to report indications, techniques, and our experience with the use of the Sextant and PathFinder percutaneous transpedicular screw fixation systems. OVERVIEW OF LITERATURE: Percutaneous pedicle screw insertion is a novel technique. Successful percutaneous placement of pedicle screws requires surgical skill and experience because of lack of anatomic surface landmarks. Fluoroscopy-guided percutaneous placement of pedicle screws is effective. Many systems are now available. METHODS: We conducted a prospective operative and postoperative analysis of 40 patients with absolute indication for thoracic or lumbar instability between January 2009 and June 2013. All procedures were performed with the Sextant (group A) and PathFinder (group B) systems under fluoroscopic guidance. Operative techniques are discussed and the results compared. RESULTS: Percutaneous transpedicular screw fixation minimizes the morbidity associated with open techniques without compromising the quality of fixation. A total of 190 screws were inserted. There was no additional morbidity. Postoperative computed tomography images and plain X-rays were analyzed. Reduction of visual analog scale scores of back pain was evident. CONCLUSIONS: Fluoroscopy-guided percutaneous pedicular screws are feasible and can be safely done. Current systems allow multi-segmental fixation with significantly less difficulties. The described techniques have acceptable intra- and postoperative complication rates, and overall sufficient pain control with early mobilization of patients. PMID- 26949467 TI - New Radiographic Index for Occipito-Cervical Instability. AB - STUDY DESIGN: Retrospective study. PURPOSE: To propose a new radiographic index for occipito-cervical instability. OVERVIEW OF LITERATURE: Symptomatic atlanto occipital instability requires the fusion of the atlanto-occipital joint. However, measurements of occipito-cervical translation using the Wiesel-Rothman technique, Power's ratio, and basion-axial interval are unreliable because the radiologic landmarks in the occipito-cervical junction lack clarity in radiography. METHODS: One hundred four asymptomatic subjects were evaluated with lateral cervical radiographs in neutral, flexion and extension. They were stratified by age and included 52 young (20-29 years) and 52 middle-aged adults (50-59 years). The four radiographic reference points were posterior edge of hard palate (hard palate), posteroinferior corner of the most posterior upper molar tooth (molar), posteroinferior corner of the C1 anterior ring (posterior C1), and posteroinferior corner of the C2 vertebral body (posterior C2). The distance from posterior C1 and posterior C2 to the above anatomical landmarks was measured to calculate the range of motion (ROM) on dynamic radiographs. To determine the difference between the two age groups, unpaired t-tests were used. The statistical significance level was set at p<0.05. RESULTS: The ROM was 4.8+/-7.3 mm between the hard palate and the posterior C1, 9.9+/-10.2 mm between the hard palate and the posterior C2, 1.7+/-7.2 mm between the molar to the posterior C1, and 10.4+/-12.1 mm between the molar to the posterior C2. There was no statistically significant difference for the ROM between the young- and the middle-aged groups. The intra-observer reliability for new radiographic index was good. The inter-observer reliability for the ROM measured by the hard palate was low, but was better than that by the molar. CONCLUSIONS: ROM measured by the hard palate might be a useful new radiographic index in cases of occipito-cervical instability. PMID- 26949469 TI - Decision-Making Process in Patients with Thoracolumbar and Lumbar Burst Fractures with Thoracolumbar Injury Severity and Classification Score Less than Four. AB - STUDY DESIGN: Cross-sectional. PURPOSE: To develop a strategy to determine a sound method for decision-making based on postoperative clinical outcome satisfaction. OVERVIEW OF LITERATURE: The ideal management of thoracolumbar and lumbar burst fractures (TLBF) without neurological compromise remains controversial. METHODS: This was a prospective study. Patients with thoracolumbar injury severity and classification score (TLICS) <4 were treated nonoperatively, with bed rest and bracing until the pain decreased sufficiently to allow mobilization. Surgery was undertaken in patients with intractable pain despite an appropriate nonoperative treatment (surgery group). The Oswestry disability index (ODI) measure was observed at baseline and at the last follow-up. Clinically success was defined at least a 30% improvement from the baseline ODI scores in both the conservative and surgery groups. All case records were assessed for gender, age, residual canal and angulations at the site of the fracture in order to determine which patients benefited from surgery or conservative treatment and which did not. RESULTS: In all 113 patients with T11-L5, TLBFs were treated. The patients' mean age was 49.2 years. Patients successfully completed either nonoperative (n=99) or surgical (n=14) treatment based on ODI. Clinical examinations revealed that all of the patients had intact neurology. The mean follow-up period was 29.5 months. There was a significant difference between the two groups based on age and residual canal. The mean ODI score significantly improved for both groups (p <0.01). According to the findings, a decision matrix was proposed. CONCLUSIONS: The findings confirm that TLICS <4, age, and residual canal can be used to guide the treatment of TLBF in conservative decision-making. PMID- 26949468 TI - Recurrent Spinal Giant Cell Tumors: A Study of Risk Factors and Recurrence Patterns. AB - STUDY DESIGN: Retrospective study. PURPOSE: To highlight risk factors, recurrence patterns and multimodal treatment in management of recurrent giant cell tumors (GCTs). OVERVIEW OF LITERATURE: GCTs of the spine are rare and challenging entities. Recurrences are very common and warrant complex management to prevent multiple recurrences. Gross total resection is preferred over subtotal procedures to prevent recurrences. However, resection is associated with morbidity and mortality. Proper understanding of risk factors and a high index of suspicion helps to spot recurrences early and aids in subsequent management. METHODS: Ten patients (six females, four males) with recurrent GCTs underwent 17 interventions. There were six lesions in the thoracic spine, two in the cervical spine and two in the lumbar spine. Recurrences were managed with preoperative digital subtraction embolization, intralesional curettage and postoperative radiotherapy. RESULTS: The average age at intervention was 31.3 years. The average duration of recurrence in patients following index surgery in a tertiary care hospital and surgery elsewhere was 7.3 years and was 40 months, respectively. The minimum recurrence-free interval after the last recurrent surgery was 10 years. CONCLUSIONS: Our study reports the largest recurrence-free interval for GCTs. Recurrent GCTs are challenging entities. Understanding of risk factors and meticulous planning is required to prevent recurrences. Intralesional surgery could be a safer and effective modality in managing recurrences. PMID- 26949470 TI - Comparison of Clinical and Radiological Results of Posterolateral Fusion and Posterior Lumbar Interbody Fusion in the Treatment of L4 Degenerative Lumbar Spondylolisthesis. AB - STUDY DESIGN: Multicenter analysis of two groups of patients surgically treated for degenerative L4 unstable spondylolisthesis. PURPOSE: To compare the clinical and radiographic outcomes of posterolateral fusion (PLF) and posterior lumbar interbody fusion (PLIF) for degenerative L4 unstable spondylolisthesis. OVERVIEW OF LITERATURE: Surgery for lumbar degenerative spondylolisthesis is widely performed. However, few reports have compared the outcome of PLF to that of PLIF for degenerative L4 unstable spondylolisthesis. METHODS: Patients with L4 unstable spondylolisthesis with Meyerding grade II or more, slip of >10 degrees or >4 mm upon maximum flexion and extension bending, and posterior opening of >5 degree upon flexion bending were studied. Patients were treated from January 2008 to January 2010. Patients who underwent PLF (n=12) and PLIF (n=19) were followed up for >2 years. Radiographic findings and clinical outcomes evaluated by the Japanese Orthopaedic Association (JOA) score were compared between the two groups. Radiographic evaluation included slip angle, translation, slip angle and translation during maximum flexion and extension bending, intervertebral disc height, lumbar lordotic angle, and fusion rate. RESULTS: JOA scores of the PLF group before surgery and at final follow-up were 12.3+/-4.8 and 24.1+/-3.7, respectively; those of the PLIF group were 14.7+/-4.8 and 24.2+/-7.8, respectively, with no significant difference between the two groups. Correction of slip estimated from postoperative slip angle, translation, and maintenance of intervertebral disc height in the PLIF group was significantly (p<0.05) better than those in the PLF group. However, there was no significant difference in lumbar lordotic angle, slip angle and translation angle upon maximum flexion, or extension bending. Fusion rates of the PLIF and PLF groups had no significant difference. CONCLUSIONS: The L4-L5 level posterior instrumented fusion for unstable spondylolisthesis using both PLF and PLIF could ameliorate clinical symptoms when local stability is achieved. PMID- 26949471 TI - Total Excision of a Giant Ventral Midline Cervical Spinal Intradural Schwannoma via Posterior Approach. AB - Schwannomas are the most common intradural extramedullary tumors of the spine. They usually occupy a posterolateral or lateral position in relation to the cord. The ventral midline is a very rare location for the origin of a spinal schwannoma. A giant one in such a location causes technical difficulties in excision. Here, we present a giant cervical spinal schwannoma, located ventral to the cord, in a 38-year-old lady who presented with features of myelopathy and bladder involvement. Magnetic resonance imaging was suggestive of an intradural extramedullary lesion extending from cervico-medullary junction to the third dorsal vertebral level with severe cord compression. The same was excised totally via a posterior approach after midline suboccipital craniectomy and C2-C6 laminoplasty. Postoperatively, she made a good recovery and was ambulant without support. Postoperative magnetic resonance imaging showed complete excision of the tumor. Histopathology was suggestive of schwannoma. PMID- 26949472 TI - Navigated Pin-Point Approach to Osteoid Osteoma Adjacent to the Facet Joint of Spine. AB - Osteoid osteoma (OO) is a benign osteoblastic tumor. Its curative treatment is complete removal of the nidus, where intraoperative localization of the nidus governs clinical results. However, treatment can be difficult since the lesion is often invisible over the bony surface. Accordingly, establishment of an ideal less invasive surgical strategy for spinal OO remains yet unsettled. We illustrate the efficacy of a computed tomography (CT)-based navigation system in excising OO located adjacent to the facet joint of spine. In our 2 cases, complete and pin-point removal of the nidus located close to the facet joint was successfully achieved, without excessive removal of the bone potentially leading to spinal instability and possible damage of nearby neurovascular structures. We advocate a less invasive approach to spinal OO, particularly in an environment with an available CT-based navigation system. PMID- 26949473 TI - Diagnosis of Lumbar Foraminal Stenosis using Diffusion Tensor Imaging. AB - Diagnosis of lumbar foraminal stenosis remains difficult. Here, we report on a case in which bilateral lumbar foraminal stenosis was difficult to diagnose, and in which diffusion tensor imaging (DTI) was useful. The patient was a 52-year-old woman with low back pain and pain in both legs that was dominant on the right. Right lumbosacral nerve compression due to a massive uterine myoma was apparent, but the leg pain continued after a myomectomy was performed. No abnormalities were observed during nerve conduction studies. Computed tomography and magnetic resonance imaging indicated bilateral L5 lumbar foraminal stenosis. DTI imaging was done. The extraforaminal values were decreased and tractography was interrupted in the foraminal region. Bilateral L5 vertebral foraminal stenosis was treated by transforaminal lumbar interbody fusion and the pain in both legs disappeared. The case indicates the value of DTI for diagnosing vertebral foraminal stenosis. PMID- 26949474 TI - Congenital Absence of Posterior Elements of C2 Vertebra with Atlanto-Axial Dislocation and Basilar Invagination: A Case Report and Review of Literature. AB - Developmental anomalies of the axis are commonly encountered, especially anomalies involving the odontoid process. Anomalies of the posterior elements are uncommon. We describe a unique case of agenesis of posterior elements of C2 with basilar invagination and atlanto-axial dislocation. An obese 8-year-old boy presented with symptoms of cervical myelopathy. Radiological workup revealed a craniovertebral junction anomaly with occipitalised atlas, absent posterior elements of axis, and hypertrophied C3 spinous process. Atlanto-axial instability and basilar invagination was present. Magnetic resonance angiography revealed hypoplastic left vertebral artery. Traction with cervical tongs failed to improve the alignment and symptoms. Anterior trans-oral release, followed by posterior decompression and custom-made instrumentation, was done. The patient recovered completely and was asymptomatic at the end of two years. X-ray and computed tomography scan demonstrated reduction of basilar invagination and maintenance of alignment. This is the first case to be reported of agenesis of posterior elements of axis associated with basilar invagination. One should look for this condition in patients with hypertrophied spinous process of C3. Utilization of hypoplastic pedicle of axis serves as an additional fixation point to increase the stability of the construct. PMID- 26949475 TI - Postoperative Spine Infections. AB - Postoperative spinal wound infection increases the morbidity of the patient and the cost of healthcare. Despite the development of prophylactic antibiotics and advances in surgical technique and postoperative care, wound infection continues to compromise patient outcome after spinal surgery. Spinal instrumentation also has an important role in the development of postoperative infections. This review analyses the risk factors that influence the development of postoperative infection. Classification and diagnosis of postoperative spinal infection is also discussed to facilitate the choice of treatment on the basis of infection severity. Preventive measures to avoid surgical site (SS) infection in spine surgery and methods for reduction of all the changeable risk factors are discussed in brief. Management protocols to manage SS infections in spine surgery are also reviewed. PMID- 26949476 TI - Osteotomies in the Cervical Spine. AB - Rigid cervical deformities are difficult problems to treat. The goals of surgical treatment include deformity correction, achieving a rigid fusion, and performing a thorough neural decompression. In stiff and ankylosed cervical spines, osteotomies are required to restore sagittal and coronal balance. In this chapter, we describe the clinical and radiographic workup for patients with cervical deformities, and delineate the various factors that must be considered when planning surgical treatment. We also describe in detail the various types of cervical osteotomies, along with their surgical technique, advantages, and potential complications. PMID- 26949477 TI - Letter to the Editor: Computed Tomography-Guided Biopsy for Potts Disease: An Institutional Experience from an Endemic Developing Country. PMID- 26949478 TI - Response to: Computed Tomography-Guided Biopsy for Potts Disease: An Institutional Experience from an Endemic Developing Country. PMID- 26949479 TI - Searching for Drug Synergy in Complex Dose-Response Landscapes Using an Interaction Potency Model. AB - Rational design of multi-targeted drug combinations is a promising strategy to tackle the drug resistance problem for many complex disorders. A drug combination is usually classified as synergistic or antagonistic, depending on the deviation of the observed combination response from the expected effect calculated based on a reference model of non-interaction. The existing reference models were proposed originally for low-throughput drug combination experiments, which make the model assumptions often incompatible with the complex drug interaction patterns across various dose pairs that are typically observed in large-scale dose-response matrix experiments. To address these limitations, we proposed a novel reference model, named zero interaction potency (ZIP), which captures the drug interaction relationships by comparing the change in the potency of the dose-response curves between individual drugs and their combinations. We utilized a delta score to quantify the deviation from the expectation of zero interaction, and proved that a delta score value of zero implies both probabilistic independence and dose additivity. Using data from a large-scale anticancer drug combination experiment, we demonstrated empirically how the ZIP scoring approach captures the experimentally confirmed drug synergy while keeping the false positive rate at a low level. Further, rather than relying on a single parameter to assess drug interaction, we proposed the use of an interaction landscape over the full dose response matrix to identify and quantify synergistic and antagonistic dose regions. The interaction landscape offers an increased power to differentiate between various classes of drug combinations, and may therefore provide an improved means for understanding their mechanisms of action toward clinical translation. PMID- 26949480 TI - SNP2Structure: A Public and Versatile Resource for Mapping and Three-Dimensional Modeling of Missense SNPs on Human Protein Structures. AB - One of the long-standing challenges in biology is to understand how non synonymous single nucleotide polymorphisms (nsSNPs) change protein structure and further affect their function. While it is impractical to solve all the mutated protein structures experimentally, it is quite feasible to model the mutated structures in silico. Toward this goal, we built a publicly available structure database resource (SNP2Structure, https://apps.icbi.georgetown.edu/snp2structure) focusing on missense mutations, msSNP. Compared with web portals with similar aims, SNP2Structure has the following major advantages. First, our portal offers direct comparison of two related 3D structures. Second, the protein models include all interacting molecules in the original PDB structures, so users are able to determine regions of potential interaction changes when a protein mutation occurs. Third, the mutated structures are available to download locally for further structural and functional analysis. Fourth, we used Jsmol package to display the protein structure that has no system compatibility issue. SNP2Structure provides reliable, high quality mapping of nsSNPs to 3D protein structures enabling researchers to explore the likely functional impact of human disease-causing mutations. PMID- 26949481 TI - Effect of metal conditioner on bonding of porcelain to cobalt-chromium alloy. AB - PURPOSE: The purpose of this study was to evaluate the efficacy of two different metal conditioners for non-precious metal alloys for the bonding of porcelain to a cobalt-chromium (Co-Cr) alloy. MATERIALS AND METHODS: Disk-shaped specimens (2.5*10.0 mm) were cast with Co-Cr alloy and used as adherend materials. The bonding surfaces were polished with a 600-grid silicon carbide paper and airborne particle abraded using 110 um alumina particles. Bonding specimens were fabricated by applying and firing either of the metal conditioners on the airborne-particle abraded surface, followed by firing porcelain into 5 mm in diameter and 3 mm in height. Specimens without metal conditioner were also fabricated. Shear bond strength for each group (n=8) were measured and compared (alpha=.05). Sectional view of bonding interface was observed by SEM. EDS analysis was performed to determine the chemical elements of metal conditioners and to determine the failure modes after shear test. RESULTS: There were significant differences among three groups, and two metal conditioner-applied groups showed significantly higher values compared to the non-metal conditioner group. The SEM observation of the sectional view at bonding interface revealed loose contact at porcelain-alloy surface for non-metal conditioner group, however, close contact at both alloy-metal conditioner and metal conditioner porcelain interfaces for both metal conditioner-applied groups. All the specimens showed mixed failures. EDS analysis showed that one metal conditioner was Si based material, and another was Ti-based material. Si-based metal conditioner showed higher bond strengths compared to the Ti-based metal conditioner, but exhibited more porous failure surface failure. CONCLUSION: Based on the results of this study, it can be stated that the application of metal conditioner is recommended for the bonding of porcelain to cobalt-chromium alloys. PMID- 26949482 TI - A study on the changes in attractive force of magnetic attachments for overdenture. AB - PURPOSE: Although magnetic attachment is used frequently for overdenture, it is reported that attractive force can be decreased by abrasion and corrosion. The purpose of this study was to establish the clinical basis about considerations and long term prognosis of overdenture using magnetic attachments by investigating the change in attractive force of magnetic attachment applied to the patients. MATERIALS AND METHODS: Among the patients treated with overdenture using magnetic attachments in Dankook University Dental Hospital, attractive force records of 61 magnetic attachments of 20 subjects who re-visited from July 2013 to June 2014 were analyzed. Dental magnet tester (Aichi Micro Intelligent Co., Aichi, Japan) was used for measurement. The magnetic attachments used in this study were Magfit IP-B Flat, Magfit DX400, Magfit DX600 and Magfit DX800 (Aichi Steel Co., Aichi, Japan) filled with Neodymium (NdFeB), a rare-earth magnet. RESULTS: Reduction ratio of attractive force had no significant correlation with conditional variables to which attachments were applied, and was higher when the maintenance period was longer (P<.05, r=.361). Reduction ratio of attractive force was significantly higher in the subject group in which attachments were used over 9 years than within 9 years (P<.05). Furthermore, 16.39% of total magnetic attachments showed detachment of keeper or assembly. CONCLUSION: Attractive force of magnetic attachment is maintained regardless of conditional variables and reduction ratio increased as the maintenance period became longer. Further study on adhesive material, attachment method and design improvement to prevent detachment of magnetic attachment is needed. PMID- 26949483 TI - Effects of different surface finishing procedures on the change in surface roughness and color of a polymer infiltrated ceramic network material. AB - PURPOSE: Polymer infiltrated ceramic network (PICN) materials, also called hybrid ceramics, are new materials in dental market. The manufacturer of the PICN material VITA Enamic suggests 3 different finishing procedures for this new material. In the present study, surface roughness and color differences caused from different finishing procedures of VITA Enamic were investigated. MATERIALS AND METHODS: 120 specimens were prepared in dimensions 2 * 10 * 12 mm from VITA Enamic hybrid ceramic blocks with 'high translucency' and 'translucency 2M2' shades. The specimens were divided into 8 groups. For each group, different finishing procedures suggested by the manufacturer were performed. Surface roughness values were determined by a tactile portable profilometer. Color changes were evaluated using a clinical spectrophotometer. The data were analyzed using one-way ANOVA and Tukey's post-hoc comparison. The significance level was set at alpha=0.05. RESULTS: The roughest surfaces were observed in Glaze Groups. Their surface roughness values were similar to that of the control group. Clinical Kit and Technical Kit groups did not show a statistically significant difference regarding surface roughness (P>.05). The largest color difference regarding DeltaE00 was observed in Clinical Kit finishing groups. There were also statistically significant color changes between the groups (P<.05). However, all the groups showed clinically acceptable color change (DeltaE00<2.25) except Clinical Kit Groups (DeltaE00>2.25). CONCLUSION: Within the limitations of the present study, it may be suggested that finishing the VITA Enamic restorations by Technical Kit instead of Glaze and Clinical Kit gives better clinical performance in regard to surface roughness and shade matching. PMID- 26949484 TI - Effect of abutment angulation in the retention and durability of three overdenture attachment systems: An in vitro study. AB - PURPOSE: This in vitro study investigated and compared the durability and retention of three types of attachments. MATERIALS AND METHODS: Three commercially available attachments were investigated: Clix(r), Dalbo-Plus(r) and Locator(r). In total, 72 samples of these attachments were placed in the acrylic resin forms and subjected to mechanical testing (5400 cycles of insertion and removal) over the respective ball or Locator abutments immersed in artificial saliva at pH 7 and 37C. The abutments were placed at angulations of 0 degrees , 10 degrees and 20 degrees . The retention force was recorded at the beginning and after 540, 1080, 2160, 3240, 4320 and 5400 insertion-removal cycles. RESULTS: The results revealed that there were significant differences in the average values of the insertion/removal force due to angulation (F (2.48) = 343619, P<.05) and the type of attachment (F (7.48) = 23.220, P<.05). CONCLUSION: Greater angulation of the abutments was found to influence the retention capacity of the attachments, and the fatigue test simulating 5 years of denture insertion and removal did not produce wear in the metal abutments. PMID- 26949486 TI - Effect of the amount of thickness reduction on color and translucency of dental monolithic zirconia ceramics. AB - PURPOSE: This study investigated the effect of amount of thickness reduction on color and translucency of dental monolithic zirconia ceramics. MATERIALS AND METHODS: One-hundred sixty-five monolithic zirconia specimens (16.3 mm * 16.3 mm * 2.0 mm) were divided into 5 groups (Group I to V) according to the number of A2 coloring liquid applications. Each group was then divided into 11 subgroups by reducing the thickness up to 1.0 mm in 0.1-mm increments (Subgroup 0 to 10, n=3). Colors and spectral distributions were measured according to CIELAB on a reflection spectrophotometer. All measurements were performed on five different areas of each specimen. Color difference (DeltaE(*) ab) and translucency parameter (TP) were calculated. Data were analyzed using one-way ANOVA and multiple comparison Scheffe test (alpha=.05). RESULTS: There were significant differences in CIE L(*) between Subgroup 0 and other subgroups in all groups. CIE a(*) increased (0.523.7) were obtained between Subgroup 0 and other subgroups. TP values generally increased as the thickness reduction increased in all groups (R(2)>0.89, P<.001). CONCLUSION: Increasing thickness reduction reduces lightness and increases a reddish, bluish appearance, and translucency of monolithic zirconia ceramics. PMID- 26949485 TI - Influence of the preparation design and artificial aging on the fracture resistance of monolithic zirconia crowns. AB - PURPOSE: The aim of this study was to evaluate the fracture resistance and fracture behavior of monolithic zirconia crowns in accordance with the preparation design and aging simulation method. MATERIALS AND METHODS: An upper first molar was prepared sequentially with three different preparation designs: shoulderless preparation, 0.4 mm chamfer and 0.8 mm chamfer preparation. For each preparation design, 30 monolithic zirconia crowns were fabricated. After cementation on Cr-Co alloy dies, the following artificial aging procedures were performed: (1) thermal cycling and mechanical loading (TCML): 5000 cycles of thermal cycling 5C-55C and chewing simulation (1,200,000 cycles, 50 N); (2) Low Temperature Degradation simulation (LTD): autoclave treatment at 137C, 2 bar for 3 hours and chewing simulation; and (3) no pre-treatment (control group). After artificial aging, the crowns were loaded until fracture. RESULTS: The mean values of fracture resistance varied between 3414 N (LTD; 0.8 mm chamfer preparation) and 5712 N (control group; shoulderless preparation). Two-way ANOVA analysis showed a significantly higher fracture loads for the shoulderless preparation, whereas no difference was found between the chamfer preparations. In contrast to TCML, after LTD simulation the fracture strength of monolithic zirconia crowns decreased significantly. CONCLUSION: The monolithic crowns tested in this study showed generally high fracture load values. Preparation design and LTD simulation had a significant influence on the fracture strength of monolithic zirconia crowns. PMID- 26949488 TI - The analysis of cost-effectiveness of implant and conventional fixed dental prosthesis. AB - PURPOSE: This study conducted an analysis of cost-effectiveness of the implant and conventional fixed dental prosthesis (CFDP) from a single treatment perspective. MATERIALS AND METHODS: The Markov model for cost-effectiveness analysis of the implant and CFDP was carried out over maximum 50 years. The probabilistic sensitivity analysis was performed by the 10,000 Monte-Carlo simulations, and cost-effectiveness acceptability curves (CEAC) were also presented. The results from meta-analysis studies were used to determine the survival rates and complication rates of the implant and CFDP. Data regarding the cost of each treatment method were collected from University Dental Hospital and Statistics Korea for 2013. Using the results of the patient satisfaction survey study, quality-adjusted prosthesis year (QAPY) of the implant and CFDP strategy was evaluated with annual discount rate. RESULTS: When only the direct cost was considered, implants were more cost-effective when the willingness to pay (WTP) was more than 10,000 won at 10(th) year after the treatment, and more cost effective regardless of the WTP from 20(th) year after the prosthodontic treatment. When the indirect cost was added to the direct cost, implants were more cost-effective only when the WTP was more than 75,000 won at the 10(th) year after the prosthodontic treatment, more than 35,000 won at the 20(th) year after prosthodontic treatment. CONCLUSION: The CFDP was more cost-effective unless the WTP was more than 75,000 won at the 10(th) year after prosthodontic treatment. But the cost-effectivenss tendency changed from CFDP to implant as time passed. PMID- 26949487 TI - Wear of primary teeth caused by opposed all-ceramic or stainless steel crowns. AB - PURPOSE: This study was conducted to evaluate the effects of full-coverage all ceramic zirconia, lithium disilicate glass-ceramic, leucite glass-ceramic, or stainless steel crowns on antagonistic primary tooth wear. MATERIALS AND METHODS: There were four study groups: the stainless steel (Steel) group, the leucite glass-ceramic (Leucite) group, the lithium disilicate glass-ceramic (Lithium) group, and the monolithic zirconia (Zirconia) group. Ten flat crown specimens were prepared per group; opposing teeth were prepared using primary canines. A wear test was conducted over 100,000 chewing cycles using a dual-axis chewing simulator and a 50 N masticating force, and wear losses of antagonistic teeth and restorative materials were calculated using a three-dimensional profiling system and an electronic scale, respectively. Statistical significance was determined using One-way ANOVA and Tukey's test (P<.05). RESULTS: The Leucite group (2.670+/ 1.471 mm(3)) showed the greatest amount of antagonist tooth wear, followed by in decreasing order by the Lithium (2.042+/-0.696 mm(3)), Zirconia (1.426+/-0.477 mm(3)), and Steel groups (0.397+/-0.192 mm(3)). Mean volume losses in the Leucite and Lithium groups were significantly greater than in the Steel group (P<.05). No significant difference was observed between mean volume losses in the Zirconia and Steel groups (P>.05). CONCLUSION: Leucite glass-ceramic and lithium disilicate glass-ceramic cause more primary tooth wear than stainless steel or zirconia. PMID- 26949489 TI - Effect of abutment screw length and cyclic loading on removal torque in external and internal hex implants. AB - PURPOSE: The purpose of this study was to evaluate the effects of abutment screw length and cyclic loading on the removal torque (RTV) in external hex (EH) and internal hex (IH) implants. MATERIALS AND METHODS: Forty screw-retained single crowns were connected to external and internal hex implants. The prepared titanium abutment screws were classified into 8 groups based on the number of threads (n = 5 per group): EH 12.5, 6.5, 3.5, 2.5 and IH 6.5, 5, 3.5, 2.5 threads. The abutment screws were tightened with 20 Ncm torque twice with 10 minute intervals. After 5 minutes, the initial RTVs of the abutment screws were measured with a digital torque gauge (MGT12). A customized jig was constructed to apply a load along the implant long axis at the central fossa of the maxillary first molar. The post-loading RTVs were measured after 16,000 cycles of mechanical loading with 50 N at a 1-Hz frequency. Statistical analysis included one-way analysis of variance and paired t-tests. RESULTS: The post-loading RTVs were significantly lower than the initial RTVs in the EH 2.5 thread and IH 2.5 thread groups (P<.05). The initial RTVs exhibited no significant differences among the 8 groups, whereas the post-loading RTVs of the EH 6.5 and EH 3.5 thread groups were higher than those of the IH 3.5 thread group (P<.05). CONCLUSION: Within the limitations of this study, the external hex implants with short screw lengths were more advantageous than internal hex implants with short screw lengths in torque maintenance after cyclic loading. PMID- 26949490 TI - Combined application of roll flap and combination onlay-interpositional graft to enhance esthetics of maxillary anterior fixed partial denture: A case report. AB - In the maxillary anterior region, reconstruction of the localized alveolar ridge defect is very important in enhancing the esthetics of fixed partial denture. A 40-year-old female patient presented with a chief complaint of the inconvenience and unesthetic problem of 3-unit maxillary anterior prosthesis due to alveolar ridge resorption. After removal of old prosthesis, intraoral examination revealed moderate (buccolingually 4 mm) ridge deficiency in missing tooth region, leading to the diagnosis of Class I alveolar ridge defect. One of the reconstruction techniques to overcome this problem might be a technique that combines two types of soft tissue augmentation techniques. The purpose of this paper was to demonstrate the new combined technique of roll flap and combination onlay interpositional graft utilized to acquire sufficient dimension of recipient area by one time of operation and to present the esthetic improvement of fixed partial denture by using this procedure in case of maxillary anterior localized ridge defect. PMID- 26949491 TI - Review of the traditional uses, phytochemistry, pharmacology and toxicology of giant fennel (Ferula communis L. subsp. communis). AB - Ferula communis L., subsp. communis, namely giant fennel, has extensively been used in traditional medicine for a wide range of ailments. Fresh plant materials, crude extracts and isolated components of F. communis showed a wide spectrum of in vitro and in vivo pharmacological properties including antidiabetic, antimicrobial, antiproliferative, and cytotoxic activities. The present paper, reviews the traditional uses, botany, phytochemistry, pharmacology and toxicology of F. communis in order to reveal its therapeutic potential and future research opportunities. A bibliographic literature search was conducted in different scientific databases and search engines including Scopus, Cochrane Library, Embase, Google Scholar, Pubmed, SciFinder, and Web of science. Phytochemical studies have led to the isolation of different compounds such as sesquiterpenes from F. communis. This plant has two different chemotypes, the poisonous and non poisonous chemotypes. Each chemotype is endowed with various constituents and different activities. The poisonous chemotype exhibits anticoagulant and cytotoxic activities with sesquiterpene coumarins as major constituents, while the non-poisonous one exhibits estrogenic and cytotoxic effects with daucane sesquiterpene esters as the main compounds. In addition, although various pharmacological properties have been reported for F. communis, anti-microbial activities of the plant have been investigated in most studies. Studies revealed that F. communis exhibits different biological activities, and contains various bioactive compounds. Although, antibacterial and cytotoxic activities are the two main pharmacological effects of this plant, further studies should focus on the mechanisms underlying these actions, as well as on those biological activities that have been reported traditionally. PMID- 26949492 TI - Resveratrol protects against diet-induced atherosclerosis by reducing low-density lipoprotein cholesterol and inhibiting inflammation in apolipoprotein E-deficient mice. AB - OBJECTIVES: Resveratrol (RES) is a polyphenol compound that has been shown a promising cardioprotective effect. However, some reports have yielded conflicting findings. Herein, we investigated the anti-atherosclerotic effects of RES in apolipoprotein E (apo E)-deficient mice on a high cholesterol diet. MATERIALS AND METHODS: Firstly, atherosclerosis was induced by feeding a high cholesterol diet to apo E-deficient mice. Then, we examined its effects on weight control, and serum interleukin-6 (IL-6) levels and used histopathological methods to analyze morphology and inflammatory marker of atherosclerotic lesions in mice orally supplemented with high (25 mg/kg/day) and low (5 mg/kg/day) doses of RES for 8 weeks. RESULTS: Mice with high dose of RES had reduced epididymal fat pads, and lower serum IL-6 levels compared with those of control mice. Moreover, RES in high doses also decreased the low-density lipoprotein cholesterol (LDL-C) levels and atherogenic index (LDL-C/HDL-C) in the mice. Dissection of high-dose RES treated mice revealed a marked reduction in fat deposition, percentage of mice with atherosclerotic lesion, and intima/media ratio in the aortic areas. The expressions of macrophage-specific marker F4/80 and cardiovascular inflammatory marker NF-kappaB in atherosclerotic vessels were both diminished in the atherosclerotic vessels of high-dose RES-supplementated apo E-deficient mice. CONCLUSION: These results suggest that RES prevented the effects of a high cholesterol diet on the rate of accretion in atherosclerosis progression by reducing the LDL-C levels and suppressing atherosclerotic inflammation. RES can therefore be valuable in the development of new anti-atherosclerotic agents. PMID- 26949493 TI - Effect of exogenous leptin on serum levels of lipids, glucose, renal and hepatic variables in both genders of obese and streptozotocin-induced diabetic rats. AB - OBJECTIVES: Leptin exerts various effects on appetite and body weight. Disruption of the obesity gene is precedent to fatness. Insulin or glucose elevates leptin, but streptozotocin reduces it. However, controversial data exist for the effects of leptin on diabetes and leptin level in each gender. Leptin can damage the kidney function but little evidence exists for its hepatic effects. The aim of this study was to investigate the probable sex-dependent differences in blood sugar levels, lipid profile, and renal and hepatic biochemical factors in the obesity and streptozotocin-induced diabetic rats after leptin administration. MATERIALS AND METHODS: Wistar rats of both sexes were randomly divided into two groups, namely obese and diabetic rats. Each group was further divided into male and female subgroups. Extra fat and carbohydrate was added to the diet to induce obesity. Furthermore, streptozotocin (55 mg/kg, IP) was injected to induce diabetes. The treatment groups received leptin (0.1 mg/kg SC) for 10 days, and then, blood samples were taken from the orbital sinus for laboratory evaluations. RESULTS: Leptin resulted in a significant weight loss in both sexes (P<0.001), food intake reduction in male rats (P<0.05), LDL reduction in female rats (obese (P<0.05) and diabetic (P<0.001)), and glucose level decline in the female diabetic rats (P<0.001). However, total protein concentration, LFT (liver function tests), urea and creatinin concentrations among different groups did not show any significant changes. CONCLUSION: Leptin caused some discrepant results, especially regarding the LDL and glucose levels in diabetic female rats. PMID- 26949494 TI - Interaction of cholesterol ester transfer protein polymorphisms, body mass index, and birth weight with the risk of dyslipidemia in children and adolescents: the CASPIAN-III study. AB - OBJECTIVES: This study aims to investigate joint association between cholesterol ester transfer protein (CETP) polymorphisms and body mass index (BMI) or birth weight with the risk of dyslipidemia in Iranian children and adolescents. MATERIALS AND METHODS: This study was conducted as a sub-study of the "school based nationwide health survey" (CASPIAN-III). We randomly selected 750 samples from the whole blood samples. Real-time PCR and high resolution melt (HRM) analysis were performed to determine Taq1B (rs708272) and A373P (rs5880) polymorphisms. RESULTS: Taq1B polymorphism increased HDL-C, and total cholesterol (TC) as well as decreased triglyceride and LDL-C concentrations. LDL-C and triglyceride levels were significantly higher and HDL-C and TC levels were significantly lower among those with A373P polymorphism. CT/TT genotype in Taq1B polymorphism showed a protective effect on dyslipidemia (OR= 0.12, 95% CI: 0.07 0.20). G allele of A373P polymorphism increased the risk of dyslipidemia (OR=4.10, 95% CI: 2.14, 7.83) after adjusting the confounders. We observed interactive effects of CETP gene polymorphisms and BMI or birth weight on dyslipidemia. CONCLUSION: Findings showed Taq1B polymorphism might have a protective effect and A373P polymorphism had deleterious effect on dyslipidemia in Iranian children and adolescents. These associations interacted with BMI and birth weight. PMID- 26949495 TI - Effects of prenatal exposure to different colors on offsprings mood. AB - OBJECTIVES: There is much evidence indicating that depression is influenced by the levels of neurotransmitters such as dopamine, GABA and adrenaline. The current study we designed to investigate the effect of exposure of pregnant rats to different colors on neurotransmitters level, as indicators of mood disorders in off springs. MATERIALS AND METHODS: Five groups of pregnant female Wistar rats (eight rats in each group) were enrolled in this study. Dopamine, adrenaline and GABA concentration in sera of rats were measured using ELISA. RESULTS: The colors black and red elevated the GABA levels in serum and CSF while the colors green and blue decreased the GABA levels. The colors black and red also decreased the sera and CSF levels of dopamine compared to the control group. The concentration of adrenaline was increased following exposure to the colors black, red and blue but decreased only following color green exposure. These results showed serious changes in neurotransmitter levels due to exposure to different colors which can be translated as mood and behavior changes. CONCLUSION: It can be concluded that exposure during pregnancy can lead to postpartum behavioral changes even at adulthood and such changes can be made by colors. PMID- 26949497 TI - Improving the neuronal differentiation efficiency of umbilical cord blood-derived mesenchymal stem cells cultivated under appropriate conditions. AB - OBJECTIVES: Umbilical cord blood-derived mesenchymal stromal cells (UCB-MSCs) are ideally suited for use in various cell-based therapies. We investigated a novel induction protocol (NIP) to improve the neuronal differentiation of human UCB MSCs under appropriate conditions. MATERIALS AND METHODS: This experimental study was performed in Iranian Blood Transfusion Organization (IBTO), Tehran, Iran. UCB MSCs were cultured in DMEM medium supplemented with 10% FBS in a humidified incubator in equilibration with 5% CO2 at 37 degrees C. For neuronal differentiation of UCB-MSCs, DMEM was removed and replaced with pre-induction medium containing RA, bFGF, EGF, and basal medium for two days. Then, NGF, IBMX, AsA, and Neurobasal medium were used for six days for this purpose. Real-time PCR was performed to analyze the neuronal differentiation of UCB-MSCs for the first time in Iran. RESULTS: We found that the maximum and minimum levels of gene expression were related to GFAP and nestin, respectively. In addition, our study showed that compared to other neuronal inducers, RA might play the main role in neuronal differentiation and fate of MSCs compared to other neuronal inducers. CONCLUSION: Our data showed that the combination of chemical (RA, IBMX, AsA) and growth factors (NGF, EGF, bFGF) in NIP may improve the efficiency of neuronal differentiation of UCB-MSCs and may provide a new method for easy and quick application of UCB-MSCs in regenerative medicine in the future. However, the functionality of neuron-like cells must be carefully assessed in animal experiments prior to use in clinical applications. PMID- 26949496 TI - Is adalimumab protective in ischemia-reperfusion injury in lung? AB - OBJECTIVES: Increasing cytokines and reactive oxygen species (ROS) during ischemia reperfusion (I-R) leads to the lung damage. Adalimumab (Ada) is a potent tumor necrosis factor-alpha (TNF-alpha) inhibitor agent. We aimed to evaluate whether Ada would prevent the lung tissue from damage development over the I-R process. MATERIALS AND METHODS: Twenty seven Wistar albino male rats were divided into three groups (each group had 9 rats). To the control group, only laparotomy procedure was carried out. For I-R group, first infrarenal abdominal aorta was cross-clamped during 2 hr, and then reperfusion was performed for 2 hr. To I R+Ada group, first a single dose of 50 mg/kg Ada was given intraperitoneally and 5 days later, same I-R procedure was carried out. RESULTS: Levels of TNF-alpha, malondialdehyde (MDA), myeloperoxidase (MPO), endothelin-1 (ET-1) and caspase-3 enzyme activity of I-R group were higher than that of both I-R+ Ada [TNF-alpha (P=0.021), MDA (P=0.029), MPO (P=0.012), ET-1 (P=0.036, caspase-3 (P=0.007), respectively] and control group [TNF-alpha (P=0.008), MDA (P<0.001), MPO (P=0.001), ET-1 (P<0.001), caspase-3 (P<0.001), respectively]. In I-R group, severe damage was detected by hematoxylin-eosin staining. This damage was found less severe in Ada treatment group. CONCLUSION: The release of cytokines and ET-1 in a large proportion after I-R injury, and generating of ROS in excessive quantity could cause severe damage in the lung tissue. Ada could be considered as a protective agent for lung tissue during I-R process. PMID- 26949498 TI - Influence of vitamin D on cell cycle, apoptosis, and some apoptosis related molecules in systemic lupus erythematosus. AB - OBJECTIVES: Genetic and environmental factors are involved in the pathogenesis of systemic lupus erythematosus (SLE). Autoreactive lymphocytes are cleared through apoptosis and any disturbance in the apoptosis or clearance of apoptotic cells may disturb tolerance and lead to autoimmunity. Vitamin D has anti-proliferative effects and controls cell cycle progression. In this study we investigated the effects of vitamin D on cell cycle and apoptosis induction in lupus patients. MATERIALS AND METHODS: Isolated peripheral blood mononuclear cells (PBMCs) from 25 SLE patients were cultured in the presence of 50 nM of 1,25(OH)2D3; then one part of the cells were stained with FITC labeled Annexin V and PI and were analyzed for apoptosis determination. For gene expression assessment of FasL, Bcl 2 and Bax, RNA was extracted from one another part of the cells, cDNA was synthesized and gene expression analysis was performed using Real time PCR. An additional part of the cells were treated with PI and the cell cycle was analyzed using flowcytometer. RESULTS: The mean number of early apoptotic cells in vitamin D treated cells decreased significantly (18.48+/-7.9%) compared to untreated cells (22.02+/-9.4%) (P=0.008). Cell cycle analysis showed a significant increase in G1 phase in vitamin D treated cells (67.33+/-5.2%) compared to non treated ones (60.77+/-5.7%) (P =0.02). Vitamin D up-regulated the expression levels of Bcl-2 by (18.87 fold increase), and down-regulated expression of Bax (23%) and FasL (25%). CONCLUSION: Vitamin D has regulatory effects on cell cycle progression, apoptosis and apoptosis related molecules in lupus patients. PMID- 26949499 TI - Interactions of smoking with rs833061 polymorphism on the risk of non-alcoholic fat liver disease in Hubei Han population: a preliminary case-control study. AB - OBJECTIVES: Vascular endothelial growth factor (VEGF) has biological actions on energy homeostasis, inflammation and insulin resistance. The present study aimed to investigate the association between VEGF -460 T/C (rs833061), and +936 C/T (rs3025039) polymorphism and risk of non-alcohol fatty liver disease (NAFLD) in Hubei Han population and to further explore the interactions of smoking with rs833061 and rs3025039. MATERIALS AND METHODS: 341 healthy controls and 246 cases were recruited. Two variants, rs833061 and rs3025039, were genotyped by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP). The unconditional logistic regression (ULR) was performed to assess the association of the two variants with risk of NAFLD. Gene-environment interactions on the risk of NAFLD were preliminarily explored by generalized multifactor dimensionality reduction (GMDR) and further confirmed by ULR methods. RESULTS: After adjusting for covariates, increased risk of NAFLD was observed in patients carrying CT/CC genotypes in rs833061 and rs3025039 (ORa=1.80, 95% confidence interval (CI): 1.51, 2.36, Pa =0.000; ORa=1.89, 95% CI: 1.41, 2.82, Pa =0.000, respectively). Interaction of smoking with rs833061 was found by GMDR, with maximum prediction accuracy (67.91%) and a maximum cross-validation consistency (10/10). ULR method confirmed that, smoking-positive patients with genotype CT/CC had 4.93 times risk of NAFLD compared to smoking-negative participants with genotype TT (ORadd (a)=4.93, 95% CI: 2.91, 8.54, P add (a)=0.000), which further confirmed synergistic effects. CONCLUSION: The results indicated that both rs833061 and rs3025039 are associated with NAFLD risk. Furthermore, rs833061 is likely to have an interaction with smoking, and they have synergistic effects on risk of NAFLD in Hubei Han population. PMID- 26949500 TI - Comparison of the effects of resveratrol and caloric restriction on learning and memory in juvenile C57BL/6J mice. AB - OBJECTIVES: Both caloric restriction (CR) and resveratrol (RSV) have been shown to improve learning and memory, but their potential effects in juvenile animals were unknown. Here, we evaluated the effects of RSV and CR on learning and memory function in juvenile mice and investigated potential molecular mechanisms. METHODS: Six-week-old C57BL/6J mice were assigned to one of three different dietary groups: normal control (stock diet) (n=12), CR diet (30% caloric reduction diet) (n=12), and RSV diet (stock diet supplemented with 18.6 mg/kg RSV) (n=12), for 6 months. Body weight and blood glucose were measured every 4 weeks. Serum cholesterol and serum triglyceride levels were examined using biochemical methods. Serum insulin and insulin-like growth factor 1 (IGF-1) levels were evaluated using enzyme linked immunosorbant assay (ELISA), and protein expression of silent mating type information regulation 2 homology 1 (SIRT1), p53, p16, peroxisome proliferator-activated receptor gamma (PPARgamma), phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), phosphorylated-cAMP response element-binding protein (p-CREB), and IGF-1 were examined with immunohistochemistry. RESULTS: Although long-term CR diet did not alter physiological conditions in juvenile mice relative to control, RSV supplementation slightly elevated blood glucose, serum triglyceride, and serum insulin levels. Both CR and RSV improved learning and memory function, although the effect of CR was significantly greater. Both CR and RSV downregulated p53 and upregulated IGF-1 in hippocampal CA1 region of mice. CONCLUSION: We demonstrate that CR and RSV may improve learning and memory by downregulating p53 and upregulating IGF-1 in hippocampal CA1 region of juvenile mice. PMID- 26949501 TI - Establishment of a novel rat model of severe acute cholangitis. AB - OBJECTIVES: This study aimed to establish a novel non-binding, reversible rat model of acute cholangitis of the severe type (ACST). MATERIALS AND METHODS: Twenty-six rats were randomly divided into the sham-operated group (n=13) and the ACST group (n=13). All rats were intubated with a modified catheter through the external jugular vein. The ACST model was established by ligation of the distal bile duct, placing one end of a modified catheter in the common bile duct, and then injecting lipopolysaccharides from the other end of the catheter and sealing it. The common bile duct pressure was measured before and at 0, 24, 48, and 72 hr after the model was established; similarly, the levels of serum total bilirubin (TBIL), alanine aminotransferase (ALT), and tumor necrosis factor (TNF)-alpha were measured at 0, 12, 24, and 48 hr after the model was established. RESULTS: Pathological examination of liver tissues was carried out at 24 and 72 hr. The common bile duct pressure increased gradually after the operation. Serum levels of TBIL, ALT, and TNF-alpha in the ACST group progressively increased and were significantly higher than those in the sham-operated group, at each time point (P<0.05). CONCLUSION: Obvious pathological changes were observed in the liver tissue of rats in the ACST group. This model appears to reflect the early course of human ACST and thus, can be used in postoperative experimental studies of ACST. PMID- 26949503 TI - The role of noggin in regulation of high glucose-induced apoptosis and insulin secretion in INS-1 rat beta cells. AB - OBJECTIVES: The purpose of this study was to investigate the effects of Noggin on high glucose-induced apoptosis and insulin secretion in pancreatic beta cells. MATERIALS AND METHODS: Different concentrations of glucose were used to examine their effects on INS-1 rat beta cells in vitro. When specific siRNA targeting Noggin and recombinant Noggin were added, apoptosis and insulin secretion were measured, respectively to determine their effects in INS-1 cells. RESULTS: Glucose stimulated the expression of Noggin in a dose-dependent manner. Knockdown of Noggin further increased apoptosis and reduced insulin secretion when INS-1 cells were exposed to high glucose. Conversely, administration of recombinant Noggin significantly reduced apoptotic cell number, and promoted insulin secretion. Finally, treatment with inhibitor of Smad phosphorylation exerted similar effects on cell apoptosis and insulin production to Noggin administration in glucose-treated INS-1 cells. CONCLUSION: Our findings indicate that Noggin inhibits apoptosis and promotes insulin secretion in pancreatic beta cells through the inhibition of Smad signaling. Gene therapy of delivering Noggin may facilitate the treatment for patients with type 2 diabetes mellitus. PMID- 26949502 TI - Rs401681 polymorphism in TERT-CLPTM1L was associated with bladder cancer risk: A meta-analysis. AB - OBJECTIVES: Genome-wide association studies have identified a number of genetic variants of telomerase reverse transcriptase (TERT), cleft lip and palate transmembrane1-like (CLPTM1L) associated with the risk of bladder cancer. Rs401681 polymorphism in TERT-CLPTM1L was of special interest for bladder cancer risk, whereas the results were inconclusive. MATERIALS AND METHODS: Publications illustrating the association between rs401681 polymorphism and bladder cancer risk were collected from the Embase, PubMed and Google scholar. Three independent reviewers worked on the data extraction. The meta-analysis was performed by STATA 12.0. The odds ratio (OR) with 95% confidence interval (CI) was calculated for these data. RESULTS: Six case-control studies were retrieved reporting a total of 9196 bladder cancer patients and 42570 controls. The strength of the relevance between rs401681 polymorphism and bladder cancer risk was evaluated by Stata 12.0 software. Rs401681[C] allele was identified marginally associated with increased bladder cancer risk, with per allele OR of 1.132 (95% CI=1.080-1.187, P heterogeneity=0.701); in the stratified analysis by ethnicity, the increased cancer risk was revealed in Asian and Caucasian groups. Moreover, we also revealed that rs401681 polymorphism was associated with an increased risk of bladder cancer in Asian population with three publications under allele model (OR=3.722, 95% CI=1.311-10.568, P=0.014), whereas a decreased risk was identified in homozygote model (OR=0.692, 95 % CI=0.513-0.934, P= 0.016) and recessive model (OR=0.728, 95% CI=0.541-0.980, P=0.036). CONCLUSION: In summary, our study provided evidence that rs401681 polymorphism is associated with the risk of bladder cancer. PMID- 26949504 TI - Dietary saffron reduced the blood pressure and prevented remodeling of the aorta in L-NAME-induced hypertensive rats. AB - OBJECTIVES: The aim of this study was to investigate the effects of nutritional saffron (Crocus sativus L.) stigma hydroalcoholic extract on blood pressure (BP) and histology of the aorta in normotensive and hypertensive rats. MATERIALS AND METHODS: Saffron (200 mg/kg/day) was given orally for 5 weeks to normotensive and hypertensive rats. Hypertension was induced by NG-nitro-L-arginine methyl ester (L-NAME; 40 mg/kg/day) administration in drinking water, and BP was measured weekly. Histological examination of the thoracic aorta included staining with hematoxylin and eosin, orcein, and periodic acid Schiff methods. RESULTS: Saffron had no effect on normotensive rats, but on hypertensive rats, prevented BP elevation form the third week of treatment (P<0.001). Furthermore, saffron reduced the cross-section area, media thickness, and elastic lamellae number of the aorta (P<0.05). CONCLUSION: Nutritional saffron prevented BP increases and remodeling of the aorta in hypertensive rats. It may be useful for preventing hypertension. PMID- 26949505 TI - Lavandula angustifolia extract improves deteriorated synaptic plasticity in an animal model of Alzheimer's disease. AB - OBJECTIVES: Neurodegenerative Alzheimer's disease (AD) is associated with profound deficits in synaptic transmission and synaptic plasticity. Long-term potentiation (LTP), an experimental form of synaptic plasticity, is intensively examined in hippocampus. In this study we evaluated the effect of aqueous extract of lavender (Lavandula angustifolia) on induction of LTP in the CA1 area of hippocampus. In response to stimulation of the Schaffer collaterals the baseline or tetanized field extracellular postsynaptic potentials (fEPSPs) were recorded in the CA1 area. MATERIALS AND METHODS: The electrophysiological recordings were carried out in four groups of rats; two control groups including the vehicle (CON) and lavender (CE) treated rats and two Alzheimeric groups including the vehicle (ALZ) and lavender (AE) treated animals. RESULTS: The extract inefficiently affected the baseline responses in the four testing groups. While the fEPSPs displayed a considerable LTP in the CON animals, no potentiation was evident in the tetanized responses in the ALZ rats. The herbal medicine effectively restored LTP in the AE group and further potentiated fEPSPs in the CE group. CONCLUSION: The positive effect of the lavender extract on the plasticity of synaptic transmission supports its previously reported behavioral effects on improvement of impaired spatial memory in the Alzheimeric animals. PMID- 26949506 TI - Errors in statistical analysis and questionable randomization lead to unreliable conclusions. PMID- 26949507 TI - The discovery of a novel antibiotic for the treatment of Clostridium difficile infections: a story of an effective academic-industrial partnership. AB - Academic drug discovery is playing an increasingly important role in the identification of new therapies for a wide range of diseases. There is no one model that guarantees success. We describe here a drug discovery story where chance, the ability to capitalise on chance, and the assembling of a range of expertise, have all played important roles in the discovery and subsequent development of an antibiotic chemotype based on the bis-benzimidazole scaffold, with potency against a number of current therapeutically challenging diseases. One compound in this class, SMT19969, has recently entered Phase 2 human clinical trials for the treatment of Clostridium difficile infections. PMID- 26949508 TI - Using Semantic Web technologies for the generation of domain-specific templates to support clinical study metadata standards. AB - BACKGROUND: The Biomedical Research Integrated Domain Group (BRIDG) model is a formal domain analysis model for protocol-driven biomedical research, and serves as a semantic foundation for application and message development in the standards developing organizations (SDOs). The increasing sophistication and complexity of the BRIDG model requires new approaches to the management and utilization of the underlying semantics to harmonize domain-specific standards. The objective of this study is to develop and evaluate a Semantic Web-based approach that integrates the BRIDG model with ISO 21090 data types to generate domain-specific templates to support clinical study metadata standards development. METHODS: We developed a template generation and visualization system based on an open source Resource Description Framework (RDF) store backend, a SmartGWT-based web user interface, and a "mind map" based tool for the visualization of generated domain specific templates. We also developed a RESTful Web Service informed by the Clinical Information Modeling Initiative (CIMI) reference model for access to the generated domain-specific templates. RESULTS: A preliminary usability study is performed and all reviewers (n = 3) had very positive responses for the evaluation questions in terms of the usability and the capability of meeting the system requirements (with the average score of 4.6). CONCLUSIONS: Semantic Web technologies provide a scalable infrastructure and have great potential to enable computable semantic interoperability of models in the intersection of health care and clinical research. PMID- 26949509 TI - Modelling heterogeneity among fitness functions using random regression. PMID- 26949510 TI - Sex-specific IL-6-associated signaling activation in ozone-induced lung inflammation. AB - BACKGROUND: Acute ozone (O3) exposure has known deleterious effects on the respiratory system and has been linked with respiratory disease and infection. Inflammatory lung disease induced by air pollution has demonstrated greater severity and poorer prognosis in women vs. men. Both severe damage to the bronchial-alveolar epithelium and malfunctioning of bronchial-blood barrier have been largely attributed to the pathobiology of O3-induced inflammatory response, but the associated mechanisms in the male and female lung remain unknown. METHODS: Here, we investigated sex-based differential regulation of lung interleukin-6 (IL-6) and its downstream signaling pathways JAK2/STAT3 and AKT1/NF kappaB in response to O3 exposure in a mouse model. We exposed male and female mice (in different stages of the estrous cycle) to 2 ppm of O3 or filtered air (FA) for 3 h, and we harvested lung tissue for protein expression analysis by Western blot. RESULTS: We found significant up-regulation of IL-6 and IL-6R in females and IL-6 in males in response to O3 vs. FA. Ozone exposure induced a significant increase in STAT3-Y705 phosphorylation in both females and males. Males exposed to O3 had decreased levels of JAK2, but increased JAK2 (Y1007+Y1008) phosphorylation, while females exposed to O3 showed significant up regulation of both proteins. Both NF-kappaB (p105/p50) and AKT1 protein levels were significantly increased only in females exposed to O3. In addition, females exposed to O3 during proestrus displayed increased expression of selected genes when compared to females exposed to O3 in other estrous cycle stages. CONCLUSIONS: Together, our observations indicate a sex-based and estrous cycle dependent differential lung inflammatory response to O3 and involvement of two converging JAK2/STAT3 and AKT1/NF-kappaB pathways. To our knowledge, this is the first study specifically addressing the impact of the estrous cycle in O3 associated lung inflammatory pathways. PMID- 26949511 TI - Prolyl hydroxylase domain 2 deficiency promotes skeletal muscle fiber-type transition via a calcineurin/NFATc1-dependent pathway. AB - BACKGROUND: Hypoxia exposure is known to induce an alteration in skeletal muscle fiber-type distribution mediated by hypoxia-inducible factor (HIF)-alpha. The downstream pathway of HIF-alpha leading to fiber-type shift, however, has not been elucidated. The calcineurin pathway is one of the pathways responsible for slow muscle fiber transition. Because calcineurin pathway is activated by vascular endothelial growth factor (VEGF), one of the factors induced by HIF 1alpha, we hypothesized that the stabilization of HIF-1alpha may lead to slow muscle fiber transition via the activation of calcineurin pathway in skeletal muscles. To induce HIF-1alpha stabilization, we used a loss of function strategy to abrogate Prolyl hydroxylase domain protein (PHD) 2 responsible for HIF-1alpha hydroxylation making HIF-1alpha susceptible to ubiquitin dependent degradation by proteasome. The purpose of this study was therefore to examine the effect of HIF 1alpha stabilization in PHD2 conditional knockout mouse on skeletal muscle fiber type transition and to elucidate the involvement of calcineurin pathway on muscle fiber-type transition. RESULTS: PHD2 deficiency resulted in an increased capillary density in skeletal muscles due to the induction of vascular endothelial growth factor. It also elicited an alteration of skeletal muscle phenotype toward the type I fibers in both of the soleus (35.8 % in the control mice vs. 46.7 % in the PHD2-deficient mice, p < 0.01) and the gastrocnemius muscle (0.94 vs. 1.89 %, p < 0.01), and the increased proportion of type I fibers appeared to correspond to the area of increased capillary density. In addition, calcineurin and nuclear factor of activated T cell (NFATc1) protein levels were increased in both the gastrocnemius and soleus muscles, suggesting that the calcineurin/NFATc1 pathway was responsible for the type I fiber transition regardless of PGC-1alpha, which responded minimally to PHD2 deficiency. Indeed, we found that tacrolimus (FK-506), a calcineurin inhibitor, successfully suppressed slow fiber-type formation in PHD2-deficient mice. CONCLUSIONS: Taken together, stabilized HIF-1alpha induced by PHD2 conditional knockout resulted in the transition of muscle fibers toward a slow fiber type via a calcineurin/NFATc1 signaling pathway. PHD2 conditional knockout mice may serve as a model for chronic HIF-1alpha stabilization as in mice exposed to low oxygen concentration. PMID- 26949512 TI - Buccal injection of synthetic HPV long peptide vaccine induces local and systemic antigen-specific CD8+ T-cell immune responses and antitumor effects without adjuvant. AB - BACKGROUND: Human Papillomavirus is responsible for over 99 % of cervical cancers and is associated with cancers of the head and neck. The currently available prophylactic vaccines against HPV do not generate therapeutic effects against established HPV infections and associated lesions and disease. Thus, the need for a therapeutic vaccine capable of treating HPV-induced malignancies persists. Synthetic long peptides vaccination is a popular antigen delivery method because of its safety, stability, production feasibility, and its need to be processed by professional antigen presenting cells before it can be presented to cytotoxic CD8+ T lymphocytes. Cancers in the buccal mucosa have been shown to elicit cancer related inflammations that are capable of recruiting inflammatory and immune cells to generate antitumor effects. In the current study, we evaluated the therapeutic potential of synthetic HPV long peptide vaccination in the absence of adjuvant in the TC-1 buccal tumor model. RESULT: We show that intratumoral vaccination with E7 long peptide alone effectively controls buccal TC-1 tumors in mice. Furthermore, we observed an increase in systemic as well as local E7 specific CD8+ T cells in buccal tumor-bearing mice following the vaccination. Finally, we show that induction of immune responses against buccal tumors by intratumoral E7 long peptide vaccination is independent of CD4+ T cells, and that the phenomenon may be related to the unique environment associated with mucosal tissues. CONCLUSION: Our results suggest the possibility for clinical translation of the administration of adjuvant free therapeutic long peptide vaccine as a potentially effective and safe strategy for mucosal HPV-associated tumor treatment. PMID- 26949514 TI - Improving access to essential health care services: the case of Israel. AB - In a recent article in this journal Simon-Tuval, Horev and Kaplan argue that in order to improve the protection of consumers there might be a need to impose a threshold on the medical loss ratio (MLR) for voluntary health insurance (VHI) in Israel [1]. Their argument is that VHI in Israel covers several essential services that are not covered by the mandatory benefits package due to budget constraints, while there are market failures in the VHI market that justify regulation to assure consumer protection such as high accessibility to high quality coverage. In this commentary it will be argued that in addition to market failures there are also government failures. It is doubtful whether imposing a threshold on MLR is effective because of government failures. It can be even counter-productive. Therefore, alternative regulatory measures are discussed to promote the protection of the beneficiaries. If essential services covered by VHI are unaffordable for some low-income people, government can extend the current mandatory basic health insurance so that it covers all essential services. If there is a budget restriction, the amount of government funds could be increased, or the health plans could be allowed to request an additional flat rate premium, set by them and to be paid by the consumer directly to their health plan. Also, effective out-of-pocket payments could be introduced. Subsidies could be given to low-income people to compensate for their additional expenses under the mandatory health insurance. If these changes are adopted, then the government would no longer be held responsible for access to benefits outside the mandatory health insurance. Accordingly, all VHI could be sold on the normal free insurance market, just as other types of indemnity insurance. In addition, the Israeli health insurance and healthcare markets could be made more competitive by introducing procompetitive regulation. This would increase the efficiency and affordability of healthcare. PMID- 26949516 TI - Social Network: a Cytoscape app for visualizing co-publication networks. AB - Networks that represent connections between individuals can be valuable analytic tools. The Social Network Cytoscape app is capable of creating a visual summary of connected individuals automatically. It does this by representing relationships as networks where each node denotes an individual and an edge linking two individuals represents a connection. The app focuses on creating visual summaries of individuals connected by co-publication links in academia, created from bibliographic databases like PubMed, Scopus and InCites. The resulting co-publication networks can be visualized and analyzed to better understand collaborative research networks or to communicate the extent of collaboration and publication productivity among a group of researchers, like in a grant application or departmental review report. It can also be useful as a research tool to identify important research topics, researchers and papers in a subject area. PMID- 26949513 TI - Low expression of Aldo-keto reductase 1B10 is a novel independent prognostic indicator for nasopharyngeal carcinoma. AB - BACKGROUND: Nasopharyngeal carcinoma (NPC) is one of the most common human head and neck cancers with high incidence in Southern China, Southeast Asia and North Africa. Because of its nonspecific symptoms, the early diagnosis of NPC is very difficult. The 5-year survival rate is not ideal in spite of great innovations in radiation and chemotherapy treatments. Highly sensitive and specific prognostic biomarkers are eager for NPC clinical diagnosis. To find specific target molecules is very important for individualized treatment. Aldo-keto reductase B10 (AKR1B10) is closely related to tumorigenesis and tumor development, and however, its expression level in NPC tissues is not clear. RESULTS: AKR1B10 expression levels were validated in benign, para-cancerous nasopharyngeal and NPC tissues by immunohistochemical evaluation. AKR1B10 was positively expressed in 42 (82.4 %) of 51 benign specimens, and 235 (98.7 %) of 238 para-carcinoma specimens. This percentage was significantly higher than 44.5 % (133/299) in nasopharyngeal carcinoma tissue (p < 0.01). AKR1B10 mRNA quantitative levels detected by real time quantitative RT-PCR in 90 NPC tissue samples (0.10 +/- 0.21) were significantly lower than that in 15 benign tissue samples (1.03 +/- 1.12) (p < 0.01). AKR1B10 expression levels in NPC were correlated negatively with T classification, lymph node metastasis (p < 0.05). We established nasopharyngeal cancer monoclonal cells CNE-2/AKR1B10 with AKR1B10 stable expression and CNE 2/vector cells without AKR1B10 expression by using a modified lentivirus-mediated method, and found that AKR1B10 inhibited the proliferation of CNE-2/AKR1B10 cells by using MTT assay and flow cytometry, and cell migration by in vitro scratch test. CONCLUSION: Taken together, our data suggest that low expression of AKR1B10 is an independent prognostic indicator in nasopharyngeal carcinoma, and that AKR1B10 may be involved in regulating the proliferation and migration of nasopharyngeal cancer cells. PMID- 26949515 TI - The unfolded protein response and its potential role in Huntington 's disease elucidated by a systems biology approach. AB - Huntington 's disease (HD) is a progressive, neurodegenerative disease with a fatal outcome. Although the disease-causing gene (huntingtin) has been known for over 20 years, the exact mechanisms leading to neuronal cell death are still controversial. One potential mechanism contributing to the massive loss of neurons observed in the brain of HD patients could be the unfolded protein response (UPR) activated by accumulation of misfolded proteins in the endoplasmic reticulum (ER). As an adaptive response to counter-balance accumulation of un- or misfolded proteins, the UPR upregulates transcription of chaperones, temporarily attenuates new translation, and activates protein degradation via the proteasome. However, persistent ER stress and an activated UPR can also cause apoptotic cell death. Although different studies have indicated a role for the UPR in HD, the evidence remains inconclusive. Here, we present extensive bioinformatic analyses that revealed UPR activation in different experimental HD models based on transcriptomic data. Accordingly, we have identified 58 genes, including RAB5A, HMGB1, CTNNB1, DNM1, TUBB, TSG101, EEF2, DYNC1H1 and SLC12A5 that provide a potential link between UPR and HD. To further elucidate the potential role of UPR as a disease-relevant process, we examined its connection to apoptosis based on molecular interaction data, and identified a set of 40 genes including ADD1, HSP90B1, IKBKB, IKBKG, RPS3A and LMNB1, which seem to be at the crossroads between these two important cellular processes. PMID- 26949517 TI - Pain and sickness behavior associated with corneal lesions in dairy calves. AB - Infectious bovine keratoconjunctivitis (IBK) is a common corneal disease of calves that adversely affects animal welfare by causing pain and weight loss. Identifying behavioral indicators of pain and sickness in calves with IBK is necessary for designing studies that aim to identify effective means of pain mitigation. Consistent with principles of the 3Rs for animal use in research, data from a randomized blinded challenge study was used to identify and describe variation of behaviors that could serve as reliable indicators of pain and sickness in calves with corneal injuries. Behavioral observations were collected from 29 Holstein calves 8 to 12 weeks of age randomly allocated to one of three treatments: (1) corneal scarification only, (2) corneal scarification with inoculation with Moraxella bovoculi and (3) corneal scarification with inoculation with Moraxella bovis. Behavior was continuously observed between time 1230 - 1730 h on day -1 (baseline time period) and day 0 (scarification time period). Corneal scarification and inoculation occurred between 0800 - 1000 h on day 0. Frequency of head-directed behaviors (head shaking, head rubbing, head scratching) and durations of head rubbing, feeding, standing with head lifted, lying with head lifted and sleeping were compared between study days and groups. Following scarification, the frequency of head-directed behavior significantly increased (p = 0.0001), as did duration of head rubbing (p=0.02). There was no significant effect of trial, trial day, treatment or treatment-day interaction on other behaviors studied. Our study demonstrated that head-directed behavior, such as head shaking, rubbing and scratching, was associated with scarification of eyes using an IBK challenge model, but sickness behavior was not observed. PMID- 26949518 TI - A dynamic architecture of life. AB - In recent decades, a profound conceptual transformation has occurred comprising different areas of biological research, leading to a novel understanding of life processes as much more dynamic and changeable. Discoveries in plants and animals, as well as novel experimental approaches, have prompted the research community to reconsider established concepts and paradigms. This development was taken as an incentive to organise a workshop in May 2014 at the Academia Nazionale dei Lincei in Rome. There, experts on epigenetics, regeneration, neuroplasticity, and computational biology, using different animal and plant models, presented their insights on important aspects of a dynamic architecture of life, which comprises all organisational levels of the organism. Their work demonstrates that a dynamic nature of life persists during the entire existence of the organism and permits animals and plants not only to fine-tune their response to particular environmental demands during development, but underlies their continuous capacity to do so. Here, a synthesis of the different findings and their relevance for biological thinking is presented. PMID- 26949519 TI - Computer-aided drug discovery. AB - Computational approaches are an integral part of interdisciplinary drug discovery research. Understanding the science behind computational tools, their opportunities, and limitations is essential to make a true impact on drug discovery at different levels. If applied in a scientifically meaningful way, computational methods improve the ability to identify and evaluate potential drug molecules, but there remain weaknesses in the methods that preclude naive applications. Herein, current trends in computer-aided drug discovery are reviewed, and selected computational areas are discussed. Approaches are highlighted that aid in the identification and optimization of new drug candidates. Emphasis is put on the presentation and discussion of computational concepts and methods, rather than case studies or application examples. As such, this contribution aims to provide an overview of the current methodological spectrum of computational drug discovery for a broad audience. PMID- 26949520 TI - Advances in Understanding and Managing Chronic Urticaria. AB - There have been recent advances in the classification and management of chronic urticaria. The new term chronic spontaneous urticaria (CSU) has replaced chronic idiopathic urticaria and chronic autoimmune urticaria. In addition, chronic inducible urticaria (CINDU) has replaced physical urticaria and includes other forms of inducible urticaria, such as cholinergic and aquagenic urticaria. Furthermore, novel research has resulted in a new understanding with guidelines being revised in the past year by both the American Academy of Allergy, Asthma, and Immunology (AAAAI) and the European Academy of Allergy and Clinical Immunology (EAACI)/Global Allergy and Asthma European Network (GA (2)LEN)/European Dermatology Forum (EDF)/World Allergy Organization (WAO). There are some differences in the recommendations, which will be discussed, but the core updates are common to both groups. The basic treatment for chronic urticaria involves second-generation non-sedating non-impairing H 1 antihistamines as first line treatment. This is followed by up to a 4-fold increase in the licensed dose of these H 1 antihistamines. The major therapeutic advance in recent years has been in third-line treatment with omalizumab, a humanized monoclonal anti immunoglobulin E (anti-IgE) antibody that prevents binding of IgE to the high affinity IgE receptor. Several multicenter randomized controlled trials have shown safety and efficacy of omalizumab for CSU. There are also some small studies showing efficacy of omalizumab in CINDU. While there were previously many treatment options which were lacking in strong evidence, we are moving into an era where the treatment algorithm for chronic urticaria is simplified and contains more evidence-based, effective, and less toxic treatment options. PMID- 26949521 TI - The role of COP1 in repression of photoperiodic flowering. AB - Plants use the circadian clock as a timekeeping mechanism to regulate photoperiodic flowering in response to the seasonal changes. CONSTITUTIVELY PHOTOMORPHOGENIC 1 (COP1), initially identified as a central repressor of seedling photomorphogenesis, was recently shown to be involved in the regulation of light input to the circadian clock, modulating the circadian rhythm and flowering. COP1 encodes a RING-finger E3 ubiquitin ligase and works in concert with SUPPRESSOR of phyA-105 (SPA) proteins to repress photoperiodic flowering by regulating proteasome-mediated degradation of CONSTANS (CO), a central regulator of photoperiodic flowering. In addition, COP1 and EARLY FLOWERING 3 (ELF3) indirectly modulate CO expression via the degradation of GIGANTEA (GI). Here, we summarize the current understanding of the molecular mechanisms underlying COP1's role in controlling of photoperiodic flowering. PMID- 26949522 TI - Contemporary Management of Prostate Cancer. AB - Prostate cancer represents a spectrum ranging from low-grade, localized tumors to devastating metastatic disease. We discuss the general options for treatment and recent developments in the field. PMID- 26949523 TI - Recent advances in dermoscopy. AB - The use of dermoscopy has offered a new morphological dimension of skin lesions and has provided an effective diagnostic tool to differentiate melanoma from other benign or malignant skin tumors but also to support the clinical diagnosis in general dermatology. The aim of this article is to provide an overview of the most recent and important advances in the rising world of dermoscopy. PMID- 26949525 TI - Plant-based biofuels. AB - This review is a short synopsis of some of the latest breakthroughs in the areas of lignocellulosic conversion to fuels and utilization of oils for biodiesel. Although four lignocellulosic ethanol factories have opened in the USA and hundreds of biodiesel installations are active worldwide, technological improvements are being discovered that will rapidly evolve the biofuels industry into a new paradigm. These discoveries involve the feedstocks as well as the technologies to process them. PMID- 26949526 TI - Forest dynamics. AB - Forest dynamics encompass changes in stand structure, species composition, and species interactions with disturbance and environment over a range of spatial and temporal scales. For convenience, spatial scale is defined as individual tree, neighborhood, stand, and landscape. Whether a given canopy-leveling disturbance will initiate a sequence of development in structure with little change in composition or initiate an episode of succession depends on a match or mismatch, respectively, with traits of the dominant tree species that allow the species to survive disturbance. When these match, certain species-disturbance type combinations lock in a pattern of stand and landscape dynamics that can persist for several generations of trees; thus, dominant tree species regulate, as well as respond to, disturbance. A complex interaction among tree species, neighborhood effects, disturbance type and severity, landform, and soils determines how stands of differing composition form and the mosaic of stands that compose the landscape. Neighborhood effects (e.g., serotinous seed rain, sprouting, shading, leaf-litter chemistry, and leaf-litter physical properties) operate at small spatial extents of the individual tree and its neighbors but play a central role in forest dynamics by contributing to patch formation at stand scales and dynamics of the entire landscape. Dominance by tree species with neutral to negative neighborhood effects leads to unstable landscape dynamics in disturbance-prone regions, wherein most stands are undergoing succession; stability can only occur under very low-severity disturbance regimes. Dominance by species with positive effects leads to stable landscape dynamics wherein only a small proportion of stands undergo succession at any one time. Positive neighborhood effects are common in temperate and boreal zones, whereas negative effects are more common in tropical climates. Landscapes with positive dynamics have alternate categories of dynamics stabilized by high-severity and low severity disturbance regimes. Contrary to prevailing ecological theory, systems with positive neighborhood effects can have similar levels of compositional stability across tree, stand, and landscape scales. Neighborhood effect theory can help explain responses of landscapes to large-scale land clearing and novel effects brought on by factors such as invasive species and deer overabundance. PMID- 26949524 TI - Single-cell transcriptome sequencing: recent advances and remaining challenges. AB - Single-cell RNA-sequencing methods are now robust and economically practical and are becoming a powerful tool for high-throughput, high-resolution transcriptomic analysis of cell states and dynamics. Single-cell approaches circumvent the averaging artifacts associated with traditional bulk population data, yielding new insights into the cellular diversity underlying superficially homogeneous populations. Thus far, single-cell RNA-sequencing has already shown great effectiveness in unraveling complex cell populations, reconstructing developmental trajectories, and modeling transcriptional dynamics. Ongoing technical improvements to single-cell RNA-sequencing throughput and sensitivity, the development of more sophisticated analytical frameworks for single-cell data, and an increasing array of complementary single-cell assays all promise to expand the usefulness and potential applications of single-cell transcriptomic profiling. PMID- 26949527 TI - Recent advances in the understanding of endometriosis: the role of inflammatory mediators in disease pathogenesis and treatment. AB - In this review, we focus on recent advancements in our understanding of the roles of inflammatory mediators in endometriosis pathophysiology and the potential for improved therapies based upon targeting these pathways. We review the association between endometriosis and inflammation and the initial promise of anti-tumor necrosis factor therapies based upon experimental evidence, and how and why these studies have not translated to the clinic. We then discuss emerging data on the role of inter-relationship among macrophage migration inhibitory factor, prostaglandin E 2, and estrogen receptor-beta, and the potential utility of targeting these factors in endometriosis treatment. In doing so, we highlight the strengths and discuss the current research on identification of novel, anti inflammatory-based therapy and the necessity to expand experimental endpoints to include clinically relevant measures when assessing the efficacy of potential new therapies for endometriosis. PMID- 26949529 TI - "Pop-slide" patterning: Rapid fabrication of microstructured PDMS gasket slides for biological applications. AB - We describe a "pop-slide" patterning approach to easily produce thin film microstructures on the surface of glass with varying feature sizes (3 MUm - 250 MUm) and aspect ratios (0.066 - 3) within 45 minutes. This low cost method does not require specialized equipment while allowing us to produce micro structured gasket layers for sandwich assays and could be readily applied to many biological applications. PMID- 26949528 TI - Signaling in T cells - is anything the m(a)TOR with the picture(s)? AB - The excitement surrounding checkpoint inhibitors in the treatment of patients with cancer exemplifies a triumph of the long-term value of investing in basic science and fundamental questions of T-cell signaling. The pharmaceutical future actively embraces ways of making more patients' cancers responsive to these inhibitors. Such a process will be aided by elucidation of signaling and regulation. With thousands of articles spread across almost 30 years, this commentary can touch only on portions of the canonical picture of T-cell signaling and provide a few parables from work on mammalian (or mechanistic) target of rapamycin (mTOR) pathways as they link to early and later phases of lymphocyte activation. The piece will turn a critical eye to some issues with models about these pathways in T cells. Many of the best insights lie in the future despite all that is uncovered already, but a contention is that further therapeutic successes will be fostered by dealing with disparities among findings and attention to the temporal, spatial, and stochastic aspects of T-cell responses. Finally, thoughts on some (though not all) items urgently needed for future progress will be mooted. PMID- 26949530 TI - Jejunoileal diverticulosis, a rare cause of ileal perforation - Case report. AB - INTRODUCTION: Jejunoileal diverticulosis (JID) is a rare condition associated with nonspecific symptoms, consisting of acquired false diverticula. It frequently co-exists with colonic diverticulosis. Diagnosis is usually made incidentally or after complications. These include hemorrhage, obstruction and diverticulitis, with or without perforation. PRESENTATION OF CASE: 81-year-old man presented with a painful abdominal mass in the right lower quadrant (RLQ), diffuse abdominal discomfort and fever. Abdominal examination confirmed a well defined mass in the RLQ without rebound tenderness. Laboratory analysis revealed elevated inflammatory markers and CT scan showed a cavitated lesion with an air fluid level in the RLQ, without evidence of intraperitoneal free air or fluid. Admitted for conservative treatment, failure to improve led to laparotomy on the 6th day of hospitalization, with identification of jejunoileal diverticulosis complicated with diverticulitis and walled-off perforation. We performed segmental enterectomy. DISCUSSION: The incidence of JID is estimated at 0.2-7% and it is usually diagnosed in the sixth/seventh decade of life. From a diagnostic perspective, JID is a challenging disorder, without reliable diagnostic tests. Diverticulitis is the most common complication. Perforation generally causes only localized peritonitis, as involved diverticula are often walled off by the surrounding mesentery. In selected cases, medical therapy may suffice. For all other patients prompt laparotomy with segmental intestinal resection is the treatment of choice. CONCLUSION: JID remains under diagnosed. When it presents as an acute complication it may require immediate surgical intervention. In an elderly person, especially with known gastrointestinal diverticulosis, one must have a high index of suspicion for perforation. PMID- 26949531 TI - Egg quality, fatty acid composition and immunoglobulin Y content in eggs from laying hens fed full fat camelina or flax seed. AB - BACKGROUND: The current study was conducted to evaluate egg quality and egg yolk fatty acids and immunoglobulin (IgY) content from laying hens fed full fat camelina or flax seed. METHODS: A total of 75, 48-week-old Lohman brown hens were randomly allocated to 3 treatments, with 5 replicates containing 5 laying hens each replicate. The hens were fed corn-soybean basal diet (Control), or Control diet with 10 % of full fat camelina (Camelina) or flax seed (Flax) for a period of 16 wk. Hen production performance egg quality, egg yolk lipids, fatty acids and IgY were determined every 28 d during the experimental period. RESULTS: Egg production was higher in hens fed Camelina and Flax than in Control hens (P < 0.05). Egg weight and albumen weight was lowest in eggs from hens fed Camelina (P < 0.05). Shell weight relative to egg weight (shell weight %), and shell thickness was lowest in eggs from hens fed Flax (P < 0.05). No difference was noted in Haugh unit, yolk:albumen ratio, and yolk weight. Significant increase in alpha-linolenic (18:3 n-3), docosapentaenoic (22:5 n-3) and docoshexaenoic (22:6 n-3) acids were observed in egg yolk from hens fed Camelina and Flax. Total n-3 fatty acids constituted 1.19 % in Control eggs compared to 3.12 and 3.09 % in Camelina and Flax eggs, respectively (P < 0.05). Eggs from hens fed Camelina and Flax had the higher IgY concentration than those hens fed Control diet when expressed on a mg/g of yolk basis (P < 0.05). Although the egg weight was significantly lower in Camelina-fed hens, the total egg content of IgY was highest in eggs from hens fed Camelina (P < 0.05). CONCLUSIONS: The egg n-3 fatty acid and IgY enhancing effect of dietary camelina seed warrants further attention into the potential of using camelina as a functional feed ingredient in poultry feeding. PMID- 26949532 TI - Impact of the source and serial passaging of goat mesenchymal stem cells on osteogenic differentiation potential: implications for bone tissue engineering. AB - BACKGROUND: Adult mesenchymal stem cells (MSCs) can be conveniently sampled from bone marrow, peripheral blood, muscle, adipose and connective tissue, harvested from various species, including, rodents, dogs, cats, horses, sheep, goats and human beings. The MSCs isolated from adult tissues vary in their morphological and functional properties. These variations are further complicated when cells are expanded by passaging in culture. These differences and changes in MSCs must be considered prior to their application in the clinic or in a basic research study. Goats are commonly used as animal models for bone tissue engineering to test the potential of stem cells for bone regeneration. As a result, goat MSCs isolated from bone marrow or adipose tissue should be evaluated using in vitro assays, prior to their application in a tissue engineering project. RESULTS: In this study, we compared the stem cell properties of MSCs isolated from goat bone marrow and adipose tissue. We used quantitative and qualitative assays with a focus on osteogenesis, including, colony forming unit, rate of cell proliferation, tri-lineage differentiation and expression profiling of key signal transduction proteins to compare MSCs from low and high passages. Primary cultures generated from each source displayed the stem cell characteristics, with variations in their osteogenic potentials. Most importantly, low passaged bone marrow MSCs displayed a significantly higher and superior osteogenic potential, and hence, will be the preferred choice for bone tissue engineering in future in vivo experiments. In the bone marrow MSCs, this process is potentially mediated by the p38 MAPK pathway. On the other hand, osteogenic differentiation in the adipose tissue MSCs may involve the p44/42 MAPK pathway. CONCLUSIONS: Based on these data, we can conclude that bone marrow and fat-derived MSCs undergo osteogenesis via two distinct signaling pathways. Even though the bone marrow MSCs are the preferred source for bone tissue engineering, the adipose tissue MSCs are an attractive alternative source and undergo osteo-differentiation differently from the bone marrow MSCs and hence, might require a cell-based enhancer/inducer to improve their osteogenic regenerative capacity. PMID- 26949533 TI - Sperm cryodamage occurs after rapid freezing phase: flow cytometry approach and antioxidant enzymes activity at different stages of cryopreservation. AB - BACKGROUND: In order to improve the efficiency of bovine sperm cryopreservation process, it is important to understand how spermatozoa respond to differences in temperature as well as the ability to recover its own metabolism. The combination between flow cytometry approach and antioxidant enzymes activity allows a more sensible evaluation of sperm cell during cryopreservation. The aim of this study was to evaluate sperm attributes and antioxidant enzymes activity during different stages of cryopreservation process. Semen samples from Holstein bulls (n = 4) were separated in 3 treatments: fresh (37 degrees C); cooled (5 degrees C); and thawed. Evaluation occurred at 0 h and 2 h after incubation. Membrane integrity, mitochondrial membrane potential (MMP) and DNA damages were evaluated by flow cytometry; activities of antioxidant enzymes such as catalase, superoxide dismutase and gluthatione peroxidase were measured by spectrofotometry. RESULTS: There was an increase in the percentage of sperm with DNA damage in the thawed group, compared to fresh and cooled, and for 2 hs of incubation when compared to 0 h. Considering MMP, there was an increase in the percentage of cells with medium potential in thawed group when compared to fresh and cooled groups. Opposingly, a decrease was observed in the thawed group considering high mitochondrial potential. Also in the thawed group, there was an increase on cells with damaged acrosome and membrane when compared to fresh and cooled groups. Significant correlations were found between antioxidant enzymes activity and membrane or mitochondrial parameters. CONCLUSION: Based on our results, we conclude that cryopreservation affects cellular and DNA integrity and that the critical moment is when sperm cells are exposed to freezing temperature. Also, our study indicates that intracellular antioxidant machinery (SOD and GPX enzymes) is not enough to control cryodamage. PMID- 26949534 TI - SOX11 is a biomarker for cyclin D1-negative mantle cell lymphoma. AB - Cyclin D1 (CCND1) protein overexpression and/or the t(11;14)(q13;q32) translocation are the pathognomonic hallmarks of mantle cell lymphoma (MCL). However, there have been cases that lacked both t(11;14) and cyclin D1 protein but still had a gene expression profile suggesting a diagnosis of MCL. SOX11 expression was detected in most cyclin D1- negative MCL and can serve as a specific biomarker for the diagnosis of this subset of MCL. Lack of SOX11 expression in MCL was associated with an indolent subset and favorable prognosis. PMID- 26949536 TI - Radiation-induced breast cancer: the question of early breast cancer screening in Hodgkin's lymphoma survivors. AB - Chest irradiation is associated with numerous early and late complications that arise from ionizing radiation-induced damage to cellular structures within the field of therapy. In patients exposed to chest irradiation at an early age as part of the treatment of childhood cancer, specifically Hodgkin's lymphoma, the increased risk of breast cancer in the long run should be considered. A case of a 35-year-old woman who exposed to chest irradiation as part of the treatment of Hodgkin's lymphoma at the age of 20 years is presented here and serves as a reminder of this somewhat overlooked complication. The article presents the evidence available for and against breast cancer screening in this particular patient population. PMID- 26949537 TI - Hip fractures and dementia: clinical decisions for the future. AB - Severe dementia is a life-limiting condition; hip fractures are more common in patients who have dementia. This study outlines the case of a 92-year-old female with severe dementia who sustained a hip fracture. Despite having a terminal diagnosis (severe dementia and hip fracture) and poor premorbid quality of life, she had a life-prolonging surgery. The report outlines issues around treatment options in such circumstances, informed consent and substitute decision-making. The authors propose a 'goals of care' approach to manage patients in whom the best treatment is unclear, during their attendance to the emergency department. It is suggested that utilization of such a model may help with substitute decision-making and true informed consent. PMID- 26949535 TI - An updated review of case-control studies of lung cancer and indoor radon-Is indoor radon the risk factor for lung cancer? AB - Lung cancer is a leading cause of cancer-related death in the world. Smoking is definitely the most important risk factor for lung cancer. Radon ((222)Rn) is a natural gas produced from radium ((226)Ra) in the decay series of uranium ((238)U). Radon exposure is the second most common cause of lung cancer and the first risk factor for lung cancer in never-smokers. Case-control studies have provided epidemiological evidence of the causative relationship between indoor radon exposure and lung cancer. Twenty-four case-control study papers were found by our search strategy from the PubMed database. Among them, seven studies showed that indoor radon has a statistically significant association with lung cancer. The studies performed in radon-prone areas showed a more positive association between radon and lung cancer. Reviewed papers had inconsistent results on the dose-response relationship between indoor radon and lung cancer risk. Further refined case-control studies will be required to evaluate the relationship between radon and lung cancer. Sufficient study sample size, proper interview methods, valid and precise indoor radon measurement, wide range of indoor radon, and appropriate control of confounders such as smoking status should be considered in further case-control studies. PMID- 26949538 TI - A possible association between the resumption of agricultural activities and a venomous snakebite after Fukushima nuclear crisis. PMID- 26949540 TI - A rare case of Kearns-Sayre syndrome in a 17-year-old Venezuelan male with bilateral ptosis as the initial presentation. AB - Kearns-Sayre syndrome (KSS) was first described in 1958 as 'a rare neuromuscular disorder defined by a characteristic triad of progressive external ophthalmoplegia, pigmentary retinopathy, atrioventricular block and cerebellar ataxia'. The prevalence rate of KSS is ~1-3 per 100 000 individuals. Here, we report a rare case of a 17-year-old Venezuelan male with KSS. PMID- 26949539 TI - Alcoholic ketoacidosis: a case report and review of the literature. AB - Alcoholic ketoacidosis (AKA) is a cause of severe metabolic acidosis usually occurring in malnourished patients with a history of recent alcoholic binge, often on a background of alcohol dependency. AKA can be fatal due to associated electrolyte abnormalities and subsequent development of cardiac arrhythmias. This is a diagnosis that is often delayed or missed, in patients who present with a severe lactic and ketoacidosis. Here we report the case of a 64-year-old female who presented with generalized abdominal pain, nausea and shortness of breath. Blood gas analysis showed significant acidaemia with a pH of 7.10, bicarbonate of 2.9 mmol/l, and lactate of 11.7 mmol/l. Serum ketones were raised at 5.5 mmol/l. The diagnosis of AKA was suspected, and subsequent aggressive fluid resuscitation, management and monitoring were instituted. Given the early recognition of AKA and appropriate multidisciplinary team management, our patient had a good outcome and was discharged home without any complication. PMID- 26949541 TI - Feasibility study of short hydration using oral rehydration solution in cisplatin including chemotherapy of lung cancer. AB - BACKGROUND: Cisplatin (CDDP) is used as a key anticancer drug for solid cancers, including lung cancer. However, a large quantity of fluid replacement is required to prevent renal dysfunction. This requirement have made outpatient chemotherapies including CDDP administration less popular among the available therapeutic options. We designed a short-term hydration regimen combined with oral rehydration solution (ORS) that has a supplementary water ability equivalent to intravenous electrolyte maintenance infusion and investigated its safety and feasibility in the CDDP including chemotherapy. METHODS: The subjects received chemotherapy including CDDP administration (60-80 mg/m(2)) for untreated lung cancer were recruited. The intravenous hydration was infused at around 2000 mL on Day 1, and patients drank ORS at a dose of 1000 mL/day for 3 days. Any renal dysfunction, gastrointestinal symptoms or other tolerability variables pertaining to the remaining three cycles of this regimen were analyzed in the patients who were able to continue treatment after the second cycle. RESULTS: The majority (29/35, 82.9 %) of patients completed intake of ORS for 3 days. The mean +/- standard deviation of patient body-surface area-adjusted estimated glomerular filtration rate (eGFR), serum creatinine (sCre) and urea nitrogen from the initial therapy to 1 month after the last administration changed from 79.8 +/- 11.7-67.0 +/- 16.9 mL/min (p = 0.15), 0.70 +/- 0.13-0.85 +/- 0.27 mg/dL (p = 0.02), and 14.3 +/- 3.8-17.1 +/- 5.4 mg/dL (p = 0.09), respectively. The CTCAE ver 4.0 grades 1 or 2 adverse events pertaining to renal function after the last administration were 2 (5.7 %)/2 (5.7 %) patients assessed by sCre, and 14 (40.0 %)/12 (34.3 %) patients assessed by eGFR, respectively. There was no patient with >=3 grade renal dysfunction based on either evaluation. CONCLUSIONS: Based on the results of this study, supplementary use of the ORS as a method of short-term hydration may be a feasible regimen for shortening infusion times and improving safety for those undergoing chemotherapy including CDDP administration. PMID- 26949542 TI - High MMP-9 Expression May Contribute to Retroprosthetic Membrane Formation after KPro Implantation in Rabbit Corneal Alkali Burn Model. AB - Purpose. To evaluate aqueous humor MMP-9 levels in alkali-burned rabbit cornea following KPr implantation and their roles in RPMs formation. Methods. Left eyes of 36 rabbits received a deep corneal alkali wound. 12 corneas were implanted with KPro and the other 24 control corneas were either penetrating keratoplasty or left without keratoplasty. Aqueous humor MMP-9 and TIMP-1 levels were determined and RPMs were obtained for histopathological and ultrastructural examination. Results. Alkali exposure induced significant increase in aqueous humor MMP-9 level and the data were further enhanced by KPro implantation. By contrast, TMIP-1 levels in aqueous humor showed a decreased trend following corneal alkali burn and KPro surgery. RPMs were developed in 5 out of 10 cases of KPro successfully implanted eyes. Histopathology showed the presence of a large number of fibroblasts and collagen fibers arranged irregularly with inflammatory cells infiltration, and an ingrowth of new blood vessels in this retrokeratoprosthesis fibrous tissue. Immunohistochemical analysis showed positive stain of RPMs for both MMP-9 and TIMP-1. Aqueous humor MMP-9 levels were significantly higher in RPM group postoperatively, while TIMP-1 levels were comparatively lower than that of No-RPM group. Conclusions. Our study evidenced the potential pathophysiological role of MMP-9 expression in RPM formation following KPro implantation. PMID- 26949543 TI - Determinants of Mean Blood Pressure and Hypertension among Workers in West Africa. AB - Background. This review was undertaken to estimate the mean blood pressure and evaluate its determinants as well as the determinants of hypertension among workers in West Africa. Methods. In a follow-up to an earlier study, a systematic search for articles published between 1980 and August 2015 was undertaken using major databases. Results. A total of 55 articles involving 34,919 different cadres of workers from six countries were retrieved. The mean systolic blood pressure (BP) ranged from 116.6 +/- 1.3 mmHg to 151.7 +/- 13.6 mmHg while the mean diastolic BP ranged from 69.6 +/- 11.0 mmHg to 97.1 +/- 9.1 mmHg. Population wide prehypertension was common. The major determinants of mean BP and hypertension were similar and included male sex, older age group, higher socioeconomic status, obesity, alcohol consumption, plasma glucose, and sodium excretion. Ethnicity and educational level were inconsistently associated with hypertension. Workers at higher risk of cardiovascular event did not perceive themselves as such. Conclusion. The prevailing mean prehypertensive BP, low perception of risk, and clustering of risk factors call for interventions such as healthy diets, improved physical activity, and a favourable work environment. Successful models for improving the cardiovascular health of sedentary informal sector workers in Africa are urgently needed. PMID- 26949545 TI - Mechanical Ventilation Boot Camp: A Simulation-Based Pilot Study. AB - Objectives. Management of mechanically ventilated patients may pose a challenge to novice residents, many of which may not have received formal dedicated critical care instruction prior to starting their residency training. There is a paucity of data regarding simulation and mechanical ventilation training in the medical education literature. The purpose of this study was to develop a curriculum to educate first-year residents on addressing and troubleshooting ventilator alarms. Methods. Prospective evaluation was conducted of seventeen residents undergoing a twelve-hour three-day curriculum. Residents were assessed using a predetermined critical action checklist for each case, as well as pre- and postcurriculum multiple-choice cognitive knowledge questionnaires and confidence surveys. Results. Significant improvements in cognitive knowledge, critical actions, and self-reported confidence were demonstrated. The mean change in test score from before to after intervention was +26.8%, and a median score increase of 25% was noted. The ARDS and the mucus plugging cases had statistically significant improvements in critical actions, p < 0.001. A mean increase in self-reported confidence was realized (1.55 to 3.64), p = 0.049. Conclusions. A three-day simulation curriculum for residents was effective in increasing competency, knowledge, and confidence with ventilator management. PMID- 26949544 TI - Sickle-Cell Disease Healthcare Cost in Africa: Experience of the Congo. AB - Background. Lack of medical coverage in Africa leads to inappropriate care that has an impact on the mortality rate. In this study, we aimed to evaluate the cost of severe acute sickle-cell related complications in Brazzaville. Methods. A retrospective study was conducted in 2014 in the Paediatric Intensive Care Unit. It concerned 94 homozygote sickle-cell children that developed severe acute sickle-cell disease related complications (average age 69 months). For each patient, we calculated the cost of care complication. Results. The household income was estimated as low ( 65 years and II < 65 years old). Following variables were collected: stage of the tumor, associated diseases, previous chemotherapy, the type of surgical procedures, blood transfusions, intraoperative and postoperative morbidity, mortality, and hospital stay. Median values between the two groups were compared using Mann Whitney test and frequency data using chi2. Statistical significance was defined as P < 0.05. A total of 179 patients were identified, they were divided into 2 groups: 64 patients were age 65 years or older (group I) and 115 patients were younger than age 65 (group II). In the whole series, 157 patients (87%) did not experience any complication. Overall, postoperative complications occurred in 10 (15%) patients in the group I and in 12 (10%) in the group II (p = NS). In conclusion, elderly patients may tolerate well surgical procedures within acceptable postoperative morbidity, a length of hospital stay and a need for intensive care quite similar to that of younger patients. PMID- 26949565 TI - Towards Better Precision Medicine: PacBio Single-Molecule Long Reads Resolve the Interpretation of HIV Drug Resistant Mutation Profiles at Explicit Quasispecies (Haplotype) Level. AB - Development of HIV-1 drug resistance mutations (HDRMs) is one of the major reasons for the clinical failure of antiretroviral therapy. Treatment success rates can be improved by applying personalized anti-HIV regimens based on a patient's HDRM profile. However, the sensitivity and specificity of the HDRM profile is limited by the methods used for detection. Sanger-based sequencing technology has traditionally been used for determining HDRM profiles at the single nucleotide variant (SNV) level, but with a sensitivity of only >= 20% in the HIV population of a patient. Next Generation Sequencing (NGS) technologies offer greater detection sensitivity (~ 1%) and larger scope (hundreds of samples per run). However, NGS technologies produce reads that are too short to enable the detection of the physical linkages of individual SNVs across the haplotype of each HIV strain present. In this article, we demonstrate that the single-molecule long reads generated using the Third Generation Sequencer (TGS), PacBio RS II, along with the appropriate bioinformatics analysis method, can resolve the HDRM profile at a more advanced quasispecies level. The case studies on patients' HIV samples showed that the quasispecies view produced using the PacBio method offered greater detection sensitivity and was more comprehensive for understanding HDRM situations, which is complement to both Sanger and NGS technologies. In conclusion, the PacBio method, providing a promising new quasispecies level of HDRM profiling, may effect an important change in the field of HIV drug resistance research. PMID- 26949567 TI - A Proposal for Public and Private Partnership in Extension. AB - Public funding for Extension in the United States has been decreasing for many years, but farmers' need for robust information on which to make management decisions has not diminished. The current Extension funding challenges provide motivation to explore a different model for developing and delivering extension. The private sector has partnered with the public sector to fund and conduct agricultural research, but partnering on extension delivery has occurred far less frequently. The fundamental academic strength and established Extension network of the public sector combined with the ability of the private sector to encourage and deliver practical, implementable solutions has the potential to provide measurable benefits to farmers. This paper describes the current Extension climate, presents data from a survey about Extension and industry relationships, presents case studies of successful public- and private-sector extension partnerships, and proposes a framework for evaluating the state of effective partnerships. Synergistic public-private extension efforts could ensure that farmers receive the most current and balanced information available to help with their management decisions. PMID- 26949566 TI - Influences of barriers to cessation and reasons for quitting on substance use among treatment-seeking smokers who report heavy drinking. AB - OBJECTIVES: We examined behavioral and cognitively-based quit processes among concurrent alcohol and tobacco users and assessed whether smoking and drinking were differentially influenced. METHODS: Participants were 200 treatment-seeking smokers (37.50% female; Mage = 30.72; SD = 12.68) who reported smoking an average of 10 or more cigarettes daily for at least one year. RESULTS: Barriers to cessation (BCS) and reasons for quitting (RFQ) were generally correlated with substance use. BCS moderated the relationship between quit methods and cigarette use such that quit methods were negatively associated with smoking, particularly among those with more BCS. RFQ moderated the association between quit methods and cigarette use such that quit methods were negatively linked with smoking among those with fewer RFQ, but positively linked with smoking among those with more RFQ. Two 3-way interactions emerged. The first 3-way indicated that among individuals with fewer RFQ, quit methods was negatively associated with smoking, and this was strongest among those with more BCS. However, among those with more RFQ, smoking and quit methods were positively associated, particularly among those with more BCS. The second 3-way showed that among those with fewer RFQ, quit methods was negatively linked with drinking frequency, and this was strongest among those with more BCS. However, among those with fewer BCS, drinking and quit methods were positively linked. CONCLUSIONS: The relationship between behavioral and cognitively-based quit processes and substance use is not straightforward. There may be concurrent substance-using individuals for whom these processes might be associated with increased substance use. PMID- 26949568 TI - Sparse Multidimensional Patient Modeling using Auxiliary Confidence Labels. AB - In this work, we focus on the problem of learning a classification model that performs inference on patient Electronic Health Records (EHRs). Often, a large amount of costly expert supervision is required to learn such a model. To reduce this cost, we obtain confidence labels that indicate how sure an expert is in the class labels she provides. If meaningful confidence information can be incorporated into a learning method, fewer patient instances may need to be labeled to learn an accurate model. In addition, while accuracy of predictions is important for any inference model, a model of patients must be interpretable so that clinicians can understand how the model is making decisions. To these ends, we develop a novel metric learning method called Confidence bAsed MEtric Learning (CAMEL) that supports inclusion of confidence labels, but also emphasizes interpretability in three ways. First, our method induces sparsity, thus producing simple models that use only a few features from patient EHRs. Second, CAMEL naturally produces confidence scores that can be taken into consideration when clinicians make treatment decisions. Third, the metrics learned by CAMEL induce multidimensional spaces where each dimension represents a different "factor" that clinicians can use to assess patients. In our experimental evaluation, we show on a real-world clinical data set that our CAMEL methods are able to learn models that are as or more accurate as other methods that use the same supervision. Furthermore, we show that when CAMEL uses confidence scores it is able to learn models as or more accurate as others we tested while using only 10% of the training instances. Finally, we perform qualitative assessments on the metrics learned by CAMEL and show that they identify and clearly articulate important factors in how the model performs inference. PMID- 26949569 TI - A New Automated Method and Sample Data Flow for Analysis of Volatile Nitrosamines in Human Urine. AB - Volatile nitrosamines (VNAs) are a group of compounds classified as probable (group 2A) and possible (group 2B) carcinogens in humans. Along with certain foods and contaminated drinking water, VNAs are detected at high levels in tobacco products and in both mainstream and sidestream smoke. Our laboratory monitors six urinary VNAs-N-nitrosodimethylamine (NDMA), N nitrosomethylethylamine (NMEA), N-nitrosodiethylamine (NDEA), N-nitrosopiperidine (NPIP), N-nitrosopyrrolidine (NPYR), and N-nitrosomorpholine (NMOR)-using isotope dilution GC-MS/MS (QQQ) for large population studies such as the National Health and Nutrition Examination Survey (NHANES). In this paper, we report for the first time a new automated sample preparation method to more efficiently quantitate these VNAs. Automation is done using Hamilton STARTM and Caliper StaccatoTM workstations. This new automated method reduces sample preparation time from 4 hours to 2.5 hours while maintaining precision (inter-run CV < 10%) and accuracy (85% - 111%). More importantly this method increases sample throughput while maintaining a low limit of detection (<10 pg/mL) for all analytes. A streamlined sample data flow was created in parallel to the automated method, in which samples can be tracked from receiving to final LIMs output with minimal human intervention, further minimizing human error in the sample preparation process. This new automated method and the sample data flow are currently applied in bio monitoring of VNAs in the US non-institutionalized population NHANES 2013-2014 cycle. PMID- 26949570 TI - Male Hormonal Contraception: Where Are We Now? AB - Hormonal male contraception clinical trials began in the 1970s. The method is based on the use of exogenous testosterone alone or in combination with a progestin to suppress the endogenous production of testosterone and spermatogenesis. Studies using testosterone alone showed that the method was very effective with few adverse effects. Addition of a progestin increases the rate and extent of suppression of spermatogenesis. Common adverse effects include acne, injection site pain, mood change including depression, and changes in libido that are usually mild and rarely lead to discontinuation. Current development includes long-acting injectables and transdermal gels and novel androgens that may have both androgenic and progestational activities. Surveys showed that over 50 % of men will accept a new male method and female partners will trust their partner to take oral "male pills." Partnership between government, nongovernment agencies, academia, and industry may generate adequate interest and collaboration to develop and market the first male hormonal contraception. PMID- 26949571 TI - Rare MLL-ELL fusion transcripts in childhood acute myeloid leukemia-association with young age and myeloid sarcomas? AB - BACKGROUND: The chromosomal translocation t(11;19)(q23;p13) with a breakpoint within subband 19p13.1 is found mainly in acute myeloid leukemia (AML) and results in the MLL-ELL fusion gene. Variations in the structure of MLL-ELL seem to influence the leukemogenic potency of the fusion in vivo and may lie behind differences in clinical features. The number of cases reported so far is very limited and the addition of more information about MLL-ELL variants is essential if the possible clinical significance of rare fusions is to be determined. CASE PRESENTATION: Cytogenetic and molecular genetic analyses were done on the bone marrow cells of a 20-month-old boy with an unusual form of myelomonocytic AML with multiple myeloid sarcomas infiltrating bone and soft tissues. The G-banding analysis together with FISH yielded the karyotype 47,XY, +6,t(8;19;11)(q24;p13;q23). FISH analysis also demonstrated that MLL was split. RNA-sequencing showed that the translocation had generated an MLL-ELL chimera in which exon 9 of MLL (nt 4241 in sequence with accession number NM_005933.3) was fused to exon 6 of ELL (nt 817 in sequence with accession number NM_006532.3). RT PCR together with Sanger sequencing verified the presence of the above-mentioned fusion transcript. CONCLUSIONS: Based on our findings and information on a few previously reported patients, we speculate that young age, myelomonoblastic AML, and the presence of extramedullary disease may be typical of children with rare MLL-ELL fusion transcripts. PMID- 26949573 TI - DNA microsatellite markers for Swartzia glazioviana (Fabaceae), a threatened species from the Brazilian Atlantic Forest. AB - PREMISE OF THE STUDY: Development and characterization of a set of DNA microsatellite markers for Swartzia glazioviana (Fabaceae), a naturally rare and threatened tree species, were carried out to investigate its conservation genetics. METHODS AND RESULTS: Through an enriched genomic library procedure, 10 DNA microsatellite loci were isolated and characterized for the species. The mean expected heterozygosity was 0.776 (0.424-0.894). Cross-species amplifications of these loci were successfully tested for six congener taxa (S. apetala var. apetala, S. flaemingii, S. langsdorffii, S. macrostachya, S. myrtifolia var. elegans, and S. simplex var. continentalis). CONCLUSIONS: The 10 polymorphic microsatellite markers developed are quite informative and will provide a valuable resource to study the population and conservation genetics of S. glazioviana and other Swartzia species. PMID- 26949572 TI - Pathogenesis, Emerging therapeutic targets and Treatment in Sialidosis. AB - INTRODUCTION: Sialidosis is a neurosomatic, lysosomal storage disease (LSD) caused by mutations in the NEU1 gene, encoding the lysosomal sialidase NEU1. Deficient enzyme activity results in impaired processing/degradation of sialo glycoproteins, and accumulation of oversialylated metabolites. Sialidosis is considered an orphan disorder for which no therapy is currently available. AREAS COVERED: The review describes the clinical forms of sialidosis and the NEU1 mutations so far identified; NEU1 requirement to complex with the protective protein/cathepsin A for stability and activation; and the pathogenic effects of NEU1 deficiency. Studies of the molecular mechanisms of pathogenesis in animal models uncovered basic cellular pathways downstream of NEU1 and its substrates, which may be implicated in more common adult (neurodegenerative) diseases. The development of a Phase I/II clinical trial for patients with galactosialidosis may prove suitable for sialidosis patients with the attenuated form of the disease. EXPERT OPINION: Recently, there has been a renewed interest in the development of therapies for orphan LSDs, like sialidosis. Given the small number of potentially eligible patients, the way to treat sialidosis would be through the coordinated effort of clinical centers, which provide diagnosis and care for these patients, and the basic research labs that work towards understanding the disease pathogenesis. PMID- 26949574 TI - Transcriptome-derived microsatellite markers for Dioon (Zamiaceae) cycad species. AB - PREMISE OF THE STUDY: Dioon (Zamiaceae) is an endangered North American cycad genus of evolutionary and ornamental value. We designed and validated a set of microsatellite markers from D. edule that can be used for population-level and conservation studies, and that transferred successfully to D. angustifolium, D. spinulosum, and D. holmgrenii. METHODS AND RESULTS: We tested 50 primers from 80 microsatellite candidate loci in the OneKP D. edule transcriptome. Genotypes from 21 loci in 20 D. edule individuals revealed up to 14 alleles per locus and observed heterozygosity from 0.15 to 0.92; one locus was monomorphic. Seven of those 21 loci were polymorphic in D. angustifolium, D. spinulosum, and D. holmgrenii, with up to seven alleles, and an observed heterozygosity up to 0.89. CONCLUSIONS: The transcriptome-derived microsatellites generated here will serve as tools to advance population genetic studies and inform conservation strategies of Dioon, including the identification and origin of illegal plants in the cycad trade. PMID- 26949575 TI - Development of microsatellite markers for the semi-natural grassland herb Veronicastrum japonicum (Plantaginaceae). AB - PREMISE OF THE STUDY: Veronicastrum japonicum (Plantaginaceae) grows in grasslands on Honshu Island, Japan, and is threatened by habitat loss because of rapid land development over recent decades. For the genetic characterization of the remaining populations, microsatellite markers were developed. METHODS AND RESULTS: Twelve polymorphic microsatellite loci were developed using next generation sequencing. The number of alleles per locus ranged from two to 24 (mean 7.7), and the expected heterozygosity per locus ranged from 0.35 to 0.94 (mean 0.68). CONCLUSIONS: These markers can be used for genetic studies in conservation, such as the evaluation of genetic diversity and genetic structure. PMID- 26949576 TI - Isolation and characterization of novel microsatellite loci for the endangered orchid Cypripedium japonicum (Orchidaceae). AB - PREMISE OF THE STUDY: Twenty-six microsatellite markers were developed for the endangered orchid Cypripedium japonicum (Orchidaceae) to estimate the clonal diversity and genetic structure of the remaining populations in Japan. METHODS AND RESULTS: Microsatellite loci of C. japonicum were isolated using Ion Personal Genome Machine (PGM) sequencing. The primer sets were tested on 55 ramets sampled from two populations in Japan. Sixteen loci showed polymorphism in at least one population, with two to five alleles per locus. Observed and expected heterozygosities for the two populations ranged from 0.00 to 0.92 and 0.00 to 0.71, respectively. CONCLUSIONS: The microsatellite markers developed here provide a useful tool to analyze clonal structure and sexual regeneration status and will help to manage the remaining genetic variation within C. japonicum. PMID- 26949577 TI - Isolation and characterization of 13 microsatellites for the rare endemic shrub Tetratheca erubescens (Elaeocarpaceae). AB - PREMISE OF THE STUDY: Microsatellite markers were developed for the rare Tetratheca erubescens (Elaeocarpaceae) to assess genetic diversity and spatial structuring. METHODS AND RESULTS: We generated ca. 2.7 million sequence reads using a Personal Genome Machine (PGM) semiconductor sequencer. Using the QDD pipeline, we designed primers for >12,000 sequences with PCR product lengths of 80-480 bp. From these, 30 primer pairs were selected and screened using PCR, from which 11 loci were found to be polymorphic and amplified reliably. For a sample of 95 plants from three populations, the number of alleles observed for these 11 loci ranged from two to seven and expected heterozygosity ranged from 0.06 to 0.72. No consistent evidence for null alleles or departure from Hardy-Weinberg equilibrium was found for any of the 11 loci. CONCLUSIONS: These markers will enable the quantification of genetic impact of proposed mining activities on the narrow endemic T. erubescens. PMID- 26949578 TI - Microsatellites for Oenothera gayleana and O. hartwegii subsp. filifolia (Onagraceae), and their utility in section Calylophus. AB - PREMISE OF THE STUDY: Eleven nuclear and four plastid microsatellite markers were screened for two gypsum endemic species, Oenothera gayleana and O. hartwegii subsp. filifolia, and tested for cross-amplification in the remaining 11 taxa within Oenothera sect. Calylophus (Onagraceae). METHODS AND RESULTS: Microsatellite markers were tested in two to three populations spanning the ranges of both O. gayleana and O. hartwegii subsp. filifolia. The nuclear microsatellite loci consisted of both di- and trinucleotide repeats with one to 17 alleles per population. Several loci showed significant deviation from Hardy Weinberg equilibrium, which may be evidence of chromosomal rings. The plastid microsatellite markers identified one to seven haplotypes per population. The transferability of these markers was confirmed in all 11 taxa within Oenothera sect. Calylophus. CONCLUSIONS: The microsatellite loci characterized here are the first developed and tested in Oenothera sect. Calylophus. These markers will be used to assess whether pollinator foraging distance influences population genetic parameters in predictable ways. PMID- 26949580 TI - WARACS: Wrappers to Automate the Reconstruction of Ancestral Character States. AB - PREMISE OF THE STUDY: Reconstructions of ancestral character states are among the most widely used analyses for evaluating the morphological, cytological, or ecological evolution of an organismic lineage. The software application Mesquite remains the most popular application for such reconstructions among plant scientists, even though its support for automating complex analyses is limited. A software tool is needed that automates the reconstruction and visualization of ancestral character states with Mesquite and similar applications. METHODS AND RESULTS: A set of command line-based Python scripts was developed that (a) communicates standardized input to and output from the software applications Mesquite, BayesTraits, and TreeGraph2; (b) automates the process of ancestral character state reconstruction; and (c) facilitates the visualization of reconstruction results. CONCLUSIONS: WARACS provides a simple tool that streamlines the reconstruction and visualization of ancestral character states over a wide array of parameters, including tree distribution, character state, and optimality criterion. PMID- 26949581 TI - Effect of pooled comparative information on judgments of quality. AB - Quality assessment is the focus of many health care initiatives. Yet it is not well understood how the type of information used in decision support tools to enable judgments of quality based on data impacts the accuracy, consistency and reliability of judgments made by physicians. Comparative pooled information could allow physicians to judge the quality of their practice by making comparisons to other practices or other specific populations of patients. In this study, resident physicians were provided with varying types of information derived from pooled patient data sets: quality component measures at the individual and group level, a qualitative interpretation of the quality measures using percentile rank, and an aggregate composite quality score. 32 participants viewed thirty quality profiles consisting of information applicable to the practice of thirty de-identified resident physicians. Those provided with quality component measures and a qualitative interpretation of the quality measures (rankings) judged quality of care more similarly to experts and were more internally consistent compared to participants who were provided with quality component measures alone. Reliability between participants was significantly less for those who were provided with a composite quality score compared to those who were not. PMID- 26949579 TI - Are microsatellite fragment lengths useful for population-level studies? The case of Polygala lewtonii (Polygalaceae). AB - PREMISE OF THE STUDY: Microsatellites, despite being commonly used population level markers, contain biases because scoring relies solely on fragment length. Their complexity can lead to homoplasy, the effects of which are poorly understood. We investigated the impact of using fragment lengths, repeats, or flanking region sequences on common population-level analyses. METHODS: Five polymorphic microsatellite markers amplified across the central Florida scrub endemic Polygala lewtonii (Polygalaceae) and its close, widespread congener P. polygama. We genotyped 147 individuals of P. lewtonii and 156 of P. polygama, and sequenced the amplicons of four markers across all individuals. We ran basic statistics, spatial clustering analysis, historical demographics, and migration tests. RESULTS: One population of intermediate morphology was genetically clearly identified as P. polygama, making it the southernmost population of this species. Statistics were comparable between the fragment length and repeat numbers, with some notable differences. Flanking regions exhibited surprisingly high polymorphism between species, and between geographically distant conspecific populations. DISCUSSION: The increasing use of markers developed in one species and amplified in another is only a good practice if precautions are taken, notably the sequencing of the fragments between species and populations. Flanking region sequences are a useful marker at the interspecific level. PMID- 26949583 TI - Nasal Deformities Following Nasoseptal Flap Reconstruction of Skull Base Defects. AB - Objectives To identify the prevalence and risk factors for nasal deformities after endoscopic endonasal surgery (EES) of the skull base. Design Retrospective case series. Setting Tertiary referral academic center. Participants EES patients from January 2011 to October 2013. Main Outcome Measures Surgical approach, method of skull base reconstruction, and postoperative nasal deformities. Results Of 328 patients, 19 patients (5.8%) had nasal dorsum collapse, 3 (0.9%) with new septal perforations and 2 (0.6%) with septal deviations requiring surgical correction. Postoperative deformities were only found in the setting of nasoseptal flap reconstruction (p = 0.0001) and were most common in patients who had undergone an approach involving more than one anatomical subsite (p = 0.0021). Patients with nasal deformities were on average 6 years younger (p = 0.08) and were more likely to have a malignant pathology (p = 0.08). Conclusions All deformities were associated with use of a nasoseptal flap for reconstruction and were most common in combined approaches, suggesting that flap size may play a role in the development of nasal deformities. The mechanism of nasal dorsum collapse is unclear but does not appear to be related to septal cartilage necrosis. These findings warrant a prospective analysis to identify risk factors for postoperative nasal deformities and data for counseling of patients. PMID- 26949582 TI - Imaging Characteristics of Olfactory Neuroblastoma (Esthesioneuroblastoma). AB - This presentation outlines the clinical and imaging characteristics of esthesioneuroblastoma. PMID- 26949584 TI - Anatomical Factors Influencing Selective Vestibular Neurectomy: A Comparison of Posterior Fossa Approaches. AB - Objectives To identify measurable anatomical factors that may guide the surgical approach for posterior fossa selective vestibular neurectomy (SVN) and predict identification of the vestibulocochlear cleavage (VCC) plane. Study Design Dissection of fixed cadaveric heads through retrolabyrinthine and retrosigmoid internal auditory canal (RSG-IAC) approaches with measurement of landmarks. Setting Cadaveric dissection model. Main Outcome Measures Area of the Trautmann triangle (TT) and the distance from the posterior semicircular canal to the anterior border of the sigmoid along the posterior Donaldson line (pDL). VCC planes from each approach were calculated and compared. Results Overall mean pDL was 8.53 mm (range: 5-11.5 mm); mean TT area was 124 mm(2) (range: 95-237 mm(2)). The VCC was identified in 63% of ears through the retrolabyrinthine (RVN) approach alone, whereas 37% of ears required the RSG-IAC approach. In ears requiring IAC dissection, the VCC was found within 1 to 2 mm distal to the porus. The pDL (p < 0.05) and area of TT (p < 0.05) were significantly larger in the RVN group compared with the RSG-IAC group. Conclusion Ears amenable to the RVN approach had a greater pDL and TT area. These anatomical measurements may have a role in surgical planning and the choice of approach for SVN. PMID- 26949585 TI - A Quantitative Analysis of Published Skull Base Endoscopy Literature. AB - Objectives Skull base endoscopy allows for minimal access approaches to the sinonasal contents and cranial base. Advances in endoscopic technique and applications have been published rapidly in recent decades. Setting We utilized an Internet-based scholarly database (Web of Science, Thomson Reuters) to query broad-based phrases regarding skull base endoscopy literature. Participants All skull base endoscopy publications. Main Outcome Measures Standard bibliometrics outcomes. Results We identified 4,082 relevant skull base endoscopy English language articles published between 1973 and 2014. The 50 top-cited publications (n = 51, due to articles with equal citation counts) ranged in citation count from 397 to 88. Most of the articles were clinical case series or technique descriptions. Most (96% [49/51])were published in journals specific to either neurosurgery or otolaryngology. Conclusions A relatively small number of institutions and individuals have published a large amount of the literature. Most of the publications consisted of case series and technical advances, with a lack of randomized trials. PMID- 26949586 TI - Scalp Rotation Flap for Reconstruction of Complex Soft Tissue Defects. AB - Importance Scalp reconstructions may be required after tumor resection or trauma. The inherent anatomy of the scalp presents challenges and may limit reconstructive options. Objective To describe and investigate the scalp rotation flap as a reconstructive technique for complex soft tissue defects. Design Retrospective case series with a mean follow-up of 13 months. Setting Tertiary academic center. Participants A total of 22 patients with large scalp soft tissue defects undergoing scalp rotation flap reconstruction. Interventions The flap is designed adjacent to the defect and elevated in the subgaleal plane. The flap is rotated into the defect, and a split-thickness skin graft is placed over the donor site periosteum. Main Outcomes and Measure Data points collected included defect size, operative time, hospital stay, and patient satisfaction with cosmetic outcome. Results Mean patient age was 71 years. Mean American Society of Anesthesiologist classification was 2.8. Mean defect size was 41 cm(2) (range: 7.8-120 cm(2)), and 19 of 22 defects resulted from a neoplasm resection. Mean operative time was 181 minutes, and mean hospital stay was 2.4 days. There were no intraoperative complications. Three patients with previous radiation therapy had distal flap necrosis. Twenty-one patients (95%) reported an acceptable cosmetic result. Conclusions and Relevance The scalp rotation flap is an efficient and reliable option for reconstructing complex soft tissue defects. This can be particularly important in patients with significant medical comorbidities who cannot tolerate a lengthy operative procedure. PMID- 26949587 TI - Adjuvant Stereotactic Radiosurgery and Radiation Therapy for the Treatment of Intracranial Chordomas. AB - Objective Chordomas are locally aggressive, highly recurrent tumors requiring adjuvant radiotherapy following resection for successful management. We retrospectively reviewed patients treated for intracranial chordomas with adjuvant stereotactic radiosurgery (SRS) and stereotactic radiation therapy (SRT). Methods A total of 57 patients underwent 83 treatments at the UCLA Medical Center between February 1990 and August 2011. Mean follow-up was 57.8 months. Mean tumor diameter was 3.36 cm. Overall, 8 and 34 patients received adjuvant SRS and SRT, and the mean maximal dose of radiation therapy was 1783.3 cGy and 6339 cGy, respectively. Results Overall rate of recurrence was 51.8%, and 1- and 5 year progression-free survival (PFS) was 88.2% and 35.2%, respectively. Gross total resection was achieved in 30.9% of patients. Adjuvant radiotherapy improved outcomes following subtotal resection (5-year PFS 62.5% versus 20.1%; p = 0.036). SRS and SRT produced comparable rates of tumor control (p = 0.28). Higher dose SRT (> 6,000 cGy) (p = 0.013) and younger age (< 45 years) (p = 0.03) was associated with improved rates of tumor control. Conclusion Adjuvant radiotherapy is critical following subtotal resection of intracranial chordomas. Adjuvant SRT and SRS were safe and improved PFS following subtotal resection. Higher total doses of SRT and younger patient age were associated with improved rates of tumor control. PMID- 26949588 TI - Management of Recurrent Trigeminal Neuralgia Associated with Petroclival Meningioma. AB - Objective Petroclival meningioma (PM) presents with trigeminal neuralgia (TN) in < 5% of cases. Neurosurgeons often face the dilemma of formulating a treatment protocol when TN recurs. In this study, we sought to set up a protocol in patients with PM who had a recurrent TN. Materials and Methods We performed a retrospective review of 57 patients with PM. Of the 57 patients, only 7 patients presented with TN, and six patients experienced recurrent TN. The study population was evaluated clinically and radiographically after treatment. Results Overall improvement of pain control after various treatments was 67%, and tumor control was 100%. The pain-free period was 2 years for the Gamma Knife radiosurgery (GKRS) group and 4 years for the resection group when treated as a primary treatment (p = 0.034). Of the six patients, four patients had Barrow Neurosurgical Institute (BNI) score I (no TN, no medication), and two patients had BNI score III (some pain controlled with medication). The Karnofsky performance scale score was significantly improved after treatment compared with the pretreated status (78 versus 88; p = 0.044). Conclusion Microsurgical resection is superior to GKRS in achieving and maintaining pain-free status in patients with recurrent trigeminal pain associated with PM. PMID- 26949589 TI - Endoscopic Endonasal Transsphenoidal Approach for Apoplectic Pituitary Tumor: Surgical Outcomes and Complications in 45 Patients. AB - Objective To assess the safety and effectiveness of the endoscopic endonasal transsphenoidal approach (EETA) for apoplectic pituitary adenoma. Design A retrospective study. Setting Qilu Hospital of Shandong University; Brain Science Research Institute, Shandong University. Participants Patients admitted to Qilu Hospital of Shandong University who were diagnosed with an apoplectic pituitary tumor and underwent EETA for resection of the tumor. Main Outcome Measures In total 45 patients were included in a retrospective chart review. Data regarding patient age, sex, presentation, lesion size, surgical procedure, extent of resection, clinical outcome, and surgical complications were obtained from the chart review. Results In total, 38 (92.7%) of 41 patients with loss of vision obtained visual remission postoperatively. In addition, 16 patients reported a secreting adenoma, and postsurgical hormonal levels were normal or decreased in 14 patients. All other symptoms, such as headache and alteration of mental status, recovered rapidly after surgery. Two patients (4.4%) incurred cerebrospinal fluid leakage. Six patients (13.3%) experienced transient diabetes insipidus (DI) postoperatively, but none of these patients developed permanent DI. Five patients (11.1%) developed hypopituitarism and were treated with replacement of hormonal medicine. No cases of meningitis, carotid artery injury, or death related to surgery were reported. Conclusion EETA offers a safe and effective surgical option for apoplectic pituitary tumors and is associated with low morbidity and mortality. PMID- 26949590 TI - Plasmacytoma of the Skull Base: A Meta-Analysis. AB - Objective Extramedullary plasmacytomas are rare tumors. In the current study we aim to characterize its clinical course at the skull base and define the most appropriate therapeutic protocol. Methods We conducted a meta-analysis of articles in the English language that included data on the treatment and outcome of plasmacytoma of the base of skull. Results The study cohort consisted of 47 patients. The tumor originated from the clivus and sphenoclival region in 28 patients (59.5%), the nasopharynx in 10 patients (21.2%), the petrous apex in 5 patients (10.6%), and the orbital roof in 4 patients (8.5%). The chief complaints at presentation included recurrent epistaxis and cranial nerve palsy, according to the site of tumor. Twenty-two patients (46.8%) had surgical treatment; 25 (53.2%) received radiation therapy. Adjuvant therapy was administered in 11 cases (50%) with concurrent multiple myeloma. The 2-year and 5-year overall survival rates were 78% and 59%, respectively. Clear margin resection was achieved in a similar proportion of patients who underwent endoscopic surgery and open surgery (p = 0.83). A multivariate analysis of outcome showed a similar survival rate of patients treated surgically or with radiotherapy. Conclusions The mainstay of treatment for plasmacytoma is based on radiation therapy, but when total resection is feasible, endoscopic resection is a valid option. PMID- 26949591 TI - Effect of Incremental Endoscopic Maxillectomy on Surgical Exposure of the Pterygopalatine and Infratemporal Fossae. AB - Objective Access to the pterygopalatine and infratemporal fossae presents a significant surgical challenge, owing to their deep-seated location and complex neurovascular anatomy. This study elucidates the benefits of incremental medial maxillectomies to access this region. We compared access to the medial aspect of the infratemporal fossa provided by medial maxillectomy, anteriorly extended medial maxillectomy, endoscopic Denker approach (i.e., Sturmann-Canfield approach), contralateral transseptal approach, and the sublabial anterior maxillotomy (SAM). Methods We studied 10 cadaveric specimens (20 sides) dissecting the pterygopalatine and infratemporal fossae bilaterally. Radius of access was calculated using a navigation probe aligned with the endoscopic line of sight. Area of exposure was calculated as the area removed from the posterior wall of maxillary sinus. Surgical freedom was calculated by computing the working area at the proximal end of the instrument with the distal end fixed at a target. Results The endoscopic Denker approach offered a superior area of exposure (8.46 +/- 1.56 cm(2)) and superior surgical freedom. Degree of lateral access with the SAM approach was similar to that of the Denker. Conclusion Our study suggests that an anterior extension of the medial maxillectomy or a cross-court approach increases both the area of exposure and surgical freedom. Further increases can be seen upon progression to a Denker approach. PMID- 26949592 TI - Fractionated Stereotactic Radiotherapy for Facial Nerve Schwannomas. AB - Purpose Data on the clinical course of irradiated facial nerve schwannomas (FNS) are lacking. We evaluated fractionated stereotactic radiotherapy (FSRT) for FNS. Methods Eight consecutive patients with FNS treated at our institution between 1998 and 2011 were included. Patients were treated with FSRT to a median dose of 50.4 Gy (range: 46.8-54 Gy) in 1.8 or 2.0 Gy fractions. We report the radiographic response, symptom control, and toxicity associated with FSRT for FNS. Results The median follow-up time was 43 months (range: 10-75 months). All patients presented with symptoms including pain, tinnitus, facial asymmetry, diplopia, and hearing loss. The median tumor volume was 1.57 cc. On the most recent follow-up imaging, five patients were noted to have stable tumor size; three patients had a net reduction in tumor volume. Additionally, six patients had improvement in clinical symptoms, one patient had stable clinical findings, and one patient had worsened House-Brackmann grade due to cystic degeneration. Conclusion FSRT treatment of FNS results in excellent control of growth and symptoms with a small rate of radiation toxicity. Given the importance of maintaining facial nerve function, FSRT could be considered as a primary management modality for enlarging or symptomatic FNS. PMID- 26949371 TI - Search for an additional, heavy Higgs boson in the [Formula: see text] decay channel at [Formula: see text] in [Formula: see text] collision data with the ATLAS detector. AB - A search is presented for a high-mass Higgs boson in the [Formula: see text], [Formula: see text], [Formula: see text], and [Formula: see text] decay modes using the ATLAS detector at the CERN Large Hadron Collider. The search uses proton-proton collision data at a centre-of-mass energy of 8 TeV corresponding to an integrated luminosity of 20.3 fb[Formula: see text]. The results of the search are interpreted in the scenario of a heavy Higgs boson with a width that is small compared with the experimental mass resolution. The Higgs boson mass range considered extends up to [Formula: see text] for all four decay modes and down to as low as 140 [Formula: see text], depending on the decay mode. No significant excess of events over the Standard Model prediction is found. A simultaneous fit to the four decay modes yields upper limits on the production cross-section of a heavy Higgs boson times the branching ratio to [Formula: see text] boson pairs. 95 % confidence level upper limits range from 0.53 pb at [Formula: see text] GeV to 0.008 pb at [Formula: see text] GeV for the gluon-fusion production mode and from 0.31 pb at [Formula: see text] GeV to 0.009 pb at [Formula: see text] GeV for the vector-boson-fusion production mode. The results are also interpreted in the context of Type-I and Type-II two-Higgs-doublet models. PMID- 26949593 TI - Modeling and optimization of degree of folate grafted on chitosan and carboxymethyl-chitosan. AB - Chitosan is a cationic polysaccharide with great properties and so is considered as an attractive biopolymer. However, chitosan shows its antibacterial activity only in acidic environment and this restricts its uses. So water-soluble chitosan derivatives such as carboxymethyl chitosan could be good candidates for such biomedical applications. Modified chitosan with hydrophobic functional groups such as folate (FA) is able to make self-assembled nanoparticles in aqueous media. One of the most important factors affecting the properties of resulting nanoparticles such as size, morphology, amount and efficiency of drug loading and also drug release profile is the amount of FA groups grafted on the chitosan chains. In this study FA modified chitosan and carboxymethyl chitosan have been synthesized using folic acid, N-hydroxy succinimide (NHS), N, N dicyclohexylcarbodiimide (DCC) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC). The effect of molecular weight, degree of substitution of carboxymethyl hydrophilic group and primary molar ratio of folic acid to chitosan/carboxymethyl chitosan (CMCS) on degree of substitution of folate functional groups grafted on chitosan chains was modeled using a statistical software package (Design of Expert 8, Trial version). Degree of substitution of grafted folate was measured using UV/Vis spectroscopy. Results show that degree of substitution of CMC and molar ratio of folic acid to chitosan/carboxymethyl chitosan has direct effect on substitution degree of folate and molecular weight has an inverse impact. Also results show that molar ratio of folic acid to chitosan/(CMCS) has the most effect on substitution degree of folate and the proposed model is statistically valid to predict degree of substitution of FA groups on chitosan chains. PMID- 26949594 TI - Electrospun silk-based nanofibrous scaffolds: fiber diameter and oxygen transfer. AB - In this study, silk fibroin was extracted from cocoons of silkworms and fabricated into nonwoven mats by electrospinning method. A new model based on the group method of data handling (GMDH) and artificial neural network (ANN) was developed for estimation of the average diameter of electrospun silk fibroin nanofibers. In this regard, concentration, flow rate, voltage, distance, and speed of collector were used as input parameters and average diameter of the fibers was considered as output parameter. Two models were capable to estimate average diameter of fibers with good accuracy. The average absolute relative deviation for GMDH and ANN models was equal to 3.56 and 2.28 %, respectively. Furthermore, due to importance of oxygen delivery to site of injury to promote wound healing, continuity equation for mass transport was employed for prediction of oxygen profile in the system containing wound dressing and skin. The result showed that our prepared wound dressing is capable to pass the oxygen completely to the skin layer and is not acting as a barrier for oxygen delivery to wound site. Since average nanofibers diameter can influence the mat physical, mechanical and biological properties then this model may serve as a useful guide to obtain tailor made and uniform silk nanofibers at various combinations of process variables. PMID- 26949595 TI - Are Eating Disorders Related to Attention Deficit/Hyperactivity Disorder? AB - Attention deficit/hyperactivity disorder (ADHD) is a disorder characterized by impulsivity, hyperactivity, and inattention. Binge-eating behavior is often impulsive and is the hallmark of the two eating disorders, binge-eating disorder (BED) and bulimia nervosa (BN), both of which are associated with significant health impairment. Bingeing behavior is also seen in the binge purge subtype of anorexia nervosa. Individuals with AN of the binge purge subtypes, BN and BED, have been found to exhibit impulsive behaviors that are often not limited to binge eating alone. There is preliminary evidence linking ADHD to BN and to BED in both adults and children. The neurobiological mechanisms behind these associations are only beginning to emerge; however, they suggest that impulse control deficits may play a role in these eating disorders. Additionally, although they may not meet full criteria for one of these eating disorders, some adults and children with ADHD present with dysregulated, impulsive eating disorder behaviors and there is a growing association between ADHD, obesity, and binge-eating behavior in both children and adults. The relationship between ADHD and binge eating is novel, supported by growing evidence and worthy of further research. We will review the underlying neurobiological underpinnings, neuroimaging data, and possible psychopharmacological treatment options, which target both ADHD and binge-eating behaviors as well as future research and treatment directions. PMID- 26949597 TI - Acquired multi-azole resistance in Candida tropicalis during persistent urinary tract infection in a dog. AB - Multi-azole resistance acquisition by Candida tropicalis after prolonged antifungal therapy in a dog with urinary candidiasis is reported. Pre- and post azole treatment isolates were clonally related and had identical silent mutations in the ERG11 gene, but the latter displayed increased azole minimum inhibitory concentrations. A novel frameshift mutation in ERG3 was found in some isolates recovered after resistance development, so it appears unlikely that this mutation is responsible for multi-azole resistance. PMID- 26949598 TI - Dissociated pulmonary vein potentials: Expression of the cardiac autonomic nervous system following pulmonary vein isolation? PMID- 26949599 TI - Corrigendum to "Detection of BRAF mutations from solid tumors using TumorplexTM technology" [MethodsX 2 (2015), 316-322]. AB - [This corrects the article DOI: 10.1016/j.mex.2015.06.002.]. PMID- 26949596 TI - Development and characterization of in-situ gel for ophthalmic formulation containing ciprofloxacin hydrochloride. AB - In situ gels are systems which are applied as solutions or suspensions and are capable of undergoing rapid sol-to-gel transformation triggered by external stimulus such as temperature, pH etc. on instillation. The aim of the present study was to formulate and evaluate pH responsive in-situ gel for ophthalmic delivery. Ciprofloxacin hydrochloride is popularly used as a broad spectrum antibiotic in the treatment of corneal ulcers of ocular infections. However, rapid dilution on instillation, wash out, poor retention of drug concentration delimit the therapeutic benefits of the drug when used in form of conventional eye drops. Sodium alginate, an ophthalmic gel forming mucoadhesive polymer was chosen as polymer which undergoes instantaneous gel formation due to formation of calcium alginate by virtue of its interaction with divalent cation (Ca(+2)) present in lachrymal fluid. Hydroxy Propyl Methyl Cellulose (HPMC K4M and E5 0LV) was further incorporated as a viscosity enhancer in order to achieve the desired consistency so as to facilitate sustained drug release. The developed formulations were evaluated for clarity, pH measurement, gelling capacity, drug content, rheological study, and in vitro drug release. Thus, in situ gel based systems containing gums can be a valuable approach for ophthalmic drug delivery when compared to conventional systems. PMID- 26949601 TI - Restricted Pax3 Deletion within the Neural Tube Results in Congenital Hydrocephalus. AB - Congenital hydrocephalus is a common birth-defect whose developmental origins are poorly understood. Pax3-null mutants show defects in myogenesis, neural tube closure, neural crest morphogenesis, and heart development that, consequently, results in embryonic lethality. Here we demonstrate that conditional deletion of the mouse Pax3 transcription factor results in fully-penetrant congenital obstructive hydrocephalus. To identify the role of Pax3 during cranial development, we deleted Pax3 within the neuroepithelium (via Pax7-Cre ), in the neural crest (via P0-Cre), and in both the neuroepithelium and the neural crest (via Wnt1-Cre). Only conditional mutants generated using Pax7-Cre or Wnt1-Cre developed early onset congenital hydrocephalus due to stenosis of the third ventricle, suggesting that loss of neuroepithelial Pax3 is sufficient to disturb third ventricle morphogenesis. Dilation of lateral ventricles occurs as early as E14.5, and lineage-mapping revealed that the neuroepithelial cells in the conditional mutants are present, but fail to undergo normal differentiation at the stenotic site. Concomitant with a narrowing of the mutant third ventricle, we detected ectopic apoptosis, reduced proliferation, and abnormal beta-catenin localization. Furthermore, consistent with the overlapping expression pattern of Pax3 and Pax7 in early cranial neuroepithelium, we demonstrated a combinatorial role, as compound Pax3/Pax7 heterozygotes display partially-penetrant congenital hydrocephalus. These murine data provide an experimental paradigm underpinning clinical observations of the presence of PAX3 mutations in some hydrocephalic patients. PMID- 26949602 TI - Acellular porcine corneal matrix as a carrier scaffold for cultivating human corneal epithelial cells and fibroblasts in vitro. AB - AIM: To investigate the feasibility of corneal anterior lamellar reconstruction with human corneal epithelial cells and fibroblasts, and an acellular porcine cornea matrix (APCM) in vitro. METHODS: The scaffold was prepared from fresh porcine corneas which were treated with 0.5% sodium dodecyl sulfate (SDS) solution and the complete removal of corneal cells was confirmed by hematoxylin eosin (HE) staining and 4', 6-diamidino-2-phenylindole (DAPI) staining. Human corneal fibroblasts and epithelial cells were cultured with leaching liquid extracted from APCM, and then cell proliferative ability was evaluated by MTT assay. To construct a human corneal anterior lamellar replacement, corneal fibroblasts were injected into the APCM and cultured for 3d, followed by culturing corneal epithelial cells on the stroma construction surface for another 10d. The corneal replacement was analyzed by HE staining, and immunofluorescence staining. RESULTS: Histological examination indicated that there were no cells in the APCM by HE staining, and DAPI staining did not detect any residual DNA. The leaching liquid from APCM had little influence on the proliferation ability of human corneal fibroblasts and epithelial cells. At 10d, a continuous 3 to 5 layers of human corneal epithelial cells covering the surface of the APCM was observed, and the injected corneal fibroblasts distributed within the scaffold. The phenotype of the construction was similar to normal human corneas, with high expression of cytokeratin 12 in the epithelial cell layer and high expression of vimentin in the stroma. CONCLUSION: Corneal anterior lamellar replacement can be reconstructed in vitro by cultivating human corneal epithelial cells and fibroblasts with an acellular porcine cornea matrix. This laid the foundation for the further transplantation in vivo. PMID- 26949603 TI - Inhibition of zymosan-induced cytokine and chemokine expression in human corneal fibroblasts by triptolide. AB - AIM: To investigate the effects of triptolide on proinflammatory cytokine and chemokine expression induced by the fungal component zymosan in cultured human corneal fibroblasts (HCFs). METHODS: HCFs were cultured in the absence or presence of zymosan or triptolide. The release of interleukin (IL)-6, IL-8, and monocyte chemoattractant protein-1 (MCP-1) into culture supernatants was measured with enzyme-linked immunosorbent assays. The cellular abundance of the mRNAs for these proteins was determined by reverse transcription and real-time polymerase chain reaction analysis. The phosphorylation of mitogen-activated protein kinases (MAPKs) and the endogenous nuclear factor-kappaB (NF-kappaB) inhibitor IkappaB alpha was examined by immunoblot analysis. The release of lactate dehydrogenase (LDH) activity from HCFs was measured with a colorimetric assay. RESULTS: Triptolide inhibited the zymosan-induced release of IL-6, IL-8, and MCP-1 from HCFs in a concentration- and time-dependent manner. It also inhibited the zymosan induced up-regulation of IL-6, IL-8, and MCP-1 mRNA abundance in these cells. Furthermore, triptolide attenuated zymosan-induced phosphorylation of the MAPKs extracellular signal-regulated kinase (ERK), c-Jun NH2-terminal kinase (JNK), and p38 as well as the phosphorylation and degradation of IkappaB-alpha. Triptolide did not exhibit cytotoxicity for HCFs. CONCLUSION: Triptolide inhibited proinflammatory cytokine and chemokine production by HCFs exposed to zymosan, with this action likely being mediated by suppression of MAPK and NF-kappaB signaling pathways. This compound might thus be expected to limit the infiltration of inflammatory cells into the cornea associated with fungal infection. PMID- 26949600 TI - Post splenectomy related pulmonary hypertension. AB - Splenectomy predisposes patients to a slew of infectious and non-infectious complications including pulmonary vascular disease. Patients are at increased risk for venous thromboembolic events due to various mechanisms that may lead to chronic thromboembolic pulmonary hypertension (CTEPH). The development of CTEPH and pulmonary vasculopathy after splenectomy involves complex pathophysiologic mechanisms, some of which remain unclear. This review attempts congregate the current evidence behind our understanding about the etio-pathogenesis of pulmonary vascular disease related to splenectomy and highlight the controversies that surround its management. PMID- 26949604 TI - Aquaporin-1 down regulation associated with inhibiting cell viability and inducing apoptosis of human lens epithelial cells. AB - AIM: To investigate the role of Aquaporin-1 (AQP-1) in lens epithelial cells (LECs) and its potential target genes. AQP-1 is specifically expressed in LECs of eyes and is significant for lens homeostasis and transparency maintenance. Herein, AQP-1 expression in LECs was investigated to evaluate its influence on cell survival in association with its potential role in cataract formation. METHODS: LECs were transfected with lentivirus carrying AQP-1 small interfering RNA (siRNA). Real-time polymerase chain reaction (PCR) and Western blotting were conducted to detect AQP-1 expression in LECs from different groups. Meanwhile, cell counting kit-8 (CCK-8) assay and flow cytometry were performed to measure LEC proliferation and apoptosis, respectively. RESULTS: AQP-1 expression was significantly reduced in LECs, both at mRNA and protein levels (P<0.05), after siRNA treatment. Decreased cell viability was detected by CCK-8 assay in LECs with siRNA interference, compared to control cells (P<0.05). The apoptosis rate significantly increased in cells after siRNA interference (P<0.05). CONCLUSION: The decreased cell viability following AQP-1 down regulation is largely due to its induction of apoptosis of LECs. AQP-1 reduction might lead to changes of physiological functions in LECs, which might be associated with the occurrence and development of cataracts. PMID- 26949606 TI - Effect of NF-kappaB p65 antisense oligodeoxynucleotide on transdifferentiation of normal human lens epithelial cells induced by transforming growth factor-beta2. AB - AIM: To study the inhibition of nuclear factor kappa-B p65 (NF-kappaB p65) antisense oligodeoxynucleotide (ASODN) on transdifferentiation of normal human lens epithelial cells induced by transforming growth factor-beta2 (TGF-beta2) in vitro. METHODS: NF-kappaB p65 ASODN and NF-kappaB p65 missense oligodeoxynucleotide (MSODN) were designed and synthesized. Human lens epithelial cell line (HLE B-3) cells were prepared for study and divided into 7 groups. Control group was HLE B-3 cells cultured in vitro in dulbecco's modified eagle medium (DMEM). T1, T2, and T3 group were HLE B-3 cells cultured in vitro in DMEM with 10 ng/mL TGF-beta2 for 6h, 12h, 24h respectively. A+T group was HLE B-3 cells cultured with 10 ng/mL TGF-beta2 for 24h after transfected by NF-kappaB p65 ASODN for 24h. M+T group was HLE B-3 cells cultured with 10 ng/mL TGF-beta2 for 24h after transfected by NF-kappaB p65 MSODN for 24h. The negative control group was HLE B-3 cells cultured with 10 ng/mL TGF-beta2 for 24h after cultured with transfer agent (HiPerFect) for 24h. Cell morphology was observed at different time points using an inverted microscope. The expression of NF-kappaB p65 mRNA was detected with reverse transcription-polymerase chain reaction (RT-PCR), and the expression of alpha-smooth muscle actin (alpha-SMA) protein was assayed with ELISA. RESULTS: With the TGF-beta2 stimulation prolongation, the expression of NF kappaB p65 mRNA and alpha-SMA protein increased in T1, T2, T3 groups compared with the control group, and the difference was statistically significant (P<0.05). NF-kappaB p65 ASODN lowered the expression of NF-kappaB p65 mRNA and alpha-SMA protein induced by TGF-beta2. NF-kappaB p65 MSODN and HiPerFect did not lower the expression of NF-kappaB p65 mRNA and alpha-SMA protein induced by TGF beta2. The difference between control group and A+T group was not statistically significant (P>0.05), but the difference among A+T group and other groups was statistically significant (P<0.05). CONCLUSION: NF-kappaB p65 ASODN could lower the expression of NF-kappaB p65 mRNA and alpha-SMA protein induced by TGF-beta2, and antagonized TGF-beta2-induced transdifferentiation of HLE B-3 in vitro. NF kappaB p65 ASODN could be used as a new biological therapeutic target of posterior capsular opacification. PMID- 26949605 TI - Effects of lentiviral RNA interference-mediated downregulation of integrin-linked kinase on biological behaviors of human lens epithelial cells. AB - AIM: To investigate the effects of lentivirus (LV) mediated integrin-linked kinase (ILK) RNA interference (RNAi) on biological behaviors of human lens epithelial cells (LECs). METHODS: Human cataract LECs and immortalized human LEC line, human lens epithelial (HLE) B-3 cells were transfected by lentiviral vector expressing ILK-specific short hairpin RNA (shRNA) and then stimulated by transforming growth factor-beta (TGF-beta), the silencing of ILK gene and protein was identified by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot methods; biological behaviors including cell cycle and apoptosis, cell morphology, alpha-smooth muscle actin (SMA) stress fiber formation and cell migration were examined. RESULTS: Remarkable decreases of ILK protein expression were detected in LECs carrying lentiviral ILK-shRNA vector; flow cytometry revealed arresting of cell cycle progression through the G1/S transition and higher apoptosis rate in ILK-RNAi-LV transfected cells. Less alpha-SMA stress fiber formation and migration was observed in ILK-RNAi-LV transfected LECs. CONCLUSION: The present study demonstrated that ILK was an important regulator for LECs proliferation and migration. LV mediated ILK RNAi is an effective way to decrease ILK-regulated cell growth by arresting cell cycle progression and increasing cell apoptosis, as well as, to prevent cell migration by inhibiting TGF-beta induced alpha-SMA stress fiber formation. Thus, LV mediated ILK RNAi might be useful to prevent posterior capsular opacification. PMID- 26949608 TI - Differentiation of isolated human umbilical cord mesenchymal stem cells into neural stem cells. AB - AIM: To investigate whether umbilical cord human mesenchymal stem cell (UC-MSC) was able to differentiate into neural stem cell and neuron in vitro. METHODS: The umbilical cords were obtained from pregnant women with their written consent and the approval of the Clinic Ethnics Committee. UC-MSC were isolated by adherent culture in the medium contains 20% fetal bovine serum (FBS), then they were maintained in the medium contain 10% FBS and induced to neural cells in neural differentiation medium. We investigated whether UC-MSC was able to differentiate into neural stem cell and neuron in vitro by using flow cytometry, reverse transcriptase-polymerase chain reaction (RT-PCR) and immunofluorescence (IF) analyzes. RESULTS: A substantial number of UC-MSC was harvested using the tissue explants adherent method at about 2wk. Flow cytometric study revealed that these cells expressed common markers of MSCs, such as CD105 (SH2), CD73 (SH3) and CD90. After induction of differentiation of neural stem cells, the cells began to form clusters; RT-PCR and IF showed that the neuron specific enolase (NSE) and neurogenic differentiation 1-positive cells reached 87.3%+/-14.7% and 72.6%+/ 11.8%, respectively. Cells showed neuronal cell differentiation after induced, including neuron-like protrusions, plump cell body, obviously and stronger refraction. RT-PCR and IF analysis showed that microtubule-associated protein 2 (MAP2) and nuclear factor-M-positive cells reached 43.1%+/-10.3% and 69.4%+/ 19.5%, respectively. CONCLUSION: Human umbilical cord derived MSCs can be cultured and proliferated in vitro and differentiate into neural stem cells, which may be a valuable source for cell therapy of neurodegenerative eye diseases. PMID- 26949607 TI - Involvement of microRNA-181a and Bim in a rat model of retinal ischemia reperfusion injury. AB - AIM: To investigate the changes in the expression of microRNA-181a (miR-181a) and Bim in a rat model of retinal ischemia-reperfusion (RIR), to explore their target relationship in RIR and their involvement in regulating apoptosis of retinal ganglion cells (RGCs). METHODS: Target gene prediction for miR-181a was performed with the aid of bioinformatics and Bim was identified as a potential target gene of miR-181a. A rat model of RIR was created by increasing the intraocular pressure. RGCs in the flatmounted retinas were labeled with Brn3, a marker for alive RGCs, by immunofluorescent staining. The changes in the number of RGCs after RIR were recorded. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used to determine the expression level of miR-181a in the retina. Bim/Brn3 double immunofluorescence was used to detect the localization of Bim. The expression of Bim in the retina was determined with the aids of Western blot and qRT-PCR. RESULTS: Compared with the negative control group, the density of RGCs was significantly lower in the ischemia/reperfusion (I/R)-24h and I/R-72h groups (P<0.001). The expression level of miR-181a started to decrease at 0h after RIR, and further decreased at 24h and 72h compared with the negative control group (P<0.001). Bim was significantly upregulated at 12h after RIR (P<0.05) and reached peak at 24, 72h compared with the negative control group (P<0.01). Pearson correlation analysis showed that the expression level of Bim was negatively correlated with the expression level of miR-181a and the density of RGCs. CONCLUSION: Bim may be a potential target gene of miR-181a. Both miR 181a and Bim are involved in RGCs death in RIR. RIR may promote RGCs apoptosis in the retina via downregulation of miR-181a and its inhibition on Bim expression. PMID- 26949609 TI - Changing trends in corneal graft surgery: a ten-year review. AB - AIM: To review indications and corneal tissue use for penetrating and lamellar surgery between 2002 and 2011. METHODS: The surgical reports of corneal grafts performed during 2002-2011, using tissues supplied by the Eye Bank of Piedmont (Italy), were reviewed retrospectively. Patient demographic data, date of intervention, indication for surgery, and surgical technique used were recorded. Surgical techniques included penetrating keratoplasty (PK), deep anterior lamellar keratoplasty (DALK) and endothelial keratoplasty (EK). The chi (2) test was used to compare the distribution of indications and types of surgical technique used, for corneal grafts done during 2002-2006 versus those done during 2007-2011. RESULTS: The number of corneal grafts increased by 30.7% from 2002 2006 to 2007-2011 (from 1567 to 2048). Comparing the two periods, both main indications and surgical techniques changed significantly. In 2007-2011, the proportion of interventions for aphakic/pseudophakic bullous keratopathy (from 16.8% to 21.3%), graft failure (from 16.4% to 19.1%) and Fuchs endothelial dystrophy (from 12.8% to 16.7%) all increased significantly (P<0.05), while those for keratoconus decreased significantly (from 35.6% to 27.3%; P<0.001). In 2007 2011, the proportion of PK decreased significantly (from 92.4% to 57.2%; P<0.001) while that of EK and DALK went from 0.4% to 30.2% (P<0.001) and from 7.2% to 12.6% (P<0.001) respectively. CONCLUSION: During 2002-2011 the number of interventions increased significantly for corneal endothelial diseases and graft failure. The growing demand for interventions for these diseases corresponded to the widespread adoption of EK techniques. The use of DALK also increased, but more moderately than EK procedures. PMID- 26949610 TI - Corneal infection in Shandong peninsula of China: a 10-year retrospective study on 578 cases. AB - AIM: To determine the epidemiological characteristics, clinical signs, laboratory findings, and outcomes in patients with corneal infection in Shandong peninsula of China. METHODS: The medical records of 578 inpatients (578 eyes) with corneal infection were reviewed retrospectively for demographic characteristics, risk factors, seasonal variation, clinical signs, laboratory findings, and treatment strategy. Patient history, ocular examination findings using slit-lamp biomicroscopy, laboratory findings resulted from microbiological cultures, and treatment. RESULTS: Fungal keratitis constituted 58.48% of cases of infectious keratitis among the inpatients, followed by herpes simplex keratitis (20.76%), bacterial keratitis (19.03%) and acanthamoeba keratitis (1.73%). The most common risk factor was corneal trauma (71.80%). The direct microscopic examination (338 cases) using potassium hydroxide (KOH) wet mounts was positive in 296 cases (87.57%). Among the 298 fungal culture-positive cases, Fusarium species were the most common isolates (70.47%). A total of 517 cases (89.45%) received surgical intervention, including 255 (44.12%) cases of penetrating keratoplasty, 74 (12.80%) cases of lamellar keratoplasty which has become increasingly popular, and 77 cases (13.32%) of evisceration or enucleation. CONCLUSION: At present, infectious keratitis is a primary corneal disease causing blindness in China. With Fusarium species being the most commonly identified pathogens, fungal keratitis is the leading cause of severe infectious corneal ulcers in Shandong peninsula of China. PMID- 26949612 TI - Management strategies in malignant glaucoma secondary to antiglaucoma surgery. AB - AIM: To assess the outcomes of various interventions for malignant glaucoma (MG). METHODS: A retrospective, comparative analysis of case series were performed on 38 eyes of 35 MG patients treated in Aier Eye Hospital of Wuhan between Jan. 2009 and Dec. 2012. Numerous treatments were administered including medical therapy, neodymium: yttrium- aluminium-garnet (Nd:YAG) laser posterior capsulotomy and hyaloidotomy as well as 3 surgical options. The characteristic, treatment option and outcome of MG in every individual patient were reviewed and analyzed among all patients who were followed up for an average of 27.1+/-9.1mo. RESULTS: Four eyes of 3 patients achieved complete resolution with medical therapy. Nd:YAG laser posterior capsulotomy and hyaloidotomy were performed on 2 eyes, both of which achieved resolution after initial intervention. Thirty-two eyes were given surgical treatments with anterior vitrectomy- reformation of anterior chamber in 13 eyes, phacoemulsification- intraocular lens implantation in 10 eyes and phacoemulsification- intraocular lens implantation- anterior vitrectomy in 9 eyes. Resolution of MG was seen in almost all patients. The mean intraocular pressure decreased from 41.87+/-9.44 mm Hg at presentation to 15.84+/-3.73 mm Hg at the last visit. The mean anterior chamber depth improved from 0.28+/-0.27 mm to 2.28+/-0.19 mm. Twenty eyes with preoperative visual acuity better than counting figure/ 50 cm had various visual improvements. Complications occurred in 3 eyes of 3 patients including bleeding at the entry site of vitrectomy into vitreous cavity, corneal endothelial decompensation and allergic to atropine respectively. CONCLUSION: MG occurs as a result of multiple mechanisms involved simultaneously or sequentially.Medical therapy is advocated as the initial treatment, laser therapy is beneficial in pseudophakic eyes, and different surgical regimen is recommended based on different pathogenesis of MG when non response occurs to nonsurgical management. MG can be managed successfully by appropriate and timely interventions with good visual outcome. PMID- 26949611 TI - Comparison of anterior section parameters using anterior segment optical coherence tomography and ultrasound biomicroscopy in myopic patients after ICL implantation. AB - AIM: To compare the agreement of anterior chamber depth (ACD) and central vault measurements obtained by anterior segment optical coherence tomography (AS-OCT) and ultrasound biomicroscopy (UBM) of post surgical high myopic eyes with posterior chamber phakic intraocular lens (Visian ICL; STAAR Surgical) implantation. METHODS: Fifty-two phakic eyes of 28 high myopic patients who underwent implantable Collamer lens (ICL) surgery for the correction of high myopia were studied. The postoperative ACD, the distance between the corneal endothelium and the anterior surface of ICL (cornea-ICL) and the central vault were measured with the AS-OCT system and the UBM system. Intraclass correlation coefficient (ICC) and the Bland-Altman plot were used to evaluate the repeatability and agreement of two devices. RESULTS: The mean ACD, cornea-ICL and central vault in the 52 phakic eyes after ICL surgery was 3.19+/-0.28 mm, 2.47+/ 0.28 mm, 0.50+/-0.19 mm by AS-OCT and 3.13+/-0.25 mm, 2.49+/-0.25 mm, 0.44+/-0.19 mm by UBM, respectively. Pairwise comparison of ACD and central vault measurements showed significant differences between AS-OCT and UBM (P<0.05). However, no statistically significant difference was found between these imaging techniques in cornea-ICL (P>0.05). The Pearson correlation coefficient (r) between AS-OCT and UBM measurements for ACD, cornea-ICL and vault was 0.88, 0.80 and 0.89, respectively (P<0.001). The ICC was 0.89-0.94 for the measurements of AS-OCT and UBM. Bland-Altman analysis showed the 95% limits of agreement of ACD, cornea-ICL, central vault measurements between these two devices were -0.20 to 0.32 mm, -0.36 to 0.32 mm and -0.12 to 0.24 mm, respectively. CONCLUSION: Central ACD and vault measurements using AS-OCT demonstrated a slight significantly higher value than using UBM in phakic eyes after ICL surgery. These two devices should not be used interchangeably for measurements of central ACD and vault in patients after phakic intraocular lens implantation. PMID- 26949613 TI - Bimatoprost/timolol fixed combination (BTFC) in patients with primary open angle glaucoma or ocular hypertension in Greece. AB - AIM: To evaluate the efficacy and tolerability of the fixed combination of bimatoprost 0.03% and timolol 0.5% (BTFC) in patients in Greece with primary open angle glaucoma (POAG) or ocular hypertension (OHT) whose previous therapy provided insufficient lowering of intraocular pressure (IOP). METHODS: A multicenter, prospective, open-label, non-interventional, observational study of the use of BTFC in clinical practice was conducted at 41 sites in Greece. The primary endpoint was the reduction in IOP from baseline at study end, approximately 12wk after initiation of BTFC therapy. RESULTS: A total of 785 eligible patients were enrolled in the study and 97.6% completed the study. The mean+/-SD IOP reduction from baseline at 12wk after initiation of BTFC was 6.3+/ 2.8 mm Hg (n=764; P<0.001). In patients (n=680) who replaced their previous IOP lowering monotherapy (a single drug, or a fixed combination of 2 drugs in a single ophthalmic drop) with once-daily BTFC, the mean+/-SD IOP reduction from baseline at 12wk was 6.2+/-2.8 mm Hg (P<0.001). IOP was reduced from baseline in 99.2% of patients, and 58.0% of patients reached or exceeded their target IOP. Substantial mean IOP reductions were observed regardless of the previous therapy. BTFC was well tolerated, with 96.0% of patients who completed the study rating the tolerability of BTFC as "good" or "very good." Adverse events were reported in 8.3% of patients; only 0.6% of patients discontinued the study due to adverse events. CONCLUSION: In clinical practice in Greece, BTFC is well tolerated and effectively lower the IOP in patients with POAG or OHT who requires additional IOP lowering on their previous therapy. PMID- 26949615 TI - Macular edema after cataract surgery in diabetic eyes evaluated by optical coherence tomography. AB - AIM: To assess quantitative changes of the macula in diabetic eyes after cataract surgery using optical coherence tomography (OCT) and to estimate the incidence of development or worsening of macular edema (ME) in diabetic eyes with or without pre-existing ME. METHODS: In this prospective, observational study, 92 eyes of 60 diabetic patients who underwent cataract surgery were evaluated before surgery and 1, 3mo after surgery using OCT. Macular thickness was measured with OCT at nine macular subfields defined by the 9 zones early treatment of diabetic retinopathy study (ETDRS), as well as total macular volume obtained by OCT at 1, 3mo after surgery were compared with baseline features obtained before surgery. In addition, the incidence of development or worsening of ME was analyzed in diabetic eyes with or without pre-existing ME. RESULTS: The central subfield mean thickness increased 21.0 um and 25.5 um at 1, 3mo follow-up, respectively (P<0.01). The average thickness of inner ring and outer ring increased 14.2 um and 9.5 um at 1mo, 18.2 um and 12.9 um at 3mo. Central-involved ME developed in 12 eyes at 3mo, including 4 eyes with pre-existing central-involved and 8 eyes with pre-existing non-central involved ME. Pre-existing diabetic macular edema (DME) was significantly associated with central-involved ME development (P<0.001). CONCLUSION: A statistically significant increase could be detected in the central subfield as well as perifoveal and parafoveal sectors though the increase was mild. And eyes with pre-operative DME prior to cataract surgery are at higher risk for developing central-involved ME. PMID- 26949614 TI - Comparison of intraocular pressure measurements with different contact tonometers in young healthy persons. AB - AIM: To analyze the correlation of Goldmann applanation tonometer (GAT), I-Care tonometer and Tono-Pen tonometer results in young healthy persons, and to investigate the influence of central corneal thickness (CCT) on intraocular pressure (IOP) measurements recorded with these tonometers. METHODS: We conducted a pilot clinical study in 78 eyes of 78 subjects aged 22-28 years old (44 women and 34 men; mean age 23.8+/-1.19y). IOP was measured using GAT, I-Care and Tono Pen tonometers, followed by measurements of CCT. Statistical analysis was performed using SPSS 20.0. RESULTS: The mean IOPs and standard deviation (+/-SD) for GAT, I-Care and Tono-Pen were 15.62+/-2.281 mm Hg, 16.29+/-2.726 mm Hg and 16.32+/-2.393 mm Hg, respectively. The mean CCT was 555.15+/-29.648 um. Clear positive correlations between GAT and I-Care, GAT and Tono-Pen, and I-Care and Tono-Pen tonometers were found (r=0.867, P<0.001; r=0.861, P<0.001; r=0.915, P<0.001, respectively). In comparison between devices, Bland-Altman analysis showed a significant mean difference (MD) in the measurements by GAT and I-Care of -0.679 mm Hg and by GAT and Tono-Pen of -0.705 mm Hg ( P<0.001), but there was no significant difference between I-Care and Tono-Pen ( P>0.05). Both non-gold standard tonometers were affected by CCT; that is, both I-Care and Tono-Pen tonometer values were significantly higher with higher CCT means (>555 um; MD= 1.282, P<0.001; MD=-0.949, P<0.001, respectively) compared with GAT. CONCLUSION: Both I-Care and Tono-Pen tonometers overestimated IOP compared with the GAT values. Either the I-Care or Tono-Pen tonometer could be used instead of GAT because there was no significant difference between their results. Higher CCT values (>555 um) were associated with overestimated IOP values. PMID- 26949616 TI - Predictors of short-term outcomes related to central subfield foveal thickness after intravitreal bevacizumab for macular edema due to central retinal vein occlusion. AB - AIM: To investigate the predictive factors for short-term effects of intravitreal bevacizumab injections on central subfield foveal thickness (CSFT) in patients with macular edema (ME) secondary to central retinal vein occlusion (CRVO). METHODS: This was a retrospective study in 60 eyes treated with intravitreal bevacizumab injections for ME due to CRVO. Follow-up was three months. The Early Treatment Diabetic Retinopathy Study (ETDRS) score and CSFT measured by spectral domain optical coherence tomography (SD-OCT) were used to observe the changes in best-corrected visual acuity (BCVA). Baseline BCVA, CSFT, age, CRVO duration and the presence of cystoid macular edema (CME) or subretinal fluid (SRF) were analyzed as potential predictive factors of the effects of intravitreal bevacizumab injections. RESULTS: BCVA improved from 0.9 logMAR at baseline to 0.6 logMAR at 3mo, which was associated with a significant reduction in CSFT from 721 um to 392 um 3mo after injection. About 50% of CME cases and more than 90% of SRF cases responded to treatment with a complete resolution at 3mo. Age (P=0.036) and low baseline CSFT (P=0.037) were associated with a good 3-month prognosis. Patients >60 years old achieved better CME resolution (P=0.031) and lower CSFT at 3mo (305 um vs 474 um, P=0.003). CONCLUSION: Intravitreal bevacizumab significantly improved visual acuity and CSFT in patients with CRVO after 3mo. Older age and lower baseline CSFT were good predictors of short-term CSFT outcomes. The retinal thickness response to bevacizumab might depend on the resolution of CME rather than SRF. PMID- 26949617 TI - Reflectivity and thickness analysis of epiretinal membranes using spectral-domain optical coherence tomography. AB - AIM: To compare thickness and reflectivity spectral domain optical coherence tomography (SD-OCT) findings in patients with idiopathic epiretinal membranes (ERMs), before and after ERM peeling surgery, with normal controls. METHODS: A retrospective study analyzed SD-OCTs of eyes with ERMs undergoing ERM peeling surgery by one surgeon from 2008 to 2010 and normal control eyes. SD-OCTs were analyzed using a customized algorithm to measure reflectivity and thickness. The relationship between the SD-OCT findings and best corrected visual acuity (BCVA) outcomes was also studied. RESULTS: Thirty-four ERM eyes and 12 normal eyes were identified. Preoperative eyes had high reflectivity and thickness of the group of layers from the internal limiting membrane (ILM) to the retinal pigment epithelium (RPE) and the group of layers from the ILM to the external limiting membrane (ELM). The values of reflectivity of these two groups of layers decreased postoperatively, but were still higher than normal eyes. In contrast, preoperative eyes had lower reflectivity of two 10*15 pixel regions of interest (ROIs) incorporating: 1) ELM + outer nuclear layer (ONL) and 2) photoreceptor layer (PRL) + RPE, compared to controls. The values of reflectivity of these ROIs increased postoperatively, but were still lower than normal controls. A larger improvement in BCVA postoperatively was correlated with a greater degree of abnormal preoperative reflectivity and thickness findings. CONCLUSION: Quantitative differences in reflectivity and thickness between preoperative, postoperative, and normal SD-OCTs allow assessment of changes in the retina secondary to ERM. Our study identified hyperreflective inner retina changes and hyporeflective outer retina changes in patients with ERMs. SD-OCT quantitative measures of reflectivity and/or thickness of specific groups of retinal layers and/or ROIs correlate with improvement in BCVA. PMID- 26949618 TI - Study of retinal vessel oxygen saturation in ischemic and non-ischemic branch retinal vein occlusion. AB - AIM: To explore how oxygen saturation in retinal blood vessels is altered in ischemic and non-ischemic branch retinal vein occlusion (BRVO). METHODS: Fifty BRVO eyes were divided into ischemic (n=26) and non-ischemic (n=24) groups, based on fundus fluorescein angiography. Healthy individuals (n=52 and n=48, respectively) were also recruited as controls for the two groups. The mean oxygen saturations of the occluded vessels and central vessels were measured by oximetry in the BRVO and control groups. RESULTS: In the ischemic BRVO group, the occluded arterioles oxygen saturation (SaO2-A, 106.0%+/-14.3%), instead of the occluded venule oxygen saturation (SaO2-V, 60.8%+/-9.4%), showed increases when compared with those in the same quadrant vessels (SaO2-A, 86.1%+/-16.5%) in the contralateral eyes (P<0.05). The oxygen saturations of the central vessels showed similar trends with those of the occluded vessels. In the non-ischemic BRVO group, the occluded and central SaO2-V and SaO2-A showed no significant changes. In both the ischemic and non-ischemic BRVOs, the central SaO2-A was significantly increased when compared to healthy individuals. CONCLUSION: Obvious changes in the occluded and central SaO2-A were found in the ischemic BRVO group, indicating that disorders of oxygen metabolism in the arterioles may participate in the pathogenesis of ischemic BRVO. PMID- 26949619 TI - Visual outcome after removal of silicone oil in patients undergoing retinectomy for complex retinal detachment. AB - AIM: To evaluate the functional outcome after removal of silicone oil (ROSO) in patients undergoing retinectomy for complex retinal detachment. METHODS: We performed a retrospective case note review of patients who underwent ROSO after retinectomy for complex retinal detachment. Patients with less than 6mo follow up and recurrent retinal detachment following ROSO were excluded. RESULTS: Thirty six patients were included. The mean best corrected visual acuity (BCVA) pre-ROSO was 1.13 logMAR (SD 0.5). The mean BCVA 3mo following ROSO was 1.16 logMAR (SD 0.53), 6mo following ROSO 1.13 (SD 0.63), and 12mo following ROSO 1.18 (SD 0.69). At 12mo after ROSO, the BCVA improved in 38.9% of patients, remained unchanged in 25%, and deteriorated in 36.1%, although there was no statistical significant difference in BCVA after ROSO at 3, 6 and 12mo (P=0.93). The size of retinectomy ranged from 15 degrees to 270 degrees (SD 53) and did not influence the visual outcome (P=0.11). CONCLUSION: There was no statistically significanT difference in BCVA between pre- and post- ROSO following retinectomy for complex retinal detachment. There was no statistical difference in visual outcome related to the size of the retinectomy. PMID- 26949620 TI - C-reactive protein and diabetic retinopathy in Chinese patients with type 2 diabetes mellitus. AB - AIM: To investigate the relationship between C-reactive protein (CRP) and diabetic retinopathy (DR) in a cohort of Chinese patients with type 2 diabetes mellitus (T2DM). METHODS: Community-based observational cohort study. There were 1131 participants recruited from November 2009 to September 2011 in Desheng community in urban Beijing. Patients diagnosed T2DM were recruited and underwent a standardized evaluation consisting of a questionnaire, ocular and anthropometric examinations and laboratory investigation. The presence and severity of DR were assessed by seven fields 30 degrees color fundus photographs. Subjects were then classified into groups with no DR, any DR, or vision-threatening DR. CRP was analyzed from serum of study subjects. RESULTS: A total of 1007 patients with T2DM were included for analysis, including 408 (40.5%) men and 599 (59.5%) women. The median CRP level was 1.5 mg/L for women and 1.1 mg/L for men (P=0.004, OR 0.37, 95% CI 0.18-0.74). After adjusting for possible covariates, higher levels of CRP were associated with lower prevalence of any DR (P=0.02, OR 0.55, 95% CI 0.35-0.89), but not associated with vision threatening DR (P=0.62, OR 0.78, 95% CI 0.28-2.14). After stratification by sex, the inverse association between CRP and DR was found to be statistically significant in men (P=0.006, OR 0.35, 95% CI 0.16-0.73), but not in women (P=0.58, OR 0.88, 95% CI 0.29-1.16). CONCLUSION: The data drawn from a Chinese population with T2DM suggest that increasing CRP levels may be inversely associated with development of DR. PMID- 26949622 TI - Efficacy and economic analysis of Ex-PRESS implantation versus trabeculectomy in uncontrolled glaucoma: a systematic review and Meta-analysis. AB - AIM: To systematically review the current evidence based on the efficacy and cost of Ex-PRESS implantation and trabeculectomy (Trab) for uncontrolled glaucoma. METHODS: Clinical trials were identified by electronic databases (PubMed, EMBASE, ISI Web of science and Cochrane library), and data, such as intraocular pressure (IOP), the complete and qualified success rate, the postoperative complications and the cost, were exacted from these relevant studies. Weighted mean difference (WMD), odds ratio (OR) and 95% confidence intervals (CIs) were calculated and were pooled using a random-effects model. RESULTS: Eleven relevant publications and two abstracts met the inclusion criteria. The efficacy of Ex-PRESS was similar to that of Trab in the percentage of IOP reduction (IOPR %) at 1, 2y (WMD: -2.01; 95% CI: -7.92-3.90; P=0.50 and WMD: 2.89; 95% CI: -8.05-13.83; P=0.60, respectively). Ex-PRESS possessed a significant higher complete and qualified success rate (OR: 1.59; 95% CI: 1.07-2.35; P=0.02 and OR: 1.74; 95% CI: 1.06-2.86; P=0.03, respectively). Moreover, Ex-PRESS exerted a significantly lower frequency of hypotony and hyphema than Trab (OR: 0.39; 95% CI: 0.21-0.72; P=0.003 and OR: 0.27; 95% CI: 0.10-0.69; P=0.003, respectively). However, there was no consistent result on the cost between the two groups according to the previous three studies. CONCLUSION: Both Trab and Ex-PRESS have equivalent efficacy in lowering IOP, yet Ex-PRESS had a lower risk of hypotony and hyphema than Trab. Nevertheless, whether the cost of Ex-PRESS was less than that of Trab should be further investigated to ensure evidence-based conclusion in the long run. PMID- 26949621 TI - Comparison of Snellen and Early Treatment Diabetic Retinopathy Study charts using a computer simulation. AB - AIM: To compare accuracy, reproducibility and test duration for the Snellen and the Early Treatment Diabetic Retinopathy Study (ETDRS) charts, two main tools used to measure visual acuity (VA). METHODS: A computer simulation was programmed to run multiple virtual patients, each with a unique set of assigned parameters, including VA, false-positive and false-negative error values. For each virtual patient, assigned VA was randomly chosen along a continuous scale spanning the range between 1.0 to 0.0 logMAR units (equivalent to 20/200 to 20/20). Each of 30 000 virtual patients were run ten times on each of the two VA charts. RESULTS: Average test duration (expressed as the total number of characters presented during the test +/-SD) was 12.6+/-11.1 and 31.2+/-14.7 characters, for the Snellen and ETDRS, respectively. Accuracy, defined as the absolute difference (+/ SD) between the assigned VA and the measured VA, expressed in logMAR units, was superior in the ETDRS charts: 0.12+/-0.14 and 0.08+/-0.08, for the Snellen and ETDRS charts, respectively. Reproducibility, expressed as test-retest variability, was superior in the ETDRS charts: 0.23+/-0.17 and 0.11+/-0.09 logMAR units, for the Snellen and ETDRS charts, respectively. CONCLUSION: A comparison of true (assigned) VA to measured VA, demonstrated, on average, better accuracy and reproducibility of the ETDRS chart, but at the penalty of significantly longer test duration. These differences were most pronounced in the low VA range. The reproducibility using a simulation approach is in line with reproducibility values found in several clinical studies. PMID- 26949623 TI - Macular laser photocoagulation with or without intravitreal triamcinolone pretreatment for diabetic macular edema: a result from five randomized controlled trials. AB - AIM: To assess possible benefits of intravitreal triamcinolone acetonide (IVTA) injection as pretreatment for macular laser photocoagulation (MLP) in patients with diabetic macular edema (DME). METHODS: Published randomized controlled trials (RCTs) concerning MLP with or without IVTA pretreatment for DME were retrieved from databases CNKI, Medline, EMbase, Web of Science, and the Cochrane Library. A Meta-analysis on eligible studies was conducted using RevMan 5.0 software. Two investigators independently assessed the quality of the trials and extracted data. Main outcome measures included the change in best corrected visual acuity (BCVA), difference in central macular thickness (CMT) and adverse events reporting in particular elevated intraocular pressure within the follow-up period. The results were pooled using weight mean difference (WMD) or odds risk (OR) with their corresponding 95% confidence intervals (CI). A fixed- or random effect model was employed depending on the heterogeneity of the inclusion trials. RESULTS: Finally, five independent RCTs were identified and used for comparing MLP with IVTA pretreatment (131 eyes) with MLP alone (133 eyes, control group). The overall study quality was relatively higher according to the modified Jadad scale. The Meta-analysis showed that MLP with IVTA pretreatment significantly reduced CMT at one, three and six months (P=0.002, 0.0003 and 0.04, respectively), compared with MLP alone. The IVTA pretreatment group showed statistically significant improvements in BCVA at the one-month follow up as compared with the control group (P=0.03). At three- and six-month follow up, there was a beneficial trend towards improving visual acuity in the IVTA pretreatment group without statistical significance between groups (P=0.06 and 0.20, respectively). The incidence of elevation of intraocular pressure was significantly higher in the IVTA pretreatment group than in the control group (P<0.0001). No evidence of publication bias was present according to Begg's test and Egger's test. There was a low level of heterogeneity in the included studies. CONCLUSION: This Meta-analysis indicates that MLP with IVTA pretreatment has a better therapeutic effect in terms of CMT reduction and earlier (1mo) visual improvement for patients with DME as compared with MLP alone. Further confirmation with rigorously well-designed multi-center trials is needed. PMID- 26949624 TI - Intraocular pressure elevation after intravitreal triamcinolone acetonide injection: a Meta-analysis. AB - AIM: To report on intraocular pressure (IOP) after intravitreal injections of triamcinolone acetonide. METHODS: Systematic literature review of studies that investigated the effects of an injection of triamcinolone intravitreal triamcinolone acetonide on IOP was conducted according to the Cochrane Collaboration methodology and the reported effects have been analyzed with Meta analysis. RESULTS: We found that the IOP follows an inverted-U shape pattern over time starting with an average value of 14.81+/-1.22 mm Hg before the injection, rising to a maximum of 19.48+/-2.15 mm Hg after one month of injection and falling down to 16.16+/-1.92 mm Hg after 6mo. Moreover, country of study, age, previous history of glaucoma and gender compositions matter for cross-study were different in reported IOP changes. CONCLUSION: Our findings may be helpful in determining pressure elevation risk of intravitreal triamcinolone acetonide therapy as well as comparing it with those of more recent therapies such as the anti-vascular endothelial growth factor agents. PMID- 26949625 TI - Photobiomodulation for the treatment of retinal diseases: a review. AB - Photobiomodulation (PBM), also known as low level laser therapy, has recently risen to the attention of the ophthalmology community as a promising new approach to treat a variety of retinal conditions including age-related macular degeneration, retinopathy of prematurity, diabetic retinopathy, Leber's hereditary optic neuropathy, amblyopia, methanol-induced retinal damage, and possibly others. This review evaluates the existing research pertaining to PBM applications in the retina, with a focus on the mechanisms of action and clinical outcomes. All available literature until April 2015 was reviewed using PubMed and the following keywords: "photobiomodulation AND retina", "low level light therapy AND retina", "low level laser therapy AND retina", and "FR/NIR therapy AND retina". In addition, the relevant references listed within the papers identified through PubMed were incorporated. The literature supports the conclusion that the low-cost and non-invasive nature of PBM, coupled with the first promising clinical reports and the numerous preclinical-studies in animal models, make PBM well-poised to become an important player in the treatment of a wide range of retinal disorders. Nevertheless, large-scale clinical trials will be necessary to establish the PBM therapeutic ranges for the various retinal diseases, as well as to gain a deeper understanding of its mechanisms of action. PMID- 26949626 TI - Anthocyanin can arrest the cone photoreceptor degeneration and act as a novel treatment for retinitis pigmentosa. AB - Retinitis pigmentosa (RP) is a group of heterogeneous inherited retinal diseases that is characterized by primary death rod photoreceptors and the secondary loss of cones. The degeneration of cones causes gradual constriction of visual fields, leaving the central islands that are eventually snuffed out. Studies indicate that the hyperoxia causes oxidative damage in the retina and contributes to the cone death of RP. Moreover, abundant reactive oxidative species (ROS) which are generated in cones may result in mitochondria membrane depolarization, which has been ascribed a central role in the apoptotic process and has been proposed to act as a forward feeding loop for the activation of downstream cascades. Anthocyanin is a potent antioxidant which has been evidenced to be able to counteract oxidative damages, scavenge surplus ROS, and rectify abnormities in the apoptotic cascade. Taken together with its ability to attenuate inflammation which also contributes to the etiology of RP, it is reasonable to hypothesize that the anthocyanin could act as a novel therapeutic strategy to retard or prevent cone degeneration in RP retinas, particularly if the treatment is timed appropriately and delivered efficiently. Future pharmacological investigations will identify the anthocyanin as an effective candidate for PR therapy and refinements of that knowledge would ignite the hope of restoring the visual function in RP patients. PMID- 26949627 TI - Ophthalmologic manifestations of celiac disease. AB - Celiac disease is an autoimmune disorder that affects the small intestine of genetically predisposed individuals. Ophthalmic manifestations are within the extra-intestinal manifestations, and can be divided into those of autoimmune disorders or those due to absorptive disabilities. This article reviewed the ophthalmologic manifestation of celiac disease. Ophthalmic symptoms are rare, but should be investigated in patients with celiac disease and taken into consideration as the first systemic manifestation. PMID- 26949628 TI - 8-iso-prostaglandin-F2alpha: a possible trigger or accelerator of diabetic retinopathy. PMID- 26949629 TI - Clinical comparative analysis of the outcomes with a yellow- and a violet-tinted intraocular lens. PMID- 26949630 TI - Microperimetry and spectral domain optical coherence tomography in myelinated retinal nerve fibers. PMID- 26949632 TI - A case of severe refractive changes induced by Galyfilcon A silicone hydrogel contact lenses. PMID- 26949631 TI - Rare primary presentation of chronic lymphocytic leukemia as chronic orbital space occupying lesion. PMID- 26949633 TI - Co-regulation of Dectin-1 and TLR2 in inflammatory response of human corneal epithelial cells induced by Aspergillus fumigates. AB - AIM: To investigate the co-regulation of dendritic cell-associated C-type lectin 1 (Dectin-1), Toll-like receptor 2 (TLR2), and relative chemotactic factors in the Telomease-immortalized human corneal epithelial (THCE) cells after exposure to Aspergillus fumigatus (Af) hyphae. METHODS: The normal THCE cells were investigated as control. After cultured in vitro with Af hyphae, with or without laminarin and anti-TLR2 antibody for 4, 8, 16 and 24h, THCE cells were harvested. The expression of Dectin-1, TLR2, CXCL1 and CXCL8 mRNA were measured by real-time quantitative polymerase chain reaction at the stimulation of 4, 8 and 16h separately. The protein expression of Dectin-1 and TLR2 were analyzed at 8, 16, and 24h by Western blot. RESULTS: The mRNA expression of CXCL1 and CXCL8 increased in THCE cells after stimulated by Af hyphae. The stimulatory effects on these inflammatory chemokines were shown in a dose-dependent manner and reached the peak at 8h. Af hyphae significantly stimulated the production of Dectin-1 and TLR2 in THCE cells at both mRNA and protein levels. The protein of Dectin-1 and TLR2 gradually increased till 16h. While pretreated with laminarin (a Dectin-1 inhibitor), the expression of TLR2, CXCL1 and CXCL8 all decreased dramatically at the peak point. Interestingly, when pretreated with TLR2 neutralizing antibody, the expression of Dectin-1, CXCL1 and CXCL8 also decreased dramatically at the peak point. CONCLUSION: These findings suggest that Dectin-1 and TLR2 co regulated with each other after treated with inactive Af hyphae in the THCE cells, and they contribute together to the inflammatory responses by induction of chemokines CXCL1 and CXCL8. PMID- 26949634 TI - Expression of S100B during the innate immune of corneal epithelium against fungi invasion. AB - AIM: To explore the expression of S100B in corneal epithelial cells under Aspergillus stimulation both in vivo and in vitro. METHODS: Immortalized human corneal epithelial cells (HCECs) were exposed to inactive Aspergillus fumigatus (A. fumigatus) conidia at 0, 4, 8, 12, 16, and 24h respectively. The corneas of Wistar rats were exposed to active A. fumigatus at 0, 12, 24, 48h and the normal rat corneas were used for normal control. The mRNA level of S100B was evaluated by real time quantitative reverse transcription-polymerase chain reaction (qRT PCR). S100B protein expression in cornea epithelium was detected by immunohistochemical/immunocytochemical staining (IHC/ICC). RESULTS: Histopathology revealed a significant inflammatory cell infiltration in fungal keratitis human and rat cornea. Corneal epithelial cells didn't express or rarely express S100B at baseline. A. fumigatus significantly induced S100B mRNA expression in cultured corneal epithelial cells in a time depended manner in vitro, the mRNA began to rise significantly at 8h in vitro (P<0.05) and continue to rise as time prolonged (P<0.01). In vivo, S100B mRNA level was low in the normal corneas. However, it was increased in keratitis corneas from 12h after infection (P<0.05) and reached to a peak at 24h (P<0.001). Immunochemistry revealed an obvious staining in fungal keratitis corneas as well as immortalized HCECs compared to the normal ones respectively, indicating an increased expression of S100B protein. CONCLUSION: S100B exists in corneal epithelial cells and is over-expressed under A. fumigatus stimulation. S100B may play an important role in the innate immune response of the corneal epithelium during A. fumigatus infection. PMID- 26949635 TI - Uncovering the profile of mutations of transforming growth factor beta-induced gene in Chinese corneal dystrophy patients. AB - AIM: To uncover the mutations profile of transforming growth factor beta-induced (TGFBI) gene in Chinese corneal dystrophy patients and further investigate the characteristics of genotype-phenotype correlations. METHODS: Forty-two subjects (6 unrelated families including 15 patients and 8 unaffected members, and 19 sporadic patients) of Chinese origin were subjected to phenotypic and genotypic characterization. The corneal phenotypes of patients were documented by slit lamp photography. Mutation screening of the coding regions of TGFBI was performed by direct sequencing. RESULTS: We detected four corneal dystrophy types. The most frequent phenotypes were granular corneal dystrophy (GCD) (including 3 families and 8 sporadic patients) and lattice corneal dystrophy (LCD) (including 2 families and 9 sporadic patients). The next phenotypes were corneal dystrophy of Bowman layer (CDB) (1 family and 1 sporadic patient) and epithelial basement membrane dystrophy (EBMD) (1 sporadic patient). Six distinct mutations responsible for TGFBI corneal dystrophies were identified in 30 individuals with corneal dystrophies. Those were, p.R124H mutation in 1 family and 2 sporadic patients with GCD, p.R555W mutation in 2 families and 3 sporadic patients with GCD, p.R124C mutation in 2 families and 7 sporadic patients with LCD, p.A620D mutation in 1 sporadic patient with LCD, p.H626R mutation in 1 sporadic patient with LCD, and p.R555Q in 1 family and 1 sporadic patient with CDB. No mutation was detected in the remaining 3 atypical GCD patients and 1 EBMD patient. CONCLUSION: GCD and LCD are the most frequent phenotypes in Chinese population. R555W was the most common mutation for GCD; R124C was the most common mutation for LCD. Our findings extend the mutational spectrum of TFGBI, and this is the extensively delineated TGFBI mutation profile associated with the various corneal dystrophies in the Chinese population. PMID- 26949636 TI - Effect of vasoactive intestinal peptide on the wound healing of alkali-burned corneas. AB - AIM: To study the effect of vasoactive intestinal peptide (VIP) on wound healing in experimental alkali burns of the cornea. METHODS: Twenty-seven albino rabbits, weighing 3.2+/-0.75 kg were used. Alkali burns were induced on corneas by applying 10 mm Whatman paper No:50 soaked in 1 mol/L NaOH. They have further classified into 5 groups as follows: 1) control group given no treatment (n=5); 2) VIP given subconjunctivally (n=6); 3) VIP injected into anterior chamber (n=6); 4) NaCl 0.9% given subconjunctivally (n=5); 5) NaCl 0.9% given into the anterior chamber (n=5). All treatment protocols except control group were followed by topical eye drops composed of VIP at two hourly intervals for one week from 8 a.m. to 6 p.m. RESULTS: VIP treated groups of rabbits with alkali burns were found to have better wound healing findings histo-pathologically when compared to those of control group who have received no treatment on day 30. No differences were observed between groups in respect to degree of polymorphonuclear leukocytes (PMNL) infiltration and degree of loss of amorphous substrate on day 15. However, PMNL infiltration and degree of loss of amorphous substrate were lower in Groups 2 and 3 when compared to that of control group on day 30 (P<0.05). CONCLUSION: We have shown that VIP has positive effects on alkali induced corneal burns. VIP may inhibit PMNL migration to cornea through an immunomodulatory effect. Inhibition of PMNL migration might reduce the release of collagenases and this might prevent the extracellular amorphous substance loss. PMID- 26949637 TI - Characterization of intraocular pressure pattern and changes of retinal ganglion cells in DBA2J glaucoma mice. AB - AIM: To characterize the pattern of intraocular pressure (IOP) change and the deficit of retinal ganglion cells (RGCs) in DBA2J, which is most well characterized chronic glaucoma mouse model and wild type (WT) C57bl/6 mice, and to study the relationship between IOP change and RGCs deficit. METHODS: IOP was monitored with a rebound tonometer in WT C57bl/6 and DBA2J mice from 3 to 15 month-old. Retinal function was evaluated by dark-adapted electroretinogram (ERG) in DBA2J and WT mice of 15-month-old. A dye (Neurobiotin) was applied to optic nerve stump to retrograde label RGCs. TO-PRO-3 visualized all nuclei of cells in the RGC layer. RESULTS: The IOP in WT mice was 9.03+/-0.6 mm Hg on average and did not increase significantly as aging. The IOP in DBA2J mice, arranging from 7.2 to 28 mm Hg, was increasing significantly as aging, and it was normal at 3 month-old compared with WT mice, slightly increased from 7-month-old and increased in 50% animals at 11-month-old and in 38% animals at 15-month-old. The RGCs density in DBA2J mice started reducing by 7-month-old, continuously decreased until reached about 20% of RGC in WT retina by 15-month-old. RGC density was not linearly correlated with IOP in 15-month-old DBA2J mice. The amplitude of positive scotopic threshold response, and negative scotopic threshold response of ERG were significantly reduced in DBA2J mice of 15-month old than that in age-paired WT mice. CONCLUSION: The present study found that DBA2J mice display pathological and functional deficits of the retina that was not linearly correlated with IOP. PMID- 26949638 TI - Comparison of postoperative corneal changes between dry eye and non-dry eye in a murine cataract surgery model. AB - AIM: To compare the effects of the surgical insult of cataract surgery on corneal inflammatory infiltration, neovascularization (NV) and lymphangiogenesis (LY) between the dry eye and non-dry eye in murine cataract surgery models. METHODS: We established two groups of animals, one with normal eyes (non-dry eye) and the second with induced dry eyes. In both groups, we used surgical insults to mimic human cataract surgery, which consisted of lens extraction, corneal incision and suture. After harvesting of corneas on the 9(th) postoperative day and immunohistochemical staining, we compared NV, LY and CD11b+ cell infiltration in the corneas. RESULTS: Dry eye group had significantly more inflammatory infiltration (21.75%+/-7.17% vs 3.65%+/-1.49%; P=0.049). The dry eye group showed significantly more NV (48.21%+/-4.02% vs 26.24%+/-6.01%; P=0.016) and greater levels of LY (9.27%+/-0.48% vs 4.84%+/-1.15%; P=0.007). In corneas on which no surgery was performed, there was no induction of NV in both the dry and non-dry group, but dry eye group demonstrated more CD11b+ cells infiltration than the non dry eye group (0.360%+/-0.160% vs 0.023%+/-0.006%; P=0.068). Dry eye group showed more NV than non-dry eye group in both topical PBS application and subconjunctival PBS injection (P=0.020 and 0.000, respectively). CONCLUSION: In a murine cataract surgery model, preexisting dry eye can induce more postoperative NV, LY, and inflammation in corneal tissue. PMID- 26949639 TI - Argon laser photocoagulation versus intrastromal voriconazole injection in treatment of mycotic keratitis. AB - AIM: To compare argon laser photocoagulation and intrastromal injection of voriconazole as adjunctive treatment modalities in cases of resistant mycotic corneal ulcers. METHODS: Two groups each of them included 20 cases of resistant mycotic corneal ulcers. Both groups treated with local and systemic specific antimicrobial drugs guided with culture and sensitivity results. In one group argon laser photocoagulation was used as an adjunctive therapy to the specific antifungal drugs and in the other group, intrastromal injection of voriconazole was done besides the specific antifungal drugs. The 40 cases included in the study were proven according to culture and sensitivity to be 28 cases with pure fungal results and 12 cases with mixed (fungal and bacterial). In argon laser group, argon laser irradiation of the corneal ulcer was performed using argon laser 532 nm wavelength (Carl Zeiss LSL 532s AG; Meditec, Inc.) after fluorescein staining. In the other group, voriconazole solution (500 ug/mL) was prepared and injected in the corneal stroma. All cases were followed up for 3mo after healing was achieved. RESULTS: Complete healing of the epithelial defect and resolution of stromal infiltration with no adverse effects were achieved in argon laser group in duration ranged from 2-4wk in 90% of cases. In voriconazole group 4 cases needed amniotic membrane graft due to thinning and 16 cases healed in duration ranged from 2-6wk (80% of cases). CONCLUSION: Argon laser photocoagulation is superior to intrastromal voriconazole injection in treatment of resistant fungal corneal ulcers. PMID- 26949640 TI - Corneal biomechanical properties changes after coaxial 2.2-mm microincision and standard 3.0-mm phacoemulsification. AB - AIM: To compare the changes in corneal biomechanics measured by ocular response analyzer (ORA) after 2.2-mm microincision cataract surgery and 3.0-mm standard coaxial phacoemulsification. METHODS: The prospective nonrandomized study comprised eyes with cataract that had 2.2-mm coaxial microincision or 3.0-mm standard incision phacoemulsification. The corneal hysteresis (CH), corneal resistance factor (CRF), corneal-compensated intraocular pressure (IOPcc) and Goldmann-correlated intraocular pressure (IOPg) were measured by ORA preoperatively and at 1d, 1-, 2-, 3- and 4-week postoperatively. Results were analyzed and compared between groups. RESULTS: In both groups, CH decreased in the immediate postoperative period (P<0.05), returned to the preoperative level at one week (P=0.249) in the 2.2-mm group, and at two weeks in the 3.0-mm group (P=0.264); there was no significant change in CRF values. In 2.2-mm group, mean IOPcc and IOPg increased at 1d postoperatively (both P<0.05), and returned to preoperative level at one week (P=0.491 and P=0.923, respectively). In 3.0-mm group, mean IOPcc and IOPg increased at 1d and 1wk postoperatively (P=0.005 and P=0.029, respectively), and returned to preoperative level at 2wk (P=0.347 and P=0.887, respectively). CONCLUSION: Significant differences between preoperative and postoperative corneal biomechanical values were found for CH, IOPcc and IOPg. But the recovery time courses were different between the two groups. The 2.2-mm coaxial microincision cataract surgery group seemed recovery faster compared to the 3.0-mm standard coaxial phacoemulsification group. PMID- 26949641 TI - Ocular biomechanical measurements on post-keratoplasty corneas using a Scheimpflug-based noncontact device. AB - AIM: To analyse ocular biomechanical properties, central corneal thickness (CCT) and intraocular pressure (IOP) in post-keratoplasty eyes, as compared to normal subjects, with a new Scheimpflug-based technology. Moreover, biomechanical data were correlated with the size and age of the donor and recipient corneas. METHODS: Measurements were conducted on 46 eyes of 46 healthy patients without any corneal pathology (age: 53.83+/-20.8y) and 30 eyes of 28 patients after penetrating keratoplasty (age: 49.43+/-21.34y). Ten biomechanical parameters, the CCT and IOP were recorded by corneal visualization scheimpflug technology (CorVis ST) using high-speed Scheimpflug imaging. Keratometry values were also recorded using Pentacam HR system. Scheimpflug measurements were performed after 43.41+/ 40.17mo (range: 11-128mo) after the keratoplasty and after 7.64+/-2.34mo (range: 5-14mo) of suture removal. RESULTS: Regarding the device-specific biomechanical parameters, the highest concavity time and radius values showed a significant decrease between these two groups (P=0.01 and P<0.001). None of other biomechanical parameters disclosed a significant difference. The CCT showed a significant difference between post-keratoplasty eyes as compared to normal subjects (P=0.003) using the CorVis ST device. The IOP was within the normal range in both groups (P=0.84). There were no significant relationships between the keratometric data, the size of the donor and recipient, age of the donor and recipient and biomechanical properties obtained by CorVis ST. CONCLUSION: The ocular biomechanics remain stable after penetrating keratoplasty according to the CorVis ST measurements. Only two from the ten device-specific parameters have importance in the follow-up period after penetrating keratoplasty. PMID- 26949642 TI - Effect of 2% fluorescein on Scheimpflug central corneal thickness measurements. AB - AIM: To assess central corneal thickness (CCT) changes measured with Scheimpflug device following instillation of 2% fluorescein in normal subjects. METHODS: This was a prospective randomized study of 60 hospital volunteers. After baseline CCT measurements of both eyes of 40 subjects were obtained using Scheimpflug system, a drop of preservative-free 2% fluorescein, was instilled in one eye and in other eye, one drop of normal saline (control). Measurements were repeated after 1, 2, 5, 10, 20, 30, 40, 50 and 60min (continuous assessment group). Twenty subjects had baseline CCT taken, then fluorescein was instilled in one eye and measurements were taken at 1min. Ten eyes had saline rinse after 1min and 10 other eyes did not, measurements were repeated at 2min (eye rinse group). RESULTS: The mean baseline CCT for continuous assessment group was 546.2 +/-32.1 um (range, 489.0-606.0), control eyes was 546.6+/-30.7 um (range, 489.0-602.0). At 1min after fluorescein instillation, CCT significantly increased by 37.0+/ 34.0 um (P<0.001), then decreased gradually, reaching baseline at 60min. CCT variations were not significant in control group (P>0.05). For eye rinse group, CCT mean differences between baseline and 2min were 18.2 um (95 % CI: -54.7 to 18.3) with rinse and 26.5 um (95% CI: -62.9 to 9.9) without rinse; paired sample tests were not significant (P>0.05). CONCLUSION: The presence of fluorescein increased CCT value to a clinically relevant level of 6.8%. Eye rinse did not significantly reduce the effect at 2min post fluorescein timepoint. PMID- 26949643 TI - Therapeutic effect analysis on the treatment of congenital glaucoma through modified combined trabeculotomy-trabeculectomy. AB - AIM: To evaluate the therapeutic effect and the safety of the treatment of congenital glaucoma through modified combined trabeculotomy-trabeculectomy. METHODS: The clinical data of 27 cases (altogether 42 eyes), which included 7 cases of infants (10 eyes) and 20 cases of teenagers (32 eyes), of congenital glaucoma undertook modified combined trabeculotomy-trabeculectomy were analyzed retrospectively. The parameters evaluated included the post operation visual acuity, the anterior chamber, the filtering bleb, the intraocular pressure, the C/D ratio, visual field, the retinal nerve fiber layer changes and the complications. RESULTS: The follow-up period was 1 to 29mo, averaging 13.3+/ 7.7mo. Upon the last visit after the operation, functional filtering blebs developed in all the involved eyes. The intraocular pressure was controlled under 21 mm Hg, which was decreased by 60% when compared with that before the operation, without using any medication. There were no significant changes in the post operation visual acuity and the retinal nerve fiber layer thickness before and after the operation in teenager group (P>0.05), and both the post operation C/D ratio and the visual field mean defect (MD) were reduced compared with those before the operation (P<0.05). There were no severe complications in any of the patients. CONCLUSION: The modified combined trabeculotomy-trabeculectomy can effectively reduce the intraocular pressure and control the development of glaucoma in cases of congenital glaucoma. It is a safe and effective operative method for the treatment of congenital glaucoma. PMID- 26949645 TI - Predicting anatomical results of surgical treatment of idiopathic macular hole. AB - AIM: To determine the parameters most informative in predicting the anatomical results of surgical treatment of idiopathic full-thickness macular hole (IMH). METHODS: One hundred and sixty-two consecutive patients (170 eyes) after primary operation for IMH were enrolled. Outcomes were classified as anatomical success when both IMH closure and restoration of the outer retinal structure were achieved. "Prospective" group included 108 patients (115 eyes) followed with optical coherence tomography (OCT) and microperimetry for 1y after surgery. Potential prognostic criteria, except microperimetry data, were tested in "retrospective" group (54 patients, 55 eyes). Prognostic value of each parameter was determined using receiver operating characteristic (ROC) analysis. Combined predictive power of the best prognostic parameters was tested with the use of linear discriminant analysis. RESULTS: IMH closure was achieved in 106 eyes (92%) in the prospective group and 49 eyes (89%) in the retrospective group. Despite anatomical closure, the outer retinal structure was not restored in two eyes in the first group and in one eye in the second group. Preoperative central subfield retinal thickness demonstrated the best discriminatory capability between eyes with anatomical success and failure: area under the ROC-curve (AUC) 0.938 (95% CI: 0.881-0.995), sensitivity 64% at fixed specificity 95% (cut-off value 300 um) in the prospective group; sensitivity 57% and specificity 90% in the retrospective group. Other continuous parameters except tractional hole index (AUC: 0.796, 95% CI: 0.591-1.000) had significantly lower AUCs (P<0.05). The best combination of the parameters, established by discriminant analysis in the prospective group, could not confirm its predictive value in the retrospective group. CONCLUSION: Preoperative central subfield retinal thickness is a strong and probably the best predictor of anatomical results of IMH surgical treatment. PMID- 26949644 TI - Oxidant/antioxidant balance in the aqueous humor of patients with glaucoma. AB - AIM: To evaluate total antioxidant status (TAS), total oxidant status (TOS), and the oxidative stress index (OSI) of the aqueous humor (AH) in patients with glaucoma. METHODS: The prospective study was composed of a study group (n=31) and a control group (n=31). Fifteen patients in the study group were diagnosed with primary open angle glaucoma (POAG), and 16 patients were diagnosed with pseudoexfoliation glaucoma (PEG). The control group was composed of non glaucomatous patients with cataracts. AH samples were collected and analyzed for TAS, TOS, and OSI levels. RESULTS: Mean AH TAS level was significantly higher in patients with glaucoma than that in the control group (P<0.01). Mean TOS and OSI levels tended to increase in patients with glaucoma. No significant differences in TAS, TOS, or OSI levels were observed between patients with POAG and PEG. CONCLUSION: High levels of TAS were observed in patients with glaucoma, which was likely a response to the increased oxidative stress observed in these patients. PMID- 26949646 TI - Posterior scleral reinforcement combined with vitrectomy for myopic foveoschisis. AB - AIM: To investigate the effects of posterior scleral reinforcement (PSR) combined with vitrectomy for myopic foveoschisis. METHODS: Thirty-nine highly myopic eyes of 39 patients with myopic foveoschisis underwent PSR combined with vitrectomy. Best corrected visual acuity (BCVA), refraction error, and the foveal thickness by optical coherence tomography (OCT) were recorded before and after the surgery, and complications were noted. RESULTS: The follow-up period was 12mo, and the main focus was on the results of the 12-month follow-up visit. The mean preoperative BCVA was 0.96+/-0.43 logMAR. At the final follow-up visit, the mean BCVA was 0.46+/-0.28 logMAR, which significantly improved compared with the preoperative one (P=0.003). The BCVA improved in 33 eyes (84.62%), and unchanged in 6 eyes (15.38%). At the end of follow-up, the mean refractive error was 15.13+/-2.55 D, and the improvement was significantly compared with the preoperative one (-17.53+/-4.51 D) (P=0.002). Twelve months after surgery, OCT showed complete resolution of the myopic foveoschisis and a reat-tachment of the fovea in 37 eyes (94.87%) and partial resolution in the remained two eyes (5.13%). The foveal thickness was obviously reduced at 12-month follow-up visit (196.45+/-36.35 um) compared with the preoperative one (389.32+/-75.56 um) (P=0.002). There were no serious complications during the 12mo follow-up period. CONCLUSION: PSR combined with vitrectomy is a safe and effective procedure for myopic foveoschisis with both visual and anatomic improvement. PMID- 26949647 TI - Screening for retinopathy of prematurity: a report from upper Egypt. AB - AIM: To detect the incidence of retinopathy of prematurity (ROP) in a tertiary referral neonatal intensive care unit in upper Egypt and to describe the obstacles faced during implementing the screening protocol for the first time. METHODS: Consecutive infants were enrolled at birth and screened for ROP. We used the UK ROP guideline (May 2008) for infant selection, follow up and treatment. Repeat examinations were performed until retinal vascularisation was complete. RESULTS: Fifty-two infants were enrolled: 24 males and 28 females. Mean gestational age was 31.3wk (+/-2.8 SD) and mean birth weight was 1234.6 g (+/ 221.1 SD). Incidence of ROP was 36.5% (stages 1, 2, 3 and 4a were 9.6%, 9.6%, 15.4% and 1.9% respectively), no stages 4b or 5 were found in this series. Six infants (11.5%) died during screening without ROP, 25 infants (48.1%) were discharged from screening with retinal vascularisation reaching zone III, 5 infants (9.6%) were treated with indirect diode with or without additional cryotherapy and 16 infants (30.8%) were lost to follow up. In this series gestational age rather than birth weight was found significantly correlated and predictive (P<0.05) with ROP stages. CONCLUSION: ROP in a single site in Upper Egypt appears to have comparable incidence to other areas worldwide. The main screening obstacle was missing cases due to the absence of a national ROP screening protocol. PMID- 26949648 TI - Is myopia a protective factor against central serous chorioretinopathy? AB - AIM: To evaluate if any association exists between central serous chorioretinopathy (CSCR) and the refractive status of the eye. METHODS: This retrospective, institutional, case control study included 499 patients, wherein 262 patients diagnosed as acute CSCR, were compared with an age and gender matched control group of 237 patients. All patients were evaluated with a detailed systemic and ocular history, objective and subjective refractions for both eyes and complete ocular examination by a retina specialist, at all visits. Optical coherence tomography confirmed the diagnosis of CSCR. RESULTS: The mean age was found to be 40+/-7y in the study group (Group 1) compared to 38+/-10y in the control group (Group 2). Most common refractive status in the study group, was emmetropia seen in 191 patients (72.9%), followed by hypermetropia seen in 47 patients (17.9%) and astigmatism seen in 21 patients (8.0%). Only 3 subjects (1.1%) had myopia, which was less than or equal to 1.0 D, compared to 70 subjects (29.5%) in the control group, suggesting a statistically significant lower incidence of CSCR among the myopic patients (P< 0.0001). With respect to the systemic factors, 26 (9.9%) patients were using systemic steroids in the study group (Group 1) compared to none in the control group (Group 2) suggesting a statistically significant association of CSCR with systemic steroid use (P<0.05). No other significant systemic risk factors were noted. CONCLUSION: Though CSCR is a multifactorial disease, myopia serves as a protective factor for CSCR. Thus, myopic eyes are less likely to develop CSCR. Since both retinal pigment epithelium (RPE) and choriocapillaris are postulated in the pathogenesis of CSCR, chorio-retinal thinning and atrophy seen in myopic eyes are less likely to cause CSCR. PMID- 26949649 TI - Optical coherence tomography characteristics of responses to intravitreal bevacizumab in idiopathic choroidal neovascularization. AB - AIM: To investigate factors associated with responses to intravitreal bevacizumab (IVB) in naive idiopathic choroidal neovascularization (iCNV) by high domain optical coherence tomography (OCT). METHODS: We retrospectively reviewed clinical data of 40 eyes of iCNV patients who received a single or multiple IVB on an as needed basis (1.25 mg/0.05 mL). One month after the first injection, subretinal fluid (SRF) volume was evaluated and the eyes were divided into 3 groups based on responses to IVB. Good, moderate, and poor responses were defined as 61%-99%, 30% 60%, and <30% resolution of SRF on OCT after IVB in iCNV, respectively. OCT findings were analyzed to find factors associated with difference in response levels. Comparisons were made using Wilcoxon's matched-pairs signed-rank test, the Mann-Whitney U test for means with continuous data and Fisher's exact test for categorical data. RESULTS: The mean number of IVB was 1.28+/-1.50 and mean follow up time was 3.60+/-1.20mo. At postoperative 1mo, there were 8 (20%) eyes in good response, 20 (50%) in moderate response and 12 (30%) eyes in poor response group and at last visit there were 28 good responders (70%), 8 (20%) moderate responders and 4 (10%) poor responders. Statistically significant difference was detected between good responders and non good responders in choroidal neovessels thickness (P=0.029), SRF height (P=0.049) and SRF volume (P=0.031) at post treatment 1mo. CONCLUSION: OCT is a valuable diagnostic tool. Decrease in choroidal neovessels thickness, SRF height and volume predicts favorable response of iCNV to IVB therapy. PMID- 26949650 TI - Role of IgG4 serology in identifying common orbital lymphoproliferative disorders. AB - AIM: To explore the role of IgG4 serology in identifying common orbital lymphoproliferative disorders. METHODS: Eighty-one patients with orbital lymphoproliferative diseases were treated in the Department of Ocular Oncology, Beijing Tongren Hospital, Capital Medical University between September 2010 and December 2012. Serum IgG4 levels were measured in 46 cases of idiopathic orbital inflammatory pseudotumor (IOIP), 17 benign lymphoepithelial lesion (BLEL), 12 cases of orbital mucosa-associated lymphoid tissue (MALT), and 6 cases of diffuse large B-cell lymphoma (DLBL) using immuno-scatter turbidmetry (ISTM). RESULTS: The frequency of elevated IgG4 levels in patients with IOIP, BLEL, MALT, and DLBL was 30.43% (14/46), 76.47% (13/17), 8.33% (1/12), and 0.00 (0/6), respectively. Among the patients with elevated serum IgG4 levels, all IgG-IOIP patients were male, and 92.31% of the IgG4-BLEL patients were female (12/13). The mean serum IgG4 level of IgG4-IOIP patients was lower than that of individuals with IgG4 BLEL, but the variation in serum IgG4 levels was larger in IgG4-IOIP than IgG4 BLEL patients. Only one case of IgG4-MALT with elevated serum IgG4 levels had a medical history >10y, which was significantly longer than the MALT patients with normal serum IgG4 levels. There was no significant elevation of serum IgG4 levels in patients with DLBL. CONCLUSION: Detecting serum IgG4 levels plays an important role in the differential diagnosis of orbital lymphoproliferative diseases. PMID- 26949651 TI - Epidemiological aspects of ocular superglue injuries. AB - AIM: To report the frequency, associated risk factors and characteristics of cases referred to Farabi Eye Hospital with ocular superglue injuries. METHODS: In a descriptive cross-sectional study conducted between December 2012 and February 2013, patients with ocular superglue injuries were evaluated. Age, sex, educational level, location, time, mechanism, type, site and time of eye injury were gathered through interview using a customized questionnaire. All participants had given consent to undergo thorough eye examination. RESULTS: Over the course of three months, 105 patients with ocular superglue injuries enrolled in the study, including 56(53.3%) men and 49(46.7%) women with the mean age of 24.7+/-11.6 (range, 2 to 53)y. The right eye, left eye and both eyes were involved in 52%, 42% and 6% of the patients, respectively. Most of injuries had occurred at home (72.4%) and at night (55%). More than half of patients (52.4%) did not take any primary aids following the ocular injury. Patient carelessness (78.1%), childhood curiosity and lack of parental supervision (11.4%), storing superglue in inappropriate places and inadvertently using superglue as eye drops due to poor vision (2.9%), inadequate awareness of superglue applications [used to stick on artificial nails (3.8%), artificial eyelashes (1.9%) and broken tooth (1%)] and being assaulted with glue (1%) were common risk factors. CONCLUSION: The frequency of ocular superglue injuries in patients referred to Farabi Eye Hospital is relatively high. This finding underlines the importance of public education and awareness about superglue injuries to the eye and taking protective measures and safety strategies in order to prevent these injures. PMID- 26949652 TI - Use of the Crawford tube for symptomatic epiphora without nasolacrimal obstruction. AB - AIM: To evaluate the effectiveness of the Crawford tube in treating symptomatic epiphora without nasolacrimal obstruction. METHODS: A protocol was adopted for the management of symptomatic epiphora without nasolacrimal obstruction. Patients who suffered symptomatic epiphora without nasolacrimal obstruction in both eyes were included in the study. One eye was treated with Crawford tube intubation and the other eye was treated with medication therapy. Degree of watering, patient satisfaction, and symptomatic improvement were carefully evaluated by one of the authors at the end of the follow-up period, after Crawford tube removal, to ascertain functional results. RESULTS: Thirty-seven adult patients (37 eyes) underwent Crawford tube intubation for functional epiphora. The mean follow-up time after removal of the tube was 14.8+/-4.8mo. The procedure was an overall success in 28 eyes (75.7%), with symptoms improving significantly. Two eyes (5.4%) were relieved of indoor epiphora, two (5.4%) had minimal epiphora outdoors, but only with wind or cold, and five (13.5%) continued to experience tearing both indoors and outdoors. Thirty of the patients (81%) expressed satisfaction with the procedure. CONCLUSION: Crawford tube insertion is an effective, safe, simple, and relatively noninvasive treatment strategy for functional lacrimal system obstruction. PMID- 26949653 TI - Multifocal electroretinogram in non-pathological myopic subjects: correlation with optical coherence tomography. AB - AIM: To investigate the changes of retinal function in non-pathological myopic subjects using multifocal electroretinography (mfERG) and to correlate the data with the central macular thickness obtained using optical coherence tomography (OCT). METHODS: One hundred and thirteen subjects (113 eyes) with age range from 18 to 35y were enrolled in the study. The subjects were divided into four groups according to spherical equivalent (SE) and axial length (AL): emmetropia group (EG, n=31; SE: +0.75 to -0.50 D; AL: 22 to 24 mm), low and medium myopia group (LMMG, n=26; SE: >-0.50 to -6.00 D; AL: >24 to 26 mm), high myopia group (HMG, n=34; SE: >-6.00 to -10.00 D; AL: >26 to 28 mm) and super high myopia group (SHMG, n=22; SE: >-10.00 D; AL:>28 mm). The P1 amplitude density, P1 amplitude, and P1 implicit time of the first-order kernel mfERG responses were obtained and grouped into five rings. The central subfield macular thickness (CST) was obtained using macular cube 512*218 scan of Cirrus HD-OCT. RESULTS: With the increasing of eccentricity, the first positive peak (P1) amplitude density (P=0.0000, 0.0001, 0.0021 in ring 1-3 respectively) and P1 amplitude (all P=0.0000 in ring 1-5) of each group decreased. With the increasing of myopia, P1 implicit time gradually extended (all P=0.0000 in ring 1-3). The average CST in four diagnostic groups was 241.56+/-12.72 um, 244.56+/-12.19 um, 254.33+/-11.61 um, 261.75+/-11.83 um respectively. With the increasing of myopia, CST increased (P<0.001). There was negative relationship between CST and P1 amplitude, P1 amplitude density (r=-0.402, P<0.001; r=-0.261, P=0.003). There was positive relationship between CST and P1 implicit time (r=0.34, P<0.001). CONCLUSION: With the increasing of myopia, P1 amplitude density and P1 amplitude of the first order reaction gradually reduced. This showed potential decline in retinal function in myopia. To some extent it may reflect the functional disorder or depression of the visual cells. The exact mechanism needs further study. PMID- 26949654 TI - Comparison of two types of visual quality analyzer for the measurement of high order aberrations. AB - AIM: To compare the difference and agreement of KR-1W and iTrace for measurement of high order aberrations. METHODS: KR-1W and iTrace were respectively used in a group of healthy people (40 volunteers, 32 eyes) to measure the high order aberration (HOA) of corneal, internal and total ocular. The clinical difference and agreement of two instruments were respectively evaluated by paired-samples t test and Bland-Altman analysis. RESULTS: The paired-samples t-test showed that the corneal HOA measured by the two instruments had no statistical differences (P>0.05); but the internal and total ocular HOA had significant statistical differences (P<0.05), and the mean results measured by iTrace were higher than that of KR-1W. However, Bland-Altman analysis revealed that the HOA of corneal and internal were all in 95% limits of agreement; and just one point of total ocular HOA was beyond the 95% limits of agreement. CONCLUSION: KR-1W and iTrace were consistent well in the measurement of corneal, internal and total ocular HOA, especially for the cornea. PMID- 26949655 TI - Association between complement factor I gene polymorphisms and the risk of age related macular degeneration: a Meta-analysis of literature. AB - AIM: To systematically review the association between complement factors I (CFI) polymorphisms and age-related macular degeneration (AMD) and to explore whether CFI polymorphisms are associated with AMD. METHODS: Meta-analysis of articles published from 1995 to January 2015 of articles involved with AMD and polymorphisms of the CFI gene. Eligible data were pooled in a Meta-analysis, analyzing using STATA software (version 12.0), Review Manager (version 5.2) and different models based on the heterogeneity of effect sizes. Egger's test, Begg's rank correlation methods were used to evaluate for publication bias. RESULTS: Thirteen articles were eligible, describing two loci polymorphisms of the CFI gene (of which 12 articles focus on rs10033900T>C and 3 articles focus on rs2285714C>T). For rs10033900T>C, the results of our study revealed that having a mutant allele C, TC, CC and TC+CC was associated with a decreased risk of AMD in all population groups studied (C versus T models, OR=0.84, 95%CI: 0.72-0.99, P=0.04; TC versus TT models OR=0.89, 95%CI: 0.88-0.99, P=0.04; CC versus TT models, OR=0.76, 95%CI: 0.60-0.98, P=0.03; TC+CC versus TT models, OR=0.81, 95%CI:0.65-0.99, P=0.04). We found that C allele were related to lower AMD risk in the Caucasian population by subgroup analysis, but there was no association with AMD under the allele and genotypes comparison in Asian studies. For rs2285714 C>T, the TC, TT genotypes contributed to a higher risk of AMD, compared with the CC carriers and TC+CC (OR=1.34, 95%CI: 1.09-1.63, P=0.004; OR=1.50, 95%CI: 1.25-1.80, P<0.0001). CONCLUSION: This Meta-analysis suggests that CFI rs10033900T>C and rs2285714C>T polymorphisms may contribute to AMD. PMID- 26949657 TI - Central serous chorioretinopathy: from glucocorticoids to light intensity. AB - Central serous chorioretinopathy (CSC) is characterized by a localized accumulation of subretinal fluid and an idiopathic focal leakage from choroidal vessels. The exact pathogenesis of CSC, however, still remains obscure. In this paper, we hypothesized that CSC may result from a response of choroidal vessels to an acute increase in the environmental light intensity leading to a focal leakage from the choroidal vessels. High levels of glucocorticoids, in our proposed model, may cause persistence rather than initiation of the focal leakage, probably by suppressing the synthesis of collagen and extracellular matrix components and inhibiting fibroblastic activity. PMID- 26949656 TI - Liquefaction for cataract extraction. AB - A systematic review of the recent literature regarding the implementation of the liquefaction in cataract surgery and its short-term and long-term outcomes in various parameters that affect the quality of patients' life, including visual rehabilitation and possible complications was performed based on the PubMed, Medline, Nature and the American Academy of Ophthalmology databases in November 2013 and data from 14 comparative studies were included in this narrative review. Liquefaction is an innovative technology for cataract extraction that uses micropulses of balanced salt solution to liquefy the lens nucleus. Most studies reported that liquefaction is a reliable technology for mild to moderate cataracts, while fragmentation difficulties may be encountered with harder nuclei. PMID- 26949658 TI - New autologous material for the frontalis suspension technique: superficial temporal fascia. PMID- 26949659 TI - Penetrating keratoplasty in monocular patients. PMID- 26949660 TI - Evaluation of corneal endothelium after UVA/riboflavin cross-linking in thin keratoconic corneas. PMID- 26949661 TI - Comment on visual impact of sub-Tenon anesthesia during combined phacoemulsification and vitrectomy surgery. PMID- 26949662 TI - Diagnostic Value of Coronary Artery Calcium Score for Cardiovascular Disease in African Americans: The Jackson Heart Study. AB - BACKGROUND: The role of coronary artery calcium (CAC) as a screening tool for cardiovascular disease (CVD) risk in African Americans (AAs) is unclear. We compared the diagnostic accuracy for CVD prevalence using the CAC score and the Framingham Risk Score (FRS) in an adult population of AAs. METHODS: CAC was measured in 2944 participants AAs. Approximately 8% of this cohort had known CVD defined as prior myocardial infarction, stroke, percutaneous coronary intervention, coronary artery bypass grafting and peripheral artery disease. Logistic regression, receiver operating characteristic (ROC) and net reclassification index (NRI) analysis were used adjusting for age, gender, systolic blood pressure (SBP), total and high-density lipoprotein (HDL) cholesterol, smoking status, diabetes mellitus (DM), body mass index (BMI), blood pressure medication and statin use. Participants with prevalent clinical CVD and DM were classified as high FRS risk. RESULTS: The mean age of participants was 60 years, 65% were females, 26% had DM, 50% were obese and 30% were current or former smokers. Prevalent CVD was associated with older age, higher SBP, lower HDL and total cholesterol, and higher CAC. The prevalence of CAC was 83% in participants with prevalent CVD and 45% in those without CVD. CAC was independently associated with prevalent CVD in our multivariable model [OR (95% CI): 1.22 (1.12-1.32), p< 0.0001]. In ROC analysis, CAC improved the diagnostic accuracy (c statistic) of the FRS from 0.617 to 0.757 (p < 0.0001) for prevalent CVD. Addition of CAC to FRS resulted in net reclassification improvement of 4% for subjects with known CVD and 28.5% in those without CVD. CONCLUSION: In AAs, CAC is independently associated with prevalent CVD and improves the diagnostic accuracy of FRS for prevalent CVD by 14%. Addition of CAC improves the NRI of those with prevalent CVD by 4% and the NRI of individuals without CVD by 28.5%. Determination of CAC may be useful in CVD risk stratification in AAs. PMID- 26949663 TI - Prevalence and Characteristics of Musculoskeletal Pain in Korean Farmers. AB - OBJECTIVE: To investigate the prevalence and characteristics of musculoskeletal pain (MSK) pain in Korean farmers using initial survey data of Farmers' Cohort for Agricultural Work-Related MSK pain (FARM) study. METHODS: Farmers (534 females and 479 males; mean age 57.2+/-7.5 years) who owned or rented a farm and belonged to an agricultural cooperative unit were recruited. Presence of pain for each body part (neck, shoulder, arm/elbow, wrist/hand/finger, low back, leg/foot), and characteristics of MSK pain (prevalence, location, duration, severity, and frequency) during the last year was assessed. Additionally, demographic data such as farming duration, history of prior injury, and workload (low, moderate, somewhat hard, or hard) were collected using structured questionnaires. RESULTS: Almost all subjects (n=925; 91.3%) complained of pain in more than one body part. The frequency order was low back (63.8%), leg/foot (43.3%), shoulder (42.9%), wrist/hand/finger (26.6%), arm/elbow (25.3%), and neck (21.8%). Low back pain was more frequent in those with over 30 years of farming experience (odds ratio [OR], 1.40; 95% confidence interval, 1.08-1.81). MSK pain was related to history of prior injury (OR, 2.18-5.24; p<0.05) in all body parts except for leg/foot, and very hard workload was associated with low back, leg/foot, neck, shoulder, and wrist/hand/finger pain (OR, 2.88-10.83; p<0.05). CONCLUSION: Most Korean farmers experience MSK pain; furthermore, there is a significant association between pain, history of prior injury, and workload, suggestive of the necessity of coping and preventive strategies to reduce injury or workload. PMID- 26949664 TI - The Effect and Safety of Steroid Injection in Lumbar Spinal Stenosis: With or Without Local Anesthetics. AB - OBJECTIVE: To compare the long-term effect and safety of an epidural steroid injection in spinal stenosis patients, with or without local anesthetics. METHODS: Twenty-nine patients diagnosed with spinal stenosis were included and randomly divided into two groups. Translaminar epidural and selective nerve root spinal injection procedures were performed using steroids mixed with local anesthetics or normal saline. The effects of spinal injection procedures were measured with visual analogue scale (VAS) and functional rate index (FRI). These measurements were performed before injection, at 1 month after injection and at 3 months after injection. The occurrence of side effects was investigated each time. RESULTS: The VAS and FRI scores were significantly reduced in both the local anesthetics group and normal saline group at 1 and 3 months after the injection. However, there was no significant difference in VAS and FRI score reduction between the two groups each time. Side effects are not noted in both groups. CONCLUSION: The spinal injection procedures using steroids mixed either with local anesthetics or normal saline have an effect in reducing pain and improving functional activities. However, there was no significant difference between the two groups in relation to side effects and the long-term effects of pain and function. PMID- 26949665 TI - Crystallization of Local Anesthetics When Mixed With Corticosteroid Solutions. AB - OBJECTIVE: To evaluate at which pH level various local anesthetics precipitate, and to confirm which combination of corticosteroid and local anesthetic crystallizes. METHODS: Each of ropivacaine-HCl, bupivacaine-HCl, and lidocaine HCl was mixed with 4 different concentrations of NaOH solutions. Also, each of the three local anesthetics was mixed with the same volume of 3 corticosteroid solutions (triamcinolone acetonide, dexamethasone sodium phosphate, and betamethasone sodium phosphate). Precipitation of the local anesthetics (or not) was observed, by the naked eye and by microscope. The pH of each solution and the size of the precipitated crystal were measured. RESULTS: Alkalinized with NaOH to a certain value of pH, local anesthetics precipitated (ropivacaine pH 6.9, bupivacaine pH 7.7, and lidocaine pH 12.9). Precipitation was observed as a cloudy appearance by the naked eye and as the aggregation of small particles (<10 um) by microscope. The amount of particles and aggregation increased with increased pH. Mixed with betamethasone sodium phosphate, ropivacaine was precipitated in the form of numerous large crystals (>300 um, pH 7.5). Ropivacaine with dexamethasone sodium phosphate also precipitated, but it was only observable by microscope (a few crystals of 10-100 um, pH 7.0). Bupivacaine with betamethasone sodium phosphate formed precipitates of non-aggregated smaller particles (<10 um, pH 7.7). Lidocaine mixed with corticosteroids did not precipitate. CONCLUSION: Ropivacaine and bupivacaine can precipitate by alkalinization at a physiological pH, and therefore also produce crystals at a physiological pH when they are mixed with betamethasone sodium phosphate. Thus, the potential risk should be noted for their use in interventions, such as epidural steroid injections. PMID- 26949666 TI - Clinical Usefulness of Sonoelastography in Infants With Congenital Muscular Torticollis. AB - OBJECTIVE: To evaluate the clinical usefulness of sonoelastography in infants with congenital muscular torticollis (CMT). METHODS: The medical records of 215 infants clinically diagnosed with CMT were retrospectively reviewed. Fifty-three infants met the inclusion criteria as follows: 1) infants diagnosed as CMT with a palpable neck mass before 3 months of age, 2) infants who were evaluated initially by both B-mode ultrasonography and sonoelastography, and 3) infants who had received physical therapy after being diagnosed with CMT. We checked the thickness of the sternocleidomastoid (SCM) muscles in B-mode ultrasonography, strain ratio of the SCM muscles in sonoelastography, and treatment duration. We evaluated the correlation between the treatment duration and the following factors: SCM muscle thickness, ratio of SCM muscle thickness on the affected to unaffected side (A/U ratio), and strain ratio. RESULTS: Both the thickness of the affected SCM muscle and the A/U ratio did not show significant correlation with the treatment duration (p=0.66, p=0.90). The strain ratio of the affected SCM muscle was significantly greater than that of the unaffected SCM muscle (p<0.001), and the strain ratio showed significant correlation with the treatment duration (p=0.001). CONCLUSION: Sonoelastography may be a useful adjunctive tool to B-mode ultrasonography for evaluating infants with CMT, especially when predicting their rehabilitation outcomes. PMID- 26949667 TI - Effectiveness of Surgical Release in Patients With Neglected Congenital Muscular Torticollis According to Age at the Time of Surgery. AB - OBJECTIVE: To identify the correlation between change in spinal deformities after surgical release and age at the time of surgery, and the effectiveness of surgical release in patients with neglected congenital muscular torticollis (CMT). METHODS: This was a retrospective study of 46 subjects with neglected CMT who had undergone surgical release at age >=5 years at a tertiary medical center between January 2009 and January 2014. Spinal deformities were measured on anteroposterior plain radiographs of the cervical and whole spine, both preoperatively and postoperatively, to assess 3 parameters: cervicomandibular angle (CMA), lateral shift (LS), and Cobb angle (CA). We analyzed the change in spinal deformities after surgical release in consideration of age at the time of surgery. RESULTS: The median age at the time of surgery was 12.87 years. All 3 parameters showed significant improvement after surgical release (median values, pre- to post-surgery: CMA, 12.13 degrees to 4.02 degrees ; LS, 18.13 mm to 13.55 mm; CA, 6.10 degrees to 4.80 degrees ; all p<0.05). There was no significant correlation between age at the time of surgery and change in CMA (R=0.145, p=0.341) and LS (R=0.103, p=0.608). However, CA showed significant improvement with increasing age (R=0.150, p=0.046). CONCLUSION: We assessed the correlation between change in spinal deformities after surgical release and age at the time of surgery. We found that that surgical release is effective for spinal deformities, even in older patients. These findings enhance our understanding of the effectiveness and timing of surgical release in patients with neglected CMT. PMID- 26949668 TI - Reappraisal of Supraorbital Sensory Nerve Conduction Recordings: Orthodromic and Antidromic Techniques. AB - OBJECTIVE: To establish a supraorbital nerve sensory conduction recording method and assess its usefulness. METHODS: Thirty-one healthy subjects without a history of trauma or neurological disease were recruited. For the orthodromic procedure, the recording electrode was attached immediately superior to the supraorbital notch. The stimulation electrode was placed on points along the hairline which evoked the largest sensory nerve action potentials (SNAPs). The antidromic sensory response was recorded after switching the recording and stimulating electrodes. The measured parameters were onset latency, peak latency, and baseline to peak amplitude of the SNAPs. The electrophysiological parameters of the bilateral supraorbital nerves were compared. We also recruited two patients who had sensory deficits on one side of their foreheads because of laceration injuries. RESULTS: The parameters of orthodromically recorded SNAPs were as follows: onset latency 1.21+/-0.22 ms (range, 0.9-1.6 ms), peak latency 1.54+/ 0.23 ms (range, 1.2-2.2 ms), and baseline to peak amplitude 4.16+/-1.92 uV (range, 1.4-10 uV). Those of antidromically recorded SNAPs were onset latency 1.31+/-0.27 ms (range, 0.8-1.7 ms), peak latency 1.62+/-0.29 ms (range, 1.3-2.2 ms), and baseline to peak amplitude 4.00+/-1.89 uV (range, 1.5-9.0 uV). There was no statistical difference in onset latency, peak latency, or baseline to peak amplitude between the responses obtained using the orthodromic and antidromic methods, and the parameters also revealed no statistical difference between the supraorbital nerves on both sides. CONCLUSION: We have successfully recorded supraorbital SNAPs. This conduction technique could be quite useful in evaluating patients with supraorbital nerve lesions. PMID- 26949669 TI - Diagnostic Value of the Second Lumbrical-Interosseous Distal Motor Latency Comparison Test in Severe Carpal Tunnel Syndrome. AB - OBJECTIVE: To examine the usefulness of the second lumbrical-interosseous (2L INT) distal motor latency (DML) comparison test in localizing median neuropathy to the wrist in patients with absent median sensory and motor response in routine nerve conduction studies. METHODS: Electrodiagnostic results from 1,705 hands of patients with carpal tunnel syndrome (CTS) symptoms were reviewed retrospectively. All subjects were evaluated using routine nerve conduction studies: median sensory conduction recorded from digits 1 to 4, motor conduction from the abductor pollicis brevis muscle, and the 2L-INT DML comparison test. RESULTS: Four hundred and one hands from a total of 1,705 were classified as having severe CTS. Among the severe CTS group, 56 hands (14.0%) showed absent median sensory and motor response in a routine nerve conduction study, and, of those hands, 42 (75.0%) showed an abnormal 2L-INT response. CONCLUSION: The 2L INT DML comparison test proved to be a valuable electrodiagnostic technique in localizing median mononeuropathy at the wrist, even in the most severe CTS patients. PMID- 26949670 TI - Relationship of Vascular Factors on Electrophysiologic Severity of Diabetic Neuropathy. AB - OBJECTIVE: To investigate the impact of vascular factors on the electrophysiologic severity of diabetic neuropathy (DPN). METHODS: Total 530 patients with type 2 diabetes were enrolled retrospectively. We rated severity of DPN from 1 (normal) to 4 (severe) based on electrophysiologic findings. We collected the data concerning vascular factors (including brachial-ankle pulse wave velocity [PWV], ankle brachial index, ultrasound of carotid artery, lipid profile from the blood test, and microalbuminuria [MU] within 24 hours urine), and metabolic factors of diabetes (such as glycated hemoglobin [HbA1c]). We analyzed the differences among the four subgroups using chi(2) test and ANOVA, and ordinal logistic regression analysis was performed to investigate the relationship between significant variables and severity of DPN. RESULTS: The severity of DPN was significantly associated with duration of diabetes, HbA1c, existence of diabetic retinopathy and nephropathy, PWV, presence of plaque, low density lipoprotein-cholesterol and MU (p<0.05). Among these variables, HbA1c and presence of plaque were more significantly related with severity of DPN in logistic regression analysis (p<0.001), and presence of plaque showed the highest odds ratio (OR=2.52). CONCLUSION: Our results suggest that markers for vascular wall properties, such as PWV and presence of plaque, are significantly associated with the severity of DPN. The presence of plaque was more strongly associated with the severity of DPN than other variables. PMID- 26949671 TI - Delay of the Blink Reflex in Patients Receiving Platinum-Analogue Chemotherapy. AB - OBJECTIVE: To investigate the presence of cranial neuropathy in patients with platinum-analogue chemotherapy using electrodiagnostic evaluations. METHODS: Thirty-nine patients whose chemotherapy was completed within a month and 40 control subjects were enrolled in the study. Electrodiagnostic evaluation was performed using sensory and motor nerve conduction studies and blink reflex studies, in addition to the two-point discrimination test. RESULTS: The chemotherapy group had significantly longer latencies of bilateral R1 responses (left p<0.001; right p<0.001) and greater distance in two-point discrimination (p<0.001) compared to the control group. In the subgroup with peripheral polyneuropathy, the left R1 (p=0.01), both R2i (left p=0.02; right p=0.03) and the left R2c (p=0.02) were prolonged relative to those without the polyneuropathy, and both R1 (left p<0.001; right p<0.001), R2i (left p=0.01; right p=0.03), and the left R2c (p=0.01) were prolonged relative to the controls. On the other hand, the subgroup without the polyneuropathy showed only prolongation of both R1 (left p=0.006; right p<0.001) relative to the controls. CONCLUSION: In the present study, comparison of blink reflex and two-point discrimination showed the likelihood of subclinical cranial neuropathy following platinum-analogue chemotherapy. Cranial neuropathy caused by platinum agents was more profound in patients with peripheral polyneuropathy and may be dependent on the cumulative dose of the drug. The blink reflex may be of value in detecting subclinical cranial neuropathy in patients undergoing platinum-analogue chemotherapy. PMID- 26949672 TI - Comparison of Pulmonary Functions at Onset of Ventilatory Insufficiency in Patients With Amyotrophic Lateral Sclerosis, Duchenne Muscular Dystrophy, and Myotonic Muscular Dystrophy. AB - OBJECTIVE: To evaluate pulmonary functions of patients with amyotrophic lateral sclerosis (ALS), Duchenne muscular dystrophy (DMD), and myotonic muscular dystrophy (MMD) at the onset of ventilatory insufficiency. METHODS: This retrospective study included ALS, DMD, and MMD patients with regular outpatient clinic follow-up in the Department of Rehabilitation Medicine at Gangnam Severance Hospital before the application of non-invasive positive pressure ventilation (NIPPV). The patients were enrolled from August 2001 to March 2014. If patients experienced ventilatory insufficiency, they were treated with NIPPV, and their pulmonary functions were subsequently measured. RESULTS: Ninety-four DMD patients, 41 ALS patients, and 21 MMD patients were included in the study. The mean SpO2 was lower in the MMD group than in the other two groups. The mean forced vital capacity (FVC) in the supine position was approximately low to mid 20% on average in DMD and ALS patients, whereas it was 10% higher in MMD patients. ALS patients showed a significantly lower FVC in the supine position than in the sitting position. Maximal insufflation capacity, unassisted peak cough flow, maximum inspiratory pressure (MIP), and maximum expiratory pressure (MEP) were significantly higher in MMD group than in the other groups. MEP was significantly the lowest in DMD patients, followed by in ALS, and MMD patients, in order. CONCLUSION: Disease-specific values of pulmonary function, including FVC, MEP, and MIP, can be accurately used to assess the onset of ventilatory insufficiency in patients with ALS, DMD, and MMD. PMID- 26949673 TI - Usefulness of Transcranial Magnetic Stimulation to Assess Motor Function in Patients With Parkinsonism. AB - OBJECTIVE: To investigate the clinical significance of upper and lower extremity transcranial magnetic stimulation (TMS)-induced motor evoked potentials (MEPs) in patients with parkinsonism. METHODS: Twenty patients (14 men, 6 women; mean age 70.5+/-9.1 years) suffering from parkinsonism were included in this study. All participants underwent single-pulse TMS session to assess the corticospinal excitability of the upper and lower extremity motor cortex. The resting motor threshold (RMT) was defined as the lowest stimulus intensity able to evoke MEPs of an at least 50 uV peak-to-peak amplitude in 5 of 10 consecutive trials. Five sweeps of MEPs at 120% of the RMT were performed, and the mean amplitude and latency of the MEPs were calculated. Patients were also assessed using the Unified Parkinson's Disease Rating Scale part III (UPDRS-III) and the 5-meter Timed Up and Go (5m-TUG) test. RESULTS: There was a significant positive correlation between the RMTs of MEPs in the upper and lower extremities (r=0.612, p=0.004) and between the amplitude of MEPs in the upper and lower extremities (r=0.579, p=0.007). The RMT of upper extremity MEPs showed a significant negative relationship with the UPDRS-III score (r=-0.516, p=0.020). In addition, RMTs of lower extremity MEPs exhibited a negative relationship with the UPDRS-III score, but the association was not statistically significant (r=-406, p=0.075). CONCLUSION: These results indicated that the RMT of MEPs reflect the severity of motor dysfunction in patients with parkinsonism. MEP is a potential quantitative, electrodiagnostic method to assess motor function in patients with parkinsonism. PMID- 26949674 TI - The Relation Between the Presence of Aspiration or Penetration and the Clinical Indicators of Dysphagia in Poststroke Survivors. AB - OBJECTIVE: To examine the relation between the presence of penetration or aspiration and the occurrence of the clinical indicators of dysphagia. The presence of penetration or aspiration is closely related to the clinical indicators of dysphagia. It is essential to understand these relationships in order to implement proper diagnosis and treatment of dysphagia. METHODS: Fifty eight poststroke survivors were divided into two groups: patients with or without penetration or aspiration. Medical records and videofluoroscopic swallowing examinations were reviewed. The occurrence of clinical indicators of dysphagia between two groups was analyzed with Cross Tabulation and the Pearson chi-square test (p<0.05). RESULTS: Poststroke survivors with penetration or aspiration had significantly high occurrences of delayed initiation of the swallow (p=0.04) and reduced hyolaryngeal elevation (p<0.01) than those without penetration or aspiration. CONCLUSION: The results of this study indicate that delayed initiation of the swallow is a strong physiological indicator of penetration or aspiration during the oral stage of swallowing in poststroke survivors. For the pharyngeal stage of swallowing, hyoid and laryngeal elevation is a key event related to occurrence of penetration or aspiration. Clinical indicators should be investigated further to allow appropriate implementation of treatment strategies for stroke survivors. PMID- 26949675 TI - Diagnosis and Clinical Course of Unexplained Dysphagia. AB - OBJECTIVE: To investigate the final diagnosis of patients with unexplained dysphagia and the clinical and laboratory findings supporting the diagnosis. METHODS: We retrospectively analyzed 143 patients with dysphagia of unclear etiology who underwent a videofluoroscopic swallowing study (VFSS). The medical records were reviewed, and patients with a previous history of diseases that could affect swallowing were categorized into a missed group. The remaining patients were divided into an abnormal or normal VFSS group based on the VFSS findings. The clinical course and final diagnosis of each patient were examined. RESULTS: Among the 143 patients, 62 (43%) had a previous history of diseases that could affect swallowing. Of the remaining 81 patients, 58 (72.5%) had normal VFSS findings and 23 (27.5%) had abnormal VFSS findings. A clear cause of dysphagia was not identified in 9 of the 23 patients. In patients in whom a cause was determined, myopathy was the most common cause (n=6), followed by laryngeal neuropathy (n=4) and drug-induced dysphagia (n=3). The mean ages of the patients in the normal and abnormal VFSS groups differed significantly (62.52+/-15.00 vs. 76.83+/-10.24 years, respectively; p<0.001 by Student t-test). CONCLUSION: Careful history taking and physical examination are the most important approaches for evaluating patients with unexplained swallowing difficulty. Even if VFSS findings are normal in the pharyngeal phase, some patients may need additional examinations. Electrodiagnostic studies and laboratory tests should be considered for patients with abnormal VFSS findings. PMID- 26949676 TI - Polymorphism of Nitric Oxide Synthase 1 Affects the Clinical Phenotypes of Ischemic Stroke in Korean Population. AB - OBJECTIVE: To investigate whether four single nucleotide polymorphisms (SNPs) rs2293054 [Ile734Ile], rs1047735 [His902His], rs2293044 [Val1353Val], rs2682826 (3'UTR) of nitric oxide synthase 1 (NOS1) are associated with the development and clinical phenotypes of ischemic stroke. METHODS: We enrolled 120 ischemic stroke patients and 314 control subjects. Ischemic stroke patients were divided into subgroups according to the scores of the National Institutes of Health Stroke Survey (NIHSS, <6 and >=6) and Modified Barthel Index (MBI, <60 and >=60). SNPStats, SNPAnalyzer, and HelixTree programs were used to calculate odds ratios (ORs), 95% confidence intervals (CIs), and p-values. Multiple logistic regression models were performed to analyze genetic data. RESULTS: No SNPs of the NOS1 gene were found to be associated with ischemic stroke. However, in an analysis of clinical phenotypes, we found that rs2293054 was associated with the NIHSS scores of ischemic stroke patients in codominant (p=0.019), dominant (p=0.007), overdominant (p=0.033), and log-additive (p=0.0048) models. Also, rs2682826 revealed a significant association in the recessive model (p=0.034). In allele frequency analysis, we also found that the T alleles of rs2293054 were associated with lower NIHSS scores (p=0.007). Respectively, rs2293054 had a significant association in the MBI scores of ischemic stroke in codominant (p=0.038), dominant (p=0.031), overdominant (p=0.045), and log-additive (p=0.04) models. CONCLUSION: These results suggest that NOS1 may be related to the clinical phenotypes of ischemic stroke in Korean population. PMID- 26949677 TI - Monitoring of Functioning Status in Subjects With Chronic Stroke in South Korea Using WHODAS II. AB - OBJECTIVE: To follow up the long-term functioning in a community through assessing personal background and status based on the International Classification of Functioning, Disability and Health (ICF) after a stroke, by using a Korean version of World Health Organization Disability Assessment Scale II (K-WHODAS II). METHODS: We surveyed 146 patients diagnosed at the first-onset of acute stroke and discharged after Inha University Hospital, and 101 patients answered the K-WHODAS II survey. We analyzed the relationship of six functioning domains of K-WHODAS II with K-MMSE (Korean version of Mini-Mental State Examination) and K-MBI (Korean version of Modified Barthel Index) at admission and discharge, and personal background. All subjects were divided into five groups, according to the disease durations, to assess the functional changes and the differences of K-MMSE and K-MBI at the admission and discharge. RESULTS: K MBI and K-MMSE at admission and discharge showed no significant differences in all five groups, respectively (p>0.05), reflecting no baseline disparity for long term follow-up. All subjects showed positive gains of K-MBI and K-MMSE at discharge (p<0.05). The six functioning domains and total scores of K-WHODAS II had decreasing trends until 3 years after the stroke onset, but rose thereafter. Higher scores of K-MBI and K-MMSE, younger age, women, working status, higher educational level, and living with a partner were correlated with lower scores of K-WHODAS II (p<0.05). CONCLUSION: The long-term functioning after stroke was affected not only by cognitive and motor status in hospital, but also by certain kinds of personal background. K-WHODAS II may be used to monitor functioning status in a community and to assess personal backgrounds in subjects with chronic stroke. PMID- 26949678 TI - Relationship Between Serum Vitamin D Levels and Symptoms of Depression in Stroke Patients. AB - OBJECTIVE: To investigate the correlation between depressive symptoms and serum vitamin D levels in stroke patients. METHODS: In total, 126 stroke patients were analyzed. The 25-hydroxyvitamin D (25-OHD) concentration of each patient was used to determine their vitamin D status. Depressive symptoms were assessed using the Beck Depression Inventory II (BDI-II) and the Patient Health Questionnaire 9 (PHQ 9). Functional status was evaluated with the Korean version of the Modified Barthel Index (K-MBI). We compared the clinical questionnaires of a vitamin D deficient group and a normal group, and evaluated the correlations between BDI II, PHQ-9, K-MBI, and serum 25-OHD levels. RESULTS: In the vitamin D-deficient group, BDI-II (16.0+/-12.1) and PHQ-9 (7.4+/-4.2) scores were significantly higher than those of the normal group (BDI-II, 9.1+/-7.2; PHQ-9, 4.2+/-2.9; p<0.01). In a Spearman correlation analysis, a significant negative correlation was found between serum 25-OHD levels and BDI-II (Spearman r=0.177, p=0.048), but there were no significant correlations between serum 25-OHD levels and PHQ-9 or K MBI. CONCLUSION: Vitamin D deficiency was correlated with the symptoms of depression in stroke patients. PMID- 26949679 TI - Comparison of Diffusion Tensor Tractography and Motor Evoked Potentials for the Estimation of Clinical Status in Subacute Stroke. AB - OBJECTIVE: To compare diffusion tensor tractography (DTT) and motor evoked potentials (MEPs) for estimation of clinical status in patients in the subacute stage of stroke. METHODS: Patients with hemiplegia due to stroke who were evaluated using both DTT and MEPs between May 2012 and April 2015 were recruited. Clinical assessments investigated upper extremity motor and functional status. Motor status was evaluated using Medical Research Council grading and the Fugl Meyer Assessment of upper limb and hand (FMA-U and FMA-H). Functional status was measured using the Modified Barthel Index (MBI). Patients were classified into subgroups according to DTT findings, MEP presence, fractional anisotropy (FA) value, FA ratio (rFA), and central motor conduction time (CMCT). Correlations of clinical assessments with DTT parameters and MEPs were estimated. RESULTS: Fifty five patients with hemiplegia were recruited. In motor assessments (FMA-U), MEPs had the highest sensitivity and negative predictive value (NPV) as well as the second highest specificity and positive predictive value (PPV). CMCT showed the highest specificity and PPV. Regarding functional status (MBI), FA showed the highest sensitivity and NPV, whereas CMCT had the highest specificity and PPV. Correlation analysis showed that the resting motor threshold (RMT) ratio was strongly associated with motor status of the upper limb, and MEP parameters were not associated with MBI. CONCLUSION: DTT and MEPs could be suitable complementary modalities for analyzing the motor and functional status of patients in the subacute stage of stroke. The RMT ratio was strongly correlated with motor status. PMID- 26949680 TI - Effects of a Resting Foot Splint in Early Brain Injury Patients. AB - OBJECTIVE: To assess the effectiveness of the resting foot splint to prevent ankle contracture. METHODS: We performed a randomized controlled trial in 33 patients with brain injury with ankle dorsiflexor weakness (muscle power <=grade 2). Both groups continued conventional customized physical therapy, but the patients in the foot splint group were advised to wear a resting foot splint for more than 12 hours per day for 3 weeks. The data were assessed before and 3 weeks after the study. The primary outcome was the change in ankle dorsiflexion angle after 3 weeks. RESULTS: Before the study, there were no differences between groups in gender, age, time post-injury, brain injury type, initial edema, spasticity, passive range of ankle dorsiflexion, Fugl-Meyer score (FMS), or Functional Ambulation Classification. A significant improvement in ankle dorsiflexion angle, and FMS was found after 3 weeks in both groups. The splint group showed more spasticity than the control group after 3 weeks (p=0.04). The change of ankle dorsiflexion angle, foot circumference, spasticity, and FMS after adjusting initial value and spasticity were not significantly different between the 2 groups. CONCLUSION: Wearing a resting foot splint for 3 weeks did not affect joint mobility in patients with subacute brain injury regularly attending personalized rehabilitation programs. Further studies of larger sample sizes with well controlled in spasticity are required to evaluate the effects of the resting foot splint. PMID- 26949681 TI - The Additive Effects of Core Muscle Strengthening and Trunk NMES on Trunk Balance in Stroke Patients. AB - OBJECTIVE: To investigate an additive effect of core muscle strengthening (CMS) and trunk neuromuscular electrical stimulation (tNEMS) on trunk balance in stroke patients. METHODS: Thirty patients with acute or subacute stroke who were unable to maintain static sitting balance for >5 minutes were enrolled and randomly assigned to 3 groups, i.e., patients in the CMS (n=10) group received additional CMS program; the tNMES group (n=10) received additional tNMES over the posterior back muscles; and the combination (CMS and tNMES) group (n=10) received both treatments. Each additional treatment was performed 3 times per week for 20 minutes per day over 3 weeks. Korean version of Berg Balance Scale (K-BBS), total score of postural assessment scale for stroke patients (PASS), Trunk Impairment Scale (TIS), and Korean version of Modified Barthel Index (K-MBI) were evaluated before and after 3 weeks of therapeutic intervention. RESULTS: All 3 groups showed improvements in K-BBS, PASS, TIS, and K-MBI after therapeutic interventions, with some differences. The combination group showed more improvements in K-BBS and the dynamic sitting balance of TIS, as compared to the CMS group; and more improvement in K-BBS, as compared to the tNMES group. CONCLUSION: The results indicated an additive effect of CMS and tNMES on the recovery of trunk balance in patients with acute or subacute stroke who have poor sitting balance. Simultaneous application of CMS and tNMES should be considered when designing a rehabilitation program to improve trunk balance in stroke patients. PMID- 26949682 TI - Cognitive and Language Function in Aphasic Patients Assessed With the Korean Version of Mini-Mental Status Examination. AB - OBJECTIVE: To assess the clinical usefulness of the relatively short instrument, the Korean version of the Mini-Mental State Examination (MMSE-K), for testing the association between cognition and language function in subacute post-stroke aphasia patients. METHODS: Medical charts of 111 post-stroke patients (65 men; age 69.6+/-10.0 years; 124.6+/-80.6 days post-onset) were reviewed retrospectively. All patients were assessed longitudinally for aphasia using the validated Korean version of the Western Aphasia Battery (K-WAB) and for cognition using the MMSE-K. Patients were categorized and analyzed according to 3 aphasia severity clusters. RESULTS: All subscales of the K-WAB showed significant improvement in follow-up assessments in all groups (p<0.05 or p<0.01). Only the scores of orientation, language function, and total score of MMSE-K showed significant improvement in all groups (p<0.01). The more severely impaired group showed stronger Pearson correlation coefficients between cognition and language function. Additionally, comparisons between correlation coefficients showed that the association of improvement in orientation with that of fluency and AQ% (aphasia quotient %) was significant in the more severely impaired group. CONCLUSION: Among subacute post-stroke aphasic patients, patients with more severe aphasia showed greater impairments to cognitive function; in addition, recovery of orientation may be related to recovery of language function. PMID- 26949683 TI - A Wide Spectrum of Axial Mesodermal Dysplasia Complex With Rhombencephalic Anomaly: A Case Report. AB - Axial mesodermal dysplasia complex (AMDC) arises in variable combinations of craniocaudal anomalies such as musculoskeletal deformities, neuroschisis, or rhombencephalic developmental disorders. To the best of our knowledge, the co existence of AMDC with associated musculoskeletal anomalies, medullary neuroschisis with mirror movements, and cranial nerve anomalies has not yet been reported. Here, we report the case of a 4-year-old boy whose clinical features were suggestive of Goldenhar syndrome and Poland syndrome with Sprengel deformity. Moreover, he showed mirror movements in his hands suspected of rhombencephalic malformation, and infranuclear-type facial nerve palsy of the left side of his face, the opposite side to the facial anomalies of Goldenhar syndrome. After conducting radiological studies, he was diagnosed with medullary neuroschisis without pontine malformations and Klippel-Feil syndrome with rib anomalies. Based on these findings, we propose that clinical AMDC can be accompanied by a wide variety of musculoskeletal defects and variable degrees of central nervous system malformations. Therefore, in addition to detailed physical and neurological examinations, imaging studies should be considered in AMDC. PMID- 26949684 TI - Bilateral Cranial IX and X Nerve Palsies After Mild Traumatic Brain Injury. AB - We report a 57-year-old man with bilateral cranial nerve IX and X palsies who presented with severe dysphagia. After a mild head injury, the patient complained of difficult swallowing. Physical examination revealed normal tongue motion and no uvular deviation. Cervical X-ray findings were negative, but a brain computed tomography revealed a skull fracture involving bilateral jugular foramen. Laryngoscopy indicated bilateral vocal cord palsy. In a videofluoroscopic swallowing study, food residue remained in the vallecula and pyriform sinus, and there was reduced motion of the pharynx and larynx. Electromyography confirmed bilateral superior and recurrent laryngeal neuropathy. PMID- 26949685 TI - Calcaneal Osteomyelitis due to Non-tuberculous Mycobacteria: A Case Report. AB - Osteomyelitis is a bone infection caused by bacteria or other germs. Gram positive cocci are the most common etiological organisms of calcaneal osteomyelitis; whereas, non-tuberculous mycobacteria (NTM) are rarely documented. We reported a case of NTM calcaneal osteomyelitis in a 51-year-old female patient. She had been previously treated in many local clinics with multiple local steroid injection over 50 times and extracorporeal shock-wave therapy over 20 times with the impression of plantar fasciitis for 3 years prior. Diagnostic workup revealed a calcaneal osteomyelitis and polymerase chain reaction assay on bone aspirate specimens confirmed the diagnosis of non-tuberculous mycobacterial osteomyelitis. The patient had a partial calcanectomy with antitubercular therapy. Six months after surgery, a follow-up magnetic resonance imaging showed localized chronic osteomyelitis with abscess formation. We continued anti tubercular therapy without operation. At 18-month follow-up after surgery and comprehensive rehabilitation therapy, she was ambulating normally and able to carry out her daily activities without any discomfort. PMID- 26949686 TI - Zolpidem-Induced Arousal by Paradoxical GABAergic Stimulation: A Case Report With F-18 Flumazenil Positron Emission Tomography and Single Photon Emission Computed Tomography Study. AB - Zolpidem is a non-benzodiazepine drug that has selectivity for the gamma aminobutyric acid (GABA) receptors. We experienced paradoxical effect of zolpidem in a 48-year-old male patient with hypoxic-ischemic brain injury after cardiac arrest. The patient was in stupor and could not communicate. His Glasgow Coma Scale (GCS) was E2M4V2 and Rancho Los Amigos (RLA) was grade III to IV. Zolpidem was prescribed to induce sedation but paradoxically, he became alert (GCS 15, RLA VII) and was able to communicate. The arousal lasted for 2 hours repeatedly following each administration of the medication. While he was alert, electroencephalogram showed the reversal of slow wave into beta range fast activity and F-18 flumazenil positron emission tomography (PET) showed increased GABAergic receptor activity in both frontoparietotemporal cortices. Single photon emission computed tomography (SPECT) also showed increased cerebral perfusion and reversal of cerebellar diaschisis. PMID- 26949687 TI - Moderate Patient-Prosthesis Mismatch Has No Negative Effect on Patients' Functional Status After Aortic Valve Replacement With CarboMedics Prosthesis. AB - BACKGROUND: Patient-prosthesis mismatch (PPM) after aortic valve replacement (AVR) is the subject of continuing debate in the cardiac surgery field. OBJECTIVES: The aim of this study was to evaluate the frequency and severity of patient-prosthesis mismatch (PPM) and the functional status of patients undergoing aortic valve replacement (AVR) using a CarboMedics prosthesis in the mid-term follow up. PATIENTS AND METHODS: We retrospectively studied 66 consecutive patients who were referred to AVR with a CarboMedics prosthesis at the Rajaie cardiovascular medical and research center, a university referral hospital in Tehran, Iran. The severity of PPM as well as clinical and echocardiographic parameters and the patients' New York heat association (NYHA) functional classification status, operative data and postoperative complications, and mortality in a mid-term (4 - 5 months) follow up period was assessed. Severe PPM was defined as the effective orifice area (EOA) indexed to the patient's body surface area (BSA) < 0.65 cm(2)/m(2) and moderate PPM was defined as the indexed effective orifice area (IEOA) between 0.65 and 0.85 cm(2)/m(2). RESULTS: Of the 66 studied patients, 39 were male and 27 were female. The mean age of the patients was 43 +/- 17 with a range of 6 - 76 years. Implanted sizes of the CarboMedics AV prosthesis in 22 patients were 19 and 21 mm, and in 44 patients were 23 and 25 mm. Eleven patients had moderate PPM (IEOA < 0.85 cm(2)/m(2)) and 55 of them did not have PPM (IEOA >= 0.85 cm(2)/m(2)). There were no statistically significant differences between the two groups in the echocardiographic trans-aortic pressure gradients (35.6 +/- 19 vs. 23.2 +/- 16 mmHg; P = 0.061) and the mean NYHA functional classification (1.10 +/- 0.3 vs. 1.01 +/- 0.10; P = 0.074) after AVR in the mid-term follow up. CONCLUSIONS: Moderate PPM has no negative effect on echocardiographic trans-aortic pressure gradients or the patients' NYHA functional status after AVR with a CarboMedics prosthesis in the mid-term follow up. PMID- 26949688 TI - Assessment of Thyroid Function in Idiopathic Pulmonary Hypertension. AB - BACKGROUND: Idiopathic pulmonary hypertension (IPAH) is a rare, debilitating, and fatal disease. Late-onset treatment can lead to right heart failure, multiple organ damage, and death. Since the thyroid plays a major role in the metabolism and hemodynamics in humans, the screening of thyroid function is crucial. Thyroid dysfunction has been reported to cause pulmonary hypertension, but the thyroid is also involved in IPAH. OBJECTIVES: The aim of this study was to evaluate thyroid function in IPAH patients. PATIENTS AND METHODS: Fifty-three IPAH patients aged 16 - 75 years-old were enrolled in this cross sectional study, and their right ventricular functions, hemodynamics, and six minute walk tests (SMWTs) were evaluated. Thyroid function tests were conducted, and their associations with the patients' pulmonary arterial pressures (PAPs) and functional capacities were assessed. The data were analyzed using the SPSS 15 statistical software. RESULTS: In this research, 84.8% of the participants were women. The mean PAP was 51.6 mmHg (31-87) and mean thyroid stimulating hormone (TSH) level was 4.2 mIU/ml (0.7 - 10). Subclinical hypothyroidism was detected in 26 patients (49.1%). There were significant correlations of the TSH level with the right ventricular (RV) end diastolic dimension (P value = 0.05) and triiodothyronine (T3) with the tricuspid annular plane systolic excursion (TAPSE) (P value = 0.04), an inverse relationship between the SMWT and the TSH level (P value = 0.004), but no significant relationship between these parameters and the thyroxine (T4) level. CONCLUSIONS: IPAH is associated with subclinical hypothyroidism and low patient functional capacity, and is more common in RV failure. PMID- 26949689 TI - Effect of Hypericum perforatum Aqueous Extracts on Serum Lipids, Aminotransferases, and Lipid Peroxidation in Hyperlipidemic Rats. AB - BACKGROUND: Patients with high levels of total cholesterol (TCH), low-density lipoprotein cholesterol (LDL-CH), and triglyceride (TG) are at increased risk of coronary heart disease. Studies have shown that flavonoids and antioxidant compounds have beneficial effects on hyperlipidemia. OBJECTIVES: The aim of the present study was to evaluate the effects of extract of Hypericum perforatum (EHP) on the serum lipid profile (TCH, TG, and LDL-CH), aminotransferase, alkaline phosphatase, and lipid peroxidation in hyperlipidemic rats. MATERIALS AND METHODS: Thirty-two male rats weighting 200 +/- 10 g were randomly divided into four experimental groups: 1) control, 2) control + EHP, 3) hyperlipidemia, and 4) hyperlipidemia + EHP. The rats in the hyperlipidemic groups were fed a high-fat diet for 60 days, and EHP (300 mg/kg) was injected intraperitoneally for 2 weeks in the rats in the second and fourth groups. At the end of the experimental period, blood samples from each group were analyzed. RESULTS: There was a significant reduction in LDL-CH in the control + EHP group and the hyperlipidemia + EHP group (P < 0.05). TCH was significantly reduced in the control + EHP group (P < 0.05). There were no significant changes in the levels of TG and HDL-CH. Malondialdehyde, aspartate aminotransferase, and alanine aminotransferase were significantly reduced in the hyperlipidemia + EHP group (P < 0.05), with no significant change in alkaline phosphatase. CONCLUSIONS: EHP was able to both reduce LDL-CH and to significantly decrease markers of oxidative stress and lipid peroxidation induced by hyperlipidemia. Therefore, this herb, as a new pharmacological component, could be used to reduce certain blood lipids, lipid peroxidation, and aminotransferase markers. PMID- 26949690 TI - Right-Sided Minithoracotomy as a Surgical Approach for the Concomitant Treatment of Atrial Fibrillation. AB - BACKGROUND: Atrial fibrillation (AF) is the most common arrhythmia diagnosed in humans and therefore causes a high socioeconomic burden. The Cox-Maze IV procedure is the gold standard treatment for atrial fibrillation. Minimally invasive surgery for the treatment of AF is also promising. OBJECTIVES: Our aim is to evaluate the feasibility, safety, and immediate plus medium-term results of concomitant AF ablation therapy in patients undergoing minimally invasive valve surgery through right-sided minithoracotomy. PATIENTS AND METHODS: Retrospective data were collected from January 2012 to December 2013. Seventy-five consecutive patients underwent radiofrequency ablation during valve surgery through a right sided minithoracotomy. RESULTS: All 75 patients underwent radiofrequency ablation. The pulmonary vein was isolated in 6 (8%) by encircling the left and right pulmonary veins. In 9 (12%) patients, endocardial box lesions were created using a monopolar probe, while in 47 (62.7%), epicardial box lesions were produced with a monopolar probe. Thirteen (17.3%) patients received a box lesion created with a bipolar probe. Finally, in 22 (29.3%) patients, a line of lesions was produced leading up to the posterior mitral annulus. Only 1 (1.3%) perioperative death was observed. At discharge, 43 (57.3%) patients were in sinus rhythm and 30 (40%) were in AF. After a mean follow-up of 21.6 +/- 10.1 months, 46 patients (63%) were in a stable sinus rhythm and 27 were in (37%) in AF; 26 (56.5%) patients were free from antiarrhythmic therapy, while 19 (42.2%) were still taking at least one drug. CONCLUSIONS: We can conclude that treatment of AF using a right-sided minithoracotomy approach and RF energy in patients undergoing cardiac surgery for various valve diseases is feasible, safe, and reproducible. PMID- 26949691 TI - The Effects of Side Branch Predilation During Provisional Stenting of Coronary Bifurcation Lesions: A Double-Blind Randomized Controlled Trial. AB - BACKGROUND: There is a paucity of data regarding the role of side branch (SB) predilation during the provisional stenting of bifurcation lesions. OBJECTIVES: The present study aimed to assess the effects of SB predilation on the outcomes of true bifurcation interventions. PATIENTS AND METHODS: Sixty patients with true bifurcation lesions according to the Medina classification were included in the study and randomly assigned to receive SB predilation before stenting the main branch (n = 30) or no predilation as the control group (n = 30). RESULTS: There was a trend toward the higher occurrence of dissection in the predilated ostial lesions of the SB compared to the non-predilated group (16.7% vs. 0, P = 0.07). Performance of the SB predilation was not associated with improved flow of the SB or fewer degrees of ostial stenosis after stenting the main branch, the need to rewire, rewiring time, or the rate of use of the final kissing balloon dilation and double stents procedures. CONCLUSIONS: Routine predilation of the SB in provisional stenting of true bifurcation lesions seems to be ineffective and might be associated with some undesirable consequences. Still, there are some complex ostial lesions of the SB which could benefit from predilation. PMID- 26949692 TI - Double Guide Catheter Technique for Sealing an Iatrogenic Coronary Perforation. AB - INTRODUCTION: Coronary vessel perforation is one of the most feared complications of coronary angioplasty. The treatment of this complication relies mostly on the implantation of covered stents. However, due to their design, covered stents are difficult to advance in a tortuous or calcified vessel. CASE PRESENTATION: We present a case of a grade III coronary perforation in which the double guiding catheter technique helped us to deliver the graft stent. CONCLUSIONS: The double guiding technique is useful in emergency situations to increase the safety and efficacy of sealing a coronary perforation. PMID- 26949693 TI - A Rare Case of Acute Coronary Syndrome in a Patient With Turner Syndrome. AB - INTRODUCTION: In Turner syndrome, cardiovascular complications are the most important causes of early mortality. Congenital cardiovascular abnormalities are found in approximately one third of Turner syndrome patients. Developments in diagnosis and treatment have decreased the rate of mortality related to these abnormalities. In recent years, many papers have mentioned that coronary artery disease developing at early ages in patients with Turner syndrome causes sudden deaths. CASE PRESENTATION: The patient, a 27-year-old female was admitted to the emergency room with chest pain at rest. She was diagnosed with Turner Syndrome in her teenage years due to amenorrhea. Patients with ECG changes and cardiac enzyme elevations were treated with acute coronary syndrome. CONCLUSIONS: The young woman with Turner Syndrome have several risk factors for early Coronary Artery Disease development. In such cases, dramatic results like sudden death or heart attack at an early age may occur in cases of insufficient follow-up and treatment. PMID- 26949694 TI - Assessment of QT and JT Intervals in Patients With Left Bundle Branch Block. AB - BACKGROUND: Prolongation of the QT interval is considered a risk factor for cardiac adverse events and mortality. Left bundle branch block (LBBB) lengthens the QT interval. The corrected QT interval (QTc) is most likely overestimated because its prolongation is caused by increases in depolarization duration and not in repolarization. OBJECTIVES: In this study, we aimed to apply corrected JT interval (JTc) as an appropriate measure of ventricular repolarization for predicting QTc in a formula. PATIENTS AND METHODS: The study population consisted of 101 patients with sinus rhythm (SR) and narrow QRS complexes (< 120 milliseconds). All patients underwent electrophysiology studies or ablation. A diagnostic catheter was positioned in the right ventricular apex (RVA) to induce LBBB at two different cycle lengths (CLs; 600 and 700 mv). The intrinsic QRS complex, QT time, and JT time were measured during SR and subsequent RVA pacing. The JTc was derived simply by subtracting the QRS duration from the QTc. RESULTS: Stimulation from the RVA increased the QTc from 456.20 +/- 38.63 ms to 530.67 +/- 47.73 ms at a CL of 600 (P < 0.0001) and to 502.32 +/- 47.26 ms at 700 CL (P < 0.0001). JTc showed no significant changes with stimulation from the RVA (102.97 +/- 11.35 ms vs. 103.59 +/- 10.67 ms, P = 0.24). There was no significant correlation between JTc and QRS complex duration. A significant correlation was seen between QRS and QTc at both CLs. The ROC curve indicated that sensitivity of 80% and specificity of 67% were obtained with JTc duration of 92.6 ms. CONCLUSIONS: Right ventricular pacing increases the QT interval without increasing the JT interval. Our results confirm that JTc, as an index of repolarization, is independent of ventricular depolarization. Therefore, it can be applied for predicting QTc in patients with LBBB. PMID- 26949695 TI - Automatic Mode Switch (AMS) Causes Less Synchronization. AB - INTRODUCTION: Cardiac resynchronization devices are part of modern heart failure management. After implantation, we analyze and program devices in an attempt to ensure their success. Biventricular pacing should be 98% or more for the lowest mortality and best symptom improvement. CASE PRESENTATION: In this case series, we present a combination of far field sensing and automatic mode switching (AMS) in six patients. It is found that this combination causes ventricular sensing (VS) episodes with wide QRS and no synchronization. We turn off the AMS and alleviate the problem. CONCLUSIONS: Switching AMS off may increase biventricular pacing in some patients. PMID- 26949697 TI - Billowing Of Endologix Powerlink Stent Mimicking Endoleaks. AB - INTRODUCTION: Endoleaks remains one of the primary concerns of endovascular aortic aneurysm repair (EVAR) and is routinely followed with CT angiography (CTA). However, certain imaging findings can mimic endoleaks. CASE PRESENTATION: A 65-year-old woman who had endovascular aortic repair (EVAR) of an abdominal aortic aneurysm with Endologix Powerlink system developed marked new circumferential cauliflower-like bulging of contrast-filled sacs at mid-stent graft with enlargement of the excluded aneurysm at 3-year follow-up. CONCLUSIONS: Considering the unique construct of the Powerlink stents, this is thought to represent aneurysmal degeneration of the outer fabric material from the metal struts and may potentially pressurize the excluded sac with risk for rupture. PMID- 26949696 TI - Targeting Advanced Glycation End Products in Cardiac Surgery: The Unexplored Alternative. PMID- 26949698 TI - Letter to the editor on "Early and Mid-Term Outcome of Pediatric Congenital Mitral Valve Surgery". PMID- 26949699 TI - Developmental neurogenetics of sexual dimorphism in Aedes aegypti. AB - Sexual dimorphism, a poorly understood but crucial aspect of vector mosquito biology, encompasses sex-specific physical, physiological, and behavioral traits related to mosquito reproduction. The study of mosquito sexual dimorphism has largely focused on analysis of the differences between adult female and male mosquitoes, particularly with respect to sex-specific behaviors related to disease transmission. However, sexually dimorphic behaviors are the products of differential gene expression that initiates during development and therefore must also be studied during development. Recent technical advancements are facilitating functional genetic studies in the dengue vector Aedes aegypti, an emerging model for mosquito development. These methodologies, many of which could be extended to other non-model insect species, are facilitating analysis of the development of sexual dimorphism in neural tissues, particularly the olfactory system. These studies are providing insight into the neurodevelopmental genetic basis for sexual dimorphism in vector mosquitoes. PMID- 26949701 TI - The Comparative Evaluation of the Antimicrobial Effect of Propolis with Chlorhexidine against Oral Pathogens: An In Vitro Study. AB - This study aimed to compare the antimicrobial effectiveness of ethanolic extract of propolis (EEP) to chlorhexidine gluconate (CHX) on planktonic Streptococcus mutans, Streptococcus sobrinus, Lactobacillus acidophilus, Lactobacillus salivarius subsp. salivarius, Aggregatibacter actinomycetemcomitans, Prevotella intermedia, Porphyromonas gingivalis, Staphylococcus aureus, Enterococcus faecalis, Actinomyces israelii, Candida albicans, and their single-species biofilms by agar dilution and broth microdilution test methods. Both agents inhibited the growth of all planktonic species. On the other hand, CHX exhibited lower minimum bactericidal concentrations than EEP against biofilms of A. actinomycetemcomitans, S. aureus, and E. faecalis whereas EEP yielded a better result against Lactobacilli and P. intermedia. The bactericidal and fungicidal concentrations of both agents were found to be equal against biofilms of Streptecocci, P. gingivalis, A. israelii, and C. albicans. The results of this study revealed that propolis was more effective in inhibiting Gram-positive bacteria than the Gram-negative bacteria in their planktonic state and it was suggested that EEP could be as effective as CHX on oral microorganisms in their biofilm state. PMID- 26949702 TI - Evaluation of Hepatotoxicity with Treatment Doses of Flucytosine and Amphotericin B for Invasive Fungal Infections. AB - Invasive fungal infection is a well-known cause of morbidity and mortality in immunocompromised patients. In this study we aimed to evaluate the hepatotoxicity induced by combined therapy of flucytosine and amphotericin B, at three different doses administered to mice for 14 days: 50 mg/kg flucytosine and 300 MUg/kg amphotericin B; 100 mg/kg flucytosine and 600 MUg/kg amphotericin B; 150 mg/kg flucytosine and 900 MUg/kg amphotericin B. Liver injuries were evaluated by analysis of optic and electron microscopy samples, changes in TNF-alpha, IL-6, and NF-kappaB inflammation markers levels of expression, and evaluation of mRNA profiles. Histological and ultrastructural analysis revealed an increase in parenchymal and portal inflammation in mice and Kupffer cells activation. Combined antifungal treatment stimulated activation of an inflammatory pathway, demonstrated by a significant dose-dependent increase of TNF-alpha and IL-6 immunoreactivity, together with mRNA upregulation. Also, NF-kappaB was activated, as suggested by the high levels found in hepatic tissue and upregulation of target genes. Our results suggest that antifungal combined therapy exerts a synergistic inflammatory activation in a dose-dependent manner, through NF-kappaB pathway, which promotes an inflammatory cascade during inflammation. The use of combined antifungal therapy needs to be dose limiting due to the associated risk of liver injury, especially for those patients with hepatic dysfunction. PMID- 26949703 TI - Recombinant Brain Natriuretic Peptide for the Prevention of Contrast-Induced Nephropathy in Patients with Chronic Kidney Disease Undergoing Nonemergent Percutaneous Coronary Intervention or Coronary Angiography: A Randomized Controlled Trial. AB - The role of brain natriuretic peptide (BNP) in the prevention of contrast-induced nephropathy (CIN) is unknown. This study aimed to investigate BNP's effect on CIN in chronic kidney disease (CKD) patients undergoing elective percutaneous coronary intervention (PCI) or coronary angiography (CAG). The patients were randomized to BNP (0.005 MUg/kg/min before contrast media (CM) exposure and saline hydration, n = 106) or saline hydration alone (n = 103). Cystatin C, serum creatinine (SCr) levels, and estimated glomerular filtration rates (eGFR) were assessed at several time points. The primary endpoint was CIN incidence; secondary endpoint included changes in cystatin C, SCr, and eGFR. CIN incidence was significantly lower in the BNP group compared to controls (6.6% versus 16.5%, P = 0.025). In addition, a more significant deterioration of eGFR, cystatin C, and SCr from 48 h to 1 week (P < 0.05) was observed in controls compared to the BNP group. Although eGFR gradually deteriorated in both groups, a faster recovery was achieved in the BNP group. Multivariate logistic regression revealed that using >100 mL of CM (odds ratio: 4.36, P = 0.004) and BNP administration (odds ratio: 0.21, P = 0.006) were independently associated with CIN. Combined with hydration, exogenous BNP administration before CM effectively decreases CIN incidence in CKD patients. PMID- 26949700 TI - Commonly Used Dietary Supplements on Coagulation Function during Surgery. AB - BACKGROUND: Patients who undergo surgery appear to use dietary supplements significantly more frequently than the general population. Because they contain pharmacologically active compounds, dietary supplements may affect coagulation and platelet function during the perioperative period through direct effects, pharmacodynamic interactions, and pharmacokinetic interactions. However, in this regard, limited studies have been conducted that address the pharmacological interactions of dietary supplements. To avoid possible bleeding risks during surgery, information of potential complications of dietary supplements during perioperative management is important for physicians. METHODS: Through a systematic database search of all available years, articles were identified in this review if they included dietary supplements and coagulation/platelet function, while special attention was paid to studies published after 1990. RESULTS: Safety concerns are reported in commercially available dietary supplements. Effects of the most commonly used natural products on blood coagulation and platelet function are systematically reviewed, including 11 herbal medicines (echinacea, ephedra, garlic, ginger, ginkgo, ginseng, green tea, kava, saw palmetto, St John's wort, and valerian) and 4 other dietary supplements (coenzyme Q10, glucosamine and chondroitin sulfate, fish oil, and vitamins). Bleeding risks of garlic, ginkgo, ginseng, green tea, saw palmetto, St John's wort, and fish oil are reported. Cardiovascular instability was observed with ephedra, ginseng, and kava. Pharmacodynamic and pharmacokinetic interactions between dietary supplements and drugs used in the perioperative period are discussed. CONCLUSIONS: To prevent potential problems associated with the use of dietary supplements, physicians should be familiar with the perioperative effects of commonly used dietary supplements. Since the effects of dietary supplements on coagulation and platelet function are difficult to predict, it is prudent to advise their discontinuation before surgery. PMID- 26949704 TI - Efficacy and Safety of Novel Agent-Based Therapies for Multiple Myeloma: A Meta Analysis. AB - This study aimed at comparing bortezomib, thalidomide, and lenalidomide in patients with multiple myeloma (MM) for safety and efficacy using meta-analysis. This meta-analysis identified 17 randomized controlled trials (RCTs) including 6742 patients. These RCTs were separated according to the different agent-based regimens and to autologous stem-cell transplantation (ASCT). Complete response (CR), progression-free survival (PFS), overall survival (OS), and adverse events (AE) were combined. The total weighted risk ratio (RR) of CR was 3.29 [95% confidence interval (95% CI): 2.22-4.88] (P < 0.0001) for the novel agent-based regimens. These novel agent-based regimens showed greater benefit in terms of PFS of all subgroups irrespective of whether the patient received ASCT or not. The hazard ratio (HR) for PFS was 0.64 [95% CI: 0.60-0.69] (P < 0.00001). Improvements of OS could be found only in the bortezomib- and thalidomide-based regimens without ASCT. The pooled HRs were 0.74 [95% CI: 0.65-0.86] (P < 0.0001) and 0.80 [95% CI: 0.70-0.90] (P = 0.0004), respectively. Several AEs were shown more frequently in the novel agent-based regimens compared with controls such as hematologic events (neutropenia, anemia, and thrombocytopenia), gastrointestinal infection, peripheral neuropathy, thrombosis, and embolism events. In conclusion, in spite of the AEs, novel agent-based regimens are safe and effective for the treatment of MM. PMID- 26949706 TI - Circulating Long Noncoding RNA UCA1 as a Novel Biomarker of Acute Myocardial Infarction. AB - Acute myocardial infarction (AMI) is the most serious cardiovascular disease with high morbidity and mortality. Recent studies have showed that long noncoding RNAs (lnc RNA) play important roles in pathophysiology of cardiovascular diseases, but the investigations are still in their infancy. An lnc RNA named urothelial carcinoma-associated 1 (UCA1) is found in tumors such as bladder cancers and lung cancer. And the UCA1 could be as a predictive biomarker for bladder cancer in urine samples or lung cancer in plasma, respectively. In normal states, UCA1 is specifically expressed in heart of adult, indicating that UCA1 might be as a biomarker for heart diseases such as AMI. To test the speculation, we detect the level of UCA1 in plasma of AMI patients and health control using quantitative reverse transcription-polymerase chain reaction (qRT-PCR). In addition, we also test the level of miR-1 as it is reported to regulate the expression of UCA1. The results show that the level of plasma UCA1 is decreased at the early state of AMI patients and increased at day 3 after AMI. In addition, the UCA1 alteration is inversely associated with the expression of miR-1. These findings indicate that the circulating UCA1 could be used as a promising novel biomarker for the diagnosis and/or prognosis of AMI. PMID- 26949705 TI - Development of a Murine Infection Model with Leishmania killicki, Responsible for Cutaneous Leishmaniosis in Algeria: Application in Pharmacology. AB - In Algeria, Leishmania infantum, Leishmania major, and Leishmania killicki (Leishmania tropica) are responsible for cutaneous leishmaniosis. We established a murine model of L. killicki infection to investigate its infective capacity, some immunophysiopathological aspects, and its suitability for pharmacological purposes. Following the injection of L. major or L. killicki metacyclic promastigotes in the ear dermis of BALB/c mice, the course of infection was followed. The infection with L. killicki caused slower lesion formation than with L. major. The presence of L. killicki or L. major DNA and parasites was detected in the ear dermis and in lymph nodes, spleen, and liver. Lesions induced by L. killicki were nonulcerative in their aspect, whereas those caused by L. major were highly ulcerative and necrotic, which matches well with the lesion phenotype reported in humans for L. killicki and L. major, respectively. The treatment of L. killicki lesions by injection of Glucantime(r) significantly reduced the lesion thickness and parasite burden. Ear dermal injection of BALB/c mice constitutes a model to study lesions physiopathology caused by L. killicki and presents interest for in vivo screening of new compounds against this pathogen, emerging in Algeria. PMID- 26949707 TI - The Synthesis and Evaluations of the (6 8) Ga-Lissamine Rhodamine B (LRB) as a New Radiotracer for Imaging Tumors by Positron Emission Tomography. AB - PURPOSE: The aim of this study is to synthesize and evaluate (68)Ga-labeled Lissamine Rhodamine B (LRB) as a new radiotracer for imaging MDA-MB-231 and MCF-7 cells induced tumor mice by positron emission tomography (PET). METHODS: Firstly, we performed the radio synthesis and microPET imaging of (68)Ga(DOTA-LRB) in athymic nude mice bearing MDA-MB-231 and MCF-7 human breast cancer xenografts. Additionally, the evaluations of (18)F-fluorodeoxyglucose (FDG), as a glucose metabolism radiotracer for imaging tumors in the same xenografts, have been conducted as a comparison. RESULTS: The radiochemical purity of (68)Ga(DOTA-LRB) was >95%. MicroPET dynamic imaging revealed that the uptake of (68)Ga(DOTA-LRB) was mainly in normal organs, such as kidney, heart, liver, and brain and mainly excreted from kidney. The MDA-MB-231 and MCF-7 tumors were not clearly visible in PET images at 5, 15, 30, 40, 50, and 60 min after injection of (68)Ga(DOTA-LRB). The tumor uptake values of (18)F-FDG were 3.79 +/- 0.57 and 1.93 +/- 0.48%ID/g in MDA-MB-231 and MCF-7 tumor xenografts, respectively. CONCLUSIONS: (68)Ga(DOTA LRB) can be easily synthesized with high radiochemical purity and stability; however, it may be not an ideal PET radiotracer for imaging of MDR-positive tumors. PMID- 26949708 TI - Erratum to "NADPH Oxidase-Induced NALP3 Inflammasome Activation Is Driven by Thioredoxin-Interacting Protein Which Contributes to Podocyte Injury in Hyperglycemia". PMID- 26949709 TI - High intercorneal symmetry in corneal biomechanical metrics. AB - BACKGROUD: To evaluate the symmetry of corneal biomechanical metrics, measured using an ocular response analyzer (ORA) and self-built corneal inflation test platform, in bilateral rabbit corneas and to investigate their relationship with physical intraocular pressure (IOPp). METHODS: Twenty fresh enucleated eyes from ten rabbits were used for ex vivo whole ocular globe inflation. IOP was increased from 7.5 to 37.5 mmHg with 7.5 mmHg steps and biomechanical metrics were acquired using the ORA. At least 3 examinations were performed at each pressure stage. Two biomechanical metrics, corneal hysteresis (CH) and corneal resistance factor (CRF) were recorded and analyzed as a function of IOPp. Corneal specimens were then excised from the intact ocular globe and tested under inflation conditions up to 45.7 mmHg posterior pressure. The experimental pressure-deformation data was analyzed using an inverse modeling procedure to derive the stress-strain behavior of the cornea. RESULTS: A comparison of corneal shape parameters showed no statistically significant difference (P > 0.05) between bilateral eyes. Similarly, there were no statistically significant differences in values of CH, CRF and corneal stiffness (as measured by the tangent modulus, Et) between bilateral eyes (CH: F = 0.94, P = 0.54; CRF: F = 4.42, P = 0.35; Et: F = 3.15, P = 0.12) at different pressure levels. IOPp was highly correlated with CRF while the relationship with CH was less pronounced. CONCLUSIONS: An obvious interocular symmetry in biomechanical metrics is found in this research. IOP has been shown to have important influences on the value of CRF provided by ORA. PMID- 26949710 TI - Identifying the Attended Speaker Using Electrocorticographic (ECoG) Signals. AB - People affected by severe neuro-degenerative diseases (e.g., late-stage amyotrophic lateral sclerosis (ALS) or locked-in syndrome) eventually lose all muscular control. Thus, they cannot use traditional assistive communication devices that depend on muscle control, or brain-computer interfaces (BCIs) that depend on the ability to control gaze. While auditory and tactile BCIs can provide communication to such individuals, their use typically entails an artificial mapping between the stimulus and the communication intent. This makes these BCIs difficult to learn and use. In this study, we investigated the use of selective auditory attention to natural speech as an avenue for BCI communication. In this approach, the user communicates by directing his/her attention to one of two simultaneously presented speakers. We used electrocorticographic (ECoG) signals in the gamma band (70-170 Hz) to infer the identity of attended speaker, thereby removing the need to learn such an artificial mapping. Our results from twelve human subjects show that a single cortical location over superior temporal gyrus or pre-motor cortex is typically sufficient to identify the attended speaker within 10 s and with 77% accuracy (50% accuracy due to chance). These results lay the groundwork for future studies that may determine the real-time performance of BCIs based on selective auditory attention to speech. PMID- 26949711 TI - Isolation and sequencing of active origins of DNA replication by nascent strand capture and release (NSCR). AB - Nascent strand capture and release (NSCR) is a method for isolation of short nascent strands to identify origins of DNA replication. The protocol provided involves isolation of total DNA, denaturation, size fractionation on a sucrose gradient, 5'-biotinylation of the appropriate size nucleic acids, binding to a streptavidin coated magnetic beads, intensive washing, and specific release of only the RNA-containing chimeric nascent strand DNA using ribonuclease I (RNase I). The method has been applied to mammalian cells derived from proliferative tissues and cell culture but could be used for any system where DNA replication is primed by a small RNA resulting in chimeric RNA-DNA molecules. PMID- 26949713 TI - Erratum: Safety and Immunogenicity of Modified Vaccinia Ankara-Bavarian Nordic Smallpox Vaccine in Vaccinia-Naive and Experienced Human Immunodeficiency Virus Infected Individuals: An Open-Label, Controlled Clinical Phase II Trial. AB - [This corrects the article DOI: 10.1093/ofid/ofv040.]. PMID- 26949712 TI - Using Computer Vision and Depth Sensing to Measure Healthcare Worker-Patient Contacts and Personal Protective Equipment Adherence Within Hospital Rooms. AB - Background. We determined the feasibility of using computer vision and depth sensing to detect healthcare worker (HCW)-patient contacts to estimate both hand hygiene (HH) opportunities and personal protective equipment (PPE) adherence. Methods. We used multiple Microsoft Kinects to track the 3-dimensional movement of HCWs and their hands within hospital rooms. We applied computer vision techniques to recognize and determine the position of fiducial markers attached to the patient's bed to determine the location of the HCW's hands with respect to the bed. To measure our system's ability to detect HCW-patient contacts, we counted each time a HCW's hands entered a virtual rectangular box aligned with a patient bed. To measure PPE adherence, we identified the hands, torso, and face of each HCW on room entry, determined the color of each body area, and compared it with the color of gloves, gowns, and face masks. We independently examined a ground truth video recording and compared it with our system's results. Results. Overall, for touch detection, the sensitivity was 99.7%, with a positive predictive value of 98.7%. For gowned entrances, sensitivity was 100.0% and specificity was 98.15%. For masked entrances, sensitivity was 100.0% and specificity was 98.75%; for gloved entrances, the sensitivity was 86.21% and specificity was 98.28%. Conclusions. Using computer vision and depth sensing, we can estimate potential HH opportunities at the bedside and also estimate adherence to PPE. Our fine-grained estimates of how and how often HCWs interact directly with patients can inform a wide range of patient-safety research. PMID- 26949714 TI - Is Emtricitabine-Tenofovir Disoproxil Fumarate Pre-exposure Prophylaxis for the Prevention of Human Immunodeficiency Virus Infection Safer Than Aspirin? AB - Background. The safety and effectiveness studies of emtricitabine-tenofovir disoproxil fumarate (FTC-TDF) for human immunodeficiency virus (HIV) infection pre-exposure prophylaxis (PrEP) in men and women showed that daily use reduced the risk of HIV acquisition, but there still may concerns about safety. Methods. A narrative review was done in September 2015 comparing the 5 major studies on PrEP for HIV infection-Preexposure Prophylaxis Initiative (N = 2499; 3324 person years), Partners Preexposure Prophylaxis (N = 4747; 7830 person-years), TDF2 (N = 1219; 1563 person-years), Preexposure Prophylaxis Trial for HIV Prevention among African Women (N = 2056; 1407 person-years), and Vaginal and Oral Interventions to Control the Epidemic (N = 4969; 5509 person-years)-and the 2 major studies on aspirin safety-Physicians' Health Study (N = 22 071; over 110 000 person-years) and the Women's Health Study (N = 39 876; approximately 400 000 person-years). The numbers needed to harm (NNH) were calculated for FTC-TDF for HIV infection PrEP and aspirin. Results. The NNH for FTC-TDF in men who have sex with men and transgender women was 114 for nausea and 96 for unintentional weight loss; in heterosexual couples, the NNH was 68 for moderate decreased absolute neutrophil count. For aspirin, the NNH was 909 for major gastrointestinal bleeding, 123 for any gastrointestinal bleeding, and 15 for any bleeding problems in men. In women, the NNH for easy bruising was 10. Conclusions. We conclude that FTC-TDF for PrEP for HIV infection favorably compares with aspirin in terms of user safety. Although long-term studies are needed, providers should feel reassured about the safety of short- and medium-term PrEP for HIV infection with FTC-TDF. PMID- 26949715 TI - Chronic Osteomyelitis Due to Tissierella carlieri: First Case. PMID- 26949716 TI - Immune Control Despite Protracted Lymphopenia After Chemoradiation in an Elite Controller. AB - Elite controllers are human immunodeficiency virus-1-positive individuals capable of sustaining undetectable viral loads without treatment. We present the case of an elite controller diagnosed with extensive stage small cell lung cancer who maintained a viral load of <20 copies/mL despite the development of severe treatment-related lymphopenia. PMID- 26949718 TI - Silver Staining of Alzheimer's Disease. PMID- 26949717 TI - The Effect of Switching to Second-Line Antiretroviral Therapy on the Risk of Opportunistic Infections Among Patients Infected With Human Immunodeficiency Virus in Northern Tanzania. AB - Background. Due to the unintended potential misclassifications of the World Health Organization (WHO) immunological failure criteria in predicting virological failure, limited availability of treatment options, poor laboratory infrastructure, and healthcare providers' confidence in making switches, physicians delay switching patients to second-line antiretroviral therapy (ART). Evaluating whether timely switching and delayed switching are associated with the risk of opportunistic infections (OI) among patients with unrecognized treatment failure is critical to improve patient outcomes. Methods. A retrospective review of 637 adolescents and adults meeting WHO immunological failure criteria was conducted. Timely and delayed switching to second-line ART were defined when switching happened at <3 and >=3 months, respectively, after failure diagnosis was made. Cox proportional hazard marginal structural models were used to assess the effect of switching to second-line ART on the risk of developing OI. Results. Of 637 patients meeting WHO immunological failure criteria, 396 (62.2%) switched to second-line ART. Of those switched, 230 (58.1%) were delayed. Switching to second-line ART reduced the risk of OI (adjusted hazards ratio [AHR], 0.4; 95% CI, .2-.6). Compared with patients who received timely switch after failure diagnosis was made, those who delayed switching were more likely to develop OI (AHR, 2.2; 95% CI, 1.1-4.3). Conclusion. Delayed switching to second-line ART after failure diagnosis may increase the risk of OI. Serial immunological assessment for switching patients to second-line ART is critical to improve their outcomes. PMID- 26949719 TI - Microglial P2 Purinergic Receptor and Immunomodulatory Gene Transcripts Vary By Region, Sex, and Age in the Healthy Mouse CNS. AB - Inflammatory damage in many neurodegenerative diseases is restricted to certain regions of the CNS, and while microglia have long been implicated in the pathology of many of these disorders, information comparing their gene expression in different CNS regions is lacking. Here we tested the hypothesis that the expression of purinergic receptors, estrogen receptors and other neuroprotective and pro-inflammatory genes differed among CNS regions in healthy mice. Because neurodegenerative diseases vary in incidence by sex and age, we also examined the regional distribution of these genes in male and female mice of four different ages between 21 days and 12 months. We postulated that pro-inflammatory gene expression would be higher in older animals, and lower in young adult females. We found that microglial gene expression differed across the CNS. Estrogen receptor alpha (Esr1) mRNA levels were often lower in microglia from the brainstem/spinal cord than from the cortex, whereas tumor necrosis factor alpha (Tnfalpha) expression was several times higher. In addition, the regional pattern of gene expression often changed with animal age; for example, no regional differences in P2X7 mRNA levels were detected in 21 day-old animals, but at 7 weeks and older, expression was highest in cerebellar microglia. Lastly, the expression of some genes was sexually dimorphic. In microglia from 12 month-old animals, mRNA levels of inducible nitric oxide synthase, but not Tnfalpha, were higher in females than males. These data suggest that microglial gene expression is not uniformly more pro-inflammatory in males or older animals. Moreover, microglia from CNS regions in which neuronal damage predominates in neurodegenerative disease do not generally express more pro-inflammatory genes than microglia from regions less frequently affected. This study provides an in-depth assessment of regional-, sex and age-dependent differences in key microglial transcripts from the healthy mouse CNS. PMID- 26949721 TI - Preoperative anemia, blood transfusion, and neutrophil-to-lymphocyte ratio in patients with stage i non-small cell lung cancer. AB - Perioperative and postoperative blood transfusions (BT), anemia and inflammation are associated with poor survivals in patients with non-small cell lung cancer (NSCLC). This study investigated the impact of perioperative BT on the survival of patients with NSCLC taking into account their preoperative inflammatory status and the presence of anemia. Demographic, perioperative, and survival data for 861 patients with stage I NSCLC was collected retrospectively. The primary endpoints of interest were recurrence-free (RFS) and overall survival (OS). Before and after propensity score matching, univariate and multivariable Cox proportional hazards models were used to evaluate the association between covariates and survival. A neutrophil-to-lymphocyte ratio (NLR) < 5 (hazard ratio [HR]: 0.58, 95% CI: 0.38-0.87; p = 0.009) and normal Hb concentration (HR: 0.72, 95% CI: 0.72; p = 0.022) were independently associated with longer RFS. The administration of blood perioperatively was associated with a trend towards worse RFS (HR: 0.69, 95% CI: 0.47-1.02; p = 0.066). The multivariate analysis also revealed that an NLR < 5 (HR: 0.48, 95% CI: 0.3-0.76; p = 0.001) and the absence of BT (HR: 0.63, 95% CI: 0.4-0.98; p = 0.04) were significantly associated with lower mortality risk. The propensity score matching analysis did not confirm the association between BT and poor RFS (HR: 0.63, 95% CI: 0.35-1.1; p = 0.108) and OS (HR: 0.52, 95% CI: 0.26-1.04; p = 0.06). Inflammation and anemia are common finding in patients with stage 1 NSCLC. After adjusting for these two important confounders, this study confirms that previous reports demonstrating an association between BT and poor survival after NSCLC surgery. PMID- 26949720 TI - Asynchronous inflammation and myogenic cell migration limit muscle tissue regeneration mediated by a cellular scaffolds. AB - Volumetric muscle loss (VML) following orthopaedic trauma results in chronic loss of strength and can contribute to disability. Tissue engineering and regenerative medicine approaches to regenerate the lost skeletal muscle and improve functional outcomes are currently under development. At the forefront of these efforts, decellularized extracellular matrices (ECMs) have reached clinical testing and provide the foundation for other approaches that include stem/progenitor cell delivery. ECMs have been demonstrated to possess many qualities to initiate regeneration, to include stem cell chemotaxis and pro-regenerative macrophage polarization. However, the majority of observations indicate that ECM-repair of VML does not promote appreciable muscle fiber regeneration. In a recent study, ECM-repair of VML was compared to classical muscle fiber regeneration (Garg et al., 2014, Cell & Tissue Research) mediated by autologous minced grafts. The most salient findings of this study were: 1) Satellite cells did not migrate into the scaffold beyond ~0.5 mm from the remaining host tissue, although other migratory stem cells (Sca-1+) were observed throughout the scaffold;2) Macrophage migration to the scaffold was over two-times that observed with muscle grafts, but they appeared to be less active, as gene expression of pro- and anti-inflammatory cytokines (TNF-alpha, IL-12, IL-4, IL-10, VEGF, and TGF-beta1) was significantly reduced in scaffold-repaired muscles; And, 3) scaffolds did not promote appreciable muscle fiber regeneration. Collectively, these data suggest that the events following ECM transplantation in VML are either incongruous or asynchronous with classical muscle fiber regeneration. PMID- 26949722 TI - Prevalence of Pulmonary Tuberculosis among Prison Inmates at Mbarara Central Prison, South Western Uganda. AB - AIMS: This study was conducted to determine the prevalence of tuberculosis among prison inmates at Mbarara Central prison. DESIGN: A cross sectional study was carried out at Mbarara Central Prison in Mbarara district, Kiswahili cell in Mbarara municipality among female and male prison in mates between June 2012 to August 2012. A questionnaire was administered to each prison inmate who consented in writing and two sputum specimens were collected and examined by Ziehl-Neelsen technique. RESULTS: At the time of the study, the prison had 900 inmates (both males and females). A total of 648 in mates were screened and 248 inmates enrolled in the study. Of the 248 inmates, 5 inmates were new cases of TB while 29 inmates were already on TB treatment. The median age of participants was 28 years (23.5-33 IQR) and 96.4% were males with majority (22.6%) coming from Mbarara as a home district. The participants had stayed in prison for a median duration of 2 years (1-3 IQR) and 23.7% had ever been in prison before. The median number of inmates per cell was 140 (138-149 IQR) and inmates (female and male) had a body mass index of 21.4 (19.9-22.6 IQR) and 20.2 (19.2-26.7 IQR) respectively. Of the inmates evaluated, 68.8% reported cough for 2 or more weeks. Other symptoms reported were weight loss (in 40.7%) and night sweats (in 35.8%). Of the 248 inmates evaluated, 95 inmates were tested for HIV and 4.1% were HIV serology positive. CONCLUSION: The prevalence of TB in Mbarara Central prison South Western Uganda is low but calls for continued surveillance through regular TB screening. PMID- 26949723 TI - Mechanisms for motor timing in the cerebellar cortex. AB - In classical eyeblink conditioning a subject learns to blink to a previously neutral stimulus. This conditional response is timed to occur just before an air puff to the eye. The learning is known to depend on the cerebellar cortex where Purkinje cells respond with adaptively timed pauses in their spontaneous firing. The pauses in the inhibitory Purkinje cells cause disinhibition of the cerebellar nuclei, which elicit the overt blinks. The timing of a Purkinje cell response was previously thought to require a temporal code in the input signal but recent work suggests that the Purkinje cells can learn to time their responses through an intrinsic mechanism that is activated by metabotropic glutamate receptors (mGluR7). PMID- 26949725 TI - Data in support of proteomic analysis of pneumococcal pediatric clinical isolates to construct a protein array. AB - Surface proteins play key roles in the interaction between cells and their environment, and in pathogenic microorganisms they are the best targets for drug or vaccine discovery and/or development. In addition, surface proteins can be the basis for serodiagnostic tools aiming at developing more affordable techniques for early diagnosis of infection in patients. We carried out a proteomic analysis of a collection of pediatric clinical isolates of Streptococcus pneumoniae, an important human pathogen responsible for more than 1.5 million child deaths worldwide. For that, cultured live bacterial cells were "shaved" with trypsin, and the recovered peptides were analyzed by LC/MS/MS. We selected 95 proteins to be produced as recombinant polypeptides, and printed them on an array. We probed the protein array with a collection of patient sera to define serodiagnostic antigens. The mass spectrometry proteomics data correspond to those published in [1] and have been deposited to the ProteomeXchange Consortium [2] via the PRIDE partner repository [3] with the dataset identifier PXD001740. The protein array raw data are provided as supplemental material in this article. PMID- 26949726 TI - Dataset of long-term compressive strength of concrete with manufactured sand. AB - This paper presents 186 groups compressive strength tests data of concrete with manufactured sand (MSC) in different curing age and 262 groups compressive strength tests data of MSC at 28 days collected from authors' experiments and other researches in China. Further interpretation and discussion were described in this issues. PMID- 26949724 TI - Timing in the visual cortex and its investigation. AB - While many high-level cortical areas have been implicated in timing, timing activity has also been observed even in the earliest cortical stages of the visual system over the past decade. This activity has been formally modeled as one arising from a reinforcement signal, leading to testable hypotheses with recent experimental support, demonstrating the necessity and sufficiency of that reinforcement signal. As observed in other cortical areas implicated in timing, interval timing activity within the visual cortex abides by the temporal scalar property. Finally, perturbations of the visual cortex during interval timing results in lawful shifts in timing. These and related observations advance the notion that visual cortex is a substrate for learning and expressing visually associated temporal expectations governing behaviorally-relevant actions. PMID- 26949727 TI - Data for the identification of proteins and post-translational modifications of proteins associated to histones H3 and H4 in S. cerevisiae, using tandem affinity purification coupled with mass spectrometry. AB - Tandem affinity purification method (TAP) allows the efficient purification of native protein complexes which incorporate a target protein fused with the TAP tag. Purified multiprotein complexes can then be subjected to diverse types of proteomic analyses. Here we describe the data acquired after applying the TAP strategy on histones H3 and H4 coupled with mass spectrometry to identify associated proteins and protein post-translational modifications in the budding yeast, Saccharomyces cerevisiae. The mass spectrometry dataset described here consists of 14 files generated from four different analyses in a 5600 Triple TOF (Sciex) by information-dependent acquisition (IDA) LC-MS/MS. The above files contain information about protein identification, protein relative abundance, and PTMs identification. The instrumental raw data from these files has been also uploaded to the ProteomeXchange Consortium via the PRIDE partner repository, with the dataset identifier PRIDE: PXD002671 and http://dx.doi.org/10.6019/PXD002671. These data are discussed and interpreted in http://dx.doi.org/10.1016/j.jprot.2016.01.004. Valero et al. (2016) [1]. PMID- 26949728 TI - Data related to cyclic deformation and fatigue behavior of direct laser deposited Ti-6Al-4V with and without heat treatment. AB - Data is presented describing the strain-controlled, fully-reversed uniaxial cyclic deformation and fatigue behavior of Ti-6Al-4V specimens additively manufactured via Laser Engineered Net Shaping (LENS) - a Direct Laser Deposition (DLD) process. The data was collected by performing multiple fatigue tests on specimens with various microstructural states/conditions, i.e. in their 'as built', annealed (below the beta transus temperature), or heat treated (above the beta transus temperature) condition. Such data aids in characterizing the mechanical integrity and fatigue resistance of DLD parts. Data presented herein also allows for elucidating the strong microstructure coupling of the fatigue behavior of DLD Ti-6Al-4V, as the data trends were found to vary with material condition (i.e. as-built, annealed or heat treated) [1]. This data is of interest to the additive manufacturing and fatigue scientific communities, as well as the aerospace and biomedical industries, since additively-manufactured parts cannot be reliably deployed for public use, until their mechanical properties are understood with high certainty. PMID- 26949729 TI - Data on isolating mesenchymal stromal cells from human adipose tissue using a collagenase-free method. AB - The present dataset describes a detailed protocol to isolate mesenchymal cells from human fat without the use of collagenase. Human fat specimen, surgically cleaned from non-fat tissues (e.g., blood vessels) and reduced into smaller fat pieces of around 1-3 mm size, is incubated in complete culture media for five to seven days. Then, cells started to spread out from the fat explants and to grow in cultures according to an exponential pattern. Our data showed that primary mesenchymal cells presenting heterogeneous morphology start to acquire more homogenous fibroblastic-like shape when cultured for longer duration or when subcultured into new flasks. Cell isolation efficiency as well as cell doubling time were also calculated throughout the culturing experimentations and illustrated in a separate figure thereafter. This paper contains data previously considered as an alternative protocol to isolate adipose-derived mesenchymal stem cell published in "Proliferation and differentiation of human adipose-derived mesenchymal stem cells (ASCs) into osteoblastic lineage are passage dependent" [1]. PMID- 26949730 TI - Data and performances evaluation of the SPIDIA-DNA Pan-European External Quality Assessment: 2nd SPIDIA-DNA laboratory report. AB - Within the EU-SPIDIA project (www.spidia.eu), the quality parameters of blood genomic DNA were defined [SPIDIA-DNA: an External Quality Assessment for the pre analytical phase of blood samples used for DNA-based analyses - [1]; Influence of pre-analytical procedures on genomic DNA integrity in blood samples: the SPIDIA experience - [2]; Combining qualitative and quantitative imaging evaluation for the assessment of genomic DNA integrity: the SPIDIA experience - [3]. DNA quality parameters were used to evaluate the laboratory performance within an External Quality Assessment (EQA) [Second SPIDIA-DNA External Quality Assessment (EQA): Influence of pre-analytical phase of blood samples on genomic DNA quality - [4]. These parameters included DNA purity and yield by UV spectrophotometric measurements, the presence of PCR interferences by Kineret software and genomic DNA integrity analysis by Pulsed Field Gel Electrophoresis. Here we present the specific laboratory report of the 2nd SPIDIA-DNA EQA as an example of data and performances evaluation. PMID- 26949731 TI - Raw and processed microscope images of fixed cells at baseline and following various experimental perturbations. AB - The data included in this article comprise raw and processed images of fixed cells at baseline and subjected to various experimental perturbations. This dataset includes images of HUVEC cells fixed and subsequently incubated at either 37 degrees C or room temperature, primary rat vascular smooth muscle cells exposed to 25 mM glucose, and SH-SY5Y neurons exposed to hydrogen peroxide. Raw images appear exactly as they were captured on the microscope, while processed images show the binarization provided by software used for measurements of mitochondrial morphology. For in-depth discussion of the experiments and computational methods pertaining to this data, please refer to the corresponding research article titled "Fully automated software for quantitative measurements of mitochondrial morphology" (McClatchey et al., in press) [1]. PMID- 26949732 TI - Foxl1-expressing mesenchymal cells constitute the intestinal stem cell niche. AB - BACKGROUND & AIMS: Intestinal epithelial stem cells that express Lgr5 and/or Bmi1 continuously replicate and generate differentiated cells throughout life1. Previously, Paneth cells were suggested to constitute an epithelium-intrinsic niche that regulates the behavior of these stem cells2. However, ablating Paneth cells has no effect on maintenance of functional stem cells3-5. Here, we demonstrate definitively that a small subset of mesenchymal, subepithelial cells expressing the winged-helix transcription factor Foxl1 are a critical component of the intestinal stem cell niche. METHODS: We genetically ablated Foxl1+ mesenchymal cells in adult mice using two separate models by expressing either the human or simian diphtheria toxin receptor (DTR) under Foxl1 promoter control. CONCLUSIONS: Killing Foxl1+ cells by diphtheria toxin administration led to an abrupt cessation of proliferation of both epithelial stem- and transit-amplifying progenitor-cell populations that was associated with a loss of active Wnt signaling to the intestinal epithelium. Therefore, Foxl1-expressing mesenchymal cells constitute the fundamental niche for intestinal stem cells. PMID- 26949734 TI - A multimodal approach to dementia prevention: A report from the Cambridge Institute of Public Health. AB - INTRODUCTION: Globally, dementia is the most frequent form of degenerative condition in the older adult population and poses a major health burden with high socioeconomic costs. So far, attempts to find pharmacologic interventions that can change the onset or progression of dementia have been largely unsuccessful, prompting a shift to focus on interventions aimed at modifying risk factors that occur throughout the life course. METHODS: The Cognitive Function and Ageing Studies, funded by the Medical Research Council, UK, convened three multidisciplinary groups of experts, expert witnesses, and advocates to discuss the state of evidence on primary, secondary, and tertiary dementia prevention and recommend future direction for intervention studies. RESULTS: Using the United Kingdom Parliamentary Select Committees' approach to gathering evidence, the primary prevention working group focused their deliberation on risk factors strongly associated with dementia. The group highlighted the need for high quality studies to assess the effects of behavioral intervention on the delay of cognitive decline and dementia onset. DISCUSSION: The working group recommended that the development of a future dementia prevention trial should use a multimodal, multifactor, multilevel, community and individually tailored approach. PMID- 26949735 TI - Challenges and Benefits in Designing and Implementing a Team-Based Research Mentorship Experience in Translational Research. AB - BACKGROUND: Translational research seeks to build bridges between research and practice to address public health issues efficiently and effectively. The purpose of this paper was to evaluate a newly formed Institute that provided graduate students and adolescent behavioral health community professionals with a translational research service-learning opportunity through the creation of a community-university mentoring partnership. Goals of the team-based research mentorship approach included: 1) providing students the skills for implementing translational research; 2) providing research opportunities for community agencies to enhance operations and to encourage ongoing research involvement; and 3) developing relationships between university faculty and community agency professionals for further research collaborations. METHODS: The Institute used the National Institute on Drug Abuse's Mentoring Mosaic to select a diverse group of Community and Academic Mentors. The research mentorship experience of the initial cohort was evaluated based upon the Research Mentorship Conceptual Framework and Self-Assessment Tool. RESULTS: As a direct result of the research mentorship, outcomes for the Academic and Community Mentors and Scholars (i.e., those seeking a graduate certificate) included improved working relationships/networking and research experience. Through experiential learning, Scholars also discovered career trajectory clarity, the need for community collaboration in research, opportunities for continuing professional development, a greater understanding of public health competencies and how they align with community-based research, and skill development in best practices for translational research. CONCLUSION: The team mentoring approach is a form of pedagogy that holds promise to enhance translational research and community-based research efforts while developing public health competencies. PMID- 26949733 TI - Mild Cognitive Impairment and Dementia Prevalence: The Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS). AB - INTRODUCTION: We examined prevalence of mild cognitive impairment (MCI) and dementia in the Atherosclerosis Risk in Communities (ARIC) Neurocognitive Study. METHODS: Beginning in June, 2011, we invited all surviving ARIC participants to undergo cognitive, neurological and brain imaging assessments to diagnose MCI or dementia and assign an etiology for the cognitive disorder. RESULTS: Of 10713 surviving ARIC participants (age range 69-88 yrs), we ascertained cognitive diagnoses in 6471 in-person, 1966 by telephone interviews (participant or informant) and the remainder by medical record review. The prevalence of dementia was 9.0% and MCI 21%. Alzheimer's disease was the primary or secondary etiology in 76% of dementia and 75% of MCI participants. Cerebrovascular disease was the primary or secondary etiology in 46% of dementia and 32% of MCI participants. DISCUSSION: MCI and dementia were common among survivors from the original ARIC cohort. Nearly 30% of the ARIC cohort received diagnoses of either dementia or MCI, and for the majority of these individuals (about 75%) the etiologic basis was attributed to Alzheimer's disease. PMID- 26949736 TI - Characteristics and Outcomes of Renal Transplant Recipients with Hemolytic Uremic Syndrome in the United States. AB - BACKGROUND: Hemolytic uremic syndrome (HUS) accounts for <1% of renal transplants in the US. There are limited data on the characteristics and outcomes of HUS in pediatric and adult kidney transplant recipients in the US. METHODS: This study included all renal transplant recipients identified with HUS (N=1,233) as a cause of end-stage renal disease between 1987 and 2013 using the UNOS/OPTN database. The cohort was divided into two age groups: pediatric (N=447) and adult (N=786). Main outcomes were acute rejection rate at one-year, allograft and patient survival, and recurrence of HUS post-transplant. Both age groups were then compared with a propensity score (1:2 ratio) matched control group with an alternative primary kidney disease (non-HUS cohort: pediatric [N= 829] and adult [N=1,547]). RESULTS: In pediatric cohort, when compared to the PS matched controls, acute rejection, death censored allograft and patient survival was similar in the HUS group. However, in the adult cohort, the graft and patient survivals were significantly worse in the HUS group. HUS was associated with allograft loss (HR=1.40, 95%CI 1.14-1.71) in adult recipients. Patients with HUS recurrence had significantly lower allograft and patient survival rates compared to the non-recurrent group in both age groups. Acute rejection was one of the major predictor of HUS recurrence in adults (OR=2.64, 95%CI 1.25-5.60). Calcineurin inhibitors (CNI) were not associated HUS recurrence in both age groups. CONCLUSION: Pediatric HUS-patients, unlike adult recipients, have similar outcomes compared to the PS matched controls. Recurrence of HUS is associated with poor allograft and patient survival in pediatric and adult patients. Use of CNIs seem to be safe as a part of maintenance immunosuppression post transplantation. A comprehensive national registry is urgently needed. PMID- 26949737 TI - Genetic Testing and Neuroimaging: Trading off Benefit and Risk for Youth with Mental Illness. AB - According to the World Health Organization, mental illness is one of the leading causes of disability worldwide. The first onset of mental illness usually occurs during childhood or adolescence. Neuroimaging and genetic testing have been invaluable in research on behavioral and intentional disorders, particularly with their potential to lead to improved diagnostic and predictive capabilities and to decrease the associated burdens of disease. The present study focused specifically the perspectives of mental health providers on the role of neuroimaging and genetic testing in clinical practice with children and adolescents. We interviewed 38 psychiatrists, psychologists, and allied mental health professionals who work primarily with youth about their receptivity towards either the use of neuroimaging or genetic testing. Interviews probed the role they foresee for these modalities for prediction, diagnosis, and treatment planning, and the benefits and risks they anticipate. Practitioners anticipated three major benefits associated with clinical introduction of imaging and genetic testing in the mental health care for youth: (1) improved understanding of illness, (2) more accurate diagnosis than available through conventional clinical examination, and (3) validation of treatment plans. They also perceived three major risks: (1) potential adverse impacts on employment and insurance as adolescents reach adulthood, (2) misuse or misinterpretation of the imaging or genetic data, and (3) infringements on self-esteem or self-motivation. Movement of brain imaging and genetic testing into clinical care will require a delicate balance of biology and respect for autonomy in the still-evolving cognitive and affective world of young individuals. PMID- 26949738 TI - The effects of navigation and types of neighborhoods on timely follow-up of abnormal mammogram among black women. AB - BACKGROUND: Despite the availability of relatively simple and inexpensive screening tools, minority women are more often diagnosed at a late stage of breast cancer, in part due to delays in follow-up of abnormal screening result. One of the key factors for timely follow-up of abnormal mammogram may be neighborhood characteristics. Patient Navigation (PN) programs aim to diminish barriers, but its differential effects by neighborhood have not been fully examined. The current study examines the effect of types of neighborhoods on time to follow-up of abnormal mammogram, and the differential effects of PN by neighborhood characteristics. METHODS: We examined data from a total of 1,696 randomized patients from a randomized controlled trial, "the Patient Navigation in Medically Underserved Areas" study that explored the effect of navigation on breast health outcomes. We categorized participants' neighborhoods into three categories and compared the effect of navigation between these neighborhood types. RESULTS: Navigated women in mixed race neighborhoods had a shorter time to follow-up compared with non-navigated women in the neighborhoods. Black women living in mixed neighborhoods had a significant longer time to follow-up of abnormal mammogram, compared with black women living in middle class black neighborhoods. CONCLUSION: Patient navigation interventions improve timely follow up of abnormal mammogram. Patient navigation may be particularly beneficial for minority women who reside in racially heterogeneous neighborhoods which may be less likely to have access to affordable health clinics and social services. Health policies concerning breast cancer early detection for minority women need to pay further attention to those who might potentially be excluded from health services due to the characteristics of neighborhoods. Socioeconomic conditions of neighborhood may affect individual health through multiple interlinked mechanisms. Neighborhood characteristics, such as poverty, segregation, access to resources, and social cohesion, cannot be fully understood with simplistic measures of neighborhood disadvantage. PMID- 26949739 TI - Identification of Human Neuronal Protein Complexes Reveals Biochemical Activities and Convergent Mechanisms of Action in Autism Spectrum Disorders. AB - The prevalence of autism spectrum disorders (ASDs) is rapidly growing, yet its molecular basis is poorly understood. We used a systems approach in which ASD candidate genes were mapped onto the ubiquitous human protein complexes and the resulting complexes were characterized. The studies revealed the role of histone deacetylases (HDAC1/2) in regulating the expression of ASD orthologs in the embryonic mouse brain. Proteome-wide screens for the co-complexed subunits with HDAC1 and six other key ASD proteins in neuronal cells revealed a protein interaction network, which displayed preferential expression in fetal brain development, exhibited increased deleterious mutations in ASD cases, and were strongly regulated by FMRP and MECP2 causal for Fragile X and Rett syndromes, respectively. Overall, our study reveals molecular components in ASD, suggests a shared mechanism between the syndromic and idiopathic forms of ASDs, and provides a systems framework for analyzing complex human diseases. PMID- 26949740 TI - Translation of Genotype to Phenotype by a Hierarchy of Cell Subsystems. AB - Accurately translating genotype to phenotype requires accounting for the functional impact of genetic variation at many biological scales. Here we present a strategy for genotype-phenotype reasoning based on existing knowledge of cellular subsystems. These subsystems and their hierarchical organization are defined by the Gene Ontology or a complementary ontology inferred directly from previously published datasets. Guided by the ontology's hierarchical structure, we organize genotype data into an "ontotype," that is, a hierarchy of perturbations representing the effects of genetic variation at multiple cellular scales. The ontotype is then interpreted using logical rules generated by machine learning to predict phenotype. This approach substantially outperforms previous, non-hierarchical methods for translating yeast genotype to cell growth phenotype, and it accurately predicts the growth outcomes of two new screens of 2,503 double gene knockouts impacting DNA repair or nuclear lumen. Ontotypes also generalize to larger knockout combinations, setting the stage for interpreting the complex genetics of disease. PMID- 26949741 TI - Electrocardiographic Markers and the Left Ventricular Ejection Fraction have Cumulative Effects on Risk of Sudden Cardiac Death. AB - OBJECTIVES: To assess potential improvement in SCD risk prediction by adding selected risk markers from the 12-lead ECG to measurement of the left ventricular ejection fraction (LVEF). BACKGROUND: Novel strategies to improve risk stratification for sudden cardiac death (SCD) are needed. Given the modest odds associated with most individual risk markers, combining multiple markers may be a useful approach. METHODS: From the ongoing Oregon Sudden Unexpected Death Study, SCD cases with pre-event LVEF available were compared to matched control subjects with coronary artery disease. Resting heart rate, QRS duration (QRSD), and JTc intervals were measured from archived ECGs prior and unrelated to the SCD event. Independent odds of SCD for individual and combined ECG markers were calculated. RESULTS: SCD cases (n= 317; 67.9 +/- 12.9 years) were more likely than controls (n=317; 67.9 +/- 12.8 years) to have LVEF <= 35% (26% vs. 11%). Mean heart rate, QRSD, and JTc were significantly higher in cases (all p<0.0001). In adjusted analyses, higher heart rate [OR 2.6 (1.8 - 3.7)], QRSD [OR 1.5 (1.0 - 2.5)] and JTc [OR 2.3 (1.6 - 3.4)] were independently associated with SCD. When ECG markers were combined, SCD odds progressively increased with one [OR 3.4 (2.1 - 5.4)] and >= 2 elevated markers [OR 6.3 (3.3 - 12.1)]. Addition of ECG markers to an adjusted model with LVEF improved discrimination (C statistic 0.724 vs. 0.642) and net reclassification (by 22.7%) (p<0.0001). CONCLUSIONS: Combining selected 12-lead ECG markers with LVEF improves SCD risk prediction, and warrants further investigation in prospective studies. PMID- 26949742 TI - Detection of siRNA-mediated target mRNA cleavage activities in human cells by a novel stem-loop array RT-PCR analysis. AB - The small interfering RNA (siRNA)-mediated target mRNA cleavage activity generates cleaved mRNA fragments with varied termini, which creates major technical challenges for the accurate and efficient detection and verification of cleavage sites on target mRNAs. Here we used a sensitive stem-loop array reverse transcription polymerase chain reaction (SLA-RT-PCR) approach to detect and verify the siRNA-mediated target mRNA cleavage sites by determining precise sequences at the 3'-termini of cleaved mRNA fragments in human cells under physiological conditions. Our results demonstrated the great potential and broad applications of using the SLA-RT-PCR as a sensitive, cost-efficient, and high throughput tool to systematically detect siRNA-targeted mRNA cleavage sites and fragments in human cells. PMID- 26949743 TI - Coincidental Impact of Transcatheter Patent Foramen Ovale Closure on Migraine with and without Aura - A Comprehensive Meta-Analysis. AB - BACKGROUND: We analyzed the literature to assess the coincidental impact on migraines of transcatheter patent foramen ovale (PFO) closure performed for secondary stroke prevention. METHODS: We searched Medline, EMBASE, and the Cochrane database for studies published up until August 2013. We included English language studies that provided information on complete resolution or improvement in migraine headaches following PFO closure. Two study authors identified 375 original articles and both independently reviewed 32 relevant manuscripts. Data including study methodology, inclusion criteria, PFO closure and migraine outcomes were extracted manually from all eligible studies. Pooled odds (and probability) of resolution or improvement of migraine headaches were calculated using random-effects models. RESULTS: Twenty studies were analyzed. Most were uncontrolled studies that included a small number of patients with cryptogenic stroke who had undergone PFO closure and had variable time of followup. The probability of complete resolution of migraine with PFO closure (18 studies, 917 patients) was 0.46 (95% confidence interval 0.39, 0.53) and of any improvement in migraine (17 studies, 881 patients) was 0.78 (0.74, 0.82). There was evidence for publication bias in studies reporting on improvement in migraines (Begg's p=0.002), but not for studies on complete resolution of migraine (p=0.3). In patients with aura, the probability of complete resolution of migraine post-PFO closure was 0.54 (0.43, 0.65), and in those without aura, complete resolution occurred in 0.39 (0.29, 0.51). CONCLUSIONS: Among patients with unexplained stroke and migraine undergoing transcatheter PFO closure, resolution of headaches occurred in a majority of patients with aura and for a smaller proportion of patients without aura. PMID- 26949744 TI - Intercellular conduits in tumours: the new social network. AB - The role of intercellular communication is increasingly recognized as being critical to tumoral invasion, metastasis, and development of resistance to therapy. The recent discovery of cellular protrusions - tumour microtubes - connecting cancer cells in gliomas, and tunneling nanotubes in several other forms of cancer, sheds light on a novel mechanism for molecular networking. Interrupting and disrupting vital lines of intercellular cross-talk via these membranous cellular tubes has strong potential as a novel form of cancer-directed therapy. PMID- 26949747 TI - The Recruitment Experience of a Randomized Clinical Trial to Aid Young Adult Smokers to Stop Smoking without Weight Gain with Interactive Technology. AB - Multiple recruitment strategies are often needed to recruit an adequate number of participants, especially hard to reach groups. Technology-based recruitment methods hold promise as a more robust form of reaching and enrolling historically hard to reach young adults. The TARGIT study is a randomized two-arm clinical trial in young adults using interactive technology testing an efficacious proactive telephone Quitline versus the Quitline plus a behavioral weight management intervention focusing on smoking cessation and weight change. All randomized participants in the TARGIT study were required to be a young adult smoker (18-35 years), who reported smoking at least 10 cigarettes per day, had a BMI < 40 kg/m2, and were willing to stop smoking and not gain weight. Traditional recruitment methods were compared to technology-based strategies using standard descriptive statistics based on counts and proportions to describe the recruitment process from initial pre-screening (PS) to randomization into TARGIT. Participants at PS were majority Black (59.80%), female (52.66%), normal or over weight (combined 62.42%), 29.5 years old, and smoked 18.4 cigarettes per day. There were differences in men and women with respect to reasons for ineligibility during PS (p < 0.001; ignoring gender specific pregnancy-related ineligibility). TARGIT experienced a disproportionate loss of minorities during recruitment as well as a prolonged recruitment period due to either study ineligibility or not completing screening activities. Recruitment into longer term behavioral change intervention trials can be challenging and multiple methods are often required to recruit hard to reach groups. PMID- 26949746 TI - Cancer Evolution and the Limits of Predictability in Precision Cancer Medicine. AB - The ability to predict the future behavior of an individual cancer is crucial for precision cancer medicine. The discovery of extensive intratumor heterogeneity and ongoing clonal adaptation in human tumors substantiated the notion of cancer as an evolutionary process. Random events are inherent in evolution and tumor spatial structures hinder the efficacy of selection, which is the only deterministic evolutionary force. This review outlines how the interaction of these stochastic and deterministic processes, which have been extensively studied in evolutionary biology, limits cancer predictability and develops evolutionary strategies to improve predictions. Understanding and advancing the cancer predictability horizon is crucial to improve precision medicine outcomes. PMID- 26949745 TI - Ontogeny of Tumor-associated Macrophages and Its Implication in Cancer Regulation. AB - Macrophages are innate immune cells with evolutionarily conserved functions in tissue maintenance and host defense. As such, macrophages are among the first hematopoietic cells that seed developing tissues, and respond to inflammatory insults by in situ proliferation or de novo differentiation from monocytes. Recent studies have revealed that monocyte-derived tumor-induced macrophages represent a major tumor-associated macrophage population, which can further expand following their differentiation in tumors. Compared to tissue-resident tumor-associated macrophages, these newly differentiated cells are phenotypically distinct, and likely play a unique role in tissue dysregulation and immune modulation in cancer. These findings imply that tumor growth elicits a specific innate immune response. In this review, we explore the different routes of macrophage seeding and maintenance in tissues during steady state and inflammation and how these principles underlie the responses observed during tumor development. In addition, we highlight the relationship between the origin and function of macrophages in different settings and how this knowledge may be used to create new opportunities for cancer immunotherapy. PMID- 26949748 TI - Functional Effects of Schizophrenia-Linked Genetic Variants on Intrinsic Single Neuron Excitability: A Modeling Study. AB - BACKGROUND: Recent genome-wide association studies have identified a large number of genetic risk factors for schizophrenia (SCZ) featuring ion channels and calcium transporters. For some of these risk factors, independent prior investigations have examined the effects of genetic alterations on the cellular electrical excitability and calcium homeostasis. In the present proof-of-concept study, we harnessed these experimental results for modeling of computational properties on layer V cortical pyramidal cells and identified possible common alterations in behavior across SCZ-related genes. METHODS: We applied a biophysically detailed multicompartmental model to study the excitability of a layer V pyramidal cell. We reviewed the literature on functional genomics for variants of genes associated with SCZ and used changes in neuron model parameters to represent the effects of these variants. RESULTS: We present and apply a framework for examining the effects of subtle single nucleotide polymorphisms in ion channel and calcium transporter-encoding genes on neuron excitability. Our analysis indicates that most of the considered SCZ-related genetic variants affect the spiking behavior and intracellular calcium dynamics resulting from summation of inputs across the dendritic tree. CONCLUSIONS: Our results suggest that alteration in the ability of a single neuron to integrate the inputs and scale its excitability may constitute a fundamental mechanistic contributor to mental disease, alongside the previously proposed deficits in synaptic communication and network behavior. PMID- 26949749 TI - LOWER POSTERIOR CINGULATE CORTEX GLUTATHIONE LEVELS IN OBSESSIVE-COMPULSIVE DISORDER. AB - BACKGROUND: Several lines of evidence support the hypothesis that lower cerebral levels of glutathione (GSH), associated with increased oxidative stress, may contribute to obsessive-compulsive disorder (OCD). However, no studies to date have investigated brain GSH levels in individuals with OCD. METHODS: Twenty-nine individuals with OCD and 25 age-, sex-, and race-matched comparison individuals without OCD underwent single voxel 2D J-resolved proton magnetic resonance spectroscopy (MRS) to examine GSH levels in the posterior cingulate cortex (PCC). MRS data were analyzed using LCModel and a simulated basis set. Group metabolite differences referenced to total creatine (Cr), as well as relationships between metabolite ratios and symptom severity as measured by the Yale-Brown Obsessive Compulsive Scale (Y-BOCS), were analyzed using linear regression with adjustment for age, sex, and race. RESULTS: One OCD participant failed to produce usable PCC MRS data. We found significantly lower PCC GSH/Cr in OCD participants compared with non-OCD participants (beta = -0.027 [95% CI: -0.049 to -5.9 * 10-3]; P = 0.014). PCC GSH/Cr was not significantly associated with total Y-BOCS score in the OCD group (beta = 5.7 * 10-4 [95% CI: -4.8 * 10-3 to 5.9 * 10-3]; P = 0.83). CONCLUSIONS: Lower PCC GSH/Cr may be indicative of increased oxidative stress secondary to hypermetabolism in this brain region in OCD. Future MRS studies are warranted to investigate GSH levels in other brain regions that comprise the cortico-striato-thalamo-cortical circuit thought to be abnormal in OCD. PMID- 26949752 TI - Anti-Blur Feedback for Visually Impaired Users of Smartphone Cameras. AB - A wide range of smartphone applications are emerging that employ image processing and computer vision algorithms to interpret the contents of images acquired by the phone's built-in camera, including applications that read product barcodes and recognize a variety of documents and other objects. However, almost all of these applications are designed for normally sighted users; a major barrier for visually impaired users (who might benefit greatly from such applications) is the difficulty of taking good-quality images. To overcome this barrier, this paper focuses on reducing the incidence of motion blur, caused by camera shake and other movements, which is a common cause of poor-quality, unusable images. We propose a simple technique for detecting camera shake, using the smartphone's built-in accelerometer (i.e. tilt sensor) to alert the user in real-time to any shake, providing feedback that enables him/her to hold the camera more steadily. A preliminary experiment with a blind iPhone user demonstrates the feasibility of the approach. PMID- 26949750 TI - Shared neuroanatomical substrates of impaired phonological working memory across reading disability and autism. AB - BACKGROUND: Individuals with reading disability or individuals with autism spectrum disorder (ASD) are characterized, respectively, by their difficulties in reading or social communication, but both groups often have impaired phonological working memory (PWM). It is not known whether the impaired PWM reflects distinct or shared neuroanatomical abnormalities in these two diagnostic groups. METHODS: White-matter structural connectivity via diffusion weighted imaging was examined in sixty-four children, ages 5-17 years, with reading disability, ASD, or typical development (TD), who were matched in age, gender, intelligence, and diffusion data quality. RESULTS: Children with reading disability and children with ASD exhibited reduced PWM compared to children with TD. The two diagnostic groups showed altered white-matter microstructure in the temporo-parietal portion of the left arcuate fasciculus (AF) and in the temporo-occipital portion of the right inferior longitudinal fasciculus (ILF), as indexed by reduced fractional anisotropy and increased radial diffusivity. Moreover, the structural integrity of the right ILF was positively correlated with PWM ability in the two diagnostic groups, but not in the TD group. CONCLUSIONS: These findings suggest that impaired PWM is transdiagnostically associated with shared neuroanatomical abnormalities in ASD and reading disability. Microstructural characteristics in left AF and right ILF may play important roles in the development of PWM. The right ILF may support a compensatory mechanism for children with impaired PWM. PMID- 26949751 TI - Macrophages and the Viral Dissemination Super Highway. AB - Monocytes and macrophages are key components of the innate immune system yet they are often the victims of attack by infectious agents. This review examines the significance of viral infection of macrophages. The central hypothesis is that macrophage tropism enhances viral dissemination and persistence, but these changes may come at the cost of reduced replication in cells other than macrophages. PMID- 26949754 TI - Crosswatch: a Camera Phone System for Orienting Visually Impaired Pedestrians at Traffic Intersections. AB - Urban intersections are the most dangerous parts of a blind or visually impaired person's travel. To address this problem, this paper describes the novel "Crosswatch" system, which uses computer vision to provide information about the location and orientation of crosswalks to a blind or visually impaired pedestrian holding a camera cell phone. A prototype of the system runs on an off-the-shelf Nokia camera phone in real time, which automatically takes a few images per second, uses the cell phone's built-in computer to analyze each image in a fraction of a second and sounds an audio tone when it detects a crosswalk. Tests with blind subjects demonstrate the feasibility of the system and its ability to provide useful crosswalk alignment information under real-world conditions. PMID- 26949753 TI - Videos Influence Behavior Change Measures for Voice and Speech in Individuals with Parkinson's Disease. AB - The majority of individuals with Parkinson's disease (PD) experience voice and speech difficulties at some point over the course of the disease. Voice therapy has been found to help improve voice and speech in individuals with PD, but the majority of these individuals do not enroll in voice therapy. The purpose of this study was to determine whether watching short videos about voice symptoms and treatment in Parkinson's disease influences readiness to change, stages of change, and self-efficacy in individuals with PD. Eight individuals with PD participated in the study. Fifteen videos were chosen, three representing each of the five stages of change. We chose videos from YouTube that represented variety in speakers, content, and genre. We found that readiness to change significantly increased after watching videos, suggesting that watching videos helped these individuals move closer to actively improving their voice and speech. In addition, five of the eight participants showed forward movement in stages of change. Finally, self-efficacy demonstrated a positive trend following video watching. Overall, our results demonstrate that watching videos available on the internet can influence individuals with Parkinson's disease in changing vocal behavior. Implications for future wireless health applications are described. PMID- 26949755 TI - Search Strategies of Visually Impaired Persons using a Camera Phone Wayfinding System. AB - We report new experiments conducted using a camera phone wayfinding system, which is designed to guide a visually impaired user to machine-readable signs (such as barcodes) labeled with special color markers. These experiments specifically investigate search strategies of such users detecting, localizing and touching color markers that have been mounted in various ways in different environments: in a corridor (either flush with the wall or mounted perpendicular to it) or in a large room with obstacles between the user and the markers. The results show that visually impaired users are able to reliably find color markers in all the conditions that we tested, using search strategies that vary depending on the environment in which they are placed. PMID- 26949756 TI - Real-Time Walk Light Detection with a Mobile Phone. AB - Crossing an urban traffic intersection is one of the most dangerous activities of a blind or visually impaired person's travel. Building on past work by the authors on the issue of proper alignment with the crosswalk, this paper addresses the complementary issue of knowing when it is time to cross. We describe a prototype portable system that alerts the user in real time once the Walk light is illuminated. The system runs as a software application on an off-the-shelf Nokia N95 mobile phone, using computer vision algorithms to analyze video acquired by the built-in camera to determine in real time if a Walk light is currently visible. Once a Walk light is detected, an audio tone is sounded to alert the user. Experiments with a blind volunteer subject at urban traffic intersections demonstrate proof of concept of the system, which successfully alerted the subject when the Walk light appeared. PMID- 26949757 TI - A Mobile Phone Application Enabling Visually Impaired Users to Find and Read Product Barcodes. AB - While there are many barcode readers available for identifying products in a supermarket or at home on mobile phones (e.g., Red Laser iPhone app), such readers are inaccessible to blind or visually impaired persons because of their reliance on visual feedback from the user to center the barcode in the camera's field of view. We describe a mobile phone application that guides a visually impaired user to the barcode on a package in real-time using the phone's built-in video camera. Once the barcode is located by the system, the user is prompted with audio signals to bring the camera closer to the barcode until it can be resolved by the camera, which is then decoded and the corresponding product information read aloud using text-to-speech. Experiments with a blind volunteer demonstrate proof of concept of our system, which allowed the volunteer to locate barcodes which were then translated to product information that was announced to the user. We successfully tested a series of common products, as well as user generated barcodes labeling household items that may not come with barcodes. PMID- 26949758 TI - Performance of High-Flow-Rate Samplers for Respirable Crystalline Silica Measurement Under Field Conditions: Preliminary Study. AB - : Restoration stone work regularly involves work with high-silica-content materials (e.g., sandstone), but low-silica-content materials (<2 % quartz) such as limestone and lime mortar are also used. A combination of short sample duration and low silica content makes the quantification of worker exposure to respirable crystalline silica (RCS) difficult. This problem will be further compounded by the introduction of lower occupational exposure standards for RCS. The objective of this work was to determine whether higher-flow samplers might be an effective tool in characterizing lower RCS concentrations. A short study was performed to evaluate the performance of three high-flow samplers (FSP10, CIP10 R, and GK2.69) using side-by-side sampling with low-flow samplers (SIMPEDS and 10 mm nylon cyclones) for RCS exposure measurement at a restoration stonemasonry field site. A total of 19 side-by-side sample replicates for each high-flow and low-flow sampler pair were collected from work tasks involving limestone and sandstone. RESULTS: Most of the RCS (quartz) masses collected with the high-flow rate samplers were above the limit of detection (62 % to 84 %) relative to the low-flow-rate samplers (58 % to 78 %). The average of the respirable mass concentration ratios for CIP10-R/SIMPEDS, GK2.69/10-mm nylon, FSP10/SIMPEDS, and FSP10/10-mm nylon pairs and the range of the quartz concentration ratios for the CIP10-R/SIMPEDS, CIP10-R/10-mm nylon, GK2.69/10-mm nylon, FSP10/SIMPEDS, and FSP10/10-mm nylon pairs included unity with an average close to unity, indicating no likely difference between the reported values for each sampler. Workers reported problems related to the weight of the sampling pumps for the high-flow rate samplers. Respirable mass concentration data suggest that the high-flow-rate samplers evaluated would be appropriate for sampling respirable dust concentrations during restoration stone work. Results from the comparison of average quartz concentration ratios between high-and low-flow samplers suggest that the higher mass collected by the high-flow-rate samplers did not interfere with the quartz measurement. A sig-nificant portion of the data collected with the high-flow-rate samplers (>82 %) were greater than the limit of detection, which indicates that these samplers are suitable for quantifying exposures, even with low-quartz materials. PMID- 26949759 TI - A retrospective multicenter case series evaluating a novel 3.0-mm expanding tapered body implant for the rehabilitation of missing incisors. AB - OBJECTIVE: Narrow-diameter implants are indicated for narrow sites, small interdental/interimplant spaces, or sites with congenitally missing teeth. They also offer a substitute for invasive augmentation procedures. The authors retrospectively evaluated the performance of a new 3.0-mm diameter implant for rehabilitating small anterior spaces. METHOD AND MATERIALS: This observational multicenter retrospective case series included consecutive patients needing single-unit restoration for mandibular and lateral maxillary incisors. The outcome variables were: implant survival, Plaque Index, pocket probing depth (PPD), Jemt's papilla index, bleeding on probing (BOP), and marginal bone remodeling. RESULTS: In total, 45 patients received 58 3.0-mm implants placed in healed sites (n = 22), extraction sockets (n = 16), or sites with congenitally missing teeth (n = 20). Average follow-up time was 15.1 +/- 5.2 months. Prosthetic loading was immediate (n = 23), early (n = 16), or delayed (n = 19). Two implants were lost, and two prosthetic complications occurred. One-year bone remodeling averaged -0.36 +/- 0.85 mm (n = 44). PPD averaged 1.75 +/- 0.58 mm. Neither BOP nor plaque was detected around implants. CONCLUSIONS: At 1-year follow-up, narrow 3.0-mm diameter implants placed in mandibular and lateral maxillary incisor sites demonstrate a high survival rate and support stable marginal bone levels and healthy soft tissue. PMID- 26949760 TI - Survival of all-ceramic restorations after a minimum follow-up of five years: A systematic review. AB - OBJECTIVE: The purpose of this systematic review was to compare the survival and complication rates of all-ceramic restorations after a minimum follow-up time of 5 years. DATA SOURCES: A comprehensive search of studies published from 2005 to November 2015 and listed in the PubMed/MEDLINE, Scopus, and Cochrane Library databases was performed in accordance with the PRISMA statement. Two reviewers independently analyzed the abstracts. Relevant studies were selected according to predetermined inclusion criteria. RESULTS: Twenty-nine studies were selected for the final analysis from an initial yield of 514. Only four studies fulfilled the requirement of having a randomized design, and 25 studies were prospective with a mean follow-up period of 5 to 16 years. Overall, the 5-year complication rates were low. The most frequent complications were secondary caries, endodontic problems, ceramic fractures, ceramic chipping, and loss of retention. CONCLUSION: This systematic review showed that all-ceramic restorations fabricated using the correct clinical protocol have an adequate clinical survival for at least 5 years of clinical service with very low complication rates. Minor ceramic chipping and debonding did not affect the longevity of the restorations. CLINICAL RELEVANCE: Long-term clinical performance of all-ceramic restorations manufactured using various ceramic systems provides clinical evidence of complications and long-term management of these restorations. Available evidence indicates the effectiveness of many ceramic systems for numerous clinical applications. Correct planning and a rigorous technical execution protocol increase clinical success. Studies of ceramic prostheses indicate more problems with ceramic failure and debonding. PMID- 26949761 TI - 3D quantification of clinical marginal and internal gap of porcelain laminate veneers with minimal and without tooth preparation and 2-year clinical evaluation. AB - OBJECTIVES: The aims of this clinical study were to compare internal three dimensional (3D) adaptation of porcelain laminate veneers (PLV) with minimal tooth preparation and without tooth preparation (prepless) and to evaluate the clinical outcomes at baseline and following 6, 12, and 24 months after luting. METHOD AND MATERIALS: Thirty-one prepless PLV and 31 PLV with minimal tooth preparation were fabricated using lithium disilicate glass-ceramic material and placed in 12 patients (8 women, 4 men; 18 to 40 years old). All PLV were luted with an adhesive luting system (Variolink veneer). A silicone replica was obtained to measure internal adaptation of each PLV using a low viscosity polyvinyl siloxane impression material just before luting. Silicone replicas were scanned in x-ray micro computerized tomography (micro CT). Clinical evaluations took place at baseline (2 days after luting) and following 6, 12, and 24 months after luting. Marginal integrity, marginal discoloration, secondary caries, tooth sensitivity, and fracture were evaluated following FDI criteria. Replica scores were analyzed using Mann-Whitney U and Student's t test (alpha = .05). Kaplan Meier statistical analysis was done for the survival rate of PLV. FDI criteria scores were analyzed using Pearson's chi-square test (alpha = .05). RESULTS: The median marginal gaps for PLV-without-tooth-preparation and PLV-with-minimal-tooth preparation groups were 100 MUm and 140 MUm respectively. There was a statistically significant difference between the two groups with respect to marginal gap (P = .04). The mean internal adaptation for the PLV-without-tooth preparation group was 217.17 +/- 54.72 MUm, and was 170.67 +/- 46.54 MUm for the PLV-with-minimaltooth- preparation group. There was a statistically significant difference between the two groups (P = .001). Based on FDI criteria, 100% of the PLV were rated satisfactory during the 2-year period. CONCLUSIONS: In this in vivo study, mean and median values of marginal gap and internal adaptation for PLV with minimal tooth preparation and PLVs without tooth preparation were within a clinically acceptable range. A 100% success rate was recorded for all PLV during the 2-year period. PMID- 26949762 TI - Effects of different factors influencing clinical compliance of Chinese patients with chronic periodontitis. AB - OBJECTIVES: The aims of this study were to determine the relationship between compliance in patients with chronic periodontitis and the efficacy of nonsurgical periodontal treatment as well as to investigate the factors that influence the compliance of patients with chronic periodontitis. These aims may be useful for determining the prognosis and improving the efficacy of treatment. METHOD AND MATERIALS: Four hundred patients with chronic periodontitis were classified into three groups: the complete compliance group (S1), the erratic compliance group (S2), and the failing compliance group (S3). The patients who were in group S1 received supportive periodontal therapy (SPT) on time: they presented for their appointments within 2 months of the scheduled date; the patients who missed their appointments by more than 2 months or who completely missed a return visit one or more times, were placed in group S2; and the patients who never returned to receive SPT were assigned to group S3. They completed a questionnaire about compliance and underwent a clinical periodontal examination. SPSS 13.0 was used for the statistical analysis. RESULTS: Groups S2 (49.4%) and S3 (34.1%) were significantly different from group S1 (87.0%) (P < .05) in their understanding that periodontal disease is always associated with other diseases. The analysis of severe pain during the treatment revealed significant differences (P < .05) between group S1 (22.2%) and group S3 (39.9%). Awareness of chronic periodontitis and comfort during treatment are important factors influencing patient compliance. The distance of the patient's residence from the hospital, working hours, and attitudes of family members also affect patient compliance. CONCLUSION: Doctors should educate patients about oral health and manage their patients' comfort as much as possible during treatment, thereby enhancing patient compliance and achieving better treatment efficacy. PMID- 26949763 TI - Long-term outcome of MTA apexification in teeth with open apices. AB - OBJECTIVE: This retrospective study aimed to collect information about the long term outcome of apexification treatment with mineral trioxide aggregate (MTA) of teeth with open apices. METHOD AND MATERIALS: A total of 98 teeth in 79 patients (m:f = 1:1.3) who had completed endodontic apexification treatment with MTA between September 2005 and January 2014 at a university dental clinic were considered. Both initial treatments and retreatments of former root canal treatments other than apexification were included. All patients were invited for a standardized follow-up visit. Data regarding age, sex, tooth type, reason for treatment, detailed treatment protocol, clinical and radiographic findings, treatment quality, and outcome were also collected from the patients' records. Descriptive statistical analysis was performed. RESULTS: In the majority of cases, endodontic treatment was related to trauma with fracture (45/98, 45.9%) and luxation injuries (20/98; 20.4%), followed by unknown causes (12/98; 12.2%), retreatments (7/98; 7.1%), hypophosphatasia (7/98; 7.1%), and caries (1/98; 1%). In the beginning, the Periapical Index (PAI) showed pathologic findings with a PAI > 2 in approximately 50% of cases, while 25% presented with minor or an absence of findings. At the end of the observation period, more than 90% showed clinical-radiographic success, whereas eight teeth were associated with an elevated PAI. Only 5% of cases needed further dental treatment, such as root-end surgery or retreatment of the root canal treatment. CONCLUSION: Within the limits of this retrospective investigation, clinical and clinical-radiographic success of the apexification treatment appears to make this a good and reliable treatment option for teeth with open apices. PMID- 26949764 TI - Clinical attachment level gain and three-year maintenance of a maxillary incisor with 100% bone loss: A case report. AB - This case report discusses a patient suffering from chronic periodontal disease and diagnosed with a hopeless central incisor. The intention was to show the possibility of gaining new clinical attachment via regenerative surgery in a tooth with 100% bone loss around the root. Treatment of hopeless and questionable teeth in periodontal patients has become an ideological matter. On the one hand, dental implants have proved to be a reliable solution to replace lost teeth; on the other hand, newly emerging evidence suggests that successful periodontal treatment of teeth diagnosed as hopeless is possible. Here we describe surgical, orthodontic, and restorative treatments that led to clinical attachment gain and achieved clinical success over a three-year follow-up period. PMID- 26949766 TI - N-of-1 Clinical Trials: Removing the Hay to Find the Needle. PMID- 26949765 TI - A comparative study on the use of digital panoramic and periapical radiographs to assess proximal bone height around dental implants. AB - OBJECTIVE: The purpose of this study was to compare periapical radiographs (PA) and panoramic radiographs (PAN) in the measurement of proximal bone height around implants. METHOD AND MATERIALS: Patients files that contained digital PAN and PA together with information on implant lengths and diameters were selected for this study. For each radiograph, the implant size served as reference for calibration. Proximal radiographic bone levels and the linear distance between the bone crest and implant shoulder were measured twice by one examiner. Paired t test was used to assess intra-examiner variability and differences between the two radiographic methods. Correlation was then assessed using Pearson correlation coefficient test. Significance level was determined at 5%. RESULTS: For the PAN measurements, the median mesial distances from bone crest to implant shoulder were 0.53 and 0.56 mm (first and second sets, P = .53). Likewise, for distal measurements these readings were 0.92 and 0.86 mm respectively (P = .66). For PA measurements, the corresponding measurements were 0.33 and 0.44 mm (P = .48) and 0.99 and 0.99 mm (P = .42), respectively. When PAN and PA measurements were compared, no statistically significant differences were detected between the two radiographic modalities. A very high positive correlation (r > 0.91) was attained for the PAN PA measurements (P < .0001). CONCLUSION: PAN are potentially as reliable and reproducible as PA for the assessment of proximal bone height around dental implants. PMID- 26949767 TI - Unexpected Challenges in Noninvasive Prenatal Testing. PMID- 26949768 TI - Retraction notice to "Neuronal damage, central cholinergic dysfunction and oxidative damage correlate with cognitive deficits in rats with chronic cerebral hypoperfusion" [Neurobiology of Learning and Memory 109 (2014) 7-19]. PMID- 26949769 TI - What's your emergency? PMID- 26949770 TI - A labour of love. PMID- 26949771 TI - Learned recovery. PMID- 26949772 TI - The manuscript-editing marketplace. PMID- 26949773 TI - Web tool aims to reduce flaws in animal studies. PMID- 26949774 TI - Beyond Physicalism. PMID- 26949775 TI - Arcobacter, an emerging opportunistic food borne pathogen--A review. AB - BACKGROUND: Arcobacters, emerging aetiologic agents of food-borne diarrhoeal illness in humans and animals are more frequently isolated in meat, especially poultry meat, pork and beef. Though human infection may exist, it has not been documented in Nigeria. AIM: This review presents an update of scientific information in Nigeria on arcobacters as an emerging food-borne pathogen of public health significance in Nigeria. METHODS: A comprehensive reviews of literatures was adopted to give an update on scientific findings on the disease in Nigeria. RESULTS AND CONCLUSIONS: The review revealed scientific evidences attributing the cause of human and animal illness to Arcobacter spp. It also highlights efforts towards the development of animal models where in virulence and pathogenicity of primarily A. butzleri and A. cryaerophilus isolated from human diarrhoeal stool samples were tested. This in turn elucidated the public health significance of this emerging food-borne pathogen. The review canvases for more investigation as to the role of arcobacters in food contamination and unrecognised food-borne disease in Nigeria. PMID- 26949776 TI - Mycobacterium africanum and nontuberculous mycobacteria from fresh milk of pastoral cattle and soft cheese in Oyo State--implications for public health. AB - BACKGROUND: Milk and.milk products from cattle in tuberculosis endemic countries like Nigeria where pasteurization is not enforced could be a source of health concerns to the consumers. METHODS: We assessed randomly selected fresh milk from pastoral cattle, cheese samples and sour milk (nono) for the presence of Mycobacterium species through cultural isolation, Multiplex Polymerase Chain Reaction (PCR) and PCR-restriction enzyme analysis (PRA)-hsp65. RESULTS: Out of 269 fresh milk, 295 cheese and 150 sour milk samples screened; 8.30%, 0.34% and 0.00%, respectively were positive for Mycobacterium species. Molecular characterization revealed three M. africanum (fresh milk = 2; cheese = 1) and a high prevalence of Non-tuberculous Mycobacterium (NTM; 89.29%) from fresh milk comprising M. gordonae (n = 12), M. fortuitum (n = 4), M. senegalense (n = 7) and M. avium (n = 1). CONCLUSION: The isolation of M. africanum and NTM species from this study is a matter of public health concern considering the practice of pooling milk from different animals and the consumption of unpasteurized milk which characterize most pastoral communities in Nigeria. Given the predominance of NTM in this study, their potential to cause disease in humans should not be ignored. Urgent measures should also be taken to integrate molecular techniques that will differentiate NTM from members of the M. tuberculosis complex in the epidemiology of tuberculosis in order to avoid misdiagnosis in humans and thereby protect public health. PMID- 26949777 TI - Treatment compliance and challenges among tuberculosis patients across selected health facilities in Osun State Nigeria. AB - BACKGROUND: Tuberculosis (TB) is a major public health problem in the world and Africa has approximately one quarter of the world's cases. One of the greatest challenges facing most TB programmes is the non-compliance to TB treatment among TB patients. AIM: This study aimed at determining the challenges of management of tuberculosis (TB) across selected Osun State health facilities. The study employed a descriptive cross-sectional design. A semi-structured questionnaire was used to collect data from 102 TB patients in the health facilities. The instrument measured socio-demographic variables, patient related factors, socio economic variables, health care system related factors to TB disease and treatment. METHODS: Data were analysed and summarized using descriptive and inferential statistics. Statistical significance was placed at p < 0.05. RESULTS: TB patients who had no formal education (chi2 = 12.941, p < 0.05), who were smoking during treatment (chi2 = 13.194, p < 0.001), who consumed alcohol during TB treatment (chi2 = 6.371, p < 0.05) and those who were HIV positive (chi2 = 23.039, p < 0.001) significantly failed to comply with TB treatment. TB patients who waited for one hour or more at heath facilities (chi2 = 21.761, p < 0.001), who reported that TB treatment should be stopped before six month (chi2 = 9.804, p < 0.05) or when patient felt better (chi2 = 35.185, p < 0.001) and travelled for 10 km or more (chi2 = 13.610, p < 0.001) significantly failed to comply with TB treatment. CONCLUSION: This study concluded that non-compliance rate to tuberculosis treatment among TB patients in this study is high. Both health facility and patient-related factors were largely responsible. PMID- 26949778 TI - Hepatitis B Virus infection and its modes of prevention among clinical students of Obafemi Awolowo University (OAU), Ile-Ife, Nigeria. AB - BACKGROUND: Hepatitis B is a major global health problem and is a major infectious and occupational hazard for health workers, especially doctors, nurses, dentists and laboratory staff, including those who are under training, because of exposure to patients' body fluids during clinical activities. Clinical students are also at risk of HBV infection during their training in medical school. HBV vaccination status is very low among medical students in Nigeria AIM: This study assessed the knowledge of clinical students of the Obafemi Awolowo University (OAU), Ile-Ife about hepatitis B virus infection and its modes of prevention. METHODS: A descriptive cross-sectional study was conducted among all 594 clinical students of OAU using a pretested, self-administered, semi structured questionnaire. Data were analysed and summarized using descriptive and inferential statistics (logistic regression). RESULTS: Four hundred and thirty (72.4%) respondents correctly identified four modes of transmission, while 470 (79%) respondents reported vaccination as a mode of prevention of HBV infection. Of all the respondents, 61.6% had ever received Hepatitis B virus vaccine, while only 39.2% of the respondents had received at least three doses of HBV vaccine. At bivariate level, gender (chi2 = 23.685, p < 0.001) and level of study (chi2 = 7.383, p < 0.05) were significantly associated with HBV vaccine uptake. At multivariate level, gender (OR = 2.58, 95% CI = 1.80-3.7 1) and level of study (OR = 1.71, 95% CI =1.14-2.54) remained significantly associated with HBV vaccine uptake. CONCLUSION: The study concluded that clinical students had poor knowledge of safe sexual practices and post-exposure prophylaxis as preventive measures. The uptake of HBV vaccine was also poor. The significant correlates of vaccine uptake were gender and level of study. PMID- 26949779 TI - Prevalence of Toxoplasma gondii and HIV infection among pregnant women in Ibadan North Local Government, Oyo State. AB - BACKGROUND: Toxoplasmosis, a disease caused by Toxoplasma gondii poses a risk of congenital infection during pregnancy in infected women. The disease poses a threat of ocular and neurological sequelae in congenitally ilfected infants and HIV patients; however, there is little valuable information on its prevalence in Ibadan. METHODS: A cross sectional study of pregnant women attending antenatal care in three primary healthcare centres in Ibadan was carried out. 179 women were screened for T gondii infection using PCR, 83 of these were also screened for HIV. Forty nine (27.4%) were positive for T gondii, and 2(2.4%) were HIV positive (P = 0.002, OR = 0.28, CL = 95%). 27 (15.1%) of the infected women were in third trimester, with 20 (11.2%) and 2 (1.1%) in second and first trimester respectively. 18 (10.1%) positive cases were identified among the primigravidas and 31 (17.2%) among the multigravidas. Risk factors associated with Toxoplasma infection were assessed, and the source of drinking water and the types of animals around habitation were found to be significantly associated with the presence of Toxoplasma infection (P = 0.002, OR = 2.109 and P = 0.004, OR = 1.693 respectively). CONCLUSION: The high prevalence among women in third trimester may indicate high risk of congenital infection, and the significant association found between the source of drinking water and infection suggests environmental contamination as a major possible mode of infection. The need to educate pregnant women about the transmission mechanisms of T. gondii, and the effects of the infection on neonates and babies is pertinent in order to effectively control Toxoplasma infection. PMID- 26949780 TI - Seroprevalence of Toxoplasma gondii in recreational horses in two metropolitan cities of Southwestern Nigeria. AB - Toxoplasma gondii (T. gondii), an obligate intracellular protozoan parasite is a known etiological factor of reproductive problems and encephalomyelitis in animals and humans. This study investigated the seroprevalence of T gondii infection in recreational horses in two metropolitan cities of southwestern Nigeria. Serum samples were randomly collected from a total of 157 horses in Lagos and Ibadan. Samples were assayed for the presence of T gondii antibodies using the Modified Agglutination Test (MAT). A total of 22 (14%) of the 157 sampled horses were positive for T gondii antibodies by MAT with titers of 1:20 in 12 samples (54.5%), 1:40 in 8 samples (36.4%), 1:80 in 1 sample (4.1%) and 1:160 in 1 sample (4.1%). Seroprevalence varied among gender, breeds, age groups and sampling locations but there was no statistically significant association (p < 0.05) of any of the factors to T. gondii infection. This study showed that recreational horses in southwestern Nigeria are exposed to T. gondii and appropriate measures should be adopted to prevent and control the infection in horses in this region. The zoonotic implication of the disease is also discussed. This is probably the first report on seroprevalence of Toxoplasma gondii in horses in southwestern Nigeria. PMID- 26949781 TI - Seroprevalence of toxoplasma gondii infection in free ranged chicken from rural and urban settlements in Oyo State, Nigeria. AB - BACKGROUND: Free-range chicken preferred as source of meat by a large population in developing countries is now known to play an important role in the epidemiology of Toxoplasmosis. AIM: This study was therefore aimed at investigating the occurrence of Toxoplasma gondii infection in free-range local chicken from rural and urban settlements in Oyo State, Nigeria. METHODS: Sera from 225 chickens were assayed for T gondii antibodies using Modified Agglutination Test (MAT). RESULTS: Ninety-one (40.4%) were positive for T gondii antibodies (MAT cut-off titre of 1:20). Seroprevalence were 41%, 38.5%, 41.9% and 38.2% in adolescents, adults, female and male chicken respectively. Antibodies were detected in chickens obtained from all Local Government Areas (LGAs) with higher titre in rural than urban chickens. Chickens from rural areas had significant association with seropositivity to T gondii infection (OR = 2.534; 95% CI = 1.442 - 454; P = 0.0016). There was no significant association of T gondii (P > 0.05) with age, sex and the origin of chicken. Conclusion: The study showed that detection of high antibodies titre to T gondii in free-range chicken suggests a wide spread of T gondii oocyst in the studied environment and that consumption of undercooked meat from these birds may be sources of T gondii infection to humans. PMID- 26949782 TI - Kwame Nkrumah University of Science and Technology School of Veterinary Medicine (KNUST SVM) A Model of "One-Health Concept" Application to Veterinary Education in West Africa. AB - BACKGROUND: Veterinary education in West Africa had been skewed over decades with Nigeria and Senegal leading in the training of veterinarians in the subregion. Most nationals from Ghana, Sierra Leone, Gambia as well as francophone countries within the subregion were trained in East Africa, Europe and South America. AIM: The aim of this paper is to provide an insight into the need for veterinary education in other West African countries including Ghana METHODS: Information was sourced from individuals, literatures and other relevant archives on the history, current state and future approaches to veterinary education in Ghana. RESULTS AND CONCLUSION: The advantages, challenges and coping strategies for application of the Principles of "The One World One Health concept" to veterinary education with the use of the medical professionals in the delivery were presented. This approach to veterinary education by Kwame Nkrumah University of Science and Technology School of Veterinary Medicine showcases a means to meet the health challenges of the twenty first century which demand pragmatic innovation to solve disease challenges. PMID- 26949783 TI - The geo-spatial information infrastructure at the Centre for Control and Prevention of Zoonoses, University of Ibadan, Nigeria: an emerging sustainable One-Health pavilion. AB - BACKGROUND: The World-Wide-Web as a contemporary means of information sharing offers a platform for geo-spatial information dissemination to improve education about spatio-temporal patterns of disease spread at the human-animal-environment interface in developing countries of West Africa. METHODS: In assessing the quality of exposure to geospatial information applications among students in five purposively selected institutions in West Africa, this study reviewed course contents and postgraduate programmes in zoonoses surveillance. Geospatial information content and associated practical exercises in zoonoses surveillance were scored.. Seven criteria were used to categorize and score capability, namely, spatial data capture; thematic map design and interpretation; spatio temporal analysis; remote sensing of data; statistical modelling; the management of spatial data-profile; and web-based map sharing operation within an organization. These criteria were used to compute weighted exposure during training at the institutions. A categorical description of institution with highest-scoring of computed Cumulative Exposure Point Average (CEPA) was based on an illustration with retrospective records of rabies cases, using data from humans, animals and the environment, that were sourced from Grand Bassa County, Liberia to create and share maps and information with faculty, staff, students and the neighbourhood about animal bite injury surveillance and spatial distribution of rabies-like illness. RESULTS: Uniformly low CEPA values (0-1.3) were observed across academic departments. The highest (3.8) was observed at the Centre for Control and Prevention of Zoonoses (CCPZ), University of Ibadan, Nigeria, where geospatial techniques were systematically taught, and thematic and predictive maps were produced and shared online with other institutions in West Africa. In addition, a short course in zoonosis surveillance, which offers inclusive learning in geospatial applications, is taught at CCPZ. CONCLUSION: The paper presents a graded capability for geospatial data capture, analysis and an emerging sustainable map pavilion dedicated to zoonoses disease surveillance training among collaborating institutions in West Africa. PMID- 26949784 TI - Geographic access to street food sources for dogs and its association with spatial patterns of animal bite injuries in Enugu, Nigeria, 2005-2011. AB - BACKGROUND: Accessibility of street food source to dogs in Enugu, the capital city of Enugu State, south-eastern Nigeria was examined in relation to spatial patterns of animal bite injuries in the city. METHOD: Retrospective data on animal bite injuries were retrieved from records of selected hospitals in Enugu and its environs during the period 2005-2011. Victim's residence and street point where animal bite incidence occurred were geo-referenced. Street food sources, including garbage disposal points, meat markets, slaughter facilities and public vehicle terminals in the city were observed and geo-referenced. Thematic maps were designed usingArcGIS 10.1. Spatial scan statistics was used to identify cluster pattern of animal bite injuries and fatal rabies cases. Coefficient of area correspondence (Ca) in spatial cluster with selected variables was computed. RESULTS: One hundred and thirty one cases of animal bite injury cases were retrieved with traceable addresses. These comprised cat bites (n = 1, 0.76%), goat bites (n = 1, 0.76%), monkey bites (n = 2, 1.5%) and dog bites (n = 127, 96.98%). Fatal outcomes (n = 4, 3.15%) were recorded. Males within the age group, 0-15 (46.5%) were at the highest risk. A diffused spatial pattern showed that majority of the study area experienced animal bite injury during the study period. A primary cluster of 15.03km radius and a secondary cluster of 1.11 km radius traversed residential and non-residential areas were identified as rabies high- and low-risk areas. Interspecies bites from non-carnivores (goats and monkeys) and resultant deaths with neurologic signs were pathognomonic for rabies like-illness in Enugu State. High Ca (0.8) showed a strong correlation between access to street food sources for dogs and the distribution of animal bite injuries on humans. CONCLUSION: While access to street food may support the population of free-roaming dogs, it was also shown to be partly explanatory to spatial patterns of dog bite injury. Public education about responsible pet ownership, waste management, enforcement of animal control regulations and vaccination of free-roaming dogs is critical. PMID- 26949785 TI - Development of time-trend model for analysing and predicting case pattern of dog bite injury induced rabies-like-illness in Liberia, 2014-2017. AB - OBJECTIVE: The post-civil war records of dog bite injuries (DBI) and rabies-like illness (RLI) among humans in Liberia is a vital epidemiological resource for developing a predictive model to guide the allocation of resources towards human rabies control. Whereas DBI and RLI are high, they are largely under-reported. The objective of this study was to develop a time model of the case-pattern and apply it to derive predictors of time-trend point distribution of DBI-RLI cases. METHODS: A retrospective 6 years data of DBI distribution among humans countrywide were converted to quarterly series using a transformation technique of Minimizing Squared First Difference statistic. The generated dataset was used to train a time-trend model of the DBI-RLI syndrome in Liberia. An additive detenninistic time-trend model was selected due to its performance compared to multiplication model of trend and seasonal movement. Parameter predictors were run on least square method to predict DBI cases for a prospective 4 years period, covering 2014-2017. RESULTS: The two-stage predictive model of DBI case-pattern between 2014 and 2017 was characterised by a uniform upward trend within Liberia's coastal and hinterland Counties over the forecast period. CONCLUSION: This paper describes a translational application of the time-trend distribution pattern of DBI epidemics, 2008-2013 reported in Liberia, on which a predictive model was developed. A computationally feasible two-stage time-trend permutation approach is proposed to estimate the time-trend parameters and conduct predictive inference on DBI-RLI in Liberia. PMID- 26949786 TI - Molecular characterization of Mycobacterium bovis in slaughtered cattle in North Central Nigeria and the public health implications. AB - BACKGROUND: The molecular biological techniques of polymerase chain reaction (PCR) are accurate and rapid diagnostic methods in the epidemiology of Mycobacterium species in humans and animals, especially in developing countries. METHODS: In this study, positive cultures from suspected tuberculous lesions of slaughtered cattle from two abattoirs in north-central Nigeria were subjected to a two-step multiplex PCR technique, based on genus typing and genomic regions of difference (RD). RESULTS: Out of 50 suspected tuberculous lesions cultured, 40 isolates were obtained. Based on genus typing, 32 of the isolates were identified as Mycobacterium tuberculosis complex (MTC), one as non-tuberculous Mycobacterium (NTM) and the remaining seven were unclassified. Using genomic RD multiplex PCR, all the 32 isolates initially identified as MTC were further characterized as M. bovis. CONCLUSION: Our findings show that 80% of positive cultures from suspected tuberculous lesions were identified as M. bovis; hence, re-confirming M. bovis as the main cause of bovine tuberculosis in Nigeria. These results give further credence to the use of PCR-based molecular techniques as excellent complementary epidemiological tools in the tracking of bovine tuberculosis, a zoonotic disease of major public health importance in Nigeria. PMID- 26949787 TI - Rabies unending malady--Nigeria in perspective. AB - Rabies has been eradicated from many countries in the developed world. However, an upsurge in the incidence of rabies has been observed in recent times in areas earlier thought to be free. A wide range of animal reservoirs of rabies exist in Africa, partly due to the favorable climate and ecology. Inability to vaccinate a significant number of dogs has led to increased rabies related human deaths from dog bites with attendant socioeconomic and public health impacts. We highlighted the burden of rabies in Nigeria and indeed Africa, the monitoring strategies adopted, steps taken to tackle the problem and diagnosis as an effective prevention and control option. PMID- 26949789 TI - Mapping of Mycobacterium tuberculosis cases in post-conflict Liberia, 2008-2012: A descriptive and categorical analysis of age, gender and seasonal pattern. AB - BACKGROUND: Tuberculosis (TB) is a major public health. problem in Liberia and it is among the first five most important infectious diseases. Fourteen years of civil war in Liberia caused a large internal displacement and external migration of its citizens to neighbouring countries such as Guinea, Ivory Coast, Sierra Leone, Ghana and Nigeria. Current spatio-temporal pattern of TB cases in Liberia is essential for identifying risk factors among humans for optimal resource allocation. METHODS: Surveillance data from January, 2008 to December, 2012 were retrieved from two national TB referral hospitals in the country: TB Annex Hospital (TBAH) (Montserrado County) and Ganta TB and Leprosy Rehabilitation Hospital (GTBLRH) (Nimba County). Geographic coordinates of TB patient's locations were captured based on records in the hospital case-files using Global Positioning System (GPS). The coordinates were mapped using Geographic Information Systems (GIS) software. Data on age, gender, date of illness, dry and wet season frequency were used to compute a descriptive and categorical analysis. Kulldorff's spatio-temporal scan statistic was used to identify clusters of TB in the two Counties. RESULTS: A total of 2,890 laboratory-confirmed cases were reported during the study period. There were 1,365 (47.23%) and 1,525 (52.77%) cases from TBAH and GTBLRH respectively. The mean age of patient was 45.19 years +/- 19.49 (SD). Of this, 1,450 (50.17%) were male. There was significant association between year of TB occurrence and treatment outcome (chi2 = 14.38; p = 0.006). CONCLUSION: The paper presents TB spatial pattern, summarizing 5-year records of post-conflict surveillance of the disease in Liberia. PMID- 26949788 TI - Serological survey for emerging canine H3N8 and H3N2 influenza viruses in pet and village dogs in Nigeria. AB - BACKGROUND: In Nigeria, keeping of dogs as pets and guards is gaining popularity. To determine whether infection of dogs with novel canine influenza virus (CIV) of equine (H3N8) and avian (H3N2) origins had occurred in Nigeria, we screened pet and village dogs from Lagos, Ibadan, Odeda and Sagamu in southwestern Nigeria for antibodies to CIV H3N8 and H3N2. METHODS: Sera from 96 pet dogs presented at veterinary clinics in Lagos and Ibadan, and 89 village dogs from hunting communities in Odeda and Sagamu were tested for antibodies to CIV H3N8 and H3N2 using the hemagglutination inhibition test. RESULTS: Anti-CIV H3N8 antibodies were detected in 51 (53.1%) and 24 (27.0%) pet and village dogs, respectively. Overall, 40.5% (75/185) of the sera were positive for CIV H3N8 antibodies while none contained anti-CIV H3N2 antibodies. CONCLUSION: The presence of CIV H3N8 antibodies in pet and village dogs in this study suggests that they had natural exposure to the virus since dogs are not currently vaccinated against canine influenza in Nigeria. It is possible that the pet dogs acquired infection through contact with imported dogs in veterinary clinics, breeding kennels and dog shows while the village dogs could have been exposed through consumption of offal of infected animals killed during hunting. Considering the potential public health risk of this disease arising from the close relationship between pet and hunting dogs and their owners in Nigeria, systematic epidemiological surveillance of the Nigerian dog population for CIV H3N8, H3N2 and other influenza A virus subtypes is advocated. PMID- 26949790 TI - Subtle morbidities associated with malaria co-infection with schistosomiasis among children in South-West Nigeria. AB - BACKGROUND: Malaria co-infection with schistosomiasis is known to modulate the immune response and thereby to potentially alter the pathophysiological and immunological profile of the diseases. The aim of the study was to determine the relationship between subtle morbidities and co-infection with malaria and schistosomiasis, and the immunological responses to the two diseases, among children in rural southwest Nigeria. METHODS: A cross-sectional survey was conducted between April and July 2012 among primary and secondary school children in Eggua, Yewa.North LGA, Ogun State and Omi-Adio, Iddo LGA, Oyo State. A total of 240 children (Yewa 91, Iddo 149) participated in the study. Blood and urine samples were collected from the children and analysed by microscopy for Plasmodium falciparum and Schistosoma haematobium respectively. All the samples were analysed for IL-10, IFN-gamma, and some for antibodies to Plasmodium falciparum MSP1(19). Packed cell volume (PCV) and some anthropometric indices (height, weight) were measured as indicator of subtle morbidities of infection with the two parasites. RESULTS: The prevalence of co-infection with the two parasites in the study was 16%. Malaria prevalence was 35.6% in Eggua, 20.13% in Iddo, and highest in the 11-15 yr age group. Average malaria parasite density was 195.67 parasites/ul blood. Schistosomiasis prevalence was 20.8% in Iddo, 30.8% in Eggua, with highest intensity of infection in age group 11-15 years in both areas. Anaemia was not prevalent among co-infected people (16%). Antibodies to MSP1(19) were found in 36.7%. Peripheral IL-10 levels did not differ significantly among malaria, schistosomiasis, or co- infected individuals, but IFN-gamma was higher among older children with schistosomiasis. CONCLUSION: Anaemia was not a very discriminating index to indicate morbidity from the diseases in this study area. PMID- 26949791 TI - Prevalence of Fasciola species in ruminants under extensive management system in Ibadan southwestern Nigeria. AB - BACKGROUND: Fasciolosis is a zoonotic trematode of ruminants and a common parasite in cattle in Nigeria. With the increasing numbers of small household cattle herds kept under extensive management system as well as the more usual small ruminants, there is a possibility therefore that parasites common to these ruminants but better adapted to cattle such as Fasciola may also be on the increase within the small ruminant population as they graze freely over the same wide area and sometimes freely mix. AIM: The aim of the study is to determine the prevalence of Fasciola spp in sheep, goats and cattle in Ibadan during the short wet season, (August-October 2011). METHODS: Faecal samples were collected per rectum from 440 each of goats and sheep and 291 cattle. Helminth ova were recovered using sedimentation technique for faecal examination. RESULTS: A total of 40 goats (9.1%), 53 sheep (12.0%) and 158 cattle (54.3%) were positive for Fasciola ova which reflects an increase in prevalence in small ruminants. CONCLUSION: This implies that the entire Ibadan is endemic for Fasciola spp and small ruminants may serve as an important link in the epidemiology of Fasciola spp infection. More so, this has implications for the scavenging household animals which receive little or no medical attention and man that may acquire this trematode by inadvertently eating vegetables with encysted Fasciola metacercariae. PMID- 26949792 TI - Tissue culture isolation of lyssa viruses from apparently healthy unvaccinated dogs in Nigeria. AB - BACKGROUND: There have been previous reports of inapparent infection and intermittent secretion of rabies virus in the saliva of apparently healthy dogs in some African countries, including Nigeria. OBJECTIVE: The study was therefore aimed at examining the carrier status of rabies in apparently healthy Nigerian dogs in the settlement areas studied. METHODS: Ninety-two swabs samples from oral mucosae of domestic dogs (mongrels) without vaccination history were assayed for lyssaviruses by tissue culture isolation test in Vero cells. RESULTS: Rabies or rabies-related viruses were recovered from eighteen, representing 19.6% of the samples. The study showed that lyssaviruses were present in 4 out of the 6 settlements of the study areas. Among the areas where the viruses were present, the rate of isolation ranged from 11.1% to 66.7%. Female dogs had a little higher infection rate (12.0%) than their male counterparts (7.6%). Among age groups, the highest rate of infection (66.7%) was detected in dogs aged one to 3 years while the rate of 3.7% was found in dogs aged less than one year. CONCLUSION: The results of this study agree with the carrier state of rabies in domestic dogs, the common reservoir hosts of its etiologic agents in Nigeria and the rest of Africa andAsia; this is a serious threat to humans in these settlements. Although the load of infective virus in saliva is lower than that in brain, saliva collection for rabies diagnosis is simple, safer, faster and cheaper. Thus we suggest that saliva samples could be used as an alternative to brain specimens for rabies virus antigen testing in dogs, especially, when it is not practicable to obtain brain specimen. PMID- 26949793 TI - Detection of avian influenza virus from fecal samples of poultry birds in Lagos State. AB - BACKGROUND: Although there have been a lot of research done on Avian Influenza in the world, there are still visible indications in the Nigerian poultry farming system that the bio-security measures are not adhered to strictly. Hence, it is of great importance to identify the circulating strains of Avian Influenza virus in Nigeria, so as to prevent and control another outbreak of the disease. METHODS: Between May and June 2011, 184 stool samples were collected from seemingly healthy poultry birds in Ikorodu and Ejigbo, within Lagos state. RNA extraction using diatomaceous sand method and Reverse Transcriptase Polymerase Chain Reaction (RT-PCR) was carried out on all samples. FINDINGS: Influenza virus type A 25(13.6%) was detected from poultry B (Ejigbo poultry), while there was no positive sample from poultry A (Ikorodu Poultry), the positive samples were further sub-typed, and H1 [1(4%)] was detected. Altogether, 159 (86%) of the fecal samples collected gave a. negative result for Influenza A, and also, 24(96%) out the 25 samples positive for Influenza A gave tested negative when subtyped with H1 and H3. INTERPRETATION: Results of the samples gotten from both poultries corroboratethe effect of poor bio-security practicesin the spread of Influenza A viruses and that some poultries in Nigeria are not adhering to proper farm bio-security practices. Also the identification of H1 subtype which is human adapted is indicative of a re- emerging potential threat to public health. PMID- 26949794 TI - Lack of protection against rabies in neighbourhood dogs in some peri-urban and rural areas of Ogun and Oyo states, Nigeria. AB - BACKGROUND: Rabies is a highly fatal zoonosis that causes severe destruction to the central nervous system and remains underreported in developing countries like Nigeria. OBJECTIVES: The increasing close contact between dogs and their owners or neighbours suggest a need for investigation of the protective level of rabies virus (RABV) antibodies in dogs. METHODS: Sera from 150 apparently healthy neighbourhood dogs from some peri-urban and rural areas of Ogun and Oyo states, southwestern Nigeria were analyzed for the presence of RABV antibodies using the indirect ELISA technique. These dogs were kept as pets, used for hunting or sold for human consumption. RESULTS: The results showed that none of the dogs had optimal RABV antibody titres, 25 (16.7%) had sub-optimal antibody titres while 125 (83.3%) were negative. Detection of sub-optimal RABV antibody levels in these unvaccinated dogs suggests that they might have been exposed to rabies or rabies related viruses. Data obtained from interviews conducted revealed that 21.3% of the dog owners were informed about rabies but neglected vaccination while 44.7% were uninformed. CONCLUSIONS: We conclude that these dogs lacked protective levels of RABV antibodies and thus constitute a public, health threat. This finding underscores the need for dog anti-rabies vaccination campaigns covering peri-urban and rural areas as well as the promotion of large scale public enlightenment programmes on rabies in Nigeria. PMID- 26949795 TI - Is our health workforce prepared for future health megatrends? PMID- 26949796 TI - Editorial. PMID- 26949797 TI - Before, behind and beyond the discovery of the Higgs boson. PMID- 26949798 TI - Spontaneous symmetry breaking in gauge theories. AB - The aim of this historical article is to describe the development of the idea of spontaneous symmetry breaking in gauge theories as seen from my perspective as a member of Abdus Salam's group at Imperial College London, UK. Beginning with an account of particle physics in the years after the Second World War, I describe early attempts at constructing a unified theory of weak and electromagnetic interactions, the obstacles encountered and how they were eventually overcome with the mass-generating mechanism incorporating the idea of spontaneous symmetry breaking, one of whose features is the now-famous Higgs boson. PMID- 26949800 TI - Genesis of the Large Hadron Collider. AB - This paper describes the scientific, technical and political genesis of the Large Hadron Collider (LHC). It begins with an outline of the early history of the LHC, from first thoughts and accelerator and detector developments that underwrote the project, through the first studies of the LHC and its scientific potential and the genesis of the experimental programme, to the presentation of the proposal to build the LHC to the CERN Council in December 1993. The events that led to the proposal to build the LHC in two stages, which was approved in December 1994, are then described. Next, the role of non-Member State contributions and of the agreement that CERN could take loans, which allowed single stage construction to be approved in December 1996, despite a cut in the Members' contributions, are explained. The paper concludes by identifying points of potential relevance for the approval of possible future large particle physics projects. PMID- 26949799 TI - Symmetry breaking and the deconstruction of mass. AB - We briefly review some of the connections between symmetry breaking in condensed matter physics and in particle physics, assisting, in particular, our current understanding of the origin of mass. PMID- 26949801 TI - The pre-LHC Higgs hunt. AB - Enormous efforts at accelerators and experiments all around the world have gone into the search for the long-sought Higgs boson, postulated almost five decades ago. This search has culminated in the discovery of a Higgs-like particle by the ATLAS and CMS experiments at CERN's Large Hadron Collider in 2012. Instead of describing this widely celebrated discovery, in this article I will rather focus on earlier attempts to discover the Higgs boson, or to constrain the range of possible masses by interpreting precise data in the context of the Standard Model of particle physics. In particular, I will focus on the experimental efforts carried out during the last two decades, at the Large Electron Positron collider, CERN, Geneva, Switzerland, and the Tevatron collider, Fermilab, near Chicago, IL, USA. PMID- 26949802 TI - The technical challenges of the Large Hadron Collider. AB - The Large Hadron Collider (LHC) is a 27km circumference hadron collider, built at CERN to explore the energy frontier of particle physics. Approved in 1994, it was commissioned and began operation for data taking in 2009. The design and construction of the LHC presented many design, engineering and logistical challenges which involved pushing a number of technologies well beyond their level at the time. Since the start-up of the machine, there has been a very successful 3-year run with an impressive amount of data delivered to the LHC experiments. With an increasingly large stored energy in the beam, the operation of the machine itself presented many challenges and some of these will be discussed. Finally, the planning for the next 20 years has been outlined with progressive upgrades of the machine, first to nominal energy, then to progressively higher collision rates. At each stage the technical challenges are illustrated with a few examples. PMID- 26949803 TI - Technical challenges of the Large Hadron Collider experiments (ATLAS and CMS). AB - This review article introduces the design of the general purpose experiments ATLAS and CMS, which independently discovered the Higgs boson, showing how generic features are motivated by the characteristics needed to explore the physics landscape made accessible by the Large Hadron Collider accelerator, whose high collision rate creates an extremely challenging operating environment for instrumentation. Examples of the very different component designs chosen by the two experiment collaborations are highlighted, as an introduction to briefly describing techniques used in the construction of some of these elements and, subsequently, in the assembly of both detection systems in their respective underground caverns. PMID- 26949804 TI - The discovery and measurements of a Higgs boson. AB - In July 2012, the ATLAS and CMS collaborations at CERN's Large Hadron Collider announced the discovery of a Higgs-like boson, a new heavy particle at a mass more than 130 times the mass of a proton. Since then, further data have revealed its properties to be strikingly similar to those of the Standard Model Higgs boson, a particle expected from the mechanism introduced almost 50 years ago by six theoreticians including British physicists Peter Higgs from Edinburgh University and Tom Kibble from Imperial College London. The discovery is the culmination of a truly remarkable scientific journey and undoubtedly the most significant scientific discovery of the twenty-first century so far. Its experimental confirmation turned out to be a monumental task requiring the creation of an accelerator and experiments of unprecedented capability and complexity, designed to discern the signatures that correspond to the Higgs boson. Thousands of scientists and engineers, in each of the ATLAS and CMS teams, came together from all four corners of the world to make this massive discovery possible. PMID- 26949805 TI - Multiple solutions in supersymmetry and the Higgs. AB - Weak-scale supersymmetry is a well-motivated, if speculative, theory beyond the Standard Model of particle physics. It solves the thorny issue of the Higgs mass, namely: how can it be stable to quantum corrections, when they are expected to be 1015 times bigger than its mass? The experimental signal of the theory is the production and measurement of supersymmetric particles in the Large Hadron Collider (LHC) experiments. No such particles have been seen to date, but hopes are high for the impending run in 2015. Searches for supersymmetric particles can be difficult to interpret. Here, we shall discuss the fact that, even given a well-defined model of supersymmetry breaking with few parameters, there can be multiple solutions. These multiple solutions are physically different and could potentially mean that points in parameter space have been ruled out by interpretations of LHC data when they should not have been. We shall review the multiple solutions and illustrate their existence in a universal model of supersymmetry breaking. PMID- 26949806 TI - Beyond the standard Higgs after the 125 GeV Higgs discovery. AB - An elementary weakly coupled and solitary Higgs boson allows one to extend the validity of the Standard Model up to very high energy, maybe as high as the Planck scale. Nonetheless, this scenario fails to fill the universe with dark matter and does not explain the matter-antimatter asymmetry. However, amending the Standard Model tends to destabilize the weak scale by large quantum corrections to the Higgs potential. New degrees of freedom, new forces, new organizing principles are required to provide a consistent and natural description of physics beyond the standard Higgs. PMID- 26949807 TI - The Higgs boson and cosmology. AB - I will discuss how the Higgs field of the Standard Model may have played an important role in cosmology, leading to the homogeneity, isotropy and flatness of the Universe; producing the quantum fluctuations that seed structure formation; triggering the radiation-dominated era of the hot Big Bang; and contributing to the processes of baryogenesis and dark matter production. PMID- 26949808 TI - The upgraded ATLAS and CMS detectors and their physics capabilities. AB - The update of the European Strategy for Particle Physics from 2013 states that Europe's top priority should be the exploitation of the full potential of the LHC, including the high-luminosity upgrade of the machine and detectors with a view to collecting 10 times more data than in the initial design. The plans for upgrading the ATLAS and CMS detectors so as to maintain their performance and meet the challenges of increasing luminosity are presented here. A cornerstone of the physics programme is to measure the properties of the 125GeV Higgs boson with the highest possible precision, to test its consistency with the Standard Model. The high-luminosity data will allow precise measurements of the dominant production and decay modes, and offer the possibility of observing rare modes including Higgs boson pair production. Direct and indirect searches for additional Higgs bosons beyond the Standard Model will also continue. PMID- 26949815 TI - Synthesis, Structure, and Complex Magnetism of MIr2In8 (M = Eu, Sr). AB - We report the synthesis, crystal structure, and physical properties of two new polar intermetallic compounds, EuIr2In8 and SrIr2In8. Both were synthesized in good yield using In metal as a reactive flux medium, enabling the growth of large crystals for physical property measurements. They crystallize in the orthorhombic space group Pbam with the CeFe2Al8 structure type, which is sometimes also referred to as the CaCo2Al8 structure type. The two analogues have unit cell parameters of a = 13.847(3) A, b = 16.118(3) A, and c = 4.3885(9) A for M = Eu and a = 13.847(3) A, b = 16.113(3) A, and c = 4.3962(9) A for M = Sr at room temperature. SrIr2In8 is a diamagnetic metal with no local magnetic moments on either the Sr or Ir sites, and the diamagnetic contribution from core electrons overwhelms the expected Pauli paramagnetism normally seen in intermetallic compounds. Magnetism in EuIr2In8 is dominated by the local Eu moments, which order antiferromagnetically at 5 K in low applied fields. Increasing the field strength depresses the magnetic ordering temperature and also induces a spin reorientation at lower temperature, indicating complex competing magnetic interactions. Low-temperature heat capacity measurements show a significant enhancement of the Sommerfeld coefficient in EuIr2In8 relative to that in SrIr2In8, with estimated values of gamma = 118(3) and 18.0(2) mJ mol(-1) K(-2), respectively. PMID- 26949816 TI - Subsystem Analysis for the Fragment Molecular Orbital Method and Its Application to Protein-Ligand Binding in Solution. AB - A subsystem analysis is derived incorporating interfragment interactions into the fragment properties, such as energies or charges. The relative stabilities of three alanine isomers, the alpha-helix, the beta-turn, and the extended form are studied and the differences in fragment properties are elucidated. The analysis is further elaborated for studies of binding energies. The binding of the Trp cage protein (PDB: 1L2Y ) to two ligands is studied in detail. Binding energies defined for each fragment can be used as a convenient descriptor for analyzing contributions to binding in solution. PMID- 26949818 TI - Nonlinear effects of team tenure on team psychological safety climate and climate strength: Implications for average team member performance. AB - The teams literature suggests that team tenure improves team psychological safety climate and climate strength in a linear fashion, but the empirical findings to date have been mixed. Alternatively, theories of group formation suggest that new and longer tenured teams experience greater team psychological safety climate than moderately tenured teams. Adopting this second perspective, we used a sample of 115 research and development teams and found that team tenure had a curvilinear relationship with team psychological safety climate and climate strength. Supporting group formation theories, team psychological safety climate and climate strength were higher in new and longer tenured teams compared with moderately tenured teams. Moreover, we found a curvilinear relationship between team tenure and average team member creative performance as partially mediated by team psychological safety climate. Team psychological safety climate improved average team member task performance only when team psychological safety climate was strong. Likewise, team tenure influenced average team member task performance in a curvilinear manner via team psychological safety climate only when team psychological safety climate was strong. We discuss theoretical and practical implications and offer several directions for future research. (PsycINFO Database Record PMID- 26949817 TI - What makes professors appear credible: The effect of demographic characteristics and ideological beliefs. AB - Five studies are conducted to examine how ideology and perceptions regarding gender, race, caste, and affiliation status affect how individuals judge researchers' credibility. Support is found for predictions that individuals judge researcher credibility according to their egalitarian or elitist ideologies and according to status cues including race, gender, caste, and university affiliation. Egalitarians evaluate low-status researchers as more credible than high-status researchers. Elitists show the opposite pattern. Credibility judgments affect whether individuals will interpret subsequent ambiguous events in accordance with the researcher's findings. Effects of diffuse status cues and ideological beliefs may be mitigated when specific status cues are presented to override stereotypes. (PsycINFO Database Record PMID- 26949819 TI - Do similarities or differences between CEO leadership and organizational culture have a more positive effect on firm performance? A test of competing predictions. AB - This study examines the nature of the interaction between CEO leadership and organizational culture using 2 common metathemes (task and relationship) in leadership and culture research. Two perspectives, similarity and dissimilarity, offer competing predictions about the fit, or interaction, between leadership and culture and its predicted effect on firm performance. Predictions for the similarity perspective draw upon attribution theory and social identity theory of leadership, whereas predictions for the dissimilarity perspective are developed based upon insights from leadership contingency theories and the notion of substitutability. Hierarchical regression results from 114 CEOs and 324 top management team (TMT) members failed to support the similarity hypotheses but revealed broad support for the dissimilarity predictions. Findings suggest that culture can serve as a substitute for leadership when leadership behaviors are redundant with cultural values (i.e., they both share a task- or relationship oriented focus). Findings also support leadership contingency theories indicating that CEO leadership is effective when it provides psychological and motivational resources lacking in the organization's culture. We discuss theoretical and practical implications and delineate directions for future research. (PsycINFO Database Record PMID- 26949820 TI - From dawn till dusk: Shedding light on the recovery process by investigating daily change patterns in fatigue. AB - Although the notion that recovery is a process rather than a state lies at the heart of recovery theory, the continuous cycle of depletion and replenishment of resources itself has not yet been investigated empirically. In the present article, I therefore build on recovery theory and on evidence from chronobiological research and adopt a temporal research approach that allows investigating change trajectories in fatigue over the course of the day. Furthermore, the role of sleep quality and psychological detachment in these change trajectories is investigated. Hypotheses are tested in an experience sampling study involving 133 employees who were asked to provide fatigue ratings 4 times a day over 5 consecutive workdays. Growth curve analyses revealed that on average fatigue decreased in the morning, reaching a nadir around midday and then increased until bedtime. Additionally, daily sleep quality explained variation in individuals' fatigue change trajectories: When sleep quality was low, next day fatigue decreased between morning and midday and then increased again until bedtime; when sleep quality was high, fatigue remained stable until midday and then increased again between the end of work and bedtime. Theoretical implications for the recovery literature and practical implications are discussed in conclusion. (PsycINFO Database Record PMID- 26949821 TI - A profile of profiles: A meta-analysis of the nomological net of commitment profiles. AB - Although the majority of empirical commitment research has adopted a variable centered approach, the person-centered or profiles approach is gaining traction. One challenge in the commitment profiles literature is that names are attached to profiles based on the within-study comparison among profiles and their relative levels and shapes. Thus, it is possible that different studies name the same profiles differently or different profiles similarly because of the context of the other profiles in the study. A meta-analytic approach, combined with multilevel latent profile analysis (LPA) that accounts for both within- and between-sample variability, is used in this study to examine the antecedents and outcomes of commitment profiles. This helps solve the naming problem by examining multiple data sets (K = 40) with a large sample (N = 16,052), obtained by contacting commitment researchers who voluntarily supplied primary data to bring further consensus about the phenomenology of profiles. LPA results revealed 5 profiles (Low, Moderate, AC-dominant, AC/NC-dominant, and High). Meta-analytic results revealed that high levels of bases of commitment were associated with value-based profiles whereas low levels were associated with weak commitment profiles. Additionally, value-based profiles were associated with older, married, and less educated participants than the weak commitment profiles. Regarding outcomes of commitment, profiles were found to significantly relate to focal behaviors (e.g., performance, tenure, and turnover) and discretionary behaviors (e.g., organizational citizenship behaviors). Value-based profiles were found to have higher levels of both focal and discretionary behaviors for all analyses. Implications for the commitment and profile literature are discussed. (PsycINFO Database Record PMID- 26949822 TI - Skewed task conflicts in teams: What happens when a few members see more conflict than the rest? AB - Task conflict has been the subject of a long-standing debate in the literature when does task conflict help or hurt team performance? We propose that this debate can be resolved by taking a more precise view of how task conflicts are perceived in teams. Specifically, we propose that in teams, when a few team members perceive a high level of task disagreement while a majority of others perceive low levels of task disagreement-that is, there is positively skewed task conflict, task conflict is most likely to live up to its purported benefits for team performance. In our first study of student teams engaged in a business decision game, we find support for the positive relationship between skewed task conflict and team performance. In our second field study of teams in a financial corporation, we find that the relationship between positively skewed task conflict and supervisor ratings of team performance is mediated by reflective communication within the team. (PsycINFO Database Record PMID- 26949823 TI - Epigenetic effects of chromatin remodeling agents on organotypic cultures. AB - BACKGROUND: Tumor epigenetic defects are of increasing relevance to clinical practice, because they are 'druggable' targets for cancer therapy using chromatin remodeling agents (CRAs). New evidences highlight the importance of the microenvironment on the epigenome regulation and the need to use culture models able to preserve tissue morphology, to better understand the action of CRAs. Methods & methods: We studied the epigenetic response induced by culturing and CRAs in a preclinical model, preserving ex vivo the original tissue microenvironment and morphology, assessing different epigenetic signatures. Our overall findings suggest that culturing and CRAs cause heterogeneous effects on the genes methylation; CRAs affect the global DNA methylation and can trigger an active DNA demethylation; the culture induces alterations in the histone deacetylase expression. CONCLUSION: Despite the limited number of cases, these findings can be considered a proof of concept of the possibility to test CRAs epigenetic effects on ex vivo tissues maintained in their native tissue architecture. PMID- 26949828 TI - A Review of Cry Protein Detection with Enzyme-Linked Immunosorbent Assays. AB - The widespread use of Cry proteins in insecticide formulations and transgenic crops for insect control has led to an increased interest in the environmental fate of these proteins. Although several detection methods are available to monitor the fate of Cry proteins in the environment, enzyme-linked immunosorbent assays (ELISAs) have emerged as the preferred detection method, due to their cost effectiveness, ease of use, and rapid results. Validation of ELISAs is necessary to ensure accurate measurements of Cry protein concentrations in the environment. Validation methodology has been extensively researched and published for the areas of sensitivity, specificity, accuracy, and precision; however, cross validation of ELISA results has been studied to a lesser extent. This review discusses the use of ELISAs for detection of Cry proteins in environmental samples and validation of ELISAs and introduces cross validation. The state of Cry protein environmental fate research is considered through a critical review of published literature to identify areas where the use of validation protocols can be improved. PMID- 26949830 TI - Mental fatigue impairs soccer-specific decision-making skill. AB - This study aimed to investigate the impact of mental fatigue on soccer-specific decision-making. Twelve well-trained male soccer players performed a soccer specific decision-making task on two occasions, separated by at least 72 h. The decision-making task was preceded in a randomised order by 30 min of the Stroop task (mental fatigue) or 30 min of reading from magazines (control). Subjective ratings of mental fatigue were measured before and after treatment, and mental effort (referring to treatment) and motivation (referring to the decision-making task) were measured after treatment. Performance on the soccer-specific decision making task was assessed using response accuracy and time. Visual search behaviour was also assessed throughout the decision-making task. Subjective ratings of mental fatigue and effort were almost certainly higher following the Stroop task compared to the magazines. Motivation for the upcoming decision making task was possibly higher following the Stroop task. Decision-making accuracy was very likely lower and response time likely higher in the mental fatigue condition. Mental fatigue had unclear effects on most visual search behaviour variables. The results suggest that mental fatigue impairs accuracy and speed of soccer-specific decision-making. These impairments are not likely related to changes in visual search behaviour. PMID- 26949829 TI - Ixabepilone for the treatment of endometrial cancer. AB - INTRODUCTION: Endometrial cancer (EC) is the most common gynaecological cancer. Despite significant progress in the multimodality treatment approach, the prognosis remains poor for patients with advanced disease. Thus, there is the necessity of more effective strategies. The microtubule-stabilizing agent ixabepilone is the first drug in this new class of agents that has been approved for metastatic breast cancer treatment. Based on empiric data and on the clinical efficacy demonstrated in breast cancer, several clinical trials were proposed to define its role in EC. The aim of this review is to determine whether ixabepilone improved the clinical outcome in patients with locally advanced, recurrent or metastatic EC. AREAS COVERED: Preclinical and clinical studies of ixabepilone in endometrial cancer were analyzed and discussed. Data were obtained by searching for English peer-reviewed articles on PubMed, phase I and II studies registered on clincaltrials.gov, and related abstracts recently presented at major international congresses. EXPERT OPINION: Advanced or recurrent EC still represents a challenge and an unmet need in the panorama of gynaecological malignancies. Ixabepilone's future therapeutic role in EC remains ill defined. Nevertheless, despite its limited efficacy in EC, clinicians treating gynaecological tumours should be aware of its main aspects. PMID- 26949831 TI - Diffusion theory of decision making in continuous report. AB - I present a diffusion model for decision making in continuous report tasks, in which a continuous, circularly distributed, stimulus attribute in working memory is matched to a representation of the attribute in the stimulus display. Memory retrieval is modeled as a 2-dimensional diffusion process with vector-valued drift on a disk, whose bounding circle represents the decision criterion. The direction and magnitude of the drift vector describe the identity of the stimulus and the quality of its representation in memory, respectively. The point at which the diffusion exits the disk determines the reported value of the attribute and the time to exit the disk determines the decision time. Expressions for the joint distribution of decision times and report outcomes are obtained by means of the Girsanov change-of-measure theorem, which allows the properties of the nonzero drift diffusion process to be characterized as a function of a Euclidian-distance Bessel process. Predicted report precision is equal to the product of the decision criterion and the drift magnitude and follows a von Mises distribution, in agreement with the treatment of precision in the working memory literature. Trial-to-trial variability in criterion and drift rate leads, respectively, to direct and inverse relationships between report accuracy and decision times, in agreement with, and generalizing, the standard diffusion model of 2-choice decisions. The 2-dimensional model provides a process account of working memory precision and its relationship with the diffusion model, and a new way to investigate the properties of working memory, via the distributions of decision times. (PsycINFO Database Record PMID- 26949833 TI - Direct Oxidation of Aliphatic C-H Bonds in Amino-Containing Molecules under Transition-Metal-Free Conditions. AB - By employing a simple, inexpensive, and transition-metal-free oxidation system, secondary C-H bonds in a series of phthaloyl protected primary amines and amino acid derivatives were oxidized to carbonyls with good regioselectivities. This method could also be applied to oxidize tertiary C-H bonds and modify synthetic dipeptides. PMID- 26949834 TI - Polymer-Graft-Mediated Interactions between Colloidal Spheres. AB - Aqueous dispersions of fluorinated colloidal spheres bearing grafted poly(ethylene glycol) (PEG) are studied as a function of salt and particle concentration with the aim of improving the understanding of interactions among polymer-grafted particles. These dispersions can sustain large concentrations of salt, but crystals nucleate in dilute dispersions when a sufficient Na2CO3 concentration is reached, which is attributed to the presence of attractions between particles. On further increasing the Na2CO3 concentration, the solvent is rapidly cleared of particles. Small-angle X-ray scattering and cryogenic transmission electron microscopy are employed in order to quantify the attractions. The former is used to extract a second virial coefficient, and the latter shows that the PEG-graft contracts as a function of increasing salt concentration. The contraction not only leads to a reduction in excluded volume but also is accompanied by attractions of moderate magnitude. In contrast, dispersion of the particles in ethanol, in which bulk PEG solutions crystallize, lead to fractal structures caused by strong attractions. PMID- 26949832 TI - A Multi-Center Diabetes Eye Screening Study in Community Settings: Study Design and Methodology. AB - PURPOSE: Diabetes is the leading cause of new cases of blindness among adults aged 20-74 years within the United States. The Innovative Network for Sight Research group (INSIGHT) designed the Diabetic Eye Screening Study (DESS) to examine the feasibility and short-term effectiveness of non-mydriatic diabetic retinopathy (DR) screening for adults with diabetes in community-based settings. METHODS: Study enrollment began in December 2011 at four sites: an internal medicine clinic at a county hospital in Birmingham, Alabama; a Federally qualified community healthcare center in Miami-Dade County, Florida; a university affiliated outpatient pharmacy in Philadelphia, Pennsylvania; and a medical home in Winston-Salem, North Carolina. People 18 years or older with previously diagnosed diabetes were offered free DR screening using non-mydriatic retinal photography that was preceded by a brief questionnaire addressing demographic information and previous eye care use. Visual acuity was also measured for each eye. Images were evaluated at a telemedicine reading center by trained evaluators using the National Health System DR grading classification. Participants and their physicians were sent screening report results and telephoned for a follow up survey 3 months post-screening to determine whether participants had sought follow-up comprehensive eye care and their experiences with the screening process. RESULTS: Target enrollment at each site was a minimum of 500 persons. Three of the four sites met this enrollment goal. CONCLUSION: The INSIGHT/DESS is intended to establish the feasibility and short-term effectiveness of DR screening using non-mydriatic retinal photography in persons with diabetes who seek services in community-based clinic and pharmacy settings. PMID- 26949836 TI - Obstructive sleep apnea in children: update on the recognition, treatment and management of persistent disease. AB - Adenotonsillectomy (AT) is the recommended first-line treatment for pediatric obstructive sleep apnea (OSA) in children with adenotonsillar hypertrophy. It is now clearly established that AT results in improvement in the severity of OSA in most children. However, a significant number of OSA children undergoing AT exhibit residual persistent OSA post-surgery. Patients at increased risk of persistent OSA include those with severe disease at initial review, older or obese patients, children with underlying asthma or allergic rhinitis, and those who have concurrent underlying medical conditions, such as Trisomy 21, craniofacial syndromes or cerebral palsy. Here, we aim to highlight recent research findings into those who have persistent OSA disease, and suggest a practical approach to the management of these children. PMID- 26949835 TI - Enzymatic Kinetic Isotope Effects from First-Principles Path Sampling Calculations. AB - In this study, we develop and test a method to determine the rate of particle transfer and kinetic isotope effects in enzymatic reactions, specifically yeast alcohol dehydrogenase (YADH), from first-principles. Transition path sampling (TPS) and normal mode centroid dynamics (CMD) are used to simulate these enzymatic reactions without knowledge of their reaction coordinates and with the inclusion of quantum effects, such as zero-point energy and tunneling, on the transferring particle. Though previous studies have used TPS to calculate reaction rate constants in various model and real systems, it has not been applied to a system as large as YADH. The calculated primary H/D kinetic isotope effect agrees with previously reported experimental results, within experimental error. The kinetic isotope effects calculated with this method correspond to the kinetic isotope effect of the transfer event itself. The results reported here show that the kinetic isotope effects calculated from first-principles, purely for barrier passage, can be used to predict experimental kinetic isotope effects in enzymatic systems. PMID- 26949837 TI - Parkinson Disease: The Relationship Between Non-motor Symptoms and Motor Phenotype. AB - BACKGROUND: Parkinson disease (PD) presents with motor and non-motor symptoms (NMS). The NMS often precede the onset of motor symptoms, but may progress throughout the disease course. Tremor dominant, postural instability gait difficulty (PIGD), and indeterminate phenotypes can be distinguished using Unified PD Rating scales (UPDRS-III). We hypothesized that the PIGD phenotype would be more likely to develop NMS, and that the non-dopamine-responsive axial signs would correlate with NMS severity. METHODS: We conducted a retrospective cross-sectional chart review to assess the relationship between NMS and PD motor phenotypes. PD patients were administered the NMS Questionnaire, the UPDRS-III, and the Mini-Mental State Examination score. The relationship between NMS burden and PD subtypes was examined using linear regression models. The prevalence of each NMS among difference PD motor subtypes was analyzed using chi-square test. RESULTS: PD patients with more advanced disease based on their UPDRS-III had higher NMS Questionnaire scores. The axial component of UPDRS-III correlated with higher NMS. There was no correlation between NMS and tremor scores. There was a significant correlation between PIGD score and higher NMS burden. PIGD group had higher prevalence in most NMS domains when compared with tremor dominant and indeterminate groups independent of disease duration and severity. CONCLUSIONS: NMS profile and severity vary according to motor phenotype. We conclude that in the PD population, patients with a PIGD phenotype who have more axial involvement, associated with advanced disease and poor motor response, have a higher risk for a higher NMS burden. PMID- 26949838 TI - Dissection of a Limb of a Vertebral Artery Fenestration: Case Report. PMID- 26949840 TI - Development of Similar Broth Microdilution Methods to Determine the Antimicrobial Susceptibility of Flavobacterium columnare and F. psychrophilum. AB - Flavobacterium columnare and F. psychrophilum are major fish pathogens that cause diseases that may require antimicrobial therapy. Choice of appropriate treatment is dependent upon determining the antimicrobial susceptibility of isolates. Therefore we optimized methods for broth microdilution testing of F. columnare and F. psychrophilum to facilitate standardizing an antimicrobial susceptibility test. We developed adaptations to make reproducible broth inoculums and confirmed the proper incubation time and media composition. We tested the stability of potential quality-control bacteria and compared test results between different operators. Log phase occurred at 48 h for F. columnare and 72-96 h for F. psychrophilum, confirming the test should be incubated at 28 degrees C for approximately 48 h and at 18 degrees C for approximately 96 h, respectively. The most consistent susceptibility results were achieved with plain, 4-g/L, dilute Mueller-Hinton broth supplemented with dilute calcium and magnesium. Supplementing the broth with horse serum did not improve growth. The quality control strains, Escherichia coli ATCC 25922 and Aeromonas salmonicida subsp. salmonicida ATCC 33658, yielded stable minimal inhibitory concentrations (MIC) against all seven antimicrobials tested after 30 passes at 28 degrees C and 15 passes at 18 degrees C. In comparison tests, most MICs of the isolates agreed 100% within one drug dilution for ampicillin, florfenicol, and oxytetracycline. The agreement was lower with the ormetoprim-sulfdimethoxine combination, but there was at least 75% agreement for all but one isolate. These experiments have provided methods to help standardize antimicrobial susceptibility testing of these nutritionally fastidious aquatic bacteria. Received June 24, 2015; accepted October 2, 2015. PMID- 26949839 TI - CAF-like state in primary skin fibroblasts with constitutional BRCA1 epimutation sheds new light on tumor suppressor deficiency-related changes in healthy tissue. AB - Constitutive epimutations of tumor suppressor genes are increasingly considered as cancer predisposing factors equally to sequence mutations. In light of the emerging role of the microenvironment for cancer predisposition, initiation, and progression, we aimed to characterize the consequences of a BRCA1 epimutation in cells of mesenchymal origin. We performed a comprehensive molecular and cellular comparison of primary dermal fibroblasts taken from a monozygous twin pair discordant for recurrent cancers and BRCA1 epimutation, whose exceptional clinical case we previously reported in this journal. Comparative transcriptome analysis identified differential expression of extracellular matrix-related genes and pro-tumorigenic growth factors, such as collagens and CXC chemokines. Moreover, genes known to be key markers of so called cancer-associated fibroblasts (CAFs), such as ACTA2, FAP, PDPN, and TNC, were upregulated in fibroblasts of the affected twin (BRCA1(mosMe)) in comparison to those of the healthy twin (BRCA1(wt)). Further analyses detected CAF-typical cellular features, including an elevated growth rate, enhanced migration, altered actin architecture and increased production of ketone bodies in BRCA1(mosMe) fibroblasts compared to BRCA1(wt) fibroblasts. In addition, conditioned medium of BRCA1(mosMe) fibroblasts was more potent than conditioned medium of BRCA1(wt) fibroblasts to promote cell proliferation in an epithelial and a cancer cell line. Our data demonstrate, that a CAF-like state is not an exclusive feature of tumor-associated tissue but also exists in healthy tissue with tumor suppressor deficiency. The naturally occurring phenomenon of twin fibroblasts differing in their BRCA1 methylation status revealed to be a unique powerful tool for exploring tumor suppressor deficiency-related changes in healthy tissue, reinforcing their significance for cancer predisposition. PMID- 26949841 TI - Genomic diversity of necrotic enteritis-associated strains of Clostridium perfringens: a review. AB - The investigation of genomic variation between Clostridium perfringens isolates from poultry has been an important tool to enhance our understanding of the genetic basis of strain pathogenicity and the epidemiology of virulent and avirulent strains within the context of necrotic enteritis (NE). The earliest studies used whole genome profiling techniques such as pulsed-field gel electrophoresis to differentiate isolates and determine their relative levels of relatedness. DNA sequencing has been used to investigate genetic variation in (a) individual genes, such as those encoding the alpha and NetB toxins; (b) panels of housekeeping genes for multi-locus sequence typing and (c) most recently whole genome sequencing to build a more complete picture of genomic differences between isolates. Conclusions drawn from these studies include: differential carriage of large conjugative plasmids accounts for a large proportion of inter-strain differences; plasmid-encoded genes are more highly conserved than chromosomal genes, perhaps indicating a relatively recent origin for the plasmids; isolates from NE-affected birds fall into three distinct sequence-based clades while non pathogenic isolates from healthy birds tend to be more genomically diverse. Overall, the NE causing strains are closely related to C. perfringens isolates from other birds and other diseases whereas the non-pathogenic poultry strains are generally more remotely related to either the pathogenic strains or the strains from other birds. Genomic analysis has indicated that genes in addition to netB are associated with NE pathogenic isolates. Collectively, this work has resulted in a deeper understanding of the pathogenesis of this important poultry disease. PMID- 26949843 TI - Psychosis in Parkinson's disease: unexplained observations in a seemingly simple model. PMID- 26949845 TI - Case 1: chronic infected donor site. AB - Following a coronary bypass surgery, a vein donor site became infected and failed to heal despite use of antibiotics and a variety of topical treatments. Octenilin Wound Gel not only helped to promote healing, but also increased the patient's ability to tolerate dressing changes. PMID- 26949844 TI - Concordance with a STOPP (Screening Tool of Older Persons' Potentially Inappropriate Prescriptions) Criterion in Nova Scotia, Canada: Benzodiazepine and Zoplicone Prescription Claims by Older Adults with Fall-related Hospitalizaions. AB - BACKGROUND: Optimization of prescribing in older adults is needed. The STOPP criteria provide a systematic way of identifying potentially inappropriate prescribing in this population. Previous research indicates poor concordance between benzodiazepine prescribing and STOPP. OBJECTIVES: To determine the extent and predictors of benzodiazepine and zopiclone (BZD-Z) pharmacy dispensations in older adults with a history of a recent fall, in concordance with STOPP. METHODS: Prescription claims data from the Nova Scotia Seniors' Phamacare Program were linked with fall-related injury data from the CIHI Discharge Abstract Database. Adults aged >= 66 years making a claim for a BZD-Z in the 100 days prior to fall related hospitalization were identified. Their BZD-Z claims in the 100 days following discharge were also identified. Descriptive statistics, trend tests and logistical regression modelling were performed to examine predictors for continued use of BZD-Z post-fall. RESULTS: Over 5 years, from a pool of 8,271 older adults discharged following a fall-related hospitalization, 1,789 (21.6%) had made a claim for a BZD-Z in the 100 days prior to admission. Of these, 82% were women. Younger age and female sex were predictors of continuing BZD-Z dispensations post-fall. In the 100 days following discharge, 74.2% (n=1327) made a claim for at least one BZD-Z. CONCLUSION: BZD-Z use continued in 74% of patients following discharge from a fall-related hospitalization, representing limited concordance with the STOPP criterion. Such hospitalizations and follow-up care present an opportunity to address an ongoing modifiable risk factor. PMID- 26949842 TI - Catalytic degradation of recalcitrant pollutants by Fenton-like process using polyacrylonitrile-supported iron (II) phthalocyanine nanofibers: Intermediates and pathway. AB - Iron (II) phthalocyanine (FePc) molecules were isolated in polyacrylonitrile (PAN) nanofibers by electrospinning to prevent the formation of dimers and oligomers. Carbamazepine (CBZ) and Rhodamine B (RhB) degradation was investigated during a Fenton-like process with FePc/PAN nanofibers. Classical quenching tests with isopropanol and electron paramagnetic resonance tests with 5,5-dimethyl pyrroline-oxide as spin-trapping agent were performed to determine the formation of active species during hydrogen peroxide (H2O2) decomposition by FePc/PAN nanofibers. After eight recycles for CBZ degradation over the FePc/PAN nanofibers/H2O2 system, the removal ratios of CBZ remained at 99%. Seven by products of RhB and twelve intermediates of CBZ were identified using ultra performance liquid chromatography and high-resolution mass spectrometry. Pathways of CBZ and RhB degradation were proposed based on the identified intermediates. As the reaction proceeded, all CBZ and RhB aromatic nucleus intermediates decreased and were transformed to small acids, but also to potentially toxic epoxide-containing intermediates and acridine, because of the powerful oxidation ability of *OH in the catalytic system. PMID- 26949846 TI - Case 2: amputation site and infected toe on the diabetic foot. AB - Severe infection resulted in the amputation of one toe and surgical debridement of necrotic tissue on another toe in the same diabetic foot. The postoperative wounds healed quickly and uneventfully following use of octenilin Wound Gel and a foam dressing. PMID- 26949847 TI - Case 4: using octenilin Solution with the schulke WoundPad. AB - This case study demonstrates the use of a debridement pad with octenilin. PMID- 26949848 TI - Case 3: chronic venous leg ulcer. AB - A non-healing, sloughy venous leg ulcer quickly responded to topical treatment including octenilin Wound Gel and octenilin Wound Irrigation Solution. Full healing occurred within 6 weeks. PMID- 26949849 TI - Case 5: non-healing traumatic wound colonised with MRSA. AB - A traumatic wound colonised with MRSA failed to respond to topical antimicrobial dressings. Following the combined use of octenilin Wound Gel and octenilin Wound Irrigation Solution, the MRSA was removed in 4 weeks, the necrotic tissue was debrided and the wound started healing. PMID- 26949850 TI - Case 6: amputation site on an ulcerated diabetic foot. AB - A patient presented with diabetic gangrene on four toes and a moderately infected ulcer on the dorsum of the foot. Following amputation of the gangrenous toes, it was possible to salvage the remaining foot using a combination of antibiotics, octenilin Wound Irrigation Solution and Octiset. PMID- 26949851 TI - Case 7: highly infected post-surgical wound. AB - Following treatment with antibiotics and surgical incision, which resulted in the release of putrid exudate, the wound was rinsed thoroughly with octenisept and covered with an antimicrobial dressing. This regimen successfully eradicated the infection, with full healing occurring in 6 weeks. PMID- 26949852 TI - Case 8: extremely painful, locally infected venous leg ulcer. AB - This ulcer was so painful that the young patient concerned was unable to tolerate antimicrobial dressings and compression therapy. A treatment regimen including octenilin Wound Gel helped reduce the pain, giving the patient more control over her life. The wound healed after 6 months. PMID- 26949853 TI - Case 9: heavily exuding, malodorous, necrotic pressure ulcer. AB - In this case, the necrotic tissue was so hard it was not possible to categorise the ulcer. Octenilin products were able to debride the necrotic tissue, so that the wound depth could be determined. After 4 weeks, the wound was covered with granulation tissue, improving the patient's quality of life. PMID- 26949854 TI - Case 10: venous leg ulcer that was significantly impairing quality of life. AB - This heavily exuding, sloughy ulcer was so painful that the patient had difficulty tolerating any physical contact with it. After treatment, pain levels subsided, so that she was better able to tolerate dressing changes, could sleep in her own bed instead of a chair, and started compression therapy. PMID- 26949856 TI - Case 12: a neuroischaemic ulcer on the heel. AB - This necrotic ulcer was managed with sharp debridement, octenilin Wound Irrigation Solution and Wound Gel, plus a non-adherent dressing. The significant oedema in the lower limb was controlled with reduced compression. The wound improved steadily over time, healing on week 16. PMID- 26949855 TI - Case 11: large, infected, necrotic mixed-aetiology leg ulcer. AB - This painful and malodorous ulcer was covered with 40% necrotic tissue. Combined use of octenilin Wound gel and Wound Irrigation Solution gently debrided the necrotic tissue, and helped reduce the pain and malodour. Within 6 weeks, the wound was covered with granulation tissue. PMID- 26949857 TI - Case 13: chronic painful ulcer on the heel of a diabetic foot. AB - This painful ulcer, which had signs of biofilm, was covered in necrotic tissue. Octenilin Wound Gel was used to soften the necrosis in preparation for sharp debridement. Three weeks later, the devitalised tissue had been completely removed, while there was a 50% reduction in wound size at week 5. PMID- 26949858 TI - Case 14: Octenilin Wound Gel versus betadine/PHMB gel. AB - Here, a clinician compares 4 weeks of treatment with Prontosan Wound Gel with a subsequent 4 weeks of octenilin Wound Gel on a complex diabetic foot ulcer prone to recurrent infection. The data show that, following the switch to octenilin, the previously static wound started to heal. PMID- 26949859 TI - Case 15: use as an instillation solution with NPWT. AB - A patient with purpura fulminans, which resulted in amputation of three limbs, developed a Pseudomonas infection on the buttocks. Treatment comprised negative pressure wound therapy, with octenilin as the irrigation fluid. This eradicated the infection, resulting in granulation tissue formation. PMID- 26949860 TI - Case 16: further success as an instillation solution with NPWT. AB - An amputation stump developed a particularly painful abscess, which required incision and drainage. Combined use of NPWT and octenilin Wound Irrigation Solution as the instillation fluid proved successful, with a reduction in pain and sufficient healing for the wound to be closed in theatre. PMID- 26949861 TI - Case 17: intravenous drug user injection-site wound. AB - This patient presented with a painful, malodorous, infected wound on his right leg, which was also his main heroin injection site. Following treatment with octenilin Wound Irrigation Solution and a superabsorbent dressing, within 3 weeks all of the symptoms of infection and non-healing had gone. PMID- 26949862 TI - Case 18: infected self-harm injury on the left ankle. AB - This patient, who not only had unstable disease but also a long history of self harm, presented with an infected malodorous wound filled with soft necrotic tissue and slough. Treatment including octenilin Wound Gel and antibiotics helped kick start the wound towards healing. PMID- 26949863 TI - Octenidine dihydrochloride: chemical characteristics and antimicrobial properties. AB - The empiric use of antibiotics is being restricted due to the spread of antimicrobial resistance. However, topical antiseptics are less likely to induce resistance, owing to their unspecific mode of action and the high concentrations in which they can be used. One such antiseptic, octenidine dihydrochloride (OCT), can be used either prophylactically or therapeutically on the skin, mucosa and wounds. Evidence to support its use comes from in-vitro, animal and clinical studies on its safety, tolerability and efficacy. This article summarises the physical, chemical and antimicrobial properties of OCT in the context of wound care. PMID- 26949864 TI - Wound cleansing: a key player in the implementation of the TIME paradigm. AB - The concept of wound bed preparation can be implemented using the TIME paradigm. Chronic wounds are mostly characterised by prolonged inflammation and increased bioburden. Removal of wound biofilm and devitalised tissue, which is an ideal environment for bacterial growth, can help address the I in TIME. Wound cleansing aims to remove contaminants, debris, dressing remnants and superficial slough from the wound. Some wound cleansers contain surfactants, which reduce the surface tension of a liquid, enabling it to spread further over a surface. This article describes how these solutions can be used to debride the wound surface without damaging healthy cells. PMID- 26949865 TI - Effects of cell phone use on semen parameters: Results from the MARHCS cohort study in Chongqing, China. AB - Epidemiological and experimental evidence for detrimental effects of cell phone use on semen quality is still equivocal. And that recruiting participants from infertility clinic not from general population may raise the possibility of a selection bias. To investigate effects of cell phone use on semen parameters in a general population,We screened and documented the cell phone use information of 794 young men from the Male Reproductive Health in Chongqing College students (MARHCS) cohort study in 2013, followed by 666 and 568 in 2014 and 2015, respectively. In the univariate regression analyses, we found that the daily duration of talking on the cell phone was significantly associated with decreased semen parameters, including sperm concentration [beta coefficient=-6.32% per unit daily duration of talking on the cell phone (h); 95% confidence interval (CI), 11.94, -0.34] and total sperm count (-8.23; 95% CI, -14.38, -1.63) in 2013; semen volume (-8.37; 95% CI, -15.93, -0.13) and total sperm count (-16.59; 95% CI, 29.91, -0.73) in 2015]. Internet use via cellular networks was also associated with decreased sperm concentration and total sperm counts in 2013 and decreased semen volume in 2015. Multivariate analyses were used to adjust for the effects of potential confounders, and significant negative associations between internet use and semen parameters remained. Consistent but nonsignificant negative associations between talking on the cell phone and semen parameters persisted throughout the three study years, and the negative association was statistically significant in a mixed model that considered all three years of data on talking on the cell phone and semen quality. Our results showed that certain aspects of cell phone use may negatively affect sperm quality in men by decreasing the semen volume, sperm concentration, or sperm count, thus impairing male fertility. PMID- 26949866 TI - Eight-year (2007-2014) trends in ambient fine particulate matter (PM2.5) and its chemical components in the Capital Region of Alberta, Canada. AB - Currently there have been questions about ambient fine particulate matter (PM2.5) levels in the Capital Region of Alberta, Canada. An investigation of temporal trends in PM2.5 and its chemical components was undertaken in the City of Edmonton within the Capital Region over an 8-year period (2007-2014). A non parametric trend detection method was adopted to characterize trends in ambient concentrations. No statistically significant change was observed for ambient PM2.5 concentrations during 2007-2014, while significant decreasing trends were found for organic carbon, elemental carbon, oxalate, barium, lead and cadmium. A statistically significant increasing trend was observed for sodium chloride indicating an increase of de-icing salt contribution for winter road maintenance in recent years. Concentrations of potassium ion and zinc exhibited strong and significant seasonal variability with higher concentrations in winter than in summer likely reflecting wood smoke origins more than other potential sources in Edmonton and the surrounding region. No statistically significant changes were observed for all other chemical components examined. Notwithstanding robust population growth that has occurred in Edmonton, these findings reveal that particulate air quality and corresponding trace elements in Edmonton's air has been unchanged or improved over the investigated period (2007-2014). Longer-term air quality monitoring at least over several decades is needed to establish whether trends reported here are actually occurring. PMID- 26949867 TI - Temperature-related morbidity and mortality in Sub-Saharan Africa: A systematic review of the empirical evidence. AB - BACKGROUND: Sub-Saharan Africa (SSA) contributes very little to overall climate change and yet it is estimated to bear the highest burden of climate change, with 34% of the global DALYs attributable to the effects of climate change found in SSA. With the exception of vector-borne diseases, particularly malaria, there is very limited research on human health effects of climate change in SSA, in spite of growing awareness of the region's vulnerability to climate change. OBJECTIVES: Our objective is to systematically review all studies investigating temperature variability and non-vector borne morbidity and mortality in SSA to establish the state and quality of available evidence, identify gaps in knowledge, and propose future research priorities. METHODS: PubMed, Ovid Medline and Scopus were searched from their inception to the end of December 2014. We modified the GRADE guidelines to rate the quality of the body of evidence. RESULTS: Of 6745 studies screened, 23 studies satisfied the inclusion criteria. Moderate evidence exists to associate temperature variability with cholera outbreaks, cardiovascular disease hospitalization and deaths, and all-cause deaths in the region. The quality of evidence on child undernutrition is low, and for diarrhea occurrence, meningitis, Ebola, asthma and respiratory diseases, and skin diseases, very low. CONCLUSIONS: The evidence base is somehow weakened by the limited number of studies uncovered, methodological limitations of the studies, and notable inconsistencies in the study findings. Further research with robust study designs and standardized analytical methods is thus needed to produce more credible evidence base to inform climate change preparedness plans and public health policies for improved adaptive capacity in SSA. Investment in meteorological services, and strengthening of health information systems is also required to guarantee timely, up-to-date and reliable data. PMID- 26949868 TI - LICARA nanoSCAN - A tool for the self-assessment of benefits and risks of nanoproducts. AB - The fast penetration of nanoproducts on the market under conditions of significant uncertainty of their environmental properties and risks to humans creates a need for companies to assess sustainability of their products. Evaluation of the potential benefits and risks to build a coherent story for communication with clients, authorities, consumers, and other stakeholders is getting to be increasingly important, but SMEs often lack the knowledge and expertise to assess risks and communicate them appropriately. This paper introduces LICARA nanoSCAN, a modular web based tool that supports SMEs in assessing benefits and risks associated with new or existing nanoproducts. This tool is unique because it is scanning both the benefits and risks over the nanoproducts life cycle in comparison to a reference product with a similar functionality in order to enable the development of sustainable and competitive nanoproducts. SMEs can use data and expert judgment to answer mainly qualitative and semi-quantitative questions as a part of tool application. Risks to public, workers and consumers are assessed, while the benefits are evaluated for economic, environmental and societal opportunities associated with the product use. The tool provides an easy way to visualize results as well as to identify gaps, missing data and associated uncertainties. The LICARA nanoSCAN has been positively evaluated by several companies and was tested in a number of case studies. The tool helps to develop a consistent and comprehensive argument on the weaknesses and strengths of a nanoproduct that may be valuable for the communication with authorities, clients and among stakeholders in the value chain. LICARA nanoSCAN identifies areas for more detailed assessments, product design improvement or application of risk mitigation measures. PMID- 26949869 TI - Green spaces and General Health: Roles of mental health status, social support, and physical activity. AB - Green spaces are associated with improved health, but little is known about mechanisms underlying such association. We aimed to assess the association between greenness exposure and subjective general health (SGH) and to evaluate mental health status, social support, and physical activity as mediators of this association. This cross-sectional study was based on a population-based sample of 3461 adults residing in Barcelona, Spain (2011). We characterized outcome and mediators using the Health Survey of Barcelona. Objective and subjective residential proximity to green spaces and residential surrounding greenness were used to characterize greenness exposure. We followed Baron and Kenny's framework to establish the mediation roles and we further quantified the relative contribution of each mediator. Residential surrounding greenness and subjective residential proximity to green spaces were associated with better SGH. We found indications for mediation of these associations by mental health status, perceived social support, and to less extent, by physical activity. These mediators altogether could explain about half of the surrounding greenness association and one-third of the association for subjective proximity to green spaces. We observed indications that mental health and perceived social support might be more relevant for men and those younger than 65years. The results for objective residential proximity to green spaces were not conclusive. In conclusion, our observed association between SGH and greenness exposure was mediated, in part, by mental health status, enhanced social support, and physical activity. There might be age and sex variations in these mediation roles. PMID- 26949870 TI - Dose-Response Relation Between Work Hours and Cardiovascular Disease Risk: Findings From the Panel Study of Income Dynamics. AB - OBJECTIVES: The aim of this study was to examine the presence of a dose-response relationship between work hours and incident cardiovascular disease (CVD) in a representative sample of U.S. workers. METHODS: A retrospective cohort study of 1926 individuals from the Panel Study of Income Dynamics (1986 to 2011) employed for at least 10 years. Restricted cubic spline regression was used to estimate the dose-response relationship of work hours with CVD. RESULTS: A dose-response relationship was observed in which an average workweek of 46 hours or more for at least 10 years was associated with an increased risk of CVD. Compared with working 45 hours per week, working an additional 10 hours per week or more for at least 10 years increased CVD risk by at least 16%. CONCLUSION: Working more than 45 work hours per week for at least 10 years may be an independent risk factor for CVD. PMID- 26949871 TI - Long-Term Metal PM2.5 Exposures Decrease Cardiac Acceleration and Deceleration Capacities in Welders. AB - OBJECTIVE: The aim of the study was to clarify whether long-term metal particulates affect cardiac acceleration capacity (AC), deceleration capacity (DC), or both. METHODS: We calculated chronic exposure index (CEI) for PM2.5 over the work life of 50 boilermakers and obtained their resting AC and DC. Linear regression was used to assess the associations between CEI PM2.5 exposure and each of AC and DC, controlling for age, acute effects of welding exposure, and diurnal variation. RESULTS: Mean (standard deviation) CEI for PM2.5 exposure was 1.6 (2.4) mg/m-work years and ranged from 0.001 to 14.6 mg/m-work years. In our fully adjusted models, a 1 mg/m-work year increase in CEI for PM2.5 was associated with a decrease of 1.03 (95% confidence interval: 0.10, 1.96) ms resting AC, and a decrease of 0.67 (95% confidence interval: -0.14, 1.49) ms resting DC. CONCLUSIONS: Long-term metal particulate exposures decrease cardiac accelerations and decelerations. PMID- 26949873 TI - Financial Conflicts of Interest and Study Results in Environmental and Occupational Health Research. AB - OBJECTIVES: To date, there is no comprehensive analysis of the relationship between financial conflict of interest (COI) and a potential publication bias in environmental and occupational health studies. METHODS: We analyzed original research articles published in 2012 in 17 peer-reviewed journals. Multivariable ordinal logistic regression models were developed to evaluate the relationship between financial COI and the study outcome. RESULTS: Of the 373 studies included in the analysis, 17.2% had a financial COI associated with organizations involved with the processing, use, or disposal of industrial and commercial products, and studies with this type of COI were more likely to report negative results (Adjusted Odds Ratio = 4.31), as were studies with any COI associated with the military (employment or funding; Adjusted Odds Ratio = 9.15). CONCLUSIONS: Our findings show a clear relationship between direction of reported findings and specific types of financial COI. PMID- 26949872 TI - Are the Associations of Cardiac Acceleration and Deceleration Capacities With Fine Metal Particulate in Welders Mediated by Inflammation? AB - OBJECTIVE: The aim of this study was to investigate whether associations of acceleration capacity (AC) and deceleration capacity (DC) with metal-PM2.5 are mediated by inflammation. METHODS: We obtained PM2.5, C-reactive protein, interleukin (IL)-6, 8, and 10, and electrocardiograms to compute AC and DC, from 45 male welders. Mediation analyses were performed using linear mixed models to assess associations between PM2.5 exposure, inflammatory mediator, and AC or DC, controlling for covariates. RESULTS: The proportion of total effect of PM2.5 on AC or DC (indirect effect) mediated through IL-6 on AC was 4% at most. Controlling for IL-6 (direct effect), a 1 mg/m increase of PM2.5 was associated with a decrease of 2.16 (95% confidence interval -0.36 to 4.69) msec in AC and a decrease of 2.51 (95% confidence interval -0.90 to 5.93) msec in DC. CONCLUSION: IL-6 may be mediating the effect of metal particulates on AC. PMID- 26949874 TI - Olfactory Function in Latino Farmworkers: Subclinical Neurological Effects of Pesticide Exposure in a Vulnerable Population. AB - OBJECTIVES: We compared olfactory function in pesticide-exposed Latino farmworkers and nonfarmworkers to explore its use as a subclinical indicator of neurological pesticide effects. METHODS: We recruited 304 current farmworkers and 247 nonfarmworkers. All completed odor identification (14 odors) and threshold tests (16 concentrations of n-butanol) using a well-established methodology. RESULTS: Farmworkers reported significantly greater lifetime pesticide exposure. Performance on both olfactory tests declined with age. Odor identification performance did not differ between groups. For odor threshold, farmworkers needed significantly higher concentrations to detect the odor. Results were unchanged when adjusted for sex, age, and smoking. CONCLUSION: Olfactory function differences between farmworkers and nonfarmworkers suggest possible neurological effects. Because declining olfactory function is an early symptom of Parkinson disease and related conditions, it is a possible subclinical indicator of neurodegenerative disease in this vulnerable worker population. PMID- 26949876 TI - The Association of Workplace Social Capital With Work Engagement of Employees in Health Care Settings: A Multilevel Cross-Sectional Analysis. AB - OBJECTIVE: The aim of the study was to examine the cross-sectional multilevel association between unit-level workplace social capital and individual-level work engagement among employees in health care settings. METHODS: The data were collected from employees of a Japanese health care corporation using a questionnaire. The analyses were limited to 440 respondents from 35 units comprising five or more respondents per unit. Unit-level workplace social capital was calculated as an average score of the Workplace Social Capital Scale for each unit. Multilevel regression analysis with a random intercept model was conducted. RESULTS: After adjusting for demographic variables, unit-level workplace social capital was significantly and positively associated with respondents' work engagement (P < 0.001). The association remained significant after additionally adjusting for individual-level perceptions of workplace social capital (P < 0.001). CONCLUSIONS: Workplace social capital might exert a positive contextual effect on work engagement of employees in health care settings. PMID- 26949875 TI - A Web-Based Mindfulness Stress Management Program in a Corporate Call Center: A Randomized Clinical Trial to Evaluate the Added Benefit of Onsite Group Support. AB - OBJECTIVE: The objective of this study is to determine the effectiveness of an 8 week web-based, mindfulness stress management program (WSM) in a corporate call center and added benefit of group support. METHODS: One hundred sixty-one participants were randomized to WSM, WSM with group support, WSM with group and expert clinical support, or wait-list control. Perceived stress, burnout, emotional and psychological well-being, mindfulness, and productivity were measured at baseline, weeks 8 and 16, and 1 year. RESULTS: Online usage was low with participants favoring CD use and group practice. All active groups demonstrated significant reductions in perceived stress and increases in emotional and psychological well-being compared with control. Group support improved participation, engagement, and outcomes. CONCLUSION: A self-directed mindfulness program with group practice and support can provide an affordable, effective, and scalable workplace stress management solution. Engagement may also benefit from combining web-based and traditional CD delivery. PMID- 26949877 TI - Influence of Cytokines and Soluble Receptors in the Quality of Life and Functional Capacity of Workers Exposed to Silica. AB - OBJECTIVES: The aim of the study was to evaluate the plasma levels of inflammatory mediators in subjects exposed to silica, with and without silicosis compared with unexposed control group; and to check the association between inflammatory mediators with pulmonary function, quality of life, functional capacity, and dyspnea grade. METHODS: Inflammatory mediators were measured by enzyme-linked immunosorbent assay. There were 30 subjects exposed to silica and 24 control group. RESULTS: Interleukin-6 plasma levels were higher in subjects exposed to silica with and without silicosis than in the control group. There was a positive correlation between radiological severity and the quality of life, whereas there was a negative correlation between radiological severity and pulmonary function. A negative correlation between sTNFR1 plasma level and functional capacity was found. Interleukin-10 was negatively correlated with the quality of life total score and was positively correlated with the functional capacity and pulmonary function. PMID- 26949878 TI - Cross-Validation of the Work Organization Assessment Questionnaire Across Genders: A Study in the Australian Health Care Sector. AB - OBJECTIVES: The main aim of this study was to examine the measurement invariance of the Work Organization Assessment Questionnaire (WOAQ) across genders in a group of health care employees, using bifactor modeling. There is a very limited research that uses invariance testing of bifactor models, despite their usefulness. Establishing validity of the WOAQ in this way is important for demonstrating its relevance for both men and women. METHODS: A bifactor modeling procedure was used here to examine the validity of the WOAQ with a sample of 946 paramedics employed in a large Australian organization in the health care sector. RESULTS: The results of this study show that the WOAQ has good psychometric properties across genders in health care settings. In addition, there were significant mean differences between men and women in their perceptions of "quality of relationships with colleagues," and "reward and recognition." There were no differences between men and women in the remaining factors: "quality of relationships with the management," "quality of relationships with colleagues," and "quality of the physical environment." CONCLUSIONS: The use of bifactor modeling to establish the cross-validity of the WOAQ across male and female paramedics adds to evidence for the measure's good psychometric properties. The findings confirm those of previous research that has used higher order confirmatory factor analysis. Moreover, mean differences between men and women were found to be significant in two of the five WOAQ subscales. These findings have practical implications for health care organizations, in terms of assessing work characteristics and developing activities to support the health and well being of their employees. PMID- 26949879 TI - Exposure to Psychosocial Risk Factors at Work and the Incidence of Occupational Injuries: A Cohort Study in Spain. AB - OBJECTIVES: The aim of this study is to analyze the association between the exposure to psychosocial risk factors at work and the incidence of occupational injuries (OIs). METHODS: A prospective dynamic cohort study (n = 16,693) of 1 year follow-up. Psychosocial risk factors at work were assessed with the Spanish version of Copenhagen Psychosocial Questionnaire. Incidence rates of OI per 1000 workers-year were calculated and associations between psychosocial risk factors and OI were estimated by Poisson regression models. RESULTS: Unfavorable levels of esteem in men [rate ratio (RR) = 1.28], and unfavorable levels of social support and quality of leadership (RR = 1.87), psychological demands (RR = 2.20), and active work and possibilities for development (RR = 1.83) among women, were associated with OI incidence. CONCLUSIONS: Poor quality of psychosocial work environment increases the incidence of OI. Psychosocial intervention programs could be helpful in order to reduce OI incidence rates and their associated costs. PMID- 26949880 TI - Firefighter Shift Schedules Affect Sleep Quality. AB - OBJECTIVE: The aim of this study was to investigate the prevalence and severity of firefighter sleep quality across department shift schedules. METHODS: Sleep quality was assessed using a Pittsburgh Sleep Quality Index in a sample of 109 male career firefighters from six fire departments in three Southwestern US states. The three shift schedules studied were 24on/48off, 48on/96off, and Kelly. RESULTS: Seventy-three percent of firefighters report poor sleep quality. The 24on/48off shift schedule is associated with the best sleep quality and Kelly is associated with the worst sleep quality. Firefighters working second jobs report significantly poorer sleep quality than those who do not. CONCLUSIONS: Shift schedules that disrupt normal circadian rhythms more result in poorer sleep quality, which can lead to less effective emergency response and increased risk to firefighter health and safety. PMID- 26949882 TI - Hearing Loss and Noise Exposure Among Commercial Fishermen in the Gulf Coast. AB - OBJECTIVE: Noise is a hazard in commercial fishing. This cross-sectional study associates occupational noise exposure with hearing loss in commercial fishermen. METHODS: A comprehensive survey and audiometric testing were administered to 227 participants in the Gulf Coast. Sound-level measurements were obtained aboard a sample of fishing vessels. Criteria specific for hearing impairment (HI) and noise-induced hearing loss (NIHL) were applied to each audiogram. RESULTS: The majority of these fishermen work shifts more than 16 hours for an extended duration. Hazardous noise levels were measured in the engine rooms ranging from 94.8 to 105.0 dBA. NIHL was significantly associated with years spent fishing, but not with age. HI was significantly associated with age, but not with years fishing. CONCLUSIONS: Commercial fishermen in the Gulf may be at a considerable risk of occupational NIHL and would benefit from hearing conservation programs. PMID- 26949881 TI - Occupation and Thyroid Cancer: A Population-Based, Case-Control Study in Connecticut. AB - OBJECTIVE: The study aims to explore the associations between various occupations and thyroid cancer risk. METHODS: A population-based, case-control study involving 462 histologically confirmed incident cases and 498 controls was conducted in Connecticut in 2010 to 2011. RESULTS: A significantly increased risk of thyroid cancer, particularly papillary microcarcinoma, was observed for those working as the health care practitioners and technical workers, health diagnosing and treating practitioners, and registered nurses. Those working in building and grounds cleaning, maintenance occupations, pest control, retail sales, and customer service also had increased risk for papillary thyroid cancer. Subjects who worked as cooks, janitors, cleaners, and customer service representatives were at an increased risk of papillary thyroid cancer with tumor size more than 1 cm. CONCLUSION: Certain occupations were associated with an increased risk of thyroid cancer, with some tumor size and subtype specificity. PMID- 26949883 TI - Sleep, Dietary, and Exercise Behavioral Clusters Among Truck Drivers With Obesity: Implications for Interventions. AB - OBJECTIVE: The objectives of the study were to describe a sample of truck drivers, identify clusters of drivers with similar patterns in behaviors affecting energy balance (sleep, diet, and exercise), and test for cluster differences in health safety, and psychosocial factors. METHODS: Participants' (n = 452, body mass index M = 37.2, 86.4% male) self-reported behaviors were dichotomized prior to hierarchical cluster analysis, which identified groups with similar behavior covariation. Cluster differences were tested with generalized estimating equations. RESULTS: Five behavioral clusters were identified that differed significantly in age, smoking status, diabetes prevalence, lost work days, stress, and social support, but not in body mass index. Cluster 2, characterized by the best sleep quality, had significantly lower lost workdays and stress than other clusters. CONCLUSIONS: Weight management interventions for drivers should explicitly address sleep, and may be maximally effective after establishing socially supportive work environments that reduce stress exposures. PMID- 26949886 TI - A Response to Proposed Equal Employment Opportunity Commission Regulations on Employer-Sponsored Health, Safety, and Well-Being Initiatives. AB - OBJECTIVE: The aim of this study was to identify areas of consensus in response to proposed Equal Employment Opportunity Commission Americans with Disabilities Act of 1990 and Genetic Information Nondiscrimination Act of 2008 regulations on employer-sponsored health, safety, and well-being initiatives. METHODS: The consensus process included review of existing and proposed regulations, identification of key areas where consensus is needed, and a methodical consensus building process. RESULTS: Stakeholders representing employees, employers, consulting organizations, and wellness providers reached consensus around five areas, including adequate privacy notice on how medical data are collected, used, and protected; effective, equitable use of inducements that influence participation in programs; observance of reasonable alternative standards; what constitutes reasonably designed programs; and the need for greater congruence between federal agency regulations. CONCLUSION: Employee health and well-being initiatives that are in accord with federal regulations are comprehensive, evidence-based, and are construed as voluntary by employees and regulators alike. PMID- 26949887 TI - What Is the Mediterranean Diet and How Can It Be Used to Promote Workplace Health? PMID- 26949888 TI - Comment on Steinberg et al: Reducing Metabolic Syndrome Risk Using a Personalized Wellness Program. PMID- 26949889 TI - Response to Letter to the Editor. PMID- 26949890 TI - Femoral Neck Bone Mineral Density in Persons Over 50 Years Performing Shiftwork: An Epidemiological Study. AB - OBJECTIVE: Shiftwork has been associated with bone loss due to hormonal fluctuations. Our aim was to assess the femoral neck bone mineral density and content in persons over 50 years performing shiftwork. METHODS: We performed analysis on the femoral neck bone mineral parameters in persons over age 50 years from the National Health and Nutrition Examination Survey cross-sectional data for 2010 to 2011 in regular and shiftworkers. We also assessed the degree of moderate physical activity and smoking in both groups. RESULTS: Middle-aged men performing shiftwork had significantly higher total femur bone mineral content (37.33 +/- 11.00 vs 34.09 +/- 10.45, P = 0.01) and femoral neck bone mineral content (4.57 +/- 1.07 vs 4.29 +/- 1.0, P = 0.03). This difference was not seen in middle aged women. CONCLUSIONS: Shiftwork does not seem to affect bone mineral density in those performing moderate physical activity. PMID- 26949891 TI - Shift Work and Sleep Quality Among Urban Police Officers: The BCOPS Study. AB - OBJECTIVE: The aim of the study was to examine association of shift work with sleep quality in police officers. METHODS: Data were obtained from the Buffalo Cardio-Metabolic Occupational Police Stress study (n = 363). An electronic work history database was used to define shift as day, afternoon, or night for three durations: past month, 1 year, and 15 years. Sleep quality was determined using the Pittsburgh Sleep Quality Index. RESULTS: The overall prevalence of poor sleep quality was 54%; 44% for day, 60% for afternoon, and 69% for night shift. Poor sleep quality was 70% more prevalent among night-shift officers (P < 0.001) and 49% higher among those on the afternoon shift (P = 0.003) relative to officers working on the day shift. CONCLUSIONS: Night and evening work schedules are associated with elevated prevalence of poor sleep quality among police officers. PMID- 26949892 TI - Negative Acts at Work as Potential Bullying Behavior and Depression: Examining the Direction of the Association in a 2-Year Follow-Up Study. AB - OBJECTIVE: This study investigates the 2-year prospective association between exposure to negative acts at work and depression. METHODS: A questionnaire study was carried out among 3363 employees and followed up 2 years later. Negative acts as potential bullying behavior were assessed by the Revised Negative Acts Questionnaire and depression by The Major Depression Inventory or Schedule for Clinical Assessment in Neuropsychiatry interviews. Logistic regression analyses tested potential associations between depression and negative acts. RESULTS: Exposure to negative acts was associated with depression 2 years later; however, when adjusting for Sense of Coherence and depressive symptoms at baseline the association was no longer significant. Conversely, depression at baseline predicted self-reported exposure to negative acts at follow-up. CONCLUSIONS: Depression predicts exposure to negative acts at a 2-year follow-up, whereas negative acts do not predict depression after adjustment for Sense of Coherence and baseline depressive symptoms. PMID- 26949893 TI - Managing Safety and Operations: The Effect of Joint Management System Practices on Safety and Operational Outcomes. AB - OBJECTIVE: The aim of this study was to determine whether management system practices directed at both occupational health and safety (OHS) and operations (joint management system [JMS] practices) result in better outcomes in both areas than in alternative practices. METHODS: Separate regressions were estimated for OHS and operational outcomes using data from a survey along with administrative records on injuries and illnesses. RESULTS: Organizations with JMS practices had better operational and safety outcomes than organizations without these practices. They had similar OHS outcomes as those with operations-weak practices, and in some cases, better outcomes than organizations with safety-weak practices. They had similar operational outcomes as those with safety-weak practices, and better outcomes than those with operations-weak practices. CONCLUSIONS: Safety and operations appear complementary in organizations with JMS practices in that there is no penalty for either safety or operational outcomes. PMID- 26949894 TI - Relationship Between Opioid Prescribing Patterns and Claim Duration and Cost. AB - OBJECTIVE: The aim of this study was to assess the relationship between timing and duration of opioid prescriptions, disability duration, and claims costs for work-related injuries. METHOD: A retrospective cohort study using lost time compensation claimant data to examine the relationship between opioid prescription patterns and claim duration and cost. Logistic regression adjusted for sex, marital status, initial reserve, attorney involvement, and spinal surgeries. RESULTS: Odds ratios for claim cost at least $100,000 and duration at least 3 years were not statistically different between groups prescribed opioids less than 30 days and those not prescribed opioids. Claims with short-acting opioids continued after 180 days; the odds ratios for claim cost at least $100,000 and duration at least 3 years were 6.21 (95% confidence interval 5.30 to 7.28) and 3.32 (95% confidence interval 2.94 to 3.74). CONCLUSION: Claim cost and lost time are related to when and how long opioids are prescribed for work related injuries. PMID- 26949895 TI - Reproductive and Developmental Hazard Management. PMID- 26949898 TI - The emergence and cross species transmission of newly discovered tick-borne Bunyavirus in China. AB - A novel tick-borne Bunyavirus, discovered in China and later in South Korea and Japan, is now known as Huaiyangshan virus or severe fever with thrombocytopenia syndrome virus and has been identified as the causative agent of a hemorrhagic fever-like disease. Of five species of ticks carrying Huaiyangshan viruses, Haemaphysalis longicornis was the most abundant in regions where the virus was endemic. Its usual hosts (cattle, goats, dogs, rats and chickens) tested positive for Huaiyangshan virus RNA and had a high seroprevalence. The distribution of H. longicornis and the migratory routes of four wild fowl across China, South Korea and Japan are coincident. Thus a tick and migratory bird model for the transmission of the Huaiyangshan virus was proposed. PMID- 26949897 TI - Design of a breast phantom for quantitative MRI. AB - PURPOSE: We present a breast phantom designed to enable quantitative assessment of measurements of T1 relaxation time, apparent diffusion coefficient (ADC), and other attributes of breast tissue, with long-term support from a national metrology institute. MATERIALS AND METHODS: A breast phantom was created with two independent, interchangeable units for diffusion and T1 /T2 relaxation, each with flexible outer shells. The T1 unit was filled with corn syrup solution and grapeseed oil to mimic the relaxation behavior of fibroglandular and fatty tissues, respectively. The diffusion unit contains plastic tubes filled with aqueous solutions of polyvinylpyrrolidone (PVP) to modulate the ADC. The phantom was imaged at 1.5T and 3.0T using magnetic resonance imaging (MRI) scanners and common breast coils from multiple manufacturers to assess T1 and T2 relaxation time and ADC values. RESULTS: The fibroglandular mimic exhibited target T1 values on 1.5T and 3.0T clinical systems (25-75 percentile range: 1289 to 1400 msec and 1533 to 1845 msec, respectively) across all bore temperatures. PVP solutions mimicked the range of ADC values from malignant tumors to normal breast tissue (40% PVP median: 633 * 10(-6) mm(2) /s to 0% PVP median: 2231 * 10(-6) mm(2) /s) at temperatures of 17-24 degrees C. The interchangeable phantom units allowed both the diffusion and T1 /T2 units to be tested on the left and right sides of the coil to assess any variation. CONCLUSION: This phantom enables T1 and ADC measurements, fits in a variety of clinical breast coils, and can serve as a quality control tool to facilitate the standardization of quantitative measurements for breast MRI. J. Magn. Reson. Imaging 2016;44:610-619. PMID- 26949900 TI - [Not Available]. PMID- 26949899 TI - Meta-analysis and adjusted indirect comparison of direct oral anticoagulants in prevention of acute limb ischemia in patients with atrial fibrillation. AB - BACKGROUND: Direct oral anticoagulants are being presented as alternatives to warfarin for preventing stroke in patients with atrial fibrillation. Yet direct comparative trials between these agents in prevention of acute limb ischemia (ALI) are unavailable so far. OBJECTIVE: To conduct an adjusted indirect comparison meta-analysis between direct oral agents for prevention of acute limb ischemia in atrial fibrillation. METHODS: We conducted a systematic literature review searching electronic databases (MEDLINE and Embase) and the Cochrane Library from January 1990 through November 2014. Two blinded investigators reviewed all potentially relevant articles in a parallel manner by using a priori defined criteria. To assess the long-term efficacy and safety of these agents, only randomized clinical trials (RCTs) with follow-up durations of >1 year were included. The primary efficacy outcome was the end point of acute limb ischemia and/or extremity embolism. RESULTS: A total of 44,563 patients from three RCTs met criteria for inclusion. Patients randomized to direct oral anticoagulants had a non-significant decreased risk for acute limb ischemia (risk ratio [RR]: 0.57, 95% confidence interval [CI]: 0.26-1.2). In the analysis between agents, however, rivaroxaban significantly lowered the risk of ALI compared to warfarin (RR: 0.23, 95% CI: 0.064-0.82), apixaban (RR: 0.26, 95% CI: 0.081-0.83), and dabigatran (RR: 0.24, 95% CI: 0.077-0.83). CONCLUSIONS: Significant differences in prevention of acute limb ischemia may exist between oral anticoagulant agents in patients with atrial fibrillation. Rivaroxaban lowers the risk of limb embolism versus warfarin, apixaban and dabigatran. PMID- 26949902 TI - [Prehospitale analgesia in adults]. AB - After securing vital function, treatment of pain is an important aspect in emergency medical care. Irrespective of the underlying disease or injury, pain is an important warning symptom of the body and the most common reason for an emergency alert notification. A patient assesses quality of care and success of prehospital care using the criteria of the extent of pain relief he experiences. Since mild pain does not usually lead to an emergency alert, the criteria apply mainly to treatment of severe and very severe pain. Pain perception varies from individual to individual. Accordingly, assessment of pain intensity is the very first step in pain therapy. The Numeric Rating Scale (NRS) ranging from 0 (no pain) to 10 (worst pain imaginable) is suitable for pain assessment in adult emergency patients. Above a grade of 4, therapeutic intervention should be initiated with the goal of reducing pain to reach a value of <4, or at least to achieve a reduction by 3 points. The choice of analgesics that can be meaningfully used in pre-hospital emergency medicine is limited. The emergency physician should be aware of available drugs and administration routes. PMID- 26949903 TI - [Not Available]. PMID- 26949904 TI - [Not Available]. PMID- 26949905 TI - [Not Available]. AB - EPIDEMIOLOGY: Prevalence of Multidrug-Resistant Organisms (MDROs) varies temporally, geographically, and by healthcare setting. In general MDROs rates are higher in hospitals compared to the outpatient setting. Within the hospital the prevalence of MDRO-patients in ICUs is higher than in non-ICU wards. While the number of MRSA-patients decreased over the last years, there was a continuous increase of Gram-negative bacilli (GNB) in Germany. At present, every 60. patient in the ICU is known as colonized or infected with GNB. SURVEILLANCE: Hospitals in Germany are obliged by the "protection against infection act" (REF?)11 to establish a surveillance for MDROs. To improve the informative value of the surveillance it is recommended to participate in one of three surveillance systems for MDROs in Germany, which differ with regard to the effort required and their key messages. IMPORTANCE: MDROs may increase healthcare costs as well as patient morbidity and mortality. PMID- 26949906 TI - [Not Available]. AB - Multiresistant bacteria play an increasingly important role in everyday clinical practice. This is particularly the case in intensive care units and wards with critically ill patients. Often there is insufficient knowledge concerning diagnostic screening indications and strategies to avoid cross-transmission via infection control strategies. Hereby, we provide an orienting overview and assessment about current guidelines and recommendations with special focus on methicillin-resistant Staphylococcus aureus (MRSA) and multiresistantgramnegative bacteria (MRGN). PMID- 26949907 TI - [Antibiotic Stewardship]. AB - The adequate management of infections is an important task in critical care medicine which has an effect on patient outcome. As a result, the prevalence of antiinfective therapy is high in intensive care units. In the face of an unsettling development of worldwide microbial resistance, an optimization and reduction of antiinfective therapy is necessary. Antibiotic stewardship tries to improve antiinfective therapy with an interdisciplinary approach. One overall objective of antibiotic stewardship is the reduction of resistance induction in order to preserve the therapeutic efficiency of antibiotics. Intensive care units are important fields of action for antibiotic stewardship interventions. This article reviews available evidence and some practical aspects for antibiotic stewardship. PMID- 26949909 TI - [Not Available]. PMID- 26949908 TI - [Not Available]. AB - Infections with multi-drug resistant bacteria are increasing worldwide. Glycopeptides, linezolid, daptomycin and 5th generation cephalosporins ("MRSA cephalsoporins") are used against severe infections with MRSA, combination partners are rifampin and fosfomycin. Treatment options against VRE-infections are limited to linezolid, daptomycin and tigecyclin. New agents with activity against MRSA and VRE are tedizolid, dalbvancin and oritavancin. For monotherapy of severe infections due to 3MRGN carbapenems are available. Ceftolozane/tazobactam has been licensed by the European Medical Agency and shows good activity against a relevant proportion of ESBL-pathogens. Oral agents such as nitrofurantoin or fosfomycin are used for treatment of uncomplicated cystitis. Colistin shows best in vitro susceptibility against carbapenem-resistant Enterobacteriaceae, followed by fosfomycin and tigecycline. For serious infections with 4MRGN a colistin-based combination treatment with two to three agents is recommended. In such cases a carbapenem as combination partner may be useful. PMID- 26949914 TI - Structural and Material Mechanical Quality of Femoral Shafts in Rats Exposed to Simulated High Altitude from Infancy to Adulthood. AB - The growth of the body and bone mass and the mechanical properties of appendicular bone are impaired in immature rats exposed to different simulated high altitudes (SHA) (1850-5450 m) between the 32nd and the 74th days of postnatal life. Now, we report the effects of exposure to 4100 m on the above cited variables in female rats from infancy (age: 1 month) to adulthood (age: 8 months) to define the occurrence of catch up and to establish whether the effects of altitude are transient or permanent. The ex vivo right femur was mechanically tested in three-point bending. Body weight and length, and structural (loads at yielding and fracture, and stiffness) and architectural (diaphyseal cross sectional area, cortical area, and cross-sectional moment of inertia) properties were measured at 2, 4, 6, and 8 months of exposure to SHA. The negative influence of hypoxia on all variables was similar at different ages or, in other words, the difference among ages was maintained at any extent of hypoxia. Hypoxia did not affect the elastic modulus, thus suggesting that the mechanical properties of the bone tissue were maintained. Catch up did not occur. The resulting osteopenic bone remained appropriate to its mechanical function during the entire exposure to SHA. PMID- 26949913 TI - A phase 1/2a study to test the safety and immunogenicity of a p16(INK4a) peptide vaccine in patients with advanced human papillomavirus-associated cancers. AB - BACKGROUND: The cyclin-dependent kinase inhibitor p16(INK4a) is strongly and consistently overexpressed in all human papillomavirus (HPV)-associated cancers. Therefore, the authors hypothesized that p16(INK4a) may be a vaccine target antigen for HPV-associated cancers. To test this hypothesis, the authors performed a phase 1/2a first-in-human trial to evaluate the safety and immunogenicity of a p16(INK4a) -based peptide vaccine. METHODS: A total of 26 patients with different, advanced, p16(INK4a) -overexpressing, HPV DNA-positive cancers were included after the completion of standard treatment. According to protocol, 12 subcutaneous injections of a p16(INK4) peptide (P16_37-63) mixed in a water-in-oil emulsion with immunoadjuvant activity (Montanide ISA-51 VG) were administered over a 6-month period. RESULTS: A total of 20 patients received at least 4 injections and were evaluable for immune responses against P16_37-63. Clusters of differentiation (CD) 4 T cells were detected in 14 of 20 patients (3 of whom had preexisting CD4 T cells before vaccination), CD8 T cells were detected in 5 of 20 patients, and antibodies were detected in 14 of 20 patients (1 of whom had preexisting antibodies). No suspected unexpected serious adverse reaction or serious adverse drug reaction was documented. All reported serious adverse events were expected and not considered to be related to study therapy. None of the patients discontinued trial participation due to unacceptable toxicities and no dose-limiting toxicities occurred. Tumor response could be assessed in 14 patients. Of these, 9 patients (64%) had stable disease as their best overall response and 5 patients (36%) developed progressive disease. CONCLUSIONS: Vaccination with the p16(INK4a) -derived peptide P16_37-63 appears to induce cellular and humoral immune responses and does not cause severe toxicities. The results of the current study pave the way for the further clinical development of p16(INK4a) -based cancer immunotherapeutics. Cancer 2016;122:1425-1433. (c) 2016 American Cancer Society. PMID- 26949915 TI - Correction to Silver-Catalyzed, Aldehyde-Induced alpha-C-H Functionalization of Tetrahydroisoquinolines with Concurrent C-P Bond Formation/N-Alkylation. PMID- 26949917 TI - Cyclopentadiene-mediated hydride transfer from rhodium complexes. AB - Attempts to generate a proposed rhodium hydride catalytic intermediate instead resulted in isolation of (Cp*H)Rh(bpy)Cl (1), a pentamethylcyclopentadiene complex, formed by C-H bond-forming reductive elimination from the fleeting rhodium hydride. The hydride transfer ability of diene 1 was explored through thermochemistry and hydride transfer reactions, including the reduction of NAD(+). PMID- 26949919 TI - Conceptual constraints and mechanisms in children's selective learning. AB - Although we can support Heyes' call for more research on mechanisms, we disagree that the problem has been ignored as Heyes suggests. We also doubt that basic learning mechanisms are alone sufficient to account for the broad range of findings in the selective social learning literature. Although phylogenetically shared learning mechanisms must support selective social learning, we believe that they must also be guided by top-down conceptual considerations that may be special to humans. Research to date has been focused on establishing the boundary conditions on selective social learning, with the goal of making generalizations that will constrain theorizing about the character of that special knowledge. This is critical to our understanding of both why and how selective social learning manifests in children. PMID- 26949918 TI - Cardiovascular reactivity is independently associated with better mental health: results from the nationwide German DEGS1 study. AB - OBJECTIVE: Using data from the nationwide German DEGS1 study, we assessed whether resting blood pressure (BP) and transient changes in BP are associated with symptoms of depression and quality of life (QoL). METHODS: The study included n=4852 adult participants not taking antihypertensives, who completed the Patient Health Questionnaire-9 for assessment of depressive symptoms and the SF-36 for assessment of QoL. Resting BP was defined as the mean of the second and third reading taken at 3-min intervals. RESULTS: General linear models adjusting for age, sex, and BMI showed that both resting BP and short-term BP changes were associated with higher SF-36 mental component summary and lower Patient Health Questionnaire-9 scores. CONCLUSION: Our data showed that a greater decrease in systolic BP as an indicator for cardiovascular reactivity is related to better mental QoL and fewer depressive symptoms, suggesting a link between BP regulation and mental well-being as part of an adaptive process to mild stressors. PMID- 26949920 TI - How providing more or less time to solve a cognitive task interferes with upright stance control; a posturographic analysis on healthy young adults. AB - Contrasted postural effects have been reported in dual-task protocols associating balance control and cognitive task that could be explained by the nature and the relative difficulty of the cognitive task and the biomechanical significance of the force platform data. To better assess their respective role, eleven healthy young adults were required to stand upright quietly on a force platform while concomitantly solving mental-calculation or mental-navigation cognitive tasks. Various levels of difficulty were applied by adjusting the velocity rate at which the instructions were provided to the subject according to his/her maximal capacities measured beforehand. A condition without any concomitant cognitive task was added to constitute a baseline behavior. Two basic components, the horizontal center-of-gravity movements and the horizontal difference between center-of-gravity and center-of-pressures were computed from the complex center of-pressure recorded movements. It was hypothesized that increasing the delay should infer less interaction between postural control and task solution. The results indicate that both mental-calculation and mental-navigation tasks induce reduced amplitudes for the center-of-pressure minus center-of-gravity movements, only along the mediolateral axis, whereas center-of-gravity movements were not affected, suggesting that different circuits are involved in the central nervous system to control these two movements. Moreover, increasing the delays task does not infer any effect for both movements. Since center-of-pressure minus center-of gravity expresses the horizontal acceleration communicated to the center-of gravity, one may assume that the control of the latter should be facilitated in dual-tasks conditions, inferring reduced center-of-gravity movements, which is not seen in our results. This lack of effect should be thus interpreted as a modification in the control of these center-of-gravity movements. Taken together, these results emphasized how undisturbed upright stance control can be impacted by mental tasks requiring attention, whatever their nature (calculation or navigation) and their relative difficulty. Depending on the provided instructions, i.e. focusing our attention on body movements or on the opposite diverting this attention toward other objectives, the evaluation of upright stance control capacities might be drastically altered. PMID- 26949916 TI - Obesity and Asthma: Microbiome-Metabolome Interactions. AB - Obesity is a risk factor for asthma, but obese subjects with asthma respond poorly to standard asthma drugs. Obesity also alters gut bacterial community structure. Obesity-related changes in gut bacteria contribute to weight gain and other obesity-related conditions, including insulin resistance and systemic inflammation. Here, we review the rationale for the hypothesis that obesity related changes in gut bacteria may also play a role in obesity-related asthma. The metabolomes of the liver, serum, urine, and adipose tissue are altered in obesity. Gut bacteria produce a large number of metabolites, which can reach the blood and circulate to other organs, and gut bacteria-derived metabolites have been shown to contribute to disease processes outside the gastrointestinal tract, including cardiovascular disease. Here, we describe the potential roles for two such classes of metabolites in obesity-related asthma: short-chain fatty acids and bile acids. Greater understanding of the role of microbiota in obesity related asthma could lead to novel microbiota-based treatments for these hard-to treat patients. PMID- 26949921 TI - Characterization of functionally active gene fusions in human papillomavirus related oropharyngeal squamous cell carcinoma. AB - The Cancer Genome Atlas (TCGA) sequencing analysis of head and neck squamous cell carcinoma (HNSCC) recently reported on gene fusions, however, few human papillomavirus (HPV) positive samples were included, and the functional relevance of identified fusions was not explored. We therefore performed an independent analysis of gene fusions in HPV-positive oropharyngeal SCC (OPSCC). RNA sequencing was performed on 47 HPV-positive OPSCC primary tumors and 25 normal mucosal samples from cancer unaffected controls on an Illumina TruSeq platform. MapSplice2 was used for alignment and identification of fusion candidates. Putative fusions with less than five spanning reads, detected in normal tissues, or that mapped to the same gene were filtered out. Selected fusions were validated by RT-PCR and Sanger sequencing. Within 47 HPV-positive OPSCC tumors, 282 gene fusions were identified. Most fusions (85.1%) occurred in a single tumor, and the remaining fusions recurred in 2-16 tumors. Gene fusions were associated with significant up regulation of 16 genes (including EGFR and ERBB4) and down regulation of four genes (PTPRT, ZNF750, DLG2, SLCO5A1). Expression of these genes followed similar patterns of up regulation and down regulation in tumors without these fusions compared to normal tissue. Five of six gene fusions selected for validation were confirmed through RT-PCR and sequencing. This integrative analysis provides a method of prioritizing functionally relevant gene fusions that may be expanded to other tumor types. These results demonstrate that gene fusions may be one mechanism by which functionally relevant genes are altered in HPV-positive OPSCC. PMID- 26949922 TI - Influence of Oxygen and Nitrate on Fe (Hydr)oxide Mineral Transformation and Soil Microbial Communities during Redox Cycling. AB - Oscillations between reducing and oxidizing conditions are observed at the interface of anaerobic/oxic and anaerobic/anoxic environments, and are often stimulated by an alternating flux of electron donors (e.g., organic carbon) and electron acceptors (e.g., O2 and NO3(-)). In iron (Fe) rich soils and sediments, these oscillations may stimulate the growth of both Fe-reducing bacteria (FeRB) and Fe-oxidizing bacteria (FeOB), and their metabolism may induce cycling between Fe(II) and Fe(III), promoting the transformation of Fe (hydr)oxide minerals. Here, we examine the mineralogical evolution of lepidocrocite and ferrihydrite, and the adaptation of a natural microbial community to alternating Fe-reducing (anaerobic with addition of glucose) and Fe-oxidizing (with addition of nitrate or air) conditions. The growth of FeRB (e.g., Geobacter) is stimulated under anaerobic conditions in the presence of glucose. However, the abundance of these organisms depends on the availability of Fe(III) (hydr)oxides. Redox cycling with nitrate results in decreased Fe(II) oxidation thereby decreasing the availability of Fe(III) for FeRB. Additionally, magnetite is detected as the main product of both lepidocrocite and ferrihydrite reduction. In contrast, introduction of air results in increased Fe(II) oxidation, increasing the availability of Fe(III) and the abundance of Geobacter. In the lepidocrocite reactors, Fe(II) oxidation by dissolved O2 promotes the formation of ferrihydrite and lepidocrocite, whereas in the ferrihydrite reactors we observe a decrease in magnetite stoichiometry (e.g., oxidation). Understanding Fe (hydr)oxide transformation under environmentally relevant redox cycling conditions provides insight into nutrient availability and transport, contaminant mobility, and microbial metabolism in soils and sediments. PMID- 26949923 TI - Hepatic encephalopathy for the hospitalist. AB - The care of patients with advanced liver disease is often complicated by episodes of acute decline in alertness and cognition, termed hepatic encephalopathy (HE). Hospitalists must be familiar with HE, as it is a common reason for hospitalization in this population and is associated with significantly increased mortality. This narrative review addresses common issues related to diagnosis and classification, precipitants, inpatient management, and transitions of care for patients with HE. The initial presentation can be variable, and HE remains a clinical diagnosis. The spectrum of HE manifestations spans from mild, subclinical cognitive deficits to overt coma. The West Haven scoring system is the most widely used classification system for HE. Various metabolic insults may precipitate HE, and providers must specifically seek to rule out infection and bleeding in cirrhotic patients presenting with altered cognition. This is consistent with the 4-pronged approach of the American Association for the Study of Liver Disease practice guidelines. Patients with HE are typically treated primarily with nonabsorbable disaccharide laxatives, often with adjunctive rifaximin. The evidence for these agents is discussed, and available support for other treatment options is presented. Management issues relevant to general hospitalists include those related to acute pain management, decisional capacity, and HE following transjugular intrahepatic portosystemic shunt placement. These issues are examined individually. Successfully transitioning patients recovering from HE to outpatient care requires open communication with multiple role players including patients, caregivers, and outpatient providers. Journal of Hospital Medicine 2016;11:591-594. (c) 2016 Society of Hospital Medicine. PMID- 26949924 TI - The effect of educational information about treatments for schizophrenia on stigmatizing perceptions. AB - BACKGROUND: A promising strategy for reducing stigmatizing perceptions towards people with schizophrenia is education about treatment and recovery. The effects of different kinds of treatment information on stigmatizing perceptions, however, have yet to be compared directly. This study compared three different educational interventions focusing on medication, CBT, and psychodynamic psychotherapy in their potential to reduce stigmatizing perceptions towards people with schizophrenia. METHODS: In an online experiment 178 participants received one of three psychoeducation texts that focused on medication, CBT or psychodynamic therapy. The effects on stereotypical beliefs about psychosis (dangerousness, unpredictability, blame, prognostic pessimism) and emotional responses towards people with schizophrenia (anxiety, anger, sympathy) were tested. RESULTS: Perceptions of dangerousness, unpredictability, and anxiety towards people with schizophrenia were reduced in all conditions. Prognostic pessimism was reduced only after reading the CBT information. LIMITATIONS: No neutral control group was included. The sample was not representative with respect to level of education or gender. CONCLUSIONS: Stigmatizing perceptions may be reduced by receiving information about any type of treatment for psychosis and without producing negative side-effects, although this needs to be replicated in a controlled study. However, information on CBT seems most suitable to reduce stigma, since it was able to reduce prognostic pessimism. PMID- 26949926 TI - Relation of white-matter microstructure to reading ability and disability in beginning readers. AB - : [Correction Notice: An Erratum for this article was reported in Vol 31(5) of Neuropsychology (see record 2017-22816-001). Errors in the dataset owing to two incorrect scores have skewed results. In the 2nd paragraph of the Results section, the 2nd sentence should read: "Within the typical reader group, FA in the left AF correlated negatively with pseudoword reading (WRMT-III Word Attack: rs = .37, p = .064), but not real-word reading (WRMT-III Word Identification: rs = .07, p = .75)." The 4th sentence of the 3rd paragraph should read: "The negative correlation between FA and Word Attack in the typical reader group was driven by Daxial (Dradial: rs = .19, p = .373, Daxial: rs = .38, p = .060)." The 2nd sentence of the 4th paragraph should read: "Results of this analysis replicated those of the larger reading disability group, with a statistically greater reduction of FA in this more severely affected group (p = .008) that was associated with a significant increase in Dradial (p = .008) and no difference in Daxial (p = .47)." In Table 1, for the typical reader group, the resulting values should read: age, 94.00 +/- 7.66; KBIT-2-Matrices, 118.31 +/- 15.24; WRMT-III Word Identification, 119.00 +/- 9.33; WRMT-III-Word Attack, 114.04 +/- 9.31; and TOWRE-2-Sight Word Efficiency, 114.48 +/- 8.07. For the reading disability group, the resulting values for age and TOWRE-2- Phonemic Decoding Efficiency should be 93.65 +/- 7.81 and 81.76 +/- 9.33, respectively. The p values for age and KBIT-2 Matrices should be .87 and .172, respectively. In Figure 3, the image for the typical reader group has been replaced. All versions of this article have been corrected.] Objective: We examined the white-matter microstructure of the left arcuate fasciculus, which has been associated with reading ability, in beginning readers with or without reading disability. METHOD: Groups were typically reading children (n = 26) or children with reading disability (n = 26), Ages 6-9, and equated on nonverbal cognitive abilities. Diffusion-weighted images were collected and TRACULA was used to extract fractional anisotropy measures from the left arcuate fasciculus. RESULTS: White-matter microstructure was altered in children with reading disability, who exhibited significantly reduced fractional anisotropy in the left arcuate fasciculus. Among typically reading children, lower fractional anisotropy of the left arcuate fasciculus was associated with superior pseudoword reading performance. Both the group differences and variation in reading scores among the children with reading disability were associated with radial diffusivity (but not axial diffusivity), whereas variation in reading scores among typically reading children was associated with axial diffusivity (but not radial diffusivity). CONCLUSIONS: The paradoxical findings that lower fractional anisotropy was associated both with reading disability and also with better phonological awareness in typical reading development suggest that there are different maturational trajectories of white-matter microstructure in typical readers and children with reading disability, and that this difference is unique to the beginning stages of reading acquisition. The finding that reading disability was associated with radial diffusivity, but that variation in ability among typically developing readers was associated with axial diffusivity, suggests that different neural mechanisms may be associated with reading development in children with or without reading disability. (PsycINFO Database Record PMID- 26949928 TI - Comparison of outcome measures in allergic rhinitis in children, adolescents and adults. AB - BACKGROUND: Grass pollen-induced allergic rhinoconjunctivitis (AR) is very common worldwide. However, its symptoms may vary with the patient's age. The present study compared symptom profiles and quality of life (QoL) in children, adolescents and adults with grass pollen-induced AR. METHODS: This was a four week, multicentre, observational study of children (aged 6-11), adolescents (12 17) and adults (18-65) consulting specialist physicians in France. The management of AR was at the physicians' discretion. Participants regularly rated their symptoms (the rhinoconjunctivitis total symptom score (RTSS) and a visual analogue scale (VAS)) and QoL (the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ). RESULTS: A total of 806 patients (253 children, 250 adolescents and 303 adults, of whom 83.5% suffered from moderate-to-severe, persistent AR) provided data for at least the first 2 weeks of the study. Ocular pruritus (the most bothersome symptom in children (35%), adolescents (22%) and adults (16%)) was associated with poor QoL in all groups, whereas nasal obstruction and pruritus were associated with poor QoL in adolescents and children. Over 4 weeks, the weekly mean RTSS and VAS scores fell by around half. This change was associated with an improvement in the RQLQ scores. In all age groups, the VAS score was well correlated with the weekly mean RTSS score (Pearson's r: 0.79-0.88) and moderately correlated with the weekly mean RQLQ score (Pearson's r: 0.64-0.80). CONCLUSIONS: In moderate-to-severe grass pollen induced AR, symptom perception differs in children vs. older patients. However, the assessments of treatment outcomes (using the RTSS, VAS and RQLQ) were similar in all age groups. PMID- 26949927 TI - Impaired perception of biological motion in Parkinson's disease. AB - OBJECTIVE: We examined biological motion perception in Parkinson's disease (PD). Biological motion perception is related to one's own motor function and depends on the integrity of brain areas affected in PD, including posterior superior temporal sulcus. If deficits in biological motion perception exist, they may be specific to perceiving natural/fast walking patterns that individuals with PD can no longer perform, and may correlate with disease-related motor dysfunction. METHOD: Twenty-six nondemented individuals with PD and 24 control participants viewed videos of point-light walkers and scrambled versions that served as foils, and indicated whether each video depicted a human walking. Point-light walkers varied by gait type (natural, parkinsonian) and speed (0.5, 1.0, 1.5 m/s). Participants also completed control tasks (object motion, coherent motion perception), a contrast sensitivity assessment, and a walking assessment. RESULTS: The PD group demonstrated significantly less sensitivity to biological motion than the control group (p < .001, Cohen's d = 1.22), regardless of stimulus gait type or speed, with a less substantial deficit in object motion perception (p = .02, Cohen's d = .68). There was no group difference in coherent motion perception. Although individuals with PD had slower walking speed and shorter stride length than control participants, gait parameters did not correlate with biological motion perception. Contrast sensitivity and coherent motion perception also did not correlate with biological motion perception. CONCLUSION: PD leads to a deficit in perceiving biological motion, which is independent of gait dysfunction and low-level vision changes, and may therefore arise from difficulty perceptually integrating form and motion cues in posterior superior temporal sulcus. (PsycINFO Database Record PMID- 26949930 TI - Retrospective Review of Risk Factors Predictive of Complications in Patients After Below the Knee Mohs Micrographic Surgery. PMID- 26949929 TI - Effects of short-term severe and long-term mild STZ-induced diabetes in urethral tissue of female rats. AB - AIMS: To estimate and compare the alterations in the urethral tissues of female rats with two diabetes models: short-term severe and long-term mild diabetes. METHODS: To induce mild diabetes (blood glucose levels between 120 and 300 mg/dl), female newborns received streptozotocin (100 mg/kg body weight, sc route), and to induce short-term severe diabetes (blood glucose levels > 300 mg/d), adult animals received streptozotocin (40 mg/kg, iv route). The rats were killed on day 133 of the experimental via an i.p. Thiopentax(r) injection of 80 mg/kg, and the urethrovaginal tissues were harvested. Morphometric, pathological, immunohistochemical, and ultrastructural analyses were conducted. RESULTS: In the long-term mild diabetes group, collagen deposition, severe fibrosis, lipid droplets and numerous subsarcolemmal, and intermyofibrillar mitochondria were observed. In the short-term severe diabetes group, centrally located myonuclei and a significantly reduced striated muscle area were noted. Both diabetic models exhibited similar immunohistochemistry patterns, with changes from fast to slow fibers and a decrease in the numbers of fast fibers. CONCLUSIONS: Either long term mild hyperglycemia or short-term severe hyperglycemia have detrimental impacts on muscle health. They are both involved in the failure to maintain healthy skeletal muscle that may contribute to the development of pelvic floor dysfunctions via different pathways. These results have important implications for monitoring and prevention strategies for improving the quality of life of women with diabetes mellitus and pelvic floor muscle dysfunction. Neurourol. Urodynam. 36:574-579, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 26949931 TI - Reconstruction for Defects at the Base of the Philtrum Affecting the Upper Lip Vermilion. PMID- 26949932 TI - Commentary on Clinical and Histopathological Assessment of Facial Melasma After Low-Fluence Q-Switched Neodymium-Doped Yttrium Aluminium Garnet Laser. PMID- 26949934 TI - Detection of Chlamydia trachomatis and Neisseria gonorrhoeae based on cross priming amplification. AB - Rapid, sensitive and specific isothermal nucleic acid amplification methods of Chlamydia trachomatis (C. trachomatis) and Neisseria gonorrhoeae (N. gonorrhoeae) have been developed based on cross-priming amplification (CPA). The amplicon of CPA can be detected by a disposable amplicon cross-contamination proof device. The whole assay takes 1-1.5 h from amplification to read out. Ten fold serial dilutions of quantified plasmids were used to test the CPA assay sensitivities, with the detection limits of 45 copies per reaction and 65 copies per reaction for C. trachomatis and N. gonorrhoeae respectively. The specificities of CPA assays for C. trachomatis and N. gonorrhoeae were tested by using total DNA extracted from nine other bacterial strains, and no cross-reactivity was detected. Eighty clinical cervical or vaginal swab specimens were tested by both CPA and real-time polymerase chain reaction (PCR) with the consistencies of 98.75% (79/80) and 97.5% (78/80) for C. trachomatis and N. gonorrhoeae respectively. Using real-time PCR as a reference standard, the clinical sensitivity (positive) and specificity (negative) of CPA was found to be 98.15% (53/54) and 100% (26/26) for C. trachomatis, and 93.75% (30/32) and 100% (48/48) for N. gonorrhoeae. Eight swab specimens tested positive for both C. trachomatis and N. gonorrhoeae simultaneously by real-time PCR and CPA assay. This study demonstrated that CPA is an affordable and accessible assay for C. trachomatis and N. gonorrhoeae detection, with high sensitivity and specificity. SIGNIFICANCE AND IMPACT OF THE STUDY: Rapid and specific detection of the sexually transmitted pathogens Chlamydia trachomatis (C. trachomatis) and Neisseria gonorrhoeae (N. gonorrhoeae) would enable early treatment and management of their spread. Here, for the first time, a user friendly DNA isothermal amplification method named cross-priming amplification (CPA), was used to test C. trachomatis and N. gonorrhoeae with high sensitivity and specificity. The results indicate that CPA has great potential for improving C. trachomatis and N. gonorrhoeae diagnostics which could be particularly advantageous in resource-limited areas. PMID- 26949935 TI - Elevated Lipid Profiles in Patients with Acute Transverse Myelitis. AB - BACKGROUND: The associations and clinical relevance of serum lipid profiles in patients with acute transverse myelitis (ATM) are unknown. Our study aimed at investigating the status of serum lipid variables (including total cholesterol (TC), triglycerides (TGs), high/low density lipoproteins (HDL/LDL), apolipoprotein A-I (ApoA-I), apolipoprotein B (ApoB) and cholesterol to HDL ratio) in ATM, and to explore whether there was a correlation between serum lipid levels and disease characteristics of ATM. METHODS: We retrospectively evaluated serum lipid levels of 92 patients with ATM, 43 with multiple sclerosis (MS) on relapse and 112 healthy controls (HC). The changes of serum lipid profiles were analyzed. RESULTS: We found that ATM patients had higher serum TC, TG, LDL levels and T/H ratio than HC, but had lower levels of serum ApoA-I and ApoB. Besides, there were no significant differences between ATM and MS on relapse (except ApoB). Third, longer disease duration was associated with higher TG; higher HDL was associated with a trend for lower Expanded Disability Status Scale scores. CONCLUSIONS: Our findings showed that serum lipid levels were elevated in patients with ATM, among serum TG and HDL might be associated with clinical features. These results illustrate that a long-term follow-up and regular monitoring of serum lipid profiles are important for ATM patients. PMID- 26949933 TI - Drug-induced Raynaud's phenomenon: beyond beta-adrenoceptor blockers. AB - AIM: Drug-induced Raynaud's phenomenon (RP) has long been associated with the use of different drugs, including cancer chemotherapy or beta-adrenoceptor blockers. However, sources report extremely variable prevalence and the level of evidence for each class is heterogeneous. Moreover, new signals are emerging from case reports and small series. Our objective was therefore to review available evidence about this adverse drug effect and to propose a mechanistic approach of drug-induced RP. METHODS: A systematic review of English and French language articles was performed through Medline (1946-2015) and Embase (1974-2015). Further relevant papers were identified from the reference lists of retrieved articles. RESULTS: We identified 12 classes of drugs responsible for RP, with a variety of underlying mechanisms such as increased sympathetic activation, endothelial dysfunction, neurotoxicity or decreased red blood cell deformability. Cisplatin and bleomycin were associated with the highest risk, followed by beta adrenoceptor blockers. Recent data suggest a possible involvement of tyrosine kinase inhibitors (TKI), through an unknown mechanism. CONCLUSION: Drug-induced RP is a probably underestimated adverse drug event, with limited available evidence regarding its prevalence. Although rare, serious complications like critical digital ischaemia have been reported. When these treatments are started in patients with a history of RP, careful monitoring must be made and, if possible, alternative therapies that do not alter peripheral blood flow should be considered. PMID- 26949936 TI - Electrolytes-Enriched Hemodiafiltration Solutions for Continuous Renal Replacement Therapy in Acute Kidney Injury: A Crossover Study. AB - AIMS: To evaluate the capability of an electrolytes-enriched solution to prevent metabolic disorders during continuous veno-venous hemodiafiltration (CVVHDF). METHODS: Serum biochemistry and clinical tolerance were compared during CVVHDF treatments with an electrolyte-enriched (Phoxilium) or standard solutions in 10 acute renal failure patients. RESULTS: As compared to standard fluids, serum potassium and phosphate levels were maintained in the normal range with Phoxilium without any supplementation but total serum calcium levels were significantly lower. Bicarbonatemia was slightly higher (24-26 vs. 21.5-24.5 mmol/l, p < 0.05) with conventional solutions and was associated with a significant increased level of pH (>7.44). Despite the absence of glucose in the Phoxilium solution, blood glucose levels and glucose supplementation were similar between treatments. Clinical tolerance and efficiency of CVVHDF sessions were comparable. CONCLUSION: Phoxilium effectively prevented hypophosphatemia and hypokalemia during CVVHDF. It was, however, associated with a slight metabolic acidosis and hypocalcemia compared with conventional solutions. PMID- 26949937 TI - microRNA-34a-Mediated Down-Regulation of the Microglial-Enriched Triggering Receptor and Phagocytosis-Sensor TREM2 in Age-Related Macular Degeneration. AB - The aggregation of Abeta42-peptides and the formation of drusen in age-related macular degeneration (AMD) are due in part to the inability of homeostatic phagocytic mechanisms to clear self-aggregating Abeta42-peptides from the extracellular space. The triggering receptor expressed in myeloid/microglial cells-2 (TREM2), a trans-membrane-spanning, sensor-receptor of the immune globulin/lectin-like gene superfamily is a critical component of Abeta42-peptide clearance. Here we report a significant deficit in TREM2 in AMD retina and in cytokine- or oxidatively-stressed microglial (MG) cells. RT-PCR, miRNA-array, LED Northern and Western blot studies indicated up-regulation of a microglial enriched NF-kB-sensitive miRNA-34a coupled to a down-regulation of TREM2 in the same samples. Bioinformatics/transfection-luciferase reporter assays indicated that miRNA-34a targets the 299 nucleotide TREM2-mRNA-3'UTR, resulting in TREM2 down-regulation. C8B4-microglial cells challenged with Abeta42 were able to phagocytose these peptides, while miRNA-34a down-regulated both TREM2 and the ability of microglial-cells to phagocytose. Treatment of TNFalpha-stressed MG cells with phenyl-butyl nitrone (PBN), caffeic-acid phenethyl ester (CAPE), the NF-kB - [corrected] inhibitor/resveratrol analog CAY10512 or curcumin abrogated these responses. Incubation of anti-miRNA-34a (AM-34a) normalized miRNA-34a abundance and restored TREM2 back to homeostatic levels. These data support five novel observations: (i) that a ROS- and NF-kB - [corrected] sensitive, miRNA-34a mediated modulation of TREM2 may in part regulate the phagocytic response; (ii) that gene products encoded on two different chromosomes (miRNA-34a at chr1q36.22 and TREM2 at chr6p21.1) orchestrate a phagocytic-Abeta42-peptide clearance system; (iii) that this NF-kB-mediated-miRNA-34a-TREM2 mechanism is inducible from outside of the cell; (iv) that when operating normally, this pathway can clear Abeta42 peptide monomers from the extracellular medium; and (v) that anti NF-kB and/or anti-miRNA (AM)-based therapeutic strategies may be useful against deficits in TREM-2 receptor-based-sensing and -phagocytic signaling that promote pathogenic amyloidogenesis. PMID- 26949939 TI - Measurement of Outflow Facility Using iPerfusion. AB - Elevated intraocular pressure (IOP) is the predominant risk factor for glaucoma, and reducing IOP is the only successful strategy to prevent further glaucomatous vision loss. IOP is determined by the balance between the rates of aqueous humour secretion and outflow, and a pathological reduction in the hydraulic conductance of outflow, known as outflow facility, is responsible for IOP elevation in glaucoma. Mouse models are often used to investigate the mechanisms controlling outflow facility, but the diminutive size of the mouse eye makes measurement of outflow technically challenging. In this study, we present a new approach to measure and analyse outflow facility using iPerfusionTM, which incorporates an actuated pressure reservoir, thermal flow sensor, differential pressure measurement and an automated computerised interface. In enucleated eyes from C57BL/6J mice, the flow-pressure relationship is highly non-linear and is well represented by an empirical power law model that describes the pressure dependence of outflow facility. At zero pressure, the measured flow is indistinguishable from zero, confirming the absence of any significant pressure independent flow in enucleated eyes. Comparison with the commonly used 2 parameter linear outflow model reveals that inappropriate application of a linear fit to a non-linear flow-pressure relationship introduces considerable errors in the estimation of outflow facility and leads to the false impression of pressure independent outflow. Data from a population of enucleated eyes from C57BL/6J mice show that outflow facility is best described by a lognormal distribution, with 6 fold variability between individuals, but with relatively tight correlation of facility between fellow eyes. iPerfusion represents a platform technology to accurately and robustly characterise the flow-pressure relationship in enucleated mouse eyes for the purpose of glaucoma research and with minor modifications, may be applied in vivo to mice, as well as to eyes from other species or different biofluidic systems. PMID- 26949938 TI - Polo-Like Kinase 3 Appears Dispensable for Normal Retinal Development Despite Robust Embryonic Expression. AB - During retinogenesis seven different cell types are generated in distinct yet overlapping timepoints from a population of retinal progenitor cells. Previously, we performed single cell transcriptome analyses of retinal progenitor cells to identify candidate genes that may play roles in the generation of early-born retinal neurons. Based on its expression pattern in subsets of early retinal cells, polo-like kinase 3 (Plk3) was identified as one such candidate gene. Further characterization of Plk3 expression by in situ hybridization revealed that this gene is expressed as cells exit the cell cycle. We obtained a Plk3 deficient mouse and investigated changes in the retina's morphology and transcriptome through immunohistochemistry, in situ hybridization and gene expression profiling. These experiments have been performed initially on adult mice and subsequently extended throughout retinal development. Although morphological studies revealed no consistent changes in retinogenesis upon Plk3 loss, microarray profiling revealed potential candidate genes altered in Plk3-KO mice. Further studies will be necessary to understand the connection between these changes in gene expression and the loss of a protein kinase such as Plk3. PMID- 26949941 TI - Rapid Syphilis Testing Is Cost-Effective Even in Low-Prevalence Settings: The CISNE-PERU Experience. AB - Studies have addressed cost-effectiveness of syphilis testing of pregnant women in high-prevalence settings. This study compares costs of rapid syphilis testing (RST) with laboratory-based rapid plasma reagin (RPR) tests in low-prevalence settings in Peru. The RST was introduced in a tertiary-level maternity hospital and in the Ventanilla Network of primary health centers, where syphilis prevalence is approximately 1%. The costs per woman tested and treated with RST at the hospital were $2.70 and $369 respectively compared with $3.60 and $740 for RPR. For the Ventanilla Network the costs per woman tested and treated with RST were $3.19 and $295 respectively compared with $5.55 and $1454 for RPR. The cost per DALY averted using RST was $46 vs. $109 for RPR. RST showed lower costs compared to the WHO standard costs per DALY ($64). Findings suggest syphilis screening with RST is cost-effective in low-prevalence settings. PMID- 26949942 TI - Computational Effective Fault Detection by Means of Signature Functions. AB - The paper presents a computationally effective method for fault detection. A system's responses are measured under healthy and ill conditions. These signals are used to calculate so-called signature functions that create a signal space. The current system's response is projected into this space. The signal location in this space easily allows to determine the fault. No classifier such as a neural network, hidden Markov models, etc. is required. The advantage of this proposed method is its efficiency, as computing projections amount to calculating dot products. Therefore, this method is suitable for real-time embedded systems due to its simplicity and undemanding processing capabilities which permit the use of low-cost hardware and allow rapid implementation. The approach performs well for systems that can be considered linear and stationary. The communication presents an application, whereby an industrial process of moulding is supervised. The machine is composed of forms (dies) whose alignment must be precisely set and maintained during the work. Typically, the process is stopped periodically to manually control the alignment. The applied algorithm allows on-line monitoring of the device by analysing the acceleration signal from a sensor mounted on a die. This enables to detect failures at an early stage thus prolonging the machine's life. PMID- 26949940 TI - The Natural History of Kidney Graft Cortical Microcirculation Determined by Real Time Contrast-Enhanced Sonography (RT-CES). AB - BACKGROUND: Kidney transplantation is the therapy of choice for end-stage kidney disease. Graft's life span is shorter than expected due in part to the delayed diagnosis of various complications, specifically those related to silent progression. It is recognized that serum creatinine levels and proteinuria are poor markers of mild kidney lesions, which results in delayed clinical information. There are many investigation looking for early markers of graft damage. Decreasing kidney graft cortical microcirculation has been related to poor prognosis in kidney transplantation. Cortical capillary blood flow (CCBF) can be measured by real-time contrast-enhanced sonography (RT-CES). Our aim was to describe the natural history of CCBF over time under diverse conditions of kidney transplantation, to explore the influence of donor conditions and recipient events, and to determine the capacity of CCBF for predicting renal function in medium term. PATIENTS AND METHODS: RT-CES was performed in 79 consecutive kidney transplant recipients during the first year under regular clinical practice. Cortical capillary blood flow was measured. Clinical variables were analyzed. The influence of CCBF has been determined by univariate and multivariate analysis using mixed regression models based on sequential measurements for each patient over time. We used a first-order autoregression model as the structure of the covariation between measures. The post-hoc comparisons were considered using the Bonferroni correction. RESULTS: The CCBF values varied significantly over the study periods and were significantly lower at 48 h and day 7. Brain-death donor age and CCBF levels showed an inverse relationship (r: -0.62, p<0.001). Living donors showed higher mean CCBF levels than brain-death donors at each point in the study. These significant differences persisted at month 12 (54.5 +/- 28.2 vs 33.7 +/- 30 dB/sec, living vs brain-death donor, respectively, p = 0.004) despite similar serum creatinine levels (1.5 +/- 0.3 and 1.5 +/- 0.5 mg/dL). A sole rejection episode was associated with lower overall CCBF values over the first year. CCBF defined better than level of serum creatinine the graft function status at medium-term. CONCLUSION: RT-CES is a non invasive tool that can quantify and iteratively estimate cortical microcirculation. We have described the natural history of cortical capillary blood flow under regular clinical conditions. PMID- 26949944 TI - Influence of the Surfactant Tyloxapol on Mucociliary Clearance in Human Respiratory Cystic Fibrosis Cells. AB - Dehydration of the apical surface of cystic fibrosis (CF) airway epithelia leads to a greatly impaired mucociliary clearance function in CF patients. In an in vitro cell model of human airway epithelia taken from CF patients and cultivated for 60 days, mucociliary clearance was zero. Tyloxapol, a synthetic surfactant, is able to restore the mucociliary clearance of the CF epithelia. The velocity of mucociliary clearance, using polystyrene microbeads as markers, increased within the first minute of tyloxapol treatment from zero to 12 um/s and reached a maximum of 22 um/s after 120 min. In conclusion, tyloxapol restores mucociliary clearance in a MucilAirTM-CF model and may accordingly be efficient in CF patients to restore mucociliary clearance. PMID- 26949943 TI - Pyrosequencing the Midgut Transcriptome of the Banana Weevil Cosmopolites sordidus (Germar) (Coleoptera: Curculionidae) Reveals Multiple Protease-Like Transcripts. AB - The banana weevil Cosmopolites sordidus is an important and serious insect pest in most banana and plantain-growing areas of the world. In spite of the economic importance of this insect pest very little genomic and transcriptomic information exists for this species. In the present study, we characterized the midgut transcriptome of C. sordidus using massive 454-pyrosequencing. We generated over 590,000 sequencing reads that assembled into 30,840 contigs with more than 400 bp, representing a significant expansion of existing sequences available for this insect pest. Among them, 16,427 contigs contained one or more GO terms. In addition, 15,263 contigs were assigned an EC number. In-depth transcriptome analysis identified genes potentially involved in insecticide resistance, peritrophic membrane biosynthesis, immunity-related function and defense against pathogens, and Bacillus thuringiensis toxins binding proteins as well as multiple enzymes involved with protein digestion. This transcriptome will provide a valuable resource for understanding larval physiology and for identifying novel target sites and management approaches for this important insect pest. PMID- 26949945 TI - Association Analysis of Myosin Heavy-chain Genes mRNA Transcription with the Corresponding Proteins Expression of Longissimus Muscle in Growing Pigs. AB - The goal of this work was to investigate the correlations between MyHC mRNA transcription and their corresponding protein expressions in porcine longissimus muscle (LM) during postnatal growth of pigs. Five DLY (Duroc*Landrace*Yorkshire) crossbred pigs were selected, slaughtered and sampled at postnatal 7, 30, 60, 120, and 180 days, respectively. Each muscle was subjected to quantity MyHCs protein contents through an indirect enzyme-linked immunosorbent assay (ELISA), to quantity myosin heavy-chains (MyHCs) mRNA abundances using real-time polymerase chain reaction. We calculated the proportion (%) of each MyHC to total of four MyHC for two levels, respectively. Moreover, the activities of several key energy metabolism enzymes were determined in LM. The result showed that mRNA transcription and protein expression of MyHC I, IIa, IIx and IIb in LM all presented some obvious changes with postnatal aging of pigs, especially at the early stage after birth, and their mRNA transcriptions were easy to be influenced than their protein expressions. The relative proportion of each MyHC mRNA was significantly positively related to that of its corresponding protein (p<0.01), and MyHC I mRNA proportion was positively correlated with creatine kinase (CK), succinate dehydrogenase (SDH), malate dehydrogenase (MDH) activities (p<0.05). These data suggested that MyHC mRNA transcription can be used to reflect MyHC expression, metabolism property and adaptive plasticity of porcine skeletal muscles, and MyHC mRNA composition could be a molecular index reflecting muscle fiber type characteristics. PMID- 26949946 TI - Imputation Accuracy from Low to Moderate Density Single Nucleotide Polymorphism Chips in a Thai Multibreed Dairy Cattle Population. AB - The objective of this study was to investigate the accuracy of imputation from low density (LDC) to moderate density SNP chips (MDC) in a Thai Holstein-Other multibreed dairy cattle population. Dairy cattle with complete pedigree information (n = 1,244) from 145 dairy farms were genotyped with GeneSeek GGP20K (n = 570), GGP26K (n = 540) and GGP80K (n = 134) chips. After checking for single nucleotide polymorphism (SNP) quality, 17,779 SNP markers in common between the GGP20K, GGP26K, and GGP80K were used to represent MDC. Animals were divided into two groups, a reference group (n = 912) and a test group (n = 332). The SNP markers chosen for the test group were those located in positions corresponding to GeneSeek GGP9K (n = 7,652). The LDC to MDC genotype imputation was carried out using three different software packages, namely Beagle 3.3 (population-based algorithm), FImpute 2.2 (combined family- and population-based algorithms) and Findhap 4 (combined family- and population-based algorithms). Imputation accuracies within and across chromosomes were calculated as ratios of correctly imputed SNP markers to overall imputed SNP markers. Imputation accuracy for the three software packages ranged from 76.79% to 93.94%. FImpute had higher imputation accuracy (93.94%) than Findhap (84.64%) and Beagle (76.79%). Imputation accuracies were similar and consistent across chromosomes for FImpute, but not for Findhap and Beagle. Most chromosomes that showed either high (73%) or low (80%) imputation accuracies were the same chromosomes that had above and below average linkage disequilibrium (LD; defined here as the correlation between pairs of adjacent SNP within chromosomes less than or equal to 1 Mb apart). Results indicated that FImpute was more suitable than Findhap and Beagle for genotype imputation in this Thai multibreed population. Perhaps additional increments in imputation accuracy could be achieved by increasing the completeness of pedigree information. PMID- 26949947 TI - Genetic Diversity Analysis of South and East Asian Duck Populations Using Highly Polymorphic Microsatellite Markers. AB - Native duck populations have lower productivity, and have not been developed as much as commercials duck breeds. However, native ducks have more importance in terms of genetic diversity and potentially valuable economic traits. For this reason, population discriminable genetic markers are needed for conservation and development of native ducks. In this study, 24 highly polymorphic microsatellite (MS) markers were investigated using commercial ducks and native East and South Asian ducks. The average polymorphic information content (PIC) value for all MS markers was 0.584, indicating high discrimination power. All populations were discriminated using 14 highly polymorphic MS markers by genetic distance and phylogenetic analysis. The results indicated that there were close genetic relationships among populations. In the structure analysis, East Asian ducks shared more haplotypes with commercial ducks than South Asian ducks, and they had more independent haplotypes than others did. These results will provide useful information for genetic diversity studies in ducks and for the development of duck traceability systems in the market. PMID- 26949948 TI - Identification of Histone Deacetylase 2 as a Functional Gene for Skeletal Muscle Development in Chickens. AB - A previous genome-wide association study (GWAS) exposed histone deacetylase 2 (HDAC2) as a possible candidate gene for breast muscle weight in chickens. The present research has examined the possible role of HDAC2 in skeletal muscle development in chickens. Gene expression was measured by quantitative polymerase chain reaction in breast and thigh muscles during both embryonic (four ages) and post-hatch (five ages) development and in cultures of primary myoblasts during both proliferation and differentiation. The expression of HDAC2 increased significantly across embryonic days (ED) in breast (ED 14, 16, 18, and 21) and thigh (ED 14 and 18, and ED 14 and 21) muscles suggesting that it possibly plays a role in myoblast hyperplasia in both breast and thigh muscles. Transcript abundance of HDAC2 identified significantly higher in fast growing muscle than slow growing in chickens at d 90 of age. Expression of HDAC2 during myoblast proliferation in vitro declined between 24 h and 48 h when expression of the marker gene paired box 7 (PAX7) increased and cell numbers increased throughout 72 h of culture. During induced differentiation of myoblasts to myotubes, the abundance of HDAC2 and the marker gene myogenic differentiation 1 (MYOD1), both increased significantly. Taken together, it is suggested that HDAC2 is most likely involved in a suppressive fashion in myoblast proliferation and may play a positive role in myoblast differentiation. The present results confirm the suggestion that HDAC2 is a functional gene for pre-hatch and post-hatch (fast growing muscle) development of chicken skeletal muscle. PMID- 26949949 TI - Effects of Steroid Hormone in Avian Follicles. AB - The aim of the present study was to examine the effects of testosterone (T) and estradiol-17beta (E2) on the production of progesterone (P4) by granulosa cells, and of the E2 on the production of P4 and T by theca internal cells. In the first experiment, granulosa cells isolated from the largest (F1) and third largest (F3) preovulatory follicle were incubated for 4 h in short-term culture system, P4 production by granulosa cells of both F1 and F3 was increased in a dose-dependent manner by ovine luteinizing hormone (oLH), but not T or E2. In the second experiment, F1 and F3 granulosa cells cultured for 48 h in the developed monolayer culture system were recultured for an additional 48 h with increasing doses of various physiological active substances existing in the ovary, including T and E2. Basal P4 production for 48 h during 48 to 96 h of the cultured was about nine fold greater by F1 granulosa cells than by F3 granulosa cells. In substances examined oLH, chicken vasoactive intestinal polypeptide (cVIP) and T, but not E2, stimulated in a dose-dependent manner P4 production in both F1 and F3 granulosa cells. In addition, when the time course of P4 production by F1 granulosa cells in response to oLH, cVIP, T and E2 was examined for 48 h during 48 to 96 h of culture, although E2 had no effect on P4 production by granulosa cells of F1 during the period from 48 to 96 h of culture, P4 production with oLH was found to be increased at 4 h of the culture, with a maximal 9.14 fold level at 6 h. By contrast, P4 production with cVIP and T increased significantly (p<0.05) from 8 and 12 h of the culture, respectively, with maximal 6.50 fold response at 12 h and 6, 48 fold responses at 36 h. Furthermore, when F1 granulosa cells were precultured with E2 for various times before 4 h culture with oLH at 96 h of culture, the increase in P4 production in response to oLH with a dose related manner was only found at a pretreatment time of more than 12 h. In the third experiment, theca internal cells of F1, F2 and the largest third to fifth preovulatory follicles (F3-5) were incubated for 4 h in short-term culture system with increasing doses of E2. The production of P4 and T by theca internal cells were increased with the addition of E2 of 10(-6) M. These increases were greater in smaller follicles. These results indicate that, in granulosa cells of the hen, T may have a direct stimulatory action in the long term on P4 production, and on E2 in long-term action which may enhance the sensitivity to LH for P4 production, and thus, in theca internal cells, E2 in short term action may stimulate the production of P4 and T. PMID- 26949950 TI - Effects of Momordica charantia Saponins on In vitro Ruminal Fermentation and Microbial Population. AB - This study was conducted to investigate the effects of Momordica charantia saponin (MCS) on ruminal fermentation of maize stover and abundance of selected microbial populations in vitro. Five levels of MCS supplements (0, 0.01, 0.06, 0.30, 0.60 mg/mL) were tested. The pH, NH3-N, and volatile fatty acid were measured at 6, 24, 48 h of in vitro mixed incubation fluids, whilst the selected microbial populations were determined at 6 and 24 h. The high dose of MCS increased the initial fractional rate of degradation at t-value = 0 (FRD0) and the fractional rate of gas production (k), but decreased the theoretical maximum of gas production (V F) and the half-life (t0.5) compared with the control. The NH3-N concentration reached the lowest concentration with 0.01 mg MCS/mL at 6 h. The MSC inclusion increased (p<0.001) the molar proportion of butyrate, isovalerate at 24 h and 48 h, and the molar proportion of acetate at 24 h, but then decreased (p<0.05) them at 48 h. The molar proportion of valerate was increased (p<0.05) at 24 h. The acetate to propionate ratio (A/P; linear, p<0.01) was increased at 24 h, but reached the least value at the level of 0.30 mg/mL MCS. The MCS inclusion decreased (p<0.05) the molar proportion of propionate at 24 h and then increased it at 48 h. The concentration of total volatile fatty acid was decreased (p<0.001) at 24 h, but reached the greatest concentration at the level of 0.01 mg/mL and the least concentration at the level of 0.60 mg/mL. The relative abundance of Ruminococcus albus was increased at 6 h and 24 h, and the relative abundance of Fibrobacter succinogenes was the lowest (p<0.05) at 0.60 mg/mL at 6 h and 24 h. The relative abundance of Butyrivibrio fibrisolvens and fungus reached the greatest value (p<0.05) at low doses of MCS inclusion and the least value (p<0.05) at 0.60 mg/mL at 24 h. The present results demonstrates that a high level of MCS quickly inhibits in vitro fermentation of maize stover, while MCS at low doses has the ability to modulate the ruminal fermentation pattern by regulating the number of functional rumen microbes including cellulolytic bacteria and fungi populations, and may have potential as a feed additive applied in the diets of ruminants. PMID- 26949951 TI - Effect of Feeding Date Pits on Milk Production, Composition and Blood Parameters of Lactating Ardi Goats. AB - Twenty Ardi lactating goats were used to investigate the effect of substituting 10%, 15%, and 20% of concentrate feed with date pits on milk production, composition, and blood parameters. Four isocaloric and isonitrogenous dietary treatments were used. Four levels (0% [control], 10%, 15%, and 20%) of date pits were used to replace concentrate feed. The forages to concentrate ratio used was 60 to 40. Dry matter intake (DMI) of goats fed diets containing 10% and 15% date pits was significantly (p<0.05) higher than those fed diets containing 0% and 20%. However, goats fed a diet containing 20% date pits were significantly (p<0.05) lower in DMI compared to those fed control diet. The protein percent was significantly higher for goats fed control diet compared to the other dietary treatments. Total solids percent was significantly the lowest for goats fed diet supplemented with 10% date pits. Goats fed a diet containing 20% date pits was significantly (p<0.05) higher in the total protein compared to those fed a diet containing 10%. In addition, goats fed a diet containing 15% date pits exhibited no significant differences in the total protein percent compared to those fed a diet containing 20% date pits. Triglyceride was significantly higher for goats fed diets containing 10% and 20% date pits compared to those fed 15% date pits. Results obtained in the present study suggest that date pits can be added up to 20% of the concentrate feeds into lactating Ardi goat diets without negative effects on their productive performance. PMID- 26949952 TI - Lactic Acid Bacteria in Total Mixed Ration Silage Containing Soybean Curd Residue: Their Isolation, Identification and Ability to Inhibit Aerobic Deterioration. AB - We investigated the effects of the predominant lactic acid bacteria (LAB) on the fermentation characteristics and aerobic stability of total mixed ration (TMR) silage containing soybean curd residue (SC-TMR silage). The SC-TMR materials were ensiled in laboratory silos for 14 or 56 days. LAB predominant in SC-TMR silage were identified (Exp. 1). Lactobacillus fermentum (L. fermentum) and Streptococcus bovis (S. bovis) were found in the untreated materials, Leuconostoc pseudomesenteroides (L. pseudomesenteroides) in 14-day silage and Lactobacillus plantarum (L. plantarum) in all silages. Pediococcus acidilactici (P. acidilactici), Lactobacillus paracasei (L. paracasei), and Lactobacillus brevis (L. brevis) formed more than 90% of the isolates in 56-day silage. Italian ryegrass and whole crop maize were inoculated with P. acidilactici and L. brevis isolates and the fermentation and aerobic stability determined (Exp. 2). Inoculation with P. acidilactici and L. brevis alone or combined improved the fermentation products in ryegrass silage and markedly enhanced its aerobic stability. In maize silage, P. acidilactici and L. brevis inoculation caused no changes and suppressed deterioration when combined with increases in acetic acid content. The results indicate that P. acidilactici and L. brevis may produce a synergistic effect to inhibit SC-TMR silage deterioration. Further studies are needed to identify the inhibitory substances, which may be useful for developing potential antifungal agents. PMID- 26949953 TI - Effects of Rice Straw Supplemented with Urea and Molasses on Intermediary Metabolism of Plasma Glucose and Leucine in Sheep. AB - An isotope dilution method using [U-(13)C]glucose and [1-(13)C]leucine (Leu) was conducted to evaluate the effects of rice straw supplemented with urea and molasses (RSUM-diet) on plasma glucose and Leu turnover rates in sheep. Nitrogen (N) balance, rumen fermentation characteristics and blood metabolite concentrations were also determined. Four sheep were fed either mixed hay (MH diet), or a RSUM-diet with a crossover design for two 21 days period. Feed allowance was computed on the basis of metabolizable energy at maintenance level. The isotope dilution method was performed as the primed-continuous infusion on day 21 of each dietary period. Nitrogen intake was lower (p = 0.01) for the RSUM diet and N digestibility did not differ (p = 0.57) between diets. Concentrations of rumen total volatile fatty acids tended to be higher (p = 0.09) for the RSUM diet than the MH-diet. Acetate concentration in the rumen did not differ (p = 0.38) between diets, whereas propionate concentration was higher (p = 0.01) for the RSUM-diet compared to the MH-diet. Turnover rates as well as concentrations of plasma glucose and Leu did not differ between diets. It can be concluded that kinetics of plasma glucose and Leu metabolism were comparable between the RSUM diet and the MH-diet, and rumen fermentation characteristics were improved in sheep fed the RSUM-diet compared to the MH-diet. PMID- 26949954 TI - Characteristics of Wet Distillers Grains on In vitro Ruminal Fermentation and Its Effects on Performance and Carcass Characteristics of Finishing Hanwoo Steers. AB - Two experiments were conducted to determine the nutrient composition, in vitro ruminal ammonia concentrations and pH of wet distillers grains (WDG, produced from tapioca 70% and rice 30%) and to evaluate dietary effects of fermented total mixed ration (TMR) using WDG on the performance, blood metabolites and carcass characteristics of Hanwoo steers from mid fattening to slaughter. In Exp. I, average dry matter (DM), crude protein, ether extract, crude fiber, ash, neutral detergent fiber, acid detergent fiber, and nitrogen free extract of seven WDG samples from an ethanol plant with different sampling dates were 19.9%, 24.8%, 3.8%, 21.8%, 8.87%, 60.3%, 34.5%, and 40.7% (DM basis), respectively. For in vitro ammonia concentrations and pH, each sample was assigned to 7 incubation times (0, 4, 8, 12, 24, 48, and 72 h). Linear increase was observed between 12 and 48 h for ammonia concentrations, but final ammonia concentrations (72 h) were not significantly different among WDG samples and fermentation patterns of WDG samples showed similar tendency. In vitro pH varied among treatments from 0 to 24 h, but were not different statistically after 48 h. In Exp. II, 45 Hanwoo steers of 23 months (641+/-123 kg) from mid fattening period to slaughter (248 days) were randomly divided into three groups of 15 pens each (five repetitions/each treatment) and assigned to one of three dietary treatments; i) Control (TMR), ii) WDG 15 (TMR containing 15% of WDG, as fed basis) and iii) WDG 28 (TMR containing 28% of WDG, as fed basis). The body weight (BW), ADG, and feed conversion ratio (FCR) of control and WDG 15 and 28 during 248 days were 760.8, 740.1, and 765.5 kg, and 0.50, 0.50, and 0.52 kg/d, and 18.6, 17.6, and 17.1, respectively. The dry matter intake (DMI) (kg/d) of control (9.11) was higher (p<0.05) than WDG treatments (WDG 15%, 8.57; 28%, 8.70). Nevertheless, DMI did not affect BW, ADG, and FCR of Hanwoo finishing steers. Blood metabolites were in normal ranges and were not different among treatments except the albumin concentration. In carcass characteristics, WDG 15 (30%) showed higher frequency of A-carcass yield grade than WDG 28 (15%) and control (7%), and WDG 28 (61%) showed higher frequency of 1(++) and 1(+)-carcass quality grade than WDG 15 (40%) and control (60%). In conclusion, using WDG up to 28% in TMR did not show any negative effect on the performance and blood metabolites, and improved carcass quality of Hanwoo steers. Therefore, WDG can be a useful feed ingredient for Hanwoo steers in mid-fattening period to slaughter. PMID- 26949955 TI - Influence of Palm Kernel Meal Inclusion and Exogenous Enzyme Supplementation on Growth Performance, Energy Utilization, and Nutrient Digestibility in Young Broilers. AB - The objective of the present study was to investigate the influence of palm kernel meal (PKM) inclusion and exogenous enzyme supplementation on growth performance, nitrogen-corrected apparent metabolizable energy (AMEn), coefficient of apparent ileal digestibility (CAID) and total tract retention of nutrients in young broilers fed corn-based diets. Four inclusion levels of PKM (no PKM [PKM0], 8% [PKM8], 16% [PKM16], and 24% [PKM24]) and two enzyme additions were evaluated in a 4*2 factorial arrangement of treatments. A total of 384, one-d-old male broilers (Ross 308) were individually weighed and allocated to 48 cages (eight broilers/cage), and cages were randomly assigned to eight dietary treatments. Results indicated that the inclusion of 8% and 16% PKM increased (p<0.05) the weight gain compared to the PKM0 diet. Birds fed the PKM8 diets had the highest (p<0.05) feed intake. Weight gain and feed intake were severely reduced (p<0.05) by feeding the PKM24 diet. Enzyme supplementation increased weight gain (p<0.05), independent of PKM inclusion level. In PKM0 and PKM8 diets, enzyme addition significantly (p<0.05) lowered feed conversion ratio (FCR); whereas enzyme addition had no effect on FCR of birds fed PKM16 and PKM24 diets. In PKM0 and PKM16 diets, enzyme addition significantly (p<0.05) increased CAID of nitrogen and energy but had no effect in the PKM8 and PKM24 diets. Inclusion of PKM into the basal diet, irrespective of inclusion level, enhanced (p<0.05) starch and fat digestibility. Inclusion of PKM at 16% and 24% resulted in similar CAID of neutral detergent fiber (NDF) but higher (p<0.05) than that of the PKM0 and PKM8 diets. Enzyme addition, regardless of the level of PKM inclusion, significantly (p<0.05) increased CAID of NDF. There was a significant (p<0.05) decrease in AMEn with PKM inclusion of 24%. The present data suggest that inclusion of PKM in broiler diets could be optimized if PKM-containing diets are formulated based on digestible amino acid contents and supplemented with exogenous enzymes. If amino acid digestibility and AME of PKM considered in the formulation, it can be included in broiler diets up to 16% with no deleterious effects on growth performance. PMID- 26949956 TI - Growth Performance, Relative Meat and Organ Weights, Cecal Microflora, and Blood Characteristics in Broiler Chickens Fed Diets Containing Different Nutrient Density with or without Essential Oils. AB - The present study was conducted to investigate whether dietary essential oils could affect growth performance, relative organ weights, cecal microflora, immune responses and blood profiles of broiler chickens fed on diets containing different nutrient densities. A total of eight hundred-forty 1-d-old male broiler chicks were randomly allotted into twenty-eight pens (7 pens per treatment, 30 chicks per pen). There were four experimental diets containing two different nutrient densities and supplemented with or without essential oils. Experimental period lasted for 35 days. No clear interaction between nutrient density and essential oils on any of growth performance-related parameters was observed. Live body weights were affected (p<0.05) by nutrient density at 21 days and by dietary essential oils at 35 days. Essential oils significantly (p<0.05) increased daily body weight gain and feed conversion ratio during the periods of 22 to 35 and 1 to 35 days, but failed to affect feed intake during the entire experimental period. Daily weight gain at 1 to 21 days and feed intake at 1 to 21 and 1 to 35 days were significantly impaired (p<0.05) by nutrient density. There were significant treatment interactions (p<0.05) on relative weights of bursa of Fabricius and abdominal fat contents. Finally, either essential oil or nutrient density did not influence the relative percentages of breast and leg meats, the population of cecal microflora, blood parameters and antibody titers against Newcastle disease and infectious bronchitis in broiler chickens. It was concluded that dietary essential oils, independent to nutrient density, failed to stimulate feed intake, but increased growth performance in broiler chickens. PMID- 26949957 TI - Effects of Feeding Purple Rice (Oryza sativa L. Var. Glutinosa) on the Quality of Pork and Pork Products. AB - Purple rice is a strain of glutaneous rice rich in anthocyanins and gamma oryzanol. Both types of compounds are involved in antioxidant and lipid metabolism of mammals. Three experimental diet types were used which consisted approximately by half either of purple rice, white rice or corn. Diets were fed to 3*10 pigs growing from about 30 to 100 kg. Meat samples were investigated either as raw or cured loin chops or as smoked bacon produced from the belly. Various physicochemical traits were assessed and data were evaluated by analysis of variance. Traits describing water-holding capacity (drip, thaw, and cooking losses) and tenderness (sensory grading, shear force) of the meat were mostly not significantly affected by the diet type. However, purple rice feeding of pigs resulted in lower fat and cholesterol contents of loin and smoked bacon compared to white rice, but not compared to corn feeding except of the fat content of the loin. The shelf life of the raw loin chops was improved by purple rice as well. In detail, the occurrence of thiobarbituric acid reactive substances after 9 days of chilled storage was three to four times higher in the white rice and corn diets than with purple rice. The n-6:n-3 ratio in the raw loin chops was 9:1 with purple rice and clearly higher with 12:1 with the other diets, meat lipids. Level and kind of effect of purple rice found in raw meat was not always recovered in the cured loin chops and the smoked bacon. Still the impression of flavor and color, as well as overall acceptability were best in the smoked bacon from the purple-rice fed pigs, whereas this effect did not occur in the cured loin chops. These findings suggest that purple rice has a certain, useful, bioactivity in pigs concerning meat quality, but some of these effects are of low practical relevance. Further studies have to show ways how transiency and low recovery in meat products of some of the effects can be counteracted. PMID- 26949958 TI - Generation of Fibroblasts Lacking the Sal-like 1 Gene by Using Transcription Activator-like Effector Nuclease-mediated Homologous Recombination. AB - The Sal-like 1 gene (Sall1) is essential for kidney development, and mutations in this gene result in abnormalities in the kidneys. Mice lacking Sall1 show agenesis or severe dysgenesis of the kidneys. In a recent study, blastocyst complementation was used to develop mice and pigs with exogenic organs. In the present study, transcription activator-like effector nuclease (TALEN)-mediated homologous recombination was used to produce Sall1-knockout porcine fibroblasts for developing knockout pigs. The vector targeting the Sall1 locus included a 5.5 kb 5' arm, 1.8-kb 3' arm, and a neomycin resistance gene as a positive selection marker. The knockout vector and TALEN were introduced into porcine fibroblasts by electroporation. Antibiotic selection was performed over 11 days by using 300 MUg/mL G418. DNA of cells from G418-resistant colonies was amplified using polymerase chain reaction (PCR) to confirm the presence of fragments corresponding to the 3' and 5' arms of Sall1. Further, mono- and bi-allelic knockout cells were isolated and analyzed using PCR-restriction fragment length polymorphism. The results of our study indicated that TALEN-mediated homologous recombination induced bi-allelic knockout of the endogenous gene. PMID- 26949959 TI - Development of a Novel, Anti-idiotypic Monoclonal Anti-prolactin Antibody That Mimics the Physiological Functions of Prolactin. AB - In this work, we prepared a panel of monoclonal anti-idiotypic antibodies to ovine prolactin (oPRL) by the hybridoma technique. Among these antibodies, one anti-idotypic antibody (designated B7) was chosen for further characterization by a series of experiments. We first demonstrated that B7 behaved as a typical Ab2beta based on a series of enzyme-linked immunosorbent assays. Subsequently, the results of a competitive receptor-binding assay confirmed that B7 could specifically bind to the prolactin receptor (PRLR) expressed on target cells. Finally, we examined its biological activities in CHO-PRLR and Nb2 cells and observed that B7 could activate Janus kinase 2-signal transducer and activator of transcription signalling in CHO-PRLR and Nb2 cells and induce BaF3 proliferation. The present study suggests that i) B7 can serve as a PRLR agonist or PRL mimic and has potential applications in regulating mammary gland development, milk production and maintenance of lactation in domestic animals and ii) B7 may be a biological reagent that can be used to explore the mechanism of PRLR-mediated intracellular signalling. PMID- 26949960 TI - Factors in Dry Period Associated with Intramammary Infection and Subsequent Clinical Mastitis in Early Postpartum Cows. AB - The objective of this study was to determine cow characteristics and farm management factors during the dry period associated with early postparturient intramammary infection (IMI) and subsequent clinical mastitis (CM). Data were collected three times: before drying off (P1), during the dry period (P2), and 5 to 14 days after calving (P3), using questionnaires and farm investigation. Milk samples were aseptically collected for bacterial identification at P1 and P3. Factors associated with IMI and CM were analyzed using multiple logistic regression models. The final model showed that IMI in early postpartum was significantly associated with full insertion of dry cow antibiotic, dry cows in barns with a combination of tie and free stalls, body condition score (BCS) in dry period and after calving, and milk yield before drying off. For IMI cows, factors significantly associated with clinical expression of mastitis were having daily barn cleaning, teat disinfected with alcohol before administration of dry cow therapy, BCS before drying off, milk yield before drying off, and days in milk at drying off. In conclusion, both cow and farm management factors are associated with the IMI rate and subsequent expression of clinical signs of mastitis in early postpartum cows. PMID- 26949961 TI - Isolation and Characterization of a New Methanobacterium formicicum KOR-1 from an Anaerobic Digester Using Pig Slurry. AB - A new methanogen was isolated from an anaerobic digester using pig slurry in South Korea. Only one strain, designated KOR-1, was characterized in detail. Cells of KOR-1 were straight or crooked rods, non-motile, 5 to 15 MUm long and 0.7 MUm wide. They stained Gram-positive and produced methane from H2+CO2 and formate. Strain KOR-1 grew optimally at 38 degrees C. The optimum pH for growth was 7.0. The strain grew at 0.5% to 3.0% NaCl, with optimum growth at 2.5% NaCl. The G+C content of genomic DNA of strain KOR-1 was 41 mol%. The strain tolerated ampicillin, penicillin G, kanamycin and streptomycin but tetracycline inhibited cell growth. A large fragment of the 16S rRNA gene (~1,350 bp) was obtained from the isolate and sequenced. Comparison of 16S rRNA genes revealed that strain KOR 1 is related to Methanobacterium formicicum (98%, sequence similarity), Methanobacterium bryantii (95%) and Methanobacterium ivanovii (93%). Phylogenetic analysis of the deduced mcrA gene sequences confirmed the closest relative as based on mcrA gene sequence analysis was Methanobacterium formicicum strain (97% nucleic acid sequence identity). On the basis of physiological and phylogenetic characteristics, strain KOR-1 is proposed as a new strain within the genus Methanobacterium, Methanobacterium formicicum KOR-1. PMID- 26949962 TI - Characterization of Odorant Compounds from Mechanical Aerated Pile Composting and Static Aerated Pile Composting. AB - We studied airborne contaminants (airborne particulates and odorous compounds) emitted from compost facilities in South Korea. There are primarily two different types of composting systems operating in Korean farms, namely mechanical aerated pile composting (MAPC) and aerated static pile composting (SAPC). In this study, we analyzed various particulate matters (PM10, PM7, PM2.5, PM1, and total suspended particles), volatile organic compounds and ammonia, and correlated these airborne contaminants with microclimatic parameters, i.e., temperature and relative humidity. Most of the analyzed airborne particulates (PM7, PM2.5, and PM1) were detected in high concentration at SAPC facilities compered to MAPC; however these differences were statistically non-significant. Similarly, most of the odorants did not vary significantly between MAPC and SAPC facilities, except for dimethyl sulfide (DMS) and skatole. DMS concentrations were significantly higher in MAPC facilities, whereas skatole concentrations were significantly higher in SAPC facilities. The microclimate variables also did not vary significantly between MAPC and SAPC facilities, and did not correlate significantly with most of the airborne particles and odorous compounds, suggesting that microclimate variables did not influence their emission from compost facilities. These findings provide insight into the airborne contaminants that are emitted from compost facilities and the two different types of composting agitation systems. PMID- 26949963 TI - Characteristics of Rice Hulls, Sawdust, Wood Shavings and Mixture of Sawdust and Wood Shavings, and Their Usefulness According to the Pen Location for Hanwoo Cattle. AB - In this study, two experiments were conducted to investigate the physicochemical characteristics (Exp. I) of bedding materials such as rice hulls (RH), sawdust (SD), wood shavings (WS) and sawdust+wood shavings (S+W; 1:1 in volume), and utilization of these beddings except RH (Exp. II) for rearing beef cattle. In Exp. I, the distribution of particle size (%) with 250 MUm and below 250 MUm was greater (p<0.05) in SD (30.4) than RH (4.4), WS (18.8) and S+W (20.1). Bulk density (kg/m(3)) of bedding materials was directly proportional to the percentage of 250 MUm and below 250 MUm particles, 178, 46, 112, and 88 for SD, WD, S+W and RH, respectively. Water absorption rate (%) after submersion in water for 24 h was higher (p<0.05) in WS (540.2) compared to SD (270.2), S+W (368.2). The S+W had an intermediate value of the absorption rate between SD and WS, but had an outstanding durability of water absorption capacity. Moisture evaporation rate (%) for 12 h was higher (p<0.05) in WS (75.4) than SD (70.5), S+W (72.2) and RH (57.8). Average ammonia emission (mg/m(2)/h) for 36 h was higher (p<0.05) in RH (3.15) than SD (1.70), WS (1.63), and S+W (1.73). In Exp. II, thirty six Hanwoo cows were allocated in 9 pens with one side on feed bunk side (Side A) and another side equipped with water supply (Side B) for 3 weeks with duplicated periods. Average moisture concentrations (%) of beddings were higher (p<0.05) in WS (side A, 65.7; side B, 57.9) than SD (side A, 62.5; side B, 52.2) and S+W (side A, 61.6; side B, 50.7). Regardless of types of beddings, moisture concentrations (%) of beddings within a pen were lower (p<0.05) at side B than A, implying longer period of utilization. These results suggest that using S+W would be a better choice than SD or WS alone, considering physicochemical characteristics and economics, and RH is not a suitable material as a bedding for beef cattle. PMID- 26949964 TI - Effect of Acacia catechu (L.f.) Willd. on Oxidative Stress with Possible Implications in Alleviating Selected Cognitive Disorders. AB - In human body, several categories of degenerative processes are largely determined by free radicals originating in cell. Free radicals are also known to have correlated with a variety of cognitive disorders (CDs) resulting in neuronal injury and eventually to death. Alzheimer's disease (AD) and Parkinson's disease (PD) are such kind of killer CDs that occur due to dysfunction of cholinergic and dopaminergic neurons. Plant parts of Ginkgo biloba, Bacopa monnieri etc. are being used for the treatment of cognitive disorders in several countries. The present study was aimed to explore the detailed antioxidant and anti cholinesterase activity of Acaciacatechu leaf (ACL) over CDs. Gas chromatography Mass spectroscopy (GC-MS) analysis and Nuclear Magnetic Resonance (NMR) were employed to identify the bioactive components present in ACL. Furthermore, the extract was evaluated to check the cytotoxic effects of ACL on normal cells. Amongst several antioxidant assays, DPPH assay, hydroxyl radical, nitric oxide radical and hypochlorous acid inhibitory activities were found to be greater in ACL than that of the respective standards while other assays exhibited a moderate or at per inhibitory activity with standards. Total phenolic and flavonoid content were also found to be present in decent amount. In addition, we found, a greater acetylcholinesterase (AChE) inhibitory activity of ACL when compared to other medicinally important plants, indicating its positive effect over CDs. Forty one bioactive components were explored through GC-MS. Of these, gallic acid, epicatechin, catechin, isoquercitrin etc. were found, which are potent antioxidant and a few of them have anti-neurodegenerative properties. Eventually, ACL was found to be nontoxic and safer to consume. Further studies with animal or human model however, would determine its efficacy as a potential anti schizophrenic drug. PMID- 26949965 TI - Correction: HER2 Phosphorylation Is Maintained by a PKB Negative Feedback Loop in Response to Anti-HER2 Herceptin in Breast Cancer. PMID- 26949966 TI - Polysomnographic Characteristics of Sleep in Stroke: A Systematic Review and Meta Analysis. AB - BACKGROUND: Research on sleep after stroke has focused mainly on sleep disordered breathing. However, the extend to which sleep physiology is altered in stroke survivors, how these alterations compare to healthy volunteers, and how sleep changes might affect recovery as well as physical and mental health has yet to be fully researched. Motivated by the view that a deeper understanding of sleep in stroke is needed to account for its role in health and well-being as well as its relevance for recovery and rehabilitation, we conducted a systematic review and meta-analysis of polysomnographic studies comparing stroke to control populations. METHOD: Medline and PsycInfo databases were searched using "stroke" and words capturing polysomnographic parameters as search terms. This yielded 1692 abstracts for screening, with 15 meeting the criteria for systematic review and 9 for meta-analysis. Prisma best practice guidelines were followed for the systematic review; the Comprehensive Meta-Analysis software was used for random effects modelling. RESULTS: The meta-analysis revealed that patients with stroke have poorer sleep than controls. Patients had lower sleep efficiency (mean 75% vs 84%), shorter total-sleep-time (309.4 vs 340.3 min) and more wake-after-sleep onset (97.2 vs 53.8 min). Patients also spend more time in stage 1 (13% vs 10%) and less time in stage 2 sleep (36% vs 45%) and slow-wave-sleep (10% vs 12%). No group differences were identified for REM sleep. The systematic review revealed a strong bias towards studies in the early recovery phase of stroke, with no study reporting specifically on patients in the chronic state. Moreover, participants in the control groups included community samples as well as other patients groups. CONCLUSIONS: These results indicate poorer sleep in patients with stroke than controls. While strongly suggestive in nature, the evidence base is limited and methodologically diverse, and hands a clear mandate for further research. A particular need regards polysomnographic studies in chronic community-dwelling patients compared to age-matched individuals. PMID- 26949967 TI - First Microsatellite Markers Developed from Cupuassu ESTs: Application in Diversity Analysis and Cross-Species Transferability to Cacao. AB - The cupuassu tree (Theobroma grandiflorum) (Willd. ex Spreng.) Schum. is a fruitful species from the Amazon with great economical potential, due to the multiple uses of its fruit's pulp and seeds in the food and cosmetic industries, including the production of cupulate, an alternative to chocolate. In order to support the cupuassu breeding program and to select plants presenting both pulp/seed quality and fungal disease resistance, SSRs from Next Generation Sequencing ESTs were obtained and used in diversity analysis. From 8,330 ESTs, 1,517 contained one or more SSRs (1,899 SSRs identified). The most abundant motifs identified in the EST-SSRs were hepta- and trinucleotides, and they were found with a minimum and maximum of 2 and 19 repeats, respectively. From the 1,517 ESTs containing SSRs, 70 ESTs were selected based on their functional annotation, focusing on pulp and seed quality, as well as resistance to pathogens. The 70 ESTs selected contained 77 SSRs, and among which, 11 were polymorphic in cupuassu genotypes. These EST-SSRs were able to discriminate the cupuassu genotype in relation to resistance/susceptibility to witches' broom disease, as well as to pulp quality (SST/ATT values). Finally, we showed that these markers were transferable to cacao genotypes, and that genome availability might be used as a predictive tool for polymorphism detection and primer design useful for both Theobroma species. To our knowledge, this is the first report involving EST-SSRs from cupuassu and is also a pioneer in the analysis of marker transferability from cupuassu to cacao. Moreover, these markers might contribute to develop or saturate the cupuassu and cacao genetic maps, respectively. PMID- 26949968 TI - Intracerebellar infusion of the protein kinase M zeta (PKMzeta) inhibitor zeta inhibitory peptide (ZIP) disrupts eyeblink classical conditioning. AB - Protein kinase M zeta (PKM-zeta), a constitutively active N-terminal truncated form of PKC-zeta, has long been implicated in a cellular correlate of learning, long-term potentiation (LTP). Inhibition of PKM-zeta with zeta-inhibitory peptide (ZIP) has been shown in many brain structures to disrupt maintenance of AMPA receptors, irreversibly disrupting numerous forms of learning and memory that have been maintained for weeks. Delay eyeblink conditioning (EBC) is an established model for the assessment of cerebellar learning; here, we show that PKC-zeta and PKM-zeta are highly expressed in the cerebellar cortex, with highest expression found in Purkinje cell (PC) nuclei. Despite being highly expressed in the cerebellar cortex, no studies have examined how regulation of cerebellar PKM zeta may affect cerebellar-dependent learning and memory. Given its disruption of learning in other brain structures, we hypothesized that ZIP would also disrupt delay EBC. We have shown that infusion of ZIP into the lobulus simplex of the rat cerebellar cortex can indeed significantly disrupt delay EBC. (PsycINFO Database Record PMID- 26949969 TI - Prevalence and predictors of hospital prealerting in acute stroke: a mixed methods study. AB - BACKGROUND: Thrombolysis can significantly reduce the burden of stroke but the time window for safe and effective treatment is short. In patients travelling to hospital via ambulance, the sending of a 'prealert' message can significantly improve the timeliness of treatment. OBJECTIVE: Examine the prevalence of hospital prealerting, the extent to which prealert protocols are followed and what factors influence emergency medical services (EMS) staff's decision to send a prealert. METHODS: Cohort study of patients admitted to two acute stroke units in West Midlands (UK) hospitals using linked data from hospital and EMS records. A logistic regression model examined the association between prealert eligibility and whether a prealert message was sent. In semistructured interviews, EMS staff were asked about their experiences of patients with suspected stroke. RESULTS: Of the 539 patients eligible for this study, 271 (51%) were recruited. Of these, only 79 (29%) were eligible for prealerting according to criteria set out in local protocols but 143 (53%) were prealerted. Increasing number of Face, Arm, Speech Test symptoms (1 symptom, OR 6.14, 95% CI 2.06 to 18.30, p=0.001; 2 symptoms, OR 31.36, 95% CI 9.91 to 99.24, p<0.001; 3 symptoms, OR 75.84, 95% CI 24.68 to 233.03, p<0.001) and EMS contact within 5 h of symptom onset (OR 2.99, 95% CI 1.37 to 6.50 p=0.006) were key predictors of prealerting but eligibility for prealert as a whole was not (OR 1.92, 95% CI 0.85 to 4.34 p=0.12). In qualitative interviews, EMS staff displayed varying understanding of prealert protocols and described frustration when their interpretation of the prealert criteria was not shared by ED staff. CONCLUSIONS: Up to half of the patients presenting with suspected stroke in this study were prealerted by EMS staff, regardless of eligibility, resulting in disagreements with ED staff during handover. Aligning the expectations of EMS and ED staff, perhaps through simplified prealert protocols, could be considered to facilitate more appropriate use of hospital prealerting in acute stroke. PMID- 26949970 TI - Understanding the value of mixed methods research: the Children's Safety Initiative-Emergency Medical Services. AB - Mixed methods research has significant potential to broaden the scope of emergency care and specifically emergency medical services investigation. Mixed methods studies involve the coordinated use of qualitative and quantitative research approaches to gain a fuller understanding of practice. By combining what is learnt from multiple methods, these approaches can help to characterise complex healthcare systems, identify the mechanisms of complex problems such as medical errors and understand aspects of human interaction such as communication, behaviour and team performance. Mixed methods approaches may be particularly useful for out-of-hospital care researchers because care is provided in complex systems where equipment, interpersonal interactions, societal norms, environment and other factors influence patient outcomes. The overall objectives of this paper are to (1) introduce the fundamental concepts and approaches of mixed methods research and (2) describe the interrelation and complementary features of the quantitative and qualitative components of mixed methods studies using specific examples from the Children's Safety Initiative-Emergency Medical Services (CSI-EMS), a large National Institutes of Health-funded research project conducted in the USA. PMID- 26949971 TI - Benefits of Silica Core-Shell Structures on the Temperature Sensing Properties of Er,Yb:GdVO4 Up-Conversion Nanoparticles. AB - We studied the temperature-dependent luminescence of GdVO4 nanoparticles co-doped with Er(3+) (1 mol %) and Yb(3+) (20 mol %) and determined their thermal sensing properties through the fluorescence intensity ratio (FIR) technique. We also analyzed how a silica coating, in a core-shell structure, affects the temperature sensing properties of this material. Spectra were recorded in the range of biological temperatures (298-343 K). The absolute sensitivity for temperature determination calculated for the core-shell nanoparticles is double the one calculated for bare nanoparticles, achieving a thermal resolution of 0.4 K. Moreover, silica-coated nanoparticles show good dispersibility in different solvents, such as water, DMSO, and methanol. Also, they show good luminescence stability without interactions with solvent molecules. Furthermore, we also observed that the silica coating shell prevents progressive heating of the nanoparticles during prolonged excitation periods with the 980 nm laser, preventing effects on their thermometric applications. PMID- 26949974 TI - Sorption and Interfacial Rheology Study of Model Asphaltene Compounds. AB - The sorption and rheological properties of an acidic polyaromatic compound (C5PeC11), which can be used to further our understanding of the behavior of asphaltenes, are determined experimentally. The results show that C5PeC11 exhibits the type of pH-dependent surface activity and interfacial shear rheology observed in C6-asphaltenes with a decrease in the interfacial tension concomitant with the elastic modulus when the pH increases. Surface pressure-area (Pi-A) isotherms show evidence of aggregation behavior and pi-pi stacking at both the air/water and oil/water interfaces. Similarly, interactions between adsorbed C5PeC11 compounds are evidenced through desorption experiments at the oil/water interface. Contrary to indigenous asphaltenes, adsorption is reversible, but desorption is slower than for noninteracting species. The reversibility enables us to create layers reproducibly, whereas the presence of interactions between the compounds enables us to mimic the key aspects of interfacial activity in asphaltenes. Shear and dilatational rheology show that C5PeC11 forms a predominantly elastic film both at the liquid/air and the liquid/liquid interfaces. Furthermore, a soft glassy rheology model (SGR) fits the data obtained at the liquid/liquid interface. However, it is shown that the effective noise temperature determined from the SGR model for C5PeC11 is higher than for indigenous asphaltenes measured under similar conditions. Finally, from a colloidal and rheological standpoint, the results highlight the importance of adequately addressing the distinction between the material functions and true elasticity extracted from a shear measurement and the apparent elasticity measured in dilatational-pendant drop setups. PMID- 26949975 TI - Large-Size Star-Shaped Conjugated (Fused) Triphthalocyaninehexaazatriphenylene. AB - Star-shaped triphthalocyaninehexaazatriphenylene 1 was synthesized via condensation between a new building block 1,2-diaminophthalocyanine and cyclohexanehexaone. Compound 1 represents the largest star-shaped phthalocyanine fused hexaazatriphenylene reported so far. This largely expanded phthalocyanine shows good solubility and has a strong tendency to aggregate both in solution and on the surface, indicating its potential as an active component in organic electronic devices. PMID- 26949976 TI - HTMD: High-Throughput Molecular Dynamics for Molecular Discovery. AB - Recent advances in molecular simulations have allowed scientists to investigate slower biological processes than ever before. Together with these advances came an explosion of data that has transformed a traditionally computing-bound into a data-bound problem. Here, we present HTMD, a programmable, extensible platform written in Python that aims to solve the data generation and analysis problem as well as increase reproducibility by providing a complete workspace for simulation based discovery. So far, HTMD includes system building for CHARMM and AMBER force fields, projection methods, clustering, molecular simulation production, adaptive sampling, an Amazon cloud interface, Markov state models, and visualization. As a result, a single, short HTMD script can lead from a PDB structure to useful quantities such as relaxation time scales, equilibrium populations, metastable conformations, and kinetic rates. In this paper, we focus on the adaptive sampling and Markov state modeling features. PMID- 26949977 TI - Extrathermodynamics: Varieties of Compensation Effect. AB - There are several types of the DeltaH compensation. Along with well-known phenomenon of the DeltaH - DeltaS compensation, two more types of the DeltaH - (DeltaS + RDelta ln Omega) compensation are observed in some series of systems. The nature of these phenomena is connected with the behavior of phase volume of systems, Omega. The role of other thermodynamic parameters, which describe series in manifestation of this or that types of the DeltaH compensation, is shown in light of molecular statistical mechanics. PMID- 26949978 TI - Dioxygen Reduction by a Pd(0)-Hydroquinone Diphosphine Complex. AB - A novel p-terphenyl diphosphine ligand was synthesized with a noninnocent hydroquinone moiety as the central arene (1-H). Pseudo-tetrahedral 4-coordinate Ni(0) and Pd(0)-quinone (2 and 3, respectively) complexes proved accessible by metalating 1-H with the corresponding M(OAc)2 precursors. O2 does not react with the Pd(0)-quinone species (3) and protonation occurs at the quinone moiety indicating that the coordinated oxidized quinonoid moiety prevents reactivity at the metal. A 2-coordinate Pd(0)-hydroquinone complex (4-H) was prepared using a one-pot metalation with Pd(II) followed by reduction. The reduced quinonoid moiety in 4-H shows metal-coupled reactivity with small molecules. 4-H was capable of reducing a variety of substrates including dioxygen, nitric oxide, nitrous oxide, 1-azido adamantane, trimethylamine n-oxide, and 1,4-benzoquinone quantitatively producing 3 as the Pd-containing reaction product. Mechanistic investigations of dioxygen reduction revealed that the reaction proceeds through a eta(2)-peroxo intermediate (Int1) at low temperatures followed by subsequent ligand oxidation at higher temperatures in a reaction that consumed half an equivalent of O2 and produced water as a final oxygenic byproduct. Control compounds with methyl protected phenolic moieties (4-Me), displaying a Ag(I) center incapable of O2 binding (7-H) or a cationic Pd-H motif (6-H) allowed for the independent examination of potential reaction pathways. The reaction of 4-Me with dioxygen at low temperature produces a species (8-Me) analogous to Int1 demonstrating that initial dioxygen activation is an inner sphere Pd-based process where the hydroquinone moiety only subsequently participates in the reduction of O2, at higher temperatures, by H(+)/e(-) transfers. PMID- 26949979 TI - Controlling Solution-Mediated Reaction Mechanisms of Oxygen Reduction Using Potential and Solvent for Aprotic Lithium-Oxygen Batteries. AB - Fundamental understanding of growth mechanisms of Li2O2 in Li-O2 cells is critical for implementing batteries with high gravimetric energies. Li2O2 growth can occur first by 1e(-) transfer to O2, forming Li(+)-O2(-) and then either chemical disproportionation of Li(+)-O2(-), or a second electron transfer to Li(+)-O2(-). We demonstrate that Li2O2 growth is governed primarily by disproportionation of Li(+)-O2(-) at low overpotential, and surface-mediated electron transfer at high overpotential. We obtain evidence supporting this trend using the rotating ring disk electrode (RRDE) technique, which shows that the fraction of oxygen reduction reaction charge attributable to soluble Li(+)-O2(-) based intermediates increases as the discharge overpotential reduces. Electrochemical quartz crystal microbalance (EQCM) measurements of oxygen reduction support this picture, and show that the dependence of the reaction mechanism on the applied potential explains the difference in Li2O2 morphologies observed at different discharge overpotentials: formation of large (~250 nm-1 MUm) toroids, and conformal coatings (<50 nm) at higher overpotentials. These results highlight that RRDE and EQCM can be used as complementary tools to gain new insights into the role of soluble and solid reaction intermediates in the growth of reaction products in metal-O2 batteries. PMID- 26949980 TI - Suitability of Soybean Meal from Insect-Resistant Soybeans for Broiler Chickens. AB - Benning(M) and Benning(MGH) are near-isogenic lines (NILs) of the soybean cultivar Benning, which contain insect-resistance quantitative trait loci (QTLs) from the soybean accession PI 229358. Benning(M) contains QTL-M, which confers antibiosis and antixenosis. In addition to QTL-M, Benning(MGH) contains QTL-G, which confers antibiosis, and QTL-H, which confers antixenosis. Soybean meal was produced from Benning and the NILs. Nutritional composition, digestible amino acid content, and nitrogen-corrected true metabolizable energy (TMEN) were equivalent among soybean meals. A 21-day broiler feeding trial was carried out to determine if the QTLs affect soybean meal quality. Weight gain and feed-to-gain ratio were evaluated. No biologically significant differences were detected for broilers fed Benning, Benning(M), and Benning(MGH). This demonstrates that soybean meal produced from the insect-resistant NILs is equivalent to soybean meal produced from their non-insect-resistant parent cultivar for broiler weight gain. PMID- 26949981 TI - Why Nature Chose Selenium. AB - The authors were asked by the Editors of ACS Chemical Biology to write an article titled "Why Nature Chose Selenium" for the occasion of the upcoming bicentennial of the discovery of selenium by the Swedish chemist Jons Jacob Berzelius in 1817 and styled after the famous work of Frank Westheimer on the biological chemistry of phosphate [Westheimer, F. H. (1987) Why Nature Chose Phosphates, Science 235, 1173-1178]. This work gives a history of the important discoveries of the biological processes that selenium participates in, and a point-by-point comparison of the chemistry of selenium with the atom it replaces in biology, sulfur. This analysis shows that redox chemistry is the largest chemical difference between the two chalcogens. This difference is very large for both one electron and two-electron redox reactions. Much of this difference is due to the inability of selenium to form pi bonds of all types. The outer valence electrons of selenium are also more loosely held than those of sulfur. As a result, selenium is a better nucleophile and will react with reactive oxygen species faster than sulfur, but the resulting lack of pi-bond character in the Se-O bond means that the Se-oxide can be much more readily reduced in comparison to S oxides. The combination of these properties means that replacement of sulfur with selenium in nature results in a selenium-containing biomolecule that resists permanent oxidation. Multiple examples of this gain of function behavior from the literature are discussed. PMID- 26949982 TI - Underexposure of Seniors to Heart Failure Drug Therapy. AB - BACKGROUND: Little is known about exposure to heart failure (HF) treatment among seniors with ischemic heart disease. OBJECTIVES: In a population of seniors, we: 1) estimated the association between age and exposure to HF drug therapy at 6, 12, 36 and 60 month intervals after HF diagnosis, and 2) determined the influence of the passage of time on exposure to drug therapy. METHODS: Using the Quebec provincial administrative databases, we conducted a population-based inception cohort study that included all individuals aged >= 65 with a first HF diagnosis between 2000 and 2009 and an ischemic heart disease diagnosis in the year before HF diagnosis. We assessed exposure to HF drug therapy and to drug therapy at target doses at 6, 12, 36 and 60 month intervals after HF diagnosis. Adjusted prevalence ratios (aPR) between age at diagnosis and exposure to drug therapy and the influence of time (6-month periods) were assessed using multivariate modified Poisson regressions. RESULTS: Among the 86,428 seniors, those who were older were less likely to be exposed to both HF drug therapy and drug therapy at target doses at each time point, than were the younger ones (aged 65-69). The aPRs for exposure to drug therapy for the 90+ age group were 0.64, 0.64, 0.56 and 0.53 at the 6, 12, 36 and 60 month intervals, respectively. After HF diagnosis, exposure increased by a maximum of 8% per 6-month period. CONCLUSION: Increasing age is associated with a decrease in exposure to drug therapy, with only slight improvement in exposure after HF diagnosis. PMID- 26949983 TI - Three new oxazoline alkaloids from Gymnotheca chinensis. AB - Three novel oxazoline alkaloids, 1-oxa-3-azaspiro [4.5] dec-2-ene-8-one (1), 1 oxa-3-azaspiro [4.5] dec-2, 6-diene-8-one (2), and 1-oxa-3-azaspiro [4.5] dec-10 methoxy-2, 6-diene-8-one (3) were isolated from the methanol extract of the whole plant of Gymnotheca chinensis. The chemical structures were established by means of spectroscopic analysis including one- and two-dimensional NMR spectroscopy. PMID- 26949984 TI - The fatigue effect of a simulated futsal match protocol on sprint performance and kinematics of the lower limbs. AB - This study aimed to investigate the fatigue effects induced by a futsal-specific protocol (FIRP) on sprint performance and the kinematics of the lower limbs. Twenty-one futsal players participated in this study and performed a protocol to simulate the futsal demands. At pre-protocol, half-time and post-protocol, the athletes performed 10-m sprints that were recorded for kinematic analysis. Continuous relative phase (CRP) was calculated to assess the inter-segmental coordination. In addition, vertical (KVERT) and leg (KLEG) stiffness were calculated. Analysis of variance (ANOVA) for repeated measures was used (P < 0.05). The main results showed that sprint time increased (P < 0.01) post protocol when compared to pre- and half-time conditions. Lower values of the step rate (P = 0.01) and higher values of the leg angular velocity (P = 0.02) were verified at the end of the FIRP. The CRP of thigh-leg and leg-foot and the stiffness did not change over the protocol. In addition, the high correlation of CRP between the conditions revealed no changes in coordination pattern. We concluded that futsal related-fatigue induced a decrement on sprint time, changing the kinematics of the lower limbs (decreasing step rate and increasing leg angular velocity). However, neither stiffness nor intersegment coordination during sprints was affected by fatigue. PMID- 26949985 TI - The cDNA Sequence of Two Hemocyanin Subunits from Red Swamp Crayfish Procambarus clarkii and their Responses to White Spot Syndrome Virus Infection. AB - Hemocyanin, the respiratory protein of crustaceans, participates in the innate immune defense in these organisms. We cloned two hemocyanin subunit genes (PcHc1 and PcHc2), by using a degenerate primer PCR and rapid amplification of cDNA ends (RACE) approach, from the hepatopancreas of red swamp crayfish Procambarus clarkii. The transcripts of these two subunits were only detected in the hepatopancreas by reverse transcriptase quantitative PCR (RT-qPCR) analysis. The neighbor-joining and maximum parsimony phylogenetic analyses indicated that PcHc2 associated with a clade belong to the alpha-type hemocyanins and PcHc1 associated with another clade belonging to the beta-type hemocyanins. The data obtained from the RT-qPCR indicated that the mRNA expression levels of these subunit genes followed almost the same regulation pattern in the crayfish challenged with white spot syndrome virus (WSSV). The fluctuation of mRNA expression levels of these two subunits after the WSSV challenge indicated that both of them may participate in the antiviral immune response of crayfish. Received April 12, 2015; accepted November 22, 2015. PMID- 26949986 TI - Dysgeusia #304. PMID- 26949988 TI - Identification of Differentially Expressed Genes in RNA-seq Data of Arabidopsis thaliana: A Compound Distribution Approach. AB - Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product, which may be proteins. A gene is declared differentially expressed if an observed difference or change in read counts or expression levels between two experimental conditions is statistically significant. To identify differentially expressed genes between two conditions, it is important to find statistical distributional property of the data to approximate the nature of differential genes. In the present study, the focus is mainly to investigate the differential gene expression analysis for sequence data based on compound distribution model. This approach was applied in RNA-seq count data of Arabidopsis thaliana and it has been found that compound Poisson distribution is more appropriate to capture the variability as compared with Poisson distribution. Thus, fitting of appropriate distribution to gene expression data provides statistically sound cutoff values for identifying differentially expressed genes. PMID- 26949987 TI - A repeat motif on a Coxiella effector protein facilitates apoptosis inhibition. PMID- 26949990 TI - Infection in cystic fibrosis: impact of the environment and climate. AB - In many countries numbers of adults with cystic fibrosis (CF) exceed that of children, with median survival predicted to surpass 50 years. Increasing longevity is, in part, due to intensive therapies including eradication of early infection and suppressive therapies and pulmonary exacerbations. Initial infections with common CF pathogens are thought to arise from the natural environment. We review the impact of climate and environment on infection in CF. Specifically, several studies indicate that higher ambient temperatures, proximity to the equator and the summer season may be linked to the increased prevalence of Pseudomonas aeruginosa in people with CF. The environment may also play an important role in the acquisition of Gram negative organisms other than P. aeruginosa. There is emerging data suggesting that climatic and environmental factors are likely to impact on the risk of infection with NTM and fungi in people which are found extensively throughout the natural environment. PMID- 26949989 TI - Dietary Intake of Lutein and Diabetic Retinopathy in the Atherosclerosis Risk in Communities Study (ARIC). AB - PURPOSE: We tested the hypothesis that dietary intake of lutein is inversely associated with prevalence of diabetic retinopathy (DR) due to its antioxidant and anti-inflammatory properties and location within the retina. METHODS: We used logistic regression to examine the association between prevalent DR and energy adjusted lutein intake by quartile (Q) using data collected from 1430 Atherosclerosis Risk in Communities Study (ARIC) participants with diabetes (n = 994 white, n = 508 black). DR was assessed from 45 degrees non-mydriatic retinal photographs of one randomly chosen eye taken at visit 3 (1993-1995). Dietary lutein intake was estimated using a 66-item food frequency questionnaire at visit 1 (1987-1989). RESULTS: Median estimated daily lutein intake was 1370 ug/1000 kcals and prevalence of DR was ~21%. We found a crude association between lutein and DR (odds ratio, OR, 2.11, 95% confidence interval, CI, 1.45-3.09 for Q4, high intake, vs. Q1, low intake; p for trend <0.0001), which was attenuated after adjustment for ethnicity, duration of diabetes, glycosylated hemoglobin levels, field center and energy intake (OR 1.41, 95% CI 0.87-2.28; p for trend = 0.01). In analyses limited to persons with short diabetes duration (<6 years), the association no longer persisted (OR 0.94, 95% CI 0.31-2.16; p for trend =0.72) compared to the association in those with longer diabetes duration (>=6 years; OR 1.58, 95% CI 0.91-2.75; p for trend = 0.01). CONCLUSION: Contrary to our hypothesis, we found that the odds of higher lutein intake were greater among those with DR than those without DR. However, after adjusting for confounders, intake of lutein was not associated with DR. PMID- 26949991 TI - Living with the unknown: Posttraumatic stress disorder in pediatric bone marrow transplantation survivors and their mothers. AB - Bone marrow transplantation (BMT) is used to treat children with various hematologic, oncologic, and metabolic diseases. Although the treatment can be lifesaving, it is also physically and psychologically demanding for both the child and caregivers. In previous studies, BMT is found to be related with anxiety, posttraumatic stress disorder (PTSD), depression, and psychosocial problems both in children and parents. The aim of this study was to investigate PTSD in pediatric BMT survivors and their mothers compared with the healthy controls. Twenty-seven BMT survivors and their mothers and 28 healthy peers and their mothers were recruited as the study group and as the comparison group, respectively. All children were interviewed using Child Posttraumatic Stress Disorder-Reaction Index (CPTSD-RI) for assessing posttraumatic stress responses. As for mothers, Clinician-Administered PTSD Scale (CAPS) was used. In healthy children and mothers, instead of BMT, the most important traumatic event reported by them was included. All data were analyzed by a neutral statistician from the Department of Biostatistics of the university. The BMT group, both children and mothers, obtained significantly higher PTSD rates than the control group (66.5% and 17.8%, respectively, in children; 57.6% and 7%, respectively, in mothers). However, there was a weak correlation between survivors' and mothers' posttraumatic stress responses. These findings suggest that BMT is a significant stressor for both children and mothers. Clinicians should be aware of psychiatric symptoms of children who underwent such a life-threatening condition. Combination of medical treatment with psychosocial support is imperative. PMID- 26949992 TI - Cerebral white matter lesions, subjective cognitive failures, and objective neurocognitive functioning: A follow-up study in women after hypertensive disorders of pregnancy. AB - OBJECTIVE: Hypertensive disorders of pregnancy, like preeclampsia, are a leading cause of maternal and fetal morbidity/mortality worldwide. Preeclampsia can be complicated by the occurrence of convulsions (eclampsia). Women who experienced (pre)eclampsia more frequently report daily cognitive failures and showed increased emotional dysfunction several years later, but are not impaired on objective neurocognitive testing. In addition, women with preterm preeclampsia more often have cerebral white matter lesions (WML) on follow-up. We aimed to determine whether WML presence is related to cognitive dysfunction, anxiety, and depressive symptoms in (pre)eclamptic women. METHOD: Forty-one eclamptic, 49 preeclamptic, and 47 control women who had a normotensive pregnancy completed the Cognitive Failures Questionnaire (CFQ), the Hospital Anxiety and Depression Scale (HADS), and a broad neurocognitive test battery (visual perception and speed of information processing, motor functions, working memory, long-term memory, attention, and executive functioning). All underwent cerebral magnetic resonance imaging (MRI), and WML presence was recorded. Median elapsed time since index pregnancy was 6 years. Average age was 40 years. RESULTS: WML were more prevalent in women who had experienced preterm (pre)eclampsia (<37 weeks; 40%) than in controls (21%, p = .03). In (pre)eclamptic women, CFQ and HADS scores were higher than those in controls (44 +/- 16.1 vs. 36 +/- 11.0, p < .001, and 11 +/- 6.3 vs. 8 +/- 5.5, p < .001). There was no difference in objective cognitive performance as measured by neurocognitive tests. Subjective and objective cognitive functioning, anxiety, and depressive symptoms were not related to WML presence. CONCLUSION: Formerly (pre)eclamptic women report cognitive dysfunction, but do not exhibit overt cognitive impairment when objectively tested on average 6 years following their pregnancy. The presence of WML is not related to objective nor to subjective cognitive impairment, anxiety, and depressive symptoms. Longitudinal studies are needed to study whether the presence of WML is a risk factor for developing objective cognitive impairment in the long term. PMID- 26949993 TI - Genetic features of neuroblastic tumors associated with opsoclonus-myoclonus syndrome opens up the possibility for detection in peripheral blood. PMID- 26949994 TI - Relationship between changes in coronary atherosclerotic plaque burden measured by intravascular ultrasound and cardiovascular disease outcomes: a systematic literature review. AB - Objective Evidence from coronary imaging studies suggests an association between increased atherosclerotic plaque burden and cardiovascular disease (CVD) outcomes. A systematic review was performed to evaluate the relationship between coronary atherosclerotic plaque burden changes measured by intravascular ultrasound (IVUS) and CVD outcomes. Research design and methods Rigorous systematic review methodology was used to identify prospective studies of any design assessing the relationship between atherosclerotic plaque volume (percentage or total atheroma volume [PAV or TAV]) changes and CVD outcomes, using multivariable analyses. Main outcome measures CVD outcomes including major adverse cardiac events (MACEs) and major adverse cardiac and cerebrovascular events (MACCEs). Results Literature searches from inception to February 2015 retrieved 6958 records after de-duplication. From these four studies (14 papers) were included. One study reported a significantly lower rate of CVD outcomes associated with a greater reduction in PAV (hazard ratio [HR] 0.26, 95% confidence interval [CI] 0.07-0.83). One study reported that large plaque volume was significantly associated with a greater risk of major adverse cardiac events (MACEs) (HR 1.73, 95% CI: 1.02-2.96). Similarly, a third study reported a significant increase in MACE with an increase in baseline PAV (HR 1.51, 95% CI: 1.06-2.51). Only one potentially inadequately powered Japanese study did not find a statistically significant relationship between PAV changes and MACE. Conclusions The current evidence suggests an independent and statistically significant association between increases in coronary atherosclerotic plaque burden measured by IVUS and greater long-term risk of future CVD outcomes. However, this evidence comes from a limited number of studies which mainly focus on Japanese populations and populations after PCI. Further large prospective studies are required to confirm these findings. PMID- 26949995 TI - Intracellular Trafficking of AAV5 Vectors. AB - The present study was designed to visualize the cellular trafficking of adeno associated virus (AAV) vectors in general and AAV5 serotype vectors in particular. We fluorescently labeled AAV5 wild-type and a mutant (S652A) virus and studied their infection process by live cell imaging and confocal microscopy. Our data demonstrate considerable difference in the ability of these vectors to reach the nuclear compartment within the first 6 hr after infection. PMID- 26949996 TI - Synthesis and Shuttling Behavior of [2]Rotaxanes with a Pyrrole Moiety. AB - We synthesized [2]rotaxanes with a pyrrole moiety from a [2]rotaxane with a 1,3 diynyl moiety. The conversion of the 1,3-diynyl moiety of the axle component to the pyrrole moiety was accomplished by a Cu-mediated cycloaddition of anilines. The cycloaddition reaction was accelerated when the [2]rotaxane was used as the substrate. The effect of the structure of the pyrrole moiety on the rate of the shuttling was studied. PMID- 26949997 TI - Rapid maxillary expansion versus middle ear tube placement: Comparison of hearing improvements in children with resistance otitis media with effusion. AB - OBJECTIVE: To test the null hypothesis that there are significant differences in hearing improvements of children with resistance otitis media with effusion (OME) who undergo a rapid maxillary expansion (RME) procedure or ventilation tube placement. METHODS: Forty-two children between 4.5 and 15 years old were divided into three groups: RME, ventilation tube, and control groups. The RME group consisted of 15 children with maxillary constriction and resistance OME that indicated ventilation tube placement. The ventilation tube group consisted of 16 children for whom ventilation tube placement was indicated but no maxillary constriction. The control group consisted of 11 children with no orthodontic and/or rhinologic problems. Hearing thresholds were evaluated with three audiometric records: (1) before RME/ventilation tube placement (T0); (2) after RME/ventilation tube placement (T1), and (3) after an observation period of 10 months (T2). The control group was matched to these periods, except T1. RESULTS: Hearing thresholds decreased significantly in both the RME and ventilation tube groups (P < .001). Hearing thresholds decreased approximately 15 and 17 decibels in the RME and ventilation tube groups, respectively, but differences in improvements were insignificant between the two study groups (P > .05). Slight changes were observed in the control groups. CONCLUSION: The null hypothesis was rejected. RME showed similar effects as ventilation tube placement for release of otitis media and improvement of hearing thresholds levels. RME should be preferred as a first treatment option for children with maxillary constriction and resistance OME. PMID- 26949998 TI - Establishment and characterization of a transplantable tumor line (RMM) and cell line (RMM-C) from a malignant amelanotic melanoma in the F344 rat, with particular reference to galectin-3 expression in vivo and in vitro. AB - To investigate characteristics of malignant melanomas with various pathobiological features, a homotransplantable tumor line (RMM) was established from a spontaneous amelanotic melanoma found in the pinna of an aged F344 rat. RMM tumors were transplanted in syngeneic rats by serial subcutaneous implantation with 100% intake. The original and RMM tumors consisted of spindle shaped cells arranged mainly in interlacing bundles. Immunohistochemically, the neoplastic cells were positive to PNL-2 (melanocytes), nestin (neuroectodermal stem cells), S-100 (neurogenic cells) and vimentin (mesenchymal cells). Electron microscopically, tumor cells possessed single membrane-bound pre-melanosomes. Further, a cell line (RMM-C) was induced from an RMM tumor. RMM-C cells and the induced tumors in syngeneic rats showed immunohistochemical reactions similar to the original and RMM tumors. Interestingly, serum level of galectin-3 expression was increased with growing RMM tumors, and the expression was influenced by TNF alpha (increase) or TGF-beta1 (decrease), indicating a possible biomarker of amelanotic melanomas. The RMM tumors and RMM-C cell line could become useful tools for studies on the pathobiology, including tumor immunity, and development of therapeutic strategies against this malignancy. These tools are the first tumor lines of amelanotic melanomas in the rat. PMID- 26949999 TI - Mobility of Four Common Mercury Species in Model and Natural Unsaturated Soils. AB - Mercury (Hg) occurs as a myriad of species in environmental media, each with different physicochemical properties. The influence of Hg speciation on its transport in unsaturated soils is not well studied. Transport of four Hg species (dissolved inorganic Hg (II) species, a prepared Hg(II) and dissolved organic matter (DOM) complex, Hg(0), and HgS nanoparticles) was measured in sand and soil packed columns with partial water saturation under simulated rainfall (low ionic strength solution without DOM) and landfill leachate (high DOM content and high ionic strength) influent conditions. The Hg(II)-DOM species had the highest mobility among the four Hg species evaluated, and HgS particles (~230 nm hydrodynamic diameter) had the poorest mobility, for all soil and influent conditions tested. The addition of 2 wt % clay particles to sand greatly retarded the transport of all Hg species, especially under simulated rainfall. DOM in the column influent facilitated the transport of all four Hg species in model and natural soils. For simulated rainfall, the transport trends observed in model sands were consistent with those measured in a sandy soil, except that the mobility of dissolved inorganic Hg(II) species was significantly lower in natural soils. For simulated rainfall, Hg transport was negligible in a high organic content (~3.72 wt %) soil for all species except Hg-DOM. This work suggests that the Hg-DOM species presents the greatest potential for vertical migration to groundwater, especially with DOM in the influent solution. PMID- 26950000 TI - Defects in the calcium-binding region drastically affect the cadherin-like domains of RET tyrosine kinase. AB - Mutations in the rearranged during transfection (RET) tyrosine kinase gene leading to gain or loss of function have been associated with the development of several human cancers and Hirschsprung's disease (HSCR). However, to what extent these mutations affect individual bio-molecular functions remains unclear. In this article, the functionally significant mutations in the RET CLD1-4 calcium binding site which lead to HSCR, and depletion of calcium ions in the RET CLD1-4 calcium binding site, were investigated by molecular dynamics simulations--to understand the mechanistic action of the mutations or loss of calcium ions in altering the protein kinase structure, dynamics, and stability. The mutations or loss of calcium ions change the local conformation and change the free energy landscape. Specifically, the mutations and loss of calcium ions decrease the radius of gyration of the whole structure, leading to improper protein folding and GFL-GFRalpha contact site reduction. Furthermore, based on the most populated conformation in the wildtype MD simulations, a pharmacophore was generated by fragment docking to identify key features of the possible inhibitors targeting the calcium binding site. Overall, the findings may provide useful structural insights into the molecular mechanism underlying RET calcium-binding site mutations and assist in development of novel drugs targeting the extracellular ligand contact site of wildtype RET. PMID- 26950001 TI - Tinnitus Self-Efficacy and Other Tinnitus Self-Report Variables in Patients With and Without Post-Traumatic Stress Disorder. AB - OBJECTIVE: Individuals with tinnitus and co-occurring psychological conditions typically rate their tinnitus as more disturbing than individuals without such comorbidities. Little is known about how tinnitus self-efficacy, or the confidence that individuals have in their abilities to successfully manage the effects of tinnitus, is influenced by mental or psychological health (PH) status. The purpose of this study was to examine the influence of psychological state on tinnitus perceptions and tinnitus self-efficacy in individuals with chronic tinnitus. DESIGN: Observational study. Three groups (N = 199) were examined and included: (1) those with tinnitus without a concurrent psychological condition (tinnitus-only; n = 103), (2) those with tinnitus and concurrent PH condition other than post-traumatic stress disorder (PTSD; tinnitus + PH; n = 34), and (3) those with tinnitus and PTSD (tinnitus + PTSD; n = 62). The Self-Efficacy for Tinnitus Management Questionnaire (SETMQ) was administered. Responses on the SETMQ were compared among the groups, as well as to other indicators of tinnitus perception such as (1) the percentage of time tinnitus was audible (tinnitus awareness), (2) the percentage of time tinnitus was distressing/bothersome, (3) tinnitus loudness, (4) tinnitus handicap inventory scores, (5) subjective ratings of degree of hearing loss, and (6) subjective ratings of sound tolerance problems. RESULTS: The tinnitus + PTSD group reported significantly poorer tinnitus self-efficacy levels on average than the tinnitus-only group on all SETMQ subscales and poorer self-efficacy levels than the tinnitus + PH group for most subscales (except for routine management and devices). Tinnitus self efficacy levels were similar between the tinnitus + PH and tinnitus-only groups except for the emotional response subscale in which the tinnitus-only patients reported higher self-efficacy on average than both the other groups. Group differences were not seen for tinnitus loudness ratings nor for the amount of time individuals were aware of their tinnitus. Group differences were observed for the percentage of time tinnitus was distressing/bothersome, self-reported degree of hearing loss, sound tolerance problems ratings, and responses on the tinnitus handicap inventory (THI). In general, the group differences revealed patient ratings for the tinnitus-only group were least severe, followed by the tinnitus + PH group, and the tinnitus + PTSD group rated tinnitus effects as most severe. With all patient responses, the tinnitus + PTSD group was found to be significantly more affected by tinnitus than the tinnitus-only group; in some cases, the responses were similar between the tinnitus + PTSD and tinnitus + PH group and in other cases, responses were similar between the tinnitus + PH group and the tinnitus-only group. CONCLUSIONS: Tinnitus self-efficacy, along with other self-assessed tinnitus characteristics, varied across groups distinguished by PH diagnoses. In general, individuals with tinnitus and concurrent PTSD reported significantly poorer tinnitus self-efficacy and more handicapping tinnitus effects when compared to individuals with other psychological conditions or those with tinnitus alone. The group differences highlighted the need to consider tinnitus self-efficacy in intervention strategies, particularly for patients with tinnitus and concurrent PTSD as the results reiterated the unique ability of PTSD to interact in powerful and disturbing ways with the tinnitus experience and with patients' coping ability. PMID- 26950002 TI - ESPGHAN Distinguished Service Award 2015 to Professor C. Olle E. Hernell. PMID- 26950003 TI - Molecular Mechanisms Linking Autonomic Dysfunction and Impaired Cardiac Contractility in Critical Illness. AB - OBJECTIVES: Molecular mechanisms linking autonomic dysfunction with poorer clinical outcomes in critical illness remain unclear. We hypothesized that baroreflex dysfunction alone is sufficient to cause cardiac impairment through neurohormonal activation of (nicotinamide adenine dinucleotide phosphate oxidase dependent) oxidative stress resulting in increased expression of G-protein coupled receptor kinase 2, a key negative regulator of cardiac function. DESIGN: Laboratory/clinical investigations. SETTING: University laboratory/medical centers. SUBJECTS: Adult rats; wild-type/nicotinamide adenine dinucleotide phosphate oxidase subunit-2-deficient mice; elective surgical patients. INTERVENTIONS: Cardiac performance was assessed by transthoracic echocardiography following experimental baroreflex dysfunction (sino-aortic denervation) in rats and mice. Immunoblots assessed G-protein-coupled receptor recycling proteins expression in rodent cardiomyocytes and patient mononuclear leukocytes. In surgical patients, heart rate recovery after cardiopulmonary exercise testing, time/frequency measures of parasympathetic variables were related to the presence/absence of baroreflex dysfunction (defined by spontaneous baroreflex sensitivity of <6 ms mm Hg). The associations of baroreflex dysfunction with intraoperative cardiac function and outcomes were assessed. MEASUREMENTS AND MAIN RESULTS: Experimental baroreflex dysfunction in rats and mice resulted in impaired cardiac contractility and upregulation of G-protein-coupled receptor kinase 2 expression. In mice, genetic deficiency of gp91 nicotinamide adenine dinucleotide phosphate oxidase subunit-2 prevented upregulation of G-protein coupled receptor kinase 2 expression in conditions of baroreflex dysfunction and preserved cardiac function. Baroreflex dysfunction was present in 81 of 249 patients (32.5%) and was characterized by lower parasympathetic tone and increased G-protein-coupled receptor kinase 2 expression in mononuclear leukocytes. Baroreflex dysfunction in patients was also associated with impaired intraoperative cardiac contractility. Critical illness and mortality were more frequent in surgical patients with baroreflex dysfunction (relative risk, 1.66 [95% CI, 1.16-2.39]; p = 0.006). CONCLUSIONS: Reduced baroreflex sensitivity is associated with nicotinamide adenine dinucleotide phosphate oxidase subunit-2 mediated upregulation of G-protein-coupled receptor kinase 2 expression in cardiomyocytes and impaired cardiac contractility. Autonomic dysfunction predisposes patients to the development of critical illness and increases mortality. PMID- 26950004 TI - Biophysical constraints of optogenetic inhibition at presynaptic terminals. AB - We investigated the efficacy of optogenetic inhibition at presynaptic terminals using halorhodopsin, archaerhodopsin and chloride-conducting channelrhodopsins. Precisely timed activation of both archaerhodopsin and halorhodpsin at presynaptic terminals attenuated evoked release. However, sustained archaerhodopsin activation was paradoxically associated with increased spontaneous release. Activation of chloride-conducting channelrhodopsins triggered neurotransmitter release upon light onset. Thus, the biophysical properties of presynaptic terminals dictate unique boundary conditions for optogenetic manipulation. PMID- 26950005 TI - Hypothalamic control of male aggression-seeking behavior. AB - In many vertebrate species, certain individuals will seek out opportunities for aggression, even in the absence of threat-provoking cues. Although several brain areas have been implicated in the generation of attack in response to social threat, little is known about the neural mechanisms that promote self-initiated or 'voluntary' aggression-seeking when no threat is present. To explore this directly, we utilized an aggression-seeking task in which male mice self initiated aggression trials to gain brief and repeated access to a weaker male that they could attack. In males that exhibited rapid task learning, we found that the ventrolateral part of the ventromedial hypothalamus (VMHvl), an area with a known role in attack, was essential for aggression-seeking. Using both single-unit electrophysiology and population optical recording, we found that VMHvl neurons became active during aggression-seeking and that their activity tracked changes in task learning and extinction. Inactivation of the VMHvl reduced aggression-seeking behavior, whereas optogenetic stimulation of the VMHvl accelerated moment-to-moment aggression-seeking and intensified future attack. These data demonstrate that the VMHvl can mediate both acute attack and flexible seeking actions that precede attack. PMID- 26950007 TI - Relational categories as a bridge between cognitive and educational research. AB - Both cognitive and educational psychology literature strive to investigate human category and concept learning. However, both literatures focus on different phenomena and often use different methodologies. We identify and discuss commonalities and differences between the literatures. This literature comparison reveals that research on relational category learning offers a promising avenue to integration. We suggest that this integration would be especially beneficial to advance our understanding of conceptual change essentially, how complex scientific concepts and categories are acquired and developed in educational contexts elaborating or correcting students' prior conceptions. Furthermore, the focus on relational categories allows us to provide an integrative discussion on how recent lines of research on analogy, memory and category learning, and knowledge restructuring relate to and can inform education. In general, this article advocates the complementary nature of cognitive and educational psychology and identifies viable, and potentially synergistic paths for future research. (PsycINFO Database Record PMID- 26950008 TI - Mad genius revisited: Vulnerability to psychopathology, biobehavioral approach avoidance, and creativity. AB - Although many believe that creativity associates with a vulnerability to psychopathology, research findings are inconsistent. Here we address this possible linkage between risk of psychopathology and creativity in nonclinical samples. We propose that propensity for specific psychopathologies can be linked to basic motivational approach and avoidance systems, and that approach and avoidance motivation differentially influences creativity. Based on this reasoning, we predict that propensity for approach-based psychopathologies (e.g., positive schizotypy and risk of bipolar disorder) associates with increased creativity, whereas propensity for avoidance-based psychopathologies (e.g., anxiety, negative schizotypy, and depressive mood) associates with reduced creativity. Previous meta-analyses resonate with this proposition and showed small positive relations between positive schizotypy and creativity and small negative relations between negative schizotypy and creativity and between anxiety and creativity. To this we add new meta-analytic findings showing that risk of bipolar disorder (e.g., hypomania, mania) positively associates with creativity (k = 28, r = .224), whereas depressive mood negatively associates (albeit weakly) with creativity (k = 39, r = -.064). Our theoretical framework, along with the meta-analytic results, indicates when and why specific psychopathologies, and their inclinations, associate with increased or, instead, reduced creativity. (PsycINFO Database Record PMID- 26950006 TI - Genetically targeted magnetic control of the nervous system. AB - Optogenetic and chemogenetic actuators are critical for deconstructing the neural correlates of behavior. However, these tools have several limitations, including invasive modes of stimulation or slow on/off kinetics. We have overcome these disadvantages by synthesizing a single-component, magnetically sensitive actuator, "Magneto," comprising the cation channel TRPV4 fused to the paramagnetic protein ferritin. We validated noninvasive magnetic control over neuronal activity by demonstrating remote stimulation of cells using in vitro calcium imaging assays, electrophysiological recordings in brain slices, in vivo electrophysiological recordings in the brains of freely moving mice, and behavioral outputs in zebrafish and mice. As proof of concept, we used Magneto to delineate a causal role of striatal dopamine receptor 1 neurons in mediating reward behavior in mice. Together our results present Magneto as an actuator capable of remotely controlling circuits associated with complex animal behaviors. PMID- 26950009 TI - What limits working memory capacity? AB - We review the evidence for the 3 principal theoretical contenders that vie to explain why and how working memory (WM) capacity is limited. We examine the possibility that capacity limitations arise from temporal decay; we examine whether they might reflect a limitation in cognitive resources; and we ask whether capacity might be limited because of mutual interference of representations in WM. We evaluate each hypothesis against a common set of findings reflecting the capacity limit: The set-size effect and its modulation by domain-specificity and heterogeneity of the memory set; the effects of unfilled retention intervals and of distractor processing in the retention interval; and the pattern of correlates of WM tests. We conclude that-at least for verbal memoranda-a decay explanation is untenable. A resource-based view remains tenable but has difficulty accommodating several findings. The interference approach has its own set of difficulties but accounts best for the set of findings, and therefore, appears to present the most promising approach for future development. (PsycINFO Database Record PMID- 26950010 TI - Diagnostic and Therapeutic Capability of Double-Balloon Enteroscopy in Clinical Practice. AB - Advances in technology have facilitated the common use of small-bowel imaging. Intraoperative enteroscopy was the gold standard method for small-bowel imaging. However, noninvasive capsule endoscopy and invasive balloon enteroscopy are currently the main endoscopic procedures that are routinely used for small-bowel pathologies, and the indications for both techniques are similar. Although obstruction is a contraindication for capsule endoscopy, it is not considered to be problematic for double-balloon enteroscopy. The most important advantage of double-balloon enteroscopy is the applicability of therapeutic interventions during the procedure; however, double-balloon enteroscopy has certain advantages as well as disadvantages. PMID- 26950011 TI - Social constraints, loss-related factors, depression, and posttraumatic stress in a treatment-seeking suicide bereaved sample. AB - OBJECTIVE: Negative social responses that inhibit disclosure in the suicide bereaved may pose an obstacle to recovery. However, such social constraints have not been evaluated in this population. The purpose of this study was to evaluate extent, types, and correlates of social constraints in treatment-seeking community-based participants recently bereaved by suicide. METHOD: This cross sectional study investigated social constraints and adjustment in a treatment seeking sample of community-based participants (N = 33) recently bereaved by suicide; pretreatment, baseline data from a graduate school-based research clinic were analyzed. RESULTS: Participants endorsed a moderate level of social constraints; subtle negative social responses appeared more common than overt negative reactions. Social constraints were unrelated to kinship with the deceased or to finding the body. Constraints were positively associated with depression (r = .54, p = .001) and posttraumatic stress (r = .43, p = .012). CONCLUSION: Findings highlight the importance of the interpersonal context of adjustment in suicide postvention. (PsycINFO Database Record PMID- 26950013 TI - An assessment of the construct validity of the ICD-11 proposal for complex posttraumatic stress disorder. AB - BACKGROUND: A new diagnosis, complex posttraumatic stress disorder (CPTSD), is set to be introduced in the 11th revision to the International Classification of Diseases (ICD-11). Studies have supported a unique group of trauma-exposed individuals who exhibit symptoms consistent with CPTSD proposals. No studies have yet tested the proposed latent symptom structure of CPTSD proposed for ICD-11. This study tests the factorial validity of CPTSD and assesses the role of a range of risk factors to predict CPTSD. METHOD: A large sample (N = 453) of treatment seeking adult victims of childhood sexual abuse completed self-report measures of CPTSD. Confirmatory factor analysis (CFA) was used to compare a set of alternative factor models of CPTSD. RESULTS: Just less than half of the sample met the diagnostic criteria for CPTSD (42.8%). CFA results supported the factorial validity of the ICD-11 proposals for CPTSD. Being female and experiencing a greater number of sexual abuse acts during childhood were more strongly associated with PTSD than CPTSD symptoms. Regarding symptoms, anxiety was more strongly associated with PTSD than CPTSD, whereas higher levels of dysthymia were more strongly associated with CPTSD than PTSD symptoms. CONCLUSIONS: Results provide initial evidence regarding the factorial validity of the proposed ICD-11 model of CPTSD. In addition, current results support the proposals of the ICD-11 that exposure to abuse during early development is associated with a greater likelihood of CPTSD than PTSD. The study contributes to a growing body of empirical data supporting the construct validity of CPTSD as a unique diagnostic entity. (PsycINFO Database Record PMID- 26950012 TI - An application of an ecological framework to understand risk factors of PTSD due to prolonged conflict exposure: Israeli and Palestinian adolescents in the line of fire. AB - OBJECTIVE: Adolescents living in Israel and the Palestinian authority are exposed to political violence. This review examines psychosocial risk factors for posttraumatic stress disorder (PTSD) organized within an ecological framework. METHOD: Relevant articles were identified through PubMed and PsycINFO. Studies measuring risk and/or protective factors for PTSD in the Palestinian and/or Israeli adolescent populations because of conflict exposure from 1990 to present were included. RESULTS: A total of 20 studies met inclusion criteria. Greater violence exposure, poor economic resources, living in rural compared with urban areas, poor family and peer relations, and poor coping skills were associated with PTSD symptoms. CONCLUSIONS: The ecological framework is a useful approach to understanding factors affecting adolescent PTSD. Future research should focus on socioecological levels that have received limited attention. (PsycINFO Database Record PMID- 26950014 TI - Role of alcohol in college sexual victimization and postassault adaptation. AB - OBJECTIVE: Sexual victimization is common in college populations and has been linked to a number of deleterious outcomes, including posttraumatic stress symptoms (PTSS) and problem drinking. Research suggests that these associations may be further impacted when the victimization involves alcohol, yet little is known about how alcohol-related sexual victimization (ASV) may influence functional outcomes over time. Posttraumatic cognitions are dysfunctional trauma related beliefs that are thought to affect posttrauma adaptation and may help to shed light on the later psychological effects of ASV. METHOD: Accordingly, the present study sought to examine how ASV during college may influence PTSS and problem drinking over time in a sample of young adults (N = 116). We examined ASV in 2 ways: cumulative (since starting college) and the most recent event (during college). Further, we tested the mechanistic role of trauma cognitions in these relations, controlling for trauma severity. RESULTS: Findings revealed that ASV prospectively predicted problem drinking across models, but was not associated with PTSS. The effects of ASV became nonsignificant when baseline PTSS and problem drinking were statistically controlled. Counter to our expectations, ASV was not associated with trauma cognitions, and these cognitions did not mediate the association between ASV and later PTSS or problem drinking. In contrast, trauma severity was significantly related to trauma cognitions. CONCLUSIONS: For many young adults, the effects of college sexual victimization extend well beyond the college years. These findings add to our understanding of college sexual victimization experiences and the posttrauma adaptation process in young adults. (PsycINFO Database Record PMID- 26950015 TI - Large Molecular Weight Polymer Solar Cells with Strong Chain Alignment Created by Nanoimprint Lithography. AB - In this work, strong chain alignment in large molecular weight polymer solar cells is for the first time demonstrated by nanoimprint lithography (NIL). The polymer crystallizations in nonimprinted thin films and imprinted nanogratings with different molecular weight poly(3-hexylthiophene-2,5-diyl) (P3HT) are compared. We first observe that the chain alignment is favored by medium molecular weight (Mn = 25 kDa) P3HT for nonimprinted thin films. However, NIL allows large molecular weight P3HT (>40 kDa) to organize more strongly, which has been desired for efficient charge transport but is difficult to achieve through any other technique. Consequently P3HT/[6,6]-penyl-C61-butyric-acid-methyl-ester (PCBM) solar cells with large molecular weight P3HT nanogratings show a high power conversion efficiency of 4.4%, which is among the best reported P3HT/PCBM photovoltaics devices. PMID- 26950016 TI - Optimization and Evaluation Strategy of Esophageal Tissue Preparation Protocols for Metabolomics by LC-MS. AB - Sample preparation is a critical step in tissue metabolomics. Therefore, a comprehensive and systematic strategy for the screening of tissue preparation protocols is highly desirable. In this study, we developed an Optimization and Evaluation Strategy based on LC-MS to screen for a high-extractive efficiency and reproducible esophageal tissue preparation protocol for different types of endogenous metabolites (amino acids, carnitines, cholines, etc.), with a special focus on low-level metabolites. In this strategy, we first selected a large number of target metabolites based on literature survey, previous work in our lab, and known metabolic pathways. For these target metabolites, we tested different solvent extraction methods (biphasic solvent extraction, two-step [TS], stepwise [SW], all-in one [AO]; single-phase solvent extraction, SP) and esophageal tissue disruption methods (homogenized wet tissue [HW], ground wet tissue [GW], and ground dry tissue [GD]). A protocol involving stepwise addition of solvents and a homogenized wet tissue protocol (SWHW) was superior to the others. Finally, we evaluated the stability of endogenous metabolites in esophageal tissues and the sensitivity, reproducibility, and recovery of the optimal protocol. The results proved that the SWHW protocol was robust and adequate for bioanalysis. This strategy will provide important guidance for the standardized and scientific investigation of tissue metabolomics. PMID- 26950017 TI - Fe-Promoted Chlorobenzylation of Terminal Alkynes through Benzylic C(sp(3))-H Bond Functionalization. AB - A chlorobenzylation of terminal alkynes through Fe(II)-promoted benzylic C(sp(3)) H bond functionalization in the presence of NCS as a chloride source was developed. Compared with previous methods to prepare polysubstituted alkenyl halides, the presented procedure provides an efficient alternative with high atom and step economy under mild conditions. The transformation was established to proceed through a single-electron transfer (SET) process with benzyl cations as key intermediates. PMID- 26950018 TI - Focus on Methodology: Beyond paper and pencil: Conducting computer-assisted data collection with adolescents in group settings. AB - Computer-assisted data collection offers advantages over traditional paper and pencil measures; however, little guidance is available regarding the logistics of conducting computer-assisted data collection with adolescents in group settings. To address this gap, we draw on our experiences conducting a multi-site longitudinal study of adolescent development. Structured questionnaires programmed on laptop computers using Audio Computer Assisted Self-Interviewing (ACASI) were administered to groups of adolescents in community-based and afterschool programs. Although implementing ACASI required additional work before entering the field, we benefited from reduced data processing time, high data quality, and high levels of youth motivation. Preliminary findings from an ethnically diverse sample of 265 youth indicate favorable perceptions of using ACASI. Using our experiences as a case study, we provide recommendations on selecting an appropriate data collection device (including hardware and software), preparing and testing the ACASI, conducting data collection in the field, and managing data. PMID- 26950019 TI - Evaluating response to mood stabilizers in patients with mixed depression: A study of agreement between three different mania rating scales and a depression rating scale. AB - BACKGROUND: The aim of the present study was to evaluate agreement between three pairs formed by one of three mania scales (Young Mania Rating Scale [YMRS], Bech Rafaelsen Mania Scale [BRMS], or the Clinician-Administered Rating Scale for Mania [CARS-M]) and a single depression scale (21-item Hamilton Depression Rating Scale [21-HAM-D]) for evaluation of response to mood stabilizers in patients with mixed bipolar disorder. METHODS: Between 2010 and 2014, 68 consecutive bipolar type I and II outpatients with mixed depression as per DSM-IV-TR and Cincinnati criteria were included in this 8-week open-label trial to randomly receive carbamazepine, lithium carbonate, or valproic acid as monotherapy. RESULTS: Patterns of response (defined as a reduction of at least 50% in one of the mania scales and on the 21-HAM-D) were strikingly similar: 21-HAM-D+YMRS=22.1%, 21-HAM D+BRMS=20.6%, and 21-HAM-D+CARS-M=23.5% (p<0.368). Assessment of agreement revealed very high kappa coefficients: 21-HAM-D+YMRS vs. 21-HAM-D+CARS-M, kappa=0.87; 21-HAM-D+YMRS vs. 21-HAM-D+BRMS, kappa=0.78; 21-HAM-D+CARS-M vs. 21 HAM-D+BRMS, kappa=0.91 (p<0.001). LIMITATIONS: The decision to combine a depression rating scale with any one mania rating scale to assess treatment response in patients with mixed depression is questionable. CONCLUSIONS: The present study suggests that any one of the three tested mania rating scales (YMRS, BRMS, and CARS-M) can be combined with the 21-HAM-D to assess treatment response in patients with mixed bipolar disorder. This should give clinicians an added measure of confidence in using this strategy until valid, and specific instruments are developed for assessment of mixed states. PMID- 26950020 TI - A primary estimate of global PCDD/F release based on the quantity and quality of national economic and social activities. AB - The correlations between polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) releases and factors relevant to human social-economic activities (HSEAs) were analyzed. The multiple linear regression model was successfully developed to estimate the total global PCDD/F release. The PCDD/F releases significantly correlated with population, area, GDP and GNI, suggesting that "quantity" of HSEAs have significantly contributed to the PCDD/F releases. On another aspect, advanced technologies are usually adopted in developed countries/regions, and hence reduce the PCDD/F release. The significant correlation between PCDD/F release and CO2 emission implies the potential of simultaneous reduction of CO2 emission and PCDD/F release. The total global PCDD/F release from 196 countries/regions was estimated to be 100.4 kg-TEQ yr( 1). The estimated annual PCDD/F release per unit area ranged from 0.007 to 28 mg TEQ km(-2). Asia is estimated to have the highest PCDD/F release of 47.1 kg-TEQ yr(-1), almost half of the total world release. Oceania is estimated to have the smallest total release but the largest per-capita release. For the developed areas, such as Europe and North America, the PCDD/F release per unit GDP is lower, while for Africa, it is much higher. PMID- 26950022 TI - Stability of arsenate-bearing Fe(III)/Al(III) co-precipitates in the presence of sulfide as reducing agent under anoxic conditions. AB - Currently, the co-precipitation of arsenate with ferric iron at molar ratios Fe(III)/As(V) >= 3 by lime neutralization produces tailings solids that are stable under oxic conditions. However not much is known about the stability of these hazardous co-precipitates under anoxic conditions. These can develop in tailings storage sites by the action of co-discharged reactive sulfides, organic reagent residuals or bacterial activity. The ferric matrix can then undergo reductive dissolution reactions, which could release arsenic into the pore water. Co-ions like aluminum could provide a redox-immune sink to scavenge any mobilized arsenic as a result of reduction of ferric. As such, in this work Fe(III)/As(V) = 4 and aluminum substituted Fe(III)/Al(III)/As(V) = 2/2/1 co-precipitates were produced in a mini continuous co-precipitation process circuit and subjected to excess sulfide addition under inert gas to evaluate their stability. It was found that the ferric-arsenate co-precipitate could retain up to 99% (30 mg/L in solution) of its arsenic content despite the high pH (10.5) and extremely reducing (Eh < -200 mV) environment. There was no significant reduction of arsenate and only 45% of ferric iron was reduced. Partial aluminum substitution was found to cut the amount of mobilized arsenic by 50% (down to 15 mg/L) hence mixed Fe(III)/Al(III)-arsenate co-precipitates may offer better resistance to reductive destabilization over the long term than all iron co-precipitates. PMID- 26950021 TI - Immobilization of lead by phosphate amended Polonite. AB - Polonite is an alkaline material that is used to remove nutrients from domestic wastewater and it has been evaluated as a fertilizer. Stabilization of Pb by Polonite and Polonite amended with orthophosphate, PO4, (Polonite-P) was studied. Octacalcium phosphate (Ca8H2(PO4)6.5H2O) was a primary species of PO4 formed on the surface of Polonite-P. Lead was found to be associated with pozzolanic reaction products in Pb treated Polonite and Pb treated Polonite-P samples. Formation of Pb oxides, as precipitates or surface complexes, were substantial constituents of Pb treated Polonite. Dissolution of Ca8H2(PO4)6.5H2O followed by formation of Pb4O(PO4)2 was a probable mechanism of Pb removal by Polonite-P. Polonite-P could be a suitable replacement for current PO4 sources as a Pb stabilization agent. Finally, LDI-TOF was an effective technique for evaluating forms of Pb on Polonite and Polonite-P. PMID- 26950024 TI - Effects of effluent organic matter (EfOM) on the removal of emerging contaminants by ozonation. AB - Removal of emerging contaminants in wastewater treatment is essential to ensure the ecological health of the receiving water bodies. Ozonation is a promising technology to achieve this purpose but important wastewater characteristics affecting the optimal removal efficiency need to be elucidated. Secondary effluents contain effluent organic matter (EfOM), which can react directly with ozone as well as react as the initiator, promoter and inhibitor in the hydroxyl radical (.OH) chain reactions resulting from ozone decomposition. These different reaction modes of EfOM, coupled with alkalinity and pH value, collectively determine the ozone and .OH exposures and the degradation of pharmaceutical compounds by ozonation. In this study, we determined the rate constants of EfOM collected from two municipal wastewater treatment plants in terms of direct ozone reaction, initiation, promotion and inhibition at various pH values (pH 6.0-7.5) and temperatures (10-30 degrees C). The rate constants of direct reaction and initiation generally increased with the increasing pH value while the rate constants of promotion and inhibition did not vary significantly. All rate constants increased with the increasing temperature. The removal of ibuprofen, acetylsulfamethoxazole and metoprolol in diluted secondary effluent by ozonation can be fairly-well modeled by using the determined rate constants of EfOM. PMID- 26950023 TI - Toxicity of graphene oxide to white rot fungus Phanerochaete chrysosporium. AB - With the wide production and applications of graphene and its derivatives, their toxicity to the environment has received much attention nowadays. In this study, we investigated the toxicity of graphene oxide (GO) to white rot fungus (Phanerochaete chrysosporium). GO was prepared by modified Hummers method and well characterized before use. P. chrysosporium was exposed to GO at the concentrations of 0-4 mg/mL for 7 d. The fresh and dry weights, pH values of culture media, structures, ultrastructures, IR spectra and activities of the decomposition of pollutants were measured to reveal the hazards of GO to P. chrysosporium. Our results indicated that low concentrations of GO stimulated the growth of P. chrysosporium. The exposure to GO induced more acidic pH values of the culture media after 7 d. GO induced the disruption of the fiber structure of P. chrysosporium, while at 4 mg/mL some very long and thick fibers were formed. Such changes were reflected in the scanning electron microscopy investigations, where the disruption of fibers was observed. In the ultrastructural investigations, the shape of P. chrysosporium cells changed and more vesicles were found upon the exposure to GO. The infrared spectroscopy analyses suggested that the chemical compositions of mycelia were not changed qualitatively. Beyond the toxicity, GO did not alter the activities of P. chrysosporium at low concentrations, but led to the complete loss of activity at high concentrations. The implication to the ecological safety of graphene is discussed. PMID- 26950025 TI - Differences in the ability of two marine annelid species, Thalassodrilides sp. and Perinereis nuntia, to detoxify 1-nitronaphthalene. AB - Bioremediation is a promising method for remediating environmentally polluted water. We investigated the abilities of two benthic annelid species to biotransform 1-nitronaphthalene, a nitrated polycyclic aromatic hydrocarbon. We used an oligochaete, Thalassodrilides sp. (Naididae), collected from the sediment beneath a fish farm and a polychaete, Perinereis nuntia, which was obtained from a commercial source. Populations of both organisms were exposed to 1400 MUg L(-1) of 1-nitronaphthalene in seawater for 3 days in the dark at 20 degrees C. The concentration of the pollutant decreased to 12 MUg L(-1) in the seawater containing the Thalassodrilides sp. and to 560 MUg L(-1) in the seawater containing P. nuntia. The 1-nitronaphthalene concentration in the bodies of the animals increased from 12 to 94 MUg kg(-1) in Thalassodrilides sp. and from 0.90 MUg kg(-1) to 38,000 MUg kg(-1) in P. nuntia. After 3 days, 99% and 40% of the 1 nitronaphthalene had been biotransformed in the Thalassodrilides sp. and P. nuntia experimental groups, respectively. We then tested the acute toxicity of residual 1-nitronaphthalene from the same water using mummichog (fish) larvae. After the larvae had been exposed for 96 h, the percentage of apparently unaffected larvae remaining was 83.3% in Thalassodrilides sp. group but only 16.7% in the P. nuntia group. Clearly, of the two species we studied, Thalassodrilides sp. had a superior ability to convert 1-nitronaphthalene into substances that were nontoxic to mummichog larvae. Therefore, we recommend the use of this species for bioremediation of chemically polluted sediments. PMID- 26950026 TI - Evaluation of a universal flow-through model for predicting and designing phosphorus removal structures. AB - Phosphorus (P) removal structures have been shown to decrease dissolved P loss from agricultural and urban areas which may reduce the threat of eutrophication. In order to design or quantify performance of these structures, the relationship between discrete and cumulative removal with cumulative P loading must be determined, either by individual flow-through experiments or model prediction. A model was previously developed for predicting P removal with P sorption materials (PSMs) under flow-through conditions, as a function of inflow P concentration, retention time (RT), and PSM characteristics. The objective of this study was to compare model results to measured P removal data from several PSM under a range of conditions (P concentrations and RT) and scales ranging from laboratory to field. Materials tested included acid mine drainage residuals (AMDRs), treated and non-treated electric arc furnace (EAF) steel slag at different size fractions, and flue gas desulfurization (FGD) gypsum. Equations for P removal curves and cumulative P removed were not significantly different between predicted and actual values for any of the 23 scenarios examined. However, the model did tend to slightly over-predict cumulative P removal for calcium-based PSMs. The ability of the model to predict P removal for various materials, RTs, and P concentrations in both controlled settings and field structures validate its use in design and quantification of these structures. This ability to predict P removal without constant monitoring is vital to widespread adoption of P removal structures, especially for meeting discharge regulations and nutrient trading programs. PMID- 26950028 TI - Perfluoroalkyl substances in serum from South Korean infants with congenital hypothyroidism and healthy infants--Its relationship with thyroid hormones. AB - Exposure to perfluoroalkyl substances (PFASs) may disrupt thyroid systems, though the specific effects of PFASs are still being elucidated. Since research regarding exposure in infants is highly limited, our goal was to investigate exposure levels of PFASs in infant serum and correlate these levels with thyroid hormones (THs). This was accomplished by analyzing 16 PFASs in sera from a case group of infants with congenital hypothyroidism and a control group. Total PFAS exposure level was 2.63-44.7ng/mL in the case group and 2.44-22.4ng/mL in the control group. Concentrations of serum perfluorooctanoic acid (PFOA, p<0.01), perfluorononanoic acid (PFNA, p<0.001), perfluorooctanoic acid (PFDA, p<0.005), and perfluoroundecanoic acid (PFUnDA, p<0.005) were significantly higher in the case group than the control group. Levels of certain PFASs (PFOA, perfluorotridecanoic acid [PFTrDA], and perfluorohexane sulfonate [PFHxS]) showed a moderate to weak correlation with relevant antibodies. PMID- 26950027 TI - Spatial associations between socioeconomic groups and NO2 air pollution exposure within three large Canadian cities. AB - Previous studies of environmental justice in Canadian cities have linked lower socioeconomic status to greater air pollution exposures at coarse geographic scales, (i.e., Census Tracts). However, studies that examine these associations at finer scales are less common, as are comparisons among cities. To assess differences in exposure to air pollution among socioeconomic groups, we assigned estimates of exposure to ambient nitrogen dioxide (NO2), a marker for traffic related pollution, from city-wide land use regression models to respondents of the 2006 Canadian census long-form questionnaire in Toronto, Montreal, and Vancouver. Data were aggregated at a finer scale than in most previous studies (i.e., by Dissemination Area (DA), which includes approximately 400-700 persons). We developed simultaneous autoregressive (SAR) models, which account for spatial autocorrelation, to identify associations between NO2 exposure and indicators of social and material deprivation. In Canada's three largest cities, DAs with greater proportions of tenants and residents who do not speak either English or French were characterised by greater exposures to ambient NO2. We also observed positive associations between NO2 concentrations and indicators of social deprivation, including the proportion of persons living alone (in Toronto), and the proportion of persons who were unmarried/not in a common-law relationship (in Vancouver). Other common measures of deprivation (e.g., lone-parent families, unemployment) were not associated with NO2 exposures. DAs characterised by selected indicators of deprivation were associated with higher concentrations of ambient NO2 air pollution in the three largest cities in Canada. PMID- 26950029 TI - Association between residential proximity to environmental pollution sources and childhood renal tumors. AB - BACKGROUND: Few risk factors for childhood renal tumors are well established. While a small fraction of cases might be attributable to susceptibility genes and congenital anomalies, the role of environmental factors needs to be assessed. OBJECTIVES: To explore the possible association between residential proximity to environmental pollution sources (industrial and urban areas, and agricultural crops) and childhood renal cancer, taking into account industrial groups and toxic substances released. METHODS: We conducted a population-based case-control study of childhood renal cancer in Spain, including 213 incident cases gathered from the Spanish Registry of Childhood Tumors (period 1996-2011), and 1278 controls individually matched by year of birth, sex, and region of residence. Distances were computed from the respective subject's residences to the 1271 industries, the 30 urban areas with >=75,000 inhabitants, and the agricultural crops located in the study area. Using logistic regression, odds ratios (ORs) and 95% confidence intervals (95%CIs) for categories of distance to pollution sources were calculated, with adjustment for matching variables and socioeconomic confounders. RESULTS: Excess risk (OR; 95%CI) of childhood renal tumors was observed for children living near (<=2.5km) industrial installations as a whole (1.97; 1.13-3.42) - particularly glass and mineral fibers (2.69; 1.19-6.08), galvanization (2.66; 1.14-6.22), hazardous waste (2.59; 1.25-5.37), ceramic (2.35; 1.06-5.21), surface treatment of metals (2.25; 1.24-4.08), organic chemical industry (2.22; 1.15-4.26), food and beverage sector (2.19; 1.18-4.07), urban and waste-water treatment plants (2.14; 1.07-4.30), and production and processing of metals (1.98; 1.03-3.82) -, and in the proximity of agricultural crops (3.16; 1.54-8.89 for children with percentage of crop surface >=24.35% in a 1-km buffer around their residences). CONCLUSIONS: Our study provides some epidemiological evidence that living near certain industrial areas and agricultural crops may be a risk factor for childhood renal cancer. PMID- 26950030 TI - Accurate measurement of female genital tract fluid dilution in cervicovaginal lavage samples. AB - An ion chromatographic method with conductivity detection for the precise and accurate analysis of lithium ions in phosphate-buffered saline, used as a cervicovaginal lavage (CVL) fluid, was developed and validated. The lithium ion dilution factor during the CVL is used to calculate the volume of cervicovaginal fluid (CVF) collected. Initial CVL Li(+) concentrations of 1mM and 10mM were evaluated. The method is robust, practical, and afforded an accurate measurement (5% of the measurement, or better) at 24MUL of vaginal fluid simulant collected per mL of CVL fluid, as low as 5MULmL(-1) using 10mM Li(+) with a measurement accuracy of 6.7%. Ion chromatograms of real-world CVL samples collected in vivo from common animal models (sheep and pig-tailed macaque) and a human volunteer demonstrate that the analysis is interference-free. The method is readily transferrable and should enable the accurate measurement of CVF volume collected during CVLs benefitting a broad range of research disciplines, including pharmacokinetic, pharmacodynamic, metabolomic, and microbiome studies. PMID- 26950031 TI - Qualitative screening of veterinary anti-microbial agents in tissues, milk, and eggs of food-producing animals using liquid chromatography coupled with tandem mass spectrometry. AB - A method for the analysis of 120 drugs in animal derived food was developed using liquid chromatography-tandem mass spectrometry (LC-MS/MS). These analytes belong to 12 families of veterinary anti-microbial agents (quinolones, macrolides, beta lactams, nitroimidazoles, sulfonamides, lincomycines, chloramphenicols, quinoxalines, tetracyclines, polypeptides, and antibacterial synergists) as well as other compounds not assigned to a particular drug family. The animal derived food samples include muscle and liver of swine, bovine, sheep, and chicken, as well as hen eggs and dairy milk. The sample preparation included ultrasound assisted extraction (UAE) with acetonitrile-water and a final clean-up with auto solid-phase extraction (SPE) on HLB cartridges. The detection and quantification of 120 anti-microbial agents was performed using LC-MS/MS in positive and negative ion mode. The chromatographic separation was performed on a C18 column using acetonitrile and 0.1% formic acid as the mobile phase. The limit of detection (LOD) and limit of quantification (LOQ) of all drugs in food-producing animals were 0.5-3.0MUg/kg and 1.5-10.0MUg/kg, respectively. The developed method was successfully utilized to monitor real samples, which demonstrated that it is a simple, fast, and robust method, and could be used as a regulatory to screen for the presence of residues from veterinary anti-microbial drugs in animal derived foods. PMID- 26950032 TI - Validation of a high-throughput immunobead array technique for multiplex detection of three foodborne pathogens in chicken products. AB - This study rigorously evaluated a previously developed immunobead array method to simultaneously detect three important foodborne pathogens, Campylobacter jejuni, Listeria monocytogenes, and Salmonella spp., for its actual application in routine food testing. Due to the limitation of the detection limit of the developed method, an enrichment step was included in this study by using Campylobacter Enrichment Broth for C. jejuni and Universal Pre-enrichment Broth for L. monocytogenes and Salmonella spp.. The findings showed that the immunobead array method was capable of detecting as low as 1CFU of the pathogens spiked in the culture media after being cultured for 24h for all three pathogens. The immunobead array method was further evaluated for its pathogen detection capabilities in ready-to-eat (RTE) and ready-to-cook (RTC) chicken samples and proven to be able to detect as low as 1CFU of the pathogens spiked in the food samples after being cultured for 24h in the case of Salmonella spp., and L. monocytogenes and 48 h in the case of C. jejuni. The method was subsequently validated with three types of chicken products (RTE, n=30; RTC, n=20; raw chicken, n=20) and was found to give the same results as the conventional plating method. Our findings demonstrated that the previously developed immunobead array method could be used for actual food testing with minimal enrichment period of only 52 h, whereas the conventional ISO protocols for the same pathogens take 90 144 h. The immunobead array was therefore an inexpensive, rapid and simple method for the food testing. PMID- 26950033 TI - Review of safety and mobility issues among older pedestrians. AB - Although old people make up an extremely vulnerable road-user group, older pedestrians' difficulties have been studied less extensively than those of older drivers, and more knowledge of this issue is still required. The present paper reviews current knowledge of older-adult problems with the main components of pedestrian activity, i.e., walking and obstacle negotiation, wayfinding, and road crossing. Compared to younger ones, old pedestrians exhibit declining walking skills, with a walking speed decrease, less stable balance, less efficient wayfinding strategies, and a greater number of unsafe road crossing behaviors. These difficulties are linked to age-related changes in sensorial, cognitive, physical, and self-perception abilities. It is now known that visual impairment, physical frailty, and attention deficits have a major negative impact on older pedestrians' safety and mobility, whereas the roles of self-evaluation and self regulation are still poorly understood. All these elements must be taken into consideration, not only in developing effective safety interventions targeting older pedestrians, but also in designing roads and cars. Recent initiatives are presented here and some recommendations are proposed. PMID- 26950034 TI - Severity of disability related to road traffic crashes in the Spanish adult population. AB - BACKGROUND: The severity of disability related to road traffic crashes has been little studied, despite the significant health and socio-economic impacts that determine victims' quality of life. OBJECTIVE: To estimate the consequences of road traffic crashes on the severity of disability, in terms of individuals' capacity to execute activities and perform tasks in their current environment, using aids. METHODS: Cross-sectional study conducted on community-dwelling participants in the "2008 National Survey of Disability", with data on 91,846 households having 20,425 disabled persons, 443 of whom had disability due to road traffic crashes. We measured severity using two indicators, i.e., the Capacity (CSI) and Performance (PSI) Severity Indices. RESULTS: The highest proportion of disability was mild (CSI=70.5%; PSI=80.8%), while 7.6% (CSI) and 4.9% (PSI) was severe/complete respectively. The moderate/severe disability rate was 0.6 per thousand on the CSI, decreasing to 0.4 per thousand on the PSI. No differences were observed by age or sex. Moderate/severely disabled persons had a fourfold higher probability of being retired or unfit for work. Mental and nervous system impairments were more closely related to moderate/severe/complete problems of capacity and performance (p<0.001), disability for carrying out general tasks and demands, and interpersonal interactions and relationships (p<0.001). Being permanently bedridden (p<0.001), receiving aids (p<0.001), family support (p<0.05) and moving home (p<0.05) increased with an increase in the level of severity. CONCLUSION: Road traffic crashes mainly cause mild disability. Moderate/severe disability is associated with lower work capacity, greater functional dependence, and increased need of aids, moving home and family support. PMID- 26950035 TI - MRP1 expression in CTCs confers resistance to irinotecan-based chemotherapy in metastatic colorectal cancer. AB - Circulating tumor cells are important markers of tumor progression and can reflect tumor behavior in metastatic colorectal cancer (mCRC). Identification of proteins that confer resistance to treatment is an important step to predict response and better selection of treatment for patients. Multidrug resistance associated protein 1 (MRP1) and Multidrug resistance-associated protein 4 (MRP4) play a role in irinotecan-resistance, and Excision Repair Cross-Complementation group 1 (ERCC1) expression can confer resistance to platinum compounds. Here, we included 34 patients with mCRC and most of them received FOLFIRI or FOLFOX chemotherapy (91.1%). CTCs were isolated by ISET((r)) Technology and identified in 30 patients (88.2%), with a median of 2.0 CTCs/mL (0-31.0). We analyzed the immunocytochemical expression of MRP1, MRP4 and ERCC1 only in patients who had previously detectable CTCs, accordingly to treatment received (n = 19, 15 and 13 patients, respectively). Among patients treated with irinotecan-based chemotherapy, 4 out of 19 cases with MRP1 positive CTCs showed a worse progression free survival (PFS) in comparison to those with MRP1 negative CTCs (2.1 months vs. 9.1 months; p = 0.003). None of the other proteins studied in CTCs had significant association with PFS. We analyzed also histological sections of primary tumors and metastases by immunohistochemistry, and found no association with clinicopathological characteristics or with PFS. Our results show MRP1 as a potential biomarker of resistance to treatment with irinotecan when found in CTCs from mCRC patients. This is a small proof-of-principle study and these early findings need to be validated in a larger cohort of patients. PMID- 26950036 TI - Impact of high self-perceived burden to others with preferences for end-of-life care and its determinants for terminally ill cancer patients: a prospective cohort study. AB - BACKGROUND/OBJECTIVE: Self-perceived burden to others (SPB) is a major concern of terminally ill cancer patients and is frequently factored into end-of-life (EOL) care decision-making. However, changes in and determinants of SPB and its longitudinal impact on preferences for EOL care over the dying process have not been investigated. Our study was aimed at filling this gap in knowledge. METHODS: A convenience sample of 325 cancer patients was followed until death. High SPB was identified as scoring >20 on the Self-perceived Burden Scale. Preferences for EOL care included EOL-care goals, life-sustaining treatments, and hospice care. Factors potentially precipitating/minimizing patients' high SPB included demographics, disease characteristics and burden, and social support and were examined by multivariate logistic regression modeling with the generalized estimating equation. RESULTS: Prevalence of high SPB increased as death approached (51.78%, 58.26%, 62.66%, and 65.38% for 181-365, 91-180, 31-90, and 1 30 days before death, respectively). High SPB was precipitated by women, younger age, having inadequate financial resources, without religious affiliation, and suffering from severe symptom distress and heavy functional dependence but was independent of time proximity to patient death, disease characteristics, and social support. Furthermore, high SPB was not associated with EOL-care preferences, whether aggressive life-sustaining treatments or hospice care. CONCLUSIONS: High SPB was prevalent among terminally ill cancer patients but independent of preferences for EOL care. Cancer patients' SPB may be lessened by adequate symptom relief to facilitate functional independence. These strategies to ease SPB may improve the quality of death and dying. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26950037 TI - The complex interplay of diet, xenobiotics, and microbial metabolism in the gut: Implications for clinical outcomes. AB - From digestion to pathogen resistance and immune system development, the gut microbiota and its collection of microbial genes are redefining what it means to be human. Despite tremendous advances in this field, there is still a limited understanding of how microbial metabolism in the gut impacts human health, which precludes the development of microbiota-targeted therapies. In this article, we discuss the increasing evidence emphasizing the importance of bacterial metabolism in the gut and discuss its intricate links with diet and pharmaceutical compounds leading to altered therapeutic outcomes. We also detail how applying and testing microbial ecology hypotheses will be crucial to fully understand the therapeutic potential of this host-associated community. Going forward, functional and mechanistic studies combining biomedical research, ecology, bioinformatics, statistical modeling, and engineering will be key in our pursuit of personalized medicine. PMID- 26950038 TI - Relation between Dephasing Time and Energy Gap Fluctuations in Biomolecular Systems. AB - Excitation energy and charge transfer are fundamental processes in biological systems. Because of their quantum nature, the effect of dephasing on these processes is of interest especially when trying to understand their efficiency. Moreover, recent experiments have shown quantum coherences in such systems. As a first step toward a better understanding, we studied the relationship between dephasing time and energy gap fluctuations of the individual molecular subunits. A larger set of molecular simulations has been investigated to shed light on this dependence. This set includes bacterio-chlorophylls in Fenna-Matthews-Olson complexes, the PE545 aggregate, the LH2 complexes, DNA, photolyase, and cryptochromes. For the individual molecular subunits of these aggregates it has been confirmed quantitatively that an inverse proportionality exists between dephasing time and average gap energy fluctuation. However, for entire complexes including the respective intermolecular couplings, such a relation still needs to be verified. PMID- 26950039 TI - Risk factors and timing of venous thromboembolism after radical cystectomy in routine clinical practice: a population-based study. AB - OBJECTIVE: To describe the risk factors and timing of perioperative venous thromboembolism (VTE) and its association with survival for patients undergoing radical cystectomy (RC) in routine clinical practice. PATIENTS AND METHODS: The population-based Ontario Cancer Registry was linked to electronic records of treatment to identify all patients who underwent RC between 1994 and 2008; VTE events were identified from hospital diagnostic codes. Multivariate logistic regression analysis was used to determine the factors associated with perioperative VTE. A Cox proportional hazards regression model explored the associations between VTE and survival. RESULTS: Of the 3 879 patients included in the study, 3.6% (141 patients) were diagnosed with VTE at <=1 month of their surgical admission date. This increased to 4.7% (181) at <=2 months and 5.4% (211) at <=3 months. In all, 55% of VTE events presented after hospital discharge. In multivariate analysis, factors associated with VTE included higher surgeon volume (P = 0.004) and increased length of hospital stay (LOS; P < 0.001). Lymph node yield and adjuvant chemotherapy were not associated with VTE. VTE was associated with an inferior cancer-specific survival [hazard ratio (HR) 1.35, 95% confidence interval (CI) 1.13-1.62] and overall survival (HR 1.27, 95% CI 1.08-1.49). CONCLUSIONS: Over half of VTE events in RC patients occur after hospital discharge, with a substantial incidence up to 3 months after surgery. Limited actionable risk factors for VTE were identified other than LOS. In this population-based cohort, VTE was associated with inferior long-term survival. PMID- 26950040 TI - alpha-Hydrogen Abstraction by *OH and *SH Radicals from Amino Acids and Their Peptide Derivatives. AB - We have used computational quantum chemistry to investigate the thermochemistry of alpha-hydrogen abstraction from the full set of amino acids normally found in proteins, as well as their peptide forms, by *OH and *SH radicals. These reactions, with their reasonable complexity in the electronic structure (at the alpha-carbon), are chosen as a consistent set of models for conducting a fairly robust assessment of theoretical procedures. Our benchmarking investigation shows that, in general, the performance for the various classes of theoretical methods improves in the order nonhybrid DFT -> hybrid DFT -> double-hybrid DFT -> composite procedures. More specifically, we find that the DSD-PBE-P86 double hybrid DFT procedure yields the best agreement with our high-level W1X-2 vibrationless barriers and reaction energies for this particular set of systems. A significant observation is that, when one considers relative instead of absolute values for the vibrationless barriers and reaction energies, even nonhybrid DFT procedures perform fairly well. To exploit this feature in a cost effective manner, we have examined a number of multilayer schemes for the calculation of reaction energies and barriers for the abstraction reactions. We find that accurate values can be obtained when a "core" of glycine plus the abstracting radical is treated by DSD-PBE-P86, and the substituent effects are evaluated with M06-2X. Inspection of the set of calculated thermochemical data shows that the correlation between the free energy barriers and reaction free energies is strongest when the reactions are either endergonic or nearly thermoneutral. PMID- 26950041 TI - Rearrangements of a Water Molecule in Both Directions between Two Hydrogen Bonding Sites of 5-Hydroxyindole Cation: Experimental Determination of the Energy Threshold for the Rearrangement. AB - Rearrangements of a water molecule in both directions between two hydrogen bonding (H-bonding) sites of the 5-hydroxyindole (5HI) cation was investigated in the gas phase. IR-dip spectra of jet-cooled 5HI-(H2O)1 revealed that two structural isomers, 5HI(OH)-(H2O)1 and 5HI(NH)-(H2O)1, in which a water molecule is bound to either the OH group or the NH group of 5HI, were formed in the S0 state. The IR photodissociation spectrum of [5HI-(H2O)1](+) generated by two color resonant two-photon ionization (2C-R2PI) via the S1-S0 origin of 5HI(NH) (H2O)1 clearly showed that [5HI(OH)-(H2O)1](+) and [5HI(NH)-(H2O)1](+) coexist in the D0 state. The appearance of [5HI(OH)-(H2O)1](+) after R2PI via the S1-S0 origin of 5HI(NH)-(H2O)1 is explained by isomerization of [5HI(NH)-(H2O)1](+) to [5HI(OH)-(H2O)1](+), which corresponds to the rearrangement of the water. In addition, isomerization in the opposite direction was also observed when [5HI (H2O)1](+) was generated via the S1-S0 origin of 5HI(OH)-(H2O)1. The upper limit of the energy threshold for the rearrangement of the water in [5HI(NH)-(H2O)1](+) was experimentally determined to be 2127 +/- 30 cm(-1) from the adiabatic ionization energy of 5HI(NH)-(H2O)1. Above the energy threshold, the water molecule in [5HI-(H2O)1](+) may fluctuate between the two preferential H-bonding sites of 5HI(+). PMID- 26950042 TI - Homologous regulators, CnfR1 and CnfR2, activate expression of two distinct nitrogenase gene clusters in the filamentous cyanobacterium Anabaena variabilis ATCC 29413. AB - The cyanobacterium Anabaena variabilis has two Mo-nitrogenases that function under different environmental conditions in different cell types. The heterocyst specific nitrogenase encoded by the large nif1 gene cluster and the similar nif2 gene cluster that functions under anaerobic conditions in vegetative cells are under the control of the promoter for the first gene of each cluster, nifB1 or nifB2 respectively. Associated with each of these clusters is a putative regulatory gene called cnfR (patB) whose product has a C-terminal HTH domain and an N-terminal ferredoxin-like domain. CnfR1 activates nifB1 expression in heterocysts, while CnfR2 activates nifB2 expression. A cnfR1 mutant was unable to make nitrogenase under aerobic conditions in heterocysts while the cnfR2 mutant was unable to make nitrogenase under anaerobic conditions. Mutations in cnfR1 and cnfR2 reduced transcripts for the nif1 and nif2 genes respectively. The closely related cyanobacterium, Anabaena sp. PCC 7120 has the nif1 system but lacks nif2. Expression of nifB2:lacZ from A. variabilis in anaerobic vegetative cells of Anabaena sp. PCC 7120 depended on the presence of cnfR2. This suggests that CnfR2 is necessary and sufficient for activation of the nifB2 promoter and that the CnfR1/CnfR2 family of proteins are the primary activators of nitrogenase gene expression in cyanobacteria. PMID- 26950043 TI - Assessing the growth of Escherichia coli O157:H7 and Salmonella in spinach, lettuce, parsley and chard extracts at different storage temperatures. AB - AIMS: The objective of this work was to study the growth potential of Escherichia coli O157:H7 and Salmonella spp. in leafy vegetable extracts at different temperature conditions. METHODS AND RESULTS: Cocktails of five strains of E. coli O157:H7 and of Salmonella enterica were used. Inoculated aqueous vegetable extracts were incubated at 8, 10, 16 and 20 degrees C during 21 days. Microbial growth was monitored using Bioscreen C((r)) . In spinach extract, results showed that for E. coli O157:H7 and Salmonella significant differences (P < 0.05) for MUabs (maximum absorbance rate) were obtained. For both pathogens, growth in chard was slightly lower. In contrast, iceberg lettuce and parsley showed the lowest values of MUabs , below 0.008 h(-1) . The coefficients of variance (CoV) calculated for the different replicates evidenced that at low temperature (8 degrees C) a more variable behaviour of both pathogens is expected (CoV > 180%). CONCLUSIONS: This study provides evidence that aqueous extracts from vegetable tissues can result in distinct growth niche producing different response in various types of vegetables. SIGNIFICANCE AND IMPACT OF THE STUDY: Finally, these results can be used as basis to establish risk rankings of pathogens and leafy vegetable matrices with relation to their potential growth. PMID- 26950044 TI - Consensus on the diagnosis and treatment of cholestatic liver diseases (2015, China). PMID- 26950045 TI - Survival of lactic acid and propionibacteria in low- and full-fat Dutch-type cheese during human digestion ex vivo. AB - The survival of selected bacteria in semi-hard experimental cheeses was studied after exposure to human gastric and duodenal juices in an ex vivo model. Experimental cheeses (10 and 28% fat) were supplemented with different strains of Lactobacillus sp. and Propionibacterium sp. and ripened for 7 and 70 weeks. After digestion, greater numbers of the adjunct bacteria we rerecorded in the 7-week old cheeses compared to the well-matured cheeses (70 weeks). The bacterial survival was strain dependent, and influenced by the fat content of the cheese. Lactobacilli showed better survival, especially when in low-fat cheeses. The strains of propionibacteria also survived well during the digestion of the low fat cheeses. The results confirmed that cheese can potentially be a good carrier matrix for bacteria to the intestine. In addition, it has been shown that different strains present in cheese have different abilities to survive the conditions of the gastrointestinal tract. Younger cheese was indicated to be a better carrier, possibly because the bacteria present in those cheeses have had shorter exposure to the stress conditions occurring in cheese during prolonged maturation. SIGNIFICANCE AND IMPACT OF THE STUDY: Cheese can function as a suitable vehicle for the delivery of a variety of food-related micro-organisms to the intestine. Young cheese as well as low-fat cheeses are better carrier matrixes than full-fat and/or more well-ripened cheeses. Most of the lactobacilli and all the propionibacteria survived well during digestion of the low-fat cheeses. This study also showed the ability of cheese lactobacilli and PAB to survive the severe conditions of GIT. PMID- 26950046 TI - Nerve growth factor does not seem to be a biomarker for neurogenic lower urinary tract dysfunction after spinal cord injury. AB - AIM: To prospectively investigate the association of bladder function with the nerve growth factor (NGF) concentration in the urine of individuals with neurogenic lower urinary tract dysfunction (NLUTD) after spinal cord injury (SCI). METHODS: Individuals with chronic SCI and NLUTD presenting for a routine urologic examination at a tertiary urologic referral center were recruited for the study. Patient characteristics, the current bladder evacuation method and urodynamic parameters were collected. As controls, individuals with normal bladder function were recruited from the staff of a SCI rehabilitation center. The urinary NGF concentration was measured in triplicates by enzyme linked immunosorbent assay with a minimal sensitivity of 10 pg/ml. RESULTS: The data of 10 and 37 individuals with normal bladder function and NLUTD, respectively, were analyzed. The urinary NGF concentration was below 10 pg/ml in all investigated samples. CONCLUSIONS: The urinary NGF concentration did not differentiate between individuals with normal bladder function and those with NLUTD. At least in patients with SCI, the urinary NGF concentration does not seem to be a clinically relevant biomarker for NLUTD. Neurourol. Urodynam. 36:659-662, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 26950047 TI - Deferasirox and children: From clinical trials to the real world. PMID- 26950048 TI - Vectorization of Nucleic Acids for Therapeutic Approach: Tutorial Review. AB - Oligonucleotides present a high therapeutic potential for a wide variety of diseases. However, their clinical development is limited by their degradation by nucleases and their poor blood circulation time. Depending on the administration mode and the cellular target, these macromolecules will have to cross the vascular endothelium, to diffuse through the extracellular matrix, to be transported through the cell membrane, and finally to reach the cytoplasm. To overcome these physiological barriers, many strategies have been developed. Here, we review different methods of DNA vectorization, discuss limitations and advantages of the various vectors, and provide new perspectives for future development. PMID- 26950049 TI - Genetic Predictors of Azathioprine Toxicity and Clinical Response in Patients with Inflammatory Bowel Disease. AB - BACKGROUND: Thiopurines (Azathioprine (AZA) and 6-Mercaptopurine (6-MP) are considered a well-established therapy for patients with Inflammatory Bowel Disease (IBD) including ulcerative colitis (UC) and Crohn's Disease (CD). However, nearly 20% of patients discontinue thiopurines due to adverse events. Functional polymorphisms of several enzymes involved in the metabolism of thiopurines have been linked with toxicity. The clinical value of variant carriers such as TPMT, ITPA and GSTs in predicting toxicity and adverse events for IBD patients treated with thiopurines remains to be clarified. OBJECTIVES: To determine if variation in TPMT, ITPA and GST genotypes can predict adverse effects such as neutropenia, pancreatitis, liver enzyme elevation, as well as clinical response for patients with IBD treated with thiopurines. METHODS: Patients known to have IBD and treated with AZA or 6MP were enrolled. Adverse effects were calculated and their correlation with TPMT, ITPA and GST genotypes was evaluated. Further, the correlation between clinical response and TPMT, ITPA and GST genotypes were assessed. RESULTS: A total of 53 patients were enrolled. 16/53 patients (28.6%) responded to AZA therapy. 17 patients experienced adverse events with 10 having to discontinue treatment. Three patients (5.4%) developed severe myelosuppression (WBC< 2.0 or neutrophils <1.0). Loss of function TPMT genotype was associated with adverse events (OR 3.64, 95% CI 0.55 - 24.23, p=0.0313). ITPA and GST polymorphisms were not associated with toxicity. GSTM1 deletion was associated with poor clinical response to therapy (OR 3.75, 95% CI 0.940 - 14.97, p=0.1028), however, neither TPMT*3A nor ITPA polymorphisms were associated with clinical response. CONCLUSION: In addition to TPMT for adverse events, genotyping for GSTM1 appears to predict clinical response in IBD patients treated with thiopurines. PMID- 26950050 TI - CYP3A activity: towards dose adaptation to the individual. AB - INTRODUCTION: Co-medication, gene polymorphisms and co-morbidity are main causes for high variability in expression and function of the CYP3A isoenzymes. Pharmacokinetic variability is a major source of interindividual variability of drug effect and response of CYP3A substrates. While CYP3A genotyping is of limited use, direct testing of enzyme function ('phenotyping') may be more promising to achieve individualized dosing of CYP3A substrates. AREAS COVERED: We will discuss available phenotyping strategies for CYP3A isoenzymes and causes of intra- and interindividual variability of CYP3A. The impact of phenotyping on the dose selection and pharmacokinetics of CYP3A substrates (docetaxel, irinotecan, tyrosine kinase inhibitors, ciclosporin, tacrolimus) are reviewed. Pubmed searches were conducted during March-November 2015 to retrieve articles related to CYP3A enzyme, phenotyping, drug interactions with CYP3A probe substrates, and phenotyping-guided dosing algorithms. EXPERT OPINION: While ample data is available on the choice appropriate phenotyping drugs (midazolam, alfentanil, aplrazolam, buspirone, triazolam), less clinical trial data is available concerning strategies to usefully guide dosing in the clinical practice. Implementation into the clinical routine necessitates further research to identify (1) an easy-to-use and cheap test for CYP3A activity that (2) adequately predicts drug exposure to (3) allow a sound decision on dose adaptation and hence (4) improve clinical outcome and/or reduce the intensity or frequency of adverse drug effects. PMID- 26950051 TI - Unregulated greenhouse gas and ammonia emissions from current technology heavy duty vehicles. AB - : The study presents the measurement of carbonyl, BTEX (benzene, toluene, ethyl benzene, and xylene), ammonia, elemental/organic carbon (EC/OC), and greenhouse gas emissions from modern heavy-duty diesel and natural gas vehicles. Vehicles from different vocations that included goods movement, refuse trucks, and transit buses were tested on driving cycles representative of their duty cycle. The natural gas vehicle technologies included the stoichiometric engine platform equipped with a three-way catalyst and a diesel-like dual-fuel high-pressure direct-injection technology equipped with a diesel particulate filter (DPF) and a selective catalytic reduction (SCR). The diesel vehicles were equipped with a DPF and SCR. Results of the study show that the BTEX emissions were below detection limits for both diesel and natural gas vehicles, while carbonyl emissions were observed during cold start and low-temperature operations of the natural gas vehicles. Ammonia emissions of about 1 g/mile were observed from the stoichiometric natural gas vehicles equipped with TWC over all the driving cycles. The tailpipe GWP of the stoichiometric natural gas goods movement application was 7% lower than DPF and SCR equipped diesel. In the case of a refuse truck application the stoichiometric natural gas engine exhibited 22% lower GWP than a diesel vehicle. Tailpipe methane emissions contribute to less than 6% of the total GHG emissions. IMPLICATIONS: Modern heavy-duty diesel and natural gas engines are equipped with multiple after-treatment systems and complex control strategies aimed at meeting both the performance standards for the end user and meeting stringent U.S. Environmental Protection Agency (EPA) emissions regulation. Compared to older technology diesel and natural gas engines, modern engines and after-treatment technology have reduced unregulated emissions to levels close to detection limits. However, brief periods of inefficiencies related to low exhaust thermal energy have been shown to increase both carbonyl and nitrous oxide emissions. PMID- 26950052 TI - Locked-In Syndrome #303. PMID- 26950053 TI - New insights into the antimicrobial blue light inactivation of Candida albicans. PMID- 26950054 TI - Noninvasive in vivo imaging of embryonic beta-cell development in the anterior chamber of the eye. AB - The fetal environment plays a decisive role in modifying the risk for developing diabetes later in life. Developing novel methodology for noninvasive imaging of beta-cell development in vivo under the controlled physiological conditions of the host can serve to understand how this environment affects beta-cell growth and differentiation. A number of culture models have been designed for pancreatic rudiment but none match the complexity of the in utero or even normal physiological environment. Speier et al. recently developed a platform of noninvasive in vivo imaging of pancreatic islets using the anterior chamber of the eye where islets get vascularized, grow and respond to physiological changes. The same methodology was adapted for the study of pancreatic development. E13.0, still undifferentiated rudiments with fluorescent lineage tracing were implanted in the AC of the eye, allowing the longitudinal study of their growth and differentiation. Within 48 h the anlages get vascularized and grow but their mesenchyme displays a selective growth advantage. The resulting imbalance leads to alteration in the differentiation pattern of the progenitors. Reducing the mesenchyme to its bare minimum before implantation allows the restoration of a proper balance and a development that mimics the normal pancreatic development. These groundbreaking observations demonstrate that the anterior chamber of the eye provides a good system for noninvasive in vivo fluorescence imaging of the developing pancreas under the physiology of the host and can have important implications for designing strategies to prevent or reverse the deleterious effects of hyperglycemia on altering beta-cell function later in life. PMID- 26950055 TI - MoCha: Molecular Characterization of Unknown Pathways. AB - Automated methods for the reverse-engineering of complex regulatory networks are paving the way for the inference of mechanistic comprehensive models directly from experimental data. These novel methods can infer not only the relations and parameters of the known molecules defined in their input datasets, but also unknown components and pathways identified as necessary by the automated algorithms. Identifying the molecular nature of these unknown components is a crucial step for making testable predictions and experimentally validating the models, yet no specific and efficient tools exist to aid in this process. To this end, we present here MoCha (Molecular Characterization), a tool optimized for the search of unknown proteins and their pathways from a given set of known interacting proteins. MoCha uses the comprehensive dataset of protein-protein interactions provided by the STRING database, which currently includes more than a billion interactions from over 2,000 organisms. MoCha is highly optimized, performing typical searches within seconds. We demonstrate the use of MoCha with the characterization of unknown components from reverse-engineered models from the literature. MoCha is useful for working on network models by hand or as a downstream step of a model inference engine workflow and represents a valuable and efficient tool for the characterization of unknown pathways using known data from thousands of organisms. MoCha and its source code are freely available online under the GPLv3 license. PMID- 26950057 TI - The need for bronchoscopic services for children in low and middle-income countries. PMID- 26950058 TI - Vaccination with 2014-15 Seasonal Inactivated Influenza Vaccine Elicits Cross Reactive Anti-HA Antibodies with Strong ADCC Against Antigenically Drifted Circulating H3N2 Virus in Humans. AB - It is well established that virus neutralizing (VN) antibodies to hemagglutinin (HA) antigens of influenza A viruses provide optimal protection against antigenically matched strains of influenza A viruses. In contrast, little is known about the potential role of HA-specific, non-neutralizing antibodies in protection against human influenza illness at present. In this study, we show that individuals vaccinated with the 2014-15 seasonal inactivated influenza vaccine displayed strong A/H3N2 HA-specific antibody-dependent cell-mediated cytotoxicity (ADCC) activities against an antigenically drifted H3N2 virus, despite poor induction of cross-reactive neutralizing antibodies against the antigenic variant. Given that passive transfer of influenza HA-monospecific immune sera with negligible levels of HA-specific VN antibodies can often confer considerable cross protection against lethal challenge with heterologous influenza viruses in animal models, it is conceivable that HA-specific, non neutralizing antibodies may provide certain degree of cross protection against antigenically drifted influenza A viruses through ADCC in case of influenza vaccine mismatches. This may have important implications for public health. PMID- 26950059 TI - Dependence of Gold Nanoparticle Radiosensitization on Functionalizing Layer Thickness. AB - Gold nanoparticles functionalized with polyethylene glycol of different chain lengths are used to determine the influence of the capping layer thickness on the radiosensitizing effect of the particles. The size variations in organic coating, built up with polyethylene glycol polymers of molecular weight 1-20 kDa, allow an evaluation of the decrease in dose enhancement percentages caused by the gold nanoparticles at different radial distances from their surface. With localized eradication of malignant cells as a primary focus, radiosensitization is most effective after internalization in the nucleus. For this reason, we performed controlled radiation experiments, with doses up to 20 Gy and particle diameters in a range of 5-30 nm, and studied the relaxation pattern of supercoiled DNA. Subsequent gel electrophoresis of the suspensions was performed to evaluate the molecular damage and consecutively quantify the gold nanoparticle sensitization. In conclusion, on average up to 58.4% of the radiosensitizing efficiency was lost when the radial dimensions of the functionalizing layer were increased from 4.1 to 15.3 nm. These results serve as an experimental supplement for biophysical simulations and demonstrate the influence of an important parameter in the development of nanomaterials for targeted therapies in cancer radiotherapy. PMID- 26950056 TI - Improving Access to Eye Care among Persons at High-Risk of Glaucoma in Philadelphia--Design and Methodology: The Philadelphia Glaucoma Detection and Treatment Project. AB - PURPOSE: The Wills Eye Glaucoma Research Center initiated a 2-year demonstration project to develop and implement a community-based intervention to improve detection and management of glaucoma in Philadelphia. METHODS: The glaucoma detection examination consisted of: ocular, medical, and family history; visual acuity testing; corneal pachymetry; biomicroscopy of the anterior segment; intraocular pressure (IOP) measurement; gonioscopy; funduscopy; automated visual field testing; and fundus-color photography. Treatment included laser surgery and/or IOP-lowering medication. A cost analysis was conducted to understand resource requirements. Outcome measures included; prevalence of glaucoma-related pathology and other eye diseases among high-risk populations; the impact of educational workshops on level of knowledge about glaucoma (assessed by pre- and post-test evaluation); and patient satisfaction of the glaucoma detection examinations in the community (assessed by satisfaction survey). Treatment outcome measures were change in IOP at 4-6 weeks and 4-6 months following selective laser trabeculoplasty treatment, deepening of the anterior chamber angle following laser-peripheral iridotomy treatment, and rate of adherence to recommended follow-up examinations. Cost outcomes included total program costs, cost per case of glaucoma detected, and cost per case of ocular disease detected. RESULTS: This project enrolled 1649 participants (African Americans aged 50+ years, adults 60+ years and individuals with a family history of glaucoma). A total of 1074 individuals attended a glaucoma educational workshop and 1508 scheduled glaucoma detection examination appointments in the community setting. CONCLUSIONS: The Philadelphia Glaucoma Detection and Treatment Project aimed to improve access and use of eye care and to provide a model for a targeted community-based glaucoma program. PMID- 26950060 TI - Effectiveness and safety of dydrogesterone in regularization of menstrual cycle: a post-marketing study. AB - Oral administration of dydrogesterone during second half of menstrual cycle has been shown to reduce menstrual irregularities. This prospective, observational study aimed to determine continued effectiveness of dydrogesterone (prescribed between 1 and 6 cycles or longer) in menstrual cycle regularization in Indian women aged >=18 years with irregular menstrual cycle for at least 3 months. Those achieving regular cycles (21 to 35 days, inclusive) during treatment were followed up for 6 months after cessation of dydrogesterone treatment. Of the 910 women completing dydrogesterone treatment, 880 (96.7%) achieved cycle regularization (p<0.0001 for 90% success rate) at end of treatment (EOT). Of the 788 subjects available for follow up at 6 months, 747 (94.8%) reported cycle regularity (p<0.0001 for 90% success rate). At EOT, the mean cycle duration reduced by 16.14 (+/-24.04) days and mean amount of menstrual bleeding decreased by 0.45 (+/-1.20) pads/day. While five subjects reported worst pain at baseline, none experienced it at EOT. One serious adverse event (appendicitis) and three non-serious adverse events were reported. Dydrogesterone regularizes and improves the duration of the menstrual cycle, reduces the amount of bleeding, relieves menstrual pain and prevents relapse of irregular cycles at six months after discontinuation of treatment. PMID- 26950061 TI - Prevalence of metabolic syndrome and association with burden of atherosclerotic disease in patients with stable coronary artery disease. AB - BACKGROUND: We aimed to estimate the prevalence of metabolic syndrome (Met.S.) and to explore the association of Met.S. with the number of diseased vessels in patients with stable coronary artery disease (C.A.D.). METHODS: This cross sectional study enrolled stable C.A.D. patients who attended the outpatient cardiology departments of four hospitals between 2006 and 2008. Met.S. was defined according to the National Cholesterol Education Program Adult Treatment Panel III (N.C.E.P./A.T.P. III). RESULTS: In the study 742 patients (mean age: 62 +/- 9 years, male: n = 631, 85.0%) with stable C.A.D. were recruited. The prevalence of Met.S. was 47.3% (95% C.I. = 43.6-50.9%). Among women, a high percentage of the patients had Met.S. (n = 68, 61.3%), whereas in male patients the prevalence of Met.S. was 44.8% (n = 283). Multivariable analysis showed that C.A.D. patients with Met.S. had 84% higher odds of double or triple vessel disease, whereas those with four or five Met.S. components had two times higher odds of double or triple vessel disease after adjustment for potential confounders (O.R. = 1.84 with 95% C.I. = 1.26-2.68, p = 0.001 and O.R. = 2.08 with 95% C.I. = 1.17-3.69, p = 0.012, respectively). Met.S. as well as the accumulation of four or five Met.S. components had a positive association with the likelihood of double or triple vessel disease and this was independent of the presence of diabetes. CONCLUSIONS: Almost one out of two patients with stable C.A.D. was found to fulfill the criteria of Met.S. Met.S. as well as four or five Met.S. components increased the odds of double or triple vessel disease in patients with stable C.A.D. The study suggests that cardiologists and health care practitioners should be aware that Met.S. is highly prevalent when established C.A.D. is present and that Met.S. and accumulation of four or five Met.S. components seem to be associated more often with double or triple vessel C.A.D. PMID- 26950062 TI - Exploring Coverage of the 2008 Irish Dioxin Crisis in the Irish and UK Newsprint Media. AB - The 2008 dioxin crisis occurred as a result of contamination of Irish pork. The event had significant implications for Ireland's economy and the reputation of its agricultural industry, as well as raising concerns for human health. This study describes the results of a content analysis of Irish and UK newspaper coverage of the 2008 Irish dioxin crisis, as this is likely to provide insight into how public perceptions of this issue were shaped. Articles from 16 print publications were systematically sampled for the period December 2008 to February 2009. The resulting data set of 141 articles was examined using a coding protocol developed based on previous research and refined during piloting. Results indicated that the dioxin crisis was primarily portrayed by the media as an industry/economic crisis, dominant in 26.9% of articles in the sample. Within this dominant portrayal, the agricultural industry was frequently cited as being in crisis (42.6%); however, the implications of the crisis on the wider economic environment also received attention (17.7%). Differences between Irish and UK based media were also examined, revealing that while the Irish media most frequently described the crisis in terms of its impact on the industry and economy, the UK media were more likely to portray the crisis as a risk to health. These dominant media messages and message framings have implications for the public understanding of the issue in each country and potential consequences regarding perception of the adequacy of existing food policy and regulatory oversight. PMID- 26950064 TI - ISBP: Understanding the Security Rule of Users' Information-Sharing Behaviors in Partnership. AB - The rapid growth of social network data has given rise to high security awareness among users, especially when they exchange and share their personal information. However, because users have different feelings about sharing their information, they are often puzzled about who their partners for exchanging information can be and what information they can share. Is it possible to assist users in forming a partnership network in which they can exchange and share information with little worry? We propose a modified information sharing behavior prediction (ISBP) model that can help in understanding the underlying rules by which users share their information with partners in light of three common aspects: what types of items users are likely to share, what characteristics of users make them likely to share information, and what features of users' sharing behavior are easy to predict. This model is applied with machine learning techniques in WEKA to predict users' decisions pertaining to information sharing behavior and form them into trustable partnership networks by learning their features. In the experiment section, by using two real-life datasets consisting of citizens' sharing behavior, we identify the effect of highly sensitive requests on sharing behavior adjacent to individual variables: the younger participants' partners are more difficult to predict than those of the older participants, whereas the partners of people who are not computer majors are easier to predict than those of people who are computer majors. Based on these findings, we believe that it is necessary and feasible to offer users personalized suggestions on information sharing decisions, and this is pioneering work that could benefit college researchers focusing on user-centric strategies and website owners who want to collect more user information without raising their privacy awareness or losing their trustworthiness. PMID- 26950063 TI - Health Related Behaviours in Normal Weight and Overweight Preschoolers of a Large Pan-European Sample: The ToyBox-Study. AB - The aim of this study was to investigate the associations of health related behaviours (HRB) with Body Mass Index (BMI) in preschoolers, and to study the likelihood of being overweight/obese in relation to compliance with recommended HRB. The sample consisted of 3301 normal weight and overweight/obese preschoolers (mean age: 4.7 years; 52% boys, 85% normal weight) from six European countries (Belgium, Bulgaria, Germany, Greece, Poland, Spain). Height and weight were measured, total daily step counts were registered during six days, and HRB were assessed with validated parental surveys in 2012. Multiple linear and logistic regression analyses were performed. Only few HRB were significantly associated with BMI. In boys, higher water intake and higher soft drink and higher fruit consumption were significantly associated with higher BMI. Boys drinking less water than recommended were less likely to be overweight/obese (OR = 0.60), while boys who consume soft drinks were more likely to be overweight/obese (OR = 1.52). In girls, higher water intake, higher vegetable consumption, and more TV time on weekend days were significantly associated with higher BMI. Girls eating less vegetables than recommended were less likely to be overweight/obese (OR = 0.62), and girls who engaged in quiet play for more than 90 minutes on weekend days were more likely to be overweight/obese (OR = 1.64). In general, the associations between HRB and BMI or being overweight/obese were limited and mainly related to dietary intake. Awareness campaigns for caregivers should stress that HRB of young children are important and independent of children's weight status. PMID- 26950065 TI - Prediction of Ovarian Hyperstimulation Syndrome in Patients Treated with Corifollitropin alfa or rFSH in a GnRH Antagonist Protocol. AB - STUDY QUESTION: What is the threshold for the prediction of moderate to severe or severe ovarian hyperstimulation syndrome (OHSS) based on the number of growing follicles >= 11 mm and/or estradiol (E2) levels? SUMMARY ANSWER: The optimal threshold of follicles >=11 mm on the day of hCG to identify those at risk was 19 for both moderate to severe OHSS and for severe OHSS. Estradiol (E2) levels were less prognostic of OHSS than the number of follicles >= 11 mm. WHAT IS KNOWN ALREADY: In comparison to long gonadotropin-releasing hormone (GnRH) agonist protocols, the risk of severe OHSS is reduced by approximately 50% in a GnRH antagonist protocol for ovarian stimulation prior to in vitro fertilisation (IVF), while the two protocols provide equal chances of pregnancy per initiated cycle. Nevertheless, moderate to severe OHSS may still occur in GnRH antagonist protocols if human chorionic gonadotropin (hCG) is administered to trigger final oocyte maturation, especially in high responder patients. Severe OHSS following hCG trigger may occur with an incidence of 1-2% in a relatively young (aged 18 to 36 years) IVF population treated in a GnRH-antagonist protocol. STUDY DESIGN, SIZE, DURATION: From the Engage, Ensure and Trust trials, in total, 2,433 women who received hCG for oocyte maturation and for whom the number of follicles >= 11 mm and the level of E2 on the day of hCG administration were known were included in the analyses. PARTICIPANTS/MATERIALS, SETTING, METHODS: The threshold for OHSS prediction of moderate and severe OHSS was assessed in women treated with corifollitropin alfa or daily recombinant follicle stimulation hormone (rFSH) in a gonadotropin-releasing hormone (GnRH)-antagonist protocol. Receiver operating characteristics curve analyses for moderate to severe OHSS and severe OHSS were performed on the combined dataset and the sensitivity and specificity for the optimal threshold of number of follicles >= 11 mm, E2 levels on the day of (hCG), and a combination of both, were determined. MAIN RESULTS AND THE ROLE OF CHANCE: The optimal threshold of follicles >= 11 mm on the day of hCG to identify those at risk of moderate to severe OHSS was 19 (sensitivity and specificity 62.3% and 75.6%, respectively) and for severe OHSS was also 19 (sensitivity and specificity 74.3% and 75.3%, respectively). The positive and negative predictive values were 6.9% and 98.6%, respectively, for moderate to severe OHSS, and 4.2% and 99.5% for severe OHSS. LIMITATIONS, REASONS FOR CAUTION: This was a retrospective analysis of combined data from three trials following ovarian stimulation with two different gonadotropins. WIDER IMPLICATIONS OF THE FINDINGS: For patients with 19 follicles or more >=11 mm on the day of hCG, measures to prevent the development of OHSS should be considered. Secondary preventive measures include cycle cancellation or coasting, use of a GnRH agonist to trigger final oocyte maturation in place of hCG and a freeze all strategy. TRIAL REGISTRATION: ClinicalTrials.gov NCT00702845 NCT00696800 NCT00696878. PMID- 26950066 TI - Mouse Model of Respiratory Tract Infection Induced by Waddlia chondrophila. AB - Waddlia chondrophila, an obligate intracellular bacterium belonging to the Chlamydiales order, is considered as an emerging pathogen. Some clinical studies highlighted a possible role of W. chondrophila in bronchiolitis, pneumonia and miscarriage. This pathogenic potential is further supported by the ability of W. chondrophila to infect and replicate within human pneumocytes, macrophages and endometrial cells. Considering that W. chondrophila might be a causative agent of respiratory tract infection, we developed a mouse model of respiratory tract infection to get insight into the pathogenesis of W. chondrophila. Following intranasal inoculation of 2 x 108 W. chondrophila, mice lost up to 40% of their body weight, and succumbed rapidly from infection with a death rate reaching 50% at day 4 post-inoculation. Bacterial loads, estimated by qPCR, increased from day 0 to day 3 post-infection and decreased thereafter in surviving mice. Bacterial growth was confirmed by detecting dividing bacteria using electron microscopy, and living bacteria were isolated from lungs 14 days post-infection. Immunohistochemistry and histopathology of infected lungs revealed the presence of bacteria associated with pneumonia characterized by an important multifocal inflammation. The high inflammatory score in the lungs was associated with the presence of pro-inflammatory cytokines in both serum and lungs at day 3 post infection. This animal model supports the role of W. chondrophila as an agent of respiratory tract infection, and will help understanding the pathogenesis of this strict intracellular bacterium. PMID- 26950067 TI - Education Influences Creativity in Dyslexic and Non-Dyslexic Children and Teenagers. AB - BACKGROUND AND STUDY HYPOTHESIS: Are dyslexic children and teenagers more creative than non-dyslexic children and teenagers? Whether creativity is higher in dyslexia, and whether this could be related to neurological development specific to the dyslexic disorder, or to compensatory strategies acquired later in life, remains unclear. Here, we suggest an additional role of differential educational approaches taken in each school that could either enhance or suppress an already higher baseline creativity of dyslexic children and teenagers. RESULTS: Creativity in dyslexic and non-dyslexic children and teenagers from different schools in France and in Belgium, as well as in students from different universities, was evaluated with the Torrance Test of Creative Thinking (TTCT). Children and teenagers with dyslexia and/or with other similar dysfunctions showed higher creativity scores than non-dyslexic participants. Moreover, the educational approach could further enhance the creative scores in dyslexia, which could be as high as those measured in students from art universities. CONCLUSIONS: We conclude that dyslexic children and teenagers can be highly creative. Yet, expression of creativity can be modulated by educational approach, indicating a probable advantage for personal follow-up compared to normalizing education strategies. PMID- 26950068 TI - The BH3 Mimetic Obatoclax Accumulates in Lysosomes and Causes Their Alkalinization. AB - Obatoclax belongs to a class of compounds known as BH3 mimetics which function as antagonists of Bcl-2 family apoptosis regulators. It has undergone extensive preclinical and clinical evaluation as a cancer therapeutic. Despite this, it is clear that obatoclax has additional pharmacological effects that contribute to its cytotoxic activity. It has been claimed that obatoclax, either alone or in combination with other molecularly targeted therapeutics, induces an autophagic form of cell death. In addition, obatoclax has been shown to inhibit lysosomal function, but the mechanism of this has not been elucidated. We have evaluated the mechanism of action of obatoclax in eight ovarian cancer cell lines. Consistent with its function as a BH3 mimetic, obatoclax induced apoptosis in three cell lines. However, in the remaining cell lines another form of cell death was evident because caspase activation and PARP cleavage were not observed. Obatoclax also failed to show synergy with carboplatin and paclitaxel, chemotherapeutic agents which we have previously shown to be synergistic with authentic Bcl-2 family antagonists. Obatoclax induced a profound accumulation of LC-3 but knockdown of Atg-5 or beclin had only minor effects on the activity of obatoclax in cell growth assays suggesting that the inhibition of lysosomal function rather than stimulation of autophagy may play a more prominent role in these cells. To evaluate how obatoclax inhibits lysosomal function, confocal microscopy studies were conducted which demonstrated that obatoclax, which contains two basic pyrrole groups, accumulates in lysosomes. Studies using pH sensitive dyes demonstrated that obatoclax induced lysosomal alkalinization. Furthermore, obatoclax was synergistic in cell growth/survival assays with bafilomycin and chloroquine, two other drugs which cause lysosomal alkalinization. These studies explain, for the first time, how obatoclax inhibits lysosomal function and suggest that lysosomal alkalinization contributes to the cytotoxic activity of obatoclax. PMID- 26950069 TI - Indexed PCR Primers Induce Template-Specific Bias in Large-Scale DNA Sequencing Studies. AB - Massively parallel sequencing is rapidly emerging as an efficient way to quantify biodiversity at all levels, from genetic variation and expression to ecological community assemblage. However, the number of reads produced per sequencing run far exceeds the number required per sample for many applications, compelling researchers to sequence multiple samples per run in order to maximize efficiency. For studies that include a PCR step, this can be accomplished using primers that include an index sequence allowing sample origin to be determined after sequencing. The use of indexed primers assumes they behave no differently than standard primers; however, we found that indexed primers cause substantial template sequence-specific bias, resulting in radically different profiles of the same environmental sample. Likely the outcome of differential amplification efficiency due to primer-template mismatch, two indexed primer sets spuriously change the inferred sequence abundance from the same DNA extraction by up to 77.1%. We demonstrate that a double PCR approach alleviates these effects in applications where indexed primers are necessary. PMID- 26950070 TI - A Parallel G Quadruplex-Binding Protein Regulates the Boundaries of DNA Elimination Events of Tetrahymena thermophila. AB - Guanine (G)-rich DNA readily forms four-stranded quadruplexes in vitro, but evidence for their participation in genome regulation is limited. We have identified a quadruplex-binding protein, Lia3, that controls the boundaries of germline-limited, internal eliminated sequences (IESs) of Tetrahymena thermophila. Differentiation of this ciliate's somatic genome requires excision of thousands of IESs, targeted for removal by small-RNA-directed heterochromatin formation. In cells lacking LIA3 (DeltaLIA3), the excision of IESs bounded by specific G-rich polypurine tracts was impaired and imprecise, whereas the removal of IESs without such controlling sequences was unaffected. We found that oligonucleotides containing these polypurine tracts formed parallel G-quadruplex structures that are specifically bound by Lia3. The discovery that Lia3 binds G quadruplex DNA and controls the accuracy of DNA elimination at loci with specific G-tracts uncovers an unrecognized potential of quadruplex structures to regulate chromosome organization. PMID- 26950071 TI - Long Noncoding RNA RGMB-AS1 Indicates a Poor Prognosis and Modulates Cell Proliferation, Migration and Invasion in Lung Adenocarcinoma. AB - Lung cancer is the most common cause of cancer-related mortality worldwide. It is a complex disease involving multiple genetic and epigenetic alterations. The development of transcriptomics revealed the important role of long non-coding RNAs (lncRNAs) in lung cancer occurrence and development. Here, microarray analysis of lung adenocarcinoma tissues showed the abnormal expression of lncRNA RGMB-AS1. However, the role of lncRNA RGMB-AS1 in lung adenocarcinoma remains largely unknown. We showed that upregulation of lncRNA RGMB-AS1 was significantly correlated with differentiation, TNM stage, and lymph node metastasis. In lung adenocarcinoma cells, downregulation of lncRNA RGMB-AS1 inhibited cell proliferation, migration, invasion, and caused cell cycle arrest at the G1/G0 phase. In vivo experiments showed that lncRNA RGMB-AS1 downregulation significantly suppressed the growth of lung adenocarcinoma. The expression of lncRNA RGMB-AS1 was inversely correlated with that of repulsive guidance molecule b (RGMB) in lung adenocarcinoma tissues, and UCSC analysis and fluorescence detection assay indicated that lncRNA RGMB-AS1 may be involved in the development of human lung adenocarcinoma by regulating RGMB expression though exon2 of RGMB. In summary, our findings indicate that lncRNA RGMB-AS1 may play an important role in lung adenocarcinoma and may serve as a potential therapeutic target. PMID- 26950073 TI - Sex Differences in Reported Concussion Injury Rates and Time Loss From Participation: An Update of the National Collegiate Athletic Association Injury Surveillance Program From 2004-2005 Through 2008-2009. AB - CONTEXT: Epidemiologic studies have identified differences in concussion incidence between the sexes. However, few authors to date have updated injury rates (IRs) and time loss between male and female concussed athletes. OBJECTIVE: To examine sex differences in IRs and time loss in concussed National Collegiate Athletic Association (NCAA) athletes. DESIGN: Descriptive epidemiologic study. SETTING: National Collegiate Athletic Association athletics. PATIENTS OR OTHER PARTICIPANTS: A total of 1702 concusssed NCAA athletes, consisting of 903 females and 779 males participating in soccer, basketball, ice hockey, lacrosse, softball, or baseball over a 5-year period from 2004-2005 through 2008-2009. MAIN OUTCOME MEASURE(S): Using the NCAA Injury Surveillance Program, athletic trainers reported concussions, athlete-exposures (AEs), and time loss across 10 NCAA sports. An IR is the number of injuries in a particular category divided by the number of AEs in that category. RESULTS: During the study period, 1702 concussions were reported during 4 170 427 AEs for an overall total of 5.47 per 10 000 AEs. In sex-comparable sports, females had a 1.4 times higher overall concussion IR than males (IRs = 4.84 and 3.46, respectively), with greater rates in women's baseball/softball, basketball, ice hockey, and soccer than men. Female soccer and basketball players also displayed more time loss after concussion compared with male basketball and soccer players. CONCLUSIONS: Female athletes sustained a higher rate of concussion and, in all sports except lacrosse, had greater time loss from concussion than male athletes. Additional research is needed on sex differences in time loss after concussions. PMID- 26950074 TI - Macro-Climatic Distribution Limits Show Both Niche Expansion and Niche Specialization among C4 Panicoids. AB - Grasses are ancestrally tropical understory species whose current dominance in warm open habitats is linked to the evolution of C4 photosynthesis. C4 grasses maintain high rates of photosynthesis in warm and water stressed environments, and the syndrome is considered to induce niche shifts into these habitats while adaptation to cold ones may be compromised. Global biogeographic analyses of C4 grasses have, however, concentrated on diversity patterns, while paying little attention to distributional limits. Using phylogenetic contrast analyses, we compared macro-climatic distribution limits among ~1300 grasses from the subfamily Panicoideae, which includes 4/5 of the known photosynthetic transitions in grasses. We explored whether evolution of C4 photosynthesis correlates with niche expansions, niche changes, or stasis at subfamily level and within the two tribes Paniceae and Paspaleae. We compared the climatic extremes of growing season temperatures, aridity, and mean temperatures of the coldest months. We found support for all the known biogeographic distribution patterns of C4 species, these patterns were, however, formed both by niche expansion and niche changes. The only ubiquitous response to a change in the photosynthetic pathway within Panicoideae was a niche expansion of the C4 species into regions with higher growing season temperatures, but without a withdrawal from the inherited climate niche. Other patterns varied among the tribes, as macro-climatic niche evolution in the American tribe Paspaleae differed from the pattern supported in the globally distributed tribe Paniceae and at family level. PMID- 26950072 TI - Sulforaphane Preconditioning Sensitizes Human Colon Cancer Cells towards the Bioreductive Anticancer Prodrug PR-104A. AB - The chemoprotective properties of sulforaphane (SF), derived from cruciferous vegetables, are widely acknowledged to arise from its potent induction of xenobiotic-metabolizing and antioxidant enzymes. However, much less is known about the impact of SF on the efficacy of cancer therapy through the modulation of drug-metabolizing enzymes. To identify proteins modulated by a low concentration of SF, we treated HT29 colon cancer cells with 2.5 MUM SF. Protein abundance changes were detected by stable isotope labeling of amino acids in cell culture. Among 18 proteins found to be significantly up-regulated, aldo-keto reductase 1C3 (AKR1C3), bioactivating the DNA cross-linking prodrug PR-104A, was further characterized. Preconditioning HT29 cells with SF reduced the EC50 of PR 104A 3.6-fold. The increase in PR-104A cytotoxicity was linked to AKR1C3 abundance and activity, both induced by SF in a dose-dependent manner. This effect was reproducible in a second colon cancer cell line, SW620, but not in other colon cancer cell lines where AKR1C3 abundance and activity were absent or barely detectable and could not be induced by SF. Interestingly, SF had no significant influence on PR-104A cytotoxicity in non-cancerous, immortalized human colonic epithelial cell lines expressing either low or high levels of AKR1C3. In conclusion, the enhanced response of PR-104A after preconditioning with SF was apparent only in cancer cells provided that AKR1C3 is expressed, while its expression in non-cancerous cells did not elicit such a response. Therefore, a subset of cancers may be susceptible to combined food-derived component and prodrug treatments with no harm to normal tissues. PMID- 26950075 TI - Does Stroke Severity for Repeated Thrombolysis Matter? Response to the Letter by Wu et al. PMID- 26950076 TI - Development and Pilot Testing of 24/7 In-Ambulance Telemedicine for Acute Stroke: Prehospital Stroke Study at the Universitair Ziekenhuis Brussel-Project. AB - BACKGROUND: In-ambulance telemedicine is a recently developed and a promising approach to improve emergency care. We implemented the first ever 24/7 in ambulance telemedicine service for acute stroke. We report on our experiences with the development and pilot testing of the Prehospital Stroke Study at the Universitair Ziekenhuis Brussel (PreSSUB) to facilitate a wider spread of the knowledge regarding this technique. METHODS: Successful execution of the project involved the development and validation of a novel stroke scale, design and creation of specific hardware and software solutions, execution of field tests for mobile internet connectivity, design of new care processes and information flows, recurrent training of all professional caregivers involved in acute stroke management, extensive testing on healthy volunteers, organisation of a 24/7 teleconsultation service by trained stroke experts and 24/7 technical support, and resolution of several legal issues. RESULTS: In all, it took 41 months of research and development to confirm the safety, technical feasibility, reliability, and user acceptance of the PreSSUB approach. Stroke-specific key information can be collected safely and reliably before and during ambulance transportation and can adequately be communicated with the inhospital team awaiting the patient. CONCLUSION: This paper portrays the key steps required and the lessons learned for successful implementation of a 24/7 expert telemedicine service supporting patients with acute stroke during ambulance transportation to the hospital. PMID- 26950077 TI - Comprehension and Data-Sharing Behavior of Direct-To-Consumer Genetic Test Customers. AB - AIM: The aim of this study was to evaluate current direct-to-consumer (DTC) genetic customers' ability to interpret and comprehend test results and to determine if honest brokers are needed. METHOD: One hundred and twenty-two customers of the DTC genetic testing company 23andMe were polled in an online survey. The subjects were asked about their personal test results and to interpret the results of two mock test cases (type 2 diabetes and multiple sclerosis), where results were translated into disease probability for an individual compared to the public. RESULTS: When asked to evaluate the risk, 72.1% correctly assessed the first case and 77% were correct on the second case. Only 23.8% of those surveyed were able to interpret both cases correctly. x03C7;2 and logistic regression were used to interpret the results. Participants who took the time to read the DTC test-provided supplemental material were 3.93 times (p = 0.040) more likely to correctly interpret the test results than those who did not. The odds for correctly interpreting the test cases were 3.289 times (p = 0.011) higher for those who made more than USD 50,000 than those who made less. Survey results were compared to the Health Information National Trends Survey (HINTS) phase 4 cycle 3 data to evaluate national trends. CONCLUSIONS: Most of the subjects were able to correctly interpret the test cases, yet a majority did not share their results with a health-care professional. As the market for DTC genetic testing grows, test comprehension will become more critical. Involving more health professionals in this process may be necessary to ensure proper interpretations. PMID- 26950078 TI - Thermal Reactor Model for Large-Scale Algae Cultivation in Vertical Flat Panel Photobioreactors. AB - Microalgae can grow significantly faster than terrestrial plants and are a promising feedstock for sustainable value added products encompassing pharmaceuticals, pigments, proteins and most prominently biofuels. As the biomass productivity of microalgae strongly depends on the cultivation temperature, detailed information on the reactor temperature as a function of time and geographical location is essential to evaluate the true potential of microalgae as an industrial feedstock. In the present study, a temperature model for an array of vertical flat plate photobioreactors is presented. It was demonstrated that mutual shading of reactor panels has a decisive effect on the reactor temperature. By optimizing distance and thickness of the panels, the occurrence of extreme temperatures and the amplitude of daily temperature fluctuations in the culture medium can be drastically reduced, while maintaining a high level of irradiation on the panels. The presented model was developed and applied to analyze the suitability of various climate zones for algae production in flat panel photobioreactors. Our results demonstrate that in particular Mediterranean and tropical climates represent favorable locations. Lastly, the thermal energy demand required for the case of active temperature control is determined for several locations. PMID- 26950079 TI - Evaluating dosage effects for the positive action program: How implementation impacts internalizing symptoms, aggression, school hassles, and self-esteem. AB - Positive Action (PA) is a school-based intervention for elementary-, middle-, and high-school students that aims to decrease problem behaviors (e.g., violence, substance use) and increase positive behaviors (e.g., academic achievement, school engagement). PA has a long history of documented success achieving these aims, making it an Evidence Based Practice (EBP). Intervention research on EBP's has established the importance of implementation fidelity, especially with regard to program dosage; failure to properly implement an EBP can have negative consequences on targeted outcomes, especially if participants are exposed to a low dosage of the program (e.g., fewer lessons than specified). Much of the current research on PA has neglected to examine how program dosage impacts PA's effect on targeted outcomes. Using propensity score models, multiple imputation, and a 2-level hierarchical linear model, the current study fills this gap and examines how different dosages of PA as measured by years participating in PA and number of PA lessons, impacts adolescent internalizing symptoms, aggression, perceptions of school hassles, and self-esteem over a 3-year period. The current sample included middle school students in grades 6, 7, and 8 (N = 5,894). The findings indicate that students who received 3 years of the PA intervention and a high number of PA lessons had a significantly higher self-esteem score than those who received 0 years of PA or zero lessons. Participants who received 1 year of PA also reported significantly lower school hassle scores than those who received 0 years. Dosage had no statistically significant effects on aggression or internalizing score. Implications are discussed. (PsycINFO Database Record PMID- 26950080 TI - Caregiving-specific worry, affiliate stigma, and perceived social support on psychological distress of caregivers of children with physical disability in Hong Kong. AB - The present study tested a model on the relationship between functional status of children with physical disability, caregiving-specific worry, affiliate stigma, and psychological distress among their caregivers. One hundred thirty-one caregivers of children with physical disability in Hong Kong completed a self report questionnaire. Structural equation modeling showed that the final model had good fit to the data: chi2 = 102.05, (df = 83, p = .08), comparative fit index = .98, nonnormed fit index = .98, standardized root mean square residual = .08, root mean square error of approximation = .04. Caregivers whose children had a lower functional status reported more caregiving-specific worry. Affiliate stigma had significant and positive indirect effect on psychological distress through increasing worry. Results also supported the direct and indirect effects of perceived social support in ameliorating worry, affiliate stigma, and psychological distress. Findings suggested that health care and social service providers should consider the functional impairment of each child when designing stress reduction interventions for their caregivers. Findings implicate the importance of establishing barrier-free environment and public facilities in the society. Caregivers are encouraged to distinguish those worries that are actionable and convert them into problem solving plans and to actively engage in peer support and social activities to reduce their affiliate stigma. To truly promote inclusion and well-being of individuals with disability and their caregivers, the scope and targets of social services and stigma reduction programs by the government should include not only the persons with disabilities, but also their caregivers and family members who play essential roles in the rehabilitation journey. (PsycINFO Database Record PMID- 26950081 TI - Intraoperative hypotension is associated with myocardial damage in noncardiac surgery: An observational study. AB - BACKGROUND: Perioperative myocardial damage and infarction (MI) is associated with increased mortality and other postoperative complications. OBJECTIVES: To assess the incidence of perioperative myocardial damage in patients undergoing major elective noncardiac surgery, to elucidate any association with postoperative MI and mortality and to estimate the impact of preoperative risk factors and intraoperative hypotension. DESIGN: Observational cohort study. SETTING: Karolinska University Hospital, Stockholm, Sweden, from October 2012 to May 2013. PATIENTS: In this single-centre study, all adult patients undergoing major elective noncardiac surgery who were scheduled for an overnight admission to the postoperative unit were included. Patients undergoing phaeochromocytoma surgery were excluded. Preoperative risk factors (co-morbidities), intraoperative events (hypotension defined as a 50% decrease in SBP relative to each patient's baseline and lasting >5 min) and postoperative data were collected from medical records. Levels of high-sensitivity cardiac troponin T (hs-cTnT) were measured on postoperative day 1. Myocardial damage was defined as an increase in the hs-cTnT value above 14 ng l. A cardiologist reviewed all cases of MI occurring within 30 days after surgery. MAIN OUTCOME MEASURES: Myocardial damage, MI and mortality within 30 days after surgery. RESULTS: Of the final cohort of 300 patients, 90 (30%) had myocardial damage on postoperative day 1 and 15 (5%) developed postoperative MI within 30 days. Multivariate logistic regression analysis demonstrated that an intraoperative reduction in SBP more than 50% from baseline lasting more than 5 min was an independent predictor of postoperative hs-cTnT elevation (odds ratio, 4.4; 95% confidence interval, 1.8 to 11.1). CONCLUSIONS: In a cohort of 300 patients undergoing major elective noncardiac surgery, there was a high incidence of myocardial damage and an association between an intraoperative reduction in SBP more than 50% from baseline lasting more than 5 min and myocardial damage. PMID- 26950082 TI - Satisfaction and safety using dexmedetomidine or propofol sedation during endoscopic oesophageal procedures: A randomised controlled trial. AB - BACKGROUND: Dexmedetomidine possesses anxiolytic and hypnotic properties without respiratory side-effects, making it theoretically an ideal sedative agent for endoscopic procedures. OBJECTIVE: We aimed to compare satisfaction and safety among outpatients receiving sedation with dexmedetomidine or propofol for endoscopic oesophageal procedures. DESIGN: A randomised controlled study. SETTING: Endoscopic intervention suite at the Academic Medical Centre in Amsterdam, Netherlands. PARTICIPANTS: Patients aged at least 18 years, and American Society of Anesthesiologists' physical status 1 to 3. INTERVENTION: Total 63 patients were randomised to receive either dexmedetomidine (D) or propofol (P). Pain was treated with alfentanil in both groups. MAIN OUTCOME MEASURES: The primary outcomes were patients' and endoscopists' satisfaction levels measured by validated questionnaires (1 = very dissatisfied; 7 = highly satisfied). A secondary outcome was safety, determined by blood pressure, heart rate and oxygen saturation during and after the procedure, and respiratory rate and noninvasive cardiac output during the procedure. RESULTS: Satisfaction of patients [median (IQR); group D, 5.0 (3.75 to 5.75) vs. group P, 6.25 (5.3 to 6.5)] and satisfaction of gastroenterologists [group D, 5.0 (4.4 to 5.8) vs. group P, 6.0 (5.4 to 6.0)] were lower in group D (both P < 0.001). More patients in group D would not recommend this form of sedation to one of their friends (group D, 15 of 32 vs. group P, 1 of 31; P < 0.001). Total 30 min after the procedure, heart rate [group D, 60 bpm (52 to 69) vs. group P, 70 bpm (60 to 81), P = 0.031] and SBP group D, 112 mmHg (92 to 132) vs. group P, 120 mmHg (108 to 132); P = 0.013] were significantly lower after dexmedetomidine sedation. There were no other differences in safety between groups. CONCLUSION: Compared with propofol, sedation with dexmedetomidine resulted in less satisfaction, and caused prolonged haemodynamic depression after endoscopic oesophageal procedures. TRIAL REGISTRATION: ISRCTN Register (ISRCTN 68599804). PMID- 26950083 TI - Anaesthesia and orphan disease: rocuronium and sugammadex in the anaesthetic management of a parturient with Becker's myotonia congenita. PMID- 26950084 TI - The S66x8 benchmark for noncovalent interactions revisited: explicitly correlated ab initio methods and density functional theory. AB - The S66x8 dataset for noncovalent interactions of biochemical relevance has been re-examined by means of MP2-F12 and CCSD(F12*)(T) methods. We deem our revised benchmark data to be reliable to about 0.05 kcal mol(-1) RMS. Most levels of DFT perform quite poorly in the absence of dispersion corrections: somewhat surprisingly, that is even the case for the double hybrids and for dRPA75. Analysis of optimized D3BJ parameters reveals that the main benefit of dRPA75 and DSD double hybrids alike is the treatment of midrange dispersion. dRPA75-D3BJ is the best performer overall at RMSD = 0.10 kcal mol(-1). The nonlocal VV10 dispersion functional is especially beneficial for the double hybrids, particularly in DSD-PBEP86-NL (RMSD = 0.12 kcal mol(-1)). Other recommended dispersion-corrected functionals with favorable price/performance ratios are omegaB97X-V, and, surprisingly, B3LYP-D3BJ and BLYP-D3BJ (RMSDs of 0.23, 0.20 and 0.23 kcal mol(-1), respectively). Without dispersion correction (but parametrized for midrange interactions) M06-2X has the lead (RMSD = 0.45 kcal mol(-1)). A collection of three energy-based diagnostics yields similar information to an SAPT analysis about the nature of the noncovalent interaction. Two of those are the percentages of Hartree-Fock and of post-MP2 correlation effects in the interaction energy; the third, CSPI = [IE - IE]/[IE + IE] or its derived quantity DEBC = CSPI/(1 + CSPI(2))(1/2), describes the character of the MP2 correlation contribution, ranging from 0 (purely dispersion) to 1 (purely other effects). In addition, we propose an improved, parameter-free scaling for the (T) contribution based on the Ecorr[CCSD-F12b]/Ecorr[CCSD] and Ecorr[CCSD(F12*)]/Ecorr[CCSD] ratios. For Hartree-Fock and conventional DFT calculations, full counterpoise generally yields the fastest basis set convergence, while for double hybrids, half-counterpoise yields faster convergence, as previously established for correlated ab initio methods. PMID- 26950085 TI - Evans Syndrome Secondary to Common Variable Immune Deficiency. AB - Evans syndrome is an underdiagnosed condition consisting of simultaneous or sequential combination of autoimmune hemolytic anemia and immune-mediated thrombocytopenia. We report a case of severe Evans syndrome presenting as altered mental status, a rare presenting sign of the disease. This case highlights the difficulty in diagnosing Evans syndrome and provides a review of the literature and management strategies for treating the disorder. PMID- 26950086 TI - Cancer Incidence Among Adolescents and Young Adults (15 to 29 Years) in Brazil. AB - The spectrum of cancers commonly found in adolescents and young adults (AYAs) differs from those in children and adults; therefore, the childhood classification is not appropriate for this population. Here we used a newly proposed classification system to reclassify cases of AYAs from Brazilian population-based cancer registries (PBCRs) in 5 geographic regions of Brazil. We aimed to describe the cancer incidence rates within this age group according to PBCR. Using the world population, incidence rates per million were analyzed in each diagnostic subgroup according to sex and age at diagnosis (15 to 19 y, 20 to 24 y, and 25 to 29 y). The median incidence rate was 232.31 per million for females and 218.07 per million for males. Incidence increased with age, with the highest rate observed for 25- to 29-year-olds in both sexes. Carcinomas, lymphomas, and skin tumors were most frequent among AYAs. High incidence rates of cervix-uterus carcinoma were observed in most PBCRs. AYAs present epidemiological characteristics that differ from those of children, reinforcing the need for a new classification. This study describes, for the first time, the cancer incidence rate in AYAs in Brazil, and we believe that our findings represent the Brazilian profile. PMID- 26950088 TI - Irreversible Electroporation as an Effective Technique for Ablating Human Metastatic Osteosarcoma. AB - Irreversible electroporation (IRE) induces apoptosis in tumor cells with electric energy, allowing treatment of unresectable tumors. One potential application is metastatic osteosarcoma (OS) in the pediatric population. A 12-year-old underwent thoracotomy with resection of metastatic OS. IRE was applied to 1 resected tumor section. Using 2 probes, 100 pulses with width of 90 ms were delivered. Efficacy was measured by increase in current draw during treatment. The treated sample was analyzed with hematoxylin and eosin and transmission electron microscopy. Default voltage of 1800 kV was ineffective. Voltage of 2700 kV caused excessive current draw and was aborted to prevent thermal injury. At 2200 kV, current draw rise was 9 amps, signifying successful treatment. Untreated specimen showed viable OS, normal surrounding lung tissue. Treated tumor had edema within the tumor and in surrounding lung tissue, with intra-alveolar hemorrhage and cellular architecture destruction. There was also evidence for cellular destruction such as disruption of lipid bilayer and release of intracellular fluid. Optimal voltage for treatment was 2200 kV, likely higher due to electrical conduction variation in the aerated lung. IRE may be an option for pediatric patients with unresectable metastatic OS. PMID- 26950087 TI - Preventive Care Delivery to Young Children With Sickle Cell Disease. AB - Preventive services can reduce the morbidity of sickle cell disease (SCD) in children but are delivered unreliably. We conducted a retrospective cohort study of children aged 2 to 5 years with SCD, evaluating each child for 14 months and expecting that he/she should receive >=75% of days covered by antibiotic prophylaxis, >=1 influenza immunization, and >=1 transcranial Doppler ultrasound (TCD). We used logistic regression to quantify the relationship between ambulatory generalist and hematologist visits and preventive services delivery. Of 266 children meeting the inclusion criteria, 30% consistently filled prophylactic antibiotic prescriptions. Having >=2 generalist, non-well child care visits or >=2 hematologist visits was associated with more reliable antibiotic prophylaxis. Forty-one percent of children received >=1 influenza immunizations. Children with >=2 hematologist visits were most likely to be immunized (62% vs. 35% among children without a hematologist visit). Only 25% of children received >=1 TCD. Children most likely to receive a TCD (42%) were those with >=2 hematologist visits. One in 20 children received all 3 preventive services. Preventive services delivery to young children with SCD was inconsistent but associated with multiple visits to ambulatory providers. Better connecting children with SCD to hematologists and strengthening preventive care delivery by generalists are both essential. PMID- 26950089 TI - Significance of BAFF/APRIL Expression and Their Receptors in Pediatric Patients With Acute Lymphoblastic Leukemia. AB - In this study, we investigated the mRNA expression and protein levels of B-cell activating factor (BAFF)/a proliferation-inducing ligand (APRIL) and their receptors in acute lymphoblastic leukemia (ALL) cell lines and pediatric patients with ALL using real-time polymerase chain reaction, enzyme-linked immunosorbent assay, and Western blotting. The location and level of the BAFF/APRIL proteins in ALL cell lines were also detected by immunofluorescence cytochemistry and flow cytometry. Correlations between plasma protein levels of BAFF/APRIL and primary clinical parameters were analyzed. We found that BAFF/APRIL was highly expressed in pediatric ALL patients and ALL cell lines. The BAFF/APRIL proteins were located on the cell membrane, and the proportion of positive cells and mean fluorescence intensity were significantly higher than in the healthy control group (P<0.05). The mRNA expression and protein levels of BAFF/APRIL and their receptors in untreated ALL children were significantly higher than in healthy controls (P<0.05) as well as were significantly reduced in the remission group (P<0.05). The plasma protein levels of BAFF/APRIL were positively correlated with the white blood cell count, lactate dehydrogenase, and serum ferritin. Abnormal levels of BAFF/APRIL in pediatric ALL suggest that BAFF/APRIL are associated with the development and progression of ALL in children and may provide information for the development of BAFF-based and APRIL-based targeted therapies. PMID- 26950090 TI - Usability of American Nurses Association State Web Sites: A Follow-up Evaluation. AB - The American Nurses Association supports professional nurses through Web sites administered by state nursing associations, providing important information for current and potential members. Optimal usability of these Web sites is critical for nurses to obtain the information they seek. Heuristic evaluations are general criteria used to evaluate the usability of technology such as Web sites. A study published in 2014, using heuristic criteria from Nielsen's 10 principles and Health on The Web, evaluated 27 state nursing Web sites to identify usability concerns that could prevent nurses from obtaining accurate information regarding state nursing practice. The purpose of this study is to conduct a second heuristic evaluation to assess for changes in a subset of 12 Web sites. The analysis comparing the evaluation from 2012 to 2014 found that mean scores increased and variance decreased; however, no statistically significant difference was found between the two studies. Scores increased in 2014 for "help users to diagnose, and recover from errors," "match between the system and real world," and "consistency and standards." Scores decreased due to absence of mission statements and identification of intended audience. Ideally, Web site designers will use the feedback from this study and make changes that improve their usability to provide information to nurses. PMID- 26950091 TI - Investigating Relationships Between Health-Related Problems and Online Health Information Seeking. AB - Online health information seeking (OHIS) functions as a coping strategy to relieve health-related stress and problems. When people rate their health as poor or felt concern about their health, they frequently visit the Internet to seek health-related information in order to understand their symptoms and treatments. Regarding this role of OHIS, it is important to understand the relationships between health-related problems and OHIS. This study applies the Common-Sense Model as a theoretical lens to examine the relationship between health-related problems (ie, diagnosis of cancer, poor self-rated health, and psychological distress) and OHIS of adults in the US. Using the Health Information National Trends Survey 4 Cycle 1 (2012), a total of 2351 adult Internet users was included in this research. Hierarchical logistic regression analyses were conducted to examine the research model, and the model adding psychological distress resulted in a statistically significant improvement in model fit. In this study, lower levels of self-rated health and higher levels of psychological distress were significantly associated with higher odds of OHIS. Study findings support the idea that individuals' low levels of self-rated health and high levels of perceived psychological distress make people search for health-related information via the Internet in order to cope with health-related concern and distress. PMID- 26950092 TI - Nurses' Use of a Web-Based National Guide for Child Health Care. AB - Rikshandboken i Barnhalsovard is a Swedish Web-based guide for child healthcare, providing quality-ensured guidelines and support contributing to equality in child healthcare among all children. In 2015, a new child healthcare program was implemented and made available in this Web-based guide. The aim of this study was to investigate how child healthcare nurses use Rikshandboken i Barnhalsovard and factors affecting its use. The study was a comprehensive Web survey of 2376 child healthcare nurses in Sweden answered by 1309. Statistical processing was performed using descriptive and analytical methods. Rikshandboken i Barnhalsovard was widely used by the respondents, but regional differences and number of years in the profession affected the use. Almost all nurses were satisfied with the usability, content, and design and felt that a national guide for child healthcare is important. This indicates that an established Web-based national guide is an appropriate setting when a new national program is implemented. In order to achieve an equal and equitable child healthcare, it is essential that all nurses use the national guide to provide evidence-based practice. The value of main child healthcare units as regional facilitators in the innovation process of Rikshandboken i Barnhalsovard should not be underestimated. PMID- 26950093 TI - OsSPL13 controls grain size in cultivated rice. AB - Although genetic diversity has a cardinal role in domestication, abundant natural allelic variations across the rice genome that cause agronomically important differences between diverse varieties have not been fully explored. Here we implement an approach integrating genome-wide association testing with functional analysis on grain size in a diverse rice population. We report that a major quantitative trait locus, GLW7, encoding the plant-specific transcription factor OsSPL13, positively regulates cell size in the grain hull, resulting in enhanced rice grain length and yield. We determine that a tandem-repeat sequence in the 5' UTR of OsSPL13 alters its expression by affecting transcription and translation and that high expression of OsSPL13 is associated with large grains in tropical japonica rice. Further analysis indicates that the large-grain allele of GLW7 in tropical japonica rice was introgressed from indica varieties under artificial selection. Our study demonstrates that new genes can be effectively identified on the basis of genome-wide association data. PMID- 26950094 TI - Genomic analysis identifies new drivers and progression pathways in skin basal cell carcinoma. AB - Basal cell carcinoma (BCC) of the skin is the most common malignant neoplasm in humans. BCC is primarily driven by the Sonic Hedgehog (Hh) pathway. However, its phenotypic variation remains unexplained. Our genetic profiling of 293 BCCs found the highest mutation rate in cancer (65 mutations/Mb). Eighty-five percent of the BCCs harbored mutations in Hh pathway genes (PTCH1, 73% or SMO, 20% (P = 6.6 * 10(-8)) and SUFU, 8%) and in TP53 (61%). However, 85% of the BCCs also harbored additional driver mutations in other cancer-related genes. We observed recurrent mutations in MYCN (30%), PPP6C (15%), STK19 (10%), LATS1 (8%), ERBB2 (4%), PIK3CA (2%), and NRAS, KRAS or HRAS (2%), and loss-of-function and deleterious missense mutations were present in PTPN14 (23%), RB1 (8%) and FBXW7 (5%). Consistent with the mutational profiles, N-Myc and Hippo-YAP pathway target genes were upregulated. Functional analysis of the mutations in MYCN, PTPN14 and LATS1 suggested their potential relevance in BCC tumorigenesis. PMID- 26950097 TI - Group CBT versus MBSR for social anxiety disorder: A randomized controlled trial. AB - OBJECTIVE: The goal of this study was to investigate treatment outcome and mediators of cognitive-behavioral group therapy (CBGT) versus mindfulness-based stress reduction (MBSR) versus waitlist (WL) in patients with generalized social anxiety disorder (SAD). METHOD: One hundred eight unmedicated patients (55.6% female; mean age = 32.7 years, SD = 8.0; 43.5% Caucasian, 39% Asian, 9.3% Hispanic, 8.3% other) were randomized to CBGT versus MBSR versus WL and completed assessments at baseline, posttreatment/WL, and at 1-year follow-up, including the Liebowitz Social Anxiety Scale-Self-Report (primary outcome; Liebowitz, 1987) as well as measures of treatment-related processes. RESULTS: Linear mixed model analysis showed that CBGT and MBSR both produced greater improvements on most measures compared with WL. Both treatments yielded similar improvements in social anxiety symptoms, cognitive reappraisal frequency and self-efficacy, cognitive distortions, mindfulness skills, attention focusing, and rumination. There were greater decreases in subtle avoidance behaviors following CBGT than MBSR. Mediation analyses revealed that increases in reappraisal frequency, mindfulness skills, attention focusing, and attention shifting, and decreases in subtle avoidance behaviors and cognitive distortions, mediated the impact of both CBGT and MBSR on social anxiety symptoms. However, increases in reappraisal self efficacy and decreases in avoidance behaviors mediated the impact of CBGT (vs. MBSR) on social anxiety symptoms. CONCLUSIONS: CBGT and MBSR both appear to be efficacious for SAD. However, their effects may be a result of both shared and unique changes in underlying psychological processes. PMID- 26950098 TI - The efficacy of guided self-instruction for patients with idiopathic chronic fatigue: A randomized controlled trial. AB - OBJECTIVE: To determine the efficacy of a cognitive-behavioral intervention for patients meeting U.S. Centers for Disease Control and Prevention (CDC) criteria for idiopathic chronic fatigue (ICF). ICF is thought to be a less severe disorder than chronic fatigue syndrome (CFS). The intervention consisted of a booklet with self-instructions combined with e-mail contact with a therapist. METHOD: Randomized controlled trial conducted at an outpatient facility. All patients suffered from severe and persistent fatigue with moderate impairment levels or fewer than 4 additional symptoms. Patients were randomly allocated to either guided self-instruction or a wait-list control group. Primary outcome measures were fatigue severity assessed with the Checklist Individual Strength and level of overall impairment assessed with the Sickness Impact Profile. Outcome measures were assessed prior to randomization and following treatment or wait-list control group. RESULTS: One hundred patients were randomly allocated to the intervention or a wait-list control group and 95 completed second assessment. An intention-to treat analysis showed significant treatment effects for fatigue severity (-8.98, 95% confidence interval [CI] [-13.99, -3.97], Cohen's d = 0.68, p < .001) and for overall impairment (-317.19, 95% CI [-481.70, -152.68], Cohen's d = 0.53, p < .01) in favor of the intervention. The number of additional symptoms and overall impairment at baseline did not moderate posttreatment fatigue severity. Baseline overall impairment moderated posttreatment impairment. CONCLUSIONS: Patients with ICF can be treated effectively with a minimal intervention. This is relevant as ICF is more prevalent than CFS and treatment capacity is limited. PMID- 26950100 TI - Anticancer Effects of Sinulariolide-Conjugated Hyaluronan Nanoparticles on Lung Adenocarcinoma Cells. AB - Lung cancer is one of the most clinically challenging malignant diseases worldwide. Sinulariolide (SNL), extracted from the farmed coral species Sinularia flexibilis, has been used for suppressing malignant cells. For developing anticancer therapeutic agents, we aimed to find an alternative for non-small cell lung cancer treatment by using SNL as the target drug. We investigated the SNL bioactivity on A549 lung cancer cells by conjugating SNL with hyaluronan nanoparticles to form HA/SNL aggregates by using a high-voltage electrostatic field system. SNL was toxic on A549 cells with an IC50 of 75 ug/mL. The anticancer effects of HA/SNL aggregates were assessed through cell viability assay, apoptosis assays, cell cycle analyses, and western blotting. The size of HA/SNL aggregates was approximately 33-77 nm in diameter with a thin continuous layer after aggregating numerous HA nanoparticles. Flow cytometric analysis revealed that the HA/SNL aggregate-induced apoptosis was more effective at a lower SNL dose of 25 ug/mL than pure SNL. Western blotting indicated that caspases-3, -8, and -9 and Bcl-xL and Bax played crucial roles in the apoptotic signal transduction pathway. In summary, HA/SNL aggregates exerted stronger anticancer effects on A549 cells than did pure SNL via mitochondria-related pathways. PMID- 26950099 TI - Synthesis of Naphthalene-Based Push-Pull Molecules with a Heteroaromatic Electron Acceptor. AB - Naphthalene derivatives bearing electron-accepting and electron-donating groups at the 2,6-positions belong to the family of D-pi-A push-pull dyes. It has been found that these compounds, e.g., 2-(1-(6-((2 (fluoro)ethyl)(methyl)amino)naphthalen-2-yl)ethylidene)malononitrile (FDDNP), show not only interesting optical properties, such as solvatochromism, but they have the potential to label protein aggregates of different compositions formed in the brain of patients suffering from neurodegenerative diseases like Alzheimer's (AD). In continuation of our research we set our goal to find new FDDNP analogs, which would inherit optical and binding properties but hopefully show better specificity for tau protein aggregates, which are characteristic for neurodegeneration caused by repetitive mild trauma. In this work we report on the synthesis of new FDDNP analogs in which the acceptor group has been formally replaced with an aromatic five- or six-membered heterocycle. The heterocyclic moiety was annealed to the central naphthalene ring either by classical ring closure reactions or by modern transition metal-catalyzed coupling reactions. The chemical characterization, NMR spectra, and UV/vis properties of all new compounds are reported. PMID- 26950096 TI - Gene regulatory mechanisms underpinning prostate cancer susceptibility. AB - Molecular characterization of genome-wide association study (GWAS) loci can uncover key genes and biological mechanisms underpinning complex traits and diseases. Here we present deep, high-throughput characterization of gene regulatory mechanisms underlying prostate cancer risk loci. Our methodology integrates data from 295 prostate cancer chromatin immunoprecipitation and sequencing experiments with genotype and gene expression data from 602 prostate tumor samples. The analysis identifies new gene regulatory mechanisms affected by risk locus SNPs, including widespread disruption of ternary androgen receptor (AR)-FOXA1 and AR-HOXB13 complexes and competitive binding mechanisms. We identify 57 expression quantitative trait loci at 35 risk loci, which we validate through analysis of allele-specific expression. We further validate predicted regulatory SNPs and target genes in prostate cancer cell line models. Finally, our integrated analysis can be accessed through an interactive visualization tool. This analysis elucidates how genome sequence variation affects disease predisposition via gene regulatory mechanisms and identifies relevant genes for downstream biomarker and drug development. PMID- 26950095 TI - The spotted gar genome illuminates vertebrate evolution and facilitates human teleost comparisons. AB - To connect human biology to fish biomedical models, we sequenced the genome of spotted gar (Lepisosteus oculatus), whose lineage diverged from teleosts before teleost genome duplication (TGD). The slowly evolving gar genome has conserved in content and size many entire chromosomes from bony vertebrate ancestors. Gar bridges teleosts to tetrapods by illuminating the evolution of immunity, mineralization and development (mediated, for example, by Hox, ParaHox and microRNA genes). Numerous conserved noncoding elements (CNEs; often cis regulatory) undetectable in direct human-teleost comparisons become apparent using gar: functional studies uncovered conserved roles for such cryptic CNEs, facilitating annotation of sequences identified in human genome-wide association studies. Transcriptomic analyses showed that the sums of expression domains and expression levels for duplicated teleost genes often approximate the patterns and levels of expression for gar genes, consistent with subfunctionalization. The gar genome provides a resource for understanding evolution after genome duplication, the origin of vertebrate genomes and the function of human regulatory sequences. PMID- 26950102 TI - Constituents of Saffron (Crocus sativus L.) as Potential Candidates for the Treatment of Anxiety Disorders and Schizophrenia. AB - Anxiety disorders and schizophrenia are common public health issues. The dried stigma of the plant Crocus sativus L., (C. sativus) commonly known as saffron are used in folk medicine for various purposes. Several lines of evidence suggest that C. sativus, crocins and safranal are implicated in anxiety and schizophrenia. Here, I intend to critically review advances in research of these emerging molecules for the treatment of anxiety and schizophrenia, discuss their advantages over currently used anxiolytics and neuroleptics, as well remaining challenges. Current analysis shows that C. sativus and its components might be a promising class of compounds for the treatment of the above mentioned psychiatric diseases. PMID- 26950101 TI - Elucidation of Transport Mechanism of Paeoniflorin and the Influence of Ligustilide, Senkyunolide I and Senkyunolide A on Paeoniflorin Transport through Mdck-Mdr1 Cells as Blood-Brain Barrier in Vitro Model. AB - The objectives of the present investigation were to: (1) elucidate the transport mechanism of paeoniflorin (PF) across MDCK-MDR1 monolayers; and (2) evaluate the effect of ligustilide (LIG), senkyunolide I (SENI) and senkyunolide A (SENA) on the transport of PF through blood-brain barrier so as to explore the enhancement mechanism. Transport studies of PF were performed in both directions, from apical to basolateral side (A->B) and from basolateral to apical sides (B->A). Drug concentrations were analyzed by LC-MS/MS. PF showed relatively poor absorption in MDCK-MDR1 cells, apparent permeability coefficients (Papp) ranging from 0.587 * 10(-6) to 0.705 * 10(-6) cm/s. In vitro experiments showed that the transport of PF in both directions was concentration dependent and not saturable. The B->A/A >B permeability ER of PF was more than 2 in the MDCK-MDR1 cells, which indicated that the transport mechanism of PF might be passive diffusion as the dominating process with the active transportation mediated mechanism involved. The increased Papp of PF in A->B direction by EDTA-Na2 suggested that PF was absorbed via the paracellular route. The P-gp inhibitor verapamil could significantly increase the transport of PF in A->B direction, and ER decreased from 2.210 to 0.690, which indicated that PF was P-gp substance. The transport of PF in A->B direction significantly increased when co-administrated with increasing concentrations of LIG, SENI and SENA. An increased cellular accumulation of Rho 123 and Western blot analysis indicated that LIG, SENI and SENA had increased the transport of PF in the BBB models attribute to down-regulate P-gp expression. A decrease in transepithelial electrical resistance (TEER) during the permeation experiment can be explained by the modulation and opening of the tight junctions caused by the permeation enhancer LIG, SENI and SENA. PMID- 26950103 TI - Achillolide A Protects Astrocytes against Oxidative Stress by Reducing Intracellular Reactive Oxygen Species and Interfering with Cell Signaling. AB - Achillolide A is a natural sesquiterpene lactone that we have previously shown can inhibit microglial activation. In this study we present evidence for its beneficial effects on astrocytes under oxidative stress, a situation relevant to neurodegenerative diseases and brain injuries. Viability of brain astrocytes (primary cultures) was determined by lactate dehydrogenase (LDH) activity, intracellular ROS levels were detected using 2',7'-dichlorofluorescein diacetate, in vitro antioxidant activity was measured by differential pulse voltammetry, and protein phosphorylation was determined using specific ELISA kits. We have found that achillolide A prevented the H2O2-induced death of astrocytes, and attenuated the induced intracellular accumulation of reactive oxygen species (ROS). These activities could be attributed to the inhibition of the H2O2-induced phosphorylation of MAP/ERK kinase 1 (MEK1) and p44/42 mitogen-activated protein kinases (MAPK), and to the antioxidant activity of achillolide A, but not to H2O2 scavenging. This is the first study that demonstrates its protective effects on brain astrocytes, and its ability to interfere with MAPK activation. We propose that achillolide A deserves further evaluation for its potential to be developed as a drug for the prevention/treatment of neurodegenerative diseases and brain injuries where oxidative stress is part of the pathophysiology. PMID- 26950105 TI - Chemical Evidence for Potent Xanthine Oxidase Inhibitory Activity of Ethyl Acetate Extract of Citrus aurantium L. Dried Immature Fruits. AB - Xanthine oxidase is a key enzyme which can catalyze hypoxanthine and xanthine to uric acid causing hyperuricemia in humans. Xanthine oxidase inhibitory activities of 24 organic extracts of four species belonging to Citrus genus of the family Rutaceae were assayed in vitro. Since the ethyl acetate extract of C. aurantium dried immature fruits showed the highest xanthine oxidase inhibitory activity, chemical evidence for the potent inhibitory activity was clarified on the basis of structure identification of the active constituents. Five flavanones and two polymethoxyflavones were isolated and evaluated for inhibitory activity against xanthine oxidase in vitro. Of the compounds, hesperetin showed more potent inhibitory activity with an IC50 value of 16.48 MUM. For the first time, this study provides a rational basis for the use of C. aurantium dried immature fruits against hyperuricemia. PMID- 26950104 TI - Anti-Oxidant, Anti-Inflammatory and Anti-Angiogenic Properties of Resveratrol in Ocular Diseases. AB - Resveratrol (3,4',5 trihydroxy-trans-stilbene) is one of the best known phytophenols with pleiotropic properties. It is a phytoalexin produced by vine and it leads to the stimulation of natural plant defenses but also exhibits many beneficial effects in animals and humans by acting on a wide range of organs and tissues. These include the prevention of cardiovascular diseases, anti-cancer potential, neuroprotective effects, homeostasia maintenance, aging delay and a decrease in inflammation. Age-related macular degeneration (AMD) is one of the main causes of deterioration of vision in adults in developed countries This review deals with resveratrol and ophthalmology by focusing on the antioxidant, anti-inflammatory, and anti-angiogenic effects of this molecule. The literature reports that resveratrol is able to act on various cell types of the eye by increasing the level of natural antioxidant enzymatic and molecular defenses. Resveratrol anti-inflammatory effects are due to its capacity to limit the expression of pro-inflammatory factors, such as interleukins and prostaglandins, and also to decrease the chemo-attraction and recruitment of immune cells to the inflammatory site. In addition to this, resveratrol was shown to possess anti VEGF effects and to inhibit the proliferation and migration of vascular endothelial cells. Resveratrol has the potential to be used in a range of human ocular diseases and conditions, based on animal models and in vitro experiments. PMID- 26950106 TI - Xanthones of Lichen Source: A 2016 Update. AB - An update of xanthones encountered in lichens is proposed as more than 20 new xanthones have been described since the publication of the compendium of lichen metabolites by Huneck and Yoshimura in 1996. The last decades witnessed major advances regarding the elucidation of biosynthetic schemes leading to these fascinating compounds, accounting for the unique substitution patterns of a very vast majority of lichen xanthones. Besides a comprehensive analysis of the structures of xanthones described in lichens, their bioactivities and the emerging analytical strategies used to pinpoint them within lichens are presented here together with physico-chemical properties (including NMR data) as reported since 1996. PMID- 26950108 TI - Nanotechnology Formulations for Antibacterial Free Fatty Acids and Monoglycerides. AB - Free fatty acids and monoglycerides have long been known to possess broad spectrum antibacterial activity that is based on lytic behavior against bacterial cell membranes. Considering the growing challenges of drug-resistant bacteria and the need for new classes of antibiotics, the wide prevalence, affordable cost, and broad spectrum of fatty acids and monoglycerides make them attractive agents to develop for healthcare and biotechnology applications. The aim of this review is to provide a brief introduction to the history of antimicrobial lipids and their current status and challenges, and to present a detailed discussion of ongoing research efforts to develop nanotechnology formulations of fatty acids and monoglycerides that enable superior in vitro and in vivo performance. Examples of nano-emulsions, liposomes, solid lipid nanoparticles, and controlled release hydrogels are presented in order to highlight the potential that lies ahead for fatty acids and monoglycerides as next-generation antibacterial solutions. Possible application routes and future directions in research and development are also discussed. PMID- 26950107 TI - Optimization of Microwave-Assisted Extraction Conditions for Five Major Bioactive Compounds from Flos Sophorae Immaturus (Cultivars of Sophora japonica L.) Using Response Surface Methodology. AB - Microwave-assisted extraction was applied to extract rutin; quercetin; genistein; kaempferol; and isorhamnetin from Flos Sophorae Immaturus. Six independent variables; namely; solvent type; particle size; extraction frequency; liquid-to solid ratio; microwave power; and extraction time were examined. Response surface methodology using a central composite design was employed to optimize experimental conditions (liquid-to-solid ratio; microwave power; and extraction time) based on the results of single factor tests to extract the five major components in Flos Sophorae Immaturus. Experimental data were fitted to a second order polynomial equation using multiple regression analysis. Data were also analyzed using appropriate statistical methods. Optimal extraction conditions were as follows: extraction solvent; 100% methanol; particle size; 100 mesh; extraction frequency; 1; liquid-to-solid ratio; 50:1; microwave power; 287 W; and extraction time; 80 s. A rapid and sensitive ultra-high performance liquid chromatography method coupled with electrospray ionization quadrupole time-of flight tandem mass spectrometry (EIS-Q-TOF MS/MS) was developed and validated for the simultaneous determination of rutin; quercetin; genistein; kaempferol; and isorhamnetin in Flos Sophorae Immaturus. Chromatographic separation was accomplished on a Kinetex C18 column (100 mm * 2.1 mm; 2.6 MUm) at 40 degrees C within 5 min. The mobile phase consisted of 0.1% aqueous formic acid and acetonitrile (71:29; v/v). Isocratic elution was carried out at a flow rate of 0.35 mL/min. The constituents of Flos Sophorae Immaturus were simultaneously identified by EIS-Q-TOF MS/MS in multiple reaction monitoring mode. During quantitative analysis; all of the calibration curves showed good linear relationships (R2 > 0.999) within the tested ranges; and mean recoveries ranged from 96.0216% to 101.0601%. The precision determined through intra- and inter-day studies showed an RSD% of <2.833%. These results demonstrate that the developed method is accurate and effective and could be readily utilized for the comprehensive quality control of Flos Sophorae Immaturus. PMID- 26950109 TI - Expression and Functional Activity of the Human Bitter Taste Receptor TAS2R38 in Human Placental Tissues and JEG-3 Cells. AB - Bitter taste receptors (TAS2Rs) are expressed in mucous epithelial cells of the tongue but also outside the gustatory system in epithelial cells of the colon, stomach and bladder, in the upper respiratory tract, in the cornified squamous epithelium of the skin as well as in airway smooth muscle cells, in the testis and in the brain. In the present work we addressed the question if bitter taste receptors might also be expressed in other epithelial tissues as well. By staining a tissue microarray with 45 tissue spots from healthy human donors with an antibody directed against the best characterized bitter taste receptor TAS2R38, we observed an unexpected strong TAS2R38 expression in the amniotic epithelium, syncytiotrophoblast and decidua cells of the human placenta. To analyze the functionality we first determined the TAS2R38 expression in the placental cell line JEG-3. Stimulation of these cells with diphenidol, a clinically used antiemetic agent that binds TAS2Rs including TAS2R38, demonstrated the functionality of the TAS2Rs by inducing calcium influx. Restriction enzyme based detection of the TAS2R38 gene allele identified JEG-3 cells as PTC (phenylthiocarbamide)-taster cell line. Calcium influx induced by PTC in JEG-3 cells could be inhibited with the recently described TAS2R38 inhibitor probenecid and proved the specificity of the TAS2R38 activation. The expression of TAS2R38 in human placental tissues points to further new functions and hitherto unknown endogenous ligands of TAS2Rs far beyond bitter tasting. PMID- 26950111 TI - Chemoinformatics in the New Era: From Molecular Dynamics to Systems Dynamics. AB - Chemoinformatics, due to its power in gathering information at the molecular level, has a wide array of important applications to biology, including fundamental biochemical studies and drug discovery and optimization. As modern "omics" based profiling and network based modeling and simulation techniques grow in sophistication, chemoinformatics now faces a great opportunity to include systems-level control mechanisms as one of its pillar components to extend and refine its various applications. This viewpoint article, through the example of computer aided targeting of the PI3K/Akt/mTOR pathway, outlines major steps of integrating systems dynamics simulations into molecular dynamics simulations to facilitate a higher level of chemoinformatics that would revolutionize drug lead optimization, personalized therapy, and possibly other applications. PMID- 26950110 TI - Casbane Diterpenes from Red Sea Coral Sinularia polydactyla. AB - The soft coral genus Sinularia is a rich source of bioactive metabolites containing a diverse array of chemical structures. A solvent extract of Sinularia polydactyla resulted in the isolation of three new casbane diterpenes: sinularcasbane M (1), sinularcasbane N (2) and sinularcasbane O (3); in addition, known metabolites (4-5) were isolated. Compounds were elucidated on the basis of spectroscopic analyses; the absolute configuration was confirmed by X-ray analysis. PMID- 26950112 TI - Identification, Functional Study, and Promoter Analysis of HbMFT1, a Homolog of MFT from Rubber Tree (Hevea brasiliensis). AB - A homolog of MOTHER OF FT AND TFL1 (MFT) was isolated from Hevea brasiliensis and its biological function was investigated. Protein multiple sequence alignment and phylogenetic analysis revealed that HbMFT1 conserved critical amino acid residues to distinguish MFT, FLOWERING LOCUS T (FT) and TERMINAL FLOWER1 (TFL1)-like proteins and showed a closer genetic relationship to the MFT-like group. The accumulation of HbMFT1 was generally detected in various tissues except pericarps, with the highest expression in embryos and relatively higher expression in roots and stems of seedlings, flowering inflorescences, and male and female flowers. HbMFT1 putative promoter analysis showed that tissue specific, environmental change responsive and hormone-signaling responsive elements were generally present. HbMFT1 was strongly induced under a short-day condition at 28 degrees C, with the highest expression after the onset of a day. Overexpression of HbMFT1 inhibited seed germination, seedling growth, and flowering in transgenic Arabidopsis. The qRT-PCR further confirmed that APETALA1 (AP1) and FRUITFULL (FUL) were drastically down-regulated in 35S::HbMFT1 plants. A histochemical beta-glucuronidase (GUS) assay showed that HbMFT1::GUS activity was mainly detected in stamens and mature seeds coinciding with its original expression and notably induced in rosette leaves and seedlings of transgenic Arabidopsis by exogenous abscisic acid (ABA) due to the presence of ABA cis elements in HbMFT1 promoter. These results suggested that HbMFT1 was mainly involved in maintenance of seed maturation and stamen development, but negatively controlled germination, growth and development of seedlings and flowering. In addition, the HbMFT1 promoter can be utilized in controlling transgene expression in stamens and seeds of rubber tree or other plant species. PMID- 26950114 TI - Adjuvant Effect of Quillaja saponaria Saponin (QSS) on Protective Efficacy and IgM Generation in Turbot (Scophthalmus maximus) upon Immersion Vaccination. AB - The adjuvant effect of Quillaja saponaria saponin (QSS) on protection of turbot fry was investigated with immersion vaccination of formalin-killed Vibrio anguillarum O1 and various concentrations of QSS (5, 25, 45 and 65 mg/L). Fish were challenged at days 7, 14 and 28 post-vaccination. Significantly high relative percent of survival (RPS) ((59.1 +/- 13.6)%, (81.7 +/- 8.2)%, (77.8 +/- 9.6)%) were recorded in the fish that received bacterins immersion with QSS at 45 mg/L, which is comparable to the positive control group vaccinated by intraperitoneal injection (IP). Moreover, a remarkably higher serum antibody titer was also demonstrated after 28 days in the vaccinated fish with QSS (45 mg/L) than those vaccinated fish without QSS (p < 0.05), but lower than the IP immunized fish (p < 0.05). Significant upregulation of IgM gene expression has also been identified in the tissues of skin, gill, spleen and kidney from the immunized fish in comparison to the control fish. Taken together, the present study indicated that QSS was able to dramatically evoke systemic and mucosal immune responses in immunized fish. Therefore, QSS might be a promising adjuvant candidate for fish vaccination via an immersion administering route. PMID- 26950113 TI - The Immunology of Neuromyelitis Optica-Current Knowledge, Clinical Implications, Controversies and Future Perspectives. AB - Neuromyelitis optica (NMO) is an autoimmune, demyelinating disorder of the central nervous system (CNS) with typical clinical manifestations of optic neuritis and acute transverse myelitis attacks. Previously believed to be a variant of multiple sclerosis (MS), it is now considered an independent disorder which needs to be differentiated from MS. The discovery of autoantibodies against aquaporin-4 (AQP4-IgGs) changed our understanding of NMO immunopathogenesis and revolutionized the diagnostic process. AQP4-IgG is currently regarded as a specific biomarker of NMO and NMO spectrum disorders (NMOsd) and a key factor in its pathogenesis. Nevertheless, AQP4-IgG seronegativity in 10%-25% of NMO patients suggests that there are several other factors involved in NMO immunopathogenesis, i.e., autoantibodies against aquaporin-1 (AQP1-Abs) and antibodies against myelin oligodendrocyte glycoprotein (MOG-IgGs). This manuscript reviews current knowledge about NMO immunopathogenesis, pointing out the controversial issues and showing potential directions for future research. Further efforts should be made to broaden our knowledge of NMO immunology which could have important implications for clinical practice, including the use of potential novel biomarkers to facilitate an early and accurate diagnosis, and modern treatment strategies improving long-term outcome of NMO patients. PMID- 26950116 TI - Gleditsia sinensis Thorn Attenuates the Collagen-Based Migration of PC3 Prostate Cancer Cells through the Suppression of alpha2beta1 Integrin Expression. AB - Gleditsia sinensis thorns (GST) have been used as a traditional medicine for carbuncles and skin diseases. The purpose of this study was to decide whether non toxicological levels of water extract of GST (WEGST) are effective in inhibiting the progress of prostate cancer formation and to identify the target molecule involved in the WEGST-mediated inhibitory process of prostate cancer cell migration and in vivo tumor formation. Through the Boyden chamber migration assay, we found that non-toxic levels of WEGST could not attenuate the PC3 migration to the bottom area coated with serum but significantly inhibited PC3 cell migration to the collagen-coated bottom area. We also found that non-toxic levels of WEGST significantly attenuated collagen against adhesion. Interestingly, ectopic administration of WEGST could not affect the expression of alpha2beta1 integrin, which is known as a receptor of collagen. However, when the PC3 cells adhered to a collagen-coated plate, the expression of alpha2 integrin but not that of beta1 integrin was significantly inhibited by the administration of non-toxic levels of WEGST, leading to the inhibition of focal adhesion kinase (FAK) phosphorylation. Furthermore, oral administration of WEGST (25 mg/kg/day) significantly inhibited the size of a PC3 cell-xenografted tumor. Taken together, these results suggest a novel molecular mechanism for WEGST to inhibit prostate cancer progression at particular stages, such as collagen-mediated adhesion and migration, and it might provide further development for the therapeutic use of WEGST in the treatment of prostate cancer progression. PMID- 26950115 TI - Endoplasmic Reticulum Stress and Associated ROS. AB - The endoplasmic reticulum (ER) is a fascinating network of tubules through which secretory and transmembrane proteins enter unfolded and exit as either folded or misfolded proteins, after which they are directed either toward other organelles or to degradation, respectively. The ER redox environment dictates the fate of entering proteins, and the level of redox signaling mediators modulates the level of reactive oxygen species (ROS). Accumulating evidence suggests the interrelation of ER stress and ROS with redox signaling mediators such as protein disulfide isomerase (PDI)-endoplasmic reticulum oxidoreductin (ERO)-1, glutathione (GSH)/glutathione disuphide (GSSG), NADPH oxidase 4 (Nox4), NADPH P450 reductase (NPR), and calcium. Here, we reviewed persistent ER stress and protein misfolding-initiated ROS cascades and their significant roles in the pathogenesis of multiple human disorders, including neurodegenerative diseases, diabetes mellitus, atherosclerosis, inflammation, ischemia, and kidney and liver diseases. PMID- 26950118 TI - Evaluation of the Cytotoxic Behavior of Fungal Extracellular Synthesized Ag Nanoparticles Using Confocal Laser Scanning Microscope. AB - Silver nanoparticles have been synthesized by subjecting a reaction medium to a Fusarium oxysporum biomass at 28 degrees C for 96 h. The biosynthesized Ag nanoparticles were characterized on the basis of their anticipated peak at 405 nm using UV-Vis-NIR spectroscopy. Structural confirmation was evident from the characteristic X-ray diffraction (XRD) pattern, high-resolution transmission electron Microscopy (HRTEM) and the particle size analyzer. The Ag nanoparticles were of dimension 40 +/- 5 nm and spherical in shape. The study mainly focused on using the confocal laser scanning microscope (CLSM) to examine the cytotoxic activities of fungal synthesized Ag nanoparticles on a human breast carcinoma cell line MCF7 cell, which featured remarkable vacuolation, thus indicating a potent cytotoxic activity. PMID- 26950117 TI - Molecular Mechanisms of Floral Boundary Formation in Arabidopsis. AB - Boundary formation is a crucial developmental process in plant organogenesis. Boundaries separate cells with distinct identities and act as organizing centers to control the development of adjacent organs. In flower development, initiation of floral primordia requires the formation of the meristem-to-organ (M-O) boundaries and floral organ development depends on the establishment of organ-to organ (O-O) boundaries. Studies in this field have revealed a suite of genes and regulatory pathways controlling floral boundary formation. Many of these genes are transcription factors that interact with phytohormone pathways. This review will focus on the functions and interactions of the genes that play important roles in the floral boundaries and discuss the molecular mechanisms that integrate these regulatory pathways to control the floral boundary formation. PMID- 26950119 TI - Identification of Autophagy in the Pine Wood Nematode Bursaphelenchus xylophilus and the Molecular Characterization and Functional Analysis of Two Novel Autophagy Related Genes, BxATG1 and BxATG8. AB - The pine wood nematode, Bursaphelenchus xylophilus, causes huge economic losses in pine forests, has a complex life cycle, and shows the remarkable ability to survive under unfavorable and changing environmental conditions. This ability may be related to autophagy, which is still poorly understood in B. xylophilus and no autophagy-related genes have been previously characterized. In this study, transmission electron microscopy was used to confirm that autophagy exists in B. xylophilus. The full-length cDNAs of BxATG1 and BxATG8 were first cloned from B. xylophilus, and BxATG1 and BxATG8 were characterized using bioinformatics methods. The expression pattern of the autophagy marker BxATG8 was investigated using in situ hybridization (ISH). BxATG8 was expressed in esophageal gland and hypodermal seam cells. We tested the effects of RNA interference (RNAi) on BxATG1 and BxATG8. The results revealed that BxATG1 and BxATG8 were likely associated with propagation of nematodes on fungal mats. This study confirmed the molecular characterization and functions of BxATG1 and BxATG8 in B. xylophilus and provided fundamental information between autophagy and B. xylophilus. PMID- 26950120 TI - Biomimetic Membranes for Multi-Redox Center Proteins. AB - His-tag technology was applied for biosensing purposes involving multi-redox center proteins (MRPs). An overview is presented on various surfaces ranging from flat to spherical and modified with linker molecules with nitrile-tri-acetic acid (NTA) terminal groups to bind his-tagged proteins in a strict orientation. The bound proteins are submitted to in situ dialysis in the presence of lipid micelles to form a so-called protein-tethered bilayer lipid membrane (ptBLM). MRPs, such as the cytochrome c oxidase (CcO) from R. sphaeroides and P. denitrificans, as well as photosynthetic reactions centers (RCs) from R. sphaeroides, were thus investigated. Electrochemical and surface-sensitive optical techniques, such as surface plasmon resonance, surface plasmon-enhanced fluorescence, surface-enhanced infrared absorption spectroscopy (SEIRAS) and surface-enhanced resonance Raman spectroscopy (SERRS), were employed in the case of the ptBLM structure on flat surfaces. Spherical particles ranging from um size agarose gel beads to nm size nanoparticles modified in a similar fashion were called proteo-lipobeads (PLBs). The particles were investigated by laser-scanning confocal fluorescence microscopy (LSM) and UV/Vis spectroscopy. Electron and proton transfer through the proteins were demonstrated to take place, which was strongly affected by the membrane potential. MRPs can thus be used for biosensing purposes under quasi-physiological conditions. PMID- 26950121 TI - Functionalized Multi-Wall Carbon Nanotubes Enhance Transfection and Expression Efficiency of Plasmid DNA in Fish Cells. AB - DNA vaccines are considered to be the most promising method against infectious diseases in the aquaculture industry. In the present study, we investigated the potency of ammonium group-functionalized multi-walled carbon nanotubes (MWCNTs) in enhancing the transfection and expression efficiency of plasmid DNA (pEGFP vp5) in Ctenopharyngodon idellus kidney (CIK) cells. Agarose gel shift assay results show that ammonium group-functionalized carbon nanotubes are able to condense DNA in varying degrees. Scanning electron microscope (SEM) images shows that CIK cells show a great affinity for MWCNTs-NH3+ and the CNTs covering the cell surface tend to orient their tips perpendicularly to the cell surface, and appear to be "needle-pricking the cells". Transmission electron microscope (TEM) images confirmed that MWCNTs-NH3+ penetrate the cell membranes and are widely dispersed in the CIK cell. Real-time PCR was used to detect the transfection efficiency through the expression of the outer capsid protein (VP5). The results showed that the MWCNTs-NH3+:DNA complexes are able to transfect CIK cells effectively at different charge ratio than naked DNA. Subsequent studies confirmed that both functional groups and charge ratio are important factors that determine the transfection efficiency of plasmid DNA. All these results indicated that MWCNTs-NH3+:DNA complexes could be suitable for developing DNA vaccine for the control of virus infection in the aquaculture industry. PMID- 26950125 TI - SHM-Based Probabilistic Fatigue Life Prediction for Bridges Based on FE Model Updating. AB - Fatigue life prediction for a bridge should be based on the current condition of the bridge, and various sources of uncertainty, such as material properties, anticipated vehicle loads and environmental conditions, make the prediction very challenging. This paper presents a new approach for probabilistic fatigue life prediction for bridges using finite element (FE) model updating based on structural health monitoring (SHM) data. Recently, various types of SHM systems have been used to monitor and evaluate the long-term structural performance of bridges. For example, SHM data can be used to estimate the degradation of an in service bridge, which makes it possible to update the initial FE model. The proposed method consists of three steps: (1) identifying the modal properties of a bridge, such as mode shapes and natural frequencies, based on the ambient vibration under passing vehicles; (2) updating the structural parameters of an initial FE model using the identified modal properties; and (3) predicting the probabilistic fatigue life using the updated FE model. The proposed method is demonstrated by application to a numerical model of a bridge, and the impact of FE model updating on the bridge fatigue life is discussed. PMID- 26950122 TI - Scientific and Regulatory Perspectives in Herbal and Dietary Supplement Associated Hepatotoxicity in the United States. AB - In the United States (US), the risk of hepatotoxicity linked to the widespread use of certain herbal products has gained increased attention among regulatory scientists. Based on current US law, all dietary supplements sold domestically, including botanical supplements, are regulated by the Food and Drug Administration (FDA) as a special category of foods. Under this designation, regulatory scientists do not routinely evaluate the efficacy of these products prior to their marketing, despite the content variability and phytochemical complexity that often characterizes them. Nonetheless, there has been notable progress in the development of advanced scientific methods to qualitatively and quantitatively measure ingredients and screen for contaminants and adulterants in botanical products when hepatotoxicity is recognized. PMID- 26950126 TI - Radiometric Calibration of a Dual-Wavelength, Full-Waveform Terrestrial Lidar. AB - Radiometric calibration of the Dual-Wavelength Echidna((r)) Lidar (DWEL), a full waveform terrestrial laser scanner with two simultaneously-pulsing infrared lasers at 1064 nm and 1548 nm, provides accurate dual-wavelength apparent reflectance (rho(app)), a physically-defined value that is related to the radiative and structural characteristics of scanned targets and independent of range and instrument optics and electronics. The errors of rho(app) are 8.1% for 1064 nm and 6.4% for 1548 nm. A sensitivity analysis shows that rho(app) error is dominated by range errors at near ranges, but by lidar intensity errors at far ranges. Our semi-empirical model for radiometric calibration combines a generalized logistic function to explicitly model telescopic effects due to defocusing of return signals at near range with a negative exponential function to model the fall-off of return intensity with range. Accurate values of rho(app) from the radiometric calibration improve the quantification of vegetation structure, facilitate the comparison and coupling of lidar datasets from different instruments, campaigns or wavelengths and advance the utilization of bi and multi-spectral information added to 3D scans by novel spectral lidars. PMID- 26950127 TI - Compressive Video Recovery Using Block Match Multi-Frame Motion Estimation Based on Single Pixel Cameras. AB - Compressive sensing (CS) theory has opened up new paths for the development of signal processing applications. Based on this theory, a novel single pixel camera architecture has been introduced to overcome the current limitations and challenges of traditional focal plane arrays. However, video quality based on this method is limited by existing acquisition and recovery methods, and the method also suffers from being time-consuming. In this paper, a multi-frame motion estimation algorithm is proposed in CS video to enhance the video quality. The proposed algorithm uses multiple frames to implement motion estimation. Experimental results show that using multi-frame motion estimation can improve the quality of recovered videos. To further reduce the motion estimation time, a block match algorithm is used to process motion estimation. Experiments demonstrate that using the block match algorithm can reduce motion estimation time by 30%. PMID- 26950124 TI - Crosstalk between Autophagy and Apoptosis: Potential and Emerging Therapeutic Targets for Cardiac Diseases. AB - Autophagy is a cell survival process which is related to breaking down and reusing cytoplasm components. Moreover, autophagy regulates cell death under certain conditions. Apoptosis has the characteristics of chromatin agglutination and the shrinking of nuclear and apoptosis body form. Even if the mechanisms of autophagy and apoptosis have differences, some proteins modulate both autophagy and apoptosis. Crosstalk between them exists. This review highlights recent advances in the interaction of autophagy and apoptosis and its importance in the development of cardiovascular diseases. PMID- 26950128 TI - Signal-Conditioning Block of a 1 * 200 CMOS Detector Array for a Terahertz Real Time Imaging System. AB - A signal conditioning block of a 1 * 200 Complementary Metal-Oxide-Semiconductor (CMOS) detector array is proposed to be employed with a real-time 0.2 THz imaging system for inspecting large areas. The plasmonic CMOS detector array whose pixel size including an integrated antenna is comparable to the wavelength of the THz wave for the imaging system, inevitably carries wide pixel-to-pixel variation. To make the variant outputs from the array uniform, the proposed signal conditioning block calibrates the responsivity of each pixel by controlling the gate bias of each detector and the voltage gain of the lock-in amplifiers in the block. The gate bias of each detector is modulated to 1 MHz to improve the signal-to-noise ratio of the imaging system via the electrical modulation by the conditioning block. In addition, direct current (DC) offsets of the detectors in the array are cancelled by initializing the output voltage level from the block. Real-time imaging using the proposed signal conditioning block is demonstrated by obtaining images at the rate of 19.2 frame-per-sec of an object moving on the conveyor belt with a scan width of 20 cm and a scan speed of 25 cm/s. PMID- 26950129 TI - A Secure, Intelligent, and Smart-Sensing Approach for Industrial System Automation and Transmission over Unsecured Wireless Networks. AB - In Industrial systems, Supervisory control and data acquisition (SCADA) system, the pseudo-transport layer of the distributed network protocol (DNP3) performs the functions of the transport layer and network layer of the open systems interconnection (OSI) model. This study used a simulation design of water pumping system, in-which the network nodes are directly and wirelessly connected with sensors, and are monitored by the main controller, as part of the wireless SCADA system. This study also intends to focus on the security issues inherent in the pseudo-transport layer of the DNP3 protocol. During disassembly and reassembling processes, the pseudo-transport layer keeps track of the bytes sequence. However, no mechanism is available that can verify the message or maintain the integrity of the bytes in the bytes received/transmitted from/to the data link layer or in the send/respond from the main controller/sensors. To properly and sequentially keep track of the bytes, a mechanism is required that can perform verification while bytes are received/transmitted from/to the lower layer of the DNP3 protocol or the send/respond to/from field sensors. For security and byte verification purposes, a mechanism needs to be proposed for the pseudo-transport layer, by employing cryptography algorithm. A dynamic choice security buffer (SB) is designed and employed during the security development. To achieve the desired goals of the proposed study, a pseudo-transport layer stack model is designed using the DNP3 protocol open library and the security is deployed and tested, without changing the original design. PMID- 26950123 TI - Biomaterials with Antibacterial and Osteoinductive Properties to Repair Infected Bone Defects. AB - The repair of infected bone defects is still challenging in the fields of orthopedics, oral implantology and maxillofacial surgery. In these cases, the self-healing capacity of bone tissue can be significantly compromised by the large size of bone defects and the potential/active bacterial activity. Infected bone defects are conventionally treated by a systemic/local administration of antibiotics to control infection and a subsequent implantation of bone grafts, such as autografts and allografts. However, these treatment options are time consuming and usually yield less optimal efficacy. To approach these problems, novel biomaterials with both antibacterial and osteoinductive properties have been developed. The antibacterial property can be conferred by antibiotics and other novel antibacterial biomaterials, such as silver nanoparticles. Bone morphogenetic proteins are used to functionalize the biomaterials with a potent osteoinductive property. By manipulating the carrying modes and release kinetics, these biomaterials are optimized to maximize their antibacterial and osteoinductive functions with minimized cytotoxicity. The findings, in the past decade, have shown a very promising application potential of the novel biomaterials with the dual functions in treating infected bone defects. In this review, we will summarize the current knowledge of novel biomaterials with both antibacterial and osteoinductive properties. PMID- 26950130 TI - Research on a Lamb Wave and Particle Filter-Based On-Line Crack Propagation Prognosis Method. AB - Prognostics and health management techniques have drawn widespread attention due to their ability to facilitate maintenance activities based on need. On-line prognosis of fatigue crack propagation can offer information for optimizing operation and maintenance strategies in real-time. This paper proposes a Lamb wave-particle filter (LW-PF)-based method for on-line prognosis of fatigue crack propagation which takes advantages of the possibility of on-line monitoring to evaluate the actual crack length and uses a particle filter to deal with the crack evolution and monitoring uncertainties. The piezoelectric transducers (PZTs)-based active Lamb wave method is adopted for on-line crack monitoring. The state space model relating to crack propagation is established by the data-driven and finite element methods. Fatigue experiments performed on hole-edge crack specimens have validated the advantages of the proposed method. PMID- 26950131 TI - A Low-Noise CMOS THz Imager Based on Source Modulation and an In-Pixel High-Q Passive Switched-Capacitor N-Path Filter. AB - This paper presents the first low noise complementary metal oxide semiconductor (CMOS) deletedCMOS terahertz (THz) imager based on source modulation and in-pixel high-Q filtering. The 31 * 31 focal plane array has been fully integrated in a 0 . 13 MU m standard CMOS process. The sensitivity has been improved significantly by modulating the active THz source that lights the scene and performing on-chip high-Q filtering. Each pixel encompass a broadband bow tie antenna coupled to an N-type metal-oxide-semiconductor (NMOS) detector that shifts the THz radiation, a low noise adjustable gain amplifier and a high-Q filter centered at the modulation frequency. The filter is based on a passive switched-capacitor (SC) N path filter combined with a continuous-time broad-band Gm-C filter. A simplified analysis that helps in designing and tuning the passive SC N-path filter is provided. The characterization of the readout chain shows that a Q factor of 100 has been achieved for the filter with a good matching between the analytical calculation and the measurement results. An input-referred noise of 0 . 2 MU V RMS has been measured. Characterization of the chip with different THz wavelengths confirms the broadband feature of the antenna and shows that this THz imager reaches a total noise equivalent power of 0 . 6 nW at 270 GHz and 0 . 8 nW at 600 GHz. PMID- 26950132 TI - Sensitivity Enhancement in Si Nanophotonic Waveguides Used for Refractive Index Sensing. AB - A comparative study is given for the sensitivity of several typical Si nanophotonic waveguides, including SOI (silicon-on-insulator) nanowires, nanoslot waveguides, suspended Si nanowires, and nanofibers. The cases for gas sensing (ncl ~ 1.0) and liquid sensing (ncl ~ 1.33) are considered. When using SOI nanowires (with a SiO2 buffer layer), the sensitivity for liquid sensing (S ~ 0.55) is higher than that for gas sensing (S ~ 0.35) due to lower asymmetry in the vertical direction. By using SOI nanoslot waveguides, suspended Si nanowires, and Si nanofibers, one could achieve a higher sensitivity compared to sensing with a free-space beam (S = 1.0). The sensitivity for gas sensing is higher than that for liquid sensing due to the higher index-contrast. The waveguide sensitivity of an optimized suspended Si nanowire for gas sensing is as high as 1.5, which is much higher than that of a SOI nanoslot waveguide. Furthermore, the optimal design has very large tolerance to the core width variation due to the fabrication error (?w ~ +/-50 nm). In contrast, a Si nanofiber could also give a very high sensitivity (e.g., ~1.43) while the fabrication tolerance is very small (i.e., ?w < +/-5 nm). The comparative study shows that suspended Si nanowire is a good choice to achieve ultra-high waveguide sensitivity. PMID- 26950133 TI - Chinese Marine Materia Medica Resources: Status and Potential. AB - Chinese marine materia medica (CMMM) is a vital part of traditional Chinese medicine (TCM). Compared with terrestrial TCM, CMMM, derived from specific marine habitats, possesses peculiar chemical components with unique structures reflecting as potent pharmacological activities, distinct drug properties and functions. Nowadays, CMMM appears to be especially effective in treating such difficult diseases as cancers, diabetes, cardio-cerebrovascular diseases, immunodeficiency diseases and senile dementia, and therefore has become an important medicinal resource for the research and development of new drugs. In recent years, such development has attracted wide attention in the field of medicine. In this study, the CMMM resources in China were systematically investigated and evaluated. It was found that the historic experiences of Chinese people using CMMM have continuously accumulated over a period of more than 3600 years, and that the achievements of the research on modern CMMM are especially outstanding. By June 2015, 725 kinds of CMMMs from Chinese coastal sea areas have been identified and recorded, covering 1552 organisms and minerals. More than 3100 traditional prescriptions containing CMMMs have been imparted and inherited. However, the number of CMMMs is less than the 8188 terrestrial TCMs, from more than 12,100 medicinal terrestrial plants, animals and minerals. In the future, the research and development of CMMM should focus on the channel entries (TCM drug properties), compatibility, effective ingredients, acting mechanisms, drug metabolism and quality standard. This study reveals the high potential of CMMM development. PMID- 26950134 TI - An Application of the Multivariate Linear Mixed Model to the Analysis of Shoulder Complexity in Breast Cancer Patients. AB - In this study, four major muscles acting on the scapula were investigated in patients who had been treated in the last six years for unilateral carcinoma of the breast. Muscle activity was assessed by electromyography during abduction and adduction of the affected and unaffected arms. The main principal aim of the study was to compare shoulder muscle activity in the affected and unaffected shoulder during elevation of the arm. A multivariate linear mixed model was introduced and applied to address the principal aims. The result of fitting this model to the data shows a huge improvement as compared to the alternatives. PMID- 26950135 TI - To What Extent is Drinking Water Tested in Sub-Saharan Africa? A Comparative Analysis of Regulated Water Quality Monitoring. AB - Water quality information is important for guiding water safety management and preventing water-related diseases. To assess the current status of regulated water quality monitoring in sub-Saharan Africa, we evaluated testing programs for fecal contamination in 72 institutions (water suppliers and public health agencies) across 10 countries. Data were collected through written surveys, in person interviews, and analysis of microbial water quality testing levels. Though most institutions did not achieve the testing levels specified by applicable standards or World Health Organization (WHO) Guidelines, 85% of institutions had conducted some microbial water testing in the previous year. Institutions were more likely to meet testing targets if they were suppliers (as compared to surveillance agencies), served larger populations, operated in urban settings, and had higher water quality budgets (all p < 0.05). Our results indicate that smaller water providers and rural public health offices will require greater attention and additional resources to achieve regulatory compliance for water quality monitoring in sub-Saharan Africa. The cost-effectiveness of water quality monitoring should be improved by the application of risk-based water management approaches. Efforts to strengthen monitoring capacity should pay greater attention to program sustainability and institutional commitment to water safety. PMID- 26950136 TI - Phosphate Adsorption from Membrane Bioreactor Effluent Using Dowex 21K XLT and Recovery as Struvite and Hydroxyapatite. AB - Discharging phosphate through wastewaters into waterways poses a danger to the natural environment due to the serious risks of eutrophication and health of aquatic organisms. However, this phosphate, if economically recovered, can partly overcome the anticipated future scarcity of phosphorus (P) resulting from exhaustion of natural phosphate rock reserves. An experiment was conducted to determine the efficiency of removing phosphate from a membrane bioreactor effluent (pH 7.0-7.5, 20, 35 mg phosphate/L) produced in a water reclamation plant by adsorption onto Dowex 21K XLT ion exchange resin and recover the phosphate as fertilisers. The data satisfactorily fitted to Langmuir adsorption isotherm with a maximum adsorption capacity of 38.6 mg . P/g. The adsorbed phosphate was quantitatively desorbed by leaching the column with 0.1 M NaCl solution. The desorbed phosphate was recovered as struvite when ammonium and magnesium were added at the molar ratio of phosphate, ammonium and magnesium of 1:1:1 at pH 9.5. Phosphate was also recovered from the desorbed solution as hydroxyapatite precipitate by adding calcium hydroxide to the solution at a phosphate to calcium molar ratio of 1:2 at pH 7.0. The P contents of struvite and hydroxyapatite produced were close to those of the respective commercial phosphate fertilisers. PMID- 26950137 TI - Backcountry Travel Emergencies in Arctic Canada: A Pilot Study in Public Health Surveillance. AB - Residents in the Canadian Arctic regularly travel in remote, backcountry areas. This can pose risks for injuries and death, and create challenges for emergency responders and health systems. We aimed to describe the extent and characteristics of media-reported backcountry travel emergencies in two Northern Canadian territories (Nunavut and Northwest Territories). A case-series of all known incidents between 2004 and 2013 was established by identifying events in an online search of two media outlets, Nunatsiaq News and Northern News Services. We identified 121 incidents; these most commonly involved young men, and death occurred in just over 25% of cases. The territories differed in the seasonal patterns. News media provides a partial source of data to estimate the extent and characteristics of backcountry emergencies. This information is needed to improve emergency preparedness and health system responsiveness in the Arctic. PMID- 26950138 TI - A Lunchtime Walk in Nature Enhances Restoration of Autonomic Control during Night Time Sleep: Results from a Preliminary Study. AB - Walking within nature (Green Exercise) has been shown to immediately enhance mental well-being but less is known about the impact on physiology and longer lasting effects. Heart rate variability (HRV) gives an indication of autonomic control of the heart, in particular vagal activity, with reduced HRV identified as a risk factor for cardiovascular disease. Night-time HRV allows vagal activity to be assessed whilst minimizing confounding influences of physical and mental activity. The aim of this study was to investigate whether a lunchtime walk in nature increases night-time HRV. Participants (n = 13) attended on two occasions to walk a 1.8 km route through a built or a natural environment. Pace was similar between the two walks. HRV was measured during sleep using a RR interval sensor (eMotion sensor) and was assessed at 1-2 h after participants noted that they had fallen asleep. Markers for vagal activity were significantly greater after the walk in nature compared to the built walk. Lunchtime walks in nature-based environments may provide a greater restorative effect as shown by vagal activity than equivalent built walks. Nature walks may improve essential recovery during night-time sleep, potentially enhancing physiological health. PMID- 26950139 TI - Estimating Temperature-Mortality Exposure-Response Relationships and Optimum Ambient Temperature at the Multi-City Level of China. AB - Few studies have explored temperature-mortality relationships in China, especially at the multi-large city level. This study was based on the data of seven typical, large Chinese cities to examine temperature-mortality relationships and optimum temperature of China. A generalized additive model (GAM) was applied to analyze the acute-effect of temperature on non-accidental mortality, and meta-analysis was used to merge data. Furthermore, the lagged effects of temperature up to 40 days on mortality and optimum temperature were analyzed using the distributed lag non-linear model (DLNM). We found that for all non-accidental mortality, high temperature could significantly increase the excess risk (ER) of death by 0.33% (95% confidence interval: 0.11%, 0.56%) with the temperature increase of 1 degrees C. Similar but non-significant ER of death was observed when temperature decreased. The lagged effect of temperature showed that the relative risk of non-accidental mortality was lowest at 21 degrees C. Our research suggests that high temperatures are more likely to cause an acute increase in mortality. There was a lagged effect of temperature on mortality, with an optimum temperature of 21 degrees C. Our results could provide a theoretical basis for climate-related public health policy. PMID- 26950140 TI - Cell-Free and Cell-Based Approaches to Explore the Roles of Host Membranes and Lipids in the Formation of Viral Replication Compartment Induced by Tombusviruses. AB - Plant positive strand RNA viruses are intracellular infectious agents that take advantage of cellular lipids and membranes to support replication and protect viral RNA from degradation by host antiviral responses. In this review, we discuss how Tomato bushy stunt virus (TBSV) co-opts lipid transfer proteins and modulates lipid metabolism and transport to facilitate the assembly of the membrane-bound viral replicase complexes within intricate replication compartments. Identification and characterization of the proviral roles of specific lipids and proteins involved in lipid metabolism based on results from yeast (Saccharomyces cerevisiae) model host and cell-free approaches are discussed. The review also highlights the advantage of using liposomes with chemically defined composition to identify specific lipids required for TBSV replication. Remarkably, all the known steps in TBSV replication are dependent on cellular lipids and co-opted membranes. PMID- 26950143 TI - Effects of Cereal, Fruit and Vegetable Fibers on Human Fecal Weight and Transit Time: A Comprehensive Review of Intervention Trials. AB - Cereal fibers are known to increase fecal weight and speed transit time, but far less data are available on the effects of fruits and vegetable fibers on regularity. This study provides a comprehensive review of the impact of these three fiber sources on regularity in healthy humans. We identified English language intervention studies on dietary fibers and regularity and performed weighted linear regression analyses for fecal weight and transit time. Cereal and vegetable fiber groups had comparable effects on fecal weight; both contributed to it more than fruit fibers. Less fermentable fibers increased fecal weight to a greater degree than more fermentable fibers. Dietary fiber did not change transit time in those with an initial time of <48 h. In those with an initial transit time >=48 h, transit time was reduced by approximately 30 min per gram of cereal, fruit or vegetable fibers, regardless of fermentability. Cereal fibers have been studied more than any other kind in relation to regularity. This is the first comprehensive review comparing the effects of the three major food sources of fiber on bowel function and regularity since 1993. PMID- 26950144 TI - The Non-Genomic Actions of Vitamin D. AB - Since its discovery in 1920, a great deal of effort has gone into investigating the physiological actions of vitamin D and the impact its deficiency has on human health. Despite this intense interest, there is still disagreement on what constitutes the lower boundary of adequacy and on the Recommended Dietary Allowance. There has also been a major push to elucidate the biochemistry of vitamin D, its metabolic pathways and the mechanisms that mediate its action. Originally thought to act by altering the expression of target genes, it was realized in the mid-1980s that some of the actions of vitamin D were too rapid to be accounted for by changes at the genomic level. These rapid non-genomic actions have attracted as much interest as the genomic actions and they have spawned additional questions in an already busy field. This mini-review attempts to summarise the in vitro and in vivo work that has been conducted to characterise the rapid non-genomic actions, the mechanisms that give rise to these properties and the roles that these play in the overall action of vitamin D at the cellular level. Understanding the effects of vitamin D at the cellular level should enable the design of elegant human studies to extract the full potential of vitamin D to benefit human health. PMID- 26950142 TI - Effects of Trigonelline, an Alkaloid Present in Coffee, on Diabetes-Induced Disorders in the Rat Skeletal System. AB - Diabetes increases bone fracture risk. Trigonelline, an alkaloid with potential antidiabetic activity, is present in considerable amounts in coffee. The aim of the study was to investigate the effects of trigonelline on experimental diabetes induced disorders in the rat skeletal system. Effects of trigonelline (50 mg/kg p.o. daily for four weeks) were investigated in three-month-old female Wistar rats, which, two weeks before the start of trigonelline administration, received streptozotocin (60 mg/kg i.p.) or streptozotocin after nicotinamide (230 mg/kg i.p.). Serum bone turnover markers, bone mineralization, and mechanical properties were studied. Streptozotocin induced diabetes, with significant worsening of bone mineralization and bone mechanical properties. Streptozotocin after nicotinamide induced slight glycemia increases in first days of experiment only, however worsening of cancellous bone mechanical properties and decreased vertebral bone mineral density (BMD) were demonstrated. Trigonelline decreased bone mineralization and tended to worsen bone mechanical properties in streptozotocin-induced diabetic rats. In nicotinamide/streptozotocin-treated rats, trigonelline significantly increased BMD and tended to improve cancellous bone strength. Trigonelline differentially affected the skeletal system of rats with streptozotocin-induced metabolic disorders, intensifying the osteoporotic changes in streptozotocin-treated rats and favorably affecting bones in the non hyperglycemic (nicotinamide/streptozotocin-treated) rats. The results indicate that, in certain conditions, trigonelline may damage bone. PMID- 26950141 TI - Remodeling of the Host Cell Plasma Membrane by HIV-1 Nef and Vpu: A Strategy to Ensure Viral Fitness and Persistence. AB - The plasma membrane protects the cell from its surroundings and regulates cellular communication, homing, and metabolism. Not surprisingly, the composition of this membrane is highly controlled through the vesicular trafficking of proteins to and from the cell surface. As intracellular pathogens, most viruses exploit the host plasma membrane to promote viral replication while avoiding immune detection. This is particularly true for the enveloped human immunodeficiency virus (HIV), which assembles and obtains its lipid shell directly at the plasma membrane. HIV-1 encodes two proteins, negative factor (Nef) and viral protein U (Vpu), which function primarily by altering the quantity and localization of cell surface molecules to increase virus fitness despite host antiviral immune responses. These proteins are expressed at different stages in the HIV-1 life cycle and employ a variety of mechanisms to target both unique and redundant surface proteins, including the viral receptor CD4, host restriction factors, immunoreceptors, homing molecules, tetraspanins and membrane transporters. In this review, we discuss recent progress in the study of the Nef and Vpu targeting of host membrane proteins with an emphasis on how remodeling of the cell membrane allows HIV-1 to avoid host antiviral immune responses leading to the establishment of systemic and persistent infection. PMID- 26950145 TI - An Increase in the Omega-6/Omega-3 Fatty Acid Ratio Increases the Risk for Obesity. AB - In the past three decades, total fat and saturated fat intake as a percentage of total calories has continuously decreased in Western diets, while the intake of omega-6 fatty acid increased and the omega-3 fatty acid decreased, resulting in a large increase in the omega-6/omega-3 ratio from 1:1 during evolution to 20:1 today or even higher. This change in the composition of fatty acids parallels a significant increase in the prevalence of overweight and obesity. Experimental studies have suggested that omega-6 and omega-3 fatty acids elicit divergent effects on body fat gain through mechanisms of adipogenesis, browning of adipose tissue, lipid homeostasis, brain-gut-adipose tissue axis, and most importantly systemic inflammation. Prospective studies clearly show an increase in the risk of obesity as the level of omega-6 fatty acids and the omega-6/omega-3 ratio increase in red blood cell (RBC) membrane phospholipids, whereas high omega-3 RBC membrane phospholipids decrease the risk of obesity. Recent studies in humans show that in addition to absolute amounts of omega-6 and omega-3 fatty acid intake, the omega-6/omega-3 ratio plays an important role in increasing the development of obesity via both AA eicosanoid metabolites and hyperactivity of the cannabinoid system, which can be reversed with increased intake of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). A balanced omega 6/omega-3 ratio is important for health and in the prevention and management of obesity. PMID- 26950146 TI - Impact of Genotype on EPA and DHA Status and Responsiveness to Increased Intakes. AB - At a population level, cardioprotective and cognitive actions of the fish oil (FO) derived long-chain n-3 polyunsaturated fatty acids (LC n-3 PUFAs) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been extensively demonstrated. In addition to dietary intake, which is limited for many individuals, EPA and DHA status is dependent on the efficiency of their biosynthesis from alpha-linolenic acid. Gender and common gene variants have been identified as influencing the rate-limiting desaturase and elongase enzymes. Response to a particular intake or status is also highly heterogeneous and likely influenced by genetic variants which impact on EPA and DHA metabolism and tissue partitioning, transcription factor activity, or physiological end-point regulation. Here, available literature relating genotype to tissue LC n-3 PUFA status and response to FO intervention is considered. It is concluded that the available evidence is relatively limited, with much of the variability unexplained, though APOE and FADS genotypes are emerging as being important. Although genotype * LC n-3 PUFA interactions have been described for a number of phenotypes, few have been confirmed in independent studies. A more comprehensive understanding of the genetic, physiological and behavioural modulators of EPA and DHA status and response to intervention is needed to allow refinement of current dietary LC n-3 PUFA recommendations and stratification of advice to "vulnerable" and responsive subgroups. PMID- 26950147 TI - Nanoscale Delivery of Resveratrol towards Enhancement of Supplements and Nutraceuticals. AB - Resveratrol was investigated in terms of its stability, biocompatibility and intestinal permeability across Caco-2 cell monolayers in its free form or encapsulated in solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs). SLNs and NLCs presented a mean diameter between 160 and 190 nm, high negative zeta potential of -30 mV and resveratrol entrapment efficiency of 80%, suggesting they are suitable for resveratrol oral delivery. Nanoencapsulation effectively protected resveratrol from photodegradation, and MTT assays demonstrated that neither resveratrol nor lipid nanoparticles adversely affected cell viability and integrity of Caco-2 cell monolayers. The in vitro intestinal permeability of resveratrol was significantly increased by NLCs, and SLNs did not impair the absorption of resveratrol. Resveratrol oral absorption can be enhanced during meals, since the intestinal permeability was increased in the presence of fed-state intestinal juices. SLNs and NLCs constitute carrier systems for resveratrol oral administration, for further use as supplements or nutraceuticals. PMID- 26950149 TI - Prevalence of Nutrition and Health-Related Claims on Pre-Packaged Foods: A Five Country Study in Europe. AB - This study is part of the research undertaken in the EU funded project CLYMBOL ("Role of health-related CLaims and sYMBOLs in consumer behaviour"). The first phase of this project consisted of mapping the prevalence of symbolic and non symbolic nutrition and health-related claims (NHC) on foods and non-alcoholic beverages in five European countries. Pre-packaged foods and drinks were sampled based on a standardized sampling protocol, using store lists or a store floor plan. Data collection took place across five countries, in three types of stores. A total of 2034 foods and drinks were sampled and packaging information was analyzed. At least one claim was identified for 26% (95% CI (24.0%-27.9%)) of all foods and drinks sampled. Six percent of these claims were symbolic. The majority of the claims were nutrition claims (64%), followed by health claims (29%) and health-related ingredient claims (6%). The most common health claims were nutrient and other function claims (47% of all claims), followed by disease risk reduction claims (5%). Eight percent of the health claims were children's development and health claims but these were only observed on less than 1% (0.4% 1.1%) of the foods. The category of foods for specific dietary use had the highest proportion of NHC (70% of foods carried a claim). The prevalence of symbolic and non-symbolic NHC varies across European countries and between different food categories. This study provides baseline data for policy makers and the food industry to monitor and evaluate the use of claims on food packaging. PMID- 26950148 TI - Extract of Polygonum cuspidatum Attenuates Diabetic Retinopathy by Inhibiting the High-Mobility Group Box-1 (HMGB1) Signaling Pathway in Streptozotocin-Induced Diabetic Rats. AB - High-mobility group box-1 (HMGB1) is a well-known pro-inflammatory cytokine. We aimed to investigate the effect of the ethanol extract of the root of P. cuspidatum (PCE) on retinal inflammation in diabetic retinopathy. PCE (100 or 350 mg/kg/day) was administered to diabetic rats for 16 weeks, and hyperglycemia and body weight loss developed in the diabetic rats. The retinal expression levels of HMGB1 and receptor for advanced glycation end products (RAGE) and the activity of nuclear factor-kappa B (NF-kappaB) in the retina were examined. Additionally, a chromatin immunoprecipitation assay was performed to analyze the binding of NF kappaB binding to the RAGE promoter in the diabetic retinas. The levels of HMGB1 and RAGE expression, NF-kappaB activity, and NF-kappaB binding to the RAGE promoter were increased in the diabetic retinas. However, treatment with PCE ameliorated the increases in HMGB1 and RAGE expression, and NF-kappaB activity in the retina. In addition, in diabetic rats, retinal vascular permeability and the loosening of the tight junctions were inhibited by PCE. These findings suggest that PCE has a preventative effect against diabetes-induced vascular permeability by inhibiting HMGB1-RAGE-NF-kappaB activation in diabetic retinas. The oral administration of PCE may significantly help to suppress the development of diabetic retinopathy in patients with diabetes. PMID- 26950150 TI - Intravenous Administration of Lycopene, a Tomato Extract, Protects against Myocardial Ischemia-Reperfusion Injury. AB - BACKGROUND: Oral uptake of lycopene has been shown to be beneficial for preventing myocardial ischemia-reperfusion (I/R) injury. However, the strong first-pass metabolism of lycopene influences its bioavailability and impedes its clinic application. In this study, we determined an intravenous (IV) administration dose of lycopene protects against myocardial infarction (MI) in a mouse model, and investigated the effects of acute lycopene administration on reactive oxygen species (ROS) production and related signaling pathways during myocardial I/R. METHODS: In this study, we established both in vitro hypoxia/reoxygenation (H/R) cell model and in vivo regional myocardial I/R mouse model by ligating left anterior artery descending. TTC dual staining was used to assess I/R induced MI in the absence and presence of acute lycopene administration via tail vein injection. RESULTS: Lycopene treatment (1 MUM) before reoxygenation significantly reduced cardiomyocyte death induced by H/R. Intravenous administration of lycopene to achieve 1 MUM concentration in circulating blood significantly suppressed MI, ROS production, and JNK phosphorylation in the cardiac tissue of mice during in vivo regional I/R. CONCLUSION: Elevating circulating lycopene to 1 MUM via IV injection protects against myocardial I/R injury through inhibition of ROS accumulation and consequent inflammation in mice. PMID- 26950151 TI - Median Urinary Iodine Concentrations Are Indicative of Adequate Iodine Status among Women of Reproductive Age in Prey Veng, Cambodia. AB - Iodine deficiency disorders are estimated to affect over 1.9 million people worldwide. Iodine deficiency is especially serious for women during pregnancy and lactation because of the negative consequences for both mother and infant. The aim of this cross-sectional study was to determine the median urinary iodine concentration (UIC) as a population-level indicator of iodine status among rural women farmers of reproductive age (18-45 years) in the province of Prey Veng, Cambodia. A total of 450 women provided a spot morning urine sample in 2012. Of those women, 93% (n = 420) were non-pregnant and 7% (n = 30) were pregnant at the time of collection. UIC was quantified using the Sandell-Kolthoff reaction with modifications. The median UIC of non-pregnant (139 MUg/L) and pregnant women (157 MUg/L) were indicative of adequate iodine status using the WHO/UNICEF/ICCIDD epidemiological criteria for both groups (median UIC between 100-199 and 150-249 MUg/L, respectively). We conclude that non-pregnant and pregnant women in rural Prey Veng, Cambodia had adequate iodine status based on single spot morning urine samples collected in 2012. More research is warranted to investigate iodine status among larger and more representative populations of women in Cambodia, especially in light of recent policy changes to the national program for universal salt iodization. PMID- 26950152 TI - Occurrence of Staphylococcus aureus on Farms with Small Scale Production of Raw Milk Cheeses in Poland. AB - This paper describes the results of a 3-year study on the prevalence, enterotoxinogenicity and resistance to antimicrobials of S. aureus isolated on dairy farms with small scale production of raw cow milk cheeses. The samples of raw milk, semi-finished products and the final products as well as swabs were collected between 2011 and 2013 from nine dairy farms in Poland. A total of 244 samples were examined, of which 122 (50.0%) were contaminated with S. aureus including 18 of 26 (69.2%) mature cheese samples with log10 CFU g(-1) between <1- and 7.41. In swabs collected from the staff and production environment the highest contamination rate with coagulase positive staphylococci (CPS) was detected on hands of cheese makers (4.34 log10 CFU/swab). None of the cheese samples contaminated with CPS contained staphylococcal enterotoxins (SEs). However, 55 of 122 (45.1%) S. aureus isolates possessed SEs genes, mainly (26 of 55; 47.3%) a combination of the sed, sej and ser genes. Furthermore, the sep (15 of 55; 27.3%) as well as seg and sei (9 of 55; 16.4%) genes were also identified. The remaining S. aureus isolates possessed the sea gene (one isolate), the combination of sec, seg and sei (three isolates) as well as the sed, sej, sep and ser markers together (one CPS). Resistance to penicillin (62 of 122 isolates; 50.8%) was the most common among the tested isolates. Some CPS were also resistant to chloramphenicol (7; 5.7%) and tetracycline (5; 4.1%). The obtained results indicated that the analyzed cheeses were safe for consumers. To improve the microbiological quality of traditional cheese products more attention should be paid to animal welfare and hygiene practices during the process of cheese manufacturing in some dairy farms. PMID- 26950153 TI - Characterization and Recombinant Expression of Terebrid Venom Peptide from Terebra guttata. AB - Venom peptides found in terebrid snails expand the toolbox of active compounds that can be applied to investigate cellular physiology and can be further developed as future therapeutics. However, unlike other predatory organisms, such as snakes, terebrids produce very small quantities of venom, making it difficult to obtain sufficient amounts for biochemical characterization. Here, we describe the first recombinant expression and characterization of terebrid peptide, teretoxin Tgu6.1, from Terebra guttata. Tgu6.1 is a novel forty-four amino acid teretoxin peptide with a VI/VII cysteine framework (C-C-CC-C-C) similar to O, M and I conotoxin superfamilies. A ligation-independent cloning strategy with an ompT protease deficient strain of E. coli was employed to recombinantly produce Tgu6.1. Thioredoxin was introduced in the plasmid to combat disulfide folding and solubility issues. Specifically Histidine-6 tag and Ni-NTA affinity chromatography were applied as a purification method, and enterokinase was used as a specific cleavage protease to effectively produce high yields of folded Tgu6.1 without extra residues to the primary sequence. The recombinantly expressed Tgu6.1 peptide was bioactive, displaying a paralytic effect when injected into a Nereis virens polychaete bioassay. The recombinant strategy described to express Tgu6.1 can be applied to produce high yields of other disulfide-rich peptides. PMID- 26950155 TI - Differentially Expressed MicroRNAs in Meningiomas Grades I and II Suggest Shared Biomarkers with Malignant Tumors. AB - Meningiomas represent the most common primary tumors of the central nervous system, but few microRNA (miRNA) profiling studies have been reported so far. Deep sequencing of small RNA libraries generated from two human meningioma biopsies WHO grades I (benign) and II (atypical) were compared to excess dura controls. Nineteen differentially expressed miRNAs were validated by RT-qPCR using tumor RNA from 15 patients and 5 meninges controls. Tumor suppressor miR 218 and miR-34a were upregulated relative to normal controls, however, miR-143, miR-193b, miR-451 and oncogenic miR-21 were all downregulated. From 10 selected putative mRNA targets tested by RT-qPCR only four were differentially expressed relative to normal controls. PTEN and E-cadherin (CDH1) were upregulated, but RUNX1T1 was downregulated. Proliferation biomarker p63 was upregulated with nuclear localization, but not detected in most normal arachnoid tissues. Immunoreactivity of E-cadherin was detected in the outermost layer of normal arachnoids, but was expressed throughout the tumors. Nuclear Cyclin D1 expression was positive in all studied meningiomas, while its expression in arachnoid was limited to a few trabecular cells. Meningiomas of grades I and II appear to share biomarkers with malignant tumors, but with some additional tumor suppressor biomarkers expression. Validation in more patients is of importance. PMID- 26950154 TI - Isolation of Anti-Ricin Protective Antibodies Exhibiting High Affinity from Immunized Non-Human Primates. AB - Ricin, derived from the castor bean plant Ricinus communis, is one of the most potent and lethal toxins known, against which there is no available antidote. To date, the use of neutralizing antibodies is the most promising post-exposure treatment for ricin intoxication. The aim of this study was to isolate high affinity anti-ricin antibodies that possess potent toxin-neutralization capabilities. Two non-human primates were immunized with either a ricin-holotoxin or subunit-based vaccine, to ensure the elicitation of diverse high affinity antibodies. By using a comprehensive set of primers, immune scFv phage-displayed libraries were constructed and panned. A panel of 10 antibodies (five directed against the A subunit of ricin and five against the B subunit) was isolated and reformatted into a full-length chimeric IgG. All of these antibodies were found to neutralize ricin in vitro, and several conferred full protection to ricin intoxicated mice when given six hours after exposure. Six antibodies were found to possess exceptionally high affinity toward the toxin, with KD values below pM (k(off )< 1 * 10(-7) s(-1)) that were well correlated with their ability to neutralize ricin. These antibodies, alone or in combination, could be used for the development of a highly-effective therapeutic preparation for post-exposure treatment of ricin intoxication. PMID- 26950156 TI - The Trypanosome Flagellar Pocket Collar and Its Ring Forming Protein-TbBILBO1. AB - Sub-species of Trypanosoma brucei are the causal agents of human African sleeping sickness and Nagana in domesticated livestock. These pathogens have developed an organelle-like compartment called the flagellar pocket (FP). The FP carries out endo- and exocytosis and is the only structure this parasite has evolved to do so. The FP is essential for parasite viability, making it an interesting structure to evaluate as a drug target, especially since it has an indispensible cytoskeleton component called the flagellar pocket collar (FPC). The FPC is located at the neck of the FP where the flagellum exits the cell. The FPC has a complex architecture and division cycle, but little is known concerning its organization. Recent work has focused on understanding how the FP and the FPC are formed and as a result of these studies an important calcium-binding, polymer forming protein named TbBILBO1 was identified. Cellular biology analysis of TbBILBO1 has demonstrated its uniqueness as a FPC component and until recently, it was unknown what structural role it played in forming the FPC. This review summarizes the recent data on the polymer forming properties of TbBILBO1 and how these are correlated to the FP cytoskeleton. PMID- 26950157 TI - PP2A Phosphatase as a Regulator of ROS Signaling in Plants. AB - Reactive oxygen species (ROS) carry out vital functions in determining appropriate stress reactions in plants, but the molecular mechanisms underlying the sensing, signaling and response to ROS as signaling molecules are not yet fully understood. Recent studies have underscored the role of Protein Phosphatase 2A (PP2A) in ROS-dependent responses involved in light acclimation and pathogenesis responses in Arabidopsis thaliana. Genetic, proteomic and metabolomic studies have demonstrated that trimeric PP2A phosphatases control metabolic changes and cell death elicited by intracellular and extracellular ROS signals. Associated with this, PP2A subunits contribute to transcriptional and post-translational regulation of pro-oxidant and antioxidant enzymes. This review highlights the emerging role of PP2A phosphatases in the regulatory ROS signaling networks in plants. PMID- 26950159 TI - Cancer Metabolomics and the Human Metabolome Database. AB - The application of metabolomics towards cancer research has led to a renewed appreciation of metabolism in cancer development and progression. It has also led to the discovery of metabolite cancer biomarkers and the identification of a number of novel cancer causing metabolites. The rapid growth of metabolomics in cancer research is also leading to challenges. In particular, with so many cancer associate metabolites being identified, it is often difficult to keep track of which compounds are associated with which cancers. It is also challenging to track down information on the specific pathways that particular metabolites, drugs or drug metabolites may be affecting. Even more frustrating are the difficulties associated with identifying metabolites from NMR or MS spectra. Fortunately, a number of metabolomics databases are emerging that are designed to address these challenges. One such database is the Human Metabolome Database (HMDB). The HMDB is currently the world's largest and most comprehensive, organism-specific metabolomics database. It contains more than 40,000 metabolite entries, thousands of metabolite concentrations, >700 metabolic and disease associated pathways, as well as information on dozens of cancer biomarkers. This review is intended to provide a brief summary of the HMDB and to offer some guidance on how it can be used in metabolomic studies of cancer. PMID- 26950161 TI - Continuous Preparation of Carbon Nanotube Film and Its Applications in Fuel and Solar Cells. AB - So far, simultaneously realizing the continuous, controllable, and scalable preparation of carbon nanotube (CNT) film has remained a big challenge. Here, we report a scalable approach to continuously prepare CNT film with good control of film size and thickness. This is achieved through the layer-by-layer condensation and deposition of a cylindrical CNT assembly that is continuously produced from a floating catalyst CVD reactor on a paper strip. The promising applications of such a film are demonstrated by directly using it as an effective protecting layer for the Pt/C catalyst in proton exchange membrane fuel cells and as an efficient counter electrode material in quantum-dot-sensitized solar cells. PMID- 26950162 TI - MS/MS Digital Readout: Analysis of Binary Information Encoded in the Monomer Sequences of Poly(triazole amide)s. AB - Tandem mass spectrometry was evaluated as a reliable sequencing methodology to read codes encrypted in monodisperse sequence-coded oligo(triazole amide)s. The studied oligomers were composed of monomers containing a triazole ring, a short ethylene oxide segment, and an amide group as well as a short alkyl chain (propyl or isobutyl) which defined the 0/1 molecular binary code. Using electrospray ionization, oligo(triazole amide)s were best ionized as protonated molecules and were observed to adopt a single charge state, suggesting that adducted protons were located on every other monomer unit. Upon collisional activation, cleavages of the amide bond and of one ether bond were observed to proceed in each monomer, yielding two sets of complementary product ions. Distribution of protons over the precursor structure was found to remain unchanged upon activation, allowing charge state to be anticipated for product ions in the four series and hence facilitating their assignment for a straightforward characterization of any encoded oligo(triazole amide)s. PMID- 26950160 TI - On the placement of practice questions during study. AB - Retrieval practice improves retention of information on later tests. A question remains: When should retrieval occur during learning-interspersed throughout study or at the end of each study period? In a lab experiment, an online experiment, and a classroom study, we aimed to determine the ideal placement (interspersed vs. at-the-end) of retrieval practice questions. In the lab experiment, 64 subjects viewed slides about APA style and answered short-answer practice questions about the content or restudied the slides (restudy condition). The practice questions either appeared 1 every 1-2 slides (interspersed condition), or all at the end of the presentation (at-the-end condition). One week later, subjects returned and answered the same questions on a final test. In the online experiment, 175 subjects completed the same procedure. In the classroom study, 62 undergraduate students took quizzes as part of class lectures. Short-answer practice questions appeared either throughout the lectures (interspersed condition) or at the end of the lectures (at-the-end condition). Nineteen days after the last quiz, students were given a surprise final test. Results from the 3 experiments converge in demonstrating an advantage for interspersing practice questions on the initial tests, but an absence of this advantage on the final test. PMID- 26950158 TI - Circulating microRNAs as Potential Biomarkers in Non-Alcoholic Fatty Liver Disease and Hepatocellular Carcinoma. AB - Obesity and metabolic syndrome are growing epidemics worldwide and greatly responsible for many liver diseases, including nonalcoholic fatty liver disease (NAFLD). NAFLD often progresses to cirrhosis, end-stage liver failure and hepatocellular carcinoma (HCC), the most common primary liver cancer and one of the leading causes for cancer-related deaths globally. Currently available tools for the diagnosis of NAFLD staging and progression towards HCC are largely invasive and of limited accuracy. In light of the need for more specific and sensitive noninvasive molecular markers, several studies have assessed the potential of circulating microRNAs (miRNAs) as biomarkers of liver injury and hepatocarcinogenesis. Indeed, extracellular miRNAs are very stable in the blood, can be easily quantitated and are differentially expressed in response to different pathophysiological conditions. Although standardization procedures and larger, independent studies are still necessary, miRNAs constitute promising, clinically-useful biomarkers for the NAFLD-HCC spectrum. PMID- 26950163 TI - Controlled Release of Ciprofloxacin from Core-Shell Nanofibers with Monolithic or Blended Core. AB - Sustained controlled drug release is one of the prominent contributions for more successful treatment outcomes in the case of several diseases. However, the incorporation of hydrophilic drugs into nanofibers, a promising novel delivery system, and achieving a long-term sustained release still pose a challenging task. In this work we demonstrated a robust method of avoiding burst release of drugs and achieving a sustained drug release from 2 to 4 weeks using core-shell nanofibers with poly(methyl methacrylate) (PMMA) shell and monolithic poly(vinyl alcohol) (PVA) core or a novel type of core-shell nanofibers with blended (PVA and PMMA) core loaded with ciprofloxacin hydrochloride (CIP). It is also shown that, for core-shell nanofibers with monolithic core, drug release can be manipulated by varying flow rate of the core PVA solution, whereas for core-shell nanofibers with blended core, drug release can be manipulated by varying the ratios between PMMA and PVA in the core. During coaxial electrospinning, when the solvent from the core evaporates in concert with the solvent from the shell, the interconnected pores spanning the core and the shell are formed. The release process is found to be desorption-limited and agrees with the two-stage desorption model. Ciprofloxacin-loaded nanofiber mats developed in the present work could be potentially used as local drug delivery systems for treatment of several medical conditions, including periodontal disease and skin, bone, and joint infections. PMID- 26950164 TI - FeCl3-Mediated Radical Tandem Reactions of 3-Benzyl-2-oxindoles with Styrene Derivatives for the Stereoselective Synthesis of Spirocyclohexene Oxindoles. AB - A novel FeCl3-mediated reaction of 3-benzyl-2-oxindoles with styrene derivatives was developed. The reaction provided spirocyclohexene oxindoles in good yields and excellent diastereoselectivities via a tandem radical addition/cyclization process. PMID- 26950165 TI - Delivery of oncolytic adenovirus into the nucleus of tumorigenic cells by tumor microparticles for virotherapy. AB - Oncolytic viruses have been utilized for the treatment of various cancers. However, delivery of the viral particles to tumor cells remains a major challenge. Microparticles (MP) are vesicle forms of plasma membrane fragments of 0.1-1 MUm in size that are shed by cells. We have previously shown the delivery of chemotherapeutic drugs using tumor cell-derived MPs (T-MP). Here we report that T-MPs can be utilized as a unique carrier system to deliver oncolytic adenoviruses to human tumors, leading to highly efficient cytolysis of tumor cells needed for in vivo treatment efficacy. This T-MP-mediated oncolytic virotherapy approach holds multiple advantages, including: 1) delivery of oncolytic adenovirus by T-MPs is able to avoid the antiviral effect of host antibodies; 2) delivery of oncolytic adenovirus by T-MPs is not limited by virus specific receptor that mediates the entry of virus into tumor cells; 3) T-MPs are apt at delivering oncolytic adenoviruses to the nucleus of tumor cells as well as to stem-like tumor-repopulating cells for the desired purpose of killing them. These findings highlight a novel oncolytic adenovirus delivery system with highly promising clinical applications. PMID- 26950166 TI - Nanoparticulate mineralized collagen scaffolds induce in vivo bone regeneration independent of progenitor cell loading or exogenous growth factor stimulation. AB - Current strategies for skeletal regeneration often require co-delivery of scaffold technologies, growth factors, and cellular material. However, isolation and expansion of stem cells can be time consuming, costly, and requires an additional procedure for harvest. Further, the introduction of supraphysiologic doses of growth factors may result in untoward clinical side effects, warranting pursuit of alternative methods for stimulating osteogenesis. In this work, we describe a nanoparticulate mineralized collagen glycosaminoglycan scaffold that induces healing of critical-sized rabbit cranial defects without addition of expanded stem cells or exogenous growth factors. We demonstrate that the mechanism of osteogenic induction corresponds to an increase in canonical BMP receptor signalling secondary to autogenous production of BMP-2 and -9 early and BMP-4 later during differentiation. Thus, nanoparticulate mineralized collagen glycosaminoglycan scaffolds may provide a novel growth factor-free and ex vivo progenitor cell culture-free implantable method for bone regeneration. PMID- 26950167 TI - Active surfaces engineered by immobilizing protein-polymer nanoreactors for selectively detecting sugar alcohols. AB - We introduce active surfaces generated by immobilizing protein-polymer nanoreactors on a solid support for sensitive sugar alcohols detection. First, such selective nanoreactors were engineered in solution by simultaneous encapsulation of specific enzymes in copolymer polymersomes, and insertion of membrane proteins for selective conduct of sugar alcohols. Despite the artificial surroundings, and the thickness of the copolymer membrane, functionality of reconstituted Escherichia coli glycerol facilitator (GlpF) was preserved, and allowed selective diffusion of sugar alcohols to the inner cavity of the polymersome, where encapsulated ribitol dehydrogenase (RDH) enzymes served as biosensing entities. Ribitol, selected as a model sugar alcohol, was detected quantitatively by the RDH-nanoreactors with GlpF-mediated permeability in a concentration range of 1.5-9 mM. To obtain "active surfaces" for detecting sugar alcohols, the nanoreactors optimized in solution were then immobilized on a solid support: aldehyde groups exposed at the compartment external surface reacted via an aldehyde-amino reaction with glass surfaces chemically modified with amino groups. The nanoreactors preserved their architecture and activity after immobilization on the glass surface, and represent active biosensing surfaces for selective detection of sugar alcohols, with high sensitivity. PMID- 26950169 TI - Low-dose radiosurgery or hypofractionated stereotactic radiotherapy as treatment option in refractory epilepsy due to epileptogenic lesions in eloquent areas - Preliminary report of feasibility and safety. AB - PURPOSE: The eradication of epileptogenic lesions (e.g. focal cortical dysplasia) can be used for treatment of drug-resistant focal epilepsy, but in highly eloquent cortex areas it can also lead to a permanent neurological deficit. In such cases the neuromodulation effect of low-dose high-precision irradiation of circumscribed lesions may represent an alternative therapy. METHOD: A total of 10 patients with eloquent localized lesions causing pharmacoresistant focal epilepsy were prospectively identified. After informed consent, six patients agreed and were treated with risk adapted low-dose radiosurgery (SRS) or hypofractionated stereotactic radiotherapy (hfSRT). Comprehensive data concerning treatment modalities and outcome after short-term follow up (mean=16.3 months) were prospectively collected and evaluated. RESULTS: From the six patients, two patients were treated with hfSRT (marginal dose 36 Gy) and four with SRS (marginal dose 13 Gy). Clinical target volume (CTV) ranged from 0.70 ccm to 4.32 ccm. The short-term follow-up ranged from 6 to 27 months. There were no side effects or neurological deficits after treatment. At last available follow-up two patients were seizure-free, one of them being off antiepileptic drugs. The seizure frequency improved in one and remained unchanged in three patients. CONCLUSION: Treatment of eloquent localized epileptogenic lesions by SRS and hfSRT showed no adverse events and an acceptable seizure outcome in this small prospective patient series. The relatively short-term follow-up comprises one of the study's drawbacks and therefore a longer follow-up should be awaited in order to evaluate the neuromodulation effect of the treatment. These preliminary results may however justify the initiation of a larger prospective trial investigating whether focused low-dose stereotactic irradiation could be an option for lesions in eloquent brain areas. PMID- 26950168 TI - Serum albumin 'camouflage' of plant virus based nanoparticles prevents their antibody recognition and enhances pharmacokinetics. AB - Plant virus-based nanoparticles (VNPs) are a novel class of nanocarriers with unique potential for biomedical applications. VNPs have many advantageous properties such as ease of manufacture and high degree of quality control. Their biocompatibility and biodegradability make them an attractive alternative to synthetic nanoparticles (NPs). Nevertheless, as with synthetic NPs, to be successful in drug delivery or imaging, the carriers need to overcome several biological barriers including innate immune recognition. Plasma opsonization can tag (V)NPs for clearance by the mononuclear phagocyte system (MPS), resulting in shortened circulation half lives and non-specific sequestration in non-targeted organs. PEG coatings have been traditionally used to 'shield' nanocarriers from immune surveillance. However, due to broad use of PEG in cosmetics and other industries, the prevalence of anti-PEG antibodies has been reported, which may limit the utility of PEGylation in nanomedicine. Alternative strategies are needed to tailor the in vivo properties of (plant virus-based) nanocarriers. We demonstrate the use of serum albumin (SA) as a viable alternative. SA conjugation to tobacco mosaic virus (TMV)-based nanocarriers results in a 'camouflage' effect more effective than PEG coatings. SA-'camouflaged' TMV particles exhibit decreased antibody recognition, as well as enhanced pharmacokinetics in a Balb/C mouse model. Therefore, SA-coatings may provide an alternative and improved coating technique to yield (plant virus-based) NPs with improved in vivo properties enhancing drug delivery and molecular imaging. PMID- 26950170 TI - Impact of C34T P2Y12 ADP receptor polymorphism and smoking status on cardiovascular outcome in coronary artery disease patients receiving clopidogrel. PMID- 26950171 TI - Changes in mortality on weekend versus weekday admissions for Acute Coronary Syndrome in the United States over the past decade. AB - BACKGROUND: We assessed in-hospital mortality and utilization of invasive cardiac procedures following Acute Coronary Syndrome (ACS) admissions on the weekend versus weekdays over the past decade in the United States. METHODS: We used data from the Nationwide Inpatient Survey (2001-2011) to examine differences in all cause in-hospital mortality between patients with a principal diagnosis of ACS admitted on a weekend versus a weekday. Adjusted and hierarchical logistic regression model analysis was then used to identify if weekend admission was associated with a decreased utilization of procedural interventions and increased subsequent complications as well. RESULTS: 13,988,772 ACS admissions were identified. Adjusted mortality was higher for weekend admissions for Non-ST Elevation Acute Coronary Syndromes [OR: 1.15, 95% CI, 1.14-1.16] and only somewhat higher for ST-Elevation Myocardial Infarction [OR: 1.03; 95% CI, 1.01 1.04]. Additionally, patients were significantly less likely to receive coronary revascularization intervention/therapy on their first day of admission [OR: 0.97, 95% CI: 0.96-0.98 and OR: 0.75, 95% CI: 0.75-0.75 for STEMI and NSTE-ACS respectively]. For ACS patients admitted during the weekend who underwent procedural interventions, in-hospital mortality and complications were higher as compared to patients undergoing the same procedures on weekdays. CONCLUSION: For ACS patients, weekend admission is associated with higher mortality and lower utilization of invasive cardiac procedures, and those who did undergo these interventions had higher rates of mortality and complications than their weekday counterparts. This data leads to the possible conclusion that access to diagnostic/interventional procedures may be contingent upon the day of admission, which may impact mortality. PMID- 26950172 TI - Ovarian Leydig cell hyperplasia as a rare cause of hair loss in a postmenopausal female patient: a case report and diagnostic approach toward postmenopausal hyperandrogenism. PMID- 26950173 TI - Reporting child abuse cases by dentists working in the United Arab Emirates (UAE). AB - Reporting of suspicious cases of child abuse is a sensitive issue that is often hindered by uncertainty of diagnosis. This cross sectional study aimed to assess the UAE dentists' experiences in child abuse recognition, the factors that prevent them from reporting suspicious cases to authorities and their perceived training needs. A closed-ended, self-administered questionnaire was distributed to 350 dentists working in the UAE. Chi Square test was used to determine association between training needs on child abuse and its reporting rate. Logistic regression was used to determine the association between perceived training needs and other covariates. One hundred and ninety three respondents satisfied the inclusion criteria. Forty seven (25%) dentists reported encountering a suspicious child abuse case at least once in their career, but only 15 (32%) of those reported their suspicion. Fear of making the wrong diagnosis was the most frequent challenge hindering reporting and dentists who demonstrated a need for specialized training were more likely to express this fear (OR = 5.88, 95% CI: 0.07, 0.45; P = 0.00). The majority of UAE dentists do not report their suspicion to authorities and specialized training should be offered to build dentists' capacity in diagnosing and appropriately reporting suspicious child abuse cases. PMID- 26950174 TI - Probing Out-of-Plane Charge Transport in Black Phosphorus with Graphene-Contacted Vertical Field-Effect Transistors. AB - Black phosphorus (BP) has recently emerged as a promising narrow band gap layered semiconductor with optoelectronic properties that bridge the gap between semimetallic graphene and wide band gap transition metal dichalcogenides such as MoS2. To date, BP field-effect transistors have utilized a lateral geometry with in-plane transport dominating device characteristics. In contrast, we present here a vertical field-effect transistor geometry based on a graphene/BP van der Waals heterostructure. The resulting device characteristics include high on-state current densities (>1600 A/cm(2)) and current on/off ratios exceeding 800 at low temperature. Two distinct charge transport mechanisms are identified, which are dominant for different regimes of temperature and gate voltage. In particular, the Schottky barrier between graphene and BP determines charge transport at high temperatures and positive gate voltages, whereas tunneling dominates at low temperatures and negative gate voltages. These results elucidate out-of-plane electronic transport in BP and thus have implications for the design and operation of BP-based van der Waals heterostructures. PMID- 26950175 TI - Next-generation proteomics faces new challenges in environmental biotechnology. AB - Environmental biotechnology relies on the exploration of novel biological systems and a thorough understanding of the underlying molecular mechanisms. Next generation proteomics based on the latest generation of mass analyzers currently allows the recording of complete proteomes from any microorganism. Interpreting these data can be straightforward if the genome of the organism is established, or relatively easy to perform through proteogenomics approaches if a draft sequence can be obtained. However, next-generation proteomics faces new, interesting challenges when the organism is distantly related to previously characterized organisms or when mixtures of organisms have to be analyzed. New mass spectrometers and innovative bioinformatics tools are reshaping the possibilities of homology-based proteomics, proteogenomics, and metaproteomics for the characterization of biological systems. Novel time- and cost-effective screening strategies are also possible with this methodology, as exemplified by whole proteome thermal profiling and subpopulation proteomics. The complexity of environmental samples allows for unique developments of approaches and concepts. PMID- 26950179 TI - Nonstatistical UV Fragmentation of Gas-Phase Peptides Reveals Conformers and Their Structural Features. AB - Solving the 3D structure of a biomolecule requires recognition of its conformers and measurements of their individual structural identities, which can be compared with calculations. We employ the phenomenon of nonstatistical photofragmentation, detected by a combination of UV cold ion spectroscopy and high-resolution mass spectrometry, to identify the main conformers of gas-phase peptides and to recover individual UV absorption and mass spectra of all of these conformers in a single laser scan. We first validate this approach with a benchmark dipeptide, Tyr-Ala, and then apply it to a decapeptide, gramicidin S. The revealed characteristic structural difference between the conformers of the latter identifies some of the previously calculated structures of gramicidin S as the most likely geometries of its remaining unsolved conformer. PMID- 26950176 TI - Improved Prediction of Drug-Induced Torsades de Pointes Through Simulations of Dynamics and Machine Learning Algorithms. AB - The ventricular arrhythmia Torsades de Pointes (TdP) is a common form of drug induced cardiotoxicity, but prediction of this arrhythmia remains an unresolved issue in drug development. Current assays to evaluate arrhythmia risk are limited by poor specificity and a lack of mechanistic insight. We addressed this important unresolved issue through a novel computational approach that combined simulations of drug effects on dynamics with statistical analysis and machine learning. Drugs that blocked multiple ion channels were simulated in ventricular myocyte models, and metrics computed from the action potential and intracellular (Ca(2+) ) waveform were used to construct classifiers that distinguished between arrhythmogenic and nonarrhythmogenic drugs. We found that: (1) these classifiers provide superior risk prediction; (2) drug-induced changes to both the action potential and intracellular (Ca(2+) ) influence risk; and (3) cardiac ion channels not typically assessed may significantly affect risk. Our algorithm demonstrates the value of systematic simulations in predicting pharmacological toxicity. PMID- 26950180 TI - The putative phospholipase Lip2 counteracts oxidative damage and influences the virulence of Ustilago maydis. AB - Ustilago maydis is an obligate biotrophic fungal pathogen which causes common smut disease of corn. To proliferate in host tissue, U. maydis must gain access to nutrients and overcome plant defence responses, such as the production of reactive oxygen species. The elucidation of the mechanisms by which U. maydis meets these challenges is critical for the development of strategies to combat smut disease. In this study, we focused on the contributions of phospholipases (PLs) to the pathogenesis of corn smut disease. We identified 11 genes encoding putative PLs and characterized the transcript levels for these genes in the fungus grown in culture and during infection of corn tissue. To assess the contributions of specific PLs, we focused on two genes, lip1 and lip2, which encode putative phospholipase A2 (PLA2 ) enzymes with similarity to platelet activating factor acetylhydrolases. PLA2 enzymes are known to counteract oxidative damage to lipids in other organisms. Consistent with a role in the mitigation of oxidative damage, lip2 mutants were sensitive to oxidative stress provoked by hydrogen peroxide and by increased production of reactive oxygen species caused by inhibitors of mitochondrial functions. Importantly, mutants defective in lip2, but not lip1, were attenuated for virulence in corn seedlings. Finally, a comparative analysis of fatty acid and cardiolipin profiles in the wild-type strain and a lip2 mutant revealed differences consistent with a protective role for Lip2 in maintaining lipid homeostasis and mitochondrial health during proliferation in the hostile host environment. PMID- 26950181 TI - 6-hydroxydopamine-induced Parkinson's disease-like degeneration generates acute microgliosis and astrogliosis in the nigrostriatal system but no bioluminescence imaging-detectable alteration in adult neurogenesis. AB - Parkinson's disease is a slowly progressing neurodegenerative disorder caused by loss of dopaminergic neurons in the substantia nigra (SN), leading to severe impairment in motor and non-motor functions. Endogenous subventricular zone (SVZ) neural stem cells constantly give birth to new cells that might serve as a possible source for regeneration in the adult brain. However, neurodegeneration is accompanied by neuroinflammation and dopamine depletion, potentially compromising regeneration. We therefore employed in vivo imaging methods to study striatal deafferentation (N-omega-fluoropropyl-2beta-carbomethoxy-3beta-(4-[(123) I]iodophenyl)nortropane single photon emission computed tomography, DaTscan(TM) ) and neuroinflammation in the SN and striatum (N,N-diethyl-2-(2-(4-(2-[(18) F]fluoroethoxy)phenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)acetamide positron emission tomography, [(18) F]DPA-714 PET) in the intranigral 6 hydroxydopamine Parkinson's disease mouse model. Additionally, we transduced cells in the SVZ with a lentivirus encoding firefly luciferase and followed migration of progenitor cells in the SVZ-olfactory bulb axis via bioluminescence imaging under disease and control conditions. We found that activation of microglia in the SN is an acute process accompanying the degeneration of dopaminergic cell bodies in the SN. Dopaminergic deafferentation of the striatum does not influence the generation of doublecortin-positive neuroblasts in the SVZ, but generates chronic astrogliosis in the nigrostriatal system. PMID- 26950182 TI - Comparison of sleep disorders in chronic hepatitis C patients treated with interferon-based therapy and direct acting antivirals using actigraphy. AB - : This study aimed to compare the severity of sleep problems between chronic hepatitis C (CHC) patients treated with interferon (IFN)-based triple therapy (pegylated [Peg]-IFN plus ribavirin [RBV] plus simeprevir [SMV]) and those who received IFN-free direct-acting antiviral (DAA) therapy. METHODS: Our study included 31 patients in group A (Peg-IFN/RBV/SMV combination therapy) and 41 patients in the group B (IFN-free DAA therapy). We prospectively compared the effect of each antiviral treatment regimen on sleep conditions between the two groups adding actigraphy data. Five parameters detected by actigraphy (objective assessment) and scores of the Pittsburgh Sleep Quality Index (subjective assessment, n = 30 [group A] and 35 [group B]) were estimated. The causal effect of each therapy on sleep disturbances was evaluated at baseline and at 4 weeks after commencement of therapy. RESULTS: In terms of baseline characteristics, no significant differences between groups were found, except for hepatitis C virus genotype. In group A, sustained virological response 12 rate was 83.9% (26/31), whereas in group B it was 95.1% (39/41). In group A, each score of waking after sleep onset, activity index, wake episodes, and Pittsburgh Sleep Quality Index at 4 weeks significantly increased compared to those evaluated at baseline. In group B, scores of all variables except for sleep episodes at 4 weeks did not significantly change compared to those at baseline. CONCLUSION: Interferon-based triple therapy in patients with CHC may cause significant sleep disturbances. Interferon-free DAA therapy is less likely to deteriorate sleep conditions in patients with CHC. PMID- 26950184 TI - Reply. PMID- 26950185 TI - Cilostazol exerts antiplatelet and anti-inflammatory effects through AMPK activation and NF-kB inhibition on hypercholesterolemic rats. AB - This work presents a model of rats fed a high-cholesterol diet, receiving a long term oral administration of cilostazol, a PDE3-inhibitor. The aim of this study was to evaluate the molecular mechanisms by which cilostazol interferes with platelets signaling pathways to avoid atherosclerosis early development. Male Wistar rats were divided into 3 groups: Control group received standard rat chow (C), hypercholesterolemic group (HCD), and HCD+CIL (cilostazol group) received hypercholesterolemic diet for 45 days. HCD+CIL group received cilostazol (30 mg/kg/p.o.) once daily in the last 15 days. Platelet aggregation, lipid profile, lipid peroxidation, and cytokine serum levels were assessed. Expression of P selectin, CD40L, PKC-alpha, IkB-alpha, and iNOS and activation of AMPK, NF kappaB, and eNOS in the platelets were assessed using Western blot analysis. Cilostazol reduced the levels of total cholesterol (361.0 +/- 12.8 vs. 111.5 +/- 1.6 mg/dL), triglycerides (186.9 +/- 17.7 vs. 55.4 +/-3.1 mg/dL), cLDL (330.9 +/- 9.7 vs. 61.5 +/- 3.5 mg/dL), cVLDL (45.0 +/- 4.6 vs. 11.1 +/- 0.6 mg/dL), and malondialdehyde (9.4 +/- 0.5 vs. 3.2 +/- 0.3 nmol/mL) compared to the HCD group. Cilostazol presented antiplatelet properties and decreased inflammatory markers levels. These effects seem to be related to AMPK activation, NF-kB inhibition, and eNOS activation. PMID- 26950186 TI - Correction to Functional Reconstitution of Cellulose Synthase in Escherichia coli. PMID- 26950187 TI - A polymorphism in FASL is associated with rituximab response in follicular lymphoma patients. PMID- 26950188 TI - Rational Strategies for Efficient Perovskite Solar Cells. AB - A long-standing dream in the large scale application of solar energy conversion is the fabrication of solar cells with high-efficiency and long-term stability at low cost. The realization of such practical goals depends on the architecture, process and key materials because solar cells are typically constructed from multilayer heterostructures of light harvesters, with electron and hole transporting layers as a major component. Recently, inorganic-organic hybrid lead halide perovskites have attracted significant attention as light absorbers for the fabrication of low-cost and high-efficiency solar cells via a solution process. This mainly stems from long-range ambipolar charge transport properties, low exciton binding energies, and suitable band gap tuning by managing the chemical composition. In our pioneering work, a new photovoltaic platform for efficient perovskite solar cells (PSCs) was proposed, which yielded a high power conversion efficiency (PCE) of 12%. The platform consisted of a pillared architecture of a three-dimensional nanocomposite of perovskites fully infiltrating mesoporous TiO2, resulting in the formation of continuous phases and perovskite domains overlaid with a polymeric hole conductor. Since then, the PCE of our PSCs has been rapidly increased from 3% to over 20% certified efficiency. The unprecedented increase in the PCE can be attributed to the effective integration of the advantageous attributes of the refined bicontinuous architecture, deposition process, and composition of perovskite materials. Specifically, the bicontinuous architectures used in the high efficiency comprise a layer of perovskite sandwiched between mesoporous metal-oxide layer, which is a very thinner than that of used in conventional dye-sensitized solar cells, and hole-conducting contact materials with a metal back contact. The mesoporous scaffold can affect the hysteresis under different scan direction in measurements of PSCs. The hysteresis also greatly depends on the cell architecture and perovskite composition. In this Account, we will describe what we do with major aspects including (1) the film morphology through the development of intermediate chemistry retarding the rapid reaction between methylammonium or formamidinium iodide and lead halide (PbI2) for improved perovskite film formation; (2) the phase stability and band gap tuning of the perovskite layer through the materials engineering; (3) the development of electron and hole transporting materials for carrier-selective contacting layers; and (4) the adoption of p-i-n and n-i-p architectures depending on the position of the electron or hole conducting layer in front of incident light. Finally, we will summarize the recent incredible achievements in PSCs, and finally provide challenges facing the future development and commercialization of PSCs. PMID- 26950190 TI - Madness of bipolar driver safety assessments. PMID- 26950189 TI - Current status and opportunities for therapeutic drug monitoring in the treatment of tuberculosis. AB - INTRODUCTION: Tuberculosis remains a global health problem and pharmacokinetic variability has been postulated as one of the causes of treatment failure and acquired drug resistance. New developments enable implementation of therapeutic drug monitoring, a strategy to evaluate drug exposure in order to tailor the dose to the individual patient, in tuberculosis treatment. AREAS COVERED: Literature on pharmacokinetics and pharmacodynamics of anti-tuberculosis drugs was explored to evaluate the effect of drug exposure in relation to drug susceptibility, toxicity and efficacy. New, down-sized strategies, like dried blood spot analysis and limited sampling strategies are reviewed. In addition, molecular resistance testing of Mycobacteria tuberculosis, combining a short turn-around time with relevant information on drug susceptibility of the causative pathogen was explored. Newly emerging host biomarkers provide information on the response to treatment. EXPERT OPINION: Therapeutic drug monitoring can minimize toxicity and increase efficacy of tuberculosis treatment and prevent the development of resistance. Dried blood spot analysis and limited sampling strategies, can be combined to provide us with a more patient friendly approach. Furthermore, rapid information on drug susceptibility by molecular testing, and information from host biomarkers on the bacteriological response, can be used to further optimize tuberculosis treatment. PMID- 26950191 TI - Loss-of-Function of HtrA1 Abrogates All-Trans Retinoic Acid-Induced Osteogenic Differentiation of Mouse Adipose-Derived Stromal Cells Through Deficiencies in p70S6K Activation. AB - All-trans retinoic acid (ATRA) is a potent inducer of osteogenic differentiation in mouse adipose-derived stromal cells (mASCs), although the underlying mechanisms responsible for its mode of action have yet to be completely elucidated. High temperature requirement protease A1 (HtrA1) is a newly recognized modulator of human multipotent stromal cell (MSC) osteogenesis and as such, may play a role in regulating ATRA-dependent osteogenic differentiation of mASCs. In this study, we assessed the influence of small interfering RNA (siRNA) induced repression of HtrA1 production on mASC osteogenesis and examined its effects on ATRA-mediated mammalian target of rapamycin (mTOR) signaling. Inhibition of HtrA1 production in osteogenic mASCs resulted in a significant reduction of alkaline phosphatase activity and mineralized matrix formation. Western blot analyses revealed the rapid activation of Akt (Ser473) and p70S6K (Thr389) in ATRA-treated mASCs, and that levels of phosphorylated p70S6K were noticeably reduced in HtrA1-deficient mASCs. Further studies using mTOR inhibitor rapamycin and siRNA specific for the p70S6K gene Rps6kb1 confirmed ATRA-mediated mASC osteogenesis as being dependent on p70S6K activation. Finally, transfection of cells with a constitutively active rapamycin-resistant p70S6K mutant could restore the mineralizing capacity of HtrA1-deficient mASCs. These findings therefore lend further support for HtrA1 as a positive mediator of MSC osteogenesis and provide new insights into the molecular mode of action of ATRA in regulating mASC lineage commitment. PMID- 26950192 TI - The High Burden of Palliative Care Needs among Older Emergency General Surgery Patients. PMID- 26950193 TI - Source apportionment of PM2.5 for supporting control strategies in the Monterrey Metropolitan Area, Mexico. AB - The Monterrey Metropolitan Area (MMA) in Northeast Mexico has shown high PM2.5 concentrations since 2003. The data shows that the annual average concentration exceeds from 2 to 3 times the Mexican PM2.5 annual air quality standard of 12 ug/m(3). In a previous work we studied the chemical characterization of PM2.5 in two sites of the MMA during the winter season. Among the most important components we found ammonium sulfate and nitrate, elemental and organic carbon, and crustal matter. In this work we present the results of a second chemical characterization study performed during the summer time and the application of the chemical mass balance (CMB) model to determine the source apportionment of air pollutants in the region. The chemical analysis results show that the chemical composition of PM2.5 is similar in both sites and periods of the year. The results of the chemical analysis and the CMB model show that industrial, traffic, and combustion activities in the area are the major sources of primary PM2.5 and precursor gases of secondary inorganic and organic aerosol (SO2, NOx, NH3, and volatile organic compounds [VOCs]). We also found that black carbon and organic carbon are important components of PM2.5 in the MMA. These results are consistent with the MMA emission inventory that reports as major sources of particles and SO2 a refinery and fuel combustion, as well as nitrogen oxides and ammonium from transportation and industrial activities in the MMA and ammonium form agricultural activities in the state. The results of this work are important to identify and support effective actions to reduce direct emissions of PM2.5 and its precursor gases to improve air quality in the MMA. IMPLICATIONS: The Monterrey Metropolitan Area (MMA) has been classified as the most air-polluted area in Mexico by the World Health Organization (WHO). Effective actions need to be taken to control primary sources of PM2.5 and its precursors, reducing health risks on the population exposed and their associated costs. The results of this study identify the main sources and their estimated contribution to PM2.5 mass concentration, providing valuable information to the local environmental authorities to take decisions on PM2.5 control strategies in the MMA. PMID- 26950183 TI - Tiny giants of gene regulation: experimental strategies for microRNA functional studies. AB - The discovery over two decades ago of short regulatory microRNAs (miRNAs) has led to the inception of a vast biomedical research field dedicated to understanding these powerful orchestrators of gene expression. Here we aim to provide a comprehensive overview of the methods and techniques underpinning the experimental pipeline employed for exploratory miRNA studies in animals. Some of the greatest challenges in this field have been uncovering the identity of miRNA target interactions and deciphering their significance with regard to particular physiological or pathological processes. These endeavors relied almost exclusively on the development of powerful research tools encompassing novel bioinformatics pipelines, high-throughput target identification platforms, and functional target validation methodologies. Thus, in an unparalleled manner, the biomedical technology revolution unceasingly enhanced and refined our ability to dissect miRNA regulatory networks and understand their roles in vivo in the context of cells and organisms. Recurring motifs of target recognition have led to the creation of a large number of multifactorial bioinformatics analysis platforms, which have proved instrumental in guiding experimental miRNA studies. Subsequently, the need for discovery of miRNA-target binding events in vivo drove the emergence of a slew of high-throughput multiplex strategies, which now provide a viable prospect for elucidating genome-wide miRNA-target binding maps in a variety of cell types and tissues. Finally, deciphering the functional relevance of miRNA post-transcriptional gene silencing under physiological conditions, prompted the evolution of a host of technologies enabling systemic manipulation of miRNA homeostasis as well as high-precision interference with their direct, endogenous targets. For further resources related to this article, please visit the WIREs website. PMID- 26950196 TI - bioOTU: An Improved Method for Simultaneous Taxonomic Assignments and Operational Taxonomic Units Clustering of 16s rRNA Gene Sequences. AB - Clustering of 16s rRNA amplicon sequences into operational taxonomic units (OTUs) is the most common bioinformatics pipeline for investigating microbial community by high-throughput sequencing technologies. However, the existing algorithms of OTUs clustering still remain to be improved at reliability. Here we propose an improved method (bioOTU) that first assigns taxonomy to unique tags at genus level for separating the error-free sequences of known species in reference database from artifacts, and then cluster them into OTUs by different strategies. The remaining tags, which fail to be clustered in the previous step, are further subjected to independent OTUs clustering by the optimized algorithm of heuristic clustering. The performance tests on both mock and real communities revealed that bioOTU is powerful for recovering the underlying profiles at both microbial composition and abundance, and it also produces comparable or less number of OTUs in comparison with the prevailing tools of Mothur and UPARSE. The bioOTU is implemented in C and Python languages with source codes freely available on the GitHub repository. PMID- 26950194 TI - Bloodstream infections in HIV-infected patients. AB - In the combined antiretroviral therapy era, HIV-infected patients remain a vulnerable population for the onset of bloodstream infections (BSI). Worldwide, nontyphoid salmonellae, Streptococcus pneumoniae, Escherichia coli, Staphylococcus aureus and coagulase negative staphylococci are the most important pathogens. Intravenous catheter associated infection, skin-soft tissue infection and endocarditis are associated with Gram-positive bacteremia. Among the Gram negative, nontyphoidal Salmonella have been previously correlated to sepsis. Other causes of BSI in HIV-infected patients are mycobacteria and fungi. Mycobacteria constitute a major cause of BSI in limited resource countries. Fungal BSI are not frequent and among them Cryptococcus neoformans is the most common life-threatening infection. The degree of immunosuppression remains the key prognostic factor leading to the development of BSI. PMID- 26950198 TI - Evolving hybrid approaches: the preservation of the 'neglected' pulmonary valve function in patients with congenital heart disease. AB - The involvement of the hemodynamic expertise in the operating room led to the development of new strategies aimed to improve both early and long-term outcome of patients with congenital heart disease. During the last decade, with the aim of preserving the pulmonary valve function, we embarked on a new surgical approach, which combines surgical and interventional techniques, which are performed in the operating room. We believe that the preservation of the pulmonary valve function can be extended to any patients with classic tetralogy of Fallot and other selected patients with congenital pulmonary valve hypoplasia and dysfunction. PMID- 26950197 TI - Risk Factors for Proliferative Diabetic Retinopathy in African Americans with Type 2 Diabetes. AB - PURPOSE: To assess personal and demographic risk factors for proliferative diabetic retinopathy in African Americans with type 2 diabetes. METHODS: In this prospective, non-interventional, cross-sectional case-control study, 380 African Americans with type 2 diabetes were enrolled. Participants were recruited prospectively and had to have either: (1) absence of diabetic retinopathy after >=10 years of type 2 diabetes, or (2) presence of proliferative diabetic retinopathy when enrolled. Dilated, 7-field fundus photographs were graded using the Early Treatment Diabetic Retinopathy Study scale. Covariates including hemoglobin A1C (HbA1C), blood pressure, height, weight and waist circumference were collected prospectively. Multivariate regression models adjusted for age, sex and site were constructed to assess associations between risk factors and proliferative diabetic retinopathy. RESULTS: Proliferative diabetic retinopathy was associated with longer duration of diabetes (odds ratio, OR, 1.62, p < 0.001), higher systolic blood pressure (OR 1.65, p < 0.001) and insulin use (OR 6.65, p < 0.001) in the multivariate regression analysis. HbA1C was associated with proliferative diabetic retinopathy in the univariate analysis (OR 1.31, p = 0.002) but was no longer significant in the multivariate analysis. CONCLUSIONS: In this case-control study of African Americans with type 2 diabetes, duration of diabetes, systolic hypertension and insulin use were strong risk factors for the development of proliferative diabetic retinopathy. Interestingly, HbA1C did not confer additional risk in this cohort. PMID- 26950200 TI - Delayed Neuroendocrine Sexual Maturation in Female Rats After a Very Low Dose of Bisphenol A Through Altered GABAergic Neurotransmission and Opposing Effects of a High Dose. AB - Rat sexual maturation is preceded by a reduction of the interpulse interval (IPI) of GnRH neurosecretion. This work aims at studying disruption of that neuroendocrine event in females after early exposure to a very low dose of bisphenol A (BPA), a ubiquitous endocrine disrupting chemical. Female rats were exposed to vehicle or BPA 25 ng/kg.d, 25 MUg/kg.d, or 5 mg/kg.d from postnatal day (PND)1 to PND5 or PND15. Exposure to 25 ng/kg.d of BPA for 5 or 15 days was followed by a delay in developmental reduction of GnRH IPI studied ex vivo on PND20. After 15 days of exposure to that low dose of BPA, vaginal opening tended to be delayed. In contrast, exposure to BPA 5 mg/kg.d for 15 days resulted in a premature reduction in GnRH IPI and a trend toward early vaginal opening. RNA sequencing analysis on PND20 indicated that exposure to BPA resulted in opposing dose effects on the mRNA expression of hypothalamic genes involved in gamma aminobutyric acid A (GABAA) neurotransmission. The study of GnRH secretion in vitro in the presence of GABAA receptor agonist/antagonist confirmed an increased or a reduced GABAergic tone after in vivo exposure to the very low or the high dose of BPA, respectively. Overall, we show for the first time that neonatal exposure to BPA leads to opposing dose-dependent effects on the neuroendocrine control of puberty in the female rat. A very low and environmentally relevant dose of BPA delays neuroendocrine maturation related to puberty through increased inhibitory GABAergic neurotransmission. PMID- 26950199 TI - Melatonin Synthesis: Acetylserotonin O-Methyltransferase (ASMT) Is Strongly Expressed in a Subpopulation of Pinealocytes in the Male Rat Pineal Gland. AB - The rat pineal gland has been extensively used in studies of melatonin synthesis. However, the cellular localization of melatonin synthesis in this species has not been investigated. Here we focus on the localization of melatonin synthesis using immunohistochemical methods to detect the last enzyme in melatonin synthesis, acetylserotonin O-methyltransferase (ASMT), and in situ hybridization techniques to study transcripts encoding ASMT and two other enzymes in melatonin synthesis, tryptophan hydroxylase (TPH)-1 and aralkylamine N-acetyltransferase. In sections of the rat pineal gland, marked cell-to-cell differences were found in ASMT immunostaining intensity and in the abundance of Tph1, Aanat, and Asmt transcripts. ASMT immunoreactivity was localized to the cytoplasm in pinealocytes in the parenchyma of the superficial pineal gland, and immunopositive pinealocytes were also detected in the pineal stalk and in the deep pineal gland. ASMT was found to inconsistently colocalize with S-antigen, a widely used pinealocyte marker; this colocalization was seen in cells throughout the pineal complex and also in displaced pinealocyte-like cells of the medial habenular nucleus. Inconsistent colocalization between ASMT and TPH protein was also detected in the pineal gland. ASMT protein was not detected in extraepithalamic parts of the central nervous system or in peripheral tissues. The findings in this report are of special interest because they provide reason to suspect that melatonin synthesis varies significantly among individual pinealocytes. PMID- 26950201 TI - Multiple Transduction Pathways Mediate Thyrotropin Receptor Signaling in Preosteoblast-Like Cells. AB - It has been shown that the TSH receptor (TSHR) couples to a number of different signaling pathways, although the Gs-cAMP pathway has been considered primary. Here, we measured the effects of TSH on bone marker mRNA and protein expression in preosteoblast-like U2OS cells stably expressing TSHRs. We determined which signaling cascades are involved in the regulation of IL-11, osteopontin (OPN), and alkaline phosphatase (ALPL). We demonstrated that TSH-induced up-regulation of IL-11 is primarily mediated via the Gs pathway as IL-11 was up-regulated by forskolin (FSK), an adenylyl cyclase activator, and inhibited by protein kinase A inhibitor H-89 and by silencing of Galphas by small interfering RNA. OPN levels were not affected by FSK, but its up-regulation was inhibited by TSHR/Gi uncoupling by pertussis toxin. Pertussis toxin decreased p38 MAPK kinase phosphorylation, and a p38 inhibitor and small interfering RNA knockdown of p38alpha inhibited OPN induction by TSH. Up-regulation of ALPL expression required high doses of TSH (EC50 = 395nM), whereas low doses (EC50 = 19nM) were inhibitory. FSK-stimulated cAMP production decreased basal ALPL expression, whereas protein kinase A inhibition by H-89 and silencing of Galphas increased basal levels of ALPL. Knockdown of Galphaq/11 and a protein kinase C inhibitor decreased TSH-stimulated up-regulation of ALPL, whereas a protein kinase C activator increased ALPL levels. A MAPK inhibitor and silencing of ERK1/2 inhibited TSH-stimulated ALPL expression. We conclude that TSH regulates expression of different bone markers via distinct signaling pathways. PMID- 26950203 TI - Reference values of serum transferrin receptor (sTfR) and sTfR/log ferritin index in healthy children. AB - ABSTARCT The aims of this study were to determine appropriate reference ranges for serum transferrin receptor (sTfR) and sTfR/log ferritin (sTfR-F index) in healthy children and their relationship with iron parameters, erythropoiesis, and other conditions presented by the subject. A total of 902 children with normal iron status, aged 1-11 years, were included in a cross-sectional study. A physical examination was conducted and z-score of body mass index (zBMI) obtained. Complete blood count, iron biomarkers, erythropoietin, C-reactive protein, sTfR, and sTfR/log ferritin were determined. Linear multiple regression was applied to identify the factors that determined sTfR and sTfR-F index variability. Mean values for sTfR and sTfR-F index were 1.22 +/- 0.28 mg/L (95% confidence interval [CI]: 1.2-1.23) and 0.87 +/- 0.25 (95% CI: 0.85-0.88). The reference intervals (2.5th to 97.5th percentiles [P2.5-P97.5]) were 0.78-1.9 mg/L and 0.49-1.46, respectively. sTfR and sTfR-F values decreased with age (P <.03 and P <.0001, respectively). No changes were observed with sex. Changes in sTfR and sTfR-F index were consistent with ferritin and erythropoietin variations. Iron biomarkers, erythropoietin, and zBMI predicted 19% and 18.1% of the sTfR and sTfR-F index variability. The results provide reference ranges for sTfR and sTfR F index in healthy children for clinical use in the assessment of body iron status. Both biomarkers are predicted by iron parameters, erythropoietin, and zBMI. PMID- 26950202 TI - Hepatic PPARgamma Is Not Essential for the Rapid Development of Steatosis After Loss of Hepatic GH Signaling, in Adult Male Mice. AB - Our group has previously reported de novo lipogenesis (DNL) and hepatic triglyceride content increases in chow-fed male mice within 7 days of hepatocyte specific GH receptor knockdown (aLivGHRkd). Here, we report that these changes are associated with an increase in hepatic expression of peroxisome proliferator activated receptor gamma (PPARgamma), consistent with previous reports showing steatosis is associated with an increase in PPARgamma expression in mice with congenital loss of hepatic GH signaling. PPARgamma is thought to be an important driver of steatosis by enhancing DNL, as well as increasing the uptake and esterification of extrahepatic fatty acids (FAs). In order to determine whether hepatic PPARgamma is critical for the rapid development of steatosis in the aLivGHRkd mouse model, we have generated aLivGHRkd mice, with or without PPARgamma (ie, adult-onset, hepatocyte-specific double knockout of GHR and PPARgamma). Hepatic PPARgamma was not required for the rapid increase in liver triglyceride content or FA indexes of DNL (16:0/18:2 and 16:1/16:0). However, loss of hepatic PPARgamma blunted the rise in fatty acid translocase/CD36 and monoacylglycerol acyltransferase 1 expression induced by aLivGHRkd, and this was associated with a reduction in the hepatic content of 18:2. These results suggest that the major role of PPARgamma is to enhance pathways critical in uptake and reesterification of extrahepatic FA. Because FAs have been reported to directly increase PPARgamma expression, we speculate that in the aLivGHRkd mouse, the FA produced by DNL enhances the expression of PPARgamma, which in turn increases extrahepatic FA uptake, thereby further enhancing PPARgamma activity and exacerbating steatosis overtime. PMID- 26950204 TI - A Natural Product Telomerase Activator Lengthens Telomeres in Humans: A Randomized, Double Blind, and Placebo Controlled Study. AB - TA-65 is a dietary supplement based on an improved formulation of a small molecule telomerase activator that was discovered in a systematic screening of natural product extracts from traditional Chinese medicines. This study summarizes the findings on telomere length (TL) changes from a randomized, double blind, placebo controlled study of TA-65 over a 1 year period. The study was conducted on 117 relatively healthy cytomegalovirus-positive subjects aged 53-87 years old. Subjects taking the low dose of TA-65 (250 U) significantly increased TL over the 12 months period (530 +/- 180 bp; p = 0.005), whereas subjects in the placebo group significantly lost TL (290 +/- 100 bp; p = 0.01). The high dose of TA-65 (1000 U) showed a trend of improvements in TL compared with that of the placebo group; however, the improvements did not reach statistical significance. TL changes in the low-dose group were similar for both median and 20th percentile TLs. The findings suggest that TA-65 can lengthen telomeres in a statistically and possibly clinically significant manner. PMID- 26950205 TI - Molecular Epidemiological Survey of Glucose-6-Phosphate Dehydrogenase Deficiency and Thalassemia in Uygur and Kazak Ethnic Groups in Xinjiang, Northwest China. AB - Glucose-6-phosphate dehydrogenase (G6PD) deficiency and thalassemia occur frequently in tropical and subtropical regions, while the prevalence of relationship between the two diseases in Xinjiang has not been reported. We aimed to determine the prevalence of these diseases and clarify the relationship between genotypes and phenotypes of the two diseases in the Uygur and Kazak ethnic groups in Xinjiang. We measured G6PD activity by G6PD:6PGD (glucose acid-6 phosphate dehydrogenase) ratio, identified the gene variants of G6PD and alpha- and beta-globin genes by polymerase chain reaction (PCR)-DNA sequencing and gap PCR and compared these variants in different ethnic groups in Xinjiang with those adjacent to it. Of the 149 subjects with molecular analysis of G6PD deficiency conducted, a higher prevalence of the combined mutations c.1311C > T/IVSXI + 93T > C and IVSXI + 93T > C, both with normal enzymatic activities, were observed in the Uygur and Kazak subjects. A case of rare mutation HBB: c.135delC [codon 44 ( C) in the heterozygous state], a heterozygous case of HBB: c.68A > G [Hb G-Taipei or beta22(B4)Glu->Gly] and several common single nucleotide polymorphisms (SNPs) were found on the beta-globin gene. In conclusion, G6PD deficiency with pathogenic mutations and three common alpha-thalassemia (alpha-thal) [- -(SEA), alpha(3.7) (rightward), -alpha(4.2) (leftward)] deletions and point mutations of the alpha-globin gene were not detected in the present study. The average incidence of beta-thalassemia (beta-thal) in Uygurs was 1.45% (2/138) in Xinjiang. The polymorphisms of G6PD and beta-globin genes might be useful genetic markers to trace the origin and migration of the Uygur and Kazak in Xinjiang. PMID- 26950206 TI - Continuous patient engagement in cardiovascular disease clinical comparative effectiveness research. AB - Researchers have produced evidence that identifies interventions that reduce cardiovascular disease (CVD) risk; however, despite a significant investment in research CVD remains the leading cause of death. Engaging patients in the research process has the potential to ensure that evidence-based treatments are adopted in real-world practice to improve patient outcomes. The Patient-Centered Outcomes Research Institute has created an Engagement Rubric to guide meaningful engagement in the research process. A 10-step systematic framework to enhance patient engagement throughout the comparative effectiveness research process also has been proposed. This special report identifies the relationship between these two approaches to patient engagement and describes examples of how patients could be engaged in a hypothetical CVD study. PMID- 26950207 TI - The osteoimmunology of alveolar bone loss. AB - The mineralized structure of bone undergoes constant remodeling by the balanced actions of bone-producing osteoblasts and bone-resorbing osteoclasts (OCLs). Physiologic bone remodeling occurs in response to the body's need to respond to changes in electrolyte levels, or mechanical forces on bone. There are many pathological conditions, however, that cause an imbalance between bone production and resorption due to excessive OCL action that results in net bone loss. Situations involving chronic or acute inflammation are often associated with net bone loss, and research into understanding the mechanisms regulating this bone loss has led to the development of the field of osteoimmunology. It is now evident that the skeletal and immune systems are functionally linked and share common cells and signaling molecules. This review discusses the signaling system of immune cells and cytokines regulating aberrant OCL differentiation and activity. The role of these cells and cytokines in the bone loss occurring in periodontal disease (PD) (chronic inflammation) and orthodontic tooth movement (OTM) (acute inflammation) is then described. The review finishes with an exploration of the emerging role of Notch signaling in the development of the immune cells and OCLs that are involved in osteoimmunological bone loss and the research into Notch signaling in OTM and PD. PMID- 26950208 TI - Safety and Biodistribution Evaluation in CNGB3-deficient Mice of rAAV2tYF-PR1.7 hCNGB3, a Recombinant AAV Vector for Treatment of Achromatopsia. AB - EVALUATION OF RAAV2TYF-PR1.7-HCNGB3 IN CNGB3 KO MICE. PMID- 26950209 TI - HBpF-proBDNF: A New Tool for the Analysis of Pro-Brain Derived Neurotrophic Factor Receptor Signaling and Cell Biology. AB - Neurotrophins activate intracellular signaling pathways necessary for neuronal survival, growth and apoptosis. The most abundant neurotrophin in the adult brain, brain-derived neurotrophic factor (BDNF), is first synthesized as a proBDNF precursor and recent studies have demonstrated that proBDNF can be secreted and that it functions as a ligand for a receptor complex containing p75NTR and sortilin. Activation of proBDNF receptors mediates growth cone collapse, reduces synaptic activity, and facilitates developmental apoptosis of motoneurons but the precise signaling cascades have been difficult to discern. To address this, we have engineered, expressed and purified HBpF-proBDNF, an expression construct containing a 6X-HIS tag, a biotin acceptor peptide (BAP) sequence, a PreScissionTM Protease cleavage site and a FLAG-tag attached to the N terminal part of murine proBDNF. Intact HBpF-proBDNF has activities indistinguishable from its wild-type counterpart and can be used to purify proBDNF signaling complexes or to monitor proBDNF endocytosis and retrograde transport. HBpF-proBDNF will be useful for characterizing proBDNF signaling complexes and for deciphering the role of proBDNF in neuronal development, synapse function and neurodegenerative disease. PMID- 26950211 TI - Hormesis in Cholestatic Liver Disease; Preconditioning with Low Bile Acid Concentrations Protects against Bile Acid-Induced Toxicity. AB - INTRODUCTION: Cholestasis is characterized by accumulation of bile acids and inflammation, causing hepatocellular damage. Still, liver damage markers are highest in acute cholestasis and drop when this condition becomes chronic, indicating that hepatocytes adapt towards the hostile environment. This may be explained by a hormetic response in hepatocytes that limits cell death during cholestasis. AIM: To investigate the mechanisms that underlie the hormetic response that protect hepatocytes against experimental cholestatic conditions. METHODS: HepG2.rNtcp cells were preconditioned (24 h) with sub-apoptotic concentrations (0.1-50 MUM) of various bile acids, the superoxide donor menadione, TNF-alpha or the Farsenoid X Receptor agonist GW4064, followed by a challenge with the apoptosis-inducing bile acid glycochenodeoxycholic acid (GCDCA; 200 MUM for 4 h), menadione (50 MUM, 6 h) or cytokine mixture (CM; 6 h). Levels of apoptotic and necrotic cell death, mRNA expression of the bile salt export pump (ABCB11) and bile acid sensors, as well as intracellular GCDCA levels were analyzed. RESULTS: Preconditioning with the pro-apoptotic bile acids GCDCA, taurocholic acid, or the protective bile acids (tauro)ursodeoxycholic acid reduced GCDCA-induced caspase-3/7 activity in HepG2.rNtcp cells. Bile acid preconditioning did not induce significant levels of necrosis in GCDCA-challenged HepG2.rNtcp cells. In contrast, preconditioning with cholic acid, menadione or TNF-alpha potentiated GCDCA-induced apoptosis. GCDCA preconditioning specifically reduced GCDCA-induced cell death and not CM- or menadione-induced apoptosis. The hormetic effect of GCDCA preconditioning was concentration- and time-dependent. GCDCA-, CDCA- and GW4064- preconditioning enhanced ABCB11 mRNA levels, but in contrast to the bile acids, GW4064 did not significantly reduce GCDCA-induced caspase-3/7 activity. The GCDCA challenge strongly increased intracellular levels of this bile acid, which was not lowered by GCDCA-preconditioning. CONCLUSIONS: Sub-toxic concentrations of bile acids in the range that occur under normal physiological conditions protect HepG2.rNtcp cells against GCDCA-induced apoptosis, which is independent of FXR-controlled changes in bile acid transport. PMID- 26950210 TI - Relationships between Categorical Perception of Phonemes, Phoneme Awareness, and Visual Attention Span in Developmental Dyslexia. AB - We tested the hypothesis that the categorical perception deficit of speech sounds in developmental dyslexia is related to phoneme awareness skills, whereas a visual attention (VA) span deficit constitutes an independent deficit. Phoneme awareness tasks, VA span tasks and categorical perception tasks of phoneme identification and discrimination using a d/t voicing continuum were administered to 63 dyslexic children and 63 control children matched on chronological age. Results showed significant differences in categorical perception between the dyslexic and control children. Significant correlations were found between categorical perception skills, phoneme awareness and reading. Although VA span correlated with reading, no significant correlations were found between either categorical perception or phoneme awareness and VA span. Mediation analyses performed on the whole dyslexic sample suggested that the effect of categorical perception on reading might be mediated by phoneme awareness. This relationship was independent of the participants' VA span abilities. Two groups of dyslexic children with a single phoneme awareness or a single VA span deficit were then identified. The phonologically impaired group showed lower categorical perception skills than the control group but categorical perception was similar in the VA span impaired dyslexic and control children. The overall findings suggest that the link between categorical perception, phoneme awareness and reading is independent from VA span skills. These findings provide new insights on the heterogeneity of developmental dyslexia. They suggest that phonological processes and VA span independently affect reading acquisition. PMID- 26950212 TI - Extremely Low-Frequency Electromagnetic Fields Promote In Vitro Neuronal Differentiation and Neurite Outgrowth of Embryonic Neural Stem Cells via Up Regulating TRPC1. AB - Exposure to extremely low-frequency electromagnetic fields (ELF-EMFs) can enhance hippocampal neurogenesis in adult mice. However, little is focused on the effects of ELF-EMFs on embryonic neurogenesis. Here, we studied the potential effects of ELF-EMFs on embryonic neural stem cells (eNSCs). We exposed eNSCs to ELF-EMF (50 Hz, 1 mT) for 1, 2, and 3 days with 4 hours per day. We found that eNSC proliferation and maintenance were significantly enhanced after ELF-EMF exposure in proliferation medium. ELF-EMF exposure increased the ratio of differentiated neurons and promoted the neurite outgrowth of eNSC-derived neurons without influencing astrocyes differentiation and the cell apoptosis. In addition, the expression of the proneural genes, NeuroD and Ngn1, which are crucial for neuronal differentiation and neurite outgrowth, was increased after ELF-EMF exposure. Moreover, the expression of transient receptor potential canonical 1 (TRPC1) was significantly up-regulated accompanied by increased the peak amplitude of intracellular calcium level induced by ELF-EMF. Furthermore, silencing TRPC1 expression eliminated the up-regulation of the proneural genes and the promotion of neuronal differentiation and neurite outgrowth induced by ELF-EMF. These results suggest that ELF-EMF exposure promotes the neuronal differentiation and neurite outgrowth of eNSCs via up-regulation the expression of TRPC1 and proneural genes (NeuroD and Ngn1). These findings also provide new insights in understanding the effects of ELF-EMF exposure on embryonic brain development. PMID- 26950213 TI - Induction of Inducible Nitric Oxide Synthase by Lipopolysaccharide and the Influences of Cell Volume Changes, Stress Hormones and Oxidative Stress on Nitric Oxide Efflux from the Perfused Liver of Air-Breathing Catfish, Heteropneustes fossilis. AB - The air-breathing singhi catfish (Heteropneustes fossilis) is frequently being challenged by bacterial contaminants, and different environmental insults like osmotic, hyper-ammonia, dehydration and oxidative stresses in its natural habitats throughout the year. The main objectives of the present investigation were to determine (a) the possible induction of inducible nitric oxide synthase (iNOS) gene with enhanced production of nitric oxide (NO) by intra-peritoneal injection of lipopolysaccharide (LPS) (a bacterial endotoxin), and (b) to determine the effects of hepatic cell volume changes due to anisotonicity or by infusion of certain metabolites, stress hormones and by induction of oxidative stress on production of NO from the iNOS-induced perfused liver of singhi catfish. Intra-peritoneal injection of LPS led to induction of iNOS gene and localized tissue specific expression of iNOS enzyme with more production and accumulation of NO in different tissues of singhi catfish. Further, changes of hydration status/cell volume, caused either by anisotonicity or by infusion of certain metabolites such as glutamine plus glycine and adenosine, affected the NO production from the perfused liver of iNOS-induced singhi catfish. In general, increase of hydration status/cell swelling due to hypotonicity caused decrease, and decrease of hydration status/cell shrinkage due to hypertonicity caused increase of NO efflux from the perfused liver, thus suggesting that changes in hydration status/cell volume of hepatic cells serve as a potent modulator for regulating the NO production. Significant increase of NO efflux from the perfused liver was also observed while infusing the liver with stress hormones like epinephrine and norepinephrine, accompanied with decrease of hydration status/cell volume of hepatic cells. Further, oxidative stress, caused due to infusion of t-butyl hydroperoxide and hydrogen peroxide separately, in the perfused liver of singhi catfish, resulted in significant increase of NO efflux accompanied with decrease of hydration status/cell volume of hepatic cells. However, the reasons for these cell volume-sensitive changes of NO efflux from the liver of singhi catfish are not fully understood with the available data. Nonetheless, enhanced or decreased production of NO from the perfused liver under osmotic stress, in presence of stress hormones and oxidative stress reflected its potential role in cellular homeostasis and also for better adaptations under environmental challenges. This is the first report of osmosensitive and oxidative stress-induced changes of NO production and efflux from the liver of any teleosts. Further, the level of expression of iNOS in this singhi catfish could also serve as an important indicator to determine the pathological status of the external environment. PMID- 26950215 TI - Ion Concentration- and Voltage-Dependent Push and Pull Mechanisms of Potassium Channel Ion Conduction. AB - The mechanism of ion conduction by potassium channels is one of the central issues in physiology. In particular, it is still unclear how the ion concentration and the membrane voltage drive ion conduction. We have investigated the dynamics of the ion conduction processes in the Kv1.2 pore domain, by molecular dynamics (MD) simulations with several different voltages and ion concentrations. By focusing on the detailed ion movements through the pore including selectivity filter (SF) and cavity, we found two major conduction mechanisms, called the III-IV-III and III-II-III mechanisms, and the balance between the ion concentration and the voltage determines the mechanism preference. In the III-IV-III mechanism, the outermost ion in the pore is pushed out by a new ion coming from the intracellular fluid, and four-ion states were transiently observed. In the III-II-III mechanism, the outermost ion is pulled out first, without pushing by incoming ions. Increases in the ion concentration and voltage accelerated ion conductions, but their mechanisms were different. The increase in the ion concentrations facilitated the III-IV-III conductions, while the higher voltages increased the III-II-III conductions, indicating that the pore domain of potassium channels permeates ions by using two different driving forces: a push by intracellular ions and a pull by voltage. PMID- 26950214 TI - West Nile Virus Retinopathy and Associations with Long Term Neurological and Neurocognitive Sequelae. AB - West Nile virus (WNV) has emerged as an important vector-borne pathogen in North America, with more than 3 million estimated to have been infected. Retinopathy from WNV infection has been previously reported in acute cases, though those prior reports did not evaluate the risk of retinopathy based on clinical severity of neurologic disease. The purpose of this cross-sectional study was to perform comprehensive ophthalmological and neurological examinations on 111 patients with a history of West Nile virus infection and describe the ocular manifestations. Out of 111 patients, 27 (24%) had evidence for West Nile virus associated retinopathy (WNVR); this observation was higher (49%) in those patients who initially presented with encephalitis. Individuals with WNVR had more frequent involvement of the macula and peripheral involvement compared to those patients without WNVR (p<0.05). WNVR was also associated with a greater likelihood of abnormal reflexes on neurological exam, poorer learning, greater dependence in activities of daily living, and lower quality of life (p<0.05). WNVR was seen more frequently in elderly patients (age > 60 years), and was associated with higher rates of diabetes mellitus and a history of encephalitis (p<0.05). A multivariable logistic regression revealed that only a history of encephalitis was independently associated with WNVR [Adjusted Odds Ratio = 4.9 (1.8-13.2); p = 0.001]. Our study found that WNVR occurs in one fourth of patients with a history of WNV infection and is more frequently observed in those with apparent severe neurological sequelae (e.g., encephalitis). The clinical relevance of WNVR was supported by its associations with dependence in activities of daily living and lower quality of life. This unique evaluation of WNV patients included fundoscopic examinations and their associations with neurologic impairment. Our findings can be used during ophthalmological consultation for the evaluation, treatment and rehabilitation phases of care for WNV patients. PMID- 26950216 TI - The Adaptive Significance of Natural Genetic Variation in the DNA Damage Response of Drosophila melanogaster. AB - Despite decades of work, our understanding of the distribution of fitness effects of segregating genetic variants in natural populations remains largely incomplete. One form of selection that can maintain genetic variation is spatially varying selection, such as that leading to latitudinal clines. While the introduction of population genomic approaches to understanding spatially varying selection has generated much excitement, little successful effort has been devoted to moving beyond genome scans for selection to experimental analysis of the relevant biology and the development of experimentally motivated hypotheses regarding the agents of selection; it remains an interesting question as to whether the vast majority of population genomic work will lead to satisfying biological insights. Here, motivated by population genomic results, we investigate how spatially varying selection in the genetic model system, Drosophila melanogaster, has led to genetic differences between populations in several components of the DNA damage response. UVB incidence, which is negatively correlated with latitude, is an important agent of DNA damage. We show that sensitivity of early embryos to UVB exposure is strongly correlated with latitude such that low latitude populations show much lower sensitivity to UVB. We then show that lines with lower embryo UVB sensitivity also exhibit increased capacity for repair of damaged sperm DNA by the oocyte. A comparison of the early embryo transcriptome in high and low latitude embryos provides evidence that one mechanism of adaptive DNA repair differences between populations is the greater abundance of DNA repair transcripts in the eggs of low latitude females. Finally, we use population genomic comparisons of high and low latitude samples to reveal evidence that multiple components of the DNA damage response and both coding and non-coding variation likely contribute to adaptive differences in DNA repair between populations. PMID- 26950217 TI - Pravastatin and Sarpogrelate Synergistically Ameliorate Atherosclerosis in LDLr Knockout Mice. AB - Pravastatin is a lipid-lowering agent that attenuates atherosclerosis. However, the multifactorial pathogenesis of atherosclerosis requires other drugs with different anti-atherogenic mechanisms. We chose sarpogrelate as an anti-platelet agent and a novel component of a complex drug with pravastatin due to its high potential but little information on its beneficial effects on atherosclerosis. Low-density lipoprotein receptor-knockout mice were fed a high-fat, high cholesterol diet and treated with pravastatin alone, sarpogrelate alone, or a combination of both drugs. Although sarpogrelate alone did not significantly reduce atherosclerotic plaque areas, co-treatment with pravastatin significantly decreased aortic lesions compared to those of the pravastatin alone treated group. The combined therapy was markedly more effective than that of the single therapies in terms of foam cell formation, smooth muscle cell proliferation, and inflammatory cytokine levels. These results suggest that pravastatin and sarpogrelate combined therapy may provide a new therapeutic strategy for treating atherosclerosis. PMID- 26950219 TI - Self-Assembly of Reactive Linear Cu3 Building Blocks for Supramolecular Coordination Chemistry and Their Reactivity toward E(n) Ligand Complexes. AB - This study describes the selective synthesis of linear, trinuclear, halide bridged Cu(I) complexes [Cu3(MU-X)2(MU-dpmp)2(MeCN)2](+) (1a: X = Cl; 1b: X = Br; 1c: X = I) stabilized by the tridentate dpmp ligand obtained by self-assembly reactions in THF/MeCN. Upon drying, the MeCN ligands can be removed and the complexes are transformed to the reactive parent trinuclear [Cu3(MU-X)2(MU dpmp)2](+) (2a-c) building blocks with two vacant coordination sites on the terminal Cu atoms. Another synthesis in CH2Cl2 directly yields 2a-c. Additionally, two related isomeric compounds, 2a* and 2c*, and two CH2Cl2-ligated complexes, [Cu3(MU-X)2(MU-dpmp)2(CH2Cl2)2](+) (X = Br (3b), I (3c)), were structurally characterized. The frameworks of the cationic [Cu3(MU-X)2(MU dpmp)2](+) complexes are stable in solution at low temperatures and show dynamic coordination behavior at elevated temperatures, indicated by new signals arising in the (31)P{(1)H} NMR spectra. This evolution cannot be shifted back by decreasing the temperature again. However, cationic [Cu3(MU-X)2(MU-dpmp)2](+) (X = Cl, Br, I) complexes can be obtained selectively in the solid state upon crystallization. Although reactions of 2a-c with complexes [{CpMo(CO)2}2(MU,eta(2):eta(2)-E2)] (E = P (A1), As (A2)) led to unsymmetrically substituted [Cu3(MU-X)2(MU-dpmp)2(eta(1)-L)](+) (4a-c: X = Cl-I, L = A1; 5: X = Cl, L = A2) complexes, reactions with the cyclo-P3 complex [CpMo(CO)2(eta(3)-P3)] (B) afforded zigzag chain polymers [Cu3(MU-X)2(MU-dpmp)2(MU,eta(1):eta(1) B)]n[BF4]n (6a: X = Cl; 6b: X = Br) and symmetrically substituted complex [Cu3(MU I)2(MU-dpmp)2(eta(1)-B)2](+) (7). Reactions of 2a-c with cyclo-E5 complexes [Cp*Fe(eta(5)-E5)] (E = P (C1), As (C2)) led to the isolation of one-dimensional coordination polymers [Cu3(MU-X)2(MU-dpmp)2(MU,eta(1):eta(1)-L)]n[BF4]n (8a-b: X = Cl-Br, L = C1; 9: X = Cl, L = C2) and symmetrically substituted complex [Cu3(MU I)2(MU-dpmp)2(eta(1)-C1)2](+) (10). All products exhibit a trinuclear, cationic [Cu3(MU-X)2(MU-dpmp)2](+) complex as the central structural motif. Variation of the intramolecular Cu-Cu distances inside the Cu3 complexes is discussed, and supporting DFT computations for the model complex [Cu3(MU-Cl)2(dmmp)2{(eta(1) A1)}](+) (4a') are presented. PMID- 26950218 TI - Induced Treg Cells Augment the Th17-Mediated Intestinal Inflammatory Response in a CTLA4-Dependent Manner. AB - Th17 cells and Foxp3+ regulatory T cells (Tregs) are thought to promote and suppress inflammatory responses, respectively. However, whether they counteract each other or synergize in regulating immune reactions remains controversial. To determine their interactions, we describe the results of experiments employing mouse models of intestinal inflammation by transferring antigen-specific Th cells (Th1, Th2, and Th17) differentiated in vitro followed by the administration of the cognate antigen via enema. We show that cotransfer of induced Tregs (iTregs) suppressed Th1- and Th2-mediated colon inflammation. In contrast, colon inflammation induced by transfer of Th17 cells, was augmented by the cotransfer of iTregs. Furthermore, oral delivery of antigen potentiated Th17-mediated colon inflammation. Administration of a blocking antibody against cytotoxic T lymphocyte-associated antigen 4 (CTLA4) abrogated the effects of cotransfer of iTregs, while the injection of a soluble recombinant immunoglobulin (Ig) fusion protein, CTLA4-Ig substituted for the cotransfer of iTregs. These results suggest that antigen-specific activation of iTregs in a local environment stimulates the Th17-mediated inflammatory response in a CTLA4-dependent manner. PMID- 26950221 TI - Reasons for non-participation in scleroderma support groups. AB - OBJECTIVES: Peer-led support groups are an important resource for people living with many rare diseases, including scleroderma (systemic sclerosis, SSc). Little is known, however, about the accessibility of SSc support groups and factors that may discourage people from participating in these groups. The objective of this study was to identify reasons why people with SSc do not participate in SSc support groups. METHODS: Canadians with SSc were recruited to complete the Canadian Scleroderma Patient Survey of Health Concerns and Research Priorities. Data from respondents who answered the question "Have you participated in SSc support groups?" with "No" were analyzed. Frequencies of participants who responded (1) I'm not interested, (2) None are easily available, and (3) Other (please specify) were tallied. A content analysis approach was used to code the open-ended responses to this question. RESULTS: A total of 280 respondents provided a reason for non-participation in SSc support groups. Key reasons for not participating in support groups included: (1) Not interested or no perceived need (36%); (2) No local support group available (35%); (3) Lack of awareness of the existence of SSc support groups (13%); (4) Practical barriers (6%); (5) Emotional factors (4%); (6) Uncertainty about whether to attend (4%); and (7) Negative perceptions about support groups (3%). CONCLUSIONS: SSc organizations may be able to address current limitations in the accessibility and effectiveness of SSc support groups by implementing online support groups, as well as by providing support group leaders training to help establish and sustain successful SSc support groups. PMID- 26950220 TI - Incidental Intracranial Findings and Their Clinical Impact; The HUNT MRI Study in a General Population of 1006 Participants between 50-66 Years. AB - OBJECTIVES: Evaluate types and prevalence of all, incidental, and clinically relevant incidental intracranial findings, i.e. those referred to primary physician or clinical specialist, in a cohort between 50 and 66 years from the Nord-Trondelag Health (HUNT) study. Types of follow-up, outcome of repeated neuroimaging and neurosurgical treatment were assessed. MATERIAL AND METHODS: 1006 participants (530 women) underwent MRI of the head at 1.5T consisting of T1 weighted sagittal IR-FSPGR volume, axial T2 weighted, gradient echo T2* weighted and FLAIR sequences plus time of flight cerebral angiography covering the circle of Willis. The nature of a finding and if it was incidental were determined from previous radiological examinations, patient records, phone interview, and/or additional neuroimaging. Handling and outcome of the clinically relevant incidental findings were prospectively recorded. True and false positives were estimated from the repeated neuroimaging. RESULTS: Prevalence of any intracranial finding was 32.7%. Incidental intracranial findings were present in 27.1% and clinically relevant findings in 15.1% of the participants in the HUNT MRI cohort. 185 individuals (18.4%) were contacted by phone about their findings. 40 participants (6.2%) underwent >= 1 additional neuroimaging session to establish etiology. Most false positives were linked to an initial diagnosis of suspected glioma, and overall positive predictive value of initial MRI was 0.90 across different diagnoses. 90.8% of the clinically relevant incidental findings were developmental and acquired cerebrovascular pathologies, the remaining 9.2% were intracranial tumors, of which extra-axial tumors predominated. In total, 3.9% of the participants were referred to a clinical specialist, and 11.7% to their primary physician. 1.4% underwent neurosurgery/radiotherapy, and 1 (0.1%) experienced a procedure related postoperative deficit. CONCLUSIONS: In a general population between 50 and 66 years most intracranial findings on MRI were incidental, and >15% of the cohort was referred to clinical-follow up. Hence good routines for handling of findings need to be in place to ensure timely and appropriate handling. PMID- 26950222 TI - Comments on 'Hemodynamic Features of Non-Aneurysmal Subarachnoid Hemorrhage in a Case of Familial Moyamoya Disease' after a 4-Year Transcranial Doppler Ultrasound Follow-Up. PMID- 26950223 TI - Effects of age and environmental support for rehearsal on visuospatial working memory. AB - The present study investigated whether older adults' visuospatial working memory shows effects of environmental support for rehearsal similar to those observed in young adults (Lilienthal, Hale, & Myerson, 2014). When the duration of interitem intervals was 4 s and participants had sufficient time to rehearse, location memory spans were larger in both age groups when environmental support was present than when support was absent. Critically, however, the age-related difference in memory was actually larger when support was provided, suggesting that young and older adults may differ in their rehearsal of to-be-remembered locations. (PsycINFO Database Record PMID- 26950224 TI - Age differences in personal values: Universal or cultural specific? AB - Prior studies on value development across adulthood have generally shown that as people age, they espouse communal values more strongly and agentic values less strongly. Two studies investigated whether these age differences in personal values might differ according to cultural values. Study 1 examined whether these age differences in personal values, and their associations with subjective well being, showed the same pattern across countries that differed in individualism collectivism. Study 2 compared age differences in personal values in the Canadian culture that emphasized agentic values more and the Chinese culture that emphasized communal values more. Personal and cultural values of each individual were directly measured, and their congruence were calculated and compared across age and cultures. Findings revealed that across cultures, older people had lower endorsement of agentic personal values and higher endorsement of communal personal values than did younger people. These age differences, and their associations with subjective well-being, were generally not influenced by cultural values. (PsycINFO Database Record PMID- 26950225 TI - Category learning strategies in younger and older adults: Rule abstraction and memorization. AB - Despite the fundamental role of category learning in cognition, few studies have examined how this ability differs between younger and older adults. The present experiment examined possible age differences in category learning strategies and their effects on learning. Participants were trained on a category determined by a disjunctive rule applied to relational features. The utilization of rule- and exemplar-based strategies was indexed by self-reports and transfer performance. Based on self-reported strategies, the frequencies of rule- and exemplar-based learners were not significantly different between age groups, but there was a significantly higher frequency of intermediate learners (i.e., learners not identifying with a reliance on either rule- or exemplar-based strategies) in the older than younger adult group. Training performance was higher for younger than older adults regardless of the strategy utilized, showing that older adults were impaired in their ability to learn the correct rule or to remember exemplar-label associations. Transfer performance converged with strategy reports in showing higher fidelity category representations for younger adults. Younger adults with high working memory capacity were more likely to use an exemplar-based strategy, and older adults with high working memory capacity showed better training performance. Age groups did not differ in their self-reported memory beliefs, and these beliefs did not predict training strategies or performance. Overall, the present results contradict earlier findings that older adults prefer rule- to exemplar-based learning strategies, presumably to compensate for memory deficits. (PsycINFO Database Record PMID- 26950227 TI - Gentle touch perception across the lifespan. AB - Pleasant, affective touch provides various health benefits, including stress and depression relief. There is a dichotomy between mechanoreceptive afferents that predominantly signal discriminative (myelinated A-beta) and affective (unmyelinated C-tactile) aspects of touch. It is well documented that discriminative abilities of touch decline with age. However, a thorough investigation of how the pleasant aspects of touch develop with age has not been previously attempted. Here, we investigated the relationship between age and psychophysical ratings in response to gentle stroking touch. One hundred twenty participants (60 males, 60 females) ages 13-82 years were presented with C tactile optimal and suboptimal stroking velocities, and rated pleasantness and intensity. Moreover, to examine the specificity of age effects on touch perception, we used olfactory stimuli as a cross-sensory comparison. For all ages, we found that C-tactile optimal stimuli were rated significantly more pleasant than C-tactile suboptimal stimuli. Although, both touch and olfactory intensity ratings were negatively correlated with age, a positive correlation between pleasantness ratings of touch (but not olfactory stimuli) and age was found. We conclude that the affective, but not the discriminative, aspects of touch are enhanced with increasing age. The increase of pleasantness of all touch stimuli in late adulthood is discussed in relation to cognitive modulations. PMID- 26950226 TI - Terminal decline in well-being: The role of social orientation. AB - Well-being development at the end of life is often characterized by steep deteriorations, but individual differences in these terminal declines are substantial and not yet well understood. This study moved beyond typical consideration of health predictors and explored the role of social orientation and engagement. To do so, we used social variables at the behavioral level (self ratings of social participation) and the motivational level (valuing social and family goals), assessed 2 to 4 years before death. We applied single- and multiphase growth models to up to 27-year annual longitudinal data from 2,910 now deceased participants of the nation-wide German Socio-Economic Panel Study (Mage at death = 74 years; SD = 14; 48% women). Results revealed that leading a socially active life and prioritizing social goals in late life were independently associated with higher late-life well-being, less pronounced late life decline, and a later onset of terminal decline. Significant interaction effects suggested that the combination of (reduced) social participation and (lowered) social goals magnifies the effects of each other. Findings also indicated that less decline in social participation was associated with less severe rates and a later onset of well-being decline. We found little evidence that valuing family goals is associated with late-life trajectories of well being. Associations were independent of key correlates of well-being and mortality, including age at death, gender, education, disability, hospital stays, and goals in other life domains. We discuss possible pathways by which maintaining social orientation into late life may help mitigate terminal decline in well-being. PMID- 26950228 TI - Multi-Contrast High-Resolution Magnetic Resonance Findings of Spontaneous and Unruptured Intracranial Vertebral Artery Dissection: Qualitative and Quantitative Analysis According to Stages. AB - BACKGROUND: Although high-resolution magnetic resonance imaging (HR-MRI) has been used as a strong imaging method for diagnosing intracranial vertebral artery dissection (IVAD), the diagnosis is sometimes challenging because a dissection has geometric changes in the natural course. The radiologic features may change or disappear over time, which makes the diagnosis confusing. Our study was to present radiological findings according to the stages in spontaneous and unruptured, IVAD on 3T HR-MRI and to guide the age estimation of IVAD with the distinguishing findings according to the stages. METHODS: From January 2011 to July 2014, the 41 vertebral arteries (M:F = 18:12; age range 32-67 years) were retrospectively enrolled. Spontaneous, unruptured IVAD was diagnosed if it had a clear onset based on clinical and radiological findings. The stages were classified as acute (0-3 days), early subacute (3-10 days), late subacute (10-60 days) and chronic stage (>60 days; recovery and non-recovery groups) according to the time intervals from symptom onset, based on the prior published studies. HR MR findings were assessed and compared in the intimal flap, double lumen, aneurysmal dilatation (maximal outer diameter, maximal wall thickness, wall thickness index and remodeling index), intramural hematoma (relative signal intensity) and vessel wall enhancement according to the stages with qualitative and quantitative methods. Two radiologists analyzed the HR-MR findings with consensus reading. RESULTS: IVAD was classified into acute (n = 6), early subacute (n = 8), late subacute (n = 16) and chronic (n = 11) stages. HR-MR dissection findings such as intimal flap, double lumen, aneurysmal dilatation and intramural hematoma significantly decreased from the earlier stages to the chronic stage (p < 0.05). The quantitative indices in aneurysmal dilatation and the relative signal intensity of intramural hematoma showed significant higher values in the earlier stages followed by a significant decrease in the chronic stage recovery group (p < 0.05). The degree of vessel wall enhancement was higher in the earlier stage and decreased in the chronic stage (p < 0.05), but mild vessel wall enhancement was identified 900 days after symptom onset. CONCLUSION: The 3T HR-MRI reveals the vessel wall characteristics and provides distinguishing findings between earlier stages and the chronic stage in spontaneous and unruptured IVAD. Characterization of these radiological findings according to stages may assist with the age estimation of the dissection and may help to understand IVAD as a whole. PMID- 26950230 TI - Contamination of urinary cultures in initial-stream versus later-stream urine in children undergoing bladder catheterization for the diagnosis of urinary tract infection. AB - BACKGROUND: Urine cultures obtained by bladder catheterization can be contaminated by bacteria colonizing the distal urethra. Data are inconclusive regarding the potential advantage of discarding the first few urine drops obtained by bladder catheterization and testing only the sample of late-stream urine, thus reducing the likelihood of urine culture contamination. AIM: The aim of this study was to evaluate whether the incidence of contaminated urine cultures obtained by bladder catheterization can be reduced by splitting urine samples into 'initial' and 'late' samples and using only 'late' samples for culture. METHODS: Urine samples obtained by bladder catheterization from children younger than 2 years being evaluated for urinary tract infection were prospectively collected. Quantitative culture results were compared between initial-stream and late-stream urine samples. RESULTS: A total of 199 urine culture pairs of initial and late samples were compared. When using a cutoff value of at least 10 000 colony forming units/ml, late samples were superior to the initial ones in reducing contamination of urine cultures (P=0.029). CONCLUSION: When obtaining urine cultures by bladder catheterization in children younger than 2 years, discarding the first few urine drops and using only the late stream for culture reduces false-positive culture results and improves the accuracy of urinary tract infection diagnosis. PMID- 26950229 TI - Paediatric workload of an adult retrieval service in Scotland. AB - The Emergency Medical Retrieval Service (EMRS) provides adults with life threatening conditions in remote areas with timely interventions and rapid access to definitive medical care, including a primary response service. Paediatric patients are managed under a separate network. Despite this, there has been an increase in paediatric retrievals by EMRS. We aim to inform future service development and ascertain how EMRS can serve the needs of this cohort. This is a retrospective, observational study. Raw data were retrieved from the database of paediatric patients retrieved by EMRS for 9 years. A total of 112 paediatric patients were retrieved; 46% were primary retrievals. The most common injuries were head injuries (n=29) and orthopaedic injuries (n=16). Common interventions include fluid resuscitation (n=34), ventilation (n=22) and sedation/paralysis (n=22).This study describes the evolution of an adult retrieval service to cover paediatric patients in Scotland outside the remit of the paediatric retrieval service. PMID- 26950231 TI - Mental State Decoding in Adolescent Boys with Major Depressive Disorder versus Sex-Matched Healthy Controls. AB - BACKGROUND: Several adult depression studies have investigated mental state decoding, the basis for theory of mind, using the Reading the Mind in the Eyes Test. Findings have been mixed, but a comprehensive study found a greater severity of depression to be associated with poorer mental state decoding. Importantly, there has yet to be a similar study of adolescent depression. Converging evidence suggests that atypical mental state decoding may have particularly profound effects for psychosocial functioning among depressed adolescent boys. SAMPLING AND METHODS: Adolescent boys with major depressive disorder (MDD, n = 33) and sex-matched healthy controls (HCs, n = 84) completed structured clinical interviews, self-report measures of psychopathology and the Child Eyes Test (CET). RESULTS: The MDD group performed significantly better than HCs on the CET overall (p = 0.002), underscored by greater accuracy for negatively valenced items (p = 0.003). Group differences on items depicting positive (p = 0.129) and neutral mental states (p = 0.081) were nonsignificant. CONCLUSIONS: Enhanced mental state decoding among depressed adolescent boys may play a role in the maintenance of and vulnerability to adolescent depression. Findings and implications are discussed. Limitations of this study include a reliance on self-report data for HC boys, as well as a lack of 'pure' depression among the boys with MDD. PMID- 26950232 TI - Posture and fluids for preventing post-dural puncture headache. AB - BACKGROUND: Post-dural puncture headache (PDPH) is a common complication of lumbar punctures. Several theories have identified the leakage of cerebrospinal fluid (CSF) through the hole in the dura as a cause of this side effect. It is therefore necessary to take preventive measures to avoid this complication. Prolonged bed rest has been used to treat PDPH once it has started, but it is unknown whether prolonged bed rest can also be used to prevent it. Similarly, the value of administering fluids additional to those of normal dietary intake to restore the loss of CSF produced by the puncture is unknown. This review is an update of a previously published review in the Cochrane Database of Systematic Reviews (Issue 7, 2013) on "Posture and fluids for preventing post-dural puncture headache". OBJECTIVES: To assess whether prolonged bed rest combined with different body and head positions, as well as administration of supplementary fluids after lumbar puncture, prevent the onset of PDPH in people undergoing lumbar puncture for diagnostic or therapeutic purposes. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and LILACS, as well as trial registries up to February 2015. SELECTION CRITERIA: We identified randomized controlled trials that compared the effects of bed rest versus immediate mobilization, head-down tilt versus horizontal position, prone versus supine positions during bed rest, and administration of supplementary fluids versus no/less supplementation, as prevention measures for PDPH in people who have undergone lumbar puncture. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the studies for eligibility through the web-based software EROS (Early Review Organizing Software). Two different review authors independently assessed risk of bias using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions. We resolved any disagreements by consensus. We extracted data on cases of PDPH, severe PDPH, and any headache after lumbar puncture and performed intention-to-treat analyses and sensitivity analyses by risk of bias. We assessed the evidence using GRADE (Grading of Recommendations Assessment, Development and Evaluation) and created a 'Summary of findings' table. MAIN RESULTS: We included 24 trials with 2996 participants in this updated review. The number of participants in each trial varied from 39 to 382. Most of the included studies compared bed rest versus immediate mobilization, and only two assessed the effects of supplementary fluids versus no supplementation. We judged the overall risk of bias of the included studies as low to unclear. The overall quality of evidence was low to moderate, downgraded because of the risk of bias assessment in most cases. The primary outcome in our review was the presence of PDPH.There was low quality evidence for an absence of benefits associated with bed rest compared with immediate mobilization on the incidence of severe PDPH (risk ratio (RR) 0.98; 95% confidence interval (CI) 0.68 to 1.41; participants = 1568; studies = 9) and moderate quality evidence on the incidence of any headache after lumbar puncture (RR 1.16; 95% CI 1.02 to 1.32; participants = 2477; studies = 18). Furthermore, bed rest probably increased PDPH (RR 1.24; 95% CI 1.04 to 1.48; participants = 1519; studies = 12) compared with immediate mobilization. An analysis restricted to the most methodologically rigorous trials (i.e. those with low risk of bias in allocation method, missing data and blinding of outcome assessment) gave similar results. There was low quality evidence for an absence of benefits associated with fluid supplementation on the incidence of severe PDPH (RR 0.67; 95% CI 0.26 to 1.73; participants = 100; studies = 1) and PDPH (RR 1; 95% CI 0.59 to 1.69; participants = 100; studies = 1), and moderate quality evidence on the incidence of any headache after lumbar puncture (RR 0.94; 95% CI 0.66 to 1.34; participants = 200; studies = 2). We did not expect other adverse events and did not assess them in this review. AUTHORS' CONCLUSIONS: Since the previous version of this review, we found one new study for inclusion, but the conclusion remains unchanged. We considered the quality of the evidence for most of the outcomes assessed in this review to be low to moderate. As identified studies had shortcomings on aspects related to randomization and blinding of outcome assessment, we therefore downgraded the quality of the evidence. In general, there was no evidence suggesting that routine bed rest after dural puncture is beneficial for the prevention of PDPH onset. The role of fluid supplementation in the prevention of PDPH remains unclear. PMID- 26950235 TI - Abu Dhabi to Host Arab World's Largest International Gastroenterology Meeting Gastro 2016: EGHS-WGO International Congress. PMID- 26950234 TI - Methylnaltrexone for the Treatment of Constipation in Critically Ill Children. PMID- 26950236 TI - Serpentine-like syndrome associated with encephalocele. PMID- 26950237 TI - Broad defects in the energy metabolism of leukocytes underlie immunoparalysis in sepsis. AB - The acute phase of sepsis is characterized by a strong inflammatory reaction. At later stages in some patients, immunoparalysis may be encountered, which is associated with a poor outcome. By transcriptional and metabolic profiling of human patients with sepsis, we found that a shift from oxidative phosphorylation to aerobic glycolysis was an important component of initial activation of host defense. Blocking metabolic pathways with metformin diminished cytokine production and increased mortality in systemic fungal infection in mice. In contrast, in leukocytes rendered tolerant by exposure to lipopolysaccharide or after isolation from patients with sepsis and immunoparalysis, a generalized metabolic defect at the level of both glycolysis and oxidative metabolism was apparent, which was restored after recovery of the patients. Finally, the immunometabolic defects in humans were partially restored by therapy with recombinant interferon-gamma, which suggested that metabolic processes might represent a therapeutic target in sepsis. PMID- 26950241 TI - Near-field radiative heat transfer: The heat through the gap. PMID- 26950239 TI - A molecular threshold for effector CD8(+) T cell differentiation controlled by transcription factors Blimp-1 and T-bet. AB - T cell responses are guided by cytokines that induce transcriptional regulators, which ultimately control differentiation of effector and memory T cells. However, it is unknown how the activities of these molecular regulators are coordinated and integrated during the differentiation process. Using genetic approaches and transcriptional profiling of antigen-specific CD8(+) T cells, we reveal a common program of effector differentiation that is regulated by IL-2 and IL-12 signaling and the combined activities of the transcriptional regulators Blimp-1 and T-bet. The loss of both T-bet and Blimp-1 leads to abrogated cytotoxic function and ectopic IL-17 production in CD8(+) T cells. Overall, our data reveal two major overlapping pathways of effector differentiation governed by the availability of Blimp-1 and T-bet and suggest a model for cytokine-induced transcriptional changes that combine, quantitatively and qualitatively, to promote robust effector CD8(+) T cell differentiation. PMID- 26950240 TI - Effects of workplace intervention on affective well-being in employees' children. AB - Using a group-randomized field experimental design, this study tested whether a workplace intervention-designed to reduce work-family conflict-buffered against potential age-related decreases in the affective well-being of employees' children. Daily diary data were collected from 9- to 17-year-old children of parents working in an information technology division of a U.S. Fortune 500 company prior to and 12 months after the implementation of the Support-Transform Achieve-Results (STAR) workplace intervention. Youth (62 with parents in the STAR group, 41 in the usual-practice group) participated in 8 consecutive nightly phone calls, during which they reported on their daily stressors and affect. Well being was indexed by positive and negative affect and affective reactivity to daily stressful events. The randomized workplace intervention increased youth positive affect and buffered youth from age-related increases in negative affect and affective reactivity to daily stressors. Future research should test specific conditions of parents' work that may penetrate family life and affect youth well being. (PsycINFO Database Record PMID- 26950238 TI - Tumor-necrosis factor impairs CD4(+) T cell-mediated immunological control in chronic viral infection. AB - Persistent viral infections are characterized by the simultaneous presence of chronic inflammation and T cell dysfunction. In prototypic models of chronicity- infection with human immunodeficiency virus (HIV) or lymphocytic choriomeningitis virus (LCMV)--we used transcriptome-based modeling to reveal that CD4(+) T cells were co-exposed not only to multiple inhibitory signals but also to tumor necrosis factor (TNF). Blockade of TNF during chronic infection with LCMV abrogated the inhibitory gene-expression signature in CD4(+) T cells, including reduced expression of the inhibitory receptor PD-1, and reconstituted virus specific immunity, which led to control of infection. Preventing signaling via the TNF receptor selectively in T cells sufficed to induce these effects. Targeted immunological interventions to disrupt the TNF-mediated link between chronic inflammation and T cell dysfunction might therefore lead to therapies to overcome persistent viral infection. PMID- 26950242 TI - Nanopatterning reconfigurable magnetic landscapes via thermally assisted scanning probe lithography. AB - The search for novel tools to control magnetism at the nanoscale is crucial for the development of new paradigms in optics, electronics and spintronics. So far, the fabrication of magnetic nanostructures has been achieved mainly through irreversible structural or chemical modifications. Here, we propose a new concept for creating reconfigurable magnetic nanopatterns by crafting, at the nanoscale, the magnetic anisotropy landscape of a ferromagnetic layer exchange-coupled to an antiferromagnetic layer. By performing localized field cooling with the hot tip of a scanning probe microscope, magnetic structures, with arbitrarily oriented magnetization and tunable unidirectional anisotropy, are reversibly patterned without modifying the film chemistry and topography. This opens unforeseen possibilities for the development of novel metamaterials with finely tuned magnetic properties, such as reconfigurable magneto-plasmonic and magnonic crystals. In this context, we experimentally demonstrate spatially controlled spin wave excitation and propagation in magnetic structures patterned with the proposed method. PMID- 26950243 TI - Near-field radiative heat transfer between parallel structures in the deep subwavelength regime. AB - Thermal radiation between parallel objects separated by deep subwavelength distances and subject to large thermal gradients (>100 K) can reach very high magnitudes, while being concentrated on a narrow frequency distribution. These unique characteristics could enable breakthrough technologies for thermal transport control and electricity generation (for example, by radiating heat exactly at the bandgap frequency of a photovoltaic cell). However, thermal transport in this regime has never been achieved experimentally due to the difficulty of maintaining large thermal gradients over nanometre-scale distances while avoiding other heat transfer mechanisms, namely conduction. Here, we show near-field radiative heat transfer between parallel SiC nanobeams in the deep subwavelength regime. The distance between the beams is controlled by a high precision micro-electromechanical system (MEMS). We exploit the mechanical stability of nanobeams under high tensile stress to minimize thermal buckling effects, therefore keeping control of the nanometre-scale separation even at large thermal gradients. We achieve an enhancement of heat transfer of almost two orders of magnitude with respect to the far-field limit (corresponding to a 42 nm separation) and show that we can maintain a temperature gradient of 260 K between the cold and hot surfaces at ~100 nm distance. PMID- 26950245 TI - Common Polymorphisms in IL-27 Genes May Contribute to Risk of Various Human Diseases in Asian Populations: A Meta-Analysis. AB - BACKGROUND: Genetic variations in the IL-27 gene have been proven to be associated with various types of human cancers and diseases. The purpose of the current study was to clarify the associations of the IL-27 rs153109 A>G and rs181206 T>C variants with human diseases using a meta-analysis study. MATERIAL/METHODS: A comprehensive electronic and manual search was carried out to find potential eligible studies. The effect size was represented by the unadjusted odds ratios (ORs). A 95% confidence interval (95%CI) was tested for the pooled OR using the Z test. RESULTS: A total of 17 case-control studies (cases=4185, healthy controls=4077) were included in our study. Our study showed that the carriers of the rs181206 T>C and rs153109 A>G polymorphism in the IL-27 gene have elevated risks of diseases in the allele model (rs181206 T>C: OR=0.76, 95%CI=0.69~0.84, P<0.001; rs153109 A>G: OR=0.85, 95%CI=0.76~0.94, P=0.002) and dominant model (rs181206 T>C: OR=0.77, 95%CI=0.69~0.87, P<0.001; rs153109 A>G: OR=0.84, 95%CI=0.71~0.99, P=0.033). Disease type-stratified subgroup analysis yielded increased risk of related diseases in IL-27 rs181206 T>C carriers in the allele model in immune thrombocytopenia (ITP), asthma, and esophageal cancer (EC) subgroups (ITP: OR=0.69, 95%CI=0.53~0.88, P=0.004; asthma: OR=0.60, 95%CI=0.41~0.89, P=0.010; EC: OR=0.79, 95%CI=0.64~0.97, P=0.026); and IL-27 rs153109 A>G polymorphism was remarkably associated with the increased risk of related diseases in the allele model in ovarian cancer (OC), systemic lupus erythematosus (SLE), tuberculosis (TB), ulcerative colitis (UC), and chronic obstructive pulmonary disease (COPD) subgroups (all P<0.05). CONCLUSIONS: Our results indicate that the genetic polymorphisms of IL-27 rs153109 and rs181206 may be involved in the progression of human cancers and diseases, especially of TB, UC, COPD, OC, and ITP. PMID- 26950244 TI - Radiative heat conductances between dielectric and metallic parallel plates with nanoscale gaps. AB - Recent experiments have demonstrated that radiative heat transfer between objects separated by nanometre-scale gaps considerably exceeds the predictions of far field radiation theories. Exploiting this near-field enhancement is of great interest for emerging technologies such as near-field thermophotovoltaics and nano-lithography because of the expected increases in efficiency, power conversion or resolution in these applications. Past measurements, however, were performed using tip-plate or sphere-plate configurations and failed to realize the orders of magnitude increases in radiative heat currents predicted from near field radiative heat transfer theory. Here, we report 100- to 1,000-fold enhancements (at room temperature) in the radiative conductance between parallel planar surfaces at gap sizes below 100 nm, in agreement with the predictions of near-field theories. Our measurements were performed in vacuum gaps between prototypical materials (SiO2-SiO2, Au-Au, SiO2-Au and Au-Si) using two microdevices and a custom-built nanopositioning platform, which allows precise control over a broad range of gap sizes (from <100 nm to 10 MUm). Our experimental set-up will enable systematic studies of a variety of near-field based thermal phenomena, with important implications for thermophotovoltaic applications, that have been predicted but have defied experimental verification. PMID- 26950246 TI - Solvothermal Vapor Annealing of Lamellar Poly(styrene)-block-poly(d,l-lactide) Block Copolymer Thin Films for Directed Self-Assembly Application. AB - Solvothermal vapor annealing (STVA) was employed to induce microphase separation in a lamellar forming block copolymer (BCP) thin film containing a readily degradable block. Directed self-assembly of poly(styrene)-block-poly(d,l-lactide) (PS-b-PLA) BCP films using topographically patterned silicon nitride was demonstrated with alignment over macroscopic areas. Interestingly, we observed lamellar patterns aligned parallel as well as perpendicular (perpendicular microdomains to substrate in both cases) to the topography of the graphoepitaxial guiding patterns. PS-b-PLA BCP microphase separated with a high degree of order in an atmosphere of tetrahydrofuran (THF) at an elevated vapor pressure (at approximately 40-60 degrees C). Grazing incidence small-angle X-ray scattering (GISAXS) measurements of PS-b-PLA films reveal the through-film uniformity of perpendicular microdomains after STVA. Perpendicular lamellar orientation was observed on both hydrophilic and relatively hydrophobic surfaces with a domain spacing (L0) of ~32.5 nm. The rapid removal of the PLA microdomains is demonstrated using a mild basic solution for the development of a well-defined PS mask template. GISAXS data reveal the through-film uniformity is retained following wet etching. The experimental results in this article demonstrate highly oriented PS-b-PLA microdomains after a short annealing period and facile PLA removal to form porous on-chip etch masks for nanolithography application. PMID- 26950247 TI - Quantifying the Impact of Nanoparticle Coatings and Nonuniformities on XPS Analysis: Gold/Silver Core-Shell Nanoparticles. AB - Spectral modeling of photoelectrons can serve as a valuable tool when combined with X-ray photoelectron spectroscopy (XPS) analysis. Herein, a new version of the NIST Simulation of Electron Spectra for Surface Analysis (SESSA 2.0) software, capable of directly simulating spherical multilayer NPs, was applied to model citrate stabilized Au/Ag-core/shell nanoparticles (NPs). The NPs were characterized using XPS and scanning transmission electron microscopy (STEM) to determine the composition and morphology of the NPs. The Au/Ag-core/shell NPs were observed to be polydispersed in size, nonspherical, and contain off-centered Au-cores. Using the average NP dimensions determined from STEM analysis, SESSA spectral modeling indicated that washed Au/Ag-core-shell NPs were stabilized with a 0.8 nm layer of sodium citrate and a 0.05 nm (one wash) or 0.025 nm (two wash) layer of adventitious hydrocarbon, but did not fully account for the observed XPS signal from the Au-core. This was addressed by a series of simulations and normalizations to account for contributions of NP nonsphericity and off-centered Au-cores. Both of these nonuniformities reduce the effective Ag-shell thickness, which effect the Au-core photoelectron intensity. The off-centered cores had the greatest impact for the particles in this study. When the contributions from the geometrical nonuniformities are included in the simulations, the SESSA generated elemental compositions that matched the XPS elemental compositions. This work demonstrates how spectral modeling software such as SESSA, when combined with experimental XPS and STEM measurements, advances the ability to quantitatively assess overlayer thicknesses for multilayer core-shell NPs and deal with complex, nonideal geometrical properties. PMID- 26950249 TI - alpha-Carbamoylsulfides as N-Carbamoylimine Precursors in the Visible Light Photoredox-Catalyzed Synthesis of alpha,alpha-Disubstituted Amines. AB - A general and practical photoredox-promoted addition of nucleophiles to N acylimines generated in situ from alpha-amidosulfides using Ru(bpy)3(PF6)2 as the photocatalyst is reported. The broad scope of the reaction toward various nucleophiles and amidosulfide derivatives was explored. This novel protocol provides a rapid, mild, and efficient access to valuable alpha,alpha disubstituted amines in respectable yields. PMID- 26950248 TI - Intracellular PK/PD Relationships of Free and Liposomal Doxorubicin: Quantitative Analyses and PK/PD Modeling. AB - Nanomedicines are widely studied for intracellular delivery of cancer drugs. However, the relationship between intracellular drug concentrations and drug responses are poorly understood. In this study, cellular and nuclear concentrations of doxorubicin were quantified with LC/MS after cell exposure with free and liposomal doxorubicin (pH-sensitive and pegylated liposomes). Cellular uptake of pegylated liposomes was low (~3-fold extracellular concentrations) compared with doxorubicin in free form and pH-sensitive liposomes (up to 280-fold extracellular concentrations) in rat glioma (BT4C) and renal clear cell carcinoma (Caki-2) cells. However, after the cell exposure with pegylated liposomes, intracellular doxorubicin was distributed into the nuclear compartment in both cell types. Despite high drug concentrations in the nuclei, Caki-2 cells showed strong resistance toward doxorubicin. A model was successfully built to describe PK/PD relationship between drug concentrations in nucleus and cytotoxic responses in BT4C cells. This model is the first step to link target site concentration of doxorubicin into its effect and can be a useful part of more comprehensive future in vivo PK/PD models. PMID- 26950250 TI - Fragment Molecular Orbital Method Applied to Lead Optimization of Novel Interleukin-2 Inducible T-Cell Kinase (ITK) Inhibitors. AB - Inhibition of inducible T-cell kinase (ITK), a nonreceptor tyrosine kinase, may represent a novel treatment for allergic asthma. In our previous reports, we described the discovery of sulfonylpyridine (SAP), benzothiazole (BZT), indazole (IND), and tetrahydroindazole (THI) series as novel ITK inhibitors and how computational tools such as dihedral scans and docking were used to support this process. X-ray crystallography and modeling were applied to provide essential insight into ITK-ligand interactions. However, "visual inspection" traditionally used for the rationalization of protein-ligand affinity cannot always explain the full complexity of the molecular interactions. The fragment molecular orbital (FMO) quantum-mechanical (QM) method provides a complete list of the interactions formed between the ligand and protein that are often omitted from traditional structure-based descriptions. FMO methodology was successfully used as part of a rational structure-based drug design effort to improve the ITK potency of high throughput screening hits, ultimately delivering ligands with potency in the subnanomolar range. PMID- 26950251 TI - Developing maps of fitness consequences for plant genomes. AB - Predicting the fitness consequences of mutations, and their concomitant impacts on molecular and cellular function as well as organismal phenotypes, is an important challenge in biology that has new relevance in an era when genomic data is readily available. The ability to construct genomewide maps of fitness consequences in plant genomes is a recent development that has profound implications for our ability to predict the fitness effects of mutations and discover functional elements. Here we highlight approaches to building fitness consequence maps to infer regions under selection. We emphasize computational methods applied primarily to the study of human disease that translate physical maps of within-species genome variation into maps of fitness effects of individual natural mutations. Maps of fitness consequences in plants, combined with traditional genetic approaches, could accelerate discovery of functional elements such as regulatory sequences in non-coding DNA and genetic polymorphisms associated with key traits, including agronomically-important traits such as yield and environmental stress responses. PMID- 26950252 TI - Meiosis in autopolyploid and allopolyploid Arabidopsis. AB - All newly formed polyploids face a challenge in meiotic chromosome segregation due to the presence of an additional set of chromosomes. Nevertheless, naturally occurring auto and allopolyploids are common and generally show high fertility, showing that evolution can find solutions. Exactly how meiosis is adapted in these cases, however, remains a mystery. The rise of Arabidopsis as a model genus for polyploid and meiosis research has seen several new studies begin to shed light on this long standing question. PMID- 26950253 TI - Mechanistic and evolutionary questions about epigenetic conflicts between transposable elements and their plant hosts. AB - Transposable elements (TEs) constitute the majority of plant genomes, but most are epigenetically inactivated by their host. Research over the last decade has elucidated many of the molecular components that are required for TE silencing. In contrast, the evolutionary dynamics between TEs and silencing pathways are less clear. Here, we discuss current information about these dynamics from both mechanistic and evolutionary perspectives. We highlight new evidence that palindromic sequences within TEs may act as signals for host recognition and that cis-regulatory regions of TEs may be sites of ongoing arms races with host defenses. We also discuss patterns of TE aging after they are silenced; while there is not yet a consensus, it appears that TEs are removed more rapidly near genes, such that older TE insertions tend to be farther from genes. We conclude by discussing the energetic costs for maintaining silencing pathways, which appear to be substantive. The maintenance of silencing pathways across many species suggests that epigenetic emergencies are frequent. PMID- 26950254 TI - A Bayesian belief network approach for assessing uncertainty in conceptual site models at contaminated sites. AB - A key component in risk assessment of contaminated sites is in the formulation of a conceptual site model (CSM). A CSM is a simplified representation of reality and forms the basis for the mathematical modeling of contaminant fate and transport at the site. The CSM should therefore identify the most important site specific features and processes that may affect the contaminant transport behavior at the site. However, the development of a CSM will always be associated with uncertainties due to limited data and lack of understanding of the site conditions. CSM uncertainty is often found to be a major source of model error and it should therefore be accounted for when evaluating uncertainties in risk assessments. We present a Bayesian belief network (BBN) approach for constructing CSMs and assessing their uncertainty at contaminated sites. BBNs are graphical probabilistic models that are effective for integrating quantitative and qualitative information, and thus can strengthen decisions when empirical data are lacking. The proposed BBN approach facilitates a systematic construction of multiple CSMs, and then determines the belief in each CSM using a variety of data types and/or expert opinion at different knowledge levels. The developed BBNs combine data from desktop studies and initial site investigations with expert opinion to assess which of the CSMs are more likely to reflect the actual site conditions. The method is demonstrated on a Danish field site, contaminated with chlorinated ethenes. Four different CSMs are developed by combining two contaminant source zone interpretations (presence or absence of a separate phase contamination) and two geological interpretations (fractured or unfractured clay till). The beliefs in each of the CSMs are assessed sequentially based on data from three investigation stages (a screening investigation, a more detailed investigation, and an expert consultation) to demonstrate that the belief can be updated as more information becomes available. PMID- 26950256 TI - Comparative analysis of smoking cessation smartphone applications available in 2012 versus 2014. AB - BACKGROUND AND AIMS: Smartphone applications (apps) offer a potentially cost effective and a wide-reach aid to smoking cessation. In 2012, a content analysis of smoking cessation apps suggested that most apps did not adopt behaviour change techniques (BCTs), which according to previous research had suggested would promote higher success rates in quitting smoking. This study examined whether or not, this situation had changed by 2014 for free smoking cessation apps available in the Apple App Store. It also compared the use of engagement and ease-of-use features between the two time points. METHODS: 137 free apps available in the Apple App Sore in 2014 were coded using an established framework for the presence or absence of evidence-based BCTs, and engagement and ease-of-use features. The results from the 2014 data were compared with a similar exercise conducted on 83 free apps available in 2012. RESULTS: BCTs supporting identity change, rewarding abstinence and advising on changing routines were less prevalent in 2014 as compared with 2012 (14.6% vs. 42.2%, 18.2% vs. 48.2%, and 17.5% vs. 24.1%, respectively). Advice on coping with cravings and advice on the use of stop smoking medication were more prevalent in 2014 as compared with 2012 (27.7% vs. 20.5% and 14.6% vs 3.6%, respectively). The use of recognised engagement features was less common in 2014 than in 2012 (45.3% vs. 69.6%) while ease-of-use features remained very high (94.5% vs. 82.6%). CONCLUSION: There was little evidence of improvement in the use of evidence-based BCTs in free smoking cessation iPhone based apps between 2012 and 2014. PMID- 26950255 TI - Interlayer Transition and Infrared Photodetection in Atomically Thin Type-II MoTe2/MoS2 van der Waals Heterostructures. AB - We demonstrate the type-II staggered band alignment in MoTe2/MoS2 van der Waals (vdW) heterostructures and an interlayer optical transition at ~1.55 MUm. The photoinduced charge separation between the MoTe2/MoS2 vdW heterostructure is verified by Kelvin probe force microscopy (KPFM) under illumination, density function theory (DFT) simulations and photoluminescence (PL) spectroscopy. Photoelectrical measurements of MoTe2/MoS2 vdW heterostructures show a distinct photocurrent response in the infrared regime (1550 nm). The creation of type-II vdW heterostructures with strong interlayer coupling could improve our fundamental understanding of the essential physics behind vdW heterostructures and help the design of next-generation infrared optoelectronics. PMID- 26950257 TI - A randomized controlled trial of an audio-based treatment program for child anxiety disorders. AB - The aim of this study was to investigate the efficacy of an audio-based cognitive behavioural therapy (CBT) program for child anxiety disorders. Twenty-four children aged 5-11 years were randomly allocated into either the audio-based CBT program condition (Audio, n = 12) or a waitlist control (WL; n = 12) group. Outcome measures included a clinical diagnostic interview, clinician-rated global assessment of functioning, and parent and child self-report ratings of anxiety and internalisation. Assessments were conducted prior to treatment, 12 weeks following treatment, and at 3-month follow-up. Results indicated that at post assessment, 58.3% of children receiving treatment compared to 16.7% of waitlist children were free of their primary diagnosis, with this figure rising to 66.67% at the 3-month follow-up time point. Additionally, at post-assessment, 25.0% of children in the treatment condition compared to .0% of the waitlist condition were free of all anxiety diagnoses, with this figure rising to 41.67% for the treatment group at 3-month follow-up. Overall, the findings suggest that the audio program tested in this study has the potential to be an efficacious treatment alternative for anxious children. PMID- 26950258 TI - Hofstadter Butterfly and Many-Body Effects in Epitaxial Graphene Superlattice. AB - Graphene placed on hexagonal boron nitride (h-BN) has received a wide range of interest due to the improved electrical performance and rich physics from the interface, especially the emergence of superlattice Dirac points as well as Hofstadter butterfly in high magnetic field. Instead of transferring graphene onto h-BN, epitaxial growth of graphene directly on a single-crystal h-BN provides an alternative and promising way to study these interesting superlattice effects due to their precise lattice alignment. Here we report an electrical transport study on epitaxial graphene superlattice on h-BN with a period of ~15.6 nm. The epitaxial graphene superlattice is clean, intrinsic, and of high quality with a carrier mobility of ~27 000 cm(2) V(-1) s(-1), which enables the observation of Hofstadter butterfly features originated from the superlattice at a magnetic field as low as 6.4 T. A metal-insulator transition and magnetic field dependent Fermi velocity were also observed, suggesting prominent electron electron interaction-induced many-body effects. PMID- 26950260 TI - Probing Framework-Restricted Metal Axial Ligation and Spin State Patterns in a Post-Synthetically Reduced Iron-Porphyrin-Based Metal-Organic Framework. AB - An iron-porphyrin-based metal organic framework PCN-222(Fe) is investigated upon postsynthetic reduction with piperidine. Fe K-edge X-ray absorption and Kbeta mainline emission spectroscopy measurements reveal the local coordination geometry, oxidation, and spin state changes experienced by the Fe sites upon reaction with this axially coordinating reducing agent. Analysis and fitting of these data confirm the binding pattern predicted by a space-filling model of the structurally constrained pore environments. These results are further supported by UV-vis diffuse reflectance, IR, and resonance Raman spectroscopy data. PMID- 26950261 TI - THE EFFECT OF DEXMEDETOMIDINE ON RADIOGRAPHIC CARDIAC SILHOUETTE SIZE IN HEALTHY CATS. AB - Dexmedetomidine, an alpha2 -adrenergic agonist, may be used in companion animals for chemical restraint, including cardiac evaluation. Echocardiographic changes associated with alpha2 -adrenergic agonists have been described; however reports of radiographic changes in cats were not found at the time of this study. Aims of this observational, prospective, experimental study were to describe the effects of dexmedetomidine on the radiographic appearance of the cardiac silhouette in healthy, adult cats. Fourteen healthy adult cats received dexmedetomidine 40 mcg/kg IM. Right lateral, left lateral, ventrodorsal, and dorsoventral thoracic radiographs were obtained for each cat at three time points: presedation, intrasedation, and postsedation (>= two hours after reversal with atipamezole). Radiographs were evaluated in a blinded, randomized fashion by two independent observers using the vertebral heart score on all four views, the number of intercostal spaces on lateral projections, and the percent width of thorax on ventrodorsal and dorsoventral projections. Median vertebral heart score on right lateral view was significantly increased intrasedation (median = 7.8; range = 7.25-8.25) compared to presedation (median = 7.5; range = 7-8 [P = 0.001]). Median percentage width was significantly higher intrasedation (70% on VD; range 65-80 [P = 0.001], and 75% on DV; range 65-80 [P = 0.006]) compared to presedation (65%; range 65-75 on both projections). Dexmedetomidine was associated with a small but significant increase in cardiac silhouette size on right lateral (vertebral heart score), ventrodorsal (percentage width), and dorsoventral (percentage width) radiographs in healthy adult cats. This effect should be taken into consideration for future interpretation of thoracic radiographs in dexmedetomidine-sedated cats. PMID- 26950262 TI - Optimization of the HyPer sensor for robust real-time detection of hydrogen peroxide in the rice blast fungus. AB - Reactive oxygen species (ROS) production and breakdown have been studied in detail in plant-pathogenic fungi, including the rice blast fungus, Magnaporthe oryzae; however, the examination of the dynamic process of ROS production in real time has proven to be challenging. We resynthesized an existing ROS sensor, called HyPer, to exhibit optimized codon bias for fungi, specifically Neurospora crassa, and used a combination of microscopy and plate reader assays to determine whether this construct could detect changes in fungal ROS during the plant infection process. Using confocal microscopy, we were able to visualize fluctuating ROS levels during the formation of an appressorium on an artificial hydrophobic surface, as well as during infection on host leaves. Using the plate reader, we were able to ascertain measurements of hydrogen peroxide (H2 O2 ) levels in conidia as detected by the MoHyPer sensor. Overall, by the optimization of codon usage for N. crassa and related fungal genomes, the MoHyPer sensor can be used as a robust, dynamic and powerful tool to both monitor and quantify H2 O2 dynamics in real time during important stages of the plant infection process. PMID- 26950259 TI - Clinically significant anti-KEL RBC alloantibodies are transferred by breast milk in a murine model. AB - BACKGROUND AND OBJECTIVES: Fetuses affected by maternal RBC alloantibodies may have prolonged anaemia after birth, leading one to question whether maternal alloantibody transfer may occur outside the placenta. In response to a recent publication describing breast milk transfer of clinically significant amounts of maternal antiplatelet IgA antibodies from mother to nursing infant, we hypothesized that maternal RBC alloantibodies may also be capable of being transferred in breast milk. MATERIALS AND METHODS: The presence and clinical significance of breast milk alloantibody transfer were tested through a series of pregnancy, fostering and transfusion experiments, using a murine model in which transgenic RBCs express the human KEL glycoprotein. RESULTS: Maternal anti-KEL immunoglobulins, induced through transfusion or pregnancy, were detected in the aqueous phase of breast milk. Further, efficient transfer of maternal anti-KEL IgG and IgA to nursing pups was observed in fostering experiments. The breast milk-acquired alloantibodies were clinically significant in wild-type pups in a transfusion setting, binding to 'incompatible' KEL RBCs and leading to premature clearance from the circulation. Although breast milk-acquired alloantibodies also bound to the RBCs of transgenic KEL-positive fostered pups, no anaemia resulted. CONCLUSIONS: Taking these murine data in combination with recently published human data of maternal antiplatelet IgA antibodies in breast milk leading to sequelae in some infants, it is theoretically possible that maternal anti-RBC IgA alloantibodies may also be transferred in human breast milk and may lead to sequelae in some infants under some circumstances. PMID- 26950263 TI - Reformulation of Ensemble Averages via Coordinate Mapping. AB - A general framework is established for reformulation of the ensemble averages commonly encountered in statistical mechanics. This "mapped-averaging" scheme allows approximate theoretical results that have been derived from statistical mechanics to be reintroduced into the underlying formalism, yielding new ensemble averages that represent exactly the error in the theory. The result represents a distinct alternative to perturbation theory for methodically employing tractable systems as a starting point for describing complex systems. Molecular simulation is shown to provide one appealing route to exploit this advance. Calculation of the reformulated averages by molecular simulation can proceed without contamination by noise produced by behavior that has already been captured by the approximate theory. Consequently, accurate and precise values of properties can be obtained while using less computational effort, in favorable cases, many orders of magnitude less. The treatment is demonstrated using three examples: (1) calculation of the heat capacity of an embedded-atom model of iron, (2) calculation of the dielectric constant of the Stockmayer model of dipolar molecules, and (3) calculation of the pressure of a Lennard-Jones fluid. It is observed that improvement in computational efficiency is related to the appropriateness of the underlying theory for the condition being simulated; the accuracy of the result is however not impacted by this. The framework opens many avenues for further development, both as a means to improve simulation methodology and as a new basis to develop theories for thermophysical properties. PMID- 26950264 TI - Theoretical and Experimental Study of Inclusion Complexes of beta-Cyclodextrins with Chalcone and 2',4'-Dihydroxychalcone. AB - The inclusion complexes formed by chalcone and 2',4'-dihydroxychalcone with beta cyclodextrin have been studied combining experimental (phase solubility diagrams, Fourier transform infrared spectroscopy) and molecular modeling (molecular dynamics, quantum mechanics/molecular mechanics calculations) techniques. The formation constants of the complexes were determined at different temperatures, and the thermodynamic parameters of the process were obtained. The inclusion of chalcone in beta-cyclodextrin is an exothermic process, while the inclusion of 2',4'-dihydroxychalcone is endothermic. Free energy profiles, derived from umbrella sampling using molecular dynamics simulations, were constructed to analyze the binding affinity and the complexation reaction at a molecular level. Hybrid QM/MM calculations were also employed to obtain a better description of the energetic and structural aspects of the complexes. The intermolecular interactions that stabilize both inclusion complexes were characterized by means of quantum atoms in molecules theory and reduce density gradient method. The calculated interactions were experimentally observed using FTIR. PMID- 26950266 TI - Use of emollient in atopic dermatitis prevention. PMID- 26950265 TI - Involvement of serotonin 2C receptor RNA editing in accumbal neuropeptide Y expression and behavioural despair. AB - Serotonin 2C receptors (5-HT2 C Rs) are widely expressed in the central nervous system, and are associated with various neurological disorders. 5-HT2 C R mRNA undergoes adenosine-to-inosine RNA editing at five sites within its coding sequence, resulting in expression of 24 different isoforms. Several edited isoforms show reduced activity, suggesting that RNA editing modulates serotonergic systems in the brain with causative relevance to neuropsychiatric disorders. Transgenic mice solely expressing the non-edited 5-HT2 C R INI-isoform (INI) or the fully edited VGV-isoform exhibit various phenotypes including metabolic abnormalities, aggressive behaviour, anxiety-like behaviour, and depression-like behaviour. Here, we examined the behavioural phenotype and molecular changes of INI mice on a C57BL/6J background. INI mice showed an enhanced behavioural despair in the forced swimming test, elevated sensitivity to the tricyclic antidepressant desipramine, and significantly decreased serotonin in the nucleus accumbens (NAc), amygdala, and striatum. They also showed reduced expression of neuropeptide Y (NPY) mRNA in the NAc. In addition, by stereotactic injection of adeno-associated virus encoding NPY into the NAc, we demonstrated that accumbal NPY overexpression relieved behavioural despair. Our results suggest that accumbal NPY expression may be regulated by 5-HT2 C R RNA editing, and its impairment may be linked to mood disorders. PMID- 26950267 TI - Patterns of Cranial Development in Larval Rana macrocnemis: Chondrocranial Size and Shape Relationship With Pelophylax bedriagae (Anura: Ranidae). AB - Notwithstanding the abundance of amphibians, there are few descriptions about ranid cranial development. Herein, larval chondrocranial development of Uludag frog, Rana macrocnemis (Boulenger, 1885), is described on cleared and double stained specimens. Descriptions are related with the ontogeny of the chondrocranium and osteogenesis of the cranial skeleton. The larval chondrocranial development of R. macrocnemis is compared to those of Rana and Pelophylax larvae (Pelophylax bedriagae, Rana pipiens, R. palustris, R. sphenocephala, R. catesbeiana, R. clamitans and R. sylvatica). In R. macrocnemis, the first bones to ossify are the parasphenoid and exoccipital (Stage 33), followed by the frontoparietal and prootic (stages 35 and 40, respectively). The major reconstruction of the chondrocranium begins at Stage 41. The ossification sequence of R. macrocnemis is distinguished from other ranids. Adult cranial osteology of R. macrocnemis is compared to that of P. bedriagae. Osteologically, R. macrocnemis is different from P. bedriagae by the shape and size of the vomer and number of teeth. Additionally, geometric morphometric methods are used to analyze chondrocranial size and shape changes of ranid larva of R. macrocnemis and P. bedriagae. Anat Rec, 299:711-721, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26950268 TI - Decisions on futility in patients with cirrhosis and organ failure. PMID- 26950269 TI - The Effects of Age, Adiposity, and Physical Activity on the Risk of Seven Site Specific Fractures in Postmenopausal Women. AB - Risk factors for fracture of the neck of the femur are relatively well established, but those for fracture at other sites are little studied. In this large population study we explore the role of age, body mass index (BMI), and physical activity on the risk of fracture at seven sites in postmenopausal women. As part of the Million Women Study, 1,154,821 postmenopausal UK women with a mean age of 56.0 (SD 4.8) years provided health and lifestyle data at recruitment in 1996 to 2001. All participants were linked to National Health Service (NHS) hospital records for day-case or overnight admissions with a mean follow-up of 11 years per woman. Adjusted absolute and relative risks for seven site-specific incident fractures were calculated using Cox regression models. During follow-up, 4931 women had a fracture of the humerus; 2926 of the forearm; 15,883 of the wrist; 9887 of the neck of the femur; 1166 of the femur (not neck); 3199 a lower leg fracture; and 10,092 an ankle fracture. Age-specific incidence rates increased gradually with age for fractures of forearm, lower leg, ankle, and femur (not neck), and steeply with age for fractures of neck of femur, wrist, and humerus. When compared to women with desirable BMI (20.0 to 24.9 kg/m(2) ), higher BMI was associated with a reduced risk of fracture of the neck of femur, forearm, and wrist, but an increased risk of humerus, femur (not neck), lower leg, and ankle fractures (p < 0.001 for all). Strenuous activity was significantly associated with a decreased risk of fracture of the humerus and femur (both neck and remainder of femur) (p < 0.001), but was not significantly associated with lower leg, ankle, wrist, and forearm fractures. Postmenopausal women are at a high lifetime risk of fracture. BMI and physical activity are modifiable risk factors for fracture, but their associations with fracture risk differ substantially across fracture sites. (c) 2016 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research (ASBMR). PMID- 26950271 TI - The Evaporation Barrier of the Tear Film Lipid Layer. PMID- 26950270 TI - Epileptic encephalopathy de novo GABRB mutations impair gamma-aminobutyric acid type A receptor function. AB - OBJECTIVE: The Epi4K Consortium recently identified 4 de novo mutations in the gamma-aminobutyric acid type A (GABAA ) receptor beta3 subunit gene GABRB3 and 1 in the beta1 subunit gene GABRB1 in children with one of the epileptic encephalopathies (EEs) Lennox-Gastaut syndrome (LGS) and infantile spasms (IS). Because the etiology of EEs is often unknown, we determined the impact of GABRB mutations on GABAA receptor function and biogenesis. METHODS: GABAA receptor alpha1 and gamma2L subunits were coexpressed with wild-type and/or mutant beta3 or beta1 subunits in HEK 293T cells. Currents were measured using whole cell and single channel patch clamp techniques. Surface and total expression levels were measured using flow cytometry. Potential structural perturbations in mutant GABAA receptors were explored using structural modeling. RESULTS: LGS-associated GABRB3(D120N, E180G, Y302C) mutations located at beta+ subunit interfaces reduced whole cell currents by decreasing single channel open probability without loss of surface receptors. In contrast, IS-associated GABRB3(N110D) and GABRB1(F246S) mutations at beta- subunit interfaces produced minor changes in whole cell current peak amplitude but altered current deactivation by decreasing or increasing single channel burst duration, respectively. GABRB3(E180G) and GABRB1(F246S) mutations also produced spontaneous channel openings. INTERPRETATION: All 5 de novo GABRB mutations impaired GABAA receptor function by rearranging conserved structural domains, supporting their role in EEs. The primary effect of LGS-associated mutations was reduced GABA-evoked peak current amplitudes, whereas the major impact of IS-associated mutations was on current kinetic properties. Despite lack of association with epilepsy syndromes, our results suggest GABRB1 as a candidate human epilepsy gene. Ann Neurol 2016;79:806 825. PMID- 26950272 TI - L1 in tumor vasculature. PMID- 26950274 TI - Perspectives for immunotherapy: which applications might achieve an HIV functional cure? AB - The major advances achieved in devising successful combined antiretroviral therapy (cART) have enabled the sustained control of HIV replication. However, this is associated with costly lifelong treatment, partial immune restoration, chronic inflammation and persistent viral reservoirs. In this context, new therapeutic strategies deserve investigation as adjuncts to cART so as to potentiate immune responses that are capable of completely containing HIV pathogenicity, particularly if cART is discontinued. This may seem a dauntingly high hurdle given the results to date. This review outlines the key research efforts that have recently resurrected immunotherapeutic options, and some of the approaches tested to date. These areas include promising cytokines or vaccine strategies, using different viral or non-viral vectors based on polyvalent "mosaic" antigens and highly conserved HIV envelope peptides, broadly neutralizing antibodies or new properties of antibodies to improve the control of immune system homeostasis. These novel immunotherapeutic strategies appear promising per se, or in combination with TLR-agonists in order to bypass the complexity of the interplay between immune activation, massive CD4+ T-cell loss and viral persistence. PMID- 26950275 TI - Angiogenesis in NSCLC: is vessel co-option the trunk that sustains the branches? AB - The critical role of angiogenesis in tumor development makes its inhibition a valuable new approach in therapy, rapidly making anti-angiogenesis a major focus in research. While the VEGF/VEGFR pathway is the main target of the approved anti angiogenic molecules in NSCLC treatment, the results obtained are still modest, especially due to resistance mechanisms. Accumulating scientific data show that vessel co-option is an alternative mechanism to angiogenesis during tumor development in well-vascularized organs such as the lungs, where tumor cells highjack the existing vasculature to obtain its blood supply in a non-angiogenic fashion. This can explain the low/lack of response to current anti-angiogenic strategies. The same principle applies to lung metastases of other primary tumors. The exact mechanisms of vessel co-option need to be further elucidated, but it is known that the co-opted vessels regress by the action of Angiopoietin-2 (Ang-2), a vessel destabilizing cytokine expressed by the endothelial cells of the pre-existing mature vessels. In the absence of VEGF, vessel regression leads to tumor cell loss and hypoxia, with a subsequent switch to a neoangiogenic phenotype by the remaining tumor cells. Unravelling the vessel co-option mechanisms and involved players may be fruitful for numerous reasons, and the particularities of this form of vascularization should be carefully considered when planning anti-angiogenic interventions or designing clinical trials for this purpose. In view of the current knowledge, rationale for therapeutic approaches of dual inhibition of Ang-2 and VEGF are swiftly gaining strength and may serve as a launchpad to more successful NSCLC anti-vascular treatments. PMID- 26950276 TI - High LEF1 expression predicts adverse prognosis in chronic lymphocytic leukemia and may be targeted by ethacrynic acid. AB - Aberrant activation of lymphoid enhancer-binding factor-1 (LEF1) has been identified in several cancers, including chronic lymphocytic leukemia (CLL). As a key transcription factor of the Wnt/beta-catenin pathway, LEF1 helps to regulate important genes involved in tumor cell death mechanisms. In this study, we determined LEF1 gene expression levels in CLL (n = 197) and monoclonal B-cell lymphocytosis (MBL) (n = 6) patients through real-time RT-PCR. LEF1 was significantly up-regulated in both MBL and CLL patients compared with normal B cells. Treatment-free survival (TFS) time and overall survival (OS) time were much longer in CLL patients with low LEF1 expression than in those with high LEF1 levels. Furthermore, Wnt inhibitor ethacrynic acid (EA) induced both apoptosis and necroptosis in primary CLL cells. EA also enhanced the cytotoxicity of both fludarabine and cyclophosphamide against CLL cells in vitro. Finally, we demonstrated that EA functions by inhibiting the recruitment of LEF1 to DNA promoters and restoring cylindromatosis (CYLD) expression in CLL cells. Our results showed, for the first time, that high LEF1 expression is associated with poor survival for CLL patients. Combined with other chemotherapeutic drugs, EA may be a promising therapeutic agent for CLL. PMID- 26950273 TI - Extracellular vesicle cross-talk in the bone marrow microenvironment: implications in multiple myeloma. AB - The bone marrow (BM) represents a complex microenvironment containing stromal cells, immune cells, osteoclasts, osteoblasts, and hematopoietic cells, which are crucial for the immune response, bone formation, and hematopoiesis. Apart from soluble factors and direct cell-cell contact, extracellular vesicles (EVs), including exosomes, were recently identified as a third mediator for cell communication. Solid evidence has already demonstrated the involvement of various BM-derived cells and soluble factors in the regulation of multiple biological processes whereas the EV-mediated message delivery system from the BM has just been explored in recent decades. These EVs not only perform physiological functions but can also play a role in cancer development, including in Multiple Myeloma (MM) which is a plasma cell malignancy predominantly localized in the BM. This review will therefore focus on the multiple functions of EVs derived from BM cells, the manipulation of the BM by cancer-derived EVs, and the role of BM EVs in MM progression. PMID- 26950277 TI - High circulating activin A level is associated with tumor progression and predicts poor prognosis in lung adenocarcinoma. AB - Activin A (ActA)/follistatin (FST) signaling has been shown to be deregulated in different tumor types including lung adenocarcinoma (LADC). Here, we report that serum ActA protein levels are significantly elevated in LADC patients (n=64) as compared to controls (n=46, p=0.015). ActA levels also correlated with more advanced disease stage (p<0.0001) and T (p=0.0035) and N (p=0.0002) factors. M1 patients had significantly higher ActA levels than M0 patients (p<0.001). High serum ActA level was associated with poor overall survival (p<0.0001) and was confirmed as an independent prognostic factor (p=0.004). Serum FST levels were increased only in female LADC patients (vs. female controls, p=0.031). Two out of five LADC cell lines secreted biologically active ActA, while FST was produced in all of them. Transcripts of both type I and II ActA receptors were detected in all five LADC cell lines. In conclusion, our study does not only suggest that measuring blood ActA levels in LADC patients might improve the prediction of prognosis, but also indicates that this parameter might be a novel non-invasive biomarker for identifying LADC patients with organ metastases. PMID- 26950278 TI - Effect of HMGCR genetic variation on neuroimaging biomarkers in healthy, mild cognitive impairment and Alzheimer's disease cohorts. AB - Alzheimer's disease (AD) has become a considerable public health issue. The mechanisms underlying AD onset and progression remain largely unclear. 3-Hydroxy 3-methylglutaryl coenzyme A reductase (HMGCR) is a strong functional AD candidate gene because it encodes part of the statin-binding domain of the enzyme, which serves as the rate-limiting step in cholesterol synthesis in all mammalian cells. Here, we evaluated the potential role of HMGCR (rs3846662) in AD-related pathology by assessing neuroimaging biomarkers. We enrolled in 812 subjects from the Alzheimer's disease Neuroimaging Initiative dataset. In general, it is possible that HMGCR (rs3846662) could be involved in preventing the atrophy of right entorhinal (P=0.03385) and left hippocampus (P=0.01839) in the follow-up research of two years. What's more, it lowered the drop rate of glucose metabolism in right temporal. We then further validated them in the AD, mild cognitive impairment (MCI), normal control (NC) sub-groups. All the results in the MCI groups confirmed the association. The results of our study indicated that HMGCR (rs3846662) plays a vital role in AD pathology mainly by influencing brain structure and glucose metabolism during AD progression. PMID- 26950280 TI - 3,6-Diazaphenothiazines as potential lead molecules - synthesis, characterization and anticancer activity. AB - 3,6-Diazaphenothiazines were obtained in cyclization of 3-amino-3'-nitro-2,4' dipyridinyl sulfide and the reaction of sodium 3-amino-2-pyridinethiolate with 4 chloro-3-nitropyridine followed by alkylation and heteroarylation. The thiazine ring formation ran via the Smiles rearrangement. The structure elucidation was based on 2D NMR and X-ray analysis of N-methylated product. 3,6 Diazaphenothiazines were investigated for antitumor activity using glioblastoma SNB-19, melanoma C-32 and breast cancer MCF-7 cells. 10H-3,6-diazaphenothiazine was 10 times more active (IC50 < 0.72 MUg/mL) than cisplatin. Two diazaphenothiazines with the 2-pyrimidinyl and dimethylaminopropyl substituents were selectively active against MCF-7 and C-32 cells. The expressions of H3 (proliferation marker), TP53, CDKN1A (cell cycle regulators), BAX and BCL-2 (proapoptopic and antiapoptopic genes) were detected by RT-QPCR method. The expression analysis suggests the cell cycle arrest and the mitochondrial apoptosis pathway activation in MCF-7 and SNB-19 cells. PMID- 26950279 TI - Escitalopram attenuates beta-amyloid-induced tau hyperphosphorylation in primary hippocampal neurons through the 5-HT1A receptor mediated Akt/GSK-3beta pathway. AB - Tau hyperphosphorylation is an important pathological feature of Alzheimer's disease (AD). To investigate whether escitalopram could inhibit amyloid-beta (Abeta)-induced tau hyperphosphorylation and the underlying mechanisms, we treated the rat primary hippocampal neurons with Abeta1-42 and examined the effect of escitalopram on tau hyperphosphorylation. Results showed that escitalopram decreased Abeta1-42-induced tau hyperphosphorylation. In addition, escitalopram activated the Akt/GSK-3beta pathway, and the PI3K inhibitor LY294002 blocked the attenuation of tau hyperphosphorylation induced by escitalopram. Moreover, the 5-HT1A receptor agonist 8-OH-DPAT also activated the Akt/GSK-3beta pathway and decreased Abeta1-42-induced tau hyperphosphorylation. Furthermore, the 5-HT1A receptor antagonist WAY-100635 blocked the activation of Akt/GSK-3beta pathway and the attenuation of tau hyperphosphorylation induced by escitalopram. Finally, escitalopram improved Abeta1-42 induced impairment of neurite outgrowth and spine density, and reversed Abeta1-42 induced reduction of synaptic proteins. Our results demonstrated that escitalopram attenuated Abeta1-42-induced tau hyperphosphorylation in primary hippocampal neurons through the 5-HT1A receptor mediated Akt/GSK-3beta pathway. PMID- 26950282 TI - Development of energy efficient mixing strategies in egg-shaped anaerobic reactors through 3D CFD simulation. AB - This work describes a 3D computational fluid dynamic model, which characterizes the hydrodynamic behavior of a mixing strategy applied to egg-shaped reactors that lack a mechanical stirring device. The model is based on Navier-Stokes and material balance equations without a chemical reaction. To describe the behavior of mixing, initial water feed flows of 6, 7.5 and 9 mL s(-1) were used. An experimental validation was subsequently carried out using a pulse technique, with NaCl as a tracer. The residence time distributions were quantitatively determined. Then, the degradation process of the wastewater sludge was characterized by studying the time dependence of the dynamic viscosity, the concentration of volatile solids and the density of wastewater sludge. The data resulting were introduced into the validated model, and five feed flows from 9 to 13 mL s(-1), the best performance found was with feed flow of 11 mL s(-1). PMID- 26950281 TI - Diabetes mellitus caused by mutations in human insulin: analysis of impaired receptor binding of insulins Wakayama, Los Angeles and Chicago using pharmacoinformatics. AB - Several naturally occuring mutations in the human insulin gene are associated with diabetes mellitus. The three known mutant molecules, Wakayama, Los Angeles and Chicago were evaluated using molecular docking and molecular dynamics (MD) to analyse mechanisms of deprived binding affinity for insulin receptor (IR). Insulin Wakayama, is a variant in which valine at position A3 is substituted by leucine, while in insulin Los Angeles and Chicago, phenylalanine at positions B24 and B25 is replaced by serine and leucine, respectively. These mutations show radical changes in binding affinity for IR. The ZDOCK server was used for molecular docking, while AMBER 14 was used for the MD study. The published crystal structure of IR bound to natural insulin was also used for MD. The binding interactions and MD trajectories clearly explained the critical factors for deprived binding to the IR. The surface area around position A3 was increased when valine was substituted by leucine, while at positions B24 and B25 aromatic amino acid phenylalanine replaced by non-aromatic serine and leucine might be responsible for fewer binding interactions at the binding site of IR that leads to instability of the complex. In the MD simulation, the normal mode analysis, rmsd trajectories and prediction of fluctuation indicated instability of complexes with mutant insulin in order of insulin native insulin < insulin Chicago < insulin Los Angeles < insulin Wakayama molecules which corresponds to the biological evidence of the differing affinities of the mutant insulins for the IR. PMID- 26950283 TI - Studies of gonadal sex differentiation. AB - Gonadal differentiation has a determinative influence on sex development in human embryos. Disorders of sexual development (DSD) have been associated with persistent embryonal differentiation stages. Between 1998 and 2015, 139 female patients with various (DSD) underwent operations at the Scientific Center of Obstetrics, Gynaecology and Perynatology in Moscow, Russia. Clinical investigations included karyotyping, ultrasound imaging, hormonal measurement and investigations of gonadal morphology. The male characteristics in the embryo are imposed by testicular hormones. When these are absent or inactive, the fetus may be arrested at between developmental stages, or stay on indifferent stage and become phenotypically female. A systematic analysis of gonadal morphology in DSD patients and a literature review revealed some controversies and led us to formulate a new hypothesis about sex differentiation. Proliferation of the mesonephric system (tubules and corpuscles) in the gonads stimulates the masculinization of gonads to testis. Sustentacular Sertoli cells of the testes are derived from mesonephric excretory tubules, while interstitial Leydig cells are derived from the original mesenchyme of the mesonephros. According of the new hypothesis, the original mesonephric cells (tubules and corpuscles) potentially persist in the ovarian parenchyma. In female gonads, some mesonephric excretory tubules regress and lose the tubular structure, but form ovarian theca interna and externa, becoming analogous to the sustentacular Sertoli cells in the testis. The ovarian interstitial Leydig cells are derived from intertubal mesenchyme of the mesonephros, similar to what occurs in male gonads (testis). Surprisingly, the leading determinative factor in sexual differentiation of the gonads is the mesonephros, represented by the embryonic urinary system. PMID- 26950285 TI - Inter-Eye Agreement in Measurement of Retinal Vascular Fractal Dimension in Patients with Type 1 Diabetes Mellitus. AB - PURPOSE: To investigate inter-eye agreement in retinal vascular fractal dimension (FD) in patients with type 1 diabetes. METHODS: In a cross-sectional study, both eyes were exained in 178 patients with type 1 diabetes. All vessels in a zone 0.5 2.0 disc diameters from the optic disc were traced and FD calculated with the box counting method using SIVA-Fractal semiautomatic software. The modified Early Treatment Diabetic Retinopathy Study (ETDRS) scale was used to grade diabetic retinopathy (DR). Pitman's test of difference in variance was used to calculated inter-eye agreement in FD according to level of DR. RESULTS: Mean age and duration of diabetes was 37.0 years and 29.5 years, respectively, and 49.4% of participants were male. Mean FD of right and left eyes was 1.4540 and 1.4472, respectively. FD did not differ between eyes in patients with no or non proliferative DR (NPDR) in both eyes. This was true for patients with the same level of DR in both eyes (n = 74, p = 0.73), as well as for patients in which the ETDRS level of DR between the eyes differed by 1 (n = 43, p = 0.99) or more (n = 9, p = 0.53). In patients treated for proliferative DR in one eye, FD was significantly lower in this eye compared to the other (n = 10, p = 0.03). CONCLUSION: FD did not differ significantly between the two eyes of patients with no DR or NPDR, despite differences in severity of DR. PMID- 26950284 TI - Effect of Metformin on Fibroblast Growth Factor-21 Levels in Patients with Newly Diagnosed Type 2 Diabetes. AB - BACKGROUND: Fibroblast growth factor (FGF)-21 is an important regulator of glucose metabolism. In the present study, we investigated whether plasma levels of FGF-21 changed in patients with newly diagnosed type 2 diabetes mellitus (T2DM) and assessed the effects of metformin treatment on plasma FGF-21 levels. MATERIALS AND METHODS: The plasma FGF-21 levels and the metabolic parameters of 226 patients with newly diagnosed T2DM and 100 sex- and age-matched normal glycemic tolerant (NGT) controls were measured. Seventy-four patients among of the 226 patients with T2DM were treated with metformin throughout the 12-week study period. The fasting plasma FGF-21 and high-sensitivity C-reactive protein (hs-CRP) levels were measured using enzyme-linked immunosorbent assay kits. RESULTS: The patients with T2DM had significantly higher fasting plasma FGF-21 levels (302.2 pg/mL [range, 201.3-454.4 pg/mL] vs. 104.5 pg/mL [range, 71.6-185.6 pg/mL]; P < 0.00) and hs-CRP levels (2.63 +/- 2.81 mg/L vs. 1.58 +/- 2.16 mg/L; P < 0.00) than the NGT subjects. The fasting plasma hs-CRP and FGF-21 levels were significantly decreased in the T2DM group after metformin treatment compared with pretreatment (respectively, 2.56 +/- 1.75 mg/L vs. 3.28 +/- 1.89 mg/L [P < 0.05] and 232.6 pg/mL [range, 154.3-307.8 pg/mL] vs. 313.9 pg/mL [range, 227.7-474.2 pg/mL] [P < 0.01]). CONCLUSIONS: In patients with T2DM, the plasma FGF-21 levels are increased but are significantly decreased after metformin treatment. Metformin may play a role in reducing the FGF-21 levels in patients with T2DM, likely through the amelioration of glucose-lipid metabolism and inflammation. PMID- 26950286 TI - Surgical management of extra-regional lymph node metastasis in colorectal cancer. AB - One of the major problems in rectal cancer surgery is local recurrence, found in an average of 21% to 46% cases in 1990. However, the advent of chemo-radiotherapy (CRT) and total mesorectal excision (TME) improve local control and enhances survival rates in colorectal cancer (CRC). Regional lymph node involvement is determined to be an independent prognostic factor in local recurrence; however, extra-regional lymph node (ERLN) metastasis has a higher recurrence rate (up to 58.1%). Lack of supportive data in management of ERLN metastasis in CRC has added further strain and challenges to structure a unique treatment strategy. ERLN refers to extra-mesenteric involvement either in the para-aortic lymph node (PALN) or the lateral pelvic lymph node (LPLN). Treatment of ERLN metastasis is challenging because of the shortage of the resources. Here, we will outline and summarize approaches and management of ERLN metastasis. We also aim to clarify the role of surgical intervention in CRC. PMID- 26950287 TI - The best allergen immunotherapy choice for mite allergic patients. PMID- 26950288 TI - Methyltransferase-Glo: a universal, bioluminescent and homogenous assay for monitoring all classes of methyltransferases. AB - AIM: To develop a homogenous, nonradioactive, antibody-free and universal assay for diverse families of methyltransferases and monitor the activity of these enzymes in a high-throughput format. MATERIALS & METHODS: The assay conditions are optimized for monitoring the enzymatic activity of a broad range of methyltransferases regardless of the chemical structure or nature of the enzyme substrate in a low- and high-throughput-formatted protocols. The assay detects S adenosyl-L-homocysteine, the universal reaction products of all methyltransferases. RESULTS: We demonstrate the utility of using this protocol to determine the activity of DNA, protein methyltransferases and also to determine kinetic parameters of several inhibitors using purified enzymes. The assay is sensitive (20-30 nM of S-adenosyl-L-homocysteine) and robust. CONCLUSION: The methyltransferase Glo is nonradioactive, antibody-free and homogenous, universal assay to determine enzyme activity of diverse families of methyltransferases. The assay is formatted to meet the requirements of high-throughput screening in drug discovery programs searching for modulators of methyltransferases. PMID- 26950289 TI - Etanercept protects myocutaneous flaps from ischaemia reperfusion injury: An experimental study in a rat tram flap model. AB - Background Being an inevitable component of free tissue transfer, ischemia reperfusion injury tends to contribute to flap failure. TNF-alpha is an important proinflammatory cytokine and a prominent mediator of the ischemia-reperfusion injury. Etanercept, a soluble TNF-alpha binding protein, has shown anti inflammatory and anti-apoptotic effects in animal models of renal and myocardial ischemia-reperfusion injury. We have designed an experimental study to investigate the effect of etanercept on myocutaneous ischemia-reperfusion injury on transverse rectus abdominis myocutaneous flap model in rats. Methods Twenty four male Sprague-Dawley rats were divided into 3 groups: In group 1 (sham), the TRAM flap was raised and sutured back without further intervention. In group 2 (control), the flap was raised and the ischemia-reperfusion protocol was followed. In group 3, etanercept (10 mg/kg, i.v.) was administered 10 minutes before reperfusion. At the end of the reperfusion period, biochemical and histolopathological evaluations were performed on serum and tissue samples. Results In the etanercept group the IMA and 8-OHdG levels (p = 0.005 and p = 0.004, respectively) were found significantly lower, and the GSH and SOD levels (p = 0.01 and p < 0.001, respectively) significantly higher in comparison to the control group. The histopathological analysis has revealed a lower degree of hyalinization, degenerated muscle fibers and nuclear change in the etanercept group compared to the control group. Conclusion The results of our experimental study indicate that etanercept offers protection against ischemia-reperfusion injury in skeletal muscle tissue, enhancing the TRAM flap viability. The ability of etanercept to induce ischemic tolerance suggests that it may be applicable in free-flap surgery. PMID- 26950290 TI - Clinical characteristics and outcomes of veterans hospitalised with purulent soft tissue infections with and without systemic signs of infection. AB - Objective To describe the frequency of systemic inflammatory response syndrome (SIRS) criteria in a cohort of patients hospitalised with purulent soft tissue infections and to determine their impact on clinical characteristics, microbiology and outcomes. Methods Retrospective cohort study of adults hospitalised at the West Haven Veteran's Hospital with purulent soft tissue infections between 1 October 2008 and 30 September 2013. Results A total of 173 patients were included with purulent soft tissue infections; 60 patients had no SIRS, 48 had one SIRS and 65 had >= 2 SIRS. Most clinical characteristics were similar between the different SIRS groups, although patients with SIRS were more likely to have severe sepsis and acute kidney injury and to already be on antibiotics at the time of hospitalisation. The microbiology of the infections was similar between SIRS groups. All patients received parenteral antibiotics when admitted and the majority of patients in all SIRS categories received antibiotics with broad Gram-negative activity. Outcomes were generally benign for all SIRS groups, although patients with SIRS had a longer length of stay and a trend towards more bacteremia. Conclusions SIRS are common in patients hospitalised with purulent soft tissue infections, although one third had no systemic signs of infection. Severe sepsis and septic shock are rare. Clinical characteristics, microbiology and antibiotic use are similar among patients in different SIRS groups, although the group without SIRS had a shorter hospitalisation and no episodes of bacteremia. Over-use of antibiotics is common in all SIRS categories. PMID- 26950291 TI - Is Low Hemoglobin Concentration Highly Associated with the Onset of Cognitive Impairment in Elderly People? PMID- 26950293 TI - Memorial - Dr. Joseph C. Fratantoni. PMID- 26950292 TI - Anti-EGFR and antiangiogenic monoclonal antibodies in metastatic non-small-cell lung cancer. AB - INTRODUCTION: In recent years, several clinical trials have evaluated the efficacy and safety of biological therapies in lung cancer. Epidermal growth factor receptor (EGFR) and the axis vascular endothelial growth factor receptor (VEGF/VEGFR) are targeted by small molecules and monoclonal antibodies (mAbs), especially in non-squamous non-small-cell lung cancer (NSCLC). AREAS COVERED: The current state of the art of anti-EGFR and antiangiogenic monoclonal antibodies in metastatic NSCLC is reviewed and discussed. EXPERT OPINION: Bevacizumab and cetuximab are the most studied mAbs in NSCLC, but only bevacizumab is in clinical practice in the first-line setting. Necitumumab is a new anti-EGFR monoclonal antibody that improves survival when combined to cisplatin/gemcitabine chemotherapy and has been approved in first-line advanced NSCLC. Ramucirumab, an antiangiogenic drug binding with high affinity to VEGFR-2, improves the results of chemotherapy alone when administered with docetaxel and has been approved in second-line setting. Moreover, the novel combination of bevacizumab and erlotinib is very promising for the treatment of patients with NSCLC harbouring EGFR mutations. The association of antiangiogenic mAbs and immunotherapy is under investigation too. PMID- 26950295 TI - Reactions of Ti- and V-Doped Cu Cluster Cations with Nitric Oxide and Oxygen: Size Dependence and Preferential NO Adsorption. AB - Reactions of copper cluster cations doped with an early transition metal atom, CunTi(+) (n = 4-15) and CunV(+) (n = 5-14, 16), with NO and O2 were investigated at a near-thermal collision energy using a guided ion beam tandem mass spectrometer. Most of the clusters adsorb NO and O2 under single collision conditions, and this reaction is often followed by the release of Cu atoms. For both Ti- and V-doped Cu clusters, the total cross sections for the reaction with NO increase gradually with the cluster size up to n ~ 11 and then decrease rapidly, whereas those with O2 are almost constant in n <= 12 and then decrease. The size dependence of the reactivity toward NO is found to correlate with that of the adsorption energy calculated by the density functional theory method; CunTi(+) clusters exhibit the larger reaction cross sections when they have the larger adsorption energies. The calculations of CunTi(+) also show that a structural transition from a Ti-exposed structure to Ti-encapsulated one occurs around n = 12. This indicates that a geometric property of the clusters, i.e., the position of the dopant atom, is a determining factor of reactivity. In addition, the Ti- and V-doping dramatically improves the reactivity of Cu cluster cations toward NO but it does not affect that toward O2 significantly. As a result, most of the Ti- and V-doped Cu clusters are more reactive toward NO than toward O2. We also studied the multiple-collision reaction of Cu7Ti(+) with NO and obtained the cluster dioxide, Cu3TiO2(+), as a product ion, which suggests that the dissociation of NO and the subsequent formation/release of N2 take place. PMID- 26950294 TI - Microbial shifts associated with necrotic enteritis. AB - An outbreak of necrotic enteritis (NE) is a complex process requiring one or a number of predisposing factors rather than just the presence of pathogenic Clostridium perfringens. Examples are dietary influences, such as high levels of non-starch polysaccharides and fishmeal, and factors that evoke epithelial cell damage, such as Fusarium mycotoxins in feed and Eimeria infections. Recent studies have shown that different predisposing factors induce similar shifts in the intestinal microbiota composition. Butyrate-producing-strains of the Ruminococcaceae family are decreased in abundance by both fishmeal and Eimeria. Similarly, a decreased abundance of butyrate-producing-strains belonging to the Lachnospiraceae family has been induced by fishmeal. Also shifts are observed in the lactic acid-producing bacteria, such as decreased abundance of Lactobacillus johnsonii or Weissella confusa, when broilers were fed a fishmeal-based diet or a Fusarium mycotoxin contaminated diet. Finally, the abundance of Candidatus Savagella was decreased in broilers following Eimeria challenge or feeding a fumonisins contaminated diet. The nature of the microbiota shifts indicate that immune modulatory actions of the intestinal microbiota may play a critical role in the effect on the necrosis inducing activity of C. perfringens. Indeed, colonization with butyrate-producing bacteria plays a key role in counteracting inflammation in the gut and preserving intestinal integrity, while Candidatus Savagella is involved in stimulating Th17 and immunoglobulin A responses. Lactic acid bacteria stimulate colonization of lactate-utilizing and butyrate-producing Lachnospiraceae. Future research needs to clarify the role of the microbiota changes in the pathogenesis of NE. PMID- 26950296 TI - Identification of an Extracellular Endoglucanase That Is Required for Full Virulence in Xanthomonas citri subsp. citri. AB - Xanthomonas citri subsp. citri causes citrus canker disease, which is characterized by the formation of water-soaked lesions, white or yellow spongy pustules and brown corky canker. In this work, we report the contribution of extracellular endoglucanase to canker development during infection. The ectopic expression of nine putative cellulases in Escherichia coli indicated that two endoglucanases, BglC3 and EngXCA, show carboxymethyl cellulase activity. Both bglC3 and engXCA genes were transcribed in X. citri subsp. citri, however, only BglC3 protein was detected outside the cell in western blot analysis. The deletion of bglC3 gene resulted in complete loss of extracellular carboxymethyl cellulase activity and delayed the onset of canker symptoms in both infiltration- and wound-inoculation assays. When growing in plant tissue, the cell density of bglC3 mutant was lower than that of the wild type. Our data demonstrated that BglC3 is an extracellular endoglucanase required for the full virulence of X. citri subsp. citri. PMID- 26950297 TI - Comparative Proteomic Profiling of Divergent Phenotypes for Water Holding Capacity across the Post Mortem Ageing Period in Porcine Muscle Exudate. AB - Two dimensional Difference Gel Electrophoresis (2-D DIGE) and mass spectrometry were applied to investigate the changes in metabolic proteins that occur over a seven day (day 1, 3 and 7) post mortem ageing period in porcine centrifugal exudate from divergent meat quality phenotypes. The objectives of the research were to enhance our understanding of the phenotype (water holding capacity) and search for biomarkers of this economically significant pork quality attribute. Major changes in protein abundance across nine phenotype-by-time conditions were observed. Proteomic patterns were dominated by post mortem ageing timepoint. Using a machine learning algorithm (l1-regularized logistic regression), a model was derived with the ability to discriminate between high drip and low drip phenotypes using a subset of 25 proteins with an accuracy of 63%. Models discriminating between divergent phenotypes with accuracy of 72% and 73% were also derived comparing respectively, high drip plus intermediate phenotype (considered as one phenotype) versus low drip and comparing low drip plus intermediate phenotype (considered as one phenotype) versus high drip. In all comparisons, the general classes of discriminatory proteins identified include metabolic enzymes, stress response, transport and structural proteins. In this research we have enhanced our understanding of the protein related processes underpinning this phenotype and provided strong data to work toward development of protein biomarkers for water holding capacity. PMID- 26950298 TI - Whole-Genome Sequencing for the Investigation of a Hospital Outbreak of MRSA in China. AB - Staphylococcus aureus is a globally disseminated drug-resistant bacterial species. It remains a leading cause of hospital-acquired infection, primarily among immunocompromised patients. In 2012, the Affiliated People's Hospital of Jiangsu University experienced a putative outbreak of methicillin-resistant S. aureus (MRSA) that affected 12 patients in the Neurosurgery Department. In this study, whole-genome sequencing (WGS) was used to gain insight into the epidemiology of the outbreak caused by MRSA, and traditional bacterial genotyping approaches were also applied to provide supportive evidence for WGS. We sequenced the DNA from 6 isolates associated with the outbreak. Phylogenetic analysis was constructed by comparing single-nucleotide polymorphisms (SNPs) in the core genome of 6 isolates in the present study and another 3 referenced isolates from GenBank. Of the 6 MRSA sequences in the current study, 5 belonged to the same group, clustering with T0131, while the other one clustered closely with TW20. All of the isolates were identified as ST239-SCCmecIII clones. Whole-genome analysis revealed that four of the outbreak isolates were more tightly clustered into a group and SA13002 together with SA13009 were distinct from the outbreak strains, which were considered non-outbreak strains. Based on the sequencing results, the antibiotic-resistance gene status (present or absent) was almost perfectly concordant with the results of phenotypic susceptibility testing. Various toxin genes were also analyzed successfully. Our analysis demonstrates that using traditional molecular methods and WGS can facilitate the identification of outbreaks and help to control nosocomial transmission. PMID- 26950299 TI - Deletion of the Toll-Like Receptor 5 Gene Per Se Does Not Determine the Gut Microbiome Profile That Induces Metabolic Syndrome: Environment Trumps Genotype. AB - Over the past decade, emerging evidence has linked alterations in the gut microbial composition to a wide range of diseases including obesity, type 2 diabetes, and cardiovascular disease. Toll-like receptors (TLRs) are the major mediators for the interactions between gut microbiota and host innate immune system, which is involved in the localization and structuring of host gut microbiota. A previous study found that TLR5 deficient mice (TLR5KO1) had altered gut microbial composition which led to the development of metabolic syndrome including hyperlipidemia, hypertension, insulin resistance and increased adiposity. In the current study, a second TLR5-deficient mouse model was studied (TLR5KO2). TLR5 deficient mice did not manifest metabolic abnormalities related to the metabolic syndrome compared with littermate controls maintained on normal chow or after feeding a high fat diet. Analysis of the gut microbial composition of littermate TLR5KO2 and wild type mice revealed no significant difference in the overall microbiota structure between genotypes. However, the TLR5KO2 microbiota was distinctly different from that previously reported for TLR5KO1 mice with metabolic syndrome. We conclude that an altered composition of the microbiota in a given environment can result in metabolic syndrome, but it is not a consequence of TLR5 deficiency per se. PMID- 26950300 TI - Species-Specific Responses of Carnivores to Human-Induced Landscape Changes in Central Argentina. AB - The role that mammalian carnivores play in ecosystems can be deeply altered by human-driven habitat disturbance. While most carnivore species are negatively affected, the impact of habitat changes is expected to depend on their ecological flexibility. We aimed to identify key factors affecting the habitat use by four sympatric carnivore species in landscapes of central Argentina. Camera trapping surveys were carried out at 49 sites from 2011 to 2013. Each site was characterized by 12 habitat attributes, including human disturbance and fragmentation. Four landscape gradients were created from Principal Component Analysis and their influence on species-specific habitat use was studied using Generalized Linear Models. We recorded 74 events of Conepatus chinga, 546 of Pseudalopex gymnocercus, 193 of Leopardus geoffroyi and 45 of Puma concolor. We found that the gradient describing sites away from urban settlements and with low levels of disturbance had the strongest influence. L. geoffroyi was the only species responding significantly to the four gradients and showing a positive response to modified habitats, which could be favored by the low level of persecution by humans. P. concolor made stronger use of most preserved sites with low proportion of cropland, even though the species also used sites with an intermediate level of fragmentation. A more flexible use of space was found for C. chinga and P. gymnocercus. Our results demonstrate that the impact of human activities spans across this guild of carnivores and that species-specific responses appear to be mediated by ecological and behavioral attributes. PMID- 26950301 TI - Oral Contraceptives and Multiple Sclerosis/Clinically Isolated Syndrome Susceptibility. AB - BACKGROUND: The incidence of multiple sclerosis (MS) is rising in women. OBJECTIVE: To determine whether the use of combined oral contraceptives (COCs) are associated with MS risk and whether this varies by progestin content. METHODS: We conducted a nested case-control study of females ages 14-48 years with incident MS or clinically isolated syndrome (CIS) 2008-2011 from the membership of Kaiser Permanente Southern California. Controls were matched on age, race/ethnicity and membership characteristics. COC use up to ten years prior to symptom onset was obtained from the complete electronic health record. RESULTS: We identified 400 women with incident MS/CIS and 3904 matched controls. Forty- percent of cases and 32% of controls had used COCs prior to symptom onset. The use of COCs was associated with a slightly increased risk of MS/CIS (adjusted OR = 1.52, 95%CI = 1.21-1.91; p<0.001). This risk did not vary by duration of COC use. The association varied by progestin content being more pronounced for levenorgestrol (adjusted OR = 1.75, 95%CI = 1.29-2.37; p<0.001) than norethindrone (adjusted OR = 1.57, 95%CI = 1.16-2.12; p = 0.003) and absent for the newest progestin, drospirenone (p = 0.95). CONCLUSIONS: Our findings should be interpreted cautiously. While the use of some combination oral contraceptives may contribute to the rising incidence of MS in women, an unmeasured confounder associated with the modern woman's lifestyle is a more likely explanation for this weak association. PMID- 26950302 TI - Inferring Phylogenetic Networks with Maximum Pseudolikelihood under Incomplete Lineage Sorting. AB - Phylogenetic networks are necessary to represent the tree of life expanded by edges to represent events such as horizontal gene transfers, hybridizations or gene flow. Not all species follow the paradigm of vertical inheritance of their genetic material. While a great deal of research has flourished into the inference of phylogenetic trees, statistical methods to infer phylogenetic networks are still limited and under development. The main disadvantage of existing methods is a lack of scalability. Here, we present a statistical method to infer phylogenetic networks from multi-locus genetic data in a pseudolikelihood framework. Our model accounts for incomplete lineage sorting through the coalescent model, and for horizontal inheritance of genes through reticulation nodes in the network. Computation of the pseudolikelihood is fast and simple, and it avoids the burdensome calculation of the full likelihood which can be intractable with many species. Moreover, estimation at the quartet-level has the added computational benefit that it is easily parallelizable. Simulation studies comparing our method to a full likelihood approach show that our pseudolikelihood approach is much faster without compromising accuracy. We applied our method to reconstruct the evolutionary relationships among swordtails and platyfishes (Xiphophorus: Poeciliidae), which is characterized by widespread hybridizations. PMID- 26950305 TI - Paddle Wheel Based Triazolyl Isophthalate MOFs: Impact of Linker Modification on Crystal Structure and Gas Sorption Properties. AB - Syntheses and comprehensive characterization of two closely related series of isomorphous metal-organic frameworks (MOFs) based on triazolyl isophthalate linkers with the general formula infinity(3)[M2(R(1)-R(2)-trz-ia)2] (M = Cu, Zn) are presented. Using solvothermal synthesis and synthesis of microcrystalline materials on the gram scale by refluxing a solution of the starting materials, 11 MOFs are readily available for a systematic investigation of structure-property relationships. The networks of the two series are assigned to rutile (rtl) (1-4) and alpha-PbO2 (apo) (5-9) topology, respectively. Due to the orientation of the triazole substituents toward the cavities, both the pore volume and the pore diameter can be adjusted by choice of the alkyl substituents. Compounds 1-9 exhibit pronounced microporosity with calculated porosities of 31-53% and show thermal stability up to 390 degrees C as confirmed by simultaneous thermal analysis. Systematic investigation of adsorption properties by CO2 (298 K) and N2 (77 K) adsorption studies reveal remarkable network flexibility induced by alkyl substituents on the linker. Fine-tuning of the gate opening pressure and of the hysteresis shape is possible by adjusting the substitution pattern and by choice of the metal ion. PMID- 26950304 TI - Azathioprine-induced eosinophilic myocarditis in a patient with ANCA-associated vasculitis. PMID- 26950303 TI - Predicted Strain Coverage of a New Meningococcal Multicomponent Vaccine (4CMenB) in Spain: Analysis of the Differences with Other European Countries. AB - BACKGROUND: A novel meningococcal multicomponent vaccine, 4CMenB (Bexsero(r)), has been approved in Europe, Canada, Australia and US. The potential impact of 4CMenB on strain coverage is being estimated by using Meningococcal Antigen Typing System (MATS), an ELISA assay which measures vaccine antigen expression and diversity in each strain. Here we show the genetic characterization and the 4CMenB potential coverage of Spanish invasive strains (collected during one epidemiological year) compared to other European countries and discuss the potential reasons for the lower estimate of coverage in Spain. MATERIAL AND METHODS: A panel of 300 strains, a representative sample of all serogroup B Neisseria meningitidis notified cases in Spain from 2009 to 2010, was characterized by multilocus sequence typing (MLST) and FetA variable region determination. 4CMenB vaccine antigens, PorA, factor H binding protein (fHbp), Neisseria Heparin Binding Antigen (NHBA) and Neisserial adhesin A (NadA) were molecularly typed by sequencing. PorA coverage was assigned to strain with VR2 = 4. The levels of expression and cross-reactivity of fHbp, NHBA and NadA were analyzed using MATS ELISA. FINDINGS: Global estimated strain coverage by MATS was 68.67% (95% CI: 47.77-84.59%), with 51.33%, 15.33% and 2% of strains covered by one, two and three vaccine antigens, respectively. The predicted strain coverage by individual antigens was: 42% NHBA, 36.33% fHbp, 8.33% PorA and 1.33% NadA. Coverage within the most prevalent clonal complexes (cc) was 70.37% for cc 269, 30.19% for cc 213 and 95.83% for cc 32. CONCLUSIONS: Clonal complexes (cc) distribution accounts for variations in strain coverage, so that country-by country investigations of strain coverage and cc prevalence are important. Because the cc distribution could also vary over time, which in turn could lead to changes in strain coverage, continuous detailed surveillance and monitoring of vaccine antigens expression is needed in those countries where the multicomponent vaccine is introduced. This is really important in countries like Spain where most of the strains are predicted to be covered by only one vaccine antigen and the chance for escape mutants to emerge with vaccine use is higher. Based on the observed data, cc213 should receive special attention as it is associated with low predicted strain coverage, and has recently emerged in Spain. PMID- 26950307 TI - Efficacy and Safety of Escalation of Adalimumab Therapy to Weekly Dosing in Pediatric Patients with Crohn's Disease. AB - BACKGROUND: The efficacy of adalimumab in inducing and maintaining remission in children with moderately to severely active Crohn's disease was shown in the IMAgINE 1 trial (NCT00409682). As per protocol, nonresponders or patients experiencing flare(s) on every other week (EOW) maintenance dosing could escalate to weekly dosing; we aimed to determine the therapeutic benefits of weekly dose escalation in this subpopulation. METHODS: Week 52 remission and response rates were assessed in patients who escalated to weekly dosing from their previous EOW schedule, which was according to randomized treatment dose (higher dose [HD] adalimumab [>=40 kg, 40 mg EOW; <40 kg, 20 mg EOW] or lower dose [LD; >=40 kg, 20 mg EOW; <40 kg, 10 mg EOW]). Adverse events were reported for patients remaining on EOW dosing and patients receiving weekly dosing. RESULTS: Escalation to weekly dosing occurred in 48/95 (50.5%) patients randomized to LD and 35/93 (37.6%) patients randomized to HD adalimumab (P = 0.076). Week 52 remission and response rates were 18.8% and 47.9% for patients receiving LD adalimumab weekly and 31.4% and 57.1% for patients receiving HD adalimumab weekly, respectively (LD versus HD, P = 0.19 for remission; P = 0.41 for response). Adverse event rates were similar for patients receiving EOW and weekly adalimumab. CONCLUSIONS: Weekly adalimumab dosing was clinically beneficial for children with Crohn's disease who experienced nonresponse or flare on EOW dosing. No increased safety risks were observed with weekly dosing. PMID- 26950306 TI - Phosphatase Wip1 Masters IL-17-producing Neutrophil-mediated Colitis in Mice. AB - Wild-type p53-induced phosphatase 1 (Wip1) is currently believed to be a promising drug target for cancer therapy. Our recent studies showed that deletion of Wip1 remarkably promoted neutrophil inflammatory response. Whether Wip1 is involved in the regulation of inflammatory bowel disease is unknown. In the present study, we found that Wip1 knockout (KO) mice were more susceptible to colitis induced by dextran sulphate sodium (DSS) than wild-type mice as substantiated by the lower mouse survival ratio, rapid bodyweight loss, increased disease activity index, shorter colon length, and more severe pathology of colons in Wip1KO mice. Using full bone marrow chimera mouse models, we demonstrated that Wip1 intrinsically controls inflammatory response of immune cells. Deletion of IL 17 (Wip1/IL-17 double KO mice) significantly rescued the pathology in Wip1KO mice. Neutrophils of DSS-treated wild-type and Wip1KO mice expressed significantly higher IL-17. After adoptive transfer of sorted Wip1KO or double KO neutrophils into IL-17KO mice, mice receiving double KO neutrophils were more resistant to DSS-induced colitis than mice receiving Wip1KO neutrophils. These data collectively indicate that Wip1 modulates host sensitivity to colitis by intrinsically regulating immune cells. The enhanced IL-17 expression in neutrophils contributed to the increased sensitivity and severity of colitis in Wip1KO mice. Thus, Wip1 may be used as a drug target to treat colitis. PMID- 26950308 TI - Patients with Ulcerative Colitis Are More Concerned About Complications of Their Disease than Side Effects of Medications. AB - BACKGROUND: Patients with ulcerative colitis (UC) are often fearful about medication side effects and how the disease will affect their future. Our aim was to better understand what aspects of UC, and UC management, are most concerning to patients, and how they would like to be informed about treatment options. METHODS: A Web-based survey was sent to UC patients throughout the United States and Australia. In addition to standard closed-response questions, audio clips were embedded in the survey and respondents showed their strength of agreement or disagreement using moment-to-moment affect-trace methodology. Standard quantitative analysis was used for the survey results, and cluster analysis was performed on the affect-trace responses. RESULTS: A total of 460 patients with UC (370 patients from the United States and 90 patients from Australia) responded to the survey. Of them, 53% of the respondents were women, with a mean age of 49 (range 19-81) years. Most patients (87%) wanted to share treatment decision making with their doctors. The majority, 98%, wanted more than just a basic understanding of their disease. Patients were most concerned about the risk of colorectal cancer (37%), and the possible need for an ileostomy (29%). Only 14% of patients indicated that side effects from medications were their biggest concern. On affect-trace analysis, the most divergence in opinion centered on the appropriate timing for colectomy. CONCLUSIONS: To facilitate informed treatment decisions for UC patients, in addition to reviewing the benefits and risks of medications, it is also important to discuss the best strategies for decreasing the risk of colectomy and colorectal cancer. PMID- 26950311 TI - Impact of Concurrent Non-IBD Immunological Diseases on the Outcome of Primary Sclerosing Cholangitis. AB - BACKGROUND: The association between primary sclerosing cholangitis (PSC) and underlying inflammatory bowel disease (IBD) is well established. There are scant data on the association between non-IBD immunological diseases (NID) and PSC outcomes. Our objective was to investigate the impact of NID on the clinical outcomes in patients with PSC. METHODS: We included 287 patients with PSC from 1985 to 2013 from our tertiary care data registry. Univariate and multivariate analyses were performed to assess the risk factors for liver transplantation. RESULTS: Of the 287 patients with PSC, 38 (13.2%) patients had at least 1 concomitant immunological disease other than IBD; 241 patients (84.0%) had concurrent IBD. The most frequent NIDs were autoimmune thyroiditis, autoimmune hepatitis, and rheumatoid arthritis. The median follow-up time did not differ significantly between PSC patients with and without NID (10.5 years versus 7.0 years, P = 0.04). We did not find significant difference in the median time from PSC diagnosis to liver transplantation between PSC patients with and without NID (5.2 versus 6.3 years, P = 0.74). In the subgroup analysis, there was no significant difference in the median time from PSC diagnosis to liver transplantation between the PSC-only group, PSC with IBD group, and PSC with NID group (5.4 versus 6.4 versus 5.2 years, P = 0.22). CONCLUSIONS: The association of NID in patients with PSC did not seem to affect the need for liver transplantation or transplantation-free survival. The findings suggest that the increased load of autoimmunity, including the presence of IBD or NID, has a minimum impact on the disease outcome of PSC. PMID- 26950312 TI - Epithelial ER Stress in Crohn's Disease and Ulcerative Colitis. AB - Research in the past decade has greatly expanded our understanding of the pathogenesis of inflammatory bowel disease, which includes Crohn's disease and ulcerative colitis. In addition to the sophisticated network of immune response, the epithelial layer lining the mucosa has emerged as an essential player in the development and persistence of intestinal inflammation. As the frontline of numerous environmental insults in the gut, the intestinal epithelial cells are subject to various cellular stresses. In eukaryotic cells, disturbance of endoplasmic reticulum homeostasis may lead to the accumulation of unfolded and misfolded proteins in the ER lumen, a condition called ER stress. This cellular process activates the unfolded protein response, which functions to enhance the ER protein folding capacity, alleviates the burden of protein synthesis and maturation, and activates ER-associated protein degradation. Paneth and goblet cells, 2 secretory epithelial populations in the gut, are particularly sensitive to ER stress on environmental or genetic disturbances. Recent studies suggested that epithelial ER stress may contribute to the pathogenesis of Crohn's disease and ulcerative colitis by compromising protein secretion, inducing epithelial cell apoptosis and activating proinflammatory response in the gut. Our knowledge of ER stress in intestinal epithelial function may open avenue to new inflammatory bowel disease therapies by targeting the ER protein folding homeostasis in the cells lining the intestinal mucosa. PMID- 26950309 TI - Demographic and Clinical Predictors of High Healthcare Use in Patients with Inflammatory Bowel Disease. AB - BACKGROUND: Inflammatory bowel disease (IBD) is a heterogeneous chronic inflammatory condition requiring significant healthcare expenditure. Subgroups of individuals contribute disproportionately to spending. We aimed to determine demographic and clinical factors predictive of high healthcare expenditures for IBD patients followed over a multiyear period. METHODS: This was a registry analysis using a prospective observational, consented, natural history registry from a tertiary IBD center and associated medical charges, not including pharmacy expenses. The 100 patients with the highest medical charges (top 5%) were compared with the median 300 patients. Logistic regression determined demographic and clinical factors associated with high charge patients. RESULTS: IBD patients in the high charge group had significantly more unemployment (P < 0.0001), were of black race (P = 0.013), comorbid psychiatric illness (P = 0.002), hypertension (P = 0.01), diabetes (P = 0.004), opiate use (P < 0.0001), perianal involvement (P = 0.002), penetrating disease (P < 0.0001), and extensive colitis (P = 0.01). In multivariate analysis, unemployment (Crohn's disease [CD]: odds ratio [OR], 3.04; 95% confidence interval [CI], 1.32-7.02; ulcerative colitis [UC]: OR, 2.68; 95% CI, 1.20-5.99), psychiatric illness (UC: OR, 2.08; 95% CI, 1.03-4.19), opiates (CD: OR, 5.61; 95% CI, 2.67-11.82; UC: OR, 5.14; 95% CI, 2.52-10.48), prior surgery (CD: OR, 3.29; 95% CI, 1.59-6.82; UC: OR, 2.72; 95% CI, 1.39-5.32), penetrating CD (OR, 3.29; 95% CI, 1.02-10.62), and corticosteroid requirement (CD: OR, 3.78; 95% CI, 1.86-7.65; UC: OR, 2.98; 95% CI, 1.51-5.90) remained independently associated with high charges. CONCLUSIONS: High expenditure IBD patients were affected by more severe disease. The high prevalence of depression, anxiety, and chronic pain in these patients suggests the need for focused treatment of these comorbidities ultimately to reduce financial burden. PMID- 26950310 TI - A Critical Role for Monocytes/Macrophages During Intestinal Inflammation associated Lymphangiogenesis. AB - BACKGROUND: Inflammation-associated lymphangiogenesis (IAL) is frequently observed in inflammatory bowel diseases. IAL is believed to limit inflammation by enhancing fluid and immune cell clearance. Although monocytes/macrophages (MPhi) are known to contribute to intestinal pathology in inflammatory bowel disease, their role in intestinal IAL has never been studied mechanistically. We investigated contributions of monocytes/MPhi to the development of intestinal inflammation and IAL. METHODS: Because inflammatory monocytes express CC chemokine receptor 2 (CCR2), we used CCR2 diphtheria toxin receptor transgenic (CCR2.DTR) mice, in which monocytes can be depleted by diphtheria toxin injection, and CCR2 mice, which have reduced circulating monocytes. Acute or chronic colitis was induced by dextran sodium sulfate or adoptive transfer of CD4CD45RB T cells, respectively. Intestinal inflammation was assessed by flow cytometry, immunofluorescence, disease activity, and histopathology, whereas IAL was assessed by lymphatic vessel morphology and density. RESULTS: We demonstrated that intestinal MPhi expressed vascular endothelial growth factor-C/D. In acute colitis, monocyte-depleted mice were protected from intestinal injury and showed reduced IAL, which was reversed after transfer of wild-type monocytes into CCR2 mice. In chronic colitis, CCR2 deficiency did not attenuate inflammation but reduced IAL. CONCLUSIONS: We propose a dual role of MPhi in (1) promoting acute inflammation and (2) contributing to IAL. Our data suggest that intestinal inflammation and IAL could occur independently, because IAL was reduced in the absence of monocytes/MPhi, even when inflammation was present. Future inflammatory bowel disease therapies might exploit promotion of IAL and suppression of MPhi independently, to restore lymphatic clearance and reduce inflammation. PMID- 26950313 TI - Effects of long-term tenofovir-based combination antiretroviral therapy in HIV hepatitis B virus coinfection on persistent hepatitis B virus viremia and the role of hepatitis B virus quasispecies diversity. AB - OBJECTIVE: Hepatitis B virus (HBV) can persist in some HIV-HBV coinfected individuals on tenofovir disoproxil fumarate (TDF)-containing combination antiretroviral therapy (cART) but HBV resistance to TDF has not been reported and the source of persistent HBV DNA on TDF is poorly understood. The aims of this study were to assess long-term HBV suppression in HIV-HBV coinfected individuals receiving TDF and investigate quasispecies variation using ultradeep pyrosequencing (UDPS). METHODS: Ninety-two HIV-HBV coinfected participants on, or about to commence, TDF-containing cART were enrolled [Australia (n = 40), Thailand (n = 52)] and followed for 2 years with study visits every 6 months. HBV reverse transcriptase sequencing was performed on samples with HBV DNA more than 400 IU/ml by population-based methods and UDPS. Quasispecies diversity was assessed using Shannon entropy. RESULTS: Over 24 months, viremia was detected at least once in 17% (n = 16) of the cohort. Novel mutations were not identified in on TDF samples tested by population-based sequencing (n = 19). Using UDPS, the median Shannon entropy value in samples prior to TDF in patients aviremic on TDF was not statistically different from those who were viremic on TDF (n = 50; 8.4 and 9.1, respectively, P = 0.9). Longitudinal Shannon entropy analysis of on TDF samples from five participants showed three individuals with significant changes in viral diversity over time. CONCLUSION: Persistent viremia on TDF-containing cART is common but TDF-resistance was not detected. In some individuals, changes in viral diversity over time were observed on TDF which could potentially be active viral replication. Further follow-up will be needed to determine the clinical significance of detectable HBV DNA on TDF-containing cART. PMID- 26950314 TI - Cancer risk among the HIV-infected elderly in the United States. AB - OBJECTIVE: HIV-infected people and elderly people have higher cancer risk, but the combined effects of aging and HIV are not well described. We aimed to evaluate the magnitude of cancer risk in the HIV-infected elderly population. DESIGN: We conducted a case-cohort study including a 5% sample of U.S. Medicare enrollees and all cancer cases aged at least 65 in linked cancer registries. METHODS: HIV was identified through Medicare claims. Among the HIV-infected, absolute cancer risk was calculated accounting for the competing risk of death. Associations between HIV and cancer were estimated with weighted Cox regression adjusting for demographic characteristics. RESULTS: Among 469 954 people in the 5% sample, 0.08% had an HIV diagnosis. Overall, 825 776 cancer cases were identified in cancer registries. Over 5 years, 10.1% of the HIV-infected elderly developed cancer, the most common diagnoses comprising lung (5-year cumulative incidence=2.2%), prostate (2.7%, among men), and colorectal cancer (0.9%), and non-Hodgkin lymphoma (0.8%). HIV was strongly associated with incidence of Kaposi sarcoma [adjusted hazard ratio (aHR)=94.4, 95% confidence interval (95%CI)=54.6 163], anal cancer (aHR=34.2, 95%CI=23.9-49.0) and Hodgkin lymphoma (aHR=6.3, 95%CI=2.8-14.3). HIV was also associated with incidence of liver cancer, non Hodgkin lymphoma and lung cancer (aHR=3.4, 2.6, and 1.6, respectively). CONCLUSION: In the elderly, HIV infection is associated with higher risk for many cancers, although some associations were weaker than expected, perhaps reflecting effects of non-HIV pathways on cancer development. Due to the effects of HIV and aging, the HIV-infected elderly have a sizeable absolute risk, highlighting a need for cancer prevention. PMID- 26950315 TI - Improvements over time in short-term mortality following myocardial infarction in HIV-positive individuals. AB - OBJECTIVE: Few studies have described mortality and clinical outcomes after myocardial infarction (MI) in the HIV-positive population. This study evaluated changes in short-term mortality after MI in HIV-positive individuals in the D:A:D Study, and investigated possible reasons for any changes seen. DESIGN: Prospective cohort study. METHODS: Demographic, cardiovascular disease (CVD)/HIV related characteristics and CVD-related interventions (invasive cardiovascular procedures and drug interventions) were summarized at the time of and following an MI. Associations between calendar year and mortality in the first month after MI were identified using logistic regression with adjustment for confounders, including interventions received in the first month after MI. RESULTS: One thousand and eight HIV-positive individuals experiencing an MI over the period 1999-2014 were included. The absolute number of MIs decreased from 214 (1999 2002) to 154 (2011-2014). Whilst the CVD risk profile remained high over time, the HIV status improved. The use of CVD-related interventions after MI appeared to increase over time. The proportion of individuals who died in the first month after MI dropped from 26.6% in 1999-2002 to 8.4% in 2011-2014. Later calendar year was associated with decreased short-term mortality; this effect was attenuated after adjusting for CVD-related interventions received in the first month after MI [odds ratio changed from 0.88 (95% confidence interval 0.83, 0.93) to 0.97 (0.91, 1.02)]. CONCLUSION: Improvements in short-term survival after MI appear to be largely driven by improved medical management of CVD risk in HIV positive individuals after MI. Efforts are still needed to treat CVD risk factors and increase access to CVD-related interventions. PMID- 26950316 TI - Post-treatment effect of isoniazid preventive therapy on tuberculosis incidence in HIV-infected individuals on antiretroviral therapy. AB - BACKGROUND: In HIV-uninfected individuals, isoniazid preventive therapy (IPT) has been associated with long-term protection against tuberculosis (TB). For HIV infected/antiretroviral therapy (ART)-naive individuals, high TB rates have been observed following completion of IPT, consistent with a lack of 'cure' of infection. Recent trial data of IPT among HIV-infected individuals on ART in Khayelitsha, South Africa, have suggested that the effect of IPT persisted following completion of IPT. METHODS: Using mathematical modelling, we explored if this increased duration of protection may be due to an increased curative ability of IPT when given in combination with ART. The model was used to estimate the annual risk of infection and proportion of individuals whose latent infection was 'cured' by IPT, defined such that they must be reinfected to be at risk of disease. RESULTS: The estimated annual risk of infection was 4.0% (2.6-5.8) and the estimated proportion of individuals whose latent Mycobacterium tuberculosis infection was cured following IPT was 35.4% (2.4-76.4), higher than that previously estimated for HIV-infected/ART-naive individuals. Our results suggest that IPT can cure latent M. tuberculosis infection in approximately one-third of HIV-infected individuals on ART and therefore provide protection beyond the period of treatment. CONCLUSION: Among HIV-infected individuals on ART in low incidence settings, 12 months of IPT may provide additional long-term benefit. Among HIV-infected individuals on ART in high incidence settings, the durability of this protection will be limited because of continued risk of reinfection, and continuous preventive therapy together with improved infection control efforts will be required to provide long-term protection against TB. PMID- 26950317 TI - Tracking development assistance for HIV/AIDS: the international response to a global epidemic. AB - OBJECTIVE: To better understand the global response to HIV/AIDS, this study tracked development assistance for HIV/AIDS at a granular, program level. METHODS: We extracted data from the Institute for Health Metrics and Evaluation's Financing Global Health 2015 report that captured development assistance for HIV/AIDS from 1990 to 2015 for all major bilateral and multilateral aid agencies. To build on these data, we extracted additional budget data, and disaggregated development assistance for HIV/AIDS into nine program areas, including prevention, treatment, and health system support. RESULTS: Since 2000, $109.8 billion of development assistance has been provided for HIV/AIDS. Between 2000 and 2010, development assistance for HIV/AIDS increased at an annualized rate of 22.8%. Since 2010, the annualized rate of growth has dropped to 1.3%. Had development assistance for HIV/AIDS continued to climb after 2010 as it had in the previous decade, $44.8 billion more in development assistance would have been available for HIV/AIDS. Since 1990, treatment and prevention were the most funded HIV/AIDS program areas receiving $24.6 billion and $22.7 billion, respectively. Since 2010, these two program areas and HIV/AIDS health system strengthening have continued to grow, marginally, with majority support from the US government and the Global Fund. An average of $252.9 of HIV/AIDS development assistance per HIV/AIDS prevalent case was disbursed between 2011 and 2013. CONCLUSION: The scale-up of development assistance for HIV/AIDS from 2000 to 2010 was unprecedented. During this period, international donors prioritized HIV/AIDS treatment, prevention, and health system support. Since 2010, funding for HIV/AIDS has plateaued. PMID- 26950319 TI - Genome Sequence of Pseudomonas aeruginosa Strain DK1-NH57388A, a Stable Mucoid Cystic Fibrosis Isolate. AB - Pseudomonas aeruginosa is an important opportunistic pathogen associated with chronic pulmonary infections and mortality in cystic fibrosis (CF) patients. Here, we present the complete genome sequence of stable mucoid P. aeruginosa strain DK1-NH57388A, a CF isolate which has previously been used to establish chronic lung infections in an animal model. PMID- 26950318 TI - Draft Genome Sequence of Megasphaera sp. Strain DJF_B143, an Isolate from Pig Hindgut Unable to Produce Skatole. AB - The butyrate-producing Megasphaera spp. predominate in the pig hindgut and may play important roles in gut health. Moreover, one Megasphaera isolate has been reported to produce the boar taint compound, skatole. Here, we provide a 2.58-Mbp draft genome of a pig hindgut isolate, Megasphaera sp. DJF_B143, unable to produce skatole. PMID- 26950320 TI - Draft Genome Sequence of an Invasive Streptococcus agalactiae Isolate Lacking Pigmentation. AB - This report provides the whole-genome sequence of Streptococcus agalactiae isolate GB00037 isolated from a newborn in Calgary, Canada. This serotype V isolate is unique because it lacks pigment production previously shown to be critical for S. agalactiae virulence. PMID- 26950321 TI - Draft Genome Sequence of Pyrodictium occultum PL19T, a Marine Hyperthermophilic Species of Archaea That Grows Optimally at 105 degrees C. AB - We report here the draft genome sequence of Pyrodictium occultum PL19(T), a marine hyperthermophilic archaeon. The genome provides insights into molecular and cellular adaptation mechanisms to life in extreme environments and the evolution of early organisms on Earth. PMID- 26950323 TI - Genome Sequence of a Unique t2247-ST692-III Livestock-Associated Methicillin Resistant Staphylococcus aureus Strain from Chicken Carcass. AB - We report the draft genome sequence of a novel livestock-associated t2247-ST692 III methicillin-resistant Staphylococcus aureus strain designated K12S0375, which was isolated from a chicken carcass in South Korea. The K12S0375 strain contains uncommon genes, including antimicrobial resistance genes (tetL and tetS) and leukotoxin (lukED), and the genomic distance indicates a single lineage in a genome-based phylogenetic tree compared with 459 S. aureus genome sequences. This genome sequence will contribute to understanding epidemiological and genomic features of the ST692 lineage, including antimicrobial resistance and virulence genes. PMID- 26950322 TI - Draft Genome Sequence of a Salmonella enterica subsp. enterica Serovar Gallinarum bv. Gallinarum Isolate Associated with Fowl Typhoid Outbreaks in Brazil. AB - Salmonella enterica subsp. enterica serovar Gallinarum bv. Gallinarum strains are bird pathogens causing fowl typhoid (FT). Isolate BR_RS12 was obtained from a poultry flock with FT in 2014. The sequencing of this genome will enable to track the origin of the recent outbreaks in Brazil. PMID- 26950324 TI - Draft Genome Sequence of Pantoea ananatis GB1, a Plant-Growth-Promoting Hydrocarbonoclastic Root Endophyte, Isolated at a Diesel Fuel Phytoremediation Site Planted with Populus. AB - We report the 4.76-Mb draft genome of Pantoea ananatis GB1, a Gram-negative bacterium of the family Enterobacteriaceae, isolated from the roots of poplars planted for phytoremediation of a diesel-contaminated plume at the Ford Motor Company site in Genk, Belgium. Strain GB1 promotes plant growth in various hosts and metabolizes hydrocarbons. PMID- 26950325 TI - Draft Genome Sequence of Bacillus mycoides M2E15, a Strain Isolated from the Endosphere of Potato. AB - We present the draft genome sequence of Bacillus mycoides M2E15, a bacterium isolated from potato endosphere. Analysis of the 6.08-Mbp draft genome sequence identified 6,386 protein-encoding sequences, including potential plant growth promoting genes. Specifically, genes for proteins involved in phosphate utilization, iron acquisition, and bacteriocin production were identified. PMID- 26950326 TI - Draft Genome Sequences of Three Novel Clostridium Isolates from Northern Iraq. AB - Three Clostridium sp. strains were isolated from soil and sediment collected from the Kurdistan region of Iraq. All three isolates were found to harbor putative prophages, with a CRISPR-Cas system found in strains C105KSO13 and C105KSO14. PMID- 26950327 TI - Whole-Genome Sequence of Corynebacterium pseudotuberculosis Strain 226, Isolated from the Abscess of a Goat in California. AB - Corynebacterium pseudotuberculosis is the etiological agent of a caseous lymphadenitis disease. Herein, we present the first complete genome sequencing of C. pseudotuberculosis strain 226, isolated from an abscess of the sub-iliac lymph node of a goat from California (USA). The genome contains 2,138 coding sequences (CDSs), 12 rRNAs, 49 tRNAs, and 72 pseudogenes. PMID- 26950328 TI - Draft Genome Sequence of Olsenella scatoligenes SK9K4T, a Producer of 3 Methylindole (Skatole) and 4-Methylphenol (p-Cresol), Isolated from Pig Feces. AB - Olsenella scatoligenes SK9K4(T) is a strictly anaerobic bacterium isolated from pig feces that produces the malodorous compounds 3-methylindole (skatole) and 4 methylphenol (p-cresol). Here, we report the 2.47 Mbp draft genome sequence of SK9K4(T), exploring pathways for the synthesis of skatole and p-cresol from the amino acids tryptophan and tyrosine, respectively. PMID- 26950329 TI - Draft Genome Sequence of Trueperella bernardiae LCDC 89-0504T, Isolated from a Human Blood Culture. AB - We report here the draft genome sequence of Trueperella bernardiae LCDC 89 0504(T), an organism linked to mild to severe infections in humans and animals. The genome size is 2,028,874 bp, with a G+C content of 65.44%. Annotation of the genome revealed 5 rRNA sequences, 48 tRNA genes, and 1,762 coding sequences. PMID- 26950330 TI - Draft Genome Sequence of Lactobacillus plantarum SF2A35B. AB - The lactic acid bacterium Lactobacillus plantarum is intensively studied as a model probiotic species. Here, we present the draft genome sequence of the exopolysaccharide-producing strain SF2A35B. PMID- 26950331 TI - Genomic Sequence of Klebsiella pneumoniae IIEMP-3, a Vitamin B12-Producing Strain from Indonesian Tempeh. AB - Klebsiella pneumoniae strain IIEMP-3, isolated from Indonesian tempeh, is a vitamin B12-producing strain that exhibited a different genetic profile from pathogenic isolates. Here we report the draft genome sequence of strain IIEMP-3, which may provide insights on the nature of fermentation, nutrition, and immunological function of Indonesian tempeh. PMID- 26950332 TI - Investigation of Microbial Diversity in Geothermal Hot Springs in Unkeshwar, India, Based on 16S rRNA Amplicon Metagenome Sequencing. AB - Microbial diversity in geothermal waters of the Unkeshwar hot springs in Maharashtra, India, was studied using 16S rRNA amplicon metagenomic sequencing. Taxonomic analysis revealed the presence of Bacteroidetes, Proteobacteria, Cyanobacteria, Actinobacteria, Archeae, and OD1 phyla. Metabolic function prediction analysis indicated a battery of biological information systems indicating rich and novel microbial diversity, with potential biotechnological applications in this niche. PMID- 26950333 TI - Full Genome of Phialocephala scopiformis DAOMC 229536, a Fungal Endophyte of Spruce Producing the Potent Anti-Insectan Compound Rugulosin. AB - We present the full genome of Phialocephala scopiformis DAOMC 229536 (Helotiales, Ascomycota), a foliar endophyte of white spruce from eastern Quebec. DAOMC 229536 produces the anti-insectan compound rugulosin, which inhibits a devastating forestry pest, the spruce budworm. This genome will enable fungal genotyping and host-endophyte evolutionary genomics in inoculated trees. PMID- 26950334 TI - Modeling the Effect of Shared Care to Optimize Acne Referrals From Primary Care Clinicians to Dermatologists. AB - IMPORTANCE: Access to dermatologists remains a nationwide challenge. Optimizing referrals to a dermatologist may reduce patient wait times. OBJECTIVE: To model the effect of algorithm-based acne treatment by primary care clinicians on referral patterns and costs. DESIGN, SETTING, AND PARTICIPANTS: Overall, 253 referrals from primary care clinicians to dermatologists for acne from January 2014 through March 2015 were reviewed at Brigham and Women's Hospital. No-show rate, diagnostic concordance between primary care clinicians and dermatologists, treatment at the time of referral, and treatment by a dermatologist were ascertained, and we modeled 2 treatment algorithms-initiation of topical treatments by primary care clinicians (algorithm A) and initiation of topical treatments and oral antibiotics by primary care clinicians (algorithm B)-to identify the most effective referral patterns and costs. MAIN OUTCOMES AND MEASURES: The primary outcome was the elimination of unnecessary appointments with a dermatologist. Secondary outcomes included reduction in delay to treatment, health care cost savings, and decrease in no-show rate. RESULTS: Overall, 150 of 253 referred patients were seen and treated by a dermatologist; 127 patients (50.2%) were not on prescription acne treatment at the time of dermatology referral. Model A reduced initial referrals in 72 of 150 cases (48.0%), eliminated referrals in 60 of 150 cases (40%), and reduced average delay to-treatment by 28.6 days. This resulted in cost savings of $20.28 per patient, reduction of wait time by 5 days per patient, and decreased the no-show rate by 13%. Model B reduced initial referrals in 130 of 150 cases (86.7%), eliminated referrals in 108 of 150 cases (72%), and reduced average delay-to-treatment by 27.9 days. This resulted in cost savings of $35.68 per patient, shortened wait time by 9 days per patient, and decreased the no-show rate by 24%. CONCLUSIONS AND RELEVANCE: Algorithm-based treatment of acne by primary care clinicians may eliminate unnecessary appointments, reduce wait time for treatment, lower costs, and reduce patient no-shows. PMID- 26950335 TI - Corticosteroids as adjunctive therapy in the treatment of influenza. AB - BACKGROUND: Specific treatments for influenza are limited to neuraminidase inhibitors and adamantanes. Corticosteroids show evidence of benefit in sepsis and related conditions, most likely due to their anti-inflammatory and immunomodulatory properties. Although commonly prescribed for severe influenza, there is uncertainty over their potential benefit or harm. OBJECTIVES: To systematically assess the effectiveness and potential adverse effects of corticosteroids as adjunctive therapy in the treatment of influenza, taking into account differences in timing and doses of corticosteroids. SEARCH METHODS: We searched CENTRAL (2015, Issue 5), MEDLINE (1946 to June week 1, 2015), EMBASE (1974 to June 2015), CINAHL (1981 to June 2015), LILACS (1982 to June 2015), Web of Science (1985 to June 2015), abstracts from the last three years of major infectious disease and microbiology conferences, and references of included articles. SELECTION CRITERIA: We included randomised controlled trials (RCTs), quasi-RCTs and observational studies that compared corticosteroid treatment with no corticosteroid treatment for influenza or influenza-like illness. We did not restrict studies by language of publication, influenza subtypes, clinical setting or age of participants. We selected eligible studies in two stages: sequential examination of title and abstract, followed by full text. DATA COLLECTION AND ANALYSIS: Two pairs of review authors independently extracted data and assessed risk of bias. We pooled estimates of effect using random-effects meta-analysis models, where appropriate. We assessed heterogeneity using the I(2) statistic and assessed the quality of the evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework. MAIN RESULTS: We identified 19 eligible studies (3459 individuals), all observational; 13 studies (1917 individuals) were suitable for inclusion in the meta-analysis of mortality. Of these, 12 studied patients infected with 2009 influenza A H1N1 virus (H1N1pdm09). Risk of bias was greatest in the 'comparability domain' of the Newcastle-Ottawa scale, consistent with potential confounding by indication. Data specific to mortality were of very low quality. Reported doses of corticosteroids used were high and indications for their use were not well reported. On meta analysis, corticosteroid therapy was associated with increased mortality (odds ratio (OR) 3.06, 95% confidence interval (CI) 1.58 to 5.92). Pooled subgroup analysis of adjusted estimates of mortality from four studies found a similar association (OR 2.82, 95% CI 1.61 to 4.92). Three studies reported greater odds of hospital-acquired infection related to corticosteroid therapy; all were unadjusted estimates and we graded the data as very low quality. AUTHORS' CONCLUSIONS: We did not identify any completed RCTs of adjunctive corticosteroid therapy for treating influenza. The available evidence from observational studies is of very low quality with confounding by indication a major potential concern. Although we found that adjunctive corticosteroid therapy was associated with increased mortality, this result should be interpreted with caution. In the context of clinical trials of adjunctive corticosteroid therapy in sepsis and pneumonia that report improved outcomes, including decreased mortality, more high quality research is needed (both RCTs and observational studies). Currently, we do not have sufficient evidence in this review to determine the effectiveness of corticosteroids for patients with influenza. PMID- 26950336 TI - Isolation and Characterization of Two Lytic Bacteriophages, phiSt2 and phiGrn1; Phage Therapy Application for Biological Control of Vibrio alginolyticus in Aquaculture Live Feeds. AB - Bacterial infections are a serious problem in aquaculture since they can result in massive mortalities in farmed fish and invertebrates. Vibriosis is one of the most common diseases in marine aquaculture hatcheries and its causative agents are bacteria of the genus Vibrio mostly entering larval rearing water through live feeds, such as Artemia and rotifers. The pathogenic Vibrio alginolyticus strain V1, isolated during a vibriosis outbreak in cultured seabream, Sparus aurata, was used as host to isolate and characterize the two novel bacteriophages phiSt2 and phiGrn1 for phage therapy application. In vitro cell lysis experiments were performed against the bacterial host V. alginolyticus strain V1 but also against 12 presumptive Vibrio strains originating from live prey Artemia salina cultures indicating the strong lytic efficacy of the 2 phages. In vivo administration of the phage cocktail, phiSt2 and phiGrn1, at MOI = 100 directly on live prey A. salina cultures, led to a 93% decrease of presumptive Vibrio population after 4 h of treatment. Current study suggests that administration of phiSt2 and phiGrn1 to live preys could selectively reduce Vibrio load in fish hatcheries. Innovative and environmental friendly solutions against bacterial diseases are more than necessary and phage therapy is one of them. PMID- 26950338 TI - Whole Genome Sequence Analysis Using JSpecies Tool Establishes Clonal Relationships between Listeria monocytogenes Strains from Epidemiologically Unrelated Listeriosis Outbreaks. AB - In an effort to build a comprehensive genomic approach to food safety challenges, the FDA has implemented a whole genome sequencing effort, GenomeTrakr, which involves the sequencing and analysis of genomes of foodborne pathogens. As a part of this effort, we routinely sequence whole genomes of Listeria monocytogenes (Lm) isolates associated with human listeriosis outbreaks, as well as those isolated through other sources. To rapidly establish genetic relatedness of these genomes, we evaluated tetranucleotide frequency analysis via the JSpecies program to provide a cursory analysis of strain relatedness. The JSpecies tetranucleotide (tetra) analysis plots standardized (z-score) tetramer word frequencies of two strains against each other and uses linear regression analysis to determine similarity (r2). This tool was able to validate the close relationships between outbreak related strains from four different outbreaks. Included in this study was the analysis of Lm strains isolated during the recent caramel apple outbreak and stone fruit incident in 2014. We identified that many of the isolates from these two outbreaks shared a common 4b variant (4bV) serotype, also designated as IVb-v1, using a qPCR protocol developed in our laboratory. The 4bV serotype is characterized by the presence of a 6.3 Kb DNA segment normally found in serotype 1/2a, 3a, 1/2c and 3c strains but not in serotype 4b or 1/2b strains. We decided to compare these strains at a genomic level using the JSpecies Tetra tool. Specifically, we compared several 4bV and 4b isolates and identified a high level of similarity between the stone fruit and apple 4bV strains, but not the 4b strains co-identified in the caramel apple outbreak or other 4b or 4bV strains in our collection. This finding was further substantiated by a SNP-based analysis. Additionally, we were able to identify close relatedness between isolates from clinical cases from 1993-1994 and a single case from 2011 as well as links between two isolates from over 30 years ago. The identification of these potential links shows that JSpecies Tetra analysis can be a useful tool in rapidly assessing genetic relatedness of Lm isolates during outbreak investigations and for comparing historical isolates. Our analyses led to the identification of a highly related clonal group involved in two separate outbreaks, stone fruit and caramel apple, and suggests the possibility of a new genotype that may be better adapted for certain foods and/or environment. PMID- 26950339 TI - Prospective Memory in Older Adults: Where We Are Now and What Is Next. AB - The interplay of cognitive abilities that constitute the process of 'remembering to remember' is referred to as prospective memory. Prospective memory is an essential ability to meet everyday life challenges across the life span, constitutes a key element of autonomy and independence and is especially important in old age with increasing social and health-related prospective memory demands. The present paper first presents major findings from the current state of the art in research on age effects in prospective memory. In a second part, it presents four focus areas for future research outlining possible conceptual, methodological, and neuroscientific advancements. PMID- 26950337 TI - The A2DS2 Score as a Predictor of Pneumonia and In-Hospital Death after Acute Ischemic Stroke in Chinese Populations. AB - BACKGROUND AND PURPOSE: Stroke-associated pneumonia (SAP) is a common complication and an important cause of death during hospitalization. The A2DS2 (Age, Atrial fibrillation, Dysphagia, Sex, Stroke Severity) score was developed from the Berlin Stroke Registry and showed good predictive value for predicting SAP. We sought to identify the association between the A2DS2 score and SAP, and, furthermore, to identify whether the A2DS2 score was a predictor for in-hospital death after acute ischemic stroke in a Chinese population. METHODS: This was a retrospective study. 1239 acute ischemic stroke patients were classified to low A2DS2 group (0-4) and high A2DS2 score (5-10) group. Primary outcome was in hospital SAP. Logistic regression analyses were performed to identify the association between the A2DS2 score and SAP, and also the association between the A2DS2 score and in-hospital death. RESULTS: The overall incidence rates of SAP and in-hospital mortality after acute ischemic stroke were 7.3% and 2.4%, respectively. The incidence rate of SAP in low and high A2DS2 score groups was separately 3.3% and 24.7% (P<0.001). During hospitalization, 1.2% patients in low score group and 7.8% patients in high score group died (P<0.001). Multivariate regression demonstrated that patients in high score group had a higher risk of SAP (OR = 8.888, 95%CI: 5.552-14.229) and mortality (OR = 7.833, 95%CI: 3.580 17.137) than patients in low score group. CONCLUSIONS: The A2DS2 score was a strong predictor for SAP and in-hospital death of Chinese acute ischemic stroke patients. The A2DS2 score might be a useful tool for the identification of patients with a high risk of SAP and death during hospitalization. PMID- 26950341 TI - Adolescent Perceptions of Outgrowing Childhood Attention-Deficit Hyperactivity Disorder: Relationship to Symptoms and Quality of Life. AB - OBJECTIVE: Parental and self-perceptions about outgrowing attention-deficit hyperactivity disorder (ADHD) likely impact treatment decisions; however, little is known about these perceptions. The aim of this study was to assess adolescent and parent perceptions of outgrowing childhood ADHD and evaluate how these perceptions relate to ADHD symptoms and quality of life (QoL). METHOD: Cross sectional survey of adolescents (13-18 years) with a childhood diagnosis of ADHD and their parents. Participants were contacted by mail and completed questionnaires about: perceptions of outgrowing ADHD, current ADHD symptoms (the Conners' Scales), and QoL (PedsQL). ANCOVAs were conducted to assess the relationship between the perception of outgrowing ADHD and: (1) current ADHD symptoms and (2) QoL, controlling for co-morbidities and medication use. RESULTS: 115 adolescent-parent dyads were enrolled. Mean age was 15.5 +/- 1.7 years, 73% were male, and 63% were taking ADHD medication. Only 16% of adolescents and 9% of parents reported outgrowing ADHD, with little correlation between parent and adolescent responses (kappa 0.3). Adolescents who reported Yes or Don't Know to outgrowing ADHD, compared to those who reported No, had lower scores on the inattention (IA) and hyperactivity (H) scales of both parent report and adolescent self-report Conners' scales and higher scores on the adolescent self report PedsQL. CONCLUSION: A majority of adolescents do not endorse outgrowing their ADHD diagnosis, but those that do demonstrate fewer ADHD symptoms and better QoL than those who don't, suggesting that adolescents have insight about their level of impairment and should have a valued role in making treatment decisions. PMID- 26950340 TI - Toilet School for Children with Failure to Toilet Train: Comparing a Group Therapy Model with Individual Treatment. AB - OBJECTIVE: This study compared the toileting outcomes of children participating in Toilet School group therapy with children in individual treatment. METHOD: All children in this study failed conventional toilet training and were 4 to 6 year, 11 month old. Cases were 63 children who attended a 6-week Toilet School group therapy with their parents. Controls were 62 children who were seen in individual treatment in the same tertiary care program and were matched to cases based on treatment dates. We analyzed the number of toileting benchmarks met for cases and controls. We used a stepwise linear regression model to investigate the contribution of child and family factors in predicting the number of toileting benchmarks met. RESULTS: Compared to controls, cases achieved significantly more toileting benchmarks (p < .001) at the end of Toilet School, were more likely to have bowel movements in the toilet (p = .001), and required fewer subsequent visits until completion of toilet training (p = .013). Similarly, at the seventh provider encounter for both controls and cases, the cases continued to achieve significantly more toileting benchmarks (p < .001) and were more likely to have bowel movements in the toilet (p = .002) compared to controls. After adjusting for age, gender, neighborhood poverty level, and number of total clinical visits for fecal incontinence, treatment grouping was the only independent variable that predicted toileting progress. CONCLUSION: For children with failure to toilet train, group treatment involving both the child and the family results in greater improvement in toileting outcomes than individual treatment. PMID- 26950342 TI - Nonhomologous Chromosome Pairing in Aegilops-Secale Hybrids. AB - Intergeneric hybrids and amphidiploid hybrids from crosses of Aegilopstauschii and Secale cereale were produced using young embryo rescue. The hybrids showed complete sets of both parental chromosomes. The dihaploid plants showed an average meiotic pairing configuration of 10.84 I + 1.57 II + 0.01 III. Genomic in situ staining revealed 3 types of bivalent associations, i.e. D-D, R-R and D-R at frequencies of 8.6, 8.2 and 83.3%, respectively. Trivalents consisted of D-R-D or R-D-R associations. These results suggested that both intra- and intergenomic chromosome homology were contributed to chromosome pairing. Derived amphidiploids with 2n = 28 paired at metaphase I of meiosis as 4.51 I + 11.70 II + 0.03 III. Chromosome pairing of amphidiploids appeared more or less regular, i.e. bivalent like with some trivalent configurations. PMID- 26950344 TI - Effects of Angle Variations in Suspension Push-up Exercise. AB - Gulmez, I. Effects of angle variations in suspension push-up exercise. J Strength Cond Res 31(4): 1017-1023, 2017-This study aimed to determine and compare the amount of loads on the TRX Suspension Trainer (TRX) straps and ground reaction forces at 4 different angles during TRX push-ups. Twenty-eight male (mean age, 24.1 +/- 2.9 years; height, 179.4 +/- 8.0 m; weight, 78.8 +/- 9.8 kg) physical education and sports university students participated in this study. The subjects were tested at TRX angles (0, 15, 30, 45 degrees ) during the TRX push-ups. Force data were recorded by a force platform and load cells integrated into the TRX straps. The results show that as the TRX angle was reduced, the load applied to the TRX straps increased and simultaneously the load measured by the force platform decreased. This was true for both the elbow joint changing from flexion to extension and vice versa. When the TRX angle was set at 0 degrees and subjects' elbows were at extension during TRX push-up, 50.4% of the subjects' body weight, and when the elbows were at flexion, 75.3% of the body weight was registered by the sensors on the TRX straps. The results of this study can be used in the calculation of the training load and volume (resistance training programming) during TRX push-up exercises at varying angles. PMID- 26950343 TI - Physical Characteristics Underpinning Repetitive Lunging in Fencing. AB - Turner, AN, Marshall, G, Phillips, J, Noto, A, Buttigieg, C, Chavda, S, Downing, W, Atlay, N, Dimitriou, L, and Kilduff, L. Physical characteristics underpinning repetitive lunging in fencing. J Strength Cond Res 30(11): 3134-3139, 2016-Given the repetitive demand to execute lunging and changes in direction within fencing, the ability to sustain these at maximal capacity is fundamental to performance. The aim of this study was threefold. First, to provide normative values for this variable referred to as repeat lunge ability (RLA) and second to identify the physical characteristics that underpin it. Third, was to establish if a cause and effect relationship existed by training the associated characteristics. Assessment of lower-body power, reactive strength, speed, change of direction speed (CODS), and a sport-specific RLA were conducted on senior and junior elite male fencers (n = 36). Fencers were on average (+/-SD) 18.9 +/- 3.2 years of age, 174.35 +/- 10.42 cm tall, 70.67 +/- 7.35 kg in mass, and 8.5 +/- 4.2 years fencing experience. The RLA test had average work times of 16.03 +/- 1.40 seconds and demonstrated "large" to "very large" associations with all tested variables, but in particular CODS (r = 0.70) and standing broad jump (SBJ; r = -0.68). Through linear regression analysis, these also provided a 2-predictor model accounting for 61% of the common variance associated with RLA. A cause and effect relationship with SBJ and CODS was confirmed by the training group, where RLA performance in these fencers improved from 15.80 +/- 1.07 to 14.90 +/- 0.86 seconds, with the magnitude of change reported as "moderate" (effect size (ES) = 0.93). Concurrent improvements were also noted in both SBJ (216.86 +/- 17.15 vs. 221.71 +/- 17.59 cm) and CODS (4.44 +/- 0.29 vs. 4.31 +/- 0.09 seconds) and while differences were only significant in SBJ, magnitudes of change were classed as "small" (ES = 0.28) and "moderate" (ES = 0.61), respectively. In conclusion, to improve RLA strength and conditioning coaches should focus on improving lower body power and reactive strength, noting that jump training and plyometrics designed to enhance horizontal propulsion may be most effective, and translate to improvement in CODS also. PMID- 26950345 TI - Evaluation of Performance Improvements After Either Resistance Training or Sprint Interval-Based Concurrent Training. AB - Laird IV, RH, Elmer, DJ, Barberio, MD, Salom, LP, Lee, KA, and Pascoe, DD. Evaluation of performance improvements after either resistance training or sprint interval-based concurrent training. J Strength Cond Res 30(11): 3057-3065, 2016 The purpose of this investigation was to examine the effects of concurrent sprint interval and resistance training (CST) vs. resistance training (RT) on measures of strength, power, and aerobic fitness in recreationally active women. Twenty eight women (20.3 +/- 1.7 years; 63.0 +/- 9.1; 51.1 +/- 7.1 1 repetition maximum (1-RM) back squat (kg); V[Combining Dot Above]O2max: 35.4 +/- 4.1 ml.kg.min) were recruited to complete an 11-week training program. Participants were matched-pair assigned to CST or RT cohorts after preliminary testing, which consisted of 1-RM back squats, maximal isometric squats, anaerobic power evaluations, and maximal oxygen consumption. All subjects trained 3 days per week with sprint-interval training occurring at least 4 hours after RT in the CST cohort. Both CST and RT resulted in significant improvements (p <= 0.05) in the 1-RM back squat (37.5 +/- 7.8; 40.0 +/- 9.6 kg), maximal isometric force (55.7 +/- 51.3; 53.7 +/- 36.7 kg), average peak anaerobic power testing (7.4 +/- 6.2; 7.6 +/- 6.4%), and zero incline treadmill velocity, resulting in maximal oxygen consumption (1.8 +/- 0.6; 0.8 +/- 0.6 km.h). Only zero-incline treadmill velocity demonstrated a group-by time interaction with a greater improvement after CST (p < 0.01). Rate of force development was not altered in either group. Results provide no evidence of interference to the adaptive process by CST. Coaches desiring improvements in strength, power, and endurance may want to evaluate how spring and high-intensity interval training might supplement programs already in place. PMID- 26950346 TI - Hydration and Fluid Replacement Knowledge, Attitudes, Barriers, and Behaviors of NCAA Division 1 American Football Players. AB - Judge, LW, Kumley, RF, Bellar, DM, Pike, KL, Pierson, EE, Weidner, T, Pearson, D, and Friesen, CA. Hydration and fluid replacement knowledge, attitudes, barriers, and behaviors of NCAA Division 1 American football players. J Strength Cond Res 30(11): 2972-2978, 2016-Hydration is an important part of athletic performance, and understanding athletes' hydration knowledge, attitudes, barriers, and behaviors is critical for sport practitioners. The aim of this study was to assess National Collegiate Athletic Association (NCAA) Division 1 (D1) American football players, with regard to hydration and fluid intake before, during, and after exercise, and to apply this assessment to their overall hydration practice. The sample consisted of 100 student-athletes from 2 different NCAA D1 universities, who participated in voluntary summer football conditioning. Participants completed a survey to identify the fluid and hydration knowledge, attitudes and behaviors, demographic data, primary football position, previous nutrition education, and barriers to adequate fluid consumption. The average Hydration Knowledge Score (HKS) for the participants in the present study was 11.8 +/- 1.9 (69.4% correct), with scores ranging from 42 to 100% correct. Four key misunderstandings regarding hydration, specifically related to intervals of hydration habits among the study subjects, were revealed. Only 24% of the players reported drinking enough fluids before, during, immediately after, and 2 hours after practice. Generalized linear model analysis predicted the outcome variable HKS (chi = 28.001, p = 0.045), with nutrition education (Wald chi = 8.250, p = 0.041) and position on the football team (chi = 9.361, p = 0.025) being significant predictors. "Backs" (e.g., quarterbacks, running backs, and defensive backs) demonstrated significantly higher hydration knowledge than "Linemen" (p = 0.014). Findings indicated that if changes are not made to increase hydration awareness levels among football teams, serious health consequences, including potential fatalities, could occur on the field, especially among heavier linemen. PMID- 26950347 TI - Comparison of Physiological Variables Between the Elliptical Bicycle and Run Training in Experienced Runners. AB - Klein, IE, White, JB, and Rana, SR. Comparison of physiological variables between the elliptical bicycle and run training in experienced runners. J Strength Cond Res 30(11): 2998-3006, 2016-A novel outdoor elliptical bicycle (EBIKE) has been designed to elicit running-similar physiological adaptations while reducing the impact forces that commonly lead to injury. Various cross-training methods have been used to reduce injury risk, restore or maintain fitness, and prevent detraining. The purpose of this study was to compare 4 weeks of EBIKE-only training to run-only training on maximal oxygen consumption, ventilatory threshold, respiratory compensation point, running economy, and 5,000 m time trial times. Twelve experienced runners (age, 22.33 +/- 3.33 years; running experience, 9.25 +/- 4.53 years) completed 4 weeks of randomly assigned EBIKE or run training. Physiological and performance testing procedures were repeated, and subjects then performed a second matched 4-week training period in a crossover design. Ventilatory threshold was significantly greater after EBIKE (p <= 0.05; 41.60 +/- 6.15 ml.kg.min) and run training (p <= 0.05; 42.33 +/- 6.96 ml.kg.min) compared with the initial time point (40.17 +/- 6.47 ml.kg.min). There were no significant group differences (p > 0.05) for these variables at any time point. In conclusion, EBIKE-only training yielded similar physiological and performance maintenance or improvements compared with run-only training. These results suggest that EBIKE training can be an effective cross-training method to maintain and improve certain physiological and performance variables in experienced runners over a 4-week period. PMID- 26950348 TI - Influence of Knee-to-Feet Jump Training on Vertical Jump and Hang Clean Performance. AB - Stark, L, Pickett, K, Bird, M, and King, AC. Influence of knee-to-feet jump training on vertical jump and hang clean performance. J Strength Cond Res 30(11): 3084-3089, 2016-From a motor learning perspective, the practice/training environment can result in positive, negative, or neutral transfer to the testing conditions. The purpose of this study was to examine the training effect of a novel movement (knee-to-feet [K2F] jumps) and whether a 6-week training program induced a positive transfer effect to other power-related movements (vertical jump and hang clean [HC]). Twenty-six intercollegiate athletes from power emphasized sports were paired and counter-balanced into a control (i.e., maintained their respective sport-specific lifting regimen) or an experimental group (i.e., completed a 6-week progressive training program of K2F jumps in addition to respective lifting regimen). A pre- and posttest design was used to investigate the effect of training on K2F jump height and transfer effect to vertical jump height (VJH) and 2-repetition maximum (RM) HC performance. A significant increase in K2F jump height was found for the experimental group. Vertical jump height significantly increased from pre- to posttest but no group or interaction (group * time) effect was found, and there were nonsignificant differences for HC. Posttest data showed significant correlations between all pairs of the selected exercises with the highest correlation between K2F jump height and VJ H (R = 0.40) followed by VJH and 2RM HC (R = 0.38) and 2RM HC and K2F jump height (R = 0.23). The results suggest that K2F jump training induced the desired learning effect but was specific to the movement in that no effect of transfer occurred to the other power-related movements. This finding is value for strength and condition professionals who design training programs to enhance athletic performance. PMID- 26950349 TI - The Kansas Squat Test Modality Comparison: Free Weights vs. Smith Machine. AB - Luebbers, PE and Fry, AC. The Kansas squat test modality comparison: free weights vs. smith machine. J Strength Cond Res 30(8): 2186-2193, 2016-Standardized methods of testing power are instrumental in planning and implementing training regimens for many athletes, and also in tracking training adaptations. Previous work has demonstrated that the Kansas squat test (KST) is a valid test for measuring indices of mean and peak power when compared with the Wingate anaerobic cycle test. Although the KST was designed for use with a Smith machine (SM), many power athletes use free weights for training. The purpose of this study was to determine the feasibility of using free weights (FW) for the KST by comparing it with the SM modality. Twenty-three track and field athletes participated (mean +/ SD; weight, 69.7 +/- 10.6 kg; age, 20.1 +/- 1.1 years) in this study. Each completed familiarization sessions with the FW and SM modalities before data collection. A 1-repetition maximum squat was also determined for both the FW and SM. Correlation coefficients indicated significant relationships between the FW KST and SM KST on measures of peak test power (r = 0.955; p < 0.01) and mean test power (r = 0.959; p < 0.01) but not for relative fatigue (r = -0.198; p > 0.05) or posttest lactate (r = 0.109; p > 0.05). Paired samples t-tests indicated that the FW KST resulted in significantly higher measures of peak power and mean power (p <= 0.01), although no differences were observed for relative fatigue or lactate (p > 0.05). These data indicate that the FW KST is a valid and feasible alternative to the SM KST in measuring peak and mean power. PMID- 26950350 TI - Regional Surface Electromyography of the Vastus Lateralis During Strength and Power Exercises. AB - Neuromuscular activation during and chronic adaptation from exercise are innately linked and both can vary along a muscle's length. During high-force and high speed exercise, intramuscular hypertrophy follows set patterns that provide the greatest biomechanical advantages. However, it is unknown if muscle activity as recorded by surface electromyography (sEMG) will follow these patterns. The purpose of the present study was to compare vastus lateralis intramuscular sEMG during the heavy squat (HS) and unloaded jump squat (JS) exercises. Ten subjects performed HS with 80% of maximum load and unloaded JS to parallel-depth, while intramuscular peak sEMG and mean sEMG were measured at 33% (proximal), 50% (middle), and 67% (distal) thigh length. Muscle activity was compared between regions and exercises using a 3 * 2 repeated measures ANOVA with Bonferoni post hoc corrections. Peak sEMG was greater proximally in JS than HS (p = 0.033), but similar in the middle and distal regions (p = 0.521, 0.594, respectively), whereas mean sEMG was similar between all regions (p = 0.150-0.979). In addition, a main effect was found in which peak and mean sEMG were greater proximally than the middle and distal regions (p = 0.001, 0.006). Muscle activity measured using sEMG displayed dissimilar patterns to previously observed regional hypertrophy. Specifically, although previous research found greater proximal hypertrophy in JS than HS, in the present study peak sEMG was greater in HS than JS. Furthermore, distally where HS elicited greater hypertrophy than JS, no differences in sEMG were present. Thus, regional sEMG appears not to be a viable tool for predicting differences in regional hypertrophy, most likely due to technological constraints and intramuscular differences in muscle structure. PMID- 26950352 TI - Males and Females Pace Differently in High School Cross-Country Races. AB - Deaner, RO and Lowen, A. Males and females pace differently in high school cross country races. J Strength Cond Res 30(11): 2991-2997, 2016-Previous studies have demonstrated that men are more likely than women to slow in the marathon, but it is unknown whether the sex difference in pacing occurs for other race distances. This study addressed this question by analyzing the 5-km Virginia State Championship high school cross-country race for the years 2010, 2012, 2013, and 2014, which encompassed 3,948 performances. The pacing measure was percentage change in speed from mile 1 to mile 2. Across all runners, women (9.1%) slowed significantly (p = 0.002) more than men (8.7%), although the magnitude of the difference was trivial (effect size [ES] = -0.10). However, when women and men in physiologically equated finishing time groups (e.g., <17:00 for men; <19:03 for women) were compared, men slowed significantly more (p < 0.001) in all 4 groups, and the differences were nontrivial (ESs range 0.27-0.92). Because glycogen depletion is irrelevant for 5 km performances, these results challenge the hypothesis that the sex difference in pacing is due to males' greater susceptibility to glycogen depletion. These results instead support the hypothesis that the sex difference in pacing partly reflects a sex difference in some aspect of decision making, such as overconfidence, risk perception, or willingness to tolerate discomfort. Coaches and athletes are advised to consider individual variation in these characteristics when planning training and racing. PMID- 26950351 TI - Do Lower-Body Dimensions and Body Composition Explain Vertical Jump Ability? AB - Caia, J, Weiss, LW, Chiu, LZF, Schilling, BK, Paquette, MR, and Relyea, GE. Do lower-body dimensions and body composition explain vertical jump ability? J Strength Cond Res 30(11): 3073-3083, 2016-Vertical jump (VJ) capability is integral to the level of success attained by individuals participating in numerous sport and physical activities. Knowledge of factors related to jump performance may help with talent identification and/or optimizing training prescription. Although myriad variables are likely related to VJ, this study focused on determining if various lower-body dimensions and/or body composition would explain some of the variability in performance. Selected anthropometric dimensions were obtained from 50 university students (25 men and 25 women) on 2 occasions separated by 48 or 72 hours. Estimated body fat percentage (BF%), height, body weight, hip width, pelvic width, bilateral quadriceps angle (Q angle), and bilateral longitudinal dimensions of the feet, leg, thigh, and lower limb were obtained. Additionally, participants completed countermovement VJs. Analysis showed BF% to have the highest correlation with countermovement VJ displacement (r = -0.76, p < 0.001). When examining lower-body dimensions, right side Q-angle displayed the strongest association with countermovement VJ displacement (r = -0.58, p < 0.001). Regression analysis revealed that 2 different pairs of variables accounted for the greatest variation (66%) in VJ: (a) BF% and sex and (b) BF% and body weight. Regression models involving BF% and lower-body dimensions explained up to 61% of the variance observed in VJ. Although the variance explained by BF% may be increased by using several lower body dimensions, either sex identification or body weight explains comparatively more. Therefore, these data suggest that the lower-body dimensions measured herein have limited utility in explaining VJ performance. PMID- 26950353 TI - High-Intensity Training Improves Exercise Performance in Elite Women Volleyball Players During a Competitive Season. AB - Purkhus, E, Krustrup, P, and Mohr, M. High-intensity training improves exercise performance in elite women volleyball players during a competitive season. J Strength Cond Res 30(11): 3066-3072, 2016-Elite women volleyball players (n = 25; mean +/- SD: age, 19 +/- 5 years; height, 171 +/- 7 cm; weight, 63 +/- 10 kg) volunteered to participate in the study. They were randomized into a high intensity training (HIT; n = 13) group and a control (CON; n = 12) group. In addition to the normal team training and games, HIT performed 6-10 * 30-seconds all-out running intervals separated by 3-minute recovery periods 3 times per week during a 4-week in-season period whereas CON only completed the team training sessions and games. Preintervention and postintervention, all players completed the arrowhead agility test (AAT), a repeated sprint test (RST; 5 * 30 meters separated by 25 seconds of recovery), and the Yo-Yo Intermittent Recovery level 2 test (Yo-Yo IR2) followed by a-10 minute rest period and the Yo-Yo IR1 test. Mean running distance during HIT in week 1 was 152 +/- 4 m and increased (p <= 0.05) by 4.6% (159 +/- 3 m) in week 4. The AAT performance improved (p <= 0.05) by 2.3% (18.87 +/- 0.97-18.44 +/- 1.06 seconds) and RST by 4.3% postintervention in the HIT group only. Baseline RST fatigue index was 7.0 +/- 2.9 and 6.2 +/- 5.0% in HIT and CON, respectively, but was lowered (p <= 0.05) to 2.7 +/- 3.0% posttraining in HIT and remained unaltered in CON (5.5 +/- 5.0%). In HIT, Yo-Yo IR2 and Yo-Yo IR1 performance improved by 12.6 and 18.3% postintervention, respectively, with greater (p <= 0.05) Yo-yo IR1 change scores than in CON. In conclusion, additional high-intensity in-season training performed as interval running improved agility, repeated sprint ability, and high-intensity intermittent exercise performance in elite women volleyball players. PMID- 26950355 TI - Self-Reported Physical Tasks and Exercise Training in Special Weapons and Tactics (SWAT) Teams. AB - Davis, MR, Easter, RL, Carlock, JM, Weiss, LW, Longo, EA, Smith, LM, Dawes, JJ, and Schilling, BK. Self-reported physical tasks and exercise training in Special Weapons and Tactics (SWAT) teams. J Strength Cond Res 30(11): 3242-3248, 2016 Little research has been done examining the most physically demanding tasks a SWAT officer may perform in the line of duty. Our objective was to analyze the rankings of tasks by SWAT officers based on frequency, difficulty, and importance and assess if training is addressing traits needed for successful task completion. A survey was designed using Qualtrics (Qualtrics Labs Inc). The survey had a demographics section, performance section, and training section. Officers were contacted by phone or e-mail and asked about interest in participating. Officers who agreed were sent the survey. Our results found a strong correlation between frequency of task and importance (r = 0.69, p = 0.001), and a moderate correlation was found between task difficulty and importance (r = 0.37, p = 0.005). Task rankings were averaged across the 3 domains to assess "overall" importance, and the top 3 tasks were assessed for necessary traits for successful performance. Power and strength were determined to be the most important traits for successful performance. Officers ranked the top 2 focuses of their training program in the training section as stamina/muscular endurance and cardiovascular/respiratory endurance. Training programs for SWAT officers should be developed to improve performance of the tasks with the highest "overall" importance. Therefore, a training program should emphasize strength and power improvements while not neglecting other measures of fitness. PMID- 26950357 TI - Test-Retest Reliability of a Novel Isokinetic Squat Device With Strength-Trained Athletes. AB - Bridgeman, LA, McGuigan, MR, Gill, ND, and Dulson, DK. Test-retest reliability of a novel isokinetic squat device with strength-trained athletes. J Strength Cond Res 30(11): 3261-3265, 2016-The aim of this study was to investigate the test retest reliability of a novel multijoint isokinetic squat device. The subjects in this study were 10 strength-trained athletes. Each subject completed 3 maximal testing sessions to assess peak concentric and eccentric force (N) over a 3-week period using the Exerbotics squat device. Mean differences between eccentric and concentric force across the trials were calculated. Intraclass correlation coefficients (ICCs) and coefficients of variation (CVs) for the variables of interest were calculated using an excel reliability spreadsheet. Between trials 1 and 2 an 11.0 and 2.3% increase in mean concentric and eccentric forces, respectively, was reported. Between trials 2 and 3 a 1.35% increase in the mean concentric force production and a 1.4% increase in eccentric force production was reported. The mean concentric peak force CV and ICC across the 3 trials was 10% (7.6-15.4) and 0.95 (0.87-0.98) respectively. However, the mean eccentric peak force CV and ICC across the trials was 7.2% (5.5-11.1) and 0.90 (0.76-0.97), respectively. Based on these findings it is suggested that the Exerbotics squat device shows good test-retest reliability. Therefore practitioners and investigators may consider its use to monitor changes in concentric and eccentric peak force. PMID- 26950356 TI - Test-Retest Reliability of Physiological and Performance Responses to 120 Minutes of Simulated Soccer Match Play. AB - Harper, LD, Hunter, R, Parker, P, Goodall, S, Thomas, K, Howatson, G, West, DJ, Stevenson, E, and Russell, M. Test-retest reliability of physiological and performance responses to 120 minutes of simulated soccer match play. J Strength Cond Res 30(11): 3178-3186, 2016-This study investigated the test-retest reliability of physiological and performance responses to 120 minutes (90 minutes plus 30 minutes extra-time [ET]) of the soccer match simulation (SMS). Ten university-standard soccer players completed the SMS on 2 occasions under standardized conditions. Capillary and venous blood was taken pre-exercise, at half-time, and at 90 and 120 minutes, with further capillary samples taken every 15 minutes throughout the exercise. Core temperature (Tcore), physical (20- and 15-m sprint speeds and countermovement jump height), and technical (soccer dribbling) performance was also assessed during each trial. All variables except blood lactate demonstrated no systematic bias between trials (p > 0.05). During the last 15 minutes of ET, test-rest reliability (coefficient of variation %, Pearson's r, respectively) was moderate to strong for 20-m sprint speed (3.5%, 0.71), countermovement jump height (4.9%, 0.90), dribble speed (2.8%, 0.90), and blood glucose (7.1%, 0.93), and very strong for Tcore (1.2%, 0.99). Moderate reliability was demonstrated for 15-m sprint speed (4.6%, 0.36), dribble precision (11.5%, 0.30), plasma insulin (10.3%, 0.96), creatine kinase ([CK] 28.1%, 0.38), interleukin-6 (24%, 0.99), nonesterified fatty acids ([NEFA] 13.2%, 0.73), glycerol (12.5%, 0.86), and blood lactate (18.6%, 0.79). In the last 15 minutes of ET, concentrations of blood glucose and lactate and sprint and jump performances were reduced, whereas Tcore, NEFA, glycerol, and CK concentrations were elevated (p <= 0.05). The SMS is a reliable protocol for measuring responses across the full 120 minutes of soccer-specific exercise. Deleterious effects on performance and physiological responses occur during ET. PMID- 26950358 TI - Excess Postexercise Oxygen Consumption After High-Intensity and Sprint Interval Exercise, and Continuous Steady-State Exercise. AB - Tucker, WJ, Angadi, SS, and Gaesser, GA. Excess postexercise oxygen consumption after high-intensity and sprint interval exercise, and continuous steady-state exercise. J Strength Cond Res 30(11): 3090-3097, 2016-Higher excess postexercise oxygen consumption (EPOC) after high-intensity interval exercise (HIE) and sprint interval exercise (SIE) may contribute to greater fat loss sometimes reported after interval training compared with continuous steady-state exercise (SSE) training. We compared EPOC after HIE, SIE, and SSE. Ten recreationally active men (age 24 +/- 4 years) participated in this randomized crossover study. On separate days, subjects completed a resting control trial and 3 exercise conditions on a cycle ergometer: HIE (four 4-minute intervals at 95% peak heart rate (HRpeak), separated by 3 minutes of active recovery), SIE (six 30-second Wingate sprints, separated by 4 minutes of active recovery), and SSE (30 minutes at 80% of HRpeak). Oxygen consumption (V[Combining Dot Above]O2) was measured continuously during and for 3 hours after exercise. For all conditions, V[Combining Dot Above]O2 was higher than resting control only during the first hour postexercise. Although 3-hour EPOC and total net exercise energy expenditure (EE) after exercise were higher (p = 0.01) for SIE (22.0 +/- 9.3 L; 110 +/- 47 kcal) compared with SSE (12.8 +/- 8.5 L; 64 +/- 43 kcal), total (exercise + postexercise) net O2 consumed and net EE were greater (p = 0.03) for SSE (69.5 +/ 18.4 L; 348 +/- 92 kcal) than those for SIE (54.2 +/- 12.0 L; 271 +/- 60 kcal). Corresponding values for HIE were not significantly different from SSE or SIE. Excess postexercise oxygen consumption after SIE and HIE is unlikely to account for the greater fat loss per unit EE associated with SIE and HIE training reported in the literature. PMID- 26950359 TI - Cell therapy in chronic liver disease. AB - PURPOSE OF REVIEW: To date, the only curative treatment for end-stage liver disease is liver transplantation, which is limited by the shortage of available organs. Cell therapy, in the form of cell transplantation or cell-based extracorporeal support devices, may in the future offer an alternative to transplantation, or at least provide liver function support as a bridging therapy until surgery may be performed. The purpose of this review is to highlight the most recent advances made in the field of cell therapy and regenerative medicine for the treatment of chronic liver disease. RECENT FINDINGS: After hepatocyte transplantation, long-term engraftment in the liver and spleen may be achieved, which can be stimulated through preconditioning, multiple infusions, and inflammatory response blockade. Mesenchymal stem cells are promising candidates for cell transplantation, as they have been shown to reduce liver fibrosis and support endogenous regeneration. Adipose tissue-derived stem cells are also being tested in this setting, because of their ready availability. Bioartificial liver devices are being built that allow for effective preservation of hepatocytes, and one such device has recently demonstrated survival benefit in a porcine model of liver failure. SUMMARY: Cell transplantation of primary hepatocytes or stem cell derived hepatocyte-like cells for the treatment of chronic liver disease holds promise. Bioartificial liver systems may in the future be able to bridge acute-on chronic liver failure patients to liver transplantation. PMID- 26950360 TI - Inhibition of fatty acid oxidation as a therapy for MYC-overexpressing triple negative breast cancer. AB - Expression of the oncogenic transcription factor MYC is disproportionately elevated in triple-negative breast cancer (TNBC), as compared to estrogen receptor-, progesterone receptor- or human epidermal growth factor 2 receptor positive (RP) breast cancer. We and others have shown that MYC alters metabolism during tumorigenesis. However, the role of MYC in TNBC metabolism remains mostly unexplored. We hypothesized that MYC-dependent metabolic dysregulation is essential for the growth of MYC-overexpressing TNBC cells and may identify new therapeutic targets for this clinically challenging subset of breast cancer. Using a targeted metabolomics approach, we identified fatty acid oxidation (FAO) intermediates as being dramatically upregulated in a MYC-driven model of TNBC. We also identified a lipid metabolism gene signature in patients with TNBC that were identified from The Cancer Genome Atlas database and from multiple other clinical data sets, implicating FAO as a dysregulated pathway that is critical for TNBC cell metabolism. We found that pharmacologic inhibition of FAO catastrophically decreased energy metabolism in MYC-overexpressing TNBC cells and blocked tumor growth in a MYC-driven transgenic TNBC model and in a MYC-overexpressing TNBC patient-derived xenograft. These findings demonstrate that MYC-overexpressing TNBC shows an increased bioenergetic reliance on FAO and identify the inhibition of FAO as a potential therapeutic strategy for this subset of breast cancer. PMID- 26950363 TI - Let's not be indifferent about neutrality: Neutral ratings in the International Affective Picture System (IAPS) mask mixed affective responses. AB - The International Affective Picture System (IAPS) is a picture set used by researchers to select pictures that have been prerated on valence. Researchers rely on the ratings in the IAPS to accurately reflect the degree to which the pictures elicit affective responses. Here we show that this may not always be a safe assumption. More specifically, the scale used to measure valence in the IAPS ranges from positive to negative, implying that positive and negative feelings are end-points of the same construct. This makes interpretation of midpoint, or neutral ratings, especially problematic because it is impossible to tell whether these ratings are the result of neutral, or of mixed feelings. In other words, neutral ratings may not be as neutral as researchers assume them to be. Investigating this, in this work we show that pictures that seem neutral according to the valence ratings in the IAPS indeed vary in levels of ambivalence they elicit. Furthermore, the experience of ambivalence in response to these pictures is predictive of the arousal that people report feeling when viewing these pictures. These findings are of particular importance because neutrality differs from ambivalence in its specific psychological consequences, and by relying on seemingly neutral valance ratings, researchers may unwillingly introduce these consequences into their research design, undermining their level of experimental control. (PsycINFO Database Record PMID- 26950361 TI - A branched-chain amino acid metabolite drives vascular fatty acid transport and causes insulin resistance. AB - Epidemiological and experimental data implicate branched-chain amino acids (BCAAs) in the development of insulin resistance, but the mechanisms that underlie this link remain unclear. Insulin resistance in skeletal muscle stems from the excess accumulation of lipid species, a process that requires blood borne lipids to initially traverse the blood vessel wall. How this trans endothelial transport occurs and how it is regulated are not well understood. Here we leveraged PPARGC1a (also known as PGC-1alpha; encoded by Ppargc1a), a transcriptional coactivator that regulates broad programs of fatty acid consumption, to identify 3-hydroxyisobutyrate (3-HIB), a catabolic intermediate of the BCAA valine, as a new paracrine regulator of trans-endothelial fatty acid transport. We found that 3-HIB is secreted from muscle cells, activates endothelial fatty acid transport, stimulates muscle fatty acid uptake in vivo and promotes lipid accumulation in muscle, leading to insulin resistance in mice. Conversely, inhibiting the synthesis of 3-HIB in muscle cells blocks the ability of PGC-1alpha to promote endothelial fatty acid uptake. 3-HIB levels are elevated in muscle from db/db mice with diabetes and from human subjects with diabetes, as compared to those without diabetes. These data unveil a mechanism in which the metabolite 3-HIB, by regulating the trans-endothelial flux of fatty acids, links the regulation of fatty acid flux to BCAA catabolism, providing a mechanistic explanation for how increased BCAA catabolic flux can cause diabetes. PMID- 26950364 TI - Positive upshots of cortisol in everyday life. AB - Cortisol, the major physiological end product of the hypothalamic-pituitary adrenal axis, is usually associated with stress and negative affect. However, a new body of research highlights the complex, adaptive significance of elevated cortisol within individuals in everyday life. Whereas most studies do not have the power to test the dynamic transactions between cortisol and affect within a person throughout the entire waking day, we employed an intensive study protocol analyzing hourly diary reports of affect in relation to hourly salivary cortisol samples among 24 healthy adults from morning to bedtime, across 2 consecutive weekdays (N = 862 total samples). Utilizing multileveling modeling and focusing on within-person effects, we examined whether momentary increases in cortisol could be mood protective, or energy enhancing, in everyday life, supporting the cortisol boost hypothesis. Results revealed no significant associations between cortisol and current affective state; however, within-person increases in cortisol were significantly associated with subsequent rises in activeness, alertness, and relaxation, and trend-level reductions in stress and nervousness. This study adds to growing evidence that cortisol plays a positive role in regulating affect in everyday life. (PsycINFO Database Record PMID- 26950362 TI - p16(Ink4a)-induced senescence of pancreatic beta cells enhances insulin secretion. AB - Cellular senescence is thought to contribute to age-associated deterioration of tissue physiology. The senescence effector p16(Ink4a) is expressed in pancreatic beta cells during aging and limits their proliferative potential; however, its effects on beta cell function are poorly characterized. We found that beta cell specific activation of p16(Ink4a) in transgenic mice enhances glucose-stimulated insulin secretion (GSIS). In mice with diabetes, this leads to improved glucose homeostasis, providing an unexpected functional benefit. Expression of p16(Ink4a) in beta cells induces hallmarks of senescence--including cell enlargement, and greater glucose uptake and mitochondrial activity--which promote increased insulin secretion. GSIS increases during the normal aging of mice and is driven by elevated p16(Ink4a) activity. We found that islets from human adults contain p16(Ink4a)-expressing senescent beta cells and that senescence induced by p16(Ink4a) in a human beta cell line increases insulin secretion in a manner dependent, in part, on the activity of the mechanistic target of rapamycin (mTOR) and the peroxisome proliferator-activated receptor (PPAR)-gamma proteins. Our findings reveal a novel role for p16(Ink4a) and cellular senescence in promoting insulin secretion by beta cells and in regulating normal functional tissue maturation with age. PMID- 26950366 TI - The positivity bias in aging: Motivation or degradation? AB - The question of an emotional memory enhancement in aging, and of a positivity bias in particular, has been the subject of numerous empirical studies in the last decade. However, the roots of such positive preference are not yet well established. Partisans of a motivation-based perspective contend with those arguing that positivity is related to a cognitive or neural degradation. The aim of this study was to introduce some elements concerning positivity effect in aging. We compared immediate (i.e., immediate recall) versus delayed (i.e., delayed recall and recognition) emotional memory performance in 38 young adults, 39 old adults, 37 very old adults, and 41 Alzheimer's disease patients. Moreover, we manipulated the encoding instruction: Either participants received no particular processing instruction, or they had to process the material in a semantic way. The results indicated that the positivity bias is most likely to occur in individuals whose cognitive functions are preserved, after long retention delay, and in experimental conditions that do not constrain encoding. We concluded by highlighting that although these findings seem to be better in line with the motivation, rather than the degradation, perspective, they do not fully support either theory. (PsycINFO Database Record PMID- 26950365 TI - Culture shapes empathic responses to physical and social pain. AB - The present research investigates the extent to which cultural background moderates empathy in response to observing someone undergoing physical or social pain. In 3 studies, we demonstrate that East Asian and White British participants differ in both affective and cognitive components of their empathic reactions in response to someone else's pain. Compared with East Asian participants, British participants report greater empathic concern and show lower empathic accuracy. More important, findings cannot be explained by an in-group advantage effect. Potential reasons for observed cultural differences are discussed. (PsycINFO Database Record PMID- 26950367 TI - The burden of empathy: Partners' responses to divergence of interests in daily life. AB - Empathy has often been discussed as a beneficial process from which favorable individual and interpersonal experiences may be derived. The present work investigates whether empathy may sometimes be a burden rather than a benefit, under certain interpersonal circumstances. Specifically, we hypothesized that encountering situations of divergence of interests with a partner may cause discomfort, and that empathizing with one's partner would exacerbate this discomfort, resulting in higher levels of negative mood and stress that can affect relationship satisfaction. We tested these hypotheses using innovative experience sampling methodology in which both partners reported on their experiences in their natural environments. In support, we found that when people encountered divergence of interests with one's partner, as compared with when they did not, they experienced higher negative mood and stress and, consequently, lower relationship satisfaction. These effects were intensified, rather than reduced, by empathy. (PsycINFO Database Record PMID- 26950368 TI - Diverse functions of myosin VI elucidated by an isoform-specific alpha-helix domain. AB - Myosin VI functions in endocytosis and cell motility. Alternative splicing of myosin VI mRNA generates two distinct isoform types, myosin VI(short) and myosin VI(long), which differ in the C-terminal region. Their physiological and pathological roles remain unknown. Here we identified an isoform-specific regulatory helix, named the alpha2-linker, that defines specific conformations and hence determines the target selectivity of human myosin VI. The presence of the alpha2-linker structurally defines a new clathrin-binding domain that is unique to myosin VI(long) and masks the known RRL interaction motif. This finding is relevant to ovarian cancer, in which alternative myosin VI splicing is aberrantly regulated, and exon skipping dictates cell addiction to myosin VI(short) in tumor-cell migration. The RRL interactor optineurin contributes to this process by selectively binding myosin VI(short). Thus, the alpha2-linker acts like a molecular switch that assigns myosin VI to distinct endocytic (myosin VI(long)) or migratory (myosin VI(short)) functional roles. PMID- 26950369 TI - Structure and ligand-binding mechanism of the human OX1 and OX2 orexin receptors. AB - The orexin (also known as hypocretin) G protein-coupled receptors (GPCRs) regulate sleep and other behavioral functions in mammals, and are therapeutic targets for sleep and wake disorders. The human receptors hOX1R and hOX2R, which are 64% identical in sequence, have overlapping but distinct physiological functions and potential therapeutic profiles. We determined structures of hOX1R bound to the OX1R-selective antagonist SB-674042 and the dual antagonist suvorexant at 2.8-A and 2.75-A resolution, respectively, and used molecular modeling to illuminate mechanisms of antagonist subtype selectivity between hOX1R and hOX2R. The hOX1R structures also reveal a conserved amphipathic alpha-helix, in the extracellular N-terminal region, that interacts with orexin-A and is essential for high-potency neuropeptide activation at both receptors. The orexin receptor crystal structures are valuable tools for the design and development of selective orexin-receptor antagonists and agonists. PMID- 26950370 TI - USP7 is a SUMO deubiquitinase essential for DNA replication. AB - Post-translational modification of proteins by ubiquitin (Ub) and Ub-like modifiers regulates DNA replication. We have previously shown that chromatin around replisomes is rich in SUMO and poor in Ub, whereas mature chromatin exhibits an opposite pattern. How this SUMO-rich, Ub-poor environment is maintained at sites of DNA replication in mammalian cells remains unexplored. Here we identify USP7 as a replisome-enriched SUMO deubiquitinase that is essential for DNA replication. By acting on SUMO and SUMOylated proteins, USP7 counteracts their ubiquitination. Inhibition or genetic deletion of USP7 leads to the accumulation of Ub on SUMOylated proteins, which are displaced away from replisomes. Our findings provide a model explaining the differential accumulation of SUMO and Ub at replication forks and identify an essential role of USP7 in DNA replication that should be considered in the development of USP7 inhibitors as anticancer agents. PMID- 26950371 TI - Inhibition of telomerase RNA decay rescues telomerase deficiency caused by dyskerin or PARN defects. AB - Mutations in the human telomerase RNA component (hTR), the telomerase ribonucleoprotein component dyskerin (DKC1) and the poly(A) RNase (PARN) can lead to reduced levels of hTR and to dyskeratosis congenita (DC). However, the enzymes and mechanisms responsible for hTR degradation are unknown. We demonstrate that defects in dyskerin binding lead to hTR degradation by PAPD5-mediated oligoadenylation, which promotes 3'-to-5' degradation by EXOSC10, as well as decapping and 5'-to-3' decay by the cytoplasmic DCP2 and XRN1 enzymes. PARN increased hTR levels by deadenylating hTR, thereby limiting its degradation by EXOSC10. Telomerase activity and proper hTR localization in dyskerin- or PARN deficient cells were rescued by knockdown of DCP2 and/or EXOSC10. Prevention of hTR RNA decay also led to a rescue of localization of DC-associated hTR mutants. These results suggest that inhibition of RNA decay pathways might be a useful therapy for some telomere pathologies. PMID- 26950373 TI - Outcome of hematopoietic stem cell transplantation is similar for patients with a partial in vitro T-cell-depleted graft compared with a non-T-cell-depleted graft when stratified by the refined disease risk index. AB - Comparisons of hematopoietic stem cell transplantation (HSCT) methods in retrospective studies are often hampered by the heterogeneity of comparison groups. The refined disease risk index (DRI) is a potentially interesting tool to compare HSCT protocols as it is based on the disease type and burden at transplant and stratifies patients into four prognostic groups for overall survival (OS). We included 265 patients with partial T-cell-depleted graft (TDEP) and 163 non-TDEP patients in a retrospective study and compared outcomes following stratification using the refined DRI. The 2-year OS rate for TDEP patients was 81.6, 60.9 and 43.3% for the low-, intermediate- and high-risk groups, respectively (P<0.001). For non-TDEP patients, the 2-year OS rate was 62.9, 48.8, 44.2 and 7.6% for the low-, intermediate-, high- and very-high-risk groups, respectively (P<0.001). There was no significant difference when comparing OS between TDEP and non-TDEP for the low-, intermediate- and high-risk groups, but TDEP patients had less acute GvHD grades II-IV. In conclusion, we confirm that the refined DRI is a valuable tool to compare the outcomes of different HSCT protocols. We demonstrate also that TDEP did not impact on the outcome of HSCT, but it did reduce the incidence of acute GvHD. PMID- 26950375 TI - Decreased morbidity and mortality of autologous hematopoietic transplants for children with malignant central nervous system tumors: the 'Head Start' trials, 1991-2009. AB - Since 1991, three sequential prospective clinical trials have been conducted by the 'Head Start' (HS) Consortium in which young children with newly-diagnosed malignant central nervous system (CNS) tumors were treated with induction chemotherapy followed by single-cycle marrow-ablative chemotherapy and autologous hematopoietic rescue as a means of improving disease cure rate and quality of survival through avoidance (<6 years old at diagnosis) or reduction (6-10 years old) of brain irradiation. Bone Marrow (HS I) or filgrastim-mobilized peripheral hematopoietic cells (HS II and III) were obtained following recovery from the first and/or second induction cycles. Radiotherapy was administered following all chemotherapy only for patients with residual tumor following completion of induction or with age greater than 6 years at diagnosis. Two hundred and twenty six children were enrolled on three consecutive HS trials with primary malignant CNS tumors and underwent marrow-ablative chemotherapy. The 100-day treatment related mortality (TRM) steadily declined as did grade IV transplant-related oropharyngeal mucositis. Factors most likely associated with the decrease in TRM and morbidity are increasing experience with the marrow-ablative chemotherapy regimen combined with improved leukapheresis and post-reinfusion supportive care techniques, contributing toward improved overall survival. PMID- 26950374 TI - Gonadal shielding technique to preserve fertility in male pediatric patients treated with total body irradiation for stem cell transplantation. PMID- 26950376 TI - Outcomes in hepatitis C virus seropositive lymphoma and myeloma patients after autologous stem cell transplantation. PMID- 26950372 TI - Toxicity and efficacy of busulfan and fludarabine myeloablative conditioning for HLA-identical sibling allogeneic hematopoietic cell transplantation in AML and MDS. AB - The safety and efficacy of a 4-day myeloablative conditioning (MAC) regimen consisting of Bu 3.2 mg/kg and fludarabine 40 mg/m(2)/day for HLA-identical sibling allogeneic hematopoietic cell transplantation (HCT) in myeloid malignancies was investigated in 133 patients (median age, 47 years; range 19-74 years) with de novo AML (60%), secondary AML (20%) or myelodysplastic syndrome (20%). All patients engrafted. Hepatic veno-occlusive disease occurred in five patients (4%), and severe toxicities, mostly mucositis, occurred in twenty-three (17%) patients. The non-relapse mortality (NRM) at 100 days was 1.5%. The incidences of acute GVHD grade 2-4 and grade 3-4 were 32 and 13%, respectively. At a median follow-up of 38 months, the cumulative incidence of chronic GVHD was 67%. The relapse incidence was 30% (27 and 31%, respectively, in patients with early- and late-stage disease), and the overall NRM was 15%. The actuarial 4-year disease-free survival (DFS) and overall survival (OS) were 54 and 62%, respectively. Patients aged <50 years had better outcomes compared with older patients (DFS 64 vs 42%, P=0.006; OS 73 vs 47%, P<0.001, respectively). PMID- 26950377 TI - An intra-patient comparison of blood cell separators Spectra and Optia in patients and donors undergoing blood mononuclear cell collections at a single institution for subsequent autologous or allogeneic hematopoietic cell transplantation reveals comparable collection efficiencies. PMID- 26950378 TI - Regionalization of stem cell transplant procedures into teaching hospitals in United States: are we ready? PMID- 26950380 TI - Strong impact of extramedullary involvement in high-risk AML patients with active disease receiving the FLAMSA conditioning regimen for HSCT. PMID- 26950379 TI - Potential protective effect of Helicobacter pylori on the development of gastrointestinal GvHD. AB - Previous reports ascribe a modulating capacity of the immune response to Helicobacter pylori (HP). Our hypothesis was to demonstrate in a prospective study that HP infection could have a protective effect against development of gastrointestinal GvHD in patients receiving allogeneic hematopoietic cell transplantation (HCT). Presence of HP before transplant was determined using C(13) urea breath test. Seventy-nine patients receiving an allogeneic HCT were included and 93.7% of them received PBSC; in 51.9%, the donor was unrelated. Acute gastrointestinal GvHD was diagnosed in 51.9% (n=41). In the multivariable analysis, HP infection was associated with a lower frequency of gastrointestinal GvHD (odds ratio (OR)=0.19 (95% confidence interval (CI): 0.05-0.67); in contrast, an unrelated donor was associated with a higher frequency of gastrointestinal GvHD (odds ratio=5.4 (95% confidence interval: 1.6-18.2). One year overall survival (OS) was 74%. In the multivariate Cox proportional-hazards regression analysis, stages 0-II gastrointestinal GvHD (hazards ratio (HR)=0.19), reduced intensity conditioning (HR=0.04) and tacrolimus-sirolimus GvHD prophylaxis (HR=0.06) were all associated with a better OS. In summary, HP infection could have a role in decreasing gastrointestinal GvHD in patients receiving allogeneic HCT from peripheral blood including related and unrelated donors. PMID- 26950381 TI - Autologous and allogeneic stem cell transplant in Jehovah's Witnesses: a single center experience on 22 patients. PMID- 26950382 TI - One-Step Preparation of Oxygen/Fluorine Dual Functional MWCNTs with Good Water Dispersibility by the Initiation of Fluorine Gas. AB - It is still a challenge to prepare water-dispersible carbon nanotubes which are proved to have great potential in numerous applications. In this present work, as low as 2% fluorine gas was used as initiator to prepare oxygen/fluorine dual functional MWCNTs (OF-MWCNTs) with good water dispersibility through a one-step method under oxygen atmosphere. The aromatic structure of OF-MWCNTs is reserved to some extent resulting in better electrical conductivity than pure fluorinated MWCNTs (F-MWCNTs). The amount of oxygen atoms and fluorine atoms (hereinafter referred to as "O-content" and "F-content") of OF-MWCNTs is up to 8.8% and 7.5%. Fourier transform infrared spectroscopy (FTIR) manifests that - COOH is covalently bonded onto the surface of OF-MWCNTs. In addition, the OF-MWCNTs sample is pH-sensitive, which further validates the successful introduction of COOH. The successful covalent attachment of -COOH onto MWCNTs dramatically improves the hydrophilia of MWCNTs which always present hydrophobic character. It is deduced that fluorine creates reactive sites for oxygen, increases the oxygen content, and eventually results in the dispersibility of OF-MWCNTs in water. The corresponding hydrophilic OF-MWCNTs film shows good performance for separating oil-in-water emulsions. Meanwhile, the good dispersibility of OF-MWCNTs in organic solvents also makes it possible to be applied in various composites. PMID- 26950384 TI - Separate mechanisms for magnitude and order processing in the spatial-numerical association of response codes (SNARC) effect: The strange case of musical note values. AB - The spatial-numerical association of response codes (SNARC) effect is considered an evidence of the association between numbers and space, with faster left key press responses to small numbers and faster right key-press responses to large numbers. We examined whether visually presented note values produce a SNARC-like effect. Differently from numbers, note values are represented as a decreasing left-to-right progression, allowing us to disambiguate the contribution of order and magnitude in determining the direction of the effect. Musicians with formal education performed a note value comparison in Experiment 1 (direct task), a line orientation judgment in Experiment 2 (indirect task), and a detection task in Experiment 3 (indirect task). When note values were task relevant (direct task), participants responded faster to large note values with the left key-press, and vice versa. Conversely, when note values were task irrelevant (indirect tasks), the direction of this association was reversed. This evidence suggests the existence of separate mechanisms underlying the SNARC effect. Namely, an Order Related Mechanism (ORM) and a Magnitude-Related Mechanism (MRM) that are revealed by different task demands. Indeed, according to a new model we proposed, ordinal and magnitude related information appears to be preferentially involved in direct and indirect tasks, respectively. (PsycINFO Database Record PMID- 26950383 TI - Strategic trade-offs between quantity and quality in working memory. AB - Is working memory capacity determined by an immutable limit-for example, 4 memory storage slots? The fact that performance is typically unaffected by task instructions has been taken as support for such structural models of memory. Here, we modified a standard working memory task to incentivize participants to remember more items. Participants were asked to remember a set of colors over a short retention interval. In 1 condition, participants reported a random item's color using a color wheel. In the modified task, participants responded to all items and their response was only considered correct if all responses were on the correct half of the color wheel. We looked for a trade-off between quantity and quality-participants storing more items, but less precisely, when required to report them all. This trade-off was observed when tasks were blocked and when task-type was cued after encoding, but not when task-type was cued during the response, suggesting that task differences changed how items were actively encoded and maintained. This strategic control over the contents of working memory challenges models that assume inflexible limits on memory storage. (PsycINFO Database Record PMID- 26950386 TI - All set, indeed! N2pc components reveal simultaneous attentional control settings for multiple target colors. AB - To study whether top-down attentional control processes can be set simultaneously for different visual features, we employed a spatial cueing procedure to measure behavioral and electrophysiological markers of task-set contingent attentional capture during search for targets defined by 1 or 2 possible colors (one-color and two-color tasks). Search arrays were preceded by spatially nonpredictive color singleton cues. Behavioral spatial cueing effects indicative of attentional capture were elicited only by target-matching but not by distractor-color cues. However, when search displays contained 1 target-color and 1 distractor-color object among gray nontargets, N2pc components were triggered not only by target color but also by distractor-color cues both in the one-color and two-color task, demonstrating that task-set nonmatching items attracted attention. When search displays contained 6 items in 6 different colors, so that participants had to adopt a fully feature-specific task set, the N2pc to distractor-color cues was eliminated in both tasks, indicating that nonmatching items were now successfully excluded from attentional processing. These results demonstrate that when observers adopt a feature-specific search mode, attentional task sets can be configured flexibly for multiple features within the same dimension, resulting in the rapid allocation of attention to task-set matching objects only. (PsycINFO Database Record PMID- 26950385 TI - Differentiated audio-tactile correspondences in sighted and blind individuals. AB - The aim of the present study is to investigate whether the crossmodal correspondence robustly documented between auditory pitch and visual elevation has analogues in the audio-tactile domain. Across 4 experiments, the compatibility effects between intuitively congruent pairs of stimuli (i.e., outward tactile movement, going from the inside of the finger toward the fingertip and increasing pitch, or inward tactile movement and decreasing pitch) and incongruent pairs stimuli (i.e., the reverse associations) were measured. Two methods were compared to assess the behavioral effects of such a correspondence: One where participants have to respond to either the auditory or tactile stimulus presented simultaneously, while ignoring the other (speeded classification task), and the other where the auditory and tactile stimuli are presented sequentially and associated to different response buttons (implicit association test). No significant compatibility effect was observed under the speeded classification task. The implicit association test revealed a significant compatibility effect. This effect was similar in the conditions where the finger was placed vertically and horizontally. However, this implicit association between pitch and tactile movements was not observed in blind participants. These results have methodological implications for the explanation and testing of crossmodal correspondences, and the origin of the widely discussed association between pitch and vertical elevation. (PsycINFO Database Record PMID- 26950387 TI - Toward an integrative model of talker normalization. AB - Successful speech perception requires accurate mapping of speech signals to linguistic categories despite talker variation in signals. Although factors like intrinsic and context cues have been identified, a full understanding of talker normalization remains to be achieved. In particular, it is important to examine the cocontribution of intrinsic, extrinsic and other cues in an integrative way. In Experiment 1, we examined the effect of intrinsic cues and typicality of a talker's F0 range relative to population F0 range on word identification in isolation. In Experiment 2, we compared the effects of 4 contexts to identify those that consistently facilitate talker normalization. We found that without contexts, word identification accuracy was low and variable depending on talker typicality. Contexts improved performance across all talkers regardless of typicality. But only meaningless and meaningful speech contexts with cues to a talker's acoustic-phonological space showed consistent effects. We proposed a new model, integrating talker typicality, talker familiarity, and context. Whereas speech signals from familiar or typical talkers may be accurately identified standing alone, a context with cues to a talker's acoustic-phonological space is necessary in the case of unfamiliar and atypical talkers. It is thus the first model that integrates memory and context effects. (PsycINFO Database Record PMID- 26950390 TI - Correction to Chemical and Biological Reduction of the Radical SAM Enzyme 7 Carboxy-7-deazaguanine Synthase. PMID- 26950391 TI - Dual Catalysis: Proton/Metal-Catalyzed Tandem Benzofuran Annulation/Carbene Transfer Reaction. AB - An efficient proton/metal-catalyzed tandem benzofuran annulation/carbene transfer reaction for the synthesis of various benzofuryl-substituted cyclopropanes and cycloheptatrienes has been developed. The reaction was proposed to proceed through two key intermediates, o-quinone methide (o-QM) and benzofuryl carbene. The DFT-based computational studies indicated that the reaction was initiated through the dehydration of o-HBA via a Bronsted acid mediated proton shuttle transition state, forming the key intermediate o-QM. PMID- 26950392 TI - Small Molecule Inhibitors of Cyclophilin D To Protect Mitochondrial Function as a Potential Treatment for Acute Pancreatitis. AB - Opening of the mitochondrial permeability transition pore (MPTP) causes mitochondrial dysfunction and necrosis in acute pancreatitis (AP), a condition without specific drug treatment. Cyclophilin D (CypD) is a mitochondrial matrix peptidyl-prolyl isomerase that regulates the MPTP and is a drug target for AP. We have synthesized urea-based small molecule inhibitors of cyclophilins and tested them against CypD using binding and isomerase activity assays. Thermodynamic profiles of the CypD/inhibitor interactions were determined by isothermal titration calorimetry. Seven new high-resolution crystal structures of CypD inhibitor complexes were obtained to guide compound optimization. Compounds 4, 13, 14, and 19 were tested in freshly isolated murine pancreatic acinar cells (PACs) to determine inhibition of toxin-induced loss of mitochondrial membrane potential (DeltaPsim) and necrotic cell death pathway activation. Compound 19 was found to have a Kd of 410 nM and a favorable thermodynamic profile, and it showed significant protection of DeltaPsim and reduced necrosis of murine as well as human PACs. Compound 19 holds significant promise for future lead optimization. PMID- 26950393 TI - Are major behavioral and sociodemographic risk factors for mortality additive or multiplicative in their effects? AB - All individuals are subject to multiple risk factors for mortality. In this paper, we consider the nature of interactions between certain major sociodemographic and behavioral risk factors associated with all-cause mortality in the United States. We develop the formal logic pertaining to two forms of interaction between risk factors, additive and multiplicative relations. We then consider the general circumstances in which additive or multiplicative relations might be expected. We argue that expectations about interactions among socio demographic variables, and their relation to behavioral variables, have been stated in terms of additivity. However, the statistical models typically used to estimate the relation between risk factors and mortality assume that risk factors act multiplicatively. We examine empirically the nature of interactions among five major risk factors associated with all-cause mortality: smoking, obesity, race, sex, and educational attainment. Data were drawn from the cross-sectional NHANES III (1988-1994) and NHANES 1999-2010 surveys, linked to death records through December 31, 2011. Our analytic sample comprised 35,604 respondents and 5369 deaths. We find that obesity is additive with each of the remaining four variables. We speculate that its additivity is a reflection of the fact that obese status is generally achieved later in life. For all pairings of socio demographic variables, risks are multiplicative. For survival chances, it is much more dangerous to be poorly educated if you are black or if you are male. And it is much riskier to be a male if you are black. These traits, established at birth or during childhood, literally result in deadly combinations. We conclude that the identification of interactions among risk factors can cast valuable light on the nature of the process being studied. It also has public health implications by identifying especially vulnerable groups and by properly identifying the proportion of deaths attributable to a risk factor. PMID- 26950394 TI - Calculating flux to predict future cave radon concentrations. AB - Cave radon concentration measurements reflect the outcome of a perpetual competition which pitches flux against ventilation and radioactive decay. The mass balance equations used to model changes in radon concentration through time routinely treat flux as a constant. This mathematical simplification is acceptable as a first order approximation despite the fact that it sidesteps an intrinsic geological problem: the majority of radon entering a cavity is exhaled as a result of advection along crustal discontinuities whose motions are inhomogeneous in both time and space. In this paper the dynamic nature of flux is investigated and the results are used to predict cave radon concentration for successive iterations. The first part of our numerical modelling procedure focuses on calculating cave air flow velocity while the second part isolates flux in a mass balance equation to simulate real time dependence among the variables. It is then possible to use this information to deliver an expression for computing cave radon concentration for successive iterations. The dynamic variables in the numerical model are represented by the outer temperature, the inner temperature, and the radon concentration while the static variables are represented by the radioactive decay constant and a range of parameters related to geometry of the cavity. Input data were recorded at Driny Cave in the Little Carpathians Mountains of western Slovakia. Here the cave passages have developed along splays of the NE-SW striking Smolenice Fault and a series of transverse faults striking NW-SE. Independent experimental observations of fault slip are provided by three permanently installed mechanical extensometers. Our numerical modelling has revealed four important flux anomalies between January 2010 and August 2011. Each of these flux anomalies was preceded by conspicuous fault slip anomalies. The mathematical procedure outlined in this paper will help to improve our understanding of radon migration along crustal discontinuities and its subsequent exhalation into the atmosphere. Furthermore, as it is possible to supply the model with continuous data, future research will focus on establishing a series of underground monitoring sites with the aim of generating the first real time global radon flux maps. PMID- 26950396 TI - Enhanced electrorheological activity of polyaniline coated mesoporous silica with high aspect ratio. AB - Polyaniline-coated mesoporous silica (PANI/mSiO2) materials with different aspect ratios (L/D=1, 5, and 10) were fabricated by a vapor deposition polymerization (VDP) method to investigate the geometric effect on electrorheological (ER) activity. The PANI/mSiO2 materials were dedoped by a facile NH4OH treatment to reduce the conductivity to a level appropriate for ER applications. Notably, the PANI/mSiO2-based ER fluids exhibited enhanced ER performance with increasing aspect ratio. In particular, the PANI/mSiO2 material with the highest aspect ratio manifested the highest ER activity, which was attributed to geometric effects on flow resistance and mechanical stability. Moreover, the ER materials with higher aspect ratios showed improved dielectric properties of large achievable polarizability and short relaxation time. Hence, the synergistic contribution of geometric effects and dielectric properties resulted in enhanced ER activity. Consequently, this study provides insight into an effective method to improve ER performance by simple manipulation of the particle geometry. PMID- 26950395 TI - AhR activation by 6-formylindolo[3,2-b]carbazole and 2,3,7,8-tetrachlorodibenzo-p dioxin inhibit the development of mouse intestinal epithelial cells. AB - The intestinal epithelium plays a central role in immune homeostasis in the intestine. AhR, a ligand-activated transcription factor, plays an important role in diverse physiological processes. The intestines are exposed to various exogenous and endogenous AhR ligands. Thus, AhR may regulate the intestinal homeostasis, directly acting on the development of intestinal epithelial cells (IEC). In this study, we demonstrated that 6-formylindolo[3,2-b]carbazole (FICZ) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) inhibited the in vitro development of mouse intestinal organoids. The number of Paneth cells in the small intestine and the depth of crypts of the small and large intestines were reduced in mice administrated with FICZ. Immunohistochemical and flow cytometric assays revealed that AhR was highly expressed in Lgr5(+) stem cells. FICZ inhibited Wnt signaling lowering the level of beta-catenin protein. Gene expression analyses demonstrated that FICZ increased expression of Lgr5, Math1, BMP4, and Indian Hedgehog while inhibiting that of Lgr4. PMID- 26950397 TI - A Process for Topographically Selective Deposition on 3D Nanostructures by Ion Implantation. AB - Area-selective atomic layer deposition (AS-ALD) is attracting increasing interest because of its ability to enable both continued dimensional scaling and accurate pattern placement for next-generation nanoelectronics. Here we report a strategy for depositing material onto three-dimensional (3D) nanostructures with topographic selectivity using an ALD process with the aid of an ultrathin hydrophobic surface layer. Using ion implantation of fluorocarbons (CFx), a hydrophobic interfacial layer is formed, which in turn causes significant retardation of nucleation during ALD. We demonstrate the process for Pt ALD on both blanket and 2D patterned substrates. We extend the process to 3D structures, demonstrating that this method can achieve selective anisotropic deposition, selectively inhibiting Pt deposition on deactivated horizontal regions while ensuring that only vertical surfaces are decorated during ALD. The efficacy of the approach for metal oxide ALD also shows promise, though further optimization of the implantation conditions is required. The present work advances practical applications that require area-selective coating of surfaces in a variety of 3D nanostructures according to their topographical orientation. PMID- 26950398 TI - Biexciton Auger Recombination in CdSe/CdS Core/Shell Semiconductor Nanocrystals. AB - A theoretical study of the positive and negative trion channels in the nonradiative Auger recombination of band-edge biexcitons (BXs) in CdSe/CdS core/shell nanocrystals (NCs) is presented. The theory takes into account the BX fine-structure produced by NC asymmetry and hole-hole exchange interaction. The calculations show that growth of CdS shell upon CdSe core suppresses the rate of the Auger recombination via negative trion channel, while the more efficient Auger recombination via positive trion channel shows much weaker dependence on the shell thickness. The demonstrated oscillatory dependence of the BX Auger rate on the core and shell sizes is explained qualitatively in terms of overlap of the ground and excited carrier wave functions. The calculations show that raise of temperature accelerates the Auger recombination in CdSe/CdS NCs due to reduction of the bulk energy gaps of CdSe and CdS. PMID- 26950399 TI - Construction of quality-assured infant feeding process of care data repositories: Construction of the perinatal repository (Part 2). AB - This is the second in a series of two papers regarding the construction of data quality (DQ) assured repositories, based on population data from Electronic Health Records (EHR), for the reuse of information on infant feeding from birth until the age of two. This second paper describes the application of the computational process of constructing the first quality-assured repository for the reuse of information on infant feeding in the perinatal period, with the aim of studying relevant questions from the Baby Friendly Hospital Initiative (BFHI) and monitoring its deployment in our hospital. The construction of the repository was carried out using 13 semi-automated procedures to assess, recover or discard clinical data. The initial information consisted of perinatal forms from EHR related to 2048 births (Facts of Study, FoS) between 2009 and 2011, with a total of 433,308 observations of 223 variables. DQ was measured before and after the procedures using metrics related to eight quality dimensions: predictive value, correctness, duplication, consistency, completeness, contextualization, temporal stability, and spatial-stability. Once the predictive variables were selected and DQ was assured, the final repository consisted of 1925 births, 107,529 observations and 73 quality-assured variables. The amount of discarded observations mainly corresponds to observations of non-predictive variables (52.90%) and the impact of the de-duplication process (20.58%) with respect to the total input data. Seven out of thirteen procedures achieved 100% of valid births, observations and variables. Moreover, 89% of births and ~98% of observations were consistent according to the experts' criteria. A multidisciplinary approach along with the quantification of DQ has allowed us to construct the first repository about infant feeding in the perinatal period based on EHR population data. PMID- 26950400 TI - Design, synthesis and biological evaluation of 1H-pyrrolo[2,3-b]pyridine and 1H pyrazolo[3,4-b]pyridine derivatives as c-Met inhibitors. AB - Five novel 1H-pyrrolo[2,3-b]pyridine or 1H-pyrazolo[3,4-b]pyridine derivatives, with a methylene, sulfur, sulfoxide or cyclopropyl group as a linker, were designed, synthesized and biologically evaluated against c-Met and ALK. The development of these methods of compound synthesis may provide an important reference for the construction of novel 7-azaindole and 7-azaindazole derivatives with a single atom linker. The enzyme assay and cell assay in vitro showed that compound 9 displayed strong c-Met kinase inhibition with IC50 of 22.8nM, moderate ALK kinase inhibition, and strong cell inhibition with MKN-45 IC50 of 329nM and EBC-1 IC50 of 479nM. In order to find the better candidate compounds, compounds 8, 9 and 10 have been selected as tool compounds for further optimization. PMID- 26950401 TI - Low-grade inflammation is associated with lower haemoglobin levels in healthy individuals: results from the Danish blood donor study. AB - BACKGROUND AND OBJECTIVES: Chronic inflammation can lead to anaemia of chronic disease due to the sequestration of iron caused by inflammatory cytokines and the protein hepcidin. However, the effect of low-grade inflammation (LGI) on haemoglobin among healthy individuals is not known. This study examines the effect of LGI on haemoglobin among Danish blood donors. MATERIALS AND METHODS: We performed multivariable linear regression to assess the effect of LGI (i.e. high sensitivity C-reactive protein above 3 mg/l but below 10 mg/l) on haemoglobin in 17 322 Danish blood donors. We also performed multivariable logistic regression to evaluate the effect of LGI on the risk of having low haemoglobin (below the 10th percentile among men and women, respectively). We adjusted for donation activity, age, sex, low ferritin, oral contraceptives and menopause. All analyses were stratified by current smoking status. RESULTS: LGI was associated with lower haemoglobin (0.08 mm lower [0.12 g/dl], 95% confidence interval (CI): -0.11-0.05) and increased risk of low haemoglobin (OR = 1.22, 95% CI: 1.05-1.43) in non smokers. Conversely, LGI was associated with higher haemoglobin in smokers (0.12 mm [0.19 g/dl], 95% CI: 0.06-0.18). CONCLUSION: In this first study of LGI and haemoglobin in healthy individuals, there was a negative association between LGI and haemoglobin in non-smokers. The association was positive in smokers, probably because smoking leads to both increased inflammation and increased haemoglobin through CO exposure. PMID- 26950402 TI - D-AKAP1a is a signal-anchored protein in the mitochondrial outer membrane. AB - Dual A-kinase anchoring protein 1a (D-AKAP1a, AKAP1) regulates cAMP signaling in mitochondria. However, it is not clear how D-AKAP1a is associated with mitochondria. In this study, we show that D-AKAP1a is a transmembrane protein in the mitochondrial outer membrane (MOM). We revealed that the N-terminus of D AKAP1a is exposed to the intermembrane space of mitochondria and that its C terminus is located on the cytoplasmic side of the MOM. Moderate hydrophobicity and the positively charged flanking residues of the transmembrane domain of D AKAP1a were important for targeting. Taken together, D-AKAP1a can be classified as a signal-anchored protein in the MOM. Our topological study provides valuable information about the molecular and cellular mechanisms of mitochondrial targeting of AKAP1. PMID- 26950403 TI - A Mechanistic Link between L1 Retrotransposition and Chromothripsis. PMID- 26950404 TI - Plant hormones: a fungal point of view. AB - Most classical plant hormones are also produced by pathogenic and symbiotic fungi. The way in which these molecules favour the invasion of plant tissues and the development of fungi inside plant tissues is still largely unknown. In this review, we examine the different roles of such hormone production by pathogenic fungi. Converging evidence suggests that these fungal-derived molecules have potentially two modes of action: (i) they may perturb plant processes, either positively or negatively, to favour invasion and nutrient uptake; and (ii) they may also act as signals for the fungi themselves to engage appropriate developmental and physiological processes adapted to their environment. Indirect evidence suggests that abscisic acid, gibberellic acid and ethylene produced by fungi participate in pathogenicity. There is now evidence that auxin and cytokinins could be positive regulators required for virulence. Further research should establish whether or not fungal-derived hormones act like other fungal effectors. PMID- 26950405 TI - Theoretical Evidence for Multiple Charge Transfer Pathways in Bacteriorhodopsin. AB - The development of molecular-scale junctions utilizing biomolecules is a challenging field that requires intimate knowledge of the relationship between molecular structure and conductance characteristics. One of the key parameters to understanding conductance efficiency is the charge mobility, which strongly influences the response time of electronic devices. The charge mobility of bacteriorhodopsin (bR), a membrane protein that has been studied experimentally in detail, was theoretically investigated using extended Marcus-Hush theory. Charge mobilities of 1.3 * 10(-2) and 9.7 * 10(-4) cm(2)/(V s) for hole and electron transfer, respectively, were determined. The computed electron mobility is comparable to experimentally measured values (9 * 10(-4) cm(2)/(V s)). Interestingly, the pathways for hole and electron hopping were very distinct from each other, utilizing different transmembrane helices to traverse the protein. In particular, only the electron transfer pathway involved the retinal chromophore, indicating that the efficiency of charge transfer is directly affected by the tertiary arrangement of proteins. Our results provide a template for obtaining the molecular and electronic-level details that can reveal fundamental insights into experimental studies on protein electron transport and inform efficient design of biomolecular-based junctions on the nanoscale. PMID- 26950406 TI - Adsorption and Unfolding of Lysozyme at a Polarized Aqueous-Organic Liquid Interface. AB - The adsorption of proteins at the interface between two immiscible electrolyte solutions has been found to be key to their bioelectroactivity at such interfaces. Combined with interfacial complexation of organic phase anions by cationic proteins, this adsorption process may be exploited to achieve nanomolar protein detection. In this study, replica exchange molecular dynamics simulations have been performed to elucidate for the first time the molecular mechanism of adsorption and subsequent unfolding of hen egg white lysozyme at low pH at a polarized 1,2-dichloroethane/water interface. The unfolding of lysozyme was observed to occur as soon as it reaches the organic-aqueous interface, which resulted in a number of distinct orientations at the interface. In all cases, lysozyme interacted with the organic phase through regions rich in nonpolar amino acids, such that the side chains are directed toward the organic phase, whereas charged and polar residues were oriented toward the aqueous phase. By contrast, as expected, lysozyme in neat water at low pH does not exhibit significant structural changes. These findings demonstrate the key influence of the organic phase upon adsorption of lysozyme under the influence of an electric field, which results in the unfolding of its structure. PMID- 26950407 TI - Opening up: open access publishing, data sharing, and how they can influence your neuroscience career. PMID- 26950408 TI - Minimally invasive in vivo orbital pressure measurement. PMID- 26950409 TI - Eye Histology and Ganglion Cell Topography of Northern Elephant Seals (Mirounga angustirostris). AB - Northern elephant seals are one of the deepest diving marine mammals. As northern elephant seals often reach the bathypelagic zone, it is usually assumed that their eyes possess evolutionary adaptations that provide better ability to see in dim or scotopic environments. The purpose of this study was to carefully describe anatomical and histological traits of the eye that may improve light sensitivity. Northern elephant seals have large, somewhat elliptical eyes, with equatorial and anteroposterior diameters of 5.03 and 4.4 cm, respectively. The cornea is large in diameter and the lens is completely spherical. The iris has pronounced constrictor and dilator muscles, whereas the ciliary muscle is notably less developed. The tapetum lucidum is more prominent than in other pinnipeds, making up about 63% of retinal thickness in the posterior aspect of the globe. Within the retina, the pigmented epithelium lacks pigment except for the region close to the ora serrata. Parts of the photoreceptor and outer nuclear layers are folded. Although the photoreceptor layer is composed predominantly of rods, cone photoreceptors were also observed. Cells within the retinal ganglion cell layer are arranged in a single level. Ganglion cells reach their maximum density (~1,300 cells per mm(2) ) dorsal to the optic disc, whereas the periphery of the retina is sparsely populated (<100 cells per mm(2) ). All above mentioned features are consistent with the predicted evolutionary adaptations to the photic environment of the bathypelagic zone. Anat Rec, 299:798-805, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26950410 TI - Retinoids: The Link Between Alcohol and Interferon? PMID- 26950412 TI - Correction to Understanding Nonlinear Dielectric Properties in a Biaxially Oriented Poly(vinylidene fluoride) Film at Both Low and High Electric Fields. PMID- 26950411 TI - Rheumatoid Arthritis Exacerbates the Severity of Osteonecrosis of the Jaws (ONJ) in Mice. A Randomized, Prospective, Controlled Animal Study. AB - Rheumatoid arthritis (RA), an autoimmune inflammatory disorder, results in persistent synovitis with severe bone and cartilage destruction. Bisphosphonates (BPs) are often utilized in RA patients to reduce bone destruction and manage osteoporosis. However, BPs, especially at high doses, are associated with osteonecrosis of the jaw (ONJ). Here, utilizing previously published ONJ animal models, we are exploring interactions between RA and ONJ incidence and severity. DBA1/J mice were divided into four groups: control, zoledronic acid (ZA), collagen-induced arthritis (CIA), and CIA-ZA. Animals were pretreated with vehicle or ZA. Bovine collagen II emulsified in Freund's adjuvant was injected to induce arthritis (CIA) and the mandibular molar crowns were drilled to induce periapical disease. Vehicle or ZA treatment continued for 8 weeks. ONJ indices were measured by micro-CT (uCT) and histological examination of maxillae and mandibles. Arthritis development was assessed by visual scoring of paw swelling, and by uCT and histology of interphalangeal and knee joints. Maxillae and mandibles of control and CIA mice showed bone loss, periodontal ligament (PDL) space widening, lamina dura loss, and cortex thinning. ZA prevented these changes in both ZA and CIA-ZA groups. Epithelial to alveolar crest distance was increased in the control and CIA mice. This distance was preserved in ZA and CIA-ZA animals. Empty osteocytic lacunae and areas of osteonecrosis were present in ZA and CIA-ZA but more extensively in CIA-ZA animals, indicating more severe ONJ. CIA and CIA-ZA groups developed severe arthritis in the paws and knees. Interphalangeal and knee joints of CIA mice showed advanced bone destruction with cortical erosions and trabecular bone loss, and ZA treatment reduced these effects. Importantly, no osteonecrosis was noted adjacent to areas of articular inflammation in CIA-ZA mice. Our data suggest that ONJ burden was more pronounced in ZA treated CIA mice and that RA could be a risk factor for ONJ development. (c) 2016 American Society for Bone and Mineral Research. PMID- 26950413 TI - Sef Regulates Epithelial-Mesenchymal Transition in Breast Cancer Cells. AB - Sef (similar expression to fgf), also know as IL17RD, is a transmembrane protein shown to inhibit fibroblast growth factor signaling in developmental and cancer contexts; however, its role as a tumor suppressor remains to be fully elucidated. Here, we show that Sef regulates epithelial-mesenchymal transition (EMT) in breast cancer cell lines. Sef expression was highest in the normal breast epithelial cell line MCF10A, intermediate expression in MCF-7 cells and lowest in MDA-MB-231 cells. Knockdown of Sef increased the expression of genes associated with EMT, and promoted cell migration, invasion, and a fibroblastic morphology of MCF-7 cells. Overexpression of Sef inhibited the expression of EMT marker genes and inhibited cell migration and invasion in MCF-7 cells. Induction of EMT in MCF10A cells by TGF-beta and TNF-alpha resulted in downregulation of Sef expression concomitant with upregulation of EMT gene expression and loss of epithelial morphology. Overexpression of Sef in MCF10A cells partially blocked cytokine-induced EMT. Sef was shown to block beta-catenin mediated luciferase reporter activity and to cause a decrease in the nuclear localization of active beta-catenin. Furthermore, Sef was shown to co-immunoprecipitate with beta catenin. In a mouse orthotopic xenograft model, Sef overexpression in MDA-MB-231 cells slowed tumor growth and reduced expression of EMT marker genes. Together, these data indicate that Sef plays a role in the negative regulation of EMT in a beta-catenin dependent manner and that reduced expression of Sef in breast tumor cells may be permissive for EMT and the acquisition of a more metastatic phenotype. J. Cell. Biochem. 117: 2346-2356, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26950414 TI - Rociletinib, a third generation EGFR tyrosine kinase inhibitor: current data and future directions. AB - INTRODUCTION: Major advances have been made since the discovery of driver mutations and their targeted therapies, especially in the treatment of patients with epidermal growth factor receptor (EGFR) mutations. Despite their initial efficacy in the majority of the patients with such driver mutations, all targeted therapies are limited by the eventual development of resistance mechanisms. AREAS COVERED: EGFR T790M mutation is a common resistance mechanism after treatment with first or second generation EGFR tyrosine kinase inhibitors (TKI). Rociletinib is one of the third generation EGFR TKIs with activity against T790M and activating EGFR mutations while sparing the wild-type EGFR. In this review, we discuss the current understanding and available data on rociletinib, including the side effects associated with the medication. We will also review the BEAMing plasma test to detect T790M mutation without the need for repeat biopsy. Lastly, we review the potential resistance mechanisms after progression on rociletinib, and future directions. EXPERT OPINION: It is important to note that there are other 3(rd) generation EGFR TKIs with activity against T790M already approved by the US FDA (osimertinib) and many others in development. Future research will focus on figuring out which patients can benefit the most from a particular medication with minimal side effects, and further resistance mechanisms after rociletinib. PMID- 26950415 TI - Sex, love and money along the Namibian-Angolan border. AB - In sub-Saharan Africa, young women engaged in relationships with multiple partners in order to gain material benefits play a key role in local HIV dynamics. This paper is based upon field observations and interviews with 38 young women who live along the Angolan-Namibian border. In the last 10 years, rapid urbanisation has attracted migrants in search of opportunities to do business in the region. Our findings show that sexual-affective economic networks reflect these socioeconomic changes. Women, particularly those from particular ethnic groups and/or from Namibia, with low levels of formal education and social support are often excluded from the labour market and turn to emotional-sexual male-centred networks for material and financial benefits. Men in these networks tend to be older, have higher socioeconomic status and greater geographic mobility. This 'capitalisation' of intimate relationships is material and symbolic; it enables women to acquire goods and access to services identified with an urban and globalised lifestyle. It is also emotional because relationships include affection and pleasure. Engaging in these relationships involves some social risks (bad reputation, family rejection, discrimination and violence), but maintaining ties often takes priority over safer sex and social sanctions. PMID- 26950416 TI - Comparison of fatty acid profile in the chicken meat after feeding with narasin, nicarbazin and salinomycin sodium and phyto-additive substances. AB - The purpose of this study was an experimental investigation and a statistical evaluation of the influence of various additives in feed mixtures of broiler chickens on fatty acids content and their ratio in breast and thigh muscles. First feed additive consisted of narasin, nicarbasin and salinomycin sodium, and other five additives were of phytogenic origin. In vivo experiment was realized on the poultry experimental station with deep litter breeding system. A total of 300 one-day-old hybrid chickens Cobb 500 divided into six groups were used for the experiment. The experimental period was divided into four phases, i.e. Starter, Grower 1, Grower 2 and Final, according to the application of commercial feed mixture of soy cereal type. Additive substances used in feed mixtures were different for each group. Basic feed mixtures were equal for all groups. Fatty acid profile of breast and thigh muscles was measured by the method of FT IR Nicolet 6700. Investigated additive substances in the feed mixtures did not have statistically significant effect on fatty acid content and omega-6/omega-3 polyunsaturated fatty acid (PUFA) ratio in breast and thigh muscles. Strong statistically significant relation between omega-6 PUFAs and total PUFAs were proved by experiment. A relation between omega-3 PUFAs and total PUFAs was found only in the group with Biocitro additive. PMID- 26950417 TI - Self-DNA inhibitory effects: Underlying mechanisms and ecological implications. AB - DNA is usually known as the molecule that carries the instructions necessary for cell functioning and genetic inheritance. A recent discovery reported a new functional role for extracellular DNA. After fragmentation, either by natural or artificial decomposition, small DNA molecules (between ~50 and ~2000 bp) exert a species specific inhibitory effect on individuals of the same species. Evidence shows that such effect occurs for a wide range of organisms, suggesting a general biological process. In this paper we explore the possible molecular mechanisms behind those findings and discuss the ecological implications, specifically those related to plant species coexistence. PMID- 26950418 TI - Comparison of Different Models of Structured Self-Monitoring of Blood Glucose in Type 2 Diabetes. AB - BACKGROUND: The aim of this study is to compare the effectiveness of different models of structured self-monitoring of blood glucose (SMBG) in non-insulin treated type 2 diabetes. SUBJECTS AND METHODS: This was a prospective, three-arm, randomized, 36-week trial. There were 138 participants with a mean age of 58.7 years and glycated hemoglobin A1c (HbA1c) level of 8.72% who were allocated to the following groups: six-pair glucose test of pre- and postprandial blood glucose (BG) per week (n = 43); three-pair glucose test of pre- and postprandial BG per week (n = 39); and seven-point BG testing before and after each meal and at bedtime over a course of 3 days in 1 month (n = 40). RESULTS: The intention-to treat analysis revealed that all three groups showed significant reductions in HbA1c levels. Comparisons among the groups revealed that only the seven-point group had a significant greater reduction of HbA1c level compared with the three pair group (between-group mean difference of -0.86 and -0.80 from baseline to 24 and 36 weeks, respectively). No severe hypoglycemic events were reported. Diabetes distress was slightly higher in the six-pair group. CONCLUSIONS: Our results demonstrated that BG testing at six pairs/week, three pairs/week, and seven points for 3 days/month were all effective in improving glycemic outcome, with greater reduction of HbA1c level in the seven-point for 3 days/month group, without increasing burdensome distress in SMBG. PMID- 26950419 TI - Sortilin mediates vascular calcification via its recruitment into extracellular vesicles. AB - Vascular calcification is a common feature of major cardiovascular diseases. Extracellular vesicles participate in the formation of microcalcifications that are implicated in atherosclerotic plaque rupture; however, the mechanisms that regulate formation of calcifying extracellular vesicles remain obscure. Here, we have demonstrated that sortilin is a key regulator of smooth muscle cell (SMC) calcification via its recruitment to extracellular vesicles. Sortilin localized to calcifying vessels in human and mouse atheromata and participated in formation of microcalcifications in SMC culture. Sortilin regulated the loading of the calcification protein tissue nonspecific alkaline phosphatase (TNAP) into extracellular vesicles, thereby conferring its calcification potential. Furthermore, SMC calcification required Rab11-dependent trafficking and FAM20C/casein kinase 2-dependent C-terminal phosphorylation of sortilin. In a murine model, Sort1-deficiency reduced arterial calcification but did not affect bone mineralization. Additionally, transfer of sortilin-deficient BM cells to irradiated atherosclerotic mice did not affect vascular calcification, indicating a primary role of SMC-derived sortilin. Together, the results of this study identify sortilin phosphorylation as a potential therapeutic target for ectopic calcification/microcalcification and may clarify the mechanism that underlies the genetic association between the SORT1 gene locus and coronary artery calcification. PMID- 26950421 TI - Metabolic reprogramming of alloantigen-activated T cells after hematopoietic cell transplantation. AB - Alloreactive donor T cells are the driving force in the induction of graft-versus host disease (GVHD), yet little is known about T cell metabolism in response to alloantigens after hematopoietic cell transplantation (HCT). Here, we have demonstrated that donor T cells undergo metabolic reprograming after allogeneic HCT. Specifically, we employed a murine allogeneic BM transplant model and determined that T cells switch from fatty acid beta-oxidation (FAO) and pyruvate oxidation via the tricarboxylic (TCA) cycle to aerobic glycolysis, thereby increasing dependence upon glutaminolysis and the pentose phosphate pathway. Glycolysis was required for optimal function of alloantigen-activated T cells and induction of GVHD, as inhibition of glycolysis by targeting mTORC1 or 6 phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) ameliorated GVHD mortality and morbidity. Together, our results indicate that donor T cells use glycolysis as the predominant metabolic process after allogeneic HCT and suggest that glycolysis has potential as a therapeutic target for the control of GVHD. PMID- 26950420 TI - Macrophages sustain HIV replication in vivo independently of T cells. AB - Macrophages have long been considered to contribute to HIV infection of the CNS; however, a recent study has contradicted this early work and suggests that myeloid cells are not an in vivo source of virus production. Here, we addressed the role of macrophages in HIV infection by first analyzing monocytes isolated from viremic patients and patients undergoing antiretroviral treatment. We were unable to find viral DNA or viral outgrowth in monocytes isolated from peripheral blood. To determine whether tissue macrophages are productively infected, we used 3 different but complementary humanized mouse models. Two of these models (bone marrow/liver/thymus [BLT] mice and T cell-only mice [ToM]) have been previously described, and the third model was generated by reconstituting immunodeficient mice with human CD34+ hematopoietic stem cells that were devoid of human T cells (myeloid-only mice [MoM]) to specifically evaluate HIV replication in this population. Using MoM, we demonstrated that macrophages can sustain HIV replication in the absence of T cells; HIV-infected macrophages are distributed in various tissues including the brain; replication-competent virus can be rescued ex vivo from infected macrophages; and infected macrophages can establish de novo infection. Together, these results demonstrate that macrophages represent a genuine target for HIV infection in vivo that can sustain and transmit infection. PMID- 26950422 TI - Targeting prion-like protein doppel selectively suppresses tumor angiogenesis. AB - Controlled and site-specific regulation of growth factor signaling remains a major challenge for current antiangiogenic therapies, as these antiangiogenic agents target normal vasculature as well tumor vasculature. In this article, we identified the prion-like protein doppel as a potential therapeutic target for tumor angiogenesis. We investigated the interactions between doppel and VEGFR2 and evaluated whether blocking the doppel/VEGFR2 axis suppresses the process of angiogenesis. We discovered that tumor endothelial cells (TECs), but not normal ECs, express doppel; tumors from patients and mouse xenografts expressed doppel in their vasculatures. Induced doppel overexpression in ECs enhanced vascularization, whereas doppel constitutively colocalized and complexed with VEGFR2 in TECs. Doppel inhibition depleted VEGFR2 from the cell membrane, subsequently inducing the internalization and degradation of VEGFR2 and thereby attenuating VEGFR2 signaling. We also synthesized an orally active glycosaminoglycan (LHbisD4) that specifically binds with doppel. We determined that LHbisD4 concentrates over the tumor site and that genetic loss of doppel in TECs decreases LHbisD4 binding and targeting both in vitro and in vivo. Moreover, LHbisD4 eliminated VEGFR2 from the cell membrane, prevented VEGF binding in TECs, and suppressed tumor growth. Together, our results demonstrate that blocking doppel can control VEGF signaling in TECs and selectively inhibit tumor angiogenesis. PMID- 26950423 TI - NOTCH signaling in skeletal progenitors is critical for fracture repair. AB - Fracture nonunions develop in 10%-20% of patients with fractures, resulting in prolonged disability. Current data suggest that bone union during fracture repair is achieved via proliferation and differentiation of skeletal progenitors within periosteal and soft tissues surrounding bone, while bone marrow stromal/stem cells (BMSCs) and other skeletal progenitors may also contribute. The NOTCH signaling pathway is a critical maintenance factor for BMSCs during skeletal development, although the precise role for NOTCH and the requisite nature of BMSCs following fracture is unknown. Here, we evaluated whether NOTCH and/or BMSCs are required for fracture repair by performing nonstabilized and stabilized fractures on NOTCH-deficient mice with targeted deletion of RBPjk in skeletal progenitors, maturing osteoblasts, and committed chondrocytes. We determined that removal of NOTCH signaling in BMSCs and subsequent depletion of this population result in fracture nonunion, as the fracture repair process was normal in animals harboring either osteoblast- or chondrocyte-specific deletion of RBPjk. Together, this work provides a genetic model of a fracture nonunion and demonstrates the requirement for NOTCH and BMSCs in fracture repair, irrespective of fracture stability and vascularity. PMID- 26950425 TI - Blocking mitochondrial calcium release in Schwann cells prevents demyelinating neuropathies. PMID- 26950424 TI - H7N9 influenza virus neutralizing antibodies that possess few somatic mutations. AB - Avian H7N9 influenza viruses are group 2 influenza A viruses that have been identified as the etiologic agent for a current major outbreak that began in China in 2013 and may pose a pandemic threat. Here, we examined the human H7 reactive antibody response in 75 recipients of a monovalent inactivated A/Shanghai/02/2013 H7N9 vaccine. After 2 doses of vaccine, the majority of donors had memory B cells that secreted IgGs specific for H7 HA, with dominant responses against single HA subtypes, although frequencies of H7-reactive B cells ranged widely between donors. We isolated 12 naturally occurring mAbs with low half maximal effective concentrations for binding, 5 of which possessed neutralizing and HA-inhibiting activities. The 5 neutralizing mAbs exhibited narrow breadth of reactivity with influenza H7 strains. Epitope-mapping studies using neutralization escape mutant analysis, deuterium exchange mass spectrometry, and x-ray crystallography revealed that these neutralizing mAbs bind near the receptor-binding pocket on HA. All 5 neutralizing mAbs possessed low numbers of somatic mutations, suggesting the clones arose from naive B cells. The most potent mAb, H7.167, was tested as a prophylactic treatment in a mouse intranasal virus challenge study, and systemic administration of the mAb markedly reduced viral lung titers. PMID- 26950426 TI - Risk Factors for Progression of Early Age-Related Macular Degeneration in Koreans. AB - PURPOSE: To identify risk factors for the progression of early age-related macular degeneration (AMD) in Koreans. METHODS: This study was conducted at a health-screening center and followed a prospective cohort study design. Of 10,890 participants older than 50 years, 318 (2.92%) presented with early AMD. Among these 318 participants, we re-examined 172 participants after a mean duration of 4.4 years. Progression was defined by the Age-Related Eye Disease Study (AREDS) simplified AMD severity scale. Multivariable logistic regression was used to examine associations between AMD progression and baseline physical, demographic, behavioral, and ocular characteristics. RESULTS: Of the 172 participants with early AMD who were re-examined, 34 (19.8%) had progression. Multivariable analyses revealed that current smoking (odds ratio, OR, 7.0, 95% confidence interval, CI, 1.4-34.4, adjusted for age, alcohol consumption, body mass index, BMI, blood pressure, BP, total cholesterol, and high density lipoprotein, HDL, cholesterol) and hypertension (OR 10.3, 95% CI 1.9-55.7, adjusted for age, smoking status, alcohol consumption, BMI, total cholesterol, and HDL cholesterol) were independently associated with progression of early AMD. Additionally, the presence of a central drusen lesion within one-third disc diameter of the macula (age-adjusted OR 4.8, 95% CI 1.3-17.6) and 20 or more drusen (age adjusted OR 7.8, 95% CI 2.5-24.0) were independently associated with progression of early AMD. CONCLUSION: Current smoking, hypertension, central drusen location, and increasing number of drusen were associated with an increased risk of early AMD progression in Koreans. PMID- 26950427 TI - Biomolecular features of inflammation in obese rheumatoid arthritis patients: management considerations. AB - Adipose tissue is an active organ playing a role not only in metabolism but also in immune and inflammatory processes, releasing several pro-inflammatory mediators. This can explain the possible association between obesity and rheumatoid arthritis (RA) and its role in the progression of the disease. Adipose and synovial tissues share common histological features of local inflammation in terms of activation of target tissues infiltrating cells (i.e. myeloid cells). Among the so-called adipocytokines, PEDF and Chemerin orchestrate the cellular cross-talk between adipose and myeloid cells, being possible biomarkers to monitor the effect of weight loss or the decrease of adipose tissue in patients with RA. Moreover, dietary intervention has been demonstrated to reduce Chemerin as well as IL-6 and MCP-1 expression. Finally, epigenetic regulators such as micro-RNAs (i.e. miR-155) are key regulators of myeloid cells activation in RA and obesity as well as in adipocytes. In this review, we will summarize the biological link between obesity/overweight state and RA focusing on pathophysiological mechanisms, consequences and management considerations. PMID- 26950429 TI - Platelet-derived sphingosine-1-phosphate and inflammation: from basic mechanisms to clinical implications. AB - Beyond key functions in hemostasis and thrombosis, platelets are recognized as key players of inflammation, an underlying feature of a variety of diseases. In this regard, platelets act as a circulating source of several pro- and anti inflammatory molecules, which are secreted from their intracellular stores upon activation. Among them, mounting evidence highlights a crucial role of sphingosine-1-phosphate (S1P), a multifunctional sphingoid mediator. S1P-induced pleiotropic effects include those crucial in inflammatory processes, such as the maintenance of the endothelial barrier integrity, and leukocyte activation and recruitment at the injured site. This review outlines the peculiar features and molecular mechanisms that allow platelets for acting as a unique factory that produces and stores S1P in large quantities. A particular emphasis is placed on the autocrine and paracrine roles of S1P derived from the "inflamed" platelets, highlighting the role of its cross-talk with endothelial and blood cells involved in inflammation, and the mechanisms of its contribution to the development and progression of inflammatory diseases. Finally, potential clinical implications of platelet-derived S1P as diagnostic tool of inflammatory severity, and as therapeutic target in inflammation are discussed. PMID- 26950430 TI - Routine urine protein/creatinine ratio testing in an outpatient setting of Danish HIV-infected individuals. PMID- 26950432 TI - Daylight saving time and myocardial infarction in Finland. PMID- 26950431 TI - What is in a label? Multiple meanings of 'MSM' among same-gender-loving Black men in Mississippi. AB - Men who have sex with men (MSM) and other same-gender-loving (SGL) men continue to be disproportionately affected by HIV and AIDS, particularly among the Black population. Innovative strategies are needed to support the health of this community; however, public health efforts primarily approach MSM as a monolithic population erasing the diverse identities, practices, and sexualities within and beyond this category. To better understand diversity within MSM in a geographic region with the largest proportion of Black Americans in the U.S.A. and among the most heavily affected by the epidemic, the Deep South, we conducted four focus groups (n = 29) with Black men who reported having sex with other men residing in Jackson, Mississippi. Results suggest multiple overlapping usages of MSM as identity and behaviour, reflecting internalisation of behavioural categories and co-creation of identities unique to the Black community. These narratives contribute to the literature by documenting the evolving understandings of the category 'MSM' among Black men to reflect intersections between race, socioeconomic status, sexual behaviour, sexuality, subjectivities, and social context. Findings suggest the current monolithic approach to treating MSM may limit public health efforts in developing effective HIV prevention and promotion programmes targeting SGL Black men in the Deep South. PMID- 26950433 TI - Poultry management: a useful tool for the control of necrotic enteritis in poultry. AB - The intestinal ecosystem of poultry has been inevitably changed as a result of the ban of antimicrobial growth promoters. The re-emergence of necrotic enteritis has been the most significant threat for the poultry industry, which, in clinical form, causes high mortality and in subclinical forms, affects growth and feed conversion. It is one of the most common and economically devastating bacterial diseases in modern broiler flocks in terms of performance, welfare and mortality. Necrotic enteritis is a multi-factorial disease process, in which a number of co factors are usually required to precipitate an outbreak of the disease. Although, Clostridium perfringens has been identified as the aetiological agent of the disease, the predisposing factors that lead to over-proliferation of C. perfringens and the subsequent progression to disease are poorly understood. Any factor that causes stress in broiler chicks could suppress the immune system and disturb the balance of the intestinal ecosystem, in such a way that the risk of a necrotic enteritis (NE) outbreak increases. Poultry management could significantly affect the pathogenesis of NE. In particular, feed restriction and coccidiosis vaccination can protect against NE, while extreme house temperature, feed mycotoxins and high stocking density predispose to NE. It becomes really important to understand the pathogenesis of the disease, as well as to clarify the interactions between husbandry, nutritional and infectious factors and the outbreak of necrotic enteritis. This is necessary and extremely important in order to develop managerial strategies at the farm level to control the incidence and severity of the disease in the post-antibiotic era. PMID- 26950428 TI - Transgenerational latent early-life associated regulation unites environment and genetics across generations. AB - The origin of idiopathic diseases is still poorly understood. The latent early life associated regulation (LEARn) model unites environmental exposures and gene expression while providing a mechanistic underpinning for later-occurring disorders. We propose that this process can occur across generations via transgenerational LEARn (tLEARn). In tLEARn, each person is a 'unit' accumulating preclinical or subclinical 'hits' as in the original LEARn model. These changes can then be epigenomically passed along to offspring. Transgenerational accumulation of 'hits' determines a sporadic disease state. Few significant transgenerational hits would accompany conception or gestation of most people, but these may suffice to 'prime' someone to respond to later-life hits. Hits need not produce symptoms or microphenotypes to have a transgenerational effect. Testing tLEARn requires longitudinal approaches. A recently proposed longitudinal epigenome/envirome-wide association study would unite genetic sequence, epigenomic markers, environmental exposures, patient personal history taken at multiple time points and family history. PMID- 26950434 TI - Risk Factors and Screening for Trypanosoma cruzi Infection of Dutch Blood Donors. AB - BACKGROUND: Blood donors unaware of Trypanosoma cruzi infection may donate infectious blood. Risk factors and the presence of T. cruzi antibodies in at-risk Dutch blood donors were studied to assess whether specific blood safety measures are warranted in the Netherlands. METHODOLOGY: Birth in a country endemic for Chagas disease (CEC), having a mother born in a CEC, or having resided for at least six continuous months in a CEC were considered risk factors for T. cruzi infection. From March through September 2013, risk factor questions were asked to all donors who volunteered to donate blood or blood components. Serum samples were collected from donors reporting one or more risk factors, and screened for IgG antibodies to T. cruzi by EIA. RESULTS: Risk factors for T. cruzi infection were reported by 1,426 of 227,278 donors (0.6%). Testing 1,333 at-risk donors, none (0.0%; 95%, CI 0.0-0.4%) was seroreactive for IgG antibodies to T. cruzi. A total of 472 donors were born in a CEC; 553 donors reported their mother being born in a CEC; and 1,121 donors reported a long-term stay in a CEC. The vast majority of reported risk factors were related to Suriname and Brazil. Overall, the participants resided for 7,694 years in CECs, which equals 2.8 million overnight stays. Of those, 1.9 million nights were spent in Suriname. CONCLUSIONS/SIGNIFICANCE: Asymptomatic T. cruzi infection appears to be extremely rare among Dutch blood donors. Blood safety interventions to mitigate the risk of T. cruzi transmission by transfusion would be highly cost-ineffective in the Netherlands, and are thus not required. PMID- 26950435 TI - Characterization of Scattered X-Ray Photons in Dental Cone-Beam Computed Tomography. AB - PURPOSE: Scatter is a very important artifact causing factor in dental cone-beam CT (CBCT), which has a major influence on the detectability of details within images. This work aimed to improve the image quality of dental CBCT through scatter correction. METHODS: Scatter was estimated in the projection domain from the low frequency component of the difference between the raw CBCT projection and the projection obtained by extrapolating the model fitted to the raw projections acquired with 2 different sizes of axial field-of-view (FOV). The function for curve fitting was optimized by using Monte Carlo simulation. To validate the proposed method, an anthropomorphic phantom and a water-filled cylindrical phantom with rod inserts simulating different tissue materials were scanned using 120 kVp, 5 mA and 9-second scanning time covering an axial FOV of 4 cm and 13 cm. The detectability of the CT image was evaluated by calculating the contrast-to noise ratio (CNR). RESULTS: Beam hardening and cupping artifacts were observed in CBCT images without scatter correction, especially in those acquired with 13 cm FOV. These artifacts were reduced in CBCT images corrected by the proposed method, demonstrating its efficacy on scatter correction. After scatter correction, the image quality of CBCT was improved in terms of target detectability which was quantified as the CNR for rod inserts in the cylindrical phantom. CONCLUSIONS: Hopefully the calculations performed in this work can provide a route to reach a high level of diagnostic image quality for CBCT imaging used in oral and maxillofacial structures whilst ensuring patient dose as low as reasonably achievable, which may ultimately make CBCT scan a reliable and safe tool in clinical practice. PMID- 26950437 TI - Protective Role of Sirtuin3 (SIRT3) in Oxidative Stress Mediated by Hepatitis B Virus X Protein Expression. AB - BACKGROUND/AIM: The hepatitis B virus (HBV) infection is accompanied by the induction of oxidative stress, especially mediated by HBV X protein (HBx). Oxidative stress has been implicated in a series of pathological states, such as DNA damage, cell survival and apoptosis. However, the host factor by which cells protect themselves under this oxidative stress is poorly understood. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we first confirmed that HBV infection significantly induced oxidative stress. Moreover, viral protein HBx plays a major role in the oxidative stress induced by HBV. Importantly, we found that mitochondrial protein SIRT3 overexpression could decrease reactive oxygen species (ROS) induced by HBx while SIRT3 knockdown increased HBx-induced ROS. Importantly, SIRT3 overexpression abolished oxidative damage of HBx-expressing cells as evidenced by gammaH2AX and AP sites measurements. In contrast, SIRT3 knockdown promoted HBx-induced oxidative damage. In addition, we also observed that oxidant H2O2 markedly promoted HBV replication while the antioxidant N acetyl-L-cysteine (NAC) inhibited HBV replication. Significantly, SIRT3 overexpression inhibited HBV replication by reducing cellular ROS level. CONCLUSIONS/SIGNIFICANCE: Collectively, these data suggest HBx expression induces oxidative stress, which promotes cellular oxidative damage and viral replication during HBV pathogenesis. Mitochondrial protein SIRT3 protected HBx expressing cells from oxidative damage and inhibited HBV replication possibly by decreased cellular ROS level. These studies shed new light on the physiological significance of SIRT3 on HBx-induced oxidative stress, which can contribute to the liver pathogenesis. PMID- 26950436 TI - Effects of Ranolazine on Astrocytes and Neurons in Primary Culture. AB - Ranolazine (Rn) is an antianginal agent used for the treatment of chronic angina pectoris when angina is not adequately controlled by other drugs. Rn also acts in the central nervous system and it has been proposed for the treatment of pain and epileptic disorders. Under the hypothesis that ranolazine could act as a neuroprotective drug, we studied its effects on astrocytes and neurons in primary culture. We incubated rat astrocytes and neurons in primary cultures for 24 hours with Rn (10-7, 10-6 and 10-5 M). Cell viability and proliferation were measured using trypan blue exclusion assay, MTT conversion assay and LDH release assay. Apoptosis was determined by Caspase 3 activity assay. The effects of Rn on pro inflammatory mediators IL-beta and TNF-alpha was determined by ELISA technique, and protein expression levels of Smac/Diablo, PPAR-gamma, Mn-SOD and Cu/Zn-SOD by western blot technique. In cultured astrocytes, Rn significantly increased cell viability and proliferation at any concentration tested, and decreased LDH leakage, Smac/Diablo expression and Caspase 3 activity indicating less cell death. Rn also increased anti-inflammatory PPAR-gamma protein expression and reduced pro-inflammatory proteins IL-1 beta and TNFalpha levels. Furthermore, antioxidant proteins Cu/Zn-SOD and Mn-SOD significantly increased after Rn addition in cultured astrocytes. Conversely, Rn did not exert any effect on cultured neurons. In conclusion, Rn could act as a neuroprotective drug in the central nervous system by promoting astrocyte viability, preventing necrosis and apoptosis, inhibiting inflammatory phenomena and inducing anti-inflammatory and antioxidant agents. PMID- 26950438 TI - Past Human Disturbance Effects upon Biodiversity are Greatest in the Canopy; A Case Study on Rainforest Butterflies. AB - A key part of tropical forest spatial complexity is the vertical stratification of biodiversity, with widely differing communities found in higher rainforest strata compared to terrestrial levels. Despite this, our understanding of how human disturbance may differentially affect biodiversity across vertical strata of tropical forests has been slow to develop. For the first time, how the patterns of current biodiversity vary between three vertical strata within a single forest, subject to three different types of historic anthropogenic disturbance, was directly assessed. In total, 229 species of butterfly were detected, with a total of 5219 individual records. Butterfly species richness, species diversity, abundance and community evenness differed markedly between vertical strata. We show for the first time, for any group of rainforest biodiversity, that different vertical strata within the same rainforest, responded differently in areas with different historic human disturbance. Differences were most notable within the canopy. Regenerating forest following complete clearance had 47% lower canopy species richness than regenerating forest that was once selectively logged, while the reduction in the mid-storey was 33% and at ground level, 30%. These results also show for the first time that even long term regeneration (over the course of 30 years) may be insufficient to erase differences in biodiversity linked to different types of human disturbance. We argue, along with other studies, that ignoring the potential for more pronounced effects of disturbance on canopy fauna, could lead to the underestimation of the effects of habitat disturbance on biodiversity, and thus the overestimation of the conservation value of regenerating forests more generally. PMID- 26950439 TI - Role of Interaction and Nucleoside Diphosphate Kinase B in Regulation of the Cystic Fibrosis Transmembrane Conductance Regulator Function by cAMP-Dependent Protein Kinase A. AB - Cystic fibrosis results from mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP-dependent protein kinase A (PKA) and ATP regulated chloride channel. Here, we demonstrate that nucleoside diphosphate kinase B (NDPK-B, NM23-H2) forms a functional complex with CFTR. In airway epithelia forskolin/IBMX significantly increases NDPK-B co-localisation with CFTR whereas PKA inhibitors attenuate complex formation. Furthermore, an NDPK-B derived peptide (but not its NDPK-A equivalent) disrupts the NDPK-B/CFTR complex in vitro (19-mers comprising amino acids 36-54 from NDPK-B or NDPK-A). Overlay (Far-Western) and Surface Plasmon Resonance (SPR) analysis both demonstrate that NDPK-B binds CFTR within its first nucleotide binding domain (NBD1, CFTR amino acids 351-727). Analysis of chloride currents reflective of CFTR or outwardly rectifying chloride channels (ORCC, DIDS-sensitive) showed that the 19-mer NDPK-B peptide (but not its NDPK-A equivalent) reduced both chloride conductances. Additionally, the NDPK-B (but not NDPK-A) peptide also attenuated acetylcholine induced intestinal short circuit currents. In silico analysis of the NBD1/NDPK-B complex reveals an extended interaction surface between the two proteins. This binding zone is also target of the 19-mer NDPK-B peptide, thus confirming its capability to disrupt NDPK-B/CFTR complex. We propose that NDPK-B forms part of the complex that controls chloride currents in epithelia. PMID- 26950440 TI - Fecal Calprotectin in Healthy Children Aged 1-4 Years. AB - OBJECTIVE: Calprotectin has been well emulated recently in adults as well as in children. The aim of this study was to assess fecal calprotectin concentrations in healthy children aged from 1 to 4 years. METHODS: Volunteers were enlisted from 3 nurseries. A brief questionnaire was used to ensure these children meet the inclusion criteria, and some clinical and sociodemographic factors were collected. Anthro software (version 3.1) was used to calculated Length-for-age Z scores (LAZ), weight-for-age Z-scores (WAZ), and weight-for-length Z-scores (WLZ) respectively. Fecal calprotectin was detected by a commercially available ELISA. RESULTS: In total 274 children were recruited, with age ranging from 1 to 4 years old. The median FC concentration was 83.19 MUg/g [range 4.58 to 702.50 MUg/g, interquartile range (IQR) 14.69-419.45 MUg/g] or 1.92 log10 MUg/g (range 0.66 log10 to 2.85 log10 MUg/g, IQR 1.17 log10-2.62 log10 MUg/g). All of the children were divided into three groups, 1-2 years (12-24 months), 2-3 years (24-36 months), 3-4 years (36-48 months), with median FC concentrations 96.14 MUg/g (1.98 log10 MUg/g), 81.48 MUg/g (1.91 log10 MUg/g), 65.36 MUg/g (1.82 log10 MUg/g), respectively. There was similar FC level between boys and girls. FC concentrations showed a downward trend by the growing age groups. A statistic difference was found in FC concentrations among groups 1-2 years, 2-3 years and 3 4 years (P = 0.016). In inter-groups comparison, a significant difference was found between children aged 1-2 years and children aged 3-4 years (P = 0.007). A negative correlation trend was found between age and FC concentration (Spearman's rho = -0.167, P = 0.005) in all the participants. A simple correlation was performed among WLZ, WAZ, birth weight, or birth length with FC, and there was no correlation being observed. CONCLUSION: Children aged from 1 to 4 years old have lower FC concentrations compared with healthy infants (<1years), and higher FC concentrations when comparing with children older than 4 years and adults. PMID- 26950441 TI - A Method for Producing Protein Nanoparticles with Applications in Vaccines. AB - A practical method is described for synthesizing conjugated protein nanoparticles using thioether (thiol-maleimide) cross-linking chemistry. This method fills the need for a reliable and reproducible synthesis of protein conjugate vaccines for preclinical studies, which can be adapted to produce comparable material for clinical studies. The described method appears to be generally applicable to the production of nanoparticles from a variety of soluble proteins having different structural features. Examples presented include single-component particles of the malarial antigens AMA1, CSP and Pfs25, and two component particles comprised of those antigens covalently cross-linked with the immunogenic carrier protein EPA (a detoxified form of exotoxin A from Pseudomonas aeruginosa). The average molar masses (Mw) of particles in the different preparations ranged from 487 kDa to 3,420 kDa, with hydrodynamic radii (Rh) ranging from 12.1 nm to 38.3 nm. The antigenic properties and secondary structures of the proteins within the particles appear to be largely intact, with no significant changes seen in their far UV circular dichroism spectra, or in their ability to bind conformation dependent monoclonal antibodies. Mice vaccinated with mixed particles of Pfs25 or CSP and EPA generated significantly greater antigen-specific antibody levels compared with mice vaccinated with the respective unmodified monomeric antigens, validating the potential of antigen-EPA nanoparticles as vaccines. PMID- 26950442 TI - Norm comparisons of the Spanish-language and English-language WAIS-III: Implications for clinical assessment and test adaptation. AB - This study provides a systematic comparison of the norms of 3 Spanish-language Wechsler Adult Intelligence Scales (WAIS-III) batteries from Mexico, Spain, and Puerto Rico, and the U.S. English-language WAIS-III battery. Specifically, we examined the performance of the 4 normative samples on 2 identical subtests (Digit Span and Digit Symbol-Coding) and 1 nearly identical subtest (Block Design). We found that across most age groups the means associated with the Spanish-language versions of the 3 subtests were lower than the means of the U.S. English-language version. In addition, we found that for most age ranges the Mexican subsamples scored lower than the Spanish subsamples. Lower educational levels of Mexicans and Spaniards compared to U.S. residents are consistent with the general pattern of findings. These results suggest that because of the different norms, applying any of the 3 Spanish-language versions of the WAIS-III generally risks underestimating deficits, and that applying the English-language WAIS-III norms risks overestimating deficits of Spanish-speaking adults. There were a few exceptions to these general patterns. For example, the Mexican subsample ages 70 years and above performed significantly better on the Digit Symbol and Block Design than did the U.S. and Spanish subsamples. Implications for the clinical assessment of U.S. Spanish-speaking Latinos and test adaptation are discussed with an eye toward improving the clinical care for this community. (PsycINFO Database Record PMID- 26950443 TI - Sox9-induced chondrogenesis in mesenchymal stem cells was mediated by ERK5 signal pathway. AB - Sox9 is a member of the high-mobility-group (HMG) box protein superfamily, which is expressed predominantly among cells in mesenchymal condensations during the early development of embryonic skeletons. The extracellular-signal-regulated kinase 5 (ERK5) is one of the mitogen-activated protein kinase (MAPK) family members of protein kinases. Roles for ERK5 signaling in the regulation of chondrogenesis and adult chondrocyte homeostasis have yet to be demonstrated. In this study, we found that ERK5 could down-regulate Col2al and Sox9 expression, and this down-regulation was inhibited by MEK5beta, one of ERK5 inhibitor. Furthermore, we characterized the ERK5 response with the chromatin binding profile of Sox9 in MSCs in a genome-wide manner through an analysis of ChIP-seq data. This study will help to understand the interaction between the ERK5 and Sox9, and facilitate to decipher the mechanism of chondrogenesis in mesenchymal stem cells. PMID- 26950445 TI - Genetic analysis of Iranian autosomal dominant polycystic kidney disease: new insight to haplotype analysis. AB - Autosomal Dominant Polycystic Kidney Disease (ADPKD) caused by mutations in two PKD1 and PKD2 genes. Due to the complexity of the PKD1 gene, its direct mutation screening is an expensive and time-consuming procedure. Pedigree-based haplotype analysis is a useful indirect approach to identify the responsible gene in families with multiple affected individuals, before direct mutation analysis. Here, we applied this approach to investigate 15 appropriate unrelated ADPKD families, selected from 25 families, who referred for genetic counseling. Four polymorphic microsatellite markers were selected around each PKD1 and PKD2 loci. In addition, by investigating the genomic regions, two novel flanking tetranucleotide STR markers were identified. Haplotype analysis and calculating Lod score confirmed linkage to PKD1 in 9 families (60%) and to PKD2 in 2 families (13%). Linkage to both loci was excluded in one family (6.6%). In 2 families (13%) the Lod scores were inconclusive. Causative mutation was identified successfully by direct analysis in two families with confirmed linkage, one to PKD1 and another to PKD2 locus. The study showed that determining the causative locus prior to direct mutation analysis is an efficient strategy to reduce the resources required for genetic analysis of ADPKD families. This is more prominent in PKD2-linked families. Selection of suitable markers, and appropriate PCR multiplexing strategy, using fluorescent labeled primers and 3 primer system, will also add value to this approach. PMID- 26950444 TI - Semaphorin 3A deficiency improves hypoxia-induced myocardial injury via resisting inflammation and cardiomyocytes apoptosis. AB - Ischemia/hypoxia leads to heart injuries by inducing inflammation, cardiac fibrosis and cardiomyocyte apoptosis. Semaphorin 3A (Sema 3A) plays a regulatory role during all immune response stages, and has been demonstrated to be associated with multiple diseases. However, roles of Sema 3A during myocardial ischemia/hypoxia have not been studied in full. In this study, decline in Sema 3A was discovered in hypoxia-treated myocardial cells. When this decline was enhanced by silencing of Sema 3A gene, hypoxia-induced myocardial cell injury could be partially improved. Sema 3A deficiency can resist hypoxia-induced inflammatory factors (TNF-alpha, IL-1beta and IL-6) secretion, cell viability decline, cardiomyocyte apoptosis, ROS release, ATP generation decline as well as GSH/GSSG ratio decline in H9C2 cells. Besides, hypoxia-induced bcl-2 decrease and cleaved caspase-3 increase also can be partially reversed during Sema 3A deficiency. All these findings reflect that reduced Sema 3A is a protective strategy adopted by damaged myocardial cell. Our study first shows that Sema 3A deficiency can improve hypoxia-induced myocardial cell injury, which thus offers a new insight to treatment ischemic heart disease. PMID- 26950447 TI - Differential activation and expression of insulin receptor substrate 1 (IRS1) in mononuclear cells of type 2 diabetes patients after insulin stimulation. AB - Insulin regulates the glucose homeostasis by inducing tyrosine phosphorylation of insulin receptor substrate (IRS) proteins. IRS1 is the best studied member of this family and insulin-induced Tyrosine phosphorylation of (YXXM) motifs provides docking site for SH2 domain-containing proteins. Recent studies have suggested that genetic and/or environmental factors may affect the expression and phosphorylation levels of IRS1, and these could be important for development of insulin resistance. To shed light to the molecular basis of type 2 diabetes we wanted to determine whether YXXM motifs are genetically modified in these patients. We have isolated mononuclear cells of eighteen type 2 diabetes patients and prepared genomic DNA and protein lysates from these cells. The genomic DNA was used to sequence IRS1 gene, and protein lysates were used to determine the expression and phosphotyrosine levels of IRS1 after insulin stimulation. Although, we did not detect any mutations at/or near the YXXM coding regions in patients' DNA, immunprecipitation analysis of IRS1 indicated decreased levels of expression and tyrosine phosphorylation of IRS1 in patient's samples compared to that of healthy controls. Our results suggest that mononuclear cells of patients can be used to test the levels of insulin responsiveness before therapy. PMID- 26950446 TI - Evaluation of MMP-7 A-181G and MMP-2 C-735T polymorphisms in healthy population from western Iran. AB - Matrix metalloproteinases (MMPs) are involved in multiple physiological and pathological processes. Variable frequency of the MMPs gene variants might affect the susceptibility to certain diseases. The aim of present study was to investigate the frequency of MMP-7 A-181G and MMP-2 C-735T variants in healthy population of Western Iran with Kurdish ethnic background. Individuals were medical students and staff members of the Medical School of Kermanshah University and blood donors that consisted of 221 females and 94 males. Control subjects were free of general and genetic diseases. Two hundred and eighty available samples including 192 females and 88 males were studied for MMP-2 C-735T polymorphism. Genomic DNA was extracted from peripheral blood leukocytes. The MMP 7 A-181G and MMP-2 C-735T polymorphisms were detected using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The prevalence of MMP-7 G allele was 40% in studied individuals. The overall frequency of MMP-2 -735T allele was 15%. There was a higher frequency of MMP-2 T allele in females (16.9%) compared to males (10.8%, p=0.059). There were 30 (13.6%) women and 8 men (8.5%) with concomitant presence of MMP-7 AG and MMP-2 CT genotypes. All nine (4.1%) individuals with combined presence of MMP-7 GG and MMP 2 CT genotypes were women. The present study reports the frequency of two MMPs gene polymorphisms in healthy population of Western Iran. Our findings might be useful in evaluating the risk of MMPs in certain diseases. Also, our study suggests genetic admixture and similarities between our population with some Asian and European populations. PMID- 26950448 TI - microRNA-23a-5p acts as a potential biomarker for sepsis-induced acute respiratory distress syndrome in early stage. AB - Sepsis is a significant cause of morbidity and mortality worldwide. Acute respiratory distress syndrome (ARDS) is the most common and serious complication of sepsis, which presents with rapid and progressive acute onset respiratory failure. The microRNA-23a-5p, as a kind of circulating microRNA (miRNA), is considered to be a candidate biomarker for cardiovascular diseases. However, correlation between ARDS and miR-23a-5p is also elusive. This study aims to investigate the role of miR-23a-5p as the biomarkers for ARDS. In this study, ARDS was induced by intraperitoneally injected with LPS of Sprague-Dawley rats and serum and lung tissues were collected. The NR8383 macrophages were stimulated with LPS. TNF-alpha, IL-1beta, and miR-23a-5p levels in serum, lung tissues and NR8383 were determined using SYBR-based miRNA quantitative real-time polymerase chain reactions (qRT-PCRs). The results indicated that serum miR-23a-5p was increased by 7 fold, 4 fold and 2 fold at 3 h, 6h, and 12h after injection of LPS, respectively. While the miR-23a-5p in NR8383 was elevated by 3.5 fold, 3 fold, 2.5 fold and 5 fold, at 3 h, 6h, 12h and 24h after stimulated with LPS, respectively. In conclusion, the miR-23a-5p might be employed as the potential biomarkers for ARDS in early stage. PMID- 26950449 TI - Isoflurane preconditioning protects rat brain from ischemia reperfusion injury via up-regulating the HIF-1alpha expression through Akt/mTOR/s6K activation. AB - The volatile anesthetic isoflurane (ISO) has been widely used in ischemia reperfusion (IR) injury because its abilities to induce and trigger recovery are faster and smoother than other agents. However, the underlying molecular mechanisms for preconditioning the ISO in protecting the brain against IR injury are still largely unclear. In this paper, we investigated the neuroprotective effect of the ISO in the in vivo and in vitro models of IR injury and evaluated the possible correlation with Akt/mTOR/s6K signaling pathway. From the in vivo studies, we demonstrated that ISO preconditioning alleviated the IR-induced neurological deficits, infarct volume, brain edema and cell apoptosis, which were mainly due to the up-regulation of the p-Akt, p-mTOR and p-s6K proteins by the histopathological detections and Western blotting assay. The in vitro studies, demonstrated that ISO preconditioning reduced the release of OGD-induced lactate dehydrogenase (LDH) and enhanced the OGD-inhibited cell viability. It has also been observed that the hypoxia inducible factor-1alpha (HIF-1alpha) was increased under ISO preconditioning. Utilization of the BEZ235, a PI3K/mTOR dual inhibitor, halted the ISO-induced up-regulation of the HIF-1alpha, and inhibited the phosphorylation of the Akt, mTOR and s6K proteins. Besides, the ISO reduced the OGD-induced cell apoptosis, which was blocked by the BEZ235. In fact, these results thus suggest that the ISO preconditioning may provide potential neuroprotection against IR injury via up-regulating the HIF-1alpha expression through the Akt/mTOR/s6K activation. PMID- 26950450 TI - Association of SHMT1 gene polymorphisms with the risk of childhood acute lymphoblastic leukemia in a sample of Iranian population. AB - The enzymes serine hydroxymethyltransferase 1 (SHMT1) regulate key reaction in folate-mediated one-carbon metabolism. In the current study we aimed to examine the possible association between SHMT1 gene polymorphisms and childhood acute lymphoblastic leukemia (ALL) in a sample of Iranian population. The rs9901160, rs2273027, rs9909104, rs1979277, and rs11868708 gene polymorphisms of SHMT1 were genotyped in 120 children diagnosed with ALL and 120 healthy children by the polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). The results showed that rs9901160, rs2273027 as well as rs1979277 polymorphism significantly increased the risk of childhood ALL (P<0.05). While, rs9909104 polymorphism significantly decreased the ALL risk (P<0.05). The rs11868708 variant was not associated with risk/protection of childhood ALL (P>0.05). In conclusion, our results suggest that the polymorphisms of SHMT1 gene are associated with childhood ALL risk in a sample of Iranian population. Further studies with larger sample sizes and different ethnicities are necessary to verify our findings. PMID- 26950451 TI - Molecular versus conventional culture for detection of respiratory bacterial pathogens in poultry. AB - Acute respiratory tract infections are leading causes of morbidity in poultry farms allover the world. Six pathogens; Escherichia coli, Mycoplasma gallisepticum, Staphylococcus aureus, Pasteurella multocida, Mannheimia haemolytica and Pseudomonas aeruginosa were involved in respiratory infections in poultry. Herein, conventional identification procedures and polymerase chain reaction (PCR) were applied for detection of the most common respiratory bacterial pathogens in clinical specimens of poultry obtained from 53 Egyptian farms with various respiratory problems and the results were compared statistically. The analyzed data demonstrated a significantly higher rate of detection of the most recovered microorganisms (P<0.05) by PCR comparing to classical culture procedures. Further, multiplex PCR could detect E. coli, M. gallisepticum, S. aureus and Ps. aeruginosa in a single reaction, however, M. haemolytica was reported in a uinplex system. According to PCR results, the most commonly recorded bacterial pathogens in examined poultry farms were E. coli and Ps. aeruginosa (54.71% each), followed by M. haemolylica (35.85%) and M. gallisepticum (20.75%). In conclusion, PCR assay offered an effective alternative to traditional typing methods for the identification and simultaneous detection of the most clinically relevant respiratory pathogens in poultry. PMID- 26950452 TI - Ghrelin inhibits oxLDL-induced inflammation in RAW264.7 mouse macrophages through down-regulation of LOX-1 expression via NF-kappaB signaling pathway. AB - Oxidized low-density lipoprotein (oxLDL) is one of the many causes of the initiation and progression of atherosclerosis, which can subsequently promote the uptake of oxLDL by macrophages and lead to inflammation in the blood vessels. In the present study, we evaluated the protective effects of ghrelin on oxLDL induced RAW264.7 mouse macrophages. Ghrelin was able to inhibit the release of several pro-inflammatory cytokines including tumor necrosis factor (TNF)-alpha and interleukin (IL)-6. In addition, ghrelin also inhibited the expression of Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) in oxLDL treated macrophages. Furthermore, we demonstrated that ghrelin could inhibit the expression of p-IkappaBalpha, and the inhibitory effects could be blocked by BAY 117082. Taken together, ghrelin possesses anti-inflammatory effects on oxLDL induced inflammation in macrophages, suggesting that it can prevent or treat atherosclerosis, and deserves to be further studied and developed to be potent drug for treating atherosclerosis. PMID- 26950453 TI - Effects of Urtica dioica dichloromethane extract on cell apoptosis and related gene expression in human breast cancer cell line (MDA-MB-468). AB - Breast cancer is the most common cancer among women in worldwide, especially in developing countries. Therefore, a large number of anticancer agents with herbal origins have been reported against this deadly disease. This study is the first to examine the cytotoxic and apoptotic effects of Urtica dioica in MDA-MB-468, human breast adenocarcinoma cells. The 3-(4,5-dimethylethiazol-2 yl)-2,5- diphenyltetrazolium (MTT) reduction and trypan-blue exclusion assay were performed in MDA-MB-468 cells as well as control cell line L929 to analyze the cytotoxic activity of the dichloromethane extract. In addition, Apoptosis induction of Urtica dioica on the MDA-MB-468 cells was assessed using TUNEL (terminal deoxy transferase (TdT)-mediated dUTP nick- end labeling) assay and DNA fragmentation analysis and real-time polymerase chain reaction (PCR). The results showed that the extract significantly inhibited cell growth and viability without inducing damage to normal control cells. Nuclei Staining in TUNEL and DNA fragments in DNA fragmentation assay and increase in the mRNA expression levels of caspase-3, caspase-9, decrease in the bcl2 and no significant change in the caspase-8 mRNA expression level, showed that the induction of apoptosis was the main mechanism of cell death that induce by Urtica dioica extract. Our results suggest that urtica dioica dichloromethane extract may contain potential bioactive compound(s) for the treatment of breast adenocarcinoma. PMID- 26950454 TI - The effect of celecoxib and its combination with imatinib on human HT-29 colorectal cancer cells: Involvement of COX-2, Caspase-3, VEGF and NF-kappaB genes expression. AB - It has been shown that combination of imatinib (IM) with other agents may have some advantages in avoiding toxicity and resistance caused by this drug. The selective cyclooxygenase-2 inhibitor, celecoxib (CX), has been known to have antitumor and chemo-sensitizing effect in the treatment of colorectal cancer. In this study, we investigated the effectiveness of CX and its combination with anticancer agent IM on human colorectal cancer HT-29 cell and their probable molecular targets. Cultured HT-29 cells were exposed to IC50 dose of CX, IM, and their combination (half dose of IC50) for 24 hours to assess their effect on proliferation inhibition by MTT assay. The caspase-3 activity was estimated in HT 29 cells with colorimetric kit. COX-2, Caspase-3, VEGF and NF-kappaB genes expression was also investigated using real-time PCR method. Combined treatment with IM and CX, resulted in a significant (P?0.05) decrease in cell viability and increased caspase-3 enzyme activity. Decreased COX-2 gene expression has been found in CX and combined treated group. Significant increase in Caspase-3 gene expression has been shown in IM and combined treated cells. In conclusion, the present in vitro study with colon cancer cell line demonstrated that CX and its combination with IM improved the anticancer activity of each component. Caspase-3 and COX-2 dependent molecular targets seem to be involved in mediating the anti proliferative effects of IM and CX combination. Of course, the other molecular pathways are also likely to play the role and should be explored in future studies. PMID- 26950455 TI - Pravastatin and C reactive protein modulate protease- activated receptor-1 expression in vitro blood platelets. AB - Protease-activated receptor-1 (PAR-1) plays an important role in mediating activation of human platelets by thrombin. However, mechanism of statin in ADP induced platelet PAR-1 expression is also unknown. Aggregometry, flow cytometry, immunoblotting and ELISA were used to determine role of pravastatin participating in ADP-induced platelet activation and PAR-1 expression. ADP stimulation significantly increased PAR-1 expression on platelets. PAR-1 antagonist SCH-79797 inhibited platelet aggregation as well as decreased platelet P-selectin expression induced by ADP. CRP inhibited PAR-1 expression induced by ADP in a concentration-dependent manner. Pravastatin treatment reduced PAR-1 expression in a concentration-dependent manner. Combination treatment of CRP and Pravastatin significantly reduced platelet PAR-1 expression induced by ADP. By western-blot analysis, pravastatin treatment did not influence total PAR-1 after ADP treatment. CRP decreased platelet total PAR-1 expression induced by ADP. Pravastatin and CRP reduced TXB2 formation by ADP significantly. CRP decreased thrombin fragment F1+2 level with ADP treatment. Pravastatin, in contrast, did not influence F1+2 level. Upon treatment with Pravastatin reduced platelet LOX-1 expression induced by ADP. In conclusion, PAR-1 served as a critical mechanism to relay platelet activation process induced by ADP. CRP and pravastatin reduce PAR 1 expression in platelet by ADP pathway. PMID- 26950456 TI - Effects of c-Jun N-terminal kinase on Activin A/Smads signaling in PC12 cell suffered from oxygen-glucose deprivation. AB - Activin A (Act A), a member of transforming growth factor-beta (TGF-beta) superfamily, is an early gene in response to cerebral ischemia. Growing evidences confirm the neuroprotective effect of Act A in ischemic injury through Act A/Smads signal activation. In this process, regulation networks are involved in modulating the outcomes of Smads signaling. Among these regulators, crosstalk between c-Jun N-terminal kinase (JNK) and Smads signaling has been found in the TGF-beta induced epithelial-mesenchymal transition. However, in neural ischemia, the speculative regulation between JNK and Act A/Smads signaling pathways has not been clarified. To explore this issue, an Oxygen Glucose Deprivation (OGD) model was introduced to nerve-like PC12 cells. We found that JNK signal activation occurred at the early time of OGD injury (1 h). Act A administration suppressed JNK phosphorylation. In addition, JNK inhibition could elevate the strength of Smads signaling and attenuate neural apoptosis after OGD injury. Our results indicated a negative regulation effect of JNK on Smads signaling in ischemic injury. Taken together, JNK, as a critical site for neural apoptosis and negative regulator for Act A/Smads signaling, was presumed to be a molecular therapeutic target for ischemia. PMID- 26950457 TI - Down-regulation of miR-144 after Mycobacterium tuberculosis infection promotes inflammatory factor secretion from macrophages through the Tpl2/ERK pathway. AB - Pulmonary tuberculosis is one of the deadliest human diseases and mainly occurs when the immune system is impaired. MicroRNAs (miRNAs) have a critical role in regulating innate and adaptive immunity. Based on previous reports that Mycobacterium tuberculosis (M.tb) can modulate host cell miRNA expression, this study aimed to investigate expression changes in miR-144 and miR-144 regulate macrophage function via targeting of tumor progression locus 2 (Tpl2, also named MAP3K8) and extracellular signal-regulated kinase (ERK) signaling. I examined the miRNA expression profile of M.tb-infected monocyte-derived macrophages (MDMs) by gene expression profiling and quantitative real-time PCR (qRT-PCR). miR-144 is obviously down-regulated in MDMs infected with M.tb and directly binds to the 3' UTR of Tpl2, acting as a negative regulator. Moreover, inhibiting miR-144 or over expression of Tpl2 can activate the ERK signaling pathway by inducing ERK1/2 phosphorylation. At the same time, TNF-alpha, IL-1beta and IL-6 secretion were significantly accelerated. Taken together, these results suggest that miR-144 is expressed at a low level in M.tb-infected MDMs and acts as a negative regulator for Tpl2 target, which is closely connected with ERK signaling that regulates inflammatory factor secretion. PMID- 26950458 TI - Characterization of Methicillin Resistant Staphylococcus aureus isolated from human and animal samples in Egypt. AB - Staphylococcus aureus (S. aureus) has been one of the most problematic pathogens. Methicillin Resistant S. aureus (MRSA) has emerged as a major concern for both human and animal. Antibiotic resistance genes dissemination might be possible between human and animal bacteria. The aim of this study is to show phenotypic and genotypic diversity of human and animal MRSA isolates. Antibiogram typing and biofilm production were used as a primary phenotypic typing tool for the characterization of (40) animal and (38) human MRSA isolates. Genetic typing based on sequencing of 16S rRNA gene and virulence gene profiles were done. Antimicrobial resistance profiles of the animal isolates showed little evidence of widespread of resistance, although this was seen in many human isolates. The biofilm production was detected in higher percentage among animal isolates. Based on the genetic typing and multiple antibiotic resistance (MAR) index, the majority of animal isolates clustered into lineages that were not found in human isolates. Animal and human MRSA isolates showed diversity in antibiotic resistance and virulence gene profiles may be due to host adaptation or chances for contamination between the two hosts were not present in our study. PMID- 26950459 TI - Rapid amplification system for recombinant protein production in Chinese Hamster Ovary (CHO) Cells. AB - Recombinant therapeutic proteins have changed the face of modern medicine in the present trend and they continue to provide innovative therapies for deadly diseases. This study describes the development of a novel stable expression system for rapid amplification of genes in Chinese Hamster Ovary (CHO) cells. The expression system consists of a host CHO cell line and an expression vector (pUB PyOri-D-C) which encodes for Polyomavirus (Py) Origin of Replication (PyOri) for amplification of integrated genes in the presence of Py Large T Antigen (PyLT) and Dihydrofolate Reductase (DHFR) selectable marker gene for selection in the presence of Methotrexate (MTX). Use of both PyOri/PyLT and DHFR can reduce the number of rounds of selection and amplification required for isolation of high producing clones. The efficiency of pUB-PyOri-D-C was compared with that of pUB-D C plasmid using Green fluorescent protein (GFP) and Erythropoietin (EPO) as reporter proteins. Our results showed that pUB-PyOri-D-C-EPO can help development of high expressing clone in one round of selection/amplification as compared to multiple rounds of selection/amplification with pUB-D-C-EPO plasmid. CHO-DG44/EPO clone generated using pUB-PyOri-D-C-EPO gave a productivity of 119 mg/L in shake flask. PMID- 26950460 TI - Gastric Cancer and Helicobacter pylori: Impact of hopQII Gene. AB - The Helicobacter pylori is a Gram-negative, microaerophilic bacterium found usually in the stomach and use a number of mechanisms to survive in the stomach lumen. The presence of these bacteria in the stomach can lead to gastritis and reduction in stomach acid production. Acute inflammation can directly damage to the peripheral cells that are responsible for the secretion of acid. The risk of developing gastric carcinoma is associated to heterogeneity of Helicobacter pylori virulence factors. The HopQII is one of the outer membrane proteins involved in bacterial adherence to gastric mucosa and has been suggested to also play a role in the virulence of H. pylori. The purpose of the current study was to investigate the association between different H. pylori virulence hopQII allele and patients with gastroduodenal disorders. For this purpose 58 stomach biopsies of patients with gastric cancer and 100 saliva samples from healthy individuals were collected. Then genomic DNA was purified and PCR for was done for desired genes via specific primers. The H. pylori infections were diagnosed by PCR for GlmM gene. Then frequencies of hopQII+ and hopQII- genotypes was determined in H. pylori infected cases. Statistical analysis showed that there were not significant differences between healthy and diseased ones for genotype hopQII+. PMID- 26950461 TI - Lentiviral mediated overexpression of Insulin like Growth Factor-1 in mouse myoblast. AB - Insulin-like growth factor gene (IGF-1) is one of the most important growth factors that plays a key role in the proliferation and differentiation of muscle cells. IGF-1 is also a radial stimulant in muscle hypertrophy in mammals. In our study, we constructed a lentiviral vector inducing an overexpression of IGF-1 in order to study the regulating mechanisms of this gene. The IGF-1 gene was cloned into the lentiviral shuttle plasmid pCDH-cGFP and the recombinant lentiviral vector was transducted into myoblast C2C12 cell line. The overexpression of IGF-1 was confirmed by RT-PCR and western blotting for IGF-1 receptor gene. Additionally, chemiluminescence results also showed that the concentration of IGF 1 in the transduced cells significantly increased compared to the control group. The results of our study suggests that constructed recombinant lentiviral vector can potentially be used for regulating the expression of IGF-1 in myoblast C2C12 cells. PMID- 26950463 TI - Synthesis of Coordinatively Unsaturated Tetravalent Actinide Complexes with eta(5) Coordination of Pyrrole. AB - The synthesis of new actinide complexes utilizing bridged alpha-alkyl-pyrrolyl ligands is presented. Lithiation of the ligands followed by treatment with 1 equiv of actinide tetrachloride (uranium or thorium) produces the desired complex in good yield. X-ray diffraction studies reveal unique eta(5):eta(5) coordination of the pyrrolyl moieties; when the nonsterically demanding methylated ligand is used, rapid addition of the lithiated ligand solution to the metal precursor forms a bis-ligated complex that reveals eta(5):eta(1) coordination as determined by crystallographic analysis. PMID- 26950462 TI - A study on local expression of NF-kappaB, CCL2 and their involvement in intratumoral macrophage infiltration in breast cancer. AB - NF-kappaB has been implicated in mechanisms promoting inflammation in tumor microenvironment leading to breast cancer metastasis. Owing to critical role of CCL2 during metastasis, particularly in its capacity to act as a chemoattractant for macrophages and their precursors i.e monocytes, we decided to explore if pro metastatic function of NF-kappaB could be attributable to CCL2 and/or macrophage infiltration. Through our study we provide experimental and clinical evidence in support of co-ordinated expression of chemokines CCL2, NF-kappaB and intratumoral macrophage content particularly with respect to breast cancer, with an additional evidence of these three variables being key determinant for poor prognosis and diminished survival amongst breast cancer patients both independently as well in a coordinated manner. The mean fold increase in mRNA expression level of NF kappaB and CCL2 indicated that it was over expressed 13.57 and 13.18 fold respectively in tumor tissue as compared to adjacent normal tissue. Among these Immunohistochemistry expression of CD68 marker showed that 62 patients (66.7%) had low/moderate CD68 expression while 31 patients (33.3%) had strong expression. All three variables viz.NF-kappaB, CCL2 and CD68 showed significant (p<0.05 or p<0.01 or p<0.001) respectively associations with both clinicopathological (except CD68 with stage) and hormone receptors (ER, PR and Her2/neu) and their co expressions indicating these as predictors of breast cancer. In this study we decipher the possible molecular mechanism by way of which NF-kappaB may promote breast cancer metastasis. Our study has clinical relevance as it establishes significance of these three variables as potential predictive markers to be employed in breast cancer. PMID- 26950464 TI - Neoadjuvant Therapy for Pancreatic Cancer: Systematic Review of Postoperative Morbidity, Mortality, and Complications. AB - The purpose of this review was to assess whether neoadjuvant chemotherapy and chemoradiotherapy (CRT) result in differential postoperative morbidity and mortality as compared with pancreatic tumor resection surgery alone. Using PRISMA guidelines and the PubMed search engine, we reviewed all prospective phase II trials of neoadjuvant chemotherapy and CRT for pancreatic cancer that examined postoperative morbidities and mortalities. A total of 30 articles were identified, collated, and analyzed. Risks of postoperative complications vary based on trial. With surgery alone, the most common postoperative complications included delayed gastric emptying (DGE) (17% to 24%), pancreatic fistula (10% to 20%), anastomotic leaks (0% to 15%), postoperative bleeding (2% to 13%), and infections/sepsis (17% to 20%). With surgery alone, the mortality was <5%. Neoadjuvant chemotherapy showed comparable fistula rates (3% to 4%), leaks (3% to 11%), infection (3% to 7%), with mortality 0% to 4% in all but 1 study. CRT for resectable/borderline resectable patients also showed comparable complication rates: DGE (6% to 15%), fistulas (2% to 3%), leaks (3% to 7%), bleeding/hemorrhage (2% to 13%), infections/sepsis (3% to 19%), with 9/13 studies showing a mortality of <=4%. As compared with initially borderline/resectable tumors, CRT for initially unresectable tumors (despite less data) showed higher complication rates: DGE (13% to 33%), fistulas (3% to 25%), infections/sepsis (3% to 16%). However, the confounding factor of the potentially higher tumor burden as an associative agent remains. The only parameters slightly higher than historical surgery-only complication rates were leaks and bleeding/hemorrhage (13% to 20%). Mortality rates in these patients were consistently 0%, with 2 outliers. Hence, neoadjuvant chemotherapy/CRT is safe from a postoperative complication standpoint, without significant increases in complication rates compared with surgery alone. Resectable and borderline resectable patients have fewer complications as compared with unresectable patients, although data for the latter are lacking. PMID- 26950465 TI - Early-stage Uterine Pure and Mixed Clear Cell Carcinoma: Outcomes and Recurrence With and Without Adjuvant Therapy. AB - OBJECTIVE: Clear cell carcinoma (CCC) of the uterus is a rare but aggressive histology for which the role of adjuvant therapy for stage I-II disease is unclear. Our study investigated outcomes and patterns of failure in these patients. METHODS: We found 64 cases of CCC, including 26 of pure CCC, 22 mixed with endometrioid adenocarcinoma, and 16 mixed with uterine papillary serous carcinoma. Adjuvant treatment was given to 55%. RESULTS: Median follow-up was 51.9 months. By Kaplan-Meier estimate, 5-year vaginal recurrence-free survival (RFS) was 91.3%, pelvic RFS was 92.6%, distant metastasis RFS was 81.6%, disease free survival was 79.6%, and overall survival was 79.7%. Median time to recurrence was 20.7 months (range, 2 to 40.5 mo). Patients treated adjuvantly had higher proportion of stage II disease (40% vs. 6.9% observed, P=0.0031) and 20% (7/35) recurred. There were no significant differences in outcomes by histologic subtypes but numerically more recurrences with uterine papillary serous involvement. By univariate analysis, higher stage, presence of lymphovascular invasion, and lack of lymph node dissection were predictive of worse overall survival. Age 65 years and above was predictive of worse cancer-specific survival. Of 12 who progressed, only 1 was salvaged and 11 died of disease. Of progressors, 10 had documented distant metastasis. Median time from recurrence to death was 4.5 months (range, 0.2 to 21.2 mo). CONCLUSIONS: Given aggressive and often unsalvageable nature of recurrence, consideration of adjuvant treatment (including chemotherapy and radiation) is warranted for early-stage CCC, particularly for stage II or those with poor prognostic factors. PMID- 26950466 TI - Subtenon Triamcinolone Acetonide Removal for Uncontrolled Ocular Hypertension After Posterior Subtenon Injection of Triamcinolone Acetonide. AB - PURPOSE: To report the control of intraocular pressure (IOP) after removal of subtenon triamcinolone acetonide (TA) plaques in patients with uncontrolled ocular hypertension after posterior subtenon injection of triamcinolone acetonide (PSTA) and to evaluate the factors associated with rapid IOP normalization after subtenon TA removal. MATERIALS AND METHODS: Data from 8 eyes of 7 patients receiving excision of subtenon TA plaques for uncontrolled ocular hypertension after PSTA in 1 hospital from June 2010 to December 2012 were retrospectively collected. The percentage of IOP lowering on postoperative day 1 and the time to IOP normalization after subtenon TA removal were reported. Pearson correlation analysis was used to analyze the factors for rapid IOP normalization after subtenon TA removal. RESULTS: The IOP lowering on postoperative day 1 ranged from 12% to 75%. All cases achieved IOP normalization within a mean of 2.5+/-1.9 days (range, 1 to 5 d) after subtenon TA removal. Fewer kinds of antiglaucoma agents used before subtenon TA removal was associated with greater IOP lowering on postoperative day 1 (P=0.01) and more rapid return to normal IOP (P=0.01). Older age and more time from PSTA to ocular hypertension were both correlated with shorter time to achieve IOP normalization after operation (P=0.01 and 0.02, respectively). CONCLUSIONS: In medically uncontrolled ocular hypertension after PSTA, excision of subtenon TA plaques provided IOP normalization as rapidly as 1 to 5 days. Fewer preoperative antiglaucoma agents, older age, and more time from PSTA to ocular hypertension were correlated with more rapid IOP normalization after subtenon TA removal. PMID- 26950467 TI - Aminolevulinic Acid Photodynamic Therapy in the Treatment of Erosive Pustular Dermatosis of the Scalp: A Case Series. AB - IMPORTANCE: Erosive pustular dermatosis of the scalp (EPDS) is an inflammatory skin condition that develops on sun-damaged skin in older individuals. Patients with EPDS present a therapeutic challenge because medical treatments and surgical modalities have met with limited success. Methyl aminolevulinate photodynamic therapy has been effective in 1 case but induced the disease in others. OBSERVATIONS: Eight patients with EPDS with mean (range) age 84 (67-93) years underwent gentle curettage of the hyperkeratotic lesions followed by aminolevulinic acid photodynamic therapy (PDT) 1 to 2 weeks later. Lesions resolved in 6 patients, whereas 2 patients had residual lesions at 6-week follow up and underwent a second cycle of curettage and aminolevulinic acid PDT with resolution. One patient experienced a partial recurrence 5 months after the procedure and was successfully retreated with curettage + aminolevulinic acid PDT. No adverse effects were noted, and patients were satisfied with the treatment. CONCLUSIONS AND RELEVANCE: This series of patients demonstrated EPDS successfully treated with PDT. Lesions resolved in all patients with a protocol that included curettage followed by aminolevulinic acid PDT. Therefore, this protocol represents an efficacious modality for EPDS. PMID- 26950468 TI - Correction: Successful Recovery of Nuclear Protein-Coding Genes from Small Insects in Museums Using Illumina Sequencing. PMID- 26950469 TI - Current Trends in and Indications for Endoscopy-Assisted Breast Surgery for Breast Cancer: Results from a Six-Year Study Conducted by the Taiwan Endoscopic Breast Surgery Cooperative Group. AB - BACKGROUND: Endoscopy-assisted breast surgery (EABS) performed through minimal axillary and/or periareolar incisions is a possible alternative to open surgery for certain patients with breast cancer. In this study, we report the early results of an EABS program in Taiwan. METHODS: The medical records of patients who underwent EABS for breast cancer during the period May 2009 to December 2014 were collected from the Taiwan Endoscopic Breast Surgery Cooperative Group database. Data on clinicopathologic characteristics, type of surgery, method of breast reconstruction, complications and recurrence were analyzed to determine the effectiveness and oncologic safety of EABS in Taiwan. RESULTS: A total of 315 EABS procedures were performed in 292 patients with breast cancer, including 23 (7.8%) patients with bilateral disease. The number of breast cancer patients who underwent EABS increased initially from 2009 to 2012 and then stabilized during the period 2012-2014. The most commonly performed EABS was endoscopy-assisted total mastectomy (EATM) (85.4%) followed by endoscopy-assisted partial mastectomy (EAPM) (14.6%). Approximately 74% of the EATM procedures involved breast reconstruction, with the most common types of reconstruction being implant insertion and autologous pedicled TRAM flap surgery. During the six-year study period, there was an increasing trend in the performance of EABS for the management of breast cancer when total mastectomy was indicated. The positive surgical margin rate was 1.9%. Overall, the rate of complications associated with EABS was 15.2% and all were minor and wound-related. During a median follow-up of 26.8 (3.3-68.6) months, there were 3 (1%) cases of local recurrence, 1 (0.3%) case of distant metastasis and 1 (0.3%) death. CONCLUSION: The preliminary results from the EABS program in Taiwan show that EABS is a safe procedure and results in acceptable cosmetic outcome. These findings could help to promote this under-used surgical technique in the field of breast cancer. PMID- 26950470 TI - Frequency of Lost to Follow-Up and Associated Factors for Patients with Rheumatic Diseases. AB - OBJECTIVE: To determine the frequency of lost to follow-up (LTFU) in the setting of usual care for outpatients with rheumatic diseases including RA, SLE, AS, and Ps/PsA, to explore the associated demographic factors, and to investigate the reasons for being LTFU from the original medical care. METHODS: Patients registered between May 2011 and January 2014 at the rheumatology outpatient department of a medical center were included. Those who did not attend their scheduled appointment were defined as LTFU. Univariate and multivariate logistic regression were used to analyze the factors for being LTFU. RESULTS: A total of 781 patients were enrolled, including 406 patients with RA, 174 with SLE, 136 with AS, and 65 with Ps/PsA. The frequency of LTFU was 23.9%, 25.9%, 35.3%, and 35.4%, respectively. The frequency of LTFU was significantly different between the four rheumatic diseases (p = 0.028). In multivariate logistic regression analysis, an older age increased being LTFU in the patients with RA (OR 1.02; 95% CI 1.00-1.04; p = 0.033), but reduced being LTFU in those with Ps/PsA (OR 0.96; 95% CI 0.92-0.99; p = 0.021). Female patients with SLE and Ps/PsA were more likely to be LTFU, although this did not reach statistical significance (p = 0.056 and 0.071, respectively). The most common reason for being LTFU was moving to other district hospitals from the original medical center due to convenience for the patients with RA and SLE, and stopping medication due to minimal symptoms for the patients with AS and Ps/PsA. CONCLUSIONS: The frequency of LTFU in patients with rheumatic diseases is high. Associated demographic factors included older age in RA, female gender in SLE and Ps/PsA, and younger age in Ps/PsA, with various reasons for being LTFU. Recognizing these associated factors and reasons for being LTFU may help to improve the attendance of patients and the quality of medical care. PMID- 26950471 TI - Intralesional Rituximab for the Treatment of Recurrent Ocular Adnexal Lymphoma. AB - A 41-year-old female with Sjogren syndrome presented with a 5-month history of bilateral upper eyelid swelling. Incisional biopsy of the left lacrimal gland revealed mucosa-associated lymphoid tissue lymphoma. Due to bilateral severe dry eyes, the patient declined external beam radiotherapy and systemic rituximab was initiated. The patient responded well to intravenous rituximab and the follow-up CT revealed decrease in size of both lacrimal glands. Eleven months after systemic rituximab, the patient developed bilateral lacrimal gland recurrence. The patient declined external beam radiotherapy. Intralesional rituximab (50 mg/1 ml) was injected into the left lacrimal gland, followed by injection in the right lacrimal gland 7 months later. Twenty-three months follow-up after the injection into the right lacrimal gland, there was significant decrease in size of bilateral lacrimal glands and subjective improvement of dry eye symptoms. This case highlights the intralesional rituximab as an alternative therapy for recurrent orbital mucosa-associated lymphoid tissue lymphoma in selected cases. PMID- 26950472 TI - Modified Hotz Procedure Combined With Modified Z-Epicanthoplasty Versus Modified Hotz Procedure Alone for Epiblepharon Repair. AB - PURPOSE: To compare the outcomes of the modified Hotz procedure alone and combined with modified Z-epicanthoplasty for correction of epiblepharon. METHODS: Seventy-one Chinese patients who underwent epiblepharon repair were divided into 2 groups. In group 1, 33 patients (59 eyes) were operated on with the modified Hotz procedure. In group 2, 38 patients (71 eyes) were operated on with the modified Hotz procedure combined with modified Z-epicanthoplasty. Treatment outcomes were classified as "excellent" with no cilium-ocular surface touching, "fair" with 5 or fewer cilia-ocular surface touchings, and "poor" with more than 5 cilia-ocular surface touchings. Incision scars were evaluated by the Vancouver scar scale (VSS). RESULTS: There were no significant differences in the age or sex distribution between the two groups. For group 1, the outcome was excellent for 46 eyes (78%) and fair or poor for 13 eyes (22%). For group 2, the outcome was excellent for 70 eyes (98.6%) and fair for only 1 eye (1.4%). Thus, group 2 had significantly more excellent outcomes compared with group 1 (p < 0.001). The Vancouver scar scale of the lower eyelids in group 1 was 1.10 +/- 0.30 and 1.04 +/- 0.20 in group 2 after correcting for the follow-up period (p = 0.292). The medial canthus Vancouver scar scale in group 2 was 1.13 +/- 0.37, which was not different from the lower eyelid Vancouver scar scale (p = 0.471). CONCLUSIONS: The modified Hotz procedure combined with modified Z-epicanthoplasty is more effective in correcting lower eyelid epiblepharon than the modified Hotz procedure alone. The combined procedure does not produce obvious lower eyelid or medial canthus scars. PMID- 26950473 TI - A Simple New Technique for Treatment of Tarsal Kink Syndrome. AB - Congenital tarsal kink syndrome is a rare type of upper eyelid entropion associated with keratitis due to trichiasis. The authors describe a new technique for treatment of congenital horizontal tarsal kink syndrome by means of absorbable everting sutures via a posterior approach. A neonate was referred to eye clinic with right eye redness and corneal opacity since birth. Clinical examination revealed inversion of the eyelid margin with a horizontal kink in the tarsal plate and corneal ulcer. Surgical treatment resulted in successful correction of upper eyelid malpositioning, rapid resolution of the corneal ulcer with excellent anatomical outcome, visual development and cosmesis, with no evidence of recurrence after 6 years. Absorbable everting sutures via a posterior approach is a simple, minimally invasive, and effective surgical technique for treatment of congenital horizontal tarsal kink syndrome. PMID- 26950474 TI - Bilateral Primary Mucinous Carcinoma of the Eyelid. AB - The aim of this study is to report a case of bilateral primary mucinous carcinoma of the eyelids. This is a case report and literature review. A 71-year-old female presented with primary mucinous carcinoma of the left upper eyelid, which was excised with Mohs surgery. One year later, she developed primary mucinous carcinoma of the right upper eyelid, which was also treated Mohs surgery. Extensive workup was negative for evidence of an unknown primary carcinoma or metastasis. Primary mucinous carcinoma of the eyelids may occur as multifocal tumors, and bilateral disease is not necessarily indicative of metastatic disease. PMID- 26950475 TI - Comparison of Therapeutic Efficacies of Norethisterone, Tranexamic Acid and Levonorgestrel-Releasing Intrauterine System for the Treatment of Heavy Menstrual Bleeding: A Randomized Controlled Study. AB - BACKGROUND: Our aim was to compare the therapeutic efficacies of norethisterone acid (NETA), tranexamic acid and levonorgestrel-releasing intrauterine system (LNG-IUS) in treating idiopathic heavy menstrual bleeding (HMB). METHODS: Women with heavy uterine bleeding were randomized to receive NETA, tranexamic acid or LNG-IUS for 6 months. The primary outcome was a decrease in menstrual bleeding as assessed by pictorial blood loss assessment charts and hematological parameters analyzed at the 1st, 3rd and 6th months. Health-related quality of life (QOL) variables were also recorded and analyzed. RESULTS: Twenty-eight patients were enrolled in each treatment group, but the results of only 62 were evaluated. NETA, tranexamic acid, and LNG-IUS reduced menstrual blood loss (MBL) by 53.1, 60.8, and 85.8%, respectively, at the 6th month. LNG-IUS was more effective than NETA and tranexamic acid in decreasing MBL. LNG-IUS was also more efficient than tranexamic acid in correcting anemia related to menorrhagia. Satisfaction rates were comparable among the NETA (70%), tranexamic acid (63%) and LNG-IUS (77%) groups. QOL in physical aspects increased significantly in the tranexamic acid and LNG-IUS groups. CONCLUSION: The positive effect of LNG-IUS on QOL parameters, as well as its high efficacy, makes it a first-line option for HMB. PMID- 26950476 TI - How knowledge of adverse childhood experiences can help pediatricians prevent mental health problems. AB - INTRODUCTION: The purpose of this study was to gain a better understanding of the perspectives of low-income, minority primary caregivers to inform the design of pediatric interventions to prevent mental health problems. METHOD: The authors conducted a follow-up study of female primary caretakers of children ages 4-5 years old in an urban northeastern pediatric practice, including 5 mothers of children with low Child Adverse Childhood Experiences (C-ACE) scores and 13 mothers of children with high C-ACE scores. RESULTS: Participation in early speech therapy, preschool programs, or mental health treatment was less likely for children with high C-ACE scores. Mothers of children with behavior problems expressed the most interest in developmental behavioral evaluations, parenting interventions, and mental health treatment. Information about nutrition and exercise options was of interest to mothers from low and high C-ACE groups. DISCUSSION: Results suggest that screening for C-ACE along with developmental and behavioral screening may help pediatric health care providers to identify children who are both at greatest risk for mental health problems and in need of help in accessing services. Incorporation of nutrition and exercise components into mental health interventions may increase enrollment and retention, as may targeting mental health interventions and referrals to parents with child behavior concerns. (PsycINFO Database Record PMID- 26950478 TI - Potential of Casiopeinas(r) Copper Complexes and Antituberculosis Drug Combination against Mycobacterium tuberculosis. AB - New compounds with antituberculosis activity and their combination with classic drugs have been evaluated to determine possible interactions and antagonism. The aim of this study was to evaluate the in vitro activity of Casiopeinas(r) copper based compounds (CasIIIia, CasIIIEa, and CasIIgly) alone and combined with isoniazid (INH), rifampicin, or ethambutol (EMB) against resistant and susceptible Mycobacterium tuberculosis. Seventeen clinical M. tuberculosis isolates (5 multi-drug resistant and 2 resistant to INH and/or EMB) were subjected to determination of the minimal inhibitory concentration (MIC) by the resazurin microtiter assay and combination assessment by the resazurin drug combination microtiter assay. The Casiopeinas(r) alone showed a remarkable effect against resistant isolates with MIC values from 0.78 to 12.50 MUg/ml. Furthermore, a synergistic effect mainly with EMB is shown for both resistant and susceptible clinical isolates. Casiopeinas(r) are promising candidates for future investigation into the development of antituberculosis drugs, being one of the first examples of essential metal-based drugs used in this field. PMID- 26950479 TI - Early-childhood BMI trajectories: evidence from a prospective, nationally representative British cohort study. AB - BACKGROUND AND OBJECTIVES: By age 5, 20% of British children are classed as overweight or obese, suggesting that early childhood is crucial for lifelong body mass index (BMI) trajectories. In this paper, we identify latent trajectories of early-childhood BMI from ages 3 to 11 years. Given the current context of growing socio-economic inequalities in childhood and adult overweight and obesity, we examine the socio-economic characteristics and mechanisms during pregnancy and infancy which underscore these trajectories. SUBJECT AND METHODS: We use a nationally representative, prospective cohort study of 9699 children born in 2000 2002, living in the United Kingdom shortly after birth, with complete information on height and weight (measured by an interviewer) at ages 3, 5, 7 and 11. Trajectories of BMI are calculated using latent growth mixture models. Multinomial models characterize these trajectories by their socio-economic profiles and mechanisms during pregnancy and infancy. RESULTS: Four trajectories were identified: two separate trajectories where BMI remains within a normal range (85% of the sample), an overweight trajectory (14.4%), and an obese trajectory (3.1%). No 'declining BMI' or late-onset groups were found. The obese group is already distinct from the other trajectories by age 3. The overweight group diverges from the normal groups around age 5. Strong socio-economic inequalities emerged; for the obese group, part of this disadvantage is mediated through early mechanisms such as pregnancy smoke and not initiating breastfeeding. CONCLUSIONS: This study provides strong evidence for the idea that childhood BMI trajectories develop early, especially for children who will follow an obese trajectory. Strong socio-economic patterns in these trajectories suggest that the observed trend in growing inequalities may be rooted in early life. Mediating mechanisms for the obese appear to be in the pregnancy and infant period, further research should explore mechanisms occurring around age 5 when the overweight trajectory diverges. PMID- 26950481 TI - Predicting future weight status from measurements made in early childhood: a novel longitudinal approach applied to Millennium Cohort Study data. AB - BACKGROUND/OBJECTIVE: There are reports that childhood obesity tracks into later life. Nevertheless, some tracking statistics such as correlations do not quantify individual agreement, whereas others such as diagnostic test statistics can be difficult to translate into practice. We aimed to employ a novel analytic approach, based on ordinal logistic regression, to predict weight status of 11 year-old children from measurements at age 5 years. SUBJECTS/METHODS: The UK 1990 growth references were used to generate clinical weight status categories of 12 076 children enrolled in the Millennium Cohort Study. Using ordinal regression, we derived the predicted probability (percent chances) of 11-year-old children becoming underweight, normal weight, overweight, obese and severely obese from their weight status category at age 5 years. RESULTS: The chances of becoming obese (including severely obese) at age 11 years were 5.7% (95% confidence interval: 5.2 to 6.2%) for a normal-weight 5-year-old child and 32.3% (29.8 to 34.8%) for an overweight 5-year-old child. An obese 5-year-old child had a 68.1% (63.8 to 72.5%) chance of remaining obese at 11 years. Severely obese 5-year-old children had a 50.3% (43.1 to 57.4%) chance of remaining severely obese. There were no substantial differences between sexes. Nondeprived obese 5-year-old boys had a lower probability of remaining obese than deprived obese boys: -21.8% ( 40.4 to -3.2%). This association was not observed in obese 5-year-old girls, in whom the nondeprived group had a probability of remaining obese 7% higher (-15.2 to 29.2%). The sex difference in this interaction of deprivation and baseline weight status was therefore -28.8% (-59.3 to 1.6%). CONCLUSIONS: We have demonstrated that ordinal logistic regression can be an informative approach to predict the chances of a child changing to, or from, an unhealthy weight status. This approach is easy to interpret and could be applied to any longitudinal data set with an ordinal outcome. PMID- 26950480 TI - Intake of high-fructose corn syrup sweetened soft drinks, fruit drinks and apple juice is associated with prevalent arthritis in US adults, aged 20-30 years. AB - OBJECTIVE: There is a link between joint and gut inflammation of unknown etiology in arthritis. Existing research indicates that regular consumption of high fructose corn syrup sweetened (HFCS) soft drinks, but not diet soft drinks, may be associated with increased risk of seropositive rheumatoid arthritis (RA) in women, independent of other dietary and lifestyle factors. One unexplored hypothesis for this association is that fructose malabsorption, due to regular consumption of excess free fructose (EFF) and HFCS, contributes to fructose reactivity in the gastrointestinal tract and intestinal in situ formation of enFruAGEs, which once absorbed, travel beyond the intestinal boundaries to other tissues and promote inflammation. In separate studies, the accumulation of advanced glycation end-products has been associated with joint inflammation in RA. Objective of this study was to assess the association between EFF beverages intake and non-age, non-wear and tear-associated arthritis in US young adults. METHODS: In this cross sectional study of 1209 adults aged 20-30y, (Nutrition and Health Examination Surveys 2003-2006) exposure variables were high EFF beverages, including HFCS sweetened soft drinks, and any combination of HFCS sweetened soft drinks, fruit drinks (FD) and apple juice, referred to as tEFF. Analyses of diet soda and diet FD were included for comparison. The outcome was self-reported arthritis. Rao Scott ?(2) was used for prevalence differences and logistic regression for associations, adjusted for confounders. RESULTS: Young adults consuming any combination of high EFF beverages (tEFF) ?5 times/week (but not diet soda) were three times as likely to have arthritis as non/low consumers (odds ratios=3.01; p?0.021; 95% confidence intervals=1.20-7.59), independent of all covariates, including physical activity, other dietary factors, blood glucose and smoking. CONCLUSION: EFF beverage intake is significantly associated with arthritis in US adults aged 20-30 years, possibly due to the intestinal in situ formation of enFruAGEs. PMID- 26950482 TI - Transgenic mice overexpressing nesfatin/nucleobindin-2 are susceptible to high fat diet-induced obesity. AB - BACKGROUND: Nesfatin/Nucleobindin-2 (Nesf/NUCB2), a precursor of nesfatin-1, an anorexigenic protein, is ubiquitously expressed in peripheral tissues in addition to the hypothalamus. However, the role of intracellular Nesf/NUCB2 has not been established in the periphery. METHODS: Nesf/NUCB2-transgenic (Tg) mice were generated, and chronological changes of body weight and daily food intake were measured in Nesf/NUCB2-Tg mice fed normal laboratory chow or 45% high-fat diet (HFD). In addition, changes of metabolic markers were evaluated in those mice. RESULTS: No differences were observed in daily food intake and body weight between Nesf/NUCB2-Tg mice (n=11) and their non-Tg littermates (n=11) fed normal chow. Nesf/NUCB2-Tg mice showed increased mRNA expression of oxytocin and corticotropin-releasing hormone and decreased mRNA expression of cocaine- and amphetamine-related transcript in the hypothalamus. Nesf/NUCB2-Tg mice fed 45% HFD (n=6) showed significantly higher increase in body weight than their non-Tg littermates fed the same diet (n=8); however, no difference was observed in daily food intake between these two groups. Further, Nesf/NUCB2-Tg mice fed 45% HFD showed a significant increase in the weight of the liver, subcutaneous fat, and brown adipose tissue and decrease in the expression of uncoupling protein-1 in the subcutaneous fat. Blood glucose levels of Nesf/NUCB2-Tg mice fed 45% HFD were not different from those of their non-Tg littermates fed the same diet. Insulin levels of these Tg mice were significantly higher than those of their non-Tg littermates. Histological analysis showed marked fat deposition in the hepatocytes surrounding the hepatic central veins in Nesf/NUCB2-Tg mice fed 45% HFD. CONCLUSIONS: Overexpression of Nesf/NUCB2 did not change food intake, but increased body weight only in Nesf/NUCB2-Tg mice fed HFD. The results of this study indicate that Nesf/NUCB2 was involved in the development of insulin resistance and fat deposition in the liver, independent of the modulation of energy intake. PMID- 26950483 TI - The use of low-calorie sweeteners is associated with self-reported prior intent to lose weight in a representative sample of US adults. AB - BACKGROUND: Low-calorie sweeteners (LCSs) are said to be a risk factor for obesity and diabetes. Reverse causality may be an alternative explanation. METHODS: Data on LCS use, from a single 24-h dietary recall, for a representative sample of 22 231 adults were obtained from 5 cycles of the National Health and Nutrition Examination Survey (1999-2008 NHANES). Retrospective data on intent to lose or maintain weight during the prior 12-months and 10-year weight history were obtained from the weight history questionnaire. Objectively measured heights and weights were obtained from the examination. Primary analyses evaluated the association between intent to lose/maintain weight and use of LCSs and specific LCS product types using survey-weighted generalized linear models. We further evaluated whether body mass index (BMI) may mediate the association between weight loss intent and use of LCSs. The association between 10-year weight history and current LCS use was evaluated using restricted cubic splines. RESULTS: In cross-sectional analyses, LCS use was associated with a higher prevalence of obesity and diabetes. Adults who tried to lose weight during the previous 12 months were more likely to consume LCS beverages (prevalence ratio=1.64, 95% confidence interval (CI) 1.54-1.75), tabletop LCS (prevalence ratio=1.68, 95% CI 1.47-1.91) and LCS foods (prevalence ratio=1.93, 95% CI 1.60 2.33) as compared with those who did not. In mediation analyses, BMI only partially mediated the association between weight control history and the use of LCS beverages, tabletop LCS, but not LCS foods. Current LCS use was further associated with a history of prior weight change (for example, weight loss and gain). CONCLUSIONS: LCS use was associated with self-reported intent to lose weight during the previous 12 months. This association was only partially mediated by differences in BMI. Any inference of causality between attempts at weight control and LCS use is tempered by the cross-sectional nature of these data and retrospective self-reports of prior weight loss/maintenance intent. PMID- 26950484 TI - Development of an in vitro model to test antifibrotic drugs on primary human liver myofibroblasts. AB - We have developed a culture model to assess antifibrotic drugs using normal human liver myofibroblasts (HLMFs) obtained from 31 subjects. Activation was evaluated in terms of alpha-smooth muscle actin (alpha-SMA) and collagen 1 (Coll1) expression using RT-PCR, and proliferation as the uptake of 5-ethynil-2' deoxyuridine. Under analysis of variance, between-subject differences accounted for 70% of all variability and inter-experiment differences for 30%. The sensitivity of the model was determined by quantifying the effects in terms of relative expression, which were 0.74+/-0.03 for cyclosporine A (CsA) and 2.4+/ 0.10 for transforming growth factor-beta (TGF-beta) (P<0.0001 vs no treatment) for alpha-SMA expression. Inter-subject variations in alpha-SMA and Coll1 expression enabled the classification of subjects as potentially low or high fibrosers. Finally, we observed that pirfenidone (which has beneficial effects in vivo) significantly reduced the expressions of alpha-SMA and Coll1, whereas the angiotensin-converting enzyme inhibitor losartan (which has no effect in vivo) had no significant effect. Our model may thus detect the antifibrotic properties of drugs. Antifibrotic drugs with promising clinical relevance could possibly be selected using a bank of HLMFs from high fibrosers. PMID- 26950486 TI - Inhibition of development of laser-induced choroidal neovascularization with suppression of infiltration of macrophages in Smad3-null mice. AB - We evaluated the effects of the loss of Smad3 on the development of experimental argon laser-induced choroidal neovascularization (CNV) in mice. An in vitro angiogenesis model was also used to examine the role of transforming growth factor-beta1 (TGFbeta1)/Smad3 signaling in vessel-like tube formation by human umbilical vein endothelial cells (HUVECs). CNV was induced in eyes of 8-12-week old B6.129-background Smad3-deficient (KO) mice (n=47) and wild-type (WT) mice (n=47) by argon laser irradiation. Results showed that the size of the CNV induced was significantly smaller in KO mice as compared with WT mice at day 14 as revealed by high-resolution angiography with fluorescein isothiocyanate dextran. Immunohistochemistry and real-time reverse transcription-polymerase chain reaction of RNA extracted from laser-irradiated choroidal tissues were conducted on specimens at specific timepoints. Invasion of macrophages (F4/80+), but not neutrophils (myeloperoxidase+), and appearance of myofibroblasts (alpha smooth muscle actin+) were suppressed in laser-irradiated KO tissues. mRNA expression of inflammation-related factors, that is, vascular endothelial growth factor (VEGF), macrophage-chemoattractant protein-1 (MCP-1), interleukin-6 (IL-6) and TGFbeta1 in choroidal tissues was suppressed by the loss of Smad3. We then examined the effects of adding a Smad3 inhibitor, SIS3, or an ALK5 inhibitor, SB431542, on tube formation promoted by TGFbeta1 or VEGF in HUVECs cocultured with fibroblast feeder. Further addition of SIS3 or SB431542 augmented vessel like tube formation by HUVECs in the presence of TGFbeta1 or VEGF. In conclusion, lack of Smad3 attenuated the growth of laser-induced CNV with suppression of inflammation by macrophages in mice. Because blocking TGFbeta1/Smad3 signal stimulated the activity of angiogenesis of HUVECs in vitro, the reduction of CNV in vivo in KO mice is attributed to a decrease in growth factor levels in the tissue by the loss of Smad3. PMID- 26950485 TI - Gastric adenocarcinoma microRNA profiles in fixed tissue and in plasma reveal cancer-associated and Epstein-Barr virus-related expression patterns. AB - MicroRNA expression in formalin-fixed paraffin-embedded tissue (FFPE) or plasma may add value for cancer management. The GastroGenus miR Panel was developed to measure 55 cancer-specific human microRNAs, Epstein-Barr virus (EBV)-encoded microRNAs, and controls. This Q-rtPCR panel was applied to 100 FFPEs enriched for adenocarcinoma or adjacent non-malignant mucosa, and to plasma of 31 patients. In FFPE, microRNAs upregulated in malignant versus adjacent benign gastric mucosa were hsa-miR-21, -155, -196a, -196b, -185, and -let-7i. Hsa-miR-18a, 34a, 187, 200a, -423-3p, -484, and -744 were downregulated. Plasma of cancer versus non cancer controls had upregulated hsa-miR-23a, -103, and -221 and downregulated hsa miR-378, -346, -486-5p, -200b, -196a, -141, and -484. EBV-infected versus uninfected cancers expressed multiple EBV-encoded microRNAs, and concomitant dysregulation of four human microRNAs suggests that viral infection may alter cellular biochemical pathways. Human microRNAs were dysregulated between malignant and benign gastric mucosa and between plasma of cancer patients and non cancer controls. Strong association of EBV microRNA expression with known EBV status underscores the ability of microRNA technology to reflect disease biology. Expression of viral microRNAs in concert with unique human microRNAs provides novel insights into viral oncogenesis and reinforces the potential for microRNA profiles to aid in classifying gastric cancer subtypes. Pilot studies of plasma suggest the potential for a noninvasive addition to cancer diagnostics. PMID- 26950487 TI - PIK3C2A is a gene-specific target of microRNA-518a-5p in imatinib mesylate resistant gastrointestinal stromal tumor. AB - Imatinib mesylate resistance occurs in some patients with gastrointestinal stromal tumors (GISTs) during the course of treatment. In this study, we investigated the relationship between microRNAs (miRNAs) and imatinib-resistant GISTs, and the effect of miR-518a-5p on PIK3C2A in imatinib-resistant GISTs. A total of 20 matched-pair GIST samples from imatinib-resistant patients were included in the study. Each of the paired tumor specimens were from the same patient who had surgical removal of GISTs preimatinib and postimatinib treatment. Seven pairs of tissues were resected for microarray analysis, and the remaining 13 pairs were utilized for miRNAs analysis. Target genes were selected based on bioinformatics from multiple biological databases. Luciferase reporter assays were used to confirm the binding of miR-518a-5p to PIK3C2A 3'UTR. GIST882R-NC, 882R-miR-518a-5p-OE, and 882R-miR-518a-5p-KD cell lines were constructed using lentiviral vectors. miR-518a-5p and PIK3C2A expression in 882R-NC, 882R-OE, and 882R-KD cells was assessed by real-time PCR and western blotting. A cell counting kit was used to detect the influence of miR-518a-5p to cell proliferation. TUNEL staining was applied to detect the influence of miR-518a-5p to cell apoptosis. Microarray analysis showed that miR-518a-5p was downregulated in imatinib resistant GISTs, and the expression of miR-518a-5p was confirmed with good concordance between real-time PCR and miRNA microarray results. Luciferase reporter assays indicated that miR-518a-5p bound to the PIK3C2A 3'UTR. Compared with 882R-OE, PIK3C2A expression was significantly increased in 882R-KD cells. MiR-518a-5p reduced 882R proliferation and promoted 882R apoptosis. In conclusion, PIK3C2A is a gene-specific target of miR-518a-5p in imatinib mesylate resistant GISTs. Low expression of miR-518a-5p is likely to upregulate PIK3C2A and affect the cellular response to the drug, causing resistance to imatinib in GISTs. PMID- 26950488 TI - Mesoporous Few-Layer Graphene Platform for Affinity Biosensing Application. AB - A label-free, highly reproducible, sensitive, and selective biosensor is proposed using antiapolipoprotein B 100 (AAB) functionalized mesoporous few-layer reduced graphene oxide and nickel oxide (rGO-NiO) nanocomposite for detection of low density lipoprotein (LDL) molecules. The formation of mesoporous rGO-NiO composite on indium tin oxide conductive electrode has been accomplished via electrophoretic technique using colloidal suspension of rGO sheets and NiO nanoparticles. This biosensor shows good stability obtained by surface conjugation of antibody AAB molecules with rGO-NiO matrix by EDC-NHS coupling chemistry. The defect-less few layer rGO sheets, NiO nanoparticles (nNiO) and formation of nanocomposite has been confirmed by Raman mapping, electron microscopic studies, X-ray diffraction, and electrochemical techniques. The synthesized rGO-NiO composite is mesoporous dominated with a small percentage of micro and macroporous structure as is evident by the results of Brunauer-Emmett Teller experiment. Further, the bioconjugation of AAB with rGO-NiO has been investigated by Fourier transform-infrared spectroscopy studies. The kinetic studies for binding of antigen-antibody (LDL-AAB) and analytical performance of this biosensor have been evaluated by the impedance spectroscopic method. This biosensor exhibits an excellent sensitivity of 510 Omega (mg/dL)(-1) cm(-2) for detection of LDL molecules and is sensitive to 5 mg/dL concentration of LDL in a wide range of 0-130 mg/dL. Thus, this fabricated biosensor is an efficient and highly sensitive platform for the analysis of other antigen-antibody interactions and biomolecules detection. PMID- 26950489 TI - Qualitative contrast between knowledge-limited mixed-state and variable-resources models of visual change detection. AB - We report an experiment designed to provide a qualitative contrast between knowledge-limited versions of mixed-state and variable-resources (VR) models of visual change detection. The key data pattern is that observers often respond "same" on big-change trials, while simultaneously being able to discriminate between same and small-change trials. The mixed-state model provides a natural account of this data pattern: With some probability, the observer is in a zero memory state and is forced to guess. Thus, even on big-change trials, there is a significant probability that the observer will respond "same." On other trials, the observer retains memory for the probed study item, and these memory-based responses allow the observer to show above-chance discrimination between same and small-change trials. By contrast, we show that important versions of the VR models that we refer to as knowledge-limited models are stymied by this simple pattern of results. In agreement with Keshvari, van den Berg, and Ma (2012, 2013), alternative knowledge-rich VR models that employ ideal-observer decision rules provide a significant improvement over the knowledge-limited VR models; however, extant versions of the knowledge-rich VR models still fall short quantitatively compared to the descriptive mixed-state model. We discuss implications of the knowledge-rich assumptions that are posited in current versions of the VR models that have been used to fit change-detection data. PMID- 26950491 TI - Investigating storage and retrieval processes of directed forgetting: A model based approach. AB - Intentional forgetting of previously learned information is an adaptive cognitive capability of humans but its cognitive underpinnings are not yet well understood. It has been argued that it strongly depends on the presentation method whether forgetting instructions alter storage or retrieval stages (Basden, Basden, & Gargano, 1993). In Experiment 1, we compared the processes underlying the directed-forgetting effect in 2 mosts widely used presentation methods, namely the list-method and the item-method, and also differentiated between costs (i.e., poorer memory for to-be-forgotten information) and benefits (i.e., better memory for to-be-remembered information) of directed forgetting within both methods. Using a multinomial modeling approach (Riefer & Rouder, 1992; Rouder & Batchelder, 1998), our results showed that directed-forgetting benefits were due to better storage of to-be-remembered information in both methods. In line with current theorizing, list-method directed-forgetting costs occurred due to reduced retrieval of to-be-forgotten information. Item-method costs, however, occurred not only due to reduced storage, which is the dominant current view, but also due to reduced retrieval. In Experiment 2, we replicated the novel finding that retrieval processes contribute to item-method directed forgetting independent of recall-output order. Implications of these findings for current directed forgetting theories are discussed. (PsycINFO Database Record PMID- 26950490 TI - The costs and benefits of testing and guessing on recognition memory. AB - We examined whether 2 types of interpolated tasks (i.e., retrieval-practice via free recall or guessing a missing critical item) improved final recognition for related and unrelated word lists relative to restudying or completing a filler task. Both retrieval-practice and guessing tasks improved correct recognition relative to restudy and filler tasks, particularly when study lists were semantically related. However, both retrieval practice and guessing also generally inflated false recognition for the nonpresented critical words. These patterns were found when final recognition was completed during a short delay within the same experimental session (Experiment 1) and after a 24-hr delay (Experiment 2). In Experiment 3, task instructions were presented randomly after each list to determine whether retrieval-practice and guessing effects were influenced by task-expectancy processes. In contrast to Experiments 1 and 2, final recognition after retrieval practice and guessing was equivalent to restudy, suggesting that the observed retrieval-practice and guessing advantages were in part because of preparatory task-based processing during study. (PsycINFO Database Record PMID- 26950492 TI - Anchors aweigh: The impact of overlearning on entrenchment effects in statistical learning. AB - Previous research has revealed that when learners encounter multiple artificial languages in succession only the first is learned, unless there are contextual cues correlating with the change in structure or if exposure to the second language is protracted. These experiments provided a fixed amount of exposure irrespective of when learning occurred. Here, the authors presented learners with 2 consecutive artificial languages testing learning after each minute of familiarization. In Experiment 1, learners received fixed input, and the authors replicated the primacy effect. In Experiment 2, learners advanced to the second language immediately following robust learning of the first language (thereby limiting additional exposure past the point of learning). Remarkably, learners tended to acquire and retain both languages, although contextual cues did not boost performance further. Notably, there was no correlation between performance on this task and a flanker task that measured inhibitory control. Overall, the findings suggest that anchoring effects in statistical learning may be because of overlearning. We speculate that learners may reduce their attention to the input once they achieve a low level of estimation uncertainty. (PsycINFO Database Record PMID- 26950495 TI - A Key Evolutionary Mutation Enhances DNA Binding of the FOXP2 Forkhead Domain. AB - Forkhead box (FOX) transcription factors share a conserved forkhead DNA binding domain (FHD) and are key role players in the development of many eukaryotic species. Their involvement in various congenital disorders and cancers makes them clinically relevant targets for novel therapeutic strategies. Among them, the FOXP subfamily of multidomain transcriptional repressors is unique in its ability to form DNA binding homo and heterodimers. The truncated FOXP2 FHD, in the absence of the leucine zipper, exists in equilibrium between monomeric and domain swapped dimeric states in vitro. As a consequence, determining the DNA binding properties of the FOXP2 FHD becomes inherently difficult. In this work, two FOXP2 FHD hinge loop mutants have been generated to successfully prevent both the formation (A539P) and the dissociation (F541C) of the homodimers. This allows for the separation of the two species for downstream DNA binding studies. Comparison of DNA binding of the different species using electrophoretic mobility shift assay, fluorescence anisotropy and isothermal titration calorimetry indicates that the wild-type FOXP2 FHD binds DNA as a monomer. However, comparison of the DNA-binding energetics of the monomer and wild-type FHD, reveals that there is a difference in the mechanism of binding between the two species. We conclude that the naturally occurring reverse mutation (P539A) seen in the FOXP subfamily increases DNA binding affinity and may increase the potential for nonspecific binding compared to other FOX family members. PMID- 26950496 TI - A Synthesis of a Spirocyclic Macrocyclic Protease Inhibitor for the Treatment of Hepatitis C. AB - The development of a convergent and highly stereoselective synthesis of an HCV NS3/4a protease inhibitor possessing a unique spirocyclic and macrocyclic architecture is described. A late-stage spirocyclization strategy both enabled rapid structure-activity relationship studies in the drug discovery phase and simultaneously served as the basis for the large scale drug candidate preparation for clinical use. Also reported is the discovery of a novel InCl3-catalyzed carbonyl reduction with household aluminum foil or zinc powder as the terminal reductant. PMID- 26950497 TI - Integrating Everything: The Molecule Selection Toolkit, a System for Compound Prioritization in Drug Discovery. AB - In recent years there have been numerous papers on the topic of multiattribute optimization in pharmaceutical discovery chemistry, applied to compound prioritization. Many solutions proposed are static in nature; fixed functions are proposed for general purpose use. As needs change, these are modified and proposed as the latest enhancement. Rather than producing one more set of static functions, this work proposes a flexible approach to prioritizing compounds. Most published approaches also lack a design component. This work describes a comprehensive implementation that includes predictive modeling, multiattribute optimization, and modern statistical design. This gives a complete package for effectively prioritizing compounds for lead generation and lead optimization. The approach described has been used at our company in various stages of discovery since 2001. An adaptable system alleviates the need for different static solutions, each of which inevitably must be updated as the needs of a project change. PMID- 26950498 TI - Investigation of relationships between removals of tetracycline and degradation products and physicochemical parameters in municipal wastewater treatment plant. AB - Determination of the effect of physicochemical parameters on the removal of tetracycline (TC) and degradation products is important because of the importance of the removal of antibiotics in Wastewater Treatment Plant (WWTP). Therefore, the purpose of this study was to investigate the relationships between removals of TC and degradation products and physicochemical parameters in Municipal Wastewater Treatment Plant (MWWTP). For this aim, (i) the removals of physicochemical parameters in a MWWTP located in Elazig city (Turkey) were determined (ii) the removals of TC and degradation products in MWWTP were determined (iii) the relationships between removals of TC and degradation products and physicochemical parameters were investigated. TC, 4-epitetracycline (ETC), 4-epianhydrotetracycline (EATC), anhydrotetracycline (ATC), and physicochemical parameters (pH, temperature, electrical conductivity (EC), suspended solids (SS), BOD5, COD, total organic carbon (TOC), NH4(+)-N, NO2(-)-N, NO3(-)-N and O-PO4(-3)) were determined. The calculation of the correlation coefficients of relationships between the physicochemical parameters and TC, EATC, ATC showed that, among the investigated parameters, EATC and SS most correlated. The removals of other physicochemical parameters were not correlated with TC, EATC and ATC. PMID- 26950499 TI - Valuing shifts in the distribution of visibility in national parks and wilderness areas in the United States. AB - Environmental regulations often have the objective of eliminating the lower tail of an index of environmental quality. That part of the distribution of environmental quality moves somewhere above a threshold and where in the original distribution it moves is a function of the control strategy chosen. This paper provides an approach for estimating the economic benefits of different distributional changes as the worst environmental conditions are removed. The proposed approach is illustrated by examining shifts in visibility at Class I visibility areas (National Parks and wilderness areas) that would occur with implementation of the U.S. Environmental Protection Agency's Regional Haze Program. In this application we show that people value shifts in the distribution of visibility and place a higher value on the removal of a low visibility day than on the addition of a high visibility day. We found that respondents would pay about $120 per year in the Southeast U.S. and about $80 per year in the Southwest U.S. for improvement programs that remove the 20% worst visibility days. PMID- 26950500 TI - A comparison of simultaneous organic carbon and nitrogen removal in microbial fuel cells and microbial electrolysis cells. AB - This study demonstrates simultaneous carbon and nitrogen removal in laboratory scale continuous flow microbial fuel cell (MFC) and microbial electrolysis cell (MEC) and provides side-by side comparison of these bioelectrochemical systems. The maximum organic carbon removal rates in MFC and MEC tests were similar at 5.1 g L(-1) d(-1) and 4.16 g L(-1) d(-1), respectively, with a near 100% carbon removal efficiency at an organic load of 3.3 g L(-1) d(-1). An ammonium removal efficiency of 30-55% with near-zero nitrite and nitrate concentrations was observed in the MFC operated at an optimal external resistance, while open circuit MFC operation resulted in a reduced carbon and ammonium removal of 53% and 21%, respectively. In the MEC ammonium removal was limited to 7-12% under anaerobic conditions, while micro-aerobic conditions increased the removal efficiency to 31%. Also, at zero applied voltage both carbon and ammonium removal efficiencies were reduced to 42% and 4%, respectively. Based on the observed performance under different operating conditions, it was concluded that simultaneous carbon and nitrogen removal was facilitated by concurrent anaerobic and aerobic biotransformation pathways at the anode and cathode, which balanced bioelectrochemical nitrification and denitrification reactions. PMID- 26950501 TI - Spectrophotometric determination of L-cysteine by using polyvinylpyrrolidone stabilized silver nanoparticles in the presence of barium ions. AB - In this article a simple and selective colorimetric probe for cysteine determination using silver nano particles (AgNPS) is described. The determination process was based upon the surface plasmon resonance properties of polyvinylpyrrolidone-stabilized AgNPS. Interaction of AgNPS with cysteine molecules in the presence of barium ions induced a red shift in the surface plasmon resonance (SPR) maximum of AgNPs, as a result of nanoparticle aggregation. Consequently, yellow color of AgNP solution was changed to pink. The linear range for the determination of cysteine was 3.2-8.2 MUM (R=0.9965) with a limit of detection equal to 2.8 MUM (3sigma). The proposed method was successfully applied to the determination of cysteine in human plasma samples. Acceptable recovery results of the spiked samples confirmed the validity of the proposed method. PMID- 26950502 TI - An auto-adaptive background subtraction method for Raman spectra. AB - Background subtraction is a crucial step in the preprocessing of Raman spectrum. Usually, parameter manipulating of the background subtraction method is necessary for the efficient removal of the background, which makes the quality of the spectrum empirically dependent. In order to avoid artificial bias, we proposed an auto-adaptive background subtraction method without parameter adjustment. The main procedure is: (1) select the local minima of spectrum while preserving major peaks, (2) apply an interpolation scheme to estimate background, (3) and design an iteration scheme to improve the adaptability of background subtraction. Both simulated data and Raman spectra have been used to evaluate the proposed method. By comparing the backgrounds obtained from three widely applied methods: the polynomial, the Baek's and the airPLS, the auto-adaptive method meets the demand of practical applications in terms of efficiency and accuracy. PMID- 26950503 TI - Different spectrophotometric methods applied for the analysis of binary mixture of flucloxacillin and amoxicillin: A comparative study. AB - Three different spectrophotometric methods were applied for the quantitative analysis of flucloxacillin and amoxicillin in their binary mixture, namely, ratio subtraction, absorbance subtraction and amplitude modulation. A comparative study was done listing the advantages and the disadvantages of each method. All the methods were validated according to the ICH guidelines and the obtained accuracy, precision and repeatability were found to be within the acceptable limits. The selectivity of the proposed methods was tested using laboratory prepared mixtures and assessed by applying the standard addition technique. So, they can be used for the routine analysis of flucloxacillin and amoxicillin in their binary mixtures. PMID- 26950504 TI - Development of tobacco ringspot virus-based vectors for foreign gene expression and virus-induced gene silencing in a variety of plants. AB - We report here the development of tobacco ringspot virus (TRSV)-based vectors for the transient expression of foreign genes and for the analysis of endogenous gene function in plants using virus-induced gene silencing. The jellyfish green fluorescent protein (GFP) gene was inserted between the TRSV movement protein (MP) and coat protein (CP) regions, resulting in high in-frame expression of the RNA2-encoded viral polyprotein. GFP was released from the polyprotein via an N terminal homologous MP-CP cleavage site and a C-terminal foot-and-mouth disease virus (FMDV) 2 A catalytic peptide in Nicotiana benthamiana. The VIGS target gene was introduced in the sense and antisense orientations into a SnaBI site, which was created by mutating the sequence following the CP stop codon. VIGS of phytoene desaturase (PDS) in N. benthamiana, Arabidopsis ecotype Col-0, cucurbits and legumes led to obvious photo-bleaching phenotypes. A significant reduction in PDS mRNA levels in silenced plants was confirmed by semi-quantitative RT-PCR. PMID- 26950506 TI - Development of exploration of spatial-relational object properties in the second and third years of life. AB - Within a perception-action framework, exploration is seen as a driving force in young children's development. Through exploration, children become skilled in perceiving the affordances in their environment and acting on them. Using a perception-action framework, the current study examined the development of children's exploration of the spatial-relational properties of objects such as the possibility of containing or stacking. A total of 61 children, belonging to two age cohorts, were followed from 9 to 24 months and from 20 to 36 months of age, respectively. Exploration of a standard set of objects was observed in five home visits in each cohort conducted every 4 months. A cohort-sequential augmented growth model for categorical data, incorporating assumptions of item response theory, was constructed that fitted the data well, showing that the development of exploration of spatial-relational object properties follows an overlapping waves pattern. This is in line with Siegler's model (Emerging Minds, 1996), which suggested that skill development can be seen as ebbing and flowing of alternative (simple and advanced) behaviors. Although the probability of observing the more complex forms of exploration increased with age, the simpler forms did not disappear altogether but only became less probable. Findings support a perception-action view on development. Individual differences in observed exploration and their relations with other variables, as well as future directions for research, are discussed. PMID- 26950505 TI - Viral forensic genomics reveals the relatedness of classic herpes simplex virus strains KOS, KOS63, and KOS79. AB - Herpes simplex virus 1 (HSV-1) is a widespread global pathogen, of which the strain KOS is one of the most extensively studied. Previous sequence studies revealed that KOS does not cluster with other strains of North American geographic origin, but instead clustered with Asian strains. We sequenced a historical isolate of the original KOS strain, called KOS63, along with a separately isolated strain attributed to the same source individual, termed KOS79. Genomic analyses revealed that KOS63 closely resembled other recently sequenced isolates of KOS and was of Asian origin, but that KOS79 was a genetically unrelated strain that clustered in genetic distance analyses with HSV 1 strains of North American/European origin. These data suggest that the human source of KOS63 and KOS79 could have been infected with two genetically unrelated strains of disparate geographic origins. A PCR RFLP test was developed for rapid identification of these strains. PMID- 26950508 TI - Development of the perceptual span in reading: A longitudinal study. AB - The perceptual span is a standard measure of parafoveal processing, which is considered highly important for efficient reading. Is the perceptual span a stable indicator of reading performance? What drives its development? Do initially slower and faster readers converge or diverge over development? Here we present the first longitudinal data on the development of the perceptual span in elementary school children. Using the moving window technique, eye movements of 127 German children in three age groups (Grades 1, 2, and 3 in Year 1) were recorded at two time points (T1 and T2) 1 year apart. Introducing a new measure of the perceptual span, nonlinear mixed-effects modeling was used to separate window size effects from asymptotic reading performance. Cross-sectional differences were well replicated longitudinally. Asymptotic reading rate increased monotonously with grade, but in a decelerating fashion. A significant change in the perceptual span was observed only between Grades 2 and 3. Together with results from a cross-lagged panel model, this suggests that the perceptual span increases as a consequence of relatively well-established word reading. Stabilities of observed and predicted reading rates were high after Grade 1, whereas the perceptual span was only moderately stable for all grades. Comparing faster and slower readers as assessed at T1, in general, a pattern of stable between-group differences emerged rather than a compensatory pattern; second and third graders even showed a Matthew effect in reading rate and the perceptual span, respectively. PMID- 26950507 TI - Effects of contextual support on preschoolers' accented speech comprehension. AB - Young children often hear speech in unfamiliar accents, but relatively little research characterizes their comprehension capacity. The current study tested preschoolers' comprehension of familiar-accented versus unfamiliar-accented speech with varying levels of contextual support from sentence frames (full sentences vs. isolated words) and from visual context (four salient pictured alternatives vs. the absence of salient visual referents). The familiar accent advantage was more robust when visual context was absent, suggesting that previous findings of good accent comprehension in infants and young children may result from ceiling effects in easier tasks (e.g., picture fixation, picture selection) relative to the more difficult tasks often used with older children and adults. In contrast to prior work on mispronunciations, where most errors were novel object responses, children in the current study did not select novel object referents above chance levels. This suggests that some property of accented speech may dissuade children from inferring that an unrecognized familiar-but-accented word has a novel referent. Finally, children showed detectable accent processing difficulty despite presumed incidental community exposure. Results suggest that preschoolers' accented speech comprehension is still developing, consistent with theories of protracted development of speech processing. PMID- 26950509 TI - Lithium Titanate Confined in Carbon Nanopores for Asymmetric Supercapacitors. AB - Porous carbons suffer from low specific capacitance, while intercalation-type active materials suffer from limited rate when used in asymmetric supercapacitors. We demonstrate that nanoconfinement of intercalation-type lithium titanate (Li4Ti5O12) nanoparticles in carbon nanopores yielded nanocomposite materials that offer both high ion storage density and rapid ion transport through open and interconnected pore channels. The use of titanate increased both the gravimetric and volumetric capacity of porous carbons by more than an order of magnitude. High electrical conductivity of carbon and the small size of titanate crystals allowed the composite electrodes to achieve characteristic charge and discharge times comparable to that of the electric double-layer capacitors. The proposed composite synthesis methodology is simple, scalable, and applicable for a broad range of active intercalation materials, while the produced composite powders are compatible with commercial electrode fabrication processes. PMID- 26950510 TI - Deficits in vision and visual attention associated with motor performance of very preterm/very low birth weight children. AB - AIM: To extend understanding of impaired motor functioning of very preterm (VP)/very low birth weight (VLBW) children by investigating its relationship with visual attention, visual and visual-motor functioning. METHODS: Motor functioning (Movement Assessment Battery for Children, MABC-2; Manual Dexterity, Aiming & Catching, and Balance component), as well as visual attention (attention network and visual search tests), vision (oculomotor, visual sensory and perceptive functioning), visual-motor integration (Beery Visual Motor Integration), and neurological status (Touwen examination) were comprehensively assessed in a sample of 106 5.5-year-old VP/VLBW children. Stepwise linear regression analyses were conducted to investigate multivariate associations between deficits in visual attention, oculomotor, visual sensory, perceptive and visual-motor integration functioning, abnormal neurological status, neonatal risk factors, and MABC-2 scores. RESULTS: Abnormal MABC-2 Total or component scores occurred in 23 36% of VP/VLBW children. Visual and visual-motor functioning accounted for 9-11% of variance in MABC-2 Total, Manual Dexterity and Balance scores. Visual perceptive deficits only were associated with Aiming & Catching. Abnormal neurological status accounted for an additional 19-30% of variance in MABC-2 Total, Manual Dexterity and Balance scores, and 5% of variance in Aiming & Catching, and neonatal risk factors for 3-6% of variance in MABC-2 Total, Manual Dexterity and Balance scores. CONCLUSION: Motor functioning is weakly associated with visual and visual-motor integration deficits and moderately associated with abnormal neurological status, indicating that motor performance reflects long term vulnerability following very preterm birth, and that visual deficits are of minor importance in understanding motor functioning of VP/VLBW children. PMID- 26950511 TI - Morphology and Phase Controlled Construction of Pt-Ni Nanostructures for Efficient Electrocatalysis. AB - Highly open metallic nanoframes represent an emerging class of new nanostructures for advanced catalytic applications due to their fancy outline and largely increased accessible surface area. However, to date, the creation of bimetallic nanoframes with tunable structure remains a challenge. Herein, we develop a simple yet efficient chemical method that allows the preparation of highly composition segregated Pt-Ni nanocrystals with controllable shape and high yield. The selective use of dodecyltrimethylammonium chloride (DTAC) and control of oleylamine (OM)/oleic acid (OA) ratio are critical to the controllable creation of highly composition segregated Pt-Ni nanocrystals. While DTAC mediates the compositional anisotropic growth, the OM/OA ratio controls the shapes of the obtained highly composition segregated Pt-Ni nanocrystals. To the best of our knowledge, this is the first report on composition segregated tetrahexahedral Pt Ni NCs. Importantly, by simply treating the highly composition segregated Pt-Ni nanocrystals with acetic acid overnight, those solid Pt-Ni nanocrystals can be readily transformed into highly open Pt-Ni nanoframes with hardly changed shape and size. The resulting highly open Pt-Ni nanoframes are high-performance electrocatalysts for both oxygen reduction reaction and alcohol oxidations, which are far better than those of commercial Pt/C catalyst. Our results reported herein suggest that enhanced catalysts can be developed by engineering the structure/composition of the nanocrystals. PMID- 26950512 TI - Electro-catalytic oxidation of phenacetin with a three-dimensional reactor: Degradation pathway and removal mechanism. AB - Phenacetin is a common analgesic, anti-arthritic and anti-rheumatic drug. This study dealt with the degradation of phenacetin in alkaline media using a three dimensional reactor with particle electrodes. Particular attention was paid to the degradation pathway and the reaction mechanism in the system. Liquid chromatography coupled with time-of-flight mass spectrometry was used to identify the intermediates. The phenacetin was observed to be firstly cut off the branch chains main by direct oxidation, and then the intermediates further degraded to ring opening products by hydroxyl radical resulting from indirect oxidation and finally mineralized to CO2, H2O. A possible removal mechanism was proposed that direct and indirect oxidation together did effect on the pollutants with oxygen. PMID- 26950513 TI - Dual nuclease activity of a Cas2 protein in CRISPR-Cas subtype I-B of Leptospira interrogans. AB - Leptospira interrogans serovar Copenhageni strain Fiocruz L1-130 carries a set of cas genes associated with CRISPR-Cas subtype I-B. Herein, we report for the first time active transcription of a set of cas genes (cas1 to cas8) of L. interrogans where cas4, cas1, cas2 and cas6, cas3, cas8, cas7, cas5 are clustered together in two independent operons. As an initial step toward comprehensive understanding of CRISPR-Cas system in spirochete, the biochemical study of one of the core Leptospira Cas2 proteins (Lep_Cas2) showed nuclease activity on both DNA and RNA in a nonspecific manner. Additionally, unlike other known Cas2 proteins, Lep_Cas2 showed metal-independent RNase activity and preferential activity on RNA over DNA. These results provide insight for understanding Cas2 diversity existing in the prokaryotic adaptive immune system. PMID- 26950514 TI - Selectivity of conditioned fear of touch is modulated by somatosensory precision. AB - Learning to initiate defenses in response to specific signals of danger is adaptive. Some chronic pain conditions, however, are characterized by widespread anxiety, avoidance, and pain consistent with a loss of defensive response specificity. Response specificity depends on ability to discriminate between safe and threatening stimuli; therefore, specificity might depend on sensory precision. This would help explain the high prevalence of chronic pain in body areas of low tactile acuity, such as the lower back, and clarify why improving sensory precision may reduce chronic pain. We compared the acquisition and generalization of fear of pain-associated vibrotactile stimuli delivered to either the hand (high tactile acuity) or the back (low tactile acuity). During acquisition, tactile stimulation at one location (CS+) predicted the noxious electrocutaneous stimulation (US), while tactile stimulation at another location (CS-) did not. Responses to three stimuli with decreasing spatial proximity to the CS+ (generalizing stimuli; GS1-3) were tested. Differential learning and generalization were compared between groups. The main outcome of fear-potentiated startle responses showed differential learning only in the hand group. Self reported fear and expectancy confirmed differential learning and limited generalization in the hand group, and suggested undifferentiated fear and expectancy in the back group. Differences in generalization could not be inferred from the startle data. Specificity of fear responses appears to be affected by somatosensory precision. This has implications for our understanding of the role of sensory imprecision in the development of chronic pain. PMID- 26950515 TI - Meloidogyne graminicola: a major threat to rice agriculture. AB - TAXONOMY: Superkingdom Eukaryota; Kingdom Metazoa; Phylum Nematoda; Class Chromadorea; Order Tylenchida; Suborder Tylenchina; Infraorder Tylenchomorpha; Superfamily Tylenchoidea; Family Meloidogynidae; Subfamily Meloidogyninae; Genus Meloidogyne. BIOLOGY: Microscopic non-segmented roundworm. Plant pathogen; obligate sedentary endoparasitic root-knot nematode. Reproduction: facultative meiotic parthenogenetic species in which amphimixis can occur at a low frequency (c. 0.5%); relatively fast life cycle completed in 19-27 days on rice depending on the temperature range. HOST RANGE: Reported to infect over 100 plant species, including cereals and grass plants, as well as dicotyledonous plants. Main host: rice (Oryza sativa). SYMPTOMS: Characteristic hook-shaped galls (root swellings), mainly formed at the root tips of infected plants. Alteration of the root vascular system causes disruption of water and nutrient transport, stunting, chlorosis and loss of vigour, resulting in poor growth and reproduction of the plants with substantial yield losses in crops. DISEASE CONTROL: Nematicides, chemical priming, constant immersion of rice in irrigated fields, crop rotation with resistant or non-host plants, use of nematode-free planting material. Some sources of resistance to Meloidogyne graminicola have been identified in African rice species (O. glaberrima and O. longistaminata), as well as in a few Asian rice cultivars. AGRONOMIC IMPORTANCE: Major threat to rice agriculture, particularly in Asia. Adapted to flooded conditions, Meloidogyne graminicola causes problems in all types of rice agrosystems. PMID- 26950517 TI - Assessment of calpain and caspase systems activities during ageing of two bovine muscles by degradation patterns of alphaII spectrin and PARP-1. AB - The activities of calpain and caspase systems during ageing in Longissimus lumborum (LL) and Infraspinatus (IS) muscles of Italian Simmental young bulls (Bos taurus) were assessed. Samples from 10 animals were collected within 20 min of exsanguination (T0), after 48 h (T1) and 7 days (T2) post mortem. Calpain and caspase activity were evaluated based on the formation of alphaII spectrin cleavage products of 145 kDa (SBDP145) and 120 kDa (SBDP120), respectively. Caspase activity was also assessed by the presence of poly (adenosine diphosphate ribose) polymerase-1 (PARP-1) cleavage product. At T0, LL showed higher levels of SBDP145 than IS (P < 0.01), while SBDP120 and PARP-1 degradation products were similar between muscles. At T1, no difference was found in the level of SBDP145 between muscles, while SBDP120 and PARP-1 cleavage products were not detected. At T2 neither alphaII spectrin nor PARP-1 cleavage products were found. LL and IS showed different proteolysis after slaughter that was influenced more by calpain than caspase activity, which was detectable only in the early post mortem period. PMID- 26950518 TI - Diverse Optimal Molecular Libraries for Organic Light-Emitting Diodes. AB - Organic light-emitting diodes (OLEDs) have wide-ranging applications, from lighting to device displays. However, the repertoire of organic molecules with efficient blue emission is limited. To address this limitation, we have developed a strategy to design property-optimized, diversity-oriented libraries of structures with favorable fluorescence properties. This approach identifies novel diverse candidate organic molecules for blue emission with strong oscillator strengths and low singlet-triplet energy gaps that favor thermally activated delayed fluorescence (TADF) emission. PMID- 26950516 TI - Fermentation and microbial population dynamics during the ensiling of native grass and subsequent exposure to air. AB - To study the microbial population and fermentation dynamics of large needlegrass (LN) and Chinese leymus (CL) during ensiling and subsequent exposure to air, silages were sampled and analyzed using culture-based techniques and denaturing gradient gel electrophoresis (DGGE). A total of 112 lactic acid bacteria (LAB) strains were isolated and identified using the 16S rRNA sequencing method. Lactic acid was not detected in the first 20 days in LN silage and the pH decreased to 6.13 after 45 days of ensiling. The temperature of the LN silage increased after approximately 30 h of air exposure and the CL silage showed a slight temperature variation. Enterococcus spp. were mainly present in LN silage. The proportion of Lactobacillus brevis in CL silage increased after exposure to air. LN silage with a higher proportion of Enterococcus spp. and propionic acid concentration did not show higher fermentation quality or aerobic stability than CL silage, which had a higher concentration of acetic acid, butyric acid and increased proportion of L. brevis after exposure to air. PMID- 26950519 TI - Impact of the alpha-Synuclein Initial Ensemble Structure on Fibrillation Pathways and Kinetics. AB - The presence of intracellular filamentous alpha-synuclein (alphaS) aggregates is a common feature in Parkinson's disease. Recombinant expressed and purified human alphaS is also capable of forming fibrils in vitro. Many studies have shown that solution conditions heavily influence alphaS fibrillation kinetics, fibril structure, and morphology that exhibit differential biological effects. Nevertheless, the alphaS ensemble structure in various solution conditions is not well characterized; furthermore, how the initial solution ensemble structures impact alphaS assembly kinetics and pathways that result in diverse fibril structure and morphology remains elusive. Here, we mainly employed NMR spectroscopy to characterize the initial ensemble structure of alphaS in the presence or absence of a 150 mM sodium chloride (NaCl) solution, where two polymorphs of alphaS were demonstrated in previous studies. Our data show that alphaS exhibits distinct conformations and fibrillation kinetics in these two solutions. alphaS adopts a more compact and rigid ensemble structure that has faster fibrillation kinetics in the absence of NaCl. On the basis of the ensemble structure and dynamics, we proposed a possible molecular mechanism in which alphaS forms different polymorphs under these two conditions. Our results provide novel insights into how the initial conformation impacts fibrillation pathways and kinetics, suggesting that a microenvironment can be used to regulate the intrinsically disordered proteins assembly. PMID- 26950521 TI - Learning anatomy via mobile augmented reality: Effects on achievement and cognitive load. AB - Augmented reality (AR), a new generation of technology, has attracted the attention of educators in recent years. In this study, a MagicBook was developed for a neuroanatomy topic by using mobile augmented reality (mAR) technology. This technology integrates virtual learning objects into the real world and allow users to interact with the environment using mobile devices. The purpose of this study was to determine the effects of learning anatomy via mAR on medical students' academic achievement and cognitive load. The mixed method was applied in the study. The random sample consisted of 70 second-year undergraduate medical students: 34 in an experimental group and 36 in a control group. Academic achievement test and cognitive load scale were used as data collection tool. A one-way MANOVA test was used for analysis. The experimental group, which used mAR applications, reported higher achievement and lower cognitive load. The use of mAR applications in anatomy education contributed to the formation of an effective and productive learning environment. Student cognitive load decreased as abstract information became concrete in printed books via multimedia materials in mAR applications. Additionally, students were able to access the materials in the MagicBook anytime and anywhere they wanted. The mobile learning approach helped students learn better by exerting less cognitive effort. Moreover, the sensory experience and real time interaction with environment may provide learning satisfaction and enable students to structure their knowledge to complete the learning tasks. Anat Sci Educ 9: 411-421. (c) 2016 American Association of Anatomists. PMID- 26950520 TI - Perspectives of oncology health workers in Flanders on caring for patients of non Western descent. AB - This study was undertaken to gain insight in the views and experiences of oncology healthcare providers in Flanders, the Dutch-speaking part of Belgium, on caring for patients of non-Western descent. A qualitative research design with the constant comparative method was used. Data were collected through five focus group interviews, with 23 oncology health workers as participants. Barriers and difficulties were paramount in the provision of care to patients of non-Western descent. Participants want to act according to their professional standards, which call for treating all patients equally and providing appropriate care. However, a focus on medical aspects occurs, wherein 'cure' takes precedence over 'care', when participants were not willing or not fully able to overcome barriers. This results in feelings of inadequacy in those participants who equate professional standards to care of equal quality. Participants who interpreted their professional standard as equivalent care were irritated by 'these' patients who restrained them from providing appropriate care. The findings indicate that professional standards provide protection against possible discrimination that may result from personal beliefs. Extending professional standards from 'treating all patients equally' to 'care attuned to each patient' might be a way to prevent 'cure' taking precedence over 'care'. PMID- 26950522 TI - Stratification of archaeal membrane lipids in the ocean and implications for adaptation and chemotaxonomy of planktonic archaea. AB - Membrane lipids of marine planktonic archaea have provided unique insights into archaeal ecology and paleoceanography. However, past studies of archaeal lipids in suspended particulate matter (SPM) and sediments mainly focused on a small class of fully saturated glycerol dibiphytanyl glycerol tetraether (GDGT) homologues identified decades ago. The apparent low structural diversity of GDGTs is in strong contrast to the high diversity of metabolism and taxonomy among planktonic archaea. Furthermore, adaptation of archaeal lipids in the deep ocean remains poorly constrained. We report the archaeal lipidome in SPM from diverse oceanic regimes. We extend the known inventory of planktonic archaeal lipids to include numerous unsaturated archaeal ether lipids (uns-AELs). We further reveal (i) different thermal regulations and polar headgroup compositions of membrane lipids between the epipelagic (<= 100 m) and deep (>100 m) populations of archaea, (ii) stratification of unsaturated GDGTs with varying redox conditions, and (iii) enrichment of tetra-unsaturated archaeol and fully saturated GDGTs in epipelagic and deep oxygenated waters, respectively. Such stratified lipid patterns are consistent with the typical distribution of archaeal phylotypes in marine environments. We, thus, provide an ecological context for GDGT-based paleoclimatology and bring about the potential use of uns-AELs as biomarkers for planktonic Euryarchaeota. PMID- 26950523 TI - Growth trajectories in wild geladas (Theropithecus gelada). AB - Life history and socioecological factors have been linked to species-specific patterns of growth across female vertebrates. For example, greater maternal investment in offspring has been associated with more discrete periods of growth and reproduction. However, in primates it has been difficult to test such hypotheses because very few studies have obtained growth measurements from wild populations. Here we utilize a promising noninvasive photogrammetric method parallel lasers-to examine shoulder-rump (SR) growth in a wild primate, the gelada (Theropithecus gelada, Simien Mountains National Park, Ethiopia). In this species, a graminivorous diet coupled with high extrinsic infant mortality risk suggests that maternal investment in neonates is low. Therefore, in contrast with other closely related papionins, we expected female geladas to exhibit less discrete periods of growth and reproduction. For both sexes, we compared size-for age patterns (N = 154 females; N = 110 males) and changes in growth velocity relative to major life history milestones. Female geladas finished 88.5% of SR growth by first sexual swelling, and 97.2% by first reproduction, reaching adult body size by 7.72 years of age. Compared to closely related papionins, gelada females finished more growth by first reproduction, despite producing relatively small, and presumably "cheap," neonates. Male geladas finished 85.4% of growth at dispersal, and 96.0% at estimated first birth. Contrary to other polygynous primates, males are larger than females because they grow for a longer period of time (not because they grow faster), surpassing females around 6 years of age when female growth slows. Our results demonstrate that parallel lasers are an easy and promising new method that can be used to construct comprehensive life history perspectives that were once out of reach for wild populations. Am. J. Primatol. 78:707-719, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26950524 TI - Conduct, Oversight, and Ethical Considerations of Clinical Trials in Companion Animals with Cancer: Report of a Workshop on Best Practice Recommendations. AB - Development of effective and safe treatments for companion animals with cancer requires the collaboration of numerous animal health professionals and the full engagement of animal owners. Establishing 'Best Practice Recommendations' for clinical trials in veterinary oncology represents an important step toward meeting the goal of rigorous clinical trial design and conduct that is required to establish valid evidence. Likewise, optimizing patient welfare and owner education and advocacy is crucial to meet the unique ethical obligations to both owners and animals enrolled in these clinical trials and to ensure trust in the team conducting the research. To date, 'Best Practice Recommendations' for clinical trial conduct have not been reported for veterinary oncology. This document summarizes the consensus of a workshop held in November, 2014 to identify relevant ethical principles and to ensure responsible conduct of clinical research in companion animals with cancer. It is intended as a working document that will be updated as advances in science and ethical considerations require. To the extent possible, existing guidelines for the conduct and oversight of clinical trials in humans have been adapted for veterinary trials to avoid duplicative effort and to facilitate integration of clinical trials such that translational research with benefits for both companion animals and humans are encouraged. PMID- 26950526 TI - Biosorption of metal ions using a low cost modified adsorbent (Mauritia flexuosa): experimental design and mathematical modeling. AB - Buriti fibers were subjected to an alkaline pre-treatment and tested as an adsorbent to investigate the adsorption of copper, cadmium, lead and nickel in mono- and multi-element aqueous solutions, the results showed an increase in the adsorption capacity compared to the unmodified Buriti fiber. The effects of pH, adsorbent mass, agitation rate and initial metal ions concentration on the efficiency of the adsorption process were studied using a fractional 2(4-1) factorial design, and the results showed that all four parameters influenced metal adsorption differently. Fourier transform infrared spectrometry and X-ray fluorescence analysis were used to identify the groups that participated in the adsorption process and suggest its mechanisms and they indicated the probable mechanisms involved in the adsorption process are mainly ion exchange. Kinetic and thermodynamic equilibrium parameters were determined. The adsorption kinetics were adjusted to the homogeneous diffusion model. The adsorption equilibrium was reached in 30 min for Cu(2+) and Pb(2+), 20 min for Ni(2+) and instantaneously for Cd(2+). The results showed a significant difference was found in the competitiveness for the adsorption sites. A mathematical model was used to simulate the breakthrough curves in multi-element column adsorption considering the influences of external mass transfer and intraparticle diffusion resistance. PMID- 26950527 TI - Installation of a flow control device in an inclined air-curtain fume hood to control wake-induced exposure. AB - An inclined plate for flow control was installed at the lower edge of the sash of an inclined air-curtain fume hood to reduce the effects of the wake around a worker standing in front of the fume hood. Flow inside the fume hood is controlled by the inclined air-curtain and deflection plates, thereby forming a quad-vortex flow structure. Controlling the face velocity of the fume hood resulted in convex, straight, concave, and attachment flow profiles in the inclined air-curtain. We used the flow visualization and conducted a tracer gas test with a mannequin to determine the performance of two sash geometries, namely, the half-cylinder and inclined plate designs. When the half-cylinder design was used, the tracer gas test registered a high leakage concentration at Vf ? 57.1 fpm or less. This concentration occurred at the top of the sash opening, which was close to the breathing zone of the mannequin placed in front of the fume hood. When the inclined plate design was used, the containment was good, with concentrations of 0.002-0.004 ppm, at Vf ? 63.0 fpm. Results indicate that an inclined plate effectively reduces the leakage concentration induced by recirculation flow structures that form in the wake of a worker standing in front of an inclined air-curtain fume hood. PMID- 26950525 TI - Biological and Mechanistic Characterization of Novel Prodrugs of Green Tea Polyphenol Epigallocatechin Gallate Analogs in Human Leiomyoma Cell Lines. AB - Uterine fibroids (leiomyomas) are very common benign tumors grown on the smooth muscle layer of the uterus, present in up to 75% of reproductive-age women and causing significant morbidity in a subset of this population. Although the etiology and biology of uterine fibroids are unclear, strong evidence supports that cell proliferation, angiogenesis and fibrosis are involved in their formation and growth. Currently the only cure for uterine fibroids is hysterectomy; the available alternative therapies have limitations. Thus, there is an urgent need for developing a novel strategy for treating this condition. The green tea polyphenol epigallocatechin gallate (EGCG) inhibits the growth of uterine leiomyoma cells in vitro and in vivo, and the use of a green tea extract (containing 45% EGCG) has demonstrated clinical activity without side effects in women with symptomatic uterine fibroids. However, EGCG has a number of shortcomings, including low stability, poor bioavailability, and high metabolic transformations under physiological conditions, presenting challenges for its development as a therapeutic agent. We developed a prodrug of EGCG (Pro-EGCG or 1) which shows increased stability, bioavailability and biological activity in vivo as compared to EGCG. We also synthesized prodrugs of EGCG analogs, compounds 2a and 4a, in order to potentially reduce their susceptibility to methylation/inhibition by catechol-O-methyltransferase. Here, we determined the effect of EGCG, Pro-EGCG, and 2a and 4a on cultured human uterine leiomyoma cells, and found that 2a and 4a have potent antiproliferative, antiangiogenic, and antifibrotic activities. J. Cell. Biochem. 117: 2357-2369, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26950528 TI - Inhalation of two putative Gulf War toxins by mice. AB - We employed our inhalation methodology to examine whether biomarkers of inflammation and oxidative stress would be produced in mice following inhalation of aerosols containing carbonaceous particles or the vapor of pesticides prevalent during the first Gulf War. Exposure to two putative Gulf War Illness toxins, fine airborne particles and the pesticide malathion, increased biomarkers of inflammation and oxidative stress in Friend virus B (FVB) female mice. Mice inhaling particles 24 h before had increased lung lavage and plasma Leukotriene B4 (LTB4) (a biomarker of inflammation) and PGF2alpha (a biomarker of oxidative stress) levels, lung lavage protein and lung lavage lactic dehydrogenase (LDH) levels. These changes were a function of particle density and exposure time. Compared to particle inhalation, mice inhaling malathion 24 h before had small increase in plasma LTB4 and PGF2alpha levels but no increase in lung lavage LTB4, lung lavage protein, lung lavage LDH, and lung lavage alveolar macrophage (AM) levels compared to unexposed control mice. AM from particle-exposed mice contained phagocytosed particles, while AM from malathion-exposed mice showed no abnormalities. Our results indicate that inhaling particles or malathion can alter inflammatory and oxidative biomarkers in mice and raise the possibility that these toxins may have altered inflammation and oxidative stress biomarkers in Gulf War-exposed individuals. PMID- 26950530 TI - Evaluation of the Adherence to Continuous Glucose Monitoring in the Management of Type 1 Diabetes Patients on Sensor-Augmented Pump Therapy: The SENLOCOR Study. AB - BACKGROUND: Continuous glucose monitoring (CGM) and sensor-augmented pump (SAP) therapy improve glucose control provided good adherence. In France, not only diabetologists, nurses, and dieticians but also nurses employed by homecare providers (HCPNs) are together involved in the initiation and/or follow-up of continuous subcutaneous insulin injection (CSII) and SAP training. The SENLOCOR Study is an observational study designed to assess SAP adherence over 6 months (primary objective). Secondary objectives included the impact of SAP on metabolic control and patients' satisfaction. MATERIALS AND METHODS: CGM initiation (M0) was performed within 3 months after CSII. CGM adherence, defined by sensor wear >70% of the time, glycated hemoglobin (HbA1c) levels, and satisfaction questionnaires were collected at inclusion and at 3 (M3) and 6 (M6) months. RESULTS: The analysis population was 234 patients, including 27 children. Of the physicians, 88.0% were involved in SAP education for the whole cohort (median time, 45 min), whereas HCPNs were involved in CGM training for 190 patients (81.2%) (median time: at M0, 156 min; at M3, 20 min). Good adherence was obtained in 86.1% (M0-M3) and 68.9% (M3-M6) of the patients. The HbA1c level decreased from 8.16 +/- 1.35% (M0) to 7.67 +/- 1.01% (M6) in 189 patients (change, -0.48%; 95% confidence interval, -0.64, -0.33). The percentage of patients who experienced severe hypoglycemia decreased from 20.7% (M0) to 13.6% (M3) and 13.3% (M6). Satisfaction scores were high. CONCLUSIONS: In patients with type 1 diabetes, a 6-month training on SAP involving a multidisciplinary team, and especially HCPNs, improved metabolic control with a high level of adherence and satisfaction. PMID- 26950531 TI - Ethnic Variations in Pterygium in a Rural Population in Southwestern China: The Yunnan Minority Eye Studies. AB - PURPOSE: To determine the prevalence and associations of pterygium in a multiethnic adult population in rural China and to examine potential ethnic differences Methods: A total of 6418 adults (2133 ethnic Bai, 2130 ethnic Yi, and 2155 ethnic Han) aged 50 years or older participated in the study. Anterior segment examination was performed without pupil dilation using a slit lamp. Pterygium was defined as a raised fleshy triangular fibrovascular tissue growth of the conjunctiva encroaching onto a clear cornea. RESULTS: Pterygium was least prevalent among adults of Yi ethnicity (29.5%) compared with Bai (39.0%, p < 0.001) or Han (39.5%, p < 0.001) ethnicities. Those of Bai ethnicity were most likely to be affected by severe pterygium (7.5%), while Yi were least likely to be affected (3.8%). Multivariate analysis revealed that increasing age (odds ratio, OR, 1.017), female sex (OR 1.53), lower educational level (OR 1.25), higher blood pressure levels (OR 1.002), and greater time spent outdoors per day (OR 1.09) were significantly associated with a higher prevalence of pterygium, while Yi ethnicity (OR 0.65, comparing Yi with Han) and wearing brimmed hats outdoors (OR 0.82) were protective factors. CONCLUSION: Ethnicity was significantly associated with prevalence of pterygium. Our findings may be applicable to many other countries located within the "pterygium belt" for health resource allocation among different ethnic groups. PMID- 26950529 TI - Transcriptome landscape of Lactococcus lactis reveals many novel RNAs including a small regulatory RNA involved in carbon uptake and metabolism. AB - RNA sequencing has revolutionized genome-wide transcriptome analyses, and the identification of non-coding regulatory RNAs in bacteria has thus increased concurrently. Here we reveal the transcriptome map of the lactic acid bacterial paradigm Lactococcus lactis MG1363 by employing differential RNA sequencing (dRNA seq) and a combination of manual and automated transcriptome mining. This resulted in a high-resolution genome annotation of L. lactis and the identification of 60 cis-encoded antisense RNAs (asRNAs), 186 trans-encoded putative regulatory RNAs (sRNAs) and 134 novel small ORFs. Based on the putative targets of asRNAs, a novel classification is proposed. Several transcription factor DNA binding motifs were identified in the promoter sequences of (a)sRNAs, providing insight in the interplay between lactococcal regulatory RNAs and transcription factors. The presence and lengths of 14 putative sRNAs were experimentally confirmed by differential Northern hybridization, including the abundant RNA 6S that is differentially expressed depending on the available carbon source. For another sRNA, LLMGnc_147, functional analysis revealed that it is involved in carbon uptake and metabolism. L. lactis contains 13% leaderless mRNAs (lmRNAs) that, from an analysis of overrepresentation in GO classes, seem predominantly involved in nucleotide metabolism and DNA/RNA binding. Moreover, an A-rich sequence motif immediately following the start codon was uncovered, which could provide novel insight in the translation of lmRNAs. Altogether, this first experimental genome-wide assessment of the transcriptome landscape of L. lactis and subsequent sRNA studies provide an extensive basis for the investigation of regulatory RNAs in L. lactis and related lactococcal species. PMID- 26950532 TI - Histone deacetylase inhibitors as immunomodulators in cancer therapeutics. AB - HDAC inhibitors (HDACIs) are anticancer agents being developed in preclinical and clinical settings due to their capacity to modulate gene expression involved in cell growth, differentiation and apoptosis, through modification of both chromatin histone and nonhistone proteins. Most HDACIs in clinical development have cytotoxic or cytostatic properties and their direct inhibitory effects on tumor cells are well documented. Numerous studies have revealed that HDACIs have potent immunomodulatory activity in tumor-bearing animals and cancer patients, providing guidance to apply these agents in cancer immunotherapies. Here, we summarize recent reports addressing the effects of HDACIs on tumor cell immunogenicity, and on different components of the host immune system. In addition, we discuss the complexity of the immunomodulatory activity of these agents, which depends on the class specificity of the HDACIs, different experimental settings and the target immune cell populations. PMID- 26950533 TI - Cytokine, chemokine, and growth factor profile of platelet-rich plasma. AB - During wound healing, biologically active molecules are released from platelets. The rationale of using platelet-rich plasma (PRP) relies on the concentration of bioactive molecules and subsequent delivery to healing sites. These bioactive molecules have been seldom simultaneously quantified within the same PRP preparation. In the present study, the flexible Bio-Plex system was employed to assess the concentration of a large range of cytokines, chemokines, and growth factors in 16 healthy volunteers so as to determine whether significant baseline differences may be found. Besides IL-1b, IL-1ra, IL-4, IL-6, IL-8, IL-12, IL-13, IL-17, INF-gamma, TNF-alpha, MCP-1, MIP-1a, RANTES, bFGF, PDGF, and VEGF that were already quantified elsewhere, the authors reported also on the presence of IL-2, IL-5, IL-7, IL-9, IL-10, IL-15 G-CSF, GM-CSF, Eotaxin, CXCL10 chemokine (IP 10), and MIP 1b. Among the most interesting results, it is convenient to mention the high concentrations of the HIV-suppressive and inflammatory cytokine RANTES and a statistically significant difference between males and females in the content of PDGF-BB. These data are consistent with previous reports pointing out that gender, diet, and test system affect the results of platelet function in healthy subjects, but seem contradictory when compared to other quantification assays in serum and plasma. The inconsistencies affecting the experimental results found in literature, along with the variability found in the content of bioactive molecules, urge further research, hopefully in form of randomized controlled clinical trials, in order to find definitive evidence of the efficacy of PRP treatment in various pathologic and regenerative conditions. PMID- 26950535 TI - Willingness to pay for midwife-endorsed product: An Australian best-worst study. AB - This article examined the impact of midwife endorsement on stated choice preferences in one of the highest volume baby care product categories, diapers. An online survey was conducted testing 12 alternatives of which six were midwife endorsed. A total of 215 responses were analyzed using best-worst and multinomial logit modeling. Results indicate that package size, price, and brand are more sensitive predictors of stated choice preferences than midwife endorsement. Respondents were willing to pay 2.3% more for a diaper that was endorsed by midwives. These findings suggest that midwife endorsement should be pursued by health marketers. PMID- 26950534 TI - Transition of HIV-infected youths from paediatric to adult care, a Swedish single centre experience. AB - BACKGROUND: Transition of HIV-infected adolescents from paediatric care to adult care is vulnerable and entails a risk of treatment failure. Therefore, a Transitional Outpatient Clinic for HIV-infected adolescents and young adults was started in 2008. The aims were to describe the transition process and treatment results in a Swedish cohort of adolescents with HIV. MATERIALS AND METHODS: A cross-sectional study of the adolescent and young adults with HIV at the clinic was performed in October 2013 and a 2-year follow-up at the end of 2015. RESULTS: The 34 patients in care in October 2013 were a median of 19 years, 50% were female. Thirty-one out of 34 (91%) were perinatally infected. In 2013, 88% were on antiretroviral treatment (ART), for a median duration of 9 years, 74% were on a protease inhibitor-based regimen. Twenty-nine patients were followed-up at the end of 2015. Twenty-three were transferred to the Infectious Disease Clinic and the median age for transition was 19 years. At the end of 2015, 90% were treated with ART and 61% had an integrase inhibitor-based treatment. Of those treated with ART for more than 6 months, 90% (2013) and 96% (2015) had a viral load < 50 HIV RNA copies/mL, despite resistance problems and complicating social factors. These figures were higher than reported in other studies and similar to the treatment results in the adult HIV population in Sweden. CONCLUSIONS: The present study showed that it is possible to achieve good treatment results in adolescents with HIV. PMID- 26950536 TI - Hybrids do it better: Lessons from websites of hybrid organizations in modern health movements. AB - Hybrid organizations in modern health movements adopt multiple organizational logistics, allowing them to more effectively achieve social change. We conducted an analysis of 152 probreastfeeding organization websites categorized as institutionalized organizations, grassroots organizations, or hybrid organizations. Through a series of ANOVA analyses, we found that hybrid's websites provide significantly more useful health care information, better maintained dialogue with members, more efficiently mobilized members, commoditized health care issues less, and created member identity while maintaining institutional ties. Ultimately, hybrids tended to incorporate the positive elements from both grassroots and institutional organizations, while rejecting many of the negative elements. PMID- 26950537 TI - How much segmentation is needed in the health care marketplace? An exploratory study of HMO and non-HMO customers. AB - The health care landscape has changed dramatically. Consumers now seek plans whose benefits better fit their health care needs and desires for access to providers. This exploratory survey of more than 1,000 HMO and non-HMO customers found significant differences with respect to their selection processes for health plans and providers, and their expectations regarding access to and communication with health care providers. While there are some similarities in factors affecting choice, segmentation strategies are necessary to maximize the appeal of a plan, satisfy customers in the selection of physicians, and meet their expectations regarding access to those physicians. PMID- 26950538 TI - Care provider perspectives on medical travel: A three-country study of destination hospitals. AB - Despite growing interest in the current and potential role of medical travel in U.S. patient care, very little research has been conducted on clinician and other provider organizations' perspectives on providing international patient care. The present study sought to gain formative insights about medical travel from the providers' perspectives, by conducting structured interviews and focus groups in six hospitals from three countries catering to patients traveling from the United States. Findings highlighted the surprising role of international events and policies in the evolution of medical travel, as well as both the desire and need for more transparent quality standards. PMID- 26950539 TI - Quantitative comparison of measurements of urgent care service quality. AB - Service quality and patient satisfaction are essential to health care organization success. Parasuraman, Zeithaml, and Berry introduced SERVQUAL, a prominent service quality measure not yet applied to urgent care. We develop an instrument to measure perceived service quality and identify the determinants of patient satisfaction/ behavioral intentions. We examine the relationships among perceived service quality, patient satisfaction and behavioral intentions, and demonstrate that urgent care service quality is not equivalent using measures of perceptions only, differences of expectations minus perceptions, ratio of perceptions to expectations, and the log of the ratio. Perceptions provide the best measure of urgent care service quality. PMID- 26950540 TI - Perception of acupuncture among users and nonusers: A qualitative study. AB - This study uses a qualitative methodology to examine the perception of acupuncture among users and nonusers. Altogether 37 participants, age 35 or older, were interviewed. Participants' perception of advantages and disadvantages of adopting acupuncture, and their criteria in selecting acupuncturists, were collected. Results found that among the user group, acupuncture was perceived as being effective, having little side effects, and generating lasting impact. Among nonusers, acupuncture was perceived as lacking a clinical base, high risk, and nonstandardized. Nonusers had less confidence in acupuncture than biomedicine. Participants relied on social communication and the practitioner's professional qualifications in choosing acupuncturists. Marketing implications are discussed. PMID- 26950541 TI - Moving from theory to practice: A participatory social network mapping approach to address unmet need for family planning in Benin. AB - In West Africa, social factors influence whether couples with unmet need for family planning act on birth-spacing desires. Tekponon Jikuagou is testing a social network-based intervention to reduce social barriers by diffusing new ideas. Individuals and groups judged socially influential by their communities provide entree to networks. A participatory social network mapping methodology was designed to identify these diffusion actors. Analysis of monitoring data, in depth interviews, and evaluation reports assessed the methodology's acceptability to communities and staff and whether it produced valid, reliable data to identify influential individuals and groups who diffuse new ideas through their networks. Results indicated the methodology's acceptability. Communities were actively and equitably engaged. Staff appreciated its ability to yield timely, actionable information. The mapping methodology also provided valid and reliable information by enabling communities to identify highly connected and influential network actors. Consistent with social network theory, this methodology resulted in the selection of informal groups and individuals in both informal and formal positions. In-depth interview data suggest these actors were diffusing new ideas, further confirming their influence/connectivity. The participatory methodology generated insider knowledge of who has social influence, challenging commonly held assumptions. Collecting and displaying information fostered staff and community learning, laying groundwork for social change. PMID- 26950542 TI - Outdoor artificial light at night, obesity, and sleep health: Cross-sectional analysis in the KoGES study. AB - Obesity is a common disorder with many complications. Although chronodisruption plays a role in obesity, few epidemiological studies have investigated the association between artificial light at night (ALAN) and obesity. Since sleep health is related to both obesity and ALAN, we investigated the association between outdoor ALAN and obesity after adjusting for sleep health. We also investigated the association between outdoor ALAN and sleep health. This cross sectional survey included 8526 adults, 39-70 years of age, who participated in the Korean Genome and Epidemiology Study. Outdoor ALAN data were obtained from satellite images provided by the US Defense Meteorological Satellite Program. We obtained individual data regarding outdoor ALAN; body mass index; depression; and sleep health including sleep duration, mid-sleep time, and insomnia; and other demographic data including age, sex, educational level, type of residential building, monthly household income, alcohol consumption, smoking status and consumption of caffeine or alcohol before sleep. A logistic regression model was used to investigate the association between outdoor ALAN and obesity. The prevalence of obesity differed significantly according to sex (women 47% versus men 39%, p < 0.001) and outdoor ALAN (high 55% versus low 40%, p < 0.001). Univariate logistic regression analysis revealed a significant association between high outdoor ALAN and obesity (odds ratio [OR] 1.24, 95% confidence interval [CI] 1.14-1.35, p < 0.001). Furthermore, multivariate logistic regression analyses showed that high outdoor ALAN was significantly associated with obesity after adjusting for age and sex (OR 1.25, 95% CI 1.14-1.37, p < 0.001) and even after controlling for various other confounding factors including age, sex, educational level, type of residential building, monthly household income, alcohol consumption, smoking, consumption of caffeine or alcohol before sleep, delayed sleep pattern, short sleep duration and habitual snoring (OR 1.20, 95% CI 1.06-1.36, p = 0.003). The findings of our study provide epidemiological evidence that outdoor ALAN is significantly related to obesity. PMID- 26950543 TI - Molecular characterization of a Class I Newcastle disease virus strain isolated from a pigeon in China. AB - Constant monitoring is performed to elucidate the role of natural hosts in the ecology of Newcastle disease virus (NDV). In this study, an NDV strain isolated from an asymptomatic pigeon was sequenced and analysed. Results showed that the full-length genomes of this isolate were 15,198 nucleotides with the gene order of 3'-NP-P-M-F-HN-L-5'. This NDV isolate was lentogenic, with an intracerebral pathogenicity index of 0.00 and a mean time of death more than 148 h. The isolate possessed a motif of -(112)E-R-Q-E-R-L(117)- at the F protein cleavage site. In addition, 7 and 13 amino acid substitutions were identified in the functional domains of fusion protein (F) and haemagglutinin-neuraminidase protein (HN) proteins, respectively. Analysis of the amino acids of neutralizing epitopes of F and HN proteins showed 3 and 10 amino acid substitutions, respectively, in the isolate. Phylogenetic analysis classified the isolate into genotype Ib in Class I. This isolate shared high homologies with the NDV strains isolated from wild birds and waterfowl in southern and eastern parts of China from 2005 to 2013. To our knowledge, this study is the first to report a NDV strain isolated from pigeon that belongs to genotype Ib in Class I, rather than to the traditional genotype VI or other sub-genotypes in Class II. This study provides information to elucidate the distribution and evolution of Class I viruses for further NDV prevention. PMID- 26950544 TI - Development of Gene-Based SSR Markers in Rice Bean (Vigna umbellata L.) Based on Transcriptome Data. AB - Rice bean (Vigna umbellata (Thunb.) Ohwi & Ohashi) is a warm season annual legume mainly grown in East Asia. Only scarce genomic resources are currently available for this legume crop species and no simple sequence repeat (SSR) markers have been specifically developed for rice bean yet. In this study, approximately 26 million high quality cDNA sequence reads were obtained from rice bean using Illumina paired-end sequencing technology and assembled into 71,929 unigenes with an average length of 986 bp. Of these unigenes, 38,840 (33.2%) showed significant similarity to proteins in the NCBI non-redundant protein and nucleotide sequence databases. Furthermore, 30,170 (76.3%) could be classified into gene ontology categories, 25,451 (64.4%) into Swiss-Prot categories and 21,982 (55.6%) into KOG database categories (E-value < 1.0E-5). A total of 9,301 (23.5%) were mapped onto 118 pathways using the Kyoto Encyclopedia of Genes and Genome (KEGG) pathway database. A total of 3,011 genic SSRs were identified as potential molecular markers. AG/CT (30.3%), AAG/CTT (8.1%) and AGAA/TTCT (20.0%) are the three main repeat motifs. A total of 300 SSR loci were randomly selected for validation by using PCR amplification. Of these loci, 23 primer pairs were polymorphic among 32 rice bean accessions. A UPGMA dendrogram revealed three major clusters among 32 rice bean accessions. The large number of SSR-containing sequences and genic SSRs in this study will be valuable for the construction of high-resolution genetic linkage maps, association or comparative mapping and genetic analyses of various Vigna species. PMID- 26950545 TI - "Do unto others"? Distinct psychopathy facets predict reduced perception and tolerance of pain. AB - Recent research has sought to understand how individuals high in psychopathic traits perceive pain in others (Decety, Skelly, & Kiehl, 2013; Marsh et al., 2013). Perception of pain in others is presumed to act as a prosocial signal, and underreactivity to others' pain may contribute to engagement in exploitative aggressive behaviors among individuals high in psychopathic traits (Jackson, Meltzoff, & Decety, 2005). The current study tested for associations between facets of psychopathy as defined by the triarchic model (Patrick, Fowles, & Krueger, 2009) and decreased sensitivity to pain in 105 undergraduates tested in a laboratory pain assessment. A pressure algometer was used to index pain tolerance, and participants also rated their perceptions of and reactivity to the algometer-induced pain during the assessment and again 3 days later. A unique positive relationship was found between pain tolerance and the meanness facet of psychopathy, which also predicted reduced fear of painful algometer stimulation. Other psychopathy facets (boldness, disinhibition) showed negative relations with fear of pain stimulation during testing and at follow-up. Findings from this study extend the nomological network surrounding callousness (meanness) and suggest that increased pain tolerance may be a mechanism contributing to insensitivity to expressions of discomfort in others. (PsycINFO Database Record PMID- 26950546 TI - CG Methylation Covaries with Differential Gene Expression between Leaf and Floral Bud Tissues of Brachypodium distachyon. AB - DNA methylation has the potential to influence plant growth and development through its influence on gene expression. To date, however, the evidence from plant systems is mixed as to whether patterns of DNA methylation vary significantly among tissues and, if so, whether these differences affect tissue specific gene expression. To address these questions, we analyzed both bisulfite sequence (BSseq) and transcriptomic sequence data from three biological replicates of two tissues (leaf and floral bud) from the model grass species Brachypodium distachyon. Our first goal was to determine whether tissues were more differentiated in DNA methylation than explained by variation among biological replicates. Tissues were more differentiated than biological replicates, but the analysis of replicated data revealed high (>50%) false positive rates for the inference of differentially methylated sites (DMSs) and differentially methylated regions (DMRs). Comparing methylation to gene expression, we found that differential CG methylation consistently covaried negatively with gene expression, regardless as to whether methylation was within genes, within their promoters or even within their closest transposable element. The relationship between gene expression and either CHG or CHH methylation was less consistent. In total, CG methylation in promoters explained 9% of the variation in tissue-specific expression across genes, suggesting that CG methylation is a minor but appreciable factor in tissue differentiation. PMID- 26950547 TI - Mycobacterium tuberculosis Complex and HIV Co-Infection among Extrapulmonary Tuberculosis Suspected Cases at the University of Gondar Hospital, Northwestern Ethiopia. AB - BACKGROUND: Extrapulmonary Tuberculosis (EPTB) and Human Immunodeficiency Virus (HIV) infection are interrelated as a result of immune depression. The aim of this study was to determine the prevalence of Mycobacterium tuberculosis complex isolates and the burden of HIV co-infection among EPTB suspected patients. METHOD: An institution based cross-sectional study was conducted among EPTB suspected patients at the University of Gondar Hospital. Socio-demographic characteristics and other clinical data were collected using a pretested questionnaire. GeneXpert MTB/RIF assay was performed to diagnosis Mycobacterium tuberculosis complex and Rifampicin resistance. All samples were also investigated by cytology and culture. The HIV statuses of all patients were screened initially by KHB, and all positive cases were further re-tested by STAT pack. Data was analyzed using SPSS version 20 computer software and a P-value of < 0.05 was taken as statistically significant. RESULTS: A total of 141 extrapulmonary suspected patients were enrolled in this study. The overall prevalence of culture confirmed extrapulmonary tuberculosis infection was 29.8%, but the GeneXpert result showed a 26.2% prevalence of Mycobacterium tuberculosis complex infection. The 78.4% prevalence of extrapulmonary tuberculosis infection was found to be higher among the adult population. The prevalence of HIV infection among EPTB suspected patients was 14.1%, while it was 32.4% among GeneXpert-confirmed extrapulmonary TB cases (12/37). Tuberculosis lymphadenitis was the predominant (78.4%) type of EPTB infection followed by tuberculosis cold abscess (10.7%). Adult hood, previous history of contact with known pulmonary tuberculosis patients, and HIV co-infection showed a statistically significant association with extrapulmonary tuberculosis infection (P<0.013). CONCLUSION: The prevalence of culture confirmed-EPTB infection was high, and a higher EPTB-HIV co infection was also observed. PMID- 26950549 TI - Re(I) NHC Complexes for Electrocatalytic Conversion of CO2. AB - The modular construction of ligands around an N-heterocyclic carbene building block represents a flexible synthetic strategy for tuning the electronic properties of metal complexes. Herein, methylbenzimidazolium-pyridine and methylbenzimidazolium-pyrimidine proligands are constructed in high yield using recently established transition-metal-free techniques. Subsequent chelation to ReCl(CO)5 furnishes ReCl(N-methyl-N'-2-pyridylbenzimidazol-2-ylidine)(CO)3 and ReCl(N-methyl-N'-2-pyrimidylbenzimidazol-2-ylidine)(CO)3. These Re(I) NHC complexes are shown to be capable of mediating the two-electron conversion of CO2 following one-electron reduction; the Faradaic efficiency for CO formation is observed to be >60% with minor H2 and HCO2H production. Data from cyclic voltammetry is presented and compared to well-studied ReCl(2,2'-bipyridine)(CO)3 and MnBr(2,2'-bipyridine)(CO)3 systems. Results from density functional theory computations, infrared spectroelectrochemistry, and chemical reductions are also discussed. PMID- 26950548 TI - Identification of Gene Expression Differences between Lymphangiogenic and Non Lymphangiogenic Non-Small Cell Lung Cancer Cell Lines. AB - It is well established that lung tumors induce the formation of lymphatic vessels. However, the molecular mechanisms controlling tumor lymphangiogenesis in lung cancer have not been fully delineated. In the present study, we identify a panel of non-small cell lung cancer (NSCLC) cell lines that induce lymphangiogenesis and use genome-wide mRNA expression to characterize the molecular mechanisms regulating tumor lymphangiogenesis. We show that Calu-1, H1993, HCC461, HCC827, and H2122 NSCLC cell lines form tumors that induce lymphangiogenesis whereas Calu-3, H1155, H1975, and H2073 NSCLC cell lines form tumors that do not induce lymphangiogenesis. By analyzing genome-wide mRNA expression data, we identify a 17-gene expression signature that distinguishes lymphangiogenic from non-lymphangiogenic NSCLC cell lines. Importantly, VEGF-C is the only lymphatic growth factor in this expression signature and is approximately 50-fold higher in the lymphangiogenic group than in the non lymphangiogenic group. We show that forced expression of VEGF-C by H1975 cells induces lymphangiogenesis and that knockdown of VEGF-C in H1993 cells inhibits lymphangiogenesis. Additionally, we demonstrate that the triple angiokinase inhibitor, nintedanib (small molecule that blocks all FGFRs, PDGFRs, and VEGFRs), suppresses tumor lymphangiogenesis in H1993 tumors. Together, these data suggest that VEGF-C is the dominant driver of tumor lymphangiogenesis in NSCLC and reveal a specific therapy that could potentially block tumor lymphangiogenesis in NSCLC patients. PMID- 26950551 TI - Analysis of the Structure of Surgical Activity for a Suturing and Knot-Tying Task. AB - BACKGROUND: Surgical tasks are performed in a sequence of steps, and technical skill evaluation includes assessing task flow efficiency. Our objective was to describe differences in task flow for expert and novice surgeons for a basic surgical task. METHODS: We used a hierarchical semantic vocabulary to decompose and annotate maneuvers and gestures for 135 instances of a surgeon's knot performed by 18 surgeons. We compared counts of maneuvers and gestures, and analyzed task flow by skill level. RESULTS: Experts used fewer gestures to perform the task (26.29; 95% CI = 25.21 to 27.38 for experts vs. 31.30; 95% CI = 29.05 to 33.55 for novices) and made fewer errors in gestures than novices (1.00; 95% CI = 0.61 to 1.39 vs. 2.84; 95% CI = 2.3 to 3.37). Transitions among maneuvers, and among gestures within each maneuver for expert trials were more predictable than novice trials. CONCLUSIONS: Activity segments and state flow transitions within a basic surgical task differ by surgical skill level, and can be used to provide targeted feedback to surgical trainees. PMID- 26950550 TI - Phospholipase Cgamma2 Is Required for Luminal Expansion of the Epididymal Duct during Postnatal Development in Mice. AB - Phospholipase Cgamma2 (PLCgamma2)-deficient mice exhibit misconnections of blood and lymphatic vessels, and male infertility. However, the cell type responsible for vascular partitioning and the mechanism for male infertility remain unknown. Accordingly, we generated a mouse line that conditionally expresses endogenous Plcg2 in a Cre/loxP recombination-dependent manner, and found that Tie2-Cre- or Pf4-Cre-driven reactivation of Plcg2 rescues PLCgamma2-deficient mice from the vascular phenotype. By contrast, male mice rescued from the vascular phenotype exhibited epididymal sperm granulomas. As judged from immunostaining, PLCgamma2 was expressed in clear cells in the epididymis. PLCgamma2 deficiency did not compromise differentiation of epididymal epithelial cells, including clear cells, and tube formation at postnatal week 2. However, luminal expansion of the epididymal duct was impaired during the prepubertal period, regardless of epithelial cell polarity and tube architecture. These results suggest that PLCgamma2-deficient clear cells cause impaired luminal expansion, stenosis of the epididymal duct, attenuation of luminal flow, and subsequent sperm granulomas. Clear cell-mediated luminal expansion is also supported by the observation that PLCgamma2-deficient males were rescued from infertility by epididymal epithelium specific reactivation of Plcg2, although the edematous and hemorrhagic phenotype associated with PLCgamma2 deficiency also caused spontaneous epididymal sperm granulomas in aging males. Collectively, our findings demonstrate that PLCgamma2 in clear cells plays an essential role in luminal expansion of the epididymis during the prepubertal period in mice, and reveal an unexpected link between PLCgamma2, clear cells, and epididymal development. PMID- 26950552 TI - A Cross-Sectional Study of Water, Sanitation, and Hygiene-Related Risk Factors for Soil-Transmitted Helminth Infection in Urban School- and Preschool-Aged Children in Kibera, Nairobi. AB - Soil-transmitted helminth (STH) infections affect persons living in areas with poor water, sanitation, and hygiene (WASH). Preschool-aged children (PSAC) and school-aged children (SAC) are disproportionately affected by STH infections. We aimed to identify WASH factors associated with STH infection among PSAC and SAC in Kibera, Kenya. In 2012, households containing a PSAC or SAC were randomly selected from those enrolled in the International Emerging Infections Program, a population-based surveillance system. We administered a household questionnaire, conducted environmental assessments for WASH, and tested three stools from each child for STH eggs using the Kato-Katz method. WASH factors were evaluated for associations with STH infection using univariable and multivariable Poisson regression. Any-STH prevalence was 40.8% among 201 PSAC and 40.0% among 475 SAC enrolled. Using the Joint Monitoring Programme water and sanitation classifications, 1.5% of households reported piped water on premises versus 98.5% another improved water source; 1.3% reported improved sanitation facilities, while 81.7% used shared sanitation facilities, 13.9% had unimproved facilities, and 3.1% reported no facilities (open defecation). On univariable analysis, STH infection was significantly associated with a household toilet located off premises (prevalence ratio (PR) = 1.33; p = 0.047), while always treating water (PR = 0.81; p = 0.04), covering drinking water containers (PR = 0.75; p = 0.02), using clean towels during hand drying (PR = 0.58; p<0.01), having finished household floor material (PR = 0.76; p<0.01), having electricity (PR = 0.70; p<0.01), and increasing household elevation in 10-meter increments (PR = 0.89; p<0.01) were protective against STH infection. On multivariable analysis, usually versus always treating water was associated with increased STH prevalence (adjusted prevalence ratio (aPR) = 1.52; p<0.01), while having finished household floor material (aPR = 0.76; p = 0.03), reported child deworming in the last year (aPR = 0.76; p<0.01), and 10-meter household elevation increases (aPR = 0.89; p<0.01) were protective against infection. The intersection between WASH and STH infection is complex; site-specific WASH interventions should be considered to sustain the gains made by deworming activities. PMID- 26950553 TI - A thorough QT study to evaluate the QTc prolongation potential of two neuropsychiatric drugs, quetiapine and escitalopram, in healthy volunteers. AB - Prolongation of the QT interval on an ECG is a surrogate marker for predicting the proarrhythmic potential of a drug under development. The aim of this study was to evaluate the QTc prolongation potential of two neuropsychiatric drugs, quetiapine immediate release (IR) and escitalopram, in healthy individuals. This was a randomized, open-label, 4*4 Williams crossover study, with four single-dose treatments [placebo, 400 mg moxifloxacin (positive control), 20 mg escitalopram, and 100 mg quetiapine IR], conducted in 40 healthy volunteers. Serial blood samples for pharmacokinetics and ECG were collected. Individually, RR-corrected QTc intervals (QTcI) and placebo-adjusted changes from baseline values of QTcI (DeltaDeltaQTcI) were evaluated. Lower-bound values of the one-sided 95% confidence interval for DeltaDeltaQTcI of moxifloxacin with more than 5 ms confirmed the sensitivity of the assay. The maximum upper bound 95% confidence interval for the DeltaDeltaQTcI of quetiapine IR and escitalopram was 13.7 and 10.5 ms, with mean estimates of 10.2 and 6.9 ms, respectively. Peak effects of moxifloxacin and quetiapine IR on DeltaDeltaQTcI were observed at approximately time to maximum concentration (Tmax), whereas that of escitalopram was observed 3 h after Tmax. The concentration-DeltaDeltaQTcI relationships of quetiapine IR and escitalopram were relatively flat, as compared with that of moxifloxacin. The results demonstrated the validity of trial methodology and that quetiapine IR and escitalopram caused QT prolongation in healthy individuals. In addition, hysteresis of escitalopram-induced QTc prolongation. These results indicate that higher doses of these drugs could lead to greater QT prolongation in a dose response manner. PMID- 26950554 TI - Tuberculosis Case Fatality and Other Causes of Death among Multidrug-Resistant Tuberculosis Patients in a High HIV Prevalence Setting, 2000-2008, South Africa. AB - INTRODUCTION: South Africa has the highest reported rates of multi-drug resistant TB in Africa, typified by poor treatment outcomes, attributable mainly to high default and death rates. Concomitant HIV has become the strongest predictor of death among MDR-TB patients, while anti-retroviral therapy (ART) has dramatically reduced mortality. TB Case fatality rate (CFR) is an indicator that specifically reports on deaths due to TB. AIM: The aim of this paper was to investigate causes of death amongst MDR-TB patients, the contribution of conditions other than TB to deaths, and to determine if causes differ between HIV-uninfected patients, HIV infected patients receiving ART and those without ART. METHODS: We carried out a retrospective review of data captured from the register of the MDR-TB programme of the North West Province, South Africa. We included 671 patients treated between 2000-2008; 59% of the cohort was HIV-infected and 33% had received ART during MDR treatment. The register contained data on treatment outcomes and causes of death. RESULTS: Treatment outcomes between HIV-uninfected cases, HIV infected cases receiving ART and HIV-infected without ART differed significantly (p<0.000). The cohort death rate was 24%, 13% for HIV-uninfected cases and 31% for HIV-infected cases. TB caused most of the deaths, resulting in a cohort CFR of 15%, 9% for HIV-uninfected cases and 20% for HIV-infected cases. Cohort mortality rate due to other conditions was 2%. AIDS-conditions rather than TB caused significantly more deaths among HIV-infected cases receiving ART than those not (p = 0.02). CONCLUSIONS: The deaths among HIV-infected individuals contribute substantially to the high death rate. ART co-therapy protected HIV infected cases from death due to TB and AIDS-conditions. Mechanisms need to be in place to ensure that HIV-infected individuals are retained in care upon completion of their MDR-TB treatment. PMID- 26950556 TI - Hand washing behavior and associated factors in Vietnam based on the Multiple Indicator Cluster Survey, 2010-2011. AB - BACKGROUND: Handwashing is a cost-effective way of preventing communicable diseases such as respiratory and food-borne illnesses. However, handwashing rates are low in developing countries. Target 7C of the seventh Millennium Development Goals was to increase by half the proportion of people with sustainable access to safe drinking water and basic sanitation by 2015. Studies have found that better access to improved water sources and sanitation is associated with higher rates of handwashing. OBJECTIVE: Our goal was to describe handwashing behaviour and identify the associated factors in Vietnamese households. DESIGN: Data from 12,000 households participating in the Vietnam Multiple Indicator Cluster Survey 2011 were used. The survey used a multistage sampling method to randomly select 100 clusters and 20 households per cluster. Self-administered questionnaires were used to collect data from a household representative. Demographic variables, the presence of a specific place for handwashing, soap and water, access to improved sanitation, and access to improved water sources were tested for association with handwashing behaviour in logistic regression. RESULTS: Almost 98% of households had a specific place for handwashing, and 85% had cleansing materials and water at such a place. The prevalence of handwashing in the sample was almost 85%. Educational level, ethnicity of the household head, and household wealth were factors associated with handwashing practice (p<0.05). Those having access to an improved sanitation facility were more likely to practise handwashing [odds ratio (OR)=1.69, 95% confidence interval (CI): 1.37-2.09, p<0.001], as were those with access to improved water sources (OR=1.74, 95% CI: 1.37-2.21, p<0.001). CONCLUSIONS: Households with low education, low wealth, belonging to ethnic minorities, and with low access to improved sanitation facilities and water sources should be targeted for interventions implementing handwashing practice. In addition, the availability of soap and water at handwashing sites should be increased and practical teaching programs should be deployed in order to increase handwashing rates. PMID- 26950555 TI - Timely immunization completion among children in Vietnam from 2000 to 2011: a multilevel analysis of individual and contextual factors. AB - BACKGROUND: Since the beginning of 2014, there have been nearly 6,000 confirmed measles cases in northern Vietnam. Of these, more than 86% had neither been immunized nor was their vaccination status confirmed. OBJECTIVE: To establish the likelihood that children under five in Vietnam had 'timely immunization completion' (2000-2011) and identify factors that account for variations in timely immunization completion. DESIGN: Secondary data from the Multiple Indicator Cluster Survey (MICS), which sampled women aged 15-49 from the 1999 Vietnamese Population and Housing Census frame, were analyzed. Multilevel analysis using Poisson regression was undertaken. RESULTS: Proportions of children under five who had timely immunization completion were low, especially for HBV dose 2 and HBV dose 3, which decreased between 2000 and 2011. Among seven vaccines used in the National Expanded Program of Immunization (EPI) in 2000, 2006, and 2011, measles dose 1 had the highest timely immunization completion at 65.3%, 66.7%, and 73.6%, respectively, and hepatitis B dose 1 had the lowest at 17.5%, 19.3%, and 45.5%, respectively. Timely immunization completion was less common among children whose mothers had relatively less household wealth, were from ethnic minorities, lived in rural areas, and had less education. At the community level, the child's region of residence was the main predictor of timely immunization completion, and the availability of hospital delivery and community prenatal care in the local community were also determinants. CONCLUSION: The EPI should include 'timely immunization completion' as a quality indicator. There should also be greater focus and targeting in rural areas, and among women who have relatively low education, belong to minority groups, and have less household wealth. Further research on this topic using multilevel analysis is needed to better understand how these factors interact. PMID- 26950557 TI - Secular trends in HIV knowledge and attitudes among Vietnamese women based on the Multiple Indicator Cluster Surveys, 2000, 2006, and 2011: what do we know and what should we do to protect them? AB - BACKGROUND: In Vietnam, women are at risk of HIV infection due to many factors. However, there is limited evidence about what women know and how they behave to protect themselves from HIV. OBJECTIVE: The objective of this study was to investigate the trends in comprehensive HIV/AIDS knowledge, attitude, and associated factors among Vietnamese women from 2000 to 2011. DESIGN: Data from three waves of the Vietnam Multiple Indicator Cluster Surveys (years 2000, 2006, and 2011) were used. Logistic regression methods examined factors associated with each of two dependent variables, HIV/AIDS knowledge and attitude toward HIV/AIDS. RESULTS: Although there was an increasing trend in basic HIV/AIDS knowledge and positive attitude toward the disease, in Vietnamese women in the general population over the survey years, the prevalence of women with basic HIV/AIDS knowledge and positive attitude toward HIV/AIDS was low. Multivariable models indicated that women who had higher levels of education, lived in urban areas, had higher economic status, and knew about places of HIV-related services were more likely to have good HIV/AIDS knowledge (e.g. in 2011, AOR's=3.01; 1.27; 1.88; 2.03, respectively). Women with higher educational attainment, knew about HIV services, and had better HIV knowledge were more likely to report positive attitude toward HIV/AIDS (e.g. in 2011, AOR's=2.50; 1.72; 2.23, respectively). CONCLUSIONS: This study recommends that public health programs for the control of HIV, such as behavioral change communication campaigns or social policies for women, should focus not only in improving the quality of existing HIV/AIDS counseling and testing services but also on expanding coverage to increase accessibility to these services for women in rural areas. In addition, efforts to raise the level of knowledge about HIV/AIDS and improve attitude toward the disease should be undertaken simultaneously. The results of this study can help inform HIV control policies and practices in other developing countries. PMID- 26950558 TI - Trends in socioeconomic inequalities in child malnutrition in Vietnam: findings from the Multiple Indicator Cluster Surveys, 2000-2011. AB - BACKGROUND: Child malnutrition is not only a major contributor to child mortality and morbidity, but it can also determine socioeconomic status in adult life. The rate of under-five child malnutrition in Vietnam has significantly decreased, but associated inequality issues still need attention. OBJECTIVE: This study aims to explore trends, contributing factors, and changes in inequalities for under-five child malnutrition in Vietnam between 2000 and 2011. DESIGN: Data were drawn from the Viet Nam Multiple Indicator Cluster Survey for the years 2000 and 2011. The dependent variables used for the study were stunting, underweight, and wasting of under-five children. The concentration index was calculated to see the magnitude of child malnutrition, and the inequality was decomposed to understand the contributions of determinants to child malnutrition. The total differential decomposition was used to identify and explore factors contributing to changes in child malnutrition inequalities. RESULTS: Inequality in child malnutrition increased between 2000 and 2011, even though the overall rate declined. Most of the inequality in malnutrition was due to ethnicity and socioeconomic status. The total differential decomposition showed that the biggest and second biggest contributors to the changes in underweight inequalities were age and socioeconomic status, respectively. Socioeconomic status was the largest contributor to inequalities in stunting. CONCLUSIONS: Although the overall level of child malnutrition was improved in Vietnam, there were significant differences in under-five child malnutrition that favored those who were more advantaged in socioeconomic terms. The impact of socioeconomic inequalities in child malnutrition has increased over time. Multifaceted approaches, connecting several relevant ministries and sectors, may be necessary to reduce inequalities in childhood malnutrition. PMID- 26950559 TI - Determinants of early childhood morbidity and proper treatment responses in Vietnam: results from the Multiple Indicator Cluster Surveys, 2000-2011. AB - BACKGROUND: Despite significant achievements in health indicators during previous decades, Vietnam lags behind other developing countries in reducing common early childhood illnesses, such as diarrhea and respiratory infections. To date, there has been little research into factors that contribute to the prevalence and treatment of childhood morbidity in Vietnam. OBJECTIVE: This study examines the determinants of diarrhea and 'illness with a cough' and treatments for each of the conditions among young children in Vietnam, and describes trends over time. DESIGN: Data from the Vietnam Multiple Indicator Cluster Surveys in 2000, 2006, and 2011 were used. Multivariable logistic regressions were undertaken to investigate factors associated with these childhood illnesses and proper treatment patterns. RESULTS: Between 2000 and 2011, the prevalence of diarrhea among children under the age of five declined from 11 to 7%, while having illness with a cough increased to 40% in 2011 after falling from 69 to 28% between 2000 and 2006. During the same period, the prevalence of oral rehydration therapy (ORT) for treating diarrhea increased from 13 to 46%, whereas the rate of seeking formal treatment for illnesses with a cough fell from 24 to 7%. Multivariable models indicated that children who were older than 2 years (odds ration [OR]: 0.44, 95% confidence interval [CI]: 0.37-0.53, p<0.001), male (OR: 1.21, 95% CI: 0.64-2.37, p<0.05), living in rural areas (OR: 1.28, 95% CI: 1.00-1.64, p<0.05), or of Kinh ethnicity (OR: 0.70, 95% CI: 0.56-0.87, p<0.01) were more likely to suffer from diarrhea. Ethnic differences and higher household wealth were factors significantly associated with having illness with a cough. In particular, the effect of level of wealth on illness with a cough varied in each wave. Mothers with higher levels of education had higher odds of seeking ORT compared with mothers with the lowest level of education. Seeking formal treatment for children who have illness with a cough was associated with being in a household in the richest wealth quintile (OR: 0.56, 95% CI: 0.34-0.91, p<0.05). CONCLUSIONS: This study demonstrates the importance of identifying different risk factors for these two illnesses and also factors associated with healthcare-seeking behaviors in order to reduce the burden of childhood morbidity in Vietnam. Policies aimed at tackling childhood morbidities should include comprehensive strategies that impact on socioeconomic and environmental factors. PMID- 26950560 TI - Trends and determinants of infant and under-five childhood mortality in Vietnam, 1986-2011. AB - BACKGROUND: Although Vietnam has taken great efforts to reduce child mortality in recent years, a large number of children still die at early age. Only a few studies have been conducted to identify at-risk groups in order to provide baseline information for effective interventions. OBJECTIVE: The study estimated the overall trends in infant mortality rate (IMR) and under-five mortality rate (U5MR) during 1986-2011 and identified demographic and socioeconomic determinants of child mortality. DESIGN: Data from the Vietnam Multiple Indicator Cluster Surveys (MICSs) in 2000 (MICS2), 2006 (MICS3) and 2011 (MICS4) were analysed. The IMR and U5MR were calculated using the indirect method developed by William Brass. Unadjusted and adjusted odds ratios were estimated to assess the association between child death and demographic and socioeconomic variables. Region-stratified stepwise logistic regression was conducted to test the sensitivity of the results. RESULTS: The IMR and U5MR significantly decreased for both male and female children between 1986 and 2010. Male children had higher IMR and U5MR compared with females in all 3 years. Women who were living in the Northern Midlands and Mountain areas were more likely to experience child deaths compared with women who were living in the Red River Delta. Women who were from minor ethnic groups, had low education, living in urban areas, and had multiple children were more likely to have experienced child deaths. CONCLUSION: Baby boys require more healthcare attention during the first year of their life. Comprehensive strategies are necessary for tackling child mortality problems in Vietnam. This study shows that child mortality is not just a problem of poverty but involves many other factors. Further studies are needed to investigate pathways underlying associations between demographic and socioeconomic conditions and childhood mortality. PMID- 26950561 TI - Multiple vulnerabilities and maternal healthcare in Vietnam: findings from the Multiple Indicator Cluster Surveys, 2000, 2006, and 2011. AB - BACKGROUND: Knowledge of the aggregate effects of multiple socioeconomic vulnerabilities is important for shedding light on the determinants of growing health inequalities and inequities in maternal healthcare. OBJECTIVE: This paper describes patterns of inequity in maternal healthcare utilization and analyzes associations between inequity and multiple socioeconomic vulnerabilities among women in Vietnam. DESIGN: This is a repeated cross-sectional study using data from the Vietnam Multiple Indicator Cluster Surveys 2000, 2006, and 2011. Two maternal healthcare indicators were selected: (1) skilled antenatal care and (2) skilled delivery care. Four types of socioeconomic vulnerabilities - low education, ethnic minority, poverty, and rural location - were assessed both as separate explanatory variables and as composite indicators (combinations of three and four vulnerabilities). Pairwise comparisons and adjusted odds ratios were used to assess socioeconomic inequities in maternal healthcare. RESULTS: In all three surveys, there were increases across the survey years in both the proportions of women who received antenatal care by skilled staff (68.6% in 2000, 90.8% in 2006, and 93.7% in 2011) and the proportions of women who gave birth with assistance from skilled staff (69.9% in 2000, 87.7% in 2006, and 92.9% in 2011). The receipt of antenatal care by skilled staff and birth assistance from skilled health personnel were less common among vulnerable women, especially those with multiple vulnerabilities. CONCLUSIONS: Even though Vietnam has improved its coverage of maternal healthcare on average, policies should target maternal healthcare utilization among women with multiple socioeconomic vulnerabilities. Both multisectoral social policies and health policies are needed to tackle multiple vulnerabilities more effectively by identifying those who are poor, less educated, live in rural areas, and belong to ethnic minority groups. PMID- 26950562 TI - Trends and determinants for early initiation of and exclusive breastfeeding under six months in Vietnam: results from the Multiple Indicator Cluster Surveys, 2000 2011. AB - BACKGROUND: There is strong evidence that breastfeeding (BF) significantly benefits mothers and infants in various ways. Yet the proportion of breastfed babies in Vietnam is low and continues to decline. This study fills an important evidence gap in BF practices in Vietnam. OBJECTIVE: This paper examines the trend of early initiation of BF and exclusive BF from 2000 to 2011 in Vietnam and explores the determinants at individual and contextual levels. DESIGN: Data from three waves of the Multiple Indicator Cluster Survey were combined to estimate crude and adjusted trends over time for two outcomes - early initiation of BF and exclusive BF. Three-level logistic regressions were fitted to examine the impacts of both individual and contextual characteristics on early initiation of BF and exclusive BF in the 2011 data. RESULTS: Both types of BF showed a decreasing trend over time after controlling for individual-level characteristics but this trend was more evident for early initiation of BF. Apart from child's age, individual-level characteristics were not significant predictors of the BF outcomes, but provincial characteristics had a strong association. When controlling for individual-level characteristics, mothers living in provinces with a higher percentage of mothers with more than three children were more likely to have initiated early BF (odds ratio [OR]: 1.06; confidence interval [CI]: 1.02-1.11) but less likely to exclusively breastfeed their babies (OR: 0.94; CI: 0.88-1.01). Mothers living in areas with a higher poverty rate were more likely to breastfeed exclusively (OR: 1.07; CI: 1.02-1.13), and those who delivered by Caesarean section were less likely to initiate early BF. CONCLUSIONS: Our results suggest that environmental factors are becoming more important for determining BF practices in Vietnam. Intervention programs should therefore not only consider individual factors, but should also consider the potential impact of contextual factors on BF practices. PMID- 26950563 TI - Household trends in access to improved water sources and sanitation facilities in Vietnam and associated factors: findings from the Multiple Indicator Cluster Surveys, 2000-2011. AB - BACKGROUND: Despite progress made by the Millennium Development Goal (MDG) number 7.C, Vietnam still faces challenges with regard to the provision of access to safe drinking water and basic sanitation. OBJECTIVE: This paper describes household trends in access to improved water sources and sanitation facilities separately, and analyses factors associated with access to improved water sources and sanitation facilities in combination. DESIGN: Secondary data from the Vietnam Multiple Indicator Cluster Survey in 2000, 2006, and 2011 were analyzed. Descriptive statistics and tests of significance describe trends over time in access to water and sanitation by location, demographic and socio-economic factors. Binary logistic regressions (2000, 2006, and 2011) describe associations between access to water and sanitation, and geographic, demographic, and socio economic factors. RESULTS: There have been some outstanding developments in access to improved water sources and sanitation facilities from 2000 to 2011. In 2011, the proportion of households with access to improved water sources and sanitation facilities reached 90% and 77%, respectively, meeting the 2015 MDG targets for safe drinking water and basic sanitation set at 88% and 75%, respectively. However, despite these achievements, in 2011, only 74% of households overall had access to combined improved drinking water and sanitation facilities. There were also stark differences between regions. In 2011, only 47% of households had access to both improved water and sanitation facilities in the Mekong River Delta compared with 94% in the Red River Delta. In 2011, households in urban compared to rural areas were more than twice as likely (odds ratio [OR]: 2.2; 95% confidence interval [CI]: 1.9-2.5) to have access to improved water and sanitation facilities in combination, and households in the highest compared with the lowest wealth quintile were over 40 times more likely (OR: 42.3; 95% CI: 29.8 60.0). CONCLUSIONS: More efforts are required to increase household access to both improved water and sanitation facilities in the Mekong River Delta, South East and Central Highlands regions of Vietnam. There is also a need to address socio-economic factors associated with inadequate access to improved sanitation facilities. PMID- 26950564 TI - Changes and inequalities in early birth registration and childhood care and education in Vietnam: findings from the Multiple Indicator Cluster Surveys, 2006 and 2011. AB - INTRODUCTION: Early birth registration, childhood care, and education are essential rights for children and are important for their development and education. This study investigates changes and socioeconomic inequalities in early birth registration and indicators of care and education in children aged under 5 years in Vietnam. DESIGN: The analyses reported here used data from the Vietnam Multiple Indicator Cluster Surveys (MICS) in 2006 and 2011. The sample sizes in 2006 and 2011 were 2,680 and 3,678 for children under 5 years of age. Four indicators of childcare and preschool education were measured: birth registration, possession of books, preschool education attendance, and parental support for early childhood education. The concentration index (CI) was used to measure inequalities in gender, maternal education, geographical area, place of residence, ethnicity, and household wealth. RESULTS: There were some improvements in birth registration (86.4% in 2006; 93.8% in 2011), preschool education attendance (57.1% in 2006; 71.9% in 2011), and parental support for early childhood education (68.9 and 76.8%, respectively). However, the possession of books was lower (24.7% in 2006; 19.6% in 2011) and became more unequal over time (i.e. CI=0.370 in 2006; CI=0.443 in 2011 in wealth inequality). Inequalities in the care and education of children were still persistent. The largest inequalities were for household wealth and rural versus urban areas. CONCLUSION: Although there have been some improvements in this area, inequalities still exist. Policy efforts in Vietnam should be directed towards closing the gap between different socioeconomic groups for the care and education of children under 5 years old. PMID- 26950565 TI - Use of modern contraceptives among married women in Vietnam: a multilevel analysis using the Multiple Indicator Cluster Survey (2011) and the Vietnam Population and Housing Census (2009). AB - BACKGROUND: The prevalence of modern contraceptive use is an important indicator that reflects accessibility to reproductive health services. Satisfying unmet needs for family planning alone could reduce the number of maternal deaths by almost a third. This study uses multiple data sources to examine multilevel factors associated with the use of modern contraceptives among married women in Vietnam aged 15-49 years. DESIGN: Data from different national surveys (Vietnam Population and Housing Census, Vietnam Living Standard Survey, and Multiple Indicator Cluster Survey) were linked to create a dataset including individual and contextual (provincial) variables (N=8,341). Multilevel modeling was undertaken to examine the impact of both individual and provincial characteristics on modern contraceptive use. Odds ratios (ORs) and 95% confidence intervals (CIs) are reported. RESULTS: Individual factors significantly associated with the use of modern contraceptives were age 30-34 years (reference 15-19 years) (OR=1.63); high socioeconomic status (SES) (OR=0.8); having two living children (OR=2.4); and having a son (OR=1.4). The provincial poverty rate mediated the association between the individual's SES and the likelihood of using modern contraceptives. CONCLUSIONS: The proportion of women in Vietnam using modern contraceptive methods has remained relatively high in recent years with significant variation across Vietnam's 63 provinces. Women of lower SES are more likely to use modern contraceptive methods, especially in the poorer provinces. Achieving access to universal reproductive health is one of the Millennium Development Goals. Vietnam must continue to make progress in this area. PMID- 26950566 TI - Early sexual initiation and multiple sexual partners among Vietnamese women: analysis from the Multiple Indicator Cluster Survey, 2011. AB - INTRODUCTION: Under current HIV transmission mechanisms operating in Vietnam, women are seen as victims of their male partners. Having multiple sexual partners is one of the well-known risk factors for HIV infection. However, little is known about women's risky sexual behaviour and their vulnerability to HIV in Vietnam. This study aims to explore association between early sexual initiation and the number of lifetime sexual partners in Vietnamese women. Although the Vietnamese culture is socially conservative in this area, identifying women's risky sexual behaviour is important for the protection of women at risk of HIV and other sexually transmitted diseases. DESIGN: A total of 8,791 women, who reported having had sexual intercourse, were included in this analysis of data from the 2011 Multiple Indicator Cluster Survey in Vietnam. Data were collected using two stage strata sampling, first at the national level and second across six geographical regions (n=8,791). Multivariable logistic regressions describe association between early initiation of a sexual activity and lifetime multiple sexual partners. RESULTS: Early sexual intercourse was significantly associated with having lifetime multiple sexual partners. Women who were aged 19 or younger at first sexual intercourse were over five times more likely to have multiple sexual partners, compared with women whose first sexual intercourse was after marriage; aged 10-14 years (OR=5.9; 95% CI=1.9-18.8) at first intercourse; and aged 15-19 years (OR=5.4; 95% CI=4.0-7.2) at first intercourse. There was significant association with having multiple sexual partners for women of lower household wealth and urban residence, but the association with educational attainment was not strong. CONCLUSIONS: The study results call for health and education policies to encourage the postponement of early sexual activity in young Vietnamese women as protection against risky sexual behaviour later in life. PMID- 26950567 TI - Changes and socioeconomic factors associated with attitudes towards domestic violence among Vietnamese women aged 15-49: findings from the Multiple Indicator Cluster Surveys, 2006-2011. AB - BACKGROUND: Understanding factors associated with domestic violence-supportive attitudes among Vietnamese women is important for designing effective policies to prevent this behavior. Previous studies have largely overlooked risk factors associated with domestic violence-supportive attitudes by women in Vietnam. OBJECTIVE: This paper explores and identifies socioeconomic factors that contribute to domestic violence-supportive attitudes among Vietnamese women using data from the Multiple Indicator Cluster Surveys (MICS). DESIGN: Secondary data from two cross-sectional studies (MICS 3, 2006, and MICS 4, 2011) with representative samples (9,471 and 11,663 women, respectively) in Vietnam were analyzed. The prevalence of supportive attitudes toward domestic violence and associations with age, residence region, area, education level, household wealth index, ethnicity, and marital status were estimated using descriptive statistics and multivariate Poisson models, giving estimates of relative risk. RESULTS: Overall, the prevalence of acceptance of domestic violence declined between 2006 and 2011 in Vietnam (65.1% vs. 36.1%). Socioeconomic factors associated with women's condoning of domestic violence were age, wealth, education level, and living area. In particular, younger age and low educational attainment were key factors associated with violence-supportive attitudes, and these associations have become stronger over time. CONCLUSION: Higher educational attainment in women is an important predictor of women's attitudes toward domestic violence. To date, Doi Moi and the Vietnamese government's commitment to the Millennium Development Goals may have positively contributed to lowering the acceptance of domestic violence. Tailored interventions that focus on education will be important in further changing attitudes toward domestic violence. PMID- 26950569 TI - Millennium Development Goals in Vietnam: Taking Multi-sectoral Action to Improve Health and Address the Social Determinants. PMID- 26950568 TI - Detainees, staff, and health care services in immigration detention centres: a descriptive comparison of detention systems in Sweden and in the Benelux countries. AB - BACKGROUND: Immigration detention has been shown to negatively affect the health and well-being of detainees. The aim of the study was to describe and compare policies and practices that could affect the health and well-being of immigrant detainees in the Benelux countries (Belgium, the Netherlands, and Luxembourg) to those in Sweden. DESIGN: This was a case study. Data were collected in two phases using a questionnaire developed particularly for this study. In the first phase, authorities in the Benelux countries responded to the questionnaire via email. During the second phase, a research team visited detention centres in the Benelux countries to observe and further explore, strengthening findings through triangulation. Data on Swedish detention centres were collected in previous studies. RESULTS: Compared to the Benelux countries, Sweden has limited health care provision available in the detention centres. Swedish detention centres did not have mental health care professionals working at the centres and had fewer restrictions within the centres with regard to access to mobile phone, internet, and various recreational activities. Compared to Sweden, the detention centres in the Benelux countries have more staff categories providing services to the detainees that are provided with relevant and timely on-the-job training. All the countries, except Belgium, provide subsistence allowances to detainees. CONCLUSION: Despite the Common European Asylum System framework, differences exist among the four European Union member states in providing services to immigrant detainees. This study highlights these differences, thereby providing a window on how these diverse approaches may serve as a learning tool for improving services offered to immigrant detainees. In Sweden, the health care available to detainees and training and recruitment of staff should be improved, while the Benelux countries should strive to reduce restrictions within detention centres. PMID- 26950570 TI - Rapid and sensitive method for the determination of four EU marker polycyclic aromatic hydrocarbons in cereal-based foods using isotope-dilution GC/MS. AB - A rapid and sensitive method has been developed for the determination of the four European Union marker polycyclic aromatic hydrocarbons (PAHs; benz[a]anthracene, chrysene, benzo[b]fluoranthene and benzo[a]pyrene) in some cereal-based foods. The method is based on pressurised liquid extraction (PLE), solid-phase extraction clean-up (SPE) and isotope-dilution gas chromatography with mass spectrometric detection (GC/MS). The developed method was calibrated for the content range of 0.05-12.5 ug kg(-1) (expressed on a product basis). Recoveries of PAH were monitored in each sample via the recovery of (13)C-labelled PAHs. Recovery values were in the range between 86% and 91%, with relative standard deviations (RSDs) between 5% and 9%. The achieved limits of detection for all analytes were below 0.05 ug kg(-1). The applicability of the method for the analysis of routine samples was studied by the analysis of a set of commercial bread and breakfast cereal samples. In all analysed samples, benzo[a]pyrene (BAP) was the most prevalent PAH with the content between 0.09 and 0.30 ug kg(-1). On average, samples showed low levels of the sum of the four EU marker PAHs (SigmaPAH4) that ranged between 0.11 and 0.22 ug kg(-1) for bread samples and between 0.23 and 0.87 ug kg(-1) for breakfast cereal samples. The developed method was found suitable for the determination of PAHs in cereal-based foods like cornflakes and breads with total relative fat contents below 3.5%. PMID- 26950571 TI - Comparison of the Deep Optic Nerve Structures in Superior Segmental Optic Nerve Hypoplasia and Primary Open-Angle Glaucoma. AB - PURPOSE: The purpose of this study was to characterize the microstructure of the deep optic nerve tissues in eyes with superior segmental optic nerve hypoplasia (SSOH) in comparison with that in primary open-angle glaucoma (POAG). METHODS: Thirty-five eyes with SSOH, 37 eyes with POAG, and 54 healthy control eyes underwent enhanced depth imaging (EDI) volume scanning of the optic nerve using spectral-domain optical coherence tomography (SD-OCT). POAG patients were matched with SSOH patients in terms of the thickness of the neuroretinal rim and the retinal nerve fiber layer in the superior sector. The lamina cribrosa thickness (LCT) was determined in 3 equidistant planes, and anterior lamina cribrosa surface depth (LCD) was determined in 5 equidistant planes. The measurements were compared between groups, and the areas under the receiver operating characteristic curves (AUC) were obtained for each parameter. RESULTS: Eyes with SSOH had larger LCT and smaller LCD than POAG eyes at all locations (all P<0.001). The largest LCT was observed at the superior midperiphery in the SSOH group, but at central locations in both the POAG and control groups. The best parameters for discriminating the SSOH from glaucoma and healthy eyes were the superior midperipheral LCT (AUC=0.973) and inferior and inferior midperipheral LCD (AUCs=0.906), respectively. CONCLUSIONS: The LCT and LCD exhibited characteristic features in eyes with SSOH that were distinctive from those of POAG and healthy eyes. Investigation of the deep optic nerve structure using EDI SD-OCT may be beneficial for differentiating between SSOH and glaucoma, which may help to avoid both overtreatment and undertreatment. PMID- 26950572 TI - Trabeculectomy Outcomes by Supervised Trainees in a Veterans Affairs Medical Center. AB - PURPOSE: To evaluate the outcomes of trabeculectomy performed in an ophthalmology training program. DESIGN: Retrospective study. PARTICIPANTS: A total of 160 patients undergoing trabeculectomy performed by a resident or fellow under attending supervision. MATERIALS AND METHODS: Trabeculectomy surgeries performed by a supervised resident or fellow surgeon between October 2000 and April 2010 were reviewed. Success was considered to be complete or partial if intraocular pressure (IOP)-lowering medications were not or were required to achieve IOP<=21 mm Hg, respectively. Failure was defined as IOP>21 mm Hg on 2 consecutive visits, loss of light perception vision, IOP<=5 on 2 consecutive visits with associated visual acuity loss of >=2 lines, or need for surgical intervention. Trabeculectomy survival was determined using Kaplan-Meier analysis through 60 months of follow-up. MAIN OUTCOME MEASURES: Final IOP, success/failure rate. RESULTS: Complete success was achieved in 65 patients (41%). The average final IOP of this group was 9.1+/-3.7 mm Hg. Qualified success was achieved in 56 patients (35%). The average final IOP of this group was 11.5+/-6.4 mm Hg. At 60 months, the estimated cumulative probability of survival for complete and qualified successes was 28.9% and 63.7%, respectively. CONCLUSIONS: Among patients undergoing trabeculectomy by supervised residents or glaucoma fellows in a large Veterans Affairs Medical Center, IOP reduction was significant and similar to published studies. Trabeculectomy remains a successful intervention to lower IOP, with satisfactory success rates in the hands of trainee surgeons. PMID- 26950573 TI - Suture Trabeculotomy Ab Interno for Secondary Glaucoma Combined With Scleromalacia. AB - PURPOSE: To report 2 cases of secondary glaucoma combined with scleromalacia that were successfully treated with trabeculotomy ab interno. DESIGN: Retrospective case report METHODS: : Trabeculotomy ab interno was used to treat secondary glaucoma combined with scleromalacia, which occurred due to refractory scleritis, in 2 cases. In case 2, goniosynechialysis was performed before the trabeculotomy to identify the trabecular meshwork. The sclera and conjunctiva were not incised in either case. RESULTS: The patients' postoperative intraocular pressure (IOP) levels (which were achieved without medication) were lower than their preoperative IOP levels (which were recorded during the administration of the maximum tolerable medication dosage); that is, they had dropped from 24 to 12 mm Hg in case 1 and from 33 to 11 mm Hg in case 2 by 12 postoperative months. No recurrent scleritis or postoperative worsening of the patient's scleromalacia was seen in either case. CONCLUSIONS: Trabeculotomy ab interno is a very valuable treatment for secondary glaucoma combined with scleromalacia. PMID- 26950574 TI - Assessment of Depression, Anxiety, and Quality of Life in Singaporean Patients With Glaucoma. AB - PURPOSE: To determine the prevalence and risk factors for anxiety disorder and depression among glaucoma patients in Singapore, and to assess the relationship between quality of life (QOL) and depression/anxiety. METHODS: In this cross sectional study, glaucoma patients aged 21 and above with a known diagnosis of primary open-angle glaucoma or primary angle-closure glaucoma were recruited from a tertiary care hospital. Patients with other types of glaucoma, and coexisting ocular or psychiatric disorders were excluded.Ophthalmic examination was carried out on all participants, which included best-corrected visual acuity (BCVA), intraocular pressure (IOP), gonioscopy, standard automated perimetry, and optic disc evaluation. Sociodemographic information and treatment histories were also collected.The Hamilton Depression Rating Scale (HAM-D), Hamilton Anxiety Rating Scale (HAM-A), and Visual Function Questionnaire (VFQ25) were administered to evaluate for depression, anxiety, and impact on QOL, respectively. RESULTS: A total of 100 patients were included in this study. The mean age was 67.1+/-12.0 years (range, 24 to 90 y). The frequency of depression and anxiety among our patients was 30% and 64%, respectively. The mean HAM-D score was 4.37+/-4.17 (range, 0 to 17), whereas the mean HAM-A score was 2.38+/-2.80 (range, 0 to 13). The mean VFQ25 score was 78.8+/-16.0 (range, 42.4 to 97.0). The poorest subscale on the VFQ25 was driving, with a mean score of 42.4+/-42.6 (range, 0.0 to 100.0).We did not find any significant difference between the presence of depression/anxiety between patients with primary open-angle glaucoma (P=0.263) and primary angle-closure glaucoma (P=0.830). Risk factors for depression included: female sex (P=0.020), higher logMAR BCVA in the worse eye (P=0.004), higher cup-disc ratio (P=0.016), lower MD in the better and worse eye (P=0.022 and 0.001, respectively), and lower mean VFQ25 score (P<0.001). Risk factors for anxiety included: lower MD in the worse eye (P=0.004) and lower mean VFQ25 score (P=0.004). There was also no significant association between the use of topical beta-blockers/carbonic anhydrase inhibitors with depression (P=0.793) or anxiety (P=0.282). CONCLUSIONS: There is a relatively high prevalence of depression (30%) and anxiety disorders (64%) among glaucoma patients in Singapore. Female glaucoma patients are more likely to suffer from depression. Other risk factors for depression include higher cup-disc ratio, higher logMAR BCVA, lower MD, and a lower mean VFQ25 score. Risk factors for anxiety disorder include lower MD and lower mean VFQ25 score. Ophthalmologists could consider use of the VFQ25 as an assessment for impairments in QOL in a glaucoma patient. If a glaucoma patient is at high risk of depression or anxiety disorder, a multidisciplinary management approach involving ophthalmology and psychiatry may be required. PMID- 26950575 TI - Evaluation of Retinal Nerve Fiber Layer Thickness and Ganglion Cell Complex Progression Rates in Healthy, Ocular Hypertensive, and Glaucoma Eyes With the Avanti RTVue-XR Optical Coherence Tomograph Based on 5-Year Follow-up. AB - PURPOSE: To determine retinal nerve fiber layer thickness (RNFLT) and ganglion cell complex (GCC) progression rates for healthy eyes and undertreatment ocular hypertensive (OHT) and glaucoma eyes with the Avanti RTVue-XR optical coherence tomography. MATERIALS AND METHODS: Seventeen healthy subjects (34 eyes), 17 medically treated OHT patients (34 eyes), and 67 medically treated glaucoma patients (122 eyes) were imaged prospectively at 6-month intervals (median follow up 5.3 y, 11 visits). RESULTS: A minimal negative correlation between baseline RNFLT and RNFLT progression was found in the glaucoma group (r=-0.1708, P=0.0493). In the other groups no correlation between baseline RNFLT or GCC and RNFLT or GCC progression was found, respectively. The mean+/-SD of the rate of change was -0.33+/-0.51, -0.44+/-0.62, and -0.69+/-0.93 MUm/y for average RNFLT, and -0.53+/-0.36, -0.54+/-0.52, and -0.80+/-0.78 for average GCC, for the normal, OHT, and glaucoma eyes, respectively (P>0.05 for all between-group comparisons). In the normal group the highest progression rate was -1.52 MUm/y for average RNFLT and -1.28 MUm/y for average GCC. Despite maximal medical treatment, progression in the glaucoma group exceeded the highest progression rate of the normal group in 18 eyes (14.8%) for average RNFLT and 24 eyes (19.7%) for average GCC. CONCLUSIONS: We determined progression rates for untreated healthy and under treatment OHT and glaucoma eyes with the Avanti RTVue-XR optical coherence tomography. We found that an average RNFLT progression rate faster than -1.5 MUm/y, and an average GCC progression rate faster than -1.3 MUm/y are strongly suggestive for uncontrolled glaucomatous progression. Detection of uncontrolled structural progression with trend analysis may assist the early detection of fast progressors. PMID- 26950576 TI - The Economic Burden of Childhood Glaucoma. AB - PURPOSE: To date, there are limited data on the economic burden of childhood glaucoma, a relatively rare but visually debilitating disease. The purpose of this study is to evaluate the immediate costs of illness associated with childhood glaucoma during the first 4 years after presentation. METHODS: Data on age, sex, surgical interventions, visits, examinations under anesthesia, and medications were collected yearly following presentation in patients with childhood glaucoma. Inclusion criteria included diagnosis of primary or secondary childhood glaucoma, age less than 21 years, and follow-up of 4 years. A total of 23 patients (39 eyes) were included. Cost analysis used 2013 hospital-specific charges and US average hourly wage to calculate outcomes of total, direct, and indirect costs (significance level P<0.05). RESULTS: The annual cost of care of childhood glaucoma averaged $21,441.61 per patient, representing 1100% of annual costs in adult glaucoma and an increase of 800% in annual costs of health care per pediatric patient. The average total 4-year cost of care was $85,074.96 per patient. Surgical interventions and examinations under anesthesia were the greatest contributors to costs, representing 69.0% and 23.2% of total 4-year costs, respectively. The annual costs of care for childhood glaucoma were highest in the first year compared with subsequent years, averaging $46,293.62 per patient (P<0.05). CONCLUSIONS: Childhood glaucoma carries a substantial economic burden with the highest costs occurring in the first year after presentation. The greatest contributors to cost of illness are surgical interventions and examinations and anesthesia. PMID- 26950577 TI - Identification of the Most Accurate Spectral-domain Optical Coherence Tomography Parameters in Eyes With Early High-Tension and Low-Tension Glaucoma. AB - PURPOSE: The aim of the study was to compare the diagnostic ability of macular ganglion cell complex (GCC) and peripapillary retinal nerve fiber layer (pRNFL) thickness in high-tension glaucoma (HTG) and low-tension glaucoma (LTG). PATIENTS AND METHODS: Glaucoma was defined as glaucomatous optic neuropathy and reproducible visual field defects. Patients were classified as having LTG if untreated intraocular pressure was <=21 mm Hg on 2 different occasions. Only eyes with early glaucoma (mean deviation <-6 dB) were included. All patients underwent spectral-domain optical coherence tomography (SDOCT) imaging. RESULTS: A total of 56 normal subjects, 64 HTG patients, and 35 LTG patients were enrolled. Overall, after adjusting for mean deviation and age, the average pRNFL thickness in eyes with LTG was 18.7 um thinner than in eyes with HTG (17% difference, P<0.01). In the HTG group, no significant difference was found between areas under the receiver operating characteristic curve (AUCs) for average GCC and average pRNFL thicknesses (0.77 vs. 0.68, P=0.06). In the LTG group, average pRNFL thickness had a significantly larger AUC compared with average GCC thickness (0.95 vs. 0.81, P<0.001). Comparing AUCs between HTG and LTG groups, although the average GCC had similar AUCs in both groups (P=0.47), the average pRNFL thickness had a significantly larger AUC in the LTG group (P<0.001). CONCLUSIONS: In eyes with early glaucoma, the pRNFL thickness scan seems to be a more accurate SDOCT protocol to identify those with LTG compared with the GCC thickness scan. PMID- 26950578 TI - A New Expander for Schlemm Canal Surgery in Primary Open-angle Glaucoma-Interim Clinical Results. AB - PURPOSE: To evaluate a new canal expander in circumferential viscocanalostomy (canaloplasty) for whites with primary open-angle glaucoma (POAG). DESIGN: Prospective, single-center, noncomparative study. PARTICIPANTS: Twenty-two eyes of 22 consecutive patients with medically uncontrolled POAG underwent primary viscocanalostomy and implantation of the Stegmann Canal Expander into Schlemm canal with a follow-up time of at least 1 year. MATERIALS AND METHODS: Schlemm canal was unroofed ab externo, and dilated with viscoelastic material and microcatheter. The Stegmann Canal Expander is a flexible, fenestrated hollow implant of 9 mm in length. One expander was implanted into either side of the surgically created of ostium to keep the Schlemm canal permanently open. The superficial scleral flap was closed watertight. Laser goniopuncture of the trabeculo-Descemet membrane window was performed if postoperative intraocular pressure (IOP) exceeded 16 mm Hg. MAIN OUTCOME MEASURES: Complete successes were defined as a confirmed IOP<=21, <=18, and <=16 mm Hg without medications, respectively, combined with a 30% IOP reduction. Number of antiglaucomatous medications, best-corrected visual acuity, and intraoperative and postoperative complications were recorded. RESULTS: The mean IOP dropped from 27.1+/-5.3 mm Hg preoperatively to 13.6+/-1.6 mm Hg at 6 months, 13.0+/-1.5 mm Hg at 9 months, and 13.1+/-2.2 mm Hg at 12 months (P<0.001). The complete success rates for an IOP<=21, <=18, and <=16 mm Hg combined with a 30% IOP reduction were 91% [95% confidence interval (CI), 0.80-1.0], 91% (95% CI, 0.80-1.0), and 91.0% (95% CI, 0.80-1.0) at 6 months, and 86% (95% CI, 0.73-1.0), 82% (95% CI, 0.67-1.0), and 82.0% (95% CI, 0.67-1.0) at 12 months. The success rate of an IOP<=16 mm Hg without medications did not depend on age [hazard ratios (HR) 1.02; 95% CI, 0.85 1.12; P=0.74], preoperative IOP (HR 0.97; 95% CI, 0.83-1.23; P=0.89), and mean visual defect (HR 1.05; 95% CI, 0.72-1.27; P=0.76). Laser goniopuncture was performed on 2 eyes (9%) 4.1 months postoperatively; the mean IOP was 19.5 mm Hg before and 13.6 mm Hg after goniopuncture. The number of medications dropped from 2.9+/-0.6 before surgery to 0.05+/-0.2 after surgery (P<0.001). The postoperative best-corrected visual acuity at last visit (0.12+/-0.09; range, 0 to 0.39) was comparable to preoperative values (mean+/-SD, 0.16+/-0.10; range, 0 to 0.39) (P=0.35). Minor intraoperative or postoperative complications included microhyphema (8 eyes) and transient elevated IOP (steroid responder; 2 eyes). CONCLUSIONS: Implantation of the Stegmann Canal Expander in canaloplasty lowered IOP significantly in POAG without complications related to the device in this 1 year observation period. PMID- 26950579 TI - Bilateral Same-day Laser Peripheral Iridotomy in the Philadelphia Glaucoma Detection and Treatment Project. AB - PURPOSE: To report the outcomes of bilateral, same-day laser peripheral iridotomy (LPI) in the Philadelphia Glaucoma Detection and Treatment Project. METHODS: The Philadelphia Glaucoma Detection and Treatment Project was a community-based initiative aimed to improve detection, management, treatment, and follow-up care of individuals at high risk for glaucoma. This novel project performed LPI, where 2 eyes received laser therapy on the same day. Of the 1649 patients examined between January 1, 2013 and May 31, 2014, patients who underwent bilateral, same day LPI were included in our analysis. Main outcome measures were visual acuity, intraocular pressure (IOP), and postoperative complication rates. RESULTS: A total of 132 eyes of 66 patients underwent bilateral, same-day LPI. Mean visual acuity remained unchanged following treatment (P=0.85). Eight patients (12.1%) had IOP spikes >5 mm Hg following treatment, and 4 patients (6.1%) spiked >10 mm Hg. IOP returned to normal in all but 1 patient, who was diagnosed with chronic angle-closure glaucoma. Hyphema was reported in 2 patients (3%) and glare in 1 patient (1.5%). Thirteen patients (19.7%) had repeat LPI treatment. All patients successfully tolerated LPI treatment without serious complications. CONCLUSIONS: Performing bilateral, same-day LPI was well tolerated in a large community-based, glaucoma detection and treatment project. Applying this treatment strategy may be considered in similar settings, where patients' access to eye care is limited and it may be a cost-effective strategy. PMID- 26950580 TI - Transconjunctival Revision With Mitomycin-C Following Failed Trabeculectomy. AB - PURPOSE: To evaluate the efficacy of transconjunctival revision (TCR) with mitomycin-C (MMC) following failed trabeculectomy. MATERIALS AND METHODS: The medical records of 27 patients (27 eyes) who underwent TCR with subconjunctival injection of MMC by a single surgeon between September 2001 and August 2013 were retrospectively reviewed. The same surgical protocol was followed for all patients. Revision was performed using a microvitreoretinal blade through a small conjunctival incision. Main outcome measures included visual acuity, intraocular pressure (IOP), and number of glaucoma medications. Failure was defined as an IOP<5 or >14 mm Hg, loss of light perception, or need for additional glaucoma surgery. RESULTS: Mean interval between trabeculectomy and TCR was 56.4+/-57.2 months. Mean preoperative IOP was 21.9+/-6.8 mm Hg using 4.0+/-1.2 glaucoma medications. Fifteen (55.6%) patients met success criteria. At most recent follow up, mean IOP and number of glaucoma medications for successful patients were 9.7+/-3.8 mm Hg and 0.6+/-1.1, respectively. Kaplan-Meier analysis revealed 1-, 2 , and 3-year success rates of 62%, 58%, and 53%, respectively. Three additional patients achieved success after undergoing a second TCR, and 1 patient achieved success after a third TCR. Postoperative complications included transient choroidal effusion (n=8), shallow anterior chamber requiring reformation (n=5), 5 fluorouracil-related corneal epitheliopathy (n=10), and bleb leak (n=1). CONCLUSIONS: TCR with adjunctive MMC is a safe and effective procedure following failure of a trabeculectomy. More than 1 revision may be necessary to achieve long-term IOP reduction. PMID- 26950581 TI - Anterior-Chamber Angle and Axial Length Measurements in Normal Chinese Children. AB - PURPOSE: To establish the physiological distribution of anterior-chamber angle parameters and axial length (AL) in a randomly sampled cohort of Chinese children. PATIENTS AND METHODS: This was a prospective, cross-sectional study on randomly sampled Chinese children ages 7 to 15 years. Complete ophthalmologic examination was carried out on all participants; anterior-segment parameters and ALs were measured using Fourier-domain optical coherence tomography and automated biometers. Associations between the age, the sex, the refractive error, the iris thickness, the AL, and anterior-chamber depth (ACD) and angle measurements were analyzed using multiple correlation and regression tests. The relationship between the AL and other factors was studied by a linear regression analysis. Only the right eye data were analyzed for statistical purpose. RESULTS: A total of 541 children were enrolled in this study. There were no differences in angle parameters between sexes (P>0.05), but boys had a longer AL (P<0.01). The AL increased logarithmically with age in children (P<0.01, R=0.5552, b=6.18). Although the magnitude of myopia also increased with AL, this association was less robust (P<0.05, R=0.0917, b=-0.88). A multiple regression test indicated that the age and the ACD were independently associated with the increase in angle width (b=0.37 to 0.50 and 0.51 to 0.60, respectively; P<0.001). CONCLUSIONS: All angle measurements increased with age and were positively correlated with the ACD in children 7 to 15 years of age. The AL increased logarithmically with age. PMID- 26950582 TI - The Utility of Diaton Tonometer Measurements in Patients With Ocular Hypertension, Glaucoma, and Glaucoma Tube Shunts: A Preliminary Study for its Potential Use in Keratoprosthesis Patients. AB - PURPOSE: Glaucoma is common in patients with the Boston type 1 keratoprosthesis (KPro). Because of the inability to perform corneal applanation in KPro patients, digital palpation is currently the mainstay for assessment of intraocular pressure (IOP). The purpose of this study was to determine whether the Diaton tonometer, which estimates IOP through transpalpebral scleral indentation, can reasonably detect high IOP when compared with Goldmann applanation tonometry (GAT) in patients with ocular hypertension, glaucoma, or glaucoma tube shunts. If reliable in these patients, it may be helpful in patients with KPros. MATERIALS AND METHODS: We prospectively measured IOP using GAT and Diaton transpalpebral tonometry (DTT) on the upper and lower eyelids in 87 eyes of 57 adult participants with ocular hypertension and glaucoma, several of whom had glaucoma tube shunts. RESULTS: The correlation coefficient between GAT and DTT on the upper eyelid was 0.64 (P<0.0001). For detecting an IOP of >21 mm Hg as measured by GAT, DTT on the upper eyelid had a sensitivity and specificity of 65% and 81%, respectively. The positive and negative predictive values were 74% and 73%, respectively. Bland-Altman analysis demonstrated limits of agreement of 2.0+/ 19.5 mm Hg for GAT versus DTT on the upper eyelid. The presence of a tube shunt did not significantly affect the results. CONCLUSIONS: Diaton tonometry has a large margin of error compared with GAT in patients with ocular hypertension, glaucoma, and glaucoma tube shunts. However, given the current lack of an objective and quantitative method of IOP measurement in KPro patients, Diaton tonometry may be useful in this population as a supplement to digital palpation. PMID- 26950584 TI - Goldmann Applanation Tonometry Versus Dynamic Contour Tonometry After Vitrectomy. AB - PURPOSE: The aim of the study was to investigate the agreement of intraocular pressure (IOP) measurement using dynamic contour tonometry (DCT) and Goldmann applanation tonometry (GAT) in eyes after vitrectomy with intraocular gas endotamponade, in eyes after vitrectomy with no tamponade, and in controls. METHODS: In this prospective comparative study IOP was measured with GAT and DCT in 41 eyes with gas endotamponade (sulfur hexafluoride 20%) 1 to 3 days after vitrectomy, in 32 postvitrectomy eyes with intraocular water, and in 46 control eyes with no history of glaucoma or intraocular surgery. Corneal pachymetry and axial length measurements were additionally performed. RESULTS: The mean difference between GAT and DCT (GAT-DCT) in gas-filled eyes was 3.1 mm Hg [SD=6.2 mm Hg], that in eyes after vitrectomy with no tamponade was 0.4 mm Hg (SD=4.8 mm Hg), and in control eyes was 0.4 mm Hg (SD=3.8 mm Hg). No significant correlation was found between the differences of GAT and DCT (GAT-DCT) and the mean IOP of GAT and DCT in water-filled eyes (r=-0.25, P=0.18) and control eyes (r=0.23, P=0.13), but a significant correlation was found in the gas-filled eyes (r=0.71, P<0.0001). A significant correlation between central corneal thickness and the mean difference of both methods was seen only in the control group (r=0.36, P=0.03). CONCLUSIONS: IOP as determined by DCT underestimates IOP in gas-filled eyes compared with GAT, as GAT values were on average 3.1 mm Hg higher compared with those of DCT. The extent of IOP underestimation using DCT increases with higher IOP values. In the group of eyes after vitrectomy and in normal eyes we found a generally good agreement between the 2 methods, although high interindividual discrepancies were present. Our findings suggest that the 2 devices should not be used interchangeably in IOP evaluation after vitrectomy with gas endotamponade, which remains a difficult challenge. PMID- 26950583 TI - Impact of Peripheral Field Loss on the Execution of Natural Actions: A Study With Glaucomatous Patients and Normally Sighted People. AB - PURPOSE: We investigated the visuomotor behavior of people with reduced peripheral field due to glaucoma while they accomplished natural actions. METHODS: Twelve participants with glaucoma and 13 normally sighted controls were included. Participants were asked to accomplish a familiar sandwich-making task and a less familiar model-building task with a children's construction set while their eye movements were recorded. Both scene layouts contained task-relevant and task-irrelevant objects. There was no time constraint. RESULTS: Participants with glaucoma were slower to perform the task than were the normal observers, but the slower performance was confined to the unfamiliar model-building task. Patients and controls were equally efficient in the more familiar sandwich-making task. On initial exposure, before the first reaching movement was initiated, patients scanned the objects longer than did controls, particularly in the unfamiliar model-building task, and controls fixated irrelevant objects less than did patients. During the working phase fixations were on average longer for patients than for controls and patients made more saccades than did controls. Patients did not grasp more irrelevant objects compared with controls. CONCLUSIONS: The results provide evidence that, although slower than controls, patients with glaucoma were able to accomplish natural actions efficiently even when the task required discrimination of small structurally similar objects (nuts and screws in the model-building task). Their difficulties were reflected in longer fixation times and more head and eye movements compared with controls, presumably to compensate for lower visibility when objects fell in the part of their visual field where sensitivity was reduced. PMID- 26950585 TI - Selective Serotonin Reuptake Inhibitors and Autism. PMID- 26950586 TI - Penicillin for Pneumococcal Pneumonia. PMID- 26950588 TI - The Compensatory Reserve For Early and Accurate Prediction Of Hemodynamic Compromise: A Review of the Underlying Physiology. AB - Shock is deadly and unpredictable if it is not recognized and treated in early stages of hemorrhage. Unfortunately, measurements of standard vital signs that are displayed on current medical monitors fail to provide accurate or early indicators of shock because of physiological mechanisms that effectively compensate for blood loss. As a result of new insights provided by the latest research on the physiology of shock using human experimental models of controlled hemorrhage, it is now recognized that measurement of the body's reserve to compensate for reduced circulating blood volume is the single most important indicator for early and accurate assessment of shock. We have called this function the "compensatory reserve," which can be accurately assessed by real time measurements of changes in the features of the arterial waveform. In this paper, the physiology underlying the development and evaluation of a new noninvasive technology that allows for real-time measurement of the compensatory reserve will be reviewed, with its clinical implications for earlier and more accurate prediction of shock. PMID- 26950589 TI - Auditory Sketches: Very Sparse Representations of Sounds Are Still Recognizable. AB - Sounds in our environment like voices, animal calls or musical instruments are easily recognized by human listeners. Understanding the key features underlying this robust sound recognition is an important question in auditory science. Here, we studied the recognition by human listeners of new classes of sounds: acoustic and auditory sketches, sounds that are severely impoverished but still recognizable. Starting from a time-frequency representation, a sketch is obtained by keeping only sparse elements of the original signal, here, by means of a simple peak-picking algorithm. Two time-frequency representations were compared: a biologically grounded one, the auditory spectrogram, which simulates peripheral auditory filtering, and a simple acoustic spectrogram, based on a Fourier transform. Three degrees of sparsity were also investigated. Listeners were asked to recognize the category to which a sketch sound belongs: singing voices, bird calls, musical instruments, and vehicle engine noises. Results showed that, with the exception of voice sounds, very sparse representations of sounds (10 features, or energy peaks, per second) could be recognized above chance. No clear differences could be observed between the acoustic and the auditory sketches. For the voice sounds, however, a completely different pattern of results emerged, with at-chance or even below-chance recognition performances, suggesting that the important features of the voice, whatever they are, were removed by the sketch process. Overall, these perceptual results were well correlated with a model of auditory distances, based on spectro-temporal excitation patterns (STEPs). This study confirms the potential of these new classes of sounds, acoustic and auditory sketches, to study sound recognition. PMID- 26950590 TI - The digital history of the anglophone vocabulary of psychology: An exploration using Zipfian methods. AB - The digital humanities are being applied with increasing frequency to the analysis of historically important texts. In this study, the methods of G. K. Zipf are used to explore the digital history of the vocabulary of psychology. Zipf studied a great many phenomena, from word frequencies to city sizes, showing that they tend to have a characteristic distribution in which there are a few cases that occur very frequently and many more cases that occur very infrequently. We find that the number of new words and word senses that writers contribute to the vocabulary of psychology have such a Zipfian distribution. Moreover, those who make the most contributions, such as William James, tend also to invent new metaphorical senses of words rather than new words. By contrast, those who make the fewest contributions tend to invent entirely new words. The use of metaphor makes a text easier for a reader to understand. While the use of new words requires more effort on the part of the reader, it may lead to more precise understanding than does metaphor. On average, new words and word senses become a part of psychology's vocabulary in the time leading up to World War I, suggesting that psychology was "finding its language" (Danziger, 1997) during this period. PMID- 26950587 TI - Involvement of NADH Oxidase in Biofilm Formation in Streptococcus sanguinis. AB - Biofilms play important roles in microbial communities and are related to infectious diseases. Here, we report direct evidence that a bacterial nox gene encoding NADH oxidase is involved in biofilm formation. A dramatic reduction in biofilm formation was observed in a Streptococcus sanguinis nox mutant under anaerobic conditions without any decrease in growth. The membrane fluidity of the mutant bacterial cells was found to be decreased and the fatty acid composition altered, with increased palmitic acid and decreased stearic acid and vaccenic acid. Extracellular DNA of the mutant was reduced in abundance and bacterial competence was suppressed. Gene expression analysis in the mutant identified two genes with altered expression, gtfP and Idh, which were found to be related to biofilm formation through examination of their deletion mutants. NADH oxidase related metabolic pathways were analyzed, further clarifying the function of this enzyme in biofilm formation. PMID- 26950591 TI - Change in estimated glomerular filtration rate and outcomes in chronic kidney disease. AB - PURPOSE OF REVIEW: Estimated glomerular filtration rate (eGFR) is important in the diagnosis and prognostication of chronic kidney disease (CKD). The current standards for CKD progression in clinical trials are kidney failure and the doubling of serum creatinine (~57% decline in eGFR). These endpoints have limitations as they are only applicable to patients with later stages of CKD and often require large sample sizes to achieve adequate power. RECENT FINDINGS: Lesser declines in eGFR (30% and 40%) have been evaluated as potential endpoints in recent studies. These endpoints are more common and show a strong association with the risk of end-stage renal disease and mortality. These findings have been shown to be consistent across different causes of CKD and for different interventions. A particular limitation of reduced thresholds is an elevated risk of type I errors in the presence of acute treatment effects, particularly with a 30% eGFR decline cut off. SUMMARY: Surrogate endpoints for kidney failure and mortality are needed in clinical trials to allow for the reasonable management of timelines and resources, and the achievement of adequate sample sizes. Lesser eGFR decline thresholds should be considered to aid in the design and conduct of more randomized controlled trials in nephrology. PMID- 26950593 TI - Controlled lateral anisotropy in correlated manganite heterostructures by interface-engineered oxygen octahedral coupling. AB - Controlled in-plane rotation of the magnetic easy axis in manganite heterostructures by tailoring the interface oxygen network could allow the development of correlated oxide-based magnetic tunnelling junctions with non collinear magnetization, with possible practical applications as miniaturized high-switching-speed magnetic random access memory (MRAM) devices. Here, we demonstrate how to manipulate magnetic and electronic anisotropic properties in manganite heterostructures by engineering the oxygen network on the unit-cell level. The strong oxygen octahedral coupling is found to transfer the octahedral rotation, present in the NdGaO3 (NGO) substrate, to the La2/3Sr1/3MnO3 (LSMO) film in the interface region. This causes an unexpected realignment of the magnetic easy axis along the short axis of the LSMO unit cell as well as the presence of a giant anisotropic transport in these ultrathin LSMO films. As a result we possess control of the lateral magnetic and electronic anisotropies by atomic-scale design of the oxygen octahedral rotation. PMID- 26950592 TI - Prenatal Air Pollution Exposure and Early Cardiovascular Phenotypes in Young Adults. AB - Exposure to ambient air pollutants increases risk for adverse cardiovascular health outcomes in adults. We aimed to evaluate the contribution of prenatal air pollutant exposure to cardiovascular health, which has not been thoroughly evaluated. The Testing Responses on Youth (TROY) study consists of 768 college students recruited from the University of Southern California in 2007-2009. Participants attended one study visit during which blood pressure, heart rate and carotid artery arterial stiffness (CAS) and carotid artery intima-media thickness (CIMT) were assessed. Prenatal residential addresses were geocoded and used to assign prenatal and postnatal air pollutant exposure estimates using the U.S. Environmental Protection Agency's Air Quality System (AQS) database. The associations between CAS, CIMT and air pollutants were assessed using linear regression analysis. Prenatal PM10 and PM2.5 exposures were associated with increased CAS. For example, a 2 SD increase in prenatal PM2.5 was associated with CAS indices, including a 5% increase (beta = 1.05, 95% CI 1.00-1.10) in carotid stiffness index beta, a 5% increase (beta = 1.05, 95% CI 1.01-1.10) in Young's elastic modulus and a 5% decrease (beta = 0.95, 95% CI 0.91-0.99) in distensibility. Mutually adjusted models of pre- and postnatal PM2.5 further suggested the prenatal exposure was most relevant exposure period for CAS. No associations were observed for CIMT. In conclusion, prenatal exposure to elevated air pollutants may increase carotid arterial stiffness in a young adult population of college students. Efforts aimed at limiting prenatal exposures are important public health goals. PMID- 26950594 TI - Tuning magnetic anisotropy by interfacially engineering the oxygen coordination environment in a transition metal oxide. AB - Strong correlations between electrons, spins and lattices--stemming from strong hybridization between transition metal d and oxygen p orbitals--are responsible for the functional properties of transition metal oxides. Artificial oxide heterostructures with chemically abrupt interfaces provide a platform for engineering bonding geometries that lead to emergent phenomena. Here we demonstrate the control of the oxygen coordination environment of the perovskite, SrRuO3, by heterostructuring it with Ca0.5Sr0.5TiO3 (0-4 monolayers thick) grown on a GdScO3 substrate. We found that a Ru-O-Ti bond angle of the SrRuO3 /Ca0.5Sr0.5TiO3 interface can be engineered by layer-by-layer control of the Ca0.5Sr0.5TiO3 layer thickness, and that the engineered Ru-O-Ti bond angle not only stabilizes a Ru-O-Ru bond angle never seen in bulk SrRuO3, but also tunes the magnetic anisotropy in the entire SrRuO3 layer. The results demonstrate that interface engineering of the oxygen coordination environment allows one to control additional degrees of freedom in functional oxide heterostructures. PMID- 26950597 TI - Therapeutic radiation and the potential risk of second malignancies. AB - Radiation has long been associated with carcinogenesis. Nevertheless, it is an important part of multimodality therapy for many malignancies. It is critical to assess the risk of secondary malignant neoplasms (SMNs) after radiation treatment. The authors reviewed the literature with a focus on radiation and associated SMNs for primary hematologic, breast, gynecologic, and pediatric tumors. Radiation appeared to increase the risk of SMN in all of these; however, this risk was found to be associated with age, hormonal influences, chemotherapy use, environmental influences, genetic predisposition, infection, and immunosuppression. The risk also appears to be altered with modern radiotherapy techniques. Practitioners of all specialties who treat cancer survivors in follow up should be aware of this potential risk. Cancer 2016;122:1809-21. (c) 2016 American Cancer Society. PMID- 26950596 TI - Scalable water splitting on particulate photocatalyst sheets with a solar-to hydrogen energy conversion efficiency exceeding 1. AB - Photocatalytic water splitting using particulate semiconductors is a potentially scalable and economically feasible technology for converting solar energy into hydrogen. Z-scheme systems based on two-step photoexcitation of a hydrogen evolution photocatalyst (HEP) and an oxygen evolution photocatalyst (OEP) are suited to harvesting of sunlight because semiconductors with either water reduction or oxidation activity can be applied to the water splitting reaction. However, it is challenging to achieve efficient transfer of electrons between HEP and OEP particles. Here, we present photocatalyst sheets based on La- and Rh codoped SrTiO3 (SrTiO3:La, Rh; ref. ) and Mo-doped BiVO4 (BiVO4:Mo) powders embedded into a gold (Au) layer. Enhancement of the electron relay by annealing and suppression of undesirable reactions through surface modification allow pure water (pH 6.8) splitting with a solar-to-hydrogen energy conversion efficiency of 1.1% and an apparent quantum yield of over 30% at 419 nm. The photocatalyst sheet design enables efficient and scalable water splitting using particulate semiconductors. PMID- 26950595 TI - Biodegradable scaffold with built-in vasculature for organ-on-a-chip engineering and direct surgical anastomosis. AB - We report the fabrication of a scaffold (hereafter referred to as AngioChip) that supports the assembly of parenchymal cells on a mechanically tunable matrix surrounding a perfusable, branched, three-dimensional microchannel network coated with endothelial cells. The design of AngioChip decouples the material choices for the engineered vessel network and for cell seeding in the parenchyma, enabling extensive remodelling while maintaining an open-vessel lumen. The incorporation of nanopores and micro-holes in the vessel walls enhances permeability, and permits intercellular crosstalk and extravasation of monocytes and endothelial cells on biomolecular stimulation. We also show that vascularized hepatic tissues and cardiac tissues engineered by using AngioChips process clinically relevant drugs delivered through the vasculature, and that millimetre thick cardiac tissues can be engineered in a scalable manner. Moreover, we demonstrate that AngioChip cardiac tissues implanted with direct surgical anastomosis to the femoral vessels of rat hindlimbs establish immediate blood perfusion. PMID- 26950598 TI - Death receptor 6 (DR6) is required for mouse B16 tumor angiogenesis via the NF kappaB, P38 MAPK and STAT3 pathways. AB - Although death receptor 6 (DR6) is aberrantly expressed in certain cancer cell lines, its function, signaling pathway and potential clinical significance in tumor progression are not well characterized. We report here that knocking down DR6 in the mouse B16 cell line has no effect on B16 cell death in vitro but suppresses xenograft B16 tumor growth by preventing tumor blood vessel formation in vivo. Deficiency of DR6 changes cytokine expression and secretion; in particular, it inhibits the proinflammatory cytokine interleukin-6 (IL-6), which is able to induce the expression of the angiogenesis-related factors: vascular endothelial growth factor-A, platelet-derived growth factor-beta, vascular endothelial growth factor-D and platelet-derived growth factor receptor-alpha. Further experiments demonstrate that DR6-dependent angiogenesis is involved in the IL-6/P38 MAPK and IL-6/STAT3 pathways. Our novel findings demonstrate for the first time that DR6 expression in B16 cells facilitates tumor growth by accelerating tumor angiogenesis. Moreover, these results suggest that DR6 is involved in three important intracellular pathways that lead to homeostatic angiogenesis in tumor growth. PMID- 26950599 TI - Epigenetic suppression of neprilysin regulates breast cancer invasion. AB - In women, invasive breast cancer is the second most common cancer and the second cause of cancer-related death. Therefore, identifying novel regulators of breast cancer invasion could lead to additional biomarkers and therapeutic targets. Neprilysin, a cell-surface enzyme that cleaves and inactivates a number of substrates including endothelin-1 (ET1), has been implicated in breast cancer, but whether neprilysin promotes or inhibits breast cancer cell progression and metastasis is unclear. Here, we asked whether neprilysin expression predicts and functionally regulates breast cancer cell invasion. RT-PCR and flow cytometry analysis of MDA-MB-231 and MCF-7 breast cancer cell lines revealed decreased neprilysin expression compared with normal epithelial cells. Expression was also suppressed in invasive ductal carcinoma (IDC) compared with normal tissue. In addition, in vtro invasion assays demonstrated that neprilysin overexpression decreased breast cancer cell invasion, whereas neprilysin suppression augmented invasion. Furthermore, inhibiting neprilysin in MCF-7 breast cancer cells increased ET1 levels significantly, whereas overexpressing neprilysin decreased extracellular-signal related kinase (ERK) activation, indicating that neprilysin negatively regulates ET1-induced activation of mitogen-activated protein kinase (MAPK) signaling. To determine whether neprilysin was epigenetically suppressed in breast cancer, we performed bisulfite conversion analysis of breast cancer cells and clinical tumor samples. We found that the neprilysin promoter was hypermethylated in breast cancer; chemical reversal of methylation in MDA-MB-231 cells reactivated neprilysin expression and inhibited cancer cell invasion. Analysis of cancer databases revealed that neprilysin methylation significantly associates with survival in stage I IDC and estrogen receptor-negative breast cancer subtypes. These results demonstrate that neprilysin negatively regulates the ET axis in breast cancer, and epigenetic suppression of neprilysin in invasive breast cancer cells enables invasion. Together, this implicates neprilysin as an important regulator of breast cancer invasion and clarifies its utility as a potential biomarker for invasive breast cancer. PMID- 26950600 TI - Functional Interaction between Apolipophorins and Complement Regulate the Mosquito Immune Response to Systemic Infections. AB - The complement-like protein thioester-containing protein 1 (TEP1) is the hallmark effector molecule against Plasmodium ookinetes in the malaria vector Anopheles gambiae. We have previously shown that the knockdown of the noncatalytic clip domain serine protease CLIPA2 increased TEP1-mediated killing rendering mosquitoes more resistant to Plasmodium, bacterial and fungal infections. Here, CLIPA2 coimmunoprecipitation from the hemolymph of Beauveria bassiana-infected mosquitoes followed by mass spectrometry and functional genetic analysis led to the identification of the Apolipophorin-II/I gene, encoding the two lipid carrier proteins Apo-I and II, as a novel negative regulator of TEP1-mediated immune response during mosquito systemic infections. Apo-II/I exhibits a similar RNAi phenotype as CLIPA2 in mosquito bioassays characterized by increased resistance to B. bassiana and Escherichia coli infections. We provide evidence that this enhanced resistance to systemic infections is TEP1 dependent. Interestingly, silencing Apo-II/I but not CLIPA2 upregulated the expression of TEP1 following systemic infections with E. coli and B. bassiana in a c-Jun N-terminal kinase pathway-dependent manner. Our results suggest that mosquito Apo-II/I plays an important immune regulatory role during systemic infections and provide novel insight into the functional interplay between lipid metabolism and immune gene regulation. PMID- 26950601 TI - Three-dimensional control of the helical axis of a chiral nematic liquid crystal by light. AB - Chiral nematic liquid crystals--otherwise referred to as cholesteric liquid crystals (CLCs)--are self-organized helical superstructures that find practical application in, for example, thermography, reflective displays, tuneable colour filters and mirrorless lasing. Dynamic, remote and three-dimensional control over the helical axis of CLCs is desirable, but challenging. For example, the orientation of the helical axis relative to the substrate can be changed from perpendicular to parallel by applying an alternating-current electric field, by changing the anchoring conditions of the substrate, or by altering the topography of the substrate's surface; separately, in-plane rotation of the helical axis parallel to the substrate can be driven by a direct-current field. Here we report three-dimensional manipulation of the helical axis of a CLC, together with inversion of its handedness, achieved solely with a light stimulus. We use this technique to carry out light-activated, wide-area, reversible two-dimensional beam steering--previously accomplished using complex integrated systems and optical phased arrays. During the three-dimensional manipulation by light, the helical axis undergoes, in sequence, a reversible transition from perpendicular to parallel, followed by in-plane rotation on the substrate surface. Such reversible manipulation depends on experimental parameters such as cell thickness, surface anchoring condition, and pitch length. Because there is no thermal relaxation, the system can be driven either forwards or backwards from any light-activated intermediate state. We also describe reversible photocontrol between a two-dimensional diffraction state, a one-dimensional diffraction state and a diffraction 'off' state in a bilayer cell. PMID- 26950602 TI - Sequence-dependent but not sequence-specific piRNA adhesion traps mRNAs to the germ plasm. AB - The conserved Piwi family of proteins and piwi-interacting RNAs (piRNAs) have a central role in genomic stability, which is inextricably linked to germ-cell formation, by forming Piwi ribonucleoproteins (piRNPs) that silence transposable elements. In Drosophila melanogaster and other animals, primordial germ-cell specification in the developing embryo is driven by maternal messenger RNAs and proteins that assemble into specialized messenger ribonucleoproteins (mRNPs) localized in the germ (pole) plasm at the posterior of the oocyte. Maternal piRNPs, especially those loaded on the Piwi protein Aubergine (Aub), are transmitted to the germ plasm to initiate transposon silencing in the offspring germ line. The transport of mRNAs to the oocyte by midoogenesis is an active, microtubule-dependent process; mRNAs necessary for primordial germ-cell formation are enriched in the germ plasm at late oogenesis via a diffusion and entrapment mechanism, the molecular identity of which remains unknown. Aub is a central component of germ granule RNPs, which house mRNAs in the germ plasm, and interactions between Aub and Tudor are essential for the formation of germ granules. Here we show that Aub-loaded piRNAs use partial base-pairing characteristics of Argonaute RNPs to bind mRNAs randomly in Drosophila, acting as an adhesive trap that captures mRNAs in the germ plasm, in a Tudor-dependent manner. Notably, germ plasm mRNAs in drosophilids are generally longer and more abundant than other mRNAs, suggesting that they provide more target sites for piRNAs to promote their preferential tethering in germ granules. Thus, complexes containing Tudor, Aub piRNPs and mRNAs couple piRNA inheritance with germline specification. Our findings reveal an unexpected function for piRNP complexes in mRNA trapping that may be generally relevant to the function of animal germ granules. PMID- 26950604 TI - Insights into the Performance Limits of the Li7P3S11 Superionic Conductor: A Combined First-Principles and Experimental Study. AB - The Li7P3S11 glass-ceramic is a promising superionic conductor electrolyte (SCE) with an extremely high Li(+) conductivity that exceeds that of even traditional organic electrolytes. In this work, we present a combined computational and experimental investigation of the material performance limitations in terms of its phase and electrochemical stability, and Li(+) conductivity. We find that Li7P3S11 is metastable at 0 K but becomes stable at above 630 K (~360 degrees C) when vibrational entropy contributions are accounted for, in agreement with differential scanning calorimetry measurements. Both scanning electron microscopy and the calculated Wulff shape show that Li7P3S11 tends to form relatively isotropic crystals. In terms of electrochemical stability, first-principles calculations predict that, unlike the LiCoO2 cathode, the olivine LiFePO4 and spinel LiMn2O4 cathodes are likely to form stable passivation interfaces with the Li7P3S11 SCE. This finding underscores the importance of considering multicomponent integration in developing an all-solid-state architecture. To probe the fundamental limit of its bulk Li(+) conductivity, a comparison of conventional cold-press sintered versus spark-plasma sintering (SPS) Li7P3S11 was done in conjunction with ab initio molecular dynamics (AIMD) simulations. Though the measured diffusion activation barriers are in excellent agreement, the AIMD predicted room-temperature Li(+) conductivity of 57 mS cm(-1) is much higher than the experimental values. The optimized SPS sample exhibits a room-temperature Li(+) conductivity of 11.6 mS cm(-1), significantly higher than that of the cold pressed sample (1.3 mS cm(-1)) due to the reduction of grain boundary resistance by densification. We conclude that grain boundary conductivity is limiting the overall Li(+) conductivity in Li7P3S11, and further optimization of overall conductivities should be possible. Finally, we show that Li(+) motions in this material are highly collective, and the flexing of the P2S7 ditetrahedra facilitates fast Li(+) diffusion. PMID- 26950603 TI - Crystal structure of a substrate-engaged SecY protein-translocation channel. AB - Hydrophobic signal sequences target secretory polypeptides to a protein conducting channel formed by a heterotrimeric membrane protein complex, the prokaryotic SecY or eukaryotic Sec61 complex. How signal sequences are recognized is poorly understood, particularly because they are diverse in sequence and length. Structures of the inactive channel show that the largest subunit, SecY or Sec61alpha, consists of two halves that form an hourglass-shaped pore with a constriction in the middle of the membrane and a lateral gate that faces lipid. The cytoplasmic funnel is empty, while the extracellular funnel is filled with a plug domain. In bacteria, the SecY channel associates with the translating ribosome in co-translational translocation, and with the SecA ATPase in post translational translocation. How a translocating polypeptide inserts into the channel is uncertain, as cryo-electron microscopy structures of the active channel have a relatively low resolution (~10 A) or are of insufficient quality. Here we report a crystal structure of the active channel, assembled from SecY complex, the SecA ATPase, and a segment of a secretory protein fused into SecA. The translocating protein segment inserts into the channel as a loop, displacing the plug domain. The hydrophobic core of the signal sequence forms a helix that sits in a groove outside the lateral gate, while the following polypeptide segment intercalates into the gate. The carboxy (C)-terminal section of the polypeptide loop is located in the channel, surrounded by residues of the pore ring. Thus, during translocation, the hydrophobic segments of signal sequences, and probably bilayer-spanning domains of nascent membrane proteins, exit the lateral gate and dock at a specific site that faces the lipid phase. PMID- 26950607 TI - In memoriam Henry Krum, 1958-2015. PMID- 26950609 TI - Oxidative Cyclization of 1,5-Dienes with Hydrogen Peroxide Catalyzed by an Osmium(III) Complex: Synthesis of cis-Tetrahydrofurans. AB - Stereoselective oxidative cyclization of 1,5-dienes with hydrogen peroxide catalyzed by [Os(III)(OH)(H2O)(L-N4Me2)](PF6)2 (1: L-N4Me2 = N,N'-dimethyl-2,11 diaza-[3,3](2,6)pyridinophane) is explored. 1,5-Dienes involving geraniol derivatives are converted to the corresponding tetrahydrofurans in modest to high yields. The products exclusively have the cis-conformation with respect to the substituents at the 2- and 5-positions of the tetrahydrofuran ring. The products also have a syn-conformation with respect to the furan oxygen atom and the hydroxyl groups. Mechanistic studies including a direct reaction of the oxo hydroxo-osmium(V) complex, 2, with a dihydroxylated geraniol derivative are performed. PMID- 26950606 TI - Expression of Human Immunodeficiency Virus Type 1 Neutralizing Antibody Fragments Using Human Vaginal Lactobacillus. AB - Eradication of human immunodeficiency virus type 1 (HIV-1) by vaccination with epitopes that produce broadly neutralizing antibodies is the ultimate goal for HIV prevention. However, generating appropriate immune responses has proven difficult. Expression of broadly neutralizing antibodies by vaginal colonizing lactobacilli provides an approach to passively target these antibodies to the mucosa. We tested the feasibility of expressing single-chain and single-domain antibodies (dAbs) in Lactobacillus to be used as a topical microbicide/live biotherapeutic. Lactobacilli provide an excellent platform to express anti-HIV proteins. Broadly neutralizing antibodies have been identified against epitopes on the HIV-1 envelope and have been made into active antibody fragments. We tested single-chain variable fragment m9 and dAb-m36 and its derivative m36.4 as prototype antibodies. We cloned and expressed the antibody fragments m9, m36, and m36.4 in Lactobacillus jensenii-1153 and tested the expression levels and functionality. We made a recombinant L. jensenii 1153-1128 that expresses dAb m36.4. All antibody fragments m9, m36, and m36.4 were expressed by lactobacilli. However, we noted the smaller m36/m36.4 were expressed to higher levels, >=3 MUg/ml. All L. jensenii-expressed antibody fragments bound to gp120/CD4 complex; Lactobacillus-produced m36.4 inhibited HIV-1BaL in a neutralization assay. Using a TZM-bl assay, we characterized the breadth of neutralization of the m36.4. Delivery of dAbs by Lactobacillus could provide passive transfer of these antibodies to the mucosa and longevity at the site of HIV-1 transmission. PMID- 26950608 TI - Homologous PNA Hybridization to Noncanonical DNA G-Quadruplexes. AB - Potential guanine (G) quadruplex-forming sequences (QFSs) found throughout the genomes and transcriptomes of organisms have emerged as biologically relevant structures. These G-quadruplexes represent novel opportunities for gene regulation at the DNA and RNA levels. Recently, the definition of functional QFSs has been expanding to include a variety of unconventional motifs, including relatively long loop sequences (i.e., >7 nucleotides) separating adjacent G tracts. We have identified a QFS within the 25S rDNA gene from Saccharomyces cerevisae that features a long loop separating the two 3'-most G-tracts. An oligonucleotide based on this sequence, QFS3, folds into a stable G-quadruplex in vitro. We have studied the interaction between QFS3 and several loop mutants with a small, homologous (G-rich) peptide nucleic acid (PNA) oligomer that is designed to form a DNA/PNA heteroquadruplex. The PNA successfully invades the DNA quadruplex target to form a stable heteroquadruplex, but with surprisingly high PNA:DNA ratios based on surface plasmon resonance and mass spectrometric results. A model for high stoichiometry PNA-DNA heteroquadruplexes is proposed, and the implications for quadruplex targeting by G-rich PNA are discussed. PMID- 26950611 TI - Synergistic effect of nano-sized mackinawite with cyano-cobalamin in cement slurries for reductive dechlorination of tetrachloroethylene. AB - Experiments were conducted to investigate the reductive dechlorination of tetrachloroethylene (PCE) by nano-Mackinawite (nFeS) with cyano-cobalamin (Cbl(III)) in cement slurries. Almost complete degradation of PCE by nFeS Cbl(III) was observed in cement slurries in 5 h and its degradation kinetics (k(obs-PCE)=0.57 h(-1)) was 6-times faster than that of nFeS-Cbl(III) without the cement slurries. PCE was finally transformed to non-chlorinated organic compounds such as ethylene, acetylene, and C3-C4 hydrocarbons by nFeS-Cbl(III) in cement slurries. X-ray photoelectron spectroscopy and PCE degradation by cement components (SiO2, Al2O3, and CaO) revealed that both the reduced Co species in Cbl(III) and the presence of Ca in cement played an important role for the enhanced reductive dechlorination of PCE. The increase in the concentration of Cbl(III) (0.005-0.1 mM), cement ratio (0.05-0.2), and suspension pH (11.5-13.5) accelerated the PCE degradation kinetics by providing more favorable environments for the production of reactive Ca species and reduction of Co species. We also observed that the degradation efficiency of PCE by nFeS-Cbl(III)-cement lasted even at high concentration of PCE. The experimental results obtained from this study could provide fundamental knowledge of redox interactions among nFeS, Cbl(III), and cement, which could significantly enhance reductive dechlorination of chlorinated organics in contaminated natural and engineered environments. PMID- 26950610 TI - Tricyclic Acylphloroglucinols from Hypericum lanceolatum and Regioselective Synthesis of Selancins A and B. AB - The chemical investigation of the chloroform extract of Hypericum lanceolatum guided by (1)H NMR, ESIMS, and TLC profiles led to the isolation of 11 new tricyclic acylphloroglucinol derivatives, named selancins A-I (1-9) and hyperselancins A and B (10 and 11), along with the known compound 3-O geranylemodin (12), which is described for a Hypericum species for the first time. Compounds 8 and 9 are the first examples of natural products with a 6-acyl 2,2-dimethylchroman-4-one core fused with a dimethylpyran unit. The new compounds 1-9 are rare acylphloroglucinol derivatives with two fused dimethylpyran units. Compounds 10 and 11 are derivatives of polycyclic polyprenylated acylphloroglucinols related to hyperforin, the active component of St. John's wort. Their structures were elucidated by UV, IR, extensive 1D and 2D NMR experiments, HRESIMS, and comparison with the literature data. The absolute configurations of 5, 8, 10, and 11 were determined by comparing experimental and calculated electronic circular dichroism spectra. Compounds 1 and 2 were synthesized regioselectively in two steps. The cytotoxicity of the crude extract (88% growth inhibition at 50 MUg/mL) and of compounds 1-6, 8, 9, and 12 (no significant growth inhibition up to a concentration of 10 mM) against colon (HT 29) and prostate (PC-3) cancer cell lines was determined. No anthelmintic activity was observed for the crude extract. PMID- 26950612 TI - Shelf life of fresh meat products under LED or fluorescent lighting. AB - Enhanced pork loin chops, beef longissimus lumborum steaks, semimembranosus steaks (superficial and deep portions), ground beef, and ground turkey were displayed under light emitting diode (LED) and fluorescent (FLS) lighting in two multi-shelf, retail display cases with identical operating parameters. Visual and instrumental color, internal product temperature, case temperature, case cycling, thiobarbituric acid reactive substances (TBARS), and Enterobacteriaceae and aerobic plate counts were evaluated. Under LED, beef products (except the deep portion of beef semimembranosus steaks) showed less (P<0.05) visual discoloration. Pork loin chops had higher (P<0.05) L* values for LED lighting. Other than beef longissimus lumborum steaks, products displayed under LED lights had colder internal temperatures than products under FLS lights (P<0.05). Under LED, pork loin chops, ground turkey, and beef semimembranosus steaks had higher (P<0.05) values for TBARS. LED provides colder case and product temperatures, more case efficiency, and extended color life by at least 0.5d for longissimus and semimembranosus steaks; however, some LED cuts showed increased lipid oxidation. PMID- 26950613 TI - Heme oxygenase-1-mediated anti-inflammatory effects of tussilagonone on macrophages and 12-O-tetradecanoylphorbol-13-acetate-induced skin inflammation in mice. AB - The dried flower buds of Tussilago farfara L. have been used in traditional medicine, mainly as an antitussive in the treatment of cough and other respiratory problems. In the present study, we investigated the anti-inflammatory signaling pathway via the upregulation of heme oxygenase-1 (HO-1) in response to tussilagonone (TGN), a sesquiterpene compound isolated from T. farfara. TGN induced HO-1 expression and nuclear factor-E2-related factor 2 (Nrf2) activation in RAW 264.7 cells. Nuclear translocation of Nrf2 by TGN also increased in a time and dose-dependent manner, indicating that TGN induced HO-1 via the Nrf2 pathway. Consistent with the notion that HO-1 has anti-inflammatory properties, TGN suppressed inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX 2) expression and reduced the mRNA expression of proinflammatory cytokines, as well as nitric oxide (NO) and prostaglandin E2 (PGE2) production in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. TGN inhibited the phosphorylation and degradation of inhibitory kappaB-alpha (IkappaB-alpha) and the nuclear translocation of nuclear factor (NF)-kappaB. However, a specific inhibitor of HO-1 reversed the TGN-mediated suppression of NO production and knockdown of HO-1 by small interfering RNA abrogated inhibitory effects of TGN on iNOS and COX-2 protein expression and NF-kappaB nuclear translocation. Furthermore, TGN reduced iNOS and COX-2 expression in a 12-O-tetradecanoylphorbol 13-acetate (TPA)-induced skin inflammation mouse model. Taken together, these findings suggest an important role for TGN-induced HO-1 activation in regulating inflammatory responses. Moreover, TGN is a potent therapeutic candidate for targeting the crosstalk between Nrf2/HO-1 and the NF-kappaB signaling pathway in the prevention or treatment of inflammation-associated diseases. PMID- 26950615 TI - On the factors governing water vapor turbulence mixing in the convective boundary layer over land: Concept and data analysis technique using ground-based lidar measurements. AB - The convective boundary layer (CBL) turbulence is the key process for exchanging heat, momentum, moisture and trace gases between the earth's surface and the lower part of the troposphere. The turbulence parameterization of the CBL is a challenging but important component in numerical models. In particular, correct estimation of CBL turbulence features, parameterization, and the determination of the contribution of eddy diffusivity are important for simulating convection initiation, and the dispersion of health hazardous air pollutants and Greenhouse gases. In general, measurements of higher-order moments of water vapor mixing ratio (q) variability yield unique estimates of turbulence in the CBL. Using the high-resolution lidar-derived profiles of q variance, third-order moment, and skewness and analyzing concurrent profiles of vertical velocity, potential temperature, horizontal wind and time series of near-surface measurements of surface flux and meteorological parameters, a conceptual framework based on bottom up approach is proposed here for the first time for a robust characterization of the turbulent structure of CBL over land so that our understanding on the processes governing CBL q turbulence could be improved. Finally, principal component analyses will be applied on the lidar-derived long term data sets of q turbulence statistics to identify the meteorological factors and the dominant physical mechanisms governing the CBL turbulence features. PMID- 26950616 TI - Effects of polyacrylamide on soil erosion and nutrient losses from substrate material in steep rocky slope stabilization projects. AB - Erosion of denuded steep rocky slopes causes increasing losses of nitrogen and phosphorus, which is a severe problem in rocky slope protection. Thus, it is important to determine the appropriate materials that can reduce the erodibility and losses of nitrogen and phosphorus of the soil. In this paper, twenty-seven simulated rainfall events were carried out in a greenhouse, in which the substrate material was artificial soil; nine types of anionic polyacrylamide (PAM) were studied, which consisted of three molecular weight (6, 12, and 18 Mg mol(-1)) and three charge density (10, 20, and 30%) formulations in a 3 by 3 factorial design. The results showed that: (1) Polyacrylamide application reduced total nitrogen losses by 35.3% to 50.0% and total phosphorus losses by 34.9% to 48.0% relative to the control group. (2) The losses of total nitrogen and total phosphorus had significant correlation with the molecular weight. Besides, the losses of total phosphorus, particulate-bound phosphorus and inorganic nitrogen (NH4-N) were significantly correlated with their molecular weight and charge density. However, the losses of dissolved organic nitrogen, inorganic nitrogen (NO3-N), dissolved organic phosphorus, inorganic phosphorus (PO4-P) were non significantly correlated with molecular weight and charge density. (3) Particulate-bound nitrogen and phosphorus were responsible for the losses of nitrogen and phosphorus during runoff events, where particulate-bound nitrogen made up 71.7% to 73.2% of total nitrogen losses, and particulate-bound phosphorus made up 82.3% to 85.2% of total phosphorus losses. (4) Polyacrylamide treatments increased water-stable aggregates content by 32.3% to 59.1%, total porosity by 11.3% to 49.0%, final infiltrative rate by 41.3% to 72.5%, and reduced soil erosion by 18.9% to 39.8% compared with the control group. Overall, the results of this study indicated that polyacrylamide application in the steep rocky slope stabilization projects could significantly reduce nutrient losses and soil erosion of substrate material. PMID- 26950614 TI - Pro-inflammatory chemokines CCL2, chemerin, IP-10 and RANTES in human serum during an oral lipid tolerance test. AB - BACKGROUND: There is a strong coincidence of obesity and a chronic state of modest inflammation. Secretion of pro-inflammatory cytokines from adipocytes and immune cells represents a key mechanism in this process and is affected by fatty acids. MATERIAL AND METHODS: A study cohort of 100 overnight fasted healthy volunteers underwent an oral lipid tolerance test (OLTT) by ingestion of 160ml of a protein- and sugar-free lipid emulsion of defined composition. Venal blood was drawn at 0h (fasting) and at 2, 4, and 6h after lipid ingestion. Subjects were characterized by anthropometric and standard laboratory parameters. Serum concentrations of CCL2, IP-10, chemerin, and RANTES were measured by enzyme linked immunosorbent assay (ELISA). Murine 3T3-L1 adipocytes were stimulated with free fatty acids (FA) and with sex steroids and concentrations of CCL2 and chemerin in cell culture supernatants were measured by ELISA. RESULTS: A significant reduction of circulating CCL2, IP-10, and chemerin concentrations was observed as a consequence of triglyceride ingestion whereas RANTES levels were increased. CCL2 serum concentrations were positively correlated with resistin and visfatin levels and with LDL/HDL ratio and negatively with adiponectin. There were significant differences in chemerin and RANTES serum concentrations in female and male subjects. CCL2 secretion from 3T3-L1 adipocytes was inhibited by treatment with linoleic (LA) and oleic acid (OA) whereas chemerin secretion was induced. Chemerin release from 3T3-L1 adipocytes was inhibited by testosterone. CONCLUSIONS: Oral lipid loading is linked to reduced circulating pro-inflammatory chemokines CCL2, IP-10, and chemerin and to increased RANTES levels, suggesting that dietary lipids affect immune function. PMID- 26950618 TI - Organic contaminants in Great Lakes tributaries: Prevalence and potential aquatic toxicity. AB - Organic compounds used in agriculture, industry, and households make their way into surface waters through runoff, leaking septic-conveyance systems, regulated and unregulated discharges, and combined sewer overflows, among other sources. Concentrations of these organic waste compounds (OWCs) in some Great Lakes tributaries indicate a high potential for adverse impacts on aquatic organisms. During 2010-13, 709 water samples were collected at 57 tributaries, together representing approximately 41% of the total inflow to the lakes. Samples were collected during runoff and low-flow conditions and analyzed for 69 OWCs, including herbicides, insecticides, polycyclic aromatic hydrocarbons, plasticizers, antioxidants, detergent metabolites, fire retardants, non prescription human drugs, flavors/fragrances, and dyes. Urban-related land cover characteristics were the most important explanatory variables of concentrations of many OWCs. Compared to samples from nonurban watersheds (<15% urban land cover) samples from urban watersheds (>15% urban land cover) had nearly four times the number of detected compounds and four times the total sample concentration, on average. Concentration differences between runoff and low-flow conditions were not observed, but seasonal differences were observed in atrazine, metolachlor, DEET, and HHCB concentrations. Water quality benchmarks for individual OWCs were exceeded at 20 sites, and at 7 sites benchmarks were exceeded by a factor of 10 or more. The compounds with the most frequent water quality benchmark exceedances were the PAHs benzo[a]pyrene, pyrene, fluoranthene, and anthracene, the detergent metabolite 4-nonylphenol, and the herbicide atrazine. Computed estradiol equivalency quotients (EEQs) using only nonsteroidal endocrine-active compounds indicated medium to high risk of estrogenic effects (intersex or vitellogenin induction) at 10 sites. EEQs at 3 sites were comparable to values reported in effluent. This multifaceted study is the largest, most comprehensive assessment of the occurrence and potential effects of OWCs in the Great Lakes Basin to date. PMID- 26950617 TI - Climate change and its impacts on vegetation distribution and net primary productivity of the alpine ecosystem in the Qinghai-Tibetan Plateau. AB - Changes in climate have caused impacts on ecosystems on all continents scale, and climate change is also projected to be a stressor on most ecosystems even at the rate of low- to medium-range warming scenarios. Alpine ecosystem in the Qinghai Tibetan Plateau is vulnerable to climate change. To quantify the climate change impacts on alpine ecosystems, we simulated the vegetation distribution and net primary production in the Qinghai-Tibetan Plateau for three future periods (2020s, 2050s and 2080s) using climate projection for RCPs (Representative Concentration Pathways) RCP4.5 and RCP8.5 scenarios. The modified Lund-Potsdam Jena Dynamic Global Vegetation Model (LPJ model) was parameter and test to make it applicable to the Qinghai-Tibetan Plateau. Climate projections that were applied to LPJ model in the Qinghai-Tibetan Plateau showed trends toward warmer and wetter conditions. Results based on climate projections indicated changes from 1.3 degrees C to 4.2 degrees C in annual temperature and changes from 2% to 5% in annual precipitation. The main impacts on vegetation distribution was increase in the area of forests and shrubs, decrease in alpine meadows which mainly replaced by shrubs which dominated the eastern plateau, and expanding in alpine steppes to the northwest dominated the western and northern plateau. The NPP was projected to increase by 79% and 134% under the RCP4.5 and RCP8.5. The projected NPP generally increased about 200gC.m(-2).yr(-1) in most parts of the plateau with a gradual increase from the eastern to the western region of the Qinghai-Tibetan Plateau at the end of this century. PMID- 26950619 TI - Seasonal changes of spatial variation of some groundwater quality variables in a large irrigated coastal Mediterranean region of Turkey. AB - Soil and groundwater degradations have taken considerable attention, recently. We studied spatial and temporal variations of groundwater table depth and contours, and groundwater pH, electrical conductivity (EC), and nitrate (NO3) content in a large irrigated area in Western Mediterranean region of Turkey. These variables were monitored during 2009 and 2010 in previously constructed 220 monitoring wells. We analyzed the data by geostatistical techniques and GIS. Spatial variation of groundwater table depth (GTD) and groundwater table contours (GTC) remained similar across the four sampling campaigns. The values for groundwater NO3 content, EC, and pH values ranged from 0.01 to 454.1 gL(-1), 0.06 to 46.0 dS m(-1) and 6.53-9.91, respectively. Greatest geostatistical range (16,964 m) occurred for GTC and minimum (960 m) for groundwater EC. Groundwater NO3 concentrations varied both spatially and temporally. Temporal changes in spatial pattern of NO3 indicated that land use and farming practices influenced spatial and temporal variation of groundwater NO3. Several hot spots occurred for groundwater NO3 content and EC. These localities should be monitored more frequently and land management practices should be adjusted to avoid soil and groundwater degradation. The results may have important implications for areas with similar soil, land use, and climate conditions across the Mediterranean region. PMID- 26950621 TI - Environmental impact of electric motorcycles: Evidence from traffic noise assessment by a building-based data mining technique. AB - This study provided new evidence on the potential adoption of electric motorcycle (EM) as a cleaner alternative to gasoline-powered motorcycle. The effects of EM on human exposure to traffic noise were assessed in different urban areas with different traffic scenarios. The assessment was carried out by a developed building-based model system that took into account the contribution of motorcycle traffic. The results indicated that the EM could be an appealing solution to reduce the risk of human exposure to excessive high traffic noise in a motorcycle city. Particularly, in a historical urban area in which the total traffic volume was lower and motorcycle traffic was dominant, the proportion of noise levels meeting the standard of 70 dB(A) increased significantly from 12.2% to 41.9% when 100% of gasoline motorcycles in the real traffic scenario were replaced by EMs. On the other hand, in a modern urban area in which the total traffic volume was higher and traffic noise levels at majority of sites were higher than 75 dB(A), the proportion of noise levels above 75 dB(A) decreased significantly from 82.6% to 59.9%. Nevertheless, the effect of EM on improving the traffic noise compliance rate in the modern urban area was not significant and other policies or measures need to be sought. PMID- 26950620 TI - Thyroid disruption in male goldfish (Carassius auratus) exposed to leachate from a municipal waste treatment plant: Assessment combining chemical analysis and in vivo bioassay. AB - Several classes of thyroid-disrupting chemicals (TDCs) have been found in refuse leachate, but the potential impacts of leachate on the thyroid cascade of aquatic organisms are yet not known. In this study, we chemically analyzed frequently reported TDCs, as well as conducted a bioassay, to evaluate the potential thyroid disrupting effects of leachate. We used radioimmunoassay to determine the effects of leachate exposure on plasma 3,3',5-triiodo-l-thyronine (T3), 3,3',5,5'-l thyroxine (T4), and thyroid-stimulating hormone (TSH) levels in adult male goldfish (Carassius auratus). We also investigated the impacts of leachate treatment on hepatic and gonadal deiodinases [types I (D1), II (D2), and III (D3)] and gonadal thyroid receptor (TRalpha-1 and TRbeta) mRNA expressions by using real-time polymerase chain reaction. The results indicated the presence of five TDCs (bisphenol A, 4-t-octylphenol, di-n-butyl phthalate, di-n-octyl phthalate, and diethylhexyl phthalate); their mean concentrations in the leachate were 18.11, 2.76, 4.86, 0.21, and 9.16 MUg/L, respectively. Leachate exposure induced plasma T3 and TSH levels in male fish, without influencing the plasma T4 levels. The highly elevated D2 mRNA levels in the liver were speculated to be the primary reason for the induction of plasma T3 levels. Disruption of thyroid functions by leachate was also suggested by the up-regulation of D1 and D2 as well as TRalpha-1 mRNA levels in the gonads. Prominent thyroid disruptions despite the very low TDC concentrations in the exposure media used in the bioassay strongly indicated the existence of unidentified TDCs in the leachate. Our study indicated the necessity of conducting in vivo bioassays to detect thyroid dysfunctions caused by leachate. PMID- 26950622 TI - Characterization of unknown iodinated disinfection byproducts during chlorination/chloramination using ultrahigh resolution mass spectrometry. AB - Iodinated disinfection byproducts (I-DBPs), formed from the reaction of disinfectant(s) with organic matter in the presence of iodide in raw water, have recently been focused because of their more cytotoxic and genotoxic properties than their chlorinated or brominated analogues. To date, only a few I-DBPs in drinking water have been identified. In this study, C18 solid phase extraction coupled with electrospray ionization ultrahigh resolution Fourier transform ion cyclotron resonance mass spectrometry (ESI FT-ICR MS) was used to characterize unknown I-DBPs in chloraminated/chlorinated water spiked with iodide and humic substances. In total, 178 formulas for one-iodine-containing products, 13 formulas for two-iodine-containing products, and 15 formulas for one-chlorine and one-iodine-containing products were detected in the chloraminated water sample, while only 9 formulas for one-iodine-containing products and 6 formulas for one chlorine and one-iodine-containing products were found in the chlorinated water sample. Most I-DBPs have corresponding chlorine-containing analogues with identical CHO compositions. As indicated by the modified aromaticity index (AImod), in the C18 extracts, more than 68% of the I-DBPs have aromatic structures or polycyclic aromatic structures. This result demonstrates that the use of chloramination as an alternative disinfection method may lead to the formation of abundant species of I-DBPs in the presence of iodide. Thus, the suitability of adopting chloramination as an alternative disinfection method should be reevaluated, particularly when iodide is present in raw water. PMID- 26950623 TI - Impacts of extreme flooding on riverbank filtration water quality. AB - Riverbank filtration schemes form a significant component of public water treatment processes on a global level. Understanding the resilience and water quality recovery of these systems following severe flooding is critical for effective water resources management under potential future climate change. This paper assesses the impact of floodplain inundation on the water quality of a shallow aquifer riverbank filtration system and how water quality recovers following an extreme (1 in 17 year, duration >70 days, 7 day inundation) flood event. During the inundation event, riverbank filtrate water quality is dominated by rapid direct recharge and floodwater infiltration (high fraction of surface water, dissolved organic carbon (DOC) >140% baseline values, >1 log increase in micro-organic contaminants, microbial detects and turbidity, low specific electrical conductivity (SEC) <90% baseline, high dissolved oxygen (DO) >400% baseline). A rapid recovery is observed in water quality with most floodwater impacts only observed for 2-3 weeks after the flooding event and a return to normal groundwater conditions within 6 weeks (lower fraction of surface water, higher SEC, lower DOC, organic and microbial detects, DO). Recovery rates are constrained by the hydrogeological site setting, the abstraction regime and the water quality trends at site boundary conditions. In this case, increased abstraction rates and a high transmissivity aquifer facilitate rapid water quality recoveries, with longer term trends controlled by background river and groundwater qualities. Temporary reductions in abstraction rates appear to slow water quality recoveries. Flexible operating regimes such as the one implemented at this study site are likely to be required if shallow aquifer riverbank filtration systems are to be resilient to future inundation events. Development of a conceptual understanding of hydrochemical boundaries and site hydrogeology through monitoring is required to assess the suitability of a prospective riverbank filtration site. PMID- 26950624 TI - Comparison between traditional laboratory tests, permeability measurements and CT based fluid flow modelling for cultural heritage applications. AB - In this paper, we examine the possibility to use on-site permeability measurements for cultural heritage applications as an alternative for traditional laboratory tests such as determination of the capillary absorption coefficient. These on-site measurements, performed with a portable air permeameter, were correlated with the pore network properties of eight sandstones and one granular limestone that are discussed in this paper. The network properties of the 9 materials tested in this study were obtained from micro-computed tomography (MUCT) and compared to measurements and calculations of permeability and the capillary absorption rate of the stones under investigation, in order to find the correlation between pore network characteristics and fluid management characteristics of these sandstones. Results show a good correlation between capillary absorption, permeability and network properties, opening the possibility of using on-site permeability measurements as a standard method in cultural heritage applications. PMID- 26950625 TI - Meeting the public health challenge of protecting private wells: Proceedings and recommendations from an expert panel workshop. AB - Private wells serving fewer than 25 people are federally unregulated, and their users may be exposed to naturally occurring agents of concern such as arsenic and radionuclides, as well as anthropogenic contaminants. The Centers for Disease Control and Prevention's Clean Water for Health Program works to protect private wells and prevent adverse health outcomes for the roughly 15% of Americans who rely on them. To understand current and emerging challenges to the private drinking water supply, an interdisciplinary expert panel workshop on "Future and Emerging Issues for Private Wells" was organized to inform strategic planning for the Clean Water for Health Program. The panel assessed current conditions of ground water as a source for private wells, identified emerging threats, critical gaps in knowledge, and public health needs, and recommended strategies to guide future activities to ensure the safety of private drinking water wells. These strategies addressed topics of broad interest to the environmental public health community including: development of new methods to support citizen science; addressing contaminant mixtures; expanding capacity for well testing; evaluating treatment technologies; building an evidence base on best practices on well owner outreach and stewardship; and research and data needs. PMID- 26950626 TI - Spatiotemporal dynamics of phosphorus release, oxygen consumption and greenhouse gas emissions after localised soil amendment with organic fertilisers. AB - Organic fertilisation inevitably leads to heterogeneous distribution of organic matter and nutrients in soil, i.e. due to uneven surface spreading or inhomogeneous incorporation. The resulting localised hotspots of nutrient application will induce various biotic and abiotic nutrient turnover processes and fixation in the residue sphere, giving rise to distinct differences in nutrient availability, soil oxygen content and greenhouse gas (GHG) production. In this study we investigated the spatiotemporal dynamics of the reaction of manure solids and manure solids char with soil, focusing on their phosphorus (P) availability, as current emphasis on improving societal P efficiency through recycling waste or bio-based fertilisers necessitates a sound understanding of their behaviour. Soil layers amended at a constant P application rate with either pig manure solids or char made from pig manure solids were incubated for three weeks between layers of non-amended, P-depleted soil. Spatial and temporal changes in and around the amendment layers were simultaneously investigated in this study using a sandwich sensor consisting of a planar oxygen optode and multi element diffusive gradients in thin films (DGT) gels, combined with GHG emission measurements. After three weeks of incubation, the soil containing a layer amended with manure solids had a lower overall O2 content and had emitted significantly more CO2 than the non-amended control or the char-amended soil. The P availability from manure solids was initially higher than that from the char, but decreased over time, whereas from the char-amended layer P availability increased in the same period. In both treatments, increases in P availability were confined to the amended soil layer and did not greatly affect P availability in the directly adjacent soil layers during the three-week incubation. These results highlight the importance of placing organic P fertilisers close to where the plant roots will grow in order to facilitate optimal fertiliser use efficiency. PMID- 26950627 TI - Subcellular partitioning kinetics, metallothionein response and oxidative damage in the marine mussel Mytilus galloprovincialis exposed to cadmium-based quantum dots. AB - The environmental health impact of metal-based nanomaterials is of emerging concern, but their metabolism and detoxification pathways in marine bioindicator species remain unclear. This study investigated the role of subcellular partitioning kinetics, metallothioneins (MTs) response and oxidative damage (lipid peroxidation - LPO) in the marine mussel Mytilus galloprovincialis exposed to CdTe quantum dots (QDs) in comparison with its dissolved counterpart. Mussels were exposed to QDs and dissolved Cd for 21 days at 10 MUg Cd L(-1) followed by a 50 days depuration. Higher Cd concentrations were detected in fractions containing mitochondria, nucleus and lysosomes, suggesting potential subcellular targets of QDs toxicity in mussel tissues. Tissue specific metabolism patterns were observed in mussels exposed to both Cd forms. Although MT levels were directly associated with Cd in both forms, QDs subcellular partitioning is linked to biologically active metal (BAM), but no increase in LPO occurred, while in the case of dissolved Cd levels are in the biologically detoxified metal (BDM) form, indicating nano-specific effects. Mussel gills showed lower detoxification capability of QDs, while the digestive gland is the major tissue for storage and detoxification of both Cd forms. Both mussel tissues were unable to completely eliminate the Cd accumulated in the QDs form (estimated half-life time>50 days), highlighting the potential source of Cd and QDs toxicity for human and environmental health. Results indicate tissue specific metabolism patterns and nano-specific effects in marine mussel exposed to QDs. PMID- 26950628 TI - Recent desiccation of Western Great Basin Saline Lakes: Lessons from Lake Abert, Oregon, U.S.A. AB - Although extremely important to migrating waterfowl and shorebirds, and highly threatened globally, most saline lakes are poorly monitored. Lake Abert in the western Great Basin, USA, is an example of this neglect. Designated a critical habitat under the Western Hemisphere Shorebird Reserve Network, the lake is at near record historic low levels and ultra-high salinities that have resulted in ecosystem collapse. Determination of the direct human effects and broader climate controls on Lake Abert illustrates the broader problem of saline lake desiccation and suggests future solutions for restoration of key habitat values. A 65-year time series of lake area was constructed from Landsat images and transformed to lake volume and salinity. "Natural" (without upstream withdrawals) conditions were calculated from climate and stream flow data, and compared to measured volume and salinity. Under natural conditions the lake would have higher volume and lower salinities because annual water withdrawals account for one-third of mean lake volume. Without withdrawals, the lake would have maintained annual mean salinities mostly within the optimal range of brine shrimp and alkali fly growth. Even during the last two years of major drought, the lake would have maintained salinities well below measured values. Change in climate alone would not produce the recent low lake volumes and high salinities that have destroyed the brine shrimp and alkali fly populations and depleted shorebird use at Lake Abert. Large scale withdrawal of water for direct human use has drastically increased the imbalance between natural runoff and evaporation during periods of drought in saline lakes worldwide but could be offset by establishing an "environmental water budget" to lay a foundation for the conservation of saline lake habitats under continued threats from development and climate change. PMID- 26950629 TI - A proposed methodology for the assessment of arsenic, nickel, cadmium and lead levels in ambient air. AB - Air quality assessment, required by the European Union (EU) Air Quality Directive, Directive 2008/50/EC, is part of the functions attributed to Environmental Management authorities. Based on the cost and time consumption associated with the experimental works required for the air quality assessment in relation to the EU-regulated metal and metalloids, other methods such as modelling or objective estimation arise as competitive alternatives when, in accordance with the Air Quality Directive, the levels of pollutants permit their use at a specific location. This work investigates the possibility of using statistical models based on Partial Least Squares Regression (PLSR) and Artificial Neural Networks (ANNs) to estimate the levels of arsenic (As), cadmium (Cd), nickel (Ni) and lead (Pb) in ambient air and their application for policy purposes. A methodology comprising the main steps that should be taken into consideration to prepare the input database, develop the model and evaluate their performance is proposed and applied to a case of study in Santander (Spain). It was observed that even though these approaches present some difficulties in estimating the individual sample concentrations, having an equivalent performance they can be considered valid for the estimation of the mean values - those to be compared with the limit/target values - fulfilling the uncertainty requirements in the context of the Air Quality Directive. Additionally, the influence of the consideration of input variables related to atmospheric stability on the performance of the studied statistical models has been determined. Although the consideration of these variables as additional inputs had no effect on As and Cd models, they did yield an improvement for Pb and Ni, especially with regard to ANN models. PMID- 26950630 TI - Viability and fate of Cryptosporidium parvum and Giardia lamblia in tubular anaerobic digesters. AB - In many developing countries where pathogenic diseases of animal waste origin, such as giardiasis and cryptosporidiosis, are often prevalent, facilities are limited to treat livestock waste. However, household-scale anaerobic digesters are currently being promoted for bioenergy production from livestock manure. Since the effluent is often used as a fertilizer for food crops, it is critical to understand the effect of environmental conditions within household-scale digesters on the viability of Cryptosporidium parvum oocysts and Giardia lamblia cysts. In this study, key environmental parameters affecting (oo)cyst inactivation were measured in four tubular anaerobic digesters, which are a type of household-scale digester promoted for treatment of swine waste in rural Costa Rica. Interviews and participant observations were used to understand digester operation and maintenance procedures. Ambient temperatures (21-24 degrees C), near-neutral pH, total ammonia nitrogen (TAN) concentrations<250 mg/L and hydraulic retention times (HRTs) between 23 and 180 days were observed. Laboratory (oo)cysts inactivation studies were performed in bench-scale digesters, which were maintained under conditions similar to those observed in the field. Apparent first-order inactivation rate coefficients for Giardia lamblia and Cryptosporidium parvum were 0.155 +/- 0.041 and 0.054 +/- 0.006 day( 1), respectively. Temperature and volatile fatty acids were the main factors contributing to Cryptosporidium parvum and Giardia lamblia inactivation. A mathematical model was developed that predicts the concentration of (oo)cysts in the liquid effluent of tubular digesters like those observed in Costa Rica. A mathematical model was developed that predicts the concentration of (oo)cysts in the liquid effluent of tubular digesters like those observed in Costa Rica. Two dimensionless groups can be used to predict the performance of the digesters for inactivating pathogens; both dimensionless groups depend upon the average HRT in the digester. This is the first study to combine mathematical modeling with qualitative analysis, field and laboratory studies to predict the concentrations of (oo)cysts in tubular digester effluents. PMID- 26950631 TI - Indoor air quality in green-renovated vs. non-green low-income homes of children living in a temperate region of US (Ohio). AB - Green eco-friendly housing includes approaches to reduce indoor air pollutant sources and to increase energy efficiency. Although sealing/tightening buildings can save energy and reduce the penetration of outdoor pollutants, an adverse outcome can be increased buildup of pollutants with indoor sources. The objective of this study was to determine the differences in the indoor air quality (IAQ) between green and non-green homes in low-income housing complexes. In one housing complex, apartments were renovated using green principles (n=28). Home visits were conducted immediately after the renovation, and subsequently at 6 months and at 12 months following the renovation. Of these homes, eight homes had pre renovation home visits; this allowed pre- and post-renovation comparisons within the same homes. Parallel visits were conducted in non-green (control) apartments (n=14) in a nearby low-income housing complex. The IAQ assessments included PM2.5, black carbon, ultrafine particles, sulfur, total volatile organic compounds (VOCs), formaldehyde, and air exchange rate. Data were analyzed using linear mixed-effects models. None of the indoor pollutant concentrations were significantly different between green and non-green homes. However, we found differences when comparing the concentrations before and after renovation. Measured immediately after renovation, indoor black carbon concentrations were significantly lower averaging 682 ng/m(3) in post-renovation vs. 2364 ng/m(3) in pre-renovation home visits (p=0.01). In contrast, formaldehyde concentrations were significantly higher in post-renovated (0.03 ppm) than in pre-renovated homes (0.01 ppm) (p=0.004). Questionnaire data showed that opening of windows occurred less frequently in homes immediately post-renovation compared to pre renovation; this factor likely affected the levels of indoor black carbon (from outdoor sources) and formaldehyde (from indoor sources) more than the renovation status itself. To reduce IAQ problems and potentially improve health, careful selection of indoor building materials and ensuring sufficient ventilation are important for green building designs. PMID- 26950632 TI - Behaviors of N-ethyl perfluorooctane sulfonamide ethanol (N-EtFOSE) in a soil earthworm system: Transformation and bioaccumulation. AB - N-ethyl perfluorooctane sulfonamido ethanol (N-EtFOSE) is a typical precursor of perfluorooctane sulfonate (PFOS). In this study, the behaviors of N-EtFOSE in a soil-earthworm system, including biodegradation in soil and bioaccumulation and biotransformation in earthworms (Eisenia fetida) were investigated. N-EtFOSE could be biodegraded in soil and biotransformed in earthworms to several metabolites, including n-ethylperfluorooctane sulfonamide acetate (N-EtFOSAA), perfluorooctane sulfonamide acetate (FOSAA), perfluorooctane sulfonamide (FOSA) and PFOS, with N-EtFOSAA as the predominant intermediate and PFOS as the terminal product in both soil and earthworm. The uptake rate coefficients (ku, 0.746 goc gdw(-1)d(-1)), degradation rate constant in soil (k0, 0.138 d(-1)) and the biota to-soil accumulation factor (BSAF, 0.523 goc gdw(-1)) of N-EtFOSE were estimated. For N-EtFOSE, N-EtFOSAA, FOSAA, FOSA and PFOS, their loss rate constants in earthworms were in the range of 0.467-30.2 (alpha) and 0.006-0.415 (beta) d(-1), respectively. The results provided important information about the behaviors of N EtFOSE in the soil-earthworm system. PMID- 26950633 TI - Large interannual variability in net ecosystem carbon dioxide exchange of a disturbed temperate peatland. AB - Peatland ecosystems play an important role in the global carbon (C) cycle as significant C sinks. However, human-induced disturbances can turn these sinks into sources of atmospheric CO2. Long-term measurements are needed to understand seasonal and interannual variability of net ecosystem CO2 exchange (NEE) and effects of hydrological conditions and their disturbances on C fluxes. Continuous eddy-covariance measurements of NEE were conducted between August 2010 and April 2014 at Yenicaga temperate peatland (Turkey), which was drained for agricultural usage and for peat mining until 2009. Annual NEE during the three full years of measurement indicated that the peatland acted as a CO2 source with large interannual variability, at rates of 246, 244 and 663 g Cm(-2)yr(-1) for 2011, 2012, and 2013 respectively, except for June 2011, and May to July 2012. The emission strengths were comparable to those found for severely disturbed tropical peatlands. The peak CO2 emissions occurred in the dry summer of 2013 when water table level (WTL) was below a threshold value of -60 cm and soil water content (SCW) below a threshold value of 70% by volume. Water availability index was found to have a stronger explanatory power for variations in monthly ecosystem respiration (ER) than the traditional water status indicators (SCW and WTL). Air temperature, evapotranspiration and vapor pressure deficient were the most significant variables strongly correlated with NEE and its component fluxes of gross primary production and ER. PMID- 26950635 TI - Organophosphate ester flame retardants and plasticizers in human placenta in Eastern China. AB - Organophosphate esters (OPEs) have been widely used in various products as alternatives to brominated flame retardants. Although widespread OPE exposure is expected in humans, the accumulation of OPEs has seldom been studied in the human body. In this study, 12 OPE analogs were analyzed in 50 human placentas collected in Eastern China. The concentrations of the 9 most frequently detected OPEs (Sigma9OPEs) ranged from 34.4 to 862ng/g lipid weight (lw), with a median of 301ng/g lw. Tri(2-chloroethyl) phosphate (TCEP) was identified as the most abundant analog, with a median concentration of 142ng/g lw, followed by tributoxyethyl phosphate (TBEP) and triphenyl phosphate (TPhP). Statistical analysis showed no analog of OPEs or Sigma9OPEs was positively correlated with the lipid content of the placentas. There were no correlations observed between the OPE concentrations and maternal characteristics. Food consumption habits exhibited weak effects on OPE levels in the placentas. Further investigation is required to determine the effects of OPEs on fetuses due to the expected increase in maternal exposure to these esters. PMID- 26950634 TI - Chlorination and dechlorination rates in a forest soil - A combined modelling and experimental approach. AB - Much of the total pool of chlorine (Cl) in soil consists of naturally produced organic chlorine (Clorg). The chlorination of bulk organic matter at substantial rates has been experimentally confirmed in various soil types. The subsequent fates of Clorg are important for ecosystem Cl cycling and residence times. As most previous research into dechlorination in soils has examined either single substances or specific groups of compounds, we lack information about overall bulk dechlorination rates. Here we assessed bulk organic matter chlorination and dechlorination rates in coniferous forest soil based on a radiotracer experiment conducted under various environmental conditions (additional water, labile organic matter, and ammonium nitrate). Experiment results were used to develop a model to estimate specific chlorination (i.e., fraction of Cl(-) transformed to Clorg per time unit) and specific dechlorination (i.e., fraction of Clorg transformed to Cl(-) per time unit) rates. The results indicate that chlorination and dechlorination occurred simultaneously under all tested environmental conditions. Specific chlorination rates ranged from 0.0005 to 0.01 d(-1) and were hampered by nitrogen fertilization but were otherwise similar among the treatments. Specific dechlorination rates were 0.01-0.03d(-1) and were similar among all treatments. This study finds that soil Clorg levels result from a dynamic equilibrium between the chlorination and rapid dechlorination of some Clorg compounds, while another Clorg pool is dechlorinated more slowly. Altogether, this study demonstrates a highly active Cl cycling in soils. PMID- 26950636 TI - Technoeconomic evaluation of urban plant factories: The case of basil (Ocimum basilicum). AB - Greece is currently in a turmoil, experiencing the effects of more than half a decade of economic crisis. Public health and welfare, jobs and wages, labor market concerning employment as long as employability of the work force, inequality, life satisfaction and housing, tourism and environment, economic and energy poverty are heavily impacted by Greece's disadvantageous economic situation. Real estate market could not have gotten away from the financial commotion, being currently in a halt after years of rapid decline. Fired from the present situation of Greece's real estate market, the present study is concerned with the investigation of alternative ways to support the local real estate market. With respect to sustainable development's ethics, the development, implementation, installation and operation of small, inexpensive plant factories within the urban environment is evaluated. Installations such are those, will encourage the penetration of a new market for the untapped buildings' resource, advancing new investing opportunities, promoting economic growth and productivity while creating a new labor market. The study will rely on the basic principles of Life Cycle Costing Assessment and develop a methodology upon which different scenarios will be evaluated against the "Do Nothing" scenario. PMID- 26950637 TI - Application of a multi-method approach in characterization of natural aquatic colloids from different sources along Huangpu River in Shanghai, China. AB - Natural colloid properties and the impact of human activities on these properties are important considerations for studies seeking to understand the fate and transport of pollutants. In this study, the relationship between size and fluorescence properties of natural colloids from 4 different sources were quantified using a multi-method analytical approach including UV-visible and fluorescence spectroscopy, flow field flow fractionation (FlFFF) coupled online to fluorescence spectrometer, and atomic force microscopy (AFM). Results indicate that colloids from pristine natural river water have higher aromaticity and humification, higher fluorescent intensity, and smaller size compared to those from the rivers impacted by livestock. The majority of colloids are smaller than 10nm in size as measured by AFM and FlFFF. Colloid size measured by FlFFF coupled to fluorescence spectroscopy increases in the order peak C (Ex/Em at 300-340/400 460 nm)0.02 mg Br/L. Environ Toxicol Chem 2016;35:2425-2429. Published 2016 Wiley Periodicals Inc. on behalf of SETAC. This article is a US Government work and, as such, is in the public domain in the United States of America. PMID- 26950657 TI - Interprovincial Reliance for Improving Air Quality in China: A Case Study on Black Carbon Aerosol. AB - Black carbon (BC) is of global concern because of its adverse effects on climate and human health. It can travel long distances via atmospheric movement and can be geographically relocated through trade. Here, we explored the integrated patterns of BC transport within 30 provinces in China from the perspective of meteorology and interprovincial trade using the Weather Research and Forecasting with Chemistry (WRF/Chem) model and multiregional input-output analysis. In general, cross-border BC transport, which accounts for more than 30% of the surface concentration, occurs mainly between neighboring provinces. Specifically, Hebei contributes 1.2 MUg.m(-3) BC concentration in Tianjin. By contrast, trade typically drives virtual BC flows from developed provinces to heavily industrial provinces, with the largest net flow from Beijing to Hebei (4.2 Gg). Shanghai is most vulnerable to domestic consumption with an average interprovincial consumption influence efficiency of 1.5 * 10(-4) (MUg.m(-3))/(billion Yuan.yr( 1)). High efficiencies (~8 * 10(-5) (MUg.m(-3))/(billion Yuan.yr(-1))) are also found from regions including Beijing, Jiangsu, and Shanghai to regions including Hebei, Shandong, and Henan. The above source-receptor relationship indicates two control zones: Huabei and Huadong. Both mitigating end-of-pipe emissions and rationalizing the demand for pollution-intense products are important within the two control zones to reduce BC and other pollutants. PMID- 26950659 TI - Guidelines: Deepening or Bridging the Quality Chasm? PMID- 26950658 TI - Technology. PMID- 26950660 TI - Administration of the Rapid Estimate of Adult Literacy in Medicine Via Telephone. AB - BACKGROUND AND OBJECTIVES: Over a third of adults in the United States have limited health literacy, which has been associated with numerous negative health outcomes and high health care costs. Most commonly used, objective measures of patients' literacy skills have traditionally been administered in person. This study assessed the feasibility of administering the Rapid Estimate of Adult Literacy in Medicine (REALM) via telephone. METHODS: A total of 119 participants were recruited after participating in a separate study where the REALM was administered in person. After approximately 1 week, patients were sent copies of the REALM prompt via mail and, when provided, email. A research assistant called participants approximately 1 week later to determine if the REALM had been received and could be accessed for use during the call. Multiple attempts to reach participants were made; 84 participants were able to successfully complete the study, yielding a response rate of 70.6%. The REALM was then administered over the phone, and results were compared with the scores from the in-person administration. RESULTS: There was a high correlation between both assessments (Spearman=0.85). The agreement between literacy categories (low, marginal, and adequate) between the in-person and telephone-based assessments was also high at 84.5% (kappa=0.72). Participants who completed the study were older than participants who did not complete the study, more likely to be white, and less likely to be currently working. CONCLUSIONS: The findings from this study indicate the REALM can be administered over the phone, providing alternative methodologies for literacy assessments in future studies. PMID- 26950661 TI - Using Comprehensive Video-Module Instruction as an Alternative Approach for Teaching IUD Insertion. AB - BACKGROUND AND OBJECTIVES: Family medicine clinicians and residents have increasing educational and work demands that have made it difficult to provide and access training on specific procedures such as IUD insertion. The purpose of this study was to determine whether the use of video-module instruction could provide residents with the necessary knowledge and skills to perform an IUD insertion correctly when compared with the traditional form of instruction, which is a lecture-demonstration session provided by an academic gynecologist. METHODS: Thirty-nine family medicine residents participated in the study during the induction period at the beginning of their residency program in July 2012 at the University of Calgary. A randomized, two group pretest/posttest experimental research design was used to compare the procedural knowledge and skills performance (posttest only) of residents trained using an alternative instructional intervention (video-module teaching) with the traditional lecture demonstration approach to teaching IUD insertion. RESULTS: Both teaching methods were effective in providing procedural knowledge instruction, and the paired samples t tests results were almost identical: t (37)=1.35. On the other hand, performance scores were significantly higher in the video-module group: t (37)=2.37, 95% CI (0.61, 8.00), with a mean difference in performance of 4.31. There were no significant differences in residents' satisfaction scores, and there was no correlation between the different scores and sex or age or between performance and level of satisfaction. CONCLUSIONS: This video-module instruction is an effective method to provide comprehensive IUD insertion training, and the psychomotor skills gain (performance component) was significantly higher than the traditional method of instruction. PMID- 26950662 TI - RU4PC? Texting to Quantify Feedback About Primary Care and Its Relationship With Student Career Interest. AB - BACKGROUND: Faculty and residents routinely offer feedback about medical students' specialty career preferences, yet influence of feedback has not been quantitatively evaluated. This study aims to report incidence and balance of primary care comments heard by medical students and determine the effect of comments on career interest. METHODS: This multicenter observational cohort study used text messaging and online surveys to examine positive and negative feedback about primary care, as reported by medical students in real time between September 2012 and April 2013. Participants from three universities sent short text messages when primary care comments were heard during two 30-day periods; each period was preceded and followed by surveys assessing career interest. RESULTS: A total of 120 students (86.3% of recruits) participated in at least one texting period; 87 (62.6%) participated in all aspects of study. Overall, positive comments (851) outnumbered negative (616). Total number of negative comments reported per student was associated with a significantly lower interest in primary care career (beta=-.04). There was an association between students' negative-to-positive comment ratios and lower interest in primary care that approached significance (beta=-.145) but only became significant (beta=-.191) when variables including institution were added to a linear regression model, supporting the hypothesis that culture toward primary care within an institution can influence graduates' primary care interest. CONCLUSIONS: Negatively perceived primary care comments were associated with lower interest in primary care careers by medical students. The study provides real-time quantitative data supporting the association between feedback received about primary care and students' career choices. PMID- 26950663 TI - "I Don't Want to Go Anywhere Else": Patient Experiences of Abortion in Family Medicine. AB - BACKGROUND AND OBJECTIVES: Prior studies have demonstrated that most women are comfortable with the option of receiving early abortion care in the family medicine setting, and patients who received early abortion care in this context report satisfaction with their experience. There are few qualitative studies, however, that explore abortion experiences in the family medicine setting. This study aimed to better understand influential factors in women's choices and experiences of their family medicine setting for abortion care. METHODS: We conducted semi-structured interviews with 15 women who received early abortion care at an urban federally qualified health center offering full-spectrum family medicine. Transcripts were analyzed in NVivo, using editing and immersion/crystallization approaches. RESULTS: Women who received abortion care in this setting were highly satisfied. Though many were surprised when they learned abortion care was available, their responses were favorable, and their experiences were positive. Our results indicate that connection to the clinic setting and to the provider who performed the abortion created a context of trust and comfort. Further, women in our study appreciated the privacy offered by a general medical setting as well as the convenience and continuity of care afforded by accessing abortion care in their accustomed primary care setting. CONCLUSIONS: Women in our study reported high levels of satisfaction with care and would recommend this setting to others. In a context of increasing restrictions on abortion, family physicians are well-positioned to increase access by including abortion care in the range of reproductive health services offered in their primary care practice settings. PMID- 26950664 TI - A Curriculum on Care for Complex Patients: Resident Perspectives. AB - BACKGROUND AND OBJECTIVES: Caring for patients with a challenging mix of medical, psychological, and social problems may easily overwhelm residents. We developed a month-long "Care for Complex Patients" curriculum for second-year residents to improve their ability to care for this group of patients by increasing their understanding of why the care is complex and by building communication, teamwork, and resource management skills. METHODS: Surveys and focus groups were used to assess the impact of the curriculum. Quantitative and qualitative methods were used to evaluate responses. RESULTS: Between 2008 and 2010, 24 residents completed our rotation. Eighty-three percent completed the pre-curriculum and post-curriculum surveys. Residents' self-ratings significantly improved in all 11 complex care management skills, and residents reported increased confidence when working with patients whose care was complex. Residents were surprised to learn about all the community resources and began using these resources when providing care for these patients. Despite rating themselves improved, a large number of residents still rated themselves as not competent in many of the skills. CONCLUSIONS: A curriculum for residents focused on education in 11 key skill areas in the care of complex patients led to increased self-confidence and willingness to provide complex care. However, 1 month of training is an insufficient amount of time to help most learners achieve self-assessed ratings of capable and competent in using these key skills when caring for complex patients. PMID- 26950665 TI - Residency Curricula on Physician-Pharmaceutical Industry Interaction: A CERA Study. AB - BACKGROUND AND OBJECTIVES: Physician interaction with pharmaceutical representatives results in less evidence-based prescribing and increased costs. Many organizations have called for strong conflict of interest policies in academic institutions. Implementing policy without educational interventions may not adequately address the influence of industry on physician prescribing patterns. The objective of this study is to assess the implementation and content of family medicine residency curricula on the physician-pharmaceutical industry relationship. METHODS: We surveyed US family medicine program directors using the Council of Academic Family Medicine Educational Research Alliance (CERA) platform. The presence of a formal curriculum on the physician-industry interaction and specific curricular elements (ethics of interaction, understanding detailing sessions and advertisements, use of unbiased pharmaceutical information) were the outcome measures of interest. RESULTS: Fifty two percent (212 of 406) of program directors responded. Forty percent (95% confidence interval [CI]: 33%--46%) reported having a formal curriculum on physician-pharmaceutical industry interactions. The presence of a formal curriculum was more likely in residencies permitting interaction with industry (52% [48/92] versus 30% [36/120]) or with a university affiliation (43% [75/173] versus 19% [7/36]). The use of unbiased sources of information relating to pharmaceutical products and the ethics of the physician-pharmaceutical industry relationship were the most common curricular elements (59% and 55%, respectively). CONCLUSIONS: This study shows that less than half of US family medicine programs have a curriculum addressing physician-industry interactions. Further research on the efficacy of and barriers to curriculum creation and implementation is warranted. PMID- 26950667 TI - Third- and Fourth-Year Medical Students' Changing Views of Family Medicine. AB - BACKGROUND AND OBJECTIVES: The effect of third-year family medicine clerkships on shaping contemporary US students' knowledge and attitudes toward family medicine is not well understood. The objectives of this study were to assess third-year medical students' attitudes toward family medicine before and after a family medicine clerkship, to assess students' interest in a family medicine career before and after the clerkship, and to compare these findings to the same students' attitudes toward family medicine in the fourth year. METHODS: An anonymous questionnaire assessing attitudes toward family medicine was offered to 150 medical students in the class of 2011 at a geographically dispersed, community-based US medical school. Students were offered the questionnaire during their third year, on the first and last days of the required 8-week family medicine clerkship, and midway through the fourth year. RESULTS: At least 92 students completed participation at each time point (response rate 61%). Twenty seven percent of students initially unlikely to choose family medicine as a career became interested after the clerkship. Ninety percent of those interested in family medicine maintained their interest. Attitudes toward lifestyle and compensation, family medicine's role in research, and family physician expertise significantly improved after the clerkship. However, gains in some of these areas regressed in the fourth year. CONCLUSIONS: The clerkship improves students' attitudes toward, and interest in, family medicine. However, students' favorable attitudes deteriorate when they are no longer exposed to family medicine instruction. Educational practices focused on fourth-year students may be needed to support and maintain student interest in family medicine. PMID- 26950666 TI - Long-Term Effects of a Health Literacy Curriculum for Medical Students. AB - BACKGROUND AND OBJECTIVES: Although there are reports of short-term benefits of health literacy curricula for improving health care professionals' communication with patients, no studies have included long-term follow-up. We sought to determine (1) whether a pre-clerkship health literacy training can improve medical students' perceived knowledge and intended behaviors vis-a-vis communication with patients who have low health literacy, (2) the longevity of any such impact at 12 months, and (3) the impact of a follow-up training 1 year later. METHODS: We conducted pre- and post-training assessments of self-perceived knowledge and perceived and planned behavior following a health literacy training for first-year medical students, with a 12-month follow-up training and repeat pre/post assessment. RESULTS: Among 48 pre-clerkship students, improvement was reported on 10 of 12 items following the Year 1 training. At 12-month follow-up, prior to the Year 2 training, ratings on 8 of 10 items had regressed to baseline levels. Nine of these items again improved significantly after the Year 2 training. Students were asked after both trainings if they felt they had overestimated their understanding of health literacy; significantly more students agreed with this statement following the Year 2 training than the Year 1 training. CONCLUSIONS: Among a cohort of pre-clerkship medical students, improvements in perceived knowledge and planned behavior vis-a-vis health literacy training largely did not persist at 12-month follow-up. Efforts to teach medical students about health literacy principles and practices should include a longitudinal or integrated format, rather than a one-time lecture format. PMID- 26950668 TI - Fourth-Year Medical Student Charting of Older Persons' Cognitive and Functional Status. AB - BACKGROUND AND OBJECTIVES: Functional and cognitive impairment correlates with medical outcomes in older persons, yet documentation in the medical record is often inadequate. The purpose of this pilot study was to evaluate fourth year (M4) medical students' charting performance of cognition and functional status in older persons during non-geriatric clerkships using an audit tool. METHODS: The research assistants used a chart abstracting tool to retrospectively review patients' charts. The abstracting tool contained keywords and phrases to prompt the research assistants to look for any documentation of patient status in four domains: (1) delirium or acute confusional state, (2) chronic cognitive impairment, (3) activities of daily living, and (4) instrumental activities of daily living. The threshold was any mention of keywords in these domains. RESULTS: On non-geriatrics M4 clerkships in the hospital, students documented acute cognitive status (ACS) and presence or absence of chronic cognitive impairment (CCI) in 57% and 68% of cases respectively, with physicians and/or nurses doing it more often at 63% and 84%. Both students and other care providers documented ACS and CCI in the same charts 41% and 59% of the time, respectively. Students documented activities of daily living (ADLs) and instrumental activities of daily living (IADLs) 31% and 3% respectively, physicians and/or nurses 59% and 0%. CONCLUSIONS: Documentation of cognitive status in hospital charts for students and physicians was somewhat higher than in the literature. This may be because geriatrics is integrated into our 4-year curriculum. Documentation by both students and physicians was better for ADLs than IADLs and poor for IADLs overall. PMID- 26950669 TI - Remembrances and Reflections: Global Health, Local Needs, and One Very Special Patient. PMID- 26950670 TI - Just Like Scales. PMID- 26950673 TI - Stick-Jump (SJ) Evaporation of Strongly Pinned Nanoliter Volume Sessile Water Droplets on Quick Drying, Micropatterned Surfaces. AB - We present an experimental study of stick-jump (SJ) evaporation of strongly pinned nanoliter volume sessile water droplets drying on micropatterned surfaces. The evaporation is studied on surfaces composed of photolithographically micropatterned negative photoresist (SU-8). The micropatterning of the SU-8 enables circular, smooth, trough-like features to be formed which causes a very strong pinning of the three phase (liquid-vapor-solid) contact line of an evaporating droplet. This is ideal for studying SJ evaporation as it contains sequential constant contact radius (CCR) evaporation phases during droplet evaporation. The evaporation was studied in nonconfined conditions, and forced convection was not used. Micropatterned concentric circles were defined having an initial radius of 1000 MUm decreasing by a spacing ranging from 500 to 50 MUm. The droplet evaporates, successively pinning and depinning from circle to circle. For each pinning radius, the droplet contact angle and volume are observed to decrease quasi-linearly with time. The experimental average evaporation rates were found to decrease with decreasing pining radii. In contrast, the experimental average evaporation flux is found to increase with decreasing droplet radii. The data also demonstrate the influence of the initial contact angle on evaporation rate and flux. The data indicate that the total evaporation time of a droplet depends on the specific micropattern spacing and that the total evaporation time on micropatterned surfaces is always less than on flat, homogeneous surfaces. Although the surface patterning is observed to have little effect on the average droplet flux-indicating that the underlying evaporation physics is not significantly changed by the patterning-the total evaporation time is considerably modified by patterning, up to a factor or almost 2 compared to evaporation on a flat, homogeneous surface. The closely spaced concentric circle pinning maintains a large droplet radius and small contact angle from jump to jump; the result is a large evaporation rate leading to faster evaporation. PMID- 26950674 TI - Noralashinol A, a new norlignan from stem barks of Syringa pinnatifolia. AB - One new norlignan, namely noralashinol A (1), one known analogue (2), together with seven known lignans (3-9) were isolated from the stem barks of Syringa pinnatifolia. Their structures were elucidated extensively by spectroscopic methods, including mass spectrometry and 1D and 2D NMR spectroscopies. Compound 8 significantly inhibited NO production in LPS-induced BV-2 murine microglia cells with its IC50 value of 20.7 MUM, compared to a positive control quercetin with its IC50 value of 15.3 MUM. PMID- 26950676 TI - Direct spectral analysis and determination of high content of carcinogenic bromine in bread using UV pulsed laser induced breakdown spectroscopy. AB - Laser induced breakdown spectroscopy (LIBS) was applied for the detection of carcinogenic elements like bromine in four representative brands of loaf bread samples and the measured bromine concentrations were 352, 157, 451, and 311 ppm, using Br I (827.2 nm) atomic transition line as the finger print atomic transition. Our LIBS system is equipped with a pulsed laser of wavelength 266 nm with energy 25 mJ pulse(-1), 8 ns pulse duration, 20 Hz repetition rate, and a gated ICCD camera. The LIBS system was calibrated with the standards of known concentrations in the sample (bread) matrix and such plot is linear in 20-500 ppm range. The capability of our system in terms of limit of detection and relative accuracy with respect to the standard inductively coupled plasma mass spectrometry (ICPMS) technique was evaluated and these values were 5.09 ppm and 0.01-0.05, respectively, which ensures the applicability of our system for Br trace level detection, and LIBS results are in excellent agreement with that of ICPMS results. PMID- 26950675 TI - GSH-dependent antioxidant defense contributes to the acclimation of colon cancer cells to acidic microenvironment. AB - Due to increased glycolysis and poor local perfusion, solid tumors are usually immersed in an acidic microenvironment. While extracellular acidosis is cytotoxic, cancer cells eventually become acclimated to it. While previous studies have addressed the acute effect of acidosis on cancer cells, little is known about how cancer cells survive chronic acidosis. In this study we exposed colorectal cancer (CRC) cells (HCT15, HCT116 and LoVo) to acidic pH (pH 6.5) continuously for over three months and obtained CRC cells that become acclimated to acidic pH, designated as CRC-acidosis-acclimated or CRC-AA. We unexpectedly found that while acute exposure to low pH resulted in an increase in the level of intracellular reactive oxygen species (ROS), CRC-AA cells exhibited a significantly reduced level of ROS when compared to ancestor cells. CRC-AA cells were found to maintain a higher level of reduced glutathione, via the upregulation of CD44 and glutathione reductase (GSR), among others, than their ancestor cells. Importantly, CRC-AA cells were more sensitive to agents that deplete GSH. Moreover, downregulation of GSR by RNA interference was more deleterious to CRC-AA cells than to control cells. Together, our results demonstrate a critical role of glutathione-dependent antioxidant defense in acclimation of CRC cells to acidic extracellular pH. PMID- 26950677 TI - Modeling risk of occupational zoonotic influenza infection in swine workers. AB - Zoonotic transmission of influenza A virus (IAV) between swine and workers in swine production facilities may play a role in the emergence of novel influenza strains with pandemic potential. Guidelines to prevent transmission of influenza to swine workers have been developed but there is a need for evidence-based decision-making about protective measures such as respiratory protection. A mathematical model was applied to estimate the risk of occupational IAV exposure to swine workers by contact and airborne transmission, and to evaluate the use of respirators to reduce transmission. The Markov model was used to simulate the transport and exposure of workers to IAV in a swine facility. A dose-response function was used to estimate the risk of infection. This approach is similar to methods previously used to estimate the risk of infection in human health care settings. This study uses concentration of virus in air from field measurements collected during outbreaks of influenza in commercial swine facilities, and analyzed by polymerase chain reaction. It was found that spending 25 min working in a barn during an influenza outbreak in a swine herd could be sufficient to cause zoonotic infection in a worker. However, this risk estimate was sensitive to estimates of viral infectivity to humans. Wearing an excellent fitting N95 respirator reduced this risk, but with high aerosol levels the predicted risk of infection remained high under certain assumptions. The results of this analysis indicate that under the conditions studied, swine workers are at risk of zoonotic influenza infection. The use of an N95 respirator could reduce such risk. These findings have implications for risk assessment and preventive programs targeting swine workers. The exact level of risk remains uncertain, since our model may have overestimated the viability or infectivity of IAV. Additionally, the potential for partial immunity in swine workers associated with repeated low-dose exposures or from previous infection with other influenza strains was not considered. Further studies should explore these uncertainties. PMID- 26950679 TI - A Review of Nutritional Tracking Mobile Applications for Diabetes Patient Use. AB - Diabetes, a prevalent disease in the United States, is greatly impacted by lifestyle choices, notably nutrition. The goal of this research was to determine which of the nutritional tracking applications (apps) available for Apple (Cupertino, CA) iOS, Android(r) (Google, Mountain View, CA), and Windows (Microsoft, Redmond, WA) platforms should be a first recommendation to diabetes patients searching for a smartphone app to aid in dietary logging and, for some apps, other varying lifestyle and health data. This project did so by identifying the smartphone apps available on the iTunes(r) (Apple), Google Play, and Microsoft stores that have nutritional tracking capabilities and are of potential benefit to a patient with diabetes based on certain criteria. Each of the individual apps was then evaluated to determine which would be of most benefit to a diabetes patient. The apps were assessed based on several parameters, such as their food databases, logging options, additional tracking options, interoperability with other devices and apps, and diabetes-specific resources. This information was then compiled and evaluated to determine which apps would be of most benefit for diabetes patients. This research provides valuable information for both patients and healthcare providers because the results of this study can be used as a reference for practitioners wishing to make app recommendations for diabetes patients who are implementing lifestyle change as an aspect of therapy. PMID- 26950680 TI - Anaesthesia and Sedation For Electrocochleography. AB - Anaesthesia and sedation in electrocochleo-graphy are of paramount importance for the whole procedure, since restlessness of the patient during the measurements can invalidate the results of the test. The time needed for extensive electrocochleography amounts on average to two hours. The only pain experienced during the procedure is associated with the placement of the transtympanic electrode. A relatively long-lasting, light level of anaesthesia has to be achieved to obtain the desired relative or absolute immobility of the patient. For the psychologically normal adult, local anaesthesia and additional sedation will meet the requirements for electrocochleography, but for children and mentally disturbed or anxious patients general anaesthesia is necessary. Tor children under the age of 8 years, two types of anaesthesia are available, i.e. dissociative anaesthesia and inhalation anaesthesia. After relatively extensive experience with dissociative anaesthesia, we abandoned this method because the above-mentioned requirements for ECoG could not be adequately satisfied during the entire duration (two hours) of the procedure. Inhalation anaesthesia, using the semi-closed-circle technique, has proved to be the optimal available procedure in these cases. PMID- 26950678 TI - A novel HSD17B10 mutation impairing the activities of the mitochondrial RNase P complex causes X-linked intractable epilepsy and neurodevelopmental regression. AB - We report a Caucasian boy with intractable epilepsy and global developmental delay. Whole-exome sequencing identified the likely genetic etiology as a novel p.K212E mutation in the X-linked gene HSD17B10 for mitochondrial short-chain dehydrogenase/reductase SDR5C1. Mutations in HSD17B10 cause the HSD10 disease, traditionally classified as a metabolic disorder due to the role of SDR5C1 in fatty and amino acid metabolism. However, SDR5C1 is also an essential subunit of human mitochondrial RNase P, the enzyme responsible for 5'-processing and methylation of purine-9 of mitochondrial tRNAs. Here we show that the p.K212E mutation impairs the SDR5C1-dependent mitochondrial RNase P activities, and suggest that the pathogenicity of p.K212E is due to a general mitochondrial dysfunction caused by reduction in SDR5C1-dependent maturation of mitochondrial tRNAs. PMID- 26950681 TI - DNA methylation dynamics in neurogenesis. AB - Neurogenesis is not limited to the embryonic stage, but continually proceeds in the adult brain throughout life. Epigenetic mechanisms, including DNA methylation, histone modification and noncoding RNA, play important roles in neurogenesis. For decades, DNA methylation was thought to be a stable modification, except for demethylation in the early embryo. In recent years, DNA methylation has proved to be dynamic during development. In this review, we summarize the latest understanding about DNA methylation dynamics in neurogenesis, including the roles of different methylation forms (5 methylcytosine, 5-hydroxymethylcytosine, 5-formylcytosine and 5 carboxylcytosine), as well as their 'writers', 'readers' and interactions with histone modifications. PMID- 26950682 TI - Macronutrient Intake, Diagnosis Status, and Glycemic Control Among US Hispanics/Latinos With Diabetes. AB - CONTEXT: Diet modification is a mainstay of diabetes management. US Hispanics/Latinos are disproportionately affected by diabetes, but few studies have examined dietary intake among US Hispanics/Latinos with diabetes, and little is known regarding the influence of diabetes awareness on dietary intake. OBJECTIVE: We evaluated macronutrient intake and its associations with diabetes awareness and glycemic control among US Hispanics/Latinos with diabetes. PARTICIPANTS: This analysis included 3310 diabetic adults aged 18-74 years from the Hispanic Community Health Study/Study of Latinos (2008-2011). MAIN OUTCOME MEASURES: Diabetes was defined as diagnosed (based on medical history or antihyperglycemic medication use) or undiagnosed diabetes (based on fasting glucose >= 126 mg/dL, glycated hemoglobin [HbA1c] >= 6.5%, or 2 h glucose >= 200 mg/dL in the absence of a physician diagnosis). Dietary intake was assessed using two 24-hour recalls. RESULTS: Among Hispanic/Latino adults with diabetes, 21.2%, 55.7%, and 71.2% met the American Diabetes Association recommendations for fiber (>=14 g per 1000 kcal), saturated fat (<10% of total energy), and cholesterol intake (<300 mg), respectively. Compared with those with undiagnosed diabetes, people with diagnosed diabetes consumed less carbohydrate (50.3 vs 52.4% of total energy; P = .017), total sugar (19.1 vs 21.5% of total energy; P = .002), added sugar (9.8 vs 12.1% of total energy; P < .001), and more total fat (30.7 vs 29.3% of total energy; P = .048) and monounsaturated fat (11.5 vs 10.7% of total energy; P = .021). Association between diabetes awareness and low total and added sugar intake was observed in individuals of Mexican and Puerto Rican background but not in other groups (P for interaction < .05). Among people with diagnosed diabetes, those with HbA1c of 7% or greater consumed more total fat, saturated fat, and cholesterol than those with HbA1c less than 7% (all P < .05). CONCLUSIONS: Among US Hispanics/Latinos with diabetes, fiber intake is low, and diabetes awareness is associated with reduced carbohydrate and sugar intake and increased monounsaturated fat intake. Sugar intake may require special attention in certain Hispanic/Latino background groups. PMID- 26950684 TI - Usefulness of FTA(r) cards as a Pneumocystis-DNA extraction method in bronchoalveolar lavage samples. AB - BACKGROUND: FTA(r) cards (Fast Technology for Analysis of Nucleic Acids) are an alternative DNA extraction method in bronchoalveolar lavage (BAL) samples for Pneumocystis jirovecii molecular analyses. The goal was to evaluate the usefulness of FTA(r) cards to detect P. jirovecii-DNA by PCR in BAL samples compared to silica adsorption chromatography (SAC). METHODS: This study used 134 BAL samples from immunocompromised patients previously studied to establish microbiological aetiology of pneumonia, among them 15 cases of Pneumocystis pneumonia (PCP) documented by staining and 119 with other alternative diagnoses. The FTA(r) system and SAC were used for DNA extraction and then amplified by nested PCR to detect P. jirovecii. Performance and concordance of the two DNA extraction methods compared to P. jirovecii microscopy were calculated. The influence of the macroscopic characteristics, transportation of samples and the duration of the FTA(r) card storage (1, 7, 10 or 12 months) were also evaluated. RESULTS: Among 134 BAL samples, 56% were positive for P. jirovecii-DNA by SAC and 27% by FTA(r). All 15 diagnosed by microscopy were detected by FTA(r) and SAC. Specificity of the FTA(r) system and SAC were 82.4% and 49.6%, respectively. Compared to SAC, positivity by FTA(r) decreased with the presence of blood in BAL (62% vs 13.5%). The agreement between samples at 7, 10 and 12 months was 92.5% for FTA(r). Positive cases by FTA(r) remained the same after shipment by mail. CONCLUSIONS: Results suggest that FTA(r) is a practical, safe and economical method to preserve P. jirovecii-DNA in BAL samples for molecular studies. PMID- 26950683 TI - Effects of Transdermal Testosterone Gel or an Aromatase Inhibitor on Prostate Volume in Older Men. AB - CONTEXT: T replacement is being increasingly offered to older men with age related low T; hence, monitoring prostate health is important during T therapy. Data suggest that estrogens have an independent effect on the prostate and some effects of T on the prostate might be mediated via its aromatization to estradiol. Although some studies have assessed the effects of T replacement on prostate volume, the differential effects of T and estradiol have not been delineated. OBJECTIVE: The objective of the study was to investigate the relative effects of T and estradiol on prostate volume in older men with low T. PARTICIPANTS: Thirty-one men, 65 years old or older with total T less than 350 ng/dL (measured by mass spectrometry) participated in the study. INTERVENTION: The intervention included randomization to 5 g transdermal T gel (TT), 1 mg oral aromatase inhibitor (AI), or placebo daily for 12 months. MAIN OUTCOME MEASURES: The primary outcome was prostate volume measured by transrectal ultrasound at baseline and 12 months. Secondary outcomes included prostate-specific antigen levels and lower urinary tract symptoms score. RESULTS: Serum T levels increased in both intervention groups; estradiol levels increased in the TT group, whereas it decreased in the AI group. At 12 months, prostate volume significantly increased (4.5 +/- 1.76 cc, P < .05) only in the TT group. Increase in prostate specific antigen levels were seen in both intervention groups at 6 months (P < .01 and P < .001). The lower urinary tract symptoms score increased only in the TT group (P < .05). CONCLUSIONS: The tropic effects of T on the prostate are mediated via its aromatization to estradiol. Administration of AI for 12 months to older men was not detrimental to the prostate. PMID- 26950687 TI - Accuracy of three Android-based pedometer applications in laboratory and free living settings. AB - This study examines the accuracy of three popular, free Android-based pedometer applications (apps), namely, Runtastic (RT), Pacer Works (PW), and Tayutau (TY) in laboratory and free-living settings. Forty-eight adults (22.5 +/- 1.4 years) completed 3-min bouts of treadmill walking at five incremental speeds while carrying a test smartphone installed with the three apps. Experiment was repeated thrice, with the smartphone placed either in the pants pockets, at waist level, or secured to the left arm by an armband. The actual step count was manually counted by a tally counter. In the free-living setting, each of the 44 participants (21.9 +/- 1.6 years) carried a smartphone with installed apps and a reference pedometer (Yamax Digi-Walker CW700) for 7 consecutive days. Results showed that TY produced the lowest mean absolute percent error (APE 6.7%) and was the only app with acceptable accuracy in counting steps in a laboratory setting. RT consistently underestimated steps with APE of 16.8% in the laboratory. PW significantly underestimated steps when the smartphone was secured to the arm, but overestimated under other conditions (APE 19.7%). TY was the most accurate app in counting steps in a laboratory setting with the lowest APE of 6.7%. In the free-living setting, the APE relative to the reference pedometer was 16.6%, 18.0%, and 16.8% for RT, PW, and TY, respectively. None of the three apps counted steps accurately in the free-living setting. PMID- 26950685 TI - Beta-haemolytic streptococcal endocarditis: clinical presentation, management and outcomes. AB - BACKGROUND: Beta-haemolytic streptococcal (BHS) endocarditis is rare, but well recognised for its high morbidity and mortality. This study sought to further characterise clinical features, management and outcomes of BHS endocarditis. METHODS: Retrospective review of all adultpatients (>= 18 years old) with BHS endocarditis treated at the Mayo Clinic from 1 January 2000 to 31 December 2014. RESULTS: Forty-nine cases of BHS endocarditis were identified with a mean (+/- SD) age of 64 (+/- 14.9) years and 65% were males. The infection was community acquired in 92% of the cases, with a median (IQR) time to diagnosis from symptom onset of 6 days (5-10). Associated conditions included the presence of a prosthetic valve (41%), malignancy (33%) and diabetes mellitus (DM) (31%). Median (IQR) vegetation size was 12 mm (9-17 mm). In a univariate analysis patients with DM had larger vegetations, median (IQR) = 17 mm (10.5-26 mm) compared to non diabetic patients, median (IQR) = 11 mm (8-15 mm) (p = 0.01). Septic brain emboli occurred in 43% of cases. Eighteen patients (37%) underwent early (within 30 days) surgery. All-cause 1 month and 6 month mortality rates were 25% and 31%, respectively. CONCLUSION: BHS endocarditis has an acute onset and is complicated by relatively large vegetations with a high rate of systemic embolisation. DM was the second most common associated medical condition and patients with DM had larger vegetations. Despite medical and surgical advances, mortality due to BHS endocarditis remains high, particularly within 30 days of diagnosis. PMID- 26950686 TI - Gradients in Depressive Symptoms by Socioeconomic Position Among Men Who Have Sex With Men in the EXPLORE Study. AB - This study examines gradients in depressive symptoms by socioeconomic position (SEP; i.e., income, education, employment) in a sample of men who have sex with men (MSM). Data were used from EXPLORE, a randomized, controlled behavioral HIV prevention trial for HIV-uninfected MSM in six U.S. cities (n = 4,277). Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression scale (short form). Multiple linear regressions were fitted with interaction terms to assess additive and multiplicative relationships between SEP and depressive symptoms. Depressive symptoms were more prevalent among MSM with lower income, lower educational attainment, and those in the unemployed/other employment category. Income, education, and employment made significant contributions in additive models after adjustment. The employment-income interaction was statistically significant, indicating a multiplicative effect. This study revealed gradients in depressive symptoms across SEP of MSM, pointing to income and employment status and, to a lesser extent, education as key factors for understanding heterogeneity of depressive symptoms. PMID- 26950688 TI - Changes in Markers of Mineral and Bone Disorders and Mortality in Incident Hemodialysis Patients. AB - BACKGROUND: Abnormalities in mineral and bone disorder (MBD) markers are common in patients with chronic kidney disease. However, previous studies have not accounted for their changes over time, and it is unclear whether these changes are associated with survival. METHODS: We examined the association of change in MBD markers (serum phosphorus (Phos), albumin-corrected calcium (Ca(Alb)), intact parathyroid hormone (iPTH) and alkaline phosphatase (ALP)) during the first 6 months of hemodialysis (HD) with all-cause mortality across baseline MBD strata using survival models adjusted for clinical characteristics and laboratory measurements in 102,754 incident HD patients treated in a large dialysis organization between 2007 and 2011. RESULTS: Across all MBD markers (Phos, Ca(Alb), iPTH and ALP), among patients whose baseline MBD levels were higher than the reference range, increase in MBD levels was associated with higher mortality (reference group: MBD level within reference range at baseline and no change at 6 months follow-up). Conversely, decrease in Phos and iPTH, among baseline Phos and iPTH levels lower than the reference range, respectively, were associated with higher mortality. An increase in ALP was associated with higher mortality across baseline strata of ALP >=80 U/l. However, patients with baseline ALP <80 U/l trended towards a lower risk of mortality irrespective of the direction of change at 6 months follow-up. CONCLUSIONS: There is a differential association between changes in MBD markers with mortality across varying baseline levels in HD patients. Further study is needed to determine if consideration of both baseline and longitudinal changes in the management of MBD derangements improves outcomes in this population. PMID- 26950691 TI - Potential anti-tumor effects of FTY720 associated with PP2A activation: a brief review. AB - FTY720 (Fingolimod, Gilenya (?) ) is an FDA-approved immunosuppressant currently used in the treatment of multiple sclerosis. However, a large number of studies over the last few years have shown that FTY720 shows potent antitumor properties that suggest its potential usefulness as a novel anticancer agent. Interestingly, the restoration of protein phosphatase 2A (PP2A) activity mediated by FTY720 could play a key role in its antitumor effects. Taking into account that PP2A inactivation is a common event that determines poor outcome in several tumor types, FTY720 could serve as an alternative therapeutic strategy for cancer patients with such alterations. PMID- 26950689 TI - Drugs in early clinical development for Systemic Lupus Erythematosus. AB - INTRODUCTION: While immunosuppressive therapy has positively impacted the prognosis of systemic lupus erythematosus (SLE), many patients still do not respond to traditional therapy. Thus, active SLE disease remains a significant problem. Furthermore, conventional immunosuppressive treatments for SLE are associated a high risk of side effects. These issues call for improvement in our current therapeutic armamentarium. AREAS COVERED: In this review, the authors highlight the recent developments in therapies for SLE, and present an overview of drugs which are in early clinical development for SLE. There are many new therapeutic approaches being developed, including those focused on B-cell targets, T-cell downregulation, co-stimulatory blockade, anti-cytokine agents, and kinase inhibition, and Toll-like receptor inhibition. They also discuss peptide therapy as a potential method to re-establish immune tolerance, and some of the challenges ahead in developing and testing novel agents for SLE. EXPERT OPINION: Many novel agents are currently in development for SLE, but this encouraging news is tempered by several disappointments in clinical trials and provides a timely moment to reflect on the future of therapeutic development in SLE. It seems likely that biological heterogeneity between patients is a major contributor to difficulty in drug design in SLE. PMID- 26950690 TI - Molecular characterization of Clostridium perfringens strains isolated from diseased turkeys in Italy. AB - One hundred and six Clostridium perfringens field strains, isolated from diseased turkeys in Italy between 2006 and 2015, were toxinotyped by polymerase chain reaction. Strains were derived from intestines (87), livers (17) and subcutaneous tissues (2). In addition to the four major toxins, strains were also screened for NetB toxin, enterotoxin and beta2 toxin encoding genes. The intestinal gross lesions of turkeys with enteric disorders were statistically studied with respect to the presence of C. perfringens beta2 toxin encoding gene and coccidia in the gut. All the isolates belonged to the toxinotype A and were netB negative. Enterotoxin (cpe) and beta2 toxin (cpb2) encoding genes were detected in two (2.63%) and 76 (71.69%) strains, respectively. Toxinotype results agree with the few published reports concerning the genetic characterization of C. perfringens of turkey origin. On the contrary, the presence of netB and cpb2 genes differs from the results of a previous study where these genes were detected respectively in 6.6% and in 0.5% of the tested strains. Necrotic enteritis in turkeys was not statistically correlated either to the presence of cpb2 gene, or to the synergistic effect operated by coccidia, even though a high percentage of birds with these protozoa in the gut showed necrotic enteritis lesions (64.29%). PMID- 26950692 TI - Client attachment in a randomized clinical trial of psychoanalytic and cognitive behavioral psychotherapy for bulimia nervosa: Outcome moderation and change. AB - In the context of a randomized clinical trial of psychoanalytic psychotherapy (PPT) versus cognitive behavior therapy (CBT) for bulimia nervosa (BN), this study performed secondary analyses of (a) the relation between attachment and pretreatment symptom levels, (b) whether client pretreatment attachment moderated treatment outcome, (c) whether change in client attachment was associated with symptomatic change, and (d) whether client attachment changed differently in the 2 treatments. Sixty-nine women and 1 man of a mean age of 25.8 years diagnosed with BN were randomly assigned to either 2 years of weekly PPT or 5 months of CBT. Assessments at intake, after 5 months, and after 2 years included the Eating Disorder Examination to assess eating disorder symptoms, the Adult Attachment Interview to assess client attachment, and the Symptom Checklist 90-R to assess general psychiatric distress. Repeated measures were analyzed using multilevel analysis. Higher scores on attachment insecurity and attachment preoccupation were associated with more frequent binging pretreatment. Pretreatment attachment did not predict treatment outcome. In PPT, but not in CBT, reduction of binging was associated with an increase in attachment security. The 2 treatment types were not associated with significantly different patterns of attachment-related change. Degree and type of attachment insecurity is related to the frequency of binging in BN. Increase in attachment security may be a treatment-specific mechanism of change in PPT for BN. (PsycINFO Database Record PMID- 26950693 TI - Pentaarylcyclopentadienyl Iron, Cobalt, and Nickel Halides. AB - The preparation of new stable half-sandwich transition metal complexes, having a bulky cyclopentadienyl ligand C5(C6H4-4-Et)5 (Cp(Ar1)) or C5(C6H4-4-nBu)5 (Cp(Ar2)), is reported. The tetrahydrofuran (THF) adduct [Cp(Ar1)Fe(MU-Br)(THF)]2 (1a) was synthesized by reacting K[Cp(Ar1)] with [FeBr2(THF)2] in THF, and its molecular structure was determined by X-ray crystallography. Complex 1a easily loses its coordinated THF molecules under vacuum to form the solvent-free complex [Cp(Ar1)Fe(MU-Br)]2 (1b). The analogous complexes [Cp(Ar1)Co(MU-Br)]2 (2), [Cp(Ar1)Ni(MU-Br)]2 (3), and [Cp(Ar2)Ni(MU-Br)]2 (4) were synthesized from CoBr2 and [NiBr2(1,2-dimethoxyethane)]. The mononuclear, low-spin cobalt(III) and nickel(III) complexes [Cp(Ar2)MI2] (5, M = Co; 6, M = Ni) were prepared by reacting the radical Cp(Ar2) with NiI2 and CoI2. The complexes were characterized by NMR and UV-vis spectroscopies and by elemental analyses. Single-crystal X-ray structure analyses revealed that the dimeric complexes 1a, 1b, and 3 have a planar M2Br2 core, whereas 2 and 4 feature a puckered M2Br2 ring. PMID- 26950695 TI - A luminescent ultrathin film with reversible sensing toward pressure. AB - A flexible ultrathin film based on alternate assembly of a sodium polyacrylate (PAA) modified styrylbiphenyl derivative (BTBS) and layered double hydroxide nanosheets is fabricated, which exhibits pressure-responsive photoluminescence with a high sensitivity and good reversibility. PMID- 26950694 TI - A New Nanobody-Based Biosensor to Study Endogenous PARP1 In Vitro and in Live Human Cells. AB - Poly(ADP-ribose) polymerase 1 (PARP1) is a key player in DNA repair, genomic stability and cell survival and it emerges as a highly relevant target for cancer therapies. To deepen our understanding of PARP biology and mechanisms of action of PARP1-targeting anti-cancer compounds, we generated a novel PARP1-affinity reagent, active both in vitro and in live cells. This PARP1-biosensor is based on a PARP1-specific single-domain antibody fragment (~ 15 kDa), termed nanobody, which recognizes the N-terminus of human PARP1 with nanomolar affinity. In proteomic approaches, immobilized PARP1 nanobody facilitates quantitative immunoprecipitation of functional, endogenous PARP1 from cellular lysates. For cellular studies, we engineered an intracellularly functional PARP1 chromobody by combining the nanobody coding sequence with a fluorescent protein sequence. By following the chromobody signal, we were for the first time able to monitor the recruitment of endogenous PARP1 to DNA damage sites in live cells. Moreover, tracing of the sub-nuclear translocation of the chromobody signal upon treatment of human cells with chemical substances enables real-time profiling of active compounds in high content imaging. Due to its ability to perform as a biosensor at the endogenous level of the PARP1 enzyme, the novel PARP1 nanobody is a unique and versatile tool for basic and applied studies of PARP1 biology and DNA repair. PMID- 26950696 TI - Effects of Water Provision and Hydration on Cognitive Function among Primary School Pupils in Zambia: A Randomized Trial. AB - There is a well-established link between hydration and improved cognitive performance among adults, with evidence of similar findings among children. No trials have investigated the impact of water provision on cognitive performance among schoolchildren in hot and arid low-resource settings. We conducted a randomized-controlled trial in five schools with limited water access in Chipata district in Eastern province, Zambia, to assess the efficacy of water provision on cognition. Pupils in grades 3-6 were randomly assigned to either receive a bottle of drinking water that they could refill throughout the day (water group, n = 149) or only have access to drinking water that was normally available at the school (control group, n = 143). Hydration was assessed in the morning before provision of water and in the afternoon through urine specific gravity (Usg) measured with a portable refractometer. In the afternoon we administered six cognitive tests to assess short-term memory, concentration, visual attention, and visual motor skills. Morning prevalence of dehydration, defined as Usg>=1.020, was 42%. Afternoon dehydration increased to 67% among the control arm and dropped to 10% among the intervention arm. We did not find that provision of water or hydration impacted cognitive test scores, although there were suggestive relationships between both water provision and hydration and increased scores on tests measuring visual attention. We identified key improvements to the study design that are warranted to further investigate this relationship. TRIAL REGISTRATION: ClinicalTrials.gov NCT01924546. PMID- 26950697 TI - Comparative Validation of Conventional and RNA-Seq Data-Derived Reference Genes for qPCR Expression Studies of Colletotrichum kahawae. AB - Colletotrichum kahawae is an emergent fungal pathogen causing severe epidemics of Coffee Berry Disease on Arabica coffee crops in Africa. Currently, the molecular mechanisms underlying the Coffea arabica-C. kahawae interaction are still poorly understood, as well as the differences in pathogen aggressiveness, which makes the development of functional studies for this pathosystem a crucial step. Quantitative real time PCR (qPCR) has been one of the most promising approaches to perform gene expression analyses. However, proper data normalization with suitable reference genes is an absolute requirement. In this study, a set of 8 candidate reference genes were selected based on two different approaches (literature and Illumina RNA-seq datasets) to assess the best normalization factor for qPCR expression analysis of C. kahawae samples. The gene expression stability of candidate reference genes was evaluated for four isolates of C. kahawae bearing different aggressiveness patterns (Ang29, Ang67, Zim12 and Que2), at different stages of fungal development and key time points of the plant-fungus interaction process. Gene expression stability was assessed using the pairwise method incorporated in geNorm and the model-based method used by NormFinder software. For C. arabica-C. kahawae interaction samples, the best normalization factor included the combination of PP1, Act and ck34620 genes, while for C. kahawae samples the combination of PP1, Act and ck20430 revealed to be the most appropriate choice. These results suggest that RNA-seq analyses can provide alternative sources of reference genes in addition to classical reference genes. The analysis of expression profiles of bifunctional catalase-peroxidase (cat2) and trihydroxynaphthalene reductase (thr1) genes further enabled the validation of the selected reference genes. This study provides, for the first time, the tools required to conduct accurate qPCR studies in C. kahawae considering its aggressiveness pattern, developmental stage and host interaction. PMID- 26950698 TI - Underestimation of the Maximal Capacity of the Mitochondrial Electron Transport System in Oligomycin-Treated Cells. AB - The maximal capacity of the mitochondrial electron transport system (ETS) in intact cells is frequently estimated by promoting protonophore-induced maximal oxygen consumption preceded by inhibition of oxidative phosphorylation by oligomycin. In the present study, human glioma (T98G and U-87MG) and prostate cancer (PC-3) cells were titrated with different concentrations of the protonophore CCCP to induce maximal oxygen consumption rate (OCR) within respirometers in a conventional growth medium. The results demonstrate that the presence of oligomycin or its A-isomer leads to underestimation of maximal ETS capacity. In the presence of oligomycin, the spare respiratory capacity (SRC), i.e., the difference between the maximal and basal cellular OCR, was underestimated by 25 to 45%. The inhibitory effect of oligomycin on SRC was more pronounced in T98G cells and was observed in both suspended and attached cells. Underestimation of SRC also occurred when oxidative phosphorylation was fully inhibited by the ATP synthase inhibitor citreoviridin. Further experiments indicated that oligomycin cannot be replaced by the adenine nucleotide translocase inhibitors bongkrekic acid or carboxyatractyloside because, although these compounds have effects in permeabilized cells, they do not inhibit oxidative phosphorylation in intact cells. We replaced CCCP by FCCP, another potent protonophore and similar results were observed. Lower maximal OCR and SRC values were obtained with the weaker protonophore 2,4-dinitrophenol, and these parameters were not affected by the presence of oligomycin. In permeabilized cells or isolated brain mitochondria incubated with respiratory substrates, only a minor inhibitory effect of oligomycin on CCCP-induced maximal OCR was observed. We conclude that unless a previously validated protocol is employed, maximal ETS capacity in intact cells should be estimated without oligomycin. The inhibitory effect of an ATP synthase blocker on potent protonophore-induced maximal OCR may be associated with impaired metabolism of mitochondrial respiratory substrates. PMID- 26950700 TI - Orientation-Based Control of Microfluidics. AB - Most microfluidic chips utilize off-chip hardware (syringe pumps, computer controlled solenoid valves, pressure regulators, etc.) to control fluid flow on chip. This expensive, bulky, and power-consuming hardware severely limits the utility of microfluidic instruments in resource-limited or point-of-care contexts, where the cost, size, and power consumption of the instrument must be limited. In this work, we present a technique for on-chip fluid control that requires no off-chip hardware. We accomplish this by using inert compounds to change the density of one fluid in the chip. If one fluid is made 2% more dense than a second fluid, when the fluids flow together under laminar flow the interface between the fluids quickly reorients to be orthogonal to Earth's gravitational force. If the channel containing the fluids then splits into two channels, the amount of each fluid flowing into each channel is precisely determined by the angle of the channels relative to gravity. Thus, any fluid can be routed in any direction and mixed in any desired ratio on-chip simply by holding the chip at a certain angle. This approach allows for sophisticated control of on-chip fluids with no off-chip control hardware, significantly reducing the cost of microfluidic instruments in point-of-care or resource limited settings. PMID- 26950699 TI - Molecular Cloning, Functional Characterization and Nutritional Regulation of the Putative Elongase Elovl5 in the Orange-Spotted Grouper (Epinephelus coioides). AB - The enzymes involved in the biosynthesis of long-chain polyunsaturated fatty acids (LC-PUFAs) are widely studied in fish species, as fish are the main source of n-3 LC-PUFAs for human beings. In the present study, a putative gene for elovl5, which encodes a key enzyme involved in LC-PUFA synthesis, was cloned and functionally characterized, and its transcription in response to dietary n-3 LC PUFA exposure was investigated. Moreover, cell transfection and luciferase assays were used to explore the mechanism underlying the regulation of elovl5. The full length cDNA of elovl5 was 1242 bp (excluding the polyA tail), including an 885 bp coding region encoding a 295 amino acid protein that possesses all of the characteristic features of elovl proteins. Functional characterization of heterologously expressed grouper Elovl5 indicated that it effectively elongates both C18 (18:2n-6, 18:3n-3, 18:3n-6 and 18:4n-3) and C20 (20:4n-6 and C20:5n-3) PUFAs, but not the C22 substrates. The expression of elovl5 was significantly affected by dietary n-3 LC-PUFA exposure: a high n-3 LC-PUFA level repressed the expression of elovl5 by slightly down-regulating the expression of sterol regulatory element-binding protein (SREBP)-1 and liver X receptor (LXR) alpha, which are major regulators of hepatic lipid metabolism. Promoter studies showed that grouper elovl5 reporter activity was induced by over-expression of LXRalpha but not SREBP-1. This finding suggests that elovl5 is a direct target of LXRalpha, which is involved in the biosynthesis of PUFAs via transcriptional regulation of elovl5. These findings may contribute to a further understanding of the mechanism underlying the regulation of LC-PUFA biosynthesis in marine fish species. PMID- 26950701 TI - The Complete Plastid Genome of Lagerstroemia fauriei and Loss of rpl2 Intron from Lagerstroemia (Lythraceae). AB - Lagerstroemia (crape myrtle) is an important plant genus used in ornamental horticulture in temperate regions worldwide. As such, numerous hybrids have been developed. However, DNA sequence resources and genome information for Lagerstroemia are limited, hindering evolutionary inferences regarding interspecific relationships. We report the complete plastid genome of Lagerstroemia fauriei. To our knowledge, this is the first reported whole plastid genome within Lythraceae. This genome is 152,440 bp in length with 38% GC content and consists of two single-copy regions separated by a pair of 25,793 bp inverted repeats. The large single copy and the small single copy regions span 83,921 bp and 16,933 bp, respectively. The genome contains 129 genes, including 17 located in each inverted repeat. Phylogenetic analysis of genera sampled from Geraniaceae, Myrtaceae, and Onagraceae corroborated the sister relationship between Lythraceae and Onagraceae. The plastid genomes of L. fauriei and several other Lythraceae species lack the rpl2 intron, which indicating an early loss of this intron within the Lythraceae lineage. The plastid genome of L. fauriei provides a much needed genetic resource for further phylogenetic research in Lagerstroemia and Lythraceae. Highly variable markers were identified for application in phylogenetic, barcoding and conservation genetic applications. PMID- 26950702 TI - Evaluation of the Intussusception Risk after Pentavalent Rotavirus Vaccination in Finnish Infants. AB - BACKGROUND: An association between rotavirus immunisation and intussusception (IS) has been suggested with present rotavirus vaccines in post-licensure studies. In Finland, rotavirus vaccination programme was implemented in September 2009 using a 2, 3, and 5 months schedule with the pentavalent rotavirus vaccine. By the end of 2013, it is estimated that 719 000 rotavirus vaccine doses have been given in the national programme of which 240 000 were first doses. Nationwide register allows us to evaluate the association between rotavirus vaccination and IS. METHODS AND MATERIALS: Cases of IS diagnosed during 1999-2013 were identified from National Hospital Discharge Register. All cases under 250 days of age diagnosed during 2009-2013 were confirmed by reviewing medical charts. Self-controlled case-series method was used to assess the risk of IS during 1-21 days compared to 22-42 days post vaccination. FINDINGS: In register data the relative incidence of IS at 2 months of age between the post and pre vaccination era was 9.1 (95%CI 2.0-84.3). We identified 22 verified cases with date of admission less than 43 days after any of the three rotavirus vaccine doses. The incidence of IS in the risk period after the 1st dose relative to the control period was 2.0 (95% CI 0.5-8.4; p = 0.34.) Number of excess IS cases per 100 000 first vaccine doses was therefore estimated to be 1.04 (95% CI 0.0-2.5), i.e. one additional IS case per 96 000 first doses of rotavirus vaccine (95% CI 54 600 to infinity). There was no risk detected after 2nd and 3rd doses. CONCLUSION: The finding is in line with the recent published estimates. The benefits of rotavirus immunisation programme outweigh possible small risks of intussusception. PMID- 26950704 TI - 9th International Update on Neuroanesthesia and Neurointensive Care EURONEURO 2016: Barcelona, Spain, April 14-16, 2016. PMID- 26950703 TI - Surviving Sudden Cardiac Arrest: A Pilot Qualitative Survey Study of Survivors. AB - Research describing survivors of sudden cardiac arrest (SCA) has centered on quantifying functional ability, perceived quality of life, and neurocognitive assessment. Many gaps remain, however, regarding survivors' psychosocial perceptions of life in the aftermath of cardiac arrest. An important influence upon those perceptions is the presence of support and its role in a survivor's life. An Internet-based pilot survey study was conducted to gather data from SCA survivors and friends and/or family members (FFMs) representing their support system. The survey was distributed to members of the Sudden Cardiac Arrest Foundation (SCAF) via the Internet by SCAF leadership. Questions included both discrete multiple-choice and open-ended formats. Inductive thematic analyses were completed by three independent researchers trained in qualitative research methodology to identify primary themes consistent among study participants until thematic saturation was achieved. No statistical inferences were made. A total of 205 surveys were returned over the 5-month study period (July to November 2013); nine were received blank, leaving 196 surveys available for review. Major themes identified for survivors (N = 157) include the significance of and desire to share experiences with others; subculture identification (unique experience from those suffering a heart attack); and the need to seek a new normal, both personally and inter-personally. Major themes identified for FFMs (N = 39) include recognition of loved one's memory loss; a lack of information at discharge, including expectations after discharge; and concern for the patient experiencing another cardiac arrest. This pilot, qualitative survey study suggests several common themes important to survivors, and FFMs, of cardiac arrest. These themes may serve as a basis for future patient-centered focus groups and the development of patient-centered guidelines for patients and support persons of those surviving cardiac arrest. PMID- 26950705 TI - Anticoagulant Effect of Sugammadex: Just an In Vitro Artifact. AB - BACKGROUND: Sugammadex prolongs activated partial thromboplastin time (aPTT) and prothrombin time (PT) suggestive of anticoagulant effects. To pinpoint its presumed anticoagulant site of action, the authors assessed Sugammadex's impact on a panel of coagulation assays. METHODS: Sugammadex, Rocuronium, Sugammadex and Rocuronium combined, or saline were added to blood samples from healthy volunteers and analyzed using plasmatic (i.e., aPTT, thrombin time, and fibrinogen concentration) (n = 8 each), PT (quick), activities of plasmatic coagulation factors, and whole blood (extrinsically and intrinsically activated thromboelastometry) assays (n = 18 each). Furthermore, dose-dependent effects of Sugammadex were also assessed (n = 18 each) in diluted Russel viper venom time (DRVVT) assays with low (DRVVT1) and high (DRVVT2) phospholipid concentrations and in a highly phospholipid-sensitive aPTT assay. RESULTS: Sugammadex increased PT (+9.1%; P < 0.0001), aPTT (+13.1%; P = 0.0002), and clotting time in extrinsically (+33.1%; P = 0.0021) and intrinsically (+22.4%; P < 0.0001) activated thromboelastometric assays. Furthermore, activities of factors VIII, IX, XI, and XII decreased (-7%, P = 0.009; -7.8%, P < 0.0001; -6.9%, P < 0.0001; and -4.3%, P = 0.011, respectively). Sugammadex dose-dependently prolonged both DRVVT1 and the highly phospholipid-sensitive aPTT assays, but additional phospholipids in the DRVVT2 assay almost abolished these prolongations. Thrombin time, a thromboelastometric thrombin generation assay, clot firmness, clot lysis, fibrinogen concentration, and activities of other coagulation factors were unaltered. Rocuronium, Sugammadex and Rocuronium combined, and saline exerted no effects. CONCLUSION: Sugammadex significantly affects various coagulation assays, but this is explainable by an apparent phospholipid-binding effect, suggesting that Sugammadex's anticoagulant effects are likely an in vitro artifact. PMID- 26950707 TI - 49 Mathoura Road: Geoffrey Kaye's Center of Excellence for the Australian Society of Anaesthetists. AB - Geoffrey Kaye, M.B.B.S. (1903 to 1986), was a prominent Australian anesthetist, researcher, and educator who envisioned that anesthesia practice in Australia would be comparable to European and American anesthesia practice during the 1940s and 1950s. Kaye's close relationship with Francis Hoeffer McMechan, M.D., F.I.C.A. (1879 to 1939), which began when Kaye left a favorable impression on McMechan at a meeting of the Australasian Medical Congress in 1929, eventually led Kaye to establish an educational center for the Australian Society of Anaesthetists at 49 Mathoura Road, Toorak, Melbourne, Australia, in 1951. The center served as the "Scientific Headquarters" and the Australian Society of Anaesthetists' official headquarters from 1951 to 1955. Although anesthesia's recognition as a specialty was at the heart of the center, Kaye hoped that this "experiment in medical education"-equipped with a library, museum, laboratory, workshop, darkroom, and meeting space-would "bring anaesthetists of all lands together" in Australia. The lack of member participation in Kaye's center, however, led Kaye to dissolve the center by 1955. Previous research has documented the history of Kaye's center from correspondence between Kaye and influential American anesthesiologist Paul M. Wood, M.D. (1894 to 1953), from 1939 to 1955. Through letters Kaye sent to American anesthesiologist Paul M. Wood, M.D. (1894 to 1963), the authors see Kaye's detailed plans, design, and intent for the center at 49 Mathoura Road. Comparisons of Kaye's letters to Wood during the 1950s with his letters to Gwenifer Wilson, M.D., M.B.B.S. (1916 to 1988), during the 1980s illustrate a change in Kaye's perceptions regarding the failure of the center. PMID- 26950706 TI - Persistent Catechol-O-methyltransferase-dependent Pain Is Initiated by Peripheral beta-Adrenergic Receptors. AB - BACKGROUND: Patients with chronic pain disorders exhibit increased levels of catecholamines alongside diminished activity of catechol-O-methyltransferase (COMT), an enzyme that metabolizes catecholamines. The authors found that acute pharmacologic inhibition of COMT in rodents produces hypersensitivity to mechanical and thermal stimuli via beta-adrenergic receptor (betaAR) activation. The contribution of distinct betaAR populations to the development of persistent pain linked to abnormalities in catecholamine signaling requires further investigation. METHODS: Here, the authors sought to determine the contribution of peripheral, spinal, and supraspinal betaARs to persistent COMT-dependent pain. They implanted osmotic pumps to deliver the COMT inhibitor OR486 (Tocris, USA) for 2 weeks. Behavioral responses to mechanical and thermal stimuli were evaluated before and every other day after pump implantation. The site of action was evaluated in adrenalectomized rats receiving sustained OR486 or in intact rats receiving sustained betaAR antagonists peripherally, spinally, or supraspinally alongside OR486. RESULTS: The authors found that male (N = 6) and female (N = 6) rats receiving sustained OR486 exhibited decreased paw withdrawal thresholds (control 5.74 +/- 0.24 vs. OR486 1.54 +/- 0.08, mean +/- SEM) and increased paw withdrawal frequency to mechanical stimuli (control 4.80 +/- 0.22 vs. OR486 8.10 +/- 0.13) and decreased paw withdrawal latency to thermal heat (control 9.69 +/- 0.23 vs. OR486 5.91 +/- 0.11). In contrast, adrenalectomized rats (N = 12) failed to develop OR486-induced hypersensitivity. Furthermore, peripheral (N = 9), but not spinal (N = 4) or supraspinal (N = 4), administration of the nonselective betaAR antagonist propranolol, the beta2AR antagonist ICI 118,511, or the beta3AR antagonist SR59230A blocked the development of OR486 induced hypersensitivity. CONCLUSIONS: Peripheral adrenergic input is necessary for the development of persistent COMT-dependent pain, and peripherally-acting betaAR antagonists may benefit chronic pain patients. PMID- 26950708 TI - Auscultation versus Point-of-care Ultrasound to Determine Endotracheal versus Bronchial Intubation: A Diagnostic Accuracy Study. AB - BACKGROUND: Unrecognized malposition of the endotracheal tube (ETT) can lead to severe complications in patients under general anesthesia. The focus of this double-blinded randomized study was to assess the accuracy of point-of-care ultrasound in verifying the correct position of the ETT and to compare it with the accuracy of auscultation. METHODS: Forty-two adult patients requiring general anesthesia with ETT were consented. Patients were randomized to right main bronchus, left main bronchus, or tracheal intubation. After randomization, the ETT was placed via fiber-optic visualization. Next, the location of the ETT was assessed using auscultation by a separate blinded anesthesiologist, followed by an ultrasound performed by a third blinded anesthesiologist. Ultrasound examination included assessment of tracheal dilation via cuff inflation with air and evaluation of pleural lung sliding. Statistical analysis included sensitivity, specificity, positive predictive value, negative predictive value, and interobserver agreement for the ultrasound examination (95% CI). RESULTS: In differentiating tracheal versus bronchial intubations, auscultation showed a sensitivity of 66% (0.39 to 0.87) and a specificity of 59% (0.39 to 0.77), whereas ultrasound showed a sensitivity of 93% (0.66 to 0.99) and specificity of 96% (0.79 to 1). Identification of tracheal versus bronchial intubation was 62% (26 of 42) in the auscultation group and 95% (40 of 42) in the ultrasound group (P = 0.0005) (CI for difference, 0.15 to 0.52), and the McNemar comparison showed statistically significant improvement with ultrasound (P < 0.0001). Interobserver agreement of ultrasound findings was 100%. CONCLUSION: Assessment of trachea and pleura via point-of-care ultrasound is superior to auscultation in determining the location of ETT. PMID- 26950709 TI - Do You Believe What You See or What You Hear? Ultrasound versus Stethoscope for Perioperative Clinicians. PMID- 26950710 TI - A Co3O4-embedded porous ZnO rhombic dodecahedron prepared using zeolitic imidazolate frameworks as precursors for CO2 photoreduction. AB - Metal-organic frameworks (MOFs) are attracting considerable attention for their use as both the precursor and the template to prepare metal oxides or carbon based materials. For the first time in this paper, the core-shell ZIF-8@ZIF-67 crystals are thermally converted into porous ZnO@Co3O4 composites by combining a seed-mediated growth process with a two-step calcination. The designed porous ZnO@Co3O4 composites exhibited the highest photocatalytic activity with an excellent stability for the reduction of CO2 among the commonly reported composite photocatalysts. Their superior photocatalytic performance is demonstrated to be resulting from the unique porous structure of ZnO@Co3O4 and the co-catalytic function of Co3O4 which can effectively suppress the photocorrosion of ZnO. PMID- 26950711 TI - Antifungal Prophylaxis in Lung Transplant Recipients. AB - Invasive fungal infection remains a serious postoperative complication in lung transplant recipients and is associated with significant morbidity and mortality. Although most lung transplant centers use antifungal prophylaxis, consensus on the strategy, choice of antifungal agent(s), route of administration, and duration of prophylaxis have not been established. This review provides an overview of the epidemiology and risk factors for common fungal infections seen in lung transplant recipients, evaluates the clinical efficacy and toxicity of the various antifungal agents used to prevent infection, and offers recommendations and opportunities for future research. Currently available data evaluating the efficacy of antifungal prophylaxis strategies is limited by a lack of prospective, randomized clinical trial data and variability in patient populations, prophylactic and immunosuppressive strategies, dosing, durations of use of antifungal agents, and definitions of invasive infection. There is controversy regarding significant risk factors for invasive fungal infection, which has limited the development and validation of targeted prophylactic strategies. Inhaled formulations of amphotericin B remain the most widely studied option for universal prophylaxis and have been shown to be effective in reducing the incidence of invasive Aspergillosis as compared with no prophylaxis. Concern over early postoperative extrapulmonary infection may suggest a benefit of initial prophylaxis with a systemic azole. Long-term use of systemic antifungals is not optimal due to emerging evidence of long-term toxicities. Multicenter, randomized trials are needed to ascertain the optimal prophylactic strategy in lung transplant recipients. New agents and delivery mechanisms may offer additional opportunities for comparative research. PMID- 26950713 TI - Outcomes From Pancreatic Transplantation in Donation After Cardiac Death: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Pancreas transplantation remains the gold standard for treatment for type I diabetes providing an insulin-independent, normoglycemic state. Increasingly, donation after cardiac death (DCD) donors are used in view of the organ donor shortage. We aimed to systematically review recipient outcomes from DCD donors and where possible compared these with donor after brain death (DBD) donors. METHODS: We searched the databases MEDLINE via PubMed, EMBASE, and The Cochrane Library from inception to March 2015, for studies reporting the outcome of DCD pancreas transplants. We appraised studies using the Newcastle-Ottawa scale and meta-analyzed using a random effects model. RESULTS: We identified 18 studies, 4 retrospective and 6 prospective cohort studies and 8 case reports. Our bias assessment revealed that although studies were well conducted, some studies had potential confounding factors and absence of comparator groups. Eight of the 18 studies included a DBD comparison group comprising 23 609 transplant recipients. Importantly, there was no significant difference in allograft survival up to 10 years (hazard ratio, 0.98; 95% confidence interval [95% CI], 0.74-1.31; P = 0.92), or patient survival (hazard ratio, 1.31; 95% CI, 0.62-2.78; P = 0.47) between DCD and DBD pancreas transplants. We estimated that the odds of graft thrombosis was 1.67 times higher in DCD organs (95% CI, 1.04-2.67; P = 0.006). However, subgroup analysis found thrombosis was not higher in recipients whose DCD donors were given antemortem heparin (P = 0.62). CONCLUSIONS: Using current DCD criteria, pancreas transplantation is a viable alternative to DBD transplantation, and antemortem interventions including heparinization may be beneficial. This potential benefit of DCD pancreas donation warrants further study. PMID- 26950712 TI - Predicting Cellular Rejection With a Cell-Based Assay: Preclinical Evaluation in Children. AB - BACKGROUND: Allospecific CD154+T-cytotoxic memory cells (CD154+TcM) predict acute cellular rejection after liver transplantation (LTx) or intestine transplantation (ITx) in small cohorts of children and can enhance immunosuppression management, but await validation and clinical implementation. METHODS: To establish safety and probable benefit, CD154+TcM were measured in cryopreserved samples from 214 children younger than 21 years (National Clinical Trial 1163578). Training set samples (n = 158) were tested with research-grade reagents and 122 independent validation set samples were tested with current good manufacturing practices manufactured reagents after assay standardization and reproducibility testing. Recipient CD154+TcM induced by stimulation with donor cells were expressed as a fraction of those induced by HLA nonidentical cells in parallel cultures. The resulting immunoreactivity index (IR) if greater than 1 implies increased rejection-risk. RESULTS: Training and validation set subjects were demographically similar. Mean coefficient of test variation was less than 10% under several conditions. Logistic regression incorporating several confounding variables identified separate pretransplant and posttransplant IR thresholds for prediction of rejection in the respective training set samples. An IR of 1.1 or greater in posttransplant training samples and IR of 1.23 or greater in pretransplant training samples predicted LTx or ITx rejection in corresponding validation set samples in the 60-day postsampling period with sensitivity, specificity, positive, and negative predictive values of 84%, 80%, 64%, and 92%, respectively (area under the receiver operator characteristic curve, 0.792), and 57%, 89%, 78%, and 74%, respectively (area under the receiver operator characteristic curve, 0.848). No adverse events were encountered due to phlebotomy. CONCLUSIONS: Allospecific CD154+T-cytotoxic memory cells predict acute cellular rejection after LTx or ITx in children. Adjunctive use can enhance clinical outcomes. PMID- 26950714 TI - Long-term Follow-up of Kidney Transplant Recipients in the Spare-the-Nephron Trial. AB - In the Spare-the-Nephron (STN) Study, kidney transplant recipients randomized about 115 days posttransplant to convert from CNI (calcineurin inhibitor)/MMF to sirolimus (SRL)/MMF had a significantly greater improvement in measured GFR (mGFR) at 12 months compared with those kept on CNI/MMF. The difference at 24 months was not statistically significant. From 14 top enrolling centers, 128 of 175 patients identified with a functioning graft at 2 years consented to enroll in an observational, noninterventional extension study to collect retrospectively and prospectively annual follow-up data for the interval since baseline (completion of the parent STN study at 24 months posttransplant). Overall, 11 patients died, including 5 (7.6%) in the SRL/MMF group and 6 (9.7%) in the CNI/MMF group. Twenty-two grafts have been lost including 10 (15.2%) in the SRL/MMF arm and 12 (19.4%) in the CNI/MMF arm. Death and chronic rejection were the most common causes of graft loss in both arms. There were modestly more cardiovascular events in the MMF/SRL group. Estimated creatinine clearance (Cockcroft-Gault) from baseline out to 6 additional years (8 years posttransplant, ITT analysis, SRL/MMF, n = 34; CNI/MMF, n = 26) was 63.2 +/- 28.5 mL/min/1.73 m in the SRL/MMF group and 59.2 +/- 27.2 mL/min/1.73 m in the CNI/MMF group and was not statistically significant, but there is a clinically meaningful trend for improved long-term renal function in the SRL/MMF group compared with the CNI/MMF group. The long-term decision for immunosuppression needs to be carefully individualized. PMID- 26950715 TI - Biomarkers of Transplant Tolerance: A Provisional Analysis for an Unmet Need. PMID- 26950717 TI - Midodrine Dependence: Transplantation Barrier or Opportunity? PMID- 26950716 TI - Liver microRNA Profile of Induced Allograft Tolerance. AB - BACKGROUND: Although the liver is less immunogenic than other solid organs, most liver transplant recipients receive lifelong immunosuppression. In both experimental models and clinical transplantation, total lymphoid irradiation (TLI) has been shown to induce allograft tolerance. Our goal was to identify the microRNAs (miRNAs) expressed in tolerant liver allograft recipients in an experimental model of TLI-induced tolerance. METHODS: To identify the miRNAs associated with TLI-induced tolerance, we examined syngeneic recipients (Lewis >Lewis) and allogeneic recipients (Dark Agouti->Lewis) of orthotropic liver transplants that received posttransplant TLI, allogeneic recipients that were not treated posttransplantation and experienced acute rejection, and native Dark Agouti livers. Quantitative-polymerase chain reaction miRNA array cards were used to profile liver grafts. RESULTS: We identified 12 miRNAs that were specifically and significantly increased during acute rejection. In early tolerance, 33 miRNAs were altered compared with syngeneic livers, with 80% of the miRNAs increased. In established tolerance, 42 miRNAs were altered. In addition, miR-142-5p and miR 181a demonstrated increased expression in tolerant livers (both early and established tolerance) as compared with syngeneic livers. A principal component analysis of all miRNAs assayed demonstrated a profile in established tolerance that was closely related to that seen in syngeneic livers. CONCLUSIONS: The miRNA profile of established tolerant allografts is very similar to syngeneic grafts, suggesting tolerance may be a return to an immunological state of quiescence. PMID- 26950719 TI - Epidemiology and Outcomes of Nontuberculous Mycobacterial Infections in Solid Organ Transplant Recipients at a Midwestern Center. AB - BACKGROUND: Nontuberculous mycobacterial (NTM) infections have the potential to affect outcomes in solid organ transplant (SOT) recipients. METHODS: Retrospective cohort of adults who underwent SOT at a Midwestern hospital between January 1, 2004, and December 31, 2013. NTM-infected patients had at least 1 positive culture for NTM posttransplant. NTM disease was defined by 1) American Thoracic Society/Infectious Disease Society of America criteria for respiratory specimens or 2) NTM cultured from a sterile site with a compatible clinical syndrome. The remaining NTM infected patients were classified as colonized. Cox regression analysis was used to determine the association of NTM with mortality among lung transplant recipients. RESULTS: Of 3338 SOT recipients, 50 (1.5%) had NTM infection during a median 1038 days (range, 165-3706) follow-up posttransplant. Forty-three patients (86%) with NTM infection were lung transplant recipients; 18 of 43 (41.8%) were treated for NTM and 6 (13.9%) met disease criteria. Isolation of the same species on multiple occasions was associated with treatment among the colonized lung transplant recipients (8/12 [67%] vs 3/25 [12%] who were not treated, P = 0.014). NTM infection was not associated with increased mortality in lung transplant recipients (9/43 [20.9%] in infected died versus 161/510 [31.6%] in uninfected, age-adjusted hazard ratio, 0.56; 95% confidence interval, 0.2-1.1; P = 0.091). Three of 6 lung transplant recipients with NTM disease died compared with 6 of 37 colonized (hazard ratio, 7.0; 95% confidence interval, 1.5-31.5; P = 0.003). CONCLUSIONS: Among SOT patients, NTM were most frequently identified from lung transplant recipients. NTM infection was not associated with increased mortality, although NTM disease was associated with increased mortality compared with colonization in lung transplant recipients. PMID- 26950721 TI - Summary of the British Transplantation Society UK Guidelines for Living Donor Liver Transplantation. AB - The British Transplantation Society Guidelines for Living Donor Liver Transplantation was published in July 2015 and is the first national guideline in the field of living donor liver transplantation. The guideline aims to review the evidence relating to the evaluation process of both recipient and donor candidates; address the moral and ethical issues surrounding the procedure; outline the technical aspects of the procedure, including the middle hepatic vein controversy and the "small for size syndrome"; review donor and recipient outcomes and complications including donor mortality; and examine evidence relating to the advantages and disadvantages of living donor liver transplantation. In line with previous guidelines published by the BTS, the guideline has used the Grading of Recommendations Assessment, Development and Evaluation system to rate the strength of evidence and recommendations. This article summarizes the Statements of Recommendation contained in the guideline, which provide a framework for the delivery of living liver donation in the United Kingdom and may be of wide international interest. It is recommended that the full guideline document is consulted for details of the relevant references and evidence base. This may be accessed at http://www.bts.org.uk/BTS/Guidelines_Standards/Current/BTS/Guidelines_Standards/C rrent_Guidelines.aspx?hkey=e285ca32-5920-4613-ac08-fa9fd90915b5. PMID- 26950720 TI - Virtual HLA Crossmatching as a Means to Safely Expedite Transplantation of Imported Pancreata. AB - BACKGROUND: Imported pancreata accumulate cold ischemia time (CIT), limiting utilization and worsening outcomes. Flow cytometric crossmatching (FXM) is a standard method to assess recipient and donor compatibility, but can prolong CIT. Single-antigen bead assays allow for detection of recipient donor-specific HLA antibodies, enabling prediction of compatibility through a "virtual crossmatch" (VXM). This study investigates the utility and outcomes of VXM after transplantation of imported pancreata. METHODS: We retrospectively compared outcomes of 153 patients undergoing pancreas transplantation at our institution over a 3.5-year period. RESULTS: Three patient groups were analyzed based on geographic source of the pancreas graft and the type of prospective crossmatch performed: (1) imported VXM-only, n = 39; (2) imported VXM + FXM, n = 12; and (3) local VXM + FXM, n = 102. There were no episodes of hyperacute rejection and 1 episode of early antibody-mediated rejection (<90 days) in the imported VXM group. Death-censored graft survival, patient survival, and rejection rates were comparable among the recipient groups. For pancreata imported from United Network of Organ Sharing regions 3 and 4, proceeding to surgery without an FXM reduced CIT by 5.1 hours (P < 0.001). The time from organ arrival at the hospital to operation start was significantly shorter in the VXM-only group compared with the VXM + FXM group (P < 0.001). CONCLUSIONS: Virtual crossmatch helps minimize CIT without increasing rejection or adversely affecting graft survival, making it a viable method to increase pancreas graft utilization across distant organ sharing regions. PMID- 26950718 TI - Pretransplant Midodrine Use: A Newly Identified Risk Marker for Complications After Kidney Transplantation. AB - BACKGROUND: Midodrine is prescribed to prevent symptomatic hypotension and decrease complications associated with hypotension during dialysis. We hypothesized that midodrine use before kidney transplantation may be a novel marker for posttransplant risk. METHODS: We analyzed integrated national US transplant registry, pharmacy records, and Medicare claims data for 16 308 kidney transplant recipients transplanted 2006 to 2008, of whom 308 (1.9%) had filled midodrine prescriptions in the year before transplantation. Delayed graft function (DGF), graft failure, and patient death were ascertained from the registry. Posttransplant cardiovascular complications were identified using diagnosis codes on Medicare billing claims. Adjusted associations of pretransplant midodrine use with complications at 3 and 12 months posttransplant were quantified by multivariate Cox or logistic regression, including propensity for midodrine exposure. RESULTS: At 3 months, patients who used midodrine pretransplant had significantly (P < 0.05) higher rates of DGF, 32% versus 19%; hypotension, 14% versus 4%; acute myocardial infarction, 4% versus 2%; cardiac arrest, 2% versus 0.9%, graft failure, 5% versus 2%; and death, 4% versus 1% than nonusers. After multivariate adjustment including recipient and donor factors, as well as for the propensity of midodrine exposure, pretransplant midodrine use was independently associated with risks of DGF (adjusted odds ratio, 1.78; 95% confidence interval [CI], 1.36-2.32), and 3 month death-censored graft failure (adjusted hazard ratio, 2.0; 95% CI, 1.18-3.39), and death (adjusted hazard ratio, 3.49; 95% CI, 1.95-6.24). Patterns were similar at 12 months. CONCLUSIONS: Although associations may in part reflect underlying conditions, the need for midodrine before kidney transplantation is a risk marker for complications including DGF, graft failure, and death. PMID- 26950722 TI - Sofosbuvir-Based Antiviral Therapy Is Highly Effective In Recurrent Hepatitis C in Liver Transplant Recipients: Canadian Multicenter "Real-Life" Experience. AB - BACKGROUND: This study evaluates the efficacy, safety, and tolerability of regimens containing sofosbuvir (SOF) in the treatment of hepatitis C virus (HCV) recurrence in all genotypes in patients outside of clinical trials in all Canadian transplant centers. METHODS: One hundred twenty liver transplantation recipients from across Canada with HCV recurrence were started on SOF-based regimens (SOF + simeprevir +/- ribavirin (RBV), n = 53; SOF + pegylated interferon + RBV, n = 25; SOF + RBV, n = 36; and SOF + ledipasvir, n = 6) between January and November 2014. Mean age 58 +/- 6.85 years, majority (83%) were genotype 1, male (81%), and treatment experienced (82%). Twenty-seven percent had fibrosing cholestatic hepatitis/early aggressive HCV in the graft, and 48% had F3/4 fibrosis. The primary outcomes included patient and graft survival, on- and end-of-treatment response and sustained virological response at 12 weeks after treatment end (SVR12), and adverse events. RESULTS: One hundred thirteen of 120 (94%) patients were HCV RNA undetectable at end of treatment, and SVR12 was achieved in 102/120 (85%) patients, with 7 relapses, 1 nonresponder, and 10 deaths (liver-related complications). Sixty-three percent had HCV RNA levels below the lower limit of quantification at week 4. Serum creatinine levels remained stable throughout the treatment. Severe anemia occurred in 13% of patients, primarily in RBV-based regimens. CONCLUSIONS: Sofosbuvir-based antiviral therapy for HCV recurrence after liver transplantation was well tolerated, with an overall high SVR12 rate (85%) including patients with severe disease recurrence and F3-4 cirrhosis. The response rate was higher (91%) in mild HCV recurrence, suggesting earlier treatment might be beneficial. PMID- 26950723 TI - Short Oxygenated Warm Perfusion With Prostaglandin E1 Administration Before Cold Preservation as a Novel Resuscitation Method for Liver Grafts From Donors After Cardiac Death in a Rat In Vivo Model. AB - BACKGROUND: We previously demonstrated that short oxygenated warm perfusion (SOWP) prevented warm ischemia-reperfusion injury in rat livers from donors after cardiac death (DCDs) in an ex vivo model. In the present study, we aimed to examine the in vivo effects of SOWP and SOWP with prostaglandin E1 (PGE1) in DCD rat liver transplants. METHODS: We performed liver transplantation after 6-hour cold preservation using grafts retrieved from DCD rats, divided into nontreatment (NT), SOWP, and SOWP with PGE1 (SOWP + PG) treatment groups. The SOWP grafts were perfused with oxygenated buffer at 37 degrees C for 30 minutes before cold preservation. Prostaglandin E1 was added to the SOWP + PG group perfusate. Eleven liver transplants from each group were performed to evaluate graft function and survival; 5 rats were used for data collection after 1-hour reperfusion, and 6 rats were used for the survival study. As a positive control, the same experiment was performed in a heart-beating donor group. RESULTS: In both the SOWP and SOWP + PG groups, serum liver enzymes, intercellular adhesion molecule 1 levels, and cellular damage were significantly decreased compared with the NT group. In the SOWP + PG group, bile production and energy status were significantly improved compared with the NT group. The 4-week survival was 0% (0/6), 67% (4/6), 83% (5/6), and 100% (6/6) in the NT, SOWP, SOWP + PG, and heart-beating donor group, respectively. CONCLUSIONS: Short oxygenated warm perfusion before cold preservation and the addition of PGE1 to SOWP were thus beneficial in an in vivo rat model. PMID- 26950724 TI - High Intrapatient Tacrolimus Variability Is Associated With Worse Outcomes in Renal Transplantation Using a Low-Dose Tacrolimus Immunosuppressive Regime. AB - BACKGROUND: High intrapatient tacrolimus variability has been associated with worse clinical outcomes postrenal transplantation. Theoretically, tacrolimus levels consistently outside the target therapeutic window may result in allograft dysfunction as subtherapeutic tacrolimus levels predispose to episodes of acute rejection, whereas supratherapeutic levels may cause nephrotoxicity. METHODS: We investigated the effect of tacrolimus variability in a "Symphony" style low-dose tacrolimus based regime, by collecting data from 432 patients over a 4-year period.Three hundred seventy-six patients were included, with a mean follow-up of 1495 days. Tacrolimus variability 6 to 12 months after renal transplantation was calculated, and outcomes were compared in low (n = 186) and high variability (n = 190) groups. RESULTS: High variability patients were found to be at increased risk of rejection during the first posttransplant year (P = 0.0054) and to have reduced rejection-free survival (hazard ratio, 1.953; 95% confidence interval, 1.234-3.093; P = 0.0054). High variability patients had significantly worse (P < 0.0001) glomerular filtration rates at 1, 2, 3, and 4 years posttransplant. High variability patients were at increased risk of allograft loss (hazard ratio, 4.928; 95% confidence interval, 2.050-11.85; P = 0.0004). CONCLUSIONS: This suggests that highly variable tacrolimus levels predict worse outcomes postrenal transplantation, although the causal nature of this relationship remains unclear. High tacrolimus variability may identify a subset of patients who warrant increased surveillance and patient education regarding dietary and medication compliance. PMID- 26950725 TI - Severe Skin Complications After Small Bowel Transplantation: Graft-Versus-Host Disease, DRESS, Virus, or Drug Toxicity? AB - BACKGROUND: Severe skin problems are uncommon after small bowel transplantation. Differential diagnosis includes drug reactions, infections, graft-versus-host disease (GVHD), and mixed diseases. Early diagnosis and treatment are determinant for prognosis. METHODS AND RESULTS: We describe 6 patients with severe cutaneous complications after small bowel transplantation, the work-up, final diagnosis, and evolution. Two patients died from chronic GVHD or unrecognized drug rash with eosinophilia and systemic symptoms, the others recovered completely. In 2 patients, drugs and viruses could be implicated, and in 1 patient may have hidden or triggered chronic GVHD. Viruses (human herpesvirus 6, Epstein-Barr virus, and cytomegalovirus) were suspected to trigger drug rash with eosinophilia and systemic symptoms or GVHD. The 2 cases of acute GVHD were reversed completely by increased immunosuppression and anti-interleukin-2 receptor antibody. DISCUSSION: In these severe cases, diagnosis is urgent and should include a careful evaluation of drug history, clinical presentation, biological investigations, infections, and toxic screening. A skin biopsy and chimerism study should be performed whenever possible. An early treatment is key to a positive outcome. PMID- 26950726 TI - Ischemia-Reperfusion Injury in Fatty Liver Is Mediated by Activated NADPH Oxidase 2 in Rats. AB - BACKGROUND: Liver ischemia-reperfusion (I/R) injury is a severe complication of liver surgery, and steatosis is a risk factor for liver damage. Reactive oxygen species generated by nicotinamide adenine dinucleotide phosphate oxidase (NOX) contribute to liver dysfunction. Here we examined the role of NOX in I/R injury of fatty livers. METHODS: Rats were fed a methionine and choline-deficient diet to induce a fatty liver. Rats then underwent surgically induced partial hepatic ischemia followed by reperfusion. RESULTS: The overall survival rate after I/R was lower in rats with fatty livers than with normal livers (P < 0.01). Necrotic area and the concentrations of 8-hydroxy-2'-deoxyguanosine (8-OHdG), TNFalpha, and IL-6 were higher in fatty liver tissue than in normal liver tissue (P < 0.01). The number of p47phox-positive cells was significantly higher in fatty liver tissue than in normal liver tissue after reperfusion and peaked 24 hours after reperfusion. The number of TLR-4 positive cells was significantly higher in fatty liver tissue than in normal liver tissue after reperfusion and peaked 4 and 24 hours after reperfusion coupled with a decreased number of high-mobility group box 1-positive hepatocytes. Apocynin significantly improved the survival rate, necrotic area, and concentrations of 8-hydroxy-2'-deoxyguanosine, TNFalpha, and IL-6 (P < 0.01). The protective effect of apocynin on fatty livers was greater than on normal livers. CONCLUSIONS: Ischemia-reperfusion injury was associated with increased high-mobility group box 1, TLR4, and NOX2. Inhibition of NOX activity improved oxidative stress and may prevent I/R injury in fatty liver. PMID- 26950728 TI - Reported Nonadherence to Immunosuppressive Medication in Young Adults After Heart Transplantation: A Retrospective Analysis of a National Registry. AB - BACKGROUND: Young adult heart transplantation (HTx) recipients experience high mortality risk attributed to increased nonadherence to immunosuppressive medication in this age window. This study sought to test whether a high-risk age window in HTx recipients persisted in the absence of reported nonadherence. METHODS: Heart transplantation recipients aged 2 to 40 years, transplanted between October 1999 and January 2007, were identified in the United Network for Organ Sharing database. Multivariable survival analysis was used to estimate influences of age at transplantation and attained posttransplant age on mortality hazard among patients stratified by center report of nonadherence to immunosuppression that compromised recovery. RESULTS: Three thousand eighty-one HTx recipients were included, with univariate analysis demonstrating peak hazards of mortality and reported nonadherence among 567 patients transplanted between ages 17 and 24 years. Multivariable analysis adjusting for reported nonadherence demonstrated lower mortality among patients transplanted at younger (hazards ratio, 0.813; 95% confidence interval, 0.663-0.997; P = 0.047) or older (hazards ratio, 0.835; 95% confidence interval, 0.701-0.994; P = 0.042) ages. Peak mortality hazard at ages 17 to 24 years was confirmed in the subgroup of patients with no nonadherence reported during follow-up. This result was replicated using attained age after HTx as the time metric, with younger and older ages predicting improved survival in the absence of reported nonadherence. CONCLUSIONS: Late adolescence and young adulthood coincide with greater mortality hazard and greater chances of nonadherence to immunosuppressive medication after HTx, but the elevation of mortality hazard in this age range persists in the absence of reported nonadherence. Other causes of the high-risk age window for post-HTx mortality should be demonstrated to identify opportunities for intervention. PMID- 26950727 TI - Nox2 and Cyclosporine-Induced Renal Hypoxia. AB - BACKGROUND: We hypothesized that nicotinamide adenosine diphosphate oxidase 2 (Nox2) plays an important role in cyclosporine A (CsA)-induced chronic hypoxia. METHODS: We tested this hypothesis in Fisher 344 rats, C57BL/6 J wild type and Nox2-/- mice, and in liver transplant recipients with chronic CsA nephrotoxicity. We used noninvasive molecular imaging (blood oxygen level-dependent magnetic resonance imaging and dynamic contrast-enhanced magnetic resonance imaging) and molecular diagnostic tools to assess intrarenal oxygenation and perfusion, and the molecular phenotype of CsA nephrotoxicity. RESULTS: We observed that chemical and genetic inhibition of Nox2 in rats and mice resulted in the prevention of CsA induced hypoxia independent of regional perfusion (blood oxygen level-dependent magnetic resonance imaging and dynamic contrast-enhanced magnetic resonance imaging, pimonidazole, HIF-1alpha). Nicotinamide adenosine diphosphate oxidase 2 knockout was also associated with decreased oxidative stress (Nox2, HIF-1alpha, hydrogen peroxide, hydroxynonenal), and fibrogenesis (alpha-smooth muscle actin, picrosirius red, trichrome, vimentin). The molecular signature of chronic CsA nephrotoxicity using transcriptomic analyses demonstrated significant changes in 40 genes involved in injury repair, metabolism, and oxidative stress in Nox2-/- mice. Immunohistochemical analyses of kidney biopsies from liver transplant recipients with chronic CsA nephrotoxicity showed significantly greater Nox2, alpha-smooth muscle actin and picrosirius levels compared with controls. CONCLUSIONS: These studies suggest that Nox2 is a modulator of CsA-induced hypoxia upstream of HIF-1alpha and define the molecular characteristics that could be used for the diagnosis and monitoring of chronic calcineurin inhibitor nephrotoxicity. PMID- 26950729 TI - Different Impact of the Number of Organ Failures and Graft-Versus-Host Disease on the Outcome of Allogeneic Stem Cell Transplantation Recipients Requiring Intensive Care. AB - BACKGROUND: Admission of allogeneic stem cell transplantation (SCT) recipients to the intensive care unit (ICU) remains controversial, especially when graft-versus host disease (GVHD) is present. METHODS: We performed a retrospective study to assess prognostic factors of survival in all allogeneic SCT recipients admitted to the ICU between 2002 and 2013 in our center which has flexible admission criteria, especially regarding GVHD. RESULTS: Of 349 patients who underwent allogeneic SCT during the study period, 92 patients (26%) were admitted to the ICU. Intensive care unit and hospital discharge rates were 66% and 46%, respectively, whereas 1 year survival was 24%. Acute GVHD, either grade III to IV (30 patients, 33%) or refractory (12 patients, 13%) had a nonsignificant impact on hospital mortality (odds ratio [OR], 2.1; P = 0.1; OR, 5, P = 0.05, respectively). Fifty percent of patients required invasive mechanical ventilation, 30% required vasopressors, 17% required renal replacement therapy, and 28% had liver impairment (bilirubin >34 MUmol/L), each of these parameters defining organ failure. Mortality was closely associated with the number of organ failures as hospital discharge rates were 69%, 50%, 42%, and 0% among patients with 0 (26 patients), 1 (26 patients), 2 (26 patients), and 3 to 4 (14 patients) organ failures, respectively (OR, 2.7; 95% confidence interval, 1.6-4.6; P < 0.001 according to the number of organ failures). CONCLUSIONS: Early mortality of allogeneic SCT recipients admitted to the ICU is especially influenced by the number of organ failures and therefore patients with 0 to 2 organ failures should be considered if required. Refractory GVHD affects survival but not within the confined ICU admission. PMID- 26950730 TI - Scratching and IVF: any role? AB - PURPOSE OF REVIEW: To review updated information on the influence of endometrial scratching on IVF. RECENT FINDINGS: Endometrial receptivity remains an important rate-limiting step affecting the success of IVF. The current evidence on the effect of endometrial scratching on IVF ranges from marked improvement, no difference to a potentially negative impact. The heterogeneity of studies presents a challenge in interpretation of data for routine clinical practice. SUMMARY: Endometrial scratching performed in the preceding cycle is associated with improved clinical pregnancy and live birth rates in women with recurrent implantation failure, but not in unselected subfertile women undergoing IVF. Most of the current literature are underpowered and at high risk of bias. PMID- 26950731 TI - Performance of time-varying predictors in multilevel models under an assumption of fixed or random effects. AB - Time-varying predictors in multilevel models are a useful tool for longitudinal research, whether they are the research variable of interest or they are controlling for variance to allow greater power for other variables. However, standard recommendations to fix the effect of time-varying predictors may make an assumption that is unlikely to hold in reality and may influence results. A simulation study illustrates that treating the time-varying predictor as fixed may allow analyses to converge, but the analyses have poor coverage of the true fixed effect when the time-varying predictor has a random effect in reality. A second simulation study shows that treating the time-varying predictor as random may have poor convergence, except when allowing negative variance estimates. Although negative variance estimates are uninterpretable, results of the simulation show that estimates of the fixed effect of the time-varying predictor are as accurate for these cases as for cases with positive variance estimates, and that treating the time-varying predictor as random and allowing negative variance estimates performs well whether the time-varying predictor is fixed or random in reality. Because of the difficulty of interpreting negative variance estimates, 2 procedures are suggested for selection between fixed-effect and random-effect models: comparing between fixed-effect and constrained random effect models with a likelihood ratio test or fitting a fixed-effect model when an unconstrained random-effect model produces negative variance estimates. The performance of these 2 procedures is compared. (PsycINFO Database Record PMID- 26950732 TI - Proteomic Analysis of the Secretome of Cellulomonas fimi ATCC 484 and Cellulomonas flavigena ATCC 482. AB - The bacteria in the genus Cellulomonas are known for their ability to degrade plant cell wall biomass. Cellulomonas fimi ATCC 484 and C. flavigena ATCC 482 have been the subject of much research into secreted cellulases and hemicellulases. Recently the genome sequences of both C. fimi ATCC 484 and C. flavigena ATCC 482 were published, and a genome comparison has revealed their full spectrum of possible carbohydrate-active enzymes (CAZymes). Using mass spectrometry, we have compared the proteins secreted by C. fimi and C. flavigena during growth on the soluble cellulose substrate, carboxymethylcellulose (CMC), as well as a soluble xylan fraction. Many known C. fimi CAZymes were detected, which validated our analysis, as were a number of new CAZymes and other proteins that, though identified in the genome, have not previously been observed in the secretome of either organism. Our data also shows that many of these are co expressed on growth of either CMC or xylan. This analysis provides a new perspective on Cellulomonas enzymes and provides many new CAZyme targets for characterization. PMID- 26950733 TI - Genome-Wide Search for Host Association Factors during Ovine Progressive Pneumonia Virus Infection. AB - Ovine progressive pneumonia virus (OPPV) is an important virus that causes serious diseases in sheep and goats with a prevalence of 36% in the USA. Although OPPV was discovered more than half of a century ago, little is known about the infection and pathogenesis of this virus. In this report, we used RNA-seq technology to conduct a genome-wide probe for cellular factors that are associated with OPPV infection. A total of approximately 22,000 goat host genes were detected of which 657 were found to have been significantly up-regulated and 889 down-regulated at 12 hours post-infection. In addition to previously known restriction factors from other viral infections, a number of factors which may be specific for OPPV infection were uncovered. The data from this RNA-seq study will be helpful in our understanding of OPPV infection, and also for further study in the prevention and intervention of this viral disease. PMID- 26950734 TI - Loss of CD28 on Peripheral T Cells Decreases the Risk for Early Acute Rejection after Kidney Transplantation. AB - BACKGROUND: End-stage renal disease patients have a dysfunctional, prematurely aged peripheral T-cell system. Here we hypothesized that the degree of premature T-cell ageing before kidney transplantation predicts the risk for early acute allograft rejection (EAR). METHODS: 222 living donor kidney transplant recipients were prospectively analyzed. EAR was defined as biopsy proven acute allograft rejection within 3 months after kidney transplantation. The differentiation status of circulating T cells, the relative telomere length and the number of CD31+ naive T cells were determined as T-cell ageing parameters. RESULTS: Of the 222 patients analyzed, 30 (14%) developed an EAR. The donor age and the historical panel reactive antibody score were significantly higher (p = 0.024 and p = 0.039 respectively) and the number of related donor kidney transplantation was significantly lower (p = 0.018) in the EAR group. EAR-patients showed lower CD4+CD28null T-cell numbers (p<0.01) and the same trend was observed for CD8+CD28null T-cell numbers (p = 0.08). No differences regarding the other ageing parameters were found. A multivariate Cox regression analysis showed that higher CD4+CD28null T-cell numbers was associated with a lower risk for EAR (HR: 0.65, p = 0.028). In vitro, a significant lower percentage of alloreactive T cells was observed within CD28null T cells (p<0.001). CONCLUSION: Immunological ageing related expansion of highly differentiated CD28null T cells is associated with a lower risk for EAR. PMID- 26950736 TI - Zika Virus: A New Epidemic on Our Doorstep. AB - Zika virus, a flavivirus transmitted to humans by mosquitoes of the genus Aedes, was first described in humans as isolated cases in Africa. Outbreaks have been reported outside that region since 2007, followed by its gradual introduction to different geographical areas. In 2015, Zika virus was detected in Brazil, from where it is rapidly expanding in the continent; the first case in Mexico was detected in October 2015. Initially deemed as a cause of mild illness, confirmation of microcephaly cases associated with this infection in Brazil have resulted in the World Health Organization declaration of Zika virus infection as a Public Health Emergency of International Concern. The US Centers for Disease Control and Prevention issued travel alerts for countries with declared cases. The vector is widely distributed in Mexico and control measures are the most effective means for prevention, not only of Zika virus, but also dengue and chikungunya. PMID- 26950735 TI - Solutions that enable ablative radiotherapy for large liver tumors: Fractionated dose painting, simultaneous integrated protection, motion management, and computed tomography image guidance. AB - The emergence and success of stereotactic body radiation therapy (SBRT) for the treatment of lung cancer have led to its rapid adoption for liver cancers. SBRT can achieve excellent results for small liver tumors. However, the vast majority of physicians interpret SBRT as meaning doses of radiation (range, 4-20 Gray [Gy]) that may not be ablative but are delivered within about 1 week (ie, in 3-6 fractions). Adherence to this approach has limited the effectiveness of SBRT for large liver tumors (>7 cm) because of the need to reduce doses to meet organ constraints. The prognosis for patients who present with large liver tumors is poor, with a median survival <=12 months, and most of these patients die from tumor-related liver failure. Herein, the authors present a comprehensive solution to achieve ablative SBRT doses for patients with large liver tumors by using a combination of classic, modern, and novel concepts of radiotherapy: fractionation, dose painting, motion management, image guidance, and simultaneous integrated protection. The authors discuss these concepts in the context of large, inoperable liver tumors and review how this approach can substantially prolong survival for patients, most of whom otherwise have a very poor prognosis and few effective treatment options. Cancer 2016;122:1974-86. (c) 2016 American Cancer Society. PMID- 26950737 TI - Nicotine Addiction Development: From Epidemiology to Genetic Factors. AB - BACKGROUND: Nicotine addiction is a complex and multifactorial disease affecting the central nervous system and consists of a set of characteristic symptoms and signs. OBJECTIVE: The objective of this study was to provide an overview on smoking and the complexity of dependency, with special emphasis on the involvement of genetic factors, including neurexin and nicotinic cholinergic receptor genes. METHODS: The following two aspects are discussed in the present article: (i) epidemiology in Mexico; and (ii) a review of the published literature on genetic association studies using the National Center for Biotechnology Information (NCBI) database of the USA as a search tool. The search key words were: nicotine, smoking, dependence, genetic, tobacco, neurobiology and GWAS. The publication period of the reviewed articles was January 2005 to July 2015. RESULTS: There are numerous studies that provide evidence of the involvement of a genetic component that contributes to the risk of developing nicotine addiction, but the multifactorial nature of addiction requires coordinated research from multiple disciplines. CONCLUSION: Research is needed on the factors associated with genetic risk for nicotine addiction and their interaction with environmental factors. PMID- 26950738 TI - Serous Cystadenomas Follow a Benign and Asymptomatic Course and Do Not Present a Significant Size Change During Follow-Up. AB - BACKGROUND: Serous cystadenoma is a benign pancreatic cystic neoplasm. Conservative management is favored. We studied the clinical characteristics and course of serous cystadenoma in patients undergoing surgery or conservative management only at an academic referral center. METHODS: Patients presenting with serous cystadenoma in the years 2000-2013 were selected. Hospital records were evaluated for patient and serous cystadenoma characteristics. RESULTS: A total of 22 patients with serous cystadenoma were identified. Mean age at diagnosis was 63 years and 82% were women. Diagnosis was incidental in 59%, and 18% presented with unspecific abdominal pain, 14% unexplained weight loss, 4.5% gastrointestinal obstructive symptoms, and 4.5% cholangitis. Location was pancreas body 36%, head 32%, tail 23%, and uncinate 9%. Mean serous cystadenoma diameter at diagnosis was 37 +/- 23 mm. After diagnosis five patients underwent surgery. Initial size was similar between surgical and follow-up groups (p = 0.9). Four cases were lost to follow-up; 13 continued conservative management with a mean follow-up time of 54 +/- 27 months. The initial and last serous cystadenoma size in the follow-up group remained similar (p = 0.9). Six cases presented significant tumor growth during follow-up (p > 0.05). All patients remained asymptomatic throughout follow up. No malignancy or serous cystadenoma-related death occurred. CONCLUSIONS: Size change of serous cystadenoma was minimal and patients remained asymptomatic during follow-up. Surgery should be limited to symptomatic and selected cases. PMID- 26950739 TI - Study of Anticoagulant, Procoagulant, and Fibrinolytic Pathways in Mexican Patients With Paroxysmal Nocturnal Hemoglobinuria. AB - BACKGROUND: In Mexico, the frequency of thromboembolic events associated to paroxysmal nocturnal hemoglobinuria is 3%; a clone size > 50% in granulocytes has been associated with a higher risk of thromboembolic events. METHODS: Between 2001 and 2012, 40 patients with paroxysmal nocturnal hemoglobinuria were studied. In 12 cases anticoagulant, procoagulant, and fibrinolytic pathways were analyzed. RESULTS: Only two of 40 patients (5%) developed a thromboembolic event over a 25.5-year follow-up period. From 12 patients, 91.7% had a paroxysmal nocturnal hemoglobinuria clone > 50% in granulocytes and 83.3% a clone > 50 % in monocytes. Five of 12 cases had elevated FV levels and four showed increased FVIII, von Willebrand factor antigen, von Willebrand factor ristocetin cofactor activity and FX. Protein S and protein C were decreased in nine and three patients, respectively. Only antithrombin correlated positively with paroxysmal nocturnal hemoglobinuria clone size in monocytes (p = 0.0442), whereas von Willebrand factor ristocetin cofactor correlated negatively with lactic dehydrogenase levels (p = 0.0186). No statistically significant associations were recorded with all other factors. CONCLUSION: The low frequency of thromboembolic events in Mexican patients could partly be explained by the associations between anticoagulant system (antithrombin) with paroxysmal nocturnal hemoglobinuria monocyte clone size, and procoagulant system (von Willebrand factor ristocetin cofactor) with lactic dehydrogenase levels. PMID- 26950740 TI - Randomized Phase II Study of Talc Versus Iodopovidone for the Prevention of Seroma Formation Following Modified Radical Mastectomy. AB - BACKGROUND: The most common complication following modified radical mastectomy is seroma formation. Numerous approaches have been attempted to prevent this complication, ranging from the use of chemical substances to mechanical means, and none of these have proven to be consistently reliable. AIM: The aim of this study was to evaluate the safety and efficacy of talc in preventing postoperative seromas compared with iodine and standard care. METHODS: Patients with breast cancer undergoing modified radical mastectomy were randomly assigned to one of three study groups: control, subcutaneous talc, or iodine application. The primary endpoint was frequency of seroma formation. Secondary outcomes included wound complications (surgical site infection, flap necrosis, and wound dehiscence), analgesic use, postoperative pain, total drain outputs, and drainage duration. RESULTS: Of the 86 patients randomized in the study, 80 were analyzed. After interim analysis, the iodine intervention was discontinued because of increased adverse outcomes (drainage duration and total amount of fluid drained). Talc failed to demonstrate that its application in subcutaneous breast tissue prevents seroma formation (19.4% for talc group vs. 23.3% for control group; p = 0.70). However, patients who developed seroma in the talc group had fewer aspirations per patient seroma and less volume drained when compared with the control group (88.2 +/- 73 vs. 158.3 +/- 90.5; p = 0.17). CONCLUSIONS: Subcutaneous talc application was safe in the short term, but there was not sufficient evidence to support its use for seroma prevention following modified radical mastectomy in patients with breast cancer. PMID- 26950741 TI - Altitude Above Sea Level and Body Mass Index as Determinants of Oxygen Saturation in Children: The SON@ Study. AB - BACKGROUND: Altitude above sea level and body mass index are well-recognized determinants of oxygen saturation in adult populations; however, the contribution of these factors to oxygen saturation in children is less clear. OBJECTIVE: To explore the contribution of altitude above sea level and body mass index to oxygen saturation in children. METHODS: A multi-center, cross-sectional study conducted in nine cities in Mexico. Parents signed informed consent forms and completed a health status questionnaire. Height, weight, and pulse oximetry were recorded. RESULTS: We studied 2,200 subjects (52% girls) aged 8.7 +/- 3.0 years. Mean body mass index, z-body mass index, and oxygen saturation were 18.1 +/- 3.6 kg.m-2, 0.58 +/- 1.3, and 95.5 +/- 2.4%, respectively. By multiple regression analysis, altitude proved to be the main predictor of oxygen saturation, with non significant contributions of age, gender, and body mass index. According to quantile regression, the median estimate of oxygen saturation was 98.7 minus 1.7% per km of altitude above sea level, and the oxygen saturation fifth percentile 97.4 minus 2.7% per km of altitude. CONCLUSIONS: Altitude was the main determinant of oxygen saturation, which on average decreased 1.7% per km of elevation from a percentage of 98.7 at sea level. In contrast with adults, this study in children found no association between oxygen saturation and obesity or age. PMID- 26950742 TI - Decades of Experience in the Diagnosis of Dengue Fever in the Northwest of Mexico. AB - BACKGROUND: The State of Baja California Sur is in an arid region of Mexico, the southern half of the Baja California Peninsula. Given its aridity and physical isolation from mainland Mexico, there were no records of dengue fever in the state before 1985. Until now, no data on dengue incidence had been published. OBJECTIVE: To study some epidemiological features of dengue fever in Baja California Sur, Mexico in the last 30 years. METHODS: Total number of cases, general population, sex, age groups, serotypes, mortality, and incidence data were analyzed. RESULTS: There was a 652% increase in reported cases from 2012 through 2014. Age groups mostly affected were adults aged 15-24 and 45-64 years old. CONCLUSIONS: This study makes a thorough analysis of the incidence of dengue and makes recommendations to face the epidemiological challenge. PMID- 26950743 TI - Prevalence of Peanut, Tree Nut, Sesame, and Seafood Allergy in Mexican Adults. AB - OBJECTIVE: To identify the prevalence of perceived and probable allergic reactions to peanuts, tree nuts, sesame seed, or seafood and its association with the personal history of allergic disease. METHODS: A cross-sectional study was performed in four cities of the metropolitan area of Guadalajara, located in western Mexico. Through sampling by gender and age, 1,126 subjects were included. Using a structured questionnaire, we investigated: (i) history of atopic disease, (ii) perception of allergic reaction after food intake, and (iii) probable allergic reaction to peanuts, tree nuts, sesame, or seafood. Prevalence and 95% confidence intervals were calculated. A multivariate analysis of factors associated to perceived and probable allergic reactions to food was performed by logistic regression. RESULTS: Men were 49.8%; mean age was 28.1 years; personal history of atopic disease included: allergic rhinitis (6.9%), asthma (6.8%), and atopic dermatitis (3.8%). Prevalence of perceived and probable food allergy was, respectively: pecan 0.4 and 0.3%; peanut 0.6 and 0.6%; sesame 0.1 and 0.1%; shellfish 4.2 and 4.0% (mainly shrimp); mollusk 0.8 and 0.7%; fish 1.4 and 1.2%. Asthma was significantly associated with perceived and probable allergy to pecans, peanuts, fish, or seafood. Atopic dermatitis was associated with perceived and probable allergic reaction to sea snail, seafood, shellfish, or mollusks. Finally, allergic rhinitis was associated with allergy to shrimp and crustaceans. CONCLUSIONS: This study shows that the prevalence of peanut, tree nut, sesame seed, and seafood allergy in this Mexican population is similar to that reported in developed countries. PMID- 26950744 TI - A saposin-lipoprotein nanoparticle system for membrane proteins. AB - A limiting factor in membrane protein research is the ability to solubilize and stabilize such proteins. Detergents are used most often for solubilizing membrane proteins, but they are associated with protein instability and poor compatibility with structural and biophysical studies. Here we present a saposin-lipoprotein nanoparticle system, Salipro, which allows for the reconstitution of membrane proteins in a lipid environment that is stabilized by a scaffold of saposin proteins. We demonstrate the applicability of the method on two purified membrane protein complexes as well as by the direct solubilization and nanoparticle incorporation of a viral membrane protein complex from the virus membrane. Our approach facilitated high-resolution structural studies of the bacterial peptide transporter PeptTSo2 by single-particle cryo-electron microscopy (cryo-EM) and allowed us to stabilize the HIV envelope glycoprotein in a functional state. PMID- 26950745 TI - High-density three-dimensional localization microscopy across large volumes. AB - Extending three-dimensional (3D) single-molecule localization microscopy away from the coverslip and into thicker specimens will greatly broaden its biological utility. However, because of the limitations of both conventional imaging modalities and conventional labeling techniques, it is a challenge to localize molecules in three dimensions with high precision in such samples while simultaneously achieving the labeling densities required for high resolution of densely crowded structures. Here we combined lattice light-sheet microscopy with newly developed, freely diffusing, cell-permeable chemical probes with targeted affinity for DNA, intracellular membranes or the plasma membrane. We used this combination to perform high-localization precision, ultrahigh-labeling density, multicolor localization microscopy in samples up to 20 MUm thick, including dividing cells and the neuromast organ of a zebrafish embryo. We also demonstrate super-resolution correlative imaging with protein-specific photoactivable fluorophores, providing a mutually compatible, single-platform alternative to correlative light-electron microscopy over large volumes. PMID- 26950746 TI - T cell fate and clonality inference from single-cell transcriptomes. AB - We developed TraCeR, a computational method to reconstruct full-length, paired T cell receptor (TCR) sequences from T lymphocyte single-cell RNA sequence data. TraCeR links T cell specificity with functional response by revealing clonal relationships between cells alongside their transcriptional profiles. We found that T cell clonotypes in a mouse Salmonella infection model span early activated CD4(+) T cells as well as mature effector and memory cells. PMID- 26950747 TI - Tissue-specific regulatory circuits reveal variable modular perturbations across complex diseases. AB - Mapping perturbed molecular circuits that underlie complex diseases remains a great challenge. We developed a comprehensive resource of 394 cell type- and tissue-specific gene regulatory networks for human, each specifying the genome wide connectivity among transcription factors, enhancers, promoters and genes. Integration with 37 genome-wide association studies (GWASs) showed that disease associated genetic variants--including variants that do not reach genome-wide significance--often perturb regulatory modules that are highly specific to disease-relevant cell types or tissues. Our resource opens the door to systematic analysis of regulatory programs across hundreds of human cell types and tissues (http://regulatorycircuits.org). PMID- 26950748 TI - One-step fermentative production of poly(lactate-co-glycolate) from carbohydrates in Escherichia coli. AB - Poly(lactate-co-glycolate) (PLGA) is a widely used biodegradable and biocompatible synthetic polymer. Here we report one-step fermentative production of PLGA in engineered Escherichia coli harboring an evolved polyhydroxyalkanoate (PHA) synthase that polymerizes D-lactyl-CoA and glycolyl-CoA into PLGA. Introduction of the Dahms pathway enables production of glycolate from xylose. Deletion of ptsG enables simultaneous utilization of glucose and xylose. An evolved propionyl-CoA transferase converts D-lactate and glycolate to D-lactyl CoA and glycolyl-CoA, respectively. Deletion of adhE, frdB, pflB and poxB prevents by-product formation. We also demonstrate modulation of the monomer fractions in PLGA by overexpressing ldhA and deleting dld to increase the proportion of D-lactate or by deleting aceB, glcB, glcD, glcE, glcF and glcG to increase the proportion of glycolate. Incorporation of 2-hydroxybutyrate is prevented by deleting ilvA or feeding strains with L-isoleucine. The utility of our approach for generating diverse forms of PLGA is shown by the production of copolymers containing 3-hydroxybutyrate, 4-hydroxybutyrate or 2 hydroxyisovalerate. PMID- 26950749 TI - Targeted gene addition in human CD34(+) hematopoietic cells for correction of X linked chronic granulomatous disease. AB - Gene therapy with genetically modified human CD34(+) hematopoietic stem and progenitor cells (HSPCs) may be safer using targeted integration (TI) of transgenes into a genomic 'safe harbor' site rather than random viral integration. We demonstrate that temporally optimized delivery of zinc finger nuclease mRNA via electroporation and adeno-associated virus (AAV) 6 delivery of donor constructs in human HSPCs approaches clinically relevant levels of TI into the AAVS1 safe harbor locus. Up to 58% Venus(+) HSPCs with 6-16% human cell marking were observed following engraftment into mice. In HSPCs from patients with X-linked chronic granulomatous disease (X-CGD), caused by mutations in the gp91phox subunit of the NADPH oxidase, TI of a gp91phox transgene into AAVS1 resulted in ~15% gp91phox expression and increased NADPH oxidase activity in ex vivo-derived neutrophils. In mice transplanted with corrected HSPCs, 4-11% of human cells in the bone marrow expressed gp91phox. This method for TI into AAVS1 may be broadly applicable to correction of other monogenic diseases. PMID- 26950751 TI - Progression from Asthma to Chronic Obstructive Pulmonary Disease. Is Air Pollution a Risk Factor? AB - RATIONALE: Individuals with asthma-chronic obstructive pulmonary disease (COPD) overlap syndrome (ACOS), have more rapid decline in lung function, more frequent exacerbations, and poorer quality of life than those with asthma or COPD alone. Air pollution exposure is a known risk factor for asthma and COPD; however, its role in ACOS is not as well understood. OBJECTIVES: To determine if individuals with asthma exposed to higher levels of air pollution have an increased risk of ACOS. METHODS: Individuals who resided in Ontario, Canada, aged 18 years or older in 1996 with incident asthma between 1996 and 2009 who participated in the Canadian Community Health Survey were identified and followed until 2014 to determine the development of ACOS. Data on exposures to fine particulate matter (PM2.5) and ozone (O3) were obtained from fixed monitoring sites. Associations between air pollutants and ACOS were evaluated using Cox regression models. MEASUREMENTS AND MAIN RESULTS: Of the 6,040 adults with incident asthma who completed the Canadian Community Health Survey, 630 were identified as ACOS cases. Compared with those without ACOS, the ACOS population had later onset of asthma, higher proportion of mortality, and more frequent emergency department visits before COPD diagnosis. The adjusted hazard ratios of ACOS and cumulative exposures to PM2.5 (per 10 MUg/m(3)) and O3 (per 10 ppb) were 2.78 (95% confidence interval, 1.62-4.78) and 1.31 (95% confidence interval, 0.71-2.39), respectively. CONCLUSIONS: Individuals exposed to higher levels of air pollution had nearly threefold greater odds of developing ACOS. Minimizing exposure to high levels of air pollution may decrease the risk of ACOS. PMID- 26950753 TI - Toward an understanding of anticipatory pleasure deficits in schizophrenia: Memory, prospection, and emotion experience. AB - Anticipatory pleasure deficits have been observed in people with schizophrenia. Less is known about the extent to which interrelated processes that comprise anticipatory pleasure, including memory, prospection, and emotion experience are disrupted. We asked people with (n = 32) and without (n = 29) schizophrenia or schizoaffective disorder to provide memory and prospection narratives in response to specific cues. Half of the prospections followed a memory task, and half followed a control task. People with schizophrenia generated memories similar in content and experience as controls even as they described them less clearly. However, people with schizophrenia were less likely to explicitly reference the past in their prospections, and their prospections were less detailed and richly experienced than controls, regardless of the task completed before prospection. People with schizophrenia reported similar levels of positive emotion (current and predicted) in positive prospections that followed the memory task, but less positive emotion than controls in positive prospections that followed the control task. Taken together, these results suggest that people with schizophrenia experience difficulties drawing from past experiences and generating detailed prospections. However, asking people with schizophrenia to recall and describe memories prior to prospection may increase the likelihood of drawing from the past in prospections, and may help boost current and predicted pleasure. PMID- 26950755 TI - Investigating pyrolysis and combustion characteristics of torrefied bamboo, torrefied wood and their blends. AB - Bamboo and masson pine was torrefied with 300 degrees C of temperature for 2.0h of residence time using GSL 1600X tube furnace in the argon atmosphere. Torrefied bamboo and masson pine particles were uniform mixed with different weight ratios. Pyrolysis and combustion characteristics were investigated through thermogravimetry (TGA). The results showed that pyrolysis and combustion process of all samples included three steps even though their characteristics were different. Torrefied biomass had a higher pyrolysis and combustion temperature, due to moisture and volatile removal and thermal decomposition of hemicelluloses, cellulose and lignin during torrefaction process. Torrefaction also increased high heating value, ash content and C/H and C/O ratio of biomass. The synergy of torrefied bamboo and torrefied mason pine was not found during pyrolysis and combustion process of blends. The results from this research will be very important and helpful to develop and utilize the wastes of masson pine and bamboo for energy products. PMID- 26950754 TI - Combined Chemical Groups and Topographical Nanopattern on the Poly(epsilon Caprolactone) Surface for Regulating Human Foreskin Fibroblasts Behavior. AB - Surface chemistry and substrate topography could contribute significantly to providing a biochemical and topographical cues for governing the fate of cells on the cell-material interface. However, the synergies between these two properties have not been exploited extensively for biomaterial design. Herein, we achieved spatial-controlled patterning of chemical groups on the poly(epsilon caprolactone) (PCL) surface by elegant UV-nanoimprint lithography (UN-NIL). The introduction of chemical groups on the PCL surface was developed by our newly 6 benzyloxycarbonylmethyl-epsilon-caprolactone (BCL) monomer, which not only solved the lack of functional groups along the PCL chain but also retained the original favorable properties of PCL materials. The synergetic effect of the chemical groups and nanopatterns on the human foreskin fibroblasts (HFFs) behaviors was evaluated in detail. The results revealed that the patterned functional PCL surfaces could induce enhanced cell adhesion and proliferation, further trigger changes in HFFs morphology, orientation and collagen secretion. Taken together, this study provided a method for straightforward fabrication of reactive PCL surfaces with topographic patterns by one-step process, and they would facilitate PCL as potential candidate for cell cultivation and tissue engineering. PMID- 26950752 TI - Parasympathetic nervous system activity predicts mood repair use and its effectiveness among adolescents with and without histories of major depression. AB - Depressive disorders that onset in the juvenile years have been linked to far reaching adverse consequences, making it imperative to elucidate key mechanisms and contributory factors. Excessive use of regulatory responses that exacerbate sadness (maladaptive mood repair) or insufficient use of regulatory responses that reduce it (adaptive mood repair) may reflect behavioral mechanisms of depression risk. Cardiac vagal control, indexed by patterns of respiratory sinus arrhythmia (RSA), has received attention as a putative physiological risk factor for depression. Although mood repair and RSA are related, the nature of this relationship is not well characterized in the context of depression risk. Therefore, we tested alternative models of the relationships between RSA patterns (at rest and in response to a sad film), trait mood repair, and the effectiveness of a mood repair response in the laboratory (state mood repair) among adolescents with depression histories (n = 210) and emotionally healthy peers (n = 161). In our data, a mediation model best explained the association between the key constructs: Adolescents with normative RSA patterns exhibited lower levels of depression and trait maladaptive mood repair, and benefited more from instructed (state) mood repair in the laboratory. By contrast, adolescents with atypical RSA patterns exhibited higher levels of depression and dispositional maladaptive mood repair, which, in turn, mediated the relations of RSA patterns and depression symptoms. Atypical RSA patterns also predicted reduced benefits from laboratory mood repair. PMID- 26950756 TI - Ethanol production during semi-continuous syngas fermentation in a trickle bed reactor using Clostridium ragsdalei. AB - An efficient syngas fermentation bioreactor provides a mass transfer capability that matches the intrinsic kinetics of the microorganism to obtain high gas conversion efficiency and productivity. In this study, mass transfer and gas utilization efficiencies of a trickle bed reactor during syngas fermentation by Clostridium ragsdalei were evaluated at various gas and liquid flow rates. Fermentations were performed using a syngas mixture of 38% CO, 28.5% CO2, 28.5% H2 and 5% N2, by volume. Results showed that increasing the gas flow rate from 2.3 to 4.6sccm increased the CO uptake rate by 76% and decreased the H2 uptake rate by 51% up to Run R6. Biofilm formation after R6 increased cells activity with over threefold increase in H2 uptake rate. At 1662h, the final ethanol and acetic acid concentrations were 5.7 and 12.3g/L, respectively, at 200ml/min of liquid flow rate and 4.6sccm gas flow rate. PMID- 26950757 TI - Evaluation of hyper thermal acid hydrolysis of Kappaphycus alvarezii for enhanced bioethanol production. AB - Hyper thermal (HT) acid hydrolysis of Kappaphycus alvarezii, a red seaweed, was optimized to 12% (w/v) seaweed slurry content, 180mM H2SO4 at 140 degrees C for 5min. The maximum monosaccharide concentration of 38.3g/L and 66.7% conversion from total fermentable monosaccharides of 57.6g/L with 120gdw/L K. alvarezii slurry were obtained from HT acid hydrolysis and enzymatic saccharification. HT acid hydrolysis at a severity factor of 0.78 efficiently converted the carbohydrates of seaweed to monosaccharides and produced a low concentration of inhibitory compounds. The levels of ethanol production by separate hydrolysis and fermentation with non-adapted and adapted Kluyveromyces marxianus to high concentration of galactose were 6.1g/L with ethanol yield (YEtOH) of 0.19 at 84h and 16.0g/L with YEtOH of 0.42 at 72h, respectively. Development of the HT acid hydrolysis process and adapted yeast could enhance the overall ethanol fermentation yields of K. alvarezii seaweed. PMID- 26950758 TI - Enhancement of biohydrogen production from brewers' spent grain by calcined-red mud pretreatment. AB - This paper investigated the utilization of calcined-red mud (CRM) pretreatment to enhance fermentative hydrogen yields from brewers' spent grain (BSG). The BSG samples were treated with different concentrations (0.0-20g/L) of CRM at 55 degrees C for 48h, before the biohydrogen process with heat-treated anaerobic sludge inoculum. The highest specific hydrogen production of 198.62ml/g-VS was obtained from the BSG treated with 10g/L CRM, with the corresponding lag time of 10.60h. Hydrogen yield increments increased by 67.74%, compared to the control tests without CRM. The results demonstrated that the CRM could hydrolyze more cellulose and further provided adequate broth and suitable pH value for efficient fermentative hydrogen. The model-based analysis showed that the modified Gompertz model presented a better fit for the experimental data than the first-order model. PMID- 26950761 TI - Total Synthesis of Lycopalhine A. AB - The total synthesis of lycopalhine A has been accomplished. The synthesis features construction of the tricyclic system via cleavage of a cyclopropane ring and an ensuing intramolecular Michael addition, stereoselective introduction of a 2-aminoethyl moiety via a reaction of allyltrimethylsilane to a sulfonyliminium ion, and a stereoselective intramolecular aldol reaction. PMID- 26950759 TI - Phosphorylation or Mutation of the ERK2 Activation Loop Alters Oligonucleotide Binding. AB - The mitogen-activated protein kinase ERK2 is able to elicit a wide range of context-specific responses to distinct stimuli, but the mechanisms underlying this versatility remain in question. Some cellular functions of ERK2 are mediated through regulation of gene expression. In addition to phosphorylating numerous transcriptional regulators, ERK2 is known to associate with chromatin and has been shown to bind oligonucleotides directly. ERK2 is activated by the upstream kinases MEK1/2, which phosphorylate both tyrosine 185 and threonine 183. ERK2 requires phosphorylation on both sites to be fully active. Some additional ERK2 phosphorylation sites have also been reported, including threonine 188. It has been suggested that this phospho form has distinct properties. We detected some ERK2 phosphorylated on T188 in bacterial preparations of ERK2 by mass spectrometry and further demonstrate that phosphomimetic substitution of this ERK2 residue impairs its kinase activity toward well-defined substrates and also affects its DNA binding. We used electrophoretic mobility shift assays with oligonucleotides derived from the insulin gene promoter and other regions to examine effects of phosphorylation and mutations on the binding of ERK2 to DNA. We show that ERK2 can bind oligonucleotides directly. Phosphorylation and mutations alter DNA binding and support the idea that signaling functions may be influenced through an alternate phosphorylation site. PMID- 26950760 TI - A comparison of the effects of factor XII deficiency and prekallikrein deficiency on thrombus formation. AB - Studies with animal models implicate the plasma proteases factor XIIa (FXIIa) and alpha-kallikrein in arterial and venous thrombosis. As congenital deficiencies of factor XII (FXII) or prekallikrein (PK), the zymogens of FXIIa and alpha kallikrein respectively, do not cause bleeding disorders, inhibition of these enzymes may have therapeutic benefit without compromising hemostasis. The relative contributions of FXIIa and alpha-kallikrein to thrombosis in animal models are not clear. We compared mice lacking FXII or PK to wild type mice in established models of arterial thrombosis. Wild type mice developed carotid artery occlusion when the vessel was exposed to a 3.5% solution of ferric chloride (FeCl3). FXII-deficient mice were resistant to occlusion at 5% FeCl3 and partially resistant at 10% FeCl3. PK-deficient mice were resistant at 3.5% FeCl3 and partially resistant at 5% FeCl3. Mice lacking high molecular weight kininogen, a cofactor for PK activation and activity, were also partially resistant to thrombosis at 5% FeCl3. Induction of carotid artery thrombosis with Rose Bengal was delayed in FXII-deficient mice compared to wild type or PK deficient animals. In human plasma supplemented with silica, DNA or collagen to induce contact activation, an antibody to the FXIIa active site was more effective at preventing thrombin generation than an antibody to the alpha kallikrein active site. Similarly, the FXIIa antibody was more effective at reducing fibrin formation in human blood flowing through collagen coated-tubes. The findings suggest that inhibitors of FXIIa will have more potent anti thrombotic effects than inhibitors of alpha-kallikrein. PMID- 26950763 TI - Couples Work in Cultural Context: Te Ao Maori and Poststucturalist Practices Informing Counselor Training in Aotearoa New Zealand. AB - This article outlines key themes that appear in the teaching of poststructuralist ideas and practices for couples counseling within the Postgraduate Diploma in Counseling Program at Unitec Institute of Technology in Auckland, New Zealand, and it explores the congruence of this pedagogical approach with Maori (indigenous) understandings of relationality, collaboration, and partnership. The diploma program's curriculum includes narrative therapy and relational language making. Themes explored in this article include: understanding (heterosexual) couple relationships as contextualized entities, deconstructing dominant discourses of coupledom, and the positioning of counselors/teachers as nonexpert. Taking each theme in turn, the authors, one of them Maori and two Pakeha (European), articulate points of alignment with Maori cultural concepts and practices. PMID- 26950762 TI - Understanding transcriptional regulatory networks using computational models. AB - Transcriptional regulatory networks (TRNs) encode instructions for animal development and physiological responses. Recent advances in genomic technologies and computational modeling have revolutionized our ability to construct models of TRNs. Here, we survey current computational methods for inferring TRN models using genome-scale data. We discuss their advantages and limitations. We summarize representative TRNs constructed using genome-scale data in both normal and disease development. We discuss lessons learned about the structure/function relationship of TRNs, based on examining various large-scale TRN models. Finally, we outline some open questions regarding TRNs, including how to improve model accuracy by integrating complementary data types, how to infer condition-specific TRNs, and how to compare TRNs across conditions and species in order to understand their structure/function relationship. PMID- 26950764 TI - CXCR1 Regulates Pulmonary Anti-Pseudomonas Host Defense. AB - Pseudomonas aeruginosa is a key opportunistic pathogen causing disease in cystic fibrosis (CF) and other lung diseases such as chronic obstructive pulmonary disease (COPD). However, the pulmonary host defense mechanisms regulating anti-P. aeruginosa immunity remain incompletely understood. Here we demonstrate, by studying an airway P. aeruginosa infection model, in vivo bioluminescence imaging, neutrophil effector responses and human airway samples, that the chemokine receptor CXCR1 regulates pulmonary host defense against P. aeruginosa. Mechanistically, CXCR1 regulates anti-Pseudomonas neutrophil responses through modulation of reactive oxygen species and interference with Toll-like receptor 5 expression. These studies define CXCR1 as a novel, noncanonical chemokine receptor that regulates pulmonary anti-Pseudomonas host defense with broad implications for CF, COPD and other infectious lung diseases. PMID- 26950767 TI - Genetic characteristics of mumps viruses isolated in Korea from 2007 to 2012. AB - Mumps is a vaccine-preventable viral disease. Despite vaccine coverage of >95%, the incidence of mumps has increased in Korea since 2007. This study aimed to genetically characterize mumps virus (MuV) strains that circulated in Korea between 2007 and 2012 to determine the factors underlying mumps outbreaks. MuV was isolated from 175 clinical specimens between 2007 and 2012 in Korea. Upon analysis of the SH gene in Korean mumps virus isolates, three different genotypes were identified: I, H, and F. The MuV genotypes I and H co-circulated in Korea, and eight isolates of Korean genotype F were found within the same time period in 2008. An analysis of HN amino-acid sequence data showed that Korean isolates had no changes in their glycosylation sites. At putative neutralizing epitope sites, the Jeryl-Lynn strain showed 4-5 different amino acid sequences from those observed in Korean isolates. Korean isolates of genotypes I and H shared distinctive point mutations on putative neutralizing epitope positions in each genotype. This report describes the genetic characteristics of MuV strains circulating in Korea and provides information on endemic mumps infections. This information may be important to help prevent mumps and control outbreaks of mumps in Korea. J. Med. Virol. 88:1479-1486, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26950768 TI - Optimal Displacement Parameters in Monte Carlo Simulations. AB - An adaptive algorithm optimizing single-particle translational displacement parameters in Metropolis Monte Carlo simulations is presented. The optimization is based on maximizing the mean square displacement of a trial move. It is shown that a large mean square displacement is strongly correlated with a high precision of average potential energy. The method is here demonstrated on model systems representing a Lennard-Jones fluid and a dilute polymer solution at poor solvent conditions. Our adaptive algorithm removes the need to provide values of displacement parameters in simulations, and it is easily extendable to optimize parameters of other types of trial moves. PMID- 26950766 TI - The impact on hospital resource utilisation of treatment of hepatic encephalopathy with rifaximin-alpha. AB - BACKGROUND & AIMS: Rifaximin-alpha reduces the risk of recurrence of overt hepatic encephalopathy. However, there remain concerns regarding the financial cost of the drug. We aimed to study the impact of treatment with rifaximin-alpha on healthcare resource utilisation using data from seven UK liver treatment centres. METHODS: All seven centres agreed a standardised data set and data characterising clinical, demographic and emergency hospital admissions were collected retrospectively for the time periods 3, 6 and 12 months before and following initiation of rifaximin-alpha. Admission rates and hospital length of stay before and during therapy were compared. Costs of admissions and drug acquisition were estimated using published sources. Multivariate analyses were carried out to assess the relative impact of various factors on hospital length of stay. RESULTS: Data were available from 326 patients. Following the commencement of rifaximin, the total hospital length of stay reduced by an estimated 31-53%, equating to a reduction in inpatient costs of between L4858 and L6607 per year. Taking into account drug costs of L3379 for 1-year treatment with rifaximin-alpha, there was an estimated annual mean saving of L1480-L3228 per patient. CONCLUSIONS: Initiation of treatment with rifaximin-alpha was associated with a marked reduction in the number of hospital admissions and hospital length of stay. These data suggest that treatment of patients with rifaximin-alpha for hepatic encephalopathy was generally cost saving. PMID- 26950765 TI - Myosin Heavy Chain Expression Can Vary over the Length of Jaw and Leg Muscles. AB - Muscle fiber type classification can be determined by its myosin heavy chain (MyHC) composition based on a few consecutive sections. It is generally assumed that the MyHC expression of a muscle fiber is the same over its length since neural stimulation and systemic influences are supposed to be the same over its length. We analyzed this in detail in three muscle types: the temporalis (closer) and digastricus (opener; both first brachial arch), and the medial gastrocnemius (somite). Sections of the muscles were incubated with monoclonal antibodies against various MyHC isoforms, and the distribution of these isoforms within individual fibers was followed over a distance of approximately 1 mm. The staining intensity of a fiber was measured and compared with the other fibers in the section. In the temporalis, digastricus, and gastrocnemius, 46, 11, and 15%, respectively, of their MyHC-I fibers showed a variation in the staining intensity over the length of their fibers, as well as 47, 87, and 22%, respectively, of their MyHC-IIA fibers. Most variable fibers were found amongst those with an overall relative intermediate staining intensity, which are presumably hybrid fibers. We conclude that different parts of a muscle fiber can have different fiber type compositions and, thus, contractile properties. Some muscle parts might reach their maximum contraction peak sooner or later than a muscle part a few microns further away. Next to stimulation by the nerve and systemic influences, local influences might also have an impact on the MyHC expression of the fiber. PMID- 26950769 TI - Choice of baseline climate data impacts projected species' responses to climate change. AB - Climate data created from historic climate observations are integral to most assessments of potential climate change impacts, and frequently comprise the baseline period used to infer species-climate relationships. They are often also central to downscaling coarse resolution climate simulations from General Circulation Models (GCMs) to project future climate scenarios at ecologically relevant spatial scales. Uncertainty in these baseline data can be large, particularly where weather observations are sparse and climate dynamics are complex (e.g. over mountainous or coastal regions). Yet, importantly, this uncertainty is almost universally overlooked when assessing potential responses of species to climate change. Here, we assessed the importance of historic baseline climate uncertainty for projections of species' responses to future climate change. We built species distribution models (SDMs) for 895 African bird species of conservation concern, using six different climate baselines. We projected these models to two future periods (2040-2069, 2070-2099), using downscaled climate projections, and calculated species turnover and changes in species-specific climate suitability. We found that the choice of baseline climate data constituted an important source of uncertainty in projections of both species turnover and species-specific climate suitability, often comparable with, or more important than, uncertainty arising from the choice of GCM. Importantly, the relative contribution of these factors to projection uncertainty varied spatially. Moreover, when projecting SDMs to sites of biodiversity importance (Important Bird and Biodiversity Areas), these uncertainties altered site-level impacts, which could affect conservation prioritization. Our results highlight that projections of species' responses to climate change are sensitive to uncertainty in the baseline climatology. We recommend that this should be considered routinely in such analyses. PMID- 26950770 TI - Production of xylitol by a Coniochaeta ligniaria strain tolerant of inhibitors and defective in growth on xylose. AB - In conversion of biomass to fuels or chemicals, inhibitory compounds arising from physical-chemical pretreatment of the feedstock can interfere with fermentation of the sugars to product. Fungal strain Coniochaeta ligniaria NRRL30616 metabolizes the furan aldehydes furfural and 5-hydroxymethylfurfural, as well as a number of aromatic and aliphatic acids and aldehydes. Use of NRRL30616 to condition biomass sugars by metabolizing the inhibitors improves their fermentability. Wild-type C. ligniaria has the ability to grow on xylose as sole source of carbon and energy, with no accumulation of xylitol. Mutants of C. ligniaria unable to grow on xylose were constructed. Xylose reductase and xylitol dehydrogenase activities were reduced by approximately two thirds in mutant C8100. The mutant retained ability to metabolize inhibitors in biomass hydrolysates. Although C. ligniaria C8100 did not grow on xylose, the strain converted a portion of xylose to xylitol, producing 0.59 g xylitol/g xylose in rich medium and 0.48 g xylitol/g xylose in corn stover dilute acid hydrolysate. 2016 American Institute of Chemical Engineers Biotechnol. Prog., 2016 (c) 2016 American Institute of Chemical Engineers Biotechnol. Prog., 32:606-612, 2016. PMID- 26950771 TI - Robotics in otolaryngology and head and neck surgery: Recommendations for training and credentialing: A report of the 2015 AHNS education committee, AAO HNS robotic task force and AAO-HNS sleep disorders committee. AB - Training and credentialing for robotic surgery in otolaryngology - head and neck surgery is currently not standardized, but rather relies heavily on industry guidance. This manuscript represents a comprehensive review of this increasingly important topic and outlines clear recommendations to better standardize the practice. The recommendations provided can be used as a reference by individuals and institutions alike, and are expected to evolve over time. (c) 2016 Wiley Periodicals, Inc. Head Neck 38: E151-E158. PMID- 26950772 TI - Uptake and Accumulation of Polystyrene Microplastics in Zebrafish (Danio rerio) and Toxic Effects in Liver. AB - Microplastics have become emerging contaminants, causing widespread concern about their potential toxic effects. In this study, the uptake and tissue accumulation of polystyrene microplastics (PS-MPs) in zebrafish were detected, and the toxic effects in liver were investigated. The results showed that after 7 days of exposure, 5 MUm diameter MPs accumulated in fish gills, liver, and gut, while 20 MUm diameter MPs accumulated only in fish gills and gut. Histopathological analysis showed that both 5 MUm and 70 nm PS-MPs caused inflammation and lipid accumulation in fish liver. PS-MPs also induced significantly increased activities of superoxide dismutase and catalase, indicating that oxidative stress was induced after treatment with MPs. In addition, metabolomic analysis suggested that exposure to MPs induced alterations of metabolic profiles in fish liver and disturbed the lipid and energy metabolism. These findings provide new insights into the toxic effects of MPs on fish. PMID- 26950773 TI - RNA viruses as major contributors to Antarctic virioplankton. AB - Early work on marine algal viruses focused exclusively on those having DNA genomes, but recent studies suggest that RNA viruses, especially those with positive-sense, single-stranded RNA (+ssRNA) genomes, are abundant in tropical and temperate coastal seawater. To test whether this was also true of polar waters, we estimated the relative abundances of RNA and DNA viruses using a mass ratio approach and conducted shotgun metagenomics on purified viral samples collected from a coastal site near Palmer Station, Antarctica on six occasions throughout a summer phytoplankton bloom (November-March). Our data suggest that RNA viruses contributed up to 65% of the total virioplankton (8-65%), and that, as observed previously in warmer waters, the majority of RNA viruses in these Antarctic RNA virus metagenomes had +ssRNA genomes most closely related to viruses in the order Picornavirales. Assembly of the metagenomic reads resulted in five novel, nearly complete genomes, three of which had features similar to diatom-infecting viruses. Our data are consistent with the hypothesis that RNA viruses influence diatom bloom dynamics in Antarctic waters. PMID- 26950774 TI - Pituitary stalk lesions: systematic review and clinical guidance. AB - The spectrum of pituitary stalk (PS) pathology is vast, presenting a diagnostic challenge. Published large series of PS lesions demonstrate neoplastic conditions are most frequent, followed by inflammatory, infectious and congenital diseases. Inflammatory pathologies however, account for the majority of PS lesions in published small case series and case reports. Physicians must be familiar with the major differential diagnoses and necessary investigations. A comprehensive history and thorough clinical examination is critical. Although magnetic resonance imaging of the PS in disease is nonspecific, associated intracranial features may narrow the differential diagnosis. Initial investigations include basic pathology and computer tomography imaging of the neck, chest, abdomen and pelvis. Further investigations should be guided by the clinical context. PS biopsy should be considered when a diagnosis is regarded essential in centres where an experienced neurosurgeon is available. Treatment is dependent on the underlying disease process and may necessitate pituitary hormone replacement. PMID- 26950777 TI - Personal Primary Care. PMID- 26950775 TI - An analysis of lethal and sublethal interactions among type I and type II pyrethroid pesticide mixtures using standard Hyalella azteca water column toxicity tests. AB - A novel 2-tiered analytical approach was used to characterize and quantify interactions between type I and type II pyrethroids in Hyalella azteca using standardized water column toxicity tests. Bifenthrin, permethrin, cyfluthrin, and lambda-cyhalothrin were tested in all possible binary combinations across 6 experiments. All mixtures were analyzed for 4-d lethality, and 2 of the 6 mixtures (permethrin-bifenthrin and permethrin-cyfluthrin) were tested for subchronic 10-d lethality and sublethal effects on swimming motility and growth. Mixtures were initially analyzed for interactions using regression analyses, and subsequently compared with the additive models of concentration addition and independent action to further characterize mixture responses. Negative interactions (antagonistic) were significant in 2 of the 6 mixtures tested, including cyfluthrin-bifenthrin and cyfluthrin-permethrin, but only on the acute 4-d lethality endpoint. In both cases mixture responses fell between the additive models of concentration addition and independent action. All other mixtures were additive across 4-d lethality, and bifenthrin-permethrin and cyfluthrin permethrin were also additive in terms of subchronic 10-d lethality and sublethal responses. Environ Toxicol Chem 2016;35:2542-2549. (c) 2016 SETAC. PMID- 26950776 TI - Self-Assembly of Fluorescent Organic Nanoparticles for Iron(III) Sensing and Cellular Imaging. AB - Fluorescent organic nanoparticles have attracted increasing attentions for chemical or biological sensing and imaging due to their low-toxicity, facile fabrication and surface functionalization. In this work, we report novel fluorescent organic nanoparticles via facile self-assembly method in aqueous solution. First, the designed water-soluble fluorophore shows a weak and negligible intrinsic fluorescence in water. Upon binding with adenosine-5' triphosphate (ATP), fluorescent nanoparticles were formed immediately with strongly enhanced fluorescence. These fluorescent nanoparticles exhibit high sensitivity and selectivity toward Fe(3+) sensing with detection limit of 0.1 nM. In addition, after incubation with HeLa cells, the fluorophore shows excellent imaging performance by interaction with entogenous ATP in cells. Finally, this fluorescent system is also demonstrated to be capable of Fe(3+) sensing via fluorescence quenching in cellular environment. PMID- 26950778 TI - John P. Geyman Festschrift. PMID- 26950779 TI - Beyond the Affordable Care Act: Alternate Futures for Family Medicine and Primary Care. AB - BACKGROUND: Changes in the landscape of medical practice in recent years, accelerated since the passage of the Affordable Care Act (ACA) in 2010, have led to further fragmentation of primary care and disruption of the doctor-patient relationship for many millions of Americans. Patients face escalating costs of care and restricted choice of physician and hospital in a largely corporatized health care system. The goals of family medicine are compromised by these system trends. The ACA is unsustainable for a number of reasons, including lack of price controls and cost containment, unaffordable costs for patients and taxpayers, widespread underinsurance, and massive administrative waste. Financing reform through single-payer national health insurance will bring a fairer system of universal coverage for comprehensive care of higher quality at less cost, while enabling a renaissance of family medicine and primary care as an expanding base of our health care system. PMID- 26950780 TI - Continuity and Access in an Academic Family Medicine Center. AB - BACKGROUND AND OBJECTIVES: A personal physician and enhanced access to care are principles of the patient-centered medical home. Despite the importance of these concepts, measuring and improving interpersonal continuity of care and access to care in academic family medicine centers has received little attention. The authors describe their program's methods and results to maximize continuity of care and minimize delays for care using proven principles from improvement science. METHODS: In 2004, a diverse quality improvement team from our family medicine center joined a breakthrough collaborative with other primary care practices focused on improving appointment access and continuity of care. We followed the model for improvement with a specific aim, explicit measures, and ambitious goals. The team adapted and applied principles from a change package presented in the collaborative to improve access and continuity. We planned and performed small tests of change that were subsequently optimized and spread to the entire practice. RESULTS: Average time to third available appointment for a routine physical improved from 22 days to 8 days. Average usual provider continuity (UPC) across all primary care physicians in the practice improved from 54% to 68%. Among resident physicians, UPC improved from 55% to 68%. These results have been sustained over 5 years. CONCLUSIONS: Despite multiple challenges in academic teaching practices, the continuous use of improvement methods to apply proven change concepts minimizes delay for care and maximizes continuity of care. The residency continuity practice can and should be a cornerstone of residency curriculum. PMID- 26950781 TI - Family Medicine Clerkship Directors' Influence on the Residency Program Selection Process: A CERA Study. AB - BACKGROUND AND OBJECTIVES: Residency directors and their associated programs devote a considerable amount of time and effort recruiting medical students. Family medicine clerkship directors may be in a position to influence a student's decision regarding specific residency programs. In this study we examined the frequency and content of discussions between family medicine clerkship directors and medical students regarding residency programs. METHODS: Data were collected as part of the 2014 Council of Academic Family Medicine Educational Research Alliance (CERA) Family Medicine Clerkship Director Survey. A list of 13 residency program features was provided, and clerkship directors were asked to categorize each item on a 5-point Likert scale assessing their importance with regards to recommendation or quality. RESULTS: The response rate was 91%. Nearly all clerkship directors (99.2%) reported that medical students often or occasionally ask their opinion regarding specific residency programs. The three most common factors considered by clerkship directors to be very or extremely influential when recommending a program are accreditation status (73.1%), location (70.3%), and curriculum (68.3%). To determine quality of a program, accreditation status (80.7%), curriculum (80.0%), and faculty reputation for teaching (78.3%) were most often cited. Marginal agreement was noted for location, board pass rate, attrition rate, and curriculum. CONCLUSION: Since nearly all clerkship directors report that medical students ask their opinion regarding specific residency programs, program directors and faculty may wish to enhance their communication with these individuals in regards to specific attributes of their residency program. PMID- 26950782 TI - International Health Experiences in Family Medicine Residency Training. AB - BACKGROUND AND OBJECTIVES: International health experiences (IHEs) have been associated with improved clinical skills, altruistic attitudes, cross-cultural sensitivity, and exposure to community medicine for residents and medical students. Although an increasing number of family medicine residencies offer IHEs, there are currently no standardized competencies or guidelines for developing IHEs. The aim of this study was to examine the content of IHEs in order to provide an overview of the current landscape of global health training in family medicine residency programs. METHODS: Residency programs self identifying as offering IHEs on the American Medical Association's (AMA) FREIDA Online website were emailed an electronic survey with questions regarding IHE characteristics, resident selection criteria, faculty support, motivations for participation, challenges to implementation, and funding. RESULTS: Of the 153 programs that responded, 84% still offered IHEs. Most IHEs are 3--4 weeks (71.1%) and are funded by the resident (74.2%). Faculty from the resident's department or institution generally provide supervision (76.6%) and have undergone some type of specialized training in global health (65.6%). Being in good academic standing was the most important eligibility criteria for residents participating in an IHE (86.7%), and funding was reported as the most challenging aspect (62.5%) of offering IHEs. CONCLUSIONS: IHEs are increasing in number and receiving more funding, but the experiences are variable among residency programs. While most program directors believe residents participate in IHEs to gain exposure with underserved populations, only a small percentage (5.5%) include a commitment to community service as part of a requirement for participation in an IHE. PMID- 26950783 TI - Examining Critical Thinking Skills in Family Medicine Residents. AB - BACKGROUND AND OBJECTIVES: Our objective was to determine the relationship between critical thinking skills and objective measures of academic success in a family medicine residency program. METHODS: This prospective observational cohort study was set in a large Canadian family medicine residency program. Intervention was the California Critical Thinking Skills Test (CCTST), administered at three points in residency: upon entry, at mid-point, and at graduation. Results from the CCTST, Canadian Residency Matching Service file, and interview scores were compared to other measures of academic performance (Medical Colleges Admission Test [MCAT] and College of Family Physicians of Canada [CCFP] certification examination results). RESULTS: For participants (n=60), significant positive correlations were found between critical thinking skills and performance on tests of knowledge. For the MCAT, CCTST scores correlated positively with full scores (n=24, r=0.57) as well as with each section score (verbal reasoning: r=0.59; physical sciences: r=0.64; biological sciences: r=0.54). For CCFP examination, CCTST correlated reliably with both sections (n=49, orals: r=0.34; short answer: r=0.47). Additionally, CCTST was a better predictor of performance on the CCFP exam than was the interview score at selection into the residency program (Fisher's r-to-z test, z=2.25). CONCLUSIONS: Success on a critical thinking skills exam was found to predict success on family medicine certification examinations. Given that critical thinking skills appear to be stable throughout residency training, including an assessment of critical thinking in the selection process may help identify applicants more likely to be successful on final certification exam. PMID- 26950784 TI - Educational Value of a Free Medical Clinic Operated by Medical Students. AB - BACKGROUND AND OBJECTIVES: The Student Outreach Clinic (SOC) at the University of Nevada School of Medicine is one of several student-run free medical clinics associated with US medical schools. We report on the educational value of the SOC to medical students who volunteer at this clinic. METHODS: The records of all patients seen between August 1, 2012, and July 31, 2013, at the SOC were abstracted on a deidentified basis to collect key demographic and clinical components of the visit, including past medical history, components of the physical exam performed, clinical diagnoses recorded, patient disposition, and medications prescribed. RESULTS: A total of 593 clinic visits were reviewed. Students performed a full physical exam on 80% of patients, primarily for educational purposes. The most frequent diagnoses mapped to a considerable extent to the top diagnoses seen in primary care as well as to the medical school curriculum, and the most frequent medications prescribed mapped to a considerable extent to the pharmacology curriculum. CONCLUSIONS: The SOC provides incremental opportunities for medical students to gain valuable clinical experience during their first 2 years of medical school. The diagnoses encountered and medications prescribed parallel and supplement the medical school curriculum, with a particular focus on primary care. The educational value of these experiences should influence curriculum development and decisions. PMID- 26950785 TI - Evaluation of a Motivational Interviewing Training for Third-Year Medical Students. AB - BACKGROUND AND OBJECTIVES: Prevalence of chronic disease is rising at unprecedented rates with associated costs that account for 84% of US health care spending. Physicians have the opportunity to guide patients to make lifestyle changes for preventing and self-managing chronic diseases. However, current medical education offers limited training opportunities in behavioral change counseling approaches. Motivational interviewing (MI) is an increasingly well recognized intervention in the medical community that addresses both behavior change and self-management support. While evidence to support training in motivational interviewing for medical students is growing, more studies are needed. The purpose of this study is to evaluate changes in third-year medical students' knowledge, skills, and attitudes as a result of a 4-hour MI training. METHODS: The study utilized a quasi-experimental design with a pretest and posttest to evaluate the impact of a MI workshop. Fifty-three third-year medical students completed the 4-hour workshop. Each student completed an identical pretest and posttest assessing changes in knowledge, skills, and attitudes. Data were analyzed using t test analysis and qualitative thematic analysis. RESULTS: Medical students demonstrated statistically significant improvements in confidence, knowledge, and skills. Students' qualitative comments demonstrated increased understanding of MI and desire and confidence to use new skills. CONCLUSIONS: The study provides promising evidence that a short 4-hour training can render positive changes among medical students, which supports integration in medical student education programs. Future studies may include evaluation of curriculum enhancements with a more rigorous research design and development of additional training opportunities. PMID- 26950787 TI - Parenting During Residency: Providing Support for Dr Mom and Dr Dad. AB - BACKGROUND AND OBJECTIVES: Parenting during family medicine residency is increasingly common. Relatively little is known about how the competing demands of work and family life affect residents. METHODS: We conducted an exploratory qualitative study of parenting family medicine residents at one program in the Midwest utilizing focus groups to understand residents' perceptions of the positive and negative characteristics of their roles as physicians and parents. We used consensus coding to identify themes in the data and then developed a model to illustrate the relationships among the identified themes. RESULTS: Competing demands on their time require parenting family medicine residents to often make difficult choices, which result in both positive and negative outcomes for residents, their families, and their residency experience. CONCLUSIONS: Parenting family medicine residents experience numerous conflicts in their concurrent roles of learner, physician, and parent. Parenting-friendly residency training programs would likely offer valuable support for these individuals during this stressful life period. PMID- 26950789 TI - Remembering Gayle Stephens, MD. PMID- 26950786 TI - Novel Application of a Reverse Triage Protocol Providing Increased Access to Care in an Outpatient, Primary Care Clinic Setting. AB - BACKGROUND AND OBJECTIVES: As the number of patients with access to care increases, outpatient clinics will need to implement innovative strategies to maintain or enhance clinic efficiency. One viable alternative involves reverse triage. METHODS: A reverse triage protocol was implemented during a student-run free clinic. Each patient's chief complaint(s) were obtained at the beginning of the clinic session and ranked by increasing complexity. "Complexity" was defined as the subjective amount of time required to provide a full, thorough evaluation of a patient. Less complex cases were prioritized first since they could be expedited through clinic processing and allow for more time and resources to be dedicated to complex cases. Descriptive statistics were used to characterize and summarize the data obtained. Categorical variables were analyzed using chi square. A time series analysis of the outcome versus centered time in weeks was also conducted. RESULTS: The average number of patients seen per clinic session increased by 35% (9.5 versus 12.8) from pre-implementation of the reverse triage protocol to 6 months after the implementation of the protocol. CONCLUSIONS: The implementation of a reverse triage in an outpatient setting significantly increased clinic efficiency as noted by a significant increase in the number of patients seen during a clinic session. PMID- 26950788 TI - Memories of a Story "Not Mine:" Intern Transformation Through Shared Stories and Support. PMID- 26950793 TI - Lack of Description and Details About Textbook Inaccuracies. PMID- 26950794 TI - Authors' Reply to "Lack of Description and Details About Textbook Inaccuracies". PMID- 26950796 TI - Correction to Monitoring Nanoscale Deformations in a Drawn Polymer Melt with Single-Molecule Fluorescence Polarization Microscopy. PMID- 26950795 TI - Ecological changes in oral microcosm biofilm during maturation. AB - The aim of this study was to evaluate the ecological changes in the biofilm at different stages of maturation using 16S rDNA gene amplicon sequencing and to identify correlations between red/green (R/G) fluorescence ratio and ecological changes. An oral microcosm biofilm was initiated from the saliva of a single donor and grown anaerobically for up to 10 days in basal medium mucin. Quantitative light-induced fluorescence analysis was shown that the R/G ratio of the biofilm increased consistently, but the slope rapidly decreased after six days. The bacterial compositions of 10 species also consistently changed over time. However, there was no significant correlation between each bacteria and red fluorescence. The monitoring of the maturation process of oral microcosm biofilm over 10 days revealed that the R/G ratio and the bacterial composition within biofilm consistently changed. Therefore, the R/G fluorescence ratio of biofilm may be related with its ecological change rather than specific bacteria PMID- 26950797 TI - Low-Temperature Adsorption and Diffusion of Methanol in ZIF-8 Nanoparticle Films. AB - The adsorption of methanol by a zeolitic imidazolate framework-8 (ZIF-8) nanoparticle thin film was studied in situ using temperature-programmed desorption and X-ray photoelectron spectroscopy under low-temperature, low pressure conditions. Partial pore penetration was observed at 90 K, but upon increasing the exposure temperature of the film to 130 K pore penetration was significantly enhanced. Although many studies exist involving bulk powders, this is the first work to our knowledge that demonstrates the ability to control and monitor the entry of a molecule into a metal organic framework (MOF) film in situ using temperature. In this case, nanoparticle films of ZIF-8 were prepared and studied in ultrahigh vacuum. The ability to control and monitor surface adsorption versus pore adsorption in situ is key to future fundamental study of MOFs, for example, in the identification of active sites in reaction mechanisms. PMID- 26950798 TI - Synthesis of LoganVir, a new carbocyclic nucleoside analogue. AB - Starting from a natural cyclopentanoid monoterpene belonging to the class of iridoid glucosides called loganin, we performed the synthesis of a new carbocyclic nucleoside, allowing the preparation of a new lead compound, with a potential HIV antiviral activity as an reverse transcriptase competitive inhibitor that we named LoganVir. The stereocontrol of the coupling reaction was completed utilizing the procedure described by Mitsunobu with a purinic base. PMID- 26950799 TI - Mechanical circulatory support in pediatrics. AB - End-stage heart failure affects thousands of children yearly and mechanical circulatory support is used at many points in their care. Extracorporeal membrane oxygenation supports both the failing heart and lungs, which has led to its use as an adjunct to cardiopulmonary resuscitation as well as in post-operative cardiogenic shock. Continuous-flow ventricular assist devices (VAD) have replaced pulsatile-flow devices in adults and early studies have shown promising results in children. The Berlin paracorporeal pulsatile VAD recently gained U.S. Food and Drug Administration approval and remains the only VAD approved in pediatrics. Failing univentricular hearts and other congenitally corrected lesions are new areas for mechanical support. Finding novel uses, improving durability, and minimizing complications are areas of growth in pediatric mechanical circulatory support. PMID- 26950800 TI - Assessing the role of IKCa channels in generating the sAHP of CA1 hippocampal pyramidal cells. AB - Our previous work reported that KCa3.1 (IKCa) channels are expressed in CA1 hippocampal pyramidal cells and contribute to the slow afterhyperpolarization that regulates spike accommodation in these cells. The current report presents data from single cell RT-PCR that further reveals mRNA in CA1 cells that corresponds to the sequence of an IKCa channel from transmembrane segments 5 through 6 including the pore region, revealing the established binding sites for 4 different IKCa channel blockers. A comparison of methods to internally apply the IKCa channel blocker TRAM-34 shows that including the drug in an electrode from the onset of an experiment is unviable given the speed of drug action upon gaining access for whole-cell recordings. Together the data firmly establish IKCa channel expression in CA1 neurons and clarify methodological requirements to obtain a block of IKCa channel activity through internal application of TRAM-34. PMID- 26950801 TI - Optimization of submerged fermentation medium for citrinin-free monascin production by Monascus. AB - Microbial fermentation of citrinin-free Monascus pigments is in favor in the development of food industry. This study investigated the influences of carbon source, nitrogen source, and mineral salts on the cell growth, monascin (MS), and citrinin (CT) production in Monascus M9. A culture medium composition was established for maximizing the production of citrinin-free MS in submerged culture, as follows: 50 g/L Japonica rice powder, 20 g/L NH4NO3, 3 g/L NaNO3, 1.5 g/L KH2PO4, 1 g/L MgSO4 . 7H2O, 0.2 g/L MnSO4. Under these conditions, no CT was detectable by high performance liquid chromatography. The yield of MS reached 14.11 mg/g, improving approximately 30% compared with before optimization. PMID- 26950802 TI - Best Ways and Practices to Avoid Insulin Pump Catheter Occlusions. PMID- 26950803 TI - Characterization of particle exposure in ferrochromium and stainless steel production. AB - This study describes workers' exposure to fine and ultrafine particles in the production chain of ferrochromium and stainless steel during sintering, ferrochromium smelting, stainless steel melting, and hot and cold rolling operations. Workers' personal exposure to inhalable dust was assessed using IOM sampler with a cellulose acetate filter (AAWP, diameter 25 mm; Millipore, Bedford, MA). Filter sampling methods were used to measure particle mass concentrations in fixed locations. Particle number concentrations and size distributions were examined using an SMPS+C sequential mobile particle sizer and counter (series 5.400, Grimm Aerosol Technik, Ainring, Germany), and a hand-held condensation particle counter (CPC, model 3007, TSI Incorporated, MN). The structure and elemental composition of particles were analyzed using TEM-EDXA (TEM: JEM-1220, JEOL, Tokyo, Japan; EDXA: Noran System Six, Thermo Fisher Scientific Inc., Madison,WI). Workers' personal exposure to inhalable dust averaged 1.87, 1.40, 2.34, 0.30, and 0.17 mg m(-3) in sintering plant, ferrochromium smelter, stainless steel melting shop, hot rolling mill, and the cold rolling mill, respectively. Particle number concentrations measured using SMPS+C varied from 58 * 10(3) to 662 * 10(3) cm(-3) in the production areas, whereas concentrations measured using SMPS+C and CPC3007 in control rooms ranged from 24 * 10(3) to 243 * 10(3) cm(-3) and 5.1 * 10(3) to 97 * 10(3) cm(-3), respectively. The elemental composition and the structure of particles in different production phases varied. In the cold-rolling mill non-process particles were abundant. In other sites, chromium and iron originating from ore and recycled steel scrap were the most common elements in the particles studied. Particle mass concentrations were at the same level as that reported earlier. However, particle number measurements showed a high amount of ultrafine particles, especially in sintering, alloy smelting and melting, and tapping operations. Particle number concentration and size distribution measurements provide important information regarding exposure to ultrafine particles, which cannot be seen in particle mass measurements. PMID- 26950804 TI - Increase in migraine diagnoses and guideline-concordant treatment in veterans, 2004-2012. AB - Background and aim Health administrators, policy makers, and educators have attempted to increase guideline adherence of migraine medications while reducing inappropriate use of opioid- and barbiturate-containing medications. We evaluated the burden of migraine and proportion of guideline-concordant care in a large, national health care system over time. Methods We conducted a time-series study using data from the Veterans Health Administration (VHA) electronic health record. Veterans with migraines were identified by ICD-9 code (346.X). Prescriptions and comorbid conditions were evaluated before and after migraine diagnosis. Chi-square tests and logistic regression were performed. Results A total of 57,064 veterans were diagnosed with migraine headache (5.3%), with women significantly more likely diagnosed (11.6% vs. 4.4%, p < 0.0001). The number of veterans diagnosed with migraine has significantly increased over the years. By 2012, triptans were prescribed to 43% of people with migraine, with no difference by gender. However, triptan prescriptions increased from 2004 to 2012 in men, but not women, veterans. Preventive medicines showed a significant increase with the year of migraine diagnosis, after controlling for age, sex, race, and for comorbidities treated with medications used for migraine prevention. Conclusions The burden of migraines is increasing within the VHA, with a corresponding increase in the delivery of guideline-concordant acute and prophylactic migraine specific medication. PMID- 26950805 TI - Galectin-1 inhibitors and their potential therapeutic applications: a patent review. AB - INTRODUCTION: Galectins have affinity for beta-galactosides. Human galectin-1 is ubiquitously expressed in the body and its expression level can be a marker in disease. Targeted inhibition of galectin-1 gives potential for treatment of inflammatory disorders and anti-cancer therapeutics. AREAS COVERED: This review discusses progress in galectin-1 inhibitor discovery and development. Patent applications pertaining to galectin-1 inhibitors are categorised as monovalent- and multivalent-carbohydrate-based inhibitors, peptides- and peptidomimetics. Furthermore, the potential of galectin-1 protein as a therapeutic is discussed along with consideration of the unique challenges that galectin-1 presents, including its monomer-dimer equilibrium and oxidized and reduced forms, with regard to delivering an intact protein to a pathologically relevant site. EXPERT OPINION: Significant evidence implicates galectin-1's involvement in cancer progression, inflammation, and host-pathogen interactions. Conserved sequence similarity of the carbohydrate-binding sites of different galectins makes design of specific antagonists (blocking agents/inhibitors of function) difficult. Key challenges pertaining to the therapeutic use of galectin-1 are its monomer-dimer equilibrium, its redox state, and delivery of intact galectin-1 to the desired site. Developing modified forms of galectin-1 has resulted in increased stability and functional potency. Gene and protein therapy approaches that deliver the protein toward the target are under exploration as is exploitation of different inhibitor scaffolds. PMID- 26950806 TI - Clinical drug research in chronic central neurodegenerative disorders. AB - Several compounds developed the treatment of Alzheimer's disease and Parkinson's disease have been clinically unsuccessful. Suggested reasons for these failures have included heterogeneous symptom expression, inappropriate assessment of effects, safety and tolerability hurdles, short duration of disease-modifying trials, recruiting pressure on study centers, administrative and bureaucratic overload, and pooling results from trial centers in different health care systems with differing quality and therapeutic concepts. The solution to these problems will include reducing the costs of drug development, with a concomitant reduction of approval hurdles. Trial designs are influenced by ethics committees, health care officials, political administrations, and research scientists. None have direct contact with the treated patients. Approval of novel therapeutic agents lies in the remit of health care officials, whereby price plays a more dominant role than therapeutic efficacy. Patients and prescribing physicians, however, are better placed to act as arbiters of the efficacy, risks, and overall value of a new drug in practice. PMID- 26950807 TI - Epigenetic and genetic variations at the TNNT1 gene locus are associated with HDL C levels and coronary artery disease. AB - AIM: To assess whether epigenetic and genetic variations at the TNNT1 gene locus are associated with high-density lipoprotein cholesterol (HDL-C) and coronary artery disease (CAD). Patients, materials & methods: TNNT1 DNA methylation and c. 20G>A polymorphism were genotyped in subjects with and without familial hypercholesterolemia (FH). RESULTS: Lower TNNT1 DNA methylation levels were independently associated with lower HDL-C levels and with the TNNT1 c.-20G>A polymorphism. In FH men, carriers of the TNNT1 c.-20G>A polymorphism had lower HDL-C levels and an increased risk of CAD compared with noncarriers. In non-FH men, a higher TNNT1 DNA methylation level was associated with CAD. CONCLUSION: These results suggest that TNNT1 genetic and epigenetic variations are associated with HDL-C levels and CAD. PMID- 26950808 TI - A Randomized Trial Using 3Mixtatin Compared to MTA in Primary Molars with Inflammatory Root Resorption: A Novel Endodontic Biomaterial. AB - OBJECTIVES: Novel methods for preserving primary teeth can help to maintain their developmental, esthetic, and functional capabilities. The aim of this study was to assess the success of the repair of bony defects, caused by pre-treatment perforations, with a mixture of three antibiotics combined with simvastatin (3Mixtatin) compared to MTA in hopeless primary molars. STUDY DESIGN: In this randomized clinical trial, 80 teeth from 65 healthy children aged 3-6 years with interradicular or periapical root resorption and/or perforation in primary molars were treated either with 3Mixtatin or MTA before conventional pulpectomy and restoration. The subjects were followed up clinically and radiographically for 4, 6, 12 and 24 months after pulp treatment to evaluate and compare the healing process. The data were compared using chi-square test at a significance level of 0.05. RESULTS: By the end of 24 months in 3Mixtatin group, 31 (96.8%) teeth revealed no clinical signs or symptoms with arrested resorption progress in radiographs. In MTA group, clinical signs and symptoms including pain, mobility and sinus tract were observed in 18 (48.6%) teeth with cessation of root/interradicular radiolucency in 7 (18.9%) teeth without bone repair. CONCLUSIONS: Radiographic and clinical healing occurred more successfully following 3Mixtatin treatment compared to treatment with MTA, it may lead to a paradigm shift in the pulpal treatment of primary teeth in the future. PMID- 26950809 TI - Age Related Prevalence of Pre-Eruptive Intracoronal Radiolucent Defects in the Permanent Dentition. AB - OBJECTIVE: The present study aimed to determine if the prevalence of pre-eruptive intracoronal radiolucent defects is higher for young age groups, in which there are more unerupted teeth. STUDY DESIGN: A retrospective study of panoramic and bitewing radiographs was conducted. An inclusion criterion was the presence of un erupted permanent teeth with a formed and clearly visible crown. Age groups were: young (6-8 years), intermediate (9-12 years) and adults (13-53 years). Significance level was set at p<=0.05. RESULTS: Thirteen (3.9%) pre-eruptive lesions were detected in 335 records. No lesions were found in the young group (7.4%), in the intermediate and adult age groups six and seven lesions were found, respectively. In most cases the pre-eruptive lesion was found in a third molar. CONCLUSION: The prevalence of pre-eruptive intracoronal lesions was not higher for young age groups. The prevalence of pre-eruptive intra coronal radiolucent lesions is 3.9%, irrespective of age. PMID- 26950810 TI - Zinc Oxide-Eugenol Pulpotomy in Primary Teeth: A 24-Month Follow-up. AB - OBJECTIVE: The purpose of the present study was to evaluate the clinical and radiographic effectiveness of zinc oxide-eugenol (ZOE) as the only pulp capping agent in pulpotomies carried out on decayed primary molars after a follow-up period of 24 months. STUDY DESIGN: In total, 60 pulpotomies were performed on 38 patients aged 3 to 11 years. Pulpotomy treatment consisted of the removal of the coronal pup tissue, subsequent hemostasis, irrigation with saline solution, drying and pressure with sterile cotton pellets, and placement of a thick regular ZOE base with a minimal amount of eugenol directly over the vital radicular pulp. Additionally, a histopathologic study was carried out on some of the molars treated. RESULTS: After a 24-month follow-up, we considered 51 procedures to be successful and 9 failures using clinical and radiographic criteria; most of the failures occurred between the 12th and 18th month. CONCLUSIONS: Results suggest that the proposed pulpotomy treatment with ZOE as the only capping agent may be considered as an alternative technique in the pulp treatment of primary molars. PMID- 26950811 TI - Storing Tooth Segments for Optimal Esthetics. AB - OBJECTIVE: A fractured whole crown segment can be reattached to its remnant; crowns from extracted teeth may be used as pontics in splinting techniques. We aimed to evaluate the effect of different storage solutions on tooth segment optical properties after different durations. STUDY DESIGN: Sixty central incisor crowns were divided into 6 groups (n = 10); Group 1 was kept dry; Groups 2, 3, 4, 5, and 6 were placed in an isotonic solution, water, milk, saliva, and casein phosphopeptide-amorphous-calcium-phosphate (CPP-ACP), respectively, for 30 min, 12 h, 1 day, 1 week, and 3 weeks. Color values were measured using a colorimeter. Data were analyzed with Kruskal-Wallis tests, Mann-Whitney U-tests, and Friedman Wilcoxon tests with Bonferroni stepwise corrections (p < 0.05). RESULTS: DeltaE* values varied from 0.3 to 15.3 over the 3 week period. Group 1 demonstrated the greatest color changes over all durations; Group 6 exhibited the least. L*, a*, b*, and DeltaE* values varied between time periods in all groups; the differences were significant (p < 0.01), except for L* and DeltaE* values in Group 2 and a* values in Group 6 (p > 0.01). Comparing DeltaE* values, Group 6 was significantly different from the other groups for all durations (p < 0.01), except Group 4. CONCLUSIONS: A CPP-ACP complex solution seems a good choice for tooth fragment storage. Milk and saliva solutions may cause perceptible color changes if tooth fragments are stored for 3 weeks before use. PMID- 26950813 TI - Comparative Analysis of Protaper and Waveone Systems to Reduce Enterococcus Faecalis from Root Canal System in Primary Molars--An in Vitro Study. AB - OBJECTIVE: To assess, in vitro, the ability of the ProTaper(TM) and WaveOne(TM) systems to reduce Enterococcus faecalis contamination in primary molars. STUDY DESIGN: Sixty roots of primary molars were contaminated with E. faecalis. Roots were randomly allocated to one of four groups (n=20): ProTaper(TM), WaveOne(TM), control A, or control B. The files used were S1 and S2/F1 and F2 (ProTaper(TM) system) and 25.08 (WaveOne(TM) system). In control group A, the root canal was left uninstrumented, whereas in control group B, the root canal was irrigated with NaCl 0.9%. E. faecalis was sampled from the root canal system before and after instrumentation and the Wilcoxon test and Mann-Whitney U were used. RESULTS: There were no differences in E. faecalis counts between pre instrumentation counts in the ProTaperTM and WaveOne(TM) (p>0.05). The ProTaper(TM) system led to an 89.36% reduction in E. faecalis burden, versus 78.10% with the WaveOne(TM) system (p>0.05). Instrumentation time was shorter with WaveOne(TM) (p<0.0001). CONCLUSIONS: The ProTaper(TM) and WaveOneTM systems were equally effective in reducing Enterococcus faecalis in primary molars. The WaveOne(TM) system was associated with shorter instrumentation time. PMID- 26950812 TI - Evaluation of Possible Associated Factors for Early Childhood Caries and Severe Early Childhood Caries: A Multicenter Cross-Sectional Survey. AB - OBJECTIVES: The present study evaluated associated factors for developing early childhood caries (ECC) and Severe-ECC (S-ECC) in a group of children aged 24-71 months. Potential positive effects of early dental visit on formation of ECC is investigated as well. STUDY DESIGN: This was a multicenter, cross-sectional study conducted at three governmental and university pediatric dentistry clinics in 408 preschool children who were randomly selected from a total of 4116 children. The questionnaires administered to the mothers by interview and intraoral examination performed by calibrated pediatric dentists. The children were evaluated in three groups according to their caries experience as who had caries free, ECC and S ECC. RESULTS: The following factors were significantly associated with caries formation: 1. Prolonged (i.e., >18 months) breastfeeding in preterm babies (OR=2.4) 2. Prolonged breastfeeding in children who started tooth brushing after 1.5 years of age (OR=3.7), 3. Sugar (p<0.001) and fruit-juice consumption (p<0.0001), and 4. Lack of periodic dental examination (p<0.05). Parental smoking habit does not significantly affect ECC development. Nocturnal bottle feeding and nocturnal feeding also affected S-ECC formation significantly (p=0.043 and p=0.005, respectively). CONCLUSIONS: There is a significant difference between the children with caries and caries-free associated with the brushing initiation age started before or after 18 months. If a child is under the risk of multiple caries factors, it is very difficult to evaluate which habits affect the caries formation or increase the severity of the caries lesions. PMID- 26950814 TI - Evaluation of Microleakage of Nanoionomer and Nanocomposite Restorations, immersed in Fruit Drink, Fresh Fruit Juice and Soft Drink--An in vitro Study. AB - AIM: To evaluate microleakage of Nanoionomer (3M ESPE Ketac(TM) N100 Light cured Nanoionomer Restorative) and Nanocomposite (3M ESPE Filtek(TM) Z350 XT Universal Restorative) restorations, immersed in fruit drink, fresh fruit juice and soft drink. STUDY DESIGN: Eighty caries free maxillary premolars extracted for orthodontic purpose were used for the study. Class V cavities were prepared and restored with Nanocomposite on buccal surface and Nanoionomer on the palatal surface. The teeth were thermocycled following the restoration. The experimental groups comprised of 72 teeth (3 groups comprising 24 teeth each for fruit drink, fresh fruit juice and soft drink), while remaining 8 formed the control group. Each of experimental group was further divided into three subgroups (low, medium and high immersion). The teeth were finally immersed in Rhodamine B dye, sectioned and evaluated under stereomicroscope. Statistical analyses used were Mann-Whitney test and ANOVA test. RESULTS: The teeth showed statistically significant microleakage as the immersion regime increased. Soft drink group showed highest microleakage followed by fresh fruit juice and fruit drink. Nanocomposite exhibited more microleakage but the comparison was not statistically significant. CONCLUSION: The three beverages used in the study affected the microleakage of both restorative materials significantly. The microleakage scores increased as the frequency of the immersions increased. Soft drink caused highest microleakage followed by fresh fruit juice and fruit drink. PMID- 26950815 TI - In Vitro Evaluation of Microleakage and Microhardness of Ethanolic Extracts of Propolis in Different Proportions Added to Glass Ionomer Cement. AB - OBJECTIVE: To evaluate the effect of ethanolic extracts of propolis (EEP) addition in different proportions to glass ionomer cement (GIC) on microleakage and microhardness of GIC. STUDY DESIGN: The cement was divided into four groups: one using the original composition and three with 10%, 25%, and 50% EEP added to the liquid and then manipulated. For microleakage assessment, sixty primary molars were randomly divided into four groups (n=15). Standard Class II cavities were prepared and then filled with EEP in different proportions added to GICs. Microleakage test was performed using a dye penetration method. The data were analyzed using one-way ANOVA and Mann-Whitney U tests (alpha = 0.05). Disc shaped specimens were prepared from the tested GIC to determine Vickers hardness (VHN). The data were analyzed using one-way ANOVA and post hoc Tukey test (alpha = 0.05). RESULTS: There were no statistically significant differences between the groups in terms of microleakage (p > 0.05). There were statistically significant differences between the VHN values of groups (p < 0.05). Increasing addition of EEP to GIC statistically significantly increased VHN value of GIC (p < 0.05). CONCLUSIONS: The addition of EEP to GIC increased the microhardness of the GIC and did not adversely affect the microleakage. Thus, it might be used during routine dental practice due to its antibacterial properties. PMID- 26950816 TI - Effectiveness of Rotary Endodontic Instruments on Smear Layer Removal in Root Canals of Primary Teeth: A Scanning Electron Microscopy Study. AB - AIM: The present SEM study was undertaken to evaluate the effect of root canal instrumentation using both manual and rotary files in the root canals of primary anterior teeth. STUDY DESIGN: Thirty freshly extracted primary maxillary incisors were divided into 3 groups of 10 teeth each. In Group I, root canals were instrumented with rotary NiTi files; in Group II, the root canals were instrumented using manual NiTi K files and; in Group III, manual instrumentation was done with stainless steel K files. Longitudinal sections were prepared and processed for observation under SEM at the coronal, middle and apical thirds. Scoring of smear layer was done according to Hulsmann and the data obtained was subjected to statistical analysis. RESULTS: Rotary files cleaned the coronal and middle thirds of root canals more effectively. Statistically there was no significant difference between the groups. Lowest score of 2.6 in the apical third of root canals was seen with hand NiTi files. CONCLUSION: Rotary instrumentation was as effective as manual instrumentation in removal of smear layer in the root canals of primary anterior teeth. PMID- 26950817 TI - Cementoblastoma Solely Involving Maxillary Primary Teeth--A Rare Presentation. AB - Cementoblastoma is a rare benign neoplasm of odontogenic ectomesenchyme origin, involving the roots of any tooth, which occurs predominantly in second and third decade of life. Very few cases of cementoblastoma associated with a primary tooth or having a maxillary presentation have been reported in the past. Here, a rare case of a ten year old boy who presented to the department with a swelling in maxillary posterior region since one month is being discussed. The radiographic presentation was mimicking an odontoma. The final diagnosis was cementoblastoma. We have advocated the use of polarized microscopy to support the histopathological diagnosis with respect to its cemental origin. Cementoblastoma should be considered in the differential diagnosis of radio-opaque lesions in the transitional dentition. PMID- 26950818 TI - Primary Teeth and Hair as Indicators of Environmental Pollution. AB - OBJECTIVES: To study the influence of environmental pollution on the mineralization of dental hard tissues by using biosubstrates: teeth and hair. : STUDY DESIGN: At the first stage epidemiological survey was conducted in polluted and less polluted areas of Tbilisi (Georgia). We studied 525 children aged 3 and 4 years. Caries prevalence and intensity was defined by the methodology of World Health Organization. At the second stage the chemical elements content was studied in hair and teeth hard tissues of 24 children by X-ray fluorescent spectroscopy method. RESULTS: The prevalence of dental caries in the polluted region was 46%, caries intensity--1.92 (+/- 2.842). In the less polluted region prevalence was 37%, caries intensity--1.47 (+/- 2.571). These data are statistically reliable (p < 0.05). The study of hair and tooth tissues showed that the toxic elements (Pb, Hg, Sn, Ti) content in these tissues was higher in environmentally unfavorable than in favorable conditions. CONCLUSION: Hair and dental tissues can be used as indicators of environmental pollution. Our survey showed that toxic elements content in dental hard tissues was higher and the level of essential elements was less in polluted than in less polluted areas of Tbilisi. PMID- 26950819 TI - Deep Sedation for Pediatric Dental Procedures: Is this a Safe and Effective Option? AB - OBJECTIVE: Sedation may be needed for safe, effective completion of pediatric dental procedures. Procedural sedation is performed in a children's hospital based dental office. The three sedation approaches: a propofol-only (P-O) approach (2-3 mg/kg titrated to the needed level of sedation), an approach that includes either i.v. ketamine (K+P) (0.25 or 0.5 mg/kg) or i.v. fentanyl (F+P) (0.5-1 mcg/kg) prior to propofol administration. We sought to determine safety and efficacy of various propofol based sedation protocols. STUDY DESIGN: Retrospective review of 222 patients receiving a propofol-only (P-O), ketamine+propofol (K+P) or fentanyl+propofol (F+P) approach. RESULTS: There were 44 patients in P-O group, 154 in K+P group and 24 in F+P group with mean age (4.8+/-3.4 y) and mean weight (19.7+/-6.7 kg). All the patients completed procedures successfully. Mild hypoxemia occurred in 24% of cases and resolved with nasal cannula. Mean total dose of propofol was similar in all groups (P-O 8.2 mg/kg, K+P 9.5 mg/kg, F+P 9.6 mg/kg, p=0.15). Although procedure and recovery times were similar in all groups, discharge times in K+P group were significantly shorter than P-O group and F+P group respectively (K+P 9.35+/-8.93.min, P-O 13.57+/-10.42 min, F+P 10.42+/-4.40 p= 0.002). CONCLUSION: Sedation can be accomplished safely and effectively in a children's hospital based dental office using propofol-based sedation. PMID- 26950820 TI - Orthodontic Treatment of Maxillary Incisors with Severe Root Resorption Caused by Bilateral Canine Impaction in a Class II Division 1 Patient. AB - This case report shows the successful alignment of bilateral impacted maxillary canines. A 12-year-old male with the chief complaint of the protrusion of his maxillary anterior teeth happened to have bilateral maxillary canine impaction on the labial side of his maxillary incisors. Four maxillary incisors showed severe root resorption because of the impacted canines. The patient was diagnosed as skeletal Class II malocclusion with proclined maxillary incisors. The impacted canine was carefully retracted using sectional buccal arch wires to avoid further root resorption of the maxillary incisors. To distalize the maxillary dentition, two palatal miniscrews were used. After 25 months of treatment, the maxillary canines were well aligned without any additional root resorption of the maxillary incisors. PMID- 26950821 TI - A Comparison of Three Orthodontic Treatment Indices with Regard to Angle Classification. AB - OBJECTIVES: To calculate the agreement between the Dental Aesthetic Index (DAI) and the Index of Complexity, Outcome and Need (ICON) in assessing orthodontic treatment need and to determine correlations between the Peer Assessment Rating (PAR) and DAI and ICON scores according to Angle classification among patients referred for orthodontic evaluation. STUDY DESIGN: This study included 457 randomly selected patients between 9 to 17 years of age. Patients were divided into four groups according to Angle classification [Class I (n=154), Class II division 1(Class II/1) (n=155), Class II division 2(Class II/2) (n=52) and Class III (n=96)]. Relationships between PAR scores and ICON and DAI scores were evaluated with the Spearman correlation test. Unweighted kappa statistics were used to analyse agreement between the ICON and DAI on the need for treatment, according to Angle classification. RESULTS: Class I malocclusions scored significantly lower than other Angle classifications in all indices. Both the ICON and DAI showed significant positive correlations with the PAR in the general study population. For Class II/2 patients, no correlation was found between PAR and DAI scores. There was significant agreement between the ICON and DAI on treatment need among Class I, Class II/1 and Class II/2 patients however, no agreement was found for Class III malocclusions. CONCLUSIONS: The ICON, DAI and PAR produce similar results and can be used interchangeably for the general orthodontic patient population. However, based on Angle classification, prominent differences exist in scoring certain occlusal features. PMID- 26950822 TI - Perceived factors in return to work after acquired brain injury: A qualitative meta-synthesis. AB - OBJECTIVES: A substantial proportion of survivors after brain injuries originating from trauma, tumour, or stroke may experience reduced ability to work due to a number of challenges. The purpose of this review is to summarize and highlight factors that have been perceived and reported as important in order to return to work after an acquired brain injury. MATERIAL AND METHODS: A qualitative ethnographic meta-synthesis is used to interpret and develop concepts from studies retrieved from systematic searches in the electronic databases PubMed, PsycINFO, and ISI Web of Science. RESULTS: A total of 16 studies were included in the meta-synthesis. Four key concepts were identified as important for return to work after an acquired brain injury: empowerment, self-awareness, motivation, and facilitation. CONCLUSION: The results of the meta-synthesis indicate that personal development is experienced as essential in order to return to work after an acquired brain injury, involving identification of each individual's strengths and weaknesses. These personal factors intersect with an emphasis of the employer providing a certain degree of facilitation in the workplace. All of these aspects will affect one's motivation to return to work and can therefore be crucial to succeed. PMID- 26950824 TI - Associations between fruit, vegetable and legume intakes and prostate cancer risk: results from the prospective Supplementation en Vitamines et Mineraux Antioxydants (SU.VI.MAX) cohort. AB - Although experimental studies suggest that fruits, vegetables and legumes may exert protective effects against prostate carcinogenesis through various bioactive compounds such as dietary fibre and antioxidants, epidemiological evidence is lacking. Notably, very few prospective studies have investigated the relationship between legume intake and prostate cancer risk. Our objective was to prospectively investigate the association between fruit, vegetable, tomato products, potatoes and legume intakes and prostate cancer risk. This study included 3313 male participants to the SUpplementation en VItamines et Mineraux AntioXydants cohort (follow-up: 1994-2007) who completed at least three 24-h dietary records during the first 2 years of follow-up. Associations between tertiles of intake and prostate cancer risk were assessed by multivariate Cox proportional hazards models. After a median follow-up of 12.6 years, 139 incident prostate cancers were diagnosed. An inverse association was observed between prostate cancer risk and tertiles of legume intake (hazard ratio (HR)T3v.T1=0.53; 95 % CI 0.34, 0.85; P trend=0.009). This association was maintained after excluding soya and soya products from the legume group (HRT3 v.T1=0.56; 95 % CI 0.35, 0.89; P trend=0.02). No association was observed between prostate cancer risk and tertiles of intakes of fruits (P trend=0.25), vegetables (P trend=0.91), potatoes (P trend=0.77) and tomato products (P trend=0.09). This prospective study confirms the null association between fruit and non-starchy vegetable intakes and prostate cancer risk observed in most previous cohorts. In contrast, although very few prospective studies have been published on the topic, our results suggest an inverse association between legume intake and prostate cancer risk, supported by mechanistic plausibility. These results should be confirmed by large-scale observational and intervention studies. PMID- 26950825 TI - Diagnosis and management of bronchiolitis obliterans syndrome following lung or hematopoietic cell transplantation. PMID- 26950823 TI - Investigating elementary school children's daily physical activity and sedentary behaviours during weekdays. AB - The purpose of the study was to quantify the contributions of physical education, exergaming (active video games that also are a type of exercise), recess, lunch break and after-school time segments to children's daily physical activity and sedentary behaviours. Participants were 138 second and third graders (71 girls) who attended 20-min recess and 75-min lunch time daily, 25-min regular physical education or exergaming-based classes being alternated daily. The after-school period was defined as 3:20-10:00pm. Physical activity was assessed via accelerometry and the dependent variables were children's time spent in moderate to-vigorous physical activity (MVPA), light physical activity and sedentary behaviour. Children's percentages of time spent in MVPA (P < .001; except for the difference between exergaming and lunch break: P = .63), light physical activity (P < .001) and sedentary behaviour (P < .001) differed significantly across the time segments (i.e., physical education/exergaming, recess, lunch break and after school). Additionally, children accumulated significantly more MVPA (t = 10.22, P < .001) but less light physical activity (t = -3.17, P = .002) and sedentary behaviour (t = -3.91, P < .001) in physical education than in exergaming. Overall, physical education was more effective in generating MVPA than other segments over the school day. The after-school segment holds potential as an avenue for promoting children's MVPA, as this long period could be better utilised to organise structured physical activity. PMID- 26950826 TI - Emerging immunotherapy for the treatment of esophageal cancer. AB - INTRODUCTION: Esophageal cancer is the third most common cancer of the gastrointestinal tract. Despite new therapies, the prognosis for patients with these cancers remains poor with 5-year survival rates lower than 15%. Recently, immunotherapy has increasingly gained attention as a novel treatment strategy for advanced esophageal cancer. AREAS COVERED: Recent success of immunotherapy in treating other solid tumors has shed light on the utility of these approaches for esophageal cancers. Here, the authors focus on antibody-based, adoptive-cell therapy-based, and vaccine-based immunotherapies, and briefly address their rationale, clinical data, and implications. EXPERT OPINION: Immunotherapy is now established to be a key treatment modality that can improve the outcomes of many cancer patients and appears to be ushering in a new era in cancer treatment. Checkpoint inhibitor drugs have shown preliminary favorable results in esophageal cancer treatment. Adoptive cell therapy and vaccine studies have also shown some promise in various clinical studies. Future endeavors will need to focus on identifying patients who are likely to benefit from immunotherapy, monitoring and managing immune responses and designing optimal combination strategies where immunotherapy agents are combined with other traditional treatment modalities. PMID- 26950827 TI - Granuloma disease in flocks of productive layers caused by Tetratrichomonas gallinarum. AB - In 2013, seven outbreaks of granuloma disease occurred in Dutch flocks of productive layers housed on different farms. These outbreaks were characterized by increased mortality and high incidence of granulomas, mainly in caeca (340/408 hens = 83%) and livers (69/408 hens = 17%). Mortality started to increase between 21 and 35 weeks of age and reached 3.7% to 11.0% exceeding the breeder's norm in periods ranging from 9 to 48 weeks. Some flocks also showed decreased egg production and/or loss of mean egg weight. All affected flocks were linked to one rearing farm, which therefore seemed to be the source of the disease. However, no signs of disease had been observed at this rearing farm. Sentinel hens placed in one of the affected flocks to determine whether the disease had an infectious nature developed granulomas identical to those seen in the outbreaks. Next, by fulfilling Koch's postulates it was shown that Tetratrichomonas gallinarum was the aetiological agent of the granuloma disease. The condition was reproduced in mature specified pathogen free White Leghorn hens (GD - Animal Health, Deventer, the Netherlands) by inoculation via both an artificial and a natural route with a well-defined axenic T. gallinarum isolate obtained from one of the affected flocks. Other causes of granuloma disease were excluded. PMID- 26950828 TI - Where Is the Electronic Oscillator Strength? Mapping Oscillator Strength across Molecular Absorption Spectra. AB - The effectiveness of solar energy capture and conversion materials derives from their ability to absorb light and to transform the excitation energy into energy stored in free carriers or chemical bonds. The Thomas-Reiche-Kuhn (TRK) sum rule mandates that the integrated (electronic) oscillator strength of an absorber equals the total number of electrons in the structure. Typical molecular chromophores place only about 1% of their oscillator strength in the UV-vis window, so individual chromophores operate at about 1% of their theoretical limit. We explore the distribution of oscillator strength as a function of excitation energy to understand this circumstance. To this aim, we use familiar independent-electron model Hamiltonians as well as first-principles electronic structure methods. While model Hamiltonians capture the qualitative electronic spectra associated with pi electron chromophores, these Hamiltonians mistakenly focus the oscillator strength in the fewest low-energy transitions. Advanced electronic structure methods, in contrast, spread the oscillator strength over a very wide excitation energy range, including transitions to Rydberg and continuum states, consistent with experiment. Our analysis rationalizes the low oscillator strength in the UV-vis spectral region in molecules, a step toward the goal of oscillator strength manipulation and focusing. PMID- 26950829 TI - Effects of vildagliptin versus saxagliptin on daily acute glucose fluctuations in Chinese patients with T2DM inadequately controlled with a combination of metformin and sulfonylurea. AB - Objective The present study aimed to compare the effects of the dipeptidyl peptidase-4 (DPP-4) inhibitors vildagliptin and saxagliptin on 24 hour acute glucose fluctuations in Chinese patients with type 2 diabetes mellitus (T2DM) inadequately controlled with a combination of metformin and sulfonylurea. Research design and methods This was a 24 week, prospective, randomized, open label, active-controlled study. Patients (N = 73) with T2DM who had inadequate glycemic control (HbA1c 7.0%-10.0%) with a stable dosage of metformin plus gliclazide for more than 3 months were randomized to receive either vildagliptin 50 mg twice daily (BID, n = 37) or saxagliptin 5 mg once daily (QD, n = 36). Change in mean amplitude of glycemic excursions (MAGE) was assessed at the end of 24 weeks. Results At baseline, the mean (+/-SD) age was 62.9 +/- 6.55 years, disease duration was 7.0 +/- 2.33 years, and HbA1c was 8.4 +/- 0.68%. After 24 weeks of treatment, the MAGE decreased from 5.81 +/- 1.16 mmol/L to 4.06 +/- 0.86 mmol/L (p<0.001) in the vildagliptin group and from 5.66 +/- 1.14 mmol/L to 4.79 +/- 1.25 mmol/L (p = 0.003) in the saxagliptin group. The mean change in MAGE in the vildagliptin group was significantly greater than that in the saxagliptin group (1.74 +/- 0.48 mmol/L vs. 0.87 +/- 0.40 mmol/L, p<0.001). The mean change in HbA1c, from baseline to the study endpoint, in the vildagliptin and saxagliptin groups, was 1.22 +/- 0.40% and 1.07 +/- 0.36%, respectively, with no significant difference between the groups (p = 0.091). The overall safety and tolerability of vildagliptin and saxagliptin were similar. The limitations of the study were a small number of patients and open-label administration of the study drug. Conclusion Vildagliptin produced a significantly greater reduction in acute glucose fluctuations compared with saxagliptin when added to a dual combination of metformin and sulfonylurea in Chinese patients with T2DM. Chinese clinical trial registration number ChiCTR-TRC-13003858. PMID- 26950831 TI - [Cp(Ar)Ni{Ga(nacnac)}]: An Open-Shell Nickel(I) Complex Supported by a Gallium(I) Carbenoid (Cp(Ar) = C5(C6H4-4-Et)5, nacnac = HC[C(Me)N-(C6H3)-2,6-iPr2]2). AB - The 17 valence electron (VE) open-shell nickel gallanediyl complex [Cp(Ar)Ni{Ga(nacnac)}] (3, Ar = C5(C6H4-4-Et)5, nacnac = HC[C(Me)N(C6H3-2,6 iPr2)]2), having an unsupported Ni-Ga bond, was synthesized from [Cp(Ar)Ni(MU Br)]2 (1) by reducing the adduct [Cp(Ar)Ni(MU-Br){Ga(nacnac)}] (2) or, alternatively, trapping the "Cp(Ar)Ni(I)" synthon with Ga(nacnac); spectroscopic and DFT studies showed that the single unpaired electron in 3 resides mainly at the Ni center. PMID- 26950830 TI - Impact of Diabetes on Homocysteine Levels and Its Relationship with Coronary Artery Disease: A Single-Centre Cohort Study. AB - BACKGROUND/AIMS: Coronary artery disease (CAD) is a major cause of mortality worldwide. Hyperhomocysteinemia has been identified as a risk factor for CAD due to increased thrombogenicity, oxidative stress status and endothelial dysfunction. Few data have been provided on the impact of diabetes on homocysteine and its relationship with the prevalence and extent of CAD in this high-risk subset of patients and therefore, this is the aim of this study. METHODS: Our population is represented by a consecutive cohort of patients undergoing coronary angiography at Azienda Ospedaliera-Universitaria, 'Maggiore della Carita', Novara, Italy from March 2007 to October 2012. RESULTS: Diabetes was observed in a total of 1,125 out of 3,534 patients. Diabetes was associated with more advanced age, hypercholesterolemia, arterial hypertension, renal failure, previous myocardial infarction, coronary revascularization (p < 0.001, respectively) and smoking (p = 0.001). Patients with diabetes were more frequently on angiotensin-converting-enzyme inhibitors, angiotensin receptor blockers, beta-blockers, calcium-antagonists, diuretics, statins (p < 0.001, respectively), and acetylsalicylic acid (p = 0.004). Patients with diabetes displayed higher creatinine and triglycerides (p < 0.001), but lower total and high-density lipoprotein-cholesterol (p < 0.001) and haemoglobin (p < 0.001). Diabetes was associated with a significantly higher prevalence and extent of CAD and more complex lesions at angiography, including calcified lesion, total occlusions, in-stent restenosis. No significant difference was found in total homocysteine (tHcy) levels between diabetic and non-diabetic patients (p = 0.2). No difference in the percentage of patients with tHcy above the third tertile (>=18.2 nmol/ml) was observed between patients with or without diabetes (32.8 vs. 35%, p = 0.18; adjusted OR 0.88, 95% CI 0.73-1.05, p = 0.14). Among patients with diabetes, no significant association was found between tHcy, CAD (82.4 vs. 83.6 vs. 78.6%, p = 0.19) or severe CAD (33.2 vs. 33.1 vs. 36.9%, p = 0.18). Same results were observed after correction for baseline differences (adjusted OR 0.78, 95% CI 0.61-1.02, p = 0.11) for CAD and severe CAD (adjusted OR 0.92, 95% CI 0.76-1.13, p = 0.46). CONCLUSIONS: In our study, diabetes was not associated with higher tHcy levels. Furthermore, elevated tHcy is not a risk factor for CAD among patients with diabetes. PMID- 26950832 TI - Subjective health among LGBT persons living with disabilities: A qualitative content analysis. AB - OBJECTIVE: There exist significant health disparities among both lesbian, gay, bisexual, transexual (LGBT) and disability persons; however, there is a dearth of information regarding the subjective health experiences of LGBT persons living with disabilities (LGBTPWD). As such, the purpose of this study was to understand how LGBTPWD subjectively defined and characterized the meaning of health in their lives. METHOD: Using qualitative content analyses procedures outlined by Elo and Kyngas (2008), we conducted a secondary data analysis using a larger questionnaire study that was administered via the Internet. Participants were originally asked to answer the following prompt, "Describe what it personally means to you to be healthy?" Open-ended responses from 79 participants were thematically analyzed over several inductive and comparative coding iterations by a 3-person research team. Trustworthiness of data analysis was ensured via researcher triangulation, negative case analyses, and researcher reflexivity. RESULTS: Four dimensions of subjective health emerged during the qualitative analytic process: physical wellness, emotional vitality, functionality, and social engagement. CONCLUSIONS/IMPLICATIONS: There are contextually nuanced characteristics that constitute subjective health for LGBTPWD. These findings could help rehabilitation professionals provide culturally competent interventions. Implications for future research and limitations are provided in the discussion section. (PsycINFO Database Record PMID- 26950833 TI - A Unique Combination of Nutritionally Active Ingredients Can Prevent Several Key Processes Associated with Atherosclerosis In Vitro. AB - INTRODUCTION: Atherosclerosis is the underlying cause of cardiovascular disease that leads to more global mortalities each year than any other ailment. Consumption of active food ingredients such as phytosterols, omega-3 polyunsaturated fatty acids and flavanols are known to impart beneficial effects on cardiovascular disease although the combined actions of such agents in atherosclerosis is poorly understood. The aim of this study was to screen a nutritional supplement containing each of these active components for its anti atherosclerotic effect on macrophages in vitro. RESULTS: The supplement attenuated the expression of intercellular adhesion molecule-1 and macrophage chemoattractant protein-1 in human and murine macrophages at physiologically relevant doses. The migratory capacity of human monocytes was also hindered, possibly mediated by eicosapentaenoic acid and catechin, while the ability of foam cells to efflux cholesterol was improved. The polarisation of murine macrophages towards a pro-inflammatory phenotype was also attenuated by the supplement. CONCLUSION: The formulation was able to hinder multiple key steps of atherosclerosis development in vitro by inhibiting monocyte recruitment, foam cell formation and macrophage polarisation towards an inflammatory phenotype. This is the first time a combination these ingredients has been shown to elicit such effects and supports its further study in preclinical in vivo models. PMID- 26950834 TI - Evaluation of Equivalent Keratometry Readings Obtained by Pentacam HR (High Resolution). AB - PURPOSE: To assess the repeatability of Equivalent Keratometry Readings (EKRs) obtained by the Pentacam HR (high resolution) in untreated and post-LASIK eyes, and to compare them with the keratometry (K) values obtained by other algorithms. METHODS: In this prospective study, 100 untreated eyes and 71 post-LASIK eyes were included. In the untreated group, each eye received 3 consecutive scans using the Pentacam HR, and EKR values in all central corneal zone, the true net power (Knet) and the simulated K (SimK) were obtained for each scan. In the post LASIK group, each eye received subjective refraction and 3 consecutive scans with the Pentacam HR preoperatively. During the 3-month post-surgery exam, the same examinations and the use of an IOLMaster were conducted for each eye. The EKRs in all zone, the Knet, the mean K (Km) by IOLMaster and the K values by clinical history method (KCHM) were obtained. The repeatability of the EKRs was assessed by the within-subject standard deviation (Sw), 2.77Sw, coefficient of variation (CVw) and intraclass correlation coefficient (ICC). The bonferroni corrected multiple comparisons were performed to analyze the differences among the EKRs and K values calculated by other algorithms within the 2 groups. The 95% limits of agreement (LoA) were calculated. RESULTS: The EKR values in all central corneal zone were repeatable in both the untreated group (Sw?0.19 D, 2.77Sw?0.52 D, CVw?1%, ICC?0.978) and the post-LASIK group (Sw?0.22 D, 2.77Sw?0.62 D, CVw?1%, ICC?0.980). In the untreated group, the EKR in 4mm zone was close to SimK (P = 1.000), and the 95% LoA was (-0.13 to 0.15 D). The difference between Knet and SimK was -1.30+/-0.13 D (95% LoA -1.55 to -1.55 D, P<0.001). In the post-LASIK group, all the EKRs were significantly higher than KCHM (all P<0.001). The differences between the EKR in 4mm zone and KCHM, the EKR in 7mm zone and KCHM, Knet and KCHM, Km and KCHM, SimK and Knet were 0.64+/-0.50 D (95% LoA, -0.33 to 1.62 D), 1.77+/-0.88 D (95% LoA, 0.04 to 3.51 D), -0.98+/-0.48 D (95% LoA, -1.92 to -0.04 D), 0.64+/-0.53 D (95% LoA, -0.40 to 1.68 D), and 1.73+/-0.20 D (95% LoA, 1.33 to 2.13 D), respectively. CONCLUSIONS: The EKRs obtained by the Pentacam HR were repeatable in both untreated eyes and post-LASIK eyes. Compared to the total corneal power obtained by the clinical history method, the EKR values generally overestimated the total corneal power in post-LASIK eyes. So, further calibrations for the EKR values should be conducted, before they were used for the total corneal power assessment in post-LASIK eyes. PMID- 26950835 TI - Drinking Games Participation Among High School and Incoming College Students: A Narrative Review. PMID- 26950836 TI - The Marijuana Phenomenon: Contradictions and Silence. AB - The United States is trending toward more permissiveness regarding recreational and medicinal marijuana (MJ). Many conditions for which MJ is recommended, prescribed, or self-prescribed are symptoms that advanced practice nurses address daily. Yet, the silence of nursing scientists on ethics, practices, and policies regarding such clinical decisions is deafening. This is but one of many contradictions about MJ use that we discuss in this article. We do not propose to resolve these contradictions; that is left to the community of nurse scientists in interprofessional discourse. Collectively, we must explore these contradictions and, through evidence-based policy recommendations, overcome the silence about how providers view MJ, how it might be helpful, its risks, and cultural shifts that have accompanied a changed political/legal environment. Long term, we must close the gaps in the nursing knowledge base regarding MJ as it affects users and how it is used interventionally. PMID- 26950837 TI - Improving Outcomes of Opioid Overdose: Preparing Nursing Students to Intervene. AB - PROBLEM: Death by overdose has been steadily increasing since 1992 and has become a public health epidemic. With the rise of prescription pain medications for nonmedical use and the highest use of illicit substances by those ages 18-25, the need for action is imperative. PURPOSE: The aim of the study was to determine whether an educational intervention had an effect on nursing students' knowledge and skills regarding administration of intranasal naloxone for opioid overdose. METHOD: A convenience sample of baccalaureate nursing students was recruited for the study. A pretest/posttest design was used to evaluate the educational intervention. A paired t test was used to compare differences in pre- and posttest scores. RESULTS: A total of 49 students completed the study. The majority were women ages 25 and below, 31 (63.2%) had some or no background knowledge of opioid overdose, and 42 (85.7%) had not received previous training on intranasal naloxone. Student knowledge increased significantly (p < .001) following the educational intervention. Twenty-four students requested hands-on training for implementation of the intranasal naloxone and scored 100% accuracy in return demonstration. CONCLUSIONS: Implementation of this brief training was effective for increasing the knowledge of opioid overdose for an at-risk population. The nursing student is in a unique position to educate, train, and intervene for peers, friends, and family members who are at high risk for an opiate overdose. Nursing students have a pronounced advantage to assess for respiratory depression and initiate CPR, thereby interrupting a fatal overdose. PMID- 26950838 TI - Alcohol Use, Misuse, and Abuse Among Nursing Students: A Photovoice Study. AB - BACKGROUND: Rates and frequencies of alcohol consumption remain unknown among nursing students, and risk and protective factors associated with alcohol misuse are poorly understood. Nursing curricula often lack content on substance use disorders among nurses, which is reported to begin prior to or during college. PURPOSE: The aims of the study were to examine nursing students' perceptions of the risk and protective factors associated with alcohol behaviors among themselves and their peers and to identify substance use policies and their influence. METHODS: We used the Photovoice method, which employs participatory action research. Participants were screened for alcohol misuse via AUDIT-C, and thoughts and perceptions were obtained regarding their alcohol consumption behaviors through self-expression and group advocacy. Data were collected from four focus groups that included nine undergraduate nursing students. RESULTS: Data reflected the following key issues: stress, environmental influences, societal acceptance, and availability of alcohol. Participants identified that the following problems place them at risk for alcohol misuse: lack of addiction/alcohol education; nursing program expectations increase stress/anxiety; unhealthy habits, social isolation, and individual influences; peer influence/the college experience; and ineffective and unenforced campus policies. Protective factors included university policies; life experiences; and nursing program policies, responsibilities, peer influences, and perceived reputation. CONCLUSION: This action research informed a dialogue with colleagues regarding nursing students' stressors and resulting professional ramifications. Recommendations for future work include investigation of expressed social isolation from university peers and its effects on their alcohol consumption behaviors and increase alcohol education with emphasis on adaptive coping strategies in a stressful professional role in Bachelor of Science in Nursing curricula. PMID- 26950839 TI - Drinking Game Participation Among High School and Incoming College Students: A Narrative Review. AB - The transition from high school to college has been characterized as a potentially vulnerable period because of decreased parental supervision and increased autonomy. This transition can increase risk for participation in high risk behaviors such as drinking games (DGs), which are a social drinking activity that encourages intoxication and are associated with negative alcohol-related consequences. To date, there has not been a narrative review of DG research that examines this activity among high schoolers and incoming college students specifically, and thus, the current review bridges this gap. Findings indicate that DG participation is consistently linked to negative consequences (e.g., passing out, becoming sick) and other high-risk behaviors, such as prepartying (drinking before going to a social event). In addition, DG participation is linked to demographic (e.g., age, gender), psychological (e.g., personality, alcohol cognitions), and contextual/cultural factors (e.g., the college drinking culture). These findings have implications for current prevention and intervention efforts and suggest promising directions for future research. PMID- 26950840 TI - Interoceptive Awareness Is Important for Relapse Prevention: Perceptions of Women Who Received Mindful Body Awareness in Substance Use Disorder Treatment. AB - BACKGROUND: It is postulated that interventions aimed at facilitating interoceptive awareness (i.e., awareness of inner body sensations) may facilitate regulation and improve substance use disorder (SUD) treatment outcomes. OBJECTIVE: The aim of the study was to better understand the role of interoceptive training in SUD treatment, an identified gap in the literature. METHODS: On the basis of a National Institute on Drug Abuse (NIDA)-funded pilot randomized clinical trial that used a two-group repeated measures design to examine mindful awareness in body-oriented therapy (MABT) for women in SUD treatment, this study examined the experience of a subset of participants that received and completed MABT intervention in the larger original study. In a qualitative study using a single focus group, participants were asked to respond to multiple questions regarding their current use of interoceptive awareness skills, perceived benefit, learning processes, and suggestions for program development. Interpretive analysis was used to describe the themes that emerged from the focus group responses. RESULTS: Participants consistently used interoceptive awareness self-care skills learned in MABT. Interoceptive awareness training and daily practice were perceived as critical for emotional awareness, regulation, and relapse prevention. In addition, findings highlight the relevance of MABT educational strategies such as touch and individual delivery to teach interoceptive awareness and self-care skills for women in SUD treatment. CONCLUSION: These findings suggest the positive role of interoceptive awareness in promoting relapse prevention among women in SUD treatment, important for guiding future research, and program development for this population that apply across healthcare disciplines. PMID- 26950841 TI - Internet Addiction in High School Students in Turkey and Multivariate Analyses of the Underlying Factors. AB - The aim of this study is to examine the Internet addiction among adolescents in relation to their sociodemographic characteristics, communication skills, and perceived familial social support. This cross-sectional research is conducted in the high schools in some city centers, in Turkey, in 2013. In this study, cluster sampling was used. In each school, a class for each grade level was randomly selected, and all the students in the selected classes were included in the sample. One thousand seven hundred forty-two students aged between 14 and 20 years were included in the sample.The mean Internet Addiction Scale (IAS) score of the students was found to be 27.9 +/- 21.2. According to the scores obtained from IAS, 81.8% of the students were found to display no symptoms (<50 points), 16.9% were found to display borderline symptoms (50-79 points), and 1.3% were found to be Internet addicts (>=80 points). According to the results of the binary logistic regression, male students and the students in single sex vocational schools were found to report higher levels of borderline Internet addiction. It was also observed that the IAS score increases when the father's educational level increases and when the students' school performance is worse. On the other hand, the IAS score decreases when the student grade level, perceived family social support, and communication skills scores increase.The risk factors for Internet addiction are being a male, low academic achievement, inadequate social support and communication skills, and father's high educational level. PMID- 26950842 TI - Substance Use and Substance Abuse--What's in a Name? AB - PURPOSE: What's in a name? Because the Diagnostic Statistical Manual of Mental Disorders, 5th Edition, no longer uses the terms dependence and abuse (American Psychiatric Association, 2013a), does the continued use of these terms impact how issues related to at-risk substance use are presented in the literature? The purpose of this review is to explore the implications of the continued use of the term substance abuse in the clinical literature through the review of three articles published in 2015 that used the term substance abuse in the title. REVIEW: The use of the term substance abuse in the articles reviewed resulted in presenting a narrow focus on substance use disorders rather than the broader issues of harm that occur across the full continuum of substance use. In addition, the term "substance abuse" in one article lent itself to the use of pejorative language and stigmatization. CONCLUSION: It is imperative that we stop using the term substance abuse in clinical articles, because it is no longer clinically relevant and presents a narrow focus of the risks associated with substance use. PMID- 26950843 TI - Health Policy Watch: One State's Legislation to Prevent Opioid Deaths. PMID- 26950844 TI - Programs and Resources to Assist Nurses With Substance Use Disorders. PMID- 26950845 TI - Teen Use of Electronic Cigarettes: What Does the Research Tell Us? PMID- 26950847 TI - "TB or Not TB?" That is the Question. PMID- 26950846 TI - Association of BRAF V600E Mutation and MicroRNA Expression with Central Lymph Node Metastases in Papillary Thyroid Cancer: A Prospective Study from Four Endocrine Surgery Centers. AB - BACKGROUND: Studies have demonstrated an association of the BRAF(V600E) mutation and microRNA (miR) expression with aggressive clinicopathologic features in papillary thyroid cancer (PTC). Analysis of BRAF(V600E) mutations with miR expression data may improve perioperative decision making for patients with PTC, specifically in identifying patients harboring central lymph node metastases (CLNM). METHODS: Between January 2012 and June 2013, 237 consecutive patients underwent total thyroidectomy and prophylactic central lymph node dissection (CLND) at four endocrine surgery centers. All tumors were tested for the presence of the BRAF(V600E) mutation and miR-21, miR-146b-3p, miR-146b-5p, miR-204, miR 221, miR-222, and miR-375 expression. Bivariate and multivariable analyses were performed to examine associations between molecular markers and aggressive clinicopathologic features of PTC. RESULTS: Multivariable logistic regression analysis of all clinicopathologic features found miR-146b-3p and miR-146b-5p to be independent predictors of CLNM, while the presence of BRAF(V600E) almost reached significance. Multivariable logistic regression analysis limited to only predictors available preoperatively (molecular markers, age, sex, and tumor size) found miR-146b-3p, miR-146b-5p, miR-222, and BRAF(V600E) mutation to predict CLNM independently. While BRAF(V600E) was found to be associated with CLNM (48% mutated in node-positive cases vs. 28% mutated in node-negative cases), its positive and negative predictive values (48% and 72%, respectively) limit its clinical utility as a stand-alone marker. In the subgroup analysis focusing on only classical variant of PTC cases (CVPTC), undergoing prophylactic lymph node dissection, multivariable logistic regression analysis found only miR-146b-5p and miR-222 to be independent predictors of CLNM, while BRAF(V600E) was not significantly associated with CLNM. CONCLUSION: In the patients undergoing prophylactic CLNDs, miR-146b-3p, miR-146b-5p, and miR-222 were found to be predictive of CLNM preoperatively. However, there was significant overlap in expression of these miRs in the two outcome groups. The BRAF(V600E) mutation, while being a marker of CLNM when considering only preoperative variables among all histological subtypes, is likely not a useful stand-alone marker clinically because the difference between node-positive and node-negative cases was small. Furthermore, it lost significance when examining only CVPTC. Overall, our results speak to the concept and interpretation of statistical significance versus actual applicability of molecular markers, raising questions about their clinical usefulness as individual prognostic markers. PMID- 26950850 TI - Chronic Psychological Stress Disrupted the Composition of the Murine Colonic Microbiota and Accelerated a Murine Model of Inflammatory Bowel Disease. AB - The effect of psychological stress on the gastrointestinal microbiota is widely recognized. Chronic psychological stress may be associated with increased disease activity in inflammatory bowel disease, but the relationships among psychological stress, the gastrointestinal microbiota, and the severity of colitis is not yet fully understood. Here, we examined the impact of 12-week repeated water avoidance stress on the microbiota of two inbred strains of T cell receptor alpha chain gene knockout mouse (background, BALB/c and C57BL/6) by means of next generation sequencing of bacterial 16S rRNA genes. In both mouse strains, knockout of the T cell receptor alpha chain gene caused a loss of gastrointestinal microbial diversity and stability. Chronic exposure to repeated water-avoidance stress markedly altered the composition of the colonic microbiota of C57BL/6 mice, but not of BALB/c mice. In C57BL/6 mice, the relative abundance of genus Clostridium, some members of which produce the toxin phospholipase C, was increased, which was weakly positively associated with colitis severity, suggesting that expansion of specific populations of indigenous pathogens may be involved in the exacerbation of colitis. However, we also found that colitis was not exacerbated in mice with a relatively diverse microbiota even if their colonic microbiota contained an expanded phospholipase C-producing Clostridium population. Exposure to chronic stress also altered the concentration of free immunoglobulin A in colonic contents, which may be related to both the loss of bacterial diversity in the colonic microbiota and the severity of the colitis exacerbation. Together, these results suggest that long-term exposure to psychological stress induces dysbiosis in the immunodeficient mouse in a strain specific manner and also that alteration of microbial diversity, which may be related to an altered pattern of immunoglobulin secretion in the gastrointestinal tract, might play a crucial role in the development of chronic stress-induced colitis. PMID- 26950851 TI - Zebrafish Caudal Fin Angiogenesis Assay-Advanced Quantitative Assessment Including 3-Way Correlative Microscopy. AB - BACKGROUND: Researchers evaluating angiomodulating compounds as a part of scientific projects or pre-clinical studies are often confronted with limitations of applied animal models. The rough and insufficient early-stage compound assessment without reliable quantification of the vascular response counts, at least partially, to the low transition rate to clinics. OBJECTIVE: To establish an advanced, rapid and cost-effective angiogenesis assay for the precise and sensitive assessment of angiomodulating compounds using zebrafish caudal fin regeneration. It should provide information regarding the angiogenic mechanisms involved and should include qualitative and quantitative data of drug effects in a non-biased and time-efficient way. APPROACH & RESULTS: Basic vascular parameters (total regenerated area, vascular projection area, contour length, vessel area density) were extracted from in vivo fluorescence microscopy images using a stereological approach. Skeletonization of the vasculature by our custom made software Skelios provided additional parameters including "graph energy" and "distance to farthest node". The latter gave important insights into the complexity, connectivity and maturation status of the regenerating vascular network. The employment of a reference point (vascular parameters prior amputation) is unique for the model and crucial for a proper assessment. Additionally, the assay provides exceptional possibilities for correlative microscopy by combining in vivo-imaging and morphological investigation of the area of interest. The 3-way correlative microscopy links the dynamic changes in vivo with their structural substrate at the subcellular level. CONCLUSIONS: The improved zebrafish fin regeneration model with advanced quantitative analysis and optional 3-way correlative morphology is a promising in vivo angiogenesis assay, well-suitable for basic research and preclinical investigations. PMID- 26950849 TI - Joint Analysis of Multiple Traits Using "Optimal" Maximum Heritability Test. AB - The joint analysis of multiple traits has recently become popular since it can increase statistical power to detect genetic variants and there is increasing evidence showing that pleiotropy is a widespread phenomenon in complex diseases. Currently, most of existing methods use all of the traits for testing the association between multiple traits and a single variant. However, those methods for association studies may lose power in the presence of a large number of noise traits. In this paper, we propose an "optimal" maximum heritability test (MHT-O) to test the association between multiple traits and a single variant. MHT-O includes a procedure of deleting traits that have weak or no association with the variant. Using extensive simulation studies, we compare the performance of MHT-O with MHT, Trait-based Association Test uses Extended Simes procedure (TATES), SUM_SCORE and MANOVA. Our results show that, in all of the simulation scenarios, MHT-O is either the most powerful test or comparable to the most powerful test among the five tests we compared. PMID- 26950848 TI - Analysis of the Cerebrospinal Fluid Proteome in Alzheimer's Disease. AB - Alzheimer's disease is a neurodegenerative disorder accounting for more than 50% of cases of dementia. Diagnosis of Alzheimer's disease relies on cognitive tests and analysis of amyloid beta, protein tau, and hyperphosphorylated tau in cerebrospinal fluid. Although these markers provide relatively high sensitivity and specificity for early disease detection, they are not suitable for monitor of disease progression. In the present study, we used label-free shotgun mass spectrometry to analyse the cerebrospinal fluid proteome of Alzheimer's disease patients and non-demented controls to identify potential biomarkers for Alzheimer's disease. We processed the data using five programs (DecyderMS, Maxquant, OpenMS, PEAKS, and Sieve) and compared their results by means of reproducibility and peptide identification, including three different normalization methods. After depletion of high abundant proteins we found that Alzheimer's disease patients had lower fraction of low-abundance proteins in cerebrospinal fluid compared to healthy controls (p<0.05). Consequently, global normalization was found to be less accurate compared to using spiked-in chicken ovalbumin for normalization. In addition, we determined that Sieve and OpenMS resulted in the highest reproducibility and PEAKS was the programs with the highest identification performance. Finally, we successfully verified significantly lower levels (p<0.05) of eight proteins (A2GL, APOM, C1QB, C1QC, C1S, FBLN3, PTPRZ, and SEZ6) in Alzheimer's disease compared to controls using an antibody-based detection method. These proteins are involved in different biological roles spanning from cell adhesion and migration, to regulation of the synapse and the immune system. PMID- 26950852 TI - Safety of an Enhanced Recovery Pathway for Patients Undergoing Open Hepatic Resection. AB - BACKGROUND: Enhanced recovery pathways (ERP) have not been widely implemented for hepatic surgery. The aim of this study was to evaluate the safety of an ERP for patients undergoing open hepatic resection. METHODS: A single-surgeon, retrospective observational cohort study was performed comparing the clinical outcomes of patients undergoing open hepatic resection treated before and after implementation of an ERP. Morbidity, mortality, and length of hospital stay (LOS) were compared between pre-ERP and ERP groups. RESULTS: 126 patients (pre-ERP n = 73, ERP n = 53) were identified for the study. Patient characteristics and operative details were similar between groups. Overall complication rate was similar between pre-ERP and ERP groups (37% vs. 28%, p = 0.343). Before and after pathway implementation, the median LOS was similar, 5 (IQR 4-7) vs. 5 (IQR 4-6) days, p = 0.708. After adjusting for age, type of liver resection, and ASA, the ERP group had no increased risk of major complication (OR 0.38, 95% CI 0.14-1.02, p = 0.055) or LOS greater than 5 days (OR 1.21, 95% CI 0.56-2.62, p = 0.627). CONCLUSIONS: Routine use of a multimodal ERP is safe and is not associated with increased postoperative morbidity after open hepatic resection. PMID- 26950854 TI - Control of chylomicron export from the intestine. AB - The control of chylomicron output by the intestine is a complex process whose outlines have only recently come into focus. In this review we will cover aspects of chylomicron formation and prechylomicron vesicle generation that elucidate potential control points. Substrate (dietary fatty acids and monoacylglycerols) availability is directly related to the output rate of chylomicrons. These substrates must be converted to triacylglycerol before packaging in prechylomicrons by a series of endoplasmic reticulum (ER)-localized acylating enzymes that rapidly convert fatty acids and monoacylglycerols to triacylglycerol. The packaging of the prechylomicron with triacylglycerol is controlled by the microsomal triglyceride transport protein, another potential limiting step. The prechylomicrons, once loaded with triacylglycerol, are ready to be incorporated into the prechylomicron transport vesicle that transports the prechylomicron from the ER to the Golgi. Control of this exit step from the ER, the rate-limiting step in the transcellular movement of the triacylglycerol, is a multistep process involving the activation of PKCzeta, the phosphorylation of Sar1b, releasing the liver fatty acid binding protein from a heteroquatromeric complex, which enables it to bind to the ER and organize the prechylomicron transport vesicle budding complex. We propose that control of PKCzeta activation is the major physiological regulator of chylomicron output. PMID- 26950855 TI - Lack of VEGFR2 signaling causes maldevelopment of the intestinal microvasculature and facilitates necrotizing enterocolitis in neonatal mice. AB - The pathogenesis of necrotizing enterocolitis (NEC), a common gastrointestinal disease affecting premature infants, remains poorly understood. We previously found that intestinal VEGF-A expression is decreased in human NEC samples and in a neonatal mouse NEC model prior to detectable histological injury. Therefore, we hypothesized that lack of VEGF receptor 2 (VEGFR2) signaling facilitates neonatal intestinal injury by impairing intestinal microvasculature development. Here, we found that intestinal VEGF-A and its receptor, VEGFR2, were highly expressed at the end of fetal life and significantly decreased after birth in mice. Furthermore, selective inhibition of VEGFR2 kinase activity and exposure to a neonatal NEC protocol significantly decreased the density of the intestinal microvascular network, which was further reduced when both interventions were provided together. Furthermore, VEGFR2 inhibition resulted in greater mortality and incidence of severe injury in pups submitted to the NEC model. The percentage of lamina propria endothelial cells was decreased during NEC induction, and further decreased when VEGFR2 signaling was inhibited. This was associated with decreased endothelial cell proliferation rather than apoptosis. In conclusion, we found that VEGF-A and VEGFR2 proteins are highly expressed in the intestine before birth, and are significantly downregulated in the immediate neonatal period. Furthermore, VEGFR2 signaling is necessary to maintain the integrity of the intestinal mucosal microvasculature during the postnatal period and lack of VEGFR2 signaling predisposes to NEC in neonatal mice. PMID- 26950856 TI - Soluble guanylate cyclase activation during ischemic injury in mice protects against postischemic inflammation at the mitochondrial level. AB - The aim was to determine whether treatment with BAY 60-2770, a selective activator of oxidized soluble guanylate cyclase (sGC), near the end of an ischemic event would prevent postischemic inflammation and mitochondrial dysfunction in wild-type (WT) and heme oxygenase-1 KO (HO-1(-/-)) mice. This protocol prevented increases in leukocyte rolling (LR) and adhesion (LA) to intestinal venules along with elevated TNFalpha and circulating neutrophil levels that accompany ischemia-reperfusion (I/R) in both animal models. We further hypothesized that a component of BAY 60-2770 treatment involves maintenance of mitochondrial membrane integrity during I/R. Measurements on isolated enterocytes of calcein fluorescence (mitochondrial permeability) and JC-1 fluorescence ratio (mitochondrial membrane potential) were reduced by I/R, indicating formation of mitochondrial permeability transition pores (mPTP). These effects were abrogated by BAY 60-2770 as well as cyclosporin A and SB-216763, which prevented mPTP opening and inhibited glycogen synthase kinase-3beta (GSK-3beta), respectively. Western blots of WT and HO-1(-/-) enterocytes indicated that GSK-3beta phosphorylation on Ser(9) (inhibitory site) was reduced by half following I/R alone (increased GSK-3beta activity) and increased by one-third (reduced GSK 3beta activity) following BAY 60-2770. Other investigators have associated phosphorylation of the GSK-3beta substrate cyclophilin D (pCyPD) with mPTP formation. We observed a 60% increase in pCyPD after I/R, whereas BAY 60-2770 treatment of sham and I/R groups reduced pCyPD by about 20%. In conclusion, selective activation of oxidized sGC of WT and HO-1(-/-) during ischemia protects against I/R-induced inflammation and preserves mucosal integrity in part by reducing pCyPD production and mPTP formation. PMID- 26950853 TI - Genome-Wide Association Study for Incident Myocardial Infarction and Coronary Heart Disease in Prospective Cohort Studies: The CHARGE Consortium. AB - BACKGROUND: Data are limited on genome-wide association studies (GWAS) for incident coronary heart disease (CHD). Moreover, it is not known whether genetic variants identified to date also associate with risk of CHD in a prospective setting. METHODS: We performed a two-stage GWAS analysis of incident myocardial infarction (MI) and CHD in a total of 64,297 individuals (including 3898 MI cases, 5465 CHD cases). SNPs that passed an arbitrary threshold of 5*10-6 in Stage I were taken to Stage II for further discovery. Furthermore, in an analysis of prognosis, we studied whether known SNPs from former GWAS were associated with total mortality in individuals who experienced MI during follow-up. RESULTS: In Stage I 15 loci passed the threshold of 5*10-6; 8 loci for MI and 8 loci for CHD, for which one locus overlapped and none were reported in previous GWAS meta analyses. We took 60 SNPs representing these 15 loci to Stage II of discovery. Four SNPs near QKI showed nominally significant association with MI (p value<8.8*10-3) and three exceeded the genome-wide significance threshold when Stage I and Stage II results were combined (top SNP rs6941513: p = 6.2*10-9). Despite excellent power, the 9p21 locus SNP (rs1333049) was only modestly associated with MI (HR = 1.09, p-value = 0.02) and marginally with CHD (HR = 1.06, p-value = 0.08). Among an inception cohort of those who experienced MI during follow-up, the risk allele of rs1333049 was associated with a decreased risk of subsequent mortality (HR = 0.90, p-value = 3.2*10-3). CONCLUSIONS: QKI represents a novel locus that may serve as a predictor of incident CHD in prospective studies. The association of the 9p21 locus both with increased risk of first myocardial infarction and longer survival after MI highlights the importance of study design in investigating genetic determinants of complex disorders. PMID- 26950859 TI - Cheese Microbial Risk Assessments - A Review. AB - Cheese is generally considered a safe and nutritious food, but foodborne illnesses linked to cheese consumption have occurred in many countries. Several microbial risk assessments related to Listeria monocytogenes, Staphylococcus aureus, and Escherichia coli infections, causing cheese-related foodborne illnesses, have been conducted. Although the assessments of microbial risk in soft and low moisture cheeses such as semi-hard and hard cheeses have been accomplished, it has been more focused on the correlations between pathogenic bacteria and soft cheese, because cheese-associated foodborne illnesses have been attributed to the consumption of soft cheeses. As a part of this microbial risk assessment, predictive models have been developed to describe the relationship between several factors (pH, Aw, starter culture, and time) and the fates of foodborne pathogens in cheese. Predictions from these studies have been used for microbial risk assessment as a part of exposure assessment. These microbial risk assessments have identified that risk increased in cheese with high moisture content, especially for raw milk cheese, but the risk can be reduced by preharvest and postharvest preventions. For accurate quantitative microbial risk assessment, more data including interventions such as curd cooking conditions (temperature and time) and ripening period should be available for predictive models developed with cheese, cheese consumption amounts and cheese intake frequency data as well as more dose-response models. PMID- 26950860 TI - Identification of a Novel Single Nucleotide Polymorphism in Porcine Beta-Defensin 1 Gene. AB - Porcine beta-defensin-1 (PBD-1) gene plays an important role in the innate immunity of pigs. The peptide encoded by this gene is an antimicrobial peptide that has direct activity against a wide range of microbes. This peptide is involved in the co-creation of an antimicrobial barrier in the oral cavity of pigs. The objective of the present study was to detect polymorphisms, if any, in exon-1 and exon-2 regions of PBD-1 gene in Large White Yorkshire (LWY) and native Ankamali pigs of Kerala, India. Blood samples were collected from 100 pigs and genomic DNA was isolated using phenol chloroform method. The quantity of DNA was assessed in a spectrophotometer and quality by gel electrophoresis. Exon-1 and exon-2 regions of PBD-1 gene were amplified by polymerase chain reaction (PCR) and the products were subjected to single strand conformation polymorphism (SSCP) analysis. Subsequent silver staining of the polyacrylamide gels revealed three unique SSCP banding patterns in each of the two exons. The presence of single nucleotide polymorphisms (SNPs) was confirmed by nucleotide sequencing of the PCR products. A novel SNP was found in the 5'-UTR region of exon-1 and a SNP was detected in the mature peptide coding region of exon-2. In exon-1, the pooled population frequencies of GG, GT, and TT genotypes were 0.67, 0.30, and 0.03, respectively. GG genotype was predominant in both the breeds whereas TT genotype was not detected in LWY breed. Similarly, in exon-2, the pooled population frequencies of AA, AG, and GG genotypes were 0.50, 0.27, and 0.23, respectively. AA genotype was predominant in LWY pigs whereas GG genotype was predominant in native pigs. These results suggest that there exists a considerable genetic variation at PBD-1 locus and further association studies may help in development of a PCR based genotyping test to select pigs with better immunity. PMID- 26950858 TI - Esophageal contractions in type 3 achalasia esophagus: simultaneous or peristaltic? AB - Absence of peristalsis and impaired relaxation of lower esophageal sphincter are the hallmarks of achalasia esophagus. Based on the pressurization patterns, achalasia has been subdivided into three subtypes. The goal of our study was to evaluate the esophageal contraction pattern and bolus clearance in type 3 achalasia esophagus. High-resolution manometry (HRM) recordings of all patients diagnosed with achalasia esophagus in our center between the years 2011 and 2013 were reviewed. Recordings of 36 patients with type 3 achalasia were analyzed for the characteristics of swallow-induced "simultaneous esophageal contraction." The HRM impedance recordings of 14 additional patients with type 3 achalasia were analyzed for bolus clearance from the impedance recording. Finally, the HRM impedance along with intraluminal ultrasound imaging was conducted in six patients to further characterize the simultaneous esophageal contractions. Among 187 achalasia patients, 30 were type 1, 121 type 2, and 36 type 3. A total of 434 swallows evaluated in type 3 achalasia patients revealed that 95% of the swallow induced contractions met criteria for simultaneous esophageal contraction, based on the onset of contraction. Interestingly, the peak and termination of the majority of simultaneous esophageal contractions were sequential. The HRM impedance revealed that 94% of the "simultaneous contractions" were associated with complete bolus clearance. Ultrasound image analysis revealed that baseline muscle thickness of patients in type 3 achalasia is larger than normal but the pattern of axial shortening is similar to that in normal subjects. The majority of esophageal contractions in type 3 achalasia are not true simultaneous contractions because the peak and termination of contraction are sequential and they are associated with complete bolus clearance. PMID- 26950857 TI - Optogenetic activation of mechanically insensitive afferents in mouse colorectum reveals chemosensitivity. AB - The sensory innervation of the distal colorectum includes mechanically insensitive afferents (MIAs; ~25%), which acquire mechanosensitivity in persistent visceral hypersensitivity and thus generate de novo input to the central nervous system. We utilized an optogenetic approach to bypass the process of transduction (generator potential) and focus on transformation (spike initiation) at colorectal MIA sensory terminals, which is otherwise not possible in typical functional studies. From channelrhodopsin2-expressing mice (driven by Advillin-Cre), the distal colorectum with attached pelvic nerve was harvested for ex vivo single-fiber recordings. Afferent receptive fields (RFs) were identified by electrical stimulation and tested for response to mechanical stimuli (probing, stroking, and stretch), and afferents were classified as either MIAs or mechanosensitive afferents (MSAs). All MIA and MSA RFs were subsequently stimulated optically and MIAs were also tested for activation/sensitization with inflammatory soup (IS), acidic hypertonic solution (AHS), and/or bile salts (BS). Responses to pulsed optical stimuli (1-10 Hz) were comparable between MSAs and MIAs whereas 43% of MIAs compared with 86% of MSAs responded tonically to stepped optical stimuli. Tonic-spiking MIAs responded preferentially to AHS (an osmotic stimulus) whereas non-tonic-spiking MIAs responded to IS (an inflammatory stimulus). A significant proportion of MIAs were also sensitized by BS. These results reveal transformation as a critical factor underlying the differences between MIAs (osmosensors vs. inflammatory sensors), revealing a previously unappreciated heterogeneity of MIA endings. The current study draws attention to the sensory encoding of MIA nerve endings that likely contribute to afferent sensitization and thus have important roles in visceral pain. PMID- 26950861 TI - Analysis of Swine Leukocyte Antigen Haplotypes in Yucatan Miniature Pigs Used as Biomedical Model Animal. AB - The porcine major histocompatibility complex (MHC) is called swine leukocyte antigen (SLA), which controls immune responses and transplantation reactions. The SLA is mapped on pig chromosome 7 (SSC7) near the centromere. In this study, 3 class I (SLA-1, SLA-3, and SLA-2) and 3 class II (DRB1, DQB1, and DQA) genes were used for investigation of SLA haplotypes in Yucatan miniature pigs in Korea. This pig breed is a well-known model organism for biomedical research worldwide. The current study indicated that Korean Yucatan pig population had 3 Class I haplotypes (Lr-4.0, Lr-6.0, and Lr-25.0) and 3 class II haplotypes (Lr-0.5, Lr 0.7, and Lr-0.25). The combinations of SLA class I and II haplotype together, 2 homozygous (Lr-4.5/4.5 and Lr-6.7/6.7) and 3 heterozygous (Lr-4.5/6.7, Lr 4.5/25.25, and Lr-6.7/25.25) haplotypes were identified, including previously unidentified new heterozygous haplotypes (Lr-4.5/4.7). In addition, a new SLA allele typing method using Agilent 2100 bioanalyzer was developed that permitted more rapid identification of SLA haplotypes. These results will facilitate the breeding of SLA homozygous Yucatan pigs and will expedite the possible use of these pigs for the biomedical research, especially xenotransplantation research. PMID- 26950862 TI - Microsatellite Analysis of the Genetic Diversity and Population Structure in Dairy Goats in Thailand. AB - The genetic relationships between different populations and breeds of exotic dairy goats in Thailand were studied using 12 microsatellite markers. Blood samples were obtained from 211 goats from Department of Livestock Development breeding and research farms: 29 Anglonubian (AN), 21 Alpine (AP), 23 Jamunapari (JAM), 50 Saanen (SN), and 88 Toggenburg (TG). Five of the 12 microsatellite markers were found to be polymorphic. A mean of 7.40 alleles per locus was found, with a range from 5 (SPS115 and ETH225) to 11 (TGLA122). We found 24, 27, 19, 32, and 24 alleles in the AN, AP, JAM, SN, and TG breeds, respectively; 37 alleles were present in all breeds. The mean number of alleles in each population ranged from 3.2 (ETH225 locus) to 7.6 (TGLA122 locus). Genetic variability within the breeds was moderate as evidenced by the mean expected heterozygosity of 0.539. The average observed heterozygosity across the 5 markers in all breeds was 0.529 with the maximum observed at the BM1818 locus (0.772) and the minimum at the ETH225 locus (0.248). The observed and expected heterozygosity for all breeds for the 5 microsatellite markers ranged from 0.419 to 0.772 and 0.227 to 0.792, respectively. On the basis of their means, the TGLA122 and BM1818 loci were the most suitable markers for distinguishing genetic diversity among the goats. The estimated average F is value for the breeds ranged from -0.044 (ETH225) to 0.180 (SPS115), while the estimated average F st value ranged from 0.021 (SPS115) to 0.104 (ETH10). These results indicated that TGLA122 and BM1818 markers are suitable to be used for aiding conservation and breeding improvement strategies of dairy. PMID- 26950863 TI - Ontogenetic Expression of Lpin2 and Lpin3 Genes and Their Associations with Traits in Two Breeds of Chinese Fat-tailed Sheep. AB - Lipins play dual function in lipid metabolism by serving as phosphatidate phosphatase and transcriptional co-regulators of gene expression. Mammalian lipin proteins consist of lipin1, lipin2, and lipin3 and are encoded by their respective genes Lpin1, Lpin2, and Lpin3. To date, most studies are concerned with Lpin1, only a few have addressed Lpin2 and Lpin3. Ontogenetic expression of Lpin2 and Lpin3 and their associations with traits would help to explore their molecular and physiological functions in sheep. In this study, 48 animals with an equal number of males and females each for both breeds of fat-tailed sheep such as Guangling Large Tailed (GLT) and Small Tailed Han (STH) were chosen to evaluate the ontogenetic expression of Lpin2 and Lpin3 from eight different tissues and months of age by quantitative real-time polymerase chain reaction (PCR). Associations between gene expression and slaughter and tail traits were also analyzed. The results showed that Lpin2 mRNA was highly expressed in perirenal and tail fats, and was also substantially expressed in liver, kidney, reproductive organs (testis and ovary), with the lowest levels in small intestine and femoral biceps. Lpin3 mRNA was prominently expressed in liver and small intestine, and was also expressed at high levels in kidney, perirenal and tail fats as well as reproductive organs (testis and ovary), with the lowest level in femoral biceps. Global expression of Lpin2 and Lpin3 in GLT both were significantly higher than those in STH. Spatiotemporal expression showed that the highest levels of Lpin2 expression occurred at 10 months of age in two breeds of sheep, with the lowest expression at 2 months of age in STH and at 8 months of age in GLT. The greatest levels of Lpin3 expression occurred at 4 months of age in STH and at 10 months of age in GLT, with the lowest expression at 12 months of age in STH and at 8 months of age in GLT. Breed and age significantly influenced the tissue expression patterns of Lpin2 and Lpin3, respectively, and sex significantly influenced the spatiotemporal expression patterns of Lpin3. Meanwhile, Lpin2 and Lpin3 mRNA expression both showed significant correlations with slaughter and tail traits, and the associations appear to be related with the ontogenetic expression as well as the potential functions of lipin2 and lipin3 in sheep. PMID- 26950864 TI - Characterizing Milk Production Related Genes in Holstein Using RNA-seq. AB - Although the chemical, physical, and nutritional properties of bovine milk have been extensively studied, only a few studies have attempted to characterize milk synthesizing genes using RNA-seq data. RNA-seq data was collected from 21 Holstein samples, along with group information about milk production ability; milk yield; and protein, fat, and solid contents. Meta-analysis was employed in order to generally characterize genes related to milk production. In addition, we attempted to investigate the relationship between milk related traits, parity, and lactation period. We observed that milk fat is highly correlated with lactation period; this result indicates that this effect should be considered in the model in order to accurately detect milk production related genes. By employing our developed model, 271 genes were significantly (false discovery rate [FDR] adjusted p-value<0.1) detected as milk production related differentially expressed genes. Of these genes, five (albumin, nitric oxide synthase 3, RNA binding region (RNP1, RRM) containing 3, secreted and transmembrane 1, and serine palmitoyltransferase, small subunit B) were technically validated using quantitative real-time polymerase chain reaction (qRT-PCR) in order to check the accuracy of RNA-seq analysis. Finally, 83 gene ontology biological processes including several blood vessel and mammary gland development related terms, were significantly detected using DAVID gene-set enrichment analysis. From these results, we observed that detected milk production related genes are highly enriched in the circulation system process and mammary gland related biological functions. In addition, we observed that detected genes including caveolin 1, mammary serum amyloid A3.2, lingual antimicrobial peptide, cathelicidin 4 (CATHL4), cathelicidin 6 (CATHL6) have been reported in other species as milk production related gene. For this reason, we concluded that our detected 271 genes would be strong candidates for determining milk production. PMID- 26950865 TI - Effect of Antioxidant Flavonoids (Quercetin and Taxifolin) on In vitro Maturation of Porcine Oocytes. AB - Quercetin (QT) and taxifolin (TF) are structurally similar plant-derived flavonoids that have antioxidant properties and act as free radical scavengers. The objective of this study was to investigate effects of QT and TF on nuclear maturation of porcine oocytes. Effects of TF at 0, 1, 10, and 50 MUg/mL on oocyte nuclear maturation (polar body extrusion) were investigated. After incubation for 44 h, there were no significant differences between the treatment and control groups except in the 50 MUg/mL group which was significantly lower (59.2%, p<0.05) than the other groups (control: >80%). After parthenogenetic activation, further in vitro development of QT- or TF-treated vs control oocytes was investigated. A significantly higher proportion of QT-treated (1 MUg/mL) oocytes developed into blastocysts compared to controls (24.3% vs 16.8%, respectively); however, cleavage rate and blastocyst cell number were not affected. The TF treated group was not significantly different from controls. Levels of reactive oxygen species (ROS) and intracellular glutathione (GSH) in oocytes and embryos in a culture medium supplemented with QT or TF were measured. Both treatment groups had significantly lower (p<0.05) levels of ROS than controls, however GSH levels were different only in QT-treated oocytes. We conclude that exogenous flavonoids such as QT and TF reduce ROS levels in oocytes. Although at high concentration (50 MUg/mL) both QT and TF appear to be toxic to oocytes. PMID- 26950866 TI - Effects of Varying Levels of Fungal (Arachniotus sp.) Treated Wheat Straw as an Ingredient of Total Mixed Ration on Growth Performance and Nutrient Digestibility in Nili Ravi Buffalo Calves. AB - The study was carried out to explore the effects of replacing wheat straw with fungal treated wheat straw as an ingredient of total mixed ration (TMR) on the growth performance and nutrient digestibility in Nili Ravi buffalo male calves. Fungal treated wheat straw was prepared using Arachniotus sp. Four TMRs were formulated where wheat straw was replaced with 0 (TMR1), 33 (TMR2), 67 (TMR3), and 100% (TMR4) fungal treated wheat straw in TMR. All TMRs were iso-caloric and iso-nitrogenous. The experimental TMRs were randomly assigned to four groups of male calves (n = 6) according to completely randomized design and the experiment continued for four months. The calves fed TMR2 exhibited a significant improve in dry matter intake, average daily weight gain, feed conversion ratio and feed economics compared to other groups. The same group also showed higher digestibility of dry matter, crude protein, neutral-, and acid detergent fibers than those fed on other TMRs. It is concluded that TMR with 33% fungal-treated wheat straw replacement has a potential to give an enhanced growth performance and nutrient digestibility in male Nili Ravi buffalo calves. PMID- 26950867 TI - The In vitro Effects of Nano-encapsulated Conjugated Linoleic Acid on Stability of Conjugated Linoleic Acid and Fermentation Profiles in the Rumen. AB - This study was aimed to evaluate the stability of conjugated linoleic acids (CLAs) by nano-encapsulation against in vitro ruminal biohydrogenation by microbial enzymatic conversion. CLAs (free fatty acid form of CLA [CLA-FFA], nano encapsulated CLA-FFA, triglyceride form of CLA [CLA-TG], and nano-encapsulated CLA-TG) were used in the in vitro fermentation experiments. When Butyrivibrio fibrisolvens (B. fibrisolvens) was incubated with CLA-FFAs, the concentrations of cis-9, trans-11 CLA and vaccenic acid (VA) slightly was decreased and increased by nano-encapsulation, respectively. When B. fibrisolvens was incubated with CLA TG, the concentrations of cis-9, trans-11 CLA and VA decreased, but these were increased when B. fibrisolvens was incubated with nano-encapsulated CLA-TG. The nano-encapsulation was more effective against the in vitro biohydrogenation activity of B.fibrisolvens incubated with CLA-FFA than with CLA-TG. In the in vitro ruminal incubation test, the total gas production and concentration of total volatile fatty acids incubated with nano-encapsulated CLA-FFA and CLA-TG were increased significantly after 24 h incubation (p<0.05). Nano-encapsulated CLA-FFA might, thus, improve the ruminal fermentation characteristics without adverse effects on the incubation process. In addition, nano-encapsulated CLA-FFA increased the population of Fibrobacter succinogenes and decreased the population of B. fibrisolvens population. These results indicate that nano-encapsulation could be applied to enhance CLA levels in ruminants by increasing the stability of CLA without causing adverse effects on ruminal fermentation. PMID- 26950868 TI - Supplementing Vitamin E to the Ration of Beef Cattle Increased the Utilization Efficiency of Dietary Nitrogen. AB - The objectives of the trial were to investigate the effects of supplementing vitamin E (VE) on nutrient digestion, nitrogen (N) retention and plasma parameters of beef cattle in feedlot. Four growing Simmental bulls, fed with a total mixed ration composed of corn silage and concentrate mixture as basal ration, were used as the experimental animals. Four levels of VE product, i.e. 0, 150, 300, 600 mg/head/d (equivalent to 0, 75, 150, 300 IU VE/head/d), were supplemented to the basal ration (VE content 38 IU/kg dry matter) in a 4*4 Latin square design as experimental treatments I, II, III and IV, respectively. Each experimental period lasted 15 days, of which the first 12 days were for pretreatment and the last 3 days for sampling. The results showed that supplementing VE did not affect the nutrient digestibility (p>0.05) whereas decreased the urinary N excretion (p<0.01), increased the N retention (p<0.05) and tended to increase the microbial N supply estimated based on the total urinary purine derivatives (p = 0.057). Supplementing VE increased the plasma concentrations of VE, glucose and triglycerol (TG) (p<0.05) and tended to increase the plasma concentration of total protein (p = 0.096) whereas did not affect the plasma antioxidant indices and other parameters (p>0.05). It was concluded that supplementing VE up to 300 IU/head/d did not affect the nutrient digestibility whereas supplementing VE at 150 or 300 IU/head/d increased the N retention and the plasma concentrations of VE and TG (p<0.05) of beef cattle. PMID- 26950869 TI - Effects of Chromium Methionine Supplementation on Blood Metabolites and Fatty Acid Profile of Beef during Late Fattening Period in Holstein Steers. AB - The objective of this study was to determine the effects of chromium methionine (Cr-Met) chelate supplementation on blood metabolites and fatty acid profile of beef from Holstein steers during late fattening period. Fifteen Holstein steers were allotted randomly into two groups including the control (non Cr-Met feeding, NCM, ave. body weight [BW] = 483+/-25.7 kg) and the treatment (Cr-Met feeding for 4 months, 4CM, ave. BW = 486+/-27.5 kg) group. The feeding amount of Cr-Met to animals was limited to 400 ppb/cow/d and was supplemented to total mixed ration. No difference in blood albumin, alkaline phosphatase, urea-nitrogen, calcium, creatine, glucose, total protein, triglyceride, and cholesterol were observed between the treatment groups (p>0.05). The level of high density lipoprotein was higher in the 4CM group than the NCM group, whereas low density lipoprotein was lower in the 4CM group (p<0.05). The fatty acid composition (caprate, laurate, myristate, pentadecanoate, palmitate, palmitoleate, margarate, cis-11 heptadodecanoate, stearate, oleate, trans-vaccenate, linoleate, cis-11 eicosenoate, docosa hexaenoic acid, and docosa pentaenoic acid) of the beef showed no difference between the two groups (p>0.05). The arachidonic acid level tended to be higher in the 4CM than the NCM group (p = 0.07). Cr-Met had no influence (p>0.05) on the ratio of saturated, unsaturated, unsaturated/saturated, monounsaturated/saturated and polyunsaturated/saturated fatty acids whereas the ratio of polyunsaturated fatty acids (PUFA) in the 4CM group was comparatively higher than the NCM group (p<0.05). This study concluded that feeding Cr-Met supplementation in 400 ppb/d to Holstein steers for 4 months during late fattening period can improve some blood metabolites and beef quality by increasing PUFA and gamma-linoleate compositions of beef. PMID- 26950871 TI - Nocturnal Light Pulses Lower Carbon Dioxide Production Rate without Affecting Feed Intake in Geese. AB - This study was conducted to investigate the effect of nocturnal light pulses (NLPs) on the feed intake and metabolic rate in geese. Fourteen adult Chinese geese were penned individually, and randomly assigned to either the C (control) or NLP group. The C group was exposed to a 12L:12D photoperiod (12 h light and 12 h darkness per day), whereas the NLP group was exposed to a 12L:12D photoperiod inserted by 15-min lighting at 2-h intervals in the scotophase. The weight of the feed was automatically recorded at 1-min intervals for 1 wk. The fasting carbon dioxide production rate (CO2 PR) was recorded at 1-min intervals for 1 d. The results revealed that neither the daily feed intake nor the feed intakes during both the daytime and nighttime were affected by photoperiodic regimen, and the feed intake during the daytime did not differ from that during the nighttime. The photoperiodic treatment did not affect the time distribution of feed intake. However, NLPs lowered (p<0.05) the mean and minimal CO2 PR during both the daytime and nighttime. Both the mean and minimal CO2 PR during the daytime were significantly higher (p<0.05) than those during the nighttime. We concluded that NLPs lowered metabolic rate of the geese, but did not affect the feed intake; both the mean and minimal CO2 PR were higher during the daytime than during the nighttime. PMID- 26950870 TI - Effect of Dietary Beta-Glucan on the Performance of Broilers and the Quality of Broiler Breast Meat. AB - A total of 400, one day-old commercial broiler chicks were divided into five diet groups (negative control, positive control group with 55 ppm Zn-bacitracin, 15 ppm beta-glucan, 30 ppm beta-glucan, and 60 ppm beta-glucan) and fed for six weeks. Ten broilers were allotted to each of 40 floor pens. Eight floor pens were randomly assigned to one of the 5 diets. Each diet was fed to the broilers for 6 weeks with free access to water and diet. The survival rate, growth rate, feed efficiency, and feed conversion rate of the broilers were calculated. At the end of the feeding trial, the birds were slaughtered, breast muscles deboned, and quality parameters of the breast meat during storage were determined. The high level of dietary beta-glucan (60 ppm) showed better feed conversion ratio and survival rate than the negative control. The survival rate of 60 ppm beta-glucan treated group was the same as that of the antibiotic-treated group, which showed the highest survival rate among the treatments. There was no significant difference in carcass yield, water holding capacity, pH, color, and 2 thiobarbituric acid reactive substances values of chicken breast meat among the 5 treatment groups. Supplementation of 60 ppm beta-glucan to broiler diet improved the survival rate and feed conversion rate of broilers to the same level as 55 ppm Zn-bacitracin group. The result indicated that use of beta-glucan (60 ppm) can be a potential alternative to antibiotics to improve the survival and performance of broilers. However, dietary beta-glucan showed no effects on the quality parameters of chicken breast meat. PMID- 26950872 TI - Bioavailability of Phosphorus in Two Cultivars of Pea for Broiler Chicks. AB - The aim was to determine the relative bioavailability of phosphorus (P) in peas for 21-day old broiler chickens using slope-ratio assay. One hundred and sixty eight male Ross 308 broiler chicks were divided into 42 groups 4 balanced for body weight and fed 7 diets in a completely randomized design (6 groups/diet) from day 1 to 21 of age. The diets were a corn-soybean meal basal diet, and the corn-soybean meal basal diet to which monosodium phosphate, brown- or yellow seeded pea was added at the expense of cornstarch to supply 0.5% or 1% total phosphorus. Monosodium phosphate was included as a reference, and hence the estimated bioavailability of P in pea cultivars was relative to that in the monosodium phosphate. Birds and feed were weighed weekly and on d 21 they were killed to obtain tibia. The brown-seeded pea contained 23.4% crude protein, 0.47% P, whereas the yellow-seeded pea contained 24.3% crude protein and 0.38% P. Increasing dietary P supply improved (p<0.05) chick body weight gain and tibia ash and bone density. The estimated relative bioavailability of p values for brown- and yellow-seeded peas obtained using final body weight, average daily gain, tibia ash, and bone mineral density were 31.5% and 36.2%, 35.6% and 37.3%, 23.0% and 5.60%, and 40.3% and 30.3%, respectively. The estimated relative bioavailability of p values for brown- and yellow-seeded peas did not differ within each of the response criteria measured in this study. In conclusion, the relative bioavailability of P in pea did not differ depending on the cultivar (brown- vs yellow-seed). However, the relative bioavailability of P in pea may vary depending on the response criterion used to measure the bioavailability. PMID- 26950875 TI - Heat Shock Protein Augmentation of Angelica gigas Nakai Root Hot Water Extract on Adipogenic Differentiation in Murine 3T3-L1 Preadipocytes. AB - There is a high association of heat shock on the alteration of energy and lipid metabolism. The alterations associated with thermal stress are composed of gene expression changes and adaptation through biochemical responses. Previous study showed that Angelica gigas Nakai (AGN) root extract promoted adipogenic differentiation in murine 3T3-L1 preadipocytes under the normal temperature condition. However, its effect in heat shocked 3T3-L1 cells has not been established. In this study, we investigated the effect of AGN root hot water extract in the adipogenic differentiation of murine 3T3-L1 preadipocytes following heat shock and its possible mechanism of action. Thermal stress procedure was executed within the same stage of preadipocyte confluence (G0) through incubation at 42 degrees C for one hour and then allowed to recover at normal incubation temperature of 37 degrees C for another hour before AGN treatment for both cell viability assay and Oil Red O. Cell viability assay showed that AGN was able to dose dependently (0 to 400 MUg/mL) increase cell proliferation under normal incubation temperature and also was able to prevent cytotoxicity due to heat shock accompanied by cell proliferation. Confluent preadipocytes were subjected into heat shock procedure, recovery and then AGN treatment prior to stimulation with the differentiation solution. Heat shocked preadipocytes exhibited reduced differentiation as supported by decreased amount of lipid accumulation in Oil Red O staining and triglyceride measurement. However, those heat shocked preadipocytes that then were given AGN extract showed a dose dependent increase in lipid accumulation as shown by both evaluation procedures. In line with these results, real-time polymerase chain reaction (RT PCR) and Western blot analysis showed that AGN increased adipogenic differentiation by upregulating heat shock protection related genes and proteins together with the adipogenic markers. These findings imply the potential of AGN in heat shock amelioration among 3T3-L1 preadipocytes through heat shock factor and proteins augmentation and enhanced adipogenic marker expression. PMID- 26950873 TI - The Expression of Adipogenic Genes in Adipose Tissues of Feedlot Steers Fed Supplementary Palm Oil or Soybean Oil. AB - We hypothesized that supplementing finishing diets with palm oil would promote adipogenic gene expression and stearoyl-CoA desaturase (SCD) gene expression in subcutaneous (s.c.) and intramuscular (i.m.) adipose tissues of feedlot steers. Eighteen Angus and Angus crossbred steers were assigned to three groups of 6 steers and fed a basal diet (control), with 3% palm oil, or with 3% soybean oil, for 70 d, top-dressed daily. Tailhead s.c. adipose tissue was obtained by biopsy at 14 d before the initiation of dietary treatments and at 35 d of dietary treatments. At slaughter, after 70 d of dietary treatment, tailhead s.c. adipose tissue and i.m. adipose tissue were obtained from the longissimus thoracis muscle. Palm oil increased plasma palmitic acid and soybean oil increased plasma linoleic acid and alpha-linolenic acid relative to the initial sampling time. Expression of AMP-activated protein kinase alpha (AMPKalpha) and peroxisome proliferator-activated receptor gamma (PPARgamma) increased between the initial and intermediate biopsies and declined thereafter (p<0.03). SCD gene expression did not change between the initial and intermediate biopsies but declined by over 75% by the final period (p = 0.04), and G-coupled protein receptor 43 (GPR43) gene expression was unaffected by diet or time on trial. Soybean oil decreased (p = 0.01) PPARgamma gene expression at the intermediate sample time. At the terminal sample time, PPARgamma and SCD gene expression was less in i.m. adipose tissue than in s.c. adipose tissue (p<0.05). AMPKalpha gene expression was less in s.c. adipose tissue of palm oil-fed steers than in control steers (p = 0.04) and CCAAT enhancer binding protein-beta (CEBPbeta) gene expression was less in s.c. and i.m. adipose tissues of palm oil-fed steers than in soybean oil-fed steers (p<0.03). Soybean oil decreased SCD gene expression in s.c. adipose tissue (p = 0.05); SCD gene expression in palm oil-fed steers was intermediate between control and soybean oil-fed steers. Contrary to our original hypothesis, palm oil did not promote adipogenic gene expression in s.c. and i.m. adipose tissue. PMID- 26950874 TI - Targeted Editing of Myostatin Gene in Sheep by Transcription Activator-like Effector Nucleases. AB - Myostatin (MSTN) is a secreted growth factor expressed in skeletal muscle and adipose tissue that negatively regulates skeletal muscle mass. Gene knockout of MSTN can result in increasing muscle mass in sheep. The objectives were to investigate whether myostatin gene can be edited in sheep by transcription activator-like effector nucleases (TALENs) in tandem with single-stranded DNA oligonucleotides (ssODNs). We designed a pair of TALENs to target a highly conserved sequence in the coding region of the sheep MSTN gene. The activity of the TALENs was verified by using luciferase single-strand annealing reporter assay in HEK 293T cell line. Co-transfection of TALENs and ssODNs oligonucleotides induced precise gene editing of myostatin gene in sheep primary fibroblasts. MSTN gene-edited cells were successfully used as nuclear donors for generating cloned embryos. TALENs combined with ssDNA oligonucleotides provide a useful approach for precise gene modification in livestock animals. PMID- 26950876 TI - The Effects of Components of Grazing System on Welfare of Fattening Pigs. AB - The objective of this study was to clarify the most effective component of grazing for improving welfare of fattening pigs. This study compared welfare indicators of 20 fattening pigs aged 100 to 124 days (the prior period) and 138 to 164 days (the latter period) in an indoor housing system (IS), an outdoor pasturing system (OP), a concrete floor paddock system (CF), a concrete floor paddock system with fresh grass (FG), or a soil floor paddock system (SF). The last three treatments include important components of a grazing system: extra space, grass feed, and soil floor. Behavior, wounds on the body, and performances, measured as average daily gain (ADG) and feed conversion ratio, were observed. CF pigs behaved similarly to IS pigs. FG pigs showed higher levels of foraging, chewing and activity. SF pigs engaged in higher levels of foraging, exploring, activity, and rooting, and showed a similar amount of playing behavior as OP pigs. ADG was the same in all treatments at the prior period, and increased in the order FG, IS, CF, SF, and OP at the latter. The behaviors and performance of SF pigs resembled those of OP which seemed to indicate a consistently higher standard of welfare than the other treatments. In conclusion, the existence of a soil floor is the most important component of a pasture for improving the welfare of pigs. PMID- 26950877 TI - Effects of Ambient Temperature on Growth Performance, Blood Metabolites, and Immune Cell Populations in Korean Cattle Steers. AB - Exposure to cold may affect growth performance in accordance with the metabolic and immunological activities of animals. We evaluated whether ambient temperature affects growth performance, blood metabolites, and immune cell populations in Korean cattle. Eighteen Korean cattle steers with a mean age of 10 months and a mean weight of 277 kg were used. All steers were fed a growing stage-concentrate diet at a rate of 1.5% of body weight and Timothy hay ad libitum for 8 weeks. Experimental period 1 (P1) was for four weeks from March 7 to April 3 and period 2 (P2) was four weeks from April 4 to May 1. Mean (8.7 degrees C) and minimum (1.0 degrees C) indoor ambient temperatures during P1 were lower (p<0.001) than those (13.0 degrees C and 6.2 degrees C, respectively) during P2. Daily dry matter feed intake in both the concentrate diet and forage groups was higher (p<0.001) during P2 than P1. Average daily weight gain was higher (p<0.001) during P2 (1.38 kg/d) than P1 (1.13 kg/d). Feed efficiency during P2 was higher (p = 0.015) than P1. Blood was collected three times; on March 7, April 4, and May 2. Nonesterified fatty acids (NEFA) were higher on March 7 than April 4 and May 2. Blood cortisol, glucose, and triglyceride concentrations did not differ among months. Blood CD4+, CD8+, and CD4+CD25+ T cell percentages were higher, while CD8+CD25+ T cell percentage was lower, during the colder month of March than during May, suggesting that ambient temperature affects blood T cell populations. In conclusion, colder ambient temperature decreased growth and feed efficiency in Korean cattle steers. The higher circulating NEFA concentrations observed in March compared to April suggest that lipolysis may occur at colder ambient temperatures to generate heat and maintain body temperature, resulting in lower feed efficiency in March. PMID- 26950878 TI - Characteristics of Sawdust and Cocopeat Beddings, and Their Usefulness According to the Fan and Pen Location for Rearing Hanwoo Cattle. AB - This study was designed to examine the characteristics of sawdust and cocopeat bedding materials, including physicochemical properties (Exp. I) and on-farm trial (Exp. II). In Exp. I, the proportion of particle size was in the order of sawdust> cocopeat India>cocopeat Vietnam (p<0.05), and cocopeat contained higher proportion of small particles (250 MUm+below 250 MUm) than sawdust, causing a dust production problem. Bulk density was cocopeat India>cocopeat Vietnam>sawdust (p<0.05), thus cocopeat treatments showed 4.4 times higher bedding cost than sawdust. The water absorption rates were 702.0% in cocopeat India, 678.3% in cocopeat Vietnam, and 444.0% in sawdust, showing cocopeat had approximately 1.5 times higher water absorption rate than sawdust. Moisture evaporation rates after 12 h of air blowing (2.00 m/s) were higher (p<0.05) in cocopeat Vietnam (80.4%) than sawdust (71.2%) and cocopeat India (72.8%). In vitro ammonia emissions were higher (p<0.05) in sawdust (2.71 mg/m(2)/h) than cocopeat India (1.59 mg/m(2)/h) and Vietnam (1.22 mg/m(2)/h), and total ammonia emissions were higher (p<0.05) in sawdust (37.02 mg/m(2)) than cocopeat India (22.51 mg/m(2)) and Vietnam (13.60 mg/m(2)). In Exp. II, an on-farm trial was conducted with 48 Hanwoo cattle in 16 pens using the same bedding materials as in Exp. I, with fan (blowing 2.00 m/s) and no fan treatments, and feed bunk side (FB) and water supply side (WS) within a pen (4.5 m, width*9.0 m, length). Beddings were replaced with fresh bedding materials when moisture concentrations were over 65%. No interactions among treatments were detected for moisture concentration and increment rates, and ammonia concentrations, but a significant effect was observed (p<0.01) for each of the treatments. Both concentrations and increment rate of moisture were higher (p<0.01) in the beddings without fan than with fan. Moisture concentrations and increment rate within a pen were also higher (p<0.01) in FB than WS. Thus, the whole no-fan-FB and sawdust-fan-FB were replaced with fresh bedding material between 4 to 5 experimental weeks. The ammonia concentrations and pH of beddings were not significantly different among treatments. Therefore, using cocopeat bedding with a blowing fan can extend twice the bedding utilization period, and WS within a pen showed twice the bedding-life compared to FB. Despite the outstanding characteristics of cocopeat compared with sawdust, using cocopeat as an alternative for sawdust bedding is not recommended for cattle management, considering it has 4.4 times higher bedding cost and a dust production problem. PMID- 26950880 TI - Correction: Prevalence of Neutralizing Antibodies to Japanese Encephalitis Virus among High-Risk Age Groups in South Korea, 2010. PMID- 26950881 TI - Dynamic Clustering of the Bacterial Sensory Kinase BaeS. AB - Several bacterial sensory-kinase receptors form clusters on the cell membrane. However, the dynamics of sensory-kinase clustering are largely unclear. Using measurements of fluorescence anisotropy and time-lapse imaging of Escherichia coli cells, we demonstrate that copper ions trigger self-association of BaeS receptors and lead to rapid formation of clusters, which can be reversibly dispersed by a metal chelator. Copper ions did not trigger self-association of other fluorescently tagged sensory kinases, and other divalent metal ions could not elicit self-association of BaeS. The histidine residues in the BaeS periplasmic domain are essential for copper binding in vitro and are important for the copper-induced BaeS responses in vivo. BaeS clustering was triggered also under conditions that directly triggered BaeS-dependent transcriptional responses. Thus, clustering of sensory kinase receptors can be dynamic and context dependent and can be triggered by specific environmental cues. PMID- 26950882 TI - Distribution of CpG Motifs in Upstream Gene Domains in a Reef Coral and Sea Anemone: Implications for Epigenetics in Cnidarians. AB - Coral reefs are under assault from stressors including global warming, ocean acidification, and urbanization. Knowing how these factors impact the future fate of reefs requires delineating stress responses across ecological, organismal and cellular scales. Recent advances in coral reef biology have integrated molecular processes with ecological fitness and have identified putative suites of temperature acclimation genes in a Scleractinian coral Acropora hyacinthus. We wondered what unique characteristics of these genes determined their coordinate expression in response to temperature acclimation, and whether or not other corals and cnidarians would likewise possess these features. Here, we focus on cytosine methylation as an epigenetic DNA modification that is responsive to environmental stressors. We identify common conserved patterns of cytosine guanosine dinucleotide (CpG) motif frequencies in upstream promoter domains of different functional gene groups in two cnidarian genomes: a coral (Acropora digitifera) and an anemone (Nematostella vectensis). Our analyses show that CpG motif frequencies are prominent in the promoter domains of functional genes associated with environmental adaptation, particularly those identified in A. hyacinthus. Densities of CpG sites in upstream promoter domains near the transcriptional start site (TSS) are 1.38x higher than genomic background levels upstream of -2000 bp from the TSS. The increase in CpG usage suggests selection to allow for DNA methylation events to occur more frequently within 1 kb of the TSS. In addition, observed shifts in CpG densities among functional groups of genes suggests a potential role for epigenetic DNA methylation within promoter domains to impact functional gene expression responses in A. digitifera and N. vectensis. Identifying promoter epigenetic sequence motifs among genes within specific functional groups establishes an approach to describe integrated cellular responses to environmental stress in reef corals and potential roles of epigenetics on survival and fitness in the face of global climate change. PMID- 26950884 TI - Timely Diagnosis of Acute Kidney Injury Using Kinetic eGFR and the Creatinine Excretion to Production Ratio, E/eG - Creatinine Can Be Useful! AB - Post transplant repeated measurements of urine volume and serum creatinine (sCr) are used to assess kidney function. Under non-steady state conditions, repeated measurement of sCr allows calculation of the kinetic estimated GFR (KeGFR). Additional measurement of urinary creatinine allows the calculation of the creatinine excretion to (estimated) production ratio (E/eG). We hypothesized that post-transplant KeGFR and E/eG would predict delayed graft function (DGF), as early as 4 h and outperform a validated clinical model at 12 h. This was a retrospective analysis of prospectively acquired data in a study of 56 recipients of deceased-donor kidney transplant. We assessed predictive performance with the area under the receiver operator characteristic curve (AUC) and the added value to a clinical model with integrated discrimination improvement analysis. At 4 h, the AUC for E/eG was 0.87 (95% CI 0.77-0.96) and for KeGFR 0.69 (95% CI 0.56 0.83). Both E/eG and KeGFR improved the risk prediction of a clinical model for DGF by 32 and 18%, and for non-DGF by 17 and 10%, respectively. While E/eG had better predictive performance of DGF than KeGFR, KeGFR might also facilitate perioperative management including drug dosing after kidney transplantation. Together these measurements may facilitate the possibility of conducting trials of early intervention to ameliorate the adverse effects of ischaemia-reperfusion injury on long-term DGF. PMID- 26950883 TI - Topographic Distribution of Stimulus-Specific Adaptation across Auditory Cortical Fields in the Anesthetized Rat. AB - Stimulus-specific adaptation (SSA) in single neurons of the auditory cortex was suggested to be a potential neural correlate of the mismatch negativity (MMN), a widely studied component of the auditory event-related potentials (ERP) that is elicited by changes in the auditory environment. However, several aspects on this SSA/MMN relation remain unresolved. SSA occurs in the primary auditory cortex (A1), but detailed studies on SSA beyond A1 are lacking. To study the topographic organization of SSA, we mapped the whole rat auditory cortex with multiunit activity recordings, using an oddball paradigm. We demonstrate that SSA occurs outside A1 and differs between primary and nonprimary cortical fields. In particular, SSA is much stronger and develops faster in the nonprimary than in the primary fields, paralleling the organization of subcortical SSA. Importantly, strong SSA is present in the nonprimary auditory cortex within the latency range of the MMN in the rat and correlates with an MMN-like difference wave in the simultaneously recorded local field potentials (LFP). We present new and strong evidence linking SSA at the cellular level to the MMN, a central tool in cognitive and clinical neuroscience. PMID- 26950885 TI - Effects of Prenatal Dexamethasone on the Rat Pituitary Gland and Gonadotropic Cells in Female Offspring. AB - Glucocorticoids have a strong influence on growth and maturation of fetal organ systems, but overexposure to exogenous glucocorticoids may retard fetal growth and alter developmental processes in sensitive tissues. The aim of this study was to specifically determine whether prenatal exposure to dexamethasone (Dx) altered normal development and function of pituitary gonadotropic cells in neonatal, infant and peripubertal female offspring. On day 16 of pregnancy, rat dams received 1.0 mg Dx/kg body weight (BW) s.c., followed by 0.5 mg Dx/kg BW on days 17 and 18 of gestation. Control gravid females received the same volume of saline. Female offspring were sacrificed on days 5, 16 and 38 after delivery. The volume of the pituitary gland estimated using Cavalieri's principle was significantly reduced (p < 0.05). Using a fractionator-physical disector method, we found reduced total numbers of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) cells (p < 0.05), accompanied by a decrease (p < 0.05) in serum concentrations of FSH and LH, while the relative intensity of FSH and LH immunofluorescence remained unchanged in neonatal, infant and peripubertal female offspring prenatally exposed to Dx. The data document that overexposure to Dx during fetal development evokes developmental programming of the female reproductive system at the pituitary cellular level, which may be associated with impaired reproductive function. PMID- 26950887 TI - Management of endobronchial tumors. AB - PURPOSE OF REVIEW: Owing to the high morbidity and mortality rates related to airways obstruction, an effective management of endobronchial tumors is essential to improve survival and symptoms in these patients. As interventional pulmonology plays a major role in this context, the purpose of the present review is to focus on current evidence and indications of therapeutic bronchoscopy, in particular of ablative techniques. RECENT FINDINGS: Several ablative techniques are currently available and include 'immediate' or 'delayed' procedures according to the expected time to restore airways patency. In case of critical lesions, it is mandatory to promptly restore ventilation through the immediate techniques, whereas the delayed approaches, with a prolonged effect, should be reserved for a nonemergency setting, according to clinical and prognostic factors. Recent data confirmed that almost every technique, in experienced hands, when the specific indications are met, is highly effective in restoring airways patency, with a valuable risk-benefits profile. SUMMARY: Owing to the complex heterogeneity of different clinical settings, management of endobronchial tumors requires a multimodal approach to assess the best strategy. Despite the lack of high-quality prospective studies comparing the individual techniques or strategy, it is undisputed that therapeutic bronchoscopy should not be considered as a last resort, but rather as a key step of such multimodal management. PMID- 26950886 TI - Rising population of survivors of oral squamous cell cancer in the United States. AB - BACKGROUND: The incidence of oropharyngeal cancer (OPC) and a subset of oral cavity cancer (OCC) is increasing in the United States. To the authors' knowledge, the presumed growing prevalence of survivors of OPC and OCC has not been investigated to date. METHODS: Retrospective analysis of Surveillance, Epidemiology, and End Results data (1975-2012) estimated changes in incidence, 5 year cause-specific survival, and prevalence for OPC and OCC. Changes in incidence, cause-specific survival and prevalence were estimated by linear regression and expressed as the percentage change (B). Differences in incidence trends over time were determined by joinpoint analysis. RESULTS: The incidence of OPC increased by 62.6% from 1975 through 2012. Notable increases in OPC incidence were observed among men, white individuals, and those of younger ages. The 5-year survival for OPC increased significantly for all sexes, races, and individuals aged >30 years, with white individuals and males experiencing the largest increase in survival. By contrast, the incidence of OCC declined by 22.3% during the same time period. OCC incidence decreased across all groups but increased among individuals aged 30 to 39 years. Significant increases in survival were observed for OCC, except for those who were female, black, and aged <40 years. The prevalence of survivors of OPC increased from 2000 to 2012 (B, 115.1 per 100,000 individuals per year; P<.0001), whereas the prevalence of survivors of OCC significantly decreased (B, -15.8 per 100,000 individuals per year; P<.0001). CONCLUSIONS: The prevalence of survivors of OPC is increasing, whereas the prevalence of survivors of OCC is declining. These data portend significant implications for long-term care planning for survivors of OPC and OCC. Cancer 2016;122:1380-1387. (c) 2016 American Cancer Society. PMID- 26950888 TI - Modeling of ultrasonic nonlinearities for dislocation evolution in plastically deformed materials: Simulation and experimental validation. AB - A nonlinear constitutive relationship was established to investigate nonlinear behaviors of ultrasonic wave propagation in plastically damaged media based on analyses of mixed dislocation evolution. Finite element simulations of longitudinal wave propagation in plastically deformed martensite stainless steel were performed based on the proposed nonlinear constitutive relationship, in which the contribution of mixed dislocation to acoustic nonlinearity was considered. The simulated results were validated by experimental measurements of plastically deformed 30Cr2Ni4MoV martensite stainless steels. Simulated and experimental results both reveal a monotonically increasing tendency of the normalized acoustic nonlinearity parameter as a function of plastic strain. Microscopic studies revealed that the changes of the acoustic nonlinearity are mainly attributed to dislocation evolutions, such as dislocation density, dislocation length, and the type and fraction of dislocations during plastic loading. PMID- 26950889 TI - Time-distance domain transformation for Acoustic Emission source localization in thin metallic plates. AB - Acoustic Emission used in Non-Destructive Testing is focused on analysis of elastic waves propagating in mechanical structures. Then any information carried by generated acoustic waves, further recorded by a set of transducers, allow to determine integrity of these structures. It is clear that material properties and geometry strongly impacts the result. In this paper a method for Acoustic Emission source localization in thin plates is presented. The approach is based on the Time-Distance Domain Transform, that is a wavenumber-frequency mapping technique for precise event localization. The major advantage of the technique is dispersion compensation through a phase-shifting of investigated waveforms in order to acquire the most accurate output, allowing for source-sensor distance estimation using a single transducer. The accuracy and robustness of the above process are also investigated. This includes the study of Young's modulus value and numerical parameters influence on damage detection. By merging the Time Distance Domain Transform with an optimal distance selection technique, an identification-localization algorithm is achieved. The method is investigated analytically, numerically and experimentally. The latter involves both laboratory and large scale industrial tests. PMID- 26950891 TI - Measuring the bioactivity and molecular conformation of typically globular proteins with phenothiazine-derived methylene blue in solid and in solution: A comparative study using photochemistry and computational chemistry. AB - Methylene blue is a phenothiazine agent, that possesses a diversity of biomedical and biological therapeutic purpose, and it has also become the lead compound for the exploitation of other pharmaceuticals such as chlorpromazine and the tricyclic antidepressants. However, the U.S. Food and Drug Administration has acquired cases of detrimental effects of methylene blue toxicities such as hemolytic anemia, methemoglobinemia and phototoxicity. In this work, the molecular recognition of methylene blue by two globular proteins, hemoglobin and lysozyme was characterized by employing fluorescence, circular dichroism (CD) along with molecular modeling at the molecular scale. The recognition of methylene blue with proteins appears fluorescence quenching via static type, this phenomenon does cohere with time-resolved fluorescence lifetime decay that nonfluorescent protein-drug conjugate formation has a strength of 10(4)M(-1), and the primary noncovalent bonds, that is hydrogen bonds, pi-conjugated effects and hydrophobic interactions were operated and remained adduct stable. Meantime, the results of far-UV CD and synchronous fluorescence suggest that the alpha-helix of hemoglobin/lysozyme decreases from 78.2%/34.7% (free) to 58.7%/23.8% (complex), this elucidation agrees well with the elaborate description of three-dimensional fluorescence showing the polypeptide chain of proteins partially destabilized upon conjugation with methylene blue. Furthermore, both extrinsic fluorescent indicator and molecular modeling clearly exhibit methylene blue is situated within the cavity constituted by alpha1, beta2 and alpha2 subunits of hemoglobin, while it was located at the deep fissure on the lysozyme surface and Trp-62 and Trp-63 residues are nearby. With the aid of computational analyses and combining the wet experiments, it can evidently be found that the recognition ability of proteins for methylene blue is patterned upon the following sequence: lysozyme90% viable when incubated with NPs for up to 7 days). These features highlight the potential for use of ZIF-90 nanostructures in bioimaging and targeted drug delivery applications. PMID- 26950895 TI - High conservation level of CD8(+) T cell immunogenic regions within an unusual H1N2 human influenza variant. AB - Current seasonal influenza vaccines require regular updates due to antigenic drift causing loss of effectiveness and therefore providing little or no protection against novel influenza A subtypes. Next generation vaccines capable of eliciting CD8(+) T cell (CTL) mediated cross-protective immunity may offer a long-term alternative strategy. However, measuring pre- and existing levels of CTL cross-protection in humans is confounded by differences in infection histories across individuals. During 2000-2003, H1N2 viruses circulated persistently in the human population for the first time and we hypothesized that the viral nucleoprotein (NP) contained novel CTL epitopes that may have contributed to the survival of the viruses. This study describes the immunogenic NP peptides of H1N1, H2N2, and H3N2 influenza viruses isolated from humans over the past century, 1918-2003, by comparing this historical dataset to reference NP peptides from H1N2 that circulated in humans during 2000-2003. Observed peptides sequences ranged from highly conserved (15%) to highly variable (12%), with variation unrelated to reported immunodominance. No unique NP peptides which were exclusive to the H1N2 viruses were noted. However, the virus had inherited the NP from a recently emerged H3N2 variant containing novel peptides, which may have assisted its persistence. Any advantage due to this novelty was subsequently lost with emergence of a newer H3N2 variant in 2003. Our approach has potential to provide insight into the population context in which influenza viruses emerge, and may help to inform immunogenic peptide selection for CTL-inducing influenza vaccines. J. Med. Virol. 88:1725-1732, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26950896 TI - Neonatal risk factors of atopic dermatitis in Denmark - Results from a nationwide register-based study. AB - BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory skin condition with a multifactorial etiopathogenesis. Studies have suggested that several perinatal factors may influence the risk of AD in early childhood. We investigated possible neonatal risk factors such as jaundice, blue light phototherapy, birthweight, gestational age at birth, and season of birth on the risk of developing AD in the first 5 years of life. MATERIALS & METHODS: Data were collected through Danish nationwide administrative registers. All newborn children between 1997 and 2007 (n = 673,614) were included in the cohort. Incidence rate ratios (IRRs) were estimated with 95% confidence intervals (95% CIs) by multivariate Poisson regression analyses. RESULTS: We identified a total of 85,743 children with AD in the first 5 years of life. The risk of AD was slightly increased in children with neonatal jaundice (IRR 1.13 [95% CI 1.06-1.21]). Preterm birth was inversely associated with the risk of AD (IRR 0.74, [95% CI 0.68-0.81]) as well as low birthweight (IRR 0.68, [95% CI 0.61-0.75]). Children born in fall and winter seasons had an increased risk of AD compared to spring and summer. No association between neonatal blue light therapy and the risk of AD was found. CONCLUSIONS: Low birthweight and preterm birth were inversely associated with AD, while neonatal jaundice and cold seasons of birth were associated with an increased risk of AD. PMID- 26950897 TI - Connective tissue diseases and autoimmune thyroid disorders in the first trimester of pregnancy. AB - OBJECTIVE: To investigate the rates and coexistence of autoimmune thyroid and connective tissue diseases (CTD) during the first trimester of pregnancy and their influence on pregnancy outcome. STUDY DESIGN: A cohort study of 150 women with CTD diagnosed during first trimester of pregnancy and 150 negative controls. MAIN OUTCOME MEASURES: Screening of CTD by a self-reported questionnaire, rheumatic and thyroid autoantibody detection, clinical rheumatological evaluation and obstetric outcomes. RESULTS: Out of 3852 women screened, 61 (1.6%) were diagnosed with undefined connective tissue disease (UCTD), 28 (0.7%) with major CTD (six rheumatoid arthritis, five systemic lupus erythematosus, eight Sjogren syndrome, five anti-phospholipid syndrome, two systemic sclerosis, one mixed CTD and one monoarticular arthritis) and 61 (1.6%) had insufficient criteria for a diagnosis of a rheumatic disease. The overall prevalence of either thyroid peroxidase (TPO-a) or thyroglobulin (TG-a) autoantibodies detection was 8% (12/150) among controls, 62.3% (38/61) among UCTD and 60.7% (17/28) in women with a major CTD (p<.001 compared to controls for both comparisons). After adjustment for confounders, overall CTDs (major or undefined) (OR=3.54, 95% CI; 1.61-7.78) and TPO-a plus TG-a positivity (OR=2.78, 95% CI;1.29-5.98) were independently associated with increased risks of moderate-severe complications of pregnancy (miscarriage, fetal growth restriction, preeclampsia, delivery before 34 weeks). CONCLUSIONS: Rheumatic and thyroid autoantibodies during pregnancy are closely associated. Thyroid antibodies could add to the risk of adverse pregnancy outcome associated with connective tissue diseases. PMID- 26950899 TI - Toxic and genotoxic effects of the 2,4-dichlorophenoxyacetic acid (2,4-D)-based herbicide on the Neotropical fish Cnesterodon decemmaculatus. AB - Acute toxicity and genotoxicity of the 54.8% 2,4-D-based commercial herbicide DMA(r) were assayed on Cnesterodon decemmaculatus (Pisces, Poeciliidae). Whereas lethal effect was used as the end point for mortality, frequency of micronuclei (MNs), other nuclear abnormalities and primary DNA damage evaluated by the single cell gel electrophoresis (SCGE) assay were employed as end points for genotoxicity. Mortality studies demonstrated an LC50 96 h value of 1008 mg/L (range, 929-1070) of 2,4-D. Behavioral changes, e.g., gathering at the bottom of the aquarium, slowness in motion, slow reaction and abnormal swimming were observed. Exposure to 2,4-D within the 252-756 mg/L range increased the frequency of MNs in fish exposed for both 48 and 96 h. Whereas blebbed nuclei were induced in treatments lasting for 48 and 96 h, notched nuclei were only induced in fish exposed for 96 h. Regardless of both concentration and exposure time, 2,4-D did not induce lobed nuclei and binucleated erythrocytes. In addition, we found that exposure to 2,4-D within the 252-756 mg/L range increased the genetic damage index in treatments lasting for either 48 and 96 h. The results represent the first experimental evidence of the lethal and several sublethal effects, including behavioral alterations and two genotoxic properties namely the induction of MNs and primary DNA strand breaks, exerted by 2,4-D on an endemic organism as C. decemmaculatus. PMID- 26950900 TI - LC-MS/MS method development for quantitative analysis of acetaminophen uptake by the aquatic fungus Mucor hiemalis. AB - Acetaminophen is a pharmaceutical, frequently found in surface water as a contaminant. Bioremediation, in particular, mycoremediation of acetaminophen is a method to remove this compound from waters. Owing to the lack of quantitative analytical method for acetaminophen in aquatic organisms, the present study aimed to develop a method for the determination of acetaminophen using LC-MS/MS in the aquatic fungus Mucor hiemalis. The method was then applied to evaluate the uptake of acetaminophen by M. hiemalis, cultured in pellet morphology. The method was robust, sensitive and reproducible with a lower limit of quantification of 5 pg acetaminophen on column. It was found that M. hiemalis internalize the pharmaceutical, and bioaccumulate it with time. Therefore, M. hiemalis was deemed a suitable candidate for further studies to elucidate its pharmaceutical tolerance and the longevity in mycoremediation applications. PMID- 26950898 TI - Cause-specific long-term mortality in survivors of childhood cancer in Switzerland: A population-based study. AB - Survivors of childhood cancer have a higher mortality than the general population. We describe cause-specific long-term mortality in a population-based cohort of childhood cancer survivors. We included all children diagnosed with cancer in Switzerland (1976-2007) at age 0-14 years, who survived >=5 years after diagnosis and followed survivors until December 31, 2012. We obtained causes of death (COD) from the Swiss mortality statistics and used data from the Swiss general population to calculate age-, calendar year-, and sex-standardized mortality ratios (SMR), and absolute excess risks (AER) for different COD, by Poisson regression. We included 3,965 survivors and 49,704 person years at risk. Of these, 246 (6.2%) died, which was 11 times higher than expected (SMR 11.0). Mortality was particularly high for diseases of the respiratory (SMR 14.8) and circulatory system (SMR 12.7), and for second cancers (SMR 11.6). The pattern of cause-specific mortality differed by primary cancer diagnosis, and changed with time since diagnosis. In the first 10 years after 5-year survival, 78.9% of excess deaths were caused by recurrence of the original cancer (AER 46.1). Twenty five years after diagnosis, only 36.5% (AER 9.1) were caused by recurrence, 21.3% by second cancers (AER 5.3) and 33.3% by circulatory diseases (AER 8.3). Our study confirms an elevated mortality in survivors of childhood cancer for at least 30 years after diagnosis with an increased proportion of deaths caused by late toxicities of the treatment. The results underline the importance of clinical follow-up continuing years after the end of treatment for childhood cancer. PMID- 26950902 TI - Direct screening of tobacco indicators in urine and saliva by Atmospheric Pressure Solid Analysis Probe coupled to quadrupole-time of flight mass spectrometry (ASAP-MS-Q-TOF-). AB - A new screening method has been explored for direct analysis of tobacco smoke biomarkers in biological matrices (i.e., saliva and urine). Single run analysis using Atmospheric pressure Solid Analysis Probe (ASAP) and high resolution mass spectrometry with quadrupole and time of flight detector has been applied directly to some biological samples (i.e., urine and saliva), providing a fast, efficient and sensitive method of identification. The method has been applied to saliva and urine samples from heavy tobacco smokers for exposure studies. Nicotine itself, nicotine metabolites (i.e., cotinine, trans-3'-hydroxycotinine, nicotine-N-glucuronide) and other related tobacco smoke toxic compounds (i.e., NNK 4-[methyl(nitroso)amino]-1-(3-pyridinyl)-1-butanone, anatabine) were found in the analyzed samples. The identification of compounds was confirmed by ultrahigh performance liquid chromatography with MS-triple quadrupole detector after sample treatment. Different temporal trends and biomarkers behavior have been found in time series related samples. Both methods are compared for screening of these biological matrices. PMID- 26950903 TI - The use of asymmetrical flow field-flow fractionation with on-line detection in the study of drug retention within liposomal nanocarriers and drug transfer kinetics. AB - Due to their solubilizing capabilities, liposomes (phospholipid vesicles) are suited for designing formulations for intravenous administration of drug compounds which are poorly water-soluble. Despite the good in-vitro stability of such formulations with minimal drug leakage, upon i.v. injection there is a risk of premature drug loss due to drug transfer to plasma proteins and cell membranes. Here we report on the refinement of a recently introduced simple in vitro predictive tool by Hinna and colleagues in 2014, which brings small drug loaded (donor) liposomes in contact with large acceptor liposomes, the latter serving as a model mimicking biological sinks in the body. The donor- and acceptor-liposomes were subsequently separated using asymmetrical flow field-flow fractionation (AF4), during which the sample is exposed to a large volume of eluent which corresponds to a dilution factor of approximately 600. The model drug content in the donor- and acceptor fraction was quantified by on-line UV/VIS extinction measurements with correction for turbidity and by off-line HPLC measurements of collected fractions. The refined method allowed for (near) baseline separation of donor and acceptor vesicles as well as reliable quantification of the drug content not only of the donor- but now also of the acceptor-liposomes due to their improved size-homogeneity, colloidal stability and reduced turbidity. This improvement over the previously reported approach allowed for simultaneous quantification of both drug transfer and drug release to the aqueous phase. By sampling at specific incubation times, the release and transfer kinetics of the model compound p-THPP (5,10,15,20-tetrakis(4 hydroxyphenyl)21H,23H-porphine) was determined. p-THPP is structurally closely related to the photosensitizer temoporfin, which is in clinical use and under evaluation in liposomal formulations. The transfer of p-THPP to the acceptor vesicles followed 1st order kinetics with a half-life of approximately 300 min. As expected, equilibrium distribution between donor- and acceptor vesicles was proportional to the lipid mass ratio. An initial rapid transfer of p-THPP was found (~ 5%) and investigated further by determining the extent of transfer between donor and acceptor during separation. The donor- and acceptor phase were found to be separated within few minutes and only minor (<= 2%) transfer could be detected within the AF4 channel under the conditions applied for fractionation. These results demonstrates the potential of our AF4 based method as an in vitro tool to determine retention properties of lipophilic compounds within liposomal carriers in particular, but also within a variety of nano-particulate carriers provided that they exhibit a sufficient size difference compared to the applied colloidal acceptor phase. PMID- 26950904 TI - Unintended Consequences. PMID- 26950905 TI - Impact of the Primary Care Exception on Family Medicine Resident Coding. AB - BACKGROUND AND OBJECTIVES: The Medicare Primary Care Exception (PCE) allows residents to see and bill for less-complex patients independently in the primary care setting, requiring attending physicians only to see patients for higher level visits and complete physical exams in order to bill for them as such. Primary care residencies apply the PCE in various ways. We investigated the impact of the PCE on resident coding practices. METHODS: Family medicine residency directors in a five-state region completed a survey regarding interpretation and application of the PCE, including the number of established patient evaluation and management codes entered by residents and attending faculty at their institution. The percentage of high-level codes was compared between residencies using chi-square tests. RESULTS: We analyzed coding data for 125,016 visits from 337 residents and 172 faculty physicians in 15 of 18 eligible family medicine residencies. Among programs applying the PCE criteria to all patients, residents billed 86.7% low-mid complexity and 13.3% high-complexity visits. In programs that only applied the PCE to Medicare patients, residents billed 74.9% low-mid complexity visits and 25.2% high-complexity visits. Attending physicians coded more high-complexity visits at both types of programs. The estimated revenue loss over the 1,650 RRC-required outpatient visits was $2,558.66 per resident and $57,569.85 per year for the average residency in our sample. CONCLUSIONS: Residents at family medicine programs that apply the PCE to all patients bill significantly fewer high-complexity visits. This finding leads to compliance and regulatory concerns and suggests significant revenue loss. Further study is required to determine whether this discrepancy also reflects inaccuracy in coding. PMID- 26950901 TI - Effects of unplanned treatment interruptions on HIV treatment failure - results from TAHOD. AB - OBJECTIVES: Treatment interruptions (TIs) of combination antiretroviral therapy (cART) are known to lead to unfavourable treatment outcomes but do still occur in resource-limited settings. We investigated the effects of TI associated with adverse events (AEs) and non-AE-related reasons, including their durations, on treatment failure after cART resumption in HIV-infected individuals in Asia. METHODS: Patients initiating cART between 2006 and 2013 were included. TI was defined as stopping cART for >1 day. Treatment failure was defined as confirmed virological, immunological or clinical failure. Time to treatment failure during cART was analysed using Cox regression, not including periods off treatment. Covariables with P < 0.10 in univariable analyses were included in multivariable analyses, where P < 0.05 was considered statistically significant. RESULTS: Of 4549 patients from 13 countries in Asia, 3176 (69.8%) were male and the median age was 34 years. A total of 111 (2.4%) had TIs due to AEs and 135 (3.0%) had TIs for other reasons. Median interruption times were 22 days for AE and 148 days for non-AE TIs. In multivariable analyses, interruptions >30 days were associated with failure (31-180 days HR = 2.66, 95%CI (1.70-4.16); 181-365 days HR = 6.22, 95%CI (3.26-11.86); and >365 days HR = 9.10, 95% CI (4.27-19.38), all P < 0.001, compared to 0-14 days). Reasons for previous TI were not statistically significant (P = 0.158). CONCLUSIONS: Duration of interruptions of more than 30 days was the key factor associated with large increases in subsequent risk of treatment failure. If TI is unavoidable, its duration should be minimised to reduce the risk of failure after treatment resumption. PMID- 26950906 TI - Clinical Pharmacists as Educators in Family Medicine Residency Programs: A CERA Study of Program Directors. AB - BACKGROUND AND OBJECTIVES: The clinical pharmacist's role within family medicine residency programs (FMRPs) is well established. However, there is limited information regarding perceptions of program directors (PDs) about clinical pharmacy educators. The study objectives were (1) to estimate the prevalence of clinical pharmacists within FMRPs and (2) to determine barriers and motivations for incorporation of clinical pharmacists as educators. METHODS: The Council of Academic Family Medicine Educational Research Alliance (CERA) distributed an electronic survey to PDs. Questions addressed formalized pharmacotherapy education, clinical pharmacists in educator roles, and barriers and benefits of clinical pharmacists in FMRPs. RESULTS: The overall response rate was 50% (224/451). Seventy-six percent (170/224) of the responding PDs reported that clinical pharmacists provide pharmacotherapy education in their FMRPs, and 57% (97/170) consider clinical pharmacists as faculty members. In programs with clinical pharmacists, 72% (83/116) of PDs reported having a systematic approach for teaching pharmacotherapy versus 22% (21/95) in programs without. In programs without clinical pharmacists, the top barrier to incorporation was limited ability to bill for clinical services 48% (43/89) versus 29% (32/112) in programs with clinical pharmacists. In both programs with and without clinical pharmacists, the top benefit of having clinical pharmacists was providing a collaborative approach to pharmacotherapy education for residents (35% and 36%, respectively). CONCLUSIONS: Less than half of FMRPs incorporate clinical pharmacists as faculty members. Despite providing collaborative approaches to pharmacotherapy education, their limited ability to bill for services is a major barrier. PMID- 26950907 TI - Teaching Brief Motivational Interventions for Diabetes to Family Medicine Residents. AB - BACKGROUND AND OBJECTIVES: As time and resource constraints grow in primary care, so does the value of efficient strategies to promote patient self-management, particularly for chronic diseases such as diabetes mellitus (DM). To that end, incorporating motivational interviewing (MI) into clinical practice has been shown to improve outcomes for patients with DM. Brief motivational interventions (BMI) draw from MI and may be integrated into more concise office visits. Little research has investigated strategies for BMI training for family medicine residents, particularly in the care of patients with DM. This study evaluates the impact of BMI training on improving DM self-management. METHODS: Family medicine residents were trained in BMI for DM over four sessions, then implemented BMI during routine office visits for 1 year. Pre- and post-implementation surveys were compared between residents who received BMI training and those who did not. RESULTS: After BMI training, residents' self-reported use of MI-adherent approaches to managing unhealthy behaviors in patients with DM doubled, and knowledge of MI increased by nearly 50%. BMI-trained residents showed 19% improvement in the application of MI skills, using an objective measure of open response questions to behavioral change statements. CONCLUSIONS: After fewer than four training sessions in BMI, residents not only improved in their ability to apply motivational skills but also altered their clinical approaches to counseling patients with DM. BMI can also be used to evoke health behavior changes, thereby improving self-management. Training family medicine residents in BMI is effective and can be easily incorporated into a residency curriculum. PMID- 26950908 TI - The Status of Family Medicine Training Programs in the Asia Pacific. AB - BACKGROUND AND OBJECTIVES: The family medicine training programs in the Asia Pacific (AP) are evolving. To date, there is a lack of comprehensive and systematic documentation on the status of family medicine training in the AP. This study aims to determine the status of family medicine training at both the undergraduate and postgraduate levels in medical schools (universities or colleges) in the AP. METHODS: In 2014, the authors conducted a cross-sectional online survey to assess the undergraduate and postgraduate family medicine programs in academic family medicine departments from AP countries. A 37-item online survey questionnaire was sent to key informants from academic institutions with established family medicine departments/units. Only one response from each family medicine department/unit was included in the analysis. RESULTS: The medical school and country response rates were 31.31% and 64.1%, respectively. The majority of the medical schools (94.7%, n=71/75) reported having a department/unit for family medicine. Family medicine is recognized as a specialist degree by the governments of 20/25 countries studied. Family medicine is included in the undergraduate program of 92% (n=69/75) of all the participating medical schools. Only slightly more than half (53.3%) (n=40/75) reported conducting a postgraduate clinical program. Less than one third (26.7%) (n=20/75) of the medical schools conducted postgraduate research programs. CONCLUSIONS: Undergraduate training remains the focus of most family medicine departments/units in the AP. Nevertheless, the number of postgraduate programs is increasing. A more rigorous and long-term documentation of family medicine training in the AP is warranted. PMID- 26950909 TI - Medical Student Decision Making Regarding Pursuit of a Public Health Degree. AB - BACKGROUND AND OBJECTIVES: Few US medical school graduates receive a public health degree. We sought to identify factors involved in medical students' decisions to pursue dual medical and public health degrees and describe the decision-making process. METHODS: We conducted focus group discussions and telephone interviews with medical students considering, or enrolled in, a public health degree program. Participants described early exposures to public health, perspectives on physician public health roles, advantages and disadvantages of a public health degree, and the relative importance of factors influencing their decision to pursue a public health degree. Data were coded using open codes, and thematic analysis was performed. RESULTS: Medical students' decisions about pursuing a public health degree are based on consideration of advantages and disadvantages of academic, personal, and financial factors. Students place weights on various factors and value guidance. CONCLUSIONS: Access to training and information about public health programs and career opportunities may facilitate decision-making. Knowledge of factors involved in students' decisions and the decision-making process will allow mentors, advisors, faculty, and staff working to recruit students into MPH programs to support students interested in earning dual medical and public health degrees. Future research should explore avenues for supporting medical student decision-making and further reducing barriers to public health training. PMID- 26950910 TI - Training Future Clinician-Educators: A Track for Family Medicine Residents. AB - BACKGROUND AND OBJECTIVES: Despite a growing demand for skilled clinician educators, residents today rarely receive formal training in clinical teaching, curriculum development, administration, leadership, or educational scholarship. The authors describe the development, implementation, and preliminary evaluation of the O'Connor Stanford Leaders in Education Residency (OSLER) track, a novel clinician-educator track within the family medicine residency program affiliated with Stanford University School of Medicine. METHODS: In 2010, the OSLER track was introduced at O'Connor Hospital, a community hospital that houses an 8-8-8 family medicine residency program. Residents who are in good standing can apply to the track at the midpoint of their first postgraduate year. Residents are immersed in a flexible, experience-based, 2.5-year-long curriculum with hands-on teaching activities at its core. To foster skills in educational scholarship, track residents are required to design and complete a scholarly project. RESULTS: A comprehensive evaluation plan is currently in progress. Preliminary data indicates high levels of satisfaction with the track's overall value, impact on core teaching skills, and effect on career trajectory. Residents gained more confidence in core teaching skills as they progressed through the track. Scholarly work output by residents has increased significantly since the track was implemented. The residency program has seen an increased interest from applicants since the track was started, with data suggesting that applicant quality has increased from the pre-track to post-track years. CONCLUSIONS: More research is needed to assess the effectiveness and reproducibility of this clinician-educator track. If proven, this model may be replicated at other academic medical centers. PMID- 26950911 TI - Weighty Problems: Predictors of Family Physicians Documenting Overweight and Obesity. AB - BACKGROUND AND OBJECTIVES: Documenting obesity on the problem list has been shown to promote action about obesity and overweight, yet a majority of primary care providers do not record obesity on the medical problem list. With this in mind, our objectives were to determine the proportion of physicians' documentation of overweight (OW) or obesity on the problem list in our primary care teaching practice and to identify predictors of physician documentation of OW/obesity. METHODS: De-identified health records of 6,195 adult patients with BMI ? 25 kg/m2 seen by a family physician over a 2-year period were included. Using multivariate logistic regression, patient age, BMI, gender, race, insurance, comorbidities, number of visits, physician gender or role, and practice site (suburban versus urban) were examined in relation to inclusion of OW/obesity on the medical problem list. RESULTS: Few (21.1%) patients had OW/obesity on their problem list. In the multivariate model, female PCPs were significantly more likely to document OW/obesity (OR=1.39, 95% CI=1.18--1.63) compared to male PCPs, and faculty were 26% more likely to document obesity (95% CI=1.07--1.48) compared to residents. Female patients, those with hypertension, diabetes, hyperlipidemia, and those with six or more visits were significantly more likely to have obesity on their problem lists, while patients with Medicaid were less likely to have obesity recorded. No significant difference was seen by race. CONCLUSIONS: Nearly 80% of OW and obese patients were not identified on the problem list. Patient gender, comorbidity, and number of visits were associated with documentation. Future research should examine automatic documentation of OW/obesity on the medical problem list. PMID- 26950912 TI - The One Minute Learner: Evaluation of a New Tool to Promote Discussion of Medical Student Goals and Expectations in Clinical Learning Environments. AB - BACKGROUND AND OBJECTIVES: The transition from pre-clerkship to clerkship curriculum in medical school presents many challenges to students. Student roles and supervising physicians' expectations vary widely. Efforts to ease this transition have included third-year orientations, skills sessions, field- specific training, and peer-to-peer communication/support. We developed a new tool, called The One Minute Learner (OML), to promote and structure discussion of student goals and expectations and empower student ownership of learning. The OML can be used quickly and easily by students and faculty to facilitate integration of medical students into the clinical setting. This paper describes the OML and reports evaluation of its effectiveness through student evaluations. METHODS: We compared student responses to two end-of-clerkship questions for the academic year before the OML was implemented to the first year of implementation. Students rated their orientation to their roles and responsibility and rated the communication of what was expected of them. RESULTS: The percentage of students rating these highly increased dramatically: for "I was oriented to my responsibilities and role," the percentage rating it highly (4--5 on a 5-point Likert scale) increased from 47% to 82%. For "Expectations of my role were communicated to me clearly" the percentage rating it highly increased from 66% to 89%. CONCLUSIONS: The OML is a new tool that can promote and structure a proactive discussion between student and teacher about goals and expectations, leading to better integration of students into the variety of clinical setting in which they rotate. PMID- 26950913 TI - Take a Breath and Consider the Other's Perspective. PMID- 26950914 TI - Week One. PMID- 26950915 TI - Refugees' Journey to Their Medical Home. PMID- 26950920 TI - Power Is Not a Dirty Word. PMID- 26950921 TI - Reactive oxygen species, essential molecules, during plant-pathogen interactions. AB - Reactive oxygen species (ROS) are continually generated as a consequence of the normal metabolism in aerobic organisms. Accumulation and release of ROS into cell take place in response to a wide variety of adverse environmental conditions including salt, temperature, cold stresses and pathogen attack, among others. In plants, peroxidases class III, NADPH oxidase (NOX) locates in cell wall and plasma membrane, respectively, may be mainly enzymatic systems involving ROS generation. It is well documented that ROS play a dual role into cells, acting as important signal transduction molecules and as toxic molecules with strong oxidant power, however some aspects related to its function during plant-pathogen interactions remain unclear. This review focuses on the principal enzymatic systems involving ROS generation addressing the role of ROS as signal molecules during plant-pathogen interactions. We described how the chloroplasts, mitochondria and peroxisomes perceive the external stimuli as pathogen invasion, and trigger resistance response using ROS as signal molecule. PMID- 26950922 TI - Optimization of methyl jasmonate and beta-cyclodextrin for enhanced production of taraxerol and taraxasterol in (Taraxacum officinale Weber) cultures. AB - CONTEXT: Taraxacum officinale Weber (TO) commonly known as "dandelion", is a tropical Asian medicinal plant which contains taraxasterol (TX) and taraxerol (TA) in its roots, which are reported to be commercially important anticancer compounds. OBJECTIVE: The main objective of the present study was to evaluate the increase in yield of TX and TA through elicitation by addition of abiotic elictors like methyl jasmonate (MJ) and beta-cyclodextrin (CD), to the root callus suspension cultures of TO. MATERIALS AND METHODS: The root callus suspension was maintained on Murashige and Skoog's (MS) medium MS + IAA + BA + 2, 4-D (0.5 ppm + 1 ppm + 0.5 ppm). The concentrations of the abiotic elicitors MJ and CD were optimized using central composite design (CCD) and quantification of TA and TX in elicited cultures was done by High Performance Liquid Chromatography (HPLC) analysis. RESULT: It was observed that MJ at a concentration of 0.2 mM showed good increase in content of TX to 0.032% w/w and at concentrations 0.05 mM, 0.1 mM and 0.2 mM showed similar increase in TA content to 0.018% w/w, whereas CD at the concentration of 25 mM showed highest increase in TX content to 0.036% w/w and at the concentrations of 25 mM, 50 mM showed increase in TA content to 0.023% w/w as compared to the plant root (PR) which showed content of TX as 0.0299% w/w and TA as 0.0169% w/w. DISCUSSION AND CONCLUSION: From the present investigation it was concluded that out of the two abiotic elicitors MJ and CD, CD was found to be more effective to increase TA and TX content in Dandelion cell cultures. PMID- 26950923 TI - Comparative proteomic analysis of seed embryo proteins associated with seed storability in rice (Oryza sativa L) during natural aging. AB - Seed storability is considered an important trait in rice breeding; however, the underlying regulating mechanisms remain largely unknown. Here, we carried out a physiological and proteomic study to identify proteins possibly related to seed storability under natural conditions. Two hybrid cultivars, IIYou998 (IIY998) and BoYou998 (BY998), were analyzed in parallel because they share the same restorer line but have significant differences in seed storability. After a 2-year storage period, the germination percentage of IIY998 was significantly lower than that of BY998, whereas the level of malondialdehyde was reversed, indicating that IIY998 seeds may suffer from more severe damage than BY998 during storage. However, we did not find correlation between activities of antioxidant enzymes of superoxide dismutase, peroxidase, and catalase and seed storability. We identified 78 embryo proteins in embryo whose abundance varied more than 3-fold different during storage or between IIY998 and BY998. More proteins changed in abundance in IIY998 embryo (67 proteins) during storage than in BY998 (10 proteins). Several redox regulation proteins, mainly glutathione-related proteins, exhibited different degree of change during storage between BY998 and IIY998 and might play an important role protecting embryo proteins from oxidation. In addition, some disease/defense proteins, including DNA-damage-repair/toleration proteins, and a putative late embryogenesis abundant protein were significantly downregulated in IIY998, whereas their levels did not change in BY998, indicating that they might be correlated with seed storability. Further studies on these candidate seed storage proteins might help improve our understanding of seed aging. PMID- 26950924 TI - Assessment of female rats for studying episodic memory and its deficit associated with doxorubicin-induced chemobrain. PMID- 26950927 TI - Optical coherence tomography angiography offers comprehensive evaluation of skin optical clearing in vivo by quantifying optical properties and blood flow imaging simultaneously. AB - Tissue optical clearing (TOC) is helpful for reducing scattering and enhancing the penetration depth of light, and shows promising potential in optimizing optical imaging performances. A mixture of fructose with PEG-400 and thiazone (FPT) is used as an optical clearing agent in mouse dorsal skin and evaluated with OCT angiography (Angio-OCT) by quantifying optical properties and blood flow imaging simultaneously. It is observed that FPT leads to an improved imaging performance for the deeper tissues. The imaging performance improvement is most likely caused by the FPT-induced dehydration of skin, and the reduction of scattering coefficient (more than ~ 40.5%) and refractive-index mismatching (more than ~ 25.3%) in the superficial (epidermal, dermal, and hypodermal) layers. A high correlation (up to ~ 90%) between the relative changes in refractive-index mismatching and Angio-OCT signal strength is measured. The optical clearing rate is ~ 5.83 * 10(-5) cm/s. In addition, Angio-OCT demonstrates enhanced performance in imaging cutaneous hemodynamics with satisfactory spatiotemporal resolution and contrast when combined with TOC, which exhibits a powerful practical application in studying microcirculation. PMID- 26950926 TI - Improved cerebrospinal fluid suppression for intracranial vessel wall MRI. AB - PURPOSE: To develop and assess a three-dimensional (3D) high resolution black blood MRI (BBMRI) method for evaluation of intracranial vessels with improved cerebrospinal fluid (CSF) suppression. MATERIALS AND METHODS: The anti-driven equilibrium (ADE) pulse was incorporated into a variable flip-angle TSE-based 3D BBMRI to improve CSF suppression. ADE-BBMRI was optimized in 8 participants and compared with BBMRI, with acquired 0.5 mm isotropic resolution and scan time of 5.4 min at 3 Tesla. Contrast-enhanced ADE-BBMRI protocol was implemented in nine patients with intracranial atherosclerosis. Signal and morphological measurements were compared between ADE-BBMRI and BBMRI, as well as pre- and postcontrast ADE BBMRI. Reliability was assessed by intraclass correlations (ICC). RESULTS: ADE BBMRI effectively suppressed the surrounding CSF signal of intracranial vessels, with a 36-44% reduction compared with BBMRI. ADE-BBMRI also reduced the overall wall signal by 8-8.5%, but provided a significant improvement in wall-to-CSF contrast-to-noise ratio over BBMRI (middle cerebral artery, 5.93 +/- 0.59 versus 3.95 +/- 1.67, P < 0.01; basilar artery, 3.8 +/- 1.76 versus 1.34 +/- 0.54, P = 0.01, respectively). No differences were noted in morphological measurements between ADE-BBMRI and BBMRI (lumen area, 6.35 +/- 2.87 versus 6.32 +/- 2.84 mm(2) ; wall area, 1.28 +/- 0.52 versus 1.27 +/- 0.53 mm(2) ; mean wall thickness, 0.93 +/- 0.30 versus 0.93 +/- 0.32 mm; maximum wall thickness, 1.27 +/- 0.33 versus 1.28 +/- 0.36 mm, all P > 0.05). Contrast enhanced ADE-BBMRI improved the plaque delineation by the increased wall signal, wall-to-CSF and wall-to-blood contrast to-noise ratio. ICC ranged from 0.54 to 0.95. CONCLUSION: The 3D ADE-BBMRI provides excellent blood and CSF suppression, and accurate measurements of intracranial vessels at 0.5 mm isotropic resolution in 5 min. Its clinical application may provide insight into stroke risk. J. Magn. Reson. Imaging 2016;44:665-672. PMID- 26950928 TI - Novel Biomarkers for Renal Diseases? None for the Moment (but One). AB - Recent years have witnessed the unprecedented development and integration of genomics, epigenetics, transcriptomics, proteomics, and metabolomics, as well as a growing interest in novel single biomarkers and process-specific biomarker panels in human renal diseases. In a scenario currently dominated by kidney biopsy and established biomarkers such as serum creatinine, albuminuria, and proteinuria, novel biomarkers could potentially provide vital diagnostic and prognostic information and help to predict response to treatment in several clinical settings, including acute kidney injury, renal transplant, autosomal dominant polycystic kidney disease, and glomerulopathies. However, it is still uncertain whether and to what extent novel biomarkers will succeed in this difficult task. To date, they have generally failed to provide relevant information over and above what is already granted by established, cheap, and easily available biomarkers such as proteinuria, while the complexity and costs of these technology platforms are an important obstacle to their wide adoption. On the other hand, the successful implementation of anti-phospholipase A2 receptor antibodies as a diagnostic and prognostic biomarker of membranous nephropathy, as well as the huge number of ongoing collaborative efforts worldwide, should induce the nephrology community to be rather optimistic about a potential breakthrough in the management of kidney diseases over the next few decades. PMID- 26950929 TI - Single-Cell Phenotype Classification Using Deep Convolutional Neural Networks. AB - Deep learning methods are currently outperforming traditional state-of-the-art computer vision algorithms in diverse applications and recently even surpassed human performance in object recognition. Here we demonstrate the potential of deep learning methods to high-content screening-based phenotype classification. We trained a deep learning classifier in the form of convolutional neural networks with approximately 40,000 publicly available single-cell images from samples treated with compounds from four classes known to lead to different phenotypes. The input data consisted of multichannel images. The construction of appropriate feature definitions was part of the training and carried out by the convolutional network, without the need for expert knowledge or handcrafted features. We compare our results against the recent state-of-the-art pipeline in which predefined features are extracted from each cell using specialized software and then fed into various machine learning algorithms (support vector machine, Fisher linear discriminant, random forest) for classification. The performance of all classification approaches is evaluated on an untouched test image set with known phenotype classes. Compared to the best reference machine learning algorithm, the misclassification rate is reduced from 8.9% to 6.6%. PMID- 26950930 TI - The Natural Product Resveratrol Inhibits Yeast Cell Separation by Extensively Modulating the Transcriptional Landscape and Reprogramming the Intracellular Metabolome. AB - An increasing number of studies have shown that the promising compound resveratrol treats multiple diseases, such as cancer and aging; however, the resveratrol mode-of-action (MoA) remains largely unknown. Here, by virtue of multiple omics approaches, we adopted fission yeast as a model system with the goal of dissecting the common MoA of the anti-proliferative activity of resveratrol. We found that the anti-proliferative activity of resveratrol is mainly due to its unique role of inhibiting the separation of sister cells, similar phenotype with the C2H2 zinc finger transcription factor Ace2 knock-out strain. Microarray analysis shown that resveratrol has extensive impact on the fission yeast transcription levels. Among the changed gene's list, 40% of up regulated genes are Core Environmental Stress Responses genes, and 57% of the down-regulated genes are periodically expressed. Moreover, resveratrol leverages the metabolome, which unbalances the intracellular pool sizes of several classes of amino acids, nucleosides, sugars and lipids, thus reflecting the remodulated metabolic networks. The complexity of the resveratrol MoA displayed in previous reports and our work demonstrates that multiple omics approaches must be applied together to obtain a complete picture of resveratrol's anti-proliferative function. PMID- 26950931 TI - Lack of Host Specialization on Winter Annual Grasses in the Fungal Seed Bank Pathogen Pyrenophora semeniperda. AB - Generalist plant pathogens may have wide host ranges, but many exhibit varying degrees of host specialization, with multiple pathogen races that have narrower host ranges. These races are often genetically distinct, with each race causing highest disease incidence on its host of origin. We examined host specialization in the seed pathogen Pyrenophora semeniperda by reciprocally inoculating pathogen strains from Bromus tectorum and from four other winter annual grass weeds (Bromus diandrus, Bromus rubens, Bromus arvensis and Taeniatherum caput-medusae) onto dormant seeds of B. tectorum and each alternate host. We found that host species varied in resistance and pathogen strains varied in aggressiveness, but there was no evidence for host specialization. Most variation in aggressiveness was among strains within populations and was expressed similarly on both hosts, resulting in a positive correlation between strain-level disease incidence on B. tectorum and on the alternate host. In spite of this lack of host specialization, we detected weak but significant population genetic structure as a function of host species using two neutral marker systems that yielded similar results. This genetic structure is most likely due to founder effects, as the pathogen is known to be dispersed with host seeds. All host species were highly susceptible to their own pathogen races. Tolerance to infection (i.e., the ability to germinate even when infected and thereby avoid seed mortality) increased as a function of seed germination rate, which in turn increased as dormancy was lost. Pyrenophora semeniperda apparently does not require host specialization to fully exploit these winter annual grass species, which share many life history features that make them ideal hosts for this pathogen. PMID- 26950934 TI - Statistical Efficiency in Distance Sampling. AB - Distance sampling is a technique for estimating the abundance of animals or other objects in a region, allowing for imperfect detection. This paper evaluates the statistical efficiency of the method when its assumptions are met, both theoretically and by simulation. The theoretical component of the paper is a derivation of the asymptotic variance penalty for the distance sampling estimator arising from uncertainty about the unknown detection parameters. This asymptotic penalty factor is tabulated for several detection functions. It is typically at least 2 but can be much higher, particularly for steeply declining detection rates. The asymptotic result relies on a model which makes the strong assumption that objects are uniformly distributed across the region. The simulation study relaxes this assumption by incorporating over-dispersion when generating object locations. Distance sampling and strip transect estimators are calculated for simulated data, for a variety of overdispersion factors, detection functions, sample sizes and strip widths. The simulation results confirm the theoretical asymptotic penalty in the non-overdispersed case. For a more realistic overdispersion factor of 2, distance sampling estimation outperforms strip transect estimation when a half-normal distance function is correctly assumed, confirming previous literature. When the hazard rate model is correctly assumed, strip transect estimators have lower mean squared error than the usual distance sampling estimator when the strip width is close enough to its optimal value (+/- 75% when there are 100 detections; +/- 50% when there are 200 detections). Whether the ecologist can set the strip width sufficiently accurately will depend on the circumstances of each particular study. PMID- 26950932 TI - Serological and Genetic Evidence for Altered Complement System Functionality in Systemic Lupus Erythematosus: Findings of the GAPAID Consortium. AB - Systemic lupus erythematosus is a chronic autoimmune disease with multifactorial ethiopathogenesis. The complement system is involved in both the early and late stages of disease development and organ damage. To better understand autoantibody mediated complement consumption we examined ex vivo immune complex formation on autoantigen arrays. We recruited patients with SLE (n = 211), with other systemic autoimmune diseases (n = 65) and non-autoimmune control subjects (n = 149). Standard clinical and laboratory data were collected and serum complement levels were determined. The genotype of SNP rs1143679 in the ITGAM gene was also determined. Ex vivo formation of immune complexes, with respect to IgM, IgG, complement C4 and C3 binding, was examined using a functional immunoassay on autoantigen microarray comprising nucleic acids, proteins and lipids. Complement consumption of nucleic acids increased upon binding of IgM and IgG even when serum complement levels were decreased due to consumption in SLE patients. A negative correlation between serum complement levels and ex vivo complement deposition on nucleic acid autoantigens is demonstrated. On the contrary, complement deposition on tested protein and lipid autoantigens showed positive correlation with C4 levels. Genetic analysis revealed that the non-synonymous variant rs1143679 in complement receptor type 3 is associated with an increased production of anti-dsDNA IgG antibodies. Notwithstanding, homozygous carriers of the previously reported susceptible allele (AA) had lower levels of dsDNA specific IgM among SLE patients. Both the non-synonymous variant rs1143679 and the high ratio of nucleic acid specific IgG/IgM were associated with multiple organ involvement. In summary, secondary complement deficiency in SLE does not impair opsonization of nucleic-acid-containing autoantigens but does affect other antigens and potentially other complement dependent processes. Dysfunction of the receptor recognizing complement opsonized immune complexes promotes the development of class-switched autoantibodies targeting nucleic acids. PMID- 26950933 TI - Cirrhosis and Advanced Fibrosis in Hispanics in Texas: The Dominant Contribution of Central Obesity. AB - Liver cirrhosis is a leading cause of death in Hispanics and Hispanics who live in South Texas have the highest incidence of liver cancer in the United States. We aimed at determining the prevalence and associated risk factors of cirrhosis in this population. Clinical and demographic variables were extracted for 2466 participants in the community-based Cameron County Hispanic Cohort in South Texas. Aspartate transaminase to Platelet Ratio Index (APRI) was used to predict cirrhosis in Cameron County Hispanic Cohort. The prevalence of cirrhosis using APRI>=2 was 0.94%, which is nearly 4-fold higher than the national prevalence. Using APRI>=1, the overall prevalence of cirrhosis/advanced fibrosis was 3.54%. In both analyses, highest prevalence was observed in males, specifically in the 25-34 age group. Risk factors independently associated with APRI>=2 and APRI>=1 included hepatitis C, diabetes and central obesity with a remarkable population attributable fraction of 52.5% and 65.3% from central obesity, respectively. Excess alcohol consumption was also independently associated with APRI>=2. The presence of patatin-like phospholipase domain-containing-3 gene variants was independently associated with APRI>=1 in participants >50 years old. Males with both central obesity and excess alcohol consumption presented with cirrhosis/advanced fibrosis at a young age. Alarmingly high prevalence of cirrhosis and advanced fibrosis was identified in Hispanics in South Texas, affecting young males in particular. Central obesity was identified as the major risk factor. Public health efforts are urgently needed to increase awareness and diagnosis of advanced liver fibrosis in Hispanics. PMID- 26950935 TI - Age- and Gender-Related Mean Hearing Threshold in a Highly-Screened Population: The Korean National Health and Nutrition Examination Survey 2010-2012. AB - BACKGROUND: In evaluating hearing disability in medicolegal work, the apportionment of age- and gender-related sensorineural hearing loss should be considered as a prior factor, especially for the elderly. However, in the literature written in the English language no studies have reported on the age- and gender-related mean hearing threshold for the South Korean population. OBJECTIVE: This study aimed to identify the mean hearing thresholds in the South Korean population to establish reference data and to identify the age- and gender related characteristics. METHODS: This study is based on the Korea National Health and Nutrition Examination Survey (KNHANES) 2010-2012, which was conducted by the Korean government, the data of which was disclosed to the public. A total of 15,606 participants (unweighted) representing 33,011,778 Koreans (weighted) with normal tympanic membrane and no history of regular or occupational noise exposure were selected and analyzed in this study. The relationship between the hearing threshold level and frequency, age, and gender was investigated and analyzed in a highly-screened population by considering the sample weights of a complex survey design. RESULTS: A gender ratio difference was found between the unweighted and the weighted designs: male:female, 41.0%: 59.0% (unweighted, participants) vs. 47.2%:52.8% (weighted, representing population). As age increased, the hearing threshold increased for all frequencies. Hearing thresholds of 3 kHz, 4 kHz, and 6 kHz showed a statistical difference between both genders for people older than 30, with the 4 kHz frequency showing the largest difference. This paper presents details about the mean hearing threshold based on age and gender. CONCLUSIONS: The data from KNHANES 2010-2012 showed gender differences at hearing thresholds of 3 kHz, 4 kHz, and 6 kHz in a highly screened population. The most significant gender difference in relation to hearing threshold was observed at 4 kHz. The hearing thresholds at all of the tested frequencies worsened with increasing age. The mean hearing thresholds suggested in this study will be useful for the formulation of healthcare-related hearing policies and used as reference data for disability ratings for hearing loss due to various causes. PMID- 26950938 TI - Correction: Updated Campylobacter jejuni Capsule PCR Multiplex Typing System and Its Application to Clinical Isolates from South and Southeast Asia. PMID- 26950936 TI - The Physical Mechanism for Retinal Discrete Dark Noise: Thermal Activation or Cellular Ultraweak Photon Emission? AB - For several decades the physical mechanism underlying discrete dark noise of photoreceptors in the eye has remained highly controversial and poorly understood. It is known that the Arrhenius equation, which is based on the Boltzmann distribution for thermal activation, can model only a part (e.g. half of the activation energy) of the retinal dark noise experimentally observed for vertebrate rod and cone pigments. Using the Hinshelwood distribution instead of the Boltzmann distribution in the Arrhenius equation has been proposed as a solution to the problem. Here, we show that the using the Hinshelwood distribution does not solve the problem completely. As the discrete components of noise are indistinguishable in shape and duration from those produced by real photon induced photo-isomerization, the retinal discrete dark noise is most likely due to 'internal photons' inside cells and not due to thermal activation of visual pigments. Indeed, all living cells exhibit spontaneous ultraweak photon emission (UPE), mainly in the optical wavelength range, i.e., 350-700 nm. We show here that the retinal discrete dark noise has a similar rate as UPE and therefore dark noise is most likely due to spontaneous cellular UPE and not due to thermal activation. PMID- 26950937 TI - Identification of Novel O-Linked Glycosylated Toxoplasma Proteins by Vicia villosa Lectin Chromatography. AB - Toxoplasma gondii maintains its intracellular life cycle using an extraordinary arsenal of parasite-specific organelles including the inner membrane complex (IMC), rhoptries, micronemes, and dense granules. While these unique compartments play critical roles in pathogenesis, many of their protein constituents have yet to be identified. We exploited the Vicia villosa lectin (VVL) to identify new glycosylated proteins that are present in these organelles. Purification of VVL binding proteins by lectin affinity chromatography yielded a number of novel proteins that were subjected to further study, resulting in the identification of proteins from the dense granules, micronemes, rhoptries and IMC. We then chose to focus on three proteins identified by this approach, the SAG1 repeat containing protein SRS44, the rhoptry neck protein RON11 as well as a novel IMC protein we named IMC25. To assess function, we disrupted their genes by homologous recombination or CRISPR/Cas9. The knockouts were all successful, demonstrating that these proteins are not essential for invasion or intracellular survival. We also show that IMC25 undergoes substantial proteolytic processing that separates the C-terminal domain from the predicted glycosylation site. Together, we have demonstrated that lectin affinity chromatography is an efficient method of identifying new glycosylated parasite-specific proteins. PMID- 26950940 TI - Transfusion thresholds and beyond. PMID- 26950939 TI - Spontaneous 8bp Deletion in Nbeal2 Recapitulates the Gray Platelet Syndrome in Mice. AB - During the analysis of a whole genome ENU mutagenesis screen for thrombosis modifiers, a spontaneous 8 base pair (bp) deletion causing a frameshift in exon 27 of the Nbeal2 gene was identified. Though initially considered as a plausible thrombosis modifier, this Nbeal2 mutation failed to suppress the synthetic lethal thrombosis on which the original ENU screen was based. Mutations in NBEAL2 cause Gray Platelet Syndrome (GPS), an autosomal recessive bleeding disorder characterized by macrothrombocytopenia and gray-appearing platelets due to lack of platelet alpha granules. Mice homozygous for the Nbeal2 8 bp deletion (Nbeal2gps/gps) exhibit a phenotype similar to human GPS, with significantly reduced platelet counts compared to littermate controls (p = 1.63 x 10-7). Nbeal2gps/gps mice also have markedly reduced numbers of platelet alpha granules and an increased level of emperipolesis, consistent with previously characterized mice carrying targeted Nbeal2 null alleles. These findings confirm previous reports, provide an additional mouse model for GPS, and highlight the potentially confounding effect of background spontaneous mutation events in well characterized mouse strains. PMID- 26950942 TI - What Matters in the Results of Repeated Intravenous Thrombolysis for Recurrent Ischemic Stroke? PMID- 26950941 TI - Nitrate and Ammonium Contribute to the Distinct Nitrogen Metabolism of Populus simonii during Moderate Salt Stress. AB - Soil salinity is a major abiotic stressor affecting plant growth. Salinity affects nitrification and ammonification in the soil, however, limited information is available on the influence of different N sources on N metabolism during salt stress. To understand the N metabolism changes in response to different N sources during moderate salt stress, we investigated N uptake, assimilation and the transcript abundance of associated genes in Populus simonii seedlings treated with moderate salt stress (75mM NaCl) under hydroponic culture conditions with nitrate (NO3-) or ammonium (NH4+). Salt stress negatively affected plant growth in both NH4+-fed and NO3--fed plants. Both NH4+ uptake and the total N concentration were significantly increased in the roots of the NH4+ fed plants during salt stress. However, the NO3- uptake and nitrate reductase (NR) and nitrite reductase (NiR) activity primarily depended on the NO3- supply and was not influenced by salt stress. Salt stress decreased glutamine synthetase (GS) and glutamate synthase (GOGAT) activity in the roots and leaves. Most genes associated with NO3-uptake, reduction and N metabolism were down-regulated or remained unchanged; while two NH4+ transporter genes closely associated with NH4+ uptake (AMT1;2 and AMT1;6) were up-regulated in response to salt stress in the NH4+-fed plants. The accumulation of different amino acid compounds was observed in the NH4+- and NO3-- fed plants during salt treatment. The results suggested that N metabolism in P. simonii plants exposed to salt enhanced salt resistance in the plants that were fed with NO3- instead of NH4+ as the sole N source. PMID- 26950943 TI - Follow-Up of Children with Gastrointestinal Malformations and Postnatal Surgery and Anesthesia: Evaluation at Two Years of Age. AB - BACKGROUND: The impact of general anesthesia is considered a risk factor for developmental delay. Very few studies have been performed to measure the neurodevelopmental outcome of patients with selected malformations. OBJECTIVES: The purpose of this ambidirectional cohort study was to measure the neurodevelopmental outcome of patients with congenital gastrointestinal-tract malformations (GIM). METHODS: Forty patients with relevant congenital GIM born in the period from June 2008 to April 2011 were identified. The inclusion criteria were a gestational age >32 completed weeks and surgery that required a general anesthetic within the first 28 days of life. The neonatal characteristics and anesthesia data were retrospectively collected. Based on information about the neonatal characteristics and socioeconomic background, a matched pair was found. All participants were tested at the corrected age of 24 months with the Bayley Scales of Infant Development II assessment. RESULTS: The outcome was split into the psychomotor index (PDI) and mental developmental index (MDI). The patient group achieved a mean PDI of 103 and the control group achieved 106, i.e. these values were not significantly different. The mean MDI was 102 in the patient group and 110 in the control group. This difference was significant (p = 0.022). Detailed analysis of the items showed no significance for nonverbal items but a significant difference for verbal items (p = 0.029). Further analysis showed no correlation between relevant anesthesia data and the neurodevelopmental outcome. CONCLUSIONS: We found lower MDI scores due to worse verbal abilities in the patient group. Children born with GIM should be considered a risk group with respect to language development. PMID- 26950945 TI - Bursting through the cell cycle. AB - How are cells able to maintain constant levels of mRNA when the number of genes in a cell doubles ahead of cell division? PMID- 26950944 TI - The ROCKs on which tumour cells thrive. AB - A new study reveals that the ROCK proteins play key roles in the formation of tumours in mice. PMID- 26950946 TI - Can Vco2-Based Estimates of Resting Energy Expenditure Replace the Need for Indirect Calorimetry in Critically Ill Children? AB - BACKGROUND: Optimal energy provision, guided by measured resting energy expenditure (REE), is fundamental in the care of critically ill children. REE should be determined by indirect calorimetry (IC), which has limited availability. Recently, a novel equation was developed for estimating REE derived from carbon dioxide production (Vco2). The aim of this study was to validate the accuracy of this equation in a population of critically ill children following cardiopulmonary bypass (CPB). METHODS: This is an ancillary study to a larger trial of children undergoing CPB. Respiratory mass spectrometry was used measure oxygen consumption (Vo2) and Vco2. REE was then calculated according to the established Weir equation (REEW) and the modified, Vco2-based equation (REECO2). The agreement between the 2 measurements was assessed using Bland-Altman plots and mixed-model regressions accounting for repeated measures. RESULTS: Data from 104 patients, which included 575 paired measurements, were included. The agreement between REEW and REECO2 was biased during the 72-hour observation period post CPB, with a mean percentage error between measurements of 11% (+/ 7%). The most important determinant of the bias with the Vco2-based equation was the respiratory quotient (RQ). The percentage error between REEW and REECO2 dropped to 4.4% (+/-2.4%) in those with an RQ between 0.8 and 1. The within subject variability for RQ in this cohort was wide (11%). CONCLUSIONS: IC remains the most accurate method to determine the REE of critically ill patients. Widespread availability of Vco2 data renders Vco2-based approaches to measurement of REE attractive; however, further research is needed to ensure that REE is estimated accurately. PMID- 26950947 TI - Effect of Perioperative Probiotics and Synbiotics on Postoperative Infections After Gastrointestinal Surgery: A Systematic Review With Meta-Analysis. AB - BACKGROUND: Bacterial infection following gastrointestinal surgery remains a common morbidity. The aim of this study was to estimate the effect of the perioperative use of probiotics and synbiotics on postoperative infections. MATERIALS AND METHODS: We searched PubMed, Embase, and the Cochrane Library to identify pertinent randomized controlled trials (RCTs). The primary outcome was postoperative infection rate. The secondary outcomes were length of hospital and intensive care unit (ICU) stay, length of antibiotic therapy, and mortality. The pooled outcomes were calculated using random effects models. RESULTS: Twenty eight RCTs involving 2511 patients were included in this systematic review. The incidence of infectious complications was lower among patients who received probiotics/synbiotics than among the controls (odds ratio [OR] = 0.35; 95% confidence interval [CI], 0.24-0.50), particularly regarding respiratory (OR = 0.44; 95% CI, 0.28-0.68), urinary tract (OR = 0.30; 95% CI, 0.16-0.55), and wound infections (OR = 0.58; 95% CI, 0.42-0.80). The lengths of hospital stay (mean difference [MD] = -3.20; 95% CI, -4.87 to -1.54) and duration of antibiotic therapy (MD = -3.40; 95% CI, -4.67 to -2.13) were shorter for patients who received probiotics/synbiotics than for controls. There were no significant differences in mortality (OR = 1.19; 95% CI, 0.52-2.74) or length of ICU stay (MD = -0.46; 95% CI, -1.07 to 0.14) between the compared groups. CONCLUSION: Probiotics and synbiotics may prevent postoperative infections in patients undergoing gastrointestinal surgery. However, the results need to be interpreted with caution due to the risk of bias in the included studies and the potential publication bias. PMID- 26950948 TI - Working With the Coach. PMID- 26950950 TI - Withdrawn: Risk Areas of Liver Flukes in Surin Province of Thailand using Geographic Information System. PMID- 26950949 TI - Withdrawn: Endoscopic Management of Pancreatic Cancer. PMID- 26950951 TI - Foreword. Towards more efficient control and eradication of brucellosis in the south eastern European countries. PMID- 26950952 TI - Declaration on intersectoral and regional cooperation on control and eradication of brucellosis in south eastern Europe, Struga, November 2009. PMID- 26950953 TI - Guideline Summary: Radiation Safety. PMID- 26950954 TI - Evidence appraisal of Wei C, Yu Y, Chen Y, Wei Y, Ni X. Impact of warming blood transfusion and infusion toward cerebral oxygen metabolism and cognitive recovery in the perioperative period of elderly knee replacement. J Orthop Surg Res. 2014;9:8. PMID- 26950955 TI - Avoiding near misses and never events. PMID- 26950956 TI - Preventing patient falls. PMID- 26950957 TI - Guideline for prevention of retained surgical items. PMID- 26950958 TI - A surgical black box to prevent mistakes. PMID- 26950959 TI - DID YOU KNOW? PMID- 26950960 TI - Letter to the editor. PMID- 26950962 TI - Health indicators for renal replacement therapy in Saudi Arabia. PMID- 26950961 TI - Reply to the letter to the editor. PMID- 26950963 TI - [Ultra-wide Field Scanning Laser Ophthalmoscope]. PMID- 26950964 TI - [Multicenter Prospective Observational Study of Fungal Keratitis--Current Status of Patients' Background, Clinical Findings, Treatment and Prognosis]. AB - PURPOSE: To investigate the current status of fungal keratitis in Japan. METHODS: The patients with fungal keratitis were examined at 27 facilities in Japan from November 1st 2011 to October 31st 2013, concerning isolates, patient background, clinical findings, treatment and prognosis. RESULTS: Out of 139 cases, 133 were diagnosed as fungal keratitis, of which fungi were isolated from 72 samples of 71 cases (yeast-like fungi 32 strains and filamentous fungi 40 strains). The corrected visual acuity at the first visit of 88 cases (66.2%) was less than 20/200 and 42 cases (31.6%) were involved with deep stromal lesions, indicating high proportion of severe cases in this study. Three months later, 56 cases (42.1%) were still under treatment, and corrected visual acuity of 57 cases (42.9%) was less than 20/200. In cases with yeast-like fungi, there were significantly more cases with past history of corneal diseases, ocular surgery including keratoplasty, and eye drops' use such as steroids than those with filamentous fungi. On the other hand, there were significantly more cases of filamentous fungi, with trauma on the onset and with intervention of previously attending doctors than those with yeast-like fungi. Logistic regression analyses revealed that contact lens wearing was a significant factor of good prognosis, and yeast-like fungi as one of poor outcome compared with no fungal isolation. CONCLUSION: Although the choice of antifungal drugs has been increasing, fungal keratitis is still severe, refractory and vision-threatening disease. PMID- 26950966 TI - [Six Months Outcome in Patients with Macular Edema Due to Retinal Vein Occlusion Treated with Ranibizumab]. AB - PURPOSE: To assess the efficacy of intravitreal ranibizumab in the treatment of macular edema due to branch and central retinal vein occlusion for 6 month. SUBJECTS AND METHODS: This study was retrospective, 32 eyes with branch retinal vein occlusion (BRVO) and 15 eyes with central retinal vein occlusion (CRVO) treated with intravitreal ranibizumab injections were investigated. We estimated the changes in visual acuity, central retinal thickness and average number of injections over 6 month. We also investigated which pre-injection factors were important in patients who improved following a single-dose injection. RESULTS: The average number of injections was 1.9 in BRVO and 2.5 in CRVO. The visual acuity and central retinal thickness were improved in both BRVO and CRVO at 6 months, compared with those before injection. In patients with BRVO, it was indicated that the thinner the central fovea thickness prior to injection, the higher the rate of sustained effect following a single-dose administration. CONCLUSION: Intravitreal ranibizumab injection is effective for macular edema with retinal vein occlusion. PMID- 26950967 TI - [Efficacy of Ultra-wide Angle Fundus Imaging without Dilated Pupils in Annual Health Check-up Examination]. AB - PURPOSE: To evaluate efficacy of ultra-wide angle fundus imaging without mydriasis for health screening. METHOD: The judgment rate and the detection rate of ocular diseases in 1160 eyes of 580 patients (Optos group) who underwent ophthalmic screening with Optos 200Tx ultra-wide field scanning laser ophthalmoscope without mydriasis from May 2013 to April 2014 were compared with those of 774 eyes of 387 patients who underwent ophthalmic screening with mydriasis (Mydriasis group). RESULTS: The judgment could be made in 1156 eyes (99.7%) in the Optos group except for 4 eyes because of severe cataracts in 3 eyes and a corneal inlay to correct presbyopia in one eye. The judgment could be made in all eyes in the Mydriasis group. Peripheral retinal lesions could be detected in the Optos group including 2 eyes with retinal breaks, but the detection rate of peripheral retinal lesions including chorioretinal atrophy and retinal detachment was significantly higher in the Mydriasis group. CONCLUSION: Optos wide-angle fundus imaging can detect peripheral retinal lesion even without mydriasis and can be considered useful for health screening because of its convenience. PMID- 26950965 TI - [Multicenter Prospective Observational Study of Fungal Keratitis--Identification and Susceptibility Test of Fungi]. AB - PURPOSE: To investigate the causative fungi of fungal keratitis in Japan and their drug susceptibility. METHODS: Identification and antifungal susceptibility test for 8 drugs (micafungin, amphotericin B, flucytosine, fluconazole, itraconazole, voriconazole, miconazole and pimaricin) were performed using isolated fungi from patients with fungal keratitis treated at 27 facilities in Japan between November 1, 2011 and October 31, 2013. RESULTS: Fungal strains were detected in 72 (50.7%) out of 142 samples. The major isolates were Fusarium spp. (18), Candida parapsilosis (12), C. albicans (11) and Alternaria spp. (6), in all, fungi of 31 species were identified by gene analysis. In the yeast-like fungi, susceptibility rates were evident for more than 80% in voriconazole, pimaricin, flucytosine, micafungin, amphotericin B and fluconazole. In filamentous fungi, the susceptibility rate was less than 50% except for PMR (90%). Fusarium spp., which were susceptible to amphotericin B and pimaricin, showed lower susceptibility rates compared with other genera. CONCLUSIONS: Although various genera and species of fungi cause fungal keratitis, the obtained drug susceptibility data in this study demonstrates the different susceptibility patterns among the major isolates (Fusarium spp., C. parapsilosis, C. albicans and other groups). This is important evidence useful for fungal keratitis treatment. PMID- 26950968 TI - [Effects of Constant Intake of Lutein-rich Spinach on Macular Pigment Optical Density: a Pilot Study]. AB - PURPOSE: Anti-oxidative nutrient supplements, including lutein, are an important preventive approach for age-related macular degeneration (AMD). In this pilot study, we obtained data required for planning a future dietary intervention study investigating the prevention of AMD progression with lutein-rich spinach. METHODS: We examined 22 eyes from 11 healthy nonsmokers (ages 21-45 years) who ingested 75 g of frozen spinach containing 10 mg lutein every day for 2 months. Food frequency questionnaire, measurement of macular pigment optical density (MPOD), and eye and blood examinations were performed. RESULTS: Mean lutein +/- SD intake from food was 0.87 +/- 0.76 mg/1,000 kcal at baseline. Mean MPOD, best corrected visual acuity, and serum lutein concentrations were increased at 1 and 2 months compared with baseline. CONCLUSION: Constant intake of lutein-rich spinach increased both MPOD and serum lutein concentrations. These data are important for planning of a future interventional study examining the effects of dietary lutein. PMID- 26950969 TI - [The 54th Annual Meeting of the Japanese Society for Cataract Research]. PMID- 26950971 TI - [LETTER]. PMID- 26950970 TI - [PROGRESS REPORT FROM THE STRATEGIC PLANNING COMMITTEE]. PMID- 26950972 TI - [EDITOR'S NOTE]. PMID- 26950973 TI - [A Review 65 Diagnosis and Treatment of Allergic Conjunctival Diseases]. PMID- 26950974 TI - [Kidney and regenerative medicine]. PMID- 26950975 TI - [Vasculitis]. PMID- 26950976 TI - [Fluid and electrolytes]. PMID- 26950977 TI - [Up-to-date concept on urinary tract infections with a focus on innate immunity]. PMID- 26950978 TI - [Kidney and hypertension]. PMID- 26950979 TI - [Two cases of incidentally detected renal arteriovenous fistula over ten years after renal biopsy]. AB - CASE 1: The case was a 66-year-old Japanese woman. A renal biopsy had been carried out at 53 years of age, and she was diagnosed as IgA nephropathy. Her renal function had been stable at around 0.7 mg/dL of serum creatinine. At 66 years of age, macrohematuria was found and she was admitted to hospital. Enhanced abdominal computed tomography showed left renal arteriovenous fistula (AVF) (21 mm x 10 mm), and hydronephrosis. Her renal AVF was successfully treated with coil embolization, and hydronephrosis was improved with stable renal function. Her AVF was cirsoid type, which is usually congenital, although it was not recognized before the renal biopsy. CASE 2: A 48-year-old Japanese woman was referred to a nephrologist for proteinuria and an elevated serum creatinine level. She had undergone two renal biopsies when she was 14 and 18 years of age and her condition had been diagnosed as chronic glomerulonephritis. However, she had not received any special treatment. Upon abdominal ultrasonography, a right renal AVF (18 mm x 23 mm) was detected. Her aneurysmal type AVF was successfully treated with coil embolization. In these 2 cases, renal biopsy might be a cause of renal AVF. Regular screening test using ultrasonography is recommended to avoid missing remote complications of renal biopsy. PMID- 26950980 TI - [Rituximab therapy in the treatment of anti-neutrophil cytoplasmic antibody (ANCA) -positive interstitial pneumonia: case report]. AB - We report a patient treated with rituximab for interstitial pneumonia (IP) associated with microscopic polyangiitis (MPA) and who was undergoing hemodialysis. A 59-year-old woman who had been treated with tacrolimus for 1 year for rheumatic arthritis was referred to the Department of Nephrology for fatigue, fever, weight loss, and rapidly developing renal dysfunction. On the first admission, severe renal dysfunction, proteinuria, hematuria, and an elevated titer of MPO-ANCA were observed, and the woman was diagnosed with rapidly progressive glomerulonephritis because of MPA. At that point, IP was found to be present but not active. Although steroid semipulse therapy following an initial prednisolone (PSL) administration of 40 mg/day, IVCY, and plasma exchange were administered, renal dysfunction did not recover, and the patient required maintenance hemodialysis. Upon discharge, a high titer of MPO-ANCA was continuously observed. Nine months after the initiation of hemodialysis, respiratory discomfort and desaturation developed. Interstitial shadow and ground glass opacity were seen on a CT scan, and the patient was diagnosed with exacerbation of interstitial pneumonia caused by MPA recurrence. At the second admission, acute findings identified by imaging techniques had improved. However, the high titer of MPO-ANCA continued in spite of the steroid semi-pulse therapy following PSL administration, and rituximab corresponding to 200 mg/weekly for 1 month was also administered. The dose of rituximab was decreased subsequently because the patient was judged to be compromised by the hemodialysis. At the same time, internal administration of sulfamethoxazole/trimethoprim was initiated. After the rituximab treatment, MPO-ANCA antibodies gradually decreased, and the respiratory condition improved. Five months after the rituximab treatment, respiratory dysfunction recurred. Based on the CT findings and a high level of beta-D-glycan, the patient was diagnosed with ARDS due to pneumocystis pneumonia. In this case, rituximab was effective for IP due to MPA, but pneumocystis pneumonia could not be prevented in spite of prophylactic antibiotics. This case suggests that deliberative dose adjustments, careful patient observation, and prophylactic measures for infection are critical in rituximab treatment. PMID- 26950981 TI - [Renal thrombotic microangiopathy and antiphospholipid syndrome nephropathy in a patient with lupus nephritis]. AB - The patient was a 48-year-old Japanese woman diagnosed as having systemic lupus erythematosus at the age of 21 years when she presented with fever and an erythematous skin rash on her face and extremities. Prednisolone was initiated at that time. Thirteen days before admission to our hospital, she was referred to us by her family physician. Upon admission, blood tests showed pancytopenia, hypocomplementemia, and renal dysfunction, as well as the presence of lupus anticoagulant. Urinalysis showed abundant proteinuria and heavy microscopic hematuria. After performing a renal biopsy, we initiated immunosuppressive therapy and an anticoagulant. On the 22nd hospital day, microangiopathic hemolytic anemia appeared with the progression of thrombocytopenia and renal failure, and the patient subsequently underwent ten sessions of plasma exchange. After the commencement of the plasma exchange, her general condition improved. Her renal dysfunction, however, continued to progress, and hemodialysis was started on the 36th hospital day. The light microscopy showed severe endo- and extra-capillary proliferative glomerulonephritis with abundant crescents, and massive thrombi in the capillary lumen of the glomeruli. The arterioles contained occlusive hyaline materials. An immunofluorescence study showed granular staining of immunoglobulins and complements along the glomerular capillary wall. An electron microscopy examination revealed the presence of electron-dense deposits in the subepithelial and intramembranous areas of the glomeruli, but subendothelial deposits were absent. For cases with lupus nephritis (LN), immunosuppressive therapy based on corticosteroid remains the mainstay of treatment. However, immunosuppression alone may be insufficient when antiphospholipid antibody syndrome and thrombotic microangiopathy (TMA) are also present, and other treatment modalities including antiplatelet therapy, anticoagulation, and plasma exchange are likely to be necessary, as illustrated by the present case. Although the mechanism responsible for LN remains uncertain, we report a case of LN suggesting that TMA is associated with renal dysfunction. PMID- 26950982 TI - [ANTIBIOTICS SENSITIVITY OF STAPHYLOCOCCUS AUREUS, PSEUDOMONAS AERUGINOSA AND BACTERIA OF BURKHOLDERIA CEPACIA COMPLEX, PERSISTING IN LUNGS OF PATIENTS WITH MUCOVISCIDOSIS (MV)]. AB - AIM: Study the spectrum of resistance to antibiotics and its variability of Staphylococcus aureus, Pseudomonas aeruginosa and Burkholderia cepacia complex (BCC), persisting in lungs of MV patients. MATERIALS AND METHODS: 312 strains of S. aureus, 213 strains of P. aeruginosa, 186 strains of BCC were studied. Monitoring of antibiotics sensitivity was carried out in strains, isolated from 30 patients with chronic S. aureus infection, from 22 patients with chronic BCC infection and from 21 patients with chronic pseudomonas infection. Interval of monitoring was from 14 days to 5 years 7 months. RESULTS: Study of S. aureus, P. aeruginosa and BCC strains has shown, that 35 and 33.3% of cases of staphylococcus infection, 37 and 46% of pseudomonas infection in children and adults, respectively, 100% of BCC infections were determined by multi-resistant clones. Study of genotypically identical strains, isolated from a single patient at different stages, has shown a change in antibiotics sensitivity as a result of persistence. CONCLUSION: Persisent infection of lungs in patients with MV is determined: by exchanging clones with varying antibiotics sensitivity or prolonged circulation of a single clone with a high degree of phenotypical and genotypical variability, that determine alteration of seeding of sensitive and resistant strains from the same patient during monitoring. This confirms the necessity of study of antibiotics sensitivity of strains for prescription of antibacterial therapy. PMID- 26950983 TI - [ENTEROTOXIGENICITY OF STAPHYLOCOCCUS AUREUS STRAINS, ISOLATED FROM BREAST MILK OF WOMEN, FEEDING CHILDREN WITH INFECTIOUS PATHOLOGY]. AB - AIM: Determination of enterotoxigenicity and ability to synthesize TSST-1 in S. aureus strains, isolated from breast milk of women, feeding children with infectious pathology. MATERIALS AND METHODS: 35 S. aureus strains, isolated from breast milk of women feeding children with varying infectious pathology in hospitals and as outpatients were studied for the presence of staphylococci enterotoxins (SE) of types A and B and toxic shock syndrome toxin (TSST-1). Determination of SEA, SEB and TSST-1 was carried out by enzyme immunoassay. RESULTS: Toxins were detected in 94.2% of S. aureus strains. SEB was synthesized by 86.7%, SEA--34.3%, TSST-1--42.8% of S. aureus strains. Toxins were detected with equal frequencies in healthy women and women with inflammatory diseases of breasts. Differences in frequency of colonization of intestines of children receiving breast milk, infected with toxigenic and non-toxigenic staphylococci strains was not detected. CONCLUSION: A high frequency of occurrence of enterotoxins and TSST-1 in S. aureus, isolated from breast milk of the mother during infectious pathology in the child was discovered. Enterotoxigenic strains can be detected in breast milk in healthy women. Study of the role of breast milk, infected with S. aureus, producing SEA, SEB And TSST-1 in development of child pathology is necessary. PMID- 26950984 TI - [EFFECT OF PULSE-PERIODIC CORONA DISCHARGE ON VIABILITY OF ESCHERICHIA COLI M17 CELLS IN BIOFILMS]. AB - AIM: Detection of bactericidal effect of pulse-periodic corona discharge (PPCD) on cells and biofilms of Escherichia coli M17. MATERIALS AND METHODS: A gas discharge device was created based on PPCD in air with power supply parameters: amplitude values of voltage of 30 - 60 kV, pulse repetition rate of 250 - 400 kHz. Ultrastructure changes in cells and biofilms of E. coli M17, affected by PPCD, generated in air, were studied by typical methods of transmission electron microscopy. RESULTS: Disturbances of integrity of surface and abyssal structures of biofilms, as well as changes of morphological properties of E. coli M17 cells, characteristic for sub-lethal heat impact, were detected. Destructive changes of bacterial cells were developed by formation of focal disturbance of cytoplasmic membrane, extension of periplasmic space, formation of globular structures, characteristic for heat effect, and destruction of cytoplasm. CONCLUSION: Bactericidal effect of PPCD on E. coli M17 cells as part of biofilms was shown. Destructive morphological changes in cells and biofilms of E. coli M17 after the effect of PPCD were detected for the first time on electron-microscopic level. PMID- 26950986 TI - [MALDI-TOF MASS-SPECTROMETRIC ANAIYSIS OF LEPTOSPIRA SPP. USED IN SERODIAGNOSTICS OF LEPTOSPIROSIS]. AB - AIM: Creation of a classification model of Leptospira spp. serovar model using ClinProTools 3.0 software and evaluation of use of MALDI-TOF MS as a method of quality control of reference strains of leptospira. MATERIALS AND METHODS: 10 reference strains of Leptospira spp. were used in the study according to microscopic agglutination reaction from the collection of Pasteur RIEM. All the strains were cultivated for 10 days in Terskikh medium at 28 degrees C. Cell extracts were obtained by ethanol/formic acid method. alpha-cyano-4 hydroxycinnamic acid solution was used as a matrix. Mass-spectra were obtained in Microflex mass-spectrometer (Bruker Daltonics, Germany). External validation of the test-model was carried out using novel spectra of every reference strain during their repeated reseeding. RESULTS: Values of cross-validation and confirmatory ability of the optimal model, built on a genetic algorithm, was 99.14 and 100%, respectively. This model contained 11 biomarker peaks (m/z 2959, 3447, 3548, 3764, 3895, 5221, 5917, 6173, 6701, 7013, 8364) for serovar classification. Results of the external validation have shown a 100% correct classification in serovar classesin Sejroe, Ballum, Tarassovi; Copenhageni, Mozdoc, Grippotyphosa and Patoc, that indicates a high prognostic ability of the model in these classes. However, data from verification matrix have shown, that 50%.of the spectra from Canicola and Pomona serovars were classified as Patoc class, that could be associated with cross serological activity of Patoc serovar L. biflexa with pathogenic leptospirae. CONCLUSION: MALDI-TOF mass-spectrometry method combined with building and using the classification model could be a useful instrument for intra-laboratory control of leptospira reseeding. PMID- 26950985 TI - [PRODUCTION OF CERTAIN PRO- AND ANTI-INFLAMMATORY CYTOKINES DURING STIMULATION BY LIVE AND INACTIVATED LEPTOSPIRA PATHOGENS IN THE MODEL OF HUMAN WHOLE BLOOD]. AB - AIM: Study of the ability of clinical isolates of leptospira to cause production of certain pro- and antiinflammatory cytokines in the model of human whole blood. MATERIALS AND METHODS: Leptospira interrogans strain was taken for the experiment. Cytokine content was determined by a method based on xMAP technology using a standard panel, composed of 9 analytes: TNF-alpha, MCP-1, IL-8, IL-4, IL 6, IL-10, IL-IRa, IL- 12 (p70), IFN-gamma. RESULTS: An optimal concentration of L. interrogans was selected for stimulation of human whole blood--1 x 10(6) leptospirae/ml. For the first time in the model of human whole blood it was determined, that at early stages of incubation IFN-gamma, IL-12(p70), IL-4 and IL 1Ra are more actively produced; at later stages (6 hour incubation)--IL-8 and TNF alpha. CONCLUSION: A differential pattern of cytokine production stimulation was shown in the model of human whole blood by live and inactivated leptospirae. PMID- 26950987 TI - [DETERMINATION OF TYPES OF EPIDEMIC MANIFESTATIONS OF CHOLERA IN REGIONS OF THE CRIMEA FEDERAL DISTRICT (REPUBLIC OF CRIMEA)]. AB - The aim of the study was determination of the type of epidemic manifestations of cholera in the Republic of Crimea based on evaluation of epidemic manifestations of cholera risk of introduction and spread of the infection. It was concluded, that, based on the cholera outbreaks, that had taken place, contamination of surface water bodies (fresh and sea) and sewage by Vibrio cholerae O1 ctxA+ and Vibrio cholerae O1 ctXA- potential epidemic danger of introduction of the infection by various types of international transport, population migration, the presence of epidemiologic risk in realization of water pathway of transmission of cholera causative agent and several other social conditions, the Republic of Crimea remains in the group of territories of type I by epidemic manifestations of cholera. PMID- 26950989 TI - [STUDY OF PROTECTIVE ACTIVITY OF PROTEIN-CONTAINING ANTIGENS OF STREPTOCOCCUS PNEUMONIAE IN A HETEROLOGOUS SYSTEM]. AB - AIM: Study protective activity of protein-containing antigens of pneumococcus, obtained from serotypes 6B, 10A, 14, 19F, 23F and 36R, against infection with heterologous strains of S. pneumoniae. MATERIALS AND METHODS: S. pneumoniae strains of serotypes 3, 6B, 10A, 14, 19F, 23F and 36R, obtained from the collection of pneumococcus strains of Mechnikov RIVS, were used in the study. Protein-containing antigens of S. pneumoniae were isolated by acetone precipitations of supernatant fraction of culture medium. Protective activity of preparations of protein-containing antigens of pneumococcus as studied in experiments of active protection of BALb/c line mice. RESULTS: The data obtained give evidence, that protein-containing antigens of pneumococcus, isolated from serotypes 6B, 10A, 14, 19F and 23F, effectively protect animals from subsequent infection with a heterologous S. pneumoniae strain of serotype 3 No. 11/56. Protection was noted at a level from 80 to 100% (p <= 0.05). Similar protective effect was detected in another experiment in a group of mice, immunized with preparations of protein-containing antigens of pneumococcus, obtained from serotypes 6B and 36R, against infection with a heterologous S. pneumoniae strain of serotype 3 No. 11/56. Protection was noted at a level of 90% (p <= 0.05). CONCLUSION: The results of the experiments carried out allow to assume, that the main role in formation of cross-protection in experiments in animals is played by pneumococcus, proteins, that are a part of the studied preparations, and not polysaccharide antigens. PMID- 26950988 TI - [STUDY OF SAFETY OF PAROTITIS VACCINE]. AB - AIM: Monitoring of post-vaccinal complications in children immunized with a parotitis vaccine. MATERIALS AND METHODS: Observation of 198 945 children, immunized with 16 lots of parotitis vaccine with Leningrad-3 strain (L-3), was carried out for 3 years. Paired samples of sera and saliva were obtained from children, in whom adverse events were registered for 42 days after vaccination. Titers of specific IgM and IgG were determined in blood sera. Analysis of nucleotide sequences of genes F, SH and NH of RNA of parotitis virus was carried out from samples of blood and saliva. RESULTS: Intensive parameter of vaccine associated aseptic meningitis under the conditions of the experiments was 0 for 100 000 immunized. Frequency of occurrence of post-vaccinal parotitis was 0.06% from the number of vaccinated--18 cases of vaccine-associated parotitis were registered and laboratory confirmed. A significant difference in specific activity was detected for 3 lots of the vaccine, that were associated with cases of development of parotitis, relative to that of 13 lots of vaccine, development of parotitis was not registered after administration of those. CONCLUSION: The study carried out confirmed low neurovirulence of the parotitis vaccine with the L-3 strain of parotitis virus, as well as a low degree of its reactogenicity. A relatively high immunization dose of the used vaccine could be one of the reasons of development of post-vaccinal complications in part of the immunized children. PMID- 26950990 TI - [EFFECT OF OSMOTIC AND OXIDATIVE STRESS ON STRAINS OF GENOVARIANTS OF VIBRIO CHOLERAE EL TOR BIOVAR]. AB - AIM: Study the effect of osmotic and oxidative stress on survivability and changes in phenotypic and genetic properties of strains of genovariants of V. cholerae El Tor biovar. MATERIALS AND METHODS: 22 strains of V. cholerae El Tor biovar were used in the study. Phenotypic properties of strains were studied in LB medium with the addition of the appropriate ingredients. Surface structures of cells were studied using scanning probe microscope "Solver P47-PRO". PCR was carried out using specific primers in "Tercic" amplificator. RESULTS: After 60 minutes of incubation in 3 M solution of NaCl and after 6 minutes in 20 mM solution of hydrogen peroxide, the amount of surviving cells of genovariants was, respectively, 3.0 - 25.0 and 4.3 - 7.6 times higher than for typical strains. One of the mechanisms of increased resistance of genovariants to high concentrations of salt was associated with the production of an extra exopolysaccharide layer on the cell surface at earlier periods than in typical strains. Osmotic stress results in a reversible reduction of mobility in strains of genovariants of V. cholerae El Tor biovar. Osmotic and oxidative stress was revealed to result in a loss of a number of mobile genetic elements in strains of genovariants. CONCLUSION: Genovariants of V. cholerae El Tor biovar, that had caused cholera outbreaks in Russia in 1993 -2001, in contrast to typical strains, isolated in 1970 - 1990, are more resistant to th effect of osmotic and oxidative stress, that, probably, facilitates their higher survivability in both the environment and macroorganism. PMID- 26950991 TI - [COMPARATIVE IMMUNOGENICITY STUDIES OF ADJUVANTS FROM VARIOUS SOURCES AND WITH DIFFERENT MECHANISMS OF ACTION FOR INACTIVATED INFLUENZA VACCINES]. AB - AIM: Direct immunogenicity comparison of adjuvants from various sources and with different mechanisms of action for inactivated influenza vaccines. MATERIALS AND METHODS: Groups of mice were immunized intramuscularly twice with an inactivated whole-virion influenza vaccine based on A/California/07/2009 X-179A (H1N1) strain. The following adjuvants were added to the vaccine (10 in total): aluminium hydroxide, oligonucleotide CpG, complete Freund's adjuvant, poly(lactide-coglycolide) microparticles, monophosphoryl lipid A and polyoxidonium, as well as 2 adjuvants based on characterized chitosan substances with different physical/chemical properties and 2 experimental complex formulations (a multi-component adjuvant and an oil-in-water emulsion based on squalene and tocopherol). Immuogenicity was determined by HAI and MN (MDCK) sera antibodies. RESULTS: Different adjuvants increased immunogenicity of the vaccine against the homologous strain in varying patterns. Experimental complex formulations were the most immunogenic (antibody titer increase reached 48 - 96 times compared with unadjuvanted vaccines). Chitosan based adjuvants showed high immunogenicity. Not all the adjuvants significantly increased immunogenicity, and in some cases even an immunogenicity decrease was noted with the addition of certain adjuvants. CONCLUSION: Research and development of chitosan based adjuvants with characterization and standardization issues addressed, as well as complex adjuvants, both multi-component and emulsion based, are the most promising approaches that could lead to next generation vaccines against influenza and other human and animal infectious diseases. PMID- 26950992 TI - [ASSOCIATION OF POLYMORPHISM GENES OF SURFACTANT PROTEINS IN PATIENTS WITH INFLUENZA]. AB - AIM: Evaluate role of gene polymorphisms of surfactant proteins in susceptibility and severity of influenza infection course in representatives of Moscow population. MATERIALS AND METHODS; 320 influenza patients, infected with various influenza virus strains, and 115 healthy individuals (control group),, were included into the study. Human DNA samples genotyping for determination of SFTPA2 gene rs1965708 and rs1059046, SFTPB gene rs1130866 polymorphisms was carried out using a modified method of "adjacent samples". RESULTS: Most of the individuals of the control group and influenza patients are carries of alleles and genotypes rs1965708 and rs1059046 of SFTPA2 gene, rs1130866 of SFTPB gene, that have, based on scientific literature data, shown association with severe course of influenza A(H1N1) pdm09 and other inflammatory diseases of the respiratory tract. Generally, significant differences in frequency of occurrence of unfavorable genotypes CC rs1965708, AA rs1059046 of SFTPA2 gene and CC rs1130866 of SFTPB gene in influenza patients in comparison with individuals of the control group were not detected, that gives evidence on a high (from 19 to 51%) prevalence of these genotypes in the studied population. Allele C and genotype CC rs1965708 of SFTPA2 gene, allele A and genotype AA rs1059046 of SFTPA2 gene, allele C and genotype CC rs1130866 of SFTPB gene did not shown an association with severe course of A(H1N1) pdm09 influenza. The following pathology registered in most (88%) of the patients with severe course of influenza A (H1N1)pdm09: diseases of cardiovascilar (44%), endocrine (36%) and respiratory (12%) systems. CONCLUSION: Because in most of the deceased patients due to severe course of A (H1N1)pdm09 influenza, diseases of cardiovascular, respiratory and endocrine system were detected, and an association of unfavorable disease outcome with the studied genetic markers was not detected, dominating risk factor of development of severe course and lethal outcome for A(H1N1)pdm09 influenza in the studied cohort was comorbidity. PMID- 26950993 TI - [EXPERIENCE OF STUDY AND POSSIBLE WAYS OF ELIMINATION OF FALSE POSITIVE AND FALSE NEGATIVE RESULTS DURING EXECUTION OF POLYMERASE CHAIN REACTION ON AN EXAMPLE OF JUNIN VIRUS RNA DETECTION]. AB - AIM: Experience of study and possible ways of elimination of false positive and false negative results during execution of polymerase chain reaction on an example of Junin virus RNA detection. MATERIALSS AND METHODS: Junin virus- causative agent of Argentine hemorrhagic fever (AHF) strain XJpR37/5787 was obtained from the State collection of pathogenicity group I causative agents of the 48th Central Research Institute. Reagent kit for detection of Junin virus RNA by RT-PCR was developed in the Institute and consists of 4 sets: for isolation of RNA, execution of reverse-transcription reaction, execution of PCR and electrophoretic detection of PCR products. RT-PCR was carried out by a standard technique. Continuous cell cultures of African green monkey Vero B, GMK-AH-1(D) were obtained from the museum of cell culture department of the Centre. RESULTS: An experimental study of the effect of various factors of impact on the sample under investigation ("thawing-freezing", presence of formaldehyde, heparin) on the obtaining of false negative results during Junin virus RNA detection by using RT-PCR was studied. Addition of 0.01% heparin to the samples was shown to completely inhibit PCR. Addition of 0.05% formaldehyde significantly reduces sensitivity of the method. A possibility of reduction of analysis timeframe from 15 to 5 days was shown during detection of the causative agent in samples with low concentration of the latter by growing the samples and subsequent analysis of the material obtained by using RT-PCR. CONCLUSION: During detection of causative agent by using RT-PCR false negative results could appear in the presence of formaldehyde and heparin in the sample. A possibility of elimination of false negative PCR results due to concentration of the causative agent in the sample under investigation at a level below sensitivity threshold was shown on the example of Junin virus RNA detection by using growing of the pathogen in appropriate accumulation system with subsequent analysis of the material obtained using PCR. PMID- 26950994 TI - [DETECTION OF VENEZUELAN EQUINE ENCEPHALOMYELITIS VIRUS RNA IN BIOLOGICAL SAMPLES BY REVERSE-TRANSCRIPTION POLYMERASE CHAIN REACTION]. AB - AIM: Detection-and identification of Venezuelan equine encephalomyelitis (VEE) virus RNA in biological samples by reverse-transcription polymerase chain reaction (RT-PCR) and RT-PCR in real time (rRT-PCR). MATERIALS AND METHODS: VEE, Sindbis, West Nile, Japanese and tick-borne encephalitis viruses were studied. Cell culture of chicken fibroblasts, outbred mice and rats, Javanese macaques were used in the experiments. Biological activity determination of the running culture of causative agents used in the experiments was carried out by negative colony method in monolayer cell culture under agar coating. and using intra cerebral infection of mice. Reagent kits developed in the 48th Central Research Institute and Institute of Analytical Instrument Engineering were used during execution of experiments of VEE virus RNA detection by RT-PCR and rRT-PCR. RESULTS: VEE virus was detected in biological samples by various methods. Data from RT-PCR and rRT-PCR are in accordance with the results of virus detection in samples using sensitive animals. CONCLUSION: Use of molecular-diagnostics methods for detection in biological samples of a causative agent of a dangerous infectious disease is important for procuring biological safety of Russian Federation. PMID- 26950995 TI - [MANIFESTATIONS OF EPIDEMIC PROCESS AND TRANSMISSION ROUTES OF CAUSATIVE AGENT OF ENTEROVIRUS SEROUS MENINGITIS]. AB - AIM: Study the manifestations of epidemic process and leading transmission routes of causative agents of enterovirus serous meningitis (SM) by results of laboratory studies and epidemiologic examination of epidemic nidi. MATERIALS AND METHODS: During 2010 - 2014 a study for enterovirus was carried out in cerebrospinal fluid in 743 patients, hospitalized into medical organizations of Perm with primary diagnosis "serous meningitis", feces of 426 individuals, that had communicated with patients with SM of enterovirus etiology; 827 water samples from the distribution network, 295 water samples from open water and 57 washes from surface of vegetables and fruits. All the samples were studied in polymerase chain reaction, part--by a virological method. Epidemiologic examination of 350 epidemic nidi of SM was carried out. RESULTS: Enterovirus and (or) its RNA were detected in 62.0% of patients and 61.9% of individuals that had communicated with patients with enteroviris SM. ECHO 6 serotype enterovirus dominated among the causative agents. Maximum intensity of epidemic process of enterovirus SM, based on data from laboratory examination of patients, was detected in a group of organized pre-school and school age children during summer-autumn period. CONCLUSION: . Examination of epidemic nidi and laboratory control of environmental objects have shown that CV causative agent transmission factors are, in particular, unboiled water from decentralized sources (boreholes, wells, springs), water from open waters during bathing, as well as fresh vegetables, fruits, berries and meals produced from them. . PMID- 26950996 TI - [BIOLOGICAL PROPERTIES OF SALMONELLA, ISOLATED FROM CLINICAL MATERIAL AND AQUATIC ENVIRONMENT IN ROSTOV REGION]. AB - AIM: Study biological properties of salmonella, isolated from clinical materials and water of Don river. MATERIALS AND METHODS: Salmonella strains of various serovars were used in the study. Biochemical characteristics were studied by generally accepted methods, antigenic properties were evaluated in agglutination reactions, virulence was determined by Dlm for laboratory animals, antibiotics sensitivity was verified by disc-diffusion method. RESULTS: The presence of pathogenicity factors in isolated strains was shown: hemolytic activity--in 64 and 36.8% of cases, DNAse activity--in 28 and 26%, respectively in clinical and wild strains. Microorganism dose, resulting in death of all the animals (LD100) did not depend on serovar of salmonella and varied from 10(3) to 10(10) PFU/ml. CONCLUSION: Clinical strains were established to possess higher virulence and resistance to antibiotics compared with strains isolated from the aquatic envionment. PMID- 26950997 TI - [STUDY OF THE ROLE OF INNATE IMMUNITY FACTORS (TLR2, HBD-2, TNF-alpha, TGF-beta) IN PERIODONTITIS PATHOGENESIS]. AB - AIM: Study of the role of innate immunity factors, namely, expression of TLR2 and HBD-2 genes, as well as TNF-alpha arid TGF-beta in pathogenesis of periodontium tissue inflammation. MATERIALS AND METHODS: 59 individuals with periodontitis illnesses were included into the study; 15 healthy donors represented the comparison group. Study of the TLR2 and HBD-2 gene expression levels was carried out by rRT-PCR, cytokine production evaluation--by EIA. RESULTS: The results of the study have shown the presence of TLR-mediated disbalance in the innate immunity system in the periodontium tissue during chronic generalized periodontitis. TLR2 gene hyperexpression was accompanied by the reduction of expression of anti-microbial peptide HBD-2, as well as an increase of production of TNF-alphaand TGF-P by epithelial cells of periodontium mucosa. Conclusion.-The study carried out has shown that disturbance of molecular mechanisms of innate immunity system has an important place in pathogenesis of periodontitis. - PMID- 26950998 TI - [THE ROLE OF BIFIDOBACTERIA IN THE FORMATION OF HUMAN IMMUNE HOMEOSTASIS]. AB - In the review the materials on the formation of intestinal immune homeostasis through involvement of bifidobacteria which are the key species of microbiota of human colon biotype are presented. Key function of dominant microorganisms, bifidoflora in particular, in intestinal biotype of a host is carried out by means of maintenance of self microorganisms and pronounced antagonism concerning non-self. Realization of this principle in intermicrobial relations allowed to develop algorithm of microbial self-non-self discrimination in microsymbiocenosis on the basis of detected opposite phenomenon (enhancement/suppression) of the main physiological functions of microsymbionts survival (reproduction and adaptation) in dominant-associant pair. Primary discrimination of foreign,material by bifidobacteria is the initial stage of the following "signaling" in the regulation of host immune homeostasis. Further stages of regulation occur by activation of dendritic cells by bifidobacteria with the sequential influence on differentiation of Th0 towards regulatory lymphocytes. The formation of Treg and regulation of immune homeostasis are carried out by bifidobacteria: due to direct activation of dendritic cells (ligand-receptor interactions) and maintenance of optimal cytokine balance. PMID- 26950999 TI - [IMMUNOPATHOGENESIS OF OCCULT INFECTION CAUSED BY HEPATITIS B VIRUS]. AB - The concept of occult infection caused by hepatitis B virus (HBV) is determined as the presence of HBV DNA in blood sera or liver with the absence of detectable HBsAg. The actuality of this problem is associated with the fact, that occult hepatitis B (OHB) can be transmitted during hemotransfusions, cause reactivation of chronic hepatitis B in immune compromised individuals, facilitate development of liver cirrhosis and hepatocellular carcinoma. Several different hypotheses of OHB immunopathogenesis have been proposed, including a low number of copies of HBV DNA, altered immune response of the macroorganism, genetic variability of the S gene, integration of viral DNA into host genome, infection of mononuclear cells of peripheral blood, presence of immune complexes that hide HBsAg, and interference by other viruses such as HCV and HIV. Molecular mechanisms of HBV virus in HBsAg-negative individuals are not fully understood, however, viral mutations seem a very significant factor. Approaches of OHB prophylaxis including use of a polyvalent vaccine, that allows vaccination against wild and mutant HBV viruses, are examined. PMID- 26951000 TI - [PERSISTENCE OF BORDETELLA PERTUSSIS BACTERIA AND A POSSIBLE MECHANISM OF ITS FORMATION]. AB - A growth of pertussis morbidity is observed in many countries of the world against the background of mass vaccindtion. Forms of the disease course have changed. Atypical forms of pertussis occur predominately in adolescents and adults. Asymptomatic carriage of the causative agent has been established. Infection of infants with. BordetelIa pertussis bacteria in more than 90% of cases occurs from parents and relatives. A prolonged persistence of the causative agent has been identified. Morbidity increase in developed countries is associated with the use of acellular vaccines, that do not protect from the infection, but reduce severity of the disease. A change of genotypes of the circulating bacteria strains is observed ubiquitously. Formation of a persistent form of B. pertussis is possible due to a reversible integration of IS-elements into bvgAS operon and other virulence genes. The results of studies of invasion and survival of B. pertussis bacteria in eukaryotic cells, a change in B. pertussis bacteria population after experimental infection of laboratory mice and monkeys are presented, accumulation of avirulent insertion Bvg mutants of B. pertussis was detected. The data obtained are in accordance with the results of analysis of causative agent population in patients with typical and atypical forms of pertussis in humans. More than 50% of the population of B. pertussis bacteria in practically healthy carriers was shown to be presented by avirulent insertion Bvg mutants. B. pertussis virulence reducing as a result of inactivation of single or several virulence genes probably provide long-term persistence of bacteria in host organism and formation of apparently healthy vehicles. Follow-up studies on that front would help to formulate new attitudes to preventive measures of pertussis and lead to development of fundamentally new pharmaceuticals (vaccines) preventing formation of bacterial persistence. PMID- 26951002 TI - [Clinical and Biological Character in Mouse Models for Middle East Respiratory Syndrome Generated by Transduction with Different Doses of DPP4 Molecule]. AB - In this study, we evaluated the difference ot biological characteristics in the MERS-CoV infected mice model in prior to transduction with different dosage of human DPP4. Firstly, we transduced different dosage of DPP4 (high or low) into mice, and then challenged them with MERS-CoV in order to establish the model. After establishment of mice model, we observed the clinical signs of disease, virus replication, immunopathogenesis and antibody response. The results indicated that the infected mice showed typical pneumonia, virus replication, histological lesions, and neutralizing antibody production. Moreover, the high dosage group was superior to the low dosage group. Fourteen days after infection, the specific antibody to virus structural protein and neutralizing antibody were analyzed, the high dosage group induced higher level antibody. In summary, the MERS-CoV infected mice model were established prior transduction with DPP4, and the level of DPP4 influenced the clinical signs of disease, virus replication and antibody response in this model. PMID- 26951001 TI - [ABOUT SIGNIFICANT ISSUES IN EFFICIENCY OF THE EPIDEMIOLOGICAL SURVEILLANCE OF INFECTIOUS DISEASES IN RUSSIAN FEDERATION]. PMID- 26951003 TI - [Sample Preparation and Imaging of Single Adenovirus Particle Using Atomic Force Microscopy in Liquid]. AB - Atomic force microscopy (AFM), as a sophisticated imaging tool with nanoscale resolution, is widely used in virus research and the application of functional viral particles. To investigate single viruses by AFM in a physiologically relevant environment (liquid), an appropriate surface treatment to properly adhere the viruses to the substrate is essential. Here we discuss hydrophobic treated glass coverslips as a suitable substrate for the adhesion of single adenovirus particle (Adenovirus type 5 F35, Ad5F35) when studied with AFM in liquid. From the high resolution AFM images, the orientation of the adhered virus particles can be distinguished. Furthermore, the particles exhibit the expected height of -90 nm. This illustrates that the viruses adhere to the substrate firmly without large deformations. Hence, the described method works well on (fragile) viruses. The described experimental approach can be widely used for AFM studies in liquid of virus structure and mechanics as well as for investigating the interaction of viruses with cellular receptors. PMID- 26951004 TI - [Determination of Influenza Virus H5N1 and H7N9 Using MASA Technology]. AB - To set up a new rapid method for the rapid determination of influenza virus H5N1 and H7N9 basing on the Multi-Analyte Suspension Array (MASA) technology. Sequence analysis and design of degenerate primers and specific probes were set in the comparison and analysis of H5, N1, H7 and N9 genes. In combination with MASA technology, these primers and probes were used for the determination of samples of H5N1 and H7N9 and other subtypes ( H1N1, PH1N1, H5N2, H3N2 and H9N2). We developed a rapid determination method. This method had high specificity and sensitivity that could detect H5N1 and H7N9 at one time, and could detect samples that containing 10 copies of H5N1 and H7N9. This determination method could be used for rapid determination of influenza virus H5N1 and H7N9 at one time. PMID- 26951005 TI - [Detection of Avian Influenza Virus in Environmental Samples Collected from Live Poultry Markets in China during 2009-2013]. AB - Abstract: To investigate the distribution of avian influenza virus in environmental samples from live poultry markets (LPM) in China, samples were collected and tested by nucleic acid during 2009-2013 season. Each sample was tested by real-time RT PCR using flu A specific primers. If any real-time PCR was positive, the sample was inoculated into specific-pathogen-free (SPF) embryonated chicken eggs for viral isolation. The results indicated that the positive rate of nucleic acid in enviromental samples exhibited seasonality. The positive rate of nucleic acid was significantly higher in Winter and Spring. The positive rate of nucleic acid in LPM located in the south of China was higher than in northern China. Samples of Sewage for cleaning poultry and chopping board showed that higher positive rate of nucleic acid than other samples. The Subtype identification showed that H5 and H9 were main subtypes in the enviromental samples. Viral isolation indicated H5 subtypes was more than H9 subtypes between 2009 and 2013 while H9 subtypes increased in 2013. Our findings suggested the significance of public health based on LPM surveillance and provided the basis of prevention and early warning for avian flu infection human. PMID- 26951006 TI - [Phylogenetic and Bioinformatics Analysis of Replicase Gene Sequence of Cucumber Green Mottle Mosaic Virus]. AB - The replicase genes of five isolates of Cucumber green mottle mosaic virus from Jiangsu, Zhejiang, Hunan and Beijing were amplificated, sequenced and analyzed. The similarities of nucleotide acid sequences indicated that 129 kD and 57 kD replicase genes of CGMMV-No. 1, CGMMV-No. 2, CGMMV-No. 3, CGMMV-No. 4 and CGMMV No. 5 were 99.64% and 99.74%, respectively. The similarities of 129 kD and 57 kD replicase genes of CGMMV-No. 1, CGMMV-No. 3 and CGMMV-No. 4 were 99.95% and 99.94%, while they were lower between CGMMV-No. 2 and the rest of four reference sequences, just from 99.16% to 99.27% and from 99.04% to 99.18%. All reference sequences could be divided into six groups in neighbor-joining (NJ) phylogenetic trees based on the replicase gene sequences of 129 kD, 57 kD protein respectively. CGMMV-No. 1, CGMMV-No. 3 and CGMMV-No. 4 were clustered together with Shandong isolate (Accession No. KJ754195) in two NJ trees; CGMMV-No. 5 was clustered together with Liaoning isolate (Accession No. EF611826) in two NJ trees; CGMMV-No. 2 was clustered together with Korea watermelon isolate (Accession No. AF417242) in phylogenetic tree of 129 kD replicase gene of CGMMV; Interestingly, CGMMV-No. 2 was classified as a independent group in phylogenetic tree of 57 kD replicase gene of CGMMV. There were no significant hydrophobic and highly coiled coil regions on 129 kD and 57 kD proteins of tested CGMMV isolates. Except 129 kD protein of CGMMV-No. 4, the rest were unstable protein. The number of transmembrane helical segments (TMHs) of 129 kD protein of CGMMV-No. 1, CGMMV No. 2, CGMMV-No. 3 and CGMMV-No. 5 were 6, 6, 2 and 4, respectively, which were 13, 13 and 5 on the 57 kD protein of CGMMV-No. 2, CGMMV-No. 4 and CGMMV-No. 5. The glycosylation site of 129 kD protein of tested CGMMV isolates were 2, 4, 4, 4 and 4, and that of 57 kD protein were 2, 5, 2, 5 and 2. There were difference between the disorders, globulins, phosphorylation sites and B cell antigen epitopes of 129 kD and 57 kD proteins of tested CGMMV isolates. The current results that there was no significant difference between the replicase gene sequences, it was stable and conservative for intra-species and clearly difference for inter-species. CGMMV-No. 1, CGMMV-No. 3, CGMMV-No. 4 and CGMMV-No. 5 had. a close genetic relationship with Shandong and Liangning isolates (Accession No. KJ754195 and EF611826), they are potentially originate from the same source. CGMMV-No. 2 was closer with Korea isolate. High sequence similarity of tested samples were gathered for a class in phylogenetic tree. It didn't show regularity of the bioinformatics analysis results of 129 kD and 57 kD proteins of tested CGMMV isolates. There was no corresponding relationship among the molecular phylogeny and the bioinformatics analysis of the tested CGMMV isolates. PMID- 26951007 TI - [Construction and Expression of RNase-Resisting His-Tagged Virus-Like Particles Containing FluA/B mRNA]. AB - To prepare virus-like particles containing FluA/B mRNA as RNA standard and control in Influenza RNA detection, the genes coding the coat protein and maturase of E. coli bacteriophage MS2 were amplified and cloned into D-pET32a vector. Then we inserted 6 histidines to MS2 coat protein by QuikChange Site Directed Mutagenesis Kit to construct the universal expressing vector D-pET32a-CP His. In addition, the partial gene fragments of FluA and FluB were cloned to the down-stream of expressing vector. The recombinant plasmid D-pET32a-CP-His-FluA/B was transformed to BL21 with induction by IPTG. The virus-like particles were purified by Ni+ chromatography. The virus-like particles can be detected by RT PCR, but not PCR. They can be conserved stably for at least 3 months at both 4 degrees C and -20 degrees C. His-tagged virus-like particles are more stable and easier to purification. It can be used as RNA standard and control in Influenza virus RNA detection. PMID- 26951008 TI - [Construction of a Recombinant Replication-defective Human Adenovirus Type 5 Expressing G Protein of Irkut Virus and the Immune Test in Mouse]. AB - To develop a safe and effective new generation vaccine for IRKV-THChina12 prevention, we constructed a non-replicative recombinant human adenovirus carrying the IRKV-THChina12 G gene, named as rAd5-IRKV-G. The IRKV-THChina12 G protein expressed by the recombinant human adenovirus in 293AD cells was detected by western blot and indirect immunofluorescence test. To evaluate the immunogenicity of the recombinant, mice were immunized with rAd5-IRKV-G by intramuscular (i. m.) or intraperitoneal (i. p.) route and with non-exogenous gene expressing wild type adenovirus wt-rAd5 as a control. Results showed that the rAd5-IRKV-G could induce continuous and statistically significant (P <= 0.05) anti-IRKV neutralizing antibody (NA) production in immunized mice by i. m. or i. p. route. In particular, no significant difference (P > 0.05) of the NA titers between the two administration routes were observed, that provides an alternative choice for animal immunization method in the future application. PMID- 26951009 TI - [Development and Application of An Assay for High-throughput Antiviral Compounds Screening against Alphaviruses]. AB - To establish a cell-based rapid luciferase suppression assay for high-throughput screening (HTS) anti-alphaviruses compounds screening, which could cause viral encephalitis, raise the social issues associated directly with public health and huge economic burden to the society. The Gaussia luciferase assay system was used for HTS model for identifying inhibitors of labeled virus XJ160-GLUC. The decreased 50% GLUC activity inhibition ratio was deemed to be the screening positive index. The reaction system in this model was optimized, and the reliability of the model was evaluated. For HTS model's optimization, cells were infected with XJ160-GLUC at an MOI of 0.025 PFU/cell. The supernatant treated with compounds 48h were collected for GLUC expression detection. In the model, Z' factor was up to 0.71, demonstrating that HTS assay for identifying inhibitors that target all aspects of the viral life cycle of XJ160-GLUC was stable and reliable. After screening 8080 compounds (five-in-one), 341 positive samples were selected, and the positive rate was 4.2% with a cutoff at 50% inhibition. Then 1705 compounds were screened subsequently and the positive rate was 1.1% with obtaining 19 positive compounds. These results will lay the foundation for finding the anti-alphaviruses' drug targets. PMID- 26951010 TI - [Characterization of Serial Passage of 1b/2a Chimera Hepatitis C Virus Cell Culture System Carrying Envelope E1E2 Coding Gene from Hebei Strain of China]. AB - To character a novel chimera(1b/2a) hepatitis C virus cell culture (HCVcc) system carrying envelope E1E2 coding gene from Hebei strain of China, chimera HCVcc (cHCVcc) was developed from Huh7.5-CD81 cells after transfection with in vitro transcribed full-length 1b/2a chimera RNA, which carrying envelope E1E2 coding gene from Hebei strain of China. Then the replication, expression and infectious titer of serial passage HCVcc were assessed by Real Time RT-PCR, indirect immunofluorescence assay (IFA) and Western blotting (WB). In addition, chimeric envelope gene from HCVcc was sequenced after serial passage. We found that the number of HCV positive focus increased gradually in cell post-transfection with chimera HCVcc (1b/2a) RNA and reach a peak platform (80% to 90%) at 41 days post transfection; the expression of HCV protein was also confirmed by WAB during serial passage. At meantime, HCV RNA copy number in the supernatant peaked at 10(4)-10(7) copies/mL and the highest infectious titer of this 1b/2a cHCVcc reinfection were tested as 10(4) ffu/mL. Sequence analysis indicated 6 of adaptive amino acid substitutes occur among chimeric envelope E1E2 during serial passages. We con:luded that a novel 1b/2a chimera HCVcc carrying envelope E1E2 coding gene from Hebei strain of China was developed and its infectious titer increased after serial passage of HCVcc. This novel cHCVcc will be an effective tool for further evaluation of anti-virus drugs and immune effects against the major genotype from Chinese. PMID- 26951011 TI - [Expression and Preliminary Research on the Soluble Domain of EV-D68 3A Protein]. AB - To understand the structure of the soluble region of Enterovirus 68 3A protein, we construct a prokaryotic expression vector expressing the soluble region of EV D68 3A protein, and identify the forms of expression product after purification. The EV-D68 3A(1-61) gene was amplified by PCR and then cloned into the expression vector pET-28a-His-SUMO. The recombinant plasmid was transformed into Escherichia coli BL21 induced by IPTG to express the fusion protein His-SUMO-3A(1-61). The recombinant protein was purified by Ni-NTA Agarose and cleaved by ULP Protease to remove His-SUMO tag. After that, the target protein 3A(1-61) was purified by a series of purification methods such as Ni-NTA, anion exchange chromatography and gel filtration chromato- graphy. Chemical cross-linking reaction assay was taken to determine the multiple polymerization state of the 3A soluble region. A prokaryotic expression vector pET28a-His-SUMO-3A(1-61) expressing the solution region of EV-D68 3A was successfully constructed and plenty of highly pure target proteins were obtained by multiple purification steps . The total protein amount was about 5 mg obtained from 1L Escherichia coli BL21 with purity > 95%. At the same time, those results determined the homomultimer form of soluble 3A construct. These data demonstrated that the expression and purification system of the soluble region of 3A were successfully set up and provide some basic konwledge for the research about 3A crystal structure and the development of antiviral drugs targeted at 3A to block viral replication. PMID- 26951012 TI - [Phylogenetic Analysis of the VP1 Region of Coxsackievirus A16 Strains Isolated in Anhui Province, 2014]. AB - To study on the phylogenetic characterization of the VP1 genes of coxsackievirus A16 (CVA16) causing hand-food-mouth disease (HFMD) isolated from Anhui province in 2014. A total of 413 throat swab specimens from HFMD patients were collected during January to November, 2014 for the isolation and identification of enteroviruses using real-time RT-PCR assays. The VP1 regions of CVA16 isolates were amplified using RT-PCR and sequenced. And the phylogenetic tree was constructed among the VP1 regions of those isolates, the different genotypes and sub-genotypes of CVA16 strains. A total of 97 enteroviruses were isolated from 413 samples, the positive rate was 23.49% (97/413), including seventeen CVA16, seventy six HEV71 and four other enteroviruses. The results of the phylogenetic tree showed that 17.CVA16 strains isolated from Anhui in 2014 clustered within B1b evolution branch of B1 genotype. The nucleotide and amino acid sequence identities were 95.30%-100% and 98.70%-100% among the isolates, respectively, but within B1b branch of 17 strains formed several small transmission chains. The nucleotide acid of 17 CVA16 isolates in Anhui province were closed to the strains isolated from Yunnan, Hunan, Guangdong, Tibet and Jiangsu, especially from Hunan in 2013 and from Shenzhen of Guangdong in 2014, the identity were 96.40%-99.70%. The CVA16 strains isolated from Anhui in 2014 were all belong to genetic subtype B1b of B1 genotype was dominant, and among those isolates, several small virus transmission chains had formed with co-circulating and evolution. PMID- 26951013 TI - [Mapping of the B Cell Neutralizing Epitopes on ED III of Envelope Protein from Dengue Virus]. AB - Dengue virus (DENV) envelope [E] protein is the major surface protein of the virions that indued neutralizing antibodies. The domain III of envelope protein (EDIII) is an immunogenic region that holds potential for the development of vaccines; however, the epitopes of DENV EDIII, especially neutralizing B-cell linear epitopes, have not been comprehensively mapped. We mapped neutralizing B cell linear epitopes on DENV-1 EDIII using 27 monoclonal antibodies against DENV 1 EDIII proteins from mice immunized with the DENV-1 EDIII. Epitope recognition analysis was performed using two set of sequential overlapping peptides (16m and 12m) that spanned the entire EDIII protein from DENV-1, respectively. This strategy identified a DENV-1 type- specific and a group-specific neutralizing epitope, which were highly conserved among isolates of DENV-1 and the four DENV serotypes and located at two regions from DENV-1 E, namely amino acid residues 309-320 and 381-392(aa 309-320 and 381-392), respectively. aa310 319(310KEVAETQHGT319)was similar among the four DENV serotypes and contact residues on aa 309 -320 from E protein were defined and found that substitution of residues E309 , V312, A313 and V320 in DENV-2, -3, -4 isolates were antigenically silent. We also identified a DENV-1 type-specific strain-restricted neutralizing epitope, which was located at the region from DENV-1 E, namely amino acid residues 329-348 . These novel type- and group-specific B-cell epitopes of DENV EDIII may aid help us elucidate the dengue pathogenesis and accelerate vaccine design. PMID- 26951014 TI - [Analysis of HA and NA Genes of Influenza A H1N1 Virus in Yunnan Province during 2009-2014]. AB - To analyze influenza pathogen spectrum in Yunnan province during 2009-2014 years, and analyze HA and NA genes of influenza A H1N1. Analysis was made on the monitoring date of influenza cases in Yunnan province in recent 6 years, 23 strains of influenza virus of HA and NA gene was sequenced and analyzed by MEGA 5 software to construct phylogenetic tree. 4 times of influenza AH1N1 epidemic peak were monitored from 2009-2014 years in Yunnan Province, as the nucleic acid detection results of influenza A H1N1 accounted for 28.8% of the total. The sequencing result showed that HA and NA gene were divided into 3 groups, one was detected with H275Y mutation strains. Influenza A H1N1 is one of the important subtypes in Yunnan province and their genes have divided into three branches during the period of 2009-2014 years, the vast majority of influenza a H1N1 are still sensitive to neuraminidase inhibitors. PMID- 26951015 TI - [Advances in Parvovirus Non-structural Protein NS1 Induced Apoptosis]. AB - Until now, more than seventeen parvovirus have been reported which can infect mammals and poultries. The infected cells appeared different properties of apoptosis and death, present a typical cytopathic effect. NS1 is a major nonstructural protein of parvovirus, with a conservative structure and function, which plays an important role in the viral life cycle. In addition to the influence on viral replication, the NS1 also participates in apoptosis induced by viruses. Parvovirus induced apoptosis which is mainly mediated by mitochondrial pathway, this review summarized the latest research progresses of parvovirus induced apoptosis. PMID- 26951016 TI - [The Advances in the Contamination and Detection of Foodborne Pathogen Noroviruses in Fresh Produce]. AB - This article reviewed the researches proceeding on the contamination and detection of the foodborne pathogen noroviruses (NoVs) in fresh produce, which involved the NoVs contaminations in fresh produce, the special attachment of NoVs in fresh produce, the NoVs outbreaks associated with fresh produce and the NoVs detection in fresh produce. There had been an increase in reported infectious disease risks associated with the consumptions of fresh produce for recent 30 years. Because the NoVs, as a primary cause of viral gastroenteritis thoughout the world, were highly contagious, had a low infectious dose, and were persistent in the environment. And also the methods for NoVs detection in food had significantly developed over the last 15 years. Currently NoVs were the most common pathogen accounting for 40% of outbreaks associated with fresh produce (i. e., fruits and vegetables). Data from outbreaks investigations verified fresh produce as the high risk food products for NoVs. The fresh produce were typically eaten raw with no thermal processing, can be contaminated at any step during production and processing from faecally polluted water and fertilizers, the poor hygiene practices by food handlers and the cross-contamination. The attachment of NoVs to the fresh produce was due to the physio-chemical factors of virus protein coat, the special attachment to different fresh produce, and the possibility for internalization of NoVs. It might provide answers to why those high risk foods were more frequently implicated (i. e., lettuce and raspberries). According to the data of foodborne NoVs outbreaks which were associated with fresh produce from EU countries and the USA, the outbreaks in EU countries were mainly associated with NoVs contaminated raspberries and lettuce, while in USA which were associated with NoVs contaminated lettuce. Unfortunately, there were no NoVs detection methods for fresh produce or the data of foodborne NoVs outbreaks which were associated with fresh produce in China. That made it difficult to analyze the NoVs contamination situation in China. The heterogeneous distributions of presumably low levels of virus, which presented in contaminated fresh produce, also made it difficult to detect NoVs. To solve this problem, different sampling methods, viral elution methods and RT-qPCR methods were chosen. For example, according to the isoelectric point of NoVs particles, high pH and high ionic strength solution could be used as means for releasing NoVs. For the elution from acidic fruit, the buffer capacity and the virus recovery could be increased by the addition of tris-HCl. When analyzing pectin containing raspberries or strawberries, the viral elution usually incubated with pectinase at neutral pH to avoid from foaming jelly. In this paper, the latest ISO standard for NoV detection in food and the new approaches for NoV detection were also reviewed to provide references for domestic researches. It was necessary to establish and develop domestic methods for NoV detection in fresh produce, especially the different NoV conventional molecular detection methods with corresponding NoV extraction methods, which targeted to the different adsorption characteristics of different fruits and vegetables, in order to strengthen the national food safety monitoring. PMID- 26951017 TI - [Innate Immune Evasion Mechanisms of Pseudorabies Virus]. AB - Pseudorabies is an economically important disease in a variety ot animals caused by pseudorabies virus. Since 2011, pseudorabies outbreaks occurred in many regions of China. Related researches on this virus become a hot topic in virology and veterinary. One of the difficulties for pseudorabies prevention and control is innate immune evasion. Explorations on this issue are conducive to the development of vaccine and drugs. Therefore, this review summarized the recent research progress on the mechanisms of pseudorabies virus innate immune evasion. Theoretical direction was provided on effetive prevention and control of pseudorabies owing to this review. PMID- 26951018 TI - [Progress on the Function of Herpesvirus-encoded MicroRNAs]. AB - Since Epstein Barr virus was shown to encode microRNAs(miRNAs) in 2004, more than 470 miRNAs have been discovered in alpha-, beta-, and gamma-herpesviruses. MiRNAs are small non-coding RNA molecules and generally only have 18-25 nucleotides in length, which can regulate the expression of target genes by targeting its transcripts. Herpesvirus-encoded miRNAs not only target the key genes from latency to lytic replication, but also regulate various host cellular genes. Current data manifest that herpesvirus-encoded miRNAs can regulate viral latent infection and lytic replication, immune recognition, apoptosis, and tumorigenesis. The purpose of this paper is to summarize the targets and their fuction of hepesvirus-encoded miRNAs, in order to provide theoretical support for further analysis herpesviral pathogenesis. PMID- 26951019 TI - A dental force awakens. PMID- 26951020 TI - Wrong solution proposed for our X-ray conundrum. PMID- 26951021 TI - A conversation with 2016 CDS President George Zehak. PMID- 26951022 TI - CDS honors its members. PMID- 26951023 TI - Avoid creating a tangled web(site). PMID- 26951024 TI - Let's rise to the challenge. PMID- 26951025 TI - [Somatization disorder - an overdiagnosed but underestimated illness]. AB - Physical symptoms often occur in the absence of physical illness. This is termed somatization when the symptoms are caused by psychic factors. When abundant symptoms affect the functional capacity and cause subjective harm and seeking healthcare services, a psychic disorder may be in question. Somatization may be associated with numerous psychic disorders. It may, however, also be a question of a somatoform disorder having a physical symptom picture. Somatization disorder is one of the somatoform disorders. Recognition of the disorder is often the problem in its treatment. Establishing a long-term treatment relationship actually forms the basis for therapy. PMID- 26951026 TI - [Anti-Mullerian hormone - a marker of ovarian function]. AB - Anti-Mullerian hormone (AMH), also known as Mullerian inhibitory substance, is a useful marker of ovarian function. Granulosa cells of growing follicles secrete AMH, and its serum levels reflect the remaining follicular pool and thus the remaining length of a woman's reproductive lifespan. Serum AMH measurement can be used as a marker of ovarian dysfunction such as primary ovarian insufficiency, polycystic ovarian syndrome and granulosa cell tumors. Furthermore, it helps to estimate ovarian damage due to chemotherapy or surgery and can be used as a tool in infertility treatment. The use of AMH in clinical practice will likely become more common in the future as the new automatic assay methods become available. PMID- 26951027 TI - [Diagnosis and treatment of Lynch syndrome]. AB - Lynch syndrome (LS) refers to an autosomal dominant genetic predisposition to develop colon cancer or cancers or the uterine corpus, stomach, urinary tract, ovaries, small intestine, mammary gland or bile ducts at a young age. The predisposition to cancer is caused by a germline mutation in one of the genes of the mismatch repair (MMR) system. International recommendations suggest immunohistochemical analysis of tumor tissue from at least those having developed colorectal cancer or endometrial cancer at an age of less than 70 years. This would allow the selection of patients to be referred for gene testing as well as identification of mutation carriers, for whom a regular colonoscopy follow-up is arranged at an interval of 2 to 3 years. PMID- 26951029 TI - [Treatment of hyperhidrosis (excessive sweating)]. AB - Hyperhidrosis can be localized or generalized and may cause the patient significant discomfort. Localized hyperhidrosis is usually primary, often begins in adolescence and is partly based on genetic dispositions. As a rule it does not necessitate investigations for secondary causes (e.g. endocrine or neurologic conditions). Generalized hyperhidrosis is commonly associated with environmental or lifestyle factors, and sometimes physiological factors. In new-onset generalized sweating of unclear origin, it may be appropriate to consider secondary causes (underlying diseases, medications, infections). Relatively effective symptomatic treatments are available in localized hyperhidrosis. The treatment of generalized hyperhidrosis is almost always directed against the underlying factors. PMID- 26951028 TI - [Pregnancy and maternity of a schizophrenic patient]. AB - Aspects to be taken into consideration in the total care of women of reproductive age and affected with schizophrenia include possible contraception, pharmacological therapy during pregnancy and need for support in parenthood. Compared with other pregnant women, those affected with schizophrenia are older, are more frequently smokers during pregnancy and more often neglect health monitoring during pregnancy. Schizophrenia predisposes for preterm delivery, miscarriage and lower Apgar score of the infant. In regard to parenthood, the effects of the illness itself or the prescribed medication on the interactive mother-child relationship may emerge as problematic issues. PMID- 26951030 TI - [Congenital disorder of glycosylation type Ia (CDG Ia) - underdiagnosed entity?]. AB - Congenital disorders of glycosylation (CDG) are a relatively recently identified group of multisystem disorders caused by defective glycosylation of N glycosylated proteins. They mainly involve the central and peripheral nervous system, but other organ systems are involved as well. Type CDG Ia accounts for over 80% of cases, characterized by decreased activity of the enzyme phosphomannomutase caused by mutations in chromosome 16 PMM2 gene. Treatment of CDG Ia remains symptomatic. PMID- 26951031 TI - [Procedural skills of students qualifying as a doctor - towards blended learning]. AB - Medical students feel that their ability to carry out procedures is lower than desired. Whereas supervised learning is easily arranged at scheduled appointment clinics, experience in emergency procedures often accumulates only during practical training. A large part of the students had turned to the internet in search for advice or repetition about typical emergency procedures. With the growing yearly intake by the faculties it will be difficult to increase contact teaching at the clinical stage, but it is possible to improve its quality through flipped classroom. Procedural videos found in the internet are well suited for stimuli prior to contact teaching. PMID- 26951033 TI - An emphasis on stress. PMID- 26951032 TI - [Update on Current Care Guideline: Insomnia]. AB - Insomnia symptoms must be differentiated from insomnia disorder. The correct aiagnosis or insomnia aisoraer is important, as insomnia may also be a symptom of many other diseases. Cognitive behavioral methods are recommended as first-line treatment options. Treatment of acute insomnia with hypnotics should not exceed two weeks. In elderly persons adverse effects of hypnotics may exceed their beneficial effects in long-term use. Antidepressive medications acting on the histamine-1 system may be used in very small doses. The new guideline includes e.g. insomnia in pregnant and menopausal women and in cancer patients, and driving issues. PMID- 26951034 TI - Oxidative stress may be a common mechanism linking major depression and osteoporosis. PMID- 26951035 TI - Immunological disturbance and infectious disease in anorexia nervosa: a review. AB - OBJECTIVE: Severely malnourished patients with anorexia nervosa (AN) are reported to show fewer symptomatic viral infections and a poorer response to bacterial infection than controls. They are also reported to show mild immune system changes, although the relevance of these to altered infection disease presentation in AN and AN pathophysiology is unknown. Thus, in this paper, we suggest a range of immune system changes that might underpin these altered responses to common pathogens, and review a number of recent infectious disease findings for their utility in explaining the pathophysiology of AN. METHODS: A systematic review of the literature pertaining to immunity and infectious disease in AN was performed. RESULTS: AN is associated with leucopenia, and the increased spontaneous and stimulated levels of proinflammatory cytokines [i.e. interleukin (IL)-1beta, IL-6 and tumour necrosis factor alpha). A range of less consistent findings are also reviewed. Most of these data were not controlled for length of illness, degree of malnutrition, micronutrient or vitamin deficiencies or recent refeeding and starvation. CONCLUSION: Cytokine disturbances have been suggested to be causally related to AN symptomatology and pathophysiology of AN, although the evidence supporting this assertion is lacking. Immune and cytokine changes in AN do, however, occur in association with a decreased incidence of symptomatic viral infection, decreased clinical response to bacterial infection leading to delayed diagnosis and increased morbidity and mortality associated with the infections. PMID- 26951036 TI - Treatment of refractory ulcerative necrobiosis lipoidica diabeticorum with oral thalidomide. AB - Ulcerative necrobiosis lipoidica (NL) in diabetic patients is a rare, painful condition. It is a difficult-to-treat condition, impairing quality of life of patients. Although various drugs have been tried, none of them is consistently effective. Biologics in the form of TNF-alpha inhibitors show promising results in the treatment. But because of their high cost we chose thalidomide, which also has TNF-alpha inhibiting properties to successfully treat a long-standing case of ulcerative NL, which was refractory to various treatment modalities. PMID- 26951037 TI - Alternaria section Alternaria: Species, formae speciales or pathotypes? AB - The cosmopolitan fungal genus Alternaria consists of multiple saprophytic and pathogenic species. Based on phylogenetic and morphological studies, the genus is currently divided into 26 sections. Alternaria sect. Alternaria contains most of the small-spored Alternaria species with concatenated conidia, including important plant, human and postharvest pathogens. Species within sect. Alternaria have been mostly described based on morphology and / or host-specificity, yet molecular variation between them is minimal. To investigate whether the described morphospecies within sect. Alternaria are supported by molecular data, whole genome sequencing of nine Alternaria morphospecies supplemented with transcriptome sequencing of 12 Alternaria morphospecies as well as multi-gene sequencing of 168 Alternaria isolates was performed. The assembled genomes ranged in size from 33.3-35.2 Mb within sect. Alternaria and from 32.0-39.1 Mb for all Alternaria genomes. The number of repetitive sequences differed significantly between the different Alternaria genomes; ranging from 1.4-16.5 %. The repeat content within sect. Alternaria was relatively low with only 1.4-2.7 % of repeats. Whole-genome alignments revealed 96.7-98.2 % genome identity between sect. Alternaria isolates, compared to 85.1-89.3 % genome identity for isolates from other sections to the A. alternata reference genome. Similarly, 1.4-2.8 % and 0.8-1.8 % single nucleotide polymorphisms (SNPs) were observed in genomic and transcriptomic sequences, respectively, between isolates from sect. Alternaria, while the percentage of SNPs found in isolates from different sections compared to the A. alternata reference genome was considerably higher; 8.0-10.3 % and 6.1 8.5 %. The topology of a phylogenetic tree based on the whole-genome and transcriptome reads was congruent with multi-gene phylogenies based on commonly used gene regions. Based on the genome and transcriptome data, a set of core proteins was extracted, and primers were designed on two gene regions with a relatively low degree of conservation within sect. Alternaria (96.8 and 97.3 % conservation). Their potential discriminatory power within sect. Alternaria was tested next to nine commonly used gene regions in sect. Alternaria, namely the SSU, LSU, ITS, gapdh, rpb2, tef1, Alt a 1, endoPG and OPA10-2 gene regions. The phylogenies from the two gene regions with a relatively low conservation, KOG1058 and KOG1077, could not distinguish the described morphospecies within sect. Alternaria more effectively than the phylogenies based on the commonly used gene regions for Alternaria. Based on genome and transcriptome comparisons and molecular phylogenies, Alternaria sect. Alternaria consists of only 11 phylogenetic species and one species complex. Thirty-five morphospecies, which cannot be distinguished based on the multi-gene phylogeny, are synonymised under A. alternata. By providing guidelines for the naming and identification of phylogenetic species in Alternaria sect. Alternaria, this manuscript provides a clear and stable species classification in this section. PMID- 26951038 TI - Evolutionary Dynamics of Homophily and Heterophily. AB - Most social interactions do not take place at random. In many situations, individuals choose their interaction partners on the basis of phenotypic cues. When this happens, individuals are often homophilic, that is, they tend to interact with individuals that are similar to them. Here we investigate the joint evolution of phenotypic cues and cue-dependent interaction strategies. By a combination of individual-based simulations and analytical arguments, we show that homophily evolves less easily than earlier studies suggest. The evolutionary interplay of cues and cue-based behaviour is intricate and has many interesting facets. For example, an interaction strategy like heterophily may stably persist in the population even if it is selected against in association with any particular cue. Homophily persisted for extensive periods of time just in those simulations where homophilic interactions provide a lower (rather than a higher) payoff than heterophilic interactions. Our results indicate that even the simplest cue-based social interactions can have rich dynamics and a surprising diversity of evolutionary outcomes. PMID- 26951039 TI - Malnutrition increases NO production and induces changes in inflammatory and oxidative status in the distal colon of lactating rats. AB - BACKGROUND: Epidemiological studies have indicated the lack of breast feeding as a risk factor associated with later development of inflammatory bowel disease. Nevertheless, the repercussion of little feeding during suckling on large intestine inflammatory response and anti-oxidant resources has not yet been completely understood. This study hypothesized that unfavorable lactation is able to induce oxidative stress and release of inflammatory mediators modifying the integrity of the colon epithelium in weanling rats. METHODS: Wistar rats were reared under different early nutritional conditions according to litter size in two groups: N6 (6 pups/dam) and N15 (15 pups/dam) until the 25th postnatal day. The distal colon was removed and processed for biochemical, morphometric, and immunohistochemical analyzes. Lipoperoxidation, nitric oxide (NO), reduced (GSH) and oxidized (GSSG) glutathione, tumor necrosis factor-alpha (TNF-alpha), interleukins-1beta, 4 and 10 (IL-1beta; IL-4; IL-10) levels, and total superoxide dismutase (tSOD), and catalase (CAT) activities were assessed. Morphometric analysis was carried out using paraffin sections and wholemount myenteric plexus preparations. KEY RESULTS: Increased lipoperoxidation, NO, TNF-alpha and IL-1b levels, reduced tSOD and increased CAT activities were found in the N15 compared to N6 group. No intergroup difference was detected for IL-10, while lower levels of IL-4, GSH and GSSG and lower neuronal size and density were induced by undernutrition. CONCLUSIONS & INFERENCES: Reduced feeding during suckling changed the inflammatory response and oxidative status in the colon of weanling rats. These data suggest potential mechanisms by which malnutrition early in life may increase the vulnerability of the large intestine to insults. PMID- 26951040 TI - Immunotherapy and stereotactic ablative radiotherapy (ISABR): a curative approach? AB - Conventional radiotherapy, in addition to its well-established tumoricidal effects, can also activate the host immune system. Radiation therapy modulates tumour phenotypes, enhances antigen presentation and tumour immunogenicity, increases production of cytokines and alters the tumour microenvironment, enabling destruction of the tumour by the immune system. Investigating the combination of radiotherapy with immunotherapeutic agents, which also promote the host antitumour immune response is, therefore, a logical progression. As the spectrum of clinical use of stereotactic radiotherapy continues to broaden, the question arose as to whether the ablative radiation doses used can also stimulate immune responses and, if so, whether we can amplify these effects by combining immunotherapy and stereotactic ablative radiotherapy (SABR). In this Perspectives article, we explore the preclinical and clinical evidence supporting activation of the immune system following SABR. We then examine studies that provide data on the effectiveness of combining these two techniques - immunotherapy and SABR - in an approach that we have termed 'ISABR'. Lastly, we provide general guiding principles for the development of future clinical trials to investigate the efficacy of ISABR in the hope of generating further interest in these exciting developments. PMID- 26951042 TI - Overall survival after reirradiation of spinal metastases - independent validation of predictive models. AB - BACKGROUND: It is unknown if survival prediction tools (SPTs) sufficiently predict survival in patients who undergo palliative reirradiation of spinal metastases. We therefore set out to clarify if SPTs can predict survival in this patient population. METHODS: We retrospectively analyzed spinal reirradiations performed (n = 58, 52 patients, 44 included in analysis). SPTs for patients with spinal metastases were identified and compared to a general palliative score and to a dedicated SPT to estimate prognosis in palliative reirradiation independent of site (SPT-Nieder). RESULTS: Consistently in all tests, SPT-Nieder showed best predictive performance as compared to other tools. Items associated with survival were general condition (KPS), liver metastases, and steroid use. Other factors like primary tumor site, pleural effusion, and bone metastases were not correlated with survival. We adapted an own score to the data which performed comparable to SPT-Nieder but avoids the pleural effusion item. Both scores showed good performance in identifying long-term survivors with late recurrences. CONCLUSIONS: Survival prediction in case of spinal reirradiation is possible with sufficient predictive separation. Applying SPTs in case of reirradiation helps to identify patients with good life expectancy who might benefit from dose escalation or longer treatment courses. PMID- 26951041 TI - Diet, nutrition, and cancer: past, present and future. AB - Despite the potentially important roles of diet and nutrition in cancer prevention, the evidence to support these roles is widely perceived by the public and health professionals as being inconsistent. In this Review, we present the issues and challenges in conducting and interpreting diet-cancer research, including those relating to the design of epidemiological studies, dietary data collection methods, and factors that affect the outcome of intervention trials. Approaches to improve effect estimates, such as the use of biomarkers to improve the accuracy of characterizing dietary exposures, are also discussed. Nutritional and dietary patterns are complex; therefore, the use of a reductionist approach to investigations, by focusing on specific nutrients, can produce misleading information. The effects of tumour heterogeneity and the failure to appreciate the nonlinear, U-shaped relationship between micronutrients and cancer in both observational studies and clinical trials are discussed. New technologies and investigational approaches are enabling the exploration of complex interactions between genetic, epigenetic, metabolic, and gut-microbial processes that will inform our knowledge of the diet-cancer relationship. Communicating the status of the evolving science in the context of the overall scientific evidence base, and evidence-based dietary recommendations for cancer prevention, should be emphasized in guidance for the public and for individual patients. PMID- 26951043 TI - Adherence to interferon beta-1a therapy using an electronic self-injector in multiple sclerosis: a multicentre, single-arm, observational, phase IV study. AB - BACKGROUND: In a multicentre, single-arm, observational, phase IV study, we evaluated 24-week treatment adherence of relapsing multiple sclerosis (RMS) patients using an electronic auto-injection device (RebiSmart((r))) for subcutaneous injection of interferon (IFN) beta-1a. METHODS: A total of 162 adult participants with RMS were enrolled into the study to use RebiSmart((r)) to self administer IFN beta-1a 44 MUg three times weekly for a maximum of 96 weeks. The number of administered injections was recorded in the electronic device log. Adherence to treatment was defined as the administration of >=80% of expected injections. Cognitive impairment and injection anxiety were assessed via questionnaires. RESULTS: Overall, 91.8 and 82.9% of participants were adherent to treatment at weeks 12 and 24, respectively. By weeks 12 and 24, 8.2 and 13.9% of participants had discontinued treatment. There were no statistically significant differences in adherence rates at weeks 12 and 24 according to cognitive impairment status or injection anxiety. By week 24, 69.9% of participants were less fearful of injection than when they started the study. According to participant evaluations, the absence of a visible needle, comfort settings, and the calendar for tracking the injection schedule were all important features of the RebiSmart((r)) injection system. At week 24, 99.3% of participants reported that they would like to continue using RebiSmart((r)) as their injector. CONCLUSIONS: RebiSmart((r)) use is associated with high treatment adherence, as objectively assessed using electronic injection logs. Future research should examine if RebiSmart((r)) use improves long-term treatment outcomes in RMS. This study was registered with ClinicalTrials.gov as NCT01128075, on May 20, 2010. PMID- 26951044 TI - Targeting Rad50 sensitizes human nasopharyngeal carcinoma cells to radiotherapy. AB - BACKGROUND: The Mre11-Rad50-Nbs1 (MRN) complex is well known for its crucial role in initiating DNA double strand breaks (DSBs) repair pathways to resistant irradiation (IR) injury and thus facilitating radioresistance which severely reduces radiocurability of nasopharyngeal cancer (NPC). Targeting native cellular MRN function would sensitize NPC cells to IR. METHODS: A recombinant adenovirus containing a mutant Rad50 gene (Ad-RAD50) expressing Rad50 zinc hook domain but lacking the ATPase domain and the Mre11 interaction domain was constructed to disrupt native cellular MRN functions. The effects of Ad-RAD50 on the MRN functions were assessed in NPC cells lines using western blot, co immunoprecipitation and confocal microscopy analyses. The increased radiosensitivity of transient Ad-RAD50 to IR was examined in NPC cells, including MTT assay, colony formation. The molecular mechanisms of radiosensitization were confirmed by neutral comet assay and western bolts. Nude mice subcutaneous injection, tumor growth curve and TUNEL assay were used to evaluate tumor regression and apoptosis in vivo. RESULTS: Rad50 is remarkably upregulated in NPC cells after IR, implying the critical role of Rad50 in MRN functions. The transient expression of this mutant Rad50 decreased the levels of native cellular Rad50, Mre11 and Nbs1, weakened the interactions among these proteins, abrogated the G2/M arrest induced by DSBs and reduced the DNA repair ability in NPC cells. A combination of IR and mutant RAD50 therapy produced significant tumor cytotoxicity in vitro, with a corresponding increase in DNA damage, prevented proliferation and cell viability. Furthermore, Ad-RAD50 sensitized NPC cells to IR by causing dramatic tumor regression and inducing apoptosis in vivo. CONCLUSION: Our findings define a novel therapeutic approach to NPC radiosensitization via targeted native cellular Rad50 disruption. PMID- 26951045 TI - RNA-seq analysis of the Rhizobium tropici CIAT 899 transcriptome shows similarities in the activation patterns of symbiotic genes in the presence of apigenin and salt. AB - BACKGROUND: Rhizobium tropici strain CIAT 899 establishes effective symbioses with several legume species, including Phaseolus vulgaris and Leucaena leucocephala. This bacterium synthesizes a large variety of nodulation factors in response to nod-gene inducing flavonoids and, surprisingly, also under salt stress conditions. The aim of this study was to identify differentially expressed genes in the presence of both inducer molecules, and analyze the promoter regions located upstream of these genes. RESULTS: Results obtained by RNA-seq analyses of CIAT 899 induced with apigenin, a nod gene-inducing flavonoid for this strain, or salt allowed the identification of 19 and 790 differentially expressed genes, respectively. Fifteen of these genes were up-regulated in both conditions and were involved in the synthesis of both Nod factors and indole-3-acetic acid. Transcription of these genes was presumably activated through binding of at least one of the five NodD proteins present in this strain to specific nod box promoter sequences when the bacterium was induced by both apigenin and salt. Finally, under saline conditions, many other transcriptional responses were detected, including an increase in the transcription of genes involved in trehalose catabolism, chemotaxis and protein secretion, as well as ribosomal genes, and a decrease in the transcription of genes involved in transmembrane transport. CONCLUSIONS: To our knowledge this is the first time that a transcriptomic study shows that salt stress induces the expression of nodulation genes in the absence of flavonoids. Thus, in the presence of both nodulation inducer molecules, apigenin and salt, R. tropici CIAT 899 up-regulated the same set of symbiotic genes. It could be possible that the increases in the transcription levels of several genes related to nodulation under saline conditions could represent a strategy to establish symbiosis under abiotic stressing conditions. PMID- 26951046 TI - Sphincter of Oddi Manometry: Reproducibility of Measurements and Effect of Sphincterotomy in the EPISOD Study. AB - BACKGROUND/AIMS: The reproducibility of sphincter of Oddi manometry (SOM) measurements and results of SOM after sphincterotomy has not been studied sufficiently. The aim of our study is to evaluate the reproducibility of SOM and completeness of sphincter ablation. METHODS: The recently published Evaluating Predictors and Interventions in sphincter of Oddi dysfunction (EPISOD) study included 214 subjects with post-cholecystectomy pain, and fit the criteria of sphincter of Oddi dysfunction type III. They were randomized into 3 arms, irrespective of manometric findings: sham (no sphincterotomy), biliary sphincterotomy, and dual (biliary and pancreatic). Thirty-eight subjects had both biliary and pancreatic manometries performed twice, at baseline and at repeat endoscopic retrograde cholangiopancreatography after 1-11 months. Sham arm was examined to assess the reproducibility of manometry, and the treatment arms to assess whether the sphincterotomies were complete (elevated pressures were normalized). RESULTS: Biliary and pancreatic measurements were reproduced in 7/14 (50%) untreated subjects. All 12 patients with initially elevated biliary pressures in biliary and dual sphincterotomy groups normalized after biliary sphincterotomy. However, 2 of 8 subjects with elevated pancreatic pressures in the dual sphincterotomy group remained abnormal after pancreatic sphincterotomy. Paradoxically, normal biliary pressures became abnormal in 1 of 15 subjects after biliary sphincterotomy, and normal pancreatic pressures became abnormal in 5 of 15 patients after biliary sphincterotomy, and in 1 of 9 after pancreatic sphincterotomy. CONCLUSIONS: Our data suggest that SOM measurements are poorly reproducible, and question whether we could adequately perform pancreatic sphincterotomy. PMID- 26951047 TI - Prevalence of Irritable Bowel Syndrome in Singapore and Its Association with Dietary, Lifestyle, and Environmental Factors. AB - Background/Aims: The prevalence of irritable bowel syndrome (IBS) has risen considerably over the past decade in Singapore. We aim to explore the contribution of changes in diet, lifestyle and habits that may contribute to the increased prevalence and development of IBS. Methods: This is a survey-based cross-sectional population study aimed to gather demographic, socio-economical, lifestyle, dietary, antibiotic usage and other related information. Subjects were adult male or female Singaporeans aged 21 years or above. Association of the factors gathered with the presence or absence of IBS (by Rome III criteria) was assessed using chi-square or Fisher's exact test. Variables with a level of statistical significance of 0.1 or less in the univariate analysis were entered into a stepwise logistic regression model. Results: A total of 297 subjects participated in the study (female 60.3%). Overall, 20.9% subjects fulfilled the Rome III IBS criteria. Univariate analysis showed that IBS was associated with pet ownership, antibiotic usage, late dinner, (> 9 PM) and consumption of Western meals, coffee, and bread. The multivariate logistic regression analyses showed that IBS was independently associated with being a pet owner (P = 0.008; OR, 2.5; 95% CI, 1.278-5.037). Conclusions: The prevalence of IBS was 20.9% using the Rome III criteria in our study. The association between IBS and pet ownership will need further investigation. PMID- 26951048 TI - Genome-wide identification of WRKY family genes in peach and analysis of WRKY expression during bud dormancy. AB - Bud dormancy in deciduous fruit trees is an important adaptive mechanism for their survival in cold climates. The WRKY genes participate in several developmental and physiological processes, including dormancy. However, the dormancy mechanisms of WRKY genes have not been studied in detail. We conducted a genome-wide analysis and identified 58 WRKY genes in peach. These putative genes were located on all eight chromosomes. In bioinformatics analyses, we compared the sequences of WRKY genes from peach, rice, and Arabidopsis. In a cluster analysis, the gene sequences formed three groups, of which group II was further divided into five subgroups. Gene structure was highly conserved within each group, especially in groups IId and III. Gene expression analyses by qRT-PCR showed that WRKY genes showed different expression patterns in peach buds during dormancy. The mean expression levels of six WRKY genes (Prupe.6G286000, Prupe.1G393000, Prupe.1G114800, Prupe.1G071400, Prupe.2G185100, and Prupe.2G307400) increased during endodormancy and decreased during ecodormancy, indicating that these six WRKY genes may play a role in dormancy in a perennial fruit tree. This information will be useful for selecting fruit trees with desirable dormancy characteristics or for manipulating dormancy in genetic engineering programs. PMID- 26951049 TI - A hyperelastic fibre-reinforced continuum model of healing tendons with distributed collagen fibre orientations. AB - The healing process of ruptured tendons is problematic due to scar tissue formation and deteriorated material properties, and in some cases, it may take nearly a year to complete. Mechanical loading has been shown to positively influence tendon healing; however, the mechanisms remain unclear. Computational mechanobiology methods employed extensively to model bone healing have achieved high fidelity. This study aimed to investigate whether an established hyperelastic fibre-reinforced continuum model introduced by Gasser, Ogden and Holzapfel (GOH) can be used to capture the mechanical behaviour of the Achilles tendon under loading during discrete timepoints of the healing process and to assess the model's sensitivity to its microstructural parameters. Curve fitting of the GOH model against experimental tensile testing data of rat Achilles tendons at four timepoints during the tendon repair was used and achieved excellent fits ([Formula: see text]). A parametric sensitivity study using a three-level central composite design, which is a fractional factorial design method, showed that the collagen-fibre-related parameters in the GOH model [Formula: see text] and [Formula: see text]-had almost equal influence on the fitting. This study demonstrates that the GOH hyperelastic fibre-reinforced model is capable of describing the mechanical behaviour of healing tendons and that further experiments should focus on establishing the structural and material parameters of collagen fibres in the healing tissue. PMID- 26951050 TI - Time trends in hospital stay after hip fracture in Canada, 2004-2012: database study. AB - Changes in bed management and access policy aimed to shorten Canadian hip fracture hospital stay. Secular trends in hip fracture total, preoperative, and postoperative stay are unknown. Hip fracture stay shortened from 2004 to 2012, mostly from shortening postoperative stay. This may reflect changes in bed management rather than access policy. PURPOSE: To compare the probability of discharge by time after patient admission to hospital with first-time hip fracture over a period of nine calendar years. METHODS: We retrieved acute hospitalization records for 169,595 patients 65 years and older, who were admitted to an acute care hospital with hip fracture between 2004 and 2012 in Canada (outside of Quebec). The main outcome measure was cumulative incidence of discharge by inpatient day, accounting for competing events that end hospital stay. RESULTS: The probability of surgical discharge within 30 days of admission increased from 57.2 % in 2004 to 67.3 % in 2012. The probability of undergoing surgery on day of admission or day after fluctuated around 58.5 % over the study period. For postoperative stay, the discharge probability increased from 6.8 to 12.2 % at day 4 after surgery and from 57.2 to 66.6 % at day 21 after surgery, between 2004 and 2012. The differences across years persisted after adjustment for characteristics of patients, fracture, comorbidity, treatment, type and timing of surgery, and access to care. CONCLUSIONS: Hospital stay following hip fracture shortened substantially between 2004 and 2012 in Canada, mostly due to shortening of postoperative stays. Shorter hospital stays may reflect changes in bed management protocols rather than in access policy. PMID- 26951051 TI - Clinical and prognostic characteristics of 158 cases of relapsing polychondritis in China and review of the literature. AB - This work is aimed to study the clinical and prognostic features of relapsing polychondritis (RP) in China. A total of 158 RP cases from 1985 to 2013 in China were included and compared with international case series in terms of clinical features, systemic involvement, differential diagnosis and prognosis. (1) The average age at the onset was 45.3 years old, the average age for initial symptoms was 14.4 months, female/male ratio was 0.7:1 and misdiagnosis rate was 47 %. (2) The incidence of arthritis was lower than that in Caucasians. The incidences of auricular chondritis (68 %: 84-95 %), ocular inflammation (44 %: 49-65 %) and renal involvement (3 %: 7-26 %) were lower, and laryngotracheal symptoms (69 %: 31-67 %), skin (46 %: 4-38 %) and neurological involvement (12 %: 2-8 %) were higher during the follow-up period. The proportion of associated autoimmune disease and systemic vasculitis were 5 and 3 %, respectively, similar to that in Japanese (4 and 2 %), but less than that in Caucasians (12-31 and 8-18 %) except the Frances's study (7 and 3 %). The primary death cause is respiratory failure due to RP, followed by lung infections and cardiovascular events. (3) Juvenile RP (onset <=18 years) was more severe than adults, similar to results from the Caucasians. However, Chinese juvenile RP had more severe ocular inflammation (57 %: 40-47 %), arthritis (100 %: 71-90 %), cardiovascular (14 %: 3-10 %) and skin involvement (20 %: 10-11 %) than Caucasian juvenile RP. Although sharing most of the clinical features with case series in previous literature, Chinese patients with RP have its unique characteristics. PMID- 26951052 TI - Certain HLA alleles are associated with stress-triggered Graves' disease and influence its course. AB - There are no studies on HLA analysis in patients in whom Graves' disease (GD) hyperthyroidism has been preceded by >=1 stressful event. The aim of the present study was to identify predisposing or protecting HLA alleles and their effects on the course of GD in this subset of patients. We performed serological HLA typing in 58 Caucasian patients with stress-related GD and in 130 matched healthy controls (HC). We also performed genomic HLA typing in 20/58 patients and in all HC. Five HLA alleles and three loci were more frequent in patients compared to HC: B8, Cw7, C*07, C*17, DR3, DR4, DRB1*04, and DQ2. In contrast, B14 was less frequent in patients than in HC. Depending on outcome after ATD withdrawal (remission, exacerbation on-ATD, relapse off-ATD), in patients, some alleles/loci were over-represented, while others were under-represented. Age, FT3, and FT4 fold increase over the upper normal limit at onset were different depending on the allele/locus carried. In GD patients with stress-triggered hyperthyroidism, HLA typing may be helpful in predicting the outcome of the disease after ATD withdrawal. PMID- 26951054 TI - Spontaneous hypoglycemia: diagnostic evaluation and management. AB - Spontaneous hypoglycemia is a puzzling clinical problem and an important reason for referral to endocrinologists. Several clinical conditions such as insulinomas, non-insulinoma pancreatogenous hypoglycemia syndrome, insulin autoimmune syndrome, postprandial hypoglycemia (reactive hypoglycemia), non-islet cell tumor hypoglycemia, primary adrenal insufficiency, hypopituitarism, and critical illness can be associated with spontaneous hypoglycemia. Rarely, in patients with mental health issues, factious hypoglycemia from extrinsic insulin use or ingestion of oral hypoglycemic agents can obfuscate the clinical picture for clinicians trying to identify an organic cause. In those presenting with Whipple's triad (symptoms +/- signs of hypoglycemia, low plasma glucose, and resolution symptoms +/- signs after hypoglycemia correction), a 72-h supervised fast test with measurement of plasma insulin, c-peptide, pro-insulin, and beta hydroxybutyrate levels, coupled with plasma/urine sulphonylurea screen, forms the first step in diagnostic evaluation. A mixed meal test is preferable for those with predominantly postprandial symptoms. Additional non-invasive and/or invasive diagnostic evaluation is necessary if an organic hypoglycemic disorder is suspected. With the aid of a few brief clinical case scenarios, we discuss the diagnostic evaluation and management of spontaneous hypoglycemia through this comprehensive article. PMID- 26951053 TI - Leisure-time exercise, physical activity during work and commuting, and risk of metabolic syndrome. AB - Data are limited regarding effect of intensity of leisure-time physical activity on metabolic syndrome. Furthermore, no prospective data are available regarding effect of occupational and commuting physical activity on metabolic syndrome. We compared metabolic syndrome risk by intensity level of leisure-time exercise and by occupational and commuting physical activity in Japanese workers. We followed 22,383 participants, aged 30-64 years, without metabolic syndrome until 2014 March (maximum, 5 years of follow-up). Physical activity was self-reported. Metabolic syndrome was defined by the Joint Statement criteria. We used Cox regression models to estimate the hazard ratios (HRs) and 95 % confidence intervals (CIs) of metabolic syndrome. During a mean follow-up of 4.1 years, 5361 workers developed metabolic syndrome. After adjustment for covariates, compared with engaging in no exercise, the HRs (95 % CIs) for <7.5, 7.5 to <16.5, and >=16.5 metabolic equivalent hours of exercise per week were 0.99 (0.90, 1.08), 0.99 (0.90, 1.10), and 0.95 (0.83, 1.08), respectively, among individuals engaging in moderate-intensity exercise alone; 0.93 (0.75, 1.14), 0.81 (0.64, 1.02), and 0.84 (0.66, 1.06), among individuals engaging in vigorous-intensity exercise alone; and 0.90 (0.70, 1.17), 0.74 (0.62, 0.89), and 0.81 (0.69, 0.96) among individuals engaging in the two intensities. Higher occupational physical activity was weakly but significantly associated with lower risk of metabolic syndrome. Walking to and from work was not associated with metabolic syndrome. Vigorous-intensity exercise alone or vigorous-intensity combined with moderate intensity exercise and worksite intervention for physical activity may help prevent metabolic syndrome for Japanese workers. PMID- 26951055 TI - Inadequate iodine nutrition of pregnant women in an area of iodine sufficiency. AB - PURPOSE: I. R. Iran has been considered iodine replete since 2000, but iodine nutrition of vulnerable subjects is not clear. The main goal of this study was assessment of iodine nutrition and thyroid function in pregnant Iranian women. METHODS: A total of 1072 pregnant women from ten provinces in the different parts of the country were recruited from November to March 2014. Median urinary iodine concentration (UIC) as the measure of iodine status and serum free T4 (FT4), thyrotropin (TSH), thyroglobulin (Tg), anti-thyroglobulin and anti-thyroid peroxidase antibodies (TgAb and TPOAb) were measured. RESULTS: Mean +/- SD age of the cohort was 27.0 +/- 7.2 years and gestational age was 20.7 +/- 10.0 weeks. The median UIC for pregnant women was 87.3 MUg/L, being 92.1, 86.0 and 76.8 MUg/L, in three trimesters of pregnancy, respectively. Median UIC of <100, 100 149, 150-249, 250-499 and >=500 MUg/L was found in 58.4, 19.8, 16.2, 5.13 and 0.46 % of subjects, respectively. Median (IQR) values in the first, second, and third trimesters were 1.7 (0.9-2.8), 2.1 (1.5-2.9), and 2.1 (1.4-2.8) mIU/L for TSH, and 16.4 (12.21-21.13), 14.34 (12.16-19.69), and 14/07 (12.02-18.64) pmol/L for FT4, respectively. The frequency of elevated serum TSH was 9.0 % (6.6 % subclinical, 2.4 % overt hypothyroidism). The frequency of low serum TSH was 0.6 %. The frequency of positive TPOAb was 7.6 %. CONCLUSIONS: Results of this study have clarified that despite iodine sufficiency of school children in Iran, pregnant women have moderate iodine deficiency and need iodine supplementation. PMID- 26951056 TI - Endocrine dysfunction in hereditary hemochromatosis. AB - Hereditary hemochromatosis (HH) is a genetic disorder of iron overload and subsequent organ damage. Five types of HH are known, classified by age of onset, genetic cause, clinical manifestations and mode of inheritance. Except for the rare form of juvenile haemochromatosis, symptoms do not usually appear until after decades of progressive iron loading and may be triggered by environmental and lifestyle factors. Despite the last decades discovery of genetic and phenotype diversity of HH, early studies showed a frequent involvement of the endocrine glands where diabetes and hypogonadism are the most common encountered endocrinopathies. The pathogenesis of diabetes is still relatively unclear, but the main mechanisms include the loss of insulin secretory capacity and insulin resistance secondary to liver damage. The presence of obesity and/or genetic predisposition may represent addictive risk factor for the development of this metabolic disease. Although old cases of primary gonad involvement are described, hypogonadism is mainly secondary to selective deposition of iron on the gonadotropin-producing cells of the pituitary gland, leading to hormonal impaired secretion. Cases of hypopituitarism or selected tropin defects, and abnormalities of adrenal, thyroid and parathyroid glands, even if rare, are reported. The prevalence of individual gland dysfunction varies enormously within studies for several bias due to small numbers of and selected cases analyzed, mixed genotypes and missing data on medical history. Moreover, in the last few years early screening and awareness of the disease among physicians have allowed hemochromatosis to be diagnosed in most cases at early stages when patients have no symptoms. Therefore, the clinical presentation of this disease has changed significantly and the recognized common complications are encountered less frequently. This review summarizes the current knowledge on HH-associated endocrinopathies. PMID- 26951057 TI - GABA and glycine in the developing brain. AB - GABA and glycine are major inhibitory neurotransmitters in the CNS and act on receptors coupled to chloride channels. During early developmental periods, both GABA and glycine depolarize membrane potentials due to the relatively high intracellular Cl(-) concentration. Therefore, they can act as excitatory neurotransmitters. GABA and glycine are involved in spontaneous neural network activities in the immature CNS such as giant depolarizing potentials (GDPs) in neonatal hippocampal neurons, which are generated by the synchronous activity of GABAergic interneurons and glutamatergic principal neurons. GDPs and GDP-like activities in the developing brains are thought to be important for the activity dependent functiogenesis through Ca(2+) influx and/or other intracellular signaling pathways activated by depolarization or stimulation of metabotropic receptors. However, if GABA and glycine do not shift from excitatory to inhibitory neurotransmitters at the birth and in maturation, it may result in neural disorders including autism spectrum disorders. PMID- 26951058 TI - Vection depends on perceived surface properties. AB - Optic flow provides important information for the perception of self-motion and can be generated by both diffuse and specular reflectance. Previous self-motion research using virtual environments has primarily considered the properties of diffuse optic flow, but not of specular flow. We used graphical simulations to examine the extent to which visually induced self-motion (vection) is robust against the variations in optic flow generated by different surface optics. We found that specular flow alone was capable of generating vection that was equivalent in strength to that generated by diffuse flow (Exp. 1). To test whether this specularly induced vection depends on midlevel visual processing, we measured vection strengths under conditions in which the luminance polarity of specular highlights was inverted. We found that inverting the luminance of specular reflections impaired vection strength, as compared with the vection generated by conditions with ecologically correct diffuse and/or specular flow (Exp. 2). We also found these variations in vection strength were correlated with the perceived relief heights of the surfaces depicted in the image sequences. These findings together suggest that vection can be induced by pure specular flow and that it requires processing beyond the computation of retinal motion velocities-most likely, processes involved in the recovery of 3-D surface shape. PMID- 26951059 TI - Predictors and Moderators of Treatment Outcome in Cognitive Training for Children With ADHD. AB - OBJECTIVE: To explore whether clinical variables and initial cognitive abilities predict or moderate (far) transfer treatment outcomes of cognitive training. METHOD: A total of 98 children (aged 8-12 years) with ADHD were randomly assigned to Cogmed Working Memory Training or a new cognitive training called "Paying Attention in Class." Outcome measures included neurocognitive assessment, parent and teacher rated questionnaires of executive functioning behavior and academic performance. Predictor/moderator variables included use of medication, comorbidity, subtype of ADHD, and initial verbal and visual working memory skills. RESULTS: Parent and teacher ratings of executive functioning behavior were predicted and moderated by subtype of ADHD. Word reading accuracy was predicted by subtype of ADHD and comorbidity. Use of medication and initial verbal and visual spatial working memory skills only predicted and moderated near transfer measures. CONCLUSION: Cognitive training can be beneficial for certain subgroups of children with ADHD; individual differences should be taken into account in future trials. PMID- 26951060 TI - Editorial: GPCR-Targeted Drug Development. PMID- 26951061 TI - Targeting of Peptide Cytotoxins to LHRH Receptors For Treatment of Cancer. AB - Receptors for LHRH (luteinizing hormone-releasing hormone) are expressed in about 80% of human endometrial, ovarian and prostate cancers and are also found in more than 50% of breast cancers including triple negative breast cancers. In the human body, LHRH receptors are found at significant levels in the pituitary and reproductive organs. Other benign tissues or hematopoietic stem cells express only low levels of receptors for LHRH or no receptors. Thus LHRH receptors are promising targets for a receptor- mediated chemotherapy with cytotoxic hybrid molecules. Cytotoxic analogs of LHRH consist of a LHRH agonist, which is used as a carrier peptide and DOX or its derivatives. Cytotoxic analogs of LHRH, AEZS-108 (formerly known as AN-152) and AN-207, exhibit anti-cancer activity in various in vitro and in vivo models of LHRH-receptor positive cancers. In AEZS-108 (zoptarelin DOX) DOX is covalently linked to the LHRH agonist [D-Lys(6)]LHRH. Results of phase I and II clinical studies in patients with breast, endometrial and ovarian cancers demonstrated good anticancer activity with moderate toxic side effects and without any sign of cardiotoxicity so far. AEZS-108 is also being evaluated in phase I/II studies in castration resistant prostate cancer and metastatic bladder cancer. Because of the very promising phase II results in endometrial cancer, a multinational, multicenter phase III study of this malignancy has been initiated and is currently recruiting patients. PMID- 26951062 TI - Somatostatin and its Analogs. AB - Somatostatin (SST) is a cyclic hormone-release inhibitory peptide that has high binding affinity to all of its five SST receptors (SSTRs). SST negatively regulates cell proliferation and the release of multiple hormones via activation of its cognate receptors. A variety of SST analogs, some with high affinity and selectivity of receptor subtypes, have been synthesized and developed. Certain long-acting SST analogs such as octreotide, lanreotide and pasireotide have been clinically applied to the treatment of human diseases such as those caused by excessive release of growth hormone (acromegaly), or adrenocorticotropic hormone (Cushing's syndrome), and for the treatment of carcinoid syndrome. Investigations into new biological activities of these long-acting SSTs and their possible clinical applications are also still ongoing. Also, novel SST analogs are being designed and developed to target different receptor subtype(s) or mimic natural SST's multiple biological properties. Additionally, since SSTRs, especially SSTR2, are aberrantly expressed in many cancer cells and tumor blood vessels, internalizing SST analogs is currently being used as drug-delivery vehicle for the application of receptor-targeted therapeutics. This review will discuss recent advances in the development and applications of SST and its analogs. PMID- 26951063 TI - External Validation of the Acoustic Voice Quality Index Version 03.01 With Extended Representativity. AB - OBJECTIVES: The Acoustic Voice Quality Index (AVQI) is an objective method to quantify the severity of overall voice quality in concatenated continuous speech and sustained phonation segments. Recently, AVQI was successfully modified to be more representative and ecologically valid because the internal consistency of AVQI was balanced out through equal proportion of the 2 speech types. The present investigation aims to explore its external validation in a large data set. METHODS: An expert panel of 12 speech-language therapists rated the voice quality of 1058 concatenated voice samples varying from normophonia to severe dysphonia. The Spearman rank-order correlation coefficients (r) were used to measure concurrent validity. The AVQI's diagnostic accuracy was evaluated with several estimates of its receiver operating characteristics (ROC). RESULTS: Finally, 8 of the 12 experts were chosen because of reliability criteria. A strong correlation was identified between AVQI and auditoryperceptual rating (r = 0.815, P = .000). It indicated that 66.4% of the auditory-perceptual rating's variation was explained by AVQI. Additionally, the ROC results showed again the best diagnostic outcome at a threshold of AVQI = 2.43. CONCLUSIONS: This study highlights external validation and diagnostic precision of the AVQI version 03.01 as a robust and ecologically valid measurement to objectify voice quality. PMID- 26951064 TI - Margaret McCartney: Glasgow's lost hospital beds. PMID- 26951065 TI - Lived experiences of parents caring for a child with a life-limiting condition in Australia: A qualitative study. AB - BACKGROUND: Experiential studies in paediatric palliative care are needed to enable an ongoing international agenda which supports the development of responsive family supports. AIM: To provide an in-depth exploration of the prevalent lived experiences of parents who are currently providing care for a child with a life-limiting condition in Australia. DESIGN: Cross-sectional, prospective, qualitative study guided by an advisory group and reported according to the consolidated criteria for reporting qualitative studies. Transcripts were subjected to a thematic analysis, underpinned by an interpretative phenomenological framework. SETTING/PARTICIPANTS: Purposively sampled parents (n = 14) recruited from a statewide paediatric hospice who self-identified as a 'primary caregiver' for one or more children and/or adolescents (?18 years) with a life-limiting condition. RESULTS: Four key themes represented the prevalent experiences of parents: (1) trapped inside the house, (2) the protector, (3) living with the shadow and (4) travelling a different pathway. They describe parents' physical and social isolation, exclusion from the workforce, pervasive grief and associated impacts to their health and well-being. Limited professional and diminished social supports resulted in full ownership of care responsibility. Yet, parents embraced their role as 'protector', reporting acquired meaning and purpose. CONCLUSION: This study builds upon the growing body of evidence available in paediatric palliative care internationally. The key themes highlight the substantial demand for both physical and emotional support beyond what is currently offered and call for the implementation of carefully planned support services and other societal initiatives which seek to alleviate the broad health impacts to caregivers. PMID- 26951066 TI - Evidence still insufficient that advance care documentation leads to engagement of healthcare professionals in end-of-life discussions: A systematic review. AB - BACKGROUND: Administration of non-beneficial life-sustaining treatments in terminal elderly patients still occurs due to lack of knowledge of patient's wishes or delayed physician-family communications on preference. AIM: To determine whether advance care documentation encourages healthcare professional's timely engagement in end-of-life discussions. DESIGN: Systematic review of the English language articles published from January 2000 to April 2015. DATA SOURCES: EMBASE, MEDLINE, EBM REVIEWS, PsycINFO, CINAHL and Cochrane Library and manual searches of reference lists. RESULTS: A total of 24 eligible articles from 10 countries including 23,914 subjects met the inclusion criteria, mostly using qualitative or mixed methods, with the exception of two cohort studies. The influence of advance care documentation on initiation of end-of-life discussions was predominantly based on perceptions, attitudes, beliefs and personal experience rather than on standard replicable measures of effectiveness in triggering the discussion. While health professionals reported positive perceptions of the use of advance care documentations (18/24 studies), actual evidence of their engagement in end-of-life discussions or confidence gained from accessing previously formulated wishes in advance care documentations was not generally available. CONCLUSION: Perceived effectiveness of advance care documentation in encouraging end-of-life discussions appears to be high but is mostly derived from low-level evidence studies. This may indicate a willingness and openness of patients, surrogates and staff to perceive advance directives as an instrument to improve communication, rather than actual evidence of timeliness or effectiveness from suitably designed studies. The assumption that advance care documentations will lead to higher physicians' confidence or engagement in communicating with patients/families could not be objectively demonstrated in this review. PMID- 26951067 TI - The gut microbiome of healthy Japanese and its microbial and functional uniqueness. AB - The human gut microbiome has profound influences on the host's health largely through its interference with various intestinal functions. As recent studies have suggested diversity in the human gut microbiome among human populations, it will be interesting to analyse how gut microbiome is correlated with geographical, cultural, and traditional differences. The Japanese people are known to have several characteristic features such as eating a variety of traditional foods and exhibiting a low BMI and long life span. In this study, we analysed gut microbiomes of the Japanese by comparing the metagenomic data obtained from 106 Japanese individuals with those from 11 other nations. We found that the composition of the Japanese gut microbiome showed more abundant in the phylum Actinobacteria, in particular in the genus Bifidobacterium, than other nations. Regarding the microbial functions, those of carbohydrate metabolism were overrepresented with a concurrent decrease in those for replication and repair, and cell motility. The remarkable low prevalence of genes for methanogenesis with a significant depletion of the archaeon Methanobrevibacter smithii and enrichment of acetogenesis genes in the Japanese gut microbiome compared with others suggested a difference in the hydrogen metabolism pathway in the gut between them. It thus seems that the gut microbiome of the Japanese is considerably different from those of other populations, which cannot be simply explained by diet alone. We postulate possible existence of hitherto unknown factors contributing to the population-level diversity in human gut microbiomes. PMID- 26951069 TI - Influence of patient-related characteristics on early migration in calcar-guided short-stem total hip arthroplasty: a 2-year migration analysis using EBRA-FCA. AB - BACKGROUND: Short stems have gained popularity in recent years. Because of encouraging clinical results, indications have been expended from young to elderly and obese patients. However, long-term results are lacking. The purpose of this study was to evaluate the influence of gender, age, body weight, body mass index (BMI), and offset version on short-stem migration in correlation to the clinical outcome. METHODS: The implant migration of 202 metaphyseal anchoring, calcar-guided short stems in 151 patients was assessed by "Einzel-Bild Roentgen-Analyse" femoral component analysis (EBRA-FCA, femoral component analysis) in a 2-year follow-up. Full weight bearing was allowed directly after surgery. Patients were divided into groups regarding gender, age, body weight, BMI, and offset version. The Harris hip score (HHS) and satisfaction on visual analogue scale (VAS) were analyzed. RESULTS: After 2 years, mean axial subsidence of all 202 implants was 1.43 mm (standard deviation, SD 1.45 mm). A continuous reduction of initially pronounced subsidence over time could be observed. None of the stems had to be revised. Statistically significant increased rates of subsidence were seen in male (1.68 mm; SD 1.56 mm; p = 0.005) and heavy patients (1.54 mm; SD 1.48 mm; p = 0.022). No differences in implant migration were found regarding age, BMI, and different offset versions. HHS improved markedly from 45.8 (SD 15.9) to 98.1 (SD 4.7) while satisfaction on VAS improved from 1.8 (SD 2.2) to 9.7 (SD 0.9) after 2 years. CONCLUSIONS: The results suggest a migration pattern with initially pronounced subsidence followed by subsequent stabilization. Male and obese patients show a slightly increased initial subsidence without any signs of sustained micromovement. No correlation was found concerning clinical results and pronounced initial subsidence above the threshold of 1.5 mm. No aseptic loosening or other signs of implant failure were seen within the observation period of 2 years. TRIAL REGISTRATION: German Clinical Trials Register, DRKS00009834. PMID- 26951070 TI - Invasive urothelial carcinoma, lymphoma-like/plasmacytoid variant, successfully treated by radical cystectomy with adjuvant chemotherapy: a case report. AB - BACKGROUND: Invasive urothelial carcinoma, lymphoma-like/plasmacytoid variant, is a rare histological type of bladder cancer similar to plasma cells and is an aggressive variant of urothelial carcinoma associated with a poor prognosis. CASE PRESENTATION: A 41-year-old Asian man was referred to our hospital due to macroscopic hematuria. Cystoscopy detected a non-papillary tumor, and a transurethral resection of the bladder tumor revealed pT1N0M0 bladder cancer. A pathological examination showed high-grade invasive urothelial carcinoma and a component of signet ring cell carcinoma. A follow-up of the transurethral resection with radical cystectomy was carried out, and a pathological examination showed infiltrating urothelial carcinoma, with partial features of the plasmacytoid variant. We added chemotherapy treatment with gemcitabine and cisplatin for two cycles. Our patient has been free from recurrence for 2 years. CONCLUSIONS: We herein report the case of a patient with a plasmacytoid variant of urothelial carcinoma controlled with radial cystectomy and subsequent chemotherapy. PMID- 26951072 TI - Authors' Reply. PMID- 26951068 TI - Whole genome sequencing of turbot (Scophthalmus maximus; Pleuronectiformes): a fish adapted to demersal life. AB - The turbot is a flatfish (Pleuronectiformes) with increasing commercial value, which has prompted active genomic research aimed at more efficient selection. Here we present the sequence and annotation of the turbot genome, which represents a milestone for both boosting breeding programmes and ascertaining the origin and diversification of flatfish. We compare the turbot genome with model fish genomes to investigate teleost chromosome evolution. We observe a conserved macrosyntenic pattern within Percomorpha and identify large syntenic blocks within the turbot genome related to the teleost genome duplication. We identify gene family expansions and positive selection of genes associated with vision and metabolism of membrane lipids, which suggests adaptation to demersal lifestyle and to cold temperatures, respectively. Our data indicate a quick evolution and diversification of flatfish to adapt to benthic life and provide clues for understanding their controversial origin. Moreover, we investigate the genomic architecture of growth, sex determination and disease resistance, key traits for understanding local adaptation and boosting turbot production, by mapping candidate genes and previously reported quantitative trait loci. The genomic architecture of these productive traits has allowed the identification of candidate genes and enriched pathways that may represent useful information for future marker-assisted selection in turbot. PMID- 26951073 TI - Minimalist Running Shoes and Injury Risk Among United States Army Soldiers. AB - BACKGROUND: Minimalist running shoes (MRS) are lightweight, are extremely flexible, and have little to no cushioning. It has been thought that MRS will enhance running performance and decrease injury risk. PURPOSE: To compare physical characteristics, fitness performance, and injury risks associated with soldiers wearing MRS and those wearing traditional running shoes (TRS). STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Participants were men in a United States Army brigade (N = 1332). Physical characteristics and Army Physical Fitness Test data were obtained by survey. Fitness performance testing was administered at the brigade, and the types of footwear worn were identified by visual inspection. Shoe types were categorized into 2 groups: TRS (stability, cushioning, and motion control) and MRS. Injuries from the previous 12 months were obtained from the Defense Medical Surveillance System. A t test was used to determine mean differences between personal characteristics, training, and fitness performance metrics by shoe type. Hazard ratios and 95% CIs were calculated to determine injury risk by shoe type, controlling for other risk factors. RESULTS: A majority of soldiers wore cushioning shoes (57%), followed by stability shoes (24%), MRS (17%), and motion control shoes (2%). Soldiers wearing MRS were slightly younger than those wearing TRS (P < .01); performed more push ups, sit-ups, and pull-ups (P < .01); and ran faster during the 2-mile run (P = .01). When other risk factors were controlled, there was no difference in injury risk for running shoe type between soldiers wearing MRS compared with TRS. CONCLUSIONS: Soldiers who chose to wear MRS were younger and had higher physical performance scores compared with soldiers wearing TRS. When these differences are controlled, use of MRS does not appear to be associated with higher or lower injury risk in this population. PMID- 26951071 TI - Characterization of various cell lines from different ampullary cancer subtypes and cancer associated fibroblast-mediated responses. AB - BACKGROUND: Ampullary cancer is a relatively rare form of cancer and usually treated by pancreatoduodenectomy, followed by adjuvant therapy. The intestinal subtype is associated with markedly improved prognosis after resection. At present, only few cell lines are available for in vitro studies of ampullary cancer and they have not been collectively characterized. METHODS: We characterize five ampullary cancer cell lines by subtype maker expression, epithelial-mesenchymal transition (EMT) features, growth and invasion, drug sensitivity and response to cancer-associated fibroblast conditioned medium (CAF CM). RESULTS: On the basis of EMT features, subtype marker expression, growth, invasion and drug sensitivity three types of cell lines could be distinguished: mesenchymal-like, pancreatobiliary-like and intestinal-like. Heterogeneous effects from the cell lines in response to CAF-CM, such as different growth rates, induction of EMT markers as well as suppression of intestinal differentiation markers were observed. In addition, proteomic analysis showed a clear difference in intestinal-like cell line from other cell lines. CONCLUSION: Most of the available AMPAC cell lines seem to reflect a poorly differentiated pancreatobiliary or mesenchymal-like phenotype, which is consistent to their origin. We suggest that the most appropriate cell line model for intestinal-like AMPAC is the SNU869, while others seem to reflect aggressive AMPAC subtypes. PMID- 26951074 TI - Implantation of Autologous Cartilage Chips Improves Cartilage Repair Tissue Quality in Osteochondral Defects: A Study in Gottingen Minipigs. AB - BACKGROUND: Osteochondral injuries have poor endogenous healing potential, and no standard treatment has been established. The use of combined layered autologous bone and cartilage chips for treatment of osteochondral defects has shown promising short-term clinical results. PURPOSE/HYPOTHESIS: This study aimed to investigate the role of cartilage chips by comparing combined layered autologous bone and cartilage chips with autologous bone implantation alone in a Gottingen minipig model. The hypothesis was that the presence of cartilage chips would improve the quality of the repair tissue. STUDY DESIGN: Controlled laboratory study. METHODS: Twelve Gottingen minipigs received 2 osteochondral defects in each knee. The defects were randomized to autologous bone graft (ABG) combined with autologous cartilage chips (autologous dual-tissue transplantation [ADTT]) or ABG alone. Six animals were euthanized at 6 months and 6 animals were euthanized at 12 months. Follow-up evaluation consisted of histomorphometry, immunohistochemistry, semiquantitative scoring (International Cartilage Repair Society II), and computed tomography. RESULTS: There was significantly more hyaline cartilage in the ADTT group (25.8%) compared with the ABG group (12.8%) at 6 months after treatment. At 12 months, the fraction of hyaline cartilage in the ABG group had significantly decreased to 4.8%, whereas the fraction of hyaline cartilage in the ADTT group was unchanged (20.1%). At 6 and 12 months, there was significantly more fibrocartilage in the ADTT group (44% and 60.8%) compared with the ABG group (24.5% and 41%). The fraction of fibrous tissue was significantly lower in the ADTT group compared with the ABG group at both 6 and 12 months. The implanted cartilage chips stained >75% positive for collagen type 4 and laminin at both 6 and 12 months. Significant differences were found in a number of International Cartilage Repair Society II subcategories. The volume of the remaining bone defect significantly decreased from 6 to 12 months in both treatment groups; however, no difference in volume was found between the groups at either 6 or 12 months. CONCLUSION: The presence of cartilage chips in an osteochondral defect facilitated the formation of fibrocartilage as opposed to fibrous tissue at both 6 and 12 months posttreatment. The implanted chips were present in the defect and viable after 12 months. CLINICAL RELEVANCE: This study substantiates the chondrogenic role of cartilage chips in osteochondral defects. PMID- 26951075 TI - No Difference on Quantitative Magnetic Resonance Imaging in Patellofemoral Cartilage Composition Between Patients With Patellofemoral Pain and Healthy Controls. AB - BACKGROUND: Retropatellar cartilage damage has been suggested as an etiological factor for patellofemoral pain (PFP), a common knee condition among young and physically active individuals. To date, there is no conclusive evidence for an association between cartilage defects and PFP. Nowadays, advanced quantitative magnetic resonance imaging (MRI) techniques enable estimation of cartilage composition. PURPOSE: To investigate differences in patellofemoral cartilage composition between patients with PFP and healthy control subjects using quantitative MRI. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: Patients with PFP and healthy control subjects underwent 3.0-T MRI including delayed gadolinium-enhanced MRI of cartilage and T1rho and T2 mapping. Differences in relaxation times of patellofemoral cartilage were compared between groups by linear regression analyses, adjusted for age, body mass index, sex, sports participation, and time of image acquisition. RESULTS: This case-control study included 64 patients and 70 controls. The mean (+/-SD) age was 23.2 +/- 6.4 years and the mean body mass index was 22.9 +/- 3.4 kg/m(2); 56.7% were female. For delayed gadolinium-enhanced MRI of cartilage, the mean T1GD relaxation times of patellar (657.8 vs 669.4 ms) and femoral cartilage (661.6 vs 659.8 ms) did not significantly differ between patients and controls. In addition, no significant difference was found in mean T1rho relaxation times of patellar (46.9 vs 46.0 ms) and femoral cartilage (50.8 vs 50.2 ms) and mean T2 relaxation times of patellar (33.2 vs 32.9 ms) and femoral cartilage (36.7 vs 36.6 ms) between patients and controls. Analysis of prespecified medial and lateral subregions within the patellofemoral cartilage also revealed no significant differences. CONCLUSION: There was no difference in composition of the patellofemoral cartilage, estimated with multiple quantitative MRI techniques, between patients with PFP and healthy control subjects. However, clinically relevant differences could not be ruled out for T1rho in the adolescent population. Retropatellar cartilage damage has long been hypothesized as an important factor in the pathogenesis of PFP, but study findings suggest that diminished patellofemoral cartilage composition is not associated with PFP. PMID- 26951076 TI - A treatment-planning comparison of three beam arrangement strategies for stereotactic body radiation therapy for centrally located lung tumors using volumetric-modulated arc therapy. AB - The purpose of this study was to determine appropriate beam arrangement for volumetric-modulated arc therapy (VMAT)-based stereotactic body radiation therapy (SBRT) in the treatment of patients with centrally located lung tumors. Fifteen consecutive patients with centrally located lung tumors treated at our institution were enrolled. For each patient, three VMAT plans were generated using two coplanar partial arcs (CP VMAT), two non-coplanar partial arcs (NCP VMAT), and one coplanar full arc (Full VMAT). All plans were designed to deliver 70 Gy in 10 fractions. Target coverage and sparing of organs at risk (OARs) were compared across techniques. PTV coverage was almost identical for all approaches. The whole lung V10Gy was significantly lower with CP VMAT plans than with NCP VMAT plans, whereas no significant differences in the mean lung dose, V5Gy, V20Gy or V40Gy were observed. Full VMAT increased mean contralateral lung V5Gy by 12.57% and 9.15% when compared with NCP VMAT and CP VMAT, respectively. Although NCP VMAT plans best achieved the dose-volume constraints for mediastinal OARs, the absolute differences in dose were small when compared with CP VMAT. These results suggest that partial-arc VMAT may be preferable to minimize unnecessary exposure to the contralateral lung, and use of NCP VMAT should be considered when the dose-volume constraints are not achieved by CP VMAT. PMID- 26951077 TI - Differences in quantification of DNA double-strand breaks assessed by 53BP1/gammaH2AX focus formation assays and the comet assay in mammalian cells treated with irradiation and N-acetyl-L-cysteine. AB - The biological effect of ionizing radiation (IR) on genomic DNA is thought to be either direct or indirect; the latter is mediated by IR induction of free radicals and reactive oxygen species (ROS). This study was designed to evaluate the effect of N-acetyl-L-cysteine (NAC), a well-known ROS-scavenging antioxidant, on IR induction of genotoxicity, cytotoxicity and ROS production in mammalian cells, and aimed to clarify the conflicting data in previous publications. Although we clearly demonstrate the beneficial effect of NAC on IR-induced genotoxicity and cytotoxicity (determined using the micronucleus assay and cell viability/clonogenic assays), the data on NAC's effect on DNA double-strand break (DSB) formation were inconsistent in different assays. Specifically, mitigation of IR-induced DSBs by NAC was readily detected by the neutral comet assay, but not by the gammaH2AX or 53BP1 focus assays. NAC is a glutathione precursor and exerts its effect after conversion to glutathione, and presumably it has its own biological activity. Assuming that the focus assay reflects the biological responses to DSBs (detection and repair), while the comet assay reflects the physical status of genomic DNA, our results indicate that the comet assay could readily detect the antioxidant effect of NAC on DSB formation. However, NAC's biological effect might affect the detection of DSB repair by the focus assays. Our data illustrate that multiple parameters should be carefully used to analyze DNA damage when studying potential candidates for radioprotective compounds. PMID- 26951078 TI - Biphasic and triphasic dose responses in zebrafish embryos to low-dose 150 kV X rays with different levels of hardness. AB - The in vivo low-dose responses of zebrafish (Danio rerio) embryos to 150 kV X rays with different levels of hardness were examined through the number of apoptotic events revealed at 24 h post fertilization by vital dye acridine orange staining. Our results suggested that a triphasic dose response was likely a common phenomenon in living organisms irradiated by X-rays, which comprised an ultra-low-dose inhibition, low-dose stimulation and high-dose inhibition. Our results also suggested that the hormetic zone (or the stimulation zone) was shifted towards lower doses with application of filters. The non-detection of a triphasic dose response in previous experiments could likely be attributed to the use of hard X-rays, which shifted the hormetic zone into an unmonitored ultra-low dose region. In such cases where the subhormetic zone was missed, a biphasic dose response would be reported instead. PMID- 26951080 TI - Secondary malignant giant cell tumor of bone due to malignant transformation 40 years after surgery without radiation therapy, presenting as fever of unknown origin: a case report. AB - BACKGROUND: Malignant transformation of giant cell tumors of bones, that is, secondary malignant giant cell tumor of bone, is rare. The most common symptoms are local pain and swelling. There are no prior reports of giant cell tumor of bone with fever of unknown origin at the onset. Here we present a case of a secondary malignant giant cell tumor of bone due to malignant transformation 40 years after surgery without radiation therapy, presenting as fever of unknown origin. CASE PRESENTATION: A 75-year-old Asian man presented with a 3-week history of continuous pyrexia and left knee pain and swelling. He had been diagnosed at age 35 years with a giant cell tumor of bone of his left distal femur and underwent bone curettage and avascular fibula grafting at that time. Postoperative radiation therapy was not performed. He remained recurrence-free for 40 years after surgery. At age 75, histopathological findings suggested a secondary malignant giant cell tumor of bone. The tumor specimen expressed tumor necrosis factor-alpha. Neoplastic fever was suspected, and a naproxen test was conducted. His pyrexia showed immediate resolution. Surgery was performed under a diagnosis of a secondary malignant giant cell tumor of bone with neoplastic fever. His pyrexia and inflammatory activities diminished postoperatively. CONCLUSIONS: This is the first reported case, to the best of our knowledge, of the detection of a secondary malignant giant cell tumor of bone based on fever of unknown origin after long-term (40 years) follow-up. After curettage and bone grafting, giant cell tumor of bone may transform to malignancies within a few years or even decades after surgery. Therefore, meticulous follow-up is essential. The fever might be attributable to the tumor releasing inflammatory cytokines. Not only pain and swelling but also continuous pyrexia may suggest the diagnosis of a secondary malignant giant cell tumor of bone. PMID- 26951079 TI - Second- and third-generation ALK inhibitors for non-small cell lung cancer. AB - Crizotinib as the first-generation ALK inhibitor has shown significant activity in ALK-mutated non-small cell lung cancer (NSCLC). Second- and third-generation ALK inhibitors are entering clinical applications for ALK+ NSCLC. In addition, a third-generation ALK inhibitor, lorlatinib (PF-06463922), was reported to resensitize NSCLC to crizotinib. This review provided a summary of clinical development of alectinib, ceritinib, brigatinib (AP26113), and lorlatinib. PMID- 26951082 TI - A systematic review and meta-analysis of immunohistochemical biomarkers that differentiate chromophobe renal cell carcinoma from renal oncocytoma. AB - BACKGROUND: Numerous immunohistochemical (IHC) biomarkers have been employed to aid in the difficult differentiation between chromophobe renal cell carcinoma (chRCC) and renal oncocytoma (RO). A systematic review and meta-analysis of the published literature was carried out to summarise and analyse the evidence for discriminatory IHC biomarkers to differentiate the two entities. METHODS: PubMed database was used to identify relevant literature. Primary end point was comparison of positive immunostaining of the biomarkers in chRCC and RO, with extracted data used to calculate OR and 95% CI and statistical I(2) test of heterogeneity for multiple studies. RESULTS: One hundred and nine manuscripts were available for review. Data extracted were subjected to quantitative meta analysis. Ten most effective biomarkers (OR of chRCC/RO and CI) are: amylase alpha1A (n=129, OR=0.001, 95% CI 0.0001 to 0.019); Wnt-5a (n=38, OR=0.0076, 95% CI 0.0004 to 0.015); FXYD2 (n=57, OR=130, 95% CI 14.2 to 1192.3); ankyrin repeated protein with a proline-rich region (ARPP) (n=25, OR=0.0054, 95% CI 0.0002 to 0.12); cluster of differentiation 63 (CD63) (n=62, diffuse (chRCC) vs apical/polar (RO) stain pattern); transforming growth factor beta 1 (TGFbeta1) (n=34, membranous (chRCC) vs cytoplasmic (RO)); cytokeratin 7 (CK7) (11 studies, n=448, pooled OR=44.22, 95% CI 22.52 to 86.64, I(2)=15%); S100A1 (4 studies, n=124, pooled OR=0.01, 95% CI 0 to 0.03, I(2)=0%); caveolin-1 (2 studies, n=102, pooled OR=32.95, 95% CI 3.67 to 296.1, I(2)=70%) and claudin-7 (3 studies, n=89, pooled OR=24.7, 95% CI 6.28 to 97.1, I(2)=0%). CONCLUSIONS: We recommend a panel of IHC biomarkers of amylase alpha1A, Wnt-5a, FXYD2, ARPP, CD63, TGFbeta1, CK7, S100A1, caveolin-1 and claudin-7 to aid in the differentiation of chRCC and RO. PMID- 26951081 TI - Tumour infiltrating lymphocytes and stromal CD68 in early stage HER2 positive breast cancer. PMID- 26951083 TI - Gene of the month: Axl. AB - The interaction between Axl receptor tyrosine kinase and its main ligand Gas6 has been implicated in the progression of a wide number of malignancies. More recently, overexpression of Axl has emerged as a key molecular determinant underlying the development of acquired resistance to targeted anticancer agents. The activation of Axl is overexpression-dependent and controls a number of hallmarks of cancer progression including proliferation, migration, resistance to apoptosis and survival through a complex network of intracellular second messengers. Axl has been noted to influence clinically meaningful end points including metastatic recurrence and survival in the vast majority of tumour types. With Axl inhibitors having gained momentum as novel anticancer therapies, we provide an overview of the biological and clinical relevance of this molecular pathway, outlining the main directions of research. PMID- 26951084 TI - Kinetics of versican-expressing macrophages in bone marrow after cord blood stem cell transplantation for treatment of acute myelogenous leukaemia. AB - AIMS: To determine versican-producing cells in normocellular bone marrow and to evaluate chronological alteration in the number of versican-producing macrophages in bone marrow of patients with acute myelogenous leukaemia (AML) after cord blood stem cell transplantation (CBSCT) to gain insight in the significance of versican in recovery of haematopoiesis. METHODS: We enrolled seven age-matched unrelated patients with normocellular bone marrow for determining versican producing cells in bone marrow, CBSCT-treated patients with AML, 18 with fine and other four with poor engraftment, for determining chronological alteration of versican-expressing and CD68-expressing cells in transplanted bone marrow in reference to the total cells. Clot samples of patients with AML were collected from the +16 to +55 day after transplantation and separated into four groups. We included an AML case whose specimen was obtained on the +9 day. Cells positive in immunohistochemistry using antibodies to versican and CD68 were counted to obtain the mean+/-SD in a unit area of the bone marrow, plotted chronologically and compared with the numbers from the age-matched normocellular group. RESULTS: We determined by a double immunohistochemistry that the versican-expressing cells in bone marrow are macrophages. The time-course curve demonstrated an inverse relationship between the versican-positive macrophages and the total cells in the transplanted bone marrow for over 55 days. In bone marrow of poor engraftment cases, versican-positive macrophages appeared to be decreased in comparison with age-matched and sampling day-matched patients. CONCLUSIONS: These results suggest that versican and/or versican-expressing macrophages positively contribute to bone marrow regeneration of patients with AML after CBSCT. PMID- 26951086 TI - The Potential Application of Biomaterials in Cardiac Stem Cell Therapy. AB - Biomaterials play a vital role in the field of regenerative medicine and tissue engineering. To date, a large number of biomaterials have been used in cardiovascular research and application. Recently, biomaterials have held a lot of promise in cardiac stem cell therapy. They are used in cardiac tissue engineering to form scaffolds for cellular transplantation, promote angiogenesis, enhance transplanted cell engraftment or influence cell migration. The science of biomaterial designing has evolved to an extent where they can be designed to mimic the microenvironment of a cardiac tissue in vivo and contribute in deciding the fate of transplanted stem cells and induce cardiac lineage oriented stem cell differentiation. In this review, we focus on biomaterials used in cardiovascular stem cell research, tissue engineering and regenerative medicine and conclude with an outlook on future impacts of biomaterial in medical sciences. PMID- 26951085 TI - Anti-vascular effects of the cytosolic phospholipase A2 inhibitor AVX235 in a patient-derived basal-like breast cancer model. AB - BACKGROUND: Group IVA cytosolic phospholipase A2 (cPLA2alpha) plays an important role in tumorigenesis and angiogenesis. It is overexpressed in basal-like breast cancer (BLBC), which is aggressive and usually triple-negative, making it unresponsive to current targeted therapies. Here, we evaluated the anti angiogenic effects of a specific cPLA2alpha inhibitor, AVX235, in a patient derived triple-negative BLBC model. METHODS: Mice bearing orthotopic xenografts received i.p. injections of AVX235 or DMSO vehicle daily for 1 week and then every other day for up to 19 days. Six treated and six control mice were terminated after 2 days of treatment, and the tumors excised for high resolution magic angle spinning magnetic resonance spectroscopy (HR MAS MRS) and prostaglandin E2 (PGE2) enzyme immunoassay (EIA) analysis. A 1-week imaging study was performed on a separate cohort of mice. Longitudinal dynamic contrast enhanced (DCE)-MRI was performed before, after 4 days, and after 1 week of treatment. The mice were then perfused with a radiopaque vascular casting agent, and the tumors excised for micro-CT angiography. Subsequently, tumors were sectioned and stained with lectin and for Ki67 or alpha-smooth muscle actin to quantify endothelial cell proliferation and vessel maturity, respectively. Partial least squares discriminant analysis was performed on the multivariate HR MAS MRS data, and non-parametric univariate analyses using Mann-Whitney U tests (alpha = 0.05) were performed on all other data. RESULTS: Glycerophosphocholine and PGE2 levels, measured by HR MAS MRS and EIA, respectively, were lower in treated tumors after 2 days of treatment. These molecular changes are expected downstream effects of cPLA2alpha inhibition and were followed by significant tumor growth inhibition after 8 days of treatment. DCE-MRI revealed that AVX235 treatment caused a decrease in tumor perfusion. Concordantly, micro-CT angiography showed that vessel volume fraction, density, and caliber were reduced in treated tumors. Moreover, histology showed decreased endothelial cell proliferation and fewer immature vessels in treated tumors. CONCLUSIONS: These results demonstrate that cPLA2alpha inhibition with AVX235 resulted in decreased vascularization and perfusion and subsequent inhibition of tumor growth. Thus, cPLA2alpha inhibition may be a potential new therapeutic option for triple negative basal-like breast cancer. PMID- 26951087 TI - Kawasaki disease and hepatobiliary involvement: report of two cases. AB - BACKGROUND: Kawasaki disease (KD) without affection of the coronary artery system is rare. Optic nerve pathology together with KD has not been described earlier. CASE PRESENTATION: We present one case of KD in a 12-year-old girl predominantly with prolonged cholestasis, and a second case of multiple recurrent KD in a 9 year-old boy with hepatomegaly and ischemic optic nerve neuropathy. The coronary artery system was not involved in either case. CONCLUSIONS: KD warrants rapid diagnosis and immediate specific treatment in order to prevent the high risk of coronary artery aneurysm and stenosis. PMID- 26951088 TI - Steatocystoma simplex in penile foreskin: a case report. AB - BACKGROUND: Steatocystoma simplex is an uncommon skin lesion with a histological pattern that is identical to that of steatocystoma multiplex. We are reporting this case of steatocystoma simplex for its uncommon location in the penile foreskin, and its occurrence in a Wapishana man. CASE PRESENTATION: A 56-year-old man of Wapishana ethnicity presented with complaints of referred penile discomfort and pain during sexual intercourse for 5 years. A physical examination revealed a mobile, compressible subcutaneous non-tender mass of 4 cm diameter located on the left-side of his penile foreskin. There were no signs of inflammation, no grip on the penile shaft, and no urethral discharge or enlargement of lymph nodes. We found no evidence of other cysts on cutaneous examination. We performed classical excision of the lesion under local anesthesia and confirmed the diagnosis of steatocystoma with the pathological report. As there were no complications, we discharged him the same day. CONCLUSION: Steatocystoma can be considered a differential diagnosis for cystic lesions on and around the penis. PMID- 26951089 TI - Patterns of recurrence after selective postoperative radiation therapy for patients with head and neck squamous cell carcinoma. AB - BACKGROUND: The radiation field for patients with postoperative head and neck squamous cell carcinoma is narrower in our institution than in Western countries to reduce late radiation related toxicities. This strategy is at a risk of loco regional or distant metastasis. However, because patients are more closely checked than in Western countries by every 1 to 2 months intervals and it is supposed that regional recurrences are identified and salvage surgeries are performed more quickly. Therefore, it is considered that patient survival would not be compromised with this strategy. The aim of this study was to investigate the feasibility of this strategy retrospectively. METHODS: Patients who underwent neck dissection with close or positive margin, extra-capsular spread (ECS), multiple regional lymph node metastasis, pT4, with or without primary tumor resection were treated with postoperative radiation therapy. The volume of radiation field, especially the coverage of prophylactic regional lymph node area, was discussed among head and neck surgeons and radiation oncologists taking into account the clinical factors including patient's age, performance status, number of positive lymph nodes, size of metastatic lymph nodes, extension of primary tumor beyond the midline, and existence of ECS. RESULTS: Seventy-two patients were identified who were treated with postoperative radiation therapy for head and neck squamous cell carcinoma between November 2005 and December 2014. There were 20 patients with oropharynx, 19 with hypopharynx, 7 with larynx, 23 with oral cavity, and 3 with other sites. Thirty eight patients had their neck irradiated bilaterally and 34 unilaterally. Median follow-up period for patients without relapse was 20.7 months (5.1-100.7). Thirty two patients had disease relapse after treatment including 22 loco-regional recurrence and 14 distant metastases. Among 22 loco-regional recurrence, seven patients underwent salvage surgery and one of them was no relapse at the time of the analysis. Among patients without bilateral neck lymph node metastasis who were treated with unilateral neck irradiation, patients with oral cavity or recurrent disease had significantly lower DFS compared with those without (2-y DFS 41.7 % vs 88.2 %, p = 0.017). CONCLUSIONS: In patients without bilateral neck lymph node involvement, the postoperative unilateral neck irradiation is a reasonable treatment strategy for patients with the exception of oral cavity or recurrent disease. PMID- 26951090 TI - Anaemia is not a risk factor for progression of acute kidney injury: a retrospective analysis. AB - BACKGROUND: In hospitalised patients, anaemia increases the risk of developing acute kidney injury (AKI). Our aim was to determine whether anaemia also has an impact on the risk of progression from early AKI to more severe AKI in critically ill patients. METHODS: We retrospectively analysed the data of patients admitted to the adult intensive care unit between 2007 and 2009 who had AKI I as per the AKI Network classification, and who had undergone haemodynamic monitoring within 12 h of AKI I. We collected baseline characteristics, severity of illness, haemoglobin (Hb), and haemodynamic parameters in the first 12 h of AKI I and differentiated between patients who progressed to AKI III and those who did not. Univariate and multivariate logistic regression analyses were used to identify risk factors for progression. Associations between Hb, arterial oxygen saturation and cardiac index were explored by receiver operating characteristic curve analysis. RESULTS: Two hundred and ten patients (median age 70 years, 68% male) underwent haemodynamic monitoring within 12 h of AKI I; 85 (41.5%) progressed to AKI III. The proportion of patients with underlying cardiac disease was significantly higher among progressors versus non-progressors (58% vs 34%, respectively; p = 0.001). On the first day of AKI I, progressors had a significantly higher Sequential Organ Failure Assessment score (9 vs 8; p < 0.001), lower cardiac index (median 2.6 vs 3.3 L/min/m(2); p < 0.001), higher arterial lactate (2 vs 1.6 mmol/L; p < 0.001), higher central venous pressure (16 vs 13; p = 0.02), lower mean arterial blood pressure (median 71 vs 74 mmHg; p = 0.01) and significantly higher requirement for cardiovascular and respiratory support, but there was no difference in Hb concentration (median 96 g/L in both groups). Multivariable regression analysis showed that heart disease, need for mechanical ventilation, arterial lactate, Sequential Organ Failure Assessment score, central venous pressure and cardiac index on first day of AKI I were independently associated with progression to AKI III. There was no significant difference in the risk of progression between patients with Hb <= or >80 g/L, and <= or >100 g/L on day of AKI I. CONCLUSIONS: In critically ill patients with AKI stage 1, anaemia was not associated with an increased risk of progression to more severe AKI. PMID- 26951091 TI - Interaction of non-human primate complement and antibodies with hypermucoviscous Klebsiella pneumoniae. AB - Emergent hypermucoviscosity (HMV) phenotypes of Klebsiella pneumoniae have been associated with increased invasiveness and pathogenicity in primates. In this study, we investigated the interaction of African green monkeys (AGM) (Chlorocebus aethiops sabaeus) complement and antibody with HMV and non-HMV isolates as in vitro models of primate infection. Significantly greater survival of HMV isolates was evident after incubation in normal serum or whole blood (p < 0.05) of AGM donors when compared to non-HMV strains. Greater survival of HMV strains (p < 0.05) was found after incubation in whole blood and serum from seropositive donors when compared to seronegative donor samples. Additionally, significantly greater amounts of K. pneumoniae were phagocytozed by AGM leukocytes when complement was active (p < 0.05), but no difference in uptake was observed when serum from seropositive or seronegative animals was used in challenged cells utilizing flow cytometry. Results demonstrate that interaction of cellular and humoral immune elements play a role in the in vitro killing of K. pneumoniae, particularly HMV isolates. Neither AGM serum, nor washed whole blood effectively killed HMV isolates; however, assays using heparinized whole blood of seronegative donors significantly reduced viability of HMV and non-HMV strains. The lack of bacterial killing observed in seropositive donors treatments could be at least partially associated with low IgG2 present in these animals. A better understanding of the pathogenesis of klebsiellosis in primates and host immune response is necessary to identify surface molecules that can induce both opsonizing and bactericidal antibody facilitating killing of Klebsiella, and the development of vaccines in human and animals. PMID- 26951093 TI - Editorial: Critical Analyses of Mechanism-Based Therapies Against Parkinson's Disease: Concepts and Perspectives. PMID- 26951092 TI - Snail heterogeneity in clear cell renal cell carcinoma. AB - BACKGROUND: Intratumor heterogeneity may be responsible of the unpredictable aggressive clinical behavior that some clear cell renal cell carcinomas display. This clinical uncertainty may be caused by insufficient sampling, leaving out of histological analysis foci of high grade tumor areas. Although molecular approaches are providing important information on renal intratumor heterogeneity, a focus on this topic from the practicing pathologist' perspective is still pending. METHODS: Four distant tumor areas of 40 organ-confined clear cell renal cell carcinomas were selected for histopathological and immunohistochemical evaluation. Tumor size, cell type (clear/granular), Fuhrman's grade, Staging, as well as immunostaining with Snail, ZEB1, Twist, Vimentin, E-cadherin, beta catenin, PTEN, p-Akt, p110alpha, and SETD2, were analyzed for intratumor heterogeneity using a classification and regression tree algorithm. RESULTS: Cell type and Fuhrman's grade were heterogeneous in 12.5 and 60 % of the tumors, respectively. If cell type was homogeneous (clear cell) then the tumors were low grade in 88.57 % of cases. Immunostaining heterogeneity was significant in the series and oscillated between 15 % for p110alpha and 80 % for Snail. When Snail immunostaining was homogeneous the tumor was histologically homogeneous in 100 % of cases. If Snail was heterogeneous, the tumor was heterogeneous in 75 % of the cases. Average tumor diameter was 4.3 cm. Tumors larger than 3.7 cm were heterogeneous for Vimentin immunostaining in 72.5 % of cases. Tumors displaying negative immunostaining for both ZEB1 and Twist were low grade in 100 % of the cases. CONCLUSIONS: Intratumor heterogeneity is a common event in clear cell renal cell carcinoma, which can be monitored by immunohistochemistry in routine practice. Snail seems to be particularly useful in the identification of intratumor heterogeneity. The suitability of current sampling protocols in renal cancer is discussed. PMID- 26951095 TI - Measuring energy expenditure in the intensive care unit: a comparison of indirect calorimetry by E-sCOVX and Quark RMR with Deltatrac II in mechanically ventilated critically ill patients. AB - BACKGROUND: Indirect calorimetry allows the determination of energy expenditure in critically ill patients by measuring oxygen consumption (VO2) and carbon dioxide production (VCO2). Recent studies have demonstrated variable performance of "breath-by-breath" instruments compared to mixing chamber technology. The aim of this study was to validate two modern devices (E-sCOVX and Quark RMR) against a reference method (Deltatrac II). METHOD: Measurements of VO2/VCO2 with the test and reference devices were performed simultaneously over a 20-min period in mechanically ventilated adult intensive care unit patients. Accuracy and precision of instruments were analyzed using Bland-Altman plots. RESULTS: Forty eight measurements in 22 patients were included for analysis. Both E-sCOVX and Quark RMR overestimated VO2 and VCO2 compared to Deltatrac II, corresponding to a 10% higher mean resting energy expenditure. Limits of agreement of resting energy expenditure within +/- 2 standard deviations were +/- 461 kcal/24 h (+/- 21% expressed as percentage error) for DeltaE-sCOVX-Deltatrac II and +/- 465 kcal/24 h (+/- 22%) for DeltaQuark RMR-Deltatrac II. CONCLUSION: Both test devices overestimate VO2 and VCO2 compared to Deltatrac II. The observed limits of agreement are comparable to those commonly accepted in evaluations of circulatory monitoring, and significantly less than results from predictive equations. We hypothesize that the discrepancy between methods is due to patient/ventilator related factors that affect the synchronization of gas and spirometry waveforms. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, Trial ID ACTRN12615000205538. Date registered 3 March 2015. PMID- 26951094 TI - Methylphenidate on Cognitive Improvement in Patients with Traumatic Brain Injury: A Meta-Analysis. AB - Although methylphenidate has been used as a neurostimulant to treat patients with attention deficit hyperactivity disorder, its therapeutic role in the psychomotor or cognitive recovery of patients with traumatic brain injuries (TBIs) in both intensive care and rehabilitation settings has not been adequately explored. To address this issue, this meta-analysis searched the available electronic databases using the key words "methylphenidate", "brain injuries", "head injuries", and "traumatic brain injury". Analysis of the ten double-blind RCTs demonstrated significant benefit in using methylphenidate for enhancing vigilance associated attention (i.e., selective, sustained, and divided attention) in patients with TBIs (standardized mean difference: 0.45, 95% CI: 0.10 to 0.79), especially in sustained attention (standardized mean difference: 0.66, 95% CI: 0.22 to 1.10). However, no significant positive impact was noted on the facilitation of memory or processing speed. More studies on the efficacy and safety of methylphenidate for the cognitive improvement of patients with TBIs are warranted. PMID- 26951096 TI - Neural substrates of sexual arousal in heterosexual males: event-related fMRI investigation. AB - BACKGROUND: Sexual behavior is an important role for the survival of species. The advancement of brain imaging methods has enabled the understanding of the brain mechanism related to sexual arousal. The previous studies on the brain mechanism related to sexual arousal have mostly conducted on block design paradigm. METHODS: Despite its requirement for stricter experimental control, the event related paradigm is known to be more efficient in detecting instant emotional and cognitive responses. The paradigm also enables the observation of hemodynamic responses through time. Therefore, this study used the event-related fMRI to examine the brain activation in various areas associated with sexual arousal as well as changes in hemodynamic responses with time. RESULTS: Strong activations were observed in the various areas associated with sexual arousal comprised of various factors: (1) activation areas related to cognitive factors: the occipital lobe and parietal lobe; (2) activation areas related to emotional factors: the thalamus and amygdala; (3) activation areas related to motivational factors: the anterior cingulate gyrus, orbitofrontal cortex, and insula; and (4) activation areas related to physiological factors: the precentral gyrus, putamen, and globus pallidus. We also identified the activation of the putamen and globus pallidus that were not well observed in previous block design studies. In the result of the hemodynamic response, the neural activity in those areas showed more transient aspects of the hemodynamic responses relative to the neural activity of other areas. CONCLUSIONS: These results suggested that the event-related paradigm is better at detecting the neural activity of the brain regions, which tend to appear suddenly, but disappear soon. PMID- 26951097 TI - The efficacy of iodine-125 permanent brachytherapy versus intensity-modulated radiation for inoperable salivary gland malignancies: study protocol of a randomised controlled trial. AB - BACKGROUND: Radiation therapy is the method of choice for subjects with inoperable salivary gland malignancies. I-125 brachytherapy, delivering a high radiation dose to a tumor but sparing surrounding normal tissues, is supposed to be ideal modality for the treatment of salivary gland malignancies. We designed a randomised controlled clinical trial to compare the efficacy of I-125 permanent brachytherapy (PBT) versus intensity-modulated radiation therapy (IMRT) for inoperable salivary gland malignancies. METHODS/DESIGN: In this study, inclusion criteria are subjects with inoperable salivary gland malignancies, aged 18-80 years, have provided informed consent, with at least one measurable tumor focus, be able to survive >=3 months, Karnofsky performance status >=60, have adequate hematopoietic function of bone marrow, have normal liver and kidney function, and are willing to prevent pregnancy. Exclusion criteria include a history of radiation or chemotherapy, a history of other malignant tumors in the past 5 years, receiving other effective treatments, participating in other clinical trials, with circulatory metastasis, cognitive impairment, severe cardiovascular and cerebrovascular diseases, acute infection, uncontrolled systemic disease, history of interstitial lungdisease, and being pregnant or breast feeding. The study will be conducted as a clinical, prospective, randomised controlled trial with balanced randomisation (1:1). The planned sample size is 90 subjects. Subjects with inoperable salivary gland malignancies are randomised to receive either I-125 PBT or IMRT, with stratification by tumor size and neck lymph node metastasis. Participants in both groups will be followed up at 2, 4, 6, 9, 12, 15, 18, 21 and 24 months after randomization. The primary outcome is local control rate of the primary site (based on imaging findings and clinical examination, RECIST criteria) in 1 year. Secondary outcomes are progression-free survival, overall survival, quality of life (QOL) measured with the European Organization for Research and Treatment of Cancer QOL Questionnaire (EORTC QLQ C30 and QLQ-H&N35) of Chinese version, and safety of treatment. Chi-squared test is used to compare the local control rates in both groups. The survival curves are estimated by the Kaplan-Meier method, and log-rank test is used to test the significant difference. DISCUSSION: Only few observational studies have investigated the effect of I-125 PBT on inoperable salivary gland malignancies. To our knowledge, this is the first randomised controlled trial to investigate the efficacy of I-125 PBT for subjects with inoperable salivary gland malignancies, and will add to the knowledge base for the treatment of these subjects. TRIAL REGISTRATION: The study is registered to Clinical Trials.gov ( NCT02048254 ) on Jan 29, 2014. PMID- 26951099 TI - Formulation and Application of Biodegradable Nanoparticles Based Biopharmaceutical Delivery - An Efficient Delivery System. AB - Biodegradable polymer based drug delivery has emerged as a promising and successful clinical tool for specific targeting and controlled drug release delivery system. Various other unique advantages associated with this delivery system include prolonged circulation, biocompatibility, degradation in nontoxic by-products etc. Till date, various biopharmaceutical agents have been successfully encapsulated within biodegradable polymers and used in clinics. However, before the clinical implementation of such nanocarriers different parameters have to be considered which influence the success of these nanocarriers such as drug release profile, size of nanocarrier, degradation mechanism, toxicity profile, type of polymer used, appropriate synthesis method, selection of mode of delivery etc. The following review focuses on such considerations to explore the area of designing and development of biodegradable polymeric nanosystems which when encapsulated with biopharmaceutical agents can be efficient for clinical application. PMID- 26951100 TI - Immunology of Chronic Obstructive Pulmonary Disease and Sulfur Mustard Induced Airway Injuries: Implications for Immunotherapeutic Interventions. AB - BACKGROUND: Sulfur mustard (SM)-induced airway injuries and chronic obstructive pulmonary disease (COPD) are characterized by chronic inflammation of the respiratory tract and share some similarities regarding the cellular and molecular mechanisms orchestrating airway destruction. Since available data regarding the immunobiology of COPD is much more known compared with SM-mediated injuries, and considering the similarities in the immunopathogenesis of these diseases, comparison of the immunopathogenesis of COPD and SM-induced respiratory complications can help designing new therapeutic approaches for treatment of SM induced injuries. METHODS: A multi-database search was performed to identify articles dealing with the role of immune system function in the pathogenesis of COPD and mustard mustard-induced respiratory complications. RESULTS: This review outlines the role of different components of the immune system in the pathogenesis of COPD and mustard-induced respiratory complications, and suggests therapeutic implication for improving the management of the latter condition as the most common chronic complication of sulfur mustard exposure. CONCLUSION: Although COPD and mustard lung are overlapping phenotypes and have shared pathophysiologic features, there are certain differences between these two diseases that necessitate further scrutiny. Combination therapies to counterbalance inflammation, oxidative stress and immune imbalance hold promise for the management of SM-induced respiratory complications but the success of such combined treatments need to be confirmed in proof-ofconcept trials. PMID- 26951098 TI - Perspective on Nanoparticle Technology for Biomedical Use. AB - This review gives a short overview on the widespread use of nanostructured and nanocomposite materials for disease diagnostics, drug delivery, imaging and biomedical sensing applications. Nanoparticle interaction with a biological matrix/entity is greatly influenced by its morphology, crystal phase, surface chemistry, functionalization, physicochemical and electronic properties of the particle. Various nanoparticle synthesis routes, characterization, and functionalization methodologies to be used for biomedical applications ranging from drug delivery to molecular probing of underlying mechanisms and concepts are described with several examples (150 references). PMID- 26951101 TI - Natural Products Towards the Discovery of Potential Future Antithrombotic Drugs. AB - Globally, thrombosis-associated disorders are one of the main contributors to fatalities. Besides genetic influences, there are some acquired and environmental risk factors dominating thrombotic diseases. Although standard regimens have been used for a long time, many side effects still occur which can be life threatening. Therefore, natural products are good alternatives. Although the quest for antithrombotic natural products came to light only since the end of last century, in the last two decades, a considerable number of natural products showing antithrombotic activities (antiplatelet, anticoagulant and fibrinolytic) with no or minimal side effects have been reported. In this review, several natural products used as antithrombotic agents including medicinal plants, vegetables, fruits, spices and edible mushrooms which have been discovered in the last 15 years and their target sites (thrombogenic components, factors and thrombotic pathways) are described. In addition, the side effects, limitations and interactions of standard regimens with natural products are also discussed. The active compounds could serve as potential sources for future research on antithrombotic drug development. As a future direction, more advanced researches (in quest of the target cofactor or component involved in antithrombotic pathways) are warranted for the development of potential natural antithrombotic medications (alone or combined with standard regimens) to ensure maximum safety and efficacy. PMID- 26951102 TI - Role of Osmolytes in Regulating Immune System. AB - BACKGROUND: The immune system has evolved to protect the host organism from diverse range of pathogenic microbes that are themselves constantly evolving. It is a complex network of cells, humoral factors, chemokines and cytokines. Dysregulation of immune system results in various kinds of immunological disorders. There are several external agents which govern the regulation of immune system. Recent studies have indicated the role of osmolytes in regulation of various immunological processes such as Ag-Ab interaction, Ig assembly, Ag presentation etc. SCOPE OF REVIEW: In this present review, we have systematically discussed the role of osmolytes involved in regulation of several key immunological processes. MAJOR CONCLUSION: Osmolytes are involved in the regulation of several key immunological processes such as immunoglobulin assembly and folding, immune cells proliferation, regulation of immune cells function, Ag Ab interaction, antigen presentation, inflammatory response and protection against photo-immunosuppression. Hence, osmolytes and their transporters might be used as potential drug and drug targets respectively. GENERAL SIGNIFICANCE: This review is therefore designed to help clinicians in development of osmolyte based therapeutic strategies in the treatment of various immunological disorders. Appropriate future perspectives have also been included. PMID- 26951103 TI - Association of Oxidative Stress with Psychiatric Disorders. AB - BACKGROUND: When concentrations of both reactive oxygen species and reactive nitrogen species exceed the antioxidative capability of an organism, the cells undergo oxidative impairment. Impairments in membrane integrity and lipid and protein oxidation, protein mutilation, DNA damage, and neuronal dysfunction are some of the fundamental consequences of oxidative stress. METHODS: The purpose of this work was to review the associations between oxidative stress and psychological disorders. The search terms were the following: "oxidative stress and affective disorders," "free radicals and neurodegenerative disorders," "oxidative stress and psychological disorders," "oxidative stress, free radicals, and psychiatric disorders," and "association of oxidative stress." These search terms were used in conjunction with each of the diagnostic categories of the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders and World Health Organization's International Statistical Classification of Diseases and Related Health Problems. RESULTS: Genetic, pharmacological, biochemical, and preclinical therapeutic studies, case reports, and clinical trials were selected to explore the molecular aspects of psychological disorders that are associated with oxidative stress. We identified a broad spectrum of 83 degenerative syndromes and psychiatric disorders that were associated with oxidative stress. CONCLUSION: The multi-dimensional information identified herein supports the role of oxidative stress in various psychiatric disorders. We discuss the results from the perspective of developing novel therapeutic interventions. PMID- 26951104 TI - Metabolic Control of Type 2 Diabetes by Targeting the GLUT4 Glucose Transporter: Intervention Approaches. AB - Type 2 diabetes mellitus (T2DM), the most common form of diabetes, is characterized by insulin resistance in the hepatic and peripheral tissues. Glucose transporter 4 (GLUT4) plays a major role in the pathophysiology of T2DM. Its defective expression or translocation to the peripheral cell plasma membrane in T2DM patients hinders the entrance of glucose into the cell for energy production. In addition to suitable drugs, an appropriate diet and/or exercise can be implemented to target the increase in GLUT4 expression, GLUT4 concentrations and GLUT4 translocation to the cell surface when managing the glucose metabolism of T2DM patients. In this review, we discussed successful intervention strategies that were individually administered or coupled with diet and/or exercise and affected the expression and translocation of GLUT4 in T2DM while reducing the excess glucose load from the blood. Additionally, some potentially good synthetic and natural compounds, which can activate the insulin independent GLUT4 signaling pathways for the efficient management of T2DM, are highlighted as possible targets or emerging alternative sources for future anti diabetic drug development. PMID- 26951105 TI - Algorithm-guided goal-directed haemodynamic therapy does not improve renal function after major abdominal surgery compared to good standard clinical care: a prospective randomised trial. AB - BACKGROUND: Acute kidney injury is a common complication after major surgery. In this study, we investigated whether an algorithm-guided goal-directed haemodynamic therapy (GDT) can improve renal outcome compared to good standard clinical care. METHODS: A total of 180 patients undergoing major abdominal surgery were prospectively and randomly assigned to one of two groups: in the GDT group, patients were treated with a GDT algorithm using transpulmonary thermodilution while standard care was applied to the control patients. Change in creatinine was studied as the primary end point, postoperative complications as well as 1-year mortality as secondary outcomes. Haemodynamics in GDT and control patients were compared calculating goal-achievement rates. RESULTS: Postoperative change in creatinine (18 +/- 39 MUmol/l (control) vs. 16 +/- 42 MUmol/l (GDT); mean difference (95 % confidence interval) 1.6 MUmol/l (-10 to 13 MUmol/l)) was comparable between the GDT and the control group. Postoperative complications and mortality during hospital stay and after 1 year were not influenced by the use of a GDT algorithm. Achievement rates of haemodynamic goals were not higher in the GDT group compared to the already high (>80 %) rates in the control group. Multivariate regression analysis revealed intraoperative hypotension (MAP < 70 mmHg) and postoperative hypovolaemia (GEDI < 640 ml/m(2)) as risk factors for postoperative renal impairment. CONCLUSIONS: In this study, GDT was not superior to standard clinical care in order to avoid renal failure after major abdominal surgery. The reason for this finding is most likely the high achievement rate of haemodynamic goals in the control group, which cannot be improved by the GDT algorithm. TRIAL REGISTRATION: Clinicaltrials.gov; NCT01035541; registered 17 December 2009. PMID- 26951106 TI - Associations of anthropometric measures on breast cancer risk in pre- and postmenopausal women--a case-control study. AB - BACKGROUND: The type of silhouette and quantity of fat tissue are correlated with hormonal imbalance which plays a substantial role in breast carcinogenesis. The goal of the study was to investigate the association between various anthropometric characteristics and breast cancer risk. METHODS: Detailed anthropometric assessment was conducted on 487 women of whom 193 had diagnosed breast cancer and were consecutive patients in the Oncology Center, Cracow, Poland between 2002 and 2004. Measurements were divided into four categories: overall body size (body mass index [BMI], waist circumference [WC], waist-hip ratio [WHR]), regional body sizes (skinfold thicknesses, circumferences), thickness of the skeleton (widths, chest diameters), and body proportions. Additionally, results were analyzed in regard to menopausal status. Differences between groups were assessed using Student's t test and Mann-Whitney's test. Models of logistic regression for selected data were built to estimate the odds ratio. Results were considered statistically significant when the P value was less than 0.05. RESULTS: The BMI in both groups was negatively associated with the risk of cancer. Among premenopausal women, WHR increased the risk of breast cancer (WHR > 0.83, OR, 2.72; 95% CI, 1.01-7.27). Anthropometric indices of hip to-shoulder ratio in postmenopausal (>=84.2 mm, OR, 0.02; 95% CI, 0.01-0.11) and trunk-to-height ratio in both premenopausal women (>=32.76, OR, 0.09; 95% CI, 0.03-0.28) and postmenopausal women (>=32.76, OR, 0.13; 95% CI, 0.05-0.33) were strongly related to a decreased risk of breast cancer. Thicknesses of the triceps and subscapular skinfolds increased the risk of breast cancer. CONCLUSIONS: Women with breast cancer present with an obese type of silhouette with a specific concentration of fat tissue in the central and upper parts of the body. PMID- 26951108 TI - Tailored Multi-Target Agents. Applications and Design Considerations. AB - BACKGROUND: In contrast to the one target-one drug paradigm, multi-target agents seem as a promising alternative to manage complex disorders and health conditions linked to drug resistance issues. In fact, many longstanding drugs are in fact unintended multi-functional therapeutics that have emerged from phenotypic screening. The last two decades, however, have witnessed the emergence of tailored multi-target agents, which according to our perspective combine the best aspects of target-based and phenotypic-based drug discovery. METHODS: We discuss a number of considerations related to the design, screening and computer-aided discovery of multi-targeted drugs, along with overlooked advantages that this type of agents might have in clinical trials. A theoretic example is included to explain the reduced positive predictive value in virtual screening campaigns focused on multi-target agents. CONCLUSION: Multi-target agents present great therapeutic potential for the treatment of complex health conditions and the solution of drug resistance phenomena. However, they are certainly challenging for computer-aided drug discovery approaches. Merged or overlapping pharmacophores should be preferred whenever possible. It is thus suggested to perform a careful selection of the combination of pursued targets, preferring target combinations supported by co-evolution or similar biding sites. PMID- 26951107 TI - Peripapillary choroidal thickness after intravitreal ranibizumab injections in eyes with neovascular age-related macular degeneration. AB - BACKGROUND: The purpose of this study was to investigate peripapillary choroidal thickness (CT) in eyes with neovascular age-related macular degeneration (AMD) and to assess whether peripapillary CT is affected by intravitreal injection of ranibizumab (IVR) in eyes with neovascular AMD. METHODS: Peripapillary and subfoveal CT were measured in spectral domain optical coherence tomography images from 39 eyes of neovascular AMD patients and 39 eyes of age-matched controls retrospectively. The patients were treated with 0.5 mg IVR monthly for 3 months and retreated as needed. Peripapillary CT at baseline, 3 months and 6 months was measured at four locations (superior, nasal, inferior and temporal areas). RESULTS: The mean peripapillary and subfoveal baseline CTs of the eyes with neovascular AMD (153.3 +/- 45.3 MUm and 228.6 +/- 78.6 MUm) were not different from those of the controls (149.0 +/- 42.3 MUm and 221.4 +/- 54.1 MUm; P = 0.665 and P = 0.639, respectively). Subfoveal CT decreased at 3 months (213.8 +/- 75.8 MUm, P < 0.001) and 6 months (215.1 +/- 72.8 MUm, P = 0.002) following IVR treatment. Mean peripapillary CT did not show significant changes at 3 months (149.6 +/- 43.8 MUm, P = 0.156) or 6 months (150.0 +/- 43.4 MUm, P = 0.187). Subanalysis revealed that only temporal peripapillary CT decreased from baseline (167.1 +/- 54.5 MUm) to 3 months (159.4 +/- 50.8 MUm, P = 0.010) and was sustained at 6 months (160.6 +/- 49.6, P = 0.026). However, superior, nasal and inferior peripapillary CT did not show significant changes after IVR. CONCLUSIONS: Changes in peripapillary CT after IVR were limited to the macular area. This result may suggest that IVR does not affect CT outside of the macula in the eyes of patients with neovascular AMD. PMID- 26951109 TI - An Unusual Solitary Thyroid Nodule with Bloody Follicles: Metastatic Renal Cell Carcinoma Within an Infiltrative Follicular Variant Papillary Carcinoma. PMID- 26951110 TI - Classic Architecture with Multicentricity and Local Recurrence, and Absence of TERT Promoter Mutations are Correlates of BRAF (V600E) Harboring Pediatric Papillary Thyroid Carcinomas. AB - This study is aimed to investigate the BRAF (V600E) and TERT promoter mutation profile of 50 pediatric papillary thyroid carcinomas (PTCs) to refine their clinicopathological correlates. The median age at the time of surgery was 16 years (range, 6-18). No TERT promoter mutations were identified in this series. The BRAF (V600E) mutation was present in 15 (30 %) tumors. From genotype histologic variant correlation perspective, 13 of 24 classic variant PTCs and 2 of 7 diffuse sclerosing variant PTCs were found to harbor BRAF (V600E) mutation. One cribriform-morular variant, 3 solid variant, and 15 follicular variant PTCs were BRAF wild type. While tumors with distant metastasis were BRAF wild type, two of five tumors with extrathyroidal extension (ETE) harbored BRAF (V600E) mutation. Nine of 15 BRAF (V600E) harboring tumors had central lymph node metastases. There was no significant correlation with BRAF (V600E) mutation and age, gender, tumor size, ETE, central lymph node metastasis, the status of pT, pN1a-b, and distant metastasis. An adverse correlation between BRAF (V600E) mutation and disease-free survival (DFS) was noted in the entire cohort; however, the predictive value of BRAF (V600E) mutation disappeared within the group of tumors displaying classic architecture as well as classic variant PTCs. The present cohort identifies that the classic architecture with multicentricity and local recurrence are correlates of BRAF (V600E) harboring pediatric PTCs. While the small size of this cohort is one of the limitations, neither the BRAF mutation status nor the classic tumor architecture does seem to be an independent prognosticator of DFS in this series. Evidence also suggests that TERT promoter mutations do not seem to play a major role in the pathogenesis of pediatric PTCs. PMID- 26951111 TI - Endothelial permeability following coronary artery bypass grafting: an observational study on the possible role of angiopoietin imbalance. AB - BACKGROUND: Unresolved inflammation resulting in capillary leakage with endothelial barrier dysfunction is a major contributor to postoperative morbidity and mortality after coronary artery bypass graft (CABG). Angiopoietins (ANGs) are vascular growth factors, also mediating inflammation and disruption of the endothelium, thus inducing capillary leakage. We hypothesized that changes in the relative serum levels of ANG1 and ANG2 influence endothelial barrier function and perioperative morbidity after CABG. METHODS: After approval and informed consent, serum samples (n = 28) were collected pre CABG surgery, 1, 6, and 24 h after aortic de-clamping. ANG1, ANG2, soluble ANG receptor TIE2 (sTIE2), and IL-6 serum concentrations were analyzed by ELISA. Human pulmonary microvascular endothelial cells (HPMECs) were incubated with patient serum and FITC-dextran permeability was assessed. Furthermore, ANG2 secretion of HPMECs was analyzed after incubation with IL-6-containing patient serum. RESULTS: CABG induced an early and sustained increase of ANG2/ANG1 ratio (5-fold after 24 h compared to pre-surgery). These changes correlated with elevated serum lactate levels, fluid balance, as well as the duration of mechanical ventilation. Permeability of HPMECs significantly increased after incubation with post-surgery serum showing a marked shift of ANG2/ANG1 balance (18-fold) compared to serum with a less pronounced increase (6 fold). Furthermore, CABG resulted in increased IL-6 serum content. Pre-incubation with serum containing high levels of IL-6 amplified the ANG2 secretion by HPMECs; however, this was not influenced by blocking IL-6. CONCLUSIONS: CABG affects the balance between ANG1 and ANG2 towards a dominance of the barrier-disruptive ANG2. Our data suggest that this ANG2/ANG1 imbalance contributes to an increased postoperative endothelial permeability, likewise being reflected by the clinical course. The results strongly suggest a biological effect of altered angiopoietin balance during cardiac surgery on endothelial permeability. PMID- 26951112 TI - Recovering complete and draft population genomes from metagenome datasets. AB - Assembly of metagenomic sequence data into microbial genomes is of fundamental value to improving our understanding of microbial ecology and metabolism by elucidating the functional potential of hard-to-culture microorganisms. Here, we provide a synthesis of available methods to bin metagenomic contigs into species level groups and highlight how genetic diversity, sequencing depth, and coverage influence binning success. Despite the computational cost on application to deeply sequenced complex metagenomes (e.g., soil), covarying patterns of contig coverage across multiple datasets significantly improves the binning process. We also discuss and compare current genome validation methods and reveal how these methods tackle the problem of chimeric genome bins i.e., sequences from multiple species. Finally, we explore how population genome assembly can be used to uncover biogeographic trends and to characterize the effect of in situ functional constraints on the genome-wide evolution. PMID- 26951113 TI - Gene expression and localization of a beta-1,3-glucanase of Lotus japonicus. AB - Phytohormone abscisic acid (ABA) inhibits root nodule formation of leguminous plants. LjGlu1, a beta-1,3-glucanase gene of Lotus japonicus, has been identified as an ABA responsive gene. RNA interference of LjGlu1 increased nodule number. This suggests that LjGlu1 is involved in the regulation of nodule formation. Host legumes control nodule number by autoregulation of nodulation (AON), in which the presence of existing root nodules inhibits further nodulation. For further characterization of LjGlu1, we focused on the expression of LjGlu1 in relation to AON. In a split-root system, LjGlu1 expression peaked when AON was fully induced. Hairy roots transformed with LjCLE-RS1, a gene that induces AON, were generated. Expression of LjGlu1 was greater in the transgenic roots than in untransformed roots. LjGlu1 was not induced in a hypernodulating mutant inoculated with Mesorhizobium loti. These results suggest that the expression of LjGlu1 is involved in the system of AON. However, neither hypernodulation nor enlarged nodulation zone was observed on the transgenic hairy roots carrying LjGlu1-RNAi, suggesting that LjGlu1 is not a key player of AON. Recombinant LjGlu1 showed endo beta-1,3-glucanase activity. LjGlu1-mOrange fusion protein suggested that LjGlu1 associated with M. loti on the root hairs. Exogenous beta-1,3-glucanase inhibited infection thread formation by both the wild type and the mutant, and nodule numbers were reduced. These results suggest that LjGlu1 is expressed in response to M. loti infection and functions outside root tissues, resulting in the inhibition of infection. PMID- 26951115 TI - Temperature and rainfall are related to fertility rate after spring artificial insemination in small ruminants. AB - A total number of 1092 artificial inseminations (AIs) performed from March to May were documented over four consecutive years on 10 Payoya goat farms (36 degrees N) and 19,392 AIs on 102 Rasa Aragonesa sheep farms (41 degrees N) over 10 years. Mean, maximum, and minimum ambient temperatures, mean relative humidity, mean solar radiation, and total rainfall on each insemination day were recorded. Overall, fertility rates were 58 % in goats and 45 % in sheep. The fertility rates of the highest and lowest deciles of each of the meteorological variables indicated that temperature and rainfall had a significant effect on fertility in goats. Specifically, inseminations that were performed when mean (68 %), maximum (68 %), and minimum (66 %) temperatures were in the highest decile, and rainfall was in the lowest decile (59 %), had a significantly (P < 0.0001) higher proportion of does that became pregnant than did the ewes in the lowest decile (56, 54, 58, and 49 %, respectively). In sheep, the fertility rates of the highest decile of mean (62 %), maximum (62 %), and minimum (52 %) temperature, RH (52 %), THI (53 %), and rainfall (45 %) were significantly higher (P < 0.0001) than were the fertility rates among ewes in the lowest decile (46, 45, 45, 45, 46, and 43 %, respectively). In conclusion, weather was related to fertility in small ruminants after AI in spring. It remains to be determined whether scheduling the dates of insemination based on forecasted temperatures can improve the success of AI in goats and sheep. PMID- 26951114 TI - Murine diet/tissue and human brain tumorigenesis alter Mthfr/MTHFR 5'-end methylation. AB - Polymorphisms and decreased activity of methylenetetrahydrofolate reductase (MTHFR) are linked to disease, including cancer. However, epigenetic regulation has not been thoroughly studied. Our goal was to generate DNA methylation profiles of murine/human MTHFR gene regions and examine methylation in brain and liver tumors. Pyrosequencing in four murine tissues revealed minimal DNA methylation in the CpG island. Higher methylation was seen in liver or intestine in the CpG island shore 5' to the upstream translational start site or in another region 3' to the downstream start site. In the latter region, there was negative correlation between expression and methylation. Three orthologous regions were investigated in human MTHFR, as well as a fourth region between the two translation start sites. We found significantly increased methylation in three regions (not the CpG island) in pediatric astrocytomas compared with control brain, with decreased expression in tumors. Methylation in hepatic carcinomas was also increased in the three regions compared with normal liver, but the difference was significant for only one CpG. This work, the first overview of the Mthfr/MTHFR epigenetic landscape, suggests regulation through methylation in some regions, demonstrates increased methylation/decreased expression in pediatric astrocytomas, and should serve as a resource for future epigenetic studies. PMID- 26951116 TI - Response of deciduous trees spring phenology to recent and projected climate change in Central Lithuania. AB - The analysis of long-term time series of spring phenology for different deciduous trees species has shown that leaf unfolding for all the investigated species is the most sensitive to temperatures in March and April and illustrates that forcing temperature is the main driver of the advancement of leaf unfolding. Available chilling amount has increased by 22.5 % over the last 90 years, indicating that in the investigated geographical region there is no threat of chilling shortage. The projection of climatic parameters for Central Lithuania on the basis of three global circulation models has shown that under the optimistic climate change scenario (RCP 2.6) the mean temperature tends to increase by 1.28 degrees C and under the pessimistic scenario (RCP 8.5) by 5.03 degrees C until the end of the current century. Recently, different statistical models are used not only to analyze but also to project the changes in spring phenology. Our study has shown that when the data of long-term phenological observations are available, multiple regression models are suitable for the projection of the advancement of leaf unfolding under the changing climate. According to the RCP 8.5 scenario, the projected advancement in leaf unfolding for early-season species birch consists of almost 15 days as an average of all three used GSMs. Markedly less response to the projected far future (2071-2100), climate change is foreseen for other investigated climax species: -9 days for lime, 10 days for oak, and 11 days for maple. PMID- 26951118 TI - Erratum to: Medical care and drug-related problems: Do doctors and pharmacists speak the same language? PMID- 26951117 TI - Effects of dividing attention on memory for declarative and procedural aspects of tool use. AB - Tool-related knowledge and skills are supported by a complex set of memory processes that are not well understood. Some aspects of tools are mediated by either declarative or procedural memory, while other aspects may rely on an interaction of both systems. Although motor skill learning is believed to be primarily supported by procedural memory, there is debate in the current literature regarding the role of declarative memory. Growing evidence suggests that declarative memory may be involved during early stages of motor skill learning, although findings have been mixed. In the current experiment, healthy, younger adults were trained to use a set of novel complex tools and were tested on their memory for various aspects of the tools. Declarative memory encoding was interrupted by dividing attention during training. Findings showed that dividing attention during training was detrimental for subsequent memory for tool attributes as well as accurate demonstration of tool use and tool grasping. However, dividing attention did not interfere with motor skill learning, suggesting that declarative memory is not essential for skill learning associated with tools. PMID- 26951119 TI - Study on daptomycin use and implementation of an antimicrobial stewardship program. AB - BACKGROUND: Treatment of Gram-positive pathogens remains a major health issue due to the presence of methicillin-resistant Staphylococcus aureus (MRSA) and Vancomycin-Resistant Enterococcus spp. Daptomycin offers an alternative after therapeutic failure using glycopeptides. Yet its use requires strict control given its financial impact and environmental risks. Since 2014, the use of daptomycin within our hospital has intensified, occasionally outside the scope of its approved indications. OBJECTIVES: The aim of this study is to analyze the appropriateness of daptomycin prescriptions. SETTING: This work was conducted in a 1500-bed University Hospital. METHOD: A descriptive retrospective study was conducted from November 2013 to July 2014. All patients having received at least 2 days of treatment were included. Analysis of the appropriateness of daptomycin prescriptions was conducted by a multidisciplinary team comprised of infectious diseases specialists, pharmacists and a microbiologist. The appropriateness of daptomycin prescriptions was established based on Infectious Diseases Society of America recommendations published in 2011. MAIN OUTCOME MEASURES: The indicators chosen to determine appropriateness of prescription were: treatment indication, prescribed dose and other antibiotics associated with the daptomycin prescription. RESULTS: 19 patients (14 men/5 women) were included. Observed indications were: bone and joint infection (n = 6; 32 %), infectious endocarditis (n = 5; 26 %), bacteremia (n = 5; 26 %) and complicated skin and soft tissue infection (n = 3; 16 %). Identified pathogens were: MRSA (n = 14; 74 %), methicillin-resistant coagulase-negative Staphylococcus (n = 4; 21 %) and Streptococcus mitis (n = 1; 5 %). Daptomycin was prescribed as first-line treatment in 32 % of cases (n = 6). The mean dosage was 9 mg/kg/day (5-11 mg/kg/day) for a mean duration of 11 days (2; 55 days). Clinical success was observed in 42 % of cases (n = 8). Appropriateness for daptomycin use was only established for 15 % of prescriptions (n = 3). CONCLUSION: Faced with a lack of recent recommendations on the subject, our multidisciplinary team issued a local consensus, defining the indications and dosage modalities for this reserve antibiotic. This multidisciplinary approach enables improved use of recent anti MRSA drugs. PMID- 26951121 TI - Lack of pharmacist-physician communication associated with nimesulide-induced oligohydramnios during pregnancy. AB - CASE: The consequences of medication errors can be serious, especially in pregnant women. When decision-making is critical, physician-pharmacist communication has the potential to improve patient safety. In this report, we describe the case of a pregnant woman who developed oligohydramnios after taking nimesulide for neuropathic pain. The drug was improperly prescribed by a family physician and mistakenly dispensed by a community pharmacist. Oligohydramnios was observed during ultrasound examination and an iatrogenic cause was suspected. This case is presented to raise awareness that patient safety is threatened because of a lack of physician-pharmacist communication, especially for pregnant patients. CONCLUSION: Healthcare professionals are continually at-risk for making errors at work. Effective inter-professional communication should be an organisational tool to prevent adverse events for pregnant women. PMID- 26951120 TI - Attitudes towards polypharmacy and medication withdrawal among older inpatients in Italy. AB - BACKGROUND: From 20 to 65 % of older adults receiving polypharmacy take at least one potentially inappropriate medication (PIM), leading to a high risk of adverse drug reactions. The term deprescribing was coined to describe a process of optimization of drug regimens through the withdrawal of PIMs. There is a paucity of evidence on the attitudes, beliefs and willingness of hospitalized patients towards deprescribing. OBJECTIVE: To measure at hospital discharge inpatients' attitudes and beliefs towards polypharmacy and the potential withdrawal of one or more of their medications using the PATD (Patients' Attitudes Towards Deprescribing) questionnaire and determine if they are associated with participant characteristics. SETTING: Geriatric and internal medicine wards in an Italian teaching hospital. METHOD: Administration of the PATD questionnaire (developed and validated in an Australian outpatient setting, translated and adapted to the Italian setting for this study) to a consecutive sample of 100 older (aged >=65 years) inpatients with polypharmacy who were interviewed by a nurse or pharmacist at the time of hospital discharge. MAIN OUTCOME MEASURE: Older patients' attitudes and beliefs towards reducing medications and participant characteristics. RESULTS: Eighty-nine percent of patients surveyed would like to reduce the number of daily medications. The desire for deprescribing was not associated with age, sex or number of medications or medical conditions; older patients were less aware of the reasons for taking medications. CONCLUSION: The majority of hospitalized older adults with polypharmacy think they are taking a lot of drugs and would like to reduce this number. Older adults should not be considered a major limitation on deprescribing interventions. Future research should examine this issue with qualitative studies in order to gain a more in-depth understanding and explore how these findings can be translated into a multidisciplinary deprescribing process. PMID- 26951123 TI - Successful clozapine continuation during chemotherapy for the treatment of malignancy: a case report. AB - CASE: The need for chemotherapy treatment in a cancer patient who uses clozapine raises a clinical dilemma because both therapies can cause agranulocytosis. A 45 year-old male diagnosed with schizophrenia used clozapine together with zuclopenthixol for more than 15 years. Non-Hodgkin's lymphoma was treated with chemotherapy twice, and clozapine was continued during both courses of chemotherapy. Agranulocytosis did not occur during the first treatment. During the second treatment, agranulocytosis occurred, but was attributed to chemotherapy, and blood counts recovered spontaneously. Successful concomitant use of clozapine and cancer chemotherapy is based on a limited number of case reports. However, two case reports describe persistent neutropenia or agranulocytosis, possibly related to this combination. CONCLUSION: Clozapine should only be continued during cancer chemotherapy if favoured by the risk-to benefit ratio. PMID- 26951124 TI - The arc of Buhler: special considerations when performing pancreaticoduodenectomy. AB - A 74-year-old female was diagnosed as having a carcinoma of the papilla of Vater. Preoperative computed tomography showed stenosis of the celiac trunk and an enlarged artery arising from the superior mesenteric artery (SMA) joining the root of the splenic artery. Since this artery communicated with the SMA and the celiac trunk, independently of the gastroduodenal and dorsal pancreatic arteries, it was considered to be the arc of Buhler (AOB). The arterial blood flow to the liver, spleen, and stomach appeared to depend on the AOB, such that AOB preservation was considered to be essential. A subtotal stomach-preserving pancreaticoduodenectomy with preservation of the AOB was thus performed. Although AOB is a relatively infrequent type of arterial communication between the SMA and the celiac trunk, it needs to be preserved during pancreaticoduodenectomy when celiac trunk stenosis is present. PMID- 26951125 TI - Erratum to: Does 2,4-dichlorophenoxyacetic acid (2,4-D) induce genotoxic effects in tissue cultured Allium roots? PMID- 26951122 TI - Trastuzumab, non-pegylated liposomal-encapsulated doxorubicin and paclitaxel in the neoadjuvant setting of HER-2 positive breast cancer. AB - BACKGROUD: Neoadjuvant treatment based on the combination of trastuzumab plus chemotherapy is the standard of care in patients with HER2-positive early or locally advanced breast cancer. The concurrent use of trastuzumab, anthracyclines and taxanes is frequently used in this setting despite the potential cardiotoxicity of both anthracyclines and trastuzumab. However, not much information is available about this chemotherapy scheme. OBJECTIVE: We wanted to evaluate the efficacy and safety profile of the combination of trastuzumab, liposome-encapsulated doxorubicin and paclitaxel as neoadjuvant scheme. We also tried to establish predictive factors of pathologic complete response. SETTING: The study was carried out in a tertiary University Hospital of Spain. METHOD: This is a descriptive study of the clinical practice performed in our hospital. MAIN OUTCOME MEASURE: Efficacy was measured in terms of pathologic complete response, which was defined as the absence of invasive cancer cells in the breast and the axilla after neoadjuvant treatment. RESULTS: Thirty patients were included, the median age was 48. Seventeen (56.7 %) were hormonal receptor (HR) positive, 14 (46.6 %) had IIIa-b clinical stage and one of them had inflammatory breast cancer. 12 patients (40 %) achieved pCR. Patients with HR-negative BC achieved a higher pCR rate than those ones with HR-positive BC (61.5 % and 23.5 %, respectively; p value = 0.035). 21 patients (70 %) underwent breast conservative surgery. The treatment was in general well tolerated, most frequent grade 3-4 adverse events were neutropenia (20 %), asthenia and liver enzyme alteration (10 %) and febrile neutropenia (6.7 %). No patient developed heart failure, but one (3.3 %) presented a 10 % asymptomatic absolute reduction in left ventricular fraction ejection. CONCLUSIONS: The studied treatment for the neoadjuvant setting of HER2 positive breast cancer seems to be an effective therapeutic option. Despite the expected high rate of cardiotoxicity of this regimen, the study results shows that this treatment regimen appears to be safe. The combination of trastuzumab, non-pegylated liposomal-encapsulated doxorubicin and paclitaxel should be considered for the treatment of HER2-overexpressing breast cancer. PMID- 26951126 TI - Facile Fabrication of Bi2WO6/Ag2S Heterostructure with Enhanced Visible-Light Driven Photocatalytic Performances. AB - In this report, a novel photocatalyst based on Bi2WO6/Ag2S heterostructures was prepared by a 3-mercaptopropionic acid (MPA)-assisted route at room temperature. Compared to bare Bi2WO6 and Ag2S nanoparticles, the as-formed Bi2WO6/Ag2S heterostructures exhibit enhanced photocatalytic activity for the degradation of rhodamine B (Rh B) under visible-light irradiation. This kind of enhancement in the photocatalytic activity is considered to be the synergistic effects of both the effective electron-hole separation and expansion of the light-absorption range. The pH of the solution is of vital importance to the photocatalytic activity of the as-formed Bi2WO6/Ag2S heterostructures. Under low pH value, the photosensitization process is suppressed, while under higher pH value, the photosensitization process is favored. The mechanism of the photocatalytic process was proposed by the active-species-trapping experiments, indicating that the photogenerated holes (h(+)) play a crucial role in the degradation of Rh B under visible light. The enhanced photocatalytic performance of this heterostructure makes it a promising material for the treatment of dye-containing wastewater. PMID- 26951128 TI - Thermodynamic Complexing of Monocyclopentadienylferrum (II) Intercalates with Double-Walled Carbon Nanotubes. AB - By employing the methods of molecular mechanics, semi-empirical quantum-chemical RM3 and Monte-Carlo, the positioning of monocyclopentadienylferrum (II) molecules in double-walled (5,5)@(10,10) carbon nanotubes (CNT) depending on their concentration and temperature has been studied. The molecules have been found out to form stable bonds with CNT walls, with a tendency between intercalate stability and the CNT structure. The temperature growth (over ~500 K) causes gradual bond ruining followed by extrusion of interwall intercalate. Further temperature increase up to 600-700 K is characterised with intercalate external surface desorption, stabilising the whole system and keeping the interwall intercalate only. The CNT's UV-spectrum (5,5)@(10,10) depending on the intercalate concentration and association constant of the "double-walled CNT intercalate" system have been calculated. A combination of unique optical, electrical and magnetic behaviour of cyclopentadienyl complexes with their ability to form high-stable intercalate with CNT opens a prospect of their applying in nanotechnology. PMID- 26951129 TI - Editorial: Important Roles of PPAR in Stem Cell Differentiation. PMID- 26951127 TI - Lewis Basicity of Nitrogen-Doped Graphite Observed by CO2 Chemisorption. AB - The characteristics of CO2 adsorption sites on a nitrogen-doped graphite model system (N-HOPG) were investigated by X-ray photoelectron and absorption spectroscopy and infrared reflection absorption spectroscopy. Adsorbed CO2 was observed lying flat on N-HOPG, stabilized by a charge transfer from the substrate. This demonstrated that Lewis base sites were formed by the incorporation of nitrogen via low-energy nitrogen-ion sputtering. The possible roles of twofold coordinated pyridinic N and threefold coordinated valley N (graphitic N) sites in Lewis base site formation on N-HOPG are discussed. The presence of these nitrogen species focused on the appropriate interaction strength of CO2 indicates the potential to fine-tune the Lewis basicity of carbon based catalysts. PMID- 26951130 TI - The Pleiotropic Effects of PPARs on Vascular Cells and Angiogenesis: Implications for Tissue Engineering. AB - Angiogenesis is a complex process in which capillaries are produced from blood vessels that already exists. Endothelial cells (ECs) and endothelial progenitor cells (EPCs) are pivotal for this process and for the maintenance/restorage of the endothelium. Decreased numbers and dysfunction of these cells have been related to growing cardiovascular risks. Peroxisome-proliferator-activated receptor (PPAR) is a large family of nuclear receptors, characterized by three isotypes: alpha, beta and gamma. Numerous studies have shown that PPAR activation is involved in the pathology of a wide range of cardiovascular diseases and has a role in endothelial function, thrombosis and inflammation, etc., suggesting that PPAR agonists may be good candidates to treat the cardiovascular disease. However, controversial results exist on whether this nuclear receptor is inductive or depressive in the process of angiogenesis. Herein, this review will provide a detailed discussion of the up-to-date investigation of the role of PPARs in angiogenesis, with particular reference to their effects on angiogenesis related cells--i.e., ECs, EPCs, vascular smooth-muscle cells (VSMCs), macrophages and endometrial cells--and will discuss the current and potential future applications of PPAR activators. PMID- 26951131 TI - Selective elimination of breast cancer surgery in exceptional responders: historical perspective and current trials. AB - With improvements in chemotherapy regimens, targeted therapies, and our fundamental understanding of the relationship of tumor subtype and pathologic complete response (pCR), there has been dramatic improvement in pCR rates in the past decade, especially among triple-negative and human epidermal growth factor receptor 2-positive breast cancers. Rates of pCR in these groups of patients can be in the 60 % range and thus question the paradigm for the necessity of breast and nodal surgery in all cases, particularly when the patient will be receiving adjuvant local therapy with radiotherapy. Current practice for patients who respond well to neoadjuvant chemotherapy (NCT) is often to proceed with the same breast and axillary procedures as would have been offered women who had not received NCT, regardless of the apparent clinical response. Given these high response rates in defined subgroups among exceptional responders it is appropriate to question whether surgery is now a redundant procedure in their overall management. Further, definitive radiation without surgical resection with or without systemic therapy has been proven effective for several other malignant disease sites including some stages of esophageal, anal, laryngeal, prostate, cervical, and lung carcinoma. The main impediments for potential elimination of surgery have been the fact that prior and current standard and functional breast imaging methods are incapable of accurate prediction of residual disease and that integrating percutaneous biopsy of the breast primary and nodes following NCT may circumvent this issue. This article highlights historical attempts at omission of surgery following NCT in an earlier era, the current status of breast and nodal imaging to predict residual carcinoma, and ongoing and planned trials designed to identify appropriate patients who might be selected for clinical trials designed to test the safety of selected elimination of breast cancer surgery in percutaneous image-guided biopsy-proven exceptional responders to NCT. PMID- 26951133 TI - Takotsubo cardiomyopathy in the setting of acute hydrocephalus secondary to neurocysticercosis. AB - We report the case of a 45-year-old male who presented with transient neurogenic stunned myocardium, or takotsubo cardiomyopathy, secondary to acute hydrocephalus caused by obstruction of the third ventricle by neurocysticercosis. PMID- 26951134 TI - Cardiovascular autonomic control in paraplegic and quadriplegic. AB - INTRODUCTION: Spinal cord injury (SCI) is commonly associated with devastating paralysis. This condition also results in cardiovascular autonomic dysfunction associated with increased mortality from cardiovascular disease. The purpose of this study was to explore the differences in cardiovascular autonomic modulation in individuals with and without SCI. METHODS: The study included 60 individuals: 30 individuals without SCI, who formed the control group-CG and 30 individuals with SCI, who formed the SCI group-SCIG. The latter group was divided into two, one group of subjects with SCI above the spinal segment T6-SCIG (above T6) and a group of individuals with SCI below T6-SCIG (below T6). The subjects were evaluated by linear and nonlinear analysis of heart rate variability (HRV). RESULTS: The SCIG showed significantly lower square root of the mean squares differences of successive NN intervals (rMSSD), number of pairs of adjacent NN intervals differing by more than 50 ms (pNN50), standard deviation of short-term HRV (SD1), and high frequency power (HF). Their low frequency power (LF) in absolute units (ms(2)) was significantly lower and their normalized units (n.u.) were significantly higher. Their LF/HF ratio was significantly higher, and sample entropy (SampEn), which indicates the complexity and irregularity of the NN intervals time series, was significantly lower compared to the CG. The differences between the SCIG and CG were derived mainly from the SCIG (above T6). The correlation test revealed very low values between each of the parameters evaluated for CG and SCIG. CONCLUSIONS: The SCIG (above T6) showed greater cardiovascular autonomic impairment compared to SCIG (below T6) and CG. The SCIG (below T6) also presented some degree of autonomic dysfunction. All parameters, linear or nonlinear, are suitable to demonstrate the differences between the SCIG and CG. PMID- 26951135 TI - Meta-analysis of the safety and efficacy of droxidopa for neurogenic orthostatic hypotension. AB - PURPOSE: Droxidopa has been approved for the treatment of neurogenic orthostatic hypotension (NOH) under the US Food and Drug Administration accelerated approval program, which warrants confirmatory evidence on long-term efficacy of droxidopa. Hereby, we synthesize evidence from published randomized controlled trials (RCTs) about the safety and efficacy of droxidopa for patients with neurogenic orthostatic hypotension. METHODS: A computer literature search of PubMed, Scopus, Web of Science, and Cochrane Central was conducted using relevant keywords. Records were screened for eligible studies and data were extracted and synthesized using Review Manager version 5.3 for Windows. Subgroup analysis and sensitivity analysis were conducted to investigate long-term durability of droxidopa against placebo. RESULTS: Four RCTs with a total of 485 patients (droxidopa, n = 246; placebo, n = 239) were eligible for the final analysis. The mean difference (MD) of change in the main outcomes from baseline to endpoint favored droxidopa than placebo [Orthostatic Hypotension Questionnaire (OHQ) MD 0.61, P = 0.004; dizziness/lightheadedness score MD -0.83, P = 0.008; and standing systolic blood pressure (SBP) MD 4.09, P = 0.03]. The efficacy of droxidopa decreased gradually after 2 weeks, and its statistical significance was lost after 8 weeks (OHQ score MD -0.18, P = 0.61; dizziness/lightheadedness score MD -0.71, P = 0.11; and standing SBP MD 2.96, P = 0.29). None of the adverse events were significantly higher in the case of droxidopa compared to placebo. CONCLUSION: Droxidopa is a safe and effective drug for the short-term management of NOH symptoms. However, current evidence is insufficient to confirm the efficacy of droxidopa for long-term use. Therefore, further studies with increased sample size are needed. PMID- 26951137 TI - Increasing task demand by obstructing object recognition increases boundary extension. AB - Individuals consistently remember seeing wider-angle versions of previously viewed scenes than actually existed. The multi-source model of boundary extension (BE) suggests many sources of information contribute to this visual memory error. Color diagnosticity is known to affect object recognition with poorer recognition for atypically versus typically colored objects. Scenes with low-color diagnostic main objects and two versions of scenes with high-color diagnostic main objects (typically and atypically colored) were tested to determine if the reduced ability to identify the main object in a scene influences BE. Scenes were presented to one group of participants for 46 ms and another group for 250 ms. Each scene was followed by a mask and a request for a recognition response concerning the identity of the main object. The scene was then immediately presented again for testing and participants rated it as depicting a more close up view, more wide-angle, or the same view as before. The study demonstrates that poorer encoding of main objects in scenes leads to increased BE, but trial-by trial recognition accuracy had no relationship to BE magnitude. This finding provides further insight into the impact of task demand and main object recognition on BE. PMID- 26951132 TI - Current challenges in treatment options for visceral leishmaniasis in India: a public health perspective. AB - Visceral leishmaniasis (VL) is a serious parasitic disease causing considerable mortality and major disability in the Indian subcontinent. It is most neglected tropical disease, particularly in terms of new drug development for the lack of financial returns. An elimination campaign has been running in India since 2005 that aim to reduce the incidence of VL to below 1 per 10,000 people at sub district level. One of the major components in this endeavor is reducing transmission through early case detection followed by complete treatment. Substantial progress has been made during the recent years in the area of VL treatment, and the VL elimination initiatives have already saved many lives by deploying them effectively in the endemic areas. However, many challenges remain to be overcome including availability of drugs, cost of treatment (drugs and hospitalization), efficacy, adverse effects, and growing parasite resistance. Therefore, better emphasis on implementation research is urgently needed to determine how best to deliver existing interventions with available anti leishmanial drugs. It is essential that the new treatment options become truly accessible, not simply available in endemic areas so that they may promote healing and save lives. In this review, we highlight the recent advancement and challenges in current treatment options for VL in disease endemic area, and discuss the possible strategies to improve the therapeutic outcome. PMID- 26951136 TI - A single dose of meropenem is superior to ciprofloxacin in preventing infections after transrectal ultrasound-guided prostate biopsies in the era of quinolone resistance. AB - PURPOSE: To evaluate the efficacy of meropenem single dose before transrectal prostate biopsy, instead of ciprofloxacin in the era of fluoroquinolones resistance. METHODS: This prospective study included patients with indications for prostatic biopsy from January to December 2014. Those with known resistance in fluoroquinolones or meropenem or with decreased creatinine clearance were excluded. Patients were randomized into two groups, and statistical analysis was carried out. Group A received a 3-day course of ciprofloxacin 500 bid per os starting the day before biopsy. Group B received 1 g meropenem intravenously 1 h prior to the procedure. Patients were followed up for 15 days, and those with lower urinary tract symptoms (LUTS) and fever were called for hospitalization. Urine and blood cultures were obtained. RESULTS: A total of 110 patients, 52-75 years old (mean 67.5, median 66) participated in the study, allocated in Groups A and B. After the procedure, 18 patients (32.7 %) of Group A reported macroscopic hematuria, while 10 (18.2 %) reported rectal blood loss. Nine patients (16.3 %) presented because of fever and LUTS. One of them developed septic shock and died in the ICU. Cultures revealed multi-resistant E. coli with high sensitivity to meropenem, and patients were treated accordingly. In Group B, 20 (36.3 %) patients presented with macroscopic hematuria and 9 (16.3 %) with rectal blood loss. One patient returned to hospital with LUTS and fever. Cultures revealed Klebsiella pneumoniae sensitive to colimycine. CONCLUSIONS: A single dose of meropenem prior to prostate biopsy is a safe and effective way to avoid the possible infectious complications in high-risk patients. PMID- 26951138 TI - Supporting cardiac patient physical activity: a brief health psychological intervention. AB - BACKGROUND: One of the most important risk factors for coronary artery disease is physical inactivity. Health psychological research demonstrates the importance of planning for behaviour change success. Consequently, a health action process approach (HAPA) model-based design to support the uptake of physical activity was initiated for the first time in an acute cardiac ward. METHODS: For impact evaluation, a control group (CG) and an intervention group (IG) of coronary artery disease patients were compared in a controlled longitudinal study. Baseline assessment included socio-demographic variables, intentions regarding physical activity, and actual physical activity prior to the coronary artery disease event. Follow-up data were collected 2 and 6 months after discharge. RESULTS: In total, 193 patients participated in this controlled longitudinal study (63 +/- 9 years; CG: N = 78; IG: N = 115). The IG reported a higher increase in physical activity (p < 0.05), intentions, and coping planning (p < 0.05), and also in action planning and control (p < 0.01) 2 months after discharge. Both CG and IG increased their physical activity 6 months after discharge to the point of no significant difference (p = 0.664). CONCLUSIONS: A HAPA model-based health psychological intervention on an acute cardiac ward is able to increase patients' physical activity over the short term. However, integration of follow-up interventions (preferable in cardiac rehabilitation settings) would be necessary to support sustained physical activity. PMID- 26951141 TI - Rapid Desensitization for Immediate Hypersensitivity to Galsulfase Therapy in Patients with MPS VI. AB - Mucopolysaccharidosis type VI (MPS VI) is a progressive, chronic, and multisystem lysosomal storage disease. Enzyme replacement therapy (ERT) with the recombinant human arylsulfatase B enzyme (galsulfase [Naglazyme]) is recommended as first line therapy. It is generally reported as safe and well tolerated. Frequently observed mild to moderate infusion-related reactions which can be easily handled by reducing or interrupting the infusion and/or administering additional antihistamines, antipyretics, and corticosteroids are mostly mediated by non-IgE mechanisms. Here we report two children with MPS VI who experienced IgE-mediated reactions with galsulfase at the second year of the therapy. One child had anaphylaxis and the other had urticarial eruptions. They could receive ERT after successful rapid desensitization. To our knowledge, this is the second report on galsulfase allergy with IgE-mediated reaction. It is important to recognize IgE mediated reactions since they can be life-threatening and do not respond to the standard therapies. We recommend allergy skin tests in the evaluation of infusion related reactions unresponsive to standard therapies, so that continuation of ERT will be feasible after successful desensitization. PMID- 26951142 TI - Hypoglycemia as an indicator of good diabetes care. PMID- 26951143 TI - The clinical and biomechanical effects of subthreshold random noise on the plantar surface of the foot in diabetic patients and elder people: A systematic review. AB - BACKGROUND: Central nervous system receives information from foot mechanoreceptors in order to control balance and perform movement tasks. Subthreshold random noise seems to improve sensitivity of the cutaneous mechanoreceptor. OBJECTIVES: The purpose of this study was to systematically review published evidence conducted to evaluate the clinical and biomechanical effects of subthreshold random noise on the plantar surface of the foot in diabetic patients and elder people. STUDY DESIGN: Systematic review. METHODS: A literature search was performed in PubMed, Scopus, ScienceDirect, Web of Knowledge, CINAHL, and EMBASE databases based on population, intervention, comparison, outcomes, and study method. Quality of studies was assessed using the methodological quality assessment tool, using Physiotherapy Evidence Database scale. RESULTS: In all, 11 studies were selected for final evaluation based on inclusion criteria. Five studies evaluated the effects of subthreshold random noise in diabetic patients and six in elder people. In seven studies, biomechanical (balance and gait parameters) effects and in four studies clinical (pressure and vibration sensations) effects of subthreshold random noise were investigated. All reviewed studies were scored fair (2) to good (9) quality in terms of methodological quality assessment using Physiotherapy Evidence Database scale. CONCLUSION: The results indicated that subthreshold random noise improves balance and sensation in diabetic patients and elder people. Also gait variables can be improved in elder people with subthreshold random noise. However, further well-designed studies are needed. CLINICAL RELEVANCE: The previous studies reported that subthreshold random noise may improve gait, balance, and sensation, but more studies are needed to evaluate the long-term effect of subthreshold random noise in shoe or insole for daily living tasks in diabetic patients and elder people. PMID- 26951144 TI - Unilateral abducens and bilateral facial nerve palsies associated with posterior fossa exploration surgery. AB - Multiple cranial nerves palsies following a posterior fossa exploration confined to an extradural compartment is a rare clinical presentation. This case report describes a young man who developed a unilateral abducens and bilateral facial nerve palsies following a posterior fossa exploration confined to an extradural compartment. There are different theories to explain this presentation, but the exact mechanism remains unclear. We propose that this patient cranial nerve palsies developed following cerebrospinal fluid (CSF) leak, potentially as a consequence of rapid change in CSF dynamics. PMID- 26951140 TI - Metabolic and transcriptional response of central metabolism affected by root endophytic fungus Piriformospora indica under salinity in barley. AB - The root endophytic fungus Piriformospora indica enhances plant adaptation to environmental stress based on general and non-specific plant species mechanisms. In the present study, we integrated the ionomics, metabolomics, and transcriptomics data to identify the genes and metabolic regulatory networks conferring salt tolerance in P. indica-colonized barley plants. To this end, leaf samples were harvested at control (0 mM NaCl) and severe salt stress (300 mM NaCl) in P. indica-colonized and non-inoculated barley plants 4 weeks after fungal inoculation. The metabolome analysis resulted in an identification of a signature containing 14 metabolites and ions conferring tolerance to salt stress. Gene expression analysis has led to the identification of 254 differentially expressed genes at 0 mM NaCl and 391 genes at 300 mM NaCl in P. indica-colonized compared to non-inoculated samples. The integration of metabolome and transcriptome analysis indicated that the major and minor carbohydrate metabolism, nitrogen metabolism, and ethylene biosynthesis pathway might play a role in systemic salt-tolerance in leaf tissue induced by the root-colonized fungus. PMID- 26951145 TI - Integrated In Silico-In Vitro Discovery of Lung Cancer-related Tumor Pyruvate Kinase M2 (PKM2) Inhibitors. AB - BACKGROUND: The tumor pyruvate kinase M2 (PKM2) is involved in the glycolytic pathway of lung cancer and targeting this kinase has been observed to radiosensitize non-small cell lung cancer (NSCLC). OBJECTIVE: An integration of in silico virtual screening and in vitro kinase assay was described to discover novel PKM2 inhibitors from a candidate library containing >400,000 commercially available compounds. METHOD: The method is a stepwise screening scheme that first used empirical strategies to fast exclude those undruggable compounds in the library and then employed molecular docking and molecular dynamics (MD)-based rescoring to identify few potential hits. Subsequently, the computational findings were substantiated using a standard kinase assay protocol. RESULTS: Four compounds, i.e. nalidixic acid, indoprofen, hematoxylin and polydatin, were identified to inhibit PKM2 kinase at micromolar level, with IC50 values of 53, 21, 340 and 128 .M, respectively. CONCLUSION: Structural analysis revealed that hydrogen bonds, salt bridges, pi-pi stacking and hydrophobic forces co-confer high stability and strong specificity to PKM2-inhibitor binding. PMID- 26951147 TI - Pain and quality of life in leprosy patients in an endemic area of Northeast Brazil: a cross-sectional study. AB - BACKGROUND: Pain emerges as a challenge in the treatment of leprosy patients. In this study, we describe the prevalence and type of pain in patients with leprosy, and its effect on patients' quality of life in an endemic area of Northeast Brazil. FINDINGS: A cross-sectional survey of 260 patients attending leprosy reference centres in Sergipe, Northeast Brazil was conducted. Individuals were assessed for the presence and type of pain, skin sensory loss, peripheral nerve enlargement, touch and pinprick sensations, mechanical allodynia and nerve palpation. Participants completed the Douleur Neuropathique 4 questionnaire, and we also used the Brief Pain Inventory scale and the World Health Organization Quality of Life-BREF instrument to arrive at our results. One hundred and ninety five (75 %) patients reported pain, mostly of the neuropathic type. Pain was moderate in 84 (43.1 %) and severe in 94 (48.2 %) participants. The presence of pain was associated with disability (p = 0.001), leprosy reactions (p = 0.004) and lower quality of life. Most patients with neuropathic pain were treated with steroids, despite their low efficacy for this type of pain. CONCLUSION: Pain is highly prevalent among leprosy patients and is associated with low quality of life. Leprosy management should include a systematic assessment of the type of pain a patient experiences in order to provide adequate treatment. PMID- 26951146 TI - Comparative transcriptomics reveals the conserved building blocks involved in parallel evolution of diverse phenotypic traits in ants. AB - BACKGROUND: Reproductive division of labor in eusocial insects is a striking example of a shared genetic background giving rise to alternative phenotypes, namely queen and worker castes. Queen and worker phenotypes play major roles in the evolution of eusocial insects. Their behavior, morphology and physiology underpin many ecologically relevant colony-level traits, which evolved in parallel in multiple species. RESULTS: Using queen and worker transcriptomic data from 16 ant species we tested the hypothesis that conserved sets of genes are involved in ant reproductive division of labor. We further hypothesized that such sets of genes should also be involved in the parallel evolution of other key traits. We applied weighted gene co-expression network analysis, which clusters co-expressed genes into modules, whose expression levels can be summarized by their 'eigengenes'. Eigengenes of most modules were correlated with phenotypic differentiation between queens and workers. Furthermore, eigengenes of some modules were correlated with repeated evolution of key phenotypes such as complete worker sterility, the number of queens per colony, and even invasiveness. Finally, connectivity and expression levels of genes within the co expressed network were strongly associated with the strength of selection. Although caste-associated sets of genes evolve faster than non-caste-associated, we found no evidence for queen- or worker-associated co-expressed genes evolving faster than one another. CONCLUSIONS: These results identify conserved functionally important genomic units that likely serve as building blocks of phenotypic innovation, and allow the remarkable breadth of parallel evolution seen in ants, and possibly other eusocial insects as well. PMID- 26951148 TI - Efficacy of Early Postoperative Intraperitoneal Chemotherapy After Complete Surgical Resection of Peritoneal Metastasis from Colorectal Cancer: A Case Control Study from a Single Center. AB - BACKGROUND: Early postoperative intraperitoneal chemotherapy (EPIC) is a type of intraperitoneal chemotherapy for patients with colorectal cancer and peritoneal metastasis. However, there is a paucity of clinical studies evaluating the efficacy of EPIC after complete cytoreductive surgery. This study was designed to evaluate the efficacy of EPIC in patients who underwent complete surgical resection of peritoneal metastasis from colorectal cancer. METHODS: A 1:2 matched case-control study was conducted in patients undergoing complete surgical resection of peritoneal metastases from colorectal cancer at our institution between January 2000 and November 2013. The operative and survival outcomes of patients receiving EPIC (EPIC group) and those who did not (no EPIC group) were compared. RESULTS: Thirty patients who were treated with EPIC were matched with 15 patients who did not receive EPIC. The 3-year overall survival (OS) and disease-free survival (DFS) were 74.3 and 53.0 % in the EPIC group and 34.7 and 7.5 % in the no EPIC group (EPIC group vs. no EPIC group: OS, P = 0.016; DFS, P = 0.002). Multivariate analysis identified EPIC and adjuvant systemic chemotherapy as independent prognostic factors for OS, whereas only EPIC was prognostic factor for DFS. For peritoneal-DFS, EPIC was the only significant variable in the univariate analysis (hazard ratio, 2.70; 95 % confidence interval 1.17-6.21; P = 0.020). CONCLUSIONS: EPIC is a safe and efficacious option for intraperitoneal chemotherapy to prevent peritoneal recurrence and prolong survival after complete resection of peritoneal metastasis from colorectal cancer. PMID- 26951150 TI - Development and Life Table Parameters of Phenacoccus madeirensis Green (Hemiptera: Pseudococcidae) on Four Ornamental Plants. AB - The development, reproduction, and life table parameters of the Phenacoccus madeirensis Green (Hemiptera: Pseudococcidae) on four ornamental plant species, namely Pelargonium zonale (Geraniaceae), Hibiscus rosa-sinensis, Hibicus syriacus (Malvaceae), and Cestrum nocturnum (Solanaceae) were investigated under controlled conditions (25 +/- 2 degrees C, 60 +/- 10% R.H., and 16 h photophase). Life table data were analyzed by using an age-stage two-sex life table. The shortest total immature developmental time of females and males for P. madeirensis was obtained on C. nocturnum (20.42 and 21.90 days, respectively). The highest fecundities were 233 and 232 eggs on C. nocturnum and H. syriacus, respectively. The intrinsic rate of increase (r = 0.1511 day(-1)) and finite rate of increase (lambda = 1.1631 day(-1)) were the greatest when mealybugs were reared on C. nocturnum. Net reproductive rate (R 0 = 129.5 offspring) was the greatest when reared on H. syriacus, but this value was not statistically different from that on C. nocturnum. The shortest mean generation time (T = 31.3 days) was calculated on C. nocturnum. These results indicate that C. nocturnum and H. syriacus are more suitable hosts than H. rosa-sinensis and P. zonale for P. madeirensis. PMID- 26951149 TI - Exercise quantity-dependent muscle hypertrophy in adult zebrafish (Danio rerio). AB - Exercise is very important for maintaining and increasing skeletal muscle mass, and is particularly important to prevent and care for sarcopenia and muscle disuse atrophy. However, the dose-response relationship between exercise quantity, duration/day, and overall duration and muscle mass is poorly understood. Therefore, we investigated the effect of exercise duration on skeletal muscle to reveal the relationship between exercise quantity and muscle hypertrophy in zebrafish forced to exercise. Adult male zebrafish were exercised 6 h/day for 4 weeks, 6 h/day for 2 weeks, or 3 h/day for 2 weeks. Flow velocity was adjusted to maximum velocity during continual swimming (initial 43 cm/s). High-speed consecutive photographs revealed that zebrafish mainly drove the caudal part. Additionally, X-ray micro computed tomography measurements indicated muscle hypertrophy of the mid-caudal half compared with the mid-cranial half part. The cross-sectional analysis of the mid-caudal half muscle revealed that skeletal muscle (red, white, or total) mass increased with increasing exercise quantity, whereas that of white muscle and total muscle increased only under the maximum exercise load condition of 6 h/day for 4 weeks. Additionally, the muscle fiver size distributions of exercised fish were larger than those from non exercised fish. We revealed that exercise quantity, duration/day, and overall duration were correlated with skeletal muscle hypertrophy. The forced exercise model enabled us to investigate the relationship between exercise quantity and skeletal muscle mass. These results open up the possibility for further investigations on the effects of exercise on skeletal muscle in adult zebrafish. PMID- 26951154 TI - A Symposium on Management of Barrett's in Patients Having Bariatric Surgery. PMID- 26951152 TI - Temperature-sensitive PSII: a novel approach for sustained photosynthetic hydrogen production. AB - The need for energy and the associated burden are ever growing. It is crucial to develop new technologies for generating clean and efficient energy for society to avoid upcoming energetic and environmental crises. Sunlight is the most abundant source of energy on the planet. Consequently, it has captured our interest. Certain microalgae possess the ability to capture solar energy and transfer it to the energy carrier, H2. H2 is a valuable fuel, because its combustion produces only one by-product: water. However, the establishment of an efficient biophotolytic H2 production system is hindered by three main obstacles: (1) the hydrogen-evolving enzyme, [FeFe]-hydrogenase, is highly sensitive to oxygen; (2) energy conversion efficiencies are not economically viable; and (3) hydrogen producing organisms are sensitive to stressful conditions in large-scale production systems. This study aimed to circumvent the oxygen sensitivity of this process with a cyclic hydrogen production system. This approach required a mutant that responded to high temperatures by reducing oxygen evolution. To that end, we randomly mutagenized the green microalgae, Chlamydomonas reinhardtii, to generate mutants that exhibited temperature-sensitive photoautotrophic growth. The selected mutants were further characterized by their ability to evolve oxygen and hydrogen at 25 and 37 degrees C. We identified four candidate mutants for this project. We characterized these mutants with PSII fluorescence, P700 absorbance, and immunoblotting analyses. Finally, we demonstrated that these mutants could function in a prototype hydrogen-producing bioreactor. These mutant microalgae represent a novel approach for sustained hydrogen production. PMID- 26951151 TI - Access to oral care before hematopoietic stem cell transplantation: understand to improve. AB - PURPOSE: Although the relevance of dental intervention before transplant is recognized, many patients are undergoing transplantation without receiving dental care. The objective of this study was to identify the searching profile, access, and use of dental services by candidates to hematopoietic stem cell transplantation (HSCT), and the difficulties faced by those candidates. METHODS: All candidates for an allogeneic HSCT from a bone marrow transplant unit were invited to take part in this research from March 2014 to March 2015. A questionnaire was developed consisting of five sections with questions about personal information, hematologic disease, access to dental services, and history of dental treatment, patient's preferences, and knowledge. RESULTS: One hundred and ten candidates for allogeneic HSCT participated in this study. Fifty-five participants received professional oral care in the previous year of interview. The majority of patients (64 %) went to a dentist not linked to transplant staff, and private dental service was the most visited (42 %). To visit a dentist during the previous year was statistically associated with the habit of going to a dentist outside the hospital (p < 0.001), which was statistically associated with the family income (p = 0.001). The main barriers to access to dental treatment were lack of guidance (66 %), apprehension (45 %), and lack of confidence (29 %) in an "external" dentist. CONCLUSIONS: Most of the barriers seem to be associated to lack of confidence and information among patients and professionals, as well as a lack of parameters for scheduling or referrals to dental care, especially for those with a low-socioeconomic background. PMID- 26951155 TI - A painful foot: Lisfranc fracture-dislocations. PMID- 26951153 TI - The Controversy of the Most Proper Time for Pregnancy After Bariatric Surgery: a Review of Ten Cases. AB - BACKGROUND: Many infertile obese women conceive after bariatric surgery after many years, while guidelines prohibit them from pregnancy for at least 12-18 months after surgery, due to complications. METHODS: We hereby present 11 cases in our research center, pregnant in less than 12 months after surgery from 2011 to 2015, to evaluate their pregnancy outcome and complications. RESULTS: The mean conception time was 3.6 months after surgery and mean birth weight was 2695 g. Regarding neonatal/fetal complications, there was one case of intrauterine growth retardation and one NICU hospitalization. Among pregnancy complications, eight patients had hyperemesis gravidarum and one had pre-eclampsia. CONCLUSIONS: The results of the present study suggest revising setting a contraindication for conception for patients undergoing bariatric surgery. PMID- 26951156 TI - Mobilisation for public engagement: Benchmarking the practices of research institutes. AB - Studies on scientists' practices of public engagement have pointed to variations between disciplines. If variations at the individual level are reflected at the institutional level, then research institutes in Social Sciences (and Humanities) should perform higher in public engagement and be more involved in dialogue with the public. Using a nearly complete sample of research institutes in Portugal 2014 ( n = 234, 61% response rate), we investigate how public engagement varies in intensity, type of activities and target audiences across scientific areas. Three benchmark findings emerge. First, the Social Sciences and the Humanities profile differently in public engagement highlighting the importance of distinguishing between these two scientific areas often conflated in public engagement studies. Second, the Social Sciences overall perform more public engagement activities, but the Natural Sciences mobilise more effort for public engagement. Third, while the Social Sciences play a greater role in civic public engagement, the Natural Sciences are more likely to perform educational activities. Finally, this study shows that the overall size of research institutes, available public engagement funding and public engagement staffing make a difference in institutes' public engagement. PMID- 26951157 TI - In vitro susceptibility of methicillin-resistant and methicillin-susceptible strains of Staphylococcus aureus to two different cold atmospheric plasma sources. AB - BACKGROUND: Staphylococcus aureus may be the most important wound pathogen and causative for most of surgical site infections. As many anti-staphylococcal drugs are useless because of resistance, novel antimicrobial strategies are strongly needed and may be provided by cold atmospheric plasma (CP), which is being currently investigated for antiseptic efficacy. METHODS: To test the antimicrobial properties of CP against Staphylococcus aureus, 168 methicillin susceptible isolates (MSSA) and 50 methicillin-resistant isolates (MRSA) were treated with two technically different plasma sources [an atmospheric pressure plasma jet (APPJ) and a dielectric barrier discharge plasma (DBD)] in vitro. RESULTS: CP treatment allowed a reproducible and significant growth reduction of MRSA and MSSA. However, MRSA was significantly less susceptible to treatment with DBD than was MSSA, while no difference between MRSA and MSSA was found using APPJ. CONCLUSIONS: As the initial physical antiseptic on skin, CP may be suitable for rapid decolonization of microbial pathogens in vivo. Each device must undergo validated efficacy testing prior to clinical application, as device related differences may occur. PMID- 26951158 TI - Chronic subdural hematoma associated with mucopolysaccharidosis type III B (Sanfilippo's syndrome B). PMID- 26951159 TI - A case series of re-establishment of neuromuscular block with rocuronium after sugammadex reversal. AB - We report the use of rocuronium to re-establish neuromuscular block after reversal with sugammadex. The aim of this study was to investigate the relationship between the dose of rocuronium needed to re-establish neuromuscular block and the time interval between sugammadex administration and re administration of rocuronium. Patients who required re-establishment of neuromuscular block within 12 h after the reversal of rocuronium-induced neuromuscular block with sugammadex were included. After inducing general anesthesia and placing the neuromuscular monitor, the protocol to re-establish neuromuscular block was as follows. An initial rocuronium dose of 0.6 mg/kg was followed by additional 0.3 mg/kg doses every 2 min until train-of-four responses were abolished. A total of 11 patients were enrolled in this study. Intervals between sugammadex and second rocuronium were 12-465 min. Total dose of rocuronium needed to re-establish neuromuscular block was 0.6-1.2 mg/kg. 0.6 mg/kg rocuronium re-established neuromuscular block in all patients who received initial sugammadex more than 3 h previously. However, when the interval between sugammadex and second rocuronium was less than 2 h, more than 0.6 mg/kg rocuronium was necessary to re-establish neuromuscular block. PMID- 26951161 TI - China to train 22,000 more paediatricians in next four years. PMID- 26951160 TI - Attitudes Towards the Mentally Ill: A Study with Health Workers at a University Hospital in Rio de Janeiro. AB - As there are few studies about evaluation of attitudes of health care workers to people with mental disorders in Brazil, a cross-sectional study was carried out to assess the health professionals' attitudes working in a university hospital in Rio de Janeiro and also examine the proportion of negative and positive attitudes endorsed by healthcare professionals in Brazil towards people with mental illness in comparison with other parts of the world. Data were collected using the Community Attitudes towards the Mentally Ill (CAMI) in a random sampling frame of health professionals (n = 246) working in a University Hospital in Rio de Janeiro between April 2013 and June 2013. The CAMI consists of four sub-scales: Authoritarianism, Benevolence, Social Restrictiveness and Community Mental Health Ideology. The results showed attitudes that range from neutral to positive, with the Benevolence and Social Restrictiveness sub-scales showing the least stigmatizing results. The following individual characteristics were associated with negative attitudes: lower levels of education and less clinical experience. In general, health workers attitudes towards service users are characterized as positive when compared with other international studies. However, educational programs for health workers should be reinforced to further promote pre-existing positive attitudes towards people with mental health and the implementation of Brazilian Mental Health Policies. PMID- 26951163 TI - Partnerships in medical education: looking across disciplinary boundaries to extend knowledge. PMID- 26951162 TI - UV-induced Melanin Chemiexcitation: A New Mode of Melanoma Pathogenesis. AB - Mutations in sunlight-induced melanoma arise from cyclobutane pyrimidine dimers (CPDs), DNA photoproducts usually created picoseconds after an ultraviolet (UV) photon is absorbed at thymine or cytosine. Surprisingly, we found that, in melanocytes, CPDs were generated for hours after UVA or UVB exposure. These "dark CPDs" constituted the majority of CPDs in cultured human and murine melanocytes and in mouse skin, and they were most prominent in skin containing pheomelanin, the melanin responsible for blonde and red hair. The mechanism was also a surprise. Dark cyclobutane pyrimidine dimers (CPDs) arise when ultraviolet (UV) induced superoxide and nitric oxide combine to form peroxynitrite, one of the few biological molecules capable of exciting an electron. This process, termed "chemiexcitation," is the source of bioluminescence in lower organisms. Excitation occurred in fragments of melanin, creating a quantum triplet state that had the energy of a UV photon but which induced CPDs by radiationless energy transfer to DNA. UVA and peroxynitrite also solubilized melanin and permeabilized the nuclear membrane, allowing melanin to enter. Melanin is evidently carcinogenic as well as protective. Chemiexcitation may also trigger pathogenesis in internal tissues because the same chemistry should arise wherever superoxide and nitric oxide arise near cells that contain melanin. PMID- 26951164 TI - Exploring the transition of undergraduate medical students into a clinical clerkship using organizational socialization theory. AB - BACKGROUND: Transitions in medical education are emotionally and socially dynamic; this may affect learning. Students transitioning from preclinical to clinical training may experience negative consequences. Less is understood about students' experiences during transitions within clinical training and influential factors. METHODS: The authors used organizational socialization theory to explore a transition within the clinical years. Final-year medical students experienced a nine-week internal medicine clerkship; willing students participated. Students (n = 101; 97 %) completed a questionnaire with open-ended questions at the beginning and end of the clerkship and participated in six consecutive focus groups, until data saturation occurred (n = 37). Data were thematically analyzed. RESULTS: Socialization was challenging. Many students experienced difficulty developing relationships with team members. Students with a positive attitude experienced a smoother transition. Many students were uncertain of their roles, concerned about the workload and desired guidance to meet clerkship demands. This transition resulted in varied outcomes from enjoyment, increased confidence and student development through to disinterest. CONCLUSION: Transitions within clinical training are complex. Faculty should focus on adequate socialization in a new clerkship as this may facilitate a smoother transition. This may necessitate orientations, staff training, and formal student support. Further research is needed on the impact of these recommendations on learning and well-being. PMID- 26951165 TI - Evaluation of marking of peer marking in oral presentation. AB - BACKGROUND: Peer marking is an important skill for students, helping them to understand the process of learning and assessment. This method is increasingly used in medical education, particularly in formative assessment. However, the use of peer marking in summative assessment is not widely adopted because many teachers are concerned about biased marking by students of their peers. OBJECTIVE: The aim of this study was to investigate whether marking of summative peer assessment can improve the reliability of peer marking. METHODS: In a retrospective analysis, the peer-marking results of a summative assessment of oral presentations of two cohorts of students were compared. One group of students was told that their peer marks would be assessed against a benchmark consisting of the average of examiner marks and that these scores together with the peer and examiner marks would form their final exam results. The other group of students were just informed that their final exam results would be determined based on the examiner and peer marks. RESULTS: Based on examiner marks, both groups of students performed similarly in their summative assessment, agreement between student markers was less consistent and more polar than the examiners. When compared with the examiners, students who were told that their peer marking would be scored were more generous markers (their average peer mark was 2.4 % points higher than the average examiner mark) while students who were not being scored on their marking were rather harsh markers (their average peer mark was 4.2 % points lower than the average examiner mark), with scoring of the top performing students most affected. CONCLUSIONS: Marking of peer marking had a small effect on the marking conduct of students in summative assessment of oral presentation but possibly indicated a more balanced marking performance. PMID- 26951166 TI - Intravenous heparin dosing strategy in hospitalized patients with atrial dysrhythmias. AB - Patients with non-valvular atrial fibrillation (AF) have an elevated stroke risk that is 2-7 times greater than in those without AF. Intravenous unfractionated heparin (UFH) is commonly used for hospitalized patients with atrial fibrillation and atrial flutter (AFL) to prevent stroke. Dosing strategies exist for intravenous anticoagulation in patients with acute coronary syndromes and venous thromboembolic diseases, but there are no data to guide providers on a dosing strategy for intravenous anticoagulation in patients with AF/AFL. 996 hospitalized patients with AF/AFL on UFH were evaluated. Bolus dosing and initial infusion rates of UFH were recorded along with rates of stroke, thromboemobolic events, and bleeding events as defined by the International Society on Thrombosis and Haemostasis criteria. Among 226 patients included in the analysis, 76 bleeding events occurred. Using linear regression analysis, initial rates of heparin infusion ranging from 9.7 to 11.8 units/kilogram/hour (U/kg/h) resulted in activated partial thromboplastin times that were within therapeutic range. The median initial infusion rate in patients with bleeding was 13.3 U/kg/h, while in those without bleeding it was 11.4 U/kg/h; p = 0.012. An initial infusion rate >11.0 U/kg/h yielded an OR 1.95 (1.06-3.59); p = 0.03 for any bleeding event. Using IV heparin boluses neither increased the probability of attaining a therapeutic aPTT (56.1 vs 56.3 %; p = 0.99) nor did it significantly increase bleeding events in the study (35.7 vs 31.3 %; p = 0.48). The results suggest that higher initial rates of heparin are associated with increased bleeding risk. From this dataset, initial heparin infusion rates of 9.7-11.0 U/kg/h without a bolus can result in therapeutic levels of anticoagulation in hospitalized patients with AF/AFL without increasing the risk of bleeding. PMID- 26951167 TI - Impact of diabetes on immature platelets fraction and its relationship with platelet reactivity in patients receiving dual antiplatelet therapy. AB - Contrasting data have been reported so far on the role of reticulated platelets in suboptimal response to antiplatelet therapies. In particular, still unexplored is whether they may contribute to explain the higher risk of thrombotic complications observed in diabetic patients. Aim of the present study was to evaluate the impact of diabetes on the levels of reticulated platelets and its relationship with high residual on-treatment platelet reactivity (HRPR) in patients receiving dual antiplatelet therapy. In patients treated with ASA (100 160 mg) and clopidogrel (75 mg daily) or ticagrelor (90 mg twice a day) platelet reactivity and the reticulated platelets fraction (immature platelets fraction, IPF) were assessed at 30-90 days post-discharge for an acute coronary syndrome or elective PCI. Aggregation was assessed by multiple-electrode aggregometry. We included 386 patients, 158 (40.9 %) diabetics. The percentage of IPF was similar in diabetic and non diabetic patients, both at baseline (3.5 +/- 2.5 vs 3.6 +/- 2.7 %, p = 0.91) and at 30-90 days re-assessment (3.3 +/- 2.1 vs 3.5 +/- 2.5 %, p = 0.30), with diabetes not emerging as an independent predictor of IPF above III tertile (adjusted OR [95 %CI] = 0.58 [0.30-1.09], p = 0.10). Diabetic patients displayed an enhanced platelet reactivity and a higher rate of HRPR with ADP antagonists (32.8 vs 22.5 %, p = 0.009). However, no association was found between the percentage of IPF and platelet function (r = -0.004; p = 0.95 for ASPI test, r = -0.04; p = 0.59 for ADP-mediated aggregation), or the rate of HRPR for ADP antagonsist across IPF tertiles. Results were similar for diabetics both receiving clopidogrel and ticagrelor. Diabetic patients display a higher platelet reactivity and suboptimal response to ADP-antagonists. However, the rate of reticulated platelets is neither influenced by diabetic status nor associated with an increased platelet reactivity among diabetic patients receiving dual antiplatelet therapy for a recent acute coronary syndrome or PCI. PMID- 26951168 TI - Normative values for the spine shape parameters using 3D standing analysis from a database of 268 asymptomatic Caucasian and Japanese subjects. AB - PURPOSE: Sagittal balance analysis has gained importance and the measure of the radiographic spinopelvic parameters is now a routine part of many interventions of spine surgery. Indeed, surgical correction of lumbar lordosis must be proportional to the pelvic incidence (PI). The compensatory mechanisms [pelvic retroversion with increased pelvic tilt (PT) and decreased thoracic kyphosis] spontaneously reverse after successful surgery. MATERIALS AND METHODS: This study is the first to provide 3D standing spinopelvic reference values from a large database of Caucasian (n = 137) and Japanese (n = 131) asymptomatic subjects. RESULTS: The key spinopelvic parameters [e.g., PI, PT, sacral slope (SS)] were comparable in Japanese and Caucasian populations. Three equations, namely lumbar lordosis based on PI, PT based on PI and SS based on PI, were calculated after linear regression modeling and were comparable in both populations: lumbar lordosis (L1-S1) = 0.54*PI + 27.6, PT = 0.44*PI - 11.4 and SS = 0.54*PI + 11.90. CONCLUSION: We showed that the key spinopelvic parameters obtained from a large database of healthy subjects were comparable for Causasian and Japanese populations. The normative values provided in this study and the equations obtained after linear regression modeling could help to estimate pre-operatively the lumbar lordosis restoration and could be also used as guidelines for spinopelvic sagittal balance. PMID- 26951169 TI - Cuff-leak test combined with interventional bronchoscopy benefits early extubation for patients who received tarp surgery. AB - PURPOSE: This study explored the performance characteristics of a cuff-leak test (CLT) combined with interventional fiberoptic bronchoscopy (FBS) for evaluating whether early nasoendotracheal extubation was possible for patients who had received transoral atlantoaxial reduction plate (TARP) internal fixation surgery. METHODS: 318 patients who underwent surgery were retrospectively analyzed (between January 2006 and December 2012). Extubation was performed by conventional approach (CA group, until December 2008) and improved approach (IA group, from January 2009) including CLT and an interventional FBS procedure. The extubation success within 1-3 days after surgery, incidence of postextubation stridor and tracheal reintubation were examined. RESULTS: More IA-treated patients experienced extubation during the first 2 days than those CA-treated, median extubation time was 3 (2, 3) days in the CA group and 2 (1, 2) days in the IA group (all P < 0.01). The incidence of stridor and reintubation was 5.69 and 0.57 % in IA and 11.98 and 4.93 % in CA, respectively (both P < 0.05). For the CLT-positive patients in the IA group that remained intubated until day 3-4, interventional FBS was applied for safe extubation and achieved 100 % success. CONCLUSION: Early extubation through IA is safe and interventional FBS assists successful extubation for CLT-positive patients who underwent TARP surgery. PMID- 26951170 TI - Reliability of the axial vertebral rotation measurements of adolescent idiopathic scoliosis using the center of lamina method on ultrasound images: in vitro and in vivo study. AB - PURPOSE: This study aimed to investigate the intra- and inter-observer reliability of the axial vertebral rotation (AVR) measurements of adolescent idiopathic scoliosis (AIS) using the center of lamina (COL) method on ultrasound transverse images. METHODS: Three cadaver vertebrae were scanned with 42 AVR configurations by both ultrasound and radiograph. In this in vitro study, four observers measured the AVR using the COL method on ultrasound transverse images and three observers measured the AVR using the Stokes' method on radiographs. In the in vivo study, 13 AIS subjects were recruited. Eighteen spinal curvatures were identified and 48 vertebrae were selected for the AVR measurements. Two observers performed the AVR measurements on both the ultrasound images and radiographs. All measurements were performed twice with 1 week interval apart to reduce memory bias. The intraclass correlation coefficient (ICC), mean absolute differences (MAD), and standard deviation (SD) were used to analyze the intra- and inter-observer reliability of the AVR measurements. The Bland-Altman plot was used to analyze the 95 % limit of the differences between the two methods. RESULTS: The proposed COL method had high intra- and inter-observer reliability on both the in vitro and in vivo studies (ICCs > 0.91, MADs < 1.4 degrees ) and agreed well with the experimental setup (ICCs > 0.96, MADs < 2.3 degrees ). The COL method showed good agreement with the Stokes' method for the in vitro study (ICC 0.84-0.85, MAD 4.5 degrees -5.0 degrees ), while poor agreement for the in vivo study (ICC 0.49-0.54, MAD 2.7 degrees -3.5 degrees ). CONCLUSIONS: The pilot study indicated the proposed COL method was a simple and reliable method to evaluate the AVR on ultrasound images. Standardization of the posture during ultrasound scan and taking radiograph is important. PMID- 26951172 TI - Low back pain and health-related quality of life in community-dwelling older adults. AB - PURPOSE: Investigation of self-reported of low back pain (LBP) over the last month and associated health-related quality of life (HRQoL) in a sample of a community-dwelling population aged >=65. METHODS: Cross-sectional study including older adults selected randomly from population records. Data were collected within a sample stratified by age and sex. Physical and psychological healths were investigated using a standardized definition of LBP and the EuroQoL-5D for HRQoL. Analyses were first conducted on the entire sample (N = 3042) and subsequently considering the subsample who reported LBP and a paired sample drawn from the pool of LBP-free respondents. RESULTS: 889 (29 %) respondents reported LBP within the past month, present 'most days' or 'every day' in 52 % and limiting activities in the same proportion. Average pain score was 4.6 (SD 2.2; 0 10 scale). Age was associated with pain frequency and duration, with younger groups more often reporting pain 'some days' and 'dating back <3 months'. Results of regression analyses showed that individuals suffering from LBP had significantly more problems than LBP non-sufferers on all EQ-5D subscales, except self-care: pain/discomfort (OR 5.33; 95 % CI [4.19-6.79]), mobility (OR 2.66; 95 % CI [2.04-3.46]), usual activities (OR 1.92; 95 % CI [1.42-2.60]), anxiety/depression (OR 1.59; 95 % CI [1.23-2.04]) and self-care (OR 1.29; 95 % CI [0.84-1.98]). CONCLUSION: LBP appears to be a more permanent condition in the older groups. LBP may be a part of the definition of a subgroup of elderly at risk of becoming frail in relation with higher levels of functional limitations, psychological difficulties and social restrictions, hence globally impaired HRQoL. PMID- 26951171 TI - Prognostic value of intraoperative MEP signal improvement during surgical treatment of cervical compressive myelopathy. AB - PURPOSE: The purpose of the current study was to evaluate the prognostic value of intraoperative improved transcranial motor evoked potential (MEP) after cervical cord decompressive surgery for cervical compressive myelopathy (CCM). METHOD: A consecutive series of 59 CCM patients who underwent cervical cord decompressive surgery were studied between December 2013 and April 2015 in this study. And all patients were divided into three subgroups: the patients with intraoperative improved MEP, without obvious MEP change and MEP degeneration. MEP and modified Japanese Orthopedic Association (mJOA) score were mainly utilized to assess intra , pre- and post-operative neurologic function; all patients had reliable and stable MEP baseline. The early neurologic outcomes and the long-term mJOA improvement rate were evaluated after surgery. RESULTS: There were 21 patients with intraoperative monitoring improvement (MEP improved rate, 140 +/- 76 %), 32 patients without obvious MEP change and six patients with MEP degeneration. The early motor or sensory outcome showed varying degrees of recovery in the MEP improvement group. The long-term mJOA improvement rate among the three groups was 59.5 +/- 4.2, 48.9 +/- 3.9 and 40.6 +/- 7.4 %, respectively, after 6-month follow up, and the improvement group was better than the other two groups with statistical significance (59.5 +/- 4.2 vs. 48.9 +/- 3.9 %, p < 0.05; 59.5 +/- 4.2 vs. 40.6 +/- 7.4, p < 0.05). CONCLUSION: Patients with intraoperative MEP improvement after cervical cord decompression have better prognosis in early and long-term neurologic recovery in CCM surgery. PMID- 26951173 TI - Intraoperative cell salvage in metastatic spine tumour surgery reduces potential for reinfusion of viable cancer cells. AB - PURPOSE: This study aimed at evaluating our hypothesis that tumour cells, which pass through the intraoperative cell salvage (IOCS) machine, lose viability due to possible injury to the cell membrane during centrifugation and filtration, enabling safe reinfusion even without filtration. METHODS: Thirteen patients who underwent metastatic spine tumour surgery (MSTS) at our institution were recruited. Blood samples (5 ml each) were collected at five different stages during surgery, namely, stage A and B: from patients' vein during induction and at the time of maximum tumour manipulation; stage C, D and E: from the operative blood prior to IOCS processing, after IOCS processing and after IOCS-LDF (leucocyte depletion filter) processing, respectively. The samples were then analysed for viability of tumour cells using microwell-based culture. RESULTS: The median age of the patients was 65 years (range 37-77 years). The most common primary tumour was lung, followed by breast, hepatocellular and renal cell carcinoma. The median blood loss was 680 ml (range 300-1500 ml). Analysis of cultured blood samples showed that CTC-containing clusters were developed from some samples before IOCS-LDF processing (stage A: three patients, stage B: three patients and stage C: one patient). None of the samples from stages D and E generated clusters after culture, suggesting the absence of viable cancer cells after IOCS processing. CONCLUSIONS: The salvaged blood may contain some tumour cells after processing with IOCS machine, but these cells are damaged and hence unable to replicate and unlikely to metastasise. The results of this study support the hypothesis that salvaged blood in MSTS is safe for transfusion. PMID- 26951174 TI - One-staged combined decompression for the patients with cervico-thoracic tandem spinal stenosis. AB - PURPOSE: To report the techniques and safety of one-staged combined decompression for the patients with tandem spinal stenosis (TSS) at cervical and thoracic spine. METHODS: Sixteen TSS subjects, who received combined decompression from Aug 2005 to Feb 2012, were reviewed. The essentials of our surgical strategy included: choosing patients with TSS from cervical to upper or middle thoracic spine, using one single posterior incision, simplifying surgical maneuvers and performing circumferential decompression for thoracic compression if it was indicated. The Japanese Orthopedic Association (JOA) scale for cervical myelopathy was employed to evaluate the neurological status, and Hirabayashi's system to assess neurological recovery rate. RESULTS: The average operation duration, blood loss and postoperative hospitalization were 242.8 +/- 89.9 min, 1581.3 +/- 1237.2 ml and 11.9 +/- 7.5 days, respectively. Six subjects (37.5 %) suffered instant neurological deterioration. Other complications included cerebrospinal fluid leakage (10 subjects, 62.5 %), new radiculopathy (two subjects), urinary infection, lung infection and pulmonary thromboembolism. Four subjects received extra-thoracic decompression due to the remaining anterior compression in one subject and new emerging compression in other three subjects. Eventually, mean JOA score was elevated from 9.8 +/- 2.1 to 13.7 +/- 2.7 after this procedure, and the neurological recovery of seven subjects was rated as excellent, four as good, two as fair, three as unchanged or deteriorated. The overall recovery rate was 53.7 %. CONCLUSION: Combined cervico-thoracic decompression could provide fair neurological outcomes for patients with cervico thoracic TSS, but it was complicated with high rate of undesirable postoperative events. So, more efforts should be done against its eventful postoperative course before its wide application. PMID- 26951175 TI - Determinants of patient satisfaction after surgery for central spinal stenosis without concomitant spondylolisthesis: a register study of 5100 patients. AB - PURPOSE: Satisfaction with the outcome of treatment is a widely used outcome measure but information about the determinants of patient satisfaction after surgery for central spinal stenosis (CSS) are lacking. The aim of the study was to analyze determinants of patient satisfaction 1 year after surgery for CSS without degenerative spondylolisthesis (DS). METHODS: This prospective register study included 5100 patients operated for CSS without DS. 88 % received decompression only (D) and 12 % had decompression and fusion (DF). The patient reported outcome measures were the EuroQol-5D, the Short-Form 36, the visual analogue scale for leg and back pain, the Oswestry disability index and the self estimated walking distance. Logistic regression reporting odds ratios (OR) for being satisfied was utilized. RESULTS: There were significant baseline differences between satisfied and dissatisfied patients in all patient reported outcome measures except leg pain. Factors decreasing the likelihood for satisfaction included previous spine surgery OR: 0.4 (95 % CI: 0.3-0.5), smoking OR: 0.6 (95 % CI: 0.4-0.8), unemployment OR: 0.6 (95 % CI: 0.4-0.9), back pain exceeding 1 year OR: 0.6 (95 % CI: 0.4-0.9), back pain predominance OR: 0.7 (95 % CI: 0.5-0.8). Fusion surgery did not predict satisfaction OR: 1.3 (95 % CI: 0.9 1.9). Preoperative self-estimated walking distance >1000 m predicted satisfaction, OR: 2.4 (95 %: 1.6-3.6). CONCLUSIONS: Numerous factors have predictive value for satisfaction of outcome after surgery for CSS without DS. The results from this study can constitute background data in the shared decision making process when discussing surgery with patients suffering from CSS. PMID- 26951177 TI - Letter to the editor: a meta-analysis of preoperative circulating and disseminated tumor cells are negative predictors of survival in patients undergoing hepatic resection of colorectal liver metastases. PMID- 26951176 TI - Is duration of preoperative anti-tuberculosis treatment a risk factor for postoperative relapse or non-healing of spinal tuberculosis? AB - PURPOSE: This study evaluated the relationship between spinal TB postoperative recurrence or non-healing and duration of preoperative anti-TB treatment (ATT). METHODS: From January 2004 to January 2013, patients who underwent surgery for spinal TB and met this study's inclusion criteria were retrospectively reviewed. Observed parameters were age, sex, initial ESR, preoperative ESR, degree of ESR change, initial CRP, preoperative CRP, degree of CRP change, duration of preoperative ATT, surgical approach, presence of internal fixation, location of spinal lesion, number of involved segments, duration of operation, and intraoperative blood loss. The data were analyzed by univariate and multivariate analyses for spinal TB recurrence or non-healing to determine related risk factors. RESULTS: A total of 223 patients met the inclusion criteria. There were 84 female and 139 male patients with a mean age of 42.2 years (range 2-85 years). The follow-up period was 18-72 months (average 28.7 months). Among 223 patients observed, 23 patients had postoperative relapse or non-healing (10.3 %) during the follow-up period. Statistical analysis indicated that the location of a spinal lesion was significantly associated with postoperative relapse or non healing. Risk of postoperative relapse or non-healing in thoracolumbar TB was 2.524-fold (95 % CI 1.026-6.580) that of lumbosacral TB. CONCLUSIONS: Duration of preoperative ATT may not be a risk factor for postoperative recurrence or non healing of spinal TB. Junctional zones such as the lumbosacral and thoracolumbar junction have a higher recurrence rate than non junctional. PMID- 26951178 TI - The relation between anastomotic dehiscence following colon cancer surgery and risk factors. PMID- 26951179 TI - Barium impaction after defecography: an unusual case with a patient' request to bowel resection. PMID- 26951180 TI - Crohn's disease-associated large and small bowel adenocarcinoma with peritoneal carcinomatosis: two case reports. PMID- 26951182 TI - High incidence of postoperative hemorrhage in colorectal endoscopic submucosal dissection during anticoagulant therapy. PMID- 26951181 TI - Alterations in the mucosa-associated bacterial composition in Crohn's disease: a pilot study. AB - INTRODUCTION: Changes in the intestinal bacterial composition seem to play a major role in the pathogenesis and in the clinical course of inflammatory bowel diseases (IBD), which consist of Crohn's disease (CD), and ulcerative colitis (UC). Mutations in the NOD2 gene are the most important genetic risk factors for the development of CD. In this study, the association between mucosal biopsies and the mucosa-associated bacterial composition from CD and UC patients regarding their genetic risk factors (mutations in the NOD2 gene), their endoscopic activity, and their medical therapy (TNF-alpha blocking therapy) was examined. MATERIAL AND METHODS: Seventy biopsies from routine colonoscopies from 33 IBD patients (26 CD and 7 UC) were obtained. Disease activity and clinical characteristics were assessed. Seven different bacterial strains (Bacteroides fragilis, Escherichia coli, Prevotella melaninogenica, Clostridium coccoides, Clostridium difficile, Bifidobacterium bifidum, and Faecalibacterium prausnitzii) were quantified using real-time PCR. NOD2 genotyping from patients with CD was performed. RESULTS: Five of the 24 patients were positive for at least one mutation in the NOD2 gene. The bacterial composition was different in CD compared to UC, in macroscopic healthy compared to macroscopic inflamed biopsies, in NOD2 mutated compared to NOD2 wildtype patients, and in patients receiving TNF-alpha blocking therapy compared to patients without this treatment. CONCLUSION: This study further characterizes the mucosa-associated bacteria in IBD patients. Different clinical situations lead to an altered mucosa-associated bacterial composition. The analyzed bacteria could be promising targets for cost-effective surveillance or therapies in IBD patients. PMID- 26951183 TI - Using CRP to predict anastomotic leakage after open and laparoscopic colorectal surgery: is there a difference? AB - AIM: C-reactive protein (CRP) has proven to be a useful adjunct in early diagnosis of anastomotic leak (AL) after colorectal surgery. It would be of considerable value to examine whether modality of surgery has influence upon postoperative CRP serum levels and their predictive value in the diagnosis of AL. METHODS: All patients undergoing elective colorectal surgery with anastomosis were enrolled into a prospective database between 2011 and 2014. AL was defined with strict operative and radiological criteria. Outcomes between open and laparoscopic resections were assessed statistically and Receiver Operating Characteristic (ROC) curve analysis performed. RESULTS: Seven hundred twenty seven patients with an intestinal anastomosis were identified including 468 laparoscopic procedures (468/727; 64 %). There were 58 anastomotic leaks (58/727; 7.9 %) of which 29 (6.2 %) were laparoscopic and 29 (11.2 %) were open. Mean CRP levels were significantly higher in patients after open surgery compared with laparoscopic both with AL (p = 0.013), and without (p = 0.02). ROC curve analysis revealed postoperative day 3 (cut-off CRP 209) and day 4 (cut-off CRP 123.5) to be most predictive of leak in the open group with an area under the curve (AUC) 0.794 (sensitivity 80 %, specificity 80 %) and AUC 0.806 (sensitivity 94 %, specificity 60 %), respectively. In the laparoscopic group, day 2 proved to be the most accurate day for detection of leak with a cut-off CRP of 146.5 showing 75 % sensitivity and a 70 % specificity (AUC 0.766). CONCLUSION: CRP levels are higher after open surgery compared with laparoscopic surgery, both with and without AL. AL generates a significant detectable increase in CRP within 2-4 days after surgery. PMID- 26951184 TI - Is preoperative physical activity related to post-surgery recovery?-a cohort study of colorectal cancer patients. AB - INTRODUCTION: An increasing interest is seen in the role of preoperative physical activity (PA) in enhancing postoperative recovery. The short-term effect of preoperative PA on recovery after colorectal cancer is unknown. The aim of this study was to evaluate the association of the preoperative level of PA with postoperative recovery after surgery due to colorectal cancer disease. METHODS: This is a prospective observational cohort study, with 115 patients scheduled to undergo elective colorectal surgery. The self-reported level of preoperative PA was compared to measures of recovery. RESULTS: Regular self-reported preoperative PA was associated with a higher chance of feeling highly physically recovered 3 weeks after surgery (relative chance 3.3, p = 0.038), compared to physical inactivity. No statistically significant associations were seen with length of hospital stay, self-assessed mental recovery, re-admittances or with re operations. DISCUSSION: In clinical practice, evaluating the patients' level of PA is feasible and may potentially be used as a prognostic tool for patients undergoing colorectal cancer surgery. Given the study design, the results from this study cannot prove causality. CONCLUSION: The present study found that the preoperative level of PA was associated with a faster self-assessed physical recovery after colorectal cancer surgery. PA did not show any associations with the primary outcome measure length of hospital stay or any of the other secondary outcome measures. Assessment of PA level preoperatively could be used for prognostic reasons. If systematic preoperative/postoperative physical training will enhance recovery, this remains to be studied in a randomized controlled study. HIGHLIGHTS: We examined preoperative physical activity and the recovery after colorectal cancer surgery. Physically active individuals had faster self assessed physical recovery. Assessment of preoperative physical activity may provide prognostic clinical information. PMID- 26951185 TI - Local excision of low rectal cancer treated by chemoradiotherapy: is it safe for all patients with suspicion of complete tumor response? AB - PURPOSE: The purpose of this study is to assess if local excision (LE) could be proposed if suspicion of complete tumor response (CR) after neoadjuvant chemoradiotherapy (CRT) for low rectal cancer (LRC) and this despite a potential risk of nodes (N+) or other tumor deposits (OTD) left in place. The aim was to assess in patients with LRC treated by CRT: (a) pathologic results of LE and total mesorectal excision (TME) in case of preoperative suspicion of CR and (b) the risk of N+ or OTD on TME if ypT0-Tis-T1 tumor. PATIENTS: Among 202 patients with LRC after CRT, 33 (16 %) with suspicion of CR underwent LE (n = 20) because of comorbidities and/or indication of definitive stoma or TME (n = 13). Pathologic examination of LE and TME specimens and oncological outcomes were assessed. Furthermore, 40/202 patients with pathologic CR on TME specimen (ypT0 Tis-T1) were assessed for possible N+ or OTD. RESULTS: In the 33 patients with suspicion of CR: (a) after LE, tumor was ypT0-Tis-T1 in only 15/20 cases (75 %); (b) after TME, tumor was ypT0-Tis-T1 in only 7/13 cases (54 %). Among 40 patients with ypT0-Tis-T1 tumor on TME specimen, 4 (10 %) presented N+ and/or OTD. CONCLUSION: In LRC with suspicion of CR after CRT, LE deserves a word of caution: 25 % of patients have in fact ypT2-T3 tumors. Furthermore, in patients with ypT0 Tis or T1 on TME specimen, a 10 % risk of N+ and/or ODT is observed. Thus, patient with suspicion of CR after CRT and treated by LE is exposed to a possible incomplete oncologic treatment. PMID- 26951186 TI - Nursing home-acquired pneumonia presenting at the emergency department. AB - Nursing home-acquired pneumonia (NHAP) is one of the most common infections arising amongst nursing home residents, and its incidence is expected to increase as population ages. The NHAP recommendation for empiric broad-spectrum antibiotic therapy, arising from the concept of healthcare-associated pneumonia, has been challenged by recent studies reporting low rates of multidrug-resistant (MDR) bacteria. This single center study analyzes the results of NHAP patients admitted through the Emergency Department (ED) at a tertiary center during the year 2010. There were 116 cases, male gender corresponded to 34.5 % of patients and median age was 84 years old (IQR 77-90). Comorbidities were present in 69.8 % of cases and 48.3 % of patients had used healthcare services during the previous 90 days. In-hospital mortality rate was 46.6 % and median length-of-stay was 9 days. Severity assessment at the Emergency Department provided CURB65 index score and respective mortality (%) results: zero: n = 0; one: n = 7 (0 %); two: n = 18 (38.9 %); three: n = 26 (38.5 %); four: n = 30 (53.3 %); and five; n = 22 (68.2 %); and sepsis n = 50 (34.0 %), severe sepsis n = 43 (48.8 %) and septic shock n = 22 (72.7 %). Significant risk factors for in-hospital mortality in multivariate analysis were polypnea (p = 0.001), age >= 75 years (p = 0.02), and severe sepsis or shock (p = 0.03) at the ED. Microbiological testing in 78.4 % of cases was positive in 15.4 % (n = 15): methicillin-resistant Staphylococcus aureus (26.7 %), Pseudomonas aeruginosa (20.0 %), S. pneumoniae (13.3 %), Escherichia coli (13.3 %), others (26.7 %); the rate of MDR bacteria was 53.3 %. This study reveals high rates of mortality and MDR bacteria among NHAP hospital admissions supporting the use of empirical broad-spectrum antibiotic therapy in these patients. PMID- 26951187 TI - Development and implementation of an asynchronous emergency medicine residency curriculum using a web-based platform. AB - The Residency Review Committee in Emergency Medicine requires residency programs to deliver at least 5 hours of weekly didactics. Achieving at least a 70 % average attendance rate per resident is required for residency program accreditation, and is used as a benchmark for residency graduation in our program. We developed a web-based, asynchronous curriculum to replace 1 hour of synchronous didactics, and hypothesized that the curriculum would be feasible to implement, well received by learners, and improve conference participation. This paper describes the feasibility and learner acceptability of a longitudinal asynchronous curriculum, and describes its impact on postgraduate year-1(PGY-1) resident conference participation and annual in-training examination scores. Using formal curriculum design methods, we developed modules and paired assessment exercises to replace 1 hour of weekly didactics. We measured feasibility (development and implementation time and costs) and learner acceptability (measured on an anonymous survey). We compared pre- and post intervention conference participation and in-service training examination scores using a two sample t test. The asynchronous curriculum proved feasible to develop and implement. PGY-1 resident conference participation improved compared to the pre-intervention year (85.6 vs. 62 %; 95 % CI 0.295-0.177; p < 0.001). We are unable to detect a difference between in-training examination results in either the PGY-1 group or across all residents by the introduction of this intervention. 18/31 (58 %) residents completed the post-intervention survey. 83 % reported satisfaction with curriculum changes. Strengths of the curriculum included clarity and timeliness of assignments. Weaknesses included technical difficulties with the online platform. Our curriculum is feasible to develop and implement. Despite technical difficulties, residents report high satisfaction with this new curriculum. Among PGY-1 residents there is improved conference participation compared to the prior year. PMID- 26951190 TI - From "Buzzword" to Best Practice: Applying Intersectionality to Children Exposed to Intimate Partner Violence. AB - Empirical studies on the impact of intimate partner violence (IPV) on children have burgeoned over the last three decades. Notably absent from existing approaches to studying children exposed to IPV, however, is attention to how various positionalities intersect to impact the experiences of children and their families. In fact, while the importance of an intersectional framework for understanding IPV has been discussed for over two decades, little or no attention has been given to issues of children's exposure to IPV. In this article, we examine the current state of the literature on children exposed to IPV through an exploratory meta-analysis, finding limited application of intersectionality and a focus on discrete categories of difference. We then demonstrate why and how an intersectional framework should be applied to children exposed to IPV, with specific strategies for research and policy. We suggest a child-centered approach that recognizes diversity among children exposed to IPV, extending the challenge to traditional "one-size-fits-all" models to include an intersectionality informed stance. PMID- 26951188 TI - Complete versus culprit-only revascularization in ST-elevation myocardial infarction and multivessel disease. AB - In 30-60 % of patients presenting with ST-segment elevation myocardial infarction (STEMI), significant stenoses are present in one or more non-infarct-related arteries (IRA). This correlates with an increased risk of major adverse cardiac events (MACE). Current guidelines, do not recommend revascularization of non culprit lesions unless complicated by cardiogenic shock or persistent ischemia after primary percutaneous coronary intervention (PCI). Prior observational and small randomized controlled trials (RCTs) have demonstrated conflicting results regarding the optimal revascularization strategy in STEMI patients with multivessel disease. Recently, randomized studies (PRAMI, CvLPRIT, and DANAMI 3 PRIMULTI) provide encouraging data that suggest potential benefit with complete revascularization in STEMI patients with obstructive non-culprit lesions. Differently, in the PRAGUE-13 trial there were no differences in MACE between complete revascularization and culprit-only PCI. Several meta-analyses were recently published including randomized and non-randomized clinical trials, showing different results depending on the included trials. In conclusion, the current available evidence from the randomized clinical trials, with a total sample size of only 2000 patients, is not robust enough to firmly recommend complete revascularization in STEMI patients. This uncertainty lends support to the continuation of the COMPLETE trial. This ongoing trial is anticipated to enroll 3900 patients with STEMI from across the world, and will be powered for the hard outcomes of death and myocardial infarction. Until the results of the COMPLETE trial are reported, physicians need to individualize care regarding the opportunity and the timing of the non-IRA PCI. PMID- 26951189 TI - Perioperative coagulation assessment of patients undergoing major elective orthopedic surgery. AB - Traditional coagulative parameters are of limited use in identifying perioperative coagulopathy occurring in patients undergoing major elective orthopedic surgery (MEOS). The aim of our study was to evaluate the coagulation changes in patients undergoing MEOS and to facilitate an early detection of perioperative coagulopathy in patients experiencing major intraoperative bleeding. We enrolled 40 consecutive patients (M/F 10/30, age range 34-90 years) who underwent MEOS at the Orthopedic Unit of the Padua University Hospital, Italy, between January 2014 and January 2015. Blood samples were obtained at the following time points: T0-pre: 30 min before surgery; T0-post: 30 min after the end of the procedure; T1: morning of the first postoperative day; T2: 7 +/- 2 days after surgery. Patients who experienced an intraoperative blood loss >=250 mL/h were considered as cases. Routine coagulative parameters, thromboelastometry and thrombin generation (TG) profiles were evaluated. At baseline, a significantly lower platelet count and FIBTEM MCF/AUC were observed in patents with excessive bleeding (p < 0.05 and 0.02/0.01, respectively). At T0-post and T1 intervals, cases showed hypocoagulation characterized by a significantly low platelet count (p = 0.001), prolonged CFT INTEM/EXTEM, reduction of alpha-angle and MaxV INTEM/EXTEM, MCF and AUC INTEM/EXTEM/FIBTEM (p < 0.05 in all comparisons). The only TG parameter standing out between study groups was time to peak at T0-pre. A low platelet count and fibrinogen activity were associated with significant intraoperative bleeding in patients undergoing MEOS. Thromboelastometry performed by ROTEM((r)) identifies patients with coagulopathy. PMID- 26951191 TI - Shortened leukocyte telomere length in type 2 diabetes mellitus: genetic polymorphisms in mitochondrial uncoupling proteins and telomeric pathways. AB - Current debate in type 2 diabetes (T2DM) has focused on shortened leukocyte telomere length (LTL) as the result of a number of possible causes, including polymorphisms in mitochondrial uncoupling proteins (UCPs) leading to oxidative stress, telomere regulatory pathway gene polymorphisms, or as a direct result of associated cardiovascular complications inducing tissue organ inflammation and oxidative stress. There is evidence that a heritable shorter telomere trait is a risk factor for development of T2DM. This review discusses the contribution and balance of genetic regulation of UCPs and telomere pathways in the context of T2DM. We discuss genotypes that are well known to influence the shortening of LTL, in particular OBFC1 and telomerase genotypes such as TERC. Interestingly, the interaction between short telomeres and T2DM risk appears to involve mitochondrial dysfunction as an intermediate process. A hypothesis is presented that genetic heterogeneity within UCPs may directly affect oxidative stress that feeds back to influence the fine balance of telomere regulation, cell cycle regulation and diabetes risk and/or metabolic disease progression. PMID- 26951192 TI - Biomarkers of early chronic obstructive pulmonary disease (COPD) in smokers and former smokers. Protocol of a longitudinal study. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is an irreversible disease, diagnosed predominantly in smokers. COPD is currently the third leading cause of death worldwide. Far more than 15 % of smokers get COPD: in fact, most develop some amount of pulmonary impairment. Smoking-related COPD is associated with both acute exacerbations and is closely correlated to comorbidities, such as cardiovascular disease and lung cancer. The objective of our study (KOL-Orestad) is to identify biomarkers in smokers and ex-smokers, with early signs of COPD, and compare these biomarkers with those of non-smokers and healthy smokers/ex smokers. The participants in the study are recruited from Orestadskliniken, a primary health care clinic in Malmo, Sweden. METHODS: Two hundred smokers and ex smokers diagnosed with COPD with airflow restriction according to GOLD stages 1-4 will be included and compared with 50 healthy never-smokers, and 50 healthy smokers/ex-smokers without airflow restriction (total n = 300). The age distribution is 35-80 years. The participants undergo a health examination including medical history, smoking history, lung function measurements, and respond to a "Quality of Life" questionnaire. Blood samples are drawn every 6 months during a period of 5 years. Additional blood sample collection is performed if participants are experiencing an exacerbation. The blood fractions will be analyzed by standard clinical chemistry assays and by proteomics utilizing mass spectrometry platforms. Optimal sample integrity is ensured by rapid handling with robotic biobank processing followed by storage at -80 degrees C. The study has been approved by the Regional Ethical Review Board in Lund ( http://epn.se/en ), (Approval number: DNR 2013/480), and registered at the NIH clinical trial registry ( http://clinicaltrials.gov ). RESULTS AND DISCUSSION: Currently, 220 subjects are enrolled in the study. CONCLUSIONS AND FUTURE DIRECTIONS: The study design will enable discovery of new biomarkers by using novel mass spectrometric techniques that define early changes of COPD. Such panels of novel biomarkers may be able to distinguish COPD from closely related diseases, co-morbidities, and contribute to an increased understanding of these diseases. Graphical abstract KOL-Orestad Study. PMID- 26951193 TI - Effect of BBX-B8 overexpression on development, body weight, silk protein synthesis and egg diapause of Bombyx mori. AB - Bombyxin (BBX) is an insulin-like peptide exists in the silkworm Bombyx mori. Our previous studies on the effects of inhibiting BBX-B8 expression found that BBX-B8 is important for the development of organ, reproduction and trehalose metabolism in the silkworms. In this paper, we investigated the expression profile of the BBX-B8 gene and effect of BBX-B8 overexpression on the development, body weight, silk protein synthesis and egg diapause of B. mori to further understand BBX-B8 functions. BBX-B8 gene expression could be detected in the brains, midguts, anterior silkglands, ovaries, testes, fat bodies, hemolymph, malpighian tubules and embryos by RT-PCR, however it was mainly expressed in the brain. Western blots showed that the change in BBX-B8 expression was not obvious in the brain of 1- to 4-day-old larvae of fifth instar silkworms, but expression increased substantially at 5- to 6-day-old larvae of fifth instar silkworms. Transgenic silkworms overexpressing BBX-B8 were obtained by introducing non-transposon transgenic vector pIZT-B8 containing a BBX-B8 gene driven by Orgyia pseudotsugata nucleopolyhedrovirus IE2 promoter into the genome. Development duration of the transgenic silkworms was delayed by 2.5-3.5 days. Cocoon shell weight of transgenic silkworms was reduced by 4.79 % in females and 7.44 % in males, pupal weight of transgenic silkworms was reduced 6.75 % in females and 13.83 % in males compared to non-transgenic silkworms, and 5.56-14.29 % of transgenic moths laid nondiapausing eggs. All results indicated that BBX-B8 plays an important role in the development, silk protein synthesis and egg diapause of silkworm. PMID- 26951194 TI - [Therapy of ANCA-associated vasculitis with severe renal manifestation under routine conditions]. AB - INTRODUCTION: In the MEPEX trial the poor prognosis of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis with severe renal manifestation (AAVr) could be significantly improved in the first year by plasmapheresis. How and to what extent is this knowledge of AAVr therapy implemented into routine practice and what effectiveness and adverse events resulted? METHODS: This was a retrospective cohort study in which all patients who received remission induction therapy for AAVr under routine clinical conditions (RCC) in this hospital from 2009 to 2014 after publication of the MEPEX trial (n = 22) were compared with those in the plasmapheresis arm of the MEPEX trial (n = 70). Endpoints were dialysis-dependent chronic kidney disease and mortality after 3 and 12 months and severe life-threatening adverse events during the first 12 months. RESULTS: All patients with AAVr were treated by plasmapheresis under RCC. The two groups showed no differences with respect to the rate of dialysis dependency (after 3 months RCC 14 % versus MEPEX 16 %, P = 1.00 and after 12 months RCC 23 % versus MEPEX 14 %, P = 0.55) or mortality (after 3 months RCC 18 % versus MEPEX 16 %, P = 0.75 and after 12 months RCC 18 % versus MEPEX 27 %, P = 0.57). The rate of severe life-threatening adverse events was similar under RCC and under controlled study conditions (64 % versus 69 %, P = 0.87). CONCLUSION: Under RCC there is a high quality of medical treatment for AAVr. All patients received plasmapheresis for remission induction with comparable effectiveness and safety compared to controlled study conditions. PMID- 26951195 TI - Perioperative circulating tumor cells in surgical patients with non-small cell lung cancer: does surgical manipulation dislodge cancer cells thus allowing them to pass into the peripheral blood? AB - PURPOSE: We herein evaluated the status of circulating tumor cells (CTC) dislodged from the tumor during surgery in patients who underwent pulmonary resection for non-small cell lung cancer (NSCLC) to assess the clinical implications. METHODS: Tumor cells in the peripheral arterial blood before surgery (Before) and immediately after lung resection (After) and in the blood from the pulmonary vein of the resected lung were detected using a size selective method. The clinicopathological characteristics and the prognosis were then analyzed according to the CTC status: no tumor cells detected (N), single tumor cell or total number less than 4 cells (S), and existence of clustered cells (C). RESULTS: According to the CTC status, the patients were classified into the following three groups: Before-C and After-C, Group I (n = 6); Before-S or N and After-C, Group II (n = 9); and Before-S or N and After-S or N, Group III (n = 8). Group III showed a high rate of p-stage IA, smaller tumor size, lower CEA level, lower SUVmax level, and a higher relapse-free survival rate than the other groups. CONCLUSIONS: CTCs were detected in patients after undergoing lung resection, some of which may have been dislodged by the surgical procedure. The presence of clustered CTCs after the operation indicated an unfavorable outcome. PMID- 26951196 TI - Duplication of the Yeast Spindle Pole Body Once per Cell Cycle. AB - The yeast spindle pole body (SPB) is the functional equivalent of the mammalian centrosome. Centrosomes and SPBs duplicate exactly once per cell cycle by mechanisms that use the mother structure as a platform for the assembly of the daughter. The conserved Sfi1 and centrin proteins are essential components of the SPB duplication process. Sfi1 is an elongated molecule that has, in its center, 20 to 23 binding sites for the Ca(2+)-binding protein centrin. In the yeastSaccharomyces cerevisiae, all Sfi1 N termini are in contact with the mother SPB whereas the free C termini are distal to it. During S phase and early mitosis, cyclin-dependent kinase 1 (Cdk1) phosphorylation of mainly serine residues in the Sfi1 C termini blocks the initiation of SPB duplication ("off" state). Upon anaphase onset, the phosphatase Cdc14 dephosphorylates Sfi1 ("on" state) to promote antiparallel and shifted incorporation of cytoplasmic Sfi1 molecules into the half-bridge layer, which thereby elongates into the bridge. The Sfi1 C termini of the two Sfi1 layers localize in the bridge center, whereas the N termini of the newly assembled Sfi1 molecules are distal to the mother SPB. These free Sfi1 N termini then assemble the new SPB in G1phase. Recruitment of Sfi1 molecules into the anaphase SPB and bridge formation were also observed inSchizosaccharomyces pombe, suggesting that the Sfi1 bridge cycle is conserved between the two organisms. Thus, restricting SPB duplication to one event per cell cycle requires only an oscillation between Cdk1 kinase and Cdc14 phosphatase activities. This clockwork regulates the "on"/"off" state of the Sfi1-centrin receiver. PMID- 26951197 TI - Hsp90 Maintains Proteostasis of the Galactose Utilization Pathway To Prevent Cell Lethality. AB - Hsp90 is a molecular chaperone that aids in the folding of its metastable client proteins. Past studies have shown that it can exert a strong impact on some cellular pathways by controlling key regulators. However, it is unknown whether several components of a single pathway are collectively regulated by Hsp90. Here, we observe that Hsp90 influences the protein abundance of multiple Gal proteins and the efficiency of galactose utilization even after the galactose utilization pathway (GAL pathway) is fully induced. The effect of Hsp90 on Gal proteins is not at the transcriptional level. Moreover, Gal1 is found to physically interact with Hsp90, and its stability is reduced in low-Hsp90 cells. When Hsp90 is compromised, several Gal proteins form protein aggregates that colocalize with the disaggregase Hsp104. These results suggest that Gal1 and other Gal proteins are probably the clients of Hsp90. An unbalanced GAL pathway has been known to cause fatal growth arrest due to accumulation of toxic galactose metabolic intermediates. It is likely that Hsp90 chaperones multiple Gal proteins to maintain proteostasis and prevent cell lethality especially in a fluctuating environment. PMID- 26951198 TI - Mechanism of Regulation of Intrachromatid Recombination and Long-Range Chromosome Interactions in Saccharomyces cerevisiae. AB - The NAD-dependent histone deacetylase Sir2 controls ribosomal DNA (rDNA) silencing by inhibiting recombination and RNA polymerase II-catalyzed transcription in the rDNA of Saccharomyces cerevisiae Sir2 is recruited to nontranscribed spacer 1 (NTS1) of the rDNA array by interaction between the RENT ( RE: gulation of N: ucleolar S: ilencing and T: elophase exit) complex and the replication terminator protein Fob1. The latter binds to its cognate sites, called replication termini (Ter) or replication fork barriers (RFB), that are located in each copy of NTS1. This work provides new mechanistic insights into the regulation of rDNA silencing and intrachromatid recombination by showing that Sir2 recruitment is stringently regulated by Fob1 phosphorylation at specific sites in its C-terminal domain (C-Fob1), which also regulates long-range Ter-Ter interactions. We show further that long-range Fob1-mediated Ter-Ter interactions in trans are downregulated by Sir2. These regulatory mechanisms control intrachromatid recombination and the replicative life span (RLS). PMID- 26951199 TI - The Inositol-3-Phosphate Synthase Biosynthetic Enzyme Has Distinct Catalytic and Metabolic Roles. AB - Inositol levels, maintained by the biosynthetic enzyme inositol-3-phosphate synthase (Ino1), are altered in a range of disorders, including bipolar disorder and Alzheimer's disease. To date, most inositol studies have focused on the molecular and cellular effects of inositol depletion without considering Ino1 levels. Here we employ a simple eukaryote, Dictyostelium discoideum, to demonstrate distinct effects of loss of Ino1 and inositol depletion. We show that loss of Ino1 results in an inositol auxotrophy that can be rescued only partially by exogenous inositol. Removal of inositol supplementation from the ino1(-) mutant resulted in a rapid 56% reduction in inositol levels, triggering the induction of autophagy, reduced cytokinesis, and substrate adhesion. Inositol depletion also caused a dramatic generalized decrease in phosphoinositide levels that was rescued by inositol supplementation. However, loss of Ino1 triggered broad metabolic changes consistent with the induction of a catabolic state that was not rescued by inositol supplementation. These data suggest a metabolic role for Ino1 that is independent of inositol biosynthesis. To characterize this role, an Ino1 binding partner containing SEL1L1 domains (Q54IX5) and having homology to mammalian macromolecular complex adaptor proteins was identified. Our findings therefore identify a new role for Ino1, independent of inositol biosynthesis, with broad effects on cell metabolism. PMID- 26951201 TI - In Vitro and In Vivo Interaction Studies Between Lesinurad, a Selective Urate Reabsorption Inhibitor, and Major Liver or Kidney Transporters. AB - BACKGROUND AND OBJECTIVES: Lesinurad is a selective uric acid reabsorption inhibitor (SURI) under investigation for the treatment of gout. This study elucidated the interaction of lesinurad with major liver and kidney transporters in vitro and evaluated the drug-drug interactions (DDIs) of lesinurad and atorvastatin, metformin, and furosemide in clinical studies. METHODS: Lesinurad interaction with membrane transporters was evaluated in validated transporter expressing cell systems and analyzed by liquid scintillation counting. Healthy male subjects (ages 18-65 years; body mass index 18-32 kg/m(2)) received atorvastatin (40 mg; n = 28) with or without lesinurad 200 or 400 mg, or received metformin (850 mg; n = 12) or furosemide (40 mg; n = 11) with or without lesinurad 400 mg. Plasma concentrations of each concomitant drug were determined by validated liquid chromatography with tandem mass spectrometry methods. RESULTS: Lesinurad interacted in vitro with OATP1B1, OCT1, and OAT1/3 transporters. Co-administration of lesinurad 200 mg did not significantly alter plasma exposure (maximum concentration [C max] and area under the concentration time curve [AUC]) of total atorvastatin (atorvastatin + hydroxyl-metabolites) or atorvastatin, while co-administration of lesinurad 400 mg increased the C max of total atorvastatin and atorvastatin by 17-26 %, but had no effect on AUC. Co administration of lesinurad 400 mg had no effect on the plasma exposure of metformin. Furosemide plasma AUC was reduced by 31 % in the presence of lesinurad 400 mg, but furosemide renal clearance and diuretic activity were unchanged. CONCLUSIONS: No clinically relevant DDIs were observed between lesinurad and substrates of major liver or kidney transporters. PMID- 26951200 TI - SUMOylation Regulates Growth Factor Independence 1 in Transcriptional Control and Hematopoiesis. AB - Cell fate specification requires precise coordination of transcription factors and their regulators to achieve fidelity and flexibility in lineage allocation. The transcriptional repressor growth factor independence 1 (GFI1) is comprised of conserved Snail/Slug/Gfi1 (SNAG) and zinc finger motifs separated by a linker region poorly conserved with GFI1B, its closest homolog. Moreover, GFI1 and GFI1B coordinate distinct developmental fates in hematopoiesis, suggesting that their functional differences may derive from structures within their linkers. We show a binding interface between the GFI1 linker and the SP-RING domain of PIAS3, an E3 SUMO (small ubiquitin-related modifier) ligase. The PIAS3 binding region in GFI1 contains a conserved type I SUMOylation consensus element, centered on lysine-239 (K239). In silico prediction algorithms identify K239 as the only high probability site for SUMO modification. We show that GFI1 is modified by SUMO at K239. SUMOylation-resistant derivatives of GFI1 fail to complement Gfi1 depletion phenotypes in zebrafish primitive erythropoiesis and granulocytic differentiation in cultured human cells. LSD1/CoREST recruitment and MYC repression by GFI1 are profoundly impaired for SUMOylation-resistant GFI1 derivatives, while enforced expression of MYC blocks granulocytic differentiation. These findings suggest that SUMOylation within the GFI1 linker favors LSD1/CoREST recruitment and MYC repression to govern hematopoietic differentiation. PMID- 26951202 TI - Pharmacokinetics of Rasagiline in Healthy Adult Chinese Volunteers with Various Genotypes: A Single-Center, Open-Label, Multiple-Dose Study. AB - BACKGROUND AND OBJECTIVE: Although there is evidence indicating cytochome P450 (CYP) 1A2 is responsible for the metabolism of rasagiline, the role of other CYP isoforms is unclear. This study investigated the pharmacokinetics of rasagiline in adult Chinese healthy volunteers with various CYP genotypes. METHODS: This single-center, open-label study was conducted in 12 subjects. Fasted subjects received rasagiline 1 mg daily for 7 days. Blood samples were taken to determine plasma concentrations of rasagiline, its major metabolite R-1-aminoindan (AI), and the genotyping of CYP2D6 and CYP2C19. Safety was also assessed. RESULTS: After oral administration, rasagiline was absorbed with a median time to reach maximum concentration (tmax) of 0.5 h. Overall systemic exposure was approximately theefold on day 7 versus day 1. The mean terminal elimination half life (t1/2) was nearly doubled on day 7 compared to day 1. AI was rapidly quantifiable in plasma with median t max occurring 1-1.5 h post-dose. Overall exposure to AI on day 7 was approximately twofold higher than on day 1. Overall systemic exposure to AI was approximately four- to sixfold greater than exposure to rasagiline, whereas maximum concentration (C max) was approximately half that of rasagiline. The mean t1/2 for AI was longer than for the parent drug, and was similar between the sexes and days. Inferred metabolic status did not appear to affect the pharmacokinetics of rasagiline or AI. All adverse events were mild to moderate in severity. CONCLUSION: Multiple oral administration of rasagiline 1 mg tablet in Chinese healthy adults resulted in similar pharmacokinetics of both rasagiline and AI compared to those previously observed in Caucasians. Rasagiline was safe and well tolerated in Chinese healthy volunteers. PMID- 26951203 TI - Safety Profile of Artemether-Lumefantrine: A Cohort Event Monitoring Study in Public Health Facilities in Tanzania. AB - BACKGROUND AND OBJECTIVE: Artemisinin combination therapies such as artemether lumefantrine (AL) are effective for first-line treatment of uncomplicated acute Plasmodium falciparum malaria. However, the safety profile of AL in large populations has not been fully assessed. The objective of this study was to establish the safety of AL in public health facilities in Tanzania using the Cohort Event Monitoring (CEM) method. METHODOLOGY: Patients who presented to public health facilities in four regions of Tanzania who were prescribed AL were enrolled in a CEM study, a prospective, observational cohort study to establish a profile of adverse events (AEs) for the medicine when used in routine clinical practice. Pre- and post-treatment forms were used to record baseline information and new health events before and 7 days after treatment. RESULTS: A total of 8040 patients were enrolled in the study, of whom 6147 were included in the analysis. Following treatment initiation, a total of 530 AEs were reported in 6% (383) of the patients. The most frequent post-treatment AEs were in alimentary system (42%), including vomiting, nausea, diarrhoea, abdominal pain and anorexia, followed by AEs in the neurological system (25%). Causality assessment of the events showed that 51.9% (275/530) were possibly related to AL. There was a significant difference in the frequency of AEs by age-group with an increase in the number of AEs as age increased (P < 0.001). There was no statistically significant difference in the frequency of the events between males and females (P = 0.504). The AE profile was consistent with the AEs reported in the product information and in other studies; no new adverse drug reactions were identified. The majority of the reported AEs were the same as the symptoms of malaria and therefore indistinguishable from the underlying disease. CONCLUSIONS: The safety profile of AL for treatment of malaria continues to be favourable. CEM as a pharmacovigilance tool has proven to provide reliable safety data in a short period. PMID- 26951204 TI - Lambing rate and prolificacy in inseminated hair sheep treated with bovine somatotropin. AB - This study evaluated whether the administration of 50 and 100 mg bovine somatotropin (bST) at the start of estrous synchronization and at the time of artificial insemination improves lambing rate and prolificacy in hair sheep. Four hundred eighty adult hair ewes (Pelibuey, Blackbelly, Dorper, Katahdin, and their crosses) were synchronized with intravaginal sponge containing 40 mg of fluorogestone acetate. On the day of sponge insertion, ewes were assigned to three treatments: the bST-100 treatment (n = 156) received 100 mg bST at the start of synchronization (d 0) and at the time of insemination (d 14), the bST-50 treatment (n = 159) received 50 mg bST in the same schedule as the previous group, and the control (n = 165) did not receive any bST. Lambing rate and percentage of multiple births were analyzed using the GENMOD procedure of SAS. Prolificacy data were analyzed using the MIXED procedure of SAS. The IGF-1 and insulin concentrations were analyzed with ANOVA for repeated measures. The bST application did not affect the lambing rate (P = 0.06). The proportion of ewes with multiple births (P = 0.01) and prolificacy (P = 0.04) were higher in the bST 50 (54.3% and 1.57 +/- 0.1) than the bST-100 (18.2% and 1.25 +/- 0.1) and control (33.3% and 1.28 +/- 0.1) groups. The IGF-1 and insulin concentrations were higher (P < 0.05) in the bST-treated groups, but the insulin concentration was higher (P = 0.001) in the bST-100 group than in the bST-50 group. The administration of 50 or 100 mg bST at the start of synchronization and at the time of artificial insemination does not increase lambing rate. However, the dose of 50 mg increased the proportion of multiple births and prolificacy. PMID- 26951207 TI - Structural correlates of the creatine transporter function regulation: the undiscovered country. AB - Creatine (Cr) and phosphocreatine constitute an energy shuttle that links ATP production in mitochondria to subcellular locations of ATP consumption. Cells in tissues that are reliant on this energy shuttle, such as myocytes and neurons, appear to have very limited ability to synthesize creatine. Therefore, these cells depend on Cr uptake across the cell membrane by a specialized creatine transporter (CrT solute carrier SLC6A8) in order to maintain intracellular creatine levels. Cr supplementation has been shown to have a beneficial effect in numerous in vitro and in vivo models, particularly in cases of oxidative stress, and is also widely used by athletes as a performance enhancement nutraceutical. Intracellular creatine content is maintained within narrow limits. However, the physiological and cellular mechanisms that mediate Cr transport during health and disease (such as cardiac failure) are not understood. In this narrative mini review, we summarize the last three decades of research on CrT structure, function and regulation. PMID- 26951205 TI - Impact of phenolic-rich olive leaf extract on blood pressure, plasma lipids and inflammatory markers: a randomised controlled trial. AB - PURPOSE: Dietary polyphenols have been demonstrated to favourably modify a number of cardiovascular risk markers such as blood pressure (BP), endothelial function and plasma lipids. We conducted a randomised, double-blind, controlled, crossover trial to investigate the effects of a phenolic-rich olive leaf extract (OLE) on BP and a number of associated vascular and metabolic measures. METHODS: A total of 60 pre-hypertensive [systolic blood pressure (SBP): 121-140 mmHg; diastolic blood pressure (DBP): 81-90 mmHg] males [mean age 45 (+/-SD 12.7 years, BMI 26.7 (+/-3.21) kg/m2] consumed either OLE (136 mg oleuropein; 6 mg hydroxytyrosol) or a polyphenol-free control daily for 6 weeks before switching to the alternate arm after a 4-week washout. RESULTS: Daytime [-3.95 (+/-SD 11.48) mmHg, p = 0.027] and 24-h SBP [-3.33 (+/-SD 10.81) mmHg, p = 0.045] and daytime and 24-h DBP [ 3.00 (+/-SD 8.54) mmHg, p = 0.025; -2.42 (+/-SD 7.61) mmHg, p = 0.039] were all significantly lower following OLE intake, relative to the control. Reductions in plasma total cholesterol [-0.32 (+/-SD 0.70) mmol/L, p = 0.002], LDL cholesterol [-0.19 (+/-SD 0.56) mmol/L, p = 0.017] and triglycerides [-0.18 (+/-SD 0.48), p = 0.008] were also induced by OLE compared to control, whilst a reduction in interleukin-8 [-0.63 (+/-SD 1.13) pg/ml; p = 0.026] was also detected. Other markers of inflammation, vascular function and glucose metabolism were not affected. CONCLUSION: Our data support previous research, suggesting that OLE intake engenders hypotensive and lipid-lowering effects in vivo. PMID- 26951206 TI - Obesity and Metabolic Syndrome Among Adult Survivors of Childhood Leukemia. AB - Treatment-related obesity and the metabolic syndrome in adult survivors of childhood acute lymphoblastic leukemia (ALL) are risk factors for cardiovascular disease. Both conditions often begin during therapy. Preventive measures, including dietary counseling and tailored exercise, should be initiated early in the course of survivorship, with referral to specialists to optimize success. However, among adults who develop obesity or the metabolic syndrome and who do not respond to lifestyle therapy, medical intervention may be indicated to manage underlying pathology, such as growth hormone deficiency, or to mitigate risk factors of cardiovascular disease. Because no specific clinical trials have been done in this population to treat metabolic syndrome or its components, clinicians who follow adult survivors of childhood ALL should use the existing American Heart Association/National Heart Lung and Blood Institute Scientific Statement to guide their approach. PMID- 26951208 TI - Population Pharmacokinetics of Edoxaban in Patients with Non-Valvular Atrial Fibrillation in the ENGAGE AF-TIMI 48 Study, a Phase III Clinical Trial. AB - INTRODUCTION: Edoxaban is a novel factor Xa inhibitor. This study characterizes the population pharmacokinetics of edoxaban in patients with non-valvular atrial fibrillation (NVAF) included in the phase III ENGAGE AF-TIMI 48 study, evaluates covariates for the dose-exposure relationship in this population, and assesses the impact of protocol-specified dose reductions on exposure using simulations. METHODS: Model development was performed using NONMEM((r)) and based on sparse data from the ENGAGE AF-TIMI 48 study augmented with dense data from 13 phase I studies to inform and stabilize the model. The influence of body weight (WT), creatinine clearance (CLCR), concomitant P-glycoprotein (P-gp) inhibitors, age, sex, race, and NVAF on pharmacokinetic parameters was evaluated based on statistical significance and clinical relevance. RESULTS: A two-compartment model with first-order elimination and first-order absorption after an absorption lag time best described the data. Apparent volume and clearance terms increased with increasing WT. Apparent renal clearance increased with increasing CLCR. Apparent non-renal, renal, and inter-compartmental clearance terms differed between phase I volunteers and NVAF patients. Asian patients were found to have increased apparent central volume of distribution, bioavailability, and total apparent clearance. Concomitant P-gp inhibitors increased the bioavailability statistically significantly, but this did not reach clinical relevance. CONCLUSION: Edoxaban disposition and the variability in this disposition, including influence of covariates, after oral administration were adequately characterized in patients with NVAF. The 50 % dose reduction in patients with low WT (<=60 kg), moderate renal impairment (CLCR <=50 mL/min), or concomitant P-gp inhibitors led to 30 % lower exposure than in the other patients. PMID- 26951209 TI - Cohort profile: the Spanish WORKing life Social Security (WORKss) cohort study. AB - PURPOSE: The global economy is changing the labour market and social protection systems in Europe. The effect of both changes on health needs to be monitored in view of an ageing population and the resulting increase in prevalence of chronic health conditions. The Spanish WORKing life Social Security (WORKss) cohort study provides unique longitudinal data to study the impact of labour trajectories and employment conditions on health, in terms of sickness absence, permanent disability and death. PARTICIPANTS: The WORKss cohort originated from the Continuous Working Life Sample (CWLS) generated by the General Directorate for the Organization of the Social Security in Spain. The CWLS contains a 4% representative sample of all individuals in contact with the Social Security system. The WORKss cohort exclusively includes individuals with a labour trajectory from 1981 or later. In 2004, the cohort was initiated with 1,022 ,79 Social Security members: 840,770 (82.2%) contributors and 182,009 (17.8%) beneficiaries aged 16 and older. FINDINGS TO DATE: The WORKss cohort includes demographic characteristics, chronological data about employment history, retirement, permanent disability and death. These data make possible the measurement of incidence of permanent disability, the number of potential years of working life lost, and the number of contracts and inactive periods with the Social Security system. The WORKss cohort was linked to temporary sickness absence registries to study medical diagnoses that lead to permanent disability and consequently to an earlier exit from the labour market in unhealthy conditions. FUTURE PLANS: Thanks to its administrative source, the WORKss cohort study will continue follow-up in the coming years, keeping the representativeness of the Spanish population affiliated to the Social Security system. The linkage between the WORKss cohort and temporary sickness absence registries is envisioned to continue. Future plans include the linkage of the cohort with mortality registries. PMID- 26951210 TI - Gender-informed, psychoeducational programme for couples to prevent postnatal common mental disorders among primiparous women: cluster randomised controlled trial. AB - OBJECTIVES: Interventions to prevent postpartum common mental disorders (PCMD) among unselected populations of women have had limited success. The aim was to determine whether What Were We Thinking (WWWT) a gender-informed, psychoeducational programme for couples and babies can prevent PCMD among primiparous women 6 months postpartum. DESIGN: Cluster-randomised controlled trial. SETTING: 48 Maternal and Child Health Centres (MCHCs) from 6 Local Government Areas in Melbourne, Australia were allocated randomly to usual care (24) or usual care plus WWWT (24). PARTICIPANTS: English-speaking primiparous women receiving primary care at trial MCHCs were recruited to the intervention (204) and control (196) conditions. Of these, 187 (91.7%) and 177 (90.3%) provided complete data. INTERVENTION: WWWT is a manualised programme comprising primary care from a trained nurse, print materials and a face-to-face seminar. MAIN OUTCOME MEASURES: Data sources were standardised and study-specific measures collected in blinded computer-assisted telephone interviews at 6 and 26 weeks postpartum. The primary outcome was PCMD assessed by Composite International Diagnostic Interviews and Patient Health Questionnaire (PHQ) Depression and Generalised Anxiety Disorder modules. RESULTS: In intention-to-treat analyses the adjusted OR (AOR) of PCMD in the intervention compared to the usual care group was 0.78 (95% CI 0.38 to 1.63, ns), but mild to moderate anxiety symptoms (AOR 0.58, 95% CI 0.35 to 0.97) and poor self-rated health (AOR 0.46, 95% CI 0.22 to 0.97) were significantly lower. In a per protocol analysis, comparing the full (three component) intervention and usual care groups, the AOR of PCMD was 0.36, (95% CI 0.14 to 0.95). The WWWT seminar was appraised as salient, comprehensible and useful by >85% participants. No harms were detected. CONCLUSIONS: WWWT is readily integrated into primary care, enables inclusion of fathers and addresses modifiable risks for PCMD directly. The full intervention appears a promising programme for preventing PCMD, optimising family functioning, and as the first component of a stepped approach to mental healthcare. TRIAL REGISTRATION NUMBER: ACTRN12613000506796; Results. PMID- 26951212 TI - Post-traumatic stress disorder and occupational characteristics of police officers in Republic of Korea: a cross-sectional study. AB - OBJECTIVE: South Korean police officers have a greater workload compared to their counterparts in advanced countries. However, few studies have evaluated the occupational challenges that South Korean police officers face. Therefore, this study aimed to evaluate the police officer's job characteristics and risk of post traumatic stress disorder (PTSD) among South Korean police officers. DESIGN: Cross-sectional study. SETTING: Police officers in South Korea. PARTICIPANTS: 3817 police officers with a traumatic event over a 1-year period. MAIN OUTCOME MEASURES: Officers with a response to the Impact of Event Scale (revised Korean version) score of >= 26 were classified as high risk, and we evaluated their age, sex, department and rank, as well as the frequency and type of traumatic events that they experienced. RESULTS: Among the respondents, 41.11% were classified as having a high risk of PTSD. From the perspective of the rank, Inspector group (46.0%) and Assistant Inspector group (42.7%) show the highest frequencies of PTSD. From the perspective of their working division, Intelligence and National Security Division (43.6%) show the highest frequency, followed by the Police Precinct (43.5%) and the Traffic Affairs Management Department (43.3%). It is shown that working in different departments was associated with the prevalence of PTSD (p=0.004). CONCLUSIONS: The high-risk classification was observed in 41.11% of all officers who had experienced traumatic events, and this frequency is greater than that for other specialised occupations (eg, firefighters). Therefore, we conclude that groups with an elevated proportion of high-risk respondents should be a priority for PTSD treatment, which may help increase its therapeutic effect and improve the awareness of PTSD among South Korean police officers. PMID- 26951213 TI - ECEL1 mutation implicates impaired axonal arborization of motor nerves in the pathogenesis of distal arthrogryposis. AB - The membrane-bound metalloprotease endothelin-converting enzyme-like 1 (ECEL1) has been newly identified as a causal gene of a specific type of distal arthrogryposis (DA). In contrast to most causal genes of DA, ECEL1 is predominantly expressed in neuronal cells, suggesting a unique neurogenic pathogenesis in a subset of DA patients with ECEL1 mutation. The present study analyzed developmental motor innervation and neuromuscular junction formation in limbs of the rodent homologue damage-induced neuronal endopeptidase (DINE) deficient mouse. Whole-mount immunostaining was performed in DINE-deficient limbs expressing motoneuron-specific GFP to visualize motor innervation throughout the limb. Although DINE-deficient motor nerves displayed normal trajectory patterns from the spinal cord to skeletal muscles, they indicated impaired axonal arborization in skeletal muscles in the forelimbs and hindlimbs. Systematic examination of motor innervation in over 10 different hindlimb muscles provided evidence that DINE gene disruption leads to insufficient arborization of motor nerves after arriving at the skeletal muscle. Interestingly, the axonal arborization defect in foot muscles appeared more severe than in other hindlimb muscles, which was partially consistent with the proximal-distal phenotypic discordance observed in DA patients. Additionally, the number of innervated neuromuscular junction was significantly reduced in the severely affected DINE deficient muscle. Furthermore, we generated a DINE knock-in (KI) mouse model with a pathogenic mutation, which was recently identified in DA patients. Axonal arborization defects were clearly detected in motor nerves of the DINE KI limb, which was identical to the DINE-deficient limb. Given that the encoded sequences, as well as ECEL1 and DINE expression profiles, are highly conserved between mouse and human, abnormal arborization of motor axons and subsequent failure of NMJ formation could be a primary cause of DA with ECEL1 mutation. PMID- 26951211 TI - Cross-sectional study examining whether the extent of first-contact access to primary care differentially benefits those with certain personalities to receive preventive services. AB - OBJECTIVE: The extent of first-contact access to primary care (ie, easy availability when needed) is associated with receiving recommended preventive services. Whether this access benefits patients at risk of preventive services underutilisation, such as those with certain personality characteristics, is unclear. SETTING: Secondary analysis of the 2003-2006 round of the Wisconsin Longitudinal Study. PARTICIPANTS: 6975 respondents who reported a usual provider whose specialty was internal medicine or family medicine. Those reporting not visiting a medical provider in the past 12 months, and those who were uninsured were excluded. PRIMARY OUTCOME MEASURES: Receiving mammography, cholesterol testing and influenza vaccination. Adjusted predicted probabilities (aPP) of receiving these services were analysed stratified by personality characteristics overall, and if significant, then interacted with first-contact access. RESULTS: Lower conscientiousness as compared with higher conscientiousness predicted less of all 3 preventive services; mammography (aPP 80%; 95% CI (77% to 83%) vs aPP 85%; (95% CI 82% to 87%)), cholesterol testing (88%; (85% to 90%) vs 93% (91% to 94%), and influenza vaccination (62%; (59% to 64%) vs 66%; (63% to 68%)). Lower agreeableness as compared with higher agreeableness predicted less mammography (77%; (73% to 81%) vs 84%; (82% to 87%)) and less influenza vaccination (59%; (56% to 62%) vs 65%; (63% to 68%)). Lower extraversion predicted less cholesterol testing (88%; (86% to 91%) vs (92%; (90% to 94%)). Lower openness to experience predicted less influenza vaccination (59%; (56% to 63%) vs (68%; (65% to 70%)). For agreeableness, these differences in receiving preventive services did not persist when first-contact access to primary care was present. CONCLUSIONS: Certain personality characteristics predicted receiving less preventive care services. For those with less agreeableness, improved first-contact access to primary care mitigated this effect. If these results are replicated in other studies, primary care offices seeking to improve population health through receiving preventive services should prioritise increasing their first-contact accessibility. PMID- 26951215 TI - Erratum to: Preservice teacher knowledge of basic language constructs in Canada, England, New Zealand, and the USA. PMID- 26951214 TI - Good eggs? Evaluating consent forms for egg donation. AB - Beyond gaps in the provision of information, the informed consent process for egg donation is complicated by conflicts of interest, payment and a lack of longitudinal data about physiological and psychological risks. Recent scholarship has suggested that egg donation programmes could improve the informed consent process by revising consent documents. At a minimum, these documents should include information about eight key criteria: the nature and objectives of treatment; the benefits, risks and inconveniences of egg donation; the privacy of donors and their anonymity (where applicable); disclosure that participation is voluntary (withdrawal); the availability of counselling; financial considerations; the possibility of an unsuccessful cycle and potential uses of the eggs retrieved. This study evaluates the incorporation of these minimum criteria in consent forms for egg donation, obtained through requests to Canadian fertility clinics. Even when clinics were considered to have met criteria simply by mentioning them, among the eight consent forms assessed, none met the minimum standards. Only half of clinics addressed privacy/anonymity concerns, financial issues and the possibility of a future cycle. Improving the quality of consent documentation to meet the minimum standards established by this study may not be an onerous task. For some, this will include re-evaluating how they include one or two elements of disclosure, and for others, this will require a substantial overhaul. Using the criteria provided by this study as the minimum standard for consent could ensure that donors have the basic information they need to make informed decisions. PMID- 26951217 TI - Coping strategies predict post-traumatic stress in patients with head and neck cancer. AB - Evidence suggests that patients with head and neck cancer (HNC) are susceptible to post-traumatic stress disorder (PTSD). However, research is yet to examine predictors of PTSD symptoms in this patient group. The objective of this study was to investigate whether coping strategies at HNC diagnosis were related to outcomes of post-traumatic stress and health-related quality of life (HRQL) 6 months later. Sixty-five patients with HNC completed an assessment of coping, distress, and health-related quality of life at diagnosis and again 6 months later, and an assessment of post-traumatic stress at 6 months. Correlations and regression analyses were performed to examine relationships between coping and outcomes over time. Regression analyses showed that denial, behavioural disengagement and self-blame at diagnosis predicted post-traumatic stress symptoms. Self-blame at diagnosis also predicted poor HRQL. Results have implications for the development of psychological interventions that provide alternative coping strategies to potentially reduce PTSD symptoms and improve HRQL. PMID- 26951216 TI - Cortisol response to the Trier Social Stress Test in pregnant women at risk for postpartum depression. AB - Antepartum depression and anxiety are risk factors for postpartum depression (PPD). Postpartum abnormalities in hypothalamic-pituitary-adrenal (HPA) reactivity are associated with PPD. It is not known if antepartum HPA abnormalities exist in women at risk for PPD (AR-PPD). We measured salivary cortisol response to the Trier Social Stress Test (TSST) in 44 (24 AR-PPD, 20 healthy comparison) pregnant women. Depression and anxiety were measured using the Edinburgh Postnatal Depression Scale (EPDS) and Spielberger State-Trait Anxiety Inventory-State (STAI-S). We analyzed longitudinal changes in cortisol using generalized estimating equation methods to control for the correlation within subjects at the six TSST time points. Group differences in area under the curve (AUC) were examined. A majority (70.8 %) of the AR-PPD had prior depression. EPDS total score was higher in AR-PPD vs. comparison women (mean EPDS = 9.8 +/- 4.9 vs. mean EPDS = 2.4 +/- 2.0 respectively, p < 0.001). Mean STAI-S total score was higher in AR-PPD vs. comparison women at all TSST time points and over time (z = 2.71, df = 1, p = 0.007). There was no significant difference in cortisol concentration over time between groups. We observed no detectable difference in cortisol response to psychosocial stress induced by the TSST despite clinically significant between-group differences in current/past depression and current symptomatology. PMID- 26951218 TI - Reconstruction of the denuded nasoseptal flap donor site with a free fascia lata graft: technical note. AB - The nasoseptal flap provides hearty vascularized tissue for the reconstruction of skull base defects subsequent to expanded endonasal approaches; however, it leads to exposure of the cartilage at the septal donor site producing crusting and discomfort while it remucosalizes. We report an alternative technique to reconstruct the denuded nasal septal donor site by means of a free fascia lata graft. Fascia lata grafting of the nasoseptal flap donor site showed evidence of revascularization 4 weeks after initial surgery. Re-epithelialization was complete 4-12 weeks postoperation. Although the nasoseptal flap provides a versatile reconstructive technique, its harvest results in significant donor site morbidity. A free fascia lata graft accelerates the rate of donor site remucosalization; thus, decreasing the nasal complications. PMID- 26951219 TI - Tracheoesophageal fistula length decreases over time. AB - The objectives of this study were to demonstrate that the length of the tracheoesophageal voice prosthesis changes over time and to determine whether the prosthesis length over time increased, decreased, or showed no predictable change in size. A retrospective chart review was performed at a tertiary care referral center. Patients who underwent either primary or secondary tracheoesophageal puncture between January 2006 and August 2014 were evaluated. Patients were excluded if the tracheoesophageal prosthesis size was not consistently recorded or if they required re-puncturing for an extruded prosthesis. Data analyzed included patient demographics and the length of the tracheoesophageal voice prosthesis at each change. A total of 37 patients were identified. The mean age was 64 years. Seventy-six percent were male. 24 % underwent primary tracheoesophageal puncture and 76 % underwent secondary tracheoesophageal puncture. The length of the prosthesis decreased over time (median Kendall correlation coefficient = -0.60; mean = -0.44) and this correlation between length and time was significant (p = 0.00085). Therefore, in conclusion, tracheoesophageal prosthesis length is not constant over time. The tracheoesophageal wall thins, necessitating placement of shorter prostheses over time. Patients with a tracheoesophageal voice prosthesis will require long-term follow-up and repeat sizing of their prosthesis. Successful tracheoesophageal voicing will require periodic reevaluation of these devices, and insurers must, therefore, understand that long-term professional care will be required to manage these patients and their prostheses. PMID- 26951222 TI - Pharmaceuticals in the environment. PMID- 26951220 TI - Combined biocidal action of silver nanoparticles and ions against Chlorococcales (Scenedesmus quadricauda, Chlorella vulgaris) and filamentous algae (Klebsormidium sp.). AB - Despite the extensive research, the mechanism of the antimicrobial and biocidal performance of silver nanoparticles has not been unequivocally elucidated yet. Our study was aimed at the investigation of the ability of silver nanoparticles to suppress the growth of three types of algae colonizing the wetted surfaces or submerged objects and the mechanism of their action. Silver nanoparticles exhibited a substantial toxicity towards Chlorococcales Scenedesmus quadricauda, Chlorella vulgaris, and filamentous algae Klebsormidium sp., which correlated with their particle size. The particles had very good stability against agglomeration even in the presence of multivalent cations. The concentration of silver ions in equilibrium with nanoparticles markedly depended on the particle size, achieving about 6 % and as low as about 0.1 % or even less for the particles 5 nm in size and for larger ones (40-70 nm), respectively. Even very limited proportion of small particles together with larger ones could substantially increase concentration of Ag ions in solution. The highest toxicity was found for the 5-nm-sized particles, being the smallest ones in this study. Their toxicity was even higher than that of silver ions at the same silver concentration. When compared as a function of the Ag(+) concentration in equilibrium with 5-nm particles, the toxicity of ions was at least 17 times higher than that obtained by dissolving silver nitrite (if not taking into account the effect of nanoparticles themselves). The mechanism of the toxicity of silver nanoparticles was found complex with an important role played by the adsorption of silver nanoparticles and the ions released from the particles on the cell surface. This mechanism could be described as some sort of synergy between nanoparticles and ions. While our study clearly showed the presence of this synergy, its detailed explanation is experimentally highly demanding, requiring a close cooperation between materials scientists, physical chemists, and biologists. PMID- 26951223 TI - Pivotal role of the aryl hydrocarbon receptor in modulations caused by benzo[a]pyrene and ketoconazole in the estrogenic responses induced by 17beta estradiol in male goldfish. PMID- 26951221 TI - Earthworms, pesticides and sustainable agriculture: a review. AB - The aim of this review is to generate awareness and understand the importance of earthworms in sustainable agriculture and effect of pesticides on their action. The natural resources are finite and highly prone to degradation by the misuse of land and mismanagement of soil. The world is in utter need of a healthy ecosystem that provides with fertile soil, clean water, food and other natural resources. Anthropogenic activities have led to an increased contamination of land. The intensification of industrial and agricultural practices chiefly the utilization of pesticides has in almost every way made our natural resources concave. Earthworms help in a number of tasks that support many ecosystem services that favor agrosystem sustainability but are degraded by exhaustive practices such as the use of pesticides. The present review assesses the response of earthworm toward the pesticides and also evaluates the relationship between earthworm activity and plant growth. We strictly need to refresh and rethink on the policies and norms devised by us on sustainable ecology. In an equivalent way, the natural resources should be utilized and further, essential ways for betterment of present and future livelihood should be sought. PMID- 26951224 TI - Characterization of cadmium biosorption by Exiguobacterium sp. isolated from farmland soil near Cu-Pb-Zn mine. AB - Bacteria have the ability to bind heavy metals on their cell wall. Biosorption is a passive and energy-independent mechanism to adsorb heavy metals. The efficiency of heavy metal biosorption can vary depending on several factors such as the growth phase of bacteria, solution pH, and existence of competitive heavy metals. In this study, Exiguobacterium sp. isolated from farmland soil near a mine site were used, and optimal conditions for Cd biosorption in solution were investigated. As bacterial growth progressed, Cd biosorption increased, which is attributed to changes in the structure and composition of the cell wall during bacterial growth. The biosorption process was rapid and was completed within 30 min. Cadmium biosorption was highest at pH 7 due to the dissociation of hydrogen ions and the increase of negative charges with increasing pH. In the mixed metal solution of Cd, Pb, and Zn, the amount of biosorption was in the order of Pb>Cd>Zn while in a single metal solution, the order was Cd>=Pb>Zn. The maximum adsorption capacity for Cd by the isolated bacteria was 15.6 mg/g biomass, which was calculated from the Langmuir isotherm model. Different adsorption efficiencies under various environmental conditions indicate that, to control metal mobility, the conditions for biosorption should be optimized before applying bacteria. The results showed that the isolated bacteria can be used to immobilize metals in metal-contaminated wastewater. PMID- 26951225 TI - Multi-objective models of waste load allocation toward a sustainable reuse of drainage water in irrigation. AB - The present study proposes a waste load allocation (WLA) framework for a sustainable quality management of agricultural drainage water (ADW). Two multi objective models, namely, abatement-performance and abatement-equity-performance, were developed through the integration of a water quality model (QAUL2Kw) and a genetic algorithm, by considering (1) the total waste load abatement, and (2) the inequity among waste dischargers. For successfully accomplishing modeling tasks, we developed a comprehensive overall performance measure (E wla ) reflecting possible violations of Egyptian standards for ADW reuse in irrigation. This methodology was applied to the Gharbia drain in the Nile Delta, Egypt, during both summer and winter seasons of 2012. Abatement-performance modeling results for a target of E wla = 100 % corresponded to the abatement ratio of the dischargers ranging from 20.7 to 75.6 % and 29.5 to 78.5 % in summer and in winter, respectively, alongside highly shifting inequity values. Abatement-equity performance modeling results for a target of E wla = 90 % unraveled the necessity of increasing treatment efforts in three out of five dischargers during summer, and four out of five in winter. The trade-off curves obtained from WLA models proved their reliability in selecting appropriate WLA procedures as a function of budget constraints, principles of social equity, and desired overall performance level. Hence, the proposed framework of methodologies is of great importance to decision makers working toward a sustainable reuse of the ADW in irrigation. PMID- 26951226 TI - Effect of SiO2 nanoparticles on the removal of natural organic matter (NOM) by coagulation. AB - In order to evaluate effect of engineered nanoparticles on the removal of natural organic matter (NOM), ENPs water sample (WATERNP), and common water sample (WATERCOMMON) were prepared by mixing the SiO2 nanoparticles (SiO2 NPs, 50 nm) and common SiO2 particles (2 MUm) with water from Xiaoqing River. The removal variation, NOM fractionation, flocs properties, and IR spectra were investigated after polyaluminum chloride (PAC) coagulation. The results revealed that although the removal efficiencies of turbidity and NOM from WATERNP were moderately lower than those from WATERCOMMON, the fluorescence intensities of soluble microbial byproduct-like, humic acid-like, and aromatic protein II in coagulated WATERNP were lower than that in coagulated raw water and WATERCOMMON. What's more, flocs of WATERNP showed the smallest size and highest fractal dimension as compared with other water samples, except for those obtained at B = 2.0. PMID- 26951228 TI - Development of a Novel c-MET-Based CTC Detection Platform. AB - Amplification of the MET oncogene is associated with poor prognosis, metastatic dissemination, and drug resistance in many malignancies. We developed a method to capture and characterize circulating tumor cells (CTC) expressing c-MET using a ferromagnetic antibody. Immunofluorescence was used to characterize cells for c MET, DAPI, and pan-CK, excluding CD45(+) leukocytes. The assay was validated using appropriate cell line controls spiked into peripheral blood collected from healthy volunteers (HV). In addition, peripheral blood was analyzed from patients with metastatic gastric, pancreatic, colorectal, bladder, renal, or prostate cancers. CTCs captured by c-MET were enumerated, and DNA FISH for MET amplification was performed. The approach was highly sensitive (80%) for MET amplified cells, sensitive (40%-80%) for c-MET-overexpressed cells, and specific (100%) for both c-MET-negative cells and in 20 HVs. Of 52 patients with metastatic carcinomas tested, c-MET CTCs were captured in replicate samples from 3 patients [gastric, colorectal, and renal cell carcinoma (RCC)] with 6% prevalence. CTC FISH demonstrated that MET amplification in both gastric and colorectal cancer patients and trisomy 7 with gain of MET gene copies in the RCC patient. The c-MET CTC assay is a rapid, noninvasive, sensitive, and specific method for detecting MET-amplified tumor cells. CTCs with MET amplification can be detected in patients with gastric, colorectal, and renal cancers. IMPLICATIONS: This study developed a novel c-MET CTC assay for detecting c-MET CTCs in patients with MET amplification and warrants further investigation to determine its clinical applicability. Mol Cancer Res; 14(6); 539-47. (c)2016 AACR. PMID- 26951227 TI - Mutant Calreticulin Requires Both Its Mutant C-terminus and the Thrombopoietin Receptor for Oncogenic Transformation. AB - Somatic mutations in calreticulin (CALR) are present in approximately 40% of patients with myeloproliferative neoplasms (MPN), but the mechanism by which mutant CALR is oncogenic remains unclear. Here, we demonstrate that expression of mutant CALR alone is sufficient to engender MPN in mice and recapitulates the disease phenotype of patients with CALR-mutant MPN. We further show that the thrombopoietin receptor MPL is required for mutant CALR-driven transformation through JAK-STAT pathway activation, thus rendering mutant CALR-transformed hematopoietic cells sensitive to JAK2 inhibition. Finally, we demonstrate that the oncogenicity of mutant CALR is dependent on the positive electrostatic charge of the C-terminus of the mutant protein, which is necessary for physical interaction between mutant CALR and MPL. Together, our findings elucidate a novel paradigm of cancer pathogenesis and reveal how CALR mutations induce MPN. SIGNIFICANCE: The mechanism by which CALR mutations induce MPN remains unknown. In this report, we show that the positive charge of the CALR mutant C-terminus is necessary to transform hematopoietic cells by enabling binding between mutant CALR and the thrombopoietin receptor MPL. PMID- 26951230 TI - Gastrointestinal Disorders Associated with Common Variable Immune Deficiency (CVID) and Chronic Granulomatous Disease (CGD). AB - Common variable immune deficiency (CVID) and chronic granulomatous disease (CGD) are two of the well-characterized primary immune deficiencies with distinct pathologic defects. While CVID is predominantly a disorder of the adaptive immune system, in CGD, innate immunity is impaired. In both syndromes, the clinical manifestations include an increased susceptibility to infections and a number of non-infectious, inflammatory conditions including systemic autoimmunity, as well as organ-specific pathology. Among the organ-associated disorders, gastrointestinal (GI) manifestations are one of the most intractable. As such, non-infectious inflammatory disorders of the GI tract are clinically challenging as they have protean manifestations, often resembling inflammatory bowel disease (IBD) or celiac disease, are notoriously difficult to treat, and hence are associated with significant morbidity and mortality. Therefore, assessing the pathogenesis and defining appropriate therapeutic approaches for GI disease in patients with CVID and CGD is imperative. PMID- 26951229 TI - Small Bowel Congenital Anomalies: a Review and Update. AB - The small intestine is a complex organ system that is vital to the life of the individual. There are a number of congenital anomalies that occur and present most commonly in infancy; however, some may not present until adulthood. Most congenital anomalies of the small intestine will present with obstructive symptoms while some may present with vomiting, abdominal pain, and/or gastrointestinal bleeding. Various radiologic procedures can aid in the diagnosis of these lesions that vary depending on the particular anomaly. Definitive therapy for these congenial anomalies is surgical, and in some cases, surgery needs to be performed urgently. The overall prognosis of congenital anomalies of the small intestine is very good and has improved with improved medical management and the advent of newer surgical modalities. The congenital anomalies of the small intestine reviewed in this article include malrotation, Meckel's diverticulum, duodenal web, duodenal atresia, jejunoileal atresia, and duplications. PMID- 26951231 TI - Vitamin D Status and Supplementation in the Critically Ill. AB - Vitamin D deficiency has recently been recognized as a widespread global disorder. Generally considered a direct extension of malnutrition, even subclinical hypovitaminosis D is now recognized in adequately nourished populations. Compared to the general population, the prevalence of hypovitaminosis D is greater in the critically ill population. In fact, several studies have shown poorer outcomes in critically ill patients discovered to be vitamin D deficient or insufficient. Controversy persists regarding vitamin D measurements, quantity of supplementation, and appropriate target level in various populations. Vitamin D has a vital role in calcium homeostasis and extra skeletal health, such as immune function. Therefore, vitamin D supplementation may have a role for improving outcomes in critically ill patients. In this review, we will first discuss the metabolism and function of vitamin D under normal physiologic conditions. We will then explore the prevalence and prognostic value of vitamin D deficiency in critical illness. Finally, we will examine recent trials focusing on appropriate dosing, route of administration, and outcomes associated with vitamin D supplementation in the ICU. PMID- 26951232 TI - Increased generation of intracellular reactive oxygen species initiates selective cytotoxicity against the MCF-7 cell line resultant from redox active combination therapy using copper-thiosemicarbazone complexes. AB - The combination of cytotoxic copper-thiosemicarbazone complexes with phenoxazines results in an up to 50-fold enhancement in the cytotoxic potential of the thiosemicarbazone against the MCF-7 human breast adenocarcinoma cell line over the effect attributable to drug additivity-allowing minimization of the more toxic copper-thiosemicarbazone component of the therapy. The combination of a benzophenoxazine with all classes of copper complex examined in this study proved more effective than combinations of the copper complexes with related isoelectronic azines. The combination approach results in rapid elevation of intracellular reactive oxygen levels followed by apoptotic cell death. Normal fibroblasts representative of non-cancerous cells (MRC-5) did not display a similar elevation of reactive oxygen levels when exposed to similar drug levels. The minimization of the copper-thiosemicarbazone component of the therapy results in an enhanced safety profile against normal fibroblasts. PMID- 26951233 TI - Good Signal Detection Practices: Evidence from IMI PROTECT. AB - Over a period of 5 years, the Innovative Medicines Initiative PROTECT (Pharmacoepidemiological Research on Outcomes of Therapeutics by a European ConsorTium) project has addressed key research questions relevant to the science of safety signal detection. The results of studies conducted into quantitative signal detection in spontaneous reporting, clinical trial and electronic health records databases are summarised and 39 recommendations have been formulated, many based on comparative analyses across a range of databases (e.g. regulatory, pharmaceutical company). The recommendations point to pragmatic steps that those working in the pharmacovigilance community can take to improve signal detection practices, whether in a national or international agency or in a pharmaceutical company setting. PROTECT has also pointed to areas of potentially fruitful future research and some areas where further effort is likely to yield less. PMID- 26951236 TI - Perceived Barriers to and Facilitators of Engagement in Reverse Integrated Care. PMID- 26951235 TI - Bronchoscopic Re-biopsy for Mutational Analysis of Non-small Cell Lung Cancer. AB - OBJECTIVES: Currently, several acquired resistance mechanisms and rare driver oncogenes are identified in non-small cell lung cancer (NSCLC) relapses. Re biopsy increases valuable information to guide treatment strategies, but the utility and feasibility of bronchoscopic re-biopsy has not been investigated. METHODS: We studied 70 patients who underwent bronchoscopic for re-biopsy of NSCLC that was resistant to at least one regimen of chemotherapy or molecular targeted therapy between January 2013 and December 2014. We assessed clinical data, technical success rate, and mutational analysis. RESULTS: Procedures performed were transbronchial biopsy (n = 52) and endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) (n = 18). Overall detection rate of re-biopsy for malignant cells was 87 % (83 % for TBB and 100 % for EBUS-TBNA). Mutational analysis was possible in almost all technically successful cases; likewise, acquired-resistant mutations (55 % of EGFR mutants) and small cell lung cancer transformation were identified from the bronchoscopy specimens. Other driver mutations were seen in four cases, including ALK fusion gene (n = 2) and ROS1 fusion gene (n = 2). There were no associated severe complications. CONCLUSION: This study shows that bronchoscopic re-biopsy for NSCLC is feasible and provides adequate samples that enable identification of resistance mutations and rare driver oncogenes. PMID- 26951234 TI - Intravitreal Bevacizumab and Cardiovascular Risk in Patients with Age-Related Macular Degeneration: Systematic Review and Meta-Analysis of Randomized Controlled Trials and Observational Studies. AB - INTRODUCTION: Intravitreal bevacizumab (IVTB) is used to treat age-related macular degeneration (ARMD), although its use is off-label and its cardiovascular safety has not been unequivocally established. OBJECTIVES: Our objective was to assess the cardiovascular safety of IVTB in patients with ARMD. METHODS: We conducted a systematic review and meta-analysis of published randomized controlled trials (RCTs) and observational studies. RESULTS: Of the 2028 non duplicate records, five RCTs versus ranibizumab (N = 3038, 12/24 months), four RCTs comparing different regimens (N = 809, 12/23 months), one RCT versus pegaptanib, photodynamic therapy (PDT), or sham (N = 131, 12 months), and three observational studies versus PDT, ranibizumab, or pegaptanib (~150,000 or 1666 patients/12 months and 317 patients/1-2 years, respectively) had a low risk of bias/high quality and >=20 patients per arm with >=6 months and >=3 injections of treatment. RCT-based comparisons with PDT or pegaptanib are negligible. Observational data have not demonstrated differences [all-cause mortality, myocardial infarction (MI), stroke], but the level of evidence is "very low" (imprecise, indirect). RCT-based comparisons with ranibizumab did not demonstrate differences regarding some outcomes, although certain point estimates were at the level of a relevant harm/benefit [all-cause mortality odds ratio (OR) 1.103, 95 % confidence interval (CI) 0.641-1.898; vascular mortality OR 1.380, 95 % CI 0.476 3.997; MI OR 0.551, 95 % CI 0.265-1.146; stroke OR 0.657, 95 % CI 0.260-1.660; transitory ischemic attack OR 1.536, 95 % CI 0.444-5.313; atherothrombotic events (ATEs) OR 1.007, 95 % CI 0.641-1.593; venous thromboembolism OR 2.325, 95 % CI 0.963-5.612] or suggested a higher risk with bevacizumab (hypertension OR 7.512, 95 % CI 1.056-52.3), but estimates were based on sparse data, were extremely imprecise, and commonly exhibited considerable heterogeneity/inconsistency. The level of evidence per outcome was "low" or "very low". Observational data did not demonstrate difference (all-cause mortality, MI, stroke), or suggested a higher risk with bevacizumab (ATE), but were imprecise and indirect (level of evidence "very low"). RCT-based comparisons of different IVTB regimens suffered from the same limitations. CONCLUSION: Published data on IVTB in AMRD provide only a low level of evidence on its cardiovascular safety and do not support any finite conclusions. PMID- 26951237 TI - Evolving Strategies for the Treatment of Chronic Lymphocytic Leukemia in the Upfront Setting. AB - Chronic lymphocytic leukemia (CLL) is a disease of marked clinical heterogeneity, and while some patients have a normal life expectancy, others develop rapidly progressive disease shortly after diagnosis. The current standard for upfront treatment of CLL is chemoimmunotherapy for younger fit patients, FCR (fludarabine, cyclophosphamide, and rituximab) being the prototype. For older patients, BR (bendamustine and rituximab) exhibits excellent activity with decreased toxicity. For the frailest patients, CD20 monoclonal antibodies with or without chlorambucil have proven to be efficacious. The novel oral kinase inhibitors ibrutinib and idelalisib are FDA-approved in the relapsed/refractory setting, and ibrutinib is approved upfront for those with del(17p). These drugs have produced long-term durable responses in the relapsed/refractory setting, and studies are underway using these as single agent upfront or in combination with both chemotherapy and monoclonal antibodies. Here, we review standard upfront therapies and new agents and combinations that are on the horizon for CLL. PMID- 26951238 TI - Activation of multiple angiogenic signaling pathways in hemangiopericytoma. AB - Hemangiopericytoma (HPC) is a highly vascularized mesenchymal tumor. Local recurrence and distant metastasis are common features of HPC. Considering the remarkable hyper-vasculature phenotype of HPC, we assumed that dysregulated angiogenic signaling pathways were involved in HPC. The key components of angiogenic signaling pathways including VEGF-VEGF-R2, EphrinB2-EphB4 and DLL4 Notch were examined by real-time RT-PCR, Western blotting and immunostaining in 17 surgical specimens of HPC patients and in 6 controls. A significant upregulation of VEGF and VEGF-R2 associated with elevated levels of p-Akt and proliferating cell nuclear antigen (PCNA) was detected in HPC. Moreover, a dramatic increase in the mRNA and protein expression of EphB4 and its downstream factor p-Erk1/2 was found in HPC. A massive activation of core-components of DLL4 Notch signaling was detected in HPC. Double-immunofluorescent staining confirmed the expression of these upregulated key factors in the endothelial cells of tumor vessels. The present study identified the activation of multiple and crucial angiogenic signaling pathways, which could function individually and/or synergistically to stimulate angiogenesis in HPC and eventually contribute to tumor growth and progression. Our findings emphasize the importance to target multiple angiogenic signaling pathways when an anti-angiogenic therapy is considered for this highly vascularized tumor. PMID- 26951239 TI - Pediatric Oncology: Managing Pain at the End of Life. AB - Pain is a common and highly distressing symptom in pediatric patients with advanced malignancies. Prompt recognition, assessment, and treatment of pain are necessary, especially at the end of life. Opioid medications remain the mainstay of treatment of malignant pain in children at the end of life and the amount of opioids required for adequate pain control in patients is highly variable. Nonpharmacological approaches including behavioral and physical approaches in addition to non-opioid pain medications should be used when possible to augment pain control. Identification and treatment of any underlying pathology is important and use of adjuvant medications based on pathophysiology and source of pain should be considered. In cases where adequate pain control is not achieved through these multiple modalities, an interdisciplinary approach including potential interventional techniques and alternative treatments is required. This multimodal approach to pain management is best provided by interdisciplinary teams, as these teams can best address the complex causes of pain and associated distress that occurs in patients and within families. PMID- 26951242 TI - The Influence of Neighborhood Crime on Increases in Physical Activity during a Pilot Physical Activity Intervention in Children. AB - The purpose of this study was to examine whether neighborhood crime moderated the response (increases in steps) to a pilot intervention to increase physical activity in children. Twenty-seven insufficiently active children aged 6-10 years (mean age = 8.7 years; 56 % female; 59 % African American) were randomly assigned to an intensive intervention group (IIG) or minimal intervention group (MIG). Change in average daily number of steps from baseline was regressed against an index of neighborhood crime in a multilevel repeated-measures model that included a propensity score to reduce confounding. Safer neighborhoods were associated with higher increases in steps during the pilot intervention (interaction p = 0.008). Children in the IIG living in low-crime neighborhoods significantly increased their physical activity (5275 +/- 1040 steps/day) while those living in high-crime neighborhoods did not (1118 +/- 1007) (p for difference = 0.046). In the IIG, the increase in daily steps was highly correlated with neighborhood crime (r = 0.58, p = 0.04). These findings suggest the need for physical activity interventions to account for participants' environments in their design and/or delivery. To promote healthy behaviors in less-supportive environments, future studies should seek to understand how environments modify intervention response and to identify mediators of the relationship between environment and intervention. PMID- 26951240 TI - Pharmacological Closure of Patent Ductus Arteriosus: Selecting the Agent and Route of Administration. AB - Opinions are divided regarding the management of a persistently patent ductus arteriosus (PDA). Some of the adverse effects associated with a large hemodynamically significant duct, including prolonged ventilation, pulmonary hemorrhage, bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC), intraventricular hemorrhage (IVH), and mortality, indicate that active management of infants with large ductal shunts may sometimes be necessary. Indomethacin and ibuprofen are the two US FDA-approved cyclooxygenase (COX) inhibitors used for the closure of a ductus in preterm babies. Both these drugs are effective in 70 80% of extremely low birthweight infants. Treatment with COX inhibitors may be associated with renal impairment, gastrointestinal hemorrhage, NEC, and spontaneous intestinal perforation when given concurrently with steroids, as well as changes in cerebrovascular auto-regulation. Ibuprofen appears to be a better choice for PDA closure, with a better side effect profile and efficacy that equals that of indomethacin. However, long-term outcome studies of ibuprofen are lacking, and prophylactic ibuprofen is ineffective in decreasing severe IVH. The choice of one drug over the other also depends on local availability of both drugs and the intravenous or enteral preparation. The oral preparation of ibuprofen appears as effective as the intravenous preparation. The use of paracetamol to close a hemodynamically significant PDA has increased in recent years. Paracetamol also decreases prostacyclin synthesis; however, unlike COX inhibitors, it does not have a peripheral vaso-constrictive effect and can be given to infants with contraindications to non-steroidal anti-inflammatory drugs. It appears to have similar efficacy based on limited data available from randomized trials. Until more data are available on efficacy, safety, and long term outcomes, it cannot be recommended as the first choice. PMID- 26951243 TI - Postmortem muscle protein degradation in humans as a tool for PMI delimitation. AB - Forensic estimation of time since death relies on diverse approaches, including measurement and comparison of environmental and body core temperature and analysis of insect colonization on a dead body. However, most of the applied methods have practical limitations or provide insufficient results under certain circumstances. Thus, new methods that can easily be implemented into forensic routine work are required to deliver more and discrete information about the postmortem interval (PMI). Following a previous work on skeletal muscle degradation in the porcine model, we analyzed human postmortem skeletal muscle samples of 40 forensic cases by Western blotting and casein zymography. Our results demonstrate predictable protein degradation processes in human muscle that are distinctly associated with temperature and the PMI. We provide information on promising degradation markers for certain periods of time postmortem, which can be useful tools for time since death delimitation. In addition, we discuss external influencing factors such as age, body mass index, sex, and cause of death that need to be considered in future routine application of the method in humans. PMID- 26951244 TI - Loop Diuretics in the Treatment of Hypertension. AB - Loop diuretics are not recommended in current hypertension guidelines largely due to the lack of outcome data. Nevertheless, they have been shown to lower blood pressure and to offer potential advantages over thiazide-type diuretics. Torsemide offers advantages of longer duration of action and once daily dosing (vs. furosemide and bumetanide) and more reliable bioavailability (vs. furosemide). Studies show that the previously employed high doses of thiazide type diuretics lower BP more than furosemide. Loop diuretics appear to have a preferable side effect profile (less hyponatremia, hypokalemia, and possibly less glucose intolerance). Studies comparing efficacy and side effect profiles of loop diuretics with the lower, currently widely prescribed, thiazide doses are needed. Research is needed to fill gaps in knowledge and common misconceptions about loop diuretic use in hypertension and to determine their rightful place in the antihypertensive arsenal. PMID- 26951245 TI - Preterm Birth and Hypertension: Is There a Link? AB - Factors in perinatal life have recently been recognized as determinants of later life health and diseases, especially hypertension. The detection of higher values of blood pressure in preterm-born individuals reaching adulthood has turned the attention to preterm birth-related complications and deleterious conditions as factors triggering early cardiovascular alterations, which may increase hypertension risk and associated complications in this population. Further, preterm birth is frequently associated with pregnancy complications such as lower placental perfusion, increased blood pressure in the mother and preeclampsia, often resulting in intrauterine growth restriction. These conditions further impact the risk of hypertension in the offspring whether through inherited genetic factors or perpetuated pathophysiology leading to preeclampsia, preterm delivery, and chronic hypertension. In this review, we will highlight evidence of developmental cardiovascular alterations and potential mechanisms linking preterm birth to the risk of hypertension and cardiovascular diseases into adulthood. PMID- 26951246 TI - Role of the Collecting Duct Renin Angiotensin System in Regulation of Blood Pressure and Renal Function. AB - Recent evidence suggests that the renal tubular renin angiotensin system regulates urinary Na(+) and water excretion and blood pressure. Three key components of the tubular renin angiotensin system, namely renin, prorenin receptor, and angiotensin-II type 1 receptor, are localized to the collecting duct. This system may modulate collecting duct Na(+) and water reabsorption via angiotensin-II-dependent and angiotensin-II-independent pathways. Further, the system may be of greatest relevance in hypertensive states and particularly those characterized by high circulating angiotensin-II. In this review, we summarize the current knowledge on the synthesis, regulation, and function of collecting duct-derived renin angiotensin system components and examine recent developments with regard to regulation of blood pressure and renal fluid and Na(+) excretion. PMID- 26951247 TI - Laparoscopic repair of complex ventral hernia facilitated by pre-operative chemical component relaxation using Botulinum Toxin A. AB - PURPOSE: The operative management of complex ventral hernia poses a formidable challenge, despite recent advances in surgical techniques. Recurrence rates after complex ventral hernia repair remain high, and increase with each failed attempt. This study examines the effect of pre-operative abdominal wall chemical component relaxation using Botulinum Toxin A (BTA) to induce temporary flaccid paralysis in order to facilitate laparoscopic repair of large complex ventral hernia. METHODS: This is a prospective evaluation of 27 patients from January 2013 to August 2015 who underwent ultrasound guided BTA injections to the lateral abdominal wall muscles prior to elective complex ventral hernia repair. Non-contrast serial CT imaging was obtained pre- and post-BTA injection to measure change in fascial defect size and abdominal wall muscle thickness and length. Fascial defects were closed and hernias repaired using laparoscopic or laparoscopic-assisted intra peritoneal onlay mesh (IPOM) techniques. RESULTS: 27 patients received pre operative BTA injections which were well tolerated with no complications. Comparison of pre-BTA and post-BTA CT imaging demonstrated a significant increase in mean length of the lateral abdominal wall from 15.7 cm pre-BTA to 19.9 cm post BTA (p < 0.0001), with mean unstretched length gain of 4.2 cm/side (range 0-11.7 cm/side). All hernias were surgically reduced and repaired with mesh, with no early recurrences. CONCLUSION: Pre-operative administration of BTA is a safe and effective technique in the pre-operative preparation of patients undergoing elective complex ventral hernia repair. This technique lengthens and relaxes the laterally retracted abdominal muscles and enables laparoscopic closure of large complex ventral hernia. PMID- 26951249 TI - Alternative Stable States, Coral Reefs, and Smooth Dynamics with a Kick. AB - We consider a computer simulation, which was found to be faithful to time series data for Caribbean coral reefs, and an analytical model to help understand the dynamics of the simulation. The analytical model is a system of ordinary differential equations (ODE), and the authors claim this model demonstrates the existence of alternative stable states. The existence of an alternative stable state should consider a sudden shift in coral and macroalgae populations, while the grazing rate remains constant. The results of such shifts, however, are often confounded by changes in grazing rate. Although the ODE suggest alternative stable states, the ODE need modification to explicitly account for shifts or discrete events such as hurricanes. The goal of this paper will be to study the simulation dynamics through a simplified analytical representation. We proceed by modifying the original analytical model through incorporating discrete changes into the ODE. We then analyze the resulting dynamics and their bifurcations with respect to changes in grazing rate and hurricane frequency. In particular, a "kick" enabling the ODE to consider impulse events is added. Beyond adding a "kick" we employ the grazing function that is suggested by the simulation. The extended model was fit to the simulation data to support its use and predicts the existence cycles depending nonlinearly on grazing rates and hurricane frequency. These cycles may bring new insights into consideration for reef health, restoration and dynamics. PMID- 26951248 TI - Systematic Review of Health-Related Quality of Life in Patients with Pulmonary Arterial Hypertension. AB - BACKGROUND: The increasing survival of patients with pulmonary arterial hypertension (PAH) has shifted attention towards the disease burden that PAH imposes on patients and healthcare systems. Most studies emphasize epidemiology and medications, while large observational studies reporting on the health related quality of life (HRQOL) of patients with PAH are lacking. OBJECTIVE: Our objective was to study the HRQOL of patients with PAH and to summarize the factors that influence it. METHODS: We conducted systematic literature searches in English (PubMed, Web of Knowledge, ScienceDirect and OVID) and Chinese (China National Knowledge Infrastructure, Wanfang Data, Chongqing VIP and SinoMed) databases to identify studies published from 2000 to 2015 assessing the HRQOL of patients with PAH. Search results were independently reviewed and extracted by two reviewers. RESULTS: Of 3392 records identified in the initial search, 20 eligible papers (19 English, 1 Chinese) were finally included. Studies used a range of instruments; the generic 36-item Short Form Survey (SF-36) was the most widely used, and the disease-specific Cambridge Pulmonary Hypertension Outcome Survey (CAMPHOR) was the second mostly widely used. Mean HRQOL scores assessed via the SF-36 (physical component summary [PCS] 25.4-80.1; mental component summary [MCS] 33.2-76.0) and CAMPHOR (symptom scores 3.1-17; total HRQOL 2.8 12.6; activity scores 3.8-18.1) varied across studies, reporting decreased HRQOL in patients. Mental health (depression, anxiety, stress), physical health (exercise capacity, symptoms) and medical therapies were reported to affect HRQOL. CONCLUSION: We found that PAH places a substantial burden on patients, particularly in terms of HRQOL; however, the paucity of large observational studies in this area requires the attention of researchers, especially in China. PMID- 26951250 TI - Efficacy of vitrectomy and inner limiting membrane peeling in age-related macular degeneration resistant to anti-vascular endothelial growth factor therapy, with vitreomacular traction or epiretinal membrane. AB - PURPOSE: We assessed the efficacy of vitrectomy and inner limiting membrane (ILM) peeling, followed by anti-vascular endothelial growth factor (VEGF) therapy, anti VEGF-resistant age-related macular degeneration (AMD) due to vitreomacular traction (VMT) or epiretinal membrane (ERM). METHODS: We identified six patients with anti-VEGF-resistant AMD due to VMT or ERM amongst a total of 588 patients with AMD (821 eyes) referred to Okayama University Hospital between February 2012 and May 2014. These patients underwent vitrectomy to release the VMT (4 cases) or remove the ERM (2 cases), along with ILM peeling. The regimen used for intravitreal injections of anti-VEGF reagents after surgery was based on the severity of exudative changes in each patient. Preoperative and postoperative best-corrected visual acuity (BCVA) and central retinal thickness (CRT) measurements were compared. RESULTS: After vitrectomy and ILM peeling, all six patients responded to anti-VEGF therapy, which was then able to maintain dry retinas. Mean BCVA did not improve significantly (0.49 +/- 0.28 before vs. 0.43 +/- 0.38 after surgery, P = 0.538). However, mean CR was significantly decreased after surgery, from 423 +/- 83.5 MUm to 257 +/- 75.8 MUm (P = 0.0078). CONCLUSIONS: Vitrectomy and ILM peeling followed by anti-VEGF therapy may be a useful therapeutic option for anti-VEGF-resistant AMD with VMT or ERM. PMID- 26951251 TI - Infection and Lupus: Which Causes Which? AB - Infection is a leading cause of morbidity and mortality among patients with systemic lupus erythematous (SLE). Dysfunction of the innate and adaptive immune systems increases the risk of infection in patients with SLE. Infectious agents have also been theorized to play a role in the pathogenesis of SLE. This article summarizes our current knowledge of the infectious risk SLE patients face as a result of their underlying disease including abnormal phagocytes and T cells as well as the increased risk of infection associated with immunosuppressive agents used to treat disease. Pathogens thought to play a role in the pathogenesis of disease including EBV, CMV, human endogenous retroviruses (HERVs), and tuberculosis will also be reviewed, as well as the pathologic potential of microbial amyloids and the microbiome. PMID- 26951252 TI - What Causes Lupus Flares? AB - Systemic lupus erythematosus (SLE), the prototypic systemic autoimmune disease, follows a chronic disease course, punctuated by flares. Disease flares often occur without apparent cause, perhaps from progressive inherent buildup of autoimmunity. However, there is evidence that certain environmental factors may trigger the disease. These include exposure to UV light, infections, certain hormones, and drugs which may activate the innate and adaptive immune system, resulting in inflammation, cytotoxic effects, and clinical symptoms. Uncontrolled disease flares, as well as their treatment, especially with glucocorticoids, can cause significant organ damage. Tight surveillance and timely control of lupus flares with judicial use of effective treatments to adequately suppress the excessive immune system activation are required to bring about long term remission of the disease. We hope that new clinical trials will soon offer additional effective and target-specific biologic treatments for SLE. PMID- 26951254 TI - The Regulation of Biosimilars in Latin America. AB - This article summarizes the regulatory scenario on biological medications in Latin America focusing on comparability studies, extrapolation of indications, interchangeability and pharmacovigilance issues. In the case of comparability studies, what is being discussed is the possibility of decreasing the clinical trials requirement, but that the molecule should be well characterized in the studies of pharmacokinetics and pharmacodynamics. With the worldwide-level approval of the first monoclonal antibody biosimilar, infliximab, extrapolation of indications are being discussed, since the behavior of the Latin America regulatory agencies has been different with regard to such issue. Another issue discussed by the regulatory agencies is the interchangeability between biological medications and their biosimilars, mainly due to the fact that there is a clear confusion on interchangeability and substitution concepts. Finally, the pharmacovigilance debate, according to what takes place globally, is related to the need for identifying and differentiating the reference biological medication and its biosimilars for traceability purposes. PMID- 26951253 TI - The Roles of Cigarette Smoking and the Lung in the Transitions Between Phases of Preclinical Rheumatoid Arthritis. AB - While the etiology of rheumatoid arthritis (RA) remains to be fully elucidated, recent research has advanced the understanding of RA pathogenesis to the point where clinical trials for RA prevention are underway. The current paradigm for RA pathogenesis is that individuals progress through distinct preclinical phases prior to the onset of clinically apparent RA. These preclinical RA phases consist of genetic risk, local inflammation, presence of RA-related autoantibodies, asymptomatic systemic inflammation, and early non-specific symptoms prior to clinical seropositive RA. Epidemiologic studies have been important in forming hypotheses related to the biology occurring in preclinical RA. Specifically, studies associating cigarette smoking with overall RA risk as well as transitions between phases of preclinical RA were vital in helping to establish the lung as a potential important initiating site in the pathogenesis of seropositive RA. Herein, we review the epidemiology associating smoking with transitions in preclinical phases of RA as well as the recent literature supporting the lung as a critical site in RA pathogenesis. PMID- 26951255 TI - Polymorphisms of genes encoding interleukin-4 and its receptor in Iranian patients with juvenile idiopathic arthritis. AB - As cytokines, including interleukin-4 (IL-4), seem to have a pivotal role in the pathogenesis of juvenile idiopathic arthritis (JIA), this study is aimed at investigating of association of polymorphisms in IL-4 and IL-4 receptor alpha (IL 4RA) genes with susceptibility to JIA. A case-control study was conducted on 53 patients with JIA and 139 healthy unrelated controls. Single nucleotide polymorphisms of IL-4 gene at positions -1098, -590, and -33, as well as IL-4RA gene at position +1902 were genotyped using polymerase chain reaction with sequence-specific primers method and compared between patients and healthy individuals. At the allelic level, C allele at IL-4 -33 was found to be more frequent in patients compared to control (P value <0.01). At the genotypic level, CC genotype at IL-4 -590 (P value <0.01), together with CC and TT genotypes at IL 4 -33 (P value <0.01), were significantly higher in patients with JIA, while TC genotypes at IL-4 -590 and -33 positions were found to be lower in case group (P value <0.01). At the haplotypic level, IL-4 (positions -1098, -509, -33) TTC, GCC, and TTT haplotypes were significantly lower than controls (P value <0.01, P value = 0.03, and P value = 0.04, respectively). Although, TCC haplotype at the same positions was found to be higher in patients (P value <0.01). Polymorphic site of +1902 IL-4RA gene did not differ between cases and controls. Polymorphisms in promoter region of IL-4 but not IL-4RA genes confer susceptibility to JIA and may predispose individuals to adaptive immune responses. PMID- 26951257 TI - The impact of intra-articular methylprednisolone acetate injection on fructosamine levels in diabetic patients with osteoarthritis of the knee, a case control study. AB - Fructosamine is a glycated protein that reflects blood glucose control over the last 2-3 weeks. There are no studies that address the impact of intra-articular injection (IAI) of methylprednisolone acetate (MPA) on fructosamine levels among patients with type-2 diabetes and osteoarthritis of the knee (OAK). Non-selected patients attending the rheumatology or orthopedic clinic with type-2 diabetes and painful OAK, who failed non-steroidal anti-inflammatory drugs (NSAIDS) and physical therapy, were asked to participate in our study. After consent blood tests were drown for fructosamine, hemoglobin A1c (HbA1c) level, complete blood count, lipid profile, serum albumin, serum protein, c-reactive protein, and erythrocyte sedimentation rate. Demographic and different clinical parameters were also documented. Immediately after that, patients had IAI of 80 mg of MPA at the knee joint (group 1). Two to three weeks later, the same blood tests were repeated (except for HbA1c). Age- and sex-matched group of patients with type-2 diabetes and painful OAK attending the same clinics, but who were managed by NSAIDS were asked to participate as a control group (group 2) and had the same evaluation at enrollment and 2-3 weeks later, after consent. Eighteen patients from either group completed the study. Mean fructosamine level in group 1 patients was 263.7 +/- 31.8 mg% prior to the IAI vs. 274.6 +/- 39.3 mg% (p = 0.035), 2-3 weeks later, while mean fructosamine level in the control group (group 2) at enrollments was 274.2 +/- 31.2 mg% vs. 269 +/- 30.2 mg%, p = 0.509, 2-3 weeks later. There was no significant change in any other parameter tested at enrollment in either group, compared to those obtained 2-3 weeks afterwards. Body mass index was on the edge of significance as a predictor for a significant change in fructosamine level in group 1 patients. IAI of 80 mg of MPA in patients with type-2 diabetes and OAK had resulted in a significant, though mild increase in fructosamine levels 2-3 weeks later. PMID- 26951256 TI - The functional PTPN22 C1858T polymorphism confers risk for rheumatoid arthritis in patients from Central Mexico. AB - Rheumatoid arthritis (RA) is a complex genetic disease. Human leukocyte antigen (HLA) and non-HLA genes are reportedly associated with an increased risk of RA. The protein tyrosine phosphatase non-receptor 22 gene (PTPN22), which encodes the lymphoid tyrosine phosphatase (LYP) protein, is one of the best examples of a non HLA gene associated with a risk for RA in several populations. The functional PTPN22 C1858T (R620W) non-synonymous polymorphism is widely associated with an increased risk for RA in Europeans and non-Europeans. The aim of this study was to determine if the PTPN22 C1858T polymorphism confers susceptibility to RA in a sample of patients from Mexico. This study included 364 RA patients and 387 non related controls from Central Mexico. Genotyping of the PTPN22 C1858T (rs2476601) polymorphism was performed using allelic discrimination assays with TaqMan probes. The functional PTPN22 C1858T polymorphism was associated with an increased risk for RA in our study population. The CC vs CT genotype in RA patients versus healthy controls had an odds ratio (OR) of 4.17 (95 % CI 1.79 9.74, p = 0.00036), while T allele had an OR of 4.06 (95 % CI 1.75-9.41, p = 0.00043). PTPN22 is a genetic risk factor for developing RA in the Mexican population. PMID- 26951258 TI - Molecular Characterization of Intermediate Susceptible Typhoidal Salmonella to Ciprofloxacin, and its Impact. AB - BACKGROUND AND OBJECTIVE: Extensive use of ciprofloxacin to treat Salmonella typhi infections has led to the emergence of resistance, resulting in clinical failure and delayed treatment response. Interpretative breakpoints for ciprofloxacin were revised by the Clinical and Laboratory Standards Institute (CLSI) and the European Committee on Antimicrobial Susceptibility Testing (EUCAST) in 2012. Since the majority of S. typhi isolates fall under the category of 'intermediate susceptible' as per CLSI criteria, we undertook molecular characterization to better define the susceptibility of these isolates. METHODS: Of 113 typhoidal Salmonella isolates collected during 2014, 33 (27 S. typhi and 6 S. paratyphi A) were randomly selected to determine the presence of chromosomal (gyrA, gyrB and parC), plasmid (qnrA, qnrB, qnrS and aac(6')-lb-cr), and efflux mediated fluoroquinolone resistance. RESULTS: To the best of our knowledge, the parC mutation Glu(84)-Gly was observed for the first time in S. typhi in India. Of 33 isolates, only one harbored the qnrB gene, which is responsible for plasmid mediated resistance. No significant change in efflux pump activity was observed for ciprofloxacin, except one that showed a fivefold decrease. Ninety-six percent of isolates with intermediate minimum inhibitory concentration to ciprofloxacin (CLSI) had mutations in the gyrA and parC genes, which might translate to possible/probable clinical failure in patients if treated with ciprofloxacin. In contrast, the EUCAST criteria define these isolates as resistant and may result in appropriate therapy with reduced morbidity. CONCLUSION: It was clear that the molecular mechanism of ciprofloxacin resistance correlates better with the EUCAST criteria than the CLSI criteria, which is also in agreement with the pefloxacin results, suggesting it as a surrogate marker for identifying fluoroquinolone susceptibility. PMID- 26951260 TI - Sox10 expression in ovarian epithelial tumors is associated with poor overall survival. AB - Sox10 is a transcription factor regulating the development of several cell lineages and is involved in tumor development. However, the clinicopathological relevance of Sox10 expression in ovarian cancer has not been examined. We assessed expression of Sox10 in ovarian epithelial tumors by immunohistochemistry and assessed its prognostic value by analyzing the correlation between its expression and clinicopathological factors. We used tissue microarrays including 244 ovarian epithelial tumors. Sox10 staining was found in the cytoplasm or nucleus of tumor cells. Malignant serous, mucinous, and endometrioid tumors were significantly more likely to express Sox10 than benign and borderline tumors. Expression patterns in adenocarcinomas were different for histologic subtypes: nuclear Sox10 staining was common in clear-cell adenocarcinomas and serous adenocarcinomas, whereas all cases of mucinous and endometrioid tumors were negative for nuclear staining. Nuclear Sox10 staining was also associated with chemoresistance and shorter overall survival in ovarian adenocarcinomas, notably in high-grade serous adenocarcinoma. Sox10 is expressed in many ovarian carcinomas, suggesting that it might be involved in oncogenesis of ovarian carcinoma. Expression pattern of Sox10 differs between histological subtypes. Nuclear Sox10 expression is an independent indicator of poor prognosis in ovarian adenocarcinomas, notably in high-grade serous adenocarcinomas. PMID- 26951259 TI - Impact of Abdominal Shape on Short-Term Surgical Outcome of Laparoscopy-Assisted Distal Gastrectomy for Gastric Cancer. AB - BACKGROUND: Laparoscopy-assisted distal gastrectomy (LADG) has been widely accepted for the treatment for gastric cancer. The aim of the present study was to explore the impact of abdominal shape parameters on gastric antrum cancer patients' short-term surgical outcomes of LADG with D2 lymph node dissection in both genders, including the number of lymph nodes retrieved and surgical safety index. METHODS: This was a retrospective analysis of 177 gastric antrum cancer patients, who underwent LADG between April 2009 and January 2016. The abdominal shape parameters, including abdominal anterior-posterior diameter (APD), transverse diameter (TD), xiphoid process of the sternum-navel distance (XND), and thickness of subcutaneous fat (SCF) at the umbilicus level, were calculated by preoperative abdominal computed tomography (CT) scans. The effects of abdominal shape parameters on the short-term surgical outcomes of LADG were analyzed. RESULTS: In male patients undergoing LADG and D2 lymph node dissection, the number of retrieved lymph nodes was significantly lower in patients with APD >=17.3 cm (P = 0.005), TD >=27.4 cm (P = 0.029), SCF >=1.2 cm (P = 0.014), and BMI >=22.2 (P = 0.008), whereas in female patients, these were statistically insignificant (P > 0.05). APD, TD, SCF, and BMI were negatively correlated with the number of retrieved lymph nodes in male patients. There was no significant difference in the number of lymph nodes retrieved between high-XND group and low XND group in either gender. Operation time was significantly shorter in male patients with XND < 17.0 cm (P = 0.044) and in female patients with SCF < 2.15 cm (P = 0.013). Intraoperative blood loss and postoperative complication rate were not significantly different between high- and low-APD groups, high- and low-TD groups, high- and low-XND groups, and high- and low-SCF groups in either gender. Compared with male patients, SCF and TD were significantly higher in female patients. In addition, a higher incidence rate of hypertension was observed in patients of both genders with large APD and SCF, although statistically significant only in male patients. CONCLUSIONS: LADG with D2 lymph node dissection can effectively achieve the lymph node dissection requirement of radical distal gastrectomy for patients with various abdominal shapes. It is worth noting that APD, TD, and SCF can impact on lymph node dissection of LADG in male patients. Nevertheless, in female patients, abdominal shape do not impact on lymph node dissection of LADG. Moreover, LADG with D2 lymph node dissection is proved to be safe for various abdominal shape in both genders, even for abdominal obese patients. PMID- 26951262 TI - Association of a variable number tandem repeat in the NLRP3 gene in women with susceptibility to RVVC. AB - Vaginal infections with Candida spp. frequently occur in women of childbearing age. A small proportion of these women experience recurrent vulvovaginal candidosis (RVVC), which is characterized by at least three episodes of infection in one year. In addition to known risk factors such as antibiotics, diabetes, or pregnancy, host genetic variation and inflammatory pathways such as the IL-1/Th17 axis have been reported to play a substantial role in the pathogenesis of RVVC. In this study, we assessed a variable number tandem repeat (VNTR) polymorphism in the NLRP3 gene that encodes a component of the inflammasome, processing the proinflammatory cytokines IL-1beta and IL-18. A total of 270 RVVC patients and 583 healthy controls were analyzed, and increased diseases susceptibility was associated with the presence of the 12/9 genotype. Furthermore, functional studies demonstrate that IL-1beta production at the vaginal surface is higher in RVVC patients bearing the 12/9 genotype compared to controls, whereas IL-1Ra levels were decreased and IL-18 levels remained unchanged. These findings suggest that IL-1beta-mediated hyperinflammation conveyed by the NLRP3 gene plays a causal role in the pathogenesis of RVVC and may identify this pathway as a potential therapeutic target in the disease. PMID- 26951264 TI - Fusobacterium necrophorum otitis and mastoiditis in infants and young toddlers. AB - There is an increased recovery of Fusobacterium necrophorum from cases of otitis media and mastoiditis in the pediatric population. These infections may be highly severe, causing local osteomyelitis, bacteremia, and Lemierre's syndrome. The severity and difficulties in providing optimal treatment for these infections may be especially difficult in this age group due to immunological immaturity and delayed presentation. In this review of literature, we present and analyze the clinical presentation, management, and outcome of otic infections caused by F. necrophorum in infants and young toddlers less than 2 years old. Search in Pubmed was conducted for reported cases in the English literature for the time period of the last 50 years. Twelve well-described cases were retrieved with F. necrophorum otitis and mastoiditis and complications reported in all cases. Treatment included both intravenously with antimicrobial agents (beta lactams plus metronidazole) and mastoidectomy. Lemierre's syndrome and Lemierre's syndrome variants developed in 60 % of the patients. Dissemination of the infection as distal osteomyelitis and septic shock were also reported. The outcome was favorable in all the cases. Otitis and mastoiditis infections in children less then 2 years old are invasive infections, and severe complications can occur. PMID- 26951261 TI - A high number of IgG4-positive cells in gastric cancer tissue is associated with tumor progression and poor prognosis. AB - IgG4-related disease is a newly defined disease characterized by elevated serum IgG4 levels and infiltration of affected organs by IgG4-positive plasma cells. Recently, increased IgG4 levels were reported to be closely related with malignancy. To assess the relationship between IgG4 and the progression of gastric cancer, we immunohistochemically stained in this study gastric cancer tissue samples for IgG4-positive cells using an anti-IgG4 antibody. In addition, pre- and postoperative serum concentrations of IgG4 were measured, using an enzyme-linked immunosorbent assay. In gastric cancer samples, the number of CD138 positive plasma cells was significantly lower and the number of IgG4-positive cells significantly higher than in non-cancerous gastric mucosa. The number of IgG4-positive cells was significantly correlated with gross tumor appearance, tumor depth, lymph node metastasis, venous invasion, and lymphatic invasion. Prognosis was significantly poorer in patients with a high number of IgG4 positive cells than in those with a low number. Multivariate analysis indicated that both the number of IgG4-positive cells and the depth of tumor invasion were independently prognostic of survival. In conclusion, in gastric cancer, the number of IgG4-positive cells is increased and this is closely associated with gastric cancer progression. PMID- 26951263 TI - Relationship between pathogenic, clinical, and virulence factors of Staphylococcus aureus in infective endocarditis versus uncomplicated bacteremia: a case-control study. AB - Pathogenic factors of Staphylococcus aureus (SA) in the development of infective endocarditis (IE) have not been sufficiently investigated. The purpose of this study was to analyze the pathogenesis and virulence factors of SA in patients with IE as compared to patients with uncomplicated bacteremia (un-BAC). This is a retrospective case-control study (2002-2014) performed at a tertiary hospital in Spain. Clinical and epidemiological factors were analyzed. We assessed the presence of toxin genes [toxic shock syndrome toxin 1 (tst-1) and enterotoxins A (etA), B (etB), and D (etD)] and the potential relationship between accessory gene regulator (agr) groups and the development of IE confirmed by polymerase chain reaction (PCR). Twenty-nine patients with IE were compared with 58 patients with uncomplicated S. aureus bacteremia (SAB). As many as 75.9 % of patients had community-acquired IE (p < 0.005). Multivariate analysis revealed that there is a significant relationship between community-acquired infection and severe sepsis or septic shock and IE. Also, a minimum inhibitory concentration (MIC) of vancomycin >=1.5 MUg/ml was found to be associated with IE. The agr group I was prevalent (55.2 % vs. 31.0 %; p = 0.030). No association was observed between toxin genes (tst-1, etA, etB, and etD) and IE. The superantigen (SAg) most frequently found in SA isolates was tst-1 (12.6 %). We found no association between toxin genes and IE, probably due to the small sample size. However, a direct relationship was found between agr I and the development of IE, which suggests that agr I strains may have more potential to cause IE. PMID- 26951265 TI - Review of Geri Fox's Saying Goodbye: A Stimulus Videotape Centering on Her Conversations with Simon Fox, Her Late Father. PMID- 26951266 TI - Attitudes of Students at a US Medical School Toward Mental Illness and Its Causes. AB - OBJECTIVES: Stigma among health care providers toward people with mental illness is a worldwide problem. This study at a large US university examined medical student attitudes toward mental illness and its causes, and whether student attitudes change as they progress in their education. METHODS: An electronic questionnaire focusing on attitudes toward people with mental illness, causes of mental illness, and treatment efficacy was used to survey medical students at all levels of training. Exploratory factor analysis was used to establish attitudinal factors, and analysis of variance was used to identify differences in student attitudes among these factors. Independent-samples t tests were used to assess attitudes toward efficacy of treatments for six common psychiatric and medical conditions. RESULTS: The study response rate was 42.6 % (n = 289). Exploratory factor analysis identified three factors reflecting social acceptance of mental illness, belief in supernatural causes, and belief in biopsychosocial causes. Stages of student education did not differ across these factors. Students who had completed the psychiatry clerkship were more likely to believe that anxiety disorders and diabetes could be treated effectively. Students reporting personal experiences with mental illness showed significantly more social acceptance, and people born outside the USA were more likely to endorse supernatural causes of mental illness. CONCLUSIONS: Sociocultural influences and personal experience with mental illness have a greater effect than medical education on attitudes toward people with mental illness. Psychiatric education appears to have a small but significant effect on student attitudes regarding treatment efficacy. PMID- 26951267 TI - The Next Generation of Clinical Performance Measures. PMID- 26951268 TI - Implementing Performance Pay in Health Care: Do We Know Enough to Do It Well? PMID- 26951269 TI - Measuring What Matters in Health: Lessons from the Veterans Health Administration State of the Art Conference. PMID- 26951270 TI - Are Improvements in Measured Performance Driven by Better Treatment or "Denominator Management"? AB - BACKGROUND: Process measures of healthcare quality are usually formulated as the number of patients who receive evidence-based treatment (numerator) divided by the number of patients in the target population (denominator). When the systems being evaluated can influence which patients are included in the denominator, it is reasonable to wonder if improvements in measured quality are driven by expanding numerators or contracting denominators. OBJECTIVE: In 2003, the US Department of Veteran Affairs (VA) based executive compensation in part on performance on a substance use disorder (SUD) continuity-of-care quality measure. The first goal of this study was to evaluate if implementing the measure in this way resulted in expected improvements in measured performance. The second goal was to examine if the proportion of patients with SUD who qualified for the denominator contracted after the quality measure was implemented, and to describe the facility-level variation in and correlates of denominator contraction or expansion. DESIGN: Using 40 quarters of data straddling the implementation of the performance measure, an interrupted time series design was used to evaluate changes in two outcomes. PARTICIPANTS: All veterans with an SUD diagnosis in all VA facilities from fiscal year 2000 to 2009. MAIN MEASURES: The two outcomes were 1) measured performance-patients retained/patients qualified and 2) denominator prevalence-patients qualified/patients with SUD program contact. KEY RESULTS: Measured performance improved over time (P < 0.001). Notably, the proportion of patients with SUD program contact who qualified for the denominator decreased more rapidly after the measure was implemented (p = 0.02). Facilities with higher pre-implementation denominator prevalence had steeper declines in denominator prevalence after implementation (p < 0.001). CONCLUSIONS: These results should motivate the development of measures that are less vulnerable to denominator management, and also the exploration of "shadow measures" to monitor and reduce undesirable denominator management. PMID- 26951271 TI - Assessing the Associations of Patient-Reported Perceptions of Patient-Centered Care as Supplemental Measures of Health Care Quality in VA. AB - BACKGROUND: Patient-reported experience measures (PREMs) are useful for assessing health care quality and safety and patients' perceptions of health care. OBJECTIVE: We aimed to assess the relationship between PREMS [e.g., measures of patient-centered care (PCC)] and health care quality metrics. DESIGN: We conducted a national survey via mail. Survey data were supplemented with US Department of Veteran Affairs (VA) administrative data. PARTICIPANTS: Veteran (n = 5512) VA health care users participated in the study. MAIN MEASURES: PCC measures included: patient activation; shared decision-making (SDM); empathy and holistic care; chronic illness care; perceptions of participation, respect for choices, and support; and overall health care experience. Health care quality measures included: preventive care screening receipt; chronic condition management (diabetes, hypertension); and health care utilization (hospitalizations, emergency room (ER) visits). Analyses included: bivariate comparisons of PCC measures by health care quality measures; and multivariate linear regression to identify variables associated with attaining multiple positive health care quality indicators (when controlling for potential confounders). KEY RESULTS: PREMs assessing factors relating to patient-provider communication (e.g., empathic provider care, shared decision-making) are mainly related to clinical indicators representing good chronic condition management, while those relating more broadly to health care in general (e.g., patient activation, chronic illness care) are mainly related to measures of appropriate health care use (e.g., preventive care screening receipt; potentially avoidable hospitalizations; unscheduled care, such as ER visits). When controlling for potential confounders, higher perceptions of the decision-making effectiveness component of SDM (beta = 0.004, p = 0.03) and empathy and holistic care (beta = 0.01, p = 0.02) showed a weak but positive relationship with attaining a greater number of positive health care quality indicators, while a weak but negative relationship emerged for perceptions of participation, respect for choices, and support (beta = -0.003, p = 0.03) and overall VA experiences (beta = -0.10, p = 0.04). CONCLUSIONS: PREMs that measure PCC offer rich data about health care quality while engaging patients, and considering patient experiences and preferences, in performance assessment. PREMs may be used to supplement existing performance metrics. PMID- 26951272 TI - Metrics That Matter. AB - Increasingly, performance metrics are seen as key components for accurately measuring and improving health care value. Disappointment in the ability of chosen metrics to meet these goals is exemplified in a recent Institute of Medicine report that argues for a consensus-building process to determine a simplified set of reliable metrics. Overall health care goals should be defined and then metrics to measure these goals should be considered. If appropriate data for the identified goals are not available, they should be developed. We use examples from our work in the Veterans Health Administration (VHA) on validating waiting time and mental health metrics to highlight other key issues for metric selection and implementation. First, we focus on the need for specification and predictive validation of metrics. Second, we discuss strategies to maintain the fidelity of the data used in performance metrics over time. These strategies include using appropriate incentives and data sources, using composite metrics, and ongoing monitoring. Finally, we discuss the VA's leadership in developing performance metrics through a planned upgrade in its electronic medical record system to collect more comprehensive VHA and non-VHA data, increasing the ability to comprehensively measure outcomes. PMID- 26951273 TI - Validation of Stroke Meaningful Use Measures in a National Electronic Health Record System. AB - BACKGROUND: The Meaningful Use (MU) program has increased the national emphasis on electronic measurement of hospital quality. OBJECTIVE: To evaluate stroke MU and one VHA stroke electronic clinical quality measure (eCQM) in national VHA data and determine sources of error in using centralized electronic health record (EHR) data. DESIGN: Our study is a retrospective cross-sectional study of stroke quality measure eCQMs vs. chart review in a national EHR. We developed local SQL algorithms to generate the eCQMs, then modified them to run on VHA Central Data Warehouse (CDW) data. eCQM results were generated from CDW data in 2130 ischemic stroke admissions in 11 VHA hospitals. Local and CDW results were compared to chart review. MAIN MEASURES: We calculated the raw proportion of matching cases, sensitivity/specificity, and positive/negative predictive values (PPV/NPV) for the numerators and denominators of each eCQM. To assess overall agreement for each eCQM, we calculated a weighted kappa and prevalence-adjusted bias-adjusted kappa statistic for a three-level outcome: ineligible, eligible-passed, or eligible-failed. KEY RESULTS: In five eCQMs, the proportion of matched cases between CDW and chart ranged from 95.4 %-99.7 % (denominators) and 87.7 %-97.9 % (numerators). PPVs tended to be higher (range 96.8 %-100 % in CDW) with NPVs less stable and lower. Prevalence-adjusted bias-adjusted kappas for overall agreement ranged from 0.73-0.95. Common errors included difficulty in identifying: (1) mechanical VTE prophylaxis devices, (2) hospice and other specific discharge disposition, and (3) contraindications to receiving care processes. CONCLUSIONS: Stroke MU indicators can be relatively accurately generated from existing EHR systems (nearly 90 % match to chart review), but accuracy decreases slightly in central compared to local data sources. To improve stroke MU measure accuracy, EHRs should include standardized data elements for devices, discharge disposition (including hospice and comfort care status), and recording contraindications. PMID- 26951274 TI - Depression Quality of Care: Measuring Quality over Time Using VA Electronic Medical Record Data. AB - BACKGROUND: The Veterans Health Administration (VA) has invested substantially in evidence-based mental health care. Yet no electronic performance measures for assessing the level at which the population of Veterans with depression receive appropriate care have proven robust enough to support rigorous evaluation of the VA's depression initiatives. OBJECTIVE: Our objectives were to develop prototype longitudinal electronic population-based measures of depression care quality, validate the measures using expert panel judgment by VA and non-VA experts, and examine detection, follow-up and treatment rates over a decade (2000-2010). We describe our development methodology and the challenges to creating measures that capture the longitudinal course of clinical care from detection to treatment. DESIGN AND PARTICIPANTS: Data come from the National Patient Care Database and Pharmacy Benefits Management Database for primary care patients from 1999 to 2011, from nine Veteran Integrated Service Networks. MEASURES: We developed four population-based quality metrics for depression care that incorporate a 6-month look back and 1-year follow-up: detection of a new episode of depression, 84 and 180 day follow-up, and minimum appropriate treatment 1-year post detection. Expert panel techniques were used to evaluate the measure development methodology and results. Key challenges to creating valid longitudinal measures are discussed. KEY RESULTS: Over the decade, the rates for detection of new episodes of depression remained stable at 7-8 %. Follow-up at 84 and 180 days were 37 % and 45 % in 2000 and increased to 56 % and 63 % by 2010. Minimum appropriate treatment remained relatively stable over the decade (82-84 %). CONCLUSIONS: The development of valid longitudinal, population-based quality measures for depression care is a complex process with numerous challenges. If the full spectrum of care from detection to follow-up and treatment is not captured, performance measures could actually mask the clinical areas in need of quality improvement efforts. PMID- 26951275 TI - A Novel Method for Assessing Task Complexity in Outpatient Clinical-Performance Measures. AB - BACKGROUND: Clinical-performance measurement has helped improve the quality of health-care; yet success in attaining high levels of quality across multiple domains simultaneously still varies considerably. Although many sources of variability in care quality have been studied, the difficulty required to complete the clinical work itself has received little attention. OBJECTIVE: We present a task-based methodology for evaluating the difficulty of clinical performance measures (CPMs) by assessing the complexity of their component requisite tasks. DESIGN: Using Functional Job Analysis (FJA), subject-matter experts (SMEs) generated task lists for 17 CPMs; task lists were rated on ten dimensions of complexity, and then aggregated into difficulty composites. PARTICIPANTS: Eleven outpatient work SMEs; 133 VA Medical Centers nationwide. MAIN MEASURES: Clinical Performance: 17 outpatient CPMs (2000-2008) at 133 VA Medical Centers nationwide. Measure Difficulty: for each CPM, the number of component requisite tasks and the average rating across ten FJA complexity scales for the set of tasks comprising the measure. KEY RESULTS: Measures varied considerably in the number of component tasks (M = 10.56, SD = 6.25, min = 5, max = 25). Measures of chronic care following acute myocardial infarction exhibited significantly higher measure difficulty ratings compared to diabetes or screening measures, but not to immunization measures ([Formula: see text] = 0.45, -0.04, 0.05, and -0.06 respectively; F (3, 186) = 3.57, p = 0.015). Measure difficulty ratings were not significantly correlated with the number of component tasks (r = -0.30, p = 0.23). CONCLUSIONS: Evaluating the difficulty of achieving recommended CPM performance levels requires more than simply counting the tasks involved; using FJA to assess the complexity of CPMs' component tasks presents an alternate means of assessing the difficulty of primary-care CPMs and accounting for performance variation among measures and performers. This in turn could be used in designing performance reward programs, or to match workflow to clinician time and effort. PMID- 26951278 TI - Improving the Quality of Quality Measurement. PMID- 26951276 TI - Implementation Processes and Pay for Performance in Healthcare: A Systematic Review. AB - BACKGROUND: Over the last decade, various pay-for-performance (P4P) programs have been implemented to improve quality in health systems, including the VHA. P4P programs are complex, and their effects may vary by design, context, and other implementation processes. We conducted a systematic review and key informant (KI) interviews to better understand the implementation factors that modify the effectiveness of P4P. METHODS: We searched PubMed, PsycINFO, and CINAHL through April 2014, and reviewed reference lists. We included trials and observational studies of P4P implementation. Two investigators abstracted data and assessed study quality. We interviewed P4P researchers to gain further insight. RESULTS: Among 1363 titles and abstracts, we selected 509 for full-text review, and included 41 primary studies. Of these 41 studies, 33 examined P4P programs in ambulatory settings, 7 targeted hospitals, and 1 study applied to nursing homes. Related to implementation, 13 studies examined program design, 8 examined implementation processes, 6 the outer setting, 18 the inner setting, and 5 provider characteristics. Results suggest the importance of considering underlying payment models and using statistically stringent methods of composite measure development, and ensuring that high-quality care will be maintained after incentive removal. We found no conclusive evidence that provider or practice characteristics relate to P4P effectiveness. Interviews with 14 KIs supported limited evidence that effective P4P program measures should be aligned with organizational goals, that incentive structures should be carefully considered, and that factors such as a strong infrastructure and public reporting may have a large influence. DISCUSSION: There is limited evidence from which to draw firm conclusions related to P4P implementation. Findings from studies and KI interviews suggest that P4P programs should undergo regular evaluation and should target areas of poor performance. Additionally, measures and incentives should align with organizational priorities, and programs should allow for changes over time in response to data and provider input. PMID- 26951277 TI - Developing and Testing an Electronic Measure of Screening Colonoscopy Overuse in a Large Integrated Healthcare System. AB - BACKGROUND: Most existing performance measures focus on underuse of care, but there is growing interest in identifying and reducing overuse. OBJECTIVE: We aimed to develop a valid and reliable electronic performance measure of overuse of screening colonoscopy in the Veterans Affairs Health Care System (VA), and to quantify overuse in VA. DESIGN: This was a cross-sectional study with multiple cross-sections. SUBJECTS: U.S. Veterans who underwent screening colonoscopy between 2011 and 2013. MAIN MEASURES: Overuse of screening colonoscopy, using a validated electronic measure developed by an expert workgroup. KEY RESULTS: Compared to results obtained from manual record review, the electronic measure was highly specific (97 %) for overuse, but not sensitive (20 %). After exclusion of diagnostic and high-risk screening or surveillance procedures, the validated electronic measure identified 88,754 average-risk screening colonoscopies performed in VA during 2013. Of these, 20,530 (23 %) met the definition for probable (17 %) or possible (6 %) overuse. Substantial variation in colonoscopy overuse was noted between Veterans Integrated Care Networks (VISNs) and between facilities, with a nearly twofold difference between the maximum and minimum rates of overuse at the VISN level and a nearly eightfold difference at the facility level. Overuse at the VISN and facility level was relatively stable over time. CONCLUSIONS: Overuse of screening colonoscopy can be measured reliably and with high specificity using electronic data, and is common in a large integrated healthcare system. Overuse measures, such as those we have specified through a consensus workgroup process, could be combined with underuse measures to improve the appropriateness of colorectal cancer screening. PMID- 26951279 TI - Opportunities to Enhance Value-Related Research in the U.S. Department of Veterans Affairs. PMID- 26951280 TI - Excellent Patient Care Processes in Poor Hospitals? Why Hospital-Level and Patient-Level Care Quality-Outcome Relationships Can Differ. AB - Studies finding weak or nonexistent relationships between hospital performance on providing recommended care and hospital-level clinical outcomes raise questions about the value and validity of process of care performance measures. Such findings may cause clinicians to question the effectiveness of the care process presumably captured by the performance measure. However, one cannot infer from hospital-level results whether patients who received the specified care had comparable, worse or superior outcomes relative to patients not receiving that care. To make such an inference has been labeled the "ecological fallacy," an error that is well known among epidemiologists and sociologists, but less so among health care researchers and policy makers. We discuss such inappropriate inferences in the health care performance measurement field and illustrate how and why process measure-outcome relationships can differ at the patient and hospital levels. We also offer recommendations for appropriate multilevel analyses to evaluate process measure-outcome relationships at the patient and hospital levels and for a more effective role for performance measure bodies and research funding organizations in encouraging such multilevel analyses. PMID- 26951281 TI - Minoxidil-Associated Pleuropericardial Effusion. PMID- 26951282 TI - Nurse Practitioner Autonomy and Relationships with Leadership Affect Teamwork in Primary Care Practices: a Cross-Sectional Survey. AB - BACKGROUND: The Nurse Practitioner (NP) workforce represents a substantial supply of primary care providers able to contribute to meeting a growing demand for care. However, controversy exists regarding the expanding role of NPs in primary care in terms of challenging the teamwork between NPs and physicians. To date, no empirical evidence exists regarding how to promote teamwork in primary care between NPs and physicians. OBJECTIVE: We investigated whether NP autonomy within primary care practices and the relationships they have with leadership affect teamwork between NPs and physicians. DESIGN: Using a cross-sectional survey design, data was collected from 163 primary care practices in Massachusetts. PARTICIPANTS: Three hundred and fourteen primary care NPs completed and returned the mail survey yielding a response rate of 40 %. MAIN MEASURES: The Autonomy and Independent Practice (AIP) and NP-Administration Relations (NP-AR) scales were used to measure NP independent practice and the relationships with leadership, respectively. These measures were aggregated to the practice level. Teamwork between NPs and physicians was measured at the individual NP level using the Teamwork (TW) scale. KEY RESULTS: The multilevel linear regression models investigated the influence of practice-level NP autonomy and the relationship between NPs and leadership on teamwork. With every unit increase on the practice level mean score of AIP centered at the grand mean, the mean TW score increased by 0.271 units (p < 0.0001). With every unit increase of NP-AR centered at the grand mean, the mean TW score increased by 0.375 (p < 0.001). Over one-third (41.3 %) of the variance in teamwork could be explained by the final model. CONCLUSION: The study findings demonstrate that NP autonomy and favorable relationships with leadership improve teamwork. Policy and organizational change should focus on promoting NP autonomy and improving the relationship between NPs and leadership to improve teamwork and consequently improve patient care and outcomes. PMID- 26951283 TI - Evaluating the Risks of Opioid Use for Chronic Pain: Moving Beyond Overdose. PMID- 26951284 TI - Moral Distress Amongst Physician Trainees Regarding Futile Treatments. PMID- 26951285 TI - Capsule Commentary on Alford et al., Primary Care Patients with Drug Use Report Chronic Pain and Self-Medicate with Alcohol and Other Drugs. PMID- 26951286 TI - Vitamin D: A Narrative Review Examining the Evidence for Ten Beliefs. AB - Over the past decade, a large body of observational evidence has suggested an association between lower vitamin D status (25-hydroxyvitamin D) and multiple acute and chronic disorders, including cancer, multiple sclerosis, depression and respiratory tract infections. This evidence has fostered the hypothesis that increasing vitamin D intake may treat and prevent such disorders. Our objective was to perform a critical analysis of the highest-level evidence for ten common beliefs regarding vitamin D for the prevention of falls, fractures and respiratory tract infections, the reduction of cancer incidence/mortality and overall mortality, and the prevention or treatment of depression/mental well being, rheumatoid arthritis and multiple sclerosis, as well as maximum dosing and regular testing. We searched the Cochrane Database of Systematic Reviews and PubMed (up to August 2014) for randomized controlled trials and systematic reviews/meta-analyses based on those studies. All searches were performed, all evidence reviewed and each section written by at least two authors. The evidence shows that vitamin D supplementation provides some benefit in fracture prevention (likely ~10-15 % relative reduction), particularly at a dose >=800 IU and with calcium; a likely benefit in the rate of falls, though it is less clear whether the number of fallers changes; and a possible small (~5 %) relative reduction in mortality. Evidence does not support the use of vitamin D supplementation for the prevention of cancer, respiratory infections or rheumatoid arthritis. Similarly, evidence does not support vitamin D supplementation for the treatment of multiple sclerosis and rheumatoid arthritis or for improving depression/mental well-being. Regular testing of 25-hydroxyvitamin D is generally not required, and mega-doses (>=300,000 IU) appear to increase harms. Much of the evidence is at high risk of bias, with multiple flaws, including analyses of secondary endpoints, small and underpowered studies, inconsistent results and numerous other issues. Therefore, enthusiasm for a vitamin D panacea should be tempered. PMID- 26951288 TI - A role for the anteromedial thalamic nucleus in the acquisition of contextual fear memory to predatory threats. AB - Previous studies from our group have shown that cytotoxic lesions in the ventral portion of the anteromedial thalamic nucleus (AMv), one of the main targets of the hypothalamic predator-responsive circuit, strongly impairs contextual fear responses to an environment previously associated with a predator. The AMv is in a position to convey information to cortico-hippocampal-amygdalar circuits involved in the processing of fear memory. However, it remains to be determined whether the nucleus is involved in the acquisition or subsequent expression of contextual fear. In the present investigation, we addressed this question by inactivating the rat AMv with muscimol either prior to cat exposure or prior to exposure to the cat-related context. Accordingly, AMv pharmacological inactivation prior to cat exposure did not interfere with innate fear responses, but it drastically reduced contextual conditioning to the predator-associated environment. On the other hand, AMv inactivation prior to exposure to the environment associated with the predator threat did not affect contextual fear responses. The behavioral results were further supported by the demonstration that AMv inactivation prior to cat exposure also blocked the activation of sites critically involved in the expression of anti-predatory contextual defensive responses (i.e., the dorsal premammillary nucleus and the dorsolateral periaqueductal gray) in animals exposed to the predator-associated context. The AMv projections were also examined, and the results of this investigation outline important paths that can influence hippocampal circuitry and raise new ideas for anterior thalamic-hippocampal paths involved in emotional learning. PMID- 26951287 TI - A Comparison of Health Plan- and Provider-Delivered Chronic Care Management Models on Patient Clinical Outcomes. AB - BACKGROUND: The real world implementation of chronic care management model varies greatly. One aspect of this variation is the delivery mode. Two contrasting strategies include provider-delivered care management (PDCM) and health plan delivered care management (HPDCM). OBJECTIVE: We aimed to compare the effectiveness of PDCM vs. HPDCM on improving clinical outcomes for patients with chronic diseases. DESIGN: We used a quasi-experimental two-group pre-post design using the difference-in-differences method. PATIENTS: Commercially insured patients, with any of the five chronic diseases-congestive heart failure, chronic obstructive pulmonary disease, coronary heart disease, diabetes, or asthma, who were outreached to and engaged in either PDCM or HPDCM were included in the study. MAIN MEASURES: Outreached patients were those who received an attempted or actual contact for enrollment in care management; and engaged patients were those who had one or more care management sessions/encounters with a care manager. Effectiveness measures included blood pressure, low density lipoprotein (LDL), weight loss, and hemoglobin A1c (for diabetic patients only). Primary endpoints were evaluated in the first year of follow-up. KEY RESULTS: A total of 4,000 patients were clustered in 165 practices (31 in PDCM and 134 in HPDCM). The PDCM approach demonstrated a statistically significant improvement in the proportion of outreached patients whose LDL was under control: the proportion of patients with LDL < 100 mg/dL increased by 3 % for the PDCM group (95 % CI: 1 % to 6 %) and 1 % for the HPDCM group (95 % CI: -2 % to 5 %). However, the 2 % difference in these improvements was not statistically significant (95 % CI: -2 % to 6 %). The HPDCM approach showed 3 % [95 % CI: 2 % to 6 %] improvement in overall diabetes care among outreached patients and significant reduction in obesity rates compared to PDCM (4 %, 95 % CI: 0.3 % to 8 %). CONCLUSIONS: Both care management delivery modes may be viable options for improving care for patients with chronic diseases. In this commercially insured population, neither PDCM nor HPDCM resulted in substantial improvement in patients' clinical indicators in the first year. Different care management strategies within the provider-delivered programs need further investigation. PMID- 26951292 TI - Road Trips on the Via Regia: Introduction to Levy and Finnegan. PMID- 26951289 TI - AII amacrine cells: quantitative reconstruction and morphometric analysis of electrophysiologically identified cells in live rat retinal slices imaged with multi-photon excitation microscopy. AB - AII amacrine cells have been found in all mammalian retinas examined and play an important role for visual processing under both scotopic and photopic conditions. Whereas ultrastructural investigations have provided a detailed understanding of synaptic connectivity, there is little information available with respect to quantitative properties and variation of cellular morphology. Here, we performed whole-cell recordings from AII amacrine cells in rat retinal slices and filled the cells with fluorescent dyes. Multi-photon excitation microscopy was used to acquire image stacks and after deconvolution, we performed quantitative morphological reconstruction by computer-aided manual tracing. We reconstructed and performed morphometric analysis on 43 AII amacrine cells, with a focus on branching pattern, dendritic lengths and diameters, surface area, and number and distribution of dendritic varicosities. Compared to previous descriptions, the most surprising result was the considerable extent of branching, with the maximum branch order ranging from approximately 10-40. We found that AII amacrine cells conform to a recently described general structural design principle for neural arbors, where arbor density decreases proportionally to increasing territory size. We confirmed and quantified the bi-stratified morphology of AII amacrine cells by analyzing the arborizations as a function of retinal localization or with Sholl spheres. Principal component and cluster analysis revealed no evidence for morphological subtypes of AII amacrines. These results establish a database of morphometric properties important for studies of development, regeneration, degeneration, and disease processes, as well as a workflow compatible with compartmental modeling. PMID- 26951293 TI - A Clinical Case Presentation: Understanding and Interpreting Dreams while Working Through Developmental Trauma. AB - The purpose of this paper is to demonstrate the unique place of understanding and interpreting dreams in the psychoanalytic process while working through developmental trauma. This psychoanalytic process extended over six years and is presented in four phases: establishing the therapeutic alliance, a crisis, working through, and termination. Dreams from each of these four phases of the analysis are presented, and the collaborative work of understanding and interpreting these dreams is highlighted. Evidence is presented that from this analytic work there ensued an amelioration of the impact of developmental trauma and a furtherance of the development of internal psychic structure. PMID- 26951294 TI - Commentary on Levy and Finnegan. PMID- 26951295 TI - Commentary on Levy and Finnegan. PMID- 26951296 TI - Commentary on Levy and Finnegan. PMID- 26951297 TI - Commentary on Levy and Finnegan. PMID- 26951299 TI - Response to Commentaries. PMID- 26951300 TI - The Good Fight Continues. PMID- 26951298 TI - Commentary on Levy and Finnegan. PMID- 26951301 TI - How Much Needs to Change in Analysis? How Do We Get There? PMID- 26951302 TI - Heather Macdonald's H is for Hawk. PMID- 26951303 TI - Recent analysis of status and outcomes of peritoneal dialysis in the Tokai area of Japan: the second report of the Tokai peritoneal dialysis registry. AB - BACKGROUND: Early withdrawal within 3 years after starting peritoneal dialysis (PD) and PD-related peritonitis have been major obstacles preventing increases in the population of PD patients. To address these problems, we implemented education programs for medical staff. This study analyzed the recent status and outcomes of PD therapy, focusing on findings such as the incidence and prognosis of peritonitis as of 5 years after our last study. METHODS: We investigated background, laboratory data and status of PD therapy, reasons for withdrawal from PD and incidental statements on peritonitis from 2010 to 2012 (R2), and compared findings with those from our last study of 2005-2007 (R1). RESULTS: Early PD therapy withdrawal in R2 clearly improved to 44.7 %, compared with 50.9 % in R1. Peritonitis incidence improved slightly from once per 42.8 months/patient in R1 to once per 47.3 months/patient in R2. Notably, PD-related peritonitis as a cause of mortality improved markedly in R2, but outcomes of PD-related peritonitis did not change significantly between R1 and R2. In contrast, social problems increased as a reason for withdrawal from PD therapy. CONCLUSION: Our efforts at education might have been useful for improving early withdrawal from PD and deaths attributable to PD-related peritonitis. However, since improvements to incidence of PD-related peritonitis were limited by education, further improvement in PD-related peritonitis incidence requires development of new sterilized connecting systems during PD-bag exchanges to decrease PD-related peritonitis opportunities. Construction of medical support systems to address social problems is required to maintain long-term PD therapy. PMID- 26951305 TI - Predicting Sexual Assault Perpetration Among Heterosexually Active Young Men. AB - Data from an online community sample of young men were analyzed to test predictors of sexual assault perpetration. We used structural equation modeling to test the relative contributions of specific sub-types of childhood adversity to subsequent sexual aggression. Mediators included hostile masculinity, impersonal sexual behavior and attitudes, and substance use variables. Findings suggested that childhood sexual abuse had direct and mediated effects on sexual assault perpetration, but hostile masculinity was the only proximal factor significantly related to aggression. Childhood polytrauma was also associated with increased perpetration risk, suggesting that prevention efforts may be aided by increased attention to childhood maltreatment. PMID- 26951304 TI - Correlation with Platelet Parameters and Genetic Markers of Thrombophilia Panel (Factor II g.20210G>A, Factor V Leiden, MTHFR (C677T, A1298C), PAI-1, beta Fibrinogen, Factor XIIIA (V34L), Glycoprotein IIIa (L33P)) in Ischemic Strokes. AB - An important type of arterial thrombosis, ischemic stroke is associated with increased mortality risk, severe disability and life quality impairment. In this study, we analyzed mean platelet volume, platelet count values and genetic thrombophilia markers of patients who have ischemic stroke history and searched the relationship with genetic predisposition of ischemic strokes and platelet parameters. A retrospective, clinical trial was performed by reviewing the ischemic stroke history (except cryptogenic events) of 599 patients and 100 controls. The results of the genetic thrombophilia panel were used to classify the study group and control group into low and high risk for thrombophilia groups. The high-risk group included patients homozygous/heterozygous for Factor II g.20210G>A or Factor V Leiden mutations with/without any other polymorphism. The low-risk group included patients heterozygous or homozygous for MTHFR (C677T, A1298C), PAI-1, beta-fibrinogen, Factor XIIIA (V34L) and glycoprotein IIIa (L33P) polymorphisms or negative in terms of both mutations and polymorphisms. The results of study showed us that high-risk group mutations are important risk factors for ischemic stroke but low-risk group polymorphisms are not significant. According to platelet parameters, although there was a significant difference between MPV and PLT values of ischemic stroke and control group, thrombophilia mutations and polymorphisms have not a significant effect on MPV and PLT values in ischemic stroke patients. PMID- 26951306 TI - Perceived Impact of a Land and Property Rights Program on Violence Against Women in Rural Kenya: A Qualitative Investigation. AB - The current study focuses on a community-led land and property rights program in two rural provinces in western Kenya. The program was designed to respond to women's property rights violations to reduce violence against women and HIV risks at the community level. Through in-depth interviews with 30 women, we examine the perceived impact that this community-level property rights program had on violence against women at the individual and community level. We also examine perceptions as to how reductions in violence were achieved. Finally, we consider how our findings may aid researchers in the design of structural violence prevention strategies. PMID- 26951307 TI - Intimate Partner Violence and Patterns of Safety Strategy Use Among Women Seeking Temporary Protective Orders: A Latent Class Analysis. AB - This study examined use of safety strategies, experience of violence, and perception of danger from intimate partner violence (IPV) among 197 women seeking temporary protective orders against their abusive partners/ex-partners. Latent class analysis was used to group women into classes based on their use of safety strategies. Five classes of strategy use were identified: two high-activity classes, two moderately active classes, and one low-activity class. More severe abuse, increased perception of danger, and unemployment were associated with being in the higher activity classes. More effective interventions and outreach tools are needed to help women in IPV situations. PMID- 26951308 TI - Evolution of Randomized Trials in Advanced/Metastatic Soft Tissue Sarcoma: End Point Selection, Surrogacy, and Quality of Reporting. AB - PURPOSE: Randomized controlled trials (RCTs) in soft tissue sarcoma (STS) have used varying end points. The surrogacy of intermediate end points, such as progression-free survival (PFS), response rate (RR), and 3-month and 6-month PFS (3moPFS and 6moPFS) with overall survival (OS), remains unknown. The quality of efficacy and toxicity reporting in these studies is also uncertain. METHODS: A systematic review of systemic therapy RCTs in STS was performed. Surrogacy between intermediate end points and OS was explored using weighted linear regression for the hazard ratio for OS with the hazard ratio for PFS or the odds ratio for RR, 3moPFS, and 6moPFS. The quality of reporting for efficacy and toxicity was also evaluated. RESULTS: Fifty-two RCTs published between 1974 and 2014, comprising 9,762 patients, met the inclusion criteria. There were significant correlations between PFS and OS (R = 0.61) and between RR and OS (R = 0.51). Conversely, there were nonsignificant correlations between 3moPFS and 6moPFS with OS. A reduction in the use of RR as the primary end point was observed over time, favoring time-based events (P for trend = .02). In 14% of RCTs, the primary end point was not met, but the study was reported as being positive. Toxicity was comprehensively reported in 47% of RCTs, whereas 14% inadequately reported toxicity. CONCLUSION: In advanced STS, PFS and RR seem to be appropriate surrogates for OS. There is poor correlation between OS and both 3moPFS and 6moPFS. As such, caution is urged with the use of these as primary end points in randomized STS trials. The quality of toxicity reporting and interpretation of results is suboptimal. PMID- 26951309 TI - Randomized Open-Label Phase II Trial of Apitolisib (GDC-0980), a Novel Inhibitor of the PI3K/Mammalian Target of Rapamycin Pathway, Versus Everolimus in Patients With Metastatic Renal Cell Carcinoma. AB - PURPOSE: To the best of our knowledge, this study is the first to compare dual inhibition of PI3K/mammalian target of rapamycin (mTOR) by apitolisib (GDC-0980) against single inhibition of mTORC1 by everolimus in metastatic renal cell carcinoma (mRCC). PATIENTS AND METHODS: Patients with clear-cell mRCC who progressed on or after vascular endothelial growth factor-targeted therapy were randomly assigned to apitolisib 40 mg once per day or to everolimus 10 mg once per day. End points included progression-free survival, safety, overall survival, and objective response rate. Biomarker assessments were conducted. RESULTS: Eighty-five patients were randomly assigned. After 67 events, stratified analysis revealed that median progression-free survival was significantly shorter for apitolisib than for everolimus (3.7 v 6.1 months; hazard ratio, 2.12 [95% CI, 1.23 to 3.63; P < .01]); apitolisib was not favored in any stratification subgroup. Median overall survival was not significantly different but trended in favor of everolimus (16.5 v 22.8 months; hazard ratio, 1.77 [95% CI, 0.97 to 3.24; P = .06]). The objective response rate was 7.1% for apitolisib and 11.6% for everolimus. Patients administered apitolisib with a greater incidence of grade 3 to 4 adverse events were more likely to discontinue treatment (31% v 12% for everolimus). No drug-related deaths were observed. Apitolisib in comparison with everolimus was associated with substantially more high-grade hyperglycemia (40% v 9%) and rash (24% v 2%). Apitolisib pharmacokinetics suggested a relationship between exposure, and rash and hyperglycemia. Retrospective biomarker analyses revealed a relationship between VHL mutation status and outcome with everolimus but not with apitolisib. High hypoxia-inducible factor 1alpha protein expression was associated with better outcome in both arms. CONCLUSION: This study demonstrated that dual PI3K/mTOR inhibition by apitolisib was less effective than was everolimus in mRCC, likely because full blockade of PI3K/mTOR signaling resulted in multiple on-target adverse events. VHL mutation and hypoxia-inducible factor 1alpha expression may be predictive of an mTOR inhibitor benefit, although prospective validation is required. PMID- 26951310 TI - Evaluation of Immune-Related Response Criteria and RECIST v1.1 in Patients With Advanced Melanoma Treated With Pembrolizumab. AB - PURPOSE: We evaluated atypical response patterns and the relationship between overall survival and best overall response measured per immune-related response criteria (irRC) and Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1) in patients with advanced melanoma treated with pembrolizumab in the phase Ib KEYNOTE-001 study (clinical trial information: NCT01295827). PATIENTS AND METHODS: Patients received pembrolizumab 2 or 10 mg/kg every 2 weeks or every 3 weeks. Atypical responses were identified by using centrally assessed irRC data in patients with >= 28 weeks of imaging. Pseudoprogression was defined as >= 25% increase in tumor burden at week 12 (early) or any assessment after week 12 (delayed) that was not confirmed as progressive disease at next assessment. Response was assessed centrally per irRC and RECIST v1.1. RESULTS: Of the 655 patients with melanoma enrolled, 327 had >= 28 weeks of imaging follow up. Twenty-four (7%) of these 327 patients had atypical responses (15 [5%] with early pseudoprogression and nine [3%] with delayed pseudoprogression). Of the 592 patients who survived >= 12 weeks, 84 (14%) experienced progressive disease per RECIST v1.1 but nonprogressive disease per irRC. Two-year overall survival rates were 77.6% in patients with nonprogressive disease per both criteria (n = 331), 37.5% in patients with progressive disease per RECIST v1.1 but nonprogressive disease per irRC (n = 84), and 17.3% in patients with progressive disease per both criteria (n = 177). CONCLUSION: Atypical responses were observed in patients with melanoma treated with pembrolizumab. Based on survival analysis, conventional RECIST might underestimate the benefit of pembrolizumab in approximately 15% of patients; modified criteria that permit treatment beyond initial progression per RECIST v1.1 might prevent premature cessation of treatment. PMID- 26951311 TI - Surgical Proficiency Gain and Survival After Esophagectomy for Cancer. AB - PURPOSE: We aimed to identify the presence and length of esophagectomy proficiency gain curves in terms of short- and long-term mortality for esophageal cancer. PATIENTS AND METHODS: Patients who underwent esophagectomy for esophageal cancer between 1987 and 2010 with follow-up until 2014 were identified from a well-established, population-based, nationwide Swedish cohort study. Proficiency gain curves were created by using risk-adjusted cumulative sum analysis for 30 day, 90-day, 1-year, 3-year, and 5-year all-cause and disease-specific mortality measures. Similarly, the proficiency gain curves for lymph node harvest, resection margin status, and reoperation incidence were assessed as performance contributing factors to the observed changes in long-term survival. RESULTS: Esophagectomies in 1,821 patients with esophageal cancer were conducted by 139 surgeons. The change-point in proficiency gain curve for all-cause 30-day mortality was early, at 15 cases, when mortality decreased from 7.9% to 3.1% (P < .001). Later change-points, which ranged from 35 to 59 cases, were observed for 1 , 3- and 5-year mortality rates, for which all-cause mortality decreased from 34.9% to 27.7% (P = .011), from 47.4% to 41.5% (P = .049), and from 31.4% to 19.1% (P = .009), respectively. Similar change-points were observed in disease specific mortality at 1 and 3 years. There was a continuous increase in lymph node harvest, which did not plateau. Also, change-points were observed for resection margin with tumor involvement at 17 cases, with a reduction from 20.9% to 15.2% (P = .004), and for reoperation rate at 55 cases, with a reduction from 12.6% to 5.0% (P < .001). CONCLUSION: The gain of proficiency in esophagectomy for cancer is associated with measurable changes in short- and long-term mortality results. These findings indicate a need for structured national training and mentorship programs for esophageal cancer surgery. PMID- 26951313 TI - Reply to G. Nasti and A. Ottaiano and to A. Avallone and A. Budillon. PMID- 26951314 TI - Surrogate End Points and Their Validation in Oncology Clinical Trials. PMID- 26951315 TI - Reply to C. Cozzarini et al. PMID- 26951312 TI - Meta-Analysis Evaluating the Impact of Site of Metastasis on Overall Survival in Men With Castration-Resistant Prostate Cancer. AB - PURPOSE: Reports have suggested that metastatic site is an important predictor of overall survival (OS) in men with metastatic castration-resistant prostate cancer (mCRPC), but these were based on a limited number of patients. We investigate the impact of site of metastases on OS of a substantial sample of men with mCRPC who received docetaxel chemotherapy in nine phase III trials. PATIENTS AND METHODS: Individual patient data from 8,820 men with mCRPC enrolled onto nine phase III trials were combined. Site of metastases was categorized as lymph node (LN) only, bone with or without LN (with no visceral metastases), any lung metastases (but no liver), and any liver metastases. RESULTS: Most patients had bone with or without LN metastases (72.8%), followed by visceral disease (20.8%) and LN-only disease (6.4%). Men with liver metastases had the worst median OS (13.5 months). Although men with lung metastases had better median OS (19.4 months) compared with men with liver metastases, they had significantly worse median survival duration than men with nonvisceral bone metastases (21.3 months). Men with LN only disease had a median OS of 31.6 months. The pooled hazard ratios for death in men with lung metastases compared with men with bone with or without LN metastases and in men with any liver metastases compared with men with lung metastases were 1.14 (95% CI, 1.04 to 1.25; P = .007) and 1.52 (95% CI, 1.35 to 1.73; P < .0001), respectively. CONCLUSION: Specific sites of metastases in men with mCRPC are associated with differential OS, with successive increased lethality for lung and liver metastases compared with bone and nonvisceral involvement. These data may help in treatment decisions, the design of future clinical trials, and understanding the variation in biology of different sites of metastases in men with mCRPC. PMID- 26951316 TI - Importance of Smoking Cessation to Reduce Breast Cancer Mortality. PMID- 26951317 TI - Dose Escalation in Salvage Radiation Therapy and Urinary Toxicity: A Small Price to Pay for a Significant Prospective Benefit. PMID- 26951318 TI - Cardiovascular Disease Risk Profiles in Survivors of Adolescent and Young Adult (AYA) Cancer: The Kaiser Permanente AYA Cancer Survivors Study. AB - PURPOSE: To describe the epidemiology and risk factors for cardiovascular disease (CVD) in survivors of adolescent and young adult (AYA) cancer. METHODS: We identified a retrospective cohort of 2-year survivors of AYA cancer who were diagnosed between the ages of 15 to 39 years (1998 to 2009) at Kaiser Permanente Southern California. A comparison group without cancer was selected and matched 10:1 to cancer survivors on the basis of age, sex, Kaiser Permanente Southern California membership, and calendar year. Patients were followed through December 31, 2012, for coronary artery disease, heart failure, and stroke. Time-dependent Poisson regression was used to evaluate the effect that cancer survivorship had on the risk of developing CVD, adjusted for cardiovascular risk factors (CVRFs; ie, diabetes, hypertension, and dyslipidemia), ethnicity, smoking, and overweight/obesity. Among cancer survivors, mortality risk by CVD status was examined using Cox regression. RESULTS: A total of 5,673 2-year survivors of AYA cancer and 57,617 comparison patients were included, representing 24,839 and 239,073 person-years of follow-up, respectively. Overall, cancer survivors had more than two-fold risk of developing CVD (adjusted incidence rate ratio, 2.37; 95% CI, 1.93 to 2.93) when compared with patients without cancer; survivors of leukemia and breast cancer were at the highest risk (adjusted incidence rate ratio, 4.23; 95% CI, 1.73 to 10.31; and 3.63; 95% CI, 2.41 to 5.47, respectively) of developing CVD. Having any of the CVRFs increased the risk of CVD in cancer survivors. Cancer survivors who developed CVD had an 11-fold increased overall mortality risk (hazard ratio, 10.9; 95% CI, 8.1 to 14.8) when compared with survivors without CVD. CONCLUSION: Survivors of AYA cancer are at increased risk for developing CVD. Survival after CVD onset is compromised, and CVRFs are independent modifiers of CVD risk. These data form the basis for identifying high risk individuals and proactive management of CVRFs. PMID- 26951319 TI - Best Sequence Therapy in RAS Wild-Type Metastatic Colorectal Cancer: Waiting for Randomized Crossover Clinical Trials. PMID- 26951320 TI - Is Estradiol Monitoring Necessary in Women Receiving Ovarian Suppression for Breast Cancer? AB - The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice.A 36-year-old premenopausal woman had been diagnosed with stage III breast cancer. After an initial biopsy confirmed breast cancer, she underwent mastectomy and axillary node dissection for a left-sided breast cancer, measuring 7 cm. The tumor had lobular histology and was considered grade 2 of 3. Metastatic carcinoma was identified in 10 of 13 axillary nodes. Immunohistochemical studies showed that the tumor was strongly positive for estrogen and progesterone receptor expression and had a Ki-67 score of 15% (> 20% is considered high according to a Swedish quality control study and the St Gallen Expert Consensus).(1,2) There was no amplification of the HER2/neu gene. Staging scans were negative for metastatic disease. In the adjuvant setting, she received three cycles of anthracycline-cyclophosphamide combination chemotherapy followed by three cycles of taxane chemotherapy and then locoregional radiotherapy. After completion of chemotherapy, she developed amenorrhea. As adjuvant endocrine therapy, she began monthly goserelin administration to achieve ovarian function suppression (OFS), in combination with the aromatase inhibitor (AI) exemestane. She experienced menopausal symptoms including hot flashes, vaginal dryness, and sexual dysfunction. After two monthly treatments with goserelin and exemestane, a sensitive assay for serum estradiol was checked and returned at 16 pg/mL (61 pmol/L); postmenopausal range for sensitive assay is less than 15 pg/mL (< 50 pmol/L). The patient has now been referred to our unit to discuss further management. PMID- 26951321 TI - Impact of Subsequent Therapies on Outcome of the FIRE-3/AIO KRK0306 Trial. PMID- 26951322 TI - Patient-Reported Outcomes After Choice for Contralateral Prophylactic Mastectomy. AB - PURPOSE: The rate of contralateral prophylactic mastectomies (CPMs) continues to rise, although there is little evidence to support improvement in quality of life (QOL) with CPM. We sought to ascertain whether patient-reported outcomes and, more specifically, QOL differed according to receipt of CPM. METHODS: Volunteers recruited from the Army of Women with a history of breast cancer surgery took an electronically administered survey, which included the BREAST-Q, a well-validated breast surgery outcomes patient-reporting tool, and demographic and treatment related questions. Descriptive statistics, hypothesis testing, and regression analysis were used to evaluate the association of CPM with four BREAST-Q QOL domains. RESULTS: A total of 7,619 women completed questionnaires; of those eligible, 3,977 had a mastectomy and 1,598 reported receipt of CPM. Women undergoing CPM were younger than those who did not choose CPM. On unadjusted analysis, mean breast satisfaction was higher in the CPM group (60.4 v 57.9, P < .001) and mean physical well-being was lower in the CPM group (74.6 v 76.6, P < .001). On multivariable analysis, the CPM group continued to report higher breast satisfaction (P = .046) and psychosocial well-being (P = .017), but no difference was reported in the no-CPM group in the other QOL domains. CONCLUSION: Choice for CPM was associated with an improvement in breast satisfaction and psychosocial well-being. However, the magnitude of the effect may be too small to be clinically meaningful. Such patient-reported outcomes data are important to consider when counseling women contemplating CPM as part of their breast cancer treatment. PMID- 26951323 TI - Convergence of Self-Reports and Informant Reports on the Personality Assessment Screener. AB - The present study is the first to investigate the Personality Assessment Screener, a brief self-report measure of risk for emotional and behavioral dysfunction, in relation to the informant report version of this instrument, the Personality Assessment Screener-Other. Among a sample of undergraduate roommate dyads ( N = 174), self-report and informant report total scores on the Personality Assessment Screener/Personality Assessment Screener-Other moderately converged ( r = 0.45), with generally greater agreement between perspectives observed for externalizing behaviors compared with internalizing distress. In addition, selves tended to report more psychological difficulties relative to informant ratings ( d = 0.45) with an average absolute discrepancy between sources of 6.31 ( SD = 4.96) out of a possible range of 66. Discrepancies between self-report and informant report were significantly associated with characteristics of the dyadic relationship (e.g., length of acquaintanceship) as well as the severity of self-reported psychological difficulties and positive impression management. PMID- 26951324 TI - Resting heart rate predicts incident myocardial infarction, atrial fibrillation, ischaemic stroke and death in the general population: the Tromso Study. AB - BACKGROUND: Elevated resting heart rate (RHR) increases risk of death overall, but a comprehensive picture of the associations between RHR, cardiovascular morbidity and mortality events has not yet been presented. We aimed to investigate the effect of RHR on the risk of 5 cardiovascular events: incident myocardial infarction (MI), incident atrial fibrillation (AF), incident ischaemic stroke, total death and cardiovascular death in a general population from Norway. METHODS: We followed 24 489 men and women from the Tromso Study 1994-1995, a population-based cohort study, for 18 years, and analysed the association between RHR and the investigated cardiovascular events. Sex-specific Cox regression with time-dependent covariates was applied with the best-fitting fractional polynomials of RHR. RESULTS: Among men, an independent positive relationship was observed for MI and AF (adjusted HR for AF per 20 bpm increase=1.14; 95% CI 1.02 to 1.27). In women, the corresponding HR for MI was 1.23 (1.09 to 1.40). A J shaped association was observed for ischaemic stroke in women when compared with a RHR of 70 bpm (HR for 50 bpm=1.31; 0.90 to 1.90; HR for 100 bpm=1.32; 1.04 to 1.69). Total and cardiovascular death showed a strong positive association with RHR in men. In women, the pattern for total death was similar. CONCLUSIONS: RHR is an independent risk factor for several cardiovascular events. A novel finding is the positive association between RHR and AF in men and the sex difference in association with ischaemic stroke. PMID- 26951325 TI - Remembering parents in parent-mediated early intervention: An approach to examining impact on parents and families. AB - The goal of this review is to advance the discussion regarding meaningful outcomes of early intervention for children with autism spectrum disorder. The rapid growth in the development and evaluation of early intervention approaches for autism spectrum disorder includes both therapist-driven and parent-mediated interventions. The majority of research on both approaches to early intervention focuses on promoting child outcomes (e.g. language acquisition) with less emphasis on family and parent outcomes (e.g. quality of life, self-efficacy). Given that parent buy-in is essential for parent-mediated interventions to be effective over time, increased attention to family outcomes that are of value to families and have the potential to be impacted positively by these interventions is needed to develop, disseminate, and sustain high-quality interventions in community settings. In this review, we draw from work on parent and family outcomes targeted in related fields (e.g. Part C early intervention, pediatric chronic illness, behavior management parent training) that we propose are particularly relevant for evaluating the impact of parent-mediated interventions in early intervention for autism spectrum disorder. PMID- 26951326 TI - To include or not to include: Evaluations and reasoning about the failure to include peers with autism spectrum disorder in elementary students. AB - Given the significant role that typically developing children play in the social lives of children with autism spectrum disorder, it is important to understand how they evaluate and reason about the inclusion/exclusion of children with autism spectrum disorder in social situations. The objective of this study is to determine elementary students' evaluations, reasoning patterns, and reasoning complexity regarding the failure to include children with autism spectrum disorder in social activities. Forty-four elementary-aged students participated in interviews, which included vignettes describing four contexts in which a child with autism spectrum disorder is not invited to a social event. Responses were analyzed according to social domain theory, an approach emphasizing that children identify and coordinate different domains of social knowledge, including the moral, personal, societal, and prudential. Results showed that regardless of grade and context, most children judge that failure to include on the basis of disability status is not acceptable. However, the complexity of children's reasoning (i.e. the extent to which they drew upon and coordinated multiple domains) was higher in older children. Mean complexity scores were also higher in a birthday party context as compared to a playdate context. We offer implications for future research and practice regarding the social inclusion of children with autism spectrum disorder. PMID- 26951327 TI - Adolescent boys with an autism spectrum disorder and their experience of sexuality: An interpretative phenomenological analysis. AB - This qualitative study explored how adolescent boys with autism spectrum disorder experience their sexuality. Previous research has demonstrated that sexuality is a developmental task for boys with autism spectrum disorder, as it is for their peers. Case studies have suggested a relation between autism spectrum disorder and atypical sexual development; empirical studies on this subject, however, are scant and inconsistent. This study is based on interviews with eight boys, aged 16-20 years, with Asperger's disorder or autistic disorder. Interpretative phenomenological analysis of the data revealed three major themes relating to (a) how they experience sexual feelings, think about sexuality and think about themselves as sexual beings; (b) how they perceive messages relating to sexuality in their surroundings; and (c) how they experience finding and having a partner and partnered sex. We believe that attention to these themes is needed in assessment, education and further research. PMID- 26951328 TI - Histologic and molecular characterization of Edwardsiella piscicida infection in largemouth bass (Micropterus salmoides). AB - The genus Edwardsiella is composed of a diverse group of facultative anaerobic, gram-negative bacteria that can produce disease in a wide variety of hosts, including birds, reptiles, mammals, and fish. Our report describes the isolation and identification of Edwardsiella piscicida associated with chronic mortality events in 2 separate captive largemouth bass (Micropterus salmoides) populations in New York and Florida. Wet-mount biopsies of skin mucus, gill, kidney, and spleen from several affected largemouth bass contained significant numbers of motile bacteria. Histologic examination revealed multifocal areas of necrosis scattered throughout the heart, liver, anterior kidney, posterior kidney, and spleen. Many of the necrotic foci were encapsulated or replaced by discrete granulomas and associated with colonies of gram-negative bacteria. Initial phenotypic and matrix-assisted laser desorption ionization-time of flight mass spectrometric analysis against existing spectral databases of recovered isolates identified these bacteria as Edwardsiella tarda Subsequent molecular analysis using repetitive sequence mediated and species-specific PCR, as well as 16S rRNA, rpoB, and gyrB sequences, classified these isolates as E. piscicida As a newly designated taxon, E. piscicida should be considered as a differential for multiorgan necrosis and granulomas in largemouth bass. PMID- 26951329 TI - Dermatomycosis in three central bearded dragons (Pogona vitticeps) associated with Nannizziopsis chlamydospora. AB - Chronic dermatomycosis was identified in 3 central bearded dragons (Pogona vitticeps), held as companion animals by the same owner. Clinical signs of dermatomycosis included subcutaneous masses as well as crusty, erosive, and ulcerative skin lesions. The facial region was affected in 2 of the 3 cases. Masses were surgically excised, and histology confirmed necrotizing and granulomatous inflammatory processes associated with fungal hyphae. Two of the bearded dragons were euthanized because of their deteriorating condition. In both cases, postmortem histology confirmed systemic fungal infections despite treatment of 1 animal with itraconazole. In the third bearded dragon, therapy with voriconazole at 10 mg/kg was initially effective, but mycotic lesions reappeared 15 months later. Nannizziopsis chlamydospora was identified by PCR and subsequent DNA sequencing in 2 of these cases. PMID- 26951330 TI - Development of a duplex rapid assay for immunoglobulins M and G to evaluate the parvoviral immune status of clinically healthy dogs. AB - A duplex rapid assay for detection of serum antibodies to canine parvovirus (CPV) was developed. Canine immunoglobulin (Ig)M or IgG were captured in immunotubes with anti-canine IgM or IgG and detected with parvovirus VP2 recombinant protein followed by an anti-VP2 monoclonal antibody. The assay was tested using a collection of sera from dogs that were vaccinated against CPV on arrival at an animal shelter in Madrid, Spain. Results were compared with those of 2 commercial enzyme-linked immunosorbent assays (ELISAs) considered as reference techniques. A high correlation was found between the duplex rapid assay and the ELISAs, presenting an accuracy of 98% and 100% for IgG and IgM, respectively. According to the IgG and IgM levels at days 0-3 postvaccination, the samples were divided into 2 groups. One group of dogs showed high IgG and low IgM values at the first sampling post-vaccination and during the following 14 days, indicating that they had previously been in contact with the virus, either by vaccination or infection before arrival at the animal shelter. A second group of dogs appeared to be unvaccinated or uninfected before arrival at the animal shelter because they had negative IgM and IgG values soon after vaccination. These animals responded to vaccination, as demonstrated by seroconversion of both isotypes of immunoglobulins. The developed assay appears to be useful in determining the unknown immune status of dogs to CPV, especially in kennels and shelters where the rate of infection by CPV is relatively high. PMID- 26951331 TI - Cutaneous epitheliotropic T-cell lymphoma with systemic dissemination in a dog. AB - Cutaneous epitheliotropic T-cell lymphoma (CETL) is characterized by neoplastic T cell infiltration of the epidermis, adnexal structures, and oral mucosa. The objective of this report was to describe the pathological findings of a canine case of terminal-stage CETL. A 10-year-old, mixed-breed, neutered male dog was presented with erosion of the oral mucosa and mucocutaneous junction. The dog was diagnosed with CETL with no evidence of metastasis. Despite chemotherapy, the dog was re-presented with oral pain, vomiting, and diarrhea, and died 17 months after the first visit to the hospital. A complete autopsy was performed. Histologic examination of the primary lesion and systemic organs was performed. Gross examination revealed an advanced-stage oral lesion. Distinct tumor formation was not observed in the primary sites and systemic organs. Histologically, the primary oral lesion was characterized by massive intraepithelial infiltration of a large number of neoplastic lymphocytes. The neoplastic cells in the metastatic sites also showed exclusive epitheliotropic proliferation in organs, including the trachea, tonsils, esophagus, stomach, small intestine, colon, anal mucosa, liver, pancreas, kidneys, urinary bladder, prostate gland, ear canals, and auricular and ventral skin. Immunohistochemically, the neoplastic cells were positive for CD3 and negative for CD20 as well as CD79alpha, supporting a diagnosis of CETL with systemic dissemination. In canine CETL with systemic signs, systemic metastasis should be considered even without evident mass formation. Neoplastic lymphocytes of CETL showed distinct epitheliotropism even in the systemic metastatic sites. PMID- 26951335 TI - A human trigeminovascular biomarker for antimigraine drugs: A randomised, double blind, placebo-controlled, crossover trial with sumatriptan. AB - Current antimigraine drugs are believed, besides their direct vasoconstrictive effect, to inhibit calcitonin gene-related peptide (CGRP) release from trigeminal nerve endings during migraine. Objective The objective of this report is to establish a biomarker for the CGRP-interfering effect of antimigraine drugs. Methods We quantified the effect of sumatriptan on the trigeminal nerve-mediated rise in forehead dermal blood flow (DBF), induced by capsaicin application (0.6 mg/ml) and electrical stimulation (0.2-1.0 mA), in a randomised, double-blind, placebo-controlled, crossover study in healthy male ( n = 11, age +/- SD: 29 +/- 8 years) and female ( n = 11, 32 +/- 7 years) individuals. Results DBF responses to capsaicin were attenuated by sumatriptan (DeltaDBF, mean +/- SEM: 82 +/- 18 AU, p = 0.0002), but not by placebo (DeltaDBF: 21 +/- 12 AU, p = 0.1026). Conclusion We demonstrated that sumatriptan inhibits increases in DBF, induced by the release of, most likely, CGRP. Thus, our model may be used as a biomarker to establish the trigeminovascular effects of (potential) antimigraine drugs, such as CGRP receptor antagonists or antibodies directed against CGRP or its receptor. PMID- 26951336 TI - Coexisting vascular lesions in reversible cerebral vasoconstriction syndrome. AB - Background The pathophysiology of reversible cerebral vasoconstriction syndrome (RCVS) is not known. Published cases have documented coexisting cervical artery dissection and unruptured aneurysms, raising the possibility that ultrastructural vessel wall abnormalities underlie the development of vascular lesions as well as RCVS. Methods In this retrospective study we compared the frequency of neurovascular abnormalities in 158 consecutive RCVS patients, 44 patients with primary angiitis of the central nervous system (PACNS, positive controls), and 177 non-stroke patients with acute neurological symptoms (non-arteriopathy controls). Results Coexisting neurovascular abnormalities were significantly higher ( p < 0.001) in RCVS (23%) as compared to the PACNS (5%) or non arteriopathy groups (8%). Cervical artery dissections were noted only in the RCVS group (8%, p < 0.001). The RCVS group had more unruptured aneurysms than PACNS (13% vs. 5%, p = 0.099) or non-arteriopathy controls (13% vs. 7%, p = 0.05). Seven RCVS patients also had other vascular malformations (venous anomaly, cavernous malformations, fibromuscular dysplasia). There was no significant association between coexisting vascular abnormalities and brain lesions or discharge clinical outcome in the RCVS group. Conclusion The high prevalence and heterogeneous anatomy of coexisting vascular lesions suggest that subtle ultrastructural arterial wall abnormalities may contribute to their development and also predispose to RCVS. PMID- 26951337 TI - Response to Comments by Dr Gholami on "A Systematic Review of Iran's Medicinal Plants With Anticancer Effects". PMID- 26951333 TI - Dietary restriction improves repopulation but impairs lymphoid differentiation capacity of hematopoietic stem cells in early aging. AB - Dietary restriction (DR) improves health, delays tissue aging, and elongates survival in flies and worms. However, studies on laboratory mice and nonhuman primates revealed ambiguous effects of DR on lifespan despite improvements in health parameters. In this study, we analyzed consequences of adult-onset DR (24 h to 1 yr) on hematopoietic stem cell (HSC) function. DR ameliorated HSC aging phenotypes, such as the increase in number of HSCs and the skewing toward myeloid biased HSCs during aging. Furthermore, DR increased HSC quiescence and improved the maintenance of the repopulation capacity of HSCs during aging. In contrast to these beneficial effects, DR strongly impaired HSC differentiation into lymphoid lineages and particularly inhibited the proliferation of lymphoid progenitors, resulting in decreased production of peripheral B lymphocytes and impaired immune function. The study shows that DR-dependent suppression of growth factors and interleukins mediates these divergent effects caused by DR. Supplementation of insulin-like growth factor 1 partially reverted the DR-induced quiescence of HSCs, whereas IL-6/IL-7 substitutions rescued the impairment of B lymphopoiesis exposed to DR. Together, these findings delineate positive and negative effects of long-term DR on HSC functionality involving distinct stress and growth signaling pathways. PMID- 26951332 TI - Isocitrate dehydrogenase 1 mutations prime the all-trans retinoic acid myeloid differentiation pathway in acute myeloid leukemia. AB - Acute myeloid leukemia (AML) is characterized by the accumulation of malignant blasts with impaired differentiation programs caused by recurrent mutations, such as the isocitrate dehydrogenase (IDH) mutations found in 15% of AML patients. These mutations result in the production of the oncometabolite (R)-2 hydroxyglutarate (2-HG), leading to a hypermethylation phenotype that dysregulates hematopoietic differentiation. In this study, we identified mutant R132H IDH1-specific gene signatures regulated by key transcription factors, particularly CEBPalpha, involved in myeloid differentiation and retinoid responsiveness. We show that treatment with all-trans retinoic acid (ATRA) at clinically achievable doses markedly enhanced terminal granulocytic differentiation in AML cell lines, primary patient samples, and a xenograft mouse model carrying mutant IDH1. Moreover, treatment with a cell-permeable form of 2 HG sensitized wild-type IDH1 AML cells to ATRA-induced myeloid differentiation, whereas inhibition of 2-HG production significantly reduced ATRA effects in mutant IDH1 cells. ATRA treatment specifically decreased cell viability and induced apoptosis of mutant IDH1 blasts in vitro. ATRA also reduced tumor burden of mutant IDH1 AML cells xenografted in NOD-Scid-IL2rgamma(null)mice and markedly increased overall survival, revealing a potent antileukemic effect of ATRA in the presence of IDH1 mutation. This therapeutic strategy holds promise for this AML patient subgroup in future clinical studies. PMID- 26951334 TI - Small intestinal eosinophils regulate Th17 cells by producing IL-1 receptor antagonist. AB - Eosinophils play proinflammatory roles in helminth infections and allergic diseases. Under steady-state conditions, eosinophils are abundantly found in the small intestinal lamina propria, but their physiological function is largely unexplored. In this study, we found that small intestinal eosinophils down regulate Th17 cells. Th17 cells in the small intestine were markedly increased in the DeltadblGATA-1 mice lacking eosinophils, and an inverse correlation was observed between the number of eosinophils and that of Th17 cells in the small intestine of wild-type mice. In addition, small intestinal eosinophils suppressed the in vitro differentiation of Th17 cells, as well as IL-17 production by small intestinal CD4(+)T cells. Unlike other small intestinal immune cells or circulating eosinophils, we found that small intestinal eosinophils have a unique ability to constitutively secrete high levels of IL-1 receptor antagonist (IL 1Ra), a natural inhibitor of IL-1beta. Moreover, small intestinal eosinophils isolated from IL-1Ra-deficient mice failed to suppress Th17 cells. Collectively, our results demonstrate that small intestinal eosinophils play a pivotal role in the maintenance of intestinal homeostasis by regulating Th17 cells via production of IL-1Ra. PMID- 26951338 TI - The application of prepared porous carbon materials: Effect of different components on the heavy metal adsorption. AB - In this study, five typical municipal solid waste (MSW) components (tyres, cardboard, polyvinyl chloride (PVC), acrylic textile, toilet paper) were used as raw materials to prepare four kinds of MSW-based carbon materials (paperboard based carbon materials (AC1); the tyres and paperboard-based carbon materials (AC2); the tyres, paperboard and PVC-based carbon materials (AC3); the tyres, paperboard, toilet paper, PVC and acrylic textile-based carbon materials (AC4)) by the KOH activation method. The characteristic results illustrate that the prepared carbon adsorbents exhibited a large pore volume, high surface area and sufficient oxygen functional groups. Furthermore, the application of AC1, AC2, AC3, AC4 on different heavy metal (Cu(2+), Zn(2+), Pb(2+), Cr(3+)) removals was explored to investigate their adsorption properties. The effects of reaction time, pH, temperature and adsorbent dosage on the adsorption capability of heavy metals were investigated. Comparisons of heavy metal adsorption on carbon of different components were carried out. Among the four samples, AC1 exhibits the highest adsorption capacity for Cu(2+); the highest adsorption capacities of Pb(2+) and Zn(2+) are obtained for AC2; that of Cr(3+) are obtained for AC4. In addition, the carbon materials exhibit better adsorption capability of Cu(2+) and Pb(2+) than the other two kind of metal ions (Zn(2+) and Cr(3+)). PMID- 26951339 TI - Effects and optimization of the use of biochar in anaerobic digestion of food wastes. AB - The addition of various amounts of biochar to anaerobic digestion of food wastes at different ratios of inoculum to substrate (ISR) was investigated to evaluate the effect of biochar as a functional additive and to optimize the additive dosage of biochar. The biochar treatments at ISR 2, 1, and 0.8 shortened the lag phase of digestion by -20.0%-10.9%, 43.3%-54.4%, and 36.3%-54.0%, and raised the maximum methane production rate by 100%-275%, 100%-133.3%, and 33.3%-100%, respectively, compared to control without biochar. Biochar also enhanced the degradation rate of dissolved organics and volatile fatty acids. Furthermore, the amount of biochar with best effectiveness at ISR = 2, 1, and 0.8 was 2.5, 0.625, and 0.5 g g(-1)-waste, respectively. Therefore, the effectiveness of biochar depended on the additive amount of biochar and at the same time the inoculum amount, implying a complementary role of abiotic biochar to biotic inoculum. PMID- 26951340 TI - A sustainable process for the recovery of valuable metals from spent lithium-ion batteries. AB - In this work, an eco-friendly and hydrometallurgical process for the recovery of cobalt and lithium from spent lithium-ion batteries has been proposed, which includes pretreatment, citric acid leaching, selective chemical precipitation and circulatory leaching. After pretreatment (manual dismantling, N-methyl pyrrolidone immersion and calcination), Cu and Al foils are recycled directly and the cathode active materials are separated from the cathode efficiently. Then, the obtained cathode active materials (waste LiCoO2) was firstly leached with 1.25 mol l(-1) citric acid and 1 vol.% H2O2 solution. Then cobalt was precipitated using oxalic acid (H2C2O4) under a molar ratio of 1:1.05 (H2C2O4: Co(2+)). After filtration, the filtrate (containing Li(+)) and H2O2 was employed as a leaching agent and the optimum conditions are studied in detail. The leaching efficiencies can reach as high as 98% for Li and 90.2% for Co, respectively, using filter liquor as leaching reagent under conditions of leaching temperature of 90 degrees C, 0.9 vol.% H2O2 and a solid-to-liquid ratio of 60 ml g(-1) for 35 min. After three bouts of circulatory leaching, more than 90% Li and 80% Co can be leached under the same leaching conditions. In this way, Li and Co can be recovered efficiently and waste liquor re-utilization is achievable with this hydrometallurgical process, which may promise both economic and environmental benefits. PMID- 26951341 TI - GIS-based approach for optimised collection of household waste in Mostaganem city (Western Algeria). AB - This work proposes an optimisation of municipal solid waste collection in terms of collection cost and polluting emissions (carbon oxides, carbon dioxides, nitrogen oxides and particulate matter). This method is based on a simultaneous optimisation of the vehicles routing (distance and time travelled) and the routing system for household wastes collection based on the existing network of containers, the capacity of vehicles and the quantities generated in every collecting point. The process of vehicle routing optimisation involves a geographical information system. This optimisation has enabled a reduction of travelled distances, collection time, fuel consumption and polluting emissions. Pertinent parameters affecting the fuel consumption have been utilised, such as the state of the road, the vehicles speed in the different paths, the vehicles load and collection frequencies. Several scenarios have been proposed. The results show the importance of the construction of a waste transfer station that can reduce the cost of household waste collection and emissions of waste transfer pollutants. Among the proposed five scenarios, we have noticed that the fourth scenario (by constructing a waste transfer centre) was the most performing. So, the routes of optimised travelled distance of the new circuits have been reduced by 71.81%. The fuel consumption has been reduced by 72.05% and the total cost of the collection has been reduced by 46.8%. For the polluting emissions, the reduction has been by 60.2% for carbon oxides, by 67.9% for carbon dioxides, by 74.2% for nitrogen oxides and by 65% for particulate matter. PMID- 26951342 TI - Leaching of valuable elements from thermal power plant bottom ash using a thermo hydrometallurgical process. AB - The solid industrial wastes generated from thermal power plants (TPPs) can be considered as renewable secondary sources for recovery of valuable metals. This study presents the results from investigations that integrated a thermo-hydro metallurgical method for treatment of bottom ash obtained from the Enel Maritsa East 3 TPP in Bulgaria. Leaching was performed with 20, 30 and 40 wt% sulphuric acid, respectively, in an autoclave at 100(o)C, 120(o)C and 140(o)C for 120, 240, 360 and 480 min, at a constant value of the liquid/solid ratio. After autoclaving, the samples (suspensions) were diluted with a constant value of water and stirring at 50(o)C for 60 min. On the basis of the experimental data the leaching efficiency (alpha) of the elements in the liquid phase after filtration was estimated. The leaching of aluminium increases significantly with increasing of the temperature, reaching the maximum value of 70 wt%. The highest leaching efficiency values for the other elements are as follows: Fe (86.4%), Ca (86.6%), Na (86.6%), Ni (83.3%) and Zn (83.3%). The maximum value of leaching for Mg, K, Mn, Cu and Cr is in the interval of 46-70%. PMID- 26951343 TI - Effects of thermal treatments on the characterisation and utilisation of red mud with sawdust additive. AB - Extremely large amounts of red mud (bauxite residue) are generated globally every year from alumina refining industries, which are being disposed of on engineered landfills. The objective of this study is to investigate the effects of thermal treatments on red mud for development of utilisation strategies. Thermal treatments of red mud samples and their characterisations were investigated under inert (N2) and oxidative (air) conditions with and without sawdust addition at 200-600 degrees C. After calcination, the resulting samples were analysed using thermogravimetric-infrared spectroscopy (TG-IR) for functional group transformations, thermogravimetric analysis (TGA) for thermal loss profiles and X ray diffraction (XRD) for mineral transformations. The characterisation results showed that in N2 environment, boehmite in red mud was transferred to transition alumina at around 400 degrees C while losing water from structural components. The addition of sawdust for incubation and calcination of red mud in air increased the surface area, whereas that in nitrogen atmosphere lead to reduction of hematite to magnetite at around 500 degrees C. The incorporated carbon materials played a major role in increasing the surface area especially for pore size less than 2.5 nm. This treated red mud with altered mineral composition and improved properties for binding contaminants can be used for environmental remediation and in the process of metal recovery such as iron. PMID- 26951344 TI - A Critical Look At Trauma-Informed Care Among Agencies and Systems Serving Maltreated Youth and Their Families. AB - The past two decades have witnessed an increase in programs targeting children and youth impacted by traumatic events, with a heightened focus on ensuring that all such programs and relevant service systems are trauma informed. While such efforts are laudable, trauma-informed care (TIC) is defined in a number of ways, limiting evaluation of these initiatives, specifically as they relate to the potential for improved outcomes or reduced costs often used to advocate for TIC. Widespread interest in TIC, despite an apparent dearth of empirical research, served as the impetus for this special section. Our goal was to identify the most rigorous empirical studies available. These six papers were selected based on their inclusion of a definition of TIC, focus on at least one component of TIC in a child-serving system, and availability of empirical data demonstrating the effectiveness of their efforts. In addition to introducing these papers, we share preliminary data from a brief, anonymous survey of child-serving professionals across various systems and roles to obtain feedback about definitional and conceptual issues related to TIC. While this special section provides a representation of available empirical work, significant gaps between research and practice of TIC remain, with important implications for future work. PMID- 26951346 TI - Degradation of Artemisinin-Based Combination Therapies Under Tropical Conditions. AB - Poor quality antimalarials, including falsified, substandard, and degraded drugs, are a serious health concern in malaria-endemic countries. Guidelines are lacking on how to distinguish between substandard and degraded drugs. "Forced degradation" in an oven was carried out on three common artemisinin-based combination therapy (ACT) brands to detect products of degradation using liquid chromatography mass spectrometry and help facilitate classification of degraded drugs. "Natural aging" of 2,880 tablets each of ACTs artemether/lumefantrine and artesunate/amodiaquine was undertaken to evaluate their long-term stability in tropical climates. Samples were aged in the presence and absence of light on-site in Ghana and in a stability chamber (London), removed at regular intervals, and analyzed to determine loss of the active pharmaceutical ingredients (APIs) over time and detect products of degradation. Loss of APIs in naturally aged tablets (both in Ghana and the pharmaceutical stability chamber) was 0-7% over 3 years (~12 months beyond expiry) with low levels of degradation products detected. Using this developed methodology, it was found that a quarter of ACTs purchased in Enugu, Nigeria (concurrent study), that would have been classified as substandard, were in fact degraded. Presence of degradation products together with evidence of insufficient APIs can be used to classify drugs as degraded. PMID- 26951347 TI - Dual task cost of cognition is related to fall risk in patients with multiple sclerosis: a prospective study. AB - OBJECTIVE: To examine whether change in cognitive performance during dual task condition compared with a task in isolation, known as dual task cost, is related to fall risk of patients with multiple sclerosis. DESIGN: Prospective cohort. During baseline assessment, data about balance, walking and cognitive performance of patients with multiple sclerosis were collected under a single and dual task condition. The dual task cost was calculated as a percentage of change in parameters from single to dual task conditions. Falls were recorded prospectively for six months and participants were classified as none/one time fallers and recurrent fallers (?2 falls). The association between dual task costs and fall status was evaluated by logistic regression. SETTING: Balance research lab of university hospital. PARTICIPANTS: A total of 60 patients with relapsing remitting multiple sclerosis. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The dual task cost of the center of pressure sway area, walking velocity and correct response rate were outcome measures for balance, walking and cognitive performance, respectively. RESULTS: A total of 79 falls were reported by 38 of the participants who experienced one or more falls; 26 (43.3%) of them had recurrent falls. Dual tasking resulted in increased sway area and decreased walking velocity and correct response rate during walking (all p values <0.05). Logistic regressions showed that the dual task cost of the correct response rate during walking and walking velocity were associated with increased risk of recurrent falls ( P = 0.02, odds ratio = 1.34; confidence interval (CI) 1.04 3.74; P = 0.05, odds ratio = 1.23, CI = 1.02-4.45, respectively). CONCLUSIONS: The dual task cost of cognition was related to fall, which should be considered as a target for falls evaluation and prevention strategies. PMID- 26951348 TI - Pilates exercise training vs. physical therapy for improving walking and balance in people with multiple sclerosis: a randomized controlled trial. AB - OBJECTIVE: Evaluate the effects of a Pilates exercise programme on walking and balance in people with multiple sclerosis and compare this exercise approach to conventional physical therapy sessions. DESIGN: Randomized controlled trial. SETTING: Multiple Sclerosis Center, Sheba Medical Center, Tel-Hashomer, Israel. SUBJECTS: Forty-five people with multiple sclerosis, 29 females, mean age (SD) was 43.2 (11.6) years; mean Expanded Disability Status Scale (S.D) was 4.3 (1.3). INTERVENTIONS: Participants received 12 weekly training sessions of either Pilates ( n=22) or standardized physical therapy ( n=23) in an outpatient basis. MAIN MEASURES: Spatio-temporal parameters of walking and posturography parameters during static stance. Functional tests included the Time Up and Go Test, 2 and 6 minute walk test, Functional Reach Test, Berg Balance Scale and the Four Square Step Test. In addition, the following self-report forms included the Multiple Sclerosis Walking Scale and Modified Fatigue Impact Scale. RESULTS: At the termination, both groups had significantly increased their walking speed ( P=0.021) and mean step length ( P=0.023). According to the 2-minute and 6-minute walking tests, both groups at the end of the intervention program had increased their walking speed. Mean (SD) increase in the Pilates and physical therapy groups were 39.1 (78.3) and 25.3 (67.2) meters, respectively. There was no effect of group X time in all instrumented and clinical balance and gait measures. CONCLUSIONS: Pilates is a possible treatment option for people with multiple sclerosis in order to improve their walking and balance capabilities. However, this approach does not have any significant advantage over standardized physical therapy. PMID- 26951349 TI - On calcium channel antagonist poisoning: towards evidence-based decision making in poisoned patients. PMID- 26951350 TI - Practical recommendations for calcium channel antagonist poisoning. AB - Calcium channel antagonists (CCAs) are widely used for different cardiovascular disorders. At therapeutic doses, CCAs have a favourable side effect profile. However, in overdose, CCAs can cause serious complications, such as severe hypotension and bradycardia. Patients in whom a moderate to severe intoxication is anticipated should be observed in a monitored setting for at least 12 hours if an immediate-release formulation is ingested, and at least 24 hours when a sustained-release formulation (or amlodipine) is involved, even if the patient is asymptomatic. Initial treatment is aimed at gastrointestinal decontamination and general supportive care, i.e., fluid resuscitation and correction of metabolic acidosis and electrolyte disturbances. In moderate to severe CCA poisoning, a combined medical strategy might be indispensable, such as administration of vasopressors, intravenous calcium and hyperinsulinaemia/euglycaemia therapy. Especially hyperinsulinaemia/euglycaemia therapy is an important first-line treatment in CCA-overdosed patients in whom a large ingestion is suspected. High dose insulin, in combination with glucose, seems to be most effective when used early in the intoxication phase, even when the patient shows hardly any haemodynamic instability. Intravenous lipid emulsion therapy should only be considered in patients with life-threatening cardiovascular toxicity, such as refractory shock, which is unresponsive to conventional therapies. When supportive and specific pharmacological measures fail to adequately reverse refractory conditions in CCA overdose, the use of extracorporeal life support should be considered. The efficacy of these pharmacological and non pharmacological interventions generally advocated in CCA poisoning needs further in-depth mechanistic foundation, in order to improve individualised treatment of CCA-overdosed patients. PMID- 26951351 TI - Dutch guidelines for the diagnosis and treatment of chronic lymphocytic leukaemia. AB - In recent years, considerable progress has been made in the treatment of patients with chronic lymphocytic leukaemia (CLL). Therefore, the CLL working group of the Dutch/Belgium Haemato-Oncology Foundation for Adults in the Netherlands (HOVON) framework revised the Dutch guidelines based on new studies and expert opinion of members of the working group. PMID- 26951352 TI - Chlamydia psittaci: a relevant cause of community-acquired pneumonia in two Dutch hospitals. AB - BACKGROUND: Of all hospitalised community-acquired pneumonias (CAPs) only a few are known to be caused by Chlamydia psittaci. Most likely the reported incidence, ranging from of 0% to 2.1%, is an underestimation of the real incidence, since detection of psittacosis is frequently not incorporated in the routine microbiological diagnostics in CAP or serological methods are used. METHODS: C. psittaci real-time polymerase chain reaction (PCR) was routinely performed on the sputum of 147 patients hospitalised with CAP, who participated in a clinical trial conducted in two Dutch hospitals. In 119/147 patients the paired complement fixation test (CFT) was also performed for the presence of Chlamydia antibodies. Positive CFTs were investigated by micro- Immunofluorescence for psittacosis specificity. Case criteria for psittacosis were a positive PCR or a fourfold rise of antibody titre in CFT confirmed by micro- Immunofluorescence. Furthermore, we searched for parameters that could discriminate psittacosis from CAPs with other aetiology. RESULTS: 7/147 (4.8%) patients were diagnosed with psittacosis: six with PCR and one patient with a negative PCR, but with CFT confirmed by micro- Immunofluorescence. Psittacosis patients had had a higher temperature (median 39.6 vs. 38.2 degrees C;) but lower white blood cell count (median 7.4 vs. 13.7 x 109/l) on admission compared with other CAP patients. CONCLUSION: In this study, C. psittaci as CAP-causing pathogen was much higher than previously reported. To detect psittacosis, PCR was performed on all CAP patients for whom a sputum sample was available. For clinical use, PCR is a fast method and sputum availability allows genotyping; additional serology can optimise epidemiological investigations. PMID- 26951353 TI - Familial focal segmental glomerulosclerosis: mutation in inverted formin 2 mimicking Alport syndrome. AB - Focal segmental glomerulosclerosis (FSGS) is one of the most common patterns of glomerular injury. FSGS can be caused by mutations in genes encoding proteins that play key roles in the function of the podocyte and glomerular basement membrane. In this case report we present a family with FSGS initially suspected to be Alport syndrome. Genetic analysis according to the Dutch guidelines of FSGS revealed a mutation in INF2. PMID- 26951354 TI - A rare stress cardiomyopathy in a patient with Guillain-Barre syndrome. AB - We report on a 39-year-old woman who was intubated because of progressive respiratory failure due to muscle weakness and mucous plugging because of Guillain- Barre syndrome. Shortly after uncomplicated intubation she developed hypotension and a profound tachycardia. The electrocardiogram showed sinus tachycardia with nonspecific ST-T segment changes. Echocardiography showed akinesia of the apex, septum and inferior left ventricular wall with an estimated left ventricular ejection fraction of 10%. It was concluded that the patient was suffering from takotsubo cardiomyopathy. Following treatment, she experienced a complete recovery. Takotsubo cardiomyopathy is a rare complication in Guillain Barre syndrome; eight other cases have been reported in the literature. PMID- 26951355 TI - A lethal case of the dapsone hypersensitivity syndrome involving the myocardium. AB - In the Netherlands dapsone is used for the treatment of dermatitis herpetiformis, leprosy and Pneumocystis jiroveci pneumonia and prophylaxis in case of cotrimoxazole allergy. An idiosyncratic drug reaction, known as the dapsone hypersensitivity syndrome (DHS), appears in about 0.5-3.6% of persons treated with dapsone. DHS can be associated with fever, rash and systemic involvement. We present a 35-year-old woman who developed severe DHS seven weeks after starting dapsone. Six weeks after being discharged in a good clinical condition she died from fulminant myocarditis, 11 weeks after the first DHS symptoms and the discontinuation of dapsone. PMID- 26951356 TI - An 88-year-old woman with an ulcerous tumour on the leg. Primary cutaneous diffuse large-B-cell lymphoma, leg type. PMID- 26951358 TI - A 47-year-old woman with fever and periorbital oedema. Trichinellosis. PMID- 26951360 TI - Training in acute medicine in a peripheral teaching hospital in the Netherlands. PMID- 26951361 TI - Adherence adjustment in the Coronary Drug Project: A call for better per-protocol effect estimates in randomized trials. AB - BACKGROUND: In many randomized controlled trials, patients and doctors are more interested in the per-protocol effect than in the intention-to-treat effect. However, valid estimation of the per-protocol effect generally requires adjustment for prognostic factors associated with adherence. These adherence adjustments have been strongly questioned in the clinical trials community, especially after 1980 when the Coronary Drug Project team found that adherers to placebo had lower 5-year mortality than non-adherers to placebo. METHODS: We replicated the original Coronary Drug Project findings from 1980 and re-analyzed the Coronary Drug Project data using technical and conceptual developments that have become established since 1980. Specifically, we used logistic models for binary outcomes, decoupled the definition of adherence from loss to follow-up, and adjusted for pre-randomization covariates via standardization and for post randomization covariates via inverse probability weighting. RESULTS: The original Coronary Drug Project analysis reported a difference in 5-year mortality between adherers and non-adherers in the placebo arm of 9.4 percentage points. Using modern approaches, we found that this difference was reduced to 2.5 (95% confidence interval: -2.1 to 7.0). CONCLUSION: Valid estimation of per-protocol effects may be possible in randomized clinical trials when analysts use appropriate methods to adjust for post-randomization variables. PMID- 26951362 TI - "It was then that I thought 'whaat? This is not my Dad": The implications of the 'still the same person' narrative for children and young people who have a parent with dementia. AB - This research used auto/biographical interviews to explore the experiences of 19, 8 to 31 year olds who had a parent with dementia. Thematic analysis revealed challenges occasioned by the master narrative that people with dementia are 'still' the same person they were prior to the onset of their condition. While this notion is - rightly - at the heart of person-centered care in dementia services, the 'still' discourse conflicts with the experiences of young people. Their accounts suggest that the construction of their parent as the same person is not helpful and that, furthermore, expectations that they will behave and feel towards that parent as they did before are a source of distress in what is already a challenging situation. This paper highlights the need to equip young people with support that acknowledges that their parent may well be drastically different to the Mum or Dad they previously 'knew'. PMID- 26951363 TI - Development of a memory center for older adults in Almaty, Kazakhstan: Innovative Practice. AB - Recognizing the economic and health-outcome value of early cognitive assessment and intervention among its older citizens has guided the Innovative Research School in Gerontology of the SD Asfendiyarov Kazakh National Medical University to begin the process of establishing its nation's first memory center in Almaty, Kazakhstan. Life expectancy in Kazakhstan, which continues to undergo health-care reform since its independence in 1991 from the former Soviet Union, has steadily risen from 64.4 years in 1996 to 68.67 in 2009. With increased life expectancy has been a corresponding rise in cognitive impairments among older adults. The components of the Memory Center, which comprises assessment, education and support, non-pharmaceutical and pharmaceutical interventions, are described. PMID- 26951364 TI - Staphylococcus aureus coagulase R domain, a new evasion mechanism and vaccine target. PMID- 26951365 TI - An interpretative phenomenological analysis of the experience of self-harm repetition and recovery in young adults. AB - Six young adults (aged 19-21 years) with repeat self-harm for over 5 years were interviewed about their self-harm, why they continued and what factors might help them to stop. Interpretative phenomenological analysis identified six themes: keeping self-harm private and hidden; self-harm as self-punishment; self-harm provides relief and comfort; habituation and escalation of self-harm; emotional gains and practical costs of cutting, and not believing they will stop completely. Young adults presented self-harm as an ingrained and purposeful behaviour which they could not stop, despite the costs and risks in early adulthood. Support strategies focused on coping skills, not just eradicating self harm, are required. PMID- 26951366 TI - Laser capture microdissection to identify septum-associated proteins in Aspergillus nidulans. AB - To spatially resolve genetic differences at the cellular level, the laser-capture microdissection technique was developed. With this method cells can be cut from tissues with a laser beam and analyzed for DNA, RNA or protein composition. Here we adapted the technique to isolate septal microtubule-organizing center (MTOC) associated proteins in Aspergillus nidulans About 3000 septa were collected and subjected to peptide fingerprinting by mass-spectrometric analysis. We identified the microtubule polymerase AlpA and found it interacts with ApsB specifically at sMTOCs, suggesting that AlpA might be involved in the assembly or the functioning of this protein complex. PMID- 26951367 TI - The evolution of fungal morphogenesis, a personal account. AB - This article describes the evolution of the field of fungal morphogenesis, its beginning at the end of the 19th century and its exponential growth during the second half of the 20th century, continuing until the present day. The main theme correlates biological progress with the advent of new technologies. Accordingly the article describes the discovery of apical growth, the fibrillar nature of the fungal wall, the chemistry of the cell wall, the search for biochemical pathways in morphogenesis, the discovery of the Spitzenkorper, the apical gradient of wall synthesis, key highlights in ultrastructural research, the development of mathematical models particularly the vesicle supply center (VSC) model, the revolution brought about by molecular biology and unique discoveries such as the hydrophobins and gamma-tubulin and some the latest triumphs of the marriage between molecular genetics and confocal microscopy. Credit is given to the investigators responsible for all the advances. PMID- 26951368 TI - A comprehensive journey into the fungal cell: editorial. PMID- 26951369 TI - Microtubules and associated molecular motors in Neurospora crassa. AB - The cytoskeleton provides structure, shape and movement to various cells. Microtubules (MTs) are tubular structures made of alpha and beta-tubulin heterodimers organized in 13 protofilaments, forming a hollow cylinder. A vast group of MT-associated proteins determines the function, behavior and interaction of the MTs with other cellular components. Among these proteins, molecular motors such as the dynein-dynactin complex and kinesin superfamily play roles in MT organization and organelle transport. This article focuses on the MT cytoskeleton and associated molecular motors in the filamentous fungus Neurospora crassa In addition to reviewing current available information for this fungus and contrasting it with knowledge of other fungal species, we present new experimental results that support the role of dynein, dynactin and conventional kinesin in MT organization, dynamics and transport of subcellular structures (nuclei and secretory vesicles). In wild type hyphae of N. crassa, cytoplasmic MTs are arranged longitudinally along hyphae and display a helical curvature. They interlace with one another to form a network throughout the cytoplasm. N. crassa dynein and dynactin mutants have a scant and disorganized MT cytoskeleton, an erratic and reduced Spitzenkorper (Spk) and distorted hyphal morphology. In contrast, hyphae of mutants with defective conventional kinesin exhibit only minor disruptions in MT and Spk organization. Although nuclear positioning is affected in all mutants, the MT-associated motor proteins are not major contributors to nuclear movement during hyphal growth. Cytoplasmic bulk flow is the vehicle for nuclear displacement in growing hyphal regions of N. crassa Motors are involved in nuclei saltatory movements in both retrograde or anterograde direction. In the dynein and kinesin mutants, micro and macrovesicles can reach the Spk, although growth is slightly impaired and the Spk displays an erratic path. Hyphal growth requires MTs, and their associated motors are required for their organization and dynamics and Spk integrity. PMID- 26951370 TI - Salinity-induced reduction in root surface area and changes in major root and shoot traits at the phytomer level in wheat. AB - The aim of this study was to investigate the effect of salinity stress on root growth at the phytomer level in wheat to provide novel site-specific understanding of salinity damage in roots. Seedlings of 13 wheat varieties were grown hydroponically. Plants were exposed to three concentrations of NaCl, 0 (control), 50 and 100mM, from 47 days after sowing. In a destructive harvest 12 days later we determined the number of live leaves, adventitious roots, seminal roots and newly formed roots at the youngest phytomer; length and diameter of main axes; and length and diameter of root hairs and their number per millimetre of root axis. Elongation rate of main axes and root hair density were then derived. Root surface area at each root-bearing phytomer (Pr) was mechanistically modelled. New root formation was increased by salt exposure, while number of live leaves per plant decreased. The greatest salinity effect on root axis elongation was observed at the youngest roots at Pr1 and Pr2. Both the 50mM and the 100mM levels of salinity reduced root hair length by approximately 25% and root hair density by 40% compared with the control whereas root hairs alone contributed around 93% of the estimated total root surface area of an individual tiller. Decrease in main axis length of new roots, root hair density and root hair length combined to reduce estimated root surface area by 36-66% at the higher NaCl concentration. The varietal response towards the three salinity levels was found to be trait-specific. The data highlight reduction in root surface area as a major but previously largely unrecognized component of salinity damage. Salinity resistance is trait-specific. Selection for retention of root surface area at a specific phytomer position following salt exposure might be useful in development of salinity-tolerant crop varieties. PMID- 26951371 TI - Manipulating photorespiration to increase plant productivity: recent advances and perspectives for crop improvement. AB - Recycling of the 2-phosphoglycolate generated by the oxygenase reaction of Rubisco requires a complex and energy-consuming set of reactions collectively known as the photorespiratory cycle. Several approaches aimed at reducing the rates of photorespiratory energy or carbon loss have been proposed, based either on screening for natural variation or by means of genetic engineering. Recent work indicates that plant yield can be substantially improved by the alteration of photorespiratory fluxes or by engineering artificial bypasses to photorespiration. However, there is also evidence indicating that, under certain environmental and/or nutritional conditions, reduced photorespiratory capacity may be detrimental to plant performance. Here we summarize recent advances obtained in photorespiratory engineering and discuss prospects for these advances to be transferred to major crops to help address the globally increasing demand for food and biomass production. PMID- 26951373 TI - Phylogenetic tree-informed microRNAome analysis uncovers conserved and lineage specific miRNAs in Camellia during floral organ development. AB - In plants, miRNAs are endogenous small RNAs derived from single-stranded precursors with hairpin structures. The evolution of miRNAs and their targets represents one of the most dynamic circuits directing gene expression, which may play fundamental roles in shaping the development of distinct plant organs. Here we performed high-throughput small RNA sequencing in five organ types of Camellia azalea to capture the spatial profile of small non-coding RNA. In total we obtained >227 million high-quality reads and identified 175 miRNAs with mature and precursor sequences. We aligned the miRNAs to known miRNA databases and revealed some conserved as well as 'newly evolved' miRNA genes. Twelve miRNAs were identified to be specific in the genus Camellia, supporting the lineage specific manner of expansion of 'young' miRNAs. Through differential expression analysis, we showed that many miRNAs were preferentially abundant in certain organ types. Moreover, hierarchical clustering analysis revealed distinctive expression patterns of tissue-specific miRNAs. Gene Ontology enrichment analysis of targets of stamen- and carpel-specific miRNA subclusters showed that miRNA target regulatory circuits were involved in many important biological processes, enabling their proper specification and organogenesis, such as 'DNA integration' and 'fruit development'. Further, quantitative PCR of key miRNAs and their target genes revealed anti-correlated patterns, and uncovered the functions of key miRNA target pairs in different floral organs. Taken together, this work yielded valuable information on miRNA-target regulation in the control of floral organ development and sheds light on the evolution of lineage-specific miRNAs in Camellia. PMID- 26951372 TI - Increasing abscisic acid levels by immunomodulation in barley grains induces precocious maturation without changing grain composition. AB - Abscisic acid (ABA) accumulates in seeds during the transition to the seed filling phase. ABA triggers seed maturation, storage activity, and stress signalling and tolerance. Immunomodulation was used to alter the ABA status in barley grains, with the resulting transgenic caryopses responding to the anti-ABA antibody gene expression with increased accumulation of ABA. Calculation of free versus antibody-bound ABA reveals large excess of free ABA, increasing signficantly in caryopses from 10 days after fertilization. Metabolite and transcript profiling in anti-ABA grains expose triggered and enhanced ABA functions such as transcriptional up-regulation of sucrose-to-starch metabolism, storage protein synthesis and ABA-related signal transduction. Thus, enhanced ABA during transition phases induces precocious maturation but negatively interferes with growth and development. Anti-ABA grains display broad constitutive gene induction related to biotic and abiotic stresses. Most of these genes are ABA- and/or stress-inducible, including alcohol and aldehyde dehydrogenases, peroxidases, chaperones, glutathione-S-transferase, drought- and salt-inducible proteins. Conclusively, ABA immunomodulation results in precocious ABA accumulation that generates an integrated response of stress and maturation. Repression of ABA signalling, occurring in anti-ABA grains, potentially antagonizes effects caused by overshooting production. Finally, mature grain weight and composition are unchanged in anti-ABA plants, although germination is somewhat delayed. This indicates that anti-ABA caryopses induce specific mechanisms to desensitize ABA signalling efficiently, which finally yields mature grains with nearly unchanged dry weight and composition. Such compensation implicates the enormous physiological and metabolic flexibilities of barley grains to adjust effects of unnaturally high ABA amounts in order to ensure and maintain proper grain development. PMID- 26951374 TI - In depth analysis of the mechanism of action of metal-dependent sigma factors: characterization of CorE2 from Myxococcus xanthus. AB - Extracytoplasmic function sigma factors represent the third pillar of signal transduction mechanisms in bacteria. The variety of stimuli they recognize and mechanisms of action they use have allowed their classification into more than 50 groups. We have characterized CorE2 from Myxococcus xanthus, which belongs to group ECF44 and upregulates the expression of two genes when it is activated by cadmium and zinc. Sigma factors of this group contain a Cys-rich domain (CRD) at the C terminus which is essential for detecting metals. Point mutations at the six Cys residues of the CRD have revealed the contribution of each residue to CorE2 activity. Some of them are essential, while others are either dispensable or their mutations only slightly affect the activity of the protein. However, importantly, mutation of Cys174 completely shifts the specificity of CorE2 from cadmium to copper, indicating that the Cys arrangement of the CRD determines the metal specificity. Moreover, the conserved CxC motif located between the sigma2 domain and the sigma4.2 region has also been found to be essential for activity. The results presented here contribute to our understanding of the mechanism of action of metal-dependent sigma factors and help to define new common features of the members of this group of regulators. PMID- 26951376 TI - A conformation-induced fluorescence method for microRNA detection. AB - MicroRNAs play important roles in a large variety of biological systems and processes through their regulation of target mRNA expression, and show promise as clinical biomarkers. However, their small size presents challenges for tagging or direct detection. Innovation in techniques to sense and quantify microRNAs may aid research into novel aspects of microRNA biology and contribute to the development of diagnostics. By introducing an additional stem loop into the fluorescent RNA Spinach and altering its 3' and 5' ends, we have generated a new RNA, Pandan, that functions as the basis for a microRNA sensor. Pandan contains two sequence-variable stem loops that encode complementary sequence for a target microRNA of interest. In its sensor form, it requires the binding of a target microRNA in order to reconstitute the RNA scaffold for fluorophore binding and fluorescence. Binding of the target microRNA resulted in large changes in fluorescence intensity. The median fold change in fluorescence observed for the sensors tested was ~50-fold. Pandan RNA sensors exhibit good signal-to-noise ratios, and can detect their target microRNAs within complex RNA mixtures. PMID- 26951378 TI - Practical prediction model for the risk of 2-year mortality of individuals in the general population. AB - This study proposed to validate a prediction model and risk-stratification tool of 2-year mortality rates of individuals in the general population suitable for office practice use. A risk indicator (R) derived from data in the literature was based on only 6 variables: to calculate R for an individual, starting with 0, for each year of age above 60, add 0.14; for a male, add 0.9; for diabetes mellitus, add 0.7; for albuminuria > 30 mg/g of creatinine, add 0.7; for stage >= 3 chronic kidney disease (CKD), add 0.9; for cardiovascular disease (CVD), add 1.4; or for both CKD and CVD, add 1.7. We developed a univariate logistic regression model predicting 2-year individual mortality rates. The National Health and Nutrition Examination Survey (NHANES) data set (1999-2004 with deaths through 2006) was used as the target for validation. These 12,515 subjects had a mean age of 48.9 +/- 18.1 years, 48% males, 9.5% diabetes, 11.7% albuminuria, 6.8% CVD, 5.4% CKD, and 2.8% both CKD and CVD. Using the risk indicator R alone to predict mortality demonstrated good performance with area under the receiver operating characteristic (ROC) curve of 0.84. Dividing subjects into low-risk (R=0-1.0), low intermediate risk (R > 1.0-3.0), high intermediate risk (R > 3.0-5.0) or high risk (R > 5.0) categories predicted 2-year mortality rates of 0.52%, 1.44%, 5.19% and 15.24%, respectively, by the prediction model compared with actual mortality rates of 0.29%, 2.48%, 5.13% and 13.40%, respectively. We have validated a model of risk stratification using easily identified clinical characteristics to predict 2-year mortality rates of individuals in the general population. The model demonstrated performance adequate for its potential use for clinical practice and research decisions. PMID- 26951375 TI - Diverged composition and regulation of the Trypanosoma brucei origin recognition complex that mediates DNA replication initiation. AB - Initiation of DNA replication depends upon recognition of genomic sites, termed origins, by AAA+ ATPases. In prokaryotes a single factor binds each origin, whereas in eukaryotes this role is played by a six-protein origin recognition complex (ORC). Why eukaryotes evolved a multisubunit initiator, and the roles of each component, remains unclear. In Trypanosoma brucei, an ancient unicellular eukaryote, only one ORC-related initiator, TbORC1/CDC6, has been identified by sequence homology. Here we show that three TbORC1/CDC6-interacting factors also act in T. brucei nuclear DNA replication and demonstrate that TbORC1/CDC6 interacts in a high molecular complex in which a diverged Orc4 homologue and one replicative helicase subunit can also be found. Analysing the subcellular localization of four TbORC1/CDC6-interacting factors during the cell cycle reveals that one factor, TbORC1B, is not a static constituent of ORC but displays S-phase restricted nuclear localization and expression, suggesting it positively regulates replication. This work shows that ORC architecture and regulation are diverged features of DNA replication initiation in T. brucei, providing new insight into this key stage of eukaryotic genome copying. PMID- 26951377 TI - DUX4 recruits p300/CBP through its C-terminus and induces global H3K27 acetylation changes. AB - Ectopic expression of the double homeodomain transcription factor DUX4 causes facioscapulohumeral muscular dystrophy (FSHD). Mechanisms of action of DUX4 are currently unknown. Using immortalized human myoblasts with a titratable DUX4 transgene, we identify by mass spectrometry an interaction between the DUX4 C terminus and the histone acetyltransferases p300/CBP. Chromatin immunoprecipitation shows that DUX4 recruits p300 to its target gene, ZSCAN4, displaces histone H3 from the center of its binding site, and induces H3K27Ac in its vicinity, but C-terminal deleted DUX4 does not. We show that a DUX4 minigene, bearing only the homeodomains and C-terminus, is transcriptionally functional and cytotoxic, and that overexpression of a nuclear targeted C-terminus impairs the ability of WT DUX4 to interact with p300 and to regulate target genes. Genomic profiling of DUX4, histone H3, and H3 modifications reveals that DUX4 binds two classes of loci: DNase accessible H3K27Ac-rich chromatin and inaccessible H3K27Ac depleted MaLR-enriched chromatin. At this latter class, it acts as a pioneer factor, recruiting H3K27 acetyltransferase activity and opening the locus for transcription. In concert with local increased H3K27Ac, the strong H3K27Ac peaks at distant sites are significantly depleted of H3K27Ac, thus DUX4 uses its C terminus to induce a global reorganization of H3K27 acetylation. PMID- 26951379 TI - AVAREG: a phase II, randomized, noncomparative study of fotemustine or bevacizumab for patients with recurrent glioblastoma. AB - BACKGROUND: Few prospective studies have assessed the role of bevacizumab and included a control arm with standard treatments for recurrent glioblastoma. We conducted a noncomparative phase II trial (AVAREG) to examine the efficacy of bevacizumab or fotemustine in this setting. METHODS: Eligible patients were randomized 2:1 to receive bevacizumab (10 mg/kg every 2 weeks) or fotemustine (75 mg/m(2) on days 1, 8, and 15, then 100 mg/m(2) every 3 weeks after a 35-day interval). The primary endpoint was 6-month overall survival (OS) rate (OS-6). No formal efficacy comparison was made between the treatment arms. RESULTS: Ninety one patients were enrolled (bevacizumab n = 59; fotemustine n = 32). Median age was 57 years (range, 28-78 y), and patients had Eastern Cooperative Oncology Group performance status of 0 (n = 42), 1 (n = 35), or 2 (n = 14). OS-6 rate was 62.1% (95% confidence interval [CI], 48.4-74.5) with bevacizumab and 73.3% (95% CI, 54.1-87.7) with fotemustine. OS-6 rates were lower in bevacizumab-treated patients with MGMT promoter methylated tumors than in those with unmethylated tumors (50% and 85%, respectively), but higher in fotemustine-treated patients (87.5% and 50%, respectively). OS rates at 9 months were 37.9% (95% CI, 25.5 51.6) and 46.7% (95% CI, 28.3-65.7) with bevacizumab and fotemustine, respectively, and median OS was 7.3 months (95% CI, 5.8-9.2) and 8.7 months (95% CI, 6.3-15.4), respectively. Toxicity was as expected with the 2 agents. CONCLUSION: Single-agent bevacizumab may have a role in patients with recurrent glioblastoma. PMID- 26951380 TI - A new patient-derived orthotopic malignant meningioma model treated with oncolytic herpes simplex virus. AB - BACKGROUND: Higher-grade meningiomas (HGMs; World Health Organization grades II and III) pose a clinical problem due to high recurrence rates and the absence of effective therapy. Preclinical development of novel therapeutics requires a disease model that recapitulates the genotype and phenotype of patient HGM. Oncolytic herpes simplex virus (oHSV) has shown efficacy and safety in cancers in preclinical and clinical studies, but its utility for HGM has not been well characterized. METHODS: Tumorsphere cultures and serial orthotopic xenografting in immunodeficient mice were used to establish a patient-derived HGM model. The model was pathologically and molecularly characterized by immunohistochemistry, western blot, and genomic DNA sequencing and compared with the patient tumor. Anti-HGM effects of oHSV G47Delta were assessed using cell viability and virus replication assays in vitro and animal survival analysis following intralesional injections of G47Delta. RESULTS: We established a serially transplantable orthotopic malignant meningioma model, MN3, which was lethal within 3 months after tumorsphere implantation. MN3 xenografts exhibited the pathological hallmarks of malignant meningioma such as high Ki67 and vimentin expression. Both the patient tumor and xenografts were negative for neurofibromin 2 (merlin) and had the identical NF2 mutation. Oncolytic HSV G47Delta efficiently spread and killed MN3 cells, as well as other patient-derived HGM lines in vitro. Treatment with G47Delta significantly extended the survival of mice bearing subdural MN3 tumors. CONCLUSIONS: We established a new patient-derived meningioma model that will enable the study of targeted therapeutic approaches for HGM. Based on these studies, it is reasonable to consider a clinical trial of G47Delta for HGM. PMID- 26951381 TI - Components of the eIF4F complex are potential therapeutic targets for malignant peripheral nerve sheath tumors and vestibular schwannomas. AB - BACKGROUND: The eukaryotic initiation factor 4F (eIF4F) complex plays a pivotal role in protein translation initiation; however, its importance in malignant and benign Schwann cell tumors has not been explored, and whether blocking eIF4F function is effective for treating these tumors is not known. METHODS: Immunostaining was performed on human malignant peripheral nerve sheath tumors (MPNSTs) and vestibular schwannomas (VSs) for eIF4F components. The role of eIF4A and eIF4E in cell growth was assessed by RNA interference. Various natural compounds were screened for their growth-inhibitory activity. Flow cytometry and Western blotting were performed to characterize the action of silvestrol, and its antitumor activity was verified in orthotopic mouse models. RESULTS: MPNSTs and VSs frequently overexpressed eIF4A, eIF4E, and/or eIF4G. Depletion of eIF4A1, eIF4A2, and eIF4E substantially reduced MPNST cell growth. From screening a panel of plant-derived compounds, the eIF4A inhibitor silvestrol was identified as a leading agent with nanomolar IC50 values in MPNST and VS cells. Silvestrol induced G2/M arrest in both NF1-deficient and NF1-expressing MPNST cells and primary VS cells. Silvestrol consistently decreased the levels of multiple cyclins, Aurora A, and mitogenic kinases AKT and ERKs. Silvestrol treatment dramatically suppressed tumor growth in mouse models for NF1(-/-) MPNST and Nf2( /-) schwannoma. This decreased tumor growth was accompanied by elevated phospho histone H3 and TUNEL labeling, consistent with G2/M arrest and apoptosis in silvestrol-treated tumor cells. CONCLUSIONS: The eIF4F complex is a potential therapeutic target in MPNSTs and VS, and silvestrol may be a promising agent for treating these tumors. PMID- 26951382 TI - Primary CNS lymphoma at first relapse/progression: characteristics, management, and outcome of 256 patients from the French LOC network. AB - BACKGROUND: Treatment of relapsed/refractory (R/R) primary CNS lymphoma (PCNSL) is poorly defined, because randomized trials and large studies are lacking. The aim of this study was to analyze the characteristics, management, and outcome of R/R PCNSL patients after first-line therapy in a nationwide cohort. METHODS: We analyzed R/R PCNSL patients following first-line treatment who had been prospectively registered in the database of the French network for oculocerebral lymphoma (LOC) between 2011 and 2014. RESULTS: Among 563 PCNSL patients treated with first-line therapy, we identified 256 with relapsed (n = 93, 16.5%) or refractory (n = 163, 29.0%) disease. Patients who were asymptomatic at relapse/progression (25.5%), mostly diagnosed on routine follow-up neuroimaging, tended to have a better outcome. Patients who received salvage therapy followed by consolidation (mostly intensive chemotherapy plus autologous hematopoietic stem cell transplantation [ICT + AHSCT]) experienced prolonged survival compared with those who did not receive salvage or consolidation therapy. Independent prognostic factors at first relapse/progression were: KPS >= 70 vs KPS < 70), sensitivity to first-line therapy (relapsed vs refractory disease), duration of first remission (progression-free survival [PFS] >=1 y vs <1 y), and management at relapse/progression (palliative care vs salvage therapy). Patients who relapsed early after first-line therapy (ie, PFS < 1 y) had a poor outcome, comparable to that of refractory patients. Conversely, patients experiencing late relapses (PFS >= 1 y) and/or undergoing consolidation with ICT + AHSCT experienced prolonged survival. CONCLUSIONS: About a third of PCNSL patients are primary refractory to first line treatment. We identified several independent prognostic factors that can guide the management of R/R PCNSL patients. PMID- 26951383 TI - Decrease of VEGF-A in myeloid cells attenuates glioma progression and prolongs survival in an experimental glioma model. AB - BACKGROUND: Glioblastomas are highly vascularized tumors with a prominent infiltration of macrophages/microglia whose role in promoting glioma growth, invasion, and angiogenesis has not been fully elucidated. METHODS: The contribution of myeloid-derived vascular endothelial growth factor (VEGF) to glioma growth was analyzed in vivo in a syngeneic intracranial GL261 glioma model using a Cre/loxP system to knock out the expression of VEGF-A in CD11b + myeloid cells. Changes in angiogenesis-related gene expression profile were analyzed in mutant bone marrow-derived (BMD) macrophages in vitro. Furthermore, we studied the influence of macrophages on GL261 growth, invasiveness, and protein expression profile of angiogenic molecules as well as the paracrine effect of mutant macrophages on angiogenesis in vitro. RESULTS: Myeloid cell-restricted VEGF-A deficiency leads to a growth delay of intracranial tumors and prolonged survival. The tumor vasculature in mutant mice was more regular, with increased pericyte coverage. Expression analysis revealed significant downregulation of VEGF-A and slight upregulation of TGFbeta-1 in BMD macrophages from mutant mice. Endothelial tube formation was significantly decreased by conditioned media from mutant macrophages. The expression of angiogenesis-related proteins in GL261 glioma cells in co-culture experiments either with wild-type or mutant macrophages remained unchanged, indicating that effects observed in vivo are due to myeloid-derived VEGF-A deficiency. CONCLUSIONS: Our results highlight the importance of VEGF derived from tumor-infiltrating myeloid cells for initiating vascularization in gliomas. The combination of antiangiogenic agents with myeloid cell-targeting strategies might provide a new therapeutic approach for glioblastoma patients. PMID- 26951385 TI - Stent-assisted coiling versus coiling alone of poor-grade ruptured intracranial aneurysms: a multicenter study. AB - INTRODUCTION: Endovascular coiling is a valid treatment option for poor-grade ruptured aneurysms. However, little is known about stent-assisted coiling of poor grade aneurysms. OBJECTIVE: To compare the safety and efficacy of stent-assisted coiling with coiling alone for poor-grade aneurysms. METHODS: Using multicenter data on poor-grade aneurysms, we performed a retrospective analysis of 131 consecutive patients treated with endovascular coiling within 14 days after ictus. Patients were split into two groups: stent-assisted coiling and coiling alone. Baseline characteristics, immediate angiographic results, perioperative complications, and clinical outcomes were compared between the two groups. RESULTS: Twenty-three (17.6%) patients were treated with stent-assisted coiling and 108 (82.4%) with coiling alone. There were no statistically significant differences in patient age, sex, clinical grade, Fisher grade, modified Fisher grade, aneurysm location, and size between the stent-assisted coiling and coiling alone groups. Intraprocedural aneurysm rupture, procedure-related ischemic complication, external ventricular drainage-related hemorrhagic complication, and symptomatic vasospasm did not differ between the two groups. Immediate angiographic results and clinical outcomes at discharge and at 6 and 12 months did not differ between the groups. Aneurysm rebleeding occurred in 4 (17.4%) patients after stent-assisted coiling compared with 2 (1.9%) patients after coiling alone (p<0.007). Multivariate analysis showed that incomplete aneurysm occlusion was independently associated with aneurysm rebleeding (p=0.016), and there was a trend toward aneurysm rebleeding after stent-assisted coiling (p=0.051). CONCLUSIONS: Stent-assisted coiling of poor-grade aneurysms is feasible and safe compared with coiling alone. However, the hemorrhagic complication and aneurysm rebleeding may not be negligible. PMID- 26951386 TI - Delta, By Any Other Name. PMID- 26951384 TI - Endoplasmic reticulum stress-inducing drugs sensitize glioma cells to temozolomide through downregulation of MGMT, MPG, and Rad51. AB - BACKGROUND: Endoplasmic reticulum (ER) stress results from protein misfolding imbalance and has been postulated as a therapeutic strategy. ER stress activates the unfolded protein response which leads to a complex cellular response, including the upregulation of aberrant protein degradation in the ER, with the goal of resolving that stress. O(6)-methylguanine DNA methyltransferase (MGMT), N methylpurine DNA glycosylase (MPG), and Rad51 are DNA damage repair proteins that mediate resistance to temozolomide in glioblastoma. In this work we sought to evaluate whether ER stress-inducing drugs were able to downmodulate DNA damage repair proteins and become candidates to combine with temozolomide. METHODS: MTT assays were performed to evaluate the cytotoxicity of the treatments. The expression of proteins was evaluated using western blot and immunofluorescence. In vivo studies were performed using 2 orthotopic glioblastoma models in nude mice to evaluate the efficacy of the treatments. All statistical tests were 2 sided. RESULTS: Treatment of glioblastoma cells with ER stress-inducing drugs leads to downregulation of MGMT, MPG, and Rad51. Inhibition of ER stress through pharmacological treatment resulted in rescue of MGMT, MPG, and Rad51 protein levels. Moreover, treatment of glioblastoma cells with salinomycin, an ER stress inducing drug, and temozolomide resulted in enhanced DNA damage and a synergistic antitumor effect in vitro. Of importance, treatment with salinomycin/temozolomide resulted in a significant antiglioma effect in 2 aggressive orthotopic intracranial brain tumor models. CONCLUSIONS: These findings provide a strong rationale for combining temozolomide with ER stress-inducing drugs as an alternative therapeutic strategy for glioblastoma. PMID- 26951387 TI - When Does the Risk for Obstructive Sleep Apnea Start? The Importance of Perinatal Factors. PMID- 26951388 TI - Developing Biomarker Arrays Predicting Sleep and Circadian-Coupled Risks to Health. PMID- 26951389 TI - Exercise during Short-Term and Long-Term Continuous Exposure to Hypoxia Exacerbates Sleep-Related Periodic Breathing. AB - STUDY OBJECTIVES: Exposure to hypoxia elevates chemosensitivity, which can lead to periodic breathing. Exercise impacts gas exchange, altering chemosensitivity; however, interactions between sleep, exercise and chronic hypoxic exposure have not been examined. This study investigated whether exercise exacerbates sleep related periodic breathing in hypoxia. METHODS: Two experimental phases. Short Term Phase: a laboratory controlled, group-design study in which 16 active, healthy men (age: 25 +/- 3 y, height: 1.79 +/- 0.06 m, mass: 74 +/- 8 kg) were confined to a normobaric hypoxic environment (FIO2 = 0.139 +/- 0.003, 4,000 m) for 10 days, after random assignment to a sedentary (control, CON) or cycle exercise group (EX). Long-Term Phase: conducted at the Concordia Antarctic Research Station (3,800 m equivalent at the Equator) where 14 men (age: 36 +/- 9 y, height: 1.77 +/- 0.09 m, mass: 75 +/- 10 kg) lived for 12-14 months, continuously confined. Participants were stratified post hoc based on self reported physical activity levels. We quantified apnea-hypopnea index (AHI) and physical activity variables. RESULTS: Short-Term Phase: mean AHI scores were significantly elevated in the EX group compared to CON (Night1 = CON: 39 +/- 51, EX: 91 +/- 59; Night10 = CON: 32 +/- 32, EX: 92 +/- 48; P = 0.046). Long-Term Phase: AHI was correlated to mean exercise time (R(2) = 0.4857; P = 0.008) and the coefficient of variation in night oxyhemoglobin saturation (SpO2; R(2) = 0.3062; P = 0.049). CONCLUSIONS: Data indicate that exercise (physical activity) per se affects night SpO2 concentrations and AHI after a minimum of two bouts of moderate-intensity hypoxic exercise, while habitual physical activity in hypobaric hypoxic confinement affects breathing during sleep, up to 13+ months' duration. PMID- 26951391 TI - Sleep and Health Resilience Metrics in a Large Military Cohort. AB - STUDY OBJECTIVES: Examine the relationship between self-reported sleep parameters and indicators of resilience in a US military population (n = 55,021). METHODS: Longitudinal analyses (2001-2008) were conducted using subjective data collected from Millennium Cohort Study questionnaires and objective data from military records that included demographics, military health, and deployment information. Subjective sleep duration and insomnia symptoms were collected on the study questionnaire. Resilience metrics included lost work days, self-rated health, deployment, frequency and duration of health care utilization, and early discharge from the military. Generalized estimating equations and survival analyses were adjusted for demographic, military, behavioral, and health covariates in all models. RESULTS: The presence of insomnia symptoms was significantly associated with lower self-rated health, more lost work days, lower odds of deployment, higher odds of early discharge from military service early, and more health care utilization. Those self-reporting < 6 h (short sleepers) or > 8 h (long sleepers) of sleep per night had similar findings, except for the deployment outcome in which those with the shortest sleep were more likely to deploy. CONCLUSIONS: Poor sleep is a detriment to service members' health and readiness. Leadership should redouble efforts to emphasize the importance of healthy sleep among military service members, and future research should focus on the efficacy of interventions to promote healthy sleep and resilience in this population. COMMENTARY: A commentary on this article appears in this issue on page 963. PMID- 26951390 TI - Sleep Duration and Subsequent Cortical Thinning in Cognitively Normal Older Adults. AB - STUDY OBJECTIVES: To determine the association between self-reported sleep duration and cortical thinning among older adults. METHODS: We studied 122 cognitively normal participants in the Baltimore Longitudinal Study of Aging with a mean age = 66.6 y (range, 51-84) at baseline sleep assessment and 69.5 y (range, 56-86) at initial magnetic resonance imaging (MRI) scan. Participants reported average sleep duration and completed a mean of 7.6 1.5-T MRI scans (range, 3-11), with mean follow-up from initial scan of 8.0 y (range, 2.0-11.8). RESULTS: In analyses adjusted for age, sex, education, race, and interval between sleep assessment and initial MRI scan, participants reporting > 7 h sleep at baseline had thinner cortex in the inferior occipital gyrus and sulcus of the left hemisphere at initial MRI scan than those reporting 7 h (cluster P < 0.05). In adjusted longitudinal analyses, compared to those reporting 7 h of sleep, participants reporting < 7 h exhibited higher rates of subsequent thinning in the superior temporal sulcus and gyrus, inferior and middle frontal gyrus, and superior frontal sulcus of the left hemisphere, and in the superior frontal gyrus of the right hemisphere; those reporting > 7 h of sleep had higher rates of thinning in the superior frontal and middle frontal gyrus of the left hemisphere (cluster P < 0.05 for all). In sensitivity analyses, adjustment for apolipoprotein E (APOE) e4 genotype reduced or eliminated some effects but revealed others. When reports of < 7 h of sleep were compared to reports of 7 or 8 h combined, there were no significant associations with cortical thinning. CONCLUSIONS: Among cognitively normal older adults, sleep durations of < 7 h and > 7 h may increase the rate of subsequent frontotemporal gray matter atrophy. Additional studies, including those that use objective sleep measures and investigate mechanisms linking sleep duration to gray matter loss, are needed. PMID- 26951392 TI - Genetic Dissociation of Daily Sleep and Sleep Following Thermogenetic Sleep Deprivation in Drosophila. AB - STUDY OBJECTIVES: Sleep rebound-the increase in sleep that follows sleep deprivation-is a hallmark of homeostatic sleep regulation that is conserved across the animal kingdom. However, both the mechanisms that underlie sleep rebound and its relationship to habitual daily sleep remain unclear. To address this, we developed an efficient thermogenetic method of inducing sleep deprivation in Drosophila that produces a substantial rebound, and applied the newly developed method to assess sleep rebound in a screen of 1,741 mutated lines. We used data generated by this screen to identify lines with reduced sleep rebound following thermogenetic sleep deprivation, and to probe the relationship between habitual sleep amount and sleep following thermogenetic sleep deprivation in Drosophila. METHODS: To develop a thermogenetic method of sleep deprivation suitable for screening, we thermogenetically stimulated different populations of wake-promoting neurons labeled by Gal4 drivers. Sleep rebound following thermogenetically-induced wakefulness varies across the different sets of wake promoting neurons that were stimulated, from very little to quite substantial. Thermogenetic activation of neurons marked by the c584-Gal4 driver produces both strong sleep loss and a substantial rebound that is more consistent within genotypes than rebound following mechanical or caffeine-induced sleep deprivation. We therefore used this driver to induce sleep deprivation in a screen of 1,741 mutagenized lines generated by the Drosophila Gene Disruption Project. Flies were subjected to 9 h of sleep deprivation during the dark period and released from sleep deprivation 3 h before lights-on. Recovery was measured over the 15 h following sleep deprivation. Following identification of lines with reduced sleep rebound, we characterized baseline sleep and sleep depth before and after sleep deprivation for these hits. RESULTS: We identified two lines that consistently exhibit a blunted increase in the duration and depth of sleep after thermogenetic sleep deprivation. Neither of the two genotypes has reduced total baseline sleep. Statistical analysis across all screened lines shows that genotype is a strong predictor of recovery sleep, independent from effects of genotype on baseline sleep. CONCLUSIONS: Our data show that rebound sleep following thermogenetic sleep deprivation can be genetically separated from sleep at baseline. This suggests that genetically controlled mechanisms of sleep regulation not manifest under undisturbed conditions contribute to sleep rebound following thermogenetic sleep deprivation. PMID- 26951393 TI - An Examination of Methodological Paradigms for Calculating Upper Airway Critical Pressures during Sleep. AB - STUDY OBJECTIVES: The goal of this study was to examine different paradigms for determining critical closing pressures (Pcrit). Methods of determining Pcrit were compared, including direct observation of occluded (no flow) breaths versus inferring Pcrit from extrapolated data, and Pcrit generated by aggregating pressure-flow data from multiple runs versus Pcrit averaged across individual pressure-flow runs. The relationship between Pcrit and obstructive sleep apnea (OSA) was examined. METHODS: A total of 351 participants with and without OSA underwent overnight polysomnography with pressure-flow measurements to determine Pcrit. A series of filters were applied to raw data to provide consistent, objective criteria for determining which data to include in Pcrit calculations. Observed Pcrit values were computed as the mean nasal pressure level at which a subject had at least two breaths with peak inspiratory flow < 50 mL/sec. Extrapolated Pcrit was calculated in two ways: (1) separately for each individual run and then averaged; and (2) using all valid data from individual runs combined into one plot. RESULTS: Observed Pcrit was calculated in 67% to 69% of participants, a similar or higher proportion of study subjects compared to extrapolated Pcrit values using a +/- 3 cm H2O filter. Although raw (unfiltered) extrapolated Pcrit measures were able to be calculated among a greater proportion of participants than filtered, extrapolated Pcrit values, and thus had fewer missing values, they had larger variability. Both extrapolated and observed Pcrit were higher among individuals with OSA compared to those without OSA. CONCLUSIONS: Observed Pcrit provides a reliable descriptor of hypotonic upper airway collapsibility. Different methods for determining Pcrit were able to distinguish subjects with and without OSA. PMID- 26951394 TI - Adaptation to Life in the High Andes: Nocturnal Oxyhemoglobin Saturation in Early Development. AB - STUDY OBJECTIVES: Physiological adaptation to high altitude hypoxia may be impaired in Andeans with significant European ancestry. The respiratory 'burden' of sleep may challenge adaptation, leading to relative nocturnal hypoxia. Developmental aspects of sleep-related breathing in high-altitude native children have not previously been reported. We aimed to determine the influence of development on diurnal-nocturnal oxyhemoglobin differences in children living at high altitude. METHODS: This was a cross-sectional, observational study. Seventy five healthy Bolivian children aged 6 mo to 17 y, native to low altitude (500 m), moderate high altitude (2,500 m), and high altitude (3,700 m) were recruited. Daytime resting pulse oximetry was compared to overnight recordings using Masimo radical oximeters. Genetic ancestry was determined from DNA samples. RESULTS: Children had mixed European/Amerindian ancestry, with no significant differences between altitudes. Sixty-two participants had >= 5 h of nocturnal, artifact-free data. As predicted, diurnal mean oxyhemoglobin saturation decreased across altitudes (infants and children, both P < 0.001), with lowest diurnal values at high altitude in infants. At high altitude, there was a greater drop in nocturnal mean oxyhemoglobin saturation (infants, P < 0.001; children, P = 0.039) and an increase in variability (all P <= 0.001) compared to low altitude. Importantly, diurnal to nocturnal altitude differences diminished (P = 0.036), from infancy to childhood, with no further change during adolescence. CONCLUSIONS: Physiological adaptation to high-altitude living in native Andeans is unlikely to compensate for the significant differences we observed between diurnal and nocturnal oxyhemoglobin saturation, most marked in infancy. This vulnerability to sleep related hypoxia in early childhood has potential lifespan implications. Future studies should characterize the sleep- related respiratory physiology underpinning our observations. PMID- 26951397 TI - Disrupted Sleep in Narcolepsy: Exploring the Integrity of Galanin Neurons in the Ventrolateral Preoptic Area. AB - STUDY OBJECTIVES: To examine the integrity of sleep-promoting neurons of the ventrolateral preoptic nucleus (VLPO) in postmortem brains of narcolepsy type 1 patients. METHODS: Postmortem examination of five narcolepsy and eight control brains. RESULTS: VLPO galanin neuron count did not differ between narcolepsy patients (11,151 +/- 3,656) and controls (13,526 +/- 9,544). CONCLUSIONS: A normal number of galanin-immunoreactive VLPO neurons in narcolepsy type 1 brains at autopsy suggests that VLPO cell loss is an unlikely explanation for the sleep fragmentation that often accompanies the disease. PMID- 26951398 TI - Cerebral and Muscle Oxygenation During Intermittent Hypoxia Exposure in Healthy Humans. AB - STUDY OBJECTIVES: To evaluate changes in muscle and cerebral oxygenation during intermittent hypoxia (IH). METHODS: Fifteen healthy subjects were exposed to 45 min IH (2-min cycles). Arterial blood oxygen saturation (SpO2), prefrontal cortex and brachial biceps muscle oxygenation (assessed by near-infrared spectroscopy), heart rate, and ventilation were continuously recorded. RESULTS: During 2-min IH cycles, changes in SpO2 (9.2% +/- 3.3%) were associated with significant changes in cortex oxygenation (3.2% +/- 1.8%), minute ventilation, and heart rate, but no change in muscle oxygenation (0.2% +/- 1.0%). CONCLUSIONS: Fluctuations of blood oxygen levels comparable to severe obstructive sleep apnea translate into distinct pattern of oxygenation changes in the muscle and cortex. PMID- 26951395 TI - Wake High-Density Electroencephalographic Spatiospectral Signatures of Insomnia. AB - STUDY OBJECTIVES: Although daytime complaints are a defining characteristic of insomnia, most EEG studies evaluated sleep only. We used high-density electroencephalography to investigate wake resting state oscillations characteristic of insomnia disorder (ID) at a fine-grained spatiospectral resolution. METHODS: A case-control assessment during eyes open (EO) and eyes closed (EC) was performed in a laboratory for human physiology. Participants (n = 94, 74 female, 21-70 y) were recruited through www.sleepregistry.nl: 51 with ID, according to DSM-5 and 43 matched controls. Exclusion criteria were any somatic, neurological or psychiatric condition. Group differences in the spectral power topographies across multiple frequencies (1.5 to 40 Hz) were evaluated using permutation-based inference with Threshold-Free Cluster-Enhancement, to correct for multiple comparisons. RESULTS: As compared to controls, participants with ID showed less power in a narrow upper alpha band (11-12.7 Hz, peak: 11.7 Hz) over bilateral frontal and left temporal regions during EO, and more power in a broad beta frequency range (16.3-40 Hz, peak: 19 Hz) globally during EC. Source estimates suggested global rather than cortically localized group differences. CONCLUSIONS: The widespread high power in a broad beta band reported previously during sleep in insomnia is present as well during eyes closed wakefulness, suggestive of a round-the-clock hyperarousal. Low power in the upper alpha band during eyes open is consistent with low cortical inhibition and attentional filtering. The fine-grained HD-EEG findings suggest that, while more feasible than PSG, wake EEG of short duration with a few well-chosen electrodes and frequency bands, can provide valuable features of insomnia. PMID- 26951396 TI - Orexin-A is Associated with Increases in Cerebrospinal Fluid Phosphorylated-Tau in Cognitively Normal Elderly Subjects. AB - STUDY OBJECTIVES: To evaluate the role of orexin-A with respect to cerebrospinal fluid (CSF) Alzheimer disease (AD) biomarkers, and explore its relationship to cognition and sleep characteristics in a group of cognitively normal elderly individuals. METHODS: Subjects were recruited from multiple community sources for National Institutes of Health supported studies on normal aging, sleep and CSF biomarkers. Sixty-three participants underwent home monitoring for sleep disordered breathing, clinical, sleep and cognitive evaluations, as well as a lumbar puncture to obtain CSF. Individuals with medical history or with magnetic resonance imaging evidence of disorders that may affect brain structure or function were excluded. Correlation and linear regression analyses were used to assess the relationship between orexin-A and CSF AD-biomarkers controlling for potential sociodemographic and sleep confounders. RESULTS: Levels of orexin-A, amyloid beta 42 (Abeta42), phosphorylated-tau (P-Tau), total-tau (T-Tau), Apolipoprotein E4 status, age, years of education, reported total sleep time, number of awakenings, apnea-hypopnea indices (AHI), excessive daytime sleepiness, and a cognitive battery were analyzed. Subjects were 69.59 +/- 8.55 years of age, 57.1% were female, and 30.2% were apolipoprotein E4+. Orexin-A was positively correlated with Abeta42, P-Tau, and T-Tau. The associations between orexin-A and the AD-biomarkers were driven mainly by the relationship between orexin-A and P Tau and were not influenced by other clinical or sleep characteristics that were available. CONCLUSIONS: Orexin-A is associated with increased P-Tau in normal elderly individuals. Increases in orexin-A and P-Tau might be a consequence of the reduction in the proportion of the deeper, more restorative slow wave sleep and rapid eye movement sleep reported with aging. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov registration number NCT01962779. PMID- 26951399 TI - Objective but Not Subjective Short Sleep Duration Associated with Increased Risk for Hypertension in Individuals with Insomnia. AB - STUDY OBJECTIVES: To examine the relationship between hypertension prevalence in individuals with insomnia who have short total sleep duration < 6 h or sleep duration >= 6 h, using both objective and subjective measures of total sleep duration. METHODS: Using a cross-sectional, observational design, 255 adult volunteers (n = 165 women; 64.7%) meeting current diagnostic criteria for insomnia disorder (MAge = 46.2 y, SDAge = 13.7 y) participated in this study at two large university medical centers. Two nights of polysomnography, 2 w of sleep diaries, questionnaires focused on sleep, medical, psychological, and health history, including presence/absence of hypertension were collected. Logistic regressions assessed the odds ratios of hypertension among persons with insomnia with short sleep duration < 6 h compared to persons with insomnia with a sleep duration >= 6 h, measured both objectively and subjectively. RESULTS: Consistent with previous studies using objective total sleep duration, individuals with insomnia and short sleep duration < 6 h were associated with a 3.59 increased risk of reporting hypertension as a current medical problem as compared to individuals with insomnia with sleep duration >= 6 h. Increased risk for hypertension was independent of major confounding factors frequently associated with insomnia or hypertension. No significant risk was observed using subjectively determined total sleep time groups. Receiver operating characteristic curve analysis found that the best balance of sensitivity and specificity using subjective total sleep time was at a 6-h cutoff, but the area under the receiver operating characteristic curve showed low accuracy and did not have good discriminant value. CONCLUSIONS: Objectively measured short sleep duration increased the odds of reporting hypertension more than threefold after adjusting for potential confounders; this relationship was not significant for subjectively measured sleep duration. This research supports emerging evidence that insomnia with objective short sleep duration is associated with an increased risk of comorbid hypertension. PMID- 26951400 TI - Insomnia is Associated with Cortical Hyperarousal as Early as Adolescence. AB - STUDY OBJECTIVES: To examine whether insomnia is associated with spectral electroencephalographic (EEG) dynamics in the beta (15-35Hz) range during sleep in an adolescent general population sample. METHODS: A case-control sample of 44 adolescents from the Penn State Child Cohort underwent a 9-h polysomnography, clinical history and physical examination. We examined low-beta (15-25 Hz) and high-beta (25-35 Hz) relative power at central EEG derivations during sleep onset latency (SOL), sleep onset (SO), non-rapid eye movement (NREM) sleep, and wake after sleep onset (WASO). RESULTS: Compared to controls (n = 21), individuals with insomnia (n = 23) showed increased SOL and WASO and decreased sleep duration and efficiency, while no differences in sleep architecture were found. Insomniacs showed increased low-beta and high-beta relative power during SOL, SO, and NREM sleep as compared to controls. High-beta relative power was greater during all sleep and wake states in insomniacs with short sleep duration as compared to individuals with insomnia with normal sleep duration. CONCLUSIONS: Adolescent insomnia is associated with increased beta EEG power during sleep, which suggests that cortical hyperarousal is present in individuals with insomnia as early as adolescence. Interestingly, cortical hyperarousal is greatest in individuals with insomnia with short sleep duration and may explain the sleep complaints of those with normal sleep duration. Disturbed cortical networks may be a shared mechanism putting individuals with insomnia at risk of psychiatric disorders. PMID- 26951401 TI - Risk of Occupational Accidents in Workers with Obstructive Sleep Apnea: Systematic Review and Meta-analysis. AB - STUDY OBJECTIVES: Obstructive sleep apnea (OSA) is the single most important preventable medical cause of excessive daytime sleepiness (EDS) and driving accidents. OSA may also adversely affect work performance through a decrease in productivity, and an increase in the injury rate. Nevertheless, no systematic review and meta-analysis of the relationship between OSA and work accidents has been performed thus far. METHODS: PubMed, PsycInfo, Scopus, Web of Science, and Cochrane Library were searched. Out of an initial list of 1,099 papers, 10 studies (12,553 participants) were eligible for our review, and 7 of them were included in the meta-analysis. The overall effects were measured by odds ratios (OR) and 95% confidence intervals (CI). An assessment was made of the methodological quality of the studies. Moderator analysis and funnel plot analysis were used to explore the sources of between-study heterogeneity. RESULTS: Compared to controls, the odds of work accident was found to be nearly double in workers with OSA (OR = 2.18; 95% CI = 1.53-3.10). Occupational driving was associated with a higher effect size. CONCLUSIONS: OSA is an underdiagnosed nonoccupational disease that has a strong adverse effect on work accidents. The nearly twofold increased odds of work accidents in subjects with OSA calls for workplace screening in selected safety-sensitive occupations. COMMENTARY: A commentary on this article appears in this issue on page 1171. PMID- 26951402 TI - Localizing Effects of Leptin on Upper Airway and Respiratory Control during Sleep. AB - STUDY OBJECTIVES: Obesity hypoventilation and obstructive sleep apnea are common complications of obesity linked to defects in respiratory pump and upper airway neural control. Leptin-deficient ob/ob mice have impaired ventilatory control and inspiratory flow limitation during sleep, which are both reversed with leptin. We aimed to localize central nervous system (CNS) site(s) of leptin action on respiratory and upper airway neuroventilatory control. METHODS: We localized the effect of leptin to medulla versus hypothalamus by administering intracerbroventricular leptin (10 MUg/2 MUL) versus vehicle to the lateral (n = 14) versus fourth ventricle (n = 11) of ob/ob mice followed by polysomnographic recording. Analyses were stratified for effects on respiratory (nonflow-limited breaths) and upper airway (inspiratory flow limitation) functions. CNS loci were identified by (1) leptin-induced signal transducer and activator of transcription 3 (STAT3) phosphorylation and (2) projections of respiratory and upper airway motoneurons with a retrograde transsynaptic tracer (pseudorabies virus). RESULTS: Both routes of leptin administration increased minute ventilation during nonflow limited breathing in sleep. Phrenic motoneurons were synaptically coupled to the nucleus of the solitary tract, which also showed STAT3 phosphorylation, but not to the hypothalamus. Inspiratory flow limitation and obstructive hypopneas were attenuated by leptin administration to the lateral but not to the fourth cerebral ventricle. Upper airway motoneurons were synaptically coupled with the dorsomedial hypothalamus, which exhibited STAT3 phosphorylation. CONCLUSIONS: Leptin relieves upper airway obstruction in sleep apnea by activating the forebrain, possibly in the dorsomedial hypothalamus. In contrast, leptin upregulates ventilatory control through hindbrain sites of action, possibly in the nucleus of the solitary tract. PMID- 26951403 TI - Detection of depression in low resource settings: validation of the Patient Health Questionnaire (PHQ-9) and cultural concepts of distress in Nepal. AB - BACKGROUND: Despite recognition of the burden of disease due to mood disorders in low- and middle-income countries, there is a lack of consensus on best practices for detecting depression. Self-report screening tools, such as the Patient Health Questionnaire (PHQ-9), require modification for low literacy populations and to assure cultural and clinical validity. An alternative approach is to employ idioms of distress that are locally salient, but these are not synonymous with psychiatric categories. Therefore, our objectives were to evaluate the validity of the PHQ-9, assess the added value of using idioms of distress, and develop an algorithm for depression detection in primary care. METHODS: We conducted a transcultural translation of the PHQ-9 in Nepal using qualitative methods to achieve semantic, content, technical, and criterion equivalence. Researchers administered the Nepali PHQ-9 to randomly selected patients in a rural primary health care center. Trained psychosocial counselors administered a validated Nepali depression module of the Composite International Diagnostic Interview (CIDI) to validate the Nepali PHQ-9. Patients were also assessed for local idioms of distress including heart-mind problems (Nepali, manko samasya). RESULTS: Among 125 primary care patients, 17 (14 %) were positive for a major depressive episode in the prior 2 weeks based on CIDI administration. With a Nepali PHQ-9 cutoff >= 10: sensitivity = 0.94, specificity = 0.80, positive predictive value (PPV) =0.42, negative predictive value (NPV) =0.99, positive likelihood ratio = 4.62, and negative likelihood ratio = 0.07. For heart-mind problems: sensitivity = 0.94, specificity = 0.27, PPV = 0.17, NPV = 0.97. With an algorithm comprising two screening questions (1. presence of heart-mind problems and 2. function impairment due to heart-mind problems) to determine who should receive the full PHQ-9, the number of patients requiring administration of the PHQ-9 could be reduced by 50 %, PHQ-9 false positives would be reduced by 18 %, and 88 % of patients with depression would be correctly identified. CONCLUSION: Combining idioms of distress with a transculturally-translated depression screener increases efficiency and maintains accuracy for high levels of detection. The algorithm reduces the time needed for primary healthcare staff to verbally administer the tool for patients with limited literacy. The burden of false positives is comparable to rates in high-income countries and is a limitation for universal primary care screening. PMID- 26951404 TI - A 7-Year-Old Boy with Intractable Seizures and Snoring. PMID- 26951406 TI - Wake-up Call to Identify Obstructive Sleep Apnea in Patients with Ischemic Strokes. PMID- 26951407 TI - Another Strike Against Sleepability. PMID- 26951408 TI - Low Prevalence of Sleep Disorders in Demyelinating Disease in a Northern Tenerife Population. AB - STUDY OBJECTIVES: Sleep disorders are seen in patients with demyelinating disease (DD) more often than in the general population. Combination of physical and psychological factors such as pain, spasms, nocturia, depression, anxiety, or medication effects could contribute to sleep disruption. Frequently, these disturbances have a major impact on health and quality of life of patients. The aim of this study was to estimate the prevalence of sleep disorders in patients seen in the DD consultation. METHODS: 240 patients; mean age 43 years, 187 women; 163 patients with multiple sclerosis (MS): 144 relapsing-remitting, 19 progressive forms, 36 clinically isolated syndrome, 26 radiological isolated syndrome, and 15 patients with others DD. All participants completed questionnaires: Pittsburgh, Epworth, and Stanford scales, indirect symptoms of RLS and Obstructive Sleep Apnea, Fatigue Severity Scale, and Multiple Sclerosis Quality of Life-54. RESULTS: Moderate/severe insomnia 12.5%, OSA 5.8%, RLS 9.6% (confirmed 3 cases), narcolepsy 0, fatigue (> 4) 24.6%. Physical QoL 66.6 +/- 19.6, Mental QoL 66.1 +/- 21.9. Patients with an established diagnosis showed higher scores on insomnia compared to the group of CIS and RIS (F = 3.85; p = 0.023), no differences were in the other parameters. Fatigue showed high correlation with insomnia (r = 0.443; p < 0.001), RLS (r = 0.513; p < 0.001), and sleepiness (r = 0.211; p = 0.001). None of the variables included in the regression model were shown to be predictors of Physical and Mental QoL. CONCLUSIONS: A high percentage of our sample sleeps well. Emphasize the low prevalence of sleep disorders (insomnia, fatigue, RLS, etc). We detected an overestimation in the RLS questionnaire and the low QoL recorded. PMID- 26951409 TI - Not Only Sleepwalking But NREM Parasomnia Irrespective of the Type Is Associated with HLA DQB1*05:01. AB - STUDY OBJECTIVES: Despite the high prevalence and clinical relevance of NREM parasomnias, data on supportive genetic markers are scarce, and mainly refer to sleepwalking only. METHODS: We retrospectively analyzed clinical, polysomnographic, and HLA findings of 74 adults (37 men) with NREM parasomnia gathered from four neurological sleep centers. Parasomniac events were classified according to ICSD-2 criteria. HLA DQB1 genotyping was compared to regional matched reference allele-frequencies. RESULTS: Fifty-six patients had more than 2 different parasomnia type: 11 sleepwalking, 4 sleep terrors, 3 confusional arousals only. Parasomniac events were documented during video-polysomnography (V PSG) in 70% (49/70) of subjects (71.4% confusional arousals, 8.2% sleep terrors, 4.1% sleepwalking, 16.3% >= 2 NREM parasomnia types). Violent behavior during V PSG occurred in 8.5% (6/71). NREM parasomnia onset was reported after the age of 30 years in 6.8% (5/74). The HLA DQB1*05:01 allele was present in 41% (29/71) compared to 24.2% in the regional-matched reference allele group (p < 0.05). This haplotype prevalence did not differ within the NREM parasomnia type. Epworth Sleepiness Score was 10 or higher in 28.6%. CONCLUSIONS: This is a large polysomnography-based case series of patients with NREM parasomnia. In patients with suspected sleepwalking or sleep terrors, polysomnography is highly useful in detecting arousals from NREM sleep as a marker of NREM parasomnia. We confirmed previous findings by demonstrating a high prevalence of the HLA DQB1*05:01 genotype for different types of NREM parasomnias. Our findings therefore support a common genetic background, and corroborate the importance of video polysomnography in the work-up of parasomnia. PMID- 26951410 TI - Nocturnal Hot Flashes: Relationship to Objective Awakenings and Sleep Stage Transitions. AB - STUDY OBJECTIVES: While women report sleep interruption secondary to nighttime hot flashes, the sleep disrupting impact of nocturnal hot flashes (HF) is not well characterized. We utilized a model of induced HF to investigate the relationship of nighttime HF to sleep architecture and sleep-stage transitions. METHODS: Twenty-eight healthy, premenopausal volunteers received the depot gonadotropin-releasing hormone agonist (GnRHa) leuprolide to rapidly induce menopause, manifesting with HF. Sleep disruption was measured on 2 polysomnograms conducted before and after 4-5 weeks on leuprolide, when HF had developed. RESULTS: 165 HF episodes were recorded objectively during 48 sleep studies (mean 3.4 HF/night). After standardizing to sleep-stage time distribution, the majority of HF were recorded during wake (51.0%) and stage N1 (18.8%). Sixty-six percent of HF occurred within 5 minutes of an awakening, with 80% occurring just before or during the awakening. Objective HF were not associated with sleep disruption as measured by increased transitions to wake or N1, but self-reported nocturnal HF correlated with an increase from pre- to post-leuprolide in the rate of transitions to wake (p = 0.01), and to N1 (p = 0.008). CONCLUSIONS: By isolating the effect of HF on sleep in women without the confound of age-related sleep changes associated with natural menopause, this experimental model shows that HF arise most commonly during N1 and wake, typically preceding or occurring simultaneously with wake episodes. Perception of HF, but not objective HF, is linked to increased sleep-stage transitions, suggesting that sleep disruption increases awareness of and memory for nighttime HF events. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01116401. PMID- 26951411 TI - Nocturia, Insomnia Symptoms and Mortality among Older Men: The Health, Aging and Body Composition Study. AB - STUDY OBJECTIVES: To examine the association between nocturia (walking up from sleep for urination) and mortality risk among community dwelling older men. METHODS: This is a secondary data analysis using data obtained from the Health Aging Body Composition (Health ABC) study. Frequency of nocturia was determined at baseline using a questionnaire. RESULTS: A total of 1,478 older men, mean (SD) age 73.8 (2.9) years, were included in the analysis. During a follow up period of 9.9 years, a total of 760 deaths were reported. Mortality rate was significantly higher for participants with 3 or more nocturia episodes per night, in comparison to those with 0-1 episodes (HR [CI] : 1.21 [1.00-1.47], p = 0.055), even after controlling for baseline characteristics which included demographic variables, body mass index, lower urinary tract symptoms, use of loop diuretics, insomnia symptoms, feeling excessively sleepy during the day/daytime naps, sleep duration, and use of sleep medications. However, the association between >= 3 nocturia episodes per night and mortality risk was no longer statistically significant once prevalent diabetes mellitus and cardiovascular disease were included in the model (HR [CI]: 1.18 [0.97- 1.44], p = 0.100). CONCLUSIONS: Nocturia is associated with mortality independent of insomnia symptoms and sleep duration. The relationship is explained in part by prevalent cardiovascular disease and diabetes mellitus. The results underscore the impact of these medical conditions on the association between 3 or more nocturia episodes and increased mortality risk among older men. PMID- 26951413 TI - Sleep Apnea Is Associated with Hearing Impairment: The Hispanic Community Health Study/Study of Latinos. AB - STUDY OBJECTIVE: Sleep apnea (SA) may promote hearing impairment (HI) through ischemia and inflammation of the cochlea. Our objective was to assess an independent association between SA and HI in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) participants. METHODS: We used data from the HCHS/SOL, a multicenter population-based study of self- identifying Hispanic/Latinos 18- to 74-y-old adults from four US urban communities. We performed home SA testing and in-clinic audiometry testing in all participants. SA was defined as an apnea-hypopnea index (AHI) >= 15 events/h. HI was defined as a mean hearing threshold > 25 dB hearing level in either ear at the frequencies: 3,000 to 8,000 Hz for high-frequency HI (HF-HI) and 500 to 2,000 Hz for low frequency HI (LF-HI). Combined-frequency HI (CF-HI) was defined as both conditions present, and Any-HI was considered as HI in either low or high frequencies. RESULTS: Of 13,967 participants, 9.9% had SA and 32.3% had Any-HI. Adjusted for risk factors for HI, those with SA had a 30% higher odds of Any-HI (95% confidence interval [CI] = 8% to 57%), 26% higher odds of HF-HI (CI = 3% to 55%), 127% higher odds of LF-HI (CI = 21% to 326%), and 29% higher odds of CF-HI (CI = 0% to 65%). A dose-response association was observed between AHI severity and Any-HI (versus no SA, OR for AHI >= 15 and < 30 = 1.22, CI = 0.96 to 1.54, and OR for AHI >= 30 = 1.46, CI = 1.11 to 1.91, p = 0.002). CONCLUSION: SA is associated with HF-HI and LF-HI, independent of snoring and other confounders. COMMENTARY: A commentary on this article appears in this issue on page 641. PMID- 26951412 TI - The Visual Scoring of Sleep in Infants 0 to 2 Months of Age. AB - In March 2014, the American Academy of Sleep Medicine (AASM) Board of Directors requested the Scoring Manual Editorial Board develop rules, terminology, and technical specifications for scoring sleep/wake states in full-term infants from birth to 2 mo of age, cognizant of the 1971 Anders, Emde, and Parmelee Manual for Scoring Sleep in Newborns. On July 1, 2015, the AASM published rules for scoring sleep in infants, ages 0-2 mo. This evidence-based review summarizes the background information provided to the Scoring Manual Editorial Board to write these rules. The Anders Manual only provided criteria for coding physiological and behavioral state characteristics in polysomnograms (PSG) of infants, leaving specific sleep scoring criteria to the individual investigator. Other infant scoring criteria have been published, none widely accepted or used. The AASM Scoring Manual infant scoring criteria incorporate modern concepts, digital PSG recording techniques, practicalities, and compromises. Important tenets are: (1) sleep/wake should be scored in 30-sec epochs as either wakefulness (W), rapid eye movement, REM (R), nonrapid eye movement, NREM (N) and transitional (T) sleep; (2) an electroencephalographic (EEG) montage that permits adequate display of young infant EEG is: F3-M2, F4-M1, C3-M2, C4-M1, O1-M2, O2-M1; additionally, recording C3-Cz, Cz-C4 help detect early and asynchronous sleep spindles; (3) sleep onsets are more often R sleep until 2-3 mo postterm; (4) drowsiness is best characterized by visual observation (supplemented by later video review); (5) wide open eyes is the most crucial determinant of W; (6) regularity (or irregularity) of respiration is the single most useful PSG characteristic for scoring sleep stages at this age; (7) trace alternant (TA) is the only relatively distinctive EEG pattern, characteristic of N sleep, and usually disappears by 1 mo postterm replaced by high voltage slow (HVS); (8) sleep spindles first appear 44-48 w conceptional age (CA) and when present prompt scoring N; (9) score EEG activity in an epoch as "continuous" or "discontinuous" for inter-scorer reliability; (10) score R if four or more of the following conditions are present, including irregular respiration and rapid eye movement(s): (a) low chin EMG (for the majority of the epoch); (b) eyes closed with at least one rapid eye movement (concurrent with low chin tone); (c) irregular respiration; (d) mouthing, sucking, twitches, or brief head movements; and (e) EEG exhibits a continuous pattern without sleep spindles; (11) because rapid eye movements may not be seen on every page, epochs following an epoch of definite R in the absence of rapid eye movements may be scored if the EEG is continuous without TA or sleep spindles, chin muscle tone low for the majority of the epoch; and there is no intervening arousal; (12) Score N if four or more of the following conditions are present, including regular respiration, for the majority of the epoch: (a) eyes are closed with no eye movements; (b) chin EMG tone present; (c) regular respiration; and (d) EEG patterns of either TA, HVS, or sleep spindles are present; and (13) score T sleep if an epoch contains two or more discordant PSG state characteristics (either three NREM and two REM characteristics or two NREM and three REM characteristics). These criteria for ages 0-2 mo represent far more than baby steps. Like all the other AASM Manual rules and specifications none are fixed in stone, all open for debate, discussion and revision with the fundamental goal to provide standards for comparison of methods and results. COMMENTARY: A commentary on this article appears in this issue on page 291. PMID- 26951414 TI - Examining the Variability of Sleep Patterns during Treatment for Chronic Insomnia: Application of a Location-Scale Mixed Model. AB - STUDY OBJECTIVES: The purpose of this study was to introduce a novel statistical technique called the location-scale mixed model that can be used to analyze the mean level and intra-individual variability (IIV) using longitudinal sleep data. METHODS: We applied the location-scale mixed model to examine changes from baseline in sleep efficiency on data collected from 54 participants with chronic insomnia who were randomized to an 8-week Mindfulness-Based Stress Reduction (MBSR; n = 19), an 8-week Mindfulness-Based Therapy for Insomnia (MBTI; n = 19), or an 8-week self-monitoring control (SM; n = 16). Sleep efficiency was derived from daily sleep diaries collected at baseline (days 1-7), early treatment (days 8-21), late treatment (days 22-63), and post week (days 64-70). The behavioral components (sleep restriction, stimulus control) were delivered during late treatment in MBTI. RESULTS: For MBSR and MBTI, the pre-to-post change in mean levels of sleep efficiency were significantly larger than the change in mean levels for the SM control, but the change in IIV was not significantly different. During early and late treatment, MBSR showed a larger increase in mean levels of sleep efficiency and a larger decrease in IIV relative to the SM control. At late treatment, MBTI had a larger increase in the mean level of sleep efficiency compared to SM, but the IIV was not significantly different. CONCLUSIONS: The location-scale mixed model provides a two-dimensional analysis on the mean and IIV using longitudinal sleep diary data with the potential to reveal insights into treatment mechanisms and outcomes. PMID- 26951415 TI - Objective Sleep Assessments in Patients with Postural Tachycardia Syndrome using Overnight Polysomnograms. AB - STUDY OBJECTIVES: Patients with postural tachycardia syndrome (POTS) commonly complain of fatigue, unrefreshing sleep, daytime sleepiness, and diminished quality of life. The study objective was to assess objective sleep quality in POTS patients using overnight polysomnography. METHODS: We studied 16 patients with POTS and 15 healthy control subjects performing daytime autonomic functions tests and overnight polysomnography at the Vanderbilt Clinical Research Center. RESULTS: There were no significant differences in the objective sleep parameters including sleep efficiency, sleep onset latency, wake time after sleep onset, REM latency, percentage of time spent in N1, N2, N3, and REM sleep, arousal index, apnea-hypopnea index, or periodic leg movement index in POTS patients as compared with healthy control subjects. There were significant negative correlations between sleep efficiency and the change in HR from supine to stand (rs = -0.527; p = 0.036). CONCLUSIONS: POTS patients do not have significant differences in objective sleep parameters as compared to control subjects based on overnight polysomnograms. Activation of the sympathetic nervous system may contribute significantly to the hyper arousal state and worsening of subjective estimates of sleep quality as previously reported in POTS patients. PMID- 26951416 TI - Sleep Characteristics in Children with Attention Deficit Hyperactivity Disorder: Systematic Review and Meta-Analyses. AB - STUDY OBJECTIVES: Sleep disturbances have been associated with attention deficit hyperactivity disorder (ADHD), but such relationship is still unclear. The results from the studies conducted do not provide enough evidence to support a sleep physiology inherent to ADHD. This study tries to determine if that sleep physiology really exists by comparing children with ADHD and control children in some sleep parameters. METHODS: A search was conducted in several databases (Web of Science, Scopus, Pubmed and PsycINFO), and a manual search, to retrieve all the articles available from 1987 until March 2014. Of 8,678 non-duplicate studies retrieved, 11 studies met the inclusion and methodological quality criteria. Two meta-analyses were performed with eight of those studies, depending on data provided by them: polysomnographic or actigraphic. A fixed-effects model, and the standardized mean difference (SMD) as the index of effect size, were used in both meta-analyses. RESULTS: Significant differences were found only in the meta analysis with polysomnography as outcome. Children with ADHD were found to spend more time in stage 1 sleep than controls (pooled SMD = 0.32, 95% CI = 0.08-0.55, p value = 0.009). CONCLUSIONS: Although few differences in sleep between children with ADHD and controls have been found in this review, further studies are required on this matter. Those studies should consider some variables discussed in this review, in order to obtain useful and reliable conclusions for research and clinical practice. Particularly, the influence of assessment criteria and ADHD subtypes in the sleep characteristics of children with ADHD should be addressed. PMID- 26951418 TI - Pulseless Electrical Activity during Polysomnography. PMID- 26951417 TI - Accuracy of Automatic Polysomnography Scoring Using Frontal Electrodes. AB - STUDY OBJECTIVES: The economic cost of performing sleep monitoring at home is a major deterrent to adding sleep data during home studies for investigation of sleep apnea and to investigating non-respiratory sleep complaints. Michele Sleep Scoring System (MSS) is a validated automatic system that utilizes central electroencephalography (EEG) derivations and requires minimal editing. We wished to determine if MSS' accuracy is maintained if frontal derivations are used instead. If confirmed, home sleep monitoring would not require home setup or lengthy manual scoring by technologists. METHODS: One hundred two polysomnograms (PSGs) previously recorded from patients with assorted sleep disorders were scored using MSS once with central and once with frontal derivations. Total sleep time, sleep/stage R sleep onset latencies, awake time, time in different sleep stages, arousal/awakening index and apnea-hypopnea index were compared. In addition, odds ratio product (ORP), a continuous index of sleep depth/quality (Sleep 2015;38:641-54), was generated for every 30-sec epoch in each PSG and epoch-by-epoch comparison of ORP was performed. RESULTS: Intraclass correlation coefficients (ICCs) ranged from 0.89 to 1.0 for the various sleep variables (0.96 +/- 0.03). For epoch-by-epoch comparisons of ORP, ICC was > 0.85 in 96 PSGs. Lower values in the other six PSGs were related to signal artifacts in either derivation. ICC for whole-record average ORP was 0.98. CONCLUSIONS: MSS is as accurate with frontal as with central EEG derivations. The use of frontal electrodes along with MSS should make it possible to obtain high-quality sleep data without requiring home setup or lengthy scoring time by expert technologists. PMID- 26951419 TI - Clinical Relevance of Sleep Duration: Results from a Cross-Sectional Analysis Using NHANES. AB - STUDY OBJECTIVES: To assess the clinical relevance of sleep duration, hours slept were compared by health status, presence of insomnia, and presence of depression, and the association of sleep duration with BMI and cardiovascular risk was quantified. METHODS: Cross-sectional analysis of subjects in the US National Health and Nutrition Examination Surveys using adjusted linear and logistic regressions. RESULTS: A total of 22,281 adults were included, 37% slept <= 6 hours, 36% were obese, and 45% reported cardiovascular conditions. Mean sleep duration was 6.87 hours. Better health was associated with more hours of sleep. Subjects with poor health reported sleeping 46 min, (95% CI -56.85 to -35.67) less than subjects with excellent health. Individuals with depression (vs. not depressed) reported 40 min less sleep, (95% CI -47.14 to -32.85). Individuals with insomnia (vs. without insomnia) reported 39 min less sleep, (95% CI -56.24 to -22.45). Duration of sleep was inversely related to BMI; for every additional hour of sleep, there was a decrease of 0.18 kg/m(2) in BMI, (95% CI -0.30 to 0.06). The odds of reporting cardiovascular problems were 6.0% lower for every hour of sleep (odds ratio = 0.94, 95% CI [0.91 to 0.97]). Compared with subjects who slept <= 6 h, subjects who slept more had lower odds of reporting cardiovascular problems, with the exception of subjects >= 55 years old who slept >= 9 hours. CONCLUSIONS: Long sleep duration is associated with better health. The fewer the hours of sleep, the greater the BMI and reported cardiovascular disease. A difference of 30 minutes of sleep is associated with substantive impact on clinical well-being. PMID- 26951422 TI - Can We Assess Pulsus Paradoxus through Polysomnography in a Patient with Chronic Obstructive Pulmonary Disease and Sleep-Disordered Breathing? AB - ABSTRACT: Pulsus paradoxus (PP) is a decrease in systolic blood pressure greater than 10 mm Hg during inspiration that occurs in various medical conditions. Using polysomnography pulse oximetry signal, photoplethysmography variations of the amplitude of the pulse pressure within the respiratory cycle were observed. There is a proportional relationship between the changes of inspiratory waveform values and the generated PP. A 59-year-old male underwent polysomnography that showed sleep hypoxemia, obstructive sleep-disordered breathing (apnea hypopnea index [AHI] = 5.1and respiratory disturbance index [RDI] = 87.9), with variations of pulse pressure induced primarily by inspiration. The highest variations in the pulse wave were observed in NREM sleep during obstructive respiratory events and in biocalibration during nasal breathing. The lowest variations occurred after the correction of inspiratory obstructive events and during biocalibration when asked to hold his breath. PMID- 26951421 TI - A Pre-Screening Questionnaire to Predict Non-24-Hour Sleep-Wake Rhythm Disorder (N24HSWD) among the Blind. AB - STUDY OBJECTIVES: There is currently no questionnaire-based pre-screening tool available to detect non-24-hour sleep-wake rhythm disorder (N24HSWD) among blind patients. Our goal was to develop such a tool, derived from gold standard, objective hormonal measures of circadian entrainment status, for the detection of N24HSWD among those with visual impairment. METHODS: We evaluated the contribution of 40 variables in their ability to predict N24HSWD among 127 blind women, classified using urinary 6-sulfatoxymelatonin period, an objective marker of circadian entrainment status in this population. We subjected the 40 candidate predictors to 1,000 bootstrapped iterations of a logistic regression forward selection model to predict N24HSWD, with model inclusion set at the p < 0.05 level. We removed any predictors that were not selected at least 1% of the time in the 1,000 bootstrapped models and applied a second round of 1,000 bootstrapped logistic regression forward selection models to the remaining 23 candidate predictors. We included all questions that were selected at least 10% of the time in the final model. We subjected the selected predictors to a final logistic regression model to predict N24SWD over 1,000 bootstrapped models to calculate the concordance statistic and adjusted optimism of the final model. We used this information to generate a predictive model and determined the sensitivity and specificity of the model. Finally, we applied the model to a cohort of 1,262 blind women who completed the survey, but did not collect urine samples. RESULTS: The final model consisted of eight questions. The concordance statistic, adjusted for bootstrapping, was 0.85. The positive predictive value was 88%, the negative predictive value was 79%. Applying this model to our larger dataset of women, we found that 61% of those without light perception, and 27% with some degree of light perception, would be referred for further screening for N24HSWD. CONCLUSIONS: Our model has predictive utility sufficient to serve as a pre screening questionnaire for N24HSWD among the blind. PMID- 26951423 TI - Altered Sleep Spindles in Delayed Encephalopathy after Acute Carbon Monoxide Poisoning. AB - ABSTRACT: Delayed encephalopathy (DE) affects not only the cerebral white matter and globus pallidus but also the cortex and thalamus. However, it remains unknown whether these brain lesions alter sleep along with clinical manifestations of DE. A 46-year-old man with DE underwent repetitive hyperbaric oxygen therapy. The patient was evaluated by not only neuropsychological and neuroimaging testing but polysomnography over the clinical course. Neurological symptoms improved markedly; however, profound frontal cognitive deficits continued. The polysomnography revealed prolonged absence and delayed recovery of sleep spindles across recordings. Alterations in spindle oscillations in DE could provide further insight into sleep regulatory networks. PMID- 26951420 TI - The Association between Nocturnal Cardiac Arrhythmias and Sleep-Disordered Breathing: The DREAM Study. AB - STUDY OBJECTIVES: To determine whether sleep-disordered breathing (SDB) is associated with cardiac arrhythmia in a clinic-based population with multiple cardiovascular comorbidities and severe SDB. METHODS: This was a cross-sectional analysis of 697 veterans who underwent polysomnography for suspected SDB. SDB was categorized according to the apnea-hypopnea index (AHI): none (AHI < 5), mild (5 >= AHI < 15), and moderate-severe (AHI >= 15). Nocturnal cardiac arrhythmias consisted of: (1) complex ventricular ectopy, (CVE: non-sustained ventricular tachycardia, bigeminy, trigeminy, or quadrigeminy), (2) combined supraventricular tachycardia, (CST: atrial fibrillation or supraventricular tachycardia), (3) intraventricular conduction delay (ICD), (4) tachyarrhythmias (ventricular and supraventricular), and (5) any cardiac arrhythmia. Unadjusted, adjusted logistic regression, and Cochran-Armitage testing examined the association between SDB and cardiac arrhythmias. Linear regression models explored the association between hypoxia, arousals, and cardiac arrhythmias. RESULTS: Compared to those without SDB, patients with moderate-severe SDB had almost three-fold unadjusted odds of any cardiac arrhythmia (2.94; CI 95%, 2.01-4.30; p < 0.0001), two-fold odds of tachyarrhythmias (2.16; CI 95%,1.47-3.18; p = 0.0011), two-fold odds of CVE (2.01; 1.36-2.96; p = 0.003), and two-fold odds of ICD (2.50; 1.58-3.95; p = 0.001). A linear trend was identified between SDB severity and all cardiac arrhythmia subtypes (p value linear trend < 0.0001). After adjusting for age, BMI, gender, and cardiovascular diseases, moderate-severe SDB patients had twice the odds of having nocturnal cardiac arrhythmias (2.24; 1.48-3.39; p = 0.004). Frequency of obstructive respiratory events and hypoxia were strong predictors of arrhythmia risk. CONCLUSIONS: SDB is independently associated with nocturnal cardiac arrhythmias. Increasing severity of SDB was associated with an increasing risk for any cardiac arrhythmia. PMID- 26951425 TI - Choice architecture in code status discussions with terminally ill patients and their families. PMID- 26951426 TI - Ultrasonography evaluation during the weaning process: the heart, the diaphragm, the pleura and the lung. AB - PURPOSE: On a regular basis, the intensivist encounters the patient who is difficult to wean from mechanical ventilatory support. The causes for failure to wean from mechanical ventilatory support are often multifactorial and involve a complex interplay between cardiac and pulmonary dysfunction. A potential application of point of care ultrasonography relates to its utility in the process of weaning the patient from mechanical ventilatory support. METHODS: This article reviews some applications of ultrasonography that may be relevant to the process of weaning from mechanical ventilatory support. RESULTS: The authors have divided these applications of ultrasonography into four separate categories: the assessment of cardiac, diaphragmatic, and lung function; and the identification of pleural effusion; which can all be evaluated with ultrasonography during a dynamic process in which the intensivist is uniquely positioned to use ultrasonography at the point of care. CONCLUSIONS: Ultrasonography may have useful application during the weaning process from mechanical ventilatory support. PMID- 26951428 TI - Early goal-directed therapy: do we have a definitive answer? PMID- 26951429 TI - Erratum to: State budget transfers to Health Insurance Funds for universal health coverage: institutional design patterns and challenges of covering those outside the formal sector in Eastern European high-income countries. PMID- 26951427 TI - CAESAR: a new tool to assess relatives' experience of dying and death in the ICU. AB - PURPOSE: To develop an instrument designed specifically to assess the experience of relatives of patients who die in the intensive care unit (ICU). METHODS: The instrument was developed using a mixed methodology and validated in a prospective multicentre study. Relatives of patients who died in 41 ICUs completed the questionnaire by telephone 21 days after the death, then completed the Hospital Anxiety and Depression Scale, Impact of Event Scale-Revised and Inventory of Complicated Grief after 3, 6, and 12 months. RESULTS: A total of 600 relatives were included, 475 in the main cohort and 125 in the reliability cohort. The 15 item questionnaire, named CAESAR, covered the patient's preferences and values, interactions with/around the patient and family satisfaction. We defined three groups based on CAESAR score tertiles: lowest (<=59, n = 107, 25.9 %), middle (n = 185, 44.8 %) and highest (>=69, n = 121, 29.3 %). Factorial analysis showed a single dimension. Cronbach's alpha in the main and reliability cohorts was 0.88 (0.85-0.90) and 0.85 (0.79-0.89), respectively. Compared to a high CAESAR score, a low CAESAR score was associated with greater risks of anxiety and depression at 3 months [1.29 (1.13-1.46), p = 0.001], post-traumatic stress-related symptoms at 3 [1.34 (1.17-1.53), p < 0.001], 6 [OR = 1.24 (1.06-1.44), p = 0.008] and 12 [OR = 1.26 (1.06-1.50), p = 0.01] months and complicated grief at 6 [OR = 1.40 (1.20 1.63), p < 0.001] and 12 months [OR = 1.27 (1.06-1.52), p = 0.01]. CONCLUSIONS: The CAESAR score 21 days after death in the ICU is strongly associated with post ICU burden in the bereaved relatives. The CAESAR score should prove a useful primary endpoint in trials of interventions to improve relatives' well-being. PMID- 26951430 TI - Effect of vaginal delivery on anal sphincter function in Asian primigravida: a prospective study. AB - INTRODUCTION AND HYPOTHESIS: The true incidence of obstetric anal sphincter injuries (OASI) among Asian primigravida is not known. This study aimed to evaluate OASI in Sri Lankan primigravida. METHODS: One hundred and one consecutive primigravida in their last trimester were recruited from antenatal clinics at a tertiary care centre in Sri Lanka and followed up 6 weeks and 6 months after delivery. They were assessed using anorectal manometry (3D-ARM) and endoanal ultrasound (3D-EAUS) on both occasions. RESULTS: Seventy-three (75.3 %) had vaginal delivery without instrumentation, whereas 3 (3.1 %) each delivered using forceps or vacuum. Twelve (12.4 %) had emergency caesarean sections and 6 (6.2 %) had elective caesarean sections. None had clinically identified anal sphincter injuries. EAUS identified IAS defects in 3 (5.1 %) and EAS defects in 28 (47.5 %). Both resting (p = 0.3) and squeeze (p = 0.001) pressures had decreased following childbirth. Multivariate analysis identified antepartum RP and postpartum EAS defects to be associated with RP reduction (chi(2)(4)=17.825, p < 0.0005) and antepartum SP and postpartum EAS defects to be associated with SP reduction (chi(2)(5)=31.517, p < 0.0005). Episiotomy was protective, whereas delivering after 40 weeks' gestation and delivering a baby with a longer length increased the risk of SP reduction. EAS defects (chi(2) (6)=23.502, p = .001) were more common in mothers who had labour augmented by oxytocin and in those who delivered a baby with a larger head circumference. Labour induction and delivering a longer baby were protective for EAS defects. CONCLUSIONS: Several risk and protective factors for the structural and functional damage of sphincters were identified. These findings will help to formulate a policy to minimize future obstetric anal sphincter injuries. PMID- 26951431 TI - Community acquired fungemia caused by Candida pulcherrima: diagnostic contribution of MALDI-TOF mass spectrometry. AB - BACKGROUND: Community-onset candidemia constitute a distinct clinical entity the incidence of which is increasing. Contribution of non-albicans Candida species is rising. CASE PRESENTATION: We describe here the first reported case of community acquired fungemia due to Candida pulcherrima. Identification to the species level was performed by MALDI-TOF mass spectrometry. Treatment with fluconazole was successful. CONCLUSION: This case confirms the pathogenic role of C. pulcherrima and the contribution of MALDI-TOF mass spectrometry for identification of rare Candida species. PMID- 26951432 TI - Heat Induction of Cyclic Electron Flow around Photosystem I in the Symbiotic Dinoflagellate Symbiodinium. AB - Increases in seawater temperature impair photosynthesis (photoinhibition) in the symbiotic dinoflagellate Symbiodinium within cnidarian hosts, such as corals and sea anemones, and may destroy their symbiotic relationship. Although the degree of photoinhibition in Symbiodinium under heat stress differs among strains, the differences in their responses to increased temperatures, including cyclic electron flow (CEF), which sustains photoprotective thermal energy dissipation, have not been investigated. Here, we examined CEF in cultured Symbiodinium cells or those in an endosymbiotic relationship within a cnidarian host. The light dependent reduction of the primary electron donor photosystem I, i.e. P700(+), was enhanced in any Symbiodinium cell by increasing temperatures, indicating CEF was induced by heat, which was accompanied by thermal energy dissipation activation. The critical temperatures for inducing CEF were different among Symbiodinium strains. The clade A strains with greater susceptibility to photoinhibition, OTcH-1 and Y106, exhibited higher CEF activities under moderate heat stress than a more phototolerant clade B strain Mf1.05b, suggesting that the observed CEF induction was not a preventive measure but a stress response in Symbiodinium. PMID- 26951433 TI - The Chloroplastic Protein THF1 Interacts with the Coiled-Coil Domain of the Disease Resistance Protein N' and Regulates Light-Dependent Cell Death. AB - One branch of plant immunity is mediated through nucleotide-binding/Leu-rich repeat (NB-LRR) family proteins that recognize specific effectors encoded by pathogens. Members of the I2-like family constitute a well-conserved subgroup of NB-LRRs from Solanaceae possessing a coiled-coil (CC) domain at their N termini. We show here that the CC domains of several I2-like proteins are able to induce a hypersensitive response (HR), a form of programmed cell death associated with disease resistance. Using yeast two-hybrid screens, we identified the chloroplastic protein Thylakoid Formation1 (THF1) as an interacting partner for several I2-like CC domains. Co-immunoprecipitations and bimolecular fluorescence complementation assays confirmed that THF1 and I2-like CC domains interact in planta and that these interactions take place in the cytosol. Several HR-inducing I2-like CC domains have a negative effect on the accumulation of THF1, suggesting that the latter is destabilized by active CC domains. To confirm this model, we investigated N', which recognizes the coat protein of most Tobamoviruses, as a prototypical member of the I2-like family. Transient expression and gene silencing data indicated that THF1 functions as a negative regulator of cell death and that activation of full-length N' results in the destabilization of THF1. Consistent with the known function of THF1 in maintaining chloroplast homeostasis, we show that the HR induced by N' is light-dependent. Together, our results define, to our knowledge, novel molecular mechanisms linking light and chloroplasts to the induction of cell death by a subgroup of NB-LRR proteins. PMID- 26951434 TI - Asparagus IRX9, IRX10, and IRX14A Are Components of an Active Xylan Backbone Synthase Complex that Forms in the Golgi Apparatus. AB - Heteroxylans are abundant components of plant cell walls and provide important raw materials for the food, pharmaceutical, and biofuel industries. A number of studies in Arabidopsis (Arabidopsis thaliana) have suggested that the IRREGULAR XYLEM9 (IRX9), IRX10, and IRX14 proteins, as well as their homologs, are involved in xylan synthesis via a Golgi-localized complex termed the xylan synthase complex (XSC). However, both the biochemical and cell biological research lags the genetic and molecular evidence. In this study, we characterized garden asparagus (Asparagus officinalis) stem xylan biosynthesis genes (AoIRX9, AoIRX9L, AoIRX10, AoIRX14A, and AoIRX14B) by heterologous expression in Nicotiana benthamiana We reconstituted and partially purified an active XSC and showed that three proteins, AoIRX9, AoIRX10, and AoIRX14A, are necessary for xylan xylosyltranferase activity in planta. To better understand the XSC structure and its composition, we carried out coimmunoprecipitation and bimolecular fluorescence complementation analysis to show the molecular interactions between these three IRX proteins. Using a site-directed mutagenesis approach, we showed that the DxD motifs of AoIRX10 and AoIRX14A are crucial for the catalytic activity. These data provide, to our knowledge, the first lines of biochemical and cell biological evidence that AoIRX9, AoIRX10, and AoIRX14A are core components of a Golgi-localized XSC, each with distinct roles for effective heteroxylan biosynthesis. PMID- 26951435 TI - A DNA2 Homolog Is Required for DNA Damage Repair, Cell Cycle Regulation, and Meristem Maintenance in Plants. AB - Plant meristem cells divide and differentiate in a spatially and temporally regulated manner, ultimately giving rise to organs. In this study, we isolated the Arabidopsis jing he sheng 1 (jhs1) mutant, which exhibited retarded growth, an abnormal pattern of meristem cell division and differentiation, and morphological defects such as fasciation, an irregular arrangement of siliques, and short roots. We identified JHS1 as a homolog of human and yeast DNA Replication Helicase/Nuclease2, which is known to be involved in DNA replication and damage repair. JHS1 is strongly expressed in the meristem of Arabidopsis. The jhs1 mutant was sensitive to DNA damage stress and had an increased DNA damage response, including increased expression of genes involved in DNA damage repair and cell cycle regulation, and a higher frequency of homologous recombination. In the meristem of the mutant plants, cell cycle progression was delayed at the G2 or late S phase and genes essential for meristem maintenance were misregulated. These results suggest that JHS1 plays an important role in DNA replication and damage repair, meristem maintenance, and development in plants. PMID- 26951436 TI - The Histone Deacetylase Complex 1 Protein of Arabidopsis Has the Capacity to Interact with Multiple Proteins Including Histone 3-Binding Proteins and Histone 1 Variants. AB - Intrinsically disordered proteins can adopt multiple conformations, thereby enabling interaction with a wide variety of partners. They often serve as hubs in protein interaction networks. We have previously shown that the Histone Deacetylase Complex 1 (HDC1) protein from Arabidopsis (Arabidopsis thaliana) interacts with histone deacetylases and quantitatively determines histone acetylation levels, transcriptional activity, and several phenotypes, including abscisic acid sensitivity during germination, vegetative growth rate, and flowering time. HDC1-type proteins are ubiquitous in plants, but they contain no known structural or functional domains. Here, we explored the protein interaction spectrum of HDC1 using a quantitative bimolecular fluorescence complementation assay in tobacco (Nicotiana benthamiana) epidermal cells. In addition to binding histone deacetylases, HDC1 directly interacted with histone H3-binding proteins and corepressor-associated proteins but not with H3 or the corepressors themselves. Surprisingly, HDC1 also was able to interact with variants of the linker histone H1. Truncation of HDC1 to the ancestral core sequence narrowed the spectrum of interactions and of phenotypic outputs but maintained binding to a H3 binding protein and to H1. Thus, HDC1 provides a potential link between H1 and histone-modifying complexes. PMID- 26951437 TI - Oral ulcerations after placement of orthodontic braces and skin pustules after laser hair removal: novel inducers of pathergy reactions in new-onset Behcet's disease. AB - A 25-year-old man was admitted to our hospital, with fever, severe ulceration of the oral and pharyngeal mucosa, and pustules on his skin. These pathergy-like lesions had emerged after placement of orthodontic braces and laser therapy for hair removal, respectively. The patient's clinical condition, together with his ethnic background, pointed to the diagnosis of Behcet's disease. Treatment with colchicine and prednisone resulted in rapid improvement of his symptoms. Pathergy reactions in response to placement of dental braces and laser hair removal are a rare first presentation of Behcet's disease. PMID- 26951438 TI - Primary renal carcinoid tumour with lung metastasis misdiagnosed as renal cell carcinoma. AB - A 58-year-old man with a history of metastatic renal cell carcinoma (RCC) diagnosed 10 years prior, status post right nephrectomy, presented for evaluation of pulmonary nodules. A year after the nephrectomy, he had undergone cutaneous metastasectomy in the right flank area, and a further 2 years later he had had his second cutaneous metastasectomy in the right chest wall. Both cutaneous pathologies had, at the time, shown metastatic neoplasm with histological features compatible with those of the previous renal tumour. He was treated with sorafenib. 3 years later he developed asymptomatic pulmonary nodules, which gradually doubled in size over the next 2.5 years. He underwent bronchoscopy and left lower lobe biopsy. Pathology revealed a metastatic renal carcinoid/neuroendocrine tumour. Second review of the previous renal neoplasm and the cutaneous metastatic pathology showed trabecular architecture, consistent with carcinoid, but mimicking the long parallel arrays that have been described in some cases of papillary RCC. PMID- 26951439 TI - Single coronary artery originating from the right sinus Valsalva presenting as typical angina pectoris. AB - A single coronary artery (SCA) ostium is a rare finding. In the general population, the incidence of SCA is approximately 0.024%. We introduce a case of a warehouseman presenting with chest pain after a morning work. The exercise ECG showed ST segment depression in the V 1-4 leads. The coronary angiography procedure and the CT demonstrated an SCA dividing into the right coronary artery and left main coronary artery. We identified a borderline lesion in the distal left anterior descending artery with fractional flow reserve of 0.85. In our case, the coronary anomaly was considered at low risk of arrhythmia and sudden death, and the patient was, therefore, treated conservatively. PMID- 26951440 TI - Adjunctive vagus nerve stimulation for treatment-resistant bipolar disorder: managing device failure or the end of battery life. AB - The vagus nerve stimulation (VNS) device is used not only to treat refractory seizure disorders but also mood disorders; the latter indication received CE Mark approval in 2001 and Food and Drug Administration approval in 2005. Original estimates for the end of battery life (EOBL) were approximately 6-10 years. Many neuropsychiatric patients have or will soon face EOBL. A patient with severe, life-threatening, treatment-resistant bipolar disorder underwent 9 years of stable remission following 20 months of adjunctive VNS. The device ceased operation at EOBL. Because of logistical issues, re-initiation of VNS was delayed over several months. The patient relapsed with depression, mania and mixed states, and regained remission 17 months after device replacement. This case dictates prudence in managing stable patients in remission with VNS. If the device malfunctions, urgent surgical replacement is warranted with subsequent rapid titration to previous parameters as tolerated. Several months' delay may trigger relapse and prove difficult to re-establish remission. PMID- 26951442 TI - Reversible cerebral vasoconstriction syndrome (RCVS): a transient condition being underdiagnosed? PMID- 26951441 TI - Emphysematous cystitis: a radiographic diagnosis. PMID- 26951443 TI - Erythema gyratum repens: a paraneoplastic eruption. PMID- 26951444 TI - Preventing intra-urethral migration of a guidewire during antegrade placement of a JJ stent: a technical modification. AB - A JJ stent is usually inserted in antegrade fashion after percutaneous renal surgery. We describe a new technical modification for antegrade stent insertion that prevents intraoperative intra-urethral migration of the guidewire and saves operative time and cost. PMID- 26951446 TI - Erratum to: An extreme learning machine model for the simulation of monthly mean streamflow water level in eastern Queensland. PMID- 26951445 TI - Micro-RNA (miRNA) profile in Hodgkin lymphoma: association between clinical and pathological variables. AB - miRNAs are small RNAs and control the expression of protein-encoding genes. The aim of this study was to determine the association between miRNA profile and clinical variables including age, stage, B symptom, histopathologic subtype, response to treatment, disease-free survival (DFS) and overall survival (OS) in classical Hodgkin lymphoma (cHL). A total of 377 miRNAs were studied by qPCR in 32 cases with cHL, and results were compared with 60 samples taken from cases with reactive lymphadenopathy. Biogazelle qbasePLUS 2.0 software was used to analyze the results. miR-582-3p, miR-525-3p, miR-448, miR-512-3p, miR-642a-5p, miR-876-5p, miR-532-3p, miR-654-5p, miR-128, miR-145-5p, miR-15b-5p, miR-328 and miR-660-5p were found to be decreased in cHL compared with controls. In contrast, miR-34a-5p (2.626-fold), miR-146a-5p (4.32-fold), miR-93-5p (2.347-fold), miR-20a 5p (4.930-fold), miR-339-3p (4.948-fold), miR-324-3p (4.98-fold), miR-372 (7.038 fold), miR-127-3p (8.234-fold), miR-155-5p (4.947-fold), miR-320a (17.502-fold) and miR-370 (21.479-fold) (p < 0.05) were found to be increased in cHL. There was no difference in miRNA profile according to the age, sex, stage, response to treatment, DFS and OS. However, miR-889 was found to be increased in patients with B symptom and miR-127-3p was found to be increased in nodular sclerosing subtype. Some miRNAs increase and some decrease in cHL. However, there was no clinical association between clinical variables and with the majority of the miRNA profile studied in this study. miR-889 and miR-127-3p were related to B symptom and nodular sclerosis subtype, respectively. We need more studies evaluating miRNA profile and clinical outcome in Hodgkin Lymphoma. PMID- 26951447 TI - Erratum to: Statistical study to identify the key factors governing ground water recharge in the watersheds of the arid Central Asia. PMID- 26951448 TI - Geochemical characterization of elements in Vitis vinifera cv. Negroamaro grape berries grown under different soil managements. AB - The present geochemical study concerns the impact of viticultural practices in the chemical composition of the grape cultivar "Negroamaro" in Apulia, a southern Italian region renowned for its quality wine. Three types of soil management (SM), two cover cropping with different mixtures, and a soil tillage were considered. For each SM, the vines were irrigated according to two irrigation levels. Chemical composition of soil and of berries of Vitis vinifera cultivar "Negroamaro" were analyzed by X-ray fluorescence, inductively coupled plasma-mass spectrometry and multivariate statistics (linear discrimination analysis). In detail, we investigated major and trace elements behavior in the soil according to irrigation levels, the related index of bioaccumulation (BA) and the relationship between trace element concentration and soil management in "Negroamaro" grapes. The results indicate that soil management affects the mobility of major and trace elements. A specific assimilation of these elements in grapes from vines grown under different soil management was confirmed by BA. Multivariate statistics allowed to associate the vines to the type of soil management. This geochemical characterization of elements could be useful to develop fingerprints of vines of the cultivar "Negroamaro" according to soil management and geographical origin. PMID- 26951449 TI - Tissue specific metal characterization of selected fish species in Pakistan. AB - Concentration of various metals, i.e., zinc (Zn), copper (Cu), lead (Pb), nickel (Ni), iron (Fe), manganese (Mn), chromium (Cr), and silver (Ag), was evaluated in five indigenous fish species (namely, silver carp, common carp, mahseer, thela fish, and rainbow trout), by using atomic absorption spectrophotometer. It is proved from this study that, overall, mahseer and rainbow trout had high amount of zinc, whereas thela fish and silver carp had high concentration of copper, chromium, silver, nickel, and lead, while common carp had highest amount of iron contents. Furthermore, a tissue-specific discrimination among various fish species was observed, where higher metal concentrations were noticed in fish liver, with decreasing concentration in other organs like skin, gills, and finally the least contents in fish muscle. Multivariate data analysis showed not only a variation in heavy metals among the tissues but also discrimination among the selected fish species. PMID- 26951451 TI - New reversal agent for factor Xa inhibitors shows promise. PMID- 26951450 TI - Anesthetic management of the first pediatric bilateral hand transplant. AB - PURPOSE: The purpose of this case report is to describe the anesthetic and case management of the first vascularized composite allograft pediatric bilateral hand transplant. CLINICAL DETAILS: Our patient was an eight-year-old male with a medical history of Staphylococcus aureus sepsis at one year of age that resulted in end-stage renal disease as well as bilateral upper and lower extremity amputations. After referral for bilateral hand transplantation, the transplantation team, with expertise in all aspects of perioperative care (surgery, anesthesiology, nephrology, renal transplantation, pediatric intensive care, and therapeutic pharmacy), was consulted to help develop anesthetic and other perioperative protocols for surgery. Prior to activation of the transplantation team, the lead surgeon evaluated potential donors by comparing a three-dimensional printed model of the recipient's forearm with the donor's upper extremities to ensure an adequate match. The anesthesia team inserted bilateral ultrasound-guided infraclavicular catheters to provide a sympathetic block to facilitate blood flow to the upper extremities and to provide both intraoperative and postoperative pain control. The patient remained in the operating room for 13 hr 37 min for a surgical time of ten hours 39 min. He remained in the hospital for 34 days after the procedure and was then transferred to an inpatient rehabilitation facility for a further 15 days. The patient is currently doing well in a postoperative rehabilitation program. He has demonstrated motor power to the hands using the forearm muscles but is not expected to reach his maximum sensory function for at least one to two years. CONCLUSION: This report describes the anesthetic management of the first pediatric bilateral hand transplant. This procedure required considerable preoperative planning and communication between various teams to ensure all resources needed to deliver the care for this complex and novel transplant surgery were readily available. PMID- 26951454 TI - Zika Virus and Pregnancy: A Review of the Literature and Clinical Considerations (Podcast). PMID- 26951453 TI - No evidence of increased breast cancer risk for proven noncarriers from BRCA1 and BRCA2 families. AB - In families screened for mutations in the BRCA1 or BRCA2 genes and found to have a segregating mutation the breast cancer risk for women shown not to carry the family-specific mutation might be at above "average" risk. We assessed the risk of breast cancer in a clinic based cohort of 725 female proven noncarriers in 239 BRCA1 and BRCA2 families compared with birth-matched controls from the Danish Civil Registration System. Prospective analysis showed no significantly increased risk for breast cancer in noncarriers with a hazard ratio of 0.67 [95 % confidence interval (CI) 0.32-1.42, p = 0.29] for all family members who tested negative and 0.87 (95 % CI 0.38-1.97, p = 0.73) for non-carries who were first degree relatives of mutation carriers. Proven noncarriers from BRCA1 and BRCA2 families have no markedly increased risk for breast cancer compared to the general population, and our data do not suggest targeted breast cancer surveillance for noncarriers from BRCA1 and BRCA2 families. PMID- 26951452 TI - Important Roles of Ring Finger Protein 112 in Embryonic Vascular Development and Brain Functions. AB - Rnf112 is a member of the RING finger protein family. The expression of Rnf112 is abundant in the brain and is regulated during brain development. Our previous study has revealed that Rnf112 can promote neuronal differentiation by inhibiting the progression of the cell cycle in cell models. In this study, we further revealed the important functions of Rnf112 in embryo development and in adult brain. Our data showed that most of the Rnf112 -/- embryos exhibited blood vascular defects and died in utero. Upon further investigation, we found that the survival rate of homozygous Rnf112 knockout mice in 129/sv and C57BL/6 mixed genetic background was increased. The survived newborns of Rnf112 -/- mice manifested growth retardation as indicated by smaller size and a reduced weight. Although the overall organization of the brain did not appear to be severely affected in Rnf112 -/- mice, using in vivo 3D MRI imaging, we found that when compared to wild-type littermates, brains of Rnf112 -/- mice were smaller. In addition, Rnf112 -/- mice displayed impairment of brain functions including motor balance, and spatial learning and memory. Our results provide important aspects for the study of Rnf112 gene functions. PMID- 26951455 TI - The Influence of Finasteride on Mean and Relative Spectral Density of EEG Bands in Rat Model of Thioacetamide-Induced Hepatic Encephalopathy. AB - Liver failure is associated with a neuropsychiatric syndrome, known as hepatic encephalopathy (HE). Finasteride, inhibitor of neurosteroid synthesis, may improve the course of HE. The aim of our study was to investigate the influence of finasteride on mean and relative power density of EEG bands, determined by spectral analysis, in rat model of thioacetamide-induced HE. Male Wistar rats were divided into groups: (1) control; (2) thioacetamide-treated group, TAA (900 mg/kg); (3) finasteride-treated group, FIN (150 mg/kg); and (4) group treated with finasteride (150 mg/kg) and thioacetamide (900 mg/kg), FIN + TAA. Daily doses of FIN (50 mg/kg) and TAA (300 mg/kg) were administered during 3 subsequent days, and in FIN + TAA group FIN was administered 2 h before every dose of TAA. EEG was recorded 22-24 h after treatment and analyzed by fast Fourier transformation. While TAA did not induce significant changes in the beta band, mean and relative power in this band were significantly higher in FIN + TAA versus control group (p < 0.01). TAA caused a significant decline in mean power in alpha, theta, and delta band, and in FIN + TAA group the mean power in these bands was significantly higher compared with control. While in TAA group relative power was significantly decreased in theta (p < 0.01) and increased in delta band (p < 0.01) versus control, the opposite changes were found in FIN + TAA group: an increase in theta (p < 0.01) and a decrease in delta relative power (p < 0.01). In this study, finasteride pretreatment caused EEG changes that correspond to mild TAA-induced HE. PMID- 26951459 TI - An Overview of the Mechanisms of Microcystin-LR Genotoxicity and Potential Carcinogenicity. AB - Microcystins (MCs) are hepatotoxic cyclic peptides, and microcystin-LR (MCLR) is one of the most abundant and toxic congeners. MCLR-induced hepatotoxicity occurs through specific inhibition of serine/threonine protein phosphatases 1 and 2A, which leads to hyperphosphorylation of many cellular proteins. This eventually results in cytoskeletal damage, loss of cell morphology, and the consequent cell death. It is generally accepted that inhibition of protein phosphatases is the main mechanism associated with the potential tumor-promoting activities of MCs. MCs can induce excessive formation of reactive oxygen and nitrogen species, which results in DNA damage. Although MCLR is not a bacterial mutagen, in mammalian cells it can induce mutations, as predominantly large deletions, and it has clastogenic actions. Although MCLR disrupts the mitotic spindle, its aneugenic activity has not been studied in detail. MCLR interferes with DNA damage repair processes, which contribute to genetic instability. Furthermore, MCLR increases expression of early response genes, including proto-oncogenes, and genes involved in responses to DNA damage and repair, cell-cycle arrest, and apoptosis. However, published data on the genotoxicity and carcinogenicity of MCs have been contradictory; therefore, the aim of this review is to provide current overview of the genotoxic and potential carcionogenic activities of MCs in bacteria and mammalian cells, with a focus on MCLR. The mechanisms of MC acute toxicity, their biochemical and morphological effects, and their effects on the cell cytoskeleton are covered in detail elsewhere in the literature, including in this Special Issue on "Cellular and biochemical effects of microcystins (cyanobacterial toxins) and their potential medical consequences". PMID- 26951457 TI - Hydrogen sulfide post-conditioning preserves interfibrillar mitochondria of rat heart during ischemia reperfusion injury. AB - Cardiac mitochondrial dysfunction is considered to be the main manifestation in the pathology of ischemia reperfusion injury, and by restoring its functional activity, hydrogen sulfide (H2S), a novel endogenous gaseotransmitter renders cardioprotection. Given that interfibrillar (IFM) and subsarcolemmal (SSM) mitochondria are the two main types in the heart, the present study investigates the specific H2S-mediated action on IFM and SSM during ischemic reperfusion in the Langendorff rat heart model. Rats were randomly divided into five groups, namely normal, ischemic control, reperfusion control (I/R), ischemic post conditioning (POC), and H2S post-conditioning (POC_H2S). In reperfusion control, cardiac contractility decreased, and lactate dehydrogenase, creatine kinase, and infracted size increased compared to both normal and ischemic group. In hearts post-conditioned with H2S and the classical method improved cardiac mechanical function and decreased cardiac markers in the perfusate and infarct size significantly. Both POC and POC_H2S exerts its cardioprotective effect of preserving the IFM, as evident by significant improvement in electron transport chain enzyme activities and mitochondrial respiration. The in vitro action of H2S on IFM and SSM from normal and I/R rat heart supports H2S and mediates cardioprotection via IFM preservation. Our study indicates that IFM play an important role in POC_H2S mediated cardioprotection from reperfusion injury. PMID- 26951460 TI - Feedback learning and behavior problems after pediatric traumatic brain injury. AB - BACKGROUND: Feedback learning is essential for behavioral development. We investigated feedback learning in relation to behavior problems after pediatric traumatic brain injury (TBI). METHOD: Children aged 6-13 years diagnosed with TBI (n = 112; 1.7 years post-injury) were compared with children with traumatic control (TC) injury (n = 52). TBI severity was defined as mild TBI without risk factors for complicated TBI (mildRF- TBI, n = 24), mild TBI with ?1 risk factor for complicated TBI (mildRF+ TBI, n = 51) and moderate/severe TBI (n = 37). The Probabilistic Learning Test was used to measure feedback learning, assessing the effects of inconsistent feedback on learning and generalization of learning from the learning context to novel contexts. The relation between feedback learning and behavioral functioning rated by parents and teachers was explored. RESULTS: No evidence was found for an effect of TBI on learning from inconsistent feedback, while the moderate/severe TBI group showed impaired generalization of learning from the learning context to novel contexts (p = 0.03, d = -0.51). Furthermore, the mildRF+ TBI and moderate/severe TBI groups had higher parent and teacher ratings of internalizing problems (p's ? 0.04, d's ? 0.47) than the TC group, while the moderate/severe TBI group also had higher parent ratings of externalizing problems (p = 0.006, d = 0.58). Importantly, poorer generalization of learning predicted higher parent ratings of externalizing problems in children with TBI (p = 0.03, beta = -0.21) and had diagnostic utility for the identification of children with TBI and clinically significant externalizing behavior problems (area under the curve = 0.77, p = 0.001). CONCLUSIONS: Moderate/severe pediatric TBI has a negative impact on generalization of learning, which may contribute to post-injury externalizing problems. PMID- 26951456 TI - Impact of Plant-Derived Flavonoids on Neurodegenerative Diseases. AB - Neurodegenerative disorders have a common characteristic that is the involvement of different cell types, typically the reactivity of astrocytes and microglia, characterizing gliosis, which in turn contributes to the neuronal dysfunction and or death. Flavonoids are secondary metabolites of plant origin widely investigated at present and represent one of the most important and diversified among natural products phenolic groups. Several biological activities are attributed to this class of polyphenols, such as antitumor activity, antioxidant, antiviral, and anti-inflammatory, among others, which give significant pharmacological importance. Our group have observed that flavonoids derived from Brazilian plants Dimorphandra mollis Bent., Croton betulaster Mull. Arg., e Poincianella pyramidalis Tul., botanical synonymous Caesalpinia pyramidalis Tul. also elicit a broad spectrum of responses in astrocytes and neurons in culture as activation of astrocytes and microglia, astrocyte associated protection of neuronal progenitor cells, neuronal differentiation and neuritogenesis. It was observed the flavonoids also induced neuronal differentiation of mouse embryonic stem cells and human pluripotent stem cells. Moreover, with the objective of seeking preclinical pharmacological evidence of these molecules, in order to assess its future use in the treatment of neurodegenerative disorders, we have evaluated the effects of flavonoids in preclinical in vitro models of neuroinflammation associated with Parkinson's disease and glutamate toxicity associated with ischemia. In particular, our efforts have been directed to identify mechanisms involved in the changes in viability, morphology, and glial cell function induced by flavonoids in cultures of glial cells and neuronal cells alone or in interactions and clarify the relation with their neuroprotective and morphogetic effects. PMID- 26951461 TI - IL-4 Release from a Biomimetic Scaffold for the Temporally Controlled Modulation of Macrophage Response. AB - The interaction of immune cells with biomaterials has been identified as a possible predictor of either the success or the failure of the implant. Among immune cells, macrophages have been found to contribute to both of these possible scenarios, based on their polarization profile. This proof-of-concept study aimed to investigate if it was possible to affect the response of macrophages to biomaterials, by the release of anti-inflammatory mediators. Towards this end, a collagen scaffold, integrated with poly(lactic-co-glycolic acid)-multistage silicon particles (MSV) composite microspheres (PLGA-MSV) releasing IL-4 was developed (PLGA-MSV/IL-4). Macrophages' response to the scaffold was evaluated, both in vitro with rat bone-marrow derived macrophages, and in vivo in a rat subcutaneous pouch model. In vitro experiments revealed an overexpression of anti inflammatory associated genes (Il-10, Mrc1, Arg1) at as soon as 48 h. The analysis of the cells that infiltrated the scaffold, revealed a prevalence of CD206(+) macrophages at 24 h. Our strategy demonstrated that it is possible to tune the in vivo early response to biomaterials by the release of an anti inflammatory cytokine, and that could contribute to accelerate the resolution of the inflammatory phase, benefiting a vast range of tissue engineering applications. PMID- 26951463 TI - Development of Vibrational Culture Model Mimicking Vocal Fold Tissues. AB - The vocal folds (VFs) are connective tissues with complex matrix structures that provide the required mechanical properties for voice generation. VF injury leads to changes in tissue structure and properties, resulting in reduced voice quality. However, injury-induced biochemical changes and repair in scarred VF tissues have not been well characterized to date. To treat scarred VFs, it is essential to understand how physiological characteristics of VFs tissue change in response to external perturbation. In this study, we designed a simple vibrational culture model to mimic vibratory microenvironments observed in vivo. This model consists of a flexible culture plate, three linear actuators, a stereo splitter, and a function generator. Human vocal fold fibroblast (hVFF) monolayers were established on the flexible membrane, to which normal phonatory vibrations were delivered from linear actuators and a function generator. The hVFF monolayers were exposed to the vibrational stresses at a frequency of 205 Hz for 2, 6, and 10 h with maximum displacement of 47.1 MUm, followed by a 6 h rest. We then observed the changes in cell morphology, cell viability, and gene expression related to extracellular matrix components. In our dynamic culture device mimicking normal phonatory frequencies, cell proliferation increased and expression of hyaluronic acid synthase 2 was downregulated in response to vibrational stresses. The results presented herein will be useful for evaluating cellular responses following VF injuries in the presence or absence of vibrational stresses. PMID- 26951464 TI - [News on hyponatremia]. AB - Hyponatremia is the most common electrolyte disorder in clinical practice with often severe and devastating complications. Hyponatremia itself as well as its inappropriate management is associated with pronounced morbidity and increased mortality risk. This manuscript presents some relevant novel findings in this field and discusses them in the context of the recently elaborated first European Guideline of hyponatremia. PMID- 26951462 TI - Nanoparticle-Hydrogel: A Hybrid Biomaterial System for Localized Drug Delivery. AB - Nanoparticles have offered a unique set of properties for drug delivery including high drug loading capacity, combinatorial delivery, controlled and sustained drug release, prolonged stability and lifetime, and targeted delivery. To further enhance therapeutic index, especially for localized application, nanoparticles have been increasingly combined with hydrogels to form a hybrid biomaterial system for controlled drug delivery. Herein, we review recent progresses in engineering such nanoparticle-hydrogel hybrid system (namely 'NP-gel') with a particular focus on its application for localized drug delivery. Specifically, we highlight four research areas where NP-gel has shown great promises, including (1) passively controlled drug release, (2) stimuli-responsive drug delivery, (3) site-specific drug delivery, and (4) detoxification. Overall, integrating therapeutic nanoparticles with hydrogel technologies creates a unique and robust hybrid biomaterial system that enables effective localized drug delivery. PMID- 26951465 TI - The clinical efficacy of left atrial appendage isolation caused by extensive left atrial anterior wall ablation in patients with atrial fibrillation. AB - BACKGROUND: The left atrial appendage (LAA) can be a source of atrial fibrillation (AF) triggering or a part of reentry. We sought to determine the characteristics and clinical outcomes of patients with LAA potential delay including electrical isolation (LAAEI) following LA anterior wall (LAAW) ablation for AF. METHODS: LAAW ablation cases were collected from among 846 patients who underwent catheter ablation (CA). A total of 89 patients were enrolled; they were divided into three groups according to the extent of LAA potential injury. The ejection fractions (EFs) of the LAA and LA were measured by means of LA angiograms. RESULTS: The mean age of all patients was 56.2 +/- 10.7 years (74 males, 83 %). In 47 of the 89 patients, an LAA potential delay was identified after LAAW ablation (group 2). LAAEI was seen in 18 patients (group 3). In the remaining 24 patients, there was no LAA potential delay or LAAEI (group 1). The mean EF decreased significantly after CA in group 3 (P < 0.001). At 21-month follow-up, three patients (17 %) in group 3 had recurrence compared with 11 (42 %) in group 2 and 12 (46 %) in group 3 (P = 0.028). In multivariate analysis, diabetes mellitus and LAA potential delay were independent predictors of AF recurrence (P = 0.021, P = 0.008, respectively). CONCLUSION: Ablation of the LA anterior wall near the insertion of Bachmann's bundle and the neck of the LAA resulting in LAA potential delay or electrical isolation is effective in preventing recurrence of atrial fibrillation. PMID- 26951467 TI - Clinical significance of psychotic experiences in the context of sleep disturbance or substance use. AB - BACKGROUND: Psychotic experiences (PE) are commonly reported in the general population, where they are associated with elevated clinical need and functional impairment. Research studies typically exclude PE that occur in the context of sleep or substance use (PE-SS), based on the assumption that they are normative within these contexts. This is the first study to formally test clinical and functional outcomes associated with PE that occur in the context of sleep or substance use. METHOD: Data from the Collaborative Psychiatric Epidemiology Surveys (n = 11 776) were used to assess the associations between both PE and PE SS and a broad range of outcomes, including psychiatric co-morbidity, suicidal behavior, mental health treatment utilization and World Health Organization (WHO) domains of function, using logistic regression analyses. Lifetime PE and PE-SS were mutually exclusive categories, assessed using the WHO Composite International Diagnostic Interview psychosis screen. RESULTS: PE were associated with all 10 clinical and functional outcomes. Similarly, respondents reporting PE SS had greater clinical need and impaired function relative to controls, which was significant for seven of the 10 outcome variables. When directly compared, the PE and PE-SS groups differed only in their associations with role function (greater impairment for PE) and self-care (greater impairment for PE-SS). CONCLUSIONS: PE-SS were associated with a broad range of clinical and functional outcomes in this large general population sample. These associations were similar to those found for PE. Future studies should investigate relative differences between sleep- and substance-induced PE. PMID- 26951466 TI - Effect of fluence smoothing on the quality of intensity-modulated radiation treatment plans. AB - A fluence-smoothing function applied for reducing the complexity of a treatment plan is an optional requirement in the inverse planning optimization algorithm of intensity-modulated radiation therapy (IMRT). In this study, we investigated the consequences of fluence smoothing on the quality of highly complex and inhomogeneous plans in a treatment-planning system, EclipseTM. The smoothing function was applied both in the direction of leaf travel (X) and perpendicular to leaf travel (Y). Twenty IMRT plans from patients with cancer of the nasopharynx and lung were selected and re-optimized with use of various smoothing combinations from X = 0, Y = 0 to X = 100, Y = 100. Total monitor units (MUs), dose-volume histograms, and radiobiological estimates were computed for all plans. The study yielded a significant reduction in the average total MUs from 2079 +/- 265.4 to 1107 +/- 137.4 (nasopharynx) and from 1556 +/- 490.3 to 791 +/- 176.8 (lung) while increasing smoothing from X, Y = 0 to X, Y = 100. Both the tumor control and normal tissue complication probabilities were found to vary, but not significantly so. No appreciable differences in doses to the target and most of the organs at risk (OARs) were noticed. The doses measured with the I'MRT MatriXX 2-D system indicated improvements in deliverability of the plans with higher smoothing values. Hence, it can be concluded that increased smoothing reduced the total MUs exceptionally well without any considerable changes in OAR doses. The observed progress in plan deliverability in terms of the gamma index strongly supports the recommendation of smoothing levels up to X = 70 and Y = 60, at least for the nasopharynx and lung. PMID- 26951468 TI - Modified Two-stage Ileal Pouch-Anal Anastomosis Results in Lower Rate of Anastomotic Leak Compared with Traditional Two-stage Surgery for Ulcerative Colitis. AB - BACKGROUND AND AIMS: There is a paucity of evidence in ulcerative colitis [UC] comparing the traditional two-stage [total proctocolectomy with ileal pouch-anal anastomosis [IPAA] and diverting ileostomy, followed by ileostomy closure] vs the modified two-stage restorative proctocolectomy [subtotal colectomy with end ileostomy, followed by completion proctectomy and IPAA, without diverting ileostomy]. This study examines the risk of anastomotic leak following IPAA in traditional vs modified two-stage IPAA for UC patients. METHODS: This was a single-institution, retrospective study of all UC patients who underwent a traditional or modified two-stage IPAA between 2002 and 2013. The primary outcome was anastomotic leak following IPAA. RESULTS: In all, 460 patients had a two stage IPAA procedure; 223 [48.5%] patients underwent traditional two-stage IPAA and 237 [51.5%] patients received the modified two-stage procedure. There was more preoperative enteral corticosteroid use [44.7% vs 33.2%, p = 0.04] before the first surgery in the modified two-stage group compared with the traditional two-stage group. The modified two-stage group had higher UC disease severity at presentation [86.9% patients with moderate/severe UC vs 73.1%, p < 0.01]. However, the modified two-stage group had a lower rate of anastomotic leak following IPAA [4.6% vs 15.7%, p < 0.01] and was associated with a lower risk of anastomotic leak on univariate (odds ratio [OR] 0.26, 95% confidence interval [CI] 0.13, 0.52] and multivariate analysis [OR 0.27, 95% CI 0.12, 0.57]. CONCLUSIONS: Patients with ulcerative colitis who received the modified two-stage IPAA had a significantly lower rate of anastomotic leak following pouch creation, compared with the traditional two-stage procedure. PMID- 26951469 TI - Double-pigtail stent migration invading the spleen: rare potentially fatal complication of endoscopic internal drainage for sleeve gastrectomy leak. PMID- 26951470 TI - Endoscopic ultrasonography of solitary rectal ulcer syndrome. PMID- 26951471 TI - Polyglycolic acid sheets for closure of refractory esophago-pulmonary fistula after esophagectomy. PMID- 26951472 TI - Massive duodenal variceal bleed: endoscopic ultrasonography of ruptured varix and successful endoscopic clipping treatment. PMID- 26951473 TI - Outside the scope of our practice: an unexpected thoracoscopy and pleurocentesis during gastroscopy. PMID- 26951474 TI - Perforation during esophageal submucosal dissection resulting from idiopathic partial muscular defect. PMID- 26951475 TI - Large type I post-ERCP perforation closed immediately through the duodenoscope with through-the-scope endoclips. PMID- 26951476 TI - High resolution cholangioscopic electrohydraulic lithotripsy for fragmentation and extraction of impacted cystic duct stones. PMID- 26951477 TI - Endoscopic repair of complex pyloroduodenal stenosis resulting from post transplant lymphoproliferative disorder. PMID- 26951479 TI - Vocabulary development in Norwegian L1 and L2 learners in the kindergarten-school transition. AB - This study examined the vocabulary development of Norwegian second language (L2) learners with Urdu/Punjabi as their first language (L1) at two time-points from kindergarten to primary school, and compared it to the vocabulary development of monolingual Norwegian children. Using path models, the associations between number of picture books in the home, maternal education, and previous L1 and L2 vocabulary on the development of L2 vocabulary breadth and depth were investigated. The results indicate that despite the weaker vocabulary skills of the L2 sample, the growth trajectories of the L2 learners and the monolingual comparison group did not differ. For the L2 learners, we identified both concurrent and longitudinal predictors of vocabulary: the number of books in the home and the time of introduction of the L2 predicted concurrent vocabulary. L1 vocabulary, number of books in the home, and the time of introduction of the L2 predicted vocabulary growth. PMID- 26951478 TI - Oxidative stress induces loss of pericyte coverage and vascular instability in PGC-1alpha-deficient mice. AB - Peroxisome proliferator-activated receptor gamma co-activator 1alpha (PGC-1alpha) is a regulator of mitochondrial oxidative metabolism and reactive oxygen species (ROS) homeostasis that is known to be inactivated in diabetic subjects. This study aimed to investigate the contribution of PGC-1alpha inactivation to the development of oxygen-induced retinopathy. We analyzed retinal vascular development in PGC-1alpha(-/-) mice. Retinal vasculature of PGC-1alpha(-/-) mice showed reduced pericyte coverage, a de-structured vascular plexus, and low perfusion. Exposure of PGC-1alpha(-/-) mice to hyperoxia during retinal vascular development exacerbated these vascular abnormalities, with extensive retinal hemorrhaging and highly unstructured areas as compared with wild-type mice. Structural analysis demonstrated a reduction in membrane-bound VE-cadherin, which was suggestive of defective intercellular junctions. Interestingly, PGC-1alpha(-/ ) retinas showed a constitutive activation of the VEGF-A signaling pathway. This phenotype could be partially reversed by antioxidant administration, indicating that elevated production of ROS in the absence of PGC-1alpha could be a relevant factor in the alteration of the VEGF-A signaling pathway. Collectively, our findings suggest that PGC-1alpha control of ROS homeostasis plays an important role in the regulation of de novo angiogenesis and is required for vascular stability. PMID- 26951480 TI - Impact of High-intensity Intermittent and Moderate-intensity Continuous Exercise on Autonomic Modulation in Young Men. AB - The aim of this study was to compare heart rate variability (HRV) recovery after two iso-volume (5 km) exercises performed at different intensities. 14 subjects volunteered (25.17+/-5.08 years; 74.7+/-6.28 kg; 175+/-0.05 cm; 59.56+/-5.15 mL.kg(-1).min(-1)) and after determination of peak oxygen uptake (VO2Peak) and the speed associated with VO2Peak (sVO2Peak), the subjects completed 2 random experimental trials: high-intensity exercise (HIE - 1:1 at 100% sVO2Peak), and moderate-intensity continuous exercise (MIE - 70% sVO2Peak). HRV and RR intervals were monitored before, during and after the exercise sessions together with, the HRV analysis in the frequency domains (high-frequency - HF: 0.15 to 0.4 Hz and low-frequency - LF: 0.04 to 0.15 Hz components) and the ratio between them (LF/HF). Statistical analysis comparisons between moments and between HIE and MIE were performed using a mixed model. Both exercise sessions modified LFlog, HFlog, and LF/HF (F=16.54, F=19.32 and F=5.17, p<0.05, respectively). A group effect was also found for LFlog (F=23.91, p<0.05), and HFlog (F=57.55, p< 0.05). LF/HF returned to resting value 15 min after MIE exercise and 20 min after HIE exercise. This means that the heavy domain (aerobic and anaerobic threshold) induces dissimilar autonomic modification in physically active subjects. Both HIE and MIE modify HRV, and generally HIE delays parasympathetic autonomic modulation recovery after iso-volume exercise. PMID- 26951481 TI - The effect of disgust-related side-effects on symptoms of depression and anxiety in people treated for cancer: a moderated mediation model. AB - As maladaptive disgust responses are linked to mental health problems, and cancer patients may experience heightened disgust as a result of treatments they receive, we explored the associations between disgust-related side-effects and symptoms of depression and anxiety in people treated for cancer. One hundred and thirty two (83 women, M age = 57.48 years) participants answered questions about their treatments, side-effects, disgust responding, and mental health. Experiencing bowel and/or bladder problems, sickness and/or nausea (referred to here as "core" disgust-related side-effects) was significantly related to greater symptoms of depression and borderline increased anxiety. Further, these links were explained by a moderated mediation model, whereby the effects of core disgust side-effects on depression and anxiety were mediated by (physical and behavioural) self-directed disgust, and disgust propensity moderated the effect of core disgust side-effects on self-disgust. These findings stress the importance of emotional responses, like disgust, in psychological adaptation to the side-effects of cancer treatments. PMID- 26951482 TI - Human Papillomavirus (HPV) Vaccination Motivators, Barriers, and Brochure Preferences Among Parents in Multicultural Hawai'i: a Qualitative Study. AB - The human papillomavirus (HPV) vaccine can prevent cervical and other cancers. Unfortunately, according to the National Immunization Survey-Teen 2014 data, completion of the HPV vaccine was only 38 % for 13- to 17-year-old girls and 31 % for 13- to17-year-old boys in the USA, and prevalence was similar in Hawai'i. Parents' acceptability of the HPV vaccine is critical for the vaccine uptake, and this can be increased by educational materials and interventions. However, HPV materials are not widely distributed in Hawai'i. The purpose of this qualitative study was to identify HPV vaccination barriers, motivators, and brochure preferences among parents of teens in multicultural Hawai'i. Twenty parents were interviewed in person or by telephone. Four major themes emerged: (1) the physician is critical in the decision to vaccinate, (2) parental perception of the child's sexual activity guides the timing of their willingness to vaccinate, (3) HPV health education materials should be provided and discussed by the physician, and (4) parents would prefer an educational brochure that features local faces and testimonials, includes an immunization chart, and addresses barriers to vaccination. These findings informed the development of HPV health education materials tailored to Asian Americans and Pacific Islanders in Hawai'i. PMID- 26951483 TI - Does the Systemic Plasma Profile Inform the Liver Profile? Analysis Using a Physiologically Based Pharmacokinetic Model and Individual Compounds. AB - The physiologically based pharmacokinetic (PBPK) model for liver transporter substrates has been established previously and used for predicting drug-drug interactions (DDI) and for clinical practice guidance. So far, nearly all the published PBPK models for liver transporter substrates have one or more hepatic clearance processes (i.e., active uptake, passive diffusion, metabolism, and biliary excretion) estimated by fitting observed systemic data. The estimated hepatic clearance processes are then used to predict liver concentrations and DDI involving either systemic or liver concentration. However, the accuracy and precision of such predictions are unclear. In this study, we try to address this question by using the PBPK model to generate simulated compounds for which we know both systemic and liver profiles. We then developed an approach to assess the accuracy and precision of predicted liver concentration. With hepatic clearance processes estimated using plasma data, model predictions of liver are typically accurate (i.e., true value is bounded by predicted maximum and minimum); however, only for a few compounds are predictions also precise. The results of the current study indicate that extra attention is required when using the current PBPK approach to predict liver concentration and DDI for transporter substrates dependent upon liver concentrations. PMID- 26951485 TI - Clinical Guideline Inconsistency Regarding the Prevention of Hepatitis B and C Virus Transmission. PMID- 26951484 TI - Use of the Biopharmaceutics Drug Disposition Classification System (BDDCS) to Help Predict the Occurrence of Idiosyncratic Cutaneous Adverse Drug Reactions Associated with Antiepileptic Drug Usage. AB - Cutaneous adverse reactions (CARs) from antiepileptic drugs (AEDs) are common, ranging from mild to life-threatening, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). The identification of subjects carrying the HLA-B*15:02, an inherited allelic variant of the HLA-B gene, and the avoidance of carbamazepine (CBZ) therapy in these subjects are strongly associated with a decrease in the incidence of carbamazepine-induced SJS/TEN. In spite of the strong genetic associations, the initiation of hypersensitivity for AEDs is still not very well characterized. Predicting the potential for other AEDs to cause adverse reactions will be undoubtedly beneficial to avoid CARs, which is the focus of this report. Here, we explore the use of the Biopharmaceutics Drug Disposition Classification System (BDDCS) to distinguish AEDs associated with and without CARs by examining the binding relationship of AEDs to HLA-B*15:02 and data from extensive reviews of medical records. We also evaluate the lack of benefit from a Hong Kong population policy on the effects of screening for HLA B*15:02 and previous incorrect structure-activity hypotheses. Our analysis concludes that BDDCS class 2 AEDs are more prone to cause adverse cutaneous reactions than certain BDDCS class 1 AEDs and that BDDCS Class 3 drugs have the lowest levels of cutaneous adverse reactions. We propose that BDDCS Class 3 AEDs should be preferentially used for patients with Asian backgrounds (i.e., Han Chinese, Thai, and Malaysian populations) if possible and in patients predisposed to skin rashes. PMID- 26951486 TI - Transcatheter Intervention of Bilateral Renal Artery Stenosis in an Infant after arterial Switch to Control Arterial Hypertension. PMID- 26951487 TI - Introducing a model for optimal design of sequential objective structured clinical examinations. AB - In a sequential OSCE which has been suggested to reduce testing costs, candidates take a short screening test and who fail the test, are asked to take the full OSCE. In order to introduce an effective and accurate sequential design, we developed a model for designing and evaluating screening OSCEs. Based on two datasets from a 10-station pre-internship OSCE and considering three factors, namely, the number of stations, the criteria for selecting the stations, and the cut-off score, several hypothetical tests were proposed. To investigate their accuracy, the positive predictive value (PPV), the pass rate, and the negative predictive value (NPV) were calculated. Also, a "desirable" composite outcome was defined as PPV = 100 %, pass rate >=50 %, and NPV >=25 %. Univariate and multiple logistic regression analyses were conducted to estimate the effects of independent factors on the occurrence of the desirable outcome. In half of the screening tests no false positive result was detected. Most of the screening OSCEs had acceptable levels of pass rate and NPV. Considering the desirable composite outcome 20 screening OSCEs could have successfully predicted the results of the corresponding full OSCE. The multiple regression analysis indicated significant contributions for the selection criteria (p values = 0.019) and the cut-off score (p values = 0.017). In order to have efficient screening OSCEs with the lowest probability of the error rate, careful selection of stations with high values of discrimination or item total correlation, and use of a relatively stringent cut-off score should be considered. PMID- 26951488 TI - Presenting features and platelet anomalies in WAS: one centre's experience. PMID- 26951489 TI - Erratum to: Adenosine Deaminase Deficient Severe Combined Immunodeficiency Presenting as Atypical Haemolytic Uraemic Syndrome. PMID- 26951491 TI - Isoliquiritigenin Inhibits Proliferation and Induces Apoptosis via Alleviating Hypoxia and Reducing Glycolysis in Mouse Melanoma B16F10 Cells. AB - BACKGROUND: Isoliquiritigenin (ISL) is a licorice chalcone. According to CN104758274, CN101658513 and US009089546, it is claimed that ISL has anti inflammatory, anti-oxidative, and anti-tumoral effects. OBJECTIVE: This study aimed to investigate the potential therapeutic effect of ISL in mouse melanoma B16F10 cells. METHODS: Sulforhodamine B (SRB) colorimetric assay was used to test the effects of ISL on proliferation. Commercial assay kits were applied to assess glucose uptake, lactate production and ATP levels. Measurement of apoptosis was involved with Hoechst 33258, JC-1 and annexin V-FITC/PI staining. H2DCFDA probe was employed to detect ROS generation. Quantitative RT-PCR and western blot were utilized to measure the mRNA and protein levels. RESULTS: ISL abated hypoxia inducible factor 1alpha (HIF-1alpha) stability and reduced a series of glycolysis relevant enzymes expression, including glucose transporters 1/4 (GLUT 1/4), hexokinase 2 (HK2), pyruvate kinase M2 (PKM2) and lactate dehydrogenase A (LDHA). Exposure to ISL induced the mitochondrial membrane potential depolarization and increased intracellular reactive oxygen species (ROS) level. ISL could effectively inhibit proliferation and alleviate hypoxia in mouse melanoma B16F10 cells via inducing apoptosis and reducing the expression of significant enzymes in the glycolysis. ISL significantly inhibited B16F10 cell proliferation via inducing apoptosis, and alleviated hypoxia by recovering mitochondrial function and reversing high glycolysis. CONCLUSION: Our findings propose that ISL can be a promising therapeutic agent for the melanoma via reliving hypoxia of microenvironment and targeting energy metabolism system of cancer cells. Consistent with WO2015079213 and WO2014084494, targeting glycolysis can be an effective means to anti-cancer. PMID- 26951492 TI - Novel Mutation in the DKC1 Gene: Neonatal Hoyeraal-Hreidarsson Syndrome As a Rare Differential Diagnosis in Pontocerebellar Hypoplasia, Primary Microcephaly, and Progressive Bone Marrow Failure. AB - Primary microcephaly and severe developmental delay are complex but unspecific signs pointing to various genetic or acquired diseases. A concomitant finding of hematological failure may lead to the differential diagnosis of rare genetic diseases such as chromosome breakage disorders or diseases associated with telomere dysfunction. X-linked Hoyeraal-Hreidarsson syndrome (HHS) is a rare heterogenic disorder characterized by severe neurological impairment and progressive bone marrow failure. The latter represents the main cause of mortality, usually in early childhood. We report on the clinical course of an infant with HHS due to a novel mutation in the DKC1 gene and the particular finding of pontocerebellar hypoplasia. PMID- 26951490 TI - Spondyloenchondrodysplasia Due to Mutations in ACP5: A Comprehensive Survey. AB - PURPOSE: Spondyloenchondrodysplasia is a rare immuno-osseous dysplasia caused by biallelic mutations in ACP5. We aimed to provide a survey of the skeletal, neurological and immune manifestations of this disease in a cohort of molecularly confirmed cases. METHODS: We compiled clinical, genetic and serological data from a total of 26 patients from 18 pedigrees, all with biallelic ACP5 mutations. RESULTS: We observed a variability in skeletal, neurological and immune phenotypes, which was sometimes marked even between affected siblings. In total, 22 of 26 patients manifested autoimmune disease, most frequently autoimmune thrombocytopenia and systemic lupus erythematosus. Four patients were considered to demonstrate no clinical autoimmune disease, although two were positive for autoantibodies. In the majority of patients tested we detected upregulated expression of interferon-stimulated genes (ISGs), in keeping with the autoimmune phenotype and the likely immune-regulatory function of the deficient protein tartrate resistant acid phosphatase (TRAP). Two mutation positive patients did not demonstrate an upregulation of ISGs, including one patient with significant autoimmune disease controlled by immunosuppressive therapy. CONCLUSIONS: Our data expand the known phenotype of SPENCD. We propose that the OMIM differentiation between spondyloenchondrodysplasia and spondyloenchondrodysplasia with immune dysregulation is no longer appropriate, since the molecular evidence that we provide suggests that these phenotypes represent a continuum of the same disorder. In addition, the absence of an interferon signature following immunomodulatory treatments in a patient with significant autoimmune disease may indicate a therapeutic response important for the immune manifestations of spondyloenchondrodysplasia. PMID- 26951493 TI - Sissies, Mama's Boys, and Tomboys: Is Children's Gender Nonconformity More Acceptable When Nonconforming Traits Are Positive? AB - The evaluation of gender nonconformity in children was examined in two studies. In Study 1, 48 young adults evaluated the positivity of culturally popular labels for gender nonconformity, including "tomboy," "sissy," and two new labels generated in a pilot study, "mama's boy" and "brat." The "mama's boy" was described as a boy who has positive feminine traits (gentle and well-mannered) as opposed to the "sissy" who was described as having negative feminine traits (crying and easily frightened). In Study 2, 161 young adults read descriptions of gender-typical and nonconforming children, evaluating them in several domains. The label "mama's boy" was considered negative in Study 1 but an unlabeled positive nonconforming boy was rated as likable and competent in Study 2. However, participants worried about nonconforming boys, saying they would encourage them to behave differently and describing such children with derogatory sexual orientation slurs. "Tomboy" was generally considered a positive label in Study 1. In Study 2, gender nonconforming girls were considered neither likable nor dislikeable, and neither competent nor incompetent, reflecting ambivalence about girls' nonconformity. It may be that we use gender nonconformity labels as indicators of sexual orientation, even in young children. Therefore, even when an individual displays objectively positive traits, the stigma associated with homosexuality taints judgments about their nonconforming behavior. PMID- 26951495 TI - Use of Pregabalin - A Nationwide Pharmacoepidemiological Drug Utilization Study with Focus on Abuse Potential. AB - INTRODUCTION: Pregabalin is currently approved for the treatment of epilepsy, generalized anxiety disorder and neuropathic pain with a licensed dosage range of 150 mg to 600 mg/day. Growing concern about the abuse potential of pregabalin is partly based on reports of pregabalin being used in dosages that exceed the approved therapeutic range. METHODS: To identify predictors of pregabalin use above recommended dosage, we conducted a pharmacoepidemological drug utilization study using the Danish nationwide registers. We deployed 4 measures of abuse: high use (>=600 mg/day) or very high use (>=1 200 mg/day) over a 6- or 12-month period, respectively. Multiple logistic regression was used to identify patient and treatment characteristics that were associated with either abuse marker. RESULTS: Out of 42 520 pregabalin users 4 090 (9.6%) were treated with more than 600 mg/day for 6 months and 2 765 (6.5%) for more than 12 months. Male gender and prescription of antipsychotics and benzodiazepines were associated with increased risk of use of above the recommended dosage. DISCUSSION: Use of pregabalin above recommended dosages was rare but abuse may occur in susceptible patients. PMID- 26951494 TI - Estimated continuous cardiac output based on pulse wave transit time in off-pump coronary artery bypass grafting: a comparison with transpulmonary thermodilution. AB - To evaluate the accuracy of estimated continuous cardiac output (esCCO) based on pulse wave transit time in comparison with cardiac output (CO) assessed by transpulmonary thermodilution (TPTD) in off-pump coronary artery bypass grafting (OPCAB). We calibrated the esCCO system with non-invasive (Part 1) and invasive (Part 2) blood pressure and compared with TPTD measurements. We performed parallel measurements of CO with both techniques and assessed the accuracy and precision of individual CO values and agreement of trends of changes perioperatively (Part 1) and postoperatively (Part 2). A Bland-Altman analysis revealed a bias between non-invasive esCCO and TPTD of 0.9 L/min and limits of agreement of +/-2.8 L/min. Intraoperative bias was 1.2 L/min with limits of agreement of +/-2.9 L/min and percentage error (PE) of 64 %. Postoperatively, bias was 0.4 L/min, limits of agreement of +/-2.3 L/min and PE of 41 %. A Bland Altman analysis of invasive esCCO and TPTD after OPCAB found bias of 0.3 L/min with limits of agreement of +/-2.1 L/min and PE of 40 %. A 4-quadrant plot analysis of non-invasive esCCO versus TPTD revealed overall, intraoperative and postoperative concordance rate of 76, 65, and 89 %, respectively. The analysis of trending ability of invasive esCCO after OPCAB revealed concordance rate of 73 %. During OPCAB, esCCO demonstrated poor accuracy, precision and trending ability compared to TPTD. Postoperatively, non-invasive esCCO showed better agreement with TPTD. However, invasive calibration of esCCO did not improve the accuracy and precision and the trending ability of method. PMID- 26951496 TI - Modulatory Effects of Antidepressant Classes on the Innate and Adaptive Immune System in Depression. AB - Current reviews exploring for unique immune-modulatory profiles of antidepressant classes are limited by focusing mainly on cytokine modulation only and neglecting other aspects of the innate and adaptive immune system. These reviews also do not include recent comparative clinical trials, immune-genetic studies and therapeutics with unique neurotransmitter profiles (e. g., agomelatine). This systematic review extends the established literature by comprehensively reviewing the effects of antidepressants classes on both the innate and adaptive immune system. Antidepressants appear, in general, to reduce pro-inflammatory factor levels, particularly C-reactive protein (CRP), tumour necrosis factor (TNF) alpha, interleukin (IL)-1beta and IL-6. We caution against conclusions as to which antidepressant possesses the greater anti-inflammatory effect, given the methodological heterogeneity among studies and the small number of comparative studies. The effects of antidepressant classes on adaptive immune factors are complex and poorly understood, and few studies have been conducted. Methodological heterogeneity is high among these studies (e. g., length of study, cohort characteristics, dosage used and immune marker analysis). We recommend larger, comparative studies - in clinical and pre-clinical populations. PMID- 26951497 TI - Structural basis of interaction between the hepatitis C virus p7 channel and its blocker hexamethylene amiloride. PMID- 26951498 TI - Testing for association between RNA-Seq and high-dimensional data. AB - BACKGROUND: Testing for association between RNA-Seq and other genomic data is challenging due to high variability of the former and high dimensionality of the latter. RESULTS: Using the negative binomial distribution and a random-effects model, we develop an omnibus test that overcomes both difficulties. It may be conceptualised as a test of overall significance in regression analysis, where the response variable is overdispersed and the number of explanatory variables exceeds the sample size. CONCLUSIONS: The proposed test can detect genetic and epigenetic alterations that affect gene expression. It can examine complex regulatory mechanisms of gene expression. The R package globalSeq is available from Bioconductor. PMID- 26951501 TI - MicroRNAs in Platelet Physiology and Function. AB - Platelets are anucleate blood cells that are best known for their role in hemostasis and thrombosis. Perhaps due to the necessity of maintaining a proteome over an 8- to 9-day lifespan or the need to adapt to environmental situations, platelets retain many of the RNA metabolic processes of nucleated cells such as the ability to splice, translate, and regulate RNA levels through posttranscriptional mechanisms. In fact, in the absence of transcription, the dependence on posttranscriptional mechanisms to regulate gene expression may have resulted in microRNAs (miRNAs) making up a greater proportion of the platelet transcriptome than observed in other cells. miRNAs are ~22 nucleotide RNA molecules that regulate gene expression through messenger RNA (mRNA) degradation or inhibition of translation. miRNAs regulate differentiation of the platelet precursor, the megakaryocyte. Identification of miRNA:mRNA pairs that are associated with platelet phenotypes has led to the discovery of novel regulators of platelet function in healthy and diseased subjects. Circulating miRNAs may originate from platelets and can serve as biomarkers for platelet function. Platelet microparticles have been demonstrated to have the ability to deliver miRNAs of extracellular targets and alter gene expression in those targets. This review summarizes the current state of knowledge of miRNAs in megakaryocytes, platelets, and platelet microparticles. PMID- 26951503 TI - Comment on "Danshen and the Cardiovascular System: New Advances for an Old Remedy". PMID- 26951502 TI - Danshen and the Cardiovascular System: New Advances for an Old Remedy. PMID- 26951505 TI - Designing Solvent Exchange-Induced In Situ Forming Gel from Aqueous Insoluble Polymers as Matrix Base for Periodontitis Treatment. AB - An in situ forming gel is a dosage form which is promised for site-specific therapy such as periodontal pocket of periodontitis treatment. Ethylcellulose, bleached shellac, and Eudragit RS were applied in this study as a polymeric matrix for in situ forming gel employing N-methyl pyrrolidone (NMP) as solvent. Solutions comprising ethylcellulose, bleached shellac, and Eudragit RS in NMP were evaluated for viscosity, rheology, and rate of water penetration. Ease of administration by injection was determined as the force required to expel polymeric solutions through a needle using texture analyzer. In vitro gel formation and in vitro gel degradation were conducted after injection into phosphate buffer solution pH 6.8. Ethylcellulose, bleached shellac, and Eudragit RS could form the in situ gel, in vitro. Gel viscosity and pH value depended on percentage amount of the polymer, whereas the water diffusion at early period likely relied on types of polymer. Furthermore, the solutions containing higher polymer concentration exhibited the lower degree of degradation. All the preparations were acceptable as injectable dosage forms because the applied force was lower than 50 N. All of them inhibited Staphylococcus aureus, Escherichia coli, Candida albicans, Streptococcus mutans, and Porphyrommonas gingivalis growth owing to antimicrobial activity of NMP which exhibited a potential use for periodontitis treatment. Moreover, the developed systems presented as the solvent exchange induced in situ forming gel and showed capability to be incorporated with the suitable antimicrobial active compounds for periodontitis treatment which should be further studied. PMID- 26951506 TI - Identification and Prevention of Particulates in a Parenteral Solution of a Protein Kinase B Inhibitor. AB - The aim of this work was to identify the root cause of particulates in a parenteral solution formulation of a protein kinase B inhibitor (AKT inhibitor) and to devise a formulation fix. While standard potency/purity analyses did not reveal degradation, it was determined that the mass of the particulates corresponds to that of a "dimer-like" degradation product. The dimer-like molecule manifested itself as particulates rather than impurities in standard HPLC analysis. Particulate formation was found to be pH dependent. Consequently, an optimum formulation pH at which the compound has adequate solubility and the rate of particulate formation is slow was identified. PMID- 26951504 TI - Study of breast cancer incidence in patients of lymphangioleiomyomatosis. AB - Molecular evidence has linked the pathophysiology of lymphangioleiomyomatosis (LAM) to that of metastatic breast cancer. Following on this observation, we assessed the association between LAM and subsequent breast cancer. An epidemiological study was carried out using three LAM country cohorts, from Japan, Spain, and the United Kingdom. The number of incident breast cancer cases observed in these cohorts was compared with the number expected on the basis of the country-specific incidence rates for the period 2000-2014. Immunohistochemical studies and exome sequence analysis were performed in two and one tumors, respectively. All cohorts revealed breast cancer standardized incidence ratios (SIRs) >= 2.25. The combined analysis of all cases or restricted to pre-menopausal age groups revealed significantly higher incidence of breast cancer: SIR = 2.81, 95 % confidence interval (CI) = 1.32-5.57, P = 0.009; and SIR = 4.88, 95 % CI = 2.29-9.99, P = 0.0007, respectively. Immunohistochemical analyses showed positivity for known markers of lung metastatic potential. This study suggests the existence of increased breast cancer risk among LAM patients. Prospective studies may be warranted to corroborate this result, which may be particularly relevant for pre-menopausal women with LAM. PMID- 26951508 TI - Financial Strain, Major Family Life Events, and Parental Academic Involvement During Adolescence. AB - Parental academic involvement-whether through school participation and communication, or supervision and assistance at home-often has been cited as a way to enhance academic achievement. Yet, little is known about how the financial and life pressures faced by families can compromise parents' ability to become involved in their adolescents' education. In the current study, these dynamics were examined among Mexican-origin families, who often may face challenging financial and familial circumstances, and whose students may have more difficulty in secondary school. Parents of Mexican-origin ninth and tenth grade students from two high schools in Los Angeles (N = 428; 50 % female) completed quantitative interviews. The results revealed that financial strain predicted less involvement at school, and major family life events predicted less involvement at home, even after controlling for potentially confounding factors. Moreover, both of the associations between parental stress and parental academic involvement were mediated by lower levels of relationship quality between parents and adolescents, but not by conflict within the parent-adolescent dyad or parental depressive and somatic symptoms. The findings suggest that stress may limit parents' ability to become involved their adolescents' education, and highlight the importance of understanding family dynamics when examining parental academic involvement among Mexican-origin families. PMID- 26951507 TI - Family Structure, Maternal Dating, and Sexual Debut: Extending the Conceptualization of Instability. AB - Family structure influences the risk of early onset of sexual intercourse. This study proposes that the family structures associated with risk-single-mother, step-parent, and cohabiting-influence early sexual debut due to family instability, including shifts in family structure and maternal dating, which can undermine parental control and transmit messages about the acceptability of nonmarital sex. Previous research has not considered maternal dating as a component of family instability, assuming single mothers who date and those who do not date experience comparable levels of family disruption and transmit similar messages about the acceptability of nonmarital sex. Hypotheses are assessed using logistic regression models predicting the odds of early onset of sexual intercourse among 9959 respondents (53 % female, 47 % male) from the National Longitudinal Study of Adolescent to Adult Health. Respondents were ages 12-17 at the first wave of data collection and 18-26 at the third wave, when respondents reported the age at which they first had sexual intercourse. Results show that maternal dating is a source of family instability with repercussions for early sexual debut. Parental control and permissive attitudes towards teenage sex and pregnancy link at-risk family structures and maternal dating to early sexual initiation among females, though these variables do not fully explain family structure and maternal dating effects. Among males, the influence of maternal dating on early sexual debut is fully explained by the learning of permissive sexual attitudes. PMID- 26951510 TI - The conglomeration of diagnostic, prognostic and therapeutic potential of serum miR-199a and its association with clinicopathological features in epithelial ovarian cancer. AB - Epithelial ovarian cancer (EOC) is the most lethal cause of morbidity and mortality worldwide. miRNA deregulation evinces a remarkable role in ovarian cancer tumorigenesis. miRNA-199a (miR-199a) is known to be involved in cancer development and progression. Although miR-199a has been studied in various cell types, its correlation with clinicopathological features in EOC has not been documented. In this study, we identified the clinicopathological hallmarks which might be perturbed due to the downregulation of serum miR-199a in EOC. Seventy serum samples from histopathologically confirmed EOC patients and 70 controls were collected. Total RNA from serum was isolated by Trizol method, polyadenylated and reverse transcribed into cDNA. Expression level of miR-199a was detected by using miRNA qRT-PCR. Relative expression was determined with matched controls using U6 snRNA as reference. Level of miR-199a expression was compared with distinct clinicopathological features. Expression of miR-199a was found to be significantly downregulated in comparison with matched normal controls. The expression level of miR-199a was found to be significantly associated with tumor stage, lymph node metastasis, and distal metastasis. Receiver operating characteristic (ROC) curve for diagnostic potential yielded significant area under the curve (AUC) with a considerable sensitivity and specificity. ROC curves for prognosis yielded significant AUCs for histological grade, distal metastasis, lymph node status, and survival. Our findings suggest that miR-199a downregulation might be a potential indicator for disease progression promoting the aggressive tumor progression and be identified as a diagnostic marker to predict the prognosis and survival in EOC patients. PMID- 26951511 TI - Antigen-specific T cell response from dendritic cell vaccination using side population cell-associated antigens targets hepatocellular carcinoma. AB - Dendritic cell (DC) vaccination targeting cancer stem cells is an effective way to suppress tumor progression and reduce the metastasis and recurrence. In the present study, we explored the suitability of side population (SP) cells as source of antigens for DC vaccination against hepatocellular carcinoma (HCC) in a mouse model. In this study, we identified the "stem-like" characteristics of SP cells in the MHCC97 and Hepa 1-6 HCC cell lines. We found that SP cells express high levels of tumor-associated antigens and MHC class I molecules. Although loading with cell lysates did not change the characteristics of DCs, SP cell lysate-pulsed DCs induced antigen-specific T cell responses, including T cell proliferation and increased IFN-gamma production by stimulated CD8(+) T cells. We investigated the cytotoxicity of T cells stimulated by SP cell lysate-pulsed DCs in nude mice co-injected with MHCC97 cells. To mimic the in vivo environment, we also confirmed the result in mouse HCC cell line Hepa 1-6 induced tumor-bearing C57/BL6 immune competent mice, and we demonstrated that vaccination with DCs loaded with Hepa 1-6 SP cell lysates could induce a T cell response in vivo and suppress the tumor growth. Our results may have applications for anti-HCC immunotherapy by targeting the cancer stem cells and may provide new insight for cancer vaccines. PMID- 26951512 TI - Insight into the molecular basis of Schistosoma haematobium-induced bladder cancer through urine proteomics. AB - Infection due to Schistosoma haematobium is carcinogenic. However, the cellular and molecular mechanisms underlying urogenital schistosomiasis (UGS)-induced carcinogenesis have not been well defined. Conceptually, early molecular detection of this phenomenon, through non-invasive procedures, seems feasible and is desirable. Previous analysis of urine collected during UGS suggests that estrogen metabolites, including depurinating adducts, may be useful for this purpose. Here, a new direction was pursued: the identification of molecular pathways and potential biomarkers in S. haematobium-induced bladder cancer by analyzing the proteome profiling of urine samples from UGS patients. GeLC-MS/MS followed by protein-protein interaction analysis indicated oxidative stress and immune defense systems responsible for microbicide activity are the most representative clusters in UGS patients. Proteins involved in immunity, negative regulation of endopeptidase activity, and inflammation were more prevalent in UGS patients with bladder cancer, whereas proteins with roles in renal system process, sensory perception, and gas and oxygen transport were more abundant in subjects with urothelial carcinoma not associated with UGS. These findings highlighted a Th2-type immune response induced by S. haematobium, which seems to be further modulated by tumorigenesis, resulting in high-grade bladder cancer characterized by an inflammatory response and complement activation alternative pathway. These findings established a starting point for the development of multimarker strategies for the early detection of UGS-induced bladder cancer. PMID- 26951516 TI - Erratum: Adaptive evolution in the toxicity of a spider's venom enzymes. PMID- 26951513 TI - MicroRNA-183 promotes migration and invasion of CD133(+)/CD326(+) lung adenocarcinoma initiating cells via PTPN4 inhibition. AB - Non-small cell lung cancer (NSCLC) is the most common cancer worldwide and is a leading cause of lung cancer mortality due to early stage metastases. Cancer stem like cells (CSLCs) or tumor-initiating cells (TICs) are rare subpopulation cells that are responsible for maintaining tumor growth and invasion leading to recurrence and metastasis. Previous studies revealed that miR-183 can mediate the invasiveness and growth of NSCLC. However, the exact role of miR-183 in regulating the biological behavior of CSLCs in NSCLC remains unclear. In the present study, we explored the regulation of protein tyrosine phosphatase non receptor type 4 (PTPN4) by miR-183 in vitro using luciferase reporter assays, and we further analyzed the effects of miR-183 on the invasiveness of CSLCs in vitro and in vivo using transwell and bioluminescence assays. Following our finding that miR-183 binds to PTPN4 messenger RNA (mRNA) to prevent its translation through the 3'-untranslated region (UTR), we found that overexpression of miR-183 in CSLCs decreased PTPN4 protein levels while inhibition of miR-183 increased PTPN4 protein levels. The suppression of PTPN4 levels in CSLCs by miR-183 paralleled with a significant promotion in their motility in vitro and in vivo, while anti-sense miR-183 increased PTPN4 levels in CSLCs, which paralleled with a significant decrease in their invasiveness. Furthermore, correlation analysis between miR-183 and PTPN4 in clinical samples demonstrated a statistically significant inverse correlation between PTPN4 mRNA levels and miR-183. In brief, our data indicate that miR-183 plays a pro-invasive role by inverse regulation of PTPN4, and this axis may be a new therapeutic target for suppressing the metastatic capability of CSLCs in NSCLC. PMID- 26951514 TI - Bmi1 combines with oncogenic KRAS to induce malignant transformation of human pancreatic duct cells in vitro. AB - It is critical to understand the pathogenesis of preinvasive stages of pancreatic duct adenocarcinoma (PDAC) for developing novel potential diagnostic and therapeutic targets. The polycomb group family member B-lymphoma Moloney murine leukemia virus insertion region-1 (Bmi1) is overexpressed and involved in cancer progression in PDAC; however, its role in the multistep malignant transformation of human pancreatic duct cells has not been directly demonstrated. In this study, we stably expressed Bmi1 in a model of telomerase-immortalized human pancreatic duct-derived cells (HPNE) and showed that Bmi1 promoted HPNE cell proliferation, migration, and invasion but not malignant transformation. We then used mutant KRASG12D as a second oncogene to transform HPNE cells and showed that it further enhanced Bmi1-induced malignant potential. More importantly, coexpression of KRASG12D and Bmi1 caused anchorage-independent growth transformation in vitro but still failed to produce tumors in nude mice. Finally, we found that mutant KRASG12D induced HPNE-Bmi1 cells to undergo partial epithelial-mesenchymal transition (EMT) likely via upregulation of snail. Knockdown of KRASG12D significantly reduced the expression of snail and vimentin at both the messenger RNA (mRNA) and protein level and further impaired the anchorage-independent growth capability of invasive cells. In summary, our findings demonstrate that coexpression of Bmi1 and KRASG12D could lead to transformation of HPNE cells in vitro and suggest potential new targets for diagnosis and treatment of PDAC. PMID- 26951515 TI - The antitumor effect of TIG3 in liver cancer cells is involved in ERK1/2 inhibition. AB - Tazarotene-induced gene 3 (TIG3) was first characterized in tazarotene-treated human keratinocytes and identified as a retinoic acid responder gene, an important mediator of antitumor effects by retinoids. In this study, we aim to investigate the inhibitory effect of TIG3 on the growth of liver cancer and explore its underlying mechanism. Human hepatocellular carcinoma (HCC) Hep3B cells were transfected with plasmid GV141 carrying full-length TIG3 complementary DNA (cDNA). The effects of TIG3 on cell proliferation, apoptosis, and migration were determined in vitro. The suppressor effect of TIG3 on tumor growth was evaluated in vivo in a nude mouse HCC model. We observed that TIG3 expression is decreased in the Hep3B cell line as well as primary HCC tumors, and TIG3 expression inversely correlates with Ki-67 expression. Overexpression of TIG3 suppresses tumor growth in HCC both in vitro and in vivo via ERK1/2 inhibition by promoting apoptosis and inhibiting proliferation and migration. These findings identify TIG3 as an attractive therapeutic target for HCC. PMID- 26951517 TI - Histological parameters of the adrenal cortex after testosterone application in a rat model of the andropause. AB - Histological analysis of the adrenal cortex, after testosterone application in a rat model of the andropause, was the main subject of the present study. Middle aged Wistar rats were divided into sham-operated (SO; n=8), orchidectomized (Orx; n=8) and testosterone treated orchidectomized (Orx+T; n=8) groups. Testosterone propionate (5 mg/kg b.w. /day) was administered for three weeks, while SO and Orx groups received the vehicle alone. Histological objectives were achieved using stereology, histochemistry and steroid receptor immunostaining. The concentrations of testosterone, aldosterone, corticosterone and DHEA were determined by immunoassays. Expectedly, increased (p<0.05) serum concentration of testosterone was observed in Orx+T group. The volume of ZG cells and nuclei increased in Orx+T animals by 50% and 25% (p<0.05) respectively, but the serum concentrations of aldosterone decreased (p<0.05) by 60%, all compared to the same parameters in Orx group. The immunostaining for androgen receptors (ARs) suggested their cytoplasmic localization in ZG cells of Orx+T rats. Volume of the ZF cell nuclei in Orx+T group decreased (p<0.05) by 17%, which was followed by the significant (p<0.05) fall in corticosterone production and secretion, all in comparison with Orx animals. Also, nuclear immunolocalization of ARs of high optical density was observed through the ZF of Orx+T group. In Orx+T rats volume of ZR cells and nuclei, and circulating DHEA concentration increased (p<0.05) by 68%, 22% and about 6.6 times respectively, compared to Orx animals. Besides the extra-receptor actions in adrenal cortex, testosterone supposedly affects some steroidogenesis-related gene expression, as indicated by centripetal rise in the number of nuclear ARs. PMID- 26951518 TI - Childhood height, adult height, and the risk of prostate cancer. AB - PURPOSE: We previously showed that childhood height is positively associated with prostate cancer risk. It is, however, unknown whether childhood height exerts its effects independently of or through adult height. We investigated whether and to what extent childhood height has a direct effect on the risk of prostate cancer apart from adult height. METHODS: We included 5,871 men with height measured at ages 7 and 13 years in the Copenhagen School Health Records Register who also had adult (50-65 years) height measured in the Danish Diet, Cancer and Health study. Prostate cancer status was obtained through linkage to the Danish Cancer Registry. Direct and total effects of childhood height on prostate cancer risk were estimated from Cox regressions. RESULTS: From 1996 to 2012, 429 prostate cancers occurred. Child and adult heights were positively and significantly associated with prostate cancer risk. When adjusted for adult height, height at age 7 years was no longer significantly associated with the risk of prostate cancer. Height at 13 years was significantly and positively associated with prostate cancer risk even when adult height was adjusted for; per height z-score the hazard ratio was 1.15 [95% confidence interval (CI) 1.01-1.32]. CONCLUSIONS: The effect of height at 13 years on the risk of prostate cancer was not entirely mediated through adult height, suggesting that child height and adult height may be associated with prostate cancer through different pathways. PMID- 26951519 TI - Depressive Symptoms, Cognition, and Everyday Function Among Community-Residing Older Adults. AB - OBJECTIVE: The aim of this study was to understand the relationships among depressive symptoms, cognition, and functional performance in a community-based sample of older adults. METHOD: Older adults ( N = 885) from the Staying Keen in Later Life study completed tests of executive function, speed of processing, and memory. The Center for Epidemiologic Depression Scale assessed depressive symptoms. The Timed Instrumental Activities of Daily Living Test assessed participants' everyday functional performance. RESULTS: Depressive symptoms had significant associations with measures of executive function, speed of processing, memory, and everyday functional performance. Cognitive performance completely mediated the association between depressive symptoms and everyday function. DISCUSSION: Among community-dwelling older adults, depressive symptoms were associated with impaired cognition across multiple domains, which detrimentally affected everyday function. Health care providers should be aware of these associations to monitor and manage changes in depressive symptoms and cognitive performance and thereby potentially mitigate functional decline. PMID- 26951520 TI - How can attending physicians be more attentive? On being attentive versus producing attentiveness. AB - This article is about caregivers being attentive to patients in healthcare. From earlier work on the understanding of the other, we know that it is impossible to completely understand the experiences of others. By the sharing of subjectivity intersubjectivity-we may try to 'grasp' the other's point of view. However, we can never assume that the same experience produces the same experience. Now, if it is principally impossible to understand the experience of one another, and if paying attention always implies an understanding of what to pay attention to, then how is it possible to be attentive to the experiences of those who are entirely at the mercy of our care? How can caregivers perceive the impossibility of understanding the experiences of patients as an appeal to be attentive to their experiences? This is discussed in this article. It departs from the authors being confronted with inexplicabilities in the empirical study of attentiveness in healthcare. It presents two examples and discusses the meaning of these emergent properties. This leads to a discussion of the existent literature on the indefiniteness and openness of attentiveness. It becomes clear why, although we can understand and predict much of it, attentiveness will always be characterized by a certain uncontrollability as well. PMID- 26951521 TI - Between hype and hope: What is really at stake with personalized medicine? AB - Over the last decade, personalized medicine has become a buzz word, which covers a broad spectrum of meanings and generates many different opinions. The purpose of this article is to achieve a better understanding of the reasons why personalized medicine gives rise to such conflicting opinions. We show that a major issue of personalized medicine is the gap existing between its claims and its reality. We then present and analyze different possible reasons for this gap. We propose an hypothesis inspired by the Windelband's distinction between nomothetic and idiographic methodology. We argue that the fuzzy situation of personalized medicine results from a mix between idiographic claims and nomothetic methodological procedures. Hence we suggest that the current quandary about personalized medicine cannot be solved without getting involved in a discussion about the complex epistemological and methodological status of medicine. To conclude, we show that the Gadamer's view of medicine as a dialogical process can be fruitfully used and reveals that personalization is not a theoretical task, but a practical one, which takes place within the clinical encounter. PMID- 26951523 TI - Prosthetic mesh "slim-cigarette like" for laparoscopic repair of ventral hernias: a new technique without transabdominal fixation sutures. AB - Prosthetic mesh rolled up and fixed with stitches like a slim cigarette ("slim mesh") for laparoscopic ventral hernia (VH) repair is an new technique which allows an easy intraperitoneally introduction, distension and circumferential fixation of a prosthetic mesh without transabdominal fixation sutures even for meshes larger than 16 cm up to 30 cm for the "slim-mesh" repair of wide ventral hernias. We report the technique of laparoscopic repair of VH with "slim-mesh". This technique enables an easy intra-peritoneally introduction of the mesh through the trocar because it reduces consistently its size, it allows a rapid intra-abdominal handling of the mesh and a fast and easy fixation for VH repair. The average time of surgery with "slim-mesh" for treatment of all 28 VH was 97 min ranging from 57 to 160 min. The average time for the repair of the 24 VH smaller than 10 cm was 91 and 135 min for the four VH larger than 10-22 cm. This new surgical technique leads to a reduction of surgical risks avoiding the use of transfascial sutures with the associated complications. This new surgical procedure in our experience is fast, safe, simple and also easily reproducible by surgeons in laparoscopic training. This technique may be used in wide VH (larger than 10-22 cm) that generally require open surgery. PMID- 26951522 TI - Factors Associated with Thrombolysis Outcome in Ischemic Stroke Patients with Atrial Fibrillation. AB - The outcome of early intravenous thrombolysis for ischemic stroke in patients with atrial fibrillation (AF) is worse than that without thrombosis. How to increase the efficacy of intravenous thrombolysis for AF-related ischemic stroke remains largely unknown. In this study, we investigated factors that influence the effect of intravenous thrombolysis in these patients. Our results showed that thrombolysis was independently associated with a favorable outcome (P < 0.001) and did not influence the mortality of AF-related ischemic stroke, although it increased the risk of hemorrhage within 24 h after treatment. Risk factors for a poor outcome at admission were: heart failure (P = 0.045); high systolic pressure (P = 0.039); high blood glucose (P = 0.030); and a high National Institutes of Health Stroke Scale (NIHSS) score (P < 0.001). Moreover, high systolic pressure at admission (P = 0.007), high blood glucose (P = 0.027), and a high NIHSS score (P < 0.001) were independent risk factors for mortality at 3 months. Besides thrombolysis, a high NIHSS score (P = 0.006) and warfarin taken within 48 h before stroke onset (P = 0.032) were also independent risk factors for symptomatic hemorrhage within 24 h after treatment. Ischemic stroke patients with AF benefited from intravenous thrombolysis with recombinant tissue plasminogen activator within 4.5 h after stroke. PMID- 26951524 TI - Presumed bilateral cilioretinal artery occlusion related to relapsing white dot syndrome. AB - PURPOSE: To report a presumed case of bilateral asynchronous cilioretinal occlusion associated with white dot syndrome. METHODS: A 19-year-old woman presented with decreased vision in the right eye. Cilioretinal occlusion was diagnosed and multimodal imaging was performed. RESULTS: Laboratory workup was negative. Fluorescein and indocyanine green angiography revealed an inflammatory choroidopathy in the right eye. Spectral-domain coherence tomography (OCT) initially showed internal retinal layer edema followed by atrophy in the papillomacular bundle. Left eye presented asymptomatic decreased visual acuity and OCT findings were compatible with previous cilioretinal occlusion. CONCLUSIONS: Cilioretinal occlusion findings were present in both eyes. Multimodal fundus imaging allowed idiopathic inflammatory choroidopathy diagnosis in the right eye, suggesting that a recurrent inflammatory process caused an asynchronous vascular occlusion. PMID- 26951525 TI - Risk factors for visual impairment in patients with sickle cell disease in London. AB - PURPOSE: Dramatically improved health care in recent years has increased the life expectancy of patients with sickle cell disease (SCD) as well as the prognosis for its ocular complications. We sought to identify risk factors for visual impairment in patients with SCD in London 4 decades after Goldberg's seminal studies. METHODS: Patients 16 years and older with SCD (genotypes HbSS, HbSC, HbSbeta-thalassemia) attending hematology and ophthalmology services were offered ocular examination. Retinopathy was graded according to the Goldberg classification. Visual impairment was defined as corrected distance visual acuity of 20/40 or poorer. RESULTS: In total, 182 eyes of 182 patients (mean +/- SD age, 37.2 +/- 12.8 years; female, 65.9%) were included. Women were significantly older than men (mean +/- SD age, 38.8 +/- 13.1 vs 34.2 +/- 11.8 years; p = 0.0174). There was no difference in mean age of each genotype group (p>0.15). Risk factors for sight-threatening proliferative sickle retinopathy (PSR) were age over 35 years (odds ratio [OR] 2.01; 95% confidence interval [CI] 1.05-3.89; p = 0.0359) and HbSC genotype (OR 4.06; 95% CI 2.07-7.98; p<0.0001). Although visual impairment was related to the presence of sight-threatening PSR (OR 7.23; 95% CI 1.50-35.0; p = 0.0138), it was not related to hemoglobin genotype (p>0.50). CONCLUSIONS: We present the largest study of ocular findings in SCD in the United Kingdom. Sight-threatening PSR is a risk factor for visual impairment, but hemoglobin genotype status is not. PMID- 26951526 TI - Reply to: Mobile phones for retinopathy of prematurity screening in Lagos, Nigeria, sub-Saharan Africa. PMID- 26951527 TI - Reply to: Cataract surgery in patients with Alport syndrome. PMID- 26951528 TI - Cataract surgery in patients with Alport syndrome. PMID- 26951529 TI - Evaluation of Ex-PRESS mini glaucoma shunt implantation with preoperative intracameral bevacizumab injection in refractory neovascular glaucoma. AB - PURPOSE: To evaluate the efficacy and safety of Ex-PRESS mini glaucoma shunt implantation with preoperative intracameral bevacizumab injection in eyes with refractory neovascular glaucoma. METHODS: A retrospective chart review of patients with medically uncontrolled neovascular glaucoma who had received 50-uL intracameral bevacizumab (1.25 mg) before undergoing Ex-PRESS mini glaucoma shunt implantation was performed. Success was defined as a postoperative intraocular pressure (IOP) between 5 and 21 mm Hg without (complete success) or with or without (qualified success) glaucoma medications and no additional glaucoma surgery, or loss of light perception. RESULTS: In total, 33 eyes of 33 patients (15 female, 18 male) were enrolled in the study. The mean age of the study population was 61.2 years (range 36-78). The mean IOP decreased from 41.0 mm Hg (range 24-72) to 17.6 mm Hg (range 8-28) over a mean follow-up of 20.9 months (range 6-60) (p<0.001; Wilcoxon signed-rank test). Complete and qualified success rates were 36.4% and 66.7%, respectively. The average number of antiglaucoma medications decreased from 3.5 (range 2-4) preoperatively to 1.8 (range 1-4) postoperatively (p<0.001; Wilcoxon signed rank test). In 81.8% of cases, the decrease in IOP was 30% or more postoperatively. CONCLUSIONS: Ex-PRESS mini glaucoma shunt implantation with preoperative bevacizumab injection may be an effective alternative procedure for refractory neovascular glaucoma. PMID- 26951530 TI - Deep sclerectomy in primary open-angle glaucoma and exfoliative glaucoma. AB - PURPOSE: To study the effect of deep sclerectomy (DS) in primary open-angle glaucoma (POAG) and exfoliative glaucoma (EXG). METHODS: We retrospectively analyzed the intraocular pressure (IOP)-lowering effect of DS in 235 consecutive eyes. Eyes were divided into 2 groups according to glaucoma subtype: POAG (127 eyes) and EXG (108 eyes). Postoperative IOP was the main outcome measurement. We recorded complete and qualified surgical success, need for YAG-laser goniopuncture, and need for postoperative glaucoma medication. We studied factors related to outcome of surgery in a Cox regression model. RESULTS: In the POAG group, the mean (SD) IOP decreased from 22.6 (5.1) mm Hg preoperatively to 16.8 (7.5) mm Hg, with qualified success achieved in 70% of eyes. Postoperatively, 57% were without medication. In the EXG group, IOP decreased from 25.5 (6.5) mm Hg preoperatively to 16.5 (7.8) mm Hg postoperatively, with qualified success achieved in 66% of eyes. Postoperatively, 50% were without medication. Decrease in IOP was statistically significant in both groups (p<0.001). In the POAG group, 12%, and in the EXG group, 24% needed a reoperation in the follow-up period (p = 0.037). In the Cox regression model, 1 week IOP between 2 and 14 mm Hg without medication lowered the hazard rate of losing complete success by 34% (p = 0.031) and the hazard rate of losing qualified success by 54% (p = 0.004). CONCLUSIONS: The IOP 1 week postoperatively seems to be a prominent indicator of surgical success. Deep sclerectomy is effective in reducing IOP in POAG and EXG subgroups, with reoperations more common in EXG eyes. PMID- 26951531 TI - Efficacy and safety of postvitrectomy intravitreal triamcinolone therapy for diabetic macular edema. AB - PURPOSE: After vitrectomy, diffusion and clearance rates of numerous drugs are increased, leading to a shorter intravitreal half-life. This raises doubts about the efficacy of intravitreal therapies, as retina specialists generally believe that a shorter half-life compromises the drugs' therapeutic effect. We conducted a study to evaluate the functional and anatomical effect of intravitreal triamcinolone acetonide therapy (IVTA) in previously vitrectomized eyes with diabetic macular edema (DME). METHODS: In this retrospective, multicenter case series study including vitrectomized patients with DME who underwent IVTA injections, central macular thickness (CMT) measured with spectral-domain optical coherence tomography and best-corrected visual acuity (BCVA) in Early Treatment Diabetic Retinopathy Study letters were evaluated after each procedure. All relevant medical data were collected, including previous ophthalmologic treatments and comorbidities. RESULTS: Twenty vitrectomized eyes of 20 patients, mean age 58.1 years (range 40-72 years), were enrolled in the study. All patients presented DME and received at least one IVTA injection. Mean time between pars plana vitrectomy and IVTA was 12.9 +/- 8.7 months. Mean pretreatment and posttreatment CMT was 438.8 +/- 90.8 MUm and 301.2 +/- 76.2 MUm, respectively, a difference that reached statistical significance (p<0.001). Mean gain in BCVA letter score was 7.83 +/- 14.9 letters after treatment (p = 0.039). Mean intraocular pressure was significantly increased after IVTA (17.2 +/- 1.9 mm Hg at baseline vs 21.2 +/- 4.59 mm Hg after IVTA, p = 0.002). CONCLUSIONS: A positive anatomical and functional effect was observed in our cohort. Our results suggest that, despite prior vitrectomy, triamcinolone remains a valid therapeutic approach for eyes with persistent DME. Further prospective randomized studies with larger patient samples are needed to validate this conclusion. PMID- 26951532 TI - Retinal structural changes in systemic arterial hypertension: an OCT study. AB - PURPOSE: To assess retinal nerve fiber layer (RNFL), ganglion cell complex (GCC), and macular thickness changes in young adults with systemic arterial hypertension. METHODS: This study included 80 young patients (age 23.8 +/- 2.8 years) with systemic hypertension (sHT) without any known systemic or ocular disease and 80 age-matched (23.5 +/- 2.1 years) healthy controls. Retinal nerve fiber layer thickness, macular thickness, and GCC thickness were measured with spectral-domain optical coherence tomography. RESULTS: Mean disease duration was 3.45 +/- 1.48 years (range 2-10). Differences in intraocular pressure, body mass index, axial length, and spherical equivalent between the groups were insignificant (p>0.05). The differences in RNFL thickness did not differ between the groups. Patients with sHT had significantly lower central macular thickness (p = 0.037), inner superior macular thickness (p = 0.045), and outer temporal superior and outer temporal inferior GCC (p<0.001 for both). The RNFL thickness did not differ significantly in all quadrants between the groups (p>0.05). Systolic and diastolic blood pressure were significantly correlated with inner temporal superior and inner temporal inferior GCC thickness in a negative manner (p<0.05 for all). CONCLUSIONS: Ganglion cell complex thickness decrease is possibly a better retinal marker for hypertensive changes with respect to RNFL and macular thickness. PMID- 26951533 TI - Capillary nonperfusion by novel technology of OCT angiography in a patient with sickle cell disease with normal fluorescein angiogram. AB - PURPOSE: Retinal ischemia is a pathophysiologic feature of sickle cell retinopathy. Inner retinal thinning of retina temporal to the fovea has been reported on spectral-domain optical coherence tomography (SD-OCT) even though clinical examination is normal and fluorescein angiography (FA) does not show any capillary dropout. In a patient with sickle cell disease with temporal inner retinal thinning on SD-OCT and normal FA, the new technology of OCT angiography (OCTA) showed a corresponding area of nonperfusion. METHODS: The patient with sickle cell disease underwent visual acuity testing, refraction, slit-lamp biomicroscopy, and dilated fundus examination. The patient also underwent SD-OCT, digital FA, and OCTA. The findings are described in this case report. RESULTS: In this patient with sickle cell disease, although clinical examination was normal and FA did not show any capillary dropout, the SD-OCT showed inner retinal thinning temporal to the fovea. Corresponding to this area, OCTA showed an area of nonperfusion. CONCLUSIONS: Optical coherence tomography angiography technology may be more sensitive than the gold standard FA in identifying retinal ischemia in patients with sickle cell disease. PMID- 26951534 TI - Treatment of vitreomacular traction with intravitreal ocriplasmin preceded by anterior chamber paracentesis: case reports. AB - PURPOSE: To evaluate the efficacy of an intravitreal ocriplasmin injection using anterior chamber paracentesis to release symptomatic vitreomacular traction (VMT). METHODS: Five patients with symptomatic VMT were enrolled. All patients underwent a complete ophthalmologic examination including acquisition of spectral domain optical coherence tomography. Before intravitreal injection of ocriplasmin, anterior chamber paracentesis was performed in the study eye to induce mild ocular hypotonia. Control visits were performed the day after the injection, at 1 week, and after 1, 2, and 3 months. RESULTS: In 4 patients, we had complete release of VMT and visual improvement after the intravitreal ocriplasmin injection preceded by anterior chamber paracentesis. No adverse events were observed. CONCLUSIONS: In our small case series, anterior chamber paracentesis performed before intravitreal ocriplasmin seemed to increase the efficacy of the drug in the resolution of symptomatic VMT. Our success estimate is imprecise due to small sample size (95% confidence interval 0.28 to 0.99) and no definitive conclusion can be reached. Further research is worth being conducted to assess the potential usefulness of paracentesis before ocriplasmin injection to increase vitreoretinal traction release rate. PMID- 26951535 TI - Multifocal choroiditis with panuveitis in an 8-year-old boy with long-standing idiopathic acute anterior uveitis. AB - PURPOSE: To report successful treatment of a rare case of sight-threatening pediatric multifocal choroiditis with panuveitis (MFCPU) and the use of electrophysiology to confirm return of macular function. METHODS: Case report. RESULTS: An 8-year-old boy with a history of bilateral recurrent non-juvenile idiopathic arthritis acute anterior uveitis (AAU) presented with new-onset blurry vision and floaters in both eyes. Visual acuity had deteriorated to 20/200 right eye and 20/100 left eye. Cells were observed in the anterior chamber and vitreous of both eyes. Ophthalmoscopy showed multiple active small cream-colored chorioretinal lesions and cystoid macular edema (CME) in both eyes in the absence of systemic disease, suggestive of idiopathic MFCPU. Successful rapid visual recovery and resolution of CME confirmed by spectral-domain optical coherence tomography (SD-OCT) was achieved with prompt intensive systemic steroid therapy followed by early introduction of methotrexate. After 9 months, his visual acuities improved to 20/32, and pattern reversal visual evoked potentials and 19 hexagon multifocal electroretinography posttreatment were normal, showing recovery of macular function. CONCLUSIONS: Multifocal choroiditis with panuveitis is rare in children and has not been documented in the presence of previous longstanding recurrent AAU. Onset of floaters in children should alert the clinician to early stages of posterior pole involvement and progression to reduction in vision due to CME requires prompt aggressive steroid therapy monitored by clinical examination, SD-OCT, and electrophysiology, followed by early introduction of immunosuppressive drugs for long-term stability and to avoid steroid-induced adverse effects in children. PMID- 26951536 TI - Comparison of anterior segment parameters in juvenile diabetes mellitus and healthy eyes. AB - PURPOSE: To compare the anterior segment parameters of patients with juvenile diabetes mellitus (DM) and healthy children by optical biometry. METHODS: This prospective controlled clinical trial included 47 patients with juvenile type 1 DM and 50 age- and sex-matched healthy children. Central corneal thickness (CCT), aqueous depth (AD), lens thickness (LT), axial length, pupillary diameter (PD), K1 and K2 keratometry, and white to white distance (WTW) measurements were performed with optical biometry. The glycosylated hemoglobin (HbA1c) levels of the DM cases were obtained. Kolmogorov-Smirnov test, t test, chi2 test, and Pearson correlation test were used for statistical analysis. RESULTS: The mean age of the 20 boys and 27 girls with DM was 10.91 +/- 3.24 years and the mean age of the 29 healthy boys and 21 girls was 11.61 +/- 3.6 years (age p = 0.42; sex p = 0.09). The mean LT was thicker (p = 0.001), the mean AD was lower (p = 0.001), and the mean PD was smaller (p = 0.001) in the DM cases and all were statistically significant. There was no significant difference between the groups for AU, CCT, WTW, or K1 and K2 (p = 0.12; p = 0.83; p = 0.54; p = 0.97; p = 0.21, respectively). We also found a significant negative correlation between HbA1c levels and PD (r = -0.37 p = 0.01). CONCLUSIONS: Juvenile DM may affect anterior segment parameters and cause thicker LT, smaller PD, and lower AD. These effects may change the refractive status and should be considered during the examination of these children. PMID- 26951537 TI - Rest and stress transluminal attenuation gradient and contrast opacification difference for detection of hemodynamically significant stenoses in patients with suspected coronary artery disease. AB - This study evaluated the feasibility of stress 320 detector CT coronary angiography (CTA) derived transluminal attenuation gradient (TAG320) and contrast opacification (CO) difference to detect hemodynamically significant stenoses as determined by invasive fractional flow reserve (FFR <= 0.80). Twenty-seven patients, including 51 vessels on rest CTA were studied. 16 (31 %) vessels were not interpretable on stress CTA largely secondary to motion artefacts. Receiver operating characteristic curve analysis showed a comparable area under the curve (AUC) for rest and stress TAG320 (0.78 and 0.75) which was higher than CTA alone (0.68), and rest and stress CO difference (0.76 and 0.67). Compared with rest CTA, stress CTA demonstrated inferior image quality (Median Likert score 4 vs. 3, P < 0.0001) and required a higher mean radiation exposure (3.2 vs. 5.1 mSv, P < 0.0001). Stress TAG320 and CO difference is less feasible and was not superior in diagnostic performance when compared with rest TAG320 and CO difference. PMID- 26951538 TI - Evidence for a pathogenic role of BRCA1 L1705P and W1837X germ-line mutations. AB - BRCA1 L1705P (c.5114T>C) has been classified in the NCBI SNP database as the variant with uncertain significance and is absent in major BRCA1 databases. BRCA1 W1837X (c.5511G>A) results in a loss of only last 27 residues of BRCA1 protein, thus its pathogenic role still requires a confirmation. This report describes two breast cancer (BC) patients carrying BRCA1 L1705P and W1837X germ-line mutations, respectively. Significant evidence for BC-predisposing impact of the mentioned mutations have been obtained: (1) both index cases presented with the triple negative receptor status of BC disease; (2) complete segregation with BRCA1 related cancers was observed in the families of these patients; (3) somatic loss of the remaining (wild-type) BRCA1 allele was detected in tumor tissues of the affected women. The results of this study have to be taken into account while providing genetic counseling to cancer patients and while considering the use of BRCA1-specific therapeutic compounds for BC treatment. PMID- 26951539 TI - Prolyl hydroxylase mediated inhibition of fatty acid synthase to combat tumor growth in mammary gland carcinoma. AB - Cancer is a group of cells which grow in an uncontrolled manner and invades to the adjacent organs to form malignant tumors. Tumor hypoxia results due to contrast between the cellular oxygen expenditure and oxygen supply to the cells. Hypoxia inducible factor (HIF) is a heterodimeric transcription factor encompass of oxygen sensitive alpha subunit and constitutively expressed beta subunit both of which are basic helix-loop-helix protein. The stability of HIF is primarily regulated by post translational prolyl hydroxylation, catalyzed by prolyl hydroxylase 2 (Phd-2). Phd-2 is a group of enzymes that acts as an oxygen sensor. Cancer cells have altered metabolism as they fulfil their energy needs through glycolysis and lipid biogenesis. HIF-1alpha is known to upregulate glycolysis by activating the transcription of enzymes on the glycolytic pathway and through lipogenesis. Cancer cells have over expressed fatty acid synthase owing to altered glycolytic pathway. Considering the above, it is hypothesized that chemical activation of Phd-2 can curtail down HIF-1alpha and subsequently fatty acid synthase expression. PMID- 26951540 TI - Head Impact Exposure During a Weekend Youth Soccer Tournament. AB - Concussion is a known risk in youth soccer, but little is known about subconcussive head impacts. The authors provided a prospective cohort study measuring frequency and magnitude of subconcussive head impacts using accelerometry in a middle school-age soccer tournament, and association between head impacts and changes in (1) symptoms, (2) cognitive testing, and (3) advanced neuroimaging. A total of 17 youth completed the study (41% female, mean 12.6 years). There were 73 head impacts >15g measured (45% headers) and only 2 had a maximum peak linear acceleration >50g No youth reported symptoms consistent with concussion. After correction for multiple comparisons and a sensitivity analysis excluding clear outliers, no significant associations were found between head impact exposure and neuropsychological testing or advanced neuroimaging. The authors conclude that head impacts were relatively uncommon and low in acceleration in youth playing a weekend soccer tournament. This study adds to the limited data regarding head impacts in youth soccer. PMID- 26951541 TI - Simultaneous Determination of Potassium Sorbate, Sodium Benzoate, Quinoline Yellow and Sunset Yellow in Lemonades and Lemon Sauces by HPLC Using Experimental Design. AB - In this study, development and validation of a HPLC method was described for simultaneous determination of potassium sorbate, sodium benzoate, quinoline yellow and sunset yellow. A Box-Behnken design using three variables at three levels was employed to determine the optimum conditions of chromatographic separation: pH of mobile phase, 6.0-7.0; flow rate, 0.8-1.2 mL min(-1) and the ratio of mobile phase composed of a 0.025 M sodium acetate/acetic acid buffer, 80 90%. Resolution was chosen as a response. The optimized method was validated for linearity, the limits of detection and quantification, accuracy, precision and stability. All the validation parameters were within the acceptance range. The applicability of the developed method to the determination of these food additives in commercial lemonade and lemon sauce samples was successfully demonstrated. PMID- 26951542 TI - Isolation, Chemical Fingerprinting and Simultaneous Quantification of Four Compounds from Tanacetum gracile Using a Validated HPLC-ESI-QTOF-Mass Spectrometry Method. AB - The present study was conducted to carry out the phytochemical investigation of Tanacetum gracile Hook. f. & Thomson and to develop a method for the simultaneous quantification of the isolated compounds in the extracts ofT. gracile growing in different locations. Cluster analysis rectangular similarity matrix was performed to understand the chemical fingerprinting variations in the extracts. High performance liquid chromatography-electrospray ionization-quadrupole-time-of flight-mass spectrometry (HPLC-ESI-QTOF-MS) was used to quantify four bioactive compounds, and separation of the compounds was achieved on a reverse-phase C8 column using a mobile phase of acetonitrile: 0.1% formic acid in water with a gradient elution by maintaining the flow rate of 300 MUL/min. The QTOF-MS was operated using the electro-spray ionization technique with the positive ion polarity mode. The calibration curves of four marker compounds were linear over the concentration range of 3.12-100 ng/uL (R(2)> 0.996). A specific, accurate and precise HPLC-ESI-QTOF-MS method was optimized for the determination of kaempferol, ketoplenolide, tetramethoxyflavone and artemetin both individually and simultaneously. Quantification of these chemical markers in different extracts was carried out using this validated method. Kaempferol was isolated for the first time from T. gracile. PMID- 26951543 TI - Rapid, Bioassay-Guided Process for the Detection and Identification of Antibacterial Neem Oil Compounds. AB - Bioassay guidance was used along the whole process including method development, isolation and identification of antibacterial neem (Azadirachta indica) oil compounds. The biomonitoring was performed by direct bioautography (DB), a combination of thin-layer chromatography (TLC) and antimicrobial detection. DB of neem oil showed one antibacterial zone that was not UV-active; therefore, the TLC separation was improved under DB control. The chromatographic zone that exhibited activity against Bacillus subtilis, Xanthomonas euvesicatoria, Aliivibrio fischeri, Staphylococcus aureus and methicillin-resistant Staphylococcus aureus was characterized by TLC reagents, indicating a lipophilic, fatty acid-like chemical feature. Two compounds were found and identified in the active zone by high-performance liquid chromatography-electrospray ionization mass spectrometry as linoleic and oleic acids. Both fatty acids inhibited B. subtilis, but A. fischeri was sensitive only against linoleic acid. PMID- 26951544 TI - A novel enrichment strategy reveals unprecedented number of novel transcription start sites at single base resolution in a model prokaryote and the gut microbiome. AB - BACKGROUND: The initiating nucleotide found at the 5' end of primary transcripts has a distinctive triphosphorylated end that distinguishes these transcripts from all other RNA species. Recognizing this distinction is key to deconvoluting the primary transcriptome from the plethora of processed transcripts that confound analysis of the transcriptome. The currently available methods do not use targeted enrichment for the 5'end of primary transcripts, but rather attempt to deplete non-targeted RNA. RESULTS: We developed a method, Cappable-seq, for directly enriching for the 5' end of primary transcripts and enabling determination of transcription start sites at single base resolution. This is achieved by enzymatically modifying the 5' triphosphorylated end of RNA with a selectable tag. We first applied Cappable-seq to E. coli, achieving up to 50 fold enrichment of primary transcripts and identifying an unprecedented 16539 transcription start sites (TSS) genome-wide at single base resolution. We also applied Cappable-seq to a mouse cecum sample and identified TSS in a microbiome. CONCLUSIONS: Cappable-seq allows for the first time the capture of the 5' end of primary transcripts. This enables a unique robust TSS determination in bacteria and microbiomes. In addition to and beyond TSS determination, Cappable-seq depletes ribosomal RNA and reduces the complexity of the transcriptome to a single quantifiable tag per transcript enabling digital profiling of gene expression in any microbiome. PMID- 26951546 TI - The less invasive anterior approach for total hip arthroplasty: a comparison to other approaches and an evaluation of the learning curve - a systematic review. AB - There is still discussion about possible advantages and disadvantages of the less invasive anterior approach for total hip arthroplasty (THA). The purpose of our systematic review was to evaluate literature regarding the anterior approach in comparison to other approaches. Furthermore, we investigated if there is a description of a learning curve for the anterior approach.Data were obtained from EMBASE, Cochrane, PsycINFO, CINAHL, Web-of-Science, Scopus, Google scholar, and PubMed since their inception up to June 2015. 2 reviewers independently selected the studies and independently conducted the quality assessment. Because studies were considered heterogeneous regarding outcome measures, determinants studied, and methodological quality, we decided to perform a "best evidence synthesis". A total of 64 studies met the inclusion criteria.Strong evidence for no difference in component placement between the anterior approach and other approaches was found. Also, strong evidence for faster postoperative recovery and less need for assistive devices after the anterior approach were found. All other studied parameters only demonstrated conflicting evidence. Although the learning curve for the anterior approach is not yet clear, this learning curve should not to be neglected.In conclusion, the less invasive anterior approach provides benefits in the early postoperative period only, when compared to other approaches. PMID- 26951547 TI - The hundred most cited publications in orthopaedic hip research - a bibliometric analysis. AB - BACKGROUND: The aim of this study was to identify the 100 most cited classics in the field of hip research analysing their qualities and characteristics. METHODS: Hip joint related articles were identified and the hundred most cited selected for subsequent analysis of citation count, current citation rate, citation density (citations/article age), authorship, geographic origin institution, and level of evidence (LOE). RESULTS: In a total of 121 journals, 1,311,851 articles were published between 1945 and 2013, of which 1,287 (0.1%) possessed 250 citations or more. Total citations per article for the 100 most-cited ranged from 290 to 3,144 citations.The most common areas of research were degenerative disease and arthroplasty, followed by hip preserving surgery for which the leading authors were William H. Harris and Reinhold Ganz respectively. All articles were published in 8 journals and originated from 9 countries. 10 institutes published 48/100 of the articles. There was a significant negative correlation between both citation rate, citation density and article age. Total citation count was highest for articles published in the decade of 1970. Although 5% (2,103 articles) of hip literature comprised randomised trials (RCTs), only 1 (1%) of the citation classics was an RCT. CONCLUSIONS: The study provides intellectual milestones in hip research, reflecting on the qualities and characteristics of the research. Degenerative hip disease and arthroplasty research take up the greatest proportion of citations, followed by hip preserving research. LOE was low and there was only one RCT amongst the classics, emphasising that high LOE is not a prerequisite for a high citation count. PMID- 26951548 TI - Ipsilateral varus knee alignment correlates with increased femoral stem anteversion in primary total hip arthroplasty. AB - PURPOSE: The purpose of this study was to evaluate whether the ipsilateral knee alignment secondary to knee osteoarthritis affect positioning of the femoral component anteversion during total hip arthroplasty. METHODS: Preoperative and postoperative computed tomography-based 3-D femoral models were reconstructed for 20 total hip arthroplasty patients. Prosthetic femoral stem and native femoral anteversion was measured and compared. RESULTS: An average increase by 4.5 degrees +/- 8.1 degrees in femoral anteversion was found following total hip arthroplasty (p = 0.02). Strong positive correlation was found between the knee varus angle and the changes in femoral anteversion (R = 0.87, p<0.0001). The knee alignment was an independent factor for predicting the intraoperative positioning of femoral stem anteversion. CONCLUSIONS: The ipsilateral knee varus deformity should be considered to optimise the femoral component position during contemporary total hip arthroplasty. PMID- 26951549 TI - Transfusion of packed red blood cells stored >14 days was associated with a higher risk of infection after hip revision arthroplasty. AB - PURPOSE: Transfusion of packed red blood cells (RBCs) stored for >14 days has been associated with a higher risk of infection but there is no data about the impact in revision hip arthroplasty. METHODS: We retrospectively reviewed 280 patients who underwent revision hip arthroplasty from January 2002 to May 2012. Relevant risk factors and prosthetic joint infection (PJI) rate after 100 days after surgery were collected. RESULTS: 10 patients out of 280 (3.6%) had a PJI within the first 100 days after revision surgery. The PJI rate in patients receiving an early transfusion (during surgery or within the first 12 hours) of packed RBCs with a length of storage >14 days was higher (8.0%) than the rate in nontransfused patients (1.8%) or those receiving an early transfusion of packed RBCs with a length of storage <=14 days (2.6%, p = 0.05). A Cox regression model identified transfusion of packed RBCs stored >14 days as the only independent predictor of PJI (hazard ratio [HR] = 4.54; 95% confidence interval [CI], 1.13 18.15; p = 0.032). CONCLUSIONS: The only independent predictor of PJI was early transfusion of packed RBCs stored >14 days. Therefore, a potential way for reducing the PJI rate could be the selection of young packed RBCs. PMID- 26951545 TI - Selective Manipulation of Neural Circuits. AB - Unraveling the complex network of neural circuits that form the nervous system demands tools that can manipulate specific circuits. The recent evolution of genetic tools to target neural circuits allows an unprecedented precision in elucidating their function. Here we describe two general approaches for achieving circuit specificity. The first uses the genetic identity of a cell, such as a transcription factor unique to a circuit, to drive expression of a molecule that can manipulate cell function. The second uses the spatial connectivity of a circuit to achieve specificity: one genetic element is introduced at the origin of a circuit and the other at its termination. When the two genetic elements combine within a neuron, they can alter its function. These two general approaches can be combined to allow manipulation of neurons with a specific genetic identity by introducing a regulatory gene into the origin or termination of the circuit. We consider the advantages and disadvantages of both these general approaches with regard to specificity and efficacy of the manipulations. We also review the genetic techniques that allow gain- and loss-of-function within specific neural circuits. These approaches introduce light-sensitive channels (optogenetic) or drug sensitive channels (chemogenetic) into neurons that form specific circuits. We compare these tools with others developed for circuit-specific manipulation and describe the advantages of each. Finally, we discuss how these tools might be applied for identification of the neural circuits that mediate behavior and for repair of neural connections. PMID- 26951551 TI - Catalog of genetic progression of human cancers: breast cancer. AB - With the rapid development of next-generation sequencing, deeper insights are being gained into the molecular evolution that underlies the development and clinical progression of breast cancer. It is apparent that during evolution, breast cancers acquire thousands of mutations including single base pair substitutions, insertions, deletions, copy number aberrations, and structural rearrangements. As a consequence, at the whole genome level, no two cancers are identical and few cancers even share the same complement of "driver" mutations. Indeed, two samples from the same cancer may also exhibit extensive differences due to constant remodeling of the genome over time. In this review, we summarize recent studies that extend our understanding of the genomic basis of cancer progression. Key biological insights include the following: subclonal diversification begins early in cancer evolution, being detectable even in in situ lesions; geographical stratification of subclonal structure is frequent in primary tumors and can include therapeutically targetable alterations; multiple distant metastases typically arise from a common metastatic ancestor following a "metastatic cascade" model; systemic therapy can unmask preexisting resistant subclones or influence further treatment sensitivity and disease progression. We conclude the review by describing novel approaches such as the analysis of circulating DNA and patient-derived xenografts that promise to further our understanding of the genomic changes occurring during cancer evolution and guide treatment decision making. PMID- 26951553 TI - Craniofacial and Dental Defects in the Col1a1Jrt/+ Mouse Model of Osteogenesis Imperfecta. AB - Certain mutations in the COL1A1 and COL1A2 genes produce clinical symptoms of both osteogenesis imperfecta (OI) and Ehlers-Danlos syndrome (EDS) that include abnormal craniofacial growth, dental malocclusion, and dentinogenesis imperfecta. A mouse model (Col1a1(Jrt)/+) was recently developed that had a skeletal phenotype and other features consistent with moderate-to-severe OI and also with EDS. The craniofacial phenotype of 4- and 20-wk-old Col1a1(Jrt)/+ mice and wild type littermates was assessed by micro-computed tomography (uCT) and morphometry. Teeth and the periodontal ligament compartment were analyzed by uCT, light microscopy/histomorphometry, and electron microscopy. Over time, at 20 wk, Col1a1(Jrt)/+ mice developed smaller heads, a shortened anterior cranial base, class III occlusion, and a mandibular side shift with shorter morphology in the masticatory region (maxilla and mandible). Col1a1(Jrt)/+ mice also had changes in the periodontal compartment and abnormalities in the dentin matrix and mineralization. These findings validate Col1a1(Jrt)/+ mice as a model for OI and EDS in humans. PMID- 26951552 TI - Using Patient-Level Data to Develop Meaningful Cross-Trial Comparisons of Visual Impairment in Individuals with Diabetic Macular Edema. AB - INTRODUCTION: The aim of this study was to assess the impact of baseline characteristics on visual outcome of patients with diabetic macular edema and compare the results of clinical trials with different patient populations. METHODS: A model was created with patient-level data from the RESPOND/RESTORE trials to estimate the impact of baseline characteristics on increases in best corrected visual acuity (BCVA) with anti-vascular endothelial growth factor therapies, measured by letters gained on the Early Treatment Diabetic Retinopathy Study scale from baseline to month 12. Mean BCVA gains with ranibizumab 0.5 mg pro re nata or laser photocoagulation monotherapy were predicted, assuming baseline characteristics equivalent to those in the VIVID-DME/VISTA-DME trials. These results were compared with the gain with aflibercept 2.0 mg every 8 weeks in VIVID-DME/VISTA-DME. Sensitivity analyses assessed outcome robustness. RESULTS: Baseline BCVA and central retinal thickness differed significantly between trials. In unadjusted data, patients in RESPOND/RESTORE receiving ranibizumab gained an additional 6.6 letters [95% confidence interval (CI): 4.5 8.7] compared with patients receiving laser monotherapy. After adjusting data to assume baseline characteristics equivalent to VIVID-DME/VISTA-DME, patients receiving ranibizumab were predicted to gain an additional 9.9 letters (95% CI: 7.3-12.4) compared with those receiving laser monotherapy. These results were similar (0.1-letter difference in favor of aflibercept; 95% CI: -2.9 to 3.2; P = 0.94) to the gain in BCVA in patients receiving aflibercept in VIVID-DME/VISTA DME compared with those receiving laser monotherapy (10.0 letters, 95% CI: 8.3 11.7). CONCLUSION: After adjusting for baseline characteristics, the difference in letters gained between patients receiving ranibizumab versus aflibercept was non-significant across trials, highlighting the importance of adjusting for baseline characteristics in future comparisons. FUNDING: Novartis Pharma AG. PMID- 26951554 TI - A novel collagen/platelet-rich plasma (COL/PRP) scaffold: preparation and growth factor release analysis. AB - Platelet-rich plasma (PRP) has been widely used in clinical practice for more than 20 years because it causes the release of many growth factors. However, the burst release pattern and short release period of PRP have become obstacles to its application. An optimal controllable release system is an urgent need for researchers. This study investigated whether collagen/PRP (COL/PRP) scaffolds can serve as a vehicle for the controllable release of growth factors. We fabricated a novel scaffold that integrates PRP activated by thrombin or collagen into type I collagen. The mechanical properties, cytotoxicity, and transforming growth factor beta1 (TGF-beta1), platelet derived growth factor (PDGF), fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF) content were evaluated. Our results demonstrate that the COL/PRP scaffolds were not cytotoxic to L-929 fibroblasts. The PDGF and FGF content in the thrombin group was at a higher level and lasted for a long period of time. Collagen and thrombin played the same role in the release of TGF-beta1 and VEGF. These data suggest that the novel COL/PRP scaffolds provide a carrier for the controllable release of growth factors and may be used in tissue- regenerative therapies. PMID- 26951550 TI - Plasticity underlies tumor progression: role of Nodal signaling. AB - The transforming growth factor beta (TGFbeta) superfamily member Nodal is an established regulator of early embryonic development, with primary roles in endoderm induction, left-right asymmetry, and primitive streak formation. Nodal signals through TGFbeta family receptors at the plasma membrane and induces signaling cascades leading to diverse transcriptional regulation. While conceptually simple, the regulation of Nodal and its molecular effects are profoundly complex and context dependent. Pioneering work by developmental biologists has characterized the signaling pathways, regulatory components, and provided detailed insight into the mechanisms by which Nodal mediates changes at the cellular and organismal levels. Nodal is also an important factor in maintaining pluripotency of embryonic stem cells through regulation of core transcriptional programs. Collectively, this work has led to an appreciation for Nodal as a powerful morphogen capable of orchestrating multiple cellular phenotypes. Although Nodal is not active in most adult tissues, its reexpression and signaling have been linked to multiple types of human cancer, and Nodal has emerged as a driver of tumor growth and cellular plasticity. In vitro and in vivo experimental evidence has demonstrated that inhibition of Nodal signaling reduces cancer cell aggressive characteristics, while clinical data have established associations with Nodal expression and patient outcomes. As a result, there is great interest in the potential targeting of Nodal activity in a therapeutic setting for cancer patients that may provide new avenues for suppressing tumor growth and metastasis. In this review, we evaluate our current understanding of the complexities of Nodal function in cancer and highlight recent experimental evidence that sheds light on the therapeutic potential of its inhibition. PMID- 26951556 TI - Combined inhibition of vascular endothelial growth factor receptor signaling with temozolomide enhances cytotoxicity against human glioblastoma cells via downregulation of Neuropilin-1. AB - Glioblastoma multiforme (GBM) is the most common and aggressive type of primary brain tumor with grave prognosis. Despite the growing understanding of the complex signaling networks responsible for the initiation and progression of GBM, many experimental therapies have fallen short of their treatment goals. In the present study, we investigated the novel molecular mechanisms responsible for synergistic action of temozolomide (TMZ) and anti-VEGF therapy in GBM cells. We tested the combined effects of TMZ and VEGF blockade in four human GBM cell lines: TMZ-sensitive U251-MG and U373-MG cells, and TMZ-resistant CRT-MG and LN215-MG cells, which correlated with MGMT promoter methylation status. Treatment of TMZ along with a sublethal dosage range of SU1498, a chemical inhibitor of the VEGF receptor signaling, induced significant cell death in both TMZ-sensitive and TMZ-resistant GBM cells without changing the status of the MGMT promoter methylation. Treatment with TMZ specifically reduced the expression of NRP-1, a coreceptor of VEGF but not those of VEGF-R1 and VEGF-R2. We further confirmed the key role of NRP-1 by showing that the reduction of NRP-1 by siRNA also increased the SU1498-induced cytotoxicity of LN215-MG. These results collectively indicate that combined treatment of TMZ can sensitize GBM cells to blockade of autocrine VEGF signaling through specific down-regulation of NRP-1, which provide a rationale for further evaluation and a potential clinical trial of combinatorial therapy of TMZ and SU1498 or other VEGF inhibitors for intractable brain tumors. PMID- 26951555 TI - PET/CT evaluation of 18F-FDG uptake in pericoronary adipose tissue in patients with stable coronary artery disease: Independent predictor of atherosclerotic lesions' formation? AB - BACKGROUND: Inflammatory infiltrations in EAT which releases inflammatory cytokines correspond anatomically to the atheromatous plaques in underlying coronary vessels. However, it is unknown whether inflammatory activity of pericoronary adipose tissue (PCAT) promotes coronary atherosclerosis. METHODS AND RESULTS: 35 non-diabetic patients with confirmed CAD and 35 non-CAD controls matched for age and BMI underwent 18F-FDG-PET/CT. Maximal SUV normalized by LA blood activity was measured on the sections corresponding to the respective coronaries (RCA, LCX, LAD), as well, as in subcutaneous fat, visceral fat, and epicardial fat. Extent of CAD was determined by % stenosis in segments corresponding to 18F-FDG-PET/CT sections in coronarography using quantitative coronary analysis. PCAT SUV was significantly greater than SUV in other fat locations, as well as PCAT SUV in the controls. In CAD patients with BMI >25, PCAT SUV was positively related to % stenosis of a respective coronary artery (RCA: 0.43; P < .05; LCX 0.58; P < .05; LAD 0.65; P < .05). PCAT SUV was the only independent predictor of coronary stenosis of LAD and RCA. CONCLUSIONS: Inflammatory activity of PCAT is greater than in other fat locations, in CAD is greater than in non-CAD controls, and is independently associated with coronary stenosis. In overweight patients, PCAT SUV correlates with the extent of CAD. PMID- 26951557 TI - Tolerability of toceranib phosphate (Palladia) when used in conjunction with other therapies in 35 cats with feline oral squamous cell carcinoma: 2009-2013. AB - Objectives Squamous cell carcinoma (SCC) is the most common oral tumor in cats and typically carries a poor prognosis with current treatment options. The objective of this study was to evaluate the toxicity of toceranib phosphate (Palladia; Pfizer) in cats with oral SCC in combination with other treatment modalities. Methods In this study, 35 cats were retrospectively evaluated to determine toxicity when treated with toceranib in combination with other treatment modalities. Cats received toceranib at a median dose of 2.75 mg/kg (range 1.9-4.17 mg/kg) 3 days a week. Cats also underwent additional therapies, including surgical excision, radiation therapy, chemotherapy and/or use of non steroidal anti-inflammatory drugs. Results Toxicity was seen in six cats, with five cases of grade 1 or 2 gastrointestinal (GI) toxicity and one grade 4 metabolic toxicity. Toceranib was discontinued in one cat and two cats received dose reductions. None of the cats required treatment delays or hospitalization due to toxicity. Median toceranib treatment duration was 77 days (range 7-741 days). Conclusions and relevance This study revealed that toceranib was well tolerated by the majority of cats, with five cases of low-grade GI toxicity and one case of metabolic toxicity. Given the favorable toxicity profile, future studies further evaluating the safety and efficacy of toceranib for cats with oral SCC should be considered. PMID- 26951558 TI - Analysis of Saccharides by the Addition of Amino Acids. AB - In this work, we present the detection sensitivity improvement of electrospray ionization (ESI) mass spectrometry of neutral saccharides in a positive ion mode by the addition of various amino acids. Saccharides of a broad molecular weight range were chosen as the model compounds in the present study. Saccharides provide strong noncovalent interactions with amino acids, and the complex formation enhances the signal intensity and simplifies the mass spectra of saccharides. Polysaccharides provide a polymer-like ESI spectrum with a basic subunit difference between multiply charged chains. The protonated spectra of saccharides are not well identified because of different charge state distributions produced by the same molecules. Depending on the solvent used and other ions or molecules present in the solution, noncovalent interactions with saccharides may occur. These interactions are affected by the addition of amino acids. Amino acids with polar side groups show a strong tendency to interact with saccharides. In particular, serine shows a high tendency to interact with saccharides and significantly improves the detection sensitivity of saccharide compounds. Graphical Abstract ?. PMID- 26951560 TI - Dyadic Affective Flexibility and Emotional Inertia in Relation to Youth Psychopathology: An Integrated Model at Two Timescales. AB - The current review examines characteristics of temporal affective functioning at both the individual and dyadic level. Specifically, the review examines the following three research questions: (1) How are dyadic affective flexibility and emotional inertia operationalized, and are they related to youth psychopathology? (2) How are dyadic affective flexibility and emotional inertia related, and does this relation occur at micro- and meso-timescales? and (3) How do these constructs combine to predict clinical outcomes? Using the Flex3 model of socioemotional flexibility as a frame, the current study proposes that dyadic affective flexibility and emotional inertia are bidirectionally related at micro- and meso-timescales, which yields psychopathological symptoms for youth. Specific future directions for examining individual, dyadic, and cultural characteristics that may influence relations between these constructs and psychopathology are also discussed. PMID- 26951562 TI - Special Issue in Honour of Philip M Beart. PMID- 26951561 TI - Clinical implications of left atrial function assessed by speckle tracking echocardiography. AB - Left atrial (LA) function has a significant impact on cardiovascular diseases and has been assessed by several noninvasive methods. However, several limitations, including the dependence of image quality, single plane assessment, and time consuming procedures, have prevented widespread clinical application of the assessment of LA function. Strain imaging using tissue Doppler echocardiography enables quantification of LA function. Recently, two-dimensional speckle tracking echocardiography (2D-STE) has been developed as a noninvasive, simple, and reproducible tool for assessment of LA function in patients with cardiovascular disease. 2D-STE enables detection of early LA dysfunction even before LA morphological changes. LA dysfunction determined by 2D-STE can provide additional prognostic information to conventional echocardiographic parameters in patients with cardiovascular diseases. Hence, 2D-STE appears to be a promising technique for diagnosis and therapeutic decision-making. However, standardization of analysis techniques and software applications of 2D-STE is still lacking. Here, we review recent studies on clinical implications of LA function assessed by 2D STE and summarize the remaining problems to be solved to improve the clinical utility of this tool. PMID- 26951563 TI - Potential Transfer of Polyglutamine and CAG-Repeat RNA in Extracellular Vesicles in Huntington's Disease: Background and Evaluation in Cell Culture. AB - In Huntington's disease (HD) the imperfect expanded CAG repeat in the first exon of the HTT gene leads to the generation of a polyglutamine (polyQ) protein, which has some neuronal toxicity, potentially mollified by formation of aggregates. Accumulated research, reviewed here, implicates both the polyQ protein and the expanded repeat RNA in causing toxicity leading to neurodegeneration in HD. Different theories have emerged as to how the neurodegeneration spreads throughout the brain, with one possibility being the transport of toxic protein and RNA in extracellular vesicles (EVs). Most cell types in the brain release EVs and these have been shown to contain neurodegenerative proteins in the case of prion protein and amyloid-beta peptide. In this study, we used a model culture system with an overexpression of HTT-exon 1 polyQ-GFP constructs in human 293T cells and found that the EVs did incorporate both the polyQ-GFP protein and expanded repeat RNA. Striatal mouse neural cells were able to take up these EVs with a consequent increase in the green fluorescent protein (GFP) and polyQ-GFP RNAs, but with no evidence of uptake of polyQ-GFP protein or any apparent toxicity, at least over a relatively short period of exposure. A differentiated striatal cell line expressing endogenous levels of Hdh mRNA containing the expanded repeat incorporated more of this mRNA into EVs as compared to similar cells expressing this mRNA with a normal repeat length. These findings support the potential of EVs to deliver toxic expanded trinucleotide repeat RNAs from one cell to another, but further work will be needed to evaluate potential EV and cell-type specificity of transfer and effects of long-term exposure. It seems likely that expanded HD-associated repeat RNA may appear in biofluids and may have use as biomarkers of disease state and response to therapy. PMID- 26951559 TI - Optimizing Mass Spectrometry Analyses: A Tailored Review on the Utility of Design of Experiments. AB - Mass spectrometry (MS) has emerged as a tool that can analyze nearly all classes of molecules, with its scope rapidly expanding in the areas of post-translational modifications, MS instrumentation, and many others. Yet integration of novel analyte preparatory and purification methods with existing or novel mass spectrometers can introduce new challenges for MS sensitivity. The mechanisms that govern detection by MS are particularly complex and interdependent, including ionization efficiency, ion suppression, and transmission. Performance of both off-line and MS methods can be optimized separately or, when appropriate, simultaneously through statistical designs, broadly referred to as "design of experiments" (DOE). The following review provides a tutorial-like guide into the selection of DOE for MS experiments, the practices for modeling and optimization of response variables, and the available software tools that support DOE implementation in any laboratory. This review comes 3 years after the latest DOE review (Hibbert DB, 2012), which provided a comprehensive overview on the types of designs available and their statistical construction. Since that time, new classes of DOE, such as the definitive screening design, have emerged and new calls have been made for mass spectrometrists to adopt the practice. Rather than exhaustively cover all possible designs, we have highlighted the three most practical DOE classes available to mass spectrometrists. This review further differentiates itself by providing expert recommendations for experimental setup and defining DOE entirely in the context of three case-studies that highlight the utility of different designs to achieve different goals. A step-by-step tutorial is also provided. PMID- 26951564 TI - Immune suppression of JC virus gene expression is mediated by SRSF1. AB - Progressive multifocal leukoemcephalopathy (PML) is a fatal demyelinating disease caused by the human neurotropic JC virus (JCV). JCV infects the majority of the human population during childhood and establishes a latent/persistent life-long infection. The virus reactivates under immunosuppressive conditions by unknown mechanisms, resulting in productive infection of oligodendrocytes in the central nervous system (CNS). Given the fact that the natural occurrence of PML is strongly associated with immunosuppression, the functional and molecular interaction between glial cells and neuroimmune signaling mediated by soluble immune mediators is likely to play a major role in reactivation of JCV and the progression of the lytic viral life cycle leading to the development of PML. In order to explore the effect of soluble immune mediators secreted by peripheral blood mononuclear cells (PBMCs) on JCV transcription, primary human fetal glial (PHFG) cells were treated with conditioned media from PBMCs. We observed a strong suppression of JCV early as well as late gene transcription in cells treated with conditioned media from induced PBMCs. Using a variety of virological and molecular biological approaches, we demonstrate that immune mediators secreted by PBMCs induce the expression of SRSF1, a strong inhibitor of JCV gene expression, and inhibit the replication of JCV. Our results show that downregulation of SRSF1 in glial cells overcomes the suppression of JCV gene expression and its replication mediated by soluble immune mediators. These findings suggest the presence of a novel immune signaling pathway between glial cells and PBMCs that may control JCV gene expression during the course of viral reactivation. PMID- 26951565 TI - In Vitro Investigation of Influences of Chitosan Nanoparticles on Fluorescein Permeation into Alveolar Macrophages. AB - PURPOSE: Pulmonary infection namely tuberculosis is characterized by alveolar macrophages harboring a large microbe population. The chitosan nanoparticles exhibit fast extracellular drug release in aqueous biological milieu. This study investigated the matrix effects of chitosan nanoparticles on extracellular drug diffusion into macrophages. METHODS: Oligo, low, medium and high molecular weight chitosan nanoparticles were prepared by nanospray drying technique. These nanoparticles were incubated with alveolar macrophages in vitro and had model drug sodium fluorescein added into the same cell culture. The diffusion characteristics of sodium fluorescein and nanoparticle behavior were investigated using fluorescence microscopy, scanning electron microscopy, differential scanning calorimetry and Fourier transform infrared spectroscopy techniques. RESULTS: The oligochitosan nanoparticles enabled macrophage membrane fluidization with the extent of sodium fluorescein entry into macrophages being directly governed by the nanoparticle loading. Using nanoparticles made of higher molecular weight chitosan, sodium fluorescein permeation into macrophages was delayed due to viscous chitosan diffusion barrier at membrane boundary. CONCLUSION: Macrophage-chitosan nanoparticle interaction at membrane interface dictates drug migration into cellular domains. PMID- 26951566 TI - Characterization of Solid Dispersion of Itraconazole Prepared by Solubilization in Concentrated Aqueous Solutions of Weak Organic Acids and Drying. AB - PURPOSE: The purpose of this study was to develop an amorphous solid dispersion (SD) of an extremely water-insoluble and very weakly basic drug, itraconazole (ITZ), by interaction with weak organic acids and then drying that would enhance dissolution rate of drug and physical stability of formulation. METHODS: Aqueous solubility of ITZ in concentrated solutions of weak organic acids, such as glutaric, tartaric, malic and citric acid, was determined. Solutions with high drug solubility were dried using vacuum oven and the resulting SDs having 2 to 20% drug load were characterized by differential scanning calorimetry (DSC), powder X-ray diffractometry (PXRD) and attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy. The dissolution of SDs was initially studied in 250 mL of 0.1 N HCl (pH 1.1), and any undissolved solids were collected and analyzed by PXRD. The pH of the dissolution medium was then changed from 1.1 to 5.5, particle size of precipitates were measured, and drug concentrations in solution were determined by filtration through membrane filters of varying pore sizes. RESULTS: The aqueous solubility of ITZ was greatly enhanced in presence of weak acids. While the solubility of ITZ in water was ~4 ng/ mL, it increased to 25-40 mg per g of solution at 25 degrees C and 200 mg per g of solution at 65 degrees C at a high acid concentration leading to extremely high solubilization. PXRD of SDs indicated that ITZ was present in the amorphous form, wherein the acid formed a partially crystalline matrix. ATR-FTIR results showed possible weak interactions, such as hydrogen bonding, between drug and acid but there was no salt formation. SDs formed highly supersaturated solutions at pH 1.1 and had superior dissolution rate as compared to amorphous drug and physical mixtures of drug and acids. Following the change in pH from 1.1 to 5.5, ITZ precipitated as mostly nanoparticles, providing high surface area for relatively rapid redissolution. CONCLUSIONS: A method of highly solubilizing an extremely water-insoluble drug, ITZ, in aqueous media and converting it into an amorphous form in a physically stable SD was successfully investigated. The dissolution rate and the extent of supersaturation of the drug in dissolution media improved greatly, and any precipitate formed at high pH had very small particle size. PMID- 26951568 TI - An analysis of electronic health record-related patient safety incidents. AB - The aim of this study was to analyse electronic health record-related patient safety incidents in the patient safety incident reporting database in fully digital hospitals in Finland. We compare Finnish data to similar international data and discuss their content with regard to the literature. We analysed the types of electronic health record-related patient safety incidents that occurred at 23 hospitals during a 2-year period. A procedure of taxonomy mapping served to allow comparisons. This study represents a rare examination of patient safety risks in a fully digital environment. The proportion of electronic health record related incidents was markedly higher in our study than in previous studies with similar data. Human-computer interaction problems were the most frequently reported. The results show the possibility of error arising from the complex interaction between clinicians and computers. PMID- 26951569 TI - Formalizing clinical practice guideline for clinical decision support systems. AB - Clinical practice guidelines are valuable sources of clinical knowledge for healthcare professionals. However, the passive dissemination of clinical practice guidelines like publishing in medical journals is ineffective in changing clinical practice behaviour. In this work, we proposed a framework to help adopting an active clinical practice guideline dissemination approach by automatically extracting clinical knowledge from clinical practice guidelines into a clinical decision support system-friendly format. The proposed framework is intended to help human modellers by automating some of the manual formalization activities in order to minimize their manual effort. We evaluated our framework using all recommendations from two clinical practice guidelines produced by the Scottish Intercollegiate Guidelines Network: the 'Management of lung cancer' clinical practice guideline and the 'Management of chronic pain' clinical practice guideline. We conclude that the proposed framework can be effectively used to formalize drug and procedure recommendation in clinical contexts. PMID- 26951567 TI - Combination Nanopreparations of a Novel Proapoptotic Drug - NCL-240, TRAIL and siRNA. AB - PURPOSE: To develop a multifunctional nanoparticle system carrying a combination of pro-apoptotic drug, NCL-240, TRAIL [tumor necrosis factor-alpha (TNF-alpha) related apoptosis-inducing ligand] and anti-survivin siRNA and to test the combination preparation for anti-cancer effects in different cancer cells. METHODS: Polyethylene glycol-phosphoethanolamine (PEG-PE) - based polymeric micelles were prepared carrying NCL-240. These micelles were used in combination with TRAIL-conjugated micelles and anti-survivin siRNA-S-S-PE containing micelles. All the micelles were characterized for size, zeta potential, and drug encapsulation efficiency. Different cancer cells were used to study the cytotoxicity potential of the individual as well as the combination formulations. Other cell based assays included cellular association studies of transferrin targeted NCL-240 micelles and study of cellular survivin protein downregulation by anti-survivin siRNA-S-S-PE containing micelles. RESULTS: NCL-240 micelles and the combination NCL-240/TRAIL micelles significantly increased cytotoxicity in the resistant strains of SKOV-3, MCF-7 and A549 as compared to free drugs or single drug formulations. The NCL-240/TRAIL micelles were also more effective in NCI/ADR-RES cancer cell spheroids. Anti-survivin siRNA micelles alone displayed a dose-dependent reduction in survivin protein levels in A2780 cells. Treatment with NCL-240/TRAIL after pre-incubation with anti-survivin siRNA inhibited cancer cell proliferation. Additionally, a single multifunctional system composed of NCL 240/TRAIL/siRNA PM also had significant cytotoxic effects in vitro in multiple cell lines. CONCLUSION: These results demonstrate the efficacy of a combination of small-molecule PI3K inhibitors, TRAIL, and siRNA delivered by micellar preparations in multiple cancer cell lines. PMID- 26951570 TI - Editorial Commentary: Do We Have Strategies to Improve the Preventive Treatment of Latent Tuberculosis Infection? PMID- 26951571 TI - Factors Associated With Noncompletion of Latent Tuberculosis Infection Treatment: Experience From the PREVENT TB Trial in the United States and Canada. AB - BACKGROUND: Overall rates of noncompletion of treatment (NCT) for latent tuberculosis infection (LTBI) in the PREVENT TB trial were 18% for 3 months of directly observed once-weekly rifapentine (maximum dose, 900 mg) plus isoniazid (maximum dose, 900 mg) (3HP-DOT) and 31% for 9 months of daily self-administered isoniazid (maximum dose, 300 mg; 9H-SAT). NCT for LTBI reduces its effectiveness. The study objective was to assess factors associated with NCT for LTBI among adult participants enrolled at US and Canadian sites of the PREVENT TB trial. METHODS: This was a post hoc exploratory analysis of the randomized, open-label PREVENT TB trial. Factors were analyzed by univariate and multivariate logistic regression (with enrollment site as a random effect). RESULTS: From 6232 participants analyzed, 1406 (22.6%) did not complete LTBI treatment (317 NCT attributed to an adverse event [NCT-AE] and 1089 NCT attributed to reasons other than an adverse event [NCT-O]). The proportion of NCT-AE was similar with both regimens (3HP-DOT = 6.4% vs 9H-SAT = 5.9%; P = .23); NCT-O was higher among participants enrolled in 9H-SAT (9H-SAT = 24.5% vs 3HP-DOT = 12.7%; P = .02). Among those in the NCT-AE group, being non-Hispanic and receiving 3HP-DOT, having cirrhosis and receiving 9H-SAT, alcohol consumption among men, and use of concomitant medication were associated with NCT-AE. Among those in the NCT-O group, receiving 9H-SAT, missing >=1 early visit, men receiving 9H-SAT, men with a history of incarceration, alcohol abuse, use ever of intravenous drugs, younger age receiving 9H-SAT, and smoking were associated with NCT-O. CONCLUSIONS: Factors associated with NCT, such as missing a clinic visit early during treatment, might help identify persons for whom tailored interventions could improve completion of LTBI treatment. CLINICAL TRIALS REGISTRATION: NCT00023452. PMID- 26951572 TI - Reply to Legrand and Lafaurie. PMID- 26951574 TI - Use of Prophylactic Antibiotics in Mechanically Ventilated Patients With Burn Injuries. PMID- 26951575 TI - Frontiers in valvular heart disease. PMID- 26951573 TI - Incidence of Opportunistic Infections and the Impact of Antiretroviral Therapy Among HIV-Infected Adults in Low- and Middle-Income Countries: A Systematic Review and Meta-analysis. AB - BACKGROUND: To understand regional burdens and inform delivery of health services, we conducted a systematic review and meta-analysis to evaluate the effect of antiretroviral therapy (ART) on incidence of key opportunistic infections (OIs) in human immunodeficiency virus (HIV)-infected adults in low- and middle-income countries (LMICs). METHODS: Eligible studies describing the cumulative incidence of OIs and proportion on ART from 1990 to November 2013 were identified using multiple databases. Summary incident risks for the ART-naive period, and during and after the first year of ART, were calculated using random effects meta-analyses. Summary estimates from ART subgroups were compared using meta-regression. The number of OI cases and associated costs averted if ART was initiated at a CD4 count >=200 cells/uL were estimated using Joint United Nations Programme on HIV/AIDS (UNAIDS) country estimates and global average OI treatment cost per case. RESULTS: We identified 7965 citations, and included 126 studies describing 491 608 HIV-infected persons. In ART-naive patients, summary risk was highest (>5%) for oral candidiasis, tuberculosis, herpes zoster, and bacterial pneumonia. The reduction in incidence was greatest for all OIs during the first 12 months of ART (range, 57%-91%) except for tuberculosis, and was largest for oral candidiasis, Pneumocystis pneumonia, and toxoplasmosis. Earlier ART was estimated to have averted 857 828 cases in 2013 (95% confidence interval [CI], 828 032-874 853), with cost savings of $46.7 million (95% CI, $43.8-$49.4 million). CONCLUSIONS: There was a major reduction in risk for most OIs with ART use in LMICs, with the greatest effect seen in the first year of treatment. ART has resulted in substantial cost savings from OIs averted. PMID- 26951576 TI - CardioPulse: Valvular interventions from the Europeanperspective. PMID- 26951577 TI - The Feasibility, Safety, and Efficacy of Using a Wireless Pedometer to Improve the Activity Level in a Cohort of Nurses. AB - PURPOSE: This study had two aims: (1) to test the feasibility, safety, and efficacy of using a wireless pedometer in a cohort of nurses; and (2) to understand if wireless pedometer use increased number of steps walked, number of flights of stairs climbed, daily activity level, and improved personal perception of health. DESIGN: This study used a nonexperimental exploratory design to test the feasibility and efficacy of using a wireless pedometer in a cohort of nurses. Pre- and posttest measures captured the number of steps walked, flights of stairs climbed, activity level, and perception of health. RESULTS: Sample characteristics: 27 females, 3 males; 90% non-Hispanic Caucasian, 3% Hispanic; 47% between the ages of 55 and 65 years. Eighty percent of the participants reported that they were caregivers of other people. There was a significant increase from baseline to the end of the study in the following measures: self perception of steps walked (p < .001), flights of stairs climbed (p < .005), self perception of daily activity (p < .001), and although there was an improvement in self-perception of health, the change was not significant. CONCLUSIONS: The wireless pedometer was a feasible, safe, and efficacious device to use. This study may have implications for interventions aimed at improving caregiver health. PMID- 26951578 TI - The Effects of Tai Chi Practice With Asynchronous Music on Compliance and Fall Related Risk Factors in Middle-Aged and Older Women: A Pilot Study. AB - PURPOSE: This study examined whether practicing Tai Chi (TC) along with music can maximize the effects of TC on compliance and fall-related risk factors (Dynamic Gait Index and fear of falling). DESIGN: A convenient sample was recruited in a community senior center. Eighteen women aged 50 to 84 years (9 White, 9 Black) were block randomly assigned to a TC in silence (TC + S; n = 6) or a TC with music (TC + M; n = 12) class. METHOD: Thirteen participants (4 in TC + S group, 9 in TC + M group) with completed pre- and posttests were included in the final analysis. Paired t tests were conducted to examine changes within groups over time and analysis of covariance was used to assess group differences. FINDINGS: After 15 weeks of intervention, balance increased in both groups with significantly higher benefits in the TC + M group (p < .05). Fear of falling scores improved in TC + M group and compliance rate was higher in this group. CONCLUSIONS: Practicing TC + M may help increase adherence in White and Black middle-aged and older women, and maximize the effects of TC on fall-related risk factors. Studies with more rigorous study design, including musical considerations, are warranted. PMID- 26951581 TI - Correction. PMID- 26951579 TI - Value of Serum Cholinesterase Activity in the Diagnosis of Septic Shock Due to Bacterial Infections. AB - BACKGROUND: We aimed to investigate whether serum cholinesterase (SChE) activity can be helpful for the diagnosis of septic shock and to evaluate its usefulness in comparison with procalcitonin (PCT) and C-reactive protein (CRP). METHODS: A prospective single-blinded study conducted in an intensive care unit of university hospital. Patients were classified as having cardiogenic shock, septic shock, or hemorrhagic shock. We also included a control group without neither hemodynamic instability nor sepsis. For all included patients, SChE, PCT, and CRP were simultaneously sampled. RESULTS: The comparison of sepsis markers between all groups showed that the mean values of PCT and CRP were significantly higher in patients with septic shock. However, SChE activity was significantly lower in this group. The SChE activity was found to be more accurate than PCT and CRP for the diagnosis of septic shock. In fact, an SChE activity <= 4000 UI/L predicted the diagnosis of septic shock with a sensitivity of 78%, a specificity of 89%, a predictive negative value of 97%, and a predictive positive value of 65%. However, the prognostic value of SChE activity was poor in multivariate analysis. CONCLUSION: The SChE activity level was significantly decreased in patients with septic shock. However, its prognostic value is poor. Our results suggest that SChE activity is useful for the diagnosis of septic shock. Further studies are warranted to confirm our findings. PMID- 26951582 TI - Theory vs Practice: Should Primary Care Practice Take on Social Determinants of Health Now? Yes. PMID- 26951583 TI - Theory vs Practice: Should Primary Care Practice Take on Social Determinants of Health Now? No. PMID- 26951584 TI - Perspectives in Primary Care: A Conceptual Framework and Path for Integrating Social Determinants of Health Into Primary Care Practice. PMID- 26951586 TI - General Practitioners' Empathy and Health Outcomes: A Prospective Observational Study of Consultations in Areas of High and Low Deprivation. AB - PURPOSE: We set out to compare patients' expectations, consultation characteristics, and outcomes in areas of high and low socioeconomic deprivation, and to examine whether the same factors predict better outcomes in both settings. METHODS: Six hundred fifty-nine patients attending 47 general practitioners in high- and low-deprivation areas of Scotland participated. We assessed patients' expectations of involvement in decision making immediately before the consultation and patients' perceptions of their general practitioners' empathy immediately after. Consultations were video recorded and analyzed for verbal and non-verbal physician behaviors. Symptom severity and related well-being were measured at baseline and 1 month post-consultation. Consultation factors predicting better outcomes at 1 month were identified using backward selection methods. RESULTS: Patients in deprived areas had less desire for shared decision making (P <.001). They had more problems to discuss (P = .01) within the same consultation time. Patients in deprived areas perceived their general practitioners (GPs) as less empathic (P = .02), and the physicians displayed verbal and nonverbal behaviors that were less patient centered. Outcomes were worse at 1 month in deprived than in affluent groups (70% response rate; P <.001). Perceived physician empathy predicted better outcomes in both groups. CONCLUSIONS: Patients' expectations, GPs' behaviors within the consultation, and health outcomes differ substantially between high- and low-deprivation areas. In both settings, patients' perceptions of the physicians' empathy predict health outcomes. These findings are discussed in the context of inequalities and the "inverse care law." PMID- 26951585 TI - Practical Opportunities for Healthy Diet and Physical Activity: Relationship to Intentions, Behaviors, and Body Mass Index. AB - PURPOSE: Current strategies for improving diet and activity patterns focus on encouraging patients to make better choices, but they meet with limited success. Because the choices people make depend on the choices they have, we examined how practical opportunities for diet and physical activity shape behavioral intentions and achieved behaviors. METHODS: Participants included 746 adults who visited 8 large primary care practices in the Residency Research Network of Texas in 2012. We used structural equation models to confirm factor structures for a previously validated measure of practical opportunities, and then modeled achieved diet (Starting the Conversation - Diet questionnaire), physical activity (International Physical Activity Questionnaire), and BMI as a function of opportunities (classified as either resources or conversion factors that influence use of resources), behavioral intentions, and demographic covariates. RESULTS: In path models, resources (P <.001) and conversion factors (P = .005) predicted behavioral intentions for activity. Conversion factors (P <.001), but not resources, predicted diet intentions. Both activity resources (P = .01) and conversion factors (P <.001) were positively associated with weekly activity minutes. Diet conversion factors (P <.001), but not diet resources (P = .08), were positively associated with diet quality. The same patterns were observed for body mass index (BMI). Socioeconomic gradients in resources and conversion factors were evident. CONCLUSIONS: Individuals' feasible opportunities for healthy diet and activity have clinically meaningful associations with intentions, achieved behaviors, and BMI. Assessing opportunities as part of health behavior management could lead to more effective, efficient, and compassionate interventions. PMID- 26951587 TI - Advance Care Planning Meets Group Medical Visits: The Feasibility of Promoting Conversations. AB - PURPOSE: Primary care needs new models to facilitate advance care planning conversations. These conversations focus on preferences regarding serious illness and may involve patients, decision makers, and health care providers. We describe the feasibility of the first primary care-based group visit model focused on advance care planning. METHODS: We conducted a pilot demonstration of an advance care planning group visit in a geriatrics clinic. Patients were aged at least 65 years. Groups of patients met in 2 sessions of 2 hours each facilitated by a geriatrician and a social worker. Activities included considering personal values, discussing advance care planning, choosing surrogate decision-makers, and completing advance directives. We used the RE-AIM framework to evaluate the project. RESULTS: Ten of 11 clinicians referred patients for participation. Of 80 patients approached, 32 participated in 5 group visit cohorts (a 40% participation rate) and 27 participated in both sessions (an 84% retention rate). Mean age was 79 years; 59% of participants were female and 72% white. Most evaluated the group visit as better than usual clinic visits for discussing advance care planning. Patients reported increases in detailed advance care planning conversations after participating (19% to 41%, P = .02). Qualitative analysis found that older adults were willing to share personal values and challenges related to advance care planning and that they initiated discussions about a broad range of relevant topics. CONCLUSION: A group visit to facilitate discussions about advance care planning and increase patient engagement is feasible. This model warrants further evaluation for effectiveness in improving advance care planning outcomes for patients, clinicians, and the system. PMID- 26951588 TI - Electronic Consultations to Improve the Primary Care-Specialty Care Interface for Cardiology in the Medically Underserved: A Cluster-Randomized Controlled Trial. AB - PURPOSE: Communication between specialists and primary care clinicians is suboptimal, and access to referrals is often limited, which can lead to lower quality, inefficiency, and errors. An electronic consultation (e-consultation) is an asynchronous, non-face-to-face consultation between a primary care clinician and a specialist using a secure electronic communication platform. The purpose of this study was to conduct a randomized controlled trial of e-consultations to test its efficacy and effectiveness in reducing wait times and improving access to specialty care. METHODS: Primary care clinicians were randomized into a control (9 traditional) or an intervention (17 e-consultation) arm for referrals to cardiologists. Primary care clinicians were recruited from 12 practice sites in a community health center in Connecticut with mainly medically underserved patients. Two end points were analyzed with a Cox proportional hazards model where the hazard of either a visit or an e-consultation was linked to study arm, sex, race, and age. RESULTS: Thirty-six primary care clinicians participated in the study, referring 590 patients. In total, 69% of e-consultations were resolved without a visit to a cardiologist. After adjusting for covariates, median days to a review for an electronic consultation vs a visit for control patients were 5 and 24, respectively. A review of 6-month follow-up data found fewer cardiac related emergency department visits for the intervention group. CONCLUSION: E consultation referrals improved access to and timeliness of care for an underserved population, reduced overall specialty utilization, and streamlined specialty referrals without any increase in adverse cardiovascular outcomes. e consultations are a potential solution for improving access to specialty care. PMID- 26951591 TI - Disclosure of Sexual Orientation and Uptake of HIV Testing and Hepatitis Vaccination for Rural Men Who Have Sex With Men. AB - PURPOSE: The decision and ability of primary care clinician to make recommendations for routine human immunodeficiency virus (HIV) testing and hepatitis A virus (HAV) and hepatitis B virus (HBV) vaccines are shaped by knowledge of their patient's risk behaviors. For men who have sex with men, such knowledge requires disclosure of same-sex sexual behavior or sexual identity. METHODS: Data were analyzed from a national survey of rural men who have sex with men (N = 319) to understand whether the disclosure of sexual identity to clinicians was associated with increased uptake of HIV testing and hepatitis vaccinations. RESULTS: We found that disclosure of sexual identity to clinicians was significantly associated (OR = 1.26; 95% CI, 1.08-1.47) with uptake of routine HIV testing and HAV/HBV vaccination. CONCLUSION: Our finding reinforces the need for safe, nonjudgmental settings for patients to discuss their sexual identities freely with their clinicians. PMID- 26951589 TI - Influence of Clinical Communication on Parents' Antibiotic Expectations for Children With Respiratory Tract Infections. AB - PURPOSE: The purpose of this study was to understand clinicians' and parents' perceptions of communication within consultations for respiratory tract infections (RTI) in children and what influence clinician communication had on parents' understanding of antibiotic treatment. METHODS: We video recorded 60 primary care consultations for children aged 3 months to 12 years who presented with RTI and cough in 6 primary care practices in England. We then used purposive sampling to select 27 parents and 13 clinicians for semistructured video elicitation interviews. The videos were used as prompts to investigate participants' understanding and views of communication within the consultations. We analyzed the interview data thematically. RESULTS: While clinicians commonly told parents that antibiotics are not effective against viruses, this did not have much impact on parents' beliefs about the need to consult or on their expectations concerning antibiotics. Parents believed that antibiotics were needed to treat more severe illnesses, a belief that was supported by the way clinicians accompanied viral diagnoses with problem-minimizing language and antibiotic prescriptions with more problem-oriented language. Antibiotic prescriptions tended to confirm parents' beliefs about what indicated illness severity, which often took into account the wider impact on a child's life. While parents understood antimicrobial resistance poorly, most held beliefs that supported reduced antibiotic prescribing. A minority attributed it to resource rationing, however. CONCLUSIONS: Clinician communication and prescribing behavior confirm parents' beliefs that antibiotics are needed to treat more severe illnesses. Interventions to reduce antibiotic expectations need to address communication within the consultation, prescribing behavior, and lay beliefs. PMID- 26951590 TI - Supporting Patient Behavior Change: Approaches Used by Primary Care Clinicians Whose Patients Have an Increase in Activation Levels. AB - PURPOSE: We aimed to identify the strategies used to support patient behavior change by clinicians whose patients had an increase in patient activation. METHODS: This mixed methods study was conducted in collaboration with Fairview Health Services, a Pioneer Accountable Care Organization. We aggregated data on the change in patient activation measure (PAM) score for 7,144 patients to the primary care clinician level. We conducted in-depth interviews with 10 clinicians whose patients' score increases were among the highest and 10 whose patients' score changes were among the lowest. Transcripts of the interviews were analyzed to identify key strategies that differentiated the clinicians whose patients had top PAM change scores. RESULTS: Clinicians whose patients had relatively large activation increases reported using 5 key strategies to support patient behavior change (mean = 3.9 strategies): emphasizing patient ownership; partnering with patients; identifying small steps; scheduling frequent follow-up visits to cheer successes, problem solve, or both; and showing caring and concern for patients. Clinicians whose patients had lesser change in activation were far less likely to describe using these approaches (mean = 1.3 strategies). Most clinicians, regardless of group, reported developing their own approach to support patient behavior change. Those whose patients showed high activation change reported spending more time with patients on counseling and education than did those whose patients showed less improvement in activation. CONCLUSIONS: Clinicians vary in the strategies they use to promote behavior change and in the time spent with patients on such activities. The 5 key strategies used by clinicians with high patient activation change are promising approaches to supporting patient behavior change that should be tested in a larger sample of clinicians to validate their effectiveness. PMID- 26951592 TI - Achieving Value in Primary Care: The Primary Care Value Model. AB - The patient-centered medical home (PCMH) model provides a compelling vision for primary care transformation, but studies of its impact have used insufficiently patient-centered metrics with inconsistent results. We propose a framework for defining patient-centered value and a new model for value-based primary care transformation: the primary care value model (PCVM). We advocate for use of patient-centered value when measuring the impact of primary care transformation, recognition, and performance-based payment; for financial support and research and development to better define primary care value-creating activities and their implementation; and for use of the model to support primary care organizations in transformation. PMID- 26951594 TI - VALUABLE NEW AFMRD MEMBER-FOCUSED CHANGES. PMID- 26951595 TI - MANIFIESTO CANCUN. PMID- 26951593 TI - Family Physician-Case Manager Collaboration and Needs of Patients With Dementia and Their Caregivers: A Systematic Mixed Studies Review. AB - PURPOSE: Dementia case management (CM) in primary care is a complex intervention aimed at identifying the various needs of patients with dementia and their caregivers, as well as the organization and coordination of care. A key element of CM is the collaboration of family physicians with case managers. We conducted a systematic mixed-studies review to identify the needs of the patient-caregiver dyad and the effects of CM. METHODS: We searched MEDLINE, PsycINFO, and EMBASE up to October 2014, regardless of the study design. Our main outcomes were needs of patients and their caregivers and the effects of CM on these needs. We used narrative syntheses to develop a taxonomy of needs and to describe the effects of CM on those needs. We used meta-analysis to calculate the prevalence of needs and the standardized mean differences to evaluate the effects of CM on the needs identified. RESULTS: Fifty-four studies were included. We identified needs of the patient-caregiver dyad and needs of the patient and caregiver individually. CM addressed the majority of the identified needs. Still, some very common needs (eg, early diagnosis) are overlooked while other needs (eg, education on the disease) are well addressed. Fully establishing the value of CM is difficult given the small number of studies of CM in primary care. CONCLUSIONS: There is good evidence that case managers, in collaboration with family physicians, have a pivotal role in addressing the needs of the patient-caregiver dyad. PMID- 26951596 TI - AAFP URGES FAMILY PHYSICIANS TO INTEGRATE PRECONCEPTION CARE INTO PATIENT VISITS. PMID- 26951597 TI - A MESSAGE FROM THE ABFM PRESIDENT. PMID- 26951598 TI - STFM TACKLES PRECEPTOR SHORTAGE. PMID- 26951600 TI - The impact of levothyroxine sodium treatment on oxidative stress in Hashimoto's thyroiditis. AB - OBJECTIVE: Although several studies reported increased oxidative stress in Hashimoto's thyroiditis (HT), the effect of levothyroxine treatment on oxidative status is not studied extensively. Therefore, we conducted this study to investigate the effects of levothyroxine replacement on oxidative stress in HT. DESIGN AND METHODS: Thirty-six patients recently diagnosed with HT-related hypothyroidism and 36 healthy controls were included in the study. Levothyroxine replacement was started to patients with hypothyroidism, and had been followed-up for 6 months. RESULTS: Mean basal serum total antioxidant status (TAS), total thiol, arylesterase, and paraoxonase 1 (PON1) levels were significantly lower, and serum total oxidant status (TOS) and oxidative stress index (OSI) were significantly higher in the patients with hypothyroid than the controls. In the hypothyroid group serum TAS, total thiol, arylesterase, and PON1 levels increased and serum TOS and OSI levels decreased significantly after levothyroxine treatment. Pretreatment serum TAS, total thiol, PON1, and arylesterase levels were positively correlated with free levothyroxine (fT4) and negatively correlated with thyroid-stimulating hormone (TSH), antithyroid peroxidase (anti TPO), and antithyroglobulin (anti-TG) levels. Also, pretreatment serum TOS and OSI levels were negatively correlated with fT4 levels and positively correlated with TSH, anti-TPO, and anti-TG. We have also found that the fT4 and anti-TPO levels are independent predictors of the oxidative stress parameters in stepwise multivariable linear regression analysis. CONCLUSION: This study suggests that levothyroxine replacement decreases oxidant status and increases antioxidant status following the 6 months of levothyroxine replacement in hypothyroidism that develops in accordance with the HT. PMID- 26951599 TI - ENGAGING LEARNERS TO ACHIEVE ESCAPE VELOCITY IN TRANSFORMATIONAL EDUCATION AND PRACTICE. PMID- 26951601 TI - Derivation of a multivariate reference range for pituitary thyrotropin and thyroid hormones: diagnostic efficiency compared with conventional single reference method. AB - : Although pituitary thyrotropin (TSH) and thyroid hormones are physiologically interrelated, interpretation of measurements is conventionally done separately. Classification of subclinical thyroid dysfunction depends by definition solely on an abnormal TSH. This study examines a composite multivariate approach to disease classification. METHODS: Bivariate and trivariate reference limits were derived from a thyroid-healthy control group (n=271) and applied to a clinically diverse sample (n=820) from a prospective study, comparing their diagnostic efficiency with the conventional method. RESULTS: The following 95% reference limits were derived from the control group: (i) separate reference intervals for TSH, free thyroxine (FT4) and free triiodothyronine (FT3); (ii) bivariate composite reference limits for the logarithmically transformed TSH and FT4, and (iii) trivariate composite reference limits including all three parameters. A multivariate approach converts the "rectangular" or "cuboid" graphical representations of the independent parameters into an ellipse or ellipsoid. When applying these reference limits to the clinical sample, thyroid dysfunctions were classified differently, compared with the separate method, in 6.3 or 12% of all cases by the bivariate or trivariate method respectively. Of the established dysfunctions according to the separate intervals, 26% were reclassified to "euthyroid" by using the bivariate limit. Discrepancies from the laboratory evaluated reference range were less pronounced. CONCLUSIONS: Frequent divergencies between composite multivariate reference limits and a combination of separate univariate reference intervals suggest that statistical analytic techniques may heavily influence thyroid disease classification. This challenges the validity of the conjoined roles of TSH currently employed as both a sensitive screening test and a reliable classification tool for thyroid disease. PMID- 26951602 TI - suPAR level is associated with myocardial impairment assessed with advanced echocardiography in patients with type 1 diabetes with normal ejection fraction and without known heart disease or end-stage renal disease. AB - AIM: Heart disease is a common fatal diabetes-related complication. Early detection of patients at particular risk of heart disease is of prime importance. Soluble urokinase plasminogen activator receptor (suPAR) is a novel biomarker for development of cardiovascular disease. We investigate if suPAR is associated with early myocardial impairment assessed with advanced echocardiographic methods. METHODS: In an observational study on 318 patients with type 1 diabetes without known heart disease and with normal left ventricular ejection fraction (LVEF) (biplane LVEF >45%), we performed conventional, tissue Doppler and speckle tracking echocardiography, and measured plasma suPAR levels. Associations between myocardial function and suPAR levels were studied in adjusted models including significant covariates. RESULTS: Patients were 55+/-12 years (mean+/-s.d.) and 160 (50%) males. Median (interquartile range) suPAR was 3.4 (1.7) ng/mL and LVEF was 58+/-5%. suPAR levels were not associated with LVEF (P=0.11). In adjusted models, higher suPAR levels were independently associated with both impaired systolic function assessed with global longitudinal strain (GLS) and tissue velocity s', and with impaired diastolic measures a' and e'/a' (all P=0.034). In multivariable analysis including cardiovascular risk factors and both systolic and diastolic measures (GLS and e'/a'), both remained independently associated with suPAR levels (P=0.012). CONCLUSIONS: In patients with type 1 diabetes with normal LVEF and without known heart disease, suPAR is associated with early systolic and diastolic myocardial impairment. Our study implies that both suPAR and advanced echocardiography are useful diagnostic tools for identifying patients with diabetes at risk of future clinical heart disease, suited for intensified medical therapy. PMID- 26951603 TI - Cardiac Magnetic Resonance Reveals Signs of Subclinical Myocardial Inflammation in Asymptomatic HIV-Infected Patients. AB - BACKGROUND: People living with chronic HIV infection are at an increased risk for cardiovascular disease. With this study, we aimed to determine the extent of cardiovascular involvement in asymptomatic HIV-infected patients by a comprehensive cardiac magnetic resonance (CMR) approach. METHODS AND RESULTS: Asymptomatic patients with chronic HIV infection undergoing combination antiretroviral therapy (n=28) and control subjects (n=22) underwent CMR. HIV infected patients were successfully controlled for the disease with a consistent plasma viremia of <200 copies/mL (mean CD4(+)-cell count, 475.1+/-307.9 cells/MUL). CMR protocol allowed for the determination of cardiac function, myocardial inflammation, myocardial fibrosis, aortic stiffness, and pericardial fat volume. When compared with healthy controls, HIV-infected patients showed alterations in left ventricular function as demonstrated by a lower ejection fraction (60.9+/-7.1% versus 65.2+/-5.5%; P=0.023) and lower global peak systolic longitudinal and circumferential strain values (longitudinal strain, -17.7+/-3.4% versus -20.2+/-3.2%, circumferential strain, -21.2+/-4.6% versus -24.7+/-5.1%; P<0.001, respectively). CMR parameters indicating myocardial inflammation were elevated in HIV-infected patients (native T1 relaxation times, 1128.3+/-53.4 ms versus 1086.5+/-54.5 ms; P=0.009; relative T2 signal intensity ratio, 1.6+/-0.3 versus 1.4+/-0.3; P=0.046; early gadolinium enhancement ratio, 3.1+/-1.2 versus 2.1+/-0.6; P=0.003). Myocardial fibrosis, predominantly at the subepicardium of the midventricular and basal inferolateral wall, was prevalent in 82.1% of HIV infected patients, but only in 27.3% of healthy controls (P<0.001). CONCLUSIONS: Comprehensive CMR revealed a high burden of cardiovascular disease in asymptomatic HIV-infected patients. Subclinical myocardial inflammation as detected by CMR may be a potential precursor of the increased cardiovascular morbidity and mortality observed in patients with chronic HIV infection. PMID- 26951604 TI - Inflammation and Fibrosis in HIV: Getting to the Heart of the Matter. PMID- 26951607 TI - Measuring Attitudes About Hate: Development of the Hate Crime Beliefs Scale. AB - Employing the federal Hate Crimes Prevention Act (HCPA) of 2009 and other such legislation as a backdrop, the present study evaluated the nature of beliefs about hate-crime legislation, offenders, and victims. In addition, it investigated construct validity (i.e., political beliefs and prejudice) and predictive validity (i.e., blame attribution and sentencing recommendations). A total of 403 U.S. adults completed measures of prejudice and an initial pool of 50 items forming the proposed Hate Crime Beliefs Scale (HCBS). Participants were randomly assigned to read one of four hate-crime vignettes, which varied in regard to type of prejudice (racial-, sexual orientation-, transgender-, and religion-based prejudices) and then responded to blame and sentencing questions. Factor analyses of the HCBS resulted in four sub-scales: Negative Views (i.e., higher scores reflect negative views of legislation and minority group protection), Offender Punishment (i.e., higher scores suggest endorsement of greater punishment), Deterrence (i.e., greater scores denote support for hate crime legislation as a deterrent of more violence), and Victim Harm (i.e., higher scores reflect pro-victim attitudes). Greater pro-legislation and pro-victim beliefs were related to liberal political beliefs and less prejudicial attitudes, with some exceptions. Controlling for a number of demographic, situational, and attitudinal covariates, the Negative Views sub-scale displayed predictive utility, such that more negative views of legislation/minority group protection were associated with elevated victim blame, as well as lower perpetrator blame and sentencing recommendations. Results are discussed in the context of hate crime research and policy, with additional implications considered for trial strategy, modern prejudice, and blame attribution theory. PMID- 26951606 TI - Predictive performance of HAS-BLED risk score for long-term survival in patients with non-ST elevated myocardial infarction without atrial fibrillation. AB - BACKGROUND: Predictive value of the Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile international normalized ratio, Elderly, Drugs or alcohol use (HAS-BLED) score for clinical outcomes has been investigated in patients with and without atrial fibrillation. Many factors in the HAS-BLED model have been reported to be prognostic predictors in patients with post-myocardial infarction (MI). However, few studies have investigated the predictive value of HAS-BLED score on long-term survival in patients with post MI. METHODS: A total of 617 patients with non-ST elevation MI (NSTEMI) without atrial fibrillation were enrolled. The Thrombolysis In Myocardial Infarction (TIMI), Global Registry of Acute Coronary Events (GRACE), Can Rapid Risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA guidelines (CRUSADE), and HAS-BLED risk scores were calculated for each patient. RESULTS: The C-statistics of TIMI, GRACE, CRUSADE, and HAS-BLED scores for 3-year survival were 0.658, 0.749, 0.756, and 0.765, respectively. For 3-year survival prediction, GRACE, CRUSADE, and HAS-BLED scores, respectively demonstrated superior performance than TIMI score and there was no significant difference between these three scores (GRACE vs. TIMI: z=1.615, p=0.027; CRUSADE vs. TIMI: z=1.371, p=0.043; HAS-BLED vs. TIMI: z=1.899, p=0.014; CRUSADE vs. GRACE: z=0.078, p=0.234; HAS-BLED vs. GRACE: z=0.435, p=0.166; HAS-BLED vs. CRUSADE: z=0.353, p=0.181). Multivariate analysis showed left ventricular ejection fraction <40%, old age, stroke history, bleeding history, and abnormal renal and liver function were independent predictors for 3 year mortality. CONCLUSIONS: HAS-BLED scoring system is similar to the GRACE and CRUSADE systems but better than TIMI system to predict long-term survival outcomes in patients with NSTEMI without atrial fibrillation. However, HAS-BLED score is easier to calculate than GRACE and CRUSADE scores. PMID- 26951605 TI - HIV-1-Related Cardiovascular Disease Is Associated With Chronic Inflammation, Frequent Pericardial Effusions, and Probable Myocardial Edema. AB - BACKGROUND: Patients with treated HIV infection have clear survival benefits although with increased cardiac morbidity and mortality. Mechanisms of heart disease may be partly related to untreated chronic inflammation. Cardiovascular magnetic resonance imaging allows a comprehensive assessment of myocardial structure, function, and tissue characterization. We investigated, using cardiovascular magnetic resonance, subclinical inflammation and myocardial disease in asymptomatic HIV-infected individuals. METHODS AND RESULTS: Myocardial structure and function were assessed using cardiovascular magnetic resonance at 1.5-T in treated HIV-infected individuals without known cardiovascular disease (n=103; mean age, 45+/-10 years) compared with healthy controls (n=92; mean age, 44+/-10 years). Assessments included left ventricular volumes, ejection fraction, strain, regional systolic, diastolic function, native T1 mapping, edema, and gadolinium enhancement. Compared with controls, subjects with HIV infection had 6% lower left ventricular ejection fraction (P<0.001), 7% higher myocardial mass (P=0.02), 29% lower peak diastolic strain rate (P<0.001), 4% higher short-tau inversion recovery values (P=0.02), and higher native T1 values (969 versus 956 ms in controls; P=0.01). Pericardial effusions and myocardial fibrosis were 3 and 4* more common, respectively, in subjects with HIV infection (both P<0.001). CONCLUSIONS: Treated HIV infection is associated with changes in myocardial structure and function in addition to higher rates of subclinical myocardial edema and fibrosis and frequent pericardial effusions. Chronic systemic inflammation in HIV, which involves the myocardium and pericardium, may explain the high rate of myocardial fibrosis and increased cardiac dysfunction in people living with HIV. PMID- 26951608 TI - Solo and Multi-Offenders Who Commit Stranger Kidnapping: An Assessment of Factors That Correlate With Violent Events. AB - Research has demonstrated that co-offending dyads and groups often use more violence than individual offenders. Despite the attention given to co-offending by the research community, kidnapping remains understudied. Stranger kidnappings are more likely than non-stranger kidnappings to involve the use of a weapon. Public fear of stranger kidnapping warrants further examination of this specific crime, including differences between those committed by solo and multi-offender groups. The current study uses National Incident-Based Reporting System (NIBRS) data to assess differences in use of violence among 4,912 stranger kidnappings by solo offenders and multi-offender groups using cross-tabulations, ordinal regression, and logistic regression. The results indicate that violent factors are significantly more common in multi-offender incidents, and that multi offender groups have fewer arrests than solo offenders. The implications of these findings are discussed. PMID- 26951609 TI - Pornography, Sexual Coercion and Abuse and Sexting in Young People's Intimate Relationships: A European Study. AB - New technology has made pornography increasingly accessible to young people, and a growing evidence base has identified a relationship between viewing pornography and violent or abusive behavior in young men. This article reports findings from a large survey of 4,564 young people aged 14 to 17 in five European countries which illuminate the relationship between regular viewing of online pornography, sexual coercion and abuse and the sending and receiving of sexual images and messages, known as "sexting." In addition to the survey, which was completed in schools, 91 interviews were undertaken with young people who had direct experience of interpersonal violence and abuse in their own relationships. Rates for regularly viewing online pornography were very much higher among boys and most had chosen to watch pornography. Boys' perpetration of sexual coercion and abuse was significantly associated with regular viewing of online pornography. Viewing online pornography was also associated with a significantly increased probability of having sent sexual images/messages for boys in nearly all countries. In addition, boys who regularly watched online pornography were significantly more likely to hold negative gender attitudes. The qualitative interviews illustrated that, although sexting is normalized and perceived positively by most young people, it has the potential to reproduce sexist features of pornography such as control and humiliation. Sex and relationships education should aim to promote a critical understanding of pornography among young people that recognizes its abusive and gendered values. PMID- 26951611 TI - Chronic variable stress prevents amphetamine-elicited 50-kHz calls in rats with low positive affectivity. AB - The relationship between stress response and positive affective states is thought to be bidirectional: whilst stress can lead to a blunted hedonic response, positive affect reduces the negative effects of stress. We have previously shown that persistently high positive affectivity as measured by 50-kHz ultrasonic vocalizations (USVs) is protective against chronic variable stress (CVS). The present study examined the effect of CVS on 50-kHz USVs elicited by amphetamine administration, simultaneously considering the stable inter-individual differences in positive affectivity. Forty juvenile male Wistar rats were categorised as of high (HC) or low (LC) positive affectivity based on their 50 kHz USV response to imitation of rough-and-tumble play ('tickling'). As adults, the rats were subjected to four weeks of CVS, after which D-amphetamine was administered in five daily doses followed by a challenge dose (all 1mg/kg IP) nine days later. CVS reduced sucrose preference in LC-rats only. After CVS, amphetamine-elicited 50-kHz USVs were significantly reduced in LC-rats, the effect of stress in HC-rats being smaller and less consistent. In previously stressed and amphetamine-treated LC-rats, locomotor response to amphetamine was attenuated. In stressed LC-rats, DOPAC levels and dopamine turnover were increased in striatum after amphetamine treatment, and dopamine D1 receptor levels were upregulated in nucleus accumbens. LC-rats had lower isoleucine levels in frontal cortex. These results show that stress-related changes in response to amphetamine are dependent on inter-individual differences in positive affectivity both at neurochemical and behavioural levels, and further support the notion of higher vulnerability of animals with low positive affect. PMID- 26951613 TI - From Talking Heads to Talking Students: Driving the paradigm shift in science education. PMID- 26951610 TI - Toxic gain of function from mutant FUS protein is crucial to trigger cell autonomous motor neuron loss. AB - FUS is an RNA-binding protein involved in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Cytoplasmic FUS-containing aggregates are often associated with concomitant loss of nuclear FUS Whether loss of nuclear FUS function, gain of a cytoplasmic function, or a combination of both lead to neurodegeneration remains elusive. To address this question, we generated knockin mice expressing mislocalized cytoplasmic FUS and complete FUS knockout mice. Both mouse models display similar perinatal lethality with respiratory insufficiency, reduced body weight and length, and largely similar alterations in gene expression and mRNA splicing patterns, indicating that mislocalized FUS results in loss of its normal function. However, FUS knockin mice, but not FUS knockout mice, display reduced motor neuron numbers at birth, associated with enhanced motor neuron apoptosis, which can be rescued by cell-specific CRE-mediated expression of wild-type FUS within motor neurons. Together, our findings indicate that cytoplasmic FUS mislocalization not only leads to nuclear loss of function, but also triggers motor neuron death through a toxic gain of function within motor neurons. PMID- 26951614 TI - Two cases of systemic mantle cell lymphoma involving the skin. AB - Mantle cell lymphoma (MCL) is a form of non-Hodgkin lymphoma that rarely affects skin. Cutaneous involvement is non-specific but usually indicates widespread disease. Herein we present two cases of MCL with secondary skin involvement. One case presented as an acneiform eruption on the face and had aberrant expression of bcl-2 and bcl-6 with weak CD5 expression. The second presented with multiple tumors on the abdomen and thighs. In both cases expression of Cyclin-D1 by the tumor cells was seen. Both patients died shortly after the diagnosis was established. PMID- 26951615 TI - Evaluation of Bleeding Events Requiring Hospitalization in Patients With Atrial Fibrillation Receiving Dabigatran, Warfarin, or Antiplatelet Therapy. AB - OBJECTIVE: To determine the incidence and severity of bleeding events requiring hospitalization among patients with atrial fibrillation (AF) receiving anticoagulants (dabigatran or warfarin) or antiplatelet agents (eg, aspirin and clopidogrel). METHODS: This was a single-center, retrospective cohort study involving 1494 patients with AF hospitalized from November 1, 2010, to November 1, 2011, with prior warfarin, dabigatran, or antiplatelet therapy. RESULTS: Overall bleeding events in the dabigatran group compared to the warfarin group were 24% and 12%, respectively ( P = .004). Of these events, individually, there were no significant differences in major (56% vs 58%, P = .88), life-threatening (25% vs 36%, P = .38), or minor bleeding (44% vs 42%, P = .06). Gastrointestinal (GI) bleeding occurred more in the dabigatran group compared to the warfarin group ( P = .02). Intracranial bleeding occurred in 15% of patients in the warfarin group and did not occur at all in the dabigatran group. Warfarin patients had significantly more overall bleeding events compared to antiplatelet therapy ( P < .001), with an increasing trend seen in major bleeding ( P = .06). GI bleeding, however, favored the warfarin group over the antiplatelet group (48% vs 73%, P = .04). CONCLUSION: Anticoagulation with dabigatran was associated with an overall increased occurrence of bleeding requiring hospital admission compared to warfarin. GI bleeding was more prevalent with dabigatran and antiplatelets than with warfarin. There were more intracranial hemorrhages seen in the warfarin group. PMID- 26951617 TI - Dermpath Quiz: Which alopecia does the patient have? PMID- 26951612 TI - Bioinformatic analyses in early host response to Porcine Reproductive and Respiratory Syndrome virus (PRRSV) reveals pathway differences between pigs with alternate genotypes for a major host response QTL. AB - BACKGROUND: A region on Sus scrofa chromosome 4 (SSC4) surrounding single nucleotide polymorphism (SNP) marker WUR10000125 (WUR) has been reported to be strongly associated with both weight gain and serum viremia in pigs after infection with PRRS virus (PRRSV). A proposed causal mutation in the guanylate binding protein 5 gene (GBP5) is predicted to truncate the encoded protein. To investigate transcriptional differences between WUR genotypes in early host response to PRRSV infection, an RNA-seq experiment was performed on globin depleted whole blood RNA collected on 0, 4, 7, 10 and 14 days post-infection (dpi) from eight littermate pairs with one AB (favorable) and one AA (unfavorable) WUR genotype animal per litter. RESULTS: Gene Ontology (GO) enrichment analysis of transcripts that were differentially expressed (DE) between dpi across both genotypes revealed an inflammatory response for all dpi when compared to day 0. However, at the early time points of 4 and 7dpi, several GO terms had higher enrichment scores compared to later dpi, including inflammatory response (p < 10(-7)), specifically regulation of NFkappaB (p < 0.01), cytokine, and chemokine activity (p < 0.01). At 10 and 14dpi, GO term enrichment indicated a switch to DNA damage response, cell cycle checkpoints, and DNA replication. Few transcripts were DE between WUR genotypes on individual dpi or averaged over all dpi, and little enrichment of any GO term was found. However, there were differences in expression patterns over time between AA and AB animals, which was confirmed by genotype-specific expression patterns of several modules that were identified in weighted gene co-expression network analyses (WGCNA). Minor differences between AA and AB animals were observed in immune response and DNA damage response (p = 0.64 and p = 0.11, respectively), but a significant effect between genotypes pointed to a difference in ion transport/homeostasis and the participation of G-coupled protein receptors (p = 8e-4), which was reinforced by results from regulatory and phenotypic impact factor analyses between genotypes. CONCLUSION: We propose these pathway differences between WUR genotypes are the result of the inability of the truncated GBP5 of the AA genotyped pigs to inhibit viral entry and replication as quickly as the intact GBP5 protein of the AB genotyped pigs. PMID- 26951616 TI - Lampreys as Diverse Model Organisms in the Genomics Era. AB - Lampreys, one of the two surviving groups of ancient vertebrates, have become important models for study in diverse fields of biology. Lampreys (of which there are approximately 40 species) are being studied, for example, (a) to control pest sea lamprey in the North American Great Lakes and to restore declining populations of native species elsewhere; (b) in biomedical research, focusing particularly on the regenerative capability of lampreys; and (c) by developmental biologists studying the evolution of key vertebrate characters. Although a lack of genetic resources has hindered research on the mechanisms regulating many aspects of lamprey life history and development, formerly intractable questions are now amenable to investigation following the recent publication of the sea lamprey genome. Here, we provide an overview of the ways in which genomic tools are currently being deployed to tackle diverse research questions and suggest several areas that may benefit from the availability of the sea lamprey genome. PMID- 26951618 TI - Embolic Protection Devices in Transcatheter Aortic Valve Replacement. AB - The initially reported periprocedural neurological events rates associated with transcatheter aortic valve replacement raised concerns that ultimately led to the development and to the clinical research of novel embolic protection devices. Although the reduction of clinical stroke is a desired goal, the current research design of embolic protection devices focuses on surrogate markers of the clinical disease, primarily on silent central nervous system lesions observed in postprocedural diffuse-weighted magnetic resonance imaging and cognitive function testing. As the mere presence of particulate debris in brain matter may not correlate with the extent of brain injury, cognitive function, or quality of life, the clinical significance of embolic protection devices has yet to be determined, and interpretation of study results with regard to real-life clinical use should be viewed accordingly. The purpose of this article is to provide an overview of the updated ongoing clinical research on embolic protection devices and present its major caveats. PMID- 26951619 TI - Letter by Pacheco et al Regarding Article, "Proton Pump Inhibitors, Platelet Reactivity, and Cardiovascular Outcomes After Drug-Eluting Stents in Clopidogrel Treated Patients: The ADAPT-DES Study". PMID- 26951620 TI - Response to Letter Regarding Article, "Proton Pump Inhibitors, Platelet Reactivity, and Cardiovascular Outcomes After Drug-Eluting Stents in Clopidogrel Treated Patients: The ADAPT-DES Study". PMID- 26951621 TI - Identification of stable quantitative trait loci (QTLs) for fiber quality traits across multiple environments in Gossypium hirsutum recombinant inbred line population. AB - BACKGROUND: The identification of quantitative trait loci (QTLs) that are stable and consistent across multiple environments and populations plays an essential role in marker-assisted selection (MAS). In the present study, we used 28,861 simple sequence repeat (SSR) markers, which included 12,560 Gossypium raimondii (D genome) sequence-based SSR markers to identify polymorphism between two upland cotton strains 0-153 and sGK9708. A total of 851 polymorphic primers were finally selected and used to genotype 196 recombinant inbred lines (RIL) derived from a cross between 0 and 153 and sGK9708 and used to construct a linkage map. The RIL population was evaluated for fiber quality traits in six locations in China for five years. Stable QTLs identified in this intraspecific cross could be used in future cotton breeding program and with fewer obstacles. RESULTS: The map covered a distance of 4,110 cM, which represents about 93.2 % of the upland cotton genome, and with an average distance of 5.2 cM between adjacent markers. We identified 165 QTLs for fiber quality traits, of which 47 QTLs were determined to be stable across multiple environments. Most of these QTLs aggregated into clusters with two or more traits. A total of 30 QTL clusters were identified which consisted of 103 QTLs. Sixteen clusters in the At sub-genome comprised 44 QTLs, whereas 14 clusters in the Dt sub-genome that included 59 QTLs for fiber quality were identified. Four chromosomes, including chromosome 4 (c4), c7, c14, and c25 were rich in clusters harboring 5, 4, 5, and 6 clusters respectively. A meta-analysis was performed using Biomercator V4.2 to integrate QTLs from 11 environmental datasets on the RIL populations of the above mentioned parents and previous QTL reports. Among the 165 identified QTLs, 90 were identified as common QTLs, whereas the remaining 75 QTLs were determined to be novel QTLs. The broad sense heritability estimates of fiber quality traits were high for fiber length (0.93), fiber strength (0.92), fiber micronaire (0.85), and fiber uniformity (0.80), but low for fiber elongation (0.27). Meta-clusters on c4, c7, c14 and c25 were identified as stable QTL clusters and were considered more valuable in MAS for the improvement of fiber quality of upland cotton. CONCLUSION: Multiple environmental evaluations of an intraspecific RIL population were conducted to identify stable QTLs. Meta-QTL analyses identified a common chromosomal region that plays an important role in fiber development. Therefore, QTLs identified in the present study are an ideal candidate for MAS in cotton breeding programs to improve fiber quality. PMID- 26951625 TI - Ocular toxicities of MEK inhibitors and other targeted therapies. AB - Many classes of anticancer therapy, including chemotherapeutic agents, hormonal and molecular targeted treatments, can produce ocular toxicity. Novel agents that target different cellular pathways have been related to a wide spectrum of ophthalmologic toxicities that can range from mild to severe, and include conjunctivitis, blurred vision, keratitis and optic neuritis, among others. Special attention has been drawn to the inhibitors of the MEK signaling pathway, due to their sine qua non ocular toxicity, defined as MEK retinopathy and described as symmetrical bilateral disease that develops in a time-dependent and dose-dependent manner. In this review, we discuss ophthalmologic toxicities associated with molecular targeted therapies, with particular focus on MEK retinopathy, including its nomenclature, incidence, symptoms and management. PMID- 26951626 TI - Insertion of central venous catheters (CVCs): any changes in the past 10 years? PMID- 26951623 TI - Lactation opposes pappalysin-1-driven pregnancy-associated breast cancer. AB - Pregnancy is associated with a transient increase in risk for breast cancer. However, the mechanism underlying pregnancy-associated breast cancer (PABC) is poorly understood. Here, we identify the protease pappalysin-1 (PAPP-A) as a pregnancy-dependent oncogene. Transgenic expression of PAPP-A in the mouse mammary gland during pregnancy and involution promotes the deposition of collagen. We demonstrate that collagen facilitates the proteolysis of IGFBP-4 and IGFBP-5 by PAPP-A, resulting in increased proliferative signaling during gestation and a delayed involution. However, while studying the effect of lactation, we found that although PAPP-A transgenic mice lactating for an extended period of time do not develop mammary tumors, those that lactate for a short period develop mammary tumors characterized by a tumor-associated collagen signature (TACS-3). Mechanistically, we found that the protective effect of lactation is associated with the expression of inhibitors of PAPP-A, STC1, and STC2. Collectively, these results identify PAPP-A as a pregnancy-dependent oncogene while also showing that extended lactation is protective against PAPP-A mediated carcinogenesis. Our results offer the first mechanism that explains the link between breast cancer, pregnancy, and breastfeeding. PMID- 26951624 TI - Ambulatory Surgery Centers and Prices in Hospital Outpatient Departments. AB - Specialty providers claim to offer a new competitive benchmark for efficient delivery of health care. This article explores this view by examining evidence for price competition between ambulatory surgery centers (ASCs) and hospital outpatient departments (HOPDs). I studied the impact of ASC market presence on actual prices paid to HOPDs during 2007-2010 for four common surgical procedures that were performed in both provider types. For the procedures examined, HOPDs received payments from commercial insurers in the range of 3.25% to 5.15% lower for each additional ASC per 100,000 persons in a market. HOPDs may have less negotiating leverage with commercial insurers on price in markets with high ASC market penetration, resulting in relatively lower prices. PMID- 26951622 TI - Mitochondrial disorders in children: toward development of small-molecule treatment strategies. AB - This review presents our current understanding of the pathophysiology and potential treatment strategies with respect to mitochondrial disease in children. We focus on pathologies due to mutations in nuclear DNA-encoded structural and assembly factors of the mitochondrial oxidative phosphorylation (OXPHOS) system, with a particular emphasis on isolated mitochondrial complex I deficiency. Following a brief introduction into mitochondrial disease and OXPHOS function, an overview is provided of the diagnostic process in children with mitochondrial disorders. This includes the impact of whole-exome sequencing and relevance of cellular complementation studies. Next, we briefly present how OXPHOS mutations can affect cellular parameters, primarily based on studies in patient-derived fibroblasts, and how this information can be used for the rational design of small-molecule treatment strategies. Finally, we discuss clinical trial design and provide an overview of small molecules that are currently being developed for treatment of mitochondrial disease. PMID- 26951627 TI - Minimal residual disease-based effect and long-term outcome of first-line dasatinib combined with chemotherapy for adult Philadelphia chromosome-positive acute lymphoblastic leukemia. AB - BACKGROUND: The use of imatinib combined with chemotherapy has demonstrated improved outcome in adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL). However, a substantial proportion of patients continue to die as a result of disease progression. PATIENTS AND METHODS: We assessed the minimal residual disease (MRD)-based effect and long term outcome of first-line incorporation of dasatinib (100 mg once daily) into chemotherapy alternatively for adults with Ph-positive ALL. The primary end point was the major molecular response (MMR) rate by the end of the second dasatinib cycle. Patients with a donor proceeded to allogeneic stem cell transplantation (SCT) as early as possible. MRD monitoring was centrally evaluated by real-time quantitative polymerase chain reaction (4.5-log sensitivity) using bone marrow samples. RESULTS: Fifty-one patients (median age, 46 years) were enrolled and treated with this strategy. After the first dasatinib cycle, 50 patients (98.0%) achieved complete remission (CR). By the end of the second dasatinib cycle, 46 (93.9%) of 49 assessable patients had persistent CR, and 38 (77.6%) had MMR (32.7%) or undetectable MRD (44.9%). On the basis of the MRD kinetics by this time point, the numbers of early-stable, late, and poor molecular responders were 23 (46.9%), 15 (30.7%), and 11 (22.4%), respectively. Thirty-nine patients (76.5%) underwent allogeneic SCT in CR1. After a median follow-up of 54 months, the 4-year cumulative incidence of relapse and disease-free survival (DFS) rate for all patients were 30.0% and 52.0%, respectively, and the corresponding outcomes among those receiving allogeneic SCT in CR1 were 20.5% and 64.1%, respectively. Poor molecular responders had a higher risk of relapse and DFS than those of early-stable molecular responders. CONCLUSION: This dasatinib-based protocol was effective for achieving a good quality molecular response and durable DFS in adults with Ph-positive ALL. TRIAL REGISTRATION: clinicaltrials.gov, NCT01004497. PMID- 26951628 TI - Acute renal allograft rejection after immune checkpoint inhibitor therapy for metastatic melanoma. AB - Immune checkpoint inhibitors such as ipilimumab and nivolumab improve survival in patients with advanced melanoma and are increasingly available to clinicians for use in the clinic. Their safety in organ transplant recipients is not well defined but published case reports describing treatment with ipilimumab have not been complicated by graft rejection. No cases of anti-programmed cell death protein 1 administration are reported in this group. We describe a case of acute graft rejection in a kidney transplant recipient after treatment with nivolumab, after progression on ipilimumab. Potential factors increasing the risk of graft rejection in this case are discussed, in particular the contribution of nivolumab. PMID- 26951629 TI - Safety of the PD-1 antibody pembrolizumab in patients with high-grade adverse events under ipilimumab treatment. PMID- 26951630 TI - Pattern identification of biomedical images with time series: Contrasting THz pulse imaging with DCE-MRIs. AB - OBJECTIVE: We provide a survey of recent advances in biomedical image analysis and classification from emergent imaging modalities such as terahertz (THz) pulse imaging (TPI) and dynamic contrast-enhanced magnetic resonance images (DCE-MRIs) and identification of their underlining commonalities. METHODS: Both time and frequency domain signal pre-processing techniques are considered: noise removal, spectral analysis, principal component analysis (PCA) and wavelet transforms. Feature extraction and classification methods based on feature vectors using the above processing techniques are reviewed. A tensorial signal processing de noising framework suitable for spatiotemporal association between features in MRI is also discussed. VALIDATION: Examples where the proposed methodologies have been successful in classifying TPIs and DCE-MRIs are discussed. RESULTS: Identifying commonalities in the structure of such heterogeneous datasets potentially leads to a unified multi-channel signal processing framework for biomedical image analysis. CONCLUSION: The proposed complex valued classification methodology enables fusion of entire datasets from a sequence of spatial images taken at different time stamps; this is of interest from the viewpoint of inferring disease proliferation. The approach is also of interest for other emergent multi-channel biomedical imaging modalities and of relevance across the biomedical signal processing community. PMID- 26951632 TI - Adult-onset familial palmoplantar keratoderma: An uncommon presentation. PMID- 26951631 TI - Phylogenetic classification of yeasts and related taxa within Pucciniomycotina. AB - Most small genera containing yeast species in the Pucciniomycotina (Basidiomycota, Fungi) are monophyletic, whereas larger genera including Bensingtonia, Rhodosporidium, Rhodotorula, Sporidiobolus and Sporobolomyces are polyphyletic. With the implementation of the "One Fungus = One Name" nomenclatural principle these polyphyletic genera were revised. Nine genera, namely Bannoa, Cystobasidiopsis, Colacogloea, Kondoa, Erythrobasidium, Rhodotorula, Sporobolomyces, Sakaguchia and Sterigmatomyces, were emended to include anamorphic and teleomorphic species based on the results obtained by a multi-gene phylogenetic analysis, phylogenetic network analyses, branch length based methods, as well as morphological, physiological and biochemical comparisons. A new class Spiculogloeomycetes is proposed to accommodate the order Spiculogloeales. The new families Buckleyzymaceae with Buckleyzyma gen. nov., Chrysozymaceae with Chrysozyma gen. nov., Microsporomycetaceae with Microsporomyces gen. nov., Ruineniaceae with Ruinenia gen. nov., Symmetrosporaceae with Symmetrospora gen. nov., Colacogloeaceae and Sakaguchiaceae are proposed. The new genera Bannozyma, Buckleyzyma, Fellozyma, Hamamotoa, Hasegawazyma, Jianyunia, Rhodosporidiobolus, Oberwinklerozyma, Phenoliferia, Pseudobensingtonia, Pseudohyphozyma, Sampaiozyma, Slooffia, Spencerozyma, Trigonosporomyces, Udeniozyma, Vonarxula, Yamadamyces and Yunzhangia are proposed to accommodate species segregated from the genera Bensingtonia, Rhodosporidium, Rhodotorula, Sporidiobolus and Sporobolomyces. Ballistosporomyces is emended and reintroduced to include three Sporobolomyces species of the sasicola clade. A total of 111 new combinations are proposed in this study. PMID- 26951634 TI - Challenge for 3D culture technology: Application in carcinogenesis studies with human airway epithelial cells. AB - Lung cancer is still one of the major intractable diseases and we urgently need more efficient preventive and curative measures. Recent molecular studies have provided strong evidence that allows us to believe that classically well-known early airway lesions such as hyperplasia, metaplasia, dysplasia and carcinoma in situ are really precancerous lesions progressing toward cancer but not necessarily transient and reversible alteration. This suggests that adequate early control of the precancerous lesions may lead to improved prevention of lung cancer. This knowledge is encouraging in view of the imminent necessity for additional experimental systems to investigate the causal mechanisms of cancers directly in human cells and tissues. There are many questions with regard to various precancerous lesions of the airways. For example, should cells, before reaching a stage of invasive carcinoma, undergo all precancerous stages such as hyperplasia or metaplasia and dysplasia, or is there any shortcut to bypass one or more of the precancerous stages? For the study of such questions, the emerging 3-dimensional (3D) cell culture technology appears to provide an effective and valuable tool. Though a great challenge, it is expected that this in vitro technology will be rapidly and reliably improved to enable the cultures to be maintained in an in vivo-mimicking state of differentiation for much longer than a period of at best a few months, as is currently the case. With the help of a "causes recombination-Lox" (Cre-lox) technology, it has been possible to trace cells giving rise to specific lung tumor types. In this short review we have attempted to assess the future role of 3D technology in the study of lung carcinogenesis. PMID- 26951633 TI - Effects of drought and salt-stresses on gene expression in Caragana korshinskii seedlings revealed by RNA-seq. AB - BACKGROUND: Drought and soil salinity are major abiotic stresses. The mechanisms of stress tolerance have been studied extensively in model plants. Caragana korshinskii is characterized by high drought and salt tolerance in northwestern China; unique patterns of gene expression allow it to tolerate the stress imposed by dehydration and semi-desert saline soil. There have, however, been no reports on the differences between C. korshinskii and model plants in the mechanisms underlying their drought and salt tolerance and regulation of gene expression. RESULTS: Three sequencing libraries from drought and salt-treated whole-seedling- plants and the control were sequenced to investigate changes in the C. korshinskii transcriptome in response to drought and salt stresses. Of the 129,451 contigs, 70,662 (54.12 %) were annotated with gene descriptions, gene ontology (GO) terms, and metabolic pathways, with a cut-off E-value of 10(-5). These annotations included 56 GO terms, 148 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, and 25 Clusters of Orthologous Groups (COG). On comparison of the transcriptomes of the control, drought- and salt-treated plants, 1630 and 1521 contigs showed significant differences in transcript abundance under drought and salt stresses. Compared to the differentially expressed genes (DEGs) in drought- or salt-treated Arabidopsis in the database, 542 DEGs in drought-treated C. korshinskii and 529 DEGs in salt-treated samples were presumably unique to C. korshinskii. The transcription profiles revealed that genes related to transcription factors, protein kinases, and antioxidant enzymes are relevant to the tolerance of drought and salt stress in this species. The expression patterns of 38 randomly selected DEGs were confirmed by quantitative real-time PCR and were essentially consistent with the changes in transcript abundance identified by RNA-seq. CONCLUSIONS: The present study identified potential genes involved in drought and salt tolerance in C. korshinskii, as well as many DEGs uniquely expressed in drought- or salt-treated C. korshinskii samples compared to Arabidopsis. To our knowledge, this study is the first exploration of the C. korshinskii transcriptome under drought and salt conditions, and these results will facilitate the discovery of specific stress resistance-related genes in C. korshinskii, possibly leading to the development of novel plant cultivars through genetic engineering. PMID- 26951637 TI - Saucer Lesions in Leprosy: Anatomy of the Controversy. PMID- 26951636 TI - A Higher Cardiothoracic Ratio Is Associated with 2-Year Mortality after Hemodialysis Initiation. AB - A high cardiothoracic ratio (CTR) is indicative of a cardiac disorder. However, few reports have revealed an association between the CTR and mortality in patients starting hemodialysis (HD). METHODS: Patients with HD initiation (n = 387; mean age, 66.7 +/- 12.7 years) were divided into the following three groups according to their CTR at HD initiation: CTR <50%, 50% <= CTR < 55%, and CTR >=55%. Kaplan-Meier analysis was performed to compare 2-year all-cause mortality among these groups. Furthermore, we investigated the factors affecting their 2 year mortality using a Cox proportional hazard regression analysis. RESULTS: Sixty-five patients (17%) died within 2 years after HD initiation. Kaplan-Meier analysis showed that patients with CTR >=55% had a higher mortality rate than those in the other groups. Cox proportional hazard regression analysis was performed using parameters with p values <0.1 among these three groups [sex, age, presence or absence of ischemic heart disease, hemoglobin levels, serum albumin levels, CTR, body mass index (BMI)] and confounding factors [presence or absence of diabetes mellitus, and estimated glomerular filtration rate (eGFR)]. Age, eGFR, BMI, and CTR >=55% at HD initiation were identified as factors influencing 2-year mortality. CONCLUSION: CTR >55% is one of the most important independent factors to affect 2-year all-cause mortality. Thus, confirming the cardiac condition of patients at HD initiation with a CTR >55% may improve their survival. PMID- 26951635 TI - Circulating N-Linked Glycoprotein Acetyls and Longitudinal Mortality Risk. AB - RATIONALE: Circulating glycoprotein N-acetyl glucosamine residues have recently been associated with incident cardiovascular disease and diabetes mellitus. OBJECTIVE: Using a plasma glycan biosignature (GlycA) to identify circulating N acetyl glycan groups, we examined the longitudinal association between GlycA and mortality among initially healthy individuals. METHODS AND RESULTS: We quantified GlycA by 400 MHz (1)H nuclear magnetic resonance spectroscopy in 27,524 participants in the Women's Health Study (NCT00000479). The primary outcome was all-cause mortality. We replicated the findings in an independent cohort of 12,527 individuals in the Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial (NCT00239681). We also undertook secondary examination of cardiovascular disease and cancer mortality in the Women's Health Study. In the Women's Health Study, during 524,515 person years of follow-up (median, 20.5 years), there were 3523 deaths. Risk factor adjusted multivariable Cox proportional hazard ratio (95% confidence interval) per SD increment in GlycA for all-cause mortality was significantly increased at 5 years (1.21 [1.06-1.40]) and during maximal follow-up (1.14 [1.09-1.16]). Similar risk for all-cause mortality was observed in the replication cohort (1.33 [1.21-1.45]). In the Women's Health Study, risk of cardiovascular disease mortality was increased at 5 years (1.43 [1.05-1.95]) and during maximal follow up (1.15 [1.04-1.26]) and of cancer mortality at 5 years (1.23 [1.02-1.47]) and during maximal follow-up (1.08 [1.01-1.16]). Examination of correlations and mortality associations adjusted for high-sensitivity C-reactive protein, fibrinogen, and intercellular adhesion molecule-1, suggested that GlycA reflects summative risk related to multiple pathways of systemic inflammation. CONCLUSIONS: Among initially healthy individuals, elevated baseline circulating glycoprotein N-acetyl methyl groups were associated with longitudinal risk of all cause, cardiovascular, and cancer mortality. PMID- 26951639 TI - Reducing inappropriate testing in the diagnosis of the menopause and peri menopause. AB - The menopause should be diagnosed based on age, menstrual history and clinical symptoms, and as such, follicle stimulating hormone testing may be considered inappropriate when diagnosing the menopause or peri-menopause in women aged 45 and over. As part of a demand optimisation programme, the number of follicle stimulating hormone tests requested to diagnose the menopause in this age group was quantified and educational interventions were implemented to reduce inappropriate testing. The number of follicle stimulating hormone tests requested to diagnose the menopause in women aged 45 and over was successfully and sustainably reduced. PMID- 26951640 TI - Cervical cancer risk with the use of tumour necrosis factor inhibitors in rheumatoid arthritis: to worry or not to worry? PMID- 26951638 TI - Sororin loads to the synaptonemal complex central region independently of meiotic cohesin complexes. AB - The distribution and regulation of the cohesin complexes have been extensively studied during mitosis. However, the dynamics of their different regulators in vertebrate meiosis is largely unknown. In this work, we have analyzed the distribution of the regulatory factor Sororin during male mouse meiosis. Sororin is detected at the central region of the synaptonemal complex during prophase I, in contrast with the previously reported localization of other cohesin components in the lateral elements. This localization of Sororin depends on the transverse filaments protein SYCP1, but not on meiosis-specific cohesin subunits REC8 and SMC1beta. By late prophase I, Sororin accumulates at centromeres and remains there up to anaphase II The phosphatase activity of PP2A seems to be required for this accumulation. We hypothesize that Sororin function at the central region of the synaptonemal complex could be independent on meiotic cohesin complexes. In addition, we suggest that Sororin participates in the regulation of centromeric cohesion during meiosis in collaboration with SGO2-PP2A. PMID- 26951642 TI - Postoperative Endophthalmitis Caused by Staphylococcus haemolyticus following Femtosecond Cataract Surgery. AB - A 53-year-old Caucasian man underwent femtosecond cataract surgery and then presented with pain and hand motions vision 1 day following surgery. Anterior segment examination showed a 2-mm-layered hypopyon, a well-centered intraocular lens in the sulcus, and an obscured view to the fundus. B-scan ultrasonography showed significant vitritis and that the retina was attached. A tap and an injection of vancomycin 1 mg per 0.1 ml and of ceftazidime 2.25 mg per 0.1 ml were performed. The tap eventually yielded culture results positive for Staphylococcus haemolyticus, which was sensitive to vancomycin. We report a case of endophthalmitis that occurred on postoperative day 1 following complicated cataract surgery. This is an uncommon bacterium that is not widely reported in the literature as a cause of endophthalmitis in the postoperative period. We urge clinicians to consider S. haemolyticus as an offending agent, especially when the infection presents very early and aggressively in the postoperative period. PMID- 26951641 TI - Person-centredness in the care of older adults: a systematic review of questionnaire-based scales and their measurement properties. AB - BACKGROUND: Person-centredness is promoted as a central feature of the long-term care of older adults. Measures are needed to assist researchers, service planners and regulators in assessing this feature of quality. However, no systematic review exists to identify potential instruments and to provide a critical appraisal of their measurement properties. METHOD: A systematic review of measures of person-centredness was undertaken. Inclusion criteria restricted references to multi-item instruments designed for older adult services, or otherwise with measurement properties tested in an older adult population. A two stage critical appraisal was conducted. First, the methodological quality of included references was assessed using the COSMIN toolkit. Second, seven measurement properties were rated using widely-recognised thresholds of acceptability. These results were then synthesised to provide an overall appraisal of the strength of evidence for each measurement property for each instrument. RESULTS: Eleven measures tested in 22 references were included. Six instruments were designed principally for use in long-stay residential facilities, and four were for ambulatory hospital or clinic-based services. Only one measure was designed mainly for completion by users of home care services. No measure could be assessed across all seven measurement properties. Despite some instruments having promising measurement properties, this was consistently undermined by the poor methodological quality underpinning them. Testing of hypotheses to support construct validity was of particularly low quality, whilst measurement error was rarely assessed. Two measures were identified as having been the subject of the most rigorous testing. CONCLUSION: The review is unable to unequivocally recommend any measures of person-centredness for use in older adult care. Researchers are advised to improve methodological rigour when testing instruments. Efforts may be best focused on testing a narrower range of measurement properties but to a higher standard, and ensuring that translations to new languages are resisted until strong measurement properties are demonstrated in the original tongue. Limitations of the review include inevitable semantic and conceptual challenges involved in defining 'person-centredness'. The review protocol was registered with PROSPERO (ref: CRD42014005935). PMID- 26951643 TI - Is hip dysplasia a common deformity in skeletally mature patients with hereditary multiple exostoses? AB - BACKGROUND: Various deformities appear in hereditary multiple exostoses (HMEs). Deformities around the knee or ankle joints are easy to detect in this disease because such deformities are visible in appearance. However, deformities in the hip joints of skeletally mature patients are not well understood because their tumors are invisible. METHODS: To understand deformities around the hip joint in HMEs, we investigated 36 hip joints in 19 skeletally mature patients (12 males, 7 females). The mean age at last X-ray imaging investigation was 29.2 years (14.5 66.5 years). We evaluated the lesions of exostoses around the acetabulum and proximal femur, Wiberg's center-edge angle (CEA), neck-shaft angle (NSA), acetabular depth-width ratio (ADR), and Sharp's acetabular angle. RESULTS: No exostoses were present in four hips of three cases. Thirty-one hip joints had exostoses on the medial side of the femoral neck. Exostoses existed on the lateral side of the femoral neck in 16 hips. None of the patients had acetabuluar tumors. One patient experienced pain because of impingement between the acetabular rim and medial tumors of the femoral neck. The increase in NSA, which is an index of proximal femoral deformity, was common with a mean NSA of 147.3 degrees . Two indices of acetabular deformity, Sharp's angle and ADR, were within normal limits with a mean Sharp's angle of 41.3 degrees and mean ADR of 269. The average CEA was 29.9 degrees . CONCLUSIONS: Hip dysplasia is not necessarily common in skeletally mature patients with HMEs. To determine the possibility of hip dysplasia in skeletally immature patients with HMEs, ADR may be a useful reference index. PMID- 26951644 TI - The effect of provision of pain management advice on patient satisfaction with their pain management: a pilot, randomised, controlled trial (pain advice trial). AB - OBJECTIVE: We aimed to provide pain advice ('The treatment of pain is very important and be sure to tell the staff when you have pain') as an intervention and evaluate its effect upon patient satisfaction. The purpose of this pilot trial was to ensure the design and methods of a future trial are sound, practicable and feasible. METHOD: We undertook a pilot, randomised, controlled, clinical intervention trial in a single ED. The control arm received standard care. The intervention arm received standard care plus pain advice from an independent investigator. All patients and treating ED staff were blinded to patient enrolment. Patient satisfaction with their pain management (six-point ordinal scale) was measured 48 h post-ED discharge, by a blinded researcher. The primary outcome was satisfaction with pain management. RESULTS: Of the 280 and 275 patients randomised to the control and intervention arms, respectively, 196 and 215 had complete data, respectively. 77.6% (152/196) and 88.8% (191/215) of patients reported being provided with pain advice, respectively (difference 11.3% (95% CI 3.6 to 19.0)). The intervention was associated with absolute and relative increases in patient satisfaction of 6.3% and 14.2%, respectively. 91.3% (179/196) and 76.3% (164/215) of patients who were/were not very satisfied reported having received 'pain advice' (difference 15.0% (95% CI 7.6 to 22.5)). CONCLUSIONS: The intervention to provide pain advice resulted in a non significant increase in patient satisfaction. A larger multicentre trial is feasible and is recommended to further explore the effects of provision of pain advice. TRIAL REGISTRATION NUMBER: ACTRN12615000097549. PMID- 26951645 TI - Defining characteristics and risk indicators for diagnosing nursing home-acquired pneumonia and aspiration pneumonia in nursing home residents, using the electronically-modified Delphi Method. AB - BACKGROUND: In nursing home residents, it is not possible to distinguish pneumonia and aspiration pneumonia clinically. International literature reveals no consensus on which and how many characteristics and risk indicators must be present to diagnose (nursing home-acquired) pneumonia and aspiration pneumonia. The aim of this survey was to reach consensus among a panel of clinical medical experts in geriatrics and pulmonology about the characteristics required for diagnosing pneumonia, and about the risk indicators needed to consider the diagnosis aspiration pneumonia in nursing home residents with pneumonia. METHODS: Literature review and three expert-rating iterations using the electronically modified Delphi Method were carried out. After each expert rating iteration, data analysis was performed. Qualitative responses and additional (nursing home acquired) pneumonia characteristics which were mentioned in reply to structured open-ended questions were summarised, whilst similar responses were combined and these combinations were ordered by frequency in order to use them in the next iteration. Characteristics which failed to reach consensus were considered as inconclusive and eliminated. Consensus was reached when at least 70 % of the participants agreed. RESULTS: Literature review revealed 16 currently used common characteristics for diagnosing (nursing home-acquired) pneumonia. No consensus was reached about characteristics and the number of characteristics required for diagnosing (nursing home-acquired) pneumonia. However, 57 % agreed that dyspnea, fever, deterioration of general functioning, tachypnea and crepitation with auscultation are the most important characteristics and the responses by the participants suggested that two or three characteristics should be present. Subsequently, 80 % of the participants agreed on the risk indicators dysphagia, choking incident, (history of) tube feeding, neurological disease and cognitive impairment for considering the diagnosis aspiration pneumonia in nursing home residents with pneumonia. CONCLUSIONS: No final consensus could be reached about which and how many characteristics are required for diagnosing pneumonia in nursing home residents. However, the results indicated that dyspnea, fever, deterioration of general functioning, tachypnea and crepitation with auscultation are characteristics of some importance and that at least two or three characteristics should be present. With regard to considering aspiration pneumonia in nursing home residents with pneumonia, final consensus was reached about the risk indicators dysphagia, choking incident, (history of) tube feeding, neurological disease and cognitive impairment. PMID- 26951646 TI - Three-dimensional bioprinting of thick vascularized tissues. AB - The advancement of tissue and, ultimately, organ engineering requires the ability to pattern human tissues composed of cells, extracellular matrix, and vasculature with controlled microenvironments that can be sustained over prolonged time periods. To date, bioprinting methods have yielded thin tissues that only survive for short durations. To improve their physiological relevance, we report a method for bioprinting 3D cell-laden, vascularized tissues that exceed 1 cm in thickness and can be perfused on chip for long time periods (>6 wk). Specifically, we integrate parenchyma, stroma, and endothelium into a single thick tissue by coprinting multiple inks composed of human mesenchymal stem cells (hMSCs) and human neonatal dermal fibroblasts (hNDFs) within a customized extracellular matrix alongside embedded vasculature, which is subsequently lined with human umbilical vein endothelial cells (HUVECs). These thick vascularized tissues are actively perfused with growth factors to differentiate hMSCs toward an osteogenic lineage in situ. This longitudinal study of emergent biological phenomena in complex microenvironments represents a foundational step in human tissue generation. PMID- 26951648 TI - Shipwreck rates reveal Caribbean tropical cyclone response to past radiative forcing. AB - Assessing the impact of future climate change on North Atlantic tropical cyclone (TC) activity is of crucial societal importance, but the limited quantity and quality of observational records interferes with the skill of future TC projections. In particular, North Atlantic TC response to radiative forcing is poorly understood and creates the dominant source of uncertainty for twenty-first century projections. Here, we study TC variability in the Caribbean during the Maunder Minimum (MM; 1645-1715 CE), a period defined by the most severe reduction in solar irradiance in documented history (1610-present). For this purpose, we combine a documentary time series of Spanish shipwrecks in the Caribbean (1495 1825 CE) with a tree-growth suppression chronology from the Florida Keys (1707 2009 CE). We find a 75% reduction in decadal-scale Caribbean TC activity during the MM, which suggests modulation of the influence of reduced solar irradiance by the cumulative effect of cool North Atlantic sea surface temperatures, El Nino like conditions, and a negative phase of the North Atlantic Oscillation. Our results emphasize the need to enhance our understanding of the response of these oceanic and atmospheric circulation patterns to radiative forcing and climate change to improve the skill of future TC projections. PMID- 26951647 TI - Cell-to-cell movement of mitochondria in plants. AB - We report cell-to-cell movement of mitochondria through a graft junction. Mitochondrial movement was discovered in an experiment designed to select for chloroplast transfer from Nicotiana sylvestris into Nicotiana tabacum cells. The alloplasmic N. tabacum line we used carries Nicotiana undulata cytoplasmic genomes, and its flowers are male sterile due to the foreign mitochondrial genome. Thus, rare mitochondrial DNA transfer from N. sylvestris to N. tabacum could be recognized by restoration of fertile flower anatomy. Analyses of the mitochondrial genomes revealed extensive recombination, tentatively linking male sterility to orf293, a mitochondrial gene causing homeotic conversion of anthers into petals. Demonstrating cell-to-cell movement of mitochondria reconstructs the evolutionary process of horizontal mitochondrial DNA transfer and enables modification of the mitochondrial genome by DNA transmitted from a sexually incompatible species. Conversion of anthers into petals is a visual marker that can be useful for mitochondrial transformation. PMID- 26951650 TI - Correction for Raghavan et al., Shear stress-dependent regulation of apical endocytosis in renal proximal tubule cells mediated by primary cilia. PMID- 26951649 TI - Integrated bioprocess for conversion of gaseous substrates to liquids. AB - In the quest for inexpensive feedstocks for the cost-effective production of liquid fuels, we have examined gaseous substrates that could be made available at low cost and sufficiently large scale for industrial fuel production. Here we introduce a new bioconversion scheme that effectively converts syngas, generated from gasification of coal, natural gas, or biomass, into lipids that can be used for biodiesel production. We present an integrated conversion method comprising a two-stage system. In the first stage, an anaerobic bioreactor converts mixtures of gases of CO2 and CO or H2 to acetic acid, using the anaerobic acetogen Moorella thermoacetica The acetic acid product is fed as a substrate to a second bioreactor, where it is converted aerobically into lipids by an engineered oleaginous yeast, Yarrowia lipolytica We first describe the process carried out in each reactor and then present an integrated system that produces microbial oil, using synthesis gas as input. The integrated continuous bench-scale reactor system produced 18 g/L of C16-C18 triacylglycerides directly from synthesis gas, with an overall productivity of 0.19 g?L(-1)?h(-1) and a lipid content of 36%. Although suboptimal relative to the performance of the individual reactor components, the presented integrated system demonstrates the feasibility of substantial net fixation of carbon dioxide and conversion of gaseous feedstocks to lipids for biodiesel production. The system can be further optimized to approach the performance of its individual units so that it can be used for the economical conversion of waste gases from steel mills to valuable liquid fuels for transportation. PMID- 26951651 TI - Overcoming heterologous protein interdependency to optimize P450-mediated Taxol precursor synthesis in Escherichia coli. AB - Recent advances in metabolic engineering have demonstrated the potential to exploit biological chemistry for the synthesis of complex molecules. Much of the progress to date has leveraged increasingly precise genetic tools to control the transcription and translation of enzymes for superior biosynthetic pathway performance. However, applying these approaches and principles to the synthesis of more complex natural products will require a new set of tools for enabling various classes of metabolic chemistries (i.e., cyclization, oxygenation, glycosylation, and halogenation) in vivo. Of these diverse chemistries, oxygenation is one of the most challenging and pivotal for the synthesis of complex natural products. Here, using Taxol as a model system, we use nature's favored oxygenase, the cytochrome P450, to perform high-level oxygenation chemistry in Escherichia coli. An unexpected coupling of P450 expression and the expression of upstream pathway enzymes was discovered and identified as a key obstacle for functional oxidative chemistry. By optimizing P450 expression, reductase partner interactions, and N-terminal modifications, we achieved the highest reported titer of oxygenated taxanes (~570 +/- 45 mg/L) in E. coli. Altogether, this study establishes E. coli as a tractable host for P450 chemistry, highlights the potential magnitude of protein interdependency in the context of synthetic biology and metabolic engineering, and points to a promising future for the microbial synthesis of complex chemical entities. PMID- 26951652 TI - A mutualistic symbiosis between a parasitic mite and a pathogenic virus undermines honey bee immunity and health. AB - Honey bee colony losses are triggered by interacting stress factors consistently associated with high loads of parasites and/or pathogens. A wealth of biotic and abiotic stressors are involved in the induction of this complex multifactorial syndrome, with the parasitic mite Varroa destructor and the associated deformed wing virus (DWV) apparently playing key roles. The mechanistic basis underpinning this association and the evolutionary implications remain largely obscure. Here we narrow this research gap by demonstrating that DWV, vectored by the Varroa mite, adversely affects humoral and cellular immune responses by interfering with NF-kappaB signaling. This immunosuppressive effect of the viral pathogen enhances reproduction of the parasitic mite. Our experimental data uncover an unrecognized mutualistic symbiosis between Varroa and DWV, which perpetuates a loop of reciprocal stimulation with escalating negative effects on honey bee immunity and health. These results largely account for the remarkable importance of this mite virus interaction in the induction of honey bee colony losses. The discovery of this mutualistic association and the elucidation of the underlying regulatory mechanisms sets the stage for a more insightful analysis of how synergistic stress factors contribute to colony collapse, and for the development of new strategies to alleviate this problem. PMID- 26951654 TI - Reduced interdecadal variability of Atlantic Meridional Overturning Circulation under global warming. AB - Interdecadal variability of the Atlantic Meridional Overturning Circulation (AMOC IV) plays an important role in climate variation and has significant societal impacts. Past climate reconstruction indicates that AMOC-IV has likely undergone significant changes. Despite some previous studies, responses of AMOC-IV to global warming remain unclear, in particular regarding its amplitude and time scale. In this study, we analyze the responses of AMOC-IV under various scenarios of future global warming in multiple models and find that AMOC-IV becomes weaker and shorter with enhanced global warming. From the present climate condition to the strongest future warming scenario, on average, the major period of AMOC-IV is shortened from ~50 y to ~20 y, and the amplitude is reduced by ~60%. These reductions in period and amplitude of AMOC-IV are suggested to be associated with increased oceanic stratification under global warming and, in turn, the speedup of oceanic baroclinic Rossby waves. PMID- 26951655 TI - Infants ask for help when they know they don't know. AB - Uncertainty monitoring is a core property of metacognition, allowing individuals to adapt their decision-making strategies depending on the state of their knowledge. Although it has been argued that other animals share these metacognitive abilities, only humans seem to possess the ability to explicitly communicate their own uncertainty to others. It remains unknown whether this capacity is present early in development, or whether it emerges later with the ability to verbally report one's own mental states. Here, using a nonverbal memory-monitoring paradigm, we show that 20-month-olds can monitor and report their own uncertainty. Infants had to remember the location of a hidden toy before pointing to indicate where they wanted to recover it. In an experimental group, infants were given the possibility to ask for help through nonverbal communication when they had forgotten the toy location. Compared with a control group in which infants had no other option but to decide by themselves, infants given the opportunity to ask for help used this option strategically to improve their performance. Asking for help was used selectively to avoid making errors and to decline difficult choices. These results demonstrate that infants are able to successfully monitor their own uncertainty and share this information with others to fulfill their goals. PMID- 26951653 TI - Impaired imprinted X chromosome inactivation is responsible for the skewed sex ratio following in vitro fertilization. AB - Dynamic epigenetic reprogramming occurs during normal embryonic development at the preimplantation stage. Erroneous epigenetic modifications due to environmental perturbations such as manipulation and culture of embryos during in vitro fertilization (IVF) are linked to various short- or long-term consequences. Among these, the skewed sex ratio, an indicator of reproductive hazards, was reported in bovine and porcine embryos and even human IVF newborns. However, since the first case of sex skewing reported in 1991, the underlying mechanisms remain unclear. We reported herein that sex ratio is skewed in mouse IVF offspring, and this was a result of female-biased peri-implantation developmental defects that were originated from impaired imprinted X chromosome inactivation (iXCI) through reduced ring finger protein 12 (Rnf12)/X-inactive specific transcript (Xist) expression. Compensation of impaired iXCI by overexpression of Rnf12 to up-regulate Xist significantly rescued female-biased developmental defects and corrected sex ratio in IVF offspring. Moreover, supplementation of an epigenetic modulator retinoic acid in embryo culture medium up-regulated Rnf12/Xist expression, improved iXCI, and successfully redeemed the skewed sex ratio to nearly 50% in mouse IVF offspring. Thus, our data show that iXCI is one of the major epigenetic barriers for the developmental competence of female embryos during preimplantation stage, and targeting erroneous epigenetic modifications may provide a potential approach for preventing IVF-associated complications. PMID- 26951656 TI - Behavioral response inhibition and maturation of goal representation in prefrontal cortex after puberty. AB - Executive functions including behavioral response inhibition mature after puberty, in tandem with structural changes in the prefrontal cortex. Little is known about how activity of prefrontal neurons relates to this profound cognitive development. To examine this, we tracked neuronal responses of the prefrontal cortex in monkeys as they transitioned from puberty into adulthood and compared activity at different developmental stages. Performance of the antisaccade task greatly improved in this period. Among neural mechanisms that could facilitate it, reduction of stimulus-driven activity, increased saccadic activity, or enhanced representation of the opposing goal location, only the latter was evident in adulthood. Greatly accentuated in adults, this neural correlate of vector inversion may be a prerequisite to the formation of a motor plan to look away from the stimulus. Our results suggest that the prefrontal mechanisms that underlie mature performance on the antisaccade task are more strongly associated with forming an alternative plan of action than with suppressing the neural impact of the prepotent stimulus. PMID- 26951657 TI - Prediction, dynamics, and visualization of antigenic phenotypes of seasonal influenza viruses. AB - Human seasonal influenza viruses evolve rapidly, enabling the virus population to evade immunity and reinfect previously infected individuals. Antigenic properties are largely determined by the surface glycoprotein hemagglutinin (HA), and amino acid substitutions at exposed epitope sites in HA mediate loss of recognition by antibodies. Here, we show that antigenic differences measured through serological assay data are well described by a sum of antigenic changes along the path connecting viruses in a phylogenetic tree. This mapping onto the tree allows prediction of antigenicity from HA sequence data alone. The mapping can further be used to make predictions about the makeup of the future A(H3N2) seasonal influenza virus population, and we compare predictions between models with serological and sequence data. To make timely model output readily available, we developed a web browser-based application that visualizes antigenic data on a continuously updated phylogeny. PMID- 26951658 TI - PP2A methylation controls sensitivity and resistance to beta-amyloid-induced cognitive and electrophysiological impairments. AB - Elevated levels of the beta-amyloid peptide (Abeta) are thought to contribute to cognitive and behavioral impairments observed in Alzheimer's disease (AD). Protein phosphatase 2A (PP2A) participates in multiple molecular pathways implicated in AD, and its expression and activity are reduced in postmortem brains of AD patients. PP2A is regulated by protein methylation, and impaired PP2A methylation is thought to contribute to increased AD risk in hyperhomocysteinemic individuals. To examine further the link between PP2A and AD, we generated transgenic mice that overexpress the PP2A methylesterase, protein phosphatase methylesterase-1 (PME-1), or the PP2A methyltransferase, leucine carboxyl methyltransferase-1 (LCMT-1), and examined the sensitivity of these animals to behavioral and electrophysiological impairments caused by exogenous Abeta exposure. We found that PME-1 overexpression enhanced these impairments, whereas LCMT-1 overexpression protected against Abeta-induced impairments. Neither transgene affected Abeta production or the electrophysiological response to low concentrations of Abeta, suggesting that these manipulations selectively affect the pathological response to elevated Abeta levels. Together these data identify a molecular mechanism linking PP2A to the development of AD-related cognitive impairments that might be therapeutically exploited to target selectively the pathological effects caused by elevated Abeta levels in AD patients. PMID- 26951659 TI - Ablation of huntingtin in adult neurons is nondeleterious but its depletion in young mice causes acute pancreatitis. AB - The Huntington's disease (HD) protein, huntingtin (HTT), is essential for early development. Because suppressing the expression of mutant HTT is an important approach to treat the disease, we must first understand the normal function of Htt in adults versus younger animals. Using inducible Htt knockout mice, we found that Htt depletion does not lead to adult neurodegeneration or animal death at >4 mo of age, which was also verified by selectively depleting Htt in neurons. On the other hand, young Htt KO mice die at 2 mo of age of acute pancreatitis due to the degeneration of pancreatic acinar cells. Importantly, Htt interacts with the trypsin inhibitor, serine protease inhibitor Kazal-type 3 (Spink3), to inhibit activation of digestive enzymes in acinar cells in young mice, and transgenic HTT can rescue the early death of Htt KO mice. These findings point out age- and cell type-dependent vital functions of Htt and the safety of knocking down neuronal Htt expression in adult brains as a treatment. PMID- 26951660 TI - Oligonucleotide-directed mutagenesis screen to identify pathogenic Lynch syndrome associated MSH2 DNA mismatch repair gene variants. AB - Single-stranded DNA oligonucleotides can achieve targeted base-pair substitution with modest efficiency but high precision. We show that "oligo targeting" can be used effectively to study missense mutations in DNA mismatch repair (MMR) genes. Inherited inactivating mutations in DNA MMR genes are causative for the cancer predisposition Lynch syndrome (LS). Although overtly deleterious mutations in MMR genes can clearly be ascribed as the cause of LS, the functional implications of missense mutations are often unclear. We developed a genetic screen to determine the pathogenicity of these variants of uncertain significance (VUS), focusing on mutator S homolog 2 (MSH2). VUS were introduced into the endogenous Msh2 gene of mouse embryonic stem cells by oligo targeting. Subsequent selection for MMR deficient cells using the guanine analog 6-thioguanine allowed the detection of MMR-abrogating VUS. The screen was able to distinguish weak and strong pathogenic variants from polymorphisms and was used to investigate 59 Msh2 VUS. Nineteen of the 59 VUS were identified as pathogenic. Functional assays revealed that 14 of the 19 detected variants fully abrogated MMR activity and that five of the detected variants attenuated MMR activity. Implementation of the screen in clinical practice allows proper counseling of mutation carriers and treatment of their tumors. PMID- 26951661 TI - Focal expression of mutant huntingtin in the songbird basal ganglia disrupts cortico-basal ganglia networks and vocal sequences. AB - The basal ganglia (BG) promote complex sequential movements by helping to select elementary motor gestures appropriate to a given behavioral context. Indeed, Huntington's disease (HD), which causes striatal atrophy in the BG, is characterized by hyperkinesia and chorea. How striatal cell loss alters activity in the BG and downstream motor cortical regions to cause these disorganized movements remains unknown. Here, we show that expressing the genetic mutation that causes HD in a song-related region of the songbird BG destabilizes syllable sequences and increases overall vocal activity, but leave the structure of individual syllables intact. These behavioral changes are paralleled by the selective loss of striatal neurons and reduction of inhibitory synapses on pallidal neurons that serve as the BG output. Chronic recordings in singing birds revealed disrupted temporal patterns of activity in pallidal neurons and downstream cortical neurons. Moreover, reversible inactivation of the cortical neurons rescued the disorganized vocal sequences in transfected birds. These findings shed light on a key role of temporal patterns of cortico-BG activity in the regulation of complex motor sequences and show how a genetic mutation alters cortico-BG networks to cause disorganized movements. PMID- 26951664 TI - Computer vision cracks the leaf code. AB - Understanding the extremely variable, complex shape and venation characters of angiosperm leaves is one of the most challenging problems in botany. Machine learning offers opportunities to analyze large numbers of specimens, to discover novel leaf features of angiosperm clades that may have phylogenetic significance, and to use those characters to classify unknowns. Previous computer vision approaches have primarily focused on leaf identification at the species level. It remains an open question whether learning and classification are possible among major evolutionary groups such as families and orders, which usually contain hundreds to thousands of species each and exhibit many times the foliar variation of individual species. Here, we tested whether a computer vision algorithm could use a database of 7,597 leaf images from 2,001 genera to learn features of botanical families and orders, then classify novel images. The images are of cleared leaves, specimens that are chemically bleached, then stained to reveal venation. Machine learning was used to learn a codebook of visual elements representing leaf shape and venation patterns. The resulting automated system learned to classify images into families and orders with a success rate many times greater than chance. Of direct botanical interest, the responses of diagnostic features can be visualized on leaf images as heat maps, which are likely to prompt recognition and evolutionary interpretation of a wealth of novel morphological characters. With assistance from computer vision, leaves are poised to make numerous new contributions to systematic and paleobotanical studies. PMID- 26951662 TI - Conformational dynamics of a membrane protein chaperone enables spatially regulated substrate capture and release. AB - Membrane protein biogenesis poses enormous challenges to cellular protein homeostasis and requires effective molecular chaperones. Compared with chaperones that promote soluble protein folding, membrane protein chaperones require tight spatiotemporal coordination of their substrate binding and release cycles. Here we define the chaperone cycle for cpSRP43, which protects the largest family of membrane proteins, the light harvesting chlorophyll a/b-binding proteins (LHCPs), during their delivery. Biochemical and NMR analyses demonstrate that cpSRP43 samples three distinct conformations. The stromal factor cpSRP54 drives cpSRP43 to the active state, allowing it to tightly bind substrate in the aqueous compartment. Bidentate interactions with the Alb3 translocase drive cpSRP43 to a partially inactive state, triggering selective release of LHCP's transmembrane domains in a productive unloading complex at the membrane. Our work demonstrates how the intrinsic conformational dynamics of a chaperone enables spatially coordinated substrate capture and release, which may be general to other ATP independent chaperone systems. PMID- 26951663 TI - Use of the Fluidigm C1 platform for RNA sequencing of single mouse pancreatic islet cells. AB - This study provides an assessment of the Fluidigm C1 platform for RNA sequencing of single mouse pancreatic islet cells. The system combines microfluidic technology and nanoliter-scale reactions. We sequenced 622 cells, allowing identification of 341 islet cells with high-quality gene expression profiles. The cells clustered into populations of alpha-cells (5%), beta-cells (92%), delta cells (1%), and pancreatic polypeptide cells (2%). We identified cell-type specific transcription factors and pathways primarily involved in nutrient sensing and oxidation and cell signaling. Unexpectedly, 281 cells had to be removed from the analysis due to low viability, low sequencing quality, or contamination resulting in the detection of more than one islet hormone. Collectively, we provide a resource for identification of high-quality gene expression datasets to help expand insights into genes and pathways characterizing islet cell types. We reveal limitations in the C1 Fluidigm cell capture process resulting in contaminated cells with altered gene expression patterns. This calls for caution when interpreting single-cell transcriptomics data using the C1 Fluidigm system. PMID- 26951666 TI - Correction for Mullarky et al., Identification of a small molecule inhibitor of 3 phosphoglycerate dehydrogenase to target serine biosynthesis in cancers. PMID- 26951665 TI - Posttranslational regulation of coordinated enzyme activities in the Pup proteasome system. AB - The proper functioning of any biological system depends on the coordinated activity of its components. Regulation at the genetic level is, in many cases, effective in determining the cellular levels of system components. However, in cases where regulation at the genetic level is insufficient for attaining harmonic system function, posttranslational regulatory mechanisms are often used. Here, we uncover posttranslational regulatory mechanisms in the prokaryotic ubiquitin-like protein (Pup)-proteasome system (PPS), the bacterial equivalent of the eukaryotic ubiquitin-proteasome system. Pup, a ubiquitin analog, is conjugated to proteins through the activities of two enzymes, Dop (deamidase of Pup) and PafA (proteasome accessory factor A), the Pup ligase. As Dop also catalyzes depupylation, it was unclear how PPS function could be maintained without Dop and PafA canceling the activity of the other, and how the two activities of Dop are balanced. We report that tight Pup binding and the limited degree of Dop interaction with high-molecular-weight pupylated proteins results in preferred Pup deamidation over protein depupylation by this enzyme. Under starvation conditions, when accelerated protein pupylation is required, this bias is intensified by depletion of free Dop molecules, thereby minimizing the chance of depupylation. We also find that, in contrast to Dop, PafA presents a distinct preference for high-molecular-weight protein substrates. As such, PafA and Dop act in concert, rather than canceling each other's activity, to generate a high molecular-weight pupylome. This bias in pupylome molecular weight distribution is consistent with the proposed nutritional role of the PPS under starvation conditions. PMID- 26951667 TI - Morphogenesis of 3D vascular networks is regulated by tensile forces. AB - Understanding the forces controlling vascular network properties and morphology can enhance in vitro tissue vascularization and graft integration prospects. This work assessed the effect of uniaxial cell-induced and externally applied tensile forces on the morphology of vascular networks formed within fibroblast and endothelial cell-embedded 3D polymeric constructs. Force intensity correlated with network quality, as verified by inhibition of force and of angiogenesis related regulators. Tensile forces during vessel formation resulted in parallel vessel orientation under static stretching and diagonal orientation under cyclic stretching, supported by angiogenic factors secreted in response to each stretch protocol. Implantation of scaffolds bearing network orientations matching those of host abdominal muscle tissue improved graft integration and the mechanical properties of the implantation site, a critical factor in repair of defects in this area. This study demonstrates the regulatory role of forces in angiogenesis and their capacities in vessel structure manipulation, which can be exploited to improve scaffolds for tissue repair. PMID- 26951668 TI - Discovery of a spawning ground reveals diverse migration strategies in Atlantic bluefin tuna (Thunnus thynnus). AB - Atlantic bluefin tuna are a symbol of both the conflict between preservationist and utilitarian views of top ocean predators, and the struggle to reach international consensus on the management of migratory species. Currently, Atlantic bluefin tuna are managed as an early-maturing eastern stock, which spawns in the Mediterranean Sea, and a late-maturing western stock, which spawns in the Gulf of Mexico. However, electronic tagging studies show that many bluefin tuna, assumed to be of a mature size, do not visit either spawning ground during the spawning season. Whether these fish are spawning in an alternate location, skip-spawning, or not spawning until an older age affects how vulnerable this species is to anthropogenic stressors including exploitation. We use larval collections to demonstrate a bluefin tuna spawning ground in the Slope Sea, between the Gulf Stream and northeast United States continental shelf. We contend that western Atlantic bluefin tuna have a differential spawning migration, with larger individuals spawning in the Gulf of Mexico, and smaller individuals spawning in the Slope Sea. The current life history model, which assumes only Gulf of Mexico spawning, overestimates age at maturity for the western stock. Furthermore, individual tuna occupy both the Slope Sea and Mediterranean Sea in separate years, contrary to the prevailing view that individuals exhibit complete spawning-site fidelity. Overall, this complexity of spawning migrations questions whether there is complete independence in the dynamics of eastern and western Atlantic bluefin tuna and leads to lower estimates of the vulnerability of this species to exploitation and other anthropogenic stressors. PMID- 26951669 TI - Models for the a subunits of the Thermus thermophilus V/A-ATPase and Saccharomyces cerevisiae V-ATPase enzymes by cryo-EM and evolutionary covariance. AB - Rotary ATPases couple ATP synthesis or hydrolysis to proton translocation across a membrane. However, understanding proton translocation has been hampered by a lack of structural information for the membrane-embedded a subunit. The V/A ATPase from the eubacterium Thermus thermophilus is similar in structure to the eukaryotic V-ATPase but has a simpler subunit composition and functions in vivo to synthesize ATP rather than pump protons. We determined the T. thermophilus V/A ATPase structure by cryo-EM at 6.4 A resolution. Evolutionary covariance analysis allowed tracing of the a subunit sequence within the map, providing a complete model of the rotary ATPase. Comparing the membrane-embedded regions of the T. thermophilus V/A-ATPase and eukaryotic V-ATPase from Saccharomyces cerevisiae allowed identification of the alpha-helices that belong to the a subunit and revealed the existence of previously unknown subunits in the eukaryotic enzyme. Subsequent evolutionary covariance analysis enabled construction of a model of the a subunit in the S. cerevisae V-ATPase that explains numerous biochemical studies of that enzyme. Comparing the two a subunit structures determined here with a structure of the distantly related a subunit from the bovine F-type ATP synthase revealed a conserved pattern of residues, suggesting a common mechanism for proton transport in all rotary ATPases. PMID- 26951671 TI - Structure and mechanism of the phage T4 recombination mediator protein UvsY. AB - The UvsY recombination mediator protein is critical for efficient homologous recombination in bacteriophage T4 and is the functional analog of the eukaryotic Rad52 protein. During T4 homologous recombination, the UvsX recombinase has to compete with the prebound gp32 single-stranded binding protein for DNA-binding sites and UvsY stimulates this filament nucleation event. We report here the crystal structure of UvsY in four similar open-barrel heptameric assemblies and provide structural and biophysical insights into its function. The UvsY heptamer was confirmed in solution by centrifugation and light scattering, and thermodynamic analyses revealed that the UvsY-ssDNA interaction occurs within the assembly via two distinct binding modes. Using surface plasmon resonance, we also examined the binding of UvsY to both ssDNA and the ssDNA-gp32 complex. These analyses confirmed that ssDNA can bind UvsY and gp32 independently and also as a ternary complex. They also showed that residues located on the rim of the heptamer are required for optimal binding to ssDNA, thus identifying the putative ssDNA-binding surface. We propose a model in which UvsY promotes a helical ssDNA conformation that disfavors the binding of gp32 and initiates the assembly of the ssDNA-UvsX filament. PMID- 26951672 TI - Mutually repressive interaction between Brn1/2 and Rorb contributes to the establishment of neocortical layer 2/3 and layer 4. AB - Although several molecules have been shown to play important roles in subtype specification of neocortical neurons, the entire mechanism involved in the specification, in particular, of upper cortical plate (UCP) neurons still remains unclear. The UCP, which is responsible for intracortical connections in the neocortex, comprises histologically, functionally, and molecularly different layer 2/3 (L2/3) and L4. Here, we report the essential interactions between two types of transcription factors, Rorb (RAR-related orphan receptor beta) and Brn1/2 (Brain-1/Brain-2), for UCP specification. We found that Brn2 expression was detected in all upper layers in the immature UCP, but was subsequently restricted to L2/3, accompanied by up-regulation of Rorb in L4, suggesting demarcation of L2/3 and L4 during cortical maturation. Rorb indeed inhibited Brn2 expression and the expression of other L2/3 characteristics, revealed by ectopic expression and knockdown studies. Moreover, this inhibition occurred through direct binding of Rorb to the Brn2 locus. Conversely, Brn1/2 also inhibited Rorb expression and the expression of several L4 characteristics. Together, these results suggest that a mutually repressive mechanism exists between Brn1/2 and Rorb expression and that the established expression of Brn1/2 and Rorb further specifies those neurons into L2/3 and L4, respectively, during UCP maturation. PMID- 26951670 TI - Discovery and dissection of metabolic oscillations in the microaerobic nitric oxide response network of Escherichia coli. AB - The virulence of many pathogens depends upon their ability to cope with immune generated nitric oxide (NO.). In Escherichia coli, the major NO. detoxification systems are Hmp, an NO. dioxygenase (NOD), and NorV, an NO. reductase (NOR). It is well established that Hmp is the dominant system under aerobic conditions, whereas NorV dominates anaerobic conditions; however, the quantitative contributions of these systems under the physiologically relevant microaerobic regime remain ill defined. Here, we investigated NO. detoxification in environments ranging from 0 to 50 MUM O2, and discovered a regime in which E. coli NO. defenses were severely compromised, as well as conditions that exhibited oscillations in the concentration of NO.. Using an integrated computational and experimental approach, E. coli NO. detoxification was found to be extremely impaired at low O2 due to a combination of its inhibitory effects on NorV, Hmp, and translational activities, whereas oscillations were found to result from a kinetic competition for O2 between Hmp and respiratory cytochromes. Because at least 777 different bacterial species contain the genetic requirements of this stress response oscillator, we hypothesize that such oscillatory behavior could be a widespread phenomenon. In support of this hypothesis,Pseudomonas aeruginosa, whose respiratory and NO. response networks differ considerably from those of E. coli, was found to exhibit analogous oscillations in low O2 environments. This work provides insight into how bacterial NO. defenses function under the low O2 conditions that are likely to be encountered within host environments. PMID- 26951673 TI - Dynamic control of strand excision during human DNA mismatch repair. AB - Mismatch repair (MMR) is activated by evolutionarily conserved MutS homologs (MSH) and MutL homologs (MLH/PMS). MSH recognizes mismatched nucleotides and form extremely stable sliding clamps that may be bound by MLH/PMS to ultimately authorize strand-specific excision starting at a distant 3'- or 5'-DNA scission. The mechanical processes associated with a complete MMR reaction remain enigmatic. The purified human (Homo sapien or Hs) 5'-MMR excision reaction requires the HsMSH2-HsMSH6 heterodimer, the 5' -> 3' exonuclease HsEXOI, and the single-stranded binding heterotrimer HsRPA. The HsMLH1-HsPMS2 heterodimer substantially influences 5'-MMR excision in cell extracts but is not required in the purified system. Using real-time single-molecule imaging, we show that HsRPA or Escherichia coli EcSSB restricts HsEXOI excision activity on nicked or gapped DNA. HsMSH2-HsMSH6 activates HsEXOI by overcoming HsRPA/EcSSB inhibition and exploits multiple dynamic sliding clamps to increase tract length. Conversely, HsMLH1-HsPMS2 regulates tract length by controlling the number of excision complexes, providing a link to 5' MMR. PMID- 26951674 TI - Neuronal profilins in health and disease: Relevance for spine plasticity and Fragile X syndrome. AB - Learning and memory, to a large extent, depend on functional changes at synapses. Actin dynamics orchestrate the formation of synapses, as well as their stabilization, and the ability to undergo plastic changes. Hence, profilins are of key interest as they bind to G-actin and enhance actin polymerization. However, profilins also compete with actin nucleators, thereby restricting filament formation. Here, we provide evidence that the two brain isoforms, profilin1 (PFN1) and PFN2a, regulate spine actin dynamics in an opposing fashion, and that whereas both profilins are needed during synaptogenesis, only PFN2a is crucial for adult spine plasticity. This finding suggests that PFN1 is the juvenile isoform important during development, whereas PFN2a is mandatory for spine stability and plasticity in mature neurons. In line with this finding, only PFN1 levels are altered in the mouse model of the developmental neurological disorder Fragile X syndrome. This finding is of high relevance because Fragile X syndrome is the most common monogenetic cause for autism spectrum disorder. Indeed, the expression of recombinant profilins rescued the impairment in spinogenesis, a hallmark in Fragile X syndrome, thereby linking the regulation of actin dynamics to synapse development and possible dysfunction. PMID- 26951675 TI - Global characterization of in vivo enzyme catalytic rates and their correspondence to in vitro kcat measurements. AB - Turnover numbers, also known as kcat values, are fundamental properties of enzymes. However, kcat data are scarce and measured in vitro, thus may not faithfully represent the in vivo situation. A basic question that awaits elucidation is: how representative are kcat values for the maximal catalytic rates of enzymes in vivo? Here, we harness omics data to calculate kmax(vivo), the observed maximal catalytic rate of an enzyme inside cells. Comparison with kcat values from Escherichia coli, yields a correlation ofr(2)= 0.62 in log scale (p < 10(-10)), with a root mean square difference of 0.54 (3.5-fold in linear scale), indicating that in vivo and in vitro maximal rates generally concur. By accounting for the degree of saturation of enzymes and the backward flux dictated by thermodynamics, we further refine the correspondence between kmax(vivo) and kcat values. The approach we present here characterizes the quantitative relationship between enzymatic catalysis in vitro and in vivo and offers a high throughput method for extracting enzyme kinetic constants from omics data. PMID- 26951676 TI - Noise-driven growth rate gain in clonal cellular populations. AB - Cellular populations in both nature and the laboratory are composed of phenotypically heterogeneous individuals that compete with each other resulting in complex population dynamics. Predicting population growth characteristics based on knowledge of heterogeneous single-cell dynamics remains challenging. By observing groups of cells for hundreds of generations at single-cell resolution, we reveal that growth noise causes clonal populations of Escherichia coli to double faster than the mean doubling time of their constituent single cells across a broad set of balanced-growth conditions. We show that the population level growth rate gain as well as age structures of populations and of cell lineages in competition are predictable. Furthermore, we theoretically reveal that the growth rate gain can be linked with the relative entropy of lineage generation time distributions. Unexpectedly, we find an empirical linear relation between the means and the variances of generation times across conditions, which provides a general constraint on maximal growth rates. Together, these results demonstrate a fundamental benefit of noise for population growth, and identify a growth law that sets a "speed limit" for proliferation. PMID- 26951677 TI - Population-based 3D genome structure analysis reveals driving forces in spatial genome organization. AB - Conformation capture technologies (e.g., Hi-C) chart physical interactions between chromatin regions on a genome-wide scale. However, the structural variability of the genome between cells poses a great challenge to interpreting ensemble-averaged Hi-C data, particularly for long-range and interchromosomal interactions. Here, we present a probabilistic approach for deconvoluting Hi-C data into a model population of distinct diploid 3D genome structures, which facilitates the detection of chromatin interactions likely to co-occur in individual cells. Our approach incorporates the stochastic nature of chromosome conformations and allows a detailed analysis of alternative chromatin structure states. For example, we predict and experimentally confirm the presence of large centromere clusters with distinct chromosome compositions varying between individual cells. The stability of these clusters varies greatly with their chromosome identities. We show that these chromosome-specific clusters can play a key role in the overall chromosome positioning in the nucleus and stabilizing specific chromatin interactions. By explicitly considering genome structural variability, our population-based method provides an important tool for revealing novel insights into the key factors shaping the spatial genome organization. PMID- 26951678 TI - ppGpp negatively impacts ribosome assembly affecting growth and antimicrobial tolerance in Gram-positive bacteria. AB - The stringent response is a survival mechanism used by bacteria to deal with stress. It is coordinated by the nucleotides guanosine tetraphosphate and pentaphosphate [(p)ppGpp], which interact with target proteins to promote bacterial survival. Although this response has been well characterized in proteobacteria, very little is known about the effectors of this signaling system in Gram-positive species. Here, we report on the identification of seven target proteins for the stringent response nucleotides in the Gram-positive bacterium Staphylococcus aureus We demonstrate that the GTP synthesis enzymes HprT and Gmk bind with a high affinity, leading to an inhibition of GTP production. In addition, we identified five putative GTPases--RsgA, RbgA, Era, HflX, and ObgE- as (p)ppGpp target proteins. We show that RsgA, RbgA, Era, and HflX are functional GTPases and that their activity is promoted in the presence of ribosomes but strongly inhibited by the stringent response nucleotides. By characterizing the function of RsgA in vivo, we ascertain that this protein is involved in ribosome assembly, with an rsgA deletion strain, or a strain inactivated for GTPase activity, displaying decreased growth, a decrease in the amount of mature 70S ribosomes, and an increased level of tolerance to antimicrobials. We additionally demonstrate that the interaction of ppGpp with cellular GTPases is not unique to the staphylococci, as homologs from Bacillus subtilis and Enterococcus faecalis retain this ability. Taken together, this study reveals ribosome inactivation as a previously unidentified mechanism through which the stringent response functions in Gram-positive bacteria. PMID- 26951680 TI - Bacteroides fragilis type VI secretion systems use novel effector and immunity proteins to antagonize human gut Bacteroidales species. AB - Type VI secretion systems (T6SSs) are multiprotein complexes best studied in Gram negative pathogens where they have been shown to inhibit or kill prokaryotic or eukaryotic cells and are often important for virulence. We recently showed that T6SS loci are also widespread in symbiotic human gut bacteria of the order Bacteroidales, and that these T6SS loci segregate into three distinct genetic architectures (GA). GA1 and GA2 loci are present on conserved integrative conjugative elements (ICE) and are transferred and shared among diverse human gut Bacteroidales species. GA3 loci are not contained on conserved ICE and are confined to Bacteroides fragilis Unlike GA1 and GA2 T6SS loci, most GA3 loci do not encode identifiable effector and immunity proteins. Here, we studied GA3 T6SSs and show that they antagonize most human gut Bacteroidales strains analyzed, except for B. fragilis strains with the same T6SS locus. A combination of mutation analyses,trans-protection analyses, and in vitro competition assays, allowed us to identify novel effector and immunity proteins of GA3 loci. These proteins are not orthologous to known proteins, do not contain identified motifs, and most have numerous predicted transmembrane domains. Because the genes encoding effector and immunity proteins are contained in two variable regions of GA3 loci, GA3 T6SSs of the species B. fragilis are likely the source of numerous novel effector and immunity proteins. Importantly, we show that the GA3 T6SS of strain 638R is functional in the mammalian gut and provides a competitive advantage to this organism. PMID- 26951679 TI - Whole-exome sequencing identifies MST1R as a genetic susceptibility gene in nasopharyngeal carcinoma. AB - Multiple factors, including host genetics, environmental factors, and Epstein Barr virus (EBV) infection, contribute to nasopharyngeal carcinoma (NPC) development. To identify genetic susceptibility genes for NPC, a whole-exome sequencing (WES) study was performed in 161 NPC cases and 895 controls of Southern Chinese descent. The gene-based burden test discovered an association between macrophage-stimulating 1 receptor (MST1R) and NPC. We identified 13 independent cases carrying the MST1R pathogenic heterozygous germ-line variants, and 53.8% of these cases were diagnosed with NPC aged at or even younger than 20 y, indicating that MST1R germline variants are relevant to disease early-age onset (EAO) (age of <=20 y). In total, five MST1R missense variants were found in EAO cases but were rare in controls (EAO vs. control, 17.9% vs. 1.2%, P = 7.94 * 10(-12)). The validation study, including 2,160 cases and 2,433 controls, showed that the MST1R variant c.G917A:p.R306H is highly associated with NPC (odds ratio of 9.0). MST1R is predominantly expressed in the tissue-resident macrophages and is critical for innate immunity that protects organs from tissue damage and inflammation. Importantly, MST1R expression is detected in the ciliated epithelial cells in normal nasopharyngeal mucosa and plays a role in the cilia motility important for host defense. Although no somatic mutation of MST1R was identified in the sporadic NPC tumors, copy number alterations and promoter hypermethylation at MST1R were often observed. Our findings provide new insights into the pathogenesis of NPC by highlighting the involvement of the MST1R mediated signaling pathways. PMID- 26951681 TI - The source of high signal cooperativity in bacterial chemosensory arrays. AB - The Escherichia coli chemosensory system consists of large arrays of transmembrane chemoreceptors associated with a dedicated histidine kinase, CheA, and a linker protein, CheW, that couples CheA activity to receptor control. The kinase activity responses to receptor ligand occupancy changes can be highly cooperative, reflecting allosteric coupling of multiple CheA and receptor molecules. Recent structural and functional studies have led to a working model in which receptor core complexes, the minimal units of signaling, are linked into hexagonal arrays through a unique interface 2 interaction between CheW and the P5 domain of CheA. To test this array model, we constructed and characterized CheA and CheW mutants with amino acid replacements at key interface 2 residues. The mutant proteins proved defective in interface 2-specific in vivo cross-linking assays, and formed signaling complexes that were dispersed around the cell membrane rather than clustered at the cell poles as in wild type chemosensory arrays. Interface 2 mutants down-regulated CheA activity in response to attractant stimuli in vivo, but with much less cooperativity than the wild type. Moreover, mutant cells containing fluorophore-tagged receptors exhibited greater basal anisotropy that changed rapidly in response to attractant stimuli, consistent with facile changes in loosely packed receptors. We conclude that interface 2 lesions disrupt important network connections between core complexes, preventing receptors from operating in large, allosteric teams. This work confirms the critical role of interface 2 in organizing the chemosensory array, in directing the clustered array to the cell poles, and in producing its highly cooperative signaling properties. PMID- 26951684 TI - Sudden Appearance of Pin-point Hyperpigmented Macules: Dermoscopy Saves the Day. PMID- 26951683 TI - EBV noncoding RNA EBER2 interacts with host RNA-binding proteins to regulate viral gene expression. AB - Epstein-Barr virus (EBV) produces a highly abundant noncoding RNA called EBV encoded RNA 2 (EBER2) that interacts indirectly with the host transcription factor paired box protein 5 (PAX5) to regulate viral latent membrane protein 1/2 (LMP1/2) gene expression as well as EBV lytic replication. To identify intermediary proteins, we isolated EBER2-PAX5-containing complexes and analyzed the protein components by mass spectrometry. The top candidates include three host proteins splicing factor proline and glutamine rich (SFPQ), non-POU domain containing octamer-binding protein (NONO), and RNA binding motif protein 14 (RBM14), all reported to be components of nuclear bodies called paraspeckles. In vivo RNA-protein crosslinking indicates that SFPQ and RBM14 contact EBER2 directly. Binding studies using recombinant proteins demonstrate that SFPQ and NONO associate with PAX5, potentially bridging its interaction with EBER2. Similar to EBER2 or PAX5 depletion, knockdown of any of the three host RNA binding proteins results in the up-regulation of viral LMP2A mRNA levels, supporting a physiologically relevant interaction of these newly identified factors with EBER2 and PAX5. Identification of these EBER2-interacting proteins enables the search for cellular noncoding RNAs that regulate host gene expression in a manner similar to EBER2. PMID- 26951682 TI - Deciphering ocean carbon in a changing world. AB - Dissolved organic matter (DOM) in the oceans is one of the largest pools of reduced carbon on Earth, comparable in size to the atmospheric CO2 reservoir. A vast number of compounds are present in DOM, and they play important roles in all major element cycles, contribute to the storage of atmospheric CO2 in the ocean, support marine ecosystems, and facilitate interactions between organisms. At the heart of the DOM cycle lie molecular-level relationships between the individual compounds in DOM and the members of the ocean microbiome that produce and consume them. In the past, these connections have eluded clear definition because of the sheer numerical complexity of both DOM molecules and microorganisms. Emerging tools in analytical chemistry, microbiology, and informatics are breaking down the barriers to a fuller appreciation of these connections. Here we highlight questions being addressed using recent methodological and technological developments in those fields and consider how these advances are transforming our understanding of some of the most important reactions of the marine carbon cycle. PMID- 26951685 TI - Pathways into chronic multidimensional poverty amongst older people: a longitudinal study. AB - BACKGROUND: The use of multidimensional poverty measures is becoming more common for measuring the living standards of older people. However, the pathways into poverty are relatively unknown, nor is it known how this affects the length of time people are in poverty for. METHODS: Using Waves 1 to 12 of the nationally representative Household, Income and Labour Dynamics in Australia (HILDA) survey, longitudinal analysis was undertaken to identify the order that key forms of disadvantage develop - poor health, low income and insufficient education attainment - amongst Australians aged 65 years and over in multidimensional poverty, and the relationship this has with chronic poverty. Path analysis and linear regression models were used. RESULTS: For all older people with at least a Year 10 level of education attainment earlier mental health was significantly related to later household income (p = 0.001) and wealth (p = 0.017). For all older people with at less than a Year 10 level of education attainment earlier household income was significantly related to later mental health (p = 0.021). When limited to those in multidimensional poverty who were in income poverty and also had poor health, older people generally fell into income poverty first and then developed poor health. The order in which income poverty and poor health were developed had a significant influence on the length of time older people with less than a Year 10 level of education attainment were in multidimensional poverty for. Those who developed poor health first then fell into income poverty spend significantly less time in multidimensional poverty (-4.90, p < .0001) than those who fell into income poverty then developed poor health. CONCLUSION: Knowing the order that different forms of disadvantage develop, and the influence this has on poverty entrenchment, is of use to policy makers wishing to provide interventions to prevent older people being in long-term multidimensional poverty. PMID- 26951686 TI - Is it taking longer to die in paediatric intensive care in England and Wales? AB - INTRODUCTION: All-cause infant and childhood mortality has decreased in the UK over the last 30 years. Advances in paediatric critical care have increased survival in paediatric intensive care units (PICUs) but may have affected how and when children die in PICU. We explored factors affecting length of stay (LOS) of children who died in PICU over an 11-year period. METHODS: We analysed demographic and clinical data of 165 473 admissions to PICUs in England and Wales, from January 2003 to December 2013. We assessed time trends in LOS for survivors and non-survivors and explored the effect of demographic and clinical characteristics on LOS for non-survivors. RESULTS: LOS increased 0.310 days per year in non-survivors (95% CI 0.169 to 0.449) and 0.064 days per year in survivors (95% CI 0.046 to 0.083). The proportion of early deaths (<24 h of admission) fell 0.44% points per year (95% CI -0.971 to 0.094), but the proportion of late deaths (>28 days of PICU stay) increased by 0.44% points per year (95% CI 0.185 to 0.691). The paediatric index of mortality score in early deaths increased by 0.77% points per year (95% CI 0.31% to 1.23%). DISCUSSION: Increased LOS in children who die in PICU is driven by a decreased proportion of early deaths and an increased proportion of late deaths. This trend, combined with an increase in the severity of illness in early deaths, is consistent with a reduction in early mortality for acutely ill children, but a prolongation of life for those children admitted to PICU with life-limiting illnesses. PMID- 26951687 TI - A systematic review and meta-analysis of Synacthen tests for assessing hypothalamic-pituitary-adrenal insufficiency in children. AB - BACKGROUND: The diagnostic value of tests used in assessing hypothalamic pituitary-adrenal axis (HPA) in children remains controversial. DESIGN: A systematic review and meta-analysis with receiver-operated-characteristic curve was undertaken to assess the diagnostic values of conventional standard dose 250 MUg tetracosactrin (ACTH), short Synacthen test (SSST) and/or low-dose Synacthen test (LDSST) in the assessment of HPA insufficiency in children. Studies eligible for inclusion were any study that compared the use of the LDSST and/or SSST in the assessment of central adrenal insufficiency in children compared with reference standard test. RESULTS: There were no randomised trials found. SSST resulted in higher specificity and positive likelihood ratio than LDSST. The LDSST had a higher sensitivity (86% vs 61%) but a lower specificity (88% vs 99%) than the SSST, but there was high heterogeneity from the LDSST studies with various doses of Synacthen used. CONCLUSIONS: Lack of standardisation of assays and protocols with regard to timing, frequency and dose has resulted in diagnostic inaccuracies. There is no clear evidence to indicate that LDSST is superior to SSST in the assessment of HPA axis in children. The choice of either SSST or LDSST should be individualised based on clinical judgement for each patient. This systematic review has identified the need for a well-designed, adequately powered, randomised controlled trial on the use of diagnostic tests used in assessing HPA axis in children. PMID- 26951690 TI - [Twenty years of data in the 5th Report of the Italian National Mesothelioma Register]. PMID- 26951688 TI - Virulence of the Lyme disease spirochete before and after the tick bloodmeal: a quantitative assessment. AB - BACKGROUND: Borrelia burgdorferi, the tick-transmitted agent of Lyme disease, adapts to different environments as it cycles between an arthropod vector and vertebrate host. Signals encountered during nymphal tick feeding prior to transmission activate a regulon that is controlled by the alternative sigma factors RpoN and RpoS, which are required for mammalian infection. The ingested bloodmeal also provides nutrients that stimulate spirochete replication. Although the influence of tick feeding on spirochete growth and gene expression is well documented, a quantitative assessment of spirochete virulence before and after tick feeding has not been made. METHODS: Homogenates were prepared from unfed and fed infected Ixodes scapularis nymphs that had acquired B. burgdorferi as larvae. Serially diluted tick homogenates were needle-inoculated into mice to determine the infectious dose of tick-derived spirochetes before and after the bloodmeal. Mouse infection was assessed by sero-reactivity with B. burgdorferi whole cell lysates on immunoblots and attempted isolation of spirochetes from mouse tissues. Viable spirochetes in tick-derived inocula were quantified by colony formation in solid media. RESULTS: We found that an inoculum containing as many as 10(4) B. burgdorferi from unfed ticks is largely non-infectious, while the calculated ID50 for spirochetes from fed ticks is ~30 organisms. Engineered constitutive production of the essential virulence factor OspC by spirochetes within unfed ticks did not confer an infectious phenotype. CONCLUSION: Conditional priming of B. burgdorferi during tick feeding induces changes in addition to OspC that are required for infection of the mammalian host. PMID- 26951689 TI - LNA modification of single-stranded DNA oligonucleotides allows subtle gene modification in mismatch-repair-proficient cells. AB - Synthetic single-stranded DNA oligonucleotides (ssODNs) can be used to generate subtle genetic modifications in eukaryotic and prokaryotic cells without the requirement for prior generation of DNA double-stranded breaks. However, DNA mismatch repair (MMR) suppresses the efficiency of gene modification by >100 fold. Here we present a commercially available ssODN design that evades MMR and enables subtle gene modification in MMR-proficient cells. The presence of locked nucleic acids (LNAs) in the ssODNs at mismatching bases, or also at directly adjacent bases, allowed 1-, 2-, or 3-bp substitutions in MMR-proficient mouse embryonic stem cells as effectively as in MMR-deficient cells. Additionally, in MMR-proficient Escherichia coli, LNA modification of the ssODNs enabled effective single-base-pair substitution. In vitro, LNA modification of mismatches precluded binding of purified E. coli MMR protein MutS. These findings make ssODN-directed gene modification particularly well suited for applications that require the evaluation of a large number of sequence variants with an easy selectable phenotype. PMID- 26951691 TI - [The 2015 Whistleblower Award to Seralini, resilient scientist]. PMID- 26951692 TI - [Rare tumours: data are now available, politics has no more excuses]. PMID- 26951693 TI - [A mass murder or mere statistical data? The 2015 surplus of deaths]. PMID- 26951695 TI - [COP21: a half success]. PMID- 26951694 TI - [Nutrition and health: the receipe of Italian epidemiology. Report from the 39th Congress of the Italian Association of Epidemiology]. PMID- 26951697 TI - [Polycyclic aromatic hidrocarbons deposition in the Milazzo-Valle del Mela (Sicily Region, Southern Italy) high-risk area following an oil refinery fire]. AB - On September 2014, a fire began within an oil refinery involving a storage tank containing several hundreds of thousands cubic meters of virgin naphtha. Mayors of neighbouring municipalities asked the Epidemiology and Prevention Society "Giulio A. Maccacaro" to carry out an environmental survey in order to evaluate what was the nature and how dangerous was suspended dust deposited by the fumes. In the following days, after fire had been extinguished we conducted a sample survey on the presence of polycyclic aromatic hydrocarbons (PAH) and metals in particulate deposited on the soil on a radius of five kilometres from the refinery and we engaged the exposed population. The Milazzo-Valle del Mela (Sicily Region, Southern Italy) high-risk area includes several industrial plants; among them, an oil refinery and a fuel powered energy plant. As reference area we selected the Sarroch municipality (Sardinia Region, Southern Italy), in the coast of the Tyrrhenian Sea, which is geographically comparable, where a large oil refinery is located and where an environmental campaign with measurement of PAH and metals in particulate matter was ongoing. Qualitatively, metal composition of particulate matter resulted similar in the Sarroch and Milazzo samples. Instead, a large excess of PAH was documented in the Milazzo samples as compared to the Sarroch ones. In conclusion, the results of the analysis of the samples of particulate matter deposited in the Milazzo area in the days immediately following the oil refinery fire showed a high quantity of PAH, carcinogenic substances which pose major hazard to population health. The greater fall-out was registered in the proximity of the burnt storage tank and the West neighbourhood, and at lesser extent in the Southern neighbourhood. As a consequence, there was a population exposure to carcinogenic substances which could have reached the food chain. PMID- 26951696 TI - [EPICHANGE/1 Pollutants a la carte]. PMID- 26951698 TI - [On the increase in mortality in Italy in 2015: analysis of seasonal mortality in the 32 municipalities included in the Surveillance system of daily mortality]. AB - INTRODUCTION: the Italian National Institute of Statistics (Istat) estimated an increase in mortality in Italy of 11.3% between January and August 2015 compared to the previous year. During summer 2015, an excess in mortality, attributed to heat waves, was observed. OBJECTIVES: to estimate the excess mortality in 2015 using data from the rapid mortality surveillance system (SiSMG) operational in 32 Italian cities. DESIGN: time series models were used to estimate the excess in mortality among the elderly (65+ years) in 2015 by season (winter and summer). Excess mortality was defined as the difference between observed daily and expected (baseline) mortality for the five previous years (2009- 2013); seasonal mortality in 2015 was compared with mortality observed in 2012, 2013, and 2014. An analysis by cause of death (cardiovascular and respiratory), gender, and age group was carried out in Rome. RESULTS: data confirm an overall estimated excess in mortality of +11% in 2015. Seasonal analysis shows a greater excess in winter (+13%) compared to the summer period (+10%). The excess in winter deaths seems to be attributable to the peak in influenza rather than to low temperatures. Summer excess mortality was attributed to the heat waves of July and August 2015. The lower mortality registered in Italy during summer 2014 (-5.9%) may have contributed to the greater excess registered in 2015. In Rome, cause-specific analysis showed a higher excess among the very old (85+ years) mainly for cardiovascular and respiratory causes in winter. In summer, the excess was observed among both the elderly and in the adult population (35-64 years). CONCLUSION: results suggest the need for a more timely use of mortality data to evaluate the impact of different risk factors. Public health measures targeted to susceptible subgroups should be enhanced (e.g., Heat Prevention Plans, flu vaccination campaigns). PMID- 26951699 TI - [Health effects of air pollution in Rome in December 2015]. AB - BACKGROUND: in December 2015 Rome has been interested by a peculiar meteorological situation, with atmospheric stability, no rain and little wind. These factors, coupled with the high pollutant emissions typical of the winter pre-Christmas period (increased use of private cars and domestic heating), caused extreme peaks in air pollution concentrations persisting several weeks. OBJECTIVES: describing daily trends in PM10 over two months, November and December 2015, and their impact on the health of the population of Rome. DESIGN: we analysed PM10 time series in Rome for November and December 2015. We estimated the association between daily PM10 concentrations and daily counts of deaths for natural and cardiorespiratory causes, and urgent hospitalizations/emergency-room visits for cardiorespiratory diseases, by use of Poisson regression models adjusted for time trends, influenza epidemics, and meteorology. These risk estimates have been used to quantify attributable deaths/admissions/visits due to exceedances of daily PM10 concentrations above EU-defined limit values in Rome for the period 29 November-30 December 2015. SETTING AND PARTICIPANTS: Rome, November and December 2015; population resident in Rome and deceased or hospitalized/ admitted to emergency rooms in hospitals within the city. MAIN OUTCOME MEASURES: daily mortality for natural (0+ years), respiratory (0+) or cardiac (35+) causes; urgent (non-scheduled) hospitalizations or admissions to emergency room visits for respiratory (0+) or cardiac (35+) diseases. RESULTS: in December 2015, only three days (10th, 11th, and 26th December) had PM10 concentrations below the EU-limit value of 50 MUg/m3. Over the 31 days under analysis (from 29 November to 29 December) we estimated 26 natural deaths attributable to PM10 concentrations above 50 MUg/m3. Similarly, we estimated 20 and 30 attributable cases of cardiorespiratory hospitalizations and admissions to emergency room visits, respectively. CONCLUSIONS: monitoring and control of anthropogenic emissions are mandatory in order to minimize the adverse health effects of air pollution, especially during air pollution peaks. PMID- 26951700 TI - [Epidemiological population-based cohort study on mortality and hospitalization in the area near the waste incinerator plant of San Zeno, Arezzo (Tuscany Region, Central Italy)]. AB - OBJECTIVES: to evaluate whether exposure to an urban waste incinerator plant operating in Arezzo (Tuscany Region, Central Italy) since the 2000 is associated with mortality and morbidity. DESIGN: a population-based cohort study of inhabitants living close to the incinerator in the period 2001-2010 was conducted. The individual exposure histories to the incinerator and other sources in the area were estimated using a dispersion model producing PM10 concentration maps for each source (ADMS-URBAN model). Hazard Ratios (HR) with 95% Confidence Interval (95%CI) adjusted for the other environmental exposures, age and socioeconomic status were estimated for the highest class of exposure using the lowest one as reference. Trends of HR were evaluated too. MAIN OUTCOME MEASURES: mortality and hospitalization causes with induction-latent period overlapping the incinerator activity period were analysed. RESULTS: morbidity analysis showed an increased risk for cardiovascular diseases (No. 732; HR: 1.18; 95%CI 1.06-1.32; trend of HR: 1.08, p=0.006) and a trend of HRs for urinary diseases (trend: 1.13; p=0.063). Mortality analysis showed a trend of HRs for general mortality in males (trend: 1.10; p=0.014), for cardiovascular diseases in males (trend: 1.15; p=0.036), for respiratory diseases in females (trend: 1.30; p=0.098), and an excess of acute respiratory diseases in females with the highest exposure (No. 11; HR=2.54; 95%CI 0.84-7.68). CONCLUSIONS: the cohort study allowed to characterise the environmental exposures considering the most relevant pollution sources and providing estimation of individual environmental exposures. Residual confounding due to the overlapping of concentration maps cannot be excluded and further investigations are needed. However, the increased risks for cardiovascular and respiratory diseases reinforce the limited epidemiological evidence on health effects of incinerators. PMID- 26951701 TI - [Impacts of geocoding quality in environmental epidemiology studies: two case studies in Tuscany Region (Central Italy)]. AB - OBJECTIVES: Geographical Information Systems (GIS) are widely used in environmental epidemiology studies to locate study population by geocoding addresses and to evaluate exposures and relationship with health outcomes. Despite this, Italian environmental epidemiologists poorly discuss quality of address geocoding results. DESIGN: two case-studies have been carried out in Tuscany Region (Central Italy): one in the mountain area in the Municipality of Piancastagnaio (Siena Province) and one in the urban area around the airport of Florence. Three geocoding systems have been compared: the geographical database produced by Tuscany Region and two commercial systems (Google and Bing Microsoft); 1,549 addresses in Piancastagnaio and 2,946 addresses in Florence have been tested. RESULTS: Tuscan geographical database showed better performance than the two commercial systems, with bigger differences in Piancastagnaio. In this area, mean difference between regional system and Google service is more than 300 mt, with peaks of 7-8 km. Bing- Microsoft system does not provide any information on addresses in Piancastagnaio: all input addresses were geocoded in the centroid of the municipality or in the centre of a few principal streets. Lowest differences among the three methods were observed in the urban area of Florence: mean difference between Tuscany and Goggle systems was 150 mt, with less than 2 km peaks; between Tuscany and Bing-Microsoft mean difference was 100 mt with 3 km peaks. In both case-studies, but especially in Piancastagnaio area, these differences gave rise to great misclassification in the evaluation of individual exposure and health outcome. CONCLUSION: the study highlighted the impacts of address geocoding process in exposure assessment in environmental health research and pointed out the need of specifically evaluate the quality of cartographic data. PMID- 26951702 TI - [Evaluation of a public health programme: direct Clopidogrel administration by cardiology units in acute myocardial infarction]. AB - OBJECTIVES: to compare the benefit of a personalised outpatient therapy prescribed upon discharge by the cardiology unit to the patients undergoing a percutaneous coronary intervention with drug-eluting stent or bare-metal stent vs. the usual practice. DESIGN: controlled, multicentre, non-randomized study that enrolled patients who underwent coronary stent implantation and treated in the year after stent implantation with two protocols: the treatment group received Clopidogrel directly from the cardiology unit at each monitoring visit; the control group received a prescription for outpatient treatment through the standard retail pharmacy channel. SETTING AND PARTICIPANTS: the recruited centres adopting the new treatment protocol are Magenta, Legnano, and Rho (ASL Milano1, Magenta - Lombardy Region, Northern Italy), with 477 patients included; the recruited centres following for the standard protocol are Niguarda and San Carlo (ASL Milano), with 307 patients included. We identified all patients aged >=40 years, discharged after coronary stent implantation between January 1st, 2010 and March 31st, 2011, and followed for 1 year. MAIN OUTCOME MEASURES: all coronary events, second coronary interventions or deaths in the year after hospital discharge. RESULTS: we found differences between the two treatments in relation with coronary events: hazard ratio (HR) for the control group in patients with ST elevation myocardial infarction (STEMI) is 3.32 (95%CI 1.67- 6.62), HR in patients with non-ST elevation myocardial infarction (NSTEMI) is 2.44 (95%CI 1.07 5.57). The compliance at 1 year is 80% in the treated group vs. 70% in the control group, respectively (p-value <0.01). CONCLUSIONS: the application of the therapeutic plan, governed by the interventional cardiology, increases treatment adherence and reduces the risk of cardiovascular events subsequent to the insertion of a stent. It is crucial, therefore, to improve the adherence to dual antiplatelet therapy by using high levels of integration between inpatient and outpatient care to reduce adverse health outcomes during post-surgery phase and to ensure the taking in charge of the patient. PMID- 26951703 TI - [Inter-rater agreement on self-reported exposure to ergonomic risk factors for the upper extremities among mechanic assemblers in an automotive industry]. AB - OBJECTIVES: to assess reproducibility of self-reported exposure to ergonomic hazards for the upper limbs, measured through a questionnaire based on a diffused checklist for the assessment of ergonomic risk (OCRA) in a sample of mechanical assemblers of an automotive industry. DESIGN: cross-sectional study; reproducibility was assessed as interrater agreement of a composite index of ergonomic risk, estimated through the intraclass correlation coefficient (ICC). SETTING AND PARTICIPANTS: 58 mechanical assemblers, working in 29 twin areas, characterised by same work stations and tasks. MAIN OUTCOME MEASURES: composite index of ergonomic risk for the upper limbs. RESULTS: reproducibility of the ergonomic index was high in the overall sample (ICC: 0.81) and it was higher for the twin areas employing same-gender workers (ICC: 0.96), compared to those with workers of the opposite gender (ICC: 0.66). CONCLUSION: these results indicate that a questionnaire measuring with a great detail the exposure to the main ergonomic risk factors for the upper limbs, as the one based on the OCRA checklist used for this study, would allow to obtain a highly reproducible ergonomic index. If its validity against the corresponding observational checklist will be found elevated by future studies, this questionnaire may represent a useful tool for a preliminary assessment of workers' exposure to ergonomic hazards for the upper limbs. PMID- 26951704 TI - [Use of regional health administrative databases to estimate the prevalence of mental disorders and health service utilization in a Local Health Unit of Tuscany Region (Central Italy)]. AB - OBJECTIVES: prevalence estimation of mental disorders and mental health services (SSM) utilization in 2011, using the administrative regional health databases (hospital discharge records, pharmaceutical prescriptions) and the Regional Database on Mental Health (SIRSM). STUDY DESIGN: descriptive population-based study. SETTING AND PARTICIPANTS: residents in a Local Health Unit (Florence) of Tuscany Region (Central Italy) who have access to SSM and/or to hospital departments of psychiatry/neuropsychiatry and/ or have psycholeptic/psychoanalectic prescriptions. MAIN OUTCOME MEASURES: frequencies; crude and age-standardized prevalence of patients who have access to the SSM or have admission to a hospital psychiatric ward or have psycholeptic/psychoanalectic prescriptions. RESULTS: a high prevalence (11.2%) of residents had at least one contact with health services for mental health problems, mostly (84%) for drug prescriptions only (20% of patients had a unique prescription during 2011). Depression is the most important disease (9.8% of residents had at least one prescription of antidepressants); mood disorders are the most common cause of adult access to SSM (35%-36%) and hospitalization in psychiatric ward (about 36% of admissions). Only a small proportion (about 15%) of patients with mental health problems have access to the SSM, presumably those with more severe diseases. CONCLUSIONS: results show that the information of the SIRSM database, together with pharmaceutical prescriptions (psycholeptic/ psychoanalectic) and hospitalisation in psychiatric ward, is a useful tool for assessing the prevalence of mental health problems in a population. PMID- 26951708 TI - [ERRATA CORRIGE: Epidemiol Prev 2014;38(6) Suppl 1]. PMID- 26951705 TI - [Maternal perception of their children's weight and lifestyles]. PMID- 26951707 TI - [Tobacco smoking and alcohol intake in pregnant and breastfeeding women: preliminary data of the survey PASSI 2014]. PMID- 26951706 TI - [Italy 2015: 3 million Italians are living after a cancer diagnosis, both incidence and mortality are decreasing]. PMID- 26951709 TI - First steps in designing an all-in-one ICT-based device for persons with cognitive impairment: evaluation of the first mock-up. AB - BACKGROUND: This project Smart Assisted Living involving Informal careGivers++ (SALIG) intends to develop an ICT-based device for persons with cognitive impairment combined with remote support possibilities for significant others and formal caregivers. This paper presents the identification of the target groups' needs and requirements of such device and the evaluation of the first mock-up, demonstrated in a tablet. METHODS: The inclusive design method that includes end users in the design process was chosen. First, a scoping review was conducted in order to examine the target group's need of an ICT-based device, and to gather recommendations regarding its design and functionalities. In order to capture the users' requirements of the design and functionalities of the device three targeted focus groups were conducted. Based on the findings from the publications and the focus groups a user requirement specification was developed. After that a design concept and a first mock-up was developed in an iterative process. The mock-up was evaluated through interviews with persons with cognitive impairment, health care professionals and significant others. Data were analysed using content analysis. RESULTS: Several useful recommendations of the design and functionalities of the SALIG device for persons with cognitive impairment were identified. The main benefit of the mock-up was that it was a single device with a set of functionalities installed on a tablet and designed for persons with cognitive impairment. An additional benefit was that it could be used remotely by significant others and formal caregivers. CONCLUSION: The SALIG device has the potentials to facilitate everyday life for persons with cognitive impairment, their significant others and the work situation for formal caregivers. The results may provide guidance in the development of different types of technologies for the target population and for people with diverse disabilities. Further work will focus on developing a prototype to be empirically tested by persons with cognitive impairment, their significant others and formal caregivers. PMID- 26951710 TI - Use of Topical Rapamycin in Facial Angiofibromas in Indian Skin Type. AB - INTRODUCTION: Facial angiofibromas (FA) are the most visible cutaneous manifestations in patients with tuberous sclerosis (TS), often resulting in stigmatization of the affected individuals. Recent studies have suggested that topical rapamycin may be an effective treatment for angiofibromas. AIM: To study the safety and efficacy of topical rapamycin in treatment of FA in Type IV-VI skin type. MATERIALS AND METHODS: Five female patients with FA were included in the study, four of whom had TS, whereas one had isolated angiofibromas without systemic involvement. The age of the patients varied from 6 to 44 years. After baseline evaluation, they were advised to apply topical rapamycin (0.1-1%) in white soft paraffin base twice daily. Follow-up varied from 1 month to 6 months and is ongoing. RESULTS: A sustained improvement was observed with respect to erythema, size as well as extent of the lesions as early as within 2 weeks of starting treatment. No side effects were observed. A correlation between duration of angiofibromas and effectiveness of treatment was noted. CONCLUSION: Topical rapamycin appears to be a safe and effective alternative to surgical or laser based treatments in patients with FA. This treatment shows potential to be a first-line management for FA and appears safe to start in early childhood. PMID- 26951711 TI - Rabbit antithymocyte globulin and donor-specific antibodies in kidney transplantation--A review. AB - The mode of action of rabbit antithymocyte globulin (rATG) includes preferential inhibition of pre-existing donor-reactive memory T-cell reconstitution and possibly apoptosis of plasma cells, the source of donor specific antibodies (DSAs). In kidney transplant patients with low-strength preformed DSAs, non comparative data have shown a low incidence of antibody-mediated rejection (ABMR) and graft survival using rATG even without desensitization procedures. For high strengths of preformed DSAs, rATG induction with more aggressive desensitization appears effective, with mixed results concerning the addition of B-cell specific agents. Regarding production of de novo DSA (dnDSA), interpretation of retrospective analyses is limited by selective use of rATG in higher-risk patients. Observational data in moderately sensitized kidney transplant patients suggest that the incidence of dnDSA and ABMR is significantly lower with rATG versus basiliximab. A randomized pilot study has suggested that addition of rituximab or bortezomib may not further inhibit dnDSA production in rATG-treated patients. Overall, rATG appears to inhibit DSA production, with a potential role in reducing the risk of ABMR in kidney transplant patients with high-strength preformed DSA, or lowering dnDSA in moderately sensitized patients. Randomized trials are awaited. PMID- 26951712 TI - Effect of ivermectin on the larvae of Anopheles gambiae and Culex quinquefasciatus. AB - BACKGROUND: Ivermectin is used extensively globally for treatment of helminthic and ectoparasitic infections in animals and humans. The effect of excreted ivermectin on non-target organisms in aquatic and terrestrial environments has been increasingly reported. Due to its low water solubility and adsorption to sediments, the ivermectin exposure-risk to aquatic organisms dwelling in different strata of water bodies varies. This study assessed the survival of larvae of Anopheles gambiae Giles and Culex quinquefasciatus Say, when exposed to low concentrations of ivermectin under laboratory conditions. METHODS: A total of 1800 laboratory reared mosquito larvae of each species were used in the bioassays. Twelve replicates were performed, each testing 6 concentrations of ivermectin (0.0, 0.001, 0.01, 0.1, 1.0 and 10.0 parts per million (ppm)) against third instar larvae of An. gambiae and Cx. quinquefasciatus. Larval mortality was recorded at 24 and 48 h post addition of ivermectin. RESULTS: Survival declined markedly with increase in ivermectin concentration in both species. While mean survival of An. gambiae at 24 h of exposure was 99.6 %, 99.2 % and 61.6 % in 0.001, 0.01 and 0.1 ppm of ivermectin, respectively, the mean survival of Cx. quinquefasciatus at the same dosage and time was 89.2 %, 47.2 % and 0.0 %. A similar pattern, but with higher mortality, was observed after 48 h of exposure. Comparison between the species revealed that Cx. quinquefasciatus larvae were significantly more affected by ivermectin than those of An. gambiae, both at 24 and 48 h. CONCLUSIONS: Low concentrations of ivermectin in the aquatic environment reduced the survival of larvae of An. gambiae and Cx. quinquefasciatus, with the effect being more marked in the latter species. It is suggested that this difference may be due to the different water strata occupied by the two species, with ivermectin adsorbed in food that sediment being more readily available to the bottom feeding Cx. quinquefasciatus than the surface feeding An. gambiae larvae. PMID- 26951713 TI - Chronic prostatitis/chronic pelvic pain syndrome: a review of evaluation and therapy. AB - BACKGROUND: Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), also known as NIH Category III Prostatitis is a highly prevalent syndrome with significant impact on quality of life. As a heterogeneous syndrome, there exists no 'one size fits all' therapy with level 1 evidence to guide therapy. This often leads to a nihilistic approach to patients and clinical outcomes are poor. In this review, we examine the evidence for CP/CPPS therapies and discuss our technique of clinical phenotyping combined with multimodal therapy. METHODS: Review of Medline articles with terms 'non-bacterial prostatitis', 'abacterial prostatitis' and 'chronic pelvic pain syndrome'. RESULTS: Many individual therapies have been evaluated in the treatment of CP/CPPS; antibiotics, anti inflammatory medications (including bioflavonoids), neuromodulators, alpha blockers, pelvic floor physical therapy and cognitive behavior therapy. Each of these has been found to have varying success in alleviating symptoms. UPOINT is a system of clinical phenotyping for CP/CPPS patients that has 6 defined domains, which guide multimodal therapy. It has been validated to correlate with symptom burden and therapy guided by UPOINT leads to significant symptom improvement in 75-84% of patients based on three independent studies. CONCLUSIONS: CP/CPPS is a heterogeneous condition and, much like with prostate cancer, optimal therapy can only be achieved by classifying patients into clinically meaningful phenotypic groups (much like TNM) and letting the phenotype drive therapy. PMID- 26951714 TI - Pretreatment plasma fibrinogen as an independent prognostic indicator of prostate cancer patients treated with androgen deprivation therapy. AB - BACKGROUND: Hyperfibrinogen is thought to be associated with a higher risk of invasion and metastasis, as well as a worse outcome for multiple types of cancer. However, the prognostic significance of plasma fibrinogen has not been investigated in prostate cancer with hormonal therapy. The objective of this study was to evaluate its roles in prostate cancer patients treated with androgen deprivation therapy (ADT). METHODS: A total of 290 patients who underwent ADT as first-line therapy for prostate cancer were retrospectively analyzed. The fibrinogen level was measured at the time of diagnosis. Patients were categorized using a cutoff point of 3.225 g l(-1) according to a calculation by the receiver operating curve analysis. Correlations between the fibrinogen and clinical characteristics were analyzed. Meanwhile, univariable and multivariable cox regression analyses were performed to determine the associations of fibrinogen with progression-free survival (PFS), cancer-specific survival (CSS) and overall survival (OS). Prognostic accuracy was evaluated with the Harrell concordance index. RESULTS: Compared with patients with a lower fibrinogen level (<3.225 g l( 1)), patients with a higher fibrinogen level were more likely to have higher PSA, Gleason score, risk stratification and incidence of metastasis (P<0.05). Multivariable analyses identified hyperfibrinogen as an independent prognostic factor for PFS (hazard ratio (HR)=2.000, P<0.001), CSS (HR=2.209, P=0.006) and OS (HR=1.965, P=0.009). The final models built by the addition of fibrinogen improved predictive accuracy (c-index: 0.750, 0.799 and 0.767) for PFS, CSS and OS compared with the clinicopathological base models (c-index: 0.730, 0.778 and 0.746), which included Gleason score and metastasis. CONCLUSIONS: The pretreatment plasma fibrinogen level was associated with tumor progression and might have a significant role in the prognosis of the prostate cancer patients treated with ADT. Thus, we recommend adding fibrinogen to traditional prognostic model, which may improve its predictive accuracy. PMID- 26951716 TI - Molecular basis for the toxin insensitivity of scorpion voltage-gated potassium channel MmKv1. AB - Scorpions are insensitive to their own venoms, which contain various neurotoxins specific for mammalian or insect ion channels, whose molecular mechanism remains unsolved. Using MmKv1, a potassium channel identified from the genome of the scorpion Mesobuthus martensii, channel kinetic experiments showed that MmKv1 was a classical voltage-gated potassium channel with a voltage-dependent fast activation and slow inactivation. Compared with the human Kv1.3 channel (hKv1.3), the MmKv1 channel exhibited a remarkable insensitivity to both scorpion venom and toxin. The chimaeric channels of MmKv1 and hKv1.3 revealed that both turret and filter regions of the MmKv1 channel were critical for the toxin insensitivity of MmKv1. Furthermore, mutagenesis of the chimaeric channel indicated that two basic residues (Arg(399) and Lys(403)) in the MmKv1 turret region and Arg(425) in the MmKv1 filter region significantly affected its toxin insensitivity. Moreover, when these three basic residues of MmKv1 were simultaneously substituted with the corresponding residues from hKv1.3, the MmKv1-R399T/K403S/R425H mutant channels exhibited similar sensitivity to both scorpion venom and toxin to hKv1.3, which revealed the determining role of these three basic residues in the toxin insensitivity of the MmKv1 channel. More strikingly, a similar triad sequence structure is present in all Shaker-like channels from venomous invertebrates, which suggested a possible convergent functional evolution of these channels to enable them to resist their own venoms. Together, these findings first illustrate the mechanism by which scorpions are insensitive to their own venoms at the ion channel receptor level and enrich our knowledge of the insensitivity of scorpions and other venomous animals to their own venoms. PMID- 26951715 TI - Variation in the use of postoperative radiotherapy among high-risk patients following radical prostatectomy. AB - BACKGROUND: We used data from the Michigan Urological Surgery Improvement Collaborative (MUSIC) to investigate the use of adjuvant and salvage radiotherapy (ART, SRT) among patients with high-risk pathology following radical prostatectomy (RP). METHODS: For patients with pT3a disease or higher and/or positive surgical margins, we examined post-RP radiotherapy administration across MUSIC practices. We excluded patients with <6 months follow-up, and those that failed to achieve a postoperative PSA nadir ?0.1. ART was defined as radiation administered within 1 year post RP, with all post-nadir PSA levels <0.1 ng ml( 1). Radiation administered >1 year post RP and/or after a post-nadir PSA ?0.1 ng ml(-1) was defined as SRT. We used claims data to externally validate radiation administration. RESULTS: Among 2337 patients undergoing RP, 668 (28.6%) were at high risk of recurrence. Of these, 52 (7.8%) received ART and 56 (8.4%) underwent SRT. Patients receiving ART were younger (P=0.027), more likely to have a greater surgical Gleason sum (P=0.009), higher pathologic stage (P<0.001) and received treatment at the smallest and largest size practices (P=0.011). Utilization of both ART and SRT varied widely across MUSIC practices (P<0.001 and P=0.046, respectively), but practice-level rates of ART and SRT administration were positively correlated (P=0.003) with lower ART practices also utilizing SRT less frequently. Of the 88 patients not receiving ART and experiencing a PSA recurrence ?0.2 ng ml(-1), 38 (43.2%) progressed to a PSA ?0.5 ng ml(-1) and 20 (22.7%) to a PSA ?1.0 ng ml(-1) without receiving prior SRT. There was excellent concordance between registry and claims data kappa=0.98 (95% CI: 0.94-1.0). CONCLUSIONS: Utilization of ART and SRT is infrequent and variable across urology practices in Michigan. Although early SRT is an alternative to ART, it is not consistently utilized in the setting of post-RP biochemical recurrence. Quality improvement initiatives focused on current postoperative radiotherapy administration guidelines may yield significant gains for this high-risk population. PMID- 26951718 TI - Determination of leachate compounds relevant for landfill aftercare using FT-IR spectroscopy. AB - Controlling and monitoring of emissions from municipal solid waste (MSW) landfills is important to reduce environmental damage and health risks. Therefore, simple and meaningful monitoring tools are required. This paper presents how Fourier Transform Infrared (FT-IR) Spectroscopy can be used to monitor leachate from various landfill sites. The composition of percolated leachate provides information about reactivity or stability of organic matter in landfills. Chemical compounds of investigated leachate are depicted by distinct spectral pattern. Partial least squares regression (PLS-R) models, a multivariate analysis tool, were developed based on infrared spectra to determine simultaneously conventional parameters such as ammonium, nitrate, sulfate, and dissolved organic carbon. The developed models are appropriate for application in waste management practice with respect to their excellent coefficients of determination, namely R(2)=0.99, 0.99, 0.98, and 0.98, their low errors of cross validation and their high ratios of performance to deviation (RPD=9.3, 12.5, 6.5, 7.3). Thus, FT-IR spectroscopy turned out to be a reliable, time-saving tool to determine four parameters relevant for landfill aftercare monitoring by one single easy adaptable measurement. PMID- 26951719 TI - Comparison of alternative flue gas dry treatment technologies in waste-to-energy processes. AB - Acid gases such as HCl and SO2 are harmful both for human health and ecosystem integrity, hence their removal is a key step of the flue gas treatment of Waste to-Energy (WtE) plants. Methods based on the injection of dry sorbents are among the Best Available Techniques for acid gas removal. In particular, systems based on double reaction and filtration stages represent nowadays an effective technology for emission control. The aim of the present study is the simulation of a reference two-stage (2S) dry treatment system performance and its comparison to three benchmarking alternatives based on single stage sodium bicarbonate injection. A modelling procedure was applied in order to identify the optimal operating configuration of the 2S system for different reference waste compositions, and to determine the total annual cost of operation. Taking into account both operating and capital costs, the 2S system appears the most cost effective solution for medium to high chlorine content wastes. A Monte Carlo sensitivity analysis was carried out to assess the robustness of the results. PMID- 26951717 TI - C-reactive protein, Neopterin and Beta2 microglobulin levels pre and post TB treatment in The Gambia. AB - BACKGROUND: Tuberculosis is one of the leading causes of morbidity and mortality in developing countries. Analysis of the host immune response may help with generating point-of-care tests for personalised monitoring. Thus, the aim of this study was to assess the relationship between immune activation markers: C reactive protein (CRP), Beta2 microglobulin (B2M) and Neopterin, disease severity prior to treatment and response to therapy in adult pulmonary TB patients. METHODS: HIV negative adult pulmonary TB index cases (n = 91) were recruited from the TB clinic at MRC, The Gambia. Plasma samples were collected at enrolment and at 2 and 6 months following TB treatment initiation. An enzyme linked immunosorbent assay (ELISA) was performed for evaluation of CRP, B2M and Neopterin levels and correlated with clinical and microbiological parameters including strain of infection. Disease severity was determined using Chest X-ray (CXR), Body Mass Index (BMI) and sputum smear grade. RESULTS: Plasma levels of all three markers were highly elevated in patients at recruitment and declined significantly during TB therapy. No correlation with disease severity was seen at recruitment. CRP showed the most significant decrease by 2 months of treatment (p < 0.0001) whereas levels of B2M and Neopterin showed little change by 2 months but a significant decrease by 6 months of treatment (p = 0.0002 and p < 0.0001 respectively). At recruitment, B2M levels were significantly higher in subjects infected with Mycobacterium africanum (Maf) compared with those infected with Mycobacterium tuberculosis sensu stricto (Mtb) (p = 0.0075). In addition, while CRP and Neopterin showed a highly significant decline post-treatment regardless of strain (p < 0.0001 for all), B2M showed differential decline depending on strain (p = 0.0153 for Mtb and p = 0.0048 for Maf) and levels were still significantly higher at 6 months in Maf compared to Mtb infected subjects (p = 0.0051). CONCLUSION: Our findings suggest that activation markers, particularly CRP, may have a role in identifying good response to TB therapy regardless of the strain of infection and could be further developed as point-of-care tests. In addition, B2M levels may allow differentiation between Mtb and Maf-infected subjects. PMID- 26951720 TI - Attitudes toward waste to energy facilities and impacts on diversion in Ontario, Canada. AB - Despite progress in residential waste diversion, residual waste - that fraction which cannot be recycled or composted - must continue to be managed by municipalities. Zero waste and environmental groups worry that waste-to-energy (WtE) incinerators discourage diversion, while both incineration and landfill have been stigmatized in the popular consciousness such that WtE incinerators in particular are being cancelled more often than they are approved. We conducted a mail-back survey of 217 residents in Toronto, Durham and Peel, Ontario, to understand attitudes toward diversion, levels of support for WtE incineration and WtE landfill (landfill gas recovery) facilities, and predictors of facility support. Contrary to experiences elsewhere, diversion seems threatened by WtE when measured as attitudes with 18%, and 14% agreeing that they would be less inclined to divert recyclable/compostable materials if they knew materials went to a WtE landfill or incinerator. When forced to choose between four options landfill or incineration with and without energy recovery, WtE incineration is most preferred (65%) and landfill without WtE is the least preferred option (61%). However, measurement has a large influence on public opinion results in the sense that support for WtE incineration drops to 43% when asked as a "vote in favor" question and to only 36% when measured as a 4-item index of support. When the indexes of support for landfill and WtE incineration are modeled, the prominence of odor in the landfill model distinguishes it from the WtE incinerator model which is dominated more by community and concern about health effects. Implications for policy are discussed, particularly mandatory diversion targets to accompany WtE. PMID- 26951721 TI - Phosphorous recovery from sewage sludge ash suspended in water in a two compartment electrodialytic cell. AB - Phosphorus (P) is indispensable for all forms of life on Earth and as P is a finite resource, it is highly important to increase recovery of P from secondary resources. This investigation is focused on P recovery from sewage sludge ash (SSA) by a two-compartment electrodialytic separation (EDS) technique. Two SSAs are included in the investigation and they contained slightly less P than phosphate rock used in commercial fertilizer production and more heavy metals. The two-compartment electrodialytic technique enabled simultaneous recovery of P and separation of heavy metals. During EDS the SSA was suspended in water in the anolyte, which was separated from the catholyte by a cation exchange membrane. Electrolysis at the anode acidified the SSA suspension, and hereby P, Cu, Pb, Cd and Zn were extracted. The heavy metal ions electromigrated into the catholyte and were thus separated from the filtrate with P. More than 95% P was extracted from both SSAs. The charge transfer to obtain this varied when treating the two SSAs, and for one ash it was about 30% higher than for the other as a result of a higher buffering capacity against acidification. The repeatability of EDS results between experiments with the same SSA and the same experimental conditions was good, which shows that the process is easy to control at the studied laboratory conditions. About 80% P and 10% of the heavy metals remained in the filtrate from the anolyte after treatment of both SSAs. The heavy metal content relative to P in the filtrate by far meet the limiting values for use of industrial wastes as fertilizers, thus the filtrate is ready for direct processing into P-fertilizer. PMID- 26951722 TI - On the removal of hexavalent chromium from a Class F fly ash. AB - Coarse and fine samples of a Class F fly ash obtained from commercial combustion of Illinois bituminous coal have been exposed to two long-term leaching tests designed to simulate conditions in waste impoundments. ICP-AES analysis indicated that the coarse and fine fly ash samples contained 135 and 171mg/kg Cr, respectively. Measurements by XAFS spectroscopy showed that the ash samples originally contained 5 and 8% of the chromium, respectively, in the hexavalent oxidation state, Cr(VI). After exposure to water for more than four months, the percentage of chromium as Cr(VI) in the fly-ash decreased significantly for the coarse and fine fly-ash in both tests. Combining the XAFS data with ICP-AES data on the concentration of chromium in the leachates indicated that, after the nineteen-week-long, more aggressive, kinetic test on the coarse fly ash, approximately 60% of the Cr(VI) had been leached, 20% had been reduced to Cr(III) and retained in the ash, and 20% remained as Cr(VI) in the ash. In contrast, during the six-month-long baseline test, very little Cr was actually leached from either the coarse or the fine fly-ash (<0.1mg/kg); rather, about 66% and 20%, respectively, of the original Cr(VI) in the coarse and fine fly-ash was retained in the ash in that form, while the remainder, 34% and 80%, respectively, was reduced and retained in the ash as Cr(III). The results are interpreted as indicating that Cr(VI) present in Class F fly-ash can be reduced to Cr(III) when in contact with water and that such chemical reduction can compete with physical removal of Cr(VI) from the ash by aqueous leaching. PMID- 26951723 TI - Efficient quantile marginal regression for longitudinal data with dropouts. AB - In many biomedical studies independent variables may affect the conditional distribution of the response differently in the middle as opposed to the upper or lower tail. Quantile regression evaluates diverse covariate effects on the conditional distribution of the response with quantile-specific regression coefficients. In this paper, we develop an empirical likelihood inference procedure for longitudinal data that accommodates both the within-subject correlations and informative dropouts under missing at random mechanisms. We borrow the matrix expansion idea of the quadratic inference function and incorporate the within-subject correlations under an informative working correlation structure. The proposed procedure does not assume the exact knowledge of the true correlation structure nor does it estimate the parameters of the correlation structure. Theoretical results show that the resulting estimator is asymptotically normal and more efficient than one attained under a working independence correlation structure. We expand the proposed approach to account for informative dropouts under missing at random mechanisms. The methodology is illustrated by empirical studies and a real-life example of HIV data analysis. PMID- 26951724 TI - Optimal marker-strategy clinical trial design to detect predictive markers for targeted therapy. AB - In developing targeted therapy, the marker-strategy design (MSD) provides an important approach to evaluate the predictive marker effect. This design first randomizes patients into non-marker-based or marker-based strategies. Patients allocated to the non-marker-based strategy are then further randomized to receive either the standard or targeted treatments, while patients allocated to the marker-based strategy receive treatments based on their marker statuses. Little research has been done on the statistical properties of the MSD, which has led to some widespread misconceptions and placed clinical researchers at high risk of using inefficient designs. In this article, we show that the commonly used between-strategy comparison has low power to detect the predictive effect and is valid only under a restrictive condition that the randomization ratio within the non-marker-based strategy matches the marker prevalence. We propose a Wald test that is generally valid and also uniformly more powerful than the between strategy comparison. Based on that, we derive an optimal MSD that maximizes the power to detect the predictive marker effect by choosing the optimal randomization ratios between the two strategies and treatments. Our numerical study shows that using the proposed optimal designs can substantially improve the power of the MSD to detect the predictive marker effect. We use a lung cancer trial to illustrate the proposed optimal designs. PMID- 26951725 TI - [Identification, early diagnosis, and monitoring of workers exposed to asbestos. Where are we?]. PMID- 26951726 TI - [Initiatives promoted by the Italian Health Ministry from 2011 to 2013]. PMID- 26951727 TI - [The National Asbestos Plan in Italy]. PMID- 26951728 TI - Helsinki Criteria update 2014: asbestos continues to be a challenge for disease prevention and attribution. PMID- 26951729 TI - [Risk of lung cancer in individuals with previous exposure to asbestos]. AB - Asbestos-related lung cancer is an important and partly unrecognized public health problem. The present review summarizes the knowledge regarding some specific aspects of the association between asbestos and lung cancer. It is difficult to estimate the exact number of lung cancers in a population that are attributable to asbestos exposure. However, this number is likely to greatly exceed the number of mesotheliomas. Epidemiological studies suggest that there is a linear relationship between cumulative exposure to asbestos and risk of lung cancer. Observed differences between different types of asbestos are lower than previously believed. This highlights the necessity of banning all types of asbestos worldwide. Risk of lung cancer changes with passing time from asbestos exposure, with the strongest effect observed 10-15 years after the exposure. This highlights the importance of quitting asbestos exposure as soon as possible, even for individuals with a long-term past exposure. Quitting smoking is the most important preventive action to be taken by individuals with a past exposure to asbestos. Results of recent studies show that smoking cessation is associated with a substantial reduction of lung cancer risk among individuals exposed to asbestos. This highlights the importance of promoting smoking cessation programmes specifically targeted to individuals with a past exposure to asbestos. PMID- 26951730 TI - [Increased risk of mesothelioma and lung cancer among workers exposed to asbestos who could require an anticipated retirement]. AB - OBJECTIVES: to assess the association among malignant pleural mesothelioma (MPM) and lung cancer (LC) among workers who have been exposed to asbestos and have or not have required an anticipated leave from work, a possibility offered by the 1992 law banning asbestos in Italy, in the framework of the health surveillance programmes on going in the Veneto Region (Northern Italy). SETTING AND PARTICIPANTS: a cohort of asbestos workers derived from the rosters of selected factories and alive in 1992, followed from 1992 to 2012.MPM cases have been identified through the Regional Mesothelioma Registry, while LC cases through a link with the Regional Cancer Registry, hospital discharges, and death certificates. Risks related to asbestos exposure were calculated by mixed effects Poisson regression model. RESULTS: the risk of MPM and LC increases at any additional duration of work, up to very high values for long term durations of work for MPM, and up to a three fold increase for LC. Early retirements have been requested by a fraction only in the position of submitting it. CONCLUSION: subjects who have been exposed to asbestos should be the target of a post occupational surveillance, and further work is suggested to identify subjects at high risk of LC because of smoking habits and more heavy exposure to asbestos, in order to develop programmes for primary and secondary cancer prevention. PMID- 26951731 TI - [When research and clinical recommendations are (temporarily) in contradiction: the evaluation of lung cancer screening for high-risk subjects in Europe and in the USA]. AB - Lung cancer is the first cancer mortality cause in Italy. In last decades, incidence rates have been falling down, but the annual number of deaths is stable because of population ageing. Survival rates for population-based lung cancer cases were at maximum 17% in the last decades. In 2011, the National Lung Screening Trial (NLST) has published the results of the evaluation of efficacy of low-dose CT scan screening compared with chest X-ray showing a 20%cause-specific mortality reduction, based on the randomization, screening, and follow-up of about 53,000 subjects in USA. In Europe, 7 randomized studies are ongoing: the Nelson study, with about 16,000 people enrolled, is the largest one and its results are expected to be published soon. The US Preventive Service Task Force recommended screening for lung cancer. CT Scan screening will be made available within Medicare to high-risk subjects until 74 years or 80 years of age. In Europe, recommendations continue to discourage screening for lung cancer in all member Countries. The implementation of organised screening in Europe is conditioned by an health technology assessment aimed to the identification of the risk profile, performance of screening (false positive rates), and overdiagnosis harm. All the potential harms of screening must be balanced with expected benefits and evaluated in a formal cost-benefits analysis. Better strategies aimed to selective lung cancer screening of high risk subjects, including asbestos workers, must be evaluated in prospective studies. PMID- 26951732 TI - [Lung cancer screening in high-risk subjects: early detection with LDCT and risk stratification using miRNA-based blood test]. AB - Lung cancer still remains a high mortality disease in the face of developments in diagnostic and therapeutic methods that occurred in the last 20 years. The analysis of the experiences from the first studies - in which chest X-ray (CXR) was adopted, associated or not with sputum cytology - has failed to show a reduction in lung cancer specific mortality. Subsequent screening studies that have introduced the use of low-dose computed tomography (LDCT) have revealed a large number of early-stage lung cancers, thus potentially curable; however, this has not allowed us to demonstrate a decrease in lung cancer-specific mortality. With the results of the American study National Lung ScreeningTrial (NLST), published in 2011, for the first time a lung cancer-specific mortality reduction by 20% thanks to the use of LDCT compared to RXT, was highlighted. However, a false positive rate of 96.4% was also described with an overdiagnosis that can be up to 78.9%for bronchioalveolar lung cancer. Due to the high sensitivity of LDCT, able to identify a non-calcified pulmonary nodule in one subject on two, it becomes necessary to avail instruments to more accurately identify suspicious nodules. Until some time ago, the possible use of lung tumour markers was not viable in view of the poor organ specificity. The study and development was, then, pushed to organ- and tissue-specific markers such as microRNA (miRNA), noncoding RNA sequences involved in many processes and expression of oncogenic activity of the microenvironment. The use of biomarkers such as circulating miRNA implemented in LDCT screening has highlighted a reduction of 5 times for the rate of false positives, going from 19.4% to 3.7%, with a sensitivity of 87%, a specificity of 81%, and a negative predictive value of 99%. The need to appropriately use the available resources commensurate with the disease to treat will push more and more towards the implementation of LDCT biomarkers based screenings, stable and easily reproducible, as circulating miRNAs, obviating to problems such as false positives, unnecessary procedures of invasive surgery for benign lesions, and optimizing the cost benefit ratios.The development of new specific biomarkers appears to offer new promising prospects. PMID- 26951733 TI - [HRCT and LDCT in workers exposed to asbestos: a review of the literature in view of the Helsinki Criteria]. AB - In approaching the asbestos-related diseases with CT, both the malignant diseases and the non-malignant disease are to be considered. In the recent publication of the Helsinki Criteria research activities are encouraged in the field of lung cancer screening with low-dose CT (LDCT) in exposed workers and initiatives of data pooling and study protocols standardization are stimulated. Herein, we propose a review of the literature in the light of the Helsinki statement focused on the different techniques of imaging with CT and on the different fields of application in the asbestos-related disease. PMID- 26951734 TI - [Molecular biomarkers and early diagnosis of lung cancer: state of knowledge and future perspectives]. AB - Lung cancer is the leading cause of cancer death worldwide and it would be essential to have effective tools to diagnose the disease in its early stages, to identify individuals at highest risk of developing the disease, and to set personalised therapies. The effectiveness of screening for lung cancer with low dose CT (LDCT) in heavy smokers was demonstrated, in terms of reduction of cause specific mortality, in recently published data by the study National Lung ScreeningTrial (NLST). In Europe, the introduction of LDCT as screening in individuals at risk is the object of a debate until the results of European randomized trials, expected in 2015-2016, are published. One problem is the high rate of calls for investigations when there is a noncalcified nodule, and it is therefore essential to be able to more accurately identify malignant nodules. The development of specific biomarkers appears to offer promising prospects. Recent advances in genetics and genomics have led to a series of studies aimed at the identification of molecular markers for the diagnosis, the assessment of the risk of developing lung cancer, the molecular characterisation of the different stages of the disease and the personalisation of therapy. Subjects enrolled in trials evaluating LCDT as a test for early detection of lung cancer represent the ideal population in which to study a combined bioinstrumental approach of screening (molecular test and LDCT). This paper reports on the state of knowledge on the possible use of biomarkers in the early detection of lung cancer and molecular analysis conducted within the project ITALUNG, a randomized controlled trial to assess the effect on tumour-specific mortality of LDCT, which provided a collection of biological materials from the subjects enrolled. PMID- 26951736 TI - [Proposal of an Italian national protocol of health surveillance for former asbestos workers: an ongoing project]. AB - OBJECTIVES: to define an Italian national protocol of post-occupational health surveillance for asbestos workers according to effectiveness, appropriateness, saving, and social utility. DESIGN: data for 1,071 former asbestos workers from several Italian Regions were collected and analysed. For these workers, a retrospective estimate of asbestos exposure was carried out. A cohort study of 1,588 asbestos workers recruited from 2000 onward during statutory health examinations in Veneto and followed-up for lung cancer mortality until December 2010 was executed. A literature search on methods of follow-up of asbestos workers (imaging, spirometry, and questionnaires) and diagnosis of non-malignant (asbestosis and pleural plaques) and malignant (lung cancer) asbestos disease was done. A consensus, i.e., a process of agreeing on one result among the participants, was made. SETTING AND PARTICIPANTS: 19 Italian Regions (North: Veneto, Emilia-Romagna, Lombardia, Piemonte, Valle d'Aosta, Autonomous Province of Trento, Autonomous Province of Bolzano, Friuli Venezia Giulia, Liguria; Centre:Toscana, Umbria; South and Islands: Calabria, Abruzzo, Puglia, Campania, Basilicata,Marche, Sicilia, Sardegna), Department of Occupational Medicine at Italian National Institute for Compensation ofWork-Related Diseases and Accidents (INAIL), and Department of Cardiac, Thoracic, and Vascular Sciences at University of Padova. MAIN OUTCOME MEASURES: analysis of current regional experiences on health surveillance; retrospective estimate of asbestos exposure; data collection and analysis of a cohort of asbestos workers; search of the relevant literature; final report with the consensus document. RESULTS: the results obtained in each of the above areas of research, along with the relevant findings of the literature, were presented and discussed among the participants. The several phases of expression and evaluation of the participants' opinions were conducted according to an iterative method of investigation (Delphi method), which allows a progressive converging of different views into one shared result. CONCLUSION: based on all the above, a consensus has been reached on a proposal for an Italian national protocol of health surveillance for asbestos workers. PMID- 26951737 TI - Bullous Fixed Drug Eruption Probably Induced by Paracetamol. AB - We report a case of a 42-year-old male who presented with second episode of bullous eruptions after ingestion of paracetamol. There were no systemic complaints. The temporal correlation with the drug, history of a similar episode and the quick improvement led us to a diagnosis of bullous fixed drug due to paracetamol. Applying Naranjo's algorithm, a causality score of 8 was obtained and was categorized as probable reaction to paracetamol. Clinicians should be vigilant of the possible adverse reactions to drugs with robust safety profiles. Drug alert cards could play an important role in preventing recurrences. PMID- 26951735 TI - [Time trend in mesothelioma and lung cancer risk in asbestos workers in Italy]. AB - This study aims at investigating, in asbestos exposed workers, the time trend of their risk of mesothelioma and of other neoplasm after very long latency and after the cessation of asbestos exposure. We pooled a large number of Italian cohorts of asbestos workers and updated mortality follow-up. The pool of data for statistical analyses includes 51,988 workers, of which 6,058 women: 54.2% was alive at follow-up, 42.6% was dead, and 2.8%was lost. Cause of death is known for 94.3%: 2,548 deaths from lung cancer, 748 frompleural cancer, 173 fromperitoneal cancer, and 434 from asbestosis. An exposure index is being developed to compare the different cohorts. Data analysis is in progress. This study will have the size for analysing not only time trends in mesothelioma, but also the occurrence of rarer diseases and cancer specific mortality in women. PMID- 26951739 TI - Effect of hypovolemia on traumatic spinal cord injury. AB - OBJECTIVES: Experimentally evaluate the effect of hypovolemia in acute traumatic spinal cord injury. METHODS: Twenty adult male Wistar rats were submitted to traumatic spinal cord injury through spinal cord contusion by direct impact. Ten animals were subjected to bleeding of 20% of their estimated blood to simulate a hypovolemic condition after spinal cord contusion and 10 animals were used as control. The animals were evaluated before, 1, 3, 7 and 14 days after the production of the spinal cord injury through behavioral tests (inclined plane test and motor assessment). RESULTS: The spinal cord contusion associated with hypovolemia had a negative influence on functional outcomes of the spinal cord injury. The animals submitted to hypovolemia after spinal cord contusion had lower scores in behavioral tests (inclined plane test and motor assessment), presenting a slower recovery of the motor function. CONCLUSION: In the experimental model used, the group of animals with hypovolemia after traumatic spinal cord injury had slower recovery and lower intensity in behavioral tests. PMID- 26951738 TI - Anxiety prevalence following spinal cord injury: a meta-analysis. AB - STUDY DESIGN: Meta-analysis. OBJECTIVES: Prevalence estimates indicate that anxiety following spinal cord injury (SCI) is a common problem. However, methodological differences between studies may impact the clinical interpretation of these data. METHODS: Data from 18 independent studies (Nparticipants=3158), which reported the prevalence of an anxiety disorder or associated symptoms, were identified from the Embase, PubMed and PsycInfo databases. Proportions were the primary effect size estimate. Confidence intervals, fail-safe Ns and the I(2) statistic were additionally calculated to identify the extent to which findings were robust and consistent across studies. RESULTS: Five per cent of participants met the criteria for either GAD or panic disorder, with Agoraphobia identified in 2.5%. These diagnostic data were, however, limited to two studies. Higher rates were noted for self-reported 'caseness' of anxiety, with 27% reporting clinically significant symptoms. Anxiety prevalence estimates varied across the individual self-report measures (range: 15-32%). Method of administration (range: 26-32%) did not impact significantly on these estimates nor did recruitment source, with similarly high anxiety levels reported by hospital (27%) and community (29%) samples. CONCLUSIONS: Early identification and treatment of anxiety are important in SCI rehabilitation, with a subgroup of individuals experiencing chronic symptoms. Further research is needed to establish guidelines for the interpretation of self-report data, including the use of clinical cutoffs. PMID- 26951740 TI - Enhancing biomass and ethanol production by increasing NADPH production in Synechocystis sp. PCC 6803. AB - This study demonstrates that increased NADPH production can improve biomass and ethanol production in cyanobacteria. We over-expressed the endogenous zwf gene, which encodes glucose-6-phosphate dehydrogenase of pentose phosphate pathway, in the model cyanobacterium Synechocystis sp. PCC 6803. zwf over-expression resulted in increased NADPH production, and promoted biomass production compared to the wild type in both autotrophic and mixotrophic conditions. Ethanol production pathway including NADPH-dependent alcohol dehydrogenase was also integrated with and without zwf over-expression. Excessive NADPH production by zwf over expression could improve both biomass and ethanol production in the autotrophic conditions. PMID- 26951741 TI - Medium engineering for enhanced production of undecylprodigiosin antibiotic in Streptomyces coelicolor using oil palm biomass hydrolysate as a carbon source. AB - In this study, a biosugar obtained from empty fruit bunch (EFB) of oil palm by hot water treatment and subsequent enzymatic saccharification was used for undecylprodigiosin production, using Streptomyces coelicolor. Furfural is a major inhibitor present in EFB hydrolysate (EFBH), having a minimum inhibitory concentration (MIC) of 1.9mM, and it reduces utilization of glucose (27%), xylose (59%), inhibits mycelium formation, and affects antibiotic production. Interestingly, furfural was found to be a good activator of undecylprodigiosin production in S. coelicolor, which enhanced undecylprodigiosin production by up to 52%. Optimization by mixture analysis resulted in a synthetic medium containing glucose:furfural:ACN:DMSO (1%, 2mM, 0.2% and 0.3%, respectively). Finally, S. coelicolor was cultured in a fermenter in minimal medium with EFBH as a carbon source and addition of the components described above. This yielded 4.2MUg/mgdcw undecylprodigiosin, which was 3.2-fold higher compared to that in un optimized medium. PMID- 26951742 TI - Neonatal gram-negative infections, antibiotic susceptibility and clinical outcome: an observational study. AB - BACKGROUND: Neonatal gram-negative (GN) infections are associated with high mortality and morbidity. Early appropriate antibiotic treatment is vital and gentamicin is the most frequently used antibiotic on neonatal units (NNUs). Antimicrobial breakpoints are predominantly based on adult data and the relationship between minimum inhibitory concentrations (MICs) and outcome in neonates is unclear. We aimed to determine the MIC of GN pathogens causing neonatal infections and relate this to clinical outcomes. METHODS: MICs for eight antibiotics plus extended spectrum beta-lactamase (ESBL) production were determined for invasive GN bacterial isolates from eight UK NNUs. European Committee on Antimicrobial Susceptibility Testing breakpoints were applied. MIC was correlated with clinical outcome using multivariable regression analysis. RESULTS: 118 isolates from 116 patients were analysed. The median birth gestation and postnatal age was 27 weeks (IQR 24.6-32.3) and 20 days (IQR 5-44), respectively. Pathogens included Escherichia coli (51%), Klebsiella spp (23%) and Enterobacter spp (22%). 10-day attributable mortality was 18.1% (21 patients) with the highest mortality from Pseudomonas aeruginosa infections. ESBL producers accounted for 13.8% of the isolates. In regression analysis, increasing gentamicin MIC was associated with increased mortality in gentamicin treated patients across the full MIC range (OR per loge increase in MIC: 2.29; 95% CI 1.23 to 4.26, p=0.009), including susceptible isolates only (MIC <=4) (OR 3.05; 95% CI 1.10 to 8.46, p=0.032). CONCLUSIONS: Neonatal mortality from GN infections remains high and is associated with increasing gentamicin MIC, even for isolates deemed susceptible. A better understanding of population-specific MICs and aminoglycoside dosing is required to guide empiric antibiotic treatment. PMID- 26951743 TI - Primary Hepatic Small-Cell Carcinoma Developed during Antiviral Treatment for Chronic Hepatitis B. AB - Previously reported cases of primary hepatic small-cell carcinoma were all detected at progressed state with associated symptoms. Therefore, the natural course of primary hepatic small-cell carcinoma remains unknown. This case shows the natural course of primary hepatic small-cell carcinoma. We detected a 1.2 cm hypodense nodule 6 months ago in a patient with cirrhosis who had been taking entecavir. It was suspected to be a regenerating or degenerating nodule. Three months later, liver computed tomography (CT) revealed that the mass was increased to 2.1 cm with the same characteristics. The patient wanted to do a follow-up CT scan after 3 months instead of a biopsy. Another 3 months later, the mass was markedly increased, involving the whole left lobe and was confirmed as small-cell carcinoma on biopsy. Here, we report the first case of primary hepatic small-cell carcinoma developed during treatment for chronic hepatitis B with cirrhosis. PMID- 26951745 TI - Recurrent Bleeding Lip in an Adolescent Female - Chasing the Cause. PMID- 26951744 TI - Reciprocal cross infection of sticklebacks with the diphyllobothriidean cestode Schistocephalus solidus reveals consistent population differences in parasite growth and host resistance. AB - BACKGROUND: In host-parasite evolutionary arms races, parasites are generally expected to adapt more rapidly, due to their large population sizes and short generation times. There exist systems, though, where parasites cannot outpace their hosts because of similar generation times in both antagonists. In those cases concomitant adaptation is expected. METHODS: We tested this hypothesis in the three-spined stickleback-Schistocephalus solidus tapeworm system, where generation times are comparable in both organisms. We chose two populations of sticklebacks which differ prominently in the prevalence of S. solidus and consequently in its level of selective pressure. We performed a full factorial common garden experiment. Particularly, Norwegian (NO) and German (DE) sticklebacks, as well as hybrids between both stickleback populations and in both parental combinations, were exposed each to a single S. solidus originating from the same two host populations. RESULTS: We found the infection phenotype to depend on the host population, the parasite population, but not their interaction. NO-parasites showed higher infectivity than DE-parasites, with NO sticklebacks also being more resistant to DE-parasites than to the sympatric NO parasite. Reciprocally, DE-hosts were more susceptible to the allopatric NO parasite while DE-parasites grew less than NO-parasites in all stickleback groups. Despite this asymmetry, the ratio of worm to host weight, an indicator of parasite virulence, was identical in both sympatric combinations, suggesting an optimal virulence as a common outcome of parallel coevolved systems. In hybrid sticklebacks, intermediate infection rates and growth of S. solidus from either origin suggests a simple genetic basis of resistance. However, comparison of infection phenotypes in NO-maternal and DE-maternal hybrid sticklebacks indicates local adaptation to the sympatric counterpart in both the host and the parasite. CONCLUSIONS: Host-parasite systems with similar generation time show evidence for concomitant reciprocal adaptation resulting in parasite optimal virulence and host parasite specific resistance. PMID- 26951747 TI - Towards population-level conservation in the critically endangered Antarctic blue whale: the number and distribution of their populations. AB - Population-level conservation is required to prevent biodiversity loss within a species, but it first necessitates determining the number and distribution of populations. Many whale populations are still depleted due to 20th century whaling. Whales are one of the most logistically difficult and expensive animals to study because of their mobility, pelagic lifestyle and often remote habitat. We tackle the question of population structure in the Antarctic blue whale (Balaenoptera musculus intermedia) - a critically endangered subspecies and the largest extant animal - by capitalizing on the largest genetic dataset to date for Antarctic blue whales. We found evidence of three populations that are sympatric in the Antarctic feeding grounds and likely occupy separate breeding grounds. Our study adds to knowledge of population structure in the Antarctic blue whale. Future research should invest in locating the breeding grounds and migratory routes of Antarctic blue whales through satellite telemetry to confirm their population structure and allow population-level conservation. PMID- 26951749 TI - Design, syntheses, and anti-tuberculosis activities of conjugates of piperazino 1,3-benzothiazin-4-ones (pBTZs) with 2,7-dimethylimidazo [1,2-a]pyridine-3 carboxylic acids and 7-phenylacetyl cephalosporins. AB - Tuberculosis (TB) remains one of the most threatening diseases in the world and the need for development of new therapies is dire. Herein we describe the rationale for the design and subsequent syntheses and studies of conjugates between pBTZ and both the imidazopyridine and cephalosporin scaffolds. Overall some compounds exhibited notable anti-TB activity in the range of 2-0.2 MUM in the Microplate Alamar Blue (MABA) Assay. PMID- 26951750 TI - Identification of a 5-[3-phenyl-(2-cyclic-ether)-methylether]-4-aminopyrrolo[2,3 d]pyrimidine series of IGF-1R inhibitors. AB - We report structure-guided modifications of the benzyloxy substituent of the Insulin-like Growth Factor-1 Receptor (IGF-1R) inhibitor NVP-AEW541. This chemical group has been shown to confer selectivity against other protein kinases but at the expense of a metabolism liability. X-ray crystallography has revealed that the benzyloxy moiety interacts with a lysine cation of the IGF-1R kinase domain via its ether function and its aromatic pi-system and is nicely embedded in an induced hydrophobic pocket. We show that 1,4-diethers displaying an adequate hydrophobic and constrained shape are advantageous benzyloxy replacements. A single digit nanomolar inhibitor (compound 20, IC50=8.9 nM) was identified following this approach. PMID- 26951751 TI - Derivatization of agelastatin A leading to bioactive analogs and a trifunctional probe. AB - (-)-Agelastatin A (AglA, 1), a member of the pyrrole-aminoimidazole marine alkaloid (PAI) family, possesses a unique tetracyclic structure and is one of the most potent anticancer PAIs isolated to date. In efforts to expand the SAR of these agents and delineate sites that tolerate modification while retaining activity, we synthesized several derivatives and tested their anticancer activity. The cytotoxic effects of these derivatives were measured against several cancer cell lines including cervical cancer (HeLa), epidermoid carcinoma (A431), ovarian (Igrov and Ovcar3), osteosarcoma (SJSA1), acute T cell leukemia (A3), epidermoid carcinoma (A431) in addition to primary human chronic lymphocytic leukemia (CLL) cells. New positions for modification of AglA and new substitutions were explored leading to novel derivatives, 14-chloro AglA (3) and 14-methyl AglA (12), that retained activity toward various cancer cell lines with decreased toxicity toward B- and T-cells. The SAR data informed the synthesis of a trifunctional probe bearing an alkyne and a diazirine potentially useful for cellular target identification. PMID- 26951752 TI - Anti-tumor activity of exopolysaccharide from Rhizopus nigricans Ehrenb on S180 tumor-bearing mice. AB - In this study, the effect of antitumor and immune activities of extracellular polysaccharides (EPS) from Rhizopus nigricans Ehrenb were investigated using S180 bearing mice. The results revealed that EPS in the concentration range 50-1000 MUg/mL can inhibited S180 cell proliferation in a dose dependent manner. EPS at the highest dose of 1000 MUg/mL showed significantly antitumor activity against S180 with inhibition rate of 47.53%. However, EPS significantly simulated spleen lymphocytes in the concentration of 500 MUg/mL, and the increase proliferation ability showed a dose-dependent effect with EPS at the dose of 50-500 MUg/mL. In comparison with the control groups, the weights of tumor were declined and the inhibition rates of tumor were remarkably decreased in the treated groups. Pretreatment with EPS at the dose of 75 mg/kg/day, the inhibition rate was decreased by 44.38% (P<0.05). EPS increased the concentrations of IL-2 and TNF-a. The pathological changes of model control group were very obvious. Meanwhile, the prophylactic administration of EPS could more efficiently inhibit the growth of S180 tumor than direct administration of EPS. EPS could prolong the survival period of S180 tumor bearing mice, and the doses 75 mg/kg/day of EPS and combined with cyclophosphamide (20 mg/kg/day) were 43.36% and 36.28% respectively compared to control groups (P<0.05). The results suggested EPS confirmed in vivo anti tumor effects observed in vitro, and the mechanism of anti-tumor effect of EPS may be at least in part mediated by increased immune activity in host. PMID- 26951754 TI - Cardioscopic Tool-delivery Instrument for Beating-heart Surgery. AB - This paper describes an instrument that provides solutions to two open challenges in beating-heart intracardiac surgery - providing high-fidelity imaging of tool tissue contact and controlling tool penetration into tissue over the cardiac cycle. Tool delivery is illustrated in the context of tissue removal for which these challenges equate to visualization of the tissue as it is being removed and to control of cutting depth. Cardioscopic imaging is provided by a camera and illumination system encased in an optical window. When the optical window is pressed against tissue, it displaces the blood between the camera and tissue allowing clear visualization. Control of cutting depth is achieved via precise extension of the cutting tool from a port in the optical window. Successful tool use is demonstrated in ex vivo and in vivo experiments. PMID- 26951753 TI - Optimisation of a 5-[3-phenyl-(2-cyclic-ether)-methyl-ether]-4 aminopyrrolopyrimidine series of IGF-1R inhibitors. AB - Taking the pyrrolopyrimidine derived IGF-1R inhibitor NVP-AEW541 as the starting point, the benzyl ether back-pocket binding moiety was replaced with a series of 2-cyclic ether methyl ethers leading to the identification of novel achiral [2.2.1]-bicyclic ether methyl ether containing analogues with improved IGF-1R activities and kinase selectivities. Further exploration of the series, including a fluorine scan of the 5-phenyl substituent, and optimisation of the sugar-pocket binding moiety identified compound 33 containing (S)-2-tetrahydrofuran methyl ether 6-fluorophenyl ether back-pocket, and cis-N-Ac-Pip sugar-pocket binding groups. Compound 33 showed improved selectivity and pharmacokinetics compared to NVP-AEW541, and produced comparable in vivo efficacy to linsitinib in inhibiting the growth of an IGF-1R dependent tumour xenograft model in the mouse. PMID- 26951755 TI - Carcinoma Cuniculatum: Usefulness of Radiological Assessment. PMID- 26951756 TI - Lithium Protects Against Anaesthesia Neurotoxicity In The Infant Primate Brain. AB - Exposure of infant animals, including non-human primates (NHPs), to anaesthetic drugs causes apoptotic death of neurons and oligodendrocytes (oligos) and results in long-term neurodevelopmental impairment (NDI). Moreover, retrospective clinical studies document an association between anaesthesia exposure of human infants and significant increase in NDI. These findings pose a potentially serious dilemma because millions of human infants are exposed to anaesthetic drugs every year as part of routine medical care. Lithium (Li) at clinically established doses is neuroprotective in various cerebral injury models. We therefore investigated whether Li also protects against anaesthesia neurotoxicity in infant NHPs. On postnatal day 6 NHPs were anaesthetized with the widely used anaesthetic isoflurane (ISO) for 5 h employing the same standards as in a human pediatric surgery setting. Co-administration of Li completely prevented the acute ISO-induced neuroapoptosis and significantly reduced ISO-induced apoptosis of oligodendroglia. Our findings are highly encouraging as they suggest that a relatively simple pharmacological manipulation might protect the developing primate brain against the neurotoxic action of anaesthetic drugs while not interfering with the beneficial actions of these drugs. Further research is needed to determine Li's potential to prevent long-term NDI resulting from ISO anaesthesia, and to establish its safety in human infants. PMID- 26951757 TI - Neuromuscular conditions associated with malignant hyperthermia in paediatric patients: A 25-year retrospective study. AB - Malignant Hyperthermia (MH) is a rare pharmacogenetic syndrome that can be fatal and the risk of MH in non RYR1-related disorders is unknown. We conducted a retrospective study to determine the prevalence of neuromuscular disorders among patients with MH at our centre. Patients who were admitted to the Hospital for Sick Children during the study period of January 1, 1990 to April 1, 2015 with a CK level > 8000 IU/L, or who received dantrolene, or who had a clinical diagnosis of MH were included. Medical records of 166 patients who met the inclusion criteria were reviewed and 13 patients were identified with MH-like reactions. Nine patients were classified as having true MH after review of the anaesthesia record and genetic testing results were available for 7 patients, 5 of whom had mutations in RYR1. Of the four patients who had severe reactions to anaesthesia but did not meet the criteria for true MH, two had Duchenne muscular dystrophy (DMD). In this retrospective study over 25 years, RYR1 mutations were the most common cause of MH in our cohort, and of these, one third had an underlying neuromuscular diagnosis. Genetic testing of RYR1 is indicated for all patients with MH, and anaesthetic precautions should be considered for any child with symptoms of neuromuscular disease. PMID- 26951759 TI - Reductive debromination of 1,2-dibromides with anisidines. AB - vic -Dibromides containing the alpha-bromocarbonyl or alpha-bromoaromatic moieties were reductively debrominated to furnish alkenes in high yield. o- and m Anisidines but not p-anisidine were found to be effective debrominating agents. The reductive debrominations were found to be trans-stereospecific. PMID- 26951758 TI - When intensity of deltamethrin resistance in Anopheles gambiae s.l. leads to loss of Long Lasting Insecticidal Nets bio-efficacy: a case study in north Cameroon. AB - BACKGROUND: In Cameroon, insecticide resistance in Anopheles (An.) gambiae s.l. has been reported in several foci, prompting further investigations on associated patterns of Long-Lasting Insecticidal Nets (LLINs) bio-efficacy. The current study, conducted from June to August 2011, explored the intensity of deltamethrin resistance in An. gambiae s.l. from Pitoa and its impact on the residual bio efficacy of LifeNet, a LLIN with deltamethrin incorporated into polypropylene nets (PND). METHODS: Two-four days old females An. gambiae s.l. reared from larval collections in Pitoa were tested for susceptibility to DDT, permethrin and deltamethrin, using standard World Health Organization (WHO) tube assays. Intensity of deltamethrin resistance was explored using WHO tube assays, but across six working concentrations from 0.001 % to 0.5 %. Bio-efficacy of unwashed and washed PND was assessed using WHO cone test. Species identification and kdr 1014 genotyping were performed on mosquito samples that were not exposed to insecticides, using PCR-RFLP and HOLA methods respectively. The Kisumu reference susceptible strain of An. gambiae s.s. was used for comparisons. RESULTS: A total of 1895 An. gambiae s.l. specimens from Pitoa were used for resistance and PND bio-efficacy testing. This mosquito population was resistant to DDT, permethrin and deltamethrin, with 18-40 min knockdown times for 50 % of tested mosquitoes and 59-77 % mortality. Deltamethrin Resistance Ratio compared with the Kisumu strain was estimated at >=500 fold. LifeNets were effective against the susceptible Kisumu (100 % knockdown (KD60min) and mortality) and the resistant Pitoa samples (95 % KD60min, 83-95 % mortality). However, the bio-efficacy gradually dropped against the Pitoa samples when nets were washed (X (2) = 35.887, df = 8, p < 0.001), and fell under the WHO efficacy threshold (80 % mortality and/or 95 % KD60min) between 10 and 15 washes. The Pitoa samples were composed of three sibling species: An. arabiensis (132/154, 86 %), An. coluzzii (19/154, 12 %) and An. gambiae s.s. (3/154, 2 %). The kdr L1014F allele was found only in An. coluzzii (Npositive = 13/19), at 34 % frequency and heterozygote stage. No specimen carried the kdr L1014S allele. CONCLUSIONS: The current study showed that LifeNet might still offer some protection against the resistant An. gambiae s.l. population from Pitoa, provided appropriate dose of insecticide is available on the nets. PMID- 26951760 TI - A Rare Report of Granuloma Multiforme. PMID- 26951748 TI - Italian cancer figures--Report 2015: The burden of rare cancers in Italy. AB - OBJECTIVES: This collaborative study, based on data collected by the network of Italian Cancer Registries (AIRTUM), describes the burden of rare cancers in Italy. Estimated number of new rare cancer cases yearly diagnosed (incidence), proportion of patients alive after diagnosis (survival), and estimated number of people still alive after a new cancer diagnosis (prevalence) are provided for about 200 different cancer entities. MATERIALS AND METHODS: Data herein presented were provided by AIRTUM population- based cancer registries (CRs), covering nowadays 52% of the Italian population. This monograph uses the AIRTUM database (January 2015), which includes all malignant cancer cases diagnosed between 1976 and 2010. All cases are coded according to the International Classification of Diseases for Oncology (ICD-O-3). Data underwent standard quality checks (described in the AIRTUM data management protocol) and were checked against rare cancer specific quality indicators proposed and published by RARECARE and HAEMACARE (www.rarecarenet.eu; www.haemacare.eu). The definition and list of rare cancers proposed by the RARECAREnet "Information Network on Rare Cancers" project were adopted: rare cancers are entities (defined as a combination of topographical and morphological codes of the ICD-O-3) having an incidence rate of less than 6 per 100,000 per year in the European population. This monograph presents 198 rare cancers grouped in 14 major groups. Crude incidence rates were estimated as the number of all new cancers occurring in 2000-2010 divided by the overall population at risk, for males and females (also for gender-specific tumours).The proportion of rare cancers out of the total cancers (rare and common) by site was also calculated. Incidence rates by sex and age are reported. The expected number of new cases in 2015 in Italy was estimated assuming the incidence in Italy to be the same as in the AIRTUM area. One- and 5-year relative survival estimates of cases aged 0-99 years diagnosed between 2000 and 2008 in the AIRTUM database, and followed up to 31 December 2009, were calculated using complete cohort survival analysis. To estimate the observed prevalence in Italy, incidence and follow-up data from 11 CRs for the period 1992-2006 were used, with a prevalence index date of 1 January 2007. Observed prevalence in the general population was disentangled by time prior to the reference date (<=2 years, 2-5 years, <=15 years). To calculate the complete prevalence proportion at 1 January 2007 in Italy, the 15-year observed prevalence was corrected by the completeness index, in order to account for those cancer survivors diagnosed before the cancer registry activity started. The completeness index by cancer and age was obtained by means of statistical regression models, using incidence and survival data available in the European RARECAREnet data. RESULTS: In total, 339,403 tumours were included in the incidence analysis. The annual incidence rate (IR) of all 198 rare cancers in the period 2000-2010 was 147 per 100,000 per year, corresponding to about 89,000 new diagnoses in Italy each year, accounting for 25% of all cancer. Five cancers, rare at European level, were not rare in Italy because their IR was higher than 6 per 100,000; these tumours were: diffuse large B-cell lymphoma and squamous cell carcinoma of larynx (whose IRs in Italy were 7 per 100,000), multiple myeloma (IR: 8 per 100,000), hepatocellular carcinoma (IR: 9 per 100,000) and carcinoma of thyroid gland (IR: 14 per 100,000). Among the remaining 193 rare cancers, more than two thirds (No. 139) had an annual IR <0.5 per 100,000, accounting for about 7,100 new cancers cases; for 25 cancer types, the IR ranged between 0.5 and 1 per 100,000, accounting for about 10,000 new diagnoses; while for 29 cancer types the IR was between 1 and 6 per 100,000, accounting for about 41,000 new cancer cases. Among all rare cancers diagnosed in Italy, 7% were rare haematological diseases (IR: 41 per 100,000), 18% were solid rare cancers. Among the latter, the rare epithelial tumours of the digestive system were the most common (23%, IR: 26 per 100,000), followed by epithelial tumours of head and neck (17%, IR: 19) and rare cancers of the female genital system (17%, IR: 17), endocrine tumours (13% including thyroid carcinomas and less than 1% with an IR of 0.4 excluding thyroid carcinomas), sarcomas (8%, IR: 9 per 100,000), central nervous system tumours and rare epithelial tumours of the thoracic cavity (5%with an IR equal to 6 and 5 per 100,000, respectively). The remaining (rare male genital tumours, IR: 4 per 100,000; tumours of eye, IR: 0.7 per 100,000; neuroendocrine tumours, IR: 4 per 100,000; embryonal tumours, IR: 0.4 per 100,000; rare skin tumours and malignant melanoma of mucosae, IR: 0.8 per 100,000) each constituted <4% of all solid rare cancers. Patients with rare cancers were on average younger than those with common cancers. Essentially, all childhood cancers were rare, while after age 40 years, the common cancers (breast, prostate, colon, rectum, and lung) became increasingly more frequent. For 254,821 rare cancers diagnosed in 2000-2008, 5-year RS was on average 55%, lower than the corresponding figures for patients with common cancers (68%). RS was lower for rare cancers than for common cancers at 1 year and continued to diverge up to 3 years, while the gap remained constant from 3 to 5 years after diagnosis. For rare and common cancers, survival decreased with increasing age. Five-year RS was similar and high for both rare and common cancers up to 54 years; it decreased with age, especially after 54 years, with the elderly (75+ years) having a 37% and 20% lower survival than those aged 55-64 years for rare and common cancers, respectively. We estimated that about 900,000 people were alive in Italy with a previous diagnosis of a rare cancer in 2010 (prevalence). The highest prevalence was observed for rare haematological diseases (278 per 100,000) and rare tumours of the female genital system (265 per 100,000). Very low prevalence (<10 prt 100,000) was observed for rare epithelial skin cancers, for rare epithelial tumours of the digestive system and rare epithelial tumours of the thoracic cavity. COMMENTS: One in four cancers cases diagnosed in Italy is a rare cancer, in agreement with estimates of 24% calculated in Europe overall. In Italy, the group of all rare cancers combined, include 5 cancer types with an IR>6 per 100,000 in Italy, in particular thyroid cancer (IR: 14 per 100,000).The exclusion of thyroid carcinoma from rare cancers reduces the proportion of them in Italy in 2010 to 22%. Differences in incidence across population can be due to the different distribution of risk factors (whether environmental, lifestyle, occupational, or genetic), heterogeneous diagnostic intensity activity, as well as different diagnostic capacity; moreover heterogeneity in accuracy of registration may determine some minor differences in the account of rare cancers. Rare cancers had worse prognosis than common cancers at 1, 3, and 5 years from diagnosis. Differences between rare and common cancers were small 1 year after diagnosis, but survival for rare cancers declined more markedly thereafter, consistent with the idea that treatments for rare cancers are less effective than those for common cancers. However, differences in stage at diagnosis could not be excluded, as 1- and 3-year RS for rare cancers was lower than the corresponding figures for common cancers. Moreover, rare cancers include many cancer entities with a bad prognosis (5-year RS <50%): cancer of head and neck, oesophagus, small intestine, ovary, brain, biliary tract, liver, pleura, multiple myeloma, acute myeloid and lymphatic leukaemia; in contrast, most common cancer cases are breast, prostate, and colorectal cancers, which have a good prognosis. The high prevalence observed for rare haematological diseases and rare tumours of the female genital system is due to their high incidence (the majority of haematological diseases are rare and gynaecological cancers added up to fairly high incidence rates) and relatively good prognosis. The low prevalence of rare epithelial tumours of the digestive system was due to the low survival rates of the majority of tumours included in this group (oesophagus, stomach, small intestine, pancreas, and liver), regardless of the high incidence rate of rare epithelial cancers of these sites. This AIRTUM study confirms that rare cancers are a major public health problem in Italy and provides quantitative estimations, for the first time in Italy, to a problem long known to exist. This monograph provides detailed epidemiologic indicators for almost 200 rare cancers, the majority of which (72%) are very rare (IR<0.5 per 100,000). These data are of major interest for different stakeholders. Health care planners can find useful information herein to properly plan and think of how to reorganise health care services. Researchers now have numbers to design clinical trials considering alternative study designs and statistical approaches. Population-based cancer registries with good quality data are the best source of information to describe the rare cancer burden in a population. PMID- 26951762 TI - Environmental and Endogenous Control of Cortical Microtubule Orientation. AB - Plant growth requires a tight coordination of cell shape and anisotropic expansion. Owing to their immobility, plant cells determine body architecture through the orientation of cell division and cell expansion. Microtubule cytoskeleton represents a versatile cellular structure essential for coordinating flexible cell morphogenesis. Previous studies have identified a large number of microtubule-associated regulators that control microtubule dynamics; however, the mechanisms by which microtubule reorientation responds to exogenous and environmental stimuli are largely unknown. In this review, we describe the molecular details of microtubule dynamics that are required for cortical microtubule array pattern formation, and recapitulate current knowledge on the mechanisms by which various environmental and endogenous stimuli control cortical microtubule reorientation. PMID- 26951761 TI - Tropical secondary forests regenerating after shifting cultivation in the Philippines uplands are important carbon sinks. AB - In the tropics, shifting cultivation has long been attributed to large scale forest degradation, and remains a major source of uncertainty in forest carbon accounting. In the Philippines, shifting cultivation, locally known as kaingin, is a major land-use in upland areas. We measured the distribution and recovery of aboveground biomass carbon along a fallow gradient in post-kaingin secondary forests in an upland area in the Philippines. We found significantly higher carbon in the aboveground total biomass and living woody biomass in old-growth forest, while coarse dead wood biomass carbon was higher in the new fallow sites. For young through to the oldest fallow secondary forests, there was a progressive recovery of biomass carbon evident. Multivariate analysis indicates patch size as an influential factor in explaining the variation in biomass carbon recovery in secondary forests after shifting cultivation. Our study indicates secondary forests after shifting cultivation are substantial carbon sinks and that this capacity to store carbon increases with abandonment age. Large trees contribute most to aboveground biomass. A better understanding of the relative contribution of different biomass sources in aboveground total forest biomass, however, is necessary to fully capture the value of such landscapes from forest management, restoration and conservation perspectives. PMID- 26951763 TI - Feature selection and validated predictive performance in the domain of Legionella pneumophila: a comparative study. AB - BACKGROUND: Genetic comparisons of clinical and environmental Legionella strains form an essential part of outbreak investigations. DNA microarrays often comprise many DNA markers (features). Feature selection and the development of prediction models are particularly challenging in this domain with many variables and comparatively few subjects or data points. We aimed to compare modeling strategies to develop prediction models for classifying infections as clinical or environmental. METHODS: We applied a bootstrap strategy for preselecting important features to a database containing 222 Legionella pneumophila strains with 448 continuous markers and a dichotomous outcome (clinical or environmental). Feature selection was done with 50 bootstrap samples resulting in a top 10 of most important features for each of four modeling techniques: classification and regression trees (CART), random forests (RF), support vector machines (SVM) and least absolute shrinkage and selection operator (LASSO). Validation was done in a second bootstrap re-sampling loop (200*) for evaluation of discriminatory model performance according to the AUC. RESULTS: The top 5 of selected features differed considerably between the various modeling techniques, with only one common feature ("LePn.007B8"). The mean validated AUC-values of the SVM model and the CART model were 0.859 and 0.873 respectively. The LASSO and the RF model showed higher validated AUC-values (0.925 and 0.975 respectively). CONCLUSIONS: In the domain of Legionella pneumophila, which comprises many potential features for classifying of infections as clinical or environmental, the RF and LASSO techniques provide good prediction models. The identification of potentially biologically relevant features is highly dependent on the technique used, and should hence be interpreted with caution. PMID- 26951765 TI - Multiple Infantile Hemangiomas Treated Successfully with Oral Propranolol. PMID- 26951764 TI - Modeling the Progression of Epithelial Leak Caused by Overdistension. AB - Mechanical ventilation is necessary for treatment of the acute respiratory distress syndrome but leads to overdistension of the open regions of the lung and produces further damage. Although we know that the excessive stresses and strains disrupt the alveolar epithelium, we know little about the relationship between epithelial strain and epithelial leak. We have developed a computational model of an epithelial monolayer to simulate leak progression due to overdistension and to explain previous experimental findings in mice with ventilator-induced lung injury. We found a nonlinear threshold-type relationship between leak area and increasing stretch force. After the force required to initiate the leak was reached, the leak area increased at a constant rate with further increases in force. Furthermore, this rate was slower than the rate of increase in force, especially at end-expiration. Parameter manipulation changed only the leak initiating force; leak area growth followed the same trend once this force was surpassed. These results suggest that there is a particular force (analogous to ventilation tidal volume) that must not be exceeded to avoid damage and that changing cell physical properties adjusts this threshold. This is relevant for the development of new ventilator strategies that avoid inducing further injury to the lung. PMID- 26951767 TI - Ischemic stroke in a young patient with Fahr's disease: a case report. AB - BACKGROUND: Fahr's disease is a rare neurodegenerative disorder characterized by diffuse intracranial calcium deposition and associated cell loss mainly in bilateral basal ganglia and dentate nuclei of the cerebellum. Subarachnoid hemorrhage and epileptic syncope had been reported as acute presentation of Fahr's disease. We here report a 36-year-old male Indonesian diagnosed as Fahr's disease presenting with young-onset ischemic stroke. CASE PRESENTATION: A 36-year old male Indonesian without prior systemic disease or neurologic disorder presented with young-onset ischemic stroke involving the right posterior limb of internal capsule. Brain computed tomography and magnetic resonance imaging demonstrated symmetric calcifications in bilateral basal ganglia, internal capsules, cerebellar dentate nuclei, thalami, cerebral white matter, which were all consistent with Fahr's disease. The laboratory studies excluded the presence of other pathologic processes leading to secondary intracranial calcification. Other young stroke surveys were unremarkable. After medical treatment and sustained physical rehabilitation for 3 months, he recovered to carry out daily activities independently. CONCLUSION: We present ischemic stroke in a young patient with sporadic Fahr's disease. The differentiation between Fahr's disease and Fahr's syndrome is specially highlighted when brain CT exhibits diffuse, symmetric calcifications in bilateral basal ganglia, thalami, cerebellar dentate nuclei and cerebral white matter. The association between nonarteriosclerotic vascular calcification and cerebrovascular disease is worth special attention and further investigation. PMID- 26951768 TI - Romberg's test no longer stands up. PMID- 26951766 TI - Quantitative proteomics study of the neuroprotective effects of B12 on hydrogen peroxide-induced apoptosis in SH-SY5Y cells. AB - B12 belongs to the coumarin class of compounds that have been shown to have various physiological and pharmacological activities including anti-inflammatory, antibacterial, and antioxidant. In the present study, we characterised the neuroprotective effects of B12 against H2O2-induced neuronal cell damage in SH SY5Y cells. Protein expression profiling in combination with pathway analysis was deployed to investigate the molecular events associated with the neuroprotective effects in human neuronal cells using a label-free quantitative proteomics approach. A total of 22 proteins were significantly differentially expressed in H2O2-damaged cells with or without B12 treatment. Bioinformatics analysis using the Cytoscape platform indicated that poly pyrimidine tract binding protein 1 (PTBP1) was highly associated with the protective effect, and western blotting verified that PTBP1 was up-regulated in H2O2 + B12 treatment group, compared with the H2O2 treated group. PTBP RNAi experiments knocked down PTBP expression, which cancelled out the protective effect of B12 on cell viability. Thus, we infer that B12 neuroprotective activity involves up-regulation of PTBP1 and its associated signalling networks following H2O2-induced apoptosis in SH-SY5Y cells. B12 or related compounds may prove to be useful therapeutic agents for the treatment of neurodegenerative diseases such as Alzheimer's and Parkinson's. PMID- 26951769 TI - Preface to 'Neuromythology'. PMID- 26951770 TI - Short-term choroidal thickness changes in patients treated with either ranibizumab or aflibercept: a comparative study. AB - PURPOSE: To compare, in neovascular age-related macular degeneration (AMD) patients, short-term choroidal thickness changes in eyes treated using ranibizumab with those in eyes treated using aflibercept. METHODS: This retrospective, observational study included 240 eyes from 240 patients who had been diagnosed with treatment-naive neovascular AMD and treated using three monthly injections of either ranibizumab (ranibizumab group) or aflibercept (aflibercept group). The choroidal thickness change between the time of diagnosis and 3 months later was compared between the two groups. Eyes were then classified into three disease groups: typical neovascular AMD, polypoidal choroidal vasculopathy (PCV) and retinal angiomatous proliferation (RAP). Within each disease group, choroidal thickness change was again compared between the two treatment groups. RESULTS: In the ranibizumab group (n=155), the mean choroidal thicknesses at diagnosis and at 3 months were 255.3+/-103.9 MUm and 242.9+/-104.8 MUm, respectively. In the aflibercept group (n=85), the values were 277.5+/-119.1 MUm and 254.7+/-114.5 MUm, respectively. The decrease was significantly greater in the aflibercept group (p<0.001). In the PCV group, the decrease was greater in the aflibercept group (p=0.001), whereas the difference was not significant in either the typical neovascular AMD group or the RAP group. CONCLUSIONS: A greater decrease in choroidal thickness was noted in eyes treated with aflibercept than in eyes treated with ranibizumab. This difference was more marked in PCV than in other subtypes of neovascular AMD. PMID- 26951771 TI - Optical coherence tomography angiography in adult-onset foveomacular vitelliform dystrophy. AB - PURPOSE: To describe structural features of eyes with adult-onset foveomacular vitelliform dystrophy (AFVD) on optical coherence tomography angiography (OCT-A) and to evaluate the ability to detect the presence of choroidal neovascularisation (CNV). METHODS: Consecutive patients presenting at the University Eye Clinic of Creteil with diagnosis of AFVD were included. All patients underwent a complete ophthalmological examination, including fundus autofluorescence, fluorescein angiography, indocyanine green angiography, spectral domain optical coherence tomography and OCT-A by Optovue RTVue XR Avanti. RESULTS: Twenty-two eyes of 18 consecutive patients (8 women and 10 men; 68+/-12.8 years) were included. On OCT-A the presence of subretinal material leads to displacement of blood vessels at both the superficial and deep capillary plexuses of the retina. In one case, these vascular abnormalities were associated with long filamentous vessels running thorough the foveal avascular area. In all cases, a rarefaction of the choriocapillaris was also observed. In two eyes OCT-A distinctly disclosed the presence of a CNV secondary to AFVD while conventional imaging did not show clearly the neovascularisation due to masking effect of the subretinal vitelliform material. CONCLUSIONS: In patients with AFVD, OCT-A showed vascular network rarefaction with less blood vessels at the superficial and deep capillary plexuses, and the choriocapillaris layer. These vascular abnormalities may play a role in the pathogenesis or simply represent a consequence of material accumulation and reabsorption in AFVD. In two cases, the conventional imaging did not show clearly the neovascularisation due to masking effect of the subretinal vitelliform material, while OCT-A showed distinctly the CNV. PMID- 26951772 TI - Randomised controlled trial of video clips and interactive games to improve vision in children with amblyopia using the I-BiT system. AB - BACKGROUND: Traditional treatment of amblyopia involves either wearing a patch or atropine penalisation of the better eye. A new treatment is being developed on the basis of virtual reality technology allowing either DVD footage or computer games which present a common background to both eyes and the foreground, containing the imagery of interest, only to the amblyopic eye. METHODS: A randomised control trial was performed on patients with amblyopia aged 4-8 years with three arms. All three arms had dichoptic stimulation using shutter glass technology. One arm had DVD footage shown to the amblyopic eye and common background to both, the second used a modified shooter game, Nux, with sprite and targets presented to the amblyopic eye (and background to both) while the third arm had both background and foreground presented to both eyes (non-interactive binocular treatment (non-I-BiT) games). RESULTS: Seventy-five patients were randomised; 67 were residual amblyopes and 70 had an associated strabismus. The visual acuity improved in all three arms by approximately 0.07 logMAR in the amblyopic eye at 6 weeks. There was no difference between I-BiT DVD and non-I-BiT games compared with I-BiT games (stated primary outcome) in terms of gain in vision. CONCLUSIONS: There was a modest vision improvement in all three arms. Treatment was well tolerated and safe. There was no difference between the three treatments in terms of primary stated outcomes but treatment duration was short and the high proportion of previously treated amblyopia and strabismic amblyopia disadvantaged dichoptic stimulation treatment. TRIAL REGISTRATION NUMBER: NCT01702727, results. PMID- 26951774 TI - An Exploratory Investigation of Important Qualities and Characteristics of Alcoholics Anonymous Sponsors. AB - Alcoholics Anonymous recommends members to have sponsors, especially those early in their recovery, yet little research has been done on the qualities of an effective sponsor. 245 adults (117 females, 128 males) currently in substance use disorder recovery participated. 231 of these individuals had experience as a sponsor, sponsee or both (109 had experience as a sponsor). Qualitative results suggest effective sponsors are currently engaged in the program on a personal level, are trustworthy, and are available although a wide variety of attributes were cited. In a choice and ranking exercise, 12- step engagement and qualities of character were also most often ranked highly. No significant differences were found between genders or sponsor/sponsee roles. Implications based on breadth of responses and dominant themes are discussed as well as the need for further research on sponsor/sponsee characteristics, satisfaction, and recovery outcomes. PMID- 26951773 TI - Outcomes of intravitreal anti-VEGF therapy in eyes with both neovascular age related macular degeneration and diabetic retinopathy. AB - PURPOSE: To investigate the outcomes of intravitreal antivascular endothelial growth factor (VEGF) therapy in eyes with both neovascular age-related macular degeneration (AMD) and diabetic retinopathy (DR). METHODS: Patients from four high-volume referral centres who presented with neovascular AMD and DR, and received intravitreal anti-VEGF therapy, were included. Data retrieved from medical records and multimodal imaging were analysed. RESULTS: Forty-one eyes of 38 patients (21 male, 17 female; mean age 78+/-8 years) were enrolled. Median follow-up was 28+/-19 (12-72) months with a mean of 9.2+/-7.4 intravitreal anti VEGF injections per eye were administrated. Best-corrected visual acuity (BCVA) was 0.5+/-0.3 logMAR; it improved significantly at 1 year (0.3+/-0.3 logMAR; p=0.02) and returned to baseline values at last follow-up visit (0.6+/-0.4 logMAR; p=0.26). Mean central macular thickness (CMT) significantly decreased from 408+/-150 MUm to 328+/-104 MUm at 1 year (p=0.021) and to 335+/-127 MUm at last follow-up visit (p=0.032). The baseline severity of DR was graded as mild non-proliferative DR (NPDR) in 21 (51%) eyes, moderate NPDR in 14 (34%), severe NPDR in 4 (10%) and inactive proliferative DR in 2 (5%). At last follow-up visit, one eye graded as moderate NPDR improved to mild, one eye graded as severe NPDR improved to mild and one eye graded as severe NPDR was inactivated due to panretinal photocoagulation. CONCLUSIONS: Outcomes analysis of intravitreal anti VEGF therapy for eyes with both neovascular AMD and DR showed stabilisation of BCVA and reduction of CMT, along with stable or improved DR stage throughout follow-up. PMID- 26951775 TI - Simulating the Kibble-Zurek mechanism of the Ising model with a superconducting qubit system. AB - The Kibble-Zurek mechanism (KZM) predicts the density of topological defects produced in the dynamical processes of phase transitions in systems ranging from cosmology to condensed matter and quantum materials. The similarity between KZM and the Landau-Zener transition (LZT), which is a standard tool to describe the dynamics of some non-equilibrium physics in contemporary physics, is being extensively exploited. Here we demonstrate the equivalence between KZM in the Ising model and LZT in a superconducting qubit system. We develop a time-resolved approach to study quantum dynamics of LZT with nano-second resolution. By using this technique, we simulate the key features of KZM in the Ising model with LZT, e.g., the boundary between the adiabatic and impulse regions, the freeze-out phenomenon in the impulse region, especially, the scaling law of the excited state population as the square root of the quenching speed. Our results provide the experimental evidence of the close connection between KZM and LZT, two textbook paradigms to study the dynamics of the non-equilibrium phenomena. PMID- 26951776 TI - Cutaneous Botryomycosis: A Rare Case Report. PMID- 26951778 TI - Herbivory in the soft coral Sinularia flexibilis (Alcyoniidae). AB - Our work provides strong support for the hypothesis that Sinularia flexibilis ingests diatoms such as Thalassiosira pseudonana. We assessed algal ingestion by S. flexibilis through estimates of algal removal, histological analyses, scanning electron microscopy observations, and gene expression determination (18S and silicon transporter 1) by real time PCR. Cell counts are strongly suggestive of algal removal by the coral; light and scanning microscopy provide qualitative evidence for the ingestion of T. pseudonana by S. flexibilis, while molecular markers did not prove to be sufficiently selective/specific to give clear results. We thus propose that previous instances of inability of corals to ingest algae are reconsidered using different technical approach, before concluding that coral herbivory is not a general feature. PMID- 26951777 TI - Study protocol of SWEPIS a Swedish multicentre register based randomised controlled trial to compare induction of labour at 41 completed gestational weeks versus expectant management and induction at 42 completed gestational weeks. AB - BACKGROUND: Observational data shows that postterm pregnancy (>=42 gestational weeks, GW) and late term pregnancy (>=41 GW), as compared to term pregnancy, is associated with an increased risk for adverse outcome for the mother and infant. Standard care in many countries is induction of labour at 42 GW. There is insufficient scientific support that induction of labour at 41 GW, as compared with expectant management and induction at 42 GW will reduce perinatal mortality and morbidity without an increase in operative deliveries, negative delivery experiences or higher costs. Large randomised studies are needed since important outcomes; such as perinatal mortality and hypoxic ischaemic encephalopathy are rare events. METHODS/DESIGN: A total of 10 038 healthy women >=18 years old with a normal live singleton pregnancy in cephalic presentation at 41 GW estimated with a first or second trimester ultrasound, who is able to understand oral and written information will be randomised to labour induction at 41 GW (early induction) or expectant management and induction at 42 GW (late induction). Women will be recruited at university clinics and county hospitals in Sweden comprising more than 65 000 deliveries per year. Primary outcome will be a composite of stillbirth, neonatal mortality and severe neonatal morbidity. Secondary outcomes will be other adverse neonatal and maternal outcomes, mode of delivery, women's experience, cost effectiveness and infant morbidity up to 3 months of age. Data on background variables, obstetric and neonatal outcomes will be obtained from the Swedish Pregnancy Register and the Swedish Neonatal Quality Register. Data on women's experiences will be collected by questionnaires after randomisation and 3 months after delivery. Primary analysis will be intention to treat. The statistician will be blinded to group and intervention. DISCUSSION: It is important to investigate if an intervention at 41 GW is superior to standard care in order to reduce death and lifelong disability for the children. The pregnant population, >41 GW, constitutes 15-20% of all pregnancies and the results of the study will thus have a great impact. The use of registries for randomisation and collection of outcome data represents a unique and new study design. TRIAL REGISTRATION: The study was registered in Current Controlled Trials, ISRCTN26113652 the 30(th) of March 2015 (DOI 10.1186/ISRCTN26113652 ). PMID- 26951779 TI - Genome Sequencing of the Phytoseiid Predatory Mite Metaseiulus occidentalis Reveals Completely Atomized Hox Genes and Superdynamic Intron Evolution. AB - Metaseiulus occidentalis is an eyeless phytoseiid predatory mite employed for the biological control of agricultural pests including spider mites. Despite appearances, these predator and prey mites are separated by some 400 Myr of evolution and radically different lifestyles. We present a 152-Mb draft assembly of the M. occidentalis genome: Larger than that of its favored prey, Tetranychus urticae, but considerably smaller than those of many other chelicerates, enabling an extremely contiguous and complete assembly to be built-the best arachnid to date. Aided by transcriptome data, genome annotation cataloged 18,338 protein coding genes and identified large numbers of Helitron transposable elements. Comparisons with other arthropods revealed a particularly dynamic and turbulent genomic evolutionary history. Its genes exhibit elevated molecular evolution, with strikingly high numbers of intron gains and losses, in stark contrast to the deer tick Ixodes scapularis Uniquely among examined arthropods, this predatory mite's Hox genes are completely atomized, dispersed across the genome, and it encodes five copies of the normally single-copy RNA processing Dicer-2 gene. Examining gene families linked to characteristic biological traits of this tiny predator provides initial insights into processes of sex determination, development, immune defense, and how it detects, disables, and digests its prey. As the first reference genome for the Phytoseiidae, and for any species with the rare sex determination system of parahaploidy, the genome of the western orchard predatory mite improves genomic sampling of chelicerates and provides invaluable new resources for functional genomic analyses of this family of agriculturally important mites. PMID- 26951780 TI - In Silico Identification of Candidate Genes for Fertility Restoration in Cytoplasmic Male Sterile Perennial Ryegrass (Lolium perenne L.). AB - Perennial ryegrass (Lolium perenne L.) is widely used for forage production in both permanent and temporary grassland systems. To increase yields in perennial ryegrass, recent breeding efforts have been focused on strategies to more efficiently exploit heterosis by hybrid breeding. Cytoplasmic male sterility (CMS) is a widely applied mechanism to control pollination for commercial hybrid seed production and although CMS systems have been identified in perennial ryegrass, they are yet to be fully characterized. Here, we present a bioinformatics pipeline for efficient identification of candidate restorer of fertility (Rf) genes for CMS. From a high-quality draft of the perennial ryegrass genome, 373 pentatricopeptide repeat (PPR) genes were identified and classified, further identifying 25 restorer of fertility-like PPR (RFL) genes through a combination of DNA sequence clustering and comparison to known Rf genes. This extensive gene family was targeted as the majority of Rf genes in higher plants are RFL genes. These RFL genes were further investigated by phylogenetic analyses, identifying three groups of perennial ryegrass RFLs. These three groups likely represent genomic regions of active RFL generation and identify the probable location of perennial ryegrass PPR-Rf genes. This pipeline allows for the identification of candidate PPR-Rf genes from genomic sequence data and can be used in any plant species. Functional markers for PPR-Rf genes will facilitate map-based cloning of Rf genes and enable the use of CMS as an efficient tool to control pollination for hybrid crop production. PMID- 26951783 TI - Generating Tonal Distinctions in Mandarin Chinese Using an Electrolarynx with Preprogrammed Tone Patterns. AB - An electrolarynx (EL) is a valuable rehabilitative option for individuals who have undergone laryngectomy, but current monotone ELs do not support controlled variations in fundamental frequency for producing tonal languages. The present study examined the production and perception of Mandarin Chinese using a customized hand-held EL driven by computer software to generate tonal distinctions (tonal EL). Four native Mandarin speakers were trained to articulate their speech coincidentally with preprogrammed tonal patterns in order to produce mono- and di-syllabic words with a monotone EL and tonal EL. Three native Mandarin speakers later transcribed and rated the speech samples for intelligibility and acceptability. Results indicated that words produced using the tonal EL were significantly more intelligible and acceptable than those produced using the monotone EL. PMID- 26951784 TI - Scleromyxedema Clinically Resembling to Scleroderma. PMID- 26951781 TI - Spermatogenesis Drives Rapid Gene Creation and Masculinization of the X Chromosome in Stalk-Eyed Flies (Diopsidae). AB - Throughout their evolutionary history, genomes acquire new genetic material that facilitates phenotypic innovation and diversification. Developmental processes associated with reproduction are particularly likely to involve novel genes. Abundant gene creation impacts the evolution of chromosomal gene content and general regulatory mechanisms such as dosage compensation. Numerous studies in model organisms have found complex and, at times contradictory, relationships among these genomic attributes highlighting the need to examine these patterns in other systems characterized by abundant sexual selection. Therefore, we examined the association among novel gene creation, tissue-specific gene expression, and chromosomal gene content within stalk-eyed flies. Flies in this family are characterized by strong sexual selection and the presence of a newly evolved X chromosome. We generated RNA-seq transcriptome data from the testes for three species within the family and from seven additional tissues in the highly dimorphic species,Teleopsis dalmanni Analysis of dipteran gene orthology reveals dramatic testes-specific gene creation in stalk-eyed flies, involving numerous gene families that are highly conserved in other insect groups. Identification of X-linked genes for the three species indicates that the X chromosome arose prior to the diversification of the family. The most striking feature of this X chromosome is that it is highly masculinized, containing nearly twice as many testes-specific genes as expected based on its size. All the major processes that may drive differential sex chromosome gene content-creation of genes with male specific expression, development of male-specific expression from pre-existing genes, and movement of genes with male-specific expression-are elevated on the X chromosome ofT. dalmanni This masculinization occurs despite evidence that testes expressed genes do not achieve the same levels of gene expression on the X chromosome as they do on the autosomes. PMID- 26951782 TI - Speciation in Cloudless Sulphurs Gleaned from Complete Genomes. AB - For 200 years, zoologists have relied on phenotypes to learn about the evolution of animals. A glance at the genotype, even through several gene markers, revolutionized our understanding of animal phylogeny. Recent advances in sequencing techniques allow researchers to study speciation mechanisms and the link between genotype and phenotype using complete genomes. We sequenced and assembled a complete genome of the Cloudless Sulphur (Phoebis sennae) from a single wild-caught specimen. This genome was used as reference to compare genomes of six specimens, three from the eastern populations (Oklahoma and north Texas), referred to as a subspeciesPhoebis sennae eubule, and three from the southwestern populations (south Texas) known as a subspeciesPhoebis sennae marcellina While the two subspecies differ only subtly in phenotype and mitochondrial DNA, comparison of their complete genomes revealed consistent and significant differences, which are more prominent than those between tiger swallowtailsPterourus canadensisandPterourus glaucus The two sulphur taxa differed in histone methylation regulators, chromatin-associated proteins, circadian clock, and early development proteins. Despite being well separated on the whole-genome level, the two taxa show introgression, with gene flow mainly fromP. s. marcellinatoP. s. eubule Functional analysis of introgressed genes reveals enrichment in transmembrane transporters. Many transporters are responsible for nutrient uptake, and their introgression may be of selective advantage for caterpillars to feed on more diverse food resources. Phylogenetically, complete genomes place family Pieridae away from Papilionidae, which is consistent with previous analyses based on several gene markers. PMID- 26951785 TI - Tendinopathy and osteoarthritis: a chance to kill two birds with one stone. PMID- 26951786 TI - Corrigendum: Correlative in-resin super-resolution and electron microscopy using standard fluorescent proteins. PMID- 26951789 TI - Erratum: The role of dung beetles in reducing greenhouse gas emissions from cattle farming. PMID- 26951787 TI - Factors influencing women's preference for health facility deliveries in Jharkhand state, India: a cross sectional analysis. AB - BACKGROUND: Expanding institutional deliveries is a policy priority to achieve MDG5. India adopted a policy to encourage facility births through a conditional cash incentive scheme, yet 28% of deliveries still occur at home. In this context, it is important to understand the care experience of women who have delivered at home, and also at health facilities, analyzing any differences, so that services can be improved to promote facility births. This study aims to understand women's experience of delivery care during home and facility births, and the factors that influence women's decisions regarding their next place of delivery. METHOD: A community-based cross-sectional survey was undertaken in a district of Jharkhand state in India. Interviews with 500 recently delivered women (210 delivered at facility and 290 delivered at home) included socio demographic characteristics, experience of their recent delivery, and preference of future delivery site. Data analysis included frequencies, binary and multiple logistic regressions. RESULTS: There is no major difference in the experience of care between home and facility births, the only difference in care being with regard to pain relief through massage, injection and low cost of delivery for those having home births. 75% women wanted to deliver their next child at a facility, main reasons being availability of medicine (29.4%) and perceived health benefits for mother and baby (15%). Women with higher education (AOR = 1.67, 95% CI = 1.04-3.07), women who were above 25 years (AOR = 2.14, 95% CI = 1.26-3.64), who currently delivered at facility (AOR = 5.19, 95% CI = 2.97-9.08) and had health problem post-delivery (AOR = 1.85, 95% CI = 1.08-3.19) were significant predictors of future facility-based delivery. CONCLUSION: The predictors for facility deliveries include, availability of medicines and supplies, potential health benefits for the mother and newborn and the perception of good care from the providers. There is a growing preference for facility delivery particularly among women with higher age group, education, income and those who had antennal checkup. In order to uptake facility births, the quality improvement initiatives should regularly assess and address women's experiences of care. PMID- 26951788 TI - Pilot Outcome Results of Culturally Adapted Evidence-Based Substance Use Disorder Treatment with a Southwest Tribe. AB - INTRODUCTION: Although American Indians/Alaska Natives (AI/ANs) have exhibited high rates of alcohol and drug use disorders, there is a paucity of substance use disorder treatment outcome research. In addition, there exists controversy about whether evidence-based treatments (EBTs) are culturally appropriate given they were derived mainly by and for non-Hispanic White populations and do not explicitly include aspects of AI/AN culture and worldview. METHODS: In this pilot study, we collaboratively culturally adapted two EBTs, Motivational Interviewing and Community Reinforcement Approach (MICRA), and evaluated substance use and psychological outcomes at 4- and 8-months post baseline assessment. In preparation for a larger randomized clinical trial (RCT), eight tribal members (75% male) participated in this pilot treatment study. Measures included substance use, urine screens, self-efficacy, psychological distress, and hopelessness. All participants completed follow-up assessments at 4- and 8 months. Due to small sample size, effect sizes were calculated to evaluate outcomes pre- and post-treatment. RESULTS: Despite high rates of abstinence at baseline, percent days abstinent (PDA) increased at the 8-month time point for the most commonly used substances (alcohol, Hedges's g = 0.59, and marijuana, g = 0.60) and for all substances combined (excluding tobacco, g = 0.56). Improvements in psychological distress (g = -0.66) and 5 of the 7 Addiction Severity Index domains (range of g = -0.42 to -0.98) also emerged. CONCLUSIONS: Results suggest that culturally adapted EBTs yield significant improvements in alcohol use, psychological distress, and legal problems among AI/ANs. Future research using RCT methodology is needed to examine efficacy and effectiveness. PMID- 26951790 TI - Optimizing Design Parameters for Sets of Concentric Tube Robots using Sampling based Motion Planning. AB - Concentric tube robots are tentacle-like medical robots that can bend around anatomical obstacles to access hard-to-reach clinical targets. The component tubes of these robots can be swapped prior to performing a task in order to customize the robot's behavior and reachable workspace. Optimizing a robot's design by appropriately selecting tube parameters can improve the robot's effectiveness on a procedure-and patient-specific basis. In this paper, we present an algorithm that generates sets of concentric tube robot designs that can collectively maximize the reachable percentage of a given goal region in the human body. Our algorithm combines a search in the design space of a concentric tube robot using a global optimization method with a sampling-based motion planner in the robot's configuration space in order to find sets of designs that enable motions to goal regions while avoiding contact with anatomical obstacles. We demonstrate the effectiveness of our algorithm in a simulated scenario based on lung anatomy. PMID- 26951791 TI - Ranking reactive glutamines in the fibrinogen alphaC region that are targeted by blood coagulant factor XIII. AB - Factor XIIIa (FXIIIa) introduces covalent gamma-glutamyl-epsilon-lysyl crosslinks into the blood clot network. These crosslinks involve both the gamma and alpha chains of fibrin. The C-terminal portion of the fibrin alpha chain extends into the alphaC region (210-610). Crosslinks within this region help generate a stiffer clot, which is more resistant to fibrinolysis. Fibrinogen alphaC (233 425) contains a binding site for FXIIIa and three glutamines Q237, Q328, and Q366 that each participate in physiological crosslinking reactions. Although these glutamines were previously identified, their reactivities toward FXIIIa have not been ranked. Matrix-assisted laser desorption/ionization time of flight (MALDI TOF) mass spectrometry and nuclear magnetic resonance (NMR) methods were thus used to directly characterize these three glutamines and probe for sources of FXIIIa substrate specificity. Glycine ethyl ester (GEE) and ammonium chloride served as replacements for lysine. Mass spectrometry and 2D heteronuclear single quantum coherence NMR revealed that Q237 is rapidly crosslinked first by FXIIIa followed by Q366 and Q328. Both (15)NH4Cl and (15)N-GEE could be crosslinked to the three glutamines in alphaC (233-425) with a similar order of reactivity as observed with the MALDI-TOF mass spectrometry assay. NMR studies using the single alphaC mutants Q237N, Q328N, and Q366N demonstrated that no glutamine is dependent on another to react first in the series. Moreover, the remaining two glutamines of each mutant were both still reactive. Further characterization of Q237, Q328, and Q366 is important because they are located in a fibrinogen region susceptible to physiological truncations and mutation. The current results suggest that these glutamines play distinct roles in fibrin crosslinking and clot architecture. PMID- 26951792 TI - Neuronal activity controls transsynaptic geometry. AB - The neuronal synapse is comprised of several distinct zones, including presynaptic vesicle zone (SVZ), active zone (AZ) and postsynaptic density (PSD). While correct relative positioning of these zones is believed to be essential for synaptic function, the mechanisms controlling their mutual localization remain unexplored. Here, we employ high-throughput quantitative confocal imaging, super resolution and electron microscopy to visualize organization of synaptic subdomains in hippocampal neurons. Silencing of neuronal activity leads to reversible reorganization of the synaptic geometry, resulting in a increased overlap between immunostained AZ and PSD markers; in contrast, the SVZ-AZ spatial coupling is decreased. Bayesian blinking and bleaching (3B) reconstruction reveals that the distance between the AZ-PSD distance is decreased by 30 nm, while electron microscopy shows that the width of the synaptic cleft is decreased by 1.1 nm. Our findings show that multiple aspects of synaptic geometry are dynamically controlled by neuronal activity and suggest mutual repositioning of synaptic components as a potential novel mechanism contributing to the homeostatic forms of synaptic plasticity. PMID- 26951794 TI - Layered Double Hydroxide Nanoplatelets with Excellent Tribological Properties under High Contact Pressure as Water-Based Lubricant Additives. AB - High efficient and sustainable utilization of water-based lubricant is essential for saving energy. In this paper, a kind of layered double hydroxide (LDH) nanoplatelets is synthesized and well dispersed in water due to the surface modification with oleylamine. The excellent tribological properties of the oleylamine-modified Ni-Al LDH (NiAl-LDH/OAm) nanoplatelets as water-based lubricant additives are evaluated by the tribological tests in an aqueous environment. The modified LDH nanoplatelets are found to not only reduce the friction but also enhance the wear resistance, compared with the water-based cutting fluid and lubricants containing other particle additives. By adding 0.5 wt% LDH nanoplatelets, under 1.5 GPa initial contact pressure, the friction coefficient, scar diameter, depth and width of the wear track dramatically decrease by 83.1%, 43.2%, 88.5% and 59.5%, respectively. It is considered that the sufficiently small size and the excellent dispersion of NiAl-LDH/OAm nanoplatelets in water are the key factors, so as to make them enter the contact area, form a lubricating film and prevent direct collision of asperity peaks. Our investigations demonstrate that the LDH nanoplatelet as a water-based lubricant additive has a great potential value in industrial application. PMID- 26951793 TI - Chronic ethanol feeding promotes azoxymethane and dextran sulfate sodium-induced colonic tumorigenesis potentially by enhancing mucosal inflammation. AB - BACKGROUND: Alcohol consumption is one of the major risk factors for colorectal cancer. However, the mechanism involved in this effect of alcohol is unknown. METHODS: We evaluated the effect of chronic ethanol feeding on azoxymethane and dextran sulfate sodium (AOM/DSS)-induced carcinogenesis in mouse colon. Inflammation in colonic mucosa was assessed at a precancerous stage by evaluating mucosal infiltration of neutrophils and macrophages, and analysis of cytokine and chemokine gene expression. RESULTS: Chronic ethanol feeding significantly increased the number and size of polyps in colon of AOM/DSS treated mice. Confocal microscopic and immunoblot analyses showed a significant elevation of phospho-Smad, VEGF and HIF1alpha in the colonic mucosa. RT-PCR analysis at a precancerous stage indicated that ethanol significantly increases the expression of cytokines IL-1alpha, IL-6 and TNFalpha, and the chemokines CCL5/RANTES, CXCL9/MIG and CXCL10/IP-10 in the colonic mucosa of AOM/DSS treated mice. Confocal microscopy showed that ethanol feeding induces a dramatic elevation of myeloperoxidase, Gr1 and CD68-positive cells in the colonic mucosa of AOM/DSS treated mice. Ethanol feeding enhanced AOM/DSS-induced suppression of tight junction protein expression and elevated cell proliferation marker, Ki-67 in the colonic epithelium. CONCLUSION: This study demonstrates that chronic ethanol feeding promotes colonic tumorigenesis potentially by enhancing inflammation and elevation of proinflammatory cytokines and chemokines. PMID- 26951795 TI - Do patients' disruptive behaviours influence the accuracy of a doctor's diagnosis? A randomised experiment. AB - BACKGROUND: Literature suggests that patients who display disruptive behaviours in the consulting room fuel negative emotions in doctors. These emotions, in turn, are said to cause diagnostic errors. Evidence substantiating this claim is however lacking. The purpose of the present experiment was to study the effect of such difficult patients' behaviours on doctors' diagnostic performance. METHODS: We created six vignettes in which patients were depicted as difficult (displaying distressing behaviours) or neutral. Three clinical cases were deemed to be diagnostically simple and three deemed diagnostically complex. Sixty-three family practice residents were asked to evaluate the vignettes and make the patient's diagnosis quickly and then through deliberate reflection. In addition, amount of time needed to arrive at a diagnosis was measured. Finally, the participants rated the patient's likability. RESULTS: Mean diagnostic accuracy scores (range 0 1) were significantly lower for difficult than for neutral patients (0.54 vs 0.64; p=0.017). Overall diagnostic accuracy was higher for simple than for complex cases. Deliberate reflection upon the case improved initial diagnostic, regardless of case complexity and of patient behaviours (0.60 vs 0.68, p=0.002). Amount of time needed to diagnose the case was similar regardless of the patient's behaviour. Finally, average likability ratings were lower for difficult than for neutral-patient cases. CONCLUSIONS: Disruptive behaviours displayed by patients seem to induce doctors to make diagnostic errors. Interestingly, the confrontation with difficult patients does however not cause the doctor to spend less time on such case. Time can therefore not be considered an intermediary between the way the patient is perceived, his or her likability and diagnostic performance. PMID- 26951796 TI - Why patients' disruptive behaviours impair diagnostic reasoning: a randomised experiment. AB - BACKGROUND: Patients who display disruptive behaviours in the clinical encounter (the so-called 'difficult patients') may negatively affect doctors' diagnostic reasoning, thereby causing diagnostic errors. The present study aimed at investigating the mechanisms underlying the negative influence of difficult patients' behaviours on doctors' diagnostic performance. METHODS: A randomised experiment with 74 internal medicine residents. Doctors diagnosed eight written clinical vignettes that were exactly the same except for the patients' behaviours (either difficult or neutral). Each participant diagnosed half of the vignettes in a difficult patient version and the other half in a neutral version in a counterbalanced design. After diagnosing each vignette, participants were asked to recall the patient's clinical findings and behaviours. Main measurements were: diagnostic accuracy scores; time spent on diagnosis, and amount of information recalled from patients' clinical findings and behaviours. RESULTS: Mean diagnostic accuracy scores (range 0-1) were significantly lower for difficult than neutral patients' vignettes (0.41 vs 0.51; p<0.01). Time spent on diagnosing was similar. Participants recalled fewer clinical findings (mean=29.82% vs mean=32.52%; p<0.001) and more behaviours (mean=25.51% vs mean=17.89%; p<0.001) from difficult than from neutral patients. CONCLUSIONS: Difficult patients' behaviours induce doctors to make diagnostic errors, apparently because doctors spend part of their mental resources on dealing with the difficult patients' behaviours, impeding adequate processing of clinical findings. Efforts should be made to increase doctors' awareness of the potential negative influence of difficult patients' behaviours on diagnostic decisions and their ability to counteract such influence. PMID- 26951797 TI - Unwanted patients and unwanted diagnostic errors. PMID- 26951799 TI - ATP-Induced Inflammation Drives Tissue-Resident Th17 Cells in Metabolically Unhealthy Obesity. AB - Obesity-induced inflammation is conducted by a metabolic pathway, which eventually causes activation of specialized immune cells and leads to an unresolved inflammatory response within the tissue. For this reason, it is critically important to determine how hypertrophic fat tissue alters T cell balance to drive inflammation. In this study, we identify the purinergic signaling as a novel mechanism driving the adaptive Th17 response in human visceral adipose tissue (VAT) of metabolically unhealthy obese patients. We demonstrate that ATP acting via the P2X7 receptor pathway promotes a Th17 polarizing microenvironment with high levels of IL-1beta, IL-6, and IL-17 in VAT explants from lean donors. Moreover, in vitro blockade of the P2X7 receptor abrogates the levels of these cytokines. These findings are consistent with a greater frequency of Th17 cells in tissue from metabolically unhealthy obese donors, revealed not only by the presence of a baseline Th17-promoting milieu, but also by the higher expression of steadily recognized Th17 markers, such as RORC, IL-17 cytokine, and IL-23R, in comparison with metabolically healthy obese and lean donors. In addition, we demonstrate that CD39 expression on CD4(+)effector T cells represents a novel Th17 marker in the inflamed VAT, which also confers protection against ATP-induced cell death. The manipulation of the purinergic signaling might represent a new therapeutic target to shift the CD4(+)T cell balance under inflammatory conditions. PMID- 26951798 TI - IL-1beta and Inflammasome Activity Link Inflammation to Abnormal Fetal Airway Development. AB - Inflammation in the developing preterm lung leads to disrupted airway morphogenesis and chronic lung disease in human neonates. However, the molecular mechanisms linking inflammation and the pathways controlling airway morphogenesis remain unclear. In this article, we show that IL-1beta released by activated fetal lung macrophages is the key inflammatory mediator that disrupts airway morphogenesis. In mouse lung explants, blocking IL-1beta expression, posttranslational processing, and signaling protected the formation of new airways from the inhibitory effects ofEscherichia coliLPS. Consistent with a critical role for IL-1beta, mice expressing a gain-of-functionNlrp3allele and subsequent overactive inflammasome activity displayed abnormal saccular-stage lung morphogenesis and died soon after birth. Although the early-stage fetal lung appeared capable of mounting an NF-kappaB-mediated immune response, airway formation became more sensitive to inflammation later in development. This period of susceptibility coincided with higher expression of multiple inflammasome components that could increase the ability to release bioactive IL-1beta. Macrophages fromNlrp3gain-of-function mice also expressed higher levels of more mature cell surface markers, additionally linking inflammasome activation with macrophage maturation. These data identify developmental expression of the inflammasome and IL-1beta release by fetal lung macrophages as key mechanisms and potential therapeutic targets for neonatal lung disease. PMID- 26951802 TI - No increase in serious asthma events occurs with fluticasone plus salmeterol, study shows. PMID- 26951803 TI - Eating peanuts in early years reduces allergy risk even with later abstinence. PMID- 26951804 TI - Zika infection in pregnancy is linked to range of fetal abnormalities, data indicate. PMID- 26951800 TI - Optical Tools To Study the Isoform-Specific Roles of Small GTPases in Immune Cells. AB - Despite the 92% homology of the hematopoietic cell-specific Rac2 to the canonical isoform Rac1, these isoforms have been shown to play nonredundant roles in immune cells. To study isoform-specific dynamics of Rac in live cells, we developed a genetically encoded, single-chain FRET-based biosensor for Rac2. We also made significant improvements to our existing single-chain Rac1 biosensor. We optimized the biosensor constructs for facile expression in hematopoietic cells and performed functional validations in murine macrophage sublines of RAW264.7 cells. Rac2, Rac1, and Cdc42 have been implicated in the formation of actin-rich protrusions by macrophages, but their individual activation dynamics have not been previously characterized. We found that both Rac1 and Rac2 had similar activation kinetics, yet they had distinct spatial distributions in response to the exogenous stimulus, fMLF. Active Rac1 was mainly localized to the cell periphery, whereas active Rac2 was distributed throughout the cell, with an apparent higher concentration in the perinuclear region. We also performed an extensive morphodynamic analysis of Rac1, Rac2, and Cdc42 activities during the extension of random protrusions. We found that Rac2 appears to play a leading role in the generation of random protrusions, as we observed an initial strong activation of Rac2 in regions distal from the leading edge, followed by the activation of Rac1, a second burst of Rac2 and then Cdc42 immediately behind the leading edge. Overall, isoform-specific biosensors that have been optimized for expression should be valuable for interrogating the coordination of Rho family GTPase activities in living cells. PMID- 26951805 TI - 'Report of the Committee on Mediumistic Phenomena', by William James (1886): With an introduction by. AB - Mediumship was a topic of great interest to some nineteenth-century students of mental phenomena. Together with the phenomena of hypnosis and other manifestations, mediumship was seen by many as a dissociative phenomenon. The purpose of this Classic Text is to present an excerpt of an article about the topic that William James (1842-1910) published in 1886 in the Proceedings of the American Society for Psychical Research about American medium Leonora E. Piper (1857-1950). The article, an indication of late nineteenth-century interactions between dissociation studies and psychical research, was the first report of research with Mrs Piper, a widely investigated medium of great importance for the development of mediumship studies. In addition to studying the case as a dissociative experience, James explored the possibility that Piper's mentation contained verifiable information suggestive of 'supernormal' knowledge. Consequently, James provides an example of a topic neglected in historical studies, the ideas of those who combined conventional dissociation studies with psychical research. PMID- 26951801 TI - Notch Signaling Coordinates Progenitor Cell-Mediated Biliary Regeneration Following Partial Hepatectomy. AB - Aberrant transcriptional regulation contributes to the pathogenesis of both congenital and adult forms of liver disease. Although the transcription factor RBPJ is essential for liver morphogenesis and biliary development, its specific function in the differentiation of hepatic progenitor cells (HPC) has not been investigated, and little is known about its role in adult liver regeneration. HPCs are bipotent liver stem cells that can self-replicate and differentiate into hepatocytes or cholangiocytes in vitro. HPCs are thought to play an important role in liver regeneration and repair responses. While the coordinated repopulation of both hepatocyte and cholangiocyte compartment is pivotal to the structure and function of the liver after regeneration, the mechanisms coordinating biliary regeneration remain vastly understudied. Here, we utilized complex genetic manipulations to drive liver-specific deletion of the Rbpj gene in conjunction with lineage tracing techniques to delineate the precise functions of RBPJ during biliary development and HPC-associated biliary regeneration after hepatectomy. Furthermore, we demonstrate that RBPJ promotes HPC differentiation toward cholangiocytes in vitro and blocks hepatocyte differentiation through mechanisms involving Hippo-Notch crosstalk. Overall, this study demonstrates that the Notch-RBPJ signaling axis critically regulates biliary regeneration by coordinating the fate decision of HPC and clarifies the molecular mechanisms involved. PMID- 26951813 TI - Obituary: John Forrester (1949-2015). PMID- 26951814 TI - Paediatrician shortage is putting child services at risk, warns college. PMID- 26951815 TI - Potential of robot-assisted therapy for disabled persons with MS. PMID- 26951816 TI - Tribute to John F. Kurtzke, MD, FACP, FAAN: 1926-2015. PMID- 26951817 TI - Myocardial Infarction-Associated Transcript, a Long Noncoding RNA, Is Overexpressed During Dilated Cardiomyopathy Due to Chronic Chagas Disease. AB - Long noncoding RNAs (lncRNAs) modulate gene expression at the epigenetic, transcriptional, and posttranscriptional levels. Dysregulation of the lncRNA known as myocardial infarction-associated transcript (MIAT) has been associated with myocardial infarction. Chagas disease causes a severe inflammatory dilated chronic cardiomyopathy (CCC). We investigated the role of MIAT in CCC. A whole transcriptome analysis of heart biopsy specimens and formalin-fixed, paraffin embedded samples revealed that MIAT was overexpressed in patients with CCC, compared with subjects with noninflammatory dilated cardiomyopathy and controls. These results were confirmed in a mouse model. Results suggest that MIAT is a specific biomarker of CCC. PMID- 26951818 TI - The Association Between Cervical Human Papillomavirus Infection and Subsequent HIV Acquisition in Tanzanian and Ugandan Women: A Nested Case-Control Study. AB - OBJECTIVE: This study was performed to analyze the associations between cervical human papillomavirus (HPV) infection and human immunodeficiency virus (HIV) acquisition, using cervical samples from previous studies in Tanzania and Uganda. METHODS: A total of 161 adult women who acquired HIV infection during follow-up and 464 individually matched HIV-seronegative controls were selected from 5 cohorts of women working in bars and recreational facilities. Stored cervical samples were tested for 37 HPV genotypes, using a polymerase chain reaction assay (Roche Linear Array genotyping assay). Multivariate matched analysis using conditional logistic regression was performed to evaluate HPV infection, persistence, and clearance as predictors of HIV acquisition. RESULTS: HIV seroconverters were significantly more likely than controls to frequently drink alcohol and to be infected with Chlamydia trachomatis, Neisseria gonorrhoeae, or herpes simplex virus type 2. There was no evidence of an association between HIV acquisition and any detectable HPV at the visit prior to HIV seroconversion (adjusted odds ratio, 1.02; 95% confidence interval, .66-1.57) or between HIV acquisition and persistent HPV infection (defined as 2 positive HPV genotype specific test results at least 6 months apart), cleared HPV infection (defined as a positive HPV test result followed by negative HPV genotype-specific test result), or newly acquired HPV infection, compared with HPV-negative women. CONCLUSIONS: There was no evidence of association between HPV infection status and subsequent HIV acquisition. These results stand in contrast to other observational studies. PMID- 26951819 TI - CXCR2 Mediates Brucella-Induced Arthritis in Interferon gamma-Deficient Mice. AB - BACKGROUND: Brucella species are facultative intracellular gram-negative bacteria that cause brucellosis, a common global zoonosis. Infection of the joints is the most common focal complication of brucellosis in humans. The purpose of this study was to identify mediators of focal inflammation during brucellosis. METHODS: Wild-type (WT) mice are naturally resistant to Brucella infection; therefore, we infected anti-interferon gamma (IFN-gamma)-treated, or IFN-gamma(-/ ) mice with Brucella to induce osteoarticular and musculoskeletal inflammation, as we previously described. Mice were infected intraperitoneally with Brucella melitensis, and the clinical course of disease, histopathologic changes, and cytokine levels were compared among groups. RESULTS: Rag1(-/-) mice (B- and T cell deficient) and uMT(-/-) mice (B-cell deficient) developed paw inflammation at a similar rate and severity as WT mice following infection with B. melitensis and treatment with anti-IFN-gamma. Joints from B. melitensis-infected IFN-gamma( /-) mice had markedly increased levels of CCR2 and CXCR2 ligands. While anti-IFN gamma-treated CCR2(-/-) and WT mice behaved similarly, anti-IFN-gamma-treated CXCR2(-/-) or IFN-gamma(-/-)/CXCR2(-/-) mice had strikingly reduced focal swelling relative to anti-IFN-gamma-treated WT or IFN-gamma(-/-) mice, respectively. Additionally, neutrophil recruitment was dependent on CXCR2. CONCLUSIONS: Adaptive immune cells and CCR2 are dispensable, while CXCR2 is necessary for Brucella-induced focal neutrophil recruitment and inflammation. PMID- 26951822 TI - Coronary Artery Bypass Surgery Is Not Underutilized! PMID- 26951823 TI - Coronary Artery Bypass Grafting Is Currently Underutilized. PMID- 26951824 TI - ECG Response: March 8, 2016. PMID- 26951820 TI - Lower Viral Loads and Slower CD4+ T-Cell Count Decline in MRKAd5 HIV-1 Vaccinees Expressing Disease-Susceptible HLA-B*58:02. AB - BACKGROUND: HLA strongly influences human immunodeficiency virus type 1 (HIV-1) disease progression. A major contributory mechanism is via the particular HLA presented HIV-1 epitopes that are recognized by CD8(+) T-cells. Different populations vary considerably in the HLA alleles expressed. We investigated the HLA-specific impact of the MRKAd5 HIV-1 Gag/Pol/Nef vaccine in a subset of the infected Phambili cohort in whom the disease-susceptible HLA-B*58:02 is highly prevalent. METHODS: Viral loads, CD4(+) T-cell counts, and enzyme-linked immunospot assay-determined anti-HIV-1 CD8(+) T-cell responses for a subset of infected antiretroviral-naive Phambili participants, selected according to sample availability, were analyzed. RESULTS: Among those expressing disease-susceptible HLA-B*58:02, vaccinees had a lower chronic viral set point than placebo recipients (median, 7240 vs 122 500 copies/mL; P = .01), a 0.76 log10 lower longitudinal viremia level (P = .01), and slower progression to a CD4(+) T-cell count of <350 cells/mm(3) (P = .02). These differences were accompanied by a higher Gag-specific breadth (4.5 vs 1 responses; P = .04) and magnitude (2300 vs 70 spot-forming cells/10(6) peripheral blood mononuclear cells; P = .06) in vaccinees versus placebo recipients. CONCLUSIONS: In addition to the known enhancement of HIV-1 acquisition resulting from the MRKAd5 HIV-1 vaccine, these findings in a nonrandomized subset of enrollees show an HLA-specific vaccine effect on the time to CD4(+) T-cell count decline and viremia level after infection and the potential for vaccines to differentially alter disease outcome according to population HLA composition. CLINICAL TRIALS REGISTRATION: NCT00413725, DOH-27-0207-1539. PMID- 26951825 TI - Severe Coronary Vasculitis During a Systemic Lupus Erythematosus Flare Improved Angiographically With Immune-Suppressant Therapy. PMID- 26951826 TI - A Curious Case of Acute Myocardial Calcifications. PMID- 26951827 TI - Women and Heart Attacks. PMID- 26951828 TI - Letter by Jogia and Liang Regarding Article, "Evaluating the Atrial Myopathy Underlying Atrial Fibrillation: Identifying the Arrhythmogenic and Thrombogenic Substrate". PMID- 26951821 TI - Sudden Cardiac Death in the Young. AB - Although the occurrence of sudden cardiac death (SCD) in a young person is a rare event, it is traumatic and often widely publicized. In recent years, SCD in this population has been increasingly seen as a public health and safety issue. This review presents current knowledge relevant to the epidemiology of SCD and to strategies for prevention, resuscitation, and identification of those at greatest risk. Areas of active research and controversy include the development of best practices in screening, risk stratification approaches and postmortem evaluation, and identification of modifiable barriers to providing better outcomes after resuscitation of young SCD patients. Institution of a national registry of SCD in the young will provide data that will help to answer these questions. PMID- 26951829 TI - Response to Letter Regarding Article, "Evaluating the Atrial Myopathy Underlying Atrial Fibrillation: Identifying the Arrhythmogenic and Thrombogenic Substrate". PMID- 26951830 TI - Letter by Gupta and Rajagopalan Regarding Article, "Coronary Heart Disease Mortality Declines in the United States From 1979 Through 2011: Evidence for Stagnation in Young Adults, Especially Women". PMID- 26951831 TI - Response to Letter Regarding Article, "Coronary Heart Disease Mortality Declines in the United States From 1979 Through 2011: Evidence for Stagnation in Young Adults, Especially Women". PMID- 26951832 TI - Correction. PMID- 26951833 TI - Correction. PMID- 26951836 TI - B Cells Promote Pancreatic Tumorigenesis. AB - Three recent studies, approaching the question from different angles and using different and/or overlapping models, provide compelling evidence for the involvement of tumor-infiltrating B cells in the initiation and progression of pancreatic ductal adenocarcinoma. These studies highlight the need for a better understanding of pancreatic tumor-immune system interactions and the immunologic mechanisms that promote or inhibit tumorigenesis, paving the way for better treatment strategies. PMID- 26951837 TI - Progress on Covalent Inhibition of KRAS(G12C). AB - Recent reports of small-molecule approaches to directly inhibit oncogenic KRAS(G12C) have invigorated the RAS research community by raising the possibility of drugging a protein that was long considered "undruggable." A new iteration of covalent compounds targeting the allosteric switch II pocket of KRAS(G12C) showed improved potency and selectivity and enabled studies demonstrating that KRAS(G12C) rapidly cycles its nucleotide substrate. This report illustrates the value of chemical probes in dissecting RAS biology and raises additional hope for development of viable pharmacologic strategies for directly targeting KRAS(G12C). PMID- 26951838 TI - At last, NICE to take over the Cancer Drugs Fund. PMID- 26951839 TI - Effect of posterior decompression extent on biomechanical parameters of the spinal cord in cervical ossification of the posterior longitudinal ligament. AB - Ossification of the posterior longitudinal ligament is a common cause of the cervical myelopathy due to compression of the spinal cord. Patients with ossification of the posterior longitudinal ligament usually require the decompression surgery, and there is a need to better understand the optimal surgical extent with which sufficient decompression without excessive posterior shifting can be achieved. However, few quantitative studies have clarified this optimal extent for decompression of cervical ossification of the posterior longitudinal ligament. We used finite element modeling of the cervical spine and spinal cord to investigate the effect of posterior decompression extent for continuous-type cervical ossification of the posterior longitudinal ligament on changes in stress, strain, and posterior shifting that occur with three different surgical methods (laminectomy, laminoplasty, and hemilaminectomy). As posterior decompression extended, stress and strain in the spinal cord decreased and posterior shifting of the cord increased. The location of the decompression extent also influenced shifting. Laminectomy and laminoplasty were very similar in terms of decompression results, and both were superior to hemilaminectomy in all parameters tested. Decompression to the extents of C3-C6 and C3-C7 of laminectomy and laminoplasty could be considered sufficient with respect to decompression itself. Our findings provide fundamental information regarding the treatment of cervical ossification of the posterior longitudinal ligament and can be applied to patient-specific surgical planning. PMID- 26951841 TI - Can anyone stop the illegal sale of medicines online? PMID- 26951840 TI - Effect of olanzapine for breast cancer patients resistant to triplet antiemetic therapy with nausea due to anthracycline-containing adjuvant chemotherapy. AB - OBJECTIVE: Triplet antiemetic therapy with neurokinin 1 receptor blocker, 5 hydroxytryptamine receptor blocker and steroids is commonly used in patients who are highly emetic after chemotherapy. However, an alternative antiemetic therapy for patients who are resistant to triplet antiemetic therapy is not established. Olanzapine is recommended in the guidelines as an optional antiemetic drug. However, the effectiveness of adding olanzapine to triplet antiemetic therapy is unknown. In this study, the effectiveness and safety of adding olanzapine to triplet antiemetic therapy with aprepitant, palonosetron and dexamethasone as highly emetic anthracycline-containing adjuvant chemotherapy for primary breast cancer patients were prospectively investigated. METHODS: Forty-five patients with breast cancer who experienced >Grade 1 nausea or any vomiting after the first cycle of chemotherapy using both epirubicin and cyclophosphamide were included. Low-dose olanzapine (2.5 mg/day) was administered orally from the first day of chemotherapy for 4 days, and the number of episodes of vomiting, scale of nausea, dietary intake and somnolence were compared with the symptoms after the first cycle. RESULTS: As the primary endpoint, the nausea grade was significantly improved by adding olanzapine (P < 0.05). As the secondary endpoints, mean nausea scale (3.2->1.9, Day 1; 3->1.3-1, Days 2-6) and dietary intake (33.6->53.8%, Day 1; 42.0->60.7-78.1%, Days 2-6) were improved by adding olanzapine. Only four patients withdrew due to somnolence and/or dizziness. CONCLUSIONS: This study demonstrated the effectiveness and tolerability of adding low-dose olanzapine for patients with insufficient nausea relief with triplet antiemetic therapy consisting of palonosetron, steroid and aprepitant. PMID- 26951842 TI - Use of a knowledge-attitude-behaviour education programme for Chinese adults undergoing maintenance haemodialysis: Randomized controlled trial. AB - OBJECTIVE: To investigate the effects of a knowledge-attitude-behaviour health education model on acquisition of disease-related knowledge and self-management behaviour by patients undergoing maintenance haemodialysis. METHODS: Patients recently prescribed MHD were randomly assigned to a control group or an intervention group. Control group patients were treated with usual care and general education models. A specialist knowledge-attitude-behaviour health education model was applied to patients in the intervention group. RESULTS: Eighty-six patients were included (n = 43 per group). Before intervention, there were no significant between-group differences in disease knowledge and self management behaviour. After 6 months' intervention, a significant between-group difference in acquisition of disease knowledge was observed. Self-management behaviour scores (control of body mass, reasonable diet, correct drug intake, physical activity, correct fistula care, disease condition monitoring, psychological and social behaviours) for the intervention group were also higher than those for the control group. CONCLUSION: These preliminary findings suggest that the knowledge-attitude-behaviour model appears to be a valuable tool for the health education of MHD patients. PMID- 26951844 TI - 11beta-Hydroxysteroid Dehydrogenase-2 and Salt-Sensitive Hypertension. PMID- 26951843 TI - Conditional Deletion of Hsd11b2 in the Brain Causes Salt Appetite and Hypertension. AB - BACKGROUND: The hypertensive syndrome of Apparent Mineralocorticoid Excess is caused by loss-of-function mutations in the gene encoding 11beta-hydroxysteroid dehydrogenase type 2 (11betaHSD2), allowing inappropriate activation of the mineralocorticoid receptor by endogenous glucocorticoid. Hypertension is attributed to sodium retention in the distal nephron, but 11betaHSD2 is also expressed in the brain. However, the central contribution to Apparent Mineralocorticoid Excess and other hypertensive states is often overlooked and is unresolved. We therefore used a Cre-Lox strategy to generate 11betaHSD2 brain specific knockout (Hsd11b2.BKO) mice, measuring blood pressure and salt appetite in adults. METHODS AND RESULTS: Basal blood pressure, electrolytes, and circulating corticosteroids were unaffected in Hsd11b2.BKO mice. When offered saline to drink, Hsd11b2.BKO mice consumed 3 times more sodium than controls and became hypertensive. Salt appetite was inhibited by spironolactone. Control mice fed the same daily sodium intake remained normotensive, showing the intrinsic salt resistance of the background strain. Dexamethasone suppressed endogenous glucocorticoid and abolished the salt-induced blood pressure differential between genotypes. Salt sensitivity in Hsd11b2.BKO mice was not caused by impaired renal sodium excretion or volume expansion; pressor responses to phenylephrine were enhanced and baroreflexes impaired in these animals. CONCLUSIONS: Reduced 11betaHSD2 activity in the brain does not intrinsically cause hypertension, but it promotes a hunger for salt and a transition from salt resistance to salt sensitivity. Our data suggest that 11betaHSD2-positive neurons integrate salt appetite and the blood pressure response to dietary sodium through a mineralocorticoid receptor-dependent pathway. Therefore, central mineralocorticoid receptor antagonism could increase compliance to low-sodium regimens and help blood pressure management in cardiovascular disease. PMID- 26951846 TI - Loss of substantia nigra hyperintensity on 7 Tesla MRI of Parkinson's disease, multiple system atrophy, and progressive supranuclear palsy. AB - BACKGROUND: Seven Tesla (7T) MRI can visualize anatomical alterations occurring in a hyperintense structure of the substantia nigra in Parkinson's disease (PD). OBJECTIVE: We investigated whether 7T MRI can detect the loss of substantia nigra hyperintensity in patients with PD, multiple system atrophy (MSA), and progressive supranuclear palsy (PSP). METHODS: Using 7T MRI, we evaluated 26 healthy subjects, 30 patients with PD, 7 patients with MSA, and 3 patients with PSP. Two blinded readers independently assessed the images. We carried out a comparative analysis of five patients with hemiparkinsonism via (123)I-2beta carbomethoxy-3beta-(4-iodophenyl)-N-(3-fluoropropyl)-nortropane ((123)I-FP-CIT) SPECT. RESULTS: 7T MRI revealed a definitive shape of nigral hyperintensity in healthy subjects, nearly identical to neuropathological characterization of nigrosome 1, and enabled instantaneous determination of its presence or absence in all subjects. Nigral hyperintensity was lost in all patients with PD, MSA with predominant parkinsonism, and PSP. One of five patients with MSA with predominant cerebellar ataxia showed an intact nigral hyperintensity. The side effects were mild and tolerable, and imaging was successful in patients with dyskinesia. Motion artifact incidence was higher in elderly subjects. In hemiparkinsonism cases, we observed partial loss of nigral hyperintensity on the side of less reduced (123)I-FP-CIT binding, suggesting an ongoing iron deposition on the unaffected side in hemiparkinsonism. CONCLUSIONS: The present findings suggest that 7T MRI represents an excellent tool for evaluating nigral hyperintensity in PD, MSA, and PSP, with tolerable side effects and limited motion artifacts. Thus, imaging of parkinsonism may benefit from using 7T MRI. PMID- 26951845 TI - Clinical Trial of 2-Phenethyl Isothiocyanate as an Inhibitor of Metabolic Activation of a Tobacco-Specific Lung Carcinogen in Cigarette Smokers. AB - 2-Phenethyl isothiocyanate (PEITC), a natural product found as a conjugate in watercress and other cruciferous vegetables, is an inhibitor of the metabolic activation and lung carcinogenicity of the tobacco carcinogen 4 (methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in F344 rats and A/J mice. We carried out a clinical trial to determine whether PEITC also inhibits the metabolic activation of NNK in smokers. Cigarette smokers were recruited and asked to smoke cigarettes containing deuterium-labeled [pyridine-D4]NNK for an acclimation period of at least 1 week. Then subjects were randomly assigned to one of two arms: PEITC followed by placebo, or placebo followed by PEITC. During the 1-week treatment period, each subject took PEITC (10 mg in 1 mL of olive oil, 4 times per day). There was a 1-week washout period between the PEITC and placebo periods. The NNK metabolic activation ratio [pyridine-D4]hydroxy acid/total [pyridine-D4]NNAL was measured in urine samples to test the hypothesis that PEITC treatment modified NNK metabolism. Eighty-two smokers completed the study and were included in the analysis. Overall, the NNK metabolic activation ratio was reduced by 7.7% with PEITC treatment (P = 0.023). The results of this trial, while modest in effect size, provide a basis for further investigation of PEITC as an inhibitor of lung carcinogenesis by NNK in smokers. Cancer Prev Res; 9(5); 396-405. (c)2016 AACR. PMID- 26951847 TI - The dog-ear flap as an alternative for breast reconstruction in patients who have already undergone a DIEAP flap. AB - Breast reconstruction in patients who have previously undergone deep inferior epigastric artery perforator flap (DIEAP) reconstruction or abdominoplasty is often challenging. Depending on patients' body habitus, several second-choice flaps have been described such as the transverse upper gracilis (TUG) flap, profundus femoris artery perforator (PFAP) flap, superior gluteal artery perforator (SGAP) flap, and lumbar artery perforator (LAP) flap. Patients who have undergone a DIEAP flap reconstruction or abdominoplasty occasionally present with dog ears on both sides of the abdominal scar. The adipose tissue and skin of these dog ears are supplied by perforators of the deep circumflex iliac artery (DCIA). The DCIA flap was first described in 1979 by Taylor. We introduce this abdominal "dog-ear" flap for autologous breast reconstruction. PMID- 26951854 TI - Gene expression variability in mammalian embryonic stem cells using single cell RNA-seq data. AB - BACKGROUND: Gene expression heterogeneity contributes to development as well as disease progression. Due to technological limitations, most studies to date have focused on differences in mean expression across experimental conditions, rather than differences in gene expression variance. The advent of single cell RNA sequencing has now made it feasible to study gene expression heterogeneity and to characterise genes based on their coefficient of variation. METHODS: We collected single cell gene expression profiles for 32 human and 39 mouse embryonic stem cells and studied correlation between diverse characteristics such as network connectivity and coefficient of variation (CV) across single cells. We further systematically characterised properties unique to High CV genes. RESULTS: Highly expressed genes tended to have a low CV and were enriched for cell cycle genes. In contrast, High CV genes were co-expressed with other High CV genes, were enriched for bivalent (H3K4me3 and H3K27me3) marked promoters and showed enrichment for response to DNA damage and DNA repair. CONCLUSIONS: Taken together, this analysis demonstrates the divergent characteristics of genes based on their CV. High CV genes tend to form co-expression clusters and they explain bivalency at least in part. PMID- 26951855 TI - Novel pathogenic SLC25A46 splice-site mutation causes an optic atrophy spectrum disorder. AB - The inherited optic neuropathies comprise a group of genetically heterogeneous disorders causing optic nerve dysfunction. In some cases, optic neuropathies are associated with cerebellar atrophy which mainly affects the vermis. Here, we describe a Moroccan girl of consanguineous parents with optic atrophy and cerebellar atrophy. Exome sequencing revealed a novel homozygous mutation (c.283+3G>T) in the donor splice site for exon 1 of SLC25A46. RNA analysis revealed that an alternative splice site within exon 1 was used leading to a premature termination codon within exon 2. SLC25A46 mRNA expression showed there is no wild-type transcript present in the patient and the mutant transcript does not undergo nonsense-mediated mRNA decay. Futhermore, we observed c.283+3G>T SLC25A46 mutation induces mitochondrial fragmentation. An additional 10 patients with optic atrophy and cerebellar atrophy, which were negative for mtDNA and OPA1 variants, were tested for pathogenic mutations in the SLC25A46 gene. However, no additional variants were identified. Our findings confirm the recent report of pathogenic SLC25A46 mutations as a novel cause for optic atrophy spectrum disorder. PMID- 26951858 TI - Molecular and biological characterization of highly infectious transcripts from full-length cDNA clones of broad bean wilt virus 1. AB - Broad bean wilt virus 1 (BBWV-1), genus Fabavirus, has a genome composed of two single-stranded positive-sense RNAs of ~5.8 (RNA1) and 3.4kb (RNA2). Full-length cDNA clones of both genomic RNAs (pBenR1 and pBenR2) from BBWV-1 isolate Ben were constructed under the control of the T7 promoter. In vitro derived capped transcripts were infectious in Nicotiana benthamiana, Chenopodium quinoa and Vicia faba plants. The biological activity of viral transcripts was not affected by extra bases at the 5'-terminus introduced during in vitro transcription. Virions derived from the infectious cDNA clones displayed similar viral infectivity and accumulation, as well as symptom induction as the wild-type BBWV 1 isolate. PMID- 26951860 TI - 2015 Journal of Urology Consultants. PMID- 26951861 TI - Baby steps: Understanding normal baby behaviour. PMID- 26951859 TI - Nucleotide sequence of Zygosaccharomyces bailii virus Z: Evidence for +1 programmed ribosomal frameshifting and for assignment to family Amalgaviridae. AB - Zygosaccharomyces bailii virus Z (ZbV-Z) is a monosegmented dsRNA virus that infects the yeast Zygosaccharomyces bailii and remains unclassified to date despite its discovery >20years ago. The previously reported nucleotide sequence of ZbV-Z (GenBank AF224490) encompasses two nonoverlapping long ORFs: upstream ORF1 encoding the putative coat protein and downstream ORF2 encoding the RNA dependent RNA polymerase (RdRp). The lack of overlap between these ORFs raises the question of how the downstream ORF is translated. After examining the previous sequence of ZbV-Z, we predicted that it contains at least one sequencing error to explain the nonoverlapping ORFs, and hence we redetermined the nucleotide sequence of ZbV-Z, derived from the same isolate of Z. bailii as previously studied, to address this prediction. The key finding from our new sequence, which includes several insertions, deletions, and substitutions relative to the previous one, is that ORF2 in fact overlaps ORF1 in the +1 frame. Moreover, a proposed sequence motif for +1 programmed ribosomal frameshifting, previously noted in influenza A viruses, plant amalgaviruses, and others, is also present in the newly identified ORF1-ORF2 overlap region of ZbV-Z. Phylogenetic analyses provided evidence that ZbV-Z represents a distinct taxon most closely related to plant amalgaviruses (genus Amalgavirus, family Amalgaviridae). We conclude that ZbV-Z is the prototype of a new species, which we propose to assign as type species of a new genus of monosegmented dsRNA mycoviruses in family Amalgaviridae. Comparisons involving other unclassified mycoviruses with RdRps apparently related to those of plant amalgaviruses, and having either mono- or bisegmented dsRNA genomes, are also discussed. PMID- 26951856 TI - Changes in macrophage function modulated by the lipid environment. AB - Macrophages (Mphis) play a critical role in the defense against pathogens, orchestrating the inflammatory response during injury and maintaining tissue homeostasis. During these processes, macrophages encounter a variety of environmental conditions that are likely to change their gene expression pattern, which modulates their function. In this study, we found that murine Mphis displayed two different subpopulations characterized by differences in morphologies, expression of surface markers and phagocytic capacity under non stimulated conditions. These two subpopulations could be recapitulated by changes in the culture conditions. Thus, Mphis grown in suspension in the presence of serum were highly phagocytic, whereas subtraction of serum resulted in rapid attachment and reduced phagocytic activity. The difference in phagocytosis between these subpopulations was correlated with the expression levels of FcgammaR. These two cell subpopulations also differed in their responses to LPS and the expression of surface markers, including CD14, CD86, scavenger receptor A1, TLR4 and low-density lipoprotein receptor. Moreover, we found that the lipid/cholesterol content in the culture medium mediated the differences between these two cell subpopulations. Thus, we described a mechanism that modulates Mphi function depending on the exposure to lipids within their surrounding microenvironment. PMID- 26951862 TI - New advances in the diagnosis of canine and feline liver and pancreatic disease. AB - The diagnosis of liver and pancreatic disorders in dogs and cats present their own set of challenges. However, as new diagnostic tests are developed and the optimal ways in which to use existing tests are determined, the ability of the veterinary profession to make these diagnoses continues to improve. Histopathological assessment is considered to be the reference standard for the diagnosis of many hepatic and pancreatic diseases, but it has some inherent limitations. New classes of diagnostic tests for liver disease that are currently being studied include direct and indirect serum markers of hepatic fibrosis, such as hyaluronic acid; novel markers of hepatocellular injury, such as circulating microRNAs; and quantitative tests of hepatic microsomal function. Assays for pancreas-specific lipase have greatly improved the ability of practitioners to diagnose pancreatitis in dogs and cats. However, further research is needed to fully understand the characteristics of these assays, especially in patients with concurrent non-pancreatic disease. The more common use and refinement of CT and MRI to assess the hepatobiliary system and pancreas of dogs and cats also have huge potential to improve diagnostic capabilities. PMID- 26951864 TI - Immune disturbances in severely depressed patients: relationship with Cortisol secretion. AB - The mitogen induced lymphocyte responses were measured in 33 depressed patients categorized according to the DSM-III into minor (300.40, 309.00), simple major (296.X2) and major depression with melancholia and/or psychotic features (296.X3, 296.X4). Three distinct mitogens were used, i.e. phytohemaglutinin (PHA), pokeweed mitogen (PWM) and concanavalin A (CON A). We found that major depressives with associated features showed significantly lower mitogen induced lymphocyte responses to PHA and PWM as compared to all other depressed patients. The severity of illness was significantly inversely related to the lymphocyte responses to PHA. Cortisol nonsuppressors exhibited significantly lower PHA and PWM induced lymphocyte responses as compared with suppressors. There were significant and negative correlations between the postdexamethasone Cortisol values and the PHA and PWM stimulated lymphocyte responses. PMID- 26951865 TI - A rare complication of carcinoId carcinoma. AB - In this case report of a patient with carcinoid carcinoma we discuss the normal metabolism of tryptophan, one of the essential amino acids. We also examined the changes of this metabolism due to the metastasis of the carcinoid carcinoma and its psychiatric complications based on a central tryptophan deficiency. A less frequent complication of the changes in the tryptophan metabolism due to carcinoidosis is the disease pellagra. This disease is always accompanied with psychiatric symptoms. It plays an important role in the development of the transmethylation hypothesis of schizophrenia. PMID- 26951866 TI - Sleep and wake disorders in shift workers. Part I: Prevalence, clinical phenomena and pathogenesis. AB - The present review summarizes the prevalence, clinical phenomena, and pathogenesis of sleep and wake disorders in shift workers. Insomnia and hyper somnolence occur in more than 50% of shift workers, mainly in association with the night shift. Circadian rhythm disruption is the major determinant of these disorders. Furthermore they are frequently associated with psycho-social problems and somatic diseases. In more than 20% of the shift workers problems are so pronounced, that they fail to adapt to the rotating schedules. This is defined as 'shift maladaptation syndrome'. PMID- 26951867 TI - Sleep and wake disorders in shift workers. Part II: Prevention and treatment strategies. AB - The present review deals with preventive and treatment strategies for sleep and wake disorders, and the other problems of shift workers. Management must take into account the direction, speed and other parameters of the rotation schedule. Good sleep-wake hygiene may alleviate the problems. Further, additional napping may compensate - at least partially - for sleep deprivation and fatigue. Hypnotics must be avoided as much as possible. Finally, new techniques for manipulation of circadian rhythms are discussed: light, melatonin and benzodiazepines. PMID- 26951863 TI - Long story short: p53 mediates innate immunity. AB - The story of p53 and how we came to understand it is punctuated by fundamental insights into the essence of cancer. In the decades since its discovery, p53 has been shown to be centrally involved in most, if not all, of the cellular processes that maintain tissue homeostasis. Extensive functional analyses of p53 and its tumor-associated mutants have illuminated many of the common defects shared by most cancer cells. As the central character in a tale that continues to unfold, p53 has become increasingly familiar and yet remains surprisingly inscrutable. New relationships periodically come to light, and surprising, novel activities continue to emerge, thereby revealing new dimensions and aspects of its function. What lies at the very core of this complex protagonist? What is its prime motivation? As every avid reader knows, the elements of character are profoundly shaped by adversity--originating from within and without. And so it is with p53. This review will briefly recap the coordinated responses of p53 to viral infection, and outline a hypothetical model that would explain how an abundance of seemingly unrelated phenotypic attributes may in the end reflect a singular function. All stories eventually draw to a conclusion. This epic tale may eventually leave us with the realization that p53, most simply described, is a protein that evolved to mediate immune surveillance. PMID- 26951868 TI - Cementless total hip arthroplasty in patients aged >=80 years. AB - BACKGROUND/PURPOSE: We evaluate the clinical and radiological results of cementless total hip arthroplasties (THAs) in patients aged >=80 years. METHODS: We compared the clinical and radiological results of 30 cementless THAs done in patients aged >=80 years (older group) and aged 60-69 years (control group). RESULTS: The Harris Hip score significantly decreased in the older group 1 year after the operation and at the final follow-up observation (p = 0.001), but no joints required revision surgery due to poor initial fixation or early loosening. CONCLUSION: Cementless THA in the elderly is safe and durable at the time of the follow-up. PMID- 26951869 TI - Compounds from Caesalpinia sappan with anti-inflammatory properties in macrophages and chondrocytes. AB - The heartwood of Caesalpinia sappan is a traditional ingredient of food and beverages in South East Asia and has been used in traditional medicine as an analgesic and anti-inflammatory drug or to promote blood circulation. Scientific studies have confirmed different bioactivities associated with its use. Here, five fractions were isolated from the ethanolic extract of C. sappan heartwood, including episappanol (1), protosappanin C (2), brazilin (3), (iso-)protosappanin B (4) and sappanol (5) using high-performance liquid chromatography (HPLC). All compounds were tested for their anti-inflammatory effects in two different cell lines. Cytokine concentrations in the cell supernatant were determined using enzyme-linked immunosorbent assay (ELISA), and mRNA levels were measured using reverse-transcription quantitative polymerase chain reaction (RT-qPCR). In lipopolysaccharide-stimulated macrophages, all compounds significantly inhibited the secretion of the pro-inflammatory cytokines interleukin (IL-6) and tumor necrosis factor-alpha (TNF-alpha). Sappanol (5) increased the secretion of the anti-inflammatory IL-10. In IL-1beta-stimulated chondrocytes, all fractions reduced the mRNA expression and the secretion of the pro-inflammatory cytokines IL-6 and TNF-alpha. The highest anti-inflammatory effect was found for brazilin (3) in both cell lines. Of note, this is the first study which shows the anti inflammatory effect of sappanol and episappanol. This study provides evidence for the efficacy of the traditional use of C. sappan as an anti-inflammatory remedy. Given the high prevalence of inflammation-related pathologies including arthritis, and the urgent need to clinically intervene with these diseases, the anti-inflammatory activity of diverse compounds from C. sappan may be of interest for the development of complementary and alternative treatment strategies. PMID- 26951871 TI - [Anterior dislocation of a hypermature cataract]. PMID- 26951870 TI - Active Lifestyle Is Associated With Reduced Dyspnea and Greater Life Satisfaction in Spinal Cord Injury. AB - OBJECTIVE: To assess the relations between measures of activity with dyspnea and satisfaction with life in chronic spinal cord injury (SCI). DESIGN: Cross sectional survey. SETTING: Five SCI centers. PARTICIPANTS: Between July 2012 and March 2015, subjects (N=347) with traumatic SCI >=1 year after injury who used a manual wheelchair or walked with or without an assistive device reported hours spent away from home or yard on the previous 3 days, sports participation, and planned exercise. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Satisfaction with Life Scale (SWLS) and dyspnea. Dyspnea was defined as shortness of breath when hurrying on the level or going up a slight hill, going slower than people the same age on the level because of breathlessness, or stopping for breath when going at your own pace, or after about 100yd (or after a few minutes) on the level. RESULTS: Dyspnea prevalence was 30%. Adjusting for asthma or chronic obstructive pulmonary disease, mobility mode, race, and season, there was a significant linear trend between greater SWLS scores and quartiles of time spent away from the home or yard (P=.0002). SWLS score was greater if participating in organized sports (P=.01), although was not significantly greater with planned exercise (P=.093). Planned exercise was associated with a reduced odds ratio (OR) of dyspnea (.57; 95% confidence interval [CI], .34-.95; P=.032), but organized sports was not (P=.265). Dyspnea was not significantly increased in persons who spent the fewest hours outside their home or yard (<=7h) compared with people who spent the most hours outside their home or yard (>23h) (OR=1.69; 95% CI, 0.83-3.44; P=.145). CONCLUSIONS: In SCI, a planned exercise program is associated with less dyspnea. An active lifestyle characterized by greater time spent away from home or yard and sports participation is associated with greater SWLS scores. PMID- 26951872 TI - Acute anterior ischemic optic neuropathy in a woman with Fabry's disease. PMID- 26951873 TI - Local treatment for scleritis secondary to Wiskott-Aldrich syndrome. PMID- 26951874 TI - [Acute abducens nerve palsy as a result of bilateral internal carotid artery agenesis]. PMID- 26951875 TI - [En face OCT of dissociated optic nerve fiber layer (DONFL) after internal limiting membrane peeling for idiopathic macular hole]. PMID- 26951876 TI - [A form of macular serpiginous choroiditis]. PMID- 26951877 TI - A late discovery of familial gyrate atrophy of the choroid and retina. PMID- 26951878 TI - Know your ABCs: Characterization and gene expression dynamics of ABC transporters in the polyphagous herbivore Helicoverpa armigera. AB - Polyphagous insect herbivores are adapted to many different secondary metabolites of their host plants. However, little is known about the role of ATP-binding cassette (ABC) transporters, a multigene family involved in detoxification processes. To study the larval response of the generalist Helicoverpa armigera (Lepidoptera) and the putative role of ABC transporters, we performed developmental assays on artificial diet supplemented with secondary metabolites from host plants (atropine-scopolamine, nicotine and tomatine) and non-host plants (taxol) in combination with a replicated RNAseq experiment. A maximum likelihood phylogeny identified the subfamily affiliations of the ABC transporter sequences. Larval performance was equal on the atropine-scopolamine diet and the tomatine diet. For the latter we could identify a treatment-specific upregulation of five ABC transporters in the gut. No significant developmental difference was detected between larvae fed on nicotine or taxol. This was also mirrored in the upregulation of five ABC transporters when fed on either of the two diets. The highest number of differentially expressed genes was recorded in the gut samples in response to feeding on secondary metabolites. Our results are consistent with the expectation of a general detoxification response in a polyphagous herbivore. This is the first study to characterize the multigene family of ABC transporters and identify gene expression changes across different developmental stages and tissues, as well as the impact of secondary metabolites in the agricultural pest H. armigera. PMID- 26951879 TI - Assessing Sustained Effects of Communities That Care on Youth Protective Factors. AB - OBJECTIVE: The Communities That Care (CTC) prevention system seeks to build community capacity for a science-based approach to the promotion of healthy youth development. Prior research shows the positive effects of CTC on youth protective factors during CTC implementation. This research tests sustained effects of CTC on youth protective factors 1 year after external support to communities for CTC implementation ended. METHOD: Data come from a community-randomized trial of CTC in 24 communities across 7 states. A panel of 4,407 youth in CTC and control communities was surveyed annually from Grade 5 through Grade 10. Youth reported their exposure to protective factors identified in the social development model. Global test statistics are calculated to examine effects of CTC across 15 protective factors in 5 domains (community, school, family, peer, and individual) assessed in Grade 10, 1 year after study support for CTC implementation ended. Analyses also examine variation in sustained effects by gender and baseline risk levels. RESULTS: Global effects of CTC on protective factors across all domains are not sustained in Grade 10. However, sustained domain-specific effects are observed in the individual domain for males, in the peer domain for females, and in the individual domain for youth with low-to-medium risk at baseline. CONCLUSIONS: Greater emphasis on strengthening protective factors during high school might be needed to sustain broad effects of CTC on protective factors observed during middle school. PMID- 26951880 TI - Plant Growth-Promoting Rhizobacteria Enhance Salinity Stress Tolerance in Okra through ROS-Scavenging Enzymes. AB - Salinity is a major environmental stress that limits crop production worldwide. In this study, we characterized plant growth-promoting rhizobacteria (PGPR) containing 1-aminocyclopropane-1-carboxylate (ACC) deaminase and examined their effect on salinity stress tolerance in okra through the induction of ROS scavenging enzyme activity. PGPR inoculated okra plants exhibited higher germination percentage, growth parameters, and chlorophyll content than control plants. Increased antioxidant enzyme activities (SOD, APX, and CAT) and upregulation of ROS pathway genes (CAT, APX, GR, and DHAR) were observed in PGPR inoculated okra plants under salinity stress. With some exceptions, inoculation with Enterobacter sp. UPMR18 had a significant influence on all tested parameters under salt stress, as compared to other treatments. Thus, the ACC deaminase containing PGPR isolate Enterobacter sp. UPMR18 could be an effective bioresource for enhancing salt tolerance and growth of okra plants under salinity stress. PMID- 26951881 TI - Relationship between hyperandrogenism, obesity, inflammation and polycystic ovary syndrome. AB - This prospective study aimed to determine the status of circulating levels of C reactive protein (CRP), tumor necrosis factor alpha (TNF-alpha), IL-27, IL-35, IL 37, alpha-1 acid glycoprotein in patients with polycystic ovary syndrome (PCOS) compared with controls and to evaluate their relation with hyperandrogenism and obesity. Forty-eight patients with PCOS (29 obese, 19 lean) and 40 healthy controls (20 obese, 20 lean) were enrolled. CRP, TNF-alpha, IL-27, IL-35, IL-37, alpha-1 acid glycoprotein, sex hormone-binding globulin (SHBG), dehydroepiandrosterone sulfate (DHEA-S) levels were measured. Levels of total testosterone, A4, DHEA-S were significantly higher in patients with PCOS than in controls both in the obese and lean groups, while levels of SHBG were significantly lower in all patients with PCOS than in all (p < 0.05). Free androgen index (FAI) values were significantly higher in all patients with PCOS than in all controls (all p < 0.05). Levels of CRP, TNF-alpha, alpha-1 acid glycoprotein were significantly increased in all patients with PCOS compared with all controls (all p < 0.001). FAI had a positive correlation with CRP, TNF-alpha, alpha-1 acid glycoprotein, a negative correlation with IL-27, IL-25, IL-37 (all p < 0.01). Body mass index had a negative correlation with IL-27, IL-35, IL-37, a positive correlation with alpha-1 acid glycoprotein, FAI (p < 0.05). The findings confirm the proinflammatory state of PCOS. Moreover, obesity along with PCOS significantly elevates the inflammatory status and hyperandrogenism. PMID- 26951882 TI - Genetic contribution of CYP1A1 variant on treatment outcome in epilepsy patients: a functional and interethnic perspective. AB - CYP1A1 gene is involved in estrogen metabolism, and previously, we have reported association of variant rs2606345 with altered anti-epileptic drugs (AED) response in North Indian women with epilepsy (WWE). The present study aims to replicate the pharmacogenetic association, perform functional characterization and study its distribution within ethnically diverse Indian population. The variant was genotyped in 351 patients to assess the pharmacogenetic association and 552 healthy individuals belonging to 24 different ethnic groups to examine the distribution in Indian population. We observed significant overrepresentation of 'A' allele and 'AA' genotype in poor responders in WWE at Bonferroni-corrected significance levels. The recessive allele was found to lower the promoter activity by ~70-80% which was further substantiated by thermally less stable hairpin formed by it (DeltaTm=7 degrees C). Among all ethnic groups, west Indo European (IE-W-LP2) subpopulation showed highest genotypic frequency of the variant making women from this community more prone to poor AED response. Our results indicate that rs2606345 influences drug response in WWE by lowering CYP1A1 expression. PMID- 26951883 TI - A potentially functional polymorphism in ABCG2 predicts clinical outcome of non small cell lung cancer in a Chinese population. AB - ABCG2, CD133 and CD117 are pivotal markers of cancer stem cell, which are involved in carcinogenesis and cancer progression. The expression of these genes has been reported to be associated with the development and progression of many cancers, including non-small cell lung cancer (NSCLC). We selected and genotyped 9 potentially functional single-nucleotide polymorphisms in the 3 genes in a clinical cohort of 1001 NSCLC patients in a Chinese population. We found that variant genotypes of ABCG2 rs3114020 were associated with a significantly increased risk of death for NSCLC (additive model: adjusted hazard ratio=1.25, 95% confidence intervals=1.10-1.42, P<0.001). Further stepwise regression analysis suggested that rs3114020 was an independent risk factor for the prognosis of NSCLC. Besides, histology interacted with the genetic effect of rs3114020 in relation to NSCLC survival in the interaction analysis. Our findings show that ABCG2 rs3114020 might be one of the candidate biomarkers for NSCLC survival in this Chinese population, especially among patients with adenocarcinoma. PMID- 26951886 TI - Spatial plasticity of the auditory cortex in single-sided deafness. AB - OBJECTIVES/HYPOTHESIS: To evaluate spatial plasticity of the auditory cortex in single-sided deafness (SSD). STUDY DESIGN: Cross-sectional study comparing a cohort with adult-onset, idiopathic SSD to a cohort with normal hearing. METHODS: Demographic, audiometric, magnetoencephalographic imaging, and magnetic resonance imaging data were collected for 13 SSD adult subjects and 13 normal-hearing controls. Locations of peak activation corresponding to the M100 response in auditory cortices ipsilateral and contralateral to tonal stimuli (0.5 kHz and 4 kHz) were extracted from advanced biomagnetic source imaging analyses. Spatial extent of frequency representation across the 0.5 kHz to 4 kHz zone was computed for the two hemispheres. RESULTS: Spatial separation distance between peak locations for 0.5 kHz and 4 kHz stimuli in SSD showed increased activation spread distance in the hemisphere contralateral to the only hearing ear and decreased distance in the ipsilateral hemisphere. In contrast, normal hearing controls had nearly the same activation spread distance in the two hemispheres for ipsilateral and contralateral inputs. The difference between interhemispheric activation spread distance in SSD is significantly increased to 6.5 mm, when compared to 1.7 mm in normal controls (P < .05). CONCLUSIONS: Loss of unilateral peripheral input in SSD is associated with spatial reorganization of the auditory cortex in both hemispheres. This change in central auditory functional organization may in turn lead to higher order hearing deficits that rely on interhemispheric processing. Hearing optimization in the only hearing ear may require remediation of both spatial and temporal central auditory changes in SSD. LEVEL OF EVIDENCE: NA Laryngoscope, 126:2785-2791, 2016. PMID- 26951885 TI - Antitumor and apoptosis-inducing effects of alpha-mangostin extracted from the pericarp of the mangosteen fruit (Garcinia mangostana L.)in YD-15 tongue mucoepidermoid carcinoma cells. AB - alpha-mangostin is a dietary xanthone which has been shown to have antioxidant, anti-allergic, antiviral, antibacterial, anti-inflammatory and anticancer effects in various types of human cancer cells. In the present study, we aimed to elucidate the molecular mechanisms responsible for the apoptosis-inducing effects of alpha-mangostin on YD-15 tongue mucoepidermoid carcinoma cells. The results from MTT assays revealed that cell proliferation significantly decreased in a dose-dependent manner in the cells treated with alpha-mangostin. DAPI staining illustrated that chromatin condensation in the cells treated with 15 uM alpha mangostin was far greater than that in the untreated cells. Flow cytometric analysis indicated that alpha-mangostin suppressed YD-15 cell viability by inducing apoptosis and promoting cell cycle arrest in the sub-G1 phase. Western blot analysis of various signaling molecules revealed that alpha-mangostin targeted the extracellular signal-regulated kinase 1/2 (ERK1/2) and p38 mitogen activated protein kinase (MAPK) signaling pathways through the inhibition of ERK1/2 and p38 phosphorylation in a dose-dependent manner. alpha-mangostin also increased the levels of Bax (pro-apoptotic), cleaved caspase-3, cleaved caspase-9 and cleaved-poly(ADP-ribose) polymerase (PARP), whereas the levels of the anti apoptotic factors, Bcl-2 and c-myc, decreased in a dose-dependent manner. The anticancer effects of alpha-mangostin were also investigated in a tumor xenograft mouse model. The alpha-mangostin-treated nude mice bearing YD-15 tumor xenografts exhibited a significantly reduced tumor volume and tumor weight due to the potent promoting effects of alpha-mangostin on cancer cell apoptosis, as determined by TUNEL assay. Immunohistochemical analysis revealed that the level of cleaved caspase-3 increased, whereas the Ki-67, p-ERK1/2 and p-p38 levels decreased in the alpha-mangostin-treated mice. Taken together, the findings of our study indicate that alpha-mangostin induces the apoptosis of YD-15 tongue carcinoma cells through the ERK1/2 and p38 MAPK signaling pathways. PMID- 26951887 TI - Cobalt-Catalyzed Cyclization of N-Methoxy Benzamides with Alkynes using an Internal Oxidant through C-H/N-O Bond Activation. AB - The cyclization of substituted N-methoxy benzamides with alkynes in the presence of an easily affordable cobalt complex and NaOAc provides isoquinolone derivatives in good to excellent yields. The cyclization reaction is compatible with a range of functional group-substituted benzamides, as well as ester- and alcohol-substituted alkynes. The cobalt complex [Co(III) Cp*(OR)2 ] (R=Me or Ac) serves as an efficient catalyst for the cyclization reaction. Later, isoquinolone derivatives were converted into 1-chloro and 1-bromo substituted isoquinoline derivatives in excellent yields in the presence of POCl3 or PBr3 . PMID- 26951888 TI - B-cell lymphoma with Mott cell differentiation in a cat. AB - A 12-year-old, male castrated Domestic Shorthair cat was presented to Animal Medical Center of Gifu Univeristy with anorexia and vomiting. Physical examination revealed an enlarged left tonsil and right mandibular lymph node (approximately 2-3* the normal size), and a submucosal mass on the right side of the epiglottis (1.5 * 2.0 cm). On computed tomography images, an enlarged left tonsil, and enlarged right mandibular, right pharyngeal, and left and right cervical lymph nodes were observed. Cytologic examination of smears of tonsil and lymph nodes revealed numerous medium- to large-sized neoplastic lymphoid cells, approximately half of which contained one or several light-blue homogenous globoid cytoplasmic inclusions (5-10 MUm), which stained magenta with periodic acid-Schiff (PAS) stain. Histopathologic examination of the left tonsil revealed diffuse proliferation of medium- to large-sized neoplastic lymphoid cells effacing the original lymphoid architecture. Half of the cells contained one or several eosinophilic globoid cytoplasmic inclusions, which stained magenta with PAS and showed positive immunohistochemical reactions for immunoglobulin M (IgM) and lambda light chain. Neoplastic lymphoid cells were also CD20+ , Pax5+ , and MUM1+ , and CD3- . Thus, the neoplastic lymphoid cells expressed a B-cell immunophenotype, and the globoid cytoplasmic inclusions represented an aberrant IgM lambda light chain accumulation, similar to Russell bodies. B-cell lymphoma with Mott cell differentiation was diagnosed based on cytologic, histopathologic, and immunohistochemical features. This is the first report of B-cell lymphoma with Mott cell differentiation in a cat. PMID- 26951890 TI - Research requires deep knowledge of the modality to be tested. PMID- 26951889 TI - A comprehensive analysis on expected years of life lost due to pancreatic cancer. AB - BACKGROUND: Pancreatic cancer represents a fatal malignancy leading to premature death and loss of life expectancy. The aim of the present study was to assess how many years of life are lost due to this cancer, in relationship with surgery and ageing. METHODS: Data from 716 consecutive patients discharged from a tertiary referral hospital (2002-2012) with a diagnosis of pancreatic cancer and with complete clinical and follow-up data were used to estimate the number of years of life-lost (YLL) through a semi-parametric extrapolation having an age-, sex- and year-of-onset- matched population derived from national life tables as reference. RESULTS: The mean entire lifespan estimated for the 716 patients was 1.4 years (95% C.I.:0.8-1.9) resulting in a number of YLL after diagnosis of 12 years (95% C.I.:11.5-12.6) per person. Surgical patients (147 cases; 20.5%) were younger and experienced higher post-diagnostic lifespan (3.5 years) than non-surgical older individuals (0.8 years; p < 0.001). These figures were reflected on the number of expected YLL (EYLL) that remained substantially unaffected by surgery (p = 0.821). Patients aged <=68 years experienced the highest number of EYLL (20.8 years); whereas elderly patients had a loss of life that corresponded to only 6% of the entire life they had already lived. CONCLUSIONS: In a typical pancreatic cancer cohort, surgery was not able to modify population-based statistics because of a different age at tumor onset which nullifies any benefit from a "lifespan from birth" perspective. Pancreatic cancer in younger individuals must be ranked within the very first causes of EYLL due to malignancy. PMID- 26951891 TI - Knowledge of the modality comes from rigorous research. PMID- 26951892 TI - Novel nicotine analogues with potential anti-mycobacterial activity. AB - Tuberculosis (TB) is the second leading lethal infectious disease in the world after acquired immuno deficiency (AIDs). We have developed a series of twenty five novel nicotine analogues with de-addiction property and tested them for their activity against Mycobacterium tuberculosis (MTB). In an effort to increase the specificity of action and directing nicotine analogues to target MTB, four promising compounds were further optimized via molecular docking studies against the Dihydrofolate reductase of MTB. After lead optimization, one nicotine analogue [3-(5-(3fluorophenyl)nicotinoyl)-1-methylpyrrolidin-2-one] exhibited minimum inhibitory concentration of 1 MUg/mL (2.86 nM) against M. tuberculosis (H37Rv strain), a human pathogenic strain of clinically significant importance. Pharmacokinetic analysis of [3-(5-(3fluorophenyl)nicotinoyl)-1methylpyrrolidin-2 one] with lowest MIC value via oral route in Wistar rats revealed that at a dosage of 5 mg/kg body weight gave a maximum serum drug concentration (Cmax) of 2.86 MUg/mL, Tmax of one hour and a half-life (T1/2) of more than 24 h and Volume of distribution (Vd) of 27.36 L. Whereas the parenteral (intra venous) route showed a Cmax of 3.37 MUg/mL, Tmax of 0.05 h, T1/2 of 24 h and Vd equivalent to 23.18 L. The acute oral toxicity and repeated oral toxicity studies in female Wistar rats had an LD50>2000 mg/kg body weight. Our data suggests that nicotine derivatives developed in the present study has good metabolic stability with tunable pharmacokinetics (PK) with therapeutic potential to combat MTB. However, further in vivo studies for anti-tuberculosis activity and elucidation of mode of action could result in more promising novel drug for treating MTB. To the best of our knowledge this is the first report revealing the anti-mycobacterial potential of nicotine analogue at potential therapeutic concentrations. PMID- 26951893 TI - Isatin analogs as novel inhibitors of Candida spp. beta-carbonic anhydrase enzymes. AB - Enzyme inhibition data of structurally novel isatin-containing sulfonamides were determined for two carbonic anhydrases (CAs, EC 4.2.1.1) from pathogenic Candida species (CaNce103 from C. albicans and CgNce103 from C. glabrata). The compounds show KI values in the low nanomolar range for the fungal CAs, while they have significantly higher KI values for the human CAs. Homology models were constructed for the CaNce103 and CgNce103 and subsequently the ligands were docked into these models to rationalize their enzyme inhibitory properties. PMID- 26951895 TI - Interventions for failed wrist fistulae: Is it worthwhile? AB - A well-functioning forearm fistula is considered as the most suitable access for dialysis. It is easy to construct, has the fewest number of complications and lasts for a long time. Many patients fail to enjoy this benefit due to the high rates of thrombosis and the failure to mature associated with this procedure. Attempts to salvage failed and failing fistula suggest that there is a group of patients where interventions can help provide this benefit. This article provides a brief review of current experience using surgical and interventional techniques to salvage failing forearm fistulae. It attempts to classify modes of presentation of access failure and different modalities used to salvage them. It also suggests an algorithm that can be used to identify patients who may benefit from these interventions and a guide to make the decisions related to selection of a treatment modality. Successful salvage of a failing forearm fistula provides the patient with an opportunity to enjoy all the benefits of this access. PMID- 26951894 TI - 1,2,4-Triazolyl octahydropyrrolo[2,3-b]pyrroles: A new series of potent and selective dopamine D3 receptor antagonists. AB - A novel series of 1,2,4-triazolyl octahydropyrrolo[2,3-b]pyrroles showing high affinity and selectivity at the DA D3 receptor is reported here. Compounds endowed with high selectivity over the hERG channel were identified and their pharmacokinetic properties thoroughly analyzed. A few derivatives with appropriate developability characteristics were selected for further studies and progression along the screening cascade. In particular, derivative 60a, (DA D3 pKi=8.4, DA D2 pKi=6.0 and hERG fpKi=5.2) showed a balanced profile and further refinements are in progress around this molecule. PMID- 26951896 TI - Surgical and endovascular revision of brachio-basilic vein fistula. AB - PURPOSE: The brachio-basilic vein fistula (BBVF) is currently the third vascular access option for patients on hemodialysis, following radio-cephalic and brachio cephalic arterio-venous fistulas. Like all types of hemodialysis vascular access, a variety of procedures may have to be performed in order to maintain long-term use of the BBVF. The aim of the present study was to perform a literature review of endovascular or surgical revisions of BBVFs. METHODS: On Pubmed search, 676 records were obtained and reviewed for relevance with the aim of the search. RESULTS: A variety of endovascular and surgical revision techniques has been described to manage BBVF poor maturation, dysfunction manifested as failing BBVF (most often the result of a stenosis at the transposed/swing segment), thrombosis, aneurysm formation and hemodialysis access-induced hand ischemia (steal syndrome). The role of revision is crucial in BBVF maintenance, taking into account that around 70% of these fistulas will require some intervention by 18 months and as a result of revision, secondary patency is preserved in the vast majority, according to the results of one study. Endovascular revision is the treatment of choice for most cases of BBVF dysfunction or thrombosis, with redo surgery reserved for failures of endovascular techniques or other specific indications. CONCLUSIONS: BBVF revision, more often in the form of endovascular surgery, plays a crucial role in BBVF maintenance and its continued use for hemodialysis, necessary for reducing graft and catheter use and the associated morbidity. PMID- 26951898 TI - The pros and cons of preserving a functioning arteriovenous fistula after kidney transplantation. AB - The autologous arteriovenous fistula (AVF) for hemodialysis burdens the cardiovascular system with increased cardiac output and pulmonary artery pressure, increasing cardiovascular risk. This article reviews literature on the benefits and drawbacks of a functioning AVF after kidney transplantation and discusses the cardiovascular effects of AVF closure. Several cohort studies demonstrate a significant cardiac burden of an AVF and improvement of cardiac dimensions after AVF ligation. However, no randomized trials have been conducted on routine AVF closure after successful kidney transplantation. Therefore, clinical trials are warranted to evaluate whether the cardiovascular benefits of routine AVF closure outweigh the potential harm for patients after successful kidney transplantation. PMID- 26951897 TI - The value of intravascular ultrasound in the treatment of central venous obstructions in hemodialysis patients. AB - INTRODUCTION: Digital subtraction angiography (DSA) is the gold standard in diagnosis and treatment of central venous obstructions (CVOs) in hemodialysis access. However, growing data suggest that DSA might underestimate the degree and morphology of venous outflow stenosis. This could lead to inappropriate CVO management. Intravascular ultrasound (IVUS) has been shown to identify lesion characteristics remaining obscure with angiography. With the current study we suggest IVUS as an eminent imaging modality in CVO management. METHODS: Twelve patients (8 male, mean age 62.4 +/- 9 years) were analyzed for suspicion of symptomatic CVO. Both angiography and IVUS evaluation were performed to determine the degree of obstruction before and after PTA. Stent placement was indicated when significant residual stenosis (>50% lumen reduction) was suspected. RESULTS: Conventional plain angiography determined 8 out of 12 central venous lesions significant. Secondary signs of obstruction, i.e., collateral filling, was present in all 12 cases. After PTA, persistent significant stenosis was observed in 3 out of 12 patients. IVUS showed significant lumen reduction in all 12 cases. Additionally, IVUS showed a median cross-sectional area of 24 +/- 12 mm2 before PTA and 37 +/- 23 mm2 after PTA (NS). Furthermore, IVUS showed signs of intraluminal fibrotic trabeculations in 9 patients. Stenting was performed in 10 patients with >50% lumen reduction on IVUS after PTA. CONCLUSIONS: Conventional angiography seems unreliable to identify all significant aspects of a central venous outflow obstruction. Additional use of IVUS might aid in the decision making process and select the optimal treatment strategy. PMID- 26951899 TI - Permanent arteriovenous fistula or catheter dialysis for heart failure patients. AB - Heart failure (HF) is the most frequent cardiovascular disease associated with chronic kidney disease and represents a high risk for cardiovascular mortality in incident hemodialysis (HD) patients. This risk is especially high during the arteriovenous fistula (AVF) maturation period due to the marked hemodynamic changes related to the large increase in the blood flow and also within the first 120 days after HD inception because in this period the highest mortality rate occurs. When planning the vascular access for each incident HF patient, the risk of aggravating HF after AVF creation must be evaluated carefully alongside the risk of catheter-related complications, but avoiding a non-selective 'catheter first' approach for all these patients. HF patients classified within the New York Heart Association (NYHA) Class I-II and the American College of Cardiology/American Heart Association (ACC/AHA) Stage A-B could initiate HD through a distal arm AVF. High-flow brachial artery-based AVF creation must be avoided because it displays the highest risk of worsening the cardiac function. The decision for AVF creation or tunneled central catheter placement in HF patients classified within the NYHA Class III and the ACC/AHA Stage C must have been individualized according the degree of systolic and/or diastolic dysfunction. HF patients with significant reduction in systolic function (ejection fraction lower than 30%) or classified within the NYHA Class IV and the ACC/AHA Stage D, are candidates for tunneled catheter placement to start HD treatment. PMID- 26951901 TI - Impact of needles in vascular access for hemodialysis. AB - This article reviews pragmatic aspects of cannulation practice and types of cannulation devices, as well as their impact in vascular access for hemodialysis. Hemodialysis treatment requires successful insertion of two needles for each dialysis treatment. The first needle is the arterial needle; it removes blood with toxin accumulation from the patient and delivers it to the dialysis machine. The second needle, called the venous needle, returns the purified blood from the dialyzer to the patient. Mechanical and hemodynamic trauma related to needle insertions will be discussed. PMID- 26951900 TI - HeRO graft versus lower extremity grafts in hemodialysis patients with long standing renal failure. AB - BACKGROUND: The role of the HeRO graft in central venous pathology has been defined in the literature and clinically. There have been two publications or abstracts that have compared the patency rates and outcomes of this graft to the lower extremity graft. AIM: The outcomes of both publications leads to an algorithm suggested by the author in determining which procedure should be used for specific patients. METHODS: Both papers trend to show that lower extremity grafts have improved patency rates when compared to the HeRO device in the upper extremity. DISCUSSION: The author will use these data to demonstrate that in younger patients and in patients with low morbidity and mortality, salvaging the upper extremity area for access may show that the HeRO device provides benefit for these patients. PMID- 26951902 TI - Vascular access for elderly hemodialysis patients: what should we aim for? AB - PURPOSE: Elderly chronic kidney disease (CKD) patients are one of the fastest growing groups in hemodialysis (HD). However, overall mortality and arteriovenous fistulae failure are still high in this population. Therefore, a different vascular access policy may be advised for this group of patients. METHODS: We searched PubMed for relevant articles published in English between the years 2000 2015. Studies investigating vascular access-related outcomes in elderly CKD patients were included. RESULTS: The scarce literature on this topic suggests that elderly CKD patients are more likely to undergo unnecessary vascular access procedures. However, with appropriate vascular evaluation, arteriovenous access placement is a viable strategy for this group of patients and dialysis access related outcomes are superior for arteriovenous access in comparison with dialysis catheters. CONCLUSIONS: When deciding whether or not to create an arteriovenous vascular access in elderly CKD patients, physicians should consider the probability of CKD progression, the expected life expectancy and quality of life of the patient and the probability of success of an arteriovenous access creation. PMID- 26951903 TI - Optimization of dialysis catheter function. AB - Central venous catheters (CVCs) are essential in the management of hemodialysis patients, but they also carry unintended negative consequences and in particular thrombosis and infection, adversely affecting patient morbidity and mortality. This review will focus on the etiology, prevention, and management of CVC-related dysfunction, which is mainly associated with inadequate blood flow. CVC dysfunction is a major cause of inadequate depuration. Thrombus, intraluminal and extrinsic, as well as fibrous connective tissue sheath (traditionally indicated as fibrin sheath) formation play a central role in establishing CVC dysfunction. Thrombolysis with urokinase or recombinant tissue plasminogen activator (rTPA) can be undertaken in the dialysis unit, restoring adequate blood flow in most patients, preserving the existing catheter, and avoiding an interventional procedure. If thrombolytics fail, mainly because of the presence of fibrous connective tissue sheath, catheter exchange with fibrin sheath disruption may be successful and preserve the venous access site. Prevention of CVC dysfunction is important for containing costly pharmacologic and interventional treatments, which also affect patients' quality of life. Prevention is based on the use of anticoagulant and/or thrombolytic CVC locks, which are only partially effective. Chronic oral anticoagulation with warfarin has also been proposed, but its use for this indication is controversial and its overall risk-benefit profile has not been clearly established. PMID- 26951904 TI - Training in dialysis access - charting future success. AB - PURPOSE: Medical education and training in dialysis access skills remains complex and inadequate as learners come from diverse backgrounds and from various specialties so that appropriate training is limited. As a result, a system of progressive education including live lectures, and hands on training has emerged, but there is controversy as to what constitutes the best educational model. METHODS: Presently there is no recognized or structured training in vascular access during residency or fellowships. Here we present a model of dialysis access training for beginner to advanced surgeons. RESULTS: A structured hands-on and didactic surgery training certification course consisting of a one week curriculum with 49 hours of ACCME credit hours has been in effect for one year. The learning impact and the performance outcome are high but with limited attendance capacity. Pre- and post- training test results attest to training effectiveness. To increase access, an off-site training curriculum has been initiated, entailing 1-2 days (8-15 credit hours) consisting of didactic lectures and surgical training. This teaching module has moderate learning impact for 50 100 attendees.Finally, a tiered, web-based training curriculum (10 ACCME credit hours) can accommodate an unlimited number of learners, but has a lower skills learning impact. CONCLUSIONS: The future dialysis access training must also accommodate learners with diverse individual backgrounds, and different levels of professional (skill) development. To be effective and accessible, a variety of educational system, for example on site or web based is needed. Collaborative initiatives for global dialysis access training are currently underway. PMID- 26951905 TI - Peritoneal dialysis in centenarian patients: no age limitation? AB - BACKGROUND: The majority of dialysis patients are elderly, and the trend towards even more elderly people with end-stage renal disease (ESRD) will further determine the dialysis field in the future. METHOD: If these elderly ESRD patients do not opt for conservative ESRD care, they may still qualify for peritoneal dialysis (PD), which may be assisted or unassisted. RESULTS: Although they may be more frail and have a greater co-morbidity burden compared to their younger counterparts, elderly patients with ESRD may still be able to maintain a good functionality level with adequate quality of life by performing PD, which may be assisted (treatment performed or supported e.g. by partner or nurse) or unassisted (without support). PD may indeed further contribute to maintaining autonomy, and enhance quality of life compared to in-center conventional hemodialysis. In order to illustrate this strategy, we hereby describe a centenarian patient with ESRD who received assisted PD successfully. CONCLUSIONS: With appropriate management and infrastructure, (very) high age is not a contra indication for PD. PMID- 26951906 TI - Urgent peritoneal dialysis or hemodialysis catheter dialysis. AB - Worldwide, there is a steady incident rate of patients with end-stage kidney disease (ESKD) who require renal replacement therapy. Of these patients, approximately one-third have an "unplanned" or "urgent" start to dialysis. This can be a very challenging situation where patients have either not had adequate time for education and decision making regarding dialysis modality and appropriate dialysis access, or a decision was made and plans were altered due to unforeseen circumstances. Despite such unplanned starts, clinicians must still consider the patient's ESKD "life-plan", which includes the best initial dialysis modality and access to suit the patient's individual goals and their medical, social, logistic, and facility circumstances. This paper will discuss the considerations of peritoneal dialysis and a peritoneal dialysis catheter access and hemodialysis and central venous catheter access in patients who require an urgent start to dialysis. PMID- 26951907 TI - Access flow reduction for cardiac failure. AB - High-flow in hemodialysis arteriovenous angioaccesses is frequent. It may result in high-output cardiac failure, which should be prevented by fistula flow reduction. The most frequently reported flow reduction procedure is banding but immediate and long-term results are questionable. Alternative techniques are related here with personal results. Juxta-anastomosis "Proximal Radial Artery Ligation" (PRAL) is a very simple and effective reduction technique for side-to end radio-cephalic fistulas (82 patients; reduction rate [RR]: 54% +/- 19%). For brachial artery-based fistulas flow reduction two variants of Revision Using Distal Inflow (RUDI) procedures are used: 1) RUDI-1 using a polytetrafluoroethylene (PTFE) graft or a greater saphenous vein, which we first described in 1989 as "Distal Report of the Arterial Inflow" (35 patients; RR: 53% +/- 18%), 2) RUDI-2 procedure, "Transposition of the Radial Artery", which we described in 2009 (47 patients; RR: 66% +/- 14%). PMID- 26951908 TI - Access ligation in transplant patients. AB - Access surgeons will encounter patients with functioning transplants who want to lose their fistula, and every dialysis unit sees patients returning after a failed kidney transplant for whom an old fistula is a readily available lifeline. The decision is straightforward in patients with perfectly functioning transplants and disabling complications of their fistula, or in patients with failing transplants and a good fistula. The challenge is to make this decision in patients with good transplant function and an asymptomatic fistula. Despite improvements in one-year survival of renal grafts, the long-term graft survival has improved modestly. This means about half of the patients with a successful kidney transplant will return to dialysis within 10 years. Use of recently developed risk calculators, based on clinical parameters, may help in the decision process. A high flow fistula can lead to heart failure but most fistulae are well tolerated in asymptomatic patients and the effects of closure of the AVF on the heart are modest. Recent evidence suggests that there may be benefits of a functioning AVF that may need to be considered in this decision process. This article reviews the literature and comes to pragmatic recommendations of what to do with this conundrum. PMID- 26951909 TI - Arterial disease and vascular access in diabetic patients. AB - PURPOSE: There are conflicting reports on the effects of diabetes on the outcomes of hemodialysis access procedures. While some found no negative effects, others reported deleterious effects of diabetes on vascular access outcomes. Why is there concern about diabetes and related vascular problems on vascular access procedures? What are the differences of diabetic patients and their vasculature from that of nondiabetics? Do they have an effect on hemodialysis vascular access outcomes? We will try to find answers to these questions in light of the available evidence. METHODS: Recent literature on arterial disease in diabetes and end-stage renal disease (ESRD), and the effects on vascular access outcomes were searched in order to find answers to above questions. RESULTS: There are conflicting and controversial reports on the effects of preexisting vascular problems due to diabetes and chronic kidney disease (CKD) on the outcomes of hemodialysis access procedures. Diabetic vasculature, especially in patients with ESRD, has some specific problems, the most important of which seem to be the calcification and stiffening of the arteries. CONCLUSIONS: Although some authors report inferior outcomes of vascular access procedures in diabetic patients, there is evidence that most of the problems encountered can be dealt with by careful patient selection, surgical skill, and experience. PMID- 26951910 TI - Early cannulation graft: Acuseal. AB - AIM: To review the published literature on the early cannulation graft, Acuseal. METHODS: 235 reported cases have been published and reviewed. These cases are both prospective and retrospective, from either multicenter or single centers. Patency rates and complication rates were reviewed. Economic value of early cannulation grafts were also analyzed. RESULTS: Over 135 patients were cannulated within 2.5 days after implantation. No increase in complications were noted and similar primary and secondary patency rates were observed compared to the literature. Economic evaluation both in the UK and US demonstrate benefit of this graft when compared to catheters, fistulas and other grafts. CONCLUSION: Early stick grafts demonstrate similar patency and complication rates when compared to published literature of standard grafts.Economic benefit is also noted using this graft. PMID- 26951911 TI - Early cannulation of the FlixeneTM arteriovenous graft. AB - PURPOSE: The aim of this review was to search for evidence of the efficiency of early cannulation of the FlixeneTM (Maquet-Atrium Medical, Hudson, NH, USA) arteriovenous graft (AVG) in the current literature and to assess its patency and complication rates. METHODS: Searches in Pubmed, Medline, Embase and the Cochrane Library were performed using the following specific search terms: early cannulation AVG and/or FlixeneTM graft. The primary outcomes were mean time to first cannulation and patency rates at 12 months. Secondary outcomes were complications. RESULTS: Six studies reporting outcomes in a total of 260 procedures were included in this review. The median delay from intervention to first cannulation was documented in four studies and was less than 3 days. Primary assisted patency at 12 months ranged from 45% to 53% in the four documented series. In five studies, documented secondary patency at 12 months ranged from 63% to 92%. Two studies compared outcomes between traditional and FlixeneTM grafts: one study reported significantly (p<0.01) improved one-year patency using the FlixeneTM graft, the two studies did not report significant differences in complication rates between both groups. The rate of infection and pseudo-aneurysm formation ranged from 0 to 11% and 0 to 6%, respectively. CONCLUSIONS: This review shows that early cannulation of the FlixeneTM graft within 3 days following its implantation is feasible with one-year patency and complication rates equivalent to those of conventional grafts which can be cannulated only after 2 weeks. PMID- 26951912 TI - Heparin-bonded expanded polytetrafluorethylene grafts in hemodialysis access. AB - When options for autologous arteriovenous (AV) fistulas have been fully exhausted, AV grafts continue to play an important role in access creation for hemodialysis, offering long-term hemodialysis access that is a better alternative to central vein catheters. The drawbacks of AV grafts are their poor patency, infection and higher cost. Their main advantages are that they are widely available, are easy to create, and mature early. In the context of the "Fistula First" initiative, many patients with low quality veins suffer from fistula failure and non-maturation resulting in prolonged catheter days that would otherwise be prevented by initial creation of an AV graft. Endeavors to improve graft patency include administration of pharmacological agents, changing graft configuration, altering graft biology, and altering the graft surface. In this review, the current status of heparin-bonded AV grafts for hemodialysis is discussed. PMID- 26951913 TI - Graft modification strategies to improve patency of prosthetic arteriovenous grafts for hemodialysis. AB - Prosthetic arteriovenous grafts (AVGs) are indicated for vascular access for long term hemodialysis in patients in whom creation or maintenance of an arteriovenous fistula (AVF) has failed or is contraindicated. AVGs have an inferior long-term patency as compared to AVFs. To ameliorate patency rates of prosthetic AVGs, different strategies have emerged to improve graft materials. This review aims to describe current strategies and future perspectives on graft modification, by graft geometry, drug coatings and graft surface technology, to improve AVG patency. PMID- 26951914 TI - The Triglyceride to High-Density Lipoprotein Cholesterol Ratio Is a Useful Marker to Predict Unfavorable Cardiovascular Outcomes, But Other Confounding Factors Should Be Considered. PMID- 26951915 TI - The efficacy and safety of drug-eluting balloons for the treatment of in-stent restenosis as compared with drug-eluting stents and with conventional balloon angioplasty. AB - BACKGROUND/AIMS: Treatment of coronary in-stent restenosis (ISR) is still associated with a high incidence of recurrence. We aimed to compare the efficacy and safety of drug-eluting balloons (DEB) for the treatment of ISR as compared with conventional balloon angioplasty (BA) and drug-eluting stents (DES). METHODS: Between January 2006 and May 2012 a total of 177 patients (188 lesions, 64.1 +/- 11.7 years old) who underwent percutaneous coronary intervention for ISR were retrospectively enrolled. Clinical outcomes were compared between patients treated with DEB (n = 58, 32.8%), conventional BA (n = 65, 36.7%), or DES (n = 54, 30.5%). The primary end point was a major adverse cardiac event (MACE), defined as a composite of cardiac death, myocardial infarction, and target lesion revascularization(TLR). RESULTS: Baseline characteristics were not different except for a history of previous MI, which was more frequent in patients treated by conventional BA or DES than in patients treated by DEB (40.0% vs. 48.1% vs. 17.2%, respectively, p = 0.002). The total incidences of MACEs were 10.7%, 7.4%, and 15.4% in patients treated by DEB, DES, or conventional BA, respectively (p > 0.05). TLR was more frequent in patients treated by conventional BA than in patients treated by DEB or DES, but this was not statistically significant (10.8% vs. 6.9% vs. 3.7%, p > 0.05 between all group pairs, respectively). CONCLUSIONS: This study showed that percutaneous coronary intervention using DEB might be a feasible alternative to conventional BA or DES implantation for treatment of coronary ISR. Further large-scaled, randomized study assessing long-term clinical and angiographic outcomes will be needed. PMID- 26951916 TI - A novel c.563 T>G, p.L189R lamin A/C mutation in identical twins with dilated cardiomyopathy. PMID- 26951918 TI - Minimal change nephrotic syndrome showing complete remission after resection of a neurofibroma in a type I neurofibromatosis patient. PMID- 26951917 TI - Smoking habits and nicotine dependence of North Korean male defectors. AB - BACKGROUND/AIMS: The smoking rates and patterns in the North Korean population are not well known. More than 20,000 North Korean defectors have settled in South Korea; thus, we can estimate the current North Korean smoking situation using this group. METHODS: All North Korean defectors spend their first 3 months in a South Korean facility learning to adapt to their new home. We retrospectively analyzed the results from a questionnaire conducted among North Korean male defectors in this facility from August 2012 to February 2014. RESULTS: Of 272 men, 84.2% were current smokers, 12.5% were ex-smokers, and 3.3% were non smokers. The mean age of this group was 35.9 +/- 11.3 years, and smoking initiation occurred at a mean age of 18.2 +/- 4.7 years. Among the subjects, 78.1% had a family member who smoked. Of the 221 current smokers, 67.4% responded that they intended to quit smoking. Fagerstrom test and Kano test for social nicotine dependence (KTSND) results for current smokers were 3.35 +/- 2.26 and 13.76 +/- 4.87, respectively. Question 9 on the KTSND (doctors exaggerate the ill effects of smoking) earned a significantly higher score relative to the other questions and a significantly higher score in current smokers compared with non smokers. CONCLUSIONS: The smoking rate in North Korean male defectors was higher than that indicated previously. However, interest in smoking cessation was high and nicotine dependence was less severe than expected. Further investigation is needed to identify an efficient method for North Korean smokers to stop smoking. PMID- 26951920 TI - The In-Session and Long-Term Role of a Significant Other in Motivational Enhancement Therapy for Alcohol Use Disorders. AB - OBJECTIVE: To examine how significant other (SO) language in support of or against client abstinence from alcohol influences clients' in-session speech and drinking behavior over the 9 months post-Motivational Enhancement Therapy (MET). METHOD: Sequential analyses were used to examine the language of Project MATCH clients who invited an SO to participate in an MET session. Hierarchical regressions investigated the predictive relationship between SO language and clients' post-treatment drinking behavior. A cohort analytic design compared the change language of these SO-involved participants against a matched group who chose client-only therapy. RESULTS: 'SO Support Change' language increased the odds of client Change Talk in the next utterance (p<.01). SO Support Change did not significantly predict reduced post-treatment drinking, whereas 'SO Against Change' significantly predicted an increase in average drinks per drinking day (DDD) across months 7-9 post-MET (p=.04). In the matched comparison, the proportion of change-related client language was comparable across the SO involved and client-only groups. CONCLUSIONS: Motivational interviewing theory was supported by the sequential association between SO and client language as well as the predictive link between SO Against Change and client drinking intensity. Given the centrality of pro-sobriety language in the literature, it was surprising that SO Support Change did not predict alcohol use outcomes. Findings are discussed in relation to contemporary treatment process research and clinical practice. PMID- 26951919 TI - Intimate partner violence norms cluster within households: an observational social network study in rural Honduras. AB - BACKGROUND: Intimate partner violence (IPV) is a complex global problem, not only because it is a human rights issue, but also because it is associated with chronic mental and physical illnesses as well as acute health outcomes related to injuries for women and their children. Attitudes, beliefs, and norms regarding IPV are significantly associated with the likelihood of both IPV experience and perpetration. METHODS: We investigated whether IPV acceptance is correlated across socially connected individuals, whether these correlations differ across types of relationships, and whether social position is associated with the likelihood of accepting IPV. We used sociocentric network data from 831 individuals in rural Honduras to assess the association of IPV acceptance between socially connected individuals across 15 different types of relationships, both within and between households. We also investigated the association between network position and IPV acceptance. RESULTS: We found that having a social contact that accepts IPV is strongly associated with IPV acceptance among individuals. For women the clustering of IPV acceptance was not significant in between-household relationships, but was concentrated within households. For men, however, while IPV acceptance was strongly clustered within households, men's acceptance of IPV was also correlated with people with whom they regularly converse, their mothers and their siblings, regardless of household. We also found that IPV was more likely to be accepted by less socially-central individuals, and that the correlation between a social contact's IPV acceptance was stronger on the periphery, suggesting that, as a norm, it is held on the periphery of the community. CONCLUSION: Our results show that differential targeting of individuals and relationships in order to reduce the acceptability and, subsequently, the prevalence of IPV may be most effective. Because IPV norms seem to be strongly held within households, the household is probably the most logical unit to target in order to implement change. This approach would include the possible benefit of a generational effect. Finally, in social contexts in which perpetration of IPV is not socially acceptable, the most effective strategy may be to implement change not at the center but at the periphery of the community. PMID- 26951921 TI - National Dissemination of Motivation Enhancement Therapy in the Veterans Health Administration: Training Program Design and Initial Outcomes. AB - Motivational enhancement therapy (MET) can be defined most simply as the "....combination of Motivational Interviewing (MI) with assessment feedback...." (Miller & Rollnick, 2013, p. 250). MET has a clear evidence-base promoting its use especially for treatment of substance use disorders (SUDs). Despite its efficacy and utility, MET is not widely used in clinical settings. In 2012, to facilitate the dissemination of MET, the Veterans Health Administration [VHA; the health care component of the U.S. Department of Veterans Affairs (VA)] launched a national training program that provided competency-based training in MET to VA staff working in SUD specialty care clinics. All VA facilities are required to implement EBPs for SUDs, such as MET, and ensure that they are available to veterans. This paper describes the VA MET training program and examines the impact of the MET training program on participants' knowledge of MET and self reported MET skills. We review the components of the training and consultation and discuss adaptations made from the Project MATCH MET model to a real-world clinical setting. Of the 264 training participants we trained 2012-2013, 213 (81%) successfully completed all requirements of the training program, including requirements for demonstrating competency and attending at least 75% of scheduled consultation calls. After completion of the training program, approximately 85% of the clinicians reported implementing MET often (either 1-3 times per week or daily). Furthermore, we saw significant increases in MI knowledge from pretraining assessment to post-workshop and from pretraining to post consultations. Additional training program details and revisions are discussed. PMID- 26951922 TI - Outcome analysis of pediatric pyeloplasty in units with less than 20% differential renal function. AB - OBJECTIVE: This study was conducted to assess ureteropelvic junction obstruction (UPJO) units with differential renal function (DRF) <=20%, 3 months post pyeloplasty as well as complications and stability of function in long term follow up. MATERIAL AND METHODS: In this prospective study, children below 12 years age with unilateral UPJO and DRF <=20% undergoing open Anderson-Hynes dismembered pyeloplasty from 2002-2014 excluding associated vesicoureteric reflux were included. Drainage and function were assessed with isotope [ethylene di cysteine (EC)] scan at 3 months and later during yearly follow-up as well as by intravenous urography (IVU). RESULTS: Of a total 744 patients with UPJO in the study period, 112 had DRF <=20%. Thirty four (30%) underwent percutaneous nephrostomy. Ten with no function underwent nephrectomy. 102 (mean age 4.7 years) with DRF 0-9% (n = 40) and 10-20% (n = 62) formed the study group. Hypertension (3), small kidney (13) and crossing vessels (9) were associated. Follow up ranged from 1-8 years (4.6 +/- 1.34 years). Six patients were lost to follow up. There was significant improvement in drainage in the remaining 96 patients. Mean DRF and IVU function showed highly significant improvement (p < .001) in those with clinical signs and symptoms (n = 85), compared to asymptomatic patients in preoperative 0-9% and 10-20% group. The mean rise in DRF was significantly more in the preoperative 0-9% group, palpable mass presentation and by age at 5-12 years in the 0-9% group and 1-5 years in the 10-20% group. In the symptomatic group, except for intermittent UTIs (n = 8) and pain (n = 3) which subsided 1-2 years after surgery, all patients had resolution of initial complaints. Hypertension resolved in two patients with crossing vessels. No patient required re-do pyeloplasty or developed hypertension during followup. There was no significant difference (p = 1.000) in mean DRF between 3 month and 1-8 years post operative scans (n = 53). CONCLUSIONS: This study which appears to be the largest in the literature of pediatric UPJO with DRF <=20%, conclusively shows that there is statistically significant improvement in function after pyeloplasty which remains stable during the period of growth with no long term complications. Nephrectomy should be considered only in patients with nil or <5% uptake on isotope imaging with associated (a) no parenchyma on imaging or on exploration, (b) pyonephrosis, (c) hypertension or (d) minimal urine output on percutaneous nephrostomy. PMID- 26951924 TI - Association of a transcobalamin II genetic variant with falsely low results for the holotranscobalamin immunoassay. AB - BACKGROUND: The clinical use of holotranscobalamin (holoTC) testing to evaluate vitamin B12 status has increased in recent years. We present two patients (African Caribbean and Indian heritage), in which the holoTC assay indicated severe B12 deficiency (< 5 pmol/L). Additional clinical tests revealed that these patients had normal levels of total vitamin B12 in blood and unremarkable levels of two other markers of vitamin B12 status, homocysteine and methylmalonic acid. We hypothesized that these patients carry a variant in the transcobalamin gene (TCN2) that influences the most widely commercially available holoTC test - Active-B12 (Axis-Shield Diagnostics Ltd). DESIGN: Exon sequencing of the TCN2 gene was carried out. Protein characterization included total transcobalamin (TCN2) detection by Western blot, and holoTC by (57) Co-labelled B12 binding followed by size fractionation. RESULTS: Exon sequencing of TCN2 revealed both patients were homozygous for the minor allele of rs35838082 (p.R215W). Western blot and chromatographic analyses revealed that the serum of these patients contains intact transcobalamin and that this variant-containing protein binds vitamin B12 . The variant is rare in Caucasians (minor allele frequency (MAF) < 0.01) but more common in South Asians (MAF ~ 0.02) and those of African origin (MAF ~ 0.25). CONCLUSIONS: The impeded ability to detect normal levels of holoTC in these two patients may be due to this variant interfering with the detection of holoTC by one or both of the monoclonal antibodies currently employed in the Active-B12 test. Laboratories should be aware of this variant and use confirmatory tests when applicable. PMID- 26951923 TI - Comparison of the microbiological milieu of patients randomized to either hydrophilic or conventional PVC catheters for clean intermittent catheterization. AB - INTRODUCTION: Control of bacteriuria is problematic in patients who perform clean intermittent catheterization for management of neurogenic bladder. This population is often burdened with multiple urinary tract infections (UTIs), placing them at increased risk of end-stage renal disease. Hydrophilic catheters are a potential way to improve smooth and clean insertion, reduce disruption of the urothelium, and reduce bacterial colonization. OBJECTIVE: The goal of the study was to compare the type and virulence of microorganisms recovered from the urine of patients that use either a hydrophilic or conventional polyvinyl chloride (PVC) catheter. METHODS: Fifty patients with an underlying diagnosis of myelomeningocele were recruited for a 12-month prospective, randomized, investigator-blinded study. Twenty-five patients were allocated to the hydrophilic catheter intervention, and 25 continued use of a PVC catheter. Cultures were performed on urine obtained by catheterization at enrollment, and 3, 6, and 12 months. Bacterial species were assigned a designation as either potentially pathogenic or non-pathogenic. Escherichia coli isolates were the most predominant and were serotyped to further stratify the pathogenicity of the strains. Lastly, patients were surveyed at enrollment, and at the two later time points evaluating their current catheter for satisfaction. RESULTS: A total of 232 different bacterial isolates were obtained from the 182 collected urine cultures. In addition, seven species were recovered from the two UTI reported during the study period. Bacterial growth was not detected in 29 of the samples (16%). Although not statistically significant, collectively there was a 40% decrease in the average number of potentially pathogenic species recovered from those patients using hydrophilic catheters (0.81 per urine sample) compared with PVC catheter use (1.24 per urine sample). Since E. coli species can be either pathogenic or non-pathogenic, we examined 14 of the most commonly implicated serotypes associated with uropathogenic E. coli (UPEC). We identified the serotype of 57% of E. coli strains recovered. There was a trend for the recovery of fewer UPEC serotypes from the hydrophilic group (54% hydrophilic verses 64% PVC), further suggesting that the catheter type may influence the microbiological milieu. Although no significant differences were reported in patient satisfaction, almost half of the patients from the hydrophilic catheter cohort continue use of this type of catheter. CONCLUSIONS: There was a trend for reduced recovery of potentially pathogenic bacteria with the use of hydrophilic catheters. The reduction in potentially pathogenic species will reduce antibiotic exposures and some patients may prefer the comfort hydrophilic catheters provide. PMID- 26951925 TI - Human plasma lipocalins and serum albumin: Plasma alternative carriers? AB - Lipocalins are an evolutionarily conserved family of proteins that bind and transport a variety of exogenous and endogenous ligands. Lipocalins share a conserved eight anti-parallel beta-sheet structure. Among the different lipocalins identified in humans, alpha-1-acid glycoprotein (AGP), apolipoprotein D (apoD), apolipoprotein M (apoM), alpha1-microglobulin (alpha1-m) and retinol binding protein (RBP) are plasma proteins. In particular, AGP is the most important transporter for basic and neutral drugs, apoD, apoM, and RBP mainly bind endogenous molecules such as progesterone, pregnenolone, bilirubin, sphingosine-1-phosphate, and retinol, while alpha1-m binds the heme. Human serum albumin (HSA) is a monomeric all-alpha protein that binds endogenous and exogenous molecules like fatty acids, heme, and acidic drugs. Changes in the plasmatic levels of lipocalins and HSA are responsible for the onset of pathological conditions associated with an altered drug transport and delivery. This, however, does not necessary result in potential adverse effects in patients because many drugs can bind both HSA and lipocalins, and therefore mutual compensatory binding mechanisms can be hypothesized. Here, molecular and clinical aspects of ligand transport by plasma lipocalins and HSA are reviewed, with special attention to their role as alterative carriers in health and disease. PMID- 26951926 TI - Glucose and magnetic-responsive approach toward in situ nitric oxide bubbles controlled generation for hyperglycemia theranostics. AB - Stimuli-responsive devices that deliver drugs or imaging contrast agents in spatial-, temporal- and dosage-controlled fashions have emerged as the most promising and valuable platform for targeted and controlled drug delivery. However, implementing high performance of these functions in one single delivery carrier remains extremely challenging. Herein, we have developed a sequential strategy for developing glucose and magnetic-responsive microvesicle delivery system, which regulates the glucose levels and spatiotemporally controls the generation of nitric oxide gas free bubbles. It is observed that such injectable microvesicles loaded with enzyme and magnetic nanoparticles can firstly regulate hyperglycemic level based on the enzymatic reactions between glucose oxidase and glucose. In a sequential manner, concomitant magnetic field stimuli enhance the shell permeability while prompts the reaction between H2O2 and l-arginine to generate the gasotransmitters nitric oxide, which can be imaged by ultrasound and further delivered for diabetic nephropathy therapy. Therefore, magnetic microvesicles with glucose oxidase may be designed as a novel theranostic approach for restoring glucose homeostasis and spatiotemporally control NO release for maintaining good overall diabetic health. PMID- 26951927 TI - Antitumor effect and safety profile of systemically delivered oncolytic adenovirus complexed with EGFR-targeted PAMAM-based dendrimer in orthotopic lung tumor model. AB - Adenovirus (Ad)-mediated cancer gene therapy has been proposed as a promising alternative to conventional therapy for cancer. However, success of systemically administered naked Ad has been limited due to the immunogenicity of Ad and the induction of hepatotoxicity caused by Ad's native tropism. In this study, we synthesized an epidermal growth factor receptor (EGFR)-specific therapeutic antibody (ErbB)-conjugated and PEGylated poly(amidoamine) (PAMAM) dendrimer (PPE) for complexation with Ad. Transduction of Ad was inhibited by complexation with PEGylated PAMAM (PP) dendrimer due to steric hindrance. However, PPE-complexed Ad selectively internalized into EGFR-positive cells with greater efficacy than either naked Ad or Ad complexed with PP. Systemically administered PPE-complexed oncolytic Ad elicited significantly reduced immunogenicity, nonspecific liver sequestration, and hepatotoxicity than naked Ad. Furthermore, PPE-complexed oncolytic Ad demonstrated prolonged blood retention time, enhanced intratumoral accumulation of Ad, and potent therapeutic efficacy in EGFR-positive orthotopic lung tumors in comparison with naked Ad. We conclude that ErbB-conjugated and PEGylated PAMAM dendrimer can efficiently mask Ad's capsid and retarget oncolytic Ad to be efficiently internalized into EGFR-positive tumor while attenuating toxicity induced by systemic administration of naked oncolytic Ad. PMID- 26951928 TI - Fusion to an albumin-binding domain with a high affinity for albumin extends the circulatory half-life and enhances the in vivo antitumor effects of human TRAIL. AB - Clinical applications of recombinant human tumor necrosis factor-related apoptosis-inducing ligand (hTRAIL) have been limited by their poor pharmacokinetics. Using endogenous albumin as a carrier is an attractive approach for circulatory half-life extension. Here, we produced ABD-hTRAIL and hTRAIL-ABD by fusing the albumin-binding domain (ABD) from protein G to the N- or C-terminus of hTRAIL. We found that ABD-hTRAIL bound human serum albumin (HSA) with a high affinity (0.4 +/- 0.18 nM) and formed nanoparticles with an average diameter (~12 nm) above the threshold (~7 nm) of renal filtration. ABD-hTRAIL also bound mouse serum albumin (MSA); thus, its half-life was 40-50-fold greater than that of hTRAIL (14.1 +/- 0.87 h vs 0.32 +/- 0.14 h). Tumor uptake of ABD-hTRAIL 8-48 h post-injection was 6-16-fold that of hTRAIL. Consequently, the tumor suppression of ABD-hTRAIL in mice bearing subcutaneous xenografts was 3-4 times greater than that of hTRAIL. Additionally, the time period during which ABD-hTRAIL could kill circulating tumor cells was approximately 8 times longer than that of hTRAIL. These results demonstrate that ABD fused to the N-terminus endows hTRAIL with albumin binding ability; once it enters the vasculature, ABD mediates binding with endogenous albumin, thus prolonging the half-life and enhancing the antitumor effect of hTRAIL. However, hTRAIL-ABD did not show a high affinity for albumin and therefore did not display the prolonged circulatory half-life and enhanced antitumor effects. These results demonstrate that N-terminal, but not C terminal, ABD-fusion is an efficient technique for enhancing the antitumor effects of hTRAIL by using endogenous albumin as a carrier. PMID- 26951929 TI - Agonist-Mediated Activation of STING Induces Apoptosis in Malignant B Cells. AB - Endoplasmic reticulum (ER) stress responses through the IRE-1/XBP-1 pathway are required for the function of STING (TMEM173), an ER-resident transmembrane protein critical for cytoplasmic DNA sensing, IFN production, and cancer control. Here we show that the IRE-1/XBP-1 pathway functions downstream of STING and that STING agonists selectively trigger mitochondria-mediated apoptosis in normal and malignant B cells. Upon stimulation, STING was degraded less efficiently in B cells, implying that prolonged activation of STING can lead to apoptosis. Transient activation of the IRE-1/XBP-1 pathway partially protected agonist stimulated malignant B cells from undergoing apoptosis. In EMU-TCL1 mice with chronic lymphocytic leukemia, injection of the STING agonist 3'3'-cGAMP induced apoptosis and tumor regression. Similarly efficacious effects were elicited by 3'3'-cGAMP injection in syngeneic or immunodeficient mice grafted with multiple myeloma. Thus, in addition to their established ability to boost antitumoral immune responses, STING agonists can also directly eradicate malignant B cells. Cancer Res; 76(8); 2137-52. (c)2016 AACR. PMID- 26951931 TI - [From clinical trials to clinical practice. Experience with rivaroxaban in the anticoagulant treatment of patients with non-valvular atrial fibrillation]. AB - Despite the information provided by clinical trials is important, there are relevant clinical differences between those patients included in clinical trials and data of daily outpatient clinics. As a result, in some cases, the results of randomized clinical trials could not be directly applied to clinical practice. In this context, to perform "real-life" registries is mandatory. In the ROCKET-AF study, rivaroxaban, a once-daily direct oral anticoagulant, was at least as effective as warfarin for preventing stroke or systemic embolism, with similar rates of major bleeding, but with a lesser risk of intracranial, critical and fatal bleedings. In the last years, different large registries have confirmed that rivaroxaban is effective and even safer in real-life patients than in ROCKET AF. The aim of this review is to update the current evidence about the efficacy, effectiveness and safety of rivaroxaban in real-life patients. PMID- 26951930 TI - PDGF Engages an E2F-USP1 Signaling Pathway to Support ID2-Mediated Survival of Proneural Glioma Cells. AB - Glioblastoma is the most aggressive primary brain tumor and responds poorly to currently available therapies. Transcriptomic characterization of glioblastoma has identified distinct molecular subtypes of glioblastoma. Gain-of-function alterations leading to enhanced platelet-derived growth factor (PDGF) signaling are commonly observed in the proneural subtype of glioblastoma and can drive gliomagenesis. However, little is known about the downstream effectors of PDGF signaling in glioblastoma. Using a mouse model of proneural glioma and comparative transcriptomics, we determined that PDGF signaling upregulated ubiquitin-specific peptidase 1 (Usp1) to promote the survival of murine proneural glioma cells. Mechanistically, we found that PDGF signaling regulated the expression of the E2F transcription factors, which directly bound to and activated Usp1 Furthermore, PDGF-mediated expression of USP1 led to the stabilization of Inhibitor of DNA-binding 2 (ID2), which we found to be required for glioma cell survival. Genetic ablation of Id2 delayed tumor-induced mortality, and pharmacologic inhibition of USP1, resulting in decreased ID2 levels, also delayed tumorigenesis in mice. Notably, decreased USP1 expression was associated with prolonged survival in patients with proneural glioblastoma, but not with other subtypes of glioblastoma. Collectively, our findings describe a signaling cascade downstream of PDGF that sustains proneural glioblastoma cells and suggest that inhibition of the PDGF-E2F-USP1-ID2 axis could serve as a therapeutic strategy for proneural glioblastoma featuring increased PDGF signaling. Cancer Res; 76(10); 2964-76. (c)2016 AACR. PMID- 26951932 TI - Schizophrenia: The micro-movements perspective. AB - Traditionally conceived of and studied as a disorder of cognitive and emotional functioning, schizophrenia (SZ) is also characterized by alterations in bodily sensations. These have included subjective reports based on self-evaluations and/or clinical observations describing motor, as well as sensory-based corporeal anomalies. There has been, however, a paucity of objective methods to capture and characterize bodily issues in SZ. Here we present a new research method and statistical platform that enables precise evaluation of peripheral activity and its putative contributions to the cognitive control of visuomotor actions. Specifically, we introduce new methods that facilitate the individualized characterization of the function of sensory-motor systems so as to detect if subjects perform outside of normal limits. In this paper, we report data from a cohort of patients with a clinical diagnosis of SZ. First, we characterize neurotypical subjects performing a visually guided pointing task that requires visuomotor transformations, multi-joint coordination, and the proper balance between different degrees of intent, among other factors. Then we measure SZ patients against the normative statistical ranges empirically determined. To this end, we examine the stochastic signatures of minute fluctuations in motor performance (micro-movements) of various velocity- and geometric-transformation dependent trajectory parameters from the hand motions. These include the motions en-route to the target as well as spontaneous (without instructions) hand retractions to rest. The comparisons reveal fundamental differences between SZ patients and controls. Specifically, velocity-dependent signatures show that SZ patients move significantly slower than controls with more noise and randomness in their moment-by-moment hand micro-motions. Furthermore, the normative geometric-dependent signatures of deliberateness are absent from the goal directed reaches in SZ, but present within normative ranges in their spontaneous hand retractions to rest. Given that the continuous flow of micro-motions contributes to internally sensed feedback from self-produced movements, it is highly probable that sensory-motor integration with externally perceived inputs is impaired. Such impairments in this SZ cohort seem to specifically alter the balance between deliberate and spontaneous control of actions. We interpret these results as potential indexes of avolition and lack of agency and action ownership. We frame our results in the broad context of Precision Psychiatry initiatives and discuss possible implications on the putative contributions of the peripheral nervous system to the internal models for the cognitive control of self-produced actions in the individual with a clinical diagnosis of SZ. PMID- 26951933 TI - A new method for assessing the impact of medial temporal lobe amnesia on the characteristics of generated autobiographical events. AB - Constructing autobiographical events involves an initial phase of event selection, in which a memory or imagined future event is initially brought to mind, followed by a phase of elaboration, in which an individual accesses detailed knowledge specific to the event. While considerable research demonstrates the importance of the medial temporal lobes (MTL) in the later phase, its role in initial event selection is unknown. The present study is the first to investigate the role of the MTL in event selection by assessing whether individuals with MTL lesions select qualitatively different events for remembering and imagining than matched control participants. To do so, we created "event captions" that reflected the type of events selected for an autobiographical event narrative task by four individuals with MTL amnesia and control counterparts. Over 450 online raters assessed these event captions on qualitative dimensions known to vary with autobiographical recall (frequency, significance, emotionality, imageability, and uniqueness). Our critical finding was that individuals with MTL amnesia were more prone to select events that were rated as more frequently occurring than healthy control participants. We interpret this finding as evidence that people with impaired episodic memory from MTL damage compensate for their compromised ability to recall detailed information by relying more heavily on semantic memory processes to select generalized events. We discuss the implications for theoretical models of memory and methodological approaches to studying autobiographical memory. PMID- 26951934 TI - Recovery from lithium neurotoxicity. A case study. AB - The author describes the development of a neurotoxicity syndrome in a 68 year old women treated for 11/2 years with lithium for recurrent depressions. The syndrome developed after 10 mgr. haloperidol per day was added, during a manic episode, for 10 days. The lithium levels were 0.71 +/- 0.19 MEq/L. After 19 days all medications were discontinued. The neurotoxicity consisted succes-sivily of confusion, somnolence, agitation, extrapyramidal symptoms, cerebellair ataxia and EEG abnormalities. After 10 weeks memory impairmments were still present. At four months, memory function was restored. After five months, the patient was discharged without residual symptoms. The patient reported amnesia for the first six weeks of the syndrome. The author points out that while patients may develop tolerance to lithium maintenance after several years, they still may develop a neurotoxicity syndrome when haloperidol is added to treat a manic episode. PMID- 26951935 TI - Utility of ERP measures in clinical research. AB - Psychophysiological measures, such as late components of the event-related potentials (ERP's) may be applied in clinical nosological research in two different ways; as purely empirical or diagnostic markers and as markers of functional processes. The second application implies that ERP's may be used to increase the theoretical understanding of specific mental processes such as attention, memory and linguistic processes and the degree of impairment of these processes in psychiatric patients. Some examples derived from recent studies of dementia and aging are given of these two applications of ERP's. PMID- 26951936 TI - Diagnostic and classification systems with special emphasis on the Minicompendium. AB - With the introduction of major tranquillizers more than three decades ago symptom rating scales were soon accepted as the method of evaluating their clinical effects. The Mini-compendium is a collection of rating scales for measuring outcome of antianxiety drugs, antidepressants, antimanics, and anti-psychotics. The scales have been selected by their "cash values", i.e. the scales most frequently used for the respective dimensions. These scales have been further developed in terms of strict item definitions. The simple sum of the individual scale items has been considered as a sufficient statistic if they fulfilled latent structure analysis of shared phenomenology. PMID- 26951937 TI - Hospital treatment and the control of violent behaviour. AB - Violent behaviour between inpatients and wardpersonnel is seen from a relational viewpoint. The reactions of the staff show a strong similarity with regressive transferences from the patients. Limit-setting as a method should be employed to contain the individuel behaviour of the patient as also so further the social climate on the ward. The method of limit-setting involves the reality testing of the patient, the transference reactions between patient and staff, clarity in decision-making and regulations, and architectural arrangements. These four levels of influence are separately discussed. PMID- 26951938 TI - Psychofarmakalogika III. AB - Inleiding In deze rubriek zal worden ingegaan op recente observaties betreffende de psychofarmakologie in de breedst mogelijke zin. Vaak zullen zaken uit de Literatuur worden behandeld. De gekozen onderwerpen dienen altijd klinische relevantie te hebben. Ook zal deze rubriek gaan over gewoontes die in psychofarmakologische behandeling of in onderzoek zijn geslopen die volgens de auteur lang niet altijd logisch zijn. Soms zal deze rubriek een oproep bevatten om te reageren op een bijdrage gepubliceerd in dit of in een ander tijdschrift. Ook zal de lezer worden aangemoedigd hier zijn eigen ervaringen mee te delen. Het is niet de bedoeling in deze rubriek onderzoeken uitvoerig te rapporteren. Daarvoor staan andere pagina's van de Acta Neuropsychiatrica voor u open. PMID- 26951939 TI - Guidelines for the use of local anesthesia in office-based dermatologic surgery. AB - There are an increasing number and variety of dermatologic surgical procedures performed safely in the office setting. This evidence-based guideline addresses important clinical questions that arise regarding the use and safety of local anesthesia for dermatologic office-based procedures. In addition to recommendations for dermatologists, this guideline also takes into account patient preferences while optimizing their safety and quality of care. The clinical recommendations presented here are based on the best evidence available as well as expert opinion. PMID- 26951940 TI - Improved clinical outcome and biomarkers in adults with papulopustular rosacea treated with doxycycline modified-release capsules in a randomized trial. AB - BACKGROUND: Patients with rosacea have increased amounts of cathelicidin and protease activity but their usefulness as disease biomarkers is unclear. OBJECTIVE: We sought to evaluate the effect of doxycycline treatment on cathelicidin expression, protease activity, and clinical response in rosacea. METHODS: In all, 170 adults with papulopustular rosacea were treated for 12 weeks with doxycycline 40-mg modified-release capsules or placebo in a multicenter, randomized, double-blind, placebo-controlled study. Clinical response was compared with cathelicidin and protease activity in stratum corneum samples obtained by tape strip and in skin biopsy specimens obtained from a random subset of patients. RESULTS: Treatment with doxycycline significantly reduced inflammatory lesions and improved investigator global assessment scores compared with placebo. Cathelicidin expression and protein levels decreased over the course of 12 weeks in patients treated with doxycycline. Low levels of protease activity and cathelicidin expression at 12 weeks correlated with treatment success. Low protease activity at baseline was a predictor of clinical response in the doxycycline treatment group. LIMITATIONS: Healthy control subjects were not studied. CONCLUSIONS: Improved clinical outcome correlated with reduced cathelicidin and protease activity, supporting both the mechanism of doxycycline and the potential of these molecules as biomarkers for rosacea. PMID- 26951941 TI - Estradiol and angiotensin II crosstalk in hydromineral balance: Role of the ERK1/2 and JNK signaling pathways. AB - The angiotensin II (ANGII) receptor AT1 plays an important role in the control of hydromineral balance, mediating the dipsogenic and natriorexigenic effects and neuroendocrine responses of ANGII. While estradiol (E2) is known to modulate several actions of ANGII in the brain, the molecular and cellular mechanisms of the interaction between E2 and ANGII and its physiological role in the control of body fluids remain unclear. We investigated the influence of E2 (40 MUg/kg) pretreatment and extracellular-signal-regulated kinase (ERK1/2) and c-Jun N terminal kinase (JNK) cell signaling on the dipsogenic and natriorexigenic effects, as well as the neuroendocrine responses to angiotensinergic central stimulation in ovariectomized rats (OVX). We showed that the inhibitory effect of E2 on ANGII-induced water and sodium intake requires the ERK1/2 and JNK signaling pathways. On the other hand, E2 pretreatment prevents the ANGII-induced phosphorylation of ERK and JNK in the lamina terminalis. E2 therapy decreased oxytocin (OT) and vasopressin (AVP) secretion and decreased ERK1/2 phosphorylation in the supraoptic and paraventricular nuclei (SON and PVN, respectively). We found that the AVP secretion induced by ANGII required ERK1/2 signaling, but OT secretion did not involve ERK1/2 signaling. Taken together, these results demonstrate that E2 modulates ANGII-induced water and sodium intake and AVP secretion by affecting the ERK1/2 and JNK pathways in the lamina terminalis and ERK1/2 signaling in the hypothalamic nuclei (PVN and SON) in OVX rats. PMID- 26951942 TI - What do we not know about mitochondrial potassium channels? AB - In this review, we summarize our knowledge about mitochondrial potassium channels, with a special focus on unanswered questions in this field. The following potassium channels have been well described in the inner mitochondrial membrane: ATP-regulated potassium channel, Ca(2+)-activated potassium channel, the voltage-gated Kv1.3 potassium channel, and the two-pore domain TASK-3 potassium channel. The primary functional roles of these channels include regulation of mitochondrial respiration and the alteration of membrane potential. Additionally, they modulate the mitochondrial matrix volume and the synthesis of reactive oxygen species by mitochondria. Mitochondrial potassium channels are believed to contribute to cytoprotection and cell death. In this paper, we discuss fundamental issues concerning mitochondrial potassium channels: their molecular identity, channel pharmacology and functional properties. Attention will be given to the current problems present in our understanding of the nature of mitochondrial potassium channels. This article is part of a Special Issue entitled 'EBEC 2016: 19th European Bioenergetics Conference, Riva del Garda, Italy, July 2-6, 2016', edited by Prof. Paolo Bernardi. PMID- 26951943 TI - Glutamine transport. From energy supply to sensing and beyond. AB - Glutamine is the most abundant amino acid in plasma and is actively involved in many biosynthetic and regulatory processes. It can be synthesized endogenously but becomes "conditionally essential" in physiological or pathological conditions of high proliferation rate. To accomplish its functions glutamine has to be absorbed and distributed in the whole body. This job is efficiently carried out by a network of membrane transporters that differ in transport mechanisms and energetics, belonging to families SLC1, 6, 7, 38, and possibly, 25. Some of the transporters are involved in glutamine traffic across different membranes for metabolic purposes; others are involved in specific signaling functions through mTOR. Structure/function relationships and regulatory aspects of glutamine transporters are still at infancy. In the while, insights in involvement of these transporters in cell redox control, cancer metabolism and drug interactions are arising, stimulating basic research to uncover molecular mechanisms of transport and regulation. This article is part of a Special Issue entitled 'EBEC 2016: 19th European Bioenergetics Conference, Riva del Garda, Italy, July 2-6, 2016', edited by Prof. Paolo Bernardi. PMID- 26951944 TI - What is the impact of age on reoperation rates for femoral neck fractures treated with internal fixation and hemiarthroplasty? A comparison of hip fracture outcomes in the very elderly population. AB - METHODS: A retrospective comparative study was performed at a level 1 trauma center at which electronic medical records and digital radiographs were reviewed for 949 femoral neck fractures. For the primary outcome of reoperation based on age, Kaplan-Meier models were built and analysis applied. RESULTS: A total of 334 fractures were nondisplaced treated with closed reduction and percutaneous pinning (CRPP), and 615 were displaced managed with hemiarthroplasty (HA). Overall, 98 patients (10.33%) required reoperation. Increasing reoperation rates for CRPP was seen with each subsequent age group. The opposite was seen with HA in which increasing age groups showed lower reoperation rates. PMID- 26951946 TI - Moving Towards Minimally Invasive Genomically Based Diagnosis and Monitoring of Bladder Cancer. PMID- 26951945 TI - Assessment of the Rate of Adherence to International Guidelines for Androgen Deprivation Therapy with External-beam Radiation Therapy: A Population-based Study. AB - BACKGROUND: The National Comprehensive Cancer Network and the European Association of Urology guidelines recommend using radiation therapy (RT) with androgen deprivation therapy (ADT) to treat high-risk and locally advanced prostate cancer patients. OBJECTIVE: To evaluate the degree of adherence to these guidelines. DESIGN, SETTING, AND PARTICIPANTS: Between 2003 and 2009, in the Surveillance Epidemiology and End Results (SEER)-Medicare database, 14 180 patients were diagnosed with high-risk (T1-T2 with World Health Organization histologic grade 3) or locally advanced (T3-T4 with any histologic grade) prostatic adenocarcinoma. INTERVENTION: Administration of RT-ADT versus RT alone. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We assessed the rate of adherence to guidelines with respect to use of RT-ADT in the overall population and after stratification according to stage-grade groupings (T1-T2 G3 vs T3-T4 any grade), age (66-69, 70-74, 75-79, >=80 yr), Charlson Comorbidity Index (CCI) (0, 1, >=2), and preexisting baseline cardiovascular (CV) disease. We depicted the rate of RT ADT administration graphically over the study period. Multivariable logistic regression analyses were performed to assess the predictors of RT-ADT use. RESULTS AND LIMITATIONS: RT-ADT rates and guideline adherence were 58-75%, with the highest rate (75%) in 2003 and the lowest (58%) in 2009. When stratified according to stage-grade groupings, age, CCI, and preexisting baseline CV disease, similar results were obtained. In multivariable analyses, year of diagnosis (p<0.001), patient age (p<0.001), stage-grade groupings (p<0.001), CCI (p=0.036), race (p<0.001), marital status (p<0.001), population density (p<0.001), and US regions (p<0.001) were independent predictors of RT-ADT use. The limitations of our study include age >65 yr and exclusive Medicare coverage. CONCLUSIONS: The rate of guideline adherence regarding the use of RT-ADT is suboptimal and decreases with time instead of increasing. PATIENT SUMMARY: This population-based study provides evidence of low adherence to international urologic guidelines regarding the combination of radiation therapy (RT) with androgen deprivation therapy (ADT) for high-risk and locally advanced prostate cancer (PCa) patients. Despite the increasing number of randomized controlled trials over time that showed a survival benefit for patients with high-risk and locally advanced PCa treated with RT-ADT compared with RT alone, the rate of adherence to guidelines decreased with time. PMID- 26951947 TI - Medium-term Outcomes after Whole-gland High-intensity Focused Ultrasound for the Treatment of Nonmetastatic Prostate Cancer from a Multicentre Registry Cohort. AB - BACKGROUND: High-intensity focused ultrasound (HIFU) is a minimally-invasive treatment for nonmetastatic prostate cancer. OBJECTIVE: To report medium-term outcomes in men receiving primary whole-gland HIFU from a national multi-centre registry cohort. DESIGN, SETTING, AND PARTICIPANTS: Five-hundred and sixty-nine patients at eight hospitals were entered into an academic registry. INTERVENTION: Whole-gland HIFU (Sonablate 500) for primary nonmetastatic prostate cancer. Redo HIFU was permitted as part of the intervention. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Our primary failure-free survival outcome incorporated no transition to any of the following: (1) local salvage therapy (surgery or radiotherapy), (2) systemic therapy, (3) metastases, or (4) prostate cancer specific mortality. Secondary outcomes included adverse events and genitourinary function. RESULTS AND LIMITATIONS: Mean age was 65 yr (47-87 yr). Median prostate specific antigen was 7.0 ng/ml (interquartile range 4.4-10.2). National Comprehensive Cancer Network low-, intermediate-, and high-risk disease was 161 (28%), 321 (56%), and 81 (14%), respectively. One hundred and sixty three of 569 (29%) required a total of 185 redo-HIFU procedures. Median follow-up was 46 (interquartile range 23-61) mo. Failure-free survival at 5 yr after first HIFU was 70% (95% confidence interval [CI]: 64-74). This was 87% (95% CI: 78-93), 63% (95% CI: 56-70), and 58% (95% CI: 32-77) for National Comprehensive Cancer Network low-, intermediate-, and high-risk groups, respectively. Fifty eight of 754 (7.7%) had one urinary tract infection, 22/574 (2.9%) a recurrent urinary tract infection, 22/754 (3%) epididymo-orchitis, 227/754 (30%) endoscopic interventions, 1/754 (0.13%) recto-urethral fistula, and 1/754 (0.13%) osteitis pubis. Of 206 known to be pad-free pre-HIFU, 183/206 (88%) remained pad free, and of 236 with good baseline erectile function, 91/236 (39%) maintained good function. The main limitation is lack of long-term data. CONCLUSIONS: Whole-gland HIFU is a repeatable day-case treatment that confers low rates of urinary incontinence. Disease control at a median of just under 5 yr of follow-up demonstrates its potential as a treatment for nonmetastatic prostate cancer. Endoscopic interventions and erectile dysfunction rates are similar to other whole-gland treatments. PATIENT SUMMARY: In this report we looked at the 5-yr outcomes following whole-gland high-intensity focused ultrasound treatment for prostate cancer and found that cancer control was acceptable with a low risk of urine leakage. However, risk of erectile dysfunction and further operations was similar to other whole-gland treatments like surgery and radiotherapy. PMID- 26951948 TI - Pathophysiological signatures of functional connectomics in parkinsonian and dyskinetic striatal microcircuits. AB - A challenge in neuroscience is to integrate the cellular and system levels. For instance, we still do not know how a few dozen neurons organize their activity and relations in a microcircuit or module of histological scale. By using network theory and Ca(2+) imaging with single-neuron resolution we studied the way in which striatal microcircuits of dozens of cells orchestrate their activity. In addition, control and diseased striatal tissues were compared in rats. In the control tissue, functional connectomics revealed small-world, scale-free and hierarchical network properties. These properties were lost during pathological conditions in ways that could be quantitatively analyzed. Decorticated striatal circuits disclosed that corticostriatal interactions depend on privileged connections with a set of highly connected neurons or "hubs". In the 6-OHDA model of Parkinson's disease there was a decrease in hubs number; but the ones that remained were linked to dominant network states. l-DOPA induced dyskinesia provoked a loss in the hierarchical structure of the circuit. All these conditions conferred distinct temporal sequences to circuit activity. Temporal sequences appeared as particular signatures of disease process thus bringing the possibility of a future quantitative pathophysiology at a histological scale. PMID- 26951949 TI - Differential expression of astrocytic connexins in a mouse model of prenatal alcohol exposure. AB - Maternal alcohol consumption during gestation can cause serious injury to the fetus, and may result in a range of physiological and behavioral impairments, including increased seizure susceptibility, that are collectively termed fetal alcohol spectrum disorder (FASD). The cellular mechanisms underlying increased seizure susceptibility in FASD are not well understood, but could involve altered excitatory coupling of neuronal populations mediated by gap junction proteins. We utilized a mouse model of the prenatal alcohol exposure (PAE) to study the expression pattern of connexin (Cx) major components of gap junctions, and pannexin proteins, which form membrane channels, in the brain of 2-3weeks old PAE and control postnatal offspring. PAE during the first trimester-equivalent period of pregnancy in mice resulted in significant up-regulation of Cx30 mRNA and Cx30 total protein in the hippocampus of PAE animals compared to age-matched controls. Surface level expression of both dimeric and monomeric Cx30 were also found to be significantly up-regulated in both hippocampus and cerebral cortex of PAE animals compared to age-matched controls. On the membrane surface, the fast migrating form of Cx43 was found to be up-regulated in the hippocampus of PAE mice. However, we did not see any up-regulation of the phosphorylated forms of Cx43 on the membrane surface. These results indicate that the expression and processing of astrocytic connexins (Cx30, Cx43) are up-regulated in the brain of PAE offspring, and these changes could play a role in the cerebral hyperexcitability observed in these animals. PMID- 26951950 TI - Ultra-high resolution band-selective HSQC for nanomole-scale identification of chlorine-substituted 13 C in natural products drug discovery. AB - Ultra-high resolution band-selective HSQC (bsHSQC) has been employed for detection of 35 Cl-37 Cl isotope shifted 13 C NMR signals for assignment of regioisomerism in bromo-chloro natural products. Optimum pulse sequence and instrumental parameters for maximization of detection of the isotope shifts were explored. The chlorine isotope shifts (Deltadelta) were detected within crosspeaks and were shown to vary with hybridization of 13 C, substitution of 13 C, presence of beta-chloro substituents, and their relative configuration. Deconvolution of Cl-substituted CH bsHSQC crosspeaks may provide other useful information, including a potentially MS-independent method for quantitating 37 Cl/35 C isotopic fractionation during the biosynthesis of halogenated natural products. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26951951 TI - Immersed boundary-finite element model of fluid-structure interaction in the aortic root. AB - It has long been recognized that aortic root elasticity helps to ensure efficient aortic valve closure, but our understanding of the functional importance of the elasticity and geometry of the aortic root continues to e-volve as increasingly detailed in vivo imaging data become available. Herein, we describe a fluid structure interaction model of the aortic root, including the aortic valve leaflets, the sinsuses of Valsalva, the aortic annulus, and the sinotubular junction, that employs a version of Peskin's immersed boundary (IB) method with a finite element (FE) description of the structural elasticity. As in earlier work, we use a fiber-based model of the valve leaflets, but this study extends earlier IB models of the aortic root by employing an incompressible hyperelastic model of the mechanics of the sinuses and ascending aorta using a constitutive law fit to experimental data from human aortic root tissue. In vivo pressure loading is accounted for by a backward displacement method that determines the unloaded configurations of the root model. Our model yields realistic cardiac output at physiological pressures, with low transvalvular pressure differences during forward flow, minimal regurgitation during valve closure, and realistic pressure loads when the valve is closed during diastole. Further, results from high resolution computations indicate that although the detailed leaflet and root kinematics show some grid sensitivity, our IB model of the aortic root nonetheless produces essentially grid-converged flow rates and pressures at practical grid spacings for the high-Reynolds number flows of the aortic root. These results thereby clarify minimum grid resolutions required by such models when used as stand-alone models of the aortic valve as well as when used to provide models of the outflow valves in models of left ventricular fluid dynamics. PMID- 26951952 TI - Designing a Low-noise, High-resolution, and Portable Four Channel Acquisition System for Recording Surface Electromyographic Signal. AB - In current years, the application of biopotential signals has received a lot of attention in literature. One of these signals is an electromyogram (EMG) generated by active muscles. Surface EMG (sEMG) signal is recorded over the skin, as the representative of the muscle activity. Since its amplitude can be as low as 50 MUV, it is sensitive to undesirable noise signals such as power-line interferences. This study aims at designing a battery-powered portable four channel sEMG signal acquisition system. The performance of the proposed system was assessed in terms of the input voltage and current noise, noise distribution, synchronization and input noise level among different channels. The results indicated that the designed system had several inbuilt operational merits such as low referred to input noise (lower than 0.56 MUV between 8 Hz and 1000 Hz), considerable elimination of power-line interference and satisfactory recorded signal quality in terms of signal-to-noise ratio. The muscle conduction velocity was also estimated using the proposed system on the brachial biceps muscle during isometric contraction. The estimated values were in then normal ranges. In addition, the system included a modular configuration to increase the number of recording channels up to 96. PMID- 26951953 TI - Electronic structures of [1 1 1]-oriented free-standing InAs and InP nanowires. AB - We report on a theoretical study of the electronic structures of the [1 1 1] oriented, free-standing, zincblende InAs and InP nanowires with hexagonal cross sections by means of an atomistic sp(3)s*, spin-orbit interaction included, nearest-neighbor, tight-binding method. The band structures and the band state wave functions of these nanowires are calculated and the symmetry properties of the bands and band states are analyzed based on the C(3v) double point group. It is shown that all bands of these nanowires are doubly degenerate at the Gamma point and some of these bands will split into non-degenerate bands when the wave vector k moves away from the Gamma-point as a manifestation of spin-splitting due to spin-orbit interaction. It is also shown that the lower conduction bands of these nanowires all show simple parabolic dispersion relations, while the top valence bands show complex dispersion relations and band crossings. The band state wave functions are presented by the spatial probability distributions and it is found that all the band states show 2pi/3-rotation symmetric probability distributions. The effects of quantum confinement on the band structures of the [1 1 1]-oriented InAs and InP nanowires are also examined and an empirical formula for the description of quantization energies of the lowest conduction band and the highest valence band is presented. The formula can simply be used to estimate the enhancement of the band gaps of the nanowires at different sizes as a result of quantum confinement. PMID- 26951954 TI - Effects of season on the reproductive organs and steroid hormone profiles in guinea hens (Numida meleagris). AB - The study documented gross anatomical and histological differences in the reproductive organs of 28 breeding and non-breeding female guinea fowls. Peripheral progesterone and 17beta-oestradiol concentrations were also compared in breeding and non-breeding hens. In non-breeding females, all ovarian and oviducal gross anatomical features had significantly regressed. Histologically, some of the changes in a regressing oviduct include systematic changes in height and size of all epithelial cells in all regions of the duct, absence/sparse ciliation of portions of surface epithelium in the magnum, isthmian and uterine regions, general loss of cytoplasmic mass, reduction in size and degeneration of tubular glands. Mucosal folds in all regions of the oviduct except the infundibular lip were higher in breeding females. No difference was found between the two groups in plasma progesterone concentrations. Breeding females, however, had higher peripheral oestradiol concentrations than non-breeding females. About 2 h prior to oviposition, plasma oestradiol concentrations peaked at 2.4-fold (230 pg/ml) compared with baseline concentration and plasma progesterone concentrations by nearly 9-fold (5.29 ng/ml) of baseline. Significant regression and changes in the histological structure of the ovary and oviduct had occurred in non-breeding females, and lower peripheral oestrogen concentrations may be responsible for this phenomenon. PMID- 26951955 TI - Retroperitoneoscopic Cutaneous Ureterostomy in the Supine Position to Relieve Painful Urinary-related Symptoms in an Advanced Anal Canal Cancer Patient. AB - A case of advanced anal canal cancer with skin metastases that extended to the scrotum, penis, and lower abdomen is presented. The patient had severe pain on contact with voided urine because of skin tumors. The curved penis did not allow insertion of catheter to treat painful urination, and suprapubic cystostomy insertion was also impossible because of skin tumors. A right cutaneous ureterostomy was performed using the retroperitoneoscopic approach in supine position, and the left renal artery was embolized using ethanol to eliminate left kidney function. The patient became completely free from all urinary-related pains until he died of progressive disease. PMID- 26951956 TI - Design of 2D Porous Coordination Polymers Based on Metallacrown Units. AB - A 12-metallacrown-4 (MC) complex was designed and employed as the building block in the synthesis of coordination polymers, one of which is the first permanently porous MC architecture. The connection of the four-fold symmetric MC subunits by Cu(II) nodes led to the formation of 2D layers of metallacrowns. Channels are present in the crystalline architecture, which exhibits permanent porosity manifested in N2 and CO2 uptake capacity. PMID- 26951957 TI - Effects of Dentin Debris on the Antimicrobial Properties of Sodium Hypochlorite and Etidronic Acid. AB - INTRODUCTION: The purpose of this study was to determine the influence of dentin powder on the concentration, pH, and antimicrobial activity of sodium hypochlorite (NaOCl) alone and combined with etidronic acid (HEBP). METHODS: Biofilms of Enterococcus faecalis were grown on the surface of dentin blocks for 5 days and then exposed to 1% and 2.5% NaOCl alone or combined with 9% HEBP for 3 minutes in the absence and presence of dentin powder. The biovolumes of the biofilm were measured using confocal microscopy and the live/dead technique. The available chlorine and pH of the solutions were also measured. Nonparametric tests were used to determine statistical differences (P < .05). RESULTS: The presence of dentin powder resulted in a reduction of the free available chlorine and pH in all the irrigating solutions; 1% NaOCl lost its antimicrobial activity completely in the presence of dentin powder. The antimicrobial activity was significantly reduced in the 2.5% NaOCl and 1% NaOCl/HEBP groups, and it was not affected in the 2.5% NaOCl/HEBP group. CONCLUSIONS: The presence of dentin powder significantly decreased the available chlorine and antimicrobial activity of 1% NaOCl, 2.5% NaOCl, and 1% NaOCl/HEBP irrigating solutions. The antimicrobial activity of 2.5% NaOCl/HEBP was not affected by the dentin powder after a 3 minute contact time against E. faecalis biofilms. PMID- 26951958 TI - Effects of Extracellular pH on Dental Pulp Cells In Vitro. AB - INTRODUCTION: The proliferation and migration of dental pulp stem cells (DPSCs), a population comprised of dental pulp cells (DPCs), are important processes for pulp tissue repair. Dental pulp is exposed to changes in extracellular pH under various conditions, such as acidosis and exposure to caries-associated bacteria or a pulp capping agent. The objective of this study was to investigate the effects of extracellular pH on DPC proliferation and migration in vitro. METHODS: To evaluate the proliferation potency of DPCs in various extracellular pH conditions, 2 * 10(4) cells were seeded into 35-mm dishes. The following day, we changed to NaHCO3-free medium, which was adjusted to different extracellular pH levels. RESULTS: After 120 hours, DPCs cultured in media from a pH of 3.5 to 5.5 showed cell death, those cultured in conditions from a pH of 6.5 to 7.5 showed growth arrest or cell death, and those grown at a pH of 9.5 showed mild proliferation. The migratory activity of living DPCs was not affected by extracellular pH. For histologic analysis, human teeth possessing a small abscess in the coronal pulp chamber were sliced for histologic analysis. Proliferating cell nuclear antigen (PCNA) immunolocalization was used as an index of cell proliferation for the sections and cultured cells. Acidic extracellular pH conditions resulted in reduced numbers of PCNA-positive DPCs in the dishes. As for pulp tissue affected by a small abscess, a PCNA-negative pulp cell layer was observed in close proximity to the infectious lesion. CONCLUSIONS: Together, these results suggest that an acidic extracellular pH condition is associated with DPC growth arrest or cell death. PMID- 26951959 TI - Cytokine Expression in Patients Hospitalized for Severe Odontogenic Infection in Brazil. AB - INTRODUCTION: Severe odontogenic infections remain an important public health concern and a significant economic burden to public health care facilities. Despite this, several aspects of the disease, such as its immune response profile, remain poorly understood. The aim of this study was to search for an association between mRNA levels of the cytokines interferon-gamma, interleukin (IL)-1beta, tumor necrosis factor-alpha, IL-17A, IL-10, and transforming growth factor-beta and the chemokines IL-8, CCL2/MCP-1, and CCL5 and odontogenic infection. METHODS: The case group was composed of 12 patients hospitalized in consequence of severe odontogenic infection, and our control group included 12 individuals with healthy periapical tissues. Clinical samples were taken from the case (drainage site) and control (periapical interstitial fluid) groups with the aid of paper points. Total RNA was extracted, complementary DNA was synthesized, and mRNA levels were determined by quantitative polymerase chain reaction. Data analysis was performed by using SPSS, and the Wilcoxon signed rank test was used to determine statistical significance (P < .05). RESULTS: Data generated showed a significantly increased expression of proinflammatory cytokines (interferon gamma, IL-1beta, tumor necrosis factor-alpha, and IL-17A), IL-8, and CCL2/MCP-1 in odontogenic infection patients. The mRNA levels of IL-10, transforming growth factor-beta, and CCL5 were similar in both study groups. CONCLUSIONS: In general, individuals presenting with odontogenic infections exhibited extraordinary proinflammatory cytokine profiles paralleled with unaltered expression of regulatory mediators. PMID- 26951960 TI - Cysteamine Enhances Biofilm Eradication Efficacy of Calcium Hydroxide. AB - INTRODUCTION: Calcium hydroxide (Ca[OH]2) is a widely used interappointment dressing, but its antibacterial property is compromised by dentin. Hence, the addition of chlorhexidine (CHX) with Ca(OH)2 has been proposed. However, the antimicrobial efficacy of this mixture compared with Ca(OH)2 alone is currently still debatable. Cysteamine is a mucolytic agent used to reduce the viscosity of mucus through the disruption of proteins, which are also important components of the extracellular matrix of biofilms. The aims of this study were to determine the efficacy of cysteamine alone and in combination with Ca(OH)2 to eradicate Enterococcus faecalis biofilm compared with CHX with Ca(OH)2, and to determine if this effect is affected by dentin. METHODS: The biofilm eradication efficacies of Ca(OH)2 alone and with cysteamine were determined using 7-day E. faecalis biofilm cultured on dentin discs and compared with Ca(OH)2 with 2% CHX. The effects of dentin on the efficacies of Ca(OH)2 alone and with either cysteamine or CHX were examined. RESULTS: Cysteamine alone completely abolished E. faecalis biofilm at 200 mg/mL. The combination of Ca(OH)2 with either cysteamine at 10 mg/mL or 2% CHX completely obliterated E. faecalis biofilm. Cysteamine with Ca(OH)2 completely eradicated E. faecalis biofilm despite preincubation with dentin, whereas CHX with Ca(OH)2 was less effective. CONCLUSIONS: Cysteamine effectively eliminated E. faecalis biofilm and showed synergistic effects in combination with Ca(OH)2, which were unaffected by dentin. Hence, our findings support the use of cysteamine as a potential adjunct to Ca(OH)2 as an interappointment dressing. PMID- 26951962 TI - Altered neurotransmitter expression profile in the ganglionic bowel in Hirschsprung's disease. AB - PURPOSE: Despite having optimal pull-through (PT) surgery for Hirschsprung's disease (HSCR), many patients experience persistent bowel symptoms with no mechanical/histopathological cause. Murine models of HSCR suggest that expression of key neurotransmitters is unbalanced proximal to the aganglionic colonic segment. We aimed to investigate expression of key enteric neurotransmitters in the colon of children with HSCR. METHODS: Full-length PT specimens were collected fresh from children with HSCR (n=10). Control specimens were collected at colostomy closure from children with anorectal malformation (n=8). The distributions of neuronal nitric oxide synthase (nNOS), choline acetyltransferase (ChAT), vasoactive intestinal peptide (VIP), and substance P (SP) were evaluated using immunofluorescence and confocal microscopy. Neurotransmitter quantification was with Western blot analysis. RESULTS: ChAT expression was high in aganglionic bowel and transition zone but reduced in ganglionic bowel in HSCR relative to controls. Conversely, nNOS expression was markedly reduced in aganglionic bowel but high in ganglionic bowel in HSCR relative to controls. VIP expression was similar in ganglionic HSCR and control colon. SP expression was similar in all tissue types. CONCLUSION: Imbalance of key excitatory and inhibitory neurotransmitters in the ganglionic bowel in HSCR may explain the basis of bowel dysmotility after an optimal pull-through operation in some patients. PMID- 26951961 TI - An Fe-S cluster in the conserved Cys-rich region in the catalytic subunit of FAD dependent dehydrogenase complexes. AB - Several bacterial flavin adenine dinucleotide (FAD)-harboring dehydrogenase complexes comprise three distinct subunits: a catalytic subunit with FAD, a cytochrome c subunit containing three hemes, and a small subunit. Owing to the cytochrome c subunit, these dehydrogenase complexes have the potential to transfer electrons directly to an electrode. Despite various electrochemical applications and engineering studies of FAD-dependent dehydrogenase complexes, the intra/inter-molecular electron transfer pathway has not yet been revealed. In this study, we focused on the conserved Cys-rich region in the catalytic subunits using the catalytic subunit of FAD dependent glucose dehydrogenase complex (FADGDH) as a model, and site-directed mutagenesis and electron paramagnetic resonance (EPR) were performed. By co-expressing a hitch-hiker protein (gamma subunit) and a catalytic subunit (alpha-subunit), FADGDH gammaalpha complexes were prepared, and the properties of the catalytic subunit of both wild type and mutant FADGDHs were investigated. Substitution of the conserved Cys residues with Ser resulted in the loss of dye-mediated glucose dehydrogenase activity. ICP-AEM and EPR analyses of the wild-type FADGDH catalytic subunit revealed the presence of a 3Fe-4S-type iron-sulfur cluster, whereas none of the Ser-substituted mutants showed the EPR spectrum characteristic for this cluster. The results suggested that three Cys residues in the Cys-rich region constitute an iron-sulfur cluster that may play an important role in the electron transfer from FAD (intra molecular) to the multi-heme cytochrome c subunit (inter-molecular) electron transfer pathway. These features appear to be conserved in the other three subunit dehydrogenases having an FAD cofactor. PMID- 26951963 TI - The increasing incidence of gallbladder disease in children: A 20year perspective. AB - OBJECTIVE: The incidence of cholecystectomy in the pediatric population has increased over the last 20years but has not been described in a Canadian population. We conducted the first province-wide study to describe the incidence of cholecystectomy in children in Ontario. STUDY DESIGN: A population-based, retrospective cohort using administrative databases in Ontario, Canada, was conducted. We included patients less than 18years of age who underwent cholecystectomy from 1993 to 2012. Trends in rates of cholecystectomy were assessed with the Cochrane-Armitage test. RESULTS: There were a total of 6040 pediatric cholecystectomies performed over the study period in Ontario. The mean age was 14.3years, and 79.6% of patients were females. The crude incidence per 100,000 person-years increased from 8.8 to 13.0 (p<0.001) from 1993 96-2009-12, respectively. The sex-specific incidence showed a larger increase in the female population from 14.7 to 21.1 per 100,000 person-years (p<0.001). The vast majority (82%) of surgeries were performed in 13-17year olds and were largely performed in the community (>75%). CONCLUSIONS: There has been a significant rise in the incidence of pediatric cholecystectomy in Ontario over the last 20years. The majority of surgeries are performed in the community, and pediatricians will likely see an increase of gallbladder disease in practice. PMID- 26951964 TI - Cardiovascular PET-CT imaging: a new frontier? AB - Cardiovascular positron-emission tomography combined with computed tomography (PET-CT) has recently emerged as an imaging technology with the potential to simultaneously describe both anatomical structures and physiological processes in vivo. The scope for clinical application of this technique is vast, but to date this promise has not been realised. Nonetheless, significant research activity is underway to explore these possibilities and it is likely that the knowledge gained will have important diagnostic and therapeutic implications in due course. This review provides a brief overview of the current state of cardiovascular PET CT and the likely direction of future developments. PMID- 26951965 TI - MicroRNA-214 acts as a potential oncogene in breast cancer by targeting the PTEN PI3K/Akt signaling pathway. AB - Breast cancer ranks as the leading cause of cancer-related mortality in females worldwide. It has been proven that microRNAs (miRNAs or miRs), a type of non coding RNA, are involved in tumorigenesis. An increasing number of studies has confirmed the critical role of miR-214 in certain types of cancer. Nevertheless, the biological function of miR-214, as well as its underlying mechanisms of action in breast cancer remain largely unknown. In the present study, the expression of miR-214 was found to be upregulated in four human breast cancer cell lines in contrast to its expression level in the non-malignant breast epithelial cell line, MCF-10A. Moreover, the overexpression of miR-214 markedly increased cell viability and abrogated the apoptosis triggered by serum starvation, indicating that miR-214 plays a pivotal role in breast cancer cell growth. Further analysis suggested that the upregulation of miR-214 markedly induced the activation of the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway, which largely accounted for the protective effects of miR-124 on cancer cell growth. This was further confimed by pre-treatment with the PI3K/Akt inhibitor, LY294002, which markedly attenuated the miR-214-induced increase in cell viability and resistance to apoptosis. Furthermore, the expression of phosphatase and tensin homolog (PTEN) was decreased following transfection wtih miR-214 mimics and PTEN was confirmed as the direct target of miR-214 by bioinformatics analysis and a dual-firefly luciferase reporter assay. Importantly, the introduction of PTEN cDNA lacking the 3' untranslated region (3'UTR) significantly inhibited the miR-214-induced activation of the PI3K/Akt signaling pathway, and abrogated the protetive effects of miR-214 on cell survival and resistance to apoptosis. Taken together, these findings suggest that miR-214 possesses oncogenic activity and that its effects are mediated through the promotion of cell growth by targeting the PTEN-PI3K/Akt pathway. Thus, pharmaceutical interventions targeting miR-124 may provide a promising therapeutic strategy for the treatment of breast cancer. PMID- 26951966 TI - Pharmacotherapy Considerations in the Management of Transgender Patients: An Alternative Viewpoint. PMID- 26951967 TI - Phosphate homeostasis, parathyroid hormone, and fibroblast growth factor 23 in stages 3 and 4 chronic kidney disease. AB - AIMS: Increased concentrations of parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) often coincide with normal serum phosphorus ([P]s) in chronic kidney disease (CKD). We hypothesized that the phosphate concentration ([P]f) in the cortical distal nephron (CDN) determines [PTH] and [FGF23] in this circumstance. METHODS: We studied 29 patients with CKD at 4 visits and 28 controls at 1 visit. Assuming GFR = creatinine clearance (Ccr), we examined the following regressions: [P]s on its determinants, EP/Ccr and TRP/Ccr (P excretion and reabsorption per volume of filtrate); [PTH] and [FGF23] on [P]s and EP/Ccr; and TRP/Ccr on [PTH] and [FGF23]. We assumed that EP/Ccr is proportional to [P]f in the CDN. RESULTS: In controls, [P]s correlated with TRP/Ccr but not EP/Ccr. [PTH] and [FGF23] were unrelated to [P]s, EP/Ccr, and TRP/Ccr. In CKD, [P]s correlated with EP/Ccr and TRP/Ccr. [PTH] correlated with [P]s at 2 visits and with EP/Ccr at 4; [FGF23] correlated with [P]s and EP/Ccr at all visits. TRP/Ccr correlated with [FGF23] and [PTH] at one visit each. CONCLUSIONS: [P]f in the CDN, not [P]s, determined [PTH] in CKD. Because [FGF23] was consistently associated with only one determinant of [P]s, EP/Ccr, we infer that [P]f also determined [FGF23]. In patients with CKD, we speculate that [P]f in the CDN regulates FGF23 synthesis at that site. PMID- 26951968 TI - The effect of poly (ADP-ribose) polymerase inhibition on aminoglycoside-induced acute tubular necrosis in rats. AB - INTRODUCTION: Aminoglycosides (AG) cause nephrotoxicity in 10 - 20% of patients. One of the mechanisms is by generating reactive oxygen species (ROS), leading to DNA destruction and activation of poly(ADPribose) polymerase (PARP) causing necrotic tubular cell death. PARP inhibition on gentamicin-induced nephrotoxicity was studied. METHODS: 19 female Wistar-Kyoto rats divided into 3 groups: control (3 rats receiving no treatment); gentamicin-treated group (8 rats); and 8 rats treated with gentamicin combined with 3-aminobenzamide (3 AB). Kidney functions, protein, and gentamicin levels as well as urinary trypsin inhibitory activity (TIA) were measured. Tissue microscopic examination and immunohistochemical study for proliferative cell nuclear antigen (PCNA) were determined. The effect of PARP inhibitor on the bactericidal activity of gentamicin was also assessed. RESULTS: The following results were statistically significant: urea (mg/dL) 39.9 +/- 5.86, 88.3 +/- 50.3, and 48.5 +/- 12.7 (p = 0.048); serum creatinine (mg/dL): 0.6 +/- 0.26, 1.05 +/- 0.7, 0.6 +/- 0.06 (p = 0.043); proteinuria (mg/24-hours): 7.27 +/- 3.65, 41.2 +/- 18.1, and 17.6 +/- 13.9 (p = 0.050); the number of tubular macronuclei (per 10 mm2): 18.33 +/- 16.07, 218 +/- 101.8, 41.7 +/- 36.2 (p = 0.012); the number of dilated tubes (per 10 mm2): 61.67 +/- 12.58, 276.3 +/- 112.7, 140.0 +/- 90.9 (p = 0.04); and the number of PCNA positive nuclei (per 10 mm2): 223.3 +/- 95.69, 3,585 +/- 2,215.3, 626.7 +/- 236.9 (p = 0.034) in the control, gentamicin, and gentamicin+3AB-treated groups, respectively. The following biochemical and histologic parameters were also examined, however, they showed no statistically significant difference: TIA (p = 0.055), mitoses (p = 0.14), mononuclear infiltrate (p = 0.188), and intratubular cast formation (p = 0.084). No effect on bactericidal activity was observed. CONCLUSION: This study illustrates that PARP inhibitor significantly attenuates gentamicin-induced nephrotoxicity in rats with no effect on the bactericidal activity. PMID- 26951969 TI - Comparison between patients with IgA nephropathy with minimal change disease and patients with minimal change disease. AB - OBJECTIVE: To compare the clinicopathological characteristics, treatment response, and prognosis between patients with IgAN nephropathy with minimal change disease (MCD-IgAN) and patients with minimal change disease (MCD). METHODS: 77 patients with biopsy-proven MCD-IgAN from the Jinling Hospital IgAN Registry and 77 patients with MCD followed up for >= 3 years were retrospectively reviewed. RESULTS: MCD-IgAN and MCD patients had similar clinical presentations, both were predominantly young males, the disease mainly manifested as nephrotic syndrome, and the patients rarely presented with microscopic hematuria. Compared with the MCD group, patients with MCD-IgAN had lower levels of baseline serum albumin (p < 0.01) and eGFR (p < 0.05), a higher level of urine n acetylglucosaminidase (p < 0.01), higher proportion of mesangial hypercellularity (M1), and more severe acute tubulointerstitial lesions in renal pathology (p < 0.01, p < 0.01, respectively). After 8 weeks of corticosteroid therapy, no significant differences were observed in the rate of complete remission, partial remission, and no remission between MCDIgAN and MCD patients (88.3% vs. 90.9%, 10.4% vs. 5.2%, 1.3% vs. 3.9%, p > 0.05). The median time to achieve remission was 4 weeks (range 1 - 24 weeks) and 4 weeks (range 1 - 28 weeks), respectively. No significant difference existed in the efficacy of corticosteroid between the two groups. During 3.96 years (range 3.0 - 8.5 years) of follow-up, no patients in the two groups entered end-stage renal disease (ESRD), only 2 patients (2.6%) with MCD-IgAN had > 50% reduction of eGFR. CONCLUSIONS: MCD-IgAN may be controlled well achieving a comparable clinical outcome as MCD but more frequently necessitates additional immunosuppressive medication. PMID- 26951970 TI - Neutrophil-lymphocyte ratio as a novel predictor of survival in chronic hemodialysis patients. AB - BACKGROUND: Increased mortality rate in chronic hemodialysis (HD) patients is partly attributed to a chronic inflammatory state. Neutrophil-lymphocyte ratio (NLR), defined as the neutrophil count divided by lymphocyte count, is increasingly recognized as a marker of systemic inflammation, but its prognostic value in HD patients is unknown. The aim of this study was to assess NLR as a predictor of survival in this patient population. METHODS: In this study incident chronic HD patients were stratified in tertiles of NLR based on measurements obtained 3 months after initiation of dialysis. Multivariable Cox regression was used to calculate the adjusted hazard ratios (HR) for NLR on all-cause survival. Subsequently, similar models were developed at years 2 and 3 to assess predictive value of NLR in prevalent patients. RESULTS: We studied 5,782 incident HD patients (mean +/- SD age 62 +/- 15 years, 55% male, 43% Black, 52% diabetic). The median (interquartile, (IQR)) NLR at 3 months was 3.0 (2.1 - 4.5). NLR in the highest tertile (NLR >= 3.9) was a significant predictor of all-cause mortality after an adjustment for demographic and clinical covariates was performed. These results were confirmed at years 2 and 3. Moreover, NLR is superior to total white blood cell (WBC) count for prediction of all-cause mortality in incident hemodialysis patients (are under the receiver operating characteristic (ROC) curve of 0.66 vs. 0.56). CONCLUSION: This study identifies NLR as a novel and robust predictor of all-cause mortality in incident and prevalent HD patients. NLR is an inexpensive and readily available marker that may help to identify HD patients who are at an increased risk of death. PMID- 26951971 TI - Peritoneal dialysis as a successful treatment in patients with refractory congestive heart failure: a one-center experience. AB - INTRODUCTION: Ultrafiltration (UF) technique is a valuable alternative to pharmacological therapy in the treatment of patients with refractory congestive heart failure (HF). The aim of this study was to describe a single-center experience in the treatment of refractory HF patients with peritoneal dialysis (PD). METHODS: Retrospective study of 5 patients included in a single PD Unit, showing symptoms and signs of severe refractory congestive HF to optimal pharmacological therapy (NYHA class IV). Clinical and laboratory parameters, survival, hospitalization, and peritonitis rates were recorded. RESULTS: Patients were followed for 9.36 (+/- 6.36) months; population mean age was 62 (+/- 16) years and Charlson's comorbidity index was 7.2 (+/- 2.1). After PD therapy, functional class of NYHA significantly improved (class IV to class II in 4 patients). Doppler-echocardiography improved in terms of ejection fraction (EF) or systolic pressure of the pulmonary artery (SPPA) in 3 patients. No patient was readmitted due to HF. Hospitalization days substantially decreased in 4 patients. One patient presented with peritonitis episodes. Three patients died but the mean survival was higher than expected according to their comorbidity index. CONCLUSION: PD, applied to refractory HF in addition to optimal pharmacological therapy, improves quality of life and functional class and reduces hospitalization days due to HF. PMID- 26951972 TI - An Improved PCR-RFLP Assay for Detection and Genotyping of Asymptomatic Giardia lamblia Infection in a Resource-Poor Setting. AB - Laboratory workers, in resource-poor countries, still consider PCR detection of Giardia lamblia more costly and more time-consuming than the classical parasitological techniques. Based on 2 published primers, an in-house one-round touchdown PCR-RFLP assay was developed. The assay was validated with an internal amplification control included in reactions. Performance of the assay was assessed with DNA samples of various purities, 91 control fecal samples with various parasite load, and 472 samples of unknown results. Two cysts per reaction were enough for PCR detection by the assay with exhibited specificity (Sp) and sensitivity (Se) of 100% and 93%, respectively. Taking a published small subunit rRNA reference PCR test results (6%; 29/472) as a nominated gold standard, G. lamblia was identified in 5.9% (28/472), 5.2%, (25/472), and 3.6% (17/472) by PCR assay, RIDA((r)) Quick Giardia antigen detection test (R-Biopharm, Darmstadt, Germany), and iodine-stained smear microscopy, respectively. The percent agreements (kappa values) of 99.7% (0.745), 98.9% (0.900), and 97.7% (0.981) were exhibited between the assay results and that of the reference PCR, immunoassay, and microscopy, respectively. Restriction digestion of the 28 Giardia-positive samples revealed genotype A pattern in 12 and genotype B profile in 16 samples. The PCR assay with the described format and exhibited performance has a great potential to be adopted in basic clinical laboratories as a detection tool for G. lamblia especially in asymptomatic infections. This potential is increased more in particular situations where identification of the parasite genotype represents a major requirement as in epidemiological studies and infection outbreaks. PMID- 26951973 TI - Tamoxifen Induces Apoptosis of Leishmania major Promastigotes in Vitro. AB - Tamoxifen is an antagonist of the estrogen receptor and currently used for the treatment of breast cancer. The current treatment of cutaneous leishmaniasis with pentavalent antimony compounds is not satisfactory. Therefore, in this study, due to its antileishmanial activity, effects of tamoxifen on the growth of promastigotes and amastigotes of Leishmania major Iranian strain were evaluated in vitro. Promastigotes and amastigotes were treated with different concentrations (1, 5, 10, 20, and 50 MUg/ml) and time periods (24, 48, and 72 hr) of tamoxifen. After tamoxifen treatment, MTT assay (3-[4,5-dimethylthiazol-2-yl] 2,5 biphenyl tetrazolium bromide assay) was used to determine the percentage of live parasites and Graph Pad Prism software to calculate IC50. Flow cytometry was applied to investigate the induction of tamoxifen-induced apoptosis in promastigotes. The half maximal inhibitory concentration (IC50) of tamoxifen on promastigotes was 2.6 MUg/ml after 24 hr treatment. Flow cytometry analysis showed that tamoxifen induced early and late apoptosis in Leishmania promastigotes. While after 48 hr in control group the apoptosis was 2.0%, the 50 ug/L concentration of tamoxifen increased it to 59.7%. Based on the in vitro antileishmanial effect, tamoxifen might be used for leishmaniasis treatment; however, further researches on in vivo effects of tamoxifen in animal models are needed. PMID- 26951974 TI - Isolation and Genotyping of Toxoplasma gondii Strains in Ovine Aborted Fetuses in Khorasan Razavi Province, Iran. AB - Toxoplasmosis is an important zoonotic disease that can cause abortion in humans and animals. The aim of this study was isolation and subsequent genotyping of Toxoplasma gondii isolates in ovine aborted fetuses. During 2012-2013, 39 ovine aborted fetuses were collected from sheep flocks in Khorasan Razavi Province, Iran. The brain samples were screened for detection of the parasite DNA by nested PCR. The positive brain samples were bioassayed in Webster Swiss mice. The serum samples of mice were examined for T. gondii antibodies by IFAT at 6 weeks post inoculation, and T. gondii cysts were searched in brain tissue samples of seropositive mice. The positive samples were genotyped by using a PCR-RLFP method. Subsequently, GRA6 sequences of isolates were analyzed using a phylogenetic method. The results revealed that T. gondii DNA was detected in 54% (20/37, 95% CI 38.4-69.0%) brain samples of ovine aborted fetuses. In bioassay of mice, only 2 samples were virulent and the mice were killed at 30 days post inoculation, while the others were non-virulent to mice. The size of cysts ranged 7-22 um. Complete genotyping data for GRA6 locus were observed in 5 of the 20 samples. PCR-RLFP results and phylogenetic analysis revealed that all of the isolated samples were closely related to type I. For the first time, we could genotype and report T. gondii isolates from ovine aborted fetuses in Khorasan Razavi Province, Iran. The results indicate that the T. gondii isolates are genetically related to type I, although most of them were non-virulent for mice. PMID- 26951975 TI - A Novel Polyclonal Antiserum against Toxoplasma gondii Sodium Hydrogen Exchanger 1. AB - The sodium hydrogen exchanger 1 (NHE1), which functions in maintaining the ratio of Na(+) and H(+) ions, is widely distributed in cell plasma membranes. It plays a prominent role in pH balancing, cell proliferation, differentiation, adhesion, and migration. However, its exact subcellular location and biological functions in Toxoplasma gondii are largely unclear. In this study, we cloned the C-terminal sequence of T. gondii NHE1 (TgNHE1) incorporating the C-terminal peptide of NHE1 (C-NHE1) into the pGEX4T-1 expression plasmid. The peptide sequence was predicted to have good antigenicity based on the information obtained from an immune epitope database. After induction of heterologous gene expression with isopropyl b-D-thiogalactoside, the recombinant C-NHE1 protein successfully expressed in a soluble form was purified by glutathione sepharose beads as an immunogen for production of a rabbit polyclonal antiserum. The specificity of this antiserum was confirmed by western blotting and immunofluorescence. The antiserum could reduce T. gondii invasion into host cells, indicated by the decreased TgNHE1 expression in T. gondii parasites that were pre-incubated with antiserum in the process of cell entry. Furthermore, the antiserum reduced the virulence of T. gondii parasites to host cells in vitro, possibly by blocking the release of Ca(2+). In this regard, this antiserum has potential to be a valuable tool for further studies of TgNHE1. PMID- 26951976 TI - Afatinib Reduces STAT6 Signaling of Host ARPE-19 Cells Infected with Toxoplasma gondii. AB - Specific gene expressions of host cells by spontaneous STAT6 phosphorylation are major strategy for the survival of intracellular Toxoplasma gondii against parasiticidal events through STAT1 phosphorylation by infection provoked IFN gamma. We determined the effects of small molecules of tyrosine kinase inhibitors (TKIs) on the growth of T. gondii and on the relationship with STAT1 and STAT6 phosphorylation in ARPE-19 cells. We counted the number of T. gondii RH tachyzoites per parasitophorous vacuolar membrane (PVM) after treatment with TKIs at 12-hr intervals for 72 hr. The change of STAT6 phosphorylation was assessed via western blot and immunofluorescence assay. Among the tested TKIs, Afatinib (pan ErbB/EGFR inhibitor, 5 uM) inhibited 98.0% of the growth of T. gondii, which was comparable to pyrimethamine (5 uM) at 96.9% and followed by Erlotinib (ErbB1/EGFR inhibitor, 20 uM) at 33.8% and Sunitinib (PDGFR or c-Kit inhibitor, 10 uM) at 21.3%. In the early stage of the infection (2, 4, and 8 hr after T. gondii challenge), Afatinib inhibited the phosphorylation of STAT6 in western blot and immunofluorescence assay. Both JAK1 and JAK3, the upper hierarchical kinases of cytokine signaling, were strongly phosphorylated at 2 hr and then disappeared entirely after 4 hr. Some TKIs, especially the EGFR inhibitors, might play an important role in the inhibition of intracellular replication of T. gondii through the inhibition of the direct phosphorylation of STAT6 by T. gondii. PMID- 26951977 TI - Validation of Reference Genes for Quantitative Real-Time PCR in Bovine PBMCs Transformed and Non-transformed by Theileria annulata. AB - Theileria annulata is a tick-borne intracellular protozoan parasite that causes tropical theileriosis, a fatal bovine lymphoproliferative disease. The parasite predominantly invades bovine B lymphocytes and macrophages and induces host cell transformation by a mechanism that is not fully comprehended. Analysis of signaling pathways by quantitative real-time PCR (qPCR) could be a highly efficient means to understand this transformation mechanism. However, accurate analysis of qPCR data relies on selection of appropriate reference genes for normalization, yet few papers on T. annulata contain evidence of reference gene validation. We therefore used the geNorm and NormFinder programs to evaluate the stability of 5 candidate reference genes; 18S rRNA, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), ACTB (beta-actin), PRKG1 (protein kinase cGMP-dependent, type I) and TATA box binding protein (TBP). The results showed that 18S rRNA was the reference gene most stably expressed in bovine PBMCs transformed and non transformed with T. annulata, followed by GAPDH and TBP. While 18S rRNA and GAPDH were the best combination, these 2 genes were chosen as references to study signaling pathways involved in the transformation mechanism of T. annulata. PMID- 26951978 TI - Animal Models for Echinostoma malayanum Infection: Worm Recovery and Some Pathology. AB - Echinostomes are intestinal trematodes that infect a wide range of vertebrate hosts, including humans, in their adult stage and also parasitize numerous invertebrate and cold-blooded vertebrate hosts in their larval stages. The purpose of this study was to compare Echinostoma malayanum parasite growth, including worm recovery, body size of adult worms, eggs per worm, eggs per gram of feces, and pathological changes in the small intestine of experimental animals. In this study, 6-8-week-old male hamsters, rats, mice, and gerbils were infected with echinostome metacercariae and then sacrificed at day 60 post infection. The small intestine and feces of each infected animal were collected and then processed for analysis. The results showed that worm recovery, eggs per worm, and eggs per gram of feces from all infected hamsters were higher compared with infected rats and mice. However, in infected gerbils, no parasites were observed in the small intestine, and there were no parasite eggs in the feces. The volume of eggs per gram of feces and eggs per worm were related to parasite size. The results of histopathological changes in the small intestine of infected groups showed abnormal villi and goblet cells, as evidenced by short villi and an increase in the number and size of goblet cells compared with the normal control group. PMID- 26951979 TI - Genotype and Phenotype of Echinococcus granulosus Derived from Wild Sheep (Ovis orientalis) in Iran. AB - The aim of the present study is to determine the characteristics of genotype and phenotype of Echinococcus granulosus derived from wild sheep and to compare them with the strains of E. granulosus sensu stricto (sheep-dog) and E. granulosus camel strain (camel-dog) in Iran. In Khojir National Park, near Tehran, Iran, a fertile hydatid cyst was recently found in the liver of a dead wild sheep (Ovis orientalis). The number of protoscolices (n=6,000) proved enough for an experimental infection in a dog. The characteristics of large and small hooks of metacestode were statistically determined as the sensu stricto strain but not the camel strain (P=0.5). To determine E. granulosus genotype, 20 adult worms of this type were collected from the infected dog. The second internal transcribed spacer (ITS2) of the nuclear ribosomal DNA (rDNA) and cytochrome c oxidase 1 subunit (COX1) of the mitochondrial DNA were amplified from individual adult worm by PCR. Subsequently, the PCR product was sequenced by Sanger method. The lengths of ITS2 and COX1 sequences were 378 and 857 bp, respectively, for all the sequenced samples. The amplified DNA sequences from both ribosomal and mitochondrial genes were highly similar (99% and 98%, respectively) to that of the ovine strain in the GenBank database. The results of the present study indicate that the morpho molecular features and characteristics of E. granulosus in the Iranian wild sheep are the same as those of the sheep-dog E. granulosus sensu stricto strain. PMID- 26951980 TI - In Vitro Scolicidal Effects of Salvadora persica Root Extract against Protoscolices of Echinococcus granulosus. AB - It has been known that Arak, Salvadora persica, has a number of medicinal properties. We tried to investigate in vitro scolicidal effect of root extracts of this plant against protoscolices from hydatid cysts of Echinococcus granulosus. Protoscolices were aseptically collected from sheep livers containing hydatid cysts. S. persica root extract was used in 10, 30, and 50 mg/ml concentration for 10, 20, and 30 min. The viability of protoscolices was ascertained by 0.1% eosin staining. Scolicidal activity of S. persica extract at a concentration of 10 mg/ml was 36.3%, 50.3%, and 70.8% after 10, 20, and 30 min of exposure, respectively. The scolicidal effect of this extract at a concentration of 30 mg/ml was 52.9%, 86.7%, and 100% after 10, 20, and 30 min of exposure, respectively. S. persica extract at a concentration of 50 mg/ml, meanwhile, killed 81.4%, 100%, and 100% of protoscolices after 10, 20, and 30 min, respectively. Also, the cytotoxic potential of S. persica was assessed on human liver cells (HepG2) using trypan blue exclusion test. No cytotoxic effect was observed on HepG2 cell line. The present study confirmed for the first time that the ethanolic extract of S. persica has high scolicidal power in vitro. However, in vivo effect of this material remains to be studied for treatment of echinococcosis in humans and herbivorous animals. PMID- 26951982 TI - Influence of 120 kDa Pyruvate:Ferredoxin Oxidoreductase on Pathogenicity of Trichomonas vaginalis. AB - Trichomonas vaginalis is a flagellate protozoan parasite and commonly infected the lower genital tract in women and men. Iron is a known nutrient for growth of various pathogens, and also reported to be involved in establishment of trichomoniasis. However, the exact mechanism was not clarified. In this study, the author investigated whether the 120 kDa protein of T. vaginalis may be involved in pathogenicity of trichomonads. Antibodies against 120 kDa protein of T. vaginalis, which was identified as pyruvate:ferredoxin oxidoreductase (PFOR) by peptide analysis of MALDI-TOF-MS, were prepared in rabbits. Pretreatment of T. vaginalis with anti-120 kDa Ab decreased the proliferation and adherence to vaginal epithelial cells (MS74) of T. vaginalis. Subcutaneous tissue abscess in anti-120 kDa Ab-treated T. vaginalis-injected mice was smaller in size than that of untreated T. vaginalis-infected mice. Collectively, the 120 kDa protein expressed by iron may be involved in proliferation, adhesion to host cells, and abscess formation, thereby may influence on the pathogenicity of T. vaginalis. PMID- 26951981 TI - Infection of Taenia asiatica in a Bai Person in Dali, China. AB - We report here a human case of Taenia asiatica infection which was confirmed by genetic analyses in Dali, China. A patient was found to have symptoms of taeniasis with discharge of tapeworm proglottids. By sequencing of the mitochondrial cytochrome c oxidase subunit 1 (cox1) gene, we observed nucleotide sequence identity of 99% with T. asiatica and 96% with T. saginata. Using the cytochrome b (cytb) gene, 99% identity with T. asiatica and 96% identity with T. saginata were found. Our findings suggest that taeniasis of people in Dali, China may be mainly caused by T. asiatica. PMID- 26951983 TI - Prevalence of Trichomonas vaginalis in Women Visiting 2 Obstetrics and Gynecology Clinics in Daegu, South Korea. AB - This study explored epidemiological trends in trichomoniasis in Daegu, South Korea. Wet mount microscopy, PCR, and multiplex PCR were used to test for Trichomonas vaginalis in vaginal swab samples obtained from 621 women visiting 2 clinics in Daegu. Of the 621 women tested, microscopy detected T. vaginalis in 4 (0.6%) patients, PCR detected T. vaginalis in 19 (3.0%) patients, and multiplex PCR detected T. vaginalis in 12 (1.9%) patients. Testing via PCR demonstrated high sensitivity and high negative predictive value for T. vaginalis. Among the 19 women who tested positive for T. vaginalis according to PCR, 94.7% (18/19) reported vaginal signs and symptoms. Notably, more than 50% of T. vaginalis infections occurred in females younger than 30 years old, and 58% were unmarried. Multiplex PCR, which simultaneously detects pathogens from various sexually transmitted infections, revealed that 91.7% (11/12) of patients were infected with 2 or more pathogens. Mycoplasma hominis was the most prevalent co-infection pathogen with T. vaginalis, followed by Ureaplasma urealyticum and Chlamydia trachomatis. Our results indicate that PCR and multiplex PCR are the most sensitive tools for T. vaginalis diagnosis, rather than microscopy which has been routinely used to detect T. vaginalis infections in South Korea. Therefore, clinicians should take note of the high prevalence of T. vaginalis infections among adolescent and young women in order to prevent persistent infection and transmission of this disease. PMID- 26951984 TI - Molecular Characterization of Enterocytozoon bieneusi in Domestic Rabbits (Oryctolagus cuniculus) in Northeastern China. AB - A study of 426 rabbits from 3 cities in Jilin province (Changchun City and Jilin City) and Liaoning province (Shenyang City) was conducted between May and June 2015. The overall prevalence of E. bieneusi in rabbits was 0.94% (4/426), with 0% (0/116), 1.72% (3/174), and 0.74% (1/136) in Jilin, Changchun, and Shenyang City, respectively. Only 3 farms (farm 1 and farm 3 in Changchun City, farm 8 in Shenyang City) were PCR-positive for E. bieneusi. Moreover, rabbits of more than 6 months (1.72%) had the highest E. bieneusi prevalence, followed by rabbits of 4 6 months (1.26%), 2-3 months (0.58%), and less than 1 month (0%). Analysis of ITS gene of E. bieneusi suggested that all 4 E. bieneusi isolates were genotype D, and were classified as group 1a. The present results first demonstrated the existence of zoonotic E. bieneusi in domestic rabbits in China. Effective control measures should be implemented to prevent E. bieneusi infection in domestic rabbits, other animals, and humans. PMID- 26951985 TI - Prevalence of Anaplasma and Bartonella spp. in Ticks Collected from Korean Water Deer (Hydropotes inermis argyropus). AB - Deer serve as reservoirs of tick-borne pathogens that impact on medical and veterinary health worldwide. In the Republic of Korea, the population of Korean water deer (KWD, Hydropotes inermis argyropus) has greatly increased from 1982 to 2011, in part, as a result of reforestation programs established following the Korean War when much of the land was barren of trees. Eighty seven Haemaphysalis flava, 228 Haemaphysalis longicornis, 8 Ixodes nipponensis, and 40 Ixodes persulcatus (21 larvae, 114 nymphs, and 228 adults) were collected from 27 out of 70 KWD. A total of 89/363 ticks (266 pools, 24.5% minimum infection rate) and 5 (1.4%) fed ticks were positive for Anaplasma phagocytophilum using nested PCR targeting the 16S rRNA and groEL genes, respectively. The 16S rRNA gene fragment sequences of 88/89 (98.9%) of positive samples for A. phagocytophilum corresponded to previously described gene sequences from KWD spleen tissues. The 16S rRNA gene fragment sequences of 20/363 (5.5%) of the ticks were positive for A. bovis and were identical to previously reported sequences. Using the ITS specific nested PCR, 11/363 (3.0%) of the ticks were positive for Bartonella spp. This is the first report of Anaplasma and Bartonella spp. detected in ticks collected from KWD, suggesting that ticks are vectors of Anaplasma and Bartonella spp. between reservoir hosts in natural surroundings. PMID- 26951986 TI - Seroprevalence of Toxoplasma gondii Infection among HIV/AIDS Patients in Eastern China. AB - Toxoplasmosis, a neglected tropical disease caused by the protozoan parasite Toxoplasma gondii, occurs throughout the world. Human T. gondii infection is asymptomatic in 80% of the population; however, the infection is life-threatening and causes substantial neurologic damage in immunocompromised patients such as HIV-infected persons. The major purpose of this study was to investigate the seroprevalence of T. gondii infection in subjects infected with HIV/AIDS in eastern China. Our findings showed 9.7% prevalence of anti-T. gondii IgG antibody in HIV/AIDS patients, which was higher than in intravenous drug users (2.2%) and healthy controls (4.7%), while no significant difference was observed in the seroprevalence of anti-Toxoplasma IgM antibody among all participants (P>0.05). Among all HIV/AIDS patients, 15 men (7.7%) and 10 women (15.9%) were positive for anti-T. gondii IgG antibody; however, no significant difference was detected in the seroprevalence of anti-Toxoplasma IgG antibody between males and females. The frequency of anti-Toxoplasma IgG antibody was 8.0%, 13.2%, 5.5%, and 0% in patients with normal immune function (CD4(+) T-lymphocyte count >=500 cells/ml), immunocompromised patients (cell count >=200 and <500 cells/ml), severely immunocompromised patients (cell count >=50 and <200 cells/ml), and advanced AIDS patients, respectively (cell count <50 cells/ml), while only 3 immunocompromised patients were positive for anti-T. gondii IgM antibody. The results indicate a high seroprevalence of T. gondii infection in HIV/AIDS patients in eastern China, and a preventive therapy for toxoplasmosis may be given to HIV/AIDS patients based on CD4(+) T lymphocyte count. PMID- 26951987 TI - Serological Detection of Borrelia burgdorferi among Horses in Korea. AB - Lyme disease is a tick-borne zoonotic infectious disease caused by Borrelia burgdorferi. The present study assessed the infection status of B. burgdorferi among horses reared in Korea using ELISA and PCR. Between 2009 and 2013, blood samples were collected from 727 horses throughout Korea. Data for each animal including age, gender, breed, and region of sample collection were used for epidemiological analysis. Overall, 38 (5.2%; true prevalence: 5.5%) of 727 horses were seropositive by ELISA. There were statistically significant differences according to breed and region (P<0.001) whose differences might be attributed to the ecology of vector ticks and climate conditions. Using 2 nested PCR, none of the samples tested positive for B. burgdorferi. Thus, a positive ELISA result can indicate only that the tested horse was previously exposed to B. burgdorferi, with no certainty over the time of exposure. Since global warming is likely to increase the abundance of ticks in Korea, continuous monitoring of tick-borne diseases in Korean horses is needed. PMID- 26951988 TI - Effects of Disinfectants on Larval Development of Ascaris suum Eggs. AB - The objective of this study was to evaluate the effects of several different commercial disinfectants on the embryogenic development of Ascaris suum eggs. A 1 ml aliquot of each disinfectant was mixed with approximately 40,000 decorticated or intact A. suum eggs in sterile tubes. After each treatment time (at 0.5, 1, 5, 10, 30, and 60 min), disinfectants were washed away, and egg suspensions were incubated at 25C in distilled water for development of larvae inside. At 3 weeks of incubation after exposure, ethanol, methanol, and chlorohexidin treatments did not affect the larval development of A. suum eggs, regardless of their concentration and treatment time. Among disinfectants tested in this study, 3% cresol, 0.2% sodium hypochlorite and 0.02% sodium hypochlorite delayed but not inactivated the embryonation of decorticated eggs at 3 weeks of incubation, because at 6 weeks of incubation, undeveloped eggs completed embryonation regardless of exposure time, except for 10% povidone iodine. When the albumin layer of A. suum eggs remained intact, however, even the 10% povidone iodine solution took at least 5 min to reasonably inactivate most eggs, but never completely kill them with even 60 min of exposure. This study demonstrated that the treatment of A. suum eggs with many commercially available disinfectants does not affect the embryonation. Although some disinfectants may delay or stop the embryonation of A. suum eggs, they can hardly kill them completely. PMID- 26951990 TI - Environmental Contamination by Echinococcus granulosus sensu lato Eggs in Relation to Slaughterhouses in Urban and Rural Areas in Tunisia. AB - Hydatidosis has become a real concern for health care institutions and animal rearers in Tunisia. The Tunisian endemicity is aggravated by the growing number of dogs and the difficulty of getting rid of contaminated viscera because of the lack of equipment in most slaughterhouses. Therefore, microscopic and molecular tools were applied to evaluate the role of slaughterhouses in canine infection and Echinococcus granulosus sensu lato (s. l.) egg dissemination. Exposure risk to E. granulosus s. l. eggs in urban and rural areas was explored in order to implant preventive and adapted control strategies. Microscopic examinations detected taeniid eggs in 152 amongst 553 fecal samples. The copro-PCR demonstrated that 138 of 152 taeniid samples analyzed were positive for E. granulosus s. l. DNA. PCR-RFLP demonstrated that all isolated samples belonged to E. granulosus sensu stricto (s. s.). An important environmental contamination index (25.0%) by E. granulosus s. l. eggs was demonstrated. The average contamination index from the regions around slaughterhouses (23.3%; 95% CI: 17.7 28.9%) was in the same range as detected in areas located far from slaughterhouses (26.0%, 95% CI: 21.3-30.8%). Echinococcosis endemic areas were extended in both rural (29.9%, 95% CI: 24.8-34.9%) and urban locations (18.1%, 95% CI: 13.0-22.9%). The pathogen dissemination is related neither to the presence/absence of slaughterhouses nor to the location in urban or rural areas, but is probably influenced by human activities (home slaughtering) and behavior towards the infected viscera. PMID- 26951989 TI - Molecular Description of Macroorchis spinulosus (Digenea: Nanophyetidae) Based on ITS1 Sequences. AB - We performed a molecular genetic study on the sequences of 18S ribosomal RNA (ITS1 region) gene in 4-day-old adult worms of Macroorchis spinulosus recovered in mice experimentally infected with metacercariae from crayfish in Jeollanam-do Province, Korea. The metacercariae were round, 180 MUm in average diameter, encysted with 2 layers of thick walls, but the stylet on the oral sucker was not clearly seen. The adult flukes were oval shape, and 760-820 MUm long and 320-450 MUm wide, with anterolateral location of 2 large testes. The phylogenetic tree based on ITS1 sequences of 6 M. spinulosus samples showed their distinguished position from other trematode species in GenBank. The most closely resembled group was Paragonimus spp. which also take crayfish or crabs as the second intermediate host. The present study is the first molecular characterization of M. spinulosus and provided a basis for further phylogenetic studies to compare with other trematode fauna in Korea. PMID- 26951991 TI - Lack of benefits of mammalian target of rapamycin inhibitor in patients transplanted for hepatocellular carcinoma: Is this the end of the story? PMID- 26951992 TI - Vitamin D level and its association with adiposity among multi-ethnic adults in Kuala Lumpur, Malaysia: a cross sectional study. AB - BACKGROUND: Vitamin D deficiency is highly prevalent in both temperate as well as tropical countries. Obesity is one of the factors contributing to vitamin D deficiency. As our country has a high prevalence of overweight and obesity, we aimed to study serum 25-hydroxyvitamin D (25(OH)D) level and its association with adiposity using various adiposity indicators; and to study other risk factors that affect serum 25(OH)D level among multi-ethnic adults in Kuala Lumpur, Malaysia. METHODS: This was a cross sectional study conducted with a multistage sampling. All permanent teachers working in government secondary schools in Kuala Lumpur were invited for the study. The data collection included serum 25(OH)D, Parathyroid Hormone (PTH), body fat percentage, waist circumference, body mass index (BMI) and blood pressure. Demographic characteristics, sun avoidance, sun exposure and physical activity were enquired from the participants using a self administered questionnaire. The data was analyzed using a complex sample analysis. RESULTS: A total of 858 participants were recruited. Majority of them were Malays, females and had tertiary education. The overall prevalence of vitamin D deficiency (<20 ng/ml) was 67.4 %. Indian participants (80.9 %) had the highest proportion of vitamin D deficiency, followed by Malays (75.6 %), others (44.9 %) and Chinese (25.1 %). There was a significant negative association between serum 25(OH)D level with BMI (beta = -0.23) and body fat percentage (beta = -0.14). In the multivariate linear regression analysis, Malays, Indians and females (p < 0.001); higher BMI and larger waist circumference (p < 0.05) were significantly associated with lower serum 25(OH)D level. The full model explained 32.8 % of the variation between participants in the serum 25(OH)D level. The two most influential factors affecting serum 25(OH)D level were ethnicity and gender. CONCLUSIONS: The prevalence of vitamin D deficiency among our participants was high. Adiposity was associated with serum 25(OH)D level. Skin pigmentation and gender based behaviours were more dominant in contributing to serum 25(OH)D level. Health education should be targeted in weight management, gender based behaviours on sun exposure, as skin pigmentation is non-modifiable. PMID- 26951993 TI - Risk factors of diabetes in North Indians with metabolic syndrome. AB - AIM: Metabolic syndrome progresses to diabetes and determinants of this progression like hyperinsulinemia, hypertriglyceridemia and genetic factors have been speculative. The present study was aimed at quantifying the insulin resistance and influence of family history of diabetes in subjects with metabolic syndrome developing prediabetes and diabetes. METHODS: Consecutive subjects attending the endocrine clinic were evaluated for metabolic syndrome as per definition of International Diabetes Federation, 2005. The family history of diabetes in their first degree relatives was ascertained and Homeostasis model assessment of Insulin resistance (HOMA-IR), Homeostasis model assessment for beta cell function (HOMA-B) and Quantitative insulin sensitivity check index (QUICKI) were calculated in 163 subjects enrolled. RESULTS: HOMA-IR was higher (p<0.05) but HOMA-B and QUICKI were lower (p<0.0001) in subjects with metabolic syndrome+prediabetes or diabetes compared to metabolic syndrome with normal glucose tolerance. HOMA-B was lower and prevalence of prediabetes and diabetes was higher in metabolic syndrome subjects with family history of diabetes than in those without such family history (p<0.05). CONCLUSIONS: subjects with metabolic syndrome having prediabetes and diabetes had more severe insulin resistance than those with metabolic syndrome only. Beta cell dysfunction was remarkable and prevalence of prediabetes was high in metabolic syndrome subjects with family history of diabetes. Both the severity of the insulin resistance and family history of diabetes are therefore proposed to be determinants of diminished Beta cell function leading to diabetes in metabolic syndrome. PMID- 26951994 TI - The psychosocial outcomes of individuals with hematological cancers: Are we doing enough high quality research, and what is it telling us? AB - This systematic review assessed the quantity and quality of research examining the psychosocial outcomes among hematological cancer patients. Studies were categorised as either measurement, descriptive or intervention. Intervention studies were further assessed according to Effective Practice and Organisation of Care (EPOC) methodological criteria. A total of 261 eligible papers were identified. The number of publications increased by 8.8% each year (95% CI=7.5 10.2%; p<0.0001). The majority of studies were descriptive (n=232; 89%), with few measurement (n=8; 3%) and intervention (n=21; 8%) studies identified. Ten intervention studies met EPOC design criteria, however only two interventions, one targeted at individuals with Hodgkin's or Non-Hodgkin's lymphoma and one targeted at individuals with leukaemia, lymphoma or myelomatosis were successful in improving patients' psychosocial outcomes. Despite an increasing volume of research examining psychosocial outcomes of hematological cancer patients, there is a need for robust measurement and methodologically rigorous intervention research in this area. PMID- 26951995 TI - The prognostic value of phosphatase and tensin homolog negativity in breast cancer: A systematic review and meta-analysis of 32 studies with 4393 patients. AB - The prognostic value of phosphatase and tensin homolog (PTEN) negativity in breast cancer has been evaluated by many studies but remains controversial. We conducted a meta-analysis to assess the association of PTEN negativity with overall survival and disease-free survival. Thirty-two studies with 4393 patients were identified. PTEN negativity was significantly associated with unfavorable overall survival in breast cancer (hazard ratio=1.89, 95% confidence interval 1.58-2.26), with low heterogeneity among the studies (I(2)=25%, P=0.160) and no evidence for publication bias. Meta-analysis of multivariate hazard ratios and sensitivity analyses did not materially change the results. The data on disease free survival was heterogeneous (I(2)=61.9%, P<0.001), with a summary hazard ratio of 1.57 (95% confidence interval 1.31-1.89). The exact source of heterogeneity remains unclear. We thus concluded that PTEN negativity was significantly associated with unfavorable prognosis in terms of overall survival in breast cancer. PMID- 26951996 TI - Experimental pain induces attentional bias that is modified by enhanced motivation: An eye tracking study. AB - BACKGROUND: In this study, the effects of prior pain experience and motivation on attentional bias towards pain-related information were investigated within two visual-probe tasks via eye movement behaviours. It is hypothesized that pain experience would induce stronger attentional bias and such bias could be suppressed by the motivation to avoid impeding pain. METHODS: All participants took part in visual-probe tasks with pictures and words as stimuli that are typically used in studies of attentional bias. They were allocated to three groups: no-pain (NP) group, performing tasks without experiencing pain; pain experience (PE) group, performing the same tasks following painful stimuli; and pain-experience-with-motivation (PEM) group, undergoing the same procedure as PE group with additional instructions about avoiding impeding pain. Eye movements were recorded during the tasks. RESULTS: The eye movement data showed that: (1) participants in the PE group exhibited stronger attention bias towards painful pictures than those in the NP group; (2) the attentional bias towards painful pictures was significantly reduced in the PEM group as compared to the PE group. By contrast, the verbal task failed to find these effects using sensory pain words as stimuli. CONCLUSION: This study was the first that revealed the impact of acute experimental pain on attentional bias towards pain-related information in healthy individuals through eye tracking. It may provide a possible solution to reduce hypervigilance towards pain-related information by altering the motivational relevance. WHAT DOES THIS STUDY ADD?: (1) This study revealed the impact of experimental pain on attentional bias in healthy individuals; (2) This study may provide a possible approach of altering motivational relevance to control the pain-induced attentional bias towards pain-related information. PMID- 26951997 TI - A decade of pelvic vascular injuries during the Global War on Terror. AB - BACKGROUND: Pelvic vascular injuries (PVIs) rarely occur in isolation and are often associated with significant morbidity. The purpose of this study was to examine the incidence, trends, and early outcomes of PVIs sustained in combat. METHODS: The Department of Defense Trauma Registry was queried to identify all patients treated with PVIs during the first 10 years of Operation Enduring Freedom. Patient demographics, mechanism of injury, type of vascular injury, in theater complications, and early clinical outcomes were examined. RESULTS: From 2003 to 2012, 143 patients (99% male) sustained a PVI in Afghanistan. During this period, there was a persistent increase in the percentage of patient visits (0.4% in 2003 to 2.0% in 2012). The mean Injury Severity Score (ISS) was 24. Sixty-six percent of patient injuries were secondary to explosions. Improvised explosive devices (IEDs) encountered by dismounted personnel accounted for 47% of all injuries and were associated with a significantly higher ISS (28) compared with all other mechanisms of injury (P < .01). There were 85 (43%) arterial and 112 (57%) venous PVIs. The most frequent arterial injury was the common iliac artery. Injury to the femoral vein was associated with a higher median transfusion requirement. One patient died in combat theater. Injuries from IEDs had higher rates of coagulopathy, acidosis, and hypothermia compared with other mechanisms of injury (P = .03). Forty-two patients (29%) sustained early infectious complications. Injuries from explosions were also associated with a significantly higher rate of infectious complications compared with other mechanisms of injury (P < .01). CONCLUSIONS: PVIs have occurred with increasing frequency during Operation Enduring Freedom. Despite a persistently low mortality, complication and infection rates remain high, particularly when injuries are secondary to explosions. IEDs are associated with higher ISS and complication rates. Future studies must continue to focus on the prevention and treatment of PVIs sustained in combat, particularly those caused by explosions. PMID- 26951998 TI - Mycotic aneurysm of the superior and inferior mesenteric artery. AB - OBJECTIVE: Visceral artery aneurysms as a result of arterial degenerative disease are rare (0.1%-2%), and the superior mesenteric artery (SMA) accounts for 3.2% of all reported series. The current incidence of inferior mesenteric artery (IMA) aneurysm is unknown. However, infective causes (mycotic) of SMA and IMA aneurysm as a result of primary, secondary, and cryptogenic etiology remain a separate entity and attain fewer cases in the literature. Currently, there is no consensus on their presentation, diagnosis, and overall management. METHODS: A systematic review and meta-aggregation of literature from 1944 to March 2015 in the English language and of adult subjects in MEDLINE, Ovid, CINAHL, and the Cochrane database was conducted. RESULTS: The median age of patients with SMA aneurysm was 36 (range, 14-92) years, with a significant male predominance (73% vs 27%). In order of prevalence, abdominal pain (n = 25; 65%), low-grade fever (n = 23; 60%), malaise (n = 10; 26%), weight loss (n = 9; 23%), and nausea and vomiting (n = 8; 20%) were the most common presenting signs and symptoms. The most common microorganism was Streptococcus (n = 18; 47%), followed by Staphylococcus (n = 11; 28%). The investigative modality of choice was computed tomography (n = 22; 57.8%), followed by ultrasonography of the abdomen (n = 9; 23%). Primary etiology was noted in 5.4%, secondary in 71%, and cryptogenic in 13% of all cases. Aneurysmectomy alone was associated with bowel resection in four cases (10.5%), whereas aneurysmectomy with interposition vein grafting required no further intervention. The inpatient mortality after surgery was 7.8%, and the overall mortality was 15%. The median follow-up was 12 months (range, 2-120 months). The median age of patients with IMA aneurysm was 48 (range, 22-64) years, with a male predominance of 2:1 and abdominal pain in all cases (n = 3; 100%). The most common microorganism was Streptococcus (n = 2; 66.6%), and the operation of choice was aneurysmectomy (n = 2; 66.6%) after computed tomography scan (n = 3; 100%) as an investigative modality of choice. CONCLUSIONS: The pentad of abdominal pain, pyrexia of unknown origin, malaise, weight loss, and nausea remains the most convincing presentation of mycotic aneurysms of the SMA and IMA. Computed tomography is the investigative modality of choice, and such patients are best served with aneurysmectomy alone in IMA aneurysms and interposition vein grafting in SMA aneurysms after initiation of antimicrobial therapy on suspicion of the diagnosis. PMID- 26951999 TI - Outcomes and factors influencing prognosis in patients with vascular pythiosis. AB - OBJECTIVE: Vascular pythiosis, caused by Pythium insidiosum, is associated with a high mortality rate. We reviewed the outcomes and established the factors predicting prognosis of patients treated in our institution with surgery, antifungal therapy, or immunotherapy. METHODS: We undertook a retrospective record review of patients with vascular pythiosis treated in Siriraj Hospital, Bangkok, Thailand, between January 2005 and January 2015. Patient characteristics, type of surgery, adjunctive antifungal treatment, adjunctive immunotherapy, and disease status of surgical arterial and surrounding soft tissue margins were recorded. We calculated the mortality rate and established factors predicting prognosis. RESULTS: The records of 11 patients were reviewed. All patients had thalassemia. Nine patients (81.8%) had a history of contact with contaminated water. The clinical presentations were chronic ulcers (45.5%), toe gangrene (27.3%), pulsatile mass (27.3%), and acute limb ischemia (27.3%). Above knee amputation was required in 10 patients (90.9%). The mortality rate was 36.4%. Independent variables between survivors and nonsurvivors were lack of an arterial disease-free surgical margin (P = .003), lack of a surrounding soft tissue disease-free surgical margin (P < .05), a suprainguinal lesion (P < .05) and duration of symptoms (P < .05). Adjuvant itraconazole, terbinafine, and Pythium vaccine have a role to play in patients with a disease-free arterial surgical margin but in whom infected surrounding soft tissue could not be completely excised. CONCLUSIONS: Achieving adequate disease-free surgical margins especially the arterial margin-at amputation or debridement is the most important prognostic factor in patients with vascular pythiosis. Early detection combined with a multidisciplinary approach to treatment, including surgery, antifungal agents, and immunotherapy, allows the best possible outcome to be obtained. PMID- 26952000 TI - Impact of consensus statements and reimbursement on vena cava filter utilization. AB - OBJECTIVE: Pulmonary embolism is the third most common cause of death in hospitalized patients. Vena cava filters (VCFs) are indicated in patients with venous thromboembolism with a contraindication to anticoagulation. Prophylactic indications are still controversial. However, the utilization of VCFs during the past 15 years may have been affected by societal recommendations and reimbursement rates. The aim of this study was to evaluate the impact of societal guidelines and reimbursement on national trends in VCF placement from 1998 to 2012. METHODS: The National Inpatient Sample was used to identify patients who underwent VCF placement between 1998 and 2012. VCF placement yearly rates were evaluated. Societal guidelines and consensus statements were identified using a PubMed search. Reimbursement rates for VCF were determined on the basis of published Medicare reports. Statistical analysis was completed using descriptive statistics, Fisher exact test, and trend analysis using the Mann-Kendall test and considered significant for P < .05. RESULTS: The use of VCFs increased 350% between January 1998 and January 2008. Consensus statements in favor of VCFs published by the Eastern Association for the Surgery of Trauma (July 2002) and the Society of Interventional Radiology (March 2006) were temporally associated with a significant 138% and 122% increase in the use of VCFs, respectively (P = .014 and P = .023, respectively). The American College of Chest Physicians guidelines (February 2008 and 2012) discouraging the use of VCFs were preceded by an initial stabilization in the use of VCFs between 2008 and 2012, followed by a 16% decrease in use starting in March 2012 (P = .38). Changes in Medicare reimbursement were not followed by a change in VCF implantation rates. CONCLUSIONS: There is a temporal association between the societal guidelines' recommendations regarding VCF placement and the actual rates of insertion. More uniform consensus statements from multiple societies along with the use of level I evidence may be required to lead to a definitive change in practice. PMID- 26952001 TI - The End of Racial Disparities in Kidney Transplantation? Not So Fast! PMID- 26952003 TI - Tackling Peer Review: How to Improve Reviews and Minimize Abuse. PMID- 26952002 TI - Strengthening Biosecurity in Iraq: Development of a National Biorisk Management System. AB - Since 2004, the Republic of Iraq has undertaken a concerted effort to comply with all of its international obligations to prevent the proliferation and the use of chemical, biological, radiological, and nuclear (CBRN) weapons. A centerpiece of this effort is Iraq's development of a National Biorisk Management System. The Iraqi National Monitoring Authority (INMA), which is responsible for CBRN security and non-proliferation in Iraq, has played a key role in establishing this system. This article provides an overview of Iraq's international non proliferation commitments, describes the legal and organizational steps it has taken to implement these commitments, and examines current initiatives to strengthen Iraq's biosecurity. PMID- 26952004 TI - The analysis of dose-response curve from bioassays with quantal response: Deterministic or statistical approaches? AB - Dose-response relations can be obtained from systems at any structural level of biological matter, from the molecular to the organismic level. There are two types of approaches for analyzing dose-response curves: a deterministic approach, based on the law of mass action, and a statistical approach, based on the assumed probabilities distribution of phenotypic characters. Models based on the law of mass action have been proposed to analyze dose-response relations across the entire range of biological systems. The purpose of this paper is to discuss the principles that determine the dose-response relations. Dose-response curves of simple systems are the result of chemical interactions between reacting molecules, and therefore are supported by the law of mass action. In consequence, the shape of these curves is perfectly sustained by physicochemical features. However, dose-response curves of bioassays with quantal response are not explained by the simple collision of molecules but by phenotypic variations among individuals and can be interpreted as individual tolerances. The expression of tolerance is the result of many genetic and environmental factors and thus can be considered a random variable. In consequence, the shape of its associated dose response curve has no physicochemical bearings; instead, they are originated from random biological variations. Due to the randomness of tolerance there is no reason to use deterministic equations for its analysis; on the contrary, statistical models are the appropriate tools for analyzing these dose-response relations. PMID- 26952005 TI - Pharmacokinetics, safety and efficacy of a full dose sofosbuvir-based regimen given daily in hemodialysis patients with chronic hepatitis C. AB - BACKGROUND & AIMS: Hepatitis C virus (HCV) infection is an independent risk factor for chronic kidney disease and leads to faster liver disease progression in patients requiring hemodialysis than in those with normal renal function. Little is known about the use of a sofosbuvir-containing regimen for infected patients on hemodialysis. We aimed to describe the pharmacokinetics, safety and efficacy of sofosbuvir in 2 dosing regimens and associated antiviral agents in HCV-infected patients requiring hemodialysis. METHODS: Multicenter, prospective and observational study of patients receiving sofosbuvir, 400mg once daily (n=7) or 3 times a week (n=5), after hemodialysis with simeprevir, daclatasvir, ledipasvir or ribavirin was conducted. Drug plasma concentrations were determined by liquid chromatography-tandem mass spectrometry before and after a 4h hemodialysis and 1.5h after last drug intake at the end of hemodialysis. RESULTS: Plasma concentrations of sofosbuvir or its inactive metabolite sofosbuvir-007 did not accumulate with either regimen between hemodialysis sessions or throughout the treatment course. Sofosbuvir-007 extraction ratio (52%) was consistent with historical data. In one patient receiving the once daily regimen, sofosbuvir-007 half-life was slightly higher (38h) than for patients with normal renal function receiving a full dose. Hemodialysis did not remove any other associated anti-HCV agents. Clinical and biological tolerance was good for all patients. Two relapses occurred with the 3 times a week regimen and none with the once daily. CONCLUSIONS: A regimen including sofosbuvir, 400mg once daily, could be proposed for HCV-infected patients requiring hemodialysis and should be associated with close clinical, biological, cardiovascular, and therapeutic drug monitoring. LAY SUMMARY: Hepatitis C Virus (HCV) infection in hemodialysis patients is prevalent and aggressive. Effective anti-HCV treatment in these patients may stabilize their renal disease. However, sofosbuvir, the cornerstone of most anti-HCV containing regimens, should not be administered to these patients until more data is available. In this pharmacokinetic study, sofosbuvir full dose (400mg once daily) administered every day with another direct antiviral agent did not accumulate in hemodialysis patients and was safe and effective. PMID- 26952007 TI - Goldfish morphology as a model for evolutionary developmental biology. AB - Morphological variation of the goldfish is known to have been established by artificial selection for ornamental purposes during the domestication process. Chinese texts that date to the Song dynasty contain descriptions of goldfish breeding for ornamental purposes, indicating that the practice originated over one thousand years ago. Such a well-documented goldfish breeding process, combined with the phylogenetic and embryological proximities of this species with zebrafish, would appear to make the morphologically diverse goldfish strains suitable models for evolutionary developmental (evodevo) studies. However, few modern evodevo studies of goldfish have been conducted. In this review, we provide an overview of the historical background of goldfish breeding, and the differences between this teleost and zebrafish from an evolutionary perspective. We also summarize recent progress in the field of molecular developmental genetics, with a particular focus on the twin-tail goldfish morphology. Furthermore, we discuss unanswered questions relating to the evolution of the genome, developmental robustness, and morphologies in the goldfish lineage, with the goal of blazing a path toward an evodevo study paradigm using this teleost species as a new model species. For further resources related to this article, please visit the WIREs website. PMID- 26952006 TI - Resminostat plus sorafenib as second-line therapy of advanced hepatocellular carcinoma - The SHELTER study. AB - BACKGROUND & AIMS: No established therapies for patients with hepatocellular carcinoma (HCC) and progression on first-line sorafenib treatment currently exist. This phase I/II trial investigated safety, pharmacokinetics and potential biomarkers of the histone deacetylase inhibitor resminostat and a combination therapy with resminostat and sorafenib. METHODS: Patients with HCC and radiologically confirmed progression on sorafenib were treated in an exploratory, multi-center, open-label, uncontrolled, non-randomized, parallel group phase I/II study. In the combination group (n=38) four dose levels ranged from daily 200 to 600mg resminostat plus 400 to 800mg sorafenib. The monotherapy group (n=19) received 600mg resminostat. RESULTS: 57 patients received treatment. Most common adverse events were gastrointestinal disorders, thrombocytopenia and fatigue. Median maximal histone deacetylase inhibition and highest increase in H4 acetylation matched Tmax of resminostat. Sorafenib or the Child-Pugh score did not affect typical pharmacokinetics characteristics of resminostat. Efficacy assessment as progression-free survival-rate after 6 treatment cycles (12weeks, primary endpoint) was 12.5% for resminostat and 62.5% for resminostat plus sorafenib. Median time to progression and overall survival were 1.8 and 4.1months for resminostat and 6.5 and 8.0months for the combination, respectively. Zinc finger protein 64 (ZFP64) baseline expression in blood cells was found to correlate with overall survival. CONCLUSIONS: The combination of sorafenib and resminostat in HCC patients was safe and showed early signs of efficacy. Sorafenib did not alter the pharmacokinetic profile of resminostat or its histone deacetylase inhibitory activity in vivo. A prognostic and potentially predictive role of ZFP64 for treatment with resminostat should be further investigated in HCC and possibly other cancer indications. LAY SUMMARY: No established therapy for patients with advanced hepatocellular carcinoma and progression under first line systemic treatment with sorafenib currently exists. Epigenetic modulation by inhibition of histone deacetylases might be able to overcome therapy resistance. This exploratory phase I/II clinical study in patients with radiologically confirmed progression under first-line treatment with sorafenib investigated the histone deacetylases inhibitor resminostat as single agent or in combination with continued application of sorafenib. CLINICAL TRIAL REGISTRATION: The clinical trial has been registered at www.clinicaltrials.gov as NCT00943449. PMID- 26952008 TI - Response to Giangregorio et al.: "Intensity is a subjective construct". PMID- 26952009 TI - Trabecular bone scores and lumbar spine bone mineral density of US adults: comparison of relationships with demographic and body size variables. AB - This study examines demographic patterns and body size relationships in trabecular bone score and lumbar spine BMD of US adults from NHANES 2005-2008. INTRODUCTION: Limited data exist on demographic and body size relationships for trabecular bone score (TBS), a new variable derived from bone texture analysis of lumbar spine dual-energy X-ray absorptiometry (DXA) scans. This study compares demographic patterns and correlations with body size (body mass index (BMI), weight, waist circumference, total body fat, trunk fat, trunk lean) between TBS and lumbar spine bone mineral density (LSBMD) for adults age >=20 years from the National Health and Nutrition Examination Survey (NHANES) 2005-2008 with BMI in the optimal range for TBS (15-37 kg/m(2)). METHODS: LSBMD, TBS, body fat, and lean were obtained by DXA. Weight, height, and waist circumference were measured. BMI was calculated from height and weight. RESULTS: Sex differences in TBS varied by age and race/ethnicity (p sex X age interaction and p sex X race/ethnicity interaction < 0.001). In most of the nine demographic subgroups examined, TBS did not differ by sex (four subgroups) or was significantly higher in women (three subgroups). TBS differences by race/ethnicity were inconsistent in men; in women, non-Hispanic whites (NHWs) had higher TBS than non-Hispanic blacks (NHBs) or Mexican Americans (MAs) in all age groups. In contrast, LSBMD was either significantly higher in men (five subgroups) or did not differ by sex (four subgroups). Race/ethnic differences in LSBMD were consistent across age and sex (NHB > NHW > MA). All body size variables were negatively related to TBS but positively related to LSBMD. CONCLUSIONS: Demographic patterns and body size relationships differed between TBS and LSBMD. PMID- 26952010 TI - Young adults with cystic fibrosis have altered trabecular microstructure by ITS based morphological analysis. AB - Young adults with cystic fibrosis have compromised plate-like trabecular microstructure, altered axial alignment of trabeculae, and reduced connectivity between trabeculae that may contribute to the reduced bone strength and increased fracture risk observed in this patient population. INTRODUCTION: The risk of fracture is increased in patients with cystic fibrosis (CF). Individual trabecular segmentation (ITS)-based morphological analysis of high-resolution peripheral quantitative computed tomography (HR-pQCT) images segments trabecular bone into individual plates and rods of different alignment and connectivity, which are important determinants of trabecular bone strength. We sought to determine whether alterations in ITS variables are present in patients with CF and may help explain their increased fracture risk. METHODS: Thirty patients with CF ages 18-40 years underwent DXA scans of the hip and spine and HR-pQCT scans of the radius and tibia with further assessment of trabecular microstructure by ITS. These CF patients were compared with 60 healthy controls matched for age (+/-2 years), race, and gender. RESULTS: Plate volume fraction, thickness, and density as well as plate-plate and plate-rod connectivity were reduced, and axial alignment of trabeculae was lower in subjects with CF at both the radius and the tibia (p < 0.05 for all). At the radius, adjustment for BMI eliminated most of these differences. At the tibia, however, reductions in plate volume fraction and number, axially aligned trabeculae, and plate-plate connectivity remained significant after adjustment for BMI alone and for BMI and aBMD (p < 0.05 for all). CONCLUSIONS: Young adults with CF have compromised plate-like and axially aligned trabecular morphology and reduced connectivity between trabeculae. ITS analysis provides unique information about bone integrity, and these trabecular deficits may help explain the increased fracture risk in adults with CF not accounted for by BMD and/or traditional bone microarchitecture measurements. PMID- 26952012 TI - Lower incidence of postdural puncture headache using whitacre spinal needles after spinal anesthesia: A meta-analysis. AB - OBJECTIVE: The aim of this meta-analysis was to evaluate the postdural puncture headache after spinal anesthesia with Whitacre spinal needles compared with Quincke spine needles. METHODS: We searched several databases, including PubMed, Embase, ISI Web of Knowledge, and Cochrane Central Register of Controlled Trials until October 10th, 2014, for randomized controlled trials that compared spinal anesthesia with Whitacre spinal needles or Quincke spine needles for postdural puncture headache. Two reviewers independently screened the literature, assessed the risk for bias and extracted data. We used RevMan 5.3 software to perform the meta-analysis. Studies were included for the main end points if they addressed the following: frequency of postdural puncture headache, severity of postdural puncture headache as assessed by limitation of activities, and frequency of epidural blood patch. RESULTS: Nine randomized controlled trials were included for meta-analysis. The meta-analysis showed that spinal anesthesia with Whitacre spinal needles achieved lower incidence of postdural puncture headache(RR 0.34; 95% CI [0.22, 0.52]; P < .00001); in addition, the severity of postdural puncture headache was lower in the Whitacre spinal needle group (RR 0.32; 95% CI [0.16, 0.66]; P = .002). Furthermore, the frequency of an epidural blood patch in the Whitacre spinal needle group was lower compared with that in the Quincke spine needle group (RR 0.15; 95% CI [0.04, 0.51]; P = .002). CONCLUSION: We suggest the Whitacre spinal needles as a superior choice for spinal anesthesia compared with Quincke spine needles. PMID- 26952011 TI - Opioid doses required for pain management in lung cancer patients with different cholesterol levels: negative correlation between opioid doses and cholesterol levels. AB - BACKGROUND: Pain management has been considered as significant contributor to broad quality-of-life improvement for cancer patients. Modulating serum cholesterol levels affects analgesia abilities of opioids, important pain killer for cancer patients, in mice system. Thus the correlation between opioids usages and cholesterol levels were investigated in human patients with lung cancer. METHODS: Medical records of 282 patients were selected with following criteria, 1) signed inform consent, 2) full medical records on total serum cholesterol levels and opioid administration, 3) opioid-naive, 4) not received/receiving cancer-related or cholesterol lowering treatment, 5) pain level at level 5-8. The patients were divided into different groups basing on their gender and cholesterol levels. Since different opioids, morphine, oxycodone, and fentanyl, were all administrated at fixed low dose initially and increased gradually only if pain was not controlled, the percentages of patients in each group who did not respond to the initial doses of opioids and required higher doses for pain management were determined and compared. RESULTS: Patients with relative low cholesterol levels have larger percentage (11 out of 28 in female and 31 out of 71 in male) to not respond to the initial dose of opioids than those with high cholesterol levels (0 out of 258 in female and 8 out of 74 in male). Similar differences were obtained when patients with different opioids were analyzed separately. After converting the doses of different opioids to equivalent doses of oxycodone, significant correlation between opioid usages and cholesterol levels was also observed. CONCLUSIONS: Therefore, more attention should be taken to those cancer patients with low cholesterol levels because they may require higher doses of opioids as pain killer. PMID- 26952013 TI - [Changes in pelvic organ mobility and ligamentous laxity during pregnancy and postpartum. Review of literature and prospects]. AB - INTRODUCTION: The role of pregnancy in pelvic floor disorders occurrence remains poorly known. It might exist a link between changes in ligamentous laxity and changes in pelvic organ mobility during this period. Our objective was to conduct a non-systematic review of literature about changes in pelvic organ mobility as well as in ligamentous laxity during pregnancy and postpartum. METHODS: From the PubMed, Medline, Cochrane Library and Web of Science database we have selected works which pertains clinical assessment of pelvic organ mobility (pelvic organ prolapse quantification), ultrasound assessment of levator hiatus and urethral mobility, ligamentous laxity assessment during pregnancy and postpartum. RESULTS: Clinical assessments performed in these works show an increase of pelvic organ mobility and perineal distension during pregnancy followed by a recovery phase during postpartum. Pelvic floor imaging shows an increase of levator hiatus area and urethral mobility during pregnancy then a recovery phase in postpartum. Different authors also report an increase of ligamentous laxity (upper and lower limbs) during pregnancy followed by a decrease phase in postpartum. CONCLUSION: Pelvic organ mobility, ligamentous laxity, levator hiatus and urethral mobility change in a similarly way during pregnancy (increase of mobility or distension) and postpartum (recovery). LEVEL OF EVIDENCE: 3. PMID- 26952015 TI - Running to win or to be thin? An evaluation of body dissatisfaction and eating disorder symptoms among adult runners. AB - The current study evaluated associations between sport-performance-related body dissatisfaction (BD), general-appearance-related BD, and their relation to EAT-26 scores among a sample of adult runners who participated in middle- and long distance races in the northeastern United States (N=400, 46.5% male). Women reported elevated BD and eating disorder symptoms, as compared to men. Ridge regression was used to analyze correlations between appearance- and performance related BD with EAT-26 scores. Results demonstrated that appearance- and performance-related BD positively correlated with EAT-26 scores in women (betas=0.18 and 0.13, respectively). Race length was a significant covariate for women, such that those who ran middle-distance race events were more likely to report higher EAT-26 scores (beta=-3.12). These associations were not demonstrated in men. Results suggest that it is beneficial to address sport specific body image concerns, in addition to more general appearance-related body image concerns in female runners. PMID- 26952014 TI - Development and assessment of countermeasure formulations for treatment of lung injury induced by chlorine inhalation. AB - Chlorine is a commonly used, reactive compound to which humans can be exposed via accidental or intentional release resulting in acute lung injury. Formulations of rolipram (a phosphodiesterase inhibitor), triptolide (a natural plant product with anti-inflammatory properties), and budesonide (a corticosteroid), either neat or in conjunction with poly(lactic:glycolic acid) (PLGA), were developed for treatment of chlorine-induced acute lung injury by intramuscular injection. Formulations were produced by spray-drying, which generated generally spherical microparticles that were suitable for intramuscular injection. Multiple parameters were varied to produce formulations with a wide range of in vitro release kinetics. Testing of selected formulations in chlorine-exposed mice demonstrated efficacy against key aspects of acute lung injury. The results show the feasibility of developing microencapsulated formulations that could be used to treat chlorine-induced acute lung injury by intramuscular injection, which represents a preferred route of administration in a mass casualty situation. PMID- 26952016 TI - Relationship between self-discrepancy and worries about penis size in men with body dysmorphic disorder. AB - We explored self-discrepancy in men with body dysmorphic disorder (BDD) concerned about penis size, men without BDD but anxious about penis size, and controls. Men with BDD (n=26) were compared to those with small penis anxiety (SPA; n=31) and controls (n=33), objectively (by measuring) and investigating self-discrepancy: actual size, ideal size, and size they felt they should be according to self and other. Most men under-estimated their penis size, with the BDD group showing the greatest discrepancy between perceived and ideal size. The SPA group showed a larger discrepancy than controls. This was replicated for the perceptions of others, suggesting the BDD group internalised the belief that they should have a larger penis size. There was a significant correlation between symptoms of BDD and this discrepancy. This self-actual and self-ideal/self-should discrepancy and the role of comparing could be targeted in therapy. PMID- 26952017 TI - Facing Time in Ischemic Stroke: An Alternative Hypothesis for Collateral Failure. AB - Several randomized-controlled trials could recently demonstrate that ischemic stroke which is caused by large-cerebral-artery-occlusion can be treated effectively by endovascular recanalization. Among these studies, particularly the data from the ESCAPE study further corroborated the strong association between macrovascular pial collateral flow (before recanalization) and clinical outcome after recanalization. This review briefly gives an overview on these data and on the clinical key observations demonstrating this association in practice. Since the ischemic penumbra can only be sustained by collateral flow, the collapse of collateral blood flow or poor collateral filling, observed for example by DSA or CTA before recanalization, seems to be a primary cause of rapidly progressive infarction and futile therapeutic recanalization. However, it needs to be emphasized that the true cause-effect relationship between collateral failure and rapidly progressive infarction of the penumbra, i.e. the high probability of unfavorable clinical outcome despite recanalization, remains unclear. Along this line, an alternative hypothesis is offered viewing the collapse of collateral flow not as a cause but possibly as an inevitable secondary consequence of increasing peripheral/microvascular resistance during progressive infarction. PMID- 26952019 TI - Sampling errors in free energy simulations of small molecules in lipid bilayers. AB - Free energy simulations are a powerful tool for evaluating the interactions of molecular solutes with lipid bilayers as mimetics of cellular membranes. However, these simulations are frequently hindered by systematic sampling errors. This review highlights recent progress in computing free energy profiles for inserting molecular solutes into lipid bilayers. Particular emphasis is placed on a systematic analysis of the free energy profiles, identifying the sources of sampling errors that reduce computational efficiency, and highlighting methodological advances that may alleviate sampling deficiencies. This article is part of a Special Issue entitled: Biosimulations edited by Ilpo Vattulainen and Tomasz Rog. PMID- 26952018 TI - Differentiation of Hemangioblastoma from Metastatic Brain Tumor using Dynamic Contrast-enhanced MR Imaging. AB - PURPOSE: The aim of this study was to differentiate hemangioblastomas from metastatic brain tumors using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and compare the diagnostic performances with diffusion-weighted imaging (DWI) and dynamic susceptibility contrast magnetic resonance imaging (DSC MRI). METHODS: We retrospectively reviewed 7 patients with hemangioblastoma and 15 patients with metastatic adenocarcinoma with magnetic resonance imaging (MRI) including DWI, DSC-MRI, and DCE-MRI. Apparent diffusion coefficient (ADC), relative cerebral blood volume (rCBV), and DCE-MRI parameters (K trans, k ep, v e, and v p) were compared between the two groups. The diagnostic performance of each parameter was evaluated with receiver operating characteristic (ROC) curve analysis. RESULTS: v p, k ep, and rCBV were significantly different between patients with hemangioblastoma and those with metastatic brain tumor (p < 0.001, p = 0.005, and p = 0.017, respectively). A v p cutoff value of 0.012 and a rCBV cutoff value of 8.0 showed the highest accuracy for differentiating hemangioblastoma from metastasis. The area under the ROC curve for v p and rCBV was 0.99 and 0.89, respectively. A v p > 0.012 showed 100 % sensitivity, 93.3 % specificity, and 95.5 % accuracy and a rCBV > 8.0 showed 85.7 % sensitivity, 93.3 % specificity, and 90.9 % accuracy for differentiating hemangioblastoma from metastatic brain tumor. CONCLUSION: DCE-MRI was useful for differentiating hemangioblastoma from metastatic brain tumor. PMID- 26952022 TI - Strain-based fatigue data for Ti-6Al-4V ELI under fully-reversed and mean strain loads. AB - This article presents the experimental data supporting the study to obtain the mean strain/stress effects on the fatigue behavior of Ti-6Al-4V ELI. A series of strain-controlled fatigue experiments on Ti-6Al-4V ELI were performed at four strain ratios (-1, -0.5, 0, and 0.5). Two types of data are included for each specimen. These are the hysteresis stress-strain responses for the cycle in a log10 increment, and the maximum and minimum stress-strain responses for each cycle. Fatigue lives are also reported for all the experiments. PMID- 26952021 TI - Married women's decision making power on family planning use and associated factors in Mizan-Aman, South Ethiopia: a cross sectional study. AB - BACKGROUND: Women's use of family planning service is influenced by many factors, especially by their decision making power. A woman's decision-making power, be it individual or decision made in collaboration with a partner, is the most important factor in the use of family planning in a household. The purpose of this study was to assess the impact of women's decision making power on family planning use and its associated factors. METHODS: A community-based cross sectional study was conducted on married women in the child bearing age. The women who were living in Mizan city were selected using the simple random sampling method. Trained nurses collected the data by interview, using a structured and pre-tested questioner. Bivariable and multivariable binary logistic regression analysis was used to identify the associated factors, and the odds ratio with a 95% CI was computed to assess the strength of the association. Collinearity was also assessed by looking at standard errors in the final fitted model. RESULT: Overall, more than two-thirds [67.2%: 95% CI (63-71%)] of the married women were found to be more autonomous to decide family planning use. Secondary education [AOR: 9.04, 95% CI: (4.50, 18.16)], government employment [AOR: 4.84, 95% CI: (2.03, 11.52)], being wives of government employed spouses [AOR 2.71, 95% CI: (1.24, 7.97)], having husbands with college or university education [AOR: 11.29, 95% CI: (4.66, 27.35)], and being in the younger age [AOR: 0.27, 95% CI :(0.09, 0.75)] were significantly associated with women's decision making power on family planning. CONCLUSIONS: In this study, women had a high decision making power in family planning use. Age category (34-44-years), formal education, and occupational status had effects on women's decision making power. Promoting parental adult education and engaging women in out of house employment is essential to improve their decision making power in using family planning. PMID- 26952020 TI - Use of transient elastography in patients with HIV-HCV coinfection: A systematic review and meta-analysis. AB - BACKGROUND AND AIM: Patients with HIV-hepatitis C virus (HCV) coinfection progress towards liver fibrosis and cirrhosis more rapidly compared with HCV mono infected individuals. This necessitates an accurate assessment of liver stiffness with transient elastography to guide treatment. METHODS: Searches of PubMed, EMBASE, Web of Science, and the Cochrane Library databases were performed through January 2016 to assess the diagnostic accuracy of transient elastography for liver stiffness in the HIV-HCV population. Included studies were analyzed according to the Cochrane DTA Working Group methodology. Bivariate and hierarchical models were used to compute pooled sensitivity and specificity. Positive and negative likelihood ratios were also determined. A Fagan nomogram was constructed. Meta-regression analysis was performed with assessment of publication bias using Deeks' funnel plot asymmetry testing. RESULTS: A total of six studies (n = 756) met the inclusion criteria. The diagnostic accuracy of elastography for the diagnosis of moderate (>=F2) fibrosis was 88% (95% confidence interval [CI], 0.85-0.90). The pooled sensitivity and specificity of moderate fibrosis was 97% (95% CI, 0.82-0.91) and 64% (95% CI, 0.45-0.79), respectively. The diagnostic accuracy of elastography for the assessment of cirrhosis was 94% (95% CI, 0.91-0.95). The pooled sensitivity and specificity for cirrhosis was 90% (95% CI, 0.74-0.97) and 87% (95% CI, 0.80-0.92), respectively. Meta-regression analysis demonstrated that CD4 cell count did not impact diagnostic accuracy of elastography. CONCLUSIONS: Transient elastography is a noninvasive imaging modality with excellent ability to assess for cirrhosis in patients with HIV-HCV coinfection. PMID- 26952023 TI - Face value. PMID- 26952024 TI - Can affective instability complicate neuropsychiatric assessment? PMID- 26952025 TI - The recognition of facial expressions of emotion in Alzheimer's disease: a review of findings. AB - OBJECTIVE: To provide a selective review of the literature on the recognition of facial expressions of emotion in Alzheimer's disease (AD), to evaluate whether these patients show variation in their ability to recognise different emotions and whether any such impairments are instead because of a general decline in cognition. METHODS: A narrative review based on relevant articles identified from PubMed and PsycInfo searches from 1987 to 2007 using keywords 'Alzheimer's', 'facial expression recognition', 'dementia' and 'emotion processing'. CONCLUSION: Although the literature is as yet limited, with several methodological inconsistencies, AD patients show poorer recognition of facial expressions, with particular difficulty with sad expressions. It is unclear whether poorer performance reflects the general cognitive decline and/or verbal or spatial deficits associated with AD or whether the deficits reflect specific neuropathology. This under-represented field of study may help to extend our understanding of social functioning in AD. Future work requires more detailed analyses of ancillary cognitive measures, more ecologically valid facial displays of emotion and a reference situation that more closely approximates an actual social interaction. PMID- 26952026 TI - Addressing the burden of epilepsy: Many unmet needs. AB - Epilepsy is a heterogeneous clinical condition characterized by recurrent unprovoked seizures, their causes and complications. The incidence, prevalence and mortality of epilepsy vary with age, place and time contributing to a variable extent to the burden of the disease. Diagnostic misclassification may have strong impact on personal and societal reflections of the disease in light of its clinical manifestations and the need for chronic treatment. Epilepsy accounts for a significant proportion of the world's disease burden ranking fourth after tension-type headache, migraine and Alzheimer disease. Among neurological diseases, it accounts for the highest disability-adjusted life year rates both in men and in women. Although epilepsy is self-remitting in up to 50% of cases, variable long-term prognostic patterns can be identified based on the response to the available treatments. Epilepsy carries an overall increased risk of premature mortality with variable estimates across countries. Premature mortality predominates in patients aged less than 50 years, with epilepsies due to structural/metabolic conditions, with generalized tonic-clonic seizures, and seizures not remitting under treatment. Among deaths directly attributable to epilepsy or seizures, included are sudden unexpected death in epilepsy (SUDEP), status epilepticus, accidents, drowning, unintentional injuries, and suicide. Somatic and psychiatric disorders prevail in patients with epilepsy than in people without epilepsy. Asthma, migraine and cerebral tumors tend to occur more frequently in younger adults while cardiovascular disorders, stroke, dementia and meningioma predominate in the elderly. As being a fairly common clinical condition affecting all ages and requiring long-term (sometimes lifelong) treatment, epilepsy carries high health care costs for the society. Direct costs peak in the first year after diagnosis and then vary according to the severity of the disease, the response to treatment, and the presence of comorbidity. Although in several countries the costs of epilepsy are met by the national health systems, out-of-pocket costs may be a relevant fraction of the overall costs, especially in countries where the public management of health care is suboptimal or non-existent. Epilepsy strongly affects patients' independence, psychological health and emotional adjustment. Epilepsy impairs all aspects of health-related quality of life. Awareness and attitudes of the public about epilepsy may significantly affect the burden of the disease. All these factors add to the burden of the disease. However, many of the factors implicated in the onset of epilepsy, its course and treatment can be favorably addressed with appropriate strategic plans. More research is needed to investigate and manage the medical and psychosocial implications of epilepsy. PMID- 26952028 TI - Psychiatric symptoms and age dependency. AB - The growing populations of the elderly is frequently regarded as a homogeneous entity. In this retrospective study 140 patients above 60 years, first admitted to a psychiatric hospital, were screened for individual psychiatric symptoms. This was done according to the D.S.M.-III-R criteria and with the european ADMP IV scoring system. As expected dementia and related disorders are characteristic of the "older" categories, depressieve disorders were seen more frequently in the "younger" categories. Screening the elderly for psychiatric symptoms also shows differentiation within the group of the older patients. Symptoms related to dementia increase in frequency, also increasing are e.g. visual hallucinations. A decrease was found for hypochondriasis and phobia. So, the group patients above 60 years is clearly heterogeneous. PMID- 26952029 TI - Neuropsychiatry of corticosubcortical relations Aphasia and depression as paradigms. AB - In an introduction the evolution of a neuropsychological and neuropsychiatrie approach in the two last decades is discussed. The role of the basal ganglia, the thalamus and their cortical connections in aphasia is discussed. This review is given as a paradigm to demonstrate a neuropsychiatrie approach of psychiatric disorders. The role of corticosubcortical relations in depression is discussed. PMID- 26952030 TI - Serotoninergic findings in habitual violence and impulsivity. A review. AB - Several lines of evidence suggest that there may be abnormal brain serotonin metabolism in habitually biolent and impulsive offenders. These personality disorders are usually connected with early onset, male limited type 2 alcoholism in which one central feature is the abnormal tendency to behave aggressively and impulsively under the influence of alcohol repeatedly. Low CSF 5-HIAA has been found to correlate with familial alcoholism tendencies; paternal alcoholism. Both this and with it the tendency to abnormal oral glucose tolerance test (tendency to low blood glucose nadir) predict the new violent and impulsive crimes under the influence of alcohol. Also peripheral measures such as platelet MAO, abnormal tryptophan/LNAA ratio in plasma, whole blood serotonin, blood platelet uptake of serotonin, platelet 3H-IMI dinging (Bmax), abnormal prolactin and Cortisol secretion in fenfluramine challenge, and possibly daily urinary free Cortisol secretion correlate with impulsive aggressive behavior. PMID- 26952027 TI - Mid term results of total hip arthroplasty using polyethylene-ceramic composite (Sandwich) liner. AB - BACKGROUND: Ceramic-on-ceramic (COC) couplings are an attractive alternative bearing surfaces that have been reported to eliminate or reduce problems related to polyethylene wear debris. However, the material in total hip arthroplasty (THA) remains one of the major concern regarding the risk of fracture. The present study aims at reporting the fracture rate of bearings in a series of COC THAs with the use of a sandwich liner and attempt to detect the relative risk factors, the possible cause and assess the clinical results. MATERIALS AND METHODS: We retrospectively evaluated 153 patients (163 hips) using the sandwich liner COC THA between 2001 and 2009. Patient assessment was based on demographic factors, including age, weight, gender and body-mass index (BMI). All patients were evaluated clinically and radiographically or using computed tomography viz-a viz dislocation, osteolysis, periprosthetic fracture, infection, loosening and implant fracture. RESULTS: Three ceramic sandwich liners fracture (1.84%) were observed at an average of 7.3 years' followup. The factors which were found to be non-significant to the ceramic liner fracture, included age (P = 0.205), weight (P = 0.241), gender (P = 0.553), BMI (P = 0.736), inclination (P = 0.199) and anteversion (P = 0.223). The overall survival was 91.4% at 12-year with revision as the endpoint. Other complications included osteolysis in 4 (2.45%), dislocation in one and periprosthetic fracture in one. In no hip aseptic loosening of the implants was seen. CONCLUSIONS: Our experience with the ceramic polyethylene sandwich liner acetabular component has been disappointing because of the high rate of fracture and osteolyis. We have discontinued the use of this device and recommend the same. PMID- 26952031 TI - The tyramine conjugation test and depression. AB - In this article the value of the tyramine conjugation test (TCT) as a predictor of the response to antidepressive medication is reviewed. The TCT seems of little discomfort for the patient, is easy to perform and is suggested to have a high sensitivity and specificity. In addition, there are indications that a decreased tyamine conjugation could be a traitmarker for the vulnerability of depression. Hypotheses concerning the, as yet unclear etiology of the decreased tyramine are reviewed. PMID- 26952032 TI - Psychoffarmacologica IV. AB - Deze aflevering gaat over een probleem van naamgeving. Door de recente trends op het gebied van de indicatiestelling van psychofarmaca worden we meer en meer in de war gebracht. Uit het verloop van dit verhaal zult u wel zien waarom en de vraag is of u de redactie van advies wilt en kunt dienen. In de meeste farmacologische textboeken worden de psychofarmaca ingedeeld naar de klinische werking, zoais u weet, en drie hoofdgroepen worden onder-scheiden: de psychoanaleptica, de psycholeptica en de psychodysleptica. Hier zullen we ons beperken tot de eerste twee groepen. Tot de belangrijkste typen farmaca van de eerste groep worden de antidepressiva en soms de lithiumzouten gerekend en tot de tweede groep behoren de ataractica (zoals de ben-zodiazepinen) en de antipsychotica. Hoe verhoudt zieh zo'n indeling ten opzichte van andere farmaco therapeutische indelingen in de geneeskunde: worden eiders farmaca gerubrieeerd volgens de klinische indicaties of volgens de primaire aangrijpingspunten c.q. chemische karakteristie-ken? Soms volgt de indeling het werkingsprineipe, dan weer het ziektebeeld of symptoom, waarbij het middel het meest wordt toegepast. PMID- 26952033 TI - Brain Effective Connectivity Modeling for Alzheimer's Disease by Sparse Gaussian Bayesian Network. AB - Recent studies have shown that Alzheimer's disease (AD) is related to alteration in brain connectivity networks. One type of connectivity, called effective connectivity, defined as the directional relationship between brain regions, is essential to brain function. However, there have been few studies on modeling the effective connectivity of AD and characterizing its difference from normal controls (NC). In this paper, we investigate the sparse Bayesian Network (BN) for effective connectivity modeling. Specifically, we propose a novel formulation for the structure learning of BNs, which involves one L1-norm penalty term to impose sparsity and another penalty to ensure the learned BN to be a directed acyclic graph - a required property of BNs. We show, through both theoretical analysis and extensive experiments on eleven moderate and large benchmark networks with various sample sizes, that the proposed method has much improved learning accuracy and scalability compared with ten competing algorithms. We apply the proposed method to FDG-PET images of 42 AD and 67 NC subjects, and identify the effective connectivity models for AD and NC, respectively. Our study reveals that the effective connectivity of AD is different from that of NC in many ways, including the global-scale effective connectivity, intra-lobe, interlobe, and inter-hemispheric effective connectivity distributions, as well as the effective connectivity associated with specific brain regions. These findings are consistent with known pathology and clinical progression of AD, and will contribute to AD knowledge discovery. PMID- 26952034 TI - A novel short anionic antibacterial peptide isolated from the skin of Xenopus laevis with broad antibacterial activity and inhibitory activity against breast cancer cell. AB - A vastarray of bioactive peptides from amphibian skin secretions is attracting increasing attention due to the growing problem of bacteria resistant to conventional antibiotics. In this report, a small molecular antibacterial peptide, named Xenopus laevis antibacterial peptide-P1 (XLAsp-P1), was isolated from the skin of Xenopus laevis using reversed-phase high-performance liquid chromatography. The primary structure of XLAsp-P1, which has been proved to be a novel peptide by BLAST search in AMP database, was DEDDD with a molecular weight of 607.7 Da analysed by Edman degradation and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF/TOF-MS). The highlight of XLAsp-P1 is the strong in vitro potency against a variety of Gram positive and Gram-negative bacteria with minimum inhibitory concentrations (MICs) starting at 10 MUg/mL and potent inhibitory activity against breast cancer cell at tested concentrations from 5 to 50 MUg/mL. In addition, only 6.2 % of red blood cells was haemolytic when incubated with 64 MUg/mL (higher than MICs of all bacterial strain) of XLAsp-P1. The antimicrobial mechanism for this novel peptide was the destruction of the cell membrane investigated by transmission electron microscopy. All these showed that XLAsp-P1 is a novel short anionic antibacterial peptide with broad antibacterial activity and inhibitory activity against breast cancer cell. PMID- 26952036 TI - Analysis of silent information regulator 1 (SIRT1) gene polymorphisms in antituberculosis- drug-induced hepatotoxicity in a prospective cohort study. AB - OBJECTIVE: Antituberculosisdrug-induced hepatotoxicity (ATDH) is a common and sometimes serious side effect related to tuberculosis (TB) treatment. A number of risk factors and host genetics contribute to the development of ATDH. However, genetic factors of ATDH remain to be identified. Silent Information Regulator 1 (SIRT1), an essential metabolism gene, was proved to be involved in ATDH in mice. The aim of this investigation was to study the association between ATDH and tag single nucleotide polymorphisms (tag-SNPs) of the SIRT1 gene in a prospective cohort study in patients with TB. METHODS: 280 newly diagnosed TB patients were recruited in this study before starting first line anti-TB treatment and were followed up for 3 months after initiating anti-TB therapy. The tag-SNPs were selected by using Haploview 4.2 based on the HapMap database of Han Chinese Beijing. Genotyping was performed by polymerase chain reaction (PCR) and the Sequenom MassARRAY iPLEX platform. RESULTS: 24 (9.8%) of the 245 patients included in the final analysis developed hepatotoxicity during the following up period. No significant differences in the allele, genotype, or haplotype frequency distributions of the tag- SNPs (rs7069102, rs2273773, rs4746720) of the SIRT1 gene were identified between the ATDH and non-ATDH groups (all p > 0.05). CONCLUSIONS: The SIRT1 gene may not contribute to the risk for developing hepatotoxicity during anti-TB treatment in the Han Chinese population. PMID- 26952037 TI - Bioavailability, safety and immunogenicity of biosimilar infliximab (BOW015) compared to reference infliximab. AB - OBJECTIVES: To compare the single-dose pharmacokinetics (PK), safety, and immunogenicity of the biosimilar infliximab (BOW015) to reference infliximab (rIFX) in healthy volunteers and to establish bioequivalence. METHODS: In this randomized, double-blind, parallel-group, single-dose study, subjects received either BOW015 or rIFX. Both drugs were administered as a single IV 5 mg/kg dose over 2 hours on day 1. PK sampling occurred 10 times over 3 days and during safety and immunogenicity follow-up on day 4 and 1, 2, 3, 5, 7, 9, and 12 weeks after the infusion. RESULTS: Of the 84 healthy male Caucasian subjects randomized, 43 received BOW015 and 41 received rIFX. PK parameters (geometric mean) for BOW015 vs. rIFX were as follows; C(max) 142.47 vs. 126.74 MUg/mL, AUC(0 t) 36,211 vs. 34,304 h*MUg/mL, and AUC(0-inf) 36,775 vs. 34,801 h*MUg/mL. The point estimates of the BOW015/rIFX geometric mean ratios (90% CI) were; C(max) 1.13 (1.07 - 1.18), AUC(0-t) 1.06 (0.98 - 1.14), and AUC(0-inf) 1.06 (0.98 - 1.15). Overall, anti-drug antibodies were detected in 18.6% of BOW015-treated subjects and 24.4% of rIFX-treated subjects. A total of 26 (60.5%) subjects in the BOW015 group reported 50 treatment-emergent adverse events (TEAEs) and 27 (65.9%) subjects in the rIFX group reported 54 TEAEs. CONCLUSIONS: Bioequivalence of BOW015 to rIFX is demonstrated as 90% CIs for the study drug mean ratios of C(max), AUC(0-t), and AUC(0-inf) were within the log-transformed +/- 20% equivalence range of 0.80 - 1.25. Safety and immunogenicity were also comparable. PMID- 26952035 TI - Reproductive alterations in hyperinsulinemic but normoandrogenic MSG obese female rats. AB - Obesity and metabolic syndrome are the common causes of reproductive and fertility disorders in women. In particular, polycystic ovary syndrome, which is clinically characterized by hyperandrogenism, oligo/anovulation, and polycystic ovarian morphology, has been increasingly associated with metabolic disorders. However, given the broad interplay between metabolic and reproductive functions, this remains a field of intense research. In this study, we investigated the effect of monosodium l-glutamate (MSG)-induced obesity on reproductive biology of female rats. Newborn female rats were subcutaneously injected with MSG (4g/kg/day) or equiosmolar saline (CTR) each 2 days up to postnatal day (pnd) 10. On pnd 60, estrous cycle was evaluated using vaginal smears twice a day for 15 days, which showed MSG rats to be oligocyclic. Thereafter, animals were killed on estrous phase for blood and tissue collection. MSG rats had increased body mass, accumulation of retroperitoneal and visceral fat pads, and visceral adipocyte hypertrophy compared with CTR rats. MSG rats were also dyslipidemic and hyperinsulinemic but were normoglycemic and normoandrogenic. Ovarian morphology analysis showed that MSG rats had a two-fold decrease in oocyte count but a six fold increase on ovarian follicular cysts, along with a higher number of total primordial and atretic follicles. Moreover, MSG rats had a four-fold increase in anti-Mullerian hormone immunohistochemical staining on antral follicles. Taken together, data presented here characterize MSG obesity as a unique model to study the metabolic pathways underlying reproductive disorders in the absence of overactivated hypothalamic-pituitary-gonadal axis. PMID- 26952038 TI - Practical toolkit for monitoring endoscope reprocessing effectiveness: Identification of viable bacteria on gastroscopes, colonoscopes, and bronchoscopes. AB - BACKGROUND: Experts have recommended microbiologic surveillance by external reference laboratories for certain flexible endoscopes. There is currently insufficient evidence on the feasibility and utility of cultures. Researchers evaluated a preassembled toolkit for collecting and processing samples from endoscopes. METHODS: A pilot study was performed in a large academic medical center. A toolkit was used to aseptically sample biopsy ports and suction/biopsy channels of 5 gastroscopes, 5 colonoscopes, and 5 bronchoscopes after full reprocessing. Blinded specimens were packaged and transported on icepacks to a reference laboratory that used standard methodologies for microbial cultures. RESULTS: The laboratory detected bacteria in samples from 60% of patient-ready endoscopes, including gram-positive and gram-negative species. Viable microbes (<10 CFU) were recovered from 2 gastroscopes, 3 colonoscopes, and 4 bronchoscopes. Stenotrophomonas maltophilia and Delftia acidovorans were recovered from all 3 endoscope types. Subsequent environmental testing detected S maltophilia in the reprocessing rinse water. CONCLUSIONS: A preassembled toolkit facilitated the aseptic collection of samples for culturing by a reference laboratory that detected viable microbes on fully reprocessed endoscopes. Speciation allowed identification of potential pathogens and a possible common contamination source, demonstrating that microbial cultures may have value even when colony counts are low. PMID- 26952039 TI - Radiosensitization in esophageal squamous cell carcinoma: Effect of polo-like kinase 1 inhibition. AB - PURPOSE: This study examined the efficacy of polo-like kinase 1 (PLK1) inhibition on radiosensitivity in vitro and in vivo by a pharmacologic approach using the highly potent PLK1 inhibitor volasertib. METHODS AND MATERIALS: Human esophageal squamous cell carcinoma (ESCC) cell lines KYSE 70 and KYSE 150 were used to evaluate the synergistic effect of volasertib and irradiation in vitro using cell viability assay, colony formation assay, cell cycle phase analysis, and western blot, and in vivo using ectopic tumor models. RESULTS: Volasertib decreased ESCC cell proliferation in a dose- and time-dependent manner. Combination of volasertib and radiation caused G2/M cell cycle arrest, increased cyclin B levels, and induced apoptosis. Volasertib significantly enhanced radiation induced death in ESCC cells by a mechanism involving the enhancement of histone H3 phosphorylation and significant cell cycle interruption. The combination of volasertib plus irradiation delayed the growth of ESCC tumor xenografts markedly compared with either treatment modality alone. CONCLUSIONS: The in vitro results suggested that targeting PLK1 might be a viable approach to improve the effects of radiation in ESCC. In vivo studies showed that PLK1 inhibition with volasertib during irradiation significantly improved local tumor control when compared to irradiation or drug treatment alone. PMID- 26952041 TI - Editorial Commentary: Reprogramming autologous mesenchymal stem cells to regenerate the lost myocardium in chronic heart failure: Reboot and restore? PMID- 26952040 TI - Flap fixation reduces seroma in patients undergoing mastectomy: a significant implication for clinical practice. AB - BACKGROUND: Seroma formation is a common complication following mastectomy for invasive breast cancer. Mastectomy flap fixation is achieved by reducing dead space volume using interrupted subcutaneous sutures. METHODS: All patients undergoing mastectomy due to invasive breast cancer or ductal carcinoma in situ (DCIS) were eligible for inclusion. From May 2012 to March 2013, all patients undergoing mastectomy in two hospitals were treated using flap fixation. The skin flaps were sutured on to the pectoral muscle using polyfilament absorbable sutures. The data was retrospectively analysed and compared to a historical control group that was not treated using flap fixation (May 2011 to March 2012). RESULTS: One hundred and eighty patients were included: 92 in the flap fixation group (FF) and 88 in the historical control group (HC). A total of 33/92 (35.9%) patients developed seroma in the group that underwent flap fixation; 52/88 (59.1%) patients developed seroma in the HC group (p = 0.002). Seroma aspiration was performed in 14/92 (15.2%) patients in the FF group as opposed to 38/88 (43.2%) patients in the HC group (p < 0.001). CONCLUSIONS: Flap fixation is an effective surgical technique in reducing dead space and therefore seroma formation and seroma aspirations in patients undergoing mastectomy for invasive breast cancer or DCIS. PMID- 26952042 TI - Possible Rivaroxaban Failure during the Postpartum Period: An Alternative Viewpoint. PMID- 26952043 TI - The utilization of traditional, complementary and alternative medicine for non communicable diseases and mental disorders in health care patients in Cambodia, Thailand and Vietnam. AB - BACKGROUND: The purpose of our study was to determine the prevalence of traditional, complementary and alternative medicine (TCAM) use in patients with chronic diseases in lower Mekong countries. METHODS: A cross-sectional study was conducted in a health care setting using a random sample of 4799 adult patients (Mean age: 52.3 years, SD = 22.7) with chronic diseases in Cambodia, Vietnam and Thailand. The measure included the International Questionnaire to measure usage of complementary and alternative medicine (I-CAM). RESULTS: The 1 year prevalence of consulting TCAM providers was 26.0%; 27.0% in Cambodia, 26.3% in Thailand, 23.9% in Vietnam. The most commonly consulted TCAM providers were the herbalist (17.3%), massage therapist (6.0%), and acupuncturist (5.5%). For all different types of TCAM providers more than 80% of participants perceived the consultation as very or somewhat helpful. The own use of herbal medicine was 41.0%, own use of vitamins 26.5% and the own use of other supplements 9.7% in the past 12 months. The most common self-help practices in the past 12 months included praying for your own health (30.1%), meditation (13.9%) and relaxation techniques (9.9%). In multivariate logistic regression analyses, older age, rural residence and having two or more chronic conditions was associated with the use a TCAM provider; being female, urban residence, residing in Vietnam and having two or more chronic conditions was associated with the use of TCAM products; and being female, older age, rural residence, higher formal education, and residing in Cambodia was associated with the use of TCAM self-help practices. CONCLUSIONS: TCAM use is common among chronic disease patients in lower Mekong countries and is associated with several sociodemographic and disease specific factors. PMID- 26952046 TI - New Chiral Reagent for Installation of Pharmacophoric (S)- or (R)-2 (Alkoxyphosphono)-1-amino-2,2-difluoroethyl Groups. AB - A new chiral reagent has been developed for generalized installation of pharmacophoric (S)- or (R)-2-(alkoxyphosphono)-1-amino-2,2-difluoroethyl group into organic compounds. The original synthetic application of this new reagent is exemplified by Friedel-Crafts reactions with indoles, which proceed efficiently with excellent diastereoselectivity to give enantiomerically pure products. PMID- 26952045 TI - Kcne2 deletion attenuates acute post-ischaemia/reperfusion myocardial infarction. AB - AIMS: Most cardiac arrhythmia-associated genes encode ion channel subunits and regulatory proteins that are also expressed outside the heart, suggesting that diseases linked to their disruption may be multifactorial. KCNE2 is a ubiquitously expressed potassium channel beta subunit associated with cardiac arrhythmia, atherosclerosis, and myocardial infarction (MI) in human populations. Here, we tested the hypothesis that Kcne2 disruption in mice would influence the acute outcome of experimentally induced MI. METHODS AND RESULTS: One-year-old male Kcne2+/+ and Kcne2-/- mice were subjected to cardiac ischaemia/reperfusion injury (IRI) by left anterior descending coronary artery ligation. After reperfusion (3 h), infarct size and markers of tissue damage were quantified. Unexpectedly, post-reperfusion, Kcne2-/- mice exhibited 40% lower infarct size, decreased myocardial apoptosis and damage, and more than two-fold lower serum levels of damage markers, lactate dehydrogenase and creatine kinase, than Kcne2+/+ mice. Kcne2 deletion, despite increasing normalized heart weight and prolonging baseline QTc by 70%, helped preserve post-infarct cardiac function (quantified by a Millar catheter), with parameters including left ventricular maximum pressure, max dP/dt (P < 0.01), contractility index, and pressure/time index (P < 0.05) all greater in Kcne2-/- compared with Kcne2+/+ mice. Western blotting indicated two-fold-increased glycogen synthase kinase 3beta (GSK-3beta) phosphorylation (inactivation) before and after IRI (P < 0.05) in Kcne2-/- mice compared with Kcne2+/+ mice. GSK-3beta inhibition by SB216763 mimicked in Kcne2+/+ mice the cardioprotective effects of Kcne2 deletion, but did not further enhance them in Kcne2-/-mice, suggesting that GSK-3beta inactivation was a primary cardioprotective mechanism arising from Kcne2 deletion. CONCLUSIONS: Kcne2 deletion preconditions the heart, attenuating the acute tissue damage caused by an imposed IRI. The findings contribute further evidence that genetic disruption of arrhythmia-associated ion channel genes has cardiac ramifications beyond abnormal electrical activity. PMID- 26952044 TI - Carfilzomib reverses pulmonary arterial hypertension. AB - AIMS: Pulmonary arterial hypertension (PAH) remains a lethal disease with pronounced narrowing of pulmonary vessels due to abnormal cell growth. Agents that can reduce the pulmonary vascular thickness thus have therapeutic potential. The present study investigated the efficacy of carfilzomib (CFZ), a proteasome inhibitor and a cancer chemotherapeutic drug, on reversing PAH. METHODS AND RESULTS: In two rat models of PAH, SU5416/hypoxia and SU5416/ovalbumin, CFZ effectively reversed pulmonary vascular remodelling with the promotion of apoptosis and autophagy. In human pulmonary artery smooth muscle cells, knocking down mediators of autophagy attenuated CFZ-induced cell death. The cell death role of autophagy was promoted by the participation of tumour protein p53 inducible nuclear protein 1. CFZ increased the protein ubiquitination, and siRNA knockdown of ubiquitin inhibited cell death, suggesting that CFZ-induced cell death is ubiquitin-dependent. Mass spectrometry demonstrated the ubiquitination of major vault protein and heat shock protein 90 in response to CFZ. The siRNA knockdown of these proteins enhanced CFZ-induced cell death, revealing that they are cell survival factors. CFZ reduced right-ventricular pressure and enhanced the efficacy of a vasodilator, sodium nitroprusside. While no indications of CFZ toxicity were observed in the right ventricle of PAH rats, apoptosis was promoted in the left ventricle. Apoptosis was prevented by dexrazoxane or by pifithrin alpha without interfering with the efficacy of CFZ to reverse pulmonary vascular remodelling. CONCLUSION: The addition of anti-tumour agents such as CFZ along with cardioprotectants to currently available vasodilators may be a promising way to improve PAH therapy. PMID- 26952047 TI - Electromyographic Abnormalities Associated with Symptomatic Sacral Tarlov Cysts. AB - Tarlov or perineural cysts (TC) are commonly overlooked as a cause of sacral and ischial pain, and urogenital and bowel problems. TC can be seen on MRI, but are often considered asymptomatic. This is especially true for smaller cysts. Moreover, there are only few diagnostic characteristics that can be used to confirm that the cysts are the cause of the symptoms. As a consequence, a lot of controversy remains regarding the clinical importance of TC. Because of this underdiagnosed condition, patients often suffer for several years from unrecognized chronic neuropathic pain and neurological conditions. In this article, case reports of three patients with giant and smaller symptomatic sacral cysts are presented, in which electromyographic testing was performed to demonstrate nerve damage. We suggest that electromyography of the sacral nerve roots can be a reasonable tool for the diagnosis of symptomatic TC, as well as for the differentiation from other pathological entities causing sacral and ischial pain. Moreover, using electromyography it was also documented that smaller cysts of < 1 cm can cause nerve damage. Therefore incidence of symptomatic TC may be higher than initially thought. PMID- 26952048 TI - Growing Teratoma Syndrome After Treatment of a Nonseminomatous Germ Cell Tumor: A Case Report and a Review of Literature. AB - Growing teratoma syndrome is a rare condition among patients with nonseminomatous germ cell tumors who present with enlarging metastatic masses during appropriate systemic chemotherapy and normalized serum markers. Retroperitoneal residual masses are a common finding after chemotherapy for the nonseminomatous tumors of the testis. These might contain mature teratoma, fibrotic tissue, or tumor. Mature teratoma, which is unresponsive to chemotherapy, might result from evolution of a malignant lesion during treatment or it might represent a metastasis from a focus of mature teratoma in the primary testicular tumor. This article reviews a case of a growing teratoma syndrome. PMID- 26952049 TI - Patent Foramen Ovale and Migraine: Closing the Debate--A Review. AB - BACKGROUND: A link between patent foramen ovale (PFO) and migraine as well as the utility of closure of PFO and its effect on migraine have been subjects of debate. The present review is an effort to gather the available evidence on this topic and formulate recommendations. METHODS: A systematic search of electronic databases (Medline, Embase, Cochrane Library) was performed. A separate search in associated reference lists of identified studies was done. Observational studies and clinical trials published in English using the International Headache Society criteria for diagnosis of migraine were included in the analysis. The search was performed in 3 categories: prevalence of migraine in patients with PFO, prevalence of PFO in migraine patients, and effect of PFO closure and its effect on migraine. The quality of evidence and strength of recommendations during review of these studies was analyzed. RESULTS: About 14 observational studies with 2602 subjects who had PFO were identified. Migraine prevalence ranged from 16% to 64%. Another 20 studies reported 2444 patients with migraine; the prevalence of PFO ranged from 15% to 90%. About 20 observational studies (1194 patients) that examined the effect of PFO closure on migraine were identified. Resolution of migraine was reported in 10% to 83% of patients, improvement in 14% to 83%, no change in 1% to 54%, and worsening in 4% to 8%. The overall quality of these observational studies was poor. Finally, 3 randomized clinical trials included a total of 238 patients who underwent PFO closure compared with 234 patients in the control groups. All 3 trials failed to meet their primary end points defined as migraine resolution and greater than 50% reduction in migraine days at 1 year. In 2 of the clinical trials, there was some benefit noted in a small subset of migraine patients with aura, but the numbers were too small to extrapolate the findings to the general migraine population. CONCLUSIONS: There is no good quality evidence to support a link between migraine and PFO. Closure of PFO for migraine prevention does not significantly reduce the intensity and severity of migraine. We do not recommend the routine use of this procedure in current practice. PMID- 26952050 TI - Temporal structure of human magnetic evoked fields. AB - Nonlinear analysis of the multifocal cortical visual evoked potential has allowed the identification of neural generation of higher-order nonlinear components by magnocellular and parvocellular neural streams. However, the location of individual brain sources that make such contributions to these evoked responses has not been studied. Thus, an m-sequence pseudorandom stimulus system was developed for use in magnetoencephalographic (MEG) studies. Five normal young adults were recorded using an Elekta TRIUX MEG with 306 sensors. Visual stimuli comprised a nine-patch dartboard stimulus, and each patch fluctuated between two luminance levels with separate recordings carried out at low (24 %) and high (96 %) temporal contrast. Sensor-space analysis of MEG evoked fields identified components of the first- and second-order Wiener kernel decomposition that showed qualitative similarity with EEG-based cortical VEP recordings. The first slice of the second-order response (K2.1) was already saturated at 24 % contrast, while the major waveform of the second slice of the second-order response (K2.2) grew strongly with contrast, consistent with properties of the magnocellular and parvocellular neurons. Minimum norm estimates of cortical source localization showed almost simultaneous activation of V1 and MT+ activations with latencies only a little greater that those reported for first neural spikes in primate single cell studies. Time-frequency analysis of the kernel responses from five minimum norm estimate scout sources shows contributions from higher-frequency bands for the first compared with the second slice response, consistent with the proposed neural sources. In support of this magno/parvo break-up, the onset latencies of the K2.2 responses were delayed by approximately 30 ms compared with K2.1 responses. PMID- 26952051 TI - Role of brain hemispheric dominance in anticipatory postural control strategies. AB - Most of the cerebral functions are asymmetrically represented in the two hemispheres. Moreover, dexterity and coordination of the distal segment of the dominant limbs depend on cortico-motor lateralization. In this study, we investigated whether postural control may be also considered a lateralized hemispheric brain function. To this aim, 15 young subjects were tested in standing position by measuring center of pressure (COP) shifts along the anteroposterior axis (COP-Y) during dynamic posturography before and after continuous Theta Burst Stimulation (cTBS) intervention applied to the dominant or non-dominant M1 hand area as well as to the vertex. We show that when subjects were expecting a forward platform translation, the COP-Y was positioned significantly backward or forward after dominant or non-dominant M1 stimulation, respectively. We postulate that cTBS applied on M1 may have disrupted the functional connectivity between intra- and interhemispheric areas implicated in the anticipatory control of postural stability. This study suggests a functional asymmetry between the two homologous primary motor areas, with the dominant hemisphere playing a critical role in the selection of the appropriate postural control strategy. PMID- 26952058 TI - An issue of issues. PMID- 26952059 TI - The challenge of optimising research participation: paying participants in mental health settings. PMID- 26952060 TI - Electroconvulsive therapy versus transcranial magnetic stimulation for major depression: a review with recommendations for future research. AB - OBJECTIVE: To review the literature comparing electroconvulsive therapy (ECT) and transcranial magnetic stimulation (TMS) for major depression. METHODS: Data from the six randomised, prospective studies were agglutinated into one data set. Special attention was given to the methods of both TMS and ECT as well as data pertaining to differential outcomes in subgroups such as psychotic depressives and the elderly. RESULTS: There is a highly significant advantage for ECT in the prospective, randomised trials. The two non-randomised, retrospective comparative trials found the treatments to be equal in one study and superior for ECT in another. However, sample sizes are small in these studies, and both TMS and ECT may have been used suboptimally. Furthermore, the possibilities of differential efficacy of ECT or TMS for psychotic depressives or as a function of age have yet to be fully explored. CONCLUSIONS: The data to date do not support the contention that TMS is equivalent in efficacy to ECT. It is recommended that a large-scale trial be undertaken using aggressive forms of both TMS and ECT with sample sizes sufficiently large to detect effects of moderating variables such as age and psychosis status. PMID- 26952061 TI - Radiography Students' Learning: A Literature Review. AB - PURPOSE: To describe research methodology and findings concerning radiography students' learning. METHODS: Health sciences databases were searched to perform a traditional narrative literature review. Thirty-five peer-reviewed articles published between 2000 and 2014 were analyzed using thematic analysis. RESULTS: Specific methods of learning were found to be of the most interest. The studies focused primarily on the use and usability of a method or the students' general experiences of it. The most commonly studied methods were e-learning and interprofessional learning, which students perceived as positive methods for theoretical studies and clinical training. Students' learning regarding research was the focus of only one article reporting a wide variety of students' research interests. Most studies reported quantitative research gathered from questionnaires and surveys. CONCLUSIONS: Additional research, especially from a qualitative point of view, is needed to deepen the evidence-based knowledge of radiography student learning. PMID- 26952057 TI - NEWS for Africa: adaptation and reliability of a built environment questionnaire for physical activity in seven African countries. AB - BACKGROUND: Built environment and policy interventions are effective strategies for controlling the growing worldwide deaths from physical inactivity-related non communicable diseases. To improve built environment research and develop African specific evidence, it is important to first tailor built environment measures to African contexts and assess their psychometric properties across African countries. This study reports on the adaptation and test-retest reliability of the Neighborhood Environment Walkability Scale in seven sub-Saharan African countries (NEWS-Africa). METHODS: The original NEWS comprising 8 subscales measuring reported physical and social attributes of neighborhood environments was systematically adapted for Africa through extensive input from physical activity and public health researchers, built environment professionals, and residents in seven African countries: Cameroon, Ghana, Kenya, Mozambique, Nigeria, South Africa and Uganda. Cognitive testing of NEWS-Africa was conducted among diverse residents (N = 109, 50 youth [12 - 17 years] and 59 adults [22 - 67 years], 69 % from low socioeconomic status [SES] neighborhoods). NEWS-Africa was translated into local languages and evaluated for 2-week test-retest reliability in adult participants (N = 301; female = 50.2 %; age = 32.3 +/- 12.9 years) purposively recruited from neighborhoods varying in walkability (high and low walkable) and SES (high and low income) and from villages in six of seven participating countries. RESULTS: The original 67 NEWS items was expanded to 89 scores (76 individual NEWS items and 13 computed scales). Several modifications were made to individual items, and some new items were added to capture important attributes in the African environment. A new scale on personal safety was created, and the aesthetics scale was enlarged to reflect African specific characteristics. Over 95 % of all NEWS-Africa scores (items plus computed scales) demonstrated evidence of "excellent" (ICCs > .75 %) or "good" (ICCs = 0.60 to 0.74) reliability. Seven (53.8 %) of the 13 computed NEWS scales demonstrated "excellent" agreement and the other six had "good" agreement. No items or scales demonstrated "poor" reliability (ICCs < .40). CONCLUSIONS: The systematic adaptation and initial psychometric evaluation of NEWS-Africa indicates the instrument is feasible and reliable for use with adults of diverse demographic characteristics in Africa. The measure is likely to be useful for research, surveillance of built environment conditions for planning purposes, and to evaluate physical activity and policy interventions in Africa. PMID- 26952062 TI - Optimizing the Exposure Indicator as a Dose Management Strategy in Computed Radiography. AB - PURPOSE: To investigate a technique for optimizing radiation dose and image quality for a computed radiography system. METHODS: Entrance skin doses were measured for phantom models of the pelvis and lumbar spine imaged using the vendor's recommended exposure settings (ie, the reference doses) as well as doses above and below the vendor's recommended settings for both body parts. Images were assessed using visual grading analysis (VGA). RESULTS: The phantom dosimetry results revealed strong positive linear relationships between dose and milliampere seconds (mAs), mAs and inverse exposure indicator (EI), and dose and inverse EI for both body parts. The VGA showed that optimized values of 16 mAs/EI = 136 for the anteroposterior (AP) pelvis and 32 mAs/EI = 139 for the AP lumbar spine did not compromise image quality. DISCUSSION: Selecting optimized mAs reduced dose by 36% compared with the vendor's recommended mAs (dose) values. CONCLUSION: Optimizing the mAs and associated EIs can be an effective dose management strategy. PMID- 26952064 TI - The Pediatric Urinary Tract and Medical Imaging. AB - The pediatric urinary tract often is assessed with medical imaging. Consequently, it is essential for medical imaging professionals to have a fundamental understanding of pediatric anatomy, physiology, and common pathology of the urinary tract to provide optimal patient care. This article provides an overview of fetal development, pediatric urinary anatomy and physiology, and common diseases and conditions of the pediatric urinary tract. PMID- 26952065 TI - My Journey: Serving on the JRCERT Board of Directors. PMID- 26952063 TI - Medical Imaging of Neglected Tropical Diseases of the Americas. AB - Neglected tropical diseases are a group of protozoan, parasitic, bacterial, and viral diseases endemic in 149 countries causing substantial illness globally. Extreme poverty and warm tropical climates are the 2 most potent forces promoting the spread of neglected tropical diseases. These forces are prevalent in Central and South America, as well as the U.S. Gulf Coast. Advanced cases often require specialized medical imaging for diagnosis, disease staging, and follow-up. This article offers a review of epidemiology, pathophysiology, clinical manifestations, diagnosis (with special attention to medical imaging), and treatment of neglected tropical diseases specific to the Americas. PMID- 26952066 TI - Radiographic Techniques in the 45 degrees Posteroanterior Oblique Projection of the Hand. PMID- 26952067 TI - Advantages and Disadvantages of Screening Breast Ultrasonography. PMID- 26952068 TI - Occupational Exposure and Adverse Effects in the Radiologic Interventional Setting. PMID- 26952069 TI - Just-in-Time Teaching. PMID- 26952070 TI - Writing With Style. PMID- 26952071 TI - Expect the Unexpected. PMID- 26952072 TI - Increased Filtration and Image Receptor Exposure. PMID- 26952073 TI - In the Interest of Clarity. DBT Reimbursement. PMID- 26952074 TI - In the Interest of Clarity. Artful Insight. PMID- 26952075 TI - Narrow-minded. PMID- 26952076 TI - Regulatory Compliance in Mammography. AB - Although the Mammography Quality Standards Act (MQSA) passed when analog mammography and film processors were used across the United States, now most health care facilities have full-field digital mammography. This article reviews MQSA requirements including qualifications for personnel, the clinical image evaluation process, and components of a quality control program. In light of technological advances, the U.S. Food and Drug Administration's extension certificate for digital breast tomosynthesis is discussed, along with the American College of Radiology's Breast Imaging Center of Excellence designation and laws regarding density notification. PMID- 26952077 TI - Evidence of moderation effects in predicting active transport to school. AB - Background: Distance from home to school is an important influence on the decision to use active transport (AT); however, ecological perspectives would suggest this relationship may be moderated by individual, interpersonal and environmental factors. This study investigates whether (i) gender, (ii) biological maturation, (iii) perceived family support for physical activity (PA) and (iv) multiple deprivation moderate the relationship between distance to school and AT. Methods: A total of 611 children (11-12 years old, 334 females) were recruited from schools in Leicestershire, UK. Gender, family support for PA, and AT were self-reported. Home and school postcodes were used to determine multiple deprivation and distance to school (km). Predicted age at peak height velocity was used to indicate biological maturation. Results: Logistic regressions revealed the main effects explained 40.2% of the variance in AT; however; distance to school was the only significant predictor. Further analyses revealed that distance to school had a greater negative impact on the use of AT in late-maturing (OR: 3.60, CI: 1.45-8.96), less deprived (OR: 3.54, CI: 1.17 10.72) and children with low family support of PA (OR: 0.26, CI: 0.11-0.61). Conclusions: This study provides evidence that, although distance to school might be the strongest predictor of AT, this relationship is complex. PMID- 26952078 TI - Cost-Effectiveness of Opt-Out Chlamydia Testing for High-Risk Young Women in the U.S. AB - INTRODUCTION: In spite of chlamydia screening recommendations, U.S. testing coverage continues to be low. This study explored the cost-effectiveness of a patient-directed, universal, opportunistic Opt-Out Testing strategy (based on insurance coverage, healthcare utilization, and test acceptance probabilities) for all women aged 15-24 years compared with current Risk-Based Screening (30% coverage) from a societal perspective. METHODS: Based on insurance coverage (80%); healthcare utilization (83%); and test acceptance (75%), the proposed Opt Out Testing strategy would have an expected annual testing coverage of approximately 50% for sexually active women aged 15-24 years. A basic compartmental heterosexual transmission model was developed to account for population-level transmission dynamics. Two groups were assumed based on self reported sexual activity. All model parameters were obtained from the literature. Costs and benefits were tracked over a 50-year period. The relative sensitivity of the estimated incremental cost-effectiveness ratios to the variables/parameters was determined. This study was conducted in 2014-2015. RESULTS: Based on the model, the Opt-Out Testing strategy decreased the overall chlamydia prevalence by >55% (2.7% to 1.2%). The Opt-Out Testing strategy was cost saving compared with the current Risk-Based Screening strategy. The estimated incremental cost-effectiveness ratio was most sensitive to the female pre-opt out prevalence, followed by the probability of female sequelae and discount rate. CONCLUSIONS: The proposed Opt-Out Testing strategy was cost saving, improving health outcomes at a lower net cost than current testing. However, testing gaps would remain because many women might not have health insurance coverage, or not utilize health care. PMID- 26952079 TI - Evaluation of the first open-access hepatitis B and safe injection online training course for health professionals in China. AB - BACKGROUND: Despite the high prevalence of chronic hepatitis B virus (HBV) infection in China, HBV infection prevention and long-term care knowledge of health professionals is inadequate. To address this knowledge gap, we developed an open-access evidence-based online training course, "KnowHBV", to train health professionals on prevention of HBV transmission and safe injections. We conducted an evaluation of the course with health professionals in China to examine its effectiveness in improving knowledge and learner's satisfaction of the course. METHODS: Between July and December 2011, 1015 health professionals from selected hospitals and disease control institutions of Shandong province registered for the course and 932 (92 %) completed the three-module course. Participants' demographic information, pre- and post-course knowledge test results and learner's feedback were collected through the course website. RESULTS: Pre-course knowledge assessment confirmed gaps in HBV transmission routes, prevention and long-term care knowledge. Only 50.4 % of participants correctly identified all of the transmission routes of HBV, and only 40.7 % recognized all of the recommended tests to monitor chronically infected persons. The number of participants that answered all six multi-part multiple-choice knowledge questions correctly increased from 183 (19.7 %) before taking the course to 395 (42.4 %) on their first attempt upon completion of the course. Over 90 % of the 898 participants who completed the learner-feedback questionnaire rated the course as 'good' or 'very good'; over 94 % found the course instructional design helpful; 57.5 %, 65.7 % and 68.5 % reported that half or more than half of the course content in modules 1, 2 and 3 respectively provided new information; and 93.2 % of the participants indicated they preferred the online learning over traditional face to-face classroom learning. CONCLUSIONS: The "KnowHBV" online training course appears to be an effective online training tool to improve HBV prevention and care knowledge of the health professionals in China. PMID- 26952081 TI - Ionothermal synthesis of Fe3O4 magnetic nanoparticles as efficient heterogeneous Fenton-like catalysts for degradation of organic pollutants with H2O2. AB - Fe3O4 magnetic nanoparticles (MNPs) are attractive heterogeneous Fenton-like catalysts for oxidative degradation of organic pollutants with H2O2. Herein highly efficient and stable Fe3O4 MNPs (Fe3O4-op-DES, ca. 10nm) were successfully prepared via a novel oxidative precipitation-combined ionothermal synthesis, which comprised oxidative precipitation of FeSO4.7H2O in choline chloride:2urea deep eutectic solvent. Among five different Fe3O4 particles tested, Fe3O4-op-DES MNPs exhibited the highest catalytic activity with the activation energy of 47.6kJmol-1 for degradation of Rhodamine B (RhB) with H2O2 under the same conditions (Fe3O4 dosage of 0.50gL-1, H2O2 concentration of 40mmolL-1, pH 6.4, 55 degrees C, 2h). Fe3O4-op-DES MNPs were magnetically recoverable, and had good catalytic stability and recyclability without the need of regeneration (>98% degradation efficiency of RhB in 2h and pseudo-first-order rate constant of 0.0376min-1 after having been continuously running for 12h). The superior catalytic performance of Fe3O4-op-DES MNPs was attributed to the combination of multiple technologically important features, including the nanometer size, high Fe2+ content, large surface area, high density of surface active sites and stable crystal structure (no phase transformation, negligible iron leaching and particle aggregation after reaction). The wide applicability of Fe3O4-op-DES MNPs was also demonstrated by the degradation of four other organic pollutants. PMID- 26952080 TI - Benzimidazole covalent probes and the gastric H(+)/K(+)-ATPase as a model system for protein labeling in a copper-free setting. AB - Affinity probes are useful tools for determining molecular targets and elucidating mechanism of action for novel, bioactive compounds. In the case of covalent inhibitors, activity based probes are particularly valuable for ensuring acceptable selectivity margins. However, there is a variety of bioorthogonal chemistry reactions available for modifying compounds of interest with clickable tags. Here, we describe a direct comparison of tetrazine ligation and strain promoted azide-alkyne cycloaddition using benzimidazole based probes to bind their known target, the gastric proton pump, ATP4A. This study validates the use of chemical probes for target identification and illustrates the superior efficiency of tetrazine ligation for copper-free click systems. In addition, we have identified several novel binding partners of benzimidazole probes: Isoform 2 of deleted in malignant brain tumors 1 protein (DMBT1) and three uncharacterized proteins. PMID- 26952082 TI - Adsorption of linear alkylbenzene sulfonates on carboxyl modified multi-walled carbon nanotubes. AB - Understanding of the adsorption behavior of organic pollutants on carbon nanotubes (CNTs) and its governing factors are crucial for the assessment of transport and fate of organic pollutants. This study explored adsorption characteristics of linear alkylbenzene sulfonates (LAS) on carboxyl modified multi-walled carbon nanotubes (CMMWCNTs) and the effect of solution chemistry and temperature on LAS sorption. Results indicted LAS adsorption isotherms to display five distinct regions of sorption at 25 degrees C and 60 degrees C. Regardless of temperature, the adsorption isotherm of LAS on the CMMWCNTs was well described using the Freundlich equation. This result indicated heterogeneous distribution of adsorption sites on the CMMWCNT surface. At low initial LAS concentrations, below the critical micelle concentration, (2, 10 and 50mgL-1) LAS adsorption on the CMMWCNTs followed pseudo second-order kinetics. The highest LAS adsorption was observed at ionic strengths of 1.0molL-1 for NaCl; and 0.2molL-1 for both CaCl2 and MgCl2. However, LAS sorption was greatest in the presence of sodium divalent anion salts and at higher temperatures. These findings are of relevance to the fate and environmental risk of LAS in the presence of CMMWCNTs in high salinity wastewaters or effluents and brackish receiving surface water bodies (e.g., at estuaries). PMID- 26952083 TI - Diazo dye Congo Red degradation using a Boron-doped diamond anode: An experimental study on the effect of supporting electrolytes. AB - Diazo dye Congo Red (CR) solutions at 100mg/L, were degraded using different supporting electrolytes in an electrochemical advanced oxidation process (EAOPs), like the anodic oxidation (AOx/BDD). All experiments were carried out in a 3L flow reactor with a Boron-doped diamond (BDD) anode and stainless steel cathode (AISI 304), at 7.5, 15, 30 and 50mA/cm(2) current densities (j). Furthermore, each experiment was carried out under a flow rate of 7L/min. Additionally, HClO4, NaCl, Na2SO4, and H2SO4 were tested as supporting electrolytes at a 50mM concentration. The degradation process was at all times considerably faster in NaCl medium. Solutions containing SO4(2-) or ClO4(-) ions were less prompted to degradation due to the low oxidation power of these species into the bulk. Dissolved organic carbon (DOC) analysis, was carried out to evaluate the mineralization of CR. The degradation of CR, was evaluated with the HPLC analysis of the treated solutions. PMID- 26952084 TI - Selenite biotransformation and detoxification by Stenotrophomonas maltophilia SeITE02: Novel clues on the route to bacterial biogenesis of selenium nanoparticles. AB - A putative biosynthetic mechanism for selenium nanoparticles (SeNPs) and efficient reduction of selenite (SeO32-) in the bacterial strain Stenotrophomonas maltophilia SeITE02 are addressed here on the basis of information gained by a combined approach relying on a set of physiological, chemical/biochemical, microscopy, and proteomic analyses. S. maltophilia SeITE02 is demonstrated to efficiently transform selenite into elemental selenium (Se degrees ) by reducing 100% of 0.5mM of this toxic oxyanion to Se degrees nanoparticles within 48h growth, in liquid medium. Since the selenite reducing activity was detected in the cytoplasmic protein fraction, while biogenic SeNPs showed mainly extracellular localization, a releasing mechanism of SeNPs from the intracellular environment is hypothesized. SeNPs appeared spherical in shape and with size ranging from 160nm to 250nm, depending on the age of the cultures. Proteomic analysis carried out on the cytoplasmic fraction identified an alcohol dehydrogenase homolog, conceivably correlated with the biogenesis of SeNPs. Finally, by Fourier Transformed Infrared Spectrometry, protein and lipid residues were detected on the surface of biogenic SeNPs. Eventually, this strain might be efficaciously exploited for the remediation of selenite-contaminated environmental matrices due to its high SeO32- reducing efficiency. Biogenic SeNPs may also be considered for technological applications in different fields. PMID- 26952085 TI - A review on the distribution of Hg in the environment and its human health impacts. AB - In this letter, we have provided some recommendations on the article by Ki-Hyun Kim et al. that is published in the Journal of Hazardous Materials http://dx.doi.org/10.1016/j.jhazmat.2015.11.031. PMID- 26952086 TI - Rattling the developmental psychologist's cage? PMID- 26952087 TI - Giant kidney worms in a patient with renal cell carcinoma. AB - Dioctophyma renale (D. renale), or giant kidney worms, are the largest nematodes that infect mammals. Approximately 20 cases of human infection have been reported. We present a case of a 71-year-old man with a recent history of unintentional weight loss and painless haematuria, passing elongated erythematous tissue via his urethra. CT revealed a left renal mass with pulmonary nodules and hepatic lesions. On microscopy, the erythematous tissue passed was identified as D. renale. On subsequent renal biopsy, pathology was consistent with renal cell carcinoma. This is the first reported case of concomitant D. renale infection and renal cell carcinoma, and the second reported case of D. renale infection of the left kidney alone. PMID- 26952088 TI - The Impact of Fatigue on Baseball Pitching Mechanics in Adolescent Male Pitchers. AB - PURPOSE: To determine if shoulder and elbow kinematics, pitching velocity and accuracy, and pain change during a simulated baseball game in adolescent pitchers. METHODS: Adolescent male pitchers aged 13 to 16 years were included. Pitchers were excluded if they had undergone previous shoulder or elbow surgery, currently had a known shoulder or elbow injury, or were unable to complete the simulated game for any reason. Shoulder range of motion was assessed before and after the game. Velocity and accuracy were measured for every pitch, and every 15th pitch was videotaped from 2 orthogonal views in high definition at 240 Hz. Quantitative and qualitative mechanics were measured from these videos. Perceived fatigue and pain were assessed after each inning using a visual analog scale. Data were statistically analyzed using a repeated-measures analysis of variance. RESULTS: Twenty-eight elite adolescent pitchers were included. These pitchers, on average, were aged 14.6 +/- 0.9 years (mean +/- standard deviation), had been pitching for 6.3 +/- 1.7 years, and threw 94 +/- 58 pitches per week. Our experimental model functioned as expected in that pitchers became progressively more fatigued (0.3 +/- 0.6 to 3.5 +/- 2.1), had more pain (0.1 +/- 0.4 to 1.6 +/- 2.2), and pitched with a lower velocity (73 +/- 5 mph to 71 +/- 6 mph) as pitch number increased (P < .001, P = .001, and P < .001, respectively). Knee flexion at ball release progressively increased (49 degrees +/- 15 degrees to 53 degrees +/- 15 degrees ) with pitch number (P = .008). Hip-to-shoulder separation significantly decreased as pitch number increased, from 90% +/- 40% at pitch 15 to 40% +/- 50% at pitch 90 (P < .001). Upper extremity kinematics remained unchanged (P > .271 in all cases, 91% power for elbow flexion at ball release). External rotation and total range of motion in the pitching shoulder significantly increased after pitching (P = .007 and P = .047, respectively). CONCLUSIONS: As pitchers progress through a simulated game, they throw lower velocity pitches, become fatigued, and have more pain. Core and leg musculature becomes fatigued before upper extremity kinematics changes. CLINICAL RELEVANCE: On the basis of these results, there is the potential that core strengthening and leg strengthening may be valuable adjuncts to prevent upper extremity injury. Further studies specifically looking at this must be conducted. PMID- 26952090 TI - Lectures. PMID- 26952089 TI - Prognostic Factors in the Midterm Results of Pullout Fixation for Posterior Root Tears of the Medial Meniscus. AB - PURPOSE: To identify predictors of unfavorable clinical and radiologic outcomes a minimum of 5 years after pullout fixation for medial meniscus posterior root tears (MMPRTs). METHODS: In total, 40 patients who were followed for >5 years after pullout fixation in MMPRT were recruited. The mean follow-up duration was 71.1 months. Clinical outcomes, including Lysholm score and International Knee Documentation Committee (IKDC) score, and radiographic results, including Kellgren-Lawrence (K-L; 0/1/2/3/4) grade and medial joint space width, were evaluated preoperatively and at final follow-up. Preoperative prognostic factors, including age, sex, body mass index, degree of varus alignment, K-L grade, medial joint space width, meniscal extrusion, and cartilage status, by the modified Outerbridge classification (grades 1 or 2 v 3 or 4), for relatively unfavorable (fair or poor grade) Lysholm or IKDC score, and progression of K-L grade were investigated by multivariate logistic regression analysis. RESULTS: The mean Lysholm score (52.1 +/- 8.8 to 83.8 +/- 11.9) and IKDC score (40.1 +/- 7.6 to 73.3 +/- 10.9) were improved significantly (P < .001), although the loss of medial joint space width (4.8 +/- 1.1 to 3.9 +/- 1.1 mm) and K-L grade (6/25/9/0/0 to 0/11/20/9/0) progressed significantly (P < .001). Unfavorable prognostic factors of the Lysholm score were grade >=3 chondral lesions (odds ratio [OR] = 5.993; P = .028) and varus mechanical alignment (OR = 1.644; P = .017), for IKDC score were grade >=3 chondral lesions (OR = 11.146; P = .038) and older age (OR = 1.200; P = .017). Preoperative chondral lesion grade >=3 increased the risk of K-L grade progression (OR = 11.000; P = .031). CONCLUSIONS: Clinically, modified Outerbridge classification grade >=3 chondral lesions, varus alignment, and older age were found to predict a poor prognosis after MMPRT fixation. In terms of radiographic K-L grade progression, grade >=3 chondral lesions were identified as a poor prognostic factor. LEVEL OF EVIDENCE: Level IV, case series. PMID- 26952092 TI - Donepezil plasma concentrations, CYP2D6 and CYP3A4 phenotypes, and cognitive outcome in Alzheimer's disease. AB - PURPOSE: The purpose of the study is to evaluate whether donepezil (D) plasma concentrations and activity of CYP2D6 and CYP3A4 are associated with the therapeutic response of patients with mild to moderate Alzheimer's disease (AD). METHODS: This study comprised 54 patients affected by probable AD in therapy with D 10 mg/daily for at least 3 months. Plasma concentrations of D and its three main metabolites (6DD, 5DD, DNox) were assayed with a novel high performance liquid chromatography (HPLC) technique. Cognitive progression was assessed at baseline and at 9 months of follow-up with the mini mental state examination (MMSE). The activities of the two cytochromes involved in D metabolism-CYP2D6 and CYP3A4-were evaluated according to their metabolic ratios in plasma or urine, after test doses of probe drugs (dextromethorphan and omeprazole). RESULTS: A significant correlation was found between plasma levels of D and variations in MMSE scores after 9 months of therapy (r (2) = 0.14; p = 0.006). Neither the concentrations of D metabolites nor the metabolic ratios of CYP2D6 and CYP3A4 showed any correlations with cognitive variations. Low CYP2D6 activity and advanced age were associated with high D concentrations. Patients who were treated with CYP2D6 and P-glycoprotein (P-gp) inhibitors also had higher D plasma levels (mean difference = 19.6 ng/mL; p = 0.01) than those who were not. CONCLUSIONS: D plasma concentrations, but not cytochrome phenotyping, are associated with cognitive outcomes in AD patients. PMID- 26952093 TI - PI3K/AKT/mTOR inhibition in combination with doxorubicin is an effective therapy for leiomyosarcoma. AB - BACKGROUND: Leiomyosarcoma (LMS) is a common type of soft tissue sarcoma that responds poorly to standard chemotherapy. Thus the goal of this study was to identify novel selective therapies that may be effective in leiomyosarcoma by screening cell lines with a small molecule library comprised of 480 kinase inhibitors to functionally determine which signalling pathways may be critical for LMS growth. METHODS: LMS cell lines were screened with the OICR kinase library and a cell viability assay was used to identify potentially effective compounds. The top 10 % of hits underwent secondary validation to determine their EC50 and immunoblots were performed to confirm selective drug action. The efficacy of combination drug therapy with doxorubicin (Dox) in vitro was analyzed using the Calcusyn program after treatment with one of three dosing schedules: concurrent treatment, initial treatment with a selective compound followed by Dox, or initial treatment with Dox followed by the selective compound. Single and combination drug therapy were then validated in vivo using LMS xenografts. RESULTS: Compounds that targeted PI3K/AKT/mTOR pathways (52 %) were most effective. EC50s were determined to validate these initial hits, and of the 11 confirmed hits, 10 targeted PI3K and/or mTOR pathways with EC50 values <1 MUM. We therefore examined if BEZ235 and BKM120, two selective compounds in these pathways, would inhibit leiomyosarcoma growth in vitro. Immunoblots confirmed on target effects of these compounds in the PI3K and/or mTOR pathways. We next investigated if there was synergy with these agents and first line chemotherapy doxorubicin (Dox), which would allow for earlier introduction into patient care. Only combined treatment of BEZ235 and Dox was synergistic in vitro. To validate these findings in pre-clinical models, leiomyosarcoma xenografts were treated with single agent and combination therapy. BEZ235 treated xenografts (n = 8) demonstrated a decrease in tumor volume of 42 % whereas combining BEZ235 with Dox (n = 8) decreased tumor volume 68 % compared to vehicle alone. CONCLUSIONS: In summary, this study supports further investigation into the use of PI3K and mTOR inhibitors alone and in combination with standard treatment in leiomyosarcoma patients. PMID- 26952094 TI - Single low dose primaquine to reduce gametocyte carriage and Plasmodium falciparum transmission after artemether-lumefantrine in children with asymptomatic infection: a randomised, double-blind, placebo-controlled trial. AB - BACKGROUND: A single low dose (0.25 mg/kg) of primaquine is recommended as a gametocytocide in combination with artemisinin-based combination therapies for Plasmodium falciparum but its effect on post-treatment gametocyte circulation and infectiousness to mosquitoes has not been quantified. METHODS: In this randomised, double-blind, placebo-controlled trial, 360 asymptomatic parasitaemic children aged 2-15 years were enrolled and assigned to receive: artemether lumefantrine (AL) and a dose of placebo; AL and a 0.25 mg/kg primaquine dose; or AL and a 0.40 mg/kg primaquine dose. On days 0, 2, 3, 7, 10 and 14, gametocytes were detected and quantified by microscopy, Pfs25 mRNA quantitative nucleic acid sequence based amplification (QT-NASBA), and quantitative reverse-transcriptase PCR (qRT-PCR). For a subset of participants, pre- and post-treatment infectiousness was assessed by mosquito feeding assays on days -1, 3, 7, 10 and 14. RESULTS: Both primaquine arms had lower gametocyte prevalences after day 3 compared to the placebo arm, regardless of gametocyte detection method. The mean (95% confidence interval) number of days to gametocyte clearance in children with patent gametocytes on day 0 (N = 150) was 19.7 (14.6 - 24.8), 7.7 (6.3 - 9.1) and 8.2 (6.7 - 9.6) for the AL-placebo, the 0.25 mg/kg primaquine dose and the 0.40 mg/kg primaquine dose arms, respectively. While 38.0% (30/79) of selected gametocytaemic individuals were infectious before treatment, only 1/251 participant, from the AL-placebo group, infected mosquitoes after treatment. CONCLUSIONS: We observed similar gametocyte clearance rates after 0.25 and 0.40 mg/kg primaquine doses. Infectivity to mosquitoes after AL was very low and absent in primaquine arms. CLINICALTRIALS. GOV REGISTRATION: NCT01935882. PMID- 26952095 TI - Enteric Fever in a Multicultural Canadian Tertiary Care Pediatric Setting: A 28 Year Review. AB - We undertook a 28-year review of enteric fever at a large tertiary care pediatric center. Most cases occurred in children who visited friends and relatives in the Indian subcontinent, and there was significant antibiotic resistance. Documented vaccination rates were low, and many cases also had evidence of delays in diagnosis and treatment. PMID- 26952096 TI - Regulation of hamster sperm hyperactivation by extracellular Na. AB - Mammalian sperm motility has to be hyperactivated to be fertilization-competent. Hyperactivation is regulated by extracellular environment. Osmolality of mammalian semen is higher than that in female reproductive tract; however, the effect of them on hyperactivation has not been investigated. So we investigated the effect of osmotic environment on hyperactivation using hamster spermatozoa at first. Increase in the osmolality of the media (~370 mOsm) by increasing the concentration of NaCl (~150 mmol/L) caused the delay of the expression of hyperactivation. When NaCl concentration varied in the same range (75-150 mmol/L) whereas the osmolality was fixed at 370 mOsm by adding mannitol, the delay of hyperactivation occurred dependent on NaCl concentration. Increase in NaCl concentration also caused suppression of curvilinear velocity, bend angle, and sliding velocity of the flagellum at the onset of incubation, suggesting that NaCl concentration affect both activation and hyperactivation in hamster spermatozoa. Hamster sperm intracellular Ca(2+) concentration decreased as extracellular NaCl concentration increased, whereas membrane potential and intracellular pH were unaffected by extracellular NaCl concentration. SN-6 and SEA0400, inhibitors of Na(+)-Ca(2+) exchanger (NCX), increased intracellular Ca(2+) and accelerated hyperactivation in the presence of 150 mmol/L NaCl. Tyrosine phosphorylation on fibrous sheath proteins was unaffected by extracellular NaCl concentration. These results suggest that extracellular Na(+) suppresses hamster sperm hyperactivation by reducing intracellular Ca(2+) via an action of NCX in a tyrosine phosphorylation-independent manner. It seems that the removal of suppression by extracellular Na(+) leads to the expression of hyperactivated motility. PMID- 26952097 TI - BVDV alters uterine prostaglandin production during pregnancy recognition in cows. AB - Embryonic mortality in cows is at least in part caused by failure of pregnancy recognition (PR). Evidence has shown that bovine viral diarrhoea virus (BVDV) infection can disrupt pregnancy. Prostaglandins (PG) play important roles in many reproductive processes, such as implantation. The aim of this study was to investigate the effect of BVDV infection on uterine PG production and PR using an in vitro PR model. Bovine uterine endometrial cells isolated from ten BVDV-free cows were cultured and treated with 0 or 100ng/mL interferon-tau (IFNT) in the absence or presence of non-cytopathic BVDV (ncpBVDV). PGF2alpha and PGE2 concentrations in the spent medium were measured using radioimmunoassays, and in the treated cells expression of the genes associated with PG production and signalling was quantified using qPCR. The results showed that the IFNT challenge significantly stimulated PTGS1 and PTGER3 mRNA expression and PGE2 production; however, these stimulatory effects were neutralised in the presence of ncpBVDV infection. ncpBVDV infection significantly increased PTGS1 and mPGES1 mRNA expression and decreased AKR1B1 expression, leading to increased PGE2 and decreased PGF2alpha concentrations and an increased PGE2:PGF2alpha ratio. The other tested genes, including PGR, ESR1, OXTR, PTGS2, PTGER2 and PTGFR, were not significantly altered by IFNT, ncpBVDV or their combination. Our study suggests that BVDV infection may impair PR by (1) inhibiting the effect of IFNT on uterine PG production and (2) inducing an endocrine switch of PG production from PGF2alpha to PGE2 to decrease uterine immunity, thereby predisposing the animals to uterine disease. PMID- 26952098 TI - Brain pericytes serve as microglia-generating multipotent vascular stem cells following ischemic stroke. AB - BACKGROUND: Microglia are the resident macrophage population of the central nervous system (CNS) and play essential roles, particularly in inflammation mediated pathological conditions such as ischemic stroke. Increasing evidence shows that the population of vascular cells located around the blood vessels, rather than circulating cells, harbor stem cells and that these resident vascular stem cells (VSCs) are the likely source of some microglia. However, the precise traits and origins of these cells under pathological CNS conditions remain unclear. METHODS: In this study, we used a mouse model of cerebral infarction to investigate whether reactive pericytes (PCs) acquire microglia-producing VSC activity following ischemia. RESULTS: We demonstrated the localization of ionized calcium-binding adaptor molecule 1 (Iba1)-expressing microglia to perivascular regions within ischemic areas. These cells expressed platelet-derived growth factor receptor-beta (PDGFRbeta), a hallmark of vascular PCs. PDGFRbeta(+) PCs isolated from ischemic, but not non-ischemic, areas expressed stem/undifferentiated cell markers and subsequently differentiated into various cell types, including microglia-like cells with phagocytic capacity. CONCLUSIONS: The study results suggest that vascular PCs acquire multipotent VSC activity under pathological conditions and may thus be a novel source of microglia. PMID- 26952099 TI - Aspiration, but not injection, decreases cultured equine mesenchymal stromal cell viability. AB - BACKGROUND: Recently, equine multipotent mesenchymal stromal cells (MSC) have received significant attention as therapy for various conditions due to their proposed regenerative and immune-modulating capacity. MSC are commonly administered to the patient through a hypodermic needle. Currently, little information is available on the effect of such injection has on equine MSC immediate and delayed viability. We hypothesize that viability of equine MSC is not correlated with needle diameter during aspiration and injection. RESULTS: Using a 3 mL syringe, manual injection of equine cord blood (CB) or bone marrow derived (BM) MSC with no needle and needles ranging in size from 18 to 30 Ga did not affect immediate MSC viability. Similarly, 24 h post-injection, MSC delayed viability was not different between any of the tested needles as determined by a resazurin-based proliferation assay. Using a 3 mL syringe, aspiration of MSC through 20, 25, and 30 Ga needles resulted in significant decreases in immediate viability with no change in delayed viability when compared to aspiration without a needle. BM- and CB-MSC were observed to be of similar size with a diameter +/- SD of 19.8 +/- 2.7 and 20.4 +/- 2.2 MUm, respectively. In comparison, the smallest needles, (30 Ga) have an internal diameter of 160 MUm. CONCLUSIONS: Following injection, needle diameter did not affect immediate or delayed viability of equine MSC. Following aspiration through needles sizes 20 Ga and smaller, immediate viability, but not delayed viability, decreased. As a result, an 18 Ga or larger needle should be utilized for aspiration of cell suspensions. In contrast, needle selection for MSC injection should be based on clinical preference and experience rather than concerns over decreasing MSC viability. PMID- 26952100 TI - Prevalence of smoking before and during pregnancy and changes in this habit during pregnancy in Northwest Russia: a Murmansk county birth registry study. AB - BACKGROUND: Smoking during pregnancy leads to adverse maternal and birth outcomes. However, the prevalence of smoking among women in Russia has increased from < 5% in the 1980s to > 20% in the 2000s. We conducted a registry-based study in Murmansk County, Northwest Russia. Our aims were twofold: (i) assess the prevalence of smoking before and during pregnancy; and (ii) examine the socio demographic factors associated with giving up smoking or reducing the number of cigarettes smoked once pregnancy was established. METHODS: This study employs data from the population-based Murmansk County Birth Registry (MCBR) collected during 2006-2011. We used logistic regression to investigate associations between women's socio-demographic characteristics and changes in smoking habit during pregnancy. To avoid departure from uniform risk within specific delivery departments, we employed clustered robust standard errors. RESULTS: Of all births registered in the MCBR, 25.2% of the mothers were smokers before pregnancy and 18.9% continued smoking during pregnancy. Cessation of smoking during pregnancy was associated with education, marital status and parity but not with maternal age, place of residence, and ethnicity. Women aged <= 20-24 years had higher odds of reducing the absolute numbers of cigarettes smoked per day during pregnancy than those aged >= 30-34 years. Moreover, smoking nulliparae and pregnant women who had one child were more likely to reduce the absolute numbers of cigarettes smoked per day compared to women having >= 2 children. CONCLUSIONS: About 25.0% of smoking women in the Murmansk County in Northwest Russia quit smoking after awareness of the pregnancy, and one-third of them reduced the number cigarettes smoked during pregnancy. Our study demonstrates that women who have a higher education, husband, and are primiparous are more likely to quit smoking during pregnancy. Maternal age and number of children are indicators that influence reduction in smoking during pregnancy. Our findings are useful in identifying target groups for smoking intervention campaigns. PMID- 26952101 TI - The changing use of pediatric CT in Australia. AB - BACKGROUND: Despite the medical benefits of CT, there are concerns about increased cancer risks following CT scans in childhood. OBJECTIVE: To assess Australian temporal trends in pediatric CT scans funded through Medicare over the period 1985 to 2005, as well as changes in the types of CT scanners used. MATERIALS AND METHODS: We studied de-identified electronic records of Medicare funded services, including CT scans, that were available for children and adults younger than 20 years between 1985 and 2005. We assessed temporal trends using CT imaging rates by age, gender and anatomical region. Regulators provided CT scanner registration lists to identify new models installed in Australia and to date the introduction of new technologies. RESULTS: Between 1985 and 2005, 896,306 Medicare-funded CT services were performed on 688,260 individuals younger than 20 years. The imaging rate more than doubled during that time period. There were more than 1,000 CT scanners on registration lists during the study period. There were both a sharp increase in the availability of helical scanning capabilities from 1994 and significant growth in multi-detector CT scanners from 2000. CONCLUSION: Significant increases in the rate of pediatric CT scanning have occurred in Australia. This rate has stabilized since 2000, possibly a result of better understanding of cancer risks. PMID- 26952103 TI - Hoogsteen-position pyrimidines promote the stability and function of the MALAT1 RNA triple helix. AB - Triple-stranded RNA was first deduced to form in vitro more than 50 years ago and has since been implicated in RNA catalysis, stability, and small molecule binding. Despite the emerging biological significance of RNA triple helices, it remains unclear how their nucleotide composition contributes to their thermodynamic stability and cellular function. To investigate these properties, we used in vitro RNA electrophoretic mobility shift assays (EMSAs) and in vivo intronless beta-globin reporter assays to measure the relative contribution of 20 RNA base triples (N*A-U, N*G-C, N*C-G, N*U-A, and N*G-U) to triple-helical stability. These triples replaced a single internal U*A-U within the known structure of the triple-helical RNA stability element of human metastasis associated lung adenocarcinoma transcript 1 (MALAT1), which contains 10 major groove base triples. In addition to the canonical C*G-C triple, the noncanonical base triples U*G-C, U*G-U, C*C-G, and U*C-G exhibited at least 30% stability relative to the wild-type U*A-U base triple in both assays. Of these triples, only U*A-U, C*G-C, and U*G-C, when tested as four successive triples, formed stabilizing structures that allowed accumulation of the intronless beta-globin reporter. Overall, we find that Hoogsteen-position pyrimidines support triple helix stability and function and that thermodynamic stability, based on EMSA results, is necessary but not sufficient for stabilization activity of the MALAT1 triple helix in cells. These results suggest that additional RNA triple helices containing noncanonical triples likely exist in nature. PMID- 26952102 TI - Electroacupuncture preconditioning reduces ROS generation with NOX4 down regulation and ameliorates blood-brain barrier disruption after ischemic stroke. AB - BACKGROUND: Electroacupuncture (EA) is a modern application based on combination of traditional manual acupuncture and electrotherapy that is frequently recommended as an adjuvant treatment for ischemic stroke. EA preconditioning can ameliorate blood-brain barrier (BBB) dysfunction and brain edema in ischemia reperfusion injury; however, its mechanism remains unclear. This study investigated the preventive effects of EA preconditioning, particularly on BBB injury, followed by a transient middle cerebral artery occlusion (MCAO) model in mice. RESULTS: Mice were treated with EA (20 min) at Baihui (GV20) and Dazhui (GV14) acupoints once a day for 3 days before ischemic injury. Infarct volume, neurological deficits, oxidative stress, Evans blue leakage and brain edema were evaluated at 24 h after ischemia-reperfusion injury. EA preconditioning significantly decreased infarct volume and improved neurological function even after ischemic injury. In addition, both Evans blue leakage and water content were significantly reduced in EA preconditioned mice. Whereas the expression of tight junction proteins, ZO-1 and claudin-5, were remarkably increased by EA preconditioning. Mice with EA preconditioning showed the reduction of astrocytic aquaporin 4, which is involved in BBB permeabilization. In addition, we found that EA preconditioning decreased reactive oxygen species (ROS) in brain tissues after ischemic injury. The expression of NADPH oxidase 4 (NOX4), not NOX2, was significantly suppressed in EA preconditioned mice. CONCLUSIONS: These results suggest that EA preconditioning improve neural function after ischemic injury through diminishing BBB disruption and brain edema. And, the reduction of ROS generation and NOX4 expression by EA preconditioning might be involved in BBB recovery. Therefore, EA may serve as a potential preventive strategy for patients at high risk of ischemic stroke. PMID- 26952104 TI - The deadenylase components Not2p, Not3p, and Not5p promote mRNA decapping. AB - Decay of mRNA is essential for the efficient regulation of gene expression. A major pathway of mRNA degradation is initiated by the shortening of the poly(A) tail via the CCR4/NOT deadenylase complex. Deadenylation is followed by removal of the 5' cap (i.e., decapping) and then 5' to 3' exonucleolytic decay of the message body. The highly conserved CCR4/NOT deadenylase complex consists of the exonucleases CCR4 and POP2/CAF1, as well as a group of four or five (depending on organism) accessory factors of unknown function, i.e., the NOT proteins. In this study, we find thatSaccharomyces cerevisiaeNot2p, Not3p, and Not5p (close paralogs of each other) are involved in promoting mRNA decapping. Furthermore, we find that Not3p and Not5p bind to the decapping activator protein Pat1p. Together, these data implicate the deadenylase complex in coordinating the downstream decapping reaction via Not2p, Not3p, and Not5p. This suggests that the coupling of deadenylation with decapping is, in part, a direct consequence of coordinated assembly of decay factors. PMID- 26952106 TI - Phyllosphere Fungal Communities Differentiate More Thoroughly than Bacterial Communities Along an Elevation Gradient. PMID- 26952107 TI - Prevalence of respiratory viruses among children hospitalized from respiratory infections in Shenzhen, China. AB - BACKGROUND: The prevalence of local dominant viral etiologies is important for clinical management and prevention of common viral respiratory tract infections. Unfortunately, there is limited large-scale data about common viral respiratory infection in south China. To survey dominant viral etiology and seasonality of acute respiratory infections in hospitalized children, a 4-year consecutive study was conducted in Shenzhen, China. METHODS: Nasopharyngeal swab specimens were obtained from 30,443 hospitalized children younger than 14 years with respiratory tract diseases in Shenzhen Children's Hospital from January 2012 to December 2015. Nasopharyngeal swabs were routinely examined by direct immunofluorescence assay to detect respiratory agents including seven respiratory viruses. Data were analyzed to describe the frequency and seasonality. RESULTS: Of the 30,443 children enrolled in the study, 4428 (14.55 %) were positive for at least one viral pathogen, among whom 4110 (92.82 %) were <=3 years of age. The predominant viruses were respiratory syncytial virus (RSV, 68.11 %), adenovirus (ADV, 16.01 %) and parainfluenza virus 3 (PIV-3, 11.0 %). The common respiratory viruses detected peaked in the spring (17.69 %), and were minimal in autumn (9.73 %), but PIVs detection peaked in November. The common virus detection rate in male subjects (15.40 %) was significantly higher than in female subjects (13.02 %). PIVs detection rates were complementary with RSV in autumn in each year. CONCLUSIONS: This study demonstrated common respiratory viruses were the major cause of hospitalized acute respiratory infection (ARI) in children in Shenzhen, China. RSV was the most common detected infection, while ADV was the predominant pathogen in hospitalized children. These findings provide a better understanding of virus distribution among children of different ages, infection stratification by gender, and seasonality, all of which will contribute to modification of therapeutic approaches and development of effective prevention strategies for each respiratory virus infection during peak seasons. PMID- 26952108 TI - Integrate genome-based assessment of safety for probiotic strains: Bacillus coagulans GBI-30, 6086 as a case study. AB - Probiotics are microorganisms that confer beneficial effects on the host; nevertheless, before being allowed for human consumption, their safety must be verified with accurate protocols. In the genomic era, such procedures should take into account the genomic-based approaches. This study aims at assessing the safety traits of Bacillus coagulans GBI-30, 6086 integrating the most updated genomics-based procedures and conventional phenotypic assays. Special attention was paid to putative virulence factors (VF), antibiotic resistance (AR) genes and genes encoding enzymes responsible for harmful metabolites (i.e. biogenic amines, BAs). This probiotic strain was phenotypically resistant to streptomycin and kanamycin, although the genome analysis suggested that the AR-related genes were not easily transferrable to other bacteria, and no other genes with potential safety risks, such as those related to VF or BA production, were retrieved. Furthermore, no unstable elements that could potentially lead to genomic rearrangements were detected. Moreover, a workflow is proposed to allow the proper taxonomic identification of a microbial strain and the accurate evaluation of risk-related gene traits, combining whole genome sequencing analysis with updated bioinformatics tools and standard phenotypic assays. The workflow presented can be generalized as a guideline for the safety investigation of novel probiotic strains to help stakeholders (from scientists to manufacturers and consumers) to meet regulatory requirements and avoid misleading information. PMID- 26952109 TI - Hierarchical nanostructures of Au@ZnO: antibacterial and antibiofilm agent. AB - The perpetual use of antibiotics against pathogens inadvertently altered their genes that have translated into an unprecedented resistance in microorganisms in the twenty-first century. Many researchers have formulated bactericidal and bacteriostatic inorganic nanoparticle-based antiseptics that may be linked to broad-spectrum activity and far lower propensity to induce microbial resistance than organic-based antibiotics. Based on this line, herein, we present observations on microbial abatement using gold-based zinc oxide nanostructures (Au@ZnO) which are synthesized using hydrothermal route. Inhibition of microbial growth and biofilm using Au@ZnO is a unique feature of our study. Furthermore, this study evinces antimicrobial and antibiofilm mechanisms of photo-eradiated Au@ZnO by disruption of cellular functions and biofilms via reactive oxygen species (ROS)-dependent generation of superoxide anion radical. The present study is significant as it introduces novel functionalities to Au@ZnO in the biomedical field which can be extended to other species of microbial pathogens. PMID- 26952110 TI - K1K8: an Hp1404-derived antibacterial peptide. AB - As an alternative class of antimicrobial agents used to overcome drug-resistant infections, antimicrobial peptides (AMPs) have recently gained significant attention. In this study, we designed an improved antimicrobial peptide, K1K8, based on the molecular template of Hp1404. Compared to the wild-type Hp1404, K1K8 showed an improved antibacterial spectrum in vitro, a lower hemolytic activity, and an enhanced serum stability. Importantly, K1K8 also decreased methicillin resistant Staphylococcus aureus (MRSA) bacterial counts in the wounded region in a mouse skin infection model. Interestingly, K1K8 did not induce bacterial resistance or non-specific immune response reactions. Moreover, the peptide killed bacterial cells mainly by disrupting the bacterial membrane. In summary, K1K8 has the potential to be used as an improved anti-infection agent for topical use, which opens an avenue that potential anti-infection drugs may be designed and developed from the molecular templates of AMPs. PMID- 26952111 TI - Evasion of host antiviral innate immunity by HSV-1, an update. AB - Herpes simplex virus type 1 (HSV-1) infection triggers a rapid induction of host innate immune responses. The type I interferon (IFN) signal pathway is a central aspect of host defense which induces a wide range of antiviral proteins to control infection of incoming pathogens. In some cases, viral invasion also induces DNA damage response, autophagy, endoplasmic reticulum stress, cytoplasmic stress granules and other innate immune responses, which in turn affect viral infection. However, HSV-1 has evolved multiple strategies to evade host innate responses and facilitate its infection. In this review, we summarize the most recent findings on the molecular mechanisms utilized by HSV-1 to counteract host antiviral innate immune responses with specific focus on the type I IFN signal pathway. PMID- 26952112 TI - Bats in a Mediterranean Mountainous Landscape: Does Wind Farm Repowering Induce Changes at Assemblage and Species Level? AB - We reported data on flying bat assemblages in a Mediterranean mountain landscape of central Italy on a 5-year time span (2005-2010) where a wind farm repowering has been carried out (from 2009, 17 three-blade turbines substituted an a priori set of one-blade turbines). In 4 yearly based surveys, we calculated a set of univariate metrics at species and assemblage level and also performing a diversity/dominance analysis (k-dominance plots) to evaluate temporal changes. Nine species of bats were present (eight classified at species level, one at genus level). Number of detected taxa, Margalef richness, and Shannon-Wiener diversity apparently decreased between 2005-2007 (one-blade turbine period) and 2009-2010 (three-blade turbines period). We showed a weak temporal turnover only between 2007 and 2009. In k-dominance plots, the occurrence curves of the years before the new wind farming activity (2005 and 2007) were lower when compared to the curves related to the 2009 and 2010 years, suggesting an apparent stress at assemblage level in the second period (2009 and 2010). Myotis emarginatus and Pipistrellus pipistrellus significantly changed their relative frequency during the three-blade wind farming activity, supporting the hypothesis that some bats may be sensitive to repowering. Further research is necessary to confirm a possible sensitivity also for locally rare bats (Miniopterus schreibersii and Plecotus sp.). PMID- 26952113 TI - Prognostic Value of the Number of Retrieved Lymph Nodes in Pathological Nx or N0 Classical Papillary Thyroid Carcinoma. AB - BACKGROUND: This study evaluated the clinical implications of the number of retrieved central lymph nodes (LN) for the recurrence and recurrence-free survival (RFS) outcomes in patients with pathological Nx (pNx) or N0 classical papillary thyroid carcinoma (PTC). METHODS: In total, 464 patients were enrolled following total thyroidectomy with central LN dissection. The risk factors related to recurrence and RFS were evaluated and compared between these groups. RESULTS: Age, primary tumor size, and number of retrieved central LNs were independent risk factors for recurrence according to multivariate analysis (p < 0.05). The cut-off value for the number of retrieved central LNs related to recurrence was 4.5. Group 2 (pN0; >=5 nodes) demonstrated a significantly higher proportion of patients with an ablation-stimulated thyroglobulin (sTg) level <2.0 ng/mL (84.9 vs 61.1 %; p < 0.050) and control sTg level <1.0 ng/mL (92.1 vs 79.6 %; p < 0.050) in comparison with patients in group 1 (pNx or pN0; 1-4 nodes). Perioperative complication rates were comparable between groups. CONCLUSION: The number of retrieved central LNs is an independent risk factor for recurrence, even among patients with pNx or pN0 classical PTC. A thorough central LN dissection may therefore improve the long-term RFS rate. PMID- 26952114 TI - Major Cardiac Events After Non-cardiac Surgery. AB - INTRODUCTION: Postoperative cardiovascular complications might be difficult to assess and are known to be associated with longer hospital stay and increased costs as well as higher morbidity and mortality rates. The aim of this study was to evaluate the predictors for major cardiac events (MCE) after non-cardiac surgery. METHODS: The study included 4398 patients who were admitted to the Surgical Intensive Care Unit between January 1, 2006 and July 19, 2013. Acute physiology and chronic health evaluation II score and simplified acute physiology score (SAPS II) were calculated, and all variables entered as parameters were evaluated independently. Multivariate logistic regression analysis was performed to assess the independent factors for MCE. RESULTS: A total of 107 people experienced MCE. The independent predictors for postoperative MCE were higher fraction of inspired oxygen (FiO2) (odds ratio [OR] 38.97; 95 % confidence interval [CI] 10.81-140.36), history of ischemic heart disease (OR 3.38; 95 % CI 2.12-5.39), history of congestive heart disease (OR 2.39; 95 % CI 1.49-3.85), history of insulin therapy for diabetes (OR 2.93; 95 % CI 1.66-5.19), and increased SAPS II (OR 1.03; 95 % CI 1.01-1.05). Having a MCE was associated with a longer length of stay in the surgical intensive care unit (OR 1.01, 95 % CI 1.00-1.01). CONCLUSIONS: FiO2, ischemic heart disease, congestive heart disease, insulin therapy for diabetes, SAPS II, and length of stay in the surgical intensive care unit were independent predictors for MCE. PMID- 26952115 TI - Quantifying Intraoperative Workloads Across the Surgical Team Roles: Room for Better Balance? AB - BACKGROUND: Surgical performance, provider health, and patient safety can be compromised when workload demands exceed individual capability on the surgical team. The purpose of this study is to quantify and compare intraoperative workload among surgical team members. METHODS: Observations were conducted for an entire surgical day for 33 participating surgeons and their surgical team at one medical institution. Workload (mental, physical, case complexity, distractions, and case difficulty) was measured for each surgical team member using questions from validated questionnaires. Statistical analyses were performed with a mixed effects model. RESULTS: A total of 192 surgical team members participated in 78 operative cases, and 344 questionnaires were collected. Procedures with high surgeon mental and physical workload included endovascular and gastric surgeries, respectively. Ratings did not differ significantly among surgeons and residents, but scrub nurses physical demand ratings were 14-22 (out of 100) points lower than the surgeons, residents, and surgical assistants. Residents reported the highest mental workload, averaging 19-24 points higher than surgical assistants, scrub nurses, and circulating nurses. Mental and physical demands exceeded 50 points 28-45 % of the time for surgeons and residents. Workload did not differ between minimally invasive and open techniques. CONCLUSION: The workload questionnaires are an effective tool for quantifying intraoperative workload across the surgical team to ensure mental and physical demands do not exceed thresholds where performance may decrease and injury risk increase. This tool has the potential to measure the safety of current procedures and drive design of workload interventions. PMID- 26952116 TI - Unbound Bilirubin and Auditory Neuropathy Spectrum Disorder in Late Preterm and Term Infants with Severe Jaundice. AB - OBJECTIVE: This study evaluates whether unbound bilirubin is a better predictor of auditory neuropathy spectrum disorder (ANSD) than total serum bilirubin (TSB) or the bilirubin:albumin molar ratio (BAMR) in late preterm and term neonates with severe jaundice (TSB >=20 mg/dL or TSB that met exchange transfusion criteria). STUDY DESIGN: Infants >=34 weeks' gestation with severe jaundice during the first 2 weeks of life were eligible for the prospective observational study. A comprehensive auditory evaluation was performed within 72 hours of peak TSB. ANSD was defined as absent or abnormal auditory brainstem evoked response waveform morphology at 80-decibel click intensity in the presence of normal outer hair cell function. TSB, serum albumin, and unbound bilirubin were measured using the colorimetric, bromocresol green, and modified peroxidase method, respectively. RESULTS: Five of 44 infants developed ANSD. By logistic regression, peak unbound bilirubin but not peak TSB or peak BAMR was associated with ANSD (OR, 4.6; 95% CI, 1.6-13.5; P = .002). On comparing receiver operating characteristic curves, the area under the curve for unbound bilirubin (0.92) was significantly greater (P = .04) compared with the area under the curve for TSB (0.50) or BAMR (0.62). CONCLUSIONS: Unbound bilirubin is a more sensitive and specific predictor of ANSD than TSB or BAMR in late preterm and term infants with severe jaundice. PMID- 26952117 TI - A Risk Score for Childhood Obesity in an Urban Latino Cohort. AB - OBJECTIVE: To assess whether individual obesity risk factors, present during gestation, and the first 6 months of life, can be combined into a simple prognostic model that has the ability to accurately predict childhood obesity at age 5 years in a high-risk cohort. STUDY DESIGN: A total of 201 Latina women were recruited during pregnancy, and their infants followed longitudinally. Ten risk factors for childhood obesity were included in an initial logistic model; a second reduced model was created via stepwise deletion (confirmed with nonparametric conditional random forest classifier), after which 5 risk factors remained. From each model, an obesity risk equation was derived, and an obesity risk score was generated for each patient. Derived algorithms were assessed using discrimination, calibration, and via predictive statistics. RESULTS: Of the 166 children followed through age 5 years, 56 (32%) met criteria for childhood obesity. Discrimination accuracy for both derivation models was excellent, and after optimism-corrected bootstrapping, both models showed meaningful clinical performance. Both models were adequately calibrated, showed strong sensitivity and negative predictive value at conservatively set obesity risk thresholds, and displayed excellent specificity among those classified as highest risk. Birth weight z-score and change in weight-for-age z-score between birth and 6 months were the risk factors with the strongest contribution to the obesity risk score. CONCLUSIONS: Obesity risk algorithms are reliable in their prediction of childhood obesity and have the potential to be integrated into the electronic medical record. These models could provide a filter for directing early prevention resources to children with high obesity risk but should be evaluated in a larger external dataset. PMID- 26952118 TI - Factors influencing the outcome of deep brain stimulation: Placebo, nocebo, lessebo, and lesion effects. AB - Deep brain stimulation (DBS) is a well-established treatment option for movement disorders, especially for Parkinson's disease (PD). There is a need to determine the role of expectation of benefit and the use of placebo to better understand the effects of electrode placement including the (micro)lesion effect. These factors must be understood to better interpret and attribute the therapeutic value of DBS. In this review, we critically present currently available data on the placebo, nocebo, lessebo, and lesion effects in the context of DBS. We provide a discussion of strategies that have the potential for controlling these effects in the setting of future DBS trials. We conclude that there is a need to standardize definitions for nocebo and (micro)lesion effects and that there are intrinsic limitations in defining the effect of expectation of benefit in DBS. These issues will be challenging to overcome especially with current technology and available study designs. New stimulation paradigms, better study designs, and the use of adaptive closed-loop DBS devices may facilitate a more accurate assessment of the placebo, nocebo, and lessebo effects in future DBS trials. PMID- 26952119 TI - Corrigenda: Eldad Melamed 1942-2015: Ave atque--A memorial. PMID- 26952120 TI - Corrigenda: Minor hallucinations occur in drug-naive Parkinson's disease patients, even from the premotor phase. PMID- 26952121 TI - "Basket weave technique" for medial patellofemoral ligament reconstruction: Clinical outcome of a prospective study. AB - BACKGROUND: Bone tunneling and implants with rigid fixations for medial patellofemoral ligament (MPFL) reconstruction are known to compromise results and are avoidable, especially in skeletally immature subjects. This study was to assess if these deficiencies were overcome with the technique devised by the author which avoids implants and bone tunnels. Results were assessed for complication rate and outcome. MATERIALS AND METHODS: Fifty six knees of recurrent lateral patellar dislocation were treated in the past 49 months by MPFL reconstruction. Thirty nine were female and 17 male knees. The mean age was 20.6 years (range 9-48 years). Mean followup was 26 months. Five knees had previously failed stabilization procedures. Thirty one cases had Dejours Type A or B and 12 had Type C trochlear dysplasia. Arthroscopy was performed for associated injuries and loose bodies. Seven knees required loose body removal. Five knees underwent lateral retinacular release. Four knees had tibial tuberosity transfer. One knee had an associated anterior cruciate ligament reconstruction. An anatomical MPFL reconstruction was performed using hamstring autograft without the need for intraoperative fluoroscopy. Only soft tissue fixation was necessary with this newly devised technique and suturing. A rapid rehabilitation protocol was implemented with monthly followup until normalcy and 6 monthly thereafter. RESULTS: All achieved full range of motion and normal mediolateral stability. There was no recurrence of dislocation. No major surgery related complications. One patella fracture at 8 months was due to a fall developed terminal restriction of flexion. Those in sports could return to their sporting activities (Tegner 1 9). Cases with osteochondral fractures had occasional pain that subsided in 1 year. Mean Kujala score improved from 64.3 to 99.69 with KOOS score near normal in all. CONCLUSION: This new method of MPFL reconstruction gives excellent results. It avoids complications related to bone tunneling and implants. It is a safe, effective, reliable and reproducible technique. PMID- 26952122 TI - [Glucocorticoids as an adjunct in peripheral regional anesthesia. Move to the "Holy Grail of perineural analgesia"?!]. AB - BACKGROUND: The role of dexamethasone as an adjunct in peripheral nerve blockades is still unclear. OBJECTIVES: This article reviews the actual knowledge and scientific evidence for dexamethasone as an adjunct in peripheral regional anesthesia. Moreover, it discusses the benefits of the systemic versus the perineural mode of application. RESULTS: Dexamethasone prolongs sensible as well as motor blockades in peripheral nerve blocks when applied intravenously or perineurally. Regarding potentially local neurotoxicity, published patient data are not sufficient for final conclusions. CONCLUSIONS: After reviewing the actual literature, the authors prefer a systemic application mode (intravenously) over a perineural route of administration of dexamethasone as an adjunct for peripheral nerve blocks. This is due to the better understanding of potential side effects of the drug when applied intravenously. Dexamethasone might be a useful drug adjunct to prolong peripheral single shot nerve blocks. PMID- 26952123 TI - [Emergency departments--2016 update]. AB - Acute medical care in hospital emergency departments has experienced rapid development in recent years and gained increasing importance not only from a professional medical point of view but also from an economic and health policy perspective. The present article therefore provides an update on the situation of emergency departments in Germany. Care in emergency departments is provided with an increasing tendency to patients of all ages presenting with varying primary symptoms, complaints, illnesses and injury patterns. In the process, patients reach the emergency department by various routes and structural provision. Cross sectional communication and cooperation, prioritization and organization of emergency management and especially medical staff qualifications increasingly play a decisive role in this process. The range of necessary knowledge and skills far exceeds the scope of prehospital medical emergency care and the working environment differs substantially. In addition to existing structural and economic problems, the latest developments, as well as future proposals for the design of in-hospital emergency medical care in interdisciplinary emergency departments are described. PMID- 26952124 TI - Society of Interventional Radiology Position Statement: Staffing Guidelines for the Interventional Radiology Suite. PMID- 26952125 TI - The Influence of Flush Methods on Transfemoral Catheter Cerebral Angiography: Continuous Flush versus Intermittent Flush. AB - PURPOSE: To evaluate the influence of different flush methods on transfemoral cerebral angiography (TFCA). MATERIALS AND METHODS: This single-blind randomized controlled trial included 50 patients who had undergone TFCA. Balanced block randomization was used to allocate participants into intermittent-flush (n = 25) and continuous-flush (n = 25) groups. Differences in procedure duration, amounts of contrast medium and heparinized saline used, heparin dose, blood loss, fluoroscopy time, radiation dose, and occurrence of new embolic signal (NES) on diffusion-weighted imaging (DWI) were compared between the two groups. RESULTS: The procedure duration was shorter in the continuous-flush group (mean 26.5 min +/- 3.7) than in the intermittent-flush group (mean 29.6 min +/- 2.8) (P = .004). Amounts of injected contrast medium (mean 20.2 mL +/- 4.4 vs 57.1 mL +/- 9.0), wasted heparinized saline (mean 19.8 mL +/- 9.6 vs 92.3 mL +/- 16.7), and aspirated blood (mean 4.7 mL +/- 1.3 vs 13.2 mL +/- 2.9) were lower in the continuous-flush group than in the intermittent-flush group (P < .001). The amount of injected (or infused) heparinized saline, heparin dose, fluoroscopy time, radiation dose, and occurrence of NES on DWI did not differ between the groups (P > .05). CONCLUSIONS: The use of continuous flushing during TFCA reduced the procedure time, amount of contrast medium needed, amount of wasted heparinized saline, and blood loss, but no difference in the occurrence of NES on DWI was noted between the groups. PMID- 26952126 TI - Levator lengthening technique using cartilage or fascia graft for paralytic lagophthalmos in facial paralysis. AB - INTRODUCTION: Lid loading using gold weights has been commonly used to treat paralytic lagophthalmos (PL); however, the procedure has a relatively high complication rate and the availability of these plates varies among social circumstances. We used a levator lengthening (LL) technique, which originally elongated the levator aponeurosis by inserting a fascia graft between the edge of the levator aponeurosis and the tarsal plate. However, because this procedure tends to result in a wide residual lagophthalmos, we changed the graft material from fascia to conchal cartilage. In this study, we describe in detail our experience with LL using the cartilage graft. METHODS: LL was performed in 18 patients with PL. Fascia grafts were used in seven patients and cartilage grafts in 11. Static reconstructions of the lower eyelid and eyebrow were also performed in most patients. Efficacy was evaluated from patient reports of ocular symptoms and by measuring the palpebral fissure width at opening and closing for both eyes. RESULTS: All patients experienced improved ophthalmological symptoms, which were more apparent in cartilage cases. The average palpebral fissure at eyelid closure was 1.8 mm in cartilage cases and 4.0 mm in fascia cases. In cases where an eyebrow lift was concurrently performed, the residual lagophthalmos became wider in fascia grafting but remained acceptable in cartilage grafting. DISCUSSION: LL is a simple and useful procedure for treating PL with higher efficacy when a cartilage graft is used. However, the level of the upper eyelid can be easily adjusted by changing the fixation position of the cartilage. Additional experience is required to obtain more consistent outcomes. PMID- 26952127 TI - Assessing psychological distress in patients with facial paralysis using the Hospital Anxiety and Depression Scale. AB - OBJECTIVES: Anxiety and depression are seen among patients with facial paralysis (FP), but less is known about the exact prevalence. The aim of the current study is to assess the prevalence of anxiety and depressive disorders in the FP population and to investigate possible differences between patients with left- and right-sided FP. METHODS: Fifty-nine patients with FP and 59 healthy individuals were included in this study between March and December of 2014. The Hospital Anxiety and Depression Scale was used to assess the prevalence of anxiety and depression among these groups. RESULTS: The mean age of the patients and controls was 56 +/- 15 and 40 +/- 16 years, respectively. Twenty-eight patients had left-sided FP, 30 patients had right-sided FP, and one patient had bilateral FP. In the patient group, approximately 30% had anxiety and 25% had a depressive disorder. Compared with the control group, significantly more patients presented with mild anxiety (p = 0.031), mild depression (p = 0.047), and moderate depression (p = 0.006). No significant differences were found in terms of the prevalence of anxiety between left- and right-sided FP. However, significantly more patients with left-sided FP had mild depression (p = 0.018) than those with right-sided FP. CONCLUSION: This study found a significant difference in anxiety and depression between patients with FP and healthy controls. No clinically significant difference was noted in the prevalence of anxiety or depression between patients with left- and right-sided FP. PMID- 26952128 TI - Risk of nerve injury during arthroscopy portal placement in the elbow joint: A cadaveric study. AB - BACKGROUND: Elbow arthroscopy has become a routine procedure now. However, placing portals is fraught with dangers of injuring the neurovascular structures around elbow. There are not enough data documenting the same amongst the Indians. We aimed to determine the relative distances of nerves around the elbow to the arthroscopy portals and risk of injury in different positions of the elbow. MATERIALS AND METHODS: Six standard elbow arthroscopy portals were established in 12 cadaveric upper limbs after joint distension. Then using standard dissection techniques all the nerves around the elbow were exposed, and their distances from relevant portals were measured using digital vernier caliper in 90 degrees elbow flexion and 0 degrees extension. Descriptive statistical analysis was used for describing distance of the nerves from relevant portal. Wilcoxon-signed rank test and Friedman's test were used for comparison. RESULTS: There was no major nerve injury at all the portals studied in both positions of the elbow. The total incidence of cutaneous nerve injury was 8.3% (12/144); medial cutaneous nerve of forearm 10/48 and posterior cutaneous nerve of forearm 2/24. No significant changes were observed in the distance of a nerve to an individual portal at 90 degrees flexion or 0 degrees extension position of the elbow. CONCLUSION: This study demonstrates the risk of injury to different nerves at the standard portals of elbow arthroscopy. In practice, the actual incidence of nerve injury may still be lower. We conclude that elbow arthroscopy is a safe procedure when all precautions as described are duly followed. PMID- 26952129 TI - Drift transport of helical spin coherence with tailored spin-orbit interactions. AB - Most future information processing techniques using electron spins in non magnetic semiconductors will require both the manipulation and transfer of spins without their coherence being lost. The spin-orbit effective magnetic field induced by drifting electrons enables us to rotate the electron spins in the absence of an external magnetic field. However, the fluctuations in the effective magnetic field originating from the random scattering of electrons also cause undesirable spin decoherence, which limits the length scale of the spin transport. Here we demonstrate the drift transport of electron spins adjusted to a robust spin structure, namely a persistent spin helix. We find that the persistent spin helix enhances the spatial coherence of drifting spins, resulting in maximized spin decay length near the persistent spin helix condition. Within the enhanced distance of the spin transport, the transport path of electron spins can be modulated by employing time-varying in-plane voltages. PMID- 26952131 TI - Data in the activities of caspases and the levels of reactive oxygen species and cytochrome c in the *OH-induced fish erythrocytes treated with alanine, citrulline, proline and their combination. AB - The present study explored the effects of alanine (Ala), citrulline (Cit), proline (Pro) and their combination (Ala10Pro4Cit1) on the activities of caspases and levels of reactive oxygen species (ROS) and cytochrome c in hydroxyl radicals (*OH)-induced carp erythrocytes. The data displayed that *OH induced the increases in the activities of caspase-3, caspase-8 and caspase-9 and the levels of ROS and cytochrome c in carp erythrocytes. However, Ala, Cit, Pro and Ala10Pro4Cit1 effectively suppressed the *OH-induced increases in the activities of caspase-3, caspase-8 and caspase-9 and the levels of ROS and cytochrome c in carp erythrocytes. Furthermore, the activities of caspase-3, caspase-8 and caspase-9 and the levels of ROS and cytochrome c were gradually decreased with increasing concentrations of Ala, Cit, Pro and Ala10Pro4Cit1 (0.175-1.400 mM) in the *OH-induced carp erythrocytes. These data demonstrated that the 50% inhibitory doses (ID50) of Ala10Pro4Cit1 on the activities of caspase-8, caspase 9 and caspase-3 and levels of ROS and cytochrome c were respectively estimated to be the minimum values among amino acids examined so far. The 5% inhibitory doses (ID5) of Ala, Cit, Pro and Ala10Pro4Cit1 on the activities of caspase-8, caspase 9 and caspase-3 and levels of ROS and cytochrome c were estimated to be at their physiological concentrations in mammalian. Our research article for further interpretation and discussion from these data in Li et al. (2016) [1]. PMID- 26952132 TI - Intraneural stimulation elicits discrimination of textural features by artificial fingertip in intact and amputee humans. AB - Restoration of touch after hand amputation is a desirable feature of ideal prostheses. Here, we show that texture discrimination can be artificially provided in human subjects by implementing a neuromorphic real-time mechano-neuro transduction (MNT), which emulates to some extent the firing dynamics of SA1 cutaneous afferents. The MNT process was used to modulate the temporal pattern of electrical spikes delivered to the human median nerve via percutaneous microstimulation in four intact subjects and via implanted intrafascicular stimulation in one transradial amputee. Both approaches allowed the subjects to reliably discriminate spatial coarseness of surfaces as confirmed also by a hybrid neural model of the median nerve. Moreover, MNT-evoked EEG activity showed physiologically plausible responses that were superimposable in time and topography to the ones elicited by a natural mechanical tactile stimulation. These findings can open up novel opportunities for sensory restoration in the next generation of neuro-prosthetic hands. PMID- 26952133 TI - Sleep-disordered breathing children: Measurement of nasal nitric oxide and fractional exhaled nitric oxide. AB - OBJECTIVE: To assess the clinical significance of nasal nitric oxide (nNO) and fractional exhaled nitric oxide (FeNO) concentrations in children with sleep disordered breathing (SDB). METHODS: Enrolled in this study were 30 children with SDB and 15 healthy children. The nNO and FeNO concentrations were measured noninvasively using a NIOX MINO system (Aerocrine AB, Solna, Sweden). SPSS statistics 20.0 software (IBM SPSS statistics 20.0, Armonk, NY, USA) was used to analyze the data. RESULTS: The median (25th and 75th percentiles) nNO concentration of SDB children measured in parts per billion (ppb) was 111.0 (44.0; 349.0) ppb; FeNO concentration of SDB children was 12.0 (9.8; 14.0) ppb. The nNO concentration of healthy children was 52.0 (22.0; 139.0) ppb; FeNO concentration of healthy children was 12.0 (10.0; 16.0) ppb. Compared to healthy children, nNO concentration was significantly higher in children with SDB (Z = 2.215, P = 0.027). Correlation analysis showed that SDB children's nNO concentration directly correlated with apnea-hypopnea index (AHI; r = 0.429, P = 0.018), and inversely correlated with nadir oxygen saturation (SaO2; r = -0.482, P = 0.007). No other polysomnographic parameters significantly correlated with nNO concentration. CONCLUSION: Our data suggest that nNO concentration might be useful for diagnosis and evaluation of disease severity in SDB children. Furthermore, these results suggest that nNO concentration has a greater prognostic value than FeNO concentration. PMID- 26952134 TI - Data on Arc and Zif268 expression in the brain of the alpha-2A adrenergic receptor knockout mouse. AB - The alpha2-adrenergic receptor (alpha2-AR) is widely distributed in the brain with distinct roles for alpha2-AR subtypes (A, B and C). In this article, data are provided on Activity Regulated Cytoskeleton Associated Protein (Arc) and Zif268 expression in the brain of the alpha2A-AR knockout (alpha2A-AR KO) mouse. These data are supplemental to an original research article examining Arc and Zif268 expression in rats injected with the alpha2-AR antagonist, RX821002 (http://dx.doi.org/10.1016/j.neulet.2015.12.002. [1]). PMID- 26952135 TI - Phenotypic detection and molecular characterization of beta-lactamase genes among Citrobacter species in a tertiary care hospital. AB - OBJECTIVE: To examine the distribution, emergence, and spread of genes encoding beta-lactamase resistance in Citrobacter species isolated from hospitalized patients in a tertiary care hospital. METHODS: A prospective study was conducted in a 1000-bed tertiary care center in Pune, India from October 2010 to October 2013. A total of 221 Citrobacter spp. isolates were recovered from clinical specimens from different patients (one isolate per patient) admitted to the surgical ward, medical ward and medical and surgical Intensive Care Units. Polymerase chain reaction (PCR) assays and sequencing were used to determine the presence of beta-lactamase encoding genes. Conjugation experiments were performed to determine their transferability. Isolate relatedness were determined by repetitive element based-PCR, enterobacterial repetitive intergenic consensus-PCR and randomly amplified polymorphic DNA. RESULTS: Among 221 tested isolates of Citrobacter spp. recovered from various clinical specimens, 179 (80.9%) isolates showed minimum inhibitory concentration (MIC) >4 MUg/ml against meropenem and imipenem. One hundred and forty-five isolates with increased MICs value against carbapenems were further processed for molecular characterization of beta lactamase genes. Susceptibility profiling of the isolates indicated that 100% retained susceptibility to colistin. Conjugation experiments indicated that bla NDM-1 was transferable via a plasmid. CONCLUSION: The ease of NDM-1 plasmid transmissibility may help their dissemination among the Citrobacter species as well as to others in Enterobacteriaceae. Early detection, antimicrobial stewardship and adequate infection control measures will help in limiting the spread of these organisms. PMID- 26952136 TI - Joint attention interventions for children with autism spectrum disorder: a systematic review and meta-analysis. AB - BACKGROUND: A core social-communication deficit in children with autism spectrum disorder (ASD) is limited joint attention behaviours-important in the diagnosis of ASD and shown to be a powerful predictor of later language ability. Various interventions have been used to train joint attention skills in children with ASD. However, it is unclear which participant, intervention and interventionist factors yield more positive results. AIMS: The purpose of this systematic review and meta-analysis was to provide a quantitative assessment of the effectiveness of joint attention interventions aimed at improving joint attention abilities in children with ASD. METHODS & PROCEDURES: The researchers searched six databases for studies meeting the inclusion criteria at two levels: title/abstract and full text stages. Two independent coders completed data extraction using a coding manual and form developed specifically for this research study. Meta-analysis procedures were used to determine the overall effects of several comparisons including treatment type, treatment administrator, intervention characteristics and follow-up. MAIN CONTRIBUTION: Fifteen randomized experimental studies met inclusion criteria. All comparisons resulted in statistically significant effects, though overlapping confidence intervals suggest that none of the comparisons were statistically different from each other. Specifically, treatment administrator, dosage and design (control or comparison, etc.) characteristics of the studies do not appear to produce significantly different effects. CONCLUSIONS & IMPLICATIONS: The results of this meta-analysis provide strong support for explicit joint attention interventions for young children with ASD; however, it remains unclear which children with ASD respond to which type of intervention. PMID- 26952137 TI - Physiological and Transcriptional Analyses Reveal Differential Phytohormone Responses to Boron Deficiency in Brassica napus Genotypes. AB - Phytohormones play pivotal roles in the response of plants to various biotic and abiotic stresses. Boron (B) is an essential microelement for plants, and Brassica napus (B. napus) is hypersensitive to B deficiency. However, how auxin responds to B deficiency remained a dilemma for many years and little is known about how other phytohormones respond to B deficiency. The identification of B efficient/inefficient B. napus indicates that breeding might overcome these constraints in the agriculture production. Here, we seek to identify phytohormone related processes underlying B-deficiency tolerance in B. napus at the physiological and gene expression levels. Our study indicated low-B reduced indole-3-acetic acid (IAA) concentration in both the shoots and roots of B. napus, and affected the expression of the auxin biosynthesis gene BnNIT1 and the efflux gene BnPIN1 in a time-dependent manner. Low-B increased the jasmonates (JAs) and abscisic acid (ABA) concentrations and induced the expression of the ABA biosynthesis gene BnNCED3 and the ABA sensor gene BnPYL4 in the shoot. In two contrasting genotypes, the auxin concentration decreased more drastically in the B-inefficient genotype 'W10,' and together the expression of BnNIT1 and BnPIN1 also decreased more significantly in 'W10' under long-term B deficiency. While the JAs concentration was considerably higher in this genotype, and the ABA concentration was induced in 'W10' compared with the B-efficient genotype 'QY10.' Digital gene expression (DGE) profiling confirmed the differential expression of the phytohormone-related genes, indicating more other phyohormone differences involving in gene regulation between 'QY10' and 'W10' under low-B stress. Additionally, the activity of DR5:GFP was reduced in the root under low-B in Arabidopsis, and the application of exogenous IAA could partly restore the B defective phenotype in 'W10.' Overall, our data suggested that low-B disturbed phytohormone homeostasis in B. napus, which originated from the change of transcriptional regulation of phytohormones-related genes, and the differences between genotypes may partly account for their difference in tolerance (B efficiency) to low-B. PMID- 26952138 TI - [Histiocytoses: General classification and molecular criteria]. AB - Histiocytoses are rare and heterogeneous disease sharing histology, characterized by accumulation of histiocytes. They may be inherited or sporadic, and related to the accumulation of endo- or exogenous material in macrophages or to macrophage activation. Recent discoveries have shown that some histiocytoses, such as Langerhans cell histiocytosis or Erdheim-Chester disease, previously considered as idiopathic or inflammatory were clonal myeloid proliferations. This review presents the general classification of histiocytoses, and describes diagnostic and molecular criteria of idiopathic histiocytoses and histiocytic neoplasms. PMID- 26952140 TI - Late-stage disease at presentation to an HIV clinic in eastern Tanzania: A retrospective cross-sectional study. AB - BACKGROUND: Late presentation and delayed treatment initiation is associated with poor outcomes in patients with HIV. Little is known about the stage at which HIV patients present at HIV clinics in Tanzania. AIM: This study aimed at determining the proportion of HIV patients presenting with WHO clinical stages 3 and 4 disease, and the level of immunity at the time of enrollment at the care and treatment center. METHODS: A retrospective cross-sectional study was conducted among 366 HIV-infected adults attending HIV clinic at Mwananyamala Hospital in Dar es Salaam, Tanzania. Data were obtained from the care and treatment clinic database. RESULTS: Late stage disease at the time of presentation was found in 276 (75.4%) of the patients; out of whom 153 (41.8%) presented with CD4 count <200 cells/ul and 229 (62.6%) presented with WHO clinical stage 3 or 4 at the time of clinic enrollment. Strategies to improve early diagnosis and treatment initiation should be improved. PMID- 26952141 TI - Epidemiological survey of different clinical techniques of orthodontic bracket debonding and enamel polishing. AB - OBJECTIVES: To conduct an epidemiological survey of the orthodontic debonding techniques in Italy, and describe the most commonly used methods to remove the brackets and adhesive from the tooth surfaces. MATERIALS AND METHODS: A survey consisting of 6 questions about bracket debonding methods and instruments used was emailed to 1000 orthodontists, who were members of the Italian Orthodontics Society (SIDO. Clinicians were characterized by different sex, age, origin, and professional experience. RESULTS: Overall, 267 surveys were returned, representing a response rate of 26.7% of the participants interviewed. The 0.2% of the orthodontists responded, via email, confirming that they were not interested, while 3% of the questionnaires were sent back not completed. The 70.1% of the clinicians interviewed did not return any response. Overall, 64% of SIDO members (orthodontists) did not detect any enamel damage after debonding. The brackets used most frequently (89.14%) in clinical practice were the metal ones. The most commonly used pliers for bracket removal were cutters (37.08%) and bracket removal pliers (34.83%). For adhesive removal, low speed tungsten carbide burs under irrigation were the most widely utilized method for adhesive removal (40.08%), followed by high speed carbide burs (14.19%), and diamond burs (14.19%). The most frequently used instruments for polishing after debonding were rubber cups (36.70%) and abrasive discs (21.35%). The 31.21% of the orthodontists found esthetic enamel changes before bonding versus after debonding. CONCLUSIONS: This survey showed the high variability of different methods for bracket debonding, adhesive removal, and tooth polishing. The collected answers indicate that most orthodontists have developed their own armamentarium of debonding and polishing, basing their method on trials and errors. PMID- 26952139 TI - The molecular basis of craniofacial placode development. AB - The sensory organs of the vertebrate head originate from simple ectodermal structures known as cranial placodes. All cranial placodes derive from a common domain adjacent to the neural plate, the preplacodal region, which is induced at the border of neural and non-neural ectoderm during gastrulation. Induction and specification of the preplacodal region is regulated by the fibroblast growth factor, bone morphogenetic protein, WNT, and retinoic acid signaling pathways, and characterized by expression of the EYA and SIX family of transcriptional regulators. Once the preplacodal region is specified, different combinations of local signaling molecules and placode-specific transcription factors, including competence factors, promote the induction of individual cranial placodes along the neural axis of the head region. In this review, we summarize the steps of cranial placode development and discuss the roles of the main signaling molecules and transcription factors that regulate these steps during placode induction, specification, and development. For further resources related to this article, please visit the WIREs website. PMID- 26952142 TI - Efficacy of a Standardized Extract of Prunus mume in Liver Protection and Redox Homeostasis: A Randomized, Double-Blind, Placebo-Controlled Study. AB - The antioxidant, anti-inflammatory and hepatoprotective effects of Prunus mume (PM) have previously been demonstrated. This double-blind, placebo-controlled study was designed to evaluate the influence of two doses of a food supplement, made of 150 mg of a standardized PM extract on liver transaminases, lipid profile, glycemia, neopterin and reduced and oxidized thiols in plasma and erythrocytes, during a 3-month treatment period, in healthy subjects with transaminases levels between 20 and 40 UI/L. Forty-five subjects (56.0 +/- 11.6 years) were enrolled. The results showed a beneficial and statistically significant effect versus placebo of PM extract on liver function, with a decrease versus baseline in alanine aminotransferase (47%), aspartate aminotransferase (7%), gamma-glutamyl transpeptidase (15%) and glycemia (11%). The lipid profile modification was also positive with an increase versus baseline in HDL cholesterol (13%), and a decrease in LDL/HDL ratio (12%) and triglycerides (8%). The antioxidant action of PM translated into a decrease in oxidized glutathione, reduced/oxidized cysteine-glycine, oxidized cysteine (intracellular pro-oxidant) and neopterin (inflammation biomarker), was associated with an increase in reduced glutathione. These results are in favor of the use of a standardized extract of P. mume for the support of liver health and prevention of common metabolic and inflammation-based diseases. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26952143 TI - Evaluation of Interindividual Human Variation in Bioactivation and DNA Adduct Formation of Estragole in Liver Predicted by Physiologically Based Kinetic/Dynamic and Monte Carlo Modeling. AB - Estragole is a known hepatocarcinogen in rodents at high doses following metabolic conversion to the DNA-reactive metabolite 1'-sulfooxyestragole. The aim of the present study was to model possible levels of DNA adduct formation in (individual) humans upon exposure to estragole. This was done by extending a previously defined PBK model for estragole in humans to include (i) new data on interindividual variation in the kinetics for the major PBK model parameters influencing the formation of 1'-sulfooxyestragole, (ii) an equation describing the relationship between 1'-sulfooxyestragole and DNA adduct formation, (iii) Monte Carlo modeling to simulate interindividual human variation in DNA adduct formation in the population, and (iv) a comparison of the predictions made to human data on DNA adduct formation for the related alkenylbenzene methyleugenol. Adequate model predictions could be made, with the predicted DNA adduct levels at the estimated daily intake of estragole of 0.01 mg/kg bw ranging between 1.6 and 8.8 adducts in 10(8) nucleotides (nts) (50th and 99th percentiles, respectively). This is somewhat lower than values reported in the literature for the related alkenylbenzene methyleugenol in surgical human liver samples. The predicted levels seem to be below DNA adduct levels that are linked with tumor formation by alkenylbenzenes in rodents, which were estimated to amount to 188-500 adducts per 10(8) nts at the BMD10 values of estragole and methyleugenol. Although this does not seem to point to a significant health concern for human dietary exposure, drawing firm conclusions may have to await further validation of the model's predictions. PMID- 26952144 TI - Bcmimp1, a Botrytis cinerea Gene Transiently Expressed in planta, Encodes a Mitochondrial Protein. AB - Botrytis cinerea is a widespread necrotrophic fungus which infects more than 200 plant species. In an attempt to characterize the physiological status of the fungus in planta and to identify genetic factors contributing to its ability to infect the host cells, a differential gene expression analysis during the interaction B. cinerea-tomato was carried out. Gene Bcmimp1 codes for a mRNA detected by differential display in the course of this analysis. During the interaction with the host, it shows a transient expression pattern with maximal expression levels during the colonization and maceration of the infected tissues. Bioinformatic analysis suggested that BCMIMP1 is an integral membrane protein located in the mitochondrial inner membrane. Co-localization experiments with a BCMIMP1-GFP fusion protein confirmed that the protein is targeted to the mitochondria. DeltaBcmimp1 mutants do not show obvious phenotypic differences during saprophytic growth and their infection ability was unaltered as compared to the wild-type. Interestingly, the mutants produced increased levels of reactive oxygen species, likely as a consequence of disturbed mitochondrial function. Although Bcmimp1 expression is enhanced in planta it cannot be considered a pathogenicity factor. PMID- 26952146 TI - Can a biologic mesh survive a Candida krusei infection? A case report of infection of a biologic mesh following repair of abdominal wall hernia. AB - The use of biologic mesh, which is considered resistant to infection, has become common. It is preferred over synthetic mesh for use in contaminated fields. Fungal infection with infiltration of biologic mesh is rare and has not been reported. In this paper, we report a case of a patient who underwent multiple laparotomies and received multiple antibiotics and an azole antifungal. Biologic mesh was used, but it ultimately required removal because of chronic infection with Candida krusei. On biopsy, the yeast was found to have infiltrated the mesh. PMID- 26952145 TI - Type of Speech Material Affects Acceptable Noise Level Test Outcome. AB - The acceptable noise level (ANL) test, in which individuals indicate what level of noise they are willing to put up with while following speech, has been used to guide hearing aid fitting decisions and has been found to relate to prospective hearing aid use. Unlike objective measures of speech perception ability, ANL outcome is not related to individual hearing loss or age, but rather reflects an individual's inherent acceptance of competing noise while listening to speech. As such, the measure may predict aspects of hearing aid success. Crucially, however, recent studies have questioned its repeatability (test-retest reliability). The first question for this study was whether the inconsistent results regarding the repeatability of the ANL test may be due to differences in speech material types used in previous studies. Second, it is unclear whether meaningfulness and semantic coherence of the speech modify ANL outcome. To investigate these questions, we compared ANLs obtained with three types of materials: the International Speech Test Signal (ISTS), which is non-meaningful and semantically non-coherent by definition, passages consisting of concatenated meaningful standard audiology sentences, and longer fragments taken from conversational speech. We included conversational speech as this type of speech material is most representative of everyday listening. Additionally, we investigated whether ANL outcomes, obtained with these three different speech materials, were associated with self-reported limitations due to hearing problems and listening effort in everyday life, as assessed by a questionnaire. ANL data were collected for 57 relatively good-hearing adult participants with an age range representative for hearing aid users. Results showed that meaningfulness, but not semantic coherence of the speech material affected ANL. Less noise was accepted for the non meaningful ISTS signal than for the meaningful speech materials. ANL repeatability was comparable across the speech materials. Furthermore, ANL was found to be associated with the outcome of a hearing-related questionnaire. This suggests that ANL may predict activity limitations for listening to speech-in noise in everyday situations. In conclusion, more natural speech materials can be used in a clinical setting as their repeatability is not reduced compared to more standard materials. PMID- 26952147 TI - The effects of camera lenses and dental specialties on the perception of smile esthetics. AB - BACKGROUND AND AIM: The purpose of this study was to investigate whether different camera lenses and dental specialties can affect the perception of smile esthetics. METHODS: In the first phase of this study, 40 female smile photographs (taken from dental students) were evaluated by six orthodontists, three specialists in restorative dentistry, and three prosthodontists to select the most beautiful smiles. The 20 students with the best smile ranks were again photographed in standard conditions, but this time with two different lenses: Regular and then macro lenses. Each referee evaluated the beauty of the smiles on a visual analog scale. The referees were blinded of the type of lenses, and the images were all coded. The data were analyzed using two-way analysis of variance (ANOVA), Kruskal-Wallis and Mann-Whitney U-tests (alpha = 0.05, alpha = 0.0167). RESULTS: The lenses led to similar scores of beauty perception (Mann-Whitney P = 0.8). There was no difference between subjective beauty perception of specialties (Kruskal-Wallis P = 0.6). Two-way ANOVA indicated no significant role for lenses (P = 0.1750), specialties (P = 0.7677), or their interaction (P = 0.7852). CONCLUSION: The photographs taken by a regular lens and then digitally magnified can be as appealing as close-up photographs taken by a macro lens. Experts in different specialties (orthodontics, prosthodontics, and restorative dentistry) showed similar subjective judgments of smile beauty. PMID- 26952148 TI - Isolated left upper extremity myositis and severe rhabdomyolysis in an adult with H1N1 Influenza, a case report with literature review. AB - Acute viral myositis is a fairly rare condition and usually seen in recovery phase of illness, especially in pediatric or geriatric population. Influenza type A, specifically H1N1 may present with generalized myositis and mild elevation of creatinine kinase in addition to usual manifestations. We would like to discuss an atypical presentation of Type A Influenza (H1N1) in a middle aged male who was never immunized for influenza, presenting with fever, vomiting, anuria and acute severe left upper extremity pain. The most interesting presentation in our patient was that, it was limited to a single extremity, unlike generalized presentation, which was previously reported, acute renal failure warranting renal replacement therapy. This case serves as a reminder for clinicians about atypical manifestations of H1N1 and its threatening metabolic complications. Hence the practitioners should be aware of this rare but possible presentation of certain strains of influenza virus. It also accentuates the importance of being immunized, reminding us of the Old but Golden Adage "Prevention is better than Cure." PMID- 26952149 TI - Reference management: A critical element of scientific writing. AB - With the rapid growth of medical science, the number of scientific writing contributing to medical literature has increased significantly in recent years. Owing to considerable variation of formatting in different citation styles, strict adherence to the accurate referencing manually is labor intensive and challenging. However, the introduction of referencing tools has decreased the complexity to a great extent. These software have advanced overtime to include newer features to support effective reference management. Since scientific writing is an essential component of medical curriculum, it is imperative for medical graduates to understand various referencing systems to effectively make use of these tools in their dissertations and future researches. PMID- 26952150 TI - Chorda tympani schwannoma: one new case revealed during malignant otitis externa and review of the literature. PMID- 26952151 TI - Combined Effect of Hyperhomocysteinemia and Hypertension on the Presence of Early Carotid Artery Atherosclerosis. AB - BACKGROUND: To examine the individual effect of elevated homocysteine and its combined effect with hypertension on early carotid artery atherosclerosis (ECAS). METHODS: We recruited 1257 subjects from a community-based population in Beijing, China, aged 55 years and older. The definition of hyperhomocysteinemia was referred to as the presence of homocysteine concentrations greater than 15 umol/L. Carotid intima-media thickness (CIMT), plaque, the sum of plaque thickness (plaque score, PS), and plaque location in common carotid artery were established by ultrasonography. The presence of increased CIMT (>=1.0 mm) and plaque was defined as ECAS. Age, sex, smoking, alcohol drinking, physical activity, total cholesterol, glucose, estimated glomerular filtration rate, hypoglycemic therapy, and lipid-lowering therapy were adjusted by logistic regression analysis. RESULTS: After adjustments for all potential confounders, the risks of presence of plaque, bilateral plaque, and high PS were significantly higher in the group with hyperhomocysteinemia as compared with reference group (the normal homocysteine and normotensive). The odds ratios (ORs) were 1.56 for presence of plaque (95% CI 1.05-2.33), 1.80 for bilateral plaque (95% CI 1.08 2.99), and 1.90 for high PS (95% CI 1.09-3.30), respectively. The group with both hyperhomocysteinemia and hypertension manifested the highest ORs of ECAS. The fully adjusted ORs were 1.67 for increased CIMT (95% CI 1.15-2.42), 2.48 for bilateral plaques (95% CI 1.54-3.99), and 2.69 for high PS (95% CI 1.61-4.47), correspondingly. CONCLUSIONS: Elevated homocysteine had a mild-to-moderate independent effect on ECAS. Combined with hypertension, hyperhomocysteinemia might increase the strength of the above-mentioned effects. PMID- 26952152 TI - Transesophageal echocardiography probe shutdown in a patient with hyperthermia. AB - The use of transesophageal echocardiography (TEE) has been increasing over the past few years. It is considered a semi-invasive monitor and a safe diagnostic device. Though complications are rare, they must be known to operators who frequently perform TEE. TEE probes are known to cause tissue heating and damage on prolonged use. In this case report, we describe shutdown of the transesophageal probe in our patient with high-grade fever. PMID- 26952153 TI - Large vessel vasculitis in a patient with acute Q-fever: A case report. AB - Q fever is a zoonosis caused by the rickettsial organism Coxiella burnetii. Infection has an acute course, usually with a self-limited febrile illness and the possibility of the evaluation to a chronic course with endocardial involvement. The presence of autoantibodies and various autoimmune disorders have also been associated with C. burnetii infection. We report a case of acute Q fever in which the patient developed large vessel vasculitis. The FDG-PET/CT scan detected inflammation of the thoracic aortic wall, suggesting an unusual immunologic host response to acute Q fever infection. PMID- 26952154 TI - Inter-rater reliability and validity of the screenassist lumbar questionnaire: a pilot study. AB - OBJECTIVE: The purpose of this study was to examine the validity and test-retest reliability of the ScreenAssist Lumbar Questionnaire (SALQ). If a high degree of reliability and validity could be determined, the questionnaire could provide physical therapists with a formal instrument to assist with the identification of patients with nonmusculoskeletal back pain or emergent musculoskeletal causes of back pain requiring referral to an alternate medical provider. METHODS: Participants were patients presenting to an internal medicine physician's office with the main complaint of low back pain over a 6 months period. ScreenAssist Lumbar Questionnaire was performed twice on each patient within 48 hours of the appointment. A 4-month post-visit chart review was performed to compare scores and recommendations made by the questionnaire with the assessment and diagnosis made by the physician. RESULTS: The SALQ demonstrated a sensitivity of 0.100 (95% CI: 0.689-0.100) and specificity of 0.786 (95%CI: 0.492-0.951) compared to the assessment and diagnosis performed by the primary care physician. Overall, regarding the recommendation for referral, there was agreement on 20 of the 21 patients with a Kappa of 0.798. DISCUSSION: The overall test-retest reliability and validity for referral recommendation were high, which indicates that the SALQ may serve as an alternative to the use of red flags in isolation to assist the physical therapist in determining the need for medical referral as the practice continues to progress toward direct access. The positive outcome of this study supports the possible future benefit of the SALQ. PMID- 26952155 TI - In Response: Dexmedetomidine versus propofol in dilatation and curettage: An open label pilot randomized controlled trial. PMID- 26952156 TI - Nicotine Induces Cardiomyocyte Hypertrophy Through TRPC3-Mediated Ca2+/NFAT Signalling Pathway. AB - BACKGROUND: Nicotine is thought to be an important risk factor for the development of cardiovascular diseases. However, the effects of nicotine on cardiomyocyte hypertrophy are poorly understood. The present study was designed to explore the role of nicotine in cardiomyocyte hypertrophy and its underlying mechanism. METHODS: We used primary cardiomyocytes isolated from Wistar rats to examine the effects of nicotine on intracellular Ca2+ mobilization and hypertrophy determined by immunofluorescence, quantitative polymerase chain reaction, and western blot analysis. A luciferase reporter assay was used to examine the activity of NFAT signalling. RESULTS: We found that nicotine caused cardiomyocyte hypertrophy, which was accompanied by increased intracellular Ca2+. Nicotine-enhanced intracellular Ca2+ concentration ([Ca2+]i) was significantly abolished by store-operated Ca2+ entry (SOCE) and TRPC inhibitors. Knockdown of TRPC3 significantly decreased nicotine-induced SOCE and hypertrophy. Moreover, calcineurin-nuclear factor of activated T cells (NFAT) is involved in TRPC3 mediated Ca2+ signalling and cardiomyocyte hypertrophy. Notably, upregulation of TRPC3 by nicotine requires TRPC3-mediated Ca2+ influx and calcineurin-NFAT signalling activation. CONCLUSIONS: Our findings demonstrate that the prohypertrophic effect of nicotine on cardiomyocytes is dependent on enhanced TRPC3 expression through a calcium-dependent regulatory loop, which could become a potential target for prevention and treatment of cardiac hypertrophy. PMID- 26952157 TI - Dynamics of Endo- and Epicardial Focal Fibrillation Waves at the Right Atrium in a Patient With Advanced Atrial Remodelling. AB - Focal waves appear frequently at the epicardium during persistent atrial fibrillation (AF), however, the origin of these waves is under debate. We performed simultaneous endo-epicardial mapping of the right atrial wall during longstanding persistent AF in a patient undergoing cardiac surgery. During 10 seconds 53 and 59 focal waves appeared at random at respectively the endocardium and epicardium. Repetitive focal activity did not last longer than 3 cycles. Transmural asynchrony and conduction might be the origin of focal waves. Asynchronous propagation of fibrillation waves in 3 dimensions would stabilize the arrhythmia and could explain the limited success of persistent AF ablation. PMID- 26952158 TI - Transcranial Doppler is Complementary to Echocardiography for Detection and Risk Stratification of Patent Foramen Ovale. AB - BACKGROUND: In patients with patent foramen ovale (PFO), strategies are needed to identify patients at higher risk, who might benefit from PFO closure. METHODS: We studied the frequency of detection of a right-to-left shunt (RLS) using transesophageal echocardiography (TEE) among patients with cryptogenic stroke and transcranial Doppler (TCD) to detect RLS, and analyzed the prediction of recurrent stroke according to TCD shunt grade, by detection of RLS on TEE, and by atrial septal aneurysm or mobility. RESULTS: Among 334 patients with TCD, 69.8% were female, with a mean (SD) age of 53 (14) years, with a median follow-up of 420 days. There were 284 cases with TCD and TEE; 54 (19%) had atrial septal aneurysm or mobility. Echocardiography failed to show a RLS in 43 (15.1%) of the patients who had TCD and TEE, even in some patients with high-grade shunts on TCD: 18 (42%) were grade 3 or higher on TCD. Survival free of stroke or transient ischemic attack was predicted significantly by TCD shunt grade < 2 (P = 0.028), shunt grade < 3 (P = 0.03), and shunt grade < 4 (P < 0.0001); this was attenuated by adjustment for risk factors in Cox regression (P = 0.08). Neither RLS on TEE (P = 0.47), or atrial septal aneurysm or mobility (P = 0.08), predicted events. CONCLUSIONS: Our findings suggest that TCD might be more sensitive than TEE for detection of RLS, which misses some cases with substantial RLS, and might be valuable for prediction of recurrent stroke or transient ischemic attack in patients with PFO. TCD complements TEE for management of suspected paradoxical embolism. PMID- 26952159 TI - Use of Hospital Resources for Patients With Congenital Heart Disease in Canada. PMID- 26952160 TI - Influence of current input-output and age of first exposure on phonological acquisition in early bilingual Spanish-English-speaking kindergarteners. AB - BACKGROUND: Although some investigations of phonological development have found that segmental accuracy is comparable in monolingual children and their bilingual peers, there is evidence that language use affects segmental accuracy in both languages. AIMS: To investigate the influence of age of first exposure to English and the amount of current input-output on phonological accuracy in English and Spanish in early bilingual Spanish-English kindergarteners. Also whether parent and teacher ratings of the children's intelligibility are correlated with phonological accuracy and the amount of experience with each language. METHODS & PROCEDURES: Data for 91 kindergarteners (mean age = 5;6 years) were selected from a larger dataset focusing on Spanish-English bilingual language development. All children were from Central Texas, spoke a Mexican Spanish dialect and were learning American English. Children completed a single-word phonological assessment with separate forms for English and Spanish. The assessment was analyzed for segmental accuracy: percentage of consonants and vowels correct and percentage of early-, middle- and late-developing (EML) sounds correct were calculated. OUTCOMES & RESULTS: Children were more accurate on vowel production than consonant production and showed a decrease in accuracy from early to middle to late sounds. The amount of current input-output explained more of the variance in phonological accuracy than age of first English exposure. Although greater current input-output of a language was associated with greater accuracy in that language, English-dominant children were only significantly more accurate in English than Spanish on late sounds, whereas Spanish-dominant children were only significantly more accurate in Spanish than English on early sounds. Higher parent and teacher ratings of intelligibility in Spanish were correlated with greater consonant accuracy in Spanish, but the same did not hold for English. Higher intelligibility ratings in English were correlated with greater current English input-output, and the same held for Spanish. CONCLUSIONS & IMPLICATIONS: Current input-output appears to be a better predictor of phonological accuracy than age of first English exposure for early bilinguals, consistent with findings on the effect of language experience on performance in other language domains in bilingual children. Although greater current input-output in a language predicts higher accuracy in that language, this interacts with sound complexity. The results highlight the utility of the EML classification in assessing bilingual children's phonology. The relationships of intelligibility ratings with current input-output and sound accuracy can shed light on the process of referral of bilingual children for speech and language services. PMID- 26952161 TI - Effects of Physical Activity on Risk of Colorectal Cancer: A Case-control Study. AB - BACKGROUND: The prevalence of colorectal cancer (CRC) is rapidly increasing in Iran. It holds the most prevalent cancer after skin, breast, and gastric cancers among the Iranian population. The current study was designed to investigate the effects of leisure time, occupational and household physical activity as well as exercise on the risk of CRC in the Iranian population. METHODS: In this population-based case-control study, 100 individuals with a recent diagnosis of CRC who were eligible for the study were recruited between 2006 and 2008. The control groups were selected from patients' companions (excluding first- and second-degree relatives) without past history of cancer or any physical disability. Physical activity of the participants was evaluated using a Kriska retrospective physical activity questionnaire. The relation between CRC and physical activity was assessed via logistic regression model and calculating the odds ratio (OR) as well as a confidence interval (CI) of 95%. RESULTS: According to the findings, the adjusted OR of occupational (OR = 0.98, 95%, CI: 0.95-1.02) and house holding physical activities (OR = 1.03, 95% CI: 0.99-1.08) were not significantly different between the case and control groups for women (P > 0.05). The risk of CRC shows a significant reduction in individuals with moderate leisure physical activities compared to those with minimal activities (OR = 0.82, CI 95%: 0.73-0.98). CONCLUSIONS: The study suggests that the risk of CRC will decrease in individuals with higher leisure physical activities (especially with an increase in hours of brisk walking during the day). PMID- 26952164 TI - The In Vitro Pharmacological Profile of Drugs as a Proxy Indicator of Potential In Vivo Organ Toxicities. AB - The potential of a drug to cause certain organ toxicities is somehow implicitly contained in its full pharmacological profile, provided the drug reaches and accumulates at the various organs where the different interacting proteins in its profile, both targets and off-targets, are expressed. Under this assumption, a computational approach was implemented to obtain a projected anatomical profile of a drug from its in vitro pharmacological profile linked to protein expression data across 47 organs. It was observed that the anatomical profiles obtained when using only the known primary targets of the drugs reflected roughly the intended organ targets. However, when both known and predicted secondary pharmacology was considered, the projected anatomical profiles of the drugs were able to clearly highlight potential organ off-targets. Accordingly, when applied to sets of drugs known to cause cardiotoxicity and hepatotoxicity, the approach is able to identify heart and liver, respectively, as the organs where the proteins in the pharmacological profile of the corresponding drugs are specifically expressed. When applied to a set of drugs linked to a risk of Torsades de Pointes, heart is again the organ clearly standing out from the rest and a potential protein profile hazard is proposed. The approach can be used as a proxy indicator of potential in vivo organ toxicities. PMID- 26952165 TI - Successful treatment of a guitarist with a finger joint injury using instrument assisted soft tissue mobilization: a case report. AB - Finger injuries are common and can greatly affect a musician's quality of life. A 55-year-old man, who had injured the proximal interphalangeal joint of the left index finger 6 months prior to any intervention, was treated with a manual therapy approach incorporating instrument-assisted soft tissue mobilization (IASTM). Initial examination findings included self-reported pain and functional limitations and physical impairments that significantly impeded his ability to play the acoustic guitar. He was treated once a week for 6 weeks with IASTM, joint mobilization, therapeutic exercise, and ice massage. Additionally, a home exercise program and self-care instructions were provided. The patient gained positive outcomes with improvements in pain (Numerical Pain Rating Scale while playing the guitar: initial 5/10, discharge 1/10) and function (Disability Arm Shoulder Hand Sports-Performing Arts Optional Module: initial 75; discharge 6.25), each reaching a minimum clinically important difference. Importantly, he was able to play the guitar with minimal to no pain as desired. Physical measures also improved, including an immediate gain in finger range of motion with IASTM alone. Manual therapy approaches integrating IASTM may provide an effective conservative treatment strategy for patients with finger/hand conditions in the performing arts and other patient populations. PMID- 26952166 TI - Quantification of microcirculatory parameters by joint analysis of flow compensated and non-flow-compensated intravoxel incoherent motion (IVIM) data. AB - The aim of this study was to improve the accuracy and precision of perfusion fraction and blood velocity dispersion estimates in intravoxel incoherent motion (IVIM) imaging, using joint analysis of flow-compensated and non-flow-compensated motion-encoded MRI data. A double diffusion encoding sequence capable of switching between flow-compensated and non-flow-compensated encoding modes was implemented. In vivo brain data were collected in eight healthy volunteers and processed using the joint analysis. Simulations were used to compare the performance of the proposed analysis method with conventional IVIM analysis. With flow compensation, strong rephasing was observed for the in vivo data, approximately cancelling the IVIM effect. The joint analysis yielded physiologically reasonable perfusion fraction maps. Estimated perfusion fractions were 2.43 +/- 0.81% in gray matter, 1.81 +/- 0.90% in deep gray matter, and 1.64 +/- 0.72% in white matter (mean +/- SD, n = 8). Simulations showed improved accuracy and precision when using joint analysis of flow-compensated and non-flow compensated data, compared with conventional IVIM analysis. Double diffusion encoding with flow compensation was feasible for in vivo imaging of the perfusion fraction in the brain. The strong rephasing implied that blood flowing through the cerebral microvascular system was closer to the ballistic limit than the diffusive limit. PMID- 26952167 TI - Endothelin-1 supports clonal derivation and expansion of cardiovascular progenitors derived from human embryonic stem cells. AB - Coronary arteriogenesis is a central step in cardiogenesis, requiring coordinated generation and integration of endothelial cell and vascular smooth muscle cells. At present, it is unclear whether the cell fate programme of cardiac progenitors to generate complex muscular or vascular structures is entirely cell autonomous. Here we demonstrate the intrinsic ability of vascular progenitors to develop and self-organize into cardiac tissues by clonally isolating and expanding second heart field cardiovascular progenitors using WNT3A and endothelin-1 (EDN1) human recombinant proteins. Progenitor clones undergo long-term expansion and differentiate primarily into endothelial and smooth muscle cell lineages in vitro, and contribute extensively to coronary-like vessels in vivo, forming a functional human-mouse chimeric circulatory system. Our study identifies EDN1 as a key factor towards the generation and clonal derivation of ISL1(+) vascular intermediates, and demonstrates the intrinsic cell-autonomous nature of these progenitors to differentiate and self-organize into functional vasculatures in vivo. PMID- 26952168 TI - Sucrose release from polysaccharide gels. AB - Sucrose release from polysaccharide gels has been studied extensively because it is expected to be useful in understanding flavour release from solid foods and to find a new processing method which produces more palatable and healthier foods. We provide an overview of the release of sucrose and other sugars from gels of agar and related polysaccharides. The addition of sucrose to agar solutions leads to the increase in transparency of the resulting gels and the decrease in syneresis, which is attributed to the decrease in mesh size in gels. The syneresis occurring in the quiescent condition and fluid release induced by compression is discussed. The relationship between the sugar release and the structural, rheological and thermal properties of gels is also discussed. Finally, the future research direction is proposed. PMID- 26952170 TI - Chemotherapy Agents With Known Cardiovascular Side Effects and Their Anesthetic Implications. PMID- 26952169 TI - beta-catenin-driven binary cell fate decisions in animal development. AB - The Wnt/beta-catenin pathway plays key roles during animal development. In several species, beta-catenin is used in a reiterative manner to regulate cell fate diversification between daughter cells following division. This binary cell fate specification mechanism has been observed in animals that belong to very diverse phyla: the nematode Caenorhabditis elegans, the annelid Platynereis, and the ascidian Ciona. It may also play a role in the regulation of several stem cell lineages in vertebrates. While the molecular mechanism behind this binary cell fate switch is not fully understood, it appears that both secreted Wnt ligands and asymmetric cortical factors contribute to the generation of the difference in nuclear beta-catenin levels between daughter cells. beta-Catenin then cooperates with lineage specific transcription factors to induce the expression of novel sets of transcription factors at each round of divisions, thereby diversifying cell fate. For further resources related to this article, please visit the WIREs website. PMID- 26952171 TI - GFP tagged Vibrio parahaemolyticus Dahv2 infection and the protective effects of the probiotic Bacillus licheniformis Dahb1 on the growth, immune and antioxidant responses in Pangasius hypophthalmus. AB - In this study, the pathogenicity of GFP tagged Vibrio parahaemolyticus Dahv2 and the protective effect of the probiotic strain, Bacillus licheniformis Dahb1 was studied on the Asian catfish, Pangasius hypophthalmus. The experiment was carried out for 24 days with three groups and one group served as the control (without treatment). In the first group, P. hypophthalmus was orally infected with 1 mL of GFP tagged V. parahaemolyticus Dahv2 at two different doses (10(5) and 10(7) cfu mL(-1)). In the second group, P. hypophthalmus was orally administrated with 1 ml of the probiotic B. licheniformis Dahb1 at two different doses (10(5) and 10(7) cfu mL(-1)). In the third group, P. hypophthalmus was orally infected first with 1 mL of GFP tagged V. parahaemolyticus Dahv2 followed by the administration of 1 mL of B. licheniformis Dahb1 (combined treatment) at two different doses (10(5) and 10(7) cfu mL(-1)). The growth, immune (myeloperoxidase, respiratory burst, natural complement haemolytic and lysozyme activity) and antioxidant (glutathione S-transferase, reduced glutathione and total glutathione) responses of P. hypophthalmus were reduced after post infection of GFP tagged V. parahaemolyticus Dahv2 compared to control. However, after administration with the probiotic B. licheniformis Dahb1 at 10(5) cfu mL(-1), P. hypophthalmus showed significant increase in the growth, immune and antioxidant responses compared to 10(7) cfu mL(-1). On the otherhand, the growth, immune and antioxidant responses of P. hypophthalmus infected and administrated with combined GFP tagged Vibrio + Bacillus at 10(5) cfu mL(-1) were relatively higher than that of GFP tagged V. parahaemolyticus Dahv2 and control groups but lower than that of probiotic B. licheniformis Dahb1 groups. The results of the present study conclude that the probiotic B. licheniformis Dahb1 at 10(5) cfu mL(-1) has the potential to protect the P. hypophthalmus against V. parahaemolyticus Dahv2 infection by enhancing the growth, immune and antioxidant responses. The probiotic B. licheniformis Dahb1 would be effectively used in the treatment of aquatic diseases for improvement of aquaculture industry. PMID- 26952173 TI - The acromiohumeral distance and the subacromial clearance are correlated to the glenoid version. AB - BACKGROUND: The acromiohumeral distance (ACHD) is a radiographic parameter for evaluating the presence of a rotator cuff rupture. Previous investigations have demonstrated that several factors may influence the magnitude of the acromiohumeral distance, but glenoid version has not yet been considered. HYPOTHESIS: Our hypothesis was that there is a direct correlation between glenoid version and acromiohumeral distance as well as subacromial clearance. METHODS: Four right glenohumeral joints from adult fresh cadavers were anatomically dissected to the level of the rotator cuff. After fixation to a board and positioning of the humeral head in neutral position, an osteotomy of the glenoid neck was carried out and the version was altered in steps of 5 degrees . The ACHD as well as the subacromial clearance (SAC) were measured for every degree of glenoid version. RESULTS: The ACHD increased with increased anteversion and consistently decreased with increased retroversion of the glenoid. The SAC also depended on glenoid version. Neutral version was associated with a minimal clearance under the anterior third of the acromion, retroversion transferred the minimal SAC posteriorly and anteversion transferred minimal SAC under the coracoacromial ligament. CONCLUSION: Our results indicate that glenoid version correlates directly with the magnitude of ACHD and SAC. Therefore, variations of glenoid version can lead to false interpretations of cuff integrity. TYPE OF STUDY: Biomechanical investigation. LEVEL OF EVIDENCE: Not possible to define. PMID- 26952172 TI - The immune responses and antioxidant status of Portunus trituberculatus individuals with different body weights. AB - Vibrio alginolyticus is a virulent pathogen that affects crab aquacultures. In the present study, the immune responses and antioxidant status of big and small (based on body weight and size) 80-, 100- and 120-day-old specimens of Portunus trituberculatus, challenged for 72 h with Vibrio alginolyticus, were studied. The total hemocyte count (THC), and phagocytic, prophenoloxidase and phenoloxidase activities, of the big individuals (BIs) were higher than those of the small individuals (SIs) (P < 0.05). The antioxidant status of the organisms showed a similar pattern: superoxide dismutase (SOD) activity and glutathione/oxidized glutathione (GSH/GSSG) in the cell-free hemolymph and hepatopancreases of the BIs were higher than in the SIs (P < 0.05). There were no significant differences in alpha2-macroglobulin (alpha2-M), antibacterial and bacteriolytic activities in the cell-free hemolymph, or glutathione peroxidase activity in the cell-free hemolymph or hepatopancreas between the BIs and SIs. The alpha2-M and crustin gene expression levels in the hemocytes, and SOD expression in the hemocytes and hepatopancreas, were also significantly higher in the BIs. The results suggest that, compared with the SIs, the BIs possessed a higher resistance to V. alginolyticus infection. PMID- 26952174 TI - All arthroscopic augmented Vargas procedure: An option after failed acromioclavicular joint dislocation reconstruction. A technical note. AB - Few salvage procedures have been described after a failed Weaver-Dunn procedure. We hypothesized that it was possible to perform an all-arthroscopic revision with a reflected vascularized conjoint tendon into the distal resected clavicle (Vargas procedure) augmented by an artificial coraco-clavicular ligament. Two patients were enrolled. A minimum of 3-cm proximal conjoint tendon was dissected under arthroscopic control. The half-longitudinal conjoint tendon split, leaving its proximal end attached to the coracoid process, was made and incised transversely near the muscles fibers. While being still vascularized with the tip of the coracoid process, the tendon was tubularized, reflected proximally and transferred into the distal part of the clavicle. An artificial coraco-clavicular ligament augmented the transfer. No complication was described. After a minimum of two-year follow-up, there was no recurrence of AC instability and there was normal ROM; two patients returned to sport. LEVEL OF EVIDENCE: Level IV-a, case series. PMID- 26952175 TI - Dexmedetomidine as an additive to local anesthetics compared with intravenous dexmedetomidine in peribulbar block for cataract surgery. AB - BACKGROUND: No studies compared parenteral dexmedetomidine with its use as an adjuvant to ophthalmic block. We compared between adding dexmedetomidine to bupivacaine in peribulbar block and intravenous (IV) dexmedetomidine during peribulbar block for cataract surgery. MATERIALS AND METHODS: A prospective, randomized, double-blind study on 90 patients for cataract surgery under peribulbar anesthesia. Study included three groups; all patients received 10 ml of peribulbar anesthesia and IV infusion of drugs as follows: Group I: Received a mixture of bupivacaine 0.5% (4.5 ml) + lidocaine 2% (4.5 ml) + normal saline (1 ml) + 150 IU hyaluronidase + IV infusion of normal saline, Group II: Received mixture of bupivacaine 0.5% (4.5 ml) + lidocaine 2% (4.5 ml) + dexmedetomidine 50 MUg (1 ml) +150 IU hyaluronidase + IV infusion of normal saline and Group III: Received mixture of bupivacaine 0.5% (4.5 ml) + lidocaine 2% (4.5 ml) + normal saline (1 ml) +150 IU hyaluronidase + IV dexmedetomidine 1 MUg/kg over 10 min; followed by 0.4 MUg/kg/h IV infusion. We recorded onset, duration of block, Ramsay Sedation Score, intra-ocular pressure (IOP), hemodynamics, and adverse effects. RESULTS: There was a significant decrease in the onset of action and increase in the duration of block in Group II as compared with the Group I and Group III. Mean Ramsay Sedation Score was higher in Group III. The IOP showed a significant decrease in Group II and Group III 10 min after injection (P < 0.01). Heart rate showed a significant decrease in Group III in comparison with the two other groups (P < 0.05). Only two patients in Group III developed bradycardia. CONCLUSION: Dexmedetomidine as an additive shortens onset time, prolong block durations and significantly decreases the IOP with minimal side effects. IV dexmedetomidine, in addition, produces intra-operative sedation with hemodynamic stability. PMID- 26952176 TI - Poppers retinopathy. AB - We present a case of a 52-year-old man with sudden, bilateral central loss of vision as a result of inhalation of 'poppers'. He was found to have characteristic changes on optical coherence tomography. With conservative treatment, the patient's vision improved marginally at 3 months follow-up. An overview of previous published cases is also included. PMID- 26952177 TI - The Antibacterial Activity of Date Syrup Polyphenols against S. aureus and E. coli. AB - Plant-derived products such as date syrup (DS) have demonstrated antibacterial activity and can inhibit bacteria through numerous different mechanisms, which may be attributed to bioactive compounds including plant-derived phenolic molecules. DS is rich in polyphenols and this study hypothesized that DS polyphenols demonstrate inherent antimicrobial activity, which cause oxidative damage. This investigation revealed that DS has a high content of total polyphenols (605 mg/100 g), and is rich in tannins (357 mg/100 g), flavonoids (40.5 mg/100 g), and flavanols (31.7 mg/100 g) that are known potent antioxidants. Furthermore, DS, and polyphenols extracted from DS, the most abundant bioactive constituent of DS are bacteriostatic to both Gram positive and Gram negative Escherichia coli and Staphylococcus aureus, respectively. It has further been shown that the extracted polyphenols independently suppress the growth of bacteria at minimum inhibitory concentration (MIC) of 30 and 20 mg/mL for E. coli and S. aureus, and have observed that DS behaves as a prooxidant by generating hydrogen peroxide that mediates bacterial growth inhibition as a result of oxidative stress. At sub-lethal MIC concentrations DS demonstrated antioxidative activity by reducing hydrogen peroxide, and at lethal concentrations DS demonstrated prooxidant activity that inhibited the growth of E. coli and S. aureus. The high sugar content naturally present in DS did not significantly contribute to this effect. These findings highlight that DS's antimicrobial activity is mediated through hydrogen peroxide generation in inducing oxidative stress in bacteria. PMID- 26952178 TI - Interactive Voice/Web Response System in clinical research. AB - Emerging technologies in computer and telecommunication industry has eased the access to computer through telephone. An Interactive Voice/Web Response System (IxRS) is one of the user friendly systems for end users, with complex and tailored programs at its backend. The backend programs are specially tailored for easy understanding of users. Clinical research industry has experienced revolution in methodologies of data capture with time. Different systems have evolved toward emerging modern technologies and tools in couple of decades from past, for example, Electronic Data Capture, IxRS, electronic patient reported outcomes, etc. PMID- 26952179 TI - "Ruptured" malignant phyllodes tumor of the breast: a case report. AB - Phyllodes tumor or cystosarcoma phyllodes is a rare disease and is usually seen in middle-aged patients. Ruptured phyllodes tumor is a very rare condition. Our study reports patient presentation, diagnosis method, and treatment of an unusual case. A 58-year-old premenopausal female was diagnosed with a phyllodes tumor and presented with a rapidly growing mass for 2 months that ruptured 1 month later. She underwent simple mastectomy at the left side of her breast and received adjuvant radiotherapy. No recurrence was found 4 months after operation. PMID- 26952180 TI - Common pitfalls in statistical analysis: Absolute risk reduction, relative risk reduction, and number needed to treat. AB - In the previous article in this series on common pitfalls in statistical analysis, we looked at the difference between risk and odds. Risk, which refers to the probability of occurrence of an event or outcome, can be defined in absolute or relative terms. Understanding what these measures represent is essential for the accurate interpretation of study results. PMID- 26952181 TI - Concerns about usage of smartphones in operating room and critical care scenario. AB - Smartphones and tablets have taken a central place in the lives of health care professionals. Their use has dramatically improved the communication and has become an important learning tool as the medical information can be assessed online at anytime. In critical care settings, use of smartphone facilitates quick passage of information through E-mail messaging and getting feedback from the concerned physician quickly, thereby reducing medical errors. However, in addition to the benefits offered, these devices have become a significant source of nosocomial infections, distraction for medical professionals and interfere with medical equipments. They may also put privacy and security of patients at stake. The benefits could be severely undermined if abuse and over use are not kept in check. This review article focuses on various applications of smartphones in healthcare practices, drawback of the use of these devices and the recommendations regarding the safe use of these devices. PMID- 26952182 TI - Cutaneous lupus erythematosus of elbows: A distinct entity? AB - The elbow is not recognized as common site for cutaneous lupus erythematosus (CLE) lesions. Twelve cases of CLE over the elbows were evaluated for systemic involvement and Cutaneous Lupus Disease Area and Severity Index activity and damage scores and Systemic Lupus Erythematosus Disease Activity Index scoring was done. Histopathological examination of the affected skin was performed in doubtful cases. Most of the patients were women (10, 83.3%) with mean age of 28.75 years. Three patients had only elbow lesions and the remaining nine patients had CLE lesions at sites other than the elbows, of which five had elbow lesions preceding skin lesions elsewhere over the body and three patients were not aware of whether elbow lesions preceded or succeeded CLE lesions at other sites, and one patient had noticed malar rash 9 months prior to elbow lesions. All the patients antinuclear antibody positivity, systemic involvement, and fulfilled criteria for systemic lupus erythematosus. This peculiar localization of CLE to the elbows may be associated with a greater risk of systemic involvement and may be an predictor of flare of LE. PMID- 26952183 TI - Development and psychometric testing of a scale for the assessment of the quality of developmental care in neonatal intensive care units in Iran. AB - INTRODUCTION: Developmental care provided to infants hospitalized at neonatal intensive care units (NICU) help weaken environmental stressors and reduce infant morbidity rates. Assessments are the first step to improving the quality of any type of care. Therefore, this study was conducted to design and assess the psychometric features of a scale designed for measuring quality of developmental care in the NICU in Iran. METHODS: This study was conducted from December 2014 through September 2015 in Tehran, Iran. The present mixed-methods sequential exploratory (quantitative-qualitative) study used the Delphi method to design an initial questionnaire through a review of the literature and by using the input of experts. The validity of the questionnaire was ensured by assessing then validity of its content (qualitative-quantitative), face (qualitative quantitative), and construct (exploratory factor analysis with 500 NICU personnel from 34 hospitals in Tehran), and its reliability was ensured by assessing its internal consistency (using Cronbach's alpha) and by assessing its stability through the test-retest method. RESULTS: The qualitative stage of the study resulted in a 93-item questionnaire with eight domains. After performing the content and face analyses, a factor analysis was performed on 90 items of the questionnaire, yielding a 76-item questionnaire with five domains, including "sleep, pain and stress management," "routine care," "the family," "management," and "sensory care," which explained 62.5% of the variance. The reliability of the questionnaire was confirmed with a Cronbach's alpha of 0.9 and its stability was confirmed by an Intraclass Correlation Coefficient (ICC) of 0.93. CONCLUSION: The questionnaire developed for the assessment of developmental care in the NICU covered all of the dimensions of this type of care, and it is a valid and reliable tool for assessing and improving developmental care in the NICU. PMID- 26952184 TI - Antibiotic use in urological surgeries: a six years review at Muhimbili National Hospital, Dar es salaam-Tanzania. AB - INTRODUCTION: Antimicrobial prophylaxis for urologic procedures is a major issue, as potential advantages of antibiotic administration should be carefully weighed against potential side effects, microbial resistance, and health care costs. This study aimed to review a six years trend of antibiotic use in urological surgeries at Muhimbili National Hospital (MNH) being an experience in a typical third world environment. METHODS: This was a six years hospital based descriptive, retrospective study conducted of which all case notes of urological patients operated on in between January 2007 to December, 2012 were reviewed by using a structured data collecting tool. The data were analyzed using SPSS software. RESULTS: Male patients were the majority at 62% (450). The age range was 0 - 90 years, with a mean of 30 +/- 22.09. Among the urological surgeries done at MNH 86.5% (628) received prophylactic antibiotics regardless of the type surgery done. Majority 63.7% (463) received antibiotics during induction. Ceftriaxone was the commonly given antibiotic regardless of the type of urological surgery done. Most of patients (86.4%) were given antibiotics for five days regardless whether it was for prophylactic or treatment intention. CONCLUSION: Antibiotic use is still a challenge at our hospital with over use of prophylactic antibiotics without obvious indications. Prolonged use of prophylactic antibiotics beyond five days was the main finding. Ceftriaxone was the most given antibiotic regardless of the urological surgery done and its level of contamination. Antibiotic stewardship needs to be addressed urgently to avoid serious drug resistances leaving alone the cost implication. PMID- 26952185 TI - Meeting the educational and social needs of children with language impairment or autism spectrum disorder: the parents' perspectives. AB - BACKGROUND: There is increasing interest in examining the perspectives of parents of children with special educational needs (SEN). Exploring the view of parents of a child with language impairment (LI) or autism spectrum disorder (ASD) is particularly important because of their high prevalence, at over 30% of children with SEN in England, and the increasing evidence of overlapping profiles of their needs. AIMS: To examine the similarities and differences between the perspectives of parents of children with LI or ASD on three issues: (1) their child's educational progress, and their behavioural, emotional and social development; (2) the provision made to support their child's education and meet their SEN; and (3) their own involvement in decision-making about provision for their child. METHODS & PROCEDURES: The parents of 129 children with LI (n = 76) or ASD (n = 53) were interviewed using a semi-structured protocol that gathered both quantitative data (parent ratings) and qualitative, in-depth explorations of their perspectives. OUTCOMES & RESULTS: There were no significant differences between the perspectives of parents of children with LI and parents of children with ASD with respect to their child's educational progress; the provision made to meet their child's educational needs; or their involvement in decision-making during the statutory assessment procedure, including the determination of a statement of SEN, and the current provision made by their child's school. Both parent groups were generally positive about these but parents of children with ASD were more concerned about their child's peer relationships. Parents whose child attended a mainstream school with a specialist resource tended to be more positive about the provision made than parents whose child was included individually into a mainstream school. CONCLUSIONS & IMPLICATIONS: Although previous research indicates that parents of children with ASD are overrepresented among those who express dissatisfaction with the provision made to meet their child's needs, this study indicates high levels of satisfaction and overlap between the perspectives of parents of children with LI or ASD regarding their child's educational progress and their own involvement in decision-making about the child's provision. The findings indicate the importance for policy and practice of focusing on identified needs rather than diagnostic category; and the importance of practitioners and administrators engaging meaningfully with parents in collaborative decision-making. PMID- 26952188 TI - 1,25-Dihydroxyvitamin D increases the gene expression of enzymes protecting from glucolipotoxicity in peripheral blood mononuclear cells and human primary endothelial cells. AB - Besides its classical function as an orchestrator of calcium and phosphorus homeostasis, vitamin D also affects insulin secretion and tissue efficiency. A number of studies have consistently reported the inverse relationship between vitamin D deficiency and type 2 diabetes. Activation of certain metabolic pathways and down-stream transcription factors may protect from glucolipotoxicity and their targeted activation -e.g. by vitamin D - might explain the detrimental role of vitamin D deficiency in diabetes. The aim of the study was to quantify gene and protein expression of selected enzymes involved in the protection from glucolipotoxicity, specifically glyoxalase 1 (GLO1), and other enzymes with antioxidant activity - hemoxygenase (HMOX), thiamin pyrophosphokinase (TPK1) and transketolase (TKT), under normo- and hyperglycemic conditions and upon addition of vitamin D in peripheral blood mononuclear cells (PBMCs) and human umbilical vein endothelial cells (HUVEC). The results of our study indicate that the active form of vitamin D regulates gene expression of enzymes opposing the harmful effect of glucolipotoxicity whose activities appear to be suppressed by hyperglycemia. However, we were unable to confirm this effect on protein expression. While we cannot speculate on the effect of vitamin D on diabetes itself our results support its role in the protection against existing glucolipotoxicity therefore possibly translating into the prevention of development of diabetic complications. PMID- 26952187 TI - Inductive interactions mediated by interplay of asymmetric signalling underlie development of adult haematopoietic stem cells. AB - During embryonic development, adult haematopoietic stem cells (HSCs) emerge preferentially in the ventral domain of the aorta in the aorta-gonad-mesonephros (AGM) region. Several signalling pathways such as Notch, Wnt, Shh and RA are implicated in this process, yet how these interact to regulate the emergence of HSCs has not previously been described in mammals. Using a combination of ex vivo and in vivo approaches, we report here that stage-specific reciprocal dorso ventral inductive interactions and lateral input from the urogenital ridges are required to drive HSC development in the aorta. Our study strongly suggests that these inductive interactions in the AGM region are mediated by the interplay between spatially polarized signalling pathways. Specifically, Shh produced in the dorsal region of the AGM, stem cell factor in the ventral and lateral regions, and BMP inhibitory signals in the ventral tissue are integral parts of the regulatory system involved in the development of HSCs. PMID- 26952189 TI - Ecological Instability in Lakes: A Predictable Condition? PMID- 26952190 TI - Using NMR spectroscopy to elucidate the role of molecular motions in enzyme function. AB - Conformational motions play an essential role in enzyme function, often facilitating the formation of enzyme-substrate complexes and/or product release. Although considerable debate remains regarding the role of molecular motions in the conversion of enzymatic substrates to products, numerous examples have found motions to be crucial for optimization of enzyme scaffolds, effective substrate binding, and product dissociation. Conformational fluctuations are often rate limiting to enzyme catalysis, primarily through product release, with the chemical reaction occurring much more quickly. As a result, the direct involvement of motions at various stages along the enzyme reaction coordinate remains largely unknown and untested. In the following review, we describe the use of solution NMR techniques designed to probe various timescales of molecular motions and detail examples in which motions play a role in propagating catalytic effects from the active site and directly participate in essential aspects of enzyme function. PMID- 26952192 TI - How to tackle protein structural data from solution and solid state: An integrated approach. AB - Long-range NMR restraints, such as diamagnetic residual dipolar couplings and paramagnetic data, can be used to determine 3D structures of macromolecules. They are also used to monitor, and potentially to improve, the accuracy of a macromolecular structure in solution by validating or "correcting" a crystal model. Since crystal structures suffer from crystal packing forces they may not be accurate models for the macromolecular structures in solution. However, the presence of real differences should be tested for by simultaneous refinement of the structure using both crystal and solution NMR data. To achieve this, the program REFMAC5 from CCP4 was modified to allow the simultaneous use of X-ray crystallographic and paramagnetic NMR data and/or diamagnetic residual dipolar couplings. Inconsistencies between crystal structures and solution NMR data, if any, may be due either to structural rearrangements occurring on passing from the solution to solid state, or to a greater degree of conformational heterogeneity in solution with respect to the crystal. In the case of multidomain proteins, paramagnetic restraints can provide the correct mutual orientations and positions of domains in solution, as well as information on the conformational variability experienced by the macromolecule. PMID- 26952193 TI - Enhanced DR5 binding capacity of nanovectorized TRAIL compared to its cytotoxic version by affinity chromatography and molecular docking studies. AB - Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis of cancer cells when bound to its cognate receptors, TRAIL-R1 and TRAIL-R2 (DR4 and DR5), without being toxic to healthy cells. Nanovectorized TRAIL (abbreviated as NPT) is 10 to 20 times more efficient than one of the most potent soluble TRAIL used in preclinical studies (His-TRAIL). To determine whether differences in affinity may account for NPT superiority, a thermodynamic study was undertaken to evaluate NPT versus TRAIL binding affinity to DR5. Docking calculations showed that TRAIL in homotrimer configuration was more stable than in heterotrimer, because of the presence of one Zn ion in its structure. Indeed, TRAIL trimers can have head-to-tail orientations when Zn is missing. Altogether these data suggest that TRAIL homotrimer structures are predominant in solution and then are grafted on NPT. When docked to DR5, NPT carrying TRAIL homotrimer leads to a more stable complex than TRAIL monomer-based NPT. To comfort these observations, the extracellular domain of DR5 was immobilized on a chromatographic support using an "in situ" immobilization technique. The determination of the thermodynamic data (enthalpy ?H degrees and entropy ?S degrees *) of TRAIL and NPT binding to DR5 showed that the binding mechanism was pH dependent. The affinity of NPT to DR5 increased with pH, and the ionized energy was more important for NPT than for soluble TRAIL. Moreover, because of negative values of ?H degrees and ?S degrees * quantities, we demonstrated that van der Waals and hydrogen bonds governed the strong NPT-DR5 association for pH > 7.4 (as for TRAIL alone). Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26952194 TI - Effect of Governance Indicators on Under-Five Mortality in OECD Nations: Generalized Method of Moments. AB - INTRODUCTION: Today, it is recognized that factors other than health services are involved in health improvement and decreased inequality so identifying them is the main concern of policy makers and health authorities. The aim of this study was to investigate the effect of governance indicators on health outcomes. METHODS: A panel data study was conducted to investigate the effect of governance indicators on child mortality rate in 27 OECD countries from 1996 to 2012 using the Generalized Method of Moments (GMM) model and EVIEWS.8 software. RESULTS: According to the results obtained, under-five mortality rate was significantly related to all of the research variables (p < 0.05). One percent increase in under-five mortality in the previous period resulted in a 0.83% increase in the mortality rate in the next period, and a 1% increase in total fertility rate, increased the under-five mortality rate by 0.09%. In addition, a 1% increase in GDP per capita decreased the under-five mortality rate by 0.07%, and a 1% improvement in control of corruption and rule of law indicators decreased child mortality rate by 0.05 and 0.08%, respectively. Furthermore, 1% increase in public health expenditure per capita resulted in a 0.03% decrease in under-five mortality rate. CONCLUSION: The results of the study suggest that considering control variables, including GDP per capita, public health expenditure per capita, total fertility rate, and improvement of governance indicators (control of corruption and rule of law) would decrease the child mortality rate. PMID- 26952191 TI - Applications of NMR spectroscopy to systems biochemistry. AB - The past decades of advancements in NMR have made it a very powerful tool for metabolic research. Despite its limitations in sensitivity relative to mass spectrometric techniques, NMR has a number of unparalleled advantages for metabolic studies, most notably the rigor and versatility in structure elucidation, isotope-filtered selection of molecules, and analysis of positional isotopomer distributions in complex mixtures afforded by multinuclear and multidimensional experiments. In addition, NMR has the capacity for spatially selective in vivo imaging and dynamical analysis of metabolism in tissues of living organisms. In conjunction with the use of stable isotope tracers, NMR is a method of choice for exploring the dynamics and compartmentation of metabolic pathways and networks, for which our current understanding is grossly insufficient. In this review, we describe how various direct and isotope-edited 1D and 2D NMR methods can be employed to profile metabolites and their isotopomer distributions by stable isotope-resolved metabolomic (SIRM) analysis. We also highlight the importance of sample preparation methods including rapid cryoquenching, efficient extraction, and chemoselective derivatization to facilitate robust and reproducible NMR-based metabolomic analysis. We further illustrate how NMR has been applied in vitro, ex vivo, or in vivo in various stable isotope tracer-based metabolic studies, to gain systematic and novel metabolic insights in different biological systems, including human subjects. The pathway and network knowledge generated from NMR- and MS-based tracing of isotopically enriched substrates will be invaluable for directing functional analysis of other 'omics data to achieve understanding of regulation of biochemical systems, as demonstrated in a case study. Future developments in NMR technologies and reagents to enhance both detection sensitivity and resolution should further empower NMR in systems biochemical research. PMID- 26952195 TI - A cortical vascular model for examining the specificity of the laminar BOLD signal. AB - Blood oxygenation level dependent (BOLD) functional MRI has been used for inferring layer specific activation in humans. However, intracortical veins perpendicular to the cortical surface are suspected to degrade the laminar specificity as they drain blood from the microvasculature and BOLD signal is carried over from lower to upper cortical layers on its way to the pial surface. In this work, a vascular model of the cortex is developed to investigate the laminar specificity of the BOLD signal for Spin Echo (SE) and Gradient Echo (GE) following the integrative model presented by Uludag et al. (2009). The results of the simulation show that the laminar point spread function (PSF) of the BOLD signal presents similar features across all layers. The PSF for SE is highly localised whereas for GE there is a flat tail running to the pial surface, with amplitude less than a quarter of the response from the layer itself. Consequently the GE response at any layer will also contain a contribution accumulated from all lower layers. PMID- 26952196 TI - Identification of canonical neural events during continuous gameplay of an 8-bit style video game. AB - Cognitive neuroscience suffers from a unique and pervasive problem of generalizability. Since neural findings are often interpreted in the context of a specific manipulation during a carefully controlled task, it is hard to transfer knowledge from one task to another. In this report we address problems of generalizability with two methodological advancements. First, we aimed to transcend status quo experimental procedures with a continuous, engaging task environment. To this end, we created a novel 8-bit style continuous space shooter video game that elicits a multitude of goal-oriented events, such as crashing into a wall or blowing up an enemy with a missile. Second, we aimed to objectively define the psychological significance of these events. To achieve this aim, we used pattern classification of EEG data to derive predictive weights from carefully controlled pre-game exemplar events (oddball target detection and gambling wins and losses) and transferred those weights to EEG activities during video game events. All major goal-oriented events (crashes into the wall, crashes into an enemy, missile hit on an enemy) had a significant between-task transfer bias towards oddball target weights in the time range of the canonical P3, indicating the presence of similar salience detection processes. Missile hits on an enemy were specifically identified as gambling wins, confirming the hypothesis that this goal-oriented event was appetitive. These findings suggest that it is possible to identify the contribution of canonical neural activities during otherwise ambiguous and uncontrolled task performance. PMID- 26952197 TI - Evaluation of sliding window correlation performance for characterizing dynamic functional connectivity and brain states. AB - A promising recent development in the study of brain function is the dynamic analysis of resting-state functional MRI scans, which can enhance understanding of normal cognition and alterations that result from brain disorders. One widely used method of capturing the dynamics of functional connectivity is sliding window correlation (SWC). However, in the absence of a "gold standard" for comparison, evaluating the performance of the SWC in typical resting-state data is challenging. This study uses simulated networks (SNs) with known transitions to examine the effects of parameters such as window length, window offset, window type, noise, filtering, and sampling rate on the SWC performance. The SWC time course was calculated for all node pairs of each SN and then clustered using the k-means algorithm to determine how resulting brain states match known configurations and transitions in the SNs. The outcomes show that the detection of state transitions and durations in the SWC is most strongly influenced by the window length and offset, followed by noise and filtering parameters. The effect of the image sampling rate was relatively insignificant. Tapered windows provide less sensitivity to state transitions than rectangular windows, which could be the result of the sharp transitions in the SNs. Overall, the SWC gave poor estimates of correlation for each brain state. Clustering based on the SWC time course did not reliably reflect the underlying state transitions unless the window length was comparable to the state duration, highlighting the need for new adaptive window analysis techniques. PMID- 26952198 TI - Top-down alpha oscillatory network interactions during visuospatial attention orienting. AB - Neuroimaging and lesion studies indicate that visual attention is controlled by a distributed network of brain areas. The covert control of visuospatial attention has also been associated with retinotopic modulation of alpha-band oscillations within early visual cortex, which are thought to underlie inhibition of ignored areas of visual space. The relation between distributed networks mediating attention control and more focal oscillatory mechanisms, however, remains unclear. The present study evaluated the hypothesis that alpha-band, directed, network interactions within the attention control network are systematically modulated by the locus of visuospatial attention. We localized brain areas involved in visuospatial attention orienting using magnetoencephalographic (MEG) imaging and investigated alpha-band Granger-causal interactions among activated regions using narrow-band transfer entropy. The deployment of attention to one side of visual space was indexed by lateralization of alpha power changes between about 400ms and 700ms post-cue onset. The changes in alpha power were associated, in the same time period, with lateralization of anterior-to-posterior information flow in the alpha-band from various brain areas involved in attention control, including the anterior cingulate cortex, left middle and inferior frontal gyri, left superior temporal gyrus, and right insula, and inferior parietal lobule, to early visual areas. We interpreted these results to indicate that distributed network interactions mediated by alpha oscillations exert top-down influences on early visual cortex to modulate inhibition of processing for ignored areas of visual space. PMID- 26952199 TI - The MYpop toolbox: Putting yeast stress responses in cellular context on single cell and population scales. AB - Systems biology holds the promise to integrate multiple sources of information in order to build ever more complete models of cellular function. To do this, the field must overcome two significant challenges. First, the current strategy to model average cells must be replaced with population based models accounting for cell-to-cell variability. Second, models must be integrated with each other and with basic cellular function. This requires a core model of cellular physiology as well as a multiscale simulation platform to support large-scale simulation of culture or tissues from single cells. Here, we present such a simulation platform with a core model of yeast physiology as scaffold to integrate and simulate SBML models. The software automates this integration helping users simulate their model of choice in context of the cell division cycle. We benchmark model merging, simulation and analysis by integrating a minimal model of osmotic stress into the core model and analyzing it. We characterize the effect of single cell differences on the dynamics of osmoadaptation, estimating when normal cell growth is resumed and obtaining an explanation for experimentally observed glycerol dynamics based on population dynamics. Hence, the platform can be used to reconcile single cell and population level data. PMID- 26952200 TI - Update in treatment options in pulmonary hypertension. AB - Significant developments have occurred in the field of pulmonary hypertension (PH) in the past 2 years, especially in terms of treatment options available. These include: approval of new drugs; evidence for use of initial combination therapies in pulmonary arterial hypertension; approved drugs for use in chronic thromboembolic disease not amenable to, or persistent after surgical thromboendarterectomy; and ongoing clinical trials in PH related to left heart disease and hypoxia. The field continues to evolve and address the challenges in treatment of this multifaceted disease with the aim to provide novel solutions and meet the needs of a growing population with PH. This has led to an extensive body of literature, ranging from case series to prospective, multicenter clinical trials, which will enhance the future of patient outcomes in PH. This contemporary review highlights the key articles in treatment updates for PH for the years 2013 to 2015. PMID- 26952201 TI - Annular Lichenoid Dermatitis of Youth: A Report of 2 Cases and a Review of the Literature. AB - Annular lichenoid dermatitis of youth is a lichenoid dermatosis of unknown etiology. It mostly affects children and adolescents and has well-defined clinical and histological characteristics that permit a diagnosis. We present 2 new cases of annular lichenoid dermatitis of youth with classical clinical features in 2 girls, aged 2 and 4 years. The histologic findings, however, differed from those reported in the literature in that the lichenoid inflammatory infiltrate was located primarily at the top of the dermal papillae and not at the tips of the rete ridges. In both cases, the lesions regressed spontaneously without treatment. PMID- 26952202 TI - Majocchis Granuloma Caused by Trichophyton mentagrophytes in 2 Immunocompetent Patients. AB - Majocchi granuloma is an uncommon deep follicular inflammation caused by dermatophytes and affects immunocompetent and immunocompromised patients. The clinical findings overlap with other skin conditions such bacterial infections and inflammatory skin diseases, thereby delaying correct diagnosis. We describe 2 cases in immunocompetent patients. PMID- 26952203 TI - [The Resurgence of Sexually Transmitted Infections. A New Epidemic in Our Society?]. PMID- 26952204 TI - Greater vertical loading rate in obese compared to normal weight young adults. AB - BACKGROUND: Obesity is a risk factor for knee osteoarthritis. Altered gait biomechanics are common in obese individuals, and may contribute to the development of knee osteoarthritis. Research has focused on older obese adults with knee osteoarthritis, and it is unclear if young obese individuals display similar aberrant biomechanics. The purpose of this study was to compare gait biomechanics between normal-weight and obese young adults. METHODS: 15 normal weight (body mass index=21.5 (1.1)) and 15 obese (body mass index=33.5 (3.7)) young adults were recruited and categorized by body mass index. Lower extremity kinematics and kinetics were collected while participants walked at standardized (1m/s) and self-selected speeds. Analysis of variance (group by condition) was used to compare peak vertical ground reaction force, vertical loading rate, peak internal knee extension moment, peak internal knee abduction moment, peak knee flexion angle, and knee flexion excursion between groups. FINDINGS: Gait biomechanics did not differ between groups during walking at a self-selected speed. When walking at a standardized speed, obese subjects displayed greater instantaneous vertical loading rates (46.2 vs. 35.0 N/s, P<0.001), and lesser knee flexion excursion (5.5 degrees vs. 7.7 degrees , P=0.04). Instantaneous vertical loading rate was greater during walking at a self-selected speed compared to a standardized speed in the obese (P=0.007) and normal weight groups (P=0.001). INTERPRETATION: As greater loading rates are related to cartilage degeneration, these results suggest that obesity may contribute to knee osteoarthritis. Prospective studies are needed to identify the influence of higher loading rates on knee osteoarthritis. PMID- 26952205 TI - Difference in Postoperative Periprosthetic Bone Mineral Density Changes Between 3 Major Designs of Uncemented Stems: A 3-Year Follow-Up Study. AB - BACKGROUND: Although few studies have examined the direct effect of stress shielding on clinical outcomes, periprosthetic bone loss due to stress shielding is still an issue of concern, especially when physicians perform uncemented total hip arthroplasty (THA) in younger patients. Differences in femoral stem design may affect the degree of postoperative stress shielding. Therefore, the characteristics of the behavior for stress shielding of each type of femoral stem should be determined. This study compares differences in bone mineral density (BMD) change in the femur after primary THA between 3 major types of uncemented stems. METHODS: Among a total of 89 hips, 26 hips received THA with a fit-and fill type stem (VerSys Fiber Metal MidCoat; Zimmer, Inc, Warsaw, IN), 32 hips received a tapered rectangular Zweymuller-type stem (SL-Plus; Smith & Nephew Inc, Memphis, TN), and 31 received a tapered wedge-type stem (Accolade TMZF; Stryker Orthopaedics, Mahwah, NJ). BMD measurements were performed with a HOLOGIC Discovery device (Hologic Inc, Waltham, MA). RESULTS: BMD in the medial-proximal femur was maintained for 3 years after THA in the group with the tapered wedge type stem. BMD in the lateral-proximal femur was maintained for 3 years after THA in the group with the Zweymuller-type stem. There were no significant differences in the Harris Hip Score among the 3 stem groups preoperatively and 1, 2, and 3 years after surgery. CONCLUSION: There are clear differences in postoperative BMD loss of the proximal femur among these 3 commonly used uncemented stems. PMID- 26952206 TI - Long-Term Results of Total Hip Arthroplasty With Shortening Subtrochanteric Osteotomy in Crowe IV Developmental Dysplasia. AB - BACKGROUND: Numerous series have documented short-term successes with cementless total hip arthroplasty (THA) and subtrochanteric shortening osteotomy for Crowe IV developmental dysplasia of the hip (DDH). However, data are lacking regarding long-term implant fixation and patient function. In this study, we aimed to evaluate the 10-year results of cementless THA with simultaneous subtrochanteric shortening osteotomy for Crowe IV DDH. METHODS: We retrospectively reviewed 28 consecutive primaries cementless THAs performed in 24 patients with Crowe IV DDH between 1992 and 2005. Evaluation was performed through Harris Hip Scores, physical examination, and radiographic analysis. RESULTS: At mean follow-up 10 years, 5 hips were revised, and 3 patients had died leaving 20 hips for clinical analysis. Harris Hip Score was significantly improved compared to preoperative values (43 vs 87 P < .0001). The 10-year survivorship free from revision for aseptic loosening was 89%. Twenty-nine percent patients had an early complication, but these did not have long-term deleterious effects on the reconstruction, and there were no reoperations for any reason after 7 years. CONCLUSIONS: In the longest series to date, cementless THA combined with a subtrochanteric femoral shortening osteotomy in patients with a high hip dislocation secondary to dysplasia was associated with high rates of successful implant fixation and stable clinical improvement. PMID- 26952208 TI - Gender-related aspects of transmasculine people's vocal situations: insights from a qualitative content analysis of interview transcripts. AB - BACKGROUND: Transmasculine people assigned female gender at birth but who do not identify with this classification have traditionally received little consideration in the voice literature. Existing analyses tend to be focused on evaluating speaker voice characteristics, whereas other factors that contribute to the production of vocal gender have remained underexplored. Most studies rely on researcher-centred perspectives, whereas very little is known about how transmasculine people themselves experience and make sense of their vocal situations. AIMS: To explore how participants described their subjective gender positionings; which gender attributions they wished to receive from others; which gender they self-attributed to their voices; which gender attributions they had received from others; and how far participants were satisfied with the gender related aspects of their vocal situations. METHODS & PROCEDURES: Transcripts of semi-structured interviews with 14 German-speaking transmasculine people served as the original data corpus. Sections in which participants described the gender related aspects of their vocal situations and that were relevant to the current research objectives were selected and explored using qualitative content analysis. OUTCOMES & RESULTS: The analysis revealed diverse accounts pertaining to the factors that contribute to the production of vocal gender for individual participants and variable levels of satisfaction with vocal gender presentation and attribution. CONCLUSIONS & IMPLICATIONS: Transmasculine people need to be regarded as a heterogeneous population and clinical practice needs to follow a client-centred, individualized approach. PMID- 26952209 TI - Degradation of Gadd45 mRNA by nonsense-mediated decay is essential for viability. AB - The nonsense-mediated mRNA decay (NMD) pathway functions to degrade both abnormal and wild-type mRNAs. NMD is essential for viability in most organisms, but the molecular basis for this requirement is unknown. Here we show that a single, conserved NMD target, the mRNA coding for the stress response factor growth arrest and DNA-damage inducible 45 (GADD45) can account for lethality in Drosophila lacking core NMD genes. Moreover, depletion of Gadd45 in mammalian cells rescues the cell survival defects associated with NMD knockdown. Our findings demonstrate that degradation of Gadd45 mRNA is the essential NMD function and, surprisingly, that the surveillance of abnormal mRNAs by this pathway is not necessarily required for viability. PMID- 26952210 TI - Trifunctional cross-linker for mapping protein-protein interaction networks and comparing protein conformational states. AB - To improve chemical cross-linking of proteins coupled with mass spectrometry (CXMS), we developed a lysine-targeted enrichable cross-linker containing a biotin tag for affinity purification, a chemical cleavage site to separate cross linked peptides away from biotin after enrichment, and a spacer arm that can be labeled with stable isotopes for quantitation. By locating the flexible proteins on the surface of 70S ribosome, we show that this trifunctional cross-linker is effective at attaining structural information not easily attainable by crystallography and electron microscopy. From a crude Rrp46 immunoprecipitate, it helped identify two direct binding partners of Rrp46 and 15 protein-protein interactions (PPIs) among the co-immunoprecipitated exosome subunits. Applying it to E. coli and C. elegans lysates, we identified 3130 and 893 inter-linked lysine pairs, representing 677 and 121 PPIs. Using a quantitative CXMS workflow we demonstrate that it can reveal changes in the reactivity of lysine residues due to protein-nucleic acid interaction. PMID- 26952211 TI - Extracting grid cell characteristics from place cell inputs using non-negative principal component analysis. AB - Many recent models study the downstream projection from grid cells to place cells, while recent data have pointed out the importance of the feedback projection. We thus asked how grid cells are affected by the nature of the input from the place cells. We propose a single-layer neural network with feedforward weights connecting place-like input cells to grid cell outputs. Place-to-grid weights are learned via a generalized Hebbian rule. The architecture of this network highly resembles neural networks used to perform Principal Component Analysis (PCA). Both numerical results and analytic considerations indicate that if the components of the feedforward neural network are non-negative, the output converges to a hexagonal lattice. Without the non-negativity constraint, the output converges to a square lattice. Consistent with experiments, grid spacing ratio between the first two consecutive modules is -1.4. Our results express a possible linkage between place cell to grid cell interactions and PCA. PMID- 26952212 TI - Tracking interspecies transmission and long-term evolution of an ancient retrovirus using the genomes of modern mammals. AB - Mammalian genomes typically contain hundreds of thousands of endogenous retroviruses (ERVs), derived from ancient retroviral infections. Using this molecular 'fossil' record, we reconstructed the natural history of a specific retrovirus lineage (ERV-Fc) that disseminated widely between ~33 and ~15 million years ago, corresponding to the Oligocene and early Miocene epochs. Intercontinental viral spread, numerous instances of interspecies transmission and emergence in hosts representing at least 11 mammalian orders, and a significant role for recombination in diversification of this viral lineage were also revealed. By reconstructing the canonical retroviral genes, we identified patterns of adaptation consistent with selection to maintain essential viral protein functions. Our results demonstrate the unique potential of the ERV fossil record for studying the processes of viral spread and emergence as they play out across macro-evolutionary timescales, such that looking back in time may prove insightful for predicting the long-term consequences of newly emerging viral infections. PMID- 26952213 TI - Resistome diversity in cattle and the environment decreases during beef production. AB - Antimicrobial resistant determinants (ARDs) can be transmitted from livestock systems through meat products or environmental effluents. The public health risk posed by these two routes is not well understood, particularly in non-pathogenic bacteria. We collected pooled samples from 8 groups of 1741 commercial cattle as they moved through the process of beef production from feedlot entry through slaughter. We recorded antimicrobial drug exposures and interrogated the resistome at points in production when management procedures could potentially influence ARD abundance and/or transmission. Over 300 unique ARDs were identified. Resistome diversity decreased while cattle were in the feedlot, indicating selective pressure. ARDs were not identified in beef products, suggesting that slaughter interventions may reduce the risk of transmission of ARDs to beef consumers. This report highlights the utility and limitations of metagenomics for assessing public health risks regarding antimicrobial resistance, and demonstrates that environmental pathways may represent a greater risk than the food supply. PMID- 26952214 TI - HSF-1 activates the ubiquitin proteasome system to promote non-apoptotic developmental cell death in C. elegans. AB - Apoptosis is a prominent metazoan cell death form. Yet, mutations in apoptosis regulators cause only minor defects in vertebrate development, suggesting that another developmental cell death mechanism exists. While some non-apoptotic programs have been molecularly characterized, none appear to control developmental cell culling. Linker-cell-type death (LCD) is a morphologically conserved non-apoptotic cell death process operating in Caenorhabditis elegans and vertebrate development, and is therefore a compelling candidate process complementing apoptosis. However, the details of LCD execution are not known. Here we delineate a molecular-genetic pathway governing LCD in C. elegans. Redundant activities of antagonistic Wnt signals, a temporal control pathway, and mitogen-activated protein kinase kinase signaling control heat shock factor 1 (HSF-1), a conserved stress-activated transcription factor. Rather than protecting cells, HSF-1 promotes their demise by activating components of the ubiquitin proteasome system, including the E2 ligase LET-70/UBE2D2 functioning with E3 components CUL-3, RBX-1, BTBD-2, and SIAH-1. Our studies uncover design similarities between LCD and developmental apoptosis, and provide testable predictions for analyzing LCD in vertebrates. PMID- 26952215 TI - Anomalous correlation effects and unique phase diagram of electron-doped FeSe revealed by photoemission spectroscopy. AB - FeSe layer-based superconductors exhibit exotic and distinctive properties. The undoped FeSe shows nematicity and superconductivity, while the heavily electron doped KxFe2-ySe2 and single-layer FeSe/SrTiO3 possess high superconducting transition temperatures that pose theoretical challenges. However, a comprehensive study on the doping dependence of an FeSe layer-based superconductor is still lacking due to the lack of a clean means of doping control. Through angle-resolved photoemission spectroscopy studies on K-dosed thick FeSe films and FeSe0.93S0.07 bulk crystals, here we reveal the internal connections between these two types of FeSe-based superconductors, and obtain superconductivity below ~ 46 K in an FeSe layer under electron doping without interfacial effects. Moreover, we discover an exotic phase diagram of FeSe with electron doping, including a nematic phase, a superconducting dome, a correlation driven insulating phase and a metallic phase. Such an anomalous phase diagram unveils the remarkable complexity, and highlights the importance of correlations in FeSe layer-based superconductors. PMID- 26952216 TI - Au-Pd Bimetallic Catalysis: The Importance of Anionic Ligands in Catalyst Speciation. AB - Synergistic gold-palladium catalytic processes have been intensively sought during the past decade, because the combination of the carbophilic Lewis acidity of Au with the redox properties of Pd within a catalytic cycle is particularly appealing for the synthesis of novel functionalized compounds. We demonstrate here the feasibility of a Au-Pd bimetallic catalytic system based on the generation of competent Au and Pd species by anionic ligand exchange. This strategy enabled the preparation of a variety of substituted butenolides in a simple and efficient way. PMID- 26952217 TI - Ultrasound guidance improves the success rate of axillary plexus block: a meta analysis. AB - OBJECTIVE: To evaluate the value of real-time ultrasound (US) guidance for axillary brachial plexus block (AXB) through the success rate and the onset time. METHODS: The meta-analysis was carried out in the Anesthesiology Department of the Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China. A literature search of Medline, EMBASE, Cochrane database from the years 2004 to 2014 was performed. The literature searches were carried out using medical subject headings and free-text word: "axilla", "axillary", "brachial plexus", "ultrasonography", "ultrasound", "ultrasonics". Two different reviewers carried out the search and evaluated studies independently. RESULTS: Seven randomized controlled trials, one cohort study and three retrospective studies were included. A total of 2042 patients were identified. 1157 patients underwent AXB using US guidance (US group) and the controlled group included 885 patients (246 patients using traditional approach (TRAD) and 639 patients using nerve stimulation (NS)). Our analysis showed that the success rate was higher in the US group compared to the controlled group (90.64% vs. 82.21%, p<0.00001). The average time to perform the block and the onset of sensory time were shorter in the US group than the controlled group. CONCLUSION: The present study demonstrated that the real-time ultrasound guidance for axillary brachial plexus block improves the success rate and reduce the mean time to onset of anesthesia and the time of block performance. PMID- 26952218 TI - In vitro evaluation of the method effectiveness to limit inflation pressure cuffs of endotracheal tubes. AB - BACKGROUND AND OBJECTIVE: Cuffs of tracheal tubes protect the lower airway from aspiration of gastric contents and facilitate ventilation, but may cause many complications, especially when the cuff pressure exceeds 30cm H2O. This occurs in over 30% of conventional insufflations, so it is recommended to limit this pressure. In this study we evaluated the in vitro effectiveness of a method of limiting the cuff pressure to a range between 20 and 30cm H2O. METHOD: Using an adapter to connect the tested tube to the anesthesia machine, the relief valve was regulated to 30cm H2O, inflating the cuff by operating the rapid flow of oxygen button. There were 33 trials for each tube of three manufacturers, of five sizes (6.5-8.5), using three times inflation (10, 15 and 20s), totaling 1485 tests. After inflation, the pressure obtained was measured with a manometer. Pressure >30cm H2O or <20cm H2O were considered failures. RESULTS: There were eight failures (0.5%, 95% CI: 0.1-0.9%), with all by pressures <20cm H2O and after 10s inflation (1.6%, 95% CI: 0 5-2.7%). One failure occurred with a 6.5 tube (0.3%, 95% CI: -0.3 to 0.9%), six with 7.0 tubes (2%, 95% CI: 0.4-3.6%), and one with a 7.5 tube (0.3%, 95% CI: -0.3 to 0.9%). CONCLUSION: This method was effective for inflating tracheal tube cuffs of different sizes and manufacturers, limiting its pressure to a range between 20 and 30cm H2O, with a success rate of 99.5% (95% CI: 99.1-99.9%). PMID- 26952219 TI - Orotracheal intubation and temporomandibular disorder: a longitudinal controlled study. AB - BACKGROUND AND OBJECTIVES: To determine the incidence of signs and symptoms of temporomandibular disorder in elective surgery patients who underwent orotracheal intubation. METHODS: This was a longitudinal controlled study with two groups. The study group included patients who underwent orotracheal intubation and a control group. We used the American Academy of Orofacial Pain questionnaire to assess the temporomandibular disorder signs and symptoms one-day postoperatively (T1), and the patients' baseline status prior to surgery (T0) was also recorded. The same questionnaire was used after three months (T2). The mouth opening amplitude was measured at T1 and T2. We considered a p value of less than 0.05 to be significant. RESULTS: We included 71 patients, with 38 in the study group and 33 in the control. There was no significant difference between the groups in age (study group: 66.0 [52.5-72.0]; control group: 54.0 [47.0-68.0]; p=0.117) or in their belonging to the female gender (study group: 57.9%; control group: 63.6%; p=0.621). At T1, there were no statistically significant differences between the groups in the incidence of mouth opening limitation (study group: 23.7% vs. CONTROL GROUP: 18.2%; p=0.570) or in the mouth opening amplitude (study group: 45.0 [40.0-47.0] vs. CONTROL GROUP: 46.0 [40.0-51.0]; p=0.278). At T2 we obtained similar findings. There was no significant difference in the affirmative response to all the individual questions in the American Academy of Orofacial Pain questionnaire. CONCLUSIONS: In our population, the incidence of signs and symptoms of temporomandibular disorder of muscular origin was not different between the groups. PMID- 26952220 TI - Total knee replacement induces peripheral blood lymphocytes apoptosis and it is not prevented by regional anesthesia - a randomized study. AB - BACKGROUND: Among the many changes caused by a surgical insult one of the least studied is postoperative immunosuppression. This phenomenon is an important cause of infectious complications of surgery such as surgical site infection or hospital acquired pneumonia. One of the mechanisms leading to postoperative immunosuppression is the apoptosis of immunological cells. Anesthesia during surgery is intended to minimize harmful changes and maintain perioperative homeostasis. The aim of the study was evaluation of the effect of the anesthetic technique used for total knee replacement on postoperative peripheral blood lymphocyte apoptosis. METHODS: 34 patients undergoing primary total knee replacement were randomly assigned to two regional anesthetic protocols: spinal anesthesia and combined spinal-epidural anesthesia. 11 patients undergoing total knee replacement under general anesthesia served as control group. Before surgery, immediately after surgery, during first postoperative day and seven days after the surgery venous blood samples were taken and the immunological status of the patient was assessed with the use of flow cytometry, along with lymphocyte apoptosis using fluorescent microscopy. RESULTS: Peripheral blood lymphocyte apoptosis was seen immediately in the postoperative period and was accompanied by a decrease of the number of T cells and B cells. There were no significant differences in the number of apoptotic lymphocytes according to the anesthetic protocol. Changes in the number of T CD3/8 cells and the number of apoptotic lymphocytes were seen on the seventh day after surgery. CONCLUSION: Peripheral blood lymphocyte apoptosis is an early event in the postoperative period that lasts up to seven days and is not affected by the choice of the anesthetic technique. PMID- 26952221 TI - A comparison of two different doses of morphine added to spinal bupivacaine for inguinal hernia repair. AB - BACKGROUND AND OBJECTIVES: The aim of this study was to compare the effects of two different doses of intrathecal morphine on postoperative analgesia, postoperative first mobilization and urination times and the severity of side effects. METHODS: After Institutional Ethical Committee approval, 48 ASA I-II patients were enrolled in this randomized double-blinded study. Spinal anesthesia was performed with 0.1mg (Group I, n=22) or 0.4mg (Group II, n=26) ITM in addition to 7.5mg heavy bupivacaine. The first analgesic requirement, first mobilization and voiding times, and postoperative side effects were recorded. Statistical analyses were performed using SPSS 15.0 and p<0.05 was considered as statistically significant. The numeric data were analyzed by the t-test and presented as mean+/-SD. Categorical data were analyzed with the chi-square test and expressed as number of patients and percentage. RESULTS: Demographic data were similar among groups. There were no differences related to postoperative pain, first analgesic requirements, and first mobilization and first voiding times. The only difference between two groups was the vomiting incidence. In Group II 23% (n=6) of the patients had vomiting during the first postoperative 24h compared to 0% in Group I (p=0.025). CONCLUSION: For inguinal hernia repairs, the dose of 0.1mg of ITM provides comparable postoperative analgesia with a dose of 0.4mg, with significantly lower vomiting incidence when combined with low dose heavy bupivacaine. PMID- 26952222 TI - Effects of lidocaine and esmolol infusions on hemodynamic changes, analgesic requirement, and recovery in laparoscopic cholecystectomy operations. AB - OBJECTIVE: We compared the effects of lidocaine and esmolol infusions on intraoperative hemodynamic changes, intraoperative and postoperative analgesic requirements, and recovery in laparoscopic cholecystectomy surgery. METHODS: The first group (n=30) received IV lidocaine infusions at a rate of 1.5mg/kg/min and the second group (n=30) received IV esmolol infusions at a rate of 1mg/kg/min. Hemodynamic changes, intraoperative and postoperative analgesic requirements, and recovery characteristics were evaluated. RESULTS: In the lidocaine group, systolic arterial blood pressures values were lower after the induction of anesthesia and at 20min following surgical incision (p<0.05). Awakening time was shorter in the esmolol group (p<0.001); Ramsay Sedation Scale scores at 10min after extubation were lower in the esmolol group (p<0.05). The modified Aldrete scores at all measurement time points during the recovery period were relatively lower in the lidocaine group (p<0.05). The time to attain a modified Aldrete score of >=9 points was prolonged in the lidocaine group (p<0.01). Postoperative resting and dynamic VAS scores were higher in the lidocaine group at 10 and 20min after extubation (p<0.05, p<0.01, respectively). Analgesic supplements were less frequently required in the lidocaine group (p<0.01). CONCLUSION: In laparoscopic cholecystectomies, lidocaine infusion had superiorities over esmolol infusions regarding the suppression of responses to tracheal extubation and postoperative need for additional analgesic agents in the long run, while esmolol was more advantageous with respect to rapid recovery from anesthesia, attenuation of early postoperative pain, and modified Aldrete recovery (MAR) scores and time to reach MAR score of 9 points. PMID- 26952223 TI - Comparison of the postoperative analgesic effects of naproxen sodium and naproxen sodium-codeine phosphate for arthroscopic meniscus surgery. AB - BACKGROUND AND OBJECTIVES: Nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently used to control arthroscopic pain. Addition of oral effective opioid "codeine" to NSAIDs may be more effective and decrease parenteral opioid consumption in the postoperative period. The aim of this study was to compare the efficacy and side effects of naproxen sodium and a new preparation naproxen sodium-codeine phosphate when administered preemptively for arthroscopic meniscectomy. METHODS: Sixty-one patients were randomized into two groups to receive either oral naproxen sodium (Group N) or naproxen sodium-codeine phosphate (Group NC) before surgery. The surgery was carried out under general anesthesia. Intravenous meperidine was initiated by patient-controlled analgesia (PCA) for all patients. The primary outcome measure was pain score at the first postoperative hour assessed by the Visual Analogue Scale (VAS). Sedation assessed by Ramsey Sedation Scale, first demand time of PCA, postoperative meperidine consumption, side effects and hemodynamic data were also recorded. RESULTS: The groups were demographically comparable. Median VAS scores both at rest and on movement were significantly lower in Group NC compared with Group N, except 18(th) hour on movement (p<0.05). The median time to the first demand of PCA was shorter in Group N compared with Group NC (p<0.001). Meperidine consumption was higher in Group N compared with Group NC (p<0.001). There was no difference between groups with respect to side effects (p>0.05). CONCLUSIONS: The combination of naproxen sodium-codeine phosphate provided more effective analgesia than naproxen sodium and did not increase side effects. PMID- 26952224 TI - A comparison of different densities of levobupivacaine solutions for unilateral spinal anaesthesia. AB - BACKGROUND AND OBJECTIVES: The aim of the study was to compare the block characteristics and clinical effects of dextrose added to levobupivacaine solutions at different concentrations to provide unilateral spinal anaesthesia in lower extremity surgery. METHODS: This prospective, randomised, double-blind study comprised 75 ASA I-II risk patients for whom unilateral total knee arthroscopy was planned. The patients were assigned to three groups: in Group I, 60mg dextrose was added to 7.5mg of 0.5% levobupivacaine, in Group II, 80mg and in Group III, 100mg. Spinal anaesthesia was applied to the patient in the lateral decubitus position with the operated side below and the patient was kept in position for 10min. RESULTS: The time for the sensorial block to achieve T12 level was slower in Group I than in Groups II and III (p<0.05, p<0.00). The time to full recovery of the sensorial block was 136min in Group I, 154min in Group II and 170min in Group III. The differences were statistically significant (p<0.05). The mean duration of the motor block was 88min in Group I, 105min in Group II, and 139min in Group III and the differences were statistically significant (p<0.05). The time to urination in Group I was statistically significantly shorter than in the other groups (p<0.00). CONCLUSIONS: The results of the study showed that together with an increase in density, the sensory and motor block duration was lengthened. It can be concluded that 30mg mL(-1) concentration of dextrose added to 7.5mg levobupivacaine is sufficient to provide unilateral spinal anaesthesia in day-case arthroscopic knee surgery. PMID- 26952226 TI - The association between thenar eminence and I-gelTM dimensions in paediatric patients. AB - OBJECTIVES: A practical anatomic landmark may be helpful to perform the appropriate size of the airway devices easily in paediatric patients. The aim of this study was to investigate the association between thenar eminence and I-gel dimensions in children. METHODS: After Institutional Ethics Committee approval, two hundred and seventy ASA Class I-II patients between 0 and 12 years old, who were scheduled for elective procedures under general anaesthesia not requiring tracheal intubation, were recruited to the study. The size of the I-gel selected was based on the patient's body weight according to the manufacturer's recommendation. After successful insertion of the I-gel, thenar eminence dimensions were determined. Long-axis (Th-l) was measured from junction point of the thumb to wrist curl and short-axis (Th-w) constitutes the largest portion of the thenar eminence from lateral end of the thumb to the first hand line. The manufacturer's dimensions of the I-gel which was inserted into the patients were compared with the measurements obtained from thenar eminence. RESULTS: The mean (SD) values for (Ig-w) and (Ig-l) were 2.98cm (0.53) and 4.54cm (0.82), and the mean (SD) values for (Th-w) and (Th-l) were 2.99cm (0.60) and 3.88cm (0.93), respectively. There was a statistically significant correlation between Th-w and Ig-w (r=0.794, p<0.001), and between Th-l and Ig-l (r=0.820, p<0.001). CONCLUSION: The dimensions of thenar eminence were fitted to that of the weight based size of I-gel and this anatomic landmark may be a practical tool to assess appropriate size for paediatric patients. PMID- 26952225 TI - Prophylactic use of pregabalin for prevention of succinylcholine-induced fasciculation and myalgia: a randomized, double-blinded, placebo-controlled study. AB - BACKGROUND: Succinylcholine is commonly used to achieve profound neuromuscular blockade of rapid onset and short duration. OBJECTIVE: The present study compared the efficacy of pregabalin for prevention of succinylcholine-induced fasciculation and myalgia. DESIGN: Prospective, randomized, placebo controlled, double blinded study. MATERIALS AND METHODS: Patients of both genders undergoing elective spine surgery were randomly assigned to two groups. Patients in Group P (pregabalin group) received 150mg of pregabalin orally 1h prior to induction of anesthesia with sips of water and patients in Group C (control group) received placebo. Anesthesia was induced with fentanyl 1.5mcg/kg, propofol 1.5-2.0mg/kg followed by succinylcholine 1.5mg/kg. The intensity of fasciculations was assessed by an observer blinded to the group allotment of the patient on a 4 point scale. A blinded observer recorded postoperative myalgia grade after 24h of surgery. Patients were provided patient-controlled analgesia with fentanyl for postoperative pain relief. RESULTS: Demographic data of both groups were comparable (p>0.05). The incidence of muscle fasciculation's was not significant between two groups (p=0.707), while more patients in group C had moderate to severe fasciculation's compared to group P (p=0.028). The incidence and severity of myalgia were significantly lower in group P (p<0.05). CONCLUSION: Pregabalin 150mg prevents succinylcholine-induced fasciculations and myalgia and also decreases the fentanyl consumption in elective sine surgery. PMID- 26952227 TI - Perioperative cardiac arrest: an evolutionary analysis of the intra-operative cardiac arrest incidence in tertiary centers in Brazil. AB - BACKGROUND: Great changes in medicine have taken place over the last 25 years worldwide. These changes in technologies, patient risks, patient profile, and laws regulating the medicine have impacted the incidence of cardiac arrest. It has been postulated that the incidence of intraoperative cardiac arrest has decreased over the years, especially in developed countries. The authors hypothesized that, as in the rest of the world, the incidence of intraoperative cardiac arrest is decreasing in Brazil, a developing country. OBJECTIVES: The aim of this study was to search the literature to evaluate the publications that relate the incidence of intraoperative cardiac arrest in Brazil and analyze the trend in the incidence of intraoperative cardiac arrest. CONTENTS: There were 4 articles that met our inclusion criteria, resulting in 204,072 patients undergoing regional or general anesthesia in two tertiary and academic hospitals, totalizing 627 cases of intraoperative cardiac arrest. The mean intraoperative cardiac arrest incidence for the 25 years period was 30.72:10,000 anesthesias. There was a decrease from 39:10,000 anesthesias to 13:10,000 anesthesias in the analyzed period, with the related lethality from 48.3% to 30.8%. Also, the main causes of anesthesia-related cause of mortality changed from machine malfunction and drug overdose to hypovolemia and respiratory causes. CONCLUSIONS: There was a clear reduction in the incidence of intraoperative cardiac arrest in the last 25 years in Brazil. This reduction is seen worldwide and might be a result of multiple factors, including new laws regulating the medicine in Brazil, incorporation of technologies, better human development level of the country, and better patient care. PMID- 26952228 TI - Effectiveness of combined regional-general anesthesia for reducing mortality in coronary artery bypass: meta-analysis. AB - BACKGROUND AND OBJECTIVES: Neuraxial anesthesia (NA) has been used in association with general anesthesia (GA) for coronary artery bypass; however, anticoagulation during surgery makes us question the viability of benefits by the risk of epidural hematoma. The aim of this study was to perform a meta-analyzes examining the efficacy of NA associated with GA compared to GA alone for coronary artery bypass on mortality reduction. METHODS: Mortality, arrhythmias, cerebrovascular accident (CVA), myocardial infarction (MI), length of hospital stay (LHS), length of ICU stay (ICUS), reoperations, blood transfusion (BT), quality of life, satisfaction degree, and postoperative cognitive dysfunction were analyzed. The weighted mean difference (MD) was estimated for continuous variables, and relative risk (RR) and risk difference (RD) for categorical variables. RESULTS: 17 original articles analyzed. Meta-analysis of mortality (RD=-0.01, 95% CI=-0.03 to 0.01), CVA (RR=0.79, 95% CI=0.32-1.95), MI (RR=0.96, 95% CI=0.52-1.79) and LHS (MD=-1.94, 95% CI=-3.99 to 0.12) were not statistically significant. Arrhythmia was less frequent with NA (RR=0.68, 95% CI=0.50-0.93). ICUS was lower in NA (MD= 2.09, 95% CI=-2.92 to -1.26). CONCLUSION: There was no significant difference in mortality. Combined NA and GA showed lower incidence of arrhythmias and lower ICUS. PMID- 26952229 TI - Cardiac complications in a metamizole-induced type I Kounis syndrome. AB - Kounis syndrome is defined as the coincidental occurrence of allergic reaction and acute coronary syndrome secondary to vasospasm. Anti-inflammatory drugs are included as one of the multiple causes. Current data available about this syndrome come from case reports. We present the case of a patient who suffered Kounis syndrome with cardiogenic shock and asystole after intravenous infusion of Metamizole, and in which no lesions were observed in coronariography. PMID- 26952230 TI - Laparoscopic cholecystectomy under continuous spinal anesthesia in a patient with Steinert's disease. AB - Steinert's disease is an intrinsic disorder of the muscle with multisystem manifestations. Myotonia may affect any muscle group, is elicited by several factors and drugs used in general anesthesia like hypnotics, sedatives and opioids. Although some authors recommend the use of regional anesthesia or combined anesthesia with low doses of opioids, the safest anesthetic technique still has to be established. We performed a continuous spinal anesthesia in a patient with Steinert's disease undergoing laparoscopic cholecystectomy using 10mg of bupivacaine 0.5% and provided ventilatory support in the perioperative period. Continuous spinal anesthesia was safely used in Steinert's disease patients but is not described for laparoscopic cholecystectomy. We reported a continuous spinal anesthesia as an appropriate technique for laparoscopic cholecystectomy and particularly valuable in Steinert's disease patients. PMID- 26952231 TI - Neurogenic pulmonary edema due to ventriculo-atrial shunt dysfunction: a case report. AB - BACKGROUND AND OBJECTIVES: Pulmonary edema is caused by the accumulation of fluid within the air spaces and the interstitium of the lung. Neurogenic pulmonary edema is a clinical syndrome characterized by the acute onset of pulmonary edema following a significant central nervous system insult. It may be a less recognized consequence of raised intracranial pressure due to obstructive hydrocephalus by blocked ventricular shunts. It usually appears within minutes to hours after the injury and has a high mortality rate if not recognized and treated appropriately. CASE REPORT: We report a patient with acute obstructive hydrocephalus due to ventriculo-atrial shunt dysfunction, proposed to urgent surgery for placement of external ventricular drainage, who presented with neurogenic pulmonary edema preoperatively. She was anesthetized and supportive treatment was instituted. At the end of the procedure the patient showed no clinical signs of respiratory distress, as prompt reduction in intracranial pressure facilitated the regression of the pulmonary edema. CONCLUSIONS: This report addresses the importance of recognition of neurogenic pulmonary edema as a possible perioperative complication resulting from an increase in intracranial pressure. If not recognized and treated appropriately, neurogenic pulmonary edema can lead to acute cardiopulmonary failure with global hypoperfusion and hypoxia. Therefore, awareness of and knowledge about the occurrence, clinical presentation and treatment are essential. PMID- 26952232 TI - Use of a homemade introducer guide (bougie) for intubation in emergency situation in patients who present with difficult airway: a case series. AB - BACKGROUND AND OBJECTIVES: The incidence of difficult airway reaches 10% of emergency intubations. Although few studies address the use of handmade introducer guides in emergency and intensive care environment, there are descriptions of handmade guides available on the Internet. We describe a case series on the use of a handmade introducer guide (bougie) for emergency intubation in patients with difficult airway. CASE REPORT: The handmade introducer guide was used in five consecutive patients with difficult airways, and clinical instability and in the absence of another immediate method to obtain an airway. This technique provided successful intubation and there were no complications. CONCLUSIONS: The use of the handmade introducer guide can be a useful option for the management of difficult airways. PMID- 26952233 TI - Accidental catheterization of epidural venous plexus: tomographic analysis. AB - BACKGROUND AND OBJECTIVES: Inadvertent venous catheterizations occur in approximately 9% of lumbar epidural anesthetic procedures with catheter placement and, if not promptly recognized, can result in fatal consequences. The objective of this report is to describe a case of accidental catheterization of epidural venous plexus and its recording by computed tomography with contrast injection through the catheter. CASE REPORT: A female patient in her sixties, physical status II (ASA), underwent conventional cholecystectomy under balanced general anesthesia and an epidural with catheter for postoperative analgesia. During surgery, there was clinical suspicion of accidental catheterization of epidural venous plexus because of blood backflow through the catheter, confirmed by the administration of a test dose through the catheter. After the surgery, a CT scan was obtained after contrast injection through the catheter. Contrast was observed all the way from the skin to the azygos vein, passing through anterior and posterior epidural venous plexuses and intervertebral vein. CONCLUSION: It is possible to identify the actual placement of the epidural catheter, as well as to register an accidental catheterization of the epidural venous plexus, using computed tomography with contrast injection through the epidural catheter. PMID- 26952234 TI - Sedation with dexmedetomidine for conducting electroencephalogram in a patient with Angelman syndrome: a case report. AB - INTRODUCTION: Angelman syndrome is characterized by severe mental retardation and speech and seizure disorders. This rare genetic condition is associated with changes in GABAA receptor. Patients with Angelman syndrome need to be sedated during an electroencephalogram ordered for diagnostic purposes or evolutionary control. Dexmedetomidine, whose action is independent of GABA receptor, promotes a sleep similar to physiological sleep and can facilitate the performing of this examination in patients with Angelman syndrome. CASE REPORT: Female patient, 14 years old, with Angelman syndrome; electroencephalogram done under sedation with dexmedetomidine. The procedure was uneventful and bradycardia or respiratory depression was not recorded. The examination was successfully interpreted and epileptiform activity was not observed. CONCLUSION: Dexmedetomidine promoted satisfactory sedation, was well tolerated and enabled the interpretation of the electroencephalogram in a patient with Angelman syndrome and seizure disorder. PMID- 26952235 TI - Anesthetic management of a large mediastinal mass for tracheal stent placement. AB - The anesthetic management of patients with large mediastinal masses can be complicated due to the pressure effects of the mass on the airway or major vessels. We present the successful anesthetic management of a 64-year-old female with a large mediastinal mass that encroached on the great vessels and compressed the trachea. A tracheal stent was placed to relieve the tracheal compression under general anesthesia. Spontaneous ventilation was maintained during the perioperative period with the use of a classic laryngeal mask airway. We discuss the utility of laryngeal mask airway for anesthetic management of tracheal stenting in patients with mediastinal masses. PMID- 26952236 TI - Pressure support ventilation with the I-gel in intensive care unit: case report. AB - BACKGROUND AND OBJECTIVES: The I-gel supraglottic airway has a non-inflatable cuff made from a gel-like thermoplastic elastomer. The use of the I-gel during anesthesia for spontaneously breathing patients or intermittent positive pressure ventilation has been reported. But there are a few published reports about the use of the I-gel with pressure-controlled ventilation. CONTENTS AND CONCLUSIONS: In this case report we described the use of the I-gel supraglottic airway along 48h in intensive care unit for the management of ventilation in a patient needed mechanic ventilation but in whom tracheal intubation could not be performed. PMID- 26952237 TI - Reporting potential conflicts of interest. PMID- 26952238 TI - Acetabular fractures in skeletally immature rugby players. AB - Since the introduction of professionalism to the sport of rugby union, an increasing rate of injury has been noted in the playing population. In addition, overall participation numbers have increased globally, with more amateurs and young people involved in the sport. Acetabular fractures are generally seen after violent trauma and can be associated with poor long-term outcomes. We have previously described two acetabular fractures in young patients (16 and 24 years of age) sustained during rugby matches. We present a case series of four closed, isolated acetabular fractures in three skeletally immature male patients (13-16 years of age), two of which required open reduction and internal fixation. Three of these fractures occurred in conjunction with hip dislocations. All injuries were sustained while engaged in playing rugby union, two during seasonal match play and one during a training drill. PMID- 26952239 TI - [Psychopharmaceuticals for treatment of suicidal patients and for suicide prevention]. AB - Suicidality represents a frequent phenomenon in affective and psychotic disorders but the treatment of acute and chronic suicidality is still a controversial issue. Especially the efficacy of antidepressant and neuroleptic drugs for prevention of suicide continues to be debated. There is a lack of evidence due to limitations of methodological studies and ethical concerns are a major issue. Considering methodological problems in the conducted studies the often insufficiently valued differentiation between suicidal thoughts and actual suicidal behavior has to be emphasized. With the exception of lithium and clozapine suicide-preventing effects of antidepressants and neuroleptics could not yet be demonstrated. Regarding new antidepressant drugs, such as selective serotonin reuptake inhibitors (SSRI) and serotonin-norepinephrine reuptake inhibitors (SNRI) even the possible new onset of suicidal thoughts and ideations as an adverse effect needs to be stressed. Considering the frequent occurrence of suicidality the currently available evidence is undoubtedly insufficient. The improvement of study concepts and especially a more differentiated consideration of the vague term "suicidality" seems to be essential. An underrepresentation of the evidence-based therapeutic options with lithium and clozapine in the treatment of suicidal patients needs to be avoided. PMID- 26952241 TI - Dichotomous Relationship Between Age and 30-Day Death or Rehospitalization in Heart Failure Patients Admitted With Acute Decompensated Heart Failure: Results From the ASCEND-HF Trial. AB - BACKGROUND: Younger age as an independent predictor of death or all-cause rehospitalization at 30 days post-randomization for hospitalized heart failure (HF) patients has not been well described. METHODS AND RESULTS: ASCEND-HF enrolled 7141 hospitalized acute HF patients (categorized by age: <45, 45 to <55, 55 to <65, 65 to <75, and >=75 years) and followed them for 30 days to assess clinical outcomes, which included death or rehospitalization. Patients 45 to <55 years had the lowest percentages of death (1.4%) and total rehospitalizations (10.7%); percentages increased for younger (3.0% and 12.2%, respectively, for age <45 y) and older (5.8% and 12.5%, respectively, for age >=75 y) patients. For those rehospitalized, the total HF-induced readmissions were highest in the youngest (68%) and declined with increasing age (P = .03). Although patients >=55 years of age were more likely to die or be rehospitalized within 30 days of randomization for each additional 10 years of life, those <55 years of age had a significant reduction in death or HF rehospitalization for each 10-year increase in age (similar findings for death and HF rehospitalization). CONCLUSIONS: There is a dichotomous relationship between age and risk of death or rehospitalization, and death or HF rehospitalization-risk decreases as age increases up to age 55 years, then increases after age 55 years. PMID- 26952240 TI - Left Ventricular Deformation and Myocardial Fibrosis in Patients With Advanced Heart Failure Requiring Transplantation. AB - PURPOSE: To evaluate potential relationships between different components of left ventricular (LV) function and histopathological evidence for myocardial fibrosis in patients undergoing heart transplantation. METHODS: The study population included patients with advanced heart failure, referred for an echocardiographic examination before heart transplantation. Traditional LV function measurements and global longitudinal strain (GLS) by speckle tracking echocardiography, averaging all LV segments in 4-, 2-, and 3-chamber views were obtained in all subjects. LV tissue samples were obtained from all patients who underwent heart transplantation. Myocardial fibrosis was assessed using Masson's staining. RESULTS: Of 106 patients referred for cardiac transplantation, 47 underwent cardiac transplantation and were enrolled in the study. LV myocardial fibrosis and its grade strongly correlated with GLS (r = 0.75, P = .0001), modestly with global circumferential strain and LV torsion (r = 0.61, P = .001 and r = 0.52, P = .01, respectively) and weakly with mitral S' wave (r = -0.41; P = .01) and mitral annular plane systolic excursion (r = -0.35; P = .05) but did not correlate with LV ejection fraction (r = -0.12; P = NS). GLS had the strongest accuracy for detecting LV fibrosis (area under the curve, 0.92). None of the echo parameters correlated with patient's exercise capacity. CONCLUSION: Global longitudinal strain is the most accurate LV global function measure that correlates with the extent of myocardial fibrosis in patients with advanced systolic HF requiring heart transplantation. PMID- 26952242 TI - An investigation into bisphenol A leaching from materials used intraorally. AB - BACKGROUND: In this study, the authors quantitatively determined the bisphenol A (BPA) leached from intraoral materials during simulated intraoral exposure. METHODS: The authors subjected samples of intraoral materials to simulated abrasion, immersion in artificial saliva, thermal shock via temperature cycling, and simulated intraoral exposure. The authors collected sample aliquots for up to 2 weeks after artificial saliva immersion, derivatized, and then analyzed the aliquots for BPA by gas chromatography and mass spectroscopy. RESULTS: Quantifiable amounts of leached BPA were observed from only 1 of 13 intraoral materials tested: a silicone baby bottle nipple (20 micrograms). BPA leaching was only observed after 3 days of artificial saliva immersion, with no additional leaching thereafter. CONCLUSIONS: Under the test conditions, BPA was observed to leach from a silicone baby bottle nipple. PRACTICAL IMPLICATIONS: Although the quantities of leached BPA were below the reference dose for daily intake, investigators have shown a possible association between low levels of BPA and many medical disorders. BPA exposure, and thus the use of the leaching material identified in this study, should be reduced or eliminated. PMID- 26952243 TI - Effect of premedication to provide analgesia as a supplement to inferior alveolar nerve block in patients with irreversible pulpitis. AB - BACKGROUND: The authors' objective was to determine whether scientific evidence supports the use of oral premedication to increase the efficacy of inferior alveolar nerve block (IANB) and to decrease endodontic treatment pain in patients with diagnosed irreversible pulpitis. TYPES OF STUDIES REVIEWED: The authors included randomized controlled trials that involved enteral premedication and 2% lidocaine IANB for adults with irreversible pulpitis compared with placebo. In particular, the authors reviewed studies comparing nonsteroidal anti-inflammatory drugs (NSAIDs), benzodiazepines, acetaminophen, and corticosteroids with placebo. The authors searched the following electronic databases: the Cochrane Library, MEDLINE, and Web of Science. RESULTS: The authors analyzed 9 randomized controlled clinical trials. Patients who took the NSAIDs under study, including ibuprofen, ketorolac, diclofenac, indomethacin, and lornoxicam, 1 hour before endodontic treatment showed statistically significant improvement in the outcome of having "little or no pain" during endodontic treatment compared with patients who took a placebo 1 hour before endodontic treatment (risk ratio [RR], 1.989; 95% confidence interval [CI], 1.495-2.646; P < .001). Benzodiazepines were not as well represented in the literature, but the 2 included studies did not show a significant improvement in patients' having "little or no pain" during endodontic treatment over placebo (RR, 0.989; 95% CI, 0.677-1.444; P = .954). CONCLUSIONS AND PRACTICAL IMPLICATIONS: There is moderate evidence to support the use of oral NSAIDs-in particular, ibuprofen (600 milligrams)-1 hour before the administration of IANB local anesthetic (1.8-3.6 milliliters of 2% lidocaine) to provide additional analgesia to the patient. PMID- 26952244 TI - Distribution of Salmonella Serovars and Antimicrobial Susceptibility from Poultry and Swine Farms in Central Vietnam. AB - This study was conducted to estimate the prevalence of Salmonella spp. and their antimicrobial susceptibilities on poultry and swine farms, sampled in 2 regions in Central Vietnam. A total of 67 poultry farms and 46 swine farms were sampled in a period of 5 months (from September 2012 to January 2013). Salmonella spp. was prevalent in 46.3% and 71.7% of poultry and swine farms, respectively. Altogether, 99 non-typhoidal Salmonella were isolated and the most common serovars were Salmonella Weltevreden (19%), followed by Salmonella Typhimurium (12%) and Salmonella 4,[5],12:i:- (11%). Overall, 71 of 99 (72%) Salmonella isolates were resistant to at least one of the 14 antimicrobial agents tested. Both in poultry and swine farms, high levels of resistance were observed for ampicillin, chloramphenicol, ciprofloxacin, sulphamethoxazole and tetracycline. The presence of Salmonella isolates from poultry and swine farms which were resistant to different classes of antimicrobials suggests that alternative control measures to antimicrobials should be implemented. Moreover, an effective policy should be promoted to encourage a prudent use of these agents in animal farming in Vietnam. PMID- 26952245 TI - Non-adherence to ivabradine and placebo and outcomes in chronic heart failure: an analysis from SHIFT. AB - AIMS: In heart failure, non-adherence increases events; in turn, the effect of hospitalization on adherence is incompletely understood. We explored the relationship of non-adherence to outcomes, hospitalizations with non-adherence, and the influence of non-adherence on treatment effects of heart rate lowering with ivabradine. METHODS AND RESULTS: In the randomized, controlled Systolic Heart failure treatment with the If-inhibitor ivabradine Trial (SHIFT), we studied the effect of non-adherence (n = 1287) compared with adherence (n = 5204) on cardiovascular outcomes. After adjustment, non-adherence was associated with the primary composite endpoint of cardiovascular death and heart failure hospitalization (hazard ratio 3.47, 95% confidence interval 2.91-4.13, P < 0.0001). No interaction with the treatment groups of placebo or ivabradine (P for interaction 0.54) occurred. Similar results for cardiovascular death and heart failure hospitalization, as well as for cardiovascular hospitalization, heart failure death, and total death were observed. The effect of ivabradine was maintained in patients being adherent or becoming non-adherent during the trial (P for interaction = 0.54). Patients with a previous hospitalization were more likely to become non-adherent thereafter. CONCLUSIONS: Non-adherence identifies a group at particularly high cardiovascular event risk independent of treatment allocation. Non-adherent patients in the ivabradine group maintain a treatment benefit. Patients with previous hospitalizations are more likely to become non adherent and represent a group of particularly high-risk patients in whom special attention to stimulate adherence may be valuable. TRIAL REGISTRATION: ISRCTN70429960. PMID- 26952247 TI - Foreword. PMID- 26952246 TI - Manipulation of prenylation reactions by structure-based engineering of bacterial indolactam prenyltransferases. AB - Prenylation reactions play crucial roles in controlling the activities of biomolecules. Bacterial prenyltransferases, TleC from Streptomyces blastmyceticus and MpnD from Marinactinospora thermotolerans, catalyse the 'reverse' prenylation of (-)-indolactam V at the C-7 position of the indole ring with geranyl pyrophosphate or dimethylallyl pyrophosphate, to produce lyngbyatoxin or pendolmycin, respectively. Using in vitro analyses, here we show that both TleC and MpnD exhibit relaxed substrate specificities and accept various chain lengths (C5-C25) of the prenyl donors. Comparisons of the crystal structures and their ternary complexes with (-)-indolactam V and dimethylallyl S-thiophosphate revealed the intimate structural details of the enzyme-catalysed 'reverse' prenylation reactions and identified the active-site residues governing the selection of the substrates. Furthermore, structure-based enzyme engineering successfully altered the preference for the prenyl chain length of the substrates, as well as the regio- and stereo-selectivities of the prenylation reactions, to produce a series of unnatural novel indolactams. PMID- 26952248 TI - Heart Failure With Preserved Ejection Fraction. AB - Heart failure (HF) is one of the largest drivers of morbidity and health care expenditure in the world and continues to increase in prevalence at an alarming rate. Most of this increasing burden is related to the rapidly expanding population of HF with preserved ejection fraction (HFpEF), largely driven by the increasing rates of obesity, hypertension, and metabolic syndrome in western countries. In the last 3 decades, there have been tremendous advances in treating patients with HF with reduced ejection fraction (HFrEF), with essentially no change in outcomes for HFpEF. The lack of efficacy for established HFrEF therapies in HFpEF underscores the fundamental differences between both these phenotypically distinct forms of HF. In this review, we will summarize the current understanding of the pathophysiology of HFpEF, discuss diagnostic and therapeutic strategies, and provide future avenues to direct clinical investigation. PMID- 26952249 TI - Implementing Clinical governance in Iranian hospitals: purpose, process and pitfalls. AB - INTRODUCTION: Clinical governance as an approach to improving the quality and safety of clinical care has been run in all Iranian hospitals since 2009. This study aimed to provide a comprehensive overview of the processes and challenges faced in implementing clinical governance (CG) in acute-care hospitals in Iran. METHODS: We conducted an in-depth, qualitative, multi-case study using semi structured interviews with a range of key stakeholders and review of relevant documents. This study was conducted in 2011-2012 in six governmental hospitals affiliated with Tehran University of Medical Sciences. The data were analyzed using framework analysis. RESULTS: The interviewees, predominantly senior managers and nurses, expressed generally positive attitudes towards the benefits of CG. Four out of the six hospitals had a formal strategic plan to implement and execute CG. The emergent barriers to the implementation of CG included insufficient resources, the absence of clear supporting structures, a lack of supportive cultures, and inadequate support from senior management. The main facilitating factors were the reverse of the barriers noted above in addition to developing good relationships with key stakeholders, raising the awareness of CG among staff, and well-designed incentives. CONCLUSIONS: There is a positive sense towards CG, but its successful implementation in Iran will require raising the awareness of CG among staff and key stakeholders and the successful collaboration of internal staff and external agencies. PMID- 26952250 TI - Diiridium Bimetallic Complexes Function as a Redox Switch To Directly Split Carbonate into Carbon Monoxide and Oxygen. AB - A pair of diiridium bimetallic complexes exhibit a special type of oxidation reduction reaction that could directly split carbonate into carbon monoxide and molecular oxygen via a low-energy pathway needing no sacrificial reagent. One of the bimetallic complexes, Ir(III)(MU-Cl)2Ir(III), can catch carbonato group from carbonate and reduce it to CO. The second complex, the rare bimetallic complex Ir(IV)(MU-oxo)2Ir(IV), can react with chlorine to release O2 by the oxidation of oxygen ions with synergistic oxidative effect of iridium ions and chlorine atoms. The activation energy needed for the key reaction is quite low (~20 kJ/mol), which is far less than the dissociation energy of the C?O bond in CO2 (~750 kJ/mol). These diiridium bimetallic complexes could be applied as a redox switch to split carbonate or combined with well-known processes in the chemical industry to build up a catalytic system to directly split CO2 into CO and O2. PMID- 26952251 TI - Functional network analysis of genes differentially expressed during xylogenesis in soc1ful woody Arabidopsis plants. AB - Many plant genes are known to be involved in the development of cambium and wood, but how the expression and functional interaction of these genes determine the unique biology of wood remains largely unknown. We used the soc1ful loss of function mutant - the woodiest genotype known in the otherwise herbaceous model plant Arabidopsis - to investigate the expression and interactions of genes involved in secondary growth (wood formation). Detailed anatomical observations of the stem in combination with mRNA sequencing were used to assess transcriptome remodeling during xylogenesis in wild-type and woody soc1ful plants. To interpret the transcriptome changes, we constructed functional gene association networks of differentially expressed genes using the STRING database. This analysis revealed functionally enriched gene association hubs that are differentially expressed in herbaceous and woody tissues. In particular, we observed the differential expression of genes related to mechanical stress and jasmonate biosynthesis/signaling during wood formation in soc1ful plants that may be an effect of greater tension within woody tissues. Our results suggest that habit shifts from herbaceous to woody life forms observed in many angiosperm lineages could have evolved convergently by genetic changes that modulate the gene expression and interaction network, and thereby redeploy the conserved wood developmental program. PMID- 26952252 TI - Identification of a soybean rust resistance gene in PI 567104B. AB - KEY MESSAGE: Using a combination of phenotypic screening and molecular, statistical, and linkage analyses, we have mapped a dominant soybean rust resistance gene in soybean PI 567104B. Asian soybean rust (SBR), caused by the fungus Phakopsora pachyrhizi Syd. and P. Syd., is one of the most economically important diseases that affect soybean production worldwide. A long-term strategy for minimizing the effects of SBR is the development of genetically resistant cultivars. The objectives of the study were to identify the location of a rust resistance (Rpp) gene(s) in plant introduction (PI) 567104B, and to determine if the gene(s) in PI 567104B was different from previously mapped Rpp loci. The progeny of the cross of 'IAR 2001 BSR' * PI 567104B was phenotyped from field assays of the F 2:3 and F 4:5 generations and from a growth chamber assay of 253 F 5:6 recombinant inbred lines (RILs). For the growth chamber, the phenotyping was conducted by inoculation with a purified 2006 fungal isolate from Mississippi. A resistance gene locus on PI 567104B was mapped to a region containing the Rpp6 locus on chromosome 18. The high level of resistance of F 1 plants from two other crosses with PI 567104B as one of the parents indicated that the gene from PI 567104B was dominant. The interval containing the gene is flanked by the simple sequence repeat (SSR) markers Satt131 and Satt394, and includes the SSR markers BARCSOYSSR_18_0331 and BARCSOYSSR_18_0380. The results also indicated that the resistance gene from PI 567104B is different from the Rpp1 to the Rpp4 genes previously identified. To determine if the gene from PI 567104B is different from the Rpp6 gene from PI 567102B, additional research will be required. PMID- 26952253 TI - Erratum to: Isolation and fine mapping of Rps6: an intermediate host resistance gene in barley to wheat stripe rust. PMID- 26952266 TI - Serological Surveillance and Direct Field Searching Reaffirm the Absence of Ornithodoros Erraticus Ticks Role in African Swine Fever Cycle in Sardinia. AB - African swine fever (ASF), one of the most important diseases of swine, has been endemic in the Italian island of Sardinia for more than 35 years. During these decades, several strategies and eradication efforts have been implemented in the island with limited success. Strong climatic and ecological similarities exist between Sardinia and one area of the Iberian Peninsula where Ornithodoros erraticus ticks were involved in the persistence of ASF from 1960 to 1995. This fact leads to the hypothesis that, potentially, Ornithodoros ticks could be also involved in the ASF cycle in Sardinia, thus accounting for some of the reoccurring ASF outbreaks in this island. Initial efforts aimed at detection of Ornithodoros ticks in Sardinia were performed during the 1970s/1980s with no positive results. Accordingly, the absence of Ornithodoros ticks in Sardinia has been generally accepted. However, since a new and reinforced ASF eradication programme has been recently launched in Sardinia, it is essential to clarify the presence and role of these soft ticks in the epizootiology of ASF in this island. For that purpose, 1767 porcine serum samples collected from all around the island (1261 from domestic and 506 from wild boar) were analysed by ELISA for antibodies to salivary antigens of Ornithodoros erraticus. In addition, Ornithodoros ticks were directly searched in a number of pig premises that have suitable habitats for these ticks and were located in areas repeatedly affected by ASF. Only one serum sample resulted positive in the serological assay, and no Ornithodoros ticks were collected in none of the premises. These results indicate that these soft tick species are not involved in the epizootic cycle of ASF in Sardinia and highlight the importance of controlling other risk factors still present in the island for effectively eradicate the disease. PMID- 26952268 TI - Evaluation of an outreach education model over five years: Perception of dental students and their outreach clinical mentors. AB - INTRODUCTION: The objective was to investigate changes in students' and clinical mentors' perceptions of a model for outreach education over a 5-year period, 2006 2010. MATERIAL AND METHOD: Two cohorts of last-year students of a dental problem based curriculum and their clinical mentors in the Public Dental Service (PDS) were invited to respond to a questionnaire. In 2006, 85% of 54 students and 72% of their 54 mentors responded; 98% of 40 students and 88% of 41 of the mentors did so in 2010. Participants scored their level of agreement with different statements on a numeric rating scale and gave comments. RESULTS: Dental students and their clinical mentors reported that they shared a consistent and favourable perception of this outreach education model over 5 years. The students reported increased professional confidence and self-reliance. Clinical mentors expressed a transfer of knowledge to their clinics. Differences in scoring were seen between students and mentors for two statements in 2006 and two statements in 2010 (P < 0.05). CONCLUSIONS: The current model for outreach education received favourable and stable ratings over the 5-year period. This model resulted in that students perceived that they became self-reliant, which may facilitate their transition from being a student to becoming a professional. The current model supports exchange and professional development for students, faculty and outreach clinics. This leads us to look at outreach education as an opportunity to form a mutual learning community comprised of the outreach clinics and the dental school. PMID- 26952267 TI - Food addiction associations with psychological distress among people with type 2 diabetes. AB - AIMS: To assess the relationship between a food addiction (FA) model and psychological distress among a type 2 diabetes (t2d) sample. METHODS: A cross sectional study of 334 participants with t2d diagnoses were invited to complete a web-based questionnaire. We measured variables of psychological distress implementing the Depression Anxiety and Stress Scale (DASS-21), the Yale Food Addiction Scale (YFAS), and other factors associated with t2d. RESULTS: In our study a novel finding highlighted people with t2d meeting the FA criterion had significantly higher depression, anxiety, and stress scores as compared to participants who did not meet the FA criterion. Moreover, FA symptomology explained 35% of the unique variance in depression scores, 34% of the unique variance in anxiety scores, and 34% of the unique variance in stress scores, while surprisingly, BMI explained less than 1% of the unique variance in scores. CONCLUSION: We identified that psychological distress among people with t2d was associated with the FA model, apparently more so than BMI, thereby indicating further research being necessary lending support for future research in this realm. Moreover the FA model may be beneficial when addressing treatment approaches for psychological distress among people with t2d. PMID- 26952269 TI - The dynamic nature of the reconsolidation process and its boundary conditions: Evidence based on human tests. AB - The reconsolidation process is the mechanism by which the strength and/or content of consolidated memories are updated. This process is triggered by the presentation of a reminder (training cues). It is not always possible to trigger the reconsolidation process. For example, memory age and strength are boundary conditions for the reconsolidation process. Here, we investigated the dynamic changes in these conditions. We propose that the boundary conditions of the reconsolidation process are not fixed and vary as a consequence of the interaction between memory features and reminder characteristics. To modify memory properties, participants received a threatening social protocol that improves memory acquisition or a control condition (fake, without social interaction) prior to learning pairs of meaningless syllables. To determine whether a strong young or old declarative memory undergoes the reconsolidation process, we used an interference task (a second list of pairs of meaningless syllables) to disrupt memory re-stabilization. To assess whether the older memory could be strengthened, we repeated the triggering of reconsolidation. Strong young or old memories modulated by a threatening experience could be interfered during reconsolidation and updated (strengthened) by reconsolidation. Rather than being fixed, boundary conditions vary according to the memory features (strong memory), which indicates the dynamic nature of the reconsolidation process. Our findings demonstrate that it is possible to modify these limits by recruiting the reconsolidation process and making it functionally operative again. This novel scenario opens the possibility to new therapeutically approaches that take into account the reconsolidation process. PMID- 26952270 TI - Brain-Heart Disconnection: A Protective Effect of Diabetes Mellitus in Takotsubo Cardiomyopathy. PMID- 26952271 TI - Relation of Cardiac Dysfunction to Rhythm Abnormalities in Patients With Duchenne or Becker Muscular Dystrophies. AB - The association between systolic cardiac dysfunction and arrhythmia development in patients with Duchenne muscular dystrophy (DMD) or Becker muscular dystrophy (BMD) is generally assumed but has not been extensively studied. The purpose of this study was to describe arrhythmias in patients with DMD and BMD in the present era and determine whether arrhythmia development is associated with cardiac dysfunction. This is a single-center retrospective review of 237 Holters from 91 patients with DMD (mean = 17 +/- 4 years, range 3 to 27 years) and 64 Holters from 21 patients with BMD (mean = 18 +/- 7 years, range 4 to 31 years) with corresponding echocardiography. Holters were stratified by age of patient at the time of study and ejection fraction: normal (>=55%), mild (<55% and >=45%), moderate (<45% and >=30%), and severe (<30%). Arrhythmias included frequent atrial and ventricular premature complexes (>10/hr), couplets, and runs of supraventricular and ventricular tachycardias. Arrhythmias occurred in 44% of DMD and 57% of BMD patients and were significantly associated with decrease in cardiac function. Clinically significant arrhythmias (supraventricular tachycardia and ventricular tachycardia) occurred in 10% of all Holters obtained in patients with DMD and 25% of all Holters obtained in patients with BMD. Subgroup analysis of Holters from patients with DMD demonstrated that arrhythmias increased with decreasing ejection fraction regardless of age, but that age was also a significant predictor of arrhythmia development. In conclusion, among patients with DMD or BMD, arrhythmias increase with development of cardiac dysfunction. PMID- 26952272 TI - A compositional shift in the soil microbiome induced by tetracycline, sulfamonomethoxine and ciprofloxacin entering a plant-soil system. AB - Antibiotics entering the soil likely disturb the complex regulatory network of the soil microbiome, which is closely associated with soil quality and ecological function. This study investigated the effects of tetracycline (TC), sulfamonomethoxine (SMM), ciprofloxacin (CIP) and their combination (AM) on the bacterial community in a soil-microbe-plant system and identified the main bacterial responders. Antibiotic effects on the soil microbiome depended on antibiotic type and exposure time. TC resulted in an acute but more rapidly declining effect on soil microbiome while CIP and SMM led to a delayed antibiotic effect. The soil exposed to AM presented a highly similar bacterial structure to that exposed to TC rather than to SMM and CIP. TC, SMM and CIP had their own predominantly impacted taxonomic groups that include both resistance and sensitive bacteria. The antibiotic sensitive responders predominantly distributed within the phylum Proteobacteria. The potential bacteria resistant to each antibiotic exhibited phyla preference to some extent, particularly those resistant to TC. CIP and SMM resistance in soil was increased with exposure time while TC resistance gave the opposite result. Overall, the work extended the understanding of antibiotic effects on soil microbiome after introduced into the soil during greenhouse vegetable cultivation. PMID- 26952273 TI - Neutral and ionic per- and polyfluoroalkyl substances (PFASs) in atmospheric and dry deposition samples over a source region (Tianjin, China). AB - Per- and polyfluoroalkyl substances (PFASs) were detected in the atmosphere of a source region in Tianjin, China. Fluorotelomer alcohols (FTOHs) were the dominant neutral PFASs in the atmosphere with total concentrations of 93.6-131 pg/m(3) and 8:2 FTOH contributing the most, whereas perfluorooctane sulfonamide derivatives (PFOSAs) were two magnitudes lower or undetected. In comparison, ionic PFASs (perfluoroalkyl carboxyl acids (PFCAs)) in the atmosphere were detected at similar or even higher levels. At wastewater treatment plants (WWTPs), the air over influent was found with higher levels of FTOHs than over aeration tank and effluent; whereas in the air over the aeration tank, the concentrations of PFOSAs and nonvolatile ionic PFASs substantially increased, suggesting a possible direct release of ionic PFASs to the atmosphere besides the atmospheric conversion from volatile precursors. In the air phase, a low proportion (1-5%) of PFCAs was subjected to dry deposition in the source region. Interestingly, the dry deposition-to-bulk-air ratios of PFCA analogues were the lowest at medium chain lengths (C8 and C9) and increased with either shorter or longer chain length. The extraordinary affinity of shorter-chain PFCAs (C6-C7) to particles was presumed to be due to their smaller molecular size favoring the interactions between the carboxyl head groups and specific sorption sites on particulate matter. PMID- 26952274 TI - Brominated flame retardants (BFRs) in indoor and outdoor air in a community in Guangzhou, a megacity of southern China. AB - Indoor environments contribute a significant portion of human exposure to brominated flame retardants (BFRs) because of their extensive use in various household products. This study investigates the occurrence of a number of BFRs in the indoor and outdoor air in a megacity in southern China, in which little information on indoor BFRs contamination is available. The estimated total PBDE concentrations ranged from 1.43 to 57 pg/m(3) indoors and from 1.21 to 1522 pg/m(3) outdoors. The indoor concentrations of lower brominated PBDEs that are mainly derived from the technical penta- and octa-BDE mixtures were higher than or comparable to the outdoors, while the indoor levels of DecaBDEs and decabromodiphenyl ethane (DBDPE) were apparently lower than the outdoors. The seasonal variations of BFR concentrations indicated that evaporation from old indoor products is the primary source of Penta- and OctaBDEs in the air, whereas most DecaBDEs and DBDPE concentrations showing weak temperature-dependence are largely released from industrial activities. The PBDE congener profiles in the air were generally similar, which were dominated by BDE209, 28, and 47; whereas the appreciable indoor-outdoor differences in the compositions are possibly due to emission sources, photochemical degradation, or congener-specific transport of BFRs in the indoor and outdoor air. Significant correlations between the indoor and outdoor BFRs were observed suggesting the exchange of BFRs between the two compartments, which are more noticeable for PentaBDEs and DecaBDEs with strong indoor and outdoor emission sources, respectively. This study provides significant insights into the sources of BFRs in urban air in China. PMID- 26952275 TI - Characterization of polybrominated dibenzo-p-dioxins and dibenzo-furans (PBDDs/Fs) in environmental matrices from an intensive electronic waste recycling site, South China. AB - Information on environmental distribution and human exposures of polybrominated dibenzo-p-dioxins and dibenzo-furans (PBDDs/Fs) are little reported. In the present study, workshop dust, soil and sediment samples from Longtang and Shijiao, the intensive e-waste recycling sites within Qingyuan City, southern China, were collected and analyzed following the standard method. PBDD/F concentrations (sum of eight 2378-substituted PBDD/F congeners) in different environmental matrices were in the range of 122-4667 ng kg(-1) dry wt (dw) for workshop dust, 19.6-3793 ng kg(-1) dw for the top soils, and 527 ng kg(-1) dw for the surface sediment, which were substantially higher than those of reference sites. The long-distance transport of PBDDs/Fs also impacted the adjacent areas. Contribution of the most two toxic congeners (2,3,7,8-TBDD and 1,2,3,7,8-PeBDD) to the total toxic equivalent quantity (TEQ) increased significantly from "source" (dust) to "sink" (sediment). Dismantling and open burning were the two procedures contributing relatively higher level PBDDs/Fs to the atmosphere, while acid leaching would contaminate soils and waters directly. The estimated daily intakes of eight PBDD/F congeners via soil/dust ingestion and dermal absorption for local residents were higher than those contributed by seventeen PCDD/F congeners in the same set of samples. Children and e-waste processing workers were the most affected groups by the low-tech recycling activities there. PMID- 26952276 TI - Direct Catalytic Asymmetric Mannich Reactions for the Construction of Quaternary Carbon Stereocenters. AB - Herein, we report a Zn-ProPhenol catalyzed Mannich reaction using alpha-branched ketones as nucleophilic partners for the direct enantio- and diastereoselective construction of quaternary carbon stereocenters. The reaction can be run on a gram-scale with a low catalyst loading without impacting its efficiency. Moreover, the Mannich adducts can be further elaborated with complete diastereocontrol to access molecules possessing complex stereotriads. PMID- 26952277 TI - AMPK antagonizes hepatic glucagon-stimulated cyclic AMP signalling via phosphorylation-induced activation of cyclic nucleotide phosphodiesterase 4B. AB - Biguanides such as metformin have previously been shown to antagonize hepatic glucagon-stimulated cyclic AMP (cAMP) signalling independently of AMP-activated protein kinase (AMPK) via direct inhibition of adenylate cyclase by AMP. Here we show that incubation of hepatocytes with the small-molecule AMPK activator 991 decreases glucagon-stimulated cAMP accumulation, cAMP-dependent protein kinase (PKA) activity and downstream PKA target phosphorylation. Moreover, incubation of hepatocytes with 991 increases the Vmax of cyclic nucleotide phosphodiesterase 4B (PDE4B) without affecting intracellular adenine nucleotide concentrations. The effects of 991 to decrease glucagon-stimulated cAMP concentrations and activate PDE4B are lost in hepatocytes deleted for both catalytic subunits of AMPK. PDE4B is phosphorylated by AMPK at three sites, and by site-directed mutagenesis, Ser304 phosphorylation is important for activation. In conclusion, we provide a new mechanism by which AMPK antagonizes hepatic glucagon signalling via phosphorylation-induced PDE4B activation. PMID- 26952278 TI - The anaphase-promoting complex initiates zygote division in Arabidopsis through degradation of cyclin B1. AB - As the start of a new life cycle, activation of the first division of the zygote is a critical event in both plants and animals. Because the zygote in plants is difficult to access, our understanding of how this process is achieved remains poor. Here we report genetic and cell biological analyses of the zygote-arrest 1 (zyg1) mutant in Arabidopsis, which showed zygote-lethal and over-accumulation of cyclin B1 D-box-GUS in ovules. Map-based cloning showed that ZYG1 encodes the anaphase-promoting complex/cyclosome (APC/C) subunit 11 (APC11). Live-cell imaging studies showed that APC11 is expressed in both egg and sperm cells, in zygotes and during early embryogenesis. Using a GFP-APC11 fusion construct that fully complements zyg1, we showed that GFP-APC11 expression persisted throughout the mitotic cell cycle, and localized to cell plates during cytokinesis. Expression of non-degradable cyclin B1 in the zygote, or mutations of either APC1 or APC4, also led to a zyg1-like phenotype. Biochemical studies showed that APC11 has self-ubiquitination activity and is able to ubiquitinate cyclin B1 and promote degradation of cyclin B1. These results together suggest that APC/C mediated degradation of cyclin B1 in Arabidopsis is critical for initiating the first division of the zygote. PMID- 26952279 TI - Chronic obstructive pulmonary disease and cognitive impairment in the Chinese elderly population: a large national survey. AB - BACKGROUND: Previous studies suggested an association between chronic obstructive pulmonary disease (COPD) and cognitive impairment, mostly in developed countries. There is no evidence available on the association between these two common chronic disorders in the elderly people in People's Republic of China where the population is aging rapidly. METHODS: The study population was randomly selected from a nationally representative Disease Surveillance Point System in People's Republic of China. A standardized questionnaire was administered by trained interviewers during a face-to-face interview in the field survey conducted in 2010-2011. Cognitive function was assessed using the Mini-Mental State Examination. COPD was measured by self-report and the Medical Research Council respiratory questionnaire was used to assess respiratory symptoms. A multivariate logistic regression model was applied to examine the association between COPD and cognitive impairment with adjustment for potential confounding factors. RESULTS: A total of 16,629 subjects aged over 60 years were included in the study. The prevalence of cognitive impairment was 9.4% (95% confidence interval [CI] 7.7, 11.1). Chronic phlegm was associated with significantly higher prevalence of cognitive impairment in models adjusted for age, sex, marital status, geographic region, urban/rural, education, smoking status, alcohol drinking, and indoor air pollution (odds ratio [OR] 1.46, 95% CI 1.11, 1.93). Chronic respiratory symptoms and self-reported COPD were strongly related to cognitive impairment in urban areas. There were no significant effect modifications for sex, regions, educational level, smoking status, and alcohol drinking. CONCLUSION: There was strong association between COPD and cognitive impairment in urban Chinese elderly population. PMID- 26952285 TI - Mathematical modeling of cardiac growth and remodeling. AB - This review provides an overview of the current state of mathematical models of cardiac growth and remodeling (G&R). We concisely describe the experimental observations associated with cardiac G&R and discuss existing mathematical models that describe this process. To facilitate the discussion, we have organized the G&R models in terms of (1) the physical focus (biochemical vs mechanical) and (2) the process that they describe (myocyte hypertrophy vs extracellular matrix remodeling). The review concludes with a discussion of some possible directions that can advance the existing state of cardiac G&R mathematical modeling. WIREs Syst Biol Med 2016, 8:211-226. doi: 10.1002/wsbm.1330 For further resources related to this article, please visit the WIREs website. PMID- 26952286 TI - Outcomes, complications, utilization trends, and risk factors for primary and revision total elbow replacement. AB - BACKGROUND: Using a validated database, 30-day complications of primary and revision total elbow arthroplasty (TEA) were analyzed to identify risk factors of adverse events. METHODS: Primary and revision TEAs from 2007 to 2013 were identified in the National Surgical Quality Improvement Program database. Bivariate and multivariate analyses of risk factors for 30-day adverse events were assessed using preoperative and intraoperative variables. RESULTS: The study reviewed 189 primary and 53 revision TEA patients. Fracture (34%), osteoarthritis (24%), and rheumatoid arthritis (23%) were the most common indications for TEA. Adverse event rate was similar in primary and revision TEA (12% vs. 15%; P = .49), and infectious complications occurred in 3.2% of primary TEAs and 7.5% of revision TEAs (P = .23). Bivariate analysis of risk factors for 30-day adverse events identified dependent functional status in primary TEA (P = .03) and age in revision TEA (P = .02). Multivariate analysis of primary TEA revealed that adverse events were significantly less likely with rheumatoid arthritis compared with osteoarthritis etiology (odds ratio, 0.15; P = .02), and smoking was associated with an increased chance of infection (odds ratio, 6.96; P = .03). Revision TEA was not associated with an increased 30-day adverse event or infection rate compared with primary TEA in multivariate analysis. Among primary and revision TEA patients, dependent functional status (P = .02) and hypertension (P = .04) were independent predictors for adverse events. CONCLUSION: Modifiable risk factors should be addressed before TEA to limit postoperative complications as well as cost. The risk of short-term complications after revision TEA is comparable to that of primary TEA. PMID- 26952287 TI - Recovery of active external rotation and elevation in young active men with irreparable posterosuperior rotator cuff tear using arthroscopically assisted latissimus dorsi transfer. AB - BACKGROUND: Massive irreparable posterosuperior rotator cuff tears represent a serious functional disablement for young and active patients in their daily activities. Latissimus dorsi (LD) muscle-tendon transfer can restore elevation and external rotation where supraspinatus and infraspinatus function is lost. MATERIALS AND METHODS: Between 2009 and 2013, 45 consecutive patients underwent arthroscopically assisted LD transfer for an irreparable posterosuperior rotator cuff tear. Thirty-three patients agreed to participate in this retrospective study. For 8 patients, we used a standard passage of the LD through the plane between the infraspinatus-teres minor and the deltoid muscles. For the remaining 25 patients, we transferred the LD tendon in front of the triceps muscle according to a personal described technique. The follow-up period was 35.7 months. Final follow-up included assessment by standard radiographs, bipolar surface electromyography, pain score by visual analog scale, Constant-Murley shoulder score, and Disabilities of the Arm, Shoulder, and Hand score. For quantitative strength evaluation measurements, a Biodex dynamometer was used. RESULTS: Overall clinical outcomes improved at the final follow-up and were significantly age related. We found similar results for revision and primary patients with mean increase in Constant-Murley scores of 29.5 and 30.5 points, respectively. In our series, we recorded osteoarthritis progression in 33.3% of patients. CONCLUSION: Arthroscopic LD tendon transfer for irreparable posterosuperior rotator cuff tears can achieve good clinical outcomes at a midterm follow-up, especially in active men 60 years of age or younger and in patients with low preoperative elevation (<80 degrees ) but an intact or reparable subscapularis tendon. PMID- 26952288 TI - Asymmetric Bronsted Acid Catalyzed Substitution of Diaryl Methanols with Thiols and Alcohols for the Synthesis of Chiral Thioethers and Ethers. AB - An enantioselective addition of thiols and alcohols to aza-ortho-quinone methides, starting from diaryl methanols, was developed. The asymmetric additions occur under mild reaction conditions in the presence of chiral phosphoric acids and furnish the corresponding adducts with excellent yields and enantioselectivities. PMID- 26952289 TI - High urinary sulfate concentration is associated with reduced risk of renal disease progression in type 2 diabetes. AB - Diabetes is associated with a high incidence of microvascular disease, including nephropathy. Diabetic nephropathy is the most common cause of chronic kidney disease in the Western world. Sulfate in the urine is the metabolic end product of hydrogen sulfide (H2S), a recent discovered gaseous signaling molecule. Urinary sulfate has earlier shown beneficial predictive properties in renal transplant recipients. Based on the protective role of exogenous H2S in experimental models of diabetic nephropathy, we aimed to cross-sectionally investigate the association of sulfate with renal risk markers, and to prospectively investigate its predictive value for renal events in patients with diabetic nephropathy. Post-hoc analysis on data of the sulodexide macroalbuminuria (Sun-MACRO) trial and the Prevention of Renal and Vascular End Stage Disease (PREVEND) study was performed. A total of 1004 patients with type 2 diabetes were included. Urinary sulfate concentration was measured and cross sectionally associated to renal risk markers by linear regression. Multivariable Cox regression analysis was performed to assess the prospective association of sulfate with renal events, which was defined as end stage renal disease or a doubling of baseline serum creatinine. Mean age was 63 +/- 9 years, median sulfate concentration was 8.0 (IQR 5.8-11.4) mmol/L. Urinary sulfate positively associated with male gender, hemoglobin, and negatively associated with albuminuria at baseline. During follow-up for 12 (IQR 6-18) months, 38 renal events occurred. Each doubling of urinary sulfate was associated with a 19% (95%CI 1%-34%) lower risk of renal events, independent of adjustment for potential confounders, including age, estimated glomerular filtration rate (eGFR), and albuminuria. To conclude, higher urinary sulfate concentration is associated with a more beneficial profile of renal risk markers, and is independently associated with a reduced risk for renal events in type 2 diabetes patients with nephropathy. PMID- 26952290 TI - Plasma kallikrein-bradykinin pathway promotes circulatory nitric oxide metabolite availability during hypoxia. AB - Nitric oxide (NO) is an indispensible signalling molecule under hypoxic environment for both ethnic high altitude natives as well as lowland residents at high altitude. Several studies have reported higher levels of NO and bioactive NO products for both high altitude natives as well as healthy high altitude sojourners. But the metabolic pathways regulating the formation of NO and associated metabolites during hypoxia still remain elusive. In the present study, we profiled plasma proteomes of Ladakhi natives (3520 m) and lowland residents (post 1, 4 and 7 days stay) at the same altitude. This has resulted in the identification of 208 hypoxia responsive proteins (p < 0.05) and kininogen-plasma kallikrein-bradykinin as a major pathway regulating eNOS activity during hypoxia. In corroboration, we have also observed significant higher levels of plasma biomarkers for NO production (l-citrulline, nitrite, nitrate) for Ladakhi natives as compared to both lowland individuals healthy high altitude sojourners indicating higher NO availability. Since hypoxia-induced free radicals reduce NO availability, we also measured plasma levels of 8-isoprostanes, protein carbonyls and protein oxidation products in both Ladakhi natives and high altitude sojourners. Interestingly Ladakhi natives had significant lower levels of oxidative stress in comparison to high altitude sojourners but higher than lowland controls. These results suggest that plasma kallikrein-bradykinin-eNOS pathway along with moderate oxidative stress contributes to high altitude adaptation of Ladakhi natives. PMID- 26952291 TI - Outcomes After Elective Proximal Aortic Replacement: A Matched Comparison of Isolated Versus Multicomponent Operations. AB - BACKGROUND: Guidelines supporting the decision to replace the aorta in patients with chronic asymptomatic proximal aortic disease are limited by lack of data on operative risks and long-term effectiveness in relation to aortic size. Therefore, we assessed and compared outcomes of patients undergoing elective isolated proximal aortic replacement for this disease vs replacement during multicomponent operations. METHODS: From January 2006 to January 2011, 1,889 patients underwent proximal aortic replacement (isolated, 212; multicomponent, 1,677) for chronic asymptomatic ascending and arch pathology. Mean age was 60 +/- 14 years, and maximum proximal aortic diameter was 52 +/- 10 mm (isolated) and 49 +/- 10 mm (multicomponent; p = 0.0004). Propensity matching using 64 preoperative variables yielded 197 well-matched patient pairs. RESULTS: Patients were more likely to undergo isolated replacement if they had prior cardiac operations and a larger middescending aortic diameter (p < 0.0001). Multicomponent operations were more common among those with connective tissue disorder or porcelain aorta. Among propensity-matched patients, in-hospital mortality was 1 of 197 (0.5%) in the isolated group vs 8 of 197 (4.1%) in the multicomponent group. Occurrence of stroke, renal failure, and prolonged ventilation were similar. Median postoperative stay was 7.9 vs 8.1 days (p = 0.07). At 30 days, 1 year, and 4 years, survival was 97%, 93%, and 87%, and freedom from reintervention was 98%, 90%, and 89%, respectively, similar between groups. CONCLUSIONS: Elective ascending aortic replacement is safe and effective. Ascending aneurysms should be treated aggressively even when encountered in patients undergoing a multicomponent operation. An aggressive approach to replacement of the ascending aorta may be warranted given the increased risk of stroke during a subsequent reoperation. PMID- 26952292 TI - Left Ventricular Outflow Tract Obstruction in Aortic Arch Anomalies With Ventricular Septal Defect. AB - BACKGROUND: The predictors of left ventricular outflow tract obstruction (LVOTO) after the repair of coarctation of the aorta or interruption of the aortic arch (CoA/IAA) with ventricular septal defect have been investigated. However, the predictors remain controversial. METHODS: We performed primary repair of CoA/IAA with ventricular septal defect for 75 patients from 1996 to 2005. Four of the 75 patients died within 5 years after primary repair without relation to LVOTO. The morphology of the aortic valve of 71 survivors was bicuspid in 23 patients and tricuspid in 48 patients. The mean follow-up was 9.2 +/- 2.6 years after primary repair. RESULTS: There were 12 patients who showed LVOTO of 3.0 m/s or greater after primary repair. All of the 6 bicuspid patients demonstrated valvular aortic stenosis, and all of the 6 tricuspid patients showed discrete subvalvular LVOTO. In 5 of the 6 tricuspid patients, the aortic annular z-score before primary repair was -3.0 or less. A bicuspid aortic valve (p = 0.016) and the aortic annular z-score of -3.0 or less (p = 0.019) were significant risk factors for LVOTO after primary repair. At 10 years after primary repair, 82.6% and 95.6% of the bicuspid and tricuspid patients, respectively, were free from reoperation (p = 0.015). CONCLUSIONS: The presence of a bicuspid aortic valve and an aortic valve annular z-score of -3.0 or less before primary repair are risk factors for LVOTO, and stenotic bicuspid valves and discrete subvalvular LVOTO are the main causes of LVOTO after primary repair of CoA/IAA with ventricular septal defect. The bicuspid patients more frequently required reoperation than the tricuspid patients. PMID- 26952293 TI - Causal Model of Survival After Pulmonary Metastasectomy of Colorectal Cancer: A Nationwide Prospective Registry. AB - BACKGROUND: Although numerous existing studies have analyzed the prognostic factors of patients who have had surgical intervention for lung metastases of colorectal carcinoma (CRC), many of the results obtained until now have been contradictory. As a consequence, there is no established consensus about which group of prognostic factors could have a greater value when considered together. METHODS: This was a multicenter prospective cohort study that included all patients who underwent a first pulmonary metastasectomy of CRC, with radical intent, during a 2-year period (March 2008 to February 2010). The follow-up continued until March 2013, and an analysis of disease-specific survival (DSS), determined from the first pulmonary metastasectomy, was implemented. The selection of the best submodel was taken based on their coefficient of determination (R(2)) and how parsimonious they were depending on the number of variables included. RESULTS: The series, consisting of 522 patients, presented the following survival rates: median, 54.9 months; 3-year DSS, 69.4% (95% confidence interval [CI], 65% to 73.8%); and 5-year DSS, 46.1% (95% CI, 38.5% to 53.7%). The resulting survival model consisted of disease-free interval of 12 months or less (hazard ratio [HR], 1.76; 95% CI, 1.21 to 2.54; p = 0.003), carcinoembryonic antigen level exceeding 5 ng/mL (HR, 1.50; 95% CI, 1.04 to 2.17; p = 0.028), bilateral lung disease (HR, 1.81; 95% CI, 1.20 to 2.75; p = 0.005), and thoracic lymph node involvement (HR, 2.71; 95% CI, 1.44 to 5.12; p = 0.002). CONCLUSIONS: According to these results from the Spanish Group of Lung Metastases of Colo-Rectal Cancer, the combination of these four variables-disease-free interval, carcinoembryonic antigen level, laterality, and thoracic lymph node involvement-constitutes the first-choice survival causal model based on the clinical and pathologic factors most frequently referenced in literature. PMID- 26952294 TI - Open Seldinger-Guided Femoral Artery Cannulation Technique for Thoracic Aortic Surgery. AB - BACKGROUND: Debate regarding the optimal cannulation site for aortic surgery continues. We report our recent experience with a simple and rapid open Seldinger guided technique for femoral cannulation. Aside from speed and simplicity (no need for arterial incision or suture closure), this technique has the added benefit that the distal limb continues to be perfused, as no arterial snare is required. METHODS: We recently began routinely utilizing an open Seldinger-guided technique for femoral artery cannulation. The artery is exposed surgically but cannulated by guidewire inside a pursestring without arterial incision. The pursestring is simply tied when decannulation is performed. We report our experience with the routine application of this technique from August 2011 to April 2015. RESULTS: We reviewed the outcome of 337 consecutive peripheral arterial cannulations performed for thoracic aortic surgery (303 femoral, 34 axillary) using the open Seldinger technique. Within the femoral cannulation group, the hospital survival rate was 97% (295 of 303). The survival rate for elective operations was 98% (277 of 283), and 90% (18 of 20) for emergent/urgent. Seldinger-guided femoral cannulation was performed for replacement of the ascending/aortic arch in 88% (266 of 303), the descending thoracic aorta in 7% (22 of 303), and the thoracoabdominal aorta in 5% (15 of 303). There were no instances of intraoperative malperfusion phenomena, arterial dissection, or vascular injury or rupture. No patients had postoperative acute limb ischemia. Local wound complications were observed in 1% of patients (3 of 303). The stroke rate was 1.6% (5 of 303). The same open Seldinger technique was also used without complication in the axillary cannulation group. CONCLUSIONS: An open Seldinger guided femoral (or axillary) cannulation technique is quick and easy to perform, with minimal vascular or other complications and extremely low risk of stroke. This technique is recommended for its speed, simplicity, and effectiveness, and for its preservation of distal arterial flow (which is occluded with the traditional arterial incision/arterial snare technique). PMID- 26952295 TI - Modified In Vivo Lung Perfusion for Local Chemotherapy: A Preclinical Study With Doxorubicin. AB - BACKGROUND: In vivo lung perfusion (IVLP) is a promising adjuvant treatment of lung metastases, allowing the localized delivery of drugs to the lungs without systemic exposure. Previous experimental and clinical data resulted in variable efficacy and frequent toxicity. Our objectives were to demonstrate the feasibility and safety of a novel protective IVLP technique coupled with the delivery of sarcoma-based chemotherapy to the lung. METHODS: The left pulmonary artery and veins in pigs were cannulated and clamped. Left lung IVLP was performed for 4 hours. Doxorubicin (Dox) at a standard clinical dose of 75 mg/m(2) was used, followed by 150 and 225 mg/m(2). Dox 75 mg/m(2) combined with ifosfamide (Ifos) 6 g/m(2) was also tested. After IVLP, blood reperfusion was allowed for 4 hours. Lung physiology was assessed and biopsy samples were obtained for histologic assessment of acute lung injury (ALI), inflammatory profile, and cell death. Lung tissue levels, perfusate, and plasma levels of Dox were measured during the procedure. RESULTS: Lungs treated with Dox 75 mg/m(2) alone or combined with Ifos showed stable function throughout the procedure, without evidence of ALI (p = 0.12 and p = 0.36, respectively). Tissue levels of Dox were 70.3 MUg/g homogeneously distributed in the lung (p = 0.12). No drug was detected systemically. Dox 150 mg/m(2) and 225 mg/m(2) showed incremental ALI. CONCLUSIONS: IVLP for 4 hours with Dox 75 mg/m(2) alone or combined with Ifos was well tolerated, without measurable ALI. High drug levels in perfusate and lung tissue were found without systemic leakage. A dose-related toxicity was observed with increases in Dox doses. PMID- 26952296 TI - Management of Bronchial Stumps in Anatomic Lung Segmentectomy. AB - BACKGROUND: Stapling or suturing techniques are commonly used to close bronchial stumps in lung lobectomy, although with the segmentectomy procedure, various types of closure are likely to be performed. We investigated the safety of various types of bronchial closure methods used in anatomic lung segmentectomy. METHODS: Between 2005 and 2013, we performed anatomic lung segmentectomies including segmentectomies through open thoracotomy for 41 patients and thoracoscopy for 167 patients. Bronchial closures were performed through open and thoracoscopy methods for 66 and 231 stumps, respectively. Data were collected regarding segmental bronchus type, stump closure methods, and closure-related complications. Since 2006, bronchial caliber was measured from preoperative 1 mm(3) computed tomography. RESULTS: In the open group, 17 stumps (26%) were closed by stapling, 48 (73%) by thread ligation, and 1 (1%) by suturing. In the thoracoscopy group, 116 stumps (50%) were closed by stapling, 76 (33%) by thread ligation, and 39 (17%) by polymer clip ligation (p < 0.001). Staplers were used for all bronchial trunks that supplied more than a single segment; the mean diameter was 8.1 mm. For single segmental bronchi, ligation was used for 80% in the open group and stapling for 75% in the thoracoscopy group; the mean diameter was 6.6 mm. For subsegmental bronchi, ligation or clipping were applied for 95% in both groups; the mean diameter was 4.6 mm. One bronchopleural fistula was observed at 6 months postoperatively in upper division segmentectomy of the left upper lobe using a stapler in the open group. CONCLUSIONS: Ligation can be used safely for small-diameter segmental bronchial stump closures in anatomic lung segmentectomies or subsegmentectomies. The use of a polymer clip can be an alternative method to close the bronchial stump of subsegmentectomies. PMID- 26952297 TI - Clinical and Functional Developmental Outcomes in Neonates Undergoing Truncus Arteriosus Repair: A Cohort Study. AB - BACKGROUND: Truncus arteriosus (TA) is an uncommon congenital cardiac lesion that portends an exceedingly poor prognosis if not repaired. The objective of this study was to assess the clinical and developmental outcomes in a prospective cohort of patients who underwent TA repair. METHODS: All patients who underwent a TA repair between 1996 and 2012 were included. Follow-up clinical, neurologic, and developmental data were obtained from the Western Canadian Complex Pediatric Therapies Follow-up Program database. Functional developmental outcomes were assessed at 21.1 +/- 2.5 months of age with the Adaptive Behavior Assessment System-II, General Adaptive Composite (GAC) score. Survival and outcomes were compared between those with and without chromosomal abnormalities (CA). Survival and freedom from reintervention were assessed by Kaplan-Meier analysis. RESULTS: The study comprised 36 infants (19 male). CA was identified in 13, with 22q11.2 deletion in 10 patients. Patients underwent TA repair at a median age of 10 days; 5 patients underwent concomitant interrupted arch repair. There were 8 deaths, 2 of which occurred in the hospital. The 5-year survival was 79.4%. Survival was similar between those with and without CA. At 5 years, freedom from reoperation was 77.2%. The mean GAC was higher in the patients without CA (93.6 +/- 12.8 vs 76.1 +/- 13.1, p = 0.0016). CONCLUSIONS: Patients with surgically repaired TA continue to have significant postoperative mortality. Reoperation and cardiac catheterization are eventualities for a quarter of patients in the first 5 years of life. Functional developmental outcome in patients without CA is good, although it is significantly impaired in those with CA. PMID- 26952298 TI - Enhancing the Value of Population-Based Risk Scores for Institutional-Level Use. AB - BACKGROUND: We hypothesized that factors associated with an institution's residual risk unaccounted for by population-based models may be identifiable and used to enhance the value of population-based risk scores for quality improvement. METHODS: From January 2000 to January 2010, 4,971 patients underwent aortic valve replacement (AVR), either isolated (n = 2,660) or with concomitant coronary artery bypass grafting (AVR+CABG; n = 2,311). Operative mortality and major morbidity and mortality predicted by The Society of Thoracic Surgeons (STS) risk models were compared with observed values. After adjusting for patients' STS score, additional and refined risk factors were sought to explain residual risk. Differences between STS model coefficients (risk-factor strength) and those specific to our institution were calculated. RESULTS: Observed operative mortality was less than predicted for AVR (1.6% [42 of 2,660] vs 2.8%, p < 0.0001) and AVR+CABG (2.6% [59 of 2,311] vs 4.9%, p < 0.0001). Observed major morbidity and mortality was also lower than predicted for isolated AVR (14.6% [389 of 2,660] vs 17.5%, p < 0.0001) and AVR+CABG (20.0% [462 of 2,311] vs 25.8%, p < 0.0001). Shorter height, higher bilirubin, and lower albumin were identified as additional institution-specific risk factors, and body surface area, creatinine, glomerular filtration rate, blood urea nitrogen, and heart failure across all levels of functional class were identified as refined risk-factor variables associated with residual risk. In many instances, risk-factor strength differed substantially from that of STS models. CONCLUSIONS: Scores derived from population-based models can be enhanced for institutional level use by adjusting for institution-specific additional and refined risk factors. Identifying these and measuring differences in institution-specific versus population-based risk factor strength can identify areas to target for quality improvement initiatives. PMID- 26952299 TI - Clinicopathologic Factors Associated With Occult Lymph Node Metastasis in Patients With Clinically Diagnosed N0 Lung Adenocarcinoma. AB - BACKGROUND: In some patients, clinical N0 (cN0) lung adenocarcinoma diagnosed by preoperative computed tomography scanning and positron emission tomography scanning was staged as pathologic N1 (pN1) or N2 (pN2) postoperatively. The aim of this study was to determine the preoperative and postoperative clinicopathologic factors related to nodal upstaging after a surgical operation. METHODS: We conducted a retrospective chart review of 350 patients treated for cN0 lung adenocarcinoma by curative resection. We analyzed clinicopathologic findings, comparing pN0 patients with the nodal upstaging group. RESULTS: Of 350 patients treated for cN0 tumors, 305 (87.1%) were confirmed postoperatively as having pN0 tumors, and 45 (12.9%) were confirmed as having pN1 or pN2 tumors. The mean maximum standardized uptake value (SUVmax) was higher in the nodal upstaging group than in the pN0 group (6.9 versus 3.8, p = 0.004); the upstaging group also included more cases in which SUVmax was greater than 5 (70.5% versus 24.8%, p < 0.001). Pleural invasion, lymphatic invasion, and vascular invasion were all more frequently seen in the nodal upstaging group than in the pN0 group (all p < 0.001). The presence of tumors with a micropapillary component was higher in the nodal upstaging group (p < 0.001). Multivariate logistic regression analysis identified SUVmax greater than 5, lymphatic invasion, vascular invasion, and a micropapillary component as significant risk factors for nodal upstaging. CONCLUSIONS: In lung adenocarcinoma diagnosed as clinical N0 by chest computed tomography and positron emission tomography scanning, the possibility of occult lymph node metastasis increases with SUVmax greater than 5 and when lymphatic invasion, vascular invasion, and a micropapillary component are present. PMID- 26952301 TI - Value of self-induced plantar reflex in distinguishing Babinski from withdrawal. PMID- 26952300 TI - A Facebook-Based Obesity Prevention Program for Korean American Adolescents: Usability Evaluation. AB - INTRODUCTION: Adolescent obesity is one of the most serious global public health challenges. Social networking sites are currently popular among adolescents. Therefore, the obesity prevention program for Korean American adolescents was developed on the most popular social networking site, Facebook. The purpose of this study was to evaluate the usability of a culturally tailored Facebook-based obesity prevention program for Korean American adolescents (Healthy Teens). METHOD: An explorative descriptive design of usability testing was used. Usability testing employing one-on-one observation, the think-aloud method, audio taping, screen activity capture, and surveys was performed. Twenty participants were recruited from two Korean language schools (mean age, 15.40 +/- 1.50 years). Recruitment and user testing was performed between February and April 2014. Content analysis, using the inductive coding approach, was performed by three coders to analyze transcriptions. Descriptive statistics were used to analyze quantitative data including demographic characteristics, perceived usability, eHealth literacy, and health behaviors. RESULTS: Testing revealed several usability issues in content, appearance, and navigation. Participants' comments regarding content were positive. Although the Facebook platform provided limited flexibility with respect to building the site, participants described the program's appearance as appropriate. Most participants did not experience difficulty in navigating the program. DISCUSSION: Our preliminary findings indicated that participants perceived the Healthy Teens program as usable and useful. This program could be used as a robust platform for the delivery of health education to adolescents. Further research is required to assess the effects of Facebook-based programs on adolescent obesity prevention. PMID- 26952302 TI - ADCY5 mutations are another cause of benign hereditary chorea. PMID- 26952303 TI - Standard chemoradiation for glioblastoma results in progressive brain volume loss. PMID- 26952304 TI - Clinical Reasoning: A 58-year-old woman with loss of vision in her left eye. PMID- 26952305 TI - Teaching Video NeuroImages: Vertical supranuclear ophthalmoparesis: A diagnostic pearl for Niemann-Pick C. PMID- 26952306 TI - Clinical Reasoning: Seizures from the neglected lobe. PMID- 26952307 TI - A ligand-independent integrin beta1 mechanosensory complex guides spindle orientation. AB - Control of spindle orientation is a fundamental process for embryonic development, morphogenesis and tissue homeostasis, while defects are associated with tumorigenesis and other diseases. Force sensing is one of the mechanisms through which division orientation is determined. Here we show that integrin beta1 plays a critical role in this process, becoming activated at the lateral regions of the cell cortex in a ligand-independent manner. This activation is force dependent and polar, correlating with the spindle capture sites. Inhibition of integrin beta1 activation on the cortex and disruption of its asymmetric distribution leads to spindle misorientation, even when cell adhesion is beta1 independent. Examining downstream targets reveals that a cortical mechanosensory complex forms on active beta1, and regulates spindle orientation irrespective of cell context. We propose that ligand-independent integrin beta1 activation is a conserved mechanism that allows cell responses to external stimuli. PMID- 26952308 TI - Preterm delivery and elevated maternal total vascular resistance: signs of suboptimal cardiovascular adaptation to pregnancy? AB - OBJECTIVE: To evaluate the maternal hemodynamic profile in women with a diagnosis of threatened preterm delivery (TPD) in order to understand the possible pathophysiologic mechanism leading to an increased lifetime risk for future cardiovascular disease. METHODS: Patients with a diagnosis of TPD were enrolled and assessed using a non-invasive method (USCOM(r) ) for the determination of hemodynamic parameters. Vaginal and rectal swabs were taken, cervical length, blood inflammatory indices, fetal blood-vessel Doppler velocimetry were measured and gestational age at the time of delivery and neonatal outcomes were noted. RESULTS: A total of 68 patients were enrolled and included in the analysis. The population was divided into two groups according to total vascular resistance (TVR): Group A with a TVR of <= 1000 dynes * s/cm5 (n = 48) and Group B with a TVR of > 1000 dynes * s/cm5 (n = 20). C-reactive protein (CRP) was higher in Group B than in Group A, suggesting a systemic inflammation status. Group B delivered earlier (32 + 4 weeks vs 38 + 2 weeks; P < 0.01) and neonatal outcome was worse than in Group A. Significantly lower values of cardiac output, stroke volume, peak velocity of flow, velocity time integral, minute distance, stroke volume index, cardiac index, stroke work, cardiac power, inotropy index and potential-to-kinetic energy ratio were observed in Group B than in Group A. CONCLUSIONS: Women with a diagnosis of TPD showing TVR values of > 1000 dynes * s/cm5 and elevated levels of CRP are at high risk of preterm delivery. An impaired maternal cardiovascular adaptation during pregnancy in these patients might suggest a possible higher risk for subsequent future cardiovascular disease. Copyright (c) 2016 ISUOG. Published by John Wiley & Sons Ltd. PMID- 26952312 TI - Femoral Head Allograft for First Metatarsal Phalangeal Joint Fusion Using a Reamer Technique to Limit Graft Length. AB - The use of interpositional bone grafting for arthrodesis of the first metatarsophalangeal joint can be a technically challenging procedure. A fresh frozen femoral head allograft can provide an appropriate graft for lengthening and ultimate fusion. It has been well-documented in published studies that larger grafts at this site increase the risk of complications. When the joint is resected in a "square" fashion, length is actually lost from the first metatarsal head. We present a technique using a reamer applied to 1 side of the graft and the first metatarsal head in a "cup-and-cone" fashion, thereby limiting the total length of the actual graft size. This technique allows for easy positioning and lengthening, increasing the chance of graft incorporation at the fusion sites. PMID- 26952309 TI - Early response to inhaled bronchodilators and corticosteroids as a predictor of 12-month treatment responder status and COPD exacerbations. AB - BACKGROUND: Early treatment response markers, for example, improvement in forced expiratory volume in 1 second (FEV1) and St George's Respiratory Questionnaire (SGRQ) total score, may help clinicians to better manage patients with chronic obstructive pulmonary disease (COPD). We investigated the prevalence of clinically important improvements in FEV1 and SGRQ scores after 2-month budesonide/formoterol or formoterol treatment and whether such improvements predict subsequent improvements and exacerbation rates. METHODS: This post hoc analysis is based on data from three double-blind, randomized studies in patients with moderate-to-very-severe COPD receiving twice-daily budesonide/formoterol or formoterol alone for 6 or 12 months. Prebronchodilator FEV1 and SGRQ total score were measured before treatment and at 2 and 12 months; COPD exacerbation rates were measured during months 2-12. Responders were defined by >=100 mL improvement in prebronchodilator FEV1 and >=4-point decrease in SGRQ total score. RESULTS: Overall, 2,331 and 1,799 patients were included in the 0-2- and 0-12-month responder analyses, respectively, and 2,360 patients in the 2-12-month exacerbation rate analysis. At 2 months, 35.1% of patients were FEV1 responders and 44.3% were SGRQ responders. The probability of response was significantly greater with budesonide/formoterol than with formoterol or placebo for both parameters. Two-month responders had a greater chance of 12-month response than 2 month nonresponders for both FEV1 (odds ratio, 5.57; 95% confidence interval, 4.14-7.50) and SGRQ (odds ratio, 3.87; 95% confidence interval, 2.83-5.31). Two month response in FEV1 (P<0.001), but not SGRQ (P=0.11), was associated with greater reductions in exacerbation risk. CONCLUSION: Early FEV1 and SGRQ treatment responses relate to their changes at 12 months. FEV1 response, but not SGRQ response, at 2 months predicts the risk of a future COPD exacerbation in some, but not all patients. This is potentially useful in clinical practice, although more sensitive and specific markers of favorable treatment response are required. PMID- 26952313 TI - Endoscopic Debridement for Treatment of Chronic Plantar Fasciitis: An Innovative Surgical Technique. AB - Plantar fasciitis is one the most common pathologies seen by foot and ankle surgeons. When nonoperative therapy fails, surgical intervention is warranted. Various surgical procedures are available for the treatment of recalcitrant plantar fasciitis. The most common surgical management typically consists of open versus endoscopic plantar fascia release. The documented comorbidities associated with the release of the plantar fascia include lateral column overload and metatarsalgia. We present a new technique for this painful condition that is minimally invasive, allows visualization of the plantar fascia, and maintains the integrity of this fascia. Our hypothesis was that the use of endoscopic debridement of the plantar fascia would provide a minimally invasive technique with acceptable patient outcomes. PMID- 26952314 TI - Analytical impact time and angle guidance via time-varying sliding mode technique. AB - To concretely provide a feasible solution for homing missiles with the precise impact time and angle, this paper develops a novel guidance law, based on the nonlinear engagement dynamics. The guidance law is firstly designed with the prior assumption of a stationary target, followed by the practical extension to a moving target scenario. The time-varying sliding mode (TVSM) technique is applied to fulfill the terminal constraints, in which a specific TVSM surface is constructed with two unknown coefficients. One is tuned to meet the impact time requirement and the other one is targeted with a global sliding mode, so that the impact angle constraint as well as the zero miss distance can be satisfied. Because the proposed law possesses three guidance gain as design parameters, the intercept trajectory can be shaped according to the operational conditions and missile's capability. To improve the tolerance of initial heading errors and broaden the application, a new frame of reference is also introduced. Furthermore, the analytical solutions of the flight trajectory, heading angle and acceleration command can be totally expressed for the prediction and offline parameter selection by solving a first-order linear differential equation. Numerical simulation results for various scenarios validate the effectiveness of the proposed guidance law and demonstrate the accuracy of the analytic solutions. PMID- 26952315 TI - Structural colors: from natural to artificial systems. AB - Structural coloration has attracted great interest from scientists and engineers in recent years, owing to fascination with various brilliant examples displayed in nature as well as to promising applications of bio-inspired functional photonic structures and materials. Much research has been done to reveal and emulate the physical mechanisms that underlie the structural colors found in nature. In this article, we review the fundamental physics of many natural structural colors displayed by living organisms as well as their bio-inspired artificial counterparts, with emphasis on their connections, tunability strategies, and proposed applications, which aim to maximize the technological benefits one could derive from these photonic nanostructures. WIREs Nanomed Nanobiotechnol 2016, 8:758-775. doi: 10.1002/wnan.1396 For further resources related to this article, please visit the WIREs website. PMID- 26952316 TI - Fast-Response Turn-on Fluorescent Probes Based on Thiolysis of NBD Amine for H2 S Bioimaging. AB - Hydrogen sulfide (H2 S) is an important endogenous signaling molecule with multiple biological functions. New selective fluorescent turn-on probes based on fast thiolyling of NBD (7-nitro-1,2,3-benzoxadiazole) amine were explored for sensing H2 S in aqueous buffer and in living cells. The syntheses of both probes are simple and quite straightforward. The probes are highly sensitive and selective toward H2 S over other biologically relevant species. The fluorescein NBD-based probe showed 65-fold green fluorescent increase upon H2 S activation. The rhodamine-NBD-based probe reacted rapidly with H2 S (t1/2 ~1 min) to give a 4.5-fold increase in red fluorescence. Moreover, both probes were successfully used for monitoring H2 S in living cells and in mice. Based on such probe-based tools, we could observe H2 O2 -induced H2 S biogenesis in a concentration dependent and time-dependent fashion in living cells. PMID- 26952317 TI - Pharmacological effects of lysozyme on COPD and bronchial asthma with sputum: A randomized, placebo-controlled, small cohort, cross-over study. AB - BACKGROUND: Mucolytic agents are often used in Japan to ease excessive mucus production in patients with chronic obstructive pulmonary disease (COPD) or bronchial asthma (BA); the treatment ameliorates dyspnea and improves quality of life (QOL). AIM: Efficacy and safety of lysozyme hydrochloride (LYS), an oral mucolytic enzyme preparation, for patients with COPD or BA were investigated. PATIENTS AND METHODS: This study was a placebo-controlled, double-blind, randomized, cross-over design. Twenty-four patients with COPD and twenty-four patients with BA were enrolled. LYS or placebo was administered for 28 days in each treatment period, with a 28-day washout between the first and second treatment periods. The results of spirometry, impulse oscillometry system (IOS) examination, fractional exhaled nitric oxide (FeNO) measurement, as well as the changes in the subjective symptoms, were evaluated after the treatment period. RESULTS: On spirometry, airway function (FEV1) improved in patients with COPD after administration of LYS (LYS vs placebo: 0.08 L vs 0.029 L, p = 0.030). Similar trends were also found in %FEV1 in COPD patients. On IOS examination, resistance of the respiratory system at 5 Hz levels was significantly improved only in patients with COPD (LYS vs placebo: -0.455 cm H2O/L/s vs 0.095 cmH2O/L/s, p = 0.012). Similar trends were found in terms of the resistance of the respiratory system at 20 Hz, and of the reactance area. In the COPD assessment test, subjective symptoms also significantly improved in patients with COPD during the LYS treatment period (improvement rates-LYS vs. placebo: 69.6% vs. 39.1%; p = 0.022). A similar effect of LYS was not seen in BA patients. CONCLUSION: LYS, a mucolytic agent, has capability to improve the function of peripheral airways in patients with COPD, which leads to improvements of the patients' symptoms and QOL. PMID- 26952318 TI - Singers' Vocal Function Knowledge Levels, Sensorimotor Self-awareness of Vocal Tract, and Impact of Functional Voice Rehabilitation on the Vocal Function Knowledge and Self-awareness of Vocal Tract. AB - OBJECTIVES/HYPOTHESIS: This study investigated vocal function knowledge and vocal tract sensorimotor self-awareness and the impact of functional voice rehabilitation on vocal function knowledge and self-awareness. STUDY DESIGN: This is a prospective, randomized study. METHODS: Twenty singers (study group [SG]) completed a questionnaire before and after functional voice rehabilitation. Twenty additional singers, representing the control group, also completed the questionnaire without functional voice rehabilitation at a 3-month interval. The questionnaire consisted of three parts. The first part evaluated the singers' attitude to the anatomical and physiological knowledge of the vocal tract and their self-esteem of the knowledge level. The second part assessed the theoretical knowledge of the singers' vocal tract physiology. The third part of the questionnaire assessed singers' sensorimotor self-awareness of the vocal tract. RESULTS: The results showed that most singers indicated that knowledge of the vocal tract's anatomy and physiology is useful (59% SG, 67% control group). However, 75% of all participants defined their knowledge of the vocal tract's anatomy and physiology as weak or inadequate. In the SG, vocal function knowledge at the first assessment was 45%. After rehabilitation, the level increased to 67.7%. Vocal tract sensorimotor self-awareness initially was 38.9% in SG but rose to 66.7%. CONCLUSIONS: Findings of the study suggest that classical singers lack knowledge about the physiology of the vocal mechanism, especially the breathing patterns. In addition, they have low sensorimotor self-awareness of their vocal tract. The results suggest that singers would benefit from receiving services from phoniatrists and speech-language pathologists during their voice training. PMID- 26952319 TI - Screaming for Attention: The Vocal Demands of Actors in Violent Interactive Games. PMID- 26952320 TI - A Comparative Study of Iranian Female Primary School Teachers' Quality of Life With and Without Voice Complaints. AB - OBJECTIVES/HYPOTHESIS: As the largest group of professional voice users, teachers are more likely to face voice disorders because of their specific job conditions. This study aimed to compare the quality of life in female teachers with and without voice complaints. STUDY DESIGN: This is a cross-sectional descriptive analytical study. METHODS: This was a cross-sectional study of samples of primary school female teachers with (n = 60) and without (n = 60) voice disorders. All teachers were serving in Tehran, Iran. Professional background information was obtained through interviews, and quality of life was measured using the 36-item Short Form Health Survey questionnaire. A comparison was made between the study groups to analyze the data. RESULTS: The mean age of teachers was 44 (standard deviation = 3.95) years. There were no significant differences between the two groups regarding their professional background. However, significant differences were observed between the two groups in all subscales of the 36-item Short Form Health Survey, including physical and social functioning, role limitations because of either physical or emotional problems, bodily pain, general health, vitality, and mental health (P < 0.05). CONCLUSION: Findings of this study point to the effect of voice complaint on quality of life and showed that teachers with voice complaints suffer from poor health-related quality of life. Therefore, both voice-specific and unspecific assessment methods are required for clinical diagnostics. PMID- 26952322 TI - [And, if deaf professionals could teach us about communication?]. PMID- 26952321 TI - Predictors of Six-month Change in the Voice Handicap Index in a Treatment-seeking Population. AB - OBJECTIVE: To evaluate predictors of longitudinal change in patient-perceived voice impact as determined by the Voice Handicap Index (VHI). STUDY DESIGN: Prospective, survey study. METHODS: Patients consented to the University of Wisconsin Voice and Swallow Clinics Outcomes Database with voice, concerns with a baseline clinic visit from November 2012 to January 2014 were eligible for the study. The VHI was sent to patients 6 months post clinic visit to determine change in voice handicap from baseline. General health was screened using the 12 item Short Form Health Survey, using physical component summary and mental component summary scores. Predictor variables included treatment (medical and/or behavioral); dysphonia sub-diagnosis; grade, roughness, breathiness, asthenia, and strain rating; age; sex; socioeconomic factors; smoking history; and comorbidity score. RESULTS: Two hundred thirty-seven patients met study criteria and were followed longitudinally. Eighty-two patients returned 6-month surveys. The VHI was significantly correlated with mental component summary scores. Patients with a higher grade in baseline grade, roughness, breathiness, asthenia, and strain score were more likely to receive voice intervention (P = 0.04). Six month improvement in VHI score was associated with both higher initial VHI score and higher educational level in both univariate (P < 0.01, P = 0.04) and multivariate analyses (P < 0.01, P = 0.02). Voice treatment (medical and/or behavioral) was not a significant factor for improvement in VHI score. CONCLUSIONS: Our results suggest that it is important to consider baseline self perceived voice impact measures and educational level in setting expectations for voice treatment. Future studies examining the relationship between treatment patterns and voice-related patient outcomes are warranted. PMID- 26952323 TI - [The mouth, an unknown world?]. PMID- 26952324 TI - From Silylated Trishomoallylic Alcohols to Dioxaspiroundecanes or Oxocanes: Catalyst and Substitution Influence. AB - A versatile method for the synthesis of dioxaspiroundecanes through a tandem Sakurai-Prins cyclization of allylsilyl alcohols in the presence of TMSOTf is described. The process is general and highly stereoselective with total control in the creation of three new stereogenic centers in a single step. Moreover, a very interesting chemoselectivity has been observed depending on the nature of the catalyst used or the substitution of the trishomoallylic alcohol, since the same reaction under BF3.OEt2 catalysis or using alcohols with allylic substituents provides exclusively the corresponding oxocanes, by a direct silyl Prins cyclization. PMID- 26952326 TI - Mental illness, problem behaviour, needs and service use in adults with intellectual disability. AB - PURPOSE: Mental ill health in adults with intellectual disability (ID) is a neglected field in psychiatry and thus still widely understudied. This paper provides data on the prevalence of mental illness and problem behaviour and analyses support needs, mental health service use and psychotropic medication in a representative sample of adults with mild to moderate ID. METHODS: A set of well-established instruments was used to assess the main parameters in n = 371 participants recruited within a cross-sectional epidemiological multicentre study using a stratified randomised cluster sampling. RESULTS: Point prevalence of mental disorders was 10.8 %, that of problem behaviour 45.3 %. Most study participants needed help in specific lower order need areas (e.g., money budgeting, food, accommodation), and these need areas were mostly rated as met. The highest ratios of unmet to met need were found with respect to sexuality issues and with respect to mental health problems. The focus of psychiatric treatment was psychotropic medication. CONCLUSIONS: Referring to ICD-10 based diagnostic criteria and consequently avoiding confusing problem behaviour with mental disorders, point prevalence of mental disorders was lower than in the general population. A systematic deficit in meeting mental health problems in adults with ID indicates the need for implementing strategies to maximise the quality of identification and management of mental disorders. PMID- 26952325 TI - Cadherin-11 localizes to focal adhesions and promotes cell-substrate adhesion. AB - Cadherin receptors have a well-established role in cell-cell adhesion, cell polarization and differentiation. However, some cadherins also promote cell and tissue movement during embryonic development and tumour progression. In particular, cadherin-11 is upregulated during tumour and inflammatory cell invasion, but the mechanisms underlying cadherin-11 stimulated cell migration are still incompletely understood. Here, we show that cadherin-11 localizes to focal adhesions and promotes adhesion to fibronectin in Xenopus neural crest, a highly migratory embryonic cell population. Transfected cadherin-11 also localizes to focal adhesions in different mammalian cell lines, while endogenous cadherin-11 shows focal adhesion localization in primary human fibroblasts. In focal adhesions, cadherin-11 co-localizes with beta1-integrin and paxillin and physically interacts with the fibronectin-binding proteoglycan syndecan-4. Adhesion to fibronectin mediated by cadherin-11/syndecan-4 complexes requires both the extracellular domain of syndecan-4, and the transmembrane and cytoplasmic domains of cadherin-11. These results reveal an unexpected role of a classical cadherin in cell-matrix adhesion during cell migration. PMID- 26952327 TI - Severity of mental illness as a result of multiple childhood adversities: US National Epidemiologic Survey. AB - PURPOSE: To examine patterns of childhood adversity, their long-term consequences and the combined effect of different childhood adversity patterns as predictors of subsequent psychopathology. METHODS: Secondary analysis of data from the US National Epidemiologic Survey on alcohol and related conditions. Using latent class analysis to identify childhood adversity profiles; and using multinomial logistic regression to validate and further explore these profiles with a range of associated demographic and household characteristics. Finally, confirmatory factor analysis substantiated initial latent class analysis findings by investigating a range of mental health diagnoses. RESULTS: Latent class analysis generated a three-class model of childhood adversity in which 60 % of participants were allocated to a low adversity class; 14 % to a global adversities class (reporting exposures for all the derived latent classes); and 26 % to a domestic emotional and physical abuse class (exposed to a range of childhood adversities). Confirmatory Factor analysis defined an internalising externalising spectrum to represent lifetime reporting patterns of mental health disorders. Using logistic regression, both adversity groups showed specific gender and race/ethnicity differences, related family discord and increased psychopathology. CONCLUSIONS: We identified underlying patterns in the exposure to childhood adversity and associated mental health. These findings are informative in their description of the configuration of adversities, rather than focusing solely on the cumulative aspect of experience. Amelioration of longer term negative consequences requires early identification of psychopathology risk factors that can inform protective and preventive interventions. This study highlights the utility of screening for childhood adversities when individuals present with symptoms of psychiatric disorders. PMID- 26952333 TI - A new technique to close open abdomen using negative pressure therapy and elastic gums. PMID- 26952334 TI - Ultrafast, sensitive and large-volume on-chip real-time PCR for the molecular diagnosis of bacterial and viral infections. AB - To control future infectious disease outbreaks, like the 2014 Ebola epidemic, it is necessary to develop ultrafast molecular assays enabling rapid and sensitive diagnoses. To that end, several ultrafast real-time PCR systems have been previously developed, but they present issues that hinder their wide adoption, notably regarding their sensitivity and detection volume. An ultrafast, sensitive and large-volume real-time PCR system based on microfluidic thermalization is presented herein. The method is based on the circulation of pre-heated liquids in a microfluidic chip that thermalize the PCR chamber by diffusion and ultrafast flow switches. The system can achieve up to 30 real-time PCR cycles in around 2 minutes, which makes it the fastest PCR thermalization system for regular sample volume to the best of our knowledge. After biochemical optimization, anthrax and Ebola simulating agents could be respectively detected by a real-time PCR in 7 minutes and a reverse transcription real-time PCR in 7.5 minutes. These detections are respectively 6.4 and 7.2 times faster than with an off-the-shelf apparatus, while conserving real-time PCR sample volume, efficiency, selectivity and sensitivity. The high-speed thermalization also enabled us to perform sharp melting curve analyses in only 20 s and to discriminate amplicons of different lengths by rapid real-time PCR. This real-time PCR microfluidic thermalization system is cost-effective, versatile and can be then further developed for point of-care, multiplexed, ultrafast and highly sensitive molecular diagnoses of bacterial and viral diseases. PMID- 26952335 TI - Physiological constraints and dive behavior scale in tandem with body mass in auks: A comparative analysis. AB - Many behavioral processes scale with body mass (M) because underlying physiological constraints, such as metabolism, scale with M. A classic example is the maximum duration of dives by breath-hold divers, which scales with M0.25, as predicted from the ratio of oxygen stores (M1.0) to diving oxygen consumption rate (M0.75) - assuming classic scaling relationships for those physiological processes. However, maximum dive duration in some groups of birds does not have a 0.25 scaling exponent. We re-examined the allometric scaling of maximum dive duration in auks to test whether the discrepancy was due to poor data (earlier analyses included data from many different sources possibly leading to bias), phylogeny (earlier analyses did not account for phylogenetic inertia) or physiology (earlier analyses did not analyze physiological parameters alongside behavioral parameters). When we included only data derived from electronic recorders and after accounting for phylogeny, the equation for maximum dive duration was proportional to M0.33. At the same time, myoglobin concentration in small breath-hold divers was proportional to M0.36, implying that muscle oxygen stores were proportional to M1.36, but diving oxygen consumption rate in wing propelled divers was only proportional to M0.79. Thus, the 99% confidence interval included the exponent of 0.57 predicted from the observed relationships between oxygen stores and consumption rates. In conclusion, auks are not exceptions to the hypothesis that a trade-off between oxygen stores and oxygen utilization drives variation in maximum dive duration. Rather, the scaling exponent for maximum dive duration is higher than expected due to the higher than expected scaling of muscle oxygen stores to body mass. PMID- 26952336 TI - Impact of alcohol consumption on clinical aspects of gambling disorder. AB - Similarities between gambling disorder and substance use disorders have been extensively described. To date, however, few studies using large clinical samples have been carried out that reliably assess the relationship between different levels of alcohol consumption and gambling disorders. The present study aimed to assess the impact of baseline alcohol consumption levels on the clinical profile in a large sample of treatment-seeking individuals. Nine hundred and fifty-one consecutive outpatients diagnosed with gambling disorder according to DSM-IV criteria were compared after being included in three alcohol consumption groups (low risk, abuse and risk of dependence) based on their total raw scores on the AUDIT questionnaire. Results showed a high prevalence of risk of alcohol dependence in GD patients who were immigrants, unemployed, and had a low level of education. A positive linear trend was also found between alcohol consumption level and the prevalence of other current and life-time comorbid mental disorders, and for the presence of drug abuse. Statistically significant differences were found between the three alcohol consumption groups in terms of the evolution and severity of the gambling disorder, self-directedness personality trait, and levels of general psychopathology, hostility and paranoid ideation. In conclusion, the results showed an association between increased alcohol consumption and greater dysfunction. PMID- 26952337 TI - Thermodynamic Origin of Photoinstability in the CH3NH3Pb(I1-xBrx)3 Hybrid Halide Perovskite Alloy. AB - The formation of solid-solutions of iodide, bromide, and chloride provides the means to control the structure, band gap, and stability of hybrid halide perovskite semiconductors for photovoltaic applications. We report a computational investigation of the CH3NH3PbI3/CH3NH3PbBr3 alloy from density functional theory with a thermodynamic analysis performed within the generalized quasi-chemical approximation. We construct the phase diagram and identify a large miscibility gap, with a critical temperature of 343 K. The observed photoinstability in some mixed-halide solar cells is explained by the thermodynamics of alloy formation, where an initially homogeneous solution is subject to spinodal decomposition with I and Br-rich phases, which is further complicated by a wide metastable region defined by the binodal line. PMID- 26952338 TI - Using mutability landscapes of a promiscuous tautomerase to guide the engineering of enantioselective Michaelases. AB - The Michael-type addition reaction is widely used in organic synthesis for carbon carbon bond formation. However, biocatalytic methodologies for this type of reaction are scarce, which is related to the fact that enzymes naturally catalysing carbon-carbon bond-forming Michael-type additions are rare. A promising template to develop new biocatalysts for carbon-carbon bond formation is the enzyme 4-oxalocrotonate tautomerase, which exhibits promiscuous Michael type addition activity. Here we present mutability landscapes for the expression, tautomerase and Michael-type addition activities, and enantioselectivity of 4 oxalocrotonate tautomerase. These maps of neutral, beneficial and detrimental amino acids for each residue position and enzyme property provide detailed insight into sequence-function relationships. This offers exciting opportunities for enzyme engineering, which is illustrated by the redesign of 4-oxalocrotonate tautomerase into two enantiocomplementary 'Michaelases'. These 'Michaelases' catalyse the asymmetric addition of acetaldehyde to various nitroolefins, providing access to both enantiomers of gamma-nitroaldehydes, which are important precursors for pharmaceutically active gamma-aminobutyric acid derivatives. PMID- 26952339 TI - Behavioural interventions for sleep problems in people with an intellectual disability: a systematic review and meta-analysis of single case and group studies. AB - BACKGROUND: Behavioural interventions are frequently used to address sleep problems in people with intellectual disabilities (ID). The current study aimed to systematically review evidence on the efficacy of behavioural interventions for children and adults with ID and sleep problems. METHOD: Electronic and hand searches identified seven studies for inclusion (N = 169). Standardised mean difference effect sizes (d) were calculated for group studies (N = 4). Non overlap effect sizes (Tau-U) were calculated for single case experimental design studies (SCEDs; N = 3). RESULTS: A large effect size (weighted d = 0.923, confidence interval: 0.705 to 1.151) across group studies indicated large improvements in sleep problems following behavioural intervention. Effect size across SCEDs (weighted Tau-U: 0.528, confidence interval: 0.351 to 0.705) indicated a 53% improvement compared with baseline. Sleep initiation and sleep maintenance problems showed significant improvements post-intervention. Follow-up effects were less consistent across study designs and suggested that some sleep problems maintain gains better than others. CONCLUSION: Meta-analytic evidence from group and SCEDs can provide complementary information about efficacy. Findings propose that behavioural interventions are a promising evidence-based practice for improving sleep problems in people with ID. PMID- 26952343 TI - Traumatic Rupture of the Common Carotid Artery. PMID- 26952344 TI - Commentary on 'Selective AAA sac Embolization During EVAR to Prevent Type II Endoleaks'. PMID- 26952345 TI - Cost-effectiveness of Screening for Abdominal Aortic Aneurysm in Combination with Medical Intervention in Patients with Small Aneurysms. AB - OBJECTIVES: Screening for abdominal aortic aneurysm (AAA) among 65 year old men has been proven cost-effective, but nowadays is conducted partly under new conditions. The prevalence of AAA has decreased, and endovascular aneurysm repair (EVAR) has become the predominant surgical method for AAA repair in many centers. At the Malmo Vascular Center pharmacological secondary prevention with statins, antiplatelet therapy, and blood pressure reduction is initiated and given to all patients with AAA. This study evaluates the cost-effectiveness of AAA screening under the above mentioned conditions. METHODS: This was a Markov cohort simulation. A total of 4,300 65 year old men were invited to annual AAA screening; the attendance rate was 78.3% and AAA prevalence was 1.8%. A Markov model with 11 health states was used to evaluate cost-effectiveness of AAA screening. Background data on rupture risks, costs, and effectiveness of surgical interventions were obtained from the participating unit, the national Swedvasc Registry, and from the scientific literature. RESULTS: The additional costs of the screening strategy compared with no screening were ?169 per person and year. The incremental health gain per subject in the screened cohort was 0.011 additional quality adjusted life years (QALYs), corresponding to an incremental cost-effectiveness ratio (ICER) of ?15710 per QALY. Assuming a 10% reduction of all cause mortality, the incremental cost of screening was ?175 per person and year. The gain per subject in the screened cohort was 0.013 additional QALYs, corresponding to an ICER of ?13922 per QALY CONCLUSIONS: AAA screening remains cost-effective according to both the Swedish recommendations and the UK National Institute for Health and Care Excellence recommendations in the new era of lower AAA prevalence, EVAR as the predominant surgical method, and secondary prevention for all AAA patients. PMID- 26952346 TI - Randomized controlled trial of tranexamic acid among parturients at increased risk for postpartum hemorrhage undergoing cesarean delivery. AB - OBJECTIVE: To assess the effects of tranexamic acid among patients undergoing cesarean delivery who were at high risk of postpartum hemorrhage. METHODS: Between August 1, 2012, and April 30, 2013, a randomized controlled trial was performed at a tertiary care center in India. Women undergoing an elective or emergency cesarean delivery who were at high risk for postpartum hemorrhage were enrolled. They were randomly assigned using sealed, opaque envelopes to receive 10mg/kg tranexamic acid or normal saline 10min before skin incision. Anesthesiologists were not masked to group assignment, but patients and obstetricians were. The primary outcome was need for additional uterotonic drugs within 24h after delivery. Analyses were by intention to treat. RESULTS: Thirty patients were assigned to each group. Additional uterotonic drugs were required in 7 (23%) patients assigned to tranexamic acid and 25 (83%) patients in the control group (P<0.001). CONCLUSION: Intravenous tranexamic acid, administered before skin incision, significantly reduced the requirement for additional uterotonics among women at increased risk for postpartum hemorrhage. Clinical Trials Registry India: CTRI/2015/05/005752. PMID- 26952347 TI - Ethical issues in treating family members and close friends. PMID- 26952348 TI - Cost-effectiveness of two interventions for the prevention of postpartum hemorrhage in Senegal. AB - OBJECTIVE: To compare, at the community level, the cost-effectiveness of oxytocin and misoprostol for the prevention of postpartum hemorrhage (PPH). METHODS: The present cost-effectiveness study used data collected during a randomized trial that compared the prophylactic effectiveness of misoprostol and oxytocin for the prevention of PPH in a rural setting in Senegal between June 6 and September 21 2013. The two interventions were compared, with referral to a higher level facility owing to PPH being the outcome measure. The costs and effects were calculated for two hypothetical cohorts of patients delivering during a 1-year period, with each cohort receiving one intervention. A comparison with a third hypothetical cohort receiving the current standard of care was included. A sensitivity analysis was performed to estimate the impact of variations in model assumptions. RESULTS: The cost per PPH referral averted was US$ 38.96 for misoprostol and US$ 119.15 for oxytocin. In all the scenarios modeled the misoprostol intervention dominated, except in the worst-case scenario, where the oxytocin intervention demonstrated slightly better cost-effectiveness. CONCLUSION: The use of misoprostol for PPH prophylaxis could be cost effective and improve maternal outcomes in low-income settings. PMID- 26952349 TI - Comparison of classic terminology with the FIGO PALM-COEIN system for classification of the underlying causes of abnormal uterine bleeding. AB - OBJECTIVE: To compare classic terminology and the PALM-COEIN (polyp, adenomyosis, leiomyoma, malignancy and hyperplasia, coagulopathy, ovulatory disorders, endometrium, iatrogenic, and not classified) classification system among women who underwent surgery for abnormal uterine bleeding (AUB), and to subclassify the components of the PALM group for future studies. METHODS: In a retrospective study, data were obtained for nonpregnant women aged 18-55years who underwent hysterectomy, myomectomy, or polypectomy for AUB at a center in Turkey in 2014. The patients were retrospectively classified according to the PALM-COEIN system, and the two terminologies were compared. RESULTS: A total of 471 women were included. The term "hypermenorrhea" covered 15 different pathology combinations, "menorrhagia" nine, "metrorrhagia" 14, and "menometrorrhagia" 18. Of 92 patients with polyp, 5 (5.4%) had two polyps and 1 (1.1%) had three. Of 146 patients with adenomyosis, 131 (89.7%) had diffuse adenomyosis and 12 (8.2%) had adenomyoma. Of 309 patients with myoma uteri, 108 (34.9%) had submucous myoma and 201 (65.1%) had other types of myoma. CONCLUSION: Classic terminology for AUB is insufficient and confusing with respect to etiologic pathologies among nonpregnant women of reproductive age. Widespread adoption of the PALM-COEIN system for AUB classification will facilitate more meaningful communication among both clinicians and investigators, and clarify the populations that should be evaluated in clinical trials, thereby enhancing communication with patients. PMID- 26952350 TI - Prevalence of vitamin D deficiency in mothers and their newborns in a Tunisian population. AB - OBJECTIVE: To assess vitamin D status in mothers and their newborns and identify predictive factors of vitamin D deficiency. METHODS: A cross-sectional study was undertaken of healthy women and their full-term newborns delivered at the Charles Nicolle Hospital, Tunis, Tunisia, between October and November 2012. Maternal and neonatal serum 25-hydroxy vitamin D (25(OH)D) concentrations were measured. Correlations were tested. RESULTS: Overall, 87 mothers and their newborns were enrolled. No mother or neonate had an adequate vitamin D status. Mean maternal and neonatal serum 25(OH)D concentrations were 6.82+/-5.14ng/mL (range 3.60 23.77) and 5.92+/-4.15ng/mL (range 3.60-22.28), respectively. Vitamin D deficiency (serum 25(OH)D<20ng/mL) was found in 84 (97%) mothers and 85 (98%) neonates, of whom 76 (87%) and 78 (90%), respectively, had severe deficiency (serum 25(OH)D<12ng/mL). Maternal serum 25(OH)D showed a strong positive correlation with neonatal serum 25(OH)D (r=0.69, P<0.001). Maternal dietary vitamin D intake was the only factor shown to be associated with serum 25(OH)D concentrations (P<0.05). CONCLUSION: Vitamin D deficiency is prevalent among Tunisian mothers and their neonates. PMID- 26952351 TI - Utility of the PALM-COEIN classification of abnormal uterine bleeding for Indian gynecologists. AB - OBJECTIVE: To study the clinical utility of the PALM-COEIN classification for abnormal uterine bleeding in day-to-day practice in India. METHODS: Between April and November 2014, a cross-sectional survey was undertaken of gynecologists practicing in Chittoor and Nellore. Doctors possessing a postgraduate degree in gynecology and obstetrics, and postgraduate students in the gynecology department of medical colleges were invited to participate. A validated questionnaire containing 15 questions was distributed, the opinions were collated, and the results analyzed. RESULTS: Among 150 invited gynecologists, 120 agreed to participate, and 119 completed the survey fully. Overall, 95 (79.8%) respondents were aware of the classification, and 56 (47.1%) responded that the PALM-COEIN system is very good, 46 (38.7%) that it is average, and 17 (14.3%) that it is poor. By subgroup, 16 of 20 (80.0%) faculty members, 46 of 56 (82.1%) postgraduate students, and 33 of 43 (76.7%) practitioners responded that the system is useful. CONCLUSION: Indian doctors generally believe that the PALM COEIN system is clinically useful and a step forward in the management of abnormal uterine bleeding. PMID- 26952352 TI - Multicenter analysis comparing robotic, open, laparoscopic, and vaginal hysterectomies performed by high-volume surgeons for benign indications. AB - OBJECTIVE: To compare perioperative outcomes between robotic-assisted benign hysterectomies and abdominal, vaginal, and laparoscopic hysterectomies when performed by high-volume surgeons. METHODS: A multicenter data analysis compared 30-day outcomes from consecutive robotic-assisted hysterectomies performed by high-volume surgeons (>=60 prior procedures) at nine centers with records retrieved from the Premier Perspective database for abdominal, vaginal, and laparoscopic hysterectomies performed by high-volume gynecologic surgeons. Data on benign hysterectomy disorders from January 1, 2012 to September 30, 2013 were included. RESULTS: Data from 2300 robotic-assisted, 9745 abdominal, 8121 vaginal, and 11 952 laparoscopic hysterectomies were included. The robotic-assisted patient cohort had a significantly higher rate of adhesive disease compared with the vaginal (P<0.001) and laparoscopic cohorts (P<0.001), a significantly higher rate of morbid obesity than the vaginal (P<0.001) or laparoscopic cohorts (P<0.001), and a significantly higher rate of large uteri (>250g) than the abdominal (P<0.001), vaginal (P<0.001), or laparoscopic cohorts (P=0.017). The robotic-assisted cohort experienced significantly fewer intraoperative complications than the abdominal (P<0.001) and vaginal cohorts (P<0.001), and experienced significantly fewer postoperative complications compared with all the comparator cohorts (P<0.001). CONCLUSION: When performed by gynecologic surgeons with relevant high-volume experience, robotic-assisted benign hysterectomy provided improved outcomes compared with abdominal, vaginal, and laparoscopic hysterectomy. PMID- 26952353 TI - Prediction of vaginal birth after cesarean delivery. AB - OBJECTIVE: To examine factors associated with successful vaginal birth after cesarean (VBAC) and to validate a previously established prediction model. METHODS: In a retrospective study, data were obtained for women with one prior low-transverse cesarean procedure who underwent a trial of labor with a cephalic singleton pregnancy at term at one UK hospital between January 2000 and August 2013. Univariate analysis and logistic regression analysis were used to identify maternal demographic characteristics significantly associated with successful VBAC and factors independently associated with this outcome, respectively. A prediction model was built, and predicted probabilities were compared with observed frequencies. For validation, probabilities were also calculated by a previous prediction model. RESULTS: Overall, 1463 women formed the cohort. Successful vaginal delivery was achieved in 1050 (71.8%) women. The only factors significantly associated with unsuccessful VBAC were Asian (odds ratio [OR] 1.59, 95% confidence interval [CI] 1.14-2.23) or African (OR 1.80, 95% CI 1.23-2.64) ethnic origin, and previous cesarean for failure to progress (OR 6.39, 95% CI 4.81-8.49). The predicted and observed probability of successful VBAC were well correlated (Spearman rho, 0.905; P=0.002). The established prediction model was less accurate. CONCLUSION: Previous cesarean performed for failure to progress and Asian/African ethnic origin were associated with unsuccessful VBAC. The performance of a previous prediction model was inferior. PMID- 26952354 TI - Molecular cloning of hsf1 and hsbp1 cDNAs, and the expression of hsf1, hsbp1 and hsp70 under heat stress in the sea cucumber Apostichopus japonicus. AB - The heat shock response (HSR) is known for the elevated synthesis of heat shock proteins (HSPs) under heat stress, which is mediated primarily by heat shock factor 1 (HSF1). Heat shock factor binding protein 1 (HSBP1) and feedback control of heat shock protein 70 (HSP70) are major regulators of the activity of HSF1. We obtained full-length cDNA of genes hsf1 and hsbp1 in the sea cucumber Apostichopus japonicus, which are the second available for echinoderm (after Strongylocentrotus purpuratus), and the first available for holothurian. The full length cDNA of hsf1 was 2208bp, containing a 1326bp open reading frame encoding 441 amino acids. The full-length cDNA of hsbp1 was 2850bp, containing a 225bp open reading frame encoding 74 amino acids. The similarities of A. japonicus HSF1 with other species are low, and much higher similarity identities of A. japonicus HSBP1 were shared. Phylogenetic trees showed that A. japonicus HSF1 and HSBP1 were clustered with sequences from S. purpuratus, and fell into distinct clades with sequences from mollusca, arthropoda and vertebrata. Analysis by real-time PCR showed hsf1 and hsbp1 mRNA was expressed constitutively in all tissues examined. The expression of hsf1, hsbp1 and hsp70 in the intestine at 26 degrees C was time-dependent. The results of this study might provide new insights into the regulation of heat shock response in this species. PMID- 26952357 TI - ORCID: Not a flower but an Open Researcher and Contributor ID. PMID- 26952355 TI - Approximately half of patients with coronary spastic angina had pathologic exercise tests. AB - OBJECTIVES: We examined the clinical usefulness of treadmill exercise tests (TETs) in diagnosing coronary spastic angina (CSA). METHODS: We performed the TETs and 24-h Holter monitoring in 300 CSA patients consisting of 152 patients with rest angina, 77 patients with effort angina, and 71 patients with rest and effort angina. Organic stenosis (>75%) was observed in 44 patients. Multiple spasms were recognized in 204 patients (68%). RESULTS: Positive TETs were recognized in 113 patients (38%) and borderline was observed in 30 patients (10%). Positive response was significantly higher in patients with organic stenosis than those without fixed stenosis (63.6% vs. 33.2%, p<0.001). Moreover, ST elevation was more frequent in patients with organic stenosis than those without fixed stenosis (27.3% vs. 1.2%, p<0.001). Positive response in patients with effort angina (46.8%) was higher than those in patients with rest angina (33.6%) and rest and effort angina (36.6%), but not significant. Positive response was not different between single spasm and multiple spasms. In all 300 patients, ST segment elevation was observed in only four patients (1.3%) on the 24-h Holter monitoring. CONCLUSIONS: TET was useful in documenting ischemia in patients with CSA. More than a third of patients with CSA had positive TETs. Moreover, we obtained the pathologic TET response in approximately half of patients with CSA. PMID- 26952358 TI - Thermo-triggerable self-assembly comprising cinnamoyl polymeric beta cyclodextrin and cinnamoyl Pluronic F127. AB - Thermo-triggerable self-assembly was prepared by co-dissolving cinnamoyl Pluronic F127 (CinPlu) and cinnamoyl polymeric beta cyclodextrin (CinPbetaCD) in an aqueous phase. On TEM photo, the CinPlu/CinPbetaCD self-assembly was 100-200nm in diameter. The specific loading of Nile red (NR) in the assembly was calculated to be 5.5% (wt NR/wt polymer), and the molar ratio of NR to betaCD residue in the assembly was about 0.89:1. No significant release of NR from the assembly was observed at 10 degrees C and 20 degrees C. However, when the temperature was raised to 30 degrees C, 40 degrees C, 50 degrees C, and 60 degrees C, the cumulative release amount in 5min was 17%, 25%, 32%, and 52%, respectively. The specific loading of doxorubicin (DOX) in the assembly was about 6.8% (wt DOX/wt polymer) (corresponding to the molar ratio of DOX to betaCD residue was about 0.41:1). The DOX release from the assembly was proportional to the temperature of release medium. NR and DOX were likely to be expelled out of the cavity of betaCD residue by the interaction of the thermally hydrophobicized Pluronic F127 chain (molecular piston) and the cavity of betaCD residue (cylinder). After 4h incubation with KB cell, DOX loaded in CinPlu/CinPbetaCD self-assembly was found to be internalized into the cancer cell more than free DOX, observed on a confocal laser scanning microscope and a fluorescence activated cell sorter. CinPlu/CinPbetaCD self-assembly enhanced the in vitro anti-cancer activity of DOX against KB cell without increasing significantly the in vitro toxicity of DOX against Raw264.7 cell. PMID- 26952359 TI - Refractive index matching to develop transparent polyaphrons: Characterization of immobilized proteins. AB - Refractive index matching was used to create optically transparent polyaphrons to enable proteins adsorbed to the aphron surface to be characterized. Due to the significant light scattering created by polyaphrons, refractive index matching allowed for representative circular dichroism (CD) spectra and acceptable structural characterization. The method utilized n-hexane as the solvent phase, a mixture of glycerol and phosphate buffer (30% [w/v]) as the aqueous phase, and the non-ionic surfactants, Laureth-4 and Kolliphor P-188. Deconvolution of CD spectra revealed that the immobilized protein adapted its native conformation, showing that the adsorbed protein interacted only with the bound water layer ("soapy shell") of the aphron. Isothermal calorimetry further demonstrated that non-ionic surfactant interactions were virtually non-existent, even at the high concentrations used (5% [w/v]), proving that non-ionic surfactants can preserve protein conformation. PMID- 26952360 TI - The role of tenofovir alafenamide in future HIV management. AB - HIV infection has become a chronic condition rather than an acute life threatening disease in developed countries, thanks to consistent innovation and evolution of effective interventions. This has altered HIV management and created new challenges. People living with HIV (PLWHIV) are living longer and so encounter comorbidities linked not only with their disease, but also with ageing, lifestyle and chronic exposure to antiretroviral therapy (ART). Although longevity, viral suppression and the prevention of viral transmission remain key goals, more needs to be achieved to encompass the vision of attaining an optimum level of overall health. Treatment choices and management practices should ensure patients' long-term health with minimal comorbidity. Treatments that balance optimal efficacy with the potential for improved long-term safety are needed for all patients. In this review, we consider the evolution and development of tenofovir alafenamide (TAF), a novel prodrug of tenofovir which offers high antiviral efficacy at doses over ten times lower than that of tenofovir disoproxil fumarate (TDF). Emerging clinical data suggest that elvitegravir, cobicistat, emtricitabine and TAF (E/C/F/TAF) as a single-tablet regimen offers highly effective viral suppression in treatment-naive and treatment-experienced patients with an improved renal and bone safety profile compared with TDF, this having been demonstrated in diverse groups including patients with existing renal impairment and adolescents. The profile of TAF identifies it as an agent with a promising role within future ART regimens that aim to deliver the vision of undetectable viral load, while requiring less monitoring and having a safety profile designed to minimize comorbid risks while supporting good long-term health. PMID- 26952362 TI - [Total knee arthroplasty with the use of patient specific instruments. The VISIONAIRE system]. AB - BACKGROUND: Accurate component positioning and correct post-operative whole-leg alignment are crucial for ensuring the optimal long-term performance of a knee replacement. Patient-specific instrumentation (PSI) was introduced in an attempt to reduce outliers in the positioning of components and in the alignment of the leg axis in comparison with conventional techniques. METHODS AND RESULTS: A review of our own investigations and studies by other groups, it has been shown that PSI could reduce the amount of outliers in the positioning of tibial and femoral components and in whole-leg alignment. In this way, PSI differs from other procedures for improving component placement, such as navigation, for which no advantage could be demonstrated, especially with regard to rotation in comparison with conventional techniques. In this publication we focus on the VISIONAIRE PSI system (Smith&Nephew). In addition, the efficiency aspects of PSI are discussed, which differ from the conventional method because of the use of disposable instruments. PMID- 26952366 TI - Timing reproduction in teleost fish: cues and mechanisms. AB - Fish comprise half of extant vertebrate species and use a rich variety of reproductive strategies that have yielded insights into the basic mechanisms that evolved for sex. To maximize the chances of fertilization and survival of offspring, fish species time reproduction to occur at optimal times. For years, ethologists have performed painstaking experiments to identify sensory inputs and behavioral outputs of the brain during mating. Here we review known mechanisms that generate sexual behavior, focusing on the factors that govern the timing of these displays. The development of new technologies, including high-throughput sequencing and genome engineering, has the potential to provide novel insights into how the vertebrate brain consummates mating at the appropriate time. PMID- 26952367 TI - A targeted strategy to analyze untargeted mass spectral data: Rapid chemical profiling of Scutellaria baicalensis using ultra-high performance liquid chromatography coupled with hybrid quadrupole orbitrap mass spectrometry and key ion filtering. AB - Structural identification of natural products by tandem mass spectrometry requires laborious spectral analysis. Herein, we report a targeted post acquisition data processing strategy, key ion filtering (KIF), to analyze untargeted mass spectral data. This strategy includes four steps: (1) untargeted data acquisition by ultra-high performance liquid chromatography coupled with hybrid quadrupole orbitrap mass spectrometry (UHPLC/orbitrap-MS); (2) construction of a key ion database according to diagnostic MS/MS fragmentations and conservative substructures of natural compounds; (3) high-resolution key ion filtering of the acquired data to recognize substructures; and (4) structural identification of target compounds by analyzing their MS/MS spectra. The herbal medicine Huang-Qin (Scutellaria baicalensis Georgi) was used to illustrate this strategy. Its extract was separated within 20 min on a C18 column (1.8 MUm, 2.1*150 mm) eluted with acetonitrile, methanol, and water containing 0.1% formic acid. The compounds were detected in the (-)-ESI mode, and their MS/MS spectra were recorded in the untargeted manner. Key ions were then filtered from the LC/MS data to recognize flavones, flavanones, O-/C-glycosides, and phenylethanoid glycosides. Finally, a total of 132 compounds were identified from Huang-Qin, and 59 of them were reported for the first time. This study provides an efficient data processing strategy to rapidly profile the chemical constituents of complicated herbal extracts. PMID- 26952368 TI - The separation and analysis of symmetric and asymmetric dimethylarginine and other hydrophilic isobaric compounds using aqueous normal phase chromatography. AB - Two biologically important compounds with clinical relevance, asymmetric dimethylarginine and symmetric dimethylarginine, are analyzed using aqueous normal phase chromatography on silica hydride-based columns. Two different stationary phases were tested, a commercially available Diamond HydrideTM and a 2 acrylamido-2-methylpropane sulfonic acid experimental column. Two types of analytical protocols were investigated: analysis of the compounds when separation was achieved and analysis of the compounds with partial chromatographic separation. Urine samples from tuberculosis patients were tested for levels of asymmetric and symmetric dimethylarginine. The mass spectrometric technique of in source fragmentation that can provide data similar to a tandem mass analyzer was evaluated as a means of identification and quantitation of the two compounds when complete separation is not achieved. This same protocol was also evaluated for two other isobaric compounds, glucose-1 and glucose-6 phohsphate, and leucine and isoleucine. PMID- 26952369 TI - Affitins as robust tailored reagents for affinity chromatography purification of antibodies and non-immunoglobulin proteins. AB - Affinity chromatography is a convenient way of purifying proteins, as a high degree of purity can be reached in one step. The use of tags has greatly contributed to the popularity of this technique. However, the addition of tags may not be desirable or possible for the production of biopharmaceuticals. There is thus a need for tailored artificial affinity ligands. We have developed the use of archaeal extremophilic proteins as scaffolds to generate affinity proteins (Affitins). Here, we explored the potential of Affitins as ligand to design affinity columns. Affitins specific for human immunoglobulin G (hIgG), bacterial PulD protein, and chicken egg lysozyme were immobilized on an agarose matrix. The columns obtained were functional and highly selective for their cognate target, even in the presence of exogenous proteins as found in cell culture media, ascites and bacterial lysates, which result in a high degree of purity (~95%) and recovery (~100%) in a single step. Anti-hIgG Affitin columns withstand repetitive cycles of purification and cleaning-in-place treatments with 0.25 M NaOH as well as Protein A does. High levels of Affitin productions in Escherichia coli makes it possible to produce these affinity columns at low cost. Our results validate Affitins as a new class of tailored ligands for the affinity chromatography purification of potentially any proteins of interest including biopharmaceuticals. PMID- 26952361 TI - A Role for the Inflammasome in Spontaneous Labor at Term. AB - PROBLEM: Inflammasomes are signaling platforms that, upon sensing pathogens and sterile stressors, mediate the release of mature forms of interleukin (IL)-1beta and IL-18. The aims of this study were to determine (i) the expression of major inflammasome components in the chorioamniotic membranes in spontaneous labor at term, (ii) whether there are changes in the inflammasome components associated with the activation of caspase-1 and caspase-4, and (iii) whether these events are associated with the release of the mature forms of IL-1beta and IL-18. METHOD OF STUDY: Chorioamniotic membranes were collected from women at term with and without spontaneous labor. mRNA abundance and protein concentrations of inflammasome components, nucleotide-binding oligomerization domain-containing (NOD)1 and NOD2 proteins, caspase-1, caspase-4, IL-1beta, and IL-18 were quantified by qRT-PCR (n = 28-29 each), ELISA (n = 10 each) or immunoblotting (n = 8 each), and immunohistochemistry (n = 10 each). Active caspase-1 and caspase 4, as well as mature IL-18, were determined by immunoblotting (n = 4 each), and pro- and mature forms of IL-1beta were determined by ELISA (n = 4-7 each). RESULTS: Inflammasome components and NOD proteins were expressed in the chorioamniotic membranes obtained from women at term. The chorioamniotic membranes from women who underwent labor had (i) higher concentrations of NLRP3 (NOD-like receptor family, pyrin domain-containing protein 3) and NOD1 protein, (ii) greater immunoreactivity for caspase-1 and caspase-4, (iii) a greater quantity of the active form of caspase-1 (p20), and (iv) higher mRNA abundance and protein concentrations of pro- and mature IL-1beta. However, mRNA abundance and protein concentrations of the mature form of IL-18 were not increased in tissues from women who underwent labor at term. CONCLUSIONS: Spontaneous labor at term is characterized by the expression of inflammasome components, which may participate in the activation of caspase-1 and lead to the cleavage and release of mature IL-1beta by the chorioamniotic membranes. These results support the participation of the inflammasome in the mechanisms responsible for spontaneous parturition at term. PMID- 26952370 TI - C-reactive protein, frailty and overnight hospital admission in elderly individuals: A population-based study. AB - BACKGROUND: C-reactive protein (CRP), an important inflammatory biomarker, has been linked to various diseases (e.g., cardiovascular disease). Here, we aimed to investigate the associations of high sensitivity C-reactive protein (hsCRP) with frailty and overnight hospital admission in an elderly Chinese population. METHODS: We used cross-sectional data from 1478 participants (aged 70-84 years) who were randomly recruited from 31 villages in Jiang'an township, Rugao city, China. Frailty status was defined using a modified frailty phenotype. The number of overnight hospital admissions was ascertained. RESULTS: The sample mean age was 75.3 years, and 53.0% of participants were female (n=784). The mean level of hsCRP was 3.6 mg/L. From the low (hsCRP<=1.00 mg/L) to high hsCRP (hsCRP>=3.0mg/L) group, the proportion of overnight hospital admission increased linearly (8.7%, 10.6%, vs. 15.5%; P for trend=0.007). For frailty, the age- and sex-adjusted odds ratios (ORs) were 1.21 (95% CI: 0.89, 1.64) for participants in the intermediate hsCRP group and 1.49 (95% CI: 1.05, 2.09) for participants in the high hsCRP group compared with those in the low hsCRP group. For overnight hospital admission, the corresponding ORs were 1.26 (95% CI: 0.72, 2.19) and 1.94 (95% CI: 1.08, 3.48), respectively. After adjustment for other covariates, the significance of these associations remained. CONCLUSIONS: Elevated levels of hsCRP were associated with increased risks of frailty and overnight hospital admission among elderly individuals in Rugao. More public health concerns about inflammation and subsequent outcomes are needed to improve the quality of life in elderly populations. PMID- 26952371 TI - Consumption of star fruit juice on pro-inflammatory markers and walking distance in the community dwelling elderly. AB - PURPOSE: This study aimed to evaluate the effect of star fruit juice supplementation on tumor necrosis factor-alpha (TNF-alpha), interleukin-23 (IL 23) and interleukin-2 (IL-2), nitric oxide (NO), and 6 min walking distance (6MWD) in a group of elderly individuals. METHODS: Twenty-nine individuals (20 males, 9 females) with a mean age of 72.4+/-8.3 years completed this study. A two week control period was followed by four weeks of 100g fresh star fruit juice consumption twice per day after meals. RESULTS: Plasma TNF-alpha, IL-23, IL-2, NO and the 6MWD were evaluated twice during the control period (weeks 0 and 2) and once after the star fruit juice consumption (week 6). RESULTS: The results showed that all parameters in the blood did not change significantly during the control period. After 4 weeks of star fruit juice consumption, a significant reduction in NO, TNF-alpha and IL-23 was found; however, there was no change in IL-2. Moreover, the 6MWD increased significantly at week 6, when compared to that at week 0 and 2. Furthermore, the results also showed a significantly positive and negative correlation of NO and TNF-alpha to the 6MWD, but no correlation of IL-23 and IL-2. CONCLUSION: This preliminary study concluded that consumption of star fruit juice at 100g twice daily for one month can significantly depress the pro inflammation cytokines: TNF-alpha, IL-23, and NO, while increasing walking distance. Low TNF-alpha and high NO also present a significant correlation to walking capacity in elderly individuals. PMID- 26952372 TI - Long-term effects of an intergenerational program on functional capacity in older adults: Results from a seven-year follow-up of the REPRINTS study. AB - BACKGROUND: Social engagement activities can help older adults maintain mental and physical functioning levels. This study examined the long-term effects of the intergenerational picture-book reading program "REPRINTS" (Research of Productivity by Intergenerational Sympathy) on older adults. METHODS: After baseline assessment, participants were allowed to decide which condition they wanted to participate in: the REPRINTS intervention or control group involving only assessments. REPRINTS participants participated in group activities that involved playing a hand game and reading picture books to children at kindergartens, elementary schools, and public childcare centers, once every one two weeks. A follow-up assessment, which focused on functional capacity (i.e., instrumental activities of daily living, intellectual activity, and social function), was conducted after seven years. The analysis included responses from 62 REPRINTS (mean age [SD]=66.2 [5.7]) and 100 control-group participants (mean age [SD]=68.0 [4.7]). RESULTS: A logistic regression analysis examining intervention effects revealed that control-group participants were more likely to reduce intellectual activity and interactions with children compared to REPRINTS participants (p=.013 and .003, respectively). Furthermore, the REPRINTS group maintained greater functional reach compared to the control group (p<.001). However, the REPRINTS group was likely to stay indoors more often, compared to the control group (p=.045). CONCLUSION: The present study indicates that the REPRINTS intergenerational program has long-term, positive effects that help maintain and promote intellectual activity, physical functioning, and intergenerational exchange, although the effect of the increasing amount of physical activity is unclear. PMID- 26952373 TI - Determinants of rate of change in functional disability: An application of latent growth curve modeling. AB - Our aim was to identify disablement factors, including predisposing, intra individual, and extra-individual factors, which predict the rate of change in general functional disability (GFD) in older adults. This study utilized the Taiwan Longitudinal Study on Aging Survey in 1996-2007 (N=3,186). Multiple indicator latent growth curve modeling was used to examine how 12 disablement factors predicted the rate of change in GFD. GFD trajectories were modeled using Nagi's functional limitations, activities of daily living, and instrumental activities of daily living. Greater age (B=.025), female gender (B=.114), and greater numbers of comorbidities (B=.038) were associated with faster increase in GFD. Education (B=-.005) and participation in physically active leisure time activities (B=-.031) were associated with slower increase in GFD. Our findings add to the understanding of how disablement factors contribute to the rate of change in GFD. Predisposing factors played the main role. However, the factors we found to be associated with the rate of change in GFD in older adults were slightly different from the factors reported in the literature. Decreasing the number of comorbidities and increasing the level of physically active leisure time activity should be considered priorities for preventing disability as people age. PMID- 26952374 TI - First incident hospitalisation for Australian women aged 70 and beyond: A 10 year examination using competing risks. AB - There are increasing concerns regarding high hospital use among older adults and the capacity to manage the economic impact of the ageing population trend on healthcare systems. First hospitalisation in old age may act as a catalyst for ongoing intensification of health problems and acute care use. This study examined factors associated with first incident hospitalisation in women aged over 70, accounting for the health inequalities associated with geographic location. Survey data from 3780 women from the 1921 to 1926 cohort of the Australian Longitudinal Study on Women's Health were matched with the Admitted Patients Data Collection and National Death Index. Days to first event (hospitalisation or death) were modelled using competing risks methods. A total of 3065 (80.3%) women had at least one hospital admission. More than half of the top 15 reasons for first hospitalisation were related to cardiovascular disease, with atrial fibrillation the most common. Proportional subdistribution hazards models showed that first hospital admission was driven by enabling and need factors including asthma/bronchitis diagnosis (HR=1.16; p=0.047), private health insurance (HR=1.16; p=0.004) more than two prescribed medications in previous month (HR=1.31; p=0.001), more than four general practitioner visits in previous year (HR=1.50; p=0.034), lower physical functioning (HR=0.99; p<0.001) and living in an inner regional area (HR=1.17; p=0.003). First overnight hospitalisation was primarily related with potentially preventable and treatable chronic diseases. Primary and secondary strategies aimed at chronic disease generally, and better chronic disease management particularly for cardiovascular and respiratory diseases, may play a vital role in disease prevention or delay in readmissions among this population. PMID- 26952375 TI - Delirium is a risk factor for further cognitive decline in cognitively impaired hip fracture patients. AB - BACKGROUND: Delirium is a risk factor for dementia in cognitively intact patients. Whether an episode of delirium accelerates cognitive decline in patients with known dementia, is less explored. METHODS: This is a prospective follow-up study of 287 hip fracture patients with pre-fracture cognitive impairment. During the hospitalization, the patients were screened daily for delirium using the Confusion Assessment Method. Pre-fracture cognitive impairment was defined as a score of 3.44 or higher on the pre-fracture Informant Questionnaire on Cognitive Decline in the Elderly Short Form (IQCODE-SF). At follow-up after 4-6 months, the caregivers rated cognitive changes emerging after the fracture using the IQCODE-SF, and the patients were tested with the Mini Mental State Examination (MMSE). A sub-group of the patients had a pre-fracture MMSE score which was used to calculate the yearly decline on the MMSE in patients with and without delirium. RESULTS: 201 of the 287 patients developed delirium in the acute phase. In linear regression analysis, delirium was a significant and independent predictor of a more prominent cognitive decline at follow-up measured by the IQCODE-SF questionnaire (p=0.002). Among patients having a pre-fracture MMSE score, the patients developing delirium had a median (IQR) yearly decline of 2.4 points (1.1-3.9), compared to 1.0 points (0-1.9) in the group without delirium (p=0.001, Mann-Whitney test). CONCLUSIONS: Hip fracture patients with pre-fracture dementia run a higher risk of developing delirium. Delirium superimposed on dementia is a significant predictor of an accelerated further cognitive decline. PMID- 26952376 TI - Does a weight-training exercise programme given to patients four or more years after total knee arthroplasty improve mobility: A randomized controlled trial. AB - AIM: To investigate the effects of the home exercise therapy performed after at least four years postoperatively on skeletal muscle strength and functionality in patients with total knee arthroplasty (TKA). METHODS: Sixty patients (age; 69.66+/-7.53, weight; 81.56+/-14.43 kg, 10 male, 50 female) followed up four or more years were randomly divided into two groups. An 8-week exercise program was designed for bilateral TKA patients. While the patients in one group were assigned to weighted exercise group, the patients in the other group were assigned to non-weighted exercise group. The primary outcome was the isometric muscle strength of quadriceps femoris (QF) and hamstring muscles assessed by Hand Held Dynamometer. The secondary outcomes were the pain level, 30s sit-to-stand test, 10 m walk test, range of motion, and the knee function score of the Hospital for Special Surgery. The assessments were performed before and after the treatment. RESULTS: After treatment, significant differences were found in all evaluation parameters (except rest pain and range of motion) in favour of the weighted group. QF muscle strength changes (kg); weighted group: 1.99+/-1.70, non weighted group: 0.51+/-1.14 (p=0.000), 30s sit-to-stand test changes (repetitions); weighted group: 3.66+/-2.23, non-weighted group: 1.70+/-1.95 (p=0.000), 10 m walk test changes (seconds); weighted group: -2.60+/-1.30, non weighted group: -0.83+/-3.51 (p=0.000). CONCLUSION: Home exercise programs applied to TKA patients after at least four years postoperatively was effective in increasing muscle strength, decreasing severity of pain, and improving functional activities. The improvements were significantly greater in weighted compared with the non-weighted exercise group. PMID- 26952377 TI - Serum uric acid concentration and metabolic syndrome among elderly Koreans: The Korean Urban Rural Elderly (KURE) study. AB - BACKGROUND: Epidemiologic studies have demonstrated that elevated serum uric acid concentration is an independent risk factor for metabolic syndrome. However, few studies have focused on elderly populations. Thus, we investigated the association of serum uric acid concentration with metabolic syndrome in community dwelling elderly Koreans. METHODS: This cross-sectional analysis included 2940 participants (986 men and 1954 women) aged 65 years or older who participated in a baseline health assessment for the Korean Urban Rural Elderly cohort study from 2012 to 2014. Serum uric acid concentration was analyzed using both continuous and dichotomous variables. Hyperuricemia was defined as a uric acid concentration >=7.0 mg/dL in men and >=6.0 mg/dL in women. Metabolic syndrome was defined according to the 2009 harmonizing definition. Multiple logistic regression models were used to investigate independent association between serum uric acid and metabolic syndrome, after adjusting for age, body mass index, LDL cholesterol, glycated hemoglobin, blood urea nitrogen, estimated glomerular filtration rate health behaviors, and medications. RESULTS: Prevalence of metabolic syndrome and its components increased significantly according to uric acid concentration in both sexes. The adjusted odds ratios for having metabolic syndrome per 1.0mg/dL higher uric acid concentration were 1.16 (95% CI: 1.03-1.31) in men and 1.27 (95% CI: 1.13-1.42) in women. Hyperuricemia was also associated with metabolic syndrome, with adjusted odds ratios of 1.71 (95% CI: 1.11-2.63) in men and 1.55 (95% CI: 1.05-2.29) in women. CONCLUSIONS: Elevated serum uric acid concentration was independently associated with an increased prevalence of metabolic syndrome in community-dwelling elderly Koreans. PMID- 26952378 TI - The maintaining and improving effect of grandchild care provision on elders' mental health-Evidence from longitudinal study in Taiwan. AB - OBJECTIVE: This study aims to determine the impact of grandchild care provision on elders' mental health by self-comparison and longitudinal study design. METHOD: Information of 2930 grandparents from the Study of Health and Living Status of the Middle-Aged and Elderly in Taiwan were analysed. Elders' mental health was evaluated by Epidemiological Studies Depression Scale in both 2003 and 2007. Participants were divided into 4 groups based on their changing behaviour of caring for grandchildren from 2003 to 2007. Chi-square test was used to compare changes in elders' individual characteristics and total CESD scores between and within groups. ANOVA was used to compare the means of elders' depressive symptoms between groups while paired-t test was used to compare changes in elders' depression symptoms from 2003 to 2007. Logistic regression was performed to determine the associations between elders' changing behaviour of caring for grandchildren and changes in depressive symptoms. RESULTS: Elders continuously caring for grandchildren or started to take care of grandchildren significantly felt happier and enjoyed life more than before and more than elders who do not provide grandchild care. Logistic regression analyses exploring the impact of grandchild care provision found that elders provided no grandchild care had worst mental health amongst all. Elders stopped providing grandchild care had significantly higher risk of developing depressive symptoms (OR=1.40) than elders provided no grandchild care at all time. DISCUSSION: By self-comparison, this study illustrates how taking care of grandchildren maintains elders' mental health, especially against them from loneliness and depression. PMID- 26952379 TI - Physical activity, body composition and general health status of physically active students of the University of the Third Age (U3A). AB - OBJECTIVE: To evaluate general health status of a group of older adults, physically active students of the University of the Third Age (U3A), based on results of biochemical analyses of blood, assessment of their physical activity (PA) level, body composition and cognitive function with respect to age and sex. METHODS: A total of 104 students (85 women and 19 men, aged 63.7+/-6.6 y) of the U3A's located in the Upper Silesia region of Poland volunteered to participate in this study. A habitual PA level and body composition were objectively assessed by using ActiGraph GT1M and InBody 720, respectively. Serum lipid profile and glucose metabolism markers were measured for assessment of cardiovascular disease risk factors. Moreover, subjects' cognitive functions were tested. RESULTS: Most of the study participants reached the daily step goal of 10,000 steps and thus fulfilled the ACSM recommendations for the quantity and quality of cardiorespiratory exercise. Highly negative correlations between the number of steps per day and body adiposity markers, serum insulin and HOMA-IR confirmed that vigorous physical activity at the recommended level was associated with better body composition and lower levels of risk markers of coronary heart disease and diabetes. Most of the U3A students were characterized by a favorable lipid profile, prevalence of normal blood pressure, low rates of HOMA-estimated insulin resistance and normal cognitive function. CONCLUSION: Adherence to ACSM recommendations is associated with beneficial changes in risk factors related to cardiovascular disease. PMID- 26952380 TI - Dietary intake of elderly outpatients with chronic obstructive pulmonary disease. AB - PURPOSE: Chronic obstructive pulmonary disease (COPD) is often associated with malnutrition, which is in turn associated with poor outcomes. Accordingly, in COPD patients adequate nutrition might improve several clinical and functional outcomes. Nevertheless, information about nutrient intake of older populations with COPD is still scanty. MATERIALS AND METHODS: We analysed data of 523 elderly attending a geriatric ambulatory. Of these, 165 had a diagnosis of COPD, while 358 were control participants, matched for demographic characteristics and free from respiratory diseases. COPD was diagnosed according to the global initiative for chronic obstructive lung disease (GOLD) criteria. The intake of micro and macronutrients was recorded using the European prospective investigation into cancer and nutrition (EPIC) questionnaire. Nutrient intake of COPD patients was compared with that of the control group and with recommended dietary allowances RDA. RESULTS: COPD patients had a lower energy intake, as compared with control participants (29.4 vs 34.4 kcal/kg of ideal weight; P<.0001), due to reduced intake of carbohydrates and proteins. Accordingly, in the energy intake was lower than recommended in 52% of COPD patients, vs 30% of controls (P<.0001). The intake of calcium, potassium, folate, cholecalciferol, retinol, and thiamine was lower than RDA in over 75% of COPD patients. CONCLUSIONS: The diet of elderly COPD outpatients does not provide the recommended energy intake, nor does it meet the RDA for many micronutrients. Such deficits are more severe than in age matched non- respiratory subjects. PMID- 26952381 TI - Sociodemographic and socioeconomic characteristics of elder self-neglect in an US Chinese aging population. AB - This study aimed to examine the socio-demographic and socioeconomic characteristics associated with prevalence and severity of elder self-neglect in an U.S. Chinese older population. The PINE study is a population-based epidemiological study in the greater Chicago area. In total, 3159 Chinese older adults were interviewed from 2011 to 2013. Elder self-neglect was assessed with systematic observations of a participant's personal and home environment across five domains: hoarding, personal hygiene, house in need of repair, unsanitary conditions, and inadequate utility. Elder self-neglect was prevalent among older adults aged 80 years or over (mild self-neglect: 34.6% 95% CI 30.9-38.4; moderate/severe: 15.6% 95% CI 12.8-18.6), men (mild: 28.6% 95% CI 26.1-31.3; moderate/severe: 13.1% 95% CI 11.2-15.1), those with 0-6 years of education (mild: 32.2% 95% CI 29.7-34.9; moderate/severe: 12.6% 95% CI 10.8-14.5), and those with an annual personal income between $5000 and $10,000 (mild: 30.8% 95% CI 28.4-33.2; moderate/severe: 11.8% 95% CI 10.2-13.5). Older age (mild self neglect: OR 1.02, 95% CI 1.01-1.03; moderate/severe self-neglect: OR 1.02, 95% CI 1.00-1.03) and lower education levels (mild self-neglect: OR 1.06, 95% CI 1.03 1.08; moderate/severe self-neglect: OR 1.07, 95% CI 1.04-1.09) were associated with significantly increased odds of elder self-neglect. Women (moderate/severe self-neglect: OR 0.73, 95% CI 0.58-0.93) had significantly decreased odds of moderate/severe elder self-neglect. No significant association was found between levels of income and overall elder-self-neglect of all severities. Future research is needed to examine risk/protective factors associated with elder self neglect in U.S. Chinese older populations. PMID- 26952382 TI - Advanced life events (ALEs) that impede aging-in-place among seniors. AB - Despite the wishes of many seniors to age-in-place in their own homes, critical events occur that impede their ability to do so. A gap exists as to what these advanced life events (ALEs) entail and the planning that older adults perceive is necessary. The purpose of this study was to identify seniors' perceptions and planning toward ALEs that may impact their ability to remain in their own home. We conducted focus groups with 68 seniors, age >=65 years (mean age 73.8 years), living in the community (rural, urban, and suburban), using open-ended questions about perceptions of future heath events, needs, and planning. Three investigators coded transcriptions using constant comparative analysis to identify emerging themes, with disagreements resolved via consensus. Subjects identified five ALEs that impacted their ability to remain at home: (1) Hospitalizations, (2) Falls, (3) Dementia, (4) Spousal Loss, and (5) Home Upkeep Issues. While recognizing that ALEs frequently occur, many subjects reported a lack of planning for ALEs and perceived that these ALEs would not happen to them. Themes for the rationale behind the lack of planning emerged as: uncertainty in future, being too healthy/too sick, offspring influences, denial/procrastination, pride, feeling overwhelmed, and financial concerns. Subjects expressed reliance on offspring for navigating future ALEs, although many had not communicated their needs with their offspring. Overcoming the reasons for not planning for ALEs is crucial, as being prepared for future home needs provides seniors a voice in their care while engaging key supporters (e.g., offspring). PMID- 26952383 TI - Personalized citizen assistance for social participation (APIC): A promising intervention for increasing mobility, accomplishment of social activities and frequency of leisure activities in older adults having disabilities. AB - BACKGROUND: Social participation, a determinant of health in older adults, requires innovative interventions. The personalised citizen assistance for social participation (APIC) involves weekly three-hour personalised stimulation sessions targeting significant social and leisure activities difficult to accomplish. Recently adapted for older adults, the APIC's impact on this population is unknown. OBJECTIVE: This study explored the impact of APIC on older adults with disabilities. METHODS: A mixed-method design including a pre-experimental component was used with 16 participants (11 women) aged 66-91 (79.4+/-8.7) with disabilities, living at home. They completed functional autonomy, social participation, leisure and quality of life questionnaires, and semi-structured interviews. RESULTS: APIC increased older adults' functional autonomy (p=0.02), accomplishment (p<0.01) and satisfaction (p=0.02) with social participation, and frequency of leisure practice (p<0.01). Post-intervention, participants wished to modify the practice (p<0.01) and frequency (p<0.01) of leisure activities, and difficulties in their social environment diminished (p=0.03). Their attitude toward leisure (p=0.04) as well as their health (p<0.01) and psychological (p=0.03) quality of life improved. Older adults thought APIC helped them resume, maintain, explore and experiment with significant social activities. It also increased their psychological and physical well-being, feeling of control, connectedness, self-esteem and motivation to accomplish activities. Finally, APIC can compensate for an unavailable and crumbling social network. CONCLUSION: APIC is a promising intervention that leads to new opportunities for older adults to increase community integration and enhance the social component of their lives. It can also optimise how the needs of older adults are met, including utilisation of personal and environmental resources. PMID- 26952384 TI - Decisions in complex clinical situations: Prevalence and factors associated in general public. AB - Many studies have focused on advanced directives. However, the type of treatment that citizens would choose in critical health situations and whether their decision varies with their sociodemographic characteristics and their experiences of life both within and outside the family context, are unknown. This study analyzes the factors associated with choosing or refusing life support treatment in hypothetical situations of differing clinical complexity. This transversal descriptive study was carried out by questionnaires given to 1051 participants from primary care centres. The Life Support Preferences Questionnaire (LSPQ) used to assess preferences of life-sustaining treatment, describes six scenarios with different prognoses. Analysis of the sociodemographic characteristics and life experiences of the subjects led to the following findings. In situations of very severe prognosis, treatment is mostly rejected. When there is chance of recovery, treatment is mostly accepted, especially in the least aggressive cases and when deciding for another person. A greater propensity to reject treatment was observed among subjects over 55 years, those in poor health and those who had observed a terminal illness in a family member. Practising Catholics are more likely to accept treatment in all medical situations described. Preferences for life support treatment are linked to sociodemographic characteristics and life experiences of patients. Physicians should bear in mind these characteristics when confronted with critical clinical situations, involving difficult decisions. PMID- 26952385 TI - The geriatric mania asenapine study (GeMS). AB - RATIONALE: Population aging results in growing numbers of psychiatric disorders among older patients. Yet, there is a paucity of studies on elderly mania. OBJECTIVE: To evaluate the effect of asenapine on older manic inpatients. METHODS: Thirty-four elderly patients suffering from a manic episode, mean age 67.2 years were enrolled in an open-label 3-weeks study of asenapine treatment. INCLUSION CRITERIA: (1) DSM-IV criteria for manic episode (2) age above 60 years, (3) episode severity necessitating inpatient treatment, (4) Young Mania Rating Scale (YMRS) score at baseline >20, and (5) no prior asenapine treatment. Participants were prescribed asenapine 5 mg BID for 3 days and then dose increased to 10 mg BID till day 21 (study completion). RESULTS: Twenty-five patients completed the study. YMRS score decreased from a baseline mean of 27.0+/ 8.8 to 13.3+/-12.0 at the end of the study (p<0.001). Fourteen patients (56% of completers) achieved remission (YMRS score<12). MADRS score decreased from a baseline mean of 7.6+/-5.6 to 4.4+5.1 at the end of the study (p<0.05); low baseline score should be noted. Sleep duration increased from a baseline median of 5.7 hours to 7.0 h at the end of the study (p<0.05). Seven patients discontinued treatment due to adverse events. Two patients passed-away after study completion. CONCLUSION: We tentatively conclude that the efficacy of asenapine in reducing acute manic symptoms and achieving remission in the elderly is supported in this study. Caution is needed in patients with co-morbid physical conditions. PMID- 26952386 TI - The evolution of the Krebs cycle: A promising subject for meaningful learning of biochemistry. AB - Evolution has been recognized as a key concept for biologists. To enhance comprehension and motivate biology undergraduates for the contents of central energetic metabolism, we addressed the Krebs cycle structure and functions in an evolutionary view. To this end, we created a study guide that contextualizes the emergence of the cyclic pathway, in light of the prokaryotic influence since the early anaerobic condition of the Earth to increase oxygen in the atmosphere. The study guide is composed of three interrelated sections: (1) a problem, designed to arouse curiosity, inform and motivate students, (2) a text about life evolution, including early microorganisms and the emergence of the Krebs cycle, and (3) questions for debate. The activity consisted on individual reading and peer discussion based on this written material, under the guidance of the instructors. The questions were designed to foster debate in an ever-increasing level of complexity and to strengthen the main contextual aspects leading to emergence, evolving, and permanency of a complex metabolic pathway. Based on classroom observation, analysis of student's written responses, and individual interviews, we noticed they were engaged and motivated by the task, especially during group discussion. The whole experience suggests that the study guide was a stimulus to broaden the comprehension of the Krebs cycle, reinforcing the evolutionary approach as an important subject for learning purposes. (c) 2016 by The International Union of Biochemistry and Molecular Biology, 44:288-296, 2016. PMID- 26952387 TI - Small cell mesothelioma: A rare entity and diagnostic pitfall mimicking small cell lung carcinoma on fine-needle aspiration. AB - Small cell mesothelioma (SCM) is an extremely rare variant of epithelioid mesothelioma that can be mistaken for other forms of small round blue cell tumors, particularly small cell lung carcinoma (SCLC). Here, we describe a fine needle aspiration (FNA) from a pleural lesion in a 75-year-old man with a history of known asbestos exposure. The FNA revealed cohesive clusters of uniform small round blue cells with high nuclear-to-cytoplasmic ratio, finely powdery chromatin, small inconspicuous nucleoli, and scant amount of cytoplasm. Mitoses were infrequent and nuclear molding was absent. Immunochemical profile supported a mesothelial origin, which was later confirmed by pleurectomy with a diagnosis of SCM. This report demonstrates the difficulties in cytologic evaluation of lung FNAs in differentiating SCM from SCLC or other small round blue cell tumors. As therapy differs for SCM, early recognition of the cytologic features is essential in making the correct diagnosis needed for appropriate clinical management. Diagn. Cytopathol. 2016;44:526-529. (c) 2016 Wiley Periodicals, Inc. PMID- 26952388 TI - Structural basis of allosteric and synergistic activation of AMPK by furan-2 phosphonic derivative C2 binding. AB - The metabolic stress-sensing enzyme AMP-activated protein kinase (AMPK) is responsible for regulating metabolism in response to energy supply and demand. Drugs that activate AMPK may be useful in the treatment of metabolic diseases including type 2 diabetes. We have determined the crystal structure of AMPK in complex with its activator 5-(5-hydroxyl-isoxazol-3-yl)-furan-2-phosphonic acid (C2), revealing two C2-binding sites in the gamma-subunit distinct from nucleotide sites. C2 acts synergistically with the drug A769662 to activate AMPK alpha1-containing complexes independent of upstream kinases. Our results show that dual drug therapies could be effective AMPK-targeting strategies to treat metabolic diseases. PMID- 26952389 TI - Zika virus outbreak and the case for building effective and sustainable rapid diagnostics laboratory capacity globally. PMID- 26952390 TI - Bone restoration with cemented Exeter universal stem - Three-years longitudinal DEXA study in 165 hips for femur. AB - BACKGROUND: The pattern of strain distribution in the proximal femur changes following total hip arthroplasty (THA) and decreases in bone mineral density (BMD) occur around the stem following cemented and uncemented THA. We herein prospectively examined changes in BMD for 3 years after THA with a cemented Exeter universal stem. METHODS: One hundred and sixty five hips from 150 patients who underwent unilateral THA were included as a cohort. Our patients included 20 men (20 hips) and 130 women (145 hips) with a mean age of 63.9 years. BMD was measured 2 weeks postoperatively (baseline) and 3, 6 12, 18, 24, 30, and 36 months (3 years) after surgery using dual-energy X-ray absorptiometry (DEXA) on the lumbar spine and proximal femur of the operated side according to the Gruen zone classification. We quantified longitudinal changes in BMD for more than 3 years after surgery and detected several factors which affected these changes. RESULTS: In the first year, BMD in the most proximal femur showed a 5.5% reduction at the lateral side (zone 1) and 13% reduction at the medial side (zone 7), with no significant BMD reductions being observed thereafter. BMD reductions at 3 years were the most apparent at the proximal medial part of the femur (zone 7; -10.3%), while BMD ratio change in zone 1 was over the baseline (+2.9%). Especially in zone 7, the BMD ratio decreased with female, decreases in weight, decreases in height, decreases in BMI, and increases in age at the time of surgery. CONCLUSIONS: Bone restoration is expected with a cemented Exeter universal stem. Male patients, a younger age, a high body weight, being tall, and a high BMI were identified as factors associated with the restoration of BMD in proximal femur. PMID- 26952391 TI - Delivery of vanillin by poly(lactic-acid) nanoparticles: Development, characterization and in vitro evaluation of antioxidant activity. AB - Poly(lactic acid) (PLA) nanoparticles containing vanillin were prepared using an emulsion-solvent evaporation technique and were characterized and assessed for their in vitro antioxidant potential. Physicochemical properties of the nanoparticles were characterized by size, polydispersity index, zeta potential, encapsulation efficiency and stability. Solid state and thermal properties were assessed using X-ray diffraction and differential scanning calorimetry, while in vitro drug release profile was also evaluated. Results showed PLA nanoparticles having a characteristic amorphous structure, sizes in the range of 240 nm with high homogeneity in size distribution, zeta potential of -22 mV and vanillin encapsulation efficiency of 41%. In vitro release study showed a slow and sustained release of vanillin governed by diffusion. Nanoparticles were stable over a period of three months. Antioxidant ability of the vanillin-loaded PLA nanoparticles in scavenging the radical 2,2-azinobis (3-ethylbenzothiazoline-6 sulfonic acid) (ABTS) was inferior to free vanillin and due to its prolonged release showed a profile that was both time and concentration dependent, while free vanillin showed concentration-dependent activity. The study concluded that PLA nanoparticles are potential carriers for vanillin delivery. PMID- 26952392 TI - Nano-level monitoring of Er(III) by fabrication of coated graphite electrode based on newly synthesized Schiff base as neutral carrier. AB - Plasticized membranes using N-(-3-((thiazol-2-ylimino)methyl)benzylidene)thiazol 2-amine (S1) and 5-((-3-((5-mercapto-1,3,4-thiadiazol-2 ylimino)methyl)benzylidene)amino)-1,3,4-thiadiazole-2-thiol (S2) have been prepared and explored as Er (III) selective electrodes. Effect of various plasticizers viz. dibutylphthalate, tri-n-butylphosphate, dioctylphthalate, acetophenone, 1-chloronapthalene, o-nitrophenyloctylether, and anion excluders viz. sodium tetraphenylborate and potassium tetrakis-p-(chlorophenyl)borate was studied in detail and improved performance was observed. Optimum performance was observed for the membrane electrode having a composition of S2: PVC: o-NPOE: KTpClPB in the ratio of 4: 38: 55: 3 (w/w, mg). The performance of the PME based on S2 was compared with CGE. The electrodes exhibit Nernstian slope for Er (III) ion with detection limit 5.4 * 10(-8)mol L(-1) for PME and 6.1 * 10(-9)mol L(-1) for CGE. The response time for PME and CGE was found to be 12s and 9s respectively. The practical utility of the CGE has been demonstrated by its usage as an indicator electrode in potentiometric titration of EDTA with Er (III) solution and determination of fluoride ions in mouthwash solution. The proposed electrode was also applied to the determination of added Er(3+) ion in water and binary mixtures. It is found that the electrode could be able to recover the Er(3+) ion in 96.2-99.5%. PMID- 26952393 TI - Synthesis and characterization of bis nitrato[4-hydroxyacetophenonesemicarbazone) nickel(II) complex as ionophore for thiocyanate-selective electrode. AB - The PVC based-ion selective electrode viz., bis nitrato[4-hydroxyacetophenone semicarbazone] nickel(II) as an ionophore was prepared for the determination of thiocyanate ion. The ionophore was characterized by FT-IR, UV-vis, XRD, magnetic moment and elemental analysis (CHN). On the basis of spectral studies an octahedral geometry has been assigned. The best performance was obtained with a membrane composition of 31% PVC, 63% 2-nitrophenyl octylether, 4.0% ionophore and 2.0% trioctylmethyl ammonium chloride. The electrode exhibited an excellent Nernstian response to SCN(-) ion ranging from 1.0 * 10(-7) to 1.0 * 10(-1)M with a detection limit of 8.6 * 10(-8)M and a slope of -59.4 +/- 0.2 mV/decade over a wide pH range (1.8-10.7) with a fast response time (6s) at 25 degrees C. The proposed electrode showed high selectivity for thiocyanate ion over a number of common inorganic and organic anions. It was successfully applied to direct determination of thiocyanate in biological (urine and saliva) samples in order to distinguish between smokers and non-smokers, environmental samples and as an indicator electrode for titration of thiocyanate ions with AgNO3 solution. PMID- 26952394 TI - Endothelialization and the bioactivity of Ca-P coatings of different Ca/P stoichiometry electrodeposited on the Nitinol superelastic alloy. AB - An alternative approach to improve the cardiovascular stents with less restenosis than drug eluting stents, involves an improvement in endothelialization of implants. In this study, the bio compatibility of the modified Ti-50.9 Ni alloy was investigated. At the first step, a thermo-chemical surface modification process was used to control the Ni release of the alloy. XPS and Raman analysis revealed that the surface of the alloy contains titanium dioxide after the modification process. According to the Ni release test, this surface condition has a good durability in Ringer's solution and offers a standard range to the leached Ni. At the next step, porous Ca-P films were electrodeposited on the modified surface. The results of endothelial cell culture on the coated samples revealed that the Ca-P coating, which has the highest value of Ca/P ratio shows the best result. The coating revealed a moderately wettable surface with a water contact angle of 53.3 degrees . According to Ca content analysis of the cell culture medium, this coating has the lowest amount of Ca as a result of minimum solubility of the coating. In the other Ca-P coatings with lower Ca/P ratios, the solubility of coatings results in the detachment of the cells. Also nano indentation and SEM studies revealed that the low stiffness in the calcium deficient coating can result in the failure of the coating as a result of the tensions created by the cells. PMID- 26952395 TI - Electrochemical corrosion behavior and elasticity properties of Ti-6Al-xFe alloys for biomedical applications. AB - The present study is to investigate the microstructural characteristics, electrochemical corrosion behavior and elasticity properties of Ti-6Al-xFe alloys with Fe addition for biomedical application, and Ti-6Al-4V alloy with two-phase (alpha+beta) microstructure is also studied as a comparison. Microstructural characterization reveals that the phase and crystal structure are sensitive to the Fe content. Ti-6Al alloy displays feather-like hexagonal alpha phase, and Ti 6Al-1Fe exhibits coarse lath structure of hexagonal alpha phase and a small amount of beta phase. Ti-6Al-2Fe and Ti-6Al-4Fe alloys are dominated by elongated, equiaxed alpha phase and retained beta phase, but the size of alpha phase particle in Ti-6Al-4Fe alloy is much smaller than that in Ti-6Al-2Fe alloy. The corrosion resistance of these alloys is determined in SBF solution at 37 degrees C. It is found that the alloys spontaneously form a passive oxide film on their surface after immersion for 500 s, and then they are stable for polarizations up to 0 VSCE. In comparison with Ti-6Al and Ti-6Al-4V alloys, Ti 6Al-xFe alloys exhibit better corrosion resistance with lower anodic current densities, larger polarization resistances and higher open-circuit potentials. The passive layers show stable characteristics, and the wide frequency ranges displaying capacitive characteristics occur for high iron contents. Elasticity experiments are performed to evaluate the elasticity property at room temperature. Ti-6Al-4Fe alloy has the lowest Young's modulus (112 GPa) and exhibits the highest strength/modulus ratios as large as 8.6, which is similar to that of c.p. Ti (8.5). These characteristics of Ti-6Al-xFe alloys form the basis of a great potential to be used as biomedical implantation materials. PMID- 26952396 TI - Preparation of thermo-responsive graft copolymer by using a novel macro-RAFT agent and its application for drug delivery. AB - A methodology to prepare thermo-responsive graft copolymer by using a novel macro RAFT agent was proposed. The macro-RAFT agent with pendant dithioester (ZC(S)SR) was facilely prepared via the combination of RAFT polymerization and esterification reaction. By means of ZC(S)SR-initiated RAFT polymerization, the thermo-responsive graft copolymer consisting of poly(methyl methacrylate-co hydroxylethyl methacrylate) (P(MMA-co-HEMA)) backbone and hydrophilic poly(N isopropylacrylamide) (PNIPAAm) side chains was constructed through the "grafting from" approach. The chemical compositions and molecular weight distributions of the synthesized polymers were respectively characterized by (1)H nuclear magnetic resonance ((1)H NMR) and gel permeation chromatography (GPC). Self-assembly behavior of the amphiphilic graft copolymers (P(MMA-co-HEMA)-g-PNIPAAm) was studied by transmission electron microscopy (TEM), dynamic light scattering (DLS) and spectrofluorimeter. The critical micelle concentration (CMC) value was 0.052 mg mL(-1). These micelles have thermo-responsibility and a low critical solution temperature (LCST) of 33.5 degrees C. Further investigation indicated that the guest molecule release property of these micelles, which can be well described by a first-order kinetic model, was significantly affected by temperature. Besides, the micelles exhibited excellent biocompatibility and cellular uptake property. Hence, these micelles are considered to have potential application in controlled drug delivery. PMID- 26952397 TI - A novel disposable electrochemical sensor for determination of carbamazepine based on Fe doped SnO2 nanoparticles modified screen-printed carbon electrode. AB - An effective strategy to fabricate a novel disposable screen printing carbon electrode modified by iron doped tin dioxide nanoparticles for carbamazepine (CBZ) detection has been developed. Fe-SnO2 (Fe=0 to 5 wt.%) NPs were synthesized by a simple microwave irradiation method and assessed for their structural and morphological changes due to Fe doping into SnO2 matrix by X-ray diffraction and scanning and transmission electron microscopy. The electrochemical behaviour of carbamazepine at the Fe-SnO2 modified screen printed carbon electrode (SPCE) was investigated by cyclic voltammetry and square wave voltammetry. Electron transfer coefficient alpha (0.63) and electron transfer rate constant ks (0.69 s(-1)) values of the 5 wt.% Fe-SnO2 modified SPCE indicate that the diffusion controlled process takes place on the electrode surface. The fabricated sensor displayed a good electrooxidation response towards the detection of CBZ at a lower oxidation potential of 0.8 V in phosphate buffer solution at pH7.0. Under the optimal conditions, the sensor showed fast and sensitive current response to CBZ over a wide linear range of 0.5-100 MUM with a low detection limit of 92 nM. Furthermore, the practical application of the modified electrode has been investigated by the determination of CBZ in pharmaceutical products using standard addition method. PMID- 26952398 TI - Synthesis and photobactericidal properties of a neutral porphyrin grafted onto lignocellulosic fibers. AB - Photodynamic antimicrobial chemotherapy (PACT), as one of the promising alternative antimicrobial treatment, has received great attention in recent years. In this work, a new antimicrobial material has been elaborated by grafting a neutral porphyrin, the metallated 5-(4-azidophenyl)-10,15,20 triphenylporphyrin, onto lignocellulosic fibers by using the Copper (I)-Catalyzed Alkyne-Azide 1,3-dipolar Cycloaddition (CuAAC) reaction. The cross-linked porphyrin-Kraft pulp material was characterized by infrared and by XPS spectroscopy analyses, which proved the covalent linkage between the porphyrin and propargylated Kraft pulp fibers. The antimicrobial activity of this material was tested under visible light irradiation with a low light dose (9.5 J/cm(2)) against Staphylococcus aureus and Pseudomonas aeruginosa. The two bacterial strains deposited on the resulting photosensitizing Kraft pulp are efficiently killed after illumination. Such materials could find applications in industrial, household and medical environments as an alternative to overcome the widespread microbial multiresistance to classical treatments. PMID- 26952399 TI - Degradation testing of Mg alloys in Dulbecco's modified eagle medium: Influence of medium sterilization. AB - This work studies the in vitro degradation of Mg alloys for bioabsorbable implant applications under near physiological conditions. For this purpose, the degradation behaviour of Mg alloys in Dulbecco's modified eagle medium (DMEM) which is a commonly used cell culture medium is analysed. Unfortunately, DMEM can be contaminated by microorganisms, acidifying the medium and accelerating the Mg degradation process by dissolution of protective degradation layers, such as (Mgx,Cay)(PO4)z. In this paper the influence of sterilization by applying UV-C radiation and antibiotics (penicillin/streptomycin) is analysed with two implant material candidates: Mg-Gd and Mg-Ag alloys; and pure magnesium as well as Mg-4Y 3RE as a reference. PMID- 26952400 TI - Peri-implant tissue response and biodegradation performance of a Mg-1.0Ca-0.5Sr alloy in rat tibia. AB - Biodegradable magnesium (Mg) alloys combine the advantages of traditional metallic implants and biodegradable polymers, having high strength, low density, and a stiffness ideal for bone fracture fixation. A recently developed Mg-Ca-Sr alloy potentially possesses advantageous characteristics over other Mg alloys, such as slower degradation rates and minimal toxicity. In this study, the biocompatibility of this Mg-Ca-Sr alloy was investigated in a rat pin-placement model. Cylindrical pins were inserted in the proximal tibial metaphyses in pre drilled holes orthogonal to the tibial axis. Implant and bone morphologies were investigated using MUCT at 1, 3, and 6 weeks after implant placement. At the same time points, the surrounding tissue was evaluated using H&E, TRAP and Goldner's trichrome staining. Although gas bubbles were observed around the degrading implant at early time points, the bone remained intact with no evidence of microfracture. Principle findings also include new bone formation in the area of the implant, suggesting that the alloy is a promising candidate for biodegradable orthopedic implants. PMID- 26952402 TI - A new fluorinated urethane dimethacrylate with carboxylic groups for use in dental adhesive compositions. AB - A urethane macromer containing hexafluoroisopropylidene, poly(ethylene oxide) and carboxylic moieties (UF-DMA) was synthesized and used in proportions varying between 15 and 35 wt.% (F1-F3) in dental adhesive formulations besides BisGMA, triethylene glycol dimethacrylate and 2-hydroxyethyl methacrylate. The FTIR and (1)H ((13)C) NMR spectra confirmed the chemical structure of the UF-DMA. The experimental adhesives were characterized with regard to the degree of conversion, water sorption/solubility, contact angle, diffusion coefficient, Vickers hardness, and morphology of the crosslinked networks and compared with the specimens containing 10 wt.% hydroxyapatite (HAP) or calcium phosphate (CaP). The conversion degree (after 180 s of irradiation with visible light) ranged from 59.5% (F1) to 74.8% (F3), whereas the water sorption was between 23.15 MUg mm(-3) (F1) and 40.52 MUg mm(-3) (F3). Upon the addition of HAP or CaP this parameter attained values of 37.82-49.14 MUg mm(-3) (F1-F3-HAP) and 34.58-45.56 MUg mm(-3), respectively. Also, the formation of resin tags through the infiltration of a dental composition (F3) was visualized by SEM analysis. The results suggest that UF-DMA taken as co-monomer in dental adhesives of acrylic type may provide improved properties in the moist environment of the mouth. PMID- 26952401 TI - Influence of the surface properties on bactericidal and fungicidal activity of magnetron sputtered Ti-Ag and Nb-Ag thin films. AB - In this study the comparative investigations of structural, surface and bactericidal properties of Ti-Ag and Nb-Ag thin films have been carried out. Ti Ag and Nb-Ag coatings were deposited on silicon and fused silica substrates by magnetron co-sputtering method using innovative multi-target apparatus. The physicochemical properties of prepared thin films were examined with the aid of X ray diffraction, grazing incidence X-ray diffraction, scanning electron microscopy, atomic force microscopy and X-ray photoelectron spectroscopy methods. Moreover, the wettability of the surface was determined. It was found that both, Ti-Ag and Nb-Ag thin films were nanocrystalline. In the case of Ag-Ti film presence of AgTi3 and Ag phases was identified, while in the structure of Nb-Ag only silver occurred in a crystal form. In both cases the average size of crystallites was ca. 11 nm. Moreover, according to scanning electron microscopy and atomic force microscopy investigations the surface of Nb-Ag thin films was covered with Ag-agglomerates, while Ti-Ag surface was smooth and devoid of silver particles. Studies of biological activity of deposited coatings in contact with Bacillus subtilis, Pseudomonas aeruginosa, Enterococcus hirae, Klebisiella pneumoniae, Escherichia coli, Staphylococcus aureus and Candida albicans were performed. It was found that prepared coatings were bactericidal and fungicidal even in a short term-contact, i.e. after 2 h. PMID- 26952403 TI - Controlled release behaviour and antibacterial effects of antibiotic-loaded titania nanotubes. AB - Bacterial infections have been identified as the main cause of orthopaedic implant failure. Owing to their high antibiotic delivery efficiency, titania nanotubes loaded with antibiotics constitute one of the most promising strategies for suppressing bacterial infections. However, it is difficult to control the drug-release behaviour of such nanotubes. Although sealing the nanotubes with a polymer solution provides sustained release effects to a certain extent, it inevitably influences their initial antibacterial activity. This study reports on the controlled release of gentamicin sulphate (GS) from titania nanotube surfaces whereby their initial antibacterial activity remains unaffected. Titania nanotubes were fabricated via electrochemical anodization and loaded with GS through physical adsorption. Experimental results showed that this loading method is feasible and efficient. The GS-loaded titania nanotubes were further covered by a thin film comprising a mixture of GS and chitosan (GSCH). The release kinetics confirmed that the drug release could be controlled by this thin film. Moreover, such a film was shown to not only inhibit initial bacterial adherence owing to its strong antibacterial properties but also enhance cell viability. Thus, GS-loaded titania nanotubes coated with GSCH have considerable potential as biomaterials for preventing initial release and peri-implant infection in the field of orthopaedics. PMID- 26952404 TI - Thermoresponsive polymeric gel as an on-demand transdermal drug delivery system for pain management. AB - The main aim of this work is to design a heat triggered transdermal drug delivery system (TDDS) using a thermoresponsive polymer, poly (N-vinyl caprolactam) [PNVCL] based gel, where in patients can themselves administer a pulse of drug on mere application of heat pad over the TDDS, whenever pain is experienced. The phase transition temperature of PNVCL was tuned to 35 degrees C by grafting it onto a pH sensitive biopolymer, Chitosan, to synthesize Chitosan-g-PNVCL (CP) co polymer which render the gel both thermo- and pH-responsive property. The application of triggered delivery was explored by loading acetamidophenol (a model hydrophilic drug) and etoricoxib (a model hydrophobic drug). In vitro drug release experiments were performed at three different temperatures (25, 32 and 39 degrees C) at two different pH (5.5 and 7) to study its drug release with response to temperature and pH. Drug release profiles obtained were found to have enhanced release for both the drugs respectively at 39 degrees C (above LCST) and pH5.5 when compared to other release conditions. In vitro skin permeation of both the drugs performed in rat abdominal skin using Franz diffusion cell showed enhanced drug release when the skin was subjected to higher temperature (39 degrees C). Moreover, it was also found that skin permeation for hydrophobic drug was better than that of hydrophilic drug. The in vivo biocompatibility studies of the CP gel in rat skin proved that the gel is biocompatible. The results obtained demonstrated the potential use of the thermoresponsive CP gel as an on-demand localized drug delivery system. PMID- 26952405 TI - Evaluation of antimony microparticles supported on biochar for application in the voltammetric determination of paraquat. AB - This work describes the construction and application of carbon paste electrodes modified with biochar and antimony microparticles (SbBCPE) for voltammetric determination of paraquat using a simple and sensitive procedure based on voltammetric stripping analysis. Some parameters such as amount of biochar and antimony used in the composition of the carbon paste and instrumental parameters were examined in detail. Under optimized conditions, an analytical curve was obtained for paraquat determination employing SbBCPE, which showed a linear response ranging from 0.2 to 2.9 MUmol L(-1), with limit of detection and quantification of 34 nmol L(-1) and 113 nmol L(-1), respectively, after paraquat pre-concentration of 120 s. The repeatability study presented a RSD=2.0% for 10 consecutive measurements using the same electrode surface and the reproducibility study showed a RSD=2.7% for measurements with 10 different electrode surfaces. The proposed sensor was successfully applied for paraquat determination in tap water and citric fruit juice spiked samples and good recoveries were obtained without any sample pre-treatment, showing its promising analytical performance. PMID- 26952406 TI - Effect of microstructure on anomalous strain-rate-dependent behaviour of bacterial cellulose hydrogel. AB - This study is focused on anomalous strain-rate-dependent behaviour of bacterial cellulose (BC) hydrogel that can be strain-rate insensitive, hardening, softening, or strain-rate insensitive in various ranges of strain rate. BC hydrogel consists of randomly distributed nanofibres and a large content of free water; thanks to its ideal biocompatibility, it is suitable for biomedical applications. Motivated by its potential applications in complex loading conditions of body environment, its time-dependent behaviour was studied by means of in-aqua uniaxial tension tests at constant temperature of 37 degrees C at various strain rates ranging from 0.000 1s(-1) to 0.3s(-1). Experimental results reflect anomalous strain-rate-dependent behaviour that was not documented before. Micro-morphological observations allowed identification of deformation mechanisms at low and high strain rates in relation to microstructural changes. Unlike strain-rate softening behaviours in other materials, reorientation of nanofibres and kinematics of free-water flow dominate the softening behaviour of BC hydrogel at high strain rates. PMID- 26952407 TI - Poly(ethylene glycol)-grafted cyclic acetals based polymer networks with non water-swellable, biodegradable and surface hydrophilic properties. AB - Cyclic acetals based biomaterial without acidic products during hydrolytic degradation is a promising candidate for tissue engineering applications; however, low hydrophilicity is still one limitation for its biomedical application. In this work, we aim to achieve non-water-swellable cyclic acetal networks with improved hydrophilicity and surface wettability by copolymerization of cyclic acetal units based monomer, 5-ethyl-5-(hydroxymethyl)-beta,beta dimethyl-1, 3-dioxane-2-ethanol diacrylate (EHD) and methoxy poly(ethylene glycol) monoacrylate (mPEGA) under UV irradiation, to avoid swelling of conventional hydrogels which could limit their applicability in particular of the mechanical properties and geometry integrity. Various EHD/mPEGA networks were fabricated with different concentrations of mPEGA from 0 to 30%, and the results showed photopolymerization behavior, mechanical property and thermal stability could not be significantly affected by addition of mPEGA, while the surface hydrophilicity was dramatically improved with the increase of mPEGA and could achieve a water contact angle of 37 degrees with 30% mPEGA concentration. The obtained EHD/mPEGA network had comparative degradation rate to the PECA hydrogels reported previously, and MTT assay indicated it was biocompatible to L929 cells. PMID- 26952408 TI - Novel three-dimensional cellulose produced from trunk of Astragalus gummifer (Fabaceae) tested for protein adsorption performance. AB - This is the first study to produce three-dimensional (3D) cellulose from any plant up to now. This 3D cellulose was produced from Astragalus gummifer(Fabaceae) trunk by using a modified method in which original the shape of cellulose was kept as natural. This novel 3D cellulose was characterized by SEM, TGA, FT-IR, XRD and elemental analysis to evidence the purity and to compare it with commercially available cellulose from cotton. Results from these characterizations were found convincing because almost the same physicochemical properties were observed for both newly obtained 3D cellulose and commercial one. Both fibers and pores on the surface of 3D cellulose were observed. Thanks to its diversified surface morphology, this novel 3D cellulose was tested for its protein adsorption performance and the results were compared with commercial cellulose as follows: maximum adsorption capacity at pH 8.0 was recorded as 59.2 mg/g for 3D cellulose while 29.6 mg/g for commercial cellulose. According to this result, it is clear to say that this sorbent has high affinity for lysozyme. Also this 3D cellulose could be useful for the other areas of separation science. PMID- 26952409 TI - Versatile synthesis of PHMB-stabilized silver nanoparticles and their significant stimulating effect on fodder beet (Beta vulgaris L.). AB - Silver nanoparticles (AgNPs) are well-known bactericidal agents. However, information about the influence of AgNPs on the morphometric parameters and biochemical status of most important agricultural crops is limited. The present study reports the influence of AgNPs stabilized with cationic polymer polyhexamethylene biguanide hydrochloride (PHMB) on growth, development, and biochemical status of fodder beet Beta vulgaris L. under laboratory and greenhouse conditions. PHMB-stabilized AgNPs were obtained via sodium borohydride reduction of silver nitrate in an aqueous solution. The average diameter of thus prepared AgNPs was 10 nm. It appears that the results of experiments with laboratory-grown beets in the nanosilver-containing medium, where germination of seeds and growth of roots were suppressed, do not correlate with the results of greenhouse experiments. The observed growth-stimulating action of PHMB-stabilized AgNPs can be explained by the change of activity of oxidases and, consequently, by the change of auxins amount in plant tissues. In beets grown in the presence of PHMB-stabilized AgNPs no negative deviations of biological parameters from normal values were registered. Furthermore, the SEM/EDS examination revealed no presence of silver in the tissues of the studied plants. PMID- 26952410 TI - Morphology control of hydroxyapatite microcrystals: Synergistic effects of citrate and CTAB. AB - Using hydrothermal treatment and with the synergistic regulating effects of citrate and CTAB, various 3D hierarchical superstructure of hydroxyapatite (HAp) microcrystals were synthesized by simply adjusting the Ct/CTAB ratio and calcium citrate complex (CC) morphology. The resulting superstructure was characterized using X-ray diffraction (XRD), Fourier Transform infrared spectroscopy (FTIR), field-emission scanning electron microscopy (FESEM) etc. With the shape transformation of CC from sphere-like colloid, nano-needle to lamellar-like particles, the final products were hollow spheres, bunched-like microrods and nanorod clusters, respectively. A possible mechanism for the formation of HAp hierarchical microstructure was proposed. PMID- 26952411 TI - Hydrothermal fabrication of porous hollow hydroxyapatite microspheres for a drug delivery system. AB - Porous hollow hydroxyapatite microspheres (PHHMs) are the promising biomaterials, owing to their excellent biocompatibility, biodegradability and bioactivity. PHHMs have been used as drug controlled carriers due to their advantages such as large drug loading capacity, nanochannels for drug loading and release and high specific surface area. In this study, PHHMs were prepared successfully in Na2HPO4 solution by an anion-exchange process using vaterite CaCO3 through a hydrothermal method. The previous vaterite CaCO3 was synthesized by a polymer-templated method in the poly(styrene sulfonic acid) sodium salt (PSS) aqueous solutions. The PHHMs have a size distribution from 0.8 to 2.0 MUm, with an average pore size of about 24.3 nm. The wall of PHHMs is constructed with building units of hydroxyapatite nanofibers with an average length of 300 nm and an average width of 20 nm. The PHHMs displayed a high drug loading capacity and pH-responsive sustained controlled drug release behavior when we used doxorubicin hydrochloride (DOX) as a loading drug. Moreover, the controlled drug release system showed a high ability to kill cancer cells and less damage to normal cells. These results indicated that PHHMs are promising for applications in various biomedical fields such as drug delivery system and oncotherapy. PMID- 26952412 TI - Synthesis, characterisation and preliminary investigation of the haemocompatibility of polyethyleneimine-grafted carboxymethyl chitosan for gene delivery. AB - The development of safe and efficient gene carriers is the key to the clinical success of gene therapy. In the present study, carboxymethyl chitosan (CMCS) was prepared by chitosan (CS) alkalisation and carboxymethylation reactions. Then polyethyleneimine (PEI) was grafted to the backbone of CMCS by an amidation reaction. The CMCS-PEI copolymer showed strong complexation capability with DNA to form nanoparticles, and achieved lower cytotoxicity and higher transfection efficiency compared with PEI (25 kDa) towards 293T and 3T3 cells. Moreover, the haemocompatibility of the CMCS-PEI copolymer was investigated through the aggregation, morphology and lysis of human red blood cells (RBCs), along with the impact on the clotting function with activated partial thromboplastin time (APTT), prothrombin time (PT) and thromboelastographic (TEG) assays. The results demonstrated that the CMCS-PEI copolymer with a concentration lower than 0.05 mg/mL had little impact on the aggregation, morphology or lysis of RBCs, or on blood coagulation. Therefore, the copolymer may be a strong alternative candidate as an effective and safe non-viral vector. PMID- 26952413 TI - Hydroxyapatite from fish scale for potential use as bone scaffold or regenerative material. AB - The present paper studies the physico-chemical, bioactivity and biological properties of hydroxyapatite (HA) which is derived from fish scale (FS) (FSHA) and compares them with those of synthesized HA (sHA) obtained by co-precipitation from chemical solution as a standard. The analysis shows that the FSHA is composed of flat-plate nanocrystal with a narrow width size of about 15-20 nm and having a range of 100 nm in length and that the calcium phosphate ratio (Ca/P) is 2.01 (Ca-rich CaP). Whereas, synthesized HA consists of sub-micron HA particle having a Ca/P ratio of 1.65. Bioactivity test shows that the FSHA forms more new apatite than does the sHA after being incubated in simulated body fluid (SBF) for 7 days. Moreover, the biocompatibility study shows a higher osteoblast like cell adhesion on the FSHA surface than on the sHA substrate after 3 days of culturing. Our results also show the shape of the osteoblast cells on the FSHA changes from being a rounded shape to being a flattened shape reflecting its spreading behavior on this surface. MTT assay and ALP analysis show significant increases in the proliferation and activity of osteoblasts over the FSHA scaffold after 5 days of culturing as compared to those covering the sHA substrates. These results confirm that the bio-materials derived from fish scale (FSHA) are biologically better than the chemically synthesized HA and have the potential for use as a bone scaffold or as regenerative materials. PMID- 26952414 TI - Evaluation of sol-gel based magnetic 45S5 bioglass and bioglass-ceramics containing iron oxide. AB - Multicomponent oxide powders with nominal compositions of (45 x).SiO2.24.5CaO.24.5Na2O.6P2O5xFe2O3 (in wt.%) were prepared by a modified sol gel procedure. X-ray diffraction (XRD) patterns and high resolution transmission electron microscope images of the sol-gel products show fully amorphous structure for Fe2O3 substitutions up to 2 wt.%. Sol-gel derived 43SiO2.24.5CaO.24.5Na2O.6P2O5.2Fe2O3 glass (or bioglass 45S5 with SiO2 substituted with 2 wt.% Fe2O3), exhibited magnetic behavior with a coercive field of 21 Oe, hysteresis loop area of 33.25 erg/g and saturation magnetization of 0.66 emu/g at an applied field of 15 kOe at room temperature. XRD pattern of this glass annealed at 850 degrees C for 1h revealed the formation of a glass-ceramic containing sodium calcium silicate and magnetite phases in nanocrystalline form. Temperature dependent magnetization and room temperature electron spin resonance data have been used to obtain information on the magnetic phase and distribution of iron ions in the sol-gel glass and glass-ceramic samples. Sol-gel derived glass and glass-ceramic exhibit in-vitro bioactivity by forming a hydroxyapatite surface layer under simulated physiological conditions and their bio-response is superior to their melt quenched bulk counterparts. This new form of magnetic bioglass and bioglass ceramics opens up new and more effective biomedical applications. PMID- 26952415 TI - Protections of bovine serum albumin protein from damage on functionalized graphene-based electrodes by flavonoids. AB - A sensitive electrochemical sensor based on bovine serum albumin (BSA)/poly (diallyldimethylammonium chloride) (PDDA) functionalized graphene nanosheets (PDDA-G) composite film modified glassy carbon electrode (BSA/PDDA-G/GCE) had been developed to investigate the oxidative protein damage and protections of protein from damage by flavonoids. The performance of this sensor was remarkably improved due to excellent electrical conductivity, strong adsorptive ability, and large effective surface area of PDDA-G. The BSA/PDDA-G/GCE displayed the greatest degree of BSA oxidation damage at 40 min incubation time and in the pH 5.0 Fenton reagent system (12.5 mM FeSO4, 50 mM H2O2). The antioxidant activities of four flavonoids had been compared by fabricated sensor based on the relative peak current ratio of SWV, because flavonoids prevented BSA damage caused by Fenton reagent and affected the BSA signal in a solution containing Co(bpy)3(3+). The sensor was characterized by cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS), and scanning electron microscopy (SEM). UV-vis spectrophotometry and FTIR were also used to investigate the generation of hydroxyl radical and BSA damage, respectively. On the basis of results from electrochemical methods, the order of the antioxidant activities of flavonoids is as follows: (+)-catechin>kaempferol>apigenin>naringenin. A novel, direct SWV analytical method for detection of BSA damage and assessment of the antioxidant activities of four flavonoids was developed and this electrochemical method provided a simple, inexpensive and rapid detection of BSA damage and evaluation of the antioxidant activities of samples. PMID- 26952416 TI - Porous SiO2 nanofiber grafted novel bioactive glass-ceramic coating: A structural scaffold for uniform apatite precipitation and oriented cell proliferation on inert implant. AB - A composite bioactive glass-ceramic coating grafted with porous silica nanofibers was fabricated on inert glass to provide a structural scaffold favoring uniform apatite precipitation and oriented cell proliferation. The coating surfaces were investigated thoroughly before and after immersion in simulated body fluid. In addition, the proliferation behavior of fibroblast cells on the surface was observed for several culture times. The nanofibrous exterior of this composite bioactive coating facilitated homogeneous growth of flake-like carbonated hydroxyapatite layer within a short period of immersion. Moreover, the embedded porous silica nanofibers enhanced hydrophilicity which is required for proper cell adhesion on the surface. The cells proliferated well following a particular orientation on the entire coating by the assistance of nanofibrous scaffold-like structural matrix. This newly engineered composite coating was effective in creating a biological structural matrix favorable for homogeneous precipitation of calcium phosphate, and organized cell growth on the inert glass surface. PMID- 26952417 TI - Developing multi-cellular tumor spheroid model (MCTS) in the chitosan/collagen/alginate (CCA) fibrous scaffold for anticancer drug screening. AB - In this work, a 3D MCTS-CCA system was constructed by culturing multi-cellular tumor spheroid (MCTS) in the chitosan/collagen/alginate (CCA) fibrous scaffold for anticancer drug screening. The CCA scaffolds were fabricated by spray spinning. The interactions between the components of the spray-spun fibers were evidenced by methods of Coomassie Blue stain, X-ray diffraction (XRD) and Fourier transform-infrared spectroscopy (FTIR). Co-culture indicated that MCF-7 cells showed a spatial growth pattern of multi-cellular tumor spheroid (MCTS) in the CCA fibrous scaffold with increased proliferation rate and drug-resistance to MMC, ADM and 5-Aza comparing with the 2D culture cells. Significant increases of total viable cells were found in 3D MCTS groups after drug administration by method of apoptotic analysis. Glucose-lactate analysis indicated that the metabolism of MCTS in CCA scaffold was closer to the tumor issue in vivo than the monolayer cells. In addition, MCTS showed the characteristic of epithelial mesenchymal transition (EMT) which is subverted by carcinoma cells to facilitate metastatic spread. These results demonstrated that MCTS in CCA scaffold possessed a more conservative phenotype of tumor than monolayer cells, and anticancer drug screening in 3D MCTS-CCA system might be superior to the 2D culture system. PMID- 26952418 TI - A comparative study of zinc, magnesium, strontium-incorporated hydroxyapatite coated titanium implants for osseointegration of osteopenic rats. AB - Surface modification techniques have been applied to generate titanium implant surfaces that promote osseointegration for the implants in cementless arthroplasty. However, its effect is not sufficient for osteoporotic bone. Zinc (Zn), magnesium (Mg), and strontium (Sr) present a beneficial effect on bone growth, and positively affect bone regeneration. The aim of this study was to confirm the different effects of the fixation strength of Zn, Mg, Sr-substituted hydroxyapatite-coated (Zn-HA-coated, Mg-HA-coated, Sr-HA-coated) titanium implants via electrochemical deposition in the osteoporotic condition. Female Sprague-Dawley rats were used for this study. Twelve weeks after bilateral ovariectomy, all animals were randomly divided into four groups: group HA; group Zn-HA; group Mg-HA and group Sr-HA. Afterwards, all rats from groups HA, Zn-HA, Mg-HA and Sr-HA received implants with hydroxyapatite containing 0%, 10% Zn ions, 10% Mg ions, and 10% Sr ions. Implants were inserted bilaterally in all animals until death at 12 weeks. The bilateral femurs of rats were harvested for evaluation. All treatment groups increased new bone formation around the surface of titanium rods and push-out force; group Sr-HA showed the strongest effects on new bone formation and biomechanical strength. Additionally, there are significant differences in bone formation and push-out force was observed between groups Zn-HA and Mg-HA. This finding suggests that Zn, Mg, Sr-substituted hydroxyapatite coatings can improve implant osseointegration, and the 10% Sr coating exhibited the best properties for implant osseointegration among the tested coatings in osteoporosis rats. PMID- 26952419 TI - The efficacy and safety of a novel posterior scleral reinforcement device in rabbits. AB - PURPOSE: To evaluate the efficacy and safety of posterior scleral reinforcement (PSR) device for myopia suppression in rabbits' eyes. METHODS: PSR surgery was performed on the normal 12 8-week-old New Zealand white rabbits' right eyes. To determine efficacy of the device, ophthalmic examination would be taken at pre operation and post-operation (1 week, 1 month, 3 months, 6 months, and 1 year), such as A-ultrasound, diopter and B-ultrasound. Evaluation of safety were based on the following indicators: intraocular pressure (IOP), slit lamp, fundus photography, fundus fluorescein angiography and pathological examination after surgery. The efficacy and safety of PSR device were evaluated by comparison (treated eyes and contralateral eyes) of pre and post-operation. RESULTS: The novel PSR device could significantly shorten axial length (preoperative axial length: 16.36 +/- 0.14 mm, postoperative 1 week, 1 month, 3 months, 6 months and 1 year axial lengths: 15.03 +/- 0.28 mm, 15.23 +/- 0.32 mm, 15.39 +/- 0.31 mm, 15.45 +/- 0.22 mm and 15.45 +/- 0.22 mm; P=0.00037<0.001) in the treated eyes (right eyes) after surgery. At different postoperative time points, the B ultrasound images showed that the PSR located in appropriate position and supported the posterior sclera very well. At the same time, IOP of treated eyes kept a relatively stable level (preoperative IOP: 12.56 +/- 2.01 mmHg, postoperative IOP: ranging from 11.33 +/- 1.23 mmHg to 13.44 +/- 2.19 mmHg, P>0.05) post-operation 1 year. During observation period, there was no significant inflammatory reaction and complications such as anterior chamber flare, empyema, endophthalmitis, vitreous hemorrhage, retina detachment and retinal choroid neovascularization by slit lamp, fundus photography and fundus fluorescein angiography. In addition, there were no pathologic changes be found by comparison treated eyes group and contralateral group eyes based on pathological examinations. CONCLUSIONS: In vivo study, effectively and safely, the novel PSR device can inhibit rabbits' axial length elongation during postoperative 1 year. This study demonstrates that this novel PSR could be a potential treatment approach for myopia. PMID- 26952420 TI - Structural-mechanical and antibacterial properties of a soft elastic polyurethane surface after plasma immersion N2(+) implantation. AB - The surface of elastic polyurethane treated by plasma immersion N2(+) ion implantation at different fluences has been investigated. A folded surface structure is observed in all cases. Analysis has been performed to study the structural (roughness, steepness and fraction of folds, fractal characteristics), mechanical (stiffness, adhesion force between the AFM probe and the material) and wetting properties of surfaces. Under uniaxial stretching the cracks orthogonal to the axis of deformation and longitudinal folds are formed on the examined surfaces. After unloading the initial structure of the surface of deformed materials exposed to low fluences becomes smoother and does not recover, i.e. it has plastic properties. By contrast, the structure of the surfaces of materials subjected to high-fluence treatment recovers without visible changes and the cracks are fully closed. The study of Staphylococcus colonies grown on these materials has demonstrated significant reduction (from 3 to 5 times) in the vitality of bacteria on treated surfaces. This result was repeated on samples after 11 months of storage. Such antibacterial properties are primarily related to the structural changes of the surfaces accompanied by the increased hydrophilicity. PMID- 26952421 TI - Electrochemical and morphological investigation of silver and zinc modified calcium phosphate bioceramic coatings on metallic implant materials. AB - In our research nanostructured silver and zinc doped calcium-phosphate (CaP) bioceramic coatings were prepared on commonly used orthopaedic implant materials (Ti6Al4V). The deposition process was carried out by the pulse current technique at 70 degrees C from electrolyte containing the appropriate amount of Ca(NO3)2 and NH4H2PO4 components. During the electrochemical deposition Ag(+) and Zn(2+) ions were introduced into the solution. The electrochemical behaviour and corrosion rate of the bioceramic coatings were investigated by potentiodynamic polarization and Electrochemical Impedance Spectroscopy (EIS) measurements in conventional Ringer's solution in a three electrode open cell. The coating came into contact with the electrolyte and corrosion occurred during immersion. In order to achieve antimicrobial properties, it is important to maintain a continuous release of silver ions into physiological media, while the bioactive CaP layer enhances the biocompatibility properties of the layer by fostering the bone cell growth. The role of Zn(2+) is to shorten wound healing time. Morphology and composition of coatings were studied by Scanning Electron Microscopy, Transmission Electron Microscopy and Energy-dispersive X-ray spectroscopy. Differential thermal analyses (DTA) were performed to determine the thermal stability of the pure and modified CaP bioceramic coatings while the structure and phases of the layers were characterized by X-ray diffraction (XRD) measurements. PMID- 26952423 TI - Influence of sulfide concentration on the corrosion behavior of titanium in a simulated oral environment. AB - This study assessed the corrosion behavior of titanium in response to sulfide by determining the effects of sulfide concentration and pH over immersion period. Corrosion was evaluated through changes in color, glossiness, surface characterization, and titanium release. Sulfide solutions were prepared in 3 different concentrations with Na2S, each in pH unadjusted (sulfide-alkaline) and pH adjusted to 7.5 (sulfide-neutral). Titanium discoloration increased and glossiness decreased as sulfide concentration and immersion period increased in sulfide-alkaline solutions. Coral-like complexes were observed on the surface of these specimens, which became more pronounced as concentration increased. Small amounts of titanium release were detected in sulfide-alkaline solutions; however, this was not affected by immersion periods. Corrosion was indicated through considerable surface oxidation suggesting the formation of a thick oxide layer. No significant changes in color and glossiness, or titanium release were indicated for titanium specimens immersed in sulfide-neutral solutions indicating that pH had a significant effect on corrosion. Our findings suggest that a thick oxide layer on the titanium surface was formed in sulfide-alkaline solutions due to excessive oxidation. PMID- 26952422 TI - The comparison study of bioactivity between composites containing synthetic non substituted and carbonate-substituted hydroxyapatite. AB - Apatite forming ability of hydroxyapatite (HAP) and carbonate hydroxyapatite (CHAP) containing composites was compared. Two composite materials, intended for filling bone defects, were made of polysaccharide polymer and one of two types of hydroxyapatite. The bioactivity of the composites was evaluated in vitro by soaking in a simulated body fluid (SBF), and the formation of the apatite layer was determined by scanning electron microscopy with energy-dispersive spectrometer and Raman spectroscopy. The results showed that both the composites induced the formation of apatite layer on their surface after soaking in SBF. In addition, the sample weight changes and the ion concentration of the SBF were scrutinized. The results showed the weight increase for both materials after SBF treatment, higher weight gain and higher uptake of calcium ions by HAP containing scaffolds. SBF solution analysis indicated loss of calcium and phosphorus ions during experiment. All these results indicate apatite forming ability of both biomaterials and suggest comparable bioactive properties of composite containing pure hydroxyapatite and carbonate-substituted one. PMID- 26952424 TI - Comparison of a quasi-dynamic and a static extraction method for the cytotoxic evaluation of acrylic bone cements. AB - In this study, two different extraction approaches were compared in order to evaluate the cytotoxicity of 7 different acrylic bone cements, mainly developed for spinal applications, to osteoblastic cells. Firstly, a static extraction was carried out continuously over 24h, a method widely used in literature. Secondly, a quasi-dynamic extraction method that allowed the investigation of time dependent cytotoxic effects of curing acrylic bone cements to cells was introduced. In both cases the extraction of the cements was started at a very early stage of the polymerization process to simulate the conditions during clinical application. Data obtained by the quasi-dynamic extraction method suggest that the cytotoxicity of the setting materials mainly originates from the release of toxic components during the first hour of the polymerization reaction. It was also shown that a static extraction over 24h generally represents this initial stage of the curing process. Furthermore, compared to the static extraction, time-dependent cytotoxicity profiles could be detected using the quasi-dynamic extraction method. Specifically, a modification of commercial OsteopalV with castor oil as a plasticizer as well as a customized cement formulation showed clear differences in cytotoxic behavior compared to the other materials during the setting process. In addition, it was observed that unreacted monomer released from the castor oil modified cement was not the main component affecting the toxicity of the material extracts. The quasi-dynamic extraction method is a useful tool to get deeper insight into the cytotoxic potential of curing acrylic bone cements under relevant biological conditions, allowing systematic optimization of materials under development. PMID- 26952425 TI - Surface free energy predominates in cell adhesion to hydroxyapatite through wettability. AB - The initial adhesion of cells to biomaterials is critical in the regulation of subsequent cell behaviors. The purpose of this study was to investigate a mechanism through which the surface wettability of biomaterials can be improved and determine the effects of biomaterial surface characteristics on cellular behaviors. We investigated the surface characteristics of various types of hydroxyapatite after sintering in different atmospheres and examined the effects of various surface characteristics on cell adhesion to study cell-biomaterial interactions. Sintering atmosphere affects the polarization capacity of hydroxyapatite by changing hydroxide ion content and grain size. Compared with hydroxyapatite sintered in air, hydroxyapatite sintered in saturated water vapor had a higher polarization capacity that increased surface free energy and improved wettability, which in turn accelerated cell adhesion. We determined the optimal conditions of hydroxyapatite polarization for the improvement of surface wettability and acceleration of cell adhesion. PMID- 26952426 TI - Amelioration of excision wounds by topical application of green synthesized, formulated silver and gold nanoparticles in albino Wistar rats. AB - Wound healing, a complex biological process, has attained a lot of attention as dermatologists are primarily interested in stimulated wound closure without formation of scar or a faint scar. The recent upsurgence of nanotechnology has provided novel therapeutic materials in the form of silver and gold nanoparticles which accelerate the wound healing process. The effect of formulated nanoparticles using Coleus forskohlii root extract (green synthesized) has been tried out for ameliorating full thickness excision wounds in albino Wistar male rats. The evaluation of in vivo activity of nanoparticles in wound healing was carried out on open wounds made by excision on the dorsal sides of albino Wistar rats under anesthesia, and the healing of the wounds was assessed. Histological aspects of the healing process were studied by a HE (Hematoxylin and Eosin) staining method to assess various degrees of re-epithelialization and the linear alignment of the granulation tissue whereas Van Gieson's histochemical staining was performed to observe collagen fibers. The healing action shown by the formulated nanoparticles was remarkable during the early stages of wound healing, which resulted in the substantial reduction of the whole healing period. Topical application of formulated gold nanoparticles was found to be more effective in suppressing inflammation and stimulating re-epithelialization compared to silver nanoparticles during the healing process. The results throw light on the amelioration of excision wounds using nanoparticles which could be a novel therapeutic way of improving wound healing in clinical practice. The mechanism of advanced healing action of both types of nanoparticles could be due to their antimicrobial, antioxidant and anti-inflammatory properties. PMID- 26952427 TI - Easy fabrication of aligned PLLA nanofibers-based 2D scaffolds suitable for cell contact guidance studies. AB - An easy, low-cost and fast wet processing-based method named ASB-SANS (Auxiliary Solvent-Based Sublimation-Aided NanoStructuring) has been used to fabricate poly(l-lactic acid) (PLLA) highly ordered and hierarchically organized 2D fibrillar patterns, with fiber widths between 40 and 500 nm and lengths exceeding tens of microns. A clear contact guidance effect of these nanofibrillar scaffolds with respect to HeLa and NIH-3T3 cells growth has been observed, on top of an overall good viability. For NIH-3T3 pronounced elongation of the cells was observed, as well as a remarkable ability of the patterns to guide the extension of pseudopodia. Moreover, SEM imaging revealed filopodia stemming from both sides of the pseudopodia and aligned with the secondary PLLA nanofibrous structures created by the ASB-SANS procedure. These results validate ASB-SANS as a technique capable to provide biocompatible 2D nanofibrillar patterns suitable for studying phenomena of contact guidance (and, more in general, the behavior of cells onto nanofibrous scaffolds), at very low costs and in an extremely easy way, accessible to virtually any laboratory. PMID- 26952428 TI - A computational study of stent performance by considering vessel anisotropy and residual stresses. AB - Finite element simulations of stent deployment were carried out by considering the intrinsic anisotropic behaviour, described by a Holzapfel-Gasser-Ogden (HGO) hyperelastic anisotropic model, of individual artery layers. The model parameters were calibrated against the experimental stress-stretch responses in both circumferential and longitudinal directions. The results showed that stent expansion, system recoiling and stresses in the artery layers were greatly affected by vessel anisotropy. Following deployment, deformation of the stent was also modelled by applying relevant biomechanical forces, i.e. in-plane bending and radial compression, to the stent-artery system, for which the residual stresses generated during deployment were particularly accounted for. Residual stresses were found to have a significant influence on the deformation of the system, resulting in a re-distribution of stresses and a change of the system flexibility. The results were also utilised to interpret the mechanical performance of stent after deployment. PMID- 26952429 TI - Antibacterial behavior of polypyrrole: The influence of morphology and additives incorporation. AB - The antibacterial behavior of polypyrrole (PPy) depends on a diversity of structural parameters such as surface area, aggregation level and additives (metal nanoparticles) incorporation. This paper summarizes the influence of different preparation procedures of PPy on action of resulting antibacterial composite against Escherichia coli, Staphylococcus aureus and Klebsiella pneumoniae. The bactericidal action has been assigned to morphology (size of polypyrrole nanoparticles). The electrostatic interaction established between polymer nanoparticles and bacteria provokes the bacterial cell death and returns advantages in comparison with conventional composites of polypyrrole decorated with metal nanoparticles. PMID- 26952430 TI - Self-assembly of palladium nanoparticles on functional TiO2 nanotubes for a nonenzymatic glucose sensor. AB - Polydiallyldimethylammonium chloride, PDDA, was used as a stabilizer and linker for functionalized TiO2 nanotubes (TiO2 NTs). Self-assembled process with palladium nanoparticles (NPs) was successfully synthesized and used for the oxidation of glucose on glassy carbon electrodes. Based on the voltammetric and amperometric results, Pd NPs efficiently catalyzed the oxidation of glucose at 0.05 V in the presence of 0.1 M NaCl and showed excellent resistance toward interference poisoning from such interfering species as ascorbic acid, uric acid and urea. To further increase sensitivity, the Pd NPs-PDDA-TiO2 NTs/GCE was electrochemically treated with H2SO4 and NaOH, the glucose oxidation current was magnified 2.5 times than that before pretreatments due to greatly enhancing the electron transport property of the sensor based on the increased defect sites and surface oxide species. In view of the physiological level of glucose, the wide linear concentration range of glucose (4*10(-7)-8*10(-4)M) with a detection limit of 8*10(-8)M (S/N=3) was obviously good enough for clinical application. PMID- 26952431 TI - PLGA nanofibers blended with designer self-assembling peptides for peripheral neural regeneration. AB - Electrospun nanofibers are attractive candidates for neural regeneration due to similarity to the extracellular matrix. Several synthetic polymers have been used but they lack in providing the essential biorecognition motifs on their surfaces. Self-assembling peptide nanofiber scaffolds (SAPNFs) like RADA16 and recently, designer SAPs with functional motifs RADA16-I-BMHP1 areexamples, which showed successful spinal cord regeneration. But these peptide nanofiber scaffolds have poor mechanical properties and faster degradation rates that limit their use for larger nerve defects. Hence, we have developed a novel hybrid nanofiber scaffold of polymer poly(L-lactide-co-glycolide) (PLGA) and RADA16-I-BMHP1. The scaffolds were characterized for the presence of peptides both qualitatively and quantitatively using several techniques like SEM, EDX, FTIR, CHN analysis, Circular Dichroism analysis, Confocal and thermal analysis. Peptide self-assembly was retained post-electrospinning and formed rod-like nanostructures on PLGA nanofibers. In vitro cell compatibility was studied using rat Schwann cells and their adhesion, proliferation and gene expression levels on the designed scaffolds were evaluated. Our results have revealed the significant effects of the peptide blended scaffolds on promoting Schwann cell adhesion, extension and phenotypic expression. Neural development markers (SEM3F, NRP2 & PLX1) gene expression levels were significantly upregulated in peptide blended scaffolds compared to the PLGA scaffolds. Thus the hybrid blended novel designer scaffolds seem to be promising candidates for successful and functional regeneration of the peripheral nerve. PMID- 26952432 TI - Studies of magnetic alginate-based electrospun matrices crosslinked with different methods for potential hyperthermia treatment. AB - The magnetic electrospun mats were lately established as an innovative biomaterial for hyperthermic cancer treatment. Unlike those surface-modified magnetic nanoparticles that may not firmly adhere onto the tumor for long-term duration, the magnetic mats with nanofibrous structure can promote cell adhesion and kill the tumor directly within an alternating magnetic field. However, most magnetic electrospun mats were fabricated using non-biodegradable polymers and organic solvents, causing the problems of removal after therapy and the suspected biotoxicity associated with residual solvent. Alginate (SA) was utilized in this investigation as the main material for electrospinning because of being biodegradable and water-soluble. The alginate-based electrospun mats were then treated by an ionic or a covalent crosslinking method, and then followed by chelation with Fe(2+)/Fe(3+) for chemical coprecipitation of Fe3O4 magnetic nanoparticles. Significant less cytotoxicity was noted on both liquid extracts from the ionic-crosslinked (Fe3O4-SA/PEO) and covalent-crosslinked (Fe3O4-SA/PVA) magnetic electrospun mats as well as the surface of Fe3O4-SA/PVA. In vitro hyperthermia assay indicated that the covalent-crosslinked magnetic alginate based mats reduced tumor cell viability greater than Fe3O4 nanoparticles. Such magnetic electrospun mats are of potential for hyperthermia treatment by endoscopic/surgical delivery as well as serving as a supplementary debridement treatment after surgical tumor removal. PMID- 26952433 TI - Microstructure, mechanical properties, bio-corrosion properties and antibacterial properties of Ti-Ag sintered alloys. AB - In this research, Ag element was selected as an antibacterial agent to develop an antibacterial Ti-Ag alloy by a powder metallurgy. The microstructure, phase constitution, mechanical properties, corrosion resistance and antibacterial properties of the Ti-Ag sintered alloys have been systematically studied by X-ray diffraction (XRD), scanning electron microscope (SEM), compressive test, electrochemical measurements and antibacterial test. The effects of the Ag powder size and the Ag content on the antibacterial property and mechanical property as well as the anticorrosion property have been investigated. The microstructure results have shown that Ti-Ag phase, residual pure Ag and Ti were the mainly phases in Ti-Ag(S75) sintered alloy while Ti2Ag was synthesized in Ti-Ag(S10) sintered alloy. The mechanical test indicated that Ti-Ag sintered alloy showed a much higher hardness and the compressive yield strength than cp-Ti but the mechanical properties were slightly reduced with the increase of Ag content. Electrochemical results showed that Ag powder size had a significant effect on the corrosion resistance of Ti-Ag sintered alloy. Ag content increased the corrosion resistance in a dose dependent way under a homogeneous microstructure. Antibacterial tests have demonstrated that antibacterial Ti-Ag alloy was successfully prepared. It was also shown that the Ag powder particle size and the Ag content influenced the antibacterial activity seriously. The reduction in the Ag powder size was benefit to the improvement in the antibacterial property and the Ag content has to be at least 3wt.% in order to obtain a strong and stable antibacterial activity against Staphylococcus aureus bacteria. The bacterial mechanism was thought to be related to the Ti2Ag and its distribution. PMID- 26952434 TI - In situ observation of fracture behavior of canine cortical bone under bending. AB - Cortical bone provides many important body functions and maintains the rigidness and elasticity of bone. A common failure mode for bone structure is fracture under a bending force. In the current study, the fracture behavior of canine cortical bone under three-point bending was observed in situ using an atomic force microscope (AFM), a scanning electron microscope (SEM), and an optical microscope to examine the fracture process in detail. Nanoindentation was carried out to determine the elastic modulus and hardness of different building blocks of the canine cortical bone. The results have shown that the special structure of Haversian systems has significant effects on directing crack propagation. Although Haversian systems contain previously believed weak points, and micro cracks initiate within Haversian systems, our findings have demonstrated that macro-cracks typically form around the boundaries of Haversian systems, i.e. the cement lines. Micro-cracks that developed inside Haversian systems have the functions of absorbing and dissipating energy and slow down on expanding when interstitial tissue cannot hold any more pressure, then plastic deformation and fracture occur. PMID- 26952435 TI - Effects of Cu content on electrochemical response in Ti-based metallic glasses under simulated body fluid. AB - Systematic characterization of the corrosion response of the Cu-free Ti45Zr40Si15 and Cu-containing Ti40Zr40Si15-Cu5 and Ti45Zr20-Cu35 metallic glasses (MGs) in the Hank's solution is conducted, in terms of the open circuit potential, potentiodynamic polarization, as well as electrochemical impedance measurements. The Cu role in the Ti-based MGs, tentatively to be applied for bio-implants, is established and modeled. The presence of nobler Cu will impose two opposite effects. The minor positive effect of minor shift of Ecorr is not a major issue, but the negative effect on local pitting and ion release would cause a major drawback. The ICP-MS indicates that the release of Cu ions increases with increasing Cu content. For more promising anti-pitting ability, the Cu content in Ti-based MGs should be kept as low as possible, better to be none or less than about 5 at.%. PMID- 26952436 TI - Biomimetic synthesis of hybrid hydroxyapatite nanoparticles using nanogel template for controlled release of bovine serum albumin. AB - A biomimetic method was used to prepare hybrid hydroxyapatite (HAP) nanoparticles with chitosan/polyacrylic acid (CS-PAA) nanogel. The morphology, structure, crystallinity, thermal properties and biocompatibility of the obtained hybrid nanogel-HAP nanoparticles have been characterized. In addition, bovine serum albumin (BSA) was used as a model protein to study the loading and release behaviors of the hybrid nanogel-HAP nanoparticles. The results indicated that the obtained HAP nanoparticles were agglomerated and the nanogel could regulate the formation of HAP. When the nanogel concentration decreased, different HAP crystal shapes and agglomerate structures were obtained. The loading amount of BSA reached 67.6 mg/g for the hybrid nanoparticles when the mineral content was 90.4%, which decreased when the nanogel concentration increased. The release profile of BSA was sustained in neutral buffer. Meanwhile, an initial burst release was found at pH 4.5 due to the desorption of BSA from the surface, followed by a slow release. The hemolysis percentage of the hybrid nanoparticles was close to the negative control, and these particles were non-toxic to bone marrow stromal stem cells. The results suggest that these hybrid nanogel-HAP nanoparticles are promising candidate materials for biocompatible drug delivery systems. PMID- 26952437 TI - The labeling of stem cells by superparamagnetic iron oxide nanoparticles modified with PEG/PVP or PEG/PEI. AB - Poly(ethylene glycol) (PEG) and poly(vinyl pyrrolidone) (PVP) co-modified superparamagnetic iron oxide nanoparticles (SPIONs) (PEG/PVP-SPIONs), and PEG and poly(ethylene imine) (PEI) co-modified SPIONs (PEG/PEI-SPIONs) synthesized by thermal decomposition have been used as magnetic resonance imaging (MRI) contrast agents to label adipose-derived stem cells (ADSCs). Efficient cell labeling was achieved after incubation with PEG/PVP-SPIONs and PEG/PEI-SPIONs for 12h, and the MRI of labeled cells was evaluated. The cell viability tests showed the low cytotoxicity of PEG/PVP-SPIONs and PEG/PEI-SPIONs. The cellular iron content incubated with PEG/PVP-SPIONs at a concentration of 25 MUg/ml was 6.96 pg/cell, the cellular iron contents incubated with PEG/PEI-SPIONs at concentrations of 12 and 25 MUg/ml were 20.16, 35.4 pg/cell, respectively. The SPIONs were located predominantly in the intracellular vesicles. The cellular iron oxide uptake was significantly high after incubation with PEG/PEI-SPIONs as compared with the commercial iron oxide agents (Feridex, Feridex@PLL, Resovist and Resovist@PLL) reported. This work demonstrates that PEG/PEI-SPIONs are the competent agents for the labeling of ADSCs. PMID- 26952438 TI - Capillary microfluidics-derived doxorubicin-containing human serum albumin microbeads for transarterial chemoembolization of hepatic cancer. AB - In this study, we prepared doxorubicin (DOXO)-loaded albumin microbeads (DOXO MBs) using a capillary microfluidic device for transarterial chemoembolization of hepatic cancer. Albumin droplets were fabricated using the capillary microfluidic device and solidified by addition of glutaraldehyde. The acquired DOXO-MBs were homogeneous and the size was adjustable from 183.2 +/- 12.2 MUm to 351.5 +/- 7.9 MUm by changing the flow rate of fluidic solutions. The loading amount of DOXO was 9.7 +/- 1.5 mg/g, and over 15.7% of DOXO was released over one month in pH7.2 buffer. Intra-portal injection of DOXO-MBs on normal liver of rats proved microbeads efficiently embolized hepatic vessels. Hepatic lobes, recovered 24 days after intra-portal injection, showed that the DOXO-MBs remained in hepatic vessels and released DOXO to surrounding hepatic tissues. In the hepatic tumor xenograft mouse model, DOXO-MBs inhibited tumor growth more efficiently than intravenous (I.V.) injection of free DOXO (p<0.01). PMID- 26952439 TI - Biomimetic scaffolds containing nanofibers coated with willemite nanoparticles for improvement of stem cell osteogenesis. AB - Nowadays, discovering osteogenesis stimulating effectors is one of the major topics in bone tissue engineering and regenerative medicine. In this study, the proliferation rate and osteogenic differentiation potency of adipose-derived mesenchymal stem cells (AT-MSCs) cultured on poly (l-lactide acid) (PLLA) and willemite-coated PLLA were investigated by MTT assay and common osteogenic markers such as alkaline phosphatase (ALP) activity, calcium mineral deposition and bone-related genes expression. Willemite-coated PLLA showed a higher proliferation support to AT-MSCs in comparison to PLLA and TCPS. During the period of study, AT-MSCs cultured on willemite-coated PLLA scaffolds exhibited the greatest ALP activity and mineralization. Gene expression analysis demonstrated that the highest expression of four important osteogenic-related genes, osteonectin, Runx2, collagen type 1 and osteocalcin was observed in stem cells cultured on willemite-coated PLLA nanofibrous scaffolds. According to the results, willemite-coated PLLA could be a suitable substrate to support the proliferation and osteogenic differentiation of stem cells and holds promising potential for bone tissue engineering and regenerative medicine applications. PMID- 26952440 TI - Improvement of beta-TCP/PLLA biodegradable material by surface modification with stearic acid. AB - Poly-L-lactide (PLLA) is a biodegradable polymer and used widely. Incorporation of beta tricalcium phosphate (beta-TCP) into PLLA can enhance its osteoinductive properties. But the interfacial layer between beta-TCP particles with PLLA matrix is easy to be destroyed due to inferior interfacial compatibility of the organic/inorganic material. In this work, a method of beta-TCP surface modification with stearic acid was investigated to improve the beta-TCP/PLLA biomaterial. The effects of surface modification on the beta-TCP were investigated by FTIR, XPS, TGA and CA. It was found that the stearic acid reacted with beta-TCP and oxhydryl was formed during the surface modification. Hydrophilicity of untreated or modified beta-TCP/PLLA composite was increased by the addition of 10 wt.% beta-TCP, but it decreased as the addition amount increased from 10 wt.% to 20 wt.%. Two models were suggested to describe the effect of beta-TCP concentration on CA of the composites. Mechanical properties of beta-TCP/PLLA composites were tested by bending and tensile tests. Fractures of the composites after mechanical test were observed by SEM. It was found that surface modification with stearic acid improved bending and tensile strengths of the beta-TCP/PLLA composites obviously. The SEM results indicated that surface modification decreased the probability of interface debonding between fillers and matrix under load. PMID- 26952441 TI - Direct photo-patterning of hyaluronic acid baits onto a fouling-release perfluoropolyether surface for selective cancer cell capture and immobilization. AB - A simple photolithographic process for directly patterning glycidyl methacrylate modified hyaluronic acid features onto UV curable perfluoropolyether-based surfaces is presented. Due to the versatility of the developed method, HA spotted areas with different geometrical features could be rapidly and inexpensively designed. In addition, the excellent antifouling and fouling-release properties of the substrates enabled direct HA baits photo-grafting onto PFPEs without further surface passivation or chemical modification to avoid not specific adsorption. The aim of the study was to locally switch the surface properties of the PFPEs from cells and protein repulsive to adherent. Particularly, we exploited HA well-known preferential interactions with CD44 transmembrane receptors to selectively immobilize cancer cells. Living cell arrays offer a higher-resolution visualization of HA-CD44 interactions and may provide a deep insight into understanding molecular mechanisms needed to develop selective therapies and diagnosis against tumor growth. PMID- 26952442 TI - Fabrication of a sensitive amperometric sensor for NADH and H2O2 using palladium nanoparticles-multiwalled carbon nanotube nanohybrid. AB - Palladium nanoparticles decorated multiwalled carbon nanotubes (PdNPs-MWCNTs) were synthesized and simply cast on the surface of a glassy carbon electrode (GCE) to prepare an amperometric sensor. The fabricated sensor (PdNPs-MWCNTs/GCE) showed excellent electrocatalytic activity towards NADH and H2O2 oxidation and H2O2 reduction. A fast, linear and highly sensitive response was observed for NADH in the concentration range between 0.1 and 200 MUM with a detection limit (S/N=3) of 32 nM. Also, the sensor exhibited fast and sensitive responses (<2 s) towards H2O2. The sensitivity and detection limit for H2O2 at the operating potential of +0.35 V were 167 nA MUM(-1)cm(-2) and 1.2 MUM, respectively and better than those obtained at the operating potential of -0.25 V (68 nA MUM( 1)cm(-2) and 14 MUM). Moreover, further modification of the proposed sensor by glucose oxidase led to the fabrication of a glucose biosensor with satisfactory performance. PMID- 26952443 TI - A biocompatible hybrid material with simultaneous calcium and strontium release capability for bone tissue repair. AB - The increasing interest in the effect of strontium in bone tissue repair has promoted the development of bioactive materials with strontium release capability. According to literature, hybrid materials based on the system PDMS SiO2 have been considered a plausible alternative as they present a mechanical behavior similar to the one of the human bone. The main purpose of this study was to obtain a biocompatible hybrid material with simultaneous calcium and strontium release capability. A hybrid material, in the system PDMS-SiO2-CaO-SrO, was prepared with the incorporation of 0.05 mol of titanium per mol of SiO2. Calcium and strontium were added using the respective acetates as sources, following a sol-gel technique previously developed by the present authors. The obtained samples were characterized by FT-IR, solid-state NMR, and SAXS, and surface roughness was analyzed by 3D optical profilometry. In vitro studies were performed by immersion of the samples in Kokubo's SBF for different periods of time, in order to determine the bioactive potential of these hybrids. Surfaces of the immersed samples were observed by SEM, EDS and PIXE, showing the formation of calcium phosphate precipitates. Supernatants were analyzed by ICP, revealing the capability of the material to simultaneously fix phosphorus ions and to release calcium and strontium, in a concentration range within the values reported as suitable for the induction of the bone tissue repair. The material demonstrated to be cytocompatible when tested with MG63 osteoblastic cells, exhibiting an inductive effect on cell proliferation and alkaline phosphatase activity. PMID- 26952444 TI - Is cell viability always directly related to corrosion resistance of stainless steels? AB - It has been frequently reported that cell viability on stainless steels is improved by increasing their corrosion resistance. The question that arises is whether human cell viability is always directly related to corrosion resistance in these biostable alloys. In this work, the microstructure and in vitro corrosion behavior of a new class of medical-grade stainless steels were correlated with adult human mesenchymal stem cell viability. The samples were produced by a powder metallurgy route, consisting of mechanical alloying and liquid-phase sintering with a sintering aid of a eutectic Mn-Si alloy at 1050 degrees C for 30 and 60 min, leading to nanostructures. In accordance with transmission electron microscopic studies, the additive particles for the sintering time of 30 min were not completely melted. Electrochemical impedance spectroscopic experiments suggested the higher corrosion resistance for the sample sintered for 60 min; however, a better cell viability on the surface of the less corrosion-resistant sample was unexpectedly found. This behavior is explained by considering the higher ion release rate of the Mn-Si additive material, as preferred sites to corrosion attack based on scanning electron microscopic observations, which is advantageous to the cells in vitro. In conclusion, cell viability is not always directly related to corrosion resistance in stainless steels. Typically, the introduction of biodegradable and biocompatible phases to biostable alloys, which are conventionally anticipated to be corrosion-resistant, can be advantageous to human cell responses similar to biodegradable metals. PMID- 26952445 TI - Magnetic hydroxyapatite coatings as a new tool in medicine: A scanning probe investigation. AB - Hydroxyapatite films enriched with magnetite have been fabricated via a Pulsed Plasma Deposition (PPD) system with the final aim of representing a new platform able to disincentivate bacterial adhesion and biofilm formation. The chemical composition and magnetic properties of films were respectively examined by X-ray photoelectron spectroscopy (XPS) and Superconducting Quantum Interference Device (SQUID) measurements. The morphology and conductive properties of the magnetic films were investigated via a combination of scanning probe technologies including atomic force microscopy (AFM), electrostatic force microscopy (EFM), and scanning tunneling microscopy (STM). Interestingly, the range of adopted techniques allowed determining the preservation of the chemical composition and magnetic properties of the deposition target material while STM analysis provided new insights on the presence of surface inhomogeneities, revealing the presence of magnetite-rich islands over length scales compatible with the applications. Finally, preliminary results of bacterial adhesion tests, indicated a higher ability of magnetic hydroxyapatite films to reduce Escherichia coli adhesion at 4h from seeding compared to control hydroxyapatite films. PMID- 26952446 TI - Surface wettability and energy effects on the biological performance of poly-3 hydroxybutyrate films treated with RF plasma. AB - The surface properties of poly-3-hydroxybutyrate (P3HB) membranes were modified using oxygen and an ammonia radio-frequency (RF, 13.56 MHz) plasma. The plasma treatment procedures used in the study only affected the surface properties, including surface topography, without inducing any significant changes in the crystalline structure of the polymer, with the exception being a power level of 250 W. The wettability of the modified P3HB surfaces was significantly increased after the plasma treatment, irrespective of the treatment procedure used. It was revealed that both surface chemistry and surface roughness changes caused by the plasma treatment affected surface wettability. A treatment-induced surface aging effect was observed and resulted in an increase in the water contact angle and a decrease in the surface free energy. However, the difference in the water contact angle between the polymers that had been treated for 4 weeks and the untreated polymer surfaces was still significant. A dependence between cell adhesion and proliferation and the polar component of the surface energy was revealed. The increase in the polar component after the ammonia plasma modification significantly increased cell adhesion and proliferation on biodegradable polymer surfaces compared to the untreated P3HB and the P3HB modified using an oxygen plasma. PMID- 26952447 TI - Effect of anodization on the surface characteristics and electrochemical behaviour of zirconium in artificial saliva. AB - The paper is focused on elaboration of ZrO2 films on pure zirconium via anodizing in phosphoric acid with and without fluoride at constant potentials of 30 V and 60 V. The structure and composition of the films were investigated using scanning electronic microscopy, Raman spectroscopy and X-ray photoelectron spectroscopy. The composition of the oxides formed at both potentials can be identified as monoclinic ZrO2. In addition to Zr and O, the layers formed in phosphoric acid contain phosphorus originating from the phosphoric acid. When the phosphoric acid solution contains NaF, fluorine is also incorporated into the oxide layer. The oxides formed at a higher voltage have greater roughness than those formed at 30 V. Anodized samples exhibit smaller current densities during anodic polarization compared to the as-received zirconium covered with native oxide. PMID- 26952448 TI - Evaporation-based method for preparing gelatin foams with aligned tubular pore structures. AB - Gelatin-based foams with aligned tubular pore structures were prepared via liquid to-gas vaporization of tightly bound water in dehydrated gelatin hydrogels. This study elucidates the mechanism of the foaming process by investigating the secondary (i.e., helical) structure, molecular interactions, and water content of gelatin films before and after foaming using X-ray diffraction, Fourier transform infrared (FTIR) spectroscopy, differential scanning calorimetry and thermogravimetric analysis (TGA), respectively. Experimental data from gelatin samples prepared at various gelatin-to-water concentrations (5-30 wt.%) substantiate that resulting foam structures are similar in pore diameter (approximately 350 MUm), shape, and density (0.05-0.22 g/cm(3)) to those fabricated using conventional methods (e.g., freeze-drying). Helical structures were identified in the films but were not evident in the foamed samples after vaporization (~150 degrees C), suggesting that the primary foaming mechanism is governed by the vaporization of water that is tightly bound in secondary structures (i.e., helices, beta-turns, beta-sheets) that are present in dehydrated gelatin films. FTIR and TGA data show that the foaming process leads to more disorder and reduced hydrogen bonding to hydroxyl groups in gelatin and that no thermal degradation of gelatin occurs before or after foaming. PMID- 26952449 TI - pH- and sugar-sensitive multilayer films composed of phenylboronic acid (PBA) modified poly(allylamine hydrochloride) (PBA-PAH) and poly(vinyl alcohol) (PVA): A significant effect of PBA content on the film stability. AB - Multilayer thin films composed of phenylboronic acid (PBA)-modified poly(allylamine hydrochloride) (PAH), PBA-PAH, with different PBA contents were prepared to study the effect of PBA content on the stability of the films. An alternate deposition of PBA-PAH and poly(vinyl alcohol) (PVA) on the surface of a quartz slide afforded multilayer films through forming boronate ester bonds between PBA-PAH and PVA. The 10-layered (PBA-PAH/PVA)10 films constructed using PBA-PAHs containing 16% and 26% PBA residues were stable in aqueous solutions over the range of pH 4.0-10.0, whereas the multilayer films composed of PBA-PAHs with 5.9% and 8.3% PBA decomposed at pH 8.0 or lower. The pH-sensitive decomposition of the films was rationalized based on the destabilization of the boronate ester bonds in neutral and acidic solutions. In addition, the (PBA PAH/PVA)10 films decomposed in glucose and fructose solutions as a result of competitive binding of sugars to PBA-PAH in the films. The sugar response of the films depended on the PBA content in PBA-PAH. The (PBA-PAH/PVA)10 films consisting of 16% and 26% PBA-substituted PBA-PAHs are sensitive to physiological relevant level of glucose at pH7.4 while stable in glucose-free solution, suggesting a potential use of the films in constructing glucose-induced delivery systems. PMID- 26952450 TI - A novel voltammetric sensor for citalopram based on multiwall carbon nanotube/(poly(p-aminobenzene sulfonic acid)/beta-cyclodextrin). AB - Multi-walled carbon nanotube (MWCNTS) coated with poly p-aminobenzene sulfonic acid/beta-cyclodextrin (p-ABSA/beta-CD) film was used as an effective strategy for modification of the surface of glassy carbon electrode (GCE). Electrochemical study and determination of citalopram (CT) were investigated at the p (p ABSA)/beta-CD/MWCNT/GC using cyclic and differential pulse anodic stripping voltammetric techniques. The results indicate that the p (p-ABSA)/beta CD/MWCNT/GC significantly enhanced the oxidation peak current of CT. The modified electrode was characterized by electrochemical impedance spectroscopy (EIS), scanning electron microscopy(SEM) and cyclic voltammetry (CV).The fabricated electrochemical sensor exhibits a fast and reversible linear response toward CT within the concentration ranges of 90 nM-1 MUM, 1-11 MUM and 11-100 MUM with correlation coefficients greater than 0.99 and detection limit of 44 nM. The resulting functionalized polymer film features interesting electrochemical properties such good recovery, reproducibility and selectivity toward CT. The applicability of the proposed sensor was tested by determination of CT in pharmaceutical combinations and human body fluids. PMID- 26952451 TI - Spray dried microspheres based on chitosan: A promising new carrier for intranasal administration of polymeric antigen BLSOmp31 for prevention of ovine brucellosis. AB - Previous studies have demonstrated that parenteral immunization with polymeric antigen BLSOmp31 induced a strong immune response and conferred protection against Brucella ovis in rams. This work describes the development of a novel formulation strategy for the delivery of BLSOmp31 in the nasal mucosa. Chitosan microparticles were prepared by spray-drying technology processes and recombinant chimera BLSOmp31 was loaded by passive adsorption onto chitosan microspheres, which were characterized by means of the evaluation of size, zeta potential, morphology, and loading and release rate of BLSOmp31. The mucoadhesive properties of microspheres were evaluated by studying the interaction between microparticles and mucin. The antigen BLSOmp31 integrity was investigated by SDS-PAGE. The yield of production of spray-drying process was 68.95%. Microspheres had a good sphericity, 1-10 MUm of particle size and had a positive charge. The loading capacity was found to be 45.19%. The initial fast release of BLSOmp31 from chitosan microparticles was 60%. The BLSOmp31 integrity was not affected by passive adsorption (ionic interaction). The amount of mucin adsorbed on the surface of CMs-BLSOmp31 was lower than on the surface of blank CMs at neutral pH. In vivo studies were carried out in rams. Intranasal immunization induced systemic and local antibodies. In conclusion, the use of BLSOmp31-loaded chitosan spray-drying microspheres offers a promising way for nasal mucosal vaccination in sheep against brucellosis. PMID- 26952452 TI - Dissolution behaviour of silicon nitride coatings for joint replacements. AB - In this study, the dissolution rate of SiNx coatings was investigated as a function of coating composition, in comparison to a cobalt chromium molybdenum alloy (CoCrMo) reference. SiNx coatings with N/Si ratios of 0.3, 0.8 and 1.1 were investigated. Electrochemical measurements were complemented with solution (inductively coupled plasma techniques) and surface analysis (vertical scanning interferometry and x-ray photoelectron spectroscopy). The dissolution rate of the SiNx coatings was evaluated to 0.2-1.4 nm/day, with a trend of lower dissolution rate with higher N/Si atomic ratio in the coating. The dissolution rates of the coatings were similar to or lower than that of CoCrMo (0.7-1.2 nm/day). The highest nitrogen containing coating showed mainly Si-N bonds in the bulk as well as at the surface and in the dissolution area. The lower nitrogen containing coatings showed Si-N and/or Si-Si bonds in the bulk and an increased formation of Si-O bonds at the surface as well as in the dissolution area. The SiNx coatings reduced the metal ion release from the substrate. The possibility to tune the dissolution rate and the ability to prevent release of metal ions encourage further studies on SiNx coatings for joint replacements. PMID- 26952453 TI - Poly-Alizarin red S/multiwalled carbon nanotube modified glassy carbon electrode for the boost up of electrocatalytic activity towards the investigation of dopamine and simultaneous resolution in the presence of 5-HT: A voltammetric study. AB - Poly-Alizarin red S/multiwalled carbon nanotube film on the surface of glassy carbon electrode (poly-AzrS/MWCNT/GCE) was synthesized by electrochemical process and was used for the sensitive and selective determination of dopamine (DA) by employing voltammetric techniques. The electrocatalytic response of the modified electrode was found to exhibit admirable activity. The simultaneous determination of dopamine in the presence of serotonin (5-HT) was found to exhibit very good response at poly-AzrS/MWCNTs/GCE. The effect of pH, scan rate, accumulation time and concentration of dopamine was studied at the developed poly-AzrS/MWCNTs/GCE. The poly-AzrS/MWCNTs/GCE exhibited an efficient electron mediating behavior together with well resolved peaks for dopamine, in 0.1 mol/dm(3) phosphate buffer (PBS) solution of pH 7.0. The limit of detection (LOD) and limit of quantification (LOQ) were found to be as 1.89 * 10(-7) mol/dm(3) and 6.312 * 10( 7) mol/dm(3) respectively with a dynamic range from 1 * 10(-6) to 1.8 * 10(-5) mol/dm(3). The interfacial electron transfer behavior of DA was studied by electrochemical impedance spectroscopy (EIS); the studies showed that the charge transfer rate was enhanced at poly-AzrS/MWCNTs/GCE when compared with bare GCE and poly-AzrS/GCE. PMID- 26952454 TI - Mechanical properties of human enamel under compression: On the feature of calculations. AB - The paper is aimed at determination of the causes of shape effect in human tooth enamel under compression and correction of the relevant mechanical characteristics. For this purpose, six groups of samples with different ratios of the compression surface diagonal to the sample height, which consisted of 10 cuboid samples in each, were prepared from the backside of human enamel. The lateral deformation of a sample was calculated at the maximum compressive stress for correction of the mechanical characteristics. It is shown that the ratio between the lateral and axial deformations decreases with an increase in the ratio of the compression surface diagonal to the sample height. This is caused by the friction between the compression plates and the working surfaces of the enamel sample when the lateral deformation is suppressed. In addition, the slope of enamel sample by about 15 degrees occurred during compression due to the inclination of rigid and low deformable enamel rods. The corrections of the elastic modulus and the compression strength taking into account the lateral deformation and the sample slope are carried out. The mechanical properties of enamel samples with the 2.1 aspect ratio are closer to the intrinsic properties of human enamel samples. The elastic modulus and the compression strength of human enamel under compression are 5.64 GPa and 363 MPa, respectively. The lateral deformation (~10%) may be considered as the critical parameter that indicates the strength of human enamel. PMID- 26952455 TI - Effect of cationic grafted copolymer structure on the encapsulation of bovine serum albumin. AB - The aim of the present study was to evaluate a library of poly-L-lysine (PLL) graft (g)-polyethylene glycol (PEG) copolymers for the ability to encapsulate effectively a model protein, bovine serum albumin (BSA), and to characterize the stability and protein function of the resulting nanoparticle. A library of nine grafted copolymers was produced by varying PLL molecular weight and PEG grafting ratio. Electrostatic self-assembly of the protein and the grafted copolymer drove encapsulation. The formation of protein/polymer nanoparticles with a core/shell structure was confirmed using PAGE, dynamic light scattering, and electron microscopy. Encapsulation of the BSA into nanoparticles was strongly dependent on the copolymer-to-protein mass ratio, PEG grafting ratio, and PLL molecular weight. A copolymer-to-protein mass ratio of 7:1 and higher was generally required for high levels of encapsulation, and under these conditions, no loss of protein activity was observed. Copolymer characteristics also influenced nanoparticle resistance to polyanions and protease degradation. The results indicate that a copolymer of 15-30 kDa PLL, with a PEG grafting ratio of 10:1, is most promising for protein delivery. PMID- 26952456 TI - Uneven damage on head and liner contact surfaces of a retrieved Co-Cr-based metal on-metal hip joint bearing: An important reason for the high failure rate. AB - Detailed metallurgical investigations have been performed on a used Co-Cr-based metal-on-metal (MoM) hip joint bearing containing a type of liner that is commonly used in such joints. The damage on the metal-liner sliding surface was considerably more severe than that on the metal head counterpart, in terms of wear-scar density and width and microcrack frequency. Cross-sectional transmission electron microscopy revealed that a thick (>3 MUm) nanocrystalline layer formed on the sliding surface of the head, whereas the liner had coarse carbides embedded in it and nanocrystals were formed in a very limited region no deeper than 1 MUm. Comparative investigation of an unused head and a liner of identical type showed that although the chemical compositions of the liner and head were nearly identical, their microstructures were significantly different. Specifically, the grain size in the liner was larger than that in the head on average, and the grain boundaries of the liner were decorated with coarse carbides. Moreover, X-ray diffraction analysis revealed a large tensile residual stress only in the liner. These differences are possibly responsible for the wear damage on the liner being more serious than that on the head. PMID- 26952457 TI - Evaluation of cell viability and T2 relaxivity of fluorescein conjugated SPION PAMAM third generation nanodendrimers for bioimaging. AB - This study has investigated the possibility of using fluorescent dendronized magnetic nanoparticles (FDMNPs) for potential applications in drug delivery and imaging. FDMNPs were first synthesized, characterized and then the effect of Polyamidoamine (PAMAM) dendrimer functionalization and fluorescein isothiocyanate (FITC) conjugation on biocompatibility of superparamagnetic iron oxide nanoparticles (SPIONs) was evaluated. The nanostructures' cytotoxicity tests were performed at different concentrations from 10 to 500 MUg/mL using MCF-7 and L929 cell lines. IC50 in MTT assay were 139.22 and 201.88 MUg/mL for DMNP incubated L929 and MCF-7 cell lines respectively, whereas the cell viability for FDMNPs did not decrease to 50%. The results showed that FITC conjugation diminishes the toxicity of dendronized magnetic nanoparticles (DMNPs) mainly due to the reduction of surface charge. DMNP appears to be cytotoxic at the concentration levels being used for both cell lines. On the contrary, FDMNPs showed more biocompatibility and cell viability of MCF-7 and L929 cell lines at all concentrations. The fluorescence microscopy of FDMNPs incubated with MCF-7 cells showed a successful localization of cells indicating their ability for applications such as a magnetic fluorescent probe in cell studies and imaging purposes. T2 relaxivity measurements demonstrated the applicability of the synthesized nanostructures as the contrast agents in tissue differential assessment by altering their relaxation times. In our case, the r2 relaxivity of FDMNPs was measured as 103.67 mM(-1)S(-1). PMID- 26952458 TI - Green synthesis of silver nanoparticles using methanolic root extracts of Diospyros paniculata and their antimicrobial activities. AB - Since the discovery and subsequent widespread use of antibiotics, a variety of bacterial species of human and animal origin have developed numerous mechanisms that render bacteria resistant to some, and in certain cases to nearly all antibiotics, thereby limiting the treatment options and compromising effective therapy. In the present study, the green synthesis of nanoparticles is carried out by the reduction of silver acetate in the presence of crude methanolic root extracts of Diospyros paniculata, a member of family Ebenaceae. The UV-Vis absorption spectrum of the biologically reduced reaction mixture showed the surface plasmon peak at 428 nm, a characteristic peak of silver nanoparticles. X ray diffraction (XRD) analysis confirmed the face-centered cubic crystalline structure of metallic silver. The average diameter of Ag NPs is about 17 nm from Transmission Electron Microscopy (TEM) which is in good agreement with the average crystallite size (19 nm) calculated from XRD analysis. Further the study has been extended to the antimicrobial activity against test pathogenic Gram (+), Gram (-) bacterial and fungal strains. The biologically synthesized silver nanoparticles showed promising activity against all the tested pathogenic strains and the activity has been enhanced with the increased dose levels. PMID- 26952459 TI - Effect of ultrafine grain on tensile behaviour and corrosion resistance of the duplex stainless steel. AB - The ultrafine grained 2205 duplex stainless steel was obtained by cold rolling and annealing. The tensile properties were investigated at room temperature. Comparing with coarse grained stainless steel, ultrafine grained sample showed higher strength and plasticity. In addition, grain size changed deformation orientation. The strain induced alpha'-martensite was observed in coarse grained 2205 duplex stainless steel with large strain. However, the grain refinement inhibited the transformation of alpha'-martensite;nevertheless, more deformation twins improved the strength and plasticity of ultrafine grained 2205 duplex stainless steel. In addition, the grain refinement improved corrosion resistance of the 2205 duplex stainless steel in sodium chloride solution. PMID- 26952460 TI - Comb-like amphiphilic polypeptide-based copolymer nanomicelles for co-delivery of doxorubicin and P-gp siRNA into MCF-7 cells. AB - A comb-like amphiphilic copolymer methoxypolyethylene glycol-graft-poly(L-lysine) block-poly(L-phenylalanine) (mPEG-g-PLL-b-Phe) was successfully synthesized. To synthesize mPEG-g-PLL-b-Phe, diblock copolymer PLL-b-Phe was first synthesized by successive ring-opening polymerization of alpha-amino acid N-carboxyanhydrides followed by the removal of benzyloxycarbonyl protecting groups, and then mPEG was grafted onto PLL-b-Phe by reductive amination via Schiff's base formation. The chemical structures of the copolymers were identified by (1)H NMR. mPEG-g-PLL-b Phe copolymer had a critical micelle concentration of 6.0mg/L and could self assemble in an aqueous solution into multicompartment nanomicelles with a mean diameter of approximately 78 nm. The nanomicelles could encapsulate doxorubicin (DOX) through hydrophobic and pi-pi stacking interactions between DOX molecules and Phe blocks and simultaneously complex P-gp siRNA with cationic PLL blocks via electrostatic interactions. The DOX/P-gp siRNA-loaded nanomicelles showed spherical morphology, possessed narrow particle size distribution and had a mean particle size of 120 nm. The DOX/P-gp siRNA-loaded nanomicelles exhibited pH responsive release behaviors and displayed accelerated release under acidic conditions. The DOX/P-gp siRNA-loaded nanomicelles were efficiently internalized into MCF-7 cells, and DOX released could successfully reach nuclei. In vitro cytotoxicity assay demonstrated that the DOX/P-gp siRNA-loaded nanomicelles showed a much higher cytotoxicity in MCF-7 cells than DOX-loaded nanomicelles due to their synergistic killing effect and that the blank nanomicelles had good biocompatibility. Thus, the novel comb-like mPEG-g-PLL-b-Phe nanomicelles could be a promising vehicle for co-delivery of chemotherapeutic drug and genetic material. PMID- 26952461 TI - Cross-correlative 3D micro-structural investigation of human bone processed into bone allografts. AB - Bone allografts (BA) are a cost-effective and sustainable alternative in orthopedic practice as they provide a permanent solution for preserving skeletal architecture and function. Such BA however, must be processed to be disease free and immunologically safe as well as biologically and clinically useful. Here, we have demonstrated a processing protocol for bone allografts and investigated the micro-structural properties of bone collected from osteoporotic and normal human donor samples. In order to characterize BA at different microscopic levels, a combination of techniques such as Solid State Nuclear Magnetic Resonance (ssNMR), Scanning Electron Microscope (SEM), micro-computed tomography (MUCT) and Thermal Gravimetric Analysis (TGA) were used for delineating the ultra-structural property of bone. ssNMR revealed the extent of water, collagen fine structure and crystalline order in the bone. These were greatly perturbed in the bone taken from osteoporotic bone donor. Among the processing methods analyzed, pasteurization at 60 degrees C and radiation treatment appeared to substantially alter the bone integrity. SEM study showed a reduction in Ca/P ratio and non uniform distribution of elements in osteoporotic bones. MU-CT and MIMICS (Materialize Interactive Medical Image Control System) demonstrated that pasteurization and radiation treatment affects the BA morphology and cause a shift in the HU unit. However, the combination of all these processes restored all-important parameters that are critical for BA integrity and sustainability. Cross-correlation between the various probes we used quantitatively demonstrated differences in morphological and micro-structural properties between BA taken from normal and osteoporotic human donor. Such details could also be instrumental in designing an appropriate bone scaffold. For the best restoration of bone microstructure and to be used as a biomaterial allograft, a step-wise processing method is recommended that preserves all critical parameters of bone, showing a significant advancements over currently existing methods. PMID- 26952462 TI - Gelatin-poly(lactic-co-glycolic acid) scaffolds with oriented pore channel architecture - From in vitro to in vivo testing. AB - A gelatin-poly(lactic-co-glycolic acid), PLGA, composite scaffold, featuring a highly oriented pore channel structure, was developed as a template for articular cartilage regeneration. As a design principle the composite scaffold was optimized to contain only medical grade educts and accordingly no chemical cross linking agents or other toxicological relevant substances or methods were used. Scaffolds were synthesized using a freeze structuring method combined with an electrochemical process followed by freeze-drying. Finally, cross linking was performed using dehydrothermal treatment, which was simultaneously used for sterilization purposes. These composite scaffolds were analyzed in regard to structural and biomechanical properties, and to their degradation behavior. Furthermore, cell culture performance was tested using chondrocytes originated from joint articular cartilage tissue from 6 to 10 months old domestic pigs. Finally, the scaffolds were tested for tissue biocompatibility and their ability for tissue integration in a rat model. The scaffolds showed both excellent functional performance and high biocompatibility in vitro and in vivo. We expect that these gelatin-PLGA scaffolds can effectively support chondrogenesis in vivo demonstrating great potential for the use in cartilage defect treatment. PMID- 26952463 TI - Hierarchical electrodeposition of methylene blue on ZnO nanocrystals thin films layered on SnO2/F electrode for in vitro sensing of anti-thalassemic drug. AB - Zinc oxide nanocrystals-methylene blue nanocomposites were developed by electrodeposition of methylene blue onto the thin films of zinc oxide nanocrystals deposited onto SnO2/F coated glass substrates for in vitro sensing of anti-thalassemic drug i.e. deferiprone. Detailed morphological, electrochemical, structural and optical characterizations of ZnONC-MB/FTO electrode were done using XRD, SEM, EIS, FTIR, LSV, and CV and show quick response time (within 5 s), linearity as 1 * 10(-3) to 10(3) MUM and shelf life of about 10 weeks under refrigerated conditions. Attempts have been made to utilize this electrode for estimation of deferiprone in urine samples. The developed sensor exhibited high reproducibility and good storage stability. PMID- 26952464 TI - beta-Cyclodextrin anchoring onto pericarpium granati-derived magnetic mesoporous carbon for selective capture of lopid in human serum and pharmaceutical wastewater samples. AB - Functionalized magnetic carbonaceous nanomaterials, which are important materials with many practical and research applications in biomedical, pharmaceutical and biological fields, have recently attracted much attention. In this study, a magnetic mesoporous carbon coated with beta-cyclodextrin (MMC@beta-CD) was synthesized for the first time from natural pericarpium granati (PG). The as obtained MMC@beta-CD has high surface areas (203 m(2)g(-1)), large pore volumes (0.16 cm(3)g(-1)), relatively broad mesoporous sizes (6.8 nm) and a high saturation magnetization of 26.2 emu g(-1), which is sufficient for magnetic separation by an external magnetic field. The MMC@beta-CD was used as an innovative adsorbent for magnetic solid-phase extraction of lopid via host-guest interaction prior to spectrofluorometric analysis. The proposed method was successfully applied to analyze lopid in human serum and pharmaceutical wastewater samples with recoveries in the range of 85.0-103.5% for the spiked samples. Overall, this work not only provides an inexpensive and eco-friendly method to fabricate MMC@beta-CD (or MMC) from PG, but also develops a highly selective approach for capture of lopid in biological samples and environmental substances. PMID- 26952465 TI - In vivo drug delivery of gemcitabine with PEGylated single-walled carbon nanotubes. AB - Gemcitabine (GEM) is an anticancer agent widely used in non-small cell lung and pancreatic cancers. The clinical use of GEM has been limited by its rapid metabolism and short plasma half-life. These restrictions lead to frequent administration of high drug doses which can cause severe side effects. Therefore, new delivery strategies are needed aiming toward improved therapeutic effects. Single-walled carbon nanotubes (SWCNTs) are emerging as promising carriers for drug delivery due to their unique properties including high drug loading capacities, notable cell membrane penetrability and prolonged circulation times. In this work, pristine SWCNTs were functionalized through carboxylation, acylation, amination, PEGylation and finally GEM conjugation. The prepared SWCNT GEM and SWCNT-PEG-GEM conjugates were characterized by FTIR, NMR, DSC and TEM to confirm the successful functionalization. The amount of GEM bound to the conjugates was 43.14% (w/w) for the SWCNT-GEM and 37.32% for the SWCNT-PEG-GEM, indicating high loading capacity. MTT assay on the human lung carcinoma cell line (A549) and the human pancreatic carcinoma cell line (MIA PaCa-2) demonstrated that the SWCNT-GEM was more cytotoxic than SWCNT-PEG-GEM and GEM. The SWCNT-PEG GEM conjugates afford higher efficacy in suppressing tumor growth than SWCNT-GEM and GEM in B6 nude mice. The results demonstrate that the new formulation of GEM is useful strategy for improving the antitumor efficacy of GEM. PMID- 26952466 TI - Paclitaxel molecularly imprinted polymer-PEG-folate nanoparticles for targeting anticancer delivery: Characterization and cellular cytotoxicity. AB - The aim of this work was to synthesize molecularly imprinted polymer-poly ethylene glycol-folic acid (MIP-PEG-FA) nanoparticles for use as a controlled release carrier for targeting delivery of paclitaxel (PTX) to cancer cells. MIP nanoparticles were synthesized by a mini-emulsion polymerization technique and then PEG-FA was conjugated to the surface of nanoparticles. Nanoparticles showed high drug loading and encapsulation efficiency, 15.6 +/- 0.8 and 100%, respectively. The imprinting efficiency of MIPs was evaluated by binding experiments in human serum. Good selective binding and recognition were found in MIP nanoparticles. In vitro drug release studies showed that MIP-PEG-FA have a controlled release of PTX, because of the presence of imprinted sites in the polymeric structure, which makes it is suitable for sustained drug delivery. The drug release from polymeric nanoparticles was indeed higher at acidic pH. The molecular structure of MIP-PEG-FA was confirmed by Hydrogen-Nuclear Magnetic Resonance (H NMR), Fourier Transform InfraRed (FT-IR), and Attenuated Total Reflection (ATR) spectroscopy, and their thermal behaviors by Differential Scanning Calorimetry (DSC) and Thermogravimetric Analysis (TGA). Scanning Electron Microscopy (SEM) and Photon Correlation Spectroscopy (PCS) results showed that nanoparticles have a smooth surface and spherical shape with an average size of 181 nm. MIP-PEG-FA nanoparticles showed a greater amount of intracellular uptake in folate receptor-positive cancer cells (MDA-MB-231 cells) in comparison with the non-folate nanoparticles and free PTX, with half maximal inhibitory concentrations (IC50) of 4.9 +/- 0.9, 7.4 +/- 0.5 and 32.8 +/- 3.8 nM, respectively. These results suggest that MIP-PEG-FA nanoparticles could be a potentially useful drug carrier for targeting drug delivery to cancer cells. PMID- 26952467 TI - MgF2-coated porous magnesium/alumina scaffolds with improved strength, corrosion resistance, and biological performance for biomedical applications. AB - Porous magnesium (Mg) has recently emerged as a promising biodegradable alternative to biometal for bone ingrowth; however, its low mechanical properties and high corrosion rate in biological environments remain problematic. In this study, porous magnesium was implemented in a scaffold that closely mimics the mechanical properties of human bones with a controlled degradation rate and shows good biocompatibility to match the regeneration rate of bone tissue at the affected site. The alumina-reinforced Mg scaffold was produced by spark plasma sintering and coated with magnesium fluoride (MgF2) using a hydrofluoric acid solution to regulate the corrosion rate under physiological conditions. Sodium chloride granules (NaCl), acting as space holders, were leached out to achieve porous samples (60%) presenting an average pore size of 240 MUm with complete pore interconnectivity. When the alumina content increased from 0 to 5 vol%, compressive strength and stiffness rose considerably from 9.5 to 13.8 MPa and from 0.24 to 0.40 GPa, respectively. Moreover, the biological response evaluated by in vitro cell test and blood test of the MgF2-coated porous Mg composite was enhanced with better corrosion resistance compared with that of uncoated counterparts. Consequently, MgF2-coated porous Mg/alumina composites may be applied in load-bearing biodegradable implants. PMID- 26952468 TI - Tribological characterization of zirconia coatings deposited on Ti6Al4V components for orthopedic applications. AB - One of the most important issues leading to the failure of total joint arthroplasty is related to the wear of the plastic components, which are generally made of ultra high molecular weight polyethylene (UHMWPE). Therefore, the reduction of joint wear represents one of the main challenges the research in orthopedics is called to address nowadays. Surface treatments and coatings have been recognized as innovative methods to improve tribological properties, also in the orthopedic field. This work investigated the possibility to realize hard ceramic coatings on the metal component of a prosthesis, by means of Pulsed Plasma Deposition, in order to reduce friction and wear in the standard coupling against UHMWPE. Ti6Al4V substrates were coated with a 2 MUm thick yttria stabilized zirconia (YSZ) layer. The mechanical properties of the YSZ coatings were assessed by nanoindentation tests performed on flat Ti6Al4V substrates. Tribological performance was evaluated using a ball-on-disk tribometer in dry and lubricated (i.e. with fetal bovine serum) highly-stressing conditions, up to an overall distance of 10 km. Tribology was characterized in terms of coefficient of friction (CoF) and wear rate of the UHMWPE disk. After testing, specimens were analyzed through optical microscopy and SEM images, in order to check the wear degradation mechanisms. Progressive loading scratch tests were also performed in dry and wet conditions to determine the effects of the environment on the adhesion of the coating. Our results supported the beneficial effect of YSZ coating on metal components. In particular, the proposed solution significantly reduced UHMWPE wear rate and friction. At 10 km of sliding distance, a wear rate reduction of about 18% in dry configuration and of 4% in presence of serum, was obtained by the coated group compared to the uncoated group. As far as friction in dry condition is concerned, the coating allowed to maintain low CoF values until the end of the tests, with an overall difference of about 40% compared to the uncoated balls. In wet conditions, the friction values were found to be comparable between coated and uncoated materials, mainly due to a premature delamination of the coating. Scratch tests in wet showed in fact a reduction of the critical load required to a complete delamination due to a formation of blister, although no change or damage occurred at the coating during the soaking period. Although conditions of high values of contact pressure were considered, further analyses are however required to fully understand the behavior of YSZ coatings in wet environment and additional research on the deposition process will be mandatory in order to improve the coating tribological performance at long distances addressing orthopedic applications. PMID- 26952469 TI - Novel Cu@SiO2/bacterial cellulose nanofibers: Preparation and excellent performance in antibacterial activity. AB - The antibacterial composite based on bacterial cellulose (BC) was successfully prepared by in-situ synthesis of SiO2 coated Cu nanoparticles (Cu@SiO2/BC) and its properties were characterized. Its chemical structures and morphologies were evaluated by Fourier transformation infrared spectrum (FTIR), scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray diffraction (XRD) and X-ray photoelectron spectroscopy (XPS). The results demonstrated that the SiO2 coated Cu particles were well homogeneously precipitated on the surface of BC. The Cu@SiO2/BC was more resistant to oxidation than the Cu nanoparticles impregnated into BC (Cu/BC) and then Cu@SiO2/BC could prolong the antimicrobial activity against Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli). PMID- 26952470 TI - Bioactive surface modification of Ti-29Nb-13Ta-4.6Zr alloy through alkali solution treatments. AB - Bioactive surface modification of Ti-29Nb-13Ta-4.6Zr alloy (TNTZ) was performed through three different alkali solution treatments, including the electrochemical (E), hydrothermal (H), and hydrothermal-electrochemical (HE) processes; all of the processes lead to the formation of sodium-contained amorphous titanium oxide layers on TNTZ samples. The TNTZ samples subjected to the E, H, and HE processes exhibit a flat surface, smooth and fine mesh-like structure surface, and rough mesh-like structure surface, respectively. In the bioactive test, namely, simulated body fluid test, apatite inductivity increases as the surface morphology becomes rough. The order of inductivity for the three processes was HE>H>E. The surface chemical composition also affects the apatite induction ability. The surface with fewer niobium species exhibits better apatite inductivity. PMID- 26952471 TI - Correlation between porous texture and cell seeding efficiency of gas foaming and microfluidic foaming scaffolds. AB - In the design of scaffolds for tissue engineering applications, morphological parameters such as pore size, shape, and interconnectivity, as well as transport properties, should always be tailored in view of their clinical application. In this work, we demonstrate that a regular and ordered porous texture is fundamental to achieve an even cell distribution within the scaffold under perfusion seeding. To prove our hypothesis, two sets of alginate scaffolds were fabricated using two different technological approaches of the same method: gas in-liquid foam templating. In the first one, foam was obtained by insufflating argon in a solution of alginate and a surfactant under stirring. In the second one, foam was generated inside a flow-focusing microfluidic device under highly controlled and reproducible conditions. As a result, in the former case the derived scaffold (GF) was characterized by polydispersed pores and interconnects, while in the latter (MUFL), the porous structure was highly regular both with respect to the spatial arrangement of pores and interconnects and their monodispersity. Cell seeding within perfusion bioreactors of the two scaffolds revealed that cell population inside MUFL scaffolds was quantitatively higher than in GF. Furthermore, seeding efficiency data for MUFL samples were characterized by a lower standard deviation, indicating higher reproducibility among replicates. Finally, these results were validated by simulation of local flow velocity (CFD) inside the scaffolds proving that MUFL was around one order of magnitude more permeable than GF. PMID- 26952472 TI - Synthesis of nanofibrous gelatin/silica bioglass composite microspheres using emulsion coupled with thermally induced phase separation. AB - This study proposes an innovative way of synthesizing porous gelatin/silica bioglass composite microspheres with a nanofibrous structure using emulsion coupled with thermally induced phase separation (TIPS). In particular, a mixture of the solvent (water) and non-solvent (ethanol) was used to induce a unique phase separation of gelatin/silica mixtures (i.e. gelatin/silica hybrid-rich and liquid-rich phases) at -70 degrees C for the creation of a nanofibrous structure. All the composite microspheres synthesized with silica contents of 10 wt.%, 15 wt.%, and 20 wt.% had well-defined spherical shapes between 124 and 136 MUm in size. In addition, they were comprised of nanofibrous gelatin/silica composite walls (several tens of nanometers in thickness), where the sol-gel derived silica bioglass phase was uniformly distributed throughout the gelatin matrix. The in vitro apatite-forming ability and biocompatibility of the nanofibrous gelatin/silica bioglass composite microspheres was significantly enhanced with an increase in silica content, demonstrating their great potential for the promotion of bone tissue regeneration. PMID- 26952473 TI - Nitride coating enhances endothelialization on biomedical NiTi shape memory alloy. AB - Surface nitriding was demonstrated to be an effective process for improving the biocompatibility of implantable devices. In this study, we investigated the benefits of nitriding the NiTi shape memory alloy for vascular stent applications. Results from cell experiments indicated that, compared to untreated NiTi, a superficial gas nitriding treatment enhanced the adhesion of human umbilical vein endothelial cells (HUVECs), cell spreading and proliferation. This investigation provides data to demonstrate the possibility of improving the rate of endothelialization on NiTi by means of nitride coating. PMID- 26952474 TI - Deposition, structure, physical and invitro characteristics of Ag-doped beta Ca3(PO4)2/chitosan hybrid composite coatings on Titanium metal. AB - Pure and five silver-doped (0-5Ag) beta-tricalcium phosphate [beta-TCP, beta Ca3(PO4)2]/chitosan composite coatings were deposited on Titanium (Ti) substrates and their properties that are relevant for applications in hard tissue replacements were assessed. Silver, beta-TCP and chitosan were combined to profit from their salient and complementary antibacterial and biocompatible features.The beta-Ca3(PO4)2 powders were synthesized by co-precipitation. The characterization results confirmed the Ag(+) occupancy at the crystal lattice of beta-Ca3(PO4)2. The Ag-dopedbeta-Ca3(PO4)2/chitosan composite coatings deposited by electrophoresis showed good antibacterial activity and exhibited negative cytotoxic effects towards the human osteosarcoma cell line MG-63. The morphology of the coatings was observed by SEM and their efficiency against corrosion of metallic substrates was determined through potentiodynamic polarization tests. PMID- 26952475 TI - A novel multifunctional biomedical material based on polyacrylonitrile: Preparation and characterization. AB - Wet spun microfibers have great potential in the design of multifunctional controlled release materials. Curcumin (Cur) and vitamin E acetate (Vit. E Ac) were used as a model drug system to evaluate the potential application of the drug-loaded microfiber system for enhanced delivery. The drugs and polyacrylonitrile (PAN) were blended together and spun to produce the target drug loaded microfiber using an improved wet-spinning method and then the microfibers were successfully woven into fabrics. Morphological, mechanical properties, thermal behavior, drug release performance characteristics, and cytocompatibility were determined. The drug-loaded microfiber had a lobed "kidney" shape with a height of 50-100 MUm and width of 100-200 MUm. The addition of Cur and Vit. E Ac had a great influence on the surface and cross section structure of the microfiber, leading to a rough surface having microvoids. X-ray diffraction and Fourier transform infrared spectroscopy indicated that the drugs were successfully encapsulated and dispersed evenly in the microfilament fiber. After drug loading, the mechanical performance of the microfilament changed, with the breaking strength improved slightly, but the tensile elongation increased significantly. Thermogravimetric results showed that the drug load had no apparent adverse effect on the thermal properties of the microfibers. However, drug release from the fiber, as determined through in-vitro experiments, is relatively low and this property is maintained over time. Furthermore, in-vitro cytocompatibility testing showed that no cytotoxicity on the L929 cells was found up to 5% and 10% respectively of the theoretical drug loading content (TDLC) of curcumin and vitamin E acetate. This study provides reference data to aid the development of multifunctional textiles and to explore their use in the biomedical material field. PMID- 26952477 TI - "Synthesis, characterization and studies on antioxidant activity of silver nanoparticles using Elephantopus scaber leaf extract". AB - The simple, eco-friendly and cost effective method of green synthesis of silver nanoparticle in the leaf extract of medicinal plant Elephantopus scaber L. is illustrated in the present work. The synthesized silver nanoparticles (AgNPs) were characterized with UV-Vis-spectroscopy, nanoparticle tracking analysis (NTA), transmission electron microscopy (TEM), X-ray diffraction (XRD) and Fourier transform infrared (FTIR) analysis. The UV-spectra show maximum absorbance at 435 nm, NTA analysis shows 78 nm average sizes of nanoparticles, TEM analysis indicates spherical shape of the nanoparticles with the average diameter of 50 nm. The XRD peaks at 2theta range of 30-80 degrees correspond to (111), (200), (220), (311) reflection planes that indicate the structure of metallic silver. FTIR analysis reveals surface capping of phenolic groups. Existence of peaks in the range of 1611 to 1400 cm(-1) indicates the presence of aromatic rings in the leaf extract. The peak at 1109 cm(-1) is due to the presence of OH groups. The antioxidant activity of synthesized nanoparticles was evaluated performing DPPH assay and it is observed that the photosynthesized nanoparticle also possesses antioxidant potentials. Thus, it can be used as potential free radical scavenger. Silver particles have tremendous applications in the field of diagnostics and therapeutics. To this context, the surface coating of plant metabolite constituents has great potentials. Therefore, the present work has been undertaken to synthesize the AgNPs using leaf extract of medicinal plant, E. scaber, to characterize and access their antioxidant properties. PMID- 26952476 TI - A comparison of gold nanoparticle surface co-functionalization approaches using Polyethylene Glycol (PEG) and the effect on stability, non-specific protein adsorption and internalization. AB - To create clinically useful gold nanoparticle (AuNP) based cancer therapeutics it is necessary to co-functionalize the AuNP surface with a range of moieties; e.g. Polyethylene Glycol (PEG), peptides and drugs. AuNPs can be functionalized by creating either a mixed monolayer by attaching all the moieties directly to the surface using thiol chemistry, or by binding groups to the surface by means of a bifunctional polyethylene glycol (PEG) linker. The linker methodology has the potential to enhance bioavailability and the amount of functional agent that can be attached. While there is a large body of published work using both surface arrangements independently, the impact of attachment methodology on stability, non-specific protein adsorption and cellular uptake is not well understood, with no published studies directly comparing the two most frequently employed approaches. This paper compares the two methodologies by synthesizing and characterizing PEG and Receptor Mediated Endocytosis (RME) peptide co functionalized AuNPs prepared using both the mixed monolayer and linker approaches. Successful attachment of both PEG and RME peptide using the two methods was confirmed using Dynamic Light Scattering, Fourier Transform Infrared Spectroscopy and gel electrophoresis. It was observed that while the 'as synthesized' citrate capped AuNPs agglomerated under physiological salt conditions, all the mixed monolayer and PEG linker capped samples remained stable at 1M NaCl, and were stable in PBS over extended periods. While it was noted that both functionalization methods inhibited non-specific protein attachment, the mixed monolayer samples did show some changes in gel electrophoresis migration profile after incubation with fetal calf serum. PEG renders the AuNP stable in vivo however, studies with MDA-MB-231 and MCF 10A cell lines indicated that functionalization with PEG, blocks cellular uptake. It was observed that co functionalization with RME peptide using both the mixed monolayer and PEG linker methods greatly enhanced cellular internalization compared to PEG capped AuNPs. PMID- 26952478 TI - One pot phytosynthesis of gold nanoparticles using Genipa americana fruit extract and its biological applications. AB - In this article, rapid one pot synthesis of gold nanoparticles (GNPs) using an eco-friendly extract of Genipa americana L. fruit is described. Electrospray ionization mass spectrometry (ESI-MS) and Fourier transform infrared (FTIR) spectroscopic studies demonstrated that small molecules such as genipin, genipaol, geniposide and ranolazine can act as reducer as well as stabilizers. The monodispersed, spherical GNPs were further characterized by UV-vis spectroscopy at lambdamax=535 nm, transmission electron microscopy (TEM), dynamic light scattering (DLS) and X-ray diffraction (XRD) analysis. This synthetic approach offers a greener and alternate route to the preparation of GNPs free from toxic chemical components and stable for 6-7 months under room temperature. The green synthesized GNPs showed weak antioxidant efficacy against 1,1-diphenyl 2-picrylhydrazyl and no cytotoxicity against A-549 and HeLa human cancer cell lines, from lung and cervix. This study opens a new industrial scope of G. americana fruit in nanoscience and as surface modified GNPs can be developed into a successful drug carrier for future pharmaceutical products. PMID- 26952479 TI - Aminated polyethersulfone-silver nanoparticles (AgNPs-APES) composite membranes with controlled silver ion release for antibacterial and water treatment applications. AB - The present study reports the antibacterial disinfection properties of a series of silver nanoparticle (AgNP) immobilized membranes. Initially, polyethersulfone (PES) was functionalized through the introduction of amino groups to form aminated polyethersulfone (NH2-PES, APES). AgNPs were then coordinately immobilized on the surface of the APES composite membrane to form AgNPs-APES. The properties of the obtained membrane were examined by FT-IR, XPS, XRD, TGA, ICP OES and SEM-EDAX analyses. These structural characterizations revealed that AgNPs ranging from 5 to 40 nm were immobilized on the surface of the polymer membrane. Antibacterial tests of the samples showed that the AgNPs-APES exhibited higher activity than the AgNPs-PES un-functionalized membrane. Generally, the AgNPs-APES 1 cm * 3 cm strip revealed a four times longer life than the un-functionalized AgNPs polymer membranes. The evaluation of the Ag(+) leaching properties of the obtained samples indicated that approximately 30% of the AgNPs could be retained, even after 12 days of operation. Further analysis indicated that silver ion release can be sustained for approximately 25 days. The present study provides a systematic and novel approach to synthesize water treatment membranes with controlled and improved silver (Ag(+)) release to enhance the lifetime of the membranes. PMID- 26952480 TI - The effect of casting and masticatory simulation on strain and misfit of implant supported metal frameworks. AB - The influence of casting and masticatory simulation on marginal misfit and strain in multiple implant-supported prostheses was evaluated. Three-unit screw retained fixed dental prosthesis (FDP) and screw retained full-arch fixed dental prosthesis (FAFDP) frameworks were made using calcinable or overcasted cylinders on conical dental implant abutment. Four groups were obtained according to the cylinder and prosthesis type (n=10). Frameworks were casted in CoCr alloy and subjected to strain gauge analyses and marginal misfit measurements before and after 10(6) mechanical cycles (2 Hz/280 N). Results were submitted to ANOVA, Tukey's HSD and Pearson correlation test (alpha=0.05). No difference was found on misfit among all groups and times (p>0.05). Overcasted frameworks showed higher strain than the calcinable ones (FDP - Initial p=0.0047; Final p=0.0004; FAFDP - Initial p=0.0476; Final p=0.0115). The masticatory simulation did not influence strain (p>0.05). No correlation was observed between strain and misfit (r=0.24; p>0.05). In conclusion, the marginal misfit value in the overcasted full-arch frameworks was higher than clinical acceptable data. It proved that overcasted method is not an ideal method for full-arch prosthesis. Overcasted frameworks generate higher strain upon the system. The masticatory simulation had no influence on misfit and strain of multiple prostheses. PMID- 26952481 TI - Cytotoxic characteristics of biodegradable EW10X04 Mg alloy after Nd coating and subsequent heat treatment. AB - Porous Mg scaffolds are considered as potential bone growth promoting materials. Unfortunately, the high rate of biocorrosion inherent to Mg alloys may cause a premature loss of mechanical strength, excessive evolution of hydrogen gas, and a rapidly shifting surface topography, all of which may hinder the ability of native cells to attach and grow on the implant surface. Here we investigated the cell cytotoxicity effects during corrosion of a novel magnesium alloy, EW10X04 (Mg-1.2%Nd-0.5%Y-0.5%Zr-0.4%Ca), following diffusion coating (DC) and heat treatment to reduce the corrosion rate. Cells were exposed either to corrosion products or to the corroding scaffold surface, in vitro. The microstructure characterization of the scaffold surface was carried out by scanning electron microscopy (SEM) equipped with a Noran energy dispersive spectrometer (EDS). Phase analyses were obtained by X-ray diffraction (XRD). We found that cell viability, growth, and adhesion were all improved when cultured on the EW10X04+DC surface or under corrosion product extracts due to lower corrosion rates relative to the EW10X04 control samples. It is therefore believed that the tested alloy after Nd coating and heat treatment may introduce a good balance between its biodegradation characteristics and cytotoxic effects towards cells. PMID- 26952482 TI - Electrospun nanofiber reinforcement of dental composites with electromagnetic alignment approach. AB - Polymethylmethacrylate (PMMA) is commonly used as a base acrylic denture material with benefits of rapid and easy handling, however, when it is used in prosthetic dentistry, fracturing or cracking problems can be seen due to the relatively low strength issues. Besides, acrylic resin is the still prominent material for denture fabrication due to its handy and low cost features. Numerous proposed fillers that are used to produce PMMA composites, however electrospun polyvinylalcohol (PVA) nanofiber fillers for production of PMMA composite resins are not studied as much as the others. The other focus of the practice is to compare both mechanical properties and efficiency of aligned fibers versus non aligned PVA nanofibers in PMMA based dental composites. Field-controlled electrospinning system is manufactured and provided good alignment in lab scale as one of contributions. Some novel auxiliary electrodes in controlled structure are augmented to obtain different patterns of alignment with a certain range of fiber diameters. Scanning electron microscopy is used for physical characterization to determine the range of fiber diameters. Non-woven fiber has no unique pattern due to chaotic nature of electrospinning process, but aligned fibers have round pattern or crossed lines. These produced fibers are structured as layer-by-layer form with different features, and these features are used in producing PMMA dental composites with different volume ratios. The maximum flexural strength figure shows that fiber load by weight of 0.25% w/w and above improves in the maximum level. As a result, mechanical properties of PMMA dental composites are improved by using PVA nanofibers as a filler, however the improvement was higher when aligned PVA nanofibers are used. The maximum values were 5.1 MPa (flexural strength), 0.8 GPa (elastic modulus), and 170 kJ/m(3) (toughness) in three-point bending test. In addition to the positive results of aligned and non-aligned nanofibers it was found that they both have a non-toxic feature. PMID- 26952483 TI - Thiolated carboxymethyl dextran as a nanocarrier for colon delivery of hSET1 antisense: In vitro stability and efficiency study. AB - Gene therapy is an optimistic approach in cancer treatment. However, for efficient delivery of gene materials, designing an appropriate vector is necessary. Polyelectrolyte complexes (PECs) of chitosan and dextran could be considered a proper nanoparticulate carrier for sensitive biomaterials. In this study, PECs of chitosan and thiolated dextran were used as either an injectable or oral gene delivery system. hSET1 antisense was loaded into the PECs to suppress proliferation of colon cancer cell line. The prepared nanoparticles have ~115nm diameter size and positive zeta potential with high mucoadhesion properties. They are able to protect antisense from degradation in serum and biorelevant fluids (FaSSIF and FaSSGF). Furthermore, prepared nanoparticles demonstrated superior cellular penetration and inhibitory effect on SW480 colon cancer cell proliferation. All nanoparticles significantly down regulated hSET1 in comparison with naked antisense. It can be concluded that thiolated PECs have potential use for injectable or oral delivery of nucleic acids such as antisense. PMID- 26952484 TI - Bioactive apatite incorporated alginate microspheres with sustained drug-delivery for bone regeneration application. AB - The strontium-substituted hydroxyapatite microspheres (SrHA) incorporated alginate composite microspheres (SrHA/Alginate) were prepared via adding SrHA/alginate suspension dropwise into calcium chloride solution, in which the gel beads were formed by means of crosslinking reaction. The structure, morphology and in vitro bioactivity of the composite microspheres were studied by using XRD, SEM and EDS methods. The biological behaviors were characterized and analyzed through inductively coupled plasma optical emission spectroscopy (ICP OES), CCK-8, confocal laser microscope and ALP activity evaluations. The experimental results indicated that the synthetic SrHA/Alginate showed similar morphology to the well-known alginate microspheres (Alginate) and both of them possessed a great in vitro bioactivity. Compared with the control Alginate, the SrHA/Alginate enhanced MC3T3-E1 cell proliferation and ALP activity by releasing osteoinductive and osteogenic Sr ions. Furthermore, vancomycin was used as a model drug to investigate the drug release behaviors of the SrHA/Alginate, Alginate and SrHA. The results suggested that the SrHA/Alginate had a highest drug-loading efficiency and best controlled drug release properties. Additionally, the SrHA/Alginate was demonstrated to be pH-sensitive as well. The increase of the pH value in phosphate buffer solution (PBS) accelerated the vancomycin release. Accordingly, the multifunctional SrHA/Alginate can be applied in the field of bioactive drug carriers and bone filling materials. PMID- 26952485 TI - Fabrication and detection of tissue engineered bone aggregates based on encapsulated human ADSCs within hybrid calcium alginate/bone powder gel-beads in a spinner flask. AB - Traditional treatment for bone diseases limits their clinical application due to undesirable host immune rejection, limited donator sources and severe pain and suffering for patients. Bone tissue engineering therefore is expected to be a more effective way in treating bone diseases. In the present study, hybrid calcium alginate/bone powder gel-beads with a uniform size distribution, good biocompatibility and osteoinductive capability, were prepared to be used as an in vitro niche-like matrix. The beads were optimized using 2.5% (w/v) sodium alginate solution, 4.5% (w/v) CaCl2 solution and 5.0mg/mL bone powder using an easy-to-use method. Human ADSCs were cultured and induced into chondrocytes and osteoblasts, respectively. The cells were characterized by histological staining showing the ADSCs were able to maintain their characteristic morphology with multipotent differentiation ability. ADSCs at density of 5 * 10(6)cells/mL were encapsulated into the gel-beads aiming to explore cell expansion under different conditions and the osteogenic induction of ADSCs was verified by specific staining. Results demonstrated that the encapsulated ADSCs expanded 5.6 folds in 10 days under dynamic condition via spinner flask, and were able to differentiate into osteoblasts (OBs) with extensive mineralized nodules forming the bone aggregates over 3 weeks postosteogenic induction. In summary, hybrid gel-beads encapsulating ADSCs are proved to be feasible as a new method to fabricate tissue engineered bone aggregation with potential to treat skeletal injury in the near future. PMID- 26952486 TI - New Coll-HA/BT composite materials for hard tissue engineering. AB - The integration of ceramic powders in composite materials for bone scaffolds can improve the osseointegration process. This work was aimed to the synthesis and characterization of new collagen-hydroxyapatite/barium titanate (Coll-HA/BT) composite materials starting from barium titanate (BT) nanopowder, hydroxyapatite (HA) nanopowder and collagen (Coll) gel. BT nanopowder was produced by combining two wet-chemical approaches, sol-gel and hydrothermal methods. The resulting materials were characterized in terms of phase composition and microstructure by X-ray diffraction, Raman spectroscopy, scanning electron microscopy and transmission electron microscopy. Moreover, the biocompatibility and bioactivity of the composite materials were assessed by in vitro tests. The synthesized BT particles exhibit an average size of around 35 nm and a spherical morphology, with a pseudo-cubic or tetragonal symmetry. The diffraction spectra of Coll-HA and Coll-HA/BT composite materials indicate a pronounced interaction between Col and the mineral phases, meaning a good mineralization of Col fibres. As well, the in vitro tests highlight excellent osteoinductive properties for all biological samples, especially for Coll-HA/BT composite materials, fact that can be attributed to the ferromagnetic properties of BT. PMID- 26952487 TI - Probing the interaction of a new synthesized CdTe quantum dots with human serum albumin and bovine serum albumin by spectroscopic methods. AB - A novel CdTe quantum dots (QDs) were prepared in aqueous phase via a facile method. At first, poly (acrylic amide) grafted onto sodium alginate (PAAm-g-SA) were successfully synthesized and then TGA capped CdTe QDs (CdTe-TGA QDs) were embed into it. The prepared CdTe-PAAm-g-SA QDs were optimized and characterized by transmission electron microscopy (TEM), thermo-gravimetric (TG) analysis, Fourier transform infrared (FT-IR), UV-vis and fluorescence spectroscopy. The characterization results indicated that CdTe-TGA QDs, with particles size of 2.90 nm, were uniformly dispersed on the chains of PAAm-g-SA biopolymer. CdTe-PAAm-g SA QDs also exhibited excellent UV-vis absorption and high fluorescence intensity. To explore biological behavior of CdTe-PAAm-g-SA QDs, the interactions between CdTe-PAAm-g-SA QDs and human serum albumin (HSA) (or bovine serum albumin (BSA)) were investigated by cyclic voltammetry, FT-IR, UV-vis, and fluorescence spectroscopic. The results confirmed the formation of CdTe-PAAm-g-SA QDs-HSA (or BSA) complex with high binding affinities. The thermodynamic parameters (DeltaG<0, DeltaH<0 and DeltaS<0) were indicated that binding reaction was spontaneous and van der Waals interactions and hydrogen-bond interactions played a major role in stabilizing the CdTe-PAAm-g-SA QDs-HSA (or BSA) complexes. The binding distance between CdTe-PAAm-g-SA QDs and HSA (or BSA)) was calculated about 1.37 nm and 1.27 nm, respectively, according to Forster non-radiative energy transfer theory (FRET). Analyzing FT-IR spectra showed that the formation of QDs-HSA and QDs-BSA complexes led to conformational changes of the HSA and BSA proteins. All these experimental results clarified the effective transportation and elimination of CdTe-PAAm-g-SA QDs in the body by binding to HSA and BSA, which could be a useful guideline for the estimation of QDs as a drug carrier. PMID- 26952488 TI - Fiber from ramie plant (Boehmeria nivea): A novel suture biomaterial. AB - The quest for developing an ideal suture material prompted our interest to develop a novel suture with advantageous characters to market available ones. From natural origin only silk, cotton and linen fibers are presently available in market as non-absorbable suture biomaterials. In this study, we have developed a novel, cost-effective, and biocompatible suture biomaterial from ramie plant, Boehmeria nivea fiber. Field emission scanning electron microscopy (FE-SEM), energy-dispersive X-ray spectroscopy (EDX), attenuated total reflection Fourier transform infrared spectroscopy (ATR-FTIR) and thermo gravimetric analysis (TGA) results revealed the physicochemical properties of raw and degummed ramie fiber, where the former one showed desirable characteristics for suture preparation. The braided multifilament ramie suture prepared from degummed fiber exhibited excellent tensile strength. The suture found to be biocompatible towards human erythrocytes and nontoxic to mammalian cells. The fabricated ramie suture exhibited significant antibacterial activity against Escherichia coli, Bacillus subtilis and Staphylococcus aureus; which can be attributed to the inherent bacteriostatic ability of ramie plant fiber. In vivo wound closure efficacy was evaluated in adult male wister rats by suturing the superficial wound incisions. Within seven days of surgery the wound got completely healed leaving no rash and scar. The role of the ramie suture in complete wound healing was supported by the reduced levels of serum inflammatory mediators. Histopathology studies confirmed the wound healing ability of ramie suture, as rapid synthesis of collagen, connective tissue and other skin adnexal structures were observed within seven days of surgery. Tensile properties, biocompatibility and wound closure efficacy of the ramie suture were comparable with market available BMSF suture. The outcome of this study can drive tremendous possibility for the utilization of ramie plant fiber for various biomedical applications. PMID- 26952489 TI - Enhanced bone formation in electrospun poly(L-lactic-co-glycolic acid)-tussah silk fibroin ultrafine nanofiber scaffolds incorporated with graphene oxide. AB - To engineer bone tissue, it is necessary to provide a biocompatible, mechanically robust scaffold. In this study, we fabricated an ultrafine nanofiber scaffold by electrospinning a blend of poly(L-lactic-co-glycolic acid), tussah silk fibroin, and graphene oxide (GO) and characterized its morphology, biocompatibility, mechanical properties, and biological activity. The data indicate that incorporation of 10 wt.% tussah silk and 1 wt.% graphene oxide into poly(L-lactic co-glycolic acid) nanofibers significantly decreased the fiber diameter from 280 to 130 nm. Furthermore, tussah silk and graphene oxide boosted the Young's modulus and tensile strength by nearly 4-fold and 3-fold, respectively, and significantly enhanced adhesion, proliferation in mouse mesenchymal stem cells and functionally promoted biomineralization-relevant alkaline phosphatase (ALP) and mineral deposition. The results indicate that composite nanofibers could be excellent and versatile scaffolds for bone tissue engineering. PMID- 26952490 TI - Preparation and characterization of Ganoderma lucidum spores-loaded alginate microspheres by electrospraying. AB - Ganoderma lucidum spores (GLSs), popular functional food in preventive medicine, are susceptible to oxidative and acidic degradation during processing, storage and oral administration, resulting in the loss of sensory and nutritional qualities. The main objective of the study was to encapsulate the GLS in order to fully preserve the bioactivity of the ingredients as well as providing controlled and targeted delivery. Electrospraying was applied to prepare GLS-Alginate (GLS/A) micro beads in the current study. The size of GLS/A beads can be tailored by varying the applied voltage and drying processes. pH responsive release profiles of GLS/A beads were revealed from in vitro study in a simulated gastrointestinal environment: no release of GLS encapsulated beads in the simulated gastric fluid (pH of 1.8) was observed; while a rapid, size dependent release was found in the simulated intestinal solution (pH of 7.5). The release from smaller beads (e.g. 600 MUm) was 1.5 times faster than that of larger beads (e.g. 2000 MUm). In addition, the GLS release from freeze dried beads was almost 3 times faster than those of air and vacuum dried beads in the first 90 min. The present results illustrate the potential to protect GLS by encapsulation using electrospraying to achieve the controlled release of GLS ingredients. This will pave the way to develop effective GLS products with desirable bioactive components for healthcare applications. PMID- 26952491 TI - Effect of ZnO morphology on affecting bactericidal property of ultra high molecular weight polyethylene biocomposite. AB - Bacterial infection of implants can be controlled by selective trapping of bacteria, followed with consequent killing by targeted antibacterial agents. Herein, the role of various ZnO morphologies, viz. micro-rods (R), nanoparticles (NP), and micro-disks (D) on antibacterial efficacy of ZnO via release of Zn(2+) and H2O2 is assessed, both as isolated powders and via incorporating them in cytocompatible ultra high molecular weight polyethylene (UHMWPE). Though ZnO is antibacterial, interestingly, all ZnO morphologies elicited a supportive growth of gram-negative bacteria (Escherichia coli) in culture medium (until 28-35 MUg/ml). But, all ZnO morphologies did elicit bactericidal effect on gram positive bacteria (Staphylococcus aureus or Staphylococcus epidermidis) both in culture medium (for 0-2.5 MUg/ml) or when incorporated (5-20 wt.%) into UHMWPE. The bactericidal mechanisms were quantified for various ZnO morphologies via: (i) H2O2 production, (ii) Zn(2+) release, and (iii) the presence of surface oxygen vacancies. On one hand, where only ZnO(NP) elicited release of H2O2 in the absence of light, maximum Zn(2+) release was elicited by ZnO(D). Interestingly, when ZnO is incorporated as reinforcement (5-20 wt.%), its antibacterial action against E. coli was vividly observed due to selective proliferation of bacteria only on friendly UHMWPE matrix. Hence, luring bacteria on affable UHMWPE surface can be complemented with their targeted killing by ZnO present in composite. PMID- 26952492 TI - In situ elaboration of a binary Ti-26Nb alloy by selective laser melting of elemental titanium and niobium mixed powders. AB - Ti-Nb alloys are excellent candidates for biomedical applications such as implantology and joint replacement because of their very low elastic modulus, their excellent biocompatibility and their high strength. A low elastic modulus, close to that of the cortical bone minimizes the stress shielding effect that appears subsequent to the insertion of an implant. The objective of this study is to investigate the microstructural and mechanical properties of a Ti-Nb alloy elaborated by selective laser melting on powder bed of a mixture of Ti and Nb elemental powders (26 at.%). The influence of operating parameters on porosity of manufactured samples and on efficacy of dissolving Nb particles in Ti was studied. The results obtained by optical microscopy, SEM analysis and X-ray microtomography show that the laser energy has a significant effect on the compactness and homogeneity of the manufactured parts. Homogeneous and compact samples were obtained for high energy levels. Microstructure of these samples has been further characterized. Their mechanical properties were assessed by ultrasonic measures and the Young's modulus found is close to that of classically elaborated Ti-26 Nbingot. PMID- 26952493 TI - High-permeability functionalized silicone magnetic microspheres with low autofluorescence for biomedical applications. AB - Functionalized magnetic microspheres are widely used for cell separations, isolation of proteins and other biomolecules, in vitro diagnostics, tissue engineering, and microscale force spectroscopy. We present here the synthesis and characterization of a silicone magnetic microsphere which can be produced in diameters ranging from 0.5 to 50 MUm via emulsion polymerization of a silicone ferrofluid precursor. This bottom-up approach to synthesis ensures a uniform magnetic concentration across all sizes, leading to significant advances in magnetic force generation. We demonstrate that in a size range of 5-20 MUm, these spheres supply a full order of magnitude greater magnetic force than leading commercial products. In addition, the unique silicone matrix exhibits autofluorescence two orders of magnitude lower than polystyrene microspheres. Finally, we demonstrate the ability to chemically functionalize our silicone microspheres using a standard EDC reaction, and show that our folate functionalized silicone microspheres specifically bind to targeted HeLa and Jurkat cells. These spheres show tremendous potential for replacing magnetic polystyrene spheres in applications which require either large magnetic forces or minimal autofluorescence, since they represent order-of-magnitude improvements in each. In addition, the unique silicone matrix and proven biocompatibility suggest that they may be useful for encapsulation and targeted delivery of lipophilic pharmaceuticals. PMID- 26952494 TI - Surface and liquid-crystalline properties of FmHnFm triblock semifluorinated n alkanes. AB - A series of triblock semifluorinated n-alkanes of the general formula: F(CF2)m(CH2)n(CF2)mF, (in short FmHnFm), where m=10, 12, and n=6, 8, and 12 have been synthesized and employed for liquid crystalline studies and Langmuir monolayer characterization. Differential scanning calorimetry (DSC) measurements together with texture observation with polarizing microscope (POM) revealed the presence of liquid crystalline smectic phases for all the investigated homologs. The behavior of the studied molecules spread at the free water surface has also been investigated. Our results show for the first time that these unusual film forming materials, which are completely hydrophobic in nature and do not possess any polar group in their structure, are surface active and form insoluble (Langmuir) monolayers at the air/water interface. Due to the fact that these molecules are chemically inert and, similar to the semifluorinated diblocks, are not toxic, they may be destined for biomedical uses as gas carriers and contrast agents, as well as in drug delivery systems. PMID- 26952495 TI - The control of cell orientation using biodegradable alginate fibers fabricated by near-field electrospinning. AB - For spatially controlling cell alignment, near field electrospinning (NFES) was developed to direct-write alginate fiber patterns. Compared to randomly electrospun fibers, NFES fibers guided the extension of HEK 293T cells and the levels of cell alignment increased with decreasing fiber distances. However, these guiding fibers were unfavorable for cell adhesion and limited cell growth. To preserve cell alignment ability and improve biocompatibility, the stability of patterned alginate fibers was adjusted by regulating the level of ion crosslinking. These partially crosslinked NFES fibers demonstrated parallel line patterns in the initial stage while gradually degraded with time. The reduction of fiber density increased the available area for cell growth and enhanced cell viability. On the other hand, aligned cells were still found on these degraded patterns, suggesting that cell morphologies were mainly guided during cell seeding. This dynamically controlled fiber pattern system fulfilled the need of controlling cell orientation and biocompatibility, thus was potential to modify scaffold surfaces for tissue engineering application. PMID- 26952496 TI - PNIPAAM modified mesoporous hydroxyapatite for sustained osteogenic drug release and promoting cell attachment. AB - This work presented a sustained release system of simvastatin (SIM) based on the mesoporous hydroxyapatite (MHA) capped with poly(N-isopropylacrylamide) (PNIPAAM). The MHA was prepared by using cetyltrimethylammonium bromide (CTAB) as a template and the modified PNIPAAM layer on the surface of MHA was fabricated through surface-initiated atom transfer radical polymerization (SI-ATRP). The SIM loaded MHA-PNIPAAM showed a sustained release of SIM at 37 degrees C over 16 days. The bone marrow mesenchymal stem cell (BMSC) proliferation was assessed by cell counting kit-8 (CCK-8) assay, and the osteogenic differentiation was evaluated by alkaline phosphatase (ALP) activity and Alizarin Red staining. The release profile showed that the release of SIM from MHA-SIM-PNIPAAM lasted 16 days and the cumulative amount of released SIM was almost seven-fold than MHA SIM. Besides, SIM loaded MHA-PNIPAAM exhibited better performance on cell proliferation, ALP activity, and calcium deposition than pure MHA due to the sustained release of SIM. The quantity of ALP in MHA-SIM-PNIPAAM group was more than two fold than pure MHA group at 7 days. Compared to pure MHA, better BMSC attachment on PNIPAAM modified MHA was observed using fluorescent microscopy, indicating the better biocompatibility of MHA-PNIPAAM. PMID- 26952497 TI - Chemically crosslinked nanogels of PEGylated poly ethyleneimine (l-histidine substituted) synthesized via metal ion coordinated self-assembly for delivery of methotrexate: Cytocompatibility, cellular delivery and antitumor activity in resistant cells. AB - Self-assembled nanogels were engineered by forming Zn(2+)-coordinated micellar templates of PEGylated poly ethyleneimine (PEG-g-PEI), chemical crosslinking and subsequent removal of the metal ion. Creation of stable micellar templates is a crucial step for preparing the nanogels. To this aim, imidazole moieties were introduced to the polymer by Fmoc-l-histidine using carbodiimide chemistry. It was hypothesized the nanogels loaded with methotrexate (MTX), a chemotherapeutic agent, circumvent impaired carrier activity in HepG2 cells (MTX-resistant hepatocellular carcinoma). So, the nanogels were post-loaded with MTX and characterized by (1)H-NMR, FTIR, dynamic light scattering-zeta potential, atomic force microscopy, and drug release experiments. Cellular uptake and the antitumor activity of MTX-loaded nanogels were investigated by flow cytometry and MTT assay. Discrete, spherical and uniform nanogels, with sizes about 77-83 nm and a relatively high drug loading (54 +/- 4% w/w), showed a low polydispersity and neutral surface charges. The MTX-loaded nanogels, unlike empty nanogels, lowered viability of HepG2 cells; the nanogels demonstrated cell-cycle arrest and apoptosis comparably higher than MTX as free drug that was shown to be through i) cellular uptake of the nanogels by clathrin-mediated transport and ii) endosomolytic activity of the nanogels in HepG2 cells. These findings indicate the potential antitumor application of this preparation, which has to be investigated in-vivo. PMID- 26952498 TI - Influence of non-thermal TiCl4/Ar+O2 plasma-assisted TiOx based coatings on the surface of polypropylene (PP) films for the tailoring of surface properties and cytocompatibility. AB - The superior bulk properties (corrosion resistance, high strength to weight ratio, relatively low cost and easy processing) of hydrocarbon based polymers such as polypropylene (PP) have contributed significantly to the development of new biomedical applications such as artificial organs and cell scaffolds. However, low cell affinity is one of the main draw backs for PP due to its poor surface properties. In tissue engineering, physico-chemical surface properties such as hydrophilicity, polar functional groups, surface charge and morphology play a crucial role to enrich the cell proliferation and adhesion. In this present investigation TiOx based biocompatible coatings were developed on the surface of PP films via DC excited glow discharge plasma, using TiCl4/Ar+O2 gas mixture as a precursor. Various TiOx-based coatings are deposited on the surface of PP films as a function of discharge power. The changes in hydrophilicity of the TiOx/PP film surfaces were studied using contact angle analysis and surface energy calculations by Fowke's approximation. X-ray photo-electron spectroscopy (XPS) was used to investigate the surface chemical composition of TiOx/PP films. The surface morphology of the obtained TiOx/PP films was investigated by scanning electron and transmission electron microscopy (SEM &TEM). Moreover, the surface topography of the material was analyzed by atomic force microscopy (AFM). The cytocompatibility of the TiOx/PP films was investigated via in vitro analysis (cell viability, adhesion and cytotoxicity) using NIH3T3 (mouse embryonic fibroblast) cells. Furthermore the antibacterial activities of TiOx/PP films were also evaluated against two distinct bacterial models namely Gram positive Staphylococcus aureus (S.aureus) and Gram negative Escherichia coli DH5alpha. (E.coli) bacteria. XPS results clearly indicate the successful incorporation of TiOx and oxygen containing polar functional groups on the surface of plasma treated PP films. Moreover the surface of modified PP films exhibited nano structured morphology, as confirmed by SEM, TEM and AFM. The physico-chemical changes have improved the hydrophilicity of the PP films. The in-vitro analysis clearly confirms that the TiOx coated PP films performs as good as the standard tissue culture plates and also are unlikely to impact the bacterial cell viability. PMID- 26952499 TI - ZnO nanopellets have selective anticancer activity. AB - This research work presents the synthesis of ZnO nanopellets (ZNPs) by low temperature hydrothermal approach and evaluation of their antibacterial activity, cytotoxicity in vitro and in vivo. Structural and morphological studies conducted on the sample reveal hexagonal ZNPs in the size range of 250-500 nm. Surface area measurements showed high porosity of the sample compared to conventional ZnO nanoparticles. Antimicrobial studies revealed their bactericidal nature against both Gram-negative and Gram-positive bacteria. Furthermore, to better understand the parameters that affect the interactions between our ZNPs and mammalian cells, and thus their biocompatibility, we have examined the impact of cell culture conditions as well as of material properties on cytotoxicity by DPPH, blood hemolysis and MTT assay. The results showed good antioxidant capacity and biocompatibility of ZNPs at higher concentrations. MTT assay revealed the anticancer activity of ZNPs against prostate and breast cancer cell lines. Acute toxicity tests on Swiss albino mice showed no evident toxicity over a 14 days period. PMID- 26952500 TI - Biomaterial-based regional chemotherapy: Local anticancer drug delivery to enhance chemotherapy and minimize its side-effects. AB - Since the majority of anticancer pharmacological agents affect not only cancer tissue but also normal cells, chemotherapy is usually accompanied with severe side effects. Regional chemotherapy, as the alternative version of conventional treatment, leads to the enhancement of the therapeutic efficiency of anticancer drugs and, simultaneously, reduction of toxic effects to healthy tissues. This paper provides an insight into different approaches of local delivery of chemotherapeutics, such as the injection of anticancer agents directly into tumor tissue, the use of injectable in situ forming drug carriers or injectable platforms in a form of implants. The wide range of biomaterials used as reservoirs of anticancer drugs is described, i.e. poly(ethylene glycol) and its copolymers, polyurethanes, poly(lactic acid) and its copolymers, poly(E caprolactone), polyanhydrides, chitosan, cellulose, cyclodextrins, silk, conducting polymers, modified titanium surfaces, calcium phosphate based biomaterials, silicone and silica implants, as well as carbon nanotubes and graphene. To emphasize the applicability of regional chemotherapy in cancer treatment, the commercially available products approved by the relevant health agencies are presented. PMID- 26952501 TI - Linear-dendritic block copolymer for drug and gene delivery. AB - Dendrimers as a new class of polymeric materials have a highly ordered branched structure, exact molecular weight, multivalency and available internal cavities, which make them extensively used in biology and drug-delivery. Concurrent with the development of dendrimers, much more attention is drawn to a novel block copolymer which combines linear chains with dendritic macromolecules, the linear dendritic block copolymer (LDBC). Because of the different solubility of the contrasting regions, the amphiphilic LDBCs could self-assemble to form aggregates with special core-shell structures which exhibit excellent properties different from traditional micelles, such as lower critical micelle concentration, prolonged circulation in the bloodstream, better biocompatibility, and lower toxicity. The present review briefly describes the type of LDBC, the self assembly behavior in solution, and the application in delivery system including the application as drug carriers and gene vectors. The interactions between block copolymers and drugs are also summarized to better understand the release mechanism of drugs from the linear-dendritic block copolymers. PMID- 26952502 TI - Commercially pure titanium (cp-Ti) versus titanium alloy (Ti6Al4V) materials as bone anchored implants - Is one truly better than the other? AB - Commercially pure titanium (cp-Ti) and titanium alloys (typically Ti6Al4V) display excellent corrosion resistance and biocompatibility. Although the chemical composition and topography are considered important, the mechanical properties of the material and the loading conditions in the host have, conventionally, influenced material selection for different clinical applications: predominantly Ti6Al4V in orthopaedics while cp-Ti in dentistry. This paper attempts to address three important questions: (i) To what extent do the surface properties differ when cp-Ti and Ti6Al4V materials are manufactured with the same processing technique?, (ii) Does bone tissue respond differently to the two materials, and (iii) Do bacteria responsible for causing biomaterial associated infections respond differently to the two materials? It is concluded that: (i) Machined cp-Ti and Ti6Al4V exhibit similar surface morphology, topography, phase composition and chemistry, (ii) Under experimental conditions, cp-Ti and Ti6Al4V demonstrate similar osseointegration and biomechanical anchorage, and (iii) Experiments in vitro fail to disclose differences between cp Ti and Ti6Al4V to harbour Staphylococcus epidermidis growth. No clinical comparative studies exist which could determine if long-term, clinical differences exist between the two types of bulk materials. It is debatable whether cp-Ti or Ti6Al4V exhibit superiority over the other, and further comparative studies, particularly in a clinical setting, are required. PMID- 26952503 TI - Humic acids: Structural properties and multiple functionalities for novel technological developments. AB - Humic acids (HAs) are macromolecules that comprise humic substances (HS), which are organic matter distributed in terrestrial soil, natural water, and sediment. HAs differ from the other HS fractions (fulvic acid and humins) in that they are soluble in alkaline media, partially soluble in water, and insoluble in acidic media. Due to their amphiphilic character, HAs form micelle-like structures in neutral to acidic conditions, which are useful in agriculture, pollution remediation, medicine and pharmaceuticals. HAs have undefined compositions that vary according to the origin, process of obtainment, and functional groups present in their structures, such as quinones, phenols, and carboxylic acids. Quinones are responsible for the formation of reactive oxygen species (ROS) in HAs, which are useful for wound healing and have fungicidal/bactericidal properties. Phenols and carboxylic acids deprotonate in neutral and alkaline media and are responsible for various other functions, such as the antioxidant and anti-inflammatory properties of HAs. In particular, the presence of phenolic groups in HAs provides antioxidant properties due to their free radical scavenging capacity. This paper describes the main multifunctionalities of HAs associated with their structures and properties, focusing on human health applications, and we note perspectives that may lead to novel technological developments. To the best of our knowledge, this is the first review to address this topic from this approach. PMID- 26952504 TI - Rebound Growth of Infantile Hemangiomas After Propranolol Therapy. AB - BACKGROUND AND OBJECTIVES: Propranolol is first-line therapy for problematic infantile hemangiomas (IHs). Rebound growth after propranolol discontinuation is noted in 19% to 25% of patients. Predictive factors for rebound are not completely understood and may alter the management approach. The goal of the study was to describe a cohort of patients with IHs treated with propranolol and to identify predictors for rebound growth. METHODS: A multicenter retrospective cohort study was conducted in patients with IHs treated with propranolol. Patient demographic characteristics, IH characteristics, and specifics of propranolol therapy were obtained. Episodes of rebound growth were recorded. Patients' responses to propranolol were evaluated through a visual analog scale. RESULTS: A total of 997 patients were enrolled. The incidence of rebound growth was 231 of 912 patients (25.3%). Mean age at initial rebound was 17.1 months. The odds of rebound among those who discontinued therapy at <9 months was 2.4 (odds ratio [OR]: 2.4; 95% confidence interval [CI]: 1.3 to 4.5; P = .004) compared with those who discontinued therapy between 12 to 15 months of life. Female gender, location on head and neck, segmental pattern, and deep or mixed skin involvement were associated with rebound on univariate analysis. With multivariate analysis, only deep IHs (OR: 3.3; 95% CI: 1.9 to 6.0; P < .001) and female gender (OR: 1.7; 95% CI: 1.1 to 2.6; P = .03) were associated. Of those with rebound growth, 83% required therapeutic modification including 62% of patients with modifications in their propranolol therapy. CONCLUSIONS: Rebound growth occurred in 25% of patients, requiring modification of systemic therapy in 15%. Predictive factors for rebound growth included age of discontinuation, deep IH component, and female gender. Patients with these predictive factors may require a prolonged course of therapy. PMID- 26952505 TI - Hemangiomas and beta-Blockers: On the Rebound. PMID- 26952511 TI - RNA-Seq analysis for the potential targets and molecular mechanisms of 17 beta estradiol in squamous cell lung carcinoma. AB - The efficacy of 17 beta-estradiol (E2) was valid in some cancers, while its effects on squamous cell lung carcinoma (SCLC) were still unclear. The aim of our study was to investigate the potential targets and molecular mechanisms of E2 in SCLC cells.Two RNA libraries from human lung carcinoma cells (SK-MES-1) with and without E2 treatment were constructed and sequenced. The differentially expressed genes (DEGs) between cells with or without E2 treatment were identified by cuffdiff software. Hierarchical Clustering Analysis (HCA) was performed for displaying gene expression changes and classification. Furthermore, enrichment analyses of Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene Ontology Biological Process (GO BP) terms were performed through DAVID. The protein-protein interaction (PPI) network was constructed through STRING. Additionally, differentially expressed lncRNAs were also selected by cuffdiff software.Total 129 DEGs including 58 up- and 71 down- regulated genes were obtained. Cancer-related pathways including small cell lung cancer, hypertrophic cardiomyopathy (HCM) and pathways in cancer and biological processes including regulation of phosphorus metabolic process, protein localization and nucleus organization were enriched. The PPI network with 113 nodes and 312 edges was constructed. CASP3, ITGA2, COL4A6, PML and CDC25B were identified as hub nodes which had more interactions with others in the PPI network. Furthermore, eight up regulated and ten down-regulated lncRNAs were selected.CASP3, ITGA2 and Lnc-DLK1 4:31 (one of down-regulated lncRNAs) might play pivotal roles in E2 treated SCNC cells by influencing cell apoptosis, angiogenesis and cell invasion respectively. PMID- 26952510 TI - Systemic Inflammation and Autoimmunity in Women with Chronic Endometritis. AB - PROBLEM: To determine in women with recurrent pregnancy loss (RPL) and/or implantation failure (RIF) the prevalence of chronic endometritis (CE), systemic inflammation and autoimmunity, and whether they relate. METHOD OF STUDY: This retrospective study examined inflammatory (adiponectin, CRP, leptin, and IL6) and autoimmune (total immunoglobulins, ANA, thyroid antibodies, antiphospholipid antibodies) markers in a group of 55 women with RPL/RIF. A diagnosis of CE was reached by endometrial biopsy, demonstrating CD138-positive plasma cells on histology. The prevalence of markers of systemic inflammation and autoimmunity was compared between women with and without CE. RESULTS: Among all RPL/RIF patients, 32.7% demonstrated at least one positive inflammatory marker, 61.8% at least one autoimmune marker, and 45.5% CE. Moreover, CE patients did not differ in systematic inflammatory or autoimmune profiles from those without CE. CONCLUSIONS: Endometritis and elevated inflammatory and autoimmune markers are common in women with RPL/RIF, but endometritis cannot be predicted based on either peripheral inflammatory or autoimmune markers. PMID- 26952506 TI - State of the Art Review: Poverty and the Developing Brain. AB - In the United States, >40% of children are either poor or near-poor. As a group, children in poverty are more likely to experience worse health and more developmental delay, lower achievement, and more behavioral and emotional problems than their more advantaged peers; however, there is broad variability in outcomes among children exposed to similar conditions. Building on a robust literature from animal models showing that environmental deprivation or enrichment shapes the brain, there has been increasing interest in understanding how the experience of poverty may shape the brain in humans. In this review, we summarize research on the relationship between socioeconomic status and brain development, focusing on studies published in the last 5 years. Drawing on a conceptual framework informed by animal models, we highlight neural plasticity, epigenetics, material deprivation (eg, cognitive stimulation, nutrient deficiencies), stress (eg, negative parenting behaviors), and environmental toxins as factors that may shape the developing brain. We then summarize the existing evidence for the relationship between child poverty and brain structure and function, focusing on brain areas that support memory, emotion regulation, and higher-order cognitive functioning (ie, hippocampus, amygdala, prefrontal cortex) and regions that support language and literacy (ie, cortical areas of the left hemisphere). We then consider some limitations of the current literature and discuss the implications of neuroscience concepts and methods for interventions in the pediatric medical home. PMID- 26952512 TI - NF-kappaB/p65 expression before and after treatment in rectal cancer patients undergoing neoadjuvant (chemo)radiotherapy and surgery: prognostic marker for disease progression and survival. AB - Nuclear factor-kappaB (NF-kappaB), especially p65 subunit, has been associated with origin and progression of cancer as well as with the resistance to radiotherapy and chemotherapy in experimental models. The aim of the present study was to determine expression of NF-kappaB/p65 in tumor specimens before and after treatment of rectal cancer patients and to evaluate possible relationship between expression of NF-kappaB/p65 before and after (chemo)radiotherapy, other tumor characteristics and the clinical outcome. Furthermore, NF-kappaB/p65 was studied in relationship to pathologic response to preoperative (chemo)radiotherapy. Fifty patients with rectal cancer undergoing neoadjuvant (chemo)radiotherapy and surgery were included in the study. Pre-treatment rectal cancer specimens were obtained from diagnostic colonoscopy. Post-treatment rectal cancer specimens were obtained from surgically removed part of the rectum with the tumor. NF-kappaB/p65 expression was determined by immunohistochemistry and analysis was performed both in biopsies and in post-treatment tumor samples. Cytoplasmic positivity in tumor cells and nuclear positivity in lymphocytes were detected. High NF-kappaB/p65 positivity in pre-treatment tumor samples was significantly associated with shortened overall survival (OS). Disease-free survival (DFS) tends to be shortened as well. In post-treatment tumor samples, high NF-kappaB/p65 positivity was neither associated with shortened OS nor with shortened DFS. In post-treatment samples residual tumor cells deeply infiltrating the wall of the rectum with high NF-kappaB/p65 expression were found. The cells were linked to significantly worse clinical outcome in terms of shortened OS and DFS. NF-kappaB/p65 positivity did not correlate with pathologic response to preoperative (chemo)radiotherapy. In conclusion, our data suggest that high level of NF-kappaB/p65 subunit may be associated with more aggressive features of the tumor, higher metastatic potential, and shortened overall survival, but it does not correlate with resistance to (chemo)radiotherapy. Consequently, the level of NF-kappaB/p65 may help to select those patients who have poor prognosis and are candidates for more intensive anticancer therapy. For these purposes both pre treatment and post-treatment tumor samples may be used. PMID- 26952513 TI - Serum albumin is a strong predictor of survival in patients with advanced-stage non-small cell lung cancer treated with erlotinib. AB - Molecular targeted therapy based on tyrosine kinase inhibitors (TKI), directed at epidermal growth factor receptor (EGFR) is one of the novel effective agents in management of advanced-stage of Non Small Cell Lung cancer (NSCLC). However several candidate predictors have been extensively studied, apart from activating EGFR gene mutations, no reliable biochemical or molecular predictors of response to erlotinib have been validated. The aim of our retrospective study was to evaluate the association of baseline serum albumin with outcomes in a large cohort of patients with advanced-stage NSCLC treated with erlotinib. Clinical data of 457 patients with locally-advanced (III B) or metastatic stage (IV) NSCLC treated with erlotinib were analysed. Serum samples were collected and the measurement was performed one day before the initiation of erlotinib treatment. Before the treatment initiation, low albumin was (<35 g/l) measured in 37 (8.1%) patients and normal albumin (>= 35 g/l) was measured in 420 (91.9%). The median PFS and OS for patients with low serum albumin was 0.9 and 1.9 months compared to 1.9 and 11.4 months for patients with normal serum albumin (p=0.001 and p<0.001). The multivariate Cox proportional hazards model revealed that EGFR mutation status (HR=2.50; CI: 1.59-3.92; p<0.001) and pretreatment serum albumin (HR=1.73; CI: 1.21-2.47; p=0.003) were significant independent predictive factors for PFS, whereas EGFR mutation status (HR=3.14; CI: 1.70-5.81; p<0.001), stage (HR=1.48; CI: 1.09-2.02; p=0.013), ECOG PS (HR=1.77; CI: 1.37-2.29; p<0.001) and pretreatment serum albumin (HR=4.60; CI: 2.98-7.10; p<0.001) were significant independent predictive factors for OS. In conclusion, the results of present retrospective study indicate that pretreatment hypoalbuminemia is associated with poor outcome of NSCLC patients treated with erlotinib. Based on these results, measuement of serum albumin is an objective laboratory method feasible for estimation of prognosis of patients with advanced-stage NSCLC. PMID- 26952514 TI - Prognostic significance of GRP78/BiP expression in patients with Stage III/IV hypopharyngeal squamous cell carcinoma. AB - The immunoglobulin heavy chain binding protein (BiP)/glucose-regulated protein 78 (GRP78) plays an essential role in the endoplasmic reticulum (ER) stress, and GRP78/BiP is known to be highly expressed in various human neoplasms. The clinicopathological features of GRP78/BiP expression in patients with advanced hypopharyngeal squamous cell carcinoma (HSCC) remain unclear. The aim of this study is to elucidate the prognostic significance of GRP78/BiP for HSCC.A total of 68 patients with advanced HSCC (stage III/IV) were analyzed, and tumor specimens were stained with immunohistochemistry for GRP78/BiP, Ki-67, and microvessel density (MVD), as determined through CD34 and p53 levels. GRP78/BiP was highly expressed in 80.8% (55/68) of all patients. The expression level of GRP78/BiP disclosed no significant relationship with any variables. Multivariate analysis confirmed that low expression of GRP78/BiP was an independent prognostic factor for predicting poor overall survival and progression-free survival in patients with advanced HSCC. The decreasing expression of GRP78/BiP was identified as a significant predictor related to shorter survival duration after surgery for advanced HSCC. Our study suggests that the reduced expression of GRP78/BiP contributes to worse survival for patients with advanced head and neck cancer. PMID- 26952515 TI - Gastrointestinal stromal tumors - quantitative detection of the Ki-67, TPX2, TOP2A, and hTERT telomerase subunit mRNA levels to determine proliferation activity and a potential for aggressive biological behavior. AB - Gastrointestinal stromal tumors (GISTs) have an unpredictable biological potential ranging from benign to malignant. Molecular markers involved in the mechanisms of proliferation and cellular senescence may provide additional information about biological behavior of the tumor. The aim of the present study was to investigate Ki-67, TPX2, TOP2A and hTERT mRNA expression levels in specimens from patients with GISTs to define relationships between proliferation activity and biological potential and progression of the disease. We measured Ki 67, TPX2, TOP2A and hTERT mRNA levels using quantitative real-time reverse transcription PCR (RQ RT PCR). The highest Ki-67, TPX2, TOP2A and hTERT mRNA expression levels were found in the highly proliferative BLs (18 specimens), in comparison with GISTs (137 specimens) and LMSs (9 specimens). Patients with GISTs and adequate information about mitotic activity, tumor size and anatomical site (84 specimens) were divided into two groups - GISTs with benign (29 patients) and with malignant (55 patients) potential. We observed association between higher Ki 67, TPX2 and hTERT mRNA levels and the GISTs with malignant potential. Univariate analysis (57 patients with available follow-up information) of survival (Kaplan Meier curves method) revealed a correlation between higher levels of TPX2, Ki-67 and hTERT markers and shorter event-free survival (EFS) or poorer overall survival (OS). The results demonstrate the importance of quantitative assessment of the proliferation activity in GISTs. Proliferation markers of Ki-67, TPX2, TOP2A and hTERT are suitable markers for detection the proliferation activity and telomerase activity of these tumors. Furthermore, the assessment of TPX2, Ki-67 and hTERT expression levels is appropriate for determination of malignant potential of GISTs. PMID- 26952516 TI - Subtraction electrocardiography: Detection of ischemia-induced ST displacement without the need to identify the J point. AB - BACKGROUND: When triaging a patient with acute chest pain at first medical contact, an electrocardiogram (ECG) is routinely made and inspected for signs of myocardial ischemia. The guidelines recommend comparison of the acute and an earlier-made ECG, when available. No concrete recommendations for this comparison exist, neither is known how to handle J-point identification difficulties. Here we present a J-point independent method for such a comparison. METHODS: After conversion to vectorcardiograms, baseline and acute ischemic ECGs after 3minutes of balloon occlusion during elective PCI were compared in 81 patients of the STAFF III ECG database. Baseline vectorcardiograms were subtracted from ischemic vectorcardiograms using either the QRS onsets or the J points as synchronization instants, yielding vector magnitude difference signals, DeltaH. Output variables for the J-point synchronized differences were DeltaH at the actual J point and at 20, 40, 60 and 80ms thereafter. Output variables for the onset-QRS synchronized differences were the DeltaH at 80, 100, 120, 140 and 160ms after onset QRS. Finally, linear regressions of all combinations of DeltaHJ+... versus DeltaHQRS+... were made, and the best combination was identified. RESULTS: The highest correlation, 0.93 (p<0.01), was found between DeltaH 40ms after the J point and 160ms after the onset of the QRS complex. With a DeltaH ischemia threshold of 0.05mV, 66/81 (J-point synchronized differences) and 68/81 (onset QRS synchronized differences) subjects were above the ischemia threshold, corresponding to sensitivities of 81% and 84%, respectively. CONCLUSION: Our current study opens an alternative way to detect cardiac ischemia without the need for human expertise for determination of the J point by measuring the difference vector magnitude at 160ms after the onset of the QRS complex. PMID- 26952517 TI - Tuning selectivity of electrochemical reactions by atomically dispersed platinum catalyst. AB - Maximum atom efficiency as well as distinct chemoselectivity is expected for electrocatalysis on atomically dispersed (or single site) metal centres, but its realization remains challenging so far, because carbon, as the most widely used electrocatalyst support, cannot effectively stabilize them. Here we report that a sulfur-doped zeolite-templated carbon, simultaneously exhibiting large sulfur content (17 wt% S), as well as a unique carbon structure (that is, highly curved three-dimensional networks of graphene nanoribbons), can stabilize a relatively high loading of platinum (5 wt%) in the form of highly dispersed species including site isolated atoms. In the oxygen reduction reaction, this catalyst does not follow a conventional four-electron pathway producing H2O, but selectively produces H2O2 even over extended times without significant degradation of the activity. Thus, this approach constitutes a potentially promising route for producing important fine chemical H2O2, and also offers opportunities for tuning the selectivity of other electrochemical reactions on various metal catalysts. PMID- 26952518 TI - A decade of human genome project conclusion: Scientific diffusion about our genome knowledge. AB - The Human Genome Project (HGP) was initiated in 1990 and completed in 2003. It aimed to sequence the whole human genome. Although it represented an advance in understanding the human genome and its complexity, many questions remained unanswered. Other projects were launched in order to unravel the mysteries of our genome, including the ENCyclopedia of DNA Elements (ENCODE). This review aims to analyze the evolution of scientific knowledge related to both the HGP and ENCODE projects. Data were retrieved from scientific articles published in 1990-2014, a period comprising the development and the 10 years following the HGP completion. The fact that only 20,000 genes are protein and RNA-coding is one of the most striking HGP results. A new concept about the organization of genome arose. The ENCODE project was initiated in 2003 and targeted to map the functional elements of the human genome. This project revealed that the human genome is pervasively transcribed. Therefore, it was determined that a large part of the non-protein coding regions are functional. Finally, a more sophisticated view of chromatin structure emerged. The mechanistic functioning of the genome has been redrafted, revealing a much more complex picture. Besides, a gene-centric conception of the organism has to be reviewed. A number of criticisms have emerged against the ENCODE project approaches, raising the question of whether non-conserved but biochemically active regions are truly functional. Thus, HGP and ENCODE projects accomplished a great map of the human genome, but the data generated still requires further in depth analysis. (c) 2016 by The International Union of Biochemistry and Molecular Biology, 44:215-223, 2016. PMID- 26952519 TI - Monitoring extent of moisture variations due to leachate recirculation in an ELR/bioreactor landfill using resistivity imaging. AB - Bioreactor or enhanced leachate recirculation (ELR) landfills are designed and operated for accelerated waste stabilization, accelerated decomposition, and an increased rate of gas generation. The major aspects of a bioreactor landfill are the addition of liquid and the recirculation of collected leachate back into the waste mass through the subsurface leachate recirculation system (LRS). The performance of the ELR landfill largely depends on the existing moisture content within the waste mass; therefore, it is of utmost importance to determine the moisture variations within the landfill. Traditionally, the moisture variation of the ELR landfill is determined by collecting samples through a bucket auger boring from the landfill, followed by laboratory investigation. Collecting the samples through a bucket auger boring is time consuming, labor intensive, and cost prohibitive. Moreover, it provides the information for a single point within the waste mass, but not for the moisture distribution within the landfill. Fortunately, 2D resistivity imaging (RI) can be performed to assess the moisture variations within the landfill and provide a continuous image of the subsurface, which can be utilized to evaluate the performance of the ELR landfill. During this study, the 2D resistivity imaging technique was utilized to determine the moisture distribution and moisture movement during the recirculation process of an ELR landfill in Denton, Texas, USA. A horizontal recirculation pipe was selected and monitored periodically for 2.5years, using the RI technique, to investigate the performance of the leachate recirculation. The RI profile indicated that the resistivity of the solid waste decreased as much as 80% with the addition of water/leachate through the recirculation pipe. In addition, the recirculated leachate traveled laterally between 11m and 16m. Based on the resistivity results, it was also observed that the leachate flow throughout the pipe was non-uniform. The non-uniformity of the leachate flow confirms that the flow of leachate through waste is primarily through preferential flow paths due the heterogeneous nature of the waste. PMID- 26952523 TI - Electrochemical oxygen reduction catalysed by Ni3(hexaiminotriphenylene)2. AB - Control over the architectural and electronic properties of heterogeneous catalysts poses a major obstacle in the targeted design of active and stable non platinum group metal electrocatalysts for the oxygen reduction reaction. Here we introduce Ni3(HITP)2 (HITP=2, 3, 6, 7, 10, 11-hexaiminotriphenylene) as an intrinsically conductive metal-organic framework which functions as a well defined, tunable oxygen reduction electrocatalyst in alkaline solution. Ni3(HITP)2 exhibits oxygen reduction activity competitive with the most active non-platinum group metal electrocatalysts and stability during extended polarization. The square planar Ni-N4 sites are structurally reminiscent of the highly active and widely studied non-platinum group metal electrocatalysts containing M-N4 units. Ni3(HITP)2 and analogues thereof combine the high crystallinity of metal-organic frameworks, the physical durability and electrical conductivity of graphitic materials, and the diverse yet well-controlled synthetic accessibility of molecular species. Such properties may enable the targeted synthesis and systematic optimization of oxygen reduction electrocatalysts as components of fuel cells and electrolysers for renewable energy applications. PMID- 26952524 TI - Alberta plans change in doctor compensation. PMID- 26952525 TI - Clicking hip in a postmenopausal woman. PMID- 26952526 TI - Upholding the integrity of your CMAJ. PMID- 26952528 TI - Surveillance programs watching for colistin-resistant infections. PMID- 26952527 TI - Recommendations on screening for lung cancer. PMID- 26952530 TI - CMAJ gets interim editor amid governance shake-up. PMID- 26952529 TI - Effectiveness of N95 respirators versus surgical masks in protecting health care workers from acute respiratory infection: a systematic review and meta-analysis. AB - BACKGROUND: Conflicting recommendations exist related to which facial protection should be used by health care workers to prevent transmission of acute respiratory infections, including pandemic influenza. We performed a systematic review of both clinical and surrogate exposure data comparing N95 respirators and surgical masks for the prevention of transmissible acute respiratory infections. METHODS: We searched various electronic databases and the grey literature for relevant studies published from January 1990 to December 2014. Randomized controlled trials (RCTs), cohort studies and case-control studies that included data on health care workers wearing N95 respirators and surgical masks to prevent acute respiratory infections were included in the meta-analysis. Surrogate exposure studies comparing N95 respirators and surgical masks using manikins or adult volunteers under simulated conditions were summarized separately. Outcomes from clinical studies were laboratory-confirmed respiratory infection, influenza like illness and workplace absenteeism. Outcomes from surrogate exposure studies were filter penetration, face-seal leakage and total inward leakage. RESULTS: We identified 6 clinical studies (3 RCTs, 1 cohort study and 2 case-control studies) and 23 surrogate exposure studies. In the meta-analysis of the clinical studies, we found no significant difference between N95 respirators and surgical masks in associated risk of (a) laboratory-confirmed respiratory infection (RCTs: odds ratio [OR] 0.89, 95% confidence interval [CI] 0.64-1.24; cohort study: OR 0.43, 95% CI 0.03-6.41; case-control studies: OR 0.91, 95% CI 0.25-3.36); (b) influenza like illness (RCTs: OR 0.51, 95% CI 0.19-1.41); or (c) reported workplace absenteeism (RCT: OR 0.92, 95% CI 0.57-1.50). In the surrogate exposure studies, N95 respirators were associated with less filter penetration, less face-seal leakage and less total inward leakage under laboratory experimental conditions, compared with surgical masks. INTERPRETATION: Although N95 respirators appeared to have a protective advantage over surgical masks in laboratory settings, our meta-analysis showed that there were insufficient data to determine definitively whether N95 respirators are superior to surgical masks in protecting health care workers against transmissible acute respiratory infections in clinical settings. PMID- 26952531 TI - Transforming health through sustainable development. PMID- 26952532 TI - Introduction of selectivity and specificity to graphene using an inimitable combination of molecular imprinting and nanotechnology. AB - Recently, the nanostructured modified molecularly imprinting polymer has created a great attention in research field due to its excellent properties such as high surface to volume ratio, low cost, and easy preparation/handling. Among the nanostructured materials, the carbonaceous material such as 'graphene' has attracted the tremendous attention of researchers owing to their fascinating electrical, thermal and physical properties. In this review article, we have tried to explore as well as compile the role of graphene-based nanomaterials in the fabrication of imprinted polymers. In other words, herein the recent efforts made to introduce selectivity in graphene-based nanomaterials were tried collected together. The major concern of this review article is focused on the sensing devices fabricated via a combination of graphene, graphene@nanoparticles, graphene@carbon nanotubes and molecularly imprinted polymers. Additionally, the combination of graphene and quantum dots was also included to explore the fluorescence properties of zero-band-gap graphene. PMID- 26952533 TI - Salusin-beta Promotes Vascular Smooth Muscle Cell Migration and Intimal Hyperplasia After Vascular Injury via ROS/NFkappaB/MMP-9 Pathway. AB - AIMS: Media-to-intima migration of vascular smooth muscle cells (VSMCs) is critical to intimal thickening in atherosclerosis and restenosis after coronary angioplasty. The aim of this study is to determine the effects of salusin-beta on VSMC migration and intimal hyperplasia after vascular injury and the underlying mechanism. RESULTS: In vitro, salusin-beta promoted VSMC migration, which was attenuated by matrix metalloproteinase (MMP)-9 inhibition. Inhibition or knockdown of p65-nuclear factor kappa beta (NFkappaB) in VSMCs suppressed salusin beta-induced MMP-9 expression and VSMC migration. Salusin-beta increased NADPH oxidase 2 (NOX2) expression and reactive oxygen species (ROS) production, which were prevented by NOX2-small interfering RNA (siRNA) transfection. Salusin-beta induced p65-NFkappaB translocation, MMP-9 expression, and VSMC migration were inhibited by ROS scavenger, NADPH oxidase inhibitor, or NOX2-siRNA. In vivo, carotid artery ligation-induced vascular injury resulted in intimal hyperplasia in injured artery in rats. Salusin-beta was upregulated in the injured carotid arteries of rats, which was attributed to reduced miR-133a-3p expression. Knockdown of salusin-beta with siRNA attenuated the vascular injury-induced intimal thickening, p65-NFkappaB nuclear translocation, and NOX2 and MMP-9 expressions in rats. INNOVATION: Salusin-beta is a critical modulator in VSMC migration and neointima formation in response to vascular injury. CONCLUSIONS: Salusin-beta promotes VSMC migration and vascular injury-induced intimal hyperplasia via MMP-9 accumulation due to NOX2 activation, followed by ROS production, IkappaBalpha phosphorylation and degradation, and p65-NFkappaB translocation. We propose that salusin-beta may be important in the VSMC migration and neointima of some vascular diseases. Antioxid. Redox Signal. 24, 1045-1057. PMID- 26952537 TI - An extended U2AF(65)-RNA-binding domain recognizes the 3' splice site signal. AB - How the essential pre-mRNA splicing factor U2AF(65) recognizes the polypyrimidine (Py) signals of the major class of 3' splice sites in human gene transcripts remains incompletely understood. We determined four structures of an extended U2AF(65)-RNA-binding domain bound to Py-tract oligonucleotides at resolutions between 2.0 and 1.5 A. These structures together with RNA binding and splicing assays reveal unforeseen roles for U2AF(65) inter-domain residues in recognizing a contiguous, nine-nucleotide Py tract. The U2AF(65) linker residues between the dual RNA recognition motifs (RRMs) recognize the central nucleotide, whereas the N- and C-terminal RRM extensions recognize the 3' terminus and third nucleotide. Single-molecule FRET experiments suggest that conformational selection and induced fit of the U2AF(65) RRMs are complementary mechanisms for Py-tract association. Altogether, these results advance the mechanistic understanding of molecular recognition for a major class of splice site signals. PMID- 26952538 TI - Altered expression of micro-RNA 199a and increased levels of cardiac SIRT1 protein are associated with the occurrence of atrial fibrillation after coronary artery bypass graft surgery. AB - BACKGROUND: Postoperative atrial fibrillation (POAF) is a potentially life threatening complication after coronary artery bypass graft (CABG) surgery. The expression of the cardioprotective SIRT1 protein with its antioxidant activity is increased in cardiac tissue of patients suffering from POAF. So far, information is lacking about the relationship between SIRT1 regulating micro RNAs (miRs), SIRT1 protein and the occurrence of POAF. METHODS: A total of 63 patients undergoing CABG were recruited, and biopsies were obtained from the right atrial appendage during cannulation. Postoperative, all patients were rhythm-monitored until discharge and randomized to POAF (n=20) or sinus rhythm (n=43). The expression of the micro RNAs miR-199a and miR-195 was quantified by real-time PCR. SIRT1 protein was detected by western blot analysis. RESULTS: The relative expression of miR-199a in the POAF group was significantly decreased compared to the control group (0.77+/-0.27 vs. 1.11+/-0.69, P=.022) Accordingly, SIRT 1 protein was significantly induced in tissue probes of patients with POAF (P<.001). CONCLUSION: Altered expression of the SIRT1 protein regulating miR-199a in human atrial tissue was found to be related to the occurrence of POAF, indicating its usefulness as a biomarker for cardiac surgery management. PMID- 26952539 TI - Serum vitamin D levels and response to molecular subtypes in breast cancer. PMID- 26952540 TI - Impact of Cold Ischemia Time on Outcomes of Liver Transplantation: A Single Center Experience. AB - BACKGROUND: Significant geographic disparities exist in access to liver transplantation and consequently the current liver allocation system is being challenged. We sought to describe our unique experience with using organs with long cold ischemia times from the largest donation service area. MATERIAL AND METHODS: From 2009-2014 we performed 350 liver transplants. 167 (48%) had a cold ischemia time <8 hours, 134 (38%) between 8 and 12 hours, and 49 (14%) greater than 12 hours. RESULTS: Early allograft dysfunction was observed more commonly with increasing cold ischemia times. 53% of the recipients in the >12 h group had early allograft dysfunction compared to 28% in the 8-12 h group, and 18% in the <8 h group (P<0.001). We found no correlation between early allograft dysfunction and allograft or patient survival. One-year liver allograft survival was 92%, 94%, 87%, three-year graft survival was 82%, 89%, and 87%, and five-year graft survival was 82%, 89%, and 79% in the <8 h, 8-12 h, and >12 h cold ischemia time groups, respectively. One-year patient survival was 95%, 94%, and 92% and five year patient survival was 90%, 89%, and 83% in the <8 h, 8-12 h, and >12 h cold ischemia time groups, respectively. Both unadjusted and multivariate Cox regression analyses indicated no statistically significant associations between cold ischemia time and graft or patient survival. CONCLUSIONS: In conclusion, the prolonged cold ischemia time led to early allograft dysfunction but did not have a deleterious association with graft or patient survival. PMID- 26952541 TI - Bilateral ureteroarterial fistula: a case report and review of literature. AB - Ureteral arterial fistula (UAF) is an uncommon condition characterized by a direct fistulous communication between a ureter and an iliac artery resulting in bleeding into the ureter, which can be massive and life-threatening because of hemodynamic instability, as confirmed by the high mortality rate (7-23% overall).This condition is actually increasing in frequency because of its relation to predisposing factors such as vascular pathology, previous radiation therapy, previous surgery, and necessity of ureteral stenting. Diagnosis is often challenging, as in most patients, the only symptom is hematuria and the treatment may require a multidisciplinary approach, including the expertise of the urologist, vascular surgeon, and interventional radiologist. Endovascular approach offers advantages over open surgery decreasing morbidity (reduced risk of injury to adjacent structure) and shortening hospital staying. There is no consensus regarding the safety of intentional occlusion of the hypogastric artery: proximal occlusion of a hypogastric artery typically produces little or no clinical symptoms due to well-collateralized pelvic arterial networks. On the contrary, significant complications, such as colonic ischemia, spinal cord paralysis, buttock claudication, or erectile dysfunction, are well-recognized adverse events after hypogastric artery embolization, especially in bilateral cases. We describe our experience of a bilateral UAF treated with bilateral endvascular approach. PMID- 26952542 TI - Role of nanotechnology in HIV/AIDS vaccine development. AB - HIV/AIDS is one of the worst crises affecting global health and influencing economic development and social stability. Preventing and treating HIV infection is a crucial task. However, there is still no effective HIV vaccine for clinical application. Nanotechnology has the potential to solve the problems associated with traditional HIV vaccines. At present, various nano-architectures and nanomaterials can function as potential HIV vaccine carriers or adjuvants, including inorganic nanomaterials, liposomes, micelles and polymer nanomaterials. In this review, we summarize the current progress in the use of nanotechnology for the development of an HIV/AIDS vaccine and discuss its potential to greatly improve the solubility, permeability, stability and pharmacokinetics of HIV vaccines. Although nanotechnology holds great promise for applications in HIV/AIDS vaccines, there are still many inadequacies that result in a variety of risks and challenges. The potential hazards to the human body and environment associated with some nano-carriers, and their underlying mechanisms require in depth study. Non-toxic or low-toxic nanomaterials with adjuvant activity have been identified. However, studying the confluence of factors that affect the adjuvant activity of nanomaterials may be more important for the optimization of the dosage and immunization strategy and investigations into the exact mechanism of action. Moreover, there are no uniform standards for investigations of nanomaterials as potential vaccine adjuvants. These limitations make it harder to analyze and deduce rules from the existing data. Developing vaccine nano-carriers or adjuvants with high benefit-cost ratios is important to ensure their broad usage. Despite some shortcomings, nanomaterials have great potential and application prospects in the fields of AIDS treatment and prevention. PMID- 26952543 TI - Second trimester cervical length and prolonged pregnancy (.). AB - OBJECTIVE: To determine whether second trimester transvaginal ultrasound cervical length (CL) is associated with prolonged pregnancy (>=41 0/7 weeks) in nulliparous women who reach term (>=37 weeks) with a planned vaginal delivery. METHODS: Retrospective cohort of nulliparous singletons 18 0/7-23 6/7 weeks gestation undergoing CL screening from 1/1/12 to 12/31/13. Women who delivered at term with spontaneous labor or reached 41 weeks were included. Primary outcome was incidence of prolonged pregnancy. Risk of prolonged pregnancy was assessed by CL quartile using odds ratio, adjusted for confounders (aOR) and a receiver operating characteristic (ROC) curve. RESULTS: 722 women were included, among them 171 (24%) had a prolonged pregnancy. There was a significant difference in BMI and race across CL quartiles. The aOR of having a prolonged pregnancy with CL in quartiles 2, 3, and 4 versus quartile 1 were 2.14(1.27-3.62), 2.72(1.59-4.65), and 1.69(1.02-3.03), respectively. CL >= 37 mm (beyond first quartile) was associated with a two-fold increased risk of prolonged pregnancy versus CL < 37 mm, (27% vs 15%, p < 0.01, aOR 2.17 (1.38-3.41)). ROC curve did not identify a CL cutoff that was predictive of prolonged pregnancy (AUC 0.544, p = 0.079). CONCLUSIONS: Although a longer second trimester CL is associated with an increased risk for prolonged pregnancy, it is not predictive. PMID- 26952544 TI - Vibrio cholerae hemagglutinin(HA)/protease: An extracellular metalloprotease with multiple pathogenic activities. AB - Vibrio cholerae of serogroup O1 and O139, the etiological agent of the diarrheal disease cholera, expresses the extracellular Zn-dependent metalloprotease hemagglutinin (HA)/protease also reported as vibriolysin. This enzyme is also produced by non-O1/O139 (non-cholera) strains that cause mild, sporadic illness (i.e. gastroenteritis, wound or ear infections). Orthologs of HA/protease are present in other members of the Vibrionaceae family pathogenic to humans and fish. HA/protease belongs to the M4 neutral peptidase family and displays significant amino acid sequence homology to Pseudomonas aeruginosa elastase (LasB) and Bacillus thermoproteolyticus thermolysin. It exhibits a broad range of potentially pathogenic activities in cell culture and animal models. These activities range from the covalent modification of other toxins, the degradation of the protective mucus barrier and disruption of intestinal tight junctions. Here we review (i) the structure and regulation of HA/protease expression, (ii) its interaction with other toxins and the intestinal mucosa and (iii) discuss the possible role(s) of HA/protease in the pathogenesis of cholera. PMID- 26952545 TI - NextGen HIV prevention: new possibilities and questions. PMID- 26952547 TI - Tocilizumab for induction and maintenance of remission in giant cell arteritis: a phase 2, randomised, double-blind, placebo-controlled trial. AB - BACKGROUND: Giant cell arteritis is an immune-mediated disease of medium and large-sized arteries that affects mostly people older than 50 years of age. Treatment with glucocorticoids is the gold-standard and prevents severe vascular complications but is associated with substantial morbidity and mortality. Tocilizumab, a humanised monoclonal antibody against the interleukin-6 receptor, has been associated with rapid induction and maintenance of remission in patients with giant cell arteritis. We therefore aimed to study the efficacy and safety of tocilizumab in the first randomised clinical trial in patients with newly diagnosed or recurrent giant cell arteritis. METHODS: In this single centre, phase 2, randomised, double-blind, placebo-controlled trial, we recruited patients aged 50 years and older from University Hospital Bern, Switzerland, who met the 1990 American College of Rheumatology criteria for giant cell arteritis. Patients with new-onset or relapsing disease were randomly assigned (2:1) to receive either tocilizumab (8 mg/kg) or placebo intravenously. 13 infusions were given in 4 week intervals until week 52. Both groups received oral prednisolone, starting at 1 mg/kg per day and tapered down to 0 mg according to a standard reduction scheme defined in the study protocol. Allocation to treatment groups was done using a central computerised randomisation procedure with a permuted block design and a block size of three, and concealed using central randomisation generated by the clinical trials unit. Patients, investigators, and study personnel were masked to treatment assignment. The primary outcome was the proportion of patients who achieved complete remission of disease at a prednisolone dose of 0.1 mg/kg per day at week 12. All analyses were intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01450137. RESULTS: Between March 3, 2012, and Sept 9, 2014, 20 patients were randomly assigned to receive tocilizumab and prednisolone, and ten patients to receive placebo and glucocorticoid; 16 (80%) and seven (70%) patients, respectively, had new-onset giant cell arteritis. 17 (85%) of 20 patients given tocilizumab and four (40%) of ten patients given placebo reached complete remission by week 12 (risk difference 45%, 95% CI 11-79; p=0.0301). Relapse-free survival was achieved in 17 (85%) patients in the tocilizumab group and two (20%) in the placebo group by week 52 (risk difference 65%, 95% CI 36-94; p=0.0010). The mean survival-time difference to stop glucocorticoids was 12 weeks in favour of tocilizumab (95% CI 7-17; p<0.0001), leading to a cumulative prednisolone dose of 43 mg/kg in the tocilizumab group versus 110 mg/kg in the placebo group (p=0.0005) after 52 weeks. Seven (35%) patients in the tocilizumab group and five (50%) in the placebo group had serious adverse events. INTERPRETATION: Our findings show, for the first time in a trial setting, the efficacy of tocilizumab in the induction and maintenance of remission in patients with giant cell arteritis. FUNDING: Roche and the University of Bern. PMID- 26952546 TI - Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. AB - BACKGROUND: Patients with metastatic urothelial carcinoma have few treatment options after failure of platinum-based chemotherapy. In this trial, we assessed treatment with atezolizumab, an engineered humanised immunoglobulin G1 monoclonal antibody that binds selectively to programmed death ligand 1 (PD-L1), in this patient population. METHODS: For this multicentre, single-arm, two-cohort, phase 2 trial, patients (aged >=18 years) with inoperable locally advanced or metastatic urothelial carcinoma whose disease had progressed after previous platinum-based chemotherapy were enrolled from 70 major academic medical centres and community oncology practices in Europe and North America. Key inclusion criteria for enrolment were Eastern Cooperative Oncology Group performance status of 0 or 1, measurable disease defined by Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1), adequate haematological and end-organ function, and no autoimmune disease or active infections. Formalin-fixed paraffin-embedded tumour specimens with sufficient viable tumour content were needed from all patients before enrolment. Patients received treatment with intravenous atezolizumab (1200 mg, given every 3 weeks). PD-L1 expression on tumour infiltrating immune cells (ICs) was assessed prospectively by immunohistochemistry. The co-primary endpoints were the independent review facility-assessed objective response rate according to RECIST v1.1 and the investigator-assessed objective response rate according to immune-modified RECIST, analysed by intention to treat. A hierarchical testing procedure was used to assess whether the objective response rate was significantly higher than the historical control rate of 10% at an alpha level of 0.05. This study is registered with ClinicalTrials.gov, number NCT02108652. FINDINGS: Between May 13, 2014, and Nov 19, 2014, 486 patients were screened and 315 patients were enrolled into the study. Of these patients, 310 received atezolizumab treatment (five enrolled patients later did not meet eligibility criteria and were not dosed with study drug). The PD-L1 expression status on infiltrating immune cells (ICs) in the tumour microenvironment was defined by the percentage of PD-L1-positive immune cells: IC0 (<1%), IC1 (>=1% but <5%), and IC2/3 (>=5%). The primary analysis (data cutoff May 5, 2015) showed that compared with a historical control overall response rate of 10%, treatment with atezolizumab resulted in a significantly improved RECIST v1.1 objective response rate for each prespecified immune cell group (IC2/3: 27% [95% CI 19-37], p<0.0001; IC1/2/3: 18% [13-24], p=0.0004) and in all patients (15% [11-20], p=0.0058). With longer follow-up (data cutoff Sept 14, 2015), by independent review, objective response rates were 26% (95% CI 18-36) in the IC2/3 group, 18% (13-24) in the IC1/2/3 group, and 15% (11-19) overall in all 310 patients. With a median follow-up of 11.7 months (95% CI 11.4-12.2), ongoing responses were recorded in 38 (84%) of 45 responders. Exploratory analyses showed The Cancer Genome Atlas (TCGA) subtypes and mutation load to be independently predictive for response to atezolizumab. Grade 3-4 treatment-related adverse events, of which fatigue was the most common (five patients [2%]), occurred in 50 (16%) of 310 treated patients. Grade 3-4 immune mediated adverse events occurred in 15 (5%) of 310 treated patients, with pneumonitis, increased aspartate aminotransferase, increased alanine aminotransferase, rash, and dyspnoea being the most common. No treatment-related deaths occurred during the study. INTERPRETATION: Atezolizumab showed durable activity and good tolerability in this patient population. Increased levels of PD L1 expression on immune cells were associated with increased response. This report is the first to show the association of TCGA subtypes with response to immune checkpoint inhibition and to show the importance of mutation load as a biomarker of response to this class of agents in advanced urothelial carcinoma. FUNDING: F Hoffmann-La Roche Ltd. PMID- 26952548 TI - Teratogenic effects of the Zika virus and the role of the placenta. AB - The mechanism by which the Zika virus can cause fetal microcephaly is not known. Reports indicate that Zika is able to evade the normal immunoprotective responses of the placenta. Microcephaly has genetic causes, some associated with maternal exposures including radiation, tobacco smoke, alcohol, and viruses. Two hypotheses regarding the role of the placenta are possible: one is that the placenta directly conveys the Zika virus to the early embryo or fetus. Alternatively, the placenta itself might be mounting a response to the exposure; this response might be contributing to or causing the brain defect. This distinction is crucial to the diagnosis of fetuses at risk and the design of therapeutic strategies to prevent Zika-induced teratogenesis. PMID- 26952549 TI - Role for anti-PD-L1 immune checkpoint inhibitor in advanced urothelial carcinoma. PMID- 26952550 TI - An fMRI study to identify the neurobiological link between sex abuse and psychogenic nonepileptic seizures. PMID- 26952551 TI - Analysis and Treatment of Complications after Unicompartmental Knee Arthroplasty. AB - PURPOSE: To analyze the causes and types of complications after unicompartmental knee arthroplasty (UKA) and determine proper prevention and treatment methods. MATERIALS AND METHODS: A total of 1,576 UKAs were performed for osteoarthritis of the knee from January 2002 to December 2014 at one institution. We analyzed complications after UKA retrospectively and investigated proper methods of treatment. RESULTS: A total of 89 complications (5.6%) occurred after UKA. Regarding the type of complications after UKA, there were 42 cases of dislocation of the mobile bearing, 23 cases of loosening of the prosthesis, 6 cases of periprosthetic fracture, 3 cases of polyethylene wear, 3 cases of progression of arthritis in the contralateral compartment, 2 cases of medial collateral ligament injury, 2 cases of impingement, 5 cases of infection, 1 case of arthrofibrosis, and 2 cases of failure due to unexplained pain. The most common complication after UKA was mobile bearing dislocation in the mobile-bearing knees and loosening of the prosthesis in the fixed-bearing knees, but polyethylene wear and progression of arthritis were relatively rare. The complications were treated with conversion to total knee arthroplasty in 58 cases and simple bearing change in 21 cases. CONCLUSIONS: The most common complication after UKA was dislocation of the mobile bearing. When a complication occurs after UKA, appropriate treatment should be performed after accurate analysis of the cause of complication. PMID- 26952552 TI - Structure, cytotoxic activity and mechanism of protoilludane sesquiterpene aryl esters from the mycelium of Armillaria mellea. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Armillaria mellea (Vahl. ex. Fr.) Karst is an important traditional Chinese medicine used in dispelling wind and removing obstruction in the meridians, and strengthening tendons and bones. Armillaria mellea has been recorded in the book Caobenshiyi which was written by ancestor for the function of suppressing hyderactive liver for calming endogenous wind medicine. The aim of this study is to investigate the cytotoxic activity for liver cell lines (normal and cancerous) of protoilludane sesquiterpene aryl esters from the mycelium of A. mellea. MATERIALS AND METHODS: A systemic fractionation of the mycelium extracts of A. mellea and relative activity mechanisms were studied. RESULTS: Two new protoilludane sesquiterpene aryl esters named 5'-methoxy-armillasin (1) and 5-hydroxyl-armillarivin (2) were isolated. In addition, eight known protoilludane sesquiterpene aryl esters armillaridin (3), armillartin (4), armillarin (5), melleolide B (6), armillarilin (7), armillasin (8), armillarigin (9) and melleolide (10) were also isolated from the mycelium of A. mellea. The relative configurations of the two new compounds were confirmed by NOESY spectra. Among ten protoilludane sesquiterpene aryl esters, compounds 2, 3, 4, 7, 8, 9 and 10 were active constituents with highly cytotoxic activity against HepG2 cells (4.95-37.65MUg/mL). We reported here for the time, that compound 10 (melleolide) showed anti-tumor ability on hepatoma cell. The relative mechanism was assessed on HepG2 cells. CONCLUSIONS: Among all the ten protoilludane sesquiterpene aryl esters, melleolide (10) showed the best cytotoxic activity for HepG2 cells (4.95MUg/mL) and lower activity for L02 cells (16.05MUg/mL). Mechanism study showed that melleolide decreased the viability of the cancer cells with varying levels of cleaved-caspase 3, caspase 8, caspase 9, Bax and Ki67 expression. On the other hand, melleolide induced HepG2 cell cycle arrest at the G2/M phase. PMID- 26952554 TI - Meta-analysis of 38 placebo-controlled studies examining the antidepressant induced analgesic effect. AB - For all controlled studies that bear upon the analgesic-effect of antidepressants, a meta-analysis was conducted to get an estimation of the effect size and to get a sight on the possible modes of action. For this purpose both content and methodological variables were coded for each study. The mean size of the analgesic effect is 0.63. This means that the average patient getting an antidepressant has less pain than 74% of the patients getting a placebo. However because of selective drop-out and the use of psychometri-cally inadequate pain scales, this may be an over-estimation. Real analgesic qualities of antidepressive agents seem to offer the most plausible explanation for the effect, but the importance of serotonin reuptake blocking is not confirmed. A main objection, however, is that in all studies the depression variable was insufficiently controlled at inclusion. Because both the estimation of the effect size as the explanation of the effect are confounded with methodological doubts, it is concluded that further studies need to be done to overcome these difficulties. PMID- 26952553 TI - A general approach to visualize protein binding and DNA conformation without protein labelling. AB - Single-molecule manipulation methods, such as magnetic tweezers and flow stretching, generally use the measurement of changes in DNA extension as a proxy for examining interactions between a DNA-binding protein and its substrate. These approaches are unable to directly measure protein-DNA association without fluorescently labelling the protein, which can be challenging. Here we address this limitation by developing a new approach that visualizes unlabelled protein binding on DNA with changes in DNA conformation in a relatively high-throughput manner. Protein binding to DNA molecules sparsely labelled with Cy3 results in an increase in fluorescence intensity due to protein-induced fluorescence enhancement (PIFE), whereas DNA length is monitored under flow of buffer through a microfluidic flow cell. Given that our assay uses unlabelled protein, it is not limited to the low protein concentrations normally required for single-molecule fluorescence imaging and should be broadly applicable to studying protein-DNA interactions. PMID- 26952555 TI - HPLC analysis and pharmacokinetics of the enantiomers of R,S-oxazepam and R,S temazepam with their corresponding glucuronide conjugates in urine and plasma of man. AB - R,S-Oxazepam and R,S-temazepam can be separated in their enantiomers by means of a chiral AGP column. The corresponding R- and S-glucuronide conjugates can be separated on a normal reversed-phase C18 column. Man conjugates the S-enantiomer of oxazepam and temazepam both better than the R-enantiomer. The urinary recovery of the glucuronides following either R,S,-oxazepam or R,S-temazepam almost amounts to 100% of the dose administered. PMID- 26952556 TI - Central 5-HT2 antagonists: A preclinical evaluation of a therapeutic potential. AB - A preclinical evaluation is presented of the serotonin 5-HT2 antagonists ritanserin and risperidone. Whereas ritanserin is a relative selective 5-HT2 antagonist, risperidone is a potent 5-HT2 and catecholamine antagonist. The pharmacological differences between both drugs are also observed in the drug discrimination test procedure. Using DOM, d-amphetamine and cocaine. Ritanserin was found active in animal models of anxiety using natural aversive stimuli; and in animal models of depression. Clear differences were observed between ritanserin and the benzodiazepines and between ritanserin and the tricyclic antidepressants. Risperidone was active in animal models of psychosis. Risperidone has, as opposed to classical neuroleptics such as haloperidol, less risks of inducing a dopamine D2 overblockade. Clinically, ritanserin is described as a thymostenic agent. Risperidone is an antipsychotic with therapeutic effects on both the positive and negative symptoms of schizophrenia and with a reduced risk of extrapyramidal side-effects. PMID- 26952557 TI - Evaluation of a crossed fused renal ectopia in a paediatric patient using 99mTc DMSA SPECT/CT. PMID- 26952558 TI - Use of Hydrogen as a Novel Therapeutic Strategy Against Photoreceptor Degeneration in Retinitis Pigmentosa Patients. AB - Retinitis pigmentosa (RP) is a heterogeneous group of inherited retinal dystrophies characterized by progressive photoreceptor apoptosis. Reactive oxygen species (ROS) have been recognized as critical initiators of the photoreceptor apoptosis in RP. Photoreceptor survival in RP mutants will not only require the inhibition of effectors of apoptotic machinery, but also the elimination of the initiating upstream signals, such as ROS. These cytotoxic ROS should be neutralized by the antioxidant defense system, otherwise they would interact with the macromolecules essential for photoreceptor survival. Hydrogen is a promising gaseous agent that has come to the forefront of therapeutic research over the last few years. It has been verified that hydrogen is capable of neutralizing the cytotoxic ROS selectively, rectifying abnormities in the apoptotic cascades, and attenuating the related inflammatory response. Hydrogen is so mild that it does not disturb the metabolic oxidation-reduction reactions or disrupt the physiologic ROS involved in cell signaling. Based on these findings, we hypothesize that hydrogen might be an effective therapeutic agent to slow or prevent photoreceptor degeneration in RP retinas. It is a logical step to test hydrogen for therapeutic use in multiple RP animal models, and ultimately in human RP patients. PMID- 26952559 TI - Factors influencing fruit and vegetable intake among urban Fijians: A qualitative study. AB - Low fruit and vegetable intake is an important risk factor for micronutrient deficiencies and non-communicable diseases, but many people worldwide, including most Fijians, eat less than the World Health Organization recommended amount. The present qualitative study explores factors that influence fruit and vegetable intake among 57 urban Fijians (50 women, 7 men) of indigenous Fijian (iTaukei) and South Asian (Indian) descent. Eight focus group discussions were held in and around Suva, Fiji's capital and largest urban area, which explored motivation for eating fruit and vegetables, understandings of links to health and disease, availability and sources, determinants of product choice, and preferred ways of preparing and eating fruit and vegetables. Data were analysed using thematic content analysis. Regardless of ethnicity, participants indicated that they enjoyed and valued eating fruit and vegetables, were aware of the health benefits, and had confidence in their cooking skills. In both cultures, fruit and vegetables were essential components of traditional diets. However, increasing preferences for processed and imported foods, and inconsistent availability and affordability of high-quality, low-priced, fresh produce, were identified as important barriers. The findings indicate that efforts to improve fruit and vegetable intake in urban Fijians should target the stability of the domestic fruit and vegetable supply and access. PMID- 26952560 TI - From beef to beans: Eating motives and the replacement of animal proteins with plant proteins among Finnish consumers. AB - A better understanding of the motives underlying the adoption of sustainable and healthy diets is needed for designing more effective policies. The aim of the study was to examine how eating motives were associated with self-reported changes in the consumption of beef, beans, and soy products, i.e., changes related to reducing animal and increasing plant proteins. The study analysed a survey of an adult population living in Finland (N = 1048). The eating motives were measured with the Eating Motivation Survey (TEMS), which distinguishes between 15 eating motives. Six clusters of consumers based on self-reported changes in food choices were identified with latent class analysis (LCA). Four clusters had established food consumption patterns ("Beef only", "Beef and beans", "Beef, beans, and soy products", and "No beef"), one was undergoing a change, and one had attempted a change earlier. ANOVA with planned contrasts revealed that the motives relating to natural concerns, health, and weight control were higher, and convenience and price lower, among those who had an established diet including beans and soy products, as compared to those who consumed only beef. Those undergoing a dietary change expressed a higher endorsement of natural concerns as well as health, sociability, social image, and price motives than those with an established diet including beans and soy products. The results suggest that eating motives play an important role in changing towards more sustainable food consumption patterns in which meat/beef is replaced with plant proteins. PMID- 26952561 TI - Correlates of parental feeding practices with pre-schoolers: Parental body image and eating knowledge, attitudes, and behaviours. AB - Parental feeding practices have been linked to eating and weight status in young children; however, more research is needed to understand what influences these feeding practices. The aim of this study was to examine how parental feeding practices that are linked to unhealthy eating patterns in young children, are related to parental body image and eating knowledge, attitudes, and behaviours . Participants were 330 mothers of a 2- to 6-year-old child. Mothers completed measures of knowledge of child body image and eating patterns, overvaluation of weight and shape, internalization of general media and athletic ideals, dieting, and parental feeding practices. Higher maternal knowledge of strategies to promote positive child body image and eating patterns predicted lower weight restriction, instrumental, emotional, and pushing to eat feeding practices. Overvaluation of weight and shape predicted use of fat restriction. Maternal internalization of the athletic ideal predicted instrumental and pushing to eat feeding practices. As these feeding practices have been associated with long-term risk of children's weight gain and/or disordered eating, these findings highlight the need for prevention interventions to target knowledge, attitudes, and behaviours of parents of pre-schoolers. PMID- 26952562 TI - Pleomorphic rhabdomyosarcoma with an impressive response to chemotherapy: case report and review of the literature. AB - PURPOSE: Pleomorphic rhabdomyosarcoma (RMS) represents a rare sarcoma subtype of the adult population. Due to its clinical characteristics, treatment is currently based on the guidelines for adult soft tissue sarcoma therapy. Hence, in the metastatic setting, doxorubicin-containing regimens are used in the sarcoma community, with limited treatment benefit. Scanty published data are available on the efficacy of systemic treatment. Whether treatment response and outcome of these patients could be improved by using pediatric protocols used typically in other RMS subtypes, like embryonal and alveolar RMS, is unclear. We report on an impressive effect of multiagent pediatric chemotherapy in an adult patient with metastatic pleomorphic RMS. METHODS: We present the case of a 70-year-old man with metastatic pleomorphic RMS of his left thigh. Systemic chemotherapy according to the VAC regimen (vincristine, actinomycin, cyclophosphamide) was initiated. Follow-up clinical and radiologic assessment demonstrated an impressive treatment response. RESULTS: Sixteen months after primary diagnosis, computed tomography scan shows no signs of tumor progression. CONCLUSIONS: Our case report emphasizes that multiagent systemic therapy according to pediatric protocols should be considered in adult patients with pleomorphic RMS. PMID- 26952563 TI - Steroid-induced resolution of refractory pulmonary interstitial emphysema. AB - Pulmonary interstitial emphysema (PIE) is a familiar complication of mechanical ventilation in premature infants. Its most severe form, marked by life threatening respiratory and cardiovascular compromise, is a particularly vexing problem in neonatology. Treatment modalities rely on decubitus positioning and reduction of mean airway pressure, but refractory PIE is unresponsive to these maneuvers. Other options such as selective unilateral bronchial intubation, balloon catheter bronchial occlusion, selective lung volume reduction, and mechanical decompression each have clear limitations. In a patient with refractory, life-threatening PIE too unstable for other therapeutic modalities, we describe success with steroid therapy at a familiar dosing regimen. PMID- 26952564 TI - Should I Stay or Should I Go? Abundance as a New Null Hypothesis for Determination of mRNA Mobility. PMID- 26952565 TI - Phytochromes in Diatoms: Sensing Far-Red Light in the Deep Blue Sea. PMID- 26952566 TI - Transcript Abundance Explains mRNA Mobility Data in Arabidopsis thaliana. AB - Recently, a large population of mRNA was shown to be able to travel between plant organs via sieve elements as a putative long-distance signaling molecule. However, a mechanistic basis by which transcripts are selected for transport has not yet been identified. Here, we show that experimental mRNA mobility data in Arabidopsis can be explained by transcript abundance and half-life. This suggests that the majority of identified mobile transcripts can be accounted for by non sequence-specific movement of mRNA from companion cells into sieve elements. PMID- 26952567 TI - Women Urologists: Changing Trends in the Workforce. AB - OBJECTIVE: To characterize the current workforce of women urologists in the United States. MATERIALS AND METHODS: An anonymous electronic survey was sent to all members of the Society of Women in Urology and all female non-Society of Women in Urology members of the American Urologic Association. The survey was distributed in January of 2015. Demographic, work, and personal life data were collected. RESULTS: Of 1563 e-mails with a link to our survey sent to women urologists in the United States, 365 surveys were completed for a 23% response rate. The average age of all participants was 39 years (range 25-73 years). Practicing women urologists had an average age of 44 years (range 32-65 years) compared to the average age (53 years) of all practicing urologists reported in the 2014 American Urologic Association Census. The majority of practicing female urologists live and work in a population of >1 million whereas a few live and work in rural areas. Practicing women urologists are most likely to work academic or group practice. Twenty percent of practicing women urologists reported working part-time, but almost 70% report working >50 hours/week. CONCLUSION: Women urologists in the United States are younger than their male counterparts and most work full-time in urban academic centers. PMID- 26952568 TI - Women in Urology Residency, 1978-2013: A Critical Look at Gender Representation in Our Specialty. AB - OBJECTIVE: To evaluate changes over time in female representation among urology residents compared to those within other specialties. MATERIALS AND METHODS: Urology match data were obtained from the American Urological Association from 1996 to 2015. Trends in match rates of male and female urology applicants were assessed. Data for gender representation among residencies were extracted from reports in the Journal of the American Medical Association from 1978 to 2013. We compared the annual percentage of women among urology residents vs residents of other specialties over time. RESULTS: Mean number of male vs female urology applicants per year was 285.0 +/- 27.1 vs 76.5 +/- 21.8 (P < .001). There was no statistically significant difference in the mean successful match rate of male vs female applicants (68.2% vs 66.6%, P = .36). From 1978 to 2013, the proportion of female residents across all specialties rose from 15.4% to 46.1%, whereas female residents in urology rose from 0.9% to 23.8%. Between 2009 and 2013, obstetrics and gynecology and orthopedics had the highest and lowest average proportion of women, respectively (80.7% and 13.5%). The largest growth occurred in urology among all other specialties (P < .001), with an 11-fold increase seen during the study period. CONCLUSION: Male and female applicants to urology residency have similar match rates. Although urology demonstrated the greatest fold-increase in proportion of women among all specialties during the study period, women have remained a minority among urology residents. Gender representation within urology is a reflection of many factors and demonstrates a need for further improvement. PMID- 26952569 TI - Reprint of "Shared adversities of children and comic superheroes as resources for promoting resilience": Comic superheroes are an untapped resource for empowering vulnerable children. PMID- 26952570 TI - Advance Directives: The Key to a Good Death? PMID- 26952571 TI - Prevalence of Frailty and Aging-Related Health Conditions in Older Koreans in Rural Communities: a Cross-Sectional Analysis of the Aging Study of Pyeongchang Rural Area. AB - Frailty has been previously studied in Western countries and the urban Korean population; however, the burden of frailty and geriatric conditions in the aging populations of rural Korean communities had not yet been determined. Thus, we established a population-based prospective study of adults aged >= 65 years residing in rural communities of Korea between October 2014 and December 2014. All participants underwent comprehensive geriatric assessment that encompassed the assessment of cognitive and physical function, depression, nutrition, and body composition using bioimpedance analysis. We determined the prevalence of frailty based on the Cardiovascular Health Study (CHS) and Korean version of FRAIL (K-FRAIL) criteria, as well as geriatric conditions. We recruited 382 adults (98% of eligible adults; mean age: 74 years; 56% women). Generally, sociodemographic characteristics were similar to those of the general rural Korean population. Common geriatric conditions included instrumental activity of daily living disability (39%), malnutrition risk (38%), cognitive dysfunction (33%), multimorbidity (32%), and sarcopenia (28%), while dismobility (8%), incontinence (8%), and polypharmacy (3%) were less common conditions. While more individuals were classified as frail according to the K-FRAIL criteria (27%) than the CHS criteria (17%), the CHS criteria were more strongly associated with prevalent geriatric conditions. Older Koreans living in rural communities have a significant burden of frailty and geriatric conditions that increase the risk of functional decline, poor quality of life, and mortality. The current study provides a basis to guide public health professionals and policy-makers in prioritizing certain areas of care and designing effective public health interventions to promote healthy aging of this vulnerable population. PMID- 26952572 TI - Early-stage adenocarcinoma of the esophagus with mid to deep submucosal invasion (pT1b sm2-3): the frequency of lymph-node metastasis depends on macroscopic and histological risk patterns. AB - The rate of lymph-node (LN) metastasis in early adenocarcinoma (EAC) of the esophagus with mid to deep submucosal invasion (pT1b sm2/3) has not yet been precisely defined. The aim of the this study was to evaluate the rate of LN metastasis in pT1b sm2/3 EAC depending on macroscopic and histological risk patterns to find out whether there may also be options for endoscopic therapy as in cancers limited to the mucosa and the upper third of the submucosa. A total of 1.718 pt with suspicion of EAC were referred for endoscopic treatment (ET) to the Dept. of Internal Medicine II at HSK Wiesbaden 1996-2010. In 230/1.718 pt, the suspicion (endoscopic ultrasound, EUS) or definitive diagnosis of pT1b EAC (ER/surgery) was made. Of these, 38 pt had sm2 lesions, and 69 sm3. Rate of LN metastasis was analyzed depending on risk patterns: histologically low-risk (hisLR): G1-2, L0, V0; histologically high-risk (hisHR): >=1 criterion not fulfilled; macroscopically low-risk (macLR): gross tumor type I-II, tumor size <=2 cm; macroscopically high-risk (macHR): >=1 criterion not fulfilled; combined low-risk (combLR): hisLR+macLR; combined high-risk (combHR): at least 1 risk factor. LN rate was only evaluated in pt who had proven maximum invasion depth of sm2/sm3, and who in case of ET had a follow-up (FU) by EUS of at least 24 months. 23/38 pt with pT1b sm2 lesions and 39/69 pt with sm3 lesions fulfilled our inclusion criteria. In the pT1b sm2 group, rate of LN metastasis in the hisLR, hisHR, combLR, and combHR groups were 8.3% (1/12), 36.3% (4/11), 0% (0/5), and 27.8% (5/18). In the pT1b sm3 group, rate of LN metastasis in the hisLR, hisHR, combLR and combHR groups were 28.6% (2/7), 37.5% (12/32), 25% (1/4), and 37.1% (13/35). 30-day mortality of surgery was 1.7% (1/58 pt). In EAC with pT1b sm2/3 invasion, the frequency of LN metastasis depends on macroscopic and histological risk patterns. Surgery remains the standard treatment, because the rate of LN metastasis appears to be higher than the mortality risk of surgery. Whether a highly selected group of pT1b sm2 patients with a favourable risk pattern may be candidates for endoscopic therapy cannot be decided until the results of larger case volumes are available. PMID- 26952573 TI - beta2-Adrenergic receptor ablation modulates hepatic lipid accumulation and glucose tolerance in aging mice. AB - Catecholamines acting through beta-adrenergic receptors (beta(1)-, beta(2)-, beta(3)-AR subtypes) modulate important biological responses in various tissues. Our previous studies suggest a role for increased hepatic beta-AR-mediated signaling during aging as a mediator of hepatic steatosis, liver glucose output, and insulin resistance in rodents. In the current study, we have utilized beta(2) AR knockout (KO) and wildtype (WT) control mice to define further the role of beta(2)-AR signaling during aging on lipid and glucose metabolism. Our results demonstrate for the first time that age-related increases in hepatic triglyceride accumulation and body weight are attenuated upon beta(2)-AR ablation. Although no differences in plasma triglyceride, non-esterified fatty acids or insulin levels were detected between old WT and KO animals, an age-associated increase in hepatic expression of lipid homeostasis regulator Cidea was significantly reduced in old KO mice. Interestingly, we also observed a shift from reduced glucose tolerance in young adult KO animals to significantly improved glucose tolerance in old KO when compared to age-matched WT mice. These results provide evidence for an important role played by beta(2)-ARs in the regulation of lipid and glucose metabolism during aging. The effect of beta(2)-AR ablation on caloric intake during aging is currently not known and requires investigation. Future studies are also warranted to delineate the beta(2)-AR-mediated mechanisms involved in the control of lipid and glucose homeostasis, especially in the context of a growing aging population. PMID- 26952574 TI - Collective-Intelligence Recommender Systems: Advancing Computer Tailoring for Health Behavior Change Into the 21st Century. AB - BACKGROUND: What is the next frontier for computer-tailored health communication (CTHC) research? In current CTHC systems, study designers who have expertise in behavioral theory and mapping theory into CTHC systems select the variables and develop the rules that specify how the content should be tailored, based on their knowledge of the targeted population, the literature, and health behavior theories. In collective-intelligence recommender systems (hereafter recommender systems) used by Web 2.0 companies (eg, Netflix and Amazon), machine learning algorithms combine user profiles and continuous feedback ratings of content (from themselves and other users) to empirically tailor content. Augmenting current theory-based CTHC with empirical recommender systems could be evaluated as the next frontier for CTHC. OBJECTIVE: The objective of our study was to uncover barriers and challenges to using recommender systems in health promotion. METHODS: We conducted a focused literature review, interviewed subject experts (n=8), and synthesized the results. RESULTS: We describe (1) limitations of current CTHC systems, (2) advantages of incorporating recommender systems to move CTHC forward, and (3) challenges to incorporating recommender systems into CTHC. Based on the evidence presented, we propose a future research agenda for CTHC systems. CONCLUSIONS: We promote discussion of ways to move CTHC into the 21st century by incorporation of recommender systems. PMID- 26952575 TI - G9a inhibition promotes neuronal differentiation of human bone marrow mesenchymal stem cells through the transcriptional induction of RE-1 containing neuronal specific genes. AB - Recent studies have shown that epigenomic modifications are significantly associated with neuronal differentiation. Many neuronal specific genes contain the repressor element-1 (RE-1), which recruits epigenetic modulators, such as the histone methyltransferase G9a and interrupts the expression of neuronal genes in non-neuronal cells. This study investigated the functional role of G9a during neuronal differentiation of human bone marrow mesenchymal stem cells (BM-MSCs). Human BM-MSCs treated with the G9a inhibitor BIX01294 showed an increased expression of various neuronal-lineage genes. Using genomic sequence analysis, we identified RE-1 consensus sequences in the proximal region of several neuronal specific genes. Chromatin immunoprecipitation (ChIP) assay results have showed that H3K9me2 (dimethylation of lysine 9 on histone 3) occupancy at RE-1 containing sequences from neuronal-specific genes was significantly decreased in BIX01294-MSCs. When BIX01294-MSCs were differentiated with neuronal induction medium, cells differentiated more effectively into neuron-like cells, complete with a cell body and dendrites. Expression of neuronal-specific genes containing the RE-1 sequences was significantly increased in differentiated BIX01294-MSCs, as confirmed by immunocytochemical staining and immunoblotting. Thus, this study shows that BIX01294 pretreated human BM-MSCs can be effectively differentiated into neuron-like cells by induced expression of neuronal-specific genes containing RE-1 sequences. PMID- 26952576 TI - Associations Between Sibling Relationship Quality and Friendship Quality in Early Adolescence: Looking at the Case of Twins. AB - Bidirectional pathways between twin relationship quality and friendship quality were investigated in a large longitudinal twin cohort. We examined negative and positive relationship features in 313 monozygotic (MZ) twins and 238 same-sex dizygotic (DZ) twins from ages 13 to 14 years, using latent structural modeling. Results showed stronger stability of the twin relationship quality compared to friendship quality. Positive features in the sibling relationship were associated with increased positive features in the relationship with the best friend a year later. In contrast, no significant association between negative sibling relationship features and change in negative friendship quality features was found. These findings speak to the important role of the sibling relationship in the development of good quality friendship relations in twins. PMID- 26952577 TI - Diagnostic Performance of Endoscopic Ultrasound (EUS) for Non-Calcific Chronic Pancreatitis (NCCP) Based on Histopathology. AB - OBJECTIVES: Studies correlating endoscopic ultrasound (EUS) with histopathology for chronic pancreatitis (CP) are limited by small sample size, and/or inclusion of many patients without CP, limiting applicability to patients with painful CP. The aim of this study was to assess correlation of standard EUS features for CP with surgical histopathology in a large cohort of patients with non-calcific CP (NCCP). METHODS: Adult patients undergoing total pancreatectomy and islet autotransplantation (TPIAT) for NCCP, between 2008 and 2013, with EUS <1 year before surgery. Histology from resected pancreas at the time of TPIAT (from head, body, and tail) was graded by a GI pathologist blinded to the EUS features. A fibrosis score (FS) >=2 was abnormal, and FS>=6 was considered severe fibrosis. A multivariate regression analysis for the EUS features predicting fibrosis, after taking age, sex, smoking, and body mass index into consideration, was performed. A quantitative receiver operating characteristic (ROC) curve analysis was performed and Spearman rank correlation co-efficient (r) was calculated. RESULTS: 68 patients (56 females, mean+/-s.d. age-38.77+/-10.92) underwent TPIAT for NCCP with pre-operative EUS. ROC curve showed that four or more EUS features provided the best balance of sensitivity (61%), specificity (75%), and accuracy (63%). Although significant, correlation between standard EUS features and degree of fibrosis was poor (r=0.24, P<0.05). Multivariate regression analysis showed that main pancreatic duct irregularity was the only independent EUS feature (P=0.02) which predicted CP. CONCLUSIONS: Correlation between standard EUS features and histopathology is poor in NCCP. MPD irregularity is an independent predictor for NCCP. PMID- 26952578 TI - ACG Clinical Guideline: Nutrition Therapy in the Adult Hospitalized Patient. AB - The value of nutrition therapy for the adult hospitalized patient is derived from the outcome benefits achieved by the delivery of early enteral feeding. Nutritional assessment should identify those patients at high nutritional risk, determined by both disease severity and nutritional status. For such patients if they are unable to maintain volitional intake, enteral access should be attained and enteral nutrition (EN) initiated within 24-48 h of admission. Orogastric or nasogastric feeding is most appropriate when starting EN, switching to post pyloric or deep jejunal feeding only in those patients who are intolerant of gastric feeds or at high risk for aspiration. Percutaneous access should be used for those patients anticipated to require EN for >4 weeks. Patients receiving EN should be monitored for risk of aspiration, tolerance, and adequacy of feeding (determined by percent of goal calories and protein delivered). Intentional permissive underfeeding (and even trophic feeding) is appropriate temporarily for certain subsets of hospitalized patients. Although a standard polymeric formula should be used routinely in most patients, an immune-modulating formula (with arginine and fish oil) should be reserved for patients who have had major surgery in a surgical ICU setting. Adequacy of nutrition therapy is enhanced by establishing nurse-driven enteral feeding protocols, increasing delivery by volume-based or top-down feeding strategies, minimizing interruptions, and eliminating the practice of gastric residual volumes. Parenteral nutrition should be used in patients at high nutritional risk when EN is not feasible or after the first week of hospitalization if EN is not sufficient. Because of their knowledge base and skill set, the gastroenterologist endoscopist is an asset to the Nutrition Support Team and should participate in providing optimal nutrition therapy to the hospitalized adult patient. PMID- 26952580 TI - Malignant liver adenoma in men: report of 2 cases. PMID- 26952579 TI - Association of Vitamin D Level With Clinical Status in Inflammatory Bowel Disease: A 5-Year Longitudinal Study. AB - OBJECTIVES: Emerging data suggest that vitamin D has a significant role in inflammatory bowel disease (IBD). Prospective data evaluating the association of vitamin D serum status and disease course are lacking. We sought to determine the relationship between vitamin D status and clinical course of IBD over a multiyear time period. METHODS: IBD patients with up to 5-year follow-up from a longitudinal IBD natural history registry were included. Patients were categorized according to their mean serum 25-OH vitamin D level. IBD clinical status was approximated with patterns of medication use, health-care utilization, biochemical markers of inflammation (C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR)), pain and clinical disease activity scores, and health related quality of life. RESULTS: A total of 965 IBD patients (61.9% Crohn's disease, 38.1% ulcerative colitis) formed the study population (mean age 44 years, 52.3% female). Among them, 29.9% had low mean vitamin D levels. Over the 5 year study period, subjects with low mean vitamin D required significantly more steroids, biologics, narcotics, computed tomography scans, emergency department visits, hospital admissions, and surgery compared with subjects with normal mean vitamin D levels (P<0.05). Moreover, subjects with low vitamin D levels had worse pain, disease activity scores, and quality of life (P<0.05). Finally, subjects who received vitamin D supplements had a significant reduction in their health care utilization. CONCLUSIONS: Low vitamin D levels are common in IBD patients and are associated with higher morbidity and disease severity, signifying the potential importance of vitamin D monitoring and treatment. PMID- 26952581 TI - Acute necrotizing pancreatitis and sudden abdominal mass: An unusual complication. PMID- 26952583 TI - Growth and follow-up of primary cortical neuron cells on nonfunctionalized graphene nanosheet film. AB - BACKGROUND: Conductive biomaterials are an ideal biosubstrate for modifying cellular behaviors by conducting either internal or external electrical signals. In this study, based on a simple-preparation graphite exfoliation method in organic reagent, a nonfunctionalized graphene nanosheet film (NGNF) with high conductivity and large size was simply fabricated through spraying coating. The biocompatibility of the NGNF was carefully tested with primary cortical neuron cells, and its biocompatibility properties were compared with a chemical vapor deposition (CVD) graphene film. METHODS: Nonfunctionalized graphene nanosheet (NGN) was first exfoliated from graphite with a flat-tip ultrasonicator probe, and then spray-coated onto glass slide substrate to form the film. The morphology of NGNF was observed with light microscopy and SEM. The morphology and neuronal network formation of primary cortical neuron cells onto NGNF, as shown by DAPI and Alexa Fluor(r) 488 staining, were observed with fluorescent microscopy. Cell viability and proliferation were measured with MTT. RESULTS: NGNF had better cell biocompatibility than CVD graphene film. MTT test showed that NGNF exhibited no cytotoxicity. According to neuronal network formation at 7 days of cell culture, primary neuron cells aggregated into 50-MUm "nuclei"; the average neurite number and length were 3 and 100 MUm, respectively. However, these values were almost doubled after 14 days of cell culture. CONCLUSIONS: These results may improve the use of NGNF as a conductive scaffold for nerve regeneration. PMID- 26952582 TI - Maternal and neonatal outcomes in women with severe pre-eclampsia undergoing cesarean section: a 10-year retrospective study from a single tertiary care center: anesthetic point of view. AB - OBJECTIVE: This study is aiming to determine an actual incidence and characteristics of complications in cesarean section for severe pre-eclampsia (PE) by analysis of a large cohort from a single tertiary care center according to two choices of anesthesia. METHODS: Electronic medical records of pregnant women complicated with severe PE delivered by cesarean section from January 2002 to December 2011 were retrospectively reviewed. Medical records of their corresponding neonates were also identified and reviewed. RESULTS: A total of 701 women and 740 neonates (28 twin pairs) were identified. Anesthetic techniques were spinal anesthesia (SA) (88%) and general anesthesia (GA) (12%). Total maternal and neonatal deaths were 0.3% and 1.2%, respectively. Patients in GA group had a higher incidence of coagulopathy, immediate postpartum hemorrhage, intensive care unit admission, renal failure, respiratory complications, and death (p < 0.05). Neonates born from women in GA group had a higher incidence of lower birth weight, birth asphyxia, prematurity, neonatal intensive care admission, respiratory complications, and death (p < 0.05). CONCLUSION: Spinal anesthesia can be safely administered to severely pre-eclamptic parturients undergoing cesarean section. General anesthesia is associated with more untoward outcomes, as it has been chosen in patients with more severity of the disease. PMID- 26952584 TI - Comparison of shear bond strength of universal adhesives on etched and nonetched enamel. AB - BACKGROUND: The purpose of this study was to evaluate the effect of surface pretreatment with 37% phosphoric acid on the enamel bond strength of different universal adhesives. METHODS: One hundred and sixty bovine permanent mandibular incisors freshly extracted were used as a substitute for human teeth. The materials tested in this study included 6 universal adhesives, and 2 self-etch adhesives as control. The teeth were assigned into 2 groups: In the first group, etching was performed using 37% phosphoric acid for 30 seconds. In the second group, no pretreatment agent was applied. After adhesive application, a nanohybrid composite resin was inserted into the enamel surface by packing the material into cylindrical-shaped plastic matrices. After storing, the specimens were placed in a universal testing machine. The normality of the data was calculated using the Kolmogorov-Smirnov test. Analysis of variance (ANOVA) was applied to determine whether significant differences in debond strength values existed among the various groups. RESULTS: Groups with phosphoric acid pretreatment showed significantly higher shear bond strength values than groups with no enamel pretreatment (p<0.001). No significant variation in shear strength values was detected when comparing the different adhesive systems applied onto enamel after orthophosphoric acid application (p>0.05). CONCLUSIONS: All adhesives provide similar bond strength values when enamel pretreatment is applied even if compositions are different. Bond strength values are lower than promised by manufacturers. PMID- 26952585 TI - Toxicity assessment and selective leaching characteristics of Cu-Al-Ni shape memory alloys in biomaterials applications. AB - BACKGROUND: Cu-Al-Ni shape memory alloys (SMAs) possess two-way shape memory effects, superelasticity, and damping capacity. Nonetheless, Cu-Al-Ni SMAs remain promising candidates for use in biomedical applications, as they are more economical and machinable than other SMAs. Ensuring the biocompatibility of Cu-Al Ni SMAs is crucial to their development for biomedical applications. Therefore, this study aimed to assess the toxicity of Cu-Al-Ni SMAs using a Probit dose response model and augmented simplex design. METHODS: In this study, the effects of Cu2+, Al3+ and Ni2+ metal ions on bacteria (Escherichia coli DH5alpha) using Probit dose-response analysis and augmented simplex design to assess the actual toxicity of the Cu-Al-Ni SMAs. RESULTS: Extraction and repetition of Escherichia coli DH5alpha solutions with high Cu2+ ion concentrations and 30-hour incubation demonstrated that Escherichia coli DH5alpha was able to alter its growth mechanisms in response to toxins. Metal ions leached from Cu-Al-Ni SMAs appeared in a multitude of compositions with varying degrees of toxicity, and those appearing close to a saddle region identified in the contour plot of the augmented simplex model were identified as candidates for elevated toxicity levels. When the Cu-13.5Al-4Ni SMA plate was immersed in Ringer's solution, the selective leaching rate of Ni2+ ions far exceeded that of Cu2+ and Al3+. The number of Cu2+, Al3+ and Ni2+ ions leached from Cu-Al-Ni SMAs increased with immersion time; however, at higher ratios, toxicity interactions among the metal ions had the effect of gradually reducing overall toxicity levels with regard to Escherichia coli DH5alpha. CONCLUSIONS: The quantities of Cu2+, Al3+ and Ni2+ ions leached from the Cu-13.5Al-4Ni SMA plate increased with immersion time, the toxicity interactions associated with these compositions reduced the actual toxicity to Escherichia coli DH5alpha. PMID- 26952586 TI - Investigation into the elastic properties of ex vivo porcine corneas subjected to inflation test after cross-linking treatment. AB - BACKGROUND: The aim of this work was to evaluate the effect of cross-linking (CXL) on ex vivo porcine corneal elastic properties, using an inflation procedure. METHODS: Twelve corneas were subjected to standard CXL (370 nm, 3 mW/cm2, 30 minutes), while 12 were used as controls. Corneal thickness was measured by Visante optical coherence tomography, before and immediately after treatment, and before inflation test. Both intraocular pressure and radial apical cornea displacement were measured during inflation. Stress-strain curves were obtained by applying the linear shell theory. The elastic modulus was evaluated by calculating the slope of the stress-strain curves. RESULTS: Results showed a statistically significant increase in elastic modulus (p<0.0001), with a mean of 3,868 +/- 502 kPa for cross-linked corneas and 2,727 +/- 238 kPa for untreated corneas, when subjected to high pressure (40-60 kPa). CXL significantly increased porcine cornea stiffness by about 42%. Findings did not show any significant difference within the physiological range of pressure (2-4 kPa). CONCLUSIONS: The inflation test has been proven to be a valuable tool for the investigation of corneal biomechanics, maintaining both integrity and geometry of corneal tissue. PMID- 26952587 TI - Electrical and microstructural characterization of ceramic gadolinium-doped ceria electrolytes for ITSOFCs by sol-gel route. AB - BACKGROUND: Gadolinium-doped ceria (GDC) is a promising alternative as a solid electrolyte for intermediate temperature solid oxide fuel cells (ITSOFCs) due to its low operating temperature and its high electrical conductivity. The traditional synthesis processes require extended time for powder preparation. Sol gel methodology for electrolyte fabrication is more versatile and efficient. METHODS: In this work, nanocrystalline ceria powders, with 10 and 20 mol% of gadolinium (Ce0.9Gd0.1O1.95 and Ce0.8Gd0.2O1.9) were synthesized by a modified sol-gel technique, featuring a nitrate-fuel exothermic reaction. GDC tablets were prepared from powders and sintered at 1500 degrees C with a dwell time of 3 hours. The sintered pellets' microstructure (by SEM) and electrical conductivity (by EIS) were evaluated. The powder properties, such as crystalline structure (by XRD), thermal properties (TGA/DTA), particle size and morphology (TEM) and textural properties (BET method) were determined and, in addition, for the first time an accurate chemical structural evolution (FTIR) was studied. RESULTS: Sintered GDC0.8 samples exhibited the maximum theoretical density of 97% and an average grain size of 700 nm. The electrical conductivity vs. temperature showed values ranging from 1.9?10(-2) to 5.5?10(-2) S.cm(-1) at 600 degrees C and 800 degrees C for GDC with 20 mol% of gadolinium. CONCLUSIONS: The methodology investigated showed reduced reaction time, a better control of stoichiometry and low cost. Characterization results demonstrated that these materials can be applied in ITSOFCs due to high conductivity, even at 550 degrees C-600 degrees C. The increased conductivity is related to the improved mobility of gadolinium ions in a high-density structure, with nanometric grains. PMID- 26952588 TI - Effects of silver nanoparticles on primary cell cultures of fibroblasts and keratinocytes in a wound-healing model. AB - BACKGROUND: Nanoparticles are widely used in different technological fields, one of which is medicine. Because of their antibacterial properties, silver nanoparticles (AgNPs) are used in several types of wound dressings for the treatment of burns and nonhealing wounds, but their influence on each component of the wound-healing process remains unclear. In the present study, we evaluated the effects of AgNPs on normal human dermal fibroblasts (NHDFs) and normal human epidermal keratinocytes (NHEKs). Both cell types are important for wound healing, including with regard to inflammation, proliferation and tissue remodeling. Each phase of wound healing can be characterized by the secretion of cytokines, chemokines and growth factors. METHODS: The production of inflammatory parameters (tumor necrosis factor alpha [TNF-alpha], interleukin-6 [IL-6], IL-8 and IL-12 and cyclooxygenase-2 [COX-2]), angiogenesis parameters (vascular endothelial growth factor [VEGF], granulocyte macrophage colony-stimulating factor) and matrix metalloproteinases (MMP-1, MMP-2, MMP-3 and MMP-9) by NHDFs and NHEKs were examined by ELISA or Western blot after 24 and 48 hours of incubation with AgNPs. RESULTS: We found that AgNPs decreased some inflammatory cytokines (TNF-alpha and IL-12) and growth factors (VEGF) that were produced by NHDFs and NHEKs after 24 and 48 hours and decreased the expression of COX-2 after 24 hours but only at the highest concentration of AgNPs (25 parts per million). CONCLUSIONS: The results indicate that NHEKs are more susceptible to the application of AgNPs than NHDFs, and AgNPs may be useful for medical applications for the treatment of wounds. PMID- 26952589 TI - Structure and bonding of group 4-nickel heterobimetallics supported by 2 (diphenylphosphino)pyrrolide ligands. AB - The synthesis of a full series of group 4/nickel complexes supported by a 2 (diphenylphosphino)pyrrolide (NP) ligand is reported. Treatment of the homoleptic, 8-coordinate M(NP)4 monometallic precursors with Ni(COD)2 (COD = 1,5 cyclooctadiene) yielded the heterobimetallic complexes (kappa(2)-NP)M(MU2-NP)3Ni (M = Ti, Zr, Hf). Although X-ray crystallographic analysis reveals similarly short metal-metal distances in all three complexes, quantum chemical calculations indicate that ZrNi () and HfNi () contain only single Ni -> M dative bonds while TiNi () has an additional Ti-Ni pi-bond. All three complexes have quasireversible reductions by cyclic voltammetry, and 1-electron chemical reduction of by Na(Hg) yields the anion, [Na][(kappa(2)-NP)Ti(MU2-NP)3Ni] (). X-ray and computational analysis indicate that the 1-electron reduction of completely breaks the metal metal bond, yielding a formally Ti(III)-Ni(0) complex. Ti-Ni bonding can also be disrupted by coordination of CO, wherein Ni -> CO backbonding effectively outcompetes Ni -> Ti dative bonding. PMID- 26952590 TI - Asians compared to Whites show increased response to d-amphetamine on select subjective and cardiovascular measures. AB - OBJECTIVE: Identifying factors that moderate subjective response to stimulants is important for understanding individuals at risk for abusing these drugs. Some research suggests that Asians may respond differently to stimulants than other races, but controlled human laboratory research of stimulant administration effects in Asians is scant. METHODS: In this double-blind counterbalanced within subject study, healthy stimulant-naive participants (N = 65; 55% Asian; 63% female; age 18-35) received a single dose of 20-mg oral d-amphetamine or placebo on separate days. At each testing day, subjective measures of abuse liability and cardiovascular assessments were administered at repeated intervals before and after drug administration over a 4-hour period. RESULTS: Asians (vs. Whites) demonstrated greater d-amphetamine-induced increases in diastolic blood pressure and ratings of 'Feel High' and 'Like Drug'. CONCLUSIONS: Asian and White healthy young adults may differ in certain subjective and cardiovascular responses to acute doses of d-amphetamine. Such individual differences could help explain between-person differences in abuse potential of d-amphetamine and other stimulants. PMID- 26952591 TI - The Impact of Topical Corticosteroids Used in Conjunction with Antiamoebic Therapy on the Outcome of Acanthamoeba Keratitis. AB - PURPOSE: To examine the impact of topical corticosteroid use after the start of antiamoebic therapy (AAT) on the outcomes of Acanthamoeba keratitis (AK) therapy. DESIGN: Cohort study. PARTICIPANTS: A total of 196 patients diagnosed with AK at Moorfields Eye Hospital, London, between January 1991 and April 2012. In 13 patients with bilateral AK, 1 eye was randomly excluded from analysis. METHODS: Patient demographics and clinical examination findings were collected both at the start of AAT and subsequently at the time that topical corticosteroid therapy was initiated. Preliminary a priori investigations were used to identify effect modifiers/confounders and extreme associations requiring consideration in multivariate regression modeling. A multivariable logistic model, optimized for assessment of corticosteroid use after the start of AAT, was used to estimate the odds ratios (ORs) of a suboptimal outcome. MAIN OUTCOME MEASURES: Suboptimal outcome was defined as final visual acuity <=20/80, corneal perforation, or the need for keratoplasty. RESULTS: In multivariable analysis, restricted to 129 eyes (1 eye per patient) free of scleritis and hypopyon at the start of AAT, topical corticosteroids were not associated with worse outcomes (OR, 1.08; 95% confidence interval [CI], 0.39-3.03), even when corticosteroids had been used before the start of AAT. Risk factors significantly associated with worse outcomes were topical corticosteroid use before the start of AAT (OR, 3.85; 95% CI, 1.35 11.03), a corneal ring infiltrate (together with at least 1 other feature of AK) present at the start of AAT (OR, 5.89; 95% CI, 1.17-29.67), and age >=33 years at the start of AAT (OR, 4.02; 95% CI, 1.46-11.06). CONCLUSIONS: Many corneal specialists currently are uncertain about the risk benefit associated with the use of topical corticosteroids for the management of inflammatory complications of AK. The evidence from this study gives clinicians and patients reassurance that the potential benefits of topical corticosteroid therapy, for treating pain and discomfort, are not associated with worse outcomes when initiated after starting modern AAT. Other potential benefits, in terms of resolution of inflammatory complications, will not be demonstrated without a carefully designed randomized clinical trial. PMID- 26952592 TI - Anatomic Clinical Trial Endpoints for Nonexudative Age-Related Macular Degeneration. AB - TOPIC: To review the role of anatomic endpoints in clinical trials for the study of nonexudative age-related macular degeneration (AMD) with an emphasis on a novel composite endpoint for the study of emerging therapies for intermediate AMD (iAMD). CLINICAL RELEVANCE: Unlike clinical trials for exudative AMD, it is impractical to use the change in visual acuity (VA) as a primary endpoint for the study of nonexudative AMD. By the time VA has been lost in nonexudative AMD, proof-of-concept early-stage clinical trials would take years to run, and drug development would be a near impossible task. Surrogate endpoints are needed that reliably predict future vision loss and can be easily measured. Anatomic changes that correlate with disease progression in nonexudative AMD offer the greatest promise as primary endpoints. METHODS: In preparation for this review, the electronic PubMed database was searched for relevant research pertaining to anatomic endpoints for the study of nonexudative AMD. Paper selection was based on our knowledge of the field with the goal to be as inclusive as possible. Whenever possible, recent review articles and results from large clinical trials, preferably with outcomes from many years of follow-up were favored over trials of short duration. RESULTS: The most commonly used anatomic endpoint for the study of late, nonexudative AMD is the growth of geographic atrophy (GA). The advantages of studying GA include the appreciation that its enlargement through the foveal center leads to significant vision loss through the availability of natural history studies, the understanding that prevention of this growth would preserve vision in the future, the ability to reliably measure GA using different imaging strategies, and the development appropriate statistical tools that reliably predict the growth of GA over time. The major disadvantage of using GA is that significant, irreversible disease progression has already occurred. The use of drusen volume as a predictor of disease progression and the use of a composite endpoint that incorporates drusen growth, formation of GA, and formation of neovascularization offers an opportunity to study therapies at an earlier stage of AMD with a greater likelihood of preserving better vision over a lifetime. CONCLUSIONS: Anatomic endpoints for the study of nonexudative AMD are needed to accelerate drug development, and the availability of optical coherence tomography algorithms capable of reliably measuring drusen morphology offer the best opportunity to study therapies for iAMD. PMID- 26952594 TI - Breast Lymphatic Mapping and Sentinel Lymph Node Biopsy: State of the Art: 2015. AB - Lymphatic mapping with sentinel lymph node biopsy (SLNB) was introduced in the 1990s as a method to stage the nodal axilla in women with breast cancer. Very quickly the technique became the standard of care because pathologic staging was more accurate and sensitive and the surgical procedure resulted in low morbidity. SLNB has continued to evolve, and the applications in breast cancer have been expanded. A review of the published data was performed to update the lymphatic mapping technique and identify key issues and trends in the application of SLNB in women with breast cancer in 2015. The importance of axillary staging continues to effect the surgical treatment of patients with breast cancer. Originally described for patients with invasive cancer, the technique now plays an important role in staging women with ductal carcinoma in situ or recurrent breast cancer and patients with advanced breast cancer who are receiving neoadjuvant chemotherapy. Histologic examinations have incorporated multiple sectioning and immunostains. The morbidity has been low, and techniques for limiting lymphedema are being introduced. Lymphatic mapping will continue to play an important role in the treatment of women with breast cancer. The SLNB will evolve by eliminating the need for radioactivity in the operating room, and the technique will become more accurate and used in expanded indications by incorporating preoperative imaging and intraoperative guidance procedures. PMID- 26952593 TI - Outcomes after Failed Pneumatic Retinopexy for Retinal Detachment. AB - PURPOSE: To provide visual and anatomic outcomes for patients with retinal detachment (RD) in whom primary pneumatic retinopexy (PR) failed. DESIGN: Retrospective, single-center, consecutive case series. PARTICIPANTS: Eyes with RD that failed a primary PR. METHODS: Anatomic and functional outcomes were evaluated for patients receiving treatment for failed PR. Three secondary procedures were compared, including repeat PR, pars plana vitrectomy (PPV), and combined scleral buckle (SB) plus PPV (SB+PPV). MAIN OUTCOME MEASURES: Anatomic reattachment and visual acuity (VA) at 1 year. RESULTS: Of a total of 423 primary PRs performed for RD, this study included 73 cases that failed. The overall single surgery anatomic success rate for the secondary procedure was 75%; the final success rate at 1 year was 100%. There was no statistically significant difference in success rates between repeat PR (63%), PPV (76%), and SB+PPV (88%). Improvement in VA was similar at 1 year between all 3 groups. Visual acuity at 1 year was similar between eyes undergoing PPV and SB+PPV (0.47 logMAR VA [Snellen equivalent, 20/59] for PPV and 0.52 logMAR VA [Snellen equivalent, 20/66] for SB+PPV; P = 0.75). Visual acuity at 1 year was better for those without macular involvement at the time of secondary procedure compared with eyes whose maculae detached (0.29 logMAR VA [Snellen equivalent, 20/39] vs. 0.73 logMAR VA [Snellen equivalent, 20/106]; P < 0.005). Fifty percent of PR failures underwent a secondary procedure within 1 week of primary PR; 80% occurred within 1 month. CONCLUSIONS: Anatomic success rates for secondary PR, PPV, and SB+PPV after failed PR were lower than published success rates for their use in primary RD. This suggests that a failed primary PR selects for RDs that are inherently more difficult to reattach. There was a trend suggesting that anatomic success rates are greater with SB+PPV than PPV and, in turn, with PPV than repeat PR. However, these differences were not statistically significant and did not translate into better VA gains at 1 year for either procedure. The suitable procedure after failed PR thus depends on patient presentation, surgeon preference, and patient preference. PMID- 26952634 TI - Properties of (Ga1-x In x )2O3 over the whole x range. AB - Using density-functional ab initio theoretical techniques, we study (Ga1-x In x )2O3 in both its equilibrium structures (monoclinic [Formula: see text] and bixbyite) and over the whole range of composition. We establish that the alloy exhibits a large and temperature-independent miscibility gap. On the low-x side, the favored phase is isostructural with [Formula: see text]-Ga2O3; on the high-x side, it is isostructural with bixbyite In2O3. The miscibility gap opens between approximately 15% and 55% In content for the bixbyite alloy grown epitaxially on In2O3, and 15% and 85% In content for the free-standing bixbyite alloy. The gap, volume and band offsets to the parent compound also exhibit anomalies as function of x. Specifically, the offsets in epitaxial conditions are predominantly type-B staggered, but have opposite signs in the two end-of-range phases. PMID- 26952595 TI - Importance of Surgical Margin Status in Ductal Carcinoma In Situ. AB - BACKGROUND: The purpose of the study was to identify the effect of final surgical margin (SM) status and re-excision on outcomes in patients with ductal carcinoma in situ (DCIS) who underwent breast conservation therapy (BCT). PATIENTS AND METHODS: The study population consisted of women diagnosed with DCIS who underwent BCT between 1989 and 2014. All women received adjuvant whole breast radiation and a boost. The primary end point was local control (LC). Final SMs were defined according to margin width: negative SM was defined as > 2 mm, close SM was defined as > 0 to <= 2 mm, and a positive SM was defined as tumor on ink. The Cox proportional hazards model was used to determine predictors of outcomes on multivariable analysis. Actuarial incidence of LC was estimated using the Kaplan-Meier method. RESULTS: A total of 498 patients were included; 400 patients had a final negative SM, 87 had a close SM, and 11 had a positive SM. A total of 172 patients received adjuvant hormonal therapy, 265 patients required >= 1 re excision. Patients with positive or close SMs were more likely to receive a radiation dose > 60 Gy (P < .001) and undergo re-excision (P < .01). The 10-year LC rates were not significantly different between patients with a negative (93.5%), close (91.8%), or positive (100%) SM (P = .57). There was no difference in LC in patients who underwent re-excision for initial close or positive SMs (P = .55). CONCLUSION: This single-institution experience showed that risks of local recurrence remain poorly characterized. Re-excision and whole breast radiation with boost resulted in excellent LC for women with DCIS. Trials aimed at personalized deintensified local therapy are warranted. PMID- 26952635 TI - Supramolecular self-assembly of graphene oxide and metal nanoparticles into stacked multilayers by means of a multitasking protein ring. AB - Graphene oxide (GO) is rapidly emerging worldwide as a breakthrough precursor material for next-generation devices. However, this requires the transition of its two-dimensional layered structure into more accessible three-dimensional (3D) arrays. Peroxiredoxins (Prx) are a family of multitasking redox enzymes, self assembling into ring-like architectures. Taking advantage of both their symmetric structure and function, 3D reduced GO-based composites are hereby built up. Results reveal that the "double-faced" Prx rings can adhere flat on single GO layers and partially reduce them by their sulfur-containing amino acids, driving their stacking into 3D multi-layer reduced GO-Prx composites. This process occurs in aqueous solution at a very low GO concentration, i.e. 0.2 mg ml(-1). Further, protein engineering allows the Prx ring to be enriched with metal binding sites inside its lumen. This feature is exploited to both capture presynthesized gold nanoparticles and grow in situ palladium nanoparticles paving the way to straightforward and "green" routes to 3D reduced GO-metal composite materials. PMID- 26952636 TI - Tension Pneumopericardium after Pericardiocentesis. AB - Pneumopericardium is defined as the presence of air inside the pericardial space. Usually, it is reported as a complication of blunt or penetrating chest trauma, but rare iatrogenic and spontaneous cases have been reported. Pneumopericardium is relatively stable if it does not generate a tension effect on the heart. However, it may progress to tension pneumopericardium, which requires immediate pericardial aspiration. We report a case of iatrogenic pneumopericardium occurred in a 70-year-old man who presented dyspnea at emergency department. The patient underwent pericardiocentesis for cardiac tamponade due to large pericardial effusion, and iatrogenic tension pneumopericardium occurred due to misuse of the drainage device. After evacuating the pericardial air through the previously implanted catheter, the patient became stable. We report this case to increase the awareness of this fatal condition and to help increase the use of precautions against the development of this condition during emergency procedures. PMID- 26952637 TI - Role of S and Se atoms on the microstructural properties of kesterite Cu2ZnSn(S(x)Se(1-x))4 thin film solar cells. AB - Microstructural properties of Cu2ZnSn(S(x)Se(1-x))4 kesterite solid solutions were investigated using grazing incidence X-ray diffraction for the full interval of anion compositions in order to explore the influence of S and Se atoms on the thin film morphology. Thin films were prepared by sputtering deposition of metallic precursors, which were then submitted to a high temperature sulfo selenization process. By adjusting process parameters samples from sulfur- to selenium-pure (0 <= x <= 1) were made. Microstructural analysis shows a strong dependence of domain size and microstrain on composition. Both values increase with higher sulfur content, and depth profile analysis by grazing incidence X-ray diffraction shows selenium-rich films tend to have a more homogeneous depth distribution of domain size. The increasing trend in domain size of S-rich absorbers can be related to lower formation energies of the sulfur binary phases leading to formation of kesterites, while the increase in the microstrain is explained by the substitution of larger Se atoms with smaller S atoms in the host lattice and the presence of secondary phases. PMID- 26952638 TI - Interference with daily activities and major adverse events during esophageal pH monitoring with bravo wireless capsule versus conventional intranasal catheter: a systematic review of randomized controlled trials. AB - For three decades, ambulatory 24-hour intranasal pH monitoring has been the established gold standard for detecting acid reflux in patients with refractory gastroesophageal reflux disease. However, device-associated adverse events and unpleasant experiences, reported by patients during pH monitoring have led to the invention of more convenient pH monitors such as Bravo wireless capsule. To compare the interference with daily activities and major adverse events during pH monitoring with Bravo wireless capsule (Bravo) versus conventional intranasal catheter (catheter), PubMed, Cochrane Library, Clinical Trials.gov, and Google Scholar were searched up to March 20, 2015. Only randomized controlled trials in adult patients that compared the interference with routine daily activities and adverse events between Bravo and catheter pH monitors were included. After screening 574 articles, three unique studies with 167 patients met our inclusion criteria. The average age of patients enrolled in these studies was 51 years. Interference with normal daily activities was more in the catheter than Bravo group: 75 +/- 5 versus 92 +/- 2, P < 0.001 (Andrews et al, findings were reported as100 mm, mean visual analogue scale (VAS) +/- standard error of the mean, 100 = completely normal); Wong et al. (mean +/- standard error of the mean): 1.3 +/- 0.2 versus 0.32 +/- 0.1, P = 0.001 and Wenner et al. using 10 cm median VAS (Interquartile range),10 been the worst is 5.7 (2.3-8.0) compared to 0.7 (0.2 3.4), P < 0.0001, respectively. Overall adverse events were more in the catheter group than Bravo (39 +/- 4 vs. 26 +/- 4, P = 0.012 for Andrews et al. (100 been the worst) and 5.1 (2.0-6.6) vs. 2.1 (0.5-4.6), P < 0.001 for Wenner et al.). No overall adverse events recorded for Wong et al. Most patients in catheter group complained of nasal and throat symptoms. Significantly, runny nose in 24 out of 25 patients (96%) catheter versus 13 out of 25 (52%) Bravo, P = 0.001 and nose pain 15 out 25 (60%) versus 8 out of 25 patients (32%), P = 0.047, respectively for Wong et al. Andrews and Wenner et al also showed profound nasal discomforts in catheter group compared to Bravo (39 +/- 3 vs. 10 +/- 3, P < 0.001 and 6.5 (1.5-8.0) versus 0.2 (0.0-1.9), P < 0.0001, respectively. Throat symptoms reported in Wong et al. were mainly throat discomfort in catheter group 23 out of 25 patients (92%) versus Bravo 12 out of 25 (48%), P = 0.001 and throat pain catheter (12 out of 25 patients (48%) vs. Bravo 4 out of 25 (16%)), P = 0.032. This trend was also observed in Andrews et al. with profound throat discomfort in the catheter group 43 +/- 4 compared to Bravo 19 +/- 4, P < 0.001. Majority of the patients randomized to Bravo group reportedly perceived chest pain higher than those in catheter group; 9 out of 25 patients (36%) versus 2 out of 25 (8%), P = 0.037 in Wong et al. 29 +/- 4 versus 14 +/- 3, P = 0.001 for Andrews et al., 2.4 (0.3-5.9) versus 1.1 (0.3-2.9), P = 0.084 in Wenner et al. respectively (though not statistically significant). Bravo wireless capsule pH monitor interfered less with daily activities and adverse events were minimal compared to conventional intranasal catheter. PMID- 26952639 TI - Comparative Incidence of Acute Kidney Injury in Critically Ill Patients Receiving Vancomycin with Concomitant Piperacillin-Tazobactam or Cefepime: A Retrospective Cohort Study. AB - STUDY OBJECTIVE: The combination of vancomycin and piperacillin-tazobactam has been associated with an increased risk of acute kidney injury (AKI) in non critically ill patient populations, but it is still unknown if this association exists in critically ill patients. The objective of this study was to compare the incidence of AKI development during therapy or within 72 hours after completion of therapy in adult critically ill patients who received vancomycin with concomitant piperacillin-tazobactam or cefepime. DESIGN: Retrospective cohort study. SETTING: Medical, surgical, and neuroscience intensive care units (ICUs) within a single tertiary care hospital. PATIENTS: A total of 122 critically ill patients who received at least 48 hours of combination therapy with vancomycin and piperacillin-tazobactam (49 patients) or vancomycin and cefepime (73 patients) during an ICU admission between September 2012 and December 2014. MEASUREMENTS AND MAIN RESULTS: The primary outcome was AKI development, as determined by the Acute Kidney Injury Network criteria, during combination therapy or within 72 hours of completion of combination therapy. The inverse probability of the treatment-weighting (IPTW) approach was used to account for potential treatment selection bias. AKI incidence was assessed in the unadjusted and propensity score-weighted cohorts. Of the 122 patients, 37 patients (30.3%) developed AKI. In the unadjusted analysis, the incidence of AKI was similar in the piperacillin-tazobactam group compared with the cefepime group (32.7% vs 28.8%, p=0.647). The average treatment effect between the groups was not significant, showing no association between beta-lactam choice and AKI (beta = 0.004, p=0.958). Secondary outcomes were ICU length of stay, hospital length of stay, AKI duration, and need for renal replacement therapy. The choice of beta lactam was not a significant predictor of any of these outcomes: ICU length of stay (beta = 0.436, p=0.780), hospital length of stay (beta = 3.819, p=0.125), AKI duration (beta = -4.027, p=0.283), and need for renal replacement therapy (beta = 2.828, p=0.161). CONCLUSION: After adjusting for propensity to receive each of the treatment choices, no significant difference was found in the incidence of AKI development or other outcomes between the groups. The previously described finding that concomitant vancomycin and piperacillin-tazobactam increases AKI in non-critically ill patients may not be generalizable to the critically ill population. Prospective evaluation of this hypothesis is warranted. PMID- 26952640 TI - Medical diagnostics with mobile devices: Comparison of intrinsic and extrinsic sensing. AB - We review the recent development of mobile detection instruments used for medical diagnostics, and consider the relative advantages of approaches that utilize the internal sensing capabilities of commercially available mobile communication devices (such as smartphones and tablet computers) compared to those that utilize a custom external sensor module. In this review, we focus specifically upon mobile medical diagnostic platforms that are being developed to serve the need in global health, personalized medicine, and point-of-care diagnostics. PMID- 26952641 TI - Circulating miRNAs as Biomarkers of Acute Muscle Damage in Rats. AB - Skeletal muscle damage is an often-occurring event. Diagnosis using the classic blood marker creatine kinase sometimes yields unsatisfactory results due to great interindividual variability. Therefore, the identification of reliable biomarkers is important. Our aim was to detect and characterize circulating miRNAs in plasma in response to acute notexin-induced muscle damage in rats. Real-time quantitative RT-PCR profiling led to the identification of miRNAs that were highly increased in plasma in response to notexin injection into several muscles, namely miR-1-3p, -133a-3p, -133b-3p, -206-3p, -208b-3p, and -499-5p, as well as miR-378a-3p and miR-434-3p. Peak values of miRNAs appeared 12 hours after injury, and were contained both in the vesicular and nonvesicular fractions of plasma. Receiver operating characteristic curve analysis showed that circulating miRNAs could accurately discriminate between damaged and nondamaged tissues. Furthermore, we tested the robustness of expression profiles in slow- and fast type fibers. Upon inducing damage in slow- or fast-type muscle, we found that the damaged-muscle phenotype had a very limited impact on the miRNA response. Similarly, the circulating miRNAs selected were not affected by hemolysis or platelets, two pre-analytical factors known to affect plasma miRNA profiles. Taken together, our results show that circulating muscle-specific miRNAs, miR 378a-3p and miR-434-3p, are robust and promising biomarkers of acute muscle damage in rats. PMID- 26952642 TI - IL-19 Halts Progression of Atherosclerotic Plaque, Polarizes, and Increases Cholesterol Uptake and Efflux in Macrophages. AB - Atherosclerosis regression is an important clinical goal, and treatments that can reverse atherosclerotic plaque formation are actively being sought. Our aim was to determine whether administration of exogenous IL-19, a Th2 cytokine, could attenuate progression of preformed atherosclerotic plaque and to identify molecular mechanisms. LDLR(-/-) mice were fed a Western diet for 12 weeks, then administered rIL-19 or phosphate-buffered saline concomitant with Western diet for an additional 8 weeks. Analysis of atherosclerosis burden showed that IL-19 treated mice were similar to baseline, in contrast to control mice which showed a 54% increase in plaque, suggesting that IL-19 halted the progression of atherosclerosis. Plaque characterization showed that IL-19-treated mice had key features of atherosclerosis regression, including a reduction in macrophage content and an enrichment in markers of M2 macrophages. Mechanistic studies revealed that IL-19 promotes the activation of key pathways leading to M2 macrophage polarization, including STAT3, STAT6, Kruppel-like factor 4, and peroxisome proliferator-activated receptor gamma, and can reduce cytokine-induced inflammation in vivo. We identified a novel role for IL-19 in regulating macrophage lipid metabolism through peroxisome proliferator-activated receptor gamma-dependent regulation of scavenger receptor-mediated cholesterol uptake and ABCA1-mediated cholesterol efflux. These data show that IL-19 can halt progression of preformed atherosclerotic plaques by regulating both macrophage inflammation and cholesterol homeostasis and implicate IL-19 as a link between inflammation and macrophage cholesterol metabolism. PMID- 26952644 TI - Association between current perceived stress and incident diabetes is dependent on occupational status: Evidence from the IPC cohort study. AB - AIM: The role of stress in the onset of type 2 diabetes is a widespread lay belief, yet observational studies have produced inconsistent results. This study aimed to test the hypothesis that the association between perceived stress and incident diabetes might depend on occupational status (OS). METHODS: The four item Perceived Stress Scale (PSS-4) was completed at baseline by 22,567 participants in the labour force (16,193 men, 6374 women; mean age: 44.5+/-9.8 years) who had undergone two health checkups subsidized by the French national healthcare system. All subjects were free from diabetes at baseline, defined as a fasting blood glycaemia>=7mmol/L or the use of antidiabetic drugs. RESULTS: After a mean follow-up of 5.3+/-2.1 years, 527 participants (2.3%) had incident diabetes. After adjusting for sociodemographic, behavioural and biomedical risk factors as well as self-rated health, the association between baseline perceived stress and diabetes at follow-up was non-significant for the total study population. However, perceived stress was significantly associated with incident diabetes in participants of low OS [odds ratio (OR) for a five-point increment: 1.39; 95% confidence interval (CI): 1.02-1.90]. In contrast, there was a negative association between perceived stress and diabetes among those of high OS (OR: 0.60; 95% CI: 0.41-0.88) and no association within other occupational categories. The interaction between perceived stress and OS was significant (P<0.01). CONCLUSION: This study suggests that the association between perceived stress and diabetes onset is dependent on OS. Furthermore, this association does not appear to be explained by the classical risk factors for diabetes. PMID- 26952643 TI - Interaction between Esophageal Squamous Cell Carcinoma and Adipose Tissue in Vitro. AB - Esophageal squamous cell carcinoma (ESCC) develops within the squamous epithelial layer and invades the submucosa to the subadventitia that has adipose tissue (AT). AT seems critical to ESCC progression, but the underlying mechanism is unknown. We aimed to address the association between ESCC and AT in vitro. ESCC cells were cultured on rat or human subcutaneous AT-embedded or -non-embedded collagen gel. AT promoted the growth of ESCC cells and inhibited their apoptosis. AT promoted the expression of the squamous differentiation marker involucrin in ESCC cells. AT accelerated the expression of invasion-related factors in poorly differentiated ESCC cells only. AT promoted the expression of phosphorylated insulin-like growth factor-1 receptor in ESCC cells, whereas it inhibited that of the human epidermal growth factor receptor 2. Insulin-like growth factor-1, but not leptin, adiponectin, or resistin, promoted and inhibited the growth and apoptosis of ESCC cells, respectively. In turn, ESCC cells decreased the production of these adipokines in AT and the number of preadipocytes and mesenchymal stem cell-like cells, which developed from AT. These results suggest that i) AT may influence the progression of ESCC with increased growth or invasion and decreased apoptosis through insulin-like growth factor-1/insulin like growth factor-1 receptor signaling, ii) AT may affect human epidermal growth factor receptor 2-targeted therapy; and iii) the cancer cells may affect adipokine production in AT. PMID- 26952646 TI - US Public Health Preparedness for Zika and Other Threats Remains Vulnerable. AB - The unanticipated global outbreak of Zika virus infection is the most current but certainly not the last emerging infectious disease challenge to confront the US public heath system. Despite a number of such threats in recent years, significant gaps remain in core areas of public health system readiness. Stable, sustained investments are required to establish a solid foundation for achieving necessary national public health emergency preparedness and response capacity. PMID- 26952645 TI - Internet Cognitive Behavioral Therapy for Women With Postnatal Depression: A Randomized Controlled Trial of MumMoodBooster. AB - BACKGROUND: There are few published controlled trials examining the efficacy of Internet-based treatment for postnatal depression (PND) and none that assess diagnostic status (clinical remission) as the primary outcome. This is despite the need to improve treatment uptake and accessibility because fewer than 50% of postnatally depressed women seek help, even when identified as depressed. OBJECTIVE: In a randomized controlled trial (RCT), we aimed to test the efficacy of a 6-session Internet intervention (the MumMoodBooster program, previously evaluated in a feasibility trial) in a sample of postnatal women with a clinical diagnosis of depression. The MumMoodBooster program is a cognitive behavioral therapy (CBT) intervention, is highly interactive, includes a partner website, and was supported by low-intensity telephone coaching. METHODS: This was a parallel 2-group RCT (N=43) comparing the Internet CBT treatment (n=21) to treatment as usual (n=22). At baseline and at 12 weeks after enrollment, women's diagnostic status was assessed by telephone with the Standardized Clinical Interview for DSM-IV (SCID-IV) and symptom severity with the Beck Depression Inventory (BDI-II). Depression symptoms were measured repeatedly throughout the study period with the Patient Health Questionnaire (PHQ-9). RESULTS: At the end of the study, 79% (15/19) of women who received the Internet CBT treatment no longer met diagnostic criteria for depression on the SCID-IV (these outcome data were missing for 2 intervention participants). This contrasted with only 18% (4/22) remission in the treatment as usual condition. Depression scores on the BDI-II showed a large effect favoring the intervention group (d=.83, 95% CI 0.20 1.45). Small to medium effects were found on the PHQ-9 and on measures of anxiety and stress. Adherence to the program was very good with 86% (18/21) of users completing all sessions; satisfaction with the program was rated 3.1 out of 4 on average. CONCLUSIONS: Our results suggest that our Internet CBT program, MumMoodBooster, is an effective treatment option for women clinically diagnosed with PND. This is one of only two controlled evaluations of specialized online psychological treatment among women clinically diagnosed with PND. MumMoodBooster appears to be a feasible, effective treatment option, which is potentially accessible to large numbers of women in metropolitan, rural, and remote areas. Future work might be focused profitably on establishing comparability with face to-face treatments and purely self-guided delivery. We have commenced a larger RCT comparing MumMoodBooster with face-to-face CBT. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry (ANZCTR): ACTRN12613000113752; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=363561 (Archived by WebCite(r) at http://www.webcitation.org/6f64kuyLf). PMID- 26952647 TI - An FDA oncology view of juvenile animal studies in support of initial pediatric trials for anticancer drugs. PMID- 26952648 TI - Factors related to rational antibiotic prescriptions in community health centers in Depok City, Indonesia. AB - Irrational antibiotic prescription is common in developing countries, including in Indonesia. The aims of this study were to evaluate antibiotic prescription patterns and the factors related to the rationale for antibiotic prescriptions in community health centers in Depok City, Indonesia. The study employed a cross sectional design in eleven primary health centers in Depok City, Indonesia. The sample consisted of 28 physicians and 788 oral antibiotic prescriptions, 392 of which were evaluated for rationality according to local guidelines issued by the Ministry of Health Republic of Indonesia from October to December 2012. Data were analyzed with chi-square tests and logistic regression analysis. The most widely prescribed antibiotics were amoxicillin (73.5%) and co-trimoxazole (17.4%). The most frequent diseases were acute pharyngitis (40.2%) and non-specific respiratory infection (25.4%). Approximately 220 of the 392 prescriptions did not meet the criteria for rational antibiotic prescriptions with regard to antibiotic selection (22.7%), duration of administration (72.3%), frequency of administration (3.2%), or duration and frequency of administration (1.8%). Physicians who had attended training for rational drug use were 2.01 times more rational than physicians who had never attended training. Physicians with a short working period (i.e., <7 years) were 3.95 times more rational in prescribing antibiotics than physicians who had been working for longer periods (i.e., >7 years). Most antibiotics were prescribed irrationally. Training for rational drug use and length of practice were factors related to the rationality of antibiotic prescriptions. Suitable interventions are urgently required to encourage the rational prescription of antibiotics in the PHCs. PMID- 26952649 TI - Prenatal diagnosis of umbilical arteriovenous malformation. AB - Umbilical arteriovenous malformation (AVM) is a rare congenital malformation. We report a case of umbilical AVM that was prenatally diagnosed by further color Doppler ultrasonography because of fetal cardiomegaly. At 35 weeks gestation, a male newborn was delivered by emergent cesarean section because of rapid progress of cardiomegaly and breech presentation. Three-dimensional reconstructed computed tomography after birth demonstrated the shunt was spontaneously closed. This is the first case report of umbilical AVM, which was prenatally diagnosed, and the boy was successfully delivered, suggesting that, when fetal cardiomegaly is identified, umbilical AVM must be taken into consideration. PMID- 26952650 TI - HENRYK - An endless source of metal coordination surprises. AB - The basic knowledge about biological inorganic chemistry, thermodynamics and metal binding sites of metalloproteins is crucial for the understanding of their metal binding-structure-function relationship. Metal-peptide complexes are useful and commonly used models of metal-enzyme active sites, among which copper and zinc models are one of the most extensively studied. HENRYK is a peptide sequence present in numerous proteins, and serves as a potentially tempting binding site for Cu2+ and Zn2+. Maybe more importantly, HENRYK also happens to be the first name of our group leader. The results of this work, which, at the first glance, might seem to be a 'chemical scrabble', went far beyond our expectations and surprised us with a novel, uncommon behavior of a Cu2+ complex with a peptide with a histidine in position one. At low pH, the binding is a typical histamine like coordination, but with the increase of pH, the imidazole nitrogen is moved to the axial position and replaced with an amide; at basic pH, the binding mode is a {NH2, 3N-} one in the equatorial plane. It is important to note, that no dimeric species are formed in between. Such binding is thermodynamically much more stable than a simple complex with histamine, and quite comparable to complexes with several possible imidazole anchoring sites. PMID- 26952651 TI - Binding of molecular oxygen by an artificial heme analogue: investigation on the formation of an Fe-tetracarbene superoxo complex. AB - The dioxygen reactivity of a cyclic iron(ii) tetra-NHC-complex (NHC: N heterocyclic carbene) is investigated. Divergent oxidation behavior is observed depending on the choice of the solvent (acetonitrile or acetone). In the first case, exposure to molecular oxygen leads to an oxygen free Fe(iii) whereas in the latter case an oxide bridged Fe(iii) dimer is formed. In acetone, an Fe(iii) superoxide can be trapped, isolated and characterized as intermediate at low temperatures. An Fe(iii)-O-Fe(iii) dimer is formed from the Fe(iii) superoxide in acetone upon warming and the molecular structure has been revealed by single crystal X-ray diffraction. It is shown that the oxidation of the Fe(ii) complex in both solvents is a reversible process. For the regeneration of the initial Fe(ii) complex both organic and inorganic reducing agents can be used. PMID- 26952652 TI - [Premature immunosenescence in catecholamines syntesis deficient mice. Effect of social environment]. AB - INTRODUCTION: Healthy state depends on the appropriate function of the homeostatic systems (nervous, endocrine and immune systems) and the correct communication between them. The functional and redox state of the immune system is an excellent marker of health, and animals with premature immunosenescence show a shorter lifespan. Since catecholamines modulate the function of immune cells, the alteration in their synthesis could provoke immunosenescence. The social environment could be a strategy for modulating this immunosenescence. AIM: To determine if an haploinsufficiency of tyrosine hydroxylase (TH), the limiting enzyme of synthesis of catecholamines, may produce a premature immunosenescence and if this immunosenescence could be modulated by the social environment. MATERIALS AND METHODS: Adult (9+/-1 months) male ICR-CD1 mice with deletion of a single allele (hemi-zygotic: HZ) of the tyrosine hydroxylase enzyme (TH-HZ) and wild-type (WT) mice were used. Animals were housed in four subgroups: WT>50% (in the cage, the proportion of WT mice was higher than 50% in relation to TH-HZ), WT<50%, TH-HZ<50% and TH-HZ>50%. Peritoneal leukocytes were collected and phagocytosis, chemotaxis and proliferation of lymphocytes in the presence of lipopolysaccharide were analyzed. Glutathione reductase and glutathione peroxidase activities as well as oxidized/reduced glutathione ratio were studied. RESULTS: TH-HZ>50% mice showed a deteriorated function and redox state in leukocytes respect to WT>50% and similar to old mice. However, TH-HZ<50% animals had similar values to those found in WT<50% mice. CONCLUSION: The haploinsufficiency of TH generates premature immunosenescence, which appears to be compensated by living together with an appropriate number of WT animals. PMID- 26952653 TI - Safety of the lateral trauma position in cervical spine injuries: a cadaver model study. AB - BACKGROUND: Endotracheal intubation is not always an option for unconscious trauma patients. Prehospital personnel are then faced with the dilemma of maintaining an adequate airway without risking deleterious movement of a potentially unstable cervical spine. To address these two concerns various alternatives to the classical recovery position have been developed. This study aims to determine the amount of motion induced by the recovery position, two versions of the HAINES (High Arm IN Endangered Spine) position, and the novel lateral trauma position (LTP). METHOD: We surgically created global cervical instability between the C5 and C6 vertebrae in five fresh cadavers. We measured the rotational and translational (linear) range of motion during the different maneuvers using an electromagnetic tracking device and compared the results using a general linear mixed model (GLMM) for regression. RESULTS: In the recovery position, the range of motion for lateral bending was 11.9 degrees . While both HAINES positions caused a similar range of motion, the motion caused by the LTP was 2.6 degrees less (P = 0.037). The linear axial range of motion in the recovery position was 13.0 mm. In comparison, the HAINES 1 and 2 positions showed significantly less motion (-5.8 and -4.6 mm, respectively), while the LTP did not (-4.0 mm, P = 0.067). CONCLUSION: Our results indicate that in unconscious trauma patients, the LTP or one of the two HAINES techniques is preferable to the standard recovery position in cases of an unstable cervical spine injury. PMID- 26952654 TI - An activated factor VII variant with enhanced tissue factor-independent activity speeds wound healing in a mouse hemophilia B model. AB - Essentials Disorders of hemostasis can lead to delayed and defective wound healing. In hemophilia B (HB) mice, 7 days of Factor (F)IX or VIIa are needed to normalize wound healing. One dose of a highly active FVIIa variant (DVQ) restored normal wound closure time in HB mice. Coagulation factors with enhanced activity may acquire biological effects not due to hemostasis. SUMMARY: Introduction We have previously reported that hemophilia B (HB) mice have delayed healing of cutaneous wounds and alterations in wound histology. Administration of a single dose of either factor IX or recombinant activated FVII (rFVIIa) (NovoSeven) prior to wounding did not improve wound closure time or histology. The FVIIa analog DVQ (V158D, E296V and M298Q mutations) was designed to have higher tissue factor independent activity than rVIIa. We hypothesized that a single dose of DVQ would be more effective in restoring wound healing in HB mice. Methods Cutaneous punch wounds were made on the backs of HB and wild-type mice, and the time to wound closure was monitored. HB mice were treated with a dose of rFVIIa (10 mg kg(-1) ) or DVQ (1 mg kg(-1) ) that corrected the tail bleeding time. Skin samples were taken at various time points after wounding, fixed, and stained, and the histology was examined. Results As previously reported, wound closure times in HB mice given one dose of rFVIIa were not improved over those in untreated HB mice. Surprisingly, healing times in HB mice treated with an equally hemostatic dose of DVQ were normalized to that in wild-type mice. However, DVQ did not correct all histologic abnormalities in HB mice. Conclusions As the doses of DVQ and rFVIIa were chosen to support comparable levels of hemostasis, our data suggest that the improved healing seen with DVQ is not solely attributable to its hemostatic activity. It is possible that the improved wound healing arises through the effect of DVQ on cell signaling mechanisms. PMID- 26952655 TI - RAS Mutations as Predictive Biomarkers in Clinical Management of Metastatic Colorectal Cancer. AB - The use of anti-epidermal growth factor receptor (EGFR) monoclonal antibody therapies in patients with metastatic colorectal cancer is guided by the presence of activating point mutations in codons 12, 13, 59, 61, 117, and 146 of the KRAS and NRAS genes in the primary tumor. Although these mutations have been incorporated into the prescribing information for both cetuximab and panitumumab, highlighted in the National Comprehensive Cancer Network Guidelines, and routinely tested, a number of controversial issues and unanswered questions related to these mutations and their clinical significance remain. In the present review, we explored the contradictory data related to the prognostic value of KRAS mutations, the reported frequent discordance of KRAS mutations, and the reported nonequivalence of some of these mutations. We also considered the issues related to incorporating additional mutations into the already accredited and approved assays and the challenges created by changing an assay's analytical and clinical limits of detection. We also discuss the lack of biologic data supporting the pathogenicity of newly described clinically actionable mutations and explore the uncertainty regarding the clinical significance of low-frequency mutations, highlighting the importance of correcting allele frequencies for tumor purity. We also considered the importance of distinguishing the significance of low-frequency RAS mutations in tumors previously not treated or treated with anti EGFR therapies and explore new technologies capable of detecting emerging polyclonal RAS mutations that appear to confer drug resistance. PMID- 26952656 TI - Disease Control, Survival, and Toxicity Outcome After Intensified Neoadjuvant Chemoradiotherapy for Locally Advanced Rectal Cancer: A Single-Institution Experience. AB - PURPOSE: To report the long-term follow-up data and determine the toxicity rate concerning patients with locally advanced rectal cancer (LARC) treated with an intensified neoadjuvant treatment regimen. PATIENTS AND METHODS: Patients with histologically proven stage II to III adenocarcinoma of the rectum were included and treated with a trimodal approach. Intensified neoadjuvant treatment (chemoradiotherapy [CRT]) consisted of radiotherapy (total dose 50.4/54 Gy) and concomitant oxaliplatin (50 mg/m(2)/week) and 5-fluorouracil (200 mg/m(2)/5 daily continuous infusion). Surgery was planned 7 to 9 weeks after the end of CRT. Adjuvant chemotherapy was recommended in those patients with lymph node metastasis at diagnosis. RESULTS: One hundred patients (median age, 64 years) were eligible. Overall, the 5-year overall survival and disease-free survival (DFS) were 76.4% and 74.5%, respectively. CRT was well tolerated, with only 17% grade 3/4 acute toxicity. Twenty-four patients (24%) had a pathologic complete response (pCR), and only 1 patient had perioperative metastasis. The 5-year DFS were 95.7% and 66.7% for pCR and no-pCR tumor histology, respectively (P = .0275). CONCLUSION: Although oxaliplatin is not considered to be a standard treatment, the high 5-year rate of overall survival and DFS, the low severe toxicity rates, and the effective benefit on pCR and perioperative metastasis support an intensified treatment regimen for LARC. PMID- 26952657 TI - Identification and characterization of the RNA-binding protein Rbfox3 in zebrafish embryo. AB - Rbfox3, an RNA-binding fox protein, binds to the antibody to pan-neuronal marker, neuronal nuclei (NeuN). Rbfox3 is expressed in neural tissues across a wide range of species including mammals, birds, and amphibians. However, the molecular identity of Rbfox3 in the zebrafish is largely unknown. In this study, we cloned two zebrafish Rbfox3 genes, Rbfox3a and Rbfox3b. We also cloned the Rbfox3-d31 isoform, which excludes a 93-nucleotide alternative exon within the RNA recognition motif in both, Rbfox3a and Rbfox3b. Multiple protein sequence alignment revealed that the amino acid sequence for residues 1-20 of the zebrafish Rbfox3, which is the epitope region of NeuN antibody, was different from that of other species. Therefore, NeuN antibody lost its function as a neuronal marker antibody in zebrafish. Reverse transcriptase-polymerase chain reaction showed that both Rbfox3-d31 transcripts were abundant in the early blastula stage, after which they dramatically reduced, suggesting that these isoforms exist mainly as maternal transcripts. In contrast, full-length Rbfox3 transcripts were detected from the 24 h post-fertilization embryo, expression was also maintained at a constant level. Furthermore, full-length Rbfox3-expressing cells were located within the central nervous system during later stages of the zebrafish embryo. Our study provides insight into the molecular structure of zebrafish Rbfox3 as a step towards genetic association studies investigating the developmental role of Rbfox3. PMID- 26952669 TI - Understanding Intimate Partner Violence in Jordan: Application of the Ecological Model. AB - PURPOSE: To compare and contrast the Heise "ecological model of gender-based violence" with factors related to "intimate partner violence" (IPV) in Jordan. METHODS: Findings of empirical studies examining IPV against Jordanian women were analyzed using the Heise ecological model (1998). CONCLUSION: Factors identified in the literature were generally consistent with the ecological model. However, the literature on IPV in Jordan rarely examined the role of community-level factors in the exosystem and sociopolitical factors in the macrosystem. Consequently, little is known about how these exosystem and macrosystem factors affect IPV in Jordan. The Heise model was then adapted to reflect identified factors in the Jordanian cultural context. PRACTICAL IMPLICATION: More research aimed at uncovering barriers to identification and treatment of IPV targeting the exosystem and macrosystem is needed. PMID- 26952670 TI - Identification of vacancy defect complexes in transparent semiconducting oxides ZnO, In2O3 and SnO2. AB - Positron annihilation spectroscopy, when combined with supporting high-quality modeling of positron states and annihilation in matter, is a powerful tool for detailed defect identification of vacancy-type defects in semiconductors and oxides. Here we demonstrate that the Doppler broadening of the positron annihilation radiation is a very sensitive means for observing the oxygen environment around cation vacancies, the main open-volume defects trapping positrons in measurements made for transparent semiconducting oxides. Changes in the positron annihilation signal due to external manipulation such as irradiation and annealing can be correlated with the associated changes in the sizes of the detected vacancy clusters. Our examples for ZnO, In2O3 and SnO2 demonstrate that oxygen vacancies in oxides can be detected directly using positron annihilation spectroscopy when they are complexed with cation vacancies. PMID- 26952671 TI - Promoting Education Regarding Conflict of Interest Management. AB - Even among highly educated health professionals, there is inconsistency in the knowledge and perception concerning both conflict of interest (COI) itself and COI disclosure. The key issue is the credibility of the manuscript, which relies heavily on transparency of COI for the reader. The tendency to disregard the importance of COI disclosure among journal editors has been recently highlighted. For all types of COI, the primary question is how it is managed. To ensure the enforcement of the declared journal COI policies, it is crucial that not only authors, but also those who are involved in the assessment of manuscripts, be educated and informed of the updated guidelines concerning COI disclosure. PMID- 26952672 TI - An exploratory study on the effectiveness of "Calmare therapy" in patients with cancer-related neuropathic pain: A pilot study. AB - PURPOSE: Calmare therapy (CT) has been suggested as a novel treatment for managing chronic pain. Recently, it was reported to show a positive therapeutic outcome for managing neuropathic pain condition. We performed an exploratory prospective study on the effectiveness of CT in patients with various types of cancer-related neuropathic pain (CNP). METHOD: We performed an open-labeled, single-arm, exploratory study on the effectiveness of CT in patients with various types of cancer-related neuropathic pain (CNP). The primary endpoint was a comparison of the 11-point Numerical Rating Scale (NRS) pain score at one month with the baseline score in each patient. Brief Pain Inventory (BPI) and consumption of opioid were also evaluated during follow-up period. RESULTS: CT significantly decreased NRS pain score at one month from baseline (p < 0.001) in 20 patients with chemotherapy-induced peripheral neuropathy (n = 6), metastatic bone pain (n = 7), and post-surgical neuropathic pain (n = 7). It also improved overall BPI scores, decreased consumption of rescue opioid (p = 0.050), and was found satisfactory by a half of patients (n = 10, 50.0%). CONCLUSIONS: Our preliminary results suggest that CT may be considered for cancer patients with various types of CNP. Large studies are necessary to confirm our findings and ascertain which additional CNP show positive response to CT. PMID- 26952673 TI - An innovation in curriculum content and delivery of cancer education within undergraduate nurse training in the UK. What impact does this have on the knowledge, attitudes and confidence in delivering cancer care? AB - PURPOSE: This was an evaluation of an innovation in curriculum content and delivery within undergraduate nursing education in the UK. Its purpose was to investigate the effect on knowledge, attitudes and confidence in delivering cancer care. METHODS: The study design was a pre-test post-test survey design with a comparison group. Participants were two cohorts of undergraduate nursing students (n(intervention) = 84, n(comparison) = 91). The intervention cohort were exposed to a new 3.5 day programme of cancer education, coproduced with patients, carers and health professionals, which focused on cancer as a life changing long term condition. The comparison cohort had been exposed to a 2 day programme produced by a lecturer. RESULTS: Following exposure to the new model for the delivery of undergraduate nurse cancer education, the intervention cohort demonstrated good overall knowledge of the impact of cancer, more positive attitudes towards cancer treatment and more confidence in their ability to deliver cancer care. Attitudes were more positive and confidence in ability to support cancer patients at all stages of the cancer journey were greater than in the comparison group. Insights gained into the cancer patient and carer perspectives were highly valued. CONCLUSIONS: This study has found that a new model for the delivery of cancer education focusing on survivorship and delivered in partnership with patients, carers and clinicians, may improve knowledge, attitudes and confidence in the delivery of cancer care. Further work is now needed, using a more robust experimental design, to investigate the generalisability of the results to other education programs. PMID- 26952674 TI - Determinants of participation in colorectal cancer screening among community dwelling Chinese older people: Testing a comprehensive model using a descriptive correlational study. AB - PURPOSE: The prevalence of colorectal cancer (CRC) among older people is high. Screening for CRC presents a cost-effective secondary prevention and control strategy which results in a significant reduction in mortality. This study aims to describe the prevalence of CRC screening and examine its risk factors among Chinese community-dwelling older people guided by a comprehensive model combining Health Belief Model and Extended Parallel Processing Model. METHODS: A descriptive correlational study was conducted. A convenience sample of 240 community-dwelling adults aged >=60 was recruited in May-July in 2012 in Hong Kong. Participants were asked to complete a questionnaire which collected information on demographic variables, CRC-related psychosocial variables and whether they had a CRC screening in the past 10 years. RESULTS: Among the participants, 25.4% reported having a CRC screening test. Results of logistic regression analyses indicated that participants with a higher level in cue to action, and lower perceived knowledge barriers and severity-fear were significantly associated with participation in CRC screening. But there were no significant associations between fatalism and cancer fear with screening. CONCLUSIONS: The prevalence of CRC screening was low in Hong Kong Chinese community-dwelling elders. A number of modifiable factors associated with CRC screening were identified which provides specific targets for interventions. This study also adds to the knowledge regarding the associations between fatalism and fear with CRC screening behaviors among Chinese older people. PMID- 26952675 TI - Changes in attitudes, practices and barriers among oncology health care professionals regarding sexual health care: Outcomes from a 2-year educational intervention at a University Hospital. AB - PURPOSE: To examine the attitudes, practices and perceived barriers in relation to a sexual health care educational intervention among oncology health care professionals at the Landspitali-National University Hospital of Iceland. METHODS: The design was quasi experimental, pre - post test time series. A comprehensive educational intervention project, including two workshops, was implemented over a two year time period. A questionnaire was mailed electronically to all nurses and physicians within oncology at baseline (T1, N = 206), after 10 months (T2, N = 216) and 16 months (T3, N = 210). RESULTS: The response rate was 66% at T1, 45% at T2 and 38% at T3. At all time points, the majority of participants (90%) regarded communication about sexuality part of their responsibilities. Mean scores on having enough knowledge and training, and in six of eight practice issues increased significantly over time. Overall, 10 16% reported discussing sexuality-related issues with more than 50% of patients and the frequency was significantly higher among workshop attendants (31%) than non-attendants (11%). Overall, the most common barriers for discussing sexuality were "lack of training" (38%) and "difficult issue to discuss" (27%), but the former barrier decreased significantly by 22% over time. CONCLUSIONS: The intervention was successful in improving perception of having enough knowledge and training in providing sexual health care. Still, the issue remains sensitive and difficult to address for the majority of oncology health care professionals. Specific training in sexual health care, including workshops, should be available to health care professionals within oncology. PMID- 26952676 TI - What factors are associated with posttraumatic growth in head and neck cancer carers? AB - PURPOSE: Researchers have recently called for more work to be conducted on positive outcomes and head and neck cancer. The purpose of this study was to investigate the factors associated with posttraumatic growth in head and neck cancer caregivers. METHODS AND SAMPLE: 197 carers were surveyed. A descriptive cross-sectional survey design was used. RESULTS: In multivariate analysis the following factors were statistically significantly associated with increased posttraumatic growth: social support, longer time since diagnosis, increased worry about cancer and increased financial stress and strain stemming from caring. CONCLUSIONS: While HNC carers in the post-treatment phase of the illness trajectory can experience considerable psychological burdens, this study suggests that these burdens can lead some carers to experience growth and change and an expanded sense of themselves and their social worlds. Implications for nursing practice are discussed. PMID- 26952677 TI - An instrument to collect data on frequency and intensity of symptoms in older palliative cancer patients: A development and validation study. AB - PURPOSE: To develop and validate an instrument to collect data on symptoms (frequency/intensity) in older palliative cancer patients. METHODS: A four-phase instrument development and validation study was performed. A preliminary version of the instrument was developed through a literature review. Face- and content validity were assessed in a Delphi-procedure with eleven experts. Cognitive interviewing with 24 older cancer patients was performed to enhance content validity of the instrument. Test-retest was performed to assess the stability. RESULTS: An 40-item instrument was developed. The Assessment Symptoms Palliative Elderly (ASPE) collects data on frequency and intensity of 24 physical, 10 psychological, 3 functional, 1 spiritual and 2 social symptoms. Content validity was excellent (I-CVI 81.8%-100.0% and S-CVI 92.9%). Cognitive interviewing allowed to improve the content validity. Test-retest showed substantial to almost perfect agreement for 87.5% of the items. No item had poor or fair agreement. CONCLUSION: This study resulted in the development of the ASPE which reflects good properties for face- and content validity and reliability. Cognitive interviewing has a valuable contribution in the validation process. The instrument can be used to gain insight in symptoms in older palliative cancer patients. PMID- 26952678 TI - To what extent are patients' needs met on oncology units? The phenomenon of care rationing. AB - PURPOSE: Evidence suggests that when resources are not sufficient to provide all the care needed by their patients, nurses are forced to ration their attention between care activities. The aim of this study is to examine care omissions and their causes in oncology units. METHODS: Participants were recruited from all of the hospitals in the Republic of Cyprus with oncology in-patient units. The data were collected with the MISSCARE questionnaire consisting of demographics, part A related to the elements of missed care and part B asking the reasons why nurses omit care. RESULTS: One hundred and fifty seven registered nurses participated in the study (Response Rate = 91.8%). The mean value for part A of the MISSCARE survey was moderate (2.31 from 4). The elements of care described as frequently or always missed were: turning the patient every 2 h (66.9%); ambulation three times a day or as needed (49.1%); mouth care (61.1%); patient teaching (37.6%); emotional support (32.5%); and attend any interdisciplinary conferences (87.9%). Reported causes included inadequate number of staff, urgent patient situations and unexpected rise in patient volume/unit acuity. Spearman correlations showed that there is a relationship between care rationing and job satisfaction (r = 0.469, p < 0.05), with the less satisfied nurses reporting higher incidences of care omissions. CONCLUSION: The results of this study may facilitate a better understanding of this phenomenon and its impact on patients and nurses, but more research is needed at an international level so as to create more robust evidence that could support nursing practice. PMID- 26952679 TI - Predicting women's intentions for contralateral prophylactic mastectomy: An application of an extended theory of planned behaviour. AB - PURPOSE: Most women with unilateral breast cancer (BC) without BRCA1/2 gene mutations are at low risk of contralateral breast cancer (CBC). One CBC risk management option is contralateral prophylactic mastectomy (CPM). While there is no evidence that CPM increases life-expectancy, its uptake is increasing. This study aimed to assess the validity of an extended social-cognition model, the Theory of Planned Behaviour (TPB), in predicting women's intentions to undergo CPM. METHOD: Four hundred women previously treated for BC completed an online survey exploring demographic and disease factors, attitude, subjective norm, perceived behavioural control, anticipated regret, uncertainty avoidance, self efficacy to not have CPM and intentions to undergo CPM in a common hypothetical decision-making scenario. RESULTS: The TPB uniquely explained 25.7% of intention variance. Greater anticipated regret, uncertainty avoidance and lower self efficacy to cope with not having CPM were associated with stronger CPM intentions, explaining an additional 7.7%, 10.6% and 2.9% respectively, of variance over and above the TPB. Women who had undergone CPM, had not attended university, and had children reported stronger CPM intentions. CONCLUSIONS: A holistic understanding of CPM decision-making appears to require consideration beyond CBC risk, demographics and disease characteristics, exploring women's expectations about CPM outcomes, others' opinions, and avoidance of emotionality and difficulties associated with not undergoing surgery. This study provides a theoretical basis from which the complexity of CPM decision-making may be understood, and from which resources for patients and treating staff may be developed to support women's informed decision-making aligning with their personal values. PMID- 26952680 TI - Developing and pilot-testing a Finding Balance Intervention for older adult bereaved family caregivers: A randomized feasibility trial. AB - PURPOSE: This study aimed to test the feasibility of a psychosocially supportive writing intervention focused on finding balance for older adult bereaved family caregivers of advanced cancer patients. METHOD: The Finding Balance Intervention (FBI) was tested for feasibility, acceptability and potential influence on increasing hope, coping and balance through a multi-method pilot study employing a randomized trial design with 19 older adults with an average age of 72 years. The intervention group received the FBI and a follow up visit from an RN-RA. The control group received the FBI at a second visit. The FBI, a theory-based intervention was developed from grounded theory qualitative data, applying Delphi methods to design a self-administered, psychosocially supportive, writing intervention for older adults who had lost a spouse after caregiving. RESULTS: Feasibility was assessed and specific modifications identified. The FBI was easy to use, acceptable and of benefit. The FBI offered validation of emotions and ways to discover new ideas to find balance, which may enable bereaved caregivers to move forward on a unique journey through grief. The treatment group showed a statistically significant increase in restoration-oriented coping and higher oscillation activity. CONCLUSIONS: The results suggest the FBI was easy to use, acceptable and of benefit. A full scale study, with specific modifications to the design, is needed to test the effectiveness of this innovative intervention. PMID- 26952681 TI - The effect of individualized patient education, along with emotional support, on the quality of life of breast cancer patients - A pilot study. AB - PURPOSE: This study aimed to determine the effect of individualized patient education along with emotional support on the quality of life (QoL) of breast cancer patients undergoing chemotherapy. It also aimed to determine the intervention's feasibility in the Pakistani context. METHODS: A quasi experimental design, with pre- and post-test, in two groups, via time block, was used. The study was conducted at a public hospital in Karachi with a sample of 50 patients; 25 patients each in the intervention and control group. The intervention was delivered over a period of six weeks. It comprised verbal and written patient education, availability of a nurse during patients' chemotherapy administration and over the telephone, and a telephone follow-up of the patients by the nurse. patients' QoL was assessed at baseline and at the sixth week of receiving chemotherapy. RESULTS: Tests indicated a significant improvement in the overall QoL, breast cancer subscale scores, and the physical and emotional well being of the intervention group, as compared to the control group. The intervention effect size was moderate (0.655) for the QoL. CONCLUSION: The intervention was found to be effective in improving patients' QoL. However, a larger study, in a multi-center setting, is recommended to ascertain the findings of this pilot study. PMID- 26952682 TI - The impact of cancer and its treatment on physical activity levels and quality of life among young Hong Kong Chinese cancer patients. AB - PURPOSE: Despite the evidence that regular physical activity can have beneficial effects on the physical and psychological well-being of cancer patients, a review of the literature reveals that a majority of young cancer patients fail to attain the same levels of physical activity that they had before contracting the disease. This study is to examine the impact of cancer and its treatment on the physical activity levels and quality of life of young Hong Kong Chinese cancer patients. METHOD: A cross-sectional study was conducted, with 76 young cancer patients admitted for treatment to a pediatric oncology unit, and another similar age group of 148 healthy counterparts from the two integrated child and youth service centers were invited to join the study. RESULTS: The study found that the current physical activity levels of young cancer patients were markedly reduced when compared with their pre-cancer situation. Moreover, they were significantly less active in performing physical exercise, and reported lower levels of self efficacy and quality of life than their healthy counterparts. The results of the hierarchical multiple regression analysis showed that physical activity is an important indicator of quality of life among young cancer patients. CONCLUSION: The results provide further evidence that cancer and its treatment have negative effects on physical and psychological well-being and quality of life among young cancer patients. There is an imperative need for healthcare professionals to promote the adoption of regular physical activity among such patients, even during the treatment itself. PMID- 26952683 TI - The Immediacy of Illness and Existential Crisis: Patients' lived experience of under-going allogeneic stem cell transplantation for haematological malignancy. A phenomenological study. AB - PURPOSE: This paper reports a study exploring the lived experience of fifteen men and women treated with allogeneic stem cell transplant (SCT) for haematological malignancy. METHOD: The study followed an interpretive phenomenological methodology using semi-structured interviews. Participants aged between 22 and 68 years were purposively recruited from two specialist treatment centres and were interviewed within three months to one year post SCT between April and September 2013. Data were then analysed using interpretive phenomenological analysis. RESULTS: An overarching theme that emerged from the data was: The Immediacy of Illness and Existential Crisis. The Immediacy of Illness and Existential Crisis developed from participants' experiences of critical events accompanied by enduring uncertainty continuing into the recovery period. Participants suffer major disruption to their lives physically, psychosocially and emotionally, including facing their own mortality, without a sense of when they may resume the normality of their former lives. CONCLUSIONS: Ambiguity and uncertainty characterise the experiences of those with haematological malignancy. Whilst participants have access to specialist teams, there are opportunities for health and social care professionals to provide more support for individuals to come to terms with the critical events they have faced and to prepare them for their return home and to continue former lives and aspirations following prolonged hospitalisation. PMID- 26952684 TI - The need for social support provided by the non-profit cancer societies throughout different phases in the cancer trajectory and its integration into public healthcare. AB - PURPOSE: To describe the phases of the cancer trajectory when social support, in the form of electronic counselling services, as provided by the non-profit cancer societies, is needed, as well as how these services are integrated into the cancer care in public healthcare. METHODS: In this descriptive qualitative study a purposive sample of patients with cancer (n = 12) were interviewed. The data were content analysed inductively. RESULTS: Social support was needed when emotional well-being was weakened, when the body broke, when the care pathway induced unawareness, and when empowerment needed strengthening. There was no need for social support when well-being was considered in balance. The electronic counselling services were integrated into cancer care by supporting the patient with cancer emotionally, developing the informational expertise of the patient with cancer, expanding the opportunities for support, and supporting public healthcare. Integration required improvements to the actions of the patients and various actors involved in the healthcare system. There was no integration due to the health status of the patient and the sufficiency of the primary support sources. The received social support was not integrated into the actual cancer treatment process of the patient with cancer in the public healthcare system. CONCLUSIONS: The phases of support needed in the cancer trajectory as defined by the patient differ from the traditional biomedical phases of treatment. PMID- 26952685 TI - Support from healthcare services during transition to adulthood - Experiences of young adult survivors of pediatric cancer. AB - PURPOSE: Improved survival rates of pediatric cancer have drawn attention on how to best facilitate long-term follow up and transition from pediatric to adult care. The transition process is multifactorial and necessitates the joint involvement of the patient, the family and the healthcare providers. The purpose of this study was to explore the experiences of support from healthcare services during the transition from adolescence to adulthood described by young adult survivors of pediatric cancer. METHODS: A mixed method with a convergent parallel design was used to evaluate the experiences of receiving support from healthcare services (eg pediatric oncology and pediatric clinic) during transition from adolescence to adulthood described by young adult survivors of pediatric cancer (n = 213) in a nation wide cross-sectional survey. RESULTS: A quantitative assessment of the experienced extent and satisfaction of support from healthcare services to handle physical, mental and social changes to continue life after the disease showed that a majority of the participants had received insufficient support. The qualitative analysis indicated a need for equal roles in healthcare to promote participation, a need to manage and process consequences of the disease, and a need for continuous support. CONCLUSIONS: During transition to adulthood, there's a need for a personalized care plan that takes a holistic approach towards supporting the young cancer survivor in managing life in the best way. Identifying and handling the individual needs of pediatric cancer survivors is important for providing the resources and support required to increase the likelihood of successful transition to adulthood. PMID- 26952686 TI - Worries of childhood cancer survivors in young adulthood. AB - PURPOSE: Childhood cancer survivors worry about many issues related to their cancer history. As they grow older, additional issues may emerge. This study of a sample of Korean young adults aims to understand childhood cancer survivors' worries. METHOD: A purposeful sample of 28 childhood cancer survivors was recruited through survivor and parent-advocacy foundations and support groups in Korea. Qualitative in-depth interviews were conducted over the phone or in person. Participants ranged in age from 20 to 36, were diagnosed before age 19, and had completed treatment at the time of the study. RESULTS: Through qualitative interviews, survivors' worries were identified in the following five themes: romantic relationships and marriage, fertility and the health of future children, work and social life, family, and physical health. CONCLUSIONS: The study's findings support the importance of understanding the worries of childhood cancer survivors in young adulthood and the need for developing services and programs to help survivors acquire the appropriate social skills and coping strategies to mitigate their worries. PMID- 26952687 TI - Developing and evaluating Robocare; an innovative, nurse-led robotic prostatectomy care pathway. AB - PURPOSE: A Robotic Prostatectomy Care Pathway ("Robocare"), aiming to prepare men for robotic-assisted radical prostatectomy (RARP) and manage side-effects and long-term follow-up in a multidisciplinary fashion was established. The pathway enhances patient care by providing adequate information and support and optimizes efficiency by reducing length of stay and minimizing hospital visits. Our study assesses the pathway for patient satisfaction, co-ordination of care between disciplines, length of stay and readmission rates. METHOD: We analysed our database of all patients undergoing RARP with Robocare between July 2012 and December 2013 at Peter MacCallum Cancer Centre, Australia (PMCC). Compliance, Length of Stay and Postoperative Course were analysed. Patient satisfaction was assessed. RESULTS: Overall 124 patients underwent RARP with 105 (85%) being discharged day 1 post-op (mean 1.3 days). Post-operative support phone calls were received by >95% of patients. Thereafter, 74 patients (60%) were followed in the long-term follow-up phone clinic. Twenty-nine complications were identified of which 19 (66%) were resolved by the nurse specialist. Eighteen patients had psychologist, 44 sexual health and 44 physiotherapist referral. Patient satisfaction in 74 (60%) returned surveys revealed 71 (96%) being well/very well supported. CONCLUSIONS: The Robocare pathway is safe with high patient satisfaction. It contributes to reducing post-operative length of stay and readmission rates as well as the outpatient follow-up. A true multidisciplinary approach that is nurse-led likely improves care and outcomes for RARP patients and may lower impact on hospital resources. PMID- 26952688 TI - Estimating Surgical Procedure Times Using Anesthesia Billing Data and Operating Room Records. AB - OBJECTIVE: The median time required to perform a surgical procedure is important in determining payment under Medicare's physician fee schedule. Prior studies have demonstrated that the current methodology of using physician surveys to determine surgical times results in overstated times. To measure surgical times more accurately, we developed and validated a methodology using available data from anesthesia billing data and operating room (OR) records. DATA SOURCES: We estimated surgical times using Medicare 2011 anesthesia claims and New York Statewide Planning and Research Cooperative System 2011 OR times. Estimated times were validated using data from the National Surgical Quality Improvement Program. We compared our time estimates to those used by Medicare in the fee schedule. STUDY DESIGN: We estimate surgical times via piecewise linear median regression models. PRINCIPAL FINDINGS: Using 3.0 million observations of anesthesia and OR times, we estimated surgical time for 921 procedures. Correlation between these time estimates and directly measured surgical time from the validation database was 0.98. Our estimates of surgical time were shorter than the Medicare fee schedule estimates for 78 percent of procedures. CONCLUSIONS: Anesthesia and OR times can be used to measure surgical time and thereby improve the payment for surgical procedures in the Medicare fee schedule. PMID- 26952689 TI - Novel calcium infusion regimen after parathyroidectomy for renal hyperparathyroidism. AB - AIM: Calcium infusion is used after parathyroid surgery for renal hyperparathyroidism to treat postoperative hypocalcaemia. We compared a new infusion regimen to one commonly used in Malaysia based on 2003 K/DOQI guidelines. METHODS: Retrospective data on serum calcium and infusion rates was collected from 2011-2015. The relationship between peak calcium efflux (PER) and time was determined using a scatterplot and linear regression. A comparison between regimens was made based on treatment efficacy (hypocalcaemia duration, total infusion amount and time) and calcium excursions (outside target range, peak and trough calcium) using bar charts and an unpaired t-test. RESULTS: Fifty one and 34 patients on the original and new regimens respectively were included. Mean PER was lower (2.16 vs 2.56 mmol/h; P = 0.03) and occurred earlier (17.6 vs 23.2 h; P = 0.13) for the new regimen. Both scatterplot and regression showed a large correlation between PER and time (R-square 0.64, SE 1.53, P < 0.001). The new regimen had shorter period of hypocalcaemia (28.9 vs 66.4 h, P = 0.04), and required less calcium infusion (67.7 vs 127.2 mmol, P = 0.02) for a shorter duration (57.3 vs 102.9 h, P = 0.001). Calcium excursions, peak and trough calcium were not significantly different between regimens. Early postoperative high excursions occurred when the infusion was started in spite of elevated peri operative calcium levels. CONCLUSION: The new infusion regimen was superior to the original in that it required a shorter treatment period and resulted in less hypocalcaemia. We found that early aggressive calcium replacement is unnecessary and raises the risk of rebound hypercalcemia. PMID- 26952691 TI - Splenogonadal Fusion: A Genetic Disorder?-Report of a Case and Review of the Literature. AB - Splenogonadal fusion is a rare congenital anomaly in which there is fusion between the spleen and gonad, epididymis or vas. We treated a patient with scrotal mass. A discontinuous fusion between the spleen and epididymis was found: after frozen section mass was excised sparing testis. Although rare, the splenogonadal fusion should be considered in the differential diagnosis of scrotal masses in children, and orchiectomy should be avoided. Moreover, examination of siblings showed a brother affected from accessory spleen. This finding, not reported previously to our knowledge, suggests a possible familiarity of this disorder. PMID- 26952692 TI - Organic solar cells with graded absorber layers processed from nanoparticle dispersions. AB - The fabrication of organic solar cells with advanced multi-layer architectures from solution is often limited by the choice of solvents since most organic semiconductors dissolve in the same aromatic agents. In this work, we investigate multi-pass deposition of organic semiconductors from eco-friendly ethanol dispersion. Once applied, the nanoparticles are insoluble in the deposition agent, allowing for the application of further nanoparticulate layers and hence for building poly(3-hexylthiophene-2,5-diyl):indene-C60 bisadduct absorber layers with vertically graded polymer and conversely graded fullerene concentration. Upon thermal annealing, we observe some degrees of polymer/fullerene interdiffusion by means of X-ray photoelectron spectroscopy and Kelvin probe force microscopy. Replacing the common bulk-heterojunction by such a graded photo active layer yields an enhanced fill factor of the solar cell due to an improved charge carrier extraction, and consequently an overall power conversion efficiency beyond 4%. Wet processing of such advanced device architectures paves the way for a versatile, eco-friendly and industrially feasible future fabrication of organic solar cells with advanced multi-layer architectures. PMID- 26952690 TI - [Detection of Brachyspira pilosicoli and other Brachyspira species in Argentine poultry farms]. AB - Some species of the genus Brachyspira such as Brachyspira pilosicoli, Brachyspira intermedia and Brachyspira alvinipulli are pathogenic species capable of producing disease in laying hens. In our country, the presence of B. pilosicoli and other species of Brachyspira has been reported in pigs and dogs but there is no record of their presence in poultry. Fecal and cecal content samples from 34 laying hens of 4, 12 and 24 months of age from two farms were analyzed by isolation, biochemical tests and PCR. B. pilosicoli and Brachyspira spp. were identified in samples taken from laying hens of 12 and 24 months of age. PMID- 26952693 TI - Graphical and numerical diagnostic tools to assess suitability of multiple imputations and imputation models. AB - Multiple imputation has become a popular approach for analyzing incomplete data. Many software packages are available to multiply impute the missing values and to analyze the resulting completed data sets. However, diagnostic tools to check the validity of the imputations are limited, and the majority of the currently available methods need considerable knowledge of the imputation model. In many practical settings, however, the imputer and the analyst may be different individuals or from different organizations, and the analyst model may or may not be congenial to the model used by the imputer. This article develops and evaluates a set of graphical and numerical diagnostic tools for two practical purposes: (i) for an analyst to determine whether the imputations are reasonable under his/her model assumptions without actually knowing the imputation model assumptions; and (ii) for an imputer to fine tune the imputation model by checking the key characteristics of the observed and imputed values. The tools are based on the numerical and graphical comparisons of the distributions of the observed and imputed values conditional on the propensity of response. The methodology is illustrated using simulated data sets created under a variety of scenarios. The examples focus on continuous and binary variables, but the principles can be used to extend methods for other types of variables. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26952694 TI - Kohn-Sham calculations of NMR shifts for paramagnetic 3d metal complexes: protocols, delocalization error, and the curious amide proton shifts of a high spin iron(ii) macrocycle complex. AB - A theory for the nuclear chemical shifts of molecules in arbitrary spin states is applied to a set of paramagnetic organometallic complexes of 3d metals. Ligand chemical shifts are calculated and analyzed using Kohn-Sham (KS) density functional theory with and without relativistic corrections. The roles of the KS delocalization error, Gaussian-type versus Slater-type basis sets, relativistic effects (scalar and spin-orbit), and zero field splitting (ZFS) are investigated. A strong functional dependence of the chemical shifts is apparent and correlated with the delocalization error. The functional dependence is between one and two orders of magnitude larger than variations of the NMR shifts due the other influences that are investigated. ZFS effects are negligible in the determination of the NMR chemical shifts of the complexes except at very low temperatures. The DFT calculated shifts agree reasonably well with experiment. A 73 ppm difference in the NMR shifts of the two protons in the amide groups of a high-spin Fe(ii) macrocycle complex arises from selective O -> Fe dative bonding that only involves the transfer of beta spin density, along with orbital delocalization throughout the ligand bonding framework which electronically couples the coordinating oxygen lone pair orbitals directly to the amide trans proton. PMID- 26952695 TI - Schneiderian first rank symptoms in schizophrenia: A developmental neuroscience evaluation. AB - INTRODUCTION: Self disorders in schizophrenia have been suggested to have distinct neurobiological underpinnings. Using comprehensive neuro-scientific assessments including a neurophysiological, a neurochemical and a neuropsychological marker, this study assesses disordered-"self" in schizophrenia. METHODS: Twenty schizophrenia patients with first rank symptoms (FRS;FRS+), 20 patients without FRS (FRS-) and 20 healthy controls (HC) were assessed for psychopathology, especially on specially designed FRS score sheets with a narrow and a broad definition. Resting state electroencephalography was acquired using 256-electrodes; gamma spectral-power was measured in 8 regions of interest. Serum BDNF and self-monitoring were also assessed. Comparative and correlation analysis were conducted in addition to a step-wise discriminant function analysis. RESULTS: FRS+ group with greater positive symptom score and a lower negative symptom score, showed significantly increased gamma spectral power, especially on right hemispheric regions, along with lower BDNF levels and lower scores on self-monitoring compared to FRS- and HC. Serum BDNF levels and gamma spectral power in the region corresponding right inferior parietal lobule were identified as predictors that most accurately classified the defined groups. CONCLUSIONS: Schizophrenia patients satisfying the criteria of presence of first rank symptoms represent a distinct neurodevelopmental subgroup with associated features of predominantly positive symptoms, significantly lower neurotrophin levels, aberrant resting state brain activity in the heteromodal association cortex and performing poorer on self-monitoring tasks. PMID- 26952696 TI - Determinants of physical activity among patients with type 2 diabetes: the role of perceived autonomy support, autonomous motivation and self-care competence. AB - Based on self-determination theory (SDT), this study investigated, whether the three central SDT variables (perceived autonomy support, autonomous motivation and self-care competence), were associated with engagement in physical activity (PA) among patients with type 2 diabetes when the effect of a wide variety of other important life-context factors (perceived health, medication, duration of diabetes, mental health, stress and social support) was controlled for. Patients from five municipalities in Finland with registry-based entitlement to a special reimbursement for medicines used in the treatment of type 2 diabetes (n = 2866, mean age 63 years, 56% men) participated in this mail survey in 2011. Of all measured explanatory factors, autonomous motivation was most strongly associated with engagement in PA. Autonomous motivation mediated the effect of perceived autonomy support on patients' PA. Thus, perceived autonomy support (from one's physician) was associated with the patient's PA through autonomous motivation. This result is in line with SDT. Interventions for improved diabetes care should concentrate on supporting patients' autonomous motivation for PA. Internalizing the importance of good self-care seems to give sufficient energy to maintain a physically active lifestyle. PMID- 26952697 TI - Dementia in Parkinson's disease: Is male gender a risk factor? AB - BACKGROUND: The rates of cognitive decline in patients with Parkinson's disease (PD) are higher than in the general population. Age and disease duration have been associated with increasing rates of dementia in PD. However, the role of other factors including gender has been poorly investigated. We investigated the relationship between dementia and gender along with other established risk factors, such as age and disease duration. METHODS: We conducted a cross sectional retrospective study including all consecutive patients diagnosed with idiopathic PD attending a single out-patient tertiary clinic over an 18-year period (1995-2013). Dementia was diagnosed according to DSM-IV criteria. RESULTS: Prevalence of dementia was 11.5% (95%CI, 10.8-12.3) and 13.5% (95%CI, 12.7-14.5) in the whole population (N = 6599) and in those aged >=60 years (N = 5373), respectively. Age and disease duration were independently associated with dementia, and the latter was associated with dementia up to 84 years of age. Male gender was an independent risk factor. In addition, while the rate of dementia increased in males over all age strata, we found that in females prevalence began to increase steadily after the age of 65 years, reaching male estimates only after 80 years of age. Higher rates in male gender were observed between 60 and 80 years of age. CONCLUSION: Age and PD duration are confirmed risk factors for dementia. However, disease duration appeared to be a less important factor in cognitive decline in patients aged >=85 years. As opposed to gender-specific estimates in the general population, male gender is likely associated with higher rates of dementia in PD patients. PMID- 26952698 TI - The effect of subthalamic deep brain stimulation on gastric motility in Parkinson's disease. AB - OBJECTIVE: Deep brain stimulation of the subthalamic nucleus (STN-DBS) is well established for treating the motor symptoms for advanced Parkinson's disease (PD) but its effects on gastric myoelectrical activity and gastrointestinal symptoms have not been well studied. The aim of this study was to evaluate the effect of STN-DBS on gastric motility using electrogastrography (EGG). METHODS: Twenty patients with PD (5 females, 15 males; mean aged 58.0 +/- 9.0 years) who underwent STN-DBS were studied. EGG was performed in fasting and postprandial conditions before STN-DBS and 3 months after the surgery. We also evaluated the frequency and severity of gastrointestinal symptoms based on a structured gastrointestinal dysfunction questionnaire. RESULTS: After STN-DBS the percentage of normogastria (47.8 +/- 20.7 vs 51.3 +/- 15.1) and period dominant power (PDP) (11.8 +/- 1.2 vs 12.3 +/- 0.9) significantly increased, the percentage of arrhythmia decreased compared to the baseline during fasting and postprandial state. Abnormal response to a meal (power ratio of PDP <1 after meal) decreased from 70% to 55% after 3 months follow-up. The abnormal EGG (the percentage of normogastria <70%) decreased in both fasting (from 80% to 65% patients) and postprandial state (from 80% to 60% patients), respectively after the surgery. The most common GI symptoms reported prior to the surgery were constipation 95%, difficulty with defecation 85% and dysphagia 50%. After STN-DBS all gastrointestinal symptoms improved, the greatest improvement was observed in difficulty with defecation. CONCLUSION: Our results suggest that STN-DBS improves gastric motility as well as gastrointestinal symptoms in PD. Further studies of gastrointestinal motility in PD are warranted. PMID- 26952699 TI - Continuous leg dyskinesia assessment in Parkinson's disease -clinical validity and ecological effect. AB - INTRODUCTION: Dyskinesias in Parkinson's disease (PD) patients are a common side effect of long-term dopaminergic therapy and are associated with motor dysfunctions, including gait and balance deficits. Although promising compounds have been developed to treat these symptoms, clinical trials have failed. This failure may, at least partly, be explained by the lack of objective and continuous assessment strategies. This study tested the clinical validity and ecological effect of an algorithm that detects and quantifies dyskinesias of the legs using a single ankle-worn sensor. METHODS: Twenty-three PD patients (seven with leg dyskinesias) and 13 control subjects were investigated in the lab. Participants performed purposeful daily activity-like tasks while being video taped. Clinical evaluation was performed using the leg dyskinesia item of the Unified Dyskinesia Rating Scale. The ecological effect of the developed algorithm was investigated in a multi-center, 12-week, home-based sub-study that included three patients with and seven without dyskinesias. RESULTS: In the lab-based sub study, the sensor-based algorithm exhibited a specificity of 98%, a sensitivity of 85%, and an accuracy of 0.96 for the detection of dyskinesias and a correlation level of 0.61 (p < 0.001) with the clinical severity score. In the home-based sub-study, all patients could be correctly classified regarding the presence or absence of leg dyskinesias, supporting the ecological relevance of the algorithm. CONCLUSION: This study provides evidence of clinical validity and ecological effect of an algorithm derived from a single sensor on the ankle for detecting leg dyskinesias in PD patients. These results should motivate the investigation of leg dyskinesias in larger studies using wearable sensors. PMID- 26952700 TI - Predicting Appropriate Admission of Bronchiolitis Patients in the Emergency Department: Rationale and Methods. AB - BACKGROUND: In young children, bronchiolitis is the most common illness resulting in hospitalization. For children less than age 2, bronchiolitis incurs an annual total inpatient cost of $1.73 billion. Each year in the United States, 287,000 emergency department (ED) visits occur because of bronchiolitis, with a hospital admission rate of 32%-40%. Due to a lack of evidence and objective criteria for managing bronchiolitis, ED disposition decisions (hospital admission or discharge to home) are often made subjectively, resulting in significant practice variation. Studies reviewing admission need suggest that up to 29% of admissions from the ED are unnecessary. About 6% of ED discharges for bronchiolitis result in ED returns with admission. These inappropriate dispositions waste limited health care resources, increase patient and parental distress, expose patients to iatrogenic risks, and worsen outcomes. Existing clinical guidelines for bronchiolitis offer limited improvement in patient outcomes. Methodological shortcomings include that the guidelines provide no specific thresholds for ED decisions to admit or to discharge, have an insufficient level of detail, and do not account for differences in patient and illness characteristics including co morbidities. Predictive models are frequently used to complement clinical guidelines, reduce practice variation, and improve clinicians' decision making. Used in real time, predictive models can present objective criteria supported by historical data for an individualized disease management plan and guide admission decisions. However, existing predictive models for ED patients with bronchiolitis have limitations, including low accuracy and the assumption that the actual ED disposition decision was appropriate. To date, no operational definition of appropriate admission exists. No model has been built based on appropriate admissions, which include both actual admissions that were necessary and actual ED discharges that were unsafe. OBJECTIVE: The goal of this study is to develop a predictive model to guide appropriate hospital admission for ED patients with bronchiolitis. METHODS: This study will: (1) develop an operational definition of appropriate hospital admission for ED patients with bronchiolitis, (2) develop and test the accuracy of a new model to predict appropriate hospital admission for an ED patient with bronchiolitis, and (3) conduct simulations to estimate the impact of using the model on bronchiolitis outcomes. RESULTS: We are currently extracting administrative and clinical data from the enterprise data warehouse of an integrated health care system. Our goal is to finish this study by the end of 2019. CONCLUSIONS: This study will produce a new predictive model that can be operationalized to guide and improve disposition decisions for ED patients with bronchiolitis. Broad use of the model would reduce iatrogenic risk, patient and parental distress, health care use, and costs and improve outcomes for bronchiolitis patients. PMID- 26952701 TI - Zika: Defining the Public Health and Exposing its Vulnerabilities. PMID- 26952702 TI - Effective enhancement of hydroxyvalerate content of PHBV in Cupriavidus necator and its characterization. AB - This study investigated the effects of using a combination of substrates (fructose, propanol, citric acid, acetic acid, propionic acid and beef extract) on the synthesis of poly (3-hydroxybutyrate-co-3-hydroxyvalerate), which is also known as PHBV. The results of batch PHBV optimization by RSM, indicated that PHB was synthesized only when fructose was used as the sole carbon source. Fructose in combination with propanol and beef extract, exhibited better PHBV production performance, as compared to that of propionic acid which was used in previous studies. GC, (1)H and (13)C NMR spectroscopy revealed that the best copolymer composition was 54.1 mol% of 3-hydroxyvalerate (3HV) which was obtained in a basal medium combined with 0.3% (v/v) propanol and 0.0172% (w/v) beef extract. This is the first report on the production of PHBV with HV content of 54.1% by a wild-type Cupriavidus necator. The Fourier Transform Infrared Spectroscopy (FTIR) spectra of the PHAs indicated absorption bands at 1723, 1274, 1373, 1453, 2932cm( 1) corresponding to CO, CO stretching, CH3, -CH2 and -CH groups, respectively. This study showed that the recovered PHBV biopolymer from the optimized culture to have a melting temperature of 103.6 degrees C, melting enthalpy of 55.67J/g and crystallization temperature of 76.1 degrees C. PMID- 26952703 TI - Removal of Cr(VI) from aqueous solution using chitosan-g-poly(butyl acrylate)/silica gel nanocomposite. AB - The present work deals with the preparation of the novel sorbent, glutaraldehye crosslinked silica gel/chitosan-g-poly(butyl acrylate) (Cs-g-PBA/SG) nanocomposite by sol-gel method for removal of toxic chromium ion. Prepared nanosorbent was then characterized by FTIR, XRD, DLS, SEM, BET isotherm for its formation and suitability. Its sorption capacity and sorption isotherms were brought under batch mode to suit the optimal parameters viz., contact time, pH, adsorbent dose and initial metal ion concentration which influence the sorption. The theoretical modeling such as Langmuir and Freundlich isotherm adsorption were applied to describe isotherm constants. Equilibrium data agreed well with the Langmuir isotherm model (R(2)=0.9763) with maximum adsorption capacity of 55.71 (mg/g). The kinetic studies showed that the adsorption follows the pseudo-second order kinetics (R(2)=0.9999). From the results, it was concluded that Cs-g-PBA/SG nanocomposite is an excellent biosorbent for Cr removal from wastewater. PMID- 26952704 TI - L-tryptophan and dipeptide derivatives for supercoiled plasmid DNA purification. AB - The present study focus on the preparation of chromatography supports for affinity-based chromatography of supercoiled plasmid purification. Three l tryptophan based supports are prepared through immobilization on epoxy-activated Sepharose and characterized by HR-MAS NMR. The SPR is employed for a fast screening of l-tryptophan derivatives, as potential ligands for the biorecognition of supercoiled isoform, as well as, to establish the suitable experimental conditions for the chromatography. The results reveal that the overall affinity is high (KD=10(-9) and 10(-8)M) and the conditions tested show that the use of HEPES 100mM enables the separation and purification of supercoiled at T=10 degrees C. The STD-NMR is performed to accomplish the epitope mapping of the 5'-mononucleotides bound to l-tryptophan derivatives supports. The data shows that the interactions between the three supports and the 5' mononucleotides are mainly hydrophobic and pi-pi stacking. The chromatography experiments are performed with l-tryptophan support and plasmids pVAX-LacZ and pPH600. The supercoiled isoform separation is achieved at T=10 degrees C by decreasing the concentration of (NH4)2SO4 from 2.7 to 0M in HEPES for pVAX-LacZ and 2.65M to 0M in HEPES for pPH600. Overall, l-tryptophan derivatives can be a promising strategy to purify supercoiled for pharmaceutical applications. PMID- 26952705 TI - Biomarkers of aggression in dementia. AB - Dementia is a clinical syndrome defined by progressive global impairment of acquired cognitive abilities. It can be caused by a number of underlying conditions. The most common types of dementia are Alzheimer's disease (AD), frontotemporal dementia (FTD), vascular cognitive impairment (VCI) and dementia with Lewy bodies (DLB). Despite the fact that cognitive impairment is central to the dementia, noncognitive symptoms, most commonly described nowadays as neuropsychiatric symptoms (NPS) exist almost always at certain point of the illness. Aggression as one of the NPS represents danger both for patients and caregivers and the rate of aggression correlates with the loss of independence, cognitive decline and poor outcome. Therefore, biomarkers of aggression in dementia patients would be of a great importance. Studies have shown that different genetic factors, including monoamine signaling and processing, can be associated with various NPS including aggression. There have been significant and multiple neurotransmitter changes identified in the brains of patients with dementia and some of these changes have been involved in the etiology of NPS. Aggression specific changes have also been observed in neuropathological studies. The current consensus is that the best approach for development of such biomarkers may be incorporation of genetics (polymorphisms), neurobiology (neurotransmitters and neuropathology) and neuroimaging techniques. PMID- 26952706 TI - Adult diaphyseal both-bone forearm fractures: A clinical and biomechanical comparison of four different fixations. AB - BACKGROUND: Although there have been a small number of studies reporting single bone fixation of either radius or ulna as well as hybrid fixation, the paucity of data for the hybrid fixation method still remains. HYPOTHESIS: Hybrid fixation with plate and IM nailing would achieve good fixation and functional outcome, minimal damage to soft tissues and lower re-fracture risk. MATERIALS AND METHODS: Forty cadavers (20 males, 20 females; mean age 68.06, SD 1.58years) were selected in biomechanical study under axial loading, bending loading, and torsional loading. Eighty-seven patients (47 males, 40 females; mean age 38.03+/-0.88years) were enrolled in the clinical study and randomly received different fixation: both-bone plate fixation or both-bone intramedullary nailing, plate fixation of ulna and intramedullary nailing of radius and intramedullary nailing of ulna and plate fixation of radius. RESULTS: In the biomechanical study, intramedullary nailing of ulna and plate fixation of radius had similar results with that using both-bone plate method under axial, bending and torsional loading (All P>0.05), suggesting the more stable fixation compared with the other two groups (All P<0.05). In clinical research, both-bone intramedullary nailing was related to shortest operative time, smallest wound size and periosteal stripping area compared with other three groups (P<0.05). Patients receiving intramedullary nailing of ulna and plate fixation of radius showed the lowest incidence of postoperative complications and the best functional recovery outcome comparing with other three groups of patients (Both P<0.05). CONCLUSION: The hybrid fixation method of intramedullary nailing of ulna and plate fixation of radius showed good stability in biomechanics, fewer complications and better functional clinical outcomes. LEVEL OF EVIDENCE: Level II, prospective randomised study. PMID- 26952707 TI - Psychological issues facing obese pregnant women: a systematic review. AB - OBJECTIVE: To identify, by qualitative and quantitative studies, the psychological aspects considered and/or evaluated during the prenatal care of obese pregnant women, as well as the psychological interventions adopted by health services. METHODS: Systematic review of literature using a mixed method approach, integrating both quantitative and qualitative studies. We used databases (Medline/PubMed, Web of Science, Embase, and SciELO) and publications from January 2003 to June 2013 using "Obesity," "Pregnancy," "Psy,*" or "Psychology" as Medical Subject Headings (MeSH terms). Prospective cohort, cross sectional, case-control, clinical trial, and qualitative research studies were included. Eight articles are included in this review, three with qualitative and five with quantitative methodology. RESULTS: The majority of the studies demonstrate that emotional problems such as depression, anxiety, and stress are associated with the raising of Body Mass Index (BMI) during pregnancy. The results of the qualitative studies show psychological distress related to humiliation and exposure to stigmas surrounding obesity and its connection with gestation. CONCLUSION: There is an emotional demand related to obesity during pregnancy, which should be considered by prenatal multidisciplinary care team. There is a need to increasing attention and support provided for obese pregnant women. PMID- 26952709 TI - Validation of the Spanish-language version of the Relevant Outcome Scale for Alzheimer's Disease. AB - INTRODUCTION AND OBJECTIVES: The Relevant Outcome Scale for Alzheimer's Disease (ROSA) is a useful tool for evaluating and monitoring dementia patients. This study aims to evaluate the validity and reliability of the Spanish version of ROSA. PATIENTS AND METHODS: Spanish multicentre study involving 39 researchers and including 237 patients with Alzheimer disease (78 mild, 79 moderate, and 80 severe). The patients were tested with the following: Mini-Mental State Examination (MMSE), Fototest, Neuropsychiatric Inventory (NPI), Blessed dementia scale, and a Spanish-language version of ROSA. A subsample of 40 subjects was retested in the 14 days following the initial evaluation. The construct validity was evaluated with the Spearman correlation coefficient (r), internal consistency with Cronbach's alpha (alpha), and test-retest reliability with the intraclass correlation coefficient (ICC). RESULTS: ROSA requires 13.8+/-7.4minutes to administer and its results show a significant association with the clinical stage of AD (mild, 116.7+/-23.1; moderate, 92.9+/-19.8; and severe, 64.3+/-22.6), and with results on the MMSE (r=0.68), Fototest (r=0.63), NPI (r=0.53), and Blessed dementia scale (r=-0.80). ROSA shows high internal consistency (alpha=0.90) and excellent test-retest reliability (ICC0.97). CONCLUSION: The Spanish version of ROSA is a brief, valid, and reliable tool permitting overall evaluation of patients with dementia. PMID- 26952708 TI - Using synthetic biology to make cells tomorrow's test tubes. AB - The main tenet of physical biology is that biological phenomena can be subject to the same quantitative and predictive understanding that physics has afforded in the context of inanimate matter. However, the inherent complexity of many of these biological processes often leads to the derivation of complex theoretical descriptions containing a plethora of unknown parameters. Such complex descriptions pose a conceptual challenge to the establishment of a solid basis for predictive biology. In this article, we present various exciting examples of how synthetic biology can be used to simplify biological systems and distill these phenomena down to their essential features as a means to enable their theoretical description. Here, synthetic biology goes beyond previous efforts to engineer nature and becomes a tool to bend nature to understand it. We discuss various recent and classic experiments featuring applications of this synthetic approach to the elucidation of problems ranging from bacteriophage infection, to transcriptional regulation in bacteria and in developing embryos, to evolution. In all of these examples, synthetic biology provides the opportunity to turn cells into the equivalent of a test tube, where biological phenomena can be reconstituted and our theoretical understanding put to test with the same ease that these same phenomena can be studied in the in vitro setting. PMID- 26952710 TI - Variation in the human bicondylar angle. AB - OBJECTIVES: Investigations of the human femoral bicondylar angle have largely focused on interspecific differences and intrapopulation variation. This analysis assesses the range of variation in the bicondylar angle in humans across four populations, examining the effects of population, sex and age. MATERIALS AND METHODS: The bicondylar angle was assessed in four sex- and age-balanced adult skeletal samples-modern Terry Whites and Blacks and archaeological South Dakota Arikara and Native Alaskans. The overall range of variation was assessed, and variation specific to population, sex, and age analyzed through ANOVAs and post hoc Tukey's honestly significant difference tests. RESULTS: A one-way ANOVA highlights a significant effect of population on bicondylar angle; however, the only significant difference occurs between the Terry White and South Dakota Arikara samples. Sex displays a significant effect for the total pooled sample; yet, within population, the effect of sex is significant only among South Dakota Arikara. Age also has a significant effect on bicondylar angle in the total sample; however, the interaction between age and population is not significant. CONCLUSION: The results highlight the degree of variation in the bicondylar angle that exists intraspecifically. Differing degrees of variation due to sex suggest that sexual dimorphism is not universal in the human bicondylar angle. Furthermore, the broad impact of age on this feature is discussed, including the potential for plasticity through adulthood. By recognizing and explicitly examining morphological features that vary in human populations, we can appreciate the origins of variation and its implications for locomotor function, human diversity and evolutionary relationships. Am J Phys Anthropol 160:334-340, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26952711 TI - Collaboration of Home Visiting and Primary Care Clinicians. PMID- 26952712 TI - Hypertrophic neuropathy in Noonan syndrome with multiple lentigines. AB - RASopathies comprise several genetic syndromes with mainly cardio-facial cutaneous manifestations. We report a patient with Noonan syndrome with multiple lentigines (NSML) due to a PTPN11 (p.Thr468Met) mutation associated with hypertrophic neuropathy of lumbar plexus in an adult woman, initially referred for neuropathic pain. Differential diagnosis of neurofibromatosis type 1 (NF1) and other RASopathies is difficult without molecular testing. (c) 2016 Wiley Periodicals, Inc. PMID- 26952714 TI - Myths and Misinformation: An Analysis of Text Messages Sent to a Sexual and Reproductive Health Q&A Service in Nigeria. AB - The almost 50 million young people aged 10-24 in Nigeria face many challenges to their sexual and reproductive health (SRH). MyQuestion is a platform that allows young people to ask SRH questions via text message. Trained counselors provide responses using a database of answers to frequently asked questions or customized replies. We analyze the content of more than 300,000 text messages received by the service since 2007 to address three questions: which health topics are most frequently submitted to the MyQuestion service; what kinds of questions are asked about these topics; and what language is used to convey the questions? We find a substantial unmet need for basic SRH information, with users' questions communicated in ways that convey considerable confusion, misinformation, and urgency. The analysis can be used to improve similar Q&A services and to improve the provision of SRH services for young people more generally. PMID- 26952713 TI - The Effects of Cognitive Training for Elderly: Results from My Mind Project. AB - Cognitive decline and dementia represent very important public health problems that impact the ability to maintain social function and independent living. The aim of this study was to investigate the effects of a nonpharmacological intervention consisting of comprehensive cognitive training in elderly people having one of three different cognitive statuses. In all, 321 elderly people with a diagnoses of mild-moderate Alzheimer's disease (AD), with mild cognitive impairment (MCI) and without cognitive decline were randomly assigned to two groups: experimental group (EG, who underwent intervention) and control group (CG), according to a prospective randomized intervention study. In the three groups, immediately after the end of the intervention, we observed a significant effect on some cognitive and noncognitive outcomes in the EGs. At the end of the intervention, we found an intermediate intervention effect on the Alzheimer's Disease Assessment Scale (ADAS) score of subjects with AD, as well as on functional status, as measured by using the Instrumental Activities of Daily Living scale. A significant intervention effect was also observed on enhancement of auditory verbal short-term memory and subjective memory complaints of subjects with MCI. The group of subjects without cognitive decline obtained a significant intervention effect on subjective complaints outcomes. The obtained results demonstrated that participation in the intervention could improve performance with respect to specific cognitive functions and psychological statuses. The role of healthy lifestyle programs, such as the use of comprehensive interventions, has been shown to be efficient for enhancing memory and other abilities in aged individuals with and without cognitive decline. PMID- 26952715 TI - Improving the antidepressant action and the bioavailability of sertraline by co crystallization with coumarin 3-carboxylate. Structural determination. AB - To improve the antidepressant action of sertraline a new salt with coumarin-3 carboxylate anion (SerH-CCA) has been synthesized by two different methods and characterized by FTIR spectroscopy and structural determinations by X-ray diffraction methods. The new salt is stabilized by strong intermolecular H-bonds involving the protonated amine group of SerH and the deprotonated carboxylate group of CCA. These findings can be correlated with the interpretation of the infrared spectrum. The salt, sertraline (SerHCl) and the sodium salt of coumarin 3-carboxylate (NaCCA) were orally administered male Wistar rats (10 mg/kg, based on sertraline). Rats were evaluated in separate groups by means of the forced swimming (FST). SerH-CCA produced antidepressant effects in a magnitude that exceeded SerHCl individual effects. None of these treatments affected activity levels by the open field OFT tests. We have also determined that the ion pair also improve the binding to bovine serum albumin (BSA) of the drug but retain its antimicrobial activity. It is reasonable to conclude that the replacement of chloride anion by a large organic anion in sertraline strengthens the pharmacological action of the native drug, binding to BSA with higher activity and retaining the antimicrobial activity of the antidepressant compound. PMID- 26952716 TI - Molecular typing, virulence traits and antimicrobial resistance of diabetic foot staphylococci. AB - BACKGROUND: Diabetes mellitus is a major chronic disease that continues to increase significantly. One of the most important and costly complications of diabetes are foot infections that may be colonized by pathogenic and antimicrobial resistant bacteria, harboring several virulence factors, that could impair its successful treatment. Staphylococcus aureus is one of the most prevalent isolate in diabetic foot infections, together with aerobes and anaerobes. METHODS: In this study, conducted in the Lisbon area, staphylococci isolated (n = 53) from diabetic foot ulcers were identified, genotyped and screened for virulence and antimicrobial resistance traits. Genetic relationship amongst isolates was evaluated by pulsed-field-gel-electrophoresis with further multilocus sequence typing of the identified pulsotypes. PCR was applied for detection of 12 virulence genes and e-test technique was performed to determine minimal inhibitory concentration of ten antibiotics. RESULTS: Among the 53 isolates included in this study, 41 Staphylococcus aureus were identified. Staphylococcal isolates were positive for intercellular adhesins icaA and icaD, negative for biofilm associated protein bap and pantone-valentine leucocidin pvl. S. aureus quorum sensing genes agrI and agrII were identified and only one isolate was positive for toxic shock syndrome toxin tst. 36 % of staphylococci tested were multiresistant and higher rates of resistance were obtained for ciprofloxacin and erythromycin. Clonality analysis revealed high genomic diversity and numerous S. aureus sequence types, both community- and hospital acquired, belonging mostly to clonal complexes CC5 and C22, widely diffused in Portugal nowadays. CONCLUSIONS: This study shows that diabetic foot ulcer staphylococci are genomically diverse, present resistance to medically important antibiotics and harbour virulence determinants. These properties suggest staphylococci can contribute to persistence and severity of these infections, leading to treatment failure and to the possibility of transmitting these features to other microorganisms sharing the same niche. In this context, diabetic patients may become a transmission vehicle for microorganisms' clones between community and clinical environments. PMID- 26952717 TI - Treatment of prescription opioid disorders in Canada: looking at the 'other epidemic'? AB - The magnitude and consequences of prescription opioid (PO) misuse and harms (including rising demand for PO disorder treatment) in Canada have been well documented. Despite a limited evidence-base for PO dependence treatment, opioid maintenance therapy (OMT) - mostly by means of methadone maintenance treatment (MMT) - has become the de facto first-line treatment for PO-disorders. For example in the most populous province of Ontario, some 50,000 patients - large proportions of them young adults - are enrolled in MMT, resulting in a MMT-rate that is 3-4 times higher than that of the United States. MMT in Ontario has widely proliferated towards a quasi-treatment industry within a system context of the public fee-payer offering generous incentives for community-based MMT providers. Contrary to the proliferation of MMT, there has been no commensurate increase in availability of alternative (e.g., detox, tapering, behavioral), and less intrusive and/or costly, treatments which may provide therapeutic benefits at least for sub-sets of PO-dependent patients. Given the extensive PO-dependence burden combined with its distinct socio-demographic and clinical profile (e.g., involving many young people, less intensive or risky opioid use), an evidence based 'stepped-care' model for PO dependence treatment ought to be developed in Canada where MMT constitutes one, but likely a last resort or option, for treatment. Other, less intrusive treatment options as well as the best mix of treatment options should be systematically investigated and implemented. This case study has relevance and implications for evidence-based treatment also for the increasing number of other jurisdictions where PO misuse and disorders have been rising. PMID- 26952718 TI - Anatomical basis of the coordination between smooth and striated urethral and anal sphincters: loops of regulation between inferior hypogastric plexus and pudendal nerve. Immuno-histological study with 3D reconstruction. AB - PURPOSE: (1) Describe both nervous pathways to the sphincters, and highlight the anatomical support of their coordination. (2) Obtain a 3D representation of this complex innervation system. METHODS: A computer-assisted anatomical dissection technique was used. Serial histological sections were cut in the pelvis of four female human foetuses (aged 19-32 weeks of gestation). The sections were treated with conventional staining, and with seven different immunostainings. The sections were digitalized and, finally, a 3D representation was built from the corresponding images. RESULTS: Myelinated and sensory fibres were detected at the inferior hypogastric plexus (IHP) level. Our analysis showed that most of the afferent sensory fibres come from the urinary and anal sphincters through the anterior and posterior branches of the IHP respectively. A highly positive nitrergic (anti-NOS1) and sensitive (anti-CGRP) labelling was found in the external layer of the urethral sphincter. The 3D representation allowed describing the two components of the innervation system. A sensory-motor regulation loop was found for both sphincters. CONCLUSION: A 3D description of the components of both nervous pathways to the sphincters has been established. Our findings on the innervation of the sphincters tend to question the classical infra/supra levatorian muscle description. The coordinated work of the internal and external layers of the anal and urethral sphincter is probably mediated by multiple roles regulation. PMID- 26952719 TI - Building capacity in implementation science research training at the University of Nairobi. AB - BACKGROUND: Health care systems in sub-Saharan Africa, and globally, grapple with the problem of closing the gap between evidence-based health interventions and actual practice in health service settings. It is essential for health care systems, especially in low-resource settings, to increase capacity to implement evidence-based practices, by training professionals in implementation science. With support from the Medical Education Partnership Initiative, the University of Nairobi has developed a training program to build local capacity for implementation science. METHODS: This paper describes how the University of Nairobi leveraged resources from the Medical Education Partnership to develop an institutional program that provides training and mentoring in implementation science, builds relationships between researchers and implementers, and identifies local research priorities for implementation science. RESULTS: The curriculum content includes core material in implementation science theory, methods, and experiences. The program adopts a team mentoring and supervision approach, in which fellows are matched with mentors at the University of Nairobi and partnering institutions: University of Washington, Seattle, and University of Maryland, Baltimore. A survey of program participants showed a high degree satisfaction with most aspects of the program, including the content, duration, and attachment sites. A key strength of the fellowship program is the partnership approach, which leverages innovative use of information technology to offer diverse perspectives, and a team model for mentorship and supervision. CONCLUSIONS: As health care systems and training institutions seek new approaches to increase capacity in implementation science, the University of Nairobi Implementation Science Fellowship program can be a model for health educators and administrators who wish to develop their program and curricula. PMID- 26952720 TI - Roles of RPS41 in Biofilm Formation, Virulence, and Hydrogen Peroxide Sensitivity in Candida albicans. AB - In eukaryotes, loss of cytoplasmic ribosomal proteins (RPs) results in a reduced growth rate and other phenotypic defects. The ability to transition from a unicellular budding yeast to a filamentous form is very important for biofilm formation and virulence in Candida albicans. Our recent study found that loss of the RPS41 (C2_10620W_A) gene but not its paralog RPS42 (C1_01640W_A) resulted in altered growth and filamentation changes in C. albicans, so we hypothesized that the RPS41 gene should play important roles in virulence and biofilm formation in this pathogen. We found that both virulence and the ability to form biofilms were defective due to deletion of the RPS41 gene. We also found that loss of the RPS41 gene increased sensitivity to hydrogen peroxide, and that hydrogen peroxide induced the expression of the RPS41 gene in a wild-type strain. These results suggested that the RPS41 gene plays important roles in C. albicans biofilm formation, virulence, and susceptibility to hydrogen peroxide. PMID- 26952721 TI - Complete mitochondrial genomes of two gelechioids, Mesophleps albilinella and Dichomeris ustalella (Lepidoptera: Gelechiidae), with a description of gene rearrangement in Lepidoptera. AB - We sequenced the entire mitochondrial genome (mitogenome) of two gelechioids, Mesophleps albilinella and Dichomeris ustalella, and compared their genome organization and sequence composition to those of available gelechioid mitogenomes for an enhanced understanding of Gelechioidea genomic characteristics. We compared all available lepidopteran mitogenome arrangements, including that of M. albilinella, which is unique in Gelechioidea, to comprehend the extensiveness and mechanisms of gene rearrangement in Lepidoptera. The genomes of M. albilinella and D. ustalella are 15,274 and 15,410 bp in size, respectively, with the typical sets of mitochondrial (mt) genes. The COI gene begins with CGA (arginine) in all sequenced gelechioids, including M. albilinella and D. ustalella, reinforcing the feature as a synapomorphic trait, at least in the Gelechioidea. Each 353- and 321-bp long A + T-rich region of M. albilinella and D. ustalella contains one (D. ustalella) or two (M. albilinella) tRNA-like structures. The M. albilinella mitogenome has a unique gene arrangement among the Gelechioidea: ARNESF (the underline signifies an inverted gene) at the ND3 and ND5 junction, as opposed to the ARNSEF that is found in ancestral insects. An extensive search of available lepidopteran mitogenomes, including that of M. albilinella, turned up six rearrangements that differ from those of ancestral insects. Most of the rearrangements can be explained by the tandem duplication random loss model, but inversion, which requires recombination, is also found in two cases, including M. albilinella. Excluding the MIQ rearrangement at the A + T rich region and ND2 junction, which is found in nearly all Ditrysia, most of the remaining rearrangements found in Lepidoptera appear to be independently derived in that they are automorphic at several taxonomic scales, although current mitogenomic data are limited, particularly for congeneric data. PMID- 26952722 TI - Large-scale aerosol-assisted synthesis of biofriendly Fe2O3 yolk-shell particles: a promising support for enzyme immobilization. AB - Multiple-shelled Fe2O3 yolk-shell particles were synthesized using the spray drying method and intended as a suitable support for the immobilization of commercial enzymes such as glucose oxidase (GOx), horseradish peroxidase (HRP), and laccase as model enzymes. Yolk-shell particles have an average diameter of 1 3 MUm with pore diameters in the range of 16 to 28 nm. The maximum immobilization of GOx, HRP, and laccase resulted in the enzyme loading of 292, 307 and 398 mg per g of support, respectively. After cross-linking of immobilized laccase by glutaraldehyde, immobilization efficiency was improved from 83.5% to 90.2%. K(m) and V(max) values were 41.5 MUM and 1722 MUmol min(-1) per mg protein for cross linked laccase and those for free laccase were 29.3 MUM and 1890 MUmol min(-1) per mg protein, respectively. The thermal stability of the enzyme was enhanced up to 18-fold upon cross-linking, and the enzyme retained 93.1% of residual activity after ten cycles of reuse. The immobilized enzyme has shown up to 32-fold higher stability than the free enzyme towards different solvents and it showed higher efficiency than free laccase in the decolorization of dyes and degradation of bisphenol A. The synthesized yolk-shell particles have 3-fold higher enzyme loading efficiency and lower acute toxicity than the commercial Fe2O3 spherical particles. Therefore, the use of unique yolk-shell structure Fe2O3 particles with multiple-shells will be promising for the immobilization of various enzymes in biotechnological applications with improved electrochemical properties. To the best of our knowledge, this is the first report on the use of one pot synthesized Fe2O3 yolk-shell structure particles for the immobilization of enzymes. PMID- 26952723 TI - Psychosocial correlates of oral hygiene behaviour in people aged 9 to 19 - a systematic review with meta-analysis. AB - OBJECTIVES: This systematic and meta-analytic review aimed to quantify the association of psychosocial correlates with oral hygiene behaviour among 9- to 19 year olds. METHODS: A systematic search up to August 2015 was carried out using the following databases: PubMed, PsycInfo, Embase, CINAHL and Web of Science. If necessary, authors of studies were contacted to obtain unpublished statistical information. A study was eligible for inclusion when it evaluated the association between the psychosocial correlates and oral hygiene behaviour varying from self reports to clinical measurements, including plaque and bleeding scores. A modified New Castle Ottawa Scale was applied to examine the quality of the included studies. RESULTS: Twenty-seven data sets (k) presented in 22 publications, addressing nine psychosocial correlates, were found to be eligible for the meta-analysis. For both tooth brushing and oral hygiene behaviour, random effect models revealed significant weighted average correlation (r+ ) for the psychosocial factors: 'intention', 'self-efficacy', 'attitude' (not significant for tooth brushing), 'social influence', 'coping planning' and 'action planning' (r+ ranging from 0.18 to 0.57). Little or no associations were found for 'locus of control', 'self-esteem' and 'sense of coherence' (r+ ranges from 0.01 to 0.08). CONCLUSIONS: The data at present indicates that 'self-efficacy', 'intention', 'social influences', 'coping planning' and 'action planning' are potential psychosocial determinants of oral health behaviour. Future studies should consider a range of psychological factors that have not been studied, but have shown to be important psychosocial determinants of health behaviours, such as 'self-determination', 'anticipated regret', 'action control' and 'self identity'. Effectiveness of addressing these potential determinants to induce behaviour change should be further examined by intervention trials. PMID- 26952724 TI - Advances in Clinical PET/MRI Instrumentation. AB - In 2010, the first whole-body PET/MRI scanners installed for clinical use were the sequential Philips PET/MRI with PMT-based, TOF-capable technology and the integrated simultaneous Siemens PET/MRI. Avalanche photodiodes as non-magneto sensitive readout electronics allowed PET integrated within the MRI. The experiences with these scanners showed that improvements of software aspects, such as attenuation correction, were necessary and that efficient protocols combining optimally PET and MRI must be still developed. In 2014, General Electric issued an integrated PET/MRI with SiPM-based PET detectors, allowing TOF PET. Looking at the MRI components of current PET/MR imaging systems, primary improvements come from sequences and new coils. PMID- 26952725 TI - Innovations in Small-Animal PET/MR Imaging Instrumentation. AB - Multimodal imaging has led to a more detailed exploration of different physiologic processes with integrated PET/MR imaging being the most recent entry. Although the clinical need is still questioned, it is well recognized that it represents one of the most active and promising fields of medical imaging research in terms of software and hardware. The hardware developments have moved from small detector components to high-performance PET inserts and new concepts in full systems. Conversely, the software focuses on the efficient performance of necessary corrections without the use of CT data. The most recent developments in both directions are reviewed. PMID- 26952726 TI - The Use of Contrast Agents in Clinical and Preclinical PET-MR Imaging. AB - PET-MR imaging is an exciting field of research for imaging chemists that allows for innovative approaches such as the use of cocktails of agents or bimodal contrast. In this review, we provide an overview of some of the work in the in preclinical and clinical PET-MR imaging to date, and discuss limitations in the design and applications of these materials. PMID- 26952728 TI - Attenuation Correction for Magnetic Resonance Coils in Combined PET/MR Imaging: A Review. AB - With the introduction of clinical PET/magnetic resonance (MR) systems, novel attenuation correction methods are needed, as there are no direct MR methods to measure the attenuation of the objects in the field of view (FOV). A unique challenge for PET/MR attenuation correction is that coils for MR data acquisition are located in the FOV of the PET camera and could induce significant quantitative errors. In this review, current methods and techniques to correct for the attenuation of a variety of coils are summarized and evaluated. PMID- 26952729 TI - MR Imaging-Guided Partial Volume Correction of PET Data in PET/MR Imaging. AB - Partial volume effects are caused by the limited spatial resolution of the PET system. There is increasing evidence that partial volume correction (PVC) is necessary to guarantee quantitative accuracy in PET; however, there is reluctance to apply PVC routinely in clinical practice, partly because of uncertainty regarding the method of choice. To perform accurate PVC, it is necessary to introduce information from high-resolution anatomic images, such as MR imaging. All the methods rely on accurate coregistration between the anatomic image and the PET image. PET/MR imaging offers clear advantages for PVC and can help alleviate the image registration issues. PMID- 26952730 TI - MR-Based Cardiac and Respiratory Motion-Compensation Techniques for PET-MR Imaging. AB - Cardiac and respiratory motion cause image quality degradation in PET imaging, affecting diagnostic accuracy of the images. Whole-body simultaneous PET-MR scanners allow for using motion information estimated from MR images to correct PET data and produce motion-compensated PET images. This article reviews methods that have been proposed to estimate motion from MR images and different techniques to include this information in PET reconstruction, in order to overcome the problem of cardiac and respiratory motion in PET-MR imaging. MR based motion correction techniques significantly increase lesion detectability and contrast, and also improve accuracy of uptake values in PET images. PMID- 26952727 TI - MR Imaging-Guided Attenuation Correction of PET Data in PET/MR Imaging. AB - Attenuation correction (AC) is one of the most important challenges in the recently introduced combined PET/magnetic resonance (MR) scanners. PET/MR AC (MR AC) approaches aim to develop methods that allow accurate estimation of the linear attenuation coefficients of the tissues and other components located in the PET field of view. MR-AC methods can be divided into 3 categories: segmentation, atlas, and PET based. This review provides a comprehensive list of the state-of-the-art MR-AC approaches and their pros and cons. The main sources of artifacts are presented. Finally, this review discusses the current status of MR-AC approaches for clinical applications. PMID- 26952731 TI - MRI-Guided Derivation of the Input Function for PET Kinetic Modeling. AB - Blood samples obtained by arterial cannulation are the gold standard to measure the input function for PET pharmacokinetic modeling. There is interest in less invasive methods, such as image-derived input functions (IDAIF). MRI can be used to segment and correct partial volume effects of the PET images, improving IDAIF extraction. Preclinical studies have shown that the input function of PET tracers, namely fluorodeoxyglucose and [(18)F]fluoroethyl-l-tyrosine, can be derived from the Gd-DTPA input function. Noninvasive, MRI-guided, PET input function derivation is a promising avenue to reduce or eliminate the need for arterial plasma samples in preclinical and clinical settings. PMID- 26952732 TI - PET/MR Imaging: Advances in Instrumentation and Quantitative Procedures. PMID- 26952733 TI - Exploring the efficacy of paternity and kinship testing based on single nucleotide polymorphisms. AB - Short tandem repeats (STRs) are conventional genetic markers typically used for paternity and kinship testing. As supplementary markers of STRs, single nucleotide polymorphisms (SNPs) have less discrimination power but broader applicability to degraded samples. The rapid improvement of next-generation sequencing (NGS) and multiplex amplification technologies also make it possible now to simultaneously identify dozens or even hundreds of SNP loci in a single pool. However, few studies have been endeavored to kinship testing based on SNP loci. In this study, we genotyped 90 autosomal human identity SNP loci with NGS, and investigated their testing efficacies based on the likelihood ratio model in eight pedigree scenarios involving paternity, half/full-sibling, uncle/nephew, and first-cousin relationships. We found that these SNPs might be sufficient to discriminate paternity and full-sibling, but impractical for more distant relatives such as uncle and cousin. Furthermore, we conducted an in silico study to obtain the theoretical tendency of how testing efficacy varied with increasing number of SNP loci. For each testing battery in a given pedigree scenario, we obtained distributions of logarithmic likelihood ratio for both simulated relatives and unrelated controls. The proportion of the overlapping area between the two distributions was defined as a false testing level (FTL) to evaluate the testing efficacy. We estimated that 85, 127, 491, and 1,858 putative SNP loci were required to discriminate paternity, full-sibling, half-sibling/uncle-nephew, and first-cousin (FTL, 0.1%), respectively. To test a half-sibling or nephew, an additional uncle relative could be included to decrease the required number of putative SNP loci to ~320 (FTL, 0.1%). As a systematic computation of paternity and kinship testing based only on SNPs, our results could be informative for further studies and applications on paternity and kinship testing using SNP loci. PMID- 26952735 TI - A novel Pt-Co alloy hydrogen anode catalyst with superlative activity, CO tolerance and robustness. AB - PtCo nanoparticles, having two atomic layers of stabilized Pt skin, supported on carbon black (Pt2AL-PtCo/C), exhibited superlative mass activity for the CO tolerant hydrogen oxidation reaction (HOR), together with high robustness with respect to air exposure, as a novel anode catalyst in reformate gas-based polymer electrolyte fuel cells. The high area-specific HOR activity and CO tolerance are consistent with DFT calculations. PMID- 26952734 TI - A Unified Approach to Outcomes Assessment for Distal Radius Fractures. AB - Distal radius fractures are one of the most common upper extremity injuries. Currently, outcome assessment after treatment of these injuries varies widely with respect to the measures that are used, timing of assessment, and the end points that are considered. A more consistent approach to outcomes assessment would provide a standard by which to assess treatment options and best practices. In this summary, we review the consensus regarding outcomes assessment after distal radius fractures and propose a systematic approach that integrates performance, patient-reported outcomes, pain, complications, and radiographs. PMID- 26952736 TI - Online electrochemical system as an in vivo method to study dynamic changes of ascorbate in rat brain during 3-methylindole-induced olfactory dysfunction. AB - This study demonstrates the application of an online electrochemical system (OECS) as an in vivo method to investigate the dynamic change of microdialysate ascorbate in the olfactory bulb (OB) of rats during the acute period of olfactory dysfunction induced by intraperitoneal (i.p.) injection of 3-methylindole (3-MI). The OECS is developed by directly coupling an electrochemical detector to in vivo microdialysis for the direct monitoring of ascorbate. The system benefits from the good electrochemical activity of single-walled carbon nanotubes towards the oxidation of ascorbate and exhibits high selectivity, good stability, reproducibility and linearity for the measurement of ascorbate in the OB under physiological conditions. With this method, the basal level of microdialysate ascorbate in the OB is determined to be 48.64 +/- 5.44 MUM. The administration of 3-MI clearly increases the microdialysate ascorbate in the OB after 3-MI treatments and this increase is obviously alleviated by intravenous administration of ascorbate and glutathione (GSH) within 10 min after i.p. injection of 3-MI. These observations with the OECS suggest that ascorbate may be involved in chemical processes during the early stages of 3-MI-induced olfactory dysfunction. This study essentially validates the OECS as an in vivo method for effective measurement of ascorbate in the OB in rat brain and such a method will find interesting applications in investigating chemical process associated with ascorbate underlying olfactory dysfunction. PMID- 26952737 TI - Effects of dutasteride on serum free-testosterone and clinical significance of testosterone changes. AB - Sixty-two patients with benign prostate hyperplasia (BPH) who were being treated with dutasteride participated in this study. Prostate volume, uroflowmetry, blood tests, the International Prostate Symptom Score (IPSS) and International Index of Erectile Function (IIEF-5) were determined before and 1, 3 and 12 months after the treatment with dutasteride. Patients were divided into two groups based on changes in serum testosterone after 1 month: Group A (>20% increase; n = 33) or Group B (<20% increase; n = 29). Serum free-testosterone levels were 20.4% higher after 1 month and remained constant thereafter. When Groups A and B were compared, baseline free-testosterone levels were significantly lower in Group A, IPSS QOL was significantly better in Group A at 3 and 12 months, and no significant differences were observed in uroflowmetry, prostate volume, IPSS or IIEF-5. A univariate analysis identified serum free-testosterone levels and the IPSS storage symptom subscore as significant factors influencing IPSS QOL at 12 months, and only the IPSS storage symptom subscore appeared to be independently related to IPSS QOL. These results indicate that dutasteride increases serum free testosterone levels in BPH patients, particularly with low baseline free testosterone levels, and the increase in free-testosterone may have further add on impacts on their urinary tract symptoms. PMID- 26952738 TI - Examination of a possible J-shaped relationship between alcohol consumption and internalizing disorders in a longitudinal birth cohort. AB - BACKGROUND: Many studies have reported a J-shaped relationship between alcohol use and affective or anxiety symptoms, with abstainers experiencing more severe symptoms than moderate drinkers. It is less clear whether this relationship is also present for the risk of syndromal internalizing disorders such as depression or anxiety disorders. METHODS: A New Zealand longitudinal birth cohort study (n=1265). Participants were interviewed at ages 18, 21, 25, 30 and 35 years. Alcohol consumption level and the presence of internalizing disorders (major depression; anxiety disorder) for the previous 12 months were determined at each time point. The association between drinking status and major depression and anxiety disorders at ages 18, 21, 25, 30 and 35 years was investigated via Generalized Estimating Equation modelling. RESULTS: There was little evidence of a statistically significant (p<.05) association between alcohol consumption levels and either: (a) major depression; or (b) anxiety disorder; across the period 18-35 years. Inspection of the annual data showed considerable fluctuation in rates of disorder across alcohol consumption categories. CONCLUSION: In young adults there was little evidence of a J-shaped relationship between alcohol use and both major depression and anxiety disorder. PMID- 26952740 TI - Contrasting the grain boundary-affected performance of zinc and indium oxide transparent conductors. AB - Zinc oxide-based transparent conductors have long been advanced for their potential as low-cost, earth-abundant replacements for the indium oxide-based materials that currently dominate in practical applications. However, this potential has yet to be realized because of the difficulties in producing zinc oxide thin films with the necessary high levels of electrical conductivity and environmental stability that are readily achieved using indium oxide. To better understand the fundamental reasons for this, polycrystalline zinc and indium oxide thin films were prepared across a range of deposition temperatures using the technique of spray pyrolysis. Electrical transport measurements of these samples both as a function of temperature and UV irradiation were correlated with film morphology to illustrate that the different grain boundary behaviour of these two materials is one of the key reasons for their divergent performance. This is a critical challenge that must be addressed before any substantial increase in the adoption of ZnO-based transparent conductors can take place. PMID- 26952741 TI - Intelligent Janus nanoparticles for intracellular real-time monitoring of dual drug release. AB - Stimuli-responsive nanomaterials have been receiving much attention as drug delivery carriers, however understanding of multi-drug release from the carriers for efficient therapeutics is highly challenging. Here, we report a novel nanosystem, Janus particle Dox-CMR-MS/Au-6MP (Dox: doxorubicin, CMR: 7 hydroxycoumarin-3-carboxylate, MS: mesoporous silica, Au: gold, 6MP: 6 mercaptopurine) with opposing MS and Au faces, which can monitor intracellular dual-drug (Dox and 6MP) controlled release in real time based on fluorescence resonance energy transfer (FRET) and surface-enhanced Raman scattering (SERS). The FRET acceptor Dox is attached to CMR (as a FRET donor) conjugated MS with a pH-responsive linker hydrazone, and 6MP is conjugated to the Au surface through the gold-thiol interaction. As the Janus nanoparticle enters into tumor cells, the breakage of the hydrazone bond in an acidic environment and the substitution of glutathione (GSH) overexpressed in cancer cells give rise to the release of Dox and 6MP, respectively. Thus, the change of the CMR fluorescence signal and the SERS decrease of 6MP can be used to monitor the dual-drug release within living cells in real time. In addition, this work demonstrates the enhanced anticancer effect of the designed dual-drug loaded nanosystem. Therefore, the current study may provide new perspectives for the real-time study of intelligent multi-drug delivery and release, as well as cellular responses to drug treatment. PMID- 26952742 TI - Vertically ordered silica mesochannel films: electrochemistry and analytical applications. AB - Mesoporous silica films consisting of highly ordered and vertically aligned nanochannels (abbreviated as VMSFs) have received considerable attention because of their high surface area, long-range order, thermal and mechanical stability, controllable pore size and more importantly good molecular accessibility for rapid mass transport. These characteristics are ideal for electroanalytical chemistry and separation science. In this review, we firstly present briefly the strategies for the synthesis of VMSFs on the electrode surface, mainly the electrochemically assisted self-assembly and Stober-solution growth approaches, as well as the surface modification of channel walls with diverse terminal groups for various functionalities. In the next section, recent progress on the applications of VMSFs in electroanalytical chemistry and sensing is summarized, in terms of the spatial confinement and permselective effects (size, charge and lipophilicity selectivity of the mesochannels). We then present the preparation and application of perforated free-standing VMSFs for fast and precise molecular sieving/separation. The review ends with an outlook and perspective on the future applications of VMSFs. PMID- 26952743 TI - Toxic effects of arsenic on semen and hormonal profile and their amelioration with vitamin E in Teddy goat bucks. AB - The present environmental study has been planned to investigate the toxic effects of arsenic on reproductive functions of Teddy bucks as well as to examine whether these toxic effects are ameliorated by vitamin E. Sixteen adult Teddy bucks were divided randomly into four equal groups A, B, C and D with following treatment: A (control), B (sodium arsenite 5 mg kg-1 BW day-1 ), C (vit E 200 mg kg-1 BW day-1 + Arsenic 5 mg kg-1 BW day-1 ) and D (vit E 200 mg kg-1 BW day-1 ). This treatment was continued for 84 days. Semen quality parameters were evaluated weekly. Male testosterone, luteinising hormone (LH), follicle-stimulating hormone (FSH) and cortisol levels were measured through enzyme-linked immunosorbent assay (ELISA) after every 2 weeks. The data were subjected to two-way analysis of variance followed by Duncan test for multiple comparisons. Semen evaluation parameters were reduced significantly (P < 0.05) in arsenic-treated animals. The serum hormonal profile of testosterone, LH and FSH was reduced significantly (P < 0.05) in arsenic group, while the serum level of cortisol was increased. Vitamin E alleviated the toxic effects of arsenic on semen and hormonal parameters. It may be concluded from this study that sodium arsenite causes major toxicity changes in semen and hormonal profile in Teddy goat bucks and vitamin E has ameliorative effects on these toxic changes. PMID- 26952744 TI - [RuCl2(eta6-p-cymene)] complexes bearing phosphinous acid ligands: preparation, application in C-H bond functionalization and mechanistic investigations. AB - A series of [RuCl2(eta(6)-p-cymene)] complexes bearing phosphinous acid (PA) ligands have been straightforwardly prepared from the dimer [RuCl2(p-cymene)]2 and secondary phosphine oxides (SPOs) and fully characterized. The steric parameter quantification of PAs, other L ligands and eta(6)-p-cymene allowed a better comprehension of the coordination chemistry of these types of complexes and explained the absence of coordination in the case of bulky SPOs such as Ad2P(O)H. These complexes were tested in the C-H activation/functionalization of 2-phenylpyridine and a good activity was obtained at 80 degrees C for the complex exhibiting the highest steric bulk. A study on halide effects, either on the ruthenium complex or for the aryl halide partner, has also been carried out showing drastic differences. Further investigations on halide effects were performed notably by using a cationic ruthenacycle which was found to be an intermediate for the reaction. In order to rationalize the role played by the phosphinous acid, a mechanism involving a concerted metallation deprotonation favored by a phosphinito species has been proposed. PMID- 26952739 TI - Diffusion Decision Model: Current Issues and History. AB - There is growing interest in diffusion models to represent the cognitive and neural processes of speeded decision making. Sequential-sampling models like the diffusion model have a long history in psychology. They view decision making as a process of noisy accumulation of evidence from a stimulus. The standard model assumes that evidence accumulates at a constant rate during the second or two it takes to make a decision. This process can be linked to the behaviors of populations of neurons and to theories of optimality. Diffusion models have been used successfully in a range of cognitive tasks and as psychometric tools in clinical research to examine individual differences. In this review, we relate the models to both earlier and more recent research in psychology. PMID- 26952745 TI - Systemic inflammation induces anxiety disorder through CXCL12/CXCR4 pathway. AB - It is evidenced that inflammation is involved in the pathogenesis of anxiety disorder, as well as the dysfunction of glutamate neurotransmission in the central nervous system (CNS). Chemokine CXCL12 has been reported taking part in the regulation of neurotransmitter release, however, the roles of CXCL12 in the development of anxiety are still unclear. In this study, we found that intraperitoneal (i.p) injection of lipopolysaccharide (LPS) induced anxiety-like behaviors in adult mice as measured by elevated plus-maze test (EPM) and open field test (OFT). Astrocytes were responsible for CXCL12 induction upon LPS challenge in hippocampus and amygdala, and microinjection of CXCL12 into amygdala induced mice anxiety-like behaviors. AMD3100, which is an antagonist for CXCL12 receptor CXCR4, prevented the anxiety behaviors induced by microinjection of CXCL12 into amygdala as well as injection i.p of LPS. Knockdown of CXCR4 expression in neurons using short hairpin RNAs (shRNAs) significantly blocked anxiety behaviors mediated by CXCL12 i.c injection. Furthermore, AMD3100 or shCXCR4 prevented the impairment of nesting ability induced by CXCL12 in mice. Whole-cell patch-clamp recordings in the neurons of basolateral amygdala (BLA) revealed that CXCL12 enhanced glutamatergic transmission by increasing sEPSC frequency in the amygdala. AMD3100 inhibited the excitatory glutamatergic neural transmission and involved in the development of anxiety through CXCR4. These findings provide direct evidence that alterations of CXCL12 in BLA play critical roles in the development of anxiety induced by systemic inflammation and that CXCR4 may be a potential therapeutic target for inflammation-induced anxiety. PMID- 26952746 TI - The adoption of physical activity and eating behaviors among persons with obesity and in the general population: the role of implicit attitudes within the Theory of Planned Behavior. AB - Obesity can be prevented by the combined adoption of a regular physical activity (PA) and healthy eating behaviors (EB). Researchers mainly focused on socio cognitive models, such as the Theory of Planned Behavior (TPB), to identify the psychological antecedents of these behaviors. However, few studies were interested in testing the potential contribution of automatic processes in the prediction of PA and EB. Thus, the main objective of this study was to explore the specific role of implicit attitudes in the pattern of prediction of self reported PA and EB in the TPB framework, among persons with obesity and in adults from the general population. One hundred and fifty-three adults participated to this cross-sectional study among which 59 obese persons (74% women, age: 50.6 +/- 12.3 years, BMI: 36.8 +/- 4.03 kg m-2) and 94 people from the general population (51% women; age: 34.7 +/- 8.9 years). Implicit attitudes toward PA and EB were estimated through two Implicit Association Tests. TPB variables, PA and EB were assessed by questionnaire. Regarding to the prediction of PA, a significant contribution of implicit attitudes emerged in obese people, beta = .25; 95%[CI: .01, .50]; P = .044, beyond the TPB variables, contrary to participants from the general population. The present study suggests that implicit attitudes play a specific role among persons with obesity regarding PA. Other studies are needed to examine which kind of psychological processes are specifically associated with PA and EB among obese people. PMID- 26952748 TI - Our current understanding of the pathophysiology of equine endometritis with an emphasis on breeding-induced endometritis. AB - Equine endometritis is characterized by the expression of pro- and anti- inflammatory cytokines and an influx of polymorphonuclear neutrophils (PMNs) into the uterus. Mares resistant to persistent endometritis clear the inflammation within 24-36 h after exposure to microorganisms or semen. These mares have a rapid increase of pro-inflammatory cytokines and an upregulation of inflammatory modulating cytokines within 6h after exposure to inflammatory challenge. In conjunction with effective uterine contractions, these events are believed to be responsible for the transient nature of the inflammation. In contrast, mares that are susceptible to persistent endometritis fail to clear the inflammation in a timely fashion. They have an imbalanced endometrial mRNA expression of pro- and anti-inflammatory cytokines, and have also been shown to suffer from an accumulation of intraluminal nitric oxide, which may be related to impaired myoelectrical activity and delayed uterine clearance. As a consequence, these mares establish a chronic inflammation, which interferes with the establishment of pregnancy. Recent studies on endometrial cytokine expression in resistant and susceptible mares have revealed information that suggest an underlying immunologic basis for susceptibility to persistent endometritis. However, the inflammatory pathways have yet not been fully studied, and a relationship between cytokine expression, nitric oxide, and myometrial contractions has not been established. In addition, seminal plasma has been shown to modulate breeding induced inflammation, but the molecular basis of the modulation is not understood. A holistic approach appears to be needed to better understand the characteristics of inflammatory pathways and ultimately the pathophysiology of the disease. PMID- 26952747 TI - Mechanisms linking bacterial infections of the bovine endometrium to disease and infertility. AB - Bacterial infections of the endometrium after parturition commonly cause metritis and endometritis in dairy cattle, and these diseases are important because they compromise animal welfare and incur economic costs, as well as delaying or preventing conception. Here we highlight that uterine infections cause infertility, discuss which bacteria cause uterine disease, and review the evidence for mechanisms of inflammation and tissue damage in the endometrium. Bacteria cultured from the uterus of diseased animals include Escherichia coli, Trueperella pyogenes, and several anaerobic species, but their causative role in disease is challenged by the discovery of many other bacteria in the uterine disease microbiome. Irrespective of the species of bacteria, endometrial cell inflammatory responses to infection initially depend on innate immunity, with Toll-like receptors binding pathogen-associated molecular patterns, such as lipopolysaccharide and bacterial lipopeptides. In addition to tissue damage associated with parturition and inflammation, endometrial cell death is caused by a cholesterol-dependent cytolysin secreted by T. pyogenes, called pyolysin, which forms pores in plasma membranes of endometrial cells. However, endometrial cells surprisingly do not sense damage-associated molecular patterns, but a combination of infections followed by cell damage leads to release of the intracellular cytokine interleukin (IL)-1 alpha from endometrial cells, which then acts to scale inflammatory responses. To develop strategies to limit the impact of uterine disease on fertility, future work should focus on determining which bacteria and virulence factors cause endometritis, and understanding how the host response to infection is regulated in the endometrium. PMID- 26952750 TI - The effect of cinnamon extract on isolated rat uterine strips. AB - Cinnamon is a spice used by some populations as a traditional remedy to control blood pressure and thus hypertension. Cinnamon extract decreases contractility in some smooth muscles, but its effect on uterine smooth muscle is unknown. The aim of this study was to determine the physiological and pharmacological effects of cinnamon extract (CE) on the contractions of isolated rat uterine strips and to investigate its possible mechanism of action. Isolated longitudinal uterine strips were dissected from non-pregnant rats, mounted vertically in an organ bath chamber, and exposed to different concentrations of CE (10-20mg/mL). The effect of CE was investigated in the presence of each of the following solutions: 60mM KCl, 5nM oxytocin, and 1MUM Bay K8644. CE significantly decreased the force of uterine contraction in a concentration-dependent manner and significantly attenuated the uterine contractions elicited by KCl and oxytocin. In addition, CE significantly decreased the contractile force elicited when L-type Ca(2+) channels were activated by Bay K8644. CE's major mechanism may be inhibition of L type Ca(2+) channels, which limits calcium influx. These data demonstrate that CE can be a potent tocolytic that can decrease uterine activity regardless of how the force was produced, even when the uterus was stimulated by agonists. As a result, cinnamon may be used to alleviate menstrual pain associated with dysmenorrhoea or prevent unwanted uterine activity in early pregnancy. PMID- 26952749 TI - Slc20a2 deficiency results in fetal growth restriction and placental calcification associated with thickened basement membranes and novel CD13 and lamininalpha1 expressing cells. AB - The essential nutrient phosphorus must be taken up by the mammalian embryo during gestation. The mechanism(s) and key proteins responsible for maternal to fetal phosphate transport have not been identified. Established parameters for placental phosphate transport match those of the type III phosphate transporters, Slc20a1 and Slc20a2. Both members are expressed in human placenta, and their altered expression is linked to preeclampsia. In this study, we tested the hypothesis that Slc20a2 is required for placental function. Indeed, complete deficiency of Slc20a2 in either the maternal or embryonic placental compartment results in fetal growth restriction. We found that Slc20a2 null mice can reproduce, but are subviable; ~50% are lost prior to weaning age. We also observed that 23% of Slc20a2 deficient females develop pregnancy complications at full term, with tremors and placental abnormalities including abnormal vascular structure, increased basement membrane deposition, abundant calcification, and accumulation of novel CD13 and lamininalpha1 positive cells. Together these data support that Slc20a2 deficiency impacts both maternal and neonatal health, and Slc20a2 is required for normal placental function. In humans, decreased levels of placental Slc20a1 and Slc20a2 have been correlated with early onset preeclampsia, a disorder that can manifest from placental dysfunction. In addition, preterm placental calcification has been associated with poor pregnancy outcomes. We surveyed placental calcification in human preeclamptic placenta samples, and detected basement membrane-associated placental calcification as well as a comparable lamininalpha1 positive cell type, indicating that similar mechanisms may underlie both human and mouse placental calcification. PMID- 26952751 TI - Screening of biotechnical parameters for production of bovine inter-subspecies embryonic chimeras by the aggregation of tetraploid Bos indicus and diploid crossbred Bos taurus embryos. AB - The aggregation of a tetraploid zebu embryo (Bos indicus, a thermotolerant breed) with a diploid taurine embryo (Bos taurus, a thermosensitive breed) should create a complete taurine fetus, whose extra-embryonic components, e.g., the chorion, is derived mainly from the zebu embryo. These zebu-derived extra-embryonic components may interact positively with the taurine embryo/fetus during pregnancy in a tropical environment. We tested different parameters for the production of tetraploid Nelore (Bos indicus) embryos to be combined via aggregation with crossbred Bos taurus (diploid) embryos in order to produce viable chimeric blastocysts. Bovine (Bos indicus or crossbred Bos taurus) embryos were produced in vitro according to standard procedures. Two-cell Bos indicus embryos were submitted to electrofusion with varying numbers of pulses (1 or 2), voltages (0.4, 0.5, 0.75, 1.0, 1.4 and 5.0 kV/cm) and time (20, 25, 50 and 60 MUs) to produce tetraploid embryos. Electrofused embryos were cultured with crossbred non fused embryos to form chimeras that developed until the blastocyst stage. The best fusion parameter was 0.75 kV/cm for 60 MUs. Four chimeric blastocysts (tetraploid Nelore with diploid crossbred Holstein) were formed after 31 attempts in 4 replicates (13%). We established an optimal procedure for the production of tetraploid Bos indicus (4n) embryos and embryonic chimeras by aggregation of crossbred Bos taurus (2n) with Bos indicus (4n) embryos. This technique would be valid in applied research, by producing exclusively taurine calves, but with placental elements from the Bos indicus breed, following transfer of these chimeras into recipient cows. PMID- 26952753 TI - The presence of corpus luteum may have a negative impact on in vitro developmental competency of bovine oocytes. AB - The aim of the current study was to investigate the effects of the presence or absence of corpus luteum (CL) on in vitro developmental competence of bovine oocytes. In experiment 1, cumulus oocyte complexes (COCs) were collected from slaughterhouse ovaries and divided according to the presence (CL(+) oocytes) or absence (CL(-) oocytes) of a CL in the ovary. Control oocytes (C group) were obtained from ovaries which were not selected toward the presence or absence of CL. All oocytes were submitted to in vitro maturation, fertilization and culture. In experiment 2, the oocytes from the CL(+) and CL(-) ovaries were divided into grown (BCB(+)) and growing (BCB(-)) categories by means of the brilliant cresyl blue (BCB) test. The oocytes from all groups (CL(+)/BCB(+), CL(-)/BCB(+), CL(+)/BCB(-), CL(-)/BCB(-) and control oocytes) were subjected to in vitro embryo production. In experiment 1, the cleavage and blastocyst rates of CL(-) oocytes were higher than those of CL(+) oocytes (83.9% and 43% vs. 69.3% and 22.5%, respectively). In experiment 2, there was less BCB(+) oocytes (more competent oocytes) in the group of CL(+) oocytes than in the group of CL(-) oocytes. Furthermore, developmental competence of all CL(+) oocytes (CL(+)/BCB(+) and CL(+)/BCB(-)) was lower than that of all CL(-) oocytes (CL(-)/BCB(+) and CL( )/BCB(-)). Thus, the presence of a corpus luteum in the ovary may have negative effects on developmental competence of ipsilateral oocytes. PMID- 26952752 TI - Effects of different cryoprotectants and freezing methods on post-thaw boar semen quality. AB - The current study aimed to investigate the effects of different concentrations of glycerol (0%, 1%, 2%, 3%, and 5%) and dimethylacetamide (DMA: 0%, 1%, 3%, and 5%) on post-sperm quality characteristics following semen freezing in dry ice (D) or liquid nitrogen (N). Semen was collected from Duroc boars and was allocated to 32 treatment groups for cryopreservation. Analysis of post-thaw semen quality and fertility after artificial insemination (AI) was used to examine the combinatorial effects of different treatments. The best scores for post-thaw sperm motility, sperm viability, and sperm acrosomal integrity were observed in semen frozen in: (a) dry ice in the presence of 5% glycerol and no DMA (16D treatment); (b) dry ice in the presence of 3% glycerol and no DMA (9D-treatment); and (c) liquid nitrogen in the presence of 3% glycerol and 1% DMA (10N treatment), with no significant difference observed among these three treatments. The farrowing rates after AI with post-thawed semen after 9D- and 10N-treatments were 33% and 50%, respectively. To summarize, the results of the present study indicated that the freezing extender containing 3% glycerol in combination with the straw-freezing method using dry ice produced the best post-thaw quality parameters of boar semen. Combinations of glycerol and DMA did not enhance the cryosurvival of boar spermatozoa. PMID- 26952754 TI - Thecal cell sensitivity to luteinizing hormone and insulin in polycystic ovarian syndrome. AB - This study examined whether a defect of steroid synthesis in ovarian theca cells may lead to the development of PCOS, through contributions to excess androgen secretion. Polycystic ovarian syndrome (PCOS) is one of the leading causes of infertility worldwide affecting around 1 in 10 of women of a reproductive age. One of the fundamental abnormalities in this syndrome is the presence of hormonal irregularities, including hyperandrogenemia, hyperinsulinemia and hypersecretion of luteinizing hormone (LH). Studies suggest that insulin treatment increases progesterone and androstenedione secretion in PCOS theca cells when compared to insulin treated normal theca cells. Furthermore the augmented effects of LH and insulin have been seen to increase ovarian androgen synthesis in non-PCOS theca cultures whilst also increasing the expression of steroidogenic enzymes specific to the PI3-K pathway. Our examination of primary thecal cultures showed an increase in both the expression of the steroidogenic enzyme CYP17 and androgen secretion in PCOS theca cells under basal conditions, when compared to non-PCOS cells. This was increased significantly under treatments of LH and insulin combined. Our results support the previous reported hypothesis that a dysfunction may exist within the PI3-K pathway. Specifically, that sensitivity exists to physiological symptoms including hyperinsulinemia and hyper secretion of LH found in PCOS through co-stimulation. The impact of these findings may allow the development of a therapeutic target in PCOS. PMID- 26952755 TI - Differential influence of ampullary and isthmic derived epithelial cells on zona pellucida hardening and in vitro fertilization in ovine. AB - The central role of the oviduct, as the site of zona pellucida (ZP) maturation, fertilization and early embryogenesis, has been recognized. The objective of this study was to investigate whether ampullary and isthmic derived epithelial cells have different effects on in vitro ZP hardening, in vitro fertilization (IVF) and in vitro culture (IVC) of the resulting embryos. Cumulus oocyte complexes (COCs) were matured in a coculture system with ampullary/isthmic epithelial cells, TCM199 supplemented with insulin-like growth factor I (IGF-I) and epithelial derived growth factor (EGF) (GF treated group), conditioned media produced using ampullary (ACM), isthmic (ICM), COCs+ampullary, and COCs+isthmic epithelial cells, contactless culture system, oviductal fluid, GF+ACM/ICM, and drops of TCM199 (control), for 24h. The matured oocytes were randomly divided into two groups: Group I was subjected to ZP digestion; Group II underwent IVF. The duration of the ZP digestion, in a coculture system with ampullary epithelial cells (AE) was significantly increased (p<0.05), compared with other groups. Penetrated oocytes and monospermic fertilization were significantly increased (p<0.05) in the AE group. The mean number of spermatozoa per penetrated oocyte was reduced dramatically for the AE group (p<0.05). A significant increase (p<0.05) in the embryo development was observed in all treated groups, compared to the control. Results revealed that epithelial cells harvested from the ampullary segment of the oviduct had in vitro specialized role in ZP hardening and have subsequent IVF and IVC outcomes. PMID- 26952756 TI - Role of oxidative stress and low-grade inflammation in letrozole-induced polycystic ovary syndrome in the rat. AB - The aims of the current study were to examine the effects of temporal changes in oxidative stress (OS) and low-grade inflammation in letrozole-treated rats and to correlate these changes with the development of polycystic ovary syndrome (PCOS) like features. Rats were treated with letrozole for 7, 15 and 21 days to induce PCOS. On day 7 of the treatment, a significant increase in serum testosterone and high sensitive C-reactive protein (hsCRP), the low-grade inflammatory marker, was found in the letrozole treated rats compared to control rats. Moreover, a decreased immunoexpression of insulin receptor coincided with increased body weight. The strong correlation between the levels of hsCRP and lipid peroxidation (LPO) suggests simultaneous development of low-grade inflammation and OS in response to hyperandrogenism, and the role of OS in a formation of cystic follicles in the letrozole animal PCOS model. Therefore, the results of the present study suggest that OS and low-grade inflammation (hsCRP) are the major causes of PCOS induction in this model. PMID- 26952758 TI - In vitro culture medium (IVC) supplementation with sericin improves developmental competence of ovine zygotes. AB - This study was carried out to investigate the effects of supplementation of potassium simplex optimized medium (KSOM-aa) with various sericin concentrations (0, 0.1, 0.5, 1 and 2.5%) on ovine zygotes. The results indicate that the supplementation of oocyte in vitro culture medium with optimal concentration of sericin (0.1 and 0.5%) may have beneficial effects on developmental competence of in vitro-derived ovine embryos. PMID- 26952757 TI - Reactive oxygen species production and antioxidant enzyme activity during epididymal sperm maturation in Corynorhinus mexicanus bats. AB - Prolonged sperm storage in the epididymis of Corynorhinus mexicanus bats after testicular regression has been associated with epididymal sperm maturation in the caudal region, although the precise factors linked with this phenomenon are unknown. The aim of this work is to determine the role of reactive oxygen species (ROS) and changes in antioxidant enzymatic activity occurring in the spermatozoa and epididymal fluid over time, in sperm maturation and storage in the caput, corpus and cauda of the bat epididymis. Our data showed that an increment in ROS production coincided with an increase in superoxide dismutase (SOD) activity in epididymal fluid and with a decrease in glutathione peroxidase (GPX) activity in the spermatozoa in at different time points and epididymal regions. The increase in ROS production was not associated with oxidative damage measured by lipid peroxidation. The results of the current study suggest the existence of a shift in the redox balance, which might be associated with sperm maturation and storage. PMID- 26952759 TI - The benefits of liposomes for chilling canine sperm for 4 days at 4 degrees C. AB - This study comprises 3 experiments exploring the possible benefits and mechanism of action of liposomes for chilling (4 degrees C) canine sperm over a period of 4 days. In the first experiment, 20 ejaculates collected from 5 Beagle dogs were chilled in an extender containing 6% low density lipoproteins (LDL) (Control), or one of 7 extenders containing different concentrations (2, 4, 6, 8, 10, 15, 20%) of liposomes (LIPO). These ejaculates were chilled over 4 days and motility was assessed daily using a Hamilton Thorne analyzer (HTM-IVOS, 14.0). The 2% LIPO obtained the best results (p=0.038) after four days (72.55% motile spermatozoa and 31.4% progressive spermatozoa). In experiment 2, 10 ejaculates were collected from same 5 dogs and chilled in 6% LDL or 2% LIPO-based extenders. Sperm integrity characteristics were assessed prior to refrigeration and every 48h for four days (D0, D2, and D4). Acrosome integrity was assessed using the FITC-PSA test (Fluorescein IsoThiocyanate-Pisum Sativum Agglutinin), plasma membrane (PM) integrity using both the hypo-osmotic swelling test (HOSt) and SYBR14/Propidium Iodide test (SYBR14/PI), and DNA integrity using the Acridine-Orange test (AO). The 2% LIPO extender provided equivalent preservation of sperm integrity parameters to the reference extender (6% LDL). In experiment 3, a Langmuir Blodgett trough was used to evaluate the mechanistic interactions between LDL, LIPO, prostatic fluid, and the canine spermatozoal membrane during chilling. Results indicate that LDL and LIPO interact differently with the biomimetic membrane. The most likely conclusion of these findings is that LDL and liposomes employ different protective mechanisms during the chilling (4 degrees C) of canine spermatozoa. PMID- 26952760 TI - The potential role of juvenile hormone acid methyltransferase in methyl farnesoate (MF) biosynthesis in the swimming crab, Portunus trituberculatus. AB - Juvenile hormone (JH) and methyl farnesoate (MF) play essential roles in the development and reproduction of insects and crustaceans respectively. Juvenile hormone acid methyltransferase (JHAMT) catalyzes the methyl esterification in insect JH biosynthesis, while the corresponding step in crustacean MF biosynthesis was long thought to be catalyzed by farnesoic acid O methyltransferase (FAMeT). However, the new discovery of JHAMT orthologs in crustaceans indicates that JHAMT may also play essential role in the MF biosynthesis in crustaceans. Here we cloned and characterized the full-length cDNA encoding JHAMT in the swimming crab Portunus trituberculatus (PtJHAMT). Sequence and structure analysis of PtJHAMT revealed that it was composed of a 6 stranded beta sheet with 9 alpha helices, and contained a signature Sadenosyl-L methionine (SAM) binding motif, which is the hallmark in all SAM dependent methyltransferases (SAM-MTs). Several active sites that are critical for the interaction of SAM and JH/FA substrate were also conserved in PtJHAMT. The gene expression of PtJHAMT was highly specific to the mandibular organ, which is the sole site of MF synthesis. PtJHAMT expression significantly increased in the late vitellogenic stage and mature stage, which suggests a possible role of PtJHAMT in modulating ovarian development. The role of PtJHAMT and PtFAMeT in MF biosynthesis was further investigated by RNA interfering (RNAi). Injection of PtJHAMT and PtFAMeT dsRNA both led to a decrease in hemolymph MF titers. Injection of PtHMGR dsRNA caused the decrease in PtJHAMT expression, but had no effect on mRNA level of PtFAMeT. Together these results suggested that JHAMT and FAMeT are both involved in the MF biosynthesis in crustaceans, while the JHAMT is highly specific to FA substrate, and FAMeT may have more catalytic functions. PMID- 26952761 TI - First report on facultative parthenogenetic activation of eggs in sterlet sturgeon, Acipenser ruthenus. AB - This study reported facultative parthenogenetic cleavage development of sterlet sturgeon Acipenser ruthenus eggs and quantified the percentage of parthenogenetically developed eggs in relation to the fertilization ability of different females. When eggs were activated in freshwater, 5.1-13.7% of eggs developed parthenogenetically, while among those activated eggs 3.6-9.4% developed to 2 cells, 0.4-4.5% developed to 4 cells, and 0-0.8% developed to 8 cells. The mean percentage of fertilized and parthenogenetically activated eggs among the females was negatively correlated (R(2)=0.71, p=0.036), which indicates that parthenogenetic activation rate of sterlet eggs depends on the quality of eggs in terms of fertilization rate. PMID- 26952762 TI - Growth of the conceptus from day 33 to 45 of pregnancy is minimally associated with concurrent hormonal or metabolic status in postpartum dairy cows. AB - A hypothetical explanation for pregnancy loss in postpartum dairy cows is that the metabolic environment of the cow inhibits the growth of the conceptus and places the pregnancy at risk for loss. The objective of the current study, therefore, was to model the association between cow-level metabolic indicators and conceptus growth during early pregnancy (day 33-45 after AI) and to determine if an association (if present) is large enough to cause pregnancy loss. Metabolic indicators included milk production, changes in body weight and body condition score, parity, and concentrations of circulating hormones and metabolites (glucose, non-esterified fatty acids, growth hormone, IGF1, progesterone, and pregnancy-associated glycoproteins). One-hundred cows were enrolled. Cows that became pregnant with single conceptus pregnancies (n=53) weighed more (P<0.007) and had fewer uterine polymorphonuclear neutrophils (uterine health indicator; P<0.051) compared with cows that failed to become pregnant. The embryo and amniotic vesicle were measured by using ultrasound on day 33, 35, 38, 40, 42, and 45 of pregnancy. Most of the cow-level indicators that were included in the model of conceptus growth failed to achieve statistical significance. Day of pregnancy had the largest effect on conceptus growth (size and cross-sectional area of the embryo and amniotic vesicle; P<0.001). There were effects of sex of fetus (male fetuses larger than female), insulin (negative association), and body weigh change (positive association) on embryo length and cross-sectional area but these effects were small when compared with the range in conceptus length or area that we observed. The conclusion was that the capacity of the cow to become pregnant was associated with body weight and uterine health but we failed to find a large association with metabolic status on conceptus growth from day 33 to 45 of pregnancy in lactating dairy cows. PMID- 26952763 TI - Band alignment at the interface between Ni-doped Cr2O3 and Al-doped ZnO: implications for transparent p-n junctions. AB - The realization of transparent electronic and optoelectronic devices requires the use of transparent p-n junctions. In this context, understanding the band alignment at the interface between the p- and n-components represents a fundamental step towards the realization of high performance devices. In this work, the band alignment at the interface between Al-doped ZnO (AZO) and Ni-doped Cr2O3 has been analysed. The formation and evolution of the core levels as the interface progressively forms have been followed by means of x-ray Photoelectron Spectroscopy, x-ray diffraction and x-ray reflectivity. A type two (staggered) band alignment was identified, with the valence band offset and conduction band offset found to be 2.6 eV and 2.5 eV, respectively. The electrical behaviour will be discussed in terms of the position of the bands, the presence of band bending and the expected built-in potential and how these can be engineered in order to achieve the maximum performance for this hetero-structure. PMID- 26952764 TI - Enzymatic reduction of acetophenone derivatives with a benzil reductase from Pichia glucozyma (KRED1-Pglu): electronic and steric effects on activity and enantioselectivity. AB - A recombinant ketoreductase from Pichia glucozyma (KRED1-Pglu) was used for the enantioselective reduction of various mono-substituted acetophenones. Reaction rates of meta- and para-derivatives were consistent with the electronic effects described by sigma-Hammett coefficients; on the other hand, enantioselectivity was determined by an opposite orientation of the substrate in the binding pocket. Reduction of ortho-derivatives occurred only with substrates bearing substituents with low steric impact (i.e., F and CN). Reactivity was controlled by stereoelectronic features (C[double bond, length as m-dash]O length and charge, shape of LUMO frontier molecular orbitals), which can be theoretically calculated. PMID- 26952766 TI - Most psychotherapies do not really work, but those that might work should be assessed in biased studies. PMID- 26952765 TI - Nurse-physician collaboration impacts job satisfaction and turnover among nurses: A hospital-based cross-sectional study in Beijing. AB - This study aims to explore the impact of physician-nurse collaboration on nurse job satisfaction and turnover in a dental hospital. Physician-nurse collaboration is important for the stability of the entire nursing team. Few studies have shown the impact on job satisfaction and turnover among nurses working in Chinese dental hospitals. This was a prospective, cross-sectional study and investigated nurses from a tertiary dental hospital in Beijing using convenience non randomized sampling. A structured questionnaire was used to collect data, which included general information, the Index of Work Satisfaction, the Nurse-Physician Collaboration Scale and the Turnover Intention Scale. The scores of physician nurse collaboration correlated positively with those for job satisfaction and negatively with the stated likelihood of turnover intention. Physician-nurse collaboration scores positively predicted job satisfaction and negatively predicted the likelihood of quitting the current job. In conclusion, improving the level of physician-nurse collaboration is helpful to enhance job satisfaction and reduce turnover among nurses in a dental hospital. PMID- 26952768 TI - Six decades since Cade's six. PMID- 26952767 TI - Discovery of toll-like receptor 13 exists in the teleost fish: Miiuy croaker (Perciformes, Sciaenidae). AB - Toll-like receptors (TLRs) play an indispensable role in the immune response for pathogen recognition and triggering not only innate immunity but also adaptive immunity. Here we report the TLR13 homologue, one member of TLRs, in Perciformes (especially Sciaenidae). And we used the miiuy croaker as represented species for further functional experiments. Former study reported the TLR13 only expressed in murine, and we are the first to report the teleost TLR13 (mmiTLR13). MmiTLR13 expressed highly in immune defense related tissues, such as the liver, spleen, and kidney, and Vibrio anguillarum or poly(I:C) infection showed the immune response of mmiTLR13. Further luciferase reporter assays showed the ability for activation of ISRE luciferase reporter, but it failed to active NF-kappaB. And further gene silence by short hairpin RNA (shRNA) confirmed the results. Immunofluorescence of mmiTLR13 presents the cytoplasmic distribution in Hela cell. In addition, the Toll/interleukin 1 receptor (TIR) domain of mammal TLR5 exhibits high identity with TLR13, which indicated the high homology between TLR5 and TLR13. These findings will lay the fundamental cornerstone for further research of teleost TLR13 and expand the horizon for better understand the teleost TLRs system. PMID- 26952769 TI - Nutrition, mood and behaviour: a review. AB - OBJECTIVE: To conduct a critical review of recent empirical research regarding mood, behaviour and nutrition factors including essential fatty acids, macronutrients, micronutrients and food additives. METHOD: A literature search of databases Medline, PsycInfo, CINAHL and Embase up to October 2008. The search emphasised empirical research published in the last 10 years and also included older literature. Studies in both adults and children were addressed. RESULTS: Research into omega-3 fatty acids has been substantial but evidence for their potential in treating mood and behaviour is modest. In comparison, there has been much less research into carbohydrate and protein intakes and little evidence for their ability to influence mood and behaviour. Recent trials with food additives suggest their removal from the diet may benefit susceptible children with hyperactivity disorders. Micronutrient supplementation appears to improve mood only in those who were initially deficient in micronutrients. CONCLUSIONS: More stringent research designs such as longitudinal studies and the use of biologically inert placebos within randomised controlled trials are needed before supplemental use of omega-3 fatty acids to treat disorders of mood and behaviour can be recommended. Caution is advised regarding the indiscriminate use of diets free of artificial food additives in managing hyperactivity disorders, as they may place an undue burden on individuals and their families. Should omega-3 fatty acid supplementation or the elimination of certain food additives be established as effective, they may provide cost-effective, accessible and well-tolerated adjuncts to standard psychiatric treatments for mood and behavioural disturbances. PMID- 26952770 TI - A ventral prefrontal-amygdala neural system in bipolar disorder: a view from neuroimaging research. AB - In the past decade, neuroimaging research has identified key components in the neural system that underlies bipolar disorder (BD). The ventral prefrontal cortex (VPFC) and amygdala are highly interconnected structures that jointly play a central role in emotional regulation. Numerous research groups have reported prominent structural and functional abnormalities within the VPFC and amygdala supporting their essential role in a neural system underlying the emotional dysregulation that is a core feature of BD. Findings in BD also include those in brain regions interconnected with the VPFC and amygdala, including the ventral striatum, hippocampus and the cerebellum. Abnormalities in these regions may contribute to symptoms that reflect disruption in functions sub-served by these structures, including motivational, mnemonic and psychomotor functions. This article will first review leads from behavioural neurology that implicated these neural system abnormalities in BD. It will then review findings from structural and functional imaging studies to support the presence of abnormalities within these neural system components in BD. It will also review new findings from studies using diffusion tensor imaging (DTI) that provide increasing evidence of abnormalities in the connections between these neural system components in BD. Emerging data supporting differences in this neural system during adolescence, as well as potential beneficial effects of treatment on structure and function will also be presented. Finally, the article will discuss the implications for future investigations, including those for early identification and treatment of BD. PMID- 26952771 TI - Effects of N-acetylcysteine on substance use in bipolar disorder: a randomised placebo-controlled clinical trial. AB - OBJECTIVE: To evaluate the effect of N-acetylcysteine (NAC) on substance use in a double-blind, placebo-controlled trial of NAC in bipolar disorder. It is hypothesised that NAC will be superior to placebo for reducing scores on the Clinical Global Impressions scale for Substance Use (CGI-SU). METHODS: Participants were randomised to 6-months of treatment with 2 g/day NAC (n = 38) or placebo (n = 37). Substance use was assessed at baseline using the Habits instrument. Change in substance use was assessed at regular study visits using the CGI-SU. RESULTS: Amongst the 75 participants 78.7% drank alcohol (any frequency), 45.3% smoked tobacco and 92% consumer caffeine. Other substances were used by fewer than six participants. Caffeine use was significantly lower for NAC treated participants compared with placebo at week 2 of treatment but not at other study visits. CONCLUSION: NAC appeared to have little effect on substance use in this population. A larger study on a substance using population will be necessary to determine if NAC may be a useful treatment for substance use. PMID- 26952772 TI - Abnormal dose-response melatonin suppression by light in bipolar type I patients compared with healthy adult subjects. AB - OBJECTIVE: Among potential endophenotypes proposed for bipolar affective disorder focusing on circadian abnormalities associated with the illness has particularly high face validity. Melatonin sensitivity to light is one circadian endophenotype proposed as useful in bipolar disorder. The aim of this study was to investigate melatonin sensitivity to light over a range of light intensities in order to compare and contrast responses in bipolar I patients with those of healthy adult volunteers. METHODS: The study included seven patients (4 females, 3 males) with bipolar I disorder and 34 control participants (22 females, 12 males) with no personal or family history of affective illness. Melatonin sensitivity to light was determined in all patients and participants across a range of light intensities (0, 200, 500 and 1000 lux). RESULTS: The results indicated that patients showed melatonin super-sensitivity to light in comparison with controls, a response that was consistent across the entire light intensity range investigated. CONCLUSION: The study provides further evidence for a super sensitive response in bipolar I patients and suggests that its potential usefulness as an endophenotypic marker of the illness is deserving of further research. PMID- 26952773 TI - Standardised extract of safed musli (Chlorophytum borivilianum) increases aphrodisiac potential besides being safe in male Wistar rats. AB - The standardised extract of root of safed musli (Chlorophytum borivilianum) was evaluated for its aphrodisiac potential and safety profile on reproductive system. Wistar albino rats were trained to provide sexual experience under a dim red light (10 W) in a glass tank. Male and female rats were placed periodically in the glass tank in a particular order, that is male followed by introduction of the receptive female. Dosing of extract was carried out for 54 days at 125 and 250 mg kg-1 p.o to male rats. On 14th and 28th days, the animals were observed from the cage side for sexual behaviours. Safed musli at both dose levels enhanced sexual vigour and libido which might be useful for treatment of sexual dysfunction in male till 28th day. Safety profile was assessed after 54 days of drug treatment, where both doses showed an increase in sperm count and increase in sperm motility. Thus, it can be stated that both doses possessed the spermatogenic potential, which would be highly beneficial in treating oligospermia or low sperm count. After 54 days of study, there was increase in sperm abnormality (%) at both doses, but not more than 10%, which indicated that this formulation will not induce infertility. PMID- 26952774 TI - Facile access to zinc and cadmium selones: highly active catalysts for Barbier reactions in aqueous media. AB - The syntheses and structures of five mononuclear zinc and cadmium selone complexes along with a polynuclear cadmium selone 1D chain were described. The mononuclear homoleptic zinc selone complexes were the first examples of structurally characterized zinc(ii) selone complexes. The spectral properties of the zinc and cadmium selone derivatives were investigated. Interesting structural diversity, coordination geometry, and variable chemical and thermal stability were observed for these zinc and cadmium selone compounds. Besides this, the first metal selone mediated Barbier coupling was reported. These catalysts were highly active for Barbier coupling reactions in aqueous alcohol media. In addition, the scope of the catalytic reactions was further explored with eleven different aldehydes. PMID- 26952775 TI - Temporal changes in bile acid levels and 12alpha-hydroxylation after Roux-en-Y gastric bypass surgery in type 2 diabetes. AB - Since the publication of the above article it has been noted that the author S O'Brien should have been listed as CS O'Brien. The authors should therefore appear as follows: R Dutia, M Embrey, CS O'Brien, RA Haeusler, KK Agenor, P Homel, J McGinty, RP Vincent, J Alaghband-Zadeh, B Staels, CW le Roux, J Yu and B Laferrere The corrected article html and online pdf versions have been amended. The authors wish to apologise for any inconvenience caused. PMID- 26952777 TI - Post-translational modifications in Pseudomonas aeruginosa revolutionized by proteomic analysis. AB - Pseudomonas aeruginosa is an opportunistic pathogen that causes severe infections in vulnerable individuals. It is known that post-translational modifications (PTMs) play a key role in bacterial physiology. Their characterization is still challenging and the recent advances in proteomics allow large-scale and high throughput analyses of PTMs. Here, we provide an overview of proteomic data about the modified proteins in P. aeruginosa. We emphasize the significant contribution of proteomics in knowledge enhancement of PTMs (phosphorylation, N-acetylation and glycosylation) and we discuss their importance in P. aeruginosa physiology. PMID- 26952776 TI - Preservation of the Internal Iliac Arteries with Branched Iliac Stent Grafts (Zenith Bifurcated Iliac Side): 5 Years of Experience. AB - BACKGROUND: The extension of the aneurysmal disease to the iliac bifurcations is one of the limits of the endovascular treatment of aortoiliac aneurysms. The Zenith Bifurcated Iliac Side (ZBIS((r))) stent graft (Cook Medical) is a branched stent graft making it possible to preserve the internal iliac arteries (IIAs) using a totally endovascular procedure. METHODS: The purpose of this monocentric retrospective study was to analyze the results of the ZBIS stent graft among patients presenting aortoiliac aneurysms extending to the iliac bifurcation treated between January 1st, 2010 and January 1st, 2015 in the department of vascular surgery of the University Hospital of Toulouse. RESULTS: A total of 26 ZBIS stent grafts were implanted in 25 patients. The perioperative mortality was null, and the technical success rate was 96% (24 of 25). The median duration of follow-up was 29 months (1-60). Mortality rate at 30 days was null. The rate of early complications was 4% (1 of 25), with only one early reintervention for acute ischemia. Patency rate at 30 days was 96.1% (25 of 26) with 1 type 1a endoleak observed with 1 aortobi-iliac stent graft. The midterm patency rate without endoleak was 94.7% (18 of 19), with 2 patients presenting a persistent buttock claudication due to the embolization of the IIA. CONCLUSIONS: The ZBIS stent graft makes it possible to exclude aortoiliac aneurysms by endovascular route, whereas preserving the IIA with satisfactory results in the short and medium term. The careful study of the preoperative quality of the IIAs and the respect of the "Instructions for Use" made it possible to obtain a very satisfactory patency rate. PMID- 26952778 TI - Cervicofacial non-tuberculous mycobacteria: A report of 30 cases. AB - BACKGROUND: Mycobacterial infection is the most common cause of cervical granuloma, implicating either a tuberculous or a non-tuberculous mycobacterium (NTM). NTM is a ubiquitous organism, found in soil, water, food, etc. The most frequently implicated is Mycobacterium avium-intracellular. Most authors agree that NTM is increasingly isolated, due to a decrease in vaccination rates. Initial diagnosis is difficult and management is not clearly codified. METHODS: A retrospective study conducted in the University Hospital of Nantes, France, between 2005 and 2014, included all patients treated for head and neck NTM lymphadenitis. The research was conducted on the database of the institution's bacteriology department. Population, history, symptoms and diagnostic features were noted. Treatment, surgical complications, adverse reactions to antibiotics, patient adherence, antibiotic therapy duration, time to remission and prognosis were analyzed. RESULTS: Between 2005 and 2014, 30 patients were diagnosed with head and neck NTM lymphadenitis: 17 female, 13 male; mean age at diagnosis, 4.5 years. Locations were submandibular (n=16), parotid, (n=7), cervical (n=5), parapharyngeal (n=4) and, for 1 patient, in the auricle concha. Eight patients received first-line surgical treatment, which was effective in 75% of cases, 2 patients requiring additional antibiotic therapy. Twenty-two patients were treated with first-line antibiotherapy, which was effective in 90% of cases. There were no relapses at a mean 32 weeks' follow-up. CONCLUSIONS: Total resection of all affected nodes and infiltrated subcutaneous fatty tissue is the treatment of choice. Drug therapy (including at least a macrolide) seems indicated only in case of incomplete resection or if surgery would entail functional and/or esthetic risk. Increased incidence, since BCG vaccination was stopped, will continue to confront the practitioner with an infantile disease in which management must be multidisciplinary. PMID- 26952781 TI - In vitro fertilization outcomes after fresh and frozen blastocyst transfer in South Asian compared with Caucasian women. AB - OBJECTIVE: To study pregnancy outcomes between South Asian and Caucasian women undergoing frozen blastocyst transfer cycles. DESIGN: Retrospective cohort study. SETTING: Not applicable. PATIENT(S): Caucasian and South Asian patients undergoing frozen blastocyst transfer between January 2011 and December 2014. INTERVENTION(S): Not applicable. MAIN OUTCOME MEASURE(S): Live birth rate. RESULT(S): A total of 196 Caucasian and 117 South Asian women were included in our study. Indians were on average 2.2 years younger than Caucasian women (34.9 vs. 37.1 years), and were more likely to be nulliparous (59% vs. 43%). All other baseline characteristics were similar. In women undergoing their first frozen ET cycle, implantation rate (49% vs. 47%), clinical pregnancy rate (PR; 54% vs. 49%), and live birth rate (43% vs. 43%) were similar between South Asians and Caucasians, respectively. In patients who underwent a prior fresh blastocyst transfer, the live birth rate was significantly lower in South Asian versus Caucasian women (21% vs. 37%). CONCLUSION(S): Our data demonstrate that IVF outcomes are better in frozen versus fresh cycles among South Asian women. The IVF clinics may wish to consider these findings when counseling South Asian patients about the timing of ET. PMID- 26952782 TI - Working memory in women with polycystic ovary syndrome. PMID- 26952783 TI - Effectiveness of in vitro fertilization with preimplantation genetic screening: a reanalysis of United States assisted reproductive technology data 2011-2012. AB - OBJECTIVE: To assess effectiveness of preimplantation genetic screening (PGS) in fresh IVF cycles. DESIGN: Reanalysis of retrospective US national data. SETTING: Not applicable. PATIENT(S): A total of 5,471 fresh autologous IVF cycles with PGS and 97,069 cycles without PGS, reported in 2011-2012 to the Centers for Disease Control and Prevention. INTERVENTION(S): Not applicable. MAIN OUTCOME MEASURE(S): Cycles that reached ET, miscarriage rates, live birth rates per cycle and per transfer. RESULT(S): More PGS than non-PGS cycles reached ET (64.2% vs. 62.3%), suggesting favorable patient selection bias for patients using PGS. Nevertheless, live births rates per cycle start (25.2% vs. 28.8%) and per ET (39.3% vs. 46.2%) were significantly better in non-PGS cycles, whereas miscarriage rates were similar (13.7% vs. 13.9%). With a maternal age >37 years significantly more cycles in the PGS group reached ET (53.1% vs. 41.9%), suggesting a significant selection bias for more favorable patients in the PGS population. This bias rather than the PGS procedure may partially explain the observed improved live birth rate per cycle (17.7% vs. 12.7%) and lower miscarriage rate (16.8% vs. 26.0%) in the older PGS group. CONCLUSION(S): Overall, PGS decreased chances of live birth in association with IVF. National improvements in live birth and miscarriage rates reported with PGS in older women are likely the consequence of favorable patient selection biases. PMID- 26952784 TI - Interaction of apolipoprotein E gene polymorphisms on miscarriage risk in black and white American women. AB - OBJECTIVE: To evaluate whether [1] apolipoprotein E (APOE) polymorphisms can differentially regulate miscarriage risk and [2] whether this genotype effect could also be modulated by the race within populations. DESIGN: Data were derived from the Coronary Artery Risk Development in Young Adults (CARDIA), a longitudinal study with black and white participants from four U.S. SETTING: Not applicable. PATIENT(S): Women without miscarriages (controls) and women who miscarried at least once (cases). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): A group of women (n = 1,372) successfully followed for 25 years and with their APOE alleles identified were analyzed for miscarriage risk throughout their reproductive life. Additionally, a larger longitudinal analysis encompassing all the participants who had their APOE characterized (n = 2,140) was also performed for the association between APOE and miscarriage risk. RESULT(S): In white women followed up for 25 years, the odds ratio for miscarriage associated with APOE*2 allele presence was 1.61 (95% confidence interval, 1.04-2.50) compared with APOE*33 carriers. This was a race-dependent phenomenon as no associations between APOE alleles and miscarriage was observed in black women. Likewise, Cox regression analysis showed that cumulative miscarriage risk in white women was 37.2% in the APOE*2 carriers compared with 27.8% and 24.8% in APOE*33 and APOE*4 carriers, respectively. With APOE*33 as the reference, the age-adjusted hazard ratio associated with carrying the APOE*2 allele was 1.47 (95 confidence interval, 1.06-2.05). CONCLUSION(S): This variable miscarriage risk, produced by an interaction between genotype and race, may reconcile, at least partially, the conflicting reports of the association of APOE and miscarriage risk. PMID- 26952785 TI - Triple X syndrome and puberty: focus on the hypothalamus-hypophysis-gonad axis. AB - OBJECTIVE: To evaluate the hypothalamus-hypophysis-gonad axis in a cohort of children and adolescents with nonmosaic triple X syndrome. DESIGN: Cross sectional study with retrospective analysis. SETTING: University pediatric hospital. PATIENT(S): Fifteen prepubertal subjects (median age 9.0 years, range 6.9-11.9 years) with nonmosaic triple X syndrome and age- and pubertal-matched control group (30 girls, median age 9.1 y, range 6.9-11.6 years). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): We evaluated FSH, LH, and E2 levels and performed an autoimmunity screening as well as a pelvic ultrasonography and an LH-releasing hormone stimulation test. RESULT(S): All triple X patients (with and without pubertal signs) showed a pubertal LH peak level that was significantly different from controls. Triple X patients showed increased basal and peak FSH and LH values compared with control subjects. However, the mean E2 level was significantly lower than control subjects. However, triple X patients showed reduced DHEAS levels and reduced inhibin levels compared with control subjects. Finally, triple X patients had a significantly reduced ovarian volume compared with control subjects, in both prepubertal and pubertal patients. CONCLUSION(S): Triple X patients showed premature activation of the GnRH pulse generator, even without puberty signs. Both basal and peak LH and FSH levels were higher than in control subjects, and E2 and inhibin levels and ovarian volume were reduced, which led to a reduced gonadal function. Other studies and a longitudinal evaluation is necessary to better understand the endocrinologic features of these subjects. PMID- 26952786 TI - Forensic features of a fatal Datura poisoning case during a robbery. AB - Datura poisonings have been previously described but remain rare in forensic practice. Here, we present a homicide case involving Datura poisoning, which occurred during a robbery. Toxicological results were obtained by second autopsy performed after one previous autopsy and full body embalmment. A 35-year-old man presented with severe stomach and digestive pain, became unconscious and ultimately died during a trip in Asia. A first autopsy conducted in Asia revealed no trauma, intoxication or pathology. The corpse was embalmed with methanol/formalin. A second autopsy was performed in France, and toxicology samples were collected. Scopolamine, atropine, and hyoscyamine were found in the vitreous humor, in addition to methanol. Police investigators questioned the local travel guide, who admitted to having added Datura to a drink to stun and rob his victim. The victim's death was attributed to disordered heart rhythm due to severe anticholinergic syndrome following fatal Datura intoxication. This is a recent case of a rare homicide involving Datura that highlights general information on Datura and discusses forensic interpretation after a previous autopsy and body embalmment. PMID- 26952787 TI - Tianeptine, olanzapine and fluoxetine show similar restoring effects on stress induced molecular changes in mice brain: An FT-IR study. AB - Chronic stress which can cause a variety of disorders and illness ranging from metabolic and cardiovascular to mental leads to alterations in content, structure and dynamics of biomolecules in brain. The determination of stress-induced changes along with the effects of antidepressant treatment on these parameters might bring about more effective therapeutic strategies. In the present study, we investigated unpredictable chronic mild stress (UCMS)-induced changes in biomolecules in mouse brain and the restoring effects of tianeptine (TIA), olanzapine (OLZ) and fluoxetine (FLX) on these variations, by Fourier transform infrared (FT-IR) spectroscopy. The results revealed that chronic stress causes different membrane packing and an increase in lipid peroxidation, membrane fluidity. A significant increment for lipid/protein, C=O/lipid, CH3/lipid, CH2/lipid, PO(-)2/lipid, COO(-)/lipid and RNA/protein ratios but a significant decrease for lipid/protein ratios were also obtained. Additionally, altered protein secondary structure components were estimated, such as increment in random coils and beta structures. The administration of TIA, OLZ and FLX drugs restored these stress-induced variations except for alterations in protein structure and RNA/protein ratio. This may suggest that these drugs have similar restoring effects on the consequences of stress activity in brain, in spite of the differences in their action mechanisms. All findings might have importance in understanding molecular mechanisms underlying chronic stress and contribute to studies aimed for drug development. PMID- 26952788 TI - Abietane diterpenoids from Caryopteris incana (Thunb.) Miq. AB - Twelve new diterpenes, caryopincaolide A-L (1-4, 11-12, 16-19, 27-28), together with twenty-eight known diterpenes, have been isolated from the whole plant of Caryopteris incana (Thunb.) Miq. Their structures were elucidated on the basis of 1D and 2D NMR, IR, X-ray crystal diffraction and mass spectroscopic data, as well as ECD calculations. All compounds were tested for in vitro dipeptidyl peptidase IV (DPP-IV) inhibitory activity, with compounds 3, 4, 28, 29, and 40 exhibiting DPP-IV inhibitory effects with IC50 values ranging from 54.2 to 228.9 MUM. Compounds 1, 3 and 4 also showed potent activity toward the inhibition of the growth of human cancer cells and 1 can induce apoptosis in Hey and A-549 cells. PMID- 26952789 TI - Theoretical and experimental investigation of optical absorption anisotropy in beta-Ga2O3. AB - The question of optical bandgap anisotropy in the monoclinic semiconductor beta Ga2O3 was revisited by combining accurate optical absorption measurements with theoretical analysis, performed using different advanced computation methods. As expected, the bandgap edge of bulk beta-Ga2O3 was found to be a function of light polarization and crystal orientation, with the lowest onset occurring at polarization in the ac crystal plane around 4.5-4.6 eV; polarization along b unambiguously shifts the onset up by 0.2 eV. The theoretical analysis clearly indicates that the shift in the b onset is due to a suppression of the transition matrix elements of the three top valence bands at Gamma point. PMID- 26952790 TI - The effects of personalized care planning for adults living with chronic conditions. PMID- 26952791 TI - Acta 'Newer' Psychiatrica. PMID- 26952792 TI - An agenda for neuropsychiatry as a 21st century discipline. PMID- 26952793 TI - Psychiatric epidemiology: a Scandinavian contribution to international psychiatry. PMID- 26952795 TI - Clinical, cognitive and neural correlates of self-monitoring deficits in schizophrenia: an update. AB - BACKGROUND: An area of recent interest in schizophrenia research is to investigate specific neural and cognitive abnormalities associated with symptoms of this disorder. OBJECTIVE: To establish clinical, cognitive and neural correlates of self-monitoring deficits in schizophrenia, which according to various theoretical models can account for the first-rank symptoms of this disorder. METHODS: Relevant data were identified from PubMed and PsycInfo searches up to July 2006 using combinations of keywords including 'self monitoring', 'symptoms', 'self-agency', 'neuropsychological', 'cognitive', 'brain activity', 'PET' and 'fMRI'. CONCLUSIONS: Self-monitoring deficit is most consistently observed in patients with schizophrenia with auditory hallucinations and passivity experiences. This deficit may not be schizophrenia specific. At present, there are insufficient direct data to reach meaningful conclusions about the cognitive correlates of this deficit. Functional neuroimaging studies in patients with schizophrenia with auditory hallucinations point to defective engagement of the neural regions known to be involved in self-monitoring in healthy people. Further multimodal studies using validated cognitive and clinical measures, self-monitoring paradigms and appropriate imaging tools to analyze patients with schizophrenia with and without self-monitoring deficits are required to increase our understanding of this topic. PMID- 26952794 TI - Neural stem cell therapy for neuropsychiatric disorders. AB - OBJECTIVE: To conduct a comprehensive literature review of the area of neural stem cells and neuropsychiatry. METHODS: 'Neural stem cells' (NSCs) and 'neurogenesis' were used as keywords in Medline (1966 - November 2006) to identify relevant papers in the areas of Alzheimer's disease (AD), depression, schizophrenia and Parkinson's disease (PD). This list was supplemented with papers from reference lists of seminal reviews. RESULTS: The concept of a 'stem cell' continues to evolve and is currently defined by operational criteria related to symmetrical renewal, multipotency and functional viability. In vivo adult mammalian neurogenesis occurs in discrete niches in the subventricular and subgranular zones - however, functional precursor cells can be generated in vitro from a wide variety of biological sources. Both artificial and physiological microenvironment is therefore critical to the characteristics and behaviour of neural precursors, and it is not straightforward how results from the laboratory can be extrapolated to the living organism. Transplant strategies in PD have shown that it is possible for primitive neural tissue to engraft into neuropathic brain areas, become biologically functional and lead to amelioration of clinical signs and symptoms. However, with long-term follow-up, significant problems related to intractable side-effects and potential neoplastic growth have been reported. These are therefore the potentials and pitfalls for NSC technology in neuropsychiatry. In AD, the physiology of amyloid precursor protein may directly interact with NSCs, and a role in memory function has been speculated. The role of endogenous neurogenesis has also been implicated in the etiology of depression. The significance of NSCs and neurogenesis for schizophrenia is still emerging. CONCLUSIONS: There are a number of technical and conceptual challenges ahead before the promise of NSCs can be harnessed for the understanding and treatment of neuropsychiatric disorders. Further research into fundamental NSC biology and how this interacts with the neuropsychiatric disease processes is required. PMID- 26952796 TI - How low do we go? Is duration of a 'high' integral to the definition of bipolar disorder? AB - OBJECTIVE: There has been considerable debate about the diagnostic rules for bipolar II disorder, particularly the 4-day duration criteria for hypomanic episodes. This study examined whether highs lasting minutes or hours differed from longer highs in terms of clinical features and symptom severity. It also examined whether duration of highs predicted bipolar disorder being diagnosed. METHOD: A total of 518 subjects with significant episodes of depression and 'highs' completed a web-based self-report questionnaire. Those who reported their longest highs lasting minutes or hours were compared with those who reported longer durations of highs on a range of clinical variables and measures of symptom severity. RESULTS: Subjects whose highs lasted minutes or hours reported clinical features and severity of symptoms similar to those whose highs lasted 3 7 days. However, the odds of being diagnosed with bipolar disorder for those with highs lasting 3-7 days were almost three times higher than for those whose highs lasted minutes or hours. CONCLUSION: The 4-day DSM-IV minimum-duration criteria for hypomania may lead to failure to diagnose subjects with brief highs who have true bipolar disorder and thus should be reconsidered. PMID- 26952797 TI - Cerebrospinal fluid kynurenic acid in male patients with schizophrenia - correlation with monoamine metabolites. AB - BACKGROUND: The tryptophan metabolite kynurenic acid (KYNA) is an endogenous glutamate/nicotinic receptor antagonist. Previous studies have shown that the concentration of the compound is increased in cerebrospinal fluid (CSF) of patients with schizophrenia. Furthermore, it has been found that the CSF concentration of KYNA is positively correlated to CSF concentrations of the monoamine metabolites homovanillic acid (HVA) and 5-hydroxy indoleacetic acid (5 HIAA) in healthy control subjects. OBJECTIVES: To study the correlations between KYNA and the monoamine metabolites HVA, 5-HIAA and 4-hydroxy-3 methoxyphenylglycol (HMPG) in CSF of male patients (n= 53, ranging from 20 to 48 years of age) with verified schizophrenia. METHODS: CSF was obtained by lumbar puncture, and KYNA analysis was performed with an isocratic reversed-phase high performance liquid chromatography system connected to a fluorescence detector. HVA, 5-HIAA and HMPG concentrations were measured by mass fragmentography with deuterium-labelled internal standards. RESULTS: Positive intercorrelations were found between CSF KYNA, HVA and 5-HIAA, while CSF content of HMPG did not correlate to KYNA or any of the monoamine metabolites in CSF. CONCLUSION: The results of this study suggest that increased KYNA formation is associated with an increased dopamine and serotonin turnover in male patients with schizophrenia. PMID- 26952798 TI - Influencing negative symptoms of schizophrenia with repetitive transcranial magnetic stimulation: a case study. AB - BACKGROUND: The present trial was designed to investigate the influence of repetitive transcranial magnetic stimulation (rTMS) on negative schizophrenic symptoms using high-frequency stimulation of the left dorsolateral prefrontal cortex in a simple blind randomized design. METHODS: The study was carried out on a 42-year-old patient with schizophrenia (paranoid subtype) with prominent negative symptoms who was first treated with sham rTMS during the first 3 weeks and then with real high frequency during the following 3 weeks. He was rated before and after the sham and after the real rTMS therapy for positive, negative and depressive symptoms. RESULTS: rTMS was superior to sham treatment in reduction of negative and depressive symptoms. CONCLUSION: High-frequency rTMS applied over the left dorsolateral prefrontal cortex led to a reduction of severity of negative symptoms in a patient with chronic schizophrenia and may be beneficial as an augmentation option to antipsychotics in the treatment of negative symptoms of schizophrenia. PMID- 26952799 TI - Transcranial magnetic stimulation for the deficit syndrome of schizophrenia. PMID- 26952801 TI - Neuroimagining ... literally? PMID- 26952800 TI - Hyperventilation-stage electroencephalography in lateral temporal lobe epilepsy. AB - BACKGROUND: To observe spike activity in electroencephalograms (EEGs), patients with symptomatic partial epilepsy are rarely monitored during the hyperventilation stages. CASE: A 38-year-old woman suffered from a ruptured arteriovenous malformation in the left temporal lobe. One and a half years later, the patient experienced her first generalized convulsion. EEG showed small spikes in the posterior of the left temporal lobe, which was observed during the hyperventilation and posthyperventilation stages. Because the location of the spikes correlated with the site of the lesion as observed from radiographic findings, she was diagnosed with lateral temporal lobe epilepsy. Drug treatment resulted in no further convulsive episodes and the patient has since returned to work. CONCLUSION: EEG recordings during hyperventilation should be regarded as an effective technique in analyzing epilepsy because of its ease and cost effectiveness compared with other methods such as single-photon emission computed tomography. PMID- 26952802 TI - Functional neural correlates of mindfulness meditations in comparison with psychotherapy, pharmacotherapy and placebo effect. Is there a link? AB - Chiesa A, Brambilla P, Serretti A. Functional neural correlates of mindfulness meditations in comparison with psychotherapy, pharmacotherapy and placebo effect. Is there a link? OBJECTIVE: Mindfulness meditations (MM) are a group of meditation practices which are increasingly receiving attention. The aim of the present work is to review current findings about the neural correlates of MM and compare such findings with other specific and non-specific treatments. METHODS: A literature search was undertaken using MEDLINE, ISI web of knowledge, the Cochrane database and references of retrieved articles. Studies which focused on the functional neural correlates of MM, psychotherapy, pharmacotherapy and placebo published up to August 2009 were screened in order to be considered for the inclusion. RESULTS: Main findings suggest that long-term MM practice allows a more flexible emotional regulation by engaging frontal cortical structures to dampen automatic amygdala activation. A large overlap exists between cerebral areas activated during MM, psychotherapy, pharmacotherapy and those activated by placebo. However, while MM, psychotherapy and placebo seem to act through a top down regulation, antidepressants seem to act through a bottom-up process. CONCLUSION: MM seem to target specific brain areas related to emotions and emotional regulation. Similar mechanisms have been observed also in other interventions, particularly psychotherapy. PMID- 26952803 TI - Abnormal grey matter in victims of rape with PTSD in Mainland China: a voxel based morphometry study. AB - Sui SG, Wu MX, King ME, Zhang Y, Ling L, Xu JM, Weng XC, Duan L, Shan BC, Li LJ. Abnormal grey matter in victims of rape with PTSD in Mainland China: a voxel based morphometry study. OBJECTIVE: This study examined changes in brain grey matter in victims of rape (VoR) with and without post-traumatic stress disorder (PTSD). Previous research has focused on PTSD caused by various traumatic events, such as war and disaster, among others. Although considerable research has focused on rape-related PTSD, limited studies have been carried out in the context of Mainland China. METHODS: The study included 11 VoR with PTSD, 8 VoR without PTSD and 12 healthy comparison (HC) subjects. We used voxel-based morphometry to explore changes in brain grey-matter density (GMD) by applying statistical parametric mapping to high-resolution magnetic resonance images. RESULTS: Compared with HC, VoR with PTSD showed significant GMD reductions in the bilateral medial frontal cortex, left middle frontal cortex, middle temporal gyrus and fusiform cortex and significant GMD increases in the right posterior cingulate cortex, postcentral cortex, bilateral precentral cortex and inferior parietal lobule. Compared to VoR without PTSD, VoR with PTSD showed significant GMD reductions in the right uncus, left middle temporal gyrus, and the fusiform cortex, and increases in the left precentral cortex, inferior parietal lobule and right post-central cortex. CONCLUSION: The findings of abnormal GMD in VoR with PTSD support the hypothesis that PTSD is associated with widespread anatomical changes in the brain. The medial frontal cortex, precentral cortex, posterior cingulate cortex, post-central cortex and inferior parietal lobule may play important roles in the neuropathology of PTSD. PMID- 26952804 TI - Trait impulsivity in female patients with borderline personality disorder and matched controls. AB - Mortensen JA, Rasmussen IA, Haberg A. Trait impulsivity in female patients with borderline personality disorder and matched controls. OBJECTIVE: Impulsivity has been shown to load on two separate factors, rash impulsivity and sensitivity to reward (SR) in several factor analytic studies. The aims of the current study were to explore the nature of impulsivity in women with borderline personality disorder (BPD) and matched controls, and the underlying neuronal correlates for rash impulsivity and SR. METHODS: Fifteen females diagnosed with BPD and 15 matched controls were recruited. All completed the impulsiveness-venturesomeness scale (I7), the sensitivity to punishment (SP) - sensitivity to reward (SR) questionnaire, and performed a Go-NoGo block-design functional magnetic resonance imaging (fMRI) paradigm at 3T. Correlation analyses were done with I7, SP and SR scores with the level of activation in different brain areas in the whole group. An independent group t-test was used to explore any differences between the BPD group and the matched controls. RESULTS: I7 scores correlated negatively with activity in the left orbitofrontal cortex, amygdala and precuneus, and bilaterally in the cingulate cortices during response inhibition for the entire sample. SP yielded negative correlations in the right superior frontal gyrus and parahippocampal gyrus. No activity related to response inhibition correlated to SR. The Go-NoGo task gave similar brain activity in BPD and matched controls, but behaviourally the BPD group had significantly more commission errors in the NoGo blocks. The BPD group had increased I7 and SP scores indicating rash impulsiveness combined with heightened SP. CONCLUSION: These results imply that successful impulse inhibition involves interaction between the impulsive and the emotional systems. Furthermore, impulsivity in BPD is described as rash impulsivity, coexisting with increased SP. PMID- 26952805 TI - Genes and sex hormones interaction in neurodevelopmental disorders. AB - The prevalence, age of onset and symptomatology of many neurodevelopmental disorders strongly differ between genders. This review examines sex biases in human neurodevelopmental disorders and in validated animal models. A focus is made on disorders of well-established genetic origin, such as Rett syndrome, CDKL5-associated disorders, Fragile X and Down syndrome. Autism is also addressed, given its paradigmatic role as a sex-biased neurodevelopmental disorder. Reviewed literature confirms that a complex interaction between genetic factors and sex hormones may underlie the differential susceptibility of genders and may impact the severity of symptoms in most of the analyzed neurodevelopmental disorders. Even though further studies addressing the advantages and disadvantages conferred by biological sex in this class of disorders are needed to disentangle the underlying mechanisms, present findings suggest that modulation of sex steroid-related pathways may represent an innovative approach for these diseases. Much effort is now expected to unravel the potential therapeutic efficacy of drugs targeting sex hormones-related signaling pathways in neurodevelopmental disorders of well-established genetic origin. PMID- 26952806 TI - Estimating deep molecular responses in chronic myelogenous leukemia: a Bayesian approach. PMID- 26952807 TI - Composition-driven phase boundary and electrical properties in (Ba0.94Ca0.06)(Ti1 xMx)O3 (M = Sn, Hf, Zr) lead-free ceramics. AB - In this study, we systematically investigated the composition dependence of the phase structure, microstructure, and electrical properties of (Ba0.94Ca0.06)(Ti1 xMx)O3 (M = Sn, Hf, Zr) ceramics synthesised by the conventional solid-state reaction method. The phase boundary type strongly depends on the composition, and then different electrical properties were exhibited. The addition of Hf and Zr can more quickly shift phase transition temperatures (TR-O and TO-T) to a higher temperature with respect to Sn, leading to the formation of different phase boundaries. In addition, different phase boundaries can also be affected by their doped contents. The R-O and O-T phase boundaries can be shown in the Sn-doped ceramics with x = 0.10, and the R-O phase boundary can exist in the Hf (x = 0.07) or Zr (x = 0.075)-doped ceramics. A high piezoelectric property of d33 = 600 pC N(-1) can be achieved in the Sn-doped ceramics due to the involvement of converging R-O/O-T phase boundaries, an enhanced ferroelectric performance with Pr = 14.54 MUC cm(-2) and Ec = 1.82 kV cm(-1) can be attained in the Zr-doped ceramics, and Hf would benefit from obtaining a large strain behaviour (~0.20%). We believe that the electrical properties and the related physical mechanisms of BaTiO3-based ceramics can be well unveiled by studying their chemical modification behavior. PMID- 26952809 TI - Pharmacogenomics strategies to optimize treatments for multiple sclerosis: Insights from clinical research. AB - Multiple sclerosis (MS) is a chronic, progressive, disabling disorder characterized by immune-mediated demyelination, inflammation, and neurodegenerative tissue damage in the central nervous system (CNS), associated with frequent exacerbations and remissions of neurologic symptoms and eventual permanent neurologic disability. While there are several MS therapies that are successful in reducing MS relapses, none have been effective in treating all patients. The specific response of an individual patient to any one of the MS therapies remains largely unpredictable, and physicians and patients are forced to use a trial and error approach when deciding on treatment regimens. A priori markers to predict the optimal benefit-to-risk profile of an individual MS patient would greatly facilitate the decision-making process, thereby helping the patient receive the most optimal treatment early on in the disease process. Pharmacogenomic methods evaluate how a person's genetic and genomic makeup affects their response to therapeutics. This review focuses on how pharmacogenomics studies are being used to identify biologically relevant differences in MS treatments and provide characterization of the predictive clinical response patterns. As pharmacogenomics research is dependent on the availability of longitudinal clinical research, studies concerning glatiramer acetate and the interferon beta products which have the majority of published long term data to date are described in detail. These studies have provided considerable insight in the prognostic markers associated with MS disease and potential predictive markers of safety and beneficial response. PMID- 26952808 TI - Glutathione-deficient Plasmodium berghei parasites exhibit growth delay and nuclear DNA damage. AB - Plasmodium parasites are exposed to endogenous and exogenous oxidative stress during their complex life cycle. To minimize oxidative damage, the parasites use glutathione (GSH) and thioredoxin (Trx) as primary antioxidants. We previously showed that disruption of the Plasmodium berghei gamma-glutamylcysteine synthetase (pbggcs-ko) or the glutathione reductase (pbgr-ko) genes resulted in a significant reduction of GSH in intraerythrocytic stages, and a defect in growth in the pbggcs-ko parasites. In this report, time course experiments of parasite intraerythrocytic development and morphological studies showed a growth delay during the ring to schizont progression. Morphological analysis shows a significant reduction in size (diameter) of trophozoites and schizonts with increased number of cytoplasmic vacuoles in the pbggcs-ko parasites in comparison to the wild type (WT). Furthermore, the pbggcs-ko mutants exhibited an impaired response to oxidative stress and increased levels of nuclear DNA (nDNA) damage. Reduced GSH levels did not result in mitochondrial DNA (mtDNA) damage or protein carbonylations in neither pbggcs-ko nor pbgr-ko parasites. In addition, the pbggcs-ko mutant parasites showed an increase in mRNA expression of genes involved in oxidative stress detoxification and DNA synthesis, suggesting a potential compensatory mechanism to allow for parasite proliferation. These results reveal that low GSH levels affect parasite development through the impairment of oxidative stress reduction systems and damage to the nDNA. Our studies provide new insights into the role of the GSH antioxidant system in the intraerythrocytic development of Plasmodium parasites, with potential translation into novel pharmacological interventions. PMID- 26952810 TI - Macrophage migration inhibitory factor promotes breast cancer metastasis via activation of HMGB1/TLR4/NF kappa B axis. AB - Macrophage migration inhibitory factor (MIF) is up-regulated in diverse solid tumors and acts as the critical link between immune response and tumorigenesis. In this study, we demonstrated that MIF overexpression promoted migration of breast cancer cells by elevating TLR4 expression. Further investigation evidenced that MIF induced ROS generation. MIF-induced ROS led to ERK phosphorylation, which facilitated HMGB1 release from the nucleus to the cytoplasm. MIF overexpression also induced caveolin-1 phosphorylation. Caveolin-1 phosphorylation contributed to HMGB1 secretion from the cytoplasm to the extracellular matrix. The extracellular HMGB1 activated TLR4 signaling including NF-kappaB phosphorylation, which was responsible for the transcription of Snail and Twist as well as MMP2 activation. Furthermore, MIF-induced caveolin-1 dependent HMGB1 secretion might control the recruitment of CD11b+ immune cells. Our data suggested that MIF affected the intrinsic properties of tumors and the host immune response in tumor microenvironment by regulating the TLR4/HMGB1 axis, leading to metastasis of breast cancer. PMID- 26952811 TI - Laboratory diagnosis of Ebola virus disease and corresponding biosafety considerations in the China Ebola Treatment Center. AB - Ebola virus disease (EVD), caused by Ebola virus (EBOV), is a potent acute infectious disease with a high case-fatality rate. Etiological and serological EBOV detection methods, including techniques that involve the detection of the viral genome, virus-specific antigens and anti-virus antibodies, are standard laboratory diagnostic tests that facilitate confirmation or exclusion of EBOV infection. In addition, routine blood tests, liver and kidney function tests, electrolytes and coagulation tests and other diagnostic examinations are important for the clinical diagnosis and treatment of EVD. Because of the viral load in body fluids and secretions from EVD patients, all body fluids are highly contagious. As a result, biosafety control measures during the collection, transport and testing of clinical specimens obtained from individuals scheduled to undergo EBOV infection testing (including suspected, probable and confirmed cases) are crucial. This report has been generated following extensive work experience in the China Ebola Treatment Center (ETC) in Liberia and incorporates important information pertaining to relevant diagnostic standards, clinical significance, operational procedures, safety controls and other issues related to laboratory testing of EVD. Relevant opinions and suggestions are presented in this report to provide contextual awareness associated with the development of standards and/or guidelines related to EVD laboratory testing. PMID- 26952812 TI - Glioblastoma: Radiation treatment margins, how small is large enough? AB - Standard treatment for glioblastoma consists of surgical resection followed by radiation therapy with concurrent and adjuvant chemotherapy. Conventional radiation clinical treatment volumes include a 2- to 3-cm margin around magnetic resonance imaging or computed tomography enhancing abnormalities in the brain as well as a margin around the T2 or fluid-attenuated inversion recovery abnormality. However, there remains significant variability with respect to whether such extensive margins are necessary. Collectively, we as authors of this manuscript also use different margins, with A.G.W. employing European Organization for Research and Treatment of Cancer recommendations of a 2- to 3-cm margin on T1 enhancement for 60 Gy and M.P.M. using Radiation Therapy Oncology Group recommendations of 2 cm on T2 signal abnormality for the initial 46 Gy and 2.5-cm margin on T1 enhancement for a 14-Gy boost. Our experiences reflect the heterogeneity of margin definition and selection for this disease and underscore an important area of further research to minimize this variability. In this article, we review studies exploring recurrence patterns and outcomes in patients treated using both conventional and more limited margins. We conclude that treating to "smaller" margins does not alter recurrence patterns nor does it result in inferior survival, but whether this is because of the inherently limited benefit of radiation therapy in the first place, or whether it is truly because microscopic tumor control at larger distances is not an issue, remains unestablished. PMID- 26952814 TI - ASTRO Clinical Practice Statement for the appropriate customization of radiation therapy for rectal cancer: A European perspective. PMID- 26952813 TI - Hypofractionated radiation therapy versus standard fractionated radiation therapy with concurrent temozolomide in elderly patients with newly diagnosed glioblastoma. AB - PURPOSE: Adjuvant hypofractionated radiation therapy (HRT) for elderly patients with newly diagnosed glioblastoma (GBM) is a reasonable option compared with standard fractionation radiation therapy (SFRT). Outcomes in patients receiving HRT in the presence of temozolomide (TMZ) compared with SFRT with TMZ are unclear. We examined HRT for GBM with TMZ in comparison to SFRT with TMZ. METHODS AND MATERIALS: We conducted a retrospective analysis of patients >=60 years of age with newly diagnosed GBM who received SFRT or HRT from 1994 to 2014 in the postoperative setting. Inclusion criteria included SFRT (60 Gy/30 fractions or 59.4 Gy/33 fractions) versus HRT (40 Gy/15 fractions). RESULTS: In this cohort, 158 patients were treated with SFRT versus 26 with HRT. Median survival in patients receiving SFRT compared with HRT was 430 and 475 days (P = .550), respectively. Ninety-five percent of the SFRT patients received TMZ versus 100% of those treated with HRT. Patients receiving HRT were older (median, 72 vs 66 years). All HRT patients were treated with the intensity modulated radiation therapy (IMRT) technique versus SFRT, in which 57% had IMRT. Multivariate Cox regression showed decreased overall survival (OS) associated with patient age >70 (hazard ratio [HR], 1.84), lower Karnofsky performance status (HR, 5.25), biopsy versus surgical resection (HR, 4.18), radiation therapy planning technique 3- or 2-dimensional planning versus IMRT (HR, 1.91; HR, 3.40, respectively). Analysis restricted to patients receiving IMRT-based planning showed no difference in OS between HRT and SFRT. For patients receiving TMZ, there was no survival difference between those treated with HRT and those treated with SFRT. CONCLUSIONS: Elderly GBM patients receiving HRT and those receiving SFRT had similar OS. Subset analysis patients receiving concurrent TMZ showed no difference in OS between the HRT and SFRT groups. PMID- 26952815 TI - Short and long-term outcomes in children with suspected acute encephalopathy. AB - BACKGROUND: The time-dependent changes that occur in children after acute encephalopathy are not clearly understood. Therefore, we assessed changes in brain function after suspected acute encephalopathy over time. METHODS: We created a database of children admitted to the pediatric intensive care unit at Kobe Children's Hospital because of convulsions or impaired consciousness with fever between 2002 and 2013. Clinical courses and outcomes were reviewed and patients who met the following criteria were included in the study: (1) 6months to 15years of age, (2) no neurological abnormality before onset, (3) treated for suspected acute encephalopathy, and (4) followed after 1 (0-2) month and 12 (10 17) months of onset. Outcomes were assessed using the Pediatric Cerebral Performance Category (PCPC) scale, with a score of 1 representing normal performance; 2, mild disability; 3, moderate disability; 4, severe disability; 5, vegetative state; and 6, brain death. RESULTS: A total of 78 children (32 male) with a median (range) age at onset of 20 (6-172) months were enrolled. Fifty-one cases scored 1 on the PCPC, 13 scored 2, three scored 3, five scored 4, one scored 5, and five cases scored 6 at discharge. Whereas seven of the 13 cases that scored a 2 on the PCPC recovered normal brain function after 12months, none of the nine cases that scored a 3-5 on the PCPC recovered normal function. CONCLUSIONS: Our findings suggest moderate to severe disability caused by acute encephalopathy had lasting consequences on brain function, whereas mild disability might result in improved function. PMID- 26952816 TI - Faceting control by the stoichiometry influence on the surface free energy of low index bcc-In2O3 surfaces. AB - The faceting of In2O3(0 0 1), (0 1 1), and (1 1 1) grown by plasma-assisted molecular beam epitaxy on yttria-stabilised zirconia was investigated under different growth conditions-conventionally used oxygen-rich growth conditions with and without heavy Sn-doping, and indium-rich growth conditions-by in situ reflection high-energy electron diffraction, scanning electron microscopy, x-ray diffraction, and atomic force microscopy. In a simple thermodynamic model that considers surface free energy only, the observed faceting is compared to recent theoretical predictions of the surface tension (also termed surface free energy) anisotropy and the related equilibrium crystal shape derived from a Wulff construction. These predictions and our comparison include the variation with growth-condition-dependent oxygen chemical potential. Our results demonstrate how the experimentally changed oxygen chemical potential controls the faceting or island shape of In2O3 by changing the surface tension anisotropy. While the experimental results largely agree with the theoretically derived surface tension anisotropy, they strongly suggest a lower relative surface tension of the (0 0 1) surface at lower oxygen chemical potential (In-rich growth conditions) than theoretically predicted or a significant surface entropy contribution. PMID- 26952817 TI - Acta Alternativa? PMID- 26952818 TI - The place of placebo? The ethics of placebo-controlled trials in bipolar disorder. PMID- 26952819 TI - The psychological and neurophysiological concomitants of mindfulness forms of meditation. AB - OBJECTIVE: To provide a comprehensive review and evaluation of the psychological and neurophysiological literature pertaining to mindfulness meditation. METHODS: A search for papers in English was undertaken using PsycINFO (from 1804 onward), MedLine (from 1966 onward) and the Cochrane Library with the following search terms: Vipassana, Mindfulness, Meditation, Zen, Insight, EEG, ERP, fMRI, neuroimaging and intervention. In addition, retrieved papers and reports known to the authors were also reviewed for additional relevant literature. RESULTS: Mindfulness-based therapeutic interventions appear to be effective in the treatment of depression, anxiety, psychosis, borderline personality disorder and suicidal/self-harm behaviour. Mindfulness meditation per se is effective in reducing substance use and recidivism rates in incarcerated populations but has not been specifically investigated in populations with psychiatric disorders. Electroencephalography research suggests increased alpha, theta and beta activity in frontal and posterior regions, some gamma band effects, with theta activity strongly related to level of experience of meditation; however, these findings have not been consistent. The few neuroimaging studies that have been conducted suggest volumetric and functional change in key brain regions. CONCLUSIONS: Preliminary findings from treatment outcome studies provide support for the application of mindfulness-based interventions in the treatment of affective, anxiety and personality disorders. However, direct evidence for the effectiveness of mindfulness meditation per se in the treatment of psychiatric disorders is needed. Current neurophysiological and imaging research findings have identified neural changes in association with meditation and provide a potentially promising avenue for future research. PMID- 26952820 TI - Long chain omega-3 polyunsaturated fatty acids in the treatment of psychiatric illnesses in children and adolescents. AB - OBJECTIVE: Long chain omega-3 polyunsaturated fatty acids (LCn-3PUFA) are in increasing use in the general population to treat health problems. The objective of the current article is to review the evidence for the rationale and benefit of LCn-3PUFA in the treatment of common psychiatric disorders in children and adolescents. METHODS: A search of Psychlit, PubMed and Cochrane Databases was conducted using the terms child, adolescent, bipolar, depression, psychosis, first-episode psychosis, schizophrenia, attention deficit hyperactivity disorder (ADHD), autism, psychiatric, omega-3, n-3, docosahexaenoic acid and eicosapentaenoic acid. Further studies were identified from the bibliographies of published reviews. RESULTS: One small randomized controlled trial with LCn-3PUFA supplementation in depression in children found a small beneficial effect over placebo. Four placebo-controlled trials showed uncertain benefit of LCn-3PUFA for ADHD. Single placebo-controlled trials showed no benefit in autism or bipolar disorder. There is an absence of studies examining benefit for first-episode psychosis or schizophrenia in children and adolescents. CONCLUSIONS: While children and adolescents are receiving LCn-3PUFA for a range of psychiatric indications, there is only evidence of likely benefit for unipolar depression. PMID- 26952821 TI - The urge to change appearance in different psychopathological categories. AB - BACKGROUND: In professional literature, mainly anecdotic descriptions can be found of striking, sometimes even bizarre manipulations of the appearance by psychiatric patients. OBJECTIVE: In this study, it was examined whether the inclination to (drastically) change the appearance is related to (pre)psychotic symptoms. METHODS: By means of a questionnaire, the frequency and nature of changing the appearance was studied among a sample of healthy volunteers (n = 38) and psychiatric patients (n = 61). The psychiatric group consisted of 1) patients with schizophrenia (n = 22), 2) patients with a borderline personality disorder (n = 20) and 3) patients with a depressive disorder (n = 19). RESULTS: In accordance with previous findings, self-reports of drastic changes of appearance were associated with scores on various schizotypy scales. Psychiatric patients reported more changes of appearance, compared with healthy volunteers. Patients with schizophrenia reported most changes, followed by the group of patients with borderline personality disordered. CONCLUSIONS: Perhaps, drastic changes of the appearance are a visible expression of the loss of ego boundaries and/or of the sense of reality. PMID- 26952822 TI - Marital satisfaction, conflict communication, attachment style and psychological distress in couples with a hospitalized depressed patient. AB - BACKGROUND: There has been fairly consistent empirical support for the association between major depressive disorder and marital dissatisfaction. However, this evidence is limited mostly to out-patient and population-based samples. Further, the role of possible mediating factors such as attachment style and conflict communication are less well investigated in major depression. OBJECTIVE: The present study aims to investigate whether couples with a depressed partner and nonclinical couples differ in marital satisfaction, attachment style, psychological distress and conflict communication. Gender differences are also investigated. METHODS: Seventy-seven couples, who participated in a family intervention trial, were compared with 77 age- and gender-matched nonclinical couples. RESULTS: The depressed patients reported more psychological distress and attachment difficulties and less marital satisfaction than their partners and the nonclinical couples. Partners perceived their relationship as more satisfying than the nonclinical couples. The clinical couples reported less mutual constructive and more mutual avoidant communication in their relationship compared with the nonclinical couples. Finally, female depressed patients reported higher levels of psychological symptoms and were more avoidant attached than male patients. CONCLUSIONS: This study shows important differences in several individual and relational characteristics between couples with a depressed partner and nonclinical couples. Further research will be necessary to clarify whether the investigated psychosocial variables play a causal and/or a maintaining role in depression. PMID- 26952823 TI - Obsessive compulsive disorder in adults with rheumatic heart disease. AB - OBJECTIVE: There are considerable data on the possible association between streptococcal infection and obsessive compulsive disorder (OCD), particularly the relation between Sydenham's chorea (SC) and OCD. However, neuropsychiatric sequelae related to streptococcal infection are mainly reported in children. In this preliminary study, we examined prevalence of OCD in a group of adult subjects with established rheumatic heart disease (RHD). We hypothesized that the rate of OCD would be higher than the known general population rates. METHOD: One hundred adult subjects with RHD were evaluated for OCD and other comorbid psychiatric disorders using well-known psychiatric assessment tools. A qualified psychiatrist conducted the assessments. The diagnoses were made according to DSM IV criteria. RESULTS: The rate of clinical OCD and subclinical OCD was 10% and 3%, respectively (n = 13), a rate much higher than the 1-3% rate reported in general population. Of the 13 subjects, only three had a history of SC (23%). CONCLUSIONS: OCD could be a long-term sequel in adults with a history of rheumatic fever in childhood, even in the absence of frank chorea. The findings call for systematic research in this little explored area. PMID- 26952824 TI - Psychosis as presenting symptom in adult-onset Hallervorden-Spatz syndrome. AB - BACKGROUND: Hallervorden-Spatz syndrome is characterized by pyramidal and extrapyramidal signs, and dysarthria and dementia. Psychiatric symptomatology can emerge in the course of the disorder. Mutations in the pantothenate kinase 2 gene have been found in many cases. We report a case with psychosis as sole presenting symptom. CASE: A 41-year-old man presented with change in behavior and paranoid delusional ideation. Six months later, spasticity, extrapyramidal rigidity and dysarthria were added to the picture. Eventually, the patient became mute and wheel-chair bound. The brain magnetic resonance imaging (MRI) was consistent with iron depositions in the globus pallidus and substantia nigra. CONCLUSIONS: In this case, the combination of clinical and MRI findings was consistent with Hallervorden-Spatz syndrome. The combination of psychiatric and MRI findings should lead to further neurological investigation. PMID- 26952825 TI - Juvenile gout in methylmalonic acidemia. AB - Methylmalonic acidemia (MMA) is an inborn error of metabolism caused by either deficiency of the enzyme methylmalonyl-CoA mutase or a defect in adenosyl cobalamin synthesis. Chronic kidney disease is its common complication and, in combination with persistent acidosis, leads to hyperuricemia. Symptomatic hyperuricemia or gout, however, has not been reported in MMA. We herein report two pediatric cases of MMA caused by MMAB mutations (cblB defect) with renal tubular acidosis, chronic kidney disease, hyperuricemia, and gout. The clinical findings of gout in these cases included recurrent first metatarsophalangeal arthritis and/or tophi. The patients responded to treatment with colchicine and allopurinol. PMID- 26952826 TI - Facile synthesis of substituted 3-aminofurans through a tandem reaction of N sulfonyl-1,2,3-triazoles with propargyl alcohols. AB - A relay catalysis strategy for substituted 3-aminofurans synthesis has been developed. This transformation involves a tandem reaction sequence through aza vinyl-rhodium(ii) carbene O-H bond insertion, thermal propargyl-Claisen rearrangement and gold(i)-catalyzed intramolecular cyclization. More importantly, the current strategy employs simple feedstocks as starting materials, providing substituted 3-aminofurans in a highly efficient manner. PMID- 26952827 TI - Effects of prenatal exposure to cancer treatment on neurocognitive development, a review. AB - Due to the increasing incidence of cancer during pregnancy, the need to better understand long-term outcome after prenatal exposure to chemo- and/or radiotherapy has become more urgent. This manuscript focuses on the neurocognitive development after prenatal exposure to cancer treatment. We will review possible pathways for brain damage that could explain the subtle changes in neurocognition and behavior found after in utero exposure to cancer treatment. Contrary to radiation, which has a direct effect on the developing nervous system, chemotherapy has to pass the placental and blood brain barrier to reach the fetal brain. However, there are also indirect effects such as inflammation and oxidative stress. Furthermore, the indirect effects of the cancer itself and its treatment, e.g., poor maternal nutrition and high maternal stress, as well as prematurity, can be related to cognitive impairment. Although the available evidence suggests that cancer treatment can be administered during pregnancy without jeopardizing the fetal chances, larger numbers and longer follow up of these children are needed. PMID- 26952828 TI - Comments on "Heart rate and respiratory response to doxapram in patients with panic disorder". PMID- 26952829 TI - In the blink of an eye .... PMID- 26952830 TI - The long-term impact of bereavement upon spouse health: a 10-year follow-up. AB - Jones MP, Bartrop RW, Forcier L, Penny R. The long-term impact of bereavement upon spouse health: a 10-year follow-up. OBJECTIVES: This study is the first to examine the effect of bereavement of a first-degree family member on subsequent morbidity over a 10-year follow-up period. METHODS: A sample of bereaved subjects (n = 72) were compared with a control group (n = 80) recruited in the same period with respect to morbidity experience during follow-up. Morbidity events were ascertained from the subject themselves, their health care providers and these sources were also compared. RESULTS: Bereavement was associated with an elevated total burden of illness as well as with mental health and circulatory system categories diagnosed according to the International Classification of Diseases - Clinically Modified (ICD-9) classification system. The elevation ranged from approximately 20% for any illness to 60-100% among circulatory system disorders. Although in an earlier study there was a downregulation of T-cell function in the bereaved during the first 8 weeks, there was no evidence that the bereavement was associated with increased morbidity in the respiratory or immune system ICD-9 categories long-term. CONCLUSIONS: Past epidemiological research has indicated that bereavement of a close family member is associated with adverse health consequences of a generalised morbidity. Our study suggests an increase in mental health and circulatory system effects in particular. Further research is required to determine whether other systems are also affected by bereavement. PMID- 26952831 TI - Functional polymorphism of the myeloperoxidase gene (G-463A) in depressive patients. AB - Galecki P, Florkowski A, Bobinska K, Smigielski J, Bienkiewicz M, Szemraj J. Functional polymorphism of the myeloperoxidase gene (G-463A) in depressive patients. OBJECTIVE: Myeloperoxidase (MPO) is an enzyme involved in the production of hypochloric acid as well as other reactive oxygen species. This enzyme plays a significant role in inflammatory processes. In view of the observed associations between depression and such inflammatory processes, as well as of the reports that confirm the presence of oxidative stress in depression, this study was designed to assess the correlation, if any, between the single nucleotide polymorphism G-463A of the MPO gene and the risk of recurrent depressive disorders (DD). METHODS: The study was carried out in a group of 149 patients with recurrent DD and 149 healthy control subjects. Genotyping was performed by PCR/restriction fragment length polymorphism. RESULTS: A comparison between healthy controls and depressive patients showed a statistically significant difference in genotype distribution and allele frequency in the studied groups. Genotype distribution and allele frequency did not correlate with clinical variables of the patients. CONCLUSION: The obtained results of the study allow us to draw a cautious conclusion about the role of the analysed G-463A MPO polymorphism in recurrent DD development, which, however, requires eventual confirmation in further studies. PMID- 26952832 TI - Frequency of psychiatric disorders in blepharospasm does not differ from hemifacial spasm. AB - Dias FM, Doyle F, Kummer A, Cardoso F, Fontenelle LF, Teixeira AL. Frequency of psychiatric disorders in blepharospasm does not differ from hemifacial spasm. OBJECTIVE: To compare the frequency of psychiatric disorders and the severity of psychiatric symptoms between patients with blepharospasm (BS) and hemifacial spasm (HS). METHODS: BS is a type of primary focal dystonia characterised by recurrent and involuntary eye blinking. HS is a condition with different pathophysiology but similar clinical phenotype. Twenty-two patients with BS and 29 patients with HS participated in this study. They underwent a comprehensive psychiatric evaluation that included a structured clinical interview for current psychiatric diagnosis according to Diagnostic Statistical Manual, fourth edition (DSM-IV) (MINI-Plus) and psychometric scales, including the Yale-Brown Obsessive Compulsive Scale (YBOCS), the Beck Depression Inventory (BDI), the Hamilton Rating Scale for Depression (HRSD), the Hamilton Anxiety Scale (HAS) and the Liebowitz Social Anxiety Scale (LSAS). RESULTS: BS and HS groups did not differ in most demographic and clinical parameters, such as gender, age and length of symptoms. The frequency of psychiatric disorders and the severity of psychiatric symptoms were similar in both groups. CONCLUSION: BS does not seem to have more psychiatric disorders than HS. PMID- 26952833 TI - An event-related potential investigation of deficient inhibitory control in individuals with pathological Internet use. AB - Zhou Z-H, Yuan G-Z, Yao J-J, Li C, Cheng Z-H. An event-related potential investigation of deficient inhibitory control in individuals with pathological Internet use. OBJECTIVE: The purpose of this study was to investigate deficient inhibitory control in individuals with pathological Internet use (PIU) using a visual go/no-go task by event-related potentials (ERPs). METHODS: Subjects were 26 individuals with PIU and 26 controls. Barratt Impulsiveness Scale-11 (BIS-11) was used for measures of impulsivity. A go/no-go task involved eight different two-digit numerical stimuli. The response window was 1000 ms and the inter-trial interval (ITI) was 1500 ms. Electroencephalography (EEG) was recorded when participants performed the task. Brain electrical source analysis (BESA) 5.2.0 was used to perform data analysis and the no-go N2 amplitude was analysed for investigation of inhibitory control. RESULTS: BIS-11 total scores, attentional key and motor key scores in PIU group were higher than that of the control group. In the go/no-go task, false alarm rate of PIU group was higher, and hit rate was lower than that of the control group. A repeated measure ANOVA revealed a significant group, frontal electrode sites and group * frontal electrode sites main effect for N2 amplitudes of no-go conditions (for group: F = 3953, df = 1, p = 0.000; for frontal electrode sites: F = 541, df = 9, p = 0.000; for group * frontal electrode sites: F = 306, df = 9, p = 0.000), and a significant group, central electrode sites and group * central electrode sites main effect for N2 amplitudes of no-go conditions (for group: F = 9074, df = 1, p = 0.000; for central electrode sites: F = 163, df = 2, p = 0.000; for group * central electrode sites: F = 73, df = 2, p = 0.000). N2 amplitudes of no-go conditions were lower than those at control group. CONCLUSIONS: Individuals with PIU were more impulsive than controls and shared neuropsychological and ERPs characteristics of compulsive-impulsive spectrum disorder, which supports that PIU is an impulse disorder or at least related to impulse control disorder. PMID- 26952834 TI - The validity and internal structure of the Bipolar Depression Rating Scale: data from a clinical trial of N-acetylcysteine as adjunctive therapy in bipolar disorder. AB - Berk M, Dodd S, Dean OM, Kohlmann K, Berk L, Malhi GS. The validity and internal structure of the Bipolar Depression Rating Scale: data from a clinical trial of N acetylcysteine as adjunctive therapy in bipolar disorder. BACKGROUND: The phenomenology of unipolar and bipolar disorders differ in a number of ways, such as the presence of mixed states and atypical features. Conventional depression rating instruments are designed to capture the characteristics of unipolar depression and have limitations in capturing the breadth of bipolar disorder. METHOD: The Bipolar Depression Rating Scale (BDRS) was administered together with the Montgomery Asberg Rating Scale (MADRS) and Young Mania Rating Scale (YMRS) in a double-blind randomised placebo-controlled clinical trial of N-acetyl cysteine for bipolar disorder (N = 75). RESULTS: A factor analysis showed a two-factor solution: depression and mixed symptom clusters. The BDRS has strong internal consistency (Cronbach's alpha = 0.917), the depression cluster showed robust correlation with the MADRS (r = 0.865) and the mixed subscale correlated with the YMRS (r = 0.750). CONCLUSION: The BDRS has good internal validity and inter-rater reliability and is sensitive to change in the context of a clinical trial. PMID- 26952835 TI - Brief neuropsychological profiles in psychosis: a pilot study using the Audio Recorded Cognitive Screen (ARCS). AB - Loughland CM, Allen J, Gianacas L, Schofield PW, Lewin TJ, Hunter M, Carr VJ. Brief neuropsychological profiles in psychosis: a pilot study using the Audio Recorded Cognitive Screen (ARCS). OBJECTIVE: This pilot study examines the utility of a novel, standardised brief neuropsychological assessment tool (the ARCS, Audio Recorded Cognitive Screen) in a different clinical setting to that in which it was initially developed. We hypothesised that the ARCS would be feasible to administer to individuals with a psychotic illness and that it would detect cognitive deficits similar to those identified by an established instrument (the RBANS, Repeatable Battery for the Assessment of Neuropsychological Status). METHODS: Twenty-five people with psychosis (mean age = 43.72, SD = 9.78) and 25 age- and gender-matched controls were recruited from the Newcastle community (NSW, Australia). The ARCS and RBANS were completed about 1 week apart in a counterbalanced order. RESULTS: The ARCS was well received, performed satisfactorily and both the ARCS and RBANS were sensitive to deficits typically associated with psychosis (e.g. memory and attention). After controlling for memory deficits, the largest disparity between the psychosis and control groups was on the ARCS fluency domain [p < 0.001, partial Eta-squared (eta p 2) = 0.21]. CONCLUSION: The ARCS uses audio administration (approximately 34 min) to reduce clinician time (to 3-5 min for scoring) and appears to be a useful brief assessment tool for examining the cognitive deficits associated with psychosis. However, the potential clinical utility of the ARCS needs to be investigated further in larger samples drawn from a wider variety of specialist and non specialist settings. PMID- 26952836 TI - Nail dystrophy as the initial sign of multiple myeloma-associated systemic amyloidosis. PMID- 26952837 TI - CXCL12 promotes glycolytic reprogramming in acute myeloid leukemia cells via the CXCR4/mTOR axis. PMID- 26952839 TI - A zwitterionic macro-crosslinker for durable non-fouling coatings. AB - A novel zwitterionic macro-crosslinker was developed and applied to fabricate durable non-fouling coatings on a polyurethane substrate. The zwitterionic macro crosslinker coating exhibited superior durability over the traditional brush polymer coating and was able to retain its non-fouling property even after weeks of shearing in flowing liquid. PMID- 26952838 TI - MLL rearrangements impact outcome in HOXA-deregulated T-lineage acute lymphoblastic leukemia: a Children's Oncology Group Study. PMID- 26952840 TI - SENP1, but not fetal hemoglobin, differentiates Andean highlanders with chronic mountain sickness from healthy individuals among Andean highlanders. AB - Chronic mountain sickness (CMS) results from chronic hypoxia. It is unclear why certain highlanders develop CMS. We hypothesized that modest increases in fetal hemoglobin (HbF) are associated with lower CMS severity. In this cross-sectional study, we found that HbF levels were normal (median = 0.4%) in all 153 adult Andean natives in Cerro de Pasco, Peru. Compared with healthy adults, the borderline elevated hemoglobin group frequently had symptoms (headaches, tinnitus, cyanosis, dilatation of veins) of CMS. Although the mean hemoglobin level differed between the healthy (17.1 g/dL) and CMS (22.3 g/dL) groups, mean plasma erythropoietin (EPO) levels were similar (healthy, 17.7 mIU/mL; CMS, 12.02 mIU/mL). Sanger sequencing determined that single-nucleotide polymorphisms in endothelial PAS domain 1 (EPAS1) and egl nine homolog 1 (EGLN1), associated with lower hemoglobin in Tibetans, were not identified in Andeans. Sanger sequencing of sentrin-specific protease 1 (SENP1) and acidic nuclear phosphoprotein 32 family, member D (ANP32D), in healthy and CMS individuals revealed that non-G/G genotypes were associated with higher CMS scores. No JAK2 V617F mutation was detected in CMS individuals. Thus, HbF and other classic erythropoietic parameters did not differ between healthy and CMS individuals. However, the non G/G genotypes of SENP1 appeared to differentiate individuals with CMS from healthy Andean highlanders. PMID- 26952841 TI - [Access to care and prevention for people with disabilities in France: Analysis based on data from the 2008 French health and disabilities households surveys (Handicap-Sante-Menages)]. AB - BACKGROUND: Using data from the 2008 French health and disabilities households surveys, this study examines the use of three types of routine medical care (dental, ophthalmological and gynecological care) and four preventive services (cervical cancer screening, breast cancer screening, colon cancer screening and vaccination against hepatitis B) both for people with disabilities and for those without. Two definitions of disability were retained: (1) functional limitations (motor, cognitive, visual or hearing limitations) and (2) administrative recognition of disability. METHODS: For each type of care, binary logistic regression was used to test whether access to care is influenced by any of the disability indicators as well as by other explanatory variables. Two set of explanatory variables were included successively: (1) sociodemographic variables such as age, gender as well as a proxy variable representing medical needs and (2) socioeconomic variables such as level of education, household income per consumption unit, supplementary health insurance coverage, co-payment exemption and geographic variables. RESULTS: Persons reporting functional limitations are less likely to access to all types of care, in a proportion that varies between 5 to 27 points, compared to persons without functional limitations, except for eye care for which no gap is observed. The same results are obtained for persons reporting an administrative recognition of disability, and more precisely for those who benefit from the Disability allowance for adults (Allocation adulte handicape [AAH]). After adding the social variables to the model, problems of access to health care decrease significantly, showing that disabled persons' social situation tends to reduce their access to care. CONCLUSION: This study reveals, for a broad range of care, a negative differential access to care for persons reporting functional limitations compared to those without limitations which is confirmed when identifying disability through administrative recognition. Furthermore, it also discusses factors explaining these differentials. It highlights the role of the social situation of disabled people as an additional barrier to already limited access to healthcare. PMID- 26952842 TI - PROMIS measures of pain, fatigue, negative affect, physical function, and social function demonstrated clinical validity across a range of chronic conditions. AB - OBJECTIVE: To present an overview of a series of studies in which the clinical validity of the National Institutes of Health's Patient Reported Outcome Measurement Information System (NIH; PROMIS) measures was evaluated, by domain, across six clinical populations. STUDY DESIGN AND SETTING: Approximately 1,500 individuals at baseline and 1,300 at follow-up completed PROMIS measures. The analyses reported in this issue were conducted post hoc, pooling data across six previous studies, and accommodating the different designs of the six, within condition, parent studies. Changes in T-scores, standardized response means, and effect sizes were calculated in each study. When a parent study design allowed, known groups validity was calculated using a linear mixed model. RESULTS: The results provide substantial support for the clinical validity of nine PROMIS measures in a range of chronic conditions. CONCLUSION: The cross-condition focus of the analyses provided a unique and multifaceted perspective on how PROMIS measures function in "real-world" clinical settings and provides external anchors that can support comparative effectiveness research. The current body of clinical validity evidence for the nine PROMIS measures indicates the success of NIH PROMIS in developing measures that are effective across a range of chronic conditions. PMID- 26952844 TI - Quantitative investigation of physical factors contributing to gold nanoparticle mediated proton dose enhancement. AB - Some investigators have shown tumor cell killing enhancement in vitro and tumor regression in mice associated with the loading of gold nanoparticles (GNPs) before proton treatments. Several Monte Carlo (MC) investigations have also demonstrated GNP-mediated proton dose enhancement. However, further studies need to be done to quantify the individual physical factors that contribute to the dose enhancement or cell-kill enhancement (or radiosensitization). Thus, the current study investigated the contributions of particle-induced x-ray emission (PIXE), particle-induced gamma-ray emission (PIGE), Auger and secondary electrons, and activation products towards the total dose enhancement. Specifically, GNP-mediated dose enhancement was measured using strips of radiochromic film that were inserted into vials of cylindrical GNPs, i.e. gold nanorods (GNRs), dispersed in a saline solution (0.3 mg of GNRs/g or 0.03% of GNRs by weight), as well as vials containing water only, before proton irradiation. MC simulations were also performed with the tool for particle simulation code using the film measurement setup. Additionally, a high-purity germanium detector system was used to measure the photon spectrum originating from activation products created from the interaction of protons and spherical GNPs present in a saline solution (20 mg of GNPs/g or 2% of GNPs by weight). The dose enhancement due to PIXE/PIGE recorded on the films in the GNR-loaded saline solution was less than the experimental uncertainty of the film dosimetry (<2%). MC simulations showed highly localized dose enhancement (up to a factor 17) in the immediate vicinity (<100 nm) of GNRs, compared with hypothetical water nanorods (WNRs), mostly due to GNR-originated Auger/secondary electrons; however, the average dose enhancement over the entire GNR-loaded vial was found to be minimal (0.1%). The dose enhancement due to the activation products from GNPs was minimal (<0.1%) as well. In conclusion, under the currently investigated conditions that are considered clinically relevant, PIXE, PIGE, and activation products contribute minimally to GNP/GNR-mediated proton dose enhancement, whereas Auger/secondary electrons contribute significantly but only at short distances (<100 nm) from GNPs/GNRs. PMID- 26952843 TI - STAT3 inhibitor has potent antitumor activity in B-lineage acute lymphoblastic leukemia cells overexpressing the high mobility group A1 (HMGA1)-STAT3 pathway. PMID- 26952845 TI - Cost-effectiveness Analysis: Why and How. PMID- 26952846 TI - Stimulation artifact correction method for estimation of early cortico-cortical evoked potentials. AB - BACKGROUND: Effective connectivity can be explored using direct electrical stimulations in patients suffering from drug-resistant focal epilepsies and investigated with intracranial electrodes. Responses to brief electrical pulses mimic the physiological propagation of signals and manifest as cortico-cortical evoked potentials (CCEP). The first CCEP component is believed to reflect direct connectivity with the stimulated region but the stimulation artifact, a sharp deflection occurring during a few milliseconds, frequently contaminates it. NEW METHOD: In order to recover the characteristics of early CCEP responses, we developed an artifact correction method based on electrical modeling of the electrode-tissue interface. The biophysically motivated artifact templates are then regressed out of the recorded data as in any classical template-matching removal artifact methods. RESULTS: Our approach is able to make the distinction between the physiological responses time-locked to the stimulation pulses and the non-physiological component. We tested the correction on simulated CCEP data in order to quantify its efficiency for different stimulation and recording parameters. We demonstrated the efficiency of the new correction method on simulations of single trial recordings for early responses contaminated with the stimulation artifact. The results highlight the importance of sampling frequency for an accurate analysis of CCEP. We then applied the approach to experimental data. COMPARISON WITH EXISTING METHOD: The model-based template removal was compared to a correction based on the subtraction of the averaged artifact. CONCLUSIONS: This new correction method of stimulation artifact will enable investigators to better analyze early CCEP components and infer direct effective connectivity in future CCEP studies. PMID- 26952848 TI - Response to "Air pollution and depressed mood: Consistency of association. Air pollution and cardiovascular mortality: Caution for meta-analysis". PMID- 26952850 TI - Consciousness: a gray matter? PMID- 26952849 TI - Chronic active EBV infection with features of granulomatosis with polyangiitis. AB - Herein, we report the case of a 13-year-old boy with multiple recurrent ulcers on his legs. He developed severe sinusitis at 10 years of age and had significant weight loss (6 kg) in the 2 months prior to admission. Histology of tissue biopsied from the ulcer indicated small vessel vasculitis and granulomatous inflammation. Given that these findings met the diagnostic criteria for granulomatosis with polyangiitis (GPA), he was treated with immunosuppressive agents. Further pathology, however, indicated Epstein-Barr virus (EBV)-encoded RNA (EBER) in most lymphocytes in the same sample. The EBER-positive lymphocytes were mainly CD4-positive T cells. The EBV-DNA load in the peripheral blood was also abnormally increased (1.0 * 10(4) copies/MUg DNA). Thus, the diagnosis was established as chronic active EBV infection (CAEBV). This case illustrates the necessity of careful differential diagnosis of CAEBV owing to its clinical resemblance and pathological overlap with GPA. PMID- 26952851 TI - Neuropsychiatry and neurophilosophy. PMID- 26952847 TI - Sensor space group analysis for fNIRS data. AB - BACKGROUND: Functional near-infrared spectroscopy (fNIRS) is a method for monitoring hemoglobin responses using optical probes placed on the scalp. fNIRS spatial resolution is limited by the distance between channels defined as a pair of source and detector, and channel positions are often inconsistent across subjects. These challenges can lead to less accurate estimate of group level effects from channel-specific measurements. NEW METHOD: This paper addresses this shortcoming by applying random-effects analysis using summary statistics to interpolated fNIRS topographic images. Specifically, we generate individual contrast images containing the experimental effects of interest in a canonical scalp surface. Random-effects analysis then allows for making inference about the regionally specific effects induced by (potentially) multiple experimental factors in a population. RESULTS: We illustrate the approach using experimental data acquired during a colour-word matching Stroop task, and show that left frontopolar regions are significantly activated in a population during Stroop effects. This result agrees with previous neuroimaging findings. COMPARED WITH EXISTING METHODS: The proposed methods (i) address potential misalignment of sensor locations between subjects using spatial interpolation; (ii) produce experimental effects of interest either on a 2D regular grid or on a 3D triangular mesh, both representations of a canonical scalp surface; and (iii) enables one to infer population effects from fNIRS data using a computationally efficient summary statistic approach (random-effects analysis). Significance of regional effects is assessed using random field theory. CONCLUSIONS: In this paper, we have shown how fNIRS data from multiple subjects can be analysed in sensor space using random-effects analysis. PMID- 26952852 TI - When brains expand: mind and the evolution of cortex. AB - OBJECTIVE: To critically examine the relationship between evolutionary and developmental influences on human neocortex and the properties of the conscious mind it creates. METHODS: Using PubMed searches and the bibliographies of several monographs, we selected 50 key works, which offer empirical support for a novel understanding of the organization of the neocortex. RESULTS: The cognitive gulf between humans and our closest primate relatives has usually been taken as evidence that our brains evolved crucial new mechanisms somehow conferring advanced capacities, particularly in association areas of the neocortex. In this overview of neocortical development and comparative brain morphometry, we propose an alternative view: that an increase in neocortical size, alone, could account for novel and powerful cognitive capabilities. Other than humans' very large brain in relation to the body weight, the morphometric relations between neocortex and all other brain regions show remarkably consistent exponential ratios across the range of primate species, including humans. For an increase in neocortical size to produce new abilities, the developmental mechanisms of neocortex would need to be able to generate an interarchy of functionally diverse cortical domains in the absence of explicit specification, and in this respect, the mammalian neocortex is unique: its relationship to the rest of the nervous system is unusually plastic, allowing great changes in cortical organization to occur in relatively short periods of evolution. The fact that even advanced abilities like self-recognition have arisen in species from different mammalian orders suggests that expansion of the neocortex quite naturally generates new levels of cognitive sophistication. Our cognitive and behavioural sophistication may, therefore, be attributable to these intrinsic mechanisms' ability to generate complex interarchies when the neocortex reaches a sufficient size. CONCLUSION: Our analysis offers a parsimonious explanation for key properties of the human mind based on evolutionary influences and developmental processes. This view is perhaps surprising in its simplicity, but offers a fresh perspective on the evolutionary basis of mental complexity. PMID- 26952853 TI - Brain phylogeny, ontogeny and dysfunction: integrating evolutionary, developmental and clinical perspectives in cognitive neuroscience. AB - OBJECTIVE: One of the most popular approaches in cognitive neuroscience has been to study the normal adult human brain. However, there are likely to be limits to the knowledge that can be obtained from such studies. If we assume that no single approach can ever provide us with knowledge of causative processes whereby the mind emerges from the brain, then we need to consider how to combine more disparate approaches. I aim to illustrate here how the parallel study of brain phylogeny, ontogeny and dysfunction may bring us towards an integrative understanding of fundamental aspects of cognitive neuroscience. METHODS: A review of published literature in these research areas was carried out and representative articles selected. RESULTS: Comparative approaches, utilizing the extraordinary behavioural abilities as well as the structural and functional variants that evolution has thrown up across diverse groups of species, can inform the core neural systems that may be necessary and sufficient to support specific cognitive processes. Similarly, detailed studies of human brain development, focusing on structural and functional maturation correlated with temporal mapping of cognitive processes as they come 'on-line', may provide unique mechanistic insights. Finally, the study of brain dysfunction in neurological and psychiatric disorders such as Huntington's disease, Alzheimer's disease, schizophrenia and depression, may have the beneficial side-effect of greatly enhancing our understanding of healthy brain function. CONCLUSION: Each approach has its own epistemological advantages and disadvantages, but combined they may lead to more sophisticated, and empirically testable, models. In this review, I outline evidence for their utility, illustrate the approaches using specific examples and suggest how new advances in fields such as genomics, neurophysiology and neuroimaging may provide unprecedented opportunities in cognitive neuroscience. PMID- 26952854 TI - On the correlation/constitution distinction problem (and other hard problems) in the scientific study of consciousness. AB - OBJECTIVE: In the past decade, much has been written about 'the hard problem' of consciousness in the philosophy of mind. However, a separate hard problem faces the scientific study of consciousness. The problem arises when distinguishing the neural correlates of consciousness (NCC) and the neural constitution of consciousness. Here, I explain this correlation/constitution distinction and the problem it poses for a science of phenomenal consciousness. I also discuss potential objections to the problem, outline further hard problems in the scientific study of phenomenal consciousness and consider the ontological implications of these epistemological issues. METHODS: Scientific and philosophic analysis and discussion are presented. RESULTS: The correlation/constitution distinction does indeed present a hard problem in the scientific study of phenomenal consciousness. Refinement of the 'NCC' acronym is proposed so that this distinction may at least be acknowledged in the literature. Furthermore, in addition to the problem posed by this distinction and to 'the hard problem', the scientific study of phenomenal consciousness also faces several other hard problems. CONCLUSION: In light of the multiple hard problems, it is concluded that scientists and philosophers of consciousness ought to (i) address, analyze and discuss the problems in the hope of discovering their solution or dissolution and (ii) consider the implications of some or all of them being intractable. With respect to the latter, it is argued that ultimate epistemic limits in the study of phenomenal consciousness pose no threat to physicalist or materialist ontologies but do inform our understanding of consciousness and its place in nature. PMID- 26952855 TI - Mind the neuron! The role of the single neuron in a theory of mind. AB - OBJECTIVE: To present the argument that the only secure foundation for a theory of behaviour, and ultimately of mind, rests at the level of single neurons, and to assess progress at this level of explanation. METHODS: Relevant data were obtained by a search of PubMed, last updated in January 2007, focused on implemented models from single-neuron studies. RESULTS: Technical limitations on recording neural activity produce trade-offs between temporal and spatial resolution and the ability to track the massively parallel activity of the nervous system. The properties of the single neuron that would need to be measured and the techniques available to obtain the data are described. The concept of a fixed neuronal identity may be impeding progress and should be replaced with the concept of dynamically assigned neuron identity. CONCLUSION: Modern data collection techniques make it possible to obtain data at the single neuron level on the complete nervous systems of simple organisms. Present models based on this data do not provide an integrated explanation of behaviour. However, there do not appear to be insurmountable theoretical or practical obstacles to building such models in the future or of scaling the data collection up to more complex organisms. PMID- 26952856 TI - Studies of caloric vestibular stimulation: implications for the cognitive neurosciences, the clinical neurosciences and neurophilosophy. AB - OBJECTIVE: Caloric vestibular stimulation (CVS) has traditionally been used as a tool for neurological diagnosis. More recently, however, it has been applied to a range of phenomena within the cognitive neurosciences. Here, we provide an overview of such studies and review our work using CVS to investigate the neural mechanisms of a visual phenomenon - binocular rivalry. We outline the interhemispheric switch model of rivalry supported by this work and its extension to a metarivalry model of interocular-grouping phenomena. In addition, studies showing a slow rate of binocular rivalry in bipolar disorder are discussed, and the relationship between this finding and the interhemispheric switch model is described. We also review the effects of CVS in various clinical contexts, explain how the technique is performed and discuss methodological issues in its application. METHODS: A review of CVS and related literature was conducted. RESULTS: Despite CVS being employed with surprising effect in a wide variety of cognitive and clinical contexts, it has been a largely underutilized brain stimulation method for both exploratory and therapeutic purposes. This is particularly so given that it is well tolerated, safe, inexpensive and easy to administer. CONCLUSION: CVS can be used to investigate various cognitive phenomena including perceptual rivalry, attention and mood, as well as somatosensory representation, belief, hemispheric laterality and pain. The technique can also be used to investigate clinical conditions related to these phenomena and may indeed have therapeutic utility, especially with respect to postlesional disorders, mania, depression and chronic pain states. Furthermore, we propose that based on existing reports of the phenomenological effects of CVS and the brain regions it is known to activate, the technique could be used to investigate and potentially treat a range of other clinical disorders. Finally, the effects of CVS (and its potential effects) on several phenomena of interest to philosophy suggest that it is also likely to become a useful tool in experimental neurophilosophy. PMID- 26952857 TI - Low red cell folate levels are associated with poor response to nortriptyline in major depression. AB - BACKGROUND: There has been a long interest in the relationship between folate and depression. METHODS: In this paper, we report baseline measures of red cell folate that were collected during a randomized trial of 107 patients with major depression. Red cell folate levels were examined for association with percentage improvement in depressive symptoms during treatment with fluoxetine or nortriptyline. The influences of possible confounding factors were assessed. RESULTS: The low red cell folate group (defined in relation to the median) had a significantly poorer response to nortriptyline. This effect of red cell folate levels was not present in those treated with fluoxetine. No relationships were found between red cell folate levels and possible confounding factors of age, nutritional status, alcohol history, depression subtype, depression severity and chronicity of depression. CONCLUSION: Response to nortriptyline was affected by red cell folate status. It may, therefore, be beneficial to consider folate augmentation in patients with major depression, particularly if treated with nortriptyline. PMID- 26952858 TI - Suicidal thoughts in patients with Parkinson's disease treated by deep brain stimulation of the subthalamic nuclei: two case reports and review of the literature. AB - BACKGROUND: Deep brain stimulation (DBS) of the subthalamic nuclei (STN) can result in depression despite the obvious motor improvement. CASE PRESENTATIONS: Two patients with serious life-threatening depressive episodes are described. In the first case, the trigger for depression was a slight adjustment of the left stimulating electrode's contact. In the second case, reducing both the dopaminergic therapy and the voltage of DBS resulted in the manifestation of depressive symptoms. CONCLUSIONS: DBS-induced depression possibly has pathogenetic differences from ordinary Parkinson's disease depression. The STN region seems to be a sensitive zone that influences emotions. PMID- 26952859 TI - Adios Acta .... PMID- 26952860 TI - Comparison of language impairment in late-onset depression and Alzheimer's disease. AB - OBJECTIVES: Depression and dementia are highly prevalent in the elderly. Language impairment is an inherent component of Alzheimer's disease (AD), which can also be encountered in depressed patients. The aim of this study wasto compare the profiles of language abilities in late-onset depression and mild AD groups. METHODS: We studied 25 patients with late-onset depression (mean age 73.6 +/- 6.6 years; schooling 9.1 +/- 5.7 years) and 30 patients with mild AD (77.6 +/- 5.4 years; 7.5 +/- 7.1 years) using the Arizona Battery for Communication Disorders of Dementia (ABCD), compared to a group of 30 controls (73.8 +/- 5.8 years; 9.1 +/- 5.4 years). Cut-off scores to discriminate between Controls * Depression and Depression * AD were determined. RESULTS: Depressed patients' scores were similar to AD in confrontation naming, concept definition, following commands, repetition and reading comprehension (sentence). Episodic memory and mental status subtests were useful in differentiating depressed patients from AD, a result that was reproduced when using analysis of covariance to control for the effect of age in the same subtests (p = 0.01 and 0.04, respectively). CONCLUSION: Language impairment resembling AD was found in the aforementioned language subtests of the ABCD in elderly depressed patients; the mental status and episodic memory subtests were useful to discriminate between AD and depression. The ABCD has proven to be a suitable tool for language evaluation in this population and should aid in the differentiation of AD and pseudodementia (as that of depression). PMID- 26952861 TI - Association between metabolic syndrome and cognitive decline: a systematic review of prospective population-based studies. AB - OBJECTIVE: The association between metabolic syndrome (MS) and the risk of cognitive impairment or dementia remains unclear. In this article, we systematically review studies on the risk of cognitive disorders in patients with MS to determine the strength of the association between MS and cognitive decline. METHODS: Electronic databases through December 2009 were searched to identify prospective population-based studies that examined the association between MS and risk of cognitive disorders. Two reviewers used a standardised form to collect data and assess eligibility. The quality of study was assessed by the Newcastle Ottawa Scale. RESULTS: We found nine eligible studies that involve 19 876 participants. All studies but two indicate that MS is associated with cognitive decline (from one-fold to more than two-fold increase in risk). It seems that MS may be associated with cognitive impairment (positive results in three of five) and vascular dementia (positive results in two of three), whereas three studies involving patients with Alzheimer's disease (AD) did not find the association between MS and AD. When examining the association of the individual risk factors of the MS and cognition in seven eligible studies, glucose (three studies) and hypertension (three studies) showed positive results associated with cognitive decline. CONCLUSION: The MS may be associated with cognitive impairment and vascular dementia but not for AD, which need to be further investigated with high quality studies. PMID- 26952862 TI - Ruling out white coat hypertension with NT-proBNP. PMID- 26952863 TI - Potential therapeutic effects of the MTOR inhibitors for preventing ageing and progeria-related disorders. AB - The mammalian target of rapamycin (mTOR) pathway is an highly conserved signal transduction axis involved in many cellular processes, such as cell growth, survival, transcription, translation, apoptosis, metabolism, motility and autophagy. Recently, this signalling pathway has come to the attention of the scientific community owing to the unexpected finding that inhibition of mTOR by rapamycin, an antibiotic with immunosuppressant and chemotherapeutic properties, extends lifespan in diverse animal models. Moreover, rapamycin has been reported to rescue the cellular phenotype in a progeroid syndrome [Hutchinson-Gilford Progeria syndrome (HGPS)] that recapitulates most of the traits of physiological ageing. The promising perspectives raised by these results warrant a better understanding of mTOR signalling and the potential applications of mTOR inhibitors to counteract ageing-associated diseases and increase longevity. This review is focused on these issues. PMID- 26952864 TI - A rare missense mutation in CHRNA4 associates with smoking behavior and its consequences. AB - Using Icelandic whole-genome sequence data and an imputation approach we searched for rare sequence variants in CHRNA4 and tested them for association with nicotine dependence. We show that carriers of a rare missense variant (allele frequency=0.24%) within CHRNA4, encoding an R336C substitution, have greater risk of nicotine addiction than non-carriers as assessed by the Fagerstrom Test for Nicotine Dependence (P=1.2 * 10(-4)). The variant also confers risk of several serious smoking-related diseases previously shown to be associated with the D398N substitution in CHRNA5. We observed odds ratios (ORs) of 1.7-2.3 for lung cancer (LC; P=4.0 * 10(-4)), chronic obstructive pulmonary disease (COPD; P=9.3 * 10( 4)), peripheral artery disease (PAD; P=0.090) and abdominal aortic aneurysms (AAAs; P=0.12), and the variant associates strongly with the early-onset forms of LC (OR=4.49, P=2.2 * 10(-4)), COPD (OR=3.22, P=2.9 * 10(-4)), PAD (OR=3.47, P=9.2 * 10(-3)) and AAA (OR=6.44, P=6.3 * 10(-3)). Joint analysis of the four smoking related diseases reveals significant association (P=6.8 * 10(-5)), particularly for early-onset cases (P=2.1 * 10(-7)). Our results are in agreement with functional studies showing that the human alpha4beta2 isoform of the channel containing R336C has less sensitivity for its agonists than the wild-type form following nicotine incubation. PMID- 26952866 TI - A membrane-anchored fluorescent probe for detecting K(+) in the cell microenvironment. AB - Cell-surface fluorescent probes are effective tools in cell biology and engineering. Here, we for the first time report a diacyllipid-aptamer conjugate based fluorescent probe which could anchor on cell membrane for real-time tracking of potassium ions in the cell microenvironment. PMID- 26952865 TI - mTORC1-dependent translation of collapsin response mediator protein-2 drives neuroadaptations underlying excessive alcohol-drinking behaviors. AB - Mammalian target of rapamycin complex 1 (mTORC1) has an essential role in dendritic mRNA translation and participates in mechanisms underlying alcohol drinking and reconsolidation of alcohol-related memories. Here, we report that excessive alcohol consumption increases the translation of downstream targets of mTORC1, including collapsin response mediator protein-2 (CRMP-2), in the nucleus accumbens (NAc) of rodents. We show that alcohol-mediated induction of CRMP-2 translation is mTORC1-dependent, leading to increased CRMP-2 protein levels. Furthermore, we demonstrate that alcohol intake also blocks glycogen synthase kinase-3beta (GSK-3beta)-phosphorylation of CRMP-2, which results in elevated binding of CRMP-2 to microtubules and a concomitant increase in microtubule content. Finally, we show that systemic administration of the CRMP-2 inhibitor lacosamide, or knockdown of CRMP-2 in the NAc decreases excessive alcohol intake. These results suggest that CRMP-2 in the NAc is a convergent point that receives inputs from two signaling pathways, mTORC1 and GSK-3beta, that in turn drives excessive alcohol-drinking behaviors. PMID- 26952868 TI - Enhancement of site specific delivery of diloxanide furoate as an antiamoebic drug. AB - The basic aim of the present research work is to deliver the diloxanide furoate (DF) at specific area using pectin microspheres. The microspheres were prepared by spray drying method and cross-linked by zinc acetate. Different concentrations of polymer (pectin 0.5-3%) and cross-linking agent (0-3% w/v in a mixture of ethanol:water) are taken to optimize the entrapment efficiency, swelling behavior, size and first 6h in-vitro release in simulated gastric fluids. Optimized formulation was characterized in the terms of in-vitro release, in-vivo drug disposition in various organs and in the blood of Sprague-Dawley albino rats and in-vivo gastrointestinal tract transit behavior using X-ray imaging method on albino rabbits. Findings suggested that microspheres containing a concentration of polymer (2% w/v) have average size of 100-500 MUm, entrapment efficiency 85.82 +/- 0.5 with swelling index 18.77 +/- 5.21. In-vitro results and in-vivo gastric transit behavior (using X-ray imaging) have shown no release in first 3-6h that proved the colon specific delivery of DF. The results also suggested that the above approach have not only site specific delivery, but it improves the conversion of active drug by increasing the enzyme mediated hydrolytic degradation of DF due to the presence of polysaccharide polymer:water gel complex. PMID- 26952867 TI - A "building block" approach to the new influenza A virus entry inhibitors with reduced cellular toxicities. AB - Influenza A virus (IAV) is a severe worldwide threat to public health and economic development that results in the emergence of drug-resistant or highly virulent strains. Therefore, it is imperative to develop potent anti-IAV drugs with different modes of action to currently available drugs. Herein, we show a new class of antiviral peptides generated by conjugating two known short antiviral peptides: part-1 (named Jp with the sequence of ARLPR) and part-2 (named Hp with the sequence of KKWK). The new peptides were thus created by hybridization of these two domains at C- and N- termini, respectively. The anti IAV screening results identified that C20-Jp-Hp was the most potent peptide with IC50 value of 0.53 MUM against A/Puerto Rico/8/34 (H1N1) strain. Interestingly, these new peptides display lower toxicities toward mammalian cells and higher therapeutic indices than their prototypes. In addition, the mechanism of action of C20-Jp-Hp was extensively investigated. PMID- 26952869 TI - Embryology of the Absent Vas Supported by 2 Cases of Congenital Unilateral Absence of Vas With Varied Associations. AB - Congenital absence of the vas occurs in up to 1% of men. Congenital unilateral absence of the vas deferens can be related to cystic fibrosis transmembrane conductance regulator mutations or in 79% of cases, renal agenesis. We present a case of each, diagnosed in children at operation for elective inguinal hernia repairs. One patient had associated ipsilateral renal agenesis with a normal cystic fibrosis screen. The other patient had an ipsilateral pelvic kidney and a mutation detected on cystic fibrosis screening. Current understanding of the embryology of the relationship between these defects would seem to be supported by our cases. PMID- 26952870 TI - Zika Virus Infects Human Cortical Neural Progenitors and Attenuates Their Growth. AB - The suspected link between infection by Zika virus (ZIKV), a re-emerging flavivirus, and microcephaly is an urgent global health concern. The direct target cells of ZIKV in the developing human fetus are not clear. Here we show that a strain of the ZIKV, MR766, serially passaged in monkey and mosquito cells efficiently infects human neural progenitor cells (hNPCs) derived from induced pluripotent stem cells. Infected hNPCs further release infectious ZIKV particles. Importantly, ZIKV infection increases cell death and dysregulates cell-cycle progression, resulting in attenuated hNPC growth. Global gene expression analysis of infected hNPCs reveals transcriptional dysregulation, notably of cell-cycle related pathways. Our results identify hNPCs as a direct ZIKV target. In addition, we establish a tractable experimental model system to investigate the impact and mechanism of ZIKV on human brain development and provide a platform to screen therapeutic compounds. PMID- 26952872 TI - Prevalence of anxiety, depression and kinesiophobia in patients with low back pain and their association with the symptoms of low back spinal pain. AB - OBJECTIVE: To evaluate the prevalence of anxiety, depression and kinesiophobia and their association with the symptoms of low back pain. METHODS: A total of 65 patients were divided into three groups: Organic, Amplified Organic and Non Organic. They answered the Beck Anxiety Inventory, Beck Depression Inventory and Tampa Scale of Kinesiophobia and were evaluated according to their pain level using the Visual Analogic Scale. RESULTS: The average kinesiophobia scores of the patients in the Organic, Amplified Organic and Non-Organic groups were 36.26, 36.21 and 23.06 points, respectively. Patients who were classified into the Organic group experienced the most kinesiophobia out of all 3 groups (p=0.007). The average anxiety scores of the patients in the Organic, Amplified Organic and Non-Organic groups were 33.17, 32.79 and 32.81 points, respectively, with no significant difference among the groups (p=0.99). The average depression scores of the patients in the Organic, Amplified Organic and Non-Organic groups were 32.54, 28.79 and 37.69 points, respectively, with no significant difference among the groups (p=0.29). CONCLUSION: There was no association between the groups and anxiety and depression. However, there was a positive correlation between kinesiophobia and the Organic group. Studies of other patient samples are needed to confirm the reproducibility and validity of these data in other populations. PMID- 26952871 TI - Partitioning of naturally-occurring radionuclides (NORM) in Marcellus Shale produced fluids influenced by chemical matrix. AB - Naturally-occurring radioactive materials (NORM) associated with unconventional drilling produced fluids from the Marcellus Shale have raised environmental concerns. However, few investigations into the fundamental chemistry of NORM in Marcellus Shale produced fluids have been performed. Thus, we performed radiochemical experiments with Marcellus Shale produced fluids to understand the partitioning behavior of major radioelements of environmental health concern (uranium (U), thorium (Th), radium (Ra), lead (Pb), and polonium (Po)). We applied a novel radiotracer, (203)Pb, to understand the behavior of trace-levels of (210)Pb in these fluids. Ultrafiltration experiments indicated U, Th, and Po are particle reactive in Marcellus Shale produced fluids and Ra and Pb are soluble. Sediment partitioning experiments revealed that >99% of Ra does not adsorb to sediments in the presence of Marcellus Shale produced fluids. Further experiments indicated that although Ra adsorption is related to ionic strength, the concentrations of heavier alkaline earth metals (Ba, Sr) are stronger predictors of Ra solubility. PMID- 26952873 TI - Livedoid vasculopathy. AB - Livedoid vasculopathy is a chronic and painful skin disease that progresses to ulceration. Due to its uncertain pathogenesis, there is no single effective treatment for this condition, and current therapeutic options are based on isolated case reports, or on case series. We report a case of a female patient with livedoid vasculopathy, which achieved excellent healing of lower limb ulcers after using an anti-TNF agent. PMID- 26952874 TI - Beneficial effects of urine-derived stem cells on fibrosis and apoptosis of myocardial, glomerular and bladder cells. AB - Urine-derived stem cells (USCs) are isolated from voided urine and display high proliferative activity and multiple differentiation potentials. The applicability of USCs in the treatment of bladder dysfunction and in cell-based urological tissue engineering has been demonstrated. Whether they could serve as a potential stem cell source for the treatment of diabetes mellitus (DM) and its complications has not been investigated. Here, we report the repairing and protective effects of USCs on pancreatic islets, the myocardium, the renal glomerulus and the bladder detrusor in diabetic rat models. Type 2 diabetic rat models were induced by means of a high fat diet and intraperitoneal injection with streptozotocin. USCs isolated from voided urine were administered via tail veins. The functional changes of pancreatic islets, left ventricle, glomerulus and bladder micturition were assessed by means of insulin tolerance tests, echocardiography, urine biochemical indexes and cystometry. The histologic changes were evaluated by hematoxylin and eosin staining, Masson's trichrome staining and TUNEL staining. Treatment with USCs significantly alleviated the histological destruction and functional decline. Although the USC treatment did not decrease fasting blood glucose to a significantly different level, the fibrosis and apoptosis of the myocardium, glomerulus and detrusor were significantly inhibited. This study indicates that administration of USCs may be useful for the treatment of the complications of DM. PMID- 26952875 TI - Mucinous epithelial tumours arising from ovarian mature teratomas: a tissue genotyping study. AB - AIMS: The association of ovarian mucinous tumours with teratomas is well documented at tissue level, suggesting that some ovarian mucinous tumours arise from teratomas. Teratomas, being of germ cell origin, are genetically distinct from somatic cells, therefore providing a molecular basis for DNA genotyping to separate teratoma-derived mucinous tumours from metastatic ones. We assessed the diagnostic utility of DNA genotyping in ovarian mucinous tumours. METHODS AND RESULTS: Nine cases of ovarian mucinous borderline tumours and three mucinous carcinomas associated with teratomas were included, along with three mucinous tumours without associated teratoma for genotyping control. Target tissues (teratoma, mucinous tumour and paired normal tissue) were dissected microscopically, followed by genotyping at 15 short tandem repeat polymorphic loci. Of the 12 mucinous tumours with associated teratoma, tissue genotyping was informative in six cases, including four borderline tumours and two mucinous carcinomas. Homozygosity or partial homozygosity was observed in the teratomatous component in all six cases. Genotypical concordance between the teratoma and mucinous tumour was seen in five cases, including three borderline tumours and two mucinous carcinomas, suggesting clonal evolution. One mucinous borderline tumour showed an unmatched genotype with that of the corresponding teratoma, consistent with disparate tumour origins. All three mucinous tumours without teratoma displayed heterozygosity. CONCLUSIONS: When associated with a teratoma, ovarian mucinous tumours may arise frequently from the coexisting teratoma. In difficult cases, DNA genotyping may be used as a diagnostic tool in separating teratoma-derived primary ovarian mucinous tumours from those of somatic origin, particularly metastatic tumours from other sites. PMID- 26952876 TI - Percutaneous closure of pseudoaneurysm in the left ventricle in a young child. AB - Pseudoaneurysm in the left ventricular outflow tract is a rare complication occurring after cardiac surgery. We report on the successful percutaneous device closure of a pseudoaneurysm in the left ventricular outflow tract, which developed in a 23-month-old girl after resection of a subaortic ridge. The pseudoaneurysm was closed using an Amplatzer Vascular Plug II. PMID- 26952878 TI - The Effects of Light-Accelerated Degradation on the Aggregation of Marketed Therapeutic Monoclonal Antibodies Evaluated by Size-Exclusion Chromatography With Diode Array Detection. AB - Research into the effects that exposure to light can have on therapeutic proteins is essential for ensuring the quality and safety of the medicines in which they are used. It is important to understand the effects of light on aggregation to help avoid undesirable colloidal instabilities, both in the original medicines and in the formats in which they are finally administered. In this study, 5 marketed therapeutic mAbs, namely bevacizumab, cetuximab, infliximab, rituximab, and trastuzumab, were investigated for this purpose. The medicines and 2 diluted preparations in 0.9 NaCl (2 mg/mL and 5 mg/mL)-commonly used in clinical practice were subjected to controlled light-accelerated degradation. The formation of aggregates was monitored by size-exclusion chromatography. The results indicated that light induced protein aggregation. This process of protein damage was influenced above all by mAb concentration, although the particular characteristics of each mAb were also important. Photodegradation also produced the fragmentation of the mAbs. The damage caused to the mAbs as a result of light induced aggregation and/or fragmentation was demonstrated both in the medicines and in the diluted preparation forms. These findings should be carefully considered when handling the medicines for administration and when recommending beyond-use dates in normal hospital conditions. PMID- 26952877 TI - Oral anticoagulants in coronary heart disease (Section IV). Position paper of the ESC Working Group on Thrombosis - Task Force on Anticoagulants in Heart Disease. AB - Until recently, vitamin K antagonists (VKAs) were the only available oral anticoagulants evaluated for long-term treatment of patients with coronary heart disease (CHD), particularly after an acute coronary syndrome (ACS). Despite efficacy in this setting, VKAs are rarely used because they are cumbersome to administer. Instead, the more readily manageable antiplatelet agents are the mainstay of prevention in ACS patients. This situation has the potential to change with the introduction of non-VKA oral anticoagulants (NOACs), which are easier to administer than VKAs because they can be given in fixed doses without routine coagulation monitoring. The NOACs include dabigatran, which inhibits thrombin, and apixaban, rivaroxaban and edoxaban, which inhibit factor Xa. Apixaban and rivaroxaban were evaluated in phase III trials for prevention of recurrent ischaemia in ACS patients, most of whom were also receiving dual antiplatelet therapy with aspirin and clopidogrel. Although at the doses tested rivaroxaban was effective and apixaban was not, both agents increased major bleeding. The role for the NOACs in ACS management, although promising, is therefore complicated, because it is uncertain how they compare with newer antiplatelet agents, such as prasugrel, ticagrelor or vorapaxar, and because their safety in combination with these other drugs is unknown. Ongoing studies are also now evaluating the use of NOACs in non-valvular atrial fibrillation patients, where their role is established, with coexistent ACS or coronary stenting. Focusing on CHD, we review the results of clinical trials with the NOACs and provide a perspective on their future incorporation into clinical practice. PMID- 26952879 TI - Biowaiver Monographs for Immediate Release Solid Oral Dosage Forms: Ribavirin. AB - Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release solid oral dosage forms containing ribavirin are reviewed. Ribavirin is highly soluble, but its permeability characteristics are not well defined. Therefore according to the Biopharmaceutical Classification System, and taking a "worst case" approach, ribavirin should be assigned to class III. As ribavirin is transported across the brush border membrane of the human jejunum by hCNT2, it shows saturable uptake in the intestine. However, no common excipients have been shown to compete for ribavirin absorption, nor have problems with BE of immediate release ribavirin formulations containing different excipients and produced by different manufacturing methods been reported in the open literature. So the risk of bioinequivalence caused by these factors appears to be low. Ribavirin is considered a narrow therapeutic index drug, as judged by comparing the minimum effective concentration and minimum toxic concentrations in blood. Although ribavirin would not be eligible for approval via a Biopharmaceutical Classification System-based biowaiver procedure according to today's guidances due to its narrow therapeutic index, the risks of biowaiving should be weighed against the considerable risks associated with studying BE of ribavirin products in healthy subjects. PMID- 26952880 TI - Establishment of a Drug-Induced, Bile Acid-Dependent Hepatotoxicity Model Using HepaRG Cells. AB - Bile acid (BA) retention within hepatocytes is an underlying mechanism of cholestatic drug-induced liver injury (DILI). We previously developed an assay using sandwich-cultured human hepatocytes (SCHHs) to evaluate drug-induced hepatocyte toxicity accompanying intracellular BA accumulation. However, due to shortcomings commonly associated with the use of primary human hepatocytes (e.g., limited availability, lot-to-lot variability, and high cost), we examined if the human hepatic stem cell line, HepaRG, might also be applicable to our assay system. Consequently, mRNA expression levels of human BA efflux and uptake transporters were lower in HepaRG cells than in SCHHs but higher than in HepG2 human hepatoma cells. Nevertheless, HepaRG cells and SCHHs showed similar toxicity responses to 22 selected drugs, including cyclosporine A (CsA). CsA (10 MUM) was cytotoxic toward HepaRG cells in the presence of BAs and also reduced the biliary efflux rate of [(3)H]taurocholic acid from 38.5% to 19.2%. Therefore, HepaRG cells are useful for the evaluation of BA-dependent drug toxicity caused by biliary BA efflux inhibition. Regardless, the prediction accuracy for cholestatic DILI risk was poor for HepaRG cells versus SCHHs, suggesting that our DILI model system requires further improvements to increase the utility of HepaRG cells as a preclinical screening tool. PMID- 26952882 TI - Magnetically recoverable Cu(0)/Fe3O4 catalyzed highly regioselective synthesis of 2,3,4-trisubstituted pyrroles from unactivated terminal alkynes and isocyanides. AB - An efficient, one pot tandem nano Cu(0)/Fe3O4 catalyzed highly regioselective synthesis of 3-substituted pyrrole-2,4 dicarboxylates from unactivated terminal alkynes and isocyanides has been developed. This strategy exhibits an unprecedented double addition of isocyanides on unactivated terminal alkynes to obtain trisubstituted pyrroles in high yields. Furthermore, the catalyst was magnetically recovered and reused five times without any appreciable loss of activity. PMID- 26952881 TI - Breast Cancer Resistance Protein Abundance, but Not mRNA Expression, Correlates With Estrone-3-Sulfate Transport in Caco-2. AB - Transporter mRNA and protein expression data are used to extrapolate in vitro transporter kinetics to in vivo drug disposition predictions. Breast cancer resistance protein (BCRP) possesses broad substrate specificity; therefore, understanding BCRP expression-activity relationships are necessary for the translation to in vivo. Bidirectional transport of estrone-3-sulfate (E-3-S), a BCRP probe, was evaluated with respect to relative BCRP mRNA expression and absolute protein abundance in 10- and 29-day cultured Caco-2 cells. BCRP mRNA expression was quantified by real-time PCR against a housekeeper gene, Cyclophilin A. The BCRP protein abundance in total membrane fractions was quantified by targeted proteomics, and [(3)H]-E-3-S bidirectional transport was determined in the presence or absence of Ko143, a potent BCRP inhibitor. BCRP mRNA expression was 1.5-fold higher in 29- versus 10-day cultured cells (n = 3), whereas a 2.4-fold lower (p < 0.001) BCRP protein abundance was observed in 29- versus 10-day cultured cells (1.28 +/- 0.33 and 3.06 +/- 0.22 fmol/MUg protein, n = 6, respectively). This correlated to a 2.45-fold lower (p < 0.01) efflux ratio for E-3-S in 29- versus 10-day cultured cells (8.97 +/- 2.51 and 3.32 +/- 0.66, n = 6, respectively). Caco-2 cell BCRP protein abundance, but not mRNA levels, correlates with BCRP activity, suggesting that extrapolation strategies incorporating BCRP protein abundance-activity relationships may be more successful. PMID- 26952883 TI - Using the H-index to assess disease priorities for salmon aquaculture. AB - Atlantic salmon's (Salmo salar) annual aquaculture production exceeds 2M tonnes globally, and for the UK forms the largest single food export. However, aquaculture production is negatively affected by a range of different diseases and parasites. Effort to control pathogens should be focused on those which are most "important" to aquaculture. It is difficult to specify what makes a pathogen important; this is particularly true in the aquatic sector where data capture systems are less developed than for human or terrestrial animal diseases. Mortality levels might be one indicator, but these can cause a range of different problems such as persistent endemic losses, occasional large epidemics or control/treatment costs. Economic and multi-criteria decision methods can incorporate this range of impacts, however these have not been consistently applied to aquaculture and the quantity and quality of data required is large, so their potential for comparing aquatic pathogens is currently limited. A method that has been developed and applied to both human and terrestrial animal diseases is the analysis of published scientific literature using the H-index method. We applied this method to salmon pathogens using Web of Science searches for 23 pathogens. The top 3 H-indices were obtained for: sea lice, furunculosis, and infectious salmon anaemia; post 2000, Amoebic Gill Disease (AGD) replaced furunculosis. The number of publications per year describing bacterial disease declined significantly, while those for viruses and sea lice increased significantly. This reflects effective bacterial control by vaccination, while problems related to viruses and sea lice have increased. H-indices by country reflected different national concerns (e.g. AGD ranked top for Australia). Averaged national H-indices for salmon diseases tend to increase with log of salmon production; countries with H-Indices significantly below the trend line have suffered particularly large disease losses. The H-index method, supported by other literature analyses, is consistent with the nature and history of salmon diseases and so provides a useful quantitative measure for comparing different diseases in the absence of other measures. PMID- 26952884 TI - An assessment of the association between soil pH and ovine Johne's disease using Australian abattoir surveillance data. AB - There has long been discussion in the literature about the role of soil on ovine Johnes disease (OJD). This is especially true of soil pH, however there is very little research to support an association between pH and OJD prevalence. The primary objective of this study was to examine the hypothesis that there is an association between soil pH and OJD. Several additional hypotheses were also assessed. Sheep properties that were surveyed by the Australian National Sheep Health Monitoring Project where classified as OJD reactor positive or otherwise. A variety of explanatory variables such as soil (especially soil pH), environmental and management factors were examined. Spatial regression models were assessed using information theory to examine support for various hypotheses and to examine associations; especially that soil pH is associated with OJD. A total of 1213 properties from 10,578 were classified as OJD positive (11.5%, 95% CI: 10.9-12.1). Within the limitations of the study, only modest support was found for an association between soil pH and the presence or absence of OJD. Instead, OJD prevalence was affected by several factors concurrently, a so called multi-factorial model (hypothesis). In this supported multifactorial hypothesis soil pH was marginally associated with OJD (p=0.04) and had a relatively weak effect (OR 0.91, 95% CI 0.82 to 1.00). OJD was strongly associated with a number of biosecurity and environmental factors such as the time since infection arrived in a region, absence of biosecurity programs (such as regional biosecurity programs or state based programs) and, to a lesser extent, solar irradiation. Soil pH may play a relatively small role in explaining OJD prevalence when evaluated as part of a multifactorial model. Biosecurity and other environmental factors appear to be more strongly associated with the presence of OJD in Australia. PMID- 26952885 TI - Body mass loss correlates with cognitive performance in primates under acute caloric restriction conditions. AB - Brain functions are known to consume high levels of energy, thus, the integrity of cognitive performance can be drastically impacted by acute caloric restriction. In this study, we tested the impact of a 40% caloric restriction on the cognitive abilities of the grey mouse lemur (Microcebus murinus). Twenty three male mouse lemurs were divided into two groups: 13 control animals (CTL) that were fed with 105kJ/day and 10calorie restricted (CR) animals that received 40% less food (63kJ/day) than the CTL animals. The animals were fed according to their group for 19days. Before treatment, we assessed baseline associative learning capacities, resting metabolic rates and locomotor performance of both animal groups. After treatment, we tested the same functions as well as long-term memory. Our results showed that CR animals had lower learning performance following caloric restriction. The effects of caloric restriction on memory recall varied and depended on the metabolism of the individual animal. Body mass loss was linked to memory test performance in the CR group, and lower performance was observed in individuals losing the most weight. While CR was observed to negatively impact learning, locomotor capacities were preserved in CR animals, and there were higher resting metabolic rates in the CR group. Our data reinforce the strong link between energy allocation and brain function, and suggest that in the context of food shortage, learning capacities could be a limiting parameter in the adaptation to a changing environment. PMID- 26952886 TI - Neural correlates for aesthetic appraisal of pictograph and its referent: An fMRI study. AB - As one kind of language symbols, pictograph has a graphical structure based on its referential object. Are the aesthetic qualities of these referential objects reflected in the cognitive and neural processing of the font structure of pictographs? In this present study, participants performed aesthetic judgments on both pictographs and their referential object images whilst acquiring fMRI data. Square luminance judgment was served as baseline to control for activity in motor brain regions associated with the key responses. Behavioral results showed both font structures of pictographs and their corresponding object images which refer to beautiful objects were rated significantly higher on beauty than those refer to ugly objects. Functional MRI revealed regions of occipital lobe, frontal lobe and inferior orbitofrontal cortex (OFC) that were commonly activated for pictographs and object images referring to beautiful objects in the direct contrasts between beautiful judgment and luminance judgment. Moreover, only the aesthetic judgments of beauty for the pictographs but not the object images elicited activation of motor areas, which implied relevant embodied experience was elicited during the aesthetic perception of novel pictographs. In contrast, activities associated with pictographs referring to ugly objects were limited to visual processing regions of the bilateral inferior occipital gyri, which could be due to the intentions of avoiding ugly or aversive stimulus. In addition, object images were associated with broader recruitment in cortical areas than pictographs, likely due to the increased visual processing demands for the more visually complex object images. These findings indicate that aesthetic perceptions for the font structures of pictographs were derived from their referential objects, which could arouse a similar sense of beauty supported by common neural mechanisms with other aesthetic objects. PMID- 26952887 TI - Lost in translation? PMID- 26952888 TI - Spreading the word: disseminating research results to patients and carers. PMID- 26952889 TI - Plasma cortisol and norepinephrine in Alzheimer's disease: opposite relations with recall performance and stage of progression. AB - OBJECTIVE: Alzheimer's disease (AD) is characterized by effortful retrieval memory impairments, loss of hippocampal neurons and elevated plasma cortisol (CORT) concentrations. The latter could induce further memory decline. AD is also characterized by increased central and peripheral noradrenergic activity. Since noradrenergic function is involved in memory formation, this upregulated function could counteract memory decline. The aim of the present study was to test these hypotheses using plasma norepinephrine (NE) as a noradrenergic parameter, and recall of the prerecency part of neutral valence word lists as a measure of effortful retrieval. METHODS: Area under the curve (AUC) of morning, midday and afternoon plasma CORT and plasma NE concentrations was related to two measures of recall performance, ie summated recall scores of the prerecency and recency parts of three word lists, and to the stage of the Clinical Dementia Rating (CDR). RESULTS: Partial correlation between each hormone AUC value and prerecency recall performance, controlling for the effect of the other hormone, showed opposite relations between recall and either plasma CORT or NE. Similar stronger correlations were found with the CDR score. CONCLUSIONS: Plasma CORT and NE are oppositely related with effortful retrieval and the stage of progression in AD. PMID- 26952890 TI - MMPI-2 clusters of alcohol-dependent patients and the relation to Cloninger's temperament-character inventory. AB - OBJECTIVE: Psychometric research in the field of alcohol dependence has concentrated on identifying certain (personality) characteristics (i.e. typologies). This paper is aimed to identify such typologies and studies the relation of the Minnesota Multiphasic Personality Inventory-2 (MMPI-2) and Cloninger's temperament-character inventory (TCI). METHOD: To find MMPI-2 scales associated with maximization of group differences between 222 DSM-IV alcohol dependent inpatients and a control group of 222 normal subjects, discriminant analysis was used. In addition, a cluster analysis was performed with these scales, and the MMPI-2 mean scale values of the resulting patient clusters were examined for their TCI-correlates. RESULTS: The discriminant analyses showed several MMPI-2 scales that could clearly distinguish between alcohol-dependent patients and the normal controls. Cluster analysis resulted in semantically different MMPI-2 profiles implying qualitatively different groups of patients. When related to TCI scales, these differences revealed harm avoidance, self directedness, and persistence, amongst others, as important elements in the description of the clusters. CONCLUSION: Evidence for the validity of MMPI-2 constructs as well as those of the TCI in the assessment of alcohol-dependent patients was provided. PMID- 26952891 TI - Thoughts on the behavioural phenotypes in Prader-Willi syndrome and velo-cardio facial syndrome: a novel approach. AB - BACKGROUND: In both Prader-Willi syndrome (PWS) and 22q11 deletion syndrome [velo cardio-facial syndrome (VCFS)], an increased risk for psychotic disorders is reported, which are as a rule not included in the behavioural phenotype of these two syndromes. For the description of a behavioural phenotype, the complete spectrum of physical, developmental, neuropsychological and psychiatric aspects is generally not taken into account. Moreover, psychiatric signs and symptoms often do not meet the criteria for a categorical diagnosis. OBJECTIVE: In this study, a further specification of psychotic symptoms in PWS and VCFS is shown as well as a proposal for a new model to ascertain predictors, including behavioural, for a genetic syndrome. METHODS: Over the past years, 27 patients with PWS and 19 with VCFS were referred for neuropsychiatric evaluation because of psychotic symptoms. In all the patients, a standardised psychiatric examination was performed; seven of the patients with VCFS were evaluated by means of an extensive neuropsychological battery. RESULTS: In both patient groups, a rather specific psychopathological profile seemed to be present, which in the case of patients with PWS showed some resemblance with bipolar affective disorder. In patients with VCFS, no formal psychiatric diagnosis could be established. Because the psychopathological profiles were rather aspecific, they are not sufficient to predict membership of a certain syndrome. CONCLUSIONS: A quantitative probabilistic approach toward the description of a (behavioural) phenotype is suggested. For such a procedure, large data sets and international collaboration are required. PMID- 26952892 TI - Neurosyphilis presenting as psychiatric symptoms: an unusual case report. AB - OBJECTIVE: Neurosyphilis remains a differential diagnosis for a wide variety of psychiatric syndromes, including dementia, mood disorders and psychosis. However, the incidence of neurosyphilis presenting initially with psychiatric symptomalogy is unclear. In this article, a clinical case is reported so as to illustrate some of the issues involved. CASE PRESENTATION: A 33-year-old married man was admitted because of a depressive episode associated with somatic preoccupations and a gradual loss of ability to function a year prior to his admission. The symptoms described above raised the question of an organic brain syndrome associated with the psychotic depression. Some laboratory and additional examinations were performed. Serological tests for syphilis were positive for both the hemagglutination test, Treponema pallidum hemaglutination (TPHA), and the immunofluorescent antibody test, fluorescent treponemal antibody-absorption (FTA ABS). Based on these findings, the diagnosis of neurosyphilis was made. The patient was treated with benzathine penicillin (2 400 000 units i.m. once a week) for 3 weeks and venlafaxine (150 mg daily) and olanzapine (5 mg daily). His depression disappeared gradually, and he was discharged in partial remission. CONCLUSION: High-risk groups such as patients with neuropsychiatric diseases should be screened with serological tests so as to prevent morbidity and help eliminate syphilis. PMID- 26952893 TI - Ischaemic Colitis Associated with Adrenergic Acute Cardiomyopathy: A discovery mode of pheochromocytoma. PMID- 26952894 TI - Acta Neuropsychiatrica 4.0. PMID- 26952895 TI - Treating bipolar depression - antidepressants and alternatives: a critical review of the literature. AB - OBJECTIVE: Although depressive symptoms are preponderant in the course of bipolar (BP) disorders, the treatment of BP depression remains a controversial issue with different clinical approaches available. This review addresses the issues of whether antidepressants (ADs) are effective in treating acute and long-term BP depression, risks linked to ADs and what alternatives to ADs are available. METHODS: We searched the MEDLINE databases using the following syntax: [bipolar depression AND unipolar depression AND (antidepressants OR anticonvulsants OR lithium OR antipsychotics OR dopamine-agonists OR psychoeducation OR psychotherapy OR electroconvulsive therapy OR transcranial magnetic stimulation)]. The search included studies published up to 31 May 2009 and conducted on adults. RESULTS: In the acute treatment of BP depression ADs are effective with no differences among drug classes. However, neither the switch into (hypo)mania induction rate nor the suicide risk linked to AD use are definitely established. The effectiveness of long-term AD use is limited to highly selected samples of patients with positive acute response. The risk of long-term ADs causing cycle acceleration and rapid cycling induction concerns a subpopulation of patients. Valid alternatives to ADs in treating acute BP depression are quetiapine, an olanzapine-fluoxetine combination, and electroconvulsive therapy for more severe patients. Lamotrigine is effective and safe in preventing depressive relapses. Psychotherapy and psychoeducation represent effective adjunctive treatments. CONCLUSION: In the treatment of BP depression there is not a specific effective treatment for all the patients. Interventions should therefore be personalised and the scientific evidence should be adapted to each patient's clinical features. PMID- 26952896 TI - Mitochondrial respiratory chain activity in an animal model of mania induced by ouabain. AB - OBJECTIVES: Bipolar disorder (BD) is a mental illness associated with higher rates of suicide. The present study aims to investigate the brain mitochondrial respiratory chain activity in an animal model of mania induced by ouabain. METHODS: Adult male Wistar rats received a single intracerebroventricular administration of ouabain (10-3 and 10-2 M) or vehicle. Locomotor activity was measured using the open field test. Mitochondrial respiratory chain activity was measured in the brain of rats 1 h and 7 days after ouabain administration. RESULTS: Our results showed that spontaneous locomotion was increased 1 h and 7 days after ouabain administration. Complexes I, III and IV activities were increased in the prefrontal cortex, hippocampus and striatum immediately after the administration of ouabain, at the concentration of 10-3 and 10-2 M. Moreover, complex II activity was increased only in the prefrontal cortex at the concentration of 10-2 M. On the other hand, no significant alterations were observed in complex I activity 7 days after ouabain administration. However, an increase in complexes II, III and IV activities was observed only in the prefrontal cortex at the concentration of 10-2 M. CONCLUSION: Our findings suggest an increase in the activities of mitochondrial respiratory chain in this model of mania. A possible explanation is that these findings occur as a rebound effect trying to compensate for a decrease of ATP deprivation in BD. The present findings suggest that this model may present good face validity and a limitation in construct validity. PMID- 26952897 TI - Activity of mitochondrial respiratory chain is increased by chronic administration of antidepressants. AB - OBJECTIVE: Depressive disorders, including major depression, are serious and disabling for affected patients. Although the neurobiological understanding of major depressive disorder focuses mainly on the monoamine hypothesis, the exact pathophysiology of depression is not fully understood. METHODS: Animals received daily intra-peritoneal injections of paroxetine (10 mg/kg), nortriptyline (15 mg/kg) or venlafaxine (10 mg/kg) in 1.0 ml/kg volume for 15 days. Twelve hours after the last injection, the rats were killed by decapitation, where the brain was removed and homogenised. The activities of mitochondrial respiratory chain complexes in different brain structures were measured. RESULTS: We first verified that chronic administration of paroxetine increased complex I activity in prefrontal cortex, hippocampus, striatum and cerebral cortex. In addition, complex II activity was increased by the same drug in hippocampus, striatum and cerebral cortex and complex IV activity in prefrontal cortex. Furthermore, chronic administration of nortriptyline increased complex II activity in hippocampus and striatum and complex IV activity in prefrontal cortex, striatum and cerebral cortex. Finally, chronic administration of venlafaxine increased complex II activity in hippocampus, striatum and cerebral cortex and complex IV activity in prefrontal cortex. CONCLUSION: On the basis of the present findings, it is tempting to speculate that an increase in brain energy metabolism by the antidepressant paroxetine, nortriptyline and venlafaxine could play a role in the mechanism of action of these drugs. These data corroborate with other studies suggesting that some antidepressants modulate brain energy metabolism. PMID- 26952898 TI - Left or right temporal lesion might induce aggression or escape during awake surgery, respectively: role of the amygdala. AB - OBJECTIVE: Some patients with temporal lobe brain tumours show aggressive or escape behaviour during awake surgery. As the amygdala plays a critical role in coping with stress, we evaluated whether the left or right amygdala was involved in aggressive or escape behaviour in six patients undergoing awake surgery for temporal lobe brain tumours. METHODS: Brain tumours were located in the left temporal lobe in cases 1-3 and in the right temporal lobe in cases 4-6. In cases 1, 2, 4 and 5, the tumours invaded the amygdala. RESULTS: In case 1, the patient showed aggressive behaviour before partial removal of the left amygdala during awake surgery; just after partial removal of left amygdala, the patient was calm and cooperative. In case 2, the patient showed aggressive behaviour when the tumour near the left amygdala was removed. In case 3, the patient showed aggressive behaviour when awakening during awake surgery. In case 4, the patient showed escape behaviour when removal of the tumour near the right amygdala was initiated. In cases 5 and 6, patients showed escape behaviour upon awakening and upon initiation of tumour removal from the temporal lobe. CONCLUSION: In conclusion, these results suggest that left or right temporal lesions might induce aggressive or escape behaviour during awake surgery, respectively, and that the amygdala on the respective side may play a role in these behaviours. PMID- 26952899 TI - Neuroimaging study in subjects at high risk of psychosis revealed by the Rorschach test and first-episode schizophrenia. AB - OBJECTIVE: There is increasing evidence of neuroanatomical pathology in schizophrenia, but it is unclear whether changes exist prior to disease onset. This study aimed to examine whether changes exist prior to disease onset, especially in the temporal lobes. METHODS: T1-weighted and diffusion tensor magnetic resonance imaging were performed on 9 first-episode schizophrenia patients, 10 patients who were at high risk of schizophrenia and 10 healthy controls. Voxel-based analysis using the normalised images of cortical volume data was examined, and the fractional anisotropy value at three component fibres of the temporal lobes, inferior longitudinal fasciculus, superior longitudinal fasciculus (SLF) and cingulum hippocampal part was compared among the three groups. RESULTS: There were statistically significant volume differences at the bilateral temporal lobe between the healthy subjects and high-risk group. Between the schizophrenic group and healthy subjects, statistically significant volume differences were detected at the bilateral temporal lobes and anterior cingulate cortex. The fractional anisotropy values of the SLF in the schizophrenic and high risk groups were significantly lower than in the healthy subjects. CONCLUSION: Our findings indicate that some brain alterations may progress in patients at psychosis pre-onset, possibly because of disrupted developmental mechanisms, and these pathological changes may be predictive of functional outcome. PMID- 26952900 TI - Contactless remote induction of shear waves in soft tissues using a transcranial magnetic stimulation device. AB - This study presents the first observation of shear waves induced remotely within soft tissues. It was performed through the combination of a transcranial magnetic stimulation device and a permanent magnet. A physical model based on Maxwell and Navier equations was developed. Experiments were performed on a cryogel phantom and a chicken breast sample. Using an ultrafast ultrasound scanner, shear waves of respective amplitudes of 5 and 0.5 MUm were observed. Experimental and numerical results were in good agreement. This study constitutes the framework of an alternative shear wave elastography method. PMID- 26952901 TI - Stepwise development of a cancer care delivery research study to evaluate the prevalence of virus infections in cancer patients. AB - BACKGROUND: SWOG initiated a cancer care delivery research study of virus infection rates among newly diagnosed cancer patients. This study will inform viral screening guidelines in oncology clinics. METHODS: In a first step 'vanguard' phase, we evaluated the feasibility of multiple study procedures. Site investigators were surveyed to obtain feedback on study implementation. RESULTS: Much higher enrollment occurred at sites where all physicians participated and viral testing was performed as routine practice. These procedures will be required going forward. Additional protocol changes based on site investigator input were implemented. CONCLUSION: This multistep protocol design process illustrates how cancer care delivery research studies can adapt to real-world strategies and procedures that exist at community clinics where the predominance of cancer patients are treated. PMID- 26952902 TI - Analytical Method for Sugar Profile in Pet Food and Animal Feeds by High Performance Anion-Exchange Chromatography with Pulsed Amperometric Detection. AB - There is a need for a standardized, accurate, rugged, and consistent method to measure for sugars in pet foods and animal feeds. Many traditional standard sugar methods exist for other matrixes, but when applied in collaborative studies there was poor agreement and sources of error identified with those standard methods. The advancement in technology over the years has given us the ability to improve on these standard methods of analysis. A method is described here that addresses these common issues and was subjected to a single-laboratory validation to assess performance on a wide variety of pet foods and animal feeds. Of key importance to the method performance is the sample preparation before extraction, type of extraction solvent, postextraction cleanup, and, finally, optimized chromatography using high-performance anion exchange chromatography with pulsed amperometric detection. The results obtained from the validation demonstrate how typical issues seen with these matrixes can influence performance of sugar analysis. The results also demonstrate that this method is fit-for-purpose and can meet the challenges of sugar analysis in pet food and animal feeds to lay the foundation for a standardized method of analysis. PMID- 26952903 TI - Imiquimod in the treatment of penile intraepithelial neoplasia: An update. AB - Penile intraepithelial neoplasia (PIN), or penile squamous cell carcinoma in situ, is a rare disease and may be associated with high morbidity and mortality. In an attempt to avoid surgical intervention, which may result in poor cosmetic and functional outcomes for patients, many non-invasive treatments have been trialled with variable success rates. This review summarises the available literature describing the use of topical imiquimod for PIN. While the results of our review are limited by the heterogeneity of the methods and follow ups of the included case series and case reports, they highlight the fact that patients with PIN have variable responses to imiquimod which seem less effective than previously reported. Therefore, if imiquimod treatment is instituted in PIN, clinicians should counsel their patients about the effects associated with treatment, the potential for a partial or no response to treatment, and the risk of recurrence. A strict follow-up plan is also necessary to monitor both patient adherence and PIN recurrence after treatment completion, in case surgical options need to be considered. PMID- 26952904 TI - Environmental and Historical Determinants of Patterns of Genetic Differentiation in Wild Soybean (Glycine soja Sieb. et Zucc). AB - Wild soybean, the direct progenitor of cultivated soybean, inhabits a wide distribution range across the mainland of East Asia and the Japanese archipelago. A multidisciplinary approach combining analyses of population genetics based on 20 nuclear microsatellites and one plastid locus were applied to reveal the genetic variation of wild soybean, and the contributions of geographical, environmental factors and historic climatic change on its patterns of genetic differentiation. High genetic diversity and significant genetic differentiation were revealed in wild soybean. Wild soybean was inferred to be limited to southern and central China during the Last Glacial Maximum (LGM) and experienced large-scale post-LGM range expansion into northern East Asia. A substantial northward range shift has been predicted to occur by the 2080s. A stronger effect of isolation by environment (IBE) versus isolation by geographical distance (IBD) was found for genetic differentiation in wild soybean, which suggested that environmental factors were responsible for the adaptive eco-geographical differentiation. This study indicated that IBE and historical climatic change together shaped patterns of genetic variation and differentiation of wild soybean. Different conservation measures should be implemented on different populations according to their adaptive potential to future changes in climate and human-induced environmental changes. PMID- 26952905 TI - Encapsulation of cannabinoid drugs in nanostructured lipid carriers. AB - This study describes the development and optimization of a method to encapsulate the potent and expensive cannabinoids drugs in nanostructured lipid carriers; namely, URB597, AM251 and rimonabant have been considered. NLC production by melt and ultrasonication protocol has been specifically designed to optimize nanoparticle recovery and drug encapsulation efficiency. Special care has been devoted to the modality of oil and water phase emulsification and the entire production has been studied and discussed. NLC recovery, morphology, dimensional distribution and encapsulation efficiency are presented. PMID- 26952906 TI - Safety of MitraClip Implant in the Unstable Patient: Feasibility of Concomitant Left Ventricular Support Device. PMID- 26952908 TI - Leaflet-to-Annuloplasty Ring Clipping for Severe Mitral Regurgitation. PMID- 26952910 TI - Wait--The Inferior Vena Cava Is Thrombosed? Now What? PMID- 26952909 TI - Inferior Vena Cava Thrombosis. AB - Thrombosis of the inferior vena cava (IVC) is an under-recognized entity that is associated with significant short- and long-term morbidity and mortality. In absence of a congenital anomaly, the most common cause of IVC thrombosis is the presence of an unretrieved IVC filter. Due to the substantial increase in the number of IVC filters placed in the United States and the very low filter retrieval rates, clinicians are faced with a very large population of patients at risk for developing IVC thrombosis. Nevertheless, there is a paucity of data and societal guidelines with regards to the diagnosis and management of IVC thrombosis. This paper aims to enhance the awareness of this uncommon, but morbid, condition by providing a concise, yet comprehensive, review of the etiology, diagnostic approaches, and treatment strategies in patients with IVC thrombosis. PMID- 26952911 TI - Cutaneo-Pericardial Fistula After Transapical Approach for Transcatheter Aortic Valve Replacement. PMID- 26952912 TI - Pre-Hospital Ticagrelor in ST-Segment Elevation Myocardial Infarction? Probably Not. PMID- 26952913 TI - High-grade Neuroendocrine Carcinoma With Focal Squamous Metaplasia of Renal Pelvis Associated With Renal Calculus: Study of a Case. AB - Mixed neuroendocrine and non-neuroendocrine type of tumor in renal pelvis is rare and presents a high-grade malignancy. We present a case report that a 57-year-old man had no history of small cell cancer but presented a high-grade neuroendocrine carcinoma with focal squamous metaplasia and multiple stones simultaneously in the right renal pelvis. The patient underwent nephroureterocystectomy 9 months before this presentation, with evidence of multiple metastatic tumors in various parts of the body. The case of mixed neuroendocrine tumor with stones in the renal pelvis carries a poor prognosis and poses a therapeutic challenge to urologists. PMID- 26952914 TI - A New Induction to the Gene and Cell Therapy Hall Of Fame: Genome Editing. PMID- 26952907 TI - Effect of Pre-Hospital Ticagrelor During the First 24 h After Primary Percutaneous Coronary Intervention in Patients With ST-Segment Elevation Myocardial Infarction: The ATLANTIC-H24 Analysis. AB - OBJECTIVES: The aim of this landmark exploratory analysis, ATLANTIC-H(24), was to evaluate the effects of pre-hospital ticagrelor during the first 24 h after primary percutaneous coronary intervention (PCI) in the ATLANTIC (Administration of Ticagrelor in the cath Lab or in the Ambulance for New ST elevation myocardial infarction to open the Coronary artery) study. BACKGROUND: The ATLANTIC trial in patients with ongoing ST-segment elevation myocardial infarction showed that pre hospital ticagrelor was safe but did not improve pre-PCI coronary reperfusion compared with in-hospital ticagrelor. We hypothesized that the effect of pre hospital ticagrelor may not have manifested until after PCI due to the rapid transfer time (31 min). METHODS: The ATLANTIC-H(24) analysis included 1,629 patients who underwent PCI, evaluating platelet reactivity, Thrombolysis In Myocardial Infarction flow grade 3, >= 70% ST-segment elevation resolution, and clinical endpoints over the first 24 h. RESULTS: Following PCI, largest between group differences in platelet reactivity occurred at 1 to 6 h; coronary reperfusion rates numerically favored pre-hospital ticagrelor, and the degree of ST-segment elevation resolution was significantly greater in the pre-hospital group (median, 75.0% vs. 71.4%; p = 0.049). At 24 h, the composite ischemic endpoint was lower with pre-hospital ticagrelor (10.4% vs. 13.7%; p = 0.039), as were individual endpoints of definite stent thrombosis (p = 0.0078) and myocardial infarction (p = 0.031). All endpoints except death (1.1% vs. 0.2%; p = 0.048) favored pre-hospital ticagrelor, with no differences in bleeding events. CONCLUSIONS: The effects of pre-hospital ticagrelor became apparent after PCI, with numerical differences in platelet reactivity and immediate post-PCI reperfusion, associated with reductions in ischemic endpoints, over the first 24 h, whereas there was a small excess of mortality. (Administration of Ticagrelor in the cath Lab or in the Ambulance for New ST elevation myocardial infarction to open the Coronary artery [ATLANTIC, NCT01347580]). PMID- 26952917 TI - A Perspective on the State of Genome Editing. PMID- 26952919 TI - A CRISPR Approach for Reactivating Latent HIV-1. PMID- 26952918 TI - CRISPR/Cas9 Flexes Its Muscles: In Vivo Somatic Gene Editing for Muscular Dystrophy. PMID- 26952920 TI - Patent Law and Genome Engineering: A Short Guide to a Rapidly Changing Landscape. PMID- 26952921 TI - Circular extinction of plasmonic silver nanocaps and gas sensing. AB - Chiral plasmonic nanostructures exhibit strong rotatory optical activity and are expected to enrich the field of metaoptical materials. Potential applications of chiroplasmonic nanostructures include circular polarizers, optical polarization detectors, asymmetric catalysts, and sensors. However, chiral plasmonic materials require subwavelength structural control and involve laborious chemical or lithographic procedures for their manufacturing. Moreover, strong rotatory activity of subwavelength structures whose chirality was imparted by microfabrication, has been obtained for the red and infrared parts of the spectrum but faces new challenges for the blue and violet spectral ranges even with plasmonic materials with plasmonic bands in the 200-400 nm window. In this study, we address this problem by preparing chiral subwavelength nanostructures by glancing angle sputtering of metallic silver on ZnO nanopillar arrays. Silver deposition in two different planes is a convenient method for preparation of silver chiroplasmonic nanocaps (Ag CPNCs) with controlled asymmetry. Circular dichroism spectroscopy was used to examine the circular extinction for the left handed nanocaps (L-CPNCs) with understanding that not only circular dichroism but also many other optical effects contribute to the amplitude of these bands. The pillared silver films exhibit circular extinction in the violet area of the electromagnetic spectrum. Partial oxidation of Ag to AgxO causes the absorption and corresponding circular extinction band obtained using a conventional CD spectrometer at 400-525 nm to increase and shift. This optical material may be used to detect oxygen and extends the spectrum of application of chiroplasmonic materials to gas sensing. PMID- 26952922 TI - Determination of antazoline and tetrahydrozoline in ophthalmic solutions by capillary electrophoresis and stability-indicating HPLC methods. AB - Capillary electrophoretic (CE) and high performance liquid chromatographic (HPLC) methods were developed and optimized for the determination of antazoline (ANT) and tetrahydrozoline (TET) in ophthalmic formulations. Optimum electrophoretic conditions were achieved using a background electrolyte of 20mM phosphate buffer at pH 7.0, a capillary temperature of 25 degrees C, a separation voltage of 22 kV and a pressure injection of the sample at 50 mbar for 17s. HPLC analysis was performed with Kinetex (150 * 4.6mm ID * 5 MUm) (Phenomenex, USA) analytical column with 1 mL min(-1) flow rate of mobile phase which consisted of 0.05% TFA in bidistilled water (pH adjusted to 3.0 with 5M NaOH) and acetonitrile/buffer in the ratio of 63:37 (v/v) at room temperature. Injection volume of the samples was 10 MUL and the wavelength of the detector was set at 215 nm for monitoring both analytes. Calibration graphs showed a good linearity with a coefficient of determination (R(2)) of at least 0.998 for both methods. Intraday and interday precision (expressed as RSD%) were lower than 2.8% for CE and 0.92% for HPLC. The developed methods were demonstrated to be simple and rapid for the determination of ANT and TET in ophthalmic solutions providing recoveries in the range between 97.9 and 102.70% for CE and HPLC. PMID- 26952923 TI - Novel mutation in SUCLA2 identified on sequencing analysis. AB - Succinate-CoA ligase, ADP-forming, beta subunit (SUCLA2)-related mitochondrial DNA depletion syndrome is caused by mutations affecting the ADP-using isoform of the beta subunit in succinyl-CoA synthase, which is involved in the Krebs cycle. The SUCLA2 protein is found mostly in heart, skeletal muscle, and brain tissues. SUCLA2 mutations result in a mitochondrial disorder that manifests as deafness, lesions in the basal ganglia, and encephalomyopathy accompanied by dystonia. Such mutations are generally associated with mildly increased plasma methylmalonic acid, increased plasma lactate, elevated plasma carnitine esters, and the presence of methylmalonic acid in urine. In this case report, we describe a new mutation in a patient with a succinyl-CoA synthase deficiency caused by an SUCLA2 defect. PMID- 26952924 TI - miR-542-3p inhibits the growth and invasion of colorectal cancer cells through targeted regulation of cortactin. AB - Colorectal cancer is one of the most common malignancies. Previous studies have reported that cortactin (CTTN) is often overexpressed in tumors and is associated with metastasis and poor prognosis of patients. The abnormal expression of microRNAs (miRNAs or miRs) is closely related to the development and progression of various types of cancer, including colorectal cancer. However, little is known about the miRNAs targeting cortactin. In the present study, prediction using biological software revealed that cortactin has binding sites for miR-542-3p. Transfection with miR-542-3p mimic demonstrated that miR-542-3p reduced the expression of cortactin in colorectal cancer cells. Dual luciferase reporter assays further demonstrated that miR-542-3p regulated cortactin in a targeted manner and that miR-542-3p expression was significantly downregulated in colorectal cancer cells. A cell proliferation assay and Transwell migration assay were undertaken: we noted that miR-542-3p inhibited the proliferation and invasion of colorectal cancer cells while promoting their apoptosis. By contrast, cortactin acted antagonistically. When co-transfected with miR-542-3p mimic and CTTN overexpression vector, the inhibitory effect of miR-542-3p was blocked. This indicates that miR-542-3p regulates CTTN in a targeted manner to modulate the growth and invasion of colorectal cancer cells. The present study thus provides new targets for the prevention and treatment of colorectal cancer. PMID- 26952925 TI - Mediastinoscopic tracheal resection and reconstruction under spontaneous breathing anesthesia. PMID- 26952926 TI - Cardiac surgery is evolving, but far from dead. PMID- 26952927 TI - Rules and tools: The impact of policy and consensus statements on sternal infection. PMID- 26952928 TI - Early reperfusion for acute type A dissection complicated with distal malperfusion. PMID- 26952929 TI - Pulmonary valve-sparing techniques during repair of tetralogy of Fallot: The delamination plasty. PMID- 26952930 TI - The cardiac surgery-associated neutrophil gelatinase-associated lipocalin (CSA NGAL) score: A potential tool to monitor acute tubular damage. AB - Acute kidney injury (AKI), defined as a rise in serum creatinine (functional AKI), is a frequent complication after cardiac surgery. The expression pattern of acute tubular damage biomarkers such as neutrophil gelatinase-associated lipocalin (NGAL) has been shown to precede functional AKI and, therefore, may be useful to identify very early tubular damage. The term subclinical AKI represents acute tubular damage in the absence of functional AKI (biomarker positivity without a rise in serum creatinine) and affects hard outcome measures. This potentiates an tubular-damage-based identification of renal injury, which may guide clinical management, allowing for very early preventive-protective strategies. The aim of this paper was to review the current available evidence on NGAL applicability in adult cardiac surgery patients and combine this knowledge with the expert consensus of the authors to generate an NGAL based tubular damage score: The cardiac surgery-associated NGAL Score (CSA-NGAL score). The CSA-NGAL score might be the tool needed to improve awareness and enable interventions to possibly modify these detrimental outcomes. In boldly doing so, it is intended to introduce a different approach in study designs, which will undoubtedly expand our knowledge and will hopefully move the AKI biomarker field forward. PMID- 26952931 TI - Sutureless valves: A future without sutures. PMID- 26952932 TI - High performance Au-Cu alloy for enhanced visible-light water splitting driven by coinage metals. AB - A Au-Cu alloy strategy is, for the first time, demonstrated to be effective in enhancing visible-light photocatalytic H2 evolution via promoting metal interband transitions. Au3Cu/SrTiO3, in which oxidation of Cu was successfully restrained, showed the highest visible-light H2 evolution activity. PMID- 26952933 TI - Relationships between p53 mutation, HPV status and outcome in oropharyngeal squamous cell carcinoma. AB - BACKGROUND AND PURPOSE: This study aimed to examine the rate and type of p53 mutation in oropharyngeal cancer (OSCC). Relationships were sought between human papillomavirus (HPV) status and p53 mutation. The role of p53 mutation as a prognostic factor independent of HPV status and as a modifier of the effect of HPV on outcomes was also examined. METHODS: The HPV status of 202 cases was determined by HPV DNA by RT-PCR and p16 immunohistochemistry. P53 mutation in exon 5-8 was determined by pyrosequencing. Findings were correlated with known clinicopathological factors and outcomes. RESULTS: 48% of the cases were HPV positive and they were significantly less likely to have a p53 mutation than HPV negative OSCCs (25.8% vs 46.7%, p=0.0021). Mutation was most common in exon 5. Among patients with HPV-positive OSCC, there was no significant difference in p53 mutation by smoking status (22.2% for never smokers and 30.8% for current or ex smokers). Patients with p53 mutant OSCC had significantly worse overall survival (p=0.01). There was no statistical evidence that p53 mutation modified the effect of HPV status on outcomes. In the multivariate analysis, positive HPV status remained the strongest predictor of outcomes. p53 mutation status was not a significant predictor of outcome after adjusting for age, gender, T stage, N stage and HPV status. CONCLUSIONS: In summary, HPV-positive OSCC are less likely to have mutant p53 than HPV-negative OSCC. Our study did not show any evidence that p53 mutation could modify the effect of HPV status on outcomes. PMID- 26952937 TI - Et tu bipolar II? PMID- 26952934 TI - High throughput physiological screening of iPSC-derived cardiomyocytes for drug development. AB - Cardiac drug discovery is hampered by the reliance on non-human animal and cellular models with inadequate throughput and physiological fidelity to accurately identify new targets and test novel therapeutic strategies. Similarly, adverse drug effects on the heart are challenging to model, contributing to costly failure of drugs during development and even after market launch. Human induced pluripotent stem cell derived cardiac tissue represents a potentially powerful means to model aspects of heart physiology relevant to disease and adverse drug effects, providing both the human context and throughput needed to improve the efficiency of drug development. Here we review emerging technologies for high throughput measurements of cardiomyocyte physiology, and comment on the promises and challenges of using iPSC-derived cardiomyocytes to model disease and introduce the human context into early stages of drug discovery. This article is part of a Special Issue entitled: Cardiomyocyte biology: Integration of Developmental and Environmental Cues in the Heart edited by Marcus Schaub and Hughes Abriel. PMID- 26952938 TI - Hypertension, vascular cognitive disorders and neuroprotection. AB - OBJECTIVE: The role of the antihypertensive therapy in preventing vascular cognitive disorders in elderly persons without a history of stroke is a matter of debate. This review focuses on cognitive disorders in elderly hypertensive patients. METHODS: Relevant papers were identified by searches in PubMed from 1946 until February 2007 using the keywords 'cerebral blood flow autoregulation', 'vascular cognitive disorders', 'neuroimaging in hypertension', 'antihypertensive treatment' and 'neuroprotection in cerebral ischemia'. RESULTS: Excessive blood pressure lowering in patients with long-standing hypertension may increase the risk of cerebral hypoperfusion, white matter lesions and consequent cognitive decline. White matter lesions have been found in the majority of patients with long-standing hypertension. They correlate with vascular cognitive disorders, particularly impairments of attention and executive function, while memory is relatively preserved. Cerebral small vessel disease in elderly patients should be taken into account when antihypertensive treatment is considered. Renin angiotensin blockade, some calcium channel blockers and statins are thought to possess neuroprotective action. CONCLUSION: For prevention of cerebral hypoperfusion in elderly hypertensives blood pressure lowering should be cautiously controlled. The increased risk of white matter lesions is an indication for early neuroprotection. The combination of renin-angiotensin blockade or calcium channel blockers with statins may become a promising preventive strategy against cognitive decline in elderly hypertensives. Cerebral white matter protection is a future challenge. PMID- 26952939 TI - The perception of emotional facial expressions in stroke patients with and without depression. AB - BACKGROUND: Emotion perception may be impaired after stroke. No study on emotion perception after stroke has taken the influence of post-stroke depressive symptoms into account, although depressive symptoms themselves may hamper emotion perception. OBJECTIVE: To compare the perception of emotional facial expressions in stroke patients with and without depressive symptoms. METHODS: Twenty-two stroke patients participated whose depressive symptoms were classified using the Montgomery-Asberg Depression Rating Scale (cutoff = 10) and who were compared with healthy controls. Emotion recognition was measured using morphed images of facial expressions. RESULTS: Patients with depressive symptoms performed worse than controls on all emotions; patients without depressive symptoms performed at control level. Patients with depressive symptoms were less sensitive to the emotions anger, happiness and sadness compared with patients without depressive symptoms. CONCLUSIONS: Post-stroke depressive symptoms impair emotion perception. This extends findings in bipolar disorder indicating that emotion perception deficits are strongly related to the level of depression. PMID- 26952936 TI - Epigenetic response to environmental stress: Assembly of BRG1-G9a/GLP-DNMT3 repressive chromatin complex on Myh6 promoter in pathologically stressed hearts. AB - Chromatin structure is determined by nucleosome positioning, histone modifications, and DNA methylation. How chromatin modifications are coordinately altered under pathological conditions remains elusive. Here we describe a stress activated mechanism of concerted chromatin modification in the heart. In mice, pathological stress activates cardiomyocytes to express Brg1 (nucleosome remodeling factor), G9a/Glp (histone methyltransferase), and Dnmt3 (DNA methyltransferase). Once activated, Brg1 recruits G9a and then Dnmt3 to sequentially assemble repressive chromatin-marked by H3K9 and CpG methylation-on a key molecular motor gene (Myh6), thereby silencing Myh6 and impairing cardiac contraction. Disruption of Brg1, G9a or Dnmt3 erases repressive chromatin marks and de-represses Myh6, reducing stress-induced cardiac dysfunction. In human hypertrophic hearts, BRG1-G9a/GLP-DNMT3 complex is also activated; its level correlates with H3K9/CpG methylation, Myh6 repression, and cardiomyopathy. Our studies demonstrate a new mechanism of chromatin assembly in stressed hearts and novel therapeutic targets for restoring Myh6 and ventricular function. The stress induced Brg1-G9a-Dnmt3 interactions and sequence of repressive chromatin assembly on Myh6 illustrates a molecular mechanism by which the heart epigenetically responds to environmental signals. This article is part of a Special Issue entitled: Cardiomyocyte Biology: Integration of Developmental and Environmental Cues in the Heart edited by Marcus Schaub and Hughes Abriel. PMID- 26952940 TI - Pain perception in patients with bipolar disorder and schizophrenia. AB - OBJECTIVE: Pain perception is reported to be altered in patients with depression and schizophrenia. However, few studies have investigated the pain perception in patients with bipolar disorders. We therefore aimed to compare pain sensitivity between patients with bipolar disorder, schizophrenia and controls. METHODS: Study groups consisted of 30 patients with bipolar disorder, and control groups consisted of 27 patients with schizophrenia and 59 healthy subjects. Pain perception was assessed with cold pressor test (CPT) by exposure to ice-water. RESULTS: Patients with schizophrenia had significantly higher pain thresholds (PTh) than patients with bipolar disorder. There were no differences between the PTh of patients with schizophrenia and healthy control subjects. However, patients with bipolar disorder had significantly lower pain tolerance (PT) in the CPT than patients with schizophrenia and corresponding healthy control subjects. CONCLUSIONS: The higher PTh in the schizophrenia group compared with the bipolar group found in this study supports further investigation of a potential difference in the pain perception between patients with schizophrenia and bipolar disorder. Theoretical implications of these findings and possible relevant behavioural and neurochemical mechanisms are discussed. PMID- 26952941 TI - Combined treatment with reboxetine in depressed patients with no response to venlafaxine: a 6-week follow-up study. AB - OBJECTIVE: The purpose of present study was to evaluate the efficacy of the addition of reboxetine in patients that had not previously responded, or had done so only partially, over 6 weeks of conventional pharmacological treatment with venlafaxine. METHODS: This open-label, prospective and multicentric study included 40 outpatients diagnosed with major depressive disorder according to the DSM-IV criteria. Efficacy was assessed using the 21-item Hamilton Depression Rating Scale (HAMD) and the Clinical Global Impression-Improvement (CGI-I). Safety was evaluated by recording spontaneously reported adverse events. Data were analysed on an intent-to-treat basis, using the last-observation-carried forward method. RESULTS: Mean HAMD reduction was 34.9% (P < 0.0001). The percentages of responders (>=50% reduction in HAMD) and patients considered as benefiting from complete remission (HAMD <= 10 points) at week 6 were 27.5 and 12.5%, respectively. By the end of the treatment, the score of CGI-I decreased 24.8% (P < 0.0001). Percentage of patient improving (CGI < 4 points) was 47.5%. The most common non-serious adverse events were constipation, nervousness, anxiety and insomnia. CONCLUSION: These findings suggest that the combined treatment of reboxetine and venlafaxine, in venlafaxine-resistant patients, may be an effective and well-tolerated strategy. PMID- 26952935 TI - Interplay between cardiac function and heart development. AB - Mechanotransduction refers to the conversion of mechanical forces into biochemical or electrical signals that initiate structural and functional remodeling in cells and tissues. The heart is a kinetic organ whose form changes considerably during development and disease. This requires cardiomyocytes to be mechanically durable and able to mount coordinated responses to a variety of environmental signals on different time scales, including cardiac pressure loading and electrical and hemodynamic forces. During physiological growth, myocytes, endocardial and epicardial cells have to adaptively remodel to these mechanical forces. Here we review some of the recent advances in the understanding of how mechanical forces influence cardiac development, with a focus on fluid flow forces. This article is part of a Special Issue entitled: Cardiomyocyte Biology: Integration of Developmental and Environmental Cues in the Heart edited by Marcus Schaub and Hughes Abriel. PMID- 26952942 TI - Heroin-dependent patients attempting and not attempting suicide: a comparison. AB - OBJECTIVE: Heroin dependence is a serious illness associated with an increased risk of suicidal behaviour. There are many risk factors associated with heroin dependence. The current study examined the sociodemographic and clinical characteristics of a number of young adult heroin-dependent patients who had attempted suicide. METHODS: We studied a group of 108 young adult heroin dependent patients in our in-patient clinics. All diagnoses were made according to DSM-IV diagnostic criteria using the Structured Clinical Interview for DSM-IV Axis I-II Disorders (SCID-I, II). The age range of patients was 18-24 years. Their substance abuse histories were assessed by semistructured interview. The Addiction Severity Index (ASI) was administered to all the patients. Serum total cholesterol and high-density lipoprotein cholesterol (HDL-C) levels were routinely measured. In the statistical analyses, Student's t test, and chi squared tests were applied. RESULTS: Of the 108 heroin-dependent patients, 40 (37.0%) had histories of attempted suicide. There was a statistically significant difference in the age at which heroin use had commenced between female attempters [mean = 16.82, standard deviation (SD) = 3.06] and nonattempters (mean = 18.32, SD = 2.68, t= 2.25, P < 0.05). Both the male (mean = 33.35, SD = 4.05) and the female (mean = 28.00, SD = 5.36) attempters had significantly higher ASI scores than did the male (mean = 20.16, SD = 3.80) and the female (mean = 18.88, SD = 4.14) nonattempters (t= 14.34, P < 0.001; t= 5.25, P < 0.001, respectively). A significant difference in total cholesterol (mean = 131.8, SD = 19.3; mean = 172.2, SD = 21.3, t= 3.9, P < 0.05) and HDL-C (mean = 30.9, SD = 1.0 and mean = 54.8, SD = 13.7; t= 5.1, P < 0.05) levels between the group of violent and nonviolent suicide attempters was revealed. CONCLUSIONS: These results suggest that suicide attempts in young adult heroin-dependent patients are associated with more profound biopsychosocial pathology and decreased serum cholesterol levels. In particular, low levels of total cholesterol and HDL-C might indeed be associated with violent suicide attempts in young heroin-dependent patients. PMID- 26952943 TI - The validity of the 21-item version of the Depression Anxiety Stress Scales as a routine clinical outcome measure. AB - OBJECTIVE: This study aimed to test the validity of the 21-item Depression Anxiety Stress Scales (DASS-21) as a routine clinical outcome measure in the private in-patient setting. We hypothesized that it would be a suitable routine outcome instrument in this setting. METHOD: All in-patients treated at a private psychiatric hospital over a period of 24 months were included in the study. Data were collected on demographics, service utilization, diagnosis and a set of four routine measures both at admission and discharge. These measures consisted of the Clinical Global Impressions (CGI) scales, Health of the Nation Outcome Scales (HoNOS), the Mental Health Questionnaire (MHQ-14) and DASS-21. The results of these measures were compared. RESULTS: Of 786 admissions in total, the number of fully completed (ie paired admission and discharge) data sets for the DASS-21 depression, anxiety and stress subscales were 337, 328 and 347, respectively. All subscales showed statistically significant reductions in mean scores from admission to discharge (P < 0.001) and were significantly correlated with all MHQ 14 subscales and significantly related to CGI scale categories. The total DASS-21 and total HoNOS scores were also significantly correlated. CONCLUSIONS: The findings from the present study support the validity of DASS-21 as a routine clinical outcome measure in the private in-patient setting. PMID- 26952944 TI - Recurring deja vu associated with 5-hydroxytryptophan. AB - BACKGROUND: Deja vu occurs both in normal experience and as a neuropsychiatric symptom. Its pathogenesis is partially understood. We describe an iatrogenic case with implications for the neuropharmacological basis of deja vu. CASE PRESENTATION: A 42-year-old woman received 5-hydroxytryptophan, in combination with carbidopa, as treatment for palatal tremor, on two occasions, separated by 1 week. On each occasion, she experienced intense, protracted deja vu, lasting for several hours. We discuss her case in relation to the neuroanatomical and neuropharmacological basis of deja vu. CONCLUSION: The serotonergic system is involved in the genesis of deja vu. PMID- 26952946 TI - Progress in chemoradiotherapy-induced nausea and vomiting. PMID- 26952945 TI - Efficacy and safety of fosaprepitant for the prevention of nausea and emesis during 5 weeks of chemoradiotherapy for cervical cancer (the GAND-emesis study): a multinational, randomised, placebo-controlled, double-blind, phase 3 trial. AB - BACKGROUND: The role of the neurokinin-1 (NK-1) receptor antagonists in the prevention of radiation-induced nausea and vomiting has not been established. The purpose of the GAND-emesis study was to investigate the efficacy and safety of fosaprepitant in combination with palonosetron and dexamethasone in the prevention of nausea and vomiting during 5 weeks of fractionated radiotherapy and concomitant weekly cisplatin in patients with cervical cancer. METHODS: This investigator initiated, multinational, randomised, double-blind, placebo controlled phase 3 trial, included women with cervical cancer scheduled to receive fractionated radiotherapy and weekly cisplatin 40 mg/m(2) for 5 weeks. Patients had to be naive to chemotherapy and radiotherapy. Patients were randomly assigned to receive either single doses of fosaprepitant 150 mg intravenously or placebo (saline) in combination with palonosetron 0.25 mg intravenously and dexamethasone 16 mg orally before cisplatin administration. Randomisation was done by the unmasked pharmacist, who used a list of six numbers (a block) provided in a sealed envelope. A web-based randomisation number generator was used to generate the full list of randomisation numbers that was split up in blocks of six numbers. All patients received oral dexamethasone 8 mg twice a day on day 2, 4 mg twice a day on day 3, and 4 mg once on day 4. The treatment was repeated for 5 weeks. The primary endpoint was the proportion of patients with sustained no emesis after 5 weeks of treatment. The modified intention-to-treat population (all patients who received study medication) was used for the statistical analyses. The study was registered with ClinicalTrials.gov, number NCT01074697. FINDINGS: Between June 15, 2010, and March 8, 2015, 246 patients from four countries consented to the study and were randomly assigned. Of these, 234 patients were eligible, having received study medication (118 received fosaprepitant, 116 received placebo). The proportion of patients with sustained no emesis at 5 weeks (competing risk analysis) was 48.7% (95% CI 25.2-72.2) for the placebo group compared with 65.7% (42.2-89.2) of patients for the fosaprepitant group. There was a significantly lower cumulative risk of emesis in the fosaprepitant group compared with the placebo group (subhazard ratio 0.58 [95% CI 0.39-0.87]; p=0.008). Treatments were generally well tolerated with few grade 3 adverse events none of which were related to the study treatment; the most common grade 3 adverse event during the 5 weeks of treatment was diarrhoea (11 [9%] of 118 patients in the fosaprepitant group vs six [5%] of 116 patients in the placebo group). There was only one report of a grade 4 adverse event (neutropenia), in the fosaprepitant group. No deaths were recorded in either group. INTERPRETATION: To our knowledge, this is the first study to investigate safety and efficacy of a NK-1 receptor antagonist during 5 weeks of radiotherapy and concomitant weekly cisplatin. Patients receiving fosaprepitant in addition to palonosetron and dexamethasone were less likely to experience emesis and nausea compared with those receiving palonosetron and dexamethasone alone. Both treatments were safe and well tolerated. Further investigations in other radiotherapy settings are warranted. FUNDING: Private and hospital or university funding, unrestricted grants from Biovitrum and Helsinn Healthcare SA. PMID- 26952948 TI - Neuropeptide Y: a promising candidate in affective disorders. PMID- 26952947 TI - Spectrum-dose conversion operator of NaI(Tl) and CsI(Tl) scintillation detectors for air dose rate measurement in contaminated environments. AB - Spectrum-dose conversion operators, the G(E) functions, for common NaI(Tl) scintillation survey meters and CsI(Tl) detectors are obtained for measurements in a semi-infinite plane of contaminated ground field by photon-emitting radionuclides (ground source). The calculated doses at a height of 100 cm from the ground in 137Cs-contaminated environments by the Monte Carlo simulation technique are compared with those obtained using the G(E) functions by assuming idealized irradiation geometries such as anterior-posterior or isotropic. The simulation reveals that one could overestimate air dose rates in the environment by a maximum of 20-30% for NaI(Tl) detectors and 40-50% for CsI(Tl) detectors depending on photon energy when using the G(E) functions assuming idealized irradiation geometries for ground source measurements. Measurements obtained after the nuclear accident in Fukushima reveal that the doses calculated using a G(E) function for a unidirectional irradiation geometry are 1.17 times higher than those calculated using a G(E) function for the ground source in the case of a CsI(Tl) scintillation detector, which has a rectangular parallelepiped crystal (13 * 13 * 20 mm3). However, if a G(E) function is used assuming irradiation to a surface of the detector, the doses agree with those of the ground source within 2%. These results indicate that in contaminated environments, the commonly used scintillation-based detectors overestimate doses within the acceptable limit. In addition, the degree of overestimation depends on the irradiation direction of each detector assumed for developing the G(E) function. With regard to directional dependence of the detectors, reliable air dose rates in the environment can be obtained using the G(E) function determined in unidirectional irradiation geometry, provided that the irradiation surface of the crystal is determined properly. PMID- 26952949 TI - The neurocognition of alexithymia: evidence from neuropsychological and neuroimaging studies. AB - OBJECTIVE: Alexithymia refers to an ineffective regulation and expression of emotions. It constitutes a major risk factor for a range of medical and psychiatric problems, including chronic pain, somatisation, anxiety and depression. Alexithymia is a multi-faceted concept, described in terms of cognitive and affective aspects. From a neuropsychological perspective, alexithymia can be defined as a disturbance in affective information processing and social cognition. As the growing literature on brain structures involved in alexithymia is fragmented and sometimes even contradictory, the aim of this article was to review findings on neural substrates with regard to their convergence. METHODS: A narrative review was performed, including both early neuropsychological and more recent imaging studies, in order to achieve a better understanding of the aetiology of alexithymia. RESULTS: Corpus callosum, cingulate cortex and insula are clearly involved in alexithymia. The amygdala and the orbitofrontal part of the cortex appear to be implicated as mediators, because of their broader involvement in emotional processing and executive control. CONCLUSION: Notwithstanding the diffuse neural representation, the alexithymia construct can be usefully applied in the clinical and empirical studies of social cognition, particularly when adopting a dimensional neuropsychological approach. PMID- 26952951 TI - Increased susceptibility of mitochondria isolated from frontal cortex and hippocampus of vitamin A-treated rats to non-aggregated amyloid-beta peptides 1 40 and 1-42. AB - OBJECTIVE: Vitamin A is a redox-active molecule and its inadvertent utilisation as a preventive therapy against ageing or neurodegeneration has become a harmful habit among humans at different ages. Mitochondrial dysfunction and redox impairment may be induced by vitamin A supplementation experimentally. Nonetheless, it is still not clear by which mechanisms vitamin A elicits such effects. Then, we performed this investigation to analyse whether mitochondria isolated from frontal cortex and hippocampus of vitamin A-treated rats are more sensitive to a challenge with amyloid-beta (Abeta) peptides 1-40 or 1-42. METHODS: Adult Wistar rats received vitamin A at 1000-9000 IU/kg/day orally for 28 days. Then, mitochondria were isolated and the challenge with Abeta peptides 1 40 or 1-42 (at 0.2 or 0.1 MUM, respectively) for 10 min was carried out before mitochondrial electron transfer chain enzyme activity, superoxide anion radical (O2 -*) production and 3-nitrotyrosine content quantification. RESULTS: Mitochondria obtained from vitamin A-treated rats are more sensitive to Abeta peptides 1-40 or 1-42 than mitochondria isolated from the control group, as decreased mitochondrial complex enzyme activity and increased O2 -* production and 3-nitrotyrosine content were observed in incubated mitochondria isolated from vitamin A-treated rats. CONCLUSION: These data suggest that oral intake of vitamin A at clinical doses increases the susceptibility of mitochondria to a neurotoxic agent even at low concentrations. PMID- 26952950 TI - Association of the leucine-7 to proline-7 variation in the signal sequence of neuropeptide Y with major depression. AB - OBJECTIVE: There is clear evidence of a genetic component in major depression, and several studies indicate that neuropeptide Y (NPY) could play an important role in the pathophysiology of the disease. A well-known polymorphism encoding the substitution of leucine to proline in the signal peptide sequence of NPY (Leu7Pro variation) was previously found to protect against depression. Our study aimed at replicating this association in a large Danish population with major depression. METHOD: Leu7Pro was studied in a sample of depressed patients and ethnically matched controls, as well as psychiatric disease controls with schizophrenia. Possible functional consequences of Leu7Pro were explored in vitro. RESULTS: In contrast to previous studies, Pro7 appeared to be a risk allele for depression, being significantly more frequent in the depression sample (5.5%, n = 593; p = 0.009; odds ratio, OR: 1.46) as compared to ethnically matched controls (3.8%, n = 2912), while schizophrenia patients (4.1%, n = 503) did not differ. In vitro, the Pro7 substitution appeared to be associated with reduced levels of NPY without affecting its mRNA level. CONCLUSION: The Leu7Pro variation may increase the risk of major depression, possibly by affecting the biosynthesis of NPY. PMID- 26952952 TI - Cigarette smoking, coffee intake and alcohol consumption preceding Parkinson's disease: a case-control study. AB - OBJECTIVE: A case-control study was performed in Belgrade in order to investigate the association between Parkinson's disease (PD) and smoking, coffee and alcohol consumption. METHODS: During the period 2001-2005, 110 new PD cases and 220 hospital controls were interviewed. Cases and controls were matched by sex, age and place of residence (urban/rural). For the analysis of data conditional univariate and multivariate logistic regression methods were used. RESULTS: With PD were associated, independently from each other, current smoking [odds ratio (OR) = 0.44; 95% confidence interval (CI) = 0.23-0.82], alcohol consumption (OR = 4.78; 95% CI = 2.67-8.55) and coffee consumption (OR = 2.54; 95% CI = 1.36-4.75). In ever smokers the risk for PD significantly decreased with the increasing number of cigarettes smoked and with increasing duration of smoking. The risk for PD significantly increased with the increasing quantity of alcohol consumption. PD risk was significantly higher in subjects whose average daily consumption of coffee was 1 and 2-3 cups, and it was lower (but not significantly) in those whose daily coffee consumption was 4+ cups. Cases and controls did not differ in duration of alcohol and coffee consumption. The results of multivariate analyses did not substantially change after adjustment on family history positive on PD. CONCLUSION: The findings of this study support the hypotheses of inverse association of smoking with PD, but an inverse association with coffee was not confirmed. PD was found to be positively associated with coffee and alcohol consumption. PMID- 26952953 TI - Brain energy metabolism is increased by chronic administration of bupropion. AB - OBJECTIVES: Based on the hypothesis that energy impairment may be involved in the pathophysiology of depression, we evaluated the activities of citrate synthase, malate dehydrogenase, succinate dehydrogenase (SDH), mitochondrial respiratory chain complexes I, II, II-III, IV and creatine kinase (CK) in the brain of rats submitted to chronic administration of bupropion. METHODS: Animals received daily administration of bupropion dissolved in saline (10 mg/kg, intraperitoneal) at 1.0 ml/kg body weight. The rats received injections once a day for 14 days; control rats received an equivalent volume of saline. Twelve hours after the last administration, the rats were killed by decapitation and brain was rapidly removed and kept on an ice plate. The activities of the enzymes were measured in different brain areas. RESULTS: We observed that the activities of citrate synthase and malate dehydrogenase, mithocondrial respiratory chain complexes I, II-III and IV and CK were not altered after chronic administration of bupropion. However, SDH activity was increased in the prefrontal cortex and cerebellum. In the hippocampus, cerebellum and striatum the activity of complex II was increased after chronic administration of bupropion. CONCLUSIONS: Our results demonstrated that bupropion increased some enzymes of brain energy metabolism. These findings are in accordance with other studies which showed that some antidepressants may improve energy metabolism. The present results reinforce the hypothesis that antidepressants modulate brain energy metabolism. PMID- 26952954 TI - Clozapine-induced palilalia?. AB - INTRODUCTION: Palilalia is an acquired speech disorder characterised by involuntary and spontaneous repetition of words or phrases two or more times in a row. It can occur in a variety of disorders including postencephalic parkinsonism, pseudobulbar palsy, schizophrenia, Gilles de la Tourette syndrome and others. CLINICAL CASE: We describe a case of a 28-year-old man with refractory schizophrenia that developed palilalia with 300 mg of clozapine. In the patient evaluation we found unspecific alterations in the electroencephalogram, with normal blood tests and cerebral magnetic resonance imaging. Palilalia disappeared with lowering doses of clozapine. DISCUSSION: The appearance of palilalia induced by clozapine is a rare pharmacologic side-effect which physicians should be familiarised with when evaluating this symptom presentation. PMID- 26952955 TI - Expression and function of HSP110 family in mouse testis after vasectomy. AB - HSP110 functions to protect cells, tissues, and organs from noxious conditions. Vasectomy induces apoptosis in the testis; however, little is known about the reason leading to this outcome. The aim of the present study was to evaluate the expression and function of HSP110 in mouse testis after vasectomy. Following bilateral vasectomy, we used fluorescent Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) to detect apoptosis, Western blotting and immunohistochemistry to examine HSP110 expression and localization. Serum antisperm antibody (AsAb) and testosterone were measured by Enzyme-linked immunosorbent assay (ELISA) and radioimmunoassay, respectively. Expression of endoplasmic reticulum stress (ERS) sensors and downstream signaling components was measured by Reverse Transcription-Polymerase Chain Reaction (RT-PCR), and the phosphorylation of eIF2alpha and JNK was detected by Western blotting. Vasectomy induced morphologic changes, increased apoptosis in the testis, increased serum AsAb, and decreased testosterone levels. After vasectomy, ORP150 mRNA level was increased first and then decreased, Bcl-2 was decreased, and the expression of HSPA4l, GRP78, GADD153, PERK, ATF6, IRE-1, XBP-1s, Bax, Bak, and caspases and the phosphorylation of eIF2alpha and JNK were increased. We present that an ER stress mediated pathway is activated and involved in apoptosis in the testis after vasectomy. HSPA4l and ORP150 may play important roles in maintaining the normal structure and function of testis. PMID- 26952956 TI - An overview of the management of post-vasectomy pain syndrome. AB - Post-vasectomy pain syndrome remains one of the more challenging urological problems to manage. This can be a frustrating process for both the patient and clinician as there is no well-recognized diagnostic regimen or reliable effective treatment. Many of these patients will end up seeing physicians across many disciplines, further frustrating them. The etiology of post-vasectomy pain syndrome is not clearly delineated. Postulations include damage to the scrotal and spermatic cord nerve structures via inflammatory effects of the immune system, back pressure effects in the obstructed vas and epididymis, vascular stasis, nerve impingement, or perineural fibrosis. Post-vasectomy pain syndrome is defined as at least 3 months of chronic or intermittent scrotal content pain. This article reviews the current understanding of post-vasectomy pain syndrome, theories behind its pathophysiology, evaluation pathways, and treatment options. PMID- 26952959 TI - The importance of actively involving partners in oncofertility discussions. PMID- 26952957 TI - Male infertility: lifestyle factors and holistic, complementary, and alternative therapies. AB - While we may be comfortable with an allopathic approach to male infertility, we are also responsible for knowledge about lifestyle modifications and holistic, complementary, and alternative therapies that are used by many of our patients. This paper provides an evidence-based review separating fact from fiction for several of these therapies. There is sufficient literature to support weight reduction by diet and exercise, smoking cessation, and alcohol moderation. Supplements that have demonstrated positive effects on male fertility on small randomized controlled trial (RCT) include aescin, coenzyme Q 10 , glutathione, Korean red ginseng, L-carnitine, nigella sativa, omega-3, selenium, a combination of zinc and folate, and the Menevit antioxidant. There is no support for the use of Vitamin C, Vitamin E, or saffron. The data for Chinese herbal medications, acupuncture, mind-body practice, scrotal cooling, and faith-based healing are sparse or inconclusive. PMID- 26952958 TI - Cavernous nerve reconstruction with autologous vein graft and platelet-derived growth factors. AB - In this study, we investigated the feasibility of using autologous vein graft and platelet-derived growth factors to bridge transected cavernous nerve in a rat model. A short defect in the bilateral cavernous nerve was created and repaired with vein graft from the right jugular vein or vein graft plus platelet-derived growth factors. The 32 rats were divided into four groups, namely Group 1 - no repair as a negative control, Group 2 - vein graft alone, Group 3 - vein graft plus platelet-derived growth factors, and Group 4 - sham operation as a positive control. We evaluated nerve regeneration and functional recovery using retrograde tracing study with FluoroGold, Toluidine blue staining of cavernous nerve, and the intracavernous pressure at 3 months. Three months after surgery, rich FluoroGold-positive cells were observed in the sham and vein graft plus platelet derived growth factors group, but very few were found in the no repair group. The number of myelinated axons of regenerated cavernous nerve and intracavernous pressure were increased obviously in the two vein graft groups, especially in the vein graft plus platelet-derived growth factors group. These findings confirm the feasibility of using autologous vein as guides for cavernous nerve regeneration, and the regeneration can be further enhanced when the vein is filled with platelet-derived growth factors. PMID- 26952960 TI - Association of tracheal mucus or blood and airway neutrophilia with racing performance in Thoroughbred horses in an Australian racing yard. AB - OBJECTIVES: To determine the variation of tracheal mucus scores, tracheal blood scores and transendoscopic tracheal wash (TW) cytology in a population of Thoroughbred (TB) racehorses and assess their association with racing performance. METHODS: A total of 220 endoscopic examinations were performed and TWs obtained from 155 TB racehorses. Samples were collected 60-120 min following gallop work. Tracheal mucus score, tracheal blood score and TW cytology were analysed and their association with racing performance assessed. RESULTS: Of the total examinations and samples, 194 from 135 horses fitted the criteria for inclusion. The overall prevalence of visible tracheal mucus was 2.5% (5/194) and of increased tracheal mucus was 0%. The prevalence of visible tracheal blood was 8.8% (17/194) and of increased tracheal blood was 4.6% (9/194). A total of 36% (70/194) of TWs contained elevated percentages of neutrophils and of these, 96% (67/70) occurred in the absence of any visible tracheal mucus. There was no significant association between tracheal mucus score or TW cytology and subsequent racing performance. There was a statistically significant association (P = 0.004) between increased tracheal blood scores and poor racing performance. CONCLUSIONS: Visible tracheal blood seen after strenuous exercise in clinically normal TB racehorses was a risk factor for poor racing performance, but the presence of airway neutrophilia was not. No horses in this study were found to have increased tracheal mucus, so the association of increased tracheal mucus with racing performance could not be assessed. PMID- 26952961 TI - Physical connections between different SSVEP neural networks. AB - This work investigates the mechanism of the Steady-State Visual Evoked Potential (SSVEP). One theory suggests that different SSVEP neural networks exist whose strongest response are located in different frequency bands. This theory is based on the fact that there are similar SSVEP frequency-amplitude response curves in these bands. Previous studies that employed simultaneous stimuli of different frequencies illustrated that the distribution of these networks were similar, but did not discuss the physical connection between them. By comparing the SSVEP power and distribution under a single-eye stimulus and a simultaneous, dual-eye stimulus, this work demonstrates that the distributions of different SSVEP neural networks are similar to each other and that there should be physical overlapping between them. According to the band-pass filter theory in a signal transferring channel, which we propose in this work for the first time, there are different amounts of neurons that are involved under repetitive stimuli of different frequencies and that the response intensity of each neuron is similar to each other so that the total response (i.e., the SSVEP) that is observed from the scalp is different. PMID- 26952962 TI - Children's Discourse of Liked, Healthy, and Unhealthy Foods. AB - BACKGROUND: Food literacy and nutrition education from kindergarten to 12th grade is a recommended strategy to address obesity prevention. However, limited research has explored children's understanding and conceptualization of food and healthy eating to inform the development of curricula and messaging strategies. OBJECTIVE: To explore and identify patterns and themes regarding how children discuss and describe food and healthy eating. DESIGN: Focus groups were conducted during which children were asked to identify and describe foods they liked and perceived as healthy and unhealthy. To triangulate findings, children also completed written worksheets on which they identified and described foods. Discourse analysis was used to code and interpret data by focusing on the language children used in relation to different types of food. PARTICIPANTS/SETTING: Seven focus groups were held with children in grades 3 through 7 (n=38) from one rural community. RESULTS: Analysis indicated four main themes. Children used a heuristic based on major food groups to determine healthfulness, did not strongly connect health values with liked foods and foods perceived as unhealthy, expressed that taste, texture, and visual appeal primarily shaped likeability, and associated liked foods with positive home and family experiences. CONCLUSIONS: Children's descriptions of liked and unhealthy foods were largely disconnected from health values and connected to taste and familiarity. Nutrition education should expand strategies beyond promotion of health benefits to include taste and sociocultural familiarity. PMID- 26952963 TI - How Community Food Banks Support School Breakfast: Strategies Used and Lessons Learned. PMID- 26952964 TI - Detection of homologous recombination in closely related strains. AB - Detection of recombination events in a bacterial genome is both important from the evolutionary point of view, and of practical interest. Indeed, homologous recombination (HR) plays a major role in the exchange of antigenic determinants between strains. There exist statistical methods to detect recently recombined segments in whole-genome sequences that use a high local density of substitutions as a signal of HR events with a source outside considered strains. However, it is difficult to detect the HR events within a set of strains, which represent whole species diversity, due to a low number of substitutions in recombined segments and high level of diversity of strains. Here, we analyzed HR in 20 Escherichia coli (E. coli) strains to define what fraction of segments with a high substitution rate were introduced in a genome by HR. For detection of HR, we used the segmentation, performed by the adaptive weights smoothing (AWS) algorithm. It detects sharp changes in the structure of observed data analyzing only qualitative structural information. We validated the approach on simulated data, applied it to the analysis of E. coli strains, and determined the recombination rates between phylogroups. PMID- 26952965 TI - Involvement of miR-539-5p in the inhibition of de novo lipogenesis induced by resveratrol in white adipose tissue. AB - The epigenetic mechanisms of action of resveratrol as an anti-obesity molecule have not been fully addressed so far. The aim of the present study was to assess changes produced by resveratrol in the microRNA (miRNA) profile in white adipose tissue (WAT) and to relate these changes to those induced in the expression of genes involved in triacylglycerol metabolism. Male Wistar rats were fed (6 weeks) an obesogenic diet: a control group and a group treated with resveratrol (30 mg kg(-1) d(-1)). A miRNA microarray was carried out in perirenal adipose tissue. The overexpression of miR-539-5p and miR-1224-5p was performed in 3T3-L1 cells. Protein expression was analysed by western-blot and gene expression by qRT-PCR. Associations between variables were assessed by Pearson's correlations. The microarray showed that 3 miRNAs were decreased and 13 were increased after resveratrol treatment. Among those miRNAs increased, miR-129, miR-328-5p and miR 539-5p showed predicted target genes relevant for triacylglycerol metabolism in WAT (ppargamma: peroxisome proliferator-activated receptor gamma, hsl: hormone sensitive lipase and sp1: SP1 transcription factor) in the miRWalk database. Moreover, the literature shows that miR-1224, another miRNA up-regulated by resveratrol, can also regulate sp1. Among the three targets, only SP1 showed a reduction in protein expression. Correlation and overexpression studies revealed that the decrease in SP1 protein expression was only associated with the increase of miR-539-5p. In addition, significant reductions in SREBP1 protein expression and fasn gene expression were found in resveratrol-treated rats. In conclusion, the up-regulation of miR-539-5p is involved in the inhibition of de novo lipogenesis induced by resveratrol in WAT. PMID- 26952966 TI - Effect of Combination of Chinese Herbal Medicine versus Western Medicine on Mortality in Patients after Cardiopulmonary Resuscitation: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. AB - Introduction. Although Chinese herbal medicine (CHM) treatment combined with conventional western therapy has been widely used and reported in many clinical trials in China, there is uncertainty about the efficacy of this combination in the treatment of patients after cardiopulmonary resuscitation (CPR). This systematic review aimed to assess whether the risk of mortality has decreased comparing the combination of CHM treatment with conventional western therapy. Methods. To identify relevant studies, the literature search was conducted in Medline, Embase, the Cochrane Library, CBM, CNKI, VIP, and Wanfang database. We included all randomized controlled trials (RCTs) that compared outcomes of patients after CPR taking combination of CHM treatment with those taking just conventional western therapy. Results. This meta-analysis showed that patients randomly assigned to combined CHM treatment group had a statistically significant 23% reduction in mortality compared with those randomly assigned to conventional western therapy group (RR: 0.77; 95% CI: 0.70-0.84). Conclusions. This meta analysis provides evidence suggesting that a combined CHM therapy is associated with a decreased risk of mortality compared with conventional western therapy in patients after CPR. Further studies are needed to provide more evidence to prove or refute our conclusion and identify reasons for the reduction of mortality. PMID- 26952967 TI - Presentations of coccidioidomycosis in the ED. PMID- 26952968 TI - Weight loss surgery and subsequent emergency care use: a population-based cohort study. AB - STUDY OBJECTIVE: This study assessed long-term emergency care utilization after weight loss surgery. METHODS: We conducted a self-matched longitudinal cohort analysis of weight loss surgery patients in Ontario operated between April 1, 2006, and March 31, 2011. Using population-wide registries, we compared emergency visits in the 3-year interval after surgery to the 3 years before surgery using incidence rate ratios with 95% confidence intervals. The study excluded patients with repeat surgeries, and the analysis excluded visits in the immediate perioperative interval (ie, 3 months before and after surgery). RESULTS: A total of 8815 patients were identified of whom most were women (81%), living in an urban area (84%), and treated with gastric bypass (99%). Approximately half (53%) were aged 25 to 45 years. Approximately half of the patients 4364 (49%) had at least 1 emergency in both preoperative and postoperative intervals, 1417 (16%) in the preoperative interval only and 1661 (19%) in the postoperative interval only. Total emergencies significantly increased from 852 per 1000 patient-years to 1000 per 1000 patient-years, equal to an incidence rate ratio of 1.17 (95% confidence interval, 1.13-1.21; P<.001). Compared to baseline, emergencies from gastrointestinal, genitourinary, substance misuse, trauma, and miscellaneous complaints increased significantly after surgery. Conversely, emergencies due to cardiovascular, ear, respiratory, and dermatology complaints decreased significantly after surgery. Ambulance use, triage urgency, and hospitalizations were significantly higher for emergencies after surgery. CONCLUSION: Persistent and resource-intensive emergency care utilization after weight loss surgery underscores the need of long-term patient support. PMID- 26952969 TI - Needle guides for venous catheter insertion during chest compressions: a crossover simulation trial. AB - PURPOSE: Recent guidelines for cardiopulmonary resuscitation emphasize that all rescuers should minimize the interruption of chest compressions, even for intravenous access. We assessed the utility of needle guides during ultrasound guided central venous catheterization (US-CVC) with chest compressions via simulation. METHODS: Twenty-five anesthesiologists with more than 2years of experience performed US-CVC on a manikin with or without a needle guide and with or without chest compressions. Insertion success rate within 2minutes, insertion time, and subjective difficulty of venous puncture or guide wire insertion were measured. RESULTS: In normal trials, 1 participant failed US-CVC without compressions, whereas 6 failed with compressions (P=.04). In needle-guided trials, all participants succeeded without compressions, whereas only 1 failed with compressions (P=.31). Insertion time was significantly longer with chest compressions in both normal and needle-guided trials (P<.001, each). Ultrasound guided central venous catheterization insertion time in normal trials was significantly longer than in needle-guided trials with compressions (P<.001). Difficulty of operation on a visual analog scale for venous puncture or guide wire insertion was significantly higher in normal trials than in needle-guided trials with compressions. CONCLUSION: Needle guides shortened the insertion time and improved the success rate of US-CVC during chest compressions by anesthesiologists in simulations. PMID- 26952970 TI - Seroprevalence of Toxoplasma gondii in the Iranian pregnant women: A systematic review and meta-analysis. AB - Toxoplasmosis is a common and serious parasitic disease with high prevalence and global distribution in human and other warm-blooded vertebrates. Though the infection of Toxoplasma gondii is usually asymptomatic in healthy people, it can lead to severe pathological effects to the fetus of infected women and immunocompromised patients. So pinpointing the risk factors and control procedures are of important works among these populations. In order to reach this goal, we conducted a systematic review and meta-analysis to identify the seroprevalence rate of T. gondii infection among Iranian pregnant women population to achieve a comprehensive explanation of the disease condition in Iran for future use. English electronic databases (PubMed, Science Direct, Scopus, Ovid and Cochrane) and Persian language databases (Scientific Information Database, Iran Medex, Magiran and Iran Doc) were searched. Furthermore, the proceedings of Iranian parasitology congresses were explored manually. Our review resulted in a total of 50 publications meeting the inclusion criteria during Jan 1990-June 2015. Totally, 20221 women had been tested during this period of which 7724 women had seropositivity for IgG. According to results of heterogeneity test, either Der Simonian and Laird's random-effects method or Mantel-Haenszel's fixed-effects method were used to pool the estimations. Weighted overall prevalence of toxoplasmosis in pregnant women were obtained using random-effects model, which was estimated 41% (95% CI=36-45%). Also IgG and IgM antibodies was obtained 38% (95% CI=34-42%) and 4% (95% CI=3-5%), respectively. The highest and the lowest seroprevalence of toxoplasmosis in five geographical zones of Iran were observed in South 53% (95% CI=30-77%) and East 33% (95% CI=23-42%), respectively. In order to detect publication bias, Egger's regression test was done which revealed that publication bias might not have a significant influence on overall prevalence estimate (P=0.89). Multivariate analysis showed that there's a statistically significant correlation between toxoplasmosis and two risk factors including "place of residence" (P=0.005) and "contact with cat" (P=0.002). There was no significant difference between toxoplasmosis and the other surveyed risk factors. It is highly recommended to further study for the aim of better disease management and developing more efficient diagnostic tests. PMID- 26952971 TI - Clausena anisata-mediated protection against lipopolysaccharide-induced acute lung injury in mice. AB - Clausena anisata (Willd.) Hook.f. ex Benth. (CA), which is widely used in traditional medicine, reportedly exerts antitumor, anti-inflammatory and other important therapeutic effects. The aim of the present study was to investigate the potential therapeutic effects of CA in a mouse model of lipopolysaccharide (LPS)-induced acute lung injury (ALI) and in LPS-stimulated RAW 264.7 cells. Male C57BL/6 mice were administered treatments for 3 days by oral gavage. On day 3, the mice were instilled intranasally with LPS or PBS followed 3 h later by oral CA (30 mg/kg) or vehicle administration. In vitro, CA decreased nitric oxide (NO) production and pro-inflammatory cytokines, such as interleukin (IL)-6 and prostaglandin E2 (PGE2), in LPS-stimulated RAW 264.7 cells. CA also reduced the expression of pro-inflammatory mediators, such as cyclooxygenase-2. In vivo, CA administration significantly reduced inflammatory cell numbers in the bronchoalveolar lavage fluid (BALF) and suppressed pro-inflammatory cytokine levels, including tumor necrosis factor-alpha (TNF-alpha), IL-6, and IL-1beta, as well as reactive oxygen species production in the BALF. CA also effectively reduced airway inflammation in mouse lung tissue of an LPS-induced ALI mouse model, in addition to decreasing inhibitor kappaB (IkappaB) and nuclear factor kappaB (NF-kappaB) p65 phosphorylation. Taken together, the findings demonstrated that CA inhibited inflammatory responses in a mouse model of LPS-induced ALI and in LPS-stimulated RAW 264.7 cells. Thus, CA is a potential candidate for development as an adjunctive treatment for inflammatory disorders, such as ALI. PMID- 26952972 TI - Effects of riluzole on P2X7R expression in the spinal cord in rat model of neuropathic pain. AB - Neuropathic pain is becoming an intractable health threat, with its profound effect on quality of life, thus posing a major challenge to clinical therapy. Despite the reported efficacy of riluzole in some pain models, the underlying mechanism remains largely unknown. The present study aimed to assess the effects of riluzole in a rat model of neuropathic pain induced by chronic constriction injury (CCI). Subsequent to model establishment, paw withdrawal latencies (PWLs) and the paw withdrawal mecha threshold (PWT) rapidly decreased, coupled with inhibited microglial activation and upregulated P2X7R expression in the spinal cord dorsal horn (SCDH). Following intraperitoneal administration of riluzole (4mg/kg) once daily for 5 consecutive days as from day 3 after surgery, the mechanical allodynia and thermal hyperalgesia in the hind limbs were significantly attenuated. In addition, riluzole downregulated P2X7R expression and inhibited microglial activation in SCDH. Our results indicated that riluzole is effective in alleviating neuropathic pain and inhibiting microglial activation, presumably via the downregulated P2X7R expression in SCDH. PMID- 26952975 TI - Tardive intermittent massive vaginal bleeding from abnormal blood vessels within cesarean scar: Two more new cases should bring our attention to a new entity. AB - The two cases in this report had intermittent massive vaginal bleeding with a distant history of cesarean delivery. Such severe bleeding was life-threating but was eventually cured by surgical management. To the best of our knowledge, this is the second report of cases of tardive vaginal bleeding caused by abnormal blood vessels embedded within cesarean scars. The two new cases in this report suggest a novel cause of tardive vaginal bleeding, which should bring our special attention to post-cesarean clinical practice. PMID- 26952974 TI - Mas-related gene (Mrg) C receptors inhibit mechanical allodynia and spinal microglia activation in the early phase of neuropathic pain in rats. AB - Mas-related gene (Mrg) C receptors are exclusively expressed in the trigeminal and dorsal root ganglia (DRG). However, their functional roles are poorly understood. This study was aimed to determine the effect of MrgC receptors on pain hypersensitivity in the early phase of neuropathic pain and its underlying mechanisms. Intrathecal (i.t.) administration of the selective MrgC receptor agonist bovine adrenal medulla 8-22 (BAM8-22) at 1 or 10nmol attenuated mechanical allodynia one day after L5 spinal nerve ligation (SNL) surgery. I.t. BAM8-22 (10 nmol) inhibited SNL-induced microglia activation in the spinal dorsal horn on day 2 post-SNL. The BAM8-22 treatment also abolished SNL-induced upregulation of neuronal nitric oxide synthesis (nNOS) in the dorsal root ganglia (DRG). On the other hand, SNL, but not sham, surgery reduced the expression of MrgC receptor mRNA in the injured L5 DRG without changing thier levels in the adjacent uninjured L4 or L6 DRG on day 2 following the surgery. These results suggest that the activation of MrgC receptors can relieve pain hypersensitivity by the inhibition of nNOS increase in DRG neurons and microglia activation in the spinal dorsal horn in the early time following peripheral nerve injury. This study provides evidence that MrgC receptors could be targeted as a novel therapy for neuropathic pain with limited unwanted effects. PMID- 26952973 TI - Evaluation of heat hyperalgesia and anxiety like-behaviors in a rat model of orofacial cancer. AB - Pain and anxiety are commonly experienced by cancer patients and both significantly impair their quality of life. Some authors claim that there is a relationship between pain and anxiety, while others suggest that there is not a direct association. In any case, there is indeed a consensus that anxiety impairs the pain condition beyond be under diagnosed and undertreated in cancer pain patients. Herein we investigated if rats presenting heat hyperalgesia induced by orofacial cancer cell inoculation would display anxiety-like behaviors. In addition, we evaluated if pain blockade would result in alleviation of anxiety behaviors, as well as, if blockade of anxiety would result in pain relief. Orofacial cancer was induced in male Wistar rats by inoculation of Walker-256 cells into the right vibrissal pad. Heat facial hyperalgesia was assessed on day 6 after the inoculation, and on this time point rats were submitted to the elevated plus maze and the light-dark transition tests. The influence of lidocaine and midazolam on heat hyperalgesia and anxiety-like behaviors was assessed. The peak of facial heat hyperalgesia was detected 6 days after cancer cells inoculation, and at this time point, rats exhibited increased anxiety-like behaviors. Local treatment with lidocaine (2%/50MUL) caused a marked reduction of heat hyperalgesia, but failed to affect the anxiety-like behaviors, while midazolam (0.5mg/kg, i.p.) treatment failed to change the heat threshold, but induced an anxiolytic-like effect. Altogether, our data demonstrated that rats with orofacial cancer present pain- and anxiety-like behaviors, but brief heat hyperalgesia relief does not affect the anxiety-like behaviors, and vice-versa, in our experimental conditions. PMID- 26952976 TI - The Notch meeting: an odyssey from structure to function. PMID- 26952977 TI - Lhx2 is a direct NF-kappaB target gene that promotes primary hair follicle placode down-growth. AB - In the epidermis of mice lacking transcription factor nuclear factor-kappa B (NF kappaB) activity, primary hair follicle (HF) pre-placode formation is initiated without progression to proper placodes. NF-kappaB modulates WNT and SHH signaling at early stages of HF development, but this does not fully account for the phenotypes observed upon NF-kappaB inhibition. To identify additional NF-kappaB target genes, we developed a novel method to isolate and transcriptionally profile primary HF placodes with active NF-kappaB signaling. In parallel, we compared gene expression at the same developmental stage in NF-kappaB-deficient embryos and controls. This uncovered novel NF-kappaB target genes with potential roles in priming HF placodes for down-growth. Importantly, we identify Lhx2 (encoding a LIM/homeobox transcription factor) as a direct NF-kappaB target gene, loss of which replicates a subset of phenotypes seen in NF-kappaB-deficient embryos. Lhx2 and Tgfb2 knockout embryos exhibit very similar abnormalities in HF development, including failure of the E-cadherin suppression required for follicle down-growth. We show that TGFbeta2 signaling is impaired in NF-kappaB deficient and Lhx2 knockout embryos and that exogenous TGFbeta2 rescues the HF phenotypes in Lhx2 knockout skin explants, indicating that it operates downstream of LHX2. These findings identify a novel NF-kappaB/LHX2/TGFbeta2 signaling axis that is crucial for primary HF morphogenesis, which may also function more broadly in development and disease. PMID- 26952979 TI - A direct role for murine Cdx proteins in the trunk neural crest gene regulatory network. AB - Numerous studies in chordates and arthropods currently indicate that Cdx proteins have a major ancestral role in the organization of post-head tissues. In urochordate embryos, Cdx loss-of-function has been shown to impair axial elongation, neural tube (NT) closure and pigment cell development. Intriguingly, in contrast to axial elongation and NT closure, a Cdx role in neural crest (NC) derived melanocyte/pigment cell development has not been reported in any other chordate species. To address this, we generated a new conditional pan-Cdx functional knockdown mouse model that circumvents Cdx functional redundancy as well as the early embryonic lethality of Cdx mutants. Through directed inhibition in the neuroectoderm, we provide in vivo evidence that murine Cdx proteins impact melanocyte and enteric nervous system development by, at least in part, directly controlling the expression of the key early regulators of NC ontogenesis Pax3,Msx1 and Foxd3 Our work thus reveals a novel role for Cdx proteins at the top of the trunk NC gene regulatory network in the mouse, which appears to have been inherited from their ancestral ortholog. PMID- 26952978 TI - An anterior signaling center patterns and sizes the anterior neuroectoderm of the sea urchin embryo. AB - Anterior signaling centers help specify and pattern the early anterior neuroectoderm (ANE) in many deuterostomes. In sea urchin the ANE is restricted to the anterior of the late blastula stage embryo, where it forms a simple neural territory comprising several types of neurons as well as the apical tuft. Here, we show that during early development, the sea urchin ANE territory separates into inner and outer regulatory domains that express the cardinal ANE transcriptional regulators FoxQ2 and Six3, respectively. FoxQ2 drives this patterning process, which is required to eliminate six3 expression from the inner domain and activate the expression of Dkk3 and sFRP1/5, two secreted Wnt modulators. Dkk3 and low expression levels of sFRP1/5 act additively to potentiate the Wnt/JNK signaling pathway governing the positioning of the ANE territory around the anterior pole, whereas high expression levels of sFRP1/5 antagonize Wnt/JNK signaling. sFRP1/5 and Dkk3 levels are rigidly maintained via autorepressive and cross-repressive interactions with Wnt signaling components and additional ANE transcription factors. Together, these data support a model in which FoxQ2 initiates an anterior patterning center that implements correct size and positions of ANE structures. Comparisons of functional and expression studies in sea urchin, hemichordate and chordate embryos reveal striking similarities among deuterostome ANE regulatory networks and the molecular mechanism that positions and defines ANE borders. These data strongly support the idea that the sea urchin embryo uses an ancient anterior patterning system that was present in the common ambulacrarian/chordate ancestor. PMID- 26952980 TI - An in vitro model of hemogenic endothelium commitment and hematopoietic production. AB - Adult-type hematopoietic stem and progenitor cells are formed during ontogeny from a specialized subset of endothelium, termed the hemogenic endothelium, via an endothelial-to-hematopoietic transition (EHT) that occurs in the embryonic aorta and the associated arteries. Despite efforts to generate models, little is known about the mechanisms that drive endothelial cells to the hemogenic fate and about the subsequent molecular control of the EHT. Here, we have designed a stromal line-free controlled culture system utilizing the embryonic pre-somitic mesoderm to obtain large numbers of endothelial cells that subsequently commit into hemogenic endothelium before undergoing EHT. Monitoring the culture for up to 12 days using key molecular markers reveals stepwise commitment into the blood forming system that is reminiscent of the cellular and molecular changes occurring during hematopoietic development at the level of the aorta. Long-term single-cell imaging allows tracking of the EHT of newly formed blood cells from the layer of hemogenic endothelial cells. By modifying the culture conditions, it is also possible to modulate the endothelial cell commitment or the EHT or to produce smooth muscle cells at the expense of endothelial cells, demonstrating the versatility of the cell culture system. This method will improve our understanding of the precise cellular changes associated with hemogenic endothelium commitment and EHT and, by unfolding these earliest steps of the hematopoietic program, will pave the way for future ex vivo production of blood cells. PMID- 26952981 TI - alpha-Spectrin and integrins act together to regulate actomyosin and columnarization, and to maintain a monolayered follicular epithelium. AB - The spectrin cytoskeleton crosslinks actin to the membrane, and although it has been greatly studied in erythrocytes, much is unknown about its function in epithelia. We have studied the role of spectrins during epithelia morphogenesis using the Drosophila follicular epithelium (FE). As previously described, we show that alpha-Spectrin and beta-Spectrin are essential to maintain a monolayered FE, but, contrary to previous work, spectrins are not required to control proliferation. Furthermore, spectrin mutant cells show differentiation and polarity defects only in the ectopic layers of stratified epithelia, similar to integrin mutants. Our results identify alpha-Spectrin and integrins as novel regulators of apical constriction-independent cell elongation, as alpha-Spectrin and integrin mutant cells fail to columnarize. Finally, we show that increasing and reducing the activity of the Rho1-Myosin II pathway enhances and decreases multilayering of alpha-Spectrin cells, respectively. Similarly, higher Myosin II activity enhances the integrin multilayering phenotype. This work identifies a primary role for alpha-Spectrin in controlling cell shape, perhaps by modulating actomyosin. In summary, we suggest that a functional spectrin-integrin complex is essential to balance adequate forces, in order to maintain a monolayered epithelium. PMID- 26952983 TI - The transcription factor Glass links eye field specification with photoreceptor differentiation in Drosophila. AB - Eye development requires an evolutionarily conserved group of transcription factors, termed the retinal determination network (RDN). However, little is known about the molecular mechanism by which the RDN instructs cells to differentiate into photoreceptors. We show that photoreceptor cell identity in Drosophila is critically regulated by the transcription factor Glass, which is primarily expressed in photoreceptors and whose role in this process was previously unknown. Glass is both required and sufficient for the expression of phototransduction proteins. Our results demonstrate that the RDN member Sine oculis directly activates glass expression, and that Glass activates the expression of the transcription factors Hazy and Otd. We identified hazy as a direct target of Glass. Induced expression of Hazy in the retina partially rescues the glass mutant phenotype. Together, our results provide a transcriptional link between eye field specification and photoreceptor differentiation in Drosophila, placing Glass at a central position in this developmental process. PMID- 26952982 TI - Developmental origin of lung macrophage diversity. AB - Macrophages are specialized phagocytic cells, present in all tissues, which engulf and digest pathogens, infected and dying cells, and debris, and can recruit and regulate other immune cells and the inflammatory response and aid in tissue repair. Macrophage subpopulations play distinct roles in these processes and in disease, and are typically recognized by differences in marker expression, immune function, or tissue of residency. Although macrophage subpopulations in the brain have been found to have distinct developmental origins, the extent to which development contributes to macrophage diversity between tissues and within tissues is not well understood. Here, we investigate the development and maintenance of mouse lung macrophages by marker expression patterns, genetic lineage tracing and parabiosis. We show that macrophages populate the lung in three developmental waves, each giving rise to a distinct lineage. These lineages express different markers, reside in different locations, renew in different ways, and show little or no interconversion. Thus, development contributes significantly to lung macrophage diversity and targets each lineage to a different anatomical domain. PMID- 26952984 TI - Deficiency of the placenta- and yolk sac-specific tristetraprolin family member ZFP36L3 identifies likely mRNA targets and an unexpected link to placental iron metabolism. AB - The ZFP36L3 protein is a rodent-specific, placenta- and yolk sac-specific member of the tristetraprolin (TTP) family of CCCH tandem zinc finger proteins. These proteins bind to AU-rich elements in target mRNAs, and promote their deadenylation and decay. We addressed the hypotheses that the absence of ZFP36L3 would result in the accumulation of target transcripts in placenta and/or yolk sac, and that some of these would be important for female reproductive physiology and overall fecundity. Mice deficient in ZFP36L3 exhibited decreased neonatal survival rates, but no apparent morphological changes in the placenta or surviving offspring. We found Zfp36l3 to be paternally imprinted, with profound parent-of-origin effects on gene expression. The protein was highly expressed in the syncytiotrophoblast cells of the labyrinth layer of the placenta, and the epithelial cells of the yolk sac. RNA-Seq of placental mRNA from Zfp36l3 knockout (KO) mice revealed many significantly upregulated transcripts, whereas there were few changes in KO yolk sacs. Many of the upregulated placental transcripts exhibited decreased decay rates in differentiated trophoblast stem cells derived from KO blastocysts. Several dozen transcripts were deemed high probability targets of ZFP36L3; these include proteins known to be involved in trophoblast and placenta physiology. Type 1 transferrin receptor mRNA was unexpectedly decreased in KO placentas, despite an increase in its stability in KO stem cells. This receptor is crucial for placental iron uptake, and its decrease was accompanied by decreased iron stores in the KO fetus, suggesting that this intrauterine deficiency might have deleterious consequences in later life. PMID- 26952985 TI - Influence of ovarian muscle contraction and oocyte growth on egg chamber elongation in Drosophila. AB - Organs are formed from multiple cell types that make distinct contributions to their shape. The Drosophila egg chamber provides a tractable model to dissect such contributions during morphogenesis. Egg chambers consist of 16 germ cells (GCs) surrounded by a somatic epithelium. Initially spherical, these structures elongate as they mature. This morphogenesis is thought to occur through a 'molecular corset' mechanism, whereby structural elements within the epithelium become circumferentially organized perpendicular to the elongation axis and resist the expansive growth of the GCs to promote elongation. Whether this epithelial organization provides the hypothesized constraining force has been difficult to discern, however, and a role for GC growth has not been demonstrated. Here, we provide evidence for this mechanism by altering the contractile activity of the tubular muscle sheath that surrounds developing egg chambers. Muscle hypo-contraction indirectly reduces GC growth and shortens the egg, which demonstrates the necessity of GC growth for elongation. Conversely, muscle hyper-contraction enhances the elongation program. Although this is an abnormal function for this muscle, this observation suggests that a corset-like force from the egg chamber's exterior could promote its lengthening. These findings highlight how physical contributions from several cell types are integrated to shape an organ. PMID- 26952986 TI - Clarification of mural cell coverage of vascular endothelial cells by live imaging of zebrafish. AB - Mural cells (MCs) consisting of vascular smooth muscle cells and pericytes cover the endothelial cells (ECs) to regulate vascular stability and homeostasis. Here, we clarified the mechanism by which MCs develop and cover ECs by generating transgenic zebrafish lines that allow live imaging of MCs and by lineage tracing in vivo To cover cranial vessels, MCs derived from either neural crest cells or mesoderm emerged around the preformed EC tubes, proliferated and migrated along EC tubes. During their migration, the MCs moved forward by extending their processes along the inter-EC junctions, suggesting a role for inter-EC junctions as a scaffold for MC migration. In the trunk vasculature, MCs derived from mesoderm covered the ventral side of the dorsal aorta (DA), but not the posterior cardinal vein. Furthermore, the MCs migrating from the DA or emerging around intersegmental vessels (ISVs) preferentially covered arterial ISVs rather than venous ISVs, indicating that MCs mostly cover arteries during vascular development. Thus, live imaging and lineage tracing enabled us to clarify precisely how MCs cover the EC tubes and to identify the origins of MCs. PMID- 26952989 TI - Polydopamine-coated open cell polyurethane foams as an inexpensive, flexible yet robust catalyst support: a proof of concept. AB - Commercially available polyurethane open cell foams are readily coated with mussel-inspired polydopamine. The polydopamine film allows robust immobilisation of TiO2 nanoparticles at the surface of the three-dimensional material. The resulting catalyst is efficient for the photo-degradation of an azo dye, reusable and highly resistant to mechanical stress. A novel type of robust structured catalytic support, easily accessible via an inexpensive and green process, is thus described. PMID- 26952987 TI - The BAF chromatin remodelling complex is an epigenetic regulator of lineage specification in the early mouse embryo. AB - Dynamic control of gene expression is essential for the development of a totipotent zygote into an embryo with defined cell lineages. The accessibility of genes responsible for cell specification to transcriptional machinery is dependent on chromatin remodelling complexes such as the SWI?SNF (BAF) complex. However, the role of the BAF complex in early mouse development has remained unclear. Here, we demonstrate that BAF155, a major BAF complex subunit, regulates the assembly of the BAF complex in vivo and regulates lineage specification of the mouse blastocyst. We find that associations of BAF155 with other BAF complex subunits become enriched in extra-embryonic lineages just prior to implantation. This enrichment is attributed to decreased mobility of BAF155 in extra-embryonic compared with embryonic lineages. Downregulation of BAF155 leads to increased expression of the pluripotency marker Nanog and its ectopic expression in extra embryonic lineages, whereas upregulation of BAF155 leads to the upregulation of differentiation markers. Finally, we show that the arginine methyltransferase CARM1 methylates BAF155, which differentially influences assembly of the BAF complex between the lineages and the expression of pluripotency markers. Together, our results indicate a novel role of BAF-dependent chromatin remodelling in mouse development via regulation of lineage specification. PMID- 26952988 TI - Activation of a T-box-Otx2-Gsc gene network independent of TBP and TBP-related factors. AB - Embryonic development relies on activating and repressing regulatory influences that are faithfully integrated at the core promoter of individual genes. In vertebrates, the basal machinery recognizing the core promoter includes TATA binding protein (TBP) and two TBP-related factors. In Xenopus embryos, the three TBP family factors are all essential for development and are required for expression of distinct subsets of genes. Here, we report on a non-canonical TBP family-insensitive (TFI) mechanism of transcription initiation that involves mesoderm and organizer gene expression. Using TBP family single- and triple knockdown experiments, alpha-amanitin treatment, transcriptome profiling and chromatin immunoprecipitation, we found that TFI gene expression cannot be explained by functional redundancy, is supported by active transcription and shows normal recruitment of the initiating form of RNA polymerase II to the promoter. Strikingly, recruitment of Gcn5 (also known as Kat2a), a co-activator that has been implicated in transcription initiation, to TFI gene promoters is increased upon depletion of TBP family factors. TFI genes are part of a densely connected TBP family-insensitive T-box-Otx2-Gsc interaction network. The results indicate that this network of genes bound by Vegt, Eomes, Otx2 and Gsc utilizes a novel, flexible and non-canonical mechanism of transcription that does not require TBP or TBP-related factors. PMID- 26952990 TI - Development and Validation of a Reversed-Phase HPLC Method for the Quantitative Determination of Ten Polyphenols Extracted from Apple Peel. AB - A method based on a reversed-phase HPLC method was established, optimized, and validated for the separation and quantitation of 10 polyphenols extracted from the peel of apple species. A bidentate reversed-phase C18 column was used as stationary phase, and an acidified water buffer and methanol were used as mobile phase. The polyphenols were well separated and detected using UV at 280 and 320 nm. Validation parameters, such as linearity, LOD, LOQ, accuracy, and precision, were acceptable for all 10 polyphenols. The proposed method has enough linearity with correlation coefficient >0.99 within the investigated range for all tested polyphenols. The LOD was 0.24 MUg/mL for ellagic acid and <0.2 MUg/mL for all other polyphenols. The LOQ was 9.39 * 10(-2) MUg/mL for chlorogenic acid, and ellagic acid, 2.82 * 10(-2) MUg/mL for caffeic acid and >0.1 MUg/mL for all other polyphenols. Recovery was within the acceptable range from 98.38 to 100.39% for all polyphenols standards. Satisfactory precision was achieved for both intra- and interday assay, with RSD <2%. The method was successfully applied for simultaneous analysis of polyphenols from apple peel. PMID- 26952991 TI - Direct evidences on bacterial growth pattern regulating pyrene degradation pathway and genotypic dioxygenase expression. AB - Pyrene degradation by Mycobacterium sp. strain A1-PYR was investigated in the presence of nutrient broth, phenanthrene and fluoranthene, respectively. Fast bacterial growth in the nutrient broth considerably enhanced pyrene degradation rate, whereas degradation efficiency per cell was substantially decreased. The addition of nutrient broth could not alter the transcription levels of all dioxygenase genotypes. In the PAH-only substrates, bacterial growth completely relied on biological conversion of PAHs into the effective carbon sources, which led to a higher degradation efficiency of pyrene per cell than the case of nutrient broth. Significant correlations were only observed between nidA-related dioxygenase expression and pyrene degradation or bacterial growth. The highest pyrene degradation rate in the presence of phenanthrene was consistent with the highest transcription level of nidA and 4,5-pyrenediol as the sole initial metabolite. This study reveals that bacterial growth requirement can invigorate degradation of PAHs by regulating metabolic pathway and genotypic enzyme expression. PMID- 26952992 TI - New direction for environmental water management. AB - Japan experienced severe environmental problems including water pollution and damages to aquatic organisms and fishery industry through and after the high economic growth period in the 1960s. One of the countermeasures to address these problems was the Total Pollutant Load Control System (TPLCS), which has been implemented with the aim of reducing the total amount of pollutant loads, specifically targeting Chemical Oxygen Demand (COD), total nitrogen and total phosphorus. The TPLCS has significantly improved the quality of the coastal sea water. However, while the accumulated pollutant loads from the past industrialization have still remained, new environmental concerns have arisen. Our new environmental policies are thus to deal with conservation of biological diversity and other related marine environmental issues. Japan has entered a new phase of environmental management, setting the new direction and framework toward a beautiful, bio-diverse, bustling-with-people and bountiful sea. PMID- 26952993 TI - Biodegradation of marine crude oil pollution using a salt-tolerant bacterial consortium isolated from Bohai Bay, China. AB - This study aims at constructing an efficient bacterial consortium to biodegrade crude oil spilled in China's Bohai Sea. In this study, TCOB-1 (Ochrobactrum), TCOB-2 (Brevundimonas), TCOB-3 (Brevundimonas), TCOB-4 (Bacillus) and TCOB-5 (Castellaniella) were isolated from Bohai Bay. Through the analysis of hydrocarbon biodegradation, TCOB-4 was found to biodegrade more middle-chain n alkanes (from C17 to C23) and long-chain n-alkanes (C31-C36). TCOB-5 capable to degrade more n-alkanes including C24-C30 and aromatics. On the basis of complementary advantages, TCOB-4 and TCOB-5 were chosen to construct a consortium which was capable of degrading about 51.87% of crude oil (2% w/v) after 1week of incubation in saline MSM (3% NaCl). It is more efficient compared with single strain. In order to biodegrade crude oil, the construction of bacterial consortia is essential and the principle of complementary advantages could reduce competition between microbes. PMID- 26952996 TI - From last to first. PMID- 26952994 TI - Persistent organic pollutants and polycyclic aromatic hydrocarbons in penguins of the genus Pygoscelis in Admiralty Bay - An Antarctic specially managed area. AB - Persistent organic pollutants were assessed in fat samples of the Gentoo (Pygoscelis papua), Chinstrap (Pygoscelis antarcticus) and Adelie (Pygoscelis adeliae) penguins collected during the austral summers of 2005/06 and 2006/07 in Admiralty Bay, King George Island, Antarctica. The predominant organic pollutants were PCB (114 to 1115), polycyclic aromatic hydrocarbons (PAHs) (60.1 to 238.7), HCB (<0.3 to 132.2) and BDE-47 (<1.0 to 10.7) in ng g(-1) wet weight. The mean concentrations of the majority of organic pollutants were similar among the three species of penguins. Chicks of all three species showed similar profiles of PCB congeners, with predominance of lower chlorinated compounds. The distribution of PAHs was similar in all birds, with a predominance of naphthalene and alkyl naphthalene, which are the main constituents of arctic diesel fuel. These data contribute to the monitoring of the continued exposure to organic pollutants in the Antarctic biota. PMID- 26952997 TI - Visual hallucinations in consultation-liaison neuropsychiatry. AB - BACKGROUND: In consultation-liaison settings, neuropsychiatrists are commonly asked to assess patients with hallucinatory syndromes and to differentiate 'functional' from 'organic' psychotic presentations. METHODS: The occurrence and management of visual hallucinations (VH) in healthy individuals, lesion states, neurodegenerative disorders, intoxication/withdrawal states and delirium are reviewed. RESULTS: The presence of VH has been shown to predict a secondary rather than primary psychotic illness and an understanding of the neurobiology of the visual system - including how and where underlying neurotransmitter systems interact in visual processing and how perturbations can result in VH - allows for appropriate clinical assessment and management. PMID- 26952995 TI - Resistance to antimicrobial agents among enterococci isolated from fecal samples of wild marine species in the southern coast of Brazil. AB - The purpose of this study was to evaluate species distribution, antimicrobial resistance profiles, and presence of resistance genes in enterococci isolated from fecal samples of wild marine species, including seabirds (n=12), sea turtles (n=8), and mammals (n=3) found alive or dead in southern coast of Brazil. Enterococci were classified based on phenotypic and genotypic characteristics, tested for antibiotic susceptibility, and the presence of tet(S), tet(M), tet(L), mrsC, and erm(B) genes by PCR. Enterococcus faecalis and Enterococcus faecium were the most common species. Single (37.09%), double (25.80%), and multiple (16.12%) antibiotic resistance patterns were observed. Resistance to rifampicin occurred most frequently. The msrC, tet(M), and/or tet(L) genes were detected in 60.15%, 73.07%, and 23.07% of the resistant strains, respectively. In conclusion, the presence of antibiotic resistant strains in these species could be related to food web interactions and aquatic pollutants or linked to environmental resistome. PMID- 26952998 TI - Are obstetric complications related to adult schizophrenia? A case-control study. AB - BACKGROUND: Early environmental events may be relevant to the etiology of schizophrenia. Among such events, interest has focused especially on obstetric complications (OCs). OBJECTIVE: Aims of the study were to compare the incidence of OCs in patients, siblings and normal controls and to examine the relationship between OCs and later schizophrenia. METHOD: One hundred and thirteen patients with schizophrenia were recruited, as were 140 patients' siblings and 113 controls without schizophrenia. The OCs history of patients, their sibs and controls was obtained through interviews with patients' and controls' mothers. RESULTS: The results highlighted that more patients than sibs had at least one definite OC and a higher mean number of OCs; more patients had premature rupture of membranes, threatened abortion and a labor of more than 36 h. CONCLUSIONS: Our data provide some evidence for a link between OCs and later schizophrenia. Furthermore, this study highlights how OCs, which may cause fetal distress through a hypoxic-ischemic mechanism, could increase the risk of schizophrenia interacting with genetic susceptibility. PMID- 26952999 TI - Lack of association between dopamine D3 receptor Ser9Gly polymorphism and schizophrenia in Han Chinese population. AB - BACKGROUND: The Ser9Gly polymorphism in dopamine D3 receptor gene (DRD3) was considered an important factor in the pathogenesis of schizophrenia. Allele and genotype frequencies of this polymorphism were studied in different ethnic groups of schizophrenic patients. However, the results have been inconclusive. OBJECTIVE: To determine whether the DRD3 Ser9Gly polymorphism is associated with schizophrenia or influences its psychopathological symptoms in Han Chinese population. METHOD: We recruited 256 schizophrenic patients and 285 normal controls matched for gender, age and ethnicity. Pretreatment psychotic symptoms were evaluated with the Positive and Negative Symptom Scale (PANSS) in 128 acutely exacerbated schizophrenic in-patients. Genotyping of Ser9Gly polymorphism was performed with a polymerase chain reaction restriction fragment length polymorphism method and reconfirmed by a direct sequencing technique. RESULTS: No significant difference was found between either patients with schizophrenia or with more homogeneous schizophrenic subgroups and healthy controls in genotype distributions and allele frequencies for the DRD3 Ser9Gly polymorphism. Similarly, DRD3 Ser9Gly genotype differences failed to reach significance in PANSS global, positive, negative and general symptoms scores. There is a trend (P = 0.064) towards higher PANSS positive symptoms scores in subjects carrying the Gly/Gly genotype. CONCLUSION: This study does not support the role of DRD3 Ser9Gly polymorphism in increasing genetic risk for schizophrenia in Han Chinese population. Still, there is a possibility that the DRD3 Ser9Gly variant may reflect genetic variation of severity of positive symptoms in acutely exacerbated schizophrenia. Further studies are warranted to investigate the effect of the DRD3 Ser9Gly polymorphism in relation to longer time course of schizophrenia, including treatment response to antipsychotics. PMID- 26953000 TI - Possible association between G-protein beta3 subunit C825T polymorphism and antipsychotic-induced restless legs syndrome in schizophrenia. AB - OBJECTIVE: The incidence of restless legs syndrome (RLS) is presumed to be higher among people with schizophrenia who take antipsychotic medication, most of which blocks the dopamine D2 receptor. The purpose of this study was to determine whether the G-protein beta3 subunit (GNB3) C825T polymorphism is associated with antipsychotic-induced RLS in schizophrenia. METHODS: We examined 178 Korean patients with schizophrenia. All of the subjects were evaluated using the diagnostic criteria of the International Restless Legs Syndrome Study Group and the International Restless Legs Scale. Genotyping was performed for the C825T polymorphism in the GNB3 gene. RESULTS: The genotype distribution did not differ significantly between antipsychotic-induced RLS patients and patients who had no RLS symptoms (chi 2 = 4.30, p = 0.116). The genotypes of the C825T single nucleotide polymorphism (SNP) were classified into two groups: C+ (CC and CT genotypes) and C- (TT genotype). The presence of the C allele (C+) was associated with an increased likelihood of RLS (chi 2 = 4.14, p = 0.042; odds ratio = 2.56, 95% confidence interval = 1.02-6.47). CONCLUSIONS: These results suggest that the GNB3 C825T SNP is associated with RLS in schizophrenia. However, confirming this association requires future larger scale studies in which the effects of medication are strictly controlled. PMID- 26953001 TI - Quality of life and subthreshold obsessive-compulsive disorder. AB - OBJECTIVE: This study investigates the relationship between subthreshold obsessive-compulsive disorder (OCD) and quality of life (QoL) in a sample from the Italian general population. METHODS: A sample of 202 psychiatrically healthy (defined as absence of current axis I and axis II disorders) subjects was recruited by word of mouth from the residential population in the Siena, Salerno and Milano municipalities (Italy). All study subjects completed the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) and the Questionnaire for Obsessive-Compulsive Spectrum (OBS-SR), which explore a wide array of threshold and subthreshold OCD symptoms, behaviours and traits. A diagnostic assessment was conducted to exclude the presence of DSM-IV axis I and axis II disorders using the Mini International Neuropsychiatric Interview and the Structured Clinical Interview for DSM-III-R personality disorders, respectively. RESULTS: A statistically significant correlation was found between the OBS-SR total score and the Q-LES-Q domains of physical health, subjective feelings, work, school, social relationships and general activities. There was also a statistically significant correlation between several Q-LES-Q and OBS-SR domains. CONCLUSIONS: The presence of subthreshold OCD is correlated with poorer QoL. More research is needed to evaluate if specific therapeutic interventions targeting subthreshold obsessive-compulsive symptoms can lead to a significant improvement in the QoL of the affected individuals. PMID- 26953002 TI - Reliability and validity of the Japanese version of the 24-item Dysfunctional Attitude Scale. AB - BACKGROUND: The 24-item Dysfunctional Attitude Scale (DAS-24) is a short version of the Dysfunctional Attitude Scale, which is a self-report inventory for depressogenic schemata. OBJECTIVE: The object of this study was to examine the reliability and validity of the Japanese version of the DAS-24 (DAS-24-J). METHODS: Subjects consisted of non-clinical sample 1 (248 university students), non-clinical sample 2 (872 Japanese company employees) and a clinical sample (59 depressed out-patients). RESULTS: Internal consistency was satisfactory in all three samples, Cronbach's alpha coefficient being higher than 0.85. Test-retest reliability was satisfactory in non-clinical sample 1. The interclass correlation coefficient was 0.79 and there was no significant difference in the average score of DAS-24-J between the two points. The DAS-24-J showed satisfactory concurrent validity with the Japanese Irrational Belief Test-20 (r= 0.76); Automatic Thoughts Questionnaire - Revised total (r= 0.46), negative (r= 0.53) and positive (r=-0.41); and the Beck Depression Inventory-II (r= 0.44 for non-clinical sample, r= 0.63 for clinical sample). The clinical sample showed a significantly higher DAS-24-J score than non-clinical sample 2. According to a factor analysis combining all three samples, three factors were extracted: factor 1 (11 items) corresponded with 'achievement' in the original version, factor 2 (6 items) with 'self-control' and factor 3 (5 items) with 'dependency'. CONCLUSION: The DAS-24-J is a reliable and valid instrument to measure depressogenic schemata in Japanese. PMID- 26953003 TI - Significant alterations in peripheral blood lymphocyte subsets in patients with somatoform disorder. AB - OBJECTIVE: Previous studies have suggested that somatoform disorders (SFD) might be associated with changes in the function of the central and autonomic nervous systems. The aim of this study was to examine the possible immunological differences between SFD and healthy controls. METHODS: Twenty-four patients with SFD and 13 healthy individuals completed the psychological questionnaires to assess symptom reporting [Symptom Checklist-90 Revised (SCL-90-R)] and to diagnose for SFD [Screening for Somatoform Symptoms scale (SOMS-scale)]. Participants also provided a blood sample taken in the morning, which was analysed with an automated cell counter to determine the number of leucocytes per MUl and with flow cytometry to determine lymphocyte subsets. RESULTS: With the exception of a higher T4/T8 ratio in the patient group, which was mainly because of lower CD8 counts, there were no significant differences in the absolute number of lymphocytes (subsets) between patients with SFD and healthy subjects. A positive correlation between B-lymphocyte subsets (CD19+CD22+, CD19+CD5+, CD19+CD3-) to all scales of the SCL-90-R, except somatisation, were found in SFD. Additionally, a positive correlation was found in SFD between CD14+CD16+ monocytes and somatisation (0.573) on the SCL-90-R scale. CONCLUSION: These data indicate that patients with SFD have an enhanced humoral immunity as shown by increased B-cell numbers and furthermore an elevated T4/T8 ratio because of lower CD8 suppressor cells. Further studies will be required to determine whether these alterations in lymphocyte subsets are directly involved in the pathophysiology of SFD. PMID- 26953004 TI - Complex visual hallucinations and occipital seizures. AB - BACKGROUND: We describe the presentation of a young woman with long-standing complex partial seizures with occasional secondary generalization, who presented with complex visual hallucinations (CVHs) and delusions. METHODS: Routine biological workup including magnetic resonance imaging revealed an area of significant left-sided occipital gliosis. Video telemetry monitoring revealed a left occipital focus for the origin of the electrographic seizure discharge. CONCLUSION: CVHs occur in a range of organic states, including epilepsy, and can be understood in terms of the underpinning neuroanatomy and neurotransmitter systems of the visual system. PMID- 26953006 TI - The miracle of brain neuropeptides: targeting the brain oxytocin system is a true treatment option in numerous psychiatric disorders including schizophrenia. PMID- 26953005 TI - Anxiety symptoms and functional impairment: A systematic review of the correlation between the two measures. AB - Researchers and clinicians assume a strong, positive correlation between anxiety symptoms and functional impairment. That assumption may be well-justified since diagnostic criteria typically include functional impairment. Still, the relationship remains largely unavailable in any systematic review. Our aim with this paper was to provide empirical evidence for this assumed relationship and to document the observed correlations between anxiety symptom measures and functional impairment measures. Correlations existed for symptoms of six anxiety disorders (Panic Disorder, Agoraphobia, Social Anxiety Disorder, Post-Traumatic Stress Disorder, Generalized Anxiety Disorder, Obsessive Compulsive Disorder) across four functional domains (global, social, occupational, and physical). Overall, the mean of 497 correlations across all disorders and functional domains was modest (r=.34); since the variability between disorders and functional domains tended to be rather large, we explored these correlations further. We presented these results and the potential explanations for unexpected findings along with the clinical and research implications. PMID- 26953007 TI - Differential effects of escitalopram administration on metabolic parameters of cortical and subcortical brain regions of Wistar rats. AB - OBJECTIVE: Considering that mitochondria may be drug targets and some characteristics of drug-mitochondria interactions may still be misjudged because of the difficulty in foreseeing and understanding all possible implications of the complex pathophysiology of mitochondria, our study aimed to investigate the effect of escitalopram on the activity of enzymes of mitochondrial energy metabolism. METHODS: Animals received daily administration of escitalopram dissolved in saline [10 mg/kg, intraperitoneal (IP)] at 1.0 ml/kg volume for 14 days. Control rats received an equivalent volume of saline, 1.0 ml/kg (IP), for the same treatment period. Twelve hours after last injection, rats were killed by decapitation and brain areas were rapidly isolated. The samples were homogenised and the activities of mitochondrial respiratory chain complexes, some enzymes of Krebs cycle (citrate synthase, malate dehydrogenase and succinate dehydrogenase) and creatine kinase were measured. RESULTS: We verified that chronic administration of escitalopram decreased the activities of complexes I and II-III in cerebellum, hippocampus, striatum and posterior cortex whereas prefrontal cortex was not affected. Complex II activity was decreased only in striatum without affecting prefrontal cortex, hippocampus, cerebellum and posterior cortex. However, chronic administration of escitalopram did not affect complex IV and enzymes of Krebs cycle activities as well as creatine kinase. CONCLUSION: In this study we showed a decrease in the activities of complexes I and II-III in most of the brain structures analysed and complex II activity was decreased only in striatum. However, it remains to be determined if mitochondrial dysfunction is rather a causal or a consequential event of abnormal signalling. PMID- 26953008 TI - Association of P1635 and P1655 polymorphisms in dysbindin (DTNBP1) gene with schizophrenia. AB - OBJECTIVES: Schizophrenia (SCZ) is a severe psychiatric disorder with a lifetime prevalence of approximately 1% in most of the populations studied. SCZ is multifactorial with the contribution of multiple susceptibility genes that could act in conjunction with epigenetic processes and environmental factors. There is some evidence supporting the association between genetic variants in dysbindin (DTNBP1) gene and SCZ in populations. In this study, we investigated the association between polymorphisms P1635 and P1655 in dysbindin gene with SCZ. METHODS: Totally, 115 unrelated patients with SCZ and 117 unrelated healthy volunteers were studied. Genomic DNA was extracted from blood. Genotyping was done with the PCR-RFLP method. The allele and genotype associations were analysed with X 2 test. The Benjamini-Hochberg procedure was used to correct p values for multiple comparisons. RESULTS: The results showed no significant difference between patients and controls in allelic frequencies or genotypic distributions of SNP P1635 (p = 0.809), but a significant difference between the case and control groups for SNP P1655 (p = 0.009) was found. We could also find a significant positive association between A-C haplotype and SCZ (OR = 1.7, 95% CI 1.18-2.42; p = 0.004, p c = 0.02) and a protective effect for A-G haplotype (p = 0.003, OR = 0.57, 95% CI 1.18-2.42; p = 0.003, p c = 0.02). CONCLUSION: This study may provide further support for the association between SNP polymorphisms in DTNBP1 and SCZ in the Iranian population. Studies with more markers and subjects for various populations will be necessary to understand the genetic contribution of the gene to the development of SCZ. PMID- 26953009 TI - Changes of ultrastructure and downregulation of heat shock protein 70 and fibroblast growth factor 2 in gastric mucosa of rats with depressive-like behaviour. AB - OBJECTIVE: To understand the underlying mechanism of gastric symptoms in patients with depressive disorder. METHODS: This study tested in the rat depression model evoked with chronic mild stress whether the microstructure gastric mucosa is injured using scanning electronic microscopy and transmission electronic microscopy (TEM). In addition, the expression of heat shock protein 70 (HSP70) and fibroblast growth factor 2 (FGF2) proteins in the gastric mucosa were measured by Western blotting. RESULTS: We found that the gastric epithelial cells were ruptured and the gastric pits were widened in rats with depression. The amount of mucous granules was also reduced in the surface mucous cells. Moreover, parietal cells became active, and the secretory canaliculi were magnified. Expression of HSP70 and FGF2 was reduced in the gastric mucosa. CONCLUSIONS: These findings suggested that gastric symptoms in rats with depressive-like behaviour were caused by the injury of the gastric mucosa, AQ1 and HSP70 and FGF2 may be key molecules in the pathogenesis. PMID- 26953010 TI - Fas expression promotes proteasomal activity in toxin-induced parkinsonism. AB - OBJECTIVE: Fas (CD95), commonly categorised as a death receptor due to its well defined role in apoptosis, can paradoxically also promote neuroprotection. We have previously found that defects in Fas signalling render mice highly susceptible to neural degeneration in the 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine mouse model of Parkinson's disease (PD). Decreased activity of the ubiquitin proteasome system and accumulation of protein aggregates are implicated in PD pathogenesis. Here, we investigate the relationship between Fas and ubiquitin proteasomal activity in neuronal cells. METHODS: We performed proteasome assays in neuroblastoma cells and in midbrain cultures of wild-type and Fas-deficient mice. RESULTS: Neuroblastoma cells upregulated proteasomal activity in response to an activating Fas antibody in vitro. Furthermore, neural tissue from Fas-deficient mice showed decreased proteasomal activity compared with the tissue from wild-type mice when exposed to a PD-inducing toxin in vivo. CONCLUSION: These findings suggest that mechanisms for Fas-mediated neuroprotection may include Fas-induced upregulation of proteasomal activity, and consequently less accumulation of toxic protein aggregates. PMID- 26953011 TI - A case-control study of interleukin-12 1188A/C polymorphism in obsessive compulsive disorder in Chinese population. AB - OBJECTIVE: Previous studies indicated that the levels of serum interleukin (IL) 12 at baseline were elevated in obsessive-compulsive disorder (OCD) patients compared with control subjects, suggesting that IL-12 maybe involved in the etiopathogenesis of OCD. Therefore, we study the relationship between 1188A/C polymorphism of IL-12(rs3212227) and OCD in Chinese Han population. METHODS: We genotyped 194 OCD patients and 322 healthy individuals by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), then analyzed the data using case-control association test. RESULTS: No significant differences were found in 1188A/C genotypic and allelic frequencies between OCD cases and controls ( X 2 = 2.12, df = 2, P = 0.35 by genotype; X 2 = 0.005, df = 1, P = 0.94 by allele). CONCLUSIONS: Our results suggested that there may be lack of an association between OCD and IL-12 1188A/C polymorphism in Chinese Han population. PMID- 26953012 TI - Association between dopamine beta hydroxylase gene polymorphism and age at onset in male schizophrenia. AB - OBJECTIVES: The heterogeneity of schizophrenia mainly results from variations in clinical expressions of the disease, such as age at onset, gender differences in onset of illness, symptoms and response to antipsychotic treatment. Enhanced sensitisation of dopamine pathways in males, having consistently an earlier onset, might be implicated as disease modifiers for schizophrenia in males. METHODS: In this study, we performed a case (n = 87)-control (n = 100) association study between the DBH5'-ins/del and DBH-444g/a polymorphisms of the DBH gene and also compared the level of psychotic symptoms between patients with different DBH genotypes/haplotypes with respect to antipsychotic therapeutic response and gender difference. RESULTS: No significant differences between allele and genotype and haplotype frequencies at either groups (p < 0.05). When the age is considered in patient group, a significant difference was observed between patients with ID genotype and with II genotype (p = 0.018). Patients with ID genotype have been diagnosed as schizophrenics in early ages when compared to II genotype carriers. We also found a significant difference between II and ID genotype (p = 0.007) when the gender had taken into account, showing that the ID genotype carriers had an early onset to schizophrenia. CONCLUSIONS: This association was more significant in male schizophrenia patients than females. Thus, this finding may constitute a novel biological support for the prior finding that onset of schizophrenia varies with gender. The results also showed that critical genetic vulnerability may be associated with the presence or absence of the ID genotype of DBH5'-ins/del. PMID- 26953013 TI - Protracted delirium with Sheehan's syndrome. AB - OBJECTIVE: Delirium is a common problem, but often misdiagnosed and unidentified. Apart from the manifold clinical picture variable durations can also be an obstacle for its diagnosis. METHODS: We present a case of protracted delirium that has developed after severe somatic illness in association with previously undiagnosed Sheehan's syndrome. RESULTS: The variety of psychiatric symptoms with initial psychotic disorder and the long run of the disease delayed the diagnosis of delirium and meantime gave reason to assume personality change. CONCLUSION: This case report calls attention to the possibility of protracted delirium in patients with neuropsychiatric deficit symptoms that persist subsequent to somatic illness. PMID- 26953014 TI - Regain of visuospatial capacity after coenzyme Q10 in a patient with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes: a case report. AB - OBJECTIVE: MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes) is a neurodegenerative disorder caused by mitochondrial dysfunction. Multiple systems of the body, including cognitive function and heart conduction, can be affected by this disorder. We report a case with global cognitive impairment. METHOD: A single-case report. RESULTS: The patient got improved cognitive function, especially visuospatial function, under coenzyme Q10 treatment. CONCLUSION: First, coenzyme Q10 may give some benefit to control MELAS. Second, cognitive functions and intellectual abilities decline with disease progression. Routine neuropsychological tests should be performed. PMID- 26953015 TI - Express approval of immune checkpoint inhibitors: a conflict between science and finance. PMID- 26953017 TI - Diabetic retinopathy: Battling the global epidemic. PMID- 26953018 TI - Novel pharmacotherapies in diabetic retinopathy: Current status and what's in the horizon? AB - The blood-retinal barrier (BRB) alteration is the hallmark feature of diabetic retinopathy. Vascular endothelial growth factor (VEGF) is a potent vasopermeability factor that has been implicated in the pathogenesis of BRB alteration. Inflammation also plays a crucial role in this process with involvement of several chemokines and cytokines. Multiple anti-VEGF drugs are widely used as in the treatment of diabetic macular edema (DME) as well as proliferative diabetic retinopathy. Several clinical trials have proved the beneficial effects of these drugs in improvement of vision and prevention of vision loss. However, the response to anti-VEGF drugs in DME is not complete in a significant number of patients. The effect seems transient in this latter group, and many patients do not show complete resolution of fluid. Potential novel therapies targeting molecules beyond VEGF are being developed and examined in clinical trials. PMID- 26953020 TI - Automated detection of diabetic retinopathy in retinal images. AB - Diabetic retinopathy (DR) is a disease with an increasing prevalence and the main cause of blindness among working-age population. The risk of severe vision loss can be significantly reduced by timely diagnosis and treatment. Systematic screening for DR has been identified as a cost-effective way to save health services resources. Automatic retinal image analysis is emerging as an important screening tool for early DR detection, which can reduce the workload associated to manual grading as well as save diagnosis costs and time. Many research efforts in the last years have been devoted to developing automatic tools to help in the detection and evaluation of DR lesions. However, there is a large variability in the databases and evaluation criteria used in the literature, which hampers a direct comparison of the different studies. This work is aimed at summarizing the results of the available algorithms for the detection and classification of DR pathology. A detailed literature search was conducted using PubMed. Selected relevant studies in the last 10 years were scrutinized and included in the review. Furthermore, we will try to give an overview of the available commercial software for automatic retinal image analysis. PMID- 26953019 TI - Evidence-based review of diabetic macular edema management: Consensus statement on Indian treatment guidelines. AB - The purpose of the study was to review the current evidence and design a diabetic macular edema (DME) management guideline specific for India. The published DME guidelines from different organizations and publications were weighed against the practice trends in India. This included the recently approved drugs. DME management consisted of control of diabetes and other associated systemic conditions, such as hypertension and hyperlipidemia, and specific therapy to reduce macular edema. Quantification of macular edema is precisely made with the optical coherence tomography and treatment options include retinal laser, intravitreal anti-vascular endothelial growth factors (VEGF), and implantable dexamethasone. Specific use of these modalities depends on the presenting vision and extent of macular involvement. Invariable eyes with center-involving macular edema benefit from intravitreal anti-VEGF or dexamethasone implant therapy, and eyes with macular edema not involving the macula center benefit from retinal laser. The results are illustrated with adequate case studies and frequently asked questions. This guideline prepared on the current published evidence is meant as a guideline for the treating physicians. PMID- 26953021 TI - The effect of anterior transposition of the inferior oblique muscle on eyelid configuration and function. AB - PURPOSE: To evaluate the alteration of lower lid configuration and function with anterior transposition surgery of the inferior oblique (IO) muscle. PATIENTS AND METHODS: A prospective clinical trial was conducted on a consecutive series of patients underwent anterior transposition of the IO as a sole operation. All patients received a thorough ophthalmic examination 1 day before and 3 months after surgery. Output parameters were consisted of palpebral fissure, margin reflex distance 1-2, lower lid function, hertel value, and lower lid crease. The differences of the collected data were calculated for statistical significance by using the Wilcoxon test. RESULTS: A total of 19 eyes of 16 consecutive patients were included. The median preoperative grade of IO overaction was 3.5 (ranging from 3 to 4), which decreased to 0 (ranging from 0 to 2) postoperatively (P < 0.05). No significant change was observed in all parameters 3 months postoperatively (P > 0.05). CONCLUSION: In this study, no significant effect on lower lid configuration and function was observed following IO anterior transposition in which the disinserted muscle was placed posterior to inferior rectus insertion. PMID- 26953022 TI - Prevalence of diabetic retinopathy in India: The All India Ophthalmological Society Diabetic Retinopathy Eye Screening Study 2014. AB - AIM: The aim of this study is to ascertain the prevalence of diabetic retinopathy (DR) in diabetic patients across the nation and attempt to establish history based risk factors. MATERIALS AND METHODS: A cross-sectional study of diabetic patients was conducted as an initiative of the All India Ophthalmological Society from 14th November to 21st November 2014. Known diabetics were evaluated voluntarily by members of the society at 194 centers using a structured protocol provided by the society for examination. The results were evaluated to ascertain the prevalence of DR in the population studied and to establish relation with gender, age, and history-based risk factors such as duration of diabetes, insulin use, and other end-organ disease using the Chi-square test. RESULTS: A total of 6218 known diabetics were screened. Totally, 5130 data entry forms were considered suitable for further evaluation. About 61.2% were males, 88.6% were between 40 and 80 years of age, almost two-thirds of the patients were from the west and south zones, and over half had diabetes more than 5 years. The data set was predominantly urban 84.7% and 46.1% had no family history. DR prevalence in the entire data set was 21.7%. Prevalence was more in males (P = 0.007), diabetics more than 5 years (P = 0.001), those above 40 years (P = 0.01), insulin users (P = 0.001), and history of vascular accidents (P = 0.0014). Significantly 22.18% of patients detected with DR had a vision of 6/18 or better in the worse eye. CONCLUSION: The study reiterated the findings of earlier regional studies on a pan Indian scale and put data in perspective. PMID- 26953023 TI - Iris-claw intraocular lens implantation: Anterior chamber versus retropupillary implantation. AB - PURPOSE: To compare the outcomes of anterior chamber and retropupillary implantation of iris-claw Artisan intraocular lenses (IOL). DESIGN: Prospective, randomized, single-blinded study. PATIENTS AND METHODS: Forty eyes of forty aphakic patients were enrolled. Patients were randomized into two groups. Each group includes twenty patients. Group 1 received anterior chamber Artisan IOL implantation. Group 2 received retropupillary Artisan IOL implantation. Preoperative and postoperative corrected distance visual acuity (CDVA), intraocular pressure (IOP), and all complications were noted and compared at 6 months follow-up. RESULTS: Each two groups obtained a significant improvement in CDVA (P < 0.05). Four patients in Group 1 and five patients in Group 2 had significant but nonpermanent increase at IOP values. There were one and two pupillary irregularity in Group 1 and Group 2, respectively. In one patient, a shallow and inferior located retinal detachment were encountered in anterior chamber group. CONCLUSIONS: The results were not significantly different between the two fixation techniques for iris-claw lens. The surgery procedure is dependent to surgeon experience and eye's conditions. PMID- 26953024 TI - Diabetic care initiatives to prevent blindness from diabetic retinopathy in India. AB - It is estimated that 65 million (17%) of 382 million persons with diabetes mellitus (DM) globally reside in India. While globally 35% persons with DM have diabetic retinopathy (DR), this proportion is reportedly lower in India, other countries in South Asia and China. We reviewed published data from 2008 onwards from PubMed, which ascertained DR in population-based representative samples. We also reviewed the risk factors for DR, on awareness regarding eye complications and on accessing an eye examination. Thirteen research studies have reported on the prevalence of DR among persons with DM; this prevalence was lower than the global level in China, India, and Nepal. Eleven studies reported DR risk factors association. The duration of diabetes and level of glycemic control were universally acknowledged DR risk factors. We identified 7 studies in the Asia region that researched the level of awareness about diabetes eye complications and the practice of accessing an eye examination. Excepting 1 study in China, others reported a significant proportion being aware that diabetes leads to eye complications. But the awareness was not translated into a positive practice-most studies reported only 20-50% of the persons with diabetes actually having had their eyes examined. The present review highlights the observation that the risk factors for DR need an integrated diabetic care pathway where the eye care team has to work in close collaboration and partnership with a diabetic care team has to reduce the risk of blindness from DR. PMID- 26953025 TI - Genetic components in diabetic retinopathy. AB - Diabetic retinopathy (DR) is a serious complication of diabetes, which is fast reaching epidemic proportions worldwide. While tight glycemic control remains the standard of care for preventing the progression of DR, better insights into DR etiology require understanding its genetic basis, which in turn may assist in the design of novel treatments. During the last decade, genomic medicine is increasingly being applied to common multifactorial diseases such as diabetes and age-related macular degeneration. The contribution of genetics to the initiation and progression of DR has been recognized for some time, but the involvement of specific genes and genetic variants remains elusive. Several investigations are currently underway for identifying DR susceptibility loci through linkage studies, candidate gene approaches, and genome-wide association studies. Advent of next generation sequencing and high throughput genomic technologies, development of novel bioinformatics tools and collaborations among research teams should facilitate such investigations. Here, we review the current state of genetic studies in DR and discuss reported findings in the context of biochemical, cell biological and therapeutic advances. We propose the development of a consortium in India for genetic studies with large cohorts of patients and controls from limited geographical areas to stratify the impact of the environment. Uniform guidelines should be established for clinical phenotyping and data collection. These studies would permit identification of genetic loci for DR susceptibility in the Indian population and should be valuable for better diagnosis and prognosis, and for clinical management of this blinding disease. PMID- 26953027 TI - Diabetic retinopathy: An epidemic at home and around the world. AB - Prevention of blindness due to diabetic retinopathy (DR) requires effective screening strategies, for which eye care providers need to know the magnitude of the burden and the risk factors pertinent in their geographical location. It is estimated that around 72 million of the global adult population (around 8.2%) has diabetes and about one-fifth of all adults with diabetes lives in the South-East Asia. In India, around 65 million people have diabetes. As the global prevalence of diabetes increases, so will the number of people with diabetes-related complications, such as DR; nearly one-third of them are likely to develop this complication. This article reviews the present status of diabetes and DR in India, the current situation of DR services and the projections on the load of morbidity associated with retinopathy. The article compiles the Indian studies elucidating the risk factors for DR. PMID- 26953028 TI - Advances in retinal imaging for diabetic retinopathy and diabetic macular edema. AB - Diabetic retinopathy and diabetic macular edema (DME) are leading causes of blindness throughout the world, and cause significant visual morbidity. Ocular imaging has played a significant role in the management of diabetic eye disease, and the advent of advanced imaging modalities will be of great value as our understanding of diabetic eye diseases increase, and the management options become increasingly varied and complex. Color fundus photography has established roles in screening for diabetic eye disease, early detection of progression, and monitoring of treatment response. Fluorescein angiography (FA) detects areas of capillary nonperfusion, as well as leakage from both microaneurysms and neovascularization. Recent advances in retinal imaging modalities complement traditional fundus photography and provide invaluable new information for clinicians. Ultra-widefield imaging, which can be used to produce both color fundus photographs and FAs, now allows unprecedented views of the posterior pole. The pathologies that are detected in the periphery of the retina have the potential to change the grading of disease severity, and may be of prognostic significance to disease progression. Studies have shown that peripheral ischemia may be related to the presence and severity of DME. Optical coherence tomography (OCT) provides structural detail of the retina, and the quantitative and qualitative features are useful in the monitoring of diabetic eye disease. A relatively recent innovation, OCT angiography, produces images of the fine blood vessels at the macula and optic disc, without the need for contrast agents. This paper will review the roles of each of these imaging modalities for diabetic eye disease. PMID- 26953026 TI - Does tight control of systemic factors help in the management of diabetic retinopathy? AB - Diabetic retinopathy (DR), one of the leading causes of preventable blindness, is associated with many systemic factors that contribute to the development and progression of this microvascular complication of diabetes. While the duration of diabetes is the major risk factor for the development of DR, the main modifiable systemic risk factors for development and progression of DR are hyperglycemia, hypertension, and dyslipidemia. This review article looks at the evidence that control of these systemic factors has significant benefits in delaying the onset and progression of DR. PMID- 26953029 TI - Telemedicine in diabetic retinopathy: Access to rural India. AB - Diabetic retinopathy (DR) is a growing concern in India. The first step in management of DR is timely screening. With 10% prevalence in rural India, 11 million people are likely to have DR by the year 2030. With limited resources and skilled manpower, it will not be possible to have routine eye examination to identify and treat these patients on a regular basis. Telemedicine is a possible answer in these situations where patients could be remotely screened and appropriately advised. With the advent of several technological advances such as low cost hand-held nonmydriatic camera, increased capabilities of the smartphones to take external eye and retinal photographs coupled with improving broadband connectivity; teleophthalmology in the management of DR could be a reality in the not too distant future. PMID- 26953030 TI - An unusual presentation of nonarteritic ischemic optic neuropathy with subretinal fluid treated with intravitreal bevacizumab. AB - A 62-year-old hypertensive male presented with acute nonarteritic ischemic optic neuropathy (NAION) with contiguous macular edema and subretinal fluid in the right eye. Presenting vision was 20/1000. The patient was treated with intravitreal bevacizumab 1.25 mg/0.05 ml. At 1 month follow-up, the macular edema and the optic nerve head edema completely resolved with a good visual improvement up to 20/40. The visual improvement was maintained at the last follow-up 6 months postinjection. Intravitreal bevacizumab may be a good option for acute NAION especially in an unusual presentation with macular edema and subretinal fluid. PMID- 26953031 TI - A rare case of traumatic posterior phacocele with retinal detachment. AB - Dislocation of crystalline lens into the anterior subconjunctival or subtenon's space is a rare but known complication of blunt trauma. Dislocation into the posterior subtenon's space is even rarer and can be associated with a complication such as occult scleral tear and retinal detachment. We report a case of traumatic posterior subtenon's dislocation of crystalline lens after blunt trauma and its successful surgical management. PMID- 26953032 TI - Large exotropia after retrobulbar anesthesia. AB - A 67-year-old woman complained of horizontal diplopia shortly following bilateral cataract surgery with intraocular lens implantation performed under retrobulbar anesthesia. Retrobulbar anesthesia was administered at an inferotemporal injection site using 1 cc lidocaine hydrochloride 2% mixed with bupivacaine hydrochloride 0.5%. The initial ophthalmologic evaluation showed a 12-prism diopter (PD) exotropia, and ocular motility evaluation revealed marked limitation of adduction without vertical limitation. One year after cataract surgery, the exodeviation increased up to 60 PD. The patient underwent an 8.0-mm recession of the right lateral rectus and a 6.0-mm recession of the left lateral rectus. Both lateral rectus muscles were biopsied, and biopsy revealed dense fibrous connective tissue without viable muscular cells. The lateral rectus muscle might be injured by retrobulbar anesthesia, and it could induce large exotropia. PMID- 26953033 TI - Rehabilitation of orbital defect with silicone orbital prosthesis retained by dental implants. AB - Orbital defects can result from cancer, birth anomalies, or trauma leading to an onslaught of problems in the function and psyche of the patient. These defects are restored by surgical reconstruction and followed by placement of orbital prosthesis for cosmetic makeup. The use of dental implants in retaining orbital prosthesis improves patient acceptance of the prosthesis owing to better retention and stability than conventional adhesive retained prosthesis. This case report describes a custom-made magnetic retentive assembly anchored by a dental implant which offers the orbital prosthesis the simplicity of self-alignment and ease of use. PMID- 26953034 TI - Analyzing the role of intravitreal bevacizumab and pars plana vitrectomy in nontractional refractory diabetic macular edema. PMID- 26953035 TI - Authors' reply. PMID- 26953036 TI - Vogt-Koyanagi-Harada Syndrome following influenza vaccination. PMID- 26953037 TI - Comment on: Intraocular pressure and anetrior segment anatomy after phacoemulsification surgery. PMID- 26953038 TI - Authors' reply. PMID- 26953039 TI - Comment on: Choroidal thickness is affected by smoking and mydriatics. PMID- 26953040 TI - Authors' reply. PMID- 26953041 TI - Dual institution experience of extranodal marginal zone lymphoma reveals excellent long-term outcomes. AB - Extranodal marginal zone lymphoma (EMZL) is a B-cell lymphoma arising from mucosa associated lymphoid tissue (MALT). The disease characteristics, clinical course and treatment vary considerably based on site of involvement. Because long-term outcome data for EMZL are limited, we sought to describe the clinical details of a large number of patients with EMZL evaluated at the Case Comprehensive Cancer Center over a 12-year period to identify prognostic markers including the impact of site of involvement. We identified 211 cases of EMZL involving the stomach (30%), ocular adnexa (19%), lungs (16%) and intestines (9%). Initial treatment included antibiotics (18%), radiation (21%), rituximab (20%), chemotherapy (3%), rituximab + chemotherapy (7%), surgery (17%) or observation (8%). After a median follow-up of 44.3 months (range 2.2-214.9), median progression-free survival (PFS) was 68.2 months (95% confidence interval [CI] 54.5-111.3) and median overall survival (OS) has not been reached. Age >60 years, elevated lactate dehydrogenase level (LDH), >=4 lymph node groups involvement, and high follicular lymphoma international prognostic index (FLIPI) were associated with inferior PFS/OS. In summary, patients with EMZL have excellent prognosis with median OS in excess of 10 years. Age, elevated LDH, advanced disease, and high FLIPI score are associated with worse outcomes. PMID- 26953042 TI - Spatially multiplexed dark-field microspectrophotometry for nanoplasmonics. AB - Monitoring the effect of the substrate on the local surface plasmon resonance (LSPR) of metallic nanoparticles is key for deepening our understanding of light matter interactions at the nanoscale. This coupling gives rise to shifts of the LSPR as well as changes in the scattering pattern shape. The problem requires of high-throughput techniques that present both high spatial and spectral resolution. We present here a technique, referred to as Spatially Multiplexed Micro-Spectrophotometry (SMMS), able to perform polarization-resolved spectral and spatial analysis of the scattered light over large surface areas. The SMMS technique provides three orders of magnitude faster spectroscopic analysis than conventional dark-field microspectrophotometry, with the capability for mapping the spatial distribution of the scattered light intensity with lateral resolution of 40 nm over surface areas of 0.02 mm(2). We show polarization-resolved dark field spectral analysis of hundreds of gold nanoparticles deposited on a silicon surface. The technique allows determining the effect of the substrate on the LSPR of single nanoparticles and dimers and their scattering patterns. This is applied for rapid discrimination and counting of monomers and dimers of nanoparticles. In addition, the diameter of individual nanoparticles can be rapidly assessed with 1 nm accuracy. PMID- 26953043 TI - Clear cell variant of intraosseous calcifying epithelial odontogenic tumor: a case report and review of the literature. AB - CEOT is a rare benign, but locally aggressive odontogenic tumor, and some authors have claimed that the biologic behavior of the clear cell variant is even more aggressive, with greater propensity to recur. We report a rare case of clear cell calcifying epithelial odontogenic tumor (CEOT) and discuss its possibly aggressive behavior. A 40-year-old woman experienced an asymptomatic expansion of the left posterior mandible. After radiographic examination and biopsy, a block resection was performed. Histologic examination included analysis of Ki-67 reactivity as a marker of tumor growth activity. Ki-67 labeling was pronounced in the non-clear cell population in the tumor periphery but low in the central and clear cell portions. Clinical and radiographic follow-up 6 years after resection has not revealed any signs of recurrence. On the basis of a review of the literature and our own findings, there is no clear data to suggest that clear cell CEOT exhibits more aggressive behavior compared with conventional CEOT. PMID- 26953044 TI - Postoperative relapse after mandibular setback surgery with perioperative counterclockwise rotation of the mandibular proximal segment. AB - OBJECTIVE: This study aimed to evaluate whether the perioperative counterclockwise rotation (CCWR) of the proximal segment (PS) can reduce relapse after mandibular setback surgery. STUDY DESIGN: Patients who underwent less than 1 degrees of bilateral perioperative rotation of the PS were assigned to group I (n = 15). Group II (n = 14) included patients who showed greater than 1 degrees of perioperative CCWR bilaterally. To evaluate the PS rotation and the relapse, three-dimensional computed tomography (CT) and lateral cephalography scans were analyzed. RESULTS: Even with significantly different perioperative CCWR of the PS (.07 +/- .53 degrees vs -3.47 +/- 1.55 degrees ), the relapse was not significantly different between group I (1.96 +/- 1.15 mm) and group II (1.81 +/- .92 mm). However, postoperative CCWR of the PS was significantly greater in group I. The relapse was not influenced by the amount of setback. CONCLUSIONS: A small degree of relapse is expected after mandibular setback surgery, even with perioperative CCWR of the PS. PMID- 26953061 TI - Using Fresh Frozen Plasma for Acute Airway Angioedema to Prevent Intubation in the Emergency Department: A Retrospective Cohort Study. AB - Background. Angioedema (AE) is a common condition which can be complicated by laryngeal edema, having up to 40% mortality. Although sporadic case reports attest to the benefits of fresh frozen plasma (FFP) in treating severe acute bouts of AE, little evidence-based support for this practice is available at present. Study Objectives. To compare the frequency, duration of intubation, and length of intensive care unit (ICU) stay in patients with acute airway AE, with and without the use of FFP. Methods. A retrospective cohort study was conducted, investigating adults admitted to large community hospital ICU with a diagnosis of AE during the years of 2007-2012. Altogether, 128 charts were reviewed for demographics, comorbidities, hospital courses, and outcomes. A total of 20 patients received FFP (108 did not). Results. Demographics and comorbidities did not differ by treatment group. However, nontreated controls did worse in terms of intubation frequency (60% versus 35%; p = 0.05) and ICU stay (3.5 days versus 1.5 days; p < 0.001). Group outcomes were otherwise similar. Conclusion. In an emergency department setting, the use of FFP should be considered in managing acute airway nonhereditary AE (refractory to steroid, antihistamine, and epinephrine). Larger prospective, better controlled studies are needed to devise appropriate treatment guidelines. PMID- 26953062 TI - Cardiac Examination: Stethoscope or Pocket Echo-Why Not Both? PMID- 26953063 TI - Integrating Physical Activity in Primary Care Practice. AB - Based on a collaborative symposium in 2014 hosted by the Society of Behavioral Medicine (SBM) and the American College of Sports Medicine (ACSM), this paper presents a model for physical activity counseling for primary care physicians (PCPs). Most US adults do not meet national recommendations for physical activity levels. Socioecological factors drive differences in physical activity levels by geography, sex, age, and racial/ethnic group. The recent Patient Protection and Affordable Care Act incentivizes PCPs to offer patients physical activity counseling. However, PCPs have reported socioecological barriers to physical activity counseling and also patient barriers to physical activity, spanning from the individual to the environmental (eg, lack of safe spaces for physical activity), policy (eg, reimbursement policies), and organizational (eg, electronic medical record protocols, worksite norms/policies) levels. The aims of this paper are to: 1) discuss barriers to PCP counseling for physical activity; 2) provide evidence-based strategies and techniques to help PCPs address these counseling barriers; and 3) suggest practical steps for PCPs to counsel patients on physical activity using strategies and supports from policy, the primary care team, and other support networks. PMID- 26953065 TI - Acta Neuropsychiatrica; Tijdschrift voor een hedendaagse neuropsychiatrie. AB - Samenvatting De psychiatrie benist op een evenwichtige combinatie van gedragswetenschappelijke (ontwikkelingspsychologische en sociale) en natuurwetenschappelijke (neuropsychiatri-sche) dementen. Ofschoon klinici werkzaam in de gezondheidszorg er vaak in slaagden dit evenwicht rede-lijk te handhaven, werd de officiele psychiatrie tot voor kort meestal nogal modieus gedomineerd door een van deze deelgebieden. Uitgroei tot volwassenheid van de psychiatrie vraagt in deze fase om een aanvulling van de in de laatste decennien sterk tot de verbeelding sprekende psychologische en sociale dementen met de verworvenhe-den van een nieuwe neuropsychiatrie. Geschetst wordt waar uit deze verworvenheden bestaan en hoe deze effectief in de psychiatrische gezondheidszorg onderwijs en onderzoek ingebouwd kunnen worden. Het binnen de psychiatrie tot ontwikkeling brengen van een toegepaste klinische psychofysiologie van essentieel belang. PMID- 26953064 TI - Improving ruminal degradability and energetic values of bamboo shoot shell using chemical treatments. AB - This study evaluated effects of different treatments on nutritive value of bamboo shoot shell (BSS). Five treatments were sun-drying (control), ammoniation (5%/dry matter (DM) urea), Ca(OH)2 (4%/DM calcium hydroxide), NaOH (4%/DM sodium hydroxide), and AHP (4%/DM sodium hydroxide plus 1%/DM hydrogen peroxide). The results showed that chemical composition of BSS was greatly changed by chemicals (P < 0.01) except acid-detergent lignin. All chemical treatments significantly reduced neutral detergent fiber (NDF) content except AHP (P < 0.01), and obviously increased acid detergent fiber (ADF) content (P < 0.01) except ammoniation. The predicted organic matter digestibility, metabolizable energy and net energy for lactation of BSS were greatly increased by chemical treatments (P < 0.01), the highest for ammoniation, followed by Ca(OH)2 , NaOH and AHP. Ammoniation had higher (P = 0.03) ammonia-N concentration than the other four treatments. There were significant differences among all treatments on total volatile fatty acids (P = 0.03), propionate (P = 0.01), butyrate concentration (P < 0.01) and C2 /C3 ratio (P = 0.02). Chemical treatments greatly improved effective degradability (ED) of DM (P < 0.01) and ED of NDF (P = 0.06) and ADF (P = 0.07) numerically. Ammoniation got a higher ED of crude protein than control. In conclusion, all chemical treatments greatly improved nutritive value of BSS with highest value obtained from ammoniation, followed by strong alkalization, alkaline hydrogen peroxide and modest alkalization. PMID- 26953067 TI - Acta Neuropsychiatrica: 'A new beginning'. PMID- 26953066 TI - Combination of Analytical and Chemometric Methods as a Useful Tool for the Characterization of Extra Virgin Argan Oil and Other Edible Virgin Oils. Role of Polyphenols and Tocopherols. AB - Analysis of phenolic profile and tocopherol fractions in conjunction with chemometrics techniques were used for the accurate characterization of extra virgin argan oil and eight other edible vegetable virgin oils (olive, soybean, wheat germ, walnut, almond, sesame, avocado, and linseed) and to establish similarities among them. Phenolic profile and tocopherols were determined by HPLC coupled with diode-array and fluorescence detectors, respectively. Multivariate factor analysis (MFA) and linear correlations were applied. Significant negative correlations were found between tocopherols and some of the polyphenols identified, but more intensely (P < 0.001) between the gamma-tocopherol and oleuropein, pinoresinol, and luteolin. MFA revealed that tocopherols, especially gamma-fraction, most strongly influenced the oil characterization. Among the phenolic compounds, syringic acid, dihydroxybenzoic acid, oleuropein, pinoresinol, and luteolin also contributed to the discrimination of the oils. According to the variables analyzed in the present study, argan oil presented the greatest similarity with walnut oil, followed by sesame and linseed oils. Olive, avocado, and almond oils showed close similarities. PMID- 26953068 TI - Association between CYP1A2 gene single nucleotide polymorphisms and clinical responses to clozapine in patients with treatment-resistant schizophrenia. AB - OBJECTIVES: Despite clozapine's superior clinical efficacy in treatment-resistant schizophrenia (TRS), its adverse effects, need for periodic leukocyte monitoring, cost and variable clinical outcomes mandate a clinical need to predict its treatment response. Although cytochrome P450 1A2 (CYP1A2) is the principal determinant of metabolism of clozapine, the role of CYP1A2 gene in the clinical response to clozapine is uncertain. Hence, we investigated its association with treatment responses and adverse events of clozapine in TRS. METHODS: We evaluated four single nucleotide polymorphisms (SNP) in the CYP1A2 gene, clinical responses and serum clozapine levels in 101 consecutive patients with TRS on stable doses of clozapine. We defined clozapine response a priori and investigated allelic and genotypic associations. We assessed the socio-demographic and clinical profiles, premorbid adjustment, traumatic life events, cognition and disability of the participants, using standard assessment schedules for appropriate multivariate analyses. RESULTS: Our results revealed that CYP1A2 gene SNP (*1C, *1D, *1E and *1F) were not associated with clozapine treatment response, adverse effects, serum clozapine levels or with disability (p values > 0.10). CONCLUSION: As CYP1A2 gene SNP do not help to predict the clinical response to clozapine, routine screening for them prior to start clozapine is currently unwarranted. We suggest future longitudinal genome-wide association studies investigating clinical and pharmacogenetic variables together. PMID- 26953069 TI - Protective effect of dl-3n-butylphthalide preconditioning on focal cerebral ischaemia-reperfusion injury in rats. AB - OBJECTIVE: To investigate the effect of dl-3n-butylphthalide (NBP) on the protection of cerebral tissue and possible mechanism on ischaemia-reperfusion injury, and to find out whether NBP therapy can extend the reperfusion window in an experimental stroke model in rats. METHODS: Seventy-two Sprague-Dawley rats were randomly divided into sham operation, ischaemia-reperfusion and ischaemia reperfusion with NBP groups. Focal cerebral ischaemia was induced using the modified intraluminal thread method and maintained for 2, 3 or 4 h. The ischaemia reperfusion group received reperfusion immediately after ischaemia-reperfusion. The NBP group received intraperitoneal injection of NBP immediately after ischaemia, followed by reperfusion. The sham operation group received only injection of physiological saline. The cerebral infarction volume and neurological deficit were analysed, and vascular endothelial growth factor (VEGF) expression in brain tissues was visualised by immunohistochemistry. RESULTS: NBP treatment caused a significant decrease in both infarction volume and neurological deficit compared with the ischaemia-reperfusion group at corresponding time points in each (p < 0.05). In the NBP group, the infarction volume and neurological deficit did not change with different ischaemia times. The expression of VEGF was significantly decreased in the ischaemia-reperfusion group compared with the sham group (p < 0.01), while this change was partly prevented in the NBP group (p < 0.01). The expression of VEGF in brain tissue in both the NBP and ischaemia-reperfusion groups gradually decreased when the ischaemic period was prolonged. CONCLUSION: NBP treatment has a protective effect against cerebral ischaemia; this possible mechanism maybe related to the VEGF expression and may extend the reperfusion window for subsequent salvage of cerebral ischaemia by reperfusion. PMID- 26953070 TI - In vitro effect of antipsychotics on brain energy metabolism parameters in the brain of rats. AB - OBJECTIVE: Typical and atypical antipsychotic drugs have been shown to have different clinical, biochemical and behavioural profiles. It is well described that impairment of metabolism, especially in the mitochondria, leads to oxidative stress and neuronal death and has been implicated in the pathogenesis of a number of diseases in the brain. In this context, we investigated the in vitro effect of antipsychotic drugs on energy metabolism parameters in the brain of rats. METHODS: Clozapine (0.1, 0.5 and 1.0 mg/ml), olanzapine (0.1, 0.5 and 1.0 mg/ml) and aripiprazole (0.05, 0.15 and 0.3 mg/ml) were suspended in buffer and added to the reaction medium containing rat tissue homogenates and the respiratory chain complexes, succinate dehydrogenase and creatine kinase (CK) activities were evaluated. RESULTS: Our results showed that olanzapine and aripriprazole increased the activities of respiratory chain complexes. On the other hand, complex IV activity was inhibited by clozapine, olanzapine and aripriprazole. CK activity was increased by clozapine at 0.5 and 1.0 mg/ml in prefrontal cortex, cerebellum, striatum, hippocampus and posterior cortex of rats. Moreover, olanzapine and aripiprazole did not affect CK activity. CONCLUSION: In this context, if the hypothesis that metabolism impairment is involved in the pathophysiology of neuropsychiatric disorders is correct and these results also occur in vivo, we suggest that olanzapine may reverse a possible diminution of metabolism. PMID- 26953071 TI - Antiallodynia and antihyperalgesia effects of ceftriaxone in treatment of chronic neuropathic pain in rats. AB - OBJECTIVE: Neuropathic pain is a chronic and disabling syndrome with complex pathogenesis. It has been suggested that the function of glutamate transporters (GLTs) has a major role in the development of neuropathic pain. This study was performed to evaluate various doses of ceftriaxone, a beta-lactam antibiotic, on the symptoms in the rat chronic constriction injury (CCI) model of neuropathic pain. This drug has been recently introduced as a selective up-regulator and activator of GLT1. METHODS: Neuropathy was induced in adult male Wistar rats and animals were treated intraperitoneally with 100-400 mg/kg of ceftriaxone for seven consecutive days immediately after surgery. Gabapentin (100 mg/kg, i.p.) was used as a reference drug. von Frey filaments, acetone drop and radiant heat methods were used to assess mechanical allodynia, thermal allodynia and thermal hyperalgesia, respectively. RESULTS: Ceftriaxone in the repeated doses for 7 days showed significant antiallodynic and antihyperalgesic effects especially at a dose of 200 mg/kg twice a day. CONCLUSION: The results suggest that ceftriaxone as a modulator of glutamate uptake could provide beneficial effects in the treatment of chronic neuropathic pain, especially allodynia that is less sensitive to the most available drugs. PMID- 26953072 TI - Heart rate variability in patients with fully remitted major depressive disorder. AB - OBJECTIVE: Cardiac autonomic dysregulation has been reported in major depressive disorder (MDD), but scarce studies investigated that in fully remitted MDD. METHODS: To examine cardiac autonomic function in remitted MDD, 470 unmedicated individuals with a diagnosis of MDD earlier in life and 462 healthy volunteers, aged 18-65 years, were recruited for a case-control analysis. Cardiac autonomic function was evaluated by measuring heart rate variability (HRV) parameters. Frequency-domain indices of HRV were obtained. The obtained results were evaluated in association with personality traits assessed by the Tridimensional Personality Questionnaire. RESULTS: In patients with remitted MDD, no differences in RR intervals and all frequency-domain indices of HRV could be detected as compared with controls. Stratified analyses by the presence of a history of suicide ideation (the SI+ vs. the SI-subgroup) revealed decreased cardiac vagal control in the SI+ subgroup. The correlation analysis revealed an inverse relation between HRV levels and the harm avoidance score (which has been suggested to be associated with serotonergic activity), mainly attributable to the robust association in the SI+ subgroup. CONCLUSION: Our study shows that cardiac autonomic dysregulation is not shown in remitted MDD patients as a whole but is limited to the subgroup of remitted MDD patients with a history of suicidal ideation. In view of the higher risk for cardiac complications in these vulnerable individuals, one might consider the treatment to restore their autonomic function. PMID- 26953073 TI - The neural correlates of self-paced finger tapping in bipolar depression with motor retardation. AB - OBJECTIVE: Motor retardation is a characteristic feature of bipolar depression, and is also a core feature of Parkinson's disease. Within the framework of the functional deafferentiation theory in Parkinson's disease, we hypothesised that motor retardation in bipolar depression is mediated by disrupted subcortical activation, leading to decreased activation of cortical motor areas during finger tapping. METHODS: We used functional magnetic resonance imaging to investigate neural activity during self-paced finger tapping to elucidate whether brain regions that mediate preparation, control and execution of movement are activated differently in subjects with bipolar depression (n = 9) compared to healthy controls (n = 12). RESULTS: An uncorrected whole-brain analysis revealed significant group differences in dorsolateral and ventromedial prefrontal cortex. Corrected analyses showed non-significant differences in patients compared to controls: decreased and less widespread activation of the left putamen and left pallidum; increased activity in the left thalamus and supplementary motor area; decreased activation in the left lateral pre- and primary motor cortices; absence of activation in the pre-supplementary motor area; activation of the bilateral rostral cingulate motor area. CONCLUSION: Both movement preparation and execution may be affected in motor retardation, and the activity in the whole left-side motor circuit is altered during self-initiated motor performance in bipolar depression. PMID- 26953074 TI - Early intervention for conversion disorder: neurologists and psychiatrists working together. AB - OBJECTIVE: To evaluate the efficacy of an early multidisciplinary (neurology and psychiatry) intervention for conversion disorder (CD). METHODS: Consecutive patients newly diagnosed with CD from 2005 to 2007 were compared to a control group of newly diagnosed CD patients receiving usual care. At 3 years, a questionnaire evaluated self-rated subjective outcome, symptom severity, SF-36 scores, employment status and medical care use. RESULTS: Data from 12 cases (mean age 25.5 +/- 8.2; 9 females) and 11 controls (mean age 34.7 +/- 13.5; 10 females) showed that 83% of cases had a good subjective outcome (symptom improved or cured) when only 36% of controls had a good outcome (p < 0.05). Cases significantly improved their SF-36 scores on subscales involving physical complaints compared to controls. A minority (20%) of cases reduced or ceased professional activity when 70% of controls did (p < 0.001). Only 16% of cases sought further medical advice for the initial symptom when 73% of controls did. Both groups accepted psychiatric referrals (83% of cases and 73% of controls) and found it beneficial. CONCLUSIONS: Early intervention involving both neurologists and psychiatrists is effective for CD in alleviating physical complaints, reducing sick leave and health care use. PMID- 26953075 TI - Subclinical arterial and cardiac damage in white-coat and masked hypertension. AB - The study aimed to compare arterial and echocardiographic parameters in subjects with newly diagnosed masked (MH) or white-coat hypertension (WCH) to subjects with sustained normotension or sustained hypertension, defined according to the 2014 European Society of Hypertension practice guidelines for ambulatory blood pressure (BP) monitoring. We recruited 303 participants (mean age 46.9 years) in a family-based population study. SpaceLabs monitors and oscillometric sphygmomanometers were used to evaluate ambulatory and office BP, respectively. Central pulse pressure (PP) and aortic pulse-wave velocity (PWV) were measured with pulse-wave analysis (SphygmoCor software). Carotid intima-media thickness (IMT) and cardiac evaluation were assessed by ultrasonography. Analysing participants without antihypertensive treatment (115 sustained normotensives, 41 sustained hypertensives, 20 with WCH, 25 with MH), we detected significantly higher peripheral and central PP, PWV, IMT and left ventricular mass index in hypertensive subgroups than in those with sustained normotension. The differences between categories remained significant for peripheral PP and PWV after adjustment for confounding factors, including 24 h systolic and diastolic BP. Participants with WCH and MH, defined according to strict criteria, had more pronounced arterial and heart involvement than normotensive participants. The study demonstrates a high prevalence of these conditions in the general population that deserves special attention from physicians. PMID- 26953076 TI - The prospects and promise of chimeric antigen receptor immunotherapy in multiple myeloma. AB - Despite encouraging therapeutic advances, multiple myeloma (MM) remains an incurable malignancy. The exciting results of chimaeric antigen receptor (CAR) based immunotherapy in CD19(+) B-cell malignancies have spurred a great interest in extending the use of the CAR technology to other cancers, including MM. Availability of a specific, tumour-restricted antigen is crucial for the design of successful antibody-based CAR therapy. However, in MM, as in other malignancies, the relative dearth of such antigens-targets represents the main obstacle for the wider pre-clinical development and clinical application of the CAR technology. Here we provide an overview of the current progress and future promises of CAR technology in MM therapy. We highlight that, owing to its complexity, phenotypic and functional heterogeneity and the impact of the microenvironment, MM poses several challenges for CAR-based therapeutic approaches. Nevertheless, for the same reasons, MM can serve as a paradigm for better understanding, optimization and overall improvement of the CAR technology for the benefit of cancer and myeloma patients. PMID- 26953085 TI - Role of 5f electrons in the structural stability of light actinide (Th-U) mononitrides under pressure. AB - Pressure induced structural sequences and their mechanism for light actinide (Th U) mononitrides were studied as a function of 5f-electron number using first principles total energy and electronic structure calculations. Zero pressure lattice constants, bulk module and C11 elastic module vary systematically with 5f electron number implying its direct role on crystal binding. There is a critical 5f-electron number below which the system makes B1-B2 and above it B1-R3m-B2 structural sequence under pressure. Also, the B1-B2 transition pressure increases with increasing 5f-electron number whereas an opposite trend is obtained for the B1-R3m transition pressure. The ascending of N p anti-bonding states through the Fermi level at high pressure is responsible for the structural instability of the system. Above the critical 5f-electron number in the system a narrow 5f-band occurs very close to the Fermi level which allows the system to lower its symmetry via band Jahn-Teller type lattice distortion and the system undergoes a B1-R3m phase transition. However, below the critical 5f-electron number this mechanism is not favorable due to a lack of sufficient 5f-state occupancy and thus the system undergoes a B1-B2 phase transition like other ionic solids. PMID- 26953077 TI - Delta-proteobacterial SAR324 group in hydrothermal plumes on the South Mid Atlantic Ridge. AB - In the dark ocean, the SAR324 group of Delta-proteobacteria has been associated with a chemolithotrophic lifestyle. However, their electron transport chain for energy generation and information system has not yet been well characterized. In the present study, four SAR324 draft genomes were extracted from metagenomes sampled from hydrothermal plumes in the South Mid-Atlantic Ridge. We describe novel electron transport chain components in the SAR324 group, particularly the alternative complex III, which is involved in energy generation. Moreover, we propose that the C-type cytochrome, for example the C553, may play a novel role in electron transfer, adding to our knowledge regarding the energy generation process in the SAR324 cluster. The central carbon metabolism in the described SAR324 genomes exhibits several new features other than methanotrophy e.g. aromatic compound degradation. This suggests that methane oxidation may not be the main central carbon metabolism component in SAR324 cluster bacteria. The reductive acetyl-CoA pathway may potentially be essential in carbon fixation due to the absence of components from the Calvin-Benson cycle. Our study provides insight into the role of recombination events in shaping the genome of the SAR324 group based on a larger number of repeat regions observed, which has been overlooked thus far. PMID- 26953087 TI - Write of reply? PMID- 26953079 TI - Impact of vaginal parity and aging on the architectural design of pelvic floor muscles. AB - BACKGROUND: Vaginal delivery and aging are key risk factors for pelvic floor muscle dysfunction, which is a critical component of pelvic floor disorders. However, alterations in the pelvic floor muscle intrinsic structure that lead to muscle dysfunction because of childbirth and aging remain elusive. OBJECTIVES: The purpose of this study was to determine the impact of vaginal deliveries and aging on human cadaveric pelvic floor muscle architecture, which is the strongest predictor of active muscle function. STUDY DESIGN: Coccygeus, iliococcygeus, and pubovisceralis were obtained from younger donors who were <=51 years old, vaginally nulliparous (n = 5) and vaginally parous (n = 6) and older donors who were >51 years old, vaginally nulliparous (n = 6) and vaginally parous (n = 6), all of whom had no history of pelvic floor disorders. Architectural parameters, which are predictive of muscle's excursion and force-generating capacity, were determined with the use of validated methods. Intramuscular collagen content was quantified by hydroxyproline assay. Main effects of parity and aging and the interactions were determined with the use of 2-way analysis of variance, with Tukey's post-hoc testing and a significance level of .05. RESULTS: The mean age of younger and older donors differed by approximately 40 years (P = .001) but was similar between nulliparous and parous donors within each age group (P > .9). The median parity was 2 (range, 1-3) in younger and older vaginally parous groups (P = .7). The main impact of parity was increased fiber length in the more proximal coccygeus (P = .03) and iliococcygeus (P = .04). Aging changes manifested as decreased physiologic cross-sectional area across all pelvic floor muscles (P < .05), which substantially exceeded the age-related decline in muscle mass. The physiologic cross-sectional area was lower in younger vaginally parous, compared with younger vaginally nulliparous, pelvic floor muscles; however, the differences did not reach statistical significance. Pelvic floor muscle collagen content was not altered by parity but increased dramatically with aging (P < .05). CONCLUSIONS: Increased fiber length in more proximal pelvic floor muscles likely represents an adaptive response to the chronically increased load placed on these muscles by the displaced apical structures, presumably as a consequence of vaginal delivery. In younger specimens, a consistent trend towards decrease in force-generating capacity of all pelvic floor muscles in the parous group suggests a potential mechanism for clinically identified pelvic floor muscle weakness in vaginally parous women. The substantial decrease in predicted muscle force production and fibrosis with aging represent likely mechanisms for the pelvic floor muscle dysfunction in older women. PMID- 26953088 TI - The neurosphere assay, a method under scrutiny. AB - OBJECTIVES: The aim of this review is to provide an overview of the fundamental features of the neurosphere assay (NSA), which was initially described in 1992, and has since been used not only to detect the presence of stem cells in embryonic and adult mammalian neural tissues, but also to study their characteristics in vitro. Implicit in this review is a detailed examination of the limitations of the NSA, and how this assay is most accurately and appropriately used. Finally we will point out criteria that should be challenged to design alternative ways to overcome the limits of this assay. METHODS: NSA is used to isolate putative neural stem cells (NSCs) from the central nervous system (CNS) and to demonstrate the critical stem cell attributes of proliferation, extensive self-renewal and the ability to give rise to a large number of differentiated and functional progeny. Nevertheless, the capability of neural progenitor cells to form neurospheres precludes its utilisation to accurately quantify bona fide stem cell frequency based simply on neurosphere numbers. New culture conditions are needed to be able to distinguish the activity of progenitor cells from stem cells. CONCLUSION: A commonly used, and arguably misused, methodology, the NSA has provided a wealth of information on precursor activity of cells derived from the embryonic through to the aged CNS. Importantly, the NSA has contributed to the demise of the 'no new neurogenesis' dogma, and the beginning of a new era of CNS regenerative medicine. Nevertheless, the interpretations arising from the utilisation of the NSA need to take into consideration its limits, so as not to be used beyond its specificity and sensitivity. PMID- 26953086 TI - Unusual Presentation of Unilateral Isolated Probable Lyme Optic Neuritis. AB - Optic neuritis (ON) is one of the most common manifestations of central nervous system involvement caused by various etiologies. Lyme ON is an exceedingly rare ocular manifestation of Lyme disease (LD) and only a few cases have been published in the literature. Lyme ON is very rare but should be included in the differential diagnosis in unexplained cases, particularly in Lyme endemic areas. Careful and detailed examination and investigation are warranted to make the diagnosis. We report this case to increase awareness of clinicians to include Lyme disease in differential diagnosis of ON for unexplained cases of ON. Herein we present a unique case with a unilateral ON caused by LD along with pre- and posttreatment findings and literature review. PMID- 26953089 TI - ABSTRACTS SCANDINAVIAN COLLEGE OF NEUROPSYCHOPHARMACOLOGY SCNP 54th Annual Meeting, May 3rd - 4th, 2013 Copenhagen, Denmark. PMID- 26953090 TI - Dry powder nasal drug delivery: challenges, opportunities and a study of the commercial Teijin Puvlizer Rhinocort device and formulation. AB - PURPOSE: To discuss the challenges and opportunities for dry powder nasal medications and to put this in to perspective by evaluating and characterizing the performance of the Teijin beclomethasone dipropionate (BDP) dry powder nasal inhaler; providing a baseline for future nasal products development. METHODS: The aerosol properties of the formulation and product performance of Teijin powder intranasal spray were assessed, with a particular focus on particle size distribution (laser diffraction), powder formulation composition (confocal Raman microscope) and aerosol performance data (British Pharmacopeia Apparatus E cascade impactor, aerosol laser diffraction). RESULTS: Teijin Rhinocort((r)) (BDP) dry powder spray formulation is a simple blend of one active ingredient, BDP with hydroxypropylcellulose (HPC) carrier particles and a smaller quantity of lubricants (stearic acid and magnesium stearate). The properties of the blend are mainly those of the carrier (Dv50 = 98 +/- 1.3 um). Almost the totality of the capsule fill weight (96.5%) was emitted with eight actuations of the device. Using the pharmacopeia suggested nasal chamber deposition apparatus attached to an Apparatus E impactor. The BDP main site of deposition was found to be in the nasal expansion chamber (90.2 +/- 4.78%), while 4.64 +/- 1.38% of the BDP emitted dose was deposited on Stage 1 of the Apparatus E. CONCLUSIONS: The Teijin powder nasal device is a simple and robust device to deliver pharmaceutical powder to the nasal cavity, thus highlighting the robustness of intranasal powder delivery systems. The large number of actuations needed to deliver the total dose (eight) should be taken in consideration when compared to aqueous sprays (usually two actuations), since this will impact on patient compliance and consequently therapeutic efficacy of the formulation. PMID- 26953091 TI - Tumour-infiltrating CD8 to FOXP3 lymphocyte ratio in predicting treatment responses to neoadjuvant chemotherapy of aggressive breast cancer. AB - BACKGROUND: Tumour-infiltrating lymphocytes (TILs) can be used to monitor the immune response, and are important in predicting treatment responses and outcomes for various types of cancer. Recently, specific TIL subsets have been reported to be clinically useful in predicting treatment responses. The CD8+/FOXP3+ TIL ratio (CFR) may be a more sensitive indicator for monitoring immune function. This study investigated the clinical significance and value of CFR as a biomarker to predict treatment responses to neoadjuvant chemotherapy for breast cancer. METHODS: Patients with resectable early-stage breast cancer treated with neoadjuvant chemotherapy at Osaka City University Hospital, Japan, between 2007 and 2013 were included. Oestrogen receptor, progesterone receptor, human epidermal growth factor receptor (HER) 2, Ki-67, CD8 and FOXP3 status were assessed by immunohistochemistry, and correlated with pathological complete response (pCR). RESULTS: A total of 177 patients were included, of whom 90 had a high CFR and 87 a low CFR. Triple-negative breast cancer (TNBC) was more common in the high-CFR group than in the low-CFR group (46 versus 23 per cent; P = 0.002), as was HER2-enriched breast cancer (HER2BC) (27 versus 14 per cent; P = 0.033). Among these patients, the pCR rate was significantly higher in the high CFR group than in the low-CFR group (TNBC: P = 0.022; HER2BC: P < 0.001). In multivariable analysis high-CFR status was an independent predictor of a favourable prognosis: hazard ratio 0.24 (95 per cent c.i. 0.05 to 0.72; P = 0.015) for TNBC and 0.10 (0.10 to 0.90; P = 0.041) for HER2BC. CONCLUSION: The CFR may be a useful biomarker to predict treatment response to neoadjuvant therapy in aggressive breast cancer subtypes, such as TNBC and HER2BC. PMID- 26953092 TI - A Web Server and Mobile App for Computing Hemolytic Potency of Peptides. AB - Numerous therapeutic peptides do not enter the clinical trials just because of their high hemolytic activity. Recently, we developed a database, Hemolytik, for maintaining experimentally validated hemolytic and non-hemolytic peptides. The present study describes a web server and mobile app developed for predicting, and screening of peptides having hemolytic potency. Firstly, we generated a dataset HemoPI-1 that contains 552 hemolytic peptides extracted from Hemolytik database and 552 random non-hemolytic peptides (from Swiss-Prot). The sequence analysis of these peptides revealed that certain residues (e.g., L, K, F, W) and motifs (e.g., "FKK", "LKL", "KKLL", "KWK", "VLK", "CYCR", "CRR", "RFC", "RRR", "LKKL") are more abundant in hemolytic peptides. Therefore, we developed models for discriminating hemolytic and non-hemolytic peptides using various machine learning techniques and achieved more than 95% accuracy. We also developed models for discriminating peptides having high and low hemolytic potential on different datasets called HemoPI-2 and HemoPI-3. In order to serve the scientific community, we developed a web server, mobile app and JAVA-based standalone software (http://crdd.osdd.net/raghava/hemopi/). PMID- 26953094 TI - Ability of minus strands and modified plus strands to act as templates in Semliki Forest virus RNA replication. AB - During virus multiplication, the viral genome is recognized and recruited for replication based on specific cis-acting elements. Here, we dissected the important cis-acting sequence elements in Semliki Forest virus RNA by using a trans-replication system. As the viral replicase is expressed from a separate plasmid, the template RNA can be freely modified in this system. We show that the cis-acting element at the beginning of the non-structural protein 1 (nsP1) coding region together with the end of the 3' UTR are the minimal requirements for minus strand synthesis. To achieve a high level of replication, the native 5' UTR was also needed. The virus-induced membranous replication compartments (spherules) were only detected when a replication-competent template was present with an active replicase and minus strands were produced. No translation could be detected from the minus strands, suggesting that they are segregated from the cytoplasm. Minus strands could not be recruited directly to initiate the replication process. Thus, there is only one defined pathway for replication, starting with plus-strand recognition followed by concomitant spherule formation and minus-strand synthesis. PMID- 26953101 TI - It's all about image? PMID- 26953102 TI - Magnetic resonance spectroscopy in anxiety disorders. AB - OBJECTIVE: Magnetic resonance spectroscopy (MRS) is a non-invasive in vivo method used to quantify metabolites that are relevant to a wide range of brain processes. This paper briefly describes neuroimaging using MRS and provides a systematic review of its application to anxiety disorders. METHOD: A literature review was performed in the PubMed, Lilacs and Scielo databases using the keywords spectroscopy and anxiety disorder. References of selected articles were also hand-searched for additional citations. RESULTS: Recent studies have shown that there are significant metabolic differences between patients with anxiety disorders and healthy controls in various regions of the brain. Changes were mainly found in N-acetylaspartate, which is associated with neuronal viability, but some of them were also seen in creatine, a substance that is thought to be relatively constant among individuals with different pathological conditions. CONCLUSIONS: MRS is a sophisticated neuroimaging technique that has provided useful insights into the biochemical and neurobiological basis of many anxiety disorders. Nevertheless, its utilization in some anxiety disorders is still modest, particularly social phobia and generalised anxiety. Although it is an extremely useful advance in neuroimaging, further research in other brain areas and patient populations is highly advisable. PMID- 26953100 TI - Galactinol synthase enzyme activity influences raffinose family oligosaccharides (RFO) accumulation in developing chickpea (Cicer arietinum L.) seeds. AB - To understand raffinose family oligosaccharides (RFO) metabolism in chickpea (Cicer arietinum L.) seeds, RFO accumulation and corresponding biosynthetic enzymes activities were determined during seed development of chickpea genotypes with contrasting RFO concentrations. RFO concentration in mature seeds was found as a facilitator rather than a regulating step of seed germination. In mature seeds, raffinose concentrations ranged from 0.38 to 0.68 and 0.75 to 0.99 g/100 g, whereas stachyose concentrations varied from 0.79 to 1.26 and 1.70 to 1.87 g/100 g indicating significant differences between low and high RFO genotypes, respectively. Chickpea genotypes with high RFO concentration accumulated higher concentrations of myo-inositol and sucrose during early seed developmental stages suggesting that initial substrate concentrations may influence RFO concentration in mature seeds. High RFO genotypes showed about two to three-fold higher activity for all RFO biosynthetic enzymes compared to those with low RFO concentrations. RFO biosynthetic enzymes activities correspond with accumulation of individual RFO during seed development. PMID- 26953104 TI - Molecular cloning, expression of, and regulation by thyroid-hormone receptor alpha A in the half-smooth tongue sole Cynoglossus semilaevis during metamorphosis. AB - To elucidate the effect of thyroid hormone receptor alpha A (thraa) on metamorphosis, the full length cDNA of half-smooth tongue sole Cynoglossus semilaevis was cloned. The relative gene transcript level of thraa at different development stages was quantified using real-time PCR. Transcription of thraa increased and declined rapidly during metamorphosis. Hyperthyroidism was induced in juveniles and larvae with exposure to T3 and T4, and hypothyroidism with thiourea (TU), 2-mercapto-1-methylimidazole (MMI). thraa mRNA was higher in fish treated for 6 days with MMI than in untreated controls, although inhibited larvae did not complete metamorphosis. The addition of exogenous T4 reversed this effect in the MMI-treated group, but not in the TU-treated group. In situ hybridization revealed progressive tail end of body growth and change during developmental stages, with corresponding changes in thraa expression. This process may be induced by thyroid hormones with thraa as a major mediator. The morphological changes of tip of the tail may be associated with the development of lateral swimming. PMID- 26953103 TI - Diagnostic Value of Magnetic Resonance Spectroscopy in Radiation Encephalopathy Induced by Radiotherapy for Patients with Nasopharyngeal Carcinoma: A Meta Analysis. AB - In this study, articles in English and Chinese were selected from available electronic databases prior to September 2014. The metabolic concentrations and patterns of N-acetylaspartic acid (NAA), Choline (Cho), Creatine (Cr), NAA/Cr, NAA/Cho, and Cho/Cr ratios in radiotherapy-induced radiation encephalopathy by proton magnetic resonance spectroscopy were extracted. A meta-analysis was performed to quantitatively synthesize findings of these studies. Weighted mean difference (WMD) and 95% confidence intervals (95%CIs) were calculated using random or fixed effective models. Heterogeneity between studies was assessed using the Cochrane Q test and I (2) statistics. The results indicated that a total of 4 researches involving 214 patients met inclusion criteria. Depending on methodologies of selected studies, control groups were referred to as healthy subjects. The combined analysis revealed that there was no significant difference in value of Cr between radiotherapy group and healthy control group (WMD = 1.483, 95% CI: -67.185-64.219, p = 0.965). However, there were significant difference in values of NAA (WMD = -18.227, 95%CI: -36.317--0.137, p = 0.048), Cho (WMD = 38.003, 95%CI: 5.155-70.851, p = 0.023), NAA/Cr (WMD = -1.175, 95%CI: 1.563--0.787, p = 0.000), NAA/Cho (WMD = -1.108, 95%CI: -2.003-0.213, p = 0.015), and Cho/Cr (WMD = -0.773, 95%CI: 0.239-1.307, p = 0.005). In conclusion, MRS can be regarded as an effective and feasible imaging test for radiotherapy-induced radiation encephalopathy in NPC patients. PMID- 26953105 TI - Strain-induced water dissociation on supported ultrathin oxide films. AB - Controlling the dissociation of single water molecule on an insulating surface plays a crucial role in many catalytic reactions. In this work, we have identified the enhanced chemical reactivity of ultrathin MgO(100) films deposited on Mo(100) substrate that causes water dissociation. We reveal that the ability to split water on insulating surface closely depends on the lattice mismatch between ultrathin films and the underlying substrate, and substrate-induced in plane tensile strain dramatically results in water dissociation on MgO(100). Three dissociative adsorption configurations of water with lower energy are predicted, and the structural transition going from molecular form to dissociative form is almost barrierless. Our results provide an effective avenue to achieve water dissociation at the single-molecule level and shed light on how to tune the chemical reactions of insulating surfaces by choosing the suitable substrates. PMID- 26953115 TI - Sigmoid volvulus in children. PMID- 26953116 TI - Wandering liver. PMID- 26953117 TI - Regarding: Should we operate for an intra-abdominal emergency in the setting of disseminated cancer? PMID- 26953118 TI - Improved sensitivity for meticillin resistance detection in coagulase-negative staphylococci by moxalactam antibiotic discs or a cefoxitin investigation zone. PMID- 26953119 TI - Sound production by the Shi drum Umbrina cirrosa and comparison with the brown meagre Sciaena umbra: a passive acoustic monitoring perspective. AB - Sounds produced by the Shi drum Umbrina cirrosa were short trains of pulses with an average pulse period of 180 ms, pulse duration of c. 40 ms and an average peak frequency of 400 Hz; average values of acoustical properties differed from those recorded from the brown meagre Sciaena umbra in previous studies. The present study provides a preliminary tool for discriminating between these two species while conducting passive acoustic monitoring. The potential effects of ontogeny on sound production in both species are discussed and recommendations are made for further research. PMID- 26953120 TI - Weight Fluctuation and Postmenopausal Breast Cancer in the National Health and Nutrition Examination Survey I Epidemiologic Follow-Up Study. AB - OBJECTIVE: The aim of this study is to investigate if weight fluctuation is an independent risk factor for postmenopausal breast cancer (PBC) among women who gained weight in adult years. METHODS: NHANES I Epidemiologic Follow-Up Study (NHEFS) database was used in the study. Women that were cancers-free at enrollment and diagnosed for the first time with breast cancer at age 50 or greater were considered cases. Controls were chosen from the subset of cancers free women and matched to cases by years of follow-up and status of body mass index (BMI) at 25 years of age. Weight fluctuation was measured by the root-mean square-error (RMSE) from a simple linear regression model for each woman with their body mass index (BMI) regressed on age (started at 25 years) while women with the positive slope from this regression were defined as weight gainers. Data were analyzed using conditional logistic regression models. RESULTS: A total of 158 women were included into the study. The conditional logistic regression adjusted for weight gain demonstrated positive association between weight fluctuation in adult years and postmenopausal breast cancers (odds ratio/OR = 1.67; 95% confidence interval/CI: 1.06-2.66). CONCLUSIONS: The data suggested that long-term weight fluctuation was significant risk factor for PBC among women who gained weight in adult years. This finding underscores the importance of maintaining lost weight and avoiding weight fluctuation. PMID- 26953121 TI - Occurrence and removal of phenolic endocrine disrupting chemicals in the water treatment processes. AB - This paper evaluated the occurrence and removal efficiency of four selected phenolic endocrine disrupting chemicals (bisphenol A (BPA), octylphenol (OP), nonylphenol (NP) and diethylstilbestrol (DES)) in two drinking waterworks in Jiangsu province which take source water from Taihu Lake. The recombined yeast estrogen screen (YES) and liquid chromatography tandem mass spectrometry (LC MS/MS) were applied to assess the estrogenicity and detect the estrogens in the samples. The estrogen equivalents (EEQs) ranged from nd (not detected) to 2.96 ng/L, and the estrogenic activities decreased along the processes. Among the 32 samples, DES prevailed in all samples, with concentrations ranging 1.46-12.0 ng/L, BPA, OP and NP were partially detected, with concentrations ranging from nd to 17.73 ng/L, nd to 0.49 ng/L and nd to 3.27 ng/L, respectively. DES was found to be the main contributor to the estrogenicity (99.06%), followed by NP (0.62%), OP (0.23%) and BPA (0.09%). From the observation of treatment efficiency, the advanced treatment processes presented much higher removal ratio in reducing DES, the biodegradation played an important role in removing BPA, ozonation and pre oxidation showed an effective removal on all the four estrogens; while the conventional ones can also reduce all the four estrogens. PMID- 26953137 TI - Human exposure to metals due to consumption of fish from an artificial lake basin close to an active mining area in Katanga (D.R. Congo). AB - The concentrations of 14 essential and nonessential trace elements were determined in fish from Lake Tshangalele, Katanga province, Democratic Republic of Congo. This province has been a place of intensive mining activities for centuries, which have increased in recent years, due to the use of metals such as copper and cobalt for the industries of fast-growing countries. Lake Tshangalele, which receives effluents from metallurgical and mining plants in Likasi, is home to several fish species that are an important part of the diet of the local population, and, therefore, it constitutes a relevant site for documenting the human exposure to metals as a result of a fish diet. The highest concentrations (median levels, dry weight) of cobalt (7.25mgkg(-1)), copper (88.1mgkg(-1)), iron (197.5mgkg(-1)), manganese (65.35mgkg(-1)), zinc (122.9mgkg(-1)) and aluminum (135.4mgkg(-1)) were found in fish collected closest to the copper mining plant, with decreasing concentrations along the lake, up to the dam. In the most contaminated fish samples, values of up to 270.1mgkg(-1) for Al, 173.1mgkg(-1) for Cu, 220.9mgkg(-1) for Zn, 211.0mgkg(-1) for Mn, 324.2mgkg(-1) for Fe, 15.1mgkg(-1) for Co, 4.2mgkg(-1) for Cr, 1.6mgkg(-1) for Cd, 1.9mgkg(-1) for Pb, and 1.8mgkg(-1) for Ni were found. Metal contamination from mining activity resulted in being of great concern because of potential health risks to the local inhabitants due to the consumption of heavily contaminated fish. CAPSULE: High levels of metals, especially cobalt, aluminum, iron, manganese, zinc and cadmium were found in fish from Tshangalele water system. PMID- 26953138 TI - Environmental variation of PCDD/Fs and dl-PCBs in two tropical Andean Colombian cities using passive samplers. AB - Passive air-sampling data of polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs) and dioxin-like polychlorinated biphenyls (dl-PCBs) taken in Manizales (a medium-sized city) and Bogota (a megacity), Colombia, were analyzed in order to identify potential sources of pollution and the possible influence of meteorological variables like temperature and precipitation. The results indicate important differences in levels of PCDD/Fs and dl-PCBs between Bogota and Manizales, attributed to differences in site characteristics and potential local/regional sources. Higher PCDD/Fs concentrations were observed in Bogota (373fg/m(3)) compared to those observed in Manizales, with mean levels ranging from 64fg/m(3) in a residential zone to 151fg/m(3) around a vehicular-influenced area. Higher dl-PCBs concentrations were observed in the industrial area of Manizales compared to those observed in Bogota, with mean levels of 6668fg/m(3) and 4388fg/m(3) respectively. In terms of PCDD/Fs congener distribution, there was a predominance of octachlorodibenzodioxin (OCDD) followed by 1,2,3,4,6,7.8-heptachlorodibenzofuran (HpCDF) congeners, with both cities showing higher levels in zones of high vehicular activity. Industrial influence was most evident in dl-PCB levels. In comparison to the mean levels of dl-PCB congeners obtained in the vehicular zones of Bogota and Manizales, the industrially influenced sampling stations showed higher concentrations of dl-PCB congeners. Passive sampling results suggested that congener concentration profiles are characteristic of their different emission sources, and can be used to distinguish between their industrial or vehicular origins. PMID- 26953132 TI - miR-155 Deletion in Female Mice Prevents Diet-Induced Obesity. AB - Obesity is a growing epidemic in developed countries. Obese individuals are susceptible to comorbidities, including cardiovascular disease and metabolic disorder. Increasing the ability of adipose tissue to expend excess energy could improve protection from obesity. One promising target is microRNA (miR)-155-5p. We demonstrate that deletion of miR-155 (-5p and -3p) in female mice prevents diet-induced obesity. Body weight gain did not differ between wild-type (WT) and miR-155 knockout (KO) mice fed control diet (CD); however, miR-155 KO mice fed high-fat diet (HFD) gained 56% less body weight and 74% less gonadal white adipose tissue (WAT) than WT mice. Enhanced WAT thermogenic potential, brown adipose tissue differentiation, and/or insulin sensitivity might underlie this obesity resistance. Indeed, miR-155 KO mice on HFD had 21% higher heat release than WT HFD mice. Compared to WT adipocytes, miR-155 KO adipocytes upregulated brown (Ucp1, Cidea, Pparg) and white (Fabp4, Pnpla2, AdipoQ, Fasn) adipogenic genes, and glucose metabolism genes (Glut4, Irs1). miR-155 deletion abrogated HFD induced adipocyte hypertrophy and WAT inflammation. Therefore, miR-155 deletion increases adipogenic, insulin sensitivity, and energy uncoupling machinery, while limiting inflammation in WAT, which together could restrict HFD-induced fat accumulation. Our results identify miR-155 as a novel candidate target for improving obesity resistance. PMID- 26953139 TI - Modelling flow and inorganic nitrogen dynamics on the Hampshire Avon: Linking upstream processes to downstream water quality. AB - Managing diffuse pollution in catchments is a major issue for environmental managers planning to meet water quality standards and comply with the EU Water Framework Directive. A major source of diffuse pollution is from nitrogen, with high nitrate concentrations affecting water supplies and in-stream ecology. A dynamic, process based model of flow, nitrate and ammonium (INCA-N) has been applied to the Hampshire Avon as part of the NERC Macronutrient Cycles Programme to link upstream and downstream measurements of water chemistry. The model has been calibrated and validated against Environment Agency discharge and solute chemistry data, as well as a data set collected from a river site immediately upstream of the estuary tidal limit. Upstream measurements of denitrification at six sites have been used to evaluate nitrate removal rates in vegetated and non vegetated conditions. Results show that sediments underlying vegetation were associated with significantly higher rates of nitrate removal than un-vegetated sediments (with an average increase of 245%). These data have been used to scale up rates of nitrate loss to the whole catchment scale and have been implemented via the model. The effects of streambed geology and macrophyte cover on catchment scale nitrogen dynamics are explored and nutrient fluxes entering the estuary are evaluated. The model is used to test a strategy for nitrogen reduction assessed using a nitrate vulnerable zone (NVZ) methodology. It suggests that nitrate and ammonium concentrations could be reduced by 10% in 10years and much lower nitrogen level can be achieved but only over a long time period. PMID- 26953140 TI - Crown fire and surface fire: effects on myxomycetes inhabiting pine plantations. AB - Myxomycetes are heterotrophic eukaryote organisms that have three life stages, none of which are known to be resistant to fire. The response of myxobiota to different severity of fire is not well known either. We examined myxomycetes in Pinus mugo plantations following a crown fire and in Pinus sylvestris plantations following a surface fire during the first three years after the wildfire event in forested coastal sand dunes in western Lithuania. Additionally, we investigated myxomycetes in corresponding unburned stands. All studied sites (unburned and burned) bore rather different myxomycete assemblages but the disparities of the species compositions between both burn types were more pronounced showing that fire severity had stronger impact on myxomycete species composition than the pre fire stand type. Analysis of myxomycete assemblages (including the results from field collections, bark and litter cultures) showed that surface fire sites bore the highest number of post-fire species compared to crown fire and unburned sites. Dynamic annual changes in species composition were observed in all studied sites but only crown fire plots showed a clear chronosequence of post-fire myxomycete assemblages. Fire impact promoted establishment and/or sporulation of myxomycete species that are rare in similar unburned stands, or are usually confined to other types of forests and substrata. In addition, individual myxomycete species tended to switch substratum usage during the course of vegetation succession, with a final return to their usual substrata. This possibly signaled the end of early stage of post-fire succession. PMID- 26953131 TI - Methamphetamine compromises gap junctional communication in astrocytes and neurons. AB - Methamphetamine (meth) is a central nervous system (CNS) stimulant that results in psychological and physical dependency. The long-term effects of meth within the CNS include neuronal plasticity changes, blood-brain barrier compromise, inflammation, electrical dysfunction, neuronal/glial toxicity, and an increased risk to infectious diseases including HIV. Most of the reported meth effects in the CNS are related to dysregulation of chemical synapses by altering the release and uptake of neurotransmitters, especially dopamine, norepinephrine, and epinephrine. However, little is known about the effects of meth on connexin (Cx) containing channels, such as gap junctions (GJ) and hemichannels (HC). We examined the effects of meth on Cx expression, function, and its role in NeuroAIDS. We found that meth altered Cx expression and localization, decreased GJ communication between neurons and astrocytes, and induced the opening of Cx43/Cx36 HC. Furthermore, we found that these changes in GJ and HC induced by meth treatment were mediated by activation of dopamine receptors, suggesting that dysregulation of dopamine signaling induced by meth is essential for GJ and HC compromise. Meth-induced changes in GJ and HC contributed to amplified CNS toxicity by dysregulating glutamate metabolism and increasing the susceptibility of neurons and astrocytes to bystander apoptosis induced by HIV. Together, our results indicate that connexin containing channels, GJ and HC, are essential in the pathogenesis of meth and increase the sensitivity of the CNS to HIV CNS disease. Methamphetamine (meth) is an extremely addictive central nervous system stimulant. Meth reduced gap junctional (GJ) communication by inducing internalization of connexin-43 (Cx43) in astrocytes and reducing expression of Cx36 in neurons by a mechanism involving activation of dopamine receptors (see cartoon). Meth-induced changes in Cx containing channels increased extracellular levels of glutamate and resulted in higher sensitivity of neurons and astrocytes to apoptosis in response to HIV infection. PMID- 26953141 TI - A global review on ambient Limestone-Precipitating Springs (LPS): Hydrogeological setting, ecology, and conservation. AB - Springs are biodiversity hotspots and unique habitats that are threatened, especially by water overdraft. Here we review knowledge on ambient-temperature (non-geothermal) freshwater springs that achieve sufficient oversaturation for CaCO3 -by physical CO2 degassing and activity of photoautotrophs- to deposit limestone, locally resulting in scenic carbonate structures: Limestone Precipitating Springs (LPS). The most characteristic organisms in these springs are those that contribute to carbonate precipitation, e.g.: the mosses Palustriella and Eucladium, the crenophilous desmid Oocardium stratum, and cyanobacteria (e.g., Rivularia). These organisms appear to be sensitive to phosphorus pollution. Invertebrate diversity is modest, and highest in pools with an aquatic-terrestrial interface. Internationally, comprehensive legislation for spring protection is still relatively scarce. Where available, it covers all spring types. The situation in Europe is peculiar: the only widespread spring type included in the EU Habitat Directive is LPS, mainly because of landscape aesthetics. To support LPS inventorying and management to meet conservation legislation requirements we developed a general conceptual model to predict where LPS are more likely to occur. The model is based on the pre-requisites for LPS: an aquifer lithology that enables build-up of high bicarbonate and Ca(2+) to sustain CaCO3 oversaturation after spring emergence, combined with intense groundwater percolation especially along structural discontinuities (e.g., fault zones, joints, schistosity), and a proper hydrogeological structure of the discharging area. We validated this model by means of the LPS information system for the Emilia-Romagna Region (northern Italy). The main threats to LPS are water diversion, nutrient enrichment, and lack of awareness by non-specialized persons and administrators. We discuss an emblematic case study to provide management suggestions. The present review is devoted to LPS but the output of intense ecological research in Central Europe during the past decades has clearly shown that effective conservation legislation should be urgently extended to comprise all types of spring habitats. PMID- 26953142 TI - Role of oxidative stress in inactivation of Escherichia coli BW25113 by nanoscale zero-valent iron. AB - An Escherichia coli BW25113 wildtype strain and mutant strains lacking genes that protect against oxidative stress were examined at different growth phases for susceptibility to zero-valent iron (nZVI). Viability of cells was determined by the plate count method. All mutant strains were more susceptible than the wild type strain to nZVI; however, susceptibility differed among the mutant strains. Consistent with the role of rpoS as a global stress regulator, an rpoS gene knockout mutant exhibited the greatest susceptibility to nZVI under the majority of conditions tested (except exponential and declining phases at longer exposure time). Mutants lacking genes encoding the inducible and constitutively expressed cytosolic superoxide dismutases, sodA and sodB, respectively, were more susceptible to nZVI than a mutant lacking the gene encoding sodC, a periplasmic superoxide dismutase. This suggests that nZVI induces oxidative stress inside the cells via superoxide generation. Quantitative polymerase chain reaction was used to examine the expression of katG, a gene encoding the catalase-peroxidase enzyme, in nZVI-treated E. coli at different growth phases. Results showed that nZVI repressed the expression of katG in all but lag phases. PMID- 26953143 TI - Assessing bio-available silver released from silver nanoparticles embedded in silica layers using the green algae Chlamydomonas reinhardtii as bio-sensors. AB - Silver nanoparticles (AgNPs) because of their strong antibacterial activity are widely used in health-care sector and industrial applications. Their huge surface volume ratio enhances the silver release compared to the bulk material, leading to an increased toxicity for microorganisms sensitive to this element. This work presents an assessment of the toxic effect on algal photosynthesis due to small (size <20nm) AgNPs embedded in silica layers. Two physical approaches were originally used to elaborate the nanocomposite structures: (i) low energy ion beam synthesis and (ii) combined silver sputtering and plasma polymerization. These techniques allow elaboration of a single layer of AgNPs embedded in silica films at defined nanometer distances (from 0 to 7nm) beneath the free surface. The structural and optical properties of the nanostructures were studied by transmission electron microscopy and optical reflectance. The silver release from the nanostructures after 20h of immersion in buffered water was measured by inductively coupled plasma mass spectrometry and ranges between 0.02 and 0.49MUM. The short-term toxicity of Ag to photosynthesis of Chlamydomonas reinhardtii was assessed by fluorometry. The obtained results show that embedding AgNPs reduces the interactions with the buffered water free media, protecting the AgNPs from fast oxidation. The release of bio-available silver (impacting on the algal photosynthesis) is controlled by the depth at which AgNPs are located for a given host matrix. This provides a procedure to tailor the toxicity of nanocomposites containing AgNPs. PMID- 26953144 TI - An Evaluation of Root Phytochemicals Derived from Althea officinalis (Marshmallow) and Astragalus membranaceus as Potential Natural Components of UV Protecting Dermatological Formulations. AB - As lifetime exposure to ultraviolet (UV) radiation has risen, the deleterious effects have also become more apparent. Numerous sunscreen and skincare products have therefore been developed to help reduce the occurrence of sunburn, photoageing, and skin carcinogenesis. This has stimulated research into identifying new natural sources of effective skin protecting compounds. Alkaline single-cell gel electrophoresis (comet assay) was employed to assess aqueous extracts derived from soil or hydroponically glasshouse-grown roots of Althea officinalis (Marshmallow) and Astragalus membranaceus, compared with commercial, field-grown roots. Hydroponically grown root extracts from both plant species were found to significantly reduce UVA-induced DNA damage in cultured human lung and skin fibroblasts, although initial Astragalus experimentation detected some genotoxic effects, indicating that Althea root extracts may be better suited as potential constituents of dermatological formulations. Glasshouse-grown soil and hydroponic Althea root extracts afforded lung fibroblasts with statistically significant protection against UVA irradiation for a greater period of time than the commercial field-grown roots. No significant reduction in DNA damage was observed when total ultraviolet irradiation (including UVB) was employed (data not shown), indicating that the extracted phytochemicals predominantly protected against indirect UVA-induced oxidative stress. Althea phytochemical root extracts may therefore be useful components in dermatological formulations. PMID- 26953145 TI - Resistance and virulence potential of uropathogenic Escherichia coli strains isolated from patients hospitalized in urology departments: a French prospective multicentre study. AB - We characterized antibiotic resistance and virulence of uropathogenic Escherichia coli (UPEC) strains isolated from urinary tract infections (UTIs) in patients hospitalized in urology departments. A prospective multicentre study was initiated from March 2009 and lasted until February 2010 in French urology units. All patients with asymptomatic bacteriuria (ABU), acute cystitis, acute pyelonephritis or acute prostatitis in whom UPEC was detected were included. Antimicrobial resistance and virulence factors were compared among the different groups. To identify independent associations between virulence markers and the risk of UTI, we used a multivariate logistic regression. We included 210 patients (mean age: 65.8 years; 106 female). Episode of UTI was community acquired in 72.4 %. ABU was diagnosed in 67 cases (31.9 %), cystitis in 52 cases (24.7 %), pyelonephritis in 35 cases (16.7 %) and prostatitis in 56 cases (26.7 %). ABU was more frequent in patients with a urinary catheter (76.1 vs 23.9 %, P<0.001). The resistance rate was 7.6 and 24.8 % for cefotaxime and ciprofloxacin, respectively. UPEC isolated from infections belonged more frequently to phylotypes B2 and D (P =0.07). The papG allele II and papA, papC, papE, kpsMTII and iutA genes were significantly more frequent in infecting strains (P<0.05). In multivariate analysis, strains susceptible to ciprofloxacin were significantly associated with papG allele II (P=0.007), kpsMTK1 (P<0.001) and hlyA (P<0.001) compared with the ciprofloxacin-resistant strains. To the best of our knowledge, this is the first study evaluating the antibiotic resistance and virulence features of UPEC isolated from patients hospitalized in urology departments. High resistance rates were observed, notably for ciprofloxacin, highlighting the importance of a reinforced surveillance in this setting. PMID- 26953147 TI - Characterization of organic matter of plants from lakes by thermal analysis in a N2 atmosphere. AB - Organic matter (OM) has been characterized using thermal analysis in O2 atmospheres, but it is not clear if OM can be characterized using slow thermal degradation in N2 atmospheres (STDN). This article presents a new method to estimate the behavior of OM in anaerobic environment. Seventeen different plants from Tai Lake (Ch: Taihu), China were heated to 600 degrees C at a rate of 10 degrees C min(-1) in a N2 atmosphere and characterized by use of differential scanning calorimetry (DSC) and thermal gravimetric analysis (TGA). DSC chromatograms were compared with 9 standard compounds. Seven peaks were observed in DSC chromatograms, 2 main peaks strongly correlated with biochemical indices, and one main peak was a transitional stage. Energy absorbed by a peak at approximately 200 degrees C and total organic carbon were well correlated, while energy absorbed at approximately 460 degrees C was negatively correlated with lignin content. Presence of peaks at approximately 350 and 420 degrees C varied among plant biomass sources, providing potential evidence for biomass identification. Methods of STDN reported here were rapid and accurate ways to quantitatively characterize OM, which may provide useful information for understanding anaerobic behaviors of natural organic matters. PMID- 26953146 TI - Oligomerization of the microtubule-associated protein tau is mediated by its N terminal sequences: implications for normal and pathological tau action. AB - Despite extensive structure-function analyses, the molecular mechanisms of normal and pathological tau action remain poorly understood. How does the C-terminal microtubule-binding region regulate microtubule dynamics and bundling? In what biophysical form does tau transfer trans-synaptically from one neuron to another, promoting neurodegeneration and dementia? Previous biochemical/biophysical work led to the hypothesis that tau can dimerize via electrostatic interactions between two N-terminal 'projection domains' aligned in an anti-parallel fashion, generating a multivalent complex capable of interacting with multiple tubulin subunits. We sought to test this dimerization model directly. Native gel analyses of full-length tau and deletion constructs demonstrate that the N-terminal region leads to multiple bands, consistent with oligomerization. Ferguson analyses of native gels indicate that an N-terminal fragment (tau(45-230) ) assembles into heptamers/octamers. Ferguson analyses of denaturing gels demonstrates that tau(45 230) can dimerize even in sodium dodecyl sulfate. Atomic force microscopy reveals multiple levels of oligomerization by both full-length tau and tau(45-230) . Finally, ion mobility-mass spectrometric analyses of tau(106-144) , a small peptide containing the core of the hypothesized dimerization region, also demonstrate oligomerization. Thus, multiple independent strategies demonstrate that the N-terminal region of tau can mediate higher order oligomerization, which may have important implications for both normal and pathological tau action. The microtubule-associated protein tau is essential for neuronal development and maintenance, but is also central to Alzheimer's and related dementias. Unfortunately, the molecular mechanisms underlying normal and pathological tau action remain poorly understood. Here, we demonstrate that tau can homo oligomerize, providing novel mechanistic models for normal tau action (promoting microtubule growth and bundling, suppressing microtubule shortening) and pathological tau action (poisoning of oligomeric complexes). PMID- 26953151 TI - Melatonin action in tumor skeletal muscle cells: an ultrastructural study. AB - Melatonin (Mel), or N-acetyl-5-methoxytryptamine, is a circadian hormone that can diffuse through all the biological membranes thanks to its amphiphilic structure, also overcoming the blood-brain barrier and placenta. Although Mel has been reported to exhibit strong antioxidant properties in healthy tissues, studies carried out on tumor cultures gave a different picture of its action, often describing Mel as effective to trigger the cell death of tumor cells by enhancing oxidative stress. Based on this premise, here Mel effect was investigated using a tumor cell line representative of the human alveolar rhabdomyosarcoma (ARMS), the most frequent soft tissue sarcoma affecting childhood. For this purpose, Mel was given either dissolved in ethanol (EtOH) or dimethyl sulfoxide (DMSO) at different concentrations and time exposures. Cell viability assays and ultrastructural observations demonstrated that Mel was able to induce a dose- and time-dependent cell death independently on the dissolution solvent. Microscopy analyses highlighted the presence of various apoptotic and necrotic patterns correlating with the increasing Mel dose and time of exposure. These findings suggest that Mel, triggering apoptosis in ARMS cells, could be considered as a promising drug for future multitargeted therapies. PMID- 26953152 TI - The IL-1beta Receptor Antagonist SER140 Postpones the Onset of Diabetes in Female Nonobese Diabetic Mice. AB - The cytokine interleukin-1beta (IL-1beta) is known to stimulate proinflammatory immune responses and impair beta-cell function and viability, all critical events in the pathogenesis of type 1 diabetes (T1D). Here we evaluate the effect of SER140, a small peptide IL-1beta receptor antagonist, on diabetes progression and cellular pancreatic changes in female nonobese diabetic (NOD) mice. Eight weeks of treatment with SER140 reduced the incidence of diabetes by more than 50% compared with vehicle, decreased blood glucose, and increased plasma insulin. Additionally, SER140 changed the endocrine and immune cells dynamics in the NOD mouse pancreas. Together, the data suggest that SER140 treatment postpones the onset of diabetes in female NOD mice by interfering with IL-1beta activated pathways. PMID- 26953153 TI - Optically tuned terahertz modulator based on annealed multilayer MoS2. AB - Controlling the propagation properties of terahertz waves is very important in terahertz technologies applied in high-speed communication. Therefore a new-type optically tuned terahertz modulator based on multilayer-MoS2 and silicon is experimentally demonstrated. The terahertz transmission could be significantly modulated by changing the power of the pumping laser. With an annealing treatment as a p-doping method, MoS2 on silicon demonstrates a triple enhancement of terahertz modulation depth compared with the bare silicon. This MoS2-based device even exhibited much higher modulation efficiency than the graphene-based device. We also analyzed the mechanism of the modulation enhancement originated from annealed MoS2, and found that it is different from that of graphene-based device. The unique optical modulating properties of the device exhibit tremendous promise for applications in terahertz switch. PMID- 26953154 TI - The phenotypic evolution of Pseudomonas aeruginosa populations changes in the presence of subinhibitory concentrations of ciprofloxacin. AB - Ciprofloxacin is a widely used antibiotic, in the class of quinolones, for treatment of Pseudomonas aeruginosa infections. The immediate response of P. aeruginosa to subinhibitory concentrations of ciprofloxacin has been investigated previously. However, the long-term phenotypic adaptation, which identifies the fitted phenotypes that have been selected during evolution with subinhibitory concentrations of ciprofloxacin, has not been studied. We chose an experimental evolution approach to investigate how exposure to subinhibitory concentrations of ciprofloxacin changes the evolution of P. aeruginosa populations compared to unexposed populations. Three replicate populations of P. aeruginosa PAO1 and its hypermutable mutant DeltamutS were cultured aerobically for approximately 940 generations by daily passages in LB medium with and without subinhibitory concentration of ciprofloxacin and aliquots of the bacterial populations were regularly sampled and kept at - 80 degrees C for further investigations. We investigate here phenotypic changes between the ancestor (50 colonies) and evolved populations (120 colonies/strain). Decreased protease activity and swimming motility, higher levels of quorum-sensing signal molecules and occurrence of mutator subpopulations were observed in the ciprofloxacin-exposed populations compared to the ancestor and control populations. Transcriptomic analysis showed downregulation of the type III secretion system in evolved populations compared to the ancestor population and upregulation of denitrification genes in ciprofloxacin-evolved populations. In conclusion, the presence of antibiotics at subinhibitory concentration in the environment affects bacterial evolution and further studies are needed to obtain insight into the dynamics of the phenotypes and the mechanisms involved. PMID- 26953155 TI - Interfering with baffled B cells at the lupus tollway: Promises, successes, and failed expectations. AB - B cells play an important role in systemic lupus erythematosus by acting not only as precursors of autoantibody-producing cells but also as antigen-presenting, cytokine-secreting, and regulatory cells. Unopposed activation of B cells through their B-cell receptor for antigen, as seen in B cells lacking Lyn kinase, results in systemic autoimmunity. The B-cell activating factor of the TNF family (BAFF), nucleic acid-sensing Toll-like receptors (TLRs), and type I interferon can affect B-cell survival and decrease their threshold for activation. Herein we discuss both direct and indirect strategies aimed at targeting B cells in patients with lupus by blocking BAFF, type I interferon, or TLR7 to TLR9. Although BAFF depleting therapy with belimumab achieved approval for lupus, other BAFF inhibitors were much less beneficial in clinical trials. Inhibitors of the B-cell receptor for antigen signaling and antibodies against type I interferon are in the pipeline. The TLR7 to TLR9 blocker hydroxychloroquine has been in use in patients with lupus for more than 50 years, but oligonucleotide-based inhibitors of TLR7 to TLR9, despite showing promise in animal models of lupus, have not reached the primary end point in a recent phase 1 trial. These data point toward possible redundancies in B-cell signaling/survival pathways, which must be better understood before future clinical trials are executed. PMID- 26953157 TI - Reduction in peripheral blood eosinophil counts after bronchial thermoplasty. PMID- 26953156 TI - Prenatal and postnatal stress and asthma in children: Temporal- and sex-specific associations. AB - BACKGROUND: Temporal- and sex-specific effects of perinatal stress have not been examined for childhood asthma. OBJECTIVES: We examined associations between prenatal and/or postnatal stress and children's asthma (n = 765) and effect modification by sex in a prospective cohort study. METHODS: Maternal negative life events were ascertained prenatally and postpartum. Negative life event scores were categorized as 0, 1 to 2, 3 to 4, or 5 or greater to assess exposure response relationships. We examined effects of prenatal and postnatal stress on children's asthma by age 6 years, modeling each as independent predictors, mutually adjusting for prenatal and postnatal stress, and finally considering interactions between prenatal and postnatal stress. Effect modification by sex was examined in stratified analyses and by fitting interaction terms. RESULTS: When considering stress in each period independently, among boys, a dose-response relationship was evident for each level increase on the ordinal scale prenatally (odds ratio [OR], 1.38; 95% CI, 1.06-1.79; P value for trend = .03) and postnatally (OR, 1.53; 95% CI, 1.16-2.01; P value for trend = .001); among girls, only the postnatal trend was significant (OR, 1.60; 95% CI, 1.14-2.22; P value for trend = .005). Higher stress in both the prenatal and postnatal periods was associated with increased odds of receiving a diagnosis of asthma in girls (OR, 1.37; 95% CI, 0.98-1.91; Pinteraction = .07) but not boys (OR, 1.08; 95% CI, 0.82 1.42; Pinteraction = .61). CONCLUSIONS: Although boys were more vulnerable to stress during the prenatal period, girls were more affected by postnatal stress and cumulative stress across both periods in relation to asthma. Understanding sex and temporal differences in response to early-life stress might provide unique insight into the cause and natural history of asthma. PMID- 26953158 TI - Peanut T-cell epitope discovery: Ara h 1. AB - BACKGROUND: Identification of potential T-cell epitopes in the peanut major allergens is essential for development of peptide-based immunotherapy. Traditional methods of T-cell epitope discovery use overlapping short peptides spanning the full length of the protein in T-cell proliferation assays. Because large proteins, such as Ara h 1, require a large number of peptides, this limits screening to a small number of allergic subject-derived T-cell lines. OBJECTIVE: We sought to identify candidate peptides of Ara h 1 that display promiscuous binding to MHC class II and induce TH2 cytokine production by T cells. METHODS: In silico MHC class II binding prediction was performed with NetMHCIIpan 2.0 (peptide length, 15; 1-mer offset) and the most abundant class II alleles in the North American population and with an in vitro MHC class II peptide reporter assay performed in parallel, which used synthetic 15-mer peptides offset by 5 mer spanning the protein. High-resolution MHC class II typing and a T-cell proliferation assay using preselected peptides were performed with PBMCs from 98 subjects with peanut allergy and 14 healthy control subjects. IL-4, IL-13, IL-5, IFN-gamma, and TNF-alpha levels were measured in culture supernatants. RESULTS: Thirty-six Ara h 1 peptides were identified by using in silico predictions and MHC class II binding assays. In combination with T-cell proliferation and cytokines secreted in T-cell assays, we have identified 4 vaccine candidate Ara h 1 peptides. CONCLUSIONS: Preselection of peptides by using in silico and in vitro approaches in combination with conventional methods appears to be an effective strategy for identifying peanut T-cell peptide vaccine candidates. PMID- 26953159 TI - Inhibition of DYRK1A Stimulates Human beta-Cell Proliferation. AB - Restoring functional beta-cell mass is an important therapeutic goal for both type 1 and type 2 diabetes (1). While proliferation of existing beta-cells is the primary means of beta-cell replacement in rodents (2), it is unclear whether a similar principle applies to humans, as human beta-cells are remarkably resistant to stimulation of division (3,4). Here, we show that 5-iodotubercidin (5-IT), an annotated adenosine kinase inhibitor previously reported to increase proliferation in rodent and porcine islets (5), strongly and selectively increases human beta-cell proliferation in vitro and in vivo. Remarkably, 5-IT also increased glucose-dependent insulin secretion after prolonged treatment. Kinome profiling revealed 5-IT to be a potent and selective inhibitor of the dual specificity tyrosine phosphorylation-regulated kinase (DYRK) and cell division cycle-like kinase families. Induction of beta-cell proliferation by either 5-IT or harmine, another natural product DYRK1A inhibitor, was suppressed by coincubation with the calcineurin inhibitor FK506, suggesting involvement of DYRK1A and nuclear factor of activated T cells signaling. Gene expression profiling in whole islets treated with 5-IT revealed induction of proliferation- and cell cycle-related genes, suggesting that true proliferation is induced by 5 IT. Furthermore, 5-IT promotes beta-cell proliferation in human islets grafted under the kidney capsule of NOD-scid IL2Rg(null) mice. These results point to inhibition of DYRK1A as a therapeutic strategy to increase human beta-cell proliferation. PMID- 26953160 TI - Proinsulin Expression Shapes the TCR Repertoire but Fails to Control the Development of Low-Avidity Insulin-Reactive CD8+ T Cells. AB - NOD mice, a model strain for human type 1 diabetes, express proinsulin (PI) in the thymus. However, insulin-reactive T cells escape negative selection, and subsequent activation of the CD8(+) T-cell clonotype G9C8, which recognizes insulin B15-23 via an alphabeta T-cell receptor (TCR) incorporating TRAV8-1/TRAJ9 and TRBV19/TRBJ2-3 gene rearrangements, contributes to the development of diabetes. In this study, we used fixed TRAV8-1/TRAJ9 TCRalpha-chain transgenic mice to assess the impact of PI isoform expression on the insulin-reactive CD8(+) T-cell repertoire. The key findings were: 1) PI2 deficiency increases the frequency of insulin B15-23-reactive TRBV19(+)CD8(+) T cells and causes diabetes; 2) insulin B15-23-reactive TRBV19(+)CD8(+) T cells are more abundant in the pancreatic lymph nodes of mice lacking PI1 and/or PI2; 3) overexpression of PI2 decreases TRBV19 usage in the global CD8(+) T-cell compartment; 4) a biased repertoire of insulin-reactive CD8(+) T cells emerges in the periphery regardless of antigen exposure; and 5) low-avidity insulin-reactive CD8(+) T cells are less affected by antigen exposure in the thymus than in the periphery. These findings inform our understanding of the diabetogenic process and reveal new avenues for therapeutic exploitation in type 1 diabetes. PMID- 26953161 TI - Diabetes and Risk of Arterial Stiffness: A Mendelian Randomization Analysis. AB - We aimed to explore the causal association between type 2 diabetes (T2D) and increased arterial stiffness. We performed a Mendelian randomization (MR) analysis in 11,385 participants from a well-defined community study in Shanghai during 2011-2013. We genotyped 34 T2D-associated common variants identified in East Asians and created a genetic risk score (GRS). We assessed arterial stiffness noninvasively with the measurement of brachial-ankle pulse wave velocity (baPWV). We used the instrumental variable (IV) estimator to qualify the causal relationship between T2D and increased arterial stiffness. We found each 1 SD increase in T2D_GRS was associated with 6% higher risk in increased arterial stiffness (95% CI 1.01, 1.12), after adjustment of other metabolic confounders. Using T2D_GRS as the IV, we demonstrated a causal relationship between T2D and arterial stiffening (odds ratio 1.24, 95% CI 1.06, 1.47; P = 0.008). When categorizing the genetic loci according to their effect on insulin secretion or resistance, we found genetically determined decrease in insulin secretion was associated with increase in baPWV (betaIV = 122.3 cm/s, 95% CI 41.9, 204.6; P = 0.0005). In conclusion, our results provide evidence supporting a causal association between T2D and increased arterial stiffness in a Chinese population. PMID- 26953162 TI - Identification of Tetraspanin-7 as a Target of Autoantibodies in Type 1 Diabetes. AB - The presence of autoantibodies to multiple-islet autoantigens confers high risk for the development of type 1 diabetes. Four major autoantigens are established (insulin, glutamate decarboxylase, IA2, and zinc transporter-8), but the molecular identity of a fifth, a 38-kDa membrane glycoprotein (Glima), is unknown. Glima antibodies have been detectable only by immunoprecipitation from extracts of radiolabeled islet or neuronal cells. We sought to identify Glima to enable efficient assay of these autoantibodies. Mouse brain and lung were shown to express Glima. Membrane glycoproteins from extracts of these organs were enriched by detergent phase separation, lectin affinity chromatography, and SDS PAGE. Proteins were also immunoaffinity purified from brain extracts using autoantibodies from the sera of patients with diabetes before SDS-PAGE. Eluates from gel regions equivalent to 38 kDa were analyzed by liquid chromatography tandem mass spectrometry for protein identification. Three proteins were detected in samples from the brain and lung extracts, and in the immunoaffinity-purified sample, but not in the negative control. Only tetraspanin-7, a multipass transmembrane glycoprotein with neuroendocrine expression, had physical characteristics expected of Glima. Tetraspanin-7 was confirmed as an autoantigen by demonstrating binding to autoantibodies in type 1 diabetes. We identify tetraspanin-7 as a target of autoimmunity in diabetes, allowing its exploitation for diabetes prediction and immunotherapy. PMID- 26953163 TI - The Hypoglycemic Phenotype Is Islet Cell-Autonomous in Short-Chain Hydroxyacyl CoA Dehydrogenase-Deficient Mice. AB - Congenital hyperinsulinism of infancy (CHI) can be caused by inactivating mutations in the gene encoding short-chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD), a ubiquitously expressed enzyme involved in fatty acid oxidation. The hypersecretion of insulin may be explained by a loss of interaction between SCHAD and glutamate dehydrogenase in the pancreatic beta-cells. However, there is also a general accumulation of metabolites specific for the enzymatic defect in affected individuals. It remains to be explored whether hypoglycemia in SCHAD CHI can be uncoupled from the systemic effect on fatty acid oxidation. We therefore transplanted islets from global SCHAD knockout (SCHADKO) mice into mice with streptozotocin-induced diabetes. After transplantation, SCHADKO islet recipients exhibited significantly lower random and fasting blood glucose compared with mice transplanted with normal islets or nondiabetic, nontransplanted controls. Furthermore, intraperitoneal glucose tolerance was improved in animals receiving SCHADKO islets compared with those receiving normal islets. Graft beta-cell proliferation and apoptosis rates were similar in the two transplantation groups. We conclude that hypoglycemia in SCHAD-CHI is islet cell-autonomous. PMID- 26953164 TI - VAMP7 Regulates Autophagy to Maintain Mitochondrial Homeostasis and to Control Insulin Secretion in Pancreatic beta-Cells. AB - VAMP7 is a SNARE protein that mediates specific membrane fusions in intracellular trafficking and was recently reported to regulate autophagosome formation. However, its function in pancreatic beta-cells is largely unknown. To elucidate the physiological role of VAMP7 in beta-cells, we generated pancreatic beta-cell specific VAMP7 knockout (Vamp7(flox/Y);Cre) mice. VAMP7 deletion impaired glucose stimulated ATP production and insulin secretion, though VAMP7 was not localized to insulin granules. VAMP7-deficient beta-cells showed defective autophagosome formation and reduced mitochondrial function. p62/SQSTM1, a marker protein for defective autophagy, was selectively accumulated on mitochondria in VAMP7 deficient beta-cells. These findings suggest that accumulation of dysfunctional mitochondria that are degraded by autophagy caused impairment of glucose stimulated ATP production and insulin secretion in Vamp7(flox/Y);Cre beta-cells. Feeding a high-fat diet to Vamp7(flox/Y);Cre mice exacerbated mitochondrial dysfunction, further decreased ATP production and insulin secretion, and consequently induced glucose intolerance. Moreover, we found upregulated VAMP7 expression in wild-type mice fed a high-fat diet and in db/db mice, a model for diabetes. Thus our data indicate that VAMP7 regulates autophagy to maintain mitochondrial quality and insulin secretion in response to pathological stress in beta-cells. PMID- 26953165 TI - Direct Visualization of the Two-step Nucleation Model by Fluorescence Color Changes during Evaporative Crystallization from Solution. AB - The two-step nucleation model for crystal nuclei formation explains several experimental and theoretical results better than the classical nucleation theory. We report here direct visualization of the two-step nucleation model for organic molecular crystallization. Evaporative crystallization from a solution of a dibenzoylmethane boron complex that displays mechanofluorochromism, a fluorescence color change induced by mechanical perturbation, was probed by fluorescence change. The dependence of fluorescence change on dispersion concentration of the complex in a polymer matrix was also investigated. We detected transitional emission from the amorphous cluster state prior to crystallization. This is the first demonstration of the two-step nucleation model based on fluorescence color changes. PMID- 26953166 TI - Multimodal cancer care in poor prognosis cancers: Resection drives long-term outcomes. AB - BACKGROUND AND OBJECTIVES: Hospitals with high complex oncologic surgical volume have improved short-term outcomes. However, for long-term outcomes, the influence of other therapies must be considered. We compared effects of resection with other therapies on long-term outcomes across U.S. hospitals. METHODS: We examined claims in the Surveillance, Epidemiology, and End Results (SEER)-Medicare dataset for patients with esophageal (EC) and pancreatic (PC) cancers between 2005-2009, with follow-up through 2011, performing multivariable Cox proportional hazards analyses. We stratified hospitals by volume and compared rates of treatments in the context of survival. RESULTS: We studied 905 EC and 3,293 PC patients at 138 and 375 hospitals, respectively. For EC, resection rates were significantly higher (32.9% vs. 9.5%, P < 0.001) in the highest versus lowest volume hospitals. Adjusted survival was also statistically significantly better (48.5% vs. 43.1%, P < 0.001). For PC, resection rates were also statistically significantly higher (30.1% vs. 12.0%, P < 0.001) with higher adjusted survival (21.5% vs. 19.9%, P = 0.01). We did not find variation in rates of other cancer treatments across hospitals. CONCLUSIONS: A significant association exists between long-term survival and rates of cancer-directed surgery across hospitals, without variation in rates of other therapies. Access to resection appears to be key to reducing variation in long-term survival. J. Surg. Oncol. 2016;113:599-604. (c) 2016 Wiley Periodicals, Inc. PMID- 26953167 TI - Effect of nitrogen fertilisation on the amino acid digestibility of different triticale genotypes in caecectomised laying hens. AB - BACKGROUND: The influence of nitrogen fertilisation and genotype on the amino acid (AA) digestibility of triticale grain was investigated in caecectomised laying hens. Three genotypes, Grenado, EAW6002 and Lasko, were cultivated with and without nitrogen fertilisation at the end of the heading stage. The six triticale variants as well as a basal diet were each used to feed seven laying hens in a 7 * 7 Latin square design. RESULTS: Nitrogen fertilisation influenced the digestibility of Cys, Glu, Phe and Ser in some triticale genotypes and reduced Ala, Ile, Lys, Met and Val digestibility in all genotypes (P < 0.05). Nitrogen fertilisation increased the concentration of all AAs in the grain. Consequently, the concentration of digestible AAs in the grains was increased for most AAs upon nitrogen fertilisation. Overall, Lys had the lowest digestibility, whereas that of Glu and Pro was the highest. For the triticale genotypes, the level of AA digestibility was highest for EAW6002 followed by Lasko and Grenado, with significant differences (P < 0.05) between genotypes for some but not all AAs. CONCLUSION: The results indicated that the accuracy of the digestible AA supply for hen feeding might benefit from considering fertilisation and genotype specific digestibility data in feed formulation. (c) 2016 Society of Chemical Industry. PMID- 26953169 TI - Low-Blood Glucose Avoidance Training Improves Glycemic Variability in Adults With Type 1 Diabetes Complicated by Impaired Awareness of Hypoglycemia: HypoCOMPaSS Trial. PMID- 26953168 TI - Photomodulation of fluoride ion binding through anion-pi interactions using a photoswitchable azobenzene system. AB - The discovery of photoswitchable azobenzene-systems that undergo trans-to-cis photoisomerisation was a milestone in supramolecular chemistry. Such photoswitches have possible applications in data storage, stimuli responsive delivery systems, and molecular machines due to fast and selective switching. However, the light induced cis isomer of azobenzene is rather unstable and reverts thermally and photochemically to the thermodynamically stable trans configuration. We report, for the first time, controlled photoswitching of an azo naphthalenediimide (azo-NDI) which can be achieved upon binding of fluoride ions through anion-pi interaction. This NDI-F-NDI "sandwich" stabilises the cis configuration through the generation of an NDI(*-) radical anion, and a dianionic, NDI(2-) species that becomes unusually stable in the cis form. The sandwiched cis form reverts to the trans form only upon decomplexation of F(-). A model pollutant was successfully degraded using the photogenerated NDI-F-NDI sandwich. This opens a wide range of applications in molecular and supramolecular nanotechnology. PMID- 26953170 TI - Diabetes and Prediabetes and Risk of Hospitalization: The Atherosclerosis Risk in Communities (ARIC) Study. AB - OBJECTIVE: To examine the magnitude and types of hospitalizations among persons with prediabetes, undiagnosed diabetes, and diagnosed diabetes. RESEARCH DESIGN AND METHODS: This study included 13,522 participants in the Atherosclerosis Risk in Communities (ARIC) study (mean age 57 years, 56% female, 24% black, 18% with prediabetes, 4% with undiagnosed diabetes, 9% with diagnosed diabetes) with follow-up in 1990-2011 for hospitalizations. Participants were categorized by diabetes/HbA1c status: without diagnosed diabetes, HbA1c <5.7% (reference); prediabetes, 5.7 to <6.5%; undiagnosed diabetes, >=6.5%; and diagnosed diabetes, <7.0 and >=7.0%. RESULTS: Demographic adjusted rates per 1,000 person-years of all-cause hospitalizations were higher with increasing diabetes/HbA1c category (Ptrend < 0.001). Persons with diagnosed diabetes and HbA1c >=7.0% had the highest rates of hospitalization (3.1 times higher than those without a history of diagnosed diabetes, HbA1c <5.7%, and 1.5 times higher than those with diagnosed diabetes, HbA1c <7.0%, P < 0.001 for both comparisons). Persons with undiagnosed diabetes had 1.6 times higher rates of hospitalization and those with prediabetes had 1.3 times higher rates of hospitalization than those without diabetes and HbA1c <5.7% (P < 0.001 for both comparisons). Rates of hospitalization by diabetes/HbA1c category were different by race (Pinteraction = 0.011) and by sex (Pinteraction = 0.020). There were significantly excess rates of hospitalizations due to cardiovascular, endocrine, respiratory, gastrointestinal, iatrogenic/injury, neoplasm, genitourinary, neurologic, and infection causes among those with diagnosed diabetes compared with those without a history of diagnosed diabetes (all P < 0.05). CONCLUSIONS: Persons with diagnosed diabetes, undiagnosed diabetes, and prediabetes are at a significantly elevated risk of hospitalization compared with those without diabetes. Substantial excess rates of hospitalizations in persons with diagnosed diabetes were for endocrine, infection, and iatrogenic/injury causes, which may be preventable with improved diabetes care. PMID- 26953172 TI - Sparse time-frequency decomposition based on dictionary adaptation. AB - In this paper, we propose a time-frequency analysis method to obtain instantaneous frequencies and the corresponding decomposition by solving an optimization problem. In this optimization problem, the basis that is used to decompose the signal is not known a priori. Instead, it is adapted to the signal and is determined as part of the optimization problem. In this sense, this optimization problem can be seen as a dictionary adaptation problem, in which the dictionary is adaptive to one signal rather than a training set in dictionary learning. This dictionary adaptation problem is solved by using the augmented Lagrangian multiplier (ALM) method iteratively. We further accelerate the ALM method in each iteration by using the fast wavelet transform. We apply our method to decompose several signals, including signals with poor scale separation, signals with outliers and polluted by noise and a real signal. The results show that this method can give accurate recovery of both the instantaneous frequencies and the intrinsic mode functions. PMID- 26953171 TI - Epidermal Growth Factor Receptor Kinase Inhibitors Synergize with TCDD to Induce CYP1A1/1A2 in Human Breast Epithelial MCF10A Cells. AB - CYP1A1 and CYP1A2 are transcriptionally activated in the human normal breast epithelial cell line MCF10A following exposure to 2,3,7,8-tetrachlorodibenzo-p dioxin (TCDD). Shifting MCF10A cultures to medium deficient in serum and epidermal growth factor (EGF) caused rapid reductions in the activated (i.e., phosphorylated) forms of extracellular regulated kinases (ERKs) and the epidermal growth factor receptor (EGFR). Shifting to serum/EGF-deficient medium also enhanced TCDD-mediated induction of cytochrome P450 (CYP)1A1 Treatment of cells cultured in complete medium with the EGFR inhibitors gefitinib (Iressa), AG1478, and CI-1033 resulted in concentration-dependent reductions of active EGFR and ERKs, and increased CYP1A1 mRNA content ~3- to 18-fold above basal level. EGFR inhibitors synergized with TCDD and resulted in transient CYP1A1 and CYP1A2 mRNA accumulations ~8-fold greater (maximum at 5 hours) than that achieved with only TCDD. AG1478, gefitinib, and TCDD individually induced small increases (~1.2- to 2.5-fold) in CYP1A1 protein content but did not cause additive or synergistic accumulations of CYP1A1 protein when used in combination. The mitogen-activated protein kinase kinase inhibitor PD184352 inhibited ERK and EGFR activation in a concentration-dependent fashion without causing CYP1A1 mRNA accumulation. However, cotreatment with PD184352 potentiated TCDD-mediated CYP1A1 induction. TCDD-mediated induction of CYP1A1 in MCF7-TET on-EGFR cells, a MCF7 variant in which EGFR expression can be controlled, was not affected by the activity status of EGFR or ERKs. Hence, EGFR signaling mutes both basal and ligand-induced expression of two aryl hydrocarbon receptor-responsive P450s in MCF10A cultures. However, these effects are cell context-dependent. Furthermore, CYP1A1 mRNA and protein abundance are not closely coupled in MCF10A cultures. PMID- 26953173 TI - Fast multidimensional ensemble empirical mode decomposition for the analysis of big spatio-temporal datasets. AB - In this big data era, it is more urgent than ever to solve two major issues: (i) fast data transmission methods that can facilitate access to data from non-local sources and (ii) fast and efficient data analysis methods that can reveal the key information from the available data for particular purposes. Although approaches in different fields to address these two questions may differ significantly, the common part must involve data compression techniques and a fast algorithm. This paper introduces the recently developed adaptive and spatio-temporally local analysis method, namely the fast multidimensional ensemble empirical mode decomposition (MEEMD), for the analysis of a large spatio-temporal dataset. The original MEEMD uses ensemble empirical mode decomposition to decompose time series at each spatial grid and then pieces together the temporal-spatial evolution of climate variability and change on naturally separated timescales, which is computationally expensive. By taking advantage of the high efficiency of the expression using principal component analysis/empirical orthogonal function analysis for spatio-temporally coherent data, we design a lossy compression method for climate data to facilitate its non-local transmission. We also explain the basic principles behind the fast MEEMD through decomposing principal components instead of original grid-wise time series to speed up computation of MEEMD. Using a typical climate dataset as an example, we demonstrate that our newly designed methods can (i) compress data with a compression rate of one to two orders; and (ii) speed-up the MEEMD algorithm by one to two orders. PMID- 26953174 TI - Adaptive-projection intrinsically transformed multivariate empirical mode decomposition in cooperative brain-computer interface applications. AB - An extension to multivariate empirical mode decomposition (MEMD), termed adaptive projection intrinsically transformed MEMD (APIT-MEMD), is proposed to cater for power imbalances and inter-channel correlations in real-world multichannel data. It is shown that the APIT-MEMD exhibits similar or better performance than MEMD for a large number of projection vectors, whereas it outperforms MEMD for the critical case of a small number of projection vectors within the sifting algorithm. We also employ the noise-assisted APIT-MEMD within our proposed intrinsic multiscale analysis framework and illustrate the advantages of such an approach in notoriously noise-dominated cooperative brain-computer interface (BCI) based on the steady-state visual evoked potentials and the P300 responses. Finally, we show that for a joint cognitive BCI task, the proposed intrinsic multiscale analysis framework improves system performance in terms of the information transfer rate. PMID- 26953175 TI - ConceFT: concentration of frequency and time via a multitapered synchrosqueezed transform. AB - A new method is proposed to determine the time-frequency content of time dependent signals consisting of multiple oscillatory components, with time varying amplitudes and instantaneous frequencies. Numerical experiments as well as a theoretical analysis are presented to assess its effectiveness. PMID- 26953176 TI - Extracting a shape function for a signal with intra-wave frequency modulation. AB - In this paper, we develop an effective and robust adaptive time-frequency analysis method for signals with intra-wave frequency modulation. To handle this kind of signals effectively, we generalize our data-driven time-frequency analysis by using a shape function to describe the intra-wave frequency modulation. The idea of using a shape function in time-frequency analysis was first proposed by Wu (Wu 2013 Appl. Comput. Harmon. Anal. 35, 181-199. (doi:10.1016/j.acha.2012.08.008)). A shape function could be any smooth 2pi periodic function. Based on this model, we propose to solve an optimization problem to extract the shape function. By exploring the fact that the shape function is a periodic function with respect to its phase function, we can identify certain low-rank structure of the signal. This low-rank structure enables us to extract the shape function from the signal. Once the shape function is obtained, the instantaneous frequency with intra-wave modulation can be recovered from the shape function. We demonstrate the robustness and efficiency of our method by applying it to several synthetic and real signals. One important observation is that this approach is very stable to noise perturbation. By using the shape function approach, we can capture the intra-wave frequency modulation very well even for noise-polluted signals. In comparison, existing methods such as empirical mode decomposition/ensemble empirical mode decomposition seem to have difficulty in capturing the intra-wave modulation when the signal is polluted by noise. PMID- 26953177 TI - Hyperspectral chemical plume detection algorithms based on multidimensional iterative filtering decomposition. AB - Chemicals released in the air can be extremely dangerous for human beings and the environment. Hyperspectral images can be used to identify chemical plumes, however the task can be extremely challenging. Assuming we know a priori that some chemical plume, with a known frequency spectrum, has been photographed using a hyperspectral sensor, we can use standard techniques such as the so-called matched filter or adaptive cosine estimator, plus a properly chosen threshold value, to identify the position of the chemical plume. However, due to noise and inadequate sensing, the accurate identification of chemical pixels is not easy even in this apparently simple situation. In this paper, we present a post processing tool that, in a completely adaptive and data-driven fashion, allows us to improve the performance of any classification methods in identifying the boundaries of a plume. This is done using the multidimensional iterative filtering (MIF) algorithm (Cicone et al. 2014 (http://arxiv.org/abs/1411.6051); Cicone & Zhou 2015 (http://arxiv.org/abs/1507.07173)), which is a non-stationary signal decomposition method like the pioneering empirical mode decomposition method (Huang et al. 1998 Proc. R. Soc. Lond. A 454, 903. (doi:10.1098/rspa.1998.0193)). Moreover, based on the MIF technique, we propose also a pre-processing method that allows us to decorrelate and mean-centre a hyperspectral dataset. The cosine similarity measure, which often fails in practice, appears to become a successful and outperforming classifier when equipped with such a pre-processing method. We show some examples of the proposed methods when applied to real-life problems. PMID- 26953178 TI - Principal component analysis: a review and recent developments. AB - Large datasets are increasingly common and are often difficult to interpret. Principal component analysis (PCA) is a technique for reducing the dimensionality of such datasets, increasing interpretability but at the same time minimizing information loss. It does so by creating new uncorrelated variables that successively maximize variance. Finding such new variables, the principal components, reduces to solving an eigenvalue/eigenvector problem, and the new variables are defined by the dataset at hand, not a priori, hence making PCA an adaptive data analysis technique. It is adaptive in another sense too, since variants of the technique have been developed that are tailored to various different data types and structures. This article will begin by introducing the basic ideas of PCA, discussing what it can and cannot do. It will then describe some variants of PCA and their application. PMID- 26953179 TI - Adaptive data analysis: theory and applications. PMID- 26953180 TI - On Holo-Hilbert spectral analysis: a full informational spectral representation for nonlinear and non-stationary data. AB - The Holo-Hilbert spectral analysis (HHSA) method is introduced to cure the deficiencies of traditional spectral analysis and to give a full informational representation of nonlinear and non-stationary data. It uses a nested empirical mode decomposition and Hilbert-Huang transform (HHT) approach to identify intrinsic amplitude and frequency modulations often present in nonlinear systems. Comparisons are first made with traditional spectrum analysis, which usually achieved its results through convolutional integral transforms based on additive expansions of an a priori determined basis, mostly under linear and stationary assumptions. Thus, for non-stationary processes, the best one could do historically was to use the time-frequency representations, in which the amplitude (or energy density) variation is still represented in terms of time. For nonlinear processes, the data can have both amplitude and frequency modulations (intra-mode and inter-mode) generated by two different mechanisms: linear additive or nonlinear multiplicative processes. As all existing spectral analysis methods are based on additive expansions, either a priori or adaptive, none of them could possibly represent the multiplicative processes. While the earlier adaptive HHT spectral analysis approach could accommodate the intra-wave nonlinearity quite remarkably, it remained that any inter-wave nonlinear multiplicative mechanisms that include cross-scale coupling and phase-lock modulations were left untreated. To resolve the multiplicative processes issue, additional dimensions in the spectrum result are needed to account for the variations in both the amplitude and frequency modulations simultaneously. HHSA accommodates all the processes: additive and multiplicative, intra-mode and inter mode, stationary and non-stationary, linear and nonlinear interactions. The Holo prefix in HHSA denotes a multiple dimensional representation with both additive and multiplicative capabilities. PMID- 26953181 TI - Scale-dependent intrinsic entropies of complex time series. AB - Multi-scale entropy (MSE) was developed as a measure of complexity for complex time series, and it has been applied widely in recent years. The MSE algorithm is based on the assumption that biological systems possess the ability to adapt and function in an ever-changing environment, and these systems need to operate across multiple temporal and spatial scales, such that their complexity is also multi-scale and hierarchical. Here, we present a systematic approach to apply the empirical mode decomposition algorithm, which can detrend time series on various time scales, prior to analysing a signal's complexity by measuring the irregularity of its dynamics on multiple time scales. Simulated time series of fractal Gaussian noise and human heartbeat time series were used to study the performance of this new approach. We show that our method can successfully quantify the fractal properties of the simulated time series and can accurately distinguish modulations in human heartbeat time series in health and disease. PMID- 26953182 TI - Wave-turbulence interaction-induced vertical mixing and its effects in ocean and climate models. AB - Heated from above, the oceans are stably stratified. Therefore, the performance of general ocean circulation models and climate studies through coupled atmosphere-ocean models depends critically on vertical mixing of energy and momentum in the water column. Many of the traditional general circulation models are based on total kinetic energy (TKE), in which the roles of waves are averaged out. Although theoretical calculations suggest that waves could greatly enhance coexisting turbulence, no field measurements on turbulence have ever validated this mechanism directly. To address this problem, a specially designed field experiment has been conducted. The experimental results indicate that the wave turbulence interaction-induced enhancement of the background turbulence is indeed the predominant mechanism for turbulence generation and enhancement. Based on this understanding, we propose a new parametrization for vertical mixing as an additive part to the traditional TKE approach. This new result reconfirmed the past theoretical model that had been tested and validated in numerical model experiments and field observations. It firmly establishes the critical role of wave-turbulence interaction effects in both general ocean circulation models and atmosphere-ocean coupled models, which could greatly improve the understanding of the sea surface temperature and water column properties distributions, and hence model-based climate forecasting capability. PMID- 26953183 TI - Understanding deep convolutional networks. AB - Deep convolutional networks provide state-of-the-art classifications and regressions results over many high-dimensional problems. We review their architecture, which scatters data with a cascade of linear filter weights and nonlinearities. A mathematical framework is introduced to analyse their properties. Computations of invariants involve multiscale contractions with wavelets, the linearization of hierarchical symmetries and sparse separations. Applications are discussed. PMID- 26953184 TI - Adaptive multimode signal reconstruction from time-frequency representations. AB - This paper discusses methods for the adaptive reconstruction of the modes of multicomponent AM-FM signals by their time-frequency (TF) representation derived from their short-time Fourier transform (STFT). The STFT of an AM-FM component or mode spreads the information relative to that mode in the TF plane around curves commonly called ridges. An alternative view is to consider a mode as a particular TF domain termed a basin of attraction. Here we discuss two new approaches to mode reconstruction. The first determines the ridge associated with a mode by considering the location where the direction of the reassignment vector sharply changes, the technique used to determine the basin of attraction being directly derived from that used for ridge extraction. A second uses the fact that the STFT of a signal is fully characterized by its zeros (and then the particular distribution of these zeros for Gaussian noise) to deduce an algorithm to compute the mode domains. For both techniques, mode reconstruction is then carried out by simply integrating the information inside these basins of attraction or domains. PMID- 26953186 TI - Disentangling motivation from self-efficacy: implications for measurement, theory development, and intervention. PMID- 26953185 TI - Evaluation of Rifampin's Transporter Inhibitory and CYP3A Inductive Effects on the Pharmacokinetics of Venetoclax, a BCL-2 Inhibitor: Results of a Single- and Multiple-Dose Study. AB - Venetoclax is a selective, potent, first-in-class B-cell lymphoma-2 inhibitor that has demonstrated clinical efficacy in a variety of hematological malignancies. A single-dose and multiple-dose rifampin study was conducted to evaluate the effect of CYP3A induction and transporter inhibition on the pharmacokinetics of venetoclax. Subjects received a single dose of venetoclax 200 mg on day 1 of period 1 and days 1 and 14 of period 2, a single dose of rifampin 600 mg on day 1 of period 2, and rifampin 600 mg once daily on days 5 through 17 of period 2. Blood samples were collected up to 96 hours after each venetoclax dose on day 1 of period 1 and days 1 and 14 of period 2. Compared with venetoclax alone, coadministration with a single dose of rifampin increased venetoclax Cmax and AUCinfinity by 106% (90%CI, 73%-145%) and 78% (90%CI, 50%-111%), respectively, whereas coadministration with multiple doses of rifampin decreased venetoclax Cmax and AUCinfinity by 42% (90%CI, 31%-52%) and 71% (90%CI, 66%-76%), respectively. It was possible to isolate the net effect of chronic CYP3A induction from acute P-glycoprotein (P-gp) inhibition by comparing venetoclax exposures following coadministration with multiple doses of rifampin versus a single dose of rifampin, which showed that CYP3A induction decreased venetoclax Cmax and AUC by 72% and 84%, respectively. These results are consistent with venetoclax being a P-gp substrate and indicate that CYP3A plays a major role in venetoclax metabolism. Prescribers should consider agents with little or no CYP3A induction during treatment with venetoclax. PMID- 26953187 TI - The Paired-box protein PAX-3 regulates the choice between lateral and ventral epidermal cell fates in C. elegans. AB - The development of the single cell layer skin or hypodermis of Caenorhabditis elegans is an excellent model for understanding cell fate specification and differentiation. Early in C. elegans embryogenesis, six rows of hypodermal cells adopt dorsal, lateral or ventral fates that go on to display distinct behaviors during larval life. Several transcription factors are known that function in specifying these major hypodermal cell fates, but our knowledge of the specification of these cell types is sparse, particularly in the case of the ventral hypodermal cells, which become Vulval Precursor Cells and form the vulval opening in response to extracellular signals. Previously, the gene pvl-4 was identified in a screen for mutants with defects in vulval development. We found by whole genome sequencing that pvl-4 is the Paired-box gene pax-3, which encodes the sole PAX-3 transcription factor homolog in C. elegans. pax-3 mutants show embryonic and larval lethality, and body morphology abnormalities indicative of hypodermal cell defects. We report that pax-3 is expressed in ventral P cells and their descendants during embryogenesis and early larval stages, and that in pax-3 reduction-of-function animals the ventral P cells undergo a cell fate transformation and express several markers of the lateral seam cell fate. Furthermore, forced expression of pax-3 in the lateral hypodermal cells causes them to lose expression of seam cell markers. We propose that pax-3 functions in the ventral hypodermal cells to prevent these cells from adopting the lateral seam cell fate. pax-3 represents the first gene required for specification solely of the ventral hypodermal fate in C. elegans providing insights into cell type diversification. PMID- 26953189 TI - Explaining the variable penetrance of CNVs: Parental intelligence modulates expression of intellectual impairment caused by the 22q11.2 deletion. AB - The role of rare genetic variants, in particular copy number variants (CNVs), in the etiology of neurodevelopmental disorders is becoming increasingly clear. While the list of these disorder-related CNVs continues to lengthen, it has also become clear that in nearly all genetic variants the proportion of carriers who express the associated phenotype is far from 100%. To understand this variable penetrance of CNVs it is important to realize that even the largest CNVs represent only a tiny fraction of the entire genome. Therefore, part of the mechanism underlying the variable penetrance of CNVs is likely the modulatory impact of the rest of the genome. In the present study we used the 22q11DS as a model to examine whether the observed penetrance of intellectual impairment-one of the main phenotypes associated with 22q11DS-is modulated by the intellectual level of their parents, for which we used the parents' highest level of education as a proxy. Our results, based on data observed in 171 children with 22q11DS in the age range of 5-15 years, showed a significant association between estimated parental cognitive level and intelligence in offspring (full scale, verbal and performance IQ), with the largest effect size for verbal IQ. These results suggest that possible mechanisms involved in the variable penetrance observed in CNVs include the impact of genetic background and/or environmental influences. (c) 2016 Wiley Periodicals, Inc. PMID- 26953188 TI - Segregated Foxc2, NFATc1 and Connexin expression at normal developing venous valves, and Connexin-specific differences in the valve phenotypes of Cx37, Cx43, and Cx47 knockout mice. AB - Venous valves (VVs) are critical for unidirectional blood flow from superficial and deep veins towards the heart. Congenital valve aplasia or agenesis may, in some cases, be a direct cause of vascular disease, motivating an understanding of the molecular mechanisms underlying the development and maintenance of VVs. Three gap junction proteins (Connexins), Cx37, Cx43, and Cx47, are specifically expressed at VVs in a highly polarized fashion. VVs are absent from adult mice lacking Cx37; however it is not known if Cx37 is required for the initial formation of valves. In addition, the requirement of Cx43 and Cx47 for VV development has not been studied. Here, we provide a detailed description of Cx37, Cx43, and Cx47 expression during mouse vein development and show by gene knockout that each Cx is necessary for normal valve development. The valve phenotypes in the knockout lines exhibit Cx-specific differences, however, including whether peripheral or central VVs are affected by gene inactivation. In addition, we show that a Cx47 null mutation impairs peripheral VV development but does not affect lymphatic valve formation, a finding of significance for understanding how some CX47 mutations cause inherited lymphedema in humans. Finally, we demonstrate a striking segregation of Foxc2 and NFATc1 transcription factor expression between the downstream and upstream faces, respectively, of developing VV leaflets and show that this segregation is closely associated with the highly polarized expression of Cx37, Cx43, and Cx47. The partition of Foxc2 and NFATc1 expression at VV leaflets makes it unlikely that these factors directly cooperate during the leaflet elongation stage of VV development. PMID- 26953190 TI - Inhibitors of Ribosome Rescue Arrest Growth of Francisella tularensis at All Stages of Intracellular Replication. AB - Bacteria require at least one pathway to rescue ribosomes stalled at the ends of mRNAs. The primary pathway for ribosome rescue is trans-translation, which is conserved in >99% of sequenced bacterial genomes. Some species also have backup systems, such as ArfA or ArfB, which can rescue ribosomes in the absence of sufficient trans-translation activity. Small-molecule inhibitors of ribosome rescue have broad-spectrum antimicrobial activity against bacteria grown in liquid culture. These compounds were tested against the tier 1 select agent Francisella tularensis to determine if they can limit bacterial proliferation during infection of eukaryotic cells. The inhibitors KKL-10 and KKL-40 exhibited exceptional antimicrobial activity against both attenuated and fully virulent strains of F. tularensis in vitro and during ex vivo infection. Addition of KKL 10 or KKL-40 to macrophages or liver cells at any time after infection by F. tularensis prevented further bacterial proliferation. When macrophages were stimulated with the proinflammatory cytokine gamma interferon before being infected by F. tularensis, addition of KKL-10 or KKL-40 reduced intracellular bacteria by >99%, indicating that the combination of cytokine-induced stress and a nonfunctional ribosome rescue pathway is fatal to F. tularensis Neither KKL-10 nor KKL-40 was cytotoxic to eukaryotic cells in culture. These results demonstrate that ribosome rescue is required for F. tularensis growth at all stages of its infection cycle and suggest that KKL-10 and KKL-40 are good lead compounds for antibiotic development. PMID- 26953191 TI - Antitrypanosomal Activities and Mechanisms of Action of Novel Tetracyclic Iridoids from Morinda lucida Benth. AB - Trypanosoma brucei parasites are kinetoplastid protozoa that devastate the health and economic well-being of millions of people in Africa through the disease human African trypanosomiasis (HAT). New chemotherapy has been eagerly awaited due to severe side effects and the drug resistance issues plaguing current drugs. Recently, there has been an emphasis on the use of medicinal plants worldwide. Morinda lucida Benth. is a popular medicinal plant widely distributed in Africa, and several research groups have reported on the antiprotozoal activities of this plant. In this study, we identified three novel tetracyclic iridoids, molucidin, ML-2-3, and ML-F52, from the CHCl3 fraction of M. lucida leaves, which possess activity against the GUTat 3.1 strain of T. brucei brucei The 50% inhibitory concentrations (IC50) of molucidin, ML-2-3, and ML-F52 were 1.27 MUM, 3.75 MUM, and 0.43 MUM, respectively. ML-2-3 and ML-F52 suppressed the expression of paraflagellum rod protein subunit 2, PFR-2, and caused cell cycle alteration, which preceded apoptosis induction in the bloodstream form of Trypanosoma parasites. Novel tetracyclic iridoids may be promising lead compounds for the development of new chemotherapies for African trypanosomal infections in humans and animals. PMID- 26953192 TI - New Small Plasmid Harboring blaKPC-2 in Pseudomonas aeruginosa. AB - The aim of this study was to characterize the genetic context of blaKPC-2 in Pseudomonas aeruginosa sequence type 244 from Brazil. The blaKPC-2 gene was detected in a new small plasmid, pBH6. Complete sequencing revealed that pBH6 was 3,652 bp long and included the Tn3 resolvase and Tn3 inverted repeat (IR), a partial copy of ISKpn6, and a putative ori region but no rep genes. pBH6 replicated stably into Escherichia coli strain DH10B and P. aeruginosa strain PAO. PMID- 26953193 TI - Population Pharmacokinetics of Isavuconazole in Subjects with Mild or Moderate Hepatic Impairment. AB - Isavuconazole, administered as the prodrug isavuconazonium sulfate, was recently approved by the U.S. Food and Drug Administration and the European Medicines Agency for the treatment of adults with invasive aspergillosis and mucormycosis. The objective of this analysis was to develop a population pharmacokinetic model using NONMEM (version 7.2) for subjects with hepatic impairment, using intravenous and oral administration data from two hepatic studies, and to simulate concentration profiles to steady state, thus evaluating the need for dose adjustment. A two-compartment model with Weibull absorption function and first-order elimination process adequately described plasma isavuconazole concentrations. The population mean clearance in healthy subjects was 2.5 liters/h (5th and 95th percentiles: 2.0 and 3.1). The mean clearance values for subjects with mild and moderate hepatic impairment decreased approximately to 1.55 liters/h (5th and 95th percentiles: 1.3 and 1.8 liters/h) and 1.32 liters/h (5th and 95th percentiles: 1.05 and 1.35), respectively. Peripheral volume of distribution increased with body mass index. Simulations of mean concentration time profiles to steady state showed less than a 2-fold increase in mean trough concentrations for subjects with mild and moderate hepatic impairment compared with healthy subjects. After administration of the single dose, safety data for subjects with mild and moderate hepatic impairment were generally comparable to those for healthy subjects in both studies. Due to the <2-fold increase in trough concentrations and the established safety margin, dose adjustment appears to be unnecessary in subjects with mild or moderate hepatic impairment. PMID- 26953194 TI - Acquisition of Broad-Spectrum Cephalosporin Resistance Leading to Colistin Resistance in Klebsiella pneumoniae. AB - An extended-spectrum beta-lactamase (ESBL)-producing and colistin-resistant Klebsiella pneumoniae clinical isolate was recovered from a patient who was treated with cefotaxime. This isolate harbored a blaCTX-M-15 ESBL gene that was associated with an ISEcp1 insertion sequence. Transposition of that tandem occurred within the chromosomal mgrB gene, leading to inactivation of the mgrB gene and consequently to acquired resistance to colistin. We showed here a coselection of colistin resistance as a result of a broad-spectrum cephalosporin selective pressure. PMID- 26953196 TI - Factors Associated with Time to Appropriate Treatment in Pertussis Cases in Georgia, 2009 to 2013. AB - Pertussis is endemic in the United States, with periodic epidemics that continue to highlight its importance as a public health issue. The clinical presentation of pertussis can vary by age and vaccination status. However, little is known about the factors that affect time to antibiotic treatment of pertussis cases. We analyzed 5 years of data from the Georgia Department of Public Health to understand how factors such as age, symptoms, and vaccination status can alter the clinical picture of pertussis and affect time to treatment. We used multivariable linear regression to assess the impact of each variable on time to antibiotic treatment. There was little consistency across age groups for symptom and demographic predictors of time to antibiotic treatment. Overall, the multivariate linear regression showed that among patients <=18 years old, none of the variables had an impact on time to antibiotic treatment greater than -0.25 to 1.47 days. Among patients >18 years old, most variables had little impact on time to treatment, though two (paroxysmal cough in >18- to 40-year-olds and hospitalization in individuals over 40) were associated with an additional 5 days in time to treatment from cough onset. This study highlights how the difficulties in pertussis diagnosis, particularly among adults, can affect time to antibiotic treatment; adults may not begin antibiotic treatment until there is an accumulation of symptoms. Health care providers need to recognize the variety of symptoms that pertussis can present with and consider confirmatory testing early. PMID- 26953195 TI - Inhibition of Glutathione Biosynthesis Sensitizes Plasmodium berghei to Antifolates. AB - Glutathione plays a central role in maintaining cellular redox homeostasis, and modulations to this status may affect malaria parasite sensitivity to certain types of antimalarials. In this study, we demonstrate that inhibition of glutathione biosynthesis in the Plasmodium berghei ANKA strain through disruption of the gamma-glutamylcysteine synthetase (gamma-GCS) gene, which encodes the first and rate-limiting enzyme in the glutathione biosynthetic pathway, significantly sensitizes parasites in vivo to pyrimethamine and sulfadoxine, but not to chloroquine, artesunate, or primaquine, compared with control parasites containing the same pyrimethamine-resistant marker cassette. Treatment of mice infected with an antifolate-resistant P. berghei control line with a gamma-GCS inhibitor, buthionine sulfoximine, could partially abrogate pyrimethamine and sulfadoxine resistance. The role of glutathione in modulating the malaria parasite's response to antifolates suggests that development of specific inhibitors against Plasmodium gamma-GCS may offer a new approach to counter Plasmodium antifolate resistance. PMID- 26953197 TI - Protective Effect of a Synbiotic against Multidrug-Resistant Acinetobacter baumannii in a Murine Infection Model. AB - This study investigated the ability of the probiotic Bifidobacterium breve strain Yakult (BbY) to protect against infection, as well as the potentiation of BbY activity by the synbiotic combination of BbY and prebiotic galactooligosaccharides (GOS). The study employed a mouse model of lethal intestinal multidrug-resistant Acinetobacter baumannii (MDRAb) infection. The endogenous intestinal microbiota was disrupted by the administration of multiple antibiotics, causing the loss of endogenous Bifidobacterium Oral infection of these mice with MDRAb resulted in marked growth of this organism. Additional treatment of the infected mice with a sublethal dose of 5-fluorouracil (5-FU) induced systemic invasion by MDRAb and subsequent animal death. The continuous oral administration of BbY increased the survival rate and inhibited the intestinal growth and invasion by MDRAb in the infection model. Disruptions of the intestinal environment and barrier function in the infected mice were attenuated by BbY. Protection against the MDRAb infection was markedly potentiated by a synbiotic combination of BbY and GOS, although GOS by itself did not provide protection. Negative correlations were observed between intestinal MDRAb and BbY counts or acetic acid levels; positive correlations were observed between acetic acid levels and intestinal epithelium expression of tight-junction related genes. These results demonstrated that the probiotic and synbiotic markedly potentiated protection against fatal intestinal infection caused by a multidrug-resistant bacterium. Probiotics and synbiotics are presumed to provide protection by compensation for the disrupted indigenous populations, thereby maintaining the intestinal environments and barrier functions otherwise targeted during opportunistic infection by MDRAb. PMID- 26953198 TI - Intraspecies Transfer of the Chromosomal Acinetobacter baumannii blaNDM-1 Carbapenemase Gene. AB - The species Acinetobacter baumannii is one of the most important multidrug resistant human pathogens. To determine its virulence and antibiotic resistance determinants, the genome of the nosocomial blaNDM-1-positive A. baumannii strain R2090 originating from Egypt was completely sequenced. Genome analysis revealed that strain R2090 is highly related to the community-acquired Australian A. baumannii strain D1279779. The two strains belong to sequence type 267 (ST267). Isolate R2090 harbored the chromosomally integrated transposon Tn125 carrying the carbapenemase gene blaNDM-1 that is not present in the D1279779 genome. To test the transferability of the metallo-beta-lactamase (MBL) gene region, the clinical isolate R2090 was mated with the susceptible A. baumannii recipient CIP 70.10, and the carbapenem-resistant derivative R2091 was obtained. Genome sequencing of the R2091 derivative revealed that it had received an approximately 66-kb region comprising the transposon Tn125 embedding the blaNDM-1 gene. This region had integrated into the chromosome of the recipient strain CIP 70.10. From the four known mechanisms for horizontal gene transfer (conjugation, outer membrane vesicle-mediated transfer, transformation, and transduction), conjugation could be ruled out, since strain R2090 lacks any plasmid, and a type IV secretion system is not encoded in its chromosome. However, strain R2090 possesses three putative prophages, two of which were predicted to be complete and therefore functional. Accordingly, it was supposed that the transfer of the resistance gene region from the clinical isolate R2090 to the recipient occurred by general transduction facilitated by one of the prophages present in the R2090 genome. Hence, phage-mediated transduction has to be taken into account for the dissemination of antibiotic resistance genes within the species A. baumannii. PMID- 26953199 TI - Overcoming Chloroquine Resistance in Malaria: Design, Synthesis, and Structure Activity Relationships of Novel Hybrid Compounds. AB - Resistance to antimalarial therapies, including artemisinin, has emerged as a significant challenge. Reversal of acquired resistance can be achieved using agents that resensitize resistant parasites to a previously efficacious therapy. Building on our initial work describing novel chemoreversal agents (CRAs) that resensitize resistant parasites to chloroquine (CQ), we herein report new hybrid single agents as an innovative strategy in the battle against resistant malaria. Synthetically linking a CRA scaffold to chloroquine produces hybrid compounds with restored potency toward a range of resistant malaria parasites. A preferred compound, compound 35, showed broad activity and good potency against seven strains resistant to chloroquine and artemisinin. Assessment of aqueous solubility, membrane permeability, and in vitro toxicity in a hepatocyte line and a cardiomyocyte line indicates that compound 35 has a good therapeutic window and favorable drug-like properties. This study provides initial support for CQ-CRA hybrid compounds as a potential treatment for resistant malaria. PMID- 26953200 TI - Evaluation of Drug-Drug Interactions between Direct-Acting Anti-Hepatitis C Virus Combination Regimens and the HIV-1 Antiretroviral Agents Raltegravir, Tenofovir, Emtricitabine, Efavirenz, and Rilpivirine. AB - The three direct-acting antiviral agent (3D) regimen is a novel combination of direct-acting antiviral agents (DAAs) that has proven effective for the treatment of hepatitis C virus (HCV) infection. Given the potential for coadministration in patients with human immunodeficiency virus infection, possible drug interactions with antiretroviral drugs must be carefully considered. Four phase 1, multiple dose pharmacokinetic studies were conducted in healthy volunteers (n = 66). The 3D regimen of 150/100 mg daily paritaprevir/ritonavir, 25 mg daily ombitasvir, and 400 mg twice-daily dasabuvir was administered alone or in combination with 200 mg daily of emtricitabine and 300 mg daily of tenofovir disoproxil fumarate (tenofovir DF), 25 mg daily of rilpivirine, or 400 mg of raltegravir twice daily. A 2-DAA regimen of 150/100 mg daily paritaprevir/ritonavir and 400 mg of dasabuvir twice daily was also studied in combination with efavirenz/emtricitabine/tenofovir DF at 600/200/300 mg daily, respectively (Atripla; Bristol-Myers Squibb). Pharmacokinetic parameters were determined from plasma drug concentrations. No clinically significant drug interactions were observed (<=32% change in exposure) between the 3D regimen and that of emtricitabine plus tenofovir DF. Raltegravir exposure was increased up to 134% when the drug was coadministered with the 3D regimen. Although coadministration with rilpivirine was well tolerated in healthy volunteers, observed elevations in rilpivirine exposures may increase the potential for adverse drug reactions. Concomitant use of the 2-DAA regimen and efavirenz/emtricitabine/tenofovir DF was discontinued owing to poor tolerability and adverse events. No dose adjustment is required during coadministration of raltegravir, tenofovir DF, or emtricitabine with the 3D regimen. Rilpivirine is not recommended and efavirenz is contraindicated for coadministration with the 3D regimen. PMID- 26953201 TI - In Vitro and In Vivo Pharmacokinetics of Aminoalkylated Diarylpropanes NP085 and NP102. AB - Malaria remains a great burden on humanity. Although significant advances have been made in the prevention and treatment of malaria, malaria control is now hindered by an increasing tolerance of the parasite to one or more drugs within artemisinin combination therapies; therefore, an urgent need exists for development of novel and improved therapies. The University of the Free State Chemistry Department previously synthesized an antimalarial compound, NP046. In vitro studies illustrated an enhanced efficacy against Plasmodium falciparum However, NP046 showed low bioavailability. Efforts to enhance the bioavailability of NP046 have resulted in the synthesis of a number of aminoalkylated diarylpropanes, including NP085 and NP102. Pharmacokinetic studies were conducted in C57BL/6 mice, with 15 mg/kg NP085 or NP102 administered orally and the 5 mg/kg NP085 or NP102 administered intravenously. Blood samples were collected by means of tail bleeding at predetermined time intervals. Drug concentrations were determined using a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method, and subsequently pharmacokinetic modeling was done for both compounds. NP085 and NP102 were incubated in vitro with human and mouse liver microsomes. Both compounds were also subjected to a parallel artificial membrane permeation assay. In vitro studies of NP085 and NP102 illustrated that both of the compounds are rapidly absorbed and undergo rapid hepatic metabolism. The maximum concentration of drug (Cmax) obtained following oral administration of NP085 and NP102 was 0.2 +/- 0.4 and 0.7 +/- 0.3 MUM, respectively; the elimination half life of both compounds was 6.1 h. NP085 and NP102 showed bioavailability levels of 8% and 22%, respectively. PMID- 26953202 TI - Vancomycin 24-Hour Area under the Curve/Minimum Bactericidal Concentration Ratio as a Novel Predictor of Mortality in Methicillin-Resistant Staphylococcus aureus Bacteremia. AB - While previous studies have examined the association between vancomycin (VAN) exposure and MIC with regard to outcomes in methicillin-resistant Staphylococcus aureus bacteremia (MRSA-B), none have explored if a relationship exists with the VAN minimum bactericidal concentration (MBC). The objective of this study was to evaluate the VAN 24-h area under the curve (AUC24)/MBC ratio as a pharmacodynamic predictor of mortality. This retrospective cohort study included patients treated with VAN for MRSA-B with the primary outcome of 30-day all-cause mortality. Data collected included patient demographics, comorbidities, antimicrobial treatment data, therapeutic drug levels, and laboratory and microbiological data. Vancomycin MICs and MBCs were determined by Etest (MIC only) and broth microdilution (BMD). The vancomycin AUC24 was determined by pharmacokinetic maximum a posteriori probability Bayesian (MAP-Bayesian) analysis. The most significant breakpoint for 30-day mortality was determined by classification and regression tree (CART) analysis. The association between pharmacodynamic parameters (VAN AUC24/MICBMD, VAN AUC24/MICEtest, and AUC24/MBCBMD) and mortality were determined by chi(2) and multivariable Poisson regression. Overall mortality in this cohort (n = 53) was 20.8% (n = 11/53), and all corresponding MRSA blood isolates were VAN susceptible (MIC range, 0.5 to 2 MUg/ml; MIC50, 1 MUg/ml; MIC90, 1 MUg/ml). The CART-derived breakpoints for mortality were 176 (VAN AUC24/MBC) and 334 (VAN AUC24/MICBMD). In multivariable analysis, the association between a VAN AUC24/MBC of >=176 and survival persisted, but VAN AUC24/MICBMD values (>=334 or >=400) were not associated with improved mortality. In conclusion, VAN AUC24/MBC was a more important predictor of 30-day mortality than VAN AUC24/MIC for MRSA-B. PMID- 26953203 TI - Effects of Efflux Pump Inhibitors on Colistin Resistance in Multidrug-Resistant Gram-Negative Bacteria. AB - We tested the effects of various putative efflux pump inhibitors on colistin resistance in multidrug-resistant Gram-negative bacteria. Addition of 10 mg/liter cyanide 3-chlorophenylhydrazone (CCCP) to the test medium could significantly decrease the MICs of colistin-resistant strains. Time-kill assays showed CCCP could reverse colistin resistance and inhibit the regrowth of the resistant subpopulation, especially in Acinetobacter baumannii and Stenotrophomonas maltophilia These results suggest colistin resistance in Gram-negative bacteria can be suppressed and reversed by CCCP. PMID- 26953204 TI - Emergence of Plasmid-Mediated Colistin Resistance Gene mcr-1 in a Clinical Escherichia coli Isolate from Egypt. PMID- 26953205 TI - In Vitro and In Vivo Activities of OP0595, a New Diazabicyclooctane, against CTX M-15-Positive Escherichia coli and KPC-Positive Klebsiella pneumoniae. AB - Gram-negative bacteria are evolving to produce beta-lactamases of increasing diversity that challenge antimicrobial chemotherapy. OP0595 is a new diazabicyclooctane serine beta-lactamase inhibitor which acts also as an antibiotic and as a beta-lactamase-independent beta-lactam "enhancer" against Enterobacteriaceae Here we determined the optimal concentration of OP0595 in combination with piperacillin, cefepime, and meropenem, in addition to the antibacterial activity of OP0595 alone and in combination with cefepime, in in vitro time-kill studies and an in vivo infection model against five strains of CTX-M-15-positive Escherichia coli and five strains of KPC-positive Klebsiella pneumoniae An OP0595 concentration of 4 MUg/ml was found to be sufficient for an effective combination with all three beta-lactam agents. In both in vitro time kill studies and an in vivo model of infection, cefepime-OP0595 showed stronger efficacy than cefepime alone against all beta-lactamase-positive strains tested, whereas OP0595 alone showed weaker or no efficacy. Taken together, these data indicate that combinational use of OP0595 and a beta-lactam agent is important to exert the antimicrobial functions of OP0595. PMID- 26953206 TI - Ureolytic Biomineralization Reduces Proteus mirabilis Biofilm Susceptibility to Ciprofloxacin. AB - Ureolytic biomineralization induced by urease-producing bacteria, particularly Proteus mirabilis, is responsible for the formation of urinary tract calculi and the encrustation of indwelling urinary catheters. Such microbial biofilms are challenging to eradicate and contribute to the persistence of catheter-associated urinary tract infections, but the mechanisms responsible for this recalcitrance remain obscure. In this study, we characterized the susceptibility of wild-type (ure+) and urease-negative (ure-) P. mirabilis biofilms to killing by ciprofloxacin. Ure+ biofilms produced fine biomineral precipitates that were homogeneously distributed within the biofilm biomass in artificial urine, while ure- biofilms did not produce biomineral deposits under identical growth conditions. Following exposure to ciprofloxacin, ure+ biofilms showed greater survival (less killing) than ure- biofilms, indicating that biomineralization protected biofilm-resident cells against the antimicrobial. To evaluate the mechanism responsible for this recalcitrance, we observed and quantified the transport of Cy5-conjugated ciprofloxacin into the biofilm by video confocal microscopy. These observations revealed that the reduced susceptibility of ure+ biofilms resulted from hindered delivery of ciprofloxacin into biomineralized regions of the biofilm. Further, biomineralization enhanced retention of viable cells on the surface following antimicrobial exposure. These findings together show that ureolytic biomineralization induced by P. mirabilis metabolism strongly regulates antimicrobial susceptibility by reducing internal solute transport and increasing biofilm stability. PMID- 26953207 TI - Distribution and Relationships of Antimicrobial Resistance Determinants among Extended-Spectrum-Cephalosporin-Resistant or Carbapenem-Resistant Escherichia coli Isolates from Rivers and Sewage Treatment Plants in India. AB - To determine the distribution and relationship of antimicrobial resistance determinants among extended-spectrum-cephalosporin (ESC)-resistant or carbapenem resistant Escherichia coli isolates from the aquatic environment in India, water samples were collected from rivers or sewage treatment plants in five Indian states. A total of 446 E. coli isolates were randomly obtained. Resistance to ESC and/or carbapenem was observed in 169 (37.9%) E. coli isolates, which were further analyzed. These isolates showed resistance to numerous antimicrobials; more than half of the isolates exhibited resistance to eight or more antimicrobials. The blaNDM gene was detected in 14/21 carbapenem-resistant E. coli isolates: blaNDM-1 in 2 isolates, blaNDM-5 in 7 isolates, and blaNDM-7 in 5 isolates. The blaCTX-M gene was detected in 112 isolates (66.3%): blaCTX-M-15 in 108 isolates and blaCTX-M-55 in 4 isolates. We extracted 49 plasmids from selected isolates, and their whole-genome sequences were determined. Fifty resistance genes were detected, and 11 different combinations of replicon types were observed among the 49 plasmids. The network analysis results suggested that the plasmids sharing replicon types tended to form a community, which is based on the predicted gene similarity among the plasmids. Four communities each containing from 4 to 17 plasmids were observed. Three of the four communities contained plasmids detected in different Indian states, suggesting that the interstate dissemination of ancestor plasmids has already occurred. Comparison of the DNA sequences of the blaNDM-positive plasmids detected in this study with known sequences of related plasmids suggested that various mutation events facilitated the evolution of the plasmids and that plasmids with similar genetic backgrounds have widely disseminated in India. PMID- 26953208 TI - A PhoPQ-Regulated ABC Transporter System Exports Tetracycline in Pseudomonas aeruginosa. AB - Pseudomonas aeruginosa is an important human pathogen whose infections are difficult to treat due to its high intrinsic resistance to many antibiotics. Here, we show that the disruption of PA4456, encoding the ATP binding component of a putative ATP-binding cassette (ABC) transporter, increased the bacterium's susceptible to tetracycline and other antibiotics or toxic chemicals. Fluorescence spectroscopy and antibiotic accumulation tests showed that the interruption of the ABC transporter caused increased intracellular accumulation of tetracycline, demonstrating a role of the ABC transporter in tetracycline expulsion. Site-directed mutagenesis proved that the conserved residues of E170 in the Walker B motif and H203 in the H-loop, which are important for ATP hydrolysis, were essential for the function of PA4456. Through a genome-wide search, the PhoPQ two-component system was identified as a regulator of the computationally predicted PA4456-4452 operon that encodes the ABC transporter system. A >5-fold increase of the expression of this operon was observed in the phoQ mutant. The results obtained also show that the expression of the phzA1B1C1D1E1 operon and the production of pyocyanin were significantly higher in the ABC transporter mutant, signifying a connection between the ABC transporter and pyocyanin production. These results indicated that the PhoPQ-regulated ABC transporter is associated with intrinsic resistance to antibiotics and other adverse compounds in P. aeruginosa, probably by extruding them out of the cell. PMID- 26953210 TI - Clarithromycin Resistance Mechanisms of Epidemic beta-Lactamase-Nonproducing Ampicillin-Resistant Haemophilus influenzae Strains in Japan. AB - The aim of this study was to clarify the clarithromycin resistance mechanisms of beta-lactamase-nonproducing ampicillin-resistant Haemophilus influenzae strains. In all clarithromycin-resistant strains, the transcript level of acrB was significantly elevated, and these strains had a frameshift mutation in acrR Introduction of the acrR mutation into H. influenzae Rd generated a clarithromycin-resistant transformant with the same MIC as the donor strain. Our results indicate that the acrR mutation confers clarithromycin resistance by the increasing the transcription of acrB. PMID- 26953209 TI - Enhancement of the Replication of Hepatitis C Virus Replicons of Genotypes 1 to 4 by Manipulation of CpG and UpA Dinucleotide Frequencies and Use of Cell Lines Expressing SECL14L2 for Antiviral Resistance Testing. AB - Treatment for hepatitis C virus (HCV) has improved greatly through the use of direct-acting antivirals (DAAs). However, their effectiveness and potential for drug resistance development in non-genotype 1 variants of HCV remain relatively unexplored, as in vitro assays to assess drug susceptibility are poorly developed and unsuited for a transient-transfection format. In the current study, we have evaluated the effects of dinucleotide frequency changes in the replicon and the use of a SEC14L2-expressing cell line on the replication of HCVs of different genotypes and evaluated the resulting assay formats for measurements of susceptibility to the DAA sofosbuvir. Removal of CpG and UpA dinucleotides from the luciferase gene used in HCV replicons of genotype 1b (Con1) and genotype 2a (JFH-1) achieved between 10- and 100-fold enhancement of replication over that of the wild type posttransfection. Removal of CpG and UpA dinucleotides in the neomycin gene or deletion of the whole gene in replicons of genotype 3a (S52) and genotype 4a (ED43) enhanced replication, but phenotypic effects on altering luciferase gene composition were minimal. A further 10-fold replication enhancement of replicons from all four genotypes was achieved by using a transgenic Huh7.5 cell line expressing SECL14L2, whose expression showed a dose dependent effect on HCV replication that was reversible by small interfering RNA (siRNA) knockdown of gene expression. By combining these strategies, the 100- to 1,000-fold enhancement of replication allowed the susceptibility of all four genotypes to the RNA polymerase inhibitor sofosbuvir to be robustly determined in a transient-transfection assay format. These methods of replication enhancement provide new tools for monitoring the susceptibility and resistance of a wide range of HCV genotypes to DAAs. PMID- 26953211 TI - Role of the Cys154Arg Substitution in Ribosomal Protein L3 in Oxazolidinone Resistance in Mycobacterium tuberculosis. AB - We expressed the wild-type rplC and mutated rplC (Cys154Arg) genes, respectively, in Mycobacterium tuberculosis H37Ra and H37Rv in an attempt to delineate the role of rplC (Cys154Arg) regarding oxazolidinone resistance. An increase of the MICs of linezolid (LZD) and sutezolid (PNU-100480, PNU) against the recombinant mycobacteria with overexpressed rplC mutation (Cys154Arg) was found, suggesting the rplC gene is a determinant of bacillary susceptibilities to LZD and PNU. PMID- 26953213 TI - Use of Antipsychotics for the Treatment of Behavioral Symptoms of Dementia. AB - Antipsychotic medications are widely used in the management of behavioral and psychological symptoms of dementia. While nonpharmacological interventions should be the first-line treatment for behavioral symptoms of dementia, these are often unfeasible and/or ineffective. Conventional and atypical antipsychotic agents appear to have modest to moderate clinical efficacy in the treatment of these symptoms, though it is unclear which individual agents are most effective. No conclusive evidence exists that any available alternative medications are safer and more effective than antipsychotics. A number of studies have shown an increased risk of mortality associated with antipsychotics in patients with behavioral symptoms of dementia, though the observed risk increase may be partially confounded by illness severity and/or preexisting health determinants. The mechanisms of increased mortality risk are not fully established, but are likely to involve cardiovascular events. It is probable, though not certain, that conventional antipsychotics are associated with a greater number of poor outcomes than atypical antipsychotics. In certain patients with refractory behavioral symptoms, antipsychotics are a viable treatment option. Key considerations for antipsychotic prescribing for this population are published in regulatory guidelines, and include minimization of dosage and duration of treatment, continuous reevaluation of symptoms, and involvement of caregivers. PMID- 26953212 TI - First Report of cfr-Carrying Plasmids in the Pandemic Sequence Type 22 Methicillin-Resistant Staphylococcus aureus Staphylococcal Cassette Chromosome mec Type IV Clone. AB - Linezolid is often the drug of last resort for serious methicillin-resistant Staphylococcus aureus (MRSA) infections. Linezolid resistance is mediated by mutations in 23S rRNA and genes for ribosomal proteins; cfr, encoding phenicol, lincosamide, oxazolidinone, pleuromutilin, and streptogramin A (PhLOPSA) resistance; its homologue cfr(B); or optrA, conferring oxazolidinone and phenicol resistance. Linezolid resistance is rare in S. aureus, and cfr is even rarer. This study investigated the clonality and linezolid resistance mechanisms of two MRSA isolates from patients in separate Irish hospitals. Isolates were subjected to cfr PCR, PhLOPSA susceptibility testing, 23S rRNA PCR and sequencing, DNA microarray profiling, spa typing, pulsed-field gel electrophoresis (PFGE), plasmid curing, and conjugative transfer. Whole-genome sequencing was used for single-nucleotide variant (SNV) analysis, multilocus sequence typing, L protein mutation identification, cfr plasmid sequence analysis, and optrA and cfr(B) detection. Isolates M12/0145 and M13/0401 exhibited linezolid MICs of 64 and 16 mg/liter, respectively, and harbored identical 23S rRNA and L22 mutations, but M12/0145 exhibited the mutation in 2/6 23S rRNA alleles, compared to 1/5 in M13/0401. Both isolates were sequence type 22 MRSA staphylococcal cassette chromosome mec type IV (ST22-MRSA-IV)/spa type t032 isolates, harbored cfr, exhibited the PhLOPSA phenotype, and lacked optrA and cfr(B). They differed by five PFGE bands and 603 SNVs. Isolate M12/0145 harbored cfr and fexA on a 41-kb conjugative pSCFS3-type plasmid, whereas M13/0401 harbored cfr and lsa(B) on a novel 27-kb plasmid. This is the first report of cfr in the pandemic ST22-MRSA-IV clone. Different cfr plasmids and mutations associated with linezolid resistance in genotypically distinct ST22-MRSA-IV isolates highlight that prudent management of linezolid use is essential. PMID- 26953214 TI - Cellular cardiomyoplasty into infracted swine's hearts by retrograde infusion through the venous coronary sinus: An experimental study. AB - OBJECTIVES: The aim was to create a model of myocardial infarction with a borderline myocardial impairment which would enable evaluation of the retrograde cellular cardiomyoplasty through the venous coronary sinus in a large animal model. MATERIALS AND METHODS: Fifteen (study group) and 10 juvenile farm pigs (control group) underwent distal left anterior descending artery ligation. One month later the study group animals underwent sternotomy and a murine myoblastic line C2-C12 was injected at a constant pressure of 30mmHg, into the coronary sinus. Thirty days later all animals that survived from both groups underwent transthoracic echocardiography and 99Tc scintigraphy and were later euthanized and specimens were taken for microscopic evaluation. RESULTS: Cardiac output decreased significantly after ligation (p<0.001) and increased significantly after cardiomyoplasty (p<0.001). In all animals, the surgical induction of myocardial infarction caused a marked decline in the echocardiographic values of cardiac function; however, the cardiac function and dimensions were significantly improved in the study group after cardiomyoplasty versus the control group. All animals undergoing cardiomyoplasty demonstrated a significant reduction of the perfusion deficit in the left anterior descending artery territory, instead such data remained unchanged in the control group. The histological examination demonstrated the engrafted myoblasts could be distinguished from the activated fibroblasts in the scar tissue because they never showed any signs of collagen secretion and fiber buildup. CONCLUSIONS: In conclusion, the venous retrograde delivery route through the coronary sinus is safe and effective, providing a significant improvement in function and viability. PMID- 26953215 TI - Does Immunosuppressive Therapy Improve Outcomes in Graves' Disease? A Systematic Review and Meta-Analysis. AB - BACKGROUND: Whether the addition of immunosuppressive drugs to standard antithyroid drugs reduces the relapse risk in Graves' disease remains uncertain. PURPOSE: The aim of this study was to investigate the effects of immunosuppressive drugs on the relapse rate after a first episode of hyperthyroidism due to Graves' disease. METHODS: Based on a pre-specified protocol, PubMed (1946-July 2015), EMBASE (1947-July 2015), and Cochrane (1992 July 2015) databases were searched. The search was for (randomized) controlled trials comparing immunosuppressive drugs with a control group. PRISMA and SIGN statements were used for assessing data quality. Two reviewers extracted data, with any disagreement being resolved by consensus. Data were pooled using a random-effects model. RESULTS: The primary endpoint was relapse of disease until follow-up. Secondary endpoints included reduction of thyroid volume and decrease in thyrotropin-receptor antibody (TRAb) levels. Seven trials with 862 participants were included. Most trials were small with a moderate to high risk of bias. There were 113 relapses in 481 (23.5%) patients receiving immunosuppressive drugs compared with 225 relapses in 381 (59.1%) control patients (risk ratio for recurrence 0.55; [confidence interval (CI) 0.41-0.75]). Subgroup analyses showed similar effects for randomized trials and controlled trials (I(2) 0%), and for trials using corticosteroid and non-corticosteroid immunosuppressive drugs (I(2) 0%). Use of immunosuppressive drugs also resulted in significant reductions in thyroid volume (-10.72 mL [CI -15.59 to -5.85]) and TRAb levels (-17.01 IU/L [CI -33.31 to -0.72]). Immunosuppressive drug-related adverse effects were not systematically reported, and thus were not included in the quantitative analysis. CONCLUSIONS: Current evidence suggests a possible relevant reduction in relapse risk when immunosuppressive drugs are added to standard treatment of Graves' disease. The small number of trials with high heterogeneity in regard to treatment modalities and the lack of systematic reporting of adverse effects calls for larger, conclusive trials. PMID- 26953216 TI - Easier Control of Late-Onset Cytomegalovirus Disease Following Universal Prophylaxis Through an Early Antiviral Immune Response in Donor-Positive, Recipient-Negative Kidney Transplants. AB - Universal prophylaxis for cytomegalovirus (CMV) prevention is viable but, compared with a preemptive strategy, leads to higher incidence of late-onset disease (LOD) associated with poor patient and graft survival. The purpose of this study was to compare LOD with early onset disease (EOD), with a focus on the highest risk kidney transplant recipients (KTRs): CMV seronegative recipients transplanted from seropositive donors (D+R-). Since CMV control depends on both antiviral treatment and specific immune response, we also compared Vdelta2 negative (Vdelta2(neg) ) gammadelta T cell expansion involved in CMV infection resolution. EOD was defined as occurring <3 mo and LOD as occurring >3 mo after transplantation. Depending on the period, universal prophylaxis or preemptive treatment was used. Overall, 168 D+R- KTRs were included between 2003 and 2011. LOD was associated with a lower peak DNAemia (p = 0.04), fewer recurrences (odds ratio 0.16; 95% confidence interval 0.05-0.55; p = 0.01) and shorter anti-CMV curative treatment (40 vs. 60 days, p < 0.0001). As a corollary, we found that Vdelta2(neg) gammadelta T cell expansion was faster in LOD than in EOD (31 vs. 168 days after the beginning of CMV disease, p < 0.0001). In D+R- KTRs, universal prophylaxis is associated with more LOD, which had better infection management and a faster immune response. These results support the use of universal prophylaxis over a preemptive strategy and reappraise outcomes of LOD. PMID- 26953217 TI - Feasibility, Utility, and Safety of Midodrine During Recovery Phase From Septic Shock. AB - BACKGROUND: We describe the feasibility, utility, and safety of oral midodrine to replace IV vasopressors during recovery from septic shock. METHODS: This was a retrospective study performed in a medical ICU. All study subjects had a diagnosis of septic shock requiring at least 24 hours of IV vasopressors and demonstrated clinical stability with stable or decreasing doses of IV vasopressors. The two groups compared were those who received IV vasopressors only and those who received IV vasopressors with adjunctive midodrine. RESULTS: Of the 275 study patients, 140 received an IV vasopressor only and 135 received midodrine in addition to an IV vasopressor. There was no difference between the groups' demographics (age, sex, Acute Physiology and Chronic Health Evaluation 4 score). Mean IV vasopressor duration was 3.8 days in the IV vasopressor only group and 2.9 days in the IV vasopressor with midodrine group (P < .001). An IV vasopressor was reinstituted after discontinuation in 21 of 140 (15%) patients in the IV vasopressor only group and in 7 of 135 (5.2%) patients in the IV vasopressor with midodrine group (P = .007). ICU length of stay was 9.4 days in the IV vasopressor only group and 7.5 days in the IV vasopressor with midodrine group (P = .017). There were no complications associated with midodrine use except transient bradycardia in one patient, which resolved upon discontinuation of midodrine. CONCLUSIONS: Midodrine may reduce the duration of IV vasopressors during recovery phase from septic shock and may be associated with a reduction in length of stay in the ICU. PMID- 26953218 TI - ICU Care Before and After Lung Transplantation. AB - Lung transplantation (LTx) has become an accepted treatment for carefully selected patients with end-stage lung disease. Critical care issues have gained importance concerning bridging of candidates by mechanical respiratory support and are involved in the care after transplantation. The nature of respiratory support varies from oxygen supply and noninvasive ventilation, to mechanical respiratory support either by mechanical ventilation and/or extracorporeal life support. Recent innovations in extracorporeal life support technology have resulted in its more widespread use. Retrospective studies have demonstrated promising outcomes in candidates on mechanical respiratory support as a bridge to lung transplantation. The role of mechanical respiratory support has influenced the selection criteria for LTx, although bridging remains technically and ethically challenging. Critical care is integral to manage and prevent postoperative complications of LTx. Primary graft dysfunction and prolonged mechanical ventilation are major obstacles to hospital survival after LTx. Clear evidence is lacking on how to ventilate and optimally manage patients after LTx. Prolonged extracorporeal life support after LTx may improve outcome in selected patients with a primary graft dysfunction. PMID- 26953220 TI - Angiogenic mechanisms of human dental pulp and their relationship with substance P expression in response to occlusal trauma. AB - Angiogenesis is the formation of new blood vessels based on a pre-existing vasculature. It comprises two processes, sprouting of endothelial cells and the division of vessels due to abnormal growth of the microvasculature. It has been demonstrated that substance P (SP) can induce angiogenesis either by modulating endothelial cell growth (direct mechanism) or by attracting cells with angiogenic potential to the injury site (indirect mechanism). Therefore, the purpose of this article is to review the angiogenic mechanisms that regulate mineralized tissue formation in human dental pulp tissue and their relationship with SP expression as a defence response to stimuli such as the masticatory function and occlusal trauma. Articles included in this review were searched in PubMed, Scopus and ISI Web of Science databases, combining the following keywords: human dentine pulp, angiogenesis, angiogenic growth factors, neuropeptides, substance P, neurogenic inflammation, dentine matrix, dentinogenesis, occlusal trauma and dental occlusion. It is concluded that human dental pulp tissue responds to occlusal trauma and masticatory function with a neurogenic inflammatory phenomenon in which SP plays an important role in the direct and indirect mechanisms of angiogenesis by the action evoked via NK1 receptors at different cells, such as fibroblasts, endothelial and inflammatory cells, leading to new blood vessel formation which are needed to stimulate mineralized tissue formation as a defence mechanism. PMID- 26953219 TI - The Responsiveness of the Anxiety Inventory for Respiratory Disease Scale Following Pulmonary Rehabilitation. AB - BACKGROUND: To date, there are no studies that have examined the responsiveness of the Anxiety Inventory for Respiratory disease (AIR) scale to any intervention in patients with COPD. We examined the responsiveness of the AIR scale in an 8 week pulmonary rehabilitation (PR) program. METHODS: A total of 192 patients with COPD who were clinically stable and had a percent predicted FEV1 < 70% completed 8-week outpatient multidisciplinary PR. The duration of the program was 2 h per/week (1 h exercise and 1 h education). Pre- and postrehabilitation outcome measures were evaluated: exercise capacity by the incremental shuttle walk test, quality of life by the St Georges Respiratory Questionnaire (SGRQ), and severity of dyspnea by the Medical Research Council (nMRC) scale. Anxiety was measured using the self-administered AIR scale. RESULTS: The mean (SD) age was 71 (8.4) years and 51% were women. The AIR scale was responsive to PR with (AIR >= 8, high anxiety load) a mean change pre- vs post scores (12.25 vs 6.70, t = 7.56, P < .001), in incremental shuttle walk test (183 vs 258, t = 9.49, P < .001), in total SGRQ score (62.54 vs 55.70, t = 4.77, P < .001) and in nMRC score (3.32 vs 3.04, t = 2.57, P = .03) following PR. Change in AIR was significantly correlated with change in total SGRQ (r = 0.16, P = .02) and in nMRC (r = 0.15, P = .03). The effect size for the AIR was 1.01 and minimal clinical important difference was 5.55. Anxiety is a predictor of noncompletion of PR. CONCLUSIONS: The AIR scale is sensitive to change following PR in patients with COPD and can be used in future studies evaluating interventions that reduce anxiety in this disease. PMID- 26953221 TI - Response to article: serum total bilirubin concentrations are inversely associated with total white blood cell counts in an adult population. PMID- 26953222 TI - Bladder Instillation Therapy With Hyaluronic Acid and Chondroitin Sulfate Improves Symptoms of Postradiation Cystitis: Prospective Pilot Study. AB - BACKGROUND: After radiotherapy (RT) for prostate cancer (PCa), several patients reported lower urinary tract symptoms (LUTS) due to damage and discontinuation of the glycosaminoglycan layer of the bladder. Instillation of hyaluronic acid and chondroitin sulfate (HA-CS) represents replenishment therapy of the glycosaminoglycan layer. The aim of the study is to evaluate the efficacy and safety of HA-CS in men with symptomatic cystitis after RT for PCa. MATERIALS AND METHODS: Eighty consecutive men were treated with RT for PCa; 30 of these (37.5%) reported clinically relevant LUTS and associated bother as measured by the Interstitial Cystitis Symptom Index and Problem Index (ICSI/ICPI) Questionnaire 3 months after RT. Symptomatic patients received instillation therapy with HA-CS weekly for the first month and then at weeks 6, 8, and 12. All patients completed the ICSI/ICPI questionnaire before and after RT and at the end of HA-CS treatment. RESULTS: HA-CS significantly reduced postradiation LUTS (P < .001) and bother (P = .006). Age, Gleason score, and radiation dose were the main determinants of worsening of LUTS after radiation (ICSI score baseline vs. postradiation: P = .047, .043, and .023). In multivariate analysis, only age influenced LUTS worsening after RT (P = .01). Age, radiation dose, and radiation toxicity were related to recovery of LUTS (ICSI score postradiation vs. post-HA CS P = .041, P = .050, and P = .046). In multivariate analysis, no factor was statistically significant. CONCLUSIONS: A remarkable worsening of symptoms and bother was observed after RT. HA-CS instillation is a safe treatment and resulted in an improvement of LUTS irrespective of age and clinical features, with full recovery of urinary bother. PMID- 26953223 TI - Inter-Observer Variation in the Pathologic Identification of Minimal Extrathyroidal Extension in Papillary Thyroid Carcinoma. AB - BACKGROUND: Extrathyroidal extension (ETE) is a significant prognostic factor in papillary thyroid carcinoma (PTC). Minimal extrathyroidal extension (mETE) is characterized by involvement of the sternothyroid muscle or perithyroid soft tissue, and is generally identified by light microscope examination. Patients with mETE, identified pathologically, are automatically upstaged to pT3. However, the prognostic implications of mETE have been a source of controversy in the literature. Moreover, there is also controversy surrounding the identification of mETE on pathological specimens. The objective of this study was to determine the level of agreement among expert pathologists in the identification of mETE in PTC cases. METHODS: Eleven expert pathologists from the United States, Italy, and Canada were asked to perform a review of 69 scanned slides of representative permanent sections of PTC specimens. Each slide was evaluated for the presence of mETE. The pathologists were also asked to list the criteria they use to identify mETE. RESULTS: The overall strength of agreement for identifying mETE was slight (kappa = 0.14). Inter-pathologist agreement was best for perithyroidal skeletal muscle involvement (kappa = 0.46, moderate agreement) and worst for invasion around thick-walled vascular structures (kappa = 0.02, slight agreement). In addition, there was disagreement over the constellation of histologic features that are diagnostic for mETE, which affected overall agreement for diagnosing mETE. CONCLUSIONS: Overall agreement for the identification of mETE is poor. Disagreement is a result of both variation in individual pathologists' interpretations of specimens and disagreement on the histologic criteria for mETE. Thus, the utility of mETE in staging and treatment of PTC is brought into question. The lack of concordance may explain the apparent lack of agreement regarding the prognostic significance of this pathologic feature. PMID- 26953225 TI - GABAA receptor cysteinyl mutants and the ginkgo terpenoid lactones bilobalide and ginkgolides. AB - The terpenoid lactones from Ginkgo biloba, bilobalide and ginkgolides, have been shown to act as negative modulators at alpha1beta2gamma2L GABAA receptors. They have structural features similar to those of the chloride channel blocker picrotoxinin. Unlike picrotoxinin, however they are not known to produce convulsant effects. Using two-electrode voltage clamp electrophysiology, this study compared the effect of mutation of 2', 6' and 15' pore facing M2 domain residues to cysteine on the action of picrotoxinin, bilobalide and ginkgolides at alpha1beta2gamma2L GABAA receptors expressed in Xenopus oocytes. Picrotoxinin was affected by mutation differently from the ginkgo terpenoid lactones. Although some of these compounds were affected by the mutation at same position and/or subunit, the changes in their potency were found to be dissimilar. The results suggest that the intracellular pore binding site for picrotoxinin, bilobalide, ginkgolide A, ginkgolide B and ginkgolide C is comprised of 2'beta-6'beta6'gamma, 2'alpha2'beta-6'alpha6'beta, 2'alpha2'beta2'gamma-6'beta6'gamma, 2'alpha, 2'beta2'gamma-6'beta and 2'alpha2'beta, respectively. Unlike bilobalide and ginkgolides, the inhibitory action of picrotoxinin was not affected by mutations at 15' position. It is proposed that 15'alpha15'beta, 15'beta, 15'alpha15'beta and 15'alpha15'beta15'gamma forms an extracellular pore binding site for bilobalide, ginkgolide A, ginkgolide B and ginkgolide C, respectively. The lack of convulsant effects of bilobalide, and ginkgolide A and B may be associated in part with their different binding locations within the chloride channel. PMID- 26953224 TI - Pretransplant CD4 Count Influences Immune Reconstitution and Risk of Infectious Complications in Human Immunodeficiency Virus-Infected Kidney Allograft Recipients. AB - In current practice, human immunodeficiency virus-infected (HIV(+) ) candidates with CD4 >200 cells/mm(3) are eligible for kidney transplantation; however, the optimal pretransplant CD4 count above this threshold remains to be defined. We evaluated clinical outcomes in patients with baseline CD4 >350 and <350 cells/mm(3) among 38 anti-thymocyte globulin (ATG)-treated HIV-negative to HIV(+) kidney transplants performed at our center between 2006 and 2013. Median follow up was 2.6 years. Rates of acute rejection and patient and graft survival were not different between groups. Occurrence of severe CD4 lymphopenia (<200 cells/mm(3) ), however, was more common among patients with a baseline CD4 count 200-349 cells/mm(3) compared with those transplanted at higher counts (75% vs. 30% at 4 weeks [p = 0.04] and 71% vs. 5% at 52 weeks [p = 0.001], respectively, after transplant). After adjusting for age, baseline CD4 count of 200-349 cells/mm(3) was an independent predictor of severe CD4 lymphopenia at 4 weeks (relative risk [RR] 2.6; 95% confidence interval [CI] 1.3-5.1) and 52 weeks (RR 14.3; 95% CI 2-100.4) after transplant. Patients with CD4 <200 cells/mm(3) at 4 weeks had higher probability of serious infections during first 6 months after transplant (19% vs. 50%; log-rank p = 0.05). These findings suggest that ATG must be used with caution in HIV(+) kidney allograft recipients with a pretransplant CD4 count <350 cells/mm(3) . PMID- 26953226 TI - Multilocus genotypic data reveal high genetic diversity and low population genetic structure of Iranian indigenous sheep. AB - Iranian livestock diversity is still largely unexplored, in spite of the interest in the populations historically reared in this country located near the Fertile Crescent, a major livestock domestication centre. In this investigation, the genetic diversity and differentiation of 10 Iranian indigenous fat-tailed sheep breeds were investigated using 18 microsatellite markers. Iranian breeds were found to host a high level of diversity. This conclusion is substantiated by the large number of alleles observed across loci (average 13.83, range 7-22) and by the high within-breed expected heterozygosity (average 0.75, range 0.72-0.76). Iranian sheep have a low level of genetic differentiation, as indicated by the analysis of molecular variance, which allocated a very small proportion (1.67%) of total variation to the between-population component, and by the small fixation index (FST = 0.02). Both Bayesian clustering and principal coordinates analysis revealed the absence of a detectable genetic structure. Also, no isolation by distance was observed through comparison of genetic and geographical distances. In spite of high within-breed variation, signatures of inbreeding were detected by the FIS indices, which were positive in all and statistically significant in three breeds. Possible factors explaining the patterns observed, such as considerable gene flow and inbreeding probably due to anthropogenic activities in the light of population management and conservation programmes, are discussed. PMID- 26953227 TI - Age-Related Differences and Heterogeneity in Executive Functions: Analysis of NAB Executive Functions Module Scores. AB - Normative data from the German adaptation of the Neuropsychological Assessment Battery were used to examine age-related differences in 6 executive function tasks. A multivariate analysis of variance was employed to investigate the differences in performance in 484 participants aged 18-99 years. The coefficient of variation was calculated to compare the heterogeneity of scores between 10 age groups. Analyses showed an increase in the dispersion of scores with age, varying from 7% to 289%, in all subtests. Furthermore, age-dependent heterogeneity appeared to be associated with age-dependent decline because the subtests with the greatest increase in dispersion (i.e., Mazes, Planning, and Categories) also exhibited the greatest decrease in mean scores. In contrast, scores for the subtests Letter Fluency, Word Generation, and Judgment had the lowest increase in dispersion with the lowest decrease in mean scores. Consequently, the results presented here show a pattern of age-related differences in executive functioning that is consistent with the concept of crystallized and fluid intelligence. PMID- 26953228 TI - Effectiveness of various interventions on maintenance of gingival health during 1 year - a randomized clinical trial. AB - BACKGROUND: Rinsing with the combined use of an oxygenating-agent (OA) and chlorhexidine (CHX) in addition to mechanical oral hygiene could improve and/or maintain good gingival health over a long period. METHODS: This study had an examiner-blinded, randomized, six-group parallel design consisting of two-phases: a 3-week treatment phase and a subsequent 12-month experimental phase. A total of 267 subjects in good general health (>=18 years), without periodontitis, with at least five teeth per quadrant, and with moderate to advanced gingivitis were enrolled. A 3-week treatment phase was initiated to improve gingival health. Subjects were assigned to one of the six groups: two basic oral hygiene groups (Control I & II), one professional oral hygiene instruction group (OHI), one professional prophylaxis group (PP), an OA&CHX rinse group and a group receiving a combination of all regimens (COMBI group), being OHI + PP + OA&CHX. Dental plaque, gingival bleeding and staining assessments were performed at the start of the treatment phase, at baseline and at 4, 7, 10, and 12 months. RESULTS: There was a significant reduction in dental plaque-scores for the OA&CHX and COMBI group (0.51 [SD = 0.37], 0.38 [SD = 0.33] respectively) and a significant reduction in gingivitis scores for the OA&CHX and COMBI group (6.9% [SD = 14.0], 13.4% [SD = 13.4] respectively) from the start of the treatment phase to baseline. No clinically relevant changes were observed for the other four groups. After baseline, bleeding and plaque-scores increased back to a non-significant level between groups, and this level remained throughout the study. CONCLUSION: OA&CHX and COMBI-group showed a clinically relevant improvement after the treatment phase in terms of dental plaque and gingival bleeding levels. At the 4 month clinical assessment, there was no longer a significant difference between groups. PMID- 26953229 TI - Single base-pair deletion in ASIP exon 3 associated with recessive black phenotype in impala (Aepyceros melampus). PMID- 26953230 TI - Mechanical thrombectomy with Solitaire AB stents for the treatment of intracranial venous sinus thrombosis. AB - Background Cerebral venous sinus thrombosis (CVST) is a rare clinicopathological entity with substantial diagnostic and therapeutic dilemmas. The appropriate management of CVST remains to be defined. Purpose To evaluate the efficiency and safety of mechanical thrombectomy with Solitaire AB stents for the treatment of intracranial venous sinus thrombosis. Material and Methods Twenty-three consecutive patients with CVST who were treated with mechanical thrombectomy using Solitaire AB stents between January 2013 and October 2014 were retrospectively analyzed. The headache intensity was evaluated according to the visual analogue scale (VAS), and neurological function was assessed using the National Institute of Health Stroke Scale (NIHSS). Follow-up data were available for all patients for 6-14 months. Magnetic resonance imaging (MRI) and magnetic resonance venography (MRV) were performed at 3 and 6 months after neurointervention, and telephone interviews were performed monthly thereafter. The Wilcoxon signed-rank test was used to compare the evaluation data (VAS and NIHSS) at admission and discharge. Results Twenty-six Solitaire AB stents were used. No neurointervention-related complications were noted. The symptoms were significantly improved after neurointervention in all patients. The comparisons between the VAS and NIHSS evaluations at admission and discharge were significantly different ( P < 0.05). No recurrence was observed during the follow up period. Conclusion Mechanical thrombectomy with Solitaire AB stents is safe and effective for the treatment of CVST and can significantly improve clinical symptoms. The occurrence of complications is low, and the prognosis is favorable. PMID- 26953231 TI - Tumor necrosis factor-inducible gene 6 protein: A novel neuroprotective factor against inflammation-induced developmental brain injury. AB - Inflammation is an important factor contributing to developmental brain injury in preterm infants. Although tumor necrosis factor-inducible gene 6 protein (TSG-6) has immunomodulatory effects in several inflammatory conditions of adult animals, nothing is currently known about the role of TSG-6 in the developing brain, its impact on perinatal inflammation and its therapeutic potential. The aim of the current work was 1) to characterize the developmental expression of TSG-6 in the newborn rat brain, 2) to evaluate the impact of LPS exposure on TSG-6 expression and 3) to assess the therapeutic potential of exogenous TSG-6 administration. Brain hemispheres of healthy Wistar rats (postnatal day 1-postnatal day 15 (P1 P15)) were evaluated with regard to the physiological expression of TSG-6. LPS treated rats (0.25mg/kg LPS i.p. on P3) were analyzed for inflammation-induced changes in TSG-6 and cytokine expression. To evaluate whether exogenous recombinant human (rh)TSG-6 affects inflammation-induced brain injury, newborn Wistar rats, exposed to LPS on P3, were treated with rhTSG-6 i.p. (four repetitive doses of 2.25mg/kg every 12h, first dose 3h before LPS injection). PCR, Western blotting and multiplex ELISA were performed according to standard protocols. TSG-6 is physiologically expressed in the developing brain with a linear increase in expression from P1 to P15 at the mRNA level. At P6, regional differences in TSG-6 expression in the cortex, thalamus and striatum were detected at mRNA and protein level. Furthermore, TSG-6 gene expression was significantly increased by inflammation (induced by LPS treatment). Combined treatment with LPS and TSG-6 vs. LPS exposure alone, resulted in significant down regulation of cleaved caspase-3, a marker of apoptosis and neuronal plasticity. In addition, several inflammatory serum markers were decreased after TSG-6 treatment. Finally, TSG-6 is physiologically expressed in the developing brain. Changes of TSG-6 expression associated with inflammation suggest a role of TSG-6 in neuroinflammation. Reduction of cleaved caspase-3 by TSG-6 treatment demonstrates the putative neuroprotective potential of exogenous TSG-6 administration in inflammation-induced developmental brain injury. PMID- 26953232 TI - Pre-ictal increase in theta synchrony between the hippocampus and prefrontal cortex in a rat model of temporal lobe epilepsy. AB - The pathologically synchronized neuronal activity in temporal lobe epilepsy (TLE) can be triggered by network events that were once normal. Under normal conditions, hippocampus and medial prefrontal cortex (mPFC) work in synchrony during a variety of cognitive states. Abnormal changes in this circuit may aid to seizure onset and also help to explain the high association of TLE with mood disorders. We used a TLE rat model generated by perforant path (PP) stimulation to understand whether synchrony between dorsal hippocampal and mPFC networks is altered shortly before a seizure episode. We recorded hippocampal and mPFC local field potentials (LFPs) of animals with spontaneous recurrent seizures (SRSs) to verify the connectivity between these regions. We showed that SRSs decrease hippocampal theta oscillations whereas coherence in theta increases over time prior to seizure onset. This increase in synchrony is accompanied by a stronger coupling between hippocampal theta and mPFC gamma oscillation. Finally, using Granger causality we showed that hippocampus/mPFC synchrony increases in the pre ictal phase and this increase is likely to be caused by hippocampal networks. The dorsal hippocampus is not directly connected to the mPFC; however, the functional coupling in theta between these two structures rises pre-ictally. Our data indicates that the increase in synchrony between dorsal hippocampus and mPFC may be predictive of seizures and may help to elucidate the network mechanisms that lead to seizure generation. PMID- 26953233 TI - Interaction between protein-energy wasting and geriatric nutritional risk index in elderly patients on dialysis. PMID- 26953234 TI - Radiopharmaceuticals in Tumor Hypoxia Imaging: A Review Focused on Medicinal Chemistry Aspects. AB - Since its first description in 1955, tumor hypoxia has become a central issue in cancer treatment. Since then, it is essential to diagnose accurately the tumor oxygenation degree in order to establish the appropriate treatment. In this regard, a wide diversity of radiopharmaceuticals for in vivo imaging has been developed. Special conditions of the hypoxic microenvironment are low O2 partial pressure, enhanced levels of reductases, and genetic-adaptation-expression biomolecules involved in angiogenesis, erythropoiesis, cellular proliferation, apoptosis, metabolism- and glucose-uptake, local invasion, and metastatic spread. The development of radiolabeled hypoxia markers has been based on reductase substrates, like bioreductive ligands, or on entities capable of recognizing overexpressed proteins under hypoxia conditions, i.e. HIF-1alpha and carbonic anhydrase IX, among others. In this review these hypoxia markers are analyzed focusing on their medicinal chemistry characteristics. PMID- 26953235 TI - Acupuncture for patients with lumbar spinal stenosis: a randomised pilot trial. AB - OBJECTIVE: To assess the safety and feasibility of acupuncture for participants with symptomatic lumbar spinal stenosis (LSS) in a pilot study. METHODS: 50 participants with a clinical and radiological diagnosis of LSS were randomised to receive acupuncture combined with usual care (acupuncture group), or usual care alone (control group). Participants in the acupuncture group were offered 12-16 sessions of manual acupuncture+/-electroacupuncture over 6 weeks and maintained their usual self-management. The control group was provided with physical therapy as required and maintained their usual self-management. The primary outcome was the change in back-specific functional status, as measured by the Oswestry disability index (ODI) at the 3-month follow-up. Secondary outcomes included symptoms and other relevant domains. Outcome assessors were not blinded. RESULTS: 39 participants (78%) completed the trial with 524 treatment visits. There were no significant differences between the two groups in back-specific function (ODI: mean difference -2.5, 95% CI -8.9 to 3.8). Pain in the back and/or leg showed small improvements at 3 months, while there were no significant differences in other secondary outcomes. The total number of adverse events was 61 (12% of 524 treatment visits). All but one were minor and transient. The one severe adverse event was deemed to be unrelated to acupuncture. CONCLUSIONS: The study was feasible. Acupuncture combined with usual care did not confer significant functional improvements over usual care alone. Further randomised trials with adequate sample sizes and outcome assessor blinding are warranted to evaluate the role of acupuncture for LSS. TRIAL REGISTRATION NUMBER: NCT01987622. PMID- 26953236 TI - Experiences and Learning Needs of African American Family Dementia Caregivers. AB - Dementia family caregivers display significant rates of psychological and physical symptoms. African Americans (AAs) are disproportionately affected by dementia. African American caregivers display unique patterns of symptomology and responses to interventions designed to promote caregiver well-being. This study analyzed qualitative focus group data from 32 AA caregivers to explore how issues of race and culture may be incorporated into a culturally sensitive intervention for AA dementia family caregivers. Caregivers were asked scripted questions about their caregiving experiences and to suggest alterations to an existing psychoeducation program. Analysis revealed 4 key themes: the tradition of family care, caregiving and caregiving issues, culturally appropriate care, and navigating without a map. Suggestions for an educational program included a focus on developing caregiver skills and knowledge for caregiving, promotion of self care, and reflection on the AA family and community as resources for care. PMID- 26953237 TI - Properties of Ultraviolet Exposed Camptothecin Studied by Using Optical Spectroscopy Methods. AB - Camptothecin (CPT) and its analogs as inhibitors of topoisomerase I are anticancer compounds. Their antitumor potency is seriously limited due to hydrolysis of lactone form of camptothecins in solutions at pH>5.5, which leads to the formation of inactive carboxylate form with open lactone ring. Furthermore, the clinical application of CPT is also restricted by strong affinity of its carboxylate form to human serum albumin which destabilizes the active lactone form. By UV irradiation of the CPT carboxylate authors of this paper received camptothecin compound which has biophysical properties similar to the lactone form. The specific objective of the project is to determine the properties using the methods of absorption and steady-state fluorescence spectra analysis, fluorescence lifetime measurements as well as steady-state fluorescence anisotropy. The results suggest that the UV exposed camptothecin carboxylate changes the chemical structure. The high-throughput assays based on the steady state fluorescence anisotropy measurements proved that the form obtained as a result of UV irradiation of CPT carboxylate exhibits weaker affinity to albumin than CPT carboxylate however stronger than CPT lactone. This property is very desirable from the point of view of clinical applications. PMID- 26953238 TI - The Association Between alpha1-Antitrypsin and Coronary Artery Ectasia. AB - Coronary artery ectasia (CAE) is associated with coronary artery disease (CAD). The underlying pathophysiology of CAE is not fully understood. alpha1-antitrypsin (A1AT) plays a role in the tissue protease system, and AAT-1 deficiency (A1ATD) has been shown to be related to CAD. We compared A1AT serum levels in patients with and without CAE to determine the association between A1AT levels and the extent of ectasia using the Markis score. We included 50 patients (38 males) with isolated CAE and 46 patients (28 males) with normal coronary arteries after coronary angiography. The levels of A1AT were measured by nephelometry. The median A1AT levels were lower in patients with isolated CAE than in the control group (1.27 ng/mL [range: 1.07-1.37 ng/mL] vs 1.43 ng/mL [range: 1.27-1.59 ng/mL]; P < .001). According to the Markis classification, the extent of CAE was not correlated with A1AT levels ( P = .41). Our results demonstrate an inverse relationship between serum A1AT levels and CAE. alpha1-antitrypsin is fundamental for the stability and integrity of the arterial wall. Lack of elastase inhibition in cases of A1ATD may contribute to ectasia formation by facilitating proteolysis and weakening the arterial wall. PMID- 26953239 TI - Ursolic Acid Nanocrystals for Dissolution Rate and Bioavailability Enhancement: Influence of Different Particle Size. AB - BACKGROUND: Ursolic acid (UA), a natural pentacyclic triterpenoid, has been reported to possess a variety of pharmacological activities, but the poor oral bioavailability of UA owing to the poor aqueous solubility and membrane permeability limits the further clinical application. OBJECTIVE: The purpose of the present study was to develop UA nanocrystals and microcrystals employing high pressure homogenization (HPH) and to evaluate their effects on UA oral bioavailability. METHOD: The crystalline morphology of UA nanocrystals and microcrystals prepared by HPH was observed by scanning electron microscopy and the crystalline state was characterized by differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD). The dissolution rate of UA nanocrystals in different pH conditions was tested. Oral bioavailability of UA nanocrystals and microcrystals comparing with UA coarse suspension was evaluated in SD rats after 50 mg.kg-1 administration. RESULTS: UA nanocrystals and microcrystals, the size of which ranged between 291.7 nm and 1299.3 nm were obtained. The results of DSC and PXRD revealed a degree of crystalline-amorphous transformation during HPH preparation. A significant increase was observed in the dissolution rate of UA nanocrystals. The relative bioavailability of UA nanocrystals and microcrystals exhibited 2.56 and 1.40-fold enhancement than that of UA coarse suspension, respectively, along with an increased peak concentration and a prolonged retention. CONCLUSION: The nanosized UA crystal is a viable and efficient approach to improve the oral bioavailability of UA. PMID- 26953240 TI - Three-dimensional dominant frequency mapping using autoregressive spectral analysis of atrial electrograms of patients in persistent atrial fibrillation. AB - BACKGROUND: Areas with high frequency activity within the atrium are thought to be 'drivers' of the rhythm in patients with atrial fibrillation (AF) and ablation of these areas seems to be an effective therapy in eliminating DF gradient and restoring sinus rhythm. Clinical groups have applied the traditional FFT-based approach to generate the three-dimensional dominant frequency (3D DF) maps during electrophysiology (EP) procedures but literature is restricted on using alternative spectral estimation techniques that can have a better frequency resolution that FFT-based spectral estimation. METHODS: Autoregressive (AR) model based spectral estimation techniques, with emphasis on selection of appropriate sampling rate and AR model order, were implemented to generate high-density 3D DF maps of atrial electrograms (AEGs) in persistent atrial fibrillation (persAF). For each patient, 2048 simultaneous AEGs were recorded for 20.478 s-long segments in the left atrium (LA) and exported for analysis, together with their anatomical locations. After the DFs were identified using AR-based spectral estimation, they were colour coded to produce sequential 3D DF maps. These maps were systematically compared with maps found using the Fourier-based approach. RESULTS: 3D DF maps can be obtained using AR-based spectral estimation after AEGs downsampling (DS) and the resulting maps are very similar to those obtained using FFT-based spectral estimation (mean 90.23 %). There were no significant differences between AR techniques (p = 0.62). The processing time for AR-based approach was considerably shorter (from 5.44 to 5.05 s) when lower sampling frequencies and model order values were used. Higher levels of DS presented higher rates of DF agreement (sampling frequency of 37.5 Hz). CONCLUSION: We have demonstrated the feasibility of using AR spectral estimation methods for producing 3D DF maps and characterised their differences to the maps produced using the FFT technique, offering an alternative approach for 3D DF computation in human persAF studies. PMID- 26953241 TI - Can Dietary Polyphenols Prevent the Formation of Toxic Compounds from Maillard Reaction? AB - BACKGROUND: Polyphenols are functional compounds in edible vegetable and food such as tea, coffee and red wine and increasing evidence demonstrates a positive link between consumption of polyphenol-rich foods and disease prevention. OBJECTIVE: In this review we have focused on the current knowledge of the potential anti-glycation effects of polyphenols, particularly in regard to their influence on Maillard reaction, a non-enzymatic reaction between amino acids and reducing sugars that contributes to the production of toxic compounds, mainly reactive carbonyl species, advanced glycation end-products (AGEs) and other toxicants. METHOD AND RESULTS: The Maillard reaction occurs in the human body during hyperglycemic condition, but it is well known as browning reaction in thermally processed foods and it is responsible for flavor and toxicant formation. Dietary polyphenols can have anti-glycation effects and actively participate in Maillard reaction, mitigating the AGE formation and the heat induced production of toxic compounds. CONCLUSION: In a time in which the role of a healthy diet in the prevention of chronic diseases is welcome and the borderline between food and medicine is becoming very thin, an improved mechanistic knowledge of how polyphenols can function to reduce harmful and unhealthy substances is mandatory. PMID- 26953243 TI - Pharmacokinetic Modeling and Simulation of Biologicals in Inflammatory Bowel Disease: The Dawning of a New Era for Personalized Treatment. AB - BACKGROUND: Anti-tumor necrosis factor-alpha and anti-integrin monoclonal antibodies show great benefits for inducing and maintaining remission, healing the mucosa and restoring the quality of life of patients with inflammatory bowel disease. However, the therapeutic potential of these intrinsically powerful biologicals is abated by a high variability in response. Some patients experience no benefit from these treatments, while others lose response over time. Therapeutic Drug Monitoring (TDM) is a promising tool to further improve therapeutic outcome, substantiated by the finding that highly variable clinical response is correlated with pharmacokinetic (PK) variability. Serum Trough Concentrations (TCs) of the drug are measured and dosage regimens are adapted in order to achieve target TCs that correlate with beneficial therapeutic outcomes. The TC concept is relatively simple but gives only a partial insight in PK. PK profiles should be interpreted in the light of patient specific influences (i.e., covariates) that explain variability. OBJECTIVE: Therefore, the aim of TDM must be to dose the biological in such a way that a personal optimal PK profile is achieved. Furthermore, currently used "treat-to-target" algorithms have proven to increase the therapeutic potential of the drugs, but dosage regimen adaptations are still robust guesswork. RESULTS: A clinical decision support tool for accurately forecasting drug exposure would significantly impact TDM and is suggested to promote successful implementation of individualized predictive treatment in clinical practice. CONCLUSION: This review provides a clinician oriented overview of the state-of-the-art, the gaps in current knowledge and future potential of individualized predictive treatment. PMID- 26953242 TI - Specific Targeting of Akt Kinase Isoforms: Taking the Precise Path for Prevention and Treatment of Cancer. AB - Akt kinase is a serine threonine kinase that exists in three isoforms, located in different chromosomes and has distinct sites of expression which orchestrates diverse cellular processes required for normal functioning of the cell. Though, these Akt isoforms have some overlapping actions, but they also have specific roles and interestingly, sometimes they even perform contrasting functions. There are various alterations such as amplification, overexpression, mutation, etc. associated with these isoforms which have great implications in the development of cancer. Moreover, these alterations also induce chemo and radio resistance in cancer cells that impede the existing treatment modules. Furthermore, many reports have shown their potential as efficient prognostic biomarkers. Although, many studies have discussed the implications of Akt kinase proteins in different cancers but in-depth analysis of isoform- specific involvement is least examined and hence demands more attention. This review discusses the divergent roles of Akt isoforms comprehensively in different cancers and finding their immense prospects as potential targets for cancer prevention and treatment. PMID- 26953244 TI - IL-17A and Multiple Sclerosis: Signaling Pathways, Producing Cells and Target Cells in the Central Nervous System. AB - Multiple sclerosis (MS) is an immune mediated demyelinating disease of the central nervous system (CNS). The importance of immune cells to MS pathology is supported by clinical data linking the depletion of T and B cells, or the prevention of their migration into the brain with significant reduction in relapses and development of new lesions. In vitro studies, preclinical animal models and encouraging data with the anti-IL-17A antibody secukinumab in a small proof of concept study in man, indicate that IL-17A, a key interleukin associated with many inflammatory and autoimmune diseases, may be involved in MS. Not only cells involved in adaptive immune responses such as Th17 cells and cytotoxic T cells, or innate immune responses such as mucosa-associated invariant T (MAIT) cells and gammadeltaT cells, but also CNS resident cells such as astrocytes and oligodendrocytes might contribute to the local production of IL-17A. IL-17A synergizes with other proinflammatory cytokines, by inducing the release of additional cytokines, mediators of tissue damage and chemokines, that recruit new inflammatory cells. IL-17A adversely affects the functions of microglia, astrocytes, oligodendrocytes, neurons, neural precursor cells and endothelial cells. Blockade of IL-17A might be beneficial to MS patients not only by inhibiting inflammation and tissue destruction, but also by enhancing repair processes. PMID- 26953245 TI - Antiangiogenic Resistance and Cancer Metabolism: Opportunities for Synthetic Lethality. AB - Antiangiogenic resistance is a major problem in cancer therapeutics. Preclinical research has identified several compensatory proangiogenic pathways that arise upon vascular endothelial growth factor inhibition, several of which have led to the development of novel drugs. However, the combination of two or more targeted agents in the angiogenesis system is hampered by toxicity, as the system is involved in normal physiology. We propose a different approach for improving the efficacy of this drug class, which takes advantage of aberrant cancer metabolism. Several features distinguish cancer metabolism from that of normal cells, including increased glycolysis, glutaminolysis, and pentose-phosphate shunt, as well as an anaplerotic shift of the Krebs cycle. In addition, these aberrations are driven by most of the common mutations that can be targeted by drugs. Antiangiogenics may hamper the ability of cancer to sustain aberrant metabolism due to their impacts on nutrient and oxygen supplies, and thus they may induce some metabolic pathways to become essential for tumor survival (induced essentiality or contextual lethality, a type of synthetic lethality). Thus, some metabolic and signaling pathways that are otherwise nonessential may induce synthetic lethality when inhibited in combination with antiangiogenics. The key problems, however, are interpatient and intratumor heterogeneity, as not all patients with the same tumor type show the same metabolic traits and the same metabolic reprogramming in response to antiangiogenics. With each cancer there are heterogeneous hypoxic areas. Integrating dynamic tracking of metabolism may allow us to tailor our choices of companion drugs with antiangiogenics, taking advantage of window-of-opportunity designs. PMID- 26953246 TI - Pharmacological Chaperones that Protect Tetrahydrobiopterin Dependent Aromatic Amino Acid Hydroxylases Through Different Mechanisms. AB - The aromatic amino acid hydroxylase (AAAH) enzyme family includes phenylalanine hydroxylase (PAH), tyrosine hydroxylase (TH) and the tryptophan hydroxylases (TPH1 and TPH2). All four members of the AAAH family require iron, dioxygen and the cofactor (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin (BH4) to hydroxylate their respective substrates. The AAAHs are involved in severe diseases; whereas polymorphisms and variants in the TPH genes are associated to neuropsychiatric disorders, mutations in PAH and TH are responsible for the autosomal recessive disorders phenylketonuria (PKU) and TH deficiency (THD), respectively. A large number of PKU and THD-causing mutations give rise to unstable, misfolded proteins. The degree of conformational instability correlates well with the severity of the patient phenotypes, underlying the relevance of searching for stabilizing compounds that may protect from loss of protein and activity in vivo. Supplementation with the cofactor BH4 exerts a multifactorial response in PAH, where one of the main mechanisms for the induced increase in PAH activity in BH4- responsive PKU patients appears to be a pharmacological chaperone effect. For TH the stabilizing effect of BH4 is less established. On the other hand, a number of compounds with pharmacological chaperone potential for PKU and THD mutants have been discovered. The stabilizing effect of these compounds has been established in vitro, in cells and in animal models. A recent study with TH has revealed different mechanisms for the action of pharmacological chaperones and identifies a subtype of compounds that preserve TH activity by weak binding to the catalytic iron. It is expected that synergistic combinations of different pharmacological chaperones could provide patient-tailored therapeutic options. PMID- 26953247 TI - Pharmacoperones as a New Therapeutic Approach: In Vitro Identification and In vivo Validation of Bioactive Molecules. AB - In many conformational diseases caused by protein mutations, the intracellular traffic of the misfolded protein is compromised, leading to reduced or abolished function of the affected protein. Pharmacoperones (from "pharmacological chaperones") are compounds that enter cells and serve as a molecular scaffold to aid misfolded mutant proteins to fold properly and adopt a stable, low-energy native conformation compatible with proper intracellular trafficking. The use of pharmacoperones represents the most promising therapeutic approach to treat misfolding disorders. This class of drugs has succeeded, in vitro and in vivo, in rescuing function of mutant, misfolded proteins, including enzymes, membrane receptors and ion channels. Here we describe the strategies to rescue function of misfolded G protein-coupled receptors, mainly of the gonadotropin-releasing hormone receptor, which has served as a valuable model for the development of pharmacoperone drugs and to better understand how this class of particular compounds is sensed by the target protein to correct routing, expression and function. PMID- 26953248 TI - Tumor Stroma Manipulation By MSC. AB - Tumor stroma (TS) plays relevant roles in all steps of cancer development. We here address several fundamental aspects related with the interaction between cancer cells and their stromal counterparts. Dissecting these players is of pivotal importance to understand oncogenesis, immunoescape and drug resistance. In addition, this better comprehension will allow the introduction of novel and more effective therapeutic approaches where manipulated stromal elements may become detrimental for tumor growth. Our group and others rely on the use of multipotent mesenchymal stromal/stem cells (MSC) as anti-cancer tools, since these putative TS cell precursors can deliver potent apoptosis-inducing agents. Multimodal-armed MSC can target a variety of cancers in vitro and, when injected in vivo, they localize into tumors mediating cell death without evident toxicities to normal tissues. While several aspects of these strategies shall require further investigations, these approaches collectively indicate how TS manipulation by MSC represents a tool to influence the fate of cancer cells, creating a new generation of anti-cancer strategies. PMID- 26953249 TI - Inhibition of Plasmodium falciparum proliferation in vitro by double-stranded RNA nanoparticle against malaria topoisomerase II. AB - The need to develop new effective antimalarial agents is urgent due to the rapid emergence of drug resistance to all current drugs by the most virulent human malaria parasite, Plasmodium falciparum. A promising avenue is in the development of antimalarials based on RNA interference targeting expression of malaria parasite vital genes, viz. DNA topoisomerase II gene (PfTOP2). Biodegradable chitosan nanoparticle system has proven to be effective in delivering DNA and small double-stranded interfering RNA to target cells. We have employed a long double-stranded (dsRNA) targeting the coding region of PfTOP2 that is complexed with chitosan nanoparticles in order to interfere with the cognate mRNA expression and examined its effect on P. falciparum growth in culture. Exposure of ring stage-infected erythrocytes to 10 MUg/ml PfTOP2 chitosan/dsRNA nanoparticles for 48 h resulted in 71% growth inhibition as determined by [(3)H] hypoxanthine incorporation and microscopic assays, compared with 41% inhibition using an equivalent amount of free PfTOP2 dsRNA or 12% with unrelated chitosan/dsRNA nanoparticles. This inhibition was shown to occur during maturation of trophozoite to schizont stages. RT-PCR analysis indicated 56% and 38% decrease in PfTOP2 transcript levels in P. falciparum trophozoites treated with PfTOP2 dsRNA nanoparticles and free PfTOP2 dsRNA respectively. These results suggest that chitosan-based nanoparticles might be a useful tool for delivering dsRNA into malaria parasites. PMID- 26953250 TI - In vitro antileishmanial activity of trans-stilbene and terphenyl compounds. AB - Leishmaniasis are globally widespread parasitic diseases which often leads to death if left untreated. Currently available drugs present different drawbacks, so there is an urgent need to develop new, safe and cost-effective drugs against leishmaniasis. In this study we tested a small library of trans-stilbene and terphenyl derivatives against promastigote, amastigotes and intramacrophage amastigote forms of Leishmania infantum. Two compounds of the series, the trans stilbene 3 and the terphenyl 11, presented the best activity and safety profiles. Terphenyl 11 showed a leshmanicidal activity higher than pentostam and the ability to induce apoptosis selectively in Leishmania infantum while saving macrophages and primary epithelial cells. Our data indicate that terphenyl compounds, as well as stilbenes, are endowed with leishmanicidal activity, showing potential for further studies in the context of leishmanial therapy. PMID- 26953251 TI - Faecal chitinase 3-like 1 is a reliable marker as accurate as faecal calprotectin in detecting endoscopic activity in adult patients with inflammatory bowel diseases. AB - BACKGROUND: Faecal biomarkers are emerging tools in the assessment of mucosal healing in inflammatory bowel diseases (IBDs). AIM: To evaluate the accuracy of faecal chitinase 3-like 1(CHI3L1) compared to calprotectin in detecting endoscopic activity in IBD. METHODS: Overall, 86 IBD adults underwent colonoscopy consecutively and prospectively, with Crohn's disease Endoscopic Index of Severity (CDEIS) or Mayo endoscopic subscore calculation for ulcerative colitis, and stool collection. Faecal calprotectin was measured using quantitative immunochromatographic testing. Faecal CHI3L1 was quantified by ELISA. CHI3L1 cut off value was determined using a receiver-operating curve. RESULTS: In 54 Crohn's disease patients, faecal CHI3L1 (rho = 0.70, P < 0.001) and calprotectin (rho = 0.74, P < 0.001) levels correlated with CDEIS and were significantly increased in patients with endoscopic ulceration. In patients with ileal Crohn's disease, faecal CHI3L1 seemed to be better correlated with CDEIS than faecal calprotectin (rho = 0.78 vs. rho = 0.62, P < 0.001 for both). CHI3L1 > 15 ng/g detected endoscopic ulceration in Crohn's disease with a sensitivity of 100% and a specificity of 63.6%, compared to faecal calprotectin > 250 MUg/g showing a sensitivity of 90.5% and a specificity of 59.1%. In 32 ulcerative colitis patients, faecal CHI3L1 and calprotectin levels correlated with Mayo endoscopic subscore (rho = 0.44 and 0.61, respectively, P < 0.001 for both) and were significantly increased in ulcerative colitis patients with endoscopic activity. In ulcerative colitis patients, faecal CHI3L1 > 15 ng/g predicted endoscopic activity with a sensitivity of 81.8% and a specificity of 80.0%, compared to faecal calprotectin>250 MUg/g showing a sensitivity of 86.4% and a specificity of 80.0%. CONCLUSION: Faecal CHI3L1 is a reliable biomarker in detecting endoscopic activity in IBD. PMID- 26953252 TI - Vespa velutina nest distribution at a local scale: An 8-year survey of the invasive honeybee predator. AB - Vespa velutina is an invasive species that was observed for the first time in France and Europe in 2004, which rapidly threatened domestic honeybees with active predation. For the first time in this study, we analyzed the distribution of V. velutina nests at a local scale to understand the pattern of nesting, and in 8 years of monitoring, a total of 528 nests were surveyed. With the exception of 2 years, the nests of V. velutina were randomly distributed within the monitored area, which suggested that intraspecific competition for nesting sites and/or food was unlikely. When the data for all years were combined, an aggregated distribution of nests at the seafront in the vicinity of the oyster farm and sportfishing activities was observed. This distribution suggested that seafood, attractive to vespids, might provide a valuable alternative food source that favored colony development. We also tested the effect of spring queen trapping of V. velutina on the distribution of nests in 2014, which was the year with the greatest number of colonies within the area; the position of the traps did not influence the distribution of the nests. For the first time, this study showed that (i) intraspecific competition was unlikely to be a mechanism for population regulation, (ii) some areas were more likely favored for hornet nests, and (iii) spring queen wasp trapping was inefficient as a method to limit the distribution of the V. velutina population. PMID- 26953253 TI - Spontaneous Hemothorax Following Cardiac Surgery. AB - We report a case of spontaneous hemothorax after aortic valve replacement in a 72 year-old female resulting from rupture of a pleural adhesion leading to hemodynamic instability. doi: 10.1111/jocs.12729 (J Card Surg 2016;31:211-213). PMID- 26953254 TI - Double-stranded RNA-mediated interference of dumpy genes in Bursaphelenchus xylophilus by feeding on filamentous fungal transformants. AB - RNA interference (RNAi) is a valuable tool for studying gene function in vivo and provides a functional genomics platform in a wide variety of organisms. The pinewood nematode, Bursaphelenchus xylophilus, is a prominent invasive plant parasitic nematode and has become a serious worldwide threat to forest ecosystems. Presently, the complete genome sequence of B. xylophilus has been published, and research involving genome-wide functional analyses is likely to increase. In this study, we describe the construction of an effective silencing vector, pDH-RH, which contains a transcriptional unit for a hairpin loop structure. Utilising this vector, double-stranded (ds)RNAs with sequences homologous to the target genes can be expressed in a transformed filamentous fungus via Agrobacterium tumefaciens-mediated transformation technology, and can subsequently induce the knockdown of target gene mRNA expression in B. xylophilus by allowing the nematode to feed on the fungal transformants. Four dumpy genes (Bx-dpy-2, 4, 10 and 11) were used as targets to detect RNAi efficiency. By allowing the nematode to feed on target gene-transformed Fusarium oxysporum strains, target transcripts were knocked down 34-87% compared with those feeding on the wild-type strain as determined by real-time quantitative PCR (RT-qPCR). Morphological RNAi phenotypes were observed, displaying obviously reduced body length; weak dumpy or small (short and thin) body size; or general abnormalities. Moreover, compensatory regulation and non-specific silencing of dpy genes were found in B. xylophilus. Our results indicate that RNAi delivery by feeding in B. xylophilus is a successful technique. This platform may provide a new opportunity for undertaking RNAi-based, genome-wide gene functional studies in vitro in B. xylophilus. Moreover, as B. xylophilus feeds on endophytic fungi when a host has died, RNAi feeding technology will offer the prospect for developing a novel control strategy for the nematode. Furthermore, this platform may also be applicable to other parasitic nematodes that have a facultative, fungivorous habit. PMID- 26953256 TI - Chemical reproductive traits of diploid Bombus terrestris males: Consequences on bumblebee conservation. AB - The current bumblebee decline leads to inbreeding in populations that fosters a loss of allelic diversity and diploid male production. As diploid males are viable and their offspring are sterile, bumblebee populations can quickly fall in a vortex of extinction. In this article, we investigate for the first time a potential premating mechanism through a major chemical reproductive trait (male cephalic labial gland secretions) that could prevent monandrous virgin queens from mating with diploid males. We focus our study on the cephalic labial gland secretions of diploid and haploid males of Bombus terrestris (L.). Contrary to initial expectations, our results do not show any significant differentiation of cephalic labial gland secretions between diploid and haploid specimens. Queens seem therefore to be unable to avoid mating with diploid males based on their compositions of cephalic labial gland secretions. This suggests that the vortex of extinction of diploid males could not be stopped through premating avoidance based on the cephalic labial gland secretions but other mechanisms could avoid mating between diploid males and queens. PMID- 26953255 TI - Repeated praziquantel treatments remodel the genetic and spatial landscape of schistosomiasis risk and transmission. AB - Repeated treatments with praziquantel reduce schistosomiasis prevalence and morbidity, but transmission persists and populations often recover within a few years. To identify factors associated with persistence, we surveyed and treated all identified Schistosoma mansoni infections in two rural Brazilian communities (Jenipapo and Volta do Rio) in 2009, 2012 and 2013. Eggs were collected from all infected individuals and genotyped with 11 microsatellite markers to evaluate parasite differentiation and diversity. After successive rounds of community-wide treatment, prevalence decreased from 45% to 24% then 16%. Intensity of infection decreased by 57% over this period, and the number of eggs transmitted to the environment decreased by 92%. During all time periods the majority of eggs were excreted by those >15years of age. The incidence was 23% in 2012 and 15% in 2013, consistent with a decrease in transmission. There was little immigration or gene flow over a distance of 6km. On reinfection, infrapopulations were moderately differentiated indicating that pretreatment multilocus genotypes were not fully reacquired. The effective population size responded to census population decline more rapidly than differentiation. Reinfection was concentrated in the downstream portion of Jenipapo, consistent with the observed increased human fecal contamination. At this scale and in this area S. mansoni infections exist on a fragmented landscape with a highly focal pattern of transmission that may facilitate future elimination. PMID- 26953257 TI - Reference Intervals of Fibrosis Index Based on Four Indicators in Healthy Elderly Chinese. AB - BACKGROUND: The establishment of reference intervals of total bilirubin, Alanine aminotransferase (ALT), aspartate aminotransferases (AST), and creatinine provided necessary reference in screening and diagnosis of various kidney and liver diseases. However, these reference intervals were not available to estimate liver fibrosis degree. The purpose of this study is to establish the reference intervals of fibrosis index based on the four indicators (FIB-4) in apparently healthy elderly Chinese. METHODS: A total of 24,949 blood specimens were collected by the standard procedures, and ALT, AST, and PLT were determined. FIB 4 were calculated by the following formula: FIB-4 = (age [years] * AST [U/l])/((PLT [10(9) /l]) * (ALT [U/l])(1/2) ).The elderly's FIB-4 were analyzed between the same age of different sexes and different ages of the same sex. Statistical data were analyzed by SPSS18.0 software. RESULTS: Reference intervals of FIB-4 index, established for the healthy elderly, were 0.9923-4.5424 for males and 0.9007-4.1934 for females. CONCLUSION: We established reference intervals of FIB-4 index. This research provided reference value that can be used by relevant clinicians and inspection officers. PMID- 26953258 TI - Gene expression and localization analysis of Bombyx mori bidensovirus and its putative receptor in B. mori midgut. AB - Bombyx mori bidensovirus (BmBDV), which causes fatal flacherie disease in the silkworm, replicates only in midgut columnar cells. The viral resistance expressed by some silkworm strains, which is characterized as non-susceptibility irrespective of the viral dose, is determined by a single gene, nsd-2. We previously identified nsd-2 by positional cloning and found that this gene encodes a putative amino acid transporter that might function as a receptor for BmBDV. In this study, we investigated the relationship between the part of the midgut expressing nsd-2 (resistance gene), +(nsd-2) (susceptibility gene) and BmBDV propagation. Quantitative RT-PCR (qRT-PCR) analysis using total RNA isolated from the anterior, middle, and posterior parts of the midgut showed that nsd-2 and +(nsd-2) were strongly expressed in the posterior part of the midgut. The expression levels of both genes were very low in the anterior and middle parts. The qRT-PCR analysis showed that the expression levels of BmBDV-derived transcripts were correlated with the levels of +(nsd-2) expression. However, BmBDV-derived transcripts were clearly detected in all parts of the midgut. These results suggest that the infectivity of BmBDV depends mainly on the expression level of +(nsd-2) in the midgut and that viral infection is supported even by very faint expression of +(nsd-2). By contrast, the expression levels of +(nsd-2) were exceedingly low or undetectable in the middle part of the midgut, indicating that BmBDV infection might occur via another mechanism, independent of +(nsd-2), in the middle part of the midgut. PMID- 26953259 TI - Regulatory Implications of Non-Trivial Splicing: Isoform 3 of Rab1A Shows Enhanced Basal Activity and Is Not Controlled by Accessory Proteins. AB - Alternative splicing often affects structured and highly conserved regions of proteins, generating so called non-trivial splicing variants of unknown structure and cellular function. The human small G-protein Rab1A is involved in the regulation of the vesicle transfer from the ER to Golgi. A conserved non-trivial splice variant lacks nearly 40% of the sequence of the native Rab1A, including most of the regulatory interaction sites. We show that this variant of Rab1A represents a stable and folded protein, which is still able to bind nucleotides and co-localizes with membranes. Nevertheless, it should be mentioned that compared to other wild-typeRabGTPases, the measured nucleotide binding affinities are dramatically reduced in the variant studied. Furthermore, the Rab1A variant forms hetero-dimers with wild-type Rab1A and its presence in the cell enhances the efficiency of alkaline phosphatase secretion. However, this variant shows no specificity for GXP nucleotides, a constantly enhanced GTP hydrolysis activity and is no longer controlled by GEF or GAP proteins, indicating a new regulatory mechanism for the Rab1A cycle via alternative non-trivial splicing. PMID- 26953260 TI - Multivalent Interactions by the Set8 Histone Methyltransferase With Its Nucleosome Substrate. AB - Set8 is the only mammalian monomethyltransferase responsible for H4K20me1, a methyl mark critical for genomic integrity of eukaryotic cells. We present here a structural model for how Set8 uses multivalent interactions to bind and methylate the nucleosome based on crystallographic and solution studies of the Set8/nucleosome complex. Our studies indicate that Set8 employs its i-SET and c SET domains to engage nucleosomal DNA 1 to 1.5 turns from the nucleosomal dyad and in doing so, it positions the SET domain for catalysis with H4 Lys20. Surprisingly, we find that a basic N-terminal extension to the SET domain plays an even more prominent role in nucleosome binding, possibly by making an arginine anchor interaction with the nucleosome H2A/H2B acidic patch. We further show that proliferating cell nuclear antigen and the nucleosome compete for binding to Set8 through this basic extension, suggesting a mechanism for how nucleosome binding protects Set8 from proliferating cell nuclear antigen-dependent degradation during the cell cycle. PMID- 26953262 TI - De novo Synthesis and Assembly of rRNA into Ribosomal Subunits during Cold Acclimation in Escherichia coli. AB - During the cold adaptation that follows a cold stress, bacterial cells undergo many physiological changes and extensive reprogramming of their gene expression pattern. Bulk gene expression is drastically reduced, while a set of cold shock genes is selectively and transiently expressed. The initial stage of cold acclimation is characterized by the establishment of a stoichiometric imbalance of the translation initiation factors (IFs)/ribosomes ratio that contributes to the preferential translation of cold shock transcripts. Whereas de novo synthesis of the IFs following cold stress has been documented, nothing was known concerning the activity of the rrn operons during the cold acclimation period. In this work, we focus on the expression of the rrn operons and the fate of rRNA after temperature downshift. We demonstrate that in Escherichia coli, rRNA synthesis does not stop during the cold acclimation phase, but continues with greater contribution of the P2 compared to the P1 promoter and all seven rrn operons are active, although their expression levels change with respect to pre stress conditions. Eight hours after the 37 degrees ->10 degrees C temperature downshift, the newly transcribed rRNA represents up to 20% of total rRNA and is preferentially found in the polysomes. However, with respect to the de novo synthesis of the IFs, both rRNA transcription and maturation are slowed down drastically by cold stress, thereby accounting in part for the stoichiometric imbalance of the IFs/ribosomes. Overall, our data indicate that new ribosomes, which are possibly suitable to function at low temperature, are slowly assembled during cold acclimation. PMID- 26953263 TI - Richard Hudson and Norman Kaplan on the Coalescent Process. PMID- 26953261 TI - Mechanisms of Selective Autophagy in Normal Physiology and Cancer. AB - Selective autophagy is critical for regulating cellular homeostasis by mediating lysosomal turnover of a wide variety of substrates including proteins, aggregates, organelles, and pathogens via a growing class of molecules termed selective autophagy receptors. The molecular mechanisms of selective autophagy receptor action and regulation are complex. Selective autophagy receptors link their bound cargo to the autophagosomal membrane by interacting with lipidated ATG8 proteins (LC3/GABARAP) that are intimately associated with the autophagosome membrane. The cargo signals that selective autophagy receptors recognize are diverse but their recognition can be broadly grouped into two classes, ubiquitin dependent cargo recognition versus ubiquitin-independent. The roles of post translational modification of selective autophagy receptors in regulating these pathways in response to stimuli are an active area of research. Here we will review recent advances in the identification of selective autophagy receptors and their regulatory mechanisms. Given its importance in maintaining cellular homeostasis, disruption of autophagy can lead to disease including neurodegeneration and cancer. The role of autophagy in cancer is complex as autophagy can mediate promotion or inhibition of tumorigenesis. Here we will also review the importance of autophagy in cancer with a specific focus on the role of selective autophagy receptors. PMID- 26953264 TI - L. C. Dunn and Donald Charles on Quantitative Traits in the Mouse. PMID- 26953266 TI - Is Continued Genetic Improvement of Livestock Sustainable? AB - Large genetic improvements in the quantitative traits of growth, production, and efficiency of farmed livestock have been made over recent decades, and by introduction of genomic technology these are being enhanced. Such continued improvement requires that there be available variation to utilize. The evidence is that little variation has been lost and such rates are indeed sustainable in the future. PMID- 26953265 TI - Mutation and Human Exceptionalism: Our Future Genetic Load. AB - Although the human germline mutation rate is higher than that in any other well studied species, the rate is not exceptional once the effective genome size and effective population size are taken into consideration. Human somatic mutation rates are substantially elevated above those in the germline, but this is also seen in other species. What is exceptional about humans is the recent detachment from the challenges of the natural environment and the ability to modify phenotypic traits in ways that mitigate the fitness effects of mutations, e.g., precision and personalized medicine. This results in a relaxation of selection against mildly deleterious mutations, including those magnifying the mutation rate itself. The long-term consequence of such effects is an expected genetic deterioration in the baseline human condition, potentially measurable on the timescale of a few generations in westernized societies, and because the brain is a particularly large mutational target, this is of particular concern. Ultimately, the price will have to be covered by further investment in various forms of medical intervention. Resolving the uncertainties of the magnitude and timescale of these effects will require the establishment of stable, standardized, multigenerational measurement procedures for various human traits. PMID- 26953267 TI - WormBook: WormBiology for the 21st Century. PMID- 26953269 TI - Corrigendum. An Ancient Yeast for Young Geneticists: A Primer on the Schizosaccharomyces pombe Model System. PMID- 26953268 TI - CRISPR-Based Methods for Caenorhabditis elegans Genome Engineering. AB - The advent of genome editing techniques based on the clustered regularly interspersed short palindromic repeats (CRISPR)-Cas9 system has revolutionized research in the biological sciences. CRISPR is quickly becoming an indispensible experimental tool for researchers using genetic model organisms, including the nematode Caenorhabditis elegans. Here, we provide an overview of CRISPR-based strategies for genome editing in C. elegans. We focus on practical considerations for successful genome editing, including a discussion of which strategies are best suited to producing different kinds of targeted genome modifications. PMID- 26953271 TI - Drought responsive gene expression regulatory divergence between upland and lowland ecotypes of a perennial C4 grass. AB - Climatic adaptation is an example of a genotype-by-environment interaction (G*E) of fitness. Selection upon gene expression regulatory variation can contribute to adaptive phenotypic diversity; however, surprisingly few studies have examined how genome-wide patterns of gene expression G*E are manifested in response to environmental stress and other selective agents that cause climatic adaptation. Here, we characterize drought-responsive expression divergence between upland (drought-adapted) and lowland (mesic) ecotypes of the perennial C4 grass,Panicum hallii, in natural field conditions. Overall, we find that cis-regulatory elements contributed to gene expression divergence across 47% of genes, 7.2% of which exhibit drought-responsive G*E. While less well-represented, we observe 1294 genes (7.8%) with transeffects.Trans-by-environment interactions are weaker and much less common than cis G*E, occurring in only 0.7% oft rans-regulated genes. Finally, gene expression heterosis is highly enriched in expression phenotypes with significant G*E. As such, modes of inheritance that drive heterosis, such as dominance or overdominance, may be common among G*E genes. Interestingly, motifs specific to drought-responsive transcription factors are highly enriched in the promoters of genes exhibiting G*E and transregulation, indicating that expression G*E and heterosis may result from the evolution of transcription factors or their binding sites.P. hallii serves as the genomic model for its close relative and emerging biofuel crop, switchgrass (Panicum virgatum). Accordingly, the results here not only aid in the discovery of the genetic mechanisms that underlie local adaptation but also provide a foundation to improve switchgrass yield under water-limited conditions. PMID- 26953274 TI - Erratum for Itoh et al., Efficient PCR-Based Amplification of Diverse Alcohol Dehydrogenase Genes from Metagenomes for Improving Biocatalysis: Screening of Gene-Specific Amplicons from Metagenomes. PMID- 26953276 TI - Medicare project helps put pharmacists in primary care. PMID- 26953277 TI - Companies use value-based pricing for single-source off-patent drugs. PMID- 26953278 TI - Cost increase spurs review of "GI cocktail" components, effectiveness. PMID- 26953279 TI - Pharmacists in the emergency department: Encouraging and discouraging findings. PMID- 26953272 TI - Impaired antibacterial autophagy links granulomatous intestinal inflammation in Niemann-Pick disease type C1 and XIAP deficiency with NOD2 variants in Crohn's disease. AB - OBJECTIVE: Patients with Niemann-Pick disease type C1 (NPC1), a lysosomal lipid storage disorder that causes neurodegeneration and liver damage, can present with IBD, but neither the significance nor the functional mechanism of this association is clear. We studied bacterial handling and antibacterial autophagy in patients with NPC1. DESIGN: We characterised intestinal inflammation in 14 patients with NPC1 who developed IBD. We investigated bacterial handling and cytokine production of NPC1 monocytes or macrophages in vitro and compared NPC1 associated functional defects to those caused by IBD-associated nucleotide binding oligomerization domain-containing protein 2 (NOD2) variants or mutations in X-linked inhibitor of apoptosis (XIAP). RESULTS: Patients with the lysosomal lipid storage disorder NPC1 have increased susceptibility to early-onset fistulising colitis with granuloma formation, reminiscent of Crohn's disease (CD). Mutations in NPC1 cause impaired autophagy due to defective autophagosome function that abolishes NOD2-mediated bacterial handling in vitro similar to variants in NOD2 or XIAP deficiency. In contrast to genetic NOD2 and XIAP variants, NPC1 mutations do not impair NOD2-receptor-interacting kinase 2 (RIPK2) XIAP-dependent cytokine production. Pharmacological activation of autophagy can rescue bacterial clearance in macrophages in vitro by increasing the autophagic flux and bypassing defects in NPC1. CONCLUSIONS: NPC1 confers increased risk of early-onset severe CD. Our data support the concept that genetic defects at different checkpoints of selective autophagy cause a shared outcome of CD-like immunopathology linking monogenic and polygenic forms of IBD. Muramyl dipeptide driven cytokine responses and antibacterial autophagy induction are parallel and independent signalling cascades downstream of the NOD2-RIPK2-XIAP complex. PMID- 26953280 TI - Insulin glargine 300 units/mL: A new basal insulin product for diabetes mellitus. AB - PURPOSE: The pharmacokinetics, efficacy, and safety of U-300 insulin glargine for the management of diabetes are reviewed. SUMMARY: U-300 (300 units/mL) insulin glargine is a long-acting basal insulin with low within-day variability, high day to-day reproducibility, longer duration, and constant pharmacokinetic profile compared with U-100 (100 units/mL) insulin glargine. U-300 was evaluated in six randomized, active-comparator, open-label, Phase III clinical studies (EDITION trials) among patients with type 1 or 2 diabetes. The primary endpoint for all EDITION studies was the reduction in glycosylated hemoglobin from baseline to six months. Safety endpoints included confirmed or nocturnal hypoglycemia between week 9 and month 6 and the change in weight from baseline. For hypoglycemic episodes, U-300 insulin glargine was superior to U-100 insulin glargine when comparing the risk of hypoglycemia. U-300 insulin glargine is supplied in a prefilled device (for safety purposes) and packaged in boxes of three or five pens. It is still early to determine the role of U-300 insulin glargine in diabetes management. When compared with U-100 insulin glargine, U-300 insulin glargine appeared to be associated with a lower risk of hypoglycemia and nocturnal hypoglycemia, most likely due to its pharmacokinetics. The wholesale average cost of U-300 insulin glargine is $335.48 per box of three pens. CONCLUSION: The efficacy outcomes of U-300 insulin glargine were similar to those of U-100 insulin glargine, but the constant pharmacokinetic profile and longer duration of action of U-300 insulin glargine may help certain patients with type 1 or type 2 diabetes achieve better glycemic control. PMID- 26953281 TI - Ibrutinib for treatment of chronic lymphocytic leukemia. AB - PURPOSE: The pharmacology, pharmacokinetics, pharmacodynamics, clinical efficacy, and safety of ibrutinib are described. SUMMARY: Ibrutinib is a first-in-class oral inhibitor of Bruton tyrosine kinase (BTK) approved for treatment of relapsed chronic lymphocytic leukemia (CLL). Ibrutinib blocks downstream signaling of the B-cell receptor, disrupting stromal microenvironment interactions and B-cell cytokine signaling. BTK inhibition has been shown to be effective in relapsed or refractory CLL. A recent Phase III study evaluated ibrutinib (420 mg daily) versus ofatumumab (consistent with labeling) in relapsed or refractory CLL with a primary endpoint of progression free survival (PFS, n = 391). After a median follow-up period of 9.4 months, a PFS was not attained in ibrutinib-treated individuals with and without deletion 17p. In contrast, ofatumumab-treated individuals experienced a PFS of 8.1 months and those with deletion 17p experienced a PFS of 5.8 months. Major hemorrhage was reported in 2 (1%) patients treated with ibrutinib, and a total of 8 (4%) patients discontinued treatment due to toxicity or adverse reactions. Partial response or partial response with lymphocytosis was achieved in 63% of ibrutinib-treated individuals as determined by independent assessments. Overall, ibrutinib reduced the rate of mortality by 57%. CONCLUSION: Ibrutinib is a first-in-class, orally active, irreversible BTK inhibitor with a novel mechanism of action. This unique mechanism of action and high overall response rates observed in clinical trials make ibrutinib an attractive second-line option in patients who have disease progression while receiving monoclonal antibody therapy or chemoimmunotherapy. PMID- 26953282 TI - Prediction of area under the concentration-time curve for lopinavir from peak or trough lopinavir concentrations in patients receiving lopinavir-ritonavir therapy. AB - PURPOSE: A "single time point" strategy for predicting the area under the concentration-time curve (AUC) for lopinavir in patients receiving ritonavir boosted lopinavir therapy was investigated. METHODS: Linear regression equations describing the relationships of lopinavir peak and trough concentrations to lopinavir AUC values were established using pharmacokinetic data from published studies of patients or healthy subjects receiving lopinavir and ritonavir at standard dosages. The resulting "trough-AUC model" and "peak-AUC model" were used to predict lopinavir AUC values in the evaluated study populations (total n = 479); those values were then compared with reported AUC values. RESULTS: Lopinavir peak or trough concentrations were strongly correlated with lopinavir AUC values (r = 0.9947 and r = 0.9541, respectively). For about 94% of calculations using the peak-AUC model and 87% of calculations using the trough AUC model, differences between predicted and observed AUC values were in the range of 0.76-1.5 fold; the associated r values were 0.9514 (p < 0.001) and 0.9345 (p < 0.001), respectively. The mean absolute predictive error was less than 6% with the use of either the peak-AUC model or the trough-AUC model, with corresponding values for root-mean-square error of 17.6% and 23.5%, respectively. CONCLUSION: Equations incorporating lopinavir peak and trough concentrations were found to satisfactorily predict lopinavir AUC values in data sets describing patients receiving lopinavir with ritonavir boosting. Variability in predictions was higher with use of the trough-AUC model. PMID- 26953283 TI - A national survey of emergency pharmacy practice in the United States. AB - PURPOSE: The results of a survey to characterize pharmacy practice in emergency department (ED) settings are reported. METHODS: An electronic survey was sent to all members of the American Society of Health-System Pharmacists' Emergency Medicine Connect group and the American College of Clinical Pharmacy's Emergency Medicine Practice and Research Network. Approximately 400 nontrainee pharmacy practitioners were invited to participate in the survey, which was open for 30 days. Descriptive statistics were used for all analyses. RESULTS: Two hundred thirty-three responses to the survey that were at least partially completed were received. After the removal of duplicate responses and null records, 187 survey responses were retained. The majority of respondents were from community hospitals (59.6%) or academic medical centers (36.1%). A pharmacist's presence in the ED of more than eight hours per day on weekdays and weekends was commonly reported (68.7% of respondents); 49.4% of institutions provided more than eight hours of coverage daily. Nearly one in three institutions (34.8%) provided no weekend ED staffing. The most frequently reported hours of coverage were during the 1 p.m.-midnight time frame. The distribution of ED pharmacist activities, by category, was as follows (data are median reported time commitments): clinical, 25% (interquartile range [IQR], 15-40%); emergency response, 15% (IQR, 10-20%); order processing, 15% (IQR, 5-25%); medication reconciliation/history-taking, 10% (IQR, 5-25%); teaching, 10% (IQR, 5-15%); administrative, 5% (IQR, 3-10%); and scholarly endeavors, 0% (IQR, 0-5%). CONCLUSION: Pharmacists from academic and community EDs perform a variety of clinical, educational, and administrative activities. PMID- 26953284 TI - Comparative resource utilization and costs for patients with acute coronary syndrome managed with percutaneous coronary intervention and treated with clopidogrel or prasugrel. AB - PURPOSE: Results of a study of bleeding events and other inhospital outcomes with the use of clopidogrel versus prasugrel in patients with acute coronary syndrome (ACS) managed with percutaneous coronary intervention (PCI) are reported. METHODS: Demographic and clinical data on adults hospitalized for ACS, managed with PCI, and treated with clopidogrel or prasugrel during a two-year period were extracted from a large hospital claims database. Bleeding rates, hospital length of stay (LOS), and total hospital costs during the index hospitalization were evaluated. RESULTS: The study sample consisted of 75,297 patients who received clopidogrel and 9,477 who received prasugrel. The unadjusted bleeding rates were 5.7% with clopidogrel use and 3.2% with prasugrel use (p < 0.0001). After propensity score stratification to adjust for selection bias, rates of bleeding events were not significantly different between clopidogrel- and prasugrel treated patients (odds ratio, 0.90; 95% confidence interval [CI], 0.80-1.02; p = 0.0949). The adjusted mean +/- S.D. hospital LOS was 0.22 day lower (95% CI, 0.15 0.28; p < 0.001) with the use of prasugrel versus clopidogrel, and adjusted total mean hospital costs were $375 less for prasugrel-treated patients (p = 0.003). CONCLUSION: After adjustments for demographic and clinical characteristics, rates of inhospital bleeding in patients who received prasugrel and those who received clopidogrel were not significantly different. The adjusted analyses showed that the mean hospital LOS was shorter and total mean hospital costs were lower for patients treated with prasugrel. PMID- 26953285 TI - Implementation of American Academy of Pediatrics guidelines for palivizumab prophylaxis in a pediatric hospital. AB - PURPOSE: One hospital's implementation of revised American Academy of Pediatrics (AAP) guidelines for palivizumab prophylaxis of respiratory syncytial virus (RSV) infection is described. METHODS: Revised AAP guidelines for RSV prophylaxis in infants and young children at increased risk for RSV infection recommend that up to five doses of palivizumab be administered during the RSV season. The guidelines also recommend that inpatients not receive monthly palivizumab prophylaxis and that infants and young children eligible for prophylaxis during the RSV season receive a dose of palivizumab two or three days before discharge or promptly after discharge. To ensure compliance with the revised AAP guidelines, a 296-bed hospital implemented a quality-improvement project including (1) efforts by the antimicrobial stewardship pharmacist and the chief medical officer to notify and educate healthcare providers regarding institutional adoption of the guidelines, (2) reinforcement of guideline adherence by clinical pharmacists during daily bedside rounds and via prospective review of all palivizumab orders, and (3) a medication-use evaluation (MUE) to assess adherence to the guidelines. The MUE results showed that during the 2014 15 RSV season (after implementation of the practice changes), the number of palivizumab doses administered at the hospital declined by 56% from the previous RSV season, with 97% of doses administered for appropriate indications. CONCLUSION: Standardized, comprehensive guidelines with defined criteria for palivizumab prophylaxis of RSV infection resulted in $303,227 of cost savings without a discernible change in nosocomial transmission, or morbidity, or mortality. Hospital infection-control practices controlled nosocomial RSV transmission. PMID- 26953286 TI - ASHP Statement on the Pharmacist's Role in Clinical Informatics. PMID- 26953287 TI - Prenatal Exposure to Nitrosatable Drugs, Dietary Intake of Nitrites, and Preterm Birth. AB - Prenatal exposure to nitrosatable drugs, including secondary or tertiary amines, has been associated with preterm birth. Associations may be accentuated by higher intakes of dietary nitrites because of the increased formation of N-nitroso compounds. Using data from mothers of babies without major birth defects (controls) from the National Birth Defects Prevention Study, we examined the relationship between nitrosatable drug exposure in conjunction with dietary nitrite intake and preterm birth among 496 mothers of preterm infants and 5,398 mothers with full-term deliveries in 1997-2005. A protective association was observed with a high intake of plant nitrites (adjusted hazard ratio (AHR) = 0.72, 95% confidence interval (CI): 0.53, 0.97). Secondary amines in conjunction with high nitrite intake were associated with preterm birth during the first (AHR = 1.84, 95% CI: 1.14, 2.98), second (AHR = 1.89, 95% CI: 1.17, 3.07), and third (AHR = 2.00, 95% CI: 1.22, 3.29) trimesters. The adjusted hazard ratios for tertiary amine use in the third trimester by increasing tertiles of nitrite intake were 0.67 (95% CI: 0.35, 1.31), 1.25 (95% CI: 0.71, 2.19), and 2.02 (95% CI: 1.17, 3.49). Prenatal exposure to nitrosatable drugs, particularly secondary and tertiary amines, in conjunction with higher levels of dietary nitrite intake may increase the risk of preterm birth. PMID- 26953288 TI - Physicians, Accountable Care, And Drugs. PMID- 26953290 TI - Medicare Coverage For Advance Care Planning: Just The First Step. AB - What will it take for health care providers to begin talking about end-of-life care with their patients? PMID- 26953291 TI - Care Management Processes Used Less Often For Depression Than For Other Chronic Conditions In US Primary Care Practices. AB - Primary care physicians play an important role in the diagnosis and management of depression. Yet little is known about their use of care management processes for depression. Using national survey data for the period 2006-13, we assessed the use of five care management processes for depression and other chronic illnesses among primary care practices in the United States. We found significantly less use for depression than for asthma, congestive heart failure, or diabetes in 2012 13. On average, practices used fewer than one care management process for depression, and this level of use has not changed since 2006-07, regardless of practice size. In contrast, use of diabetes care management processes has increased significantly among larger practices. These findings may indicate that US primary care practices are not well equipped to manage depression as a chronic illness, despite the high proportion of depression care they provide. Policies that incentivize depression care management, including additional quality metrics, should be considered. PMID- 26953293 TI - The Medical Profession's Future: A Struggle Between Caring For Patients And Bottom-Line Pressures. AB - In this issue of Health Affairs, Lawrence Casalino and coauthors establish that physicians in common specialty practices spend an average of 2.6 hours per week dealing with external quality measures. This gives rise to general questions about the future of the medical profession. To what extent will quality-tracking requirements and similar practice intrusions reshape who physicians are, how many physicians there are, and how they practice? In turn, how will these changes affect patients' access to care? Data derived from the 2014 Survey of America's Physicians: Practice Patterns and Perspectives, conducted by Merritt Hawkins on behalf of the Physicians Foundation, make it clear that physician practice patterns are evolving. Responding to an increasingly intrusive practice environment, physicians report that they will choose a variety of practice models likely to reduce patients' access to care or that they will retire early, which will exacerbate the physician shortage and fundamentally change the nature of the medical profession. PMID- 26953292 TI - US Physician Practices Spend More Than $15.4 Billion Annually To Report Quality Measures. AB - Each year US physician practices in four common specialties spend, on average, 785 hours per physician and more than $15.4 billion dealing with the reporting of quality measures. While much is to be gained from quality measurement, the current system is unnecessarily costly, and greater effort is needed to standardize measures and make them easier to report. PMID- 26953294 TI - Fee-For-Service, While Much Maligned, Remains The Dominant Payment Method For Physician Visits. AB - Recent concerted efforts have sought to shift provider payment away from fee-for service and toward risk-based alternatives. Despite these efforts, fee-for service not only remains the dominant payment method but has continued to grow, with nearly 95 percent of all physician office visits in 2013 reimbursed in this fashion. PMID- 26953295 TI - Understanding The Strengths And Weaknesses Of Public Reporting Of Surgeon Specific Outcome Data. AB - Public reporting of outcome data is increasingly being used at the institutional and clinician levels and has become mandatory in some parts of the United States and the United Kingdom. The intended benefits are to drive quality improvement, demonstrate transparency, facilitate patient choice, and allow identification of poor performance. Public reporting of surgeon-specific mortality data, however, may have unintended consequences that include causing surgeons to become risk averse, discouraging innovation, having an impact on training, and prompting "gaming" in health care. Given the small number of some surgical operations performed by individual surgeons, such data are unlikely to identify outliers or poor performers in a valid way. If metrics are deemed necessary and required to be reported publicly, they should be procedure specific; account for sample size; and focus not solely on mortality but also on other outcomes such as quality of life, patient satisfaction, and experience. PMID- 26953297 TI - Hospitals Participating In ACOs Tend To Be Large And Urban, Allowing Access To Capital And Data. AB - Relationships between physicians and hospitals have changed considerably over the past decade, as hospitals and physician groups have integrated and new public and private payment policies have created financial interdependence. The extent to which accountable care organizations (ACOs) involve hospitals in their operations may prove to be vitally important, because managing hospital care is a key part of improving health care quality and lowering cost growth. Using primary data on ACO composition and capabilities paired with hospital characteristics, we found that 20 percent of US hospitals were part of an ACO in 2014. Hospitals that were in urban areas, were nonprofit, or had a smaller share of Medicare patients were more likely to participate in ACOs, compared to hospitals that were in more rural areas, were for-profit or government owned, or had a larger share of Medicare patients, respectively. Qualitative data identified the following advantages of including a hospital in an ACO: the availability of start-up capital, advanced data sharing, and engagement of providers across the care continuum. Although the 63 percent of ACOs that included hospitals offered more comprehensive services compared to ACOs without hospitals, we found no differences between the two groups in their ability to manage hospital-related aspects of patient care. PMID- 26953296 TI - Patient Population Loss At A Large Pioneer Accountable Care Organization And Implications For Refining The Program. AB - There is an ongoing move toward payment models that hold providers increasingly accountable for the care of their patients. The success of these new models depends in part on the stability of patient populations. We investigated the amount of population turnover in a large Medicare Pioneer accountable care organization (ACO) in the period 2012-14. We found that substantial numbers of beneficiaries became part of or left the ACO population during that period. For example, nearly one-third of beneficiaries who entered in 2012 left before 2014. Some of this turnover reflected that of ACO physicians-that is, beneficiaries whose physicians left the ACO were more likely to leave than those whose physicians remained. Some of the turnover also reflected changes in care delivery. For example, beneficiaries who were active in a care management program were less likely to leave the ACO than similar beneficiaries who had not yet started such a program. We recommend policy changes to increase the stability of ACO beneficiary populations, such as permitting lower cost sharing for care received within an ACO and requiring all beneficiaries to identify their primary care physician before being linked to an ACO. PMID- 26953298 TI - Variation In Accountable Care Organization Spending And Sensitivity To Risk Adjustment: Implications For Benchmarking. AB - Spending targets (or benchmarks) for accountable care organizations (ACOs) participating in the Medicare Shared Savings Program must be set carefully to encourage program participation while achieving fiscal goals and minimizing unintended consequences, such as penalizing ACOs for serving sicker patients. Recently proposed regulatory changes include measures to make benchmarks more similar for ACOs in the same area with different historical spending levels. We found that ACOs vary widely in how their spending levels compare with those of other local providers after standard case-mix adjustments. Additionally adjusting for survey measures of patient health meaningfully reduced the variation in differences between ACO spending and local average fee-for-service spending, but substantial variation remained, which suggests that differences in care efficiency between ACOs and local non-ACO providers vary widely. Accordingly, measures to equilibrate benchmarks between high- and low-spending ACOs--such as setting benchmarks to risk-adjusted average fee-for-service spending in an area- should be implemented gradually to maintain participation by ACOs with high spending. Use of survey information also could help mitigate perverse incentives for risk selection and upcoding and limit unintended consequences of new benchmarking methodologies for ACOs serving sicker patients. PMID- 26953299 TI - Retail Clinic Visits For Low-Acuity Conditions Increase Utilization And Spending. AB - Retail clinics have been viewed by policy makers and insurers as a mechanism to decrease health care spending, by substituting less expensive clinic visits for more expensive emergency department or physician office visits. However, retail clinics may actually increase spending if they drive new health care utilization. To assess whether retail clinic visits represent new utilization or a substitute for more expensive care, we used insurance claims data from Aetna for the period 2010-12 to track utilization and spending for eleven low-acuity conditions. We found that 58 percent of retail clinic visits for low-acuity conditions represented new utilization and that retail clinic use was associated with a modest increase in spending, of $14 per person per year. These findings do not support the idea that retail clinics decrease health care spending. PMID- 26953300 TI - Medicare Prescription Drug Plan Enrollees Report Less Positive Experiences Than Their Medicare Advantage Counterparts. AB - Since 2006, Medicare beneficiaries have been able to obtain prescription drug coverage through standalone prescription drug plans or their Medicare Advantage (MA) health plan, options exercised in 2015 by 72 percent of beneficiaries. Using data from community-dwelling Medicare beneficiaries older than age sixty-four in 700 plans surveyed from 2007 to 2014, we compared beneficiaries' assessments of Medicare prescription drug coverage when provided by standalone plans or integrated into an MA plan. Beneficiaries in standalone plans consistently reported less positive experiences with prescription drug plans (ease of getting medications, getting coverage information, and getting cost information) than their MA counterparts. Because MA plans are responsible for overall health care costs, they might have more integrated systems and greater incentives than standalone prescription drug plans to provide enrollees medications and information effectively, including, since 2010, quality bonus payments to these MA plans under provisions of the Affordable Care Act. PMID- 26953301 TI - Trends In Orphan New Molecular Entities, 1983-2014: Half Were First In Class, And Rare Cancers Were The Most Frequent Target. AB - The Orphan Drug Act was enacted in 1983 to stimulate drug development for rare diseases. How well this law has accomplished that goal is an important public health question. This study examined the characteristics of the 209 orphan drugs approved as new molecular entities in the period 1983-2014. As a whole, these drugs were highly innovative and provided substantial gains in reducing unmet medical needs for rare diseases: Over 50 percent of the drugs were first in class, and 78 percent received a priority review. Drugs approved as either therapeutic or supportive therapies for rare cancers represented the highest proportion of these drugs (35 percent). Additionally, in 2010-14 large companies became a strong presence in developing orphan new molecular entities for oncology indications. Overall, new orphan drugs appeared to be highly innovative and provided important advances in care for patients with rare diseases. PMID- 26953302 TI - Medicare Letters To Curb Overprescribing Of Controlled Substances Had No Detectable Effect On Providers. AB - Inappropriate prescribing is a rising threat to the health of Medicare beneficiaries and a drain on Medicare's finances. In this study we used a randomized controlled trial approach to evaluate a low-cost, light-touch intervention aimed at reducing the inappropriate provision of Schedule II controlled substances in the Medicare Part D program. Potential overprescribers were sent a letter explaining that their practice patterns were highly unlike those of their peers. Using rich administrative data, we were unable to detect an effect of these letters on prescribing. We describe ongoing efforts to build on this null result with alternative interventions. Learning about the potential of light-touch interventions, both effective and ineffective, will help produce a better toolkit for policy makers to improve the value and safety of health care. PMID- 26953304 TI - Adding A Measure Of Patient Self-Management Capability To Risk Assessment Can Improve Prediction Of High Costs. AB - We explored whether supplementing a clinical risk score with a behavioral measure could improve targeting of the patients most in need of supports that reduce their risk of costly service utilization. Using data from a large health system that determines patient self-management capability using the Patient Activation Measure, we examined utilization of hospital and emergency department care by the 15 percent of patients with the highest clinical risk scores. After controlling for risk scores and placing patients within segments based on their level of activation in 2011, we found that the lower the activation level, the higher the utilization and cost of hospital services in each of the following three years. These findings demonstrate that adding a measure of patient self-management capability to a risk assessment can improve prediction of high care costs and inform actions to better meet patient needs. PMID- 26953303 TI - Older, Less Regulated Medical Marijuana Programs Have Much Greater Enrollment Rates Than Newer 'Medicalized' Programs. AB - Twenty-three states and the District of Columbia have passed laws implementing medical marijuana programs. The nineteen programs that were in operation as of October 2014 collectively had over one million participants. All states (including D.C.) with medical marijuana laws require physicians directly or indirectly to authorize the use of marijuana at their discretion, yet little is known about how medical marijuana programs vary regarding adherence to basic principles of medical practice and associated rates of enrollment. To explore this, we analyzed marijuana programs according to seven components of traditional medical care and pharmaceutical regulation. We then examined enrollment rates, while controlling for potentially confounding state characteristics. We found that fourteen of the twenty-four programs were nonmedical and collectively enrolled 99.4 percent of participants nationwide, with enrollment rates twenty times greater than programs deemed to be "medicalized." Policy makers implementing or amending medical marijuana programs should consider the powerful relationship between less regulation and greater enrollment. Researchers should consider variations across programs when assessing programs' population-level effects. PMID- 26953305 TI - Meaningful Use Of EHRs Among Hospitals Ineligible For Incentives Lags Behind That Of Other Hospitals, 2009-13. AB - The Centers for Medicare and Medicaid Services' meaningful-use incentive program aims to promote the adoption and use of electronic health records (EHRs) throughout health care settings in the United States. However, psychiatric, long term care, and rehabilitation hospitals are ineligible for these incentive payments. Using national data from the period 2009-13, we compared eligible and ineligible hospitals' rates of EHR adoption. All three types of ineligible hospitals had significantly lower rates of adoption than eligible hospitals did, yet both groups experienced similar growth rates. This growth has widened the gap in adoption of health information technology between eligible and ineligible hospitals, which could stymie efforts to lower costs and improve quality across the health care continuum. Future policies might target ineligible hospitals specifically, as the lag in EHR adoption among this group of providers might undermine the achievement of more coordinated and collaborative health care. PMID- 26953306 TI - Understanding What Makes Americans Dissatisfied With Their Health Care System: An International Comparison. AB - For decades, public satisfaction with the health care system has been lower in the United States than in other high-income countries. To better understand the distinctive nature of US health system satisfaction, we compared the determinants of satisfaction with the health system in the United States to those in seventeen other high-income countries by applying regression decomposition methods to survey data collected in the period 2011-13. We found that concerns related to "accessing most-preferred care" (the extent to which people feel that they can access their top preferences at a time of need) were more important to satisfaction in the United States than in other high-income countries, while the reverse was true for satisfaction with recent interactions with the health system. Differences among US socioeconomic groups in survey responses regarding access to most-preferred care suggest that wide variation in insurance coverage and generosity may play a role in these differences. While reductions in the uninsured population and the movement toward minimum health plan standards could help address some concerns about access to preferred care, our results raise the possibility of public backlash as market forces push plans toward more restricted access and higher cost sharing. PMID- 26953307 TI - Evaluation Of A Maternal Health Program In Uganda And Zambia Finds Mixed Results On Quality Of Care And Satisfaction. AB - Saving Mothers, Giving Life is a multidonor program designed to reduce maternal mortality in Uganda and Zambia. We used a quasi-random research design to evaluate its effects on provider obstetric knowledge, clinical confidence, and job satisfaction, and on patients' receipt of services, perceived quality, and satisfaction. Study participants were 1,267 health workers and 2,488 female patients. Providers' knowledge was significantly higher in Ugandan and Zambian intervention districts than in comparison districts, and in Uganda there were similar positive differences for providers' clinical confidence and job satisfaction. Patients in Ugandan intervention facilities were more likely to give high ratings for equipment availability, providers' knowledge and communication skills, and care quality, among other factors, than patients in comparison facilities. There were fewer differences between Zambian intervention and comparison facilities. Country differences likely reflect differing intensity of program implementation and the more favorable geography of intervention districts in Uganda than in Zambia. National investments in the health system and provider training and the identification of intervention components most associated with improved performance will be required for scaling up and sustaining the program. PMID- 26953308 TI - Workers Without Paid Sick Leave Less Likely To Take Time Off For Illness Or Injury Compared To Those With Paid Sick Leave. AB - Paid sick leave is an important employer-provided benefit that helps people obtain health care for themselves and their dependents. But paid sick leave is not universally available to US workers. Little is known about paid sick leave and its relationship to health behaviors. Contrary to public health goals to reduce the spread of illness, our findings indicate that in 2013 both full- and part-time working adults without paid sick leave were more likely than workers with that benefit to attend work when ill. Those without paid sick leave were 3.0 times more likely to forgo medical care for themselves and 1.6 times more likely to forgo medical care for their family compared to working adults with paid sick leave benefits. Moreover, the lowest-income group of workers without paid sick leave were at the highest risk of delaying and forgoing medical care for themselves and their family members. Policy makers should consider the potential public health implications of their decisions when contemplating guaranteed sick leave benefits. PMID- 26953310 TI - Health Care And Homelessness: Foundation Funding. PMID- 26953309 TI - Mr. G And The Revolving Door: Breaking The Readmission Cycle At A Safety-Net Hospital. AB - A patient with complex needs returns to the hospital again and again, despite his care team's efforts to reduce readmissions. PMID- 26953312 TI - Declining US Life Expectancy, 1990-2010. PMID- 26953313 TI - US Life Expectancy: The Authors Reply. PMID- 26953314 TI - Team-Based Care For Unhealthy Behaviors. PMID- 26953315 TI - Treating Unhealthy Behaviors: The Author Replies. PMID- 26953316 TI - Risks And Benefits Of Breast Cancer Screening. PMID- 26953317 TI - Mammography Risks: The Authors Reply. PMID- 26953318 TI - Infection Prevention And Control In TB Programs. PMID- 26953319 TI - Chest pain with diffuse coronary ischaemia. AB - CLINICAL INTRODUCTION: An 80-year-old male with a medical history of hypertension, diabetes and moderate calcific aortic stenosis, presented with ischaemic chest pain at rest. Cardiovascular examination revealed soft systolic murmur only. ECG (see online supplementary figure S1) demonstrated inferolateral ST segment depression with ST elevation in lead aVR, suggesting diffuse subendocardial ischaemia possibly consistent with a threatening left main or proximal left anterior descending (LAD) coronary lesion. Emergency coronary angiography demonstrated tandem smooth stenoses in the proximal left circumflex (LCx) and LAD arteries (figure 1A), which persisted throughout the cardiac cycle, and after 200 mcg bolus of intracoronary nitrate. Aortogram is shown (figure 1B). QUESTION: What diagnosis underlies the cause of this patient's symptoms? Congenital coronary artery anomaly.Coronary artery vasospasm.Myocardial bridging.Obstructive coronary artery disease.Unruptured left sinus of Valsalva aneurysm. PMID- 26953320 TI - DNA methylation profiling in human Huntington's disease brain. AB - Despite extensive progress in Huntington's disease (HD) research, very little is known about the association of epigenetic variation and HD pathogenesis in human brain tissues. Moreover, its contribution to the tissue-specific transcriptional regulation of the huntingtin gene (HTT), in which HTT expression levels are highest in brain and testes, is currently unknown. To investigate the role of DNA methylation in HD pathogenesis and tissue-specific expression of HTT, we utilized the Illumina HumanMethylation450K BeadChip array to measure DNA methylation in a cohort of age-matched HD and control human cortex and liver tissues. In cortex samples, we found minimal evidence of HD-associated DNA methylation at probed sites after correction for cell heterogeneity but did observe an association with the age of disease onset. In contrast, comparison of matched cortex and liver samples revealed tissue-specific DNA methylation of the HTT gene region at 38 sites (FDR < 0.05). Importantly, we identified a novel differentially methylated binding site in the HTT proximal promoter for the transcription factor CTCF. This CTCF site displayed increased occupancy in cortex, where HTT expression is higher, compared with the liver. Additionally, CTCF silencing reduced the activity of an HTT promoter-reporter construct, suggesting that CTCF plays a role in regulating HTT promoter function. Overall, although we were unable to detect HD-associated DNA methylation alterations at queried sites, we found that DNA methylation may be correlated to the age of disease onset in cortex tissues. Moreover, our data suggest that DNA methylation may, in part, contribute to tissue-specific HTT transcription through differential CTCF occupancy. PMID- 26953323 TI - Clinical study of 459 polydactyly cases in China, 2010 to 2014. AB - Polydactyly is one of the most common hereditary limb malformations, involving additional digits on the hands and/or feet, which is a very attractive model to appreciate clinical and genetic heterogeneity. A high level of heterogeneity in polydactyly has been identified in different regions. However, such data of the medical literatures for Asian populations are relatively limited. This study was intended to shed light on the phenotypic manifestations of polydactyly in the recruited Chinese population and to characterize the medical literature on this condition. A total of 459 well-characterized polydactyly cases from Shanghai Children's Medical Center were recruited. Their phenotypes, inheritance patterns, and clinical heterogeneity were obtained from clinical medical records. It was found that 4.8% of cases were familial and 95.2% were sporadic. The proportions of preaxial and postaxial polydactyly types were 74.7% and 25.3%, respectively. In preaxial polydactyly, type I formed the overwhelming majority (95.9%). Among the postaxial polydactyly cases, type A was most prevalent at 69.8% and type B was witnessed in 30.2% of cases. Familial and sporadic polydactyly patients mainly had unilateral presentations. A total of 583 limbs with additional digits were recorded in the 459 subjects. Upper limb involvement was more common than lower, and right hand involvement was more common than left for preaxial polydactyly, and lower limb involvement was more common than upper in postaxial polydactyly. This cohort added useful clinical/epidemiological information to the polydactyly literature in the Chinese population and highlighted its marked clinical heterogeneity. PMID- 26953322 TI - Glucocorticoids Induce Nondipping Blood Pressure by Activating the Thiazide Sensitive Cotransporter. AB - Blood pressure (BP) normally dips during sleep, and nondipping increases cardiovascular risk. Hydrochlorothiazide restores the dipping BP profile in nondipping patients, suggesting that the NaCl cotransporter, NCC, is an important determinant of daily BP variation. NCC activity in cells is regulated by the circadian transcription factor per1. In vivo, circadian genes are entrained via the hypothalamic-pituitary-adrenal axis. Here, we test whether abnormalities in the day:night variation of circulating glucocorticoid influence NCC activity and BP control. C57BL6/J mice were culled at the peak (1:00 AM) and trough (1:00 PM) of BP. We found no day:night variation in NCC mRNA or protein but NCC phosphorylation on threonine(53) (pNCC), required for NCC activation, was higher when mice were awake, as was excretion of NCC in urinary exosomes. Peak NCC activity correlated with peak expression of per2 and bmal1 (clock genes) and sgk1 and tsc22d3 (glucocorticoid-responsive kinases). Adrenalectomy reduced NCC abundance and blunted the daily variation in pNCC levels without affecting variation in clock gene transcription. Chronic corticosterone infusion increased bmal1, per1, sgk1, and tsc22d3 expression during the inactive phase. Inactive phase pNCC was also elevated by corticosterone, and a nondipping BP profile was induced. Hydrochlorothiazide restored rhythmicity of BP in corticosterone-treated mice without affecting BP in controls. Glucocorticoids influence the day:night variation in NCC activity via kinases that control phosphorylation. Abnormal glucocorticoid rhythms impair NCC and induce nondipping. Night-time dosing of thiazides may be particularly beneficial in patients with modest glucocorticoid excess. PMID- 26953321 TI - Leptin Induces Hypertension and Endothelial Dysfunction via Aldosterone-Dependent Mechanisms in Obese Female Mice. AB - Obesity is a major risk factor for cardiovascular disease in males and females. Whether obesity triggers cardiovascular disease via similar mechanisms in both the sexes is, however, unknown. In males, the adipokine leptin highly contributes to obesity-related cardiovascular disease by increasing sympathetic activity. Females secrete 3* to 4* more leptin than males, but do not exhibit high sympathetic tone with obesity. Nevertheless, females show inappropriately high aldosterone levels that positively correlate with adiposity and blood pressure (BP). We hypothesized that leptin induces hypertension and endothelial dysfunction via aldosterone-dependent mechanisms in females. Leptin control of the cardiovascular function was analyzed in female mice sensitized to leptin via the deletion of protein tyrosine phosphatase 1b (knockout) and in agouti yellow obese hyperleptinemic mice (Ay). Hypersensitivity to leptin (wild-type, 115 +/- 2; protein tyrosine phosphatase 1b knockout, 124 +/- 2 mm Hg; P<0.05) and obesity elevated BP (a/a, 113 +/- 1; Ay, 128 +/- 7 mm Hg; P<0.05) and impaired endothelial function. Chronic leptin receptor antagonism restored BP and endothelial function in protein tyrosine phosphatase 1b knockout and Ay mice. Hypersensitivity to leptin and obesity reduced BP response to ganglionic blockade in both strains and plasma catecholamine levels in protein tyrosine phosphatase 1b knockout mice. Hypersensitivity to leptin and obesity significantly increased plasma aldosterone levels and adrenal CYP11B2 expression. Chronic leptin receptor antagonism reduced aldosterone levels. Furthermore, chronic leptin and mineralocorticoid receptor blockade reduced BP and improved endothelial function in both leptin-sensitized and obese hyperleptinemic female mice. Together, these data demonstrate that leptin induces hypertension and endothelial dysfunction via aldosterone-dependent mechanisms in female mice and suggest that obesity leads to cardiovascular disease via sex-specific mechanisms. PMID- 26953324 TI - Functional Equivalence of OspA and OspB, but Not OspC, in Tick Colonization by Borrelia burgdorferi. AB - Borrelia burgdorferi, a Lyme disease agent, makes different major outer surface lipoproteins at different stages of its mouse-tick infectious cycle. Outer surface protein A (OspA) coats the spirochetes from the time they enter ticks until they are transmitted to a mammal. OspA is required for normal tick colonization and has been shown to bind a tick midgut protein, indicating that OspA may serve as a tick midgut adhesin. Tick colonization by spirochetes lacking OspA is increased when the infecting blood meal is derived from mice that do not produce antibody, indicating that OspA may protect the spirochetes from host antibody, which will not recognize tick-specific proteins such as OspA. To further study the importance of OspA during tick colonization, we constructed a form of B. burgdorferi in which the ospA open reading frame, on lp54, was replaced with the ospC gene or the ospB gene, encoding a mammal-specific or tick specific lipoprotein, respectively. These fusions yielded a strain that produces OspC within a tick (from the fusion gene) and during early mammalian infection (from the normal ospC locus) and a strain that produces OspB in place of OspA within ticks. Here we show that the related, tick-specific protein OspB can fully substitute for OspA, whereas the unrelated, mammal-specific protein OspC cannot. These data were derived from three different methods of infecting ticks, and they confirm and extend previous studies indicating that OspA both protects spirochetes within ticks from mammalian antibody and serves an additional role during tick colonization. PMID- 26953326 TI - Serial Dissection of Parasite Gene Families. AB - Calcium ion signaling regulates central aspects of the biology controlling stage and life cycle transitions of apicomplexan parasites. In the current issue of Infection and Immunity, Long and coworkers (S. Long, Q. Wang, and L. D. Sibley, Infect Immun 84:1262-1273, 2016, http://dx.doi.org/10.1128/IAI.01173-15) describe a powerful genetic system enabling reliable serial genetic dissection of a large gene family encoding novel calcium-dependent protein kinases (CDPKs) that provides new insights into the roles of CDPKs during Toxoplasma gondii infection. PMID- 26953327 TI - Distinct Roles of Myosins in Aspergillus fumigatus Hyphal Growth and Pathogenesis. AB - Myosins are a family of actin-based motor proteins found in many organisms and are categorized into classes based on their structures. Class II and V myosins are known to be important for critical cellular processes, including cytokinesis, endocytosis, exocytosis, and organelle trafficking, in the model fungi Saccharomyces cerevisiae and Aspergillus nidulans However, the roles of myosins in the growth and virulence of the pathogen Aspergillus fumigatus are unknown. We constructed single- and double-deletion strains of the class II and class V myosins in A. fumigatus and found that while the class II myosin (myoB) is dispensable for growth, the class V myosin (myoE) is required for proper hyphal extension; deletion of myoE resulted in hyperbranching and loss of hyphal polarity. Both myoB and myoE are necessary for proper septation, conidiation, and conidial germination, but only myoB is required for conidial viability. Infection with the DeltamyoE strain in the invertebrate Galleria mellonella model and also in a persistently immunosuppressed murine model of invasive aspergillosis resulted in hypovirulence, while analysis of bronchoalveolar lavage fluid revealed that tumor necrosis factor alpha (TNF-alpha) release and cellular infiltration were similar compared to those of the wild-type strain. The DeltamyoE strain showed fungal growth in the murine lung, while the DeltamyoB strain exhibited little fungal burden, most likely due to the reduced conidial viability. These results show, for the first time, the important role these cytoskeletal components play in the growth of and disease caused by a known pathogen, prompting future studies to understand their regulation and potential targeting for novel antifungal therapies. PMID- 26953325 TI - STAT6 Signaling Attenuates Interleukin-17-Producing gammadelta T Cells during Acute Klebsiella pneumoniae Infection. AB - gammadelta T cells are prevalent at mucosal and epithelial surfaces and are a critical first line of defense against bacterial and fungal pathogens. gammadelta17 cells are a subset of gammadelta T cells which, in the presence of IL-23 and IL-1beta, produce large quantities of interleukin-17A (IL-17A), a cytokine crucial to these cells' antibacterial and antifungal function. STAT6, an important transcription factor in Th2 differentiation and inhibition of Th1 differentiation, is expressed at high levels in the T cells of people with parasitic infections and asthma. Our group and others have shown that STAT6 attenuates IL-17A protein expression by CD4(+) T cells. By extension, we hypothesized that STAT6 activation also inhibits innate gammadelta17 cell cytokine secretion. We show here that gammadelta17 cells expressed the type I IL 4 receptor (IL-4R), and IL-4 increased STAT6 phosphorylation in gammadelta T cells. IL-4 inhibited gammadelta17 cell production of IL-17A. IL-4 also decreased gammadelta17 cell expression of IL-23R as well as Sgk1. To determine whether STAT6 signaling regulates gammadelta17 cell numbers in vivo, we used a model of Klebsiella pneumoniae in mice deficient in STAT6. We chose K. pneumoniae for our in vivo model, since K. pneumoniae increases IL-17A expression and gammadelta17 numbers. K. pneumoniae infection of STAT6 knockout mice resulted in a statistically significant increase in the number of gammadelta17 cells compared to that of wild-type mice. These studies are the first to demonstrate that gammadelta17 cells express the type I IL-4R and that STAT6 signaling negatively regulates gammadelta17 cells, a cell population that plays a front-line role in mucosal immunity. PMID- 26953334 TI - Comment on: Resistance gene naming and numbering: is it a new gene or not? PMID- 26953331 TI - Blood alcohol and injury in Bhutan: targeted surveillance in a national referral hospital emergency department. AB - Bhutan is a low-middle-income country with poor roads, rapidly increasing motor vehicle use and heavy alcohol consumption. We estimated the proportion of emergency department patients presenting with injury who had positive blood alcohol. We sought to breathalyse and interview all adult patients (>=18 years) presenting with injury at the Jigme Dorji Wangchuck National Referral Hospital in the capital city Thimphu, from April to October 2015. Breath tests and interviews were conducted with 339 (91%) of 374 eligible adult patients. A third (34%) were alcohol-positive and 22% had blood alcohol concentrations >0.08 g/dL. The highest alcohol-positive fractions were for assault (71%), falls (31%) and traffic crashes (30%). Over a third (36%) of patients had a delay of >2 h between injury and breath test. The results underestimate blood alcohol concentrations at the time of injury so the true prevalence of pre-injury alcohol impairment is greater than our estimates suggest. Countermeasures are urgently needed, particularly roadside random breath testing and alcohol controls. PMID- 26953335 TI - Overview of skin whitening agents with an insight into the illegal cosmetic market in Europe. AB - Lightening skin tone is an ancient and well-documented practice, and remains common practice among many cultures. Whitening agents such as corticosteroids, tretinoin and hydroquinone are medically applied to effectively lighten the skin tone of hyperpigmented lesions. However, when these agents are used cosmetically, they are associated with a variety of side-effect. Alternative agents, such as arbutin and its derivatives kojic acid and nicotinamide have been subsequently developed for cosmetic purposes. Unfortunately, some cosmetics contain whitening agents that are banned for use in cosmetic products. This article provides an overview of the mode of action and potential side-effects of cosmetic legal and illegal whitening agents, and the pattern of use of these types of products. Finally, an EU analysis of the health problems due to the presence of illegal products on the market is summarized. PMID- 26953336 TI - Redox-Active Metal-Organic Composites for Highly Selective Oxygen Separation Applications. AB - A redox-active metal-organic composite material shows improved and selective O2 adsorption over N2 with respect to individual components (MIL-101 and ferrocene). The O2 sensitivity of the composite material arises due to the formation of maghemite nanoparticles with the pore of the metal-organic framework material. PMID- 26953329 TI - Crystal Structure of a Complex of Surfactant Protein D (SP-D) and Haemophilus influenzae Lipopolysaccharide Reveals Shielding of Core Structures in SP-D Resistant Strains. AB - The carbohydrate recognition domains (CRDs) of lung collectin surfactant protein D (SP-D) recognize sugar patterns on the surface of lung pathogens and promote phagocytosis. Using Haemophilus influenzae Eagan strains expressing well characterized lipopolysaccharide (LPS) surface structures of various levels of complexity, we show that bacterial recognition and binding by SP-D is inversely related to LPS chain extent and complexity. The crystal structure of a biologically active recombinant trimeric SP-D CRD complexed with a delipidated Eagan 4A LPS suggests that efficient LPS recognition by SP-D requires multiple binding interactions utilizing the three major ligand-binding determinants in the SP-D binding pocket, with Ca-dependent binding of inner-core heptose accompanied by interaction of anhydro-Kdo (4,7-anhydro-3-deoxy-d-manno-oct-2-ulosonic acid) with Arg343 and Asp325. Combined with enzyme-linked immunosorbent assays (ELISAs) and fluorescence-activated cell sorter (FACS) binding analyses, our results show that extended LPS structures previously thought to be targets for collectins are important in shielding the more vulnerable sites in the LPS core, revealing a mechanism by which pathogens with complex LPS extensions efficiently evade a first-line mucosal innate immune defense. The structure also reveals for the first time the dominant form of anhydro-Kdo. PMID- 26953328 TI - Identification and Characterization of the Rhoptry Neck Protein 2 in Babesia divergens and B. microti. AB - Apicomplexan parasites include those of the genera Plasmodium, Cryptosporidium, and Toxoplasma and those of the relatively understudied zoonotic genus Babesia In humans, babesiosis, particularly transfusion-transmitted babesiosis, has been emerging as a major threat to public health. Like malaria, the disease pathology is a consequence of the parasitemia which develops through cyclical replication of Babesia parasites in host erythrocytes. However, there are no exoerythrocytic stages in Babesia, so targeting of the blood stage and associated proteins to directly prevent parasite invasion is the most desirable option for effective disease control. Especially promising among such molecules are the rhoptry neck proteins (RONs), whose homologs have been identified in many apicomplexan parasites. RONs are involved in the formation of the moving junction, along with AMA1, but no RON has been identified and characterized in any Babesia spp. Here we identify the RON2 proteins of Babesia divergens (BdRON2) and B. microti (BmRON2) and show that they are localized apically and that anti-BdRON2 antibodies are significant inhibitors of parasite invasion in vitro Neither protein is immunodominant, as both proteins react only marginally with sera from infected animals. Further characterization of the direct role of both BdRON2 and BmRON2 in parasite invasion is required, but knowledge of the level of conformity of RON2 proteins within the apicomplexan phylum, particularly that of the AMA1 RON2 complex at the moving junction, along with the availability of an animal model for B. microti studies, provides a key to target this complex with a goal of preventing the erythrocytic invasion of these parasites and to further our understanding of the role of these conserved ligands in invasion. PMID- 26953333 TI - Prevalence and dynamics of the K65R drug resistance mutation in HIV-1-infected infants exposed to maternal therapy with lamivudine, zidovudine and either nevirapine or nelfinavir in breast milk. AB - BACKGROUND: K65R is a relatively rare drug resistance mutation (DRM) selected by the NRTIs tenofovir, didanosine, abacavir and stavudine and confers cross resistance to all NRTIs except zidovudine. Selection by other NRTIs is uncommon. OBJECTIVES: In this study we investigated the frequency of emergence of the K65R mutation and factors associated with it in HIV-1-infected infants exposed to low doses of maternal lamivudine, zidovudine and either nevirapine or nelfinavir ingested through breast milk, using specimens collected from the Kisumu Breastfeeding Study. METHODS: Plasma specimens with viral load >=1000 copies/mL collected from HIV-infected infants at 0-1, 2, 6, 14, 24 and 36 weeks of age and maternal samples at delivery were tested for HIV drug resistance using Sanger sequencing of the polymerase gene. Factors associated with K65R emergence were assessed using Fisher's exact test and the Wilcoxon rank-sum test. RESULTS: K65R was detected in samples from 6 of the 24 infants (25%) who acquired HIV-1 infection by the age of 6 months. K65R emerged in half of the infants by 6 weeks and in the rest by 14 weeks of age. None of the mothers at delivery or the infants with a positive genotype at first time of positivity had the K65R mutation. Infants with K65R had low baseline CD4 cell counts (P = 0.014), were more likely to have DRMs earlier (<=6 weeks versus >=14 weeks, P = 0.007) and were more likely to have multiclass drug resistance (P = 0.035). M184V was the most common mutation associated with K65R emergence. K65R had reverted by 3 months after cessation of breastfeeding. CONCLUSIONS: A high rate of K65R emergence may suggest that ingesting low doses of lamivudine via breast milk could select for this mutation. The presence of this mutation may have a negative impact on future responses to NRTI-based ART. More in vitro studies are, however, needed to establish the molecular mechanism for this selection. PMID- 26953337 TI - Structural Basis of the Enhanced Pollutant-Degrading Capabilities of an Engineered Biphenyl Dioxygenase. AB - Biphenyl dioxygenase, the first enzyme of the biphenyl catabolic pathway, is a major determinant of which polychlorinated biphenyl (PCB) congeners are metabolized by a given bacterial strain. Ongoing efforts aim to engineer BphAE, the oxygenase component of the enzyme, to efficiently transform a wider range of congeners. BphAEII9, a variant of BphAELB400 in which a seven-residue segment, (335)TFNNIRI(341), has been replaced by the corresponding segment of BphAEB356, (333)GINTIRT(339), transforms a broader range of PCB congeners than does either BphAELB400 or BphAEB356, including 2,6-dichlorobiphenyl, 3,3'-dichlorobiphenyl, 4,4'-dichlorobiphenyl, and 2,3,4'-trichlorobiphenyl. To understand the structural basis of the enhanced activity of BphAEII9, we have determined the three dimensional structure of this variant in substrate-free and biphenyl-bound forms. Structural comparison with BphAELB400 reveals a flexible active-site mouth and a relaxed substrate binding pocket in BphAEII9 that allow it to bind different congeners and which could be responsible for the enzyme's altered specificity. Biochemical experiments revealed that BphAEII9 transformed 2,3,4' trichlorobiphenyl and 2,2',5,5'-tetrachlorobiphenyl more efficiently than did BphAELB400 and BphAEB356 BphAEII9 also transformed the insecticide dichlorodiphenyltrichloroethane (DDT) more efficiently than did either parental enzyme (apparent kcat/Km of 2.2 +/- 0.5 mM(-1) s(-1), versus 0.9 +/- 0.5 mM(-1) s(-1) for BphAEB356). Studies of docking of the enzymes with these three substrates provide insight into the structural basis of the different substrate selectivities and regiospecificities of the enzymes. IMPORTANCE: Biphenyl dioxygenase is the first enzyme of the biphenyl degradation pathway that is involved in the degradation of polychlorinated biphenyls. Attempts have been made to identify the residues that influence the enzyme activity for the range of substrates among various species. In this study, we have done a structural study of one variant of this enzyme that was produced by family shuffling of genes from two different species. Comparison of the structure of this variant with those of the parent enzymes provided an important insight into the molecular basis for the broader substrate preference of this enzyme. The structural and functional details gained in this study can be utilized to further engineer desired enzymatic activity, producing more potent enzymes. PMID- 26953340 TI - Intramacrophage Infection Reinforces the Virulence of Edwardsiella tarda. AB - Edwardsiella tarda is an important pathogenic bacterium that can replicate in macrophages. However, how the intramacrophage infection process affects the virulence of this bacterium is essentially unknown. Here, we show that E. tarda replicates and induces a caspase-1-dependent cell pyroptosis in a murine macrophage model. Via pyroptosis, intracellular E. tarda escapes to the extracellular milieu, forming a unique bacterial population. Being different from the bacteria cultured alone, this unique population possesses a reprogrammed transcriptional profile, particularly with upregulated type III secretion system (T3SS)/T6SS cluster genes. Subsequent studies revealed that the macrophage released population gains enhanced infectivity for host epithelial cells and increases resistance to multiple host defenses and hence displays significantly promoted virulence in vivo Further studies indicated that T3SS is essentially required for the macrophage infection process, while T6SS contributes to infection-induced bacterial virulence. Altogether, this work demonstrates that E. tarda can utilize macrophages as a niche for virulence priming and for spreading infection, suggesting a positive role for intramacrophage infection in bacterial pathogenesis. IMPORTANCE: Many pathogens can replicate in macrophages, which is crucial for their pathogenesis. To survive in the macrophage cell, pathogens are likely to require fitness genes to counteract multiple host-killing mechanisms. Here, Edwardsiella tarda is proved to exit from macrophages during infection. This macrophage-released population displays a reprogrammed transcriptional profile with significantly upregulated type III secretion system (T3SS)/T6SS related genes. Furthermore, both enhanced infectivity in epithelial cells and activated resistance to complex host defenses were conferred on this macrophage primed population, which consequently promoted the full virulence of E. tarda in vivo Our work provides evidence that E. tarda can utilize macrophages as a niche for virulence priming and for spreading infection, highlighting the importance of the intramacrophage infection cycle for the pathogenesis of E. tarda. PMID- 26953338 TI - CotG-Like Modular Proteins Are Common among Spore-Forming Bacilli. AB - CotG is an abundant protein initially identified as an outer component of the Bacillus subtilis spore coat. It has an unusual structure characterized by several repeats of positively charged amino acids that are probably the outcome of multiple rounds of gene elongation events in an ancestral minigene. CotG is not highly conserved, and its orthologues are present in only two Bacillus and two Geobacillus species. In B. subtilis, CotG is the target of extensive phosphorylation by a still unidentified enzyme and has a role in the assembly of some outer coat proteins. We report now that most spore-forming bacilli contain a protein not homologous to CotG of B. subtilis but sharing a central "modular" region defined by a pronounced positive charge and randomly coiled tandem repeats. Conservation of the structural features in most spore-forming bacilli suggests a relevant role for the CotG-like protein family in the structure and function of the bacterial endospore. To expand our knowledge on the role of CotG, we dissected the B. subtilis protein by constructing deletion mutants that express specific regions of the protein and observed that they have different roles in the assembly of other coat proteins and in spore germination. IMPORTANCE: CotG of B. subtilis is not highly conserved in the Bacillus genus; however, a CotG-like protein with a modular structure and chemical features similar to those of CotG is common in spore-forming bacilli, at least when CotH is also present. The conservation of CotG-like features when CotH is present suggests that the two proteins act together and may have a relevant role in the structure and function of the bacterial endospore. Dissection of the modular composition of CotG of B. subtilis by constructing mutants that express only some of the modules has allowed a first characterization of CotG modules and will be the basis for a more detailed functional analysis. PMID- 26953332 TI - Co-location of the oxazolidinone resistance genes optrA and cfr on a multiresistance plasmid from Staphylococcus sciuri. AB - OBJECTIVES: To identify and characterize the oxazolidinone/phenicol resistance gene optrA in Staphylococcus isolates. METHODS: Fifty porcine staphylococci with florfenicol MICs of >=16 mg/L were screened by PCR for the presence of the optrA gene. Transferability of optrA was examined by transformation and conjugation. Functionality of this gene was confirmed by cloning and expression in a susceptible Staphylococcus host. The optrA-carrying plasmid was completely sequenced and analysed. RESULTS: A single Staphylococcus sciuri was optrA positive. This isolate carried the optrA gene on the 60 563 bp multiresistance plasmid pWo28-3, which also harboured the resistance genes, cfr, fexA, aadD, ble and aacA-aphD. Plasmid pWo28-3 is composed of three regions (A, B and C). Region A, which harboured all resistance genes except optrA, showed >=99.8% nucleotide sequence identity to the corresponding region of plasmids pJP1 and pJP1-like from Jeotgalicoccus pinnipedialis and Staphylococcus lentus, respectively. The optrA gene located in region B differed from the optrA gene of the Enterococcus faecalis plasmid pE349 by four nucleotide substitutions, which also resulted in amino acid substitutions. This optrA variant also conferred resistance to oxazolidinones and phenicols in staphylococci. The 28 genes in region C represent the plasmid backbone and were apparently acquired from staphylococci, enterococci and nosocomiicocci. CONCLUSIONS: This is the first report of the optrA gene in staphylococci and of the coexistence of optrA and cfr on the same plasmid. Dissemination of this plasmid will substantially limit the efficacy of oxazolidinones. Surveillance of optrA in staphylococci of both human and animal origin is urgently warranted. PMID- 26953330 TI - Minimally invasive mitral valve surgery in high-risk patients: operating outside the boxplot. AB - OBJECTIVES: (i) To establish who is at high risk for mitral surgery. (ii) To assess the performance of minimally invasive mitral valve surgery in high-risk patients by presenting early and late outcomes and compare these with those of the non-high-risk population. METHODS: We reviewed our database of prospective data of 1873 consecutive patients who underwent minimally invasive mitral surgery from 2003 to 2015. To establish an unbiased definition of risk cut-off, we considered as high-risk the 'outliers of risk' identified using boxplot analysis in relation to EuroSCORE II. RESULTS: Two hundred and five patients were outliers, with 98 as minor (EuroSCORE II >= 6%) and 107 as major outliers (EuroSCORE II >= 9%). Outliers accounted for several different comorbidities. Nineteen patients died while in hospital (9.2%); different postoperative complications were observed. Outliers had a significantly lower mean survival time and a higher risk of cardiac-related death than the general population; however, the worst outcomes were observed in major outliers. No statistically significant difference was found with regard to the need for mitral reintervention and the degree of mitral regurgitation at follow-up. CONCLUSIONS: Boxplot analysis helped to achieve an internal definition of risk cut-off, starting from EuroSCORE II >= 6%. Minimally invasive mitral surgery in these outliers of risk was associated with acceptable early and long-term results; however, major outliers with EuroSCORE II >= 9% may benefit from catheter-based procedures. PMID- 26953341 TI - Site-specific Proteolysis Mobilizes TorsinA from the Membrane of the Endoplasmic Reticulum (ER) in Response to ER Stress and B Cell Stimulation. AB - Torsin ATPases are the only representatives of the AAA+ ATPase family that reside in the lumen of the endoplasmic reticulum (ER) and nuclear envelope. Two of these, TorsinA and TorsinB, are anchored to the ER membrane by virtue of an N terminal hydrophobic domain. Here we demonstrate that the imposition of ER stress leads to a proteolytic cleavage event that selectively removes the hydrophobic domain from the AAA+ domain of TorsinA, which retains catalytic activity. Both the pharmacological inhibition profile and the identified cleavage site between two juxtaposed cysteine residues are distinct from those of presently known proteases, suggesting that a hitherto uncharacterized, membrane-associated protease accounts for TorsinA processing. This processing occurs not only in stress-exposed cell lines but also in primary cells from distinct organisms including stimulated B cells, indicating that Torsin conversion in response to physiologically relevant stimuli is an evolutionarily conserved process. By establishing 5-nitroisatin as a cell-permeable inhibitor for Torsin processing, we provide the methodological framework for interfering with Torsin processing in a wide range of primary cells without the need for genetic manipulation. PMID- 26953345 TI - Inositol Hexakisphosphate Kinase 1 (IP6K1) Regulates Inositol Synthesis in Mammalian Cells. AB - myo-Inositol, the precursor of all inositol compounds, has pivotal roles in cell metabolism and signaling pathways. Although physiological studies indicate a strong correlation between abnormal intracellular inositol levels and neurological disorders, very little is known about the regulation of inositol synthesis in mammalian cells. In this study, we report that IP6K1, an inositol hexakisphosphate kinase that catalyzes the synthesis of inositol pyrophosphate, regulates inositol synthesis in mammalian cells. Ip6k1 ablation led to profound changes in DNA methylation and expression of Isyna1 (designated mIno1), which encodes the rate-limiting enzyme inositol-3-phosphate synthase. Interestingly, IP6K1 preferentially bound to the phospholipid phosphatidic acid, and this binding was required for IP6K1 nuclear localization and the regulation of mIno1 transcription. This is the first demonstration of IP6K1 as a novel negative regulator of inositol synthesis in mammalian cells. PMID- 26953339 TI - Crystal Structure and Biochemical Characterization of a Mycobacterium smegmatis AAA-Type Nucleoside Triphosphatase Phosphohydrolase (Msm0858). AB - AAA proteins (ATPases associated with various cellular activities) use the energy of ATP hydrolysis to drive conformational changes in diverse macromolecular targets. Here, we report the biochemical characterization and 2.5-A crystal structure of a Mycobacterium smegmatis AAA protein Msm0858, the ortholog of Mycobacterium tuberculosis Rv0435c. Msm0858 is a magnesium-dependent ATPase and is active with all nucleoside triphosphates (NTPs) and deoxynucleoside triphosphates (dNTPs) as substrates. The Msm0858 structure comprises (i) an N terminal domain (amino acids [aa] 17 to 201) composed of two beta-barrel modules and (ii) two AAA domains, D1 (aa 212 to 473) and D2 (aa 476 to 744), each of which has ADP in the active site. Msm0858-ADP is a monomer in solution and in crystallized form. Msm0858 domains are structurally homologous to the corresponding modules of mammalian p97. However, the position of the N-domain modules relative to the AAA domains in the Msm0858-ADP tertiary structure is different and would impede the formation of a p97-like hexameric quaternary structure. Mutational analysis of the A-box and B-box motifs indicated that the D1 and D2 AAA domains are both capable of ATP hydrolysis. Simultaneous mutations of the D1 and D2 active-site motifs were required to abolish ATPase activity. ATPase activity was effaced by mutation of the putative D2 arginine finger, suggesting that Msm0858 might oligomerize during the ATPase reaction cycle. A truncated variant Msm0858 (aa 212 to 745) that lacks the N domain was characterized as a catalytically active homodimer. IMPORTANCE: Recent studies have underscored the importance of AAA proteins (ATPases associated with various cellular activities) in the physiology of mycobacteria. This study reports the ATPase activity and crystal structure of a previously uncharacterized mycobacterial AAA protein, Msm0858. Msm0858 consists of an N-terminal beta-barrel domain and two AAA domains, each with ADP bound in the active site. Msm0858 is a structural homolog of mammalian p97, with respect to the linear order and tertiary structures of their domains. PMID- 26953344 TI - Inactivating ARID1A Tumor Suppressor Enhances TERT Transcription and Maintains Telomere Length in Cancer Cells. AB - ARID1A is a tumor suppressor gene that belongs to the switch/sucrose non fermentable chromatin remodeling gene family. It is mutated in many types of human cancer with the highest frequency in endometrium-related ovarian and uterine neoplasms including ovarian clear cell, ovarian endometrioid, and uterine endometrioid carcinomas. We have previously reported that mutations in the promoter of human telomerase reverse transcriptase (TERT) rarely co-occur with the loss of ARID1A protein expression, suggesting a potential role of ARID1A in telomere biology. In this study, we demonstrate that ARID1A negatively regulates TERT transcriptional regulation and activity via binding to the regulatory element of TERT and promotes a repressive histone mode. Induction of ARID1A expression was associated with increased occupancy of SIN3A and H3K9me3, known transcription repressor and histone repressor marks, respectively. Thus, loss of ARID1A protein expression caused by inactivating mutations reactivates TERT transcriptional activity and confers a survival advantage of tumor cells by maintaining their telomeres. PMID- 26953346 TI - Superoxide Dismutase (SOD)-mimetic M40403 Is Protective in Cell and Fly Models of Paraquat Toxicity: IMPLICATIONS FOR PARKINSON DISEASE. AB - Parkinson disease is a debilitating and incurable neurodegenerative disorder affecting ~1-2% of people over 65 years of age. Oxidative damage is considered to play a central role in the progression of Parkinson disease and strong evidence links chronic exposure to the pesticide paraquat with the incidence of the disease, most probably through the generation of oxidative damage. In this work, we demonstrated in human SH-SY5Y neuroblastoma cells the beneficial role of superoxide dismutase (SOD) enzymes against paraquat-induced toxicity, as well as the therapeutic potential of the SOD-mimetic compound M40403. Having verified the beneficial effects of superoxide dismutation in cells, we then evaluated the effects using Drosophila melanogaster as an in vivo model. Besides protecting against the oxidative damage induced by paraquat treatment, our data demonstrated that in Drosophila M40403 was able to compensate for the loss of endogenous SOD enzymes, acting both at a cytosolic and mitochondrial level. Because previous clinical trials have indicated that the M40403 molecule is well tolerated in humans, this study may have important implication for the treatment of Parkinson disease. PMID- 26953343 TI - Glycopeptide Antibiotics Potently Inhibit Cathepsin L in the Late Endosome/Lysosome and Block the Entry of Ebola Virus, Middle East Respiratory Syndrome Coronavirus (MERS-CoV), and Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV). AB - Ebola virus infection can cause severe hemorrhagic fever with a high mortality in humans. The outbreaks of Ebola viruses in 2014 represented the most serious Ebola epidemics in history and greatly threatened public health worldwide. The development of additional effective anti-Ebola therapeutic agents is therefore quite urgent. In this study, via high throughput screening of Food and Drug Administration-approved drugs, we identified that teicoplanin, a glycopeptide antibiotic, potently prevents the entry of Ebola envelope pseudotyped viruses into the cytoplasm. Furthermore, teicoplanin also has an inhibitory effect on transcription- and replication-competent virus-like particles, with an IC50 as low as 330 nm Comparative analysis further demonstrated that teicoplanin is able to block the entry of Middle East respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS) envelope pseudotyped viruses as well. Teicoplanin derivatives such as dalbavancin, oritavancin, and telavancin can also inhibit the entry of Ebola, MERS, and SARS viruses. Mechanistic studies showed that teicoplanin blocks Ebola virus entry by specifically inhibiting the activity of cathepsin L, opening a novel avenue for the development of additional glycopeptides as potential inhibitors of cathepsin L-dependent viruses. Notably, given that teicoplanin has routinely been used in the clinic with low toxicity, our work provides a promising prospect for the prophylaxis and treatment of Ebola, MERS, and SARS virus infection. PMID- 26953348 TI - Correction: Kinetochore-localized BUB-1/BUB-3 complex promotes anaphase onset in C. elegans. PMID- 26953342 TI - Complex Formed between Intramembrane Metalloprotease SpoIVFB and Its Substrate, Pro-sigmaK. AB - Intramembrane metalloproteases (IMMPs) are conserved from bacteria to humans and control many important signaling pathways, but little is known about how IMMPs interact with their substrates. SpoIVFB is an IMMP that cleaves Pro-sigma(K) during Bacillus subtilis endospore formation. When catalytically inactive SpoIVFB was coexpressed with C-terminally truncated Pro-sigma(K)(1-126) (which can be cleaved by active SpoIVFB) in Escherichia coli, the substrate dramatically improved solubilization of the enzyme from membranes with mild detergents. Both the Pro(1-20) and sigma(K)(21-126) parts contributed to improving SpoIVFB solubilization from membranes, but only the sigma(K) part was needed to form a stable complex with SpoIVFB in a pulldown assay. The last 10 residues of SpoIVFB were required for improved solubilization from membranes by Pro-sigma(K)(1-126) and for normal interaction with the substrate. The inactive SpoIVFB.Pro sigma(K)(1-126)-His6 complex was stable during affinity purification and gel filtration chromatography. Disulfide cross-linking of the purified complex indicated that it resembled the complex formed in vivo Ion mobility-mass spectrometry analysis resulted in an observed mass consistent with a 4:2 SpoIVFB.Pro-sigma(K)(1-126)-His6 complex. Stepwise photobleaching of SpoIVFB fused to a fluorescent protein supported the notion that the enzyme is tetrameric during B. subtilis sporulation. The results provide the first evidence that an IMMP acts as a tetramer, give new insights into how SpoIVFB interacts with its substrate, and lay the foundation for further biochemical analysis of the enzyme.substrate complex and future structural studies. PMID- 26953347 TI - High substrate specificity of ipsdienol dehydrogenase (IDOLDH), a short-chain dehydrogenase from Ips pini bark beetles. AB - Ips spp. bark beetles use ipsdienol, ipsenol, ipsdienone and ipsenone as aggregation pheromone components and pheromone precursors. For Ips pini, the short-chain oxidoreductase ipsdienol dehydrogenase (IDOLDH) converts (-) ipsdienol to ipsdienone, and thus likely plays a role in determining pheromone composition. In order to further understand the role of IDOLDH in pheromone biosynthesis, we compared IDOLDH to its nearest functionally characterized ortholog with a solved structure: human L-3-hydroxyacyl-CoA dehydrogenase type II/ amyloid-beta binding alcohol dehydrogenase (hHADH II/ABAD), and conducted functional assays of recombinant IDOLDH to determine substrate and product ranges and structural characteristics. Although IDOLDH and hHADH II/ABAD had only 35% sequence identity, their predicted tertiary structures had high identity. We found IDOLDH is a functional homo-tetramer. In addition to oxidizing (-) ipsdienol, IDOLDH readily converted racemic ipsenol to ipsenone, and stereo specifically reduced both ketones to their corresponding (-)-alcohols. The (+) enantiomers were never observed as products. Assays with various substrate analogs showed IDOLDH had high substrate specificity for (-)-ipsdienol, ipsenol, ipsenone and ipsdienone, supporting that IDOLDH functions as a pheromone biosynthetic enzyme. These results suggest that different IDOLDH orthologs and or activity levels contribute to differences in Ips spp. pheromone composition. PMID- 26953349 TI - Mitochondrial RNA granules: Compartmentalizing mitochondrial gene expression. AB - In mitochondria, DNA replication, gene expression, and RNA degradation machineries coexist within a common nondelimited space, raising the question of how functional compartmentalization of gene expression is achieved. Here, we discuss the recently characterized "mitochondrial RNA granules," mitochondrial subdomains with an emerging role in the regulation of gene expression. PMID- 26953350 TI - ARHGEF17 is an essential spindle assembly checkpoint factor that targets Mps1 to kinetochores. AB - To prevent genome instability, mitotic exit is delayed until all chromosomes are properly attached to the mitotic spindle by the spindle assembly checkpoint (SAC). In this study, we characterized the function of ARHGEF17, identified in a genome-wide RNA interference screen for human mitosis genes. Through a series of quantitative imaging, biochemical, and biophysical experiments, we showed that ARHGEF17 is essential for SAC activity, because it is the major targeting factor that controls localization of the checkpoint kinase Mps1 to the kinetochore. This mitotic function is mediated by direct interaction of the central domain of ARHGEF17 with Mps1, which is autoregulated by the activity of Mps1 kinase, for which ARHGEF17 is a substrate. This mitosis-specific role is independent of ARHGEF17's RhoGEF activity in interphase. Our study thus assigns a new mitotic function to ARHGEF17 and reveals the molecular mechanism for a key step in SAC establishment. PMID- 26953352 TI - beta3 integrin-mediated spreading induced by matrix-bound BMP-2 controls Smad signaling in a stiffness-independent manner. AB - Understanding how cells integrate multiple signaling pathways to achieve specific cell differentiation is a challenging question in cell biology. We have explored the physiological presentation of BMP-2 by using a biomaterial that harbors tunable mechanical properties to promote localized BMP-2 signaling. We show that matrix-bound BMP-2 is sufficient to induce beta3 integrin-dependent C2C12 cell spreading by overriding the soft signal of the biomaterial and impacting actin organization and adhesion site dynamics. In turn, alphavbeta3 integrin is required to mediate BMP-2-induced Smad signaling through a Cdc42-Src-FAK-ILK pathway. beta3 integrin regulates a multistep process to control first BMP-2 receptor activity and second the inhibitory role of GSK3 on Smad signaling. Overall, our results show that BMP receptors and beta3 integrin work together to control Smad signaling and tensional homeostasis, thereby coupling cell adhesion and fate commitment, two fundamental aspects of developmental biology and regenerative medicine. PMID- 26953351 TI - Arl2- and Msps-dependent microtubule growth governs asymmetric division. AB - Asymmetric division of neural stem cells is a fundamental strategy to balance their self-renewal and differentiation. It is long thought that microtubules are not essential for cell polarity in asymmetrically dividing Drosophila melanogaster neuroblasts (NBs; neural stem cells). Here, we show that Drosophila ADP ribosylation factor like-2 (Arl2) and Msps, a known microtubule-binding protein, control cell polarity and spindle orientation of NBs. Upon arl2 RNA intereference, Arl2-GDP expression, or arl2 deletions, microtubule abnormalities and asymmetric division defects were observed. Conversely, overactivation of Arl2 leads to microtubule overgrowth and depletion of NBs. Arl2 regulates microtubule growth and asymmetric division through localizing Msps to the centrosomes in NBs. Moreover, Arl2 regulates dynein function and in turn centrosomal localization of D-TACC and Msps. Arl2 physically associates with tubulin cofactors C, D, and E. Arl2 functions together with tubulin-binding cofactor D to control microtubule growth, Msps localization, and NB self-renewal. Therefore, Arl2- and Msps dependent microtubule growth is a new paradigm regulating asymmetric division of neural stem cells. PMID- 26953353 TI - Strategies to regulate transcription factor-mediated gene positioning and interchromosomal clustering at the nuclear periphery. AB - In budding yeast, targeting of active genes to the nuclear pore complex (NPC) and interchromosomal clustering is mediated by transcription factor (TF) binding sites in the gene promoters. For example, the binding sites for the TFs Put3, Ste12, and Gcn4 are necessary and sufficient to promote positioning at the nuclear periphery and interchromosomal clustering. However, in all three cases, gene positioning and interchromosomal clustering are regulated. Under uninducing conditions, local recruitment of the Rpd3(L) histone deacetylase by transcriptional repressors blocks Put3 DNA binding. This is a general function of yeast repressors: 16 of 21 repressors blocked Put3-mediated subnuclear positioning; 11 of these required Rpd3. In contrast, Ste12-mediated gene positioning is regulated independently of DNA binding by mitogen-activated protein kinase phosphorylation of the Dig2 inhibitor, and Gcn4-dependent targeting is up-regulated by increasing Gcn4 protein levels. These different regulatory strategies provide either qualitative switch-like control or quantitative control of gene positioning over different time scales. PMID- 26953355 TI - ARHGEF17 sets the timer for retention of Mps1 at kinetochores. AB - The kinetochore-associated kinase Mps1 controls the spindle assembly checkpoint, but the regulation of its kinetochore recruitment and activity is unclear. In this issue, Isokane et al. (2016. J. Cell Biol. http://dx.doi.org/10.1083/jcb.201408089) show that interaction with and phosphorylation of its substrate, ARHGEF17, regulates Mps1 kinetochore retention, suggesting an autoregulated, timer-like mechanism. PMID- 26953354 TI - Lipid droplet-mediated ER homeostasis regulates autophagy and cell survival during starvation. AB - Lipid droplets (LDs) are conserved organelles for intracellular neutral lipid storage. Recent studies suggest that LDs function as direct lipid sources for autophagy, a central catabolic process in homeostasis and stress response. Here, we demonstrate that LDs are dispensable as a membrane source for autophagy, but fulfill critical functions for endoplasmic reticulum (ER) homeostasis linked to autophagy regulation. In the absence of LDs, yeast cells display alterations in their phospholipid composition and fail to buffer de novo fatty acid (FA) synthesis causing chronic stress and morphologic changes in the ER. These defects compromise regulation of autophagy, including formation of multiple aberrant Atg8 puncta and drastically impaired autophagosome biogenesis, leading to severe defects in nutrient stress survival. Importantly, metabolically corrected phospholipid composition and improved FA resistance of LD-deficient cells cure autophagy and cell survival. Together, our findings provide novel insight into the complex interrelation between LD-mediated lipid homeostasis and the regulation of autophagy potentially relevant for neurodegenerative and metabolic diseases. PMID- 26953357 TI - Catalytic activity and thermal stability of horseradish peroxidase encapsulated in self-assembled organic nanotubes. AB - Horseradish peroxidase (HRP) was encapsulated in self-assembled lithocholic acid (LCA) based organic nanotubes and its catalytic activity before and after thermal treatment was measured for comparison with free HRP. The apparent kcat (kcat/Km) for nanotube encapsulated HRP remained almost the same before and after thermal treatment, reporting an average value of 3.7 +/- 0.4 MUM(-1) s(-1). The apparent kcat value for free HRP decreased from 14.8 +/- 1.3 MUM(-1) s(-1) for samples stored at 4 degrees C to 2.4 +/- 0.1 MUM(-1) s(-1) after thermal treatment for 8 h at 55 degrees C. The Michaelis-Menten constants, Km, determined for encapsulated HRP and free HRP were relatively unperturbed by storage conditions at 4 degrees C or thermally treated at 55 degrees C for varying time periods from 2-8 h, with encapsulated HRP having a slightly higher Km than free HRP (13.4 +/- 0.9 MUM versus 11.7 +/- 0.4 MUM). The amount of HRP encapsulated in LCA nanotubes increased dramatically when the mixture of HRP and LCA nanotubes was brought to an elevated temperature. Within 4 h of thermal treatment at 55 degrees C, the amount of HRP encapsulated by the LCA nanotubes was more than 4 times the amount of HRP encapsulated when equilibrated at 4 degrees C for 7 days. Molecular dynamics (MD) simulations show that the higher degree of exposure of hydrophobic residues in HRP at elevated temperatures enhances the hydrophobic interaction between HRP and the nanotube wall, resulting in the increased amount of HRP surface adsorption and, hence, the overall amount of encapsulation inside the nanotubes. PMID- 26953358 TI - A sensitive magnetic nanoparticle-based immunoassay of phosphorylated acetylcholinesterase using protein cage templated lead phosphate for signal amplification with graphite furnace atomic absorption spectrometry detection. AB - We developed a new magnetic nanoparticle sandwich-like immunoassay using protein cage nanoparticles (PCN) for signal amplification together with graphite furnace atomic absorption spectrometry (GFAAS) for the quantification of an organophosphorylated acetylcholinesterase adduct (OP-AChE), the biomarker of exposure to organophosphate pesticides (OPs) and nerve agents. OP-AChE adducts were firstly captured by titanium dioxide coated magnetic nanoparticles (TiO2 MNPs) from the sample matrixes through metal chelation with phospho-moieties, and then selectively recognized by anti-AChE antibody labeled on PCN which was packed with lead phosphate in its cavity (PCN-anti-AChE). The sandwich-like immunoreaction was performed among TiO2-MNPs, OP-AChE and PCN-anti-AChE to form a TiO2-MNP/OP-AChE/PCN-anti-AChE immunocomplex. The complex could be easily isolated from the sample solution with the help of magnet, and the released lead ions from PCN were detected by GFAAS for the quantification of OP-AChE. Greatly enhanced sensitivity was achieved because PCN increased the amount of metal ions in the cavity of each apoferritin. The proposed immunoassay yielded a linear response over a broad range of OP-AChE concentrations from 0.01 nM to 2 nM, with a detection limit of 2 pM, which has enough sensitivity for monitoring of low dose exposure to OPs. This new method showed an acceptable stability and reproducibility and was validated with OP-AChE spiked human plasma. PMID- 26953359 TI - Synthesis of hierarchical porous beta-FeOOH catalysts in ionic liquid/water/CH2Cl2 ionogels. AB - The ionic liquid/water/CH2Cl2 ionogels were created for the first time, which were used to synthesize hierarchical porous beta-FeOOH catalysts. The pore property and crystallinity could be tuned by the CH2Cl2 content in the ionogels. The as-synthesized beta-FeOOH catalysts exhibited very high activity and stability for oxidation of benzylic carbons. PMID- 26953361 TI - Rudolf W. Ammann (1926-2015). PMID- 26953362 TI - PREFACE. PMID- 26953360 TI - Glycopeptide antibiotic analogs for selective inactivation and two-photon imaging of vancomycin-resistant strains. AB - A novel theranostic divalent vancomycin analog using a planar 1,8-diazapyrene moiety as a rigid scaffold exhibits potent and selective antibacterial activity against Gram (+) bacteria including vancomycin-resistant strains, while having minimal influence on Gram (-) bacteria and mammalian cells. Moreover, this theranostic analog can be also applied for selective two-photon fluorescence imaging of Gram (+) bacteria. PMID- 26953363 TI - [Reply]. PMID- 26953364 TI - Response. PMID- 26953365 TI - Response. PMID- 26953366 TI - [When epilepsy limits (auto)mobility]. PMID- 26953368 TI - [Epilepsy And Driving Ability: The New Guideline]. AB - The Swiss Guideline concerning epilepsy and driving has recently been revised. Recommendations have changed significantly in several respects. Some modifications arise indirectly from a change in the overall concept of epilepsy. As a consequence of the application of the new ILAE definition and diagnostic criteria for epilepsy, there are now cases in which the diagnosis of epilepsy is established even after one single seizure. Furthermore, a concept of imminent epilepsy was introduced to identify patients without seizures, but with a high risk of a first seizure within twelve months. On the other hand, the concept of a "resolved epilepsy" was established to loosen driving regulations for longterm seizure-free patients. In addition, the new guideline provides differential recommendations for provoked vs. unprovoked seizures in several clinical constellations. PMID- 26953367 TI - [Therapy of Acute Heart Failure]. PMID- 26953369 TI - [Pelvic Ring Fractures in the Elderly]. AB - Pelvic ring fractures in elderly patients are usually associated with a low energy trauma, which may hide the fact that these fractures are often a combination of anterior and posterior pelvic ring injuries with a potential significant instability with subsequent pain and immobility. Pelvic fractures in the geriatric population are associated with a high morbidity and mortality. The goals of any treatment are the restoration of mobility and independency as well as the prevention of future fractures. In order to accomplish these goals, an interdisciplinary approach is indispensable. This review is aimed to provide insight into the characteristics of geriatric pelvic ring injuries and into their diagnosis and therapy with the associated outcome. PMID- 26953371 TI - [Pain Management in the Multimorbid Patient]. AB - No treatment without risks. This is particularly true in the pharmacologic pain management of multimorbid patients. This article is meant to address some of the most relevant clinical questions, such as the use of opioids in the cognitively impaired patient or the well-known interactions between NSAID and aspirin. The advantages and disadvantages of the most frequently prescribed analgesics are highlighted. Furthermore, the most useful interventional techniques in the multimorbid patient are discussed. PMID- 26953370 TI - [Health Status of Young Men in Switzerland: Monitoring Results from Conscription]. AB - Due to their representativeness and consistent measurement standards the medical und sports data of the Swiss conscripts provide a valuable basis for a continuous health monitoring of young Swiss men. During three to four years, the prevalence of overweight and obesity seems to stabilise on a high level. After a longer period of decreasing performance at the endurance test between the 1980s and 2002, the level of physical performance in the fitness test does no longer decrease since 2006. However, health and health behaviour show significant regional and socioeconomic inequalities among young Swiss men. Besides economic resources and education, major driving factors behind these inequalities can be identified in health knowledge, values, and attitudes. PMID- 26953372 TI - [Evaluation of anemia in family practice]. PMID- 26953373 TI - [Fixed combination of long-acting bronchodilators in COPD]. PMID- 26953375 TI - [Testosterone, a new "heart medicine"? or "Can I trust a new observational study?"]. PMID- 26953376 TI - [CME-ORL 17. Dysphonia in intra- or extralaryngeal space-occupying lesion]. PMID- 26953378 TI - [Raissa Nitabuch]. PMID- 26953379 TI - [Indentations and discolorations on arms and legs]. PMID- 26953380 TI - [Intestinal lavage results in sustained imbalance of intestinal flora]. PMID- 26953381 TI - [No long-term effect on pathogen load]. PMID- 26953383 TI - [Melanoma risk? Please uncover your right arm!]. PMID- 26953382 TI - [Complications caused by food supplements]. PMID- 26953384 TI - [Better chance of survival for the overweight and elderly]. PMID- 26953385 TI - [Evidence and eminence based therapy for elderly Parkinson patients]. PMID- 26953386 TI - [First flop, now top!]. PMID- 26953387 TI - [Living conditions in childhood have relevance]. PMID- 26953388 TI - [Easing the first steps toward abstinence for your patients]. PMID- 26953389 TI - [Alcohol and phytotherapy: is this not risky?]. PMID- 26953390 TI - [Care for the dying patient: what is allowed for the physician?]. PMID- 26953391 TI - [Why does my patient have yellow hands?]. PMID- 26953392 TI - [Do corticoids affect the anti-CCP titer?]. PMID- 26953393 TI - [Calculating chronic patient consultation fees by substitute physician]. PMID- 26953394 TI - [How compression treatment fee calculation functions]. PMID- 26953395 TI - [The cannabis activist]. PMID- 26953397 TI - [Challenging the everyday time drains ]. PMID- 26953396 TI - [The alcoholic patient only wants to return home to his cats]. PMID- 26953398 TI - [How are hemorrhoid treatment fees calculated?]. PMID- 26953399 TI - [We must treat them!]. PMID- 26953400 TI - [Not arbitrarily interpreting GOA]. PMID- 26953401 TI - [Wanted: Germany's most creative physicians]. PMID- 26953402 TI - [Nut consumption reduces risk of three cancers]. PMID- 26953403 TI - [A milestone in cystic fibrosis therapy]. PMID- 26953404 TI - [The guidelines faithful - even in multi-morbid]. PMID- 26953405 TI - [Prostate cancer - unexpected prevalence]. PMID- 26953406 TI - [Three clinical cases of hypertension]. PMID- 26953407 TI - [Clinical case - a patient with mild hypertension]. PMID- 26953408 TI - [A 93-year-old patient with hypertensive crises and renal failure due to bilateral renal artery stenosis]. PMID- 26953409 TI - [Arterial hypertension with multiple comorbidities]. PMID- 26953410 TI - [A needlestick injury - what next?]. PMID- 26953411 TI - [Pneumococcal vaccination - Update 2015]. PMID- 26953412 TI - [Transient osteoporosis of the hip - a rare differential diagnosis of coxalgia]. PMID- 26953413 TI - [Sudden hearing loss - The use of hydroxyethylstarch ends]. PMID- 26953414 TI - [Hepatic encephalopathy - complex neuropsychiatric disorder in liver disease]. PMID- 26953415 TI - [Phytotherapy drugs - first choice remedies]. PMID- 26953416 TI - [Dabigatran specific antidote: new safety level in oral anticoagulation]. PMID- 26953417 TI - [Safer in everyday clinical care]. PMID- 26953418 TI - [Continuity of generations in dental faculty of Omsk State Medical University]. PMID- 26953419 TI - [Innovative activity of dental faculty staff of Omsk State Medical University: results, problems and prospects]. AB - The article summarizes innovative activity in Omsk State Medical University (OSMU) and contains the review of innovative developments of staff of dental faculty of OSMU (a line of gels for caries prevetion, the DENTEST diagnostic unit, technology of tooth shape modular restoration, personified therapy.of patients with periodontal disease, caries diagnosis and periodontontal disease prognosis software, a set of the training materials on esthetic modeling of teeth, personification of clinical approaches in oral bioaesthetic rehabilitation, etc.). The analysis of the factors stimulating and complicating innovative detail in medical school, problems of introduction of medical innovations, lack of system of an assessment of medical technologies in Russia, regulations of the organization of innovative activity in medical schools is carried out, the prospects of their solution connected with decision-making at the state level are formulated. PMID- 26953420 TI - [Experimental study of the collagen matrix for increase the gums using a 3D modeling]. AB - In an experimental study on mini-pigs demonstrated that the use of collagen matrix Mucograft open method leads to the formation of mature connective tissue around the implants, more pronounced after 70 days, and the width of attached mucosa already 45th day (from 4.4 +/- 0.3 to 7.7 +/- 0.5 mm) is comparable to that of free gingival graft. Three-dimensional computer modeling of jaws experimental animals showed the soft tissue augmentation by 0.8 +/- 0.1 cm3 after use of collagen matrix Mucograft and 1.1 +/- 0.12 cm3 after free gingival graft. PMID- 26953421 TI - [Clinical variations of chronic generalized periodontitis, genetic polymorphism and systemic production of inflammatory cytokines]. AB - Carriage of polymorphic alleles of genes of cytokines-interleukines IL-1beta, IL 1RN, TNFalpha, IL-4 can be a specific feature of chronic periodontitis patients. Genetic tests can be used to predict the course of the disease at its early manifestations. Objective: To establish the relationship of clinical manifestations of periodontal disease, inflammatory cytokines gene polymorphism and systemic levels of cytokine production. Periodontal tissue assessment and cone-beam computed tomography (CBCT) were performed in 150 periodontitis patients. A molecular--genetic testing for the presence of polymorphic alleles of genes IL-1beta -511 C>T and +3953 C>T, IL-1RN (VNTR intron 2), IL-4 (VNTR intron 3), TNFalpha-308 G>A; content determined IL-1beta, TNFalpha, IL-4 in peripheral blood was carried out in 150 patients with periodontitis and 150 healthy donors. Based on the analysis of the speed and nature of the supporting bone resorption and clinical manifestations patients are divided in "aggressive", "moderately progressive" and "slowly progressive" periodontits course groups. Disease severity was associated with distribution of genotypes and alleles of polymorphic genes cytokine IL-1RN (VNTR intron 2), TNFalpha-308 G>A and IL-4 (VNTR intron 3); haplotype IL-1beta-511 TIL-1beta +3953 T/IL-1RN 2R. There was no statistically significant difference in systemic level of IL-1beta, TNFalpha and IL-4 between periodontitis groups but the donor level of cytokines was 2-4 times less. PMID- 26953422 TI - [Expression markers of innate and adaptive immunity in gingival biopsies of patients with chronic generalized periodontitis during treatment]. AB - Objective was to evaluate changes in expression of TLR, CD4, CD8 and CD20 in the mucosa of the gums occurring under the influence of basic treatment in patients with periodontitis. Fifty-seven periodontitis patients that received basic treatment were included in the study, gingival mucosa biopsies were obtained and immunohistochemical evaluation of the expression of TLR-2, TLR-4, CD4, CD8 and CD2 and the severity of acanthosis were assessemd in course of treatment. It is shown that one month of therapy significantly reduces the amount of TLR-2 and TLR 4 in gingival epithelial cells, populations of CD4 and CD8 lymphocytes in the inflammatory infiltrates, whereas no significant differences in the quantitative distribution of CD20-lymphocytes have been identified. Marked regression of inflammatory changes in therapy and decrease the severity of acanthosis. Therapy aimed at reducing the bacterial load in the mouth was associated with good clinical effect, as evidenced by the periodontal index and the innate immune system suppression to reduce susceptibility to periodontal patogens combined with the suppression of acquired immunity cells level in the gingival mucosa during treatment. At the same time, the protective ability of pathogens supported by the persistence of populations CD20-lymphocytes with the ability to activate humoral adaptive immunity was also seen. PMID- 26953423 TI - [Clinical and microbiological rationale for laser removal of infected epithelia in patients with periodontitis]. AB - The aim of the study was to identify clinical microbiological criteria for the necessity of removal of infected epithelium in the periodontal pocket in patients with periodontitis. A total of 90 patients diagnosed with periodontal disease of varying severity were assessed. Clinical examination of the patients was performed, including the definition of index numbers and microbiological diagnosis of the content of periodontal pocket and periodontal tissues by biopsy culture seeding. Epithelial integration of lactobacilli and bifidobacteria was established, indicating the need for a differentiated approach to the removal of gingival epithelium. Diagnostic criteria for deepitalization was identified: marked inflammatory response of periodontal tissues, characterized by performance indexes PMA > 50%, Mulleman > 1.5, Svrakov > 2.7, correlated with the degree of contamination biopsy 4IgKOE/ml and Candida spp. 2IgKOE/ml. PMID- 26953424 TI - [Modern clinical and radiological approach to diagnostics of odontogenic sinusitis]. AB - Inflammatory diseases of the maxillary sinuses affect up to 70% of the adult population. Odontogenic maxillary sinusitis represents 13-86% of the inflammatory processes of maxillofacial area, with the incidence range being explained rather by varying diagnosis criteria than the true incidence difference of odontogenic lesions. The aim of the study was to summarize the clinical and radiological characteristics of odontogenic sinusitis according to patients records in the Department of Maxillofacial Surgery of Omsk Clinical Hospital No11 and the oral surgery department of BUZ GKSP No1 in 2009-2014. A total of 948 records of patient (aged 17 to 68 years) with maxillary sinusitis were identified. X-ray examinations were performed by CT PISASSO TRIO ("KoYo", South Korea) and MSCT Brillians 6 and Brillians 64 ((Philips HealthCare), Netherlands). Images were obtained in axial projection with slice thickness of 0.2-0.6 mm with multiplanar reconstructions (MPR) in a variety of direct and oblique projections. Altogether 664 patients were diagnosed with foreign bodies in the maxillary sinuses (filling material in 569 cases, roots or root fragments? implants, rubber drains, fragments of endodontic instruments in 95 cases). In 284 persons odontogenic cysts were found. Almost every fifth case was complicated by mycotic infection. Analysis of the results showed that only a multidisciplinary approach including dentists, maxillofacial surgeons, otolaryngologists and radiologists, as well as dental volumetric tomography or multislice CT can ensure the correct clinical and radiological approaches to determine the tactics of treatment in patients with sinusitis, reduce the incidence of relapses and chronic inflammatory processes in the maxillary sinuses. PMID- 26953425 TI - [Chondroprotectors in complex treatment of internal TMJ disorders]. AB - The article presents a detailed analysis of the clinical studies on the use of chondroprotector (Alflutop) in patients with persistent displacement of the articular disk of the temporomandibular joint in order to prevent the development of secondary osteoarthrosis. The study showed that the inclusion in the therapy chondroprotective action agents allows achieving short-term positive outcomes in most cases, relief of inflammation and pain, as well as improving joint function and stabilization of the thickness of the articular cartilage that provides cushioning function. PMID- 26953426 TI - [Oral rehabilitation with metalloceramic restorations in patients with non differentiated systemic connective tissue dysplasia]. AB - False formation of connective tissues have a great influence on structure and function of organs and tissues of the human body. In prosthodontics, the changes in connective tissues greatly occur during clinical stages of preparing metal ceramic dentures. The algorithm of treatment patients with connective tissue dysplasia during metal ceramic dentures was developed and introduced into practical dentistry based on studying the morphology and functionality of dentition and clinical experience. PMID- 26953427 TI - [Planning of esthetic oral rehabilitation according to correlative analysis of clinical and morphological features of the marginal gingiva]. AB - The orthopedic restoration and related to its clinical stages (preparation, gingival retraction, impression) is often associated with complications which arise from the marginal gingiva. The technology of indirect ceramic restoration requires an assessment of the clinical and morphological parameters of periodontal tissues. The study outlines correlation between the type of periodontal histhology and inflammatory and degenerative complications that has been established after the analysis of morphofunctional state of periodontal tissue. Results of clinical studies and correlation analysis of clinical and morphological parameters of marginal gingiva has shown that important parameter influencing the choice of manufacturing technology are the position of restoration margin relatively to marginal gingiva and periodontal morphotype. PMID- 26953428 TI - [Correlation of psychoemotional status and adaptation to complete dentures]. AB - Patients with full adentia are characterized by the formation of specific psycho emotional status. Rational psychotherapeutic support of these patients largely determines the efficiency of dental prosthetic treatment. At the same time, the definition of mental and emotional status is not included in the diagnostic examination protocol. Considering the above the purpose of the study was to evaluate mental and emotional status of patients receiving complete dentures. Prosthetic rehabilitation of 30 patients with complete teeth loss was performed and clinical evaluation and evaluation of mental and emotional status were carried out before and after treatment. Patients with negative experiences of prosthetics showed a higher level of personal and situational anxiety. There was correlation of adaptation to removable dentures and the patient's personality traits. It is determined that emotional instability during treatment tends to decrease affecting the timing of adaptation to complete dentures. It is noted that patients with repeated prosthetics have earlier recovery of coordination ability of the masticatory muscles. PMID- 26953429 TI - [Quantitative and qualitative analysis of oral microbiota by orthopedic rehabilitation with full and partial removable dentures]. AB - Microbiological analysis of biomaterial surface in dental prosthesis showed the most common colonizing gram-positive species to be S. aureus, Micrococcus spp., S. haemolyticus, E. faecalis, mainly massive colonization with S. aureus was seen. The highest concentration of C. albicans colonization was found in removable dentures and may have a destructive effect on prosthetic material. PMID- 26953430 TI - [Bioethics in orthodontics]. AB - The objective of the study was to reveal the necessity of implementation of bioethical principles in the treatment of patients with dentofacial anomalies. Scientific publications revealing the interrelation of basic bioethical principles and characteristics relevant during treatment of patients with dentofacial anomalies were monitored and analyzed. The patient's responsibility for the results of treatment, the revision of life values, the change of overall lifestyle contributes to the patient's recovery. An orthodontist must follow basic bioethical principles: benevolence, autonomy, causing no harm, and justice. Trust-based relations in the system "doctor-patient" allow the doctor to share the knowledge which contribute to the patient's recovery, so the necessity of implementation of bioethical principles (benevolence, autonomy, causing no harm, and justice) in the treatment of patients with dentofacial anomalies was revealed. PMID- 26953431 TI - [The impact of internal TMJ disorders on quality of life of patients with malocclusion]. AB - Articular disturbances of temporo-mandibular joint (TMJ) combined with dentofacial anomalies (DFA) decrease the quality of life. The objective of the study was ti determine dental quality of life in patients with "internal disturbances" of TMJ combined with DFA. Questionnaire survey (Oral Health Impact Profile OHIP-14-RU) of 96 young patients was carried out. The patients were treated due to DFA combined with "internal disturbances" of TMJ. It should be pointed out that patients with hyperdivergent skeletal pattern have the most evident trend towards setting the quality of life to zero in dental sphere. Moreover, the trend is more evident in the case of patients with dento-alveolar types of occlusion anomalies. Patients with dento-alveolar type of open occlusion have maximum points in "Psychological discomfort", "Psychological disability", and "Social disability". Patients with distal occlusion and hyperdivergence of jaw bones have maximum points in "Psychological disability" and "Social incapacity". Patients with the combination of distal occlusion and deep incisal occlusion have maximum points in "Psychological discomfort" and "Social disability". Patients with "internal disturbances" of TMJ combined with DFA reveal a negative shift of questionnaire information. The maximal rates were revealed in "Psychological disability" and "Social disability", the minimal ones- in "Functional limitation" and "Handicap". PMID- 26953432 TI - [Complex treatment approach for preschool children with impaired nasal breathing]. AB - During the treatment of children with impaired nasal breathing (INB) cooperation of medical specialists is needed in order to reveal risk factors. The objective of the study was to prove the necessity of complex approach to the treatment of children with risk factors for INB. Multi-variant analysis of somatic and dental health of 170 children aged 4-6 was performed. The dental health was examined gradually in several steps, including physical examination. The following risk factors of antenatal and postnatal development of a child were revealed: genetic predisposition, complication of pregnancy, birth defects, somatic pathology, mastication dyspraxia, respiratory impairment, and various speech impediments. The following dentofacial anomalies prevailed: disorder of abrasion of primary dentition tubercle, development discord of cranio-facial area. The necessity of doctors' cooperation was proved during the treatment of children with impaired nasal breathing. Accurate execution of proposed treatment schemes allows eliminating risk factors promptly and decreasing the pathology severity. PMID- 26953433 TI - [The role of clinical laboratory diagnostics in dental caries prognosis in children]. AB - The aim of the study was to identify informative, in terms of predicting caries process, laboratory parameters of homeostasis of the oral cavity in children of different age groups. A total of 1158 children of preschool and school age with caries were screened to determine laboratory parameters of homeostasis of the oral cavity by examining of the oral fluid. Caries in children was characterized by certain age specific physico-chemical parameters shift in the oral fluid. Complex set of the most informative laboratory indices reflecting the resistance and susceptibility to dental caries in children of different age groups was revealed. The obtained data allowed creating mathematical models for prenosological prediction of caries in preschool and school age, which formed the basis of "Stop caries" software. PMID- 26953434 TI - [Serial clinical examinations as the main approach to dental caries prevention in children]. AB - Leading scientific and organizational prerequisites for the feasibility of clinical examination of the entire child population of the Russian Federation to the dentist is, above all, the high prevalence and intensity of dental diseases in children of all ages. As a result of many years of research and follow-up of children of preschool and school age we have proved the need to distinguish a group of children with zero activity of dental caries. The referring criteria are determined according to the results of comprehensive clinical and laboratory examination in order to determine the degree of risk of dental caries and individual caries resistance. The age-specific risk group is settled by "Stop caries" software. In order to optimize the preventive activities children are divided in 5 groups for routine preventive dental care. Unfortunately the efforts of modern dental services aimed at eliminating the consequences of caries process by filling cavities. Individualized preventive approach will increase the effectiveness of preventive measures and save public funds allocated in the amount of compulsory health insurance for pediatric dentistry. PMID- 26953435 TI - [Specific features of oral hygiene education in preschool children]. AB - Health education of children mostly covers children of preschool age. It is not always successful because sanitary training inkindergarten is a mere formality. The aim of the study was to increase the effectiveness of prevention of oral diseases inpreschool children by improving the system of hygiene training and education. Dental examination of 225 3 to 5 years oldsliving in the city of Omsk was performed. The level of hygienic habits/oral care formation was carried out by studyingquestionnaires and interviewing children, parents, caregivers and healthcare professionals. Authors method of oral hygieneeducation in preschool children was introduced and compared to different methods of hygienic training and education may. Itsimplementation resulted in 46.5% caries incidence growth reduction The developed technique of the gradual formation of oralhygiene habits proved to be both clinically and cost effective. PMID- 26953436 TI - [The possibility of increasing the tooth enamel caries in children and adolescents through an integrated remineralizes fluoropolymer coatings with tricalcium phosphate]. AB - In the survey we conducted a prospective cohort oral 138 children and adolescents living in the same environmental conditions. To study the effect of the complex representation remineralizes fluorine-containing tricalcium phosphate coating for the prevention of caries-the process in childhood, all surveyed were divided into 3 groups with high, medium and low enough average caries based on clinical and laboratory examination. The authors found a 7-fold the efficiency of preventive measures in the group with sufficient average caries and 5 times the efficiency in the group with low average caries in relation to subgroups where remineralizes present fluorine-containing coating with tricalcium phosphate is not applicable. Furthermore, it was found that the accumulation of fluorine occurs only in a surface layer of the enamel within 100 micrometers. PMID- 26953437 TI - [Medical university teaching staff training for formation of communicative competence in dentists]. AB - Psychology and pedagogical preparation provides improvement of the ability of psychological interaction with the patient, promotes deepening of constructive cooperation between them. It facilitates collecting and analysis of clinical data and has direct impact on efficiency of treatment and prophylactic actions. Formation of communicative competence becomes one of key problems of continuous medical education. Introduction of the Medical Communication module in the program of professional development will provide modern technologies of training in technics of active hearing, effective communication, adjustment of contact, feedback, behavior in a stress situation. PMID- 26953438 TI - [Screening of the atypical oral mucosa lesions]. AB - ViziLite system was used for mucosal lesions screening in 55 patients 22 of whom showed visible changes in the oral mucosa. Diagnoses were confirmed morphologically. Authors diagnostic algorithm for precancerous lesions of the oral mucosa is presented in the paper. PMID- 26953439 TI - [Interrelationship wisdom teeth dystopia and internal TMJ disorders: a clinical case]. AB - The patient with painful restriction of jaw movements showed CT and MRI of TMJ signs of on-reducing disk displacement of the right TMJ and secondary arthrosis. Signs of occlusion obstacle and compression of the right TMJ structures have been revealed by studying of diagnostic models, MPI, investigation of TMJ with KAVO Arcus Digma II system. The etiological factor proved to be th dystopia of 4.8. Complete recovery of the TMJ function has been noted after removal of tooth 4.8. CT and MRI of TMJ, investigation of occlusion are indicated for patients with non reducing disk displacement of TMJ. Malposition of third molar can lead to development of internal derangements of TMJ. PMID- 26953442 TI - [Sebaceous gland follicles are spreading]. PMID- 26953443 TI - [Not holding the laser printer responsible for all ills]. PMID- 26953444 TI - [Is ultrasound diagnosis useless?]. PMID- 26953445 TI - [TAVI for everyone]. PMID- 26953446 TI - [Stress at work increases the risk of stroke]. PMID- 26953447 TI - [In laryngitis an allergy test is worthwhile]. PMID- 26953448 TI - [Early detection of depression improves the prognosis in cancer]. PMID- 26953449 TI - [Only a dead Helicobacter pylori is benign!]. PMID- 26953450 TI - [Always biopsies of the esophagus]. PMID- 26953451 TI - [Alarm signals from the esophagus]. PMID- 26953452 TI - [The "pill" for him remains a long-term pious aspiration]. PMID- 26953453 TI - [What helps in "malignancy " of the psyche?]. PMID- 26953454 TI - [Anticoagulation after stroke: what works, what does not?]. PMID- 26953455 TI - [Taking nonspecific symptoms in the elderly seriously]. PMID- 26953456 TI - [Smokers have different COPD risk factors than nonsmokers]. PMID- 26953457 TI - [No real alternatives to steroids yet]. PMID- 26953458 TI - [Urinalysis findings lead to the diagnosis]. PMID- 26953459 TI - [Why are copies for colleagues not paid for?]. PMID- 26953460 TI - [Payment slip is integrated into the AU bill]. PMID- 26953461 TI - [KBV representatives organize an advisory committee]. PMID- 26953462 TI - [GOA: special services to be billed alongside counseling]. PMID- 26953463 TI - [Surgical consultation is next door]. PMID- 26953464 TI - [The SoFi viewing glasses from the general practice supply room]. PMID- 26953465 TI - [Are you at ease with persons from all nations? No!]. PMID- 26953466 TI - [Home manager wants prescriptions for blood glucose test strips]. PMID- 26953467 TI - [Temporary contract for former employee?]. PMID- 26953468 TI - [Specialist for pain medicine without additional capacity]. PMID- 26953469 TI - [Outstanding innovators]. PMID- 26953470 TI - [Are doctors prevention grumps?]. PMID- 26953471 TI - [Knee prostheses were implanted too early]. PMID- 26953472 TI - [Healthy eating preserves cognition in old age]. PMID- 26953473 TI - [Why does bariatric surgery actually work?]. PMID- 26953474 TI - [MRI does not improve the prediction of dementia]. PMID- 26953475 TI - [Dental care prevents prediabetes]. PMID- 26953476 TI - [Clostridium difficile are on the rise]. PMID- 26953477 TI - [Driving ability in mental illness]. PMID- 26953478 TI - [Syncope: harmful or harmless?]. PMID- 26953479 TI - [Sensory and autonomic small fiber neuropathy]. PMID- 26953480 TI - [Very important: alleviation of pain at the end of life]. PMID- 26953481 TI - [Osteoporosis in women - well known but not treated]. PMID- 26953482 TI - [Heart failure - diagnosis and treatment in daily practice]. PMID- 26953483 TI - [Hepatitis C]. PMID- 26953484 TI - [Detecting dangerous course of the disease at cold symptoms]. PMID- 26953485 TI - [Physical activity in prevention of type 2 diabetes]. PMID- 26953486 TI - Axonal transport of AAV9 in nonhuman primate brain. AB - A pilot study in nonhuman primates was conducted, in which two Rhesus macaques received bilateral parenchymal infusions of adeno-associated virus serotype 9 encoding green fluorescent protein (AAV9-GFP) into each putamen. The post surgical in-life was restricted to 3 weeks in order to minimize immunotoxicity expected to arise from expression of GFP in antigen-presenting cells. Three main findings emerged from this work. First, the volume over which AAV9 expression was distributed (Ve) was substantially greater than the volume of distribution of MRI signal (Vd). This stands in contrast with Ve/Vd ratio of rAAV2, which is lower under similar conditions. Second, post-mortem analysis revealed expression of GFP in thalamic and cortical neurons as well as dopaminergic neurons projecting from substantia nigra pars compacta, indicating retrograde transport of AAV9. However, fibers in the substantia nigra pars reticulata, a region that receives projections from putamen, also stained for GFP, indicating anterograde transport of AAV9 as well. Finally, one hemisphere received a 10-fold lower dose of vector compared with the contralateral hemisphere (1.5 * 10(13) vg ml(-1)) and we observed a much stronger dose effect on anterograde-linked than on retrograde linked structures. These data suggest that AAV9 can be axonally transported bi directionally in the primate brain. This has obvious implications to the clinical developing of therapies for neurological disorders like Huntington's or Alzheimer's diseases. PMID- 26953487 TI - H2A/K pseudogene mutation may promote cell proliferation. AB - Little attention has been paid to the histone H2A/K pseudogene. Results from our laboratory showed that 7 of 10 kidney cancer patients carried a mutant H2A/K pseudogene; therefore, we were interested in determining the relationship between mutant H2A/K and cell proliferation. We used shotgun and label-free proteomics methods to study whether mutant H2A/K lncRNAs affected cell proliferation. Quantitative proteomic analysis indicated that the expression of mutant H2A/K lncRNAs resulted in the upregulation of many oncogenes, which promoted cell proliferation. Further interaction analyses revealed that a proliferating cell nuclear antigen (PCNA)-protein interaction network, with PCNA in the center, contributes to cell proliferation in cells expressing the mutant H2A/K lncRNAs. Western blotting confirmed the critical upregulation of PCNA by mutant H2A/K lncRNA expression. Finally, the promotion of cell proliferation by mutant H2A/K lncRNAs (C290T, C228A and A45G) was confirmed using cell proliferation assays. Although we did not determine the exact mechanism by which the oncogenes were upregulated by the mutant H2A/K lncRNAs, we confirmed that the mutant H2A/K lncRNAs promoted cell proliferation by upregulating PCNA and other oncogenes. The hypothesis that cell proliferation is promoted by the mutant H2A/K lncRNAs was supported by the protein expression and cell proliferation assay results. Therefore, mutant H2A/K lncRNAs may be a new factor in renal carcinogenesis. PMID- 26953488 TI - HACEK endocarditis: state-of-the-art. AB - The HACEK group of bacteria - Haemophilus parainfluenzae, Aggregatibacter spp. (A. actinomycetemcomitans, A. aphrophilus, A. paraphrophilus, and A. segnis), Cardiobacterium spp. (C. hominis, C. valvarum), Eikenella corrodens, and Kingella spp. (K. kingae, K. denitrificans) - are fastidious gram-negative bacteria, part of the normal microbiota of oral and upper respiratory tract in humans. Although their pathogenicity is limited, they are responsible for 1-3% of all infective endocarditis. HACEK endocarditis mostly affect patients with underlying heart disease or prosthetic valves, and are characterized by an insidious course, with a mean diagnosis delay of 1 month (Haemophilus spp.) to 3 months (Aggregatibacter and Cardiobacterium spp.). The advent of continuously monitored blood culture systems with enriched media has erased the need for extended incubation for the diagnosis of HACEK endocarditis. Medical treatment relies on third-generation cephalosporin, with a favorable outcome in 80-90% of cases, with or without cardiac surgery. PMID- 26953490 TI - Writing at the margin of the margin: medical anthropology in Southern Europe. AB - This critical review explores the problems posed in Southern Europe by the recent development of medical anthropology, focusing on three issues: the problems derived from research in languages other than English, the idiosyncratic developments of social and cultural research within European continental health sectors, and the theoretical specificity of Southern European medical anthropologies. PMID- 26953489 TI - Adjuvant-Loaded Subcellular Vesicles Derived From Disrupted Cancer Cells for Cancer Vaccination. AB - Targeted subunit vaccines for cancer immunotherapy do not capture tumor antigenic complexity, and approaches employing tumor lysate are often limited by inefficient antigen uptake and presentation, and low immunogenicity. Here, whole cancer cells are processed to generate antigen-rich, membrane-enclosed subcellular particles, termed "reduced cancer cells", that reflect the diversity and breadth of the parent cancer cell antigen repertoire, and can be loaded with disparate adjuvant payloads. These vesicular particles enhance the uptake of the adjuvant payload, and potentiate the activation of primary dendritic cells in vitro. Similarly, reduced cancer cell-associated antigens are more efficiently presented by primary dendritic cells in vitro than their soluble counterparts or lysate control. In mice, vaccination using adjuvant-loaded reduced cancer cells facilitates the induction of antigen-specific cellular and humoral immune responses. Taken together, these observations demonstrate that adjuvant-loaded reduced cancer cells could be utilized in cancer vaccines as an alternative to lysate. PMID- 26953491 TI - Mosiach is here now: just open your eyes and you can see him. AB - Religious groups deal with failed prophecy in different ways. This paper examines messianic expectations among Lubavitch Hasidim in Stamford Hill and their response to the death of their leader whom they held to be the Messiah. It is based on eight years of participant observation in the community. In agreement with Melton's theory, when the Rebbe died, Lubavitchers held that the Rebbe was more powerful in the spiritual realm without the hinderance of a physical body. However some have now claimed that he never died. Several even state that the Rebbe is God. This is a significant finding. It is unknown in the history of Judaism to hold that the religious leader is God and to this extent the group is unique. There are certain Christian elements which apparently inform the messianic ideas of this group. PMID- 26953492 TI - Three into two: the third sex in Northern Albania. AB - From the position of a formal sociology, Georg Simmel argued that the introduction of a third element into a pervasive binary system can serve to mitigate the latter's salience. The instance considered here is that of a third sex in Northern Albania. "Sworn virgins" are generally perceived as women who become men (gender crossing) rather than as an additional engendered category (multiple gender). The overarching significance of the Albanian gender system is thereby barely attenuated, and virgjinesha do not contribute to a less subdominant position for other women. PMID- 26953493 TI - Reflections on the past and present state of Russian psychiatry. AB - This paper is an analysis of three periods of Russian psychiatry: before 1917, during the Soviet period, and after the fall of the Soviet Empire. The section on Russian psychiatry before 1917 considers the biomedical model in psychiatry which was transferred from somatic medicine without recognising the difference in the character of signs and symptoms. Mechanisms of mental disorders were analysed predominately from the position of the "physiology of superior nervous activity". At the same time, the role of the social and psychological factors in psychiatric problems was not totally ignored. The psychoanalytical approach was accepted and adopted. The second section considers ideological concepts which influenced the development of Soviet psychiatry. Psychological approaches to diagnosis, treatment and explanation of the mechanisms of development of the disorders were prohibited and excluded from the practice of psychiatrists. The clinical orientation of Soviet psychiatry was directed towards the disclosure of the symptoms, syndromes and nosologies according to oversimplified interpretation of psychiatric terminology. As a result psychiatrists developed a specific mentality and skills in detecting symptoms of psychopathology in every consulted person. Psychiatric statistics were published in a wholly misleading manner. The last section reviews current situation in contemporary Russian psychiatry. Its development continues to be influenced by "negative" aspects inherited from the Soviet era. It is expressed, particularly, in the continued hyper diagnosis of schizophrenia and extremal postponement of the official use of the adapted version of ICD-10 containing several deformations as compared to the original one. However, psychological approaches are revived and many Russian psychiatrists are taking an active interest in recent developments in the field of psychodynamic and transcultural approaches, and to deploy them in their clinical practice. PMID- 26953495 TI - Providing Telehealth Services to a Public Primary Care Network: The Experience of RedeNUTES in Pernambuco, Brazil. AB - BACKGROUND: Information technologies have been applied in primary care domains to improve the delivery of health services. This article reports the telehealth network experience in Pernambuco, Brazil. MATERIALS AND METHODS: Five different data sets were used, one by each service and the structural aspects of the network, collected from 2008 until August 2015. The data include solicited themes for educational activities, users' evaluation of services, numbers of sites, municipalities participating, participants in tele-education activities, teleconsultations, telediagnosis, and remote screenings. The analysis was done in absolute and percentage values using Microsoft Excel (version 2007). RESULTS: The indicators show high utilization of tele-education resources, followed by the teleconsultation service. The synchronous modality was the most used and the general clinical question was the most frequent type of question. Nurses are the professional category that most used the teleconsultation services (36%). Telediagnosis of electrocardiography has growth utilization, overcoming teleconsulting more recently. The satisfaction rate was 89%, and 68.5% of professionals changed their planning to patients' referrals to specialists. CONCLUSIONS: Telehealth has been considered effective since it avoids inappropriate referrals of the patient and provides continuous actualization to health professionals. Our results provide evidence of the feasibility and importance of using telehealth as a tool to ensure the universality, equality, and completeness in the health system. PMID- 26953496 TI - Inhibitory Effects of Spices on Biogenic Amine Accumulation during Fish Sauce Fermentation. AB - The presence of high levels of biogenic amines is detrimental to the quality and safety of fish sauce. This study investigated the effects of ethanol extracts of spices, including garlic, ginger, cinnamon, and star anise extracts, in reducing the accumulation of biogenic amines during fish sauce fermentation. The concentrations of biogenic amines, which include histamine, putrescine, tyramine, and spermidine, all increased during fish sauce fermentation. When compared with the samples without spices, the garlic and star anise extracts significantly reduced these increases. The greatest inhibitory effect was observed for the garlic ethanolic extracts. When compared with controls, the histamine, putrescine, tyramine, and spermidine contents and the overall biogenic amine levels of the garlic extract-treated samples were reduced by 30.49%, 17.65%, 26.03%, 37.20%, and 27.17%, respectively. The garlic, cinnamon, and star anise extracts showed significant inhibitory effects on aerobic bacteria counts. Furthermore, the garlic and star anise extracts showed antimicrobial activity against amine producers. These findings may be helpful for enhancing the safety of fish sauce. PMID- 26953497 TI - A Theoretical Study on the Strain Energy of Carbon Nanobelts. AB - A theoretical study on the strain energy of carbon nanobelts, i.e. the belt shaped molecules representing the sidewall structures of carbon nanotubes, is reported. The strain energy of carbon nanobelts with chiral indices (n,n), (n,0), and (n,m) was determined without considering hypothetical homodesmotic reactions. The calculated difference between the strain energy of carbon nanobelts and their possible precursors is expected to be of great utility for future synthetic purposes. PMID- 26953498 TI - Prevalence of Pterygia in Hawaii: Examining Cumulative Surfing Hours as a Risk Factor. AB - PURPOSE: To examine the association between surfing and pterygium prevalence in Hawaii. METHODS: A convenience sampling was performed at four beaches on the island of Oahu, Hawaii. A total of 169 individuals were interviewed and underwent penlight examination to assess grade and extent of pterygium. RESULTS: Of 169 participants aged 18-80 years, 88 non-surfers, 41 occasional surfers, 15 recreational surfers and 25 surfing enthusiasts were identified based on their lifetime surfing hours. Overall, 19 participants were found to have pterygia (28 pterygia total) including two non-surfers (2.3%), five occasional surfers (12.2%), three recreational surfers (20.0%), and nine enthusiast surfers (36.0%). Variables associated with pterygium prevalence were lifetime surfing hours (p < 0.0001), outdoor occupation (p = 0.04), Hawaiian residence (p = 0.009), and Hawaiian/Pacific Islander ethnicity (p = 0.002). Multiple logistic regression with the outcome of pterygium was performed, along with multiple linear regression for the continuous outcomes of corneal extent, chord length, and apex visual axis gap, with lifetime surfing hours as the primary explanatory variable. After adjustment for confounders, a significant linear relationship was observed between chord length and lifetime surfing hours (p = 0.01). CONCLUSION: Surfing was associated with an increased pterygium prevalence and trend towards an association with increased pterygium severity. Increased risk of exposure to wind, particle irritation, and ultraviolet (UV) radiation while surfing may contribute to pterygium development. Implications for public health include promoting UV protective eyewear during surfing, in addition to raising awareness about the association of pterygia and the sport of surfing. PMID- 26953499 TI - Versatile Polymer-Free Graphene Transfer Method and Applications. AB - A new method for transferring chemical vapor deposition (CVD)-grown monolayer graphene to a variety of substrates is described. The method makes use of an organic/aqueous biphasic configuration, avoiding the use of any polymeric materials that can cause severe contamination problems. The graphene-coated copper foil sample (on which graphene was grown) sits at the interface between hexane and an aqueous etching solution of ammonium persulfate to remove the copper. With the aid of an Si/SiO2 substrate, the graphene layer is then transferred to a second hexane/water interface to remove etching products. From this new location, CVD graphene is readily transferred to arbitrary substrates, including three-dimensional architectures as represented by atomic force microscopy (AFM) tips and transmission electron microscopy (TEM) grids. Graphene produces a conformal layer on AFM tips, to the very end, allowing easy production of tips for conductive AFM imaging. Graphene transferred to copper TEM grids provides large-area, highly electron-transparent substrates for TEM imaging. These substrates can also be used as working electrodes for electrochemistry and high-resolution wetting studies. By using scanning electrochemical cell microscopy, it is possible to make electrochemical and wetting measurements at either a freestanding graphene film or a copper-supported graphene area and readily determine any differences in behavior. PMID- 26953500 TI - Time related changes of T1, T2, and T2(*)(2) of human blood in vitro. AB - In view of a potential future use for dating hemorrhage in forensic medicine the correlation of MR relaxation parameters with time was evaluated in blood samples. A systematic relationship could be valuable for using MRI for estimating the age of hemorrhage and soft tissue hematomas particularly in clinical forensic medicine. Relaxation times T1, T2, and T2(*) of venous blood samples from 6 volunteers were measured using 3T MRI regularly up to 30 days. The time progression of the relaxation parameters was systematically analyzed and examined for possible interrelations. T2 initially decreased to a minimum, and then increased again (range 24-97ms), while T1 started with a plateau phase followed by an almost linear decrease (range 333-2153ms). T2(*) remained relatively constant during the entire investigation period. The higher the initial T2 was, the lower was its minimum, and the greater was the decrease of the associated T1. The inter- and intra-individual variability was relatively large, one reason being very likely the metabolic differences in the blood samples. The observed characteristic changes in blood samples over time measured by quantitative MR techniques add objective information in view of an estimation of the age of hemorrhage. However, in vivo studies will be needed to verify the data with respect to influencing metabolic factors. PMID- 26953501 TI - Direct evidence of allele equivalency at the Dlx5/6 locus. AB - The retention of paralogous regulatory genes is a vertebrate hallmark and likely underpinned vertebrate origins. Dlx genes belong to a family of paralogous transcription factors whose evolutionary history of gene expansion and divergence is apparent from the gene synteny, shared exon-intron structure, and coding sequence homology found in extant vertebrate genomes. Dlx genes are expressed in a nested combination within the first pharyngeal arch and knockout studies in mice clearly point to a "Dlx code" that operates to define maxillary and mandibular position in the first arch. The nature of that code is not yet clear; an important goal for understanding Dlx gene function in both patterning and differentiation lies in distinguishing functional inputs that are paralog specific (a qualitative model) versus Dlx family-generic (a quantitative model) and, in the latter case, the relative contribution made by each paralog. Here, multiple developmental deficiencies were identified in derivatives of the first pharyngeal arch in neonatal Dlx5/6(+/-) mice that resembled those seen in either paralog-specific null mutants. These data clearly demonstrate a substantial degree of allele equivalency and support a quantitative model of Dlx function during craniofacial morphogenesis. genesis 54:272-276, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26953502 TI - Borderline Personality Disorder Diagnostic Criteria as Risk Factors for Suicidal Behavior Through the Lens of the Interpersonal Theory of Suicide. AB - Borderline personality disorder diagnostic criteria, particularly affective dysregulation and behavioral dysregulation, are avenues through which suicide risk is conferred, though pathways are not well understood. The interpersonal theory of suicide may help elucidate these associations. The current study examined indirect relationships between affective and behavioral dysregulation and suicidal ideation through perceived burdensomeness, thwarted belongingness, and the acquired capability for suicide. 169 outpatients completed measures prior to their intake assessment. Perceived burdensomeness accounted for the relationship between affective dysregulation and suicidal ideation. The acquired capability did not explain the association between behavioral dysregulation and suicide attempt history. Affective and behavioral dysregulation may be key targets in treatment for reducing suicide risk. PMID- 26953504 TI - Cerebellar haemangioblastoma discovered incidentally on (68)Ga-DOTA-octreotate examination. PMID- 26953503 TI - Conformational Dynamics of the Human Islet Amyloid Polypeptide in a Membrane Environment: Toward the Aggregation Prone Form. AB - Human islet amyloid polypeptide (hIAPP) is a 37-residue peptide hormone, which upon misfolding changes from the physiologically active monomer into pathological amyloid fibril aggregates in the pancreas of type 2 diabetes mellitus patients. During this process, the insulin-producing pancreatic beta-cells are damaged; however, the underlying mechanism of this mode of cytotoxicity remains elusive. It is known that anionic lipids accelerate amyloid fibril formation, implicating the importance of the cellular membrane in the process, and that a pH close to the level in the beta-cell secretory granules (pH 5.5) inhibits amyloid fibril formation. Using all-atom molecular dynamics simulations, we have investigated the membrane-associated monomer state of alpha-helical hIAPP, analyzed specific interactions of hIAPP with a mixed anionic-zwitterionic lipid membrane and examined the influence of pH on the structure and dynamics of hIAPP and its interaction with the membrane. We find that hIAPP primarily interacts with the membrane by forming favorable interactions between anionic lipids and the positively charged residues in the N-terminal part of the peptide. Rationalizing experimental findings, the simulations show that the N-terminal part of the peptide interacts with the membrane in the lipid headgroup region. At neutral pH, the C-terminal part of the peptide, which contains the residues that initiate fibril formation, displays a highly dynamic, unfolded state, which interacts with the membrane significantly less than the N-terminal part. Such an unfolded form can be proposed to contribute to the acceleration of fibril formation. At low pH, protonation of His18 mediates a stronger interaction of the C-terminal part with the membrane, resulting in the immobilization of the C-terminal part on the membrane surface that might constitute a mechanism by which low pH inhibits fibril formation. PMID- 26953505 TI - Cyclic Head Rotations Produce Modest Brain Injury in Infant Piglets. AB - Repetitive back-and-forth head rotation from vigorous shaking is purported to be a central mechanism responsible for diffuse white matter injury, subdural hemorrhage, and retinal hemorrhage in some cases of abusive head trauma (AHT) in young children. Although animal studies have identified mechanisms of traumatic brain injury (TBI) associated with single rapid head acceleration-decelerations at levels experienced in a motor vehicle crash, few experimental studies have investigated TBI from repetitive head rotations. The objective of this study was to systematically investigate the post-injury pathological time-course after cyclic, low-velocity head rotations in the piglet and compare them with single head rotations. Injury metrics were the occurrence and extent of axonal injury (AI), extra-axial hemorrhage (EAH), red cell neuronal/axonal change (RCNAC), and ocular injury (OI). Hyperflexion/extension of the neck were purposefully avoided in the study, resulting in unscaled angular accelerations at the lower end of reported infant surrogate shaking kinematics. All findings were at the mild end of the injury spectrum, with no significant findings at 6 h post-injury. Cyclic head rotations, however, produced modest AI that significantly increased with time post-injury (p < 0.035) and had significantly greater amounts of RCNAC and EAH than noncyclic head rotations after 24 h post-injury (p < 0.05). No OI was observed. Future studies should investigate the contributions of additional physiological and mechanical features associated with AHT (e.g., hyperflexion/extension, increased intracranial pressure from crying or thoracic compression, and more than two cyclic episodes) to enhance our understanding of the causality between proposed mechanistic factors and AHT in infants. PMID- 26953506 TI - The specific role of plastidial glycolysis in photosynthetic and heterotrophic cells under scrutiny through the study of glyceraldehyde-3-phosphate dehydrogenase. AB - The cellular compartmentalization of metabolic processes is an important feature in plants where the same pathways could be simultaneously active in different compartments. Plant glycolysis occurs in the cytosol and plastids of green and non-green cells in which the requirements of energy and precursors may be completely different. Because of this, the relevance of plastidial glycolysis could be very different depending on the cell type. In the associated study, we investigated the function of plastidial glycolysis in photosynthetic and heterotrophic cells by specifically driving the expression of plastidial glyceraldehyde-3-phosphate dehydrogenase (GAPCp) in a glyceraldehyde-3-phosphate dehydrogenase double mutant background (gapcp1gapcp2). We showed that GAPCp is not functionally significant in photosynthetic cells, while it plays a crucial function in heterotrophic cells. We also showed that (i) GAPCp activity expression in root tips is necessary for primary root growth, (ii) its expression in heterotrophic cells of aerial parts and roots is necessary for plant growth and development, and (iii) GAPCp is an important metabolic connector of carbon and nitrogen metabolism through the phosphorylated pathway of serine biosynthesis (PPSB). We discuss here the role that this pathway could play in the control of plant growth and development. PMID- 26953507 TI - Chilenopeptins A and B, Peptaibols from the Chilean Sepedonium aff. chalcipori KSH 883. AB - The Chilean Sepedonium aff. chalcipori strain KSH 883, isolated from the endemic Boletus loyo Philippi, was studied in a polythetic approach based on chemical, molecular, and biological data. A taxonomic study of the strain using molecular data of the ITS, EF1-alpha, and RPB2 barcoding genes confirmed the position of the isolated strain within the S. chalcipori clade, but also suggested the separation of this clade into three different species. Two new linear 15-residue peptaibols, named chilenopeptins A (1) and B (2), together with the known peptaibols tylopeptins A (3) and B (4) were isolated from the semisolid culture of strain KSH 883. The structures of 1 and 2 were elucidated on the basis of HRESIMS(n) experiments in conjunction with comprehensive 1D and 2D NMR analysis. Thus, the sequence of chilenopeptin A (1) was identified as Ac-Aib(1)-Ser(2) Trp(3)-Aib(4)-Pro(5)-Leu(6)-Aib(7)-Aib(8)-Gln(9)-Aib(10)-Aib(11)-Gln(12)-Aib(13) Leu(14)-Pheol(15), while chilenopeptin B (2) differs from 1 by the replacement of Trp(3) by Phe(3). Additionally, the total synthesis of 1 and 2 was accomplished by a solid-phase approach, confirming the absolute configuration of all chiral amino acids as l. Both the chilenopeptins (1 and 2) and tylopeptins (3 and 4) were evaluated for their potential to inhibit the growth of phytopathogenic organisms. PMID- 26953508 TI - Spontaneous Coronary Artery Dissection: Recognition, Triage, and Management in the Emergency Department. PMID- 26953509 TI - Ultrasound-Guided Peripheral Venous Catheterization in Emergency Services. PMID- 26953510 TI - Accuracy in ED Triage for Symptoms of Acute Myocardial Infarction. AB - More than 6 million people present to emergency departments across the United States annually with symptoms of acute myocardial infarction (AMI). Of the 1 million patients with AMI, 350,000 die during the acute phase. Accurate ED triage can reduce mortality and morbidity, yet accuracy rates are low. In this study we explored the relationship between patient and nurse characteristics and accuracy of triage in patients with symptoms of AMI. METHODS: This retrospective, descriptive study used patient data from electronic medical records. The sample of 286 patients was primarily white, with a mean age of 61.44 years (standard deviation [SD], +/-13.02), and no history of heart disease. The sample of triage nurses was primarily white and female, with a mean age of 45.46 years (SD, +/ 11.72) and 18 years of nursing experience. Nineteen percent of the nurses reported having earned a bachelor's degree. RESULTS: Emergency nurse triage accuracy was 54%. Patient race and presence of chest pain were significant predictors of accuracy. Emergency nurse age was a significant predictor of accuracy in triage, but years of experience in nursing was not a significant predictor. DISCUSSION: Of the 9 variables investigated, only patient race, symptom presentation, and emergency nurse age were significant predictors of triage accuracy. Inconsistency in triage decisions may be due to other conditions not yet explored, such as critical thinking skills and executive functions. This study adds to the body of evidence regarding ED triage of patients with symptoms of AMI. However, further exploration into decisions at triage is warranted to improve accuracy, expedite care, and improve outcomes. PMID- 26953512 TI - A 62-Year-Old Man with Home Oxygen Therapy Facial Burns. PMID- 26953511 TI - Improved Administration of Antibiotics in the Emergency Department: A Practice Improvement Project. AB - PROBLEM: Although consensus exists among experts that early intravenous antibiotic therapy has an impact on patient mortality, the medical literature includes little information about ensuring that the patient receives the complete dose. At our emergency department, it had become standard clinical practice to administer antibiotics with primary pump tubing and an infusion pump. Clinical pharmacy staff identified this practice as a cause for concern, because at least 20 mL (up to 40%) of the dose volume remains in the tubing. This practice improvement project was aimed at improving the administration of antibiotics by programming a secondary infusion to ensure the complete dose would be administered. METHODS: A multidisciplinary educational intervention was initiated consisting of one-on-one instruction with each emergency nurse (n = 103) at the department's annual Skills Sessions, distribution of educational tip sheets, and reinforcement of the proper procedure at the patient's bedside. Emergency nurses were educated via simulation regarding correct secondary pump programming, using smart pump technology. RESULTS: Surveys indicated that 8% of emergency nurses used secondary tubing along with a smart pump to administer antibiotics before the intervention, compared with 96% after the intervention (P < .0001). IMPLICATIONS FOR PRACTICE: This project demonstrates that our educational intervention improved awareness of the need to administer the entire antibiotic dose and adherence to the use of secondary tubing along with smart pump technology to administer antibiotics. PMID- 26953513 TI - An Older Adult with Headache and Visual Blurring. PMID- 26953514 TI - Thermally Induced Charge Reversal of Layer-by-Layer Assembled Single-Component Polymer Films. AB - Temperature can be harnessed to engineer unique properties for materials useful in various contexts and has been shown to affect the layer-by-layer (LbL) assembly of polymer thin films and cause physical changes in preassembled polymer thin films. Herein we demonstrate that exposure to relatively low temperatures (<= 100 degrees C) can induce physicochemical changes in cationic polymer thin films. The surface charge of polymer films containing primary and secondary amines reverses after heating (from positive to negative), and different characterization techniques are used to show that the change in surface charge is related to oxidation of the polymer that specifically occurs in the thin film state. This charge reversal allows for single-polymer LbL assembly to be performed with poly(allylamine) hydrochloride (PAH) through alternating heat/deposition steps. Furthermore, the negative charge induced by heating reduces the fouling and cell-association of PAH-coated planar and particulate substrates, respectively. This study highlights a unique property of thin films which is relevant to LbL assembly and biofouling and is of interest for the future development of thin polymer films for biomedical systems. PMID- 26953516 TI - Light-Induced Acid Generation on a Gatekeeper for Smart Nitric Oxide Delivery. AB - We report herein the design of a light-responsive gatekeeper for smart nitric oxide (NO) delivery. The gatekeeper is composed of a pH-jump reagent as an intermediary of stimulus and a calcium phosphate (CaP) coating as a shielding layer for NO release. The light irradiation and subsequent acid generation are used as triggers for uncapping the gatekeeper and releasing NO. The acids generated from a light-activated pH-jump agent loaded in the mesoporous nanoparticles accelerated the degradation of the CaP-coating layers on the nanoparticles, facilitating the light-responsive NO release from diazeniumdiolate by exposing a NO donor to physiological conditions. Using the combination of the pH-jump reagent and CaP coating, we successfully developed a light-responsive gatekeeper system for spatiotemporal-controlled NO delivery. PMID- 26953515 TI - Recovery Curves for Pediatric Burn Survivors: Advances in Patient-Oriented Outcomes. AB - IMPORTANCE: Patient-reported outcomes serving as benchmarks for recovery of pediatric burn survivors are lacking, and new approaches using longitudinal cohorts for monitoring their expected recovery based on statistical models are needed for patient management during the early years following the burn. OBJECTIVE: To describe multidimensional patient-reported outcomes among pediatric burn survivors younger than 5 years to establish benchmarks using recovery curve methods. DESIGN, SETTING, AND PARTICIPANTS: Prospective cohort study of pediatric burn survivors younger than 5 years at 12 burn centers. Age-matched nonburned reference groups were studied to define expected results in normal growth and development. The Burn Outcomes Questionnaire for children aged 0 to 5 years (BOQ0 5) was administered to parents of children who had burns and were younger than 5 years. Mixed models were used to generate 48-month recovery curves for each of the 10 BOQ0-5 domains. The study was conducted between January 1999 and December 2008. MAIN OUTCOMES AND MEASURES: The 10 BOQ0-5 domains including play, language, fine motor skills, gross motor skills, emotional behavior, family functioning, pain/itching, appearance, satisfaction with care, and worry/concern up to 48 months after burn injury. RESULTS: A total of 336 pediatric burn survivors younger than 5 years (mean [SD] age, 2.0 [1.2] years; 58.4% male; 60.2% white, 18.6% black, and 12.0% Hispanic) and 285 age-matched nonburned controls (mean [SD] age, 2.4 [1.3] years; 51.1% male; 67.1% white, 8.9% black, and 15.0% Hispanic) completed the study. Predicted scores improved exponentially over time for 5 of the BOQ0-5 domains (predicted scores at 1 month vs 24 months: play, 48.6 vs 52.1 [P = .03]; language, 49.2 vs 54.4 [P < .001]; gross motor skills, 48.7 vs 53.0 [P = .002]; pain/itching, 15.8 vs 33.5 [P < .001]; and worry/concern, 31.6 vs 44.9 [P < .001]). Pediatric burn survivors had higher scores in language, emotional behavior, and family functioning domains compared with healthy children in later months. CONCLUSIONS AND RELEVANCE: This study demonstrates significant deficits in multiple functional domains across pediatric burn survivors compared with controls. Recovery curves can be used to recognize deviation from the expected course and tailor care to patient needs. PMID- 26953517 TI - A Novel Mechanism of Immune Memory Unveiled at the Invertebrate-Parasite Interface. AB - Pinaud et al. recently provided the first global investigation of the molecular processes underlying innate immune memory in an invertebrate species. They showed that the memory response of the snail Biomphalaria glabrata to Schistosoma mansoni infection is associated with a shift from cellular to humoral mechanisms. PMID- 26953519 TI - Shape dynamics of growing cell walls. AB - We introduce a general theoretical framework to study the shape dynamics of actively growing and remodeling surfaces. Using this framework we develop a physical model for growing bacterial cell walls and study the interplay of cell shape with the dynamics of growth and constriction. The model allows us to derive constraints on cell wall mechanical energy based on the observed dynamics of cell shape. We predict that exponential growth in cell size requires a constant amount of cell wall energy to be dissipated per unit volume. We use the model to understand and contrast growth in bacteria with different shapes such as spherical, ellipsoidal, cylindrical and toroidal morphologies. Coupling growth to cell wall constriction, we predict a discontinuous shape transformation, from partial constriction to cell division, as a function of the chemical potential driving cell wall synthesis. Our model for cell wall energy and shape dynamics relates growth kinetics with cell geometry, and provides a unified framework to describe the interplay between shape, growth and division in bacterial cells. PMID- 26953520 TI - Globally symmetric topological phase: from anyonic symmetry to twist defect. AB - Topological phases in two dimensions support anyonic quasiparticle excitations that obey neither bosonic nor fermionic statistics. These anyon structures often carry global symmetries that relate distinct anyons with similar fusion and statistical properties. Anyonic symmetries associate topological defects or fluxes in topological phases. As the symmetries are global and static, these extrinsic defects are semiclassical objects that behave disparately from conventional quantum anyons. Remarkably, even when the topological states supporting them are Abelian, they are generically non-Abelian and powerful enough for topological quantum computation. In this article, I review the most recent theoretical developments on symmetries and defects in topological phases. PMID- 26953518 TI - Evolution of serum hyaluronan and syndecan levels in prognosis of sepsis patients. AB - OBJECTIVES: Endothelial glycocalyx shedding has been recognized as a contributor in sepsis pathophysiology. Hence, we attempted to analyze hyaluronan and syndecan (glycocalyx components) as markers of morbidity and prognosis of sepsis by performing serial measurements in these patients. DESIGN AND METHODS: Subjects were community acquired sepsis, severe sepsis and septic shock patients (150) admitted to ICU of our tertiary care hospital and controls were 50 healthy volunteers. Serum concentrations of markers were measured on days 1, 3, 5, 7 of ICU admission. Survival was assessed after 90days. Statistical analysis was performed by SPSS version 17. RESULTS: Hyaluronan and syndecan levels were significantly elevated in all categories of sepsis patients as compared to healthy controls (p<0.001). Levels of both markers were increased in severe sepsis and septic shock patients as compared to sepsis patient group at all time points. Hyaluronan and syndecan differentiated survivors from non-survivors (p<0.001). Unlike non-survivors, in the survivor group, median hyaluronan and syndecan levels decreased significantly (p<0.001) in subsequent measurements. ROC analysis for the prediction of mortality identified cut-offs of 441ng/ml and 898ng/ml for hyaluronan and syndecan respectively. The specificity and negative predictive values were 90% and 90% for hyaluronan and 86% and 91% for syndecan respectively. Kaplan Meier curves revealed similar results. Both markers correlated significantly with APACHE II and SOFA scores. CONCLUSIONS: These observations indicate that serial measurements of hyaluronan and syndecan are significant prognostic markers for morbidity and survival in sepsis. Future therapeutic interventional possibilities need to be explored in experimental interventional prospective multi-centric trials. PMID- 26953521 TI - Magnetic Exchange Couplings in Heterodinuclear Complexes Based on Differential Local Spin Rotations. AB - We analyze the performance of a new method for the calculation of magnetic exchange coupling parameters for the particular case of heterodinuclear transition metals complexes of Cu, Ni, and V. This method is based on a generalized perturbative approach which uses differential local spin rotations via formal Lagrange multipiers (Phillips, J. J.; Peralta, J. E. J. Chem. Phys. 2013, 138, 174115). The reliability of the calculated couplings has been assessed by comparing with results from traditional energy differences with different density functional approximations and with experimental values. Our results show that this method to calculate magnetic exchange couplings can be reliably used for heteronuclear transition metal complexes, and at the same time, that it is independent from the different mapping schemes used in energy difference methods. PMID- 26953522 TI - Molecular systematics of the wood-inhabiting, lichen-forming genus Xylographa (Baeomycetales, Ostropomycetidae) with eight new species. AB - The ascomycete genus Xylographa includes some of the most abundant species of wood-inhabiting lichenized fungi in boreal and temperate regions. It has never been monographed and little is known of its species diversity and evolutionary relationships. Based on a morphological and secondary metabolite-based assessment of material from North and South America, Europe and Asia, we generated a three locus phylogeny based on sequences of the internal transcribed spacer, 28S nuclear rDNA and mitochondrial small subunit rDNA. We analyzed the data within the context of putatively related genera in the order Baeomycetales. Xylographa is a strongly supported monophyletic group closely related to Lithographa and Ptychographa, as well as rock-dwelling and lichenicolous species of Rimularia s.lat. The evolution of linearized ascomata in Xylographa appears to have enabled ascomata to grow laterally, and patterns of lateral growth are diagnostic. We recognize twenty species in Xylographa and provide a thorough revision of nomenclature. The following eight species are new: Xylographa bjoerkii T. Sprib., X. constricta T. Sprib., X. erratica T. Sprib., X. lagoi T. Sprib. & Perez Ortega, X. schofieldii T. Sprib., X. septentrionalis T. Sprib., X. stenospora T. Sprib. & Resl and X. vermicularis T. Sprib. The combinations Lambiella insularis (Nyl.) T. Sprib. and Xylographa carneopallida (Rasanen) T. Sprib. are newly proposed. Xylographa constricta from southern South America represents the first known case of secondary de-lichenization in the Baeomycetales. Xylographa parallela s.str. is confirmed as bipolar on the basis of sequenced collections from both southern Chile and the northern Hemisphere. PMID- 26953523 TI - Vitamin D During Pregnancy and Multiple Sclerosis: An Evolving Association. PMID- 26953525 TI - Identification and detoxification of glycolaldehyde, an unattended bioethanol fermentation inhibitor. AB - Although there have been approximately 60 chemical compounds identified as potent fermentation inhibitors in lignocellulose hydrolysate, our research group recently discovered glycolaldehyde as a key fermentation inhibitor during second generation biofuel production. Accordingly, we have developed a yeast S. cerevisiae strain exhibiting tolerance to glycolaldehyde. During this glycolaldehyde study, we established novel approaches for rational engineering of inhibitor-tolerant S. cerevisiae strains, including engineering redox cofactors and engineering the SUMOylation pathway. These new technical dimensions provide a novel platform for engineering S. cerevisiae strains to overcome one of the key barriers for industrialization of lignocellulosic ethanol production. As such, this review discusses novel biochemical insight of glycolaldehyde in the context of the biofuel industry. PMID- 26953524 TI - CCor: A whole genome network-based similarity measure between two genes. AB - Measuring the similarity between genes is often the starting point for building gene regulatory networks. Most similarity measures used in practice only consider pairwise information with a few also consider network structure. Although theoretical properties of pairwise measures are well understood in the statistics literature, little is known about their statistical properties of those similarity measures based on network structure. In this article, we consider a new whole genome network-based similarity measure, called CCor, that makes use of information of all the genes in the network. We derive a concentration inequality of CCor and compare it with the commonly used Pearson correlation coefficient for inferring network modules. Both theoretical analysis and real data example demonstrate the advantages of CCor over existing measures for inferring gene modules. PMID- 26953526 TI - New coumarin derivatives from Ferula pseudalliacea with antibacterial activity. AB - In this study, the antibacterial activity of disesquiterpene coumarin and sesquiterpene coumarins obtained from Ferula pseudalliacea roots was evaluated by determination of minimum inhibitory concentration using the broth micro-dilution method against seven pathogenic bacterial strains (Staphylococcus aureus ATCC 25,923, vancomycin resistant clinical strain of Enterococcus faecium, Bacillus cereus PTCC 1015, Escherichia coli ATCC 25,922, Pseudomonas aeruginosa PTCC 1430, clinical strain of Klebsiella pneumoniae and a clinical strain of Helicobacter pylori). The overall inhibitory activities of the compounds were higher against Gram positive tested bacteria. Sanandajin and ethyl galbanate demonstrated significant activity against H. pylori strain, as well as S. aureus strain in concentration of 64 MUg/ml. Methyl galbanate inhibited vancomycin resistant strain of E. faecium in concentration of 64 MUg/ml. The results of the present investigation indicated that disesquiterpene and sesquiterpene coumarins isolated from F. pseudalliacea root extract can be considered as potent antibacterial agents for pharmaceutical and food industries. PMID- 26953527 TI - Reviewing the controversy surrounding pre-treatment with P2Y12 inhibitors in acute coronary syndrome patients. AB - Pretreatment with oral P2Y12 inhibitors occurs each time clopidogrel, prasugrel, ticagrelor are given to patients with suspected coronary artery disease before definition of the coronary anatomy. In acute coronary syndromes, the practice of administering oral P2Y12 inhibitors upstream has been the object of significant controversy in recent years, following the publication of two trials of pretreatment in non-ST-segment elevation acute coronary syndromes and ST-segment elevation myocardial infarction, respectively. The introduction in the market of cangrelor - the first intravenous P2Y12 inhibitor - represents a new opportunity but also a new challenge for clinicians. This article reviews current recommendations and supporting evidence surrounding pretreatment with oral and intravenous P2Y12 inhibitors in patients with acute coronary syndromes. PMID- 26953529 TI - Prioritizing and Making Time. PMID- 26953530 TI - What Motivates You? PMID- 26953531 TI - Trauma Nurses' Experience of Workplace Violence and Threats: Short- and Long-Term Consequences in a Swedish Setting. AB - Violence in health care is increasing globally and Sweden is no exception. Still, this topic is sparsely studied in the Swedish trauma care setting. This focus group study examined nurses' experience of violence and threats, and their consequences. The content analysis revealed two main categories, threatening situations and consequences, which led to a change in priorities in nursing care in order to avoid a potential violent situation. Furthermore, negative stress among the staff and greater vigilance and unwillingness to be near the patient resulted in altered communication and, in the end, a decreased quality of nursing care. PMID- 26953532 TI - Implementation of a Post-Code Pause: Extending Post-Event Debriefing to Include Silence. AB - This project arose out of a need to address two issues at our hospital: we lacked a formal debriefing process for code/trauma events and the emergency department wanted to address the psychological and spiritual needs of code/trauma responders. We developed a debriefing process for code/trauma events that intentionally included mechanisms to facilitate recognition, acknowledgment, and, when needed, responses to the psychological and spiritual needs of responders. A post-code pause process was implemented in the emergency department with the aims of standardizing a debriefing process, encouraging a supportive team-based culture, improving transition back to "normal" activities after responding to code/trauma events, and providing responders an opportunity to express reverence for patients involved in code/trauma events. The post-code pause process incorporates a moment of silence and the addition of two simple questions to a traditional operational debrief. Implementation of post-code pauses was feasible despite the fast paced nature of the department. At the end of the 1-year pilot period, staff members reported increases in feeling supported by peers and leaders, their ability to pay homage to patients, and having time to regroup prior to returning to their assignment. There was a decrease in the number of respondents reporting having thoughts or feelings associated with the event within 24 hr. The pauses create a mechanism for operational team debriefing, provide an opportunity for staff members to honor their work and their patients, and support an environment in which the psychological and spiritual effects of responding to code/trauma events can be acknowledged. PMID- 26953528 TI - The emerging role of GATA transcription factors in development and disease. AB - The GATA family of transcription factors consists of six proteins (GATA1-6) which are involved in a variety of physiological and pathological processes. GATA1/2/3 are required for differentiation of mesoderm and ectoderm-derived tissues, including the haematopoietic and central nervous system. GATA4/5/6 are implicated in development and differentiation of endoderm- and mesoderm-derived tissues such as induction of differentiation of embryonic stem cells, cardiovascular embryogenesis and guidance of epithelial cell differentiation in the adult. PMID- 26953533 TI - Distracted Biking: An Observational Study. AB - Commuting via bicycle is a very popular mode of transportation in the Northeastern United States. Boston, MA, has seen a rapid increase in bicycle ridership over the past decade, which has raised concerns and awareness about bicycle safety. An emerging topic in this field is distracted bicycle riding. This study was conducted to provide descriptive data on the prevalence and type of distracted bicycling in Boston at different times of day. This was a cross sectional study in which observers tallied bicyclists at 4 high traffic intersections in Boston during various peak commuting hours for 2 types of distractions: auditory (earbuds/phones in or on ears), and visual/tactile (electronic device or other object in hand). Nineteen hundred seventy-four bicyclists were observed and 615 (31.2%), 95% CI [29, 33%], were distracted. Of those observed, auditory distractions were the most common (N = 349; 17.7%), 95% CI [16, 19], p = .0003, followed by visual/tactile distractions (N = 266; 13.5%), 95% CI [12, 15]. The highest proportion (40.7%), 95% CI [35, 46], of distracted bicyclists was observed during the midday commute (between 13:30 and 15:00). Distracted bicycling is a prevalent safety concern in the city of Boston, as almost a third of all bicyclists exhibited distracted behavior. Education and public awareness campaigns should be designed to decrease distracted bicycling behaviors and promote bicycle safety in Boston. An awareness of the prevalence of distracted biking can be utilized to promote bicycle safety campaigns dedicated to decreasing distracted bicycling and to provide a baseline against which improvements can be measured. PMID- 26953534 TI - Advanced Practitioners Are Peers in Trauma Performance Improvement Peer Review. AB - Advanced practitioners (APs) have been successfully integrated into the clinical care of injured patients. Given the expanding role of APs in trauma care, we hypothesized that APs can perform Performance Improvement and Patient Safety (PIPS) peer review at a level comparable with trauma surgeons. For Phase 1, cases previously reviewed by a trauma surgeon were randomly selected by the PIPS coordinator and peer reviewed by an AP. The trauma surgeons' and APs' reviews were compared. For Phase 2, cases requiring concurrent review were peer reviewed by both an AP and an MD, who were blinded to each other's review. Both the APs' and trauma surgeons' reviews of the same medical record were presented at a bimonthly performance improvement (PI) meeting. In Phase 1, 46 PI cases were reviewed including 22 deaths. Trauma surgeons and APs had high concordance (96.0%) regarding appropriateness or inappropriateness of care (kappa = 0.774). Among disagreements, APs were 3 times more likely than trauma surgeons to determine care to be inappropriate. Trauma surgeons and APs had similarly high concordance (95.5%) regarding preventability of mortality (kappa = 0.861). In Phase 2, 38 PI cases were reviewed, including 31 deaths. Trauma surgeons and APs had high concordance (89.0%) regarding appropriateness or inappropriateness of care (kappa = 0.585). Among disagreements, trauma surgeons and APs had similarly high concordance (86.2%) regarding preventability of mortality (kappa = 0.266). We found that APs had high concordance with trauma surgeons regarding medical record reviews and are thus able to effectively review medical records for the purposes of PIPS. PMID- 26953535 TI - Increased Screening for Child Physical Abuse in Emergency Departments in a Regional Trauma System: Response to a Sentinel Event. AB - A pediatric patient was assaulted while being treated at a Level 1 pediatric trauma center, prompting a Centers for Medicare & Medicaid Services site visit. The process of screening for physical abuse and protection of patients was reevaluated and revised, and a new guideline was implemented and shared with referral hospitals. During this same time period, 13 referral hospitals participated in an unrelated federally funded study determining the impact of recognition and care of injured children in states with and without a pediatric emergency care facility recognition program. A pre-post study analysis revealed that screening for abuse doubled during this time period. PMID- 26953536 TI - Core Team Members' Impact on Outcomes and Process Improvement in the Initial Resuscitation of Trauma Patients. AB - Genesis Trauma Center is an American College of Surgeons-The Committee on Trauma verified Level III facility located in Southeastern Ohio. Process improvement and patient safety showed inconsistencies in trauma documentation and comfort level of the nursing staff. In February 2014, Genesis implemented a trauma nurse leader program to provide a core team of trauma nurses for the initial resuscitation. The overall goal of implementing a trauma nurse leader (TNL) program was to focus education on a core team, providing an increased level of skill of experience to oversee trauma patient care. The TNL program has shown promise in the pilot phase by decreasing emergency department length of stay and improving trauma documentation. PMID- 26953537 TI - Association of Prehospital Shock Index and Trauma Bay Uncrossmatched Red Blood Cell Transfusion With Multiple Transfusion. AB - Early resuscitation of bleeding trauma patients with multiple blood products improves outcome, yet transfusion initiation is not standardized. Shock index (heart rate/systolic blood pressure) and trauma bay uncrossmatched red blood cell (RBC) transfusion were evaluated for association with multiple transfusions, defined as 6 or more RBCs during the first 6 hrs of hospital presentation. A prehospital shock index of 1 was significantly associated with multiple transfusions (p = .02). Subjects receiving uncrossmatched RBCs required more RBCs during the first 6 hrs (10.3 units, p < .01). Consideration of these simple variables may help trauma nurses anticipate the potentially bleeding patient. PMID- 26953538 TI - The History and Evolution of the Trauma Program Manager/Coordinator. AB - The role of the trauma program manager (TPM) has evolved since the early 1980s. Duties of TPM historically included broad responsibilities such as education, data collection, system, EMS, clinical activities, research, and quality assurance. The purpose of this study was to use survey sampling to evaluate self perceived functions and scope of work of TPMs in the United States. Results show that TPMs from higher volume centers spend more time on program administration duties whereas TPMs from lower volume centers focus more on registry and clinical duties. Across time, the role has been expanded, refined, and customized, but much role variability remains. PMID- 26953539 TI - Impact of Alcohol on Outcomes in Hospitalized Major Trauma Patients: A Literature Review. AB - To critically appraise available studies investigating the impact of alcohol outcomes in hospitalized patients after major trauma. Outcomes included injury severity, mortality, complications, and hospital/intensive care length of stay. Data were sourced from MEDLINE, CINAHL, and SCOPUS databases. Abstracts were screened for inclusion/exclusion criteria with 15 articles appraised and analyzed based on in-hospital outcomes. Although alcohol intoxication is associated with a marginal increase in the incidence of in-hospital complications (sepsis and multiorgan failure), overall studies suggest it is not associated with longer intensive care or in-hospital length of stay. This literature review also demonstrated decreased mortality and injury severity in patients with traumatic brain injury. Further research is required to determine the reasons for these associations. PMID- 26953542 TI - Laser therapies for onychomycosis - critical evaluation of methods and effectiveness. AB - The number of medical devices designed specifically to treat onychomycosis has recently increased, although their mechanism of action is not clear. We evaluated available laser therapies for onychomycosis by reviewing the existing literature. Twenty-two reports, published in peer-reviewed journals and as white papers out of 926 initial search results conveyed enough details to be included in this study. In most cases, the methodology of the trials described in the papers we reviewed was not comprehensive and the reporting of outcomes was not unified. We therefore found it hard to compare different clinical trials to one another. The majority of studies (81.82%) reported using an Nd:YAG laser device to treat onychomycosis. A total of 47.37% of the studies which used a 1064 device (and 47.83% of all studies we reviewed) reported that all treated patients responded positively to laser therapy. A total of 60% of studies reported achieving a complete cure (no clinical symptoms, nor negative mycology) in at least 50% of the treated patients. A low number of adverse events and their mild intensity were consistently reported across all studies, which makes this form of therapy particularly attractive to patients with contraindications for receiving systemic antifungal medication. In order to achieve more unified, comparable studies in the future, we suggest that researchers report a minimum set of outcome measurements: the calculation of the infected nail area pre- and posttreatment, as well as the number of patients achieving mycological, clinical and complete cures. PMID- 26953544 TI - [The Male Brain]. PMID- 26953543 TI - Aided Electrophysiology Using Direct Audio Input: Effects of Amplification and Absolute Signal Level. AB - PURPOSE: This study investigated (a) the effect of amplification on cortical auditory evoked potentials (CAEPs) at different signal levels when signal-to noise ratios (SNRs) were equated between unaided and aided conditions, and (b) the effect of absolute signal level on aided CAEPs when SNR was held constant. METHOD: CAEPs were recorded from 13 young adults with normal hearing. A 1000-Hz pure tone was presented in unaided and aided conditions with a linear analog hearing aid. Direct audio input was used, allowing recorded hearing aid noise floor to be added to unaided conditions to equate SNRs between conditions. An additional stimulus was created through scaling the noise floor to study the effect of signal level. RESULTS: Amplification resulted in delayed N1 and P2 peak latencies relative to the unaided condition. An effect of absolute signal level (when SNR was constant) was present for aided CAEP area measures, such that larger area measures were found at higher levels. CONCLUSION: Results of this study further demonstrate that factors in addition to SNR must also be considered before CAEPs can be used to clinically to measure aided thresholds. PMID- 26953545 TI - [Influence of Depressive Symptoms on Group Therapeutic Psychoeducational Intervention in Psychiatric Patient Groups of Mixed Diagnosis]. AB - OBJECTIVE: To analyse the extent of influence of depressive symptoms on the efficiency of group therapeutic psychoeducative intervention in psychiatric patients groups with mixed diagnoses, independently of the primary diagnosis. METHODS: 34 psychiatric inpatients with different diagnoses were allocated to two groups according to the severity of their depressive symptoms. After the psychoeducational group intervention, patients were asked about several parameters concerning the effectiveness of the intervention. RESULTS: Patients suffering from pronounced depressive symptoms seem to benefit less from the intervention. CONCLUSIONS: Psychoeducational intervention is less effective in patients with severe symptoms of depression. This should be taken into consideration concerning the time point when patients should be integrated in such a group, as well as concerning the intensity of the intervention itself. PMID- 26953546 TI - [Cognitive Behavioral Therapy and Assertive Community Treatment Reduces Days in Hospital and Delays Hospital Admission in Severe Psychotic Disorders]. AB - The primary aim of this study was to assess the effectiveness of integrated home treatment (IV, i. e. intensive cognitive behavioral therapy and pharmacotherapy provided within a framework of assertive community treatment) in individuals with severe mental disorders (n = 13) within the German healthcare system. A treatment as-usual group (TAU, n = 13) was identified by propensity score matching. Symptoms (CGI), functioning (GAF) and service engagement (SES) were assessed. Quality of life (MSLQ-R) was rated by the IV patients. A reduction of days spent in hospital [IV: 2.3 (6.1); TAU: 33.6 (53.6); Z = 45; p = 0.044], time to admission (IV: 384 days 95% CI 309 - 459.1; TAU: 234.9 days 95% CI 127.2 - 342.5; log rank: Chi-square = 4.31, p < 0.05), severity of the illness (p < 0.01), positive symptoms (p < 0.001), and cognitive symptoms (p < 0.05), as well as functioning (p < 0.05) and service engagement (p < 0.05) was observed in IV patients. Despite differences on a descriptive level, differences in total admissions (IV: 15.3%; TAU: 53.8%; odds ratio = 0.155, 95% CI 0.0243 - 1.00) were not significant. A methodological limitation is that symptom ratings were not performed by independent and blinded raters. PMID- 26953548 TI - [Neurofeedback in the Treatment of Anorexia Nervosa: a Case Report]. AB - Anorexia nervosa has been related to alterations in brain activity in terms of hyperactive EEG patterns. This case report illustrates the principles and results of a five-week neurofeedback treatment in a 29-year-old woman suffering from anorexia nervosa. A neurofeedback protocol to enhance alpha activity (8 - 12 Hz) was developed and conducted additionally to the standardized treatment for eating disorders in training sessions twice a week. Pre- and post-test measurements included resting state EEG measurements and a psychological test battery. The results show improvements from pre- to post-test in eating disorder psychopathology including psychological wellbeing, emotional competence, and eating behavior traits. In addition, a decrease in theta power (4 - 7 Hz), a well known trait marker of anorexia nervosa, was measured. However, our data should be interpreted with caution because this is a single case study. Nevertheless, this report documents the practicability and method of neurofeedback as treatment adjunct in eating disorders from the clinical perspective. Although the use of neurofeedback in the treatment of anorexia nervosa is recommended in literature, empirical studies are still lacking. Randomized controlled trials to evaluate short- and long-term effects of neurofeedback are needed. PMID- 26953547 TI - [Comparison of Two Symptom-Triggered Treatments for Alcohol Withdrawal: HAES vs. SAB-P]. AB - INTRODUCTION: For alcohol withdrawal during hospitalization, often a medication as means for withdrawal needs to be chosen. Modern, score-controlled processes that can be used by the nursing staff after instruction by physicians are frequently not used and even unknown in hospitals. One reason for this is that some of the scores require checking several criteria and are therefore more time consuming and complicated than use of a fixed-dosage strategy. The SAB-P and HAES are short with only 6 items that can be checked by the nursing staff. METHODS: Safety of the Hamburg Alcohol Withdrawal Scale (Hamburger Alkoholentzugs-Skala (HAES)) was analyzed retrospectively and prospectively with regard to score controlled alcohol-withdrawal treatment after rating by the nurse staff (Scoregesteuerte Alkoholentzugsbehandlung nach Rating durch das Pflegepersonal (SAB-P)). RESULTS: Incidence of complications in patients treated with SAB-P and HAES was nearly similar with 1% start of delirium and 3% seizures (SAB-P) and 0.5 to 1.5% start of delirium and 0 to 0.5% seizures in the HAES group. With both scales it was possible to start medical treatment while still under falling alcohol levels (0.93 and 0.91%, respectively). Medication dosage was initially higher using the HAES, so that the time needed to monitor withdrawal symptoms could be reduced (3.8 vs. 3.1 days). DISCUSSION: Using a score-controlled strategy for alcohol withdrawal leads to a lower complication rate than found in literature. The structured procedure was helpful for the nursing staff as well as for the physicians. SAB-P as well as HAES made withdrawal for the patients more comfortable and led to fewer complaints. Because of rapid reaction and faster symptom reduction of HAES, there was less time necessary for monitoring. Simple handling, clomethiazol, oxazepam or diazepam as applicable medication and clear documentation are the advantages of HAES. PMID- 26953549 TI - [Not Available]. PMID- 26953550 TI - [Not Available]. PMID- 26953551 TI - [Neurological Disorders and Pregnancy]. AB - Neurological disorders caused by pregnancy and puerperium include the posterior reversible encephalopathy syndrome, the amniotic fluid embolism syndrome (AFES), the postpartum angiopathy due to reversible vasoconstriction syndrome, and the Sheehan syndrome. Hypertension and proteinuria are the hallmarks of preeclampsia, seizures define eclampsia. Hemolysis, elevated liver enzymes and low platelets constitute the HELLP syndrome. Vision disturbances including cortical blindness occur in the posterior reversible encephalopathy syndrome (PRES). The Sheehan syndrome presents with panhypopituitarism post partum due to apoplexia of the pituitary gland in severe peripartal blood loss leading to longstanding hypotension. Some neurological disorders occur during pregnancy and puerperium with an increased frequency. These include stroke, sinus thrombosis, the restless legs syndrome and peripheral nerve syndromes, especially the carpal tunnel syndrome. Chronic neurologic diseases need an interdisciplinary approach during pregnancy. Some anticonvulsants double the risk of birth defects. The highest risk exists for valproic acid, the lowest for lamotrigine and levetiracetam. For MS interval treatment, glatiramer acetate and interferones seem to be safe during pregnancy. All other drugs should be avoided. PMID- 26953552 TI - Silencing of USP22 suppresses high glucose-induced apoptosis, ROS production and inflammation in podocytes. AB - Ubiquitin-specific protease 22 (USP22) has been reported to mediate various cellular processes, including cell proliferation and apoptosis. However, its role in high glucose-induced podocytes and diabetic rats remains unknown. In the current study, podocytes were treated with different concentrations of d-glucose to establish a high glucose-induced injury model. Additionally, intravenous tail injection of rats with 65 mg kg(-1) of streptozotocin (STZ) was performed to establish a diabetic rat model. Our findings showed that the treatment of podocytes with high d-glucose significantly increased the USP22 expression level. Silencing of USP22 in podocytes attenuated high d-glucose-induced apoptosis and inflammatory responses, evidenced by increases in proliferation and MMP levels and decreases in the apoptotic rate, ROS production, the Bax/Bcl-2 ratio, caspase 3 expression and secretion of TNF-alpha, IL-1beta, IL-6 and TGF-beta1. In addition, podocytes with USP22 overexpression significantly enhanced the effect of high d-glucose-induced apoptosis and inflammatory responses. Similar to the protective effect of USP22 knockdown, resveratrol (RSV) depressed not only high d glucose- and USP22 overexpression-induced cytotoxicity, but also the secretion of TNF-alpha, IL-1beta, IL-6 and TGF-beta1. Notably, silencing of USP22 in diabetic rats conferred a similar protective effect against high glucose-induced apoptosis and inflammation. Taken together, the findings of the present study have demonstrated for the first time that USP22 inhibition attenuates high glucose induced podocyte injuries and inflammation. PMID- 26953553 TI - Parameter Reproducibility in Photobiomodulation. PMID- 26953554 TI - Risk Factors for Reoperation After Photoselective Vaporization of the Prostate Using a 120 W GreenLight High Performance System Laser for the Treatment of Benign Prostatic Hyperplasia. AB - OBJECTIVE: We investigated risk factors in a large cohort of patients who underwent reoperation after photoselective vaporization of the prostate using the 120 W GreenLight High Performance System laser for treatment of benign prostatic hyperplasia. BACKGROUND DATA: Complications such as recurrent/residual adenoma, urethral stricture, or bladder neck might occur after photoselective vaporization of the prostate for treatment of benign prostatic hyperplasia. MATERIALS AND METHODS: We reviewed the data of 1040 patients who underwent photoselective vaporization of the prostate between April 2009 and December 2014, and analyzed the clinical data of 630 patients who completed >12 months of follow-up. Patients were evaluated for perioperative and late complications. Reoperation was defined as the necessity for any surgical intervention to resolve recurrent/residual adenoma, urethral stricture, or bladder neck contracture. Patients with recurrent/residual adenoma, urethral stricture, or bladder neck contracture were compared with those without complications to identify the risk factors for reoperation. Logistic regression analysis was conducted to estimate the risk of reoperation. RESULTS: Reoperation was performed in 25 of 630 patients (3.9%) at 35.5 months mean follow-up: 12 had recurrent/residual adenoma, 5 had urethral stricture, and 8 had bladder neck contracture. Multivariate analysis revealed that a higher prostate-specific antigen (PSA) (OR, 1.129; p = 0.023) and longer lasing time (OR, 0.883; p = 0.024) were predictors of recurrent/residual adenoma. Urethral stricture was associated with a history of transurethral surgery (OR, 1.321; p = 0.042). Preoperative small prostate volume was a risk factor for bladder neck contracture (OR, 0.901; p = 0.011). CONCLUSIONS: In our study, the significant factors related to recurrent/residual adenoma were a high preoperative PSA and longer lasing time. A history of transurethral surgery was significantly associated with urethral stricture, whereas preoperative small prostate volume was significantly associated with bladder neck contracture. PMID- 26953556 TI - Retraction of: Effects of Photobiomodulation Therapy on Patients with Primary Open Angle Glaucoma: A Pilot Study (DOI: 10.1089/pho.2015.3944). PMID- 26953555 TI - A New Approach in the Treatment of Keloids: UVA-1 Laser. AB - Keloids are scars that grow beyond the boundaries of a cutaneous injury, inflammation, surgical incision, or burn. They are the result of an overgrowth of dense fibrous tissue that usually develops after healing of a skin injury, and do not usually regress spontaneously. In addition to symptomatic relief, cosmetic concern is the primary reason patients seek medical intervention. Therapeutic options such as occlusion dressings, intralesional corticosteroids or interferon injections, silicone gel application, cryotherapy, irradiation, and ablative lasers have been used in various combinations. We present the results from two patients who underwent UVA1 laser therapy. PMID- 26953560 TI - Strabismus Following Scleral Buckling Surgery. AB - PURPOSE: To assess the incidence of strabismus, relationship of strabismus with type and width of scleral buckle after scleral buckling surgery for retinal detachment. METHODS: Retrospective analysis was done of 360 eyes of 344 patients treated for rhegmatogenous retinal detachment with scleral buckling surgery between January 2008 and January 2013. RESULTS: The mean age of patients was 38.45 +/- 18.12 years (range: 7 to 89 years). Strabismus was detected in 48 out of 344 (13.95%) patients at 6 weeks after scleral buckling surgery. Horizontal deviation was the commonest type. Incidence of strabismus was higher after repeat scleral buckling surgery (4/9, 44.4%) compared to patients who had single scleral buckling surgery (44/335, 13.1%) (P=0.02). Strabismus was observed in 18.5% of patients with implants, compared to 11.3% of patients who received explants (P=0.02). Strabismus surgery was performed on 2 (4.1%) cases. CONCLUSION: Horizontal strabismus is common after scleral buckling surgery for repair of retinal detachment. Repeat scleral buckling and use of implants resulted in a higher incidence of strabismus in the postoperative period. Majority of these cases resolve with conservative management. PMID- 26953557 TI - Decreased physical activity, reduced QoL and presence of debilitating fatigue in patients with Addison's disease. AB - BACKGROUND: Health-related quality of life in patients with Addison's disease has been assessed in various European countries, indicating a reduced quality of life. However, no studies have addressed the impact of Addison's disease on physical activity. OBJECTIVE: The aim of this study was to investigate the quality of life in Dutch patients with Addison's disease particularly regarding the presence of fatigue and the ability to be physically active. METHODS: In this cross-sectional study, a postal survey was performed among Dutch patients with Addison's disease on stable glucocorticoid replacement therapy with hydrocortisone or cortisone acetate. For quality of life and physical activity assessment, patients completed general and health-related quality of life and physical activity questionnaires, and scores were compared to Dutch controls. RESULTS: A total of 328 patients with Addison's disease were studied. In patients with Addison's disease, only 45.7% met the standard of physical activity (Combinorm) compared to 67.8% of Dutch controls (P < 0.01). Forty-eight per cent of patients showed abnormal fatigue, while 61% had severe fatigue. The CIS fatigue scores were significantly higher compared to controls (P < 0.01). We found reduced general subjective health-related QoL scores in both male and female patients, especially in younger patients <65 years of age. CONCLUSION: Physical activity is decreased in patients with Addison's disease, combined with a reduced subjective health-related QoL and increased fatigue. PMID- 26953562 TI - Decoding the Morphological Diversity in Two Dimensional Crystalline Porous Polymers by Core Planarity Modulation. AB - Two new chemically stable triazine- and phenyl-core-based crystalline porous polymers (CPPs) have been synthesized using a single-step template-free solvothermal route. Unique morphological diversities were observed for these CPPs [2,3-DhaTta (ribbon) and 2,3-DhaTab (hollow sphere)] by simply altering the linker planarity. A detailed time-dependent study established a significant correlation between the molecular level structures of building blocks with the morphology of CPPs. Moreover, a DFT study was done for calculating the interlayer stacking energy, which revealed that the extent of stacking efficiency is responsible for governing the morphological diversity in these CPPs. PMID- 26953561 TI - Mitochondria in pluripotent stem cells: stemness regulators and disease targets. AB - Beyond their canonical role in efficient ATP production through oxidative metabolism, mitochondria are increasingly recognized as critical in defining stem cell function and fate. Implicating a fundamental interplay within the epigenetics of eukaryotic cell systems, the integrity of mitochondria is found vital across the developmental/differentiation spectrum from securing pluripotency maintenance to informing organotypic decisions. This overview will discuss recent progress on examining the plasticity of mitochondria in enabling the execution of programming and reprogramming regimens, as well as the application of nuclear reprogramming and somatic cell nuclear transfer as rescue techniques to generate genetically and functionally corrected pluripotent stem cells from patients with mitochondrial DNA-based disease. PMID- 26953563 TI - Gait analysis in children with haemophilia: first Italian experience at the Turin Haemophilia Centre. AB - AIM: To investigate the functional status in haemophilia patients referred to an Italian paediatric haemophilia centre using gait analysis, verifying any differences between mild, moderate or severe haemophilia at a functional level. METHODS: Forty-two patients (age 4-18) presenting to the Turin Paediatric Haemophilia Centre who could walk independently were included. Therapy included prophylaxis (n = 21), on-demand (n = 17) or immune tolerance induction + inhibitor (n = 4). Patients performed a test of gait analysis. Temporal, spatial and kinematic parameters were calculated for patient subgroups by disease severity and background treatment, and compared with normal values. RESULTS: Moderate (35.7%) or severe (64.3%) haemophilia patients showed obvious variations from normal across a variety of temporal and spatial gait analysis parameters, including step speed and length, double support, swing phase, load asymmetry, stance phase, swing phase and speed. Kinematic parameters were characterized by frequent foot external rotation with deficient plantar flexion during the stance phase, retropelvic tilt, impaired power generation distally and reduced ground reaction forces. Both Gait Deviation Index and Gait Profile Score values for severe haemophilia patients indicated abnormal gait parameters, which were worst in patients with a history of past or current use of inhibitors and those receiving on-demand therapy. CONCLUSION: Functional evaluation identified changes in gait pattern in patients with severe and moderate haemophilia, compared with normal values. Gait analysis may be a useful tool to facilitate early diagnosis of joint damage, prevent haemophilic arthropathy, design a personalized rehabilitative treatment and monitor functional status over time. PMID- 26953564 TI - High Levels of Gadolinium Deposition in the Skin of a Patient With Normal Renal Function. AB - OBJECTIVE: The aim of this study was to assess gadolinium deposition in the skin of a patient with normal renal function, based on estimated glomerular filtration rate values greater than 59 mL/min/1.73 m(2) after exposure to large cumulative doses of gadolinium-based contrast agents (GBCAs). MATERIALS AND METHODS: The patient underwent 61 contrasted brain MRI scans over the course of 11 years. Skin biopsies from the forearm and lower extremity were analyzed with inductively coupled plasma mass spectrometry (ICP-MS), laser ablation ICP-MS, and hydrophilic interaction liquid chromatography ICP-MS. RESULTS: The ICP-MS demonstrated high levels of gadolinium deposition (14.5 +/- 0.4 MUg/g), similar to previously reported gadolinium levels within the skin of patients with nephrogenic systemic fibrosis. The laser ablation ICP-MS demonstrated deposition of gadolinium within the deep layers of skin. Speciation analysis using hydrophilic interaction liquid chromatography ICP-MS demonstrated the presence of intact gadolinium-chelate species, although most of the gadolinium present could not be further characterized. Light microscopy demonstrated increased CD34 immunoreactivity in the connective tissue septations of the subcutaneous adipose tissue. The patient had no history of skin disorders and did not have a history of nephrogenic systemic fibrosis but did have severe joint contractures of unknown etiology. CONCLUSIONS: Our results, in contradiction to published literature, suggest that in patients with normal renal function, exposure to GBCAs in extremely high cumulative doses can lead to significant gadolinium deposition in the skin. This finding is in line with more recent reports of gadolinium deposition in the brain of patients with normal renal function. Future studies are required to address possible clinical consequences of gadolinium deposition in the skin, brain, and potentially other organs in patients with normal renal function. We recommend, in addition to following current US Food and Drug Administration and American College of Radiology guidelines based on estimated glomerular filtration rate values, that caution be used when administering large cumulative doses of GBCAs and that total cumulative dose of each agent administered is recorded in the patient's medical record. PMID- 26953565 TI - Comprehensive Comparison of Virtual Monoenergetic and Linearly Blended Reconstruction Techniques in Third-Generation Dual-Source Dual-Energy Computed Tomography Angiography of the Thorax and Abdomen. AB - OBJECTIVES: The aim of this study was to perform an objective and subjective image analysis of traditional and advanced noise-optimized virtual monoenergetic imaging (VMI) algorithms and standard linearly blended images in third-generation dual-source dual-energy computed tomography angiography (DE-CTA) of the thorax and abdomen. MATERIALS AND METHODS: Thoracoabdominal DE-CTA examinations of 55 patients (36 male; mean age, 64.2 +/- 12.7 years) were included in this retrospective institutional review board-approved study. Dual-energy computed tomography angiography data were reconstructed using standard linearly blended M_0.6 (merging 60% low kiloelectron volt [90 kV] with 40% high kiloelectron volt [150 kV] spectrum), traditional (VMI), and advanced VMI (VMI+) algorithms. Monoenergetic series were calculated ranging from 40 to 120 keV with 10 keV increments. Attenuation and standard deviation of 8 arteries and various anatomical landmarks of the thorax and abdomen were measured to calculate contrast-to-noise ratio values. Two radiologists subjectively assessed image quality, contrast conditions, noise, and visualization of small arterial branches using 5-point Likert scales. RESULTS: Vascular attenuation of VMI and VMI+ series showed a gradual increase from high to low kiloelectron volt levels without significant differences between both algorithms (P < 0.894). VMI+ 40-keV series showed the highest contrast-to-noise ratio for both thoracic and abdominal DE-CTA (P < 0.001), albeit revealing higher noise than M_0.6 images (objectively and subjectively, P < 0.001) and were rated best for visualization of small arterial branches in the subjective analysis (P < 0.109). Substantially increased noise was found for VMI 40 and 50 keV series compared with all other reconstructions (objectively and subjectively, P < 0.001). VMI+ images at 100 keV+ were rated best regarding image noise (P < 0.843), whereas VMI+ reconstructions at 70 keV were found to have superior subjective image quality (P < 0.031) compared with other series except for 60 and 80 keV VMI+ series (P < 0.587). Contrast conditions at 50 keV VMI+ were rated superior compared with 60 to 100 keV VMI and VMI+ reconstructions (P < 0.012). CONCLUSIONS: General image quality of DE-CTA examinations can be substantially improved using the VMI+ algorithm with observer preference of 70 keV, while 40 to 50 keV series provide superior contrast and improved visualization of small arterial branches compared with traditional VMI and standard linearly blended series. PMID- 26953566 TI - "Debriefing-on-Demand": A Pilot Assessment of Using a "Pause Button" in Medical Simulation. AB - INTRODUCTION: Simulation is an effective tool in medical education with debriefing as the cardinal educational component. Alternate debriefing strategies might further enhance the educational value of simulation. Here, we pilot a novel strategy that allows trainees to initiate debriefing at any point during the scenario, when they consider it necessary. METHODS: With ethics approval, 8 postgraduate year 1 anesthesia residents (with no previous exposure to high fidelity simulation) were randomly assigned to lead 2 of 8 scenarios with 2 debriefing strategies. With "debriefing-on-demand," residents had the option to initiate debriefing at any point in the scenario by activation of a "pause button"-in addition to undergoing conventional debriefing at the end of the scenario. Those randomized to "conventional debriefing" were debriefed only at the end of the scenario. All were allocated as team leader with both debriefing strategies and as a participant in remaining scenarios. Residents provided feedback regarding each method using Likert scales and completion of open-ended statements. RESULTS: Debriefing-on-demand was easily integrated into all scenarios, and most learners (88%) supported its use in future simulation sessions. The following 4 themes emerged from qualitative analyses: (1) improvements in the clarification and integration of knowledge, (2) reductions in stress/anxiety, (3) facilitated reflection on action, and (4) maintained realism comparable with conventional debriefing. CONCLUSIONS: Debriefing-on-demand was easily integrated into all scenarios and well received by these trainees new to simulation. Larger trials that use validated tools are needed to determine the absolute impact of debriefing-on-demand on stress levels and the overall learning value of simulation for trainees at different levels of training. PMID- 26953567 TI - Increased Levels of Interleukin-33 and Thymic Stromal Lymphopoietin in Exhaled Breath Condensate in Chronic Bronchial Asthma. AB - BACKGROUND: Epithelium-derived cytokines such as thymic stromal lymphopoietin (TSLP), interleukin (IL)-25, and IL-33 are important contributors to inflammation in asthma. Exhaled breath condensate (EBC) is a noninvasive method used to assess the inflammation of airways. Our aim was to assess the levels of TSLP, IL-25, IL 33, and its receptor ST2l/IL-1 R4 in EBC in patients with asthma and to correlate these with serum levels and asthma control. METHODS: EBC and serum levels of TSLP, IL-25, IL-33, and ST2l/IL-1 R4 were measured in 44 patients with chronic bronchial asthma (14 in the uncontrolled phase) and 19 healthy control participants. RESULTS: EBC levels of IL-33 and TSLP and serum levels of IL-33 were statistically higher in patients with asthma than in controls. IL-25 and ST2l/IL-1 R4 were present in EBC at barely detectable levels and were not analyzed. The EBC and serum levels of all studied mediators did not differ between controlled and uncontrolled asthma patients, except for the serum level of ST2l/IL-1 R4, which was higher in uncontrolled asthma. There were no correlations between serum and EBC levels of TSLP and IL-33 or between either serum and EBC levels and the forced expiratory volume in 1 s or the total IgE level. CONCLUSIONS: Higher levels of IL-33 and TSLP in EBC provide evidence supporting a role for these mediators in asthma. Their levels do not discriminate between controlled and uncontrolled asthma. The local reaction within the epithelium is independent of the systemic reaction. PMID- 26953568 TI - Stoichiometry and Change of the mRNA Closed-Loop Factors as Translating Ribosomes Transit from Initiation to Elongation. AB - Protein synthesis is a highly efficient process and is under exacting control. Yet, the actual abundance of translation factors present in translating complexes and how these abundances change during the transit of a ribosome across an mRNA remains unknown. Using analytical ultracentrifugation with fluorescent detection we have determined the stoichiometry of the closed-loop translation factors for translating ribosomes. A variety of pools of translating polysomes and monosomes were identified, each containing different abundances of the closed-loop factors eIF4E, eIF4G, and PAB1 and that of the translational repressor, SBP1. We establish that closed-loop factors eIF4E/eIF4G dissociated both as ribosomes transited polyadenylated mRNA from initiation to elongation and as translation changed from the polysomal to monosomal state prior to cessation of translation. eIF4G was found to particularly dissociate from polyadenylated mRNA as polysomes moved to the monosomal state, suggesting an active role for translational repressors in this process. Consistent with this suggestion, translating complexes generally did not simultaneously contain eIF4E/eIF4G and SBP1, implying mutual exclusivity in such complexes. For substantially deadenylated mRNA, however, a second type of closed-loop structure was identified that contained just eIF4E and eIF4G. More than one eIF4G molecule per polysome appeared to be present in these complexes, supporting the importance of eIF4G interactions with the mRNA independent of PAB1. These latter closed-loop structures, which were particularly stable in polysomes, may be playing specific roles in both normal and disease states for specific mRNA that are deadenylated and/or lacking PAB1. These analyses establish a dynamic snapshot of molecular abundance changes during ribosomal transit across an mRNA in what are likely to be critical targets of regulation. PMID- 26953570 TI - Implied Spatial Meaning and Visuospatial Bias: Conceptual Processing Influences Processing of Visual Targets and Distractors. AB - Concepts with implicit spatial meaning (e.g., "hat", "boots") can bias visual attention in space. This result is typically found in experiments with a single visual target per trial, which can appear at one of two locations (e.g., above vs. below). Furthermore, the interaction is typically found in the form of speeded responses to targets appearing at the compatible location (e.g., faster responses to a target above fixation, after reading "hat"). It has been argued that these concept-space interactions could also result from experimentally induced associations between the binary set of locations and the conceptual categories with upward and downward meaning. Thus, rather than reflecting a conceptually driven spatial bias, the effect could reflect a benefit for compatible cue-target sequences that occurs only after target onset. We addressed these concerns by going beyond a binary set of locations and employing a search display consisting of four items (above, below, left, and right). Within each search trial, before performing a visual search task, participants performed a conceptual task involving concepts with implicit upward or downward meaning. The search display, in addition to including a target, could also include a salient distractor. Assuming a conceptually driven visual bias, we expected to observe, first, a benefit for target processing at the compatible location and, second, an increase in the cost of the salient distractor. The findings confirmed both predictions, suggesting that concepts do indeed generate a spatial bias. Finally, results from a control experiment, without the conceptual task, suggest the presence of an axis-specific effect, in addition to the location-specific effect, suggesting that concepts might cause both location-specific and axis-specific spatial bias. Taken together, our findings provide additional support for the involvement of spatial processing in conceptual understanding. PMID- 26953571 TI - Correction: Assessment of the Geographic Distribution of Ornithodoros turicata (Argasidae): Climate Variation and Host Diversity. PMID- 26953572 TI - The Association of Anger with Symptom Subtypes in Severe Obsessive-Compulsive Disorder Outpatients. AB - BACKGROUND: Despite the theoretical and clinical relevance of psychopathological dimensions in obsessive-compulsive disorder (OCD), no studies to date have investigated their possible association with obsession subtypes. Thus, we aimed to examine whether, in OCD patients, anger and other psychopathological dimensions are associated with specific obsession subtypes. METHODS: We consecutively recruited 57 first-visit OCD patients (66.7% female, mean age 34 years) at our Psychiatric Outpatient Clinic. We used the point biserial coefficient (rpbi) to measure the correlation between psychopathological dimensions and obsession subtypes. RESULTS: We found significant correlations (p < 0.05) between the following: (1) anger/aggressiveness dimension and aggressive, contamination, and sexual obsessions; (2) apprehension/fear dimension and contamination, religious, and somatic obsessions; (3) sadness/demoralization dimension and contamination and somatic obsessions; (4) impulsivity dimension and aggressive and sexual obsessions, and (5) somatic concern/somatization dimension and contamination and somatic obsessions. We also found that OCD patients with comorbid obsessive-compulsive personality disorder--but not schizotypal or histrionic disorders--showed higher levels (p < 0.05) of obsessiveness/iterativity and anger/aggressiveness than OCD patients without the personality disorder. CONCLUSIONS: Anger and other psychopathological dimensions seem to be linked with specific obsession subtypes in OCD patients, suggesting an association between these dimensions and OCD. PMID- 26953569 TI - Tissue-Specific Suppression of Thyroid Hormone Signaling in Various Mouse Models of Aging. AB - DNA damage contributes to the process of aging, as underscored by premature aging syndromes caused by defective DNA repair. Thyroid state changes during aging, but underlying mechanisms remain elusive. Since thyroid hormone (TH) is a key regulator of metabolism, changes in TH signaling have widespread effects. Here, we reveal a significant common transcriptomic signature in livers from hypothyroid mice, DNA repair-deficient mice with severe (Csbm/m/Xpa-/-) or intermediate (Ercc1-/Delta-7) progeria and naturally aged mice. A strong induction of TH-inactivating deiodinase D3 and decrease of TH-activating D1 activities are observed in Csbm/m/Xpa-/- livers. Similar findings are noticed in Ercc1-/Delta-7, in naturally aged animals and in wild-type mice exposed to a chronic subtoxic dose of DNA-damaging agents. In contrast, TH signaling in muscle, heart and brain appears unaltered. These data show a strong suppression of TH signaling in specific peripheral organs in premature and normal aging, probably lowering metabolism, while other tissues appear to preserve metabolism. D3-mediated TH inactivation is unexpected, given its expression mainly in fetal tissues. Our studies highlight the importance of DNA damage as the underlying mechanism of changes in thyroid state. Tissue-specific regulation of deiodinase activities, ensuring diminished TH signaling, may contribute importantly to the protective metabolic response in aging. PMID- 26953573 TI - A Landmark-Free Method for Three-Dimensional Shape Analysis. AB - BACKGROUND: The tools and techniques used in morphometrics have always aimed to transform the physical shape of an object into a concise set of numerical data for mathematical analysis. The advent of landmark-based morphometrics opened new avenues of research, but these methods are not without drawbacks. The time investment required of trained individuals to accurately landmark a data set is significant, and the reliance on readily-identifiable physical features can hamper research efforts. This is especially true of those investigating smooth or featureless surfaces. METHODS: In this paper, we present a new method to perform this transformation for data obtained from high-resolution scanning technology. This method uses surface scans, instead of landmarks, to calculate a shape difference metric analogous to Procrustes distance and perform superimposition. This is accomplished by building upon and extending the Iterative Closest Point algorithm. We also explore some new ways this data can be used; for example, we can calculate an averaged surface directly and visualize point-wise shape information over this surface. Finally, we briefly demonstrate this method on a set of primate skulls and compare the results of the new methodology with traditional geometric morphometric analysis. PMID- 26953575 TI - Natural mineral bottled waters available on the Polish market as a source of minerals for the consumers. Part 1. Calcium and magnesium. AB - BACKGROUND: Natural mineral waters may be an essential source of calcium, magnesium and other minerals. In bottled waters, minerals occur in an ionized form which is very well digestible. However, the concentration of minerals in underground waters (which constitute the material for the production of bottled waters) varies. In view of the above, the type of water consumed is essential. OBJECTIVE: The aim of the study was to estimate the calcium and magnesium contents in products available on the market and to evaluate calcium and magnesium consumption with natural mineral water by different consumer groups with an assumed volume of the consumed product. MATERIAL AND METHODS: These represented forty different brands of natural mineral available waters on Polish market. These waters were produced in Poland or other European countries. Among the studied products, about 30% of the waters were imported from Lithuania, Latvia, Czech Republic, France, Italy and Germany. The content of calcium and magnesium in mineral waters was determined using flame atomic absorption spectrometry in an acetylene-air flame. Further determinations were carried out using atomic absorption spectrometer--ICE 3000 SERIES-THERMO-England, equipped with a GLITE data station, background correction (a deuterium lamp) as well as other cathode lamps. RESULTS: Over half of the analysed natural mineral waters were medium-mineralized. The natural mineral waters available on the market can be characterized by a varied content of calcium and magnesium and a high degree of product mineralization does not guarantee significant amounts of these components. Among the natural mineral waters available on the market, only a few feature the optimum calcium-magnesium proportion (2:1). Considering the mineralization degree of the studied products, it can be stated that the largest percentage of products with significant calcium and magnesium contents can be found in the high-mineralized water group. CONCLUSIONS: For some natural mineral waters, the consumption of 1 litre daily may ensure the recommended intake levels of calcium and magnesium in some consumer groups to a considerable degree. For 1 3-year-old children it is recommended to consume less than 1 litre daily of natural mineral waters containing an excess of 700 mg of calcium and 80 mg of magnesium in 1 litre. PMID- 26953574 TI - Selection of Patients and Anesthetic Types for Endovascular Treatment in Acute Ischemic Stroke: A Meta-Analysis of Randomized Controlled Trials. AB - BACKGROUND: and Purpose Recent randomized controlled trials have demonstrated consistent effectiveness of endovascular treatment (EVT) for acute ischemic stroke, leading to update on stroke management guidelines. We conducted this meta analysis to assess the efficacy and safety of EVT overall and in subgroups stratified by age, baseline stroke severity, brain imaging feature, and anesthetic type. METHODS: Published randomized controlled trials comparing EVT and standard medical care alone were evaluated. The measured outcomes were 90-day functional independence (modified Rankin Scale <=2), all-cause mortality, and symptomatic intracranial hemorrhage. RESULTS: Nine trials enrolling 2476 patients were included (1338 EVT, 1138 standard medical care alone). For patients with large vessel occlusions confirmed by noninvasive vessel imaging, EVT yielded improved functional outcome (pooled odds ratio [OR], 2.02; 95% confidence interval [CI], 1.64-2.50), lower mortality (OR, 0.75; 95% CI, 0.58-0.97), and similar symptomatic intracranial hemorrhage rate (OR, 1.12; 95% CI, 0.72-1.76) compared with standard medical care. A higher proportion of functional independence was seen in patients with terminus intracranial artery occlusion (+/ M1) (OR, 3.16; 95% CI, 1.64-6.06), baseline Alberta Stroke Program Early CT score of 8-10 (OR, 2.11; 95% CI, 1.25-3.57) and age <=70 years (OR, 3.01; 95% CI, 1.73 5.24). EVT performed under conscious sedation had better functional outcomes (OR, 2.08; 95% CI, 1.47-2.96) without increased risk of symptomatic intracranial hemorrhage or short-term mortality compared with general anesthesia. CONCLUSIONS: Vessel-imaging proven large vessel occlusion, a favorable scan, and younger age are useful predictors to identify anterior circulation stroke patients who may benefit from EVT. Conscious sedation is feasible and safe in EVT based on available data. However, firm conclusion on the choice of anesthetic types should be drawn from more appropriate randomized controlled trials. PMID- 26953576 TI - Nutritional knowledge, diet quality and breast or lung cancer risk: a case control study of adults from Warmia and Mazury region in Poland. AB - BACKGROUND: Knowledge on proper nutrition favours the creation of pro-healthy nutritional behaviours of people. Studies related to the nutritional knowledge of adults, diet quality and incidence of breast or lung cancers are limited. OBJECTIVE: Analysis of the relationship between the level of nutritional knowledge, diet quality and risk of breast cancer in women or lung cancer in men from the Warmia and Mazury region in Poland. MATERIAL AND METHODS: The study was carried out in 202 subjects aged 23-80 years, including 107 women (17 cases of breast cancer) and 95 men (54 cases of lung cancer) from the Warmia and Mazury region in Poland. Nutritional knowledge was evaluated with the Questionnaire of Eating Behaviours (QEB), including 25 statements. Based on the frequency of the consumption of 16 food items, two diet quality indices were created: the pro Healthy-Diet-Index-8 (pHDI-8) and the non-Healthy-Diet-Index-8 (nHDI-8). The values of pHDI-8 and nHDI-8 were calculated on the basis of the sum of the daily frequency of consumption of the selected food items and expressed as times/day. The Odds Ratio (OR) of both breast cancer or lung cancer in relation to the level of nutritional knowledge was calculated based on a logistic regression analysis. RESULTS: The incidence of breast or lung cancer in the bottom, middle and upper tertile of nutritional knowledge was 57.6%, 32.6% and 15.8%, respectively. As nutritional knowledge grew in the subsequent tertiles, pHDI-8 was on the increase (2.63 vs. 3.78 vs. 4.22 times/day) and n-HDI-8 was on the decrease (1.32 vs. 1.21 vs. 0.94 times/day). In the upper tertile of nutritional knowledge, the Odds Ratio for the incidence of breast or lung cancers varied from 0.06 (95% CI: 0.02; 0.17; p<0.05, with adjustment for cancer type and age) to 0.17 (95% CI: 0.04; 0.69; p<0.05, with adjustment for age and sex) when compared to the bottom tertile (OR=1.00). In the middle tertile of nutritional knowledge, the Odds Ratio of both cancers varied from 0.27 (95% CI: 0.12; 0.62, p<0.05, with adjustment for cancer type and age) to 0.35 (95% CI: 0.18; 0.71, p<0.05, variables without adjustment) when compared to the bottom tertile. CONCLUSIONS: A higher level of nutritional knowledge was associated with the higher quality of a pro-healthy diet and lower risk of breast cancer in women or lung cancer in men. In contrast, a lower level of nutritional knowledge was associated with a lower diet quality and a higher risk of both types of cancers. PMID- 26953577 TI - Qualitative evaluation of diets of students at the University of the Third Age at Koszalin University of Technology. AB - BACKGROUND: Nutrition plays an important role in the elderly stage of life. A proper proportion of the individual nutritional ingredients in a diet may positively impact the ageing body. This positive influence consists in slowing down the undesired and unfavourable physiological alterations leading inevitably to the general weakness of the body. OBJECTIVE: The aim of the paper was to perform a qualitative analysis with the Starzynska scoring system for diets, the daily food rations (DFR), among students of the University of the Third Age at the Koszalin University of Technology (Poland). MATERIAL AND METHODS: The studied materials consisted of the 7-day current records made by 79 students (16 males and 63 females) of the University of the Third Age at the Koszalin University of Technology and the measurements of body weight, height and waistline. The records were qualitatively evaluated with Starzynska's test. RESULTS: It was found that approximately half of the students were overweight or obese. The majority consumed the recommended number of meals. About 44% of the students consumed animal protein with all meals. Milk and cheese were ingested daily with at least two meals by approximately 11% of the students. Fruit and vegetables are eaten on a daily basis by about 60% of the students. Almost 40% ate wholegrain bread, groats, and dried legumes. The statistical analysis of the means for the points of individual indicators did not reveal any statistically significant difference between women and men (p>0.05). CONCLUSIONS: Approximately 3/4 of the evaluated diets were inaccurately formulated and required radical modification. The low frequency of animal protein, milk and cheese, wholegrain bread, groats and dried legume consumption may result in deficiencies in certain nutrients. Nutritional education is recommended, focusing on the correct way to formulate meals. The recorded level of overweight and obesity in the students indicates a need for a quantitative assessment of consumption considering, among others, the energy input in their diets. PMID- 26953578 TI - Frequency of consumption of foods rich in calcium and vitamin D among school-age children. AB - BACKGROUND: Calcium is one of the most important minerals for the human body which is essential for healthy bones and teeth. Vitamin D has hormone-like properties in the human body. It is supplied with the diet, but it is also synthesized by the body under exposure to UV radiation. Vitamin D controls calcium and phosphorus metabolism and is responsible for bone modeling and mineralization. OBJECTIVE: The objective of this study was to evaluate eating habits and food preferences of school-age children meet the demand for calcium and vitamin D, and estimate the frequency of consumption of foods rich in these nutrients. MATERIAL AND METHODS: A total of 197 parents of 7- to 9-year-olds attending randomly selected primary schools in Lublin and Swidnik were asked to fill out a questionnaire designed by the authors. The results were processed by the Chi-squared test in the Excel application. RESULTS: Considerable differences in the consumption of milk and dairy products were observed between age groups. In the group of 7-year-olds, 57.5% of children drank milk and ate dairy products at least once a day, whereas in the group of 9-year-olds, only 16.6% of children ate dairy products at least once a day. The intake of foods rich in vitamin D was equally low among the surveyed children. CONCLUSIONS: School-age children may be at risk of calcium and vitamin D deficiencies due to low consumption of milk, dairy products and fish, and inadequate vitamin D supplementation. Parents should be educated about nutrition to change the family's eating habits. PMID- 26953579 TI - Association between general self-efficacy level and use of dietary supplements in the group of American football players. AB - BACKGROUND: Increased nutritional demands of athletes should be covered with a variable well-balanced diet, supported by dietary supplements stimulating synthesis of energy, development of muscle mass and strength, and improving physical capacity. OBJECTIVE: The aim of this study was to analyze an association between the level of general self-efficacy and dietary supplement use among Polish athletes practicing American football on a competitive basis. MATERIAL AND METHODS: The study included the group of 100 athletes (20-30 years of age, mean 24.27+/-2.76 years) who practiced American football on a competitive basis. The popularity of various dietary supplements was determined with an original survey, and the level of general self-efficacy with General Self-Efficacy Scale (GSES) by Schwarzer et al. Statistical analysis, conducted with Statistica 10.0 PL software, included intergroup comparisons with the Chi-square test. RESULTS: Isotonic drinks (74%), vitamin (65%) and mineral supplements (50%) and protein concentrates (53%) turned out to be the most popular ergogenic supplements among the American footballers. The group of less popular supplements included caffeine and/or guarana (44%), joint supporting supplements (40%), BCAA amino acids (39%), creatine (36%), carbohydrate concentrates (30%) and omega-3 fatty acids (30%). Analysis of a relationship between the popularity of ergogenic supplements and general self-efficacy showed that the athletes presenting with lower levels of this trait used multivitamin supplements significantly more often than did the persons characterized by lower self-efficacy levels (p<0.05). CONCLUSIONS: The popularity of some dietary supplements varied depending on the general self efficacy level of the athletes; the popularity of vitamins was significantly higher among the sportsmen who presented with lower levels of this trait. PMID- 26953580 TI - Relationship between diet and physical activity level in adolescents from post grammar schools. AB - INTRODUCTION: Appropriate diet and physical activity are vital determinants of psychophysical development in children and adolescents. OBJECTIVE: The aim of the study was to analyse an association between dietary habits and physical activity levels of adolescents from post-grammar schools. MATERIAL AND METHODS: The study included 110 girls and 65 boys between 16 and 19 years of age from two post grammar schools in Biala Podlaska in Poland. They were subjected to a diagnostic survey providing information on their diet (number of meals a day, their regularity, frequency of bread, dairy, meat, fish, sweet, fruit, vegetable and fast food consumption, preferred ways of food processing). Physical activity levels were determined with the International Physical Activity Questionnaire- Short Form (IPAQ-SF). Based on these data, the respondents were stratified to high, moderate and low physical activity groups. Due to small number of participants presenting with low physical activity levels, we did not include this group in further analyses. The significance of differences in the dietary habits of adolescents presenting with high and moderate physical activity levels was verified with the chi2 test. RESULTS: Most girls and boys presented with high levels of physical activity. However, we did not find an evident relationship between dietary habits and physical activity levels. Girls from high and moderate physical activity groups differed solely in terms of the number of daily meals, frequency of meat and sweet consumption, and significant intergroup differences observed among boys pertained to the frequencies of whole-wheat bread, meat and fast food consumption. The abovementioned food products were consumed more often by girls and boys presenting with high physical activity levels. CONCLUSIONS: The dietary mistakes observed in physically active adolescents from post-secondary schools justify intensification of their dietary education programs. PMID- 26953581 TI - Evaluation of selected dietary behaviours of students according to gender and nutritional knowledge. AB - INTRODUCTION: Nutrition is a factor influencing physical and mental fitness. In this study we examine the lifestyle of university students and its impact on nutritional errors. OBJECTIVE: To evaluate the dietary behaviours of students taking into account gender and nutritional knowledge. MATERIAL AND METHODS: Using a QEB questionnaire, we were able to evaluate dietary behaviours and nutritional knowledge of respondents. Our analysis was conducted on data obtained from 456 students. RESULTS: We found that nutritional knowledge for women was 34.7% satisfactory and 34.7% good. In contrast, nutritional knowledge for men varied, amounting to 40.2% satisfactory and 25.1% good. The number of meals and their regular consumption did not depend on gender or the nutritional knowledge of students, however, significant differences were recorded for the types of snacks they eat. A greater number of women than men snacked on sweets and biscuits, nuts and seeds, while in the case of salty snacks an opposite trend was observed. A higher level of nutritional knowledge correlated with the number of students snacking on fruit and vegetables instead of salty snacks. Moreover, it was observed that health-promoting behaviours such as not adding sugar to beverages and not adding salt to dishes were more common with women and individuals with a higher level of nutritional knowledge. CONCLUSIONS: Women more frequently snack on sweets, biscuits, nuts and seeds. More men snack on salty snacks, add sugar to beverages and add salt to dishes. Individuals with insufficient nutritional knowledge more frequently snack on salty snacks rather than fruit. Students with insufficient nutritional knowledge more often commit nutritional errors. PMID- 26953582 TI - Nutrition of students from dietetics profile education in the Siedlce University of Natural Sciences and Humanities compared with students from other academic centres. AB - BACKGROUND: Appropriate nutrition in humans is one of the most important factors affecting normal development, nutritional status and keeping healthy. University students can be overburdened with responsibilities arising from their studies which may result in abnormal diet/nutrition and decrease their levels of physical activity. OBJECTIVE: To determine and assess nutrition and eating habits for selected female students studying nutrition at the Siedlce University of Natural Sciences & Humanities (UPH), compared with young people from other academic centres also studying nutrition and having a similar education profile. MATERIAL AND METHODS: A diagnostic survey was undertaken anonymously on 100 female student subjects using a proprietary questionnaire. Students were undergraduates at the UPH during their 2nd and 3rd year. RESULTS: Dietetics students considered that the practical application of proper nutrition principles is very important. Nevertheless, 44% assessed themselves to follow abnormal diets; 58% declared they ate whole grains frequently whereas 58% and 65% respectively consumed fruit and vegetables daily. Dietary irregularities were identified, particularly in how often fish was eaten, where 46% either never ate fish or did so only occasionally. Subjects preferred lean cuts of poultry meat (65%), and the most common cooking practice was frying (52%). CONCLUSIONS: Subjects did not follow dietary recommendations, although responses varied in the different academic centres. Despite learning from their studies about normal nutritional requirements it seems that, to large degree, students follow eating habits acquired during their childhoods in the home. PMID- 26953583 TI - Evaluation of dietary intake of vitamins and minerals in 13-15-years-old boys from a sport school in Warsaw. AB - BACKGROUND: Insufficient intake of vitamins and minerals, in teenagers engaged in physical activity increases the risk of health disorders. OBJECTIVE: The aim of this study was to evaluate selected vitamins and minerals intake in 13-15-year old boys from sport school. MATERIAL AND METHODS: The study of dietary intake was conducted among 44 boys from the School of Sport Championship (SSC). Nutritional data was collected using 24-hour recall for 3 days of week. Daily intake of minerals: sodium, potassium, calcium, phosphorus, magnesium, iron, zinc, copper, iodine and vitamins: A, E, D, B1, B2, B6, B12, C, folate and niacin was estimated. The probability of insufficient intake of nutrients in relation to the standard levels: Estimated Average Requirement (EAR) or Adequate Intake (AI) as well as excessive intake of them in relation to the Tolerable Upper Intake Level (UL) were assessed. RESULTS: The highest percentage of insufficient intake concerned vitamin D (100%), potassium (69%), folate (53%), and calcium (50%), slightly lower of magnesium (27%), vitamins C (24%) and E (15%). The risk of inadequate intake of other minerals: sodium, copper, iron, zinc, phosphorus, iodine and vitamins: B6, B1, B2, A, B12, niacin, was relatively lower and amounted from 0.3% to 5.4%. The disturbingly high probability of exceeding the UL for sodium (99.5%) was observed. CONCLUSIONS: A significant disproportion between the mean intake and the percentage of inadequate diets indicates a large diversity in the intake of vitamins and minerals in the group of studied boys, what was the reason of unbalanced diet. The insufficient intake concerns especially vitamin D, potassium, folate, calcium and a lesser extent magnesium, vitamins C and E. Sodium intake was disturbingly high. In order to avoid nutritional mistakes in the future education on the rational nutrition among students, their parents, and teachers is necessary. PMID- 26953585 TI - Tobacco smokers and electronic cigarettes users among Polish universities students. AB - BACKGROUND: Electronic cigarettes (e-cigarettes) are small battery-powered electronic devices, heating the liquid to produce vapour--in most cases the latter contains nicotine and several flavourings. E-cigarettes are highly advertised across the media, mainly as healthy substitute to conventional cigarettes, aid in quitting smoking addiction or way of circumventing ban on smoking in public places. OBJECTIVE: The aim of study was obtaining epidemiological data on cigarette smoking and electronic cigarette usage among Polish universities students. MATERIAL AND METHODS: Students of different Polish state universities were asked to fill a self-prepared survey on cigarette-smoking and electronic cigarette usage. 1068 fulfilled questionnaires were gathered. The population was divided into two subgroups--medical universities' students (n=545) and non-medical universities students (n=523). RESULTS: 23.78% of respondents declared current smoking while 57.0% admitted ever smoking. The mean duration of smoking among current smokers was 4.17+/-2.53 years. 56.30% of current smokers tried quitting at least once. 31.46% of students declared ever using e-cigarettes (37.28% (n=195) among non-medical universities' students and 25.87% (n=141) among medical universities' students and 8.33% current usage. Among the latter 52.81% admitted simultaneous smoking. 26.97% of current e-cigarettes' users declared having experienced side effects of e-cigarettes. 42.70% (n=456) of respondents viewed e-cigarettes as safer than conventional cigarettes, this group comprises of 40.54% (n=212) non-medical and 44.77% (n=244) medical universities' students. 85.39% (n=912) of students viewed e-cigarettes as generally unhealthy, there were 83.56% (n=437) non-medical and 87.16% (n=475) medical universities' students among this group. CONCLUSIONS: The frequency of e-cigarettes usage resembles current status in many Western countries. Collected data shows high frequency of e-cigarettes usage and conventional cigarettes smoking among students (also medical universities' students). The situation requires intensive preventive measures to limit and reduce the popularity of tobacco products along with modern equivalents like electronic cigarettes. PMID- 26953584 TI - Association of occupational stress factors on nicotine dependence among patients visiting dental care unit of Indo-Tibetian border police force station in India. AB - BACKGROUND: Tobacco use is the foremost preventable cause of death and disease in the world today and work strain might be related with nicotine dependence by its provoking effect. OBJECTIVE: To assess the association between occupational stress and nicotine dependence. MATERIAL AND METHODS: A cross sectional survey was conducted among 200 subjects visiting a satellite dental clinic of Swami Devi Dyal Hospital and Dental College, Barwala, Panchkula, India. Nicotine dependence was measured using the Fagerstrom Test for Nicotine Dependence (FTND). The extent of the stress factors experienced at work was assessed using the Effort-Reward Imbalance scale (ERI). Chi-square test and multiple logistic regression analysis were employed for statistical analysis. Confidence level and level of significance were set at 95% and 5% respectively. RESULTS: The results of bivariate analysis revealed association of occupational stress with age, marital status, educational status, level of nicotine dependence, frequency of cigarette smoking and religious attendance. However, multivariate analysis elicited the significant association of occupational stress with only two variables, level of nicotine dependence and frequency of smoking. CONCLUSION: Occupational stress was found to be associated with nicotine dependence in the present study implying a need of other tranquil measures to be incorporated for the relief of work related stress. PMID- 26953586 TI - Impact of health and nutrition risks perception on the interest in pro-healthy food on the example of bread. AB - BACKGROUND: Bread is a basic food product in the diet of a majority of people. It is a good source of energy and it is also abundant in carbohydrates. Simultaneously, because it is consumed on a large scale by Polish people, it provides large amounts of salt and some additives like preservative and raising agents. The perception of the risk influences the choice of food and impacts eating behaviors. However, it is still unknown if there is an impact of perceived risk on the choice and the consumption of bread. OBJECTIVE: The objective of the research was to assess the importance of perceived health and nutrition risk in conditioning the willingness to buy bread with decreased amounts of salt and bread without preservative and raising agents. MATERIAL AND METHODS: Empirical research was conducted in October 2014 in a group of 1.014 adult consumers, with the use of the method of interview. The questions covered the following issues: the frequency of white and wholemeal bread consumption, the willingness to consume bread with reduced salt content and one produced without the preservatives and raising agents, the self-assessment of health and socio demographic characteristics of respondents. To evaluate the perceived health and nutrition risks modification of Health Concern Scale was used. Opinions on the tendency to purchase both kind of breads were compared taking into account socio demographic characteristics, health risk, nutrition risk and frequency of eating white and wholemeal bread. To determine the differences ANOVA and Tukey post hoc test at the significance level of p<0.05 were used. The relations between variables were assessed using Pearson's correlation coefficient. RESULTS: There was a higher tendency to consume bread without preservatives and raising agents than with low salt content. Women, people over 55 years old, and people who often consume white bread were characterized by higher willingness to consume bread with reduced salt content. People with higher education, aged over 45 years, and those who rarely consumed wholemeal bread were more willing to eat bread without additives. The greater was the nutrition and health risk perceived by the person, the greater was the willingness to consume both types of bread. CONCLUSIONS: The importance of perceived risks in conditioning consumers' willingness to eat healthy food shows that the educational campaigns informing about risky behaviors may promote behavioral change towards a more favorable food choice. PMID- 26953587 TI - Professor Wieslaw Magdzik, MD--Nestor of Polish Epidemiology (1932-2015). PMID- 26953588 TI - The Clinical Efficacy and Cardiotoxicity of Fixed-Dose Monthly Trastuzumab in HER2-Positive Breast Cancer: A Single Institutional Analysis. AB - OBJECTIVE: Trastuzumab-containing treatment regimens have been shown to improve survival outcomes in HER2-positive breast cancer (BC). It is much easier to infuse a fixed one-vial dose to every patient on a regular schedule in the general clinical setting. The aims of this study were evaluating the efficacy of a 440 mg fixed-dose of trastuzumab administered on a monthly infusion schedule, and the risk factors for cardiac events. PATIENTS AND METHODS: We retrospectively reviewed data from 300 HER2-positive BC patients in our institute: 208 were early stage BC patients undergoing adjuvant trastuzumab treatment, and 92 were metastatic BC patients treated with trastuzumab infusions until disease progression. There were 181 patients receiving regular trastuzumab infusions every 3 weeks (Q3W; 8 mg/kg loading dose followed by 6 mg/kg every 3 weeks), and the other 119 patients were treated monthly with a fixed 440 mg dose (QM; fixed 440 mg every 4 weeks). RESULTS: The medians of progression-free survival (PFS) and overall survival (OS) in the adjuvant setting were not reached in both treatment groups. In the metastatic setting, there was no significant difference between groups in PFS or OS. The median time to significant cardiovascular (CV) dysfunction was 4.54 months. The incidence of congestive heart failure requiring medication in our cohort was 3.4%. CONCLUSION: In our study, we found that fixed dose monthly trastuzumab was feasible and effective. In addition, the CV risk was not higher with the fixed-dose protocol. This treatment modality could lower the cost and was easier to implement in clinical practice. Larger prospective randomized studies with longer-term follow up are needed to confirm our results. PMID- 26953589 TI - Posttraumatic Stress Reactions in Parents of Children Esophageal Atresia. AB - OBJECTIVE: The aim of this study was to investigate psychological stress in parents of children with esophageal atresia and to explore factors associated with the development of Posttraumatic Stress disorder (PTSD). DESIGN: Self-report questionnaires were administered to parents of children with EA. Domains included: (1) sociodemographic data, current personal difficulties, assessment scales for the quality of life and for the global health status of the child (2) French-validated versions of the Perinatal Posttraumatic Stress disorder Questionnaire and of the State-Trait Anxiety Inventory. Associations between PTSD and severity of the neonatal course, presence of severe sequelae at 2 years of age, and quality of life and global health status of children according to their parents' perception were studied. SETTING: A Tertiary care University Hospital. RESULTS: Among 64 eligible families, 54 parents of 38 children (59%) participated to the study. PTSD was present in 32 (59%) parents; mothers were more frequently affected than fathers (69 vs 46%, p = 0.03). Four mothers (8%) had severe anxiety. PTSD was neither associated with neonatal severity nor with severe sequelae at 2 years. Parents with PTSD rated their child's quality of life and global health status significantly lower (7.5 vs 8.6; p = 0.01 and 7.4 vs 8.3; p = 0.02 respectively). CONCLUSIONS: PTSD is frequent in parents of children with esophageal atresia, independently of neonatal severity and presence of severe sequelae at 2 years of age. Our results highlight the need for a long-term psychological support of families. PMID- 26953591 TI - Factors Associated with Delay in Presentation to the Hospital for Young Adults with Ischemic Stroke. AB - OBJECTIVES: Young adults with ischemic stroke may present late to medical care, but the reasons for these delays are unknown. We sought to identify factors that predict delay in presentation. METHODS: We performed a retrospective cohort study of adults aged 18-50 admitted to a single academic medical center between 2007 and 2012. RESULTS: Eighty six of 141 (61%) young adults with ischemic stroke presented at the health center more than 4.5 h after stroke onset. Diabetes was associated with delays in presentation (p = 0.033, relative risk (RR) 1.4 (95% CI 1.1-1.8)), whereas systemic cancer was associated with early presentations (p = 0.033, RR 0.26 (95% CI 0.044-1.6)). Individuals who were single were more likely to present late than those who were married or living with a partner (p = 0.0045, RR 1.7 (95% CI 1.3-2.2)). Individuals who were unemployed were more likely to present late than those who were employed or in school (p = 0.020, RR 1.4 (95% CI 1.1-1.8)). Age (dichotomized as 18-35 and 36-50), race, home medications, other medical conditions (including common stroke mimics in young adults), and stroke subtype were not determinants of delay in presentation, although there was a trend toward delayed presentations in women (p = 0.076) and with low stroke severity (dichotomized as National Institutes of Health Stroke Scale (NIHSS) <=5 and NIHSS >5, p = 0.061). CONCLUSIONS: A majority of young adults with ischemic stroke presented outside the time window for intravenous fibrinolysis. Diabetes, single status, and unemployed status were associated with delayed presentation. PMID- 26953590 TI - Lateral Inhibition in the Human Visual System in Patients with Glaucoma and Healthy Subjects: A Case-Control Study. AB - In glaucoma, the density of retinal ganglion cells is reduced. It is largely unknown how this influences retinal information processing. An increase in spatial summation and a decrease in contrast gain control and contrast adaptation have been reported. A decrease in lateral inhibition might also arise. This could result in a larger than expected response to some stimuli, which could mask ganglion cell loss on functional testing (structure-function discrepancy). The aim of this study was to compare lateral inhibition between glaucoma patients and healthy subjects; we used a case-control design. Cases (n = 18) were selected to have advanced visual field loss in combination with a normal visual acuity. Controls (n = 50) were not allowed to have symptoms or signs of any eye disease. Lateral inhibition was measured psychophysically on a computer screen, with (1) a modified illusory movement experiment and (2) a contrast sensitivity (CS) test. Illusory movement was quantified by nulling it with a real movement; measure of lateral inhibition was the amount of illusory movement. CS was measured at 1 and 4 cycles per degree (cpd); measure of lateral inhibition was the difference between log CS at 4 and 1 cpd. Both measures were compared between cases and controls; analyses were adjusted for age and gender. There was no difference between cases and controls for these two measures of lateral inhibition (p = 0.58 for illusory movement; p = 0.20 for CS). The movement threshold was higher in cases than in controls (p = 0.008) and log CS was lower, at both 1 (-0.20; p = 0.008) and 4 (-0.28; p = 0.001) cpd. Our results indicate that spatially antagonistic mechanisms are not specifically affected in glaucoma, at least not in the intact center of a severely damaged visual field. This suggests that the structure-function discrepancy in glaucoma is not related to a decrease in lateral inhibition. PMID- 26953593 TI - Supporting nurses' transition to rural healthcare environments through mentorship. AB - INTRODUCTION: The global shortage of rural healthcare professionals threatens the access these communities have to adequate healthcare resources. Barriers to recruitment and retention of nurses in rural facilities include limited resources, professional development opportunities, and interpersonal ties to the area. Mentorship programs have been used to successfully recruit and retain rural nurses. This study aimed to explore (i) employee perceptions of mentorship in rural healthcare organizations, (ii) the processes involved in creating mentoring relationships in rural healthcare organizations, and (iii) the organizational features supporting and inhibiting mentorship in rural healthcare organizations. This study was conducted in one rural health region in Saskatchewan, Canada. METHODS: Volunteer participants who were employed at one rural healthcare facility were interviewed. A semi-structured interview guide that focused on exploring and gaining an understanding of participants' perceptions of mentorship in rural communities was employed. Data were analyzed using interpretive description methodology, which places high value on participants' subjective perspective and knowledge of their experience. RESULTS: All seven participants were female and employed as registered nurses or licensed practical nurses. Participants recognized that the rural environment offered unique challenges and opportunities for the transition of nurses new to rural healthcare. Participants believed mentorships facilitated this transition and were vital to the personal and professional success of new employees. Specifically, their insights indicated that this transition was influenced by three factors: rural community influences, organizational influences, and mentorship program influences. Facilitators for mentorships hinged on the close working relationships that facilitated the development of trust. Barriers to mentorship included low staff numbers, limited selection of volunteer mentors, and lack of mentorship education. CONCLUSIONS: The rural community context clearly presents challenges for the transition of nurses. Participants described mentorship as a vital component to personal and professional success of new employees in rural areas. The findings of this qualitative exploratory study inform the development of creative and supportive ways to establish mentorships to address the challenges specifically associated with integration of nurses into rural practice. PMID- 26953594 TI - New Insight into the Nature of Bonding in the Dimers of Lappert's Stannylene and Its Ge Analogs: A Quantum Mechanical Study. AB - The strength and nature of the connection in Lappert's stannylene dimer ({Sn[CH(SiMe3)2]2}2) and its smaller analogs, simplified stannylenes, as well as similar Ge complexes were studied by means of DFT-D3 calculations, energy decomposition analysis (EDA), electrostatic potential (ESP), and natural population analysis. The trans-bent structure of the investigated molecules was rationalized by means of EDA, ESP, and molecular orbital (MO) analyses. The different ESPs for the monomers studied are a result of different hybridization of the Sn (Ge) atoms. The comparably strong stabilization in the largest and the smallest systems with a dramatically different substituent size is explained by the different nature of the binding between monomers. For all complexes, it has been found that the total attractive interaction is mostly provided by the electrostatic component (>50%), followed by orbital interaction and dispersion. In the largest molecule (Lappert's stannylene), the dispersion interaction plays a more significant role in stabilization and its magnitude is comparable to that of orbital interaction; on the other hand in the smallest molecule (SnH2), where bulky substituents are replaced by H only, the dispersion energy is less important and the E-E bond is more of a charge-transfer character, caused by donor-acceptor orbital interactions. The charge transfer in Ge dimers is greater than in the Sn ones due to shorter distances between monomers, which cause better ?HOMO/LUMO? overlaps. The easier dimerization of Lappert's stannylene as compared to Kira's ({Sn[(Me3Si)2CHCH2CH2CH(SiMe3)2-kappa(2)C,C']}) stannylene is explained by the different orientation of their substituents-asymmetry promotes dimerization. PMID- 26953595 TI - Effect of Intramolecular High-Frequency Vibrational Mode Excitation on Ultrafast Photoinduced Charge Transfer and Charge Recombination Kinetics. AB - A model of photoinduced ultrafast charge separation and ensuing charge recombination into the ground state has been developed. The model includes explicit description of the formation and evolution of nonequilibrium state of both the intramolecular vibrations and the surrounding medium. An effect of the high-frequency intramolecular vibrational mode excitation by a pumping pulse on ultrafast charge separation and charge recombination kinetics has been investigated. Simulations, in accord with experiment, have shown that the effect may be both positive (the vibrational mode excitation increases the charge transfer rate constant) and negative (opposite trend). The effect on charge separation kinetics is predicted to be bigger than that on the charge recombination rate but nevertheless the last is large enough to be observable. The amplitude of both effects falls with decreasing vibrational relaxation time constant, but the effects are expected to be observable up to the time constants as short as 200 fs. Physical interpretation of the effects has been presented. Comparisons with the experimental data have shown that the simulations, in whole, provide results close to that obtained in the experiment. The reasons of the deviations have been discussed. PMID- 26953592 TI - Association between low birth weight and childhood-onset chronic kidney disease in Japan: a combined analysis of a nationwide survey for paediatric chronic kidney disease and the National Vital Statistics Report. AB - BACKGROUND: Although numerous epidemiological surveys performed across several continents and ethnic groups have linked low birth weight (LBW) to increased risk of chronic kidney disease (CKD) in adulthood, the effects of birth weight and prematurity on development of CKD in childhood have not been clearly established. METHODS: Data on sex, LBW incidence and gestational age were compared between paediatric CKD cases and a control group. Paediatric CKD cases were obtained from a nationwide survey conducted by the Pediatric CKD Study Group in Japan. The population attributable fraction was calculated to evaluate the effects of reducing the prevalence of LBW infants (LBWI). RESULTS: Of 447 individuals born between 1993 and 2010 that fulfilled the eligibility criteria, birth weight data were obtained for 381 (85.2%) (231 boys and 150 girls), 106 (27.8%) of whom were LBWI. The proportion of LBWI in the general population during the same period was much lower (8.6%). Therefore, the risk ratio (RR) for paediatric CKD was significantly higher in the LBW group [crude RR: 4.10; 95% confidence interval (CI) 3.62-5.01], and the overall impact on paediatric CKD for removal of LBW amounted to 21.1% (95% CI 16.0-26.1%). In addition, 82 patients (21.9%) with paediatric CKD were born prematurely (before 37 weeks of gestation), and as with LBW, a strong correlation was observed between prematurity and CKD (RR: 4.73; 95% CI 3.91-5.73). CONCLUSIONS: Both birth weight and gestational age were strongly associated with childhood-onset CKD in this study. PMID- 26953596 TI - Suppressing the Coffee-Ring Effect in Semitransparent MnO2 Film for a High Performance Solar-Powered Energy Storage Window. AB - We introduce a simple and effective method to deposit a highly uniform and semitransparent MnO2 film without coffee-ring effect (CRE) by adding ethanol into MnO2 ink for transparent capacitive energy storage devices. By carefully controlling the amount of ethanol added in the MnO2 droplet, we could significantly reduce the CRE and thus improve the film uniformity. The electrochemical properties of supercapacitor (SC) devices using semitransparent MnO2 film electrodes with or without CRE were measured and compared. The SC device without CRE shows a superior capacitance, high rate capability, and lower contact resistance. The CRE-free device could achieve a considerable volumetric capacitance of 112.2 F cm(-3), resulting in a high volumetric energy density and power density of 10 mWh cm(-3) and 8.6 W cm(-3), respectively. For practical consideration, both flexible SC and large-area rigid SC devices were fabricated to demonstrate their potential for flexible transparent electronic application and capacitive energy-storage window application. Moreover, a solar-powered energy storage window which consists of a commercial solar cell and our studied semitransparent MnO2-film-based SCs was assembled. These SCs could be charged by the solar cell and light up a light emitting diode (LED), demonstrating their potential for self-powered systems and energy-efficient buildings. PMID- 26953597 TI - Diverse, uncultivated bacteria and archaea underlying the cycling of dissolved protein in the ocean. AB - Dissolved organic nitrogen (DON) supports a significant amount of heterotrophic production in the ocean. Yet, to date, the identity and diversity of microbial groups that transform DON are not well understood. To better understand the organisms responsible for transforming high molecular weight (HMW)-DON in the upper ocean, isotopically labeled protein extract from Micromonas pusilla, a eukaryotic member of the resident phytoplankton community, was added as substrate to euphotic zone water from the central California Current system. Carbon and nitrogen remineralization rates from the added proteins ranged from 0.002 to 0.35 MUmol C l(-1) per day and 0.03 to 0.27 nmol N l(-1) per day. DNA stable-isotope probing (DNA-SIP) coupled with high-throughput sequencing of 16S rRNA genes linked the activity of 77 uncultivated free-living and particle-associated bacterial and archaeal taxa to the utilization of Micromonas protein extract. The high-throughput DNA-SIP method was sensitive in detecting isotopic assimilation by individual operational taxonomic units (OTUs), as substrate assimilation was observed after only 24 h. Many uncultivated free-living microbial taxa are newly implicated in the cycling of dissolved proteins affiliated with the Verrucomicrobia, Planctomycetes, Actinobacteria and Marine Group II (MGII) Euryarchaeota. In addition, a particle-associated community actively cycling DON was discovered, dominated by uncultivated organisms affiliated with MGII, Flavobacteria, Planctomycetes, Verrucomicrobia and Bdellovibrionaceae. The number of taxa assimilating protein correlated with genomic representation of TonB dependent receptor (TBDR)-encoding genes, suggesting a possible role of TBDR in utilization of dissolved proteins by marine microbes. Our results significantly expand the known microbial diversity mediating the cycling of dissolved proteins in the ocean. PMID- 26953598 TI - Beyond the Black Queen Hypothesis. AB - The Black Queen Hypothesis, recently proposed to explain an evolution of dependency based on gene loss, is gaining ground. This paper focuses on how the evolution of dependency transforms interactions and the community. Using agent based modeling we suggest that species specializing in the consumption of a common good escape competition and therefore favor coexistence. This evolutionary trajectory could open the way for novel long-lasting interactions and a need to revisit the classically accepted assembly rules. Such evolutionary events also reshape the structure and dynamics of communities, depending on the spatial heterogeneity of the common good production. Let Black be the new black! PMID- 26953599 TI - Ecological robustness of the gut microbiota in response to ingestion of transient food-borne microbes. AB - Resident gut microbes co-exist with transient bacteria to form the gut microbiota. Despite increasing evidence suggesting a role for transient microbes on gut microbiota function, the interplay between resident and transient members of this microbial community is poorly defined. We aimed to determine the extent to which a host's autochthonous gut microbiota influences niche permissivity to transient bacteria using a fermented milk product (FMP) as a vehicle for five food-borne bacterial strains. Using conventional and gnotobiotic rats and gut microbiome analyses (16S rRNA genes pyrosequencing and reverse transcription qPCR), we demonstrated that the clearance kinetics of one FMP bacterium, Lactococcus lactis CNCM I-1631, were dependent on the structure of the resident gut microbiota. Susceptibility of the resident gut microbiota to modulation by FMP intervention correlated with increased persistence of L. lactis. We also observed gut microbiome configurations that were associated with altered stability upon exposure to transient bacteria. Our study supports the concept that allochthonous bacteria have transient and subject-specific effects on the gut microbiome that can be leveraged to re-engineer the gut microbiome and improve dysbiosis-related diseases. PMID- 26953600 TI - Population genomics reveals that within-fungus polymorphism is common and maintained in populations of the mycorrhizal fungus Rhizophagus irregularis. AB - Arbuscular mycorrhizal (AM) fungi are symbionts of most plants, increasing plant growth and diversity. The model AM fungus Rhizophagus irregularis (isolate DAOM 197198) exhibits low within-fungus polymorphism. In contrast, another study reported high within-fungus variability. Experiments with other R. irregularis isolates suggest that within-fungus genetic variation can affect the fungal phenotype and plant growth, highlighting the biological importance of such variation. We investigated whether there is evidence of differing levels of within-fungus polymorphism in an R. irregularis population. We genotyped 20 isolates using restriction site-associated DNA sequencing and developed novel approaches for characterizing polymorphism among haploid nuclei. All isolates exhibited higher within-isolate poly-allelic single-nucleotide polymorphism (SNP) densities than DAOM 197198 in repeated and non-repeated sites mapped to the reference genome. Poly-allelic SNPs were independently confirmed. Allele frequencies within isolates deviated from diploids or tetraploids, or that expected for a strict dikaryote. Phylogeny based on poly-allelic sites was robust and mirrored the standard phylogeny. This indicates that within-fungus genetic variation is maintained in AM fungal populations. Our results predict a heterokaryotic state in the population, considerable differences in copy number variation among isolates and divergence among the copies, or aneuploidy in some isolates. The variation may be a combination of all of these hypotheses. Within isolate genetic variation in R. irregularis leads to large differences in plant growth. Therefore, characterizing genomic variation within AM fungal populations is of major ecological importance. PMID- 26953601 TI - Ecological patterns, diversity and core taxa of microbial communities in groundwater-fed rapid gravity filters. AB - Here, we document microbial communities in rapid gravity filtration units, specifically serial rapid sand filters (RSFs), termed prefilters (PFs) and after- filters (AFs), fed with anoxic groundwaters low in organic carbon to prepare potable waters. A comprehensive 16S rRNA-based amplicon sequencing survey revealed a core RSF microbiome comprising few bacterial taxa (29-30 genera) dominated by Nitrospirae, Proteobacteria and Acidobacteria, with a strikingly high abundance (75-87+/-18%) across five examined waterworks in Denmark. Lineages within the Nitrospira genus consistently comprised the second most and most abundant fraction in PFs (27+/-23%) and AFs (45.2+/-23%), respectively, and were far more abundant than typical proteobacterial ammonium-oxidizing bacteria, suggesting a physiology beyond nitrite oxidation for Nitrospira. Within the core taxa, sequences closely related to types with ability to oxidize ammonium, nitrite, iron, manganese and methane as primary growth substrate were identified and dominated in both PFs (73.6+/-6%) and AFs (61.4+/-21%), suggesting their functional importance. Surprisingly, operational taxonomic unit richness correlated strongly and positively with sampling location in the drinking water treatment plant (from PFs to AFs), and a weaker negative correlation held for evenness. Significant spatial heterogeneity in microbial community composition was detected in both PFs and AFs, and was higher in the AFs. This is the first comprehensive documentation of microbial community diversity in RSFs treating oligotrophic groundwaters. We have identified patterns of local spatial heterogeneity and dispersal, documented surprising energy-diversity relationships, observed a large and diverse Nitrospira fraction and established a core RSF microbiome. PMID- 26953602 TI - Biofilm plasmids with a rhamnose operon are widely distributed determinants of the 'swim-or-stick' lifestyle in roseobacters. AB - Alphaproteobacteria of the metabolically versatile Roseobacter group (Rhodobacteraceae) are abundant in marine ecosystems and represent dominant primary colonizers of submerged surfaces. Motility and attachment are the prerequisite for the characteristic 'swim-or-stick' lifestyle of many representatives such as Phaeobacter inhibens DSM 17395. It has recently been shown that plasmid curing of its 65-kb RepA-I-type replicon with >20 genes for exopolysaccharide biosynthesis including a rhamnose operon results in nearly complete loss of motility and biofilm formation. The current study is based on the assumption that homologous biofilm plasmids are widely distributed. We analyzed 33 roseobacters that represent the phylogenetic diversity of this lineage and documented attachment as well as swimming motility for 60% of the strains. All strong biofilm formers were also motile, which is in agreement with the proposed mechanism of surface attachment. We established transposon mutants for the four genes of the rhamnose operon from P. inhibens and proved its crucial role in biofilm formation. In the Roseobacter group, two-thirds of the predicted biofilm plasmids represent the RepA-I type and their physiological role was experimentally validated via plasmid curing for four additional strains. Horizontal transfer of these replicons was documented by a comparison of the RepA I phylogeny with the species tree. A gene content analysis of 35 RepA-I plasmids revealed a core set of genes, including the rhamnose operon and a specific ABC transporter for polysaccharide export. Taken together, our data show that RepA-I type biofilm plasmids are essential for the sessile mode of life in the majority of cultivated roseobacters. PMID- 26953606 TI - Chemometrics of Wheat Composites with Hemp, Teff, and Chia Flour: Comparison of Rheological Features. AB - The mixolab, a rheological device developed recently, combines approved farinograph and amylograph test procedures. Analysing wheat flour composites with hemp, teff, or chia in terms of all three mentioned rheological methods, correspondence of farinograph, and amylograph versus mixolab features was examined by principal component analysis. The first two principal components, PC1 and PC2, explained 75% of data scatter and allowed a satisfying confirmation of presumed relationships between farinograph or amylograph and mixolab parameters. Dough development time and stability were associated with gluten strength (C1 torque point) and also dough softening (mixing tolerance index) had a link to protein weakening (C1-C2 difference). In the second mentioned case, amylograph viscosity maximum and amylase activity (C3-C4) closeness was verified. Starch and starch gel properties during mixing (C3, C3-C2, and C4) affect dough viscosity (C1) and rheological behaviour (dough development time and stability). Another important finding is unequivocal distinguishing of the composite subsets (of hemp, teff, and chia ones) by the used rheological methods and statistical treatment of multivariable data. PMID- 26953605 TI - The microbiome of coral surface mucus has a key role in mediating holobiont health and survival upon disturbance. AB - Microbes are well-recognized members of the coral holobiont. However, little is known about the short-term dynamics of mucus-associated microbial communities under natural conditions and after disturbances, and how these dynamics relate to the host's health. Here we examined the natural variability of prokaryotic communities (based on 16S ribosomal RNA gene amplicon sequencing) associating with the surface mucus layer (SML) of Porites astreoides, a species exhibiting cyclical mucus aging and shedding. Shifts in the prokaryotic community composition during mucus aging led to the prevalence of opportunistic and potentially pathogenic bacteria (Verrucomicrobiaceae and Vibrionaceae) in aged mucus and to a twofold increase in prokaryotic abundance. After the release of aged mucus sheets, the community reverted to its original state, dominated by Endozoicimonaceae and Oxalobacteraceae. Furthermore, we followed the fate of the coral holobiont upon depletion of its natural mucus microbiome through antibiotics treatment. After re-introduction to the reef, healthy-looking microbe depleted corals started exhibiting clear signs of bleaching and necrosis. Recovery versus mortality of the P. astreoides holobiont was related to the degree of change in abundance distribution of the mucus microbiome. We conclude that the natural prokaryotic community inhabiting the coral SML contributes to coral health and that cyclical mucus shedding has a key role in coral microbiome dynamics. PMID- 26953603 TI - Regulatory (pan-)genome of an obligate intracellular pathogen in the PVC superphylum. AB - Like other obligate intracellular bacteria, the Chlamydiae feature a compact regulatory genome that remains uncharted owing to poor genetic tractability. Exploiting the reduced number of transcription factors (TFs) encoded in the chlamydial (pan-)genome as a model for TF control supporting the intracellular lifestyle, we determined the conserved landscape of TF specificities by ChIP-Seq (chromatin immunoprecipitation-sequencing) in the chlamydial pathogen Waddlia chondrophila. Among 10 conserved TFs, Euo emerged as a master TF targeting >100 promoters through conserved residues in a DNA excisionase-like winged helix-turn helix-like (wHTH) fold. Minimal target (Euo) boxes were found in conserved developmentally-regulated genes governing vertical genome transmission (cytokinesis and DNA replication) and genome plasticity (transposases). Our ChIP Seq analysis with intracellular bacteria not only reveals that global TF regulation is maintained in the reduced regulatory genomes of Chlamydiae, but also predicts that master TFs interpret genomic information in the obligate intracellular alpha-proteobacteria, including the rickettsiae, from which modern day mitochondria evolved. PMID- 26953607 TI - [18]Annulene put into a new perspective. AB - New insights into [18]annulene were gained by looking more closely at its X-ray structure, revealing a close face-to-face stacking of 3.16 A in a herringbone like crystal packing. Hexadehydro[18]annulene was co-crystalized in a benzene matrix, demonstrating the stabilizing role of intercalated solvent molecules in solid annulenes. PMID- 26953604 TI - Local diversity of heathland Cercozoa explored by in-depth sequencing. AB - Cercozoa are abundant free-living soil protozoa and quantitatively important in soil food webs; yet, targeted high-throughput sequencing (HTS) has not yet been applied to this group. Here we describe the development of a targeted assay to explore Cercozoa using HTS, and we apply this assay to measure Cercozoan community response to drought in a Danish climate manipulation experiment (two sites exposed to artificial drought, two unexposed). Based on a comparison of the hypervariable regions of the 18S ribosomal DNA of 193 named Cercozoa, we concluded that the V4 region is the most suitable for group-specific diversity analysis. We then designed a set of highly specific primers (encompassing ~270 bp) for 454 sequencing. The primers captured all major cercozoan groups; and >95% of the obtained sequences were from Cercozoa. From 443 350 high-quality short reads (>300 bp), we recovered 1585 operational taxonomic units defined by >95% V4 sequence similarity. Taxonomic annotation by phylogeny enabled us to assign >95% of our reads to order level and ~85% to genus level despite the presence of a large, hitherto unknown diversity. Over 40% of the annotated sequences were assigned to Glissomonad genera, whereas the most common individually named genus was the euglyphid Trinema. Cercozoan diversity was largely resilient to drought, although we observed a community composition shift towards fewer testate amoebae. PMID- 26953611 TI - Burden and Depression in Caregivers of Blind Patients in New York State. AB - PURPOSE: To describe the degree of burden of care and the proportion at risk of depression among individuals caring for legally blind patients. METHODS: We performed a cross-sectional study of 486 individuals providing care to their family members who were legally blind. Best-corrected visual acuity of the better seeing eye in patients determined group placement: Group 1, 20/200-10/200; group 2, 10/200 to light perception (LP); group 3, no light perception (NLP); group VF, visual field loss to <20 central degrees. Burden was evaluated using the Burden Index of Caregivers (BIC-11) and the prevalence at risk of depression was determined by the Center for Epidemiologic Studies Depression (CES-D) scale. RESULTS: Total mean BIC-11 scores ranged from 8.78 +/- 4.82 (group 1) to 12.03 +/ 5.22 (group 3; p = 0.04). Daily hours spent on close supervision, intensity of caregiving and presence of multiple chronic illnesses in caregivers were the significant covariates affecting BIC-11 scores (p < 0.05). The prevalence of caregivers at risk of depression increased with vision loss from 6.9% (group 1) to 17.9% (group 3; p < 0.05). Female caregivers had an odds ratio (OR) of 2.89 for depression (95% confidence interval, CI, 1.07-3.97; p = 0.04). Caregivers with >=2 comorbidities had OR 4.24 (95% CI 2.41-6.11) for risk of depression (p < 0.01). CONCLUSION: Burden of care was highest among caregivers who provided greater hours of supervision. Patients with more limitations in their activities of daily living had caregivers who reported higher burden. Female caregivers and caregivers with multiple chronic illnesses were at higher risk of depression. PMID- 26953612 TI - Polymorphism identification and cardiac gene expression analysis of the calsequestrin 2 gene in broiler chickens with sudden death syndrome. AB - Sudden death syndrome (SDS) in broilers is a cardiac disease associated with ventricular tachycardia (VT) and ventricular fibrillation (VF); however, its pathogenesis at the molecular level is not precisely determined. Downregulation and mutations of calsequestrin 2 (CASQ2), a major intracellular Ca(2+) buffer, have been associated with VT and sudden cardiac death (SCD) in humans but in chickens there is no report describing CASQ2 abnormalities in cardiac diseases. In order to better understand the molecular mechanisms predisposing the myocardium to fatal arrhythmia in broilers, the mRNA expression level of chicken CASQ2 gene (chCASQ2) in the left ventricle of dead broilers with SDS was determined and compared to healthy broilers using quantitative real-time PCR (qPCR). To determine the probable mutations in chCASQ2, PCR and direct sequencing were also done. Results showed a reduction in chCASQ2 expression in broilers dead by SDS. Three novel mutations (K289R, P308S, D310H) which are absent in healthy broilers were observed in chCASQ2. It is concluded that susceptibility to fatal cardiac arrhythmia in SDS may be associated with changes in intracellular Ca(2+) balance due to mutation and downregulation of chCASQ2. PMID- 26953614 TI - Canine lymphoma: a review. AB - Canine lymphoma (cL) is a common type of neoplasia in dogs with an estimated incidence rate of 20-100 cases per 100,000 dogs and is in many respects comparable to non-Hodgkin lymphoma in humans. Although the exact cause is unknown, environmental factors and genetic susceptibility are thought to play an important role. cL is not a single disease, and a wide variation in clinical presentations and histological subtypes is recognized. Despite this potential variation, most dogs present with generalized lymphadenopathy (multicentric form) and intermediate to high-grade lymphoma, more commonly of B-cell origin. The most common paraneoplastic sign is hypercalcemia that is associated with the T-cell immunophenotype. Chemotherapy is the treatment of choice and a doxorubicin-based multidrug protocol is currently the standard of care. A complete remission is obtained for most dogs and lasts for a median period of 7-10 months, resulting in a median survival of 10-14 months. Many prognostic factors have been reported, but stage, immunophenotype, tumor grade, and response to chemotherapy appear of particular importance. Failure to respond to chemotherapy suggests drug resistance, which can be partly attributed to the expression of drug transporters of the ABC-transporter superfamily, including P-gp and BCRP. Ultimately, most lymphomas will become drug resistant and the development of treatments aimed at reversing drug resistance or alternative treatment modalities (e.g. immunotherapy and targeted therapy) are of major importance. This review aims to summarize the relevant data on cL, as well as to provide an update of the recent literature. PMID- 26953616 TI - Dissociation dynamics of ethylene molecules on a Ni cluster using ab initio molecular dynamics simulations. AB - The atomistic mechanism of dissociative adsorption of ethylene molecules on a Ni cluster is investigated by ab initio molecular-dynamics simulations. The activation free energy to dehydrogenate an ethylene molecule on the Ni cluster and the corresponding reaction rate is estimated. A remarkable finding is that the adsorption energy of ethylene molecules on the Ni cluster is considerably larger than the activation free energy, which explains why the actual reaction rate is faster than the value estimated based on only the activation free energy. It is also found from the dynamic simulations that hydrogen molecules and an ethane molecule are formed from the dissociated hydrogen atoms, whereas some exist as single atoms on the surface or in the interior of the Ni cluster. On the other hand, the dissociation of the C-C bonds of ethylene molecules is not observed. On the basis of these simulation results, the nature of the initial stage of carbon nanotube growth is discussed. PMID- 26953617 TI - A new antifungal eudesmanolide glycoside isolated from Sphaeranthus indicus Linn. (Family Compositae). AB - A new antifungal eudesmanolide glycoside 11,13-dihydro-3-O-(beta digitoxopyranose)-7alpha-hydroxy eudasman-6,12-olide (2) in addition to known compounds 1 and 3, has been isolated from Sphaeranthus indicus Linn. Its structure was determined by spectral analysis (UV, IR, 1D and 2D NMR and mass spectrum). PMID- 26953615 TI - Timing of manual placenta removal to prevent postpartum hemorrhage: is it time to act? AB - OBJECTIVE: The length of the third stage of labor is an important risk factor for postpartum hemorrhage (PPH). Current practice recommends manual placenta removal, if not delivered spontaneously, within 30 min. The review reexamines the evidence to determine the optimal length of the third stage of labor. METHODS: A MEDLINE search that associated the length of the third stage of labor with the risk of PPH was undertaken. RESULTS: A retrospective cohort study revealed the risk of a PPH became significant at 10 min (odds ratio = 2.1, 95% confidence interval: 1.6 2.6), and had doubled by 20 min (odds ratio = 4.3, 95% confidence interval: 3.3 5.5). A receiver operator curve determined the optimal length of the third stage of labor to prevent PPH was 18 min. A follow up randomized controlled trial showed that hemodynamic compromise secondary to a PPH can be reduced with manual placenta removal at 10 compared to 15 min (6.4 versus 19.2%, p = 0.001). CONCLUSION: The time interval of 15 min may be a more appropriate time interval to recommend placental removal to prevent PPH. PMID- 26953619 TI - Chronotype of South African adults is affected by solar entrainment. AB - Our daily lives are influenced by three different daily timers: the solar clock, our endogenous circadian clock and the societal clock. The way an individual's endogenous clock synchronises to the solar clock, through either advances or delays relative to sunrise and sunset, results in a phenomenon known as diurnal preference or chronotype. South Africa uses just one time zone, but in the most easterly regions of the country, the sun rises and sets up to an hour earlier than in the most westerly regions throughout the year. It was hypothesised first that South Africans living in the east of the country may have a greater preference for mornings (more morning chronotypes) than those living in the west; and second, that this difference would not be due to genetic differences in the populations, particularly a genetic polymorphism previously shown to influence chronotype. Here, we describe and compare the distribution of chorotype and PERIOD3 variable number tandem repeat (VNTR) polymorphism frequency in eastern (n = 129) and western (n = 175) sample populations. Using the Horne-Ostberg Morningness, Eveningness Questionnaire we found that there was a significantly higher proportion of morning-types in the eastern population (56.6%) than in the western population (39.4%), and there were higher proportions of neither-types and evening-types in the western population (51.4% and 9.1%, respectively) than in the eastern population (37.2% and 6.2%, respectively) (p = 0.009). There were no significant differences in distribution of the PER3 genotype (p = 0.895) and allele (p = 0.636) frequencies. Although previous studies have shown associations between chronotype and PER3 VNTR genotypes, no significant associations were observed in either the eastern (p = 0.695) or the western (p = 0.630) populations. These findings indicate that, in South African populations, longitude influences chronotype independently of PER3 genotype. The impacts of the differences in chronotype whilst maintaining the same societal temporal organisation in the eastern and western regions were not assessed. PMID- 26953620 TI - The potential role for romidepsin as a component in early HIV-1 curative efforts. PMID- 26953621 TI - Alcohol Consumption as a Risk Factor for Suicidal Behavior: A Systematic Review of Associations at the Individual and at the Population Level. AB - The objective of this study was to provide an updated review of the magnitude of the relationship between alcohol use and suicidal behaviour at the individual and the population level. Systematic literature searches retrieved 14 reviews of individual level studies and 16 primary population level studies. Alcohol abuse and alcohol intoxication are often present in suicidal behaviour; risk of suicide is elevated in alcohol abusers and increasing population drinking tends to be associated with increase in suicide rates. Estimated magnitude of the relationship differs for men and women and it varies at the population level across cultures with different drinking pattern. These variations probably reflect gender differences and cultural variation in drinking behavior generally. Empirical evidence for a causal relationship is still urgently needed. PMID- 26953622 TI - Purinergic signaling-induced neuroinflammation and status epilepticus. PMID- 26953625 TI - Local effect of lysophosphatidic acid on prostaglandin production in the bovine oviduct. AB - The mammalian oviduct plays an important role in the fertilisation and transport of gametes and embryo. Prostaglandins (PGs) are local mediators of oviductal functions and are involved in fertilisation and the transport of gametes and embryo. Lysophosphatidic acid (LPA), a kind of phospholipid, is involved in various physiological actions. We hypothesised that LPA regulates PG production in the bovine oviduct. To test this hypothesis, we examined the mRNA expression of LPA receptors (LPAR1-6) and LPA-producing enzymes (ATX, PLA1alpha, PLA1beta) in ampullary and isthmic tissues and in cultured epithelial and stromal cells isolated from the bovine oviduct. We also investigated the effects of LPA on PG synthase expression and PG production in cultured cells. The mRNA of LPAR1-4, 6, ATX and PLA1alpha were expressed in cultured epithelial and stromal cells. The expressions of LPAR1-3 were significantly lower and the expression of LPAR4 was significantly higher in the isthmic than in the ampullary tissues. Lysophosphatidic acid significantly stimulated PG production in the cultured isthmic stromal cells. The overall findings suggest that LPA stimulates PG production via LPAR4 in the bovine oviduct. Since PGs are important for fertilisation and the transport of gametes and embryo, these findings show that locally produced LPA regulates oviductal functions. PMID- 26953624 TI - Lycibarbarspermidines A-O, New Dicaffeoylspermidine Derivatives from Wolfberry, with Activities against Alzheimer's Disease and Oxidation. AB - Fifteen new dicaffeoylspermidine derivatives, lycibarbarspermidines A-O (1-15), were isolated from the fruit of Lycium barbarum (wolfberry). The structures were unambiguously determined by spectroscopic analyses and chemical methods. Dicaffeoylspermidine derivatives, a rare kind of plant secondary metabolites, are primarily distributed in the family of Solanaceae. Only six compounds were structurally identified, and all of them are acyclic aglycones. Compounds 1-15 are the first glycosidic products of dicaffeoylspermidine derivatives, and compounds 14-15 are the first cyclization products of dicaffeoylspermidine derivatives. Moreover, dicaffeoylspermidine derivatives were first isolated and identified from wolfberry. The short-term memory assay on a transgenic fly Alzheimer's disease (AD) model showed that 1-15 exhibited different levels of anti-AD activity. The oxygen radical absorbance capacity assay revealed that 1-15 all displayed antioxidant capacity. Both anti-AD and antioxidant functions are related to the effects of wolfberry. Therefore, dicaffeoylspermidine derivatives are considered beneficial constituents responsible for the antiaging, neuroprotective, anti-AD, and antioxidant effects of wolfberry. PMID- 26953626 TI - Sex-dependent effects of sleep deprivation on myocardial sensitivity to ischemic injury. AB - Sleep deprivation is associated with increased risk of myocardial infarction. However, it is unknown whether the effects of sleep deprivation are limited to increasing the likelihood of experiencing a myocardial infarction or if sleep deprivation also increases the extent of myocardial injury. In this study, rats were deprived of paradoxical sleep for 96 h using the platform-over-water method. Control rats were subjected to the same condition except the control platform was large enough for the rats to sleep. Hearts from sleep deprived and control rats were subjected to 20 min ischemia on a Langendorff isolated heart system. Infarct size and post ischemic recovery of contractile function were unaffected by sleep deprivation in male hearts. In contrast, hearts from sleep-deprived females exhibited significantly larger infarcts than hearts from control females. Post ischemic recovery of rate pressure product and + dP/dT were significantly attenuated by sleep deprivation in female hearts, and post ischemic recovery of end diastolic pressure was significantly elevated in hearts from sleep deprived females compared to control females, indicating that post ischemic recovery of both systolic and diastolic function were worsened by sleep deprivation. These data provide evidence that sleep deprivation increases the extent of ischemia induced injury in a sex-dependent manner. PMID- 26953628 TI - Novel insights into the early histopathogenesis of immunodeficiency-associated Burkitt lymphoma: a case report of Burkitt microlymphoma arising within HIV lymphadenitis. AB - AIMS: To report a case detailing the early histopathogenesis of Burkitt lymphoma (BL), Epstein-Barr virus (EBV) positive, in the clinical setting of HIV infection. METHODS AND RESULTS: We describe a 57 year-old woman with newly diagnosed HIV infection who presented with unilateral localized axillary lymphadenopathy. Histopathological, immunohistochemical, and flow cytometric analyses were performed and showed EBV-positive nests of Burkitt cells, including rare nests also positive for cytomegalovirus, exclusively located within hyperplastic monocytoid B-cell areas of HIV lymphadenitis. Due to positron emission tomography/computed tomography findings of persistent localized lymphadenopathy with markedly increased fludeoxyglucose avidity a core needle biopsy was performed. Histopathological, immunohistochemical, fluorescence in situ hybridization, and flow cytometric analyses confirmed BL. CONCLUSIONS: Early histopathogenesis of HIV-associated BL occurred as nests of EBV-positive Burkitt cells within prominent monocytoid B-cell areas in our case. The results equip the pathologist to identify a very subtle Burkitt microlymphoma which would allow for prompt and appropriate chemotherapeutic intervention and may promote research into the possible relationship between monocytoid B cells and BL. PMID- 26953630 TI - The microbiome-systemic diseases connection. AB - The human microbiome consists of all microorganisms occupying the skin, mucous membranes and intestinal tract of the human body. The contact of the mucosal immune system with the human microbiome is a balanced interplay between defence mechanisms of the immune system and symbiotic or pathogenic microbial factors, such as microbial antigens and metabolites. In systemic autoimmune diseases (SADs) such as rheumatoid arthritis, systemic lupus erythematosus and Sjogren's syndrome, the immune system is deranged to a chronic inflammatory state and autoantibodies are an important hallmark. Specific bacteria and/or a dysbiosis in the human microbiome can lead to local mucosal inflammation and increased intestinal permeability. Proinflammatory lymphocytes and cytokines can spread to the systemic circulation and increase the risk of inflammation at distant anatomical sites, such as the joints or salivary glands. Increased intestinal permeability increases antigen exposure and the risk of autoantibody production. If the human microbiome indeed plays such a critical role in SADs, this finding holds a great promise for new therapeutic strategies, such as diet interventions and probiotics and prebiotics. This review provides a background on the human microbiome and mucosal immunity in the gut and oral cavity and gives a summary of the current knowledge on the microbiome-SADs connection. PMID- 26953627 TI - Engineered Biomaterials to Enhance Stem Cell-Based Cardiac Tissue Engineering and Therapy. AB - Cardiovascular disease is a leading cause of death worldwide. Since adult cardiac cells are limited in their proliferation, cardiac tissue with dead or damaged cardiac cells downstream of the occluded vessel does not regenerate after myocardial infarction. The cardiac tissue is then replaced with nonfunctional fibrotic scar tissue rather than new cardiac cells, which leaves the heart weak. The limited proliferation ability of host cardiac cells has motivated investigators to research the potential cardiac regenerative ability of stem cells. Considerable progress has been made in this endeavor. However, the optimum type of stem cells along with the most suitable matrix-material and cellular microenvironmental cues are yet to be identified or agreed upon. This review presents an overview of various types of biofunctional materials and biomaterial matrices, which in combination with stem cells, have shown promises for cardiac tissue replacement and reinforcement. Engineered biomaterials also have applications in cardiac tissue engineering, in which tissue constructs are developed in vitro by combining stem cells and biomaterial scaffolds for drug screening or eventual implantation. This review highlights the benefits of using biomaterials in conjunction with stem cells to repair damaged myocardium and give a brief description of the properties of these biomaterials that make them such valuable tools to the field. PMID- 26953629 TI - LCPT once-daily extended-release tacrolimus tablets versus twice-daily capsules: a pooled analysis of two phase 3 trials in important de novo and stable kidney transplant recipient subgroups. AB - African-American and elderly kidney transplant recipients (KTR) have increased risk for poor clinical outcomes post-transplant. Management of immunosuppression may be challenging in these patients and contribute to worse outcomes. A novel once-daily formulation of tacrolimus (LCPT) has demonstrated noninferiority, similar safety, improved bioavailability, a consistent concentration time profile, and less peak and peak-trough fluctuations vs. tacrolimus twice-daily (Tac BID). This pooled analysis of two phase 3 randomized, controlled trials, including 861 (LCPT N = 428; Tac BID N = 433; 38% of patients were stable KTR, and 62% were de novo KTR) patients, examined the efficacy of LCPT in KTR subgroups (blacks, females, and age >=65). Overall, treatment failure [death, graft failure, centrally read biopsy-proven acute rejection (BPAR), or lost to follow-up] at 12 months was as follows: LCPT: 11.9%, BID Tac: 13.4% [-1.48% ( 5.95%, 2.99%)]. BPAR rates were as follows: LCPT: 8.2%, Tac BID: 9.5% [-1.29% ( 5.14%, 2.55%)]. Numerically, fewer treatment failure events with LCPT were found in the majority of subgroups, with significantly less treatment failure associated with LCPT among black KTR [-13.82% (-27.22%, -0.31%)] and KTR >=65 [ 13.46% (-25.27%, -0.78%)]. This pooled analysis suggests numerically lower efficacy failure rates associated with LCPT among high-risk subgroups, in particular black KTR and KTR >=65 years old. PMID- 26953631 TI - Evaluation of Prerequisite Programs Implementation and Hygiene Practices at Social Food Services through Audits and Microbiological Surveillance. AB - Prerequisite programs are considered the most efficient tool for a successful implementation of self-control systems to ensure food safety. The main objective of this study was to evaluate the implementation of these programs in 15 catering services located in Navarra and the Basque Country (regions in northern Spain), through on-site audits and microbiological analyses. The implementation of the prerequisite program was incomplete in 60% of the sample. The unobserved temperature control during both the storage and preparation of meals in 20% of the kitchens reveals misunderstanding in the importance of checking these critical control points. A high level of food safety and hygiene (absence of pathogens) was observed in the analyzed meals, while 27.8% of the tested surfaces exceeded the established limit for total mesophilic aerobic microorganisms (<=100 CFU/25 cm2). The group of hand-contact surfaces (oven door handles and aprons) showed the highest level of total mesophilic aerobic microorganisms and Enterobacteriaceae, and the differences observed with respect to the food-contact surfaces (work and distribution utensils) were statistically significant (P < 0.001). With regard to the food workers' hands, lower levels of microorganisms were observed in the handlers wearing gloves (that is, for Staphylococcus spp we identified 43 CFU/cm2 on average compared with 4 CFU/cm2 (P < 0.001) for those not wearing and wearing gloves, respectively). For a proper implementation of the prerequisites, it is necessary to focus on attaining a higher level of supervision of activities and better hygiene training for the food handlers, through specific activities such as informal meetings and theoretical-practical sessions adapted to the characteristics of each establishment. PMID- 26953632 TI - Molecular Calcium Hydride: Dicalcium Trihydride Cation Stabilized by a Neutral NNNN-Type Macrocyclic Ligand. AB - Hydrogenolysis of bis(triphenylsilyl)calcium containing the neutral NNNN-type macrocyclic amine ligand Me4TACD [Ca(Me4TACD)(SiPh3)2] (2), gave the cationic dinuclear calcium hydride [Ca2H3(Me4TACD)2](SiPh3) (3), characterized by NMR spectroscopy, single-crystal X-ray analysis, and DFT calculations. Compound 3 reacted with deuterium to give the deuteride [D3]-3. PMID- 26953633 TI - Spatial scan statistics for detection of multiple clusters with arbitrary shapes. AB - In applying scan statistics for public health research, it would be valuable to develop a detection method for multiple clusters that accommodates spatial correlation and covariate effects in an integrated model. In this article, we connect the concepts of the likelihood ratio (LR) scan statistic and the quasi likelihood (QL) scan statistic to provide a series of detection procedures sufficiently flexible to apply to clusters of arbitrary shape. First, we use an independent scan model for detection of clusters and then a variogram tool to examine the existence of spatial correlation and regional variation based on residuals of the independent scan model. When the estimate of regional variation is significantly different from zero, a mixed QL estimating equation is developed to estimate coefficients of geographic clusters and covariates. We use the Benjamini-Hochberg procedure (1995) to find a threshold for p-values to address the multiple testing problem. A quasi-deviance criterion is used to regroup the estimated clusters to find geographic clusters with arbitrary shapes. We conduct simulations to compare the performance of the proposed method with other scan statistics. For illustration, the method is applied to enterovirus data from Taiwan. PMID- 26953634 TI - Developmental aspects of the direct-developing frog Adelophryne maranguapensis. AB - Direct development in amphibians is characterized by the loss of aquatic breeding. The anuran Adelophryne maranguapensis is one example of a species with direct development, and it is endemic to the state of Ceara, Brazil. Detailed morphological features of A. maranguapensis embryos and the stages of sequential development have not been described before. Here, we analyzed all available genetic sequence tags in A. maranguapensis (tyr exon 1, pomc and rag1) and compared them with sequences from other species of Adelophryne frogs. We describe the A. maranguapensis reproductive tract and embryonic body development, with a focus on the limbs, tail, ciliated cells of the skin, and the egg tooth, which were analyzed using scanning electron microscopy. Histological analyses revealed ovaries containing oocytes surrounded by follicular cells, displaying large nuclei with nucleoli inside. Early in development, the body is unpigmented, and the neural tube forms dorsally to the yolk vesicle, typical of a direct developing frog embryo. The hindlimbs develop earlier than the forelimbs. Ciliated cells are abundant during the early stages of skin development and are less common during later stages. The egg tooth appears in the later stages and develops as a keratinized microridge structure. The developmental profile of A. maranguapensis presented here will contribute to our understanding of the direct development model and may help preserve this endangered native Brazilian frog. genesis 54:257-271, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26953635 TI - TiO2 Sub-microsphere Film as Scaffold Layer for Efficient Perovskite Solar Cells. AB - TiO2 sub-microspheres composed of anatase granular-like nanocrystallines with an average diameter ~250 nm are synthesized using sol-gel method and employed as the scaffold layer for efficient mesocopic perovskite solar cells. Compared with mesoporous TiO2 films composed of ~18 nm nanoparticles, the sub-microsphere films show superior light-trapping characteristics and significantly improve the light harvesting capability of the solar cells. In addition, the charge-transport performance is also dramatically improved according to the transient photocurrent decay despite there being no significant difference in the perovskite layer surface morphology. As a result, an average power conversion efficiency of 15% with a highly uniform distribution is achieved for the solar cells with TiO2 sub microsphere films, 12% higher than those with TiO2 nanoparticle films. The combination of light-harvesting capability and fast charge transfer make the TiO2 sub-microsphere film a good candidate as the scaffold layer for efficient perovskite solar cells. PMID- 26953636 TI - Towards a Neuronal Gauge Theory. AB - Given the amount of knowledge and data accruing in the neurosciences, is it time to formulate a general principle for neuronal dynamics that holds at evolutionary, developmental, and perceptual timescales? In this paper, we propose that the brain (and other self-organised biological systems) can be characterised via the mathematical apparatus of a gauge theory. The picture that emerges from this approach suggests that any biological system (from a neuron to an organism) can be cast as resolving uncertainty about its external milieu, either by changing its internal states or its relationship to the environment. Using formal arguments, we show that a gauge theory for neuronal dynamics--based on approximate Bayesian inference--has the potential to shed new light on phenomena that have thus far eluded a formal description, such as attention and the link between action and perception. PMID- 26953638 TI - Measurement methods of ultrasonic transducer sensitivity. AB - Sensitivity is an important parameter to describe the electro-acoustic energy conversion efficiency of ultrasonic transducer. In this paper, the definition of sensitivity and reciprocity of ultrasonic transducer is studied. The frequency response function of a transducer is the spectrum of its sensitivity, which reflects the response sensitivity of the transducer for input signals at different frequencies. Four common methods which are used to measure the disc vibrator transducer sensitivity are discussed in current investigation. The reciprocity method and the pulse-echo method are based on the reciprocity of the transducer. In the laser vibrometer method measurement, the normal velocity on the transducer radiating surface is directly measured by a laser vibrometer. In the measurement process of the hydrophone method, a calibrated hydrophone is used to measure the transmitted field. The validity of these methods is checked by experimental test. All of the four methods described are sufficiently accurate for transducer sensitivity measurement, while each method has its advantages and limitations. In practical applications, the appropriate method to measure transducer sensitivity should be selected based on actual conditions. PMID- 26953639 TI - Role of Naphthenic Acids in Controlling Self-Aggregation of a Polyaromatic Compound in Toluene. AB - In this work, a series of molecular dynamics simulations were performed to investigate the effect of naphthenic acids (NAs) in early stage self-assembly of polyaromatic (PA) molecules in toluene. By exploiting NA molecules of the same polar functional group but different aliphatic/cycloaliphatic nonpolar tails, it was found that irrespective of the presence of the NA molecules in the system, the dominant mode of pi-pi stacking is a twisted, offset parallel stacking of a slightly larger overlapping area. Unlike large NA molecules, the presence of small NA molecules enhanced the number of pi-pi stacked PA molecules by suppressing the hydrogen bonding interactions among the PA molecules. Smaller NA molecules were found to have a higher tendency to associate with PA molecules than larger NA molecules. Moreover, the size and distribution of pi-pi stacking structures were affected to different degrees by changing the size and structural features of the NA molecules in the system. It was further revealed that the association between NA and PA molecules, mainly through hydrogen bonding, creates a favorable local environment for the overlap of PA cores (i.e., pi-pi stacking growth) by depressing the hydrogen bonding between PA molecules, which results in the removal of some toluene molecules from the vicinity of the PA molecules. PMID- 26953637 TI - Health Coaching and Chronic Obstructive Pulmonary Disease Rehospitalization. A Randomized Study. AB - RATIONALE: Hospital readmission for chronic obstructive pulmonary disease (COPD) has attracted attention owing to the burden to patients and the health care system. There is a knowledge gap on approaches to reducing COPD readmissions. OBJECTIVES: To determine the effect of comprehensive health coaching on the rate of COPD readmissions. METHODS: A total of 215 patients hospitalized for a COPD exacerbation were randomized at hospital discharge to receive either (1) motivational interviewing-based health coaching plus a written action plan for exacerbations (the use of antibiotics and oral steroids) and brief exercise advice or (2) usual care. MEASUREMENTS AND MAIN RESULTS: We evaluated the rate of COPD-related hospitalizations during 1 year of follow-up. The absolute risk reductions of COPD-related rehospitalization in the health coaching group were 7.5% (P = 0.01), 11.0% (P = 0.02), 11.6% (P = 0.03), 11.4% (P = 0.05), and 5.4% (P = 0.24) at 1, 3, 6, 9, and 12 months, respectively, compared with the control group. The odds ratios for COPD hospitalization in the intervention arm compared with the control arm were 0.09 (95% confidence interval [CI], 0.01-0.77) at 1 month postdischarge, 0.37 (95% CI, 0.15-0.91) at 3 months postdischarge, 0.43 (95% CI, 0.20-0.94) at 6 months postdischarge, and 0.60 (95% CI, 0.30-1.20) at 1 year postdischarge. The missing value rate for the primary outcome was 0.4% (one patient). Disease-specific quality of life improved significantly in the health coaching group compared with the control group at 6 and 12 months, based on the Chronic Respiratory Disease Questionnaire emotional score (emotion and mastery domains) and physical score (dyspnea and fatigue domains) (P < 0.05). There were no differences between groups in measured physical activity at any time point. CONCLUSIONS: Health coaching may represent a feasible and possibly effective intervention designed to reduce COPD readmissions. Clinical trial registered with www.clinicaltrials.gov (NCT01058486). PMID- 26953641 TI - Comparison of Surfactant Distributions in Pressure-Sensitive Adhesive Films Dried from Dispersion under Lab-Scale and Industrial Drying Conditions. AB - Film-forming latex dispersions are an important class of material systems for a variety of applications, for example, pressure-sensitive adhesives, which are used for the manufacturing of adhesive tapes and labels. The mechanisms occurring during drying have been under intense investigations in a number of literature works. Of special interest is the distribution of surfactants during the film formation. However, most of the studies are performed at experimental conditions very different from those usually encountered in industrial processes. This leaves the impact of the drying conditions and the resulting influence on the film properties unclear. In this work, two different 2-ethylhexyl-acrylate (EHA) based adhesives with varying characteristics regarding glass transition temperature, surfactants, and particle size distribution were investigated on two different substrates. The drying conditions, defined by film temperature and mass transfer in the gas phase, were varied to emulate typical conditions encountered in the laboratory and industrial processes. Extreme conditions equivalent to air temperatures up to 250 degrees C in a belt dryer and drying rates of 12 g/(m(2).s) were realized. The surfactant distributions were measured by means of 3D confocal Raman spectroscopy in the dry film. The surfactant distributions were found to differ significantly with drying conditions at moderate film temperatures. At elevated film temperatures the surfactant distributions are independent of the investigated gas side transport coefficients: the heat and mass transfer coefficient. Coating on substrates with significantly different surface energies has a large impact on surfactant concentration gradients, as the equilibrium between surface and bulk concentration changes. Dispersions with higher colloidal stability showed more homogeneous lateral surfactant distributions. These results indicate that the choice of the drying conditions, colloidal stability, and substrates is crucial to control the surfactant distribution. Results obtained under lab-scale drying conditions cannot be transferred directly to the industrial application. The results were similar for both tested adhesive material systems, despite their different properties. This indicates that other properties, such as the particle size distribution and glass transition temperature, have surprisingly little effect on the development of the surfactant distribution. PMID- 26953642 TI - [Bipolar dislocation of the forearm (floating forearm)]. PMID- 26953640 TI - Rhodium-Catalyzed Enantioselective Cycloisomerization to Cyclohexenes Bearing Quaternary Carbon Centers. AB - We report a Rh-catalyzed enantioselective cycloisomerization of alpha,omega heptadienes to afford cyclohexenes bearing quaternary carbon centers. Rhodium(I) and a new SDP ligand promote chemoselective formation of a cyclohex-3 enecarbaldehyde motif that is inaccessible by the Diels-Alder cycloaddition. Various alpha,alpha-bisallylaldehydes rearrange to generate six-membered rings by a mechanism triggered by aldehyde C-H bond activation. Mechanistic studies suggest a pathway involving regioselective carbometalation and endocyclic beta hydride elimination. PMID- 26953644 TI - Tracking and Resolving CT Dose Metric Outliers Using Root-Cause Analysis. AB - PURPOSE: The aim of this study was to examine the frequency and type of outlier dose metrics for three common CT examination types on the basis of a root-cause analysis (RCA) approach. METHODS: Institutional review board approval was obtained for this retrospective observational study. The requirement to obtain informed consent was waived. Between January 2010 and December 2013, radiation dose metric data from 34,615 CT examinations, including 26,878 routine noncontrast CT head, 2,992 CT pulmonary angiographic (CTPA), and 4,745 renal colic examinations, were extracted from a radiation dose index monitoring database and manually cleaned. Dose outliers were identified on the basis of the statistical distribution of volumetric CT dose index and dose-length product for each examination type; values higher than the 99th percentile and less than the 1st percentile were flagged for RCA. RESULTS: There were 397 noncontrast CT head, 52 CTPA, and 80 renal colic outliers. Root causes for high-outlier examinations included repeat examinations due to patient motion (n = 122 [31%]), modified protocols mislabeled as "routine" (n = 69 [18%]), higher dose examinations for patients with large body habitus (n = 27 [7%]), repeat examinations due to technical artifacts (n = 20 [5%]), and repeat examinations due to suboptimal contrast timing (CTPA examinations) (n = 18 [5%]). Root causes for low-outlier examinations included low-dose protocols (n = 112 [29%]) and aborted examinations (n = 8 [2%]). On the basis of examination frequency over a 3-month period, the 90th and 10th percentile values were set in the radiation dose index monitoring database as thresholds for sending notifications to staff members responsible for outlier investigations. CONCLUSIONS: Systematic RCA of dose outliers identifies sources of variation and dose excess and pinpoints specific protocol and technical shortcomings for corrective action. PMID- 26953645 TI - A Multidisciplinary Approach to Improving Appropriate Follow-Up Imaging of Ovarian Cysts: A Quality Improvement Initiative. AB - PURPOSE: Incidental ovarian cysts are frequently detected on imaging. Despite published follow-up consensus statements, there remains variability in radiologist follow-up recommendations and clinician practice patterns. The aim of this study was to evaluate if collaborative ovarian cyst management recommendations and a radiologist decision support tool can improve adherence to follow-up recommendations. METHODS: Gynecologic oncologists and abdominal radiologists convened to develop collaborative institutional recommendations for the management of incidental, asymptomatic simple ovarian cysts detected on ultrasound, CT, and MRI. The recommendations were developed by modifying the published consensus recommendations developed by the Society of Radiologists in Ultrasound on the basis of local practice patterns and the experience of the group members. A less formal process involved the circulation of the published consensus recommendations, followed by suggestions for revisions and subsequent consensus, in similar fashion to the ACR Incidental Findings Committee II. The recommendations were developed by building on the published work of experienced groups to provide the authors' medical community with a set of recommendations that could be endorsed by both the Department of Gynecology and the Department of Radiology to provide supportive guidance to the clinicians who manage incidental ovarian cysts. The recommendations were integrated into a radiologist decision support tool accessible from the dictation software. Nine months after tool launch, institutional review board approval was obtained, and radiology reports mentioning ovarian cysts in the prior 34 months were retrospectively reviewed. For cysts detected on ultrasound, adherence rates to Society of Radiologists in Ultrasound recommendations were calculated for examinations before tool launch and compared with adherence rates to the collaborative institutional recommendations after tool launch. Additionally, electronic medical records were reviewed to determine the follow-up chosen by the clinician. RESULTS: For cysts detected on ultrasound, radiologist adherence to recommendations improved from 50% (98 of 197) to 80% (111 of 139) (P < .05). Overmanagement decreased from 34% (67 of 197) to 10% (14 of 139) (P < .05). A recommendation was considered "overmanaged" if the radiologist recommended follow-up when it was not indicated or if the recommended follow-up time was at a shorter interval than indicated. Clinician adherence to radiologist recommendations showed statistically nonsignificant improvement from 49% (36 of 73) to 57% (27 of 47) (P = .5034). CONCLUSIONS: Management recommendations developed through collaboration with clinicians may help standardize follow-up of ovarian cysts and reduce overutilization. PMID- 26953646 TI - Resveratrol attenuates neuropathic pain through balancing pro-inflammatory and anti-inflammatory cytokines release in mice. AB - Anti-inflammatory activity of resveratrol has been widely studied, while its beneficial effect on the management of neuropathic pain, a refractory chronic syndrome with pro-inflammation implicated in, is very little investigated. In the present study, the effects of different doses and various time window of administration of resveratrol were explored in a neuropathic mouse model of chronic constriction injury (CCI) of the sciatic nerve. It was demonstrated that pretreatment of resveratrol (5, 10, 20 and 40 mg/kg) for 7 consecutive days before CCI did not alleviate neuropathic pain, while it clearly relieved the pain when administrated after CCI and such pain relief effect was more pronounced when administrated right after the peak of pain symptom at day 7 after CCI, as evidenced by the alleviation of thermal hyperalgesia and mechanical allodynia. Such a beneficial effect of resveratrol was in a dose-dependent manner. Mechanistic study showed that resveratrol repressed the expression of pro inflammatory cytokines, including TNF-alpha, IL-1beta and IL-6, and promoted the expression of anti-inflammatory cytokine IL-10 at the same time, which was further confirmed in a cell model of microglia. It was also shown that neuropathic pain inversely correlated with pro-inflammatory cytokines, such as TNF-alpha, IL-1beta and IL-6, but not with anti-inflammatory cytokine IL-10 in all experimental mice from Spearman correlation coefficient. Our study reveals that resveratrol displays a significant neuropathic pain relief effect and paved a way for novel treatment of chronic pain. PMID- 26953647 TI - Airway oxidative stress causes vascular and hepatic inflammation via upregulation of IL-17A in a murine model of allergic asthma. AB - Oxidants are generated in asthmatic airways due to infiltration of inflammatory leukocytes and resident cells in the lung. Reactive oxygen species (ROS) such as hydrogen peroxide and superoxide radical may leak into systemic circulation when generated in uncontrolled manner and may impact vasculature. Our previous studies have shown an association between airway inflammation and systemic inflammation; however so far none has investigated the impact of airway oxidative inflammation on hepatic oxidative stress and Th1/Th2/Th17 cytokine markers in liver/vasculature in a murine model of asthma. Therefore, this study investigated the contribution of oxidative stress encountered in asthmatic airways in modulation of systemic/hepatic Th1/Th2/Th17 cytokines balance and hepatic oxidative stress. Mice were sensitized intraperitoneally with cockroach extract (CE) in the presence of aluminum hydroxide followed by several intranasal (i.n.) challenges with CE. Mice were then assessed for systemic/hepatic inflammation through assessment of Th1/Th2/Th17 cytokines and oxidative stress (iNOS, protein nitrotyrosine, lipid peroxides and myeloperoxidase activity). Challenge with CE led to increased Th2/Th17 cytokines in blood/liver and hepatic oxidative stress. However, only Th17 related pro-inflammatory markers were upregulated by hydrogen peroxide (H2O2) inhalation in vasculature and liver, whereas antioxidant treatment, N-acetyl cysteine (NAC) downregulated them. Hepatic oxidative stress was also upregulated by H2O2 inhalation, whereas NAC attenuated it. Therefore, our study shows that airway oxidative inflammation may contribute to systemic inflammation through upregulation of Th17 immune responses in blood/liver and hepatic oxidative stress. This might predispose these patients to increased risk for the development of cardiovascular disorders. PMID- 26953649 TI - Greedy adaptive walks on a correlated fitness landscape. AB - We study adaptation of a haploid asexual population on a fitness landscape defined over binary genotype sequences of length L. We consider greedy adaptive walks in which the population moves to the fittest among all single mutant neighbors of the current genotype until a local fitness maximum is reached. The landscape is of the rough mount Fuji type, which means that the fitness value assigned to a sequence is the sum of a random and a deterministic component. The random components are independent and identically distributed random variables, and the deterministic component varies linearly with the distance to a reference sequence. The deterministic fitness gradient c is a parameter that interpolates between the limits of an uncorrelated random landscape (c=0) and an effectively additive landscape (c->infinity). When the random fitness component is chosen from the Gumbel distribution, explicit expressions for the distribution of the number of steps taken by the greedy walk are obtained, and it is shown that the walk length varies non-monotonically with the strength of the fitness gradient when the starting point is sufficiently close to the reference sequence. Asymptotic results for general distributions of the random fitness component are obtained using extreme value theory, and it is found that the walk length attains a non-trivial limit for L->infinity, different from its values for c=0 and c=infinity, if c is scaled with L in an appropriate combination. PMID- 26953648 TI - Mathematical model for calcium-assisted epidermal homeostasis. AB - Using a mathematical model of the epidermis, we propose a mechanism of epidermal homeostasis mediated by calcium dynamics. We show that calcium dynamics beneath the stratum corneum can reduce spatio-temporal fluctuations of the layered structure of the epidermis. We also demonstrate that our model can reproduce experimental results that the recovery from a barrier disruption is faster when the disrupted site is exposed to air. In particular, simulation results indicate that the recovery speed depends on the size of barrier disruption. PMID- 26953650 TI - The ribosome as a missing link in prebiotic evolution II: Ribosomes encode ribosomal proteins that bind to common regions of their own mRNAs and rRNAs. AB - We have proposed that the ribosome may represent a missing link between prebiotic chemistries and the first cells. One of the predictions that follows from this hypothesis, which we test here, is that ribosomal RNA (rRNA) must have encoded the proteins necessary for ribosomal function. In other words, the rRNA also functioned pre-biotically as mRNA. Since these ribosome-binding proteins (rb proteins) must bind to the rRNA, but the rRNA also functioned as mRNA, it follows that rb-proteins should bind to their own mRNA as well. This hypothesis can be contrasted to a "null" hypothesis in which rb-proteins evolved independently of the rRNA sequences and therefore there should be no necessary similarity between the rRNA to which rb-proteins bind and the mRNA that encodes the rb-protein. Five types of evidence reported here support the plausibility of the hypothesis that the mRNA encoding rb-proteins evolved from rRNA: (1) the ubiquity of rb-protein binding to their own mRNAs and autogenous control of their own translation; (2) the higher-than-expected incidence of Arginine-rich modules associated with RNA binding that occurs in rRNA-encoded proteins; (3) the fact that rRNA-binding regions of rb-proteins are homologous to their mRNA binding regions; (4) the higher than expected incidence of rb-protein sequences encoded in rRNA that are of a high degree of homology to their mRNA as compared with a random selection of other proteins; and (5) rRNA in modern prokaryotes and eukaryotes encodes functional proteins. None of these results can be explained by the null hypothesis that assumes independent evolution of rRNA and the mRNAs encoding ribosomal proteins. Also noteworthy is that very few proteins bind their own mRNAs that are not associated with ribosome function. Further tests of the hypothesis are suggested: (1) experimental testing of whether rRNA-encoded proteins bind to rRNA at their coding sites; (2) whether tRNA synthetases, which are also known to bind to their own mRNAs, are encoded by the tRNA sequences themselves; (3) and the prediction that archaeal and prokaryotic (DNA-based) genomes were built around rRNA "genes" so that rRNA-related sequences will be found to make up an unexpectedly high proportion of these genomes. PMID- 26953651 TI - Estimation from moments measurements for amyloid depolymerisation. AB - Estimating reaction rates and size distributions of protein polymers is an important step for understanding the mechanisms of protein misfolding and aggregation, a key feature for amyloid diseases. This study aims at setting this framework problem when the experimental measurements consist in the time-dynamics of a moment of the population (i.e. for instance the total polymerised mass, as in Thioflavin T measurements, or the second moment measured by Static Light Scattering). We propose a general methodology, and we solve the problem theoretically and numerically in the case of a depolymerising system. We then apply our method to experimental data of depolymerising oligomers, and conclude that smaller aggregates of ovPrP protein should be more stable than larger ones. This has an important biological implication, since it is commonly admitted that small oligomers constitute the most cytotoxic species during prion misfolding process. PMID- 26953656 TI - Systemic hypertension and diabetes mellitus as predictors of malignancy among women with endometrial polyps: a meta-analysis of observational studies. AB - OBJECTIVE: Diabetes mellitus (DM) and systemic hypertension (SH) are frequent benign diseases which might coexist with endometrial polyps. We sought to evaluate whether women who suffer from these diseases have an increased incidence of premalignant and malignant lesions. METHODS: We systematically searched the literature using the Medline (by using Pubmed) (1966-2015), Scopus (2004-2015), ClinicalTrials.gov (2008-2015), Cochrane Central Register (CENTRAL), and Google Scholar (2004-2015) databases along with the references of all articles which were retrieved in full text. We performed the meta-analysis with the RevMan 5.1 software. RESULTS: Both DM and SH seem to be correlated with increased odds of developing premalignant and malignant endometrial polyps (odds ratio 2.43, 95% confidence interval 1.51, 3.91) and (odds ratio 2.36, 95% confidence interval 1.16, 4.81). However, it remains unclear whether type I or type II DM exert a more pronounced effect and whether the severity of SH has an impact on these odds. Also, the potential relation of antidiabetic and antihypertensive treatment with these lesions cannot be excluded. CONCLUSIONS: Physicians should increase their awareness among women with endometrial polyps who suffer from DM and/or SH. Further studies are needed to corroborate our findings and elucidate the underlying mechanisms of this relation. PMID- 26953655 TI - Venous thromboembolism and cardiovascular disease complications in menopausal women using transdermal versus oral estrogen therapy. AB - OBJECTIVE: To evaluate the risk of venous thromboembolism (VTE) and cardiovascular disease (CVD) complications, and assess healthcare costs in menopausal women using an estradiol transdermal system versus oral estrogen therapy (ET). METHODS: Health insurance claims from 60 self-insured US companies from 1999 to 2011 were analyzed. Women at least 50 years of age, newly initiated on transdermal or oral ET, were included. Cohorts were matched 1:1 based on exact factors and propensity score-matching methods. The incidence rate ratios (IRRs) of CVD complications, as well as VTE and other CVD events separately, were assessed through conditional Poisson models. Cohorts were also compared for healthcare costs using linear regression models to assess per-patient per-month cost differences. Confidence intervals (CIs) and P values were determined using a nonparametric method for cost outcomes. RESULTS: From each cohort, 2,551 users were matched to form the study population. A total of 274 transdermal ET users developed CVD complications compared with 316 women in the oral ET cohort (adjusted IRR 0.81; 95% CI, 0.67-0.99). Transdermal ET users also incurred lower adjusted all-cause and VTE/CVD-related healthcare costs relative to oral ET users (all-cause per-patient per-month cost difference [95% CI] = $41 [-34; 137], P = 0.342). CONCLUSIONS: This large matched-cohort study based on real-world data suggests that women receiving transdermal ET have significantly lower incidences of CVD events compared with those receiving oral ET, and that they also incur lower healthcare costs. PMID- 26953657 TI - Prenatal and Perinatal Determinants of Lung Health and Disease in Early Life: A National Heart, Lung, and Blood Institute Workshop Report. AB - Human lung growth and development begins with preconception exposures and continues through conception and childhood into early adulthood. Numerous environmental exposures (both positive and negative) can affect lung health and disease throughout life. Infant lung health correlates with adult lung function, but significant knowledge gaps exist regarding the influence of preconception, perinatal, and postnatal exposures on general lung health throughout life. On October 1 and 2, 2015, the National Heart, Lung, and Blood Institute convened a group of extramural investigators to develop their recommendations for the direction(s) for future research in prenatal and perinatal determinants of lung health and disease in early life and to identify opportunities for scientific advancement. They identified that future investigations will need not only to examine abnormal lung development, but also to use developing technology and resources to better define normal and/or enhanced lung health. Birth cohort studies offer key opportunities to capture the important influence of preconception and obstetric risk factors on lung health, development, and disease. These studies should include well-characterized obstetrical data and comprehensive plans for prospective follow-up. The importance of continued basic science, translational, and animal studies for providing mechanisms to explain causality using new methods cannot be overemphasized. Multidisciplinary approaches involving obstetricians, neonatologists, pediatric and adult pulmonologists, and basic scientists should be encouraged to design and conduct comprehensive and impactful research on the early stages of normal and abnormal human lung growth that influence adult outcome. PMID- 26953658 TI - Silicon Injection Granulomata: 67Ga Citrate Findings in Free Silicon Buttock Augmentation. AB - Ga citrate is frequently used in the workup of fever of unknown origin. Here, we report a case of avid Ga-citrate in bilateral gluteal regions of a patient with a history of free silicon injection buttock augmentation referred for suspected diagnosis of sarcoidosis. CT findings were equivocal for inflammation/infection in the buttock region, and nuclear scintigraphy allowed for more definitive diagnosis. PMID- 26953660 TI - Optical tweezers study of red blood cell aggregation and disaggregation in plasma and protein solutions. AB - Kinetics of optical tweezers (OT)-induced spontaneous aggregation and disaggregation of red blood cells (RBCs) were studied at the level of cell doublets to assess RBC interaction mechanics. Measurements were performed under in vitro conditions in plasma and fibrinogen and fibrinogen + albumin solutions. The RBC spontaneous aggregation kinetics was found to exhibit different behavior depending on the cell environment. In contrast, the RBC disaggregation kinetics was similar in all solutions qualitatively and quantitatively, demonstrating a significant contribution of the studied proteins to the process. The impact of the study on assessing RBC interaction mechanics and the protein contribution to the reversible RBC aggregation process is discussed. PMID- 26953659 TI - Prognostic Role of Early and End-of-Neoadjuvant Treatment 18F-FDG PET/CT in Patients With Breast Cancer. AB - AIM: To determine the use of early and final treatment F-FDG PET/CT in the prediction of response to neoadjuvant chemotherapy (NAC) and its role in the prognosis of patients with locally advanced breast cancer (LABC). METHODS: One hundred thirty-two patients underwent a baseline FDG PET/CT (PET-1) after the second course of chemotherapy (PET-2) and after the last course (PET-3). Breast tumors were categorized into molecular phenotypes and risk categories according to the biological prognostic factors obtained by immunohistochemistry. PET/CT scans were semiquantitatively evaluated, obtaining the Delta% SUV1-2 and SUV1-3 in primary tumor and axillary lymph nodes to establish response groups attending to EORTC criteria. Moreover, a binary assessment was obtained classifying the studies as positive or negative. Histopathological response was obtained in breast and lymph node specimens. Overall survival (OS) and disease-free survival (DFS) were obtained after the follow-up. ROC analysis was performed to determine a cutoff value of Delta% SUV1-2 and SUV1-3 for the prediction of response and prognosis. Relations between phenotypes, metabolic behavior, final histopathological response, OS, and DFS were evaluated. RESULTS: In binary analysis, only PET-3 was able to predict histopathological response in lymph nodes. The cutoff values of %Delta SUV1-2 and %Delta SUV1-3 with the best sensitivity and specificity in the prediction of response in breast tumor were 62% (Se: 70% and Sp: 69%) and 84% (Se: 70% and Sp: 88%). A %DeltaSUV1-3 of 74% in breast tumor was a predictor of DFS (AUC = 0.647; P = 0.037, Se: 52% and Sp: 66%). Kaplan-Meier analysis revealed significant relations between the binary lymph node assessment of PET-3 with OS (P = 0.016, chi = 5.78) and DFS (P = 0.003, chi = 9.10). CONCLUSIONS: End-of-treatment F-FDG PET/CT was a predictor of lymph node response and prognosis. Most of metabolic response variables related to histopathological response showed association with the prognosis. PMID- 26953661 TI - Two-photon spectral fluorescence lifetime and second-harmonic generation imaging of the porcine cornea with a 12-femtosecond laser microscope. AB - Five dimensional microscopy with a 12-fs laser scanning microscope based on spectrally resolved two-photon autofluorescence lifetime and second-harmonic generation (SHG) imaging was used to characterize all layers of the porcine cornea. This setup allowed the simultaneous excitation of both metabolic cofactors, NAD(P)H and flavins, and their discrimination based on their spectral emission properties and fluorescence decay characteristics. Furthermore, the architecture of the stromal collagen fibrils was assessed by SHG imaging in both forward and backward directions. Information on the metabolic state and the tissue architecture of the porcine cornea were obtained with subcellular resolution, and high temporal and spectral resolutions. PMID- 26953663 TI - Mitochondrial Encephalomyopathy With Lactic Acidosis and Strokelike Episodes Presenting Before 50 Years of Age: When a Stroke Is Not Just a Stroke. PMID- 26953664 TI - Micro-CT as a Tool to Investigate the Efficacy of Tetramethylpyrazine in a Rat Spinal Cord Injury Model. AB - STUDY DESIGN: The micro-computed tomography (micro-CT) was applied to assess the effect of tetramethylpyrazine (TMP) on experimental spinal cord injury (SCI). OBJECTIVE: The aim of the study was to explore the therapeutic effect of TMP on a rat SCI model using micro-CT. SUMMARY OF BACKGROUND DATA: SCI is a devastating event and always accompanied by severe vascular injury. Promoting angiogenesis after SCI has recently been recognized as a potential way to enhance the neurological function recovery. How the TMP promotes angiogenesis and improved locomotor function recovery after SCI has, however, not been fully clarified. In this study, we used micro-CT to evaluate the effect on the microvasculature changes after TMP treatment. METHODS: The contusion SCI model was induced in rats by a modified Allen's impact method. In the TMP treatment group, rats were injected intraperitoneally with TMP. The control group was treated with saline. Hindlimb motor function was evaluated using the Basso, Beattie, Bresnahan score. Histology was employed to examine the pathological changes and quantified at 28 days after injury. Spinal cord vessel network and angiogenesis were assessed using micro-CT. RESULTS: Angiogenesis was increased in groups treated with TMP compared with rat in the control groups (P < 0.05). Micro-CT vividly depicted the three-dimensional morphology changes of the spinal cord microvasculature after injury and demonstrated more vessels number, vessel volume fraction, and vessel connectivity value in the groups treated with TMP than in the control groups (P < 0.05). In addition, the injury-induced lesion area in TMP group was attenuated in comparison with control groups. Similarly, neurological functions were greatly improved in groups treated with TMP compared with rats in the control groups. CONCLUSION: Micro-CT is useful for detecting angiogenesis after SCI. TMP therapy reduced the neuronal loss, promoted angiogenesis, and exerted a positive effect on neurological function recovery after SCI. LEVEL OF EVIDENCE: N/A. PMID- 26953662 TI - Radiative transfer equation modeling by streamline diffusion modified continuous Galerkin method. AB - Optical tomography has a wide range of biomedical applications. Accurate prediction of photon transport in media is critical, as it directly affects the accuracy of the reconstructions. The radiative transfer equation (RTE) is the most accurate deterministic forward model, yet it has not been widely employed in practice due to the challenges in robust and efficient numerical implementations in high dimensions. Herein, we propose a method that combines the discrete ordinate method (DOM) with a streamline diffusion modified continuous Galerkin method to numerically solve RTE. Additionally, a phase function normalization technique was employed to dramatically reduce the instability of the DOM with fewer discrete angular points. To illustrate the accuracy and robustness of our method, the computed solutions to RTE were compared with Monte Carlo (MC) simulations when two types of sources (ideal pencil beam and Gaussian beam) and multiple optical properties were tested. Results show that with standard optical properties of human tissue, photon densities obtained using RTE are, on average, around 5% of those predicted by MC simulations in the entire/deeper region. These results suggest that this implementation of the finite element method-RTE is an accurate forward model for optical tomography in human tissues. PMID- 26953665 TI - Deformity Angular Ratio Describes the Severity of Spinal Deformity and Predicts the Risk of Neurologic Deficit in Posterior Vertebral Column Resection Surgery. AB - STUDY DESIGN: Retrospective review of prospectively collected data. OBJECTIVE: To assess the value of the deformity angular ratio (DAR, maximum Cobb measurement divided by number of vertebrae involved) in evaluating the severity of spinal deformity, and predicting the risk of neurologic deficit in posterior vertebral column resection (PVCR). SUMMARY OF BACKGROUND DATA: Although the literature has demonstrated that PVCR in spinal deformity patients has achieved excellent outcomes, it is still high risk neurologically. This study, to our knowledge, is the largest series of PVCR patients from a single center, evaluating deformity severity, and potential neurologic deficit risk. METHODS: A total of 202 consecutive pediatric and adult patients undergoing PVCRs from November 2002 to September 2014 were reviewed. The DAR (coronal DAR, sagittal DAR, and total DAR) was used to evaluate the complexity of the deformity. RESULTS: The incidence of spinal cord monitoring (SCM) events was 20.5%. Eight patients (4.0%) had new neurologic deficits. Patients with a high total DAR (>=25) were significantly younger (20.3 vs. 29.0 yr, P = 0.001), had more severe coronal and sagittal deformities, were more myelopathic (33.3% vs. 11.7%, P = 0.000), needed larger vertebral resections (1.8 vs. 1.3, P = 0.000), and had a significantly higher rate of SCM events than seen in the low total DAR (<25) patients (41.1% vs. 10.8%; P = 0.000). Patients with a high sagittal DAR (>=15) also had a significantly higher rate of SCM events (34.0% vs. 15.1%, P = 0.005) and a greater chance of neurologic deficits postoperatively (12.5% vs. 0, P = 0.000). CONCLUSION: For patients undergoing a PVCR, the DAR can be used to quantify the angularity of the spinal deformity, which is strongly correlated to the risk of neurologic deficits. Patients with a total DAR greater than or equal to 25 or sagittal DAR greater than or equal to 15 are at much higher risk for intraoperative SCM events and new neurologic deficits. LEVEL OF EVIDENCE: 3. PMID- 26953666 TI - Cell-Based Therapies for Lumbar Discogenic Low Back Pain: Systematic Review and Single-Arm Meta-analysis. AB - STUDY DESIGN: A systematic review and single-arm meta-analysis of clinical trials. OBJECTIVE: To assess the efficacy of mesenchymal stem cells or chondrocyte in patients with discogenic low back pain. SUMMARY OF BACKGROUND DATA: There is no previous review evaluated the efficacy of mesenchymal stem cell or chondrocyte therapy in adults with discogenic low back pain. METHODS: A comprehensive literature search was conducted on PubMed, Ovid MEDLINE, Ovid EMBASE, EBSCO, and Web of Science from database inception through on September 10th, 2015. We included clinical trials that evaluated stem cells or chondrocyte based therapy in patients with discogenic back pain. The primary outcomes of interest were pain score and Oswestry Disability Index (ODI). We performed random effects model meta-analyses to assess net changes in the same outcome variables. Heterogeneity between studies was estimated by I statistic. RESULTS: The initial search identified 1393 articles, of which 6 studies were eligible for this review. The pooled mean difference in pain score from baseline to follow-up points was 44.2 points decreased (95% CI: -61.8 to -26.5, P < 0.001, I = 99.4%). Meanwhile, the pooled mean difference in ODI from baseline to follow-up points was 32.2 points decreased (95% CI: -41.6 to -22.9, P < 0.001, I = 99.5%). No related adverse effects were reported by the included studies. CONCLUSION: Cell based therapy is for patients who have discogenic low back pain associated with improved pain relief and ODI. More stringently designed randomized double-blind clinical trials with appropriately determined sample sizes will be needed to confirm its clinical efficacy and safety. LEVEL OF EVIDENCE: 4. PMID- 26953667 TI - Preoperative Nutritional Status is an Independent Predictor of 30-day Hospital Readmission After Elective Spine Surgery. AB - STUDY DESIGN: A retrospective cohort review. OBJECTIVE: The aim of this study is to investigate whether preoperative malnutrition is an independent risk factor for unplanned 30-day readmission after elective spine surgery. SUMMARY OF BACKGROUND DATA: Thirty-day hospital readmission rate is being used as a proxy for quality of care. Accordingly, hospitals and health systems are investing considerable resources into the identification of patients at risk of hospital readmission and designing interventions to reduce the rate of hospital readmissions. METHODS: The medical records of 145 patients undergoing elective spine surgery at a major academic medical center were reviewed. Preoperative serum albumin level was assessed on all patients and used to quantify nutritional status. Albumin less than 3.5 g/dL was recognized malnourished. Patient demographics, comorbidities, and postoperative complication rates were collected. The association between preoperative serum albumin level and 30-day readmission rate was assessed via multivariate logistic regression analysis. RESULTS: Baseline characteristics were similar between both groups. Low albumin was found in 28% of patients in this study. Malnourished patients were more likely to experience a postoperative complication and a prolonged duration of hospital stay (3.80 vs. 8.67 days), P = 0.03. Overall, 14.48% of patients were readmitted within 30 days of discharge, with malnourished patients experiencing a three-fold increase in 30-day readmission rates (malnourished: 27.50% vs. nourished: 9.52%, P = 0.02). Binary logistic regression with and without propensity score adjustment for risk factors demonstrated that preoperative malnutrition (low serum albumin level) is an independent predictor of 30-day readmission after elective spine surgery (P = 0.01). CONCLUSION: Pre-operative malnutrition is an independent risk factor for readmission within 30 days of discharge after elective spine surgery. Laboratory markers of nutrition can identify patients at risk of unplanned hospital readmission. This risk determination identifies a potentially modifiable risk factor for early readmission. LEVEL OF EVIDENCE: 3. PMID- 26953668 TI - The Effect of Coagulopathies on Perioperative Complications and Clinical Outcomes in Patients Treated With Posterior Lumbar Fusions. AB - STUDY DESIGN: A retrospective database review. OBJECTIVE: The aim of this study was to compare complication rates following one to two-level lumbar spine surgery in patients with primary hypercoagulable states and coagulopathies. SUMMARY OF BACKGROUND DATA: Both hypercoagulable states and coagulopathies are not uncommon conditions that have the potential to significantly alter perioperative patient management. However, there are few studies that document the added risk of medical complications following spine surgery in these patient populations. METHODS: The PearlDiver database (2005-2012) was utilized to determine perioperative complication rates in patients with primary hypercoagulable states and coagulopathies who underwent primary one to two-level posterolateral lumbar spine fusion. Control cohorts without specific hematologic disorders were matched by demographics and comorbidities. Ninety-day complication rates were determined, along with revision rates at one and two years. When considering complication rate comparisons between matched cohorts, P < 0.005 was considered significant. RESULTS: In total, 746 patients with coagulopathies and 2753 patients with primary hypercoagulable states were selected. Matched control cohorts contained 74,879 and 54,007 patients, respectively. Hypercoagulable patients had significantly increased rates of medical complications [odds ratio (OR) 1.4], infections (OR 1.6), and venous thromboembolisms (OR 9.0) during the three months following spine surgery and same-day transfusions (OR 1.2) when compared with matched controls (P < 0.001). Patients with von Willebrand disease or hemophilia had increased rates of three-month infections (OR 2.3) and transfusion (OR 2.0) when compared with a matched control group (P < 0.005). One- and two-year revisions rates were not significantly higher for either pathologic cohort when compared to matched controls. CONCLUSION: Both primary hypercoagulable states and coagulopathies increase infection and transfusion rates following one to two level lumbar spine surgery. LEVEL OF EVIDENCE: 3. PMID- 26953669 TI - Is There an Association Between Pain and Magnetic Resonance Imaging Parameters in Patients With Lumbar Spinal Stenosis? AB - STUDY DESIGN: A prospective multicenter cohort study. OBJECTIVE: The aim of this study was to identify an association between pain and magnetic resonance imaging (MRI) parameters in patients with lumbar spinal stenosis (LSS). SUMMARY OF BACKGROUND DATA: At present, the relationship between abnormal MRI findings and pain in patients with LSS is still unclear. METHODS: First, we conducted a systematic literature search. We identified relationships of relevant MRI parameters and pain in patients with LSS. Second, we addressed the study question with a thorough descriptive and graphical analysis to establish a relationship between MRI parameters and pain using data of the LSS outcome study (LSOS). RESULTS: In the systematic review including four papers about the associations between radiological findings in the MRI and pain, the authors of two articles reported no association and two of them did. Of the latters, only one study found a moderate correlation between leg pain measured by Visual Analog Scale (VAS) and the degree of stenosis assessed by spine surgeons. In the data of the LSOS study, we could not identify a relevant association between any of the MRI parameters and buttock, leg, and back pain, quantified by the Spinal Stenosis Measure (SSM) and the Numeric Rating Scale (NRS). Even by restricting the analysis to the level of the lumbar spine with the most prominent radiological "stenosis," no relevant association could be shown. CONCLUSION: Despite a thorough analysis of the data, we were not able to prove any correlation between radiological findings (MRI) and the severity of pain. There is a need for innovative "methods/techniques" to learn more about the causal relationship between radiological findings and the patients' pain-related complaints. LEVEL OF EVIDENCE: 2. PMID- 26953670 TI - Heparin-Based Polyelectrolyte Complex Enhances the Therapeutic Efficacy of Bone Morphogenetic Protein-2 for Posterolateral Fusion in a Large Animal Model. AB - STUDY DESIGN: The study was based on porcine posterolateral fusion model. OBJECTIVE: The study aims to prove that polyelectrolyte complex (PEC) carrier could enhance the efficacy and safety profile of bone morphogenetic protein-2 (BMP-2). SUMMARY OF BACKGROUND DATA: BMP-2 was introduced to enhance posterolateral fusion; however, extremely high doses of this molecule were often used which contributed to various complications. This was attributed to the poor modulation capacity of the traditional carrier absorbable collagen sponge (ACS). To reduce the efficacious dose of BMP-2 and its associated complications, heparin based PEC was introduced. METHODS: L3/L4 and L5/L6 two-level posterolateral spinal fusion was performed on six pigs using two doses of BMP-2 with PEC or ACS: (1) PEC with 800 MUg BMP-2 (n = 2); (2) PEC with 400 MUg BMP-2 (n = 2); (3) ACS with 800 MUg BMP-2 (n = 1); (4) ACS with 400 MUg of BMP-2 (n = 1). The construct was loaded into a rigid bioabsorbable cage for implantation. Fusion rate and quality were assessed 2 months after operation. RESULTS: Manual palpation revealed successful fusion in all groups. Radiological fusion score of PEC groups was, however, higher than that of ACS groups. The newly formed bone in PEC groups appeared to be well integrated into the native bone with no overgrowth into the adjacent structure. On comparison, in ACS groups, large gaps were observed between the newly formed bone and the fusion bed with heterotopic ossification into the psoas muscle. The microarchitecture on the newly formed bone in PEC groups was superior to that in ACS groups, which was demonstrated by higher three dimensional parameters. CONCLUSION: The present study demonstrated that BMP-2 delivered by PEC induced successful posterolateral fusion in porcine model. The efficacy of BMP-2 was improved and bony overgrowth was reduced. The microarchitecture of BMP-2-induced bone tissue was also enhanced by PEC. LEVEL OF EVIDENCE: N/A. PMID- 26953671 TI - Radiation Exposure to the Surgeon and Patient During a Fluoroscopic Procedure: How High Is the Exposure Dose? A Cadaveric Study. AB - STUDY DESIGN: Using fresh cadavers, real-time dosimeters were used to estimate the radiation exposure dose from C-arm fluoroscopy to surgeons, medical staff, and patients during various procedures. OBJECTIVE: The aim of this study was to evaluate the radiation exposure dose from C-arm fluoroscopy, which is used to generate real-time images of the human body, under a variety of conditions and in different areas. SUMMARY OF BACKGROUND DATA: Awareness of the harmful effects of long-term low-dose radiation is rising. There are no all-inclusive reports evaluating the radiation exposure dose to medical staff associated with fluoroscopic procedures that can accurately simulate the real clinical situation. METHODS: Seven fresh cadavers were irradiated for 1, 3, and 5 minutes with C-arm fluoroscopy. The x-ray source was positioned under the table, over the table, and laterally. Radiation exposure doses were measured at different simulated areas such as the center area, and the surgeon's hand or thyroid gland. RESULTS: There were significant differences in the radiation exposure dose under different conditions and for different irradiated areas. The risk of direct and scatter radiation exposure was the greatest with the lateral position, which increased by more than 200 times and more than 30 times, respectively, compared with that from a position under the table. Direct radiation was attenuated to less than one hundredth after passing through the body of the cadaver. All radiation exposure doses were positively correlated with total exposure time. CONCLUSION: Our study revealed the direct and scatter radiation exposure dose from C-arm fluoroscopy to different areas under a variety of conditions when fluoroscopy is used to generate real-time images of the human body. Our results serve as a guide for medical staff to understand the risk of radiation exposure during each fluoroscopic procedure. Medical staff, especially surgeons, should consider how to protect themselves and reduce radiation exposure by using appropriate shielding. LEVEL OF EVIDENCE: 4. PMID- 26953672 TI - Specialty distribution of physician assistants and nurse practitioners in North Carolina. AB - Physician workforce projections often include scenarios that forecast physician shortages under different assumptions about the deployment of physician assistants (PAs) and nurse practitioners (NPs). These scenarios generally assume that PAs and NPs are an interchangeable resource and that their specialty distributions do not change over time. This study investigated changes in PA and NP specialty distribution in North Carolina between 1997 and 2013. The data show that over the study period, PAs and NPs practiced in a wide range of specialties, but each profession had a specific pattern. The proportion of PAs-but not NPs reporting practice in primary care dropped significantly. PAs were more likely than NPs to report practice in urgent care, emergency medicine, and surgical subspecialties. Physician workforce models need to account for the different and changing specialization trends of NPs and PAs. PMID- 26953673 TI - Zika virus: A rapidly emerging infectious disease. AB - Zika virus is a flavivirus transmitted to humans via the bite of infected mosquitoes. A recent outbreak in Brazil has spread to several surrounding countries, and the virus also has been reported in the United States. The virus is associated with microcephaly among newborns whose mothers were infected. Because no vaccine or treatment is available, efforts have focused on preventing mosquito bites and advising pregnant women and women trying to get pregnant to avoid active areas of Zika virus transmission. Clinicians should understand the infection, its diagnosis and testing, and monitor pregnant women for travel history to outbreak regions and for the presence of clinical symptoms. Patient education on preventive measures offers the best option to avoid Zika virus infection. PMID- 26953675 TI - Ion pair complexes and anion binding in the solution of a ditopic receptor. AB - The synthesis and crystal structures with alkali halides of a ditopic benzo-15 crown-5 bis-urea receptor have been presented. In addition, the anion binding properties of and its alkali metal complexes in solution are presented. A comprehensive single-crystal X-ray crystallographic study of , all together 13 crystal structures, including the ion pair complexes with NaCl, NaBr, NaI, KF, KCl, KBr, KI, RbF, RbCl, and RbI, give a detailed view of how behaves in the solid-state with different alkali halides depending on the size of the cation and anion. In the solid-state forms a 1 : 1 complex with a sodium cation and the anion is complexed as a contact (NaCl) or a separate ion pair (NaBr, NaI). With larger potassium and rubidium cations assembles into a 2 : 1 complex and forms a separated ion pair complex with the anion. Reflecting the crystal structures the forms a 1 : 1 complex with Na(+) in solution, and a 2 : 1 complex with K(+), which were verified by Job's plot analysis in 4 : 1 CDCl3/dimethyl sulfoxide. The binding strength of the monomeric [.Na](+) and the dimeric [2.K](+) toward chloride, bromide and iodide anions was studied by (1)H NMR titrations in 4 : 1 CDCl3/DMSO, and a clear turn-on effect of the cation complexation compared to the neutral receptor alone (Ka with for Cl(-), Br(-) and I(-) being 832, 174 and 32 M(-1), respectively) was observed. The monomeric [.Na](+) binds chloride 9, bromide 8, and iodide 12 times stronger than , while for the dimeric [2K](+) the corresponding increase in binding is 51 (Cl(-)), 84 (Br(-)), and 22 (I(-)) times with the same stoichiometric ratios as observed for the ion pair complexes in the solid-state. PMID- 26953674 TI - Use of Temperature Sensors to Determine Exclusivity of Improved Stove Use and Associated Household Air Pollution Reductions in Kenya. AB - Household air pollution (HAP) contributes to 3.5-4 million annual deaths globally. Recent interventions using improved cookstoves (ICS) to reduce HAP have incorporated temperature sensors as stove use monitors (SUMs) to assess stove use. We deployed SUMs in an effectiveness study of 6 ICSs in 45 Kenyan rural homes. Stove were installed sequentially for 2 weeks and kitchen air monitoring was conducted for 48 h during each 2-week period. We placed SUMs on the ICSs and traditional cookstoves (TCS), and the continuous temperature data were analyzed using an algorithm to examine the number of cooking events, days of exclusive use of ICS, and how stove use patterns affect HAP. Stacking, defined as using both a TCS and an ICS in the same day, occurred on 40% of the study days, and exclusive use of the ICS occurred on 25% of study days. When researchers were not present, ICS use declined, which can have implications for long-term stove adoption in these communities. Continued use of TCSs was also associated with higher HAP levels. SUMs are a valuable tool for characterizing stove use and provide additional information to interpret HAP levels measured during ICS intervention studies. PMID- 26953676 TI - Solid state carbon nanotube device for controllable trion electroluminescence emission. AB - Semiconducting carbon nanotubes (CNTs) have a direct chirality-dependent bandgap and reduced dimensionality-related quantum confinement effects, which are closely related to the performance of optoelectronic devices. Here, taking advantage of the large energy separations between neutral singlet excitons and charged excitons, i.e. trions in CNTs, we have achieved for the first time all trion electroluminescence (EL) emission from chirality-sorted (8,3) and (8,4) CNT-based solid state devices. We showed that strong trion emission can be obtained as a result of localized impact excitation and electrically injected holes, with an estimated efficiency of ~5 * 10(-4) photons per injected hole. The importance of contact-controlled carrier injection (including symmetric and asymmetric contact configurations) and EL spectral stability for gradually increasing bias were also investigated. The realization of electrically induced pure trion emission opens up a new opportunity for CNT film-based optoelectronic devices, providing a new degree of freedom in controlling the devices to extend potential applications in spin or magnetic optoelectronics fields. PMID- 26953677 TI - Impact of High-Fidelity Pediatric Simulation on Paramedic Seizure Management. AB - BACKGROUND: A simulation-based course, Pediatric Simulation Training for Emergency Prehospital Providers (PediSTEPPs), was developed to optimize pediatric prehospital care. Seizures are common in Emergency Medical Services (EMS), and no studies have evaluated pediatric outcomes after EMS simulation training. OBJECTIVES: The primary objective was to determine if PediSTEPPs enhances seizure protocol adherence in blood glucose measurement and midazolam administration for seizing children. The secondary objective was to describe management of seizing patients by EMS and Emergency Departments (EDs). METHODS: This is a two-year retrospective cohort study of paramedics who transported 0-18 year old seizing patients to ten urban EDs. Management was compared between EMS crews with at least one paramedic who attended PediSTEPPs and crews that had none. Blood glucose measurement, medications administered, intravenous (IV) access, seizure recurrence, and respiratory failure data were collected from databases and run reports. Data were compared using Pearson's chi(2) test and odds ratios with 95% confidence intervals (categorical) and the Mann-Whitney test (continuous). RESULTS: Of 2200 pediatric transports with a complaint of seizure, 250 (11%) were actively seizing at the time of transport. Of these, 65 (26%) were treated by a PediSTEPPs-trained paramedic. Blood glucose was slightly more likely to be checked by trained than untrained paramedics (OR = 1.35, 95% CI 0.72-2.51). Overall, 58% received an indicated dose of midazolam, and this was slightly more likely in the trained than untrained paramedics (OR = 1.39, 95% CI 0.77-2.49). There were no differences in secondary outcomes between groups. The prevalence of hypoglycemia was low (2%). Peripheral IVs were attempted in 80%, and midazolam was predominantly given by IV (68%) and rectal (12%) routes, with 51% receiving a correct dose. Seizures recurred in 22%, with 34% seizing on ED arrival. Respiratory failure occurred in the prehospital setting in 25 (10%) patients in the study. CONCLUSION: Simulation-based training on pediatric seizure management may have utility. Data support the need to optimize the route and dose of midazolam for seizing children. Blood glucose measurement in seizure protocols may warrant reprioritization due to low hypoglycemia prevalence. KEY WORDS: seizure; emergency medical services; simulation; pediatrics. PMID- 26953680 TI - Comparison of Copy Number of HSF Genes in Two Buffalo Genomes. AB - The copy number variation (CNV) is the number of copies of a particular gene in the genotype of an individual. Recent evidences show that the CNVs can vary in frequency and occurrence between breeds. These variations reportedly allowed different breeds to adapt to different environments. As copy number variations follow Mendelian pattern of inheritance, identification and distribution of these variants between populations can be used to infer the evolutionary history of the species. In this study, we have examined the absolute copy number of four Heat shock factor genes viz. HSF-1, 2, 4, and 5 in two different breeds of buffalo species using real-time PCR. Here, we report that the absolute copy number of HSF2 varies between the two breeds. In contrast no significant difference was observed in the copy number for HSF-1, 4, and 5 between the two breeds. Our results provide evidence for the presence of breed specific differences in HSF2 genomic copy number. This seems to be the first step in delineating the genetic factors underlying environmental adaptation between the two breeds. Nevertheless, a more detailed study is needed to characterize the functional consequence of this variation. PMID- 26953681 TI - Visual, tangible, and touch-screen: Comparison of platforms for displaying simple graphics. AB - Four different platforms were compared in a task of exploring an angular stimulus and reporting its value. The angle was explored visually, tangibly as raised fine grit sandpaper, or on a touch-screen with a frictional or vibratory signal. All platforms produced highly accurate angle judgments. Differences were found, however, in exploration time, with vision fastest as expected, followed by tangible, vibration, and friction. Relative to the tangible display, touch screens evidenced greater noise in the perceived angular value, with a particular disadvantage for friction. The latter must be interpreted in the context of a first-generation display and a rapidly advancing technology. On the whole, the results point both to promise and barriers in the use of refreshable graphical displays for blind users. PMID- 26953683 TI - Uncovering the behavior of Hf2Te2P and the candidate Dirac metal Zr2Te2P. AB - Results are reported for single crystal specimens of Hf2Te2P and compared to its structural analogue Zr2Te2P, which was recently proposed to be a potential reservoir for Dirac physics [1]. Both materials are produced using the iodine vapor phase transport method and the resulting crystals are exfoliable. The bulk electrical transport and thermodynamic properties indicate Fermi liquid behavior at low temperature for both compounds. Quantum oscillations are observed in magnetization measurements for fields applied parallel but not perpendicular to the c-axis, suggesting that the Fermi surfaces are quasi-two dimensional. Frequencies are determined from quantum oscillations for several parts of the Fermi surfaces. Lifshitz-Kosevich fits to the temperature dependent amplitudes of the oscillations reveal small effective masses, with a particularly small value [Formula: see text] for the alpha branch of Zr2Te2P. Electronic structure calculations are in good agreement with quantum oscillation results and illustrate the effect of a stronger spin-orbit interaction going from Zr to Hf. These results suggest that by using appropriate tuning parameters this class of materials may deepen the pool of novel Dirac phenomena. PMID- 26953684 TI - Amniotic fluid calreticulin in pregnancies complicated by the preterm prelabor rupture of membranes. AB - OBJECTIVE: This study aimed to determine the amniotic fluid calreticulin concentrations in women with the preterm prelabor rupture of membranes (PPROM) based on the microbial invasion of the amniotic cavity (MIAC), intraamniotic inflammation (IAI) and microbial-associated IAI. METHODS: One hundred sixty-eight women with singleton pregnancies were included in this study. Amniotic fluid samples were obtained by transabdominal amniocentesis and were assayed for calreticulin concentrations by ELISA. IAI was defined as an amniotic fluid interleukin-6 concentration > 745 pg/ml. Microbial-associated IAI was defined as the presence of both MIAC and IAI. RESULT: Women with MIAC (with MIAC: median 54.4 ng/ml, versus without MIAC: median 32.6 ng/ml; p < 0.0001), IAI (with IAI: median 66.8 ng/ml, versus without IAI: median 33.0 ng/ml; p < 0.0001) and microbial-associated IAI (with microbial-associated IAI: median 82.5 ng/ml, versus without microbial-associated IAI: median 33.7 ng/ml; p < 0.0001) had higher concentrations of calreticulin than women without these complications. An amniotic fluid calreticulin concentration of 81.4 ng/ml was found to be the best cutoff point for identifying women with microbial-associated IAI. CONCLUSIONS: The presence of microbial-associated IAI is associated with increased amniotic fluid calreticulin concentrations. Calreticulin seems to be a promising marker for the early identification of PPROM complicated by microbial-associated IAI. PMID- 26953685 TI - Determination of trans-resveratrol in Solanum americanum Mill. by HPLC. AB - Solanum americanum Mill. is a plant that belongs to the Solanaceae family, its respective ripe fruit is dark purple. Ripe S. americanum Mill. fruits were submitted to physicochemical characterisation, and their trans-resveratrol contents were quantified by high-performance liquid chromatography. Such determination was executed with fruits at different stages of ripeness and freeze stored fruits as well. In natura ripe fruit pulp and peel presented average trans resveratrol amounts of 1.07 and 0.7960 MUg per gram of sample, respectively. These amounts are significantly higher when compared to freeze-stored fruit (0.1353 MUg of trans-resveratrol per gram of sample) and to other berries. All ripe fruits showed significant amounts of total anthocyanins and total antioxidants. Thus, for the first time, trans-resveratrol has been identified and quantified in S. americanum Mill. fruit samples. PMID- 26953687 TI - Monoamine oxidase-induced hydroxyl radical production and cardiomyocyte injury during myocardial ischemia-reperfusion in rats. AB - To elucidate the involvement of monoamine oxidase (MAO) in hydroxyl radical production and cardiomyocyte injury during ischemia as well as after reperfusion, we applied microdialysis technique to the heart of anesthetized rats. Dialysate samples were collected during 30 min of induced ischemia followed by 60 min of reperfusion. We monitored dialysate 3,4-dihydrobenzoic acid (3,4-DHBA) concentration as an index of hydroxyl radical production using a trapping agent (4-hydroxybenzoic acid), and dialysate myoglobin concentration as an index of cardiomyocyte injury in the ischemic region. The effect of local administration of a MAO inhibitor, pargyline, was investigated. Dialysate 3,4-DHBA concentration increased from 1.9 +/- 0.5 nM at baseline to 3.5 +/- 0.7 nM at 20-30 min of occlusion. After reperfusion, dialysate 3,4-DHBA concentration further increased reaching a maximum (4.5 +/- 0.3 nM) at 20-30 min after reperfusion, and stabilized thereafter. Pargyline suppressed the averaged increase in dialysate 3,4-DHBA concentration by ~72% during occlusion and by ~67% during reperfusion. Dialysate myoglobin concentration increased from 235 +/- 60 ng/ml at baseline to 1309 +/- 298 ng/ml at 20-30 min after occlusion. After reperfusion, dialysate myoglobin concentration further increased reaching a peak (5833 +/- 1017 ng/ml) at 10-20 min after reperfusion, and then declined. Pargyline reduced the averaged dialysate myoglobin concentration by ~56% during occlusion and by ~41% during reperfusion. MAO plays a significant role in hydroxyl radical production and cardiomyocyte injury during ischemia as well as after reperfusion. PMID- 26953688 TI - Executive Functions in Tobacco Dependence: Importance of Inhibitory Capacities. AB - BACKGROUND: Executive functions are linked to tobacco dependence and craving. In this cross-sectional study, we assessed the impact of three executive functions: updating, inhibition and shifting processes on tobacco craving and dependence. METHOD: 134 tobacco consumers were included in this study: 81 moderately (Fagerstrom score <7) and 53 heavily dependent (Fagerstrom score >7). Dependence was assessed with the Fagerstrom test and craving with the tobacco craving questionnaire (TCQ 12). We used the Stroop test and the Hayling test to measure inhibition, the Trail Making Test to measure shifting processes and the n-back test to measure updating processes. A multivariate logistic model was used to assess which variables explained best the level of nicotine dependence. RESULTS: Inhibition (p = 0.002) and updating (p = 0.014) processes, but not shifting processes, were associated with higher tobacco dependence. Inhibition capacity had a significant effect on the nicotine dependence level independently of age, education, time since last cigarette, intellectual quotient, craving, updating and shifting process. CONCLUSIONS: Nicotine dependence level seems better explained by inhibition capacities than by craving and updating effects. The capacity to inhibit our behaviours is a good predictor of the severity of tobacco dependence. Our results suggest a prefrontal cortex dysfunction affecting the inhibitory capacities of heavy tobacco dependent smokers. Further studies are needed to investigate the application of these findings in the treatment of tobacco dependence. PMID- 26953689 TI - Reasons for Non-Suicidal Self-Harm in Adult Male Offenders With and Without Borderline Personality Traits. AB - The presented study aimed to advance understanding of the reasons for non suicidal self-harm (NSSH) in adult male offenders, with and without borderline personality traits. 179 offenders completed self-report measures of NSSH and other clinical constructs, with 42 being identified as having self-harmed. Results were consistent with past research and supported the relative importance of intrapersonal over interpersonal functions, but also highlight that self-harm is performed rarely for one type of reason. The results also show that the presence of borderline personality traits increases the likelihood of endorsing a range of interpersonal reasons. These findings highlight the importance of understanding the range of reasons for engaging in NSSH to help manage the behaviour within the prison. PMID- 26953690 TI - Seasonally Changing Cryptochrome 1b Expression in the Retinal Ganglion Cells of a Migrating Passerine Bird. AB - Cryptochromes, blue-light absorbing proteins involved in the circadian clock, have been proposed to be the receptor molecules of the avian magnetic compass. In birds, several cryptochromes occur: Cryptochrome 2, Cryptochrome 4 and two splice products of Cryptochrome 1, Cry1a and Cry1b. With an antibody not distinguishing between the two splice products, Cryptochrome 1 had been detected in the retinal ganglion cells of garden warblers during migration. A recent study located Cry1a in the outer segments of UV/V-cones in the retina of domestic chickens and European robins, another migratory species. Here we report the presence of cryptochrome 1b (eCry1b) in retinal ganglion cells and displaced ganglion cells of European Robins, Erithacus rubecula. Immuno-histochemistry at the light microscopic and electron microscopic level showed eCry1b in the cell plasma, free in the cytosol as well as bound to membranes. This is supported by immuno blotting. However, this applies only to robins in the migratory state. After the end of the migratory phase, the amount of eCry1b was markedly reduced and hardly detectable. In robins, the amount of eCry1b in the retinal ganglion cells varies with season: it appears to be strongly expressed only during the migratory period when the birds show nocturnal migratory restlessness. Since the avian magnetic compass does not seem to be restricted to the migratory phase, this seasonal variation makes a role of eCry1b in magnetoreception rather unlikely. Rather, it could be involved in physiological processes controlling migratory restlessness and thus enabling birds to perform their nocturnal flights. PMID- 26953691 TI - A Quantitative Dynamic Simulation of Bremia lactucae Airborne Conidia Concentration above a Lettuce Canopy. AB - Lettuce downy mildew, caused by the oomycete Bremia lactucae Regel, is a major threat to lettuce production worldwide. Lettuce downy mildew is a polycyclic disease driven by airborne spores. A weather-based dynamic simulation model for B. lactucae airborne spores was developed to simulate the aerobiological characteristics of the pathogen. The model was built using the STELLA platform by following the system dynamics methodology. The model was developed using published equations describing disease subprocesses (e.g., sporulation) and assembled knowledge of the interactions among pathogen, host, and weather. The model was evaluated with four years of independent data by comparing model simulations with observations of hourly and daily airborne spore concentrations. The results show an accurate simulation of the trend and shape of B. lactucae temporal dynamics of airborne spore concentration. The model simulated hourly and daily peaks in airborne spore concentrations. More than 95% of the simulation runs, the daily-simulated airborne conidia concentration was 0 when airborne conidia were not observed. Also, the relationship between the simulated and the observed airborne spores was linear. In more than 94% of the simulation runs, the proportion of the linear variation in the hourly-observed values explained by the variation in the hourly-simulated values was greater than 0.7 in all years except one. Most of the errors came from the deviation from the 1:1 line, and the proportion of errors due to the model bias was low. This model is the only dynamic model developed to mimic the dynamics of airborne inoculum and represents an initial step towards improved lettuce downy mildew understanding, forecasting and management. PMID- 26953692 TI - Exploring Entrainment Patterns of Human Emotion in Social Media. AB - Emotion entrainment, which is generally defined as the synchronous convergence of human emotions, performs many important social functions. However, what the specific mechanisms of emotion entrainment are beyond in-person interactions, and how human emotions evolve under different entrainment patterns in large-scale social communities, are still unknown. In this paper, we aim to examine the massive emotion entrainment patterns and understand the underlying mechanisms in the context of social media. As modeling emotion dynamics on a large scale is often challenging, we elaborate a pragmatic framework to characterize and quantify the entrainment phenomenon. By applying this framework on the datasets from two large-scale social media platforms, we find that the emotions of online users entrain through social networks. We further uncover that online users often form their relations via dual entrainment, while maintain it through single entrainment. Remarkably, the emotions of online users are more convergent in nonreciprocal entrainment. Building on these findings, we develop an entrainment augmented model for emotion prediction. Experimental results suggest that entrainment patterns inform emotion proximity in dyads, and encoding their associations promotes emotion prediction. This work can further help us to understand the underlying dynamic process of large-scale online interactions and make more reasonable decisions regarding emergency situations, epidemic diseases, and political campaigns in cyberspace. PMID- 26953694 TI - Reliability of System Identification Techniques to Assess Standing Balance in Healthy Elderly. AB - OBJECTIVES: System identification techniques have the potential to assess the contribution of the underlying systems involved in standing balance by applying well-known disturbances. We investigated the reliability of standing balance parameters obtained with multivariate closed loop system identification techniques. METHODS: In twelve healthy elderly balance tests were performed twice a day during three days. Body sway was measured during two minutes of standing with eyes closed and the Balance test Room (BalRoom) was used to apply four disturbances simultaneously: two sensory disturbances, to the proprioceptive and the visual system, and two mechanical disturbances applied at the leg and trunk segment. Using system identification techniques, sensitivity functions of the sensory disturbances and the neuromuscular controller were estimated. Based on the generalizability theory (G theory), systematic errors and sources of variability were assessed using linear mixed models and reliability was assessed by computing indexes of dependability (ID), standard error of measurement (SEM) and minimal detectable change (MDC). RESULTS: A systematic error was found between the first and second trial in the sensitivity functions. No systematic error was found in the neuromuscular controller and body sway. The reliability of 15 of 25 parameters and body sway were moderate to excellent when the results of two trials on three days were averaged. To reach an excellent reliability on one day in 7 out of 25 parameters, it was predicted that at least seven trials must be averaged. CONCLUSION: This study shows that system identification techniques are a promising method to assess the underlying systems involved in standing balance in elderly. However, most of the parameters do not appear to be reliable unless a large number of trials are collected across multiple days. To reach an excellent reliability in one third of the parameters, a training session for participants is needed and at least seven trials of two minutes must be performed on one day. PMID- 26953693 TI - Cellular and Physiological Effects of Dietary Supplementation with beta-Hydroxy beta-Methylbutyrate (HMB) and beta-Alanine in Late Middle-Aged Mice. AB - There is growing evidence that severe decline of skeletal muscle mass and function with age may be mitigated by exercise and dietary supplementation with protein and amino acid ingredient technologies. The purposes of this study were to examine the effects of the leucine catabolite, beta-hydroxy-beta methylbutyrate (HMB), in C2C12 myoblasts and myotubes, and to investigate the effects of dietary supplementation with HMB, the amino acid beta-alanine and the combination thereof, on muscle contractility in a preclinical model of pre sarcopenia. In C2C12 myotubes, HMB enhanced sarcoplasmic reticulum (SR) calcium release beyond vehicle control in the presence of all SR agonists tested (KCl, P<0.01; caffeine, P = 0.03; ionomycin, P = 0.03). HMB also improved C2C12 myoblast viability (25 MUM HMB, P = 0.03) and increased proliferation (25 MUM HMB, P = 0.04; 125 MUM HMB, P<0.01). Furthermore, an ex vivo muscle contractility study was performed on EDL and soleus muscle from 19 month old, male C57BL/6nTac mice. For 8 weeks, mice were fed control AIN-93M diet, diet with HMB, diet with beta-alanine, or diet with HMB and beta-alanine. In beta-alanine fed mice, EDL muscle showed a 7% increase in maximum absolute force compared to the control diet (202 +/- 3vs. 188+/- 5 mN, P = 0.02). At submaximal frequency of stimulation (20 Hz), EDL from mice fed HMB plus beta-alanine showed an 11% increase in absolute force (88.6 +/- 2.2 vs. 79.8 +/- 2.4 mN, P = 0.025) and a 13% increase in specific force (12.2 +/- 0.4 vs. 10.8 +/- 0.4 N/cm2, P = 0.021). Also in EDL muscle, beta-alanine increased the rate of force development at all frequencies tested (P<0.025), while HMB reduced the time to reach peak contractile force (TTP), with a significant effect at 80 Hz (P = 0.0156). In soleus muscle, all experimental diets were associated with a decrease in TTP, compared to control diet. Our findings highlight beneficial effects of HMB and beta-alanine supplementation on skeletal muscle function in aging mice. PMID- 26953695 TI - Genome Analysis of Listeria monocytogenes Sequence Type 8 Strains Persisting in Salmon and Poultry Processing Environments and Comparison with Related Strains. AB - Listeria monocytogenes is an important foodborne pathogen responsible for the disease listeriosis, and can be found throughout the environment, in many foods and in food processing facilities. The main cause of listeriosis is consumption of food contaminated from sources in food processing environments. Persistence in food processing facilities has previously been shown for the L. monocytogenes sequence type (ST) 8 subtype. In the current study, five ST8 strains were subjected to whole-genome sequencing and compared with five additionally available ST8 genomes, allowing comparison of strains from salmon, poultry and cheese industry, in addition to a human clinical isolate. Genome-wide analysis of single-nucleotide polymorphisms (SNPs) confirmed that almost identical strains were detected in a Danish salmon processing plant in 1996 and in a Norwegian salmon processing plant in 2001 and 2011. Furthermore, we show that L. monocytogenes ST8 was likely to have been transferred between two poultry processing plants as a result of relocation of processing equipment. The SNP data were used to infer the phylogeny of the ST8 strains, separating them into two main genetic groups. Within each group, the plasmid and prophage content was almost entirely conserved, but between groups, these sequences showed strong divergence. The accessory genome of the ST8 strains harbored genetic elements which could be involved in rendering the ST8 strains resilient to incoming mobile genetic elements. These included two restriction-modification loci, one of which was predicted to show phase variable recognition sequence specificity through site-specific domain shuffling. Analysis indicated that the ST8 strains harbor all important known L. monocytogenes virulence factors, and ST8 strains are commonly identified as the causative agents of invasive listeriosis. Therefore, the persistence of this L. monocytogenes subtype in food processing facilities poses a significant concern for food safety. PMID- 26953696 TI - Mutational and Structural Analysis of Conserved Residues in Ribose-5-Phosphate Isomerase B from Leishmania donovani: Role in Substrate Recognition and Conformational Stability. AB - Ribose-5-phosphate isomerase B from Leishmania donovani (LdRpiB) is one of the potential drug targets against visceral leishmaniasis. In the present study, we have targeted several conserved amino acids for mutational analysis (i.e. Cys69, His11, His102, His138, Asp45, Tyr46, Pro47 and Glu149) to gain crucial insights into their role in substrate binding, catalysis and conformational stability of the enzyme. All the eight LdRpiB variants were cloned, sequenced, expressed and purified. C69S, H102N, D45N and E149A mutants exhibited complete loss of enzyme activity indicating that they are indispensable for the enzyme activity. Kinetic parameters were altered in case of H138N, H11N and P47A variants; however Y46F exhibited similar kinetic behaviour as wild type. All the mutants except H138N exhibited altered protein structure as determined by CD and fluorescence spectral analysis. This data was supported by the atomic level details of the conformational changes and substrate binding using molecular dynamic simulations. LdRpiB also exhibited activity with D-form of various aldose substrates in the order of D-ribose > D-talose > D-allose > D-arabinose. Our study provides insights for better understanding of substrate enzyme interactions which can rationalize the process of drug design against parasite RpiB. PMID- 26953699 TI - Life cycle assessment of dairy farms. AB - In 2013 the population of dairy cattle in Indonesia had reached 636,000 head with a 4.61% growth rate per year. The inputs were energy, water, and feed. These inputs produced outputs, such as emissions, solid waste and liquid waste. This research compared the maintenance systems in modern farms and local farms. The data were collected from 30 local farmers and one modern farm. This research used the life cycle assessment (LCA) method. LCA is based on ISO 14040. LCA consists of several stages: the goal and scope definition, inventory analysis, impact assessment, and interpretation. This research used the cradle to gate concept and fat corrected milk (FCM) as the function unit. The impacts of these activities could generate global warming potential (GWP), acidification potential (AP), and eutrophication potential (EP). The calculations showed that the systems in local farms had the greatest emissions result over all impacts. In the case of local farms, the GWP was 2.34 kg CO2 eq/L of milk FCM, AP was 0.12 g SO2 eq/L of milk FCM, and EP was 18.28 g PO43- $P{O_{?rm{4}}}^{{?rm{3}} - }$ eq/L milk FCM. While the impact from the modern farm was GWP of 1.52 kg CO2 eq/L of milk FCM, AP of 0.02 g SO2 eq/L of milk FCM, and EP of 0.353 g PO43- $P{O_{?rm{4}}}^{{?rm{3}} - }$ eq/L of milk FCM. Based on the total-weighted result, the GWP had the greatest impact from the overall life cycle phase of milk production. The total-weighted result obtained was of 0.298 EUR/L of FCM from a local farm and 0.189 EUR/L of FCM from the modern farm. This amount could be used to remediate the global warming, acidification, and eutrophication impacts of milk production. PMID- 26953697 TI - Origin of Bacteriochlorophyll a and the Early Diversification of Photosynthesis. AB - Photosynthesis originated in the domain Bacteria billions of years ago; however, the identity of the last common ancestor to all phototrophic bacteria remains undetermined and speculative. Here I present the evolution of BchF or 3-vinyl bacteriochlorophyll hydratase, an enzyme exclusively found in bacteria capable of synthetizing bacteriochlorophyll a. I show that BchF exists in two forms originating from an early divergence, one found in the phylum Chlorobi, including its paralogue BchV, and a second form that was ancestral to the enzyme found in the remaining anoxygenic phototrophic bacteria. The phylogeny of BchF is consistent with bacteriochlorophyll a evolving in an ancestral phototrophic bacterium that lived before the radiation event that gave rise to the phylum Chloroflexi, Chlorobi, Acidobacteria, Proteobacteria, and Gemmatimonadetes, but only after the divergence of Type I and Type II reaction centers. Consequently, it is suggested that the lack of phototrophy in many groups of extant bacteria is a derived trait. PMID- 26953700 TI - Proteomics of Sphingobium indicum B90A for a deeper understanding of hexachlorocyclohexane (HCH) bioremediation. AB - Genome wide expression profiling of Sphingobium indicum B90A revealed induction of lin genes, linA and linB, involved in dechlorination of hexachlorocyclohexane (HCH), in the presence of all four isomers of HCH. Supporting proteomics data, the qPCR and promoter assay showed upregulation of linA transcription in the presence of HCH isomers. Analysis of the upstream region of the linA gene revealed the existence of the GntR binding site overlapping the -10 hexamer of the putative promoter motif. As GntR is a known transcription repressor its dissociation from the linA promoter is expected to induce lin genes in the presence of HCH isomers. Comparison of in situ and in-culture proteomics indicated expression lin genes at the dumpsite, an indication for the in situ HCH degradation. PMID- 26953701 TI - Exposure assessment of lead from food and airborne dusts and biomonitoring in pregnant mothers, their fetus and siblings in Karachi, Pakistan and Shimotsuke, Japan. AB - AIM: Exposure assessment of lead (Pb) and Arsenic (As) from food, water, and house dust intake were assessed among pregnant women, their children and fetuses in Pakistan and Japan, as well as their body burden of the metals in their blood. METHOD: Fifty families which included a pregnant woman, a fetus and the 1-3-year old siblings were recruited in Karachi and Khairpur in Pakistan, and Shimotsuke and Asahikawa in Japan, respectively. Their dietary exposure to Pb and As was measured in 3-day food duplicates and drinking water by ICP-MP. Pb in house dust and respirable dust was evaluated with an energy dispersive X-ray fluorescence spectrometry. Non-radioactive isotope Pb profiles of blood specimens will be compared with those of the exposure origins, such as food duplicates, respirable house dust, the soils nearby, and gasoline. RESULTS: Judging from the data collected and analyzed so far, contribution from dietary intake is highly correlated to higher body burden of Pb among Pakistani mothers. Additional data analyses will reveal the status of Pb and As body burden in Pakistani mothers, fetuses and their siblings, and causal sources of high body burden is delineated by Pb isotope profile analysis of different sources of Pb exposure. PMID- 26953702 TI - The "CHILD" framework for the study of artisanal mercury mining communities. AB - In this paper, our group reports the use of a new framework in sites contaminated with mercury. This is significant because under the Minamata Convention on Mercury each Party shall endeavor to develop appropriate strategies for identifying and assessing sites contaminated by mercury or mercury compounds. This new approach, the "CHILD" framework has five steps: i) Community-based risk characterization; ii) Habilitation; iii) Intervention; iv) Laws and Regulation; and v) Development. We are using this framework in three mercury artisanal mining sites, and preliminary results are depicted in this report. PMID- 26953703 TI - Community-based efforts in health promotion in indigenous villages on the Thailand-Myanmar border. AB - This case study of mainly Karen and Mon communities in Kanchanaburi Province, western Thailand, offers insight into the challenges that these rural villages face with regard to food security and environmental health issues. As non-Thai communities, these villages receive little support from the Thai government, and are often vulnerable in terms of access to food markets, infrastructure, and education and livelihood opportunities. This discussion further considers the involvement of Pattanarak Foundation, a Thai NGO, in health promotion and economic development in these villages as an example of a community partnership at the grassroots level. Examining Pattanarak's efforts to build skills in household vegetable gardening and livestock-raising, raise awareness about child nutrition issues, and improve community sanitation illustrates the value of a participatory process, and also demonstrates some of the challenges associated with on-the-ground health promotion in disadvantaged rural communities. Applying a community-based participatory research (CBPR) framework to pursue partnerships between communities, NGOs, and researchers may offer an avenue for effective interventions to improve health in marginalized communities. PMID- 26953704 TI - Pacific connections for health, ecosystems and society: new approaches to the land-water-health nexus. AB - Renewed effort to understand the social-ecological context of health is drawing attention to the dynamics of land and water resources and their combined influence on the determinants of health. A new area of research, education and policy is emerging that focuses on the land-water-health nexus: this orientation is applicable from small wetlands through to large-scale watersheds or river basins, and draws attention to the benefits of combined land and water governance, as well as the interrelated implications for health, ecological and societal concerns. Informed by research precedents, imperatives and collaborations emerging in Canada and parts of Oceania, this review profiles three integrative, applied approaches that are bringing attention to the importance the land-water-health nexus within the Pacific Basin: wetlands and watersheds as intersectoral settings to address land-water-health dynamics; tools to integrate health, ecological and societal dynamics at the land-water-health nexus; and indigenous leadership that is linking health and well-being with land and water governance. Emphasis is given to key characteristics of a new generation of inquiry and action at the land-water-health nexus, as well as capacity-building, practice and policy opportunities to address converging environmental, social and health objectives linked to the management and governance of land and water resources. PMID- 26953705 TI - Arsenic projects in SE Asia. AB - Early life exposure to inorganic arsenic is associated with a wide range of malignant and chronic disease outcomes in humans. Prenatal arsenic exposure may give rise to adverse effects on child health and development as arsenic readily passes through the placenta in human beings. The impact of maternal arsenic exposure on fetal gene expression was conducted in pregnant women living in Southern Thailand. Arsenic exposed newborns had significantly higher levels of arsenic in cord blood, and a set of genes associated with numerous biological pathways, including cell signaling, apoptosis, inflammatory and stress response. A slight increase in promoter methylation of p53 in cord blood lymphocytes which correlated with arsenic accumulation in nails was observed in these exposed newborns. A follow-up study on these exposed children showed a significant increase in oxidative DNA damage, measured as 8-hydroxydeoxyguanosine (8-OHdG) in saliva. In addition, levels of urinary 8-OHdG excretion and salivary hOGG1 expression were significantly decreased in exposed children suggesting a defect in repair of 8-OHdG in arsenic-exposed children. Our study indicates that prenatal arsenic and continued exposure through early childhood can trigger various genetic and epigenetic alterations that may lead to disease development later in life. PMID- 26953706 TI - Protecting health from metal exposures in drinking water. AB - Drinking water is essential to us as human beings. According to the World Health Organization "The quality of drinking-water is a powerful environmental determinant of health" (http://www.who.int/water_sanitation_health/dwq/en/), but clean drinking water is a precious commodity not always readily available. Surface and ground water are the major sources of drinking water. Both can be contaminated, surface water with bacteria while ground water frequently contains salts of metals that occur naturally or are introduced by human activity. This paper will briefly review the metallic salts found in drinking water in areas around the world, as well as list some of the methods used to reduce or remove them. It will then discuss our research on reducing the risk of pollution of drinking water by removal of metal ions from wastewater. PMID- 26953707 TI - Prevalence and clinical features of polycystic ovarian syndrome in adolescents with previous childhood growth hormone deficiency. AB - BACKGROUND: Growth hormone (GH) plays a role in the regulation of ovarian function but there are limited data in women with GH deficiency (GHD). Our aim was to evaluate the features of polycystic ovarian syndrome (PCOS) in women with previous GHD. METHODS: Data of 22 adolescents previously GH-treated (group A) were compared with those of 22 women with classical PCOS (group B) and 20 controls (group C). RESULTS: Group A showed higher testosterone (p=0.048) and prevalence of menstrual irregularities (p<0.001) than group C. Compared to the group B, group A showed lower diastolic blood pressure (p=0.004), degree of hirsutism (p=0.005), testosterone (p=0.003) and prevalence of polycsytic ovaries (POC) morphology (p=0.024), with higher HDL-cholesterol (p=0.035) and 17-beta estradiol (p=0.009). CONCLUSIONS: Adolescents with previous GHD show a higher prevalence of PCOS than controls, but with milder metabolic and hormonal features than adolescents with classical PCOS. A careful long-term follow-up is advisable in these patients. PMID- 26953708 TI - Prenatal cocaine exposure and its impact on cognitive functions of offspring: a pathophysiological insight. AB - It is estimated that approximately 0.5%-3% of fetuses are prenatally exposed to cocaine (COC). The neurodevelopmental implications of this exposure are numerous and include motor skill impairments, alterations of social function, predisposition to anxiety, and memory function and attention deficits; these implications are commonly observed in experimental studies and ultimately affect both learning and IQ. According to previous studies, the clinical manifestations of prenatal COC exposure seem to persist at least until adolescence. The pathophysiological cellular processes that underlie these impairments include dysfunctional myelination, disrupted dendritic architecture, and synaptic alterations. On a molecular level, various neurotransmitters such as serotonin, dopamine, catecholamines, and gamma-aminobutyric acid seem to participate in this process. Finally, prenatal COC abuse has been also associated with functional changes in the hormones of the hypothalamic-pituitary-adrenal axis that mediate neuroendocrine responses. The purpose of this review is to summarize the neurodevelopmental consequences of prenatal COC abuse, to describe the pathophysiological pathways that underlie these consequences, and to provide implications for future research in the field. PMID- 26953709 TI - Identifying risk in the use of tumor markers to improve patient safety. AB - BACKGROUND: Tumor markers (TM) are a routine test that are not always used well, and can lead to unnecessary additional tests, which are not without risks for the patients. So, to implement appropriate strategies to improve the adequate use of TM and, therefore, improve patient safety, is required to analyze the use of TM, identifying risks and establishing if there are differences in their use as a function of their utility. METHODS: The study was a descriptive, longitudinal, retrospective and systematic study in the area covered by the University Hospital of Padua. In the follow-up 2-year study, 23,059 analytical requests of TM, corresponding to 14,728 patients, were analyzed. For the level of statistical significance it applies an approximation of the normal law (Z statistic) and chi2 test. RESULTS: Only 9196 requests (39.88%) out of a total of 23,059 on 5080 patients with neoplastic diseases have been classified as adecuate according to current guidelines. The number of requests per patient was variable (1.57+/ 1.35). In patients with neoplastic diseases this increased to 1.80+/-1.68. The mean of number of TM per request was 2.4+/-1.73. The analysis showed an association between the number of requests and the type of marker used. CONCLUSIONS: The use of TM is variable, mainly of the follow-up markers, when they are used as screening. This inappropriate use, minimizes their utility favoring erroneous interpretations and increases the risk of damage to the patient. So it is essential to implement safe practices in the use of TM. PMID- 26953710 TI - The physiology of functional hypothalamic amenorrhea associated with energy deficiency in exercising women and in women with anorexia nervosa. AB - An energy deficiency is the result of inadequate energy intake relative to high energy expenditure. Often observed with the development of an energy deficiency is a high drive for thinness, dietary restraint, and weight and shape concerns in association with eating behaviors. At a basic physiologic level, a chronic energy deficiency promotes compensatory mechanisms to conserve fuel for vital physiologic function. Alterations have been documented in resting energy expenditure (REE) and metabolic hormones. Observed metabolic alterations include nutritionally acquired growth hormone resistance and reduced insulin-like growth factor-1 (IGF-1) concentrations; hypercortisolemia; increased ghrelin, peptide YY, and adiponectin; and decreased leptin, triiodothyronine, and kisspeptin. The cumulative effect of the energetic and metabolic alterations is a suppression of the hypothalamic-pituitary-ovarian axis. Gonadotropin releasing hormone secretion is decreased with consequent suppression of luteinizing hormone and follicle stimulating hormone release. Alterations in hypothalamic-pituitary secretion alters the production of estrogen and progesterone resulting in subclinical or clinical menstrual dysfunction. PMID- 26953711 TI - A link between hypothyroidism, obesity and male reproduction. AB - Hypothyroidism is a condition in which the serum levels of thyroid hormones are below that necessary to carry out physiological functions in the body. Hypothyroidism is related to obesity as an increase in body weight gain is seen in hypothyroid patients. Moreover, an inverse correlation between free thyroxine values and body mass index has been reported. Leptin, a polypeptide hormone produced by adipocytes, was originally thought to be an antiobesity hormone due its anorexic effects on hypothalamic appetite regulation. However, nowadays it is known that leptin conveys information about the nutritional status to the brain being considered a crucial endocrine factor for regulating several physiological processes including reproduction. Since the identification of thyroid hormone and leptin receptors on the testes, these hormones are being recognized as having important roles in male reproductive functions. A clear link exists among thyroid hormones, leptin and reproduction. Both hormones can negatively affect spermatogenesis and consequently may cause male infertility. The World Health Organization (WHO) estimates the overall prevalence of primary infertility ranging from 8 to 15%. The fact that 30% of couples' inability to conceive is related to a male factor and that the longer hypothyroidism persisted, the greater the damage to the testes, strongly suggest that more studies attempting to clarify both hormones actions directly in the testes need to be conducted specially in cases of congenital hypothyroidism. Therefore, the goal of this review is to highlight the relationship of such hormones in the reproductive system. PMID- 26953712 TI - Molecular mechanisms redirecting the GLP-1 receptor signalling profile in pancreatic beta-cells during type 2 diabetes. AB - Treatments with beta-cell preserving properties are essential for the management of type 2 diabetes (T2D), and the new therapeutic avenues, developed over the last years, rely on the physiological role of glucagon-like peptide-1 (GLP-1). Sustained pharmacological levels of GLP-1 are achieved by subcutaneous administration of GLP-1 analogues, while transient and lower physiological levels of GLP-1 are attained following treatment with inhibitors of dipeptidylpeptidase 4 (DPP4), an endoprotease which degrades the peptide. Both therapeutic classes display a sustained and durable hypoglycaemic action in patients with T2D. However, the GLP-1 incretin effect is known to be reduced in patients with T2D, and GLP-1 analogues and DPP4 inhibitors were shown to lose their effectiveness over time in some patients. The pathological mechanisms behind these observations can be either a decrease in GLP-1 secretion from intestinal L-cells and, as a consequence, a reduction in GLP-1 plasma concentrations, combined or not with a reduced action of GLP-1 in the beta-cell, the so-called GLP-1 resistance. Much evidence for a GLP-1 resistance of the beta-cell in subjects with T2D have emerged. Here, we review the potential roles of the genetic background, the hyperglycaemia, the hyperlipidaemia, the prostaglandin E receptor 3, the nuclear glucocorticoid receptor, the GLP-1R desensitization and internalisation processes, and the beta-arrestin-1 expression levels on GLP-1 resistance in beta cells during T2D. PMID- 26953715 TI - Furoxan-Bearing Micelles for Nitric Oxide Delivery. AB - Furoxans, or 1,2,5-oxadiazole-N-oxides, are a class of nitric oxide (NO)-donating compounds that release NO in response to thiol-containing molecules. In this study, polymeric micelles bearing furoxan moieties are prepared from an amphiphilic block copolymer consisting of a hydrophobic furoxan-bearing block and a hydrophilic poly(N-acryloylmorpholine) block. The block copolymer is prepared using a combination of the reversible addition-fragmentation chain transfer polymerization and the copper-catalyzed Huisgen cycloaddition techniques. The block copolymers form spherical micelles with a diameter of 50 nm by self assembly in water. The micelles release NO in response to cysteine and show improved stability against hydrolytic decomposition. Furthermore, the micelles show a synergistic anti-proliferative effect with ibuprofen in human colon cancer cells. PMID- 26953717 TI - One-Pot Trimetallic Relay Catalysis: A Unified Approach for the Synthesis of beta Carbolines and Other [c]-Fused Pyridines. AB - A divergent strategy is presented for the synthesis of 1,3-di- and 1,3,4 trisubstituted beta-carbolines through an unprecedented one-pot triple-orthogonal metal relay catalysis, and 1,3-disubstituted 4-hydroxy-beta-carbolines through a one-pot bimetallic relay catalysis from readily accessible 3-(2-aminophenyl)-5 hexenyn-3-ols. These strategies were elaborated to enable the synthesis of benzofuro[2,3-c]pyridines, benzothieno[2,3-c]pyridines, and isoquinolines, which otherwise require multistep synthesis. PMID- 26953716 TI - Imatinib prevents beta cell death in vitro but does not improve islet transplantation outcome. AB - Introduction Improving islet transplantation outcome could not only bring benefits to individual patients but also widen the patient pool to which this life-changing treatment is available. Imatinib has previously been shown to protect beta cells from apoptosis in a variety of in vitro and in vivo models. The aim of this study was to investigate whether imatinib could be used to improve islet transplantation outcome. Methods Islets were isolated from C57Bl/6 mice and pre-cultured with imatinib prior to exposure to streptozotocin and cytokines in vitro. Cell viability and glucose-induced insulin secretion were measured. For transplantation experiments, islets were pre-cultured with imatinib for either 72 h or 24 h prior to transplantation into streptozotocin-diabetic C57Bl/6 mice. In one experimental series mice were also administered imatinib after islet transplantation. Results Imatinib partially protected islets from beta cell death in vitro. However, pre-culturing islets in imatinib or administering the drug to the mice in the days following islet transplantation did not improve blood glucose concentrations more than control-cultured islets. Conclusion Although imatinib protected against beta cell death from cytokines and streptozotocin in vitro, it did not significantly improve syngeneic islet transplantation outcome. PMID- 26953718 TI - Are Biometric Parameters Helpful to Assess the Health Risk of Consuming Organochlorine Compounds Contaminated Silver European Eel (Anguilla anguilla)? AB - Several organochlorine compounds (OCs) were measured in European eels from the Tevere river (Italy). It followed that some of them are still important chemical contaminants. Concentrations of dichlorodiphenyltrichloroethanes (DDTs) are hazardous for the consumer health; those of the 6 indicator polychlorinated biphenyls (PCBs) are often close to the current European maximum residue limit and always higher than the former limit. The relationship between OC concentrations, biometric parameters and the lipid content was then investigated. A strong positive correlation with eel size emerged for the indicator PCBs and DDTs concentrations expressed on wet weight basis. This is explained by the corresponding higher lipid percentage that characterizes bigger eels and the absence of a dilution effect for compounds of main concerns. On the basis of the PCB-TDI threshold for a 70 kg person, we suggest that 1 should consume no more than 2 eels per week each weighing about 100 g. Thus, we conclude that eel consumption should be limited and restricted to eels relatively shorter and lighter. PMID- 26953720 TI - Piezo-Catalytic Effect on the Enhancement of the Ultra-High Degradation Activity in the Dark by Single- and Few-Layers MoS2 Nanoflowers. AB - Single- and few-layer MoS2 nanoflowers are first discovered to have a piezo catalyst effect, exhibiting an ultra-high degradation activity in the dark by introducing external mechanical strains. The degradation ratio of the Rhodamine-B dye solution reaches 93% within 60 s under ultrasonic-wave assistance in the dark. PMID- 26953719 TI - A single-center experience with infections due to daptomycin-nonsusceptible Enterococcus faecium in liver transplant recipients. AB - BACKGROUND: Infections caused by vancomycin-resistant Enterococcus faecium (VRE) are a major cause of morbidity and mortality in the liver transplant population. Daptomycin (DAP) is often used to treat infections caused by VRE, but DAP nonsusceptibility in Enterococcus is increasing. METHOD: Patients with DAP nonsusceptible Enterococcus (DNSE) infections who had undergone liver transplantation between January 1, 2010 and July 31, 2014 were retrospectively reviewed. A convenience sample of DNSE isolates was analyzed by pulsed-field gel electrophoresis (PFGE). RESULTS: We identified 14 liver transplant recipients (LTRs) who developed DNSE infections post transplantation. Postoperative complications were common, and most patients required repeat abdominal surgery within 90 days of transplantation. The initial DNSE culture was taken a median of 74.5 days post transplant and was secondary to an intra-abdominal infection in all but 1 patient. Half of patients were VRE colonized before or at the time of organ transplantation, and all those who were not VRE colonized at the time of transplantation later became colonized, a median of 27 days post transplant. Overall mortality in this cohort was 71%. PFGE did not demonstrate genetic relatedness among DNSE isolates. CONCLUSION: This study, the largest published series to our knowledge of DNSE infections in LTRs, demonstrates that these infections occur in patients with serious surgical complications and are associated with high morbidity and mortality. Established risk factors for VRE infection were common, as was DAP exposure. Although many risk factors for DNSE infection cannot be changed, this case series identifies several potentially modifiable variables. Further work is needed to identify interventions to decrease the risk of developing DNSE infections in this complex patient population. PMID- 26953722 TI - Improving efficiency using the Rao-Blackwell theorem in corrected and conditional score estimation methods for joint models. AB - Longitudinal covariates in survival models are generally analyzed using random effects models. By framing the estimation of these survival models as a functional measurement error problem, semiparametric approaches such as the conditional score or the corrected score can be applied to find consistent estimators for survival model parameters without distributional assumptions on the random effects. However, in order to satisfy the standard assumptions of a survival model, the semiparametric methods in the literature only use covariate data before each event time. This suggests that these methods may make inefficient use of the longitudinal data. We propose an extension of these approaches that follows a generalization of Rao-Blackwell theorem. A Monte Carlo error augmentation procedure is developed to utilize the entirety of longitudinal information available. The efficiency improvement of the proposed semiparametric approach is confirmed theoretically and demonstrated in a simulation study. A real data set is analyzed as an illustration of a practical application. PMID- 26953723 TI - Vulnerable Dark Triad Personality Facets Are Associated with Religious Fundamentalist Tendencies. AB - BACKGROUND: This study explores the possibility that religious fundamentalism (RF) may be linked to deficits in personality structure, which is in contrast to the general assumption that religiosity and spirituality are positively related to mature personality development. SAMPLING AND METHODS: To test this hypothesis, 327 (232 female) college students completed the Multidimensional Inventory for Religious/Spiritual Well-Being together with the Innsbrucker Religious Fundamentalism Scale. In addition, the 'vulnerable dark triad' of personality ('vulnerable narcissism', subscale of the Pathological Narcissism Inventory; 'secondary psychopathy', subscale of Levenson's Self-Report Psychopathy Scale; 'borderline personality', of the Borderline Personality Inventory) was assessed. RESULTS: In general, the relation between spirituality and healthy personality functioning was confirmed. In addition to greatly overlapping with 'general religiosity' (p < 0.001), RF was also relevantly predicted by narcissistic ('hiding the self') and borderline ('primitive defenses') personality facets (p < 0.05 for both). CONCLUSIONS: Based on these preliminary data, we conclude that specific structural deficits in personality might lead to more rigorous variants of religious/spiritual beliefs such as RF. Further research in clinical surroundings as well as in religious extremist groups is recommended. PMID- 26953724 TI - Blood Leukocytes as Prognostic Parameter in Stroke Thrombectomy. AB - PURPOSE: Despite the recent success of mechanical thrombectomy (MT) in the treatment of acute ischemic stroke, prognostic parameters and criteria for patient selection are yet uncertain. Elevated levels of white blood cells (WBCs) constitute an independent risk factor for unfavorable outcome. Here we studied the link between outcome and WBC counts obtained before and after successful MT. METHODS: One hundred fifteen acute stroke patients successfully treated with MT (thrombolysis in cerebral infarction-scores 2b or 3) were included. WBC counts and C-reactive protein (CRP) levels were obtained prior to (WBC-pre, CRP-pre) and 1 day after MT (WBC-post, CRP-post). Clinical outcome measures consisted of National Institute of Health Stroke Scale (NIHSS) scores, and modified Rankin Scale (mRS) on day 90 (mRS-d90), dichotomized between scores <=5 and >5 (NIHSS) and <=2 and >2 (mRS). The association between WBC-/CRP-levels and outcome was assessed by correlation- and receiver-operating characteristic analyses. RESULTS: WBC counts on day 1 after MT correlated significantly with NIHSS scores at discharge and mRS-d90. Among patients >50 years, no patient with WBC-post counts exceeding 14.2 G/l had favorable NIHSS scores (<=5), and no one with WBC-post counts >=12.6 G/l had favorable mRS-d90 outcome-scores (<=2). Further, even WBC pre counts >=10.6 G/l predicted unfavorable mRS-d90-scores in this subgroup. CONCLUSION: Elevated WBC counts obtained in routine blood tests may constitute a simple and economic parameter to estimate outcome after successful MT. Moreover, present data suggest that in patients older than 50 years, WBC counts may help to predict outcome even when obtained prior to MT. PMID- 26953725 TI - Associations between Milk and Egg Allergens and the HLA-DRB1/DQ Polymorphism: A Bioinformatics Approach. AB - BACKGROUND: Little is known about the associations between human leukocyte antigens (HLAs) and food allergies. Our aim was to analyze the associations between the HLA class II polymorphism and food allergy using bioinformatics. METHODS: A two-step algorithm was developed which mimics the food allergen processing in the human body. In the first step, the allergen is digested by pepsin, trypsin and chymotrypsin. In the second step, the digested fragments bind to the most frequent 12 HLA-DRB1 and 5 HLA-DQ alleles, and the binding affinities are predicted. RESULTS: The algorithm was applied to 13 well-known milk and egg allergens. The predicted HLA binders were compared to known T-cell and IgE epitopes originating from the same allergens, and 77% of them were found to overlap. We found that the peptides generated from milk allergens bind to DRB1*01:01, DQ7 and DQ8 but not to DRB1*03:01, DRB1*04:04, DRB1*12:01 and DRB1*15:01. The peptides generated from egg allergens bind to DRB1*01:01, DQ4, DQ7 and DQ8 but not to DRB1*03:01, DRB1*04:04 and DRB1*12:01. They bind to all the DQs studied. The alleles that bind to allergen peptides could be considered as susceptible to the particular allergy and the nonbinding alleles as protective. CONCLUSIONS: The alleles DRB1*01:01, DQ7 and DQ8 are considered as susceptible to cow's milk allergy and DRB1*03:01, DRB1*04:04, DRB1*12:01 and DRB1*15:01 as protective. The alleles DRB1*01:01, DQ4, DQ7 and DQ8 are considered as susceptible to egg allergy and DRB1*03:01, DRB1*04:04 and DRB1*12:01 as protective. Protective DQs against egg allergy were not revealed in this study. PMID- 26953726 TI - Graft selection strategy in adult-to-adult living donor liver transplantation: When both hemiliver grafts meet volumetric criteria. AB - To ensure donor safety in living donor liver transplantation (LDLT), the left and caudate lobe (LL) is the preferred graft choice. However, patient prognosis may still be poor even if graft volume (GV) selection criteria are met. Our aim was to evaluate the effects of right lobe (RL) donation when the LL graft selection criteria are met. Consecutive donors (n = 135) with preoperative LL graft volumetric GV/standard liver volume (SLV) of >=35% and RL remnant of >=35% were retrospectively studied. Patients were divided into 2 groups: LL graft and RL graft. Recipient's body surface area (BSA), Model for End-Stage Liver Disease (MELD) score, and the donor's age were higher in the RL group. The donor's BSA and preoperative volumetric GV/SLV of the LL graft were smaller in the RL group. The predicted score (calculated using data for graft size, donor age, MELD score, and the presence of portosystemic shunt, which correlated well with graft function and with 6-month graft survival) of the RL group, was significantly lower if the LL graft were used, but using the actual RL graft improved the score equal to that of the LL group. Six-month and 12-month graft survival rates did not differ between the 2 groups. In patients with a poor prognosis, a larger RL graft improved the predicted score and survival was equal to that of patients who received LL grafts. In conclusion, graft selection by GV, donor age, and recipient MELD score improves outcomes in LDLT. Liver Transplantation 22 914-922 2016 AASLD. PMID- 26953727 TI - Glucose Sensing Using Functionalized Amorphous In-Ga-Zn-O Field-Effect Transistors. AB - Recent advances in glucose sensing have focused on the integration of sensors into contact lenses to allow noninvasive continuous glucose monitoring. Current technologies focus primarily on enzyme-based electrochemical sensing which requires multiple nontransparent electrodes to be integrated. Herein, we leverage amorphous indium gallium zinc oxide (IGZO) field-effect transistors (FETs), which have found use in a wide range of display applications and can be made fully transparent. Bottom-gated IGZO-FETs can have significant changes in electrical characteristics when the back-channel is exposed to different environments. We have functionalized the back-channel of IGZO-FETs with aminosilane groups that are cross-linked to glucose oxidase and have demonstrated that these devices have high sensitivity to changes in glucose concentrations. Glucose sensing occurs through the decrease in pH during glucose oxidation, which modulates the positive charge of the aminosilane groups attached to the IGZO surface. The change in charge affects the number of acceptor-like surface states which can deplete electron density in the n-type IGZO semiconductor. Increasing glucose concentrations leads to an increase in acceptor states and a decrease in drain source conductance due to a positive shift in the turn-on voltage. The functionalized IGZO-FET devices are effective in minimizing detection of interfering compounds including acetaminophen and ascorbic acid. These studies suggest that IGZO FETs can be effective for monitoring glucose concentrations in a variety of environments, including those where fully transparent sensing elements may be of interest. PMID- 26953728 TI - Long-Term Outcomes after Critical Illness. The Best Predictor of the Future Is the Past. PMID- 26953729 TI - Treatment of pharmaceutical wastewater using interior micro-electrolysis/Fenton oxidation-coagulation and biological degradation. AB - The synthesis of steroid hormones produces wastewater that is difficult to manage and characterize due to its complex components and high levels of toxicity and bio-refractory compounds. In this work, interior micro-electrolysis (IME) and Fenton oxidation-coagulation (FOC) were investigated as wastewater pretreatment processes in combination with biological treatments using a hydrolysis acidification unit (HA) and two-stage biological contact oxidation (BCO) in laboratory and field experiments. In laboratory experiments with an average initial COD load of about 15,000 mg/L, pH of 4, Fe-C/water (V/V) ratio of 1:1, air/water ratio of 10, and reaction time of 180 min, IME achieved a COD removal efficiency of 31.8% and a 1.7-fold increase in the BOD5/COD (B/C) ratio of wastewater. The Fe(2+) concentration of 458.5 mg/L in the IME effluent meets the requirements of the Fenton oxidation (FO) process. FOC further reduced the COD with an efficiency of 30.1%, and the B/C ratio of the wastewater reached 0.59. Excitation-emission matrix (EEM) analysis showed that complex higher molecular weight organic compounds in the wastewater were degraded after the pretreatment process. In addition, a field experiment with a continuous flow of 96 m(3)/d was conducted for over 90 d. The combined process system operated steadily, though the Fe-C fillings should be soaked in a sulfuric acid solution (50/00) for 12 h to recover activity every two weeks. The COD and BOD5 concentrations in the final effluent were less than 90 mg/L and 15 mg/L, respectively. PMID- 26953730 TI - A highly facile and selective Chemo-Paper-Sensor (CPS) for detection of strontium. AB - Chemosensors have attracted increasing attention for their usefulness on-site detection and monitoring. In this study, we elucidated a novel, facile, and highly selective Chemo-Paper-Sensor (CPS) for detection and monitoring of strontium (Sr(2+)) ions, which means a potent colorimetric sensor based on a Chrysoidine G (CG)-coated paper strip. The CPS for highly selective colorimetric detection of strontium ion was handily analyzed to determine the red-green-blue (RGB) value using portable devices such as desktop digital scanner and mobile phone camera, quantitatively. Interestingly, an orange to dark orange color transition was observed when the aqueous and solid paper colorimetric sensor was introduced to Sr(2+) ion, respectively. It was demonstrated that the value of the signal has a linear relationship with concentrations of the strontium in the 500 ppm to 100 ppb range with a detection limit of 200 ppb. We believe that a newly developed Chemo-Paper-Sensor will be useful in a wide range of sensing applications. PMID- 26953731 TI - Degradation of Verapamil hydrochloride in water by gliding arc discharge. AB - This study investigated the influence of gliding arc plasma discharge on the degradation of Verapamil hydrochloride in water. The plasma discharge was characterized by means of optical emission spectroscopy. Spectra of various atomic and molecular species were observed. Aqueous solution of Verapamil hydrochloride was exposed to gliding arc discharge operated in continuous discharge at atmospheric pressure and room temperature. The identification of Verapamil, the degradation mechanisms of Verapamil and its transformation products were performed using liquid chromatography - mass spectrometry (HPLC MS). Experimental results indicate that the atmospheric pressure gliding arc plasma treatment has noticeable effects on Verapamil with satisfactory degradation efficiency. Plausible mechanisms of the degradation were discussed. PMID- 26953732 TI - Correction: Iron Regulation of the Major Virulence Factors in the AIDS-Associated Pathogen Cryptococcus neoformans. PMID- 26953733 TI - Impact of female age and nulligravidity on fecundity in an older reproductive age cohort. AB - OBJECTIVE: To provide female age-related estimates of fecundity and incidence of infertility by history of prior pregnancy among women 30-44 years of age. DESIGN: Prospective, time-to-pregnancy cohort study. SETTING: Not applicable. PATIENT(S): Women, between 30 and 44 years of age, attempting to conceive for <=3 months, and no known history of infertility, polycystic ovarian syndrome (PCOS), or endometriosis. INTERVENTION(S): Not applicable. MAIN OUTCOME MEASURE(S): Fecundability and incidence of infertility. RESULT(S): Compared to women aged 30 31 years, fecundability was reduced by 14% in women 34-35 years of age (fecundability ratio [FR] 0.86, 95% confidence interval [CI] 0.68-1.08), 19% in women 36-37 years of age (FR 0.81, 95% CI 0.60-1.08, 30% in women 38-39 years of age (FR 0.70, 95% CI 0.48-1.01), 53% in women 40-41 years of age (FR 0.47, 95% CI 0.28-0.78), and 59% in women 42-44 years of age (FR 0.39, 95% CI 0.16-0.93). Fecundability did not differ between women aged 30-31 years and 32-33 years. In general, fecundability and cumulative probability of pregnancy was lower for women who had never had a prior pregnancy. CONCLUSION(S): Women experience a significant reduction in fecundity and increase in the probability of infertility in their late thirties. At any age >30 years, women who have never conceived have a lower probability of achieving a pregnancy. CLINICAL TRIAL REGISTRATION NUMBER: NCT01028365. PMID- 26953734 TI - Inequity between male and female coverage in state infertility laws. AB - OBJECTIVE: To analyze state insurance laws mandating coverage for male factor infertility and identify possible inequities between male and female coverage in state insurance laws. DESIGN: We identified states with laws or codes related to infertility insurance coverage using the National Conference of States Legislatures' and the National Infertility Association's websites. We performed a primary, systematic analysis of the laws or codes to specifically identify coverage for male factor infertility services. SETTING: Not applicable. PATIENT(S): Not applicable. INTERVENTION(S): Not applicable. MAIN OUTCOME MEASURE(S): The presence or absence of language in state insurance laws mandating coverage for male factor infertility care. RESULT(S): There are 15 states with laws mandating insurance coverage for female factor infertility. Only eight of those states (California, Connecticut, Massachusetts, Montana, New Jersey, New York, Ohio, and West Virginia) have mandates for male factor infertility evaluation or treatment. Insurance coverage for male factor infertility is most specific in Massachusetts, New Jersey, and New York, yet significant differences exist in the male factor policies in all eight states. Three states (Massachusetts, New Jersey, and New York) exempt coverage for vasectomy reversal. CONCLUSION(S): Despite national recommendations that male and female partners begin infertility evaluations together, only 8 of 15 states with laws mandating infertility coverage include coverage for the male partner. Excluding men from infertility coverage places an undue burden on female partners and risks missing opportunities to diagnose serious male health conditions, correct reversible causes of infertility, and provide cost-effective treatments that can downgrade the intensity of intervention required to achieve a pregnancy. PMID- 26953735 TI - Metal Organic Frameworks Combining CoFe2O4 Magnetic Nanoparticles as Highly Efficient SERS Sensing Platform for Ultrasensitive Detection of N-Terminal Pro Brain Natriuretic Peptide. AB - N-terminal pro-brain natriuretic peptide (NT-proBNP) has been demonstrated to be a sensitive and specific biomarker for heart failure (HF). Surface-enhanced Raman spectroscopy (SERS) technology can be used to accurately detect NT-proBNP at an early stage for its advantages of high sensitivity, less wastage and time consumption. In this work, we have demonstrated a new SERS-based immunosensor for ultrasensitive analysis of NT-proBNP by using metal-organic frameworks (MOFs)@Au tetrapods (AuTPs) immobilized toluidine blue as SERS tag. Here, MOFs@AuTPs complexes were utilized to immobilize antibody and Raman probe for their excellent characteristics of high porosity, large surface area, and good biocompatibility which can obviously enhance the fixing amount of biomolecule. To simplify the experimental operation and improve the uniformity of the substrate, Au nanoparticles functionalized CoFe2O4 magnetic nanospheres (CoFe2O4@AuNPs) were further prepared to assemble primary antibody. Through sandwiched antibody antigen interactions, the immunosensor can produce a strong SERS signal to detect NT-proBNP fast and effectively. With such design, the proposed immunosensor can achieve a large dynamic range of 6 orders of magnitude from 1 fg mL(-1) to 1 ng mL(-1) with a detection limit of 0.75 fg mL(-1). And this newly designed amplification strategy holds high probability for ultrasensitive immunoassay of NT-proBNP. PMID- 26953738 TI - [Benin epithelioid kidney angiomyolipoma: report of two cases]. PMID- 26953736 TI - Malignant Fibrous Histiocytoma of the Testicular Appendages Mimicking an Obstructed Hernia in an Elderly Man: Case Report and Review of the Literature. PMID- 26953739 TI - The quest to resolve recent radiations: Plastid phylogenomics of extinct and endangered Hawaiian endemic mints (Lamiaceae). AB - The Hawaiian mints (Lamiaceae), one of the largest endemic plant lineages in the archipelago, provide an excellent system to study rapid diversification of a lineage with a remote, likely paleohybrid origin. Since their divergence from New World mints 4-5 million years ago the members of this lineage have diversified greatly and represent a remarkable array of vegetative and reproductive phenotypes. Today many members of this group are endangered or already extinct, and molecular phylogenetic work relies largely on herbarium samples collected during the last century. So far a gene-by-gene approach has been utilized, but the recent radiation of the Hawaiian mints has resulted in minimal sequence divergence and hence poor phylogenetic resolution. In our quest to trace the reticulate evolutionary history of the lineage, a resolved maternal phylogeny is necessary. We applied a high-throughput approach to sequence 12 complete or nearly complete plastid genomes from multiple Hawaiian mint species and relatives, including extinct and rare taxa. We also targeted 108 hypervariable regions from throughout the chloroplast genomes in nearly all of the remaining Hawaiian species, and relatives, using a next-generation amplicon sequencing approach. This procedure generated ~20Kb of sequence data for each taxon and considerably increased the total number of variable sites over previous analyses. Our results demonstrate the potential of high-throughput sequencing of historic material for evolutionary studies in rapidly evolving lineages. Our study, however, also highlights the challenges of resolving relationships within recent radiations even at the genomic level. PMID- 26953740 TI - Homoplasious colony morphology and mito-nuclear phylogenetic discordance among Eastern Pacific octocorals. AB - Octocorals are a diverse and ecologically important group of cnidarians. However, the phylogenetic relationships of many octocoral groups are not well understood and are based mostly on mitochondrial sequence data. In addition, the discovery and description of new gorgonian species displaying unusual or intermediate morphologies and uncertain phylogenetic affinities further complicates the study of octocoral systematics and raises questions about the role played by processes such as plasticity, crypsis, and convergence in the evolution of this group of organisms. Here, we use nuclear (i.e. 28S rDNA) and mitochondrial (mtMutS) markers and a sample of Eastern Pacific gorgonians thought to be remarkable from a morphological point of view to shed light on the morphological diversification among these organisms. Our study reveals the loss of the anastomosed colony morphology in two unrelated lineages of the seafan genus Pacifigorgia and offers strong evidence for the independent evolution of a whip-like morphology in two lineages of Eastern Pacific Leptogorgia. Additionally, our data revealed one instance of mito-nuclear discordance in the genera Leptogorgia and Eugorgia, which may be the results of incomplete lineage sorting or ancient hybridization introgression events. Our study stresses the importance of comprehensive taxonomic sampling and the use of independent sources of evidence to address the phylogenetic relationships and clarifying the evolution of octocorals. PMID- 26953741 TI - Complete genome sequence of Halocynthiibacter arcticus PAMC 20958(T) from an Arctic marine sediment sample. AB - Here, we present the first complete genome sequence of the strain PAMC 20958(T) from the genus Halocynthiibacter. Halocynthiibacter arcticus PAMC 20958(T), isolated from a marine sediment of the Arctic, is a gram-negative, aerobic, and rod-shaped bacterium. The complete genome contains 4,329,554 base pairs with 53.21% GC content and a 44,566 base pair plasmid with 48.72% GC content. This genome contained genes encoding alkaline phosphatase and lipase, and genes that confer resistance to arsenic, cadmium, tellurite, and acriflavin. PMID- 26953742 TI - Complete genome sequence of Deinococcus actinosclerus BM2(T), a bacterium with Gamma-radiation resistance isolated from soil in South Korea. AB - A Gram-positive, short-rod shaped and non-motile bacterium Deinococcus actinosclerus BM2(T), resistant to gamma and UV radiation, was isolated from a soil sample collected in South Korea. Strain BM2(T) showed high resistance to gamma radiation with D10 value of 9 kGy. The complete genome of D. actinosclerus BM2(T) consists of a single chromosome (3,264,334bp). The genome features showed the presence of intracellular proteases that help to eliminate radiation-induced ROS during recovery from ionizing radiation damage. PMID- 26953743 TI - Substitution of the native srfA promoter by constitutive Pveg in two B. subtilis strains and evaluation of the effect on Surfactin production. AB - The genetic enhancement of Surfactin production increasingly gained attention in the last years, since relatively low product yields limit the industrial application of this biosurfactant. The natural quorum sensing regulation of the srfA operon (coding for the Surfactin synthetase) can reasonably be assumed to be the bottleneck of Surfactin synthesis. Therefore, the replacement of the naturally quorum sensing regulated, and herewith cell density dependent, promoter PsrfA against the Bacillus subtilis endogenous and constitutive promoter Pveg was hypothesized to generally enhance Surfactin yields. The markerless promoter replacement was conducted in the two B. subtilis Surfactin producer strains 3A38 and DSM 10(T). The promoter substitution led to an enhancement of Surfactin concentrations in the producer strain 3A38, initially producing only minor amounts of Surfactin (0.07g/L increased to 0.26g/L). In contrast, promoter exchange in B. subtilis DSM 10(T) (wild-type strain producing 0.62g/L Surfactin) did not achieve an enhancement of Surfactin concentrations (detrimental reduction to 0.04g/L). These findings implicate that Surfactin synthesis is differently regulated in minor and strong Surfactin producer strains. The hypothesized general enhancement of Surfactin yields after substitution of the native promoter was therefore not confirmed. PMID- 26953744 TI - Engineering an Escherichia coli platform to synthesize designer biodiesels. AB - Biodiesels, fatty acid esters (FAEs), can be synthesized by condensation of fatty acid acyl CoAs and alcohols via a wax ester synthase in living cells. Biodiesels have advantageous characteristics over petrodiesels such as biodegradability, a higher flash point, and less emission. Controlling fatty acid and alcohol moieties are critical to produce designer biodiesels with desirable physiochemical properties (e.g., high cetane number, low kinematic viscosity, high oxidative stability, and low cloud point). Here, we developed a flexible framework to engineer Escherichia coli cell factories to synthesize designer biodiesels directly from fermentable sugars. In this framework, we designed each FAE pathway as a biodiesel exchangeable production module consisting of acyl CoA, alcohol, and wax ester synthase submodules. By inserting the FAE modules in an engineered E. coli modular chassis cell, we generated E. coli cell factories to produce targeted biodiesels (e.g., fatty acid ethyl (FAEE) and isobutyl (FAIbE) esters) with tunable and controllable short-chain alcohol moieties. The engineered E. coli chassis carrying the FAIbE production module produced 54mg/L FAIbEs with high specificity, accounting for>90% of the total synthesized FAEs and ~4.7 fold increase in FAIbE production compared to the wildtype. Fed-batch cultures further improved FAIbE production up to 165mg/L. By mixing ethanol and isobutanol submodules, we demonstrated controllable production of mixed FAEEs and FAIbEs. We envision the developed framework offers a flexible, alternative route to engineer designer biodiesels with tunable and controllable properties using biomass-derived fermentable sugars. PMID- 26953745 TI - Complete genome sequence of Lactobacillus helveticus CAUH18, a potential probiotic strain originated from koumiss. AB - Here we report the complete genome sequence of Lactobacillus helveticus CAUH18, a new strain isolated from traditional fermented dairy product koumiss. Its genome has a circular 2.16Mb chromosome with no plasmid. The genome sequence indicated that this strain harbors a gene cluster involved in a novel exopolysaccharides (EPS) biosynthesis and a gene encoding cell-surface aggregation-promoting factors (APFs) to facilitate its colonization in gastrointestinal tract (GIT). This genome sequence provides a basis for further studies about its molecular genetics and probiotic functions. PMID- 26953747 TI - Recommendations. PMID- 26953746 TI - Novel approaches to microalgal and cyanobacterial cultivation for bioenergy and biofuel production. AB - Growing demand for energy and food by the global population mandates finding water-efficient renewable resources. Microalgae/cyanobacteria have shown demonstrated capacity to contribute to global energy and food security. Yet, despite proven process technology and established net energy-effectiveness and cost-effectiveness through co-product generation, microalgal biofuels are not a reality. This review outlines novel biofilm cultivation strategies that are water smart, the opportunity for direct energy conversion via anaerobic digestion of N2 fixing cyanobacterial biomass and integrative strategies for microalgal biodiesel and/or biocrude production via supercritical methanol-direct transesterification and hydrothermal liquefaction, respectively. Additionally, fermentation of cyanobacterial biofilms could supply bioethanol to feed wet transesterification to biodiesel conversion for on-site use in remote locations. PMID- 26953748 TI - Duration of untreated psychosis: What are we talking about? PMID- 26953749 TI - Schizophrenia: genetics, prevention and rehabilitation. AB - OBJECTIVE: Genetic factors are largely implicated in predisposing to schizophrenia. Environmental factors contribute to the onset of the disorder in individuals at increased genetic risk. Cognitive deficits have emerged as endophenotypes and potential therapeutic targets for schizophrenia because of their association with functional outcome. The aims of this review were to analyse the joint effect of genetic and environmental (G*E) factors on liability to schizophrenia and to investigate relationships between genes and cognitive endophenotypes focusing on practical applications for prevention and rehabilitation. METHODS: Medline search of relevant studies published between 1990 and 2008. RESULTS: In schizophrenia, examples of G*E interaction include the catechol-O-methyl transferase (COMT) (Val158Met) polymorphism, which was found to moderate the onset of psychotic manifestations in response to stress and to increase the risk for psychosis related to cannabis use, and neurodevelopmental genes such as AKT1 (serine-threonine kinase), brain-derived neurotrophic factor (BDNF), DTNBP1 (dysbindin) and GRM3 (metabotropic glutamate receptor 3), which were associated with development of schizophrenia in adulthood after exposure to perinatal obstetric complications. Neurocognitive deficits are recognised as core features of schizophrenia that facilitate the onset of the disorder and have a great impact on functional outcome. Neurocognitive deficits are also endophenotypes that have been linked to a variety of genes [COMT, neuregulin (NRG1), BDNF, Disrupted-In-Schizophrenia 1 (DISC1) and dysbindin] conferring susceptibility to schizophrenia. Recently, it has emerged that cognitive improvement during rehabilitation therapy was under control of COMT (Val158Met) polymorphism. CONCLUSION: This review could indicate a pivotal role of psychiatric genetics in prevention and rehabilitation of schizophrenic psychoses. PMID- 26953750 TI - Safety, tolerability and efficacy of a rapid dose escalation of quetiapine in bipolar I mania: the FATIMA study. AB - OBJECTIVE: The FATIMA study (FAst TItration of quetiapine fumarate in bipolar I MAnia) evaluated the safety, tolerability and efficacy of a rapid dose escalation of quetiapine in acutely ill bipolar I patients experiencing a manic episode. METHODS: In an open-label, phase II pilot study, 29 patients aged 18 years or older, hospitalised with a bipolar I manic episode, received quetiapine twice daily for 21 days. Quetiapine was administered at 200, 400, 600, then 800 mg/day on the first 4 days, with flexible dosing (400-800 mg/day) subsequently. The primary endpoint was the proportion of patient dropouts because of adverse drug reactions during the first 7 days. Secondary safety assessments included incidences of adverse drug reactions and significant changes in vital signs. Efficacy assessments included Young Mania Rating Scale (YMRS) and Clinical Global Impressions Severity of Illness (CGI-S) score changes from day 1 to day 21. RESULTS: Twenty patients (69%) completed the study. No patients withdrew as a result of drug-related adverse events (AEs) during the first 7 days. Twenty-three patients reported 58 adverse events, and most of the adverse events were mild or moderate. No clinically relevant abnormalities in vital signs were reported. Mean YMRS and CGI-S scores decreased significantly from baseline to day 21 (p < 0.001). Response and remission rates were 78 and 70%, respectively, at the end of the study. CONCLUSION: Rapid dose escalation of quetiapine to 800 mg/day over 4 days was well tolerated and effective in reducing symptoms within 5 days in acutely ill bipolar I patients with a manic episode. PMID- 26953751 TI - Upstream genetic variant near INSIG2, influences response to carnitine supplementation in bipolar patients with valproate-induced weight gain. AB - BACKGROUND: The protein product of INSIG2 is involved in cholesterol and triglyceride metabolism and homeostasis. Variation at rs7566605 near the gene INSIG2 has been associated with increased BMI. OBJECTIVE: To evaluate the effect of rs7566605/INSIG2 genotype on the ability of valproate-treated bipolar patients (BMI >= 25 kg/m2) to lose weight using carnitine supplementation during a 26-week lifestyle intervention study. DESIGN: Forty-eight bipolar patients with clinically significant treatment emergent weight gain were genotyped at the rs7566605 SNP. Participants were randomised to l-carnitine (15 mg/kg/day) or placebo for 26 weeks in conjunction with a moderately energy restricted, low-fat diet. Weight and body fat percent were measured fortnightly. Waist circumference measurements and dual-energy X-ray absorptiometry were used to assess changes in body composition. Obesity-related biomarkers were measured at baseline and 26 weeks. RESULTS: There was a significant interaction between rs7566605/INSIG2 genetic status and treatment with carnitine or placebo. Carnitine had no significant effect on body composition measures in G allele homozygous patients who lost between 0.97 and 2.23 kg of fat. However C allele carriers on average gained 2.28 kg when given a placebo. Carnitine supplementation in this group enabled average weight loss of 2.22 kg of fat (p = 0.01). Approximately half of this mass was in the vital truncal compartment (p = 0.002). Bioinformatic analysis detected that the SNP lies in a highly conserved 336 bp sequence which potentially affects INSIG2 gene expression. CONCLUSIONS: C-carriers at rs7566605, possibly regulating the homeostasis gene INSIG2, lost significantly less weight in this lifestyle intervention study. This effect was reversed by carnitine supplementation. PMID- 26953752 TI - Involving Parents in Pediatric Patients' Decisions About Long-Acting Reversible Contraception. PMID- 26953753 TI - Suberoylanilide hydroxamic acid prevents downregulation of spinal glutamate transporter-1 and attenuates spinal nerve ligation-induced neuropathic pain behavior. AB - Glutamate transporter-1 (GLT-1) reduction causes dysregulation of excitatory inhibitory balance, contributing toward neuropathic pain development. However, the mechanisms underlying GLT-1 downregulation are still unclear. Histone acetylation plays a pivotal role in the regulation of gene expression. We sought to examine the contribution of histone acetylation on pain hypersensitivity and GLT-1 downregulation in neuropathic pain development. Histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) was intrathecally infused to rats through osmotic pumps from -5 days to 7 days after spinal nerve ligation (SNL). Behavioral tests indicated that SAHA could significantly prevent SNL induced mechanical allodynia and thermal hyperalgesia. The effect was dose related and lasted to 10 days after SNL when the SAHA infusion was stopped on day 7. Immunohistochemistry, western blot, and real-time reverse transcription PCR analysis showed that SAHA significantly prevented SNL-induced downregulation of GLT-1 in the spinal dorsal horn. In addition, SNL-induced weakened acetylation of histone H3 (AcH3) was significantly inhibited by SAHA. Immunofluorescent histochemistry showed that both GLT-1 and AcH3 had high expressions in the dorsal horn. Double staining indicated that several GLT-1-positive cells were colocalized with AcH3. Our data provide evidence that histone deacetylation may contribute toward the loss of GLT-1 and this could be a new consideration for the development of more effective strategies for treating neuropathic pain. PMID- 26953756 TI - Low-intensity exercise in the acute phase of lipopolysaccharide-induced sepsis improves lipid metabolism and survival in mice by stimulating PGC-1alpha expression. AB - BACKGROUND: The effect of exercise during the acute phase following sepsis onset is poorly understood. We investigated how low-intensity exercise during acute sepsis alters energy-substrate metabolism and survival in mice with lipopolysaccharide (LPS)-induced sepsis. METHODS: Mice were divided into control (C, saline), low-dose LPS (L, 1 mg/kg), medium-dose LPS (M, 5 mg/kg), and high dose LPS (H, 10 mg/kg) groups. Each group was subdivided into sedentary (SED) and exercise (EX) groups; the EX group mice were exercised at low intensity on a treadmill after LPS administration. Survival proportions and vital functions were measured, and indirect calorimetry through respiratory gas analysis was performed until 72 hours after treatment. Organ weight and lipid levels in the plasma and liver were measured, and the messenger RNA and protein levels of peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) were evaluated using quantitative polymerase chain reaction and Western blotting. RESULTS: Survival proportions of H-EX mice were higher than those of H-SED mice. At 16 hours after LPS administration, fatty acid oxidation was decreased in M-SED and H-SED groups but increased in all EX groups and was higher in surviving mice in H-SED and H-EX groups than in nonsurviving mice, suggesting that fatty acid oxidation is related to survival. Epididymal fat weight was lower in the EX groups than in the SED groups, whereas plasma and liver lipid levels were elevated in all EX groups; this suggests that exercise induces the transport of lipids from endogenous fat into the blood and the liver for use as the energy source. Lastly, PGC-1alpha messenger RNA and protein levels were lower in L-, M-, and H-SED groups than in the C-SED group but were high in all EX groups. CONCLUSION: Our study provides the revolutionary finding that exercise during the acute phase following sepsis onset might exert a therapeutic effect. PMID- 26953754 TI - Trauma team discord and the role of briefing. AB - BACKGROUND: Briefing of the trauma team before patient arrival is unstructured in many centers. We surveyed trauma teams regarding agreement on patient care priorities and evaluated the impact of a structured, physician-led briefing on concordance during simulated resuscitations. METHODS: Trauma nurses at our Level II center were surveyed, and they participated in four resuscitation scenarios, randomized to "briefed" or "nonbriefed." For nonbriefed scenarios, nurses independently reviewed triage sheets with written information. Briefed scenarios had a structured 4-minute physician-led briefing reviewing triage sheets identical to nonbriefed scenarios. Teams included three to four nurses (subjects) and two to four confederates (physicians, respiratory therapists). Each team served as their own control group. Confederates were blinded to nurses' briefed or nonbriefed status. Immediately before, and at the midpoint of each scenario, nurses estimated patients' morbidity and mortality and ranked the top 3 of 16 designated immediate care priorities. Briefed and nonbriefed groups' responses were compared for (1) agreement using intraclass correlation coefficient, (2) concordance with physicians' responses using the Fisher exact test, (3) teamwork via T-NOTECHS ratings by nurses and physicians using t-test, and (4) time to complete clinical tasks using t test. RESULTS: Thirty-eight nurses participated. Ninety-seven percent "agreed/strongly agreed" briefing is important, but only 46% agreed briefing was done well. Comparing briefed versus nonbriefed scenarios, nurses' estimation of morbidity and mortality in the briefed scenarios showed significantly greater agreement with each other and with physicians' answers (p < 0.01). Rank lists also better agreed with each other (intraclass correlation coefficient, 0.64 vs 0.59) and with physicians' answers in the briefed scenarios. T-NOTECHS Leadership ratings were significantly higher in the briefed scenarios (3.70 vs 3.39; p < 0.01). Time to completion of key clinical tasks was significantly faster for one of the briefed scenarios. CONCLUSIONS: Discordant perceptions of patient care goals was frequently observed. Structured physician led briefing seemed to improve interprofessional team concordance, leadership, and task completion in simulated trauma resuscitations. PMID- 26953757 TI - Injury prevention programs against distracted driving among students. AB - BACKGROUND: Motor vehicle crashes are the leading cause of death and nonfatal injury among young adults. The aims of this study were to assess the magnitude of distracted driving (DD) among students and to examine the effectiveness of awareness campaign against DD. We hypothesized that DD is prevalent among students and educational efforts such as DD awareness campaign can effectively reduce it. METHODS: This study was conducted within the University of Arizona that has a student enrollment of 42,000 students. We conducted our prospective interventional study in four phases at the university campus. Phase 1 involved 1 week preintervention observation, Phase 2 involved 1-week intervention, Phase 3 involved 1-week postintervention observation, and Phase 4 involved 1-week 6-month postintervention observation. We used a combination of e-mails, pamphlets, interactive sessions, and banners as intervention tools in student union. Our primary outcome was the prevalence of DD before, after, and 6 months after intervention. RESULTS: A total of 47,764 observations (before, 14,844; after, 17,939; 6 months after, 14,981) were performed. During the study period, overall rate of DD rate among the students was 8.8 (5.4) per 100 drivers (texting, 4.8 [3.7] per 100 drivers; talking, 3.9 [2.0] per 100 drivers).The baseline rate of DD among students during the phase one was 9.0 (1.2) per 100 drivers (texting, 4.8 [1.7] per 100 drivers; talking, 4.1 [1.1] per 100 drivers). Following intervention, there was a 32% significant reduction in overall DD (9.0 [1.2] vs. 6.1 [1.7], p < 0.001) in the immediate postintervention phase; however, the rate of DD returned to baseline at 6 months after intervention and trended toward increase (9.0 [1.2] vs. 11.1 [8.4], p = 0.34). CONCLUSION: DD is prevalent among university students. Following a comprehensive preventive campaign against DD, there was a 32% reduction in the rate of DD in the immediate postintervention period. However, a single episode of intervention did not have a sustainable preventive effect on the DD, and the rate increased to the baseline at 6-month follow-up. Targeting DD with a successful injury prevention campaign with repeated boosters may decrease its prevalence among the students. PMID- 26953758 TI - Percutaneously drained intra-abdominal infections do not require longer duration of antimicrobial therapy. AB - BACKGROUND: The length of antimicrobial therapy in complicated intra-abdominal infections (CIAIs) is controversial. A recent prospective, multicenter, randomized controlled trial found that 4 days of antimicrobial therapy after source control of CIAI resulted in similar outcomes when compared with longer duration. We sought to examine whether outcomes remain similar in the subpopulation who received percutaneous drainage for source control of CIAI. METHODS: With the use of the STOP-IT database, patients with a CIAI who received percutaneous drainage were analyzed. Patients were randomized to receive antibiotics until 2 days after the resolution of fever, leukocytosis, and ileus, with a maximum of 10 days of therapy or to receive a fixed course of antibiotics for 4 +/- 1 days. Outcomes included incidence of and time to recurrent intra abdominal infection, Clostridium difficile infection, and extra-abdominal infections as well as hospital days and mortality. RESULTS: Of 518 enrolled patients, 129 met inclusion criteria. Baseline characteristics, including demographics, comorbidities, and severity of illness, were similar. When comparing outcomes of the 4-day group (n = 72) with those of the longer group (n = 57), rates of recurrent intra-abdominal infection (9.7% vs. 10.5%, p = 1.00), C. difficile infection (0% vs. 1.8%, p = 0.442), and hospital days (4.0 [2.0-7.5] vs. 4.0 [3.0-8.0], p = 0.91) were similar. Time to recurrent infection was shorter in the 4-day group (12.7 [6.2] days vs. 21.3 [4.2] days, p = 0.015). There was no mortality. CONCLUSION: In this post hoc analysis of a prospective, multicenter, randomized trial, there was no difference in outcome between a shorter and longer duration of antimicrobial therapy in those with percutaneously drained source control of CIAI. LEVEL OF EVIDENCE: Therapeutic/care management study, level IV. PMID- 26953759 TI - Severe acute pancreatitis for the acute care surgeon. PMID- 26953760 TI - Delayed management of Grade III blunt aortic injury: Series from a Level I trauma center. AB - BACKGROUND: Blunt aortic injuries (BAIs) are traditionally treated as surgical emergencies, with the majority of repairs performed in an urgent fashion within 24 hours, irrespective of the grade of aortic injury. These patients are often underresuscitated and often have multiple other trauma issues that need to be addressed. This study reviews a single center's experience comparing urgent (<24 hours) thoracic endovascular aneurysm repair (TEVAR) versus delayed (>24 hours) TEVAR for Grade III BAI. METHODS: All patients undergoing TEVAR for BAI at a single institution between March 2004 and March 2014 were reviewed (n = 43). Patients with Grade I, II, or IV aortic injuries as well as those who were repaired with an open procedure or who lacked preoperative imaging were excluded from the analysis. Demographics, intraoperative data, postoperative survival, and complications were compared. RESULTS: During this period, there were 43 patients with blunt thoracic aortic injury. There were 29 patients with Grade III or higher aortic injuries. Of these 29 patients, 1 declined surgery, 2 were repaired with an open procedure, 10 underwent urgent TEVAR, and 16 had initial observation. Of these 16, 13 underwent TEVAR in a delayed fashion (median, 9 days; range, 2-91 days), and 3 died of non-aortic-related pathology. Comparing the immediate repair group versus the delayed repair group, there were no significant demographic differences. Trauma classification scores were similar, although patients in the delayed group had a higher number of nonaortic injuries. The 30-day survival was similar between the two groups (9 of 10 vs. 12 of 16), with no mortalities caused by aortic pathology in either group. CONCLUSION: Watchful waiting may be permissible in patients with Grade III BAI with other associated multisystem trauma. This allows for a repair in a more controlled environment. LEVEL OF EVIDENCE: Therapeutic study, level V. PMID- 26953761 TI - Intensity of treatment, end-of-life care, and mortality for older patients with severe traumatic brain injury. AB - BACKGROUND: The Eastern Association for the Surgery of Trauma (EAST) recommends that clinicians consider limiting further aggressive treatment in geriatric patients with severe traumatic brain injury (TBI) who do not improve in 72 hours (nonresponders) owing to their poor prognosis. However, little is known about how these guidelines are followed in practice. This study compared mortality and patient care among geriatric patients with severe TBI classified as "responders" and "nonresponders" 72 hours after injury. METHODS: Retrospective review of patients 65 years or older at a Level I trauma center with severe TBI (GCS < 8) from 2011 to 2014. We compared in-hospital mortality, end-of-life (EOL) decision making, discharge functional status, and 12-month survival in responders (GCS > 8 at 72 hours) and nonresponders (GCS <= 8 at 72 hours). RESULTS: Of 90 patients, 29 (32%) died within 3 days of injury, 29 (32%) were nonresponders, and 32 (34%) were responders. An additional 19 patients (21%) died before hospital discharge, of whom 17 (89%) were nonresponders. Nonresponders had higher odds of in-hospital death (odds ratio, 31.8; 95% confidence interval [CI], 3.71-272.9; p = 0.002). Family meetings to discuss goals of care were more common in the nonresponder group (p < 0.001) and fewer nonresponders were full code at discharge or death (p < 0.001). There were no significant differences in functional status at discharge. Among patients discharged alive, there were no differences in 12-month survival. CONCLUSION: The responder/nonresponder dichotomy identifies patients with higher in-hospital mortality outcomes and is associated with differences in EOL decision making. However, functional impairment and poor survival were prevalent, irrespective of neurologic status at 72 hours. LEVEL OF EVIDENCE: Prognostic/epidemiologic study, level III; therapeutic study, level IV. PMID- 26953762 TI - Sulfur Dioxide Accelerates the Heterogeneous Oxidation Rate of Organic Aerosol by Hydroxyl Radicals. AB - There remains considerable uncertainty in how anthropogenic gas phase emissions alter the oxidative aging of organic aerosols in the troposphere. Here we observe a 10-20 fold acceleration in the effective heterogeneous OH oxidation rate of organic aerosol in the presence of SO2. This acceleration originates from the radical chain reactions propagated by alkoxy radicals, which are formed efficiently inside the particle by the reaction of peroxy radicals with SO2. As the OH approaches atmospheric concentrations, the radical chain length increases, transforming the aerosol at rates predicted to be up to 10 times the OH-aerosol collision frequency. Model predictions, constrained by experiments over orders of magnitude changes in [OH] and [SO2], suggest that in polluted regions the heterogeneous processing of organic aerosols by OH ([SO2] >= 40 ppb) occur on similar time scales as analogous gas-phase oxidation reactions. These results provide evidence for a previously unidentified mechanism by which organic aerosol oxidation is enhanced by anthropogenic gas phase emissions. PMID- 26953763 TI - Paradoxically Decreased Mean Transit Time in Patients Presenting With Acute Stroke. AB - OBJECTIVE: Computed tomography perfusion (CTP) has become a mainstay in acute stroke management. The aim of this study was to investigate the occurrence of an unreported phenomenon of a paradoxically decreased mean transit time (MTT) in the cerebral area of ischemia. METHODS: In this retrospective study, patients with an acute anterior circulation ischemic stroke were selected. Computed tomography perfusion diffusion maps of all patients were reviewed by 2 blinded and experienced neuroradiologists. RESULTS: A total of 31 patients were included in the study. Eighteen subjects (58%) had a paradoxical MTT perfusion map, whereas only 13 (42%) had an expected CTP profile. No significant associations between the paradoxical MTT perfusion and the size of the infarct, the side of the occlusion, or the age of the patients were observed. However, a trend in collateral circulation status and paradoxical MTT was noted. CONCLUSIONS: A paradoxical MTT response is a frequent finding in CTP analysis of patients with acute stroke. Its presence is not associated to the location or size of the affected cerebral territory and could be related to the presence of collateral circulation. PMID- 26953764 TI - Computed Tomographic Pulmonary Angiographic Findings Can Predict Short-Term Mortality of Saddle Pulmonary Embolism: A Retrospective Multicenter Study. AB - OBJECTIVE: In patients with saddle pulmonary embolism (PE), the correlation between computed tomographic pulmonary angiographic (CTPA) findings and short term outcome remains unclear. The purpose is to determine if CTPA findings predict 1-month mortality of patients with saddle PE. METHODS: This is a multicenter, retrospective study of saddle PE. Computed tomographic pulmonary angiographic findings of 115 consecutive patients (male-to-female ratio, 65:50; mean age, 64.3 +/- 16.3 years) with saddle PE were evaluated. One-month mortality after diagnosis was the primary end point. RESULTS: Twenty-four patients died within 1 month. Among CTPA findings, quantitative parameters including right/left ventricular area ratios (RVa/LVa), right/left atrial diameter ratios, Cobb angle, and Mastora score were significantly enlarged in survivors. Also, qualitative findings including contrast agent reflux into the azygos vein and pericardial effusion were significantly different between survivors and nonsurvivors. Areas under the curve on receiver operating characteristic curves revealed the cutoff values for predicting early mortality of saddle PE using right/left atrial diameter ratios, RVa/LVa, Mastora score, and Cobb angle, respectively, were 2.15, 2.00, 69%, and 58 degrees . Logistic regression analysis suggested that both RVa/LVa (odds ratio, 5.100; P = 0.0004) and Cobb angle (odds ratio, 1.596; P = 0.0321) were independent predictors of early mortality. The combination of RVa/LVa and Cobb angle increased the area under the curve to 0.882, but the difference did not reach significance compared with RVa/LVa or Cobb angle, alone (P > 0.05). CONCLUSION: In patients with saddle PE, RVa/LVa and Cobb angle seem valuable in predicting short-term mortality. PMID- 26953766 TI - Multiphase Multi-Detector Row Computed Tomography Imaging Characteristics of Large (>5 cm) Focal Hepatocellular Carcinoma. AB - OBJECTIVE: The aim of this study was to describe the multiphase multi-detector row computed tomography (MDCT) imaging findings of large (>5 cm) focal hepatocellular carcinoma (HCC). METHODS: Following review of the medical records of 321 patients with newly diagnosed HCC who underwent MDCT within the radiology database from January 2007 to November 2014, 27 patients (20 men and 7 women; mean age, 69 [SD, 10.1] years [range, 49-87 years]) with histologically confirmed HCC greater than 5 cm were included in this institutional review board-approved study. Multiphase, dedicated liver MDCT images of these cases were retrospectively reviewed by 2 radiologists in consensus to describe the enhancement characteristics of these lesions. RESULTS: Mean tumor diameter was 8.4 (SD, 2.4) cm (range, 5.2-13.5 cm). Cirrhosis was present in 16 (59%) of 27 patients. Seventeen (85%) of 20 patients with available laboratory data presented with elevated alpha-fetoprotein (median, 97 ng/mL). Twenty-three (85%) of 27 demonstrated either heterogeneous enhancement with gradual fill-in (14/27 [52%]) or peripheral enhancement with centripetal fill-in (9/27 [33%]). Twenty-two (81%) of 27 lacked washout on delayed phase images, and 21 (78%) of 27 demonstrated a pseudocapsule. Twenty-seven of 27 lesions were well defined, 8 (30%) of 27 were exophytic, 15 (56%) of 27 were unifocal, 5 (25%) of 20 cases demonstrated vascular invasion, and 7 (26%) of 27 cases presented with extrahepatic metastases. CONCLUSIONS: Large (>5 cm) focal HCC may present as a dominant mass with a pseudocapsule and initial heterogeneous or peripheral enhancement with gradual or centripetal fill-in without washout on multiphase MDCT. Awareness of this variant is important to allow distinction from other benign (eg, hemangioma) and malignant (eg, cholangiocarcinoma) focal liver lesions. PMID- 26953765 TI - Association of Quadriceps Muscle Fat With Isometric Strength Measurements in Healthy Males Using Chemical Shift Encoding-Based Water-Fat Magnetic Resonance Imaging. AB - Magnetic resonance-based assessment of quadriceps muscle fat has been proposed as surrogate marker in sarcopenia, osteoarthritis, and neuromuscular disorders. We presently investigated the association of quadriceps muscle fat with isometric strength measurements in healthy males using chemical shift encoding-based water fat magnetic resonance imaging. Intermuscular adipose tissue fraction and intramuscular proton density fat fraction correlated significantly (P < 0.05) with isometric strength (up to r = -0.83 and -0.87, respectively). Reproducibility of intermuscular adipose tissue fraction and intramuscular proton density fat fraction was 1.5% and 5.7%, respectively. PMID- 26953767 TI - Utility of MDCT MIP Postprocessing Reconstruction Images in Children With Hereditary Hemorrhagic Telangiectasia. AB - OBJECTIVE: The aim of the study was to evaluate whether maximum intensity projection (MIP) images improve the detection and the delineation of the anatomic makeup of pulmonary nodules and/or arteriovenous malformations (pAVMs) in children with hereditary hemorrhagic telangiectasia (HHT). MATERIALS AND METHODS: Two radiologists (D.M., E.I.C.) performed a blinded review of chest multidetector computed tomography scans in 39 children (age, 0-18 years) with proven HHT. Multiplanar 2.5 mm slices were blindly compared with multiplanar MIP for the presence of nodules and/or overt pAVMs and for the ability to identify vessels associated with the pAVMs. Parameters that were assessed included number of definitive nodules, number of definitive pAVMs, and the ability to detect the feeding artery or draining vein in both conventional and MIP images. RESULTS: Our study showed similar detection rates between axial scans and MIP images for the detection of nodules (axial R1: 75 vs 62, P = 0.05; MIPS: 78 vs 86, P = 0.05) and in the determination of definite pAVMS (axials: 21 vs 29, P = 0.0007; MIPS: 27 vs 35, P = 0.01). Statistically significant differences were obtained in the ability to identify the feeding artery and draining vein between standard 2.5 mm slices and MIP images (axials: 13 vs 13, P = 0.0008; MIPS: 27 vs 23, P = 0.01). No other data parameters achieved statistically significance. CONCLUSIONS: Maximum intensity projection images in children with HHT can help identify the presence and the anatomy of pAVMs for future embolization. PMID- 26953768 TI - Evaluating the Microcirculation of Normal Extraocular Muscles Using Quantitative Dynamic Contrast-Enhanced Magnetic Resonance Imaging. AB - PURPOSE: The purpose of this work was to evaluate the microcirculation of normal extraocular muscles using quantitative dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) (DCE-MRI). MATERIALS AND METHODS: The institutional review board approved the study. Forty-eight eyes were examined using quantitative DCE-MRI on a 3-T MRI system. Quantitative parameters, including the volume transfer constant (Ktrans), the fractional volume of extravascular extracellular space (Ve), and the rate constant (Kep) of each extraocular muscles, were analyzed. The type of DEC time-intensity curve (TIC) was evaluated. The parameters of bilateral extraocular muscles were compared using the Wilcoxon test. The difference in quantitative values of different extraocular muscles was compared using independent-samples Kruskal-Wallis test. RESULTS: No statistical differences of parameters were found between the left and right extraocular muscles (P > 0.05). Volume transfer constant values in medial rectus (MR) muscles and inferior rectus (IR) muscles were significantly higher than those in the lateral rectus (LR) muscles and superior rectus (SR) muscles (P < 0.05). The median Ktrans value of the MR (0.170) was higher than that of the IR (0.151); however, the difference was not significant (P > 0.05). In the 4 extraocular muscles, the Ve values of MR are the largest, followed by the IR, LR, and SR values. The DCE time-intensity curves of extraocular muscles are type II or type III. Medial rectus and IR are mainly type III, and LR and SR are mainly type II. CONCLUSION: The quantitative DCE-MRI can be used as an important and noninvasive technique to evaluate the microcirculation of extraocular muscles. Further investigations for other extraocular muscles diseases by using quantitative DCE MRI are warranted. PMID- 26953769 TI - Intravoxel Incoherent Motion Diffusion Weighted Magnetic Resonance Imaging for Differentiation Between Nasopharyngeal Carcinoma and Lymphoma at the Primary Site. AB - OBJECTIVE: The aim of the study was to investigate the utility of intravoxel incoherent motion (IVIM) diffusion-weighted magnetic resonance imaging (DWI) for differentiating nasopharyngeal carcinoma (NPC) from lymphoma. METHODS: Intravoxel incoherent motion-based parameters including the apparent diffusion coefficient (ADC), pure diffusion coefficient (D), pseudodiffusion coefficient (D*), perfusion fraction (f), and fD* (the product of D* and f) were retrospectively compared between 102 patients (82 with NPC, 20 with lymphoma) who received pretreatment IVIM DWI. RESULTS: Compared with lymphoma, NPC exhibited higher ADC, D, D*, fD* values (P < 0.001) and f value (P = 0.047). The optimal cutoff values (area under the curve, sensitivity, and specificity, respectively) for distinguishing the 2 tumors were as follows: ADC value of 0.761 * 10 mm/s (0.781, 93.90%, 55.00%); D, 0.66 * 10 mm/s (0.802, 54.88%, 100.00%); D*, 7.89 * 10 mm/s (0.898, 82.93%, 85.00%); f, 0.29 (0.644, 41.46%, 95.00%); and fD*, 1.99 * 10 mm/s (0.960, 85.37%, 100.00%). CONCLUSIONS: Nasopharyngeal carcinoma exhibits different IVIM-based imaging features from lymphoma. Intravoxel incoherent motion DWI is useful for differentiating lymphoma from NPC. PMID- 26953770 TI - Use of a Balloon Rectal Catheter in Magnetic Resonance Imaging of Complex Anal Fistula to Improve Detection of Internal Openings. AB - OBJECTIVE: The aim of this study was to investigate the utility of a balloon rectal channel catheter (BRCC) in complex anal fistula magnetic resonance imaging (MRI). METHODS: A prospective study was done on 54 patients with clinical diagnosis of complex anal fistula. Eighteen patients had preoperative MRI before and after inserting BRCC. Another 18 underwent MRI with BRCC and the rest without. Fistulas, internal openings, extensions, and abscesses were identified on MRI and compared with surgical findings. Intraindividual and interindividual differences with and without BRCC were analyzed. RESULTS: In intragroup patients, the accuracy of MRI in detecting the number of fistulas, internal openings, extensions, and abscesses before and after using BRCC was 100%/100%, 67%/90%, 95%/95%, and 100%/100%, respectively, with a significant difference on internal openings (P < 0.05). In intergroup patients with and without BRCC, the accuracy was 98%/96%, 88%/71%, 97%/100%, and 100%/100%, respectively, still with a significant difference on internal openings (P < 0.05). CONCLUSIONS: Magnetic resonance imaging with BRCC may facilitate detection of internal openings in complex anal fistula. PMID- 26953773 TI - Photo-induced coupling reactions of tetrazoles with carboxylic acids in aqueous solution: application in protein labelling. AB - The photo-induced reactions of diaryltetrazoles with carboxylic acids in aqueous solution were investigated. Besides measuring the apparent second-order rate constant and evaluating the functional group compatibility of these reactions, we further incorporated the tetrazoles into SAHA, leading to a new active-site directed probe for labelling HDACs in both cell lysates and living cells. PMID- 26953774 TI - Guided Transabdominal U-Stitches Gastropexy: A Simplified Technique for Secure Laparoscopic Gastrostomy Tube Insertion. AB - INTRODUCTION: Insecure gastropexy, gastric mucosa overgrowth, granulation tissue formation, and a nonhealing gastrostomy are unwanted consequences encountered in the current minimally invasive gastrostomy tube (GT) placement techniques. Aiming to overcome these problems we have developed a simplified laparoscopic-assisted GT insertion (LAG) procedure using guided transabdominal U-stitches (GTU) gastropexy. MATERIALS AND METHODS: We retrospectively reviewed all LAG cases performed in our institute using the GTU technique. In brief, a curved clamp is inserted intragastrically through the laparoscopic port and guides a needle across the abdominal and gastric walls to exit, then re-enter back, through the port in an out-in-out fashion creating multiple spaced transabdominal U-stitches that are tied over pledgets. RESULTS: Between March 2008 and January 2015, 31 cases had LAG attempted using GTU. Two cases were converted to open procedures for non-LAG-related reasons. The median age of the remaining 29 cases was 37 (range, 0.3-154.9) months. Of those patients, 20 had fundoplication (LAG-Fundo), whereas the remaining 9 had LAG-only. The mean operative times for LAG-Fundo and LAG-only were 148 +/- 57.5 minutes and 41 +/- 12.4 minutes, respectively. During a median follow-up of 21 (range, 4-81) months we did not encounter any procedure related mortality, intraabdominal leaks, or bowel injuries. One patient required redo gastropexy due to unplanned early U-stitch removal, and 7 cases had transient external GT leak, granuloma formation, and/or skin infection. CONCLUSIONS: GTU can achieve a simple and secure LAG, avoiding the catastrophic complications of intraabdominal leak without the need of special instruments or enlarging the port's wound. Using a smaller wound and intraabdominally placed mucosa helps in minimizing the risk of wound infection and external leak. Transient complications are expected during the earlier phase of the learning curve. PMID- 26953771 TI - Prognostic Utility of Computed Tomography Histogram Analysis in Patients With Post-Cardiac Arrest Syndrome: Evaluation Using an Automated Whole-Brain Extraction Algorithm. AB - OBJECTIVE: The aim of the study was to evaluate the prognostic utility of computed tomography (CT) histogram analysis with an automated whole-brain extraction algorithm in patients with post-cardiac arrest syndrome (PCAS). METHODS: Computed tomography data from consecutive patients between January 2009 and February 2012 were obtained and retrospectively analyzed. All CT images were obtained using a 64-detector-row CT scanner with a slice thickness of 4.0 mm. A brain region was extracted from the whole-brain CT images using our original automated algorithm and used for the subsequent histogram analysis. The obtained histogram statistics (mean brain tissue CT value, kurtosis, and skewness), as well as clinical parameters, were compared between the good and poor outcome groups using the Student t test. In addition, receiver operating characteristic curve analysis was performed for the discrimination between the 2 groups for each parameter. RESULTS: One hundred thirty-eight consecutive PCAS patients were enrolled. The patients were classified into good (n = 47) and poor (n = 91) outcome groups. The mean brain tissue CT value was significantly higher in the good outcome group than in the poor outcome group (P < 0.05). Kurtosis, skewness, and age were significantly lower in the good outcome group than in the poor outcome group (P < 0.0001, P < 0.05, and P < 0.05, respectively). The area-under the-curve values for kurtosis, mean brain tissue CT value, skewness, and age were 0.751, 0.639, 0.623, and 0.626, respectively. A combination of the 4 parameters increased the diagnostic performance (area under the curve = 0.814). CONCLUSIONS: Histogram analysis of whole-brain CT images with our automated extraction algorithm is useful for assessing the outcome of PCAS patients. PMID- 26953775 TI - Fabricating vertically aligned sub-20 nm Si nanowire arrays by chemical etching and thermal oxidation. AB - Silicon nanowires (SiNWs) are appealing building blocks in various applications, including photovoltaics, photonics, and sensors. Fabricating SiNW arrays with diameters <100 nm remains challenging through conventional top-down approaches. In this work, chemical etching and thermal oxidation are combined to fabricate vertically aligned, sub-20 nm SiNW arrays. Defect-free SiNWs with diameters between 95 and 200 nm are first fabricated by nanosphere (NS) lithography and chemical etching. The key aspects for defect-free SiNW fabrication are identified as: (1) achieving a high etching selectivity during NS size reduction; (2) retaining the circular NS shape with smooth sidewalls; and (3) using a directional metal deposition technique. SiNWs with identical spacing but variable diameters are demonstrated by changing the reactive ion etching power. The diameter of the SiNWs is reduced by thermal oxidation, where self-limiting oxidation is encountered after oxidizing the SiNWs at 950 degrees C for 1 h. A second oxidation is performed to achieve vertically aligned, sub-20 nm SiNW arrays. Si/SiO2 core/shell NWs are obtained before removing the oxidized shell. HRTEM imaging shows that the SiNWs have excellent crystallinity. PMID- 26953776 TI - Contemporary Prehospital Emergency Medical Services Response Times for Suspected Stroke in the United States. AB - BACKGROUND AND PURPOSE: There are no contemporary national-level data on Emergency Medical Services (EMS) response times for suspected stroke in the United States (US). Because effective stroke treatment is time-dependent, we characterized response times for suspected stroke, and examined whether they met guideline recommendations. METHODS: Using the National EMS Information System dataset, we included 911 calls for patients >= 18 years with an EMS provider impression of stroke. We examined variation in the total EMS response time by dispatch notification of stroke, age, sex, race, region, time of day, day of the week, as well as the proportion of EMS responses that met guideline recommended response times. Total EMS response time included call center dispatch time (receipt of call by dispatch to EMS being notified), EMS dispatch time (dispatch informing EMS to EMS starts moving), time to scene (EMS starts moving to EMS arrival on scene), time on scene (EMS arrival on scene to EMS leaving scene), and transport time (EMS leaving scene to reaching treatment facility). RESULTS: We identified 184,179 events with primary impressions of stroke (mean age 70.4 +/- 16.4 years, 55% male). Median total EMS response time was 36 (IQR 28.7-48.0) minutes. Longer response times were observed for patients aged 65-74 years, of white race, females, and from non-urban areas. Dispatch identification of stroke versus "other" was associated with marginally faster response times (36.0 versus 36.7 minutes, p < 0.01). When compared to recommended guidelines, 78% of EMS responses met dispatch delay of <1 minute, 72% met time to scene of <8 minutes, and 46% met on-scene time of <15 minutes. CONCLUSIONS: In the United States, time from receipt of 9-1-1 calls to treatment center arrival takes a median of 36 minutes for stroke patients, an improvement upon previously published times. The fact that 22%-46% of EMS responses did not meet stroke guidelines highlights an opportunity for improvement. Future studies should examine EMS diagnostic accuracy nationally or regionally using outcomes based approaches, as accurate recognition of prehospital strokes is vital in order to improve response times, adhere to guidelines, and ultimately provide timely and effective stroke treatment. PMID- 26953777 TI - Statistical analysis of polarization-inhomogeneous Fourier spectra of laser radiation scattered by human skin in the tasks of differentiation of benign and malignant formations. AB - The optical model of formation of polarization structure of laser radiation scattered by polycrystalline networks of human skin in Fourier plane was elaborated. The results of investigation of the values of statistical (statistical moments of the 1st to 4th order) parameters of polarization inhomogeneous images of skin surface in Fourier plane were presented. The diagnostic criteria of pathological process in human skin and its severity degree differentiation were determined. PMID- 26953781 TI - A Fast and Exact Algorithm for the Exemplar Breakpoint Distance. AB - A fundamental problem in comparative genomics is to compute the distance between two genomes. For two genomes without duplicate genes, we can easily compute a variety of distance measures in linear time, but the problem is NP-hard under most models when genomes contain duplicate genes. Sankoff proposed the use of exemplars to tackle the problem of duplicate genes and gene families: each gene family is represented by a single gene (the exemplar for that family), chosen so as to optimize some metric. Unfortunately, choosing exemplars is itself an NP hard problem. In this article, we propose a very fast and exact algorithm to compute the exemplar breakpoint distance, based on new insights in the underlying structure of genome rearrangements and exemplars. We evaluate the performance of our algorithm on simulation data and compare its performance to the best effort to date (a divide-and-conquer approach), showing that our algorithm runs much faster and scales much better. We also devise a new algorithm for the intermediate breakpoint distance problem, which can then be applied to assign orthologs. We compare our algorithm with the state-of-the-art method MSOAR by assigning orthologs among five well annotated mammalian genomes, showing that our algorithm runs much faster and is slightly more accurate than MSOAR. PMID- 26953778 TI - Vitamin D Status During Pregnancy and Risk of Multiple Sclerosis in Offspring of Women in the Finnish Maternity Cohort. AB - IMPORTANCE: Vitamin D has been associated with a decreased risk of multiple sclerosis (MS) in adulthood; however, some, but not all, previous studies have suggested that in utero vitamin D exposure may be a risk factor for MS later in life. OBJECTIVE: To examine whether serum 25-hydroxyvitamin D (25[OH]D) levels in early pregnancy are associated with risk of MS in offspring. DESIGN, SETTING, AND PARTICIPANTS: Prospective, nested case-control study in the Finnish Maternity Cohort conducted in May 2011. We identified 193 individuals with a diagnosis of MS before December 31, 2009, whose mothers are in the Finnish Maternity Cohort and had an available serum sample from the pregnancy with the affected child. We matched 176 cases with 326 controls on region of birth in Finland, date of maternal serum sample collection, date of mother's birth, and date of child's birth. MAIN OUTCOMES AND MEASURES: Maternal serum 25(OH)D levels were measured using a chemiluminescence assay. The risk of MS among offspring and association with maternal 25(OH)D levels were the main outcomes. Conditional logistic regression was used and further adjusted for sex of the child, gestational age at the time of sample collection, and season of sample collection to estimate the relative risks and 95% CIs. RESULTS: Of the 193 cases in the study, 163 were female. Of the 331 controls in the study, 218 were female. Seventy percent of serum samples were collected during the first trimester of pregnancy. The mean (SD) maternal vitamin D levels were in the insufficient vitamin D range, but higher in maternal control than case samples (15.02 [6.41] ng/mL vs 13.86 [5.49] ng/mL [to convert to nanomoles per liter, multiply by 2.496]). Maternal vitamin D deficiency (25[OH]D levels <12.02 ng/mL) during early pregnancy was associated with a nearly 2-fold increased risk of MS in the offspring (relative risk, 1.90; 95% CI, 1.20-3.01; P = .006) compared with women who did not have deficient 25(OH)D levels. There was no statistically significant association between the risk of MS and increasing serum 25(OH)D levels (P = .12). CONCLUSIONS AND RELEVANCE: Insufficient maternal 25(OH)D during pregnancy may increase the risk of MS in offspring. PMID- 26953782 TI - Measuring the Effectiveness of Mass-Mediated Health Campaigns Through Meta Analysis. AB - A meta-analytic review was undertaken to examine the effects of mass communication campaigns on changes in behavior, knowledge, and self-efficacy in the general public. A review of the academic literature was undertaken and identified 1,638 articles from 1966 through 2012. Using strict inclusion criteria, we included 63 studies for coding and analyses. Results from these efforts indicated that campaigns produced positive effects in behavior change (r = .05, k = 61) and knowledge (r = .10, k = 26) but failed to produce significant increases in self-efficacy (r = .02, k = 14). Several moderators (e.g., health topic, the theory underlying the campaign) were examined in relation to campaign principles that are prescribed to increase campaign effects. The major findings are reviewed, and the implications for future campaign design are discussed. PMID- 26953783 TI - Sex, germs, and health: pathogen-avoidance motives and health-protective behaviour. AB - OBJECTIVE: Recent work suggests that the psychology of pathogen-avoidance has wide-reaching effects on how people interact with the world. These processes - part of what has been referred to as the behavioural immune system - are, in a way, our 'evolved' health psychology. However, scholars have scarcely investigated how the behavioural immune system relates to health-protective behaviours. The current research attempts to fill this gap. DESIGN: Across two cross-sectional studies (N = 386 and 470, respectively), we examined the relationship between pathogen-avoidance motives and health-protective behaviour. OUTCOME MEASURES: The studies used self-reported measures of attitude and intention as indicators of health-protective behaviour. RESULTS: Data collected in Study 1 revealed that pathogen-avoidance motivation related to participants' attitude and intention towards sexually transmitted infections screening. High levels of pathogen-avoidance motivation were also related to having had fewer sexual partners, which partially mediated the effect of pathogen-avoidance variables on testing motivation. Study 2 extended these findings by showing moderate associations between pathogen-avoidance motivation and a broad range of health-protective behaviours, including but not limited to pathogen-related health concerns. CONCLUSION: We argue that understanding and targeting pathogen avoidance psychology can add novel and important understanding of health protective behaviour. PMID- 26953788 TI - The ultrasound meal accommodation test in 509 patients with functional gastrointestinal disorders. AB - AIM: The Ultrasound Meal Accommodation Test (UMAT) is a clinical test used to assess gastric accommodation, gastric emptying, and visceral sensitivity. It has been used as a clinical tool at Haukeland University Hospital, Bergen for more than 20 years. MATERIAL AND METHODS: Five-hundred and nine patients were retrospectively evaluated, 71% females, and 51% were referred from other hospitals or specialists. The aim was to explore the usefulness of UMAT in patients with suspected functional GI disorders (FGID). RESULTS: One hundred and sixty patients were diagnosed with functional dyspepsia (FD), and 154 patients were diagnosed with irritable bowel syndrome (IBS). The overlap between IBS and FD was 41%. In 36% of FD patients, ultrasound assessment showed impaired gastric accommodation. Of 262 patients filling out all required fields for the FD diagnosis (ROMA II and III), 198 (74%) met the criteria for FD, but only 91 (34%) were later diagnosed with FD by an experienced clinician. CONCLUSIONS: By combining ultrasonography, the symptom response to a standardized meal, and psychological assessment, the UMAT is useful in diagnosis and management of patients with FGID. PMID- 26953790 TI - Correction: Ability to Generate Patient-Derived Breast Cancer Xenografts Is Enhanced in Chemoresistant Disease and Predicts Poor Patient Outcomes. PMID- 26953789 TI - The Interactive Effect of Major Depression and Nonsuicidal Self-Injury on Current Suicide Risk and Lifetime Suicide Attempts. AB - This study examined the main and interactive effects of MDD and lifetime nonsuicidal self-injury (NSSI) on current suicide risk and past suicide attempts. We predicted that individuals with a history of NSSI and current MDD would be at greater suicide risk than those with either risk factor alone. An interaction between lifetime MDD and NSSI was hypothesized for past suicide attempts. 204 substance dependent inpatients completed self-report measures and a diagnostic interview. Patients with both a history of NSSI and current MDD, relative to all other groups, had the greatest suicide risk. No support was found for the lifetime MDD by NSSI interaction. CONCLUSION: Findings suggest the relevance of both NSSI and MDD in suicide risk. PMID- 26953791 TI - Localisation of the Putative Magnetoreceptive Protein Cryptochrome 1b in the Retinae of Migratory Birds and Homing Pigeons. AB - Cryptochromes are ubiquitously expressed in various animal tissues including the retina. Some cryptochromes are involved in regulating circadian activity. Cryptochrome proteins have also been suggested to mediate the primary mechanism in light-dependent magnetic compass orientation in birds. Cryptochrome 1b (Cry1b) exhibits a unique carboxy terminus exclusively found in birds so far, which might be indicative for a specialised function. Cryptochrome 1a (Cry1a) is so far the only cryptochrome protein that has been localised to specific cell types within the retina of migratory birds. Here we show that Cry1b, an alternative splice variant of Cry1a, is also expressed in the retina of migratory birds, but it is primarily located in other cell types than Cry1a. This could suggest different functions for the two splice products. Using diagnostic bird-specific antibodies (that allow for a precise discrimination between both proteins), we show that Cry1b protein is found in the retinae of migratory European robins (Erithacus rubecula), migratory Northern Wheatears (Oenanthe oenanthe) and pigeons (Columba livia). In all three species, retinal Cry1b is localised in cell types which have been discussed as potentially well suited locations for magnetoreception: Cry1b is observed in the cytosol of ganglion cells, displaced ganglion cells, and in photoreceptor inner segments. The cytosolic rather than nucleic location of Cry1b in the retina reported here speaks against a circadian clock regulatory function of Cry1b and it allows for the possible involvement of Cry1b in a radical-pair based magnetoreception mechanism. PMID- 26953792 TI - SMN Protein Can Be Reliably Measured in Whole Blood with an Electrochemiluminescence (ECL) Immunoassay: Implications for Clinical Trials. AB - Spinal muscular atrophy (SMA) is caused by defects in the survival motor neuron 1 (SMN1) gene that encodes survival motor neuron (SMN) protein. The majority of therapeutic approaches currently in clinical development for SMA aim to increase SMN protein expression and there is a need for sensitive methods able to quantify increases in SMN protein levels in accessible tissues. We have developed a sensitive electrochemiluminescence (ECL)-based immunoassay for measuring SMN protein in whole blood with a minimum volume requirement of 5MUL. The SMN-ECL immunoassay enables accurate measurement of SMN in whole blood and other tissues. Using the assay, we measured SMN protein in whole blood from SMA patients and healthy controls and found that SMN protein levels were associated with SMN2 copy number and were greater in SMA patients with 4 copies, relative to those with 2 and 3 copies. SMN protein levels did not vary significantly in healthy individuals over a four-week period and were not affected by circadian rhythms. Almost half of the SMN protein was found in platelets. We show that SMN protein levels in C/C-allele mice, which model a mild form of SMA, were high in neonatal stage, decreased in the first few weeks after birth, and then remained stable throughout the adult stage. Importantly, SMN protein levels in the CNS correlated with SMN levels measured in whole blood of the C/C-allele mice. These findings have implications for the measurement of SMN protein induction in whole blood in response to SMN-upregulating therapy. PMID- 26953794 TI - Guano-Derived Nutrient Subsidies Drive Food Web Structure in Coastal Ponds. AB - A stable isotope study was carried out seasonally in three coastal ponds (Marinello system, Italy) affected by different gull guano input to investigate the effect of nutrient subsidies on food web structure and dynamics. A marked 15N enrichment occurred in the pond receiving the highest guano input, indicating that gull-derived fertilization (guanotrophication) had a strong localised effect and flowed across trophic levels. The main food web response to guanotrophication was an overall erosion of the benthic pathway in favour of the planktonic. Subsidized primary consumers, mostly deposit feeders, switched their diet according to organic matter source availability. Secondary consumers and, in particular, fish from the guanotrophic pond, acted as couplers of planktonic and benthic pathways and showed an omnivorous trophic behaviour. Food web structure showed substantial variability among ponds and a marked seasonality in the subsidized one: an overall simplification was evident only in summer when guano input maximises its trophic effects, while higher trophic diversity and complexity resulted when guano input was low to moderate. PMID- 26953795 TI - Implementing the use of a biobank in the endangered black-footed ferret (Mustela nigripes). AB - In the current global health climate, many conservation biologists are managing crisis situations, including increased species extinction rates. One strategy for securing wildlife populations into the future is to preserve biomaterials in genome resource banks (GRB; or 'biobanks'). However, for GRBs to be successful we must understand the fundamental reproductive biology of species, along with developing assisted reproductive techniques (ARTs), including AI and semen cryopreservation. ART has been successfully used for several taxa, from amphibians to mammals, including ungulates, carnivores and primates. Not all these success stories implemented the use of a biobank, but one example that discussed herein is the black-footed ferret (Mustela nigripes) GRB. From a founder population of seven individuals, this species has been breeding in a managed setting for nearly 30 years. The goal of the breeding program is to maintain genetic integrity by ensuring each individual has the opportunity to pass his/her genes onto the next generation, while simultaneously providing animals for release into the wild. Scientists have used ART (e.g. AI) in the recovery program. Recently, semen from an individual of the founder population that was cryopreserved for up to 20 years was used successfully for AI, which improved the genetic diversity of the population. The black-footed ferret recovery program can serve as a model for other endangered species and demonstrates the usefulness of ART and GRBs to maintain highly endangered species into the future. PMID- 26953793 TI - Rapid HIV-1 Disease Progression in Individuals Infected with a Virus Adapted to Its Host Population. AB - HIV-1 escape from CTL is predictable based on the Human Leukocyte Antigen (HLA) class I alleles expressed by the host. As such, HIV-1 sequences circulating in a population of hosts will harbor escape mutations specific to the HLA alleles of that population. In theory, this should increase the frequency of escape mutation transmission to persons expressing the restricting HLA allele, thereby compromising host immunity to the incoming HIV-1 strain. However, the clinical impact of infection with HIV-1 containing immune escape mutations has not conclusively been demonstrated. Japan's population features limited HLA diversity which is driving population-level HIV adaptation: for example, >60% of Japanese express HLA-A*24:02 and its associated Nef-Y135F escape mutation represents the population consensus. As such, Japan is an ideal population in which to examine this phenomenon. Here, we combine genetic and immunological analyses to identify A*24:02-positive individuals likely to have been infected with Y135F-containing HIV-1. Over a ~5 year follow-up, these individuals exhibited significantly lower CD4 counts compared to individuals inferred to have been infected with wild-type HIV-1. Our results support a significant negative clinical impact of pathogen adaptation to host pressures at the population level. PMID- 26953796 TI - What Do Contrast Threshold Equivalent Noise Studies Actually Measure? Noise vs. Nonlinearity in Different Masking Paradigms. AB - The internal noise present in a linear system can be quantified by the equivalent noise method. By measuring the effect that applying external noise to the system's input has on its output one can estimate the variance of this internal noise. By applying this simple "linear amplifier" model to the human visual system, one can entirely explain an observer's detection performance by a combination of the internal noise variance and their efficiency relative to an ideal observer. Studies using this method rely on two crucial factors: firstly that the external noise in their stimuli behaves like the visual system's internal noise in the dimension of interest, and secondly that the assumptions underlying their model are correct (e.g. linearity). Here we explore the effects of these two factors while applying the equivalent noise method to investigate the contrast sensitivity function (CSF). We compare the results at 0.5 and 6 c/deg from the equivalent noise method against those we would expect based on pedestal masking data collected from the same observers. We find that the loss of sensitivity with increasing spatial frequency results from changes in the saturation constant of the gain control nonlinearity, and that this only masquerades as a change in internal noise under the equivalent noise method. Part of the effect we find can be attributed to the optical transfer function of the eye. The remainder can be explained by either changes in effective input gain, divisive suppression, or a combination of the two. Given these effects the efficiency of our observers approaches the ideal level. We show the importance of considering these factors in equivalent noise studies. PMID- 26953797 TI - Excessive Pro-Inflammatory Serum Cytokine Concentrations in Virulent Canine Babesiosis. AB - Babesia rossi infection causes a severe inflammatory response in the dog, which is the result of the balance between pro- and anti-inflammatory cytokine secretion. The aim of this study was to determine whether changes in cytokine concentrations were present in dogs with babesiosis and whether it was associated with disease outcome. Ninety-seven dogs naturally infected with B. rossi were studied and fifteen healthy dogs were included as controls. Diagnosis of babesiosis was confirmed by polymerase chain reaction and reverse line blot. Blood samples were collected from the jugular vein at admission, prior to any treatment. Cytokine concentrations were assessed using a canine-specific multiplex assay on an automated analyser. Serum concentrations of interleukin (IL)-2, IL-6, IL-8, IL-10, IL-18, granulocyte-macrophage colony stimulating factor (GM-CSF) and monocyte chemotactic protein-1 (MCP-1) were measured. Twelve of the Babesia-infected dogs died (12%) and 85 survived (88%). Babesia-infected dogs were also divided into those that presented within 48 hours from displaying clinical signs, and those that presented more than 48 hours after displaying clinical signs. Cytokine concentrations were compared between the different groups using the Mann-Whitney U test. IL-10 and MCP-1 concentrations were significantly elevated for the Babesia-infected dogs compared to the healthy controls. In contrast, the IL-8 concentration was significantly decreased in the Babesia-infected dogs compared to the controls. Concentrations of IL-6 and MCP-1 were significantly increased in the non-survivors compared to the survivors. Concentrations for IL-2, IL-6, IL-18 and GM-CSF were significantly higher in those cases that presented during the more acute stage of the disease. These findings suggest that a mixed cytokine response is present in dogs with babesiosis caused by B. rossi, and that an excessive pro-inflammatory response may result in a poor outcome. PMID- 26953799 TI - Considerations in centralizing whole genome sequencing for microbiology in a public health setting. PMID- 26953798 TI - Benefits of Bifidobacterium breve M-16V Supplementation in Preterm Neonates - A Retrospective Cohort Study. AB - BACKGROUND: Systematic reviews of randomised controlled trials report that probiotics reduce the risk of necrotising enterocolitis (NEC) in preterm neonates. AIM: To determine whether routine probiotic supplementation (RPS) to preterm neonates would reduce the incidence of NEC. METHODS: The incidence of NEC >= Stage II and all-cause mortality was compared for an equal period of 24 months 'before' (Epoch 1) and 'after' (Epoch 2) RPS with Bifidobacterium breve M-16V in neonates <34 weeks. Multivariate logistic regression analysis was conducted to adjust for relevant confounders. RESULTS: A total of 1755 neonates (Epoch I vs. II: 835 vs. 920) with comparable gestation and birth weights were admitted. There was a significant reduction in NEC >= Stage II: 3% vs. 1%, adjusted odds ratio (aOR) = 0.43 (95%CI: 0.21-0.87); 'NEC >= Stage II or all-cause mortality': 9% vs. 5%, aOR = 0.53 (95%CI: 0.32-0.88); but not all-cause mortality alone: 7% vs. 4%, aOR = 0.58 (95% CI: 0.31-1.06) in Epoch II. The benefits in neonates <28 weeks did not reach statistical significance: NEC >= Stage II: 6% vs. 3%, aOR 0.51 (95%CI: 0.20-1.27), 'NEC >= Stage II or all-cause mortality', 21% vs. 14%, aOR = 0.59 (95%CI: 0.29-1.18); all-cause mortality: 17% vs. 11%, aOR = 0.63 (95%CI: 0.28-1.41). There was no probiotic sepsis. CONCLUSION: RPS with Bifidobacterium breve M-16V was associated with decreased NEC>= Stage II and 'NEC>= Stage II or all-cause mortality' in neonates <34 weeks. Large sample size is required to assess the potential benefits of RPS in neonates <28 weeks. PMID- 26953800 TI - Enzymatic Modification of Soluble Cyanophycin Using the Type II Peptidyl Arginine Deiminase from Oryctolagus cuniculus. AB - An increased structural variety expands the number of putative applications for cyanophycin (multi-l-arginyl-poly-[l-aspartic acid], CGP). Therefore, structural modifications of CGP are of major interest; these are commonly obtained by modification and optimization of the bacterial producing strain or by chemical modification. In this study, an enzymatic modification of arginine side chains from lysine-rich CGP is demonstrated using the peptidyl arginine deiminase from Oryctolagus cuniculus, purified from Escherichia coli after heterologous expression. About 10% of the arginine side chains are converted to citrulline which corresponds to 4% of the polymer's total side chains. An inhibition of the reaction in the presence of small amounts of l-citrulline is observed, thereby explaining the low conversion rate. CGP dipeptides can be modified with about 7.5 mol% of the Asp-Arg dipeptides being converted to Asp-Cit. These results show that the enzymatic modification of CGP is feasible, opening up a whole new area of possible CGP modifications for further research. PMID- 26953801 TI - [The Functional Basic Model for the Psychiatric Care of Persons with Severe Mental Illness--Minimum Standard of Treatment and Participation]. PMID- 26953803 TI - [Benchmarking is an Effective Instrument to Improve Clinical Services--Pro]. PMID- 26953802 TI - [Let's Open the Doors ...]. PMID- 26953804 TI - [Benchmarking is an Effective Instrument to Improve Clinical Services--Contra]. PMID- 26953805 TI - [Not Available]. PMID- 26953806 TI - [Not Available]. PMID- 26953807 TI - Notable differences between oxidized diruthenium complexes bridged by four isomeric diethynyl benzodithiophene ligands. AB - Four new diruthenium complexes [{(eta(5)-C5Me5)Ru(dppe)}2(MU-C[triple bond, length as m-dash]C-L-C[triple bond, length as m-dash]C)] featuring different bridging isomeric diethynyl benzodithiophenes viz. L = benzo[1,2-b;4,5 b']dithiophene (complex ), benzo[2,1-b;4,5-b']dithiophene (complex ), benzo[1,2 b;3,4-b']dithiophene (complex ) and benzo[1,2-b;4,3-b']dithiophene (complex ), were synthesized and characterized by molecular spectroscopic and crystallographic methods. The subtle changes in the molecular structure introduced by the diethynyl benzodithiophene isomers have a notable impact on the stability of the oxidized complexes and their absorption characteristics in the visible-NIR and IR spectral domains. Electronic properties of stable oxidized complexes [](n+) and [](n+) (n = 1, 2) were investigated by cyclic voltammetry, UV-vis-NIR and IR spectroelectrochemistry as well as DFT and TDDFT calculations. The results document the largely bridge-localized character of the oxidation of parents and . Cations [](+) and [](+) are too unstable at ambient temperature to afford their unambiguous characterization. UV-vis-NIR absorption spectral data combined with TDDFT calculations (BLYP35) reveal that the broad electronic absorption of [](+) and [](+) in the NIR region has a mixed intraligand pi-pi* and MLCT character, with similar contribution from their spin-delocalized trans and cis conformers. A spin-localized (mixed-valence) rotamer was only observed for [](+) at ambient temperature as a minor component on the time scale of IR spectroscopy. PMID- 26953808 TI - A hard (metal) case: Value of analytical scanning electron microscopy. AB - Exposure to hard metal (tungsten carbide) dust is a rare cause of interstitial lung disease. Although most cases have a distinctive morphology known as giant cell interstitial pneumonitis, other patterns have been described as well. In such cases, the true nature of the interstitial process may be difficult to recognize. We present a case with unusual morphological features in which analytical scanning electron microscopy (SEM) was used to detect the presence of tungsten as well as other metallic particles. A combination of careful exposure history and examination by analytical SEM is useful for arriving at the correct diagnosis in such difficult cases. PMID- 26953809 TI - Structural Characterization of N-Alkylated Twisted Amides: Consequences for Amide Bond Resonance and N-C Cleavage. AB - Herein, we describe the first structural characterization of N-alkylated twisted amides prepared directly by N-alkylation of the corresponding non-planar lactams. This study provides the first experimental evidence that N-alkylation results in a dramatic increase of non-planarity around the amide N-C(O) bond. Moreover, we report a rare example of a molecular wire supported by the same amide C=O-Ag bonds. Reactivity studies demonstrate rapid nucleophilic addition to the N-C(O) moiety of N-alkylated amides, indicating the lack of n(N) to pi*(C=O) conjugation. Most crucially, we demonstrate that N-alkylation activates the otherwise unreactive amide bond towards sigma N-C cleavage by switchable coordination. PMID- 26953810 TI - Microbial Decontamination of Dried Alaska Pollock Shreds Using Corona Discharge Plasma Jet: Effects on Physicochemical and Sensory Characteristics. AB - Nonthermal techniques for microbial decontamination are becoming more common for ensuring food safety. In this study, a corona discharge plasma jet (CDPJ) was used for inactivation of microbial contaminants of dried Alaska pollock shreds. Corona plasma jet was generated at a current strength of 1.5 A, and a span length of 25 mm was maintained between the electrode tip and the sample. Upon the CDPJ treatment (0 to 3 min) of dried shreds, microbial contaminants namely aerobic and marine bacteria, and Staphylococcus aureus were inactivated by 2.5, 1.5, and >1.0 log units, respectively. Also, a one-log reduction of molds and yeasts contaminants was observed. The inactivation patterns are fitted well to the pseudo-first-order kinetics or Singh-Heldman model. The CDPJ treatment did not exert statistically significant (P > 0.05) changes in physicochemical properties, namely color characteristics, volatile basic nitrogen, and peroxide value of dried fish shreds, with some exceptions, as compared to untreated controls. Furthermore, CDPJ treatment had no significant impact on the sensory characteristics of dried fish shreds. PMID- 26953811 TI - Fabrication of Conductive 3D Gold-Containing Microstructures via Direct Laser Writing. AB - 3D conductive microstructures containing gold are fabricated by simultaneous photopolymerization and photoreduction via direct laser writing. The photoresist employed consists of water-soluble polymers and a gold precursor. The fabricated microstructures show good conductivity and are successfully employed for 3D connections between gold pads. PMID- 26953812 TI - Atomistic Description of Reaction Intermediates for Supported Metathesis Catalysts Enabled by DNP SENS. AB - Obtaining detailed structural information of reaction intermediates remains a key challenge in heterogeneous catalysis because of the amorphous nature of the support and/or the support interface that prohibits the use of diffraction-based techniques. Combining isotopic labeling and dynamic nuclear polarization (DNP) increases the sensitivity of surface enhanced solid-state NMR spectroscopy (SENS) towards surface species in heterogeneous alkene metathesis catalysts; this in turn allows direct determination of the bond connectivity and measurement of the carbon-carbon bond distance in metallacycles, which are the cycloaddition intermediates in the alkene metathesis catalytic cycle. Furthermore, this approach makes possible the understanding of the slow initiation and deactivation steps in these heterogeneous metathesis catalysts. PMID- 26953813 TI - Asymmetric Distribution of GFAP in Glioma Multipotent Cells. AB - Asymmetric division (AD) is a fundamental mechanism whereby unequal inheritance of various cellular compounds during mitosis generates unequal fate in the two daughter cells. Unequal repartitions of transcription factors, receptors as well as mRNA have been abundantly described in AD. In contrast, the involvement of intermediate filaments in this process is still largely unknown. AD occurs in stem cells during development but was also recently observed in cancer stem cells. Here, we demonstrate the asymmetric distribution of the main astrocytic intermediate filament, namely the glial fibrillary acid protein (GFAP), in mitotic glioma multipotent cells isolated from glioblastoma (GBM), the most frequent type of brain tumor. Unequal mitotic repartition of GFAP was also observed in mice non-tumoral neural stem cells indicating that this process occurs across species and is not restricted to cancerous cells. Immunofluorescence and videomicroscopy were used to capture these rare and transient events. Considering the role of intermediate filaments in cytoplasm organization and cell signaling, we propose that asymmetric distribution of GFAP could possibly participate in the regulation of normal and cancerous neural stem cell fate. PMID- 26953816 TI - Electrical Stimulation of the Spinal Dorsal Root Inhibits Reflex Bladder Contraction and External Urethra Sphincter Activity: Is This How Sacral Neuromodulation Works? AB - INTRODUCTION: Using a rat model, we aimed to confirm the inhibitory effect of dorsal spinal root (afferent) stimulation and test if bilateral stimulation is more effective than unilateral stimulation. External urethral sphincter (EUS) electromyography (EMG) is also assessed in conjunction with cystometrogram. MATERIALS AND METHODS: Eighteen female Sprague-Dawley rats were tested following urethane anesthesia. Via urethral catheterization, the bladder was infused with normal saline to evoke rhythmic bladder reflex contractions (BRC). L6 spinal nerves were isolated and stimulated. RESULTS: L6 stimulation was effective in inhibiting BRC. L6 bilateral dorsal root (DR) stimulation of 50% intensity was required to cause inhibition as compared to unilateral stimulation. In EUS EMG recordings, there was a strong association between EUS EMG activities and bladder contraction. When the bladder contraction was inhibited effectively by L6 DR stimulation, a considerable reduction was also found in the EUS EMG activities. CONCLUSIONS: L6 DR stimulation abolished BRC in our rat model. Bilateral L6 DR stimulation produced a 50% reduction in stimulation intensity, providing a similar BRC block. Abolishing BRC also appeared to coincide with a reduction in EUS EMG, implicating that sacral neuromodulation might act centrally, at least rostrally at the T8-9 spinal level. PMID- 26953815 TI - In-depth characterization of the salivary adenoid cystic carcinoma transcriptome with emphasis on dominant cell type. AB - BACKGROUND: Adenoid cystic carcinoma (ACC), 1 of the most common salivary gland malignancies, arises from the intercalated ducts, which are composed of inner ductal epithelial cells and outer myoepithelial cells. The objective of this study was to determine the genomic subtypes of ACC with emphasis on dominant cell type to identify potential specific biomarkers for each subtype and to improve the understanding of this disease. METHODS: A whole-genome expression study was performed based on 42 primary salivary ACCs and 5 normal salivary glands. RNA from these specimens was subjected to expression profiling with RNA sequencing, and results were analyzed to identify transcripts in epithelial-dominant ACC (E ACC), myoepithelial-dominant ACC (M-ACC), and all ACC that were expressed differentially compared with the transcripts in normal salivary tissue. RESULTS: In total, the authors identified 430 differentially expressed transcripts that were unique to E-ACC, 392 that were unique to M-ACC, and 424 that were common to both M-ACC and E-ACC. The sets of E-ACC-specific and M-ACC-specific transcripts were sufficiently large to define and differentiate E-ACC from M-ACC. Ingenuity pathway analysis identified known cancer-related genes for 60% of the E-ACC transcripts, 69% of the M-ACC transcripts, and 68% of the transcripts that were common in both E-ACC and M-ACC. Three sets of highly expressed candidate genes distal-less homeobox 6 (DLX6) for E-ACC; protein keratin 16 (KRT16), SRY box 11 (SOX11), and v-myb avian myeloblastosis viral oncogene homolog (MYB) for M-ACC; and engrailed 1 (EN1) and statherin (STATH), which are common to both E-ACC and M ACC)-were further validated at the protein level. CONCLUSIONS: The current results enabled the authors to identify novel potential therapeutic targets and biomarkers in E-ACC and M-ACC individually, with the implication that EN1, DLX6, and OTX1 (orthodenticle homeobox 1) are potential drivers of these cancers. Cancer 2016;122:1513-22. (c) 2016 American Cancer Society. PMID- 26953817 TI - Microphase-Separated PE/PEO Thin Films Prepared by Plasma-Assisted Vapor Phase Deposition. AB - Immiscible polymer blends tend to undergo phase separation with the formation of nanoscale architecture which can be used in a variety of applications. Different wet-chemistry techniques already exist to fix the resultant polymeric structure in predictable manner. In this work, an all-dry and plasma-based strategy is proposed to fabricate thin films of microphase-separated polyolefin/polyether blends. This is achieved by directing (-CH2-)100 and (-CH2-CH2-O-)25 oligomer fluxes produced by vacuum thermal decomposition of poly(ethylene) and poly(ethylene oxide) onto silicon substrates through the zone of the glow discharge. The strategy enables mixing of thermodynamically incompatible macromolecules at the molecular level, whereas electron-impact-initiated radicals serve as cross-linkers to arrest the subsequent phase separation at the nanoscale. The mechanism of the phase separation as well as the morphology of the films is found to depend on the ratio between the oligomeric fluxes. For polyolefin-rich mixtures, polyether molecules self-organize by nucleation and growth into spherical domains with average height of 22 nm and average diameter of 170 nm. For equinumerous fluxes and for mixtures with the prevalence of polyethers, spinodal decomposition is detected that results in the formation of bicontinuous structures with the characteristic domain size and spacing ranging between 5 * 10(1) -7 * 10(1) nm and 3 * 10(2)-4 * 10(2) nm, respectively. The method is shown to produce films with tunable wettability and biologically nonfouling properties. PMID- 26953818 TI - Use of a pressure wire to evaluate right heart pressures in a pre-liver transplant recipient through a peripheral IV. PMID- 26953819 TI - Cationic Noncovalent Interactions: Energetics and Periodic Trends. AB - In this review, noncovalent interactions of ions with neutral molecules are discussed. After defining the scope of the article, which excludes anionic and most protonated systems, methods associated with measuring thermodynamic information for such systems are briefly recounted. An extensive set of tables detailing available thermodynamic information for the noncovalent interactions of metal cations with a host of ligands is provided. Ligands include small molecules (H2, NH3, CO, CS, H2O, CH3CN, and others), organic ligands (O- and N-donors, crown ethers and related molecules, MALDI matrix molecules), pi-ligands (alkenes, alkynes, benzene, and substituted benzenes), miscellaneous inorganic ligands, and biological systems (amino acids, peptides, sugars, nucleobases, nucleosides, and nucleotides). Hydration of metalated biological systems is also included along with selected proton-based systems: 18-crown-6 polyether with protonated peptides and base-pairing energies of nucleobases. In all cases, the literature thermochemistry is evaluated and, in many cases, reanchored or adjusted to 0 K bond dissociation energies. Trends in these values are discussed and related to a variety of simple molecular concepts. PMID- 26953820 TI - Aortic Valve Gradient and Clinical Outcome in Patients Undergoing Transcatheter Aortic Valve Implantation for Severe Aortic Stenosis. AB - OBJECTIVES: To explore the relation between the baseline aortic valve gradient (AVG) as a continuous variable and clinical outcomes following transcatheter aortic valve implantation (TAVI) in general and specifically in patients with high-gradient aortic stenosis (AS). METHODS: We reviewed 317 consecutive patients who underwent TAVI at our institution. We investigated the relation between AVG as a continuous/categorical variable and outcome among all patients and in patients without low-flow low-gradient AS, using the Cox proportional hazard model adjusting for multiple prognostic variables. RESULTS: Patients had a peak AVG of 79.9 +/- 22.8 mm Hg (mean 50.5 +/-15.7). During a mean follow-up of 2.7 years, AVG was inversely associated with mortality and mortality or cardiac hospitalization. Every 10-mm-Hg increase in peak AVG was associated with 18% reduction in mortality (p = 0.003) and 19% reduction in mortality/cardiac hospitalization (p < 0.001). Every 10-mm-Hg increase in mean AVG was associated with a 24% reduction in both outcomes (p = 0.005 and p < 0.001). Subgroup analysis of patients with left-ventricular ejection fraction >40% or peak AVG >64 mm Hg yielded similar results. CONCLUSIONS: Mean and peak baseline AVGs are directly associated with improved outcomes after TAVI; AVG can be used to select the patients most likely to benefit from TAVI. PMID- 26953822 TI - Sepsis-associated thrombocytopenia. PMID- 26953821 TI - Systolic blood pressure response after high-intensity interval exercise is independently related to decreased small arterial elasticity in normotensive African American women. AB - Aerobic exercise transiently lowers blood pressure. However, limited research has concurrently evaluated blood pressure and small arterial elasticity (SAE), an index of endothelial function, among African American (AA) and European American (EA) women the morning after (i.e., ~22 h later) acute bouts of moderate intensity continuous (MIC) and high-intensity interval (HII) exercise matched for total work. Because of greater gradients of shear stress, it was hypothesized that HII exercise would elicit a greater reduction in systolic blood pressure (SBP) compared to MIC exercise. After baseline, 22 AA and EA women initiated aerobic exercise training 3 times/week. Beginning at week 8, three follow-up assessments were conducted over the next 8 weeks at random to measure resting blood pressure and SAE. In total all participants completed 16 weeks of training. Follow-up evaluations were made: (i) in the trained state (TS; 8-16 weeks of aerobic training); (ii) ~22 h after an acute bout of MIC exercise; and (iii) ~22 h after an acute bout of HII exercise. Among AAs, the acute bout of HII exercise incited a significant increase in SBP (mm Hg) (TS, 121 +/- 14 versus HII, 128 +/- 14; p = 0.01) whereas responses (TS, 116 +/- 12 versus HII, 113 +/- 9; p = 0.34) did not differ in EAs. After adjusting for race, changes in SAE were associated (partial r = -0.533; p = 0.01) with changes in SBP following HII exercise. These data demonstrate an acute, unaccustomed bout of HII exercise produces physiological perturbations resulting in a significant increase in SBP that are independently associated with decreased SAE among AA women, but not EA women. PMID- 26953823 TI - Efficacy of group psychotherapy for social anxiety disorder: A meta-analysis of randomized-controlled trials. AB - Group psychotherapy for social anxiety disorder (SAD) is an established treatment supported by findings from primary studies and earlier meta-analyses. However, a comprehensive summary of the recent evidence is still pending. This meta-analysis investigates the efficacy of group psychotherapy for adult patients with SAD. A literature search identified 36 randomized-controlled trials examining 2171 patients. Available studies used mainly cognitive-behavioral group therapies (CBGT); therefore, quantitative analyses were done for CBGT. Medium to large positive effects emerged for wait list-controlled trials for specific symptomatology: g=0.84, 95% CI [0.72; 0.97] and general psychopathology: g=0.62, 95% CI [0.36; 0.89]. Group psychotherapy was also superior to common factor control conditions in alleviating symptoms of SAD, but not in improving general psychopathology. No differences appeared for direct comparisons of group psychotherapy and individual psychotherapy or pharmacotherapy. Hence, group psychotherapy for SAD is an efficacious treatment, equivalent to other treatment formats. PMID- 26953824 TI - Extinction of fish-shaped marine reptiles associated with reduced evolutionary rates and global environmental volatility. AB - Despite their profound adaptations to the aquatic realm and their apparent success throughout the Triassic and the Jurassic, ichthyosaurs became extinct roughly 30 million years before the end-Cretaceous mass extinction. Current hypotheses for this early demise involve relatively minor biotic events, but are at odds with recent understanding of the ichthyosaur fossil record. Here, we show that ichthyosaurs maintained high but diminishing richness and disparity throughout the Early Cretaceous. The last ichthyosaurs are characterized by reduced rates of origination and phenotypic evolution and their elevated extinction rates correlate with increased environmental volatility. In addition, we find that ichthyosaurs suffered from a profound Early Cenomanian extinction that reduced their ecological diversity, likely contributing to their final extinction at the end of the Cenomanian. Our results support a growing body of evidence revealing that global environmental change resulted in a major, temporally staggered turnover event that profoundly reorganized marine ecosystems during the Cenomanian. PMID- 26953825 TI - Years in Review: Recent Progress in Cellular Allergology. AB - This review highlights the recent key advances in the biology of CD4+ effector T cells, antigen-presenting cells, Th17 and T regulatory cells, as well as immediate effector cells, such as mast cells, basophils and eosinophils, which are critically contributing to the better understanding of the pathophysiology of allergic diseases and are helping to improve their diagnosis and therapy. Some of the key advances with a direct impact on allergic asthma research and treatment are summarized. PMID- 26953826 TI - Correction: A Systematic Computational Analysis of Biosynthetic Gene Cluster Evolution: Lessons for Engineering Biosynthesis. PMID- 26953827 TI - Reducing Ice Adhesion on Nonsmooth Metallic Surfaces: Wettability and Topography Effects. AB - The effects of ice formation and accretion on external surfaces range from being mildly annoying to potentially life-threatening. Ice-shedding materials, which lower the adhesion strength of ice to its surface, have recently received renewed research attention as a means to circumvent the problem of icing. In this work, we investigate how surface wettability and surface topography influence the ice adhesion strength on three different surfaces: (i) superhydrophobic laser inscribed square pillars on copper, (ii) stainless steel 316 Dutch-weave meshes, and (iii) multiwalled carbon nanotube-covered steel meshes. The finest stainless steel mesh displayed the best performance with a 93% decrease in ice adhesion relative to polished stainless steel, while the superhydrophobic square pillars exhibited an increase in ice adhesion by up to 67% relative to polished copper. Comparisons of dynamic contact angles revealed little correlation between surface wettability and ice adhesion. On the other hand, by considering the ice formation process and the fracture mechanics at the ice-substrate interface, we found that two competing mechanisms governing ice adhesion strength arise on nonplanar surfaces: (i) mechanical interlocking of the ice within the surface features that enhances adhesion, and (ii) formation of microcracks that act as interfacial stress concentrators, which reduce adhesion. Our analysis provides insight toward new approaches for the design of ice-releasing materials through the use of surface topographies that promote interfacial crack propagation. PMID- 26953828 TI - Definitions of Sexual Dysfunctions in Women and Men: A Consensus Statement From the Fourth International Consultation on Sexual Medicine 2015. AB - INTRODUCTION: Definitions of sexual dysfunctions in women and men are critical in facilitating research and enabling clinicians to communicate accurately. AIMS: To present the new set of definitions of all forms of sexual dysfunction in women and men adopted by the Fourth International Consultation on Sexual Medicine (ICSM) held in 2015. METHODS: Classification systems, including the International Classification of Diseases, 10th Edition and the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, and systems that focus on only specific types of sexual dysfunctions (e.g., the International Society for Sexual Medicine definition for premature ejaculation) were reviewed. MAIN OUTCOME MEASURES: Evidence-based definitions were retained, gaps in definitions were identified, and outdated definitions were updated or discarded. Where evidence was insufficient or absent, expert opinion was used. Some definitions were self evident and termed clinical principles. RESULTS: The evidence to support the various classification systems was carefully evaluated. A more comprehensive analysis of this evidence can be found in two other articles in this journal that consider the incidence and prevalence and the risk factors for sexual dysfunction in men and women. These data were used to shape the definitions for sexual dysfunction that have been recommended by the 2015 ICSM. CONCLUSION: The definitions that have been adopted are those that are most strongly supported by the literature at this time or are considered clinical principles or consensus of experts' opinions. As more research and clinical studies are conducted, there likely will be modifications of at least some definitions. PMID- 26953829 TI - Incidence and Prevalence of Sexual Dysfunction in Women and Men: A Consensus Statement from the Fourth International Consultation on Sexual Medicine 2015. AB - INTRODUCTION: The incidence and prevalence of various sexual dysfunctions in women and men are important to understand to designate priorities for epidemiologic and clinical research. AIM: This manuscript was designed to conduct a review of the literature to determine the incidence and prevalence of sexual dysfunction in women and men. METHODS: Members of Committee 1 of the Fourth International Consultation on Sexual Medicine (2015) searched and reviewed epidemiologic literature on the incidence and prevalence of sexual dysfunctions. Key older studies and most studies published after 2009 were included in the text of this article. MAIN OUTCOME MEASURES: The outcome measures were the reports in the various studies of the incidence and prevalence of sexual dysfunction among women and men. RESULTS: There are more studies on incidence and prevalence for men than for women and many more studies on prevalence than incidence for women and men. The data indicate that the most frequent sexual dysfunctions for women are desire and arousal dysfunctions. In addition, there is a large proportion of women who experience multiple sexual dysfunctions. For men, premature ejaculation and erectile dysfunction are the most common sexual dysfunctions, with less comorbidity across sexual dysfunctions for men compared with women. CONCLUSION: These data need to be treated with caution, because there is a high level of variability across studies caused by methodologic differences in the instruments used to assess presence of sexual dysfunction, ages of samples, nature of samples, methodology used to gather the data, and cultural differences. Future research needs to use well-validated tools to gather data and ensure that the data collection strategy is clearly described. PMID- 26953830 TI - Risk Factors for Sexual Dysfunction Among Women and Men: A Consensus Statement From the Fourth International Consultation on Sexual Medicine 2015. AB - INTRODUCTION: This article presents a review of previous research concerning risk factors for sexual dysfunction in women and men. AIM: The aim is to evaluate past research studies to determine the contribution of all risk factors to the development and maintenance of sexual dysfunction among women and men. METHODS: Studies were organized under a biopsychosocial framework, with the bulk of studies of women and men having investigated the role of biological factors. MAIN OUTCOME MEASURES: The outcome measures were the data on factors for sexual dysfunction. RESULTS: Many more studies investigated risk factors for sexual dysfunction in men than in women. For women and men, diabetes, heart disease, urinary tract disorders, and chronic illness were significant risk factors for sexual dysfunction. Depression and anxiety and the medications used to treat these disorders also were risk factors for sexual dysfunction in women and men. In addition, substance abuse was associated with sexual dysfunction. Many other social and cultural factors were related to sexual dysfunction in women and men. CONCLUSION: Psychosocial factors are clearly risk factors for sexual dysfunction. Women and men with sexual dysfunction should be offered psychosocial evaluation and treatment, if available, in addition to medical evaluation and treatment. The impact of social and cultural factors on sexual function requires substantially more research. The evidence that erectile dysfunction is a harbinger of other forms of cardiovascular disease is strong enough to recommend that clinical evaluation for occult cardiovascular disease should be undertaken in men who do not have known cardiovascular disease but who develop organic erectile dysfunction, especially in men younger than 70 years. PMID- 26953831 TI - Androgens and Female Sexual Function and Dysfunction--Findings From the Fourth International Consultation of Sexual Medicine. AB - INTRODUCTION: Androgens have been implicated as important for female sexual function and dysfunction. AIM: To review the role of androgens in the physiology and pathophysiology of female sexual functioning and the evidence for efficacy of androgen therapy for female sexual dysfunction (FSD). METHODS: We searched the literature using online databases for studies pertaining to androgens and female sexual function. Major reviews were included and their findings were summarized to avoid replicating their content. MAIN OUTCOME MEASURES: Quality of data published in the literature and recommendations were based on the GRADES system. RESULTS: The literature supports an important role for androgens in female sexual function. There is no blood androgen level below which women can be classified as having androgen deficiency. Clinical trials have consistently demonstrated that transdermal testosterone (T) therapy improves sexual function and sexual satisfaction in women who have been assessed as having hypoactive sexual desire disorder. The use of T therapy is limited by the lack of approved formulations for women and long-term safety data. Most studies do not support the use of systemic dehydroepiandrosterone therapy for the treatment of FSD in women with normally functioning adrenals or adrenal insufficiency. Studies evaluating the efficacy and safety of vaginal testosterone and dehydroepiandrosterone for the treatment of vulvovaginal atrophy are ongoing. CONCLUSION: Available data support an important role of androgens in female sexual function and dysfunction and efficacy of transdermal T therapy for the treatment of some women with FSD. Approved T formulations for women are generally unavailable. In consequence, the prescribing of T mostly involves off-label use of T products formulated for men and individually compounded T formulations. Long-term studies to determine the safety of T therapy for women and possible benefits beyond that of sexual function are greatly needed. PMID- 26953832 TI - Vascular and Chronological Age in Men With Erectile Dysfunction: A Longitudinal Study. AB - INTRODUCTION: Impaired penile color Doppler ultrasound predicts major adverse cardiovascular (CV) events (MACE), particularly in men at low-risk. However, penile color Doppler ultrasound is not recommended in routine clinical checkups. AIM: To evaluate whether the difference between vascular and chronological age (Deltaage), as derived from the SCORE algorithm, is a predictor of MACE in subjects consulting for erectile dysfunction (ED) independently from other CV risk factors, including penile color Doppler ultrasound parameters. METHODS: A consecutive series of 1687 male patients attending the Outpatient Clinic for ED for the first time was retrospectively studied. Among them, the SCORE was applicable in 49.9% (n = 841) men, of whom 87.9% (n = 739) were free from previous MACE and were analyzed. MAIN OUTCOME MEASURES: Vascular age was derived from the SCORE algorithm and the Deltaage was considered. Information on MACE was obtained through the City of Florence Registry Office. MACE were identified using the International Classification of Diseases, and fatal and nonfatal MACE were coded as 410-414 (ischemic heart disease), 420-429 (other heart diseases), or 798 799 (sudden death from cardiac diseases), 430-434 or 436-438 (cerebrovascular disease), and 440 (peripheral arterial disease). RESULTS: Deltaage was associated with incident MACE. When dividing the population according to the median age (56 years), family history of CV diseases, and the presence of metabolic syndrome, the association between Deltaage and MACE was maintained only in low-risk subjects, even after adjusting for confounders [HR = 1.09(1.03-1.16), 1.05(1.01 1.10) and 1.08(1.01-1.16) for younger men, without CV family history or metabolic syndrome, respectively, all P < .05], including penile color Doppler ultrasound parameters. CONCLUSION: In subjects consulting for ED, Deltaage is associated with incident MACE, in particular in low-risk men. The prediction of MACE by Deltaage is independent from other risk factors including penile color Doppler ultrasound parameters, so it can be used as a costless and safe surrogate marker of penile vascular damage. PMID- 26953833 TI - Editorial Comment on "Vascular and Chronological Age in Men With Erectile Dysfunction: A Longitudinal Study". PMID- 26953835 TI - Editorial Comment on "Sexual Activity, Psychosexual Distress, and Fear of Progression in Women With Human Papillomavirus-Related Premalignant Genital Lesions". PMID- 26953837 TI - Partial Plaque Excision and Grafting With Collagen Fleece in Peyronie Disease. PMID- 26953839 TI - Preparation, characterization and usage of molecularly imprinted polymer for the isolation of quercetin from hydrolyzed nettle extract. AB - Quercetin (3,3',4',5,7-pentahydroxyflavone, QC) is a health-beneficial flavonoid, widely occurring in leaves, fruits, and flowers of various plants. In this work aiming isolation, purification and pre-concentration of QC, QC imprinted polymers (QC-MIPs) in different molar ratios {template:monomer:cross-linker (1:4:20, 1:5:30, 1:8:40, 1:10:50)} were prepared thermally through bulk polymerization by using QC as the template molecule, 4-vinylpyridine (4-VP), methacrylic acid (MAA), acrylamide (AA) as the functional monomers, ethylene glycol dimethacrylate (EDMA) as the cross-linker and 2,2'-azobisisobutyronitrile (AIBN) as initiator in the porogens of acetone and tetrahydrofuran. Their recognition and selectivity properties were investigated in solutions containing QC and other similar structure phenolics by equilibrium binding experiments using different proportions of acetonitrile (ACN)-dimethylsulfoxide (DMSO) mixtures and methanol (MeOH) as solvents. The MIP with 1:4:20 molar ratio of QC:4-VP:EDMA was established as the most suitable for recognition of QC. Sorption parameters of the MIP and the NIP (non-imprinted polymer) were calculated by using Freundlich and Langmuir isotherms with QC solutions in ACN:DMSO (98:2, v/v). The mentioned MIP was found to be highly selective for quercetin over other phenolic compounds (rutin, catechin, etc.). Thus, molecularly imprinted solid-phase extraction (MISPE) procedures were applied for selective pre-concentration and purification of QC from synthetic mixtures of phenolic compounds and nettle extract, known as a source of official and folk medicine. The results demonstrated the possibility of direct extraction of certain pharmacophoric constituents such as QC and QC derivatives from nettle by MIP separation. PMID- 26953840 TI - Familial dyskeratotic comedones: A rare entity. AB - Familial dyskeratotic comedones is an inherited disorder with distinctive clinical features and a disease course that is refractory to treatment. It is clinically characterized by numerous, discrete, disseminate, hyperkeratotic papules and comedones. On histopathology, it shows crater-like invaginations filled with keratinous material and evidence of dyskeratosis. We report here one family from central India with this rare disorder. PMID- 26953841 TI - Preparation of chain-end clickable recombinant protein and its bio-orthogonal modification. AB - Introducing unique functional group into protein is an attractive approach for site-selective protein modification applications. In this report, we systemically investigated four site-selective strategies to introduce azide functionality into recombinant thrombomodulin (TM456), via direct recombinant expression with unnatural amino acid, chemical, and enzymatic modification for its bio-orthogonal modification application. First, a straightforward recombinant method to express TM456 with azide functionality near C-terminus by replacing methionine with azidohomoanlanine from methionine auxotroph Escherichia coli cell was investigated. Next, a sortase-mediated ligation (SML) method to incorporate azide functionality into the C-terminus of recombinant TM456 was demonstrated. The third is to add azide functionality to the N-terminal amine of recombinant TM456via amidation chemistry, and the fourth is tyrosine selective three component Mannich reaction to introduce azide functionality to recombinant TM456. Overall, SML of recombinant protein affords the highest overall yield for incorporating azide functionality into the C-terminus recombinant TM456 since the key protein expression step uses natural amino acids. Also, single site modification facilitates the highest TM456 activity. PMID- 26953842 TI - Differences in impact of Aboriginal and Torres Strait Islander status on cancer stage and survival by level of socio-economic disadvantage and remoteness of residence-A population-based cohort study in Australia. AB - BACKGROUND: Aboriginal and Torres Strait Islander people (referred to in this paper as "Aboriginal people") generally have lower cancer survivals and more advanced stages at diagnosis than non-Aboriginal people. There is conflicting evidence on whether these disparities vary by socio-economic disadvantage and geographic remoteness. This study examines variations in these disparities in New South Wales (NSW), Australia. METHODS: Data for cancers diagnosed in 2000-2008 were extracted from the NSW Cancer Registry (n=264,219). Missing Aboriginal status (13.3%) was multiply imputed. Logistic regression and competing risk regression models were used to examine likelihood of advanced summary stage and risk of cancer death among Aboriginal compared with non-Aboriginal people by socio-economic disadvantage (categorised into quintiles 1: least disadvantaged-5: most disadvantaged) and remoteness. RESULTS: Aboriginal people showed a general pattern of more advanced stage at diagnosis compared with non-Aboriginal people across socio-economic disadvantage and remoteness categories. After adjusting for demographic factors, year of diagnosis, summary stage and cancer site, Aboriginal people living outside the least disadvantaged areas had an increased risk of cancer death compared with non-Aboriginal people living in similar areas (sub hazard ratio SHR 1.41, 95% confidence interval CI 1.09-1.81; SHR 1.59, 95%CI 1.31 1.93; SHR 1.42, 95%CI 1.22-1.64 and SHR 1.34, 95%CI 1.22-1.48 for quintiles 2-5, respectively). Compared with non-Aboriginal people, Aboriginal people had an elevation in the risk of cancer death irrespective of the remoteness, with the most pronounced elevations detected in remote/very remote areas (SHR 1.56, 95%CI 1.10-2.21). CONCLUSION: Compared with non-Aboriginal people, Aboriginal people had a higher risk of cancer death and higher likelihood of more advanced stage across socio-economic disadvantage and remoteness categories. All areas appear to require attention in endeavours to improve cancer survival outcomes for Aboriginal people. PMID- 26953843 TI - Attributing seizures to TBI: Validation of a brief patient questionnaire. AB - PURPOSE: Traumatic brain injury (TBI) is an important cause of epilepsy and has also been associated with psychogenic nonepileptic seizures (PNES). We designed a brief questionnaire assessing patient beliefs regarding TBI as the cause of their seizures (Patient Seizure Etiology Questionnaire; PSEQ). This study reports content validity for the PSEQ. METHODS: Ninety Veterans undergoing comprehensive evaluation at 3 VA epilepsy centers completed the PSEQ, a series of questions regarding possible causes for their seizures, including TBI. The PSEQ was scored as YES vs. NO for TBI as the proposed cause of seizures. For each patient, two expert reviewers independently completed a structured chart review to determine whether TBI was the proposed cause of seizures (n=180 reviews). Kappa statistic was used to assess agreement between the PSEQ and each chart review and between the PSEQ and combined chart reviews where both reviewers agreed on a TBI seizure etiology. RESULTS: The PSEQ scored higher overall rates for a TBI seizure etiology than did expert chart reviews (40% vs. 28%; p<0.001). The PSEQ agreed with 82% of 180 independent chart reviews (sensitivity 88%; specificity 79%). Kappa statistic for agreement was 0.60. The two reviewers agreed on a probable TBI seizure etiology for 83% of chart reviews. The PSEQ sensitivity increased to 100% when both reviewers were in agreement. CONCLUSION: The PSEQ provides a direct, standardized measure of patient beliefs regarding TBI as the cause of their seizures and has moderate-substantial agreement with expert chart reviews. PMID- 26953844 TI - A description of Canadian epilepsy monitoring units: An initial step toward developing nursing practice consensus guidelines. AB - OBJECTIVE: The epilepsy monitoring unit (EMU) is a well-established resource for investigating patients' seizures but is known to be heterogeneous in organization and clinical practice. The purpose of this study was to gain a better understanding of similarities and differences in EMU characteristics across Canada, with specific emphasis on EMU organization and nursing resources, which were currently unknown. Results would be used to develop a consensus on best nursing practice guidelines in EMUs with the goal to improve patient care and safety during epilepsy monitoring admissions. METHODS: An 18-item survey was developed addressing EMU locations, types, nursing ratios, nursing roles, and other allied health resources. Surveys were distributed to lead nurses, physicians, and administrators in 29 EMUs across Canada. Results were tabulated and presented for each question in the survey. CONCLUSION: All EMUs were located in urban, teaching centers and divided similarly by patient age. The survey demonstrated considerable variability in EMU bed location and organization with the majority of EMUs being smaller, open units embedded in wards rather than larger, closed units. Independent of patient acuity, variability also existed in nurse-to-patient ratios, nursing skill level, specialty nursing support, and EEG technician availability. These findings highlight that EMU heterogeneity contributes to the challenges in the development of standardized safe care practices and that nursing education and nursing best practice recommendations need to be developed with baseline EMU nursing competencies, skills, and knowledge in mind. PMID- 26953845 TI - Health resource utilization varies by comorbidities in children with epilepsy. AB - OBJECTIVES: Comorbidities in adults with epilepsy have been shown to significantly increase health resource utilization (HRU). The current study aimed to determine whether a similar association exists among children with epilepsy in a universal health insurance system. METHODS: Health administrative databases in Ontario, Canada were used to evaluate the frequency of neurologist visits, emergency department (ED) visits, and hospitalizations. We evaluated the association between HRU and comorbidities, including depression, anxiety, learning disability, attention deficit hyperactivity disorder (ADHD), and autistic spectrum disorder (ASD), adjusting for age, sex, residence, and socio economic status. RESULTS: The frequency of neurology visits was increased by comorbid depression, ASD, and learning disability (adjusted relative risk [aRR]=1.29-2.07; p<.01). The frequency of ED visits was increased by all comorbidities (aRR=1.26-2.83; p<.0001). The frequency of hospitalizations was increased by comorbid depression, anxiety, ASD, and learning disability (aRR=1.77 7.20; p<.0001). Learning disability had the largest impact on HRU. For each additional comorbidity, the frequency of neurology visits, ED visits, and hospitalizations increased by 1.64 to 3.16 times (p<.0001). CONCLUSIONS: Among children with epilepsy, mental health and developmental comorbidities were associated with increased HRU, and different comorbidities influenced different types of HRU. In addition, we highlight the importance of identifying and managing these comorbidities, as they increased the risks of costly HRU such as ED visits and hospitalizations. PMID- 26953846 TI - Methods for the absolute quantification of N-glycan biomarkers. AB - BACKGROUND: Many treatment options especially for cancer show a low efficacy for the majority of patients demanding improved biomarker panels for patient stratification. Changes in glycosylation are a hallmark of many cancers and inflammatory diseases and show great potential as clinical disease markers. The large inter-subject variability in glycosylation due to hereditary and environmental factors can complicate rapid transfer of glycan markers into the clinical practice but also presents an opportunity for personalized medicine. SCOPE OF REVIEW: This review discusses opportunities of glycan biomarkers in personalized medicine and reviews the methodology for N-glycan analysis with a specific focus on methods for absolute quantification. MAJOR CONCLUSIONS: The entry into the clinical practice of glycan markers is delayed in large part due to a lack of adequate methodology for the precise and robust quantification of protein glycosylation. Only absolute glycan quantification can provide a complete picture of the disease related changes and will provide the method robustness required by clinical applications. GENERAL SIGNIFICANCE: Glycan biomarkers have a huge potential as disease markers for personalized medicine. The use of stable isotope labeled glycans as internal standards and heavy-isotope labeling methods will provide the necessary method precision and robustness acceptable for clinical use. This article is part of a Special Issue entitled "Glycans in personalized medicine" Guest Editor: Professor Gordan Lauc. PMID- 26953847 TI - Sex and cognition: gender and cognitive functions. AB - Gender stereotypes hold that males outperform females in mathematics and spatial tests, and females outperform males on verbal tests. According to meta-analyses, however, among both children and adults, females perform equally to males on mathematics assessments. The gender difference in verbal skills is small and varies depending on the type of skill assessed (e.g., vocabulary, essay writing). The gender difference in 3D mental rotation shows a moderate advantage for males, but this gender difference occurs in the absence of a spatial curriculum in the schools. Meta-analyses of gender differences across a wide array of psychological qualities support the Gender Similarities Hypothesis, which states that males and females are quite similar on most-but not all-psychological variables. PMID- 26953848 TI - Effect of Ixekizumab Treatment on Work Productivity for Patients With Moderate-to Severe Plaque Psoriasis: Analysis of Results From 3 Randomized Phase 3 Clinical Trials. AB - IMPORTANCE: Therapies that reduce psoriasis symptoms may improve work productivity. OBJECTIVE: To assess the effect of ixekizumab therapy on work productivity, measured by the Work Productivity and Activity Impairment-Psoriasis (WPAI-PSO). DESIGN, SETTING, AND PARTICIPANTS: Three multicenter, randomized double-blind phase 3 trials conducted during the following periods: December 2011 through August 2014 (UNCOVER-1), May 2012 through April 2015 (UNCOVER-2), and August 2012 through July 2014 (UNCOVER-3). Adult outpatients with moderate-to severe chronic plaque psoriasis were included. INTERVENTIONS: In UNCOVER-1, patients were randomized 1:1:1 to subcutaneous placebo or 80 mg ixekizumab every 2 weeks (Q2W) or every 4 weeks (Q4W) for 12 weeks; UNCOVER-2 and UNCOVER-3 also had an etanercept arm (50 mg twice weekly). Maintenance of initial ixekizumab response was evaluated in UNCOVER-1 and UNCOVER-2 during a randomized withdrawal period following week 12 through week 60. The WPAI-PSO questionnaire was administered at baseline and week 12 for all patients and at weeks 24, 36, 52, and 60 for patients in UNCOVER-1 and UNCOVER-2. MAIN OUTCOMES AND MEASURES: Change in work productivity from baseline as measured by WPAI-PSO scores. RESULTS: Across trials, 5101 patients consented; 3866 were randomized (mean [SD] age, UNCOVER-1, 45.7 [12.9] y, 68.1% male; UNCOVER-2: 45.0 [13.0] y, 67.1% male; UNCOVER-3: 45.8 [13.1] y, 68.2% male). At week 12 in UNCOVER-1, the ixekizumab Q4W and ixekizumab Q2W groups showed significantly greater improvements in WPAI PSO scores (least squares mean change from baseline [SE]) relative to placebo: absenteeism (-3.5 [0.87], P < .001; -2.6 [0.84], P = .003, respectively, vs 0.2 [0.88]), presenteeism (-18.8 [1.28], P < .001; -18.3 [1.24], P < .001, vs 0.5 [1.30]), work productivity loss (-20.6 [1.38], P < .001; -19.8 [1.33], P < .001, vs -0.8 [1.40]), and activity impairment (-24.5 [1.18], P < .001; -25.2 [1.15], P < .001, vs 0.8 [1.18]). Similar results were obtained for UNCOVER-2 and UNCOVER 3, with the exception of absenteeism with ixekizumab Q4W in UNCOVER-2. Additionally, ixekizumab-treated patients showed significantly greater improvements in WPAI-PSO scores vs etanercept-treated patients: UNCOVER-2: presenteeism, work productivity loss, activity impairment (P < .001 both doses), UNCOVER-3: activity impairment (ie, regular activities outside of work) (ixekizumab Q2W; P = .009). Improvements in WPAI-PSO scores at week 12 were sustained to at least week 60. CONCLUSIONS AND RELEVANCE: Ixekizumab-treated patients reported short- and long-term improvements in work productivity, which could lead to reduced productivity-related cost burden in patients with psoriasis. TRIAL REGISTRATION: clinicaltrials.gov Identifiers: NCT01474512, NCT01597245, NCT01646177. PMID- 26953849 TI - A developmental neuroscience approach to the search for biomarkers in autism spectrum disorder. AB - PURPOSE OF REVIEW: The delineation of biomarkers in autism spectrum disorder (ASD) offers a promising approach to inform precision-medicine-based approaches to ASD diagnosis and treatment and to move toward a mechanistic description of the disorder. However, biomarkers with sufficient sensitivity or specificity for clinical application in ASD are yet to be realized. Here, we review recent evidence for early, low-level alterations in brain and behavior development that may offer promising avenues for biomarker development in ASD. RECENT FINDINGS: Accumulating evidence suggests that signs associated with ASD may unfold in a manner that maps onto the hierarchical organization of brain development. Genetic and neuroimaging evidence points towards perturbations in brain development early in life, and emerging evidence indicates that sensorimotor development may be among the earliest emerging signs associated with ASD, preceding social and cognitive impairment. SUMMARY: The search for biomarkers of risk, prediction and stratification in ASD may be advanced through a developmental neuroscience approach that looks outside of the core signs of ASD and considers the bottom-up nature of brain development alongside the dynamic nature of development over time. We provide examples of assays that could be incorporated in studies to target low-level circuits. PMID- 26953851 TI - Global Estimates of Fine Particulate Matter using a Combined Geophysical Statistical Method with Information from Satellites, Models, and Monitors. AB - We estimated global fine particulate matter (PM2.5) concentrations using information from satellite-, simulation- and monitor-based sources by applying a Geographically Weighted Regression (GWR) to global geophysically based satellite derived PM2.5 estimates. Aerosol optical depth from multiple satellite products (MISR, MODIS Dark Target, MODIS and SeaWiFS Deep Blue, and MODIS MAIAC) was combined with simulation (GEOS-Chem) based upon their relative uncertainties as determined using ground-based sun photometer (AERONET) observations for 1998 2014. The GWR predictors included simulated aerosol composition and land use information. The resultant PM2.5 estimates were highly consistent (R(2) = 0.81) with out-of-sample cross-validated PM2.5 concentrations from monitors. The global population-weighted annual average PM2.5 concentrations were 3-fold higher than the 10 MUg/m(3) WHO guideline, driven by exposures in Asian and African regions. Estimates in regions with high contributions from mineral dust were associated with higher uncertainty, resulting from both sparse ground-based monitoring, and challenging conditions for retrieval and simulation. This approach demonstrates that the addition of even sparse ground-based measurements to more globally continuous PM2.5 data sources can yield valuable improvements to PM2.5 characterization on a global scale. PMID- 26953853 TI - Developing New Approaches to Continuing Education and Critically Assessing Current Practice. PMID- 26953852 TI - Analysis of enzyme-responsive peptide surfaces by Raman spectroscopy. AB - We report on the use of Raman spectroscopy as a tool to characterise model peptide functionalised surfaces. By taking advantage of Raman reporters built into the peptide sequence, the enzymatic hydrolysis of these peptides could be determined. PMID- 26953854 TI - The 2015 JCEHP Award for Excellence in Research. PMID- 26953850 TI - Interictal high-frequency oscillations in focal human epilepsy. AB - PURPOSE OF REVIEW: Localization of focal epileptic brain is critical for successful epilepsy surgery and focal brain stimulation. Despite significant progress, roughly half of all patients undergoing focal surgical resection, and most patients receiving focal electrical stimulation, are not seizure free. There is intense interest in high-frequency oscillations (HFOs) recorded with intracranial electroencephalography as potential biomarkers to improve epileptogenic brain localization, resective surgery, and focal electrical stimulation. The present review examines the evidence that HFOs are clinically useful biomarkers. RECENT FINDINGS: Performing the PubMed search 'High-Frequency Oscillations and Epilepsy' for 2013-2015 identifies 308 articles exploring HFO characteristics, physiological significance, and potential clinical applications. SUMMARY: There is strong evidence that HFOs are spatially associated with epileptic brain. There remain, however, significant challenges for clinical translation of HFOs as epileptogenic brain biomarkers: Differentiating true HFO from the high-frequency power changes associated with increased neuronal firing and bandpass filtering sharp transients. Distinguishing pathological HFO from normal physiological HFO. Classifying tissue under individual electrodes as normal or pathological. Sharing data and algorithms so research results can be reproduced across laboratories. Multicenter prospective trials to provide definitive evidence of clinical utility. PMID- 26953855 TI - Analyzing Fallacies in Argumentation to Enhance Effectiveness of Educational Interventions: The Case of Care Providers' Arguments Against Using Professional Interpretation. AB - INTRODUCTION: Although research has shown that professional interpreters improve health care to patients who do not speak the same language as their care provider, care providers underuse professional interpretation services. To get more insight into the reasons of care providers to underuse professional interpreters, we studied fallacies in their arguments. Fallacies in reasoning may explain why care providers avoid changing their behavior even if they are aware of evidence in favor of such behavior. METHODS: We did a secondary analysis of interviews about immigrant patients with care providers collected in two studies on in-hospital pediatric care. Interviews (N = 37) were held in 2009, in the Netherlands. Interviews were analyzed using a contextual approach to fallacious argumentation: a method that can identify fallacies as "wrong" arguments compared with the context in they are made. RESULTS: We identified six main fallacies that care providers used to argue that they prefer not to use a professional interpreter while having free access to professional interpreters: 1) There are also some negative side effects to using professional interpreters, 2) there is no language problem, 3) it is such an enormous hassle to organize it, 4) I am a good doctor, 5) my medical information is not complex, and 6) patients do not want it. DISCUSSION: Familiarizing care providers with these fallacies can raise their awareness of the wrong arguments to defend their underuse of professional interpreters and can be made part of their training. PMID- 26953856 TI - Acceptability and Effectiveness of a Long-Term Educational Intervention to Reduce Physicians' Stress-Related Conditions. AB - INTRODUCTION: This study aimed to test the acceptability and effectiveness of a two-phase mindfulness-based stress reduction program (8-week initial treatment plus a 10-month maintenance phase) in alleviating work stress-related symptoms (i.e., burnout, heart rate [HR], and blood pressure [BP]) in a sample of 42 physicians. METHODS: A randomized controlled trial and a simple pre-post design were used, respectively, for each of the two phases of the study. Outcome measures included the Five Facets of Mindfulness Questionnaire and the Maslach Burnout Questionnaire. HR and BP measures were also obtained in the experimental group by means of a digital monitor. RESULTS: After the initial 8 weeks of treatment, significant improvements for the experimental group in mindfulness levels and reductions in emotional exhaustion, HR, and BP were obtained. Effect sizes (Cohen d) significantly increased over the 10-month maintenance period, especially for mindfulness and systolic BP. Acceptance was notably high (low attrition rate and high compliance with program activities). DISCUSSION: Outcomes are significant in terms of practical consequences for reducing and controlling risks of developing burnout and cardiovascular disease in this population and enhancing well-being in life. PMID- 26953857 TI - Enhancing Education Activities for Health Care Trainees and Professionals Using Audience Response Systems: A Systematic Review. AB - INTRODUCTION: This review examines the effect of incorporating clickers within practice-based education sessions on educational outcomes of health care trainees and professionals. METHODS: A systematic literature review was conducted on primary research studies published up until August 2014. Studies were identified by database searching (Ovid MEDLINE, EMBASE, CINAHL, Scopus, Web of Science, and PsychInfo), citation searching, and reference list checking. Studies were restricted to those evaluating the use of clickers as part of the provision of postgraduate education or continuing education programs and were evaluated according to Kirkpatrick's four levels of training evaluation (reaction, learning, behavior, and results). RESULTS: Seventeen studies met the eligibility criteria. Twelve studies assessed learner and/or speaker reactions, with feedback overwhelmingly positive in all studies. Reported learner benefits included increased attentiveness, engagement, and enjoyment of presentations. Speakers reported that using clickers engaged the audience and assisted in assessing audience comprehension. Eight studies assessed learning outcomes. Higher level evidence obtained from four randomized studies demonstrated significant improvements in knowledge with the use of clickers compared with traditional didactic presentations, but no differences when clickers were compared with an interactive lecture with integrated questions. No studies adequately assessed higher level educational outcomes (behavior and results). CONCLUSION: Although the use of clickers improves learning environment and learner satisfaction, the limited high-quality data for improvements in learning and behavior outcomes make it uncertain whether the acceptance and implementation of clickers within routine practice-based education programs are warranted at this stage. PMID- 26953858 TI - Improving Transfer of Learning: An Innovative Comentoring Program to Enhance Workplace Implementation After an Occupational Therapy Course on Autism Spectrum Disorders. AB - INTRODUCTION: Research suggests that learning gained through training is infrequently implemented in the workplace. A short-term postcourse comentoring program was developed with the aim of facilitating workplace implementation of learning after a 3-day course for occupational therapists. The program was evaluated for usefulness, successes, challenges, recommended improvements, and associations with changes in self-rated knowledge and confidence. METHOD: Two months after the course, 42 participants completed an evaluation of the comentoring program with closed- and open-ended questions addressing usefulness, successes, challenges, pairing preferences, and recommendations. They also completed a record on whether or not they had worked on goals nominated in their comentoring contract. Before and 2 months after the course, they completed a self rated questionnaire on knowledge and confidence. RESULTS: The comentoring program was recommended by 80% of participants. Benefits included opportunities for information and resource sharing, debriefing, problem solving, reassurance, and implementation of ideas. Ninety-five percent of participants worked on some or all their comentoring goals. Although there were significant improvements in knowledge (P < 0.001) and confidence (P < 0.001), the total comentoring evaluation score was not significantly associated with these changes. It is therefore possible that these improvements related to the course itself rather than the comentoring program. Challenges related to time, scheduling, distance, and pairing of comentors. CONCLUSION: Reported benefits of the program included enhanced psychosocial support and prompting to trial newly learned strategies. Effectiveness may be improved by setting aside time for comentoring in the workplace and better matching of comentors. PMID- 26953859 TI - Development of a Curriculum on the Child With Medical Complexity: Filling a Gap When Few Practice Guidelines Exist. AB - BACKGROUND: Pediatric hospitalists are increasingly involved in the clinical management of children with medical complexity (CMC), specifically those with neurologic impairment and technology dependence. Clinical care guidelines and educational resources on management of the diseases and devices prevalent in CMC are scarce. The objective of this study was to develop and evaluate a web-based curriculum on care of CMC for hospitalists at our institution using a novel approach to validate educational content. METHODS: Junior faculty collaborated with senior hospitalist peer mentors to create multimedia learning modules on highly-desired topics as determined by needs assessment. Module authors were encouraged to work with subspecialty experts from within the institution and to submit their modules for external peer review. Pilot study participants were asked to complete all modules, associated knowledge tests, and evaluations over a 4-month period. RESULTS: Sixteen of 33 eligible hospitalists completed the curriculum and associated assessments. High scores with respect to satisfaction were seen across all modules. There was a significant increase in posttest knowledge scores (P < 0.001) with sustained retention at 6 months posttest (P < 0.013). Participants were most likely to make changes to their teaching and clinical practice based on participation in this curriculum. CONCLUSIONS: We used a novel approach for content development in this curriculum that incorporated consultation with experts and external peer review, resulting in improved knowledge, high satisfaction, and behavior change. Our approach may be a useful method to improve content validity for educational resources on topics that do not have established clinical care guidelines. PMID- 26953860 TI - Reciprocal Feedback: Closing the Loop on Postactivity Surveys. AB - Those who conduct feedback surveys, which follow almost every CME presentation and medical-school lecture, would do well to offer participants' reciprocal feedback. That is, the course director should provide each survey respondent, on request, a brief summary of the comments received from this survey and the extent to which the recommendations will lead to objective improvements in the future. Surveyors who provide respondents with reciprocal feedback can expect heightened credibility, more reliable feedback in the future, and an added incentive to effect significant change for the better. Feedback has not circled all the way back until we have provided a succinct summary of results to those who have offered us their comments and suggestions. Let us close the loop; let reciprocal feedback become the last word in CME surveys. PMID- 26953863 TI - Risk Factors for Portal Vein System Thrombosis After Laparoscopic Splenectomy in Cirrhotic Patients with Hypersplenism. AB - BACKGROUND: Portal vein system thrombosis (PVST) is a frequent and potentially life-threatening complication after laparoscopic splenectomy (LS) in cirrhotic patients with hypersplenism. The mechanisms and risk factors of PVST are poorly understood. This study investigated risk factors for PVST following LS in cirrhotic patients with hypersplenism. MATERIALS AND METHODS: A total of 56 consecutive cirrhotic patients with hypersplenism who underwent successful LS between 2013 and 2014 were included in this retrospective study. Based on the absence or presence of postoperative PVST on postoperative day (POD) 7, the patients were divided into non-PVST and PVST groups. Demographic and preoperative factors were analyzed. RESULTS: PVST increased in size in 24 (42.9%) of 56 patients after LS on POD 7. Logistic multivariate regression showed that a portal vein diameter >13 mm (relative risk 35.796, 95% confidence interval 4.534 282.614, and P = .001) and age >50 years (relative risk 20.127, 95% confidence interval 3.598-112.578, and P = .001) were significant independent risk factors for PVST. The incidence of PVST after LS in the portal vein diameter >13 mm group was significantly higher than that in the portal vein diameter <=13 mm group (P = .001). Similarly, the incidence of PVST after LS in the age >50 years group was significantly higher than that in the age <=50 years group (P = .001). CONCLUSION: A portal vein diameter >13 mm and age >50 years are independent risk factors for PVST after LS in cirrhotic patients with hypersplenism due to portal hypertension. PMID- 26953864 TI - High-performance graphene-based supercapacitors made by a scalable blade-coating approach. AB - Graphene oxide (GO) sheets can form liquid crystals (LCs) in their aqueous dispersions that are more viscous with a stronger LC feature. In this work we combine the viscous LC-GO solution with the blade-coating technique to make GO films, for constructing graphene-based supercapacitors in a scalable way. Reduced GO (rGO) films are prepared by wet chemical methods, using either hydrazine (HZ) or hydroiodic acid (HI). Solid-state supercapacitors with rGO films as electrodes and highly conductive carbon nanotube films as current collectors are fabricated and the capacitive properties of different rGO films are compared. It is found that the HZ-rGO film is superior to the HI-rGO film in achieving high capacitance, owing to the 3D structure of graphene sheets in the electrode. Compared to gelled electrolyte, the use of liquid electrolyte (H2SO4) can further increase the capacitance to 265 F per gram (corresponding to 52 mF per cm(2)) of the HZ-rGO film. PMID- 26953865 TI - Medical Monitoring During Firefighter Incident Scene Rehabilitation. AB - OBJECTIVE: The objective of this study was to retrospectively investigate aspects of medical monitoring, including medical complaints, vital signs at entry, and vital sign recovery, in firefighters during rehabilitation following operational firefighting duties. RESULTS: Incident scene rehabilitation logs obtained over a 5-year span that included 53 incidents, approximately 40 fire departments, and more than 530 firefighters were reviewed. Only 13 of 694 cases involved a firefighter reporting a medical complaint. In most cases, vital signs were similar between firefighters who registered a complaint and those who did not. On average, heart rate was 104 +/- 23 beats.min(-1), systolic blood pressure was 132 +/- 17 mmHg, diastolic blood pressure was 81 +/- 12 mmHg, and respiratory rate was 19 +/- 3 breaths.min(-1) upon entry into rehabilitation. At least two measurements of heart rate, systolic blood pressure, diastolic blood pressure, and respiratory rate were obtained for 365, 383, 376, and 160 cases, respectively. Heart rate, systolic and diastolic blood pressures, and respiratory rate decreased significantly (p < 0.001) during rehabilitation. Initial vital signs and changes in vital signs during recovery were highly variable. CONCLUSIONS: Data from this study indicated that most firefighters recovered from the physiological stress of firefighting without any medical complaint or symptoms. Furthermore, vital signs were within fire service suggested guidelines for release within 10 or 20 minutes of rehabilitation. The data suggested that vital signs of firefighters with medical symptoms were not significantly different from vital signs of firefighters who had an unremarkable recovery. PMID- 26953866 TI - Placental levels of total oxidative and anti-oxidative status, ADAMTS-12 and decorin in early- and late-onset severe preeclampsia. AB - OBJECTIVE: Preeclampsia (PE), can be classified according to the timing of disease onset: early-onset PE occurs before the 34th gestational week and late onset PE occurs in the 34th gestational week or later. The aim of this study was to determine whether total antioxidant status (TAS), and total oxidant status (TOS), ADAMTS-12 and decorin levels differ among early-onset severe PE (EOS-PE), late-onset severe PE (LOS-PE) and uncomplicated pregnancies. METHODS: In this case-control study, placental samples obtained from 25 pregnant patients with EOS PE, 26 pregnant patients with LOS-PE and 28 healthy patients with uncomplicated pregnancies (control group). RESULTS: Placenta levels of decorin and TOS were significantly higher and TAS was significantly lower in the EOS-PE and LOS-PE groups than in the control group. These alterations were more prominent in patients with EOS-PE than in patients with LOS-PE. There were no significant differences in the ADAMTS-12 levels of the groups. CONCLUSION: The distinctly higher rate of negative perinatal outcomes in both EOS-PE and LOS-PE patients is well evidenced. However, the main questions that need to be answered are whether the only difference between these two diseases is the time of their onset and whether the only difference between them with respect to fetal morbidity and mortality is prematurity. PMID- 26953867 TI - Multiple Sclerosis: Changes in Thalamic Resting-State Functional Connectivity Induced by a Home-based Cognitive Rehabilitation Program. AB - Purpose To investigate thalamic connectivity changes after use of a video game based cognitive rehabilitation program, as thalamic damage and alterations in thalamocortical functional connectivity (FC) are important factors in cognitive dysfunction in patients with multiple sclerosis (MS). Materials and Methods This prospective study was approved by the local ethical committee. Twenty-four patients with MS and cognitive impairment were randomly assigned to either an intervention or a wait-list group. Patients were evaluated with cognitive tests and 3-T resting-state functional magnetic resonance (MR) imaging at baseline and after an 8-week period. In addition, 11 healthy subjects underwent baseline resting-state functional MR imaging. Patients in the intervention group performed the video game-based cognitive rehabilitation program, while those in the wait list group served as control subjects. Repeated measures analysis of variance was used to test efficacy of the intervention. The thalamic resting-state network was identified with a seed-based method; both first-level and high-level analyses were performed by using software tools. Results Patients showed lower baseline FC compared with healthy subjects. A significant improvement was seen in results of the Paced Auditory Serial Addition Test and the Stroop Test after 8 weeks of cognitive rehabilitation (F = 6.616, [P = .018] and F = 5.325 [P = .030], respectively). At follow-up, the intervention group had an increased FC in the cingulum, precuneus, and bilateral parietal cortex and a lower FC in the cerebellum and in left prefrontal cortex compared with the wait-list group (P < .05, family-wise error corrected); correlations were found between FC changes in these regions and cognitive improvement (P < .05, family-wise error corrected). Conclusion The results of this study show the relevance of thalamic regulation of the brain networks involved in cognition and suggest that changes in thalamic resting-state network connectivity may represent a functional substrate for cognitive improvement associated with a video game-based cognitive rehabilitation program. ((c)) RSNA, 2016. PMID- 26953868 TI - Desert, detention, and deportation: Mexican women's descriptions of migration stressors and sources of strength. AB - I analyzed interviews (n = 10) of women recently deported from the United States of America to Mexico, exploring what women experienced immediately after deportation. The women who were residing in a short-term shelter in Nogales, Mexico, described their greatest stressors and sources of strength. Women identified the border crossing experience, apprehension, detention, and family separation due to deportation as stressors. Sources of strength included God and family. Irregular migration is not unique between the United States and Mexico. Women migrate in search of work, education, and safety. I offer these women's stories as exemplars and this study as one to be replicated with women in other contexts across the globe. PMID- 26953869 TI - Development and optimization of boswellic acid-loaded proniosomal gel. AB - CONTEXT: Boswellic acids (BAs) are isolated from oleo gum of Boswellia serrata and are mainly used as potential anti-inflammatory, hypolipidemic, immunomodulatory, and antitumor agents. Pharmacokinetic investigations of BAs uncover its poor bioavailability through digestive system thus creates a need for improved therapeutic responses which can possibly be achieved by developing formulations through novel delivery system. OBJECTIVE: Present study was conducted to design topical BA-loaded proniosomal gel for the management of inflammatory disorders with enhanced bioavailability. MATERIALS AND METHODS: Nonionic surfactant vesicles were prepared using the coacervation phase separation method. A central composite design was employed to statistically optimize formulation variables using Design-Expert software. Three independent variables were evaluated: amount of surfactant (X1), amount of soya lecithin (X2), and amount of cholesterol (X3). The encapsulation efficiency percentage (Y1) and particle size (Y2) were selected as dependent variables. RESULTS AND DISCUSSION: The optimum formulation (F10) displayed spherical bi-layered vesicles under transmission electron microscopy with optimum particle size of 707.9 nm and high entrapment efficiency as 98.52%. In vitro skin permeation study demonstrated the most sustained release of 84.83 +/- 0.153 mg/cm2 in 24 h. Anti-inflammatory activity of the gel showed a significant (p < 0.001) higher percentage inhibition as compared to the marketed gel at the same dose. CONCLUSION: The present study exhibited that BA-loaded proniosomal gel was better in terms of absorption, bioavailability, and release kinetics. PMID- 26953870 TI - Immunologic Effects of Metformin and Pioglitazone Treatment on Metabolic Syndrome and Multiple Sclerosis. AB - IMPORTANCE: Metabolic syndrome (MetS) is thought to influence several autoimmune diseases, including multiple sclerosis (MS). Anti-inflammatory effects of treatments used for MetS, such as metformin hydrochloride and pioglitazone hydrochloride, have been demonstrated, although clinical evidence supporting use of these treatments in MS is lacking. OBJECTIVES: To determine whether metformin and/or pioglitazone are associated with a reduction in disease activity as measured by brain magnetic resonance imaging in patients with MS and MetS and to evaluate the potential mechanisms underlying this anti-inflammatory effect. DESIGN, SETTING, AND PARTICIPANTS: A prospective cohort study was conducted from March 1, 2012, to December 30, 2014, at a private MS referral center among 50 obese patients with MS who also developed MetS. Twenty patients received metformin hydrochloride, 850 to 1500 mg/d, and 10 patients received pioglitazone hydrochloride, 15 to 30 mg/d; 20 untreated patients served as controls. Groups were comparable in terms of sex, age, body mass index, Expanded Disability Status Scale score, disease duration, annual relapse rate, and treatment status. Patients were followed up for a mean (SD) of 26.7 (2.7) months (range, 24-33 months). MAIN OUTCOMES AND MEASURES: Magnetic resonance imaging of the brain was performed at 6-month intervals, and the presence of new or enlarging T2 lesions or gadolinium-enhancing lesions was registered. Serum leptin and adiponectin levels were measured. The production of cytokines by peripheral blood mononuclear cells was assayed, as were regulatory T-cell numbers and function. RESULTS: Of 50 patients, after 6 months of treatment, 20 patients with MS who were treated with metformin and 10 who received pioglitazone showed a significant decrease in the number of new or enlarging T2 lesions (metformin, 2.5 at study entry to 0.5 at month 24; pioglitazone, 2.3 at study entry to 0.6 at month 24), as well as of gadolinium-enhancing lesions (metformin, 1.8 at study entry to 0.1 at month 24; pioglitazone, 2.2 at study entry to 0.3 at month 24). Compared with controls, both treatments led to a decrease in mean (SD) leptin levels (metformin, 5.5 [2.4] vs 10.5 [3.4] ng/mL, P < .001; pioglitazone, 4.1 [0.8] vs 11.0 [2.6] ng/mL, P < .001) and increase in mean (SD) adiponectin serum levels (metformin, 15.4 [5.5] vs 4.5 [2.4] MUg/mL, P < .001; pioglitazone, 12.6 [3.6] vs 4.8 [0.6] MUg/mL, P < .001). Mean (SD) number of myelin basic protein peptide-specific cells secreting interferon gamma and interleukin (IL)-17 were significantly reduced in patients receiving metformin compared with controls (interferon gamma, 30.3 [11.5] vs 82.8 [18.8], P < .001; IL-17, 212.4 [85.5] vs 553.8 [125.9], P < .001). Patients treated with pioglitazone showed significant decreases in the mean (SD) number of myelin basic protein peptide-specific cells secreting IL-6 and tumor necrosis factor compared with controls (IL-6, 361.6 [80.5] vs 1130.7 [149.21], P < .001; tumor necrosis factor, 189.9 [53.4] vs 341.0 [106.0], P < .001). Both metformin and pioglitazone resulted in a significant increase in the number and regulatory functions of CD4+CD25+FoxP3+ regulatory T cells compared with controls (metformin, 6.7 [1.5] vs 2.1 [1.0], P = .001; pioglitazone, 6.9 [0.8] vs 3.0 [0.8], P = .001). CONCLUSIONS AND RELEVANCE: Treatment with metformin and pioglitazone has beneficial anti-inflammatory effects in patients with MS and MetS and should be further explored. PMID- 26953873 TI - Identification of Novel Variants in the PVRL1 Gene in Patients With Nonsyndromic Cleft Lip With or Without Cleft Palate. AB - OBJECTIVE: Nonsyndromic cleft lip with/without cleft palate (nsCL/P, OMIM 119530) is one of the most common birth defects with a prevalence of ~1/1000 in Caucasians. Studies have demonstrated an association between nsCL/P and the variants of the poliovirus receptor like-1 gene (PVRL1). The aim of this study was to describe novel variants in exon 3 of the PVRL1 gene and to investigate the association between exon 3 of the PVRL1 gene and Turkish patients with nsCL/P. METHODS: 205 Turkish subjects were enrolled: 80 nsCL/P patients and 125 unrelated control individuals. Genomic DNA was isolated from peripheral blood leukocytes, and exon 3 of the PVRL1 gene was amplified using polymerase chain reaction (PCR). After PCR, the amplied DNA was sequenced using an automated sequencer. RESULTS: We identified two new variants of the PVRL1 gene at codons 174 and 187 in exon 3. These variants had nucleotide substitutions 520T>A and 560C>A, resulting in S174T and T187N amino acid changes, respectively. CONCLUSION: Two novel variants of the PVRL 1 gene were identified in nsCL/P patients. These findings suggest that PVRL1 variants make a contribution to nsCL/P in Turkish patients. PMID- 26953874 TI - LSG: An External-Memory Tool to Compute String Graphs for Next-Generation Sequencing Data Assembly. AB - The large amount of short read data that has to be assembled in future applications, such as in metagenomics or cancer genomics, strongly motivates the investigation of disk-based approaches to index next-generation sequencing (NGS) data. Positive results in this direction stimulate the investigation of efficient external memory algorithms for de novo assembly from NGS data. Our article is also motivated by the open problem of designing a space-efficient algorithm to compute a string graph using an indexing procedure based on the Burrows-Wheeler transform (BWT). We have developed a disk-based algorithm for computing string graphs in external memory: the light string graph (LSG). LSG relies on a new representation of the FM-index that is exploited to use an amount of main memory requirement that is independent from the size of the data set. Moreover, we have developed a pipeline for genome assembly from NGS data that integrates LSG with the assembly step of SGA (Simpson and Durbin, 2012 ), a state-of-the-art string graph-based assembler, and uses BEETL for indexing the input data. LSG is open source software and is available online. We have analyzed our implementation on a 875-million read whole-genome dataset, on which LSG has built the string graph using only 1GB of main memory (reducing the memory occupation by a factor of 50 with respect to SGA), while requiring slightly more than twice the time than SGA. The analysis of the entire pipeline shows an important decrease in memory usage, while managing to have only a moderate increase in the running time. PMID- 26953875 TI - Algorithms for Regular Tree Grammar Network Search and Their Application to Mining Human-viral Infection Patterns. AB - Network querying is a powerful approach to mine molecular interaction networks. Most state-of-the-art network querying tools either confine the search to a prespecified topology in the form of some template subnetwork, or do not specify any topological constraints at all. Another approach is grammar-based queries, which are more flexible and expressive as they allow for expressing the topology of the sought pattern according to some grammar-based logic. Previous grammar based network querying tools were confined to the identification of paths. In this article, we extend the patterns identified by grammar-based query approaches from paths to trees. For this, we adopt a higher order query descriptor in the form of a regular tree grammar (RTG). We introduce a novel problem and propose an algorithm to search a given graph for the k highest scoring subgraphs matching a tree accepted by an RTG. Our algorithm is based on the combination of dynamic programming with color coding, and includes an extension of previous k-best parsing optimization approaches to avoid isomorphic trees in the output. We implement the new algorithm and exemplify its application to mining viral infection patterns within molecular interaction networks. Our code is available online. PMID- 26953882 TI - Online Discovery of Search Objectives for Test-Based Problems. AB - In test-based problems, commonly approached with competitive coevolutionary algorithms, the fitness of a candidate solution is determined by the outcomes of its interactions with multiple tests. Usually, fitness is a scalar aggregate of interaction outcomes, and as such imposes a complete order on the candidate solutions. However, passing different tests may require unrelated "skills," and candidate solutions may vary with respect to such capabilities. In this study, we provide theoretical evidence that scalar fitness, inherently incapable of capturing such differences, is likely to lead to premature convergence. To mitigate this problem, we propose disco, a method that automatically identifies the groups of tests for which the candidate solutions behave similarly and define the above skills. Each such group gives rise to a derived objective, and these objectives together guide the search algorithm in multi-objective fashion. When applied to several well-known test-based problems, the proposed approach significantly outperforms the conventional two-population coevolution. This opens the door to efficient and generic countermeasures to premature convergence for both coevolutionary and evolutionary algorithms applied to problems featuring aggregating fitness functions. PMID- 26953872 TI - The association of serum trans-nonachlor levels with atherosclerosis. AB - Recent epidemiological studies suggest a strong association between exposure to environmental contaminants, including organochlorine (OC) insecticides or their metabolites, and development of pathologies, such as atherosclerosis, in which oxidative stress plays a significant etiological role. Biomarkers of systemic oxidative stress have the potential to link production of reactive oxygen species (ROS), which are formed as a result of exposure to xenobiotic toxicants, and underlying pathophysiological states. Measurement of F2-isoprostane concentrations in body fluids is the most accurate and sensitive method currently available for assessing in vivo steady-state oxidative stress levels. In the current study, urinary concentrations of F2-isoprostanes and serum levels of persistent OC compounds p,p'-dichlorodiphenyldichloroethene (DDE), trans nonachlor (a component of the technical chlordane mixture), and oxychlordane (a chlordane metabolite) were quantified in a cross-sectional study sample and the association of these factors with a clinical diagnosis of atherosclerosis determined. Urinary isoprostane levels were not associated with atherosclerosis or serum concentrations of OC compounds in this study sample. However, occurrence of atherosclerosis was found to be associated with serum trans-nonachlor levels. DDE and oxychlordane were not associated with atherosclerosis. This finding supports current evidence that exposure to environmental factors is a risk factor for atherosclerosis, in addition to other known risk factors. PMID- 26953883 TI - Particle Swarm Optimization for Single Objective Continuous Space Problems: A Review. AB - This paper reviews recent studies on the Particle Swarm Optimization (PSO) algorithm. The review has been focused on high impact recent articles that have analyzed and/or modified PSO algorithms. This paper also presents some potential areas for future study. PMID- 26953884 TI - Net Assimilation Rate Determines the Growth Rates of 14 Species of Subtropical Forest Trees. AB - Growth rates are of fundamental importance for plants, as individual size affects myriad ecological processes. We determined the factors that generate variation in RGR among 14 species of trees and shrubs that are abundant in subtropical Chinese forests. We grew seedlings for two years at four light levels in a shade-house experiment. We monitored the growth of every juvenile plant every two weeks. After one and two years, we destructively harvested individuals and measured their functional traits and gas-exchange rates. After calculating individual biomass trajectories, we estimated relative growth rates using nonlinear growth functions. We decomposed the variance in log(RGR) to evaluate the relationships of RGR with its components: specific leaf area (SLA), net assimilation rate (NAR) and leaf mass ratio (LMR). We found that variation in NAR was the primary determinant of variation in RGR at all light levels, whereas SLA and LMR made smaller contributions. Furthermore, NAR was strongly and positively associated with area-based photosynthetic rate and leaf nitrogen content. Photosynthetic rate and leaf nitrogen concentration can, therefore, be good predictors of growth in woody species. PMID- 26953885 TI - An initial typology of contexts of dyadic sexual encounters between men and associations with sexual risk and pleasure: findings from an observational study. AB - Background Although many within-subjects comparisons conducted on samples of men who have sex with men have sought to understand the association between specific situational characteristics (e.g. drug use or location of sex) and sexual risk behaviour, none have considered the 'clustering' of patterns of situational characteristics. An initial typology of sexual encounters is derived and the relationship of this typology to condomless anal intercourse (CAI) and pleasure is tested. METHODS: Data from a longitudinal survey of men who have sex with men living in England were used. Multilevel latent class analyses were estimated to determine an optimal class solution on the situational characteristics, and then pseudo-imputation was used to estimate the association between class and both CAI and pleasure. RESULTS: A three-class solution fit the data best, with a scaled relative entropy of 92.4%. Classes were characterised as featuring: regular steady partners in private locations with low drug use (class 1), casual partners with increased probability of sex occurring in a sex-on-premises venue (class 2), and high levels of polydrug use together with increased probability of casual partners (class 3). Encounters were different both in pairwise comparisons and overall on probability of CAI. They were different overall but not necessarily pairwise on pleasure. CONCLUSIONS: These initial findings demonstrate the possibility of understanding sexual encounters in terms of the contexts, or classes, within which they occur. This may have implications for tailoring HIV prevention to specific encounter types. Future research should seek to extend encounter-level typologies to specific drug use variables. PMID- 26953886 TI - Global Neuromagnetic Cortical Fields Have Non-Zero Velocity. AB - Globally coherent patterns of phase can be obscured by analysis techniques that aggregate brain activity measures across-trials, whether prior to source localization or for estimating inter-areal coherence. We analyzed, at single trial level, whole head MEG recorded during an observer-triggered apparent motion task. Episodes of globally coherent activity occurred in the delta, theta, alpha and beta bands of the signal in the form of large-scale waves, which propagated with a variety of velocities. Their mean speed at each frequency band was proportional to temporal frequency, giving a range of 0.06 to 4.0 m/s, from delta to beta. The wave peaks moved over the entire measurement array, during both ongoing activity and task-relevant intervals; direction of motion was more predictable during the latter. A large proportion of the cortical signal, measurable at the scalp, exists as large-scale coherent motion. We argue that the distribution of observable phase velocities in MEG is dominated by spatial filtering considerations in combination with group velocity of cortical activity. Traveling waves may index processes involved in global coordination of cortical activity. PMID- 26953887 TI - Serotypes and Clonal Diversity of Streptococcus pneumoniae Causing Invasive Disease in the Era of PCV13 in Catalonia, Spain. AB - The aim of this study was to study the serotypes and clonal diversity of pneumococci causing invasive pneumococcal disease in Catalonia, Spain, in the era of 13-valent pneumococcal conjugate vaccine (PCV13). In our region, this vaccine is only available in the private market and it is estimated a PCV13 vaccine coverage around 55% in children. A total of 1551 pneumococcal invasive isolates received between 2010 and 2013 in the Molecular Microbiology Department at Hospital Sant Joan de Deu, Barcelona, were included. Fifty-two serotypes and 249 clonal types-defined by MLST-were identified. The most common serotypes were serotype 1 (n = 182; 11.7%), 3 (n = 145; 9.3%), 19A (n = 137; 8.8%) and 7F (n = 122; 7.9%). Serotype 14 was the third most frequent serotype in children < 2 years (15 of 159 isolates). PCV7 serotypes maintained their proportion along the period of study, 16.6% in 2010 to 13.4% in 2013, whereas there was a significant proportional decrease in PCV13 serotypes, 65.3% in 2010 to 48.9% in 2013 (p<0.01). This decrease was mainly attributable to serotypes 19A and 7F. Serotype 12F achieved the third position in 2013 (n = 22, 6.4%). The most frequent clonal types found were ST306 (n = 154, 9.9%), ST191 (n = 111, 7.2%), ST989 (n = 85, 5.5%) and ST180 (n = 80, 5.2%). Despite their decrease, PCV13 serotypes continue to be a major cause of disease in Spain. These results emphasize the need for complete PCV13 vaccination. PMID- 26953888 TI - miR-130b-3p Modulates Epithelial-Mesenchymal Crosstalk in Lung Fibrosis by Targeting IGF-1. AB - Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and usually lethal fibrotic lung disease with largely unknown etiology and pathogenesis. Evidence suggests microRNAs (miRNA) contribute to pathogenesis of IPF. In this study, we sought to identify miRNA expression signatures and determine the role of miR-130b 3p in lung fibrosis. The miRNA expression profile of the lungs from patients with IPF and normal donors was determined by Affymetrix microarray, and transcriptome with Affymetrix array. The functions and signal pathways as well as miRNA-mRNA networks were established by bioinformatics analysis. Luciferase assays and ELISA were used to confirm the miRNA target gene. The effect of miRNA-transfected epithelium on fibroblast activities was assessed using a co-culture system. The fibroblast activities were determined by qRT-PCR, western blotting, Transwell and BrdU assays. Seven miRNAs were significantly decreased in IPF lungs, with miR 130b-3p being the highest in the miRNA-mRNA network. Insulin-like growth factor (IGF-1) was a target gene of miR-130b-3p in the epithelium. miR-130b-3p inhibition in the epithelium induced collagen I expression and enhanced the proliferation and migration ability of fibroblast in co-culture systems, which mimicked the functions of exogenous IGF-1 on fibroblasts. Neutralizing IGF-1 with an antibody significantly reduced the modulatory effects of miR-130b-3p inhibitor transfected epithelium on the activation of fibroblasts. Our results show that miR-130b-3p was downregulated in IPF lungs. miR-130b-3p downregulation contributed to the activation of fibroblasts and the dysregulated epithelial mesenchymal crosstalk by promoting IGF-1 secretion from lung epithelium, suggesting a key regulatory role for this miRNA in preventing lung fibrosis. PMID- 26953889 TI - The Mechanism of Mycobacterium smegmatis PafA Self-Pupylation. AB - PafA, the prokaryotic ubiquitin-like protein (Pup) ligase, catalyzes the Pup modification of bacterial proteins and targets the substrates for proteasomal degradation. It has been reported that that M. smegmatis PafA can be poly pupylated. In this study, the mechanism of PafA self-pupylation is explored. We found that K320 is the major target residue for the pupylation of PafA. During the self-pupylation of PafA, the attachment of the first Pup to PafA is catalyzed by the other PafA molecule through an intermolecular reaction, while the formation of the polymeric Pup chain is carried out in an intramolecular manner through the internal ligase activity of the already pupylated PafA. Among the three lysine residues, K7, K31 and K61, in M. smegmatis Pup, K7 and K31 are involved in the formation of the poly-Pup chain in PafA poly-pupylation. Poly pupylation of PafA can be reversibly regulated by depupylase Dop. The polymeric Pup chain formed through K7/K31 linkage is much more sensitive to Dop than the mono-Pup directly attached to PafA. Moreover, self-pupylation of PafA is involved in the regulation of its stability in vivo in a proteasome-dependent manner, suggesting that PafA self-pupylation functions as a mechanism in the auto regulation of the Pup-proteasome system. PMID- 26953890 TI - Monascus Pigment Rubropunctatin: A Potential Dual Agent for Cancer Chemotherapy and Phototherapy. AB - The Monascus pigment, rubropunctatin, was extracted and purified from red mold rice (RMR), and its cytotoxic activities against human cervical carcinoma HeLa cells were studied under the conditions with or without light irradiation. The IC50 value of rubropunctatin against HeLa cells in the dark was 93.71 +/- 1.96 MUM (24 h), while the cytotoxic activity was enhanced more than 3 times (IC50 = 24.02 +/- 2.17 MUM) under light irradiation (halogen lamp, 500 W; wavelength, 597 622 nm; and fluence rate, 15 mW cm(-2), for 30 min). However, the IC50 value of rubropunctatin against the immortalized human cervical epithelial H8 cells was more than 300 MUM, even under light irradiation, indicating that rubropunctatin has a favorable selectivity index (SI). Treatment of HeLa cells with rubropunctatin in the dark or under light irradiation resulted in a dose dependent apoptosis, as validated by the increase in the percentage of cells in the sub-G1 phase and phosphatidylserine externalization, and the inductive effect on HeLa cell apoptosis was boosted by the light irradiation. In addition, treatment with rubropunctatin alone or under light irradiation was found to induce apoptosis in HeLa cells via the mitochondrial pathway, including loss of mitochondrial membrane potential, activation of caspase-3, caspase-8, and caspase 9, and increase of the level of intracellular reactive oxygen species (ROS). It was suggested that rubropunctatin could be a promising natural dual anticancer agent for photodynamic therapy and chemotherapy. PMID- 26953892 TI - Adaptation of the Transverse Carpal Ligament Associated with Repetitive Hand Use in Pianists. AB - The transverse carpal ligament (TCL) plays a critical role in carpal tunnel biomechanics through interactions with its surrounding tissues. The purpose of this study was to investigate the in vivo adaptations of the TCL's mechanical properties in response to repetitive hand use in pianists using acoustic radiation force impulse (ARFI) imaging. It was hypothesized that pianists, in comparison to non-pianists, would have a stiffer TCL as indicated by an increased acoustic shear wave velocity (SWV). ARFI imagining was performed for 10 female pianists and 10 female non-pianists. The median SWV values of the TCL were determined for the entire TCL, as well as for its radial and ulnar portions, rTCL and uTCL, respectively. The TCL SWV was significantly increased in pianists relative to non-pianists (p < 0.05). Additionally, the increased SWV was location dependent for both pianist and non-pianist groups (p < 0.05), with the rTCL having a significantly greater SWV than the uTCL. Between groups, the rTCL SWV of pianists was 22.2% greater than that of the non-pianists (p < 0.001). This localized increase of TCL SWV, i.e. stiffening, may be primarily attributable to focal biomechanical interactions that occur at the radial TCL aspect where the thenar muscles are anchored. Progressive stiffening of the TCL may become constraining to the carpal tunnel, leading to median nerve compression in the tunnel. TCL maladaptation helps explain why populations who repeatedly use their hands are at an increased risk of developing musculoskeletal pathologies, e.g. carpal tunnel syndrome. PMID- 26953893 TI - Effects of Heavy Strength Training on Running Performance and Determinants of Running Performance in Female Endurance Athletes. AB - PURPOSE: The purpose of the current study was to investigate the effects of adding strength training to normal endurance training on running performance and running economy in well-trained female athletes. We hypothesized that the added strength training would improve performance and running economy through altered stiffness of the muscle-tendon complex of leg extensors. METHODS: Nineteen female endurance athletes [maximal oxygen consumption (VO2max): 53+/-3 ml?kg-1?min-1, 5.8 h weekly endurance training] were randomly assigned to either normal endurance training (E, n = 8) or normal endurance training combined with strength training (E+S, n = 11). The strength training consisted of four leg exercises [3 x 4-10 repetition maximum (RM)], twice a week for 11 weeks. Muscle strength, 40 min all-out running distance, running performance determinants and patellar tendon stiffness were measured before and after the intervention. RESULTS: E+S increased 1RM in leg exercises (40 +/- 15%) and maximal jumping height in counter movement jump (6 +/- 6%) and squat jump (9 +/- 7%, p < 0.05). This was accompanied by increased muscle fiber cross sectional area of both fiber type I (13 +/- 7%) and fiber type II (31 +/- 20%) in m. vastus lateralis (p < 0.05), with no change in capillary density in m. vastus lateralis or the stiffness of the patellar tendon. Neither E+S nor E changed running economy, fractional utilization of VO2max or VO2max. There were also no change in running distance during a 40 min all-out running test in neither of the groups. CONCLUSION: Adding heavy strength training to endurance training did not affect 40 min all-out running performance or running economy compared to endurance training only. PMID- 26953894 TI - Erythrocyte sedimentation rate and C-reactive protein to monitor treatment outcomes in diabetic foot osteomyelitis. AB - This study sought to evaluate the effectiveness of the inflammatory markers, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), in monitoring treatment of osteomyelitis in the diabetic foot. We screened 150 charts of patients admitted to our hospital with diabetic foot osteomyelitis (DFO), confirmed by positive results of bone culture and/or histopathology. We included patients who had an initial ESR/CRP within 72 hours of admission and two reported follow-up values. We dichotomised patients based on the outcomes wound healing, re-infection, recurrent ulceration, re-hospitalisation, additional surgery, re amputation and death, all within 12 months, and analysed the trajectories of the markers over time. Our primary outcome, DFO remission, was defined as wound healing within 12 months of follow-up without re-infection. We included 122 subjects; 65 patients (53.3%) had a combination of positive culture and histopathology. Factors associated with DFO remission (n = 46) were a lower white blood count (WBC) at admission (P = 0.006) and a higher glomerular filtration rate (GFR, P = 0.049). Factors associated with healing were a lower WBC (P = 0.004), a higher GFR (P = 0.01), longer wound duration before admission (P = 0.01), location of the ulcer on the great toe (P = 0.01) and higher glycated haemoglobin (P = 0.03). Logistic regression analysis demonstrated no associations between DFO remission and other variables collected. Trajectories of the inflammatory markers showed an association between stagnating values of ESR and CRP and poor clinical outcomes. In this study population, the trajectories of both ESR and CRP during 12 months follow-up suggest a predictive role of both inflammatory markers when monitoring treatment of DFO. PMID- 26953891 TI - Predominant Bacteria Detected from the Middle Ear Fluid of Children Experiencing Otitis Media: A Systematic Review. AB - BACKGROUND: Otitis media (OM) is amongst the most common childhood diseases and is associated with multiple microbial pathogens within the middle ear. Global and temporal monitoring of predominant bacterial pathogens is important to inform new treatment strategies, vaccine development and to monitor the impact of vaccine implementation to improve progress toward global OM prevention. METHODS: A systematic review of published reports of microbiology of acute otitis media (AOM) and otitis media with effusion (OME) from January, 1970 to August 2014, was performed using PubMed databases. RESULTS: This review confirmed that Streptococcus pneumoniae and Haemophilus influenzae, remain the predominant bacterial pathogens, with S. pneumoniae the predominant bacterium in the majority reports from AOM patients. In contrast, H. influenzae was the predominant bacterium for patients experiencing chronic OME, recurrent AOM and AOM with treatment failure. This result was consistent, even where improved detection sensitivity from the use of polymerase chain reaction (PCR) rather than bacterial culture was conducted. On average, PCR analyses increased the frequency of detection of S. pneumoniae and H. influenzae 3.2 fold compared to culture, whilst Moraxella catarrhalis was 4.5 times more frequently identified by PCR. Molecular methods can also improve monitoring of regional changes in the serotypes and identification frequency of S. pneumoniae and H. influenzae over time or after vaccine implementation, such as after introduction of the 7-valent pneumococcal conjugate vaccine. CONCLUSIONS: Globally, S. pneumoniae and H. influenzae remain the predominant otopathogens associated with OM as identified through bacterial culture; however, molecular methods continue to improve the frequency and accuracy of detection of individual serotypes. Ongoing monitoring with appropriate detection methods for OM pathogens can support development of improved vaccines to provide protection from the complex combination of otopathogens within the middle ear, ultimately aiming to reduce the risk of chronic and recurrent OM in vulnerable populations. PMID- 26953896 TI - Expectation and quality of life after aortic valve replacement over 85 years of age match those of the contemporary general population. AB - BACKGROUND: In the transcatheter aortic valve implantation (TAVI) years, very elderly patients with aortic stenosis (AS) are referred to surgery with reluctance despite excellent hospital outcomes. A poorly assessed outcome of discharged survivors might further overlook the actual efficacy of the surgical strategy in this cohort. We thus evaluated life-expectancy and functional results in discharged survivors over 85 years operated on for AS. METHODS: Between January 2001 and December 2013, 57 consecutive patients aged >=85 years underwent aortic valve replacement (AVR) with or without concomitant procedures at our institution. Late survival rate (SR), New York Heart Associaion (NYHA) functional class and quality of life (RAND SF-36) were assessed. SR and quality of life (QoL) were than compared to the contemporary general population matched for age and gender, as calculated by the Italian National Institute of Statistics. RESULTS: Overall in-hospital mortality was 8.8% (5 pts). In patients without concomitant coronary artery bypass grafting (CABG), in-hospital mortality was 2.9%. Survival at 5 and 9 years was 57.7 +/- 8.4% and 17.9 +/- 11.4%, respectively. No predictors of late mortality including concomitant CABG were identified at Cox analysis. The mean NYHA class for long-term survivors improved from 3.1 to 1.6 (p<0.001). Survivors reported better QoL-scores compared to the age- and gender-matched contemporary general population in 4 RAND SF-36 domains. Life-expectancy resulted comparable to that predicted for the age and gender matched general population. CONCLUSIONS: Isolated AVR in patients aged >=85 years can be performed with acceptable risk. Survivors improve in NYHA class and, when compared to age- and gender-matched individuals, show a similar life expectancy and a no lower QoL. PMID- 26953895 TI - Exercise: a "new drug" for elderly patients with chronic heart failure. AB - Patients with chronic heart failure (CHF) experience progressive deterioration of functional capacity and quality of life (QoL). This prospective, randomized, controlled trial assesses the effect of exercise training (ET) protocol on functional capacity, rehospitalization, and QoL in CHF patients older than 70 years compared with a control group. A total of 343 elderly patients with stable CHF (age, 76.90+/-5.67, men, 195, 56.9%) were randomized to ET (TCG, n=170) or usual care (UCG, n=173). The ET protocol involved supervised training sessions for 3 months in the hospital followed by home-telemonitored sessions for 3 months. Assessments, performed at baseline and at 3 and 6 months, included: ECG, resting echocardiography, NT-proBNP, 6-minute walk test (6MWT), Minnesota Living with Heart Failure Questionnaire, and comprehensive geriatric assessment with the InterRAI-HC instrument. As compared to UCG, ET patients at 6 months showed: i) significantly increased 6MWT distance (450+/-83 vs. 290+/-97 m, p=0.001); ii) increased ADL scores (5.00+/-2.49 vs. 6.94+/-5.66, p=0.037); iii) 40% reduced risk of rehospitalisation (hazard ratio=0.558, 95%CI, 0.326-0.954, p=0.033); and iv) significantly improved perceived QoL (28.6+/-12.3 vs. 44.5+/-12.3, p=0.001). In hospital and home-based telemonitored exercise confer significant benefits on the oldest CHF patients, improving functional capacity and subjective QoL and reducing risk of rehospitalisation. PMID- 26953898 TI - Can brackets be bonded with a composite resin after expiration date? AB - INTRODUCTION: The aim of the study was to compare shear bond strengths of brackets bonded with a composite resin before and after expiration dates. METHODS: Forty-five freshly extracted premolar teeth were randomly divided into 3 groups of 15. Ormco Mini 2000 (Ormco Corp, Glendora, Calif) bicuspid metal brackets were used in the study. Group I: the brackets were bonded with Blugloo (Ormco Corp, Glendora, Calif) adhesive paste before the expiration date. Groups II and III: the brackets were bonded with same light cure composite resin 1 and 2 years after the expiration date. All of the groups were cured with a LED light. After bonding, the shear bond strengths of the brackets were tested with a universal testing machine. One-way ANOVA with post-hoc Tukey tests were used to compare shear bond strengths of the groups. The chi-square test was used to determine significant differences in the adhesive remnant index (ARI) scores between the groups. Significance for all statistical tests was predetermined at p<0.05. RESULTS: No statistically significant difference was found in shear bond strengths and ARI scores between three groups (p<0.05). There was a greater frequency of ARI scores of 2 and 3 and 4 in all groups. CONCLUSIONS: Expiration dates do not have a significant effect on the shear bond strength of the composite material. Further studies are needed to investigate in other ways such as cytotoxicity of the composite resins after expiration date. PMID- 26953897 TI - To explore the characteristics of fatality in children poisoned by paraquat--with analysis of 146 cases. AB - PURPOSE: The incidence of paraquat (PQ) poisoning in China is increasing, so it is important to identify the characteristics of fatalities in children with acute PQ poisoning in order to prevent and treat future cases. METHODS: A prospective study that enrolled 146 children with PQ poisoning was performed. A novel evaluation system called the score of lethal factors for PQ poisoning (SLFPP) was established, including 1 contributing factor and 4 weakening factors. Comparisons with the Pediatric Logistic Organ Dysfunction (PELOD) score, the Poisoning Severity Score (PSS) in admission and the SLFPP were made to determine their values for prognosis. RESULTS: Younger patients (71/146, <10 years) had accidental exposure to PQ (64/71, 90.14%), whereas older patients (75/146, >=10 years) had ingested PQ intentionally (46/75, 61.33%) (p<0.01); 21/146 (14.38%) died of PQ poisoning. Of these 21 children, 20 committed suicide with ages >=10 years. Significant differences (p<0.01) were found between nonsurvivors and survivors with regard to the Pediatric Logistic Organ Dysfunction (PELOD) scores (19.76 +/- 18.44 vs. 4.17 +/- 5.98), PSS in admission (2.48 +/- 0.60 vs. 1.43 +/- 0.59), the SLFPP (10.40 +/- 1.07 vs. 3.60 +/- 1.89). In PELOD score and PSS in admission, there were relative large overlaps in scores between nonsurvivors and survivors. But for SLFPP, there were smaller overlaps. CONCLUSIONS: Deliberate ingestion of PQ to commit suicide occurred mainly in older children (>=10 years), while accidental exposure to PQ occurred mainly in younger children (<10 years). Owing to small overlaps, the SLFPP may exceed PELOD and PSS in predicting the prognosis of PQ poisoning, but the SLFPP scores still require further clinical validation. PMID- 26953899 TI - Design and evaluation of a novel subatmospheric pressure bioreactor for the preconditioning of tissue-engineered vascular constructs. AB - PURPOSE: The pre-conditioning of tissue-engineered vascular scaffolds with mechanical stimuli is being recognised as an essential step in producing a functional vascular construct. In this study we design and evaluate a novel bioreactor, which exerts a mechanical strain on developing vascular scaffolds via subatmospheric pressure. METHODS: We design and construct a bioreactor, which exerts subatmospheric pressure via a vacuum assisted closure unit. Vascular scaffolds seeded with human umbilical endothelial cells were evaluated for structural integrity, microbial contamination, cellular viability, von Willebrand factor (VWF) production, cell proliferation and morphology under a range of subatmospheric pressures (75-200mmHg). RESULTS: The bioreactor produced sustained subatmospheric pressures, which exerted a mechanical strain on the vascular scaffold. No microbial contamination was found during the study. The structural integrity of the vascular construct was maintained. There was no difference in cellular viability between control or subatmospheric pressure groups (p = 0.817). Cells continued to produce VWF under a range of subatmospheric pressures. Cells subjected to subatmospheric pressures of 125mmHg and 200mmHg exhibited higher levels of growth than cells in atmospheric pressure at 24 (p<=0.016) and 48 hour (p<=0.001). Negative pressure affected cellular morphology, which were more organised, elongated and expanded when exposed to subatmospheric pressure. CONCLUSIONS: We have constructed and validated a novel subatmospheric bioreactor. The bioreactor maintained a continuous subatmospheric pressure to the vascular scaffolds in a stable, sterile and constant environment. The bioreactor exerted a strain on the vascular sheets, which was shown to alter cellular morphology and enhance cellular proliferation. PMID- 26953900 TI - In vivo heat inactivation of serum can distinguish false positive cross matches in renal transplants. AB - INTRODUCTION: Renal transplants have traditionally been performed despite positive cross match if results are presumptively due to IgM antibodies. False positives have been distinguishable from true positives by dithiothreitol or dithioerythritol treatment to inactivate IgM antibodies. Heat inactivation, which renders the antibodies inactive, is an alternative to chemical amelioration. METHODS: We retrospectively evaluated clinical outcomes of patients who had positive cross matches presumed to be falsely positive as determined by treatment with heat inactivation compared to controls with negative cross matches over a six-year period. A total of 414 transplanted patients had available cross match data: 355 with a negative cross match and 59 with a positive cross match rendered negative after heat inactivation. Serum creatinine was reviewed at 6, 12 and 24 months posttransplant. RESULTS: Graft function was considered stable at 12 and 24 months post-transplant if the change in creatinine compared to the 6-month value was >0.5 mg/dL. Repeated and nonrepeated measures analysis showed equivalence in the change in sCr from 6 to 12 (p = 0.525) and from 6 to 24 months (p = 0.752). Kaplan-Meier curves to evaluate graft survival demonstrated no significant difference in function over 24 months. Curves were censored for patient death, treated as death with functioning (p = 0.48) and nonfunctioning (p = 0.64) grafts. DISCUSSIONS: We have demonstrated comparable long-term function and survival for living donor renal transplants using heat inactivation to detect false positive cross matches. This simple and cost-effective method can be used to safely evaluate histocompatibility for living donor renal transplant recipients. PMID- 26953901 TI - Cost calculations during "dire straits": a cost-of-illness analysis of regular hemodialysis for end-stage renal disease in Greece. AB - PURPOSE: More than 3 million people worldwide suffer from end-stage renal disease (ESRD). Even though regular hemodialysis is considered very costly, it is still the most commonly used method of treatment in Greece. The aim of this study is to provide a current estimate of the annual patient cost for ESRD-related regular hemodialysis, especially during a period of economic instability for Greece. METHODS: Data was collected from 113 anonymous patient files from 3 dialysis units. The cost analysis includes the following parameters: hospitalization, disposable supplies, medication, meals, contaminants, human resources and equipment depreciation/utilization. RESULTS: The cost of a regular hemodialysis session was estimated at ?177.12. Human resources account for 43.53% of the hemodialysis cost, while expendable supplies and medication account for 24.79% and 21.16%, respectively. The total annual cost of ESRD per patient was calculated at ?34,012.31, which breaks down into ?27,630.72 (81.24%) for hemodialysis, ?4,800.64 (14.11%) for hospitalization, ?1,454.84 (4.28%) for laboratory tests and ?126.11 (0.37%) for microsurgery. CONCLUSIONS: ESRD entails a significant economic burden for the Greek health care system. In a current context of ongoing austerity measures, which severely pressure the health care budget, further research should be performed in order to identify possible ways to reduce costs and improve management of the disease. PMID- 26953902 TI - Toward catecholamine responsiveness in cardiogenic shock: insights from the CRASH score. AB - PURPOSE: To model a prognostic score in patients with cardiogenic shock that incorporates catecholamine responsiveness and hemodynamics. METHODS: Assessment of the best accuracy of the score (CRASH score: Catecholamine Refractoriness and Assistance guide based on cardiogenic Shock Hemodynamics) to predict in-hospital mortality and/or extracorporeal life support, based on a retrospective study performed in a medical-surgical intensive care unit. We included 66 patients with cardiogenic shock from various etiologies. We modeled the CRASH score to be a simple score with the best accuracy to predict in-hospital mortality and/or extracorporeal life support. The CRASH score was defined as the cardiac power index (CPI) divided by the square root of 1 + inotropic score (IS, sum of different catecholamines pondered with their variable efficiency): CRASH score = CPI/square root (IS + 1). RESULTS: A CRASH score <0.0375 predicted death and/or extracorporeal life support with a sensitivity of 68% and a specificity of 92%. The area under the ROC curve was 0.851, achieving an overall accuracy of 0.833. The CRASH score had improved accuracy when compared with Simplified Acute Physiology, Sleeper, and CardSHOCK scores (p<0.05 for all). With a threshold of 0.300 we found even higher specificity (95%) at the price of decreased sensibility (52%) and accuracy. CONCLUSIONS: In patients with cardiogenic shock, the CRASH score (= CPI/square root (IS + 1)) <0.0375 allowed patients at high risk of adverse outcome to be identified. PMID- 26953903 TI - Evaluation of apically extruded debris during root canal retreatment with two different rotary systems followed by a self-adjusting file. AB - PURPOSE: To compare the amount of apically extruded debris during root canal retreatment using ProTaper retreatment system (Dentsply Maillefer, Ballaigues, Switzerland), ProTaper retreatment system with Self-Adjusting File (SAF) system (ReDent-Nova, Ra'anana, Israel), Mtwo retreatment system (VDW, Munich, Germany), Mtwo retreatment system with SAF instruments. METHODS: In total, 72 extracted human mandibular incisor teeth were used. All root canals were prepared with ProTaper universal (Dentsply Maillefer) up to F2 file and filled with gutta percha and AH plus sealer using cold lateral condensation before being assembled randomly into 4 groups (n = 18 each). Root canal filling materials were removed using the ProTaper retreatment system, the ProTaper retreatment system followed by SAF system, Mtwo retreatment system and Mtwo retreatment system followed by SAF system. Debris extruded apically during the removal of canal filling material was collected into preweighed Eppendorf tubes. The tubes were then stored in an incubator at 70 degrees C for 5 days. The weight of the dry extruded debris was established by subtracting the preretreatment and postretreatment weight of the Eppendorf tubes for each group. The data obtained were analyzed using Kruskal Wallis test. RESULTS: All retreatment techniques caused the apical extrusion of debris. There was no significant difference between the groups statistically (p>0.05). CONCLUSIONS: The results of this study showed that SAF system after Mtwo retreatment system and ProTaper retreatment system for improving retreatment has no significant effect on the amount of debris extruded apically. PMID- 26953904 TI - Reappraisal of risk factors for monoclonal gammopathy of undetermined significance. AB - A number of epidemiologic studies have demonstrated associations between obesity and diabetes and the risk of monoclonal gammopathy of undetermined significance (MGUS). However, since MGUS is an asymptomatic condition we evaluated whether these are true associations or the result of detection-bias. We conducted a nested case-control study using a large primary-care database. Cases were defined as those with incident diagnosis of MGUS. For every case, four eligible controls matched on age, sex, practice site, and duration of follow-up were selected. Exposure variables included obesity and diabetes (including antidiabetic therapies) as well as other metabolic risk factors. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using conditional logistic regression. The study included 2363 MGUS patients and 9193 matched controls. In the primary analysis, obesity and diabetes were associated with higher MGUS risk with an adjusted ORs of 1.15 (95% CI 1.02-1.29) and 1.30 (95% CI 1.13-1.50), respectively. However, after adjustment to the number of laboratory tests prior to the MGUS diagnosis, there was no association between obesity and diabetes and MGUS risk (ORs of 1.08, 95% CI 0.96-1.22 and 1.08, 95% CI 0.93-1.25, respectively). In an additional analysis of antidiabetic therapies and MGUS risk, there was a nonsignificant decrease in MGUS risk among diabetes patients treated with metformin alone compared to subjects without diabetes (OR 0.77, 95% CI 0.56 1.05). In summary, while previously described risk factors for MGUS might be the result of detection bias, metformin should be further evaluated as a possible chemoprevention modality. Am. J. Hematol. 91:581-584, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26953905 TI - Fully Borylated Methane and Ethane by Ruthenium-Mediated Cleavage and Coupling of CO. AB - Many transition-metal complexes and some metal-free compounds are able to bind carbon monoxide, a molecule which has the strongest chemical bond in nature. However, very few of them have been shown to induce the cleavage of its C-O bond and even fewer are those that are able to transform CO into organic reagents with potential in organic synthesis. This work shows that bis(pinacolato)diboron, B2pin2, reacts with ruthenium carbonyl to give metallic complexes containing borylmethylidyne (CBpin) and diborylethyne (pinBC=CBpin) ligands and also metal free perborylated C1 and C2 products, such as C(Bpin)4 and C2 (Bpin)6, respectively, which have great potential as building blocks for Suzuki-Miyaura cross-coupling and other reactions. The use of (13)CO-enriched ruthenium carbonyl has demonstrated that the boron-bound carbon atoms of all of these reaction products arise from CO ligands. PMID- 26953907 TI - Editing Animals. Gene editing applications expanding with advancing technology. PMID- 26953908 TI - Concern with anesthesia-free dental cleanings. PMID- 26953909 TI - The contribution of biomedical informatics to one health. PMID- 26953910 TI - What Is Your Diagnosis? A large cranial mediastinal mass. PMID- 26953911 TI - What Is Your Neurologic Diagnosis? Nasopharyngeal lymphoma. PMID- 26953912 TI - Pathology in Practice. Clostridium perfringens. PMID- 26953913 TI - Pathology in Practice. Pulmonary alveolar proteinosis. PMID- 26953914 TI - Development of an optional clinical skills laboratory for surgical skills training of veterinary students. PMID- 26953915 TI - Effects of an optional clinical skills laboratory on surgical performance of third-year veterinary students. AB - OBJECTIVE: To determine whether addition of an optional clinical skills laboratory (OCSL) to the traditional surgery curriculum would affect total surgery time or incision closure time in veterinary students performing ovariohysterectomy of a dog during a third-year surgery course. DESIGN: Retrospective and prospective study of veterinary student attendance at OCSL sessions and student performance during the third-year surgery course. SAMPLE: Students from the classes of 2012, 2013, and 2014 at the Washington State University College of Veterinary Medicine. PROCEDURES: For all students, total surgery time and incision closure time were recorded when students performed an ovariohysterectomy of a dog during their third-year live-animal surgery course. Times were analyzed to identify differences among classes and determine whether times were associated with number of OCSL sessions attended, previous experience performing ovariohysterectomies, or enrollment in an elective clinical skills course. RESULTS: Total surgery and incision closure times were not significantly different between students in the class of 2012 (no access to the OCSL prior to the third-year surgery course) and students in the class of 2013 (ie, access to 4 OCSL sessions during the spring semester prior to the third-year surgery course). However, times were significantly shorter for students in the class of 2014 (ie, students who had access to OCSL sessions during the 3 semesters prior to the third-year surgery course) than for students in the other 2 classes. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that attendance in the OCSL sessions was associated with improvements in surgical performance, as reflected in faster total surgery and incision closure times while performing an ovariohysterectomy during the third-year surgery course. PMID- 26953919 TI - Associations between sex, body weight, age, and ultrasonographically determined adrenal gland thickness in dogs with non-adrenal gland illness. AB - OBJECTIVE: To determine whether body weight, age, or sex was associated with ultrasonographically determined adrenal gland thickness (AT) in dogs with non adrenal gland illness. DESIGN: Retrospective cross-sectional study. ANIMALS: 266 dogs (22 sexually intact and 119 castrated males and 19 sexually intact and 106 spayed females representing 12 breeds) with non-adrenal gland illness. PROCEDURES: Thickness of the caudal pole of the left and right adrenal glands was measured on longitudinal ultrasonographic images. Dogs were stratified into age and body weight categories to investigate associations with AT. RESULTS: AT was significantly lower in dogs that weighed <= 12 kg (26.4 lb) than in dogs that weighed > 12 kg and left AT increased with age. Both left and right AT were larger in male than in female dogs that weighed > 12 to <= 20 kg, and left AT was larger in male than in female dogs that weighed > 20 to <= 30 kg. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that body weight, age, and sex were significantly associated with AT, indicating that these variables should be considered when evaluating AT in dogs with non-adrenal gland illness and when developing reference intervals for AT in dogs. Further, findings indicated that dogs with non-adrenal gland illness that weigh <= 12 kg should have an AT no greater than 0.62 cm, whereas dogs that weigh > 12 kg should have an AT no greater than 0.72 cm. PMID- 26953920 TI - Primary splenic torsion in dogs: 102 cases (1992-2014). AB - OBJECTIVE: To determine the percentage of dogs surviving to hospital discharge and identify factors associated with death prior to hospital discharge among dogs undergoing surgery because of primary splenic torsion (PST). DESIGN: Retrospective case series. ANIMALS: 102 client-owned dogs. PROCEDURES: Medical records of dogs with a confirmed diagnosis of PST that underwent surgery between August 1992 and May 2014 were reviewed. History, signalment, results of physical examination and preoperative bloodwork, method of splenectomy, concurrent surgical procedures, perioperative complications, duration of hospital stay, splenic histopathologic findings, and details of follow-up were recorded. Best fit multivariate logistic regression was performed to identify perioperative factors associated with survival to hospital discharge. RESULTS: 93 of the 102 (91.2%) dogs survived to hospital discharge. German Shepherd Dogs (24/102 [23.5%]), Great Danes (15/102 [14.7%]), and English Bulldogs (12/102 [11.8%]) accounted for 50% of cases. Risk factors significantly associated with death prior to hospital discharge included septic peritonitis at initial examination (OR, 32.4; 95% confidence interval [CI], 2.1 to 502.0), intraoperative hemorrhage (OR, 22.6; 95% CI, 1.8 to 289.8), and postoperative development of respiratory distress (OR, 35.7; 95% CI, 2.7 to 466.0). Histopathologic evidence of splenic neoplasia was not found in any case. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that the prognosis for dogs undergoing splenectomy because of PST was favorable. Several risk factors for death prior to discharge were identified, including preexisting septic peritonitis, intraoperative hemorrhage, and postoperative development of respiratory distress. PMID- 26953921 TI - Abortions in Thoroughbred mares associated with consumption of bulbosus buttercups (Ranunculus bulbosus L). AB - CASE DESCRIPTION: Unexplained clinical signs of weight loss and emaciation were reported in a herd of Thoroughbred horses grazing spring pastures on a central Kentucky farm, even though supplemental grain and hay were provided. CLINICAL FINDINGS: A buttercup plant, Ranunculus bulbosus L, was abundantly present in all pastures and paddocks on the farm. All horses, especially lactating mares and their foals, had mild to severe weight loss as assessed by body condition. Seven mares on the farm had been confirmed pregnant between 30 and 45 days of gestation, but were later found to have aborted. Two 2-year-old fillies developed severe diarrhea, incoordination, recumbency, and paralysis and were euthanized. Necropsy of these horses revealed ulcers and erosions in the stomach and large intestine. The findings were considered consistent with buttercup toxicosis. TREATMENT AND OUTCOME: The horses were moved from the buttercup-infested pastures to a farm free of the weed. All horses made an uneventful recovery, and clinical signs resolved after the horses were transferred to buttercup-free pastures. Mares that had aborted conceived successfully in the next breeding season. CLINICAL RELEVANCE: The buttercup plant is toxic for all classes of livestock. The clinical signs associated with buttercup toxicosis may mimic other disease syndromes affecting the gastrointestinal tract of herbivores. On-farm epidemiological investigations are an essential part of the diagnosis of this condition. Consumption of buttercups has previously been associated with abortions in cattle, but to the author's knowledge, this has not previously been described in horses. PMID- 26953922 TI - Ophthalmic variables in rehabilitated juvenile Kemp's ridley sea turtles (Lepidochelys kempii). AB - OBJECTIVE: To determine central corneal thickness (total corneal thickness [TCT], epithelial thickness [ET], and stromal thickness [ST]), anterior chamber depth (ACD), and intraocular pressure (IOP) in Kemp's ridley sea turtles (Lepidochelys kempii). DESIGN: Prospective cross-sectional study. ANIMALS: 25 healthy rehabilitated juvenile Kemp's ridley sea turtles. PROCEDURES; Body weight and straight-line standard carapace length (SCL) were recorded. All turtles underwent a complete anterior segment ophthalmic examination. Central TCT, ET, ST, and ACD were determined by use of a spectral-domain optical coherence tomography device. Intraocular pressure was determined with a rebound tonometer; the horse setting was used to measure IOP in all 25 turtles, and the undefined setting was also used to measure IOP in 20 turtles. For each variable, 3 measurements were obtained bilaterally. The mean was calculated for each eye and used for analysis purposes. RESULTS: The mean +/- SD body weight and SCL were 3.85 +/- 1.05 kg (8.47 +/- 2.31 lb) and 29 +/- 3 cm, respectively. The mean +/- SD TCT, ET, ST, and ACD were 288 +/- 23 MUm, 100 +/- 6 MUm, 190 +/- 19 MUm, and 581 +/- 128 MUm, respectively. Mean +/- SD IOP was 6.5 +/- 1.0 mm Hg when measured with the horse setting and 3.8 +/- 1.1 mm Hg when measured with the undefined setting. CONCLUSIONS AND CLINICAL RELEVANCE: Results provided preliminary reference ranges for objective assessment of ophthalmic variables in healthy juvenile Kemp's ridley sea turtles. PMID- 26953923 TI - Use of veterinary services by Latino dog and cat owners with various degrees of English-language proficiency. AB - OBJECTIVE: To characterize patterns of dog and cat ownership and veterinary service use among Latino dog and cat owners with various degrees of English language proficiency. DESIGN :Cross-sectional telephone survey. SAMPLE: Data from 393 Latino pet owners. PROCEDURES: Telephone surveys were conducted with Latino dog and cat owners from a random sample of US households to determine the number of dogs and cats owned, factors associated with veterinary service use, and satisfaction with veterinary care. RESULTS: 393 of 1,026 (38.3%) respondents were pet owners. Two hundred fifty-nine of 330 (78.5%) dog owners and 70 of 115 (60.9%) cat owners reported taking their pet to the veterinarian in the past 12 months, most commonly for vaccination or examination or because of illness. Respondents were most satisfied with veterinary care provided, least satisfied with cost, and moderately satisfied with quality of communication. English language proficiency was not significantly associated with whether owners sought veterinary care. A large proportion of respondents who wanted to receive pet health information in Spanish described themselves as speaking English well or very well. CONCLUSIONS AND CLINICAL RELEVANCE: Although having limited proficiency in English was not associated with Latino pet owners seeking veterinary care, opportunities exist for veterinary personnel to improve communications with these clients. Personnel can assess their clients' language needs by asking each about the language in which they would prefer to receive their pet's health information. PMID- 26953924 TI - Preparedness of small animal veterinary practices to communicate with Spanish speaking pet owners with limited proficiency in English. AB - OBJECTIVE: To investigate the preparedness of small animal veterinary personnel to communicate with Spanish-speaking pet owners with limited English-language proficiency (LEP). DESIGN: Cross-sectional telephone survey. SAMPLE: Data from 383 small animal veterinary practices. PROCEDURES: Telephone surveys were conducted with veterinarians and office or practice managers from a random sample of US small animal veterinary practices in 10 states to estimate the number of Spanish-speaking pet owners with LEP visiting these practices, proportion of practices that used services to facilitate communication with Spanish-speaking clients with LEP, and degree of veterinarian satisfaction with their communication with those clients. RESULTS: Responses were obtained from 383 of 1,245 (31%) eligible practices, of which 340 (89%) had Spanish-speaking clients with LEP and 200 (52%) had such clients on a weekly basis. Eight percent of practices had veterinary personnel who were conversant or fluent in spoken Spanish. Veterinarians who depended on clients' friends or family to translate were significantly less satisfied with client communication than were those who could converse in Spanish with clients directly. Availability of Spanish-speaking staff and offering of Spanish-language resources were associated with an increase in the number of Spanish-speaking clients with LEP seen on a weekly basis. Industry- and practice-generated Spanish-language materials were offered at 32% (124/383) and 21% (81/383) of practices, respectively; 329 (86%) practices had no Spanish-language marketing. CONCLUSIONS AND CLINICAL RELEVANCE: Opportunities were identified for improving communication with pet owners with LEP in the veterinary clinical setting, which could ultimately positively impact patient well-being and client compliance. PMID- 26953926 TI - New Insights into the Diels-Alder Reaction of Graphene Oxide. AB - Graphene oxide is regarded as a major precursor for graphene-based materials. The development of graphene oxide based derivatives with new functionalities requires a thorough understanding of its chemical reactivity, especially for canonical synthetic methods such as the Diels-Alder cycloaddition. The Diels-Alder reaction has been successfully extended with graphene oxide as a source of diene by using maleic anhydride as a dienophile, thereby outlining the presence of the cis diene present in the graphene oxide framework. This reaction provides fundamental information for understanding the exact structure and chemical nature of graphene oxide. On the basis of high-resolution (13) C-SS NMR spectra, we show evidence for the formation of new sp(3) carbon centers covalently bonded to graphene oxide following hydrolysis of the reaction product. DFT calculations are also used to show that the presence of a cis dihydroxyl and C vacancy on the surface of graphene oxide are promoting the reaction with significant negative reaction enthalpies. PMID- 26953927 TI - Effect of Cultivar, Temperature, and Environmental Conditions on the Dynamic Change of Melatonin in Mulberry Fruit Development and Wine Fermentation. AB - High levels of melatonin have been reported in various foods but not in mulberry or its wine. This study investigated the dynamic changes of melatonin levels during mulberry fruit development and ethanol fermentation of 2 different colored mulberry cultivars ("Hongguo2? Morus nigra, black and "Baiyuwang? Morus alba, white) at 2 fermentation temperatures (16 and 25 degrees C). Our results showed that the melatonin level increased in the beginning of mulberry development but decreased in the end. The MnTDC gene expression level correlated with melatonin production, which implied that TDC may be the rate-limiting enzyme of the melatonin biosynthetic process in mulberries. During mulberry fermentation, the melatonin concentration increased rapidly in the beginning and then decreased gradually. Low temperature delayed the melatonin production during fermentation. A relatively high level of melatonin was found in "Hongguo2? compared with "Baiyuwang? during fruit development and fermentation. The variation of melatonin correlated with the ethanol production rate, suggesting that melatonin may participate in physiological regulation of Saccharomyces cerevisiae during the fermentation stage. PMID- 26953925 TI - A contemporary perspective on the molecular characteristics of mitochondrial autoantigens and diagnosis in primary biliary cholangitis. AB - Primary biliary cholangitis (PBC) is an autoimmune hepatobiliary disease characterized by immune mediated destruction of the intrahepatic small bile ducts and the presence of antimitochondrial antibodies (AMAs). The mitochondrial autoantigens have been identified as the E2 subunits of the 2-oxo-acid dehydrogenase complex, including the E2 subunits of pyruvate dehydrogenase, branched-chain 2-oxo acid dehydrogenase complex, oxoglutarate dehydrogenase complex, E3 binding protein and PDC E1 alpha subunit. The AMA epitope is mapped within the E2 lipoic acid binding domain, which is particularly important for oxidative phosphorylation. In addition, lipoic acid, which serves as a swinging arm to capture electrons, is particularly susceptible to an electrophilic attack and may provide clues to the etiology of PBC. This review emphasizes the molecular characteristics of AMAs, including detection, immunochemistry and the putative role in disease. These data have significance not only specifically for PBC, but generically for autoimmunity. PMID- 26953928 TI - Solid-State Conformational Flexibility at Work: Zipping and Unzipping within a Cyclic Peptoid Single Crystal. AB - A peptidomimetic compound undergoes a reversible single-crystal-to-single-crystal transformation upon guest release/uptake with the transformation involving a drastic conformational change. The extensive and reversible alteration in the solid state is connected to the formation of an unprecedented "CH-pi zipper" which can reversibly open and close (through the formation of CH-pi interactions), thus allowing for guest sensing. PMID- 26953930 TI - Label-free detection of immune complexes with myeloid cells. AB - The aim of this study was to provide proof-of-concept for quantitative and qualitative label-free detection of immune complexes through myeloid cells with imaging surface plasmon resonance. Surface plasmon resonance imaging was first applied to monitor the binding of human sera from healthy and rheumatoid arthritis (RA) patients to immobilized citrullinated RA-specific peptide antigens, histone citrullinated peptide 2 (HCP2) and viral citrullinated peptide 2 (VCP2). Next, the binding of monocytoid cell line U937 to the resulting immune complexes on the sensor surface was monitored. As control, binding of U937 was monitored to immunoglobulin (Ig)G subclasses simultaneously. Cell response results were compared to results of cyclic citrullinated peptide 2 (CCP2) enzyme linked immunosorbent assay (ELISA), clinical RA diagnosis and antigen-specific antibody distribution of the samples. Human IgG3 triggered the most pronounced response, followed by IgG1 and IgG4, while IgG2 did not result in U937 cell binding. Serum samples obtained from RA patients resulted in a significantly increased cell response to VCP2 compared to healthy controls. The strength of cell response towards VCP2 immune complexes showed significant correlation with levels of antigen-specific IgA, IgG and IgG3. Cellular responses on VCP2 immune complexes showed significant association with both CCP2-based serological positivity and European League Against Rheumatism (EULAR) criteria-based clinical RA diagnosis. Immunoglobulin-triggered binding of monocytoid cells can be monitored using a label-free multiplex technology. Because these binding events are presumably initiated by Fc receptors, the system provides a tool for biological detection of autoantibodies with diagnostic value, here exemplified by anti-citrullinated antibodies. This provides added information to antibody levels, as interaction with Fc-receptor-expressing cells is also affected by post translational modification of the immunoglobulins. PMID- 26953932 TI - Penile Fracture: A Meta-Analysis. AB - OBJECTIVES: To review the causes and management of penile fracture and to compare between surgical and conservative management as well as immediate and delayed interventions in terms of overall and specific complications. METHODS: A search of all reported literature was conducted for all articles reporting on the management and outcomes of penile fractures. Full texts of relevant articles were obtained and screened according to the inclusion criteria. Outcomes measures were numbers of patients receiving surgical or conservative management, aetiology of fracture, length of admission, complications as well as the specifics of diagnostic approaches and operative management. Data was collated and where possible meta-analysed using Revman software. RESULTS: A total of 58 relevant studies involving 3,213 patients demonstrated that intercourse accounts for only 48% of cases with masturbation and forced flexion accounting for 39%. Meta analysis shows that surgical intervention was associated with significantly fewer complications vs. conservative management (p < 0.000001). Surgical intervention results in significantly less erectile dysfunction (ED), curvature and painful erection than conservative management. There was no significant difference in the number of patients developing plaques/nodules (p = 0.94). Meta-analysis shows that overall early surgery is preferable to delayed surgery but that rates of ED are not significantly different. DISCUSSION: Early surgical intervention is associated with significantly fewer complications than conservative management or delayed surgery. The combined outcome of rapid diagnosis by history and clinical examination and swift surgical intervention is key for reconstruction with minimal long-term complications. PMID- 26953931 TI - Mobilization of Genomic Islands of Staphylococcus aureus by Temperate Bacteriophage. AB - The virulence of Staphylococcus aureus, in both human and animal hosts, is largely influenced by the acquisition of mobile genetic elements (MGEs). Most S. aureus strains carry a variety of MGEs, including three genomic islands (nuSaalpha, nuSabeta, nuSagamma) that are diverse in virulence gene content but conserved within strain lineages. Although the mobilization of pathogenicity islands, phages and plasmids has been well studied, the mobilization of genomic islands is poorly understood. We previously demonstrated the mobilization of nuSabeta by the adjacent temperate bacteriophage phiSaBov from strain RF122. In this study, we demonstrate that phiSaBov mediates the mobilization of nuSaalpha and nuSagamma, which are located remotely from phiSaBov, mostly to recipient strains belonging to ST151. Phage DNA sequence analysis revealed that chromosomal DNA excision events from RF122 were highly specific to MGEs, suggesting sequence specific DNA excision and packaging events rather than generalized transduction by a temperate phage. Disruption of the int gene in phiSaBov did not affect phage DNA excision, packaging, and integration events. However, disruption of the terL gene completely abolished phage DNA packing events, suggesting that the primary function of temperate phage in the transfer of genomic islands is to allow for phage DNA packaging by TerL and that transducing phage particles are the actual vehicle for transfer. These results extend our understanding of the important role of bacteriophage in the horizontal transfer and evolution of genomic islands in S. aureus. PMID- 26953934 TI - Insights into Interfacial Changes and Photoelectrochemical Stability of In(x)Ga(1 x)N (0001) Photoanode Surfaces in Liquid Environments. AB - The long-term stability of InGaN photoanodes in liquid environments is an essential requirement for their use in photoelectrochemistry. In this paper, we investigate the relationships between the compositional changes at the surface of n-type In(x)Ga(1-x)N (x ~ 0.10) and its photoelectrochemical stability in phosphate buffer solutions with pH 7.4 and 11.3. Surface analyses reveal that InGaN undergoes oxidation under photoelectrochemical operation conditions (i.e., under solar light illumination and constant bias of 0.5 VRHE), forming a thin amorphous oxide layer having a pH-dependent chemical composition. We found that the formed oxide is mainly composed of Ga-O bonds at pH 7.4, whereas at pH 11.3 the In-O bonds are dominant. The photoelectrical properties of InGaN photoanodes are intimately related to the chemical composition of their surface oxides. For instance, after the formation of the oxide layer (mainly Ga-O bonds) at pH 7.4, no photocurrent flow was observed, whereas the oxide layer (mainly In-O bonds) at pH 11.3 contributes to enhance the photocurrent, possibly because of its reported high photocatalytic activity. Once a critical oxide thickness was reached, especially at pH 7.4, no significant changes in the photoelectrical properties were observed for the rest of the test duration. This study provides new insights into the oxidation processes occurring at the InGaN/liquid interface, which can be exploited to improve InGaN stability and enhance photoanode performance for biosensing and water-splitting applications. PMID- 26953936 TI - Simultaneous implantation of bilateral liver grafts in living donor liver transplantation with fusion venoplasty. PMID- 26953935 TI - BIITE: A Tool to Determine HLA Class II Epitopes from T Cell ELISpot Data. AB - Activation of CD4+ T cells requires the recognition of peptides that are presented by HLA class II molecules and can be assessed experimentally using the ELISpot assay. However, even given an individual's HLA class II genotype, identifying which class II molecule is responsible for a positive ELISpot response to a given peptide is not trivial. The two main difficulties are the number of HLA class II molecules that can potentially be formed in a single individual (3-14) and the lack of clear peptide binding motifs for class II molecules. Here, we present a Bayesian framework to interpret ELISpot data (BIITE: Bayesian Immunogenicity Inference Tool for ELISpot); specifically BIITE identifies which HLA-II:peptide combination(s) are immunogenic based on cohort ELISpot data. We apply BIITE to two ELISpot datasets and explore the expected performance using simulations. We show this method can reach high accuracies, depending on the cohort size and the success rate of the ELISpot assay within the cohort. PMID- 26953937 TI - Pathology and Molecular Characterization of Escherichia Coli Associated With the Avian Salpingitis-Peritonitis Disease Syndrome. AB - Outbreaks of salpingitis and peritonitis cause major economic losses due to high mortality, reduced egg-production, and culling. The aim of the present study was to characterize, in detail, lesions associated with increased mortality in layers due to avianpathogenic Escherichia coli (APEC) and to investigate the population structure of the E. coli involved, which is important for selection of optimal treatment and prophylactic strategies. Among 322 layers received from eight farms with increased mortality due to E. coli, three lesion types were observed; sepsis like lesions, chronic salpingitis and peritonitis, and chronic salpingitis and peritonitis associated with sepsis-like lesions. One hundred isolates of E. coli obtained in pure culture from the different lesion types were selected for genetic characterization. Six out of 10 submissions (two farms with two submissions) were considered clonal as defined by more than 85% of the typed isolates of E. coli belonging to the same sequence-type (ST). B2 was the most prevalent phylogroup, including the clonal complex of ST95. The most-important virulence genes of E. coli were demonstrated from both clonal and nonclonal outbreaks, and major differences as to phylogeny and virulence genes were not observed between the lesion types. Cannibalism was more-often observed during polyclonal outbreaks. A new pathotype of APEC is suggested based upon lesions and route of infection, high similarity of virulence genes including plasmid associated genes, and high frequency of ST95 and other isolates belonging to phylogroup B2. Compared to the best-known pathotypes of E. coli, this needs further investigations, including infection experiments to show if single virulence factors can be pointed out that are specific for the salpingitis peritonitis pathotype and possibly not found in other pathotypes of E. coli. PMID- 26953938 TI - Incidence, Severity, and Welfare Implications of Lesions Observed Postmortem in Laying Hens from Commercial Noncage Farms in California and Iowa. AB - The egg industry is moving away from the use of conventional cages to enriched cage and noncage laying hen housing systems because of animal welfare concerns. In this study, the prevalence and severity of lesions in noncage laying hens from commercial farms in two of the largest egg-producing states, California and Iowa, were evaluated by postmortem examination. Hens that died or were culled were collected during early, mid, and late stages of the laying cycle from 16 houses on three farms. Of the 25 gross lesions identified for study, 22 were observed, with an average of four lesions per hen. Vent cannibalism, reduced feather cover, keel bone deformation, and beak abnormalities were the most frequent lesions, observed in >=40% of hens. Other common lesions were cloacal prolapse (30.5%), footpad dermatitis (24.3%), and septicemia (23.1%). Beak abnormality and enteric disease had the highest proportion of severe lesions. Pearson chi-square analysis revealed a number of stage-of-lay effects (P <= 0.05), some of which differed by state. For both states combined, the lesions observed more frequently during early lay were beak abnormalities, northern fowl mite infestation, and cage layer fatigue, whereas during mid lay, they were poor feather cover, vent cannibalism, footpad dermatitis, keel bone deformation, respiratory disease and roundworms. Feather pecking and cloacal prolapse were most common during late lay. Although differences in hen genetics, farm management practices, and environmental factors could all have affected the results of this study, the information provides a better understanding of hen health in noncage housing systems and could help to identify potential interventions to reduce hen welfare problems. PMID- 26953939 TI - A Real-Time Reverse-Transcription Polymerase Chain Reaction for Differentiation of Massachusetts Vaccine and Brazilian Field Genotypes of Avian Infectious Bronchitis Virus. AB - The avian infectious bronchitis virus is classified into serotypes or genotypes (or both) in different poultry-producing countries of the world. In Brazil, Massachusetts type (Mass), used as a live vaccine, and local field Brazilian variants (genotypes; BR) predominate in the commercial poultry flocks. This study describes the development and validation of two real-time reverse-transcription polymerase chain reactions (RT-qPCR) for the specific detection of Mass and BR genotypes in allantoic fluids and clinical samples. Genotype-specific primers, combined with a generic probe targeted to the S1 gene, originated Mass RT-qPCR and BR RT-qPCR-specific assays. Analytical sensitivity and linearity of these assays were determined in comparison with an IBV generic real-time RT-PCR based on the 5' untranslated region (5'UTR RT-qPCR). Mass RT-qPCR detected five Mass field isolates, three vaccine samples, and one coinfected sample (BR and Mass) while BR RT-qPCR detected 16 BR field isolates. Both assays were linear (R(2) > 0.98), reproducible, and as sensitive as the classical 5'UTR RT-qPCR used to detect IBV. In the analysis of 141 IBV clinical samples, 8 were positive for Mass RT-qPCR, 76 for BR RT-qPCR, and 2 for both assays. In the remaining 55 samples, 25 were positive only for 5'UTR RT-qPCR and 30 were negative for the three assays. In conclusion, both assays were able to detect Mass and BR genotypes, allowing rapid and easy IBV molecular typing from allantoic fluids and clinical samples. PMID- 26953940 TI - Efficacy of a Recombinant Turkey Herpesvirus H5 Vaccine Against Challenge With H5N1 Clades 1.1.2 and 2.3.2.1 Highly Pathogenic Avian Influenza Viruses in Domestic Ducks (Anas platyrhynchos domesticus). AB - Domestic ducks are the second most abundant poultry species in many Asian countries and have played a critical role in the epizootiology of H5N1 highly pathogenic avian influenza (HPAI).In this study, the protective efficacy of a live recombinant vector vaccine based on a turkey herpesvirus (HVT) expressing the H5 gene from a clade 2.2 H5N1 HPAI strain (A/Swan/Hungary/4999/ 2006) (rHVT H5/2.2), given at 3 days of age, was examined in Pekin ducks (Anas platyrhynchos domesticus). The vaccine was given alone or in combination with an inactivated H5N1 clade 2.3.2.1 reverse genetic (rgGD/2.3.2.1) vaccine given at 16 days of age, either as a single vaccination or in a prime-boost regime. At 30 days of age, ducks were challenged with one of two H5N1 HPAI viruses: A/duck/Vietnam/NCVD 2721/2013 (clade 1.1.2) or A/duck/Vietnam/NCVD-1584/2012 (clade 2.3.2.1.C). These viruses produced 100% mortality in less than 5 days in nonvaccinated control ducks. Ducks vaccinated with the rgGD/2.3.2.1 vaccine, with or without the rHVT H5/2.2 vaccine, were 90%-100% protected against mortality after challenge with either of the two H5N1 HPAI viruses. The rHVT-H5/2.2 vaccine alone, however, conferred only 30% protection against mortality after challenge with either H5N1 HPAI virus; the surviving ducks from these groups shed higher amount of virus and for longer than the single-vaccinated rgGD/2.3.2.1 group. Despite low protection, ducks vaccinated with the rHVT-H5/2.2 vaccine and challenged with the clade 1.1.2 Vietnam virus had a longer mean death time than nonvaccinated controls (P = 0.02). A booster effect was found on reduction of virus shedding when using both vaccines, with lower oropharyngeal viral titers at 4 days after challenge with either HPAI virus (P < 0.05). Neither rHVT-H5/2.2 nor standard HVT vaccine could be detected in samples collected from multiple tissues at different time points, indicting minimal levels of viral replication. In conclusion, although a minor effect on survival was observed, this study demonstrates the suboptimal protection with the rHVT-H5/2.2 vaccine given alone in Pekin ducks against H5N1 HPAI viruses and only a minor additive effect on virus shedding reduction when used with an inactivated vaccine in a prime-boost regime. PMID- 26953942 TI - Association of Beta2-Positive Clostridium perfringens Type A With Focal Duodenal Necrosis in Egg-Laying Chickens in the United States. AB - Focal duodenal necrosis (FDN) is a poorly understood intestinal disease of egg layers, and has been associated with drops in egg production and decreased egg weights. The etiology of this disease is still unknown, but the condition has been associated with Clostridium colinum and Clostridium perfringens. In order to investigate the etiology, duodenal samples were taken from hens with FDN. The hens originated from table egg layer farms in three states. The samples were examined by histopathology, bacteriology, and immunohistochemistry. Macroscopically, all samples contained focal to multifocal, variably sized, reddened or brownish gray areas of mucosal erosion. Histopathology revealed mild to severe heterophilic and lymphoplasmacytic enteritis with loss of enterocytes at the villous tips, luminal fibrinonecrotic exudate, and variable numbers of Gram-positive and Gram-negative rod-shaped bacteria within the lesions in 16/30 samples. Clostridium perfringens was isolated by anaerobic bacteriology from 4/13 samples that had characteristic microscopic lesions of FDN. Polymerase chain reaction (PCR) revealed that all four isolates were Type A C. perfringens, positive for beta2 gene and negative for necrotic enteritis toxin B and enterotoxin genes. PCR for Clostridium colinum applied to DNA extracted from frozen intestinal samples yielded negative results in 14/14 duodenal samples. Immunohistochemistry (IHC) for 7C. perfringens, alpha and beta2 toxins stained a few to numerous long rod-shaped bacteria present in the lesions. IHC for alpha and beta2 toxins also stained enterocytes at the villous tips, inflammatory cells in the lamina propria, as well as degenerated and sloughed enterocytes present within the luminal exudate. These findings suggest that C. perfringens may play a role in the development of FDN. Experimental challenge studies with these isolates still need to be performed in order to reproduce the disease and fulfill Koch's postulates. PMID- 26953941 TI - Characterization of Seven Outbreaks of Hemorrhagic Hepatopathy Syndrome in Commercial Pullets Following the Administration of a Salmonella Enteritidis Bacterin in California. AB - Between April 2013 and April 2015, seven flocks belonging to three different major commercial egg producers inCalifornia experienced a mild increase in mortality 2 to 3 wk after administration of Salmonella Enteritidis bacterins. Strains of chickens involved were H&N (flock A1, A2, B2, C1, C2, and C3) and Lohmann white (flock B1). Vaccination was administered individually through injection either in the breast muscles or subcutis in the legs between 11 and 18 wk of age in all flocks. Clinical signs ranged from inapparent to lameness, reluctance to walk, greenish diarrhea, and retching-like symptoms. The mortality ranged from 0.16% to 1.38% per week, with the highest peaks occurring usually 2 to 3 wk postvaccination, and then declined rapidly. Postmortem examinations revealed enlarged livers with disseminated hemorrhages and pale foci of necrosis. Also, severe extensive hemorrhages in the intestine, heart, and proventriculus were observed in a few birds. Various degrees of productive, exudative giant cell granulomatous myositis were observed invading deeply the muscles and subcutis at the site of vaccination. The myositis was always associated with optically empty vacuoles positive for neutral lipids by Oil Red O stain. Droplets of Oil Red O material were also noticed in the affected livers and intestines. Congo red stain highlighted the presence of amyloid in moderate to severe amounts in the breast muscles and moderate amounts in livers, spleens, and intestines. Salmonella antigens were detected in the injection sites and livers by immunohistochemical staining. No viruses or toxic substances were recovered from the liver, spleen, intestine, and pectoral muscles, and the few bacteria isolated were interpreted as secondary postmortem invaders. In addition, livers and bile tested for hepatitis E virus were negative by reverse-transcriptase polymerase chain reaction. PMID- 26953943 TI - Heat Production and Energy Efficiency of Broilers Infected With Necrotic Enteritis. AB - Necrotic enteritis (NE) in poultry is the most important bacterial disease in terms of economic losses. The present study was conducted to evaluate the effect of an experimental challenge with necrotic enteritis on respiration and heat production in birds pretreated with dietary acylated starch or antibiotics (AB) zinc bacitracin (50 mg/kg) plus salinomycin (60 mg/kg). In total, 48 1-day-old Ross 308 male broilers were assigned to floor pens until day 10. On day 11, birds were randomly placed into 16 calorimetric chambers with four replicates of three birds per treatment. Treatments were: control, AB, acetylated high-amylose maize starch (SA), or butyrylated high-amylose maize starch (SB). Birds were NE challenged by inoculation with 5000 sporulated oocysts each of Eimeria maxima and Eimeria acervulina and 2500 sporulated oocysts of Eimeria brunetti on day 9 and Clostridium perfringens (3.8 * 10(8) colony-forming units) on day 14. The results showed that heat production (HP), respiratory quotient (RQ), heat increment, weight gain (WG), feed intake (FI), and livability (LV) of birds fed control, SA, and SB diets were lower than birds fed AB at 19 and 42 hr postinoculation (P < 0.05). At 65 hr postchallenge, increased FI and WG of birds were observed, indicating recovery from NE. During the entire period, from day 14 to day 17, birds fed control, SA, and SB had lower WG, FI, HP, RQ, metabolizable energy intake (MEI), and metabolizable energy (P < 0.01) than those fed AB. The data demonstrate that Eimeria sp. and C. perfringens challenge reduces growth performance, HP, RQ, metabolizable energy, and MEI of birds fed control, SA, and SB but not AB diets. PMID- 26953944 TI - Effects of T-2 Toxin on Turkey Herpesvirus-Induced Vaccinal Immunity Against Marek's Disease. AB - T-2 toxin, a very potent immunotoxic Type A trichothecene, is a secondary metabolite produced primarily by Fusarium spp., which grows on cereal grains and can lead to contaminated livestock feed. Repeated exposure to T-2 toxin has been shown to cause immunosuppression and decrease the resistance of exposed animals to a variety of infectious diseases; however, the effects of T-2 toxin on Marek's disease (MD) vaccinal immunity have not been reported. Four trials were conducted to determine the effects of T-2 toxin on vaccinal immunity against MD. Day-old, white leghorn chicks of Avian Disease and Oncology Laboratory line 15I5 * 71 were treated daily for 7 days via crop gavage with T-2 toxin at a sublethal dose of 1.25 mg/kg body weight. Treated and untreated chicks were also vaccinated with turkey herpesvirus (HVT) at hatch and were challenged with the JM strain of MD virus (MDV) at 8 days of age. Chickens were tested for HVT viremia at 1 wk postvaccination immediately before challenge, and for HVT and MDV viremia at 3 wk postchallenge. Chickens were observed for the development of MD lesions and mortality within 8 wk of age. T-2 toxin significantly reduced body weight and titers of HVT viremia within 7 days after hatch. T-2 toxin shortened the incubation period for the development of MD lesions and mortality, but only in unvaccinated chickens. The percent MD protection in T-2-toxin-treated, HVT vaccinated chickens ranged from 82% to 96% and was comparable to that in HVT vaccinated untreated control chickens (89%-100%). The data suggest that exposure of chickens to sublethal doses of T-2 toxin for 7 consecutive days after hatch may influence the development of 1) HVT viremia; and 2) MD lesions and mortality, but only in unvaccinated chickens. PMID- 26953945 TI - Very Virulent Infectious Bursal Disease Virus Produces More-Severe Disease and Lesions in Specific-Pathogen-Free (SPF) Leghorns Than in SPF Broiler Chickens. AB - Infectious bursal disease virus (IBDV) is an important pathogen of chickens causing negative economic impacts in poultry industries worldwide. IBDV has a variable range of virulence, with very virulent (vvIBDV) strains being responsible for the greatest losses from mortality and decreased performance. Previous vvIBDV studies using conventional broilers reported resistance to lethal effects and decreased performance as compared to specific-pathogen-free (SPF) layers, but the potential contribution of the conventional vs. SPF status to resistance has not been examined. In this study we compared differences in the acute pathologic effects of infection by the California rA strain of vvIBDV for SPF white leghorn egg-laying chickens and SPF white Plymouth Rock broiler chickens over a 7-day experimental period. Based on the clinical signs and mortality observed, as well as on the more-severe pathologic changes in lymphoid tissues and kidneys, white leghorns were shown to be more susceptible to the deleterious effects of vvIBDV infection than were white Plymouth Rocks. This study provides important information on the impact of chicken breed on susceptibility to vvIBDV and the absence of impact from conventional vs. SPF status on the outcome. PMID- 26953946 TI - Relationship Between Values of Fowlpox ELISA and the Presence of "Takes" After Vaccination. AB - Values from an ELISA for evaluating the immune response induced by a commercial vaccine against fowlpox virus and the lesion at the site of inoculation (i.e., swelling of the skin or a pox where the vaccine was applied) were compared. The ELISA was carried out with an antigen prepared by precipitation of a cell culture propagated virus suspension with ammonium sulfate and concentration by centrifugation. A 0.1 M acetate buffer (pH 5) was used as the sensitizing solution for maximum specific binding of the antigen to the microplate plastic well. Four experiments were conducted where the birds were bled once a week before and after vaccination and then were examined simultaneously for evidence of "takes." This study showed that there is a relationship between the ELISA values to the fowlpox vaccine that are considered positive and the presence of postvaccination lesions. PMID- 26953947 TI - Occurrence and Phylogenetic Studies of Chicken Anemia Virus from Polish Broiler Flocks. AB - Chicken anemia virus (CAV) is a widespread chicken pathogen of significant economic importance. In 2013, broiler chicken flocks in Poland were examined for the presence of CAV, and phylogenetic relatedness between the strains was established. Ten cloacal swabs from each of 106 broiler flocks (birds aged 3-6 wk) were collected in different regions of the country and tested with the use of real-time PCR (all samples) and conventional PCR (those samples positive in real time PCR) assays. The presence of CAV was detected in 16 of the flocks tested. Phylogenetic analysis clearly confirmed the existence of genetic diversity within the group of circulating CAV strains and their distinctiveness from vaccine strains used in Poland. PMID- 26953949 TI - Natural Unusual Myeloblastosis in a Budgerigar (Melopsittacus undulatus): Histopathologic Diagnosis. AB - The subgroup J avian leukosis virus favors the myelocytic series cells and causes myeloid leukosis (myeloblastosis and myelocytomatosis). Natural cases of myeloblastosis (myeloblastic myeloid leukosis) are uncommon and usually occur in adult chickens. This paper describes clinical signs and gross and histopathologic features of myeloblastosis in an adult female budgerigar (Melopsittacus undulatus) that was infected naturally. At necropsy, the spleen was greatly enlarged (enlarged seven or eight times normal) while the other visceral organs were normal. Histologic examination of the spleen indicated a massive intravascular and extravascular accumulation of myeloblasts with a variable proportion of promyelocytes and myelocytes in the red pulp of the spleen. PMID- 26953948 TI - Coinfection of Avibacterium paragallinarum and Ornithobacterium rhinotracheale in Chickens from Peru. AB - The coinfection of Avibacterium paragallinarum and Ornithobacterium rhinotracheale in two outbreaks of infectious coryza from Peru is reported. The diagnosis was confirmed by bacteriologic isolation, PCR testing, and sequencing of the 16S rRNA gene. The susceptibility of the isolates to 12 antimicrobial agents was tested by a disk diffusion method. The isolates were susceptible to amoxicillin/clavulanic acid and florfenicol and were resistant to oxacillin and sulfamethoxazole/trimethoprim. The coinfection of Av. paragallinarum and O. rhinotracheale and the severity of clinical signs were evaluated by experimental infection of specific-pathogen-free chickens. The group inoculated with O. rhinotracheale alone presented minimal clinical signs in 3 of 10 chickens. However, the groups inoculated with both Av. paragallinarum and O. rhinotracheale induced the most-severe clinical signs compared with the group inoculated with Av. paragallinarum alone. In conclusion, coinfections with Av. paragallinarum and O. rhinotracheale may occur, and these outbreaks could be more severe than single infections. Hence, the prevention, control, and diagnosis of Av. paragallinarum with O. rhinotracheale are important in outbreaks of infectious coryza. PMID- 26953950 TI - Yersinia pseudotuberculosis in Eurasian Collared Doves (Streptopelia decaocto) and Retrospective Study of Avian Yersiniosis at the California Animal Health and Food Safety Laboratory System (1990-2015). AB - In February 2015, two Eurasian collared doves (Streptopelia decaocto) were submitted dead to the California Animal Health and Food Safety (CAHFS) Laboratory, Turlock branch, from a private aviary experiencing sudden, high mortality (4/9) in adult doves. In both doves, the gross and histologic lesions were indicative of acute, fatal septicemia. Grossly, there were numerous pale yellow foci, 1 to 2 mm in diameter, in the liver and spleen. Microscopically, these foci were composed of acute severe multifocal coagulative necrosis of hepatocytes and splenic pulp with infiltration of heterophils mixed with fibrin and dense colonies of gram-negative bacteria. Yersinia pseudotuberculosis was isolated from the lung, liver, spleen, heart, ovary, kidney, and trachea. The organism was susceptible to most antibiotics it was tested against, except erythromycin. Based on a retrospective study of necropsy submissions to CAHFS between 1990 and 2015, there were 77 avian case submissions of Y. pseudotuberculosis. There were 75/77 cases identified from a wide range of captive avian species from both zoo and private facilities and 2/77 cases from two backyard turkeys submitted from one premise. The largest number of cases originated from psittacine species (31/77). The lesions most commonly described were hepatitis (63/77), splenitis (49/77), pneumonia (30/77), nephritis (16/77), and enteritis (12/77). From 1990 to 2015, there was an average of three cases of avian pseudotuberculosis per year at CAHFS. Although there were no cases diagnosed in 1993 and 1994, in all other years, there were between one and eight cases of Y. pseudotuberculosis detected from avian diagnostic submissions. PMID- 26953951 TI - Surveillance for Pasteurella multocida in Ring-Necked Pheasants (Phasianus colchicus) After an Outbreak of Avian Cholera and Apparently Successful Antibiotic Treatment. AB - Avian cholera is a significant disease of domestic and wild birds caused by the bacterium Pasteurella multocida (PM). In poultry, a major source of PM infection is chronic carriers, domestic birds that have become infected and recovered or had subclinical infections. Although outbreaks of avian cholera in ring-necked pheasants (Phasianus colchicus) have been reported, the potential for chronic carriers is unknown. To address this, we conducted surveillance for PM in a flock of captive ring-necked pheasants after an outbreak of avian cholera that responded positively to antibiotic treatment based on resolution of morbidity and mortality. At approximately 1 mo after antibiotic treatment, oropharyngeal swabs were collected from 300 pheasants (out of a total population of ~2300) in a single winter holding pen. All samples were tested for PM through routine aerobic bacterial culture, but none of the samples were positive. In addition, there were no additional outbreaks within this infected pen over the subsequent months. These data provide preliminary evidence to suggest that pheasants that respond to antibiotic therapy may be less likely to become chronic carriers of PM than other poultry species, such as chickens (Gallus domesticus). However, due to marked phenotypic and biologic differences between PM strains, additional studies are needed to further support or refute these findings and better understand avian cholera in this species. PMID- 26953952 TI - Outbreak of Type C Botulism in Commercial Layer Chickens. AB - This report describes an outbreak of type C botulism in two organic, free-range commercial layer farms in the Midwest. Hens affected were 64-wk-old Hy-Line brown hens and 34-wk-old Hy-Line brown hens owned by the same company, but housed on different premises, with approximately 20,000 birds per house. Mortality over the 2 wk of investigation was estimated to be up to 8% and 2.8%, respectively, with birds acting listless, lethargic, and depressed. Clinical signs consisted of progressive paralysis, and severely affected birds were moribund and laterally recumbent. Hens had ruffled feathers that easily epilated, with loss of muscular tone in the neck, tail, and wings. Hens had closed eyes and were reluctant to move. There were no significant gross or histopathologic lesions. Intestinal samples were submitted to the University of Pennsylvania Botulism Diagnostic Laboratory for real-time PCR and were positive for Clostridium botulinum organisms containing the Type C neurotoxin gene. Speculations on the source of the botulinum toxins include poor mortality removal leading to cannibalism of decomposing carcasses, as well as birds on the farm having access to putrid carcasses in the compost pile from a hole in their outdoor access fence. PMID- 26953959 TI - Reductions in the diurnal rigidity of anxiety predict treatment outcome in cognitive behavioral therapy for generalized anxiety disorder. AB - Generalized anxiety disorder (GAD) is a chronic and disabling disorder which is characterized by worrisome mentation about future outcomes. Because the evocative stimuli in GAD are largely internally derived, the feared outcomes contained in worry episodes can be invoked--and responded to--regardless of external context. We hypothesized that individuals with GAD would be entrained to internally regulated, fixed patterns of anxiety on a day-to-day basis and that successful therapeutic intervention would serve to mitigate this entrainment. Thus, the present study examined the constructs of flexibility and rigidity as they apply to the daily fluctuation of anxious symptoms in individuals with GAD. We aimed to demonstrate that an apparently variable system can be conceptualized as rigid when the variability maps onto stable and predictable periodic oscillations. Sixty-nine individuals completed cognitive-behavioral treatment for GAD. Average age was 36.62 years (SD = 11.56), and participants were mostly Caucasian (89.5%) and female (68.4%). Daily-diary data indicating level of anxiety on a 0 to 100 point scale and collected four times per day were subjected to spectral analysis in order to determine the spectral power attributable to daily oscillations- which was related to the degree of rigidity in daily anxiety. Diurnal rigidity decreased throughout therapy and the degree to which rigidity was reduced significantly predicted reliable change at post-treatment. Thus, symptom rigidity can be conceptualized as stable periodic fluctuation and is discernible from other metrics of volatility in repeated measures data. Moreover, diurnal rigidity is significantly reduced during treatment, facilitating flexible responding to environmental demands. PMID- 26953961 TI - Investigation of hyperelastic models for nonlinear elastic behavior of demineralized and deproteinized bovine cortical femur bone. AB - In this study, the hyperelastic models of demineralized and deproteinized bovine cortical femur bone were investigated and appropriate models were developed. Using uniaxial compression test data, the strain energy versus stretch was calculated and the appropriate hyperelastic strain energy functions were fitted on data in order to calculate the material parameters. To obtain the mechanical behavior in other loading conditions, the hyperelastic strain energy equations were investigated for pure shear and equi-biaxial tension loadings. The results showed the Mooney-Rivlin and Ogden models cannot predict the mechanical response of demineralized and deproteinized bovine cortical femur bone accurately, while the general exponential-exponential and general exponential-power law models have a good agreement with the experimental results. To investigate the sensitivity of the hyperelastic models, a variation of 10% in material parameters was performed and the results indicated an acceptable stability for the general exponential exponential and general exponential-power law models. Finally, the uniaxial tension and compression of cortical femur bone were studied using the finite element method in VUMAT user subroutine of ABAQUS software and the computed stress-stretch curves were shown a good agreement with the experimental data. PMID- 26953962 TI - 3D analysis of thermal and stress evolution during laser cladding of bioactive glass coatings. AB - Thermal and strain-stress transient fields during laser cladding of bioactive glass coatings on the Ti6Al4V alloy basement were numerically calculated and analysed. Conditions leading to micro-cracking susceptibility of the coating have been investigated using the finite element based modelling supported by experimental results of microscopic investigation of the sample coatings. Consecutive temperature and stress peaks are developed within the cladded material as a result of the laser beam moving along the complex trajectory, which can lead to micro-cracking. The preheated to 500 degrees C base plate allowed for decrease of the laser power and lowering of the cooling speed between the consecutive temperature peaks contributing in such way to achievement of lower cracking susceptibility. The cooling rate during cladding of the second and the third layer was lower than during cladding of the first one, in such way, contributing towards improvement of cracking resistance of the subsequent layers due to progressive accumulation of heat over the process. PMID- 26953963 TI - Stratified coastal ocean interactions with tropical cyclones. AB - Hurricane-intensity forecast improvements currently lag the progress achieved for hurricane tracks. Integrated ocean observations and simulations during hurricane Irene (2011) reveal that the wind-forced two-layer circulation of the stratified coastal ocean, and resultant shear-induced mixing, led to significant and rapid ahead-of-eye-centre cooling (at least 6 degrees C and up to 11 degrees C) over a wide swath of the continental shelf. Atmospheric simulations establish this cooling as the missing contribution required to reproduce Irene's accelerated intensity reduction. Historical buoys from 1985 to 2015 show that ahead-of-eye centre cooling occurred beneath all 11 tropical cyclones that traversed the Mid Atlantic Bight continental shelf during stratified summer conditions. A Yellow Sea buoy similarly revealed significant and rapid ahead-of-eye-centre cooling during Typhoon Muifa (2011). These findings establish that including realistic coastal baroclinic processes in forecasts of storm intensity and impacts will be increasingly critical to mid-latitude population centres as sea levels rise and tropical cyclone maximum intensities migrate poleward. PMID- 26953964 TI - Calcium binding characteristics and structural changes of phosvitin. AB - Phosvitin is a unique highly phosphorylated protein that plays a role in the regulation of calcification. We conducted a comprehensive study of the chemical, thermodynamic and structural aspects of the interaction of phosvitin with calcium ions using a calcium ion selective electrode (ISE), isothermal titration calorimetry (ITC), circular dichroism spectrum (CD) and fluorescence spectroscopy, respectively. The results showed that under neutral and alkaline conditions, distinct high affinity and low affinity binding modes existed in the interaction between phosvitin and calcium. The high affinity association constant was approximately 10(4)mol(-1), while the binding sites contained nearly 30mol of calcium per mole of phosvitin. This reaction was driven by enthalpy. The unordered and beta-turn conformations of phosvitin increased, while the beta sheet conformation decreased. The main interaction forces were electrostatic force, hydrogen bonds or van der Waals force. The low affinity association constant and binding sites were not constant, as many calcium ions were sequestered by phosvitin. The binding reaction was driven by entropy, and the beta-sheet conformation of phosvitin increased while the unordered conformation decreased. The main interaction force was hydrophobic force. However, under acidic conditions, the interaction between phosvitin and calcium was an entropy driven endothermic reaction, and the main interaction force was weak hydrophobic force. This calcium-binding characteristic of phosvitin may play a specific role in its biological function. PMID- 26953966 TI - Topological Influence of Lyotropic Liquid Crystalline Systems on Excited-State Proton Transfer Dynamics. AB - In the present work, we have investigated the excited-state proton transfer (ESPT) dynamics inside lipid-based reverse hexagonal (HII), gyroid Ia3d, and diamond Pn3m LLC phases. Polarized light microscopy (PLM) and small-angle X-ray scattering (SAXS) techniques have been employed for the characterization of LLC systems. Time-resolved fluorescence results reveal the retarded ESPT dynamics inside liquid crystalline systems compared to bulk water, and it follows the order HII < Ia3d < Pn3m < H2O. The slower solvation, hampered "Grotthuss" proton transfer process, and most importantly, topological influence, of the LLC systems are believed to be mainly responsible for the slower and different extent of ESPT dynamics. Interestingly, recombination dynamics is found to be faster with respect to bulk water and it follows the order H2O < Pn3m < Ia3d < HII. Faster recombination dynamics arises due to lower dielectric constant and different channel diameters of these LLC systems. However, the dissociation dynamics is found to be slower than bulk water and it follows the order HII < Ia3d < Pn3m < H2O. Differences in critical packing parameter of LLC systems are believed to be the governing factors for the slower dissociation dynamics in these liquid crystalline systems. PMID- 26953965 TI - Validating hierarchical verbal autopsy expert algorithms in a large data set with known causes of death. AB - BACKGROUND: Physician assessment historically has been the most common method of analyzing verbal autopsy (VA) data. Recently, the World Health Organization endorsed two automated methods, Tariff 2.0 and InterVA-4, which promise greater objectivity and lower cost. A disadvantage of the Tariff method is that it requires a training data set from a prior validation study, while InterVA relies on clinically specified conditional probabilities. We undertook to validate the hierarchical expert algorithm analysis of VA data, an automated, intuitive, deterministic method that does not require a training data set. METHODS: Using Population Health Metrics Research Consortium study hospital source data, we compared the primary causes of 1629 neonatal and 1456 1-59 month-old child deaths from VA expert algorithms arranged in a hierarchy to their reference standard causes. The expert algorithms were held constant, while five prior and one new "compromise" neonatal hierarchy, and three former child hierarchies were tested. For each comparison, the reference standard data were resampled 1000 times within the range of cause-specific mortality fractions (CSMF) for one of three approximated community scenarios in the 2013 WHO global causes of death, plus one random mortality cause proportions scenario. We utilized CSMF accuracy to assess overall population-level validity, and the absolute difference between VA and reference standard CSMFs to examine particular causes. Chance-corrected concordance (CCC) and Cohen's kappa were used to evaluate individual-level cause assignment. RESULTS: Overall CSMF accuracy for the best-performing expert algorithm hierarchy was 0.80 (range 0.57-0.96) for neonatal deaths and 0.76 (0.50 0.97) for child deaths. Performance for particular causes of death varied, with fairly flat estimated CSMF over a range of reference values for several causes. Performance at the individual diagnosis level was also less favorable than that for overall CSMF (neonatal: best CCC = 0.23, range 0.16-0.33; best kappa = 0.29, 0.23-0.35; child: best CCC = 0.40, 0.19-0.45; best kappa = 0.29, 0.07-0.35). CONCLUSIONS: Expert algorithms in a hierarchy offer an accessible, automated method for assigning VA causes of death. Overall population-level accuracy is similar to that of more complex machine learning methods, but without need for a training data set from a prior validation study. PMID- 26953967 TI - Free-Text Notes as a Marker of Needed Improvements in Electronic Prescribing. PMID- 26953968 TI - Rethinking maternal health. PMID- 26953969 TI - Spatial Variability of AERONET Aerosol Optical Properties and Satellite Data in South Korea during NASA DRAGON-Asia Campaign. AB - We investigated spatial variability in aerosol optical properties, including aerosol optical depth (AOD), fine-mode fraction (FMF), and single scattering albedo (SSA), observed at 21 Aerosol Robotic Network (AERONET) sites and satellite remote sensing data in South Korea during the spring of 2012. These dense AERONET networks established in a National Aeronautics and Space Administration (NASA) field campaign enabled us to examine the spatially detailed aerosol size distribution and composition as well as aerosol levels. The springtime particle air quality was characterized by high background aerosol levels and high contributions of coarse-mode aerosols to total aerosols. We found that between-site correlations and coefficient of divergence for AOD and FMF strongly relied on the distance between sites, particularly in the south-north direction. Higher AOD was related to higher population density and lower distance from highways, and the aerosol size distribution and composition reflected source specific characteristics. The ratios of satellite NO2 to AOD, which indicate the relative contributions of local combustion sources to aerosol levels, represented higher local contributions in metropolitan Seoul and Pusan. Our study demonstrates that the aerosol levels were determined by both local and regional pollution and that the relative contributions of these pollutions to aerosols generated spatial heterogeneity in the particle air quality. PMID- 26953970 TI - Re: "Intralesional Tetracycline Injection for Treatment of Lower Eyelid Festoons". PMID- 26953971 TI - Reply re: "Intralesional Tetracycline Injection for Treatment of Lower Eyelid Festoons". PMID- 26953972 TI - Re: "Pediatric Acute Dacryocystitis". PMID- 26953973 TI - Reply re: "Pediatric Acute Dacryocystitis". PMID- 26953974 TI - Re: "Twelve-Year Experience of Lester Jones Tubes-Results and Comparison of Three Different Tube Types". PMID- 26953975 TI - Reply re: "Twelve-Year Experience of Lester Jones Tubes-Results and Comparison of 3 Different Tube Types". PMID- 26953976 TI - How the Mueller Muscle-Conjunctival Resection Ptosis Procedure Was Developed. PMID- 26953977 TI - Sonographic Diagnosis of Periorbital Dermoid Cyst. AB - Periorbital dermoid cysts occur mainly in children. Sonography is useful for the noninvasive, nonionizing evaluation of soft tissue lesions in infants and children without requiring sedation or anesthesia. We report the sonographic appearance of 25 periorbital dermoid cysts and identified that all are avascular oval lesions located below the aponeurotic plane. Nonaggressive bone remodeling was present in 52% of the cases. These finding in pediatric periorbital lesions are highly suspicious of a periorbital dermoid cyst. PMID- 26953978 TI - 3D imaging using combined neutron-photon fan-beam tomography: A Monte Carlo study. AB - The application of combined neutron-photon tomography for 3D imaging is examined using MCNP5 simulations for objects of simple shapes and different materials. Two dimensional transmission projections were simulated for fan-beam scans using 2.5MeV deuterium-deuterium and 14MeV deuterium-tritium neutron sources, and high energy X-ray sources, such as 1MeV, 6MeV and 9MeV. Photons enable assessment of electron density and related mass density, neutrons aid in estimating the product of density and material-specific microscopic cross section- the ratio between the two provides the composition, while CT allows shape evaluation. Using a developed imaging technique, objects and their material compositions have been visualized. PMID- 26953980 TI - Effect of vitamin E on 24(S)-hydroxycholesterol-induced necroptosis-like cell death and apoptosis. AB - 24(S)-Hydroxycholesterol (24S-OHC) has diverse physiological and pathological functions. In particular, cytotoxic effects of 24S-OHC in neuronal cells are important in development of neurodegenerative diseases. 24S-OHC induces necroptosis-like cell death in SH-SY5Y cells expressing little caspase-8. In the present study, 24S-OHC was found to induce apoptosis as determined by caspase-3 activation in all-trans-retinoic acid (atRA)-treated SH-SY5Y cells in which expression of caspase-8 was induced. 24S-OHC-induced cell death was inhibited by alpha-tocopherol (alpha-Toc) but not by alpha-tocotrienol (alpha-Toc3) in SH-SY5Y cells regardless of whether cells were treated with atRA. In contrast, cumene hydroperoxide (CumOOH)-induced cell death was significantly inhibited by alpha Toc and alpha-Toc3. In atRA-treated SH-SY5Y cells, generation of reactive oxygen species (ROS) was induced by stimulation with CumOOH but was not induced by stimulation with 24S-OHC. These results suggest that inhibition of 24S-OHC induced cell death by alpha-Toc cannot be explained by its radical scavenging antioxidant activity. Esterification of 24S-OHC followed by lipid droplet (LD) formation due to acyl-CoA:cholesterol acyltransferase 1 (ACAT1) are key events in 24S-OHC-induced cell death in atRA-treated SH-SY5Y cells as demonstrated by inhibition of cell death by ACAT1 inhibitor. LD number was not changed by treatment with either alpha-Toc or alpha-Toc3. The different physical properties of alpha-Toc and alpha-Toc3 may account for their different inhibitory effects on 24S-OHC-induced cell death. PMID- 26953981 TI - Conditional Survival: Changing the Frame of Reference in Anal Cancer Follow-up. PMID- 26953979 TI - 25-Hydroxyvitamin D in pregnancy and genome wide cord blood DNA methylation in two pregnancy cohorts (MoBa and ALSPAC). AB - The aim of the study was to investigate whether maternal mid-pregnancy 25 hydroxyvitamin D concentrations are associated with cord blood DNA methylation. DNA methylation was assessed using the Illumina HumanMethylation450 BeadChip, and maternal plasma 25-hydroxyvitamin D was measured in 819 mothers/newborn pairs participating in the Norwegian Mother and Child Cohort (MoBa) and 597 mothers/newborn pairs participating in the Avon Longitudinal Study of Parents and Children (ALSPAC). Across 473,731CpG DNA methylation sites in cord blood DNA, none were strongly associated with maternal 25-hydroxyvitamin D after adjusting for multiple tests (false discovery rate (FDR)>0.5; 473,731 tests). A meta analysis of the results from both cohorts, using the Fisher method for combining p-values, also did not strengthen findings (FDR>0.2). Further exploration of a set of CpG sites in the proximity of four a priori defined candidate genes (CYP24A1, CYP27B1, CYP27A1 and CYP2R1) did not result in any associations with FDR<0.05 (56 tests). In this large genome wide assessment of the potential influence of maternal vitamin D status on DNA methylation, we did not find any convincing associations in 1416 newborns. If true associations do exist, their identification might require much larger consortium studies, expanded genomic coverage, investigation of alternative cell types or measurements of 25 hydroxyvitamin D at different gestational time points. PMID- 26953982 TI - Decisional Conflict in Rectal Cancer: Does Quality of Life Measurement Reflect True Preferences? PMID- 26953983 TI - Pathologic Complete Response in Rectal Cancer: Can We Detect It? Lessons Learned From a Proposed Randomized Trial of Watch-and-Wait Treatment of Rectal Cancer. AB - BACKGROUND: Chemoradiotherapy has the potential to downsize and downstage tumors before surgery, decrease locoregional recurrence, and induce a complete sterilization of tumor cells for middle and low locally advanced rectal cancer. A watch-and-wait tactic has been proposed for patients with clinical complete response. OBJECTIVE: The purpose of this study was to verify our ability to identify complete clinical response in patients with rectal cancer based on clinical and radiologic criteria. DESIGN: This was a prospective study. SETTINGS: The study was conducted at a single institution, in the setting of a watch-and wait randomized trial. PATIENTS: Consecutive patients with stage T3 to T4N0M0 or T(any)N+M0 cancer located within 10 cm from anal verge or T2N0 within 7 cm from anal verge were included in the study. Patients were staged and restaged 8 weeks after completion of chemoradiation (5-fluorouracil, 5040 cGy) by digital examination, colonoscopy, pelvic MRI, and thorax and abdominal CT scans. MAIN OUTCOME MEASURES: Clinical and radiologic judgments of tumor response were compared with pathologic response of patients treated by total mesorectal excision or clinical follow-up of patients selected for nonoperative treatment. RESULTS: A total of 118 patients were treated. Six patients were considered clinic complete responders (2 randomly assigned for surgery (1 ypT0N0 and 1 ypT2N0) and 4 patients randomly assigned for observation (3 sustained clinic complete response and 1 had tumor regrowth)). The 112 clinic incomplete responders underwent total mesorectal excision, and 18 revealed pathologic complete response. These 18 patients were not considered complete responders at restaging because they presented at least 1 of the following conditions: mucosal ulceration and/or deformity and/or substenosis of rectal lumen at digital rectal examination and colonoscopy (n = 16), ymrT1 to T4 (n = 16), ymrN+ (n = 2), involvement of circumferential resection margin on MRI (n = 3), extramural vascular invasion on MRI (n = 4), MRI tumor response grade 2 to 4 (n = 15), and pelvic side wall lymph node involvement on MRI (n = 1). Sensitivity for identification of ypT0N0 or sustained clinic complete response was 18.2%. LIMITATIONS: This study has a short follow-up and small sample size. Radiologists who reviewed the restaging examination were not blinded to the pretreatment stage. Only 1 radiologist read the images of each patient. CONCLUSIONS: Evaluation of clinic complete response according to current adopted criteria has low sensitivity because pathologic complete response more frequently presented as clinic incomplete response (see Video, Supplemental Digital Content 1, http://links.lww.com/DCR/A221). PMID- 26953984 TI - Impact of Organ-Preserving Strategies on Anorectal Function in Patients with Distal Rectal Cancer Following Neoadjuvant Chemoradiation. AB - BACKGROUND: Organ-preserving strategies have been considered for patients with distal rectal cancer and complete or near-complete response to neoadjuvant chemoradiation to avoid the functional consequences of radical surgery. Transanal endoscopic microsurgery and no immediate surgery (watch and wait) have been considered in selected patients. OBJECTIVE: The aim of this study is to compare anorectal function following these 2 organ-preserving strategies (transanal endoscopic microsurgery and watch and wait) for rectal cancer with complete or near-complete response to neoadjuvant chemoradiation. DESIGN: This study is based on the comparison of prospectively collected data. SETTINGS: This study was conducted at a single center. PATIENTS: Consecutive patients with distal rectal cancer undergoing neoadjuvant chemoradiation (50.4-54 Gy and 5-fluorouracil-based chemotherapy) were prospectively studied. Patients with complete clinical response were managed by watch and wait. Patients with near-complete response (<=3 cm, ycT1-2N0) were managed by transanal endoscopic microsurgery. MAIN OUTCOME MEASURES: Functional outcomes were determined by anorectal manometry and Fecal Incontinence Index and Quality of Life assessment. RESULTS: Two groups of patients were included in the study. Twenty-nine patients with near-complete response undergoing transanal endoscopic microsurgery and 53 with complete response after watch and wait were assessed. Baseline features were similar between groups. Patients undergoing transanal endoscopic microsurgery had worse resting/squeeze pressures (p = 0.004) and rectal capacity (p = 0.002). In addition, their incontinence scores (2.3 vs. 6.5; p < 0.001) and quality-of-life questionnaire responses (in all domains; p <= 0.01) were significantly worse in comparison with patients undergoing watch and wait. LIMITATIONS: This study was limited by the small sample size and the absence of baseline anorectal function information. CONCLUSIONS: Nonoperative management of patients with complete clinical response following chemoradiation results in better anorectal function in comparison with patients with near-complete response managed by transanal endoscopic microsurgery. In the absence of clinically detectable residual cancer, this latter approach may result in significant worsening of anorectal function. PMID- 26953986 TI - Quality of Life and Timing of Stoma Closure in Patients With Rectal Cancer Undergoing Low Anterior Resection With Diverting Stoma: A Multicenter Longitudinal Observational Study. AB - BACKGROUND: After low anterior resection for rectal cancer, creation of a diverting stoma is recommended. Data on the impact of a diverting stoma on quality of life are conflicting. Optimal timing of stoma closure in the setting of adjuvant chemotherapy is unclear. OBJECTIVE: The purpose of this study was to investigate the impact of a diverting stoma on quality of life in patients undergoing rectal cancer resection before and after stoma closure. Furthermore, the study was conducted to look at the timing of stoma reversal and the potential influence of factors such as adjuvant chemotherapy. DESIGN: This was a longitudinal, observational, multicenter study. SETTINGS: The study was conducted at 17 German colorectal centers. PATIENTS: Patients with rectal cancer who planned for elective curative surgery with creation of temporary diverting stoma were included. MAIN OUTCOME MEASURES: This longitudinal observational study assessed quality of life at 3 occasions using European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core Questionnaire/Colorectal Cancer Module before cancer resection, before stoma closure, and 6 months after stoma closure. Furthermore, the timing of stoma closure and continence were evaluated. RESULTS: A total of 120 patients (64% men; mean age, 63.2 +/- 11.5 years) were analyzed. Longitudinal global quality of life was not influenced by the presence of a stoma. Several functional and GI symptom scales were markedly impaired after stoma creation. Physical, role functioning, and sexual interest recovered after stoma closure. Social functioning stayed impaired (p < 0.0001). Median time to stoma closure was 5 months (range, 17 days to 18 months). A total of 3.4% of patients had very early stoma closure (within 30 days). Adjuvant chemotherapy delayed stoma closure (median, 5.6 vs 3.4 months without chemotherapy; p = 0.0001). LIMITATIONS: The study was limited by its missing quality-of-life data for sexual function. CONCLUSIONS: The presence of a stoma had a negative impact on social functioning and GI symptoms. However, this had no clinically relevant influence on global quality of life. Time to stoma closure was nearly doubled when patients underwent adjuvant chemotherapy. PMID- 26953985 TI - Predicting the Risk of Bowel-Related Quality-of-Life Impairment After Restorative Resection for Rectal Cancer: A Multicenter Cross-Sectional Study. AB - BACKGROUND: Restorative anterior resection is considered the optimal procedure for most patients with rectal cancer and is frequently preceded by radiotherapy. Both surgery and preoperative radiotherapy impair bowel function, which adversely affects quality of life. OBJECTIVE: This study aimed to report symptoms associated with and key predictors for bowel-related quality-of-life impairment. DESIGN: The study included a cross-sectional cohort. SETTINGS: This was a multicenter study from 12 United Kingdom centers. PATIENTS: A total of 578 patients with rectal cancer underwent curative restorative anterior resection between 2001 and 2012 (median, 5.25 years postsurgery). MAIN OUTCOME MEASURES: Patients completed outcome measures that assessed bowel dysfunction (low anterior resection syndrome score), incontinence (Wexner score), and quality of life (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30), plus an anchor question: "Overall how does bowel function affect your quality of life?" RESULTS: The response rate was 80% (462/578). Overall, 85% (391/462) of patients reported bowel-related quality-of-life impairment, with 40% (187/462) reporting major impairment. A large difference in global quality of life (22 points; p < 0.001) was reported for "none" versus "major" impairment, with greatest symptom severity being diarrhea (25 points; p < 0.001), insomnia (24 points; p < 0.001), and fatigue (20 points; p < 0.001). Regression analysis identified major impairment in 60% and 45% of patients with low rectal cancer treated with and without preoperative radiotherapy compared with 47% and 33% of middle/upper rectal cancers with and without preoperative radiotherapy. LIMITATIONS: Advances in radiotherapy delivery and improvements in posttreatment symptom control, although currently of limited efficacy, imply that the content of this consent aid should be re-evaluated in 5 to 10 years. CONCLUSIONS: Before a restorative anterior resection, patients with rectal cancer should be informed that bowel-related quality-of-life impairment is common. The key risk factors are neoadjuvant therapy and a low tumor height. This study presents quality-of-life and functional outcome data, along with a consent aid, that will enhance this preoperative patient discussion. PMID- 26953987 TI - Conditional Survival in Anal Carcinoma Using the National Population-Based Survey of Epidemiology and End Results Database (1988-2012). AB - BACKGROUND: Conditional survival can provide valuable information for both patients and healthcare providers about the changing prognosis in surviving patients over time. OBJECTIVE: This study estimated conditional survival for patients with anal cancer in the United States through analysis of a national population-based cancer registry. DESIGN: Log-rank test identified significant covariates of cause-specific survival (defined as time from diagnosis until death from anal cancer). Significant covariates were considered in the multivariable regression of cause-specific survival using Cox proportional hazards models. SETTINGS: Covariates included cancer stage and demographic variables. PATIENTS: Patients in Surveillance, Epidemiology, and End Results regions diagnosed with anal squamous cell carcinoma as their first and only cancer diagnosis from 1988 to 2012 were selected from this database, and 5145 patients were included in the retrospective cohort study. MAIN OUTCOME MEASURE: Five-year conditional survival stratified by each variable in the final Cox models was measured RESULTS: : The final multivariable models of overall and cause-specific survivals included stage, grade, sex, age, race, and relationship status. Over the first 6 years after diagnosis, conditional survival of distant stage increased from 37% to 89%, whereas regional stage increased from 65% to 93% and localized stage increased from 84% to 96%. The other variables had increasing prognosis as well, but the subgroups increased at a more similar rate over time. LIMITATIONS: The data source used does not include information on chemotherapy treatment, patient comorbidities, or socioeconomic status. CONCLUSIONS: Conditional survival showed improvement over time. Patients with advanced stage had the greatest improvement in conditional survival. This is the first study to provide specific conditional survival probabilities for patients with anal cancer. PMID- 26953989 TI - Treatment and Survival of Small-bowel Adenocarcinoma in the United States: A Comparison With Colon Cancer. AB - BACKGROUND: Small-bowel adenocarcinoma is rare and fatal. Because of data paucity, there is a tendency to extrapolate treatment from colon cancer, particularly in the adjuvant stetting. OBJECTIVE: The purpose of this study was to evaluate the current surgical and adjuvant treatments of small-bowel adenocarcinoma and compare with colon cancer. DESIGN: This was a retrospective cohort study. SETTINGS: The linked Surveillance, Epidemiology, and End Results and Medicare database was used at a tertiary referral hospital. PATIENTS: Patients with small-bowel adenocarcinoma and colon cancer identified from 1992 to 2010, using International Classification of Diseases for Oncology, 3 Revision, site, behavior, and histology codes were included. MAIN OUTCOME MEASURES: Overall survival and cancer-specific survival were estimated using the Kaplan-Meier method and competing risk analysis. RESULTS: A total of 2123 patients with small bowel adenocarcinoma and 248,862 patients with colon cancer were identified. Five year overall survival rates for patients with small-bowel adenocarcinoma and colon cancer were 34.9% and 51.5% (p < 0.0001). A total of 1550 patients with small-bowel adenocarcinoma (73.0%) underwent surgery, compared with 177,017 patients with colon cancer (71.1%). The proportion of patients who received chemotherapy was similar, at 21.3% for small bowel and 20.0% for colon. In contrast to colon cancer, chemotherapy did not improve overall or cancer-specific survival for patients with small-bowel adenocarcinoma, regardless of stage. Predictors of poor survival for small-bowel adenocarcinoma on multivariate analysis included advanced age, black race, advanced stage, poor tumor differentiation, high comorbidity index, and distal location. Chemotherapy did not confer additional survival benefit compared with surgery alone (HR, 1.04 (95% CI, 0.90-1.22)). LIMITATIONS: This was a retrospective review. The reliance on Medicare data limited granularity and may have affected the generalizability of the results. CONCLUSIONS: The prognosis for small-bowel adenocarcinoma is worse than that for colon cancer, and only surgery improves survival. In contrast to colon cancer, a survival benefit from current chemotherapy regimens for small bowel adenocarcinoma is not seen, suggesting that it may be overused and needs more rigorous study. PMID- 26953988 TI - Surgical Resection of the Primary Tumor in Stage IV Colorectal Cancer Without Metastasectomy is Associated With Improved Overall Survival Compared With Chemotherapy/Radiation Therapy Alone. AB - BACKGROUND: Controversy exists over whether resection of the primary tumor in stage IV colorectal cancer with inoperable metastases improves patient outcomes. OBJECTIVE: The purpose of this study was to evaluate whether resection of the primary tumor without metastasectomy in patients with stage IV colorectal cancer is associated with improved overall survival compared with patients undergoing chemotherapy and/or radiation therapy alone. DESIGN: This was a retrospective review of a multi-institutional dataset. SETTINGS: This study was conducted in all participating commission on cancer (CoC)-accredited facilities. PATIENTS: The 2003-2006 National Cancer Data Base was reviewed to identify patients with stage IV adenocarcinoma of the colon or rectum who underwent palliative treatment without curative intent, either in the form of surgical resection of the primary tumor without metastasectomy consisting of a colectomy or rectal resection with or without chemotherapy and/or radiation or chemotherapy and/or radiation alone. MAIN OUTCOME MEASURES: Groups were compared for baseline characteristics. Overall survival was compared using Kaplan-Meier analysis before and after propensity matching with a 1:1 nearest-neighbor algorithm. RESULTS: Of the 1446 patients included in the analysis, 231 (16%) underwent surgical resection of the primary tumor without metastasectomy. Surgical resection was associated with a significant survival benefit on unadjusted analysis (median survival, 9.2 vs. 7.6 months; p < 0.01). After propensity matching to adjust for nonrandom treatment selection, surgical resection continued to be associated with a significant survival benefit (median survival, 9.2 vs. 7.3 months; p < 0.01). LIMITATIONS: This study was limited by the potential for selection bias regarding which patients received surgical resection. There was also a lack of data regarding the indication for operation, specifically whether a patient was symptomatic or asymptomatic before resection. The inability to account for tumor size or grade among patients who did not receive surgical resection was another limitation. CONCLUSIONS: Surgical resection of the primary tumor without metastasectomy in patients with metastatic colorectal cancer is associated with improved survival as compared with chemotherapy/radiation therapy alone. Additional research is necessary to determine which patients may benefit from this intervention. PMID- 26953990 TI - Increased Incidence of Surgical Site Infection in IBD Patients. AB - BACKGROUND: Surgical site infection is a key hospital-level patient safety indicator. All risk factors for surgical site infection are not always taken into account and adjusted for. OBJECTIVE: This study aimed to measure the impact of IBD in comparison with diverticulitis and colorectal cancer on the national rates of surgical site infection. DESIGN: The American College of Surgeons National Surgical Quality Improvement Project database was queried for all patients undergoing elective colectomy for colon cancer, diverticulitis, and IBD from 2008 through 2012. OUTCOME MEASURES: The association between surgical site infection and IBD patients was assessed. Patient demographics, rates of surgical site infection, wound class, return to operating room, and various patient characteristics were analyzed. Logistic regression was performed to determine the association with surgical site infection. RESULTS: The query yielded 71,845 patients undergoing elective colectomy. Of these patients, 42,132 had colon cancer, 22,143 had diverticulitis, and 7570 had IBD. The rate of surgical site infection was 12.0% for colon cancer, 12.8% for diverticulitis, and 18.0% for IBD. Return to operating room within 30 days was 7.3% for IBD patients, 4.4% for patients with diverticulitis, and 4.9% for patients with colorectal cancer. Return to operating room within 30 days had the highest correlation to surgical site infection in both univariate and multivariable analysis. Other associative factors for surgical site infection common to both analyses included diabetes mellitus, smoking, open procedures, and obesity. LIMITATIONS: This study was limited by the data collection errors inherent to large databases, exclusion of emergent operations, and the inability to identify patients taking immunosuppressive agents. CONCLUSIONS: Patients with IBD undergoing elective colectomy have significantly increased rates of surgical site infection, specifically deep and organ/space infections. Given this information, risk adjustment models for surgical site infection may need to include IBD in their calculation. PMID- 26953991 TI - High Variability in Nosocomial Clostridium difficile Infection Rates Across Hospitals After Colorectal Resection. AB - BACKGROUND: Hospital-acquired Clostridium difficile infection is associated with adverse patient outcomes and high medical costs. The incidence and severity of C. difficile has been rising in both medical and surgical patients. OBJECTIVE: Our aim was to assess risk factors and variation associated with the development of nosocomial C. difficile colitis among patients undergoing colorectal resection. DESIGN: This was a retrospective cohort study. SETTINGS: The study included segmental colectomy and proctectomy cases in New York State from 2005 to 2013. PATIENTS: The study cohort included 150,878 colorectal resections. Patients with a documented previous history of C. difficile infection or residence outside of New York State were excluded. MAIN OUTCOME MEASURES: A diagnosis of C. difficile colitis either during the index hospital stay or on readmission within 30 days was the main measure. RESULTS: C. difficile colitis occurred in 3323 patients (2.2%). Unadjusted C. difficile colitis rates ranged from 0% to 11.3% among surgeons and 0% to 6.8% among hospitals. After controlling for patient, surgeon, and hospital characteristics using mixed-effects multivariable analysis, significant unexplained variation in C. difficile rates remained present across hospitals but not surgeons. Patient factors explained only 24% of the total hospital-level variation, and known surgeon and hospital-level characteristics explained an additional 8% of the total hospital-level variation. Therefore, ~70% of the hospital variation in C. difficile infection rates remained unexplained by captured patient, surgeon, and hospital factors. Furthermore, there was an ~5 fold difference in adjusted C. difficile rates across hospitals. LIMITATIONS: A limited set of hospital and surgeon characteristics was available. CONCLUSIONS: Colorectal surgery patients appear to be at high risk for C. difficile infection, and alarming variation in nosocomial C. difficile infection rates currently exists among hospitals after colorectal resection. Given the high morbidity and cost associated with C. difficile colitis, adopting institutional quality improvement programs and maintaining strict prevention strategies are of the utmost importance. PMID- 26953992 TI - The Decline of Elective Colectomy Following Diverticulitis: A Population-Based Analysis. AB - BACKGROUND: The indications for interval elective colectomy following diverticulitis are unclear; evidence lends increasing support for nonoperative management. OBJECTIVE: This study aims to evaluate the temporal trends in the use of elective colectomy following diverticulitis. DESIGN: This is a population based retrospective cohort study using administrative discharge data. SETTING: This study was conducted in Ontario, Canada. PATIENTS: Patients who had had an episode of diverticulitis managed nonoperatively and were eligible for elective colectomy, from 2002 to 2012, were selected. MAIN OUTCOME MEASURES: Changes in the proportion of patients who undergo elective colectomy following an episode of diverticulitis treated nonoperatively were evaluated. Cochran-Armitage was used to test for trends; adjusted analysis was performed by using multivariable logistic regression with generalized estimating equations. RESULTS: A total of 14,124 patients were admitted with an episode of diverticulitis and treated nonoperatively, making them eligible for interval elective colectomy. Median follow-up was 3.9 years (maximum, 10; interquartile range, 1.7-6.4). Overall, 1342 (9.5%) patients underwent elective colectomy; 33% of these colectomies were performed laparoscopically, and 7.5% patients received an ostomy. In-hospital mortality was 0.2%. The majority (76%) of elective operations were performed within 1 year of discharge (median, 160 days; interquartile range, 88-346). The proportion of patients undergoing elective colectomy within 1 year of discharge declined from 9.6% of patients in 2002 to 3.9% by 2011 (p < 0.001). The decline was most pronounced in patients <50 years of age (from 17% to 5%), and those with complicated disease (from 28% to 8%) (all p < 0.001). In multivariable regression, younger age, lower medical comorbidity, complicated disease, and early readmission were associated with elective colectomy. After adjusting for changes in patient characteristics, the odds of elective surgery decreased by 0.93 per annum (adjusted OR; 95% CI, 0.90-0.95). LIMITATIONS: Administrative health databases contain limited clinical detail; the rationale for elective surgery was not available. CONCLUSIONS: Consistent with evolving practice guidelines, there has been a decrease in the use of elective colectomy following an episode of diverticulitis. PMID- 26953993 TI - A Systematic Review of Outcomes After Transanal Mesorectal Resection for Rectal Cancer. AB - BACKGROUND: Transanal mesorectal resection has been developed to facilitate minimally invasive proctectomy for rectal cancer. OBJECTIVE: The purpose of this study was to evaluate the evidence regarding technical parameters, oncological outcomes, morbidity, and mortality after transanal mesorectal resection. DATA SOURCES: The Cochrane Library, PubMed, and MEDLINE databases were reviewed. STUDY SELECTION: Systematic review of the literature from January 2005 to September 2015 was used for study selection. INTERVENTION: Intervention included transanal mesorectal resection for rectal cancer. MAIN OUTCOME MEASURES: Technical parameters, histological outcomes, morbidity, and mortality were the outcomes measured. RESULTS: Fifteen predominately retrospective studies involving 449 patients were included (mean age, 64.3 years; 64.1% men). Different platforms were used. The operative mortality rate was 0.4% and the cumulative morbidity rate 35.5%. Circumferential resection margins were clear in 98%, and the resected mesorectum was grade III in 87% of patients. Median follow-up was 14.7 months. There were 4 local recurrences (1.5%) and 12 patients (5.6%) with metastatic disease. No study followed patients long enough to report on 5-year overall and disease-free survival rates. Functional outcome was only reported in 3 studies. LIMITATIONS: A low number of procedures were performed by expert early adopters. There are no comparative or randomized data included in this study and inconsistent reporting of outcome variables. CONCLUSIONS: Transanal mesorectal resection for rectal cancer may enhance negative circumferential margin rates with a reasonable safety profile. Contemporary randomized, controlled studies are required before there can be universal recommendation. PMID- 26953994 TI - Robotic Lateral Pelvic Lymph Node Dissection for Distal Rectal Cancer. PMID- 26953995 TI - The Prone Position for Performing Perineal Dissection During Extralevator Abdominoperineal Resection: A Necessary Waste of Time? PMID- 26953996 TI - The Prone Position for Abdominoperineal Excision: Why Not? PMID- 26953999 TI - Remote ischaemic preconditioning shortens QT intervals during exercise in healthy subjects. AB - The protective action of remote ischaemic preconditioning (RIPC) has been demonstrated in the context of surgical interventions in cardiology. Application of RIPC to sports performance has been proposed, but its effect on the electrocardiogram (ECG) during exercise remains unknown. This exploratory study aims to measure the changes in ventricular repolarization observed during exercise following RIPC in healthy subjects. In an experimental randomized crossover study, 17 subjects underwent two bouts of constant load exercise tests at 75% and 115% of gas exchange threshold (GET). Prior to exercise, they were allocated to either control or RIPC intervention with four cycles of 5 min of ischaemia followed by 5 min of reperfusion. ECG was continuously recorded during the protocol. QT and RR intervals were measured every 30 s (on an average tracing of the preceding 10 s). Although the time course of RR intervals did not differ between the two interventions (p = .56 at 75% GET and p = .74 at 115% GET), a significant shortening of QT intervals (measured from Q onset to T end) was observed during exercise (mean +/- standard deviation of RIPC vs. CONTROL: -32 +/ 19 ms at 75% GET (p < .001) and -34 +/- 12 ms at 115% GET (p < .001)) as well as during recovery (-21 +/- 8 ms at 75% GET (p < .001) and -16 +/- 11 ms at 115% GET (p < .001)). This effect was not present at rest. These RIPC-related changes were clearly identifiable on the QT-RR loops after hysteresis reduction. RIPC therefore induces heart rate-independent shortening of QT intervals that is revealed during exercise. PMID- 26954000 TI - Reflections on Terminology in the Continuing Education of Health Professionals. PMID- 26954001 TI - Terminology in Continuing Education: A Hybrid Methodology for Improving the Use and Reporting of Interventions in Continuing Education. AB - Researchers and leaders working in quality improvement and continuing education have a variety of interventions available to change clinician behavior and to improve patient outcomes. Evidence from systematic reviews and meta-analyses of such interventions is often mixed, with methodological weaknesses contributing to challenges in summarizing and interpreting evidence. Confusion and inconsistency surrounding many of the terms contributes to this challenge. This international study was commissioned by the Society for Academic Continuing Medical Education to use expert opinion to improve the consistency of important educational terminology by describing the essential components of a set of educational interventions, such as educational meetings. This article will describe how this project uses the literature and an expert consensus process to improve precision around the conceptualization and implementation of educational interventions. This article will offer an in-depth description of a hybrid methodology that blends the Chaffee framework for concept explication with a modified Delphi technique that constitutes a novel expert consensus process. This article concludes with recommendations for other scholars replicating this process. PMID- 26954002 TI - Society for Academic Continuing Medical Education Intervention Guideline Series: Guideline 1, Performance Measurement and Feedback. AB - The Society for Academic Continuing Medical Education commissioned a study to clarify and, if possible, to standardize the terminology for a set of important educational interventions. In the form of a guideline, this article describes one such intervention, performance measurement and feedback, which is a common intervention in health professions education. In the form of a summary report, performance measurement and feedback is an opportunity for clinicians to view data about the care they provide compared with some standard and often with peer and benchmark comparisons. Based on a review of recent evidence and a facilitated discussion with the US and Canadian experts, we describe proper terminology for performance measurement and feedback and other important information about the intervention. We encourage leaders and researchers to consider and build on this guideline as they plan, implement, evaluate, and report efforts with performance measurement and feedback. Clear and consistent use of terminology is imperative, along with complete and accurate descriptions of interventions, to improve the use and study of performance measurement and feedback. PMID- 26954003 TI - Society for Academic Continuing Medical Education Intervention Guideline Series: Guideline 2, Practice Facilitation. AB - The Society for Academic Continuing Medical Education commissioned a study to clarify and, if possible, standardize the terminology for a set of important educational interventions. In the form of a guideline, this article describes one such intervention, practice facilitation, which is a common strategy in primary care to help practices develop capacity and infrastructure to support their ability to improve patient care. Based on a review of recent evidence and a facilitated discussion with US and Canadian experts, we describe practice facilitation, its terminology, and other important information about the intervention. We encourage leaders and researchers to consider and build on this guideline as they plan, implement, evaluate, and report practice facilitation efforts. Clear and consistent use of terminology is imperative, along with complete and accurate descriptions of interventions, to improve the use and study of practice facilitation. PMID- 26954004 TI - Society for Academic Continuing Medical Education Intervention Guideline Series: Guideline 3, Educational Meetings. AB - The Society for Academic Continuing Medical Education commissioned a study to clarify and, if possible, to standardize the terminology for a set of important educational interventions. In the form of a guideline, this article describes one such intervention, educational meetings, which is a common intervention in health professions' education. An educational meeting is an opportunity for clinicians to assemble to discuss and apply important information relevant to patient care. Based on a review of recent evidence and a facilitated discussion with US and Canadian experts, we describe proper educational meeting terminology and other important information about the intervention. We encourage leaders and researchers to consider and to build on this guideline as they plan, implement, evaluate, and report educational meeting efforts. Clear and consistent use of terminology is imperative, along with complete and accurate descriptions of interventions, to improve the use and study of educational meetings. PMID- 26954005 TI - Society for Academic Continuing Medical Education Intervention Guideline Series: Guideline 4, Interprofessional Education. AB - The Society for Academic Continuing Medical Education commissioned a study to clarify and, if possible, to standardize the terminology for a set of important educational interventions. In the form of a guideline, this article describes one such intervention, interprofessional education (IPE), which is a common intervention in health professions education. IPE is an opportunity for individuals of multiple professions to interact to learn together, to break down professional silos, and to achieve interprofessional learning outcomes in the service of high-value patient care. Based on a review of recent evidence and a facilitated discussion with US and Canadian experts, we describe IPE, its terminology, and other important information about the intervention. We encourage leaders and researchers to consider and to build on this guideline as they plan, implement, evaluate, and report IPE efforts. Clear and consistent use of terminology is imperative, along with complete and accurate descriptions of interventions, to improve the use and study of IPE. PMID- 26954006 TI - Conceptualization and Reporting of Context in the North American Continuing Medical Education Literature: A Scoping Review Protocol. AB - Within continuing medication education (CME), it has been argued that an "authentic" clinical context should be built into CME activities for knowledge to be effectively translated into clinical practice. However, although context is considered significant in the success (or lack thereof) of an intervention, there is a lack of consensus on what exactly context is. This scoping review arises from concerns surrounding the opaque, complex, and potentially problematic relationship between context and the effective design and implementation of CME interventions. In this article, we present a protocol for examining how context is discussed within the CME literature. The specific purpose of this scoping review is to summarize the breadth of existing evidence on context within the North American CME literature. The scoping review methodology will also highlight gaps in the current literature, which can inform future research endeavors. PMID- 26954007 TI - The Effect of Water and Bases on the Clustering of a Cyclohexene Autoxidation Product C6H8O7 with Sulfuric Acid. AB - We investigate the molecular interaction between sulfuric acid and a C6H8O7 ketodiperoxy acid compound (a proxy for highly oxidized products of, e.g., monoterpene autoxidation) in the presence of water, ammonia, or dimethylamine. The molecular geometries are obtained using density functional theory (M06-2X, PW91, and omegaB97X-D) with the 6-31++G(d,p) basis set, and the binding energy is corrected utilizing a high-level DLPNO-CCSD(T)/def2-QZVPP calculation. The formation free energies were calculated (DeltaG at 298 K and 1 atm), and the stability of the molecular clusters was evaluated. The presence of bases is found to enhance the interaction between ketodiperoxy acid compounds and sulfuric acid. The addition of C6H8O7 compounds to (H2SO4)(NH3) or (H2SO4)((CH3)2NH) clusters is, however, not able to compete with the corresponding uptake of another sulfuric acid molecule, even at a high loading of organic compounds. We furthermore investigate the origin of the weak binding of peroxyacid compounds using atoms in molecules and natural bonding orbital analysis. The weak binding is caused by an internal hydrogen bond and the lack of a strong hydrogen bond acceptor in the peroxyacid group. These findings indicate that autoxidation products containing solely or mainly hydroperoxide and carbonyl functional groups do not participate in the initial step of new particle formation and thereby only contribute to the growth of atmospheric particles. PMID- 26954009 TI - Antimicrobial-Resistant Fecal Bacteria from Ceftiofur-Treated and Nonantimicrobial-Treated Comingled Beef Cows at a Cow-Calf Operation. AB - We compared the occurrences of 3rd-generation cephalosporin-resistant (3GCr), tetracycline-resistant (TETr), and trimethoprim-sulfamethoxazole-resistant (COTr) Escherichia coli, 3GCr and nalidixic acid-resistant (NALr) Salmonella enterica, and erythromycin-resistant (ERYr) enterococci from the fecal samples of ceftiofur treated (n = 162) and nonantimicrobial-treated (n = 207) comingled beef cows >=8 years old, for which complete antimicrobial treatment records were available. The prevalence of 3GCr (17%; n = 369), TETr (88%), COTr E. coli (22%), and ERYr enterococci (69%) was not significantly (p > 0.05) associated with ceftiofur treatment, prior history of other antimicrobial treatments, or duration of time between last antimicrobial treatment and sampling. 3GCr and NALr S. enterica were not detected. The prevalence of tetB was significantly (p < 0.05) higher compared with tetA among TETr E. coli. However, the prevalence of tetA was significantly (p < 0.05) higher than tetB among 3GCr and COTr E. coli. There was a significant (p < 0.05) association between tetM and ermB among ERYr enterococci. In conclusion, occurrences of 3GCr, TETr, and COTr E. coli and ERYr enterococci in comingled antimicrobial-treated and nonantimicrobial-treated beef cows were not associated with ceftiofur or other antimicrobial use, indicating that other factors influenced the observed levels of antimicrobial-resistant bacteria in feces of beef cows. PMID- 26954010 TI - Does the Clearance of Inhaled (99m)Tc-Sestamibi Correlate with Multidrug Resistance Protein 1 Expression in the Human Lung? AB - Purpose To examine the relation between the lung elimination rate of inhaled technetium 99m ((99m)Tc)-sestamibi and immunohistochemical expression of bronchopulmonary multidrug resistance protein 1 (MRP1) and permeability glycoprotein (P-gp) and assess the repeatability of the inhaled (99m)Tc-sestamibi clearance technique. Materials and Methods (99m)Tc-sestamibi is a known substrate for P-gp and MRP1, which are established cellular drug efflux transporters. The elimination rate of (99m)Tc-sestamibi from the lungs after inhalation as an aerosol has been hypothesized to be regulated by expression of these transporters. Institutional ethics committee approval was received for this prospective study. Written informed consent was obtained from all participants. The clearance of inhaled (99m)Tc-sestamibi from the lungs of 13 patients due to undergo surgery for primary lung cancer (five of 13) or spontaneous pneumothorax (eight of 13) was estimated after dynamic imaging of the lungs during a period of 40 minutes. The time taken to clear 50% of inhaled sestamibi (T1/2) was compared with a semiquantitative immunohistochemical assessment (grade 0-3) of MRP1 and P gp expression in the lung by using parametric and nonparametric tests. The study was repeated in five participants to assess the repeatability of the technique by using a Bland Altman analysis method. Results MRP1 expression was seen in 12 of 13 patients, while P-gp expression was seen in only two. The mean (99m)Tc sestamibi elimination rate was faster in patients (n = 6) with low levels of MRP1 expression (grade 0-1) and mean T1/2 of 105 minutes +/- 20 (standard deviation), compared with those with higher levels of MRP1 expression (grade 2-3, n = 7) and mean T1/2 of 149 minutes +/- 28 (P = .008). Bland-Altman analysis revealed excellent agreement between test and retest values. Conclusion Inhaled (99m)Tc sestamibi clearance study is a repeatable technique demonstrating significant correlation with MRP1 expression in the lungs. ((c)) RSNA, 2016. PMID- 26954011 TI - Dual-gate polysilicon nanoribbon biosensors enable high sensitivity detection of proteins. AB - We demonstrate the advantages of dual-gate polysilicon nanoribbon biosensors with a comprehensive evaluation of different measurement schemes for pH and protein sensing. In particular, we compare the detection of voltage and current changes when top- and bottom-gate bias is applied. Measurements of pH show that a large voltage shift of 491 mV pH(-1) is obtained in the subthreshold region when the top-gate is kept at a fixed potential and the bottom-gate is varied (voltage sweep). This is an improvement of 16 times over the 30 mV pH(-1) measured using a top-gate sweep with the bottom-gate at a fixed potential. A similar large voltage shift of 175 mV is obtained when the protein avidin is sensed using a bottom-gate sweep. This is an improvement of 20 times compared with the 8.8 mV achieved from a top-gate sweep. Current measurements using bottom-gate sweeps do not deliver the same signal amplification as when using bottom-gate sweeps to measure voltage shifts. Thus, for detecting a small signal change on protein binding, it is advantageous to employ a double-gate transistor and to measure a voltage shift using a bottom-gate sweep. For top-gate sweeps, the use of a dual-gate transistor enables the current sensitivity to be enhanced by applying a negative bias to the bottom-gate to reduce the carrier concentration in the nanoribbon. For pH measurements, the current sensitivity increases from 65% to 149% and for avidin sensing it increases from 1.4% to 2.5%. PMID- 26954012 TI - Simultaneous Qualitative Assessment and Quantitative Analysis of Metabolites (Phenolics, Nucleosides and Amino Acids) from the Roots of Fresh Gastrodia elata Using UPLC-ESI-Triple Quadrupole Ion MS and ESI- Linear Ion Trap High-Resolution MS. AB - A sensitive, effective and optimized method, based on ultra performance liquid chromatography (UPLC) coupled with ESI-triple quadrupole ion MS and ESI-linear ion trap high-resolution MS, has been developed for the simultaneous quantitative and qualitative determination of phenolics, nucleosides and amino acids in the roots of fresh Gastrodia elata. Optimization of the analytical method provided higher separation efficiency and better peak resolution for the targeted compounds. The simultaneous separation protocols were also optimized by routinely using accurate mass measurements, within 5 ppm error, for each molecular ion and the subsequent fragment ions. In total, 31 compounds, including 23 phenolics, two nucleosides, four amino acids, one gastrodin and one other compound were identified or tentatively characterized. Mono-substituted parishin glucoside (9), methoxy mono-substituted parishin (13), methyl parishin (26), p-hydroxybenzyl di substituted parishin (29), and p-hydroxybenzyl parishin (31) were tentatively identified as new compounds. Principal metabolite content analysis and the composition of eight representative G. elata cultivars of various species indicated that geographic insulation was the main contributor to clustering. PMID- 26954013 TI - Comparison of Airway Management Methods in Entrapped Patients: A Manikin Study. AB - INTRODUCTION: Endotracheal intubation remains one of the most challenging skills in prehospital care. There is a minimal amount of data on the optimal technique to use when managing the airway of an entrapped patient. We hypothesized that use of a blindly placed device would result in both the shortest time to airway management and highest success rate. METHODS: A difficult airway manikin was placed in a cervical collar and secured upside down in an overturned vehicle. Experienced paramedics and prehospital registered nurses used four different methods to secure the airway: direct laryngoscopy, digital intubation, King LT-D, and CMAC video laryngoscopy. Each participant was given three opportunities to secure the airway using each technique in random order. A study investigator timed each attempt and confirmed successful placement, which was determined upon inflation of the manikin's lungs. Intubation success rates were analyzed using a general estimating equations model to account for repeated measures and a linear mixed effects model for average time. RESULTS: Twenty-two prehospital providers participated in the study. The one-pass success rate for the King LT-D was significantly higher than direct laryngoscopy (OR 0.048, CI 0.006-0.351, p < 0.01) and digital intubation (OR 0.040, CI 0.005-0.297, p < 0.01). However, there was no statistical difference between the one-pass success rate of the King LT-D and CMAC video laryngoscopy (OR 0.302, 95% CI 0.026-3.44, p = 0.33). The one-pass median placement time of the King LT-D (22 seconds, IQR 17-26) was significantly lower (p < 0.001) than direct laryngoscopy (60 seconds, IQR 42-75), digital intubation (38 seconds, IQR 26-74), and the CMAC (51 seconds, IQR 43-76). CONCLUSIONS: In this study, while the King LT-D offered the quickest airway placement, success rates were not significantly greater than intubation using the CMAC video laryngoscope. Intubation using direct laryngoscopy and digital intubation were less successful and took more time. Use of a blindly placed device or a video laryngoscope may provide the best avenues for airway management of entrapped patients. PMID- 26954014 TI - Anthropogenic Habitats Facilitate Dispersal of an Early Successional Obligate: Implications for Restoration of an Endangered Ecosystem. AB - Landscape modification and habitat fragmentation disrupt the connectivity of natural landscapes, with major consequences for biodiversity. Species that require patchily distributed habitats, such as those that specialize on early successional ecosystems, must disperse through a landscape matrix with unsuitable habitat types. We evaluated landscape effects on dispersal of an early successional obligate, the New England cottontail (Sylvilagus transitionalis). Using a landscape genetics approach, we identified barriers and facilitators of gene flow and connectivity corridors for a population of cottontails in the northeastern United States. We modeled dispersal in relation to landscape structure and composition and tested hypotheses about the influence of habitat fragmentation on gene flow. Anthropogenic and natural shrubland habitats facilitated gene flow, while the remainder of the matrix, particularly development and forest, impeded gene flow. The relative influence of matrix habitats differed between study areas in relation to a fragmentation gradient. Barrier features had higher explanatory power in the more fragmented site, while facilitating features were important in the less fragmented site. Landscape models that included a simultaneous barrier and facilitating effect of roads had higher explanatory power than models that considered either effect separately, supporting the hypothesis that roads act as both barriers and facilitators at all spatial scales. The inclusion of LiDAR-identified shrubland habitat improved the fit of our facilitator models. Corridor analyses using circuit and least cost path approaches revealed the importance of anthropogenic, linear features for restoring connectivity between the study areas. In fragmented landscapes, human modified habitats may enhance functional connectivity by providing suitable dispersal conduits for early successional specialists. PMID- 26954015 TI - Leisure-time physical activity and direct cost of short-term sickness absence among Finnish municipal employees. AB - We aimed to examine the direct costs of short-term (1-14 days) sickness absence and the effect of employees' physical activity on the costs. The Finnish Helsinki Health Study survey (2007) was used in the analysis (n = 3,935). Physical activity was classified into inactive, moderately active, and vigorously active. Sickness absence (3 years follow-up) and salary data were derived from the employer's registers. On average, an employee was absent 6 days a year due to short-term sickness absence, with a production loss of 2,350 EUR during the 3 years. The vigorously active had less sickness absence than those less active. The direct cost of sickness absence of a vigorously active employee was 404 EUR less than that of an inactive employee. Promoting physical activity among employees may decrease direct cost of short-term sickness absence. PMID- 26954016 TI - Association Between the Transforming Growth Factor Beta 1 Gene Polymorphisms and Turkish Patients with Nonsyndromic Cleft Lip With/Without Cleft Palate. AB - OBJECTIVE: To examine transforming growth factor beta 1 (TGFbeta1) gene polymorphisms in Turkish patients with nonsyndromic cleft lip with/without cleft palate (nsCL/P). METHODS: A total of 205 Turkish subjects were included; 80 nsCL/P patients and 125 unrelated control individuals. Analysis of gene polymorphisms was carried out by polymerase chain reaction and DNA sequencing. RESULTS: We found the substitution of a proline by a leucine at codon 10 (Pro10Leu) and the substitution of an arginine by a proline at codon 25 (Arg25Pro) in exon 1 of the TGFbeta1 gene in nsCL/P patients. CONCLUSION: This is the first report investigating prevalence of TGFbeta1 polymorphisms in Turkish patients with nsCL/P. PMID- 26954018 TI - Inward leakage variability between respirator fit test panels - Part II. Probabilistic approach. AB - This study aimed to quantify the variability between different anthropometric panels in determining the inward leakage (IL) of N95 filtering facepiece respirators (FFRs) and elastomeric half-mask respirators (EHRs). We enrolled 144 experienced and non-experienced users as subjects in this study. Each subject was assigned five randomly selected FFRs and five EHRs, and performed quantitative fit tests to measure IL. Based on the NIOSH bivariate fit test panel, we randomly sampled 10,000 pairs of anthropometric 35 and 25 member panels without replacement from the 144 study subjects. For each pair of the sampled panels, a Chi-Square test was used to test the hypothesis that the passing rates for the two panels were not different. The probability of passing the IL test for each respirator was also determined from the 20,000 panels and by using binomial calculation. We also randomly sampled 500,000 panels with replacement to estimate the coefficient of variation (CV) for inter-panel variability. For both 35 and 25 member panels, the probability that passing rates were not significantly different between two randomly sampled pairs of panels was higher than 95% for all respirators. All efficient (passing rate >=80%) and inefficient (passing rate <=60%) respirators yielded consistent results (probability >90%) for two randomly sampled panels. Somewhat efficient respirators (passing rate between 60% and 80%) yielded inconsistent results. The passing probabilities and error rates were found to be significantly different between the simulation and binomial calculation. The CV for the 35-member panel was 16.7%, which was slightly lower than that for the 25-member panel (19.8%). Our results suggested that IL inter panel variability exists, but is relatively small. The variability may be affected by passing level and passing rate. Facial dimension-based fit test panel stratification was also found to have significant impact on inter-panel variability, i.e., it can reduce alpha and beta errors, and inter-panel variability. PMID- 26954017 TI - Traditional Chinese Nootropic Medicine Radix Polygalae and Its Active Constituent Onjisaponin B Reduce beta-Amyloid Production and Improve Cognitive Impairments. AB - Decline of cognitive function is the hallmark of Alzheimer's disease (AD), regardless of the pathological mechanism. Traditional Chinese medicine has been used to combat cognitive impairments and has been shown to improve learning and memory. Radix Polygalae (RAPO) is a typical and widely used herbal medicine. In this study, we aimed to follow the beta-amyloid (Abeta) reduction activity to identify active constituent(s) of RAPO. We found that Onjisaponin B of RAPO functioned as RAPO to suppress Abeta production without direct inhibition of beta site amyloid precursor protein cleaving enzyme 1 (BACE1) and gamma-secretase activities. Our mechanistic study showed that Onjisaponin B promoted the degradation of amyloid precursor protein (APP). Further, oral administration of Onjisaponin B ameliorated Abeta pathology and behavioral defects in APP/PS1 mice. Taken together, our results indicate that Onjisaponin B is effective against AD, providing a new therapeutic agent for further drug discovery. PMID- 26954022 TI - Editorial. AB - Welcome to the autumn issue of Nurse Researcher. A new editorial team has just been appointed at the journal - Ian McMillan has taken over as editor and Paula Roberts, lecturer at Keele University's department of nursing and midwifery, is the new consultant editor. We feel very enthusiastic about our roles and share a determination that the journal will continue to grow and develop in the coming years. Our predecessors have set firm foundations since Nurse Researcher was launched in 1993, and we are keen that those involved in conducting research continue to see the journal as vital resource. We hope that authors - both those whose work has appeared in past issues of the journal and those who have never been published before - will submit articles to be considered for publication. Our particular thanks go to Dr Jacqueline Oldham from the University of Manchester, the former consultant editor whose efforts on behalf of Nurse Researcher have been unstinting since its launch. PMID- 26954019 TI - Drug Repositioning for Cancer Therapy Based on Large-Scale Drug-Induced Transcriptional Signatures. AB - An in silico chemical genomics approach is developed to predict drug repositioning (DR) candidates for three types of cancer: glioblastoma, lung cancer, and breast cancer. It is based on a recent large-scale dataset of ~20,000 drug-induced expression profiles in multiple cancer cell lines, which provides i) a global impact of transcriptional perturbation of both known targets and unknown off-targets, and ii) rich information on drug's mode-of-action. First, the drug induced expression profile is shown more effective than other information, such as the drug structure or known target, using multiple HTS datasets as unbiased benchmarks. Particularly, the utility of our method was robustly demonstrated in identifying novel DR candidates. Second, we predicted 14 high-scoring DR candidates solely based on expression signatures. Eight of the fourteen drugs showed significant anti-proliferative activity against glioblastoma; i.e., ivermectin, trifluridine, astemizole, amlodipine, maprotiline, apomorphine, mometasone, and nortriptyline. Our DR score strongly correlated with that of cell based experimental results; the top seven DR candidates were positive, corresponding to an approximately 20-fold enrichment compared with conventional HTS. Despite diverse original indications and known targets, the perturbed pathways of active DR candidates show five distinct patterns that form tight clusters together with one or more known cancer drugs, suggesting common transcriptome-level mechanisms of anti-proliferative activity. PMID- 26954023 TI - General overview of the use of computers in nursing research. AB - Carol Cooper offers some useful tips on using computer programs to enhance nursing research. PMID- 26954020 TI - Assessing Hepatitis C Burden and Treatment Effectiveness through the British Columbia Hepatitis Testers Cohort (BC-HTC): Design and Characteristics of Linked and Unlinked Participants. AB - BACKGROUND: The British Columbia (BC) Hepatitis Testers Cohort (BC-HTC) was established to assess and monitor hepatitis C (HCV) epidemiology, cost of illness and treatment effectiveness in BC, Canada. In this paper, we describe the cohort construction, data linkage process, linkage yields, and comparison of the characteristics of linked and unlinked individuals. METHODS: The BC-HTC includes all individuals tested for HCV and/or HIV or reported as a case of HCV, hepatitis B (HBV), HIV or active tuberculosis (TB) in BC linked with the provincial health insurance client roster, medical visits, hospitalizations, drug prescriptions, the cancer registry and mortality data using unique personal health numbers. The cohort includes data since inception (1990/1992) of each database until 2012/2013 with plans for annual updates. We computed linkage rates by year and compared the characteristics of linked and unlinked individuals. RESULTS: Of 2,656,323 unique individuals available in the laboratory and surveillance data, 1,427,917(54%) were included in the final linked cohort, including about 1.15 million tested for HCV and about 1.02 million tested for HIV. The linkage rate was 86% for HCV tests, 89% for HCV cases, 95% for active TB cases, 48% for HIV tests and 36% for HIV cases. Linkage rates increased from 40% for HCV negatives and 70% for HCV positives in 1992 to ~90% after 2005. Linkage rates were lower for males, younger age at testing, and those with unknown residence location. Linkage rates for HCV testers co-infected with HIV, HBV or TB were very high (90-100%). CONCLUSION: Linkage rates increased over time related to improvements in completeness of identifiers in laboratory, surveillance, and registry databases. Linkage rates were higher for HCV than HIV testers, those testing positive, older individuals, and females. Data from the cohort provide essential information to support the development of prevention, care and treatment initiatives for those infected with HCV. PMID- 26954024 TI - Using computers in nursing research. AB - The advent of the computer age has brought with it some powerful new ways of making nursing research a more efficient process. Michael Tait and Julie Slater report. PMID- 26954025 TI - The philosophical bases of grounded theory and their implications for research practice. AB - What are the implications of using a grounded theory approach in nursing research? Liz Norton discusses the issues and offers some personal insights. PMID- 26954026 TI - Participant observation, peripheral observation or apart-icipant observation? AB - Katharine Kite found it impossible to conduct research as a participant observer in an intensive care unit. Here she discusses the obstacles she faced and how she attempted to overcome them. PMID- 26954027 TI - Participant observation as a research tool in a practice based profession. AB - This paper by Catriona Kennedy offers a personal account of the use of participant observation as a tool for exploring and uncovering the knowledge base of experienced district nurses in relation to first assessment visits. Currently, many district nurses (DNs) are educated to degree level. However, despite a long history of educational provision for DNs, the research base available to support their practice is limited. PMID- 26954028 TI - Policy analysis. AB - While policy is central to our understanding of the government and conduct of everyday life in both our professional and personal capacities, it is a slippery concept. This paper explores various writers' definitions of the term and looks at some aspects ofpolicy analysis. This is a form of research in its own right as well as one element in the mixed bag of research approaches and tools from which small scale researchers are likely to draw in the course of conducting a study. PMID- 26954030 TI - Pancreatic B-13 Cell Trans-Differentiation to Hepatocytes Is Dependent on Epigenetic-Regulated Changes in Gene Expression. AB - The proliferative B-13 pancreatic cell line is unique in its ability to generate functional hepatocyte-like (B-13/H) cells in response to exposure to glucocorticoid. In these studies, quantitatively comparable hepatic levels of liver-specific and liver-enriched transcription factor and hepatocyte defining mRNA transcripts were expressed after 10-14 days continuous treatment with glucocorticoid. This conversion in phenotype was associated with increased Gr alpha mRNA expression and translation of a functional N-terminally truncated variant protein that localized to the nucleus in B-13/H cells. A short (6 hours) pulse exposure to glucocorticoid was also sufficient to transiently activate the Gr and irreversibly drive near identical conversion to B-13/H cells. Examination of epigenetic-related mechanisms demonstrated that B-13 DNA was rapidly methylated and de-methylated over the initial 2 days in response to both continuous or pulse exposure with glucocorticoid. DNA methylation and glucocorticoid-dependent conversion to an hepatic B-13/H phenotype was blocked by the methylation inhibitor, 5-azacytidine. Conversion to an hepatic B-13/H phenotype was also blocked by histone deacetylase inhibitors. Previous experiments have identified N-terminal Sgk1 variant proteins as pivotal to the mechanism(s) associated with pancreatic-hepatic differentiation. Both continuous and pulse exposure to DEX was sufficient to result in a near-similar robust transcriptional increase in Sgk1c mRNA expression from undetectable levels in B 13 cells. Notably, expression of Sgk1c mRNA remained constitutive 14 days later; including after pulse exposure to glucocorticoid and this induction was inhibited by 5-azacytidine or by histone deacetylase inhibitors. These data therefore suggest that exposing B-13 cells to glucocorticoid results in a Gr-dependent pulse in DNA methylation and likely other epigenetic changes such as histone modifications that leads to constitutive expression of Sgk1c and irreversible reprogramming of B-13 cells into B-13/H cells. Understanding and application of these mechanism(s) may enhance the functionality of stem cell-derived hepatocytes generated in vitro. PMID- 26954033 TI - Recommendations for the Management of Strokelike Episodes in Patients With Mitochondrial Encephalomyopathy, Lactic Acidosis, and Strokelike Episodes. AB - IMPORTANCE: Strokelike episodes are a cardinal feature of several mitochondrial syndromes, including mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS). Recent advances in the understanding of the pathophysiologic mechanisms of strokelike episodes in MELAS have led to improved treatment options. OBSERVATIONS: Current understanding of the cause of strokelike episodes in MELAS and present recommendations to assist in the identification and treatment of patients with MELAS who present with stroke are presented. Mounting evidence points toward a benefit of the nitric oxide precursors, arginine, to both prevent and reduce the severity of strokes in patients with MELAS. CONCLUSIONS AND RELEVANCE: Although much information is still needed regarding the appropriate dosing and timing of arginine therapy in patients with MELAS, urgent administration of nitric oxide precursors in patients with MELAS ameliorates the clinical symptoms associated with strokelike episodes. PMID- 26954031 TI - Frataxin Deficiency Promotes Excess Microglial DNA Damage and Inflammation that Is Rescued by PJ34. AB - An inherited deficiency in the frataxin protein causes neurodegeneration of the dorsal root ganglia and Friedreich's ataxia (FA). Frataxin deficiency leads to oxidative stress and inflammatory changes in cell and animal models; however, the cause of the inflammatory changes, and especially what causes brain microglial activation is unclear. Here we investigated: 1) the mechanism by which frataxin deficiency activates microglia, 2) whether a brain-localized inflammatory stimulus provokes a greater microglial response in FA animal models, and 3) whether an anti-inflammatory treatment improves their condition. Intracerebroventricular administration of LPS induced higher amounts of microglial activation in the FA mouse model vs controls. We also observed an increase in oxidative damage in the form of 8-oxoguanine (8-oxo-G) and the DNA repair proteins MUTYH and PARP-1 in cerebellar microglia of FA mutant mice. We hypothesized that frataxin deficiency increases DNA damage and DNA repair genes specifically in microglia, activating them. siRNA-mediated frataxin knockdown in microglial BV2 cells clearly elevated DNA damage and the expression of DNA repair genes MUTYH and PARP-1. Frataxin knockdown also induced a higher level of PARP-1 in MEF cells, and this was suppressed in MUTYH-/- knockout cells. Administration of the PARP-1 inhibitor PJ34 attenuated the microglial activation induced by intracerebroventricular injection of LPS. The combined administration of LPS and angiotensin II provoke an even stronger activation of microglia and neurobehavioral impairment. PJ34 treatment attenuated the neurobehavioral impairments in FA mice. These results suggest that the DNA repair proteins MUTYH and PARP-1 may form a pathway regulating microglial activation initiated by DNA damage, and inhibition of microglial PARP-1 induction could be an important therapeutic target in Friedreich's ataxia. PMID- 26954032 TI - Application of Laser Capture Microdissection to Craniofacial Biology: Characterization of Anatomically Relevant Gene Expression in Normal and Craniosynostotic Rabbit Sutures. AB - OBJECTIVE: Fusion of the cranial sutures is thought to depend on signaling among perisutural tissues. Mapping regional variations in gene expression would improve current models of craniosynostosis. Laser capture microdissection (LCM) isolates discrete cell populations for gene expression analysis. LCM has rarely been used in the study of mineralized tissue. This study sought to evaluate the potential use of LCM for mapping of regional gene expression within the cranial suture. DESIGN: Coronal sutures were isolated from 10-day-old wild-type and craniosynostotic (CS) New Zealand White rabbits, and LCM was used to isolate RNA from the sutural ligament (SL), osteogenic fronts (OF), dura mater, and periosteum. Relative expression levels for Fibroblast Growth Factor 2 (FGF2), Fibroblast Growth Factor Receptor 2 (FGFR2), Transforming Growth Factor Beta 2 (TGFbeta-2), Transforming Growth Factor Beta 3 (TGFbeta-3), Bone Morphogenetic Protein 2 (BMP-2), Bone Morphogenetic Protein 4 (BMP-4), and Noggin were determined using quantitative real-time PCR. RESULTS: A fivefold increase in TGFbeta2 expression was detected in the CS SL relative to wild type, whereas 152 fold less TGFbeta-3 was detected within the OF of CS animals. Noggin expression was increased by 10-fold within the CS SL, but reduced by 13-fold within the CS dura. Reduced expression of FGF2 was observed within the CS SL and dura, whereas increased expression of FGFR2 was observed within the CS SL. Reduced expression of BMP-2 was observed in the CS periosteum, and elevated expression of BMP-4 was observed in the CS SL and dura. CONCLUSIONS: LCM provides an effective tool for measuring regional variations in cranial suture gene expression. More precise measurements of regional gene expression with LCM may facilitate efforts to correlate gene expression with suture morphogenesis and pathophysiology. PMID- 26954034 TI - The Inhibitory Effect of Non-Substrate and Substrate DNA on the Ligation and Self Adenylylation Reactions Catalyzed by T4 DNA Ligase. AB - DNA ligases are essential both to in vivo replication, repair and recombination processes, and in vitro molecular biology protocols. Prior characterization of DNA ligases through gel shift assays has shown the presence of a nick site to be essential for tight binding between the enzyme and its dsDNA substrate, with no interaction evident on dsDNA lacking a nick. In the current study, we observed a significant substrate inhibition effect, as well as the inhibition of both the self-adenylylation and nick-sealing steps of T4 DNA ligase by non-nicked, non substrate dsDNA. Inhibition by non-substrate DNA was dependent only on the total DNA concentration rather than the structure; with 1 MUg/mL of 40-mers, 75-mers, or circular plasmid DNA all inhibiting ligation equally. A >15-fold reduction in T4 DNA ligase self-adenylylation rate when in the presence of high non-nicked dsDNA concentrations was observed. Finally, EMSAs were utilized to demonstrate that non-substrate dsDNA can compete with nicked dsDNA substrates for enzyme binding. Based upon these data, we hypothesize the inhibition of T4 DNA ligase by non-nicked dsDNA is direct evidence for a two-step nick-binding mechanism, with an initial, nick-independent, transient dsDNA-binding event preceding a transition to a stable binding complex in the presence of a nick site. PMID- 26954035 TI - Virilizing oncocytic adrenocortical carcinoma: clinical and immunohistochemical studies. AB - CONTEXT: Oncocytic tumors of the adrenal cortex are rare, mostly nonfunctioning and benign. SETTING: Report virilizing oncocytic adrenocortical carcinoma in a 50 year-old woman. PATIENT: She presented a recent and progressive virilization syndrome, associated with high blood pressure. Hormonal evaluation showed elevated serum testosterone and delta-4-androstenedione levels, normal urinary free cortisol level and incomplete suppression of cortisol at the 1 mg dexamethasone suppression test. CT scan of the abdomen revealed a 35 mm left adrenal mass. INTERVENTION: The patient underwent a left adrenalectomy, and the histological study showed a 3 cm oncocytic adrenocortical carcinoma with signs of malignancy. RESULTS: Immunohistochemical study revealed that tumor cells expressed the steroidogenic enzymes involved into androgen synthesis (3betaHSD and P450c17alpha), P450 aromatase and luteinizing hormone (LH) receptors. Post operatively, signs of virilization improved rapidly, serum testosterone and delta 4-androstenedione levels returned to normal, as did the dexamethasone suppression test. During follow-up CT-scan and 18-FDG PET/CT showed a right ovary mass, corresponding to a follicular cyst associated with hyperthecosis. The patient is alive with no recurrence 48 months after adrenal surgery. CONCLUSION: Oncocytic adrenocortical carcinomas, although extremely rare, should be considered in women with a virilization syndrome. In this woman immunohistochimical studies revealed the presence of steroidogenic enzymes involved into androgen synthesis and aromatization, and LH receptors could be implicated in this pathology. PMID- 26954039 TI - Inaccurate Reporting of Insulin Reimbursement. PMID- 26954036 TI - BRAF inhibitors - do we need to worry about kidney injury? PMID- 26954040 TI - Inaccurate Reporting of Insulin Reimbursement. PMID- 26954042 TI - Discontinuation of Antihypertensive Treatment in Elderly Patients and Cognitive Function. PMID- 26954041 TI - Inaccurate Reporting of Insulin Reimbursement-Reply. PMID- 26954043 TI - Discontinuation of Antihypertensive Treatment in Elderly Patients and Cognitive Function-Reply. PMID- 26954044 TI - Potential Benefits of Computer-Aided Detection for Cancer Identification and Treatment. PMID- 26954045 TI - Discretionary Interpretations of Accountable Care Organization Data. PMID- 26954046 TI - Potential Benefits of Computer-Aided Detection for Cancer Identification and Treatment-Reply. PMID- 26954047 TI - Toxin Immunoassays and Clostridium difficile Infection. PMID- 26954049 TI - Toxin Immunoassays and Clostridium difficile Infection. PMID- 26954048 TI - Discretionary Interpretations of Accountable Care Organization Data-Reply. PMID- 26954050 TI - Toxin Immunoassays and Clostridium difficile Infection. PMID- 26954051 TI - Toxin Immunoassays and Clostridium difficile Infection-Reply. PMID- 26954052 TI - Neuraminidase Inhibitors and Influenza Infection. PMID- 26954054 TI - Neuraminidase Inhibitors and Influenza Infection-Reply. PMID- 26954055 TI - Error in Text. PMID- 26954053 TI - Neuraminidase Inhibitors and Influenza Infection. PMID- 26954056 TI - Error in Reference List. PMID- 26954057 TI - The Role of Physicians in Asylum Evaluation: Documenting Torture and Trauma. PMID- 26954058 TI - HIF repressors under chronic hypoxia. PMID- 26954059 TI - Are there lessons from the cluster of neonatal deaths in Victoria for emergency physicians? PMID- 26954060 TI - Moenomycin Biosynthesis: Structure and Mechanism of Action of the Prenyltransferase MoeN5. AB - The structure of MoeN5, a unique prenyltransferase involved in the biosynthesis of the antibiotic moenomycin, is reported. MoeN5 catalyzes the reaction of geranyl diphosphate (GPP) with the cis-farnesyl group in phosphoglycolipid 5 to form the (C25) moenocinyl-sidechain-containing lipid 7. GPP binds to an allylic site (S1) and aligns well with known S1 inhibitors. Alkyl glycosides, glycolipids, can bind to both S1 and a second site, S2. Long sidechains in S2 are "bent" and co-locate with the homoallylic substrate isopentenyl diphosphate in other prenyltransferases. These observations support a MoeN5 mechanism in which 5 binds to S2 with its C6-C11 group poised to attack C1 in GPP to form the moenocinyl sidechain, with the more distal regions of 5 aligning with the distal glucose in decyl maltoside. The results are of general interest because they provide the first structures of MoeN5 and a structural basis for its mechanism of action, results that will facilitate the design of new antibiotics. PMID- 26954061 TI - Lifetime and 12-Month Nonsuicidal Self-Injury and Academic Performance in College Freshmen. AB - We examined whether nonsuicidal self-injury (NSSI) is associated with academic performance in college freshmen, using census-based web surveys (N = 7,527; response = 65.4%). NSSI was assessed with items from the Self-Injurious Thoughts and Behaviors Interview and subsequently linked with the administratively recorded academic year percentage (AYP). Freshmen with lifetime and 12-month NSSI showed a reduction in AYP of 3.4% and 5.9%, respectively. The college environment was found to moderate the effect of 12-month NSSI, with more strongly reduced AYPs in departments with higher-than-average mean departmental AYPs. The findings suggest that overall stress and test anxiety are underlying processes between NSSI membership and academic performance. PMID- 26954062 TI - Correction: Mitochondrial Dysfunction Plus High-Sugar Diet Provokes a Metabolic Crisis That Inhibits Growth. PMID- 26954063 TI - Construction of Vicinal Quaternary Stereogenic Centers by Enantioselective Direct Mannich-Type Reaction Using a Chiral Bis(guanidino)iminophosphorane Catalyst. AB - A novel asymmetric direct Mannich-type reaction of alpha-iminophenylacetate esters with thionolactones, bearing a substituent at the alpha-position, as a less acidic pronucleophile was developed. Using bis(guanidino)iminophosphorane as the chiral organosuperbase catalyst, the reaction afforded densely functionalized amino-acid derivatives having vicinal quaternary stereogenic centers, one of which is an all-carbon quaternary stereogenic center, in good yield with high diastereo- and enantioselectivities. PMID- 26954064 TI - Transition from Reconstruction toward Thin Film on the (110) Surface of Strontium Titanate. AB - The surfaces of metal oxides often are reconstructed with a geometry and composition that is considerably different from a simple termination of the bulk. Such structures can also be viewed as ultrathin films, epitaxed on a substrate. Here, the reconstructions of the SrTiO3 (110) surface are studied combining scanning tunneling microscopy (STM), transmission electron diffraction, and X-ray absorption spectroscopy (XAS), and analyzed with density functional theory calculations. Whereas SrTiO3 (110) invariably terminates with an overlayer of titania, with increasing density its structure switches from n * 1 to 2 * n. At the same time the coordination of the Ti atoms changes from a network of corner sharing tetrahedra to a double layer of edge-shared octahedra with bridging units of octahedrally coordinated strontium. This transition from the n * 1 to 2 * n reconstructions is a transition from a pseudomorphically stabilized tetrahedral network toward an octahedral titania thin film with stress-relief from octahedral strontia units at the surface. PMID- 26954065 TI - A de novo frameshift in HNRNPK causing a Kabuki-like syndrome with nodular heterotopia. AB - Kabuki syndrome is a heterogeneous condition characterized by distinctive facial features, intellectual disability, growth retardation, skeletal abnormalities and a range of organ malformations. Although at least two major causative genes have been identified, these do not explain all cases. Here we describe a patient with a complex Kabuki-like syndrome that included nodular heterotopia, in whom testing for several single-gene disorders had proved negative. Exome sequencing uncovered a de novo c.931_932insTT variant in HNRNPK (heterogeneous nuclear ribonucleoprotein K). Although this variant was identified in March 2012, its clinical relevance could only be confirmed following the August 2015 publication of two cases with HNRNPK mutations and an overlapping phenotype that included intellectual disability, distinctive facial dysmorphism and skeletal/connective tissue abnormalities. Whilst we had attempted (unsuccessfully) to identify additional cases through existing collaborators, the two published cases were 'matched' using GeneMatcher, a web-based tool for connecting researchers and clinicians working on identical genes. Our report therefore exemplifies the importance of such online tools in clinical genetics research and the benefits of periodically reviewing cases with variants of unproven significance. Our study also suggests that loss of function variants in HNRNPK should be considered as a molecular basis for patients with Kabuki-like syndrome. PMID- 26954066 TI - Mechanisms for 1,3-Dichloropropene Dissipation in Biochar-Amended Soils. AB - Biochar, which is organic material heated under a limited supply of oxygen, has the potential to reduce fumigant emissions when incorporated in the soil, but the mechanisms are not fully understood. The objective of this study was to determine the effects of biochar properties, amendment rate, soil microbe, moisture, temperature, and soil type on the fate of 1,3-dichloropropene (1,3-D) isomers in laboratory incubation experiments by assessing the 1,3-D degradation rate and adsorption capacity. 1,3-D dissipation rates were significantly reduced due to strong adsorption by biochar, which was also strongly affected by biochar type. Following a 1% biochar amendment, the half-lives of 1,3-D in soil were increased 2.5-35 times. The half-lives of 1,3-D in soil were strongly affected by soil moisture, temperature, and amendment rate. The effects of sterilization on 1,3-D degradation were much smaller in biochar-amended soils than in nonsterilized soils, which suggests the importance of abiotic pathways with biochar's presence. Dissipation of 1,3-D in biochar was divided into adsorption (49-93%) and chemical degradation pathways. Biochar properties, such as specific surface area (SSA), pH, water content, carbon content, and feedstock, all appeared to affect 1,3-D dissipation with potentially complex interactions. The biochar (air-dry) water content was highly correlated with 1,3-D adsorption capacity and thus can serve as an important predictor for fumigant mitigation use. The fate of the adsorbed fumigant onto biochar requires further examination on potential long-term environmental impacts before guidelines for biochar as a field practice to control fumigant emissions can be formulated. PMID- 26954068 TI - Innovative Soaking and Grinding Methods and Cooking Affect the Retention of Isoflavones, Antioxidant and Antiproliferative Properties in Soymilk Prepared from Black Soybean. AB - This study's objective was to characterize the effect of traditional and 3 newly devised (soaking+grinding) methods combined with cooking on the content and composition of phenolic substances, antioxidant, and antiproliferative properties of soymilk prepared from black soybean. Phenolic substances and antioxidant profile were characterized and antiproliferation of prostate cancer DU145 cells was conducted using a cell culture assay. Results indicated Grinding Method 4 produced significantly (P < 0.05) higher total phenolic content (TPC), total flavonoid content (TFC), condensed tannin content (CTC), and total isoflavone content in both raw and cooked black soymilk as compared to Method 1. Cooking soymilk reduced 23% to 38% of total phenolic substances. Raw black soymilk produced by Method 4 displayed the highest antioxidant capability, which was determined using ORAC, FRAP, and DPPH assays, and a higher antiprostate cell proliferation ability. Cooking only slightly reduced the potency to inhibit DU145 prostate cancer cells as IC50 value was increased from the average of about 4.0 mg/mL of raw soymilk extracts to 5.5 mg/mL of cooked soymilk extracts of all grinding methods. Overall, total isoflavone content was the only component that was negatively correlated with IC50 value (r = -0.93, P < 0.05) which indicates the ability to inhibit prostate cancer cell is associated with the increase in total isoflavone content, not with any other phenolic substances or antioxidant properties. PMID- 26954067 TI - Neurovascular Interface in Porcine Small Intestine: Specific for Nitrergic rather than Nonnitrergic Neurons. AB - In the 1970s, by using classic histological methods, close topographical relationships between special areas of enteric ganglia and capillaries were shown in the pig. In this study, by application of double and triple immunohistochemistry, we confirmed this neurovascular interface and demonstrated that these zones are mainly confined to nitrergic neurons in the myenteric and the external submucosal plexus. In the upper small intestine of the pig, the respective neurons display type III morphology, i.e. they have long, slender and branched dendrites and a single axon. In another set of experiments, we prepared specimens for electron-microscopical analysis of these zones. Both ganglia and capillaries display continuous basement membranes, the smallest distances between them being 1,000 nm at the myenteric and 300 nm at the external submucosal level. The capillary endothelium was mostly continuous but, at the external submucosal level, scattered fenestrations were observed. This particular neurovascular relationship suggests that nitrergic neurons may require a greater amount of oxygen and/or nutrients. In guinea pig and mouse, previous ischemia/reperfusion experiments showed that nitrergic neurons are selectively damaged. Thus, a preferential blood supply of enteric nitrergic neurons may indicate that these neurons are more vulnerable in ischemia. PMID- 26954069 TI - Association between VEGF-A, C and D expression and lymph node involvement in breast cancer: a meta-analysis. AB - BACKGROUND: Metastasis is the primary cause of death in patients with breast cancer. Although VEGF-A, C and D are considered to be prime factors in lymph node metastasis in breast cancer, the published studies have conflicting conclusions. METHODS: To resolve this conflict, we conducted a meta-analysis of 37 studies (n = 5,001 patients) evaluating the correlation between VEGF-A, C and D immunohistochemical expression and lymph node metastasis (LNM). The meta-analysis included 22 studies of VEGF-A, 17 of VEGF-C, and 6 of VEGF-D. The relationships between VEGF-A, C and D and clinicopathological parameters were also examined. RESULTS: The results showed a significant association between VEGF-A or VEGF-C overexpression and LNM (risk ratio [RR] = 1.28 [95% CI 1.04-1.58], p = 0.02; and RR = 1.36 [95% CI 1.07-1.72], p = 0.01, respectively). Subgroup evaluation showed a significant association between VEGF-A, C and D overexpression and LNM when analyses were limited to Asian patients (RR = 1.78 [95% CI 1.28-2.46], p = 0.0005; RR = 1.38 [95% CI 1.04-1.84], p = 0.03, and RR = 2.62 [95% CI 1.35-5.09], p = 0.004, respectively). VEGF-A overexpression was significantly associated with lymph vessel invasion (RR = 1.86 [95% CI 1.33-2.60], p = 0.0003). Overexpression of VEGF-C or VEGF-D was significantly associated with HER-2 positivity (RR = 1.30 [95% CI 1.06-1.59], p = 0.01; and RR = 1.75 [95% CI 1.01-3.03], p = 0.05, respectively). CONCLUSIONS: With some limitations, our meta-analysis indicated that VEGF-A and C could predict LNM in patients with breast cancer, particularly Asian patients. PMID- 26954070 TI - Polymorphisms in cancer susceptibility genes XRCC1, RAD51 and TP53 and the risk of breast cancer in Serbian women. AB - BACKGROUND: Thanks to immense improvements in technology over the past few decades, we have witnessed a major shift towards the idea that breast cancer results from a combined effect of multiple common alleles conferring low risk. This study investigates the role of 3 nonsynonymous SNPs in the DNA repair genes XRCC1 (R399Q), RAD51 (G135C) and TP53 (Arg72Pro) in breast cancer in Serbian women. PATIENTS AND METHODS: Cases of BRCA1/2-negative hereditary breast cancer (n = 52), sporadic breast cancer (n = 106) and age-matched cancer-free female controls (n = 104) were obtained from the Institute for Oncology and Radiology of Serbia's blood bank. Restriction fragment length polymorphism analysis was used for genotyping. Descriptive analyses included genotype and allelic frequencies; the odds ratio and 95% confidence interval were calculated as an estimate of the relative risk. RESULTS: A significant difference in QQ+RQ versus RR genotype distribution of XRCC1 was observed between hereditary breast cancer patients and cancer-free controls. The association was confirmed among young breast cancer patients from these high-risk families. The existence of 3 recessive alleles in the RAD51 and XRCC1 genotype combination showed an association with hereditary breast cancer. Odds ratio analysis indicated a strong protective role of the RAD51 GG + TP53 ArgArg + XRCC1 RR combined genotype against hereditary breast cancer negative for BRCA1/2 mutations. CONCLUSIONS: The XRCC1 R399Q polymorphism showed an association with increased breast cancer risk in Serbia, especially in the hereditary form of the disease and in young breast cancer patients. Dominant alleles of RAD51, TP53 and XRCC1 combined genotypes indicated a strong protective role against hereditary breast cancer. PMID- 26954071 TI - CYP17A1 polymorphisms and clinical outcome of castration-resistant prostate cancer patients treated with abiraterone. AB - BACKGROUND: We evaluated the role of single nucleotide polymorphisms in the CYP17A1 gene for predicting clinical outcome in castration-resistant prostate cancer (CRPC) patients treated with abiraterone. METHODS: Sixty-four patients were genotyped for the selected polymorphisms (rs743572, rs10883783, rs17115100 and rs284849) in CYP17A1. We hypothesized that different genotypes could be associated with progression-free survival (PFS) and overall survival (OS). RESULTS: Statistical analyses highlighted no significant associations between these polymorphisms and clinical outcome. However, individuals with the most common TT genotype for rs10883783 had a 3 months' longer PFS than individuals with the TA + AA genotype. CONCLUSIONS: With the limitation of the retrospective study design and the small sample size, the analyzed polymorphisms do not seem to be correlated with clinical outcome of CRPC patients treated with abiraterone. PMID- 26954072 TI - Evaluating serum insulin-like growth factor 1 and insulin-like growth factor binding protein 3 as markers in prostate cancer diagnosis. AB - BACKGROUND: Prostate-specific antigen (PSA) lacks specificity and sensitivity in discriminating prostate cancer (PCa) from benign prostatic hyperplasia (BPH) when the total PSA (tPSA) level is between 4 and 10 ng/mL. It remains to be investigated if additional tumor-associated molecules may improve the PCa diagnostic accuracy. The aim of the present study was to investigate whether serum levels of insulin-like growth factor 1 (IGF1), insulin-like growth factor binding protein 3 (IGFBP3) and their combinations with PSA may enhance the diagnosis of PCa. METHODS: Serum tPSA and free PSA (fPSA) levels were measured using an automated chemiluminescence-based method. IGF1 and IGFBP3 levels were evaluated by radioimmunoassays in a prospectively and consecutively enrolled subset of 149 patients with tPSA <=10 ng/mL made up of patients with benign prostatic hyperplasia (BPH; n = 113) and PCa (n = 36). RESULTS: IGF1 and IGFBP3 serum levels did not significantly differ between the PCa and BPH groups. No important correlation was found between the IGF molecules and PSA isoforms in both groups. Statistical analysis of the combination of markers indicated that only the free/total PSA ratio (f/tPSA%) was informative and independent in predicting the presence of PCa, considering that for high values of this percentage (17%) the probability of finding PCa decreased. Receiver operating characteristics areas under the curve (AUC) for IGF1 and IGFBP3 were not informative (AUC ~0.5 in both cases) contrary to the AUC for f/tPSA% (AUC = 0.689, p = 0.0002). CONCLUSIONS: The present study showed that neither IGF1 and IGFBP3 alone nor in combination with PSA enhance the diagnostic performance of PSA in PCa. PMID- 26954073 TI - MicroRNAs as noninvasive biomarkers in bladder cancer detection: a diagnostic meta-analysis based on qRT-PCR data. AB - OBJECTIVE: As the diagnostic significance of microRNAs (miRNAs) in the detection of bladder cancer is controversial, we aimed to perform a meta-analysis to comprehensively assess the diagnostic value of miRNAs in blood and urine for detecting bladder cancer. METHODS: A systematic literature search of public databases was conducted to obtain qualified studies. Sensitivity was utilized to plot the summary receiver operator characteristic (SROC) curve against specificity and the area under the SROC curve (AUC) was generated to evaluate the pooled diagnostic efficiency. Subgroup analyses and meta-regression were applied to investigate the underlying sources of heterogeneity. The STATA 12.0 software was used to perform all statistic analyses. RESULTS: A total of 58 studies from 22 articles comprising 4,558 bladder cancer patients and 4,456 controls were included in our meta-analysis. MiRNAs in blood and urine manifested relatively good diagnostic efficiency in detecting bladder cancer, with a sensitivity of 0.74, a specificity of 0.78, and an AUC of 0.83. Multiple-miRNA assays were more accurate than single-miRNA ones in bladder cancer diagnosis. Blood-based miRNA assays displayed better diagnostic performance than urine-based ones. In addition, miRNAs showed reduced diagnostic value in bladder cancer among Caucasians compared with Asians. CONCLUSIONS: MiRNAs in blood and urine, especially the combination of multiple miRNAs, may serve as hopeful noninvasive biomarkers for early diagnosis of bladder cancer. Further extensive prospective research is needed to verify their clinical significance in bladder cancer diagnosis. PMID- 26954074 TI - Growth Assisted by Glancing Angle Deposition: A New Technique to Fabricate Highly Porous Anisotropic Thin Films. AB - We report a new methodology based on glancing angle deposition (GLAD) of an organic molecule in combination with perpendicular growth of a second inorganic material. The resulting thin films retain a very well-defined tilted columnar microstructure characteristic of GLAD with the inorganic material embedded inside the columns. We refer to this new methodology as growth assisted by glancing angle deposition or GAGLAD, since the material of interest (here, the inorganic) grows in the form of tilted columns, though it is deposited under a nonglancing configuration. As a "proof of concept", we have used silver and zinc oxide as the perpendicularly deposited material since they usually form ill-defined columnar microstructures at room temperature by GLAD. By means of our GAGLAD methodology, the typical tilted columnar microstructure can be developed for materials that otherwise do not form ordered structures under conventional GLAD. This simple methodology broadens significantly the range of materials where control of the microstructure can be achieved by tuning the geometrical deposition parameters. The two examples presented here, Ag/Alq3 and ZnO/Alq3, have been deposited by physical vapor deposition (PVD) and plasma enhanced chemical vapor deposition (PECVD), respectively: two different vacuum techniques that illustrate the generality of the proposed technique. The two type of hybrid samples present very interesting properties that demonstrate the potentiality of GAGLAD. On one hand, the Ag/Alq3 samples present highly optical anisotropic properties when they are analyzed with linearly polarized light. To our knowledge, these Ag/Alq3 samples present the highest angular selectivity reported in the visible range. On the other hand, ZnO/Alq3 samples are used to develop highly porous ZnO thin films by using Alq3 as sacrificial material. In this way, antireflective ZnO samples with very low refractive index and extinction coefficient have been obtained. PMID- 26954075 TI - Facile Fabrication of Water Dispersible Latex Particles with Homogeneous or Chain Segregated Surface from RAFT Polymerization Using a Mixture of Two Macromolecular Chain Transfer Agents. AB - Water dispersible latex particles with randomly mixed shells or chain segregated surface are synthesized from one-pot reversible addition-fragmentation chain transfer heterogeneous polymerization of benzyl methacrylate (BzMA) using a mixture of poly(glycerol monomethacrylate) (PGMA) and poly(2,3 bis(succinyloxy)propyl methacrylate) (PBSPMA) macromolecular chain transfer agents. In methanol, the two in situ synthesized PGMA-b-PBzMA and PBSPMA-b-PBzMA diblock copolymers coaggregate into spherical micelles, which contain PBzMA core and discrete PGMA and PBSPMA nanodomains on the shell. In contrast, in water methanol mixture (V/V = 9/1), latex particles with homogeneous distribution of PGMA and PBSPMA polymer chains on the shell are obtained. The reasons leading to formation of latex particles with homogenous or chain-segregated surface are discussed, and polymerization kinetics and physical state of PBSPMA in methanol and water-methanol mixtures are ascribed. These polymeric micelles with patterned functional group on the surface are potentially important for application in supracolloidal hierarchical assemblies and catalysis. PMID- 26954076 TI - Research activities to improve the utilization of antibiotics in Africa. AB - There is a need to improve the rational use of antibiotics across continents including Africa. This has resulted in initiatives in Botswana including treatment guidelines and the instigation of Antibiotic Stewardship Programs (ASPs). The next steps involve a greater understanding of current antibiotic utilization and resistance patterns (AMR). This resulted in a 2-day meeting involving key stakeholders principally from Botswana to discuss key issues including AMR rates as well as ASPs in both the public and private sectors. Following this, the findings will be used to plan future studies across Africa including point prevalence studies. The findings will be presented in July 2016 at the next Medicines Utilization Research in Africa meeting will ideally serve as a basis for planning future pertinent interventional studies to enhance the rational use of antibiotics in Botswana and wider. PMID- 26954079 TI - The Unstated Murphy's Law of the Operating Room: If Something Goes Wrong, Blame Anesthesia. PMID- 26954080 TI - Editorial Comment: Manufacturer's Response. PMID- 26954078 TI - Intravirion cohesion of matrix protein M1 with ribonucleocapsid is a prerequisite of influenza virus infectivity. AB - Influenza virus has two major structural modules, an external lipid envelope and an internal ribonucleocapsid containing the genomic RNA in the form of the ribonucleoprotein (RNP) complex, both of which are interlinked by the matrix protein M1. Here we studied M1-RNP cohesion within virus exposed to acidic pH in vitro. The effect of acidification was dependent on the cleavage of the surface glycoprotein HA. Acidic pH caused a loss of intravirion RNP-M1 cohesion and activated RNP polymerase activity in virus with cleaved HA (HA1/2) but not in the uncleaved (HA0) virus. The in vitro acidified HA1/2 virus rapidly lost infectivity whereas the HA0 one retained infectivity, following activation by trypsin, suggesting that premature activation and release of the RNP is detrimental to viral infectivity. Rimantadine, an inhibitor of the M2 ion channel, was found to protect the HA1/2 virus interior against acidic disintegration, confirming that M2-dependent proton translocation is essential for the intravirion RNP release and suggesting that the M2 ion channel is only active in virions with cleaved HA. Acidic treatment of both HA0 and HA1/2 influenza viruses induces formation of spikeless bleb-like protrusion of ~ 25 nm in diameter on the surface of the virion, though only the HA1/2 virus was permeable to protons and permitted RNP release. It is likely that this bleb corresponds to the M2-enriched and M1-depleted focus arising from pinching off of the virus during the completion of budding. Cooperatively, the data suggest that the influenza virus has an asymmetric structure where the M1-mediated organization of the RNP inside the virion is a prerequisite for infectious entry into target cell. PMID- 26954081 TI - Shifting Goals in Operating Room Management. PMID- 26954082 TI - Superelastic, superabsorbent and 3D nanofiber-assembled scaffold for tissue engineering. AB - Fabrication of 3D scaffold to mimic the nanofibrous structure of the nature extracellular matrix (ECM) with appropriate mechanical properties and excellent biocompatibility, remain an important technical challenge in tissue engineering. The present study reports the strategy to fabricate a 3D nanofibrous scaffold with similar structure to collagen in ECM by combining electrospinning and freeze drying technique. With the technique reported here, a nanofibrous structure scaffold with hydrophilic and superabsorbent properties can be readily prepared by Gelatin and Polylactic acid (PLA). In wet state the scaffold also shows a super-elastic property, which could bear a compressive strain as high as 80% and recovers its original shape afterwards. Moreover, after 6 days of culture, L-929 cells grow, proliferate and infiltrated into the scaffold. The results suggest that this 3D nanofibrous scaffold would be promising for varied field of tissue engineering application. PMID- 26954083 TI - Orientating lipase molecules through surface chemical control for enhanced activity: A QCM-D and ToF-SIMS investigation. AB - Bio-active materials consisting of lipase encapsulated within porous silica particles were engineered to control the adsorption kinetics and molecular orientation of lipase, which play critical roles in the digestion kinetics of triglycerides. The adsorption kinetics of Candida antartica lipase A (CalA) was monitored using quartz crystal microbalance with dissipation (QCM-D) and controlled by altering the hydrophobicity of a silica binding support. The extent of adsorption was 2-fold greater when CalA was adsorbed onto hydrophobic silica compared to hydrophilic silica. Time-of-flight secondary ion mass spectrometry (ToF-SIMS) fragmentation patterns, in conjunction with multivariate statistics, demonstrated enhanced exposure of the lipase's catalytic domain, specifically the histidine group responsible for activity, when CalA was adsorbed on hydrophilic silica. Consequently, lipid digestion kinetics were enhanced when CalA was loaded in hydrophilic porous silica particles, i.e., a 2-fold increase in the pseudo first-order rate constant for digestion when compared to free lipase. In contrast, digestion kinetics were inhibited when CalA was hosted in hydrophobic porous silica, i.e., a 5-fold decrease in pseudo-first-order rate constant for digestion when compared to free lipase. These findings provide valuable insights into the mechanism of lipase action which can be exploited to develop smarter food and drug delivery systems consisting of porous lipid-based materials. PMID- 26954084 TI - Enhanced cellular uptake of protoporphyrine IX/linolenic acid-conjugated spherical nanohybrids for photodynamic therapy. AB - Protoporphyrin IX (PpIX) has wide applications in photodynamic diagnosis and photodynamic therapy (PDT) in many human diseases. However, poor water solubility and cancer cell localization limit its direct application for PDT. We improved the water-solubility and cellular internalization of PpIX to enhance PDT efficacy by developing biocompatible PpIX/linolenic acid-conjugated polyhedral oligomeric silsesquioxane (PPLA) nanohybrids. The resulting PPLA nanohybrids exhibited a quasi-spherical shape with a size of <200nm. (1)H NMR analysis confirmed the synthesis of PPLA. The singlet oxygen formation of PPLA nanohybrids on laser irradiation was detected by photoluminescence emission. Fluorescence-activated cell sorting (FACS) analysis displayed higher cellular internalization of PPLA compared with free PpIX. In addition, PPLA nanohybrids exhibited significantly reduced dark-toxicity and a high phototoxicity mostly because of apoptotic cell death against human gastric cancer cells. These results imply that the PPLA nanohybrid system may be applicable in PDT. PMID- 26954085 TI - Enhanced osteogenic activity of poly ether ether ketone using calcium plasma immersion ion implantation. AB - As a promising implantable material, poly ether ether ketone (PEEK) possesses similar elastic modulus to that of cortical bones yet suffers from bio-inertness and poor osteogenic properties, which limits its application as orthopedic implants. In this work, calcium is introduced onto PEEK surface using calcium plasma immersion ion implantation (Ca-PIII). The results obtained from scanning electron microscopy (SEM) and X-ray photoelectron spectroscopy (XPS) confirm the modified layer with varying contents of calcium are formed on PEEK surfaces. Water contact angle measurements reveal the increasing hydrophobicity of both Ca PIII treated surfaces. In vitro cell adhesion, viability assay, alkaline phosphatase activity and collagen secretion analyses disclose improved the adhesion, proliferation, and osteo-differentiation of rat bone mesenchymal stem cells (bMSCs) on Ca-PIII treated surfaces. The obtained results indicate that PEEK surface with enhanced osteogenic activity can be produced by calcium incorporation. PMID- 26954086 TI - The use of zeta potential as a tool to study phase transitions in binary phosphatidylcholines mixtures. AB - Temperature dependence of the zeta potential (ZP) is proposed as a tool to analyze the thermotropic behavior of unilamellar liposomes prepared from binary mixtures of phosphatidylcholines in the absence or presence of ions in aqueous suspensions. Since the lipid phase transition influences the surface potential of the liposome reflecting a sharp change in the ZP during the transition, it is proposed as a screening method for transition temperatures in complex systems, given its high sensitivity and small amount of sample required, that is, 70% less than that required in the use of conventional calorimeters. The sensitivity is also reflected in the pre-transition detection in the presence of ions. Plots of phase boundaries for these mixed-lipid vesicles were constructed by plotting the delimiting temperatures of both main phase transition and pre-transition vs. the lipid composition of the vesicle. Differential scanning calorimetry (DSC) studies, although subject to uncertainties in interpretation due to broad bands in lipid mixtures, allowed the validation of the temperature dependence of the ZP method for determining the phase transition and pre-transition temperatures. The system chosen was dipalmitoylphosphatidylcholine/dimyristoyl phosphatidylcholine (DMPC/DPPC), the most common combination in biological membranes. This work may be considered as a starting point for further research into more complex lipid mixtures with functional biological importance. PMID- 26954087 TI - Sapindus saponins' impact on hydrocarbon biodegradation by bacteria strains after short- and long-term contact with pollutant. AB - The introduction of high toxicity petroleum contaminants to the natural environment causes damage to ecosystems and the aesthetics of the surroundings. Therefore it is critical to enhance microbial community performance to manage the degradation process. This paper analyses the effect of natural surfactants from the tree Sapindus mukorossi on biodegradation of hydrocarbons. Analysis of cell surface hydrophobicity and zeta potential confirmed effective modifications of the cell surface parameters essential for the bioavailability of contaminants to microorganisms. Interestingly, favorable differences were observed only for microorganisms from non-contaminated soil. There was also recorded an increase in diesel oil biodegradation to 41% for Sphingomonas sp. and 56% for Pseudomonas alcaligenes on addition of 100mgL(-1) of Sapindus saponins. The addition of natural surfactants has no significant impact on bacterial strains isolated from long-term contaminated soil. This research demonstrates that the addition of Sapindus extract could be a useful tool to improve the effectiveness of microbial degradation of hydrocarbon pollutants by environmental strains in recently contaminated. PMID- 26954088 TI - Delivery of fluorophores by calcium phosphate-coated nanoliposomes and interaction with Staphylococcus aureus biofilms. AB - The delivery capacity and mechanical stability of calcium phosphate (CaP) coated 1,2-dioleoyl-sn-glycero-3-phosphate (DOPA) liposomes free and adsorbed on bacterial surface was investigated introducing either acridine orange (AO) or 5,10,15,20-Tetrakis(1-methyl-4-pyridinio)porphyrin (TMP) in the aqueous core of the liposomes. The obtained nanomaterials were thoroughly characterized by electron and optical microscopy and by fluorescence techniques. Distribution of the AO and TMP molecules between the aqueous liposomes core and the outer solution was demonstrated by the band shifts and broadening of the excitation emission matrices and the modified Stern-Volmer model for fluorescence quenching. In aqueous suspensions, c.a. 40% of AO was released to the outer solution while only a small percentage of TMP was observed to reach the outer liposome surface. The nanoliposomes adhesion capacity and the leaking of fluorophore molecules to Staphylococcus aureus (S. aureus) biofilms were further evaluated. A close interaction between liposomes and S. aureus biofilm was evidenced by TEM and SEM imaging. Epifluorescence experiments demonstrated that CaP-coated liposomes have good biofilm staining capability after two hours incubation of the biofilms with the liposomes, thus supporting an important release of the fluorophores when in contact with the biofilm. Altogether, the obtained results strongly suggest that CaP-coated liposomes are capable of activating drug release when in presence of S. aureus biofilms and smears. The studies herein presented, indicate that CaP coated liposomes are potential vehicles for the selective delivery of drugs to S. aureus biofilms, as is the case of the singlet oxygen photosensitizer TMP, a well known photodynamic antibacterial agent. PMID- 26954089 TI - Polyamine/salt-assembled microspheres coated with hyaluronic acid for targeting and pH sensing. AB - The poly(allylamine hydrochloride)/trisodium citrate aggregates were fabricated and further covalently crosslinked via the coupling reaction of carboxylic sites on trisodium citrate with the amine groups on polyamine, onto which poly-L-lysine and hyaluronic acid were sequentially assembled, forming stable microspheres. The pH sensitive dye and pH insensitive dye were further labeled to enable the microspheres with pH sensing property. Moreover, these microspheres could be specifically targeted to HeLa tumor cells, since hyaluronic acid can specifically recognize and bind to CD44, a receptor overexpressed on many tumor cells. Quantitative pH measurement by confocal laser scanning microscopy demonstrated that the microspheres were internalized into HeLa cells, and accumulated in acidic compartments. By contrast, only a few microspheres were adhered on the NIH 3T3 cells surface. The microspheres with combined pH sensing property and targeting ability can enhance the insight understanding of the targeted drug vehicles trafficking after cellular internalization. PMID- 26954090 TI - The influence of hyaluronan on the structure of a DPPC-bilayer under high pressures. AB - The superior lubrication properties of synovial joints have inspired many studies aiming at uncovering the molecular mechanisms which give rise to low friction and wear. However, the mechanisms are not fully understood yet, and, in particular, it has not been elucidated how the biolubricants present at the interface of cartilage respond to high pressures, which arise during high loads of joints. In this study we utilize a simple model system composed of two biomolecules that have been implied as being important for joint lubrication. It consists of a solid supported dipalmitoylphosphatidylcholin (DPPC) bilayer, which was formed via vesicles fusion on a flat Si wafer, and the anionic polysaccharide hyaluronan (HA). We first characterized the structure of the HA layer that adsorbed to the DPPC bilayers at ambient pressure and different temperatures using X-ray reflectivity (XRR) measurements. Next, XRR was utilized to evaluate the response of the system to high hydrostatic pressures, up to 2kbar (200MPa), at three different temperatures. By means of fluorescence microscopy images the distribution of DPPC and HA on the surface was visualized. Our data suggest that HA adsorbs to the headgroup region that is oriented towards the water side of the supported bilayer. Phase transitions of the bilayer in response to temperature and pressure changes were also observed in presence and absence of HA. Our results reveal a higher stability against high hydrostatic pressures for DPPC/HA composite layers compared to that of the DPPC bilayer in absence of HA. PMID- 26954094 TI - Quality Improvement Initiatives: The Way to Go to Increase Breastfeeding Success. PMID- 26954091 TI - The Oryza sativa Regulator HDR1 Associates with the Kinase OsK4 to Control Photoperiodic Flowering. AB - Rice is a facultative short-day plant (SDP), and the regulatory pathways for flowering time are conserved, but functionally modified, in Arabidopsis and rice. Heading date 1 (Hd1), an ortholog of Arabidopsis CONSTANS (CO), is a key regulator that suppresses flowering under long-day conditions (LDs), but promotes flowering under short-day conditions (SDs) by influencing the expression of the florigen gene Heading date 3a (Hd3a). Another key regulator, Early heading date 1 (Ehd1), is an evolutionarily unique gene with no orthologs in Arabidopsis, which acts as a flowering activator under both SD and LD by promoting the rice florigen genes Hd3a and RICE FLOWERING LOCUST 1 (RFT1). Here, we report the isolation and characterization of the flowering regulator Heading Date Repressor1 (HDR1) in rice. The hdr1 mutant exhibits an early flowering phenotype under natural LD in a paddy field in Beijing, China (39 degrees 54'N, 116 degrees 23'E), as well as under LD but not SD in a growth chamber, indicating that HDR1 may functionally regulate flowering time via the photoperiod-dependent pathway. HDR1 encodes a nuclear protein that is most active in leaves and floral organs and exhibits a typical diurnal expression pattern. We determined that HDR1 is a novel suppressor of flowering that upregulates Hd1 and downregulates Ehd1, leading to the downregulation of Hd3a and RFT1 under LDs. We have further identified an HDR1 interacting kinase, OsK4, another suppressor of rice flowering under LDs. OsK4 acts similarly to HDR1, suppressing flowering by upregulating Hd1 and downregulating Ehd1 under LDs, and OsK4 can phosphorylate HD1 with HDR1 presents. These results collectively reveal the transcriptional regulators of Hd1 for the day-length-dependent control of flowering time in rice. PMID- 26954095 TI - Sinuleptolide inhibits proliferation of oral cancer Ca9-22 cells involving apoptosis, oxidative stress, and DNA damage. AB - OBJECTIVE: Sinuleptolide, a soft corals-derived bioactive norditerpenoid, is a marine natural product with a potent anti-inflammatory effect. We evaluate the potential anti-oral cancer effects of sinuleptolide and investigate the possible mechanisms involved. DESIGNS: Cell viability, cell cycle, apoptosis, reactive oxygen species (ROS), mitochondrial membrane potential (MMP), and DNA damage analyses were performed. RESULTS: In a cell viability assay, we found that sinuleptolide is dose-responsively antiproliferative against oral gingival cancer Ca9-22 cells but less harmful to normal human gingival fibroblast (HGF-1) cells (P<0.001). In cell cycle analysis, sinuleptolide induced subG1 accumulation at a higher dose and led to G2/M arrest of Ca9-22 cells (P<0.005). Apoptosis was significantly increased in sinuleptolide-treated Ca9-22 cells based on annexin V and poly(ADP-ribose) polymerase (PARP) expressions (P<0.05-0.0001). Based on flow cytometer analysis, sinuleptolide also induced the generation of ROS and decreased MMP in a dose-responsive manner (P<0.05-0.0001). DNA damage increased dose-responsively after sinuleptolide treatments (P < 0.001) based on comet and gammaH2AX assays. CONCLUSION: Sinuleptolide can induce an antiproliferation of oral cancer Ca9-22 cells involving apoptosis, oxidative stress and DNA damage, suggesting that sinuleptolide represents a potential chemotherapeutic drug for oral cancer treatment. PMID- 26954096 TI - Comparison of proliferation, apoptosis and expression of syndecan-1 and alpha-SMA in edentulous ridge oral mucosa of successful and early failed submerged dental implants--An immunohistochemical study. AB - AIMS: Pathogenic mechanisms involved in early submerged implant failure are poorly understood. In this study we immunohistochemically analyse differences in proliferation, apoptosis and inflammation in edentulous ridge oral mucosa (ERM) of successful and early failed submerged implants. MATERIALS AND METHODS: 30 samples of ERM covering successful and early failed submerged implants were obtained at the end of osseointegration period along with control samples of healthy ERM. Sections were stained with Ki-67 (proliferation), caspase-3 (apoptosis) and syndecan-1 (epithelial marker). Percentage of positive cells was analysed by Kruskal-Wallis test and Dunn's post hoc test. Co-localization of Ki 67 and caspase-3 with alpha-SMA, CD68 and TGF-beta was done by double immunofluorescence. RESULTS: There was no significant difference in number of Ki 67 positive cells within surface epithelium (SE) in all groups. Proliferation was significantly higher in underlying connective tissue (UCT) of ERM of early failed submerged implants (26%) compared to ERM of successful submerged implants (3%) and controls (4%). More apoptotic cells appeared in UCT of early failed submerged implants (8%) compared to UCT of successful submerged implants (4%) and UCT of control ERM (3%). Co-localization of Ki-67 and alpha-SMA in ERM of early failed submerged implants disclosed proliferating fibroblasts and pericytes of blood vessels. Macrophages and cells expressing TGF-beta appeared in UCT of failed implants. Expression of syndecan-1 was significantly weaker in SE of early failed submerged implants. CONCLUSIONS: Imbalance between proliferation and apoptosis, changes in syndecan-1 expression and inflammation are histopathological features of ERM of early failed submerged implants. PMID- 26954098 TI - Theory of Phase Separation and Polarization for Pure Ionic Liquids. AB - Room temperature ionic liquids are attractive to numerous applications and particularly, to renewable energy devices. As solvent free electrolytes, they demonstrate a paramount connection between the material morphology and Coulombic interactions: the electrode/RTIL interface is believed to be a product of both polarization and spatiotemporal bulk properties. Yet, theoretical studies have dealt almost exclusively with independent models of morphology and electrokinetics. Introduction of a distinct Cahn-Hilliard-Poisson type mean-field framework for pure molten salts (i.e., in the absence of any neutral component), allows a systematic coupling between morphological evolution and the electrokinetic phenomena, such as transient currents. Specifically, linear analysis shows that spatially periodic patterns form via a finite wavenumber instability and numerical simulations demonstrate that while labyrinthine type patterns develop in the bulk, lamellar structures are favored near charged surfaces. The results demonstrate a qualitative phenomenology that is observed empirically and thus, provide a physically consistent methodology to incorporate phase separation properties into an electrochemical framework. PMID- 26954097 TI - Experimental evidence for compositional syntax in bird calls. AB - Human language can express limitless meanings from a finite set of words based on combinatorial rules (i.e., compositional syntax). Although animal vocalizations may be comprised of different basic elements (notes), it remains unknown whether compositional syntax has also evolved in animals. Here we report the first experimental evidence for compositional syntax in a wild animal species, the Japanese great tit (Parus minor). Tits have over ten different notes in their vocal repertoire and use them either solely or in combination with other notes. Experiments reveal that receivers extract different meanings from 'ABC' (scan for danger) and 'D' notes (approach the caller), and a compound meaning from 'ABC-D' combinations. However, receivers rarely scan and approach when note ordering is artificially reversed ('D-ABC'). Thus, compositional syntax is not unique to human language but may have evolved independently in animals as one of the basic mechanisms of information transmission. PMID- 26954099 TI - Synthetic Approaches To Construct the 6,8-DOBCO Framework in Natural Products. AB - 6,8-Dioxabicyclo[3.2.1]octane skeleton (6,8-DOBCO) is a very common structural motif in many biologically active natural products. This synopsis surveys various approaches used to access the 6,8-DOBCO framework present in natural products and summarizes total syntheses of 6,8-DOBCO-containing psoracorylifol B, ent psoracorylifol C, didemniserinolipid B, and attenol B from our laboratory and others. PMID- 26954100 TI - Hollow Au-Cu2O Core-Shell Nanoparticles with Geometry-Dependent Optical Properties as Efficient Plasmonic Photocatalysts under Visible Light. AB - Hollow Au-Cu2O core-shell nanoparticles were synthesized by using hollow gold nanoparticles (HGNs) as the plasmon-tailorable cores to direct epitaxial growth of Cu2O nanoshells. The effective geometry control of hollow Au-Cu2O core-shell nanoparticles was achieved through adjusting the HGN core sizes, Cu2O shell thicknesses, and morphologies related to structure-directing agents. The morphology-dependent plasmonic band red-shifts across the visible and near infrared spectral regions were observed from experimental extinction spectra and theoretical simulation based on the finite-difference time-domain method. Moreover, the hollow Au-Cu2O core-shell nanoparticles with synergistic optical properties exhibited higher photocatalytic performance in the photodegradation of methyl orange when compared to pristine Cu2O and solid Au-Cu2O core-shell nanoparticles under visible-light irradiation due to the efficient photoinduced charge separation, which could mainly be attributed to the Schottky barrier and plasmon-induced resonant energy transfer. Such optical tunability achieved through the hollow cores and structure-directed shells is of benefit to the performance optimization of metal-semiconductor nanoparticles for photonic, electronic, and photocatalytic applications. PMID- 26954102 TI - Selective Removal of Technetium from Water Using Graphene Oxide Membranes. AB - The effective removal of radioactive technetium ((99)Tc) from contaminated water is of enormous importance from an environmental and public health perspective, yet many current methodologies are highly ineffective. In this work, however, we demonstrate that graphene oxide membranes may remove (99)Tc, present in the form of pertechnetate (TcO4(-)), from water with a high degree of selectivity, suggesting they provide a cost-effective and efficient means of achieving (99)Tc decontamination. The results were obtained by quantifying and comparing the free energy changes associated with the entry of the ions into the membrane capillaries (DeltaFperm), using molecular dynamics simulations. Initially, three capillary widths were investigated (0.35, 0.68, and 1.02 nm). In each case, the entry of TcO4(-) from aqueous solution into the capillary is associated with a decrease in free energy, unlike the other anions (SO4(2-), I(-), and Cl(-)) investigated. For example, in the model with a capillary width of 0.68 nm, DeltaFperm(TcO4(-)) = -6.3 kJ mol(-1), compared to DeltaFperm(SO4(2-)) = +22.4 kJ mol(-1). We suggest an optimum capillary width (0.48 nm) and show that a capillary with this width results in a difference between DeltaFperm(TcO4(-)) and DeltaFperm(SO4(2-)) of 89 kJ mol(-1). The observed preference for TcO4(-) is due to its weakly hydrating nature, reflected in its low experimental hydration free energy. PMID- 26954101 TI - Mechanobiology of Ciliogenesis. AB - Cilia are force-generating and -sensing organelles that serve as mechanical interfaces between the cell and the extracellular environment. Cilia are present in tissues that adaptively respond to mechanical loading and fluid flow, and defects in ciliary function can lead to diseases affecting these tissues. As might be expected for a mechanical interface, the formation of cilia is, itself, regulated by mechanical forces, and these links between mechanics and ciliary formation are providing new entry points for dissecting the regulatory pathways of ciliogenesis. PMID- 26954103 TI - Reducing Readmissions--Destination or Journey? PMID- 26954104 TI - Knowledge about Hepatitis C Virus Infection and Acceptability of Testing in the 1945-1965 Birth Cohort (Baby Boomers) Presenting to a Large Urban Emergency Department: A Pilot Study. AB - BACKGROUND: Hepatitis C virus (HCV) is responsible for the most common chronic bloodborne infection in the United States. The Centers for Disease Control (CDC) recently recommended screening all patients born between 1945-1965 (baby boomers) at least once for HCV infection. New York State has since mandated screening of baby boomers for HCV in nearly all patient care settings and encouraged it in the emergency department (ED). OBJECTIVES: This pilot study aimed to ascertain acceptability of an HCV screening test among the 1945-1965 birth cohort presenting to the ED in advance of a study investigating the prevalence of HCV infection in this birth cohort in the ED setting. METHODS: We conducted a cross sectional study of health knowledge about HCV and government recommendations regarding HCV testing using a convenience sample of baby boomers in an ED in a large public hospital in the New York metropolitan area. Surveys were administered via a series of semistructured interviews. RESULTS: There were 81 patient participants. Fifty-two percent of patients were born outside of the United States, 69% had a high school diploma level of education or lower, and 37% were unemployed. Patients demonstrated misconceptions about HCV transmission and curability and poor knowledge about the necessity of testing in their age cohort. Knowledge that "HCV can cause the liver to stop working" was significantly associated with acceptance of testing. CONCLUSIONS: Baby boomers showed limited knowledge about the necessity of HCV screening in their age group, but testing for HCV infection in the ED was acceptable for the majority. PMID- 26954105 TI - Bacteremia and Deep Vein Thrombosis in an Infant. AB - BACKGROUND: Deep vein thrombosis (DVT) is rare in infancy. In pediatric populations, thrombosis occurs most frequently in hospitalized children and those with central venous catheters. The presence of a DVT in the general pediatric population indicates a hypercoagulable state and requires rapid diagnosis and treatment of both the thrombosis and the underlying process. CASE REPORT: A previously healthy 6-month-old male was brought to the emergency department by his family with a chief complaint of left leg swelling. Duplex ultrasonography in the emergency department revealed multiple DVTs in the leg vasculature. The patient was treated with anticoagulation and antibiotic therapy in the emergency department and admitted. Blood cultures revealed the subsequent growth of methicillin-resistant Staphylococcus aureus (MRSA). WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: While rare in infants, new-onset swelling in an extremity may be caused by thrombosis and be the initial symptom of an underlying hypercoagulable state. Duplex ultrasonography is a relatively benign test that can be readily performed in most emergency departments, and it allows physicians to rule out thrombosis. When present, DVT in the general pediatric population can indicate a critical illness, such as malignancy or infection, and requires rapid treatment and admission to a pediatric service for management. PMID- 26954106 TI - Severity of mumps disease is related to MMR vaccination status and viral shedding. AB - BACKGROUND: During recent years, various mumps outbreaks have occurred among measles, mumps, and rubella (MMR) vaccinated persons in various countries worldwide, including the Netherlands. We studied mumps virus shedding in MMR vaccinated and unvaccinated mumps patients and related these findings to clinical data. METHODS: In this study, we included 1112 mumps patients of whom diagnostic samples were tested positive in our laboratory between 1 January 2007 and 31 December 2014. We compared mumps virus shedding and severity of disease between patients who had received 2 doses of MMR (n=592) and unvaccinated mumps patients (n=195). Mumps virus shedding in saliva and urine specimens was measured by qPCR. Severity of disease was studied in a subset of patients with clinical data available. RESULTS: Mumps patients who had received 2 MMR doses shed less often mumps virus in their urine than unvaccinated patients. Salivary viral loads were higher at day of onset of disease in twice MMR vaccinated patients with viruria than in twice MMR vaccinated patients without viruria. However, salivary viral loads did not significantly differ between patients who had received 2 MMR doses and unvaccinated patients. Bilateral parotitis and orchitis were less often reported in patients who had received 2 MMR doses than in unvaccinated patients. Furthermore, the prevalence of bilateral parotitis and orchitis was higher among twice MMR vaccinated patients with viruria than among twice MMR vaccinated patients without viruria. CONCLUSIONS: MMR vaccination was associated with less severe disease among mumps patients. Systemic spread of virus was associated with more severe disease. The elevated salivary viral loads in patients with systemic mumps disease suggest that these patients pose a higher risk for mumps virus transmission. Our study contributes to the understanding of mumps virus pathogenesis and shows the protective effect of MMR vaccination on severity of disease. PMID- 26954107 TI - Immunization practices in solid organ transplant recipients. AB - Vaccine-preventable diseases are a significant cause of morbidity and mortality in solid organ transplant recipients who undergo immunosuppression after transplantation. The primary strategy for immunizing transplant recipients is to deliver all potential vaccines prior to transplantation. However, time constraints limit the number of vaccines that may be delivered. In such cases, the administration of live attenuated vaccines that are contraindicated after transplantation should be prioritized. Simultaneous vaccination is also encouraged to maximize the number of vaccines delivered. Immunity induced by both inactivated and live vaccines wane after transplantation. The limited but available evidence suggests that immunization using inactivated vaccines in transplant recipients is both effective and safe. An increasing number of studies also suggest that once patients are under minimal immunosuppression, live attenuated vaccines may be given effectively and safely. The need for serologic monitoring and booster immunizations remain issues for future research. PMID- 26954108 TI - Dynamic Self-Referencing Approach to Whispering Gallery Mode Biosensing and Its Application to Measurement within Undiluted Serum. AB - Biosensing within complex biological samples requires a sensor that can compensate for fluctuations in the signal due to changing environmental conditions and nonspecific binding events. To achieve this, we developed a novel self-referenced biosensor consisting of two almost identically sized dye-doped polystyrene microspheres placed on adjacent holes at the tip of a microstructured optical fiber (MOF). Here self-referenced biosensing is demonstrated with the detection of Neutravidin in undiluted, immunoglobulin-deprived human serum samples. The MOF allows remote excitation and collection of the whispering gallery modes (WGMs) of the microspheres while also providing a robust and easy to manipulate dip-sensing platform. By taking advantage of surface functionalization techniques, one microsphere acts as a dynamic reference, compensating for nonspecific binding events and changes in the environment (such as refractive index and temperature), while the other microsphere is functionalized to detect a specific interaction. The almost identical size allows the two spheres to have virtually identical refractive index sensitivity and surface area, while still having discernible WGM spectra. This ensures their responses to nonspecific binding and environmental changes are almost identical, whereby any specific changes, such as binding events, can be monitored via the relative movement between the two sets of WGM peaks. PMID- 26954109 TI - Oral Propranolol as an Alternative Therapy for Orbital Angiolymphoid Hyperplasia With Eosinophilia. AB - An 8-year-old female patient presented with left upper eyelid swelling and erythema. Magnetic resonance imaging revealed an orbital mass involving the left lacrimal gland with subsequent incisional biopsy leading to the diagnosis of angiolymphoid hyperplasia with eosinophilia. Initially prescribed an oral corticosteroid, alternative management was sought after 4 months due to unwanted side effects of steroid therapy. Oral propranolol (2 mg/kg/day) was initiated with concurrent steroid taper. Interval decrease in lesion size was observed on subsequent magnetic resonance imaging with complete resolution of subjective symptoms (Fig. 1). She remains stable 14 months after starting beta-blocker therapy. To our knowledge, our case is the second case report suggesting oral beta-blocker may be an alternative therapy for orbital angiolymphoid hyperplasia with eosinophilia. PMID- 26954110 TI - Hydrolytic Cleavage Products of Globin Adducts in Urine as Possible Biomarkers of Cumulative Dose: Proof of Concept Using Styrene Oxide as a Model Adduct-Forming Compound. AB - A new experimental model was designed to study the fate of globin adducts with styrene 7,8-oxide (SO), a metabolic intermediate of styrene and a model electrophilic compound. Rat erythrocytes were incubated with SO at 7 or 22 degrees C. Levels of specific amino acid adducts in globin were determined by LC/MS analysis of the globin hydrolysate, and erythrocytes with known adduct content were administered intravenously to recipient rats. The course of adduct elimination from the rat blood was measured over the following 50 days. In the erythrocytes incubated at 22 degrees C, a rapid decline in the adduct levels on the first day post-transfusion followed by a slow phase of elimination was observed. In contrast, the adduct elimination in erythrocytes incubated at 7 degrees C was nearly linear, copying elimination of intact erythrocytes. In the urine of recipient rats, regioisomeric SO adducts at cysteine, valine, lysine, and histidine in the form of amino acid adducts and/or their acetylated metabolites as well as SO-dipeptide adducts were identified by LC/MS supported by synthesized reference standards. S-(2-Hydroxy-1-phenylethyl)cysteine and S-(2 hydroxy-2-phenylethyl)cysteine, the most abundant globin adducts, were excreted predominantly in the form of the corresponding urinary mercapturic acids (HPEMAs). Massive elimination of HPEMAs via urine occurred within the first day from the erythrocytes incubated at both 7 and 22 degrees C. However, erythrocytes incubated at 7 degrees C also showed a slow second phase of elimination such that HPEMAs were detected in urine up to 50 days post transfusion. These results indicate for the first time that globin adducts can be cleaved in vivo to modified amino acids and dipeptides. The cleavage products and/or their predictable metabolites are excreted in urine over the whole life span of erythrocytes. Some of the urinary adducts may represent a new type of noninvasive biomarker for exposure to adduct-forming chemicals. PMID- 26954111 TI - Substitution of Wheat for Corn in Beef Cattle Diets: Digestibility, Digestive Enzyme Activities, Serum Metabolite Contents and Ruminal Fermentation. AB - The objective of this study was to evaluate the effect of diets containing different amounts of wheat, as a partial or whole substitute for corn, on digestibility, digestive enzyme activities, serum metabolite contents and ruminal fermentation in beef cattle. Four Limousin*LuXi crossbred cattle with a body weight (400+/-10 kg), fitted with permanent ruminal, proximal duodenal and terminal ileal cannulas, were used in a 4*4 Latin square design with four treatments: Control (100% corn), 33% wheat (33% substitution for corn), 67% wheat (67% substitution for corn), and 100% wheat (100% substitution for corn) on a dry matter basis. The results showed that replacing corn with increasing amounts of wheat increased the apparent digestibility values of dry matter, organic matter, and crude protein (p<0.05). While the apparent digestibility of acid detergent fiber and neutral detergent fiber were lower with increasing amounts of wheat. Digestive enzyme activities of lipase, protease and amylase in the duodenum were higher with increasing wheat amounts (p<0.05), and showed similar results to those for the enzymes in the ileum except for amylase. Increased substitution of wheat for corn increased the serum alanine aminotransferase concentration (p<0.05). Ruminal pH was not different between those given only corn and those given 33% wheat. Increasing the substitution of wheat for corn increased the molar proportion of acetate and tended to increase the acetate-to-propionate ratio. Cattle fed 100% wheat tended to have the lowest ruminal NH3-N concentration compared with control (p<0.05), whereas no differences were observed among the cattle fed 33% and 67% wheat. These findings indicate that wheat can be effectively used to replace corn in moderate amounts to meet the energy and fiber requirements of beef cattle. PMID- 26954113 TI - Effect of Grape Pomace Powder, Mangosteen Peel Powder and Monensin on Nutrient Digestibility, Rumen Fermentation, Nitrogen Balance and Microbial Protein Synthesis in Dairy Steers. AB - This study was designed to investigate the effect of grape pomace powder (GPP), mangosteen peel powder (MPP) and monensin on feed intake, nutrients digestibility, microorganisms, rumen fermentation characteristic, microbial protein synthesis and nitrogen balance in dairy steers. Four, rumen fistulated dairy steers with initial body weight (BW) of 220+/-15 kg were randomly assigned according to a 4*4 Latin square design to receive four treatments. The treatments were as follows: T1 = control, T2 = supplementation with monensin at 33 mg/kg diet, T3 = supplementation with GPP at 2% of dry matter intake, and T4 = supplementation with MPP at 30 g/kg diet. The steers were offered the concentrate diet at 0.2% BW and 3% urea treated rice straw (UTRS) was fed ad libitum. It was found that GPP supplemented group had higher UTRS intake and nutrient digestibility in terms of neutral detergent fiber and acid detergent fiber than those in control group (p<0.05). Ammonia nitrogen (NH3-N) and blood urea-nitrogen concentration were higher in monensin, GPP and MPP supplemented groups (p<0.05). Total volatile fatty acids and propionate in the GPP group were higher than those in the control group (p<0.05) while acetate concentration, and acetate to propionate ratio were decreased (p<0.01) when steers were supplemented with GPP, monensin, and MPP, respectively. Moreover, protozoal populations in GPP, MPP, and monensin supplementation were significantly lower than those in the control group (p<0.05), while cellulolytic bacterial population was significantly higher in the control group (p<0.05). Nitrogen retention, microbial crude protein and efficiency of microbial nitrogen synthesis were found significantly higher in steers that received GPP (p<0.05). Based on this study it could be concluded that the GPP has potential as an alternative feed supplement in concentrate diets which can result in improved rumen fermentation efficiency, digestibility and microbial protein synthesis in steers fed on treated rice straw. PMID- 26954112 TI - Role of Growth Differentiation Factor 9 and Bone Morphogenetic Protein 15 in Ovarian Function and Their Importance in Mammalian Female Fertility - A Review. AB - Growth factors play an important role during early ovarian development and folliculogenesis, since they regulate the migration of germ cells to the gonadal ridge. They also act on follicle recruitment, proliferation/atresia of granulosa cells and theca, steroidogenesis, oocyte maturation, ovulation and luteinization. Among the growth factors, the growth differentiation factor 9 (GDF9) and the bone morphogenetic protein 15 (BMP15), belong to the transforming growth factor beta (TGF-beta) superfamily, have been implicated as essential for follicular development. The GDF9 and BMP15 participate in the evolution of the primordial follicle to primary follicle and play an important role in the later stages of follicular development and maturation, increasing the steroidogenic acute regulatory protein expression, plasminogen activator and luteinizing hormone receptor (LHR). These factors are also involved in the interconnections between the oocyte and surrounding cumulus cells, where they regulate absorption of amino acids, glycolysis and biosynthesis of cholesterol cumulus cells. Even though the mode of action has not been fully established, in vitro observations indicate that the factors GDF9 and BMP15 stimulate the growth of ovarian follicles and proliferation of cumulus cells through the induction of mitosis in cells and granulosa and theca expression of genes linked to follicular maturation. Thus, seeking greater understanding of the action of these growth factors on the development of oocytes, the role of GDF9 and BMP15 in ovarian function is summarized in this brief review. PMID- 26954114 TI - Differences in Physicochemical and Nutritional Properties of Breast and Thigh Meat from Crossbred Chickens, Commercial Broilers, and Spent Hens. AB - The objective of this study was to compare the physicochemical and nutritional properties of breast and thigh meat from commercial Chinese crossbred chickens (817 Crossbred chicken, 817C), imported commercial broilers (Arbor Acres broiler, AAB), and commercial spent hens (Hyline Brown, HLB). The crossbred chickens, commercial broilers and spent hens were slaughtered at their typical market ages of 45 d, 40 d, and 560 d, respectively. The results revealed that several different characteristic features for the three breeds. The meat of the 817C was darker than that of the other two genotypes. The 817C were also characterized by higher protein, lower intramuscular fat, and better texture attributes (cooking loss, pressing loss and Warner-Bratzler shear force [WBSF]) compared with AAB and HLB. The meat of the spent hens (i.e. HLB) was higher in WBSF and total collagen content than meat of the crossbred chickens and imported broilers. Furthermore, correlation analysis and principal component analysis revealed that there was a clear relationship among physicochemical properties of chicken meats. With regard to nutritional properties, it was found that 817C and HLB exhibited higher contents of essential amino acids and essential/non-essential amino acid ratios. In addition, 817C were noted to have highest content of microelements whereas AAB have highest content of potassium. Besides, 817C birds had particularly higher proportions of desirable fatty acids, essential fatty acids, polyunsaturated/saturated and (18:0+18:1)/16:0 ratios. The present study also revealed that there were significant differences on breast meat and thigh meat for the physicochemical and nutritional properties, regardless of chicken breeds. In conclusion, meat of crossbred chickens has some unique features and exhibited more advantages over commercial broilers and spent hens. Therefore, the current investigation would provide valuable information for the chicken meat product processing, and influence the consumption of different chicken meat. PMID- 26954115 TI - Estimation of Genetic Parameters and Trends for Length of Productive Life and Lifetime Production Traits in a Commercial Landrace and Yorkshire Swine Population in Northern Thailand. AB - The objective of this research was to estimate genetic parameters and trends for length of productive life (LPL), lifetime number of piglets born alive (LBA), lifetime number of piglets weaned (LPW), lifetime litter birth weight (LBW), and lifetime litter weaning weight (LWW) in a commercial swine farm in Northern Thailand. Data were gathered during a 24-year period from July 1989 to August 2013. A total of 3,109 phenotypic records from 2,271 Landrace (L) and 838 Yorkshire sows (Y) were analyzed. Variance and covariance components, heritabilities and correlations were estimated using an Average Information Restricted Maximum Likelihood (AIREML) procedure. The 5-trait animal model contained the fixed effects of first farrowing year-season, breed group, and age at first farrowing. Random effects were sow and residual. Estimates of heritabilities were medium for all five traits (0.17+/-0.04 for LPL and LBA to 0.20+/-0.04 for LPW). Genetic correlations among these traits were high, positive, and favorable (p<0.05), ranging from 0.93+/-0.02 (LPL-LWW) to 0.99+/ 0.02 (LPL-LPW). Sow genetic trends were non-significant for LPL and all lifetime production traits. Sire genetic trends were negative and significant for LPL ( 2.54+/-0.65 d/yr; p = 0.0007), LBA (-0.12+/-0.04 piglets/yr; p = 0.0073), LPW ( 0.14+/-0.04 piglets/yr; p = 0.0037), LBW (-0.13+/-0.06 kg/yr; p = 0.0487), and LWW (-0.69+/-0.31 kg/yr; p = 0.0365). Dam genetic trends were positive, small and significant for all traits (1.04+/-0.42 d/yr for LPL, p = 0.0217; 0.16+/-0.03 piglets/yr for LBA, p<0.0001; 0.12+/-0.03 piglets/yr for LPW, p = 0.0002; 0.29+/ 0.04 kg/yr for LBW, p<0.0001 and 1.23+/-0.19 kg/yr for LWW, p<0.0001). Thus, the selection program in this commercial herd managed to improve both LPL and lifetime productive traits in sires and dams. It was ineffective to improve LPL and lifetime productive traits in sows. PMID- 26954116 TI - Effects of Rumen Protozoa of Brahman Heifers and Nitrate on Fermentation and In vitro Methane Production. AB - Two experiments were conducted assessing the effects of presence or absence of rumen protozoa and dietary nitrate addition on rumen fermentation characteristics and in vitro methane production in Brahman heifers. The first experiment assessed changes in rumen fermentation pattern and in vitro methane production post refaunation and the second experiment investigated whether addition of nitrate to the incubation would give rise to methane mitigation additional to that contributed by defaunation. Ten Brahman heifers were progressively adapted to a diet containing 4.5% coconut oil distillate for 18 d and then all heifers were defaunated using sodium 1-(2-sulfonatooxyethoxy) dodecane (Empicol). After 15 d, the heifers were given a second dose of Empicol. Fifteen days after the second dosing, all heifers were allocated to defaunated or refaunated groups by stratified randomisation, and the experiment commenced (d 0). On d 0, an oral dose of rumen fluid collected from unrelated faunated cattle was used to inoculate 5 heifers and form a refaunated group so that the effects of re establishment of protozoa on fermentation characteristics could be investigated. Samples of rumen fluid collected from each animal using oesophageal intubation before feeding on d 0, 7, 14, and 21 were incubated for in vitro methane production. On d 35, 2% nitrate (as NaNO3) was included in in vitro incubations to test for additivity of nitrate and absence of protozoa effects on fermentation and methane production. It was concluded that increasing protozoal numbers were associated with increased methane production in refaunated heifers 7, 14, and 21 d after refaunation. Methane production rate was significantly higher from refaunated heifers than from defaunated heifers 35 d after refaunation. Concentration and proportions of major volatile fatty acids, however, were not affected by protozoal treatments. There is scope for further reducing methane output through combining defaunation and dietary nitrate as the addition of nitrate in the defaunated heifers resulted in 86% reduction in methane production in vitro. PMID- 26954117 TI - Identification of Gene Expression Signatures in the Chicken Intestinal Intraepithelial Lymphocytes in Response to Herb Additive Supplementations. AB - Anethole and garlic have an immune modulatory effects on avian coccidiosis, and these effects are correlated with gene expression changes in intestinal epithelial lymphocytes (IELs). In this study, we integrated gene expression datasets from two independent experiments and investigated gene expression profile changes by anethole and garlic respectively, and identified gene expression signatures, which are common targets of these herbs as they might be used for the evaluation of the effect of plant herbs on immunity toward avian coccidiosis. We identified 4,382 and 371 genes, which were differentially expressed in IELs of chickens supplemented with garlic and anethole respectively. The gene ontology (GO) term of differentially expressed genes (DEGs) from garlic treatment resulted in the biological processes (BPs) related to proteolysis, e.g., "modification-dependent protein catabolic process", "proteolysis involved in cellular protein catabolic process", "cellular protein catabolic process", "protein catabolic process", and "ubiquitin-dependent protein catabolic process". In GO analysis, one BP term, "Proteolysis", was obtained. Among DEGs, 300 genes were differentially regulated in response to both garlic and anethole, and 234 and 59 genes were either up- or down-regulated in supplementation with both herbs. Pathway analysis resulted in enrichment of the pathways related to digestion such as "Starch and sucrose metabolism" and "Insulin signaling pathway". Taken together, the results obtained in the present study could contribute to the effective development of evaluation system of plant herbs based on molecular signatures related with their immunological functions in chicken IELs. PMID- 26954118 TI - Comparative Proteomic Analysis of Yak Follicular Fluid during Estrus. AB - The breeding of yaks is highly seasonal, there are many crucial proteins involved in the reproduction control program, especially in follicular development. In order to isolate differential proteins between mature and immature follicular fluid (FF) of yak, the FF from yak follicles with different sizes were sampled respectively, and two-dimensional gel electrophoresis (2-DE) of the proteins was carried out. After silver staining, the Image Master 2D platinum software was used for protein analysis and matrix-assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF-MS) was performed for differential protein identification. The expression level of transferrin and enolase superfamily member 1 (ENOSF1) was determined by Western blotting for verification analysis. The results showed that 2-DE obtained an electrophoresis map of proteins from mature and immature yak FF with high resolution and repeatability. A comparison of protein profiles identified 12 differently expressed proteins, out of which 10 of them were upregulated while 2 were downregulated. Western blotting showed that the expression of transferrin and ENOSF1 was enhanced with follicular development. Both the obtained protein profiles and the differently expressed proteins identified in this study provided experimental data related to follicular development during yak breeding seasons. This study also laid the foundation for understanding the microenvironment during oocyte development. PMID- 26954119 TI - Optimal Cultivation Time for Yeast and Lactic Acid Bacteria in Fermented Milk and Effects of Fermented Soybean Meal on Rumen Degradability Using Nylon Bag Technique. AB - The objectives of this study were to determine an optimal cultivation time for populations of yeast and lactic acid bacteria (LAB) co-cultured in fermented milk and effects of soybean meal fermented milk (SBMFM) supplementation on rumen degradability in beef cattle using nylon bag technique. The study on an optimal cultivation time for yeast and LAB growth in fermented milk was determined at 0, 4, 8, 24, 48, 72, and 96 h post-cultivation. After fermenting for 4 days, an optimal cultivation time of yeast and LAB in fermented milk was selected and used for making the SBMFM product to study nylon bag technique. Two ruminal fistulated beef cattle (410+/-10 kg) were used to study on the effect of SBMFM supplementation (0%, 3%, and 5% of total concentrate substrate) on rumen degradability using in situ method at incubation times of 0, 2, 4, 6, 12, 24, 48, and 72 h according to a Completely randomized design. The results revealed that the highest yeast and LAB population culture in fermented milk was found at 72 h post cultivation. From in situ study, the soluble fractions at time zero (a), potential degradability (a+b) and effective degradability of dry matter (EDDM) linearly (p<0.01) increased with the increasing supplemental levels and the highest was in the 5% SBMFM supplemented group. However, there was no effect of SBMFM supplement on insoluble degradability fractions (b) and rate of degradation (c). In conclusion, the optimal fermented time for fermented milk with yeast and LAB was at 72 h-post cultivation and supplementation of SBMFM at 5% of total concentrate substrate could improve rumen degradability of beef cattle. However, further research on effect of SBMFM on rumen ecology and production performance in meat and milk should be conducted using in vivo both digestion and feeding trials. PMID- 26954120 TI - Red Color Light at Different Intensities Affects the Performance, Behavioral Activities and Welfare of Broilers. AB - Red light (RL) marked higher weight gain (WG) and preference of broilers compared to other light colors. This study aimed to investigate how different intensities of RL affect the performance, behavior and welfare of broilers. RL treatments were T1 = high intensity (320 lux), T2 = medium intensity (20 lux); T3 = dim intensity (5 lux), T4 = control/white light at (20 lux) provided on 20L:4D schedule and T5 = negative control; 12 hours dark: 12 hours day light. Cobb strain broilers were used in a Complete Randomize Design with 6 replicates. WG, water/feed intake, feed conversion ratio (FCR), mortality, behavior and welfare were assessed. At 35 d, significantly (p<0.05) highest body weight (2,147.06 g+/ 99) was recorded by T3. Lowest body weight (1,640.55 g+/-56) and FCR (1.34) were recorded by T5. Skin weight was the only carcass parameter showed a significant (p<0.05) influence giving the highest (56.2 g) and the lowest (12.6 g) values for T5 and T1 respectively. Reduced welfare status indicated by significantly (p<0.05) higher foot pad lesions, hock burns and breast blisters was found under T3, due to reduced expression of behavior. Highest walking (2.08%+/-1%) was performed under T1 in the evening during 29 to 35 days. Highest dust bathing (3.01%+/-2%) was performed in the morning during 22 to 28 days and highest bird interaction (BI) (4.87%+/-4%) was observed in the evening by T5 during 14 to 21 days. Light intensity*day session*age interaction was significantly (p<0.05) affected walking, dust bathing and BI. Light intensity significantly (p<0.05) affected certain behaviors such as lying, eating, drinking, standing, walking, preening while lying, wing/leg stretching, sleeping, dozing, BI, vocalization, idling. In conclusion, birds essentially required provision of light in the night for better performance. Exposed to 5 lux contributed to higher WG, potentially indicating compromised welfare status. Further researches are suggested to investigate RL intensity based lighting regimen that favors for both production and welfare of Broilers. PMID- 26954121 TI - Evaluation of Salmonella Growth at Low Concentrations of NaNO2 and NaCl in Processed Meat Products Using Probabilistic Model. AB - This study developed probabilistic models to predict Salmonella growth in processed meat products formulated with varying concentrations of NaCl and NaNO2. A five-strain mixture of Salmonella was inoculated in nutrient broth supplemented with NaCl (0%, 0.25%, 0.5%, 0.75%, 0.5%, 1.0%, 1.25%, and 1.75%) and NaNO2 (0, 15, 30, 45, 60, 75, 90, 105, and 120 ppm). The inoculated samples were then incubated under aerobic and anaerobic conditions at 4 degrees C, 7 degrees C, 10 degrees C, 12 degrees C, and 15 degrees C for up to 60 days. Growth (assigned the value of 1) or no growth (assigned the value of 0) for each combination was evaluated by turbidity. These growth response data were analyzed with a logistic regression to evaluate the effect of NaCl and NaNO2 on Salmonella growth. The results from the developed model were compared to the observed data obtained from the frankfurters to evaluate the performance of the model. Results from the developed model showed that a single application of NaNO2 at low concentrations did not inhibit Salmonella growth, whereas NaCl significantly (p<0.05) inhibited Salmonella growth at 10 degrees C, 12 degrees C, and 15 degrees C, regardless of the presence of oxygen. At 4 degrees C and 7 degrees C, Salmonella growth was not observed in either aerobic or anaerobic conditions. When NaNO2 was combined with NaCl, the probability of Salmonella growth decreased. The validation value confirmed that the performance of the developed model was appropriate. This study indicates that the developed probabilistic models should be useful for describing the combinational effect of NaNO2 and NaCl on inhibiting Salmonella growth in processed meat products. PMID- 26954122 TI - Ramie Leaf Extracts Suppresses Adipogenic Differentiation in 3T3-L1 Cells and Pig Preadipocytes. AB - The present study was carried out to evaluate the anti-obesity effect of different concentrations of extracts of hot air-dried ramie leaf (HR) and freeze dried ramie leaf (FR) in 3T3-L1 cells and pig preadipocytes. To analyze the effect on cell proliferation, cells were treated with 25 MUg/mL or 100 MUg/mL HR or FR extract for 2 days. Cell differentiation was evaluated by measuring glycerol-3-phosphate dehydrogenase and lipoprotein lipase (LPL) activities and intracellular triglyceride content. Treatment with either HR or FR extracts inhibited the proliferation of 3T3-L1 cells and pig preadipocytes in a dose dependent manner. HR extract treatment inhibited the differentiation of both cell types more effectively than FR treatment. The extent of triglyceride accumulation decreased significantly in both cells following either HR or FR treatment. Furthermore, LPL activity significantly decreased after treatment with HR or FR extract. These results indicated that HR and FR extracts may inhibit proliferation and differentiation of 3T3-L1 cells and pig preadipocytes. Further studies are needed to explore the anti-obesity effect of HR and FR extracts. PMID- 26954123 TI - Effects of Direct-fed Microbial and Pine Cone Extract on Carcass Traits and Meat Quality of Hanwoo (Korean Native Cattle). AB - The carcass traits and meat quality of Hanwoo (Korean native cattle) whose diets were supplemented with direct-fed microbial (DFM) and pine cone extract (PCE) were evaluated. Twenty head of Hanwoo steers were divided equally into four groups and for a period of 6 months were given different diets: One group was fed a basal diet as control (CON), the other three groups were fed a basal diet supplemented with DFM-1%, DFM+PCE-1% and DFM+PEC-3%, respectively. DFM+PCE3% diet resulted the lowest carcass quality grade. The loins of DFM-1% contained higher moisture and lower fat than did the loins from the CON group. The crude protein content of DFM+PCE-3% group was significantly higher than that of the other groups. The water holding capacity and Warner-Bratzler shear force of the DFM+PCE 1% and 3% groups were lower than those of the CON and DFM-1% groups. The DFM-1% and 3% groups contained lower saturated fatty acid, higher unsaturated fatty acid, mono-unsaturated fatty acid, and poly-unsaturated fatty acid than did CON and DFM+PCE 1% group. Moreover, the n6:n3 ratios of DFM-1% and DFM+PCE-1% and 3% groups were slightly lower than that of the CON group. Thus we concluded that DFM and PCE supplementation resulted healthier Hanwoo beef with lower fat content and n6:n3 ratio. PMID- 26954124 TI - Characterization and Profiling of Liver microRNAs by RNA-sequencing in Cattle Divergently Selected for Residual Feed Intake. AB - MicroRNAs (miRNAs) are short non-coding RNAs that post-transcriptionally regulate expression of mRNAs in many biological pathways. Liver plays an important role in the feed efficiency of animals and high and low efficient cattle demonstrated different gene expression profiles by microarray. Here we report comprehensive miRNAs profiles by next-gen deep sequencing in Angus cattle divergently selected for residual feed intake (RFI) and identify miRNAs related to feed efficiency in beef cattle. Two microRNA libraries were constructed from pooled RNA extracted from livers of low and high RFI cattle, and sequenced by Illumina genome analyser. In total, 23,628,103 high quality short sequence reads were obtained and more than half of these reads were matched to the bovine genome (UMD 3.1). We identified 305 known bovine miRNAs. Bta-miR-143, bta-miR-30, bta-miR-122, bta-miR 378, and bta-let-7 were the top five most abundant miRNAs families expressed in liver, representing more than 63% of expressed miRNAs. We also identified 52 homologous miRNAs and 10 novel putative bovine-specific miRNAs, based on precursor sequence and the secondary structure and utilizing the miRBase (v. 21). We compared the miRNAs profile between high and low RFI animals and ranked the most differentially expressed bovine known miRNAs. Bovine miR-143 was the most abundant miRNA in the bovine liver and comprised 20% of total expressed mapped miRNAs. The most highly expressed miRNA in liver of mice and humans, miR-122, was the third most abundant in our cattle liver samples. We also identified 10 putative novel bovine-specific miRNA candidates. Differentially expressed miRNAs between high and low RFI cattle were identified with 18 miRNAs being up-regulated and 7 other miRNAs down-regulated in low RFI cattle. Our study has identified comprehensive miRNAs expressed in bovine liver. Some of the expressed miRNAs are novel in cattle. The differentially expressed miRNAs between high and low RFI give some insights into liver miRNAs regulating physiological pathways underlying variation in this measure of feed efficiency in bovines. PMID- 26954125 TI - Assessment of the Contribution of Poultry and Pig Production to Greenhouse Gas Emissions in South Korea Over the Last 10 Years (2005 through 2014). AB - The goal of this study was to estimate the emissions of greenhouse gases (GHG), namely methane (CH4), nitrous oxide (N2O), and carbon dioxide (CO2) from poultry and pig production in South Korea over the last 10 years (2005 through 2014). The calculations of GHG emissions were based on Intergovernmental Panel on Climate Change (IPCC) guidelines. Over the study period, the CH4 emission from manure management decreased in layer chickens, nursery to finishing pigs and gestating to lactating sows, but there was a gradual increase in CH4 emission from broiler chickens and male breeding pigs. Both sows and nursery to finishing pigs were associated with greater emissions from enteric fermentation than the boars, especially in 2009. Layer chickens produced lower direct and indirect N2O emissions from 2009 to 2014, whereas the average direct and indirect N2O emissions from manure management for broiler chickens were 12.48 and 4.93 Gg CO2 eq/yr, respectively. Annual direct and indirect N2O emissions for broiler chickens tended to decrease in 2014. Average CO2 emission from direct on-farm energy uses for broiler and layer chickens were 46.62 and 136.56 Gg CO2-eq/yr, respectively. For pig sectors, the N2O emission from direct and indirect sources gradually increased, but they decreased for breeding pigs. Carbon dioxide emission from direct on-farm energy uses reached a maximum of 53.93 Gg CO2-eq/yr in 2009, but this total gradually declined in 2010 and 2011. For boars, the greatest CO2 emission occurred in 2012 and was 9.44 Gg CO2-eq/yr. Indirect N2O emission was the largest component of GHG emissions in broilers. In layer chickens, the largest contributing factor to GHG emissions was CO2 from direct on farm energy uses. For pig production, the largest component of GHG emissions was CH4 from manure management, followed by CO2 emission from direct on-farm energy use and CH4 enteric fermentation emission, which accounted for 8.47, 2.85, and 2.82 Gg-CO2/yr, respectively. The greatest GHG emission intensity occurred in female breeding sows relative to boars. Overall, it is an important issue for the poultry and pig industry of South Korea to reduce GHG emissions with the effective approaches for the sustainability of agricultural practices. PMID- 26954126 TI - Effects of Nitrogen Application Rate on the Yields, Nutritive Value and Silage Fermentation Quality of Whole-crop Wheat. AB - Whole-crop wheat (Triticum aestivum L.) as forage has been extensively used in the world. In this study, the effects of N application rates on the yields, nutritive value and silage quality were investigated. The N application rates were 0, 75, 150, 225, and 300 kg/ha. The research results indicated that the dry matter yield of whole-crop wheat increased significantly with increasing N rate up to 150 kg/ha, and then leveled off. The crude protein content and in vitro dry matter digestibility of whole-crop wheat increased significantly with increasing N up to 225 kg/ha, while they no longer increased at N 300 kg/ha. On the contrary, the content of various fibers tended to decrease with the increase of N application. The content of lactic acid, acetic acid and propionic acid in silages increased with the increase of N rate (p<0.05). The ammonia-N content of silages with higher N application rates (>=225 kg/ha) was significantly higher than that with lower N application rates (<=150 kg/ha). Whole-crop wheat applied with high levels of N accumulated more nitrate-N. In conclusion, taking account of yields, nutritive value, silage quality and safety, the optimum N application to whole-crop wheat should be about 150 kg/ha at the present experiment conditions. PMID- 26954127 TI - Characteristics and Gel Properties of Gelatin from Goat Skin as Influenced by Alkaline-pretreatment Conditions. AB - Characteristics and properties of gelatin from goat skin pretreated with NaOH solutions (0.50 and 0.75 M) for various times (1 to 4 days) were investigated. All gelatins contained alpha-chains as the predominant component, followed by beta-chain. Gelling and melting temperatures of those gelatins were 23.02 degrees C to 24.16 degrees C and 33.07 degrees C to 34.51 degrees C, respectively. Gel strength of gelatins increased as NaOH concentration and pretreatment time increased (p<0.05). Pretreatment for a longer time yielded gelatin with a decrease in L*-value but an increase in b*-value. Pretreatment of goat skin using 0.75 M NaOH for 2 days rendered the highest yield (15.95%, wet weight basis) as well as high gel strength (222.42 g), which was higher than bovine gelatin (199.15 g). Gelatin obtained had the imino acid content of 226 residues/1,000 residues and the gelatin gel had a fine and ordered structure. Therefore, goat skin gelatin could be used as a potential replacer of commercial gelatin. PMID- 26954128 TI - Testicular Characteristics and the Block to Spermatogenesis in Mature Hinny. AB - Most hinnies (female donkey*male horse) and mules (female horse*male donkey) are sterile with few reports of equine fertile hybrids. The main cause of this sterility is thought to be a meiotic block to spermatogenesis and oogenesis. This study compared the developmental features of the testes and a histological analyses of spermatogenesis in a male hinny with those of a normal, fertile stallion and Jack donkey. Hinny testes showed a thicker tunica albuginea, fewer blood vessels and more connective tissue in the testis parenchyma than those of the stallion and Jack donkey. Although the mean number of seminiferous tubules was significantly higher in stallion and hinny than Jack donkey (p<0.01), the mean proportion of seminiferous tubules was lower in the hinny (p<0.01) which resulted in a smaller diameter of seminiferous tubules. The mean number of spermatogonia and spermatocytes per unit area were significantly lower in hinny testis (p<0.01) and no spermatids or mature spermatozoa cells were found during immunofluorescent analyses. These results indicated that defects in seminiferous tubule development and structure occur in the testis of hinnies. Furthermore, most spermatogonia and spermatocytes cease development in synapsis during mid meiosis of spermatocytes, which results in a block to spermatogenesis that prevents the formation of spermatids and matured spermatozoa during meiosis in male hinnies. PMID- 26954129 TI - Role of Fermentation in Improving Nutritional Quality of Soybean Meal - A Review. AB - Soybean meal (SBM), a commonly used protein source for animal feed, contains anti nutritional factors such as trypsin inhibitor, phytate, oligosaccharides among others, which limit its utilization. Microbial fermentation using bacteria or fungi has the capability to improve nutritional value of SBM by altering the native composition. Both submerged and solid state fermentation processes can be used for this purpose. Bacterial and fungal fermentations result in degradation of various anti-nutritional factors, an increase in amount of small-sized peptides and improved content of both essential and non-essential amino acids. However, the resulting fermented products vary in levels of nutritional components as the two species used for fermentation differ in their metabolic activities. Compared to SBM, feeding non-ruminants with fermented SBM has several beneficial effects including increased average daily gain, improved growth performance, better protein digestibility, decreased immunological reactivity and undesirable morphological changes like absence of granulated pinocytotic vacuoles. PMID- 26954130 TI - Effects of Dietary Glucose on Serum Estrogen Levels and Onset of Puberty in Gilts. AB - Metabolic signals and the state of energy reserves have been shown to play a crucial role in the regulation of reproductive function. This study was carried out to investigate the effects of dietary glucose levels on puberty onset in gilts. Weight-matched, landrace gilts (n = 36) 162+/-3 days old, weighing about 71.05+/-4.53 kg, were randomly assigned to 3 dietary treatment groups of 12 gilts each. The trial lasted until the onset of puberty. Gilts in each group were supplied with diets containing different levels of glucose as follows: i) starch group (SG) was free of glucose, contained 64% corn derived starch; ii) low-dose group (LDG) contained 19.2% glucose and 44.8% corn derived starch; iii) high-dose group (HDG) contained 30% glucose and 30% corn derived starch. Results indicated: i) The growth performance of gilts were not affected by the addition of glucose, but the age of puberty onset was advanced significantly (p<0.05); ii) Compared with the SG, the concentration of insulin significantly increased before puberty in HDG (p<0.05); iii) There was no difference in serum progesterone (P) levels amongst the different feed groups, however, levels of estradiol (E2), luteinizing hormone, and follicle-stimulating hormone were significantly higher at puberty onset in HDG (p<0.05). Overall, our findings indicate that glucose supplementation significantly advances puberty onset, which can have practical purposes for commercial breeding. PMID- 26954131 TI - Dietary Phytoncide Supplementation Improved Growth Performance and Meat Quality of Finishing Pigs. AB - We conducted this 10-wk experiment to evaluate the effects of dietary phytoncide, Korean pine extract as phytogenic feed additive (PFA), on growth performance, blood characteristics, and meat quality in finishing pigs. A total of 160 pigs ([Landrace*Yorkshire]*Duroc, body weight (BW) = 58.2+/-1.0 kg) were randomly allocated into 1 of 4 treatments according to their BW and sex, 10 replicate pens per treatment with 4 pigs per pen were used (2 barrows and 2 gilts). Dietary treatments were: CON, control diet; PT2, CON+0.02% PFA; PT4, CON+0.04% PFA; PT6, CON+0.06% PFA. Overall, average daily gain (ADG) was higher in PT4 (p<0.05) than in PT6, average daily feed intake (ADFI) was lower in PT6 than in CON (p<0.05). Besides ADFI decreased linearly (p<0.05) with the increased level of phytoncide and gain:feed ratio in PT4 treatment was higher (p<0.05) than CON treatment. During 5 to 10 weeks and overall, quadratic (p<0.05) effect was observed in ADG among the treatments. At the end of this experiment, pigs fed with PT4 diet had a greater (p<0.05) red blood cell concentration compared to the pigs fed CON diet. Water holding capacity increased linearly (p<0.05) with the increased level of phytoncide supplementation. Moreover, firmness, redness, yellowness, and drip loss at day 3 decreased linearly (p<0.05) with the increase in the level of phytoncide supplementation. In conclusion, inclusion of phytoncide could enhance growth performance without any adverse effects on meat quality in finishing pigs. PMID- 26954133 TI - Preparation and Characterization of an Antibody Antagonist That Targets the Porcine Growth Hormone Receptor. AB - A series of antagonists specifically targeting growth hormone receptors (GHR) in different species, such as humans, rats, bovines, and mice, have been designed; however, there are currently no antagonists that target the porcine growth hormone (GH). Therefore, in this study, we developed and characterized a porcine GHR (pGHR) antibody antagonist (denoted by AN98) via the hybridoma technique. The results from enzyme-linked immunosorbent assay, fluorescence activated cell sorter, indirect immunoinfluscent assay, and competitive receptor binding analysis showed that AN98 could specifically recognize pGHR, and further experiments indicated that AN98 could effectively inhibit pGH-induced signalling in CHO-pGHR cells and porcine hepatocytes. In addition, AN98 also inhibited GH induced insulin-like growth factor-1 (IGF-1) secretion in porcine hepatocytes. In summary, these findings indicated that AN98, as a pGHR-specific antagonist, has potential applications in pGH-pGHR-related research on domestic pigs. PMID- 26954132 TI - Comparison of Fecal Microbiota of Mongolian and Thoroughbred Horses by High throughput Sequencing of the V4 Region of the 16S rRNA Gene. AB - The hindgut of horses is an anaerobic fermentative chamber for a complex and dynamic microbial population, which plays a critical role in health and energy requirements. Research on the gut microbiota of Mongolian horses has not been reported until now as far as we know. Mongolian horse is a major local breed in China. We performed high-throughput sequencing of the 16S rRNA genes V4 hypervariable regions from gut fecal material to characterize the gut microbiota of Mongolian horses and compare them to the microbiota in Thoroughbred horses. Fourteen Mongolian and 19 Thoroughbred horses were used in the study. A total of 593,678 sequence reads were obtained from 33 samples analyzed, which were found to belong to 16 phyla and 75 genera. The bacterial community compositions were similar for the two breeds. Firmicutes (56% in Mongolian horses and 53% in Thoroughbred horses) and Bacteroidetes (33% and 32% respectively) were the most abundant and predominant phyla followed by Spirochaete, Verrucomicrobia, Proteobacteria, and Fibrobacteres. Of these 16 phyla, five (Synergistetes, Planctomycetes, Proteobacteria, TM7, and Chloroflexi) were significantly different (p<0.05) between the two breeds. At the genus level, Treponema was the most abundant genus (43% in Mongolian horses vs 29% in Thoroughbred horses), followed by Ruminococcus, Roseburia, Pseudobutyrivibrio, and Anaeroplasma, which were detected in higher distribution proportion in Mongolian horses than in Thoroughbred horses. In contrast, Oscillibacter, Fibrobacter, Methanocorpusculum, and Succinivibrio levels were lower in Mongolian horses. Among 75 genera, 30 genera were significantly different (p<0.05) between the two breeds. We found that the environment was one of very important factors that influenced horse gut microbiota. These findings provide novel information about the gut microbiota of Mongolian horses and a foundation for future investigations of gut bacterial factors that may influence the development and progression of gastrointestinal disease in horses. PMID- 26954134 TI - Prediction of Carcass Composition Using Carcass Grading Traits in Hanwoo Steers. AB - The prediction of carcass composition in Hanwoo steers is very important for value-based marketing, and the improvement of prediction accuracy and precision can be achieved through the analyses of independent variables using a prediction equation with a sufficient dataset. The present study was conducted to develop a prediction equation for Hanwoo carcass composition for which data was collected from 7,907 Hanwoo steers raised at a private farm in Gangwon Province, South Korea, and slaughtered in the period between January 2009 and September 2014. Carcass traits such as carcass weight (CWT), back fat thickness (BFT), eye-muscle area (EMA), and marbling score (MAR) were used as independent variables for the development of a prediction equation for carcass composition, such as retail cut weight and percentage (RC, and %RC, respectively), trimmed fat weight and percentage (FAT, and %FAT, respectively), and separated bone weight and percentage (BONE, and %BONE), and its feasibility for practical use was evaluated using the estimated retail yield percentage (ELP) currently used in Korea. The equations were functions of all the variables, and the significance was estimated via stepwise regression analyses. Further, the model equations were verified by means of the residual standard deviation and the coefficient of determination (R(2)) between the predicted and observed values. As the results of stepwise analyses, CWT was the most important single variable in the equation for RC and FAT, and BFT was the most important variable for the equation of %RC and %FAT. The precision and accuracy of three variable equation consisting CWT, BFT, and EMA were very similar to those of four variable equation that included all for independent variables (CWT, BFT, EMA, and MAR) in RC and FAT, while the three variable equations provided a more accurate prediction for %RC. Consequently, the three-variable equation might be more appropriate for practical use than the four variable equation based on its easy and cost-effective measurement. However, a relatively high average difference for the ELP in absolute value implies a revision of the official equation may be required, although the current official equation for predicting RC with three variables is still valid. PMID- 26954135 TI - Novel Polymorphisms of Adrenergic, Alpha-1B-, Receptor and Peroxisome Proliferator-activated Receptor Gamma, Coactivator 1 Beta Genes and Their Association with Egg Production Traits in Local Chinese Dagu Hens. AB - Adrenergic, alpha-1B-, receptor (ADRA1B) and peroxisome proliferator-activated receptor gamma, coactivator 1 beta (PPARGC1B) genes are involved in regulation of hen ovarian development. In this study, these two genes were investigated as possible molecular markers associated with hen-housed egg production, egg weight (EW) and body weight in Chinese Dagu hens. Samples were analyzed using the polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) technique, followed by sequencing analysis. Two novel single nucleotide polymorphisms (SNPs) were identified within the candidate genes. Among them, an A/G transition at base position 1915 in exon 2 of ADRA1B gene and a T/C mutation at base position 6146 in the 3'-untranslated region (UTR) of PPARGC1B gene were found to be polymorphic and named SNP A1915G and T6146C, respectively. The SNP A1915G (ADRA1B) leads to a non-synonymous substitution (aspartic acid 489-to glycine). The 360 birds from the Dagu population were divided into genotypes AA and AG, allele A was found to be present at a higher frequency. Furthermore, the AG genotype correlated with significantly higher hen-housed egg production (HHEP) at 30, 43, 57, and 66 wks of age and with a higher EW at 30 and 43 wks (p<0.05). For the SNP T6146C (PPARGC1B), the hens were typed into TT and TC genotypes, with the T allele shown to be dominant. The TC genotype was also markedly correlated with higher HHEP at 57 and 66 wks of age and EW at 30 and 43 wks (p<0.05). Moreover, four haplotypes were reconstructed based on these two SNPs, with the AGTC haplotype found to be associated with the highest HHEP at 30 to 66 wks of age and with higher EW at 30 and 43 wks (p<0.05). Collectively, the two SNPs identified in this study might be used as potential genetic molecular markers favorable in the improvement of egg productivity in chicken breeding. PMID- 26954136 TI - Beneficial Effects of Traditional Seasonings on Quality Characteristics of Fermented Sausages. AB - Though traditional seasonings are widely used in many dishes, however, no attention has been paid to the investigation of their effects on quality characteristics of food products. The present investigation was undertaken to study the effects of incorporating several traditional seasonings including doenjang (fermented soybean paste), gochu-jang (red pepper paste), fresh medium hot, and hot peppers, and fresh garlic on the lipid oxidation, cholesterol content and sensory characteristics of fermented sausages. Six fermented sausage treatments (5 with 1% (w/w) each test seasoning and 1 without added test seasoning (control) were prepared. The addition of seasonings generally had beneficial effects on the improvement of fermented sausage's quality however the effects differed depending on the each type of seasonings added. Significant lower pH values were found in all fermented sausages made with the seasonings while, lower levels of lipid oxidation were found in the treatments with hot peppers and garlic as compared with the control (p<0.05). The treatment with seasonings did not cause color or texture defects in the products whereas the sausages made with gochu-jang had significantly higher Commission International de l'Eclairagea* (redness) value in comparison with the control. Noticeably, incorporating doenjang, medium-hot peppers, hot peppers and garlic resulted in reduction of 26.50, 32.54, 47.04, and 48.54 mg cholesterol/100 g samples, respectively (p<0.05). Higher scores for the sensory traits such as aroma, taste, color and acceptability were also given for the sausages made with seasonings. The current work demonstrates that the test seasonings represent potentially natural ingredients to be used for producing healthier fermented sausages. PMID- 26954137 TI - Estimation of Genetic Parameters for First Lactation Monthly Test-day Milk Yields using Random Regression Test Day Model in Karan Fries Cattle. AB - A single trait linear mixed random regression test-day model was applied for the first time for analyzing the first lactation monthly test-day milk yield records in Karan Fries cattle. The test-day milk yield data was modeled using a random regression model (RRM) considering different order of Legendre polynomial for the additive genetic effect (4th order) and the permanent environmental effect (5th order). Data pertaining to 1,583 lactation records spread over a period of 30 years were recorded and analyzed in the study. The variance component, heritability and genetic correlations among test-day milk yields were estimated using RRM. RRM heritability estimates of test-day milk yield varied from 0.11 to 0.22 in different test-day records. The estimates of genetic correlations between different test-day milk yields ranged 0.01 (test-day 1 [TD-1] and TD-11) to 0.99 (TD-4 and TD-5). The magnitudes of genetic correlations between test-day milk yields decreased as the interval between test-days increased and adjacent test day had higher correlations. Additive genetic and permanent environment variances were higher for test-day milk yields at both ends of lactation. The residual variance was observed to be lower than the permanent environment variance for all the test-day milk yields. PMID- 26954138 TI - Evaluation of Optimum Moisture Content for Composting of Beef Manure and Bedding Material Mixtures Using Oxygen Uptake Measurement. AB - Moisture content influences physiological characteristics of microbes and physical structure of solid matrices during composting of animal manure. If moisture content is maintained at a proper level, aerobic microorganisms show more active oxygen consumption during composting due to increased microbial activity. In this study, optimum moisture levels for composting of two bedding materials (sawdust, rice hull) and two different mixtures of bedding and beef manure (BS, Beef cattle manure+sawdust; BR, Beef cattle manure+rice hull) were determined based on oxygen uptake rate measured by a pressure sensor method. A broad range of oxygen uptake rates (0.3 to 33.3 mg O2/g VS d) were monitored as a function of moisture level and composting feedstock type. The maximum oxygen consumption of each material was observed near the saturated condition, which ranged from 75% to 98% of water holding capacity. The optimum moisture content of BS and BR were 70% and 57% on a wet basis, respectively. Although BS's optimum moisture content was near saturated state, its free air space kept a favorable level (above 30%) for aerobic composting due to the sawdust's coarse particle size and bulking effect. PMID- 26954139 TI - Isolation and Identification of Prepubertal Buffalo (Bubalus bubalis) Spermatogonial Stem Cells. AB - Isolation and culture of spermatogonial stem cells (SSCs) are attractive for production of genetic modified offspring. In the present study, buffalo spermatogonial stem-like cells were isolated, cultured and expression pattern of different germ cell marker genes were determined. To recover spermatogonia, testes from age 3 to 7 months of buffalo were decapsulated, and seminiferous tubules were enzymatically dissociated. Two types of cells, immature sertoli cell and type A spermatogonia were observed in buffalo testes in this stage. Germ cell marker genes, OCT3/4 (Pou5f1), THY-1, c-kit, PGP9.5 (UCHL-1) and Dolichos biflorus agglutinin, were determined to be expressed both in mRNA and protein level by reverse transcription polymerase chain reaction and immunostaining in buffalo testes and buffalo spermatogonial stem-like cells, respectively. In the following, when the isolated buffalo buffalo spermatogonial stem-like cells were cultured in the medium supplemented 2.5% fetal bovine serum and 40 ng/mL glial cell-derived neurotrophic factor medium, SSCs proliferation efficiency and colony number were significantly improved than those of other groups (p<0.05). These findings may help in isolation and establishing long term in vitro culture system for buffalo spermatogonial stem-like cells, and accelerating the generation of genetic modified buffaloes. PMID- 26954140 TI - Effect of Dietary Supplementation of Red Ginseng By-product on Laying Performance, Blood Biochemistry, Serum Immunoglobulin and Microbial Population in Laying Hens. AB - This study was carried out to investigate the effect of dietary supplementation of red ginseng by-product (RGB) on the laying performance, blood biochemistry, and microbial population in laying hens. A total of 120 Hy-Line Brown laying hens (75 weeks old) were randomly allotted to 1 of 3 dietary treatments with 4 replicates per treatment. A commercial-type basal diet was prepared, and 2 additional diets were prepared by supplementing 5.0 or 10.0 g/kg of RGB to the basal diet at the expense of corn. The diets were fed to hens on an ad libitum basis for 4 weeks. There were no differences in feed intake, egg weight, and feed conversion ratio during 4 weeks of the feeding trial. However, hen-day egg production was significantly greater (p<0.05) for the RGB treatment groups than that for the basal treatment group. There were no differences in triglyceride, aspartate aminotransferase, and alanine aminotransferase during the 4-week feeding trial. However, RGB supplementation increased (p<0.05) the serum immunoglobulin G (IgG) and IgM content compared with basal treatment group. The total cholesterol was lower (p<0.05) in the RGB treatments groups than that in the basal treatment group. The intestinal Lactobacillus population was greater (p<0.05) for the RGB treatments groups than that for the basal treatment group. However, the numbers of Salmonella and Escherichia coli were not different among dietary treatments. During the entire experiment, there was no significant difference in egg quality among all the treatments. In conclusion, in addition to improving hen-day production, there were positive effects of dietary RGB supplementation on serum immunoglobulin and cholesterol levels in laying hens. PMID- 26954141 TI - Carcass Traits and Meat Quality of Prestice Black-Pied Pig Breed. AB - The objective of the study was to evaluate fattening performance, carcass value and meat quality in pigs of Prestice Black-Pied breed in relation to slaughter weight (SW) and gender (barrows and gilts, resp.). Pigs were divided into weight categories: SW1 (75 to 99.9 kg), SW2 (100 to 109.9 kg) and SW3 (110 to 130 kg) and all individual traits were analyzed by the general linear model procedure (SAS 9.3). Average SW of each weight group was as follows: SW1 94.2 kg, SW2 105.8 kg, and SW3 115.2 kg. Differences among average backfat thickness of 36.07 mm in SW1, 40.16 mm in SW2, and 43.21 mm in SW3 were significant (p<0.01). Lean meat content was 48.94% (SW1), 48.78% (SW2), and 48.76% (SW3). Pigs were slaughtered at average weight of 105.7 kg for barrows and 104.4 kg for gilts. Average backfat thickness for barrows was 40.90 mm and 38.72 mm for gilts (significant difference p<0.05). Lean meat content was 48.75% in barrows and 48.91% in gilts. The values of pH45, characterizing the meat of very good quality. The loin in SW3 was darker than the muscles of SW1 and SW2. Drip loss was the lowest in SW1 (1.96%), compared to the highest drip loss in SW3 (2.59%). Content of intramuscular fat was 2.68% in SW3, 2.79% in SW2, and SW1 had the lowest content 2.47%. The values of pH45, colour lightness and drip loss were similar in both genders. However barrows had higher intramuscular fat content by 0.31% than gilts (p<0.05). PMID- 26954142 TI - Quality Characteristics and Composition of the Longissimus Muscle from Entire and Castrate Elk in Korea. AB - The objective of the research was to determine the chemical composition as well as the physicochemical properties of the longissimus muscle from Korean entire and castrate elk. Twelve elk stags were raised and fed on concentrate with ad libitum hay. All animals were equally divided into castrated and non-castrated (entire) males, and slaughtered at 5 year of age. It was found that entire elk, in comparison with castrate elk, had higher content of moisture and lower content of fat (p<0.05). Compared with entire males, the castrates had lower pH and shear force values (p<0.05). However, castrates had higher L*, a*, and b* values compared with entires (p<0.05). An analysis of the fatty acid profile revealed that the muscles of entire and castrate elk had the most abundant concentrations of the following fatty acids: palmitic acid (C16:0) of the saturated fatty acid, and oleic acid (C18:1n-9) of the unsaturated fatty acid. The entire elk contains higher proportions of linoleic acid (C18:3n6), eicosenoic acid (C20:1n9), and arachidonic acid (C20:4n6) (p<0.05). Cholesterol content in elk was not affected by castration. The predominant free amino acid was glutamic acid related to umami taste. It is apparent that the castrate animals carried higher content of histidine, isoleucine, and leucine than those of the entire group (p<0.05). In this study, it was concluded that venison quality of elk is affected by castration and these results can provide fundamental information for venison production. PMID- 26954143 TI - Characterization of the Methylation Status of Pax7 and Myogenic Regulator Factors in Cell Myogenic Differentiation. AB - Epigenetic processes in the development of skeletal muscle have been appreciated for over a decade. DNA methylation is a major epigenetic modification important for regulating gene expression and suppressing spurious transcription. Up to now, the importance of epigenetic marks in the regulation of Pax7 and myogenic regulatory factors (MRFs) expression is far less explored. In the present study, semi-quantitative the real-time polymerase chain reaction (RT-PCR) analyses showed MyoD and Myf5 were expressed in activated and quiescent C2C12 cells. MyoG was expressed in a later stage of myogenesis. Pax7 was weakly expressed in differentiated C2C12 cells. To further understand the regulation of expression of these genes, the DNA methylation status of Pax7, MyoD, and Myf5 was determined by bisulfite sequencing PCR. During the C2C12 myoblasts fusion process, the changes of promoter and exon 1 methylation of Pax7, MyoD, and Myf5 genes were observed. In addition, an inverse relationship of low methylation and high expression was found. These results suggest that DNA methylation may be an important mechanism regulating Pax7 and MRFs transcription in cell myogenic differentiation. PMID- 26954145 TI - Relationship between Molecular Structure Characteristics of Feed Proteins and Protein In vitro Digestibility and Solubility. AB - The nutritional value of feed proteins and their utilization by livestock are related not only to the chemical composition but also to the structure of feed proteins, but few studies thus far have investigated the relationship between the structure of feed proteins and their solubility as well as digestibility in monogastric animals. To address this question we analyzed soybean meal, fish meal, corn distiller's dried grains with solubles, corn gluten meal, and feather meal by Fourier transform infrared (FTIR) spectroscopy to determine the protein molecular spectral band characteristics for amides I and II as well as alpha helices and beta-sheets and their ratios. Protein solubility and in vitro digestibility were measured with the Kjeldahl method using 0.2% KOH solution and the pepsin-pancreatin two-step enzymatic method, respectively. We found that all measured spectral band intensities (height and area) of feed proteins were correlated with their the in vitro digestibility and solubility (p<=0.003); moreover, the relatively quantitative amounts of alpha-helices, random coils, and alpha-helix to beta-sheet ratio in protein secondary structures were positively correlated with protein in vitro digestibility and solubility (p<=0.004). On the other hand, the percentage of beta-sheet structures was negatively correlated with protein in vitro digestibility (p<0.001) and solubility (p = 0.002). These results demonstrate that the molecular structure characteristics of feed proteins are closely related to their in vitro digestibility at 28 h and solubility. Furthermore, the alpha-helix-to-beta-sheet ratio can be used to predict the nutritional value of feed proteins. PMID- 26954144 TI - Gut Health of Pigs: Challenge Models and Response Criteria with a Critical Analysis of the Effectiveness of Selected Feed Additives - A Review. AB - The gut is the largest organ that helps with the immune function. Gut health, especially in young pigs has a significant benefit to health and performance. In an attempt to maintain and enhance intestinal health in pigs and improve productivity in the absence of in-feed antibiotics, researchers have evaluated a wide range of feed additives. Some of these additives such as zinc oxide, copper sulphate, egg yolk antibodies, mannan-oligosaccharides and spray dried porcine plasma and their effectiveness are discussed in this review. One approach to evaluate the effectiveness of these additives in vivo is to use an appropriate disease challenge model. Over the years, researchers have used a number of challenge models which include the use of specific strains of enterotoxigenic Escherichia coli, bacteria lipopolysaccharide challenge, oral challenge with Salmonella enteric serotype Typhimurium, sanitation challenge, and Lawsonia intercellularis challenge. These challenge models together with the criteria used to evaluate the responses of the animals to them are also discussed in this review. PMID- 26954146 TI - The Effects of Glucagon-like Peptide-2 on the Tight Junction and Barrier Function in IPEC-J2 Cells through Phosphatidylinositol 3-kinase-Protein Kinase B-Mammalian Target of Rapamycin Signaling Pathway. AB - Glucagon-like peptide-2 (GLP-2) is important for intestinal barrier function and regulation of tight junction (TJ) proteins, but the intracellular mechanisms of action remain undefined. The purpose of this research was to determine the protective effect of GLP-2 mediated TJ and transepithelial electrical resistance (TER) in lipopolysaccharide (LPS) stressed IPEC-J2 cells and to test the hypothesis that GLP-2 regulate TJ and TER through the phosphatidylinositol 3 kinase (PI3K)-protein kinase B (Akt)-mammalian target of rapamycin (mTOR) signaling pathway in IPEC-J2 cells. Wortmannin and LY294002 are specific inhibitors of PI3K. The results showed that 100 MUg/mL LPS stress decreased TER and TJ proteins occludin, claudin-1 and zonula occludens protein 1 (ZO-1) mRNA, proteins expressions (p<0.01) respectively. GLP-2 (100 nmol/L) promote TER and TJ proteins occludin, claudin-1, and zo-1 mRNA, proteins expressions in LPS stressed and normal IPEC-J2 cells (p<0.01) respectively. In normal cells, both wortmannin and LY294002, PI3K inhibitors, prevented the mRNA and protein expressions of Akt and mTOR increase induced by GLP-2 (p<0.01) following with the significant decreasing of occludin, claudin-1, ZO-1 mRNA and proteins expressions and TER (p<0.01). In conclusion, these results indicated that GLP-2 can promote TJ's expression and TER in LPS stressed and normal IPEC-J2 cells and GLP-2 could regulate TJ and TER through the PI3K/Akt/mTOR pathway. PMID- 26954147 TI - Nutritional Performance of Cattle Grazing during Rainy Season with Nitrogen and Starch Supplementation. AB - The objective of this work was to evaluate the effects of supplementation with nitrogen and starch on the nutritional performance of grazing cattle during the rainy season. Five rumen cannulated Nellore steers, averaging 211 kg of body weight (BW), were used. Animals grazed on five signal grass paddocks. Five treatments were evaluated: control (forage only), ruminal supplementation with nitrogen at 1 g of crude protein (CP)/kg BW, ruminal supplementation with starch at 2.5 g/kg BW, supplementation with nitrogen (1 g CP/kg BW) and starch (2.5 g/kg BW), and supplementation with nitrogen (1 g CP/kg BW) and a mixture of corn starch and nitrogenous compounds (2.5 g/kg BW), thereby resulting in an energy part of the supplement with 150 g CP/kg of dry matter (DM). This last treatment was considered an additional treatment. The experiment was carried out according to a 5 *5 Latin square design following a 2*2+1 factorial arrangement (with or without nitrogen, with or without starch, and the additional treatment). Nitrogen supplementation did not affect (p>0.10) forage intake. Starch supplementation increased (p<0.10) total intake but did not affect (p<0.10) forage intake. There was an interaction between nitrogen and starch (p<0.10) for organic matter digestibility. Organic matter digestibility was increased only by supplying starch and nitrogen together. Nitrogen balance (NB) was increased (p<0.10) by the nitrogen supplementation as well as by starch supplementation. Despite this, even though a significant interaction was not observed (p>0.10), NB obtained with nitrogen plus starch supplementation was greater than NB obtained with either nitrogen or starch exclusive supplementation. Supplementation with starch and nitrogen to beef cattle grazing during the rainy season can possibly improve digestion and nitrogen retention in the animal.. PMID- 26954148 TI - Antioxidant Enzyme Activity, Iron Content and Lipid Oxidation of Raw and Cooked Meat of Korean Native Chickens and Other Poultry. AB - This study was conducted to observe antioxidant enzyme activity, iron content and lipid oxidation of Korean native chickens and other poultry. The breast and thigh meat of three Korean native chicken breeds including Woorimatdak, Hyunin black and Yeonsan ogye, and three commercial poultry breeds including the broiler, White Leghorn and Pekin duck (Anasplatyrhyncos domesticus) were studied. The analyses of the antioxidant enzymes activity, iron content and lipid oxidation were performed in raw and cooked samples. The activity of catalase (CAT) in the thigh meat was higher than that of the breast meat of three Korean native chickens and the broiler, respectively. The activity of glutathione peroxidase (GPx) in the uncooked thigh meat of three Korean native chickens was higher than that of the breasts. The breast meat of Woorimatdak and Pekin duck had higher superoxide dismutase (SOD) activity than the others, while only the thigh meat of Pekin duck had the highest activity. Cooking inactivated CAT and decreased the activity of GPx and SOD. The thigh meat of Woorimatdak, White Leghorn, Yeonsan ogye and Hyunin black contained more total iron than the breast meat of those breeds. The heme-iron lost during cooking ranged from 3.2% to 14.8%. It is noted that the thigh meat had higher thiobarbituric acid reactive substances values than the breast in all chicken breeds. Though Woorimatdak showed higher antioxidant enzyme activity and lower released-iron percentage among Korean native chickens, no differences were found on lipid oxidation. We confirm that the dark meat of poultry exhibited higher antioxidant enzyme activity and contained more iron than the white meat. PMID- 26954149 TI - Performance and Metabolism of Calves Fed Starter Feed Containing Sugarcane Molasses or Glucose Syrup as a Replacement for Corn. AB - The aim of this study was to evaluate the effect of replacing corn grain for sugar cane molasses (MO) or glucose syrup (GS) in the starter concentrate on performance and metabolism of dairy calves. Thirty-six individually housed Holstein male calves were blocked according to weight and date of birth and assigned to one of the starter feed treatments, during an 8 week study: i) starter containing 65% corn with no MO or GS (0MO); ii) starter containing 60% corn and 5% MO (5MO); iii) starter containing 55% corn and 10% MO (10MO); and iv) starter containing 60% corn and 5% GS (5GS). Animals received 4 L of milk replacer daily (20 crude protein, 16 ether extract, 12.5% solids), divided in two meals (0700 and 1700 h). Starter and water were provided ad libitum. Starter intake and fecal score were monitored daily until animals were eight weeks old. Body weight and measurements (withers height, hip width and heart girth) were measured weekly before the morning feeding. From the second week of age, blood samples were collected weekly, 2 h after the morning feeding, for glucose, beta hydroxybutyrate and lactate determination. Ruminal fluid was collected at 4, 6, and 8 weeks of age using an oro-ruminal probe and a suction pump for determination of pH and short-chain fatty acids (SCFA). At the end of the eighth week, animals were harvested to evaluate development of the proximal digestive tract. The composition of the starter did not affect (p>0.05) concentrate intake, weight gain, fecal score, blood parameters, and rumen development. However, treatment 5MO showed higher (p<0.05) total concentration of SCFAs, acetate and propionate than 0MO, and these treatments did not differ from 10MO and 5GS (p>0.05). Thus, it can be concluded that the replacement of corn by 5% or 10% sugar cane molasses or 5% GS on starter concentrate did not impact performance, however it has some positive effects on rumen fermentation which may be beneficial for calves with a developing rumen. PMID- 26954150 TI - Investigations on Genetic Architecture of Hairy Loci in Dairy Cattle by Using Single and Whole Genome Regression Approaches. AB - Development of body hair is an important physiological and cellular process that leads to better adaption in tropical environments for dairy cattle. Various studies suggested a major gene and, more recently, associated genes for hairy locus in dairy cattle. Main aim of this study was to i) employ a variant of the discordant sib pair model, in which half sibs from the same sires are randomly sampled using their affection statues, ii) use various single marker regression approaches, and iii) use whole genome regression approaches to dissect genetic architecture of the hairy gene in the cattle. Whole and single genome regression approaches detected strong genomic signals from Chromosome 23. Although there is a major gene effect on hairy phenotype sourced from chromosome 23: whole genome regression approach also suggested polygenic component related with other parts of the genome. Such a result could not be obtained by any of the single marker approaches. PMID- 26954151 TI - Production of Transgenic Pigs with an Introduced Missense Mutation of the Bone Morphogenetic Protein Receptor Type IB Gene Related to Prolificacy. AB - In the last few decades, transgenic animal technology has witnessed an increasingly wide application in animal breeding. Reproductive traits are economically important to the pig industry. It has been shown that the bone morphogenetic protein receptor type IB (BMPR1B) A746G polymorphism is responsible for the fertility in sheep. However, this causal mutation exits exclusively in sheep and goat. In this study, we attempted to create transgenic pigs by introducing this mutation with the aim to improve reproductive traits in pigs. We successfully constructed a vector containing porcine BMPR1B coding sequence (CDS) with the mutant G allele of A746G mutation. In total, we obtained 24 cloned male piglets using handmade cloning (HMC) technique, and 12 individuals survived till maturation. A set of polymerase chain reactions indicated that 11 of 12 matured boars were transgene-positive individuals, and that the transgenic vector was most likely disrupted during cloning. Of 11 positive pigs, one (No. 11) lost a part of the terminator region but had the intact promoter and the CDS regions. cDNA sequencing showed that the introduced allele (746G) was expressed in multiple tissues of transgene-positive offspring of No.11. Western blot analysis revealed that BMPR1B protein expression in multiple tissues of transgene-positive F1 piglets was 0.5 to 2-fold higher than that in the transgene-negative siblings. The No. 11 boar showed normal litter size performance as normal pigs from the same breed. Transgene-positive F1 boars produced by No. 11 had higher semen volume, sperm concentration and total sperm per ejaculate than the negative siblings, although the differences did not reached statistical significance. Transgene-positive F1 sows had similar litter size performance to the negative siblings, and more data are needed to adequately assess the litter size performance. In conclusion, we obtained 24 cloned transgenic pigs with the modified porcine BMPR1B CDS using HMC. cDNA sequencing and western blot indicated that the exogenous BMPR1B CDS was successfully expressed in host pigs. The transgenic pigs showed normal litter size performance. However, no significant differences in litter size were found between transgene-positive and negative sows. Our study provides new insight into producing cloned transgenic livestock related to reproductive traits. PMID- 26954152 TI - Behavioral Characteristics of Weaned Piglets Mixed in Different Groups. AB - With regard to animal welfare concerns, behavioral information of weaned and mixed piglets is great interest in swine production. The aim of this study was to demonstrate the change in behavior of weaned piglets over time in two different groups (littermates and piglets from different litters) after mixing. Two weaned groups of piglets (72 individuals in all) housed either with littermates or with foreign piglets (6 individuals in 1.8 m*1.4 m pens, 28 degrees C+/-1 degrees C temperature) were observed with the aid of video technology for 9 consecutive hours on days 1, 2, and 3 after mixing. The behaviors of the weaned piglets in the control and treatment groups were significantly different among the days after mixing. Piglets were, however, more active and aggressive in the groups with foreign piglets. This study reveals a lower level of agonistic behavior in groups of piglets that came from the same litter. PMID- 26954153 TI - Effects of Condensed Tannins in Mao (Antidesma thwaitesianum Muell. Arg.) Seed Meal on Rumen Fermentation Characteristics and Nitrogen Utilization in Goats. AB - Mao seed is a by-product of the wine and juice industry, which could be used in animal nutrition. The current study was designed to determine the effect of supplementation of mao (Antidesma thwaitesianum Muell. Arg.) seed meal (MOSM) containing condensed tannins (CT) on rumen fermentation, nitrogen (N) utilization and microbial protein synthesis in goats. Four crossbred (Thai Native*Anglo Nubian) goats with initial body weight (BW) 20+/-2 kg were randomly assigned to a 4*4 Latin square design. The four dietary treatments were MOSM supplementation at 0%, 0.8%, 1.6%, and 2.4% of total dry matter (DM) intake, respectively. During the experimental periods, all goats were fed a diet containing roughage to concentrate ratio of 60:40 at 3.0% BW/d and pangola grass hay was used as a roughage source. Results showed that supplementation with MOSM did not affect feed intake, nutrient intakes and apparent nutrient digestibility (p>0.05). In addition, ruminal pH and ammonia nitrogen (NH3-N) were not influenced by MOSM supplementation, whilst blood urea nitrogen was decreased quadraticly (p<0.05) in goats supplemented with MOSM at 2.4% of total DM intake. Propionate was increased linearly with MOSM supplementation, whereas acetate and butyrate were remained the same. Moreover, estimated ruminal methane (CH4) was decreased linearly (p<0.05) when goats were fed with MOSM at 1.6% and 2.4% of total DM intake. Numbers of bacteria and protozoa were similar among treatments (p>0.05). There were linear decreases in urinary N (p<0.01) and total N excretion (p<0.01) by MOSM supplementation. Furthermore, N retention was increased linearly (p<0.05) when goats were fed with MOSM supplementation at 1.6% and 2.4% of total DM intake. Microbial protein synthesis were not significantly different among treatments (p>0.05). From the current study, it can be concluded that supplementation of MOSM at 1.6% to 2.4% of total DM intake can be used to modify ruminal fermentation, especially propionate and N utilization in goats, without affecting the nutrient digestibility, microbial populations and microbial protein synthesis. PMID- 26954154 TI - Ginsenoside Rg1 Improves In vitro-produced Embryo Quality by Increasing Glucose Uptake in Porcine Blastocysts. AB - Ginsenoside Rg1 is a natural compound with various efficacies and functions. It has beneficial effects on aging, diabetes, and immunity, as well as antioxidant and proliferative functions. However, its effect on porcine embryo development remains unknown. We investigated the effect of ginsenoside Rg1 on the in vitro development of preimplantation porcine embryos after parthenogenetic activation in high-oxygen conditions. Ginsenoside treatment did not affect cleavage or blastocyst formation rates, but did increase the total cell number and reduced the rate of apoptosis. In addition, it had no effect on the expression of four apoptosis-related genes (Bcl-2 homologous antagonist/killer, B-cell lymphoma extra large, Caspase 3, and tumor protein p53) or two metabolism-related genes (mechanistic target of rapamycin, carnitine palmitoyltransferase 1B), but increased the expression of Glucose transporter 1 (GLUT1), indicating that it may increase glucose uptake. In summary, treatment with the appropriate concentration of ginsenoside Rg1 (20 MUg/mL) can increase glucose uptake, thereby improving the quality of embryos grown in high-oxygen conditions. PMID- 26954155 TI - Evaluation of Relative Bioavailability of 25-Hydroxycholecalciferol to Cholecalciferol for Broiler Chickens. AB - This study was conducted to evaluate the relative bioavailability (RBV) of 25 hydroxycholecalciferol (25-OH-D3) to cholecalciferol (vitamin D3) in 1- to 21-d old broiler chickens fed with calcium (Ca)- and phosphorus (P)-deficient diets. On the day of hatch, 450 female Ross 308 broiler chickens were assigned to nine treatments, with five replicates of ten birds each. The basal diet contained 0.50% Ca and 0.25% non-phytate phosphorus (NPP) and was not supplemented with vitamin D. Vitamin D3 was fed at 0, 2.5, 5.0, 10.0, and 20.0 MUg/kg, and 25-OH-D3 was fed at 1.25, 2.5, 5.0, and 10.0 MUg/kg. The RBV of 25-OH-D3 was determined using vitamin D3 as the standard source by the slope ratio method. Vitamin D3 and 25-OH-D3 intake was used as the independent variable for regression analysis. The linear relationships between the level of vitamin D3 or 25-OH-D3 and body weight gain (BWG) and the weight, length, ash weight, and the percentage of ash, Ca, and P in femur, tibia, and metatarsus of broiler chickens were observed. Using BWG as the criterion, the RBV value of 25-OH-D3 to vitamin D3 was 1.85. Using the mineralization of the femur, tibia, and metatarsus as criteria, the RBV of 25-OH D3 to vitamin D3 ranged from 1.82 to 2.45, 1.86 to 2.52, and 1.65 to 2.05, respectively. These data indicate that 25-OH-D3 is approximately 2.03 times as active as vitamin D3 in promoting growth performance and bone mineralization in broiler chicken diets. PMID- 26954156 TI - Carcass and Meat Quality Traits in an Embden*Toulouse Goose Cross Raised in Organic Dehesa. AB - This study assessed the influence of genetic type (Embden-Anser anser, EE; Toulouse-Anser anser, TT and F1 cross, ET) for meat characteristics (carcass, meat quality and fatty acid (FA) profiles), of domestic geese "Anser anser domesticus" raised in dehesa as an alternative, organic feeding system. Carcass and breast muscle weight (p<0.01) were greater for the ET group at the same live weight. None of the groups showed differences in the production of fatty liver with this type of feeding. Higher values were found for maximum Warner-Bratzler shear force (between 7.62 and 8.87 kg/cm(2)), which implies the improvement of this parameter. High levels of oleic FAs were obtained, especially for the TT group. The polyunsaturated/saturated FA ratio was highest for the ET group (p<0.001), reflecting the optimum nutritional values as a component of a healthy consumer diet. PMID- 26954157 TI - In vitro Screening of Essential Oil Active Compounds for Manipulation of Rumen Fermentation and Methane Mitigation. AB - The objective of this study was to investigate the effects of 11 active compounds of essential oils (ACEO) on rumen fermentation characteristics and methane production. Two trials were conducted. In trial 1, ACEO (eugenol, carvacrol, citral, limonene, 1,4-cineole, p-cymene, linalool, bornyl acetate, alpha-pinene, and beta-pinene) at a dose of 1,000 MUL/L were incubated for 24 h in diluted rumen fluid with a 70:30 forage:concentrate substrate (16.2% crude protein; 36.6% neutral detergent fiber). Three fistulated Holstein cows were used as donors of rumen fluid. The reduction in methane production was observed with nine ACEO (up to 86% reduction) compared with the control (p<0.05). Among these, only limonene, 1,4-cineole, bornyl acetate, and alpha-pinene did not inhibit volatile fatty acid (VFA) production, and only bornyl acetate produced less methane per mol of VFA compared with the control (p<0.05). In a subsequent trial, the effects on rumen fermentation and methane production of two concentrations (500 and 2,000 MUL/L) of bornyl acetate, the most promising ACEO from the first trial, were evaluated using the same in vitro incubation method that was used in the first trial. In trial 2, monensin was used as a positive control. Both doses of bornyl acetate decreased (p<0.05) methane production and did not inhibit VFA production. Positive effects of bornyl acetate on methane and VFA production were more pronounced than the effects of monensin. These results confirm the ability of bornyl acetate to decrease methane production, which may help to improve the efficiency of energy use in the rumen. PMID- 26954158 TI - Rapamycin Influences the Efficiency of In vitro Fertilization and Development in the Mouse: A Role for Autophagic Activation. AB - The mammalian target of rapamycin (mTOR) regulates cellular processes such as cell growth, metabolism, transcription, translation, and autophagy. Rapamycin is a selective inhibitor of mTOR, and induces autophagy in various systems. Autophagy contributes to clearance and recycling of macromolecules and organelles in response to stress. We previously reported that vitrified-warmed mouse oocytes show acute increases in autophagy during warming, and suggested that it is a natural response to cold stress. In this follow-up study, we examined whether the modulation of autophagy influences survival, fertilization, and developmental rates of vitrified-warmed mouse oocytes. We used rapamycin to enhance autophagy in metaphase II (MII) oocytes before and after vitrification. The oocytes were then subjected to in vitro fertilization (IVF). The fertilization and developmental rates of vitrified-warmed oocytes after rapamycin treatment were significantly lower than those for control groups. Modulation of autophagy with rapamycin treatment shows that rapamycin-induced autophagy exerts a negative influence on fertilization and development of vitrified-warmed oocytes. PMID- 26954159 TI - Improvement of Nutritive Value and In vitro Ruminal Fermentation of Leucaena Silage by Molasses and Urea Supplementation. AB - Leucaena silage was supplemented with different levels of molasses and urea to study its nutritive value and in vitro rumen fermentation efficiency. The ensiling study was randomly assigned according to a 3*3 factorial arrangement in which the first factor was molasses (M) supplement at 0%, 1%, and 2% of crop dry matter (DM) and the second was urea (U) supplement as 0%, 0.5%, and 1% of the crop DM, respectively. After 28 days of ensiling, the silage samples were collected and analyzed for chemical composition. All the nine Leucaena silages were kept for study of rumen fermentation efficiency using in vitro gas production techniques. The present result shows that supplementation of U or M did not affect DM, organic matter, neutral detergent fiber, and acid detergent fiber content in the silage. However, increasing level of U supplementation increased crude protein content while M level did not show any effect. Moreover, the combination of U and M supplement decreased the content of mimosine concentration especially with M2U1 (molasses 2% and urea 1%) silage. The result of the in vitro study shows that gas production kinetics, cumulation gas at 96 h and in vitro true digestibility increased with the increasing level of U and M supplementation especially in the combination treatments. Supplementation of M and U resulted in increasing propionic acid and total volatile fatty acid whereas, acetic acid, butyric acid concentrations and methane production were not changed. In addition, increasing U level supplementation increased NH3-N concentration. Result from real-time polymerase chain reaction revealed a significant effect on total bacteria, whereas F. succinogenes and R. flavefaciens population while R. albus was not affected by the M and U supplementation. Based on this study, it could be concluded that M and urea U supplementation could improve the nutritive value of Leucaena silage and enhance in vitro rumen fermentation efficiency. This study also suggested that the combination use of M and U supplementation level was at 2% and 1%, respectively. PMID- 26954160 TI - The Effects of Dietary Phosphorus on the Growth Performance and Phosphorus Excretion of Dairy Heifers. AB - The objective of this study was to investigate the effects of reducing dietary phosphorus (P) on the frame size, udder traits, blood parameters and nutrient digestibility coefficient in 8- to 10-month-old Holstein heifers. Forty-five heifers were divided into 15 blocks according to the mo of age and were randomly assigned one of three dietary treatments: 0.26% (low P [LP]), 0.36% (medium P [MP]), or 0.42% (high P [HP]) (dry matter basis). Samples were collected at the wk 1, 4, 8. The results show that low dietary P had no effect on body measurement. The blood P concentration decreased with decreasing dietary P (p<0.05), while the blood calcium content of LP was higher than that of the MP and HP groups (p<0.05), though still in the normal range. The serum contents of alkalinephosphatase, potassium, and magnesium were similar among the treatments. No differences were found in all nutrients' apparent digestibility coefficients with varied dietary P. However, with P diet decreased from HP to LP, the total fecal P and urine P concentration declined significantly, as did fecal water soluble P (p<0.05). In conclusion, reducing the dietary P from 0.42% to 0.26% did not negatively affect the heifers' growth performance but did significantly lessen manure P excretion into the environment. PMID- 26954161 TI - Effect of Sodium Chloride Replacement on the Sensory and Physico-Chemical Properties of Restructured Chicken Jerky. AB - Replacement of sodium chloride (NaCl) with potassium chloride (KCl) and potassium lactate (KLact) in restructured chicken jerky was studied. The experiment was conducted considering three levels of each NaCl (1%, 1.5%, 2%), KCl (0%, 0.5%, 1%) and KLact (0%, 0.5%, 1%) resulting in six treatments with a total salt content of 2% in the product. Physico-chemical and sensory properties of the jerky containing salt replacers were examined and the most suitable NaCl replacement was to be identified. The jerky samples had moisture content below 25%, more than 60% protein and about 5-6% fat. All samples attained a water activity level below 0.8 after 5 hours of drying. Reduction of NaCl in jerky led to increased shrinkage and shear force values. Significant difference was also observed in the hunter color values especially in the case of L* values which increased as the NaCl content in the samples decreased. Scanning electron microscopy images showed that replacing NaCl reduced the structural density and compactness in jerky. Sensory panelists preferred treatments with only KCl. According to principal component analysis carried out and from sensory point of view, 50% replacement of NaCl with KCl was found to be most suitable strategy for developing low sodium jerky without compromising the product quality. (Key words: Restructured jerky, salt replacement, Sensory analysis, JAR profile, Microstructure, Dried meat). PMID- 26954162 TI - Genome-association analysis of Korean Holstein milk traits using genomic estimated breeding value. AB - OBJECTIVE: Holsteins are known as the world's highest-milk producing dairy cattle. The purpose of this study was to identify genetic regions strongly associated with milk traits (milk production, fat, and protein) using Korean Holstein data. METHODS: This study was performed using single nucleotide polymorphism (SNP) chip data (Illumina BovineSNP50 Beadchip) of 911 Korean Holstein individuals. We inferred each genomic estimated breeding values based on best linear unbiased prediction (BLUP) and ridge regression using BLUPF90 and R. We then performed a genome-wide association study and identified genetic regions related to milk traits. RESULTS: We identified 9, 6, and 17 significant genetic regions related to milk production, fat and protein, respectively. These genes are newly reported in the genetic association with milk traits of Holstein. CONCLUSION: This study complements a recent Holstein genome-wide association studies that identified other SNPs and genes as the most significant variants. These results will help to expand the knowledge of the polygenic nature of milk production in Holsteins. PMID- 26954163 TI - Chemical Composition, Nitrogen Fractions and Amino Acids Profile of Milk from Different Animal Species. AB - Milk composition is an imperative aspect which influences the quality of dairy products. The objective of study was to compare the chemical composition, nitrogen fractions and amino acids profile of milk from buffalo, cow, sheep, goat, and camel. Sheep milk was found to be highest in fat (6.82%+/-0.04%), solid not-fat (11.24%+/-0.02%), total solids (18.05%+/-0.05%), protein (5.15%+/-0.06%) and casein (3.87%+/-0.04%) contents followed by buffalo milk. Maximum whey proteins were observed in camel milk (0.80%+/-0.03%), buffalo (0.68%+/-0.02%) and sheep (0.66%+/-0.02%) milk. The non-protein-nitrogen contents varied from 0.33% to 0.62% among different milk species. The highest r-values were recorded for correlations between crude protein and casein in buffalo (r = 0.82), cow (r = 0.88), sheep (r = 0.86) and goat milk (r = 0.98). The caseins and whey proteins were also positively correlated with true proteins in all milk species. A favorable balance of branched-chain amino acids; leucine, isoleucine, and valine were found both in casein and whey proteins. Leucine content was highest in cow (108+/-2.3 mg/g), camel (96+/-2.2 mg/g) and buffalo (90+/-2.4 mg/g) milk caseins. Maximum concentrations of isoleucine, phenylalanine, and histidine were noticed in goat milk caseins. Glutamic acid and proline were dominant among non-essential amino acids. Conclusively, current exploration is important for milk processors to design nutritious and consistent quality end products. PMID- 26954164 TI - Effect of Bacillus subtilis Natto on Meat Quality and Skatole Content in TOPIGS Pigs. AB - This study investigated the effect of Bacillus subtilis (B. subtilis) natto on meat quality and skatole in TOPIGS pigs. Sixty TOPIGS pigs were randomly assigned to 3 groups (including 5 pens per group, with 4 pigs in each pen) and fed with basic diet (control group), basic diet plus 0.1% B. subtilis natto (B group), and basic diet plus 0.1% B. subtilis natto plus 0.1% B. coagulans (BB group), respectively. All pigs were sacrificed at 100 kg. Growth performance, meat quality, serum parameters and oxidation status in the three groups were assessed and compared. Most parameters regarding growth performance and meat quality were not significantly different among the three groups. However, compared with the control group, meat pH24, fat and feces skatole and the content of Escherichia coli (E. Coli), Clostridium, NH3-N were significantly reduced in the B and BB groups, while serum total cholesterol, high density lipoprotein, the levels of liver P450, CYP2A6, and CYP2E1, total antioxidant capability (T-AOC) and glutathione peroxidase and Lactobacilli in feces were significantly increased in the B and BB groups. Further, the combined supplementation of B. subtilis natto and B. coagulans showed more significant effects on the parameters above compared with B. subtilis, and Clostridium, and NH3-N. Our results indicate that the supplementation of pig feed with B. subtilis natto significantly improves meat quality and flavor, while its combination with B. coagulans enhanced these effects. PMID- 26954165 TI - Effect of Monochromic Light-emitting Diode Light with Different Color on the Growth and Reproductive Performances of Breeder Geese. AB - The purpose of this study was to investigate the effect of monochromic light emitting diode (LED) light with different color on the growth and reproductive performances of white Roman breeder geese. A randomized complete batch design was utilized for the trial, and the replicate was regarded as one batch. Twenty ganders and fifty-five dames were used in batch 1 (started on 2011/6/17 and ended on 2012/1/31), thirty ganders and eighty-four dames were used in batch 2 (started on 2012/3/23 and ended on 2012/10/26), and thirty ganders and seventy-two dames were used in batch 3 (started on 2013/3/12 and ended on 2013/12/20). Two hundred and ninety-one geese were randomly assigned to 6 rooms in an environmentally controlled house. They were randomly allotted into one of three monochromatic light treatments: Blue, red, or white. The results showed that there was no significant difference in body weight among the three lighting groups at any point throughout the experimental period. However, compared to the blue light group, significantly more eggs were produced by the red and white light groups (p<0.05). Furthermore, the laying period of the red light group was significantly longer than that of other two groups (p<0.05). In conclusion, our results suggested that red LED-light has the best effect on reproductive performance (i.e. longer laying period and higher total eggs number) at 30 lux light intensity, and is therefore a better choice for the management of breeding geese than blue or white LED-light. PMID- 26954166 TI - Tudor Domain Containing Protein TDRD12 Expresses at the Acrosome of Spermatids in Mouse Testis. AB - Tdrd12 is one of tudor domain containing (Tdrd) family members. However, the expression pattern of Tdrd12 has not been well studied. To compare the expression levels of Tdrd12 in various tissues, real time-polymerase chain reaction was performed using total RNAs from liver, small intestine, heart, brain, kidney, lung, spleen, stomach, uterus, ovary, and testis. Tdrd12 mRNA was highly expressed in testis. Antibody against mouse TDRD12 were generated using amino acid residues SQRPNEKPLRLTEKKDC of TDRD12 to investigate TDRD12 localization in testis. Immunostaining assay shows that TDRD12 is mainly localized at the spermatid in the seminiferous tubules of adult testes. During postnatal development, TDRD12 is differentially expressed. TDRD12 was detected in early spermatocytes at 2 weeks and TDRD12 was localized at acrosome of the round spermatids. TDRD12 expression was not co-localized with TDRD1 which is an important component of piRNA pathway in germ cells. Our results indicate that TDRD12 may play an important role in spermatids and function as a regulator of spermatogenesis in dependent of TDRD1. PMID- 26954167 TI - Yeast Culture and Vitamin E Supplementation Alleviates Heat Stress in Dairy Goats. AB - This study was conducted to determine and compare the effects of yeast yeast culture (YC) and vitamin E (VE) supplementation on endotoxin absorption and antioxidant status in lactating dairy goats suffering from heat stress (HS). Three first lactation Saanen dairy goats (body weight 30+/-1.5 kg) were surgically fitted with indwelling catheters in the portal vein, mesenteric vein and carotid artery, and were randomly assigned to a 3*3 Latin square design. Dietary treatments were the basal diet, and the basal diet supplemented with either 100 IU VE or 30 g YC. Goats were kept in temperature and humidity controlled room at 35 degrees C from 8:00 to 20:00 and at 24 degrees C from 20:00 till the next morning at 8:00. The relative humidity was kept at 55%. HS increased dairy goats' rectum temperature and respiration frequency (p<0.01). HS reduced plasma flux rate of milk goats (p<0.01), but the plasma flux rate increased when the animal was under the conditions of the thermo-neutral period (p<0.01). The VE supplementation lowered dairy goats' rectum temperature during thermo-neutral period (p<0.01). Meanwhile, no significant differences were observed between the control and YC treatment in rectum temperature and respiration frequency (p>0.05). Dietary supplementation of VE and YC reduced heat stressed dairy goats' endotoxin concentration of the carotid artery and portal vein (p<0.01). However, the endotoxin concentration of the YC treatment was higher than that of the VE treatment (p<0.01). Both VE and YC supplementation decreased heat stressed dairy goats' absorption of endotoxin in portal vein (p<0.01). The endotoxin absorption of YC treatment was higher than the VE treatment (p<0.01). The addition of VE and YC decreased dairy goats' superoxide dismutase (SOD) concentration during HS and the whole experiment period (p<0.01). The addition of VE lowered SOD concentration during thermo-neutral period (p<0.01). Likewise, the addition of VE and YC lowered dairy goats' malonaldehyde (MDA) concentration during HS and the whole experimental period, and the MDA concentration in the VE treatment was lower than the YC treatment (p<0.05). The addition of VE decreased MDA concentration during thermo-neutral period. On the contrast, the addition of VE increased dairy goats total antioxidant potential (TAP) concentration during HS, thermo-neutral and the whole experimental period (p<0.01). The addition of YC increased TAP concentration only during HS period (p<0.01). It is concluded that both VE and YC are useful in alleviating HS of dairy goats by weakening endotoxin absorption and promoting antioxidant capacity. Compared with YC, VE is much more powerful in easing dairy goats HS. PMID- 26954168 TI - Effect of Supplemental Corn Dried Distillers Grains with Solubles Fed to Beef Steers Grazing Native Rangeland during the Forage Dormant Season. AB - Two experiments were conducted to evaluate the effects of the level of corn dry distillers grains with solubles (CDDGS) supplementation on growing performance, blood metabolites, digestion characteristics and ruminal fermentation patterns in steers grazing dormant forage. In Exp. 1, of growth performance, 120 steers (204+/-5 kg initial body weight [BW]) were distributed randomly into 3 groups (each of 40 steers), which were provided with the following levels of CDDGS supplement: 0%, 0.25%, or 0.50% BW. All groups of steers were grazed for 30 days in each of 3 grazing periods (March, April, and May). Approximately 1,000 ha of the land was divided with electric fencing into 3 equally sized pastures (333 ha in size). Blood samples were collected monthly from 20 steers in each grazing group for analysis of glucose (G), urea-nitrogen (UN) and non-esterified fatty acids. Final BW, average daily gain (ADG) and supplement conversion (CDDGS-C) increased with increasing levels of CDDGS supplementation (p<0.05).The CDDGS supplementation also increased the plasma G and UN concentrations (p<0.05). In Exp. 2, of digestive metabolism, 9 ruminally cannulated steers (BW = 350+/-3 kg) were distributed, following a completely randomized design, into groups of three in each pasture. The ruminally cannulated steers were provided the same levels of CDDGS supplementation as in the growing performance study (0%, 0.25%, and 0.50% BW), and they grazed along with the other 40 steers throughout the grazing periods. The dry matter intake, crude protein intake, neutral detergent fiber intake (NDFI), apparent digestibility of dry matter (ADDM), crude protein (ADCP) and neutral detergent fiber (ADNDF) increased with increasing levels of CDDGS supplementation (p<0.05). The ruminal degradation rates of CP (kdCP), NDF (kdNDF) and passage rate (kp) also increased with increasing levels of CDDGS supplementation (p<0.05). Ruminal ammonia nitrogen (NH3-N) and propionate concentrations also increased with increasing levels of CDDGS supplementation (p<0.05). However, acetate concentrations decreased with increasing levels of CDDGS supplementation (p<0.05). Liquid dilution rate increased with increasing levels of CDDGS supplementation but ruminal liquid volume decreased (p<0.05). On the basis of these findings, we can conclude that CDDGS supplementation enhanced the productive performance of cattle grazing native rangeland without negatively affecting forage intake, glucose and urea-nitrogen blood concentrations, ruminal degradation and ruminal fermentation patterns. PMID- 26954169 TI - Effects of Weaning and Spatial Enrichment on Behavior of Turkish Saanen Goat Kids. AB - As is in all economic activities, the highest yield per unit area is the main goal in animal production, while addressing the temperamental needs of animals often is ignored. Animal welfare is not only an ethical fact; it also has an economic value. Spatial environmental enrichment contributes positively to animal welfare by addressing their behavioral and mental requirements. The present study was conducted to determine the effects of weaning and spatial environmental arrangements on behaviors of goat-kids. Experimental groups were arranged in structured and unstructured spatial environments. Roughage feeder, semi-automatic concentrate feeder, bunk, bridge, and wood block were placed in the structured environment. No equipment was placed in the unstructured environment and paddock sides were enclosed with an iron sheet to prevent bipedal stance and to provide environmental isolation. In the study 10 male and 10 female Turkish Saanen goat kids were used in each group. Spatial environmental arrangements did not have significant impacts on the growth performance of kids (p>0.05). All objects in the structured group were accepted by the kids. Average use ratios of roughage feeder, semi-automatic concentrate feeder, bunk, bridge and wood block were observed as 19.3%, 14.0%, 12.6%, 3.8%, and 0.7%, respectively. There were significant differences between before- and after-weaning in use of all objects except for underneath bridge (p<=0.05). Concentrate feed consumption, locomotion, and resting behaviors in kids showed significant differences by structural group and growth period. Roughage consumption was similar between groups, while it differed by growth period (p<=0.05). Interaction frequency was significantly higher in structured group (p = 0.0023). Playing behavior significantly differentiated based on the growth period rather than on groups (p<=0.05). Playing behavior significantly decreased after weaning. Abnormal oral activity was significantly higher in the structured group before weaning (p<=0.05). Despite there being no installations facilitating climbing and bipedal stance, the kids of the unstructured group were able to exhibit 1/3 as much bipedal stance behavior as the kids of the structured group through leaning over slippery paddock wall or over their groupmates. Bipedal stance behavior of unstructured group was similar before and after weaning, while bipedal stance behavior before weaning was about 2 times that of after weaning in structured group. It was concluded that unstructured environmental arrangement limited the behavior repertoire of the goat kids. PMID- 26954170 TI - Low-density Lipoprotein Improves Motility and Plasma Membrane Integrity of Cryopreserved Canine Epididymal Spermatozoa. AB - Cryopreservation of caudal epididymal spermatozoa is an effective technique to conserve genetic potentials of superior dogs when it is not possible to collect ejaculated spermatozoa. Although hen egg yolk is commonly supplemented into the semen extender, active substances within the egg yolk which protect sperm against cryoinjury remain to be discovered. Among its compositions, low-density lipoprotein (LDL) has been reported to have a cryoprotective property for sperm cryopreservation. However, the effects of LDL on dog epididymal spermatozoa during cryopreservation have not yet been investigated. This study aimed to investigate the effects of LDL on epididymal spermatozoa quality following cryopreservation and thawing. After routine castration of 12 dogs, caudal epididymides from individuals were separated from the testes and cut into a few pieces in a Tris-buffer. Spermatozoa recovered from each sample were examined at once for sperm quality and divided into six groups of extender: no LDL, 20% egg yolk, 4%, 8%, 16%, and 24% LDL, before cryopreservation. The sperm aliquots were then equilibrated and conventionally frozen. After thawing, sperm motility, morphology, plasma membrane integrity, and acrosome integrity were evaluated. The results revealed that 4% LDL and 20% egg yolk yielded significantly higher sperm motility (57.69% and 52.69%, respectively, p<0.05) than other LDLs. In addition, 4% LDL yielded the significantly highest plasma membrane integrity (70.54%, p<0.05). In conclusion, the supplementation of 4% LDL in Tris-glucose extender could be applied for cryopreservation of canine epididymal spermatozoa. PMID- 26954171 TI - Effects of Furnished Cage Type on Behavior and Welfare of Laying Hens. AB - This study was conducted to compare the effects of layout of furniture (a perch, nest, and sandbox) in cages on behavior and welfare of hens. Two hundred and sixteen Hyline Brown laying hens were divided into five groups (treatments) with four replicates per group: small furnished cages (SFC), medium furnished cages type I (MFC-I), medium furnished cages type II (MFC-II), and medium furnished cages type III (MFC-III) and conventional cages (CC). The experiment started at 18 week of age and finished at 52 week of age. Hens' behaviors were filmed during the following periods: 8:00 to 10:00; 13:00 to 14:00; 16:00 to 17:00 on three separate days and two hens from each cage were measured for welfare parameters at 50 wk of age. The results showed that feeding and laying of all hens showed no effect by cage type (p>0.05), and the hens in the furnished cages had significantly lower standing and higher walking than CC hens (p<0.05). The birds in MFC-III had significant higher preening, scratching and feather-pecking behavior than in the other cages (p<0.05). No difference in nesting behavior was found in the hens between the furnished cages (p>0.05). The hens in MFC-I, -II, and -III showed a significant higher socializing behavior than SFC and CC (p<0.05). The lowest perching was for the hens in SFC and the highest perching found for the hens in MFC-III. Overall, the hens in CC showed poorer welfare conditions than the furnished cages, in which the feather condition score, gait score and tonic immobility duration of the hens in CC was significantly higher than SFC, MFC-I, MFC-II, and MFC-III (p<0.05). In conclusion, the furnished cage design affected both behavior and welfare states of hens. Overall, MFC-III cage design was better than SFC, MFC-I, and MFC-II cage designs. PMID- 26954172 TI - Seminal Plasma Heparin Binding Proteins Improve Semen Quality by Reducing Oxidative Stress during Cryopreservation of Cattle Bull Semen. AB - Heparin binding proteins (HBPs) are produced by accessory glands. These are secreted into the seminal fluid, bind to the spermatozoa at the time of ejaculation, favour capacitation, acrosome reaction, and alter the immune system response toward the sperm. The present study was conducted with an objective to assess the effect of purified seminal plasma-HBPs (SP-HBPs) on cross bred cattle bull sperm attributes during two phases of cryopreservation: Pre freezing and freezing-thawing. SP-HBPs were purified from pooled seminal plasma by heparin affinity chromatography. Three doses of SP-HBPs i.e. 10, 20, 40 MUg/mL semen were standardized to find out the optimum dose and 20 MUg/mL was found to be an optimum dose. Semen as such and treated with SP-HBPs was diluted with sodium citrate-egg yolk diluter and cryopreserved as per the standard protocol. Sperm parameters i.e. motility, viability, Hypo-osmotic swelling test (HOST), acrosome damage, in vitro capacitation and lipid peroxidation were evaluated in SP-HBP treated and untreated (control) semen at both phases of cryopreservation. A considerable variation in percent sperm motility, viability, membrane integrity (HOST), acrosome damage, acrosome reaction and lipid peroxidation was observed at both phases among the bulls irrespective of the treatment. Incubation of neat semen with 20 MUg/mL SP-HBP before processing for cryopreservation enhanced the average motility, viability, membrane integrity by 7.2%, 1.5%, 7.9%, and 5.6%, 6.6%, 7.4% in pre-frozen and frozen-thawed semen in comparison to control. There was also an average increase of 4.1%/3.9% in in vitro capacitation and acrosome reaction in SP-HBPs-treated frozen-thawed semen as compared to control. However, binding of SP-HBPs to the sperm declined acrosome damage and lipid peroxidation by 1.3%/4.1% and 22.1/32.7 MUM/10(9) spermatozoa in SP-HBP treated pre frozen/frozen-thawed semen as compared to control, respectively. Significant (p<0.05) effects were observed only in motility, HOST and in vitro acrosome reaction. It can be concluded that treatment of neat semen with SP-HBPs before cryopreservation minimized the cryoinjury by decreasing the generation of reactive oxygen species. PMID- 26954173 TI - Influence of Quaternary Benzophenantridine and Protopine Alkaloids on Growth Performance, Dietary Energy, Carcass Traits, Visceral Mass, and Rumen Health in Finishing Ewes under Conditions of Severe Temperature-humidity Index. AB - Twenty Pelibuey*Katahdin ewes (35+/-2.3 kg) were used to determine the effects of the consumption of standardized plant extract containing a mixture of quaternary benzophenanthridine alkaloids and protopine alkaloids (QBA+PA) on growth performance, dietary energetics, visceral mass, and ruminal epithelial health in heat-stressed ewes fed with a high-energy corn-based diet. The basal diet (13.9% crude protein and 2.09 Mcal of net energy [NE] of maintenance/kg of dry matter) contained 49.7% starch and 15.3% neutral detergent fiber. Source of QBA+PA was Sangrovit RS (SANG) which contains 3 g of quaternary benzophenathridine and protopine alkaloids per kg of product. Treatments consisted of a daily consumption of 0 or 0.5 g SANG/ewe. Ewes were grouped by weight and assigned to 10 pens (5 pens/treatment), with two ewes per pen. The experimental period lasted 70 days. The mean temperature humidity index during the course of this experiment was 81.7+/-1.0 (severe heat stress). There were no treatment effects on water intake. Dry matter intake was not affected (p = 0.70) by treatments, but the group fed SANG had a numerically (11.2%) higher gain in comparison to the control group, SANG improved gain efficiency (8.3%, p = 0.04), dietary NE (5.2%, p<0.01) and the observed-to-expected NE (5.9%, p<0.01). Supplemental SANG did not affect (p>=0.12) carcass characteristics, chemical composition of shoulder, and organ weights (g/kg empty body weight) of stomach complex, intestines, and heart/lung. Supplemental SANG decreased liver weight (10.3%, p = 0.02) and increased visceral fat (16.9%, p = 0.02). Rumen epithelium of ewes fed SANG had lower scores for cellular dropsical degeneration (2.08 vs 2.34, p = 0.02), parakeratosis (1.30 vs 1.82, p = 0.03) and neutrophil infiltration (2.08 vs 2.86, p = 0.05) than controls. It is concluded that SANG supplementation helped ameliorate the negative effects of severe heat on growth performance of feedlot ewes fed high energy corn-based diets. Improvement in energetic efficiency may have been mediated, in part, by anti-inflammatory effects of supplemental SANG and corresponding enhancement of nutrient uptake. PMID- 26954174 TI - Estimation of Sensory Pork Loin Tenderness Using Warner-Bratzler Shear Force and Texture Profile Analysis Measurements. AB - This study investigated the degree to which instrumental measurements explain the variation in pork loin tenderness as assessed by the sensory evaluation of trained panelists. Warner-Bratzler shear force (WBS) had a significant relationship with the sensory tenderness variables, such as softness, initial tenderness, chewiness, and rate of breakdown. In a regression analysis, WBS could account variations in these sensory variables, though only to a limited proportion of variation. On the other hand, three parameters from texture profile analysis (TPA)-hardness, gumminess, and chewiness-were significantly correlated with all sensory evaluation variables. In particular, from the result of stepwise regression analysis, TPA hardness alone explained over 15% of variation in all sensory evaluation variables, with the exception of perceptible residue. Based on these results, TPA analysis was found to be better than WBS measurement, with the TPA parameter hardness likely to prove particularly useful, in terms of predicting pork loin tenderness as rated by trained panelists. However, sensory evaluation should be conducted to investigate practical pork tenderness perceived by consumer, because both instrumental measurements could explain only a small portion (less than 20%) of the variability in sensory evaluation. PMID- 26954175 TI - Effects of Supplemental Levels of Saccharomyces cerevisiae Fermentation Product on Lactation Performance in Dairy Cows under Heat Stress. AB - The objectives of this study were to evaluate the effects of different supplemental levels of Saccharomyces cerevisiae fermentation product (SCFP; Original XP; Diamond V) on lactation performance in Holstein dairy cows under heat stress. Eighty-one multiparous Holstein dairy cows were divided into 27 blocks of 3 cows each based on milk yield (23.6+/-0.20 kg/d), parity (2.88+/ 0.91) and day in milk (204+/-46 d). The cows were randomly assigned within blocks to one of three treatments: 0 (control), 120, or 240 g/d of SCFP mixed with 240, 120, or 0 g of corn meal, respectively. The experiment was carried out during the summer season of 2014, starting from 14 July 2014 and lasting for 9 weeks with the first week as adaption period. During the experimental period, average daily temperature-humidity index (measured at 08:00, 14:00, and 20:00) was above 68, indicating that cows were exposed to heat stress throughout the study. Rectal temperatures tended to decrease linearly (p = 0.07) for cows supplemented with SCFP compared to the control cows at 14:30, but were not different at 06:30 (p>0.10). Dry matter intake was not affected by SCFP supplementation (p>0.10). Milk yield increased linearly (p<0.05) with increasing levels of SCFP. Feed efficiency (milk yield/dry matter intake) was highest (p<0.05) for cows fed 240 g/d SCFP. Cows supplemented with SCFP gained (p<0.01) body weight, while cows in the control lost body weight. Net energy balance also increased linearly (p<0.01) with increasing levels of SCFP. Concentrations of milk urea nitrogen (p<0.01) decreased linearly with increasing levels of SCFP, while no difference (p>0.10) was observed among the treatments in conversion of dietary crude protein to milk protein yield. In summary, supplementation of SCFP alleviated the negative effect of heat stress in lactating Holstein dairy cows and allowed cows to maintain higher milk production, feed efficiency and net energy balance. Effects of SCFP were dose-dependent and greater effects were observed from higher doses. PMID- 26954176 TI - Random Regression Models Are Suitable to Substitute the Traditional 305-Day Lactation Model in Genetic Evaluations of Holstein Cattle in Brazil. AB - The aim of this study was to compare two random regression models (RRM) fitted by fourth (RRM4) and fifth-order Legendre polynomials (RRM5) with a lactation model (LM) for evaluating Holstein cattle in Brazil. Two datasets with the same animals were prepared for this study. To apply test-day RRM and LMs, 262,426 test day records and 30,228 lactation records covering 305 days were prepared, respectively. The lowest values of Akaike's information criterion, Bayesian information criterion, and estimates of the maximum of the likelihood function ( 2LogL) were for RRM4. Heritability for 305-day milk yield (305MY) was 0.23 (RRM4), 0.24 (RRM5), and 0.21 (LM). Heritability, additive genetic and permanent environmental variances of test days on days in milk was from 0.16 to 0.27, from 3.76 to 6.88 and from 11.12 to 20.21, respectively. Additive genetic correlations between test days ranged from 0.20 to 0.99. Permanent environmental correlations between test days were between 0.07 and 0.99. Standard deviations of average estimated breeding values (EBVs) for 305MY from RRM4 and RRM5 were from 11% to 30% higher for bulls and around 28% higher for cows than that in LM. Rank correlations between RRM EBVs and LM EBVs were between 0.86 to 0.96 for bulls and 0.80 to 0.87 for cows. Average percentage of gain in reliability of EBVs for 305 day yield increased from 4% to 17% for bulls and from 23% to 24% for cows when reliability of EBVs from RRM models was compared to those from LM model. Random regression model fitted by fourth order Legendre polynomials is recommended for genetic evaluations of Brazilian Holstein cattle because of the higher reliability in the estimation of breeding values. PMID- 26954177 TI - Quality and Acceptability of Meat Nuggets with Fresh Aloe vera Gel. AB - Aloe vera has been used worldwide for pharmaceutical, food, and cosmetic industries due to its wide biological activities. However, quality improvement of low fat meat products and their acceptability with added Aloe vera gel (AVG) is scanty. The aim of this study was to explore the feasibility of using fresh AVG on physicochemical, textural, sensory and nutritive qualities of goat meat nuggets. The products were prepared with 0%, 2.5%, and 5% fresh AVG replacing goat meat and were analyzed for proximate composition, physicochemical and textural properties, fatty acid profile and sensory parameters. Changes in lipid oxidation and microbial growth of nuggets were also evaluated over 9 days of refrigerated storage. The results showed that AVG significantly (p<0.05) decreased the pH value and protein content of meat emulsion and nuggets. Product yield was affected at 5% level of gel. Addition of AVG in the formulation significantly affected the values of texture profile analysis. The AVG reduced the lipid oxidation and microbial growth in nuggets during storage. Sensory panelists preferred nuggets with 2.5% AVG over nuggets with 5% AVG. Therefore, AVG up to 2.5% level could be used for quality improvement in goat meat nuggets without affecting its sensorial, textural and nutritive values. PMID- 26954178 TI - Toxicity of Mycotoxins from Contaminated Corn with or withoutYeast Cell Wall Adsorbent on Broiler Chickens. AB - This study investigated the effects of feeds naturally contaminated with mycotoxins on growth performance, serum biochemical parameters, carcass traits, and splenic heat shock protein 70 (Hsp70) mRNA expression levels in broiler chickens. The efficacy of yeast cell wall (YCW) adsorbent in preventing mycotoxicosis was also evaluated. Three hundred 1-d-old Arbor Acres broiler chicks were randomly allotted to 3 treatments in completely randomized design for 42 d. Each treatment group had 5 replicate pens with 20 birds. The treatments were as follows: i) basal diet (control), ii) naturally contaminated diet (NCD), and iii) NCD+0.2% YCW adsorbent (NCDD). The NCD decreased average daily gain (ADG) (p<0.01) of 0 to 21 d, 22 to 42 d, and 0 to 42 d, and increased feed conversion ratio (p<0.01) of 22 to 42 d and 0 to 42 d. Both the breast meat percentage and thigh meat percentage of the NCD group were significantly higher (p<0.01) than that of the control group on d 21. The NCD group showed significantly increased levels of triglycerides (p<0.05) and cholesterol (p<0.05) on both d 21 and d 42 compared to the control group. However, the NCD significantly reduced (p<0.01) the high-density lipoprotein (HDL) on d 42 compared to controls. Compared with the NCD, supplementation with YCW significantly improved (p<0.01) the ADG of 0 to 21 d and 0 to 42 d, and increased (p<0.01) concentrations of HDL on d 42, and on d 21, and triglycerides (p<0.05) on d 21 and d 42. Supplementation with YCW reduced (p<0.01) the breast meat percentage, the thigh meat percentage, the concentrations of cholesterol (p<0.01) and the low-density lipoprotein (p<0.05) on d 21, and improved (p<0.01) the splenic Hsp70 mRNA expression levels compared with the NCD group. The results of this study indicated that feeding NCD for 42 d had adverse effects on broiler chickens, and that YCW might be beneficial in counteracting the effects of mycotoxins. PMID- 26954179 TI - Effect of Glutamine, Glutamic Acid and Nucleotides on the Turnover of Carbon (delta(13)C) in Organs of Weaned Piglets. AB - Morphological and physiological alterations occur in the digestive system of weanling piglets, compromising the performance in subsequent phases. This experiment aimed at verifying the influence of glutamine, glutamate and nucleotides on the carbon turnover in the pancreas and liver of piglets weaned at 21 days of age. Four diets were evaluated: glutamine, glutamic acid or nucleotides-free diet (CD); containing 1% glutamine (GD); containing 1% glutamic acid (GAD) and containing 1% nucleotides (ND). One hundred and twenty-three piglets were utilized with three pigs slaughtered at day zero (weaning day) and three at each one of the experimental days (1, 2, 4, 5, 7, 9, 13, 20, 27, and 49 post-weaning), in order to collect organ samples, which were analyzed for the delta(13)C isotopic composition and compared by means of time. No differences were found (p>0.05) among treatments for the turnover of the (13)C in the pancreas (T50% = 13.91, 14.37, 11.07, and 9.34 days; T95% = 46.22, 47.73, 36.79, and 31.04 days for CD, GD, GAD, and ND, respectively). In the liver, the ND presented accelerated values of carbon turnover (T50% = 7.36 and T95% = 24.47 days) in relation to the values obtained for the GD (T50% = 10.15 and T95% = 33.74 days). However, the values obtained for the CD (T50% = 9.12 and T95% = 30.31 days) and GAD (T50% = 7.83 and T95% = 26.03 days) had no differences (p>0.05) among other diets. The technique of (13)C isotopic dilution demonstrated trophic action of nucleotides in the liver. PMID- 26954180 TI - Effect of Floor Space Allowance on Pig Productivity across Stages of Growth: A Field-scale Analysis. AB - A total of 152 pig farms were randomly selected from the five provinces in South Korea. During the experiment, the average temperature and relative humidity was 24.7 degrees C and 74% in summer and 2.4 degrees C and 53% in winter, respectively. The correlation between floor space allowance (FSA) and productivity index was analyzed, including non-productive sow days (NPD), number of weaners (NOW), survival rate (SR), appearance rate of A-grade pork (ARA), and days at a slaughter weight of 110 kg (d-SW) at different growth stages. The objectives of the present study were i) to determine the effect of FSA on the pig productivity index and ii) to suggest the minimum FSA for pigs based on scientific baseline data. For the pregnant sow, NPD could be decreased if pregnant sows were raised with a medium level (M) of FSA (3.10 to 3.67 m(2)/head) while also keeping the pig house clean which improves hygiene, and operating the ventilation system properly. For the farrowing sows, the NOW tended to decrease as the FSA increased. Similarly, a high level of FSA (H) is significantly negative with weaner SR of farrowing sows (p-value = 0.017), indicating this FSA tends to depress SR. Therefore, a FSA of 2.30 to 6.40 m(2)/head (very low) could be appropriate for weaners because a limited space can provide a sense of security and protection from external interruptions. The opposite trend was observed that an increase in floor space (>1.12 m(2)/head) leads to increase the SR of growing pigs. For the fattening pigs, H level of FSA was negatively correlated with SR, but M level of FSA was positively correlated with SR, indicating that SR tended to increase with the FSA of 1.10 to 1.27 m(2)/head. In contrast, ARA of male fattening pigs showed opposite results. H level of FSA (1.27 to 1.47 m(2)/head) was suggested to increase productivity because ARA was most affected by H level of space allowance with positive correlation (R(2) = 0.523). The relationship between the FSA and d-SW of fattening pigs was hard to identify because of the low R(2) value. However, the farms that provided a relatively large floor space (1.27 to 1.54 m(2)/head) during the winter period showed d-SW was significantly and negatively affected by FSA. PMID- 26954181 TI - Effects of Three Feeding Systems on Production Performance, Rumen Fermentation and Rumen Digesta Particle Structure of Beef Cattle. AB - The effects of three different feeding systems on beef cattle production performance, rumen fermentation, and rumen digesta particle structure were investigated by using 18 Limousin (steers) with a similar body weight (575+/-10 kg) in a 80-d experiment. The animals were equally and randomly divided into three treatment groups, namely, total mixed ration group (cattle fed TMR), SI1 group (cattle fed concentrate firstly then roughage), and SI2 group (cattle fed roughage firstly then concentrate). The results showed that the average daily gain was significantly higher in cattle receiving TMR than in those receiving SI1 and SI2 (p<0.05). Consumption per kg weight gain of concentrate, silage, and combined net energy (NEmf) were significantly decreased when cattle received TMR, unlike when they received SI1 and SI2 (p<0.05), indicating that the feed efficiency of TMR was the highest. Blood urea nitrogen (BUN) was significantly decreased when cattle received TMR compared with that in cattle receiving SI1 (p<0.05), whereas there was no difference compared with that in cattle receiving SI2. Ammonia nitrogen concentration was significantly lower in cattle receiving TMR than in those receiving SI1 and SI2 (p<0.05). The rumen area of cattle that received TMR was significantly larger than that of cattle receiving SI1 (p<0.05), but there was no difference compared with that of cattle receiving SI2. Although there was no significant difference among the three feeding systems in rumen digesta particle distribution, the TMR group trended to have fewer large- and medium-sized particles and more small-sized particles than those in the SI1 and SI2 groups. In conclusion, cattle with dietary TMR showed increased weight gain and ruminal development and decreased BUN. This indicated that TMR feeding was more conducive toward improving the production performance and rumen fermentation of beef cattle. PMID- 26954182 TI - Computational Prediction of Alzheimer's and Parkinson's Disease MicroRNAs in Domestic Animals. AB - As the most common neurodegenerative diseases, Alzheimer's disease (AD) and Parkinson's disease (PD) are two of the main health concerns for the elderly population. Recently, microRNAs (miRNAs) have been used as biomarkers of infectious, genetic, and metabolic diseases in humans but they have not been well studied in domestic animals. Here we describe a computational biology study in which human AD- and PD-associated miRNAs (ADM and PDM) were utilized to predict orthologous miRNAs in the following domestic animal species: dog, cow, pig, horse, and chicken. In this study, a total of 121 and 70 published human ADM and PDM were identified, respectively. Thirty-seven miRNAs were co-regulated in AD and PD. We identified a total of 105 unrepeated human ADM and PDM that had at least one 100% identical animal homolog, among which 81 and 54 showed 100% sequence identity with 241 and 161 domestic animal miRNAs, respectively. Over 20% of the total mature horse miRNAs (92) showed perfect matches to AD/PD-associated miRNAs. Pigs, dogs, and cows have similar numbers of AD/PD-associated miRNAs (63, 62, and 59). Chickens had the least number of perfect matches (34). Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses suggested that humans and dogs are relatively similar in the functional pathways of the five selected highly conserved miRNAs. Taken together, our study provides the first evidence for better understanding the miRNA-AD/PD associations in domestic animals, and provides guidance to generate domestic animal models of AD/PD to replace the current rodent models. PMID- 26954183 TI - Complete Mitochondrial Genome Sequences of Chinese Indigenous Sheep with Different Tail Types and an Analysis of Phylogenetic Evolution in Domestic Sheep. AB - China has a long history of sheep (Ovis aries [O. aries]) breeding and an abundance of sheep genetic resources. Knowledge of the complete O. aries mitogenome should facilitate the study of the evolutionary history of the species. Therefore, the complete mitogenome of O. aries was sequenced and annotated. In order to characterize the mitogenomes of 3 Chinese sheep breeds (Altay sheep [AL], Shandong large-tailed sheep [SD], and small-tailed Hulun Buir sheep [sHL]), 19 sets of primers were employed to amplify contiguous, overlapping segments of the complete mitochondrial DNA (mtDNA) sequence of each breed. The sizes of the complete mitochondrial genomes of the sHL, AL, and SD breeds were 16,617 bp, 16,613 bp, and 16,613 bp, respectively. The mitochondrial genomes were deposited in the GenBank database with accession numbers KP702285 (AL sheep), KP981378 (SD sheep), and KP981380 (sHL sheep) respectively. The organization of the 3 analyzed sheep mitochondrial genomes was similar, with each consisting of 22 tRNA genes, 2 rRNA genes (12S rRNA and 16S rRNA), 13 protein-coding genes, and 1 control region (D-loop). The NADH dehydrogenase subunit 6 (ND6) and 8 tRNA genes were encoded on the light strand, whereas the rest of the mitochondrial genes were encoded on the heavy strand. The nucleotide skewness of the coding strands of the 3 analyzed mitogenomes was biased toward A and T. We constructed a phylogenetic tree using the complete mitogenomes of each type of sheep to allow us to understand the genetic relationships between Chinese breeds of O. aries and those developed and utilized in other countries. Our findings provide important information regarding the O. aries mitogenome and the evolutionary history of O. aries inside and outside China. In addition, our results provide a foundation for further exploration of the taxonomic status of O. aries. PMID- 26954185 TI - Factors Affecting the Incidence of Angel Wing in White Roman Geese: Stocking Density and Genetic Selection. AB - The present study investigated stocking density and genetic lines, factors that may alter the severity and incidence of angel wing (AW), in White Roman geese. Geese (n = 384) from two genetically selected lines (normal- winged line, NL, and angel-winged line, AL, respectively) and one commercial line (CL) were raised in four pens. Following common commercial practice, low-stocking-density (LD), medium-stocking-density, and high-stocking-density treatments were respectively administered to 24, 32, and 40 geese per pen at 0 to 3 weeks (1.92 m(2)/pen) and 4 to 6 weeks (13.2 m(2)/pen) of age and to 24, 30, and 36 geese at 7 to 14 weeks (20.0 m(2)/pen) of age. The results revealed that stocking density mainly affected body weight gain in geese younger than 4 weeks, and that geese subjected to LD had a high body weight at 2 weeks of age. However, the effect of stocking density on the severity score of AW (SSAW) and incidence of AW (IAW) did not differ significantly among the treatments. Differences were observed among the genetic stocks; that is, SSAW and IAW were significantly higher in AL than in NL and CL. Genetic selection generally aggravates AW, complicating its elimination. To effectively reduce IAW, stocking density, a suspected causal factor, should be lower than that presently applied commercially. PMID- 26954184 TI - Models for Estimating Genetic Parameters of Milk Production Traits Using Random Regression Models in Korean Holstein Cattle. AB - The objectives of the study were to estimate genetic parameters for milk production traits of Holstein cattle using random regression models (RRMs), and to compare the goodness of fit of various RRMs with homogeneous and heterogeneous residual variances. A total of 126,980 test-day milk production records of the first parity Holstein cows between 2007 and 2014 from the Dairy Cattle Improvement Center of National Agricultural Cooperative Federation in South Korea were used. These records included milk yield (MILK), fat yield (FAT), protein yield (PROT), and solids-not-fat yield (SNF). The statistical models included random effects of genetic and permanent environments using Legendre polynomials (LP) of the third to fifth order (L3-L5), fixed effects of herd-test day, year season at calving, and a fixed regression for the test-day record (third to fifth order). The residual variances in the models were either homogeneous (HOM) or heterogeneous (15 classes, HET15; 60 classes, HET60). A total of nine models (3 orders of polynomials*3 types of residual variance) including L3-HOM, L3-HET15, L3-HET60, L4-HOM, L4-HET15, L4-HET60, L5-HOM, L5-HET15, and L5-HET60 were compared using Akaike information criteria (AIC) and/or Schwarz Bayesian information criteria (BIC) statistics to identify the model(s) of best fit for their respective traits. The lowest BIC value was observed for the models L5 HET15 (MILK; PROT; SNF) and L4-HET15 (FAT), which fit the best. In general, the BIC values of HET15 models for a particular polynomial order was lower than that of the HET60 model in most cases. This implies that the orders of LP and types of residual variances affect the goodness of models. Also, the heterogeneity of residual variances should be considered for the test-day analysis. The heritability estimates of from the best fitted models ranged from 0.08 to 0.15 for MILK, 0.06 to 0.14 for FAT, 0.08 to 0.12 for PROT, and 0.07 to 0.13 for SNF according to days in milk of first lactation. Genetic variances for studied traits tended to decrease during the earlier stages of lactation, which were followed by increases in the middle and decreases further at the end of lactation. With regards to the fitness of the models and the differential genetic parameters across the lactation stages, we could estimate genetic parameters more accurately from RRMs than from lactation models. Therefore, we suggest using RRMs in place of lactation models to make national dairy cattle genetic evaluations for milk production traits in Korea. PMID- 26954186 TI - mRNA Expression of Ovine Angiopoietin-like Protein 4 Gene in Adipose Tissues. AB - Angiopoietin-like protein 4 (ANGPTL4) is involved in a variety of functions, including lipoprotein metabolism and angiogenesis. To reveal the role of ANGPTL4 in fat metabolism of sheep, ovine ANGPTL4 mRNA expression was analyzed in seven adipose tissues from two breeds with distinct tail types. Forty-eight animals with the gender ratio of 1:1 for both Guangling Large Tailed (GLT) and Small Tailed Han (STH) sheep were slaughtered at 2, 4, 6, 8, 10, and 12 months of age, respectively. Adipose tissues were collected from greater and lesser omental, subcutaneous, retroperitoneal, perirenal, mesenteric, and tail fats. Ontogenetic mRNA expression of ANGPTL4 in these adipose tissues from GTL and STH was studied by quantitative real time polymerase chain reaction. The results showed that ANGPTL4 mRNA expressed in all adipose tissues studied with the highest in subcutaneous and the lowest in mesenteric fat depots. Months of age, tissue and breed are the main factors that significantly influence the mRNA expression. These results provide new insights into ovine ANGPTL4 gene expression and clues for its function mechanism. PMID- 26954187 TI - Influence of Wheat Straw Pelletizing and Inclusion Rate in Dry Rolled or Steam flaked Corn-based Finishing Diets on Characteristics of Digestion for Feedlot Cattle. AB - Eight Holstein steers (216+/-48 kg body weight) fitted with ruminal and duodenal cannulas were used to evaluate effects of wheat straw processing (ground vs pelleted) at two straw inclusion rates (7% and 14%; dry matter basis) in dry rolled or steam-flaked corn-based finishing diets on characteristics of digestion. The experimental design was a split plot consisting of two simultaneous 4*4 Latin squares. Increasing straw level reduced ruminal (p<0.01) and total tract (p = 0.03) organic matter (OM) digestion. As expected, increasing wheat straw level from 7% to 14% decreased (p<0.05) ruminal and total tract digestion of OM. Digestion of neutral detergent fiber (NDF) and starch, per se, were not affected (p>0.10) by wheat straw level. Likewise, straw level did not influence ruminal acetate and propionate molar proportions or estimated methane production (p>0.10). Pelleting straw did not affect (p>=0.48) ruminal digestion of OM, NDF, and starch, or microbial efficiency. Ruminal feed N digestion was greater (7.4%; p = 0.02) for ground than for pelleted wheat straw diets. Although ruminal starch digestion was not affected by straw processing, post-ruminal (p<0.01), and total-tract starch (p = 0.05) digestion were greater for ground than for pelleted wheat straw diets, resulting in a tendency for increased post ruminal (p = 0.06) and total tract (p = 0.07) OM digestion. Pelleting wheat straw decreased (p<0.01) ruminal pH, although ruminal volatile fatty acids (VFA) concentration and estimated methane were not affected (p>=0.27). Ruminal digestion of OM and starch, and post-ruminal and total tract digestion of OM, starch and N were greater (p<0.01) for steam-flaked than for dry rolled corn based diets. Ruminal NDF digestion was greater (p = 0.02) for dry rolled than for steam-flaked corn, although total tract NDF digestion was unaffected (p = 0.94). Ruminal microbial efficiency and ruminal degradation of feed N were not affected (p>0.14) by corn processing. However, microbial N flow to the small intestine and ruminal N efficiency (non-ammonia N flow to the small intestine/N intake) were greater (p<0.01) for steam-flaked than for dry rolled corn-based diets. Ruminal pH and total VFA concentration were not affected (p>= 0.16) by corn processing method. Compared with dry rolled corn, steam-flaked corn-based diets resulted in decreased acetate:propionate molar ratio (p = 0.02). It is concluded that at 7% or 14% straw inclusion rate, changes in physical characteristics of wheat straw brought about by pelleting negatively impact OM digestion of both steam-flaked and dry-rolled corn-based finishing diets. This effect is due to decreased post ruminal starch digestion. Replacement of ground straw with pelleted straw also may decrease ruminal pH. PMID- 26954188 TI - Identification of Molecular Signatures from Different Vaccine Adjuvants in Chicken by Integrative Analysis of Microarray Data. AB - The present study compared the differential functions of two groups of adjuvants, Montanide incomplete Seppic adjuvant (ISA) series and Quil A, cholesterol, dimethyl dioctadecyl ammonium bromide, and Carbopol (QCDC) formulations, in chicken by analyzing published microarray data associated with each type of vaccine adjuvants. In the biological function analysis for differentially expressed genes altered by two different adjuvant groups, ISA series and QCDC formulations showed differential effects when chickens were immunized with a recombinant immunogenic protein of Eimeria. Among the biological functions, six categories were modified in both adjuvant types. However, with respect to "Response to stimulus", no biological process was modified by the two adjuvant groups at the same time. The QCDC adjuvants showed effects on the biological processes (BPs) including the innate immune response and the immune response to the external stimulus such as toxin and bacterium, while the ISA adjuvants modified the BPs to regulate cell movement and the response to stress. In pathway analysis, ISA adjuvants altered the genes involved in the functions related with cell junctions and the elimination of exogenous and endogenous macromolecules. The analysis in the present study could contribute to the development of precise adjuvants based on molecular signatures related with their immunological functions. PMID- 26954189 TI - Fiber source and inclusion level affects characteristics of excreta from growing pigs. AB - OBJECTIVE: The objective of the study was to determine the influence of varying fibrous diets on fecal characteristics of growing pigs. METHODS: A total of 104 pigs (initial weight 18+/-2.0 kg) were used in the study. They were housed in individual pens and fed on diets containing maize cob, grass hay, lucerne hay, maize stover, and sunflower husk. These fibers were included at 0, 80, 160, 240, 320 and 400 g/kg. Fecal and urine samples were collected. RESULTS: Fecal output was largest amongst pigs fed on diets containing grass hay and maize stover (p<0.05). Nitrogen content was highest in feces from pigs fed on sunflower husk (p< 0.05). Pigs fed on diets containing maize stover and maize cobs produced the largest concentrations of short chain fatty acids. Acetate concentration was high in feces of pigs fed maize stover than those fed grass hay and lucerne hay (p<0.05). As the level of fiber inclusion increased, fecal consistency and nitrogen content increased linearly (p<0.05). Urea nitrogen decreased as the inclusion level increased across all the fibers (p<0.05), with maize cobs containing the largest content of urea nitrogen. As dietary fiber content increased, fecal nitrogen content also increased (p<0.05). CONCLUSION: It was concluded that different fiber sources influence fecal characteristics, thereby having different implications on pig waste management. It is vital to monitor fiber inclusion thresholds so as to easily manage environmental pollutants such as butyrate that contribute to odors. PMID- 26954190 TI - Development of Dot Enzyme Linked Immuno Sorbent Assay Using Recombinant Hexon Protein for Detecting Antibodies to Hydropericardium Syndrome Disease Virus. AB - Dot enzyme linked immuno sorbent assay (ELISA) using recombinant hexon protein of fowl adenovirus 4 (FAdV 4) was standardized to detect antibody levels against hydropericardium syndrome disease in chickens. Results were compared with the dot ELISA using purified virus protein antigen of FAdV 4. In an experimental vaccination of broiler chicken, the antibody levels by dot ELISA with recombinant protein and purified virus protein antigen ranged from 2.240+/-0.09 log10 to 2.0+/-0.04 during 5th to 8th weeks of age. Serum samples collected randomly from breeder flocks vaccinated against the FAdV-4 were found to have protective titres by both dot ELISA using recombinant protein and purified virus protein antigen at 10th and 24th weeks but only 75% samples were positive at 14th weeks and all samples were negative at 32th weeks. Receiver operating characteristic analysis showed that the dot ELISA has a diagnostic sensitivity, specificity and accuracy of 100%, 92.2%, and 96.2% respectively in comparison to agar gel immuno diffusion. PMID- 26954191 TI - Effects of Starvation on Lipid Metabolism and Gluconeogenesis in Yak. AB - This research was conducted to investigate the physiological consequences of undernourished yak. Twelve Maiwa yak (110.3+/-5.85 kg) were randomly divided into two groups (baseline and starvation group). The yak of baseline group were slaughtered at day 0, while the other group of yak were kept in shed without feed but allowed free access to water, salt and free movement for 9 days. Blood samples of the starvation group were collected on day 0, 1, 2, 3, 5, 7, 9 and the starved yak were slaughtered after the final blood sample collection. The liver and muscle glycogen of the starvation group decreased (p<0.01), and the lipid content also decreased while the content of moisture and ash increased (p<0.05) both in Longissimus dorsi and liver compared with the baseline group. The plasma insulin and glucose of the starved yak decreased at first and then kept stable but at a relatively lower level during the following days (p<0.01). On the contrary, the non-esterified fatty acids was increased (p<0.01). Beyond our expectation, the ketone bodies of beta-hydroxybutyric acid and acetoacetic acid decreased with prolonged starvation (p<0.01). Furthermore, the mRNA expression of lipogenetic enzyme fatty acid synthase and lipoprotein lipase in subcutaneous adipose tissue of starved yak were down-regulated (p<0.01), whereas the mRNA expression of lipolytic enzyme carnitine palmitoyltransferase-1 and hormone sensitive lipase were up-regulated (p<0.01) after 9 days of starvation. The phosphoenolpyruvate carboxykinase and pyruvate carboxylase, responsible for hepatic gluconeogenesis were up-regulated (p<0.01). It was concluded that yak derive energy by gluconeogenesis promotion and fat storage mobilization during starvation but without ketone body accumulation in the plasma. PMID- 26954192 TI - Random Regression Models Using Legendre Polynomials to Estimate Genetic Parameters for Test-day Milk Protein Yields in Iranian Holstein Dairy Cattle. AB - The objective of this study was to estimate the genetic parameters of milk protein yields in Iranian Holstein dairy cattle. A total of 1,112,082 test-day milk protein yield records of 167,269 first lactation Holstein cows, calved from 1990 to 2010, were analyzed. Estimates of the variance components, heritability, and genetic correlations for milk protein yields were obtained using a random regression test-day model. Milking times, herd, age of recording, year, and month of recording were included as fixed effects in the model. Additive genetic and permanent environmental random effects for the lactation curve were taken into account by applying orthogonal Legendre polynomials of the fourth order in the model. The lowest and highest additive genetic variances were estimated at the beginning and end of lactation, respectively. Permanent environmental variance was higher at both extremes. Residual variance was lowest at the middle of the lactation and contrarily, heritability increased during this period. Maximum heritability was found during the 12th lactation stage (0.213+/-0.007). Genetic, permanent, and phenotypic correlations among test-days decreased as the interval between consecutive test-days increased. A relatively large data set was used in this study; therefore, the estimated (co)variance components for random regression coefficients could be used for national genetic evaluation of dairy cattle in Iran. PMID- 26954193 TI - Changes in Salivary Cortisol Concentration in Horses during Different Types of Exercise. AB - This study aimed to estimate the change of stress level in horses based on cortisol concentration levels in their saliva. A total of 61 horses were divided into the following three groups: i) tourist riding experience (TR, n = 23); ii) resting group (RR, n = 14); and iii) horse-riding education (ER, n = 24). The saliva samples of TR and ER groups were taken using plain cotton Salivettes four times a day: at 07:00 (basal), 11:00 (Exercise 1, after 1-hour exercise in the morning), 14:00 (Exercise 2, after 1-hour exercise in the afternoon), and 16:00 (Exercise 3, after 1-hour exercise in the afternoon). The saliva samples of RR were measured at the same time. The samples were analyzed using the SAS program general linear model procedure. In a percentage relative to the base value, cortisol levels in Exercise 3 were confirmed to decrease in all groups as compared to the basal value percentage in the following sequence: ER>TR>RR. The highest peak was confirmed in Exercise 2 (approximately 131%) of RR group and the lowest peak appeared in Exercise 3 (approximately 52%) of ER group. Therefore, resting without any particular exercise can also increase the stress level of horses. Thus, it is better to exercise, as exercise can reduce the stress level, even in cases when riders are clumsy or lack appropriate horse-riding experience. The results of the present study are useful to equestrian center owners and educational riding instructors in that they provide a meaningful insight into a better horse management. PMID- 26954194 TI - Role of oxytocin in improving the welfare of farm animals - A review. AB - Recently, increasing attention has been paid to the welfare of farm animals, which have been evaluated using behavioral and physiological measures. However, so far, the measures have almost always been used to estimate poor welfare. In this review, firstly we focus on how oxytocin (OT) relates to positive social behavior, pleasure, and stress tolerance, and second on which management factors stimulate OT release. OT induces maternal and affiliative behaviors and has an anti-stress effect. Further, OT is produced during enjoyable events, and has positive feedback on its own release as well. Therefore, to some extent, the relationship of OT to positive normal behavior was mutually beneficial-heightened OT concentration owing to comfortable rearing conditions induces positive social behavior, which in turn may increase OT concentration. Hence, studies on animal welfare should pay more attention to increasing comfort and the stress tolerance, rather than only focusing on when stress occurs in farm animals. PMID- 26954195 TI - Marination and Physicochemical Characteristics of Vacuum-aged Duck Breast Meat. AB - We investigated marinade absorption and physicochemical characteristics of vacuum aged duck breasts that were halved and individually vacuum-packed for chiller aging at 4 degrees C for 14 d. One half was marinated for 0, 7, or 14 d, while the second half was used as a control. Marinade absorption, cooking loss, cooking yield, texture profile, pH, color, protein solubility, and thiobarbituric acid reactive substances (TBARS) values were evaluated, and protein sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) was performed. Marinade absorption and pH did not vary significantly after 14 d of aging. Marination increased the pH, color (a* and b*) values, and cooking yield and reduced cooking loss. TBARS values significantly increased with aging time, but were significantly reduced by marination. Myofibril and total protein solubility increased with aging and marination, while SDS-PAGE showed protein degradation. Hence, aging and marination can be used simultaneously to improve physicochemical quality and cooking yield of vacuum-aged duck breast. PMID- 26954197 TI - The Effects of Freezing and Supplementation of Molasses and Inoculants on Chemical and Nutritional Composition of Sunflower Silage. AB - This study was conducted to determine the effects of freezing and supplementation of molasses (M), lactic acid bacteria (LAB) and LAB+enzyme mixture on chemical and nutritional composition of sunflower silage (SF). Sunflower crops were harvested (at about 29.2%+/-1.2% dry matter) and half of fresh sunflower was ensiled alone and half was frozen (F) at -20 degrees C for 7 days. Silage additives were admixed into frozen SF material. All samples were ensiled in glass jars with six replicates for 90 days. The treatments were as follows: i) positive control (non-frozen and no additives, NF), ii) negative control (frozen, no additives, F), iii) F+5% molasses (FM), iv) F+LAB (1.5 g/tons, Lactobacillus plantarum and Enterococcus faecium, FLAB); v) F+LAB+enzyme (2 g/tons Lactobacillus plantarum and Enterococcus faecium and cellulase and amylase enzymes, FLEN). Freezing silage increased dry matter, crude ash, neutral detergent fiber, and acid detergent lignin. The organic matter, total digestible nutrient, non-fiber carbohydrate, metabolizable energy and in vitro dry matter digestibility were negatively influenced by freezing treatments (p<0.05). In conclusion, freezing sunflower plants prior to ensiling may negatively affect silage quality, while molasses supplementation improved some quality traits of frozen silage. Lactic acid bacteria and LAB+enzyme inoculations did not effectively compensate the negative impacts of freezing on sunflower silage. PMID- 26954196 TI - Polyunsaturated Fatty Acids in Male Ruminant Reproduction - A Review. AB - Fatty acids such as n-3 and n-6 polyunsaturated fatty acids (PUFA) are critical nutrients, used to improve male reproductive performance through modification of fatty acid profile and maintenance of sperm membrane integrity, especially under cold shock or cryopreservation condition. Also, PUFA provide the precursors for prostaglandin synthesis and can modulate the expression patterns of many key enzymes involved in both prostaglandin and steroid metabolism. Many studies carried out on diets supplemented with PUFA have demonstrated their capability to sustain sperm motility, viability and fertility during chilling and freezing as well as improving testis development and spermatogenesis in a variety of livestock species. In addition to the type and quantity of dietary fatty acids, ways of addition of PUFA to diet or semen extender is very crucial as it has different effects on semen quality in male ruminants. Limitation of PUFA added to ruminant ration is due to biohydrogenation by rumen microorganisms, which causes conversion of unsaturated fatty acids to saturated fatty acids, leading to loss of PUFA quantity. Thus, many strategies for protecting PUFA from biohydrogenation in rumen have been developed over the years. This paper reviews four aspects of PUFA in light of previous research including rumen metabolism, biological roles, influence on reproduction, and strategies to use in male ruminants. PMID- 26954198 TI - Relationship between Body Weight of Primiparous Sows during Late Gestation and Subsequent Reproductive Efficiency over Six Parities. AB - The present study investigated the impact of parity 1 gilt body weight during late gestation (d 109) on subsequent reproductive performance of sows and performance of suckling pigs. A total of 2,404 farrowing records over 6 parities were divided into six groups on the basis of body weight (190, 200, 210, 220, 230, and 240 kg) at d 109 of gestation of 585 gilts. Significant effects (p< 0.05) of body weight on sow retention rate was noticed, with the 210 kg group having the lowest culling rate and highest total number of piglets born alive over the 6 parities. With increase of body weight, a linear increase (p<0.05) in losses of body weight and backfat during the lactation period of parity 1 and a linear decrease (p<0.05) in backfat loss for parities 4 and 6 were found. Compared with light sows, heavy sows had higher (p<0.05) litter weight at birth for parities 1 and 2 and at weaning in parity 1. Sow weaning-to-estrus interval of sows was not influenced (p>0.05) by body weight. In conclusion, maintaining optimal body weight during gestation would be beneficial to sows and suckling piglets. PMID- 26954199 TI - Validation of Single Nucleotide Polymorphisms Associated with Carcass Traits in a Commercial Hanwoo Population. AB - Four carcass traits, namely carcass weight (CW), eye muscle area (EMA), back fat thickness (BF), and marbling score (MS), are the main price decision parameters used for purchasing Hanwoo beef. The development of DNA markers for these carcass traits for use in a beef management system could result in substantial profit for beef producers in Korea. The objective of this study was to validate the association of highly significant single nucleotide polymorphisms (SNPs) identified in a previous genome-wide association study (GWAS) with the four carcass traits in a commercial Hanwoo population. We genotyped 83 SNPs distributed across all 29 autosomes in 867 steers from a Korean Hanwoo feedlot. Six SNPs, namely ARS-BFGL-NGS-22774 (Chr4, Pos:4889229), ARS-BFGL-NGS-100046 (Chr6, Pos:61917424), ARS-BFGL-NGS-39006 (Chr27, Pos:38059196), ARS-BFGL-NGS 18790 (Chr10, Pos:26489109), ARS-BFGL-NGS-43879 (Chr9, Pos:39964297), and BTB 00775794 (Chr20, Pos:20476265), were found to be associated with CW, EMA, BF, and MS. The ARS-BFGL-NGS-22774, BTB-00775794, and ARS-BFGL-NGS-39006 markers accounted for 1.80%, 1.72%, and 1.35% (p<0.01), respectively, of the phenotypic variance in the commercial Hanwoo population. Many genes located in close proximity to the significant SNPs identified in this study were previously reported to have roles in carcass traits. The results of this study could be useful for marker-assisted selection programs. PMID- 26954200 TI - Antioxidant, Liver Protective and Angiotensin I-converting Enzyme Inhibitory Activities of Old Laying Hen Hydrolysate in Crab Meat Analogue. AB - The purpose of this study was to evaluate the antioxidative activities of Crab meat analogue prepared with protein hydrolysates obtained from mechanically deboned chicken meat (MDCM) from spent laying hens. 2,2-diphenyl-1-picrylhydrazyl hydrate (DPPH) radical-scavenging activity was increased by adding MDCM hydrolysates during storage, and activity correlated with the concentration of DPPH added up to 6 weeks of storage. Hydroxyl radical-scavenging activity was increased in all analogues containing MDCM hydrolysates. At 0 days of storage, angiotensin I-converting enzyme (ACE)-inhibitory activity was increased by the addition of MDCM hydrolysates. Activity did not correlate after 6 weeks of storage, in which ACE-inhibitory activity was increased with low concentrations of MDCM hydrolysates, but no ACE-inhibitory activity was observed at higher concentrations. The liver-protecting activity of crab meat analogue was shown to be around 60% of the positive control; however, it was not significantly different among the samples during storage. These results support the use of MDCM as a source of health-promoting constituents in crab meat analogue. PMID- 26954201 TI - Discovery of Gene Sources for Economic Traits in Hanwoo by Whole-genome Resequencing. AB - Hanwoo, a Korean native cattle (Bos taurus coreana), has great economic value due to high meat quality. Also, the breed has genetic variations that are associated with production traits such as health, disease resistance, reproduction, growth as well as carcass quality. In this study, next generation sequencing technologies and the availability of an appropriate reference genome were applied to discover a large amount of single nucleotide polymorphisms (SNPs) in ten Hanwoo bulls. Analysis of whole-genome resequencing generated a total of 26.5 Gb data, of which 594,716,859 and 592,990,750 reads covered 98.73% and 93.79% of the bovine reference genomes of UMD 3.1 and Btau 4.6.1, respectively. In total, 2,473,884 and 2,402,997 putative SNPs were discovered, of which 1,095,922 (44.3%) and 982,674 (40.9%) novel SNPs were discovered against UMD3.1 and Btau 4.6.1, respectively. Among the SNPs, the 46,301 (UMD 3.1) and 28,613 SNPs (Btau 4.6.1) that were identified as Hanwoo-specific SNPs were included in the functional genes that may be involved in the mechanisms of milk production, tenderness, juiciness, marbling of Hanwoo beef and yellow hair. Most of the Hanwoo-specific SNPs were identified in the promoter region, suggesting that the SNPs influence differential expression of the regulated genes relative to the relevant traits. In particular, the non-synonymous (ns) SNPs found in CORIN, which is a negative regulator of Agouti, might be a causal variant to determine yellow hair of Hanwoo. Our results will provide abundant genetic sources of variation to characterize Hanwoo genetics and for subsequent breeding. PMID- 26954202 TI - Green Light-emitting Diodes Light Stimuli during Incubation Enhances Posthatch Growth without Disrupting Normal Eye Development of Broiler Embryos and Hatchlings. AB - Monochromatic green light-emitting diodes (LED) light stimuli influences the posthatch growth performance of chicks. This study was undertaken with the following objectives: i) to examine whether the green LED light stimuli induces an overheating effect by determining weight loss rate of fertile eggs during incubation period; ii) to look for the development of eyes and other primary organs at different ages of embryos and newly hatched chicks. Arbor Acres fertile broiler eggs (n = 480) were randomly assigned to 3 incubation groups and exposed to continuous white light, green light, or a dark environment (control) from the first day to 19 d of incubation. The light sourced from LED lamps with the intensity of 30 lx at eggshell level. The results showed that either green or white light stimuli during incubation did not significantly affect the weight loss rate of fertile eggs, hatching time, hatchability, chick embryo, or body weight (BW), the weight percentage of heart, liver, and eyes, as well as obvious systematic abnormalities in eye weight, side-to-side, back-to-front, or corneal diameter from 15 d of embryogenesis to 6 d of posthatch (p>0.05). Compared with the dark condition, green light stimuli during incubation tended to increase feed intake (p = 0.080), improved the BW gain of chicks during 0 to 6 day posthatch (p<0.05), and increased the percentage of pectoral muscle to the BW on 3- and 6 day-old chicks. In addition, embryos or chicks in green light had lower weight percentage of yolk retention on 19 d of embryogenesis and 1 d of posthatch in comparison to those in dark or white group (p<0.05). These results suggest that providing 30 lx green LED light stimuli during incubation has no detrimental effect on the development of eyes, heart and liver of embryos and hatchlings, but does have potential benefits in terms of enhancement of the chick growth during the early posthatch stages. In addition, the fertile broiler eggs stimulated with 30 lx green LED light during incubation does not cause an overheating effect. PMID- 26954203 TI - Residual frying oil in the diets of sheep: intake, digestibility, nitrogen balance and ruminal parameters. AB - OBJECTIVE: The objective of this study was to evaluate the intake and nutrient digestibility, nitrogen balance and ruminal ammonia nitrogen in lambs of diets containing different levels of residual frying oil. METHODS: Levels of 0, 20, 40, 60, and 80 g/kg dry matter (DM) base of residual frying oil in the diets of lambs were evaluated. Five castrated lambs with initial body weights of 36.8+/-3.3 kg, distributed in a Latin square (5*5) design, were used. RESULTS: There was a decreasing linear effect on the intake of DM, organic matter (OM), crude protein (CP), neutral detergent fiber (NDF), total carbohydrates (TCH), and nonfibrous carbohydrates (NFC). There was an increased linear intake of ether extract (EE). The apparent digestibility of DM, OM, CP, NDF, TCH, and NFC, as well as urine nitrogen excretion, nitrogen balance and ruminal parameters, were not influenced by different levels of residual frying oil in the diet. EE digestibility presented a crescent linear effect. CONCLUSION: It can be concluded that the addition of residual frying oil to the diets of sheep can affect nutrient intake without affecting the digestibility of most nutrients (with the exception of EE), nitrogen balance and ruminal ammonia nitrogen concentration. PMID- 26954204 TI - Quantitative Microbial Risk Assessment for Clostridium perfringens in Natural and Processed Cheeses. AB - This study evaluated the risk of Clostridium perfringens (C. perfringens) foodborne illness from natural and processed cheeses. Microbial risk assessment in this study was conducted according to four steps: hazard identification, hazard characterization, exposure assessment, and risk characterization. The hazard identification of C. perfringens on cheese was identified through literature, and dose response models were utilized for hazard characterization of the pathogen. For exposure assessment, the prevalence of C. perfringens, storage temperatures, storage time, and annual amounts of cheese consumption were surveyed. Eventually, a simulation model was developed using the collected data and the simulation result was used to estimate the probability of C. perfringens foodborne illness by cheese consumption with @RISK. C. perfringens was determined to be low risk on cheese based on hazard identification, and the exponential model (r = 1.82*10(-11)) was deemed appropriate for hazard characterization. Annual amounts of natural and processed cheese consumption were 12.40+/-19.43 g and 19.46+/-14.39 g, respectively. Since the contamination levels of C. perfringens on natural (0.30 Log CFU/g) and processed cheeses (0.45 Log CFU/g) were below the detection limit, the initial contamination levels of natural and processed cheeses were estimated by beta distribution (alpha 1 = 1, alpha 2 = 91; alpha 1 = 1, alpha 2 = 309)*uniform distribution (a = 0, b = 2; a = 0, b = 2.8) to be -2.35 and -2.73 Log CFU/g, respectively. Moreover, no growth of C. perfringens was observed for exposure assessment to simulated conditions of distribution and storage. These data were used for risk characterization by a simulation model, and the mean values of the probability of C. perfringens foodborne illness by cheese consumption per person per day for natural and processed cheeses were 9.57*10(-14) and 3.58*10(-14), respectively. These results indicate that probability of C. perfringens foodborne illness by consumption cheese is low, and it can be used to establish microbial criteria for C. perfringens on natural and processed cheeses. PMID- 26954205 TI - Nitric oxide and ovarian folliculogenesis: a possible role in follicular atresia. AB - Ovarian follicles are basic structural and functional unit of the mammalian ovary. At birth, ovaries contain a large pool of primordial/preantral follicles. Although, most of the follicles undergo follicular atresia during folliculogenesis and only few get chance to reach ovulatory stage that eventually limit the propagation of superior germplasm and success rate of assisted reproductive technologies (ART) program in livestock. Understanding of the mechanism that lead to the follicular growth and maturation, the relevant endocrine compounds and locally produced factors that are involved during folliculogenesis is important to recognize and know their functions. In last two decades, considerable progress has been made to unreveal the role of nitric oxide (NO) at the peripheral, cellular and molecular level in domestic animal reproduction. However, role of NO and their mechanism that govern in vivo folliculogenesis is not well understood. This review provides a general overview of role of NO as a vital molecule controlling various reproductive functions with special emphasis on ovarian folliculogenesis in large domestic ungulates. PMID- 26954206 TI - Comparison of Carcass Characteristics, Meat Quality, and Blood Parameters of Slow and Fast Grown Female Broiler Chickens Raised in Organic or Conventional Production System. AB - The objective of the study was to compare the carcass characteristics, meat quality, and blood parameters of slow and fast grown female broiler chickens fed in organic or conventional production system. The two genotypes tested were medium slow-growing chickens (SG, Hubbard Red JA) and commercial fast-growing chickens (FG, Ross 308). Both genotypes (each represented by 400 chickens) were divided into two sub-groups fed either organic (O) or conventional (C) systems. Chickens of each genotype and system were raised in a semi environmentally controlled poultry house until 21 d of age and were assigned to 5 pens of 40 chickens each. Then, O system chickens were transferred into an open-side poultry house with an outdoor run. At 81 d of age, 10 female chickens from each genotype and from each production system (n = 40) were randomly chosen to provide material for analysis, and were weighed and brought to the slaughterhouse to assess carcass characteristics and meat quality. The blood parameters were determined by using 5 female chickens from each genotype and from each production system (n = 20). FG had the higher live weight, along with carcass, breast, and thigh drumstick weights compared to SG (p<0.05). FG had the higher breast yield, whereas SG had the higher thigh-drumstick yield (p<0.05). The O system resulted in a higher amount of abdominal fat (p<0.05). In addition, the O system values were higher for dry matter, crude ash, crude protein, and pH(15) values in breast meat, and for crude ash, crude protein, and pH(15) values in drumstick meat (p<0.05). In addition, total saturated fatty acids, total mono-unsaturated fatty acids, and total omega 3 were significantly higher in the O system than in the C system. Thus, the O system showed a positive advantage compared to the C system regarding female chicken meat quality, primarily within the ash, protein, and total omega 3 fatty acid profiles. In conclusion, the present study indicated that the main factor affecting the carcass characteristics of female chickens was genotype, whereas the organic system contributed to enhanced meat quality. These findings provide a better understanding of the relative roles of genotype and production systems in female broiler characteristics, and might aid producers in designing their facilities to optimize yield and quality while maintaining acceptable animal welfare standards. PMID- 26954207 TI - The Use of Fermented Soybean Meals during Early Phase Affects Subsequent Growth and Physiological Response in Broiler Chicks. AB - The objectives of this experiment was to evaluate the subsequent growth and organ weights, blood profiles and cecal microbiota of broiler chicks fed pre-starter diets containing fermented soybean meal products during early phase. A total of nine hundred 1-d-old chicks were randomly assigned into six groups with six replicates of 25 chicks each. The chicks were fed control pre-starter diet with dehulled soybean meal (SBM) or one of five experimental diets containing fermented SBM products (Bacillus fermented SBM [BF-SBM], yeast by product and Bacillus fermented SBM [YBF-SBM]; Lactobacillus fermented SBM 1 [LF-SBM 1]; Lactobacillus fermented SBM 2 [LF-SBM 2]) or soy protein concentrate (SPC) for 7 d after hatching, followed by 4 wk feeding of commercial diets without fermented SBMs or SPC. The fermented SBMs and SPC were substituted at the expense of dehulled SBM at 3% level on fresh weight basis. The body weight (BW) during the starter period was not affected by dietary treatments, but BW at 14 d onwards was significantly higher (p<0.05) in chicks that had been fed BF-SBM and YBF-SBM during the early phase compared with the control group. The feed intake during grower and finisher phases was not affected (p>0.05) by dietary treatments. During total rearing period, the daily weight gains in six groups were 52.0 (control), 57.7 (BF-SBM), 58.5 (YBF-SBM), 52.0 (LF-SBM 1), 56.7 (LF-SBM 2), and 53.3 g/d (SPC), respectively. The daily weight gain in chicks fed diet containing BF-SBM, YBF-SBM, and LF-SBM 2 were significantly higher values (p<0.001) than that of the control group. Chicks fed BF-SBM, YBF-SBM, and LF-SBM 2 had significantly lower (p<0.01) feed conversion ratio compared with the control group. There were no significant differences in the relative weight of various organs and blood profiles among groups. Cecal microbiota was altered by dietary treatments. At 35 d, chicks fed on the pre-starter diets containing BF-SBM and YBF-SBM had significantly increased (p<0.001) lactic acid bacteria, but lowered Coli-form bacteria in cecal contents compared with those fed the control diet. The number of Bacillus spp. was higher (p<0.001) in all groups except for LF-SBM 1 compared with control diet-fed chicks. At 7 d, jejunal villi were significantly lengthened (p<0.001) in chicks fed the fermented SBMs vs control diet. Collectively, the results indicate that feeding of fermented SBMs during early phase are beneficial to the subsequent growth performance in broiler chicks. BF SBM and YBF-SBM showed superior overall growth performance as compared with unfermented SBM and SPC. PMID- 26954208 TI - Effects of Extracellular Matrix Protein-derived Signaling on the Maintenance of the Undifferentiated State of Spermatogonial Stem Cells from Porcine Neonatal Testis. AB - In general, the seminiferous tubule basement membrane (STBM), comprising laminin, collagen IV, perlecan, and entactin, plays an important role in self-renewal and spermatogenesis of spermatogonial stem cells (SSCs) in the testis. However, among the diverse extracellular matrix (ECM) proteins constituting the STBM, the mechanism by which each regulates SSC fate has yet to be revealed. Accordingly, we investigated the effects of various ECM proteins on the maintenance of the undifferentiated state of SSCs in pigs. First, an extracellular signaling-free culture system was optimized, and alkaline phosphatase (AP) activity and transcriptional regulation of SSC-specific genes were analyzed in porcine SSCs (pSSCs) cultured for 1, 3, and 5 days on non-, laminin- and collagen IV-coated Petri dishes in the optimized culture system. The microenvironment consisting of glial cell-derived neurotrophic factor (GDNF)-supplemented mouse embryonic stem cell culture medium (mESCCM) (GDNF-mESCCM) demonstrated the highest efficiency in the maintenance of AP activity. Moreover, under the established extracellular signaling-free microenvironment, effective maintenance of AP activity and SSC specific gene expression was detected in pSSCs experiencing laminin-derived signaling. From these results, we believe that laminin can serve as an extracellular niche factor required for the in vitro maintenance of undifferentiated pSSCs in the establishment of the pSSC culture system. PMID- 26954211 TI - Performance of Broiler Chickens Fed Low Protein, Limiting Amino Acid Supplemented Diets Formulated Either on Total or Standardized Ileal Digestible Amino Acid Basis. AB - The aim of present experiment was to investigate the effect of protein reduction in commercial broiler chicken rations with incorporation of de-oiled rice bran (DORB) and supplementation of limiting amino acids (valine, isoleucine, and/or tryptophan) with ration formulation either on total amino acid (TAA) or standardized ileal digestible amino acids (SIDAA). The experimental design consisted of T1, TAA control; T2 and T3, 0.75% and 1.5% protein reduction by 3% and 6% DORB incorporation, respectively by replacing soybean meal with supplemental limiting amino acids to meet TAA requirement; T4, SIDAA control, T5 and T6, 0.75% and 1.5% protein reduction by DORB incorporation (3% and 6%) with supplemental limiting amino acids on SIDAA basis. A total of 360 d-old fast growing broiler chicks (Vencobb-400) were divided into 36 homogenous groups of ten chicks each, and six dietary treatments described were allocated randomly with six replications. During 42 days trial, the feed intake was significantly (p<0.05) reduced by TAA factor compared to SIDAA factor and protein factor significantly (p<0.05) reduced the feed intake at 1.5% reduction compared to normal protein group. This was observed only during pre-starter phase but not thereafter. The cumulative body weight gain (BWG) was significantly (p<0.05) reduced in TAA formulations with protein step-down of 1.5% (T3, 1,993 g) compared to control (T1, 2,067 g), while under SIDAA formulations, BWG was not affected with protein reduction of 1.5% (T6, 2,076 g) compared to T4 (2,129 g). The feed conversion ratio (FCR) was significantly (p<0.05) reduced in both TAA and SIDAA formulations with 1.5% protein step-down (T3, 1.741; T6, 1.704) compared to respective controls (T1, 1.696; T4, 1.663). The SIDAA formulation revealed significantly (p<0.05) higher BWG (2,095 g) and better FCR (1.684) compared to TAA formulation (2,028 g; 1.721). Intake of crude protein and all limiting amino acids (SID basis) was higher in SIDAA group than TAA group with resultant higher nitrogen retention (4.438 vs 4.027 g/bird/d). The nitrogen excretion was minimized with 1.5% protein reduction (1.608 g/bird) compared to normal protein group (1.794 g/bird). The serum uric acid concentration was significantly reduced in T3 (9.45 mg/dL) as compared to T4 (10.75 mg/dL). All carcass parameters were significantly (p<0.05) higher in SIDAA formulation over TAA formulation and 1.5% protein reduction significantly reduced carcass, breast and thigh yields. In conclusion, the dietary protein can be reduced by 0.75% with TAA formulation and 1.5% with SIDAA formulation through DORB incorporation and supplementation of limiting amino acids and among formulations, SIDAA formulation was better than TAA formulation. PMID- 26954209 TI - Dynamical Expression of MicroRNA-127-3p in Proliferating and Differentiating C2C12 Cells. AB - MicroRNAs (miRNAs) are highly conserved, short non-coding RNAs that regulate gene expression at the posttranscriptional level. Although many miRNAs are identified in muscles and muscle cells, their individual roles are still not fully understood. In the present study, we investigated a muscle highly-expressed miRNA, miR-127-3p, in C2C12 myoblasts and tissues of goats with different muscle phenotypes (Boer vs Wushan black goats). Our results demonstrated that i) miR-127 3p was extensively expressed in tissues of goats; ii) miR-127-3p was higher expressed in muscle, spleen, heart, and skin in the muscular goats (Boer goats) than the control (Wushan black goats). Then we further characterized the dynamical expression of miR-127-3p, MyoD, MyoG, Myf5, Mef2c, and Myosin in the proliferating and differentiating C2C12 myoblasts at day of 0, 1, 3, 5, and 7 in culture mediums. Especially, we found that miR-127-3p was significantly higher expressed in the proliferating than differentiating cells. Our findings suggest that miR-127-3p probably plays roles in the proliferation and differentiation of myoblasts, which further underlies regulation of muscle phenotype in goats. PMID- 26954210 TI - Effects of Dietary Supplementation with Astaxanthin on Histamine Induced Lesions in the Gizzard and Proventriculus of Broiler Chicks. AB - Astaxanthin (ASX) is a xanthophyll pigment isolated from crustaceans and salmonids. Owing to its powerful antioxidant activity, ASX has been reported to have the potential to protect against gastric ulcers and a variety of other illnesses. Histamine (His) is a dietary factor that causes gastric erosion and ulceration in young chicks. In this study, we examined whether ASX had protective effects on dietary histamine-induced lesions in the gizzard and proventriculus of broiler chickens. Four experimental treatment groups were planned: basal diet (BD), BD+His, BD+ASX, and BD+ASX+His, with four chicks (5 days old) in each group and three replications (i.e., a total of 12 chicks per group). The BD was supplemented with either 0.4% His or 100 ppm ASX. The birds were fed ad libitum for 3 weeks, and diets contained no antimicrobial compounds. Supplementing the diet with His significantly decreased body weight gain, but increased the weights of the gizzard and proventriculus of the chicks as compared with those of chicks in the BD group (p<0.05). ASX did not affect His-dependent changes in chick body weight or weights of the gizzard and proventriculus. The loss of gastric glands in the proventriculus, which was observed in His-treated chicks, was not prevented by ASX administration. The frequency of proventricular ulceration, however, was lowered by treatment with ASX, without significant differences between the two supplementation levels. In conclusion, our data showed that ASX might be helpful for alleviating structural damage to the digestive system in poultry under certain stressful conditions. PMID- 26954212 TI - Casein Supplementation Does Not Affect the Estimates of True Total Tract Digestibility of Phosphorus in Soybean Meal for Growing Pigs Determined by the Regression Method. AB - Forty-eight barrows with an average initial body weight of 25.5+/-0.3 kg were assigned to 6 dietary treatments arranged in a 3*2 factorial of 3 graded levels of P at 1.42, 2.07, or 2.72 g/kg, and 2 levels of casein at 0 or 50 g/kg to compare the estimates of true total tract digestibility (TTTD) of P in soybean meal (SBM) for pigs fed diets with or without casein supplementation. The SBM is the only source of P in diets without casein, and in the diet with added casein, 1.0 to 2.4 g/kg of total dietary P was supplied by SBM as dietary level of SBM increased. The experiment consisted of a 5-d adjustment period and a 5-d total collection period with ferric oxide as a maker to indicate the initiation and termination of fecal collection. There were interactive effects of casein supplementation and total dietary P level on the apparent total tract digestibility (ATTD) and retention of P (p<0.05). Dietary P intake, fecal P output, digested P and retained P were increased linearly with graded increasing levels of SBM in diets regardless of casein addition (p<0.01). Compared with diets without casein, there was a reduction in fecal P in the casein-supplemented diets, which led to increases in digested P, retained P, ATTD, and retention of P (p<0.01). Digested N, ATTD of N, retained N, and N retention were affected by the interaction of casein supplementation and dietary P level (p<0.05). Fecal N output, urinary N output, digested N, and retained N increased linearly with graded increasing levels of SBM for each type of diet (p<0.01). The estimates of TTTD of P in SBM, derived from the regression of daily digested P against daily P intake, for pigs fed diets without casein and with casein were calculated to be 37.3% and 38.6%, respectively. Regressing daily digested N against daily N intake, the TTTD of N in SBM were determined at 94.3% and 94.4% for diets without casein and with added casein, respectively. There was no difference in determined values of TTTD of P or N in SBM for pigs fed diets with or without casein (p>0.05). In summary, our results demonstrate that the estimates of TTTD of P in SBM for pigs were not affected by constant casein inclusion in the basal diets. PMID- 26954213 TI - Effects of Supplemental Liquid DL-methionine Hydroxy Analog Free Acid in Diet on Growth Performance and Gastrointestinal Functions of Piglets. AB - This study was conducted to determine the effect of dietary supplementation of liquid DL-methionine hydroxy analog free acid (DL-MHA) on growth performance and gastrointestinal conditions of piglets. One hundred and eighty crossbred barrow piglets (Large White*Landrace, body weight: 12.48+/-0.33 kg) were divided into three groups with ten replications of six piglets each. Piglets received DL-MHA in diet at a concentration of 0 (control group), 0.15%, or 0.24%. The results indicated that increasing the standardized ileal digestible (SID) of sulfur amino acids (SAA) to lysine (SID SAA:Lys) ratio by supplementation of DL-MHA tended to increase (quadratic; p<0.10) weight gain and ADG, and showed slightly greater (linear; p<0.10) gain:feed ratio. The pH in the diet and cecum linearly decreased (p<0.01), whereas pH in colon had a quadratic response (p<0.01) with increasing supplementation of DL-MHA. By greater supplementation of DL-MHA, the population of Lactobacillus spp. in rectum was likely to increase (quadratic; p<0.10), but Escherichia coli population in the diet was reduced (quadratic; p<0.05). Acetic acid concentration and total short-chain fatty acids in cecum linearly increased (p<0.05), whereas valeric acid in cecum quadratically increased (p<0.05) with increasing DL-MHA levels. Moreover, the villous height of the jejunum quadratically increased (p<0.01) as the supplementation of DL-MHA was increased. It is concluded that the addition of DL-MHA in diet improved the growth performance and the morphology of gastrointestinal tract of piglets. PMID- 26954214 TI - Effect of L- or DL-methionine Supplementation on Nitrogen Retention, Serum Amino Acid Concentrations and Blood Metabolites Profile in Starter Pigs. AB - The objective of the current study was to evaluate the effect of supplementation of either L-methionine (L-Met) or DL-methionine (DL-Met) to diets of starter pigs on nitrogen (N) balance, metabolism, and serum amino acid profile. Eighteen crossbred (Duroc*Landrace*Yorkshire) barrows weighing 15.45+/-0.88 kg were randomly allotted to 1 of 3 diets with 6 pigs per treatment. The diets included a basal diet (Met-deficient diet) containing 0.24% standardized ileal digestibility Met with all other essential nutrients meeting the pig's requirements. The other two diets were produced by supplementing the basal diet with 0.12% DL-Met or L Met. The experiment lasted for 18 days, consisting of a 13-day adaptation period to the diets followed by a 5-day experimental period. Pigs were fed ad libitum and free access to water throughout the experiment. Results showed that the supplementation of either L-Met or DL-Met improved N retention, and serum methionine concentration, and decreased N excretion compared with basal diet (p<0.01). The N retention of pigs fed diets supplemented with the same inclusion levels of DL-Met or L-Met were not different (p>0.05). In conclusion, on equimolar basis DL-Met and L-Met are equally bioavailable as Met sources for starter pigs. PMID- 26954216 TI - A Comparison of Natural (D-alpha-tocopherol) and Synthetic (DL-alpha-tocopherol Acetate) Vitamin E Supplementation on the Growth Performance, Meat Quality and Oxidative Status of Broilers. AB - The present study was conducted to compare the supplementation of natural (D alpha-tocopherol) and synthetic (DL-alpha-tocopherol acetate) vitamin E on the growth performance, meat quality, muscular antioxidant capacity and genes expression related to oxidative status of broilers. A total of 144 1 day-old Arbor Acres broiler chicks were randomly allocated into 3 groups with 6 replicates of 8 birds each. Birds were given a basal diet (control group), and basal diet supplemented with either 20 IU D-alpha-tocopherol or DL-alpha tocopherol acetate for 42 days, respectively. The results indicated that treatments did not alter growth performance of broilers (p>0.05). Compared with the control group, concentration of alpha-tocopherol in the breast muscle was increased by the supplementation of vitamin E (p<0.05). In the thigh, alpha tocopherol content was also enhanced by vitamin E inclusion, and this effect was more pronounced in the natural vitamin E group (p<0.05). Vitamin E supplementation increased the redness of breast (p<0.05). In the contrast, the inclusion of synthetic vitamin E decreased lightness of thigh (p<0.05). Dietary vitamin E inclusion reduced drip loss at 24 h of thigh muscle (p<0.05), and this effect was maintained for drip loss at 48 h in the natural vitamin E group (p<0.05). Broilers given diet supplemented with vitamin E showed decreased malondialdehyde (MDA) content in the breast (p<0.05). Additionally, natural rather than synthetic vitamin E reduced MDA accumulation in the thigh (p<0.05). Neither natural nor synthetic vitamin E supplementation altered muscular mRNA abundance of genes related to oxidative stress (p>0.05). It was concluded that vitamin E supplementation, especially the natural vitamin E, can enhance the retention of muscular alpha-tocopherol, improve meat quality and muscular antioxidant capacity of broilers. PMID- 26954217 TI - Effects of Dietary Calcium Levels on Productive Performance, Eggshell Quality and Overall Calcium Status in Aged Laying Hens. AB - This study was conducted to investigate the effects of diets with varying levels of calcium on egg production, shell quality and overall calcium status in aged laying hens. A total of five hundred 70-wk-old Hy-Line Brown layers were divided five groups and fed one of the five experimental diets with 3.5%, 3.8%, 4.1%, 4.4%, or 4.7% Ca, for 10 weeks. There were no significant differences in feed intake, egg production and egg weight among groups. The cracked eggs were linearly reduced as dietary Ca levels increased to 4.7% (p<0.01). A significant linear improvement for eggshell strength and thickness were determined with increasing dietary Ca levels (p<0.01). The contents of serum Ca and phosphorus were not affected by dietary Ca levels. With increase in dietary Ca levels, the tibial breaking strength slightly increased. There were no significant differences in the tibial contents of ash, Ca and phosphorus among groups. In conclusion, eggshell quality, as measured by appearance, strength and thickness of eggshell, were influenced by dietary Ca content as expected (p<0.05). These results suggested that aged laying hens require relatively higher level of Ca than required levels from current Korean feeding standards for poultry. PMID- 26954218 TI - Screening of Probiotic Activities of Lactobacilli Strains Isolated from Traditional Tibetan Qula, A Raw Yak Milk Cheese. AB - In this study, 69 lactobacilli isolated from Tibetan Qula, a raw yak milk cheese, were screened for their potential use as probiotics. The isolates were tested in terms of: Their ability to survive at pH 2.0, pH 3.0, and in the presence of 0.3% bile salts; tolerance of simulated gastric and intestinal juices; antimicrobial activity; sensitivity against 11 specific antibiotics; and their cell surface hydrophobicity. The results show that out of the 69 strains, 29 strains (42%) had survival rates above 90% after 2 h of incubation at pH values of 2.0 or 3.0. Of these 29 strains, 21 strains showed a tolerance for 0.3% bile salt. Incubation of these 21 isolates in simulated gastrointestinal fluid for 3 h revealed survival rates above 90%; the survival rate for 20 of these isolates remained above 90% after 4 h of incubation in simulated intestinal fluid. The viable counts of bacteria after incubation in simulated gastric fluid for 3 h and simulated intestinal fluid for 4 h were both significantly different compared with the counts at 0 h (p<0.001). Further screening performed on the above 20 isolates indicated that all 20 lactobacilli strains exhibited inhibitory activity against Micrococcus luteus ATCC 4698, Bacillus subtilis ATCC 6633, Listeria monocytogenes ATCC 19115, and Salmonella enterica ATCC 43971. Moreover, all of the strains were resistant to vancomycin and streptomycin. Of the 20 strains, three were resistant to all 11 elected antibiotics (ciprofloxacin, erythromycin, tetracycline, penicillin G, ampicillin, streptomycin, polymyxin B, vancomycin, chloramphenicol, rifampicin, and gentamicin) in this study, and five were sensitive to more than half of the antibiotics. Additionally, the cell surface hydrophobicity of seven of the 20 lactobacilli strains was above 70%, including strains Lactobacillus casei 1,133 (92%), Lactobacillus plantarum 1086-1 (82%), Lactobacillus casei 1089 (81%), Lactobacillus casei 1138 (79%), Lactobacillus buchneri 1059 (78%), Lactobacillus plantarum1141 (75%), and Lactobacillus plantarum 1197 (71%). Together, these results suggest that these seven strains are good probiotic candidates, and that tolerance against bile acid, simulated gastric and intestinal juices, antimicrobial activity, antibiotic resistance, and cell surface hydrophobicity could be adopted for preliminary screening of potentially probiotic lactobacilli. PMID- 26954219 TI - Negative Trends in Transport-related Mortality Rates in Broiler Chickens. AB - The high incidence of deaths during transport for slaughter is associated with poor welfare and represents a considerable loss to the poultry industry. In the period from 2009 to 2014, all shipments of broiler chickens to poultry processing plants were monitored in the Czech Republic and the numbers of chickens transported and those dying as a result of their transport were recorded and analysed. Overall transport-related mortality of broiler chickens transported for slaughter in the Czech Republic was 0.37%. It ranged from 0.31% to 0.72%, the increase approximately corresponding to the increasing transport distance. Statistically highly significant (p<0.001) differences were found when comparing transport-related mortality rates in individual seasons of the year. The greatest mortality (0.55%) was associated with transports carried out in winter months whereas the lowest death losses (0.30%) were found in chickens transported for slaughter in summer months. Our study revealed greater transport-related mortality rates in broiler chickens transported for slaughter in the Czech Republic than expected when considering earlier studies. The most pronounced increases were found in transports for shorter distances and in winter months. However, an increase was found at all transport distances monitored except for distances exceeding 300 km and all seasons except for summer. Furthermore, a general increasing tendency in chicken losses during the monitored period was found. The particularly alarming finding is that the mortality of broiler chickens being transported to processing plants has been showing a long-term increasing tendency over the last two decades. Further research should focus on the identification of specific factors leading to such high and growing mortality rates and developing practical guidelines to improve the welfare of the birds in transit accordingly. PMID- 26954220 TI - Methodologies for the Determination of Endogenous Phosphorus Losses in Growing Pigs. AB - A study was conducted to compare the endogenous basal losses of phosphorus (EBLP) in pigs fed diets containing gelatin (GEL) or spray-dried porcine plasma (SDPP) as protein sources and to determine the standardized total tract digestibility (STTD) of phosphorus (P) in SDPP. The trial was carried out at the Federal University of Santa Maria, Brazil. Twelve castrated pigs with an initial body weight of 55 kg were individually allotted in metabolic crates during two 12-day periods, each with 7 days of adaptation and 5 days of total fecal collection. The beginning and the end of the collecting periods were determined according to the marker-to-marker approach, using ferric oxide as an indigestible marker. Pigs were submitted to four semi-purified diets, one being a P-free diet with 30% of GEL as the protein source and three were diets with 10%, 20%, and 30% inclusion of SDPP respectively. Data were subjected to analysis of variance and the model included the effects of period, animal and treatments; the results of the three diets with increased levels of SDPP were subjected to linear regression analysis. The intercept of the relation of between ingested P and absorbed P represented the EBLP, while the slope indicated the STTD of P in SDPP. The EBLP means obtained by P-free diet and regression method were compared with the Student t test. The EBLP were 128.95 mg/kg dry matter intake (DMI) and 153.63 mg/kg DMI (standard error = 77.0; p<0.06) using the P-free diet with GEL as the protein source and the regression method, obtained with diets containing increased levels of SDPP, respectively. The apparent digestibility of P was 87.9%, 94.2%, and 92.9% for the treatments containing 10%, 20%, and 30% inclusion of SDPP, respectively. The estimated STTD of P obtained with the linear regression was 97.4%. When the EBLP estimated by the P-free diet was used to corrected the apparent digestibility of P in diets containing SDPP, the STTD of P in SDPP was 96.9%, 98.8%, and 95.9% for 10%, 20%, and 30% SDPP, respectively. Therefore, it can be concluded that SDPP can replace GEL to estimate the endogenous losses of P. In addition, the STTD of P in SDPP estimated with the P-free diet was 97.2% and it was 97.4% by the regression method, utilizing SDPP. PMID- 26954221 TI - Performance, Carcass Quality and Fatty Acid Profile of Crossbred Wagyu Beef Steers Receiving Palm and/or Linseed Oil. AB - The objective of this study was to determine the effect of palm and/or linseed oil (LSO) supplementation on carcass quality, sensory evaluation and fatty acid profile of beef from crossbred Wagyu beef steers. Twenty four fattening Wagyu crossbred beef steers (50% Wagyu), averaging 640+/-18 kg live weight (LW) and approximately 30 mo old, were stratified and randomly assigned in completely randomized design into 3 treatment groups. All steers were fed approximately 7 kg/d of 14% crude protein concentrate with ad libitum rice straw and had free access to clean water and were individually housed in a free-stall unit. The treatments were i) control concentrate plus 200 g/d of palm oil; ii) control concentrate plus 100 g/d of palm oil and 100 g/d of LSO, iii) control concentrate plus 200 g/d of LSO. This present study demonstrated that supplementation of LSO rich in C18:3n-3 did not influence feed intakes, LW changes, carcass and muscle characteristics, sensory and physical properties. LSO increased C18:3n-3, C22:6n 3, and n-3 polyunsaturated fatty acids (PUFA), however, it decreased C18:1t-11, C18:2n-6, cis-9, trans-11, and trans-10,cis-12 conjugated linoleic acids, n-6 PUFA and n-6:n-3 ratio in Longissimus dorsi and Semimembranosus muscles. PMID- 26954222 TI - Optimization of Swine Breeding Programs Using Genomic Selection with ZPLAN. AB - The objective of this study was to evaluate the present conventional selection program of a swine nucleus farm and compare it with a new selection strategy employing genomic enhanced breeding value (GEBV) as the selection criteria. The ZPLAN+ software was employed to calculate and compare the genetic gain, total cost, return and profit of each selection strategy. The first strategy reflected the current conventional breeding program, which was a progeny test system (CS). The second strategy was a selection scheme based strictly on genomic information (GS1). The third scenario was the same as GS1, but the selection by GEBV was further supplemented by the performance test (GS2). The last scenario was a mixture of genomic information and progeny tests (GS3). The results showed that the accuracy of the selection index of young boars of GS1 was 26% higher than that of CS. On the other hand, both GS2 and GS3 gave 31% higher accuracy than CS for young boars. The annual monetary genetic gain of GS1, GS2 and GS3 was 10%, 12%, and 11% higher, respectively, than that of CS. As expected, the discounted costs of genomic selection strategies were higher than those of CS. The costs of GS1, GS2 and GS3 were 35%, 73%, and 89% higher than those of CS, respectively, assuming a genotyping cost of $120. As a result, the discounted profit per animal of GS1 and GS2 was 8% and 2% higher, respectively, than that of CS while GS3 was 6% lower. Comparison among genomic breeding scenarios revealed that GS1 was more profitable than GS2 and GS3. The genomic selection schemes, especially GS1 and GS2, were clearly superior to the conventional scheme in terms of monetary genetic gain and profit. PMID- 26954223 TI - Effects of Dietary Methionine Levels on Choline Requirements of Starter White Pekin Ducks. AB - A 2*5 factorial experiment, using 2 dietary methionine levels (0.28% and 0.48%) and 5 dietary choline levels (0, 394, 823, 1,239, and 1,743 mg/kg), was conducted to study the effects of dietary methionine status on choline requirements of starter white Pekin ducks from 7 to 28 days of age. Four hundred eighty 7-d-old male White Pekin ducks were randomly allotted to ten dietary treatments, each containing 6 replicate pens with 8 birds per pen. At 28 d of age, weight gain, feed intake, and feed/gain were measured and the legs of all ducks from each pen were examined for incidence of perosis. Perosis and growth depression were observed in choline-deficient ducks and supplementation of choline reduced perosis and significantly increased weight gain and feed intake regardless of dietary methionine levels (p<0.05). In addition, significant positive effects of dietary methionine supplementation on weight gain, feed intake, and feed/gain were observed at any choline level (p<0.05). Supplementation of 1,743 mg/kg choline in diets alleviated the depression of weight gain and feed intake caused by methionine deficiency at 0.28% methionine level. The interaction between choline and methionine influenced weight gain and feed intake of ducks (p<0.05). At 0.28% methionine level, 1,743 mg/kg choline group caused 4.92% and 3.23% amount of improvement in weight gain and feed intake compared with 1,239 mg/kg choline group, respectively. According to the broken-line regression, the choline requirements of starter Pekin ducks for weight gain and feed intake were 1,472 and 1,424 mg/kg at 0.28% methionine level and 946 and 907 mg/kg at 0.48% methionine level, respectively. It suggested the choline recommendations of starter Pekin ducks on a semi-purified diet were 1448 mg/kg at 0.28% methionine level and 927 mg/kg at 0.48% methionine level, respectively. Compared with the adequate methionine level, menthionine deficiency markedly increased the choline requirements of ducks. PMID- 26954225 TI - Genetic diversity and effect of selection at the mitochondrial hypervariable region in major Nigerian indigenous goat breeds. AB - Mitochondrial DNA (mtDNA) hypervariable region 1 ( HV1) sequences of three Nigerian indigenous goat breeds; West African Dwarf (WAD), Red Sokoto (RS) and Sahel were used to investigate the genetic diversity and effect of selection between and among these populations. Deoxyribonucleic acid (DNA) of Nigerian indigenous chicken was extracted from blood samples collected and preserved on Fast Technology for Analysis (FTA) paper. The extracted DNA were amplified and sequenced with predefined mitochondria (mtDNA) primer sets for HV1. Eighty-seven (87) polymorphic sites were found in 115 sequences which were grouped into 92 haplotypes. The mean haplotypic and nucleotide diversity were found to be 0.996+/ 0.002 and 0.092+/-0.04 respectively. Genetic variation within population and between populations accounted for 97.26% and 2.74% of the total maternal variation respectively, with FST value of 0.0274. The Tajima's (D) and Fu's (F) test of neutrality were significant (P<0.05) and negative with the mean value of 1.12 and -21.34 respectively which is an indication of population expansion. The result further revealed that the WAD and RS goats are closely related with less genetic distance value of 0.01, and high genetic distance value (0.02) was observed between RS and Sahel goats and WAD and Sahel goats. Selection analysis result shows that there is more positive selection site (6 sites) to negative site (5 sites) among the Nigerian goats, which signifies how diverse they are as well as how nature has being trying to confer genetic fitness to these breeds. PMID- 26954224 TI - Rapamycin Inhibits Expression of Elongation of Very-long-chain Fatty Acids 1 and Synthesis of Docosahexaenoic Acid in Bovine Mammary Epithelial Cells. AB - Mammalian target of rapamycin complex 1 (mTORC1) is a central regulator of cell growth and metabolism and is sufficient to induce specific metabolic processes, including de novo lipid biosynthesis. Elongation of very-long-chain fatty acids 1 (ELOVL1) is a ubiquitously expressed gene and the product of which was thought to be associated with elongation of carbon (C) chain in fatty acids. In the present study, we examined the effects of rapamycin, a specific inhibitor of mTORC1, on ELOVL1 expression and docosahexaenoic acid (DHA, C22:6 n-3) synthesis in bovine mammary epithelial cells (BMECs). We found that rapamycin decreased the relative abundance of ELOVL1 mRNA, ELOVL1 expression and the level of DHA in a time dependent manner. These data indicate that ELOVL1 expression and DHA synthesis are regulated by mTORC1 in BMECs. PMID- 26954226 TI - Expression and Distribution of the Guanine Nucleotide-binding Protein Subunit Alpha-s in Mice Skin Tissues and Its Association with White and Black Coat Colors. AB - Guanine nucleotide-binding protein subunit alpha-s (Gnalphas) is a small subunit of the G protein-couple signaling pathway, which is involved in the formation of coat color. The expression level and distribution of Gnalphas were detected by quantitative real-time-polymerase chain reaction (qPCR), western blot, and immunohistochemistry to investigate the underlying mechanisms of coat color in white and black skin tissues of mice. qPCR and western blot results suggested that Gnalphas was expressed at significantly higher levels in black mice compared with that of white mice, and transcripts and protein possessed the same expression in both colors. Immunohistochemistry demonstrated Gnalphas staining in the root sheath and dermal papilla in hair follicle of mice skins. The results indicated that the Gnalphas gene was expressed in both white and black skin tissues, and the expression level of Gnalphas in the two types of color was different. Therefore, Gnalphas may be involved in the coat color formation in mice. PMID- 26954227 TI - Standardized Ileal Amino Acid Digestibility of Commonly Used Feed Ingredients in Growing Broilers. AB - This experiment was conducted to determine standardized ileal amino acid digestibility (SIAAD) of commonly used feed ingredients in poultry diets in Pakistan. These feed ingredients included corn, rice broken (RB), rice polishings (RP), wheat bran (WB), sunflower meal (SFM), cottonseed meal (CSM), guar meal (GM), soybean meal (SBM) from India and Argentine and fish meal (FM). The SIAAD of each ingredient was determined in triplicate using 21-days-old broilers. Day old male broiler chicks (Hubbard* Hubbard) were reared on corn-SBM based diet from 1 to 13 days and thereafter birds were fed experimental diets from day 14 to 21. Each diet was fed to 36 birds kept in six replicate cages, each cage had six birds. In cereals, the SIAAD of corn's amino acid (AA) (90.1%) was similar (p>0.05) to RB (89.0%). Isoleucine (97.8%) and lysine (96.9%) were highly digestible AA in corn and RB, respectively. Among cereal-by products, WB's SIAAD (76.9%) was same (p>0.05) as RP (71.9%). Arginine from WB (82.5%) and RP (83.2%) was highly digestible. However, threonine in WB (72.7%) and leucine in RP (69.6%) were the lowest digestible AAs. In plant protein meals, AAs from Argentine-SBM (85.1%) and Indian-SBM (83.4%) had higher (p<0.5) SIAAD than other protein meals. However, SIAAD of SFM (77.1%) and CSM (71.7%) was intermediate while GM (60.3%) exhibited the lowest (p<0.05) SIAAD among all ingredients. Arginine from GM (76.9%), CSM (85.8%), SBM-India (89.5%) and SBM-Argentine (91.5%) was highly digestible from indispensable AAs. In SFM, methionine (91.4%) SIAAD was the greatest. The average SIAAD of FM was 77.6%. Alanine from FM had the highest (84.0%) but cysteine (62.8%) had the lowest SIAAD. In conclusion, cereals i.e. corn and RB had higher (p<0.05) SIAAD of the cereals by-products. The SIAAD of RP and WB was same (p>0.05). The SBM from plant protein meals had higher (p<0.05) SIAAD than other studied feed ingredients. However, the GM had the lowest (p<0.05) SIAAD among protein meals. PMID- 26954228 TI - Effect of Simulated Heat Stress on Digestibility, Methane Emission and Metabolic Adaptability in Crossbred Cattle. AB - The present experiment was conducted to evaluate the effect of simulated heat stress on digestibility and methane (CH4) emission. Four non-lactating crossbred cattle were exposed to 25 degrees C, 30 degrees C, 35 degrees C, and 40 degrees C temperature with a relative humidity of 40% to 50% in a climatic chamber from 10:00 hours to 15:00 hours every day for 27 days. The physiological responses were recorded at 15:00 hours every day. The blood samples were collected at 15:00 hours on 1st, 6th, 11th, 16th, and 21st days and serum was collected for biochemical analysis. After 21 days, fecal and feed samples were collected continuously for six days for the estimation of digestibility. In the last 48 hours gas samples were collected continuously to estimate CH4 emission. Heat stress in experimental animals at 35 degrees C and 40 degrees C was evident from an alteration (p<0.05) in rectal temperature, respiratory rate, pulse rate, water intake and serum thyroxin levels. The serum lactate dehydrogenase, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase activity and protein, urea, creatinine and triglyceride concentration changed (p<0.05), and body weight of the animals decreased (p<0.05) after temperature exposure at 40 degrees C. The dry matter intake (DMI) was lower (p<0.05) at 40 degrees C exposure. The dry matter and neutral detergent fibre digestibilities were higher (p<0.05) at 35 degrees C compared to 25 degrees C and 30 degrees C exposure whereas, organic matter (OM) and acid detergent fibre digestibilities were higher (p<0.05) at 35 degrees C than 40 degrees C thermal exposure. The CH4 emission/kg DMI and organic matter intake (OMI) declined (p<0.05) with increase in exposure temperature and reached its lowest levels at 40 degrees C. It can be concluded from the present study that the digestibility and CH4 emission were affected by intensity of heat stress. Further studies are necessary with respect to ruminal microbial changes to justify the variation in the digestibility and CH4 emission during differential heat stress. PMID- 26954229 TI - Haplogroup Classification of Korean Cattle Breeds Based on Sequence Variations of mtDNA Control Region. AB - Many studies have reported the frequency and distribution of haplogroups among various cattle breeds for verification of their origins and genetic diversity. In this study, 318 complete sequences of the mtDNA control region from four Korean cattle breeds were used for haplogroup classification. 71 polymorphic sites and 66 haplotypes were found in these sequences. Consistent with the genetic patterns in previous reports, four haplogroups (T1, T2, T3, and T4) were identified in Korean cattle breeds. In addition, T1a, T3a, and T3b sub-haplogroups were classified. In the phylogenetic tree, each haplogroup formed an independent cluster. The frequencies of T3, T4, T1 (containing T1a), and T2 were 66%, 16%, 10%, and 8%, respectively. Especially, the T1 haplogroup contained only one haplotype and a sample. All four haplogroups were found in Chikso, Jeju black and Hanwoo. However, only the T3 and T4 haplogroups appeared in Heugu, and most Chikso populations showed a partial of four haplogroups. These results will be useful for stable conservation and efficient management of Korean cattle breeds. PMID- 26954230 TI - Peripheral Insulin Doesn't Alter Appetite of Broiler Chicks. AB - An experiment was conducted to investigate the effect of peripheral insulin treatment on appetite in chicks. Six-d-age chicks with ad libitum feeding or fasting for 3 h before injection received a subcutaneous injection of 0, 1, 3, 5, 10, or 20 IU of insulin or vehicle (saline). The results showed peripheral insulin treatment (1 to 20 IU) did not alter significantly the feed intake in chicks under either ad libitum feeding or fasting conditions within 4 h (p>0.05). Compared with the control, plasma glucose concentration was significantly decreased after insulin treatment of 3, 5, 10, and 20 IU for 4 h in chicks with ad libitum feeding (p<0.05). In fasted chicks, 10 and 20 IU insulin treatments significantly decreased the plasma glucose level for 4 h (p<0.05). Peripheral insulin treatment of 10 IU for 2 or 4 h did not significantly affect the hypothalamic genes expression of neuropeptide Y, proopiomelanocortin, corticotropin-releasing factor and insulin receptors (p>0.05). All results suggest peripheral administration of insulin has no effect on appetite in chicks. PMID- 26954231 TI - A fluorescent surrogate of thymidine in duplex DNA. AB - is a new fluorescent thymidine mimic composed of 2'-deoxyuridine fused to dimethylaniline. exhibits the same pKa and base pairing characteristics as native thymidine residues, and its fluorescence properties are highly sensitive to nucleobase ionization, base pairing and metal binding. PMID- 26954232 TI - Photosynthetic electron-transfer reactions in the gametophyte of Pteris multifida reveal the presence of allelopathic interference from the invasive plant species Bidens pilosa. AB - To date, the response of the fern gametophyte to its environment has received considerable attention. However, studies on the influence of plant invasion on the fern gametophyte are fewer. Allelopathy has been hypothesized to play an important role in biological invasion. Hence, it is necessary to study the allelopathy of invasive plant species to the fern gametophyte and elucidate the mechanisms by which invasive plants cause phytotoxicity. As one of the main invasive plants in China, Bidens pilosa exhibits allelopathic effects on the gametophytic growth of Pteris multifida. The root exudate plays an important role among various allelochemical delivery mechanisms in B. pilosa. The effect invasive plant species has on photosynthesis in native species is poorly understood. To elucidate this effect, the changes in photosynthesis in the gametophytes of P. multifida are analyzed to examine the mechanisms of the root exudates of B. pilosa. Meanwhile, a non-invasive plant, Coreopsis basalis, was also applied to investigate the effects on fluorescence and pigments in P. multifida gametophytes. We found that gametophytes exposed to both B. pilosa and C. basalis had decreased fluorescence parameters in comparison with the control, except for non-photochemical quenching. Furthermore, it was found that these parameters were markedly affected from day 2 to day 10 in the presence of both exudates at a concentration of 25% or above. B. pilosa exudate had a negative dose-dependent effect on chlorophyll a, chlorophyll b, carotenoid, and the total chlorophyll in the gametophyte. The inhibitory effects increased with increasing exudate concentrations of both species, exhibiting the greatest inhibition at day 10. In conclusion, B. pilosa irreversibly affected the photosynthesis of P. multifida on both PS I and PS II. Root exudates caused the primary damage with respect to the decrease of the acceptors and donors of photon and electron in photosynthetic units and the production and the relative yield of photochemical quantum in PS II. With the effects of exudates, part of the energy is released as heat in chloroplasts. The comparison of invasive and non-invasive plants in allelopathic experiments demonstrated that invasive plants were responsible for the critical damage to the photosynthetic process in local species. PMID- 26954233 TI - Extracellular Release of CD11b by TLR9 Stimulation in Macrophages. AB - CpG-DNA upregulates the expression of pro-inflammatory cytokines, chemokines and cell surface markers. Investigators have shown that CD11b (integrin alphaM) regulates TLR-triggered inflammatory responses in the macrophages and dendritic cells. Therefore, we aimed to identify the effects of CpG-DNA on the expression of CD11b in macrophages. There was no significant change in surface expression of CD11b after CpG-DNA stimulation. However, CD11b was released into culture supernatants after stimulation with phosphorothioate-backbone modified CpG-DNA such as PS-ODN CpG-DNA 1826(S). In contrast, MB-ODN 4531 and non-CpG-DNA control (regardless of backbone type and liposome-encapsulation) failed to induce release of CD11b. Therefore, the context of the CpG-DNA sequence and phosphorothioate backbone modification may regulate the effects of CpG-DNA on CD11b release. Based on inhibitor studies, CD11b release is mediated by p38 MAP kinase activation, but not by the PI3K and NF-kappaB activation. CD11b release is mediated by lysosomal degradation and by vacuolar acidification in response to CpG-DNA stimulation. The amount of CD11b in the exosome precipitant was significantly increased by CpG-DNA stimulation in vivo and in vitro depending on TLR9. Our observations perhaps give more insight into understanding of the mechanisms involved in CpG-DNA-induced immunomodulation in the innate immunity. PMID- 26954235 TI - Fluorescence polarization-based assays for detecting compounds binding to inactive c-Jun N-terminal kinase 3 and p38alpha mitogen-activated protein kinase. AB - Two fluorescein-labeled pyridinylimidazoles were synthesized and evaluated as probes for the binding affinity determination of potential kinase inhibitors to the c-Jun N-terminal kinase 3 (JNK3) and p38alpha mitogen-activated protein kinase (MAPK). Fluorescence polarization (FP)-based competition binding assays were developed for both enzymes using 1-(3',6'-dihydroxy-3-oxo-3H spiro[isobenzofuran-1,9'-xanthen]-5-yl)-3-(4-((4-(4-(4-fluorophenyl)-2 (methylthio)-1H-imidazol-5-yl)pyridin-2-yl)amino)phenyl)thiourea (5) as an FP probe (JNK3: Kd = 3.0 nM; p38alpha MAPK: Kd = 5.7 nM). The validation of the assays with known inhibitors of JNK3 and p38alpha MAPK revealed that both FP assays correlate very well with inhibition data received by the activity assays. This, in addition to the viability of both FP-based binding assays for the high throughput screening procedure, makes the assays suitable as inexpensive prescreening protocols for JNK3 and p38alpha MAPK inhibitors. PMID- 26954234 TI - The Effectiveness of Electronic Differential Diagnoses (DDX) Generators: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Diagnostic errors are costly and they can contribute to adverse patient outcomes, including avoidable deaths. Differential diagnosis (DDX) generators are electronic tools that may facilitate the diagnostic process. METHODS AND FINDINGS: We conducted a systematic review and meta-analysis to investigate the efficacy and utility of DDX generators. We undertook a comprehensive search of the literature including 16 databases from inception to May 2015 and specialist patient safety databases. We also searched the reference lists of included studies. Article screening, selection and data extraction were independently conducted by 2 reviewers. 36 articles met the eligibility criteria and the pooled accurate diagnosis retrieval rate of DDX tools was high with high heterogeneity (pooled rate = 0.70, 95% CI = 0.63 to 0.77; I2 = 97%, p<0.0001). DDX generators did not demonstrate improved diagnostic retrieval compared to clinicians but small improvements were seen in the before and after studies where clinicians had the opportunity to revisit their diagnoses following DDX generator consultation. Clinical utility data generally indicated high levels of user satisfaction and significant reductions in time taken to use for newer web-based tools. Lengthy differential lists and their low relevance were areas of concern and have the potential to increase diagnostic uncertainty. Data on the number of investigations ordered and on cost-effectiveness remain inconclusive. CONCLUSIONS: DDX generators have the potential to improve diagnostic practice among clinicians. However, the high levels of heterogeneity, the variable quality of the reported data and the minimal benefits observed for complex cases suggest caution. Further research needs to be undertaken in routine clinical settings with greater consideration of enablers and barriers which are likely to impact on DDX use before their use in routine clinical practice can be recommended. PMID- 26954236 TI - Annual trainer peer-review: impact on educational practice and sense of community. AB - INTRODUCTION: The General Medical Council (GMC) requires all doctors to undertake annual appraisal for all roles for which they hold a licence to practise. General Practitioner (GP) educational supervisors (ES) in the North of Scotland have undertaken annual ES peer-appraisal since 2002 which focuses on their role as ES and is separate to GMC appraisal. AIM: To investigate whether participation in annual peer appraisal by GP trainers had affected their professional practice and sense of community Methods: Focus group methodology was utilised, supported by written reflective narratives. Thirty-five educational supervisors participated in three focus groups, moderated by educators from the north region of Scotland Deanery. The data included 35 narratives, flip charts and field notes. These were analysed using a thematic approach. RESULTS: Thirty-five trainers participated and themes emerged around four areas: organisational, process, outcomes and challenges. Due to its formative peer related features, peer appraisal was more valued than mandatory annual NHS appraisal. The value of a personally known peer as appraiser emerged as a major recurrent theme. Positive affective and effective outcomes were described by several participants. These included feeling more valued and confident. Some reported empowering and motivating effects to implement changes and tackle difficult situations. Some felt that appraisal added to the sense of community by developing new relationships and deepening existing ones. The risk of collusion was raised in several narratives and explored more deeply during focus group discussions. There was agreement that the process could be improved by making explicit what to do if concerns were identified. DISCUSSION: This study demonstrated the importance of peer appraisal for GP trainers, particularly in the context of locally based valued and trusted trainer groups. It affects their professional practice as educators and deepens their sense of community. This is of particular relevance to current discussions on medical educator appraisal in the context of re-approval and revalidation. PMID- 26954238 TI - What is an Educational Problem? Guidance for Authors Submitting to JCEHP. PMID- 26954237 TI - Biotin-Streptavidin Competition Mediates Sensitive Detection of Biomolecules in Enzyme Linked Immunosorbent Assay. AB - Enzyme Linked Immunosorbent Assay (ELISA) is the gold standard assay for detecting and identifying biomolecules using antibodies as the probe. Improving ELISA is crucial for detecting disease-causing agents and facilitating diagnosis at the early stages of disease. Biotinylated antibody and streptavidin-conjugated horse radish peroxide (streptavidin-HRP) often are used with ELISA to enhance the detection of various kinds of targets. In the present study, we used a competition-based strategy in which we pre-mixed free biotin with streptavidin HRP to generate high-performance system, as free biotin occupies some of the biotin binding sites on streptavidin, thereby providing more chances for streptavidin-HRP to bind with biotinylated antibody. ESAT-6, which is a protein secreted early during tuberculosis infection, was used as the model target. We found that 8 fM of free biotin mixed with streptavidin-HRP anchored the higher detection level of ESAT-6 by four-fold compared with detection without free biotin (only streptavidin-HRP), and the limit of detection of the new method was 250 pM. These results suggest that biotin-streptavidin competition can be used to improve the diagnosis of analytes in other types of sensors. PMID- 26954239 TI - Does Compassion-Focused Therapy Training for Health Care Educators and Providers Increase Self-Compassion and Reduce Self-Persecution and Self-Criticism? AB - INTRODUCTION: There is a growing body of evidence within the health care community suggesting that developing feelings of compassion can profoundly affect physical and psychological health. This is an important area of work, and initial research with nonprofessional groups has found that practicing compassion through a variety of experiential practices and meditations can lead to higher levels of compassion for others, sensitivity to suffering, motivation to help, and altruism. This study examines outcome measures after a 3-day introductory workshop on compassion-focused therapy provided to health care providers and educators. The aim of the research is to explore whether the training would increase self-compassion and reduce self-criticism and self-persecution. METHODS: A total of 28 participants who were classified into three groups "nurses and midwives," "counselors/psychotherapists," and "other health care providers" completed the Self-Compassion Scale and Functions of Self-Criticizing and Self Attacking Scale before and after training. RESULTS: Results reveal an overall statistically significant increase in self-compassion and statistically significant reduction in self-critical judgment after training. There was no statistically significant reduction in self-persecution or self-correction scores after training. DISCUSSION: Developing self-compassion and compassionately responding to our own "self-critic" may lead the way forward in the development of more compassionate care among health care professionals. Training people in compassion-based exercises may bring changes in levels of self-compassion and self-critical judgment. The findings are exciting in that they suggest the potential benefits of training health care providers and educators in compassion focused practices. PMID- 26954241 TI - A Flipped Classroom Approach to Improving the Quality of Delirium Care Using an Interprofessional Train-the-Trainer Program. AB - INTRODUCTION: Given the prevalence and morbidity associated with delirium, there is a need for effective and efficient institutional approaches to delirium training in health care settings. Novel education methods, specifically the "flipped classroom" (FC) and "train-the-trainer" (TTT), have the potential to address these delirium training gaps. This study evaluates the effect of a TTT FC interprofessional delirium training program on participants' perceived ability to manage delirium, delirium knowledge, and clinicians' delirium assessment behaviors. METHODS: FC Delirium TTT sessions were implemented in a large four hospital network and consisted of presession online work and a 3-hour in-session component. The 156 TTT interprofessional participants who attended the sessions (ie, trainers) were expected to then deliver delirium training to their patient care units. Delirium care self-efficacy and knowledge test scores were measured before, after, and 6 months after the training session. Clinician delirium assessment rates were measured by chart audits before and 3 months after trainer's implementation of delirium training sessions. RESULTS: Delirium knowledge test scores (7.8 +/- 1.6 versus 9.7 +/- 1.2, P < .001) and delirium care self-efficacy were significantly higher immediately after the TTT session compared with those of presession and these differences remained significant at 6 month after the TTT session. Trainer sessions significantly improved clinician delirium assessment rates from 53% for pretraining to 66% for posttraining. DISCUSSION: Our data suggest that a TTT FC delirium training approach can improve participants' perceived delirium care skills and confidence, and delirium knowledge up to 6 months after the session. This approach provides a model for implementing hospitalwide delirium education that can change delirium assessment behavior while minimizing time and personnel requirements. PMID- 26954240 TI - Enhancing Clinicians' Well-Being and Patient-Centered Care Through Mindfulness. AB - INTRODUCTION: Mindful clinicians are resilient and more likely to provide patient centered care. We aimed to enhance clinicians' well-being by offering a Mindfulness-Based Stress Reduction (MBSR) course that teaches mindfulness and stress management and then determine whether this impacted their subsequent medical encounters. METHODS: In a longitudinal cohort study with 27 clinicians, MBSR was taught by a certified instructor. Pre-MBSR and post-MBSR online questionnaires assessed burnout, depression, stress, meaningfulness, and mindfulness. Patients independently rated their clinicians using the Rochester Communication Rating Scale (RCRS) after a clinical encounter before and after their clinician took the MBSR course. Nine medical doctors audiorecorded the consultations before and after MBSR; the tapes were coded and analyzed by an independent team using the Roter interaction analyses system. RESULTS: Significant reductions in stress and burnout were found, and increases in mindfulness and meaningfulness. The decrease in stress was correlated with less judgmental attitudes and less reactivity-facets of mindfulness. The decrease in emotional exhaustion was correlated with more acting with awareness and less judgmental attitudes-facets of mindfulness. Patients' perceptions of the clinical encounter suggested that patient-centered care improved after MBSR. Decreased depersonalization was significantly associated with the RCRS subscale, "understanding of the patient's experience of illness." At both time points, doctors dominated the exchange and were patient-centered. DISCUSSION: Mindfulness has a direct and positive impact on clinicians' well-being. When clinicians' experienced less depersonalization, their patients reported being better understood. PMID- 26954242 TI - Effects of a Longitudinal Interprofessional Educational Outreach Program on Collaboration. AB - INTRODUCTION: Interprofessional education (IPE) interventions lack clarity regarding development and implementation, impeding a clear understanding of their role and effectiveness. The aim of this study was to identify whether and how an outreach program targeting interprofessional health care teams can improve self efficacy and interprofessional collaboration (IPC). METHODS: A cohort study was conducted to explore the effect of the program on individual self-efficacy and perceived IPC and investigate factors affecting interprofessional learning and collaboration. The program was a two-year IPE program consisting of workshops, educational materials, and interworkshop support. Participants were physicians, nurses, dietitians, pharmacists, and social workers at two primary care teams in Toronto. Self-efficacy and team function were measured five times throughout the program. We used analysis of variance and t-tests to compare between teams and used Pearson correlations to estimate the relationship between self-efficacy and team function. One-on-one interviews investigated factors affecting IPC and the program's effect on IPC. RESULTS: Team function improved as the program progressed (P = .02); although it did not affect self-efficacy, there was an increasing correlation between self-efficacy and team function as the program progressed (P < .01 for workshop 5). Interviews revealed that trust, liability concerns, and geographic proximity were mediators of IPC. The workshops were perceived to enable trust building by increasing knowledge and allowing nonphysician team members to showcase their expertise. DISCUSSION: Our findings demonstrate that an IPE workshop, through role clarification, cultivation of trust, and a community of practice, can promote these elements. Trust in team members and geographic proximity are potential facilitators to IPC developed during an interprofessional program. PMID- 26954243 TI - Comparison of the Effectiveness of Interactive Didactic Lecture Versus Online Simulation-Based CME Programs Directed at Improving the Diagnostic Capabilities of Primary Care Practitioners. AB - INTRODUCTION: Diagnostic errors in primary care contribute to increased morbidity and mortality, and billions in costs each year. Improvements in the way practicing physicians are taught so as to optimally perform differential diagnosis can increase patient safety and lower the costs of care. This study represents a comparison of the effectiveness of two approaches to CME training directed at improving the primary care practitioner's diagnostic capabilities against seven common and important causes of joint pain. METHODS: Using a convenience sampling methodology, one group of primary care practitioners was trained by a traditional live, expert-led, multimedia-based training activity supplemented with interactive practice opportunities and feedback (control group). The second group was trained online with a multimedia-based training activity supplemented with interactive practice opportunities and feedback delivered by an artificial intelligence-driven simulation/tutor (treatment group). RESULTS: Before their respective instructional intervention, there were no significant differences in the diagnostic performance of the two groups against a battery of case vignettes presenting with joint pain. Using the same battery of case vignettes to assess postintervention diagnostic performance, there was a slight but not statistically significant improvement in the control group's diagnostic accuracy (P = .13). The treatment group, however, demonstrated a significant improvement in accuracy (P < .02; Cohen d, effect size = 0.79). DISCUSSION: These data indicate that within the context of a CME activity, a significant improvement in diagnostic accuracy can be achieved by the use of a web-delivered, multimedia-based instructional activity supplemented by practice opportunities and feedback delivered by an artificial intelligence-driven simulation/tutor. PMID- 26954244 TI - Aged-Care Professionals' and Health Care Professionals' Self-Reported Impact of Printed Educational Material on Clinical Practice. AB - INTRODUCTION: This study aimed to evaluate the impact of the printed educational material (PEM), the Residential Aged-Care (RAC) Communique, on the changing clinical practice of health and aged-care professionals. METHODS: The RAC Communique is a PEM that contains case narratives from Coroners' investigations into potentially preventable deaths in nursing homes. A population-based cross sectional study was conducted, using an anonymous electronic survey distributed to all subscribers of the RAC Communique. The questionnaire consisted of 40 questions in five sections, such as respondent characteristics, respondent preferences and reading behavior, respondent opinion about the RAC Communique content, and the mode of its delivery, impact of the RAC Communique, and the details of changes in professional practice. RESULTS: The response rate was 58.3% (367/630). Respondents were mostly women aged 45 years and older (n = 319, 86.9%) with more than 10 years of experience (n = 241, 65.7%) in management (n = 171, 46.6%) or nursing (n = 65, 17.7%). Of the 367 respondents, 204 (55.6%) reported changing their practice. Multivariate analysis revealed that women (odds ratio [OR] = 2.10, 95% confidence interval [CI] = 1.01-4.35) aged between 45 and 54 (OR = 2.06, CI = 1.13-3.75), who read most of the RAC Communique (OR = 2.77, CI = 1.34-5.72) and were subscribed for more than 1 year (OR = 3.58, CI = 1.61-7.95) were significantly associated with practice change. DISCUSSION: More than half of the survey respondents who read the RAC Communique self-reported a change in practice highlighting its impact and efficacy as PEM. PMID- 26954245 TI - Unraveling Motivational Profiles of Health Care Professionals for Continuing Education: The Example of Pharmacists in the Netherlands. AB - INTRODUCTION: Continuing education (CE) can support health care professionals in maintaining and developing their knowledge and competencies. Although lack of motivation is one of the most important barriers of pharmacists' participation in CE, we know little about the quality or the quantity of motivation. We used the self-determination theory, which describes autonomous motivation (AM) as originating from within an individual and controlled motivation (CM) as originating from external factors, as a framework for this study. Our aim was to obtain insight into the quality and quantity of pharmacists' motivation for CE. METHODS: The scores of 425 pharmacists on Academic Motivation Scale were subjected to K-means cluster analysis to generate motivational profiles. RESULTS: We unraveled four motivational profiles: (1) good quality with high AM/low CM, (2) high quantity with high AM/high CM, (3) poor quality with low AM/high CM, and (4) low quantity with low AM/low CM. Female pharmacists, pharmacists working in a hospital pharmacy, pharmacists working for more than 10 years, and pharmacists not in training were highly represented in the good-quality profile. Pharmacists working in a community pharmacy, pharmacists working for less than 10 years, and pharmacists in training were highly represented in the high-quantity profile. Male pharmacists were more or less equally distributed over the four profiles. The highest percentage of pharmacy owners was shown in the low-quantity profile, and the highest percentage of the nonowners was shown in the good-quality profile. DISCUSSION: Pharmacists exhibit different motivational profiles, which are associated with their background characteristics, such as gender, ownership of business, practice setting, and current training. Motivational profiles could be used to tailor CE courses for pharmacists. PMID- 26954246 TI - Physician Satisfaction With and Practice Changes Resulting From American Board of Family Medicine Maintenance of Certification Performance in Practice Modules. AB - INTRODUCTION: Physician payment in the United States will be increasingly tied to quality measurement and performance. Whether participation in quality improvement (QI) through Maintenance of Certification for Family Physicians Performance in Practice Modules (PPMs) is useful and results in practice change remains unknown. METHODS: All PPM feedback data from inception to April 2014 were analyzed using descriptive statistics by year, topic, and number of PPMs completed. Qualitative content analysis was applied to analyze responses to open-ended questions on practice changes. RESULTS: Of note, 29,755 diplomates completed 38,201 PPMs; median 1 interquartile range (1, 1). Nearly two-thirds (65.8%, n = 25,150) of PPMs had completed feedback surveys. Of note, 78.7% of respondents indicated that they would change patient care and 90.2% indicated that they would continue QI activities after completing the PPM. Respondents endorsed high relevance to practice (90.5%), high currency of clinical information (86.4%), and high usefulness of clinical information (80.5%). When feedback was analyzed by the number of PPMs completed, respondents were less likely to change care but reported increased usefulness to practice and stable intention to continue QI efforts with more PPMs completed. Of note, 86.0% of respondents who said that they would change care provided examples: these varied by PPM topic but "doing more," focusing on patients, and education were common. DISCUSSION: These findings suggest that QI completed through the PPMs may assist family physicians in improving the care they provide. Furthermore, ratings by the number of PPMs completed suggest that repeated exposure to QI efforts produce continued relevance and usefulness, even when changes in practice decline. PMID- 26954247 TI - Providing Feedback on Clinical Performance to Hospitalists: Experience Using a New Metric Tool to Assess Inpatient Satisfaction With Care From Hospitalists. AB - INTRODUCTION: Physicians have been shown to possess limited ability for accurate self-assessment; thus, effective feedback is crucial for their professional development. This study describes providers' reflections on their data and evaluates the hospitalist physicians' impressions about receiving this feedback derived from a new survey metric specifically designed to obtain patient assessment of their treating hospitalist provider coupled with reflective sessions. METHODS: Participants were 26 hospitalists from one institution. These physicians' data were used for the development and validation of a new metric, Tool to Assess Inpatient Satisfaction with Care from Hospitalists (TAISCH). Participants received a summary of ratings from patients for whom they were the primary provider. This was followed by a 15-minute semistructured telephone interview to discuss the data. Participants then completed an online survey to assess their perceptions about the data and the efficacy of the feedback. Both quantitative and qualitative results were analyzed. RESULTS: All 26 providers reviewed their evaluation data, participated in the discussion of results by phone, and completed the online survey. Most (54%) agreed that TAISCH was superior to Hospital Consumer Assessment of Healthcare Providers and Systems in providing hints on how to improve the quality of the care and in providing detailed information about the performance in specific areas (62%). After stratifying hospitalists according to their performance, it was observed that those who scored better responded more favorably to the data. The two main themes that emerged from the qualitative analysis were "reflection on one's performance" and "feedback using TAISCH." DISCUSSION: Most hospitalists in our study felt that TAISCH provided meaningful feedback. PMID- 26954248 TI - Measuring Participants' Attitudes Toward Mobile Device Conference Applications in Continuing Medical Education: Validation of an Instrument. AB - INTRODUCTION: Mobile device applications (apps) may enhance live CME courses. We aimed to (1) validate a measure of participant attitudes toward using a conference app and (2) determine associations between participant characteristics and attitudes toward CME apps with conference app usage. METHODS: We conducted a cross-sectional validation study of participants at the Mayo Clinic Selected Topics in Internal Medicine Course. A conference app was developed that included presentation slides, note-taking features, search functions, social networking with other attendees, and access to presenter information. The CME app attitudes survey instrument (CMEAPP-10) was designed to determine participant attitudes toward conference apps. RESULTS: Of the 602 participants, 498 (82.7%) returned surveys. Factor analysis revealed a two-dimensional model for CMEAPP-10 scores (Cronbach alpha, 0.97). Mean (SD) CMEAPP-10 scores (maximum possible score of five) were higher for women than for men (4.06 [0.91] versus 3.85 [0.92]; P = .04). CMEAPP-10 scores (mean [SD]) were significantly associated (P = .02) with previous app usage as follows: less than once per month, 3.73 (1.05); monthly, 3.41 (1.16); weekly, 4.03 (0.69); and daily or more, 4.06 (0.89). Scores were unrelated to participant age, specialty, practice characteristics, or previous app use. DISCUSSION: This is the first validated measure of attitudes toward CME apps among course participants. App usage was higher among younger participants who had previously used educational or professional apps. Additionally, attitudes were more favorable among women and those who had previously used apps. These findings have important implications regarding efforts to engage participants with portable and accessible technology. PMID- 26954249 TI - Applying Knowledge Translation Concepts and Strategies in Dementia Care Education for Health Professionals: Recommendations From a Narrative Literature Review. AB - INTRODUCTION: Dementia education programs are being developed for health professionals, but with limited guidance about "what works" in design and content to promote best practice in dementia care. Knowledge translation (KT) is a conceptual framework for putting evidence to work in health care. This narrative literature review examined the question: What does the field KT offer, conceptually and practically, for education of health professionals in dementia care? It seeks to identify the types of strategies currently used within education to facilitate effective KT for the wide range of health professionals who may be involved in the care of people with dementia, plus explore enablers and barriers to KT in this context. METHODS: From 76 articles identified in academic databases and manual bibliographic searching, 22 met review criteria. RESULTS: The literature synthesis indicated four hallmarks of successful KT oriented dementia education for health professionals: (1) multimodal delivery, (2) tailored approaches, (3) relationship building, and (4) organizational support for change in the work setting. Participatory action frameworks were also favored, based on interactive knowledge exchange (eg, blended learning) rather than passive unidirectional approaches alone (eg, lectures). DISCUSSION: The following six principles are proposed for educating health professionals in dementia care: (1) Match the education strategy to the KT goal and learner preferences; (2) Use integrated multimodal learning strategies and provide opportunities for multiple learning exposures plus feedback; (3) Build relationships to bridge the research-practice gap; (4) Use a simple compelling message with formats and technologies relevant to the audience; (5) Provide incentives to achieve KT goals; and (6) Plan to change the workplace, not just the individual health professional. PMID- 26954250 TI - Challenges and Opportunities for Genomics Education: Insights from an Institute of Medicine Roundtable Activity. AB - Despite the growing availability of genomic tools for clinical care, many health care providers experience gaps in genomics knowledge and skills that serve as impediments to widespread and appropriate integration of genomics into routine care. A workshop recently held by the Institute of Medicine (IOM) Roundtable on Translating Genomics-Based Research for Health explored 1) the barriers that result in a perception among health care providers that the need for genomics education is not urgent and 2) the drivers that may spur a change in that attitude. This commentary promotes continuing and graduate education-informed by an awareness of barriers, drivers, and best practices-as the most effective approaches for preparing the workforce for genomic medicine and ultimately improving patient care, and argues that the time for education is now. PMID- 26954251 TI - Reactions of Chemically Activated Formic Acid Formed via HCO + OH. AB - The chemistry of formyl radicals plays an important role in the kinetic modeling of oxygenated hydrocarbons. Here, the fate of rovibrationally excited formic acid produced via HCO + OH is evaluated in a RRKM/Master Equation study. For that purpose, the HCO + OH potential energy surface is studied theoretically using high-level quantum mechanics. Direct reaction from HCO + OH to the bimolecular products is found to dominate for most relevant conditions due to formic acid well-skipping. The kinetics of these well-skipping reactions can only be evaluated when including the unimolecular intermediate, formic acid. Further, hydrogen abstraction from rovibrationally excited formic acid is found to be important at low-temperature conditions and for high radical concentrations. PMID- 26954252 TI - Adverse events of postoperative thoracic epidural analgesia: A retrospective analysis of 7273 cases in a tertiary care teaching hospital. AB - BACKGROUND: Thoracic epidural analgesia is a well established technique for postoperative pain relief after major abdominal and thoracic surgery. Safety remains a major concern because of serious adverse events including epidural haematoma, abscess and permanent neurological deficit. OBJECTIVE: The aim of this study was to evaluate the incidence and the long-term outcome of serious adverse events associated with thoracic epidural analgesia. DESIGN: Retrospective cohort study. SETTING: The study was conducted at a single institution, a tertiary care teaching hospital. Data were collected over a 10-year period from 2003 until 2012. PATIENTS: Data from 7430 patients were prospectively entered into a standardised acute pain service database. A total of 7273 study participants met the inclusion criteria and were included in the final analyses. The inclusion criteria involved surgical patients receiving a postoperative thoracic epidural analgesia catheter treatment for pain control. Exclusion criteria were defined as obstetric, non-surgical, non-epidural analgesia patients and epidural analgesia catheters that had not been placed by an anaesthesiologist. MAIN OUTCOME MEASURES: The database was queried for serious adverse events which were defined as spinal or epidural haemorrhage; spinal or epidural abscess; permanent neurological deficits; cardiac arrest; death and incomplete removal of the epidural analgesia catheter. Patients' charts were comprehensively reviewed in case of a major adverse event. Patients with an unclear outcome received a mailed questionnaire or were contacted by telephone to determine long-term sequelae. RESULTS: Seven serious adverse events were identified: epidural abscess [n = 1; incidence 1 : 7273 (0.014%, 95% confidence interval, CI, 0 to 0.08%)], persistent neurological damage [n = 1; incidence 1 : 7273 (0.014%, 95% CI, 0 to 0.08%)], cardiac arrest [n = 1; incidence 1 : 7273 (0.014%, 95% CI, 0 to 0.08%)] and catheter breakage leaving a catheter fragment in situ [n = 4; incidence 1 : 1818 (0.055%, 95% CI, 0.01 to 0.14%)]. Apart from the one patient with persistent neurologic deficit, the patients with serious adverse events associated with thoracic epidural analgesia in our cohort suffered no long-term consequences. CONCLUSION: In our single-centre study of thoracic epidural analgesia, serious adverse events occurred in 0.1% cases (1 : 1000), whereas long-term outcome was compromised in 0.014% (1.4 : 10 000) which is similar to the serious adverse event rates and outcomes reported in the current literature. PMID- 26954253 TI - Reply to: postoperative shoulder pain after laparoscopic hysterectomy with deep neuromuscular blockade and low-pressure pneumoperitoneum. PMID- 26954255 TI - Characterization of salA, syrF, and syrG Genes and Attendant Regulatory Networks Involved in Plant Pathogenesis by Pseudomonas syringae pv. syringae B728a. AB - Pseudomonas syringae pv. syringae B728a, causal agent of brown spot on bean, is an economically important plant pathogen that utilizes extracellular signaling to initiate a lifestyle change from an epiphyte to a pathogen. LuxR regulatory proteins play an important role in the transcriptional regulation of a variety of biological processes involving two-component signaling, quorum sensing, and secondary metabolism. Analysis of the B728a genome identified 24 LuxR-like proteins, three of which are encoded by salA, syrF, and syrG located adjacent to the syringomycin gene cluster. The LuxR-like proteins encoded by these three genes exhibit a domain architecture that places them in a subfamily of LuxR-like proteins associated with regulation of secondary metabolism in B728a. Deletion mutants of salA, syrF, and syrG failed to produce syringomycin and displayed reduction of virulence on bean. The transcriptional start sites of salA, syrG, and syrF were located 63, 235, and 498 bp upstream of the start codons, respectively, using primer extension analysis. The predicted -10/-35 promoter regions of syrF and syrG were confirmed using site-directed mutagenesis and GFP reporters that showed conserved promoter sequences around the -35 promoter region. Overexpression analysis and GFP reporters identified SyrG as an upstream transcriptional activator of syrF, where both SyrG and SyrF activate promoters of syringomycin biosynthesis genes. This study shows that syrG and syrF encode important transcriptional regulators of syringomycin biosynthesis genes. PMID- 26954254 TI - Mouse Model of Cat Allergic Rhinitis and Intranasal Liposome-Adjuvanted Refined Fel d 1 Vaccine. AB - Cats (Felis domesticus) are rich source of airborne allergens that prevailed in the environment and sensitized a number of people to allergy. In this study, a mouse model of allergic rhinitis caused by the cat allergens was developed for the first time and the model was used for testing therapeutic efficacy of a novel intranasal liposome-entrapped vaccines made of native Fel d 1 (major cat allergen) in comparison with the vaccine made of crude cat hair extract (cCE). BALB/c mice were sensitized with cCE mixed with alum intraperitoneally and intranasally. The allergic mice were treated with eight doses of either liposome (L)-entrapped native Fel d 1 (L-nFD1), L-cCE), or placebo on every alternate day. Vaccine efficacy evaluation was performed one day after provoking the treated mice with aerosolic cCE. All allergenized mice developed histological features of allergic rhinitis with rises of serum specific-IgE and Th2 cytokine gene expression. Serum IgE and intranasal mucus production of allergic mice reduced significantly after vaccination in comparison with the placebo mice. The vaccines also caused a shift of the Th2 response (reduction of Th2 cytokine expressions) towards the non-pathogenic responses: Th1 (down-regulation of the Th1 suppressive cytokine gene, IL-35) and Treg (up-regulation of IL-10 and TGF-beta). In conclusions, a mouse model of allergic rhinitis to cat allergens was successfully developed. The intranasal, liposome-adjuvanted vaccines, especially the refined single allergen formulation, assuaged the allergic manifestations in the modeled mice. The prototype vaccine is worthwhile testing further for clinical use in the pet allergic patients. PMID- 26954259 TI - Musculoskeletal symptoms among hospital cleaners. AB - Studies have indicated that cleaners are at risk for musculoskeletal symptoms (MSS). In 2001, the Norwegian Labor Inspectorate suggested improvements in cleaners' work environment to reduce MSS. We estimate prevalence of MSS among cleaners in a Norwegian hospital that had implemented improvements to reduce risk of MSS and calculate relative risk of MSS among cleaners compared to a group of office workers. Data were collected from 255 participants. MSS were investigated using the Nordic Questionnaire for Analysis of Musculoskeletal Symptoms. Cleaners reported a significantly higher prevalence of MSS compared to office workers but a lower prevalence compared to similar studies among cleaners in other countries. This may indicate that working conditions in Norway are better than in other countries; further studies are needed to compare MSS and working conditions in different settings. PMID- 26954256 TI - The HEX 110 Hexamerin Is a Cytoplasmic and Nucleolar Protein in the Ovaries of Apis mellifera. AB - Hexamerins are insect storage proteins abundantly secreted by the larval fat body into the haemolymph. The canonical role of hexamerins consists of serving as an amino acid reserve for development toward the adult stage. However, in Apis mellifera, immunofluorescence assays coupled to confocal laser-scanning microscopy, and high-throughput sequencing, have recently shown the presence of hexamerins in other organs than the fat body. These findings have led us to study these proteins with the expectation of uncovering additional functions in insect development. We show here that a honeybee hexamerin, HEX 110, localizes in the cytoplasm and nucleus of ovarian cells. In the nucleus of somatic and germline cells, HEX 110 colocalized with a nucleolar protein, fibrillarin, suggesting a structural or even regulatory function in the nucleolus. RNase A provoked the loss of HEX 110 signals in the ovarioles, indicating that the subcellular localization depends on RNA. This was reinforced by incubating ovaries with pyronin Y, a RNA-specific dye. Together, the colocalization with fibrillarin and pyronin Y, and the sensitivity to RNase, highlight unprecedented roles for HEX110 in the nucleolus, the nuclear structure harbouring the gene cluster involved in ribosomal RNA production. However, the similar patterns of HEX 110 foci distribution in the active and inactive ovaries of queens and workers preclude its association with the functional status of these organs. PMID- 26954258 TI - Decreased Laminin Expression by Human Lung Epithelial Cells and Fibroblasts Cultured in Acellular Lung Scaffolds from Aged Mice. AB - The lung changes functionally and structurally with aging. However, age-related effects on the extracellular matrix (ECM) and corresponding effects on lung cell behavior are not well understood. We hypothesized that ECM from aged animals would induce aging-related phenotypic changes in healthy inoculated cells. Decellularized whole organ scaffolds provide a powerful model for examining how ECM cues affect cell phenotype. The effects of age on ECM composition in both native and decellularized mouse lungs were assessed as was the effect of young vs old acellular ECM on human bronchial epithelial cells (hBECs) and lung fibroblasts (hLFs). Native aged (1 year) lungs demonstrated decreased expression of laminins alpha3 and alpha4, elastin and fibronectin, and elevated collagen, compared to young (3 week) lungs. Proteomic analyses of decellularized ECM demonstrated similar findings, and decellularized aged lung ECM contained less diversity in structural proteins compared to young ECM. When seeded in old ECM, hBECs and hLFs demonstrated lower gene expression of laminins alpha3 and alpha4, respectively, as compared to young ECM, paralleling the laminin deficiency of aged ECM. ECM changes appear to be important factors in potentiating aging related phenotypes and may provide clues to mechanisms that allow for aging related lung diseases. PMID- 26954260 TI - Using transprofessional care in the emergency department to reduce patient admissions: A retrospective audit of medical histories. AB - The demand for emergency department (ED) services has increased significantly, due to our increasingly ageing population and limited access to primary care. This article reports outcomes from a transprofessional model of care in an ED in Victoria, Australia. Nurses, physiotherapists, social workers, and occupational therapists undertook additional education to increase the range of services they could provide and thereby expedite patient flow through the ED. One hundred patients who received this service were matched against 50 patients who did not. The most common reasons for patient admission were limb injury/limb pain (n = 47, 23.5%) and falls (n = 46, 23.0%). Transprofessional interventions included applying supportive bandages, slings, zimmer splints and controlled ankle motion (CAM) boots, and referral to new services such as case management and mental health teams. The rate of hospital admissions was significantly lower in the transprofessional group (n = 27, 18.0%) than in the reference group (n = 19, 38%, p = 0.005). This group also had a slightly lower re-presentation rate (n = 4, 2.7%) than patients in the reference group (n = 2, 4.0%). There are many benefits that support this model of care that in turn reduces ED overcrowding and work stress. A transprofessional model may offer a creative solution to meeting the varied needs of patients presenting for emergency care. PMID- 26954261 TI - Mutation screening of the PRRT2 gene for benign epilepsy with centrotemporal spikes in Chinese mainland population. AB - Proline-rich transmembrane protein 2 gene (PRRT2) mutations are reported to cause common paroxysmal neurological disorders and show a remarkable pleiotropy. Benign epilepsy with centrotemporal spikes (BECTS) is considered to be the most common epilepsy syndrome in childhood. It is placed among the idiopathic localization related epilepsies. Recently, it was reported that a girl with a PRRT2 mutation c.649_650insC developed infantile focal epilepsy with bilateral spikes which resembled the rolandic spikes. Hereby we performed a comprehensive genetic mutation screening of PRRT2 gene in a cohort of 53 sporadic BECTS patients. None of the 53 sporadic BECTS patients and other 250 controls carried mutations including c.649_650insC in PRRT2. Our data indicated that the PRRT2 mutations might most likely not be associated with BECTS in Chinese mainland population. PMID- 26954262 TI - Comparison of the AVPU Scale and the Pediatric GCS in Prehospital Setting. AB - OBJECTIVE: The pediatric Glasgow coma scale (pGCS) is a consciousness score that, although widely applied, requires skill to apply. The AVPU scale uses four simple categories (Alert; Verbal response; response to Pain; Unresponsive), but has not been studied in a large pediatric population. We compared the performance of the AVPU and pGCS scales in a large pediatric cohort in an acute, prehospital setting. METHODS: In a six-month-long prospective cohort study, AVPU and pGCS scores were determined by emergency physicians in children less than 10 years of age at their first prehospital encounter. RESULTS: We included 302 children (median age 2.3 years) with a broad spectrum of diagnoses. Data were complete for 287 children. AVPU and pGCS scores showed good a correlation in the extreme categories A and U (positive predictive values of 98% and 100%, respectively). Corresponding pGCS scores for each AVPU category were as follows: 11-15 for A; 5 15 for V; 4-12 for P; and 3-5 for U. The positive predictive value to detect patients with pGCS >= 8 for AVPU category V was 100%. CONCLUSIONS: We demonstrated good correlation of simple and fast consciousness AVPU scoring to the standard pGCS in a large cohort of pediatric patients in a prehospital setting. The AVPU category "V" identifies patients with a pGCS of or exceeding 8 and, therefore, identifies children at low risk requiring more invasive procedures or intensive care treatment. KEY WORDS: Glasgow coma scale (GCS); Alert-verbal-pain-unresponsive-score; AVPU-score; consciousness assessment; children, pediatric emergency. PMID- 26954263 TI - Seedless synthesis of gold nanorods using resveratrol as a reductant. AB - Gold nanorods (GNRs) attract extensive attention in current diagnostic and therapeutic applications which require the synthesis of GNRs with high yields, adjustable aspect ratio, size monodispersity, and easy surface decoration. In the seed-mediated synthesis of GNRs using cetyl trimethyl ammonium bromide (CTAB) micelles as templates, the additives of aromatic compounds have been found to be important for improving the size monodispersity of the as-synthesized GNRs; this is hopeful in terms of the further optimization of the synthetic methodology of GNRs. In this work, resveratrol, a natural polyphenol in grapes with an anti oxidization behavior, is employed as the reductant for the seedless synthesis of GNRs with a good size monodispersity and a tunable aspect ratio. Accordingly, the longitudinal localized surface plasmon resonance (LSPR) peak is tunable from 570 to 950 nm. The success of our approach is attributed to the aromatic structure and mild reducibility of resveratrol. The embedment of resveratrol into CTAB micelles strengthens the facet-selective adsorption of CTAB, and therewith facilitates the anisotropic growth of GNRs. In addition, the mild reducibility of resveratrol is capable of supporting GNR growth by avoiding secondary nucleation, thus allowing the seedless synthesis of GNRs with a good size monodispersity. As a chemopreventive agent, the combination of resveratrol in GNR synthesis will consolidate the theranostic applications of GNRs. PMID- 26954264 TI - Suppressing the voltage-fading of layered lithium-rich cathode materials via an aqueous binder for Li-ion batteries. AB - Guar gum (GG) has been applied as a binder for layered lithium-rich cathode materials of Li-ion batteries for the first time. Compared with the conventional PVDF binder, electrodes with GG as the binder exhibit significantly suppressed voltage and capacity fading. This study has introduced a multi-functional binder for layered lithium-rich cathode materials. PMID- 26954265 TI - Comparison of estimated core body temperature measured with the BioHarness and rectal temperature under several heat stress conditions. AB - Monitoring and measuring core body temperature is important to prevent or minimize physiological strain and cognitive dysfunction for workers such as first responders (e.g., firefighters) and military personnel. The purpose of this study is to compare estimated core body temperature (Tco-est), determined by heart rate (HR) data from a wearable chest strap physiology monitor, to standard rectal thermometry (Tre) under different conditions. Tco-est and Tre measurements were obtained in thermoneutral and heat stress conditions (high temperature and relative humidity) during four different experiments including treadmill exercise, cycling exercise, passive heat stress, and treadmill exercise while wearing personal protective equipment (PPE). Overall, the mean Tco-est did not differ significantly from Tre across the four conditions. During exercise at low moderate work rates under heat stress conditions, Tco-est was consistently higher than Tre at all-time points. Tco-est underestimated temperature compared to Tre at rest in heat stress conditions and at a low work rate under heat stress while wearing PPE. The mean differences between the two measurements ranged from -0.1 +/- 0.4 to 0.3 +/- 0.4 degrees C and Tco-est correlated well with HR (r = 0.795 - 0.849) and mean body temperature (r = 0.637 - 0.861). These results indicate that, the comparison of Tco-est to Tre may result in over- or underestimation which could possibly lead to heat-related illness during monitoring in certain conditions. Modifications to the current algorithm should be considered to address such issues. PMID- 26954266 TI - Impact of psm-mec in Methicillin-Resistant Staphylococcus aureus (ST764) Strains Isolated from Keratitis Patients. AB - Staphylococcus aureus is a predominant pathogen in keratitis, and the rate of methicillin-resistant S. aureus (MRSA) is increasing. In our previous study, genotypes of MRSA isolates from keratitis cases were classified into ST5 or ST764 lineage by multi-locus sequence typing. In this study, we examined the virulence properties of these MRSA keratitis isolates and its virulence determinants. There was no difference in the prevalence of virulence genes, such as adhesion and toxins, between ST5 and ST764 isolates. All ST5 isolates carried the intact psm mec gene, which suppresses exotoxin production and colony spreading, but promotes biofilm formation. In contrast, all ST764 isolates had one point mutation in the psm-mec gene. Biofilm production in ST5 isolates was significantly higher than that in ST764 isolates, whereas colony spreading, hemolytic activity, and production of alpha-phenol-soluble modulins were higher in ST764 than in ST5 isolates. The toxicity of ST764 supernatants to corneal epithelial cells was higher than that of ST5 supernatants. These results suggest that the point mutation in the psm-mec gene contributes to the difference in virulence properties between ST5 and ST764 isolates in MRSA keratitis. PMID- 26954268 TI - Postural Cueing to Increase Lumbar Lordosis Increases Lumbar Multifidus Activation During Trunk Stabilization Exercises: Electromyographic Assessment Using Intramuscular Electrodes. AB - STUDY DESIGN: Controlled laboratory study, repeated-measures design. BACKGROUND: Diminished multifidus activation and cross-sectional area are frequent findings in persons with low back pain. Increasing lumbar lordosis has been shown to increase activation of the multifidus with a minimal increase in activation of the long global extensors during unsupported sitting. OBJECTIVES: To examine the influence of postural cueing to increase lumbar lordosis on lumbar extensor activation during trunk stabilization exercises. METHODS: Thirteen asymptomatic participants (9 male, 4 female) were instructed to perform 6 trunk stabilization exercises using a neutral position and increasing lumbar lordosis. Electrical activity of the deep multifidus and longissimus thoracis was recorded using fine wire intramuscular electrodes. The mean root-mean-square of the electromyography (EMG) signal obtained during each exercise was normalized to a maximum voluntary isometric contraction (MVIC). A 2-way, repeated-measures analysis of variance (posture by exercise) was performed for each muscle. RESULTS: When averaged across the 6 exercises, postural cueing to increase lumbar lordosis resulted in greater multifidus EMG activity compared to performing the exercises in a neutral posture (35.3% +/- 15.1% versus 29.5% +/- 11.2% MVIC). No significant increase in longissimus thoracis EMG activity was observed when exercising with cueing to increase lumbar lordosis. CONCLUSION: This study suggests that postural cueing to increase lumbar lordosis during trunk stabilization exercises may better promote multifidus activation than traditional stabilization exercises alone. Future studies are needed to determine whether increasing lumbar lordosis improves multifidus activation in persons with low back pain. PMID- 26954269 TI - Shedding Light on the Etiology of Sports Injuries: A Look Behind the Scenes of Time-to-Event Analyses. AB - SYNOPSIS: The etiological mechanism underpinning any sports-related injury is complex and multifactorial. Frequently, athletes perceive "excessive training" as the principal factor in their injury, an observation that is biologically plausible yet somewhat ambiguous. If the applied training load is suddenly increased, this may increase the risk for sports injury development, irrespective of the absolute amount of training. Indeed, little to no rigorous scientific evidence exists to support the hypothesis that fluctuations in training load, compared to absolute training load, are more important in explaining sports injury development. One reason for this could be that prospective data from scientific studies should be analyzed in a different manner. Time-to-event analysis is a useful statistical tool in which to analyze the influence of changing exposures on injury risk. However, the potential of time-to-event analysis remains insufficiently exploited in sports injury research. Therefore, the purpose of the present article was to present and discuss measures of association used in time-to-event analyses and to present the advanced concept of time-varying exposures and outcomes. In the paper, different measures of association, such as cumulative relative risk, cumulative risk difference, and the classical hazard rate ratio, are presented in a nontechnical manner, and suggestions for interpretation of study results are provided. To summarize, time to-event analysis complements the statistical arsenal of sports injury prevention researchers, because it enables them to analyze the complex and highly dynamic reality of injury etiology, injury recurrence, and time to recovery across a range of sporting contexts. PMID- 26954267 TI - Longitudinal Effects of Adaptive Interventions With a Speech-Generating Device in Minimally Verbal Children With ASD. AB - There are limited data on the effects of adaptive social communication interventions with a speech-generating device in autism. This study is the first to compare growth in communications outcomes among three adaptive interventions in school-age children with autism spectrum disorder (ASD) who are minimally verbal. Sixty-one children, ages 5-8 years, participated in a sequential, multiple-assignment randomized trial (SMART). All children received a developmental behavioral communication intervention: joint attention, symbolic play, engagement and regulation (JASP) with enhanced milieu teaching (EMT). The SMART included three 2-stage, 24-week adaptive interventions with different provisions of a speech-generating device (SGD) in the context of JASP+EMT. The first adaptive intervention, with no SGD, initially assigned JASP+EMT alone, then intensified JASP+EMT for slow responders. In the second adaptive intervention, slow responders to JASP+EMT were assigned JASP+EMT+SGD. The third adaptive intervention initially assigned JASP+EMT+SGD; then intensified JASP+EMT+SGD for slow responders. Analyses examined between-group differences in change in outcomes from baseline to Week 36. Verbal outcomes included spontaneous communicative utterances and novel words. Nonlinguistic communication outcomes included initiating joint attention and behavior regulation, and play. The adaptive intervention beginning with JASP+EMT+SGD was estimated as superior. There were significant (p < .05) between-group differences in change in spontaneous communicative utterances and initiating joint attention. School-age children with ASD who are minimally verbal make significant gains in communication outcomes with an adaptive intervention beginning with JASP+EMT+SGD. Future research should explore mediators and moderators of the adaptive intervention effects and second-stage intervention options that further capitalize on early gains in treatment. PMID- 26954270 TI - Cervico-occipital Posture in Women With Migraine: A Case-Control Study. AB - STUDY DESIGN: Case-control study. BACKGROUND: Previous studies have assessed forward head posture in patients with migraine using photographs. To date, no study has compared postural differences using both radiographs and photographs. OBJECTIVE: To determine the differences in head extension posture between women with migraine and healthy women assessed with radiographic and photographic measures. METHODS: Thirty-three women (mean +/- SD age, 32 +/- 11.3 years) with migraine and 33 matched controls (age, 33 +/- 12.6 years) participated. Radiographs were used to measure the high cervical angle (HCA), the angle between the most inferior line from the occipital surface to the posterior portion of C1 and the posterior surface of the odontoid process of C2, and the vertical distance between C0 and C1 (C0-C1). Photographs and commercially available software were used to assess the craniovertebral angle (CVA). RESULTS: None of the outcomes differed significantly between women with migraine and control participants. Outcomes for women with migraine were HCA, 66.1 degrees (95% confidence interval [CI]: 64.2 degrees , 68.1 degrees ); CVA, 46.1 degrees (95% CI: 45.0 degrees , 47.1 degrees ); and C0-C1, 8.5 mm (95% CI: 7.7, 9.2). Outcomes for the control group were HCA, 67.9 degrees (95% CI: 66.5 degrees , 69.3 degrees ); CVA, 44.5 degrees (95% CI: 43.2 degrees , 45.7 degrees ); and C0-C1, 8.7 mm (95% CI: 7.9, 9.4). Relationships between the frequency (r = -0.42, P = .01, R (2) = 10%) of migraine and the HCA were found. CONCLUSION: This study demonstrated that women with migraine did not exhibit forward head posture compared to women with no history of headache in either radiographic or photographic postural analysis. However, there was a weak association of the frequency of migraine attacks with a variation in the HCA as assessed by radiographs. LEVEL OF EVIDENCE: Differential diagnosis/symptom prevalence, level 4. PMID- 26954271 TI - Abdominal Bracing Increases Ground Reaction Forces and Reduces Knee and Hip Flexion During Landing. AB - STUDY DESIGN: Controlled laboratory study. BACKGROUND: Abdominal bracing (AB) is a widely advocated method of increasing spine stability, yet the influence of AB on the execution of sporting movements has not been quantified. Landing is a common task during sporting endeavors; therefore, investigating the effect of performing AB during a drop-landing task is relevant. OBJECTIVE: To quantify the effect of AB on kinematics (ankle, knee, hip, and regional lumbar spine peak flexion angles) and peak vertical ground reaction force (vGRF) during a drop landing task. METHODS: Sixteen healthy adults (7 female, 9 male; mean +/- SD age, 27 +/- 7 years; height, 170.6 +/- 8.1 cm; mass, 68.0 +/- 11.3 kg) were assessed using 3-D motion analysis, electromyography (EMG), and a force platform while performing a drop-landing task with and without AB. Abdominal bracing was achieved with the assistance of real-time internal oblique EMG feedback. Lower limb and regional lumbar spine kinematics, peak vGRF, and normalized EMG of the left and right internal obliques and lumbar multifidus were quantified. Paired samples t tests were used to compare variables between the AB and no-AB conditions. RESULTS: Abdominal bracing resulted in significantly reduced knee and hip flexion and increased peak vGRF during landing. No differences in lumbar multifidus EMG or lumbar spine kinematics were observed. CONCLUSION: Abdominal bracing reduces impact attenuation during landing. These altered biomechanics may have implications for lower-limb and spinal injury risk during dynamic tasks. PMID- 26954272 TI - M-Mode Ultrasound Reveals Earlier Gluteus Minimus Activity in Individuals With Chronic Hip Pain During a Step-down Task. AB - STUDY DESIGN: Controlled laboratory study. BACKGROUND: The hip abductor muscles are important hip joint stabilizers. Hip joint pain may alter muscle recruitment. Motion-mode (M-mode) ultrasound enables noninvasive measurements of the onset of deep and superficial muscle motion, which is associated with activation onset. OBJECTIVES: To compare (1) the onset of superficial and deep gluteus medius and gluteus minimus muscle motion relative to the instant of peak ground reaction force and (2) the level of swing-phase muscle motion during step-down between subjects with chronic hip pain and controls using M-mode ultrasound. METHODS: Thirty-five subjects with anterior, nontraumatic hip pain for more than 6 months (mean +/- SD age, 54 +/- 9 years) and 35 controls (age, 57 +/- 7 years) were scanned on the lateral hip of the leading leg during frontal step-down onto a force platform using M-mode ultrasound. Computerized motion detection with the Teager-Kaiser energy operator was applied on the gluteus minimus and the deep and superficial gluteus medius to determine the time lag between muscle motion onset and instant of peak ground reaction force and the level of gluteus minimus motion during the swing phase. Time lags and motion levels were averaged per subject, and t tests were used to determine between-group differences. RESULTS: In participants with hip pain, gluteus minimus motion onset was 103 milliseconds earlier (P = .002) and superficial gluteus medius motion was 70 milliseconds earlier (P = .047) than those in healthy control participants. The level of gluteus minimus swing-phase motion was higher with pain (P = .006). CONCLUSION: Increased gluteus minimus motion during the swing phase and earlier gluteus minimus and superficial gluteus medius motion in individuals with hip pain suggest an overall increase of muscle activity, possibly a protective behavior. PMID- 26954273 TI - A Prescriptively Selected Nonthrust Manipulation Versus a Therapist-Selected Nonthrust Manipulation for Treatment of Individuals With Low Back Pain: A Randomized Clinical Trial. AB - STUDY DESIGN: Randomized controlled trial. BACKGROUND: Several studies that have investigated the effects of a therapist-selected versus a randomly assigned segmental approach have looked at immediate effects only for pain-related outcomes. OBJECTIVES: To examine differences in outcomes following a therapist selected nonthrust manipulation versus a prescriptively selected nonthrust manipulation in subjects with low back pain. METHODS: Subjects with mechanically producible low back pain were randomly treated with nonthrust manipulation in a therapist-selected approach or a prescriptively selected approach. All subjects received a standardized home exercise program. Outcome measures included pain, disability, global rating of change, and patient acceptable symptom state. Analyses of covariance, chi-square tests, and Mann-Whitney U tests were used to determine differences between groups. RESULTS: Sixty-three subjects were tracked for 6 months, during which subjects in both groups significantly improved. There were no differences between groups in pain, disability, or patient acceptable symptom state scores at 6 months. There was a significant difference in global rating of change scores favoring the therapist-selected manipulation group at 6 months. CONCLUSION: This study measured long-term differences between a prescriptively selected nonthrust manipulation and a therapist-selected approach to nonthrust manipulation. In pain, disability, and patient acceptable symptom state there were no differences in outcomes, findings similar to studies of immediate effects. After 6 months, perceived well-being was significantly higher for those in the therapist-selected treatment group. The study was registered at ClinicalTrials.gov (NCT01940744). LEVEL OF EVIDENCE: Therapy, level 1b. PMID- 26954274 TI - Reduced Physical Activity in People Following Ankle Fractures: A Longitudinal Study. AB - STUDY DESIGN: Longitudinal observational cohort. BACKGROUND: The impact of ankle fracture on physical activity and sitting time and the course of recovery of physical activity are unclear. OBJECTIVES: To assess the course of recovery of physical activity after ankle fracture and the extent to which this population may be less physically active and more sedentary than the general population. METHODS: A cohort of individuals with ankle fracture was derived from a randomized trial and assessed with the International Physical Activity Questionnaire-Short Form (IPAQ-SF) at immobilization removal and 1, 3, and 6 months later. Total metabolic equivalent (MET) minutes per week were calculated to evaluate the course of recovery of physical activity. Sitting time (minutes per day) and the percentage of those who met the World Health Organization physical activity guidelines were calculated. Normative data were derived from a population-based cohort study that assessed physical activity using the IPAQ-SF. RESULTS: In people with ankle fracture (n = 214), physical activity increased in the first month (from a median of 99 at immobilization removal to 979 MET min/wk) and leveled off by 6 months (1386 MET min/wk). Only 22% of the ankle fracture cohort met World Health Organization guidelines at immobilization removal, compared to 80% of the cohort from the general population (P<.001). This difference diminished over time. Sitting time in the ankle fracture cohort was higher than population norms at all time points (P<.001). CONCLUSION: People with ankle fracture are less physically active and more sedentary than the general population. Strategies to increase physical activity must be considered. LEVEL OF EVIDENCE Prognosis, level 4. PMID- 26954277 TI - Editorial. AB - Many people who are relative newcomers to the field of healthcare research are often wary about seeking to have their findings published in a journal. Ask them why, and they are likely to tell you that the articles they read in peer-reviewed journals bear little relationship to their own, flawed studies. PMID- 26954275 TI - Safety and tolerability of beta3-adrenoceptor agonists in the treatment of overactive bladder syndrome - insight from transcriptosome and experimental studies. AB - INTRODUCTION: We have reviewed the safety and tolerability of beta3-adrenoceptor agonists, specifically mirabegron and solabegron, a newly emerging drug class for the treatment of the overactive bladder syndrome. We discuss them mechanistically in the context of expression and other preclinical data. AREAS COVERED: Based on a systematic PubMed search, incidence of overall adverse events, hypertension, dry mouth, and constipation are comparable between mirabegron or solabegron and placebo. Hypertension is the most frequently observed adverse event, but has a similar incidence with mirabegron and placebo. Nevertheless, severe uncontrolled hypertension has become a contraindication for use of mirabegron based on observation of severe hypertension in association with mirabegron exposure. The overall incidence of adverse events is also similar between mirabegron and the muscarinic receptor antagonist tolterodine, but the incidence of dry mouth is much lower with mirabegron. EXPERT OPINION: The high beta3-adrenoceptor mRNA expression in the human ovaries is not associated with reproductive side effects. Generally, beta3-adrenoceptors exhibit a rather restricted expression in human tissues, which may explain the overall good tolerability of agonists acting on this receptor. We propose that expression profiles and functional preclinical studies can be important tools in the prediction of adverse event profiles in first-in-class drugs. PMID- 26954276 TI - The double face of mitochondrial dysfunction. PMID- 26954278 TI - Practical issues in 'writing up' a research thesis. AB - Beginning to 'write up' your research thesis can seem a daunting prospect. While the experience can be stressful, with careful planning, the process can be managed effectively, and prove both rewarding and pleasurable. Paula Roberts offers a practical guide to managing the process of writing-up. Three distinct phases are discussed: the input phase of planning the write-up; the process phase of writing-up; and the output phase ofpreparing the finished document for submission. PMID- 26954279 TI - The use of electronic mail in the research process. AB - Carol Cooper targets both novice researchers who want to use email and readers who would like to make better use of electronic mail (email) in their research. She examines the growing use of email and outlines its uses as found in nursing literature for sample recruitment, data collection and sample interviews, and networking and collaboration. PMID- 26954280 TI - Getting started in research. AB - Everybody has to start at the beginning when they enter the field of research. This step by step guide by Ben Hannigan is intended to help fledgling researchers to choose an appropriate methodology and enter their field of investigation with feelings of confidence. PMID- 26954281 TI - The relevance of participatory research in developing nursing research and practice. AB - The need to incorporate the views of patients or service users is at the heart of contemporary healthcare policy. But there is always the risk that researchers and policy makers will merely pay lip service to such an approach or that it will be conducted in a 'top down' manner. Ruth Northway describes how a participative approach can ensure that users are genuinely involved in research into their needs and aims to explore the potential contribution that participatory research can make to nursing, with particular reference to evaluating services. The practical implications that need to be considered by nurses choosing to use participatory methodologies are also explored. PMID- 26954282 TI - Quantity or quality? AB - The aim of nursing as a profession is to deliver a high quality service based on reliable and valid research findings. As a result, there is an urgent need to address the methodological issues arising from the quantitative-qualitative debate and the nature and resolution of the perceived theory-practice gap. Billy Kelly and Ann Long examines the key issues. PMID- 26954283 TI - Writing for publication. AB - In the final paper in a four part series, Karen Jackson and Lesley Sheldon outline the key aspects of writing articles for publication in nursing journals. PMID- 26954284 TI - Conducting an interview. AB - The traditional guidance to researchers conducting interviews in the field is that the researcher should say as little as possible and encourage the respondents to talk in an untramelled way about the issues under discussion. But is this approach appropriate in all circumstances? Keith Melia examines the issues by focusing on research carried out in an intensive care unit. PMID- 26954286 TI - Will Biomarkers Determine What Is Next in Multiple Sclerosis?: Biomarkers in Multiple Sclerosis. PMID- 26954288 TI - The use of intraoral ultrasound in the characterization of minor salivary gland malignancy: report of two cases. AB - It is generally accepted that ultrasound is now the first line of imaging of palpable lumps of the neck. Standardized protocols exist for the evaluation of thyroid, salivary gland and nodal disease, and sonography is increasingly being used in the characterization of intraoral soft tissue lesions. Here, we present two cases where intraoral sonography was invaluable in the early detection of oral malignancy. PMID- 26954289 TI - Dental panoramic indices and fractal dimension measurements in osteogenesis imperfecta children under pamidronate treatment. AB - OBJECTIVES: To verify radiomorphometric indices and fractal dimension (FD) in dental panoramic radiographs (DPRs) of children with different types of osteogenesis imperfecta (OI) and also to verify the effect of pamidronate (PAM) treatment in such panoramic analyses. METHODS: In this retrospective study, 197 DPRs of 62 children with OI Types I, III and IV who were in treatment with a comparable dosage of intravenous PAM were selected. The mandibular cortical width (MCW), mandibular cortical index, visual estimation of the cortical width and FD of three standardized trabecular and cortical mandibular regions of interest were obtained from the radiographs. Factorial analysis of variance and Fisher test were used to compare FD and MCW measurements in children with different types of OI for different PAM cycles. RESULTS: Children with all types of OI have thinner and more porous mandibular cortices at the beginning of treatment. There were significant differences between MCW and FD of the cortical bone, regarding different types of OI and number of PAM cycles (p = 0.037 and p = 0.044, respectively). FD measurements of the trabecular bone were not statistically different among OI types nor were PAM cycles (p > 0.05). CONCLUSIONS: Children with OI presented cortical bone alterations after PAM treatment. Both MCW and the FD of the cortical bone were higher in children with OI after PAM treatment. It is argued that cortical bone should be considered for analyzing patients with OI, as well as to monitor the progress of PAM treatment. PMID- 26954290 TI - Contrast-to-noise ratio with different settings in a CBCT machine in presence of different root-end filling materials: an in vitro study. AB - OBJECTIVES: To compare the contrast-to-noise ratio (CNR) of multiple acquisition settings for four types of retrograde filling materials in CBCT images taken for endodontic surgery follow-up. METHODS: 20 maxillary central incisors were endodontically treated and obturated with 4 different root-end filling materials: amalgam, mineral trioxide aggregate, SuperEBA(TM) (Harry J Bosworth Company, Skokie, IL) and BiodentineTM (Septodont, Saint-Maur-des-Fausses, France). Teeth were placed in a skull and scanned, one by one, with the Planmeca ProMax((r)) 3D Max (Planmeca, Helsinki, Finland); at different voltages: 66, 76, 84 and 96 kVp; with low, normal and high resolution and high definition (HD); with and without metal artefact reduction (MAR). Images were analyzed using ImageJ software (National Institutes of Health, Bethesda, MD) to calculate the CNR. The dose-area product was registered, and the effective dose calculated. RESULTS: No statistically significant difference was noted between the four materials. 84 and 96 kVp with low resolution and the use of MAR-generated images that have statistically better CNR than 66 and 76 kVp with HD, normal and high resolutions and without MAR. The use of low resolution also generated the smallest value of effective dose. CONCLUSIONS: The best setting for radiographic follow-up in an endodontic surgery with retrograde filling on the Planmeca ProMax is 96 kVp with low resolution and high MAR; this setting produced one of the lowest effective doses. PMID- 26954291 TI - Anti-human CD138 monoclonal antibodies and their bispecific formats: generation and characterization. AB - Syndecan-1 (CD138), a heparan sulfate proteoglycan, acts as a co-receptor for growth factors and chemokines and is a molecular marker associated with the epithelial-mesenchymal transition during development and carcinogenesis. In this study, we generated two specific mouse anti-human CD138 monoclonal antibodies (mAbs, clone ID: 480CT5.4.3, 587CT7.3.6.5) using hybridoma technology and identified their immunological characteristics. After hybridoma sequencing, the single-chain variable fragments (ScFvs) cloned from two hybridoma cells were combined with anti-CD3 OKT-3 ScFv to generate two recombinant bispecific antibodies (h-STL002, m-STL002) against CD138 and CD3 molecules, respectively. The bispecific antibodies were able to specifically target CD138 + multiple myeloma (MM) cells and CD3 + T cells, and showed the potent cytotoxicity against MM RPMI-8226 cell line through T cell activation. However, these bispecific antibodies without T cells did not cause toxic side effect on MM cells. Overall, the two hybridoma clones and their bispecific formats have great potential to promote diagnosis and immunotherapy of plasma cell malignancy. PMID- 26954292 TI - Highly Predictive Model for a Protective Immune Response to the A(H1N1)pdm2009 Influenza Strain after Seasonal Vaccination. AB - Understanding the immune response after vaccination against new influenza strains is highly important in case of an imminent influenza pandemic and for optimization of seasonal vaccination strategies in high risk population groups, especially the elderly. Models predicting the best sero-conversion response among the three strains in the seasonal vaccine were recently suggested. However, these models use a large number of variables and/or information post- vaccination. Here in an exploratory pilot study, we analyzed the baseline immune status in young (<31 years, N = 17) versus elderly (>=50 years, N = 20) donors sero-negative to the newly emerged A(H1N1)pdm09 influenza virus strain and correlated it with the serological response to that specific strain after seasonal influenza vaccination. Extensive multi-chromatic FACS analysis (36 lymphocyte sub populations measured) was used to quantitatively assess the cellular immune status before vaccination. We identified CD4+ T cells, and amongst them particularly naive CD4+ T cells, as the best correlates for a successful A(H1N1)pdm09 immune response. Moreover, the number of influenza strains a donor was sero-negative to at baseline (NSSN) in addition to age, as expected, were important predictive factors. Age, NSSN and CD4+ T cell count at baseline together predicted sero-protection (HAI>=40) to A(H1N1)pdm09 with a high accuracy of 89% (p-value = 0.00002). An additional validation study (N = 43 vaccinees sero negative to A(H1N1)pdm09) has confirmed the predictive value of age, NSSN and baseline CD4+ counts (accuracy = 85%, p-value = 0.0000004). Furthermore, the inclusion of donors at ages 31-50 had shown that the age predictive function is not linear with age but rather a sigmoid with a midpoint at about 50 years. Using these results we suggest a clinically relevant prediction model that gives the probability for non-protection to A(H1N1)pdm09 influenza strain after seasonal multi-valent vaccination as a continuous function of age, NSSN and baseline CD4 count. PMID- 26954294 TI - Activation of Methane and Ethane as Mediated by the Triatomic Anion HNbN(-): Electronic Structure Similarity with a Pt Atom. AB - Investigations of the intrinsic properties of gas-phase transition metal nitride (TMN) ions represent one approach to gain a fundamental understanding of the active sites of TMN catalysts, the activities and electronic structures of which are known to be comparable to those of noble metal catalysts. Herein, we investigate the structures and reactivities of the triatomic anions HNbN(-) by means of mass spectrometry and photoelectron imaging spectroscopy, in conjunction with density functional theory calculations. The HNbN(-) anions are capable of activating CH4 and C2H6 through oxidative addition, exhibiting similar reactivities to free Pt atoms. The similar electronic structures of HNbN(-) and Pt, especially the active orbitals, are responsible for this resemblance. Compared to the inert NbN(-), the coordination of the H atom in HNbN(-) is indispensable. New insights into how to replace noble metals with TMNs may be derived from this combined experimental/computational study. PMID- 26954293 TI - Medical scribes in emergency medicine produce financially significant productivity gains for some, but not all emergency physicians. AB - OBJECTIVE: The present study aims to determine if a scribe in an Australian ED can assist emergency physicians to work with increased productivity and to investigate when and where to allocate a scribe and to whom. METHODS: This was a prospective observational single-centre study conducted at a private ED in Melbourne. It evaluated one American scribe and five doctors over 6 months. A scribe is a trained assistant who performs non-clinical tasks usually performed by the doctor. The primary outcomes were patients/hour/doctor and billings/patient. Additional analyses included individual doctor productivity, productivity by ED region, shift time, day of the week and physician learning curves. Door-to-doctor time, time spent on ambulance bypass and door-to-discharge time were examined, also complaints or issues with the scribe. RESULTS: There was an overall increase in doctor consultations of 0.11 (95%CI 0.07-0.15) primary consultations per hour (13%). There was variation seen between individual doctors (lowest increase 0.06 [6%] to highest increase 0.12 [15%]). Billings per patients, door-to-doctor, door-to-discharge and ambulance bypass times remained the same. There was no advantage to allocating a scribe to a specific time of day, day of week or region of the ED. There was no learning period found. CONCLUSIONS: In the present study, scribe usage was associated with overall improvements in primary consultations per hour of 13% per scribed hour, and this varied depending on the physician. There is an economic argument for allocating scribes to some emergency physicians on days, evenings and weekends, not to trainees. PMID- 26954297 TI - The colorectal surgeon's liposarcoma. PMID- 26954295 TI - Resting-state connectivity predicts levodopa-induced dyskinesias in Parkinson's disease. AB - BACKGROUND: Levodopa-induced dyskinesias are a common side effect of dopaminergic therapy in PD, but their neural correlates remain poorly understood. OBJECTIVES: This study examines whether dyskinesias are associated with abnormal dopaminergic modulation of resting-state cortico-striatal connectivity. METHODS: Twelve PD patients with peak-of-dose dyskinesias and 12 patients without dyskinesias were withdrawn from dopaminergic medication. All patients received a single dose of fast-acting soluble levodopa and then underwent resting-state functional magnetic resonance imaging before any dyskinesias emerged. Levodopa-induced modulation of cortico-striatal resting-state connectivity was assessed between the putamen and the following 3 cortical regions of interest: supplementary motor area, primary sensorimotor cortex, and right inferior frontal gyrus. These functional connectivity measures were entered into a linear support vector classifier to predict whether an individual patient would develop dyskinesias after levodopa intake. Linear regression analysis was applied to test which connectivity measures would predict dyskinesia severity. RESULTS: Dopaminergic modulation of resting-state connectivity between the putamen and primary sensorimotor cortex in the most affected hemisphere predicted whether patients would develop dyskinesias with a specificity of 100% and a sensitivity of 91% (P < .0001). Modulation of resting-state connectivity between the supplementary motor area and putamen predicted interindividual differences in dyskinesia severity (R(2) = 0.627, P = .004). Resting-state connectivity between the right inferior frontal gyrus and putamen neither predicted dyskinesia status nor dyskinesia severity. CONCLUSIONS: The results corroborate the notion that altered dopaminergic modulation of cortico-striatal connectivity plays a key role in the pathophysiology of dyskinesias in PD. PMID- 26954296 TI - Correction: The Influence of Hormonal Factors on the Risk of Developing Cervical Cancer and Pre-Cancer: Results from the EPIC Cohort. PMID- 26954298 TI - Deterministic Integration of Single Photon Sources in Silicon Based Photonic Circuits. AB - A major step toward fully integrated quantum optics is the deterministic incorporation of high quality single photon sources in on-chip optical circuits. We show a novel hybrid approach in which preselected III-V single quantum dots in nanowires are transferred and integrated in silicon based photonic circuits. The quantum emitters maintain their high optical quality after integration as verified by measuring a low multiphoton probability of 0.07 +/- 0.07 and emission line width as narrow as 3.45 +/- 0.48 GHz. Our approach allows for optimum alignment of the quantum dot light emission to the fundamental waveguide mode resulting in very high coupling efficiencies. We estimate a coupling efficiency of 24.3 +/- 1.7% from the studied single-photon source to the photonic channel and further show by finite-difference time-domain simulations that for an optimized choice of material and design the efficiency can exceed 90%. PMID- 26954299 TI - Electrokinetics of isolated electrified drops. AB - Using a recently developed multiphase electrokinetic model, we simulate the transient electrohydrodynamic response of a liquid drop containing ions, to both small and large values of electric field. The temporal evolution is found to be governed primarily by two dimensionless groups: (i) Ohnesorge number (Oh), a ratio of viscous to inertio-capillary effects, and (ii) inverse dimensionless Debye length (kappa), a measure of the diffuse regions of charge that develop in the drop. The effects of dielectric polarization dominate at low Oh, while effects of separated charge gain importance with increase in Oh. For small values of electric field, the deformation behaviour of a drop is shown to be accurately described by a simple analytical expression. At large electric fields, the drops are unstable and eject progeny drops. Depending on Oh and kappa this occurs via dripping or jetting; the regime transitions are shown by a Oh-kappa phase map. In contrast to previous studies, we find universal scaling relations to predict size and charge of progeny drops. Our simulations suggest charge transport plays a significant role in drop dynamics for 0.1 <= Oh <= 10, a parameter range of interest in microscale flows. PMID- 26954301 TI - Manganese Oxide Nanoarray-Based Monolithic Catalysts: Tunable Morphology and High Efficiency for CO Oxidation. AB - A generic one-pot hydrothermal synthesis route has been successfully designed and utilized to in situ grow uniform manganese oxide nanorods and nanowires onto the cordierite honeycomb monolithic substrates, forming a series of nanoarray-based monolithic catalysts. During the synthesis process, three types of potassium salt oxidants have been used with different reduction potentials, i.e., K2Cr2O7, KClO3, and K2S2O8, denoted as HM-DCM, HM-PCR, and HM-PSF, respectively. The different reduction potentials of the manganese source (Mn(2+)) and oxidants induced the formation of manganese oxide nanoarrays with different morphology, surface area, and reactivity of carbon monoxide (CO) oxidation. K2Cr2O7 and KClO3 can induce sharp and long nanowires with slow growth rates due to their low reduction potentials. In comparison, the nanoarrays of HM-PSF presented shorter nanorods but displayed an efficient 90% CO oxidation conversion at 200 degrees C (T90) without noble-metal loading. Reducibility tests for the three monolithic catalysts by hydrogen temperature-programmed reduction revealed an activation energy order of HM-PSF > HM-DCM > HM-PCR for CO oxidation. The characterizations of oxygen temperature-programmed desorption and X-ray photoelectron spectroscopy indicated the abundant surface-adsorbed oxygen and lattice oxygen contributing to the superior reactivity of HM-PSF. The straightforward synthetic process showed a scalable, low-cost, and template-free method to fabricate manganese oxide nanoarray monolithic catalysts for exhaust treatment. PMID- 26954302 TI - Preparation and characterization of baru (Dipteryx alata Vog) nut protein isolate and comparison of its physico-chemical properties with commercial animal and plant protein isolates. AB - BACKGROUND: The Brazilian leguminous tree locally known in the Cerrado Biome as baru (Dipteryx alata Vog), provides a healthy edible oil source. The proteinaceous cake remaining after oil extraction could be transformed into new products to foodstuff development, such as protein concentrates and isolates, adding value to the production chain. In this study, it is described the preparation and characterization of baru nut protein isolate (BPI) from deffated baru flour, and measurements of its functional, nutritional, and thermal properties, in comparison to the more common vegetable (soybeans) and animal (casein and albumin) protein sources of the food industry. RESULTS: BPI presented higher protein content than soybean, casein and albumin commercial protein isolates, despite losses of albumins and low molecular weight globulins during the isolation procedure. Thermodynamics studies suggested that BPI has a well conserved protein arrangement and lower thermostability than the other protein sources. BPI showed high in vitro digestibility and suitable and desirable functional properties such as water and oil absorption capacity, emulsifying activity, and foam formation and stability at mild and neutral pH. CONCLUSION: BPI could be used either as a substitute ingredient in oily food formulations or in the development of new products of its own. (c) 2016 Society of Chemical Industry. PMID- 26954303 TI - Innovative Poly(Ionic Liquid)s by the Polymerization of Deep Eutectic Monomers. AB - The incorporation of ionic liquid (IL) chemistry into functional polymers has extended the properties and applications of polyelectrolytes. However, ILs are expensive due to the presence of fluorinated anions or complicated synthetic steps which limit their technological viability. Here, we show a new family of poly(ionic liquid)s (PILs) which are based in cheap and renewable chemicals and involves facile synthetic approaches. Thus, deep eutectic monomers (DEMs) are prepared for the first time by using quaternary ammonium compounds and various hydrogen bond donors such as citric acid, terephthalic acid or an amidoxime. The deep eutectic formation is made through a simple mixing of the ingredients. Differential scanning calorimetry, nuclear magnetic resonance (NMR) and computational studies reveal the formation of the DEMs due to the ionic interactions. The resulting DEMs are liquid which facilitates their polymerization using mild photopolymerization or polycondensation strategies. Spectroscopic characterizations reveal the successful formation of the polymers. By this way, a new family of PILs can be synthesized which can be used for different applications. As an example, the polymers show promising performance as solid CO2 sorbents. Altogether the deep eutectic monomer route can lead to non toxic, cheap and easy-to-prepare alternatives to current PILs for different applications. PMID- 26954304 TI - Patients with Rosacea Have Increased Risk of Depression and Anxiety Disorders: A Danish Nationwide Cohort Study. AB - BACKGROUND: Rosacea is a chronic skin condition that affects self-esteem and quality of life. However, data on depression and anxiety in patients with rosacea are scarce. OBJECTIVE: The aim of this study was to investigate the relationship between rosacea and new-onset depression and anxiety disorders. METHODS: Data on all Danish citizens aged >=18 years between January 1, 1997, and December 31, 2011, were linked at individual level in nationwide registers. Incidence rates per 1,000 person-years were calculated, and crude and adjusted incidence rate ratios (IRRs) with 95% confidence intervals (95% CIs) were estimated by Poisson regression models. RESULTS: The study comprised a total of 4,632,341 individuals, including 30,725 and 24,712 patients with mild and moderate-to-severe rosacea, respectively. Mild and moderate-to-severe rosacea increased the risk of both depression [IRR 1.89 (95% CI 1.82-1.96) and IRR 2.04 (95% CI 1.96-2.12)] and anxiety disorders [IRR 1.80 (95% CI 1.75-1.86) and IRR 1.98 (95% CI 1.91-2.05)]. CONCLUSIONS: Rosacea was associated with a disease severity-dependent, increased risk of depression and anxiety disorders. The findings may call for increased awareness of psychiatric morbidity in patients with rosacea. PMID- 26954305 TI - Improving accuracy of prognosis in patients with myelodysplastic syndromes using self-reported quality of life data. Opportunities for a new research agenda in developing prognostic models. PMID- 26954307 TI - Advanced age and high-residual platelet reactivity in patients receiving dual antiplatelet therapy with clopidogrel or ticagrelor: comment. PMID- 26954306 TI - Total Synthesis of (-)-Mandelalide A Exploiting Anion Relay Chemistry (ARC): Identification of a Type II ARC/CuCN Cross-Coupling Protocol. AB - Anion relay chemistry (ARC), an effective, multicomponent union tactic, was successfully employed for the total synthesis of the highly cytotoxic marine macrolide (-)-mandelalide A (1). The northern hemisphere was constructed via a new type II ARC/CuCN cross-coupling tactic, while the southern hemisphere was secured via a highly efficient four-component type I ARC union. Importantly, the synthesis of 1 showcases ARC as a rapid, scalable coupling strategy for the union of simple readily available building blocks to access diverse complex molecular fragments with excellent stereochemical control. PMID- 26954308 TI - Characterization and potential of three temperature ranges for hydrogen fermentation of cellulose by means of activity test and 16s rRNA sequence analysis. AB - A series of standardized activity experiments were performed to characterize three different temperature ranges of hydrogen fermentation from different carbon sources. 16S rRNA sequences analysis showed that the bacteria were close to Enterobacter genus in the mesophilic mixed culture (MMC) and Thermoanaerobacterium genus in the thermophilic and hyper-thermophilic mixed cultures (TMC and HMC). The MMC was able to utilize the glucose and cellulose to produce methane gas within a temperature range between 25 and 45 degrees C and hydrogen gas from 35 to 60 degrees C. While, the TMC and HMC produced only hydrogen gas at all temperature ranges and the highest activity of 521.4mlH2/gVSSd was obtained by TMC. The thermodynamic analysis showed that more energy is consumed by hydrogen production from cellulose than from glucose. The experimental results could help to improve the economic feasibility of cellulosic biomass energy using three-phase technology to produce hythane. PMID- 26954310 TI - Distribution patterns of nitrogen micro-cycle functional genes and their quantitative coupling relationships with nitrogen transformation rates in a biotrickling filter. AB - The present study explored the distribution patterns of nitrogen micro-cycle genes and the underlying mechanisms responsible for nitrogen transformation at the molecular level (genes) in a biotrickling filter (biofilter). The biofilter achieved high removal efficiencies for ammonium (NH4(+)-N) (80-94%), whereas nitrate accumulated at different levels under a progressive NH4(+)-N load. Combined analyses revealed the anammox, nas, napA, narG, nirS, and nxrA genes were the dominant enriched genes in different treatment layers. The presence of simultaneous nitrification, ammonium oxidation (anammox), and dissimilatory nitrate reduction to ammonium (DNRA) were the primary factors accounted for the robust NH4(+)-N treatment performance. The presence of DNRA, nitrification, and denitrification was determined to be a pivotal pathway that contributed to the nitrate accumulation in the biofilter. The enrichment of functional genes at different depth gradients and the multi-path coupled cooperation at the functional gene level are conducive to achieving complete nitrogen removal. PMID- 26954309 TI - Torrefaction of invasive alien plants: Influence of heating rate and other conversion parameters on mass yield and higher heating value. AB - With the aim of controlling their proliferation, two invasive alien plants, Lantana camara (LC) and Mimosa pigra (MP), both widespread in Africa, were considered for torrefaction for renewable energy applications. Using thermogravimetric analysis, the influence of heating rate (HR: 2.18-19.82 degrees Cmin(-1)) together with variable temperature and hold time on char yield and HHV (in a bomb calorimeter) were determined. Statistically significant effects of HR on HHV with optima at 10.5 degrees Cmin(-1) for LC and 20 degrees Cmin(-1) for MP were obtained. Increases of HHV up to 0.8MJkg(-1) or energy yield greater than 10%, together with a 3-fold reduction in torrefaction conversion time could be achieved by optimisation of HR. Analysis of the torrefaction volatiles by TG-MS showed that not only hemicelluloses, but also lignin conversion, could influence the optimum HR value. PMID- 26954311 TI - Improvement of Nail and Scalp Psoriasis Using Apremilast in Patients With Chronic Psoriasis: Phase 2b and 3, 52-Week Randomized, Placebo-Controlled Trial Results. AB - INTRODUCTION: A significant portion of patients with psoriasis have scalp and nail involvement. It has been reported that 40% to 45% of patients with psoriasis have nail psoriasis, and up to 80% have scalp involvement. Nail and scalp psoriasis have often been found to be difficult to treat, due to the poor penetration and poor compliance of topical medication. Oral and biologic therapies have shown significant efficacy but often with undesirable side effects. Herein, we analyze the efficacy of apremilast, an oral phosphodiesterase 4 (PDE-4) inhibitor, in the treatment of nail and scalp psoriasis at 16-, 32-, and 52 weeks. METHODS: We reviewed the results of the phase IIb and phase III clinical trials for apremilast in treating nail and scalp psoriasis. RESULTS: In ESTEEM 1, patients on apremilast showed a 22.5%, 43.6%, and 60.2% improvement in NAPSI at weeks 16, 32, and 52. 33.3%, 45.2%, and 63% of patients achieved NAPSI 50, respectively. In ESTEEM 2, patients on apremilast showed a 29%, 60%, and 59.7% improvement in NAPSI at weeks 16, 32, and 52, with 44.6%, 55.4%, and 68.6% of patients achieving NAPSI-50. In PSOR-005 at week 16, patients on a dose of 30 mg twice weekly had a 42.9% improvement in NAPSI with 45.5% reaching NAPSI-50. For scalp psoriasis, 46.5%, 37.4%, and 73% of patients achieved an Sc-PGA of 0 or 1 at weeks 16, 32, and 52 in ESTEEM 1. In ESTEEM 2, 40.9%, 32.4%, and 62.5% of patients achieved an Sc-PGA of 0 or 1 at weeks 16, 32, and 52. CONCLUSION: With its limited safety profile of only diarrhea and headache and no additional lab requirements, apremilast may be a safer and more convenient alternative for patients with severe nail and scalp psoriasis. PMID- 26954313 TI - Efficacy and Safety of Imiquimod 3.75% from Lmax in Actinic Keratosis According to Fitzpatrick Skin Type. AB - BACKGROUND: Imiquimod 3.75% is an effective actinic keratosis (AK) treatment that detects and clears clinical and subclinical lesions across an entire sun-exposed field such as the full face or balding scalp. OBJECTIVE: To determine the efficacy and safety of imiquimod 3.75% according to patients' Fitzpatrick skin type. METHODS: Data were pooled from two identical 14-week, double-blind studies. Patients were randomized to imiquimod 3.75% or placebo and applied study medication to the full face or balding scalp each day for 2 two-week treatment cycles separated by a two-week treatment-free interval. End of study (EOS) was eight weeks after the last treatment application. Patients were subgrouped according to whether they had Fitzpatrick skin types I or II (FST I/II), or types III or IV (FST III/IV). Efficacy was analyzed using the reduction in lesions from Lmax (maximum lesion count during treatment) to EOS. This assesses whether clinical lesions, and subclinical lesions which become detectable during treatment, are cleared. Safety was assessed by monitoring local skin reactions. RESULTS: In total, 173 patients with FST I/II and 142 with FST III/IV were included. The median percentage reductions in lesions from Lmax to EOS were similar in patients treated with imiquimod 3.75% with FST I/II and FST III/IV (94.2% and 89.7%, respectively) as were the median absolute reductions in lesions from Lmax to EOS (19.0 and 17.0, respectively). These reductions were significantly greater with imiquimod 3.75% versus placebo in the two respective FST subgroups (P<0.0001). The frequency of local skin reactions was similar in the two imiquimod 3.75% FST subgroups. CONCLUSIONS: Imiquimod 3.75% is well tolerated and effective at clearing clinical and subclinical lesions across large areas of sun-exposed skin in patients with FST I-IV, and so can be considered for AK patients with any of these skin types. PMID- 26954312 TI - Onychomycosis: Strategies to Minimize Recurrence. AB - Recurrence (relapse or re-infection) in onychomycosis is common, occurring in 10% to 53% of patients. However, data on prevalence is limited as few clinical studies follow patients beyond 12 months. It has been suggested that recurrence after continuous terbinafine treatment may be less common than with intermittent or continuous itraconazole therapy, probably due to the fungicidal activity of terbinafine, although these differences tended not to be significant. Relapse rates also increase with time, peaking at month 36. Although a number of factors have been suggested to play a role in recurrence, only the co-existence of diabetes has been shown to have a significant impact. Data with topical therapy is sparse; a small study showed amorolfine prophylaxis may delay recurrence. High concentrations of efinaconazole have been reported in the nail two weeks' post treatment suggesting twice monthly prophylaxis with topical treatments may be a realistic option, and may be an important consideration in diabetic patients with onychomycosis. Data suggest that prophylaxis may need to be continued for up to three years for optimal effect. Treating tinea pedis and any immediate family members is also critical. Other preventative strategies include avoiding communal areas where infection can spread (such as swimming pools), and decontaminating footwear. PMID- 26954314 TI - Comparison of Guidelines for the Use of Cyclosporine for Psoriasis: A Critical Appraisal and Comprehensive Review. AB - There are several well-established guidelines for the treatment of psoriasis. Guidelines have been proposed in the United States by the American Academy of Dermatology (AAD), in Europe by the European S3, in the United Kingdom by the National Institute for Health and Care Excellence (NICE), and in Canada by the Canadian Dermatology Association. These guidelines are predominantly evidence based, supported by expert panel consensus where evidence is lacking. Cyclosporine, a potent calcineurin inhibitor that acts selectively on T-cells, revolutionized the world of immunosuppression upon its discovery in 1970. Since its approval in 1997 by the U.S. Food and Drug Administration for the treatment of psoriasis, cyclosporine has been used with great efficacy in the treatment of not only psoriasis but also a wide consortium of dermatological diseases. However, in the past decade or so, many dermatologists have become increasingly hesitant to use this important drug because of its potent toxicity profile. The purpose of this article is to review and compare the current evidence-based guideline recommendations for the use of cyclosporine in the treatment of psoriasis. Although the various guidelines are similar in their initial treatment recommendations, significant differences exist in recommendations on maximal treatment duration (1 year versus 2 years), intermittent short-term versus continuous therapy, use in erythrodermic and palmoplantar psoriasis, as well as recommendations on managing cyclosporine-associated side effects. By following guideline recommendations, cyclosporine remains an excellent and indispensable tool for the dermatologist treating moderate-to-severe psoriasis. PMID- 26954315 TI - Costs of Common Psoriasis Medications, 2010-2014. AB - BACKGROUND: Costs for psoriasis have increased in recent years, in part due to the introduction of biologic agents. OBJECTIVE: To identify the most common and most costly (from the payer perspective) drugs used in the treatment of psoriasis. METHODS: We analyzed patient data from a large claims-based database in order to identify the most common and most costly medications used in the treatment of psoriasis from 2010 to 2014. RESULTS: The three most common psoriasis medications, accounting for 81.1% of all psoriasis medications, were topical corticosteroids. The three most costly drugs, accounting for only 9.6% of all psoriasis medications, were biologics, accounting for 86% of the cost of psoriasis medications. CONCLUSIONS: Biologic agents are used far less commonly in the treatment of psoriasis than topical treatments. Despite the relatively small number of patients using biologic agents, biologics are responsible for a large proportion of the cost of psoriasis pharmacotherapy. PMID- 26954316 TI - Anti-IL-17 Agents for Psoriasis: A Review of Phase III Data. AB - BACKGROUND: Studies investigating the molecular basis of psoriasis have established the central roles of TNFa, interleukin (IL)-12, IL-22 and IL-23, and now there is increasing evidence that IL-17 plays a vital role in the complex pathophysiology of this disease. Preclinical and phase II studies of medications targeting IL-17 and its receptor have thus far proved to be promising. METHODS: We reviewed the results of the phase III clinical trials for the anti-IL-17 agents secukinumab, ixekizumab and brodalumab in order to assess the efficacy and safety profile of each agent. RESULTS: By week 12, the proportion of patients reaching a 75% improvement from baseline Psoriasis Area and Severity Index (PASI 75) was comparable between the different agents (secukinumab 83%, ixekizumab 89%, and brodalumab 85%). The safety profiles of the agents were similar with the most frequently reported adverse events of nasopharyngitis, upper respiratory infections, headache, and injection site reaction. CONCLUSION: The anti-IL-17 agents demonstrated a rapid and robust clinical improvement accompanied by a favorable short-term safety profile. The results of the phase III trials continue to reinforce the theory that the IL-17 pathway is an essential target in psoriasis treatment. PMID- 26954317 TI - A Review of Indigo Naturalis as an Alternative Treatment for Nail Psoriasis. AB - INTRODUCTION: Nail psoriasis is challenging to treat. The few currently available therapies are limited in efficacy, and often produce unfavorable side effects. A plant extract widely used in Traditional Chinese Medicine, indigo naturalis (Qing Dai), is presented in this review as an alternative topical treatment for skin and nail psoriasis. The purpose of this article is to present information on a viable alternative treatment with a favorable side effect profile for a difficult disease to treat. METHODS: A PubMed search for the term "indigo naturalis" was performed, and literature from 2006 to the present relevant to indigo naturalis and treatment of psoriasis and nail psoriasis was reviewed. RESULTS: Indigo naturalis shares several therapeutic mechanisms with current psoriasis treatments, such as regulation of keratinocyte proliferation and differentiation, restoration of epidermal barrier function, and reduction of inflammatory processes. Clinically, it is well tolerated. CONCLUSION: Recent research of indigo naturalis suggests that it is a safe, inexpensive, and effective alternative topical treatment for skin and nail psoriasis. PMID- 26954318 TI - Over 25 Years of Clinical Experience With Ivermectin: An Overview of Safety for an Increasing Number of Indications. AB - Although the broad-spectrum anti-parasitic effects of the avermectin derivative ivermectin are well documented, its anti-inflammatory activity has only recently been demonstrated. For over 25 years, ivermectin has been used to treat parasitic infections in mammals, with a good safety profile that may be attributed to its high affinity to invertebrate neuronal ion channels and its inability to cross the blood-brain barrier in humans and other mammals. Numerous studies report low rates of adverse events, as an oral treatment for parasitic infections, scabies and head lice. Ivermectin has been used off-label to treat diseases associated with Demodex mites, such as blepharitis and demodicidosis. New evidence has linked Demodex mites to rosacea, a chronic inflammatory disease. Ivermectin has recently received FDA and EU approval for the treatment of adult patients with inflammatory lesions of rosacea, a disease in which this agent has been shown to be well tolerated. After more than 25 years of use, ivermectin continues to provide a high margin of safety for a growing number of indications based on its anti-parasitic and anti-inflammatory activities. PMID- 26954319 TI - Improvement in Extensive Moderate Plaque Psoriasis With a Novel Emollient Spray Formulation of Betamethasone Dipropionate 0.05. AB - BACKGROUND: A novel formulation of 0.05% betamethasone dipropionate in an emollient spray vehicle (DFD-01) was developed to deliver steroid to the skin layers most affected by psoriasis. OBJECTIVE: To compare the efficacy and safety of DFD-01 to its vehicle for the treatment of moderate plaque psoriasis over 4 weeks. METHODS: Two Phase 3 trials enrolled adults with moderate psoriasis (Investigator Global Assessment [IGA]=3; 10-20% body surface area [BSA]) and randomized them 2:1 to DFD-01 or Vehicle. Products were applied twice daily to affected areas for 28 days. Treatment success was defined as an IGA=0 or 1 and >= 2-grade improvement from baseline. Primary endpoint was the proportion of subjects achieving treatment success at day 15. RESULTS: Moderate psoriasis subjects were enrolled in Study 1 (174 DFD-01; 87 Vehicle) and Study 2 (182 DFD 01; 95 Vehicle). Mean BSA was 13-14%. Treatment success was achieved in significantly more subjects using DFD-01 than Vehicle at day 15 in both Study 1 (P<0.001) and Study 2 (P=0.002), and at day 29 (both studies P<0.001). Treatment success with DFD-01 was significant at day 8 in Study 1 (P=0.003) but not in Study 2 (P=0.156). Erythema, scaling, and plaque elevation scores of target lesions were significantly reduced as early as day 4 with DFD-01. Adverse events were similar between groups, with no increase between 2 and 4 weeks. CONCLUSION: These studies demonstrate DFD-01's excellent efficacy and safety for the treatment of extensive psoriasis (10-20% BSA). DFD-01 achieved treatment success in significantly more subjects than Vehicle after 2 and 4 weeks of treatment, and showed early onset of action with improved signs of erythema, scaling and elevation of target lesions after 4 days of treatment. This medium potency formulation provides a safe and effective choice for topical steroid treatment of psoriasis. PMID- 26954320 TI - Effectiveness of Subcutaneous Methotrexate in Chronic Plaque Psoriasis. AB - BACKGROUND: Oral methotrexate (MTX) has been a first line systemic agent in the treatment of chronic plaque psoriasis (CPP) for more than 50 years. Parenteral MTX, administered as a subcutaneous (SC) injection has gained favour in recent years. The effectiveness of SC MTX has been proven in rheumatological conditions but there has been no assessment of its role in CPP. METHODS: We retrospectively reviewed case notes of 85 patients prescribed SC MTX for psoriasis in three dermatology centres in the UK (Betsi Cadwaladr University Health Board, Western Infirmary, Glasgow, and Salford Royal NHS Foundation Trust). Audit department approval was sought and granted. RESULTS: A total of 85 patients (44 male; 41 female; age range 14 - 78 years, mean 44 years; 79 Caucasian, 6 Asian) with CPP were identified. The average duration of psoriasis was 19 years [range 3 - 60 years]. Co-morbidities included depression, diabetes mellitus, hypertension, epilepsy, obesity, ischaemic heart disease, and hyperlipidaemia; 29 patients had no associated co-morbidities. Psoriatic arthritis was noted in 18 patients. Previous treatments included phototherapy (both narrow band ultraviolet B [TLO1] and psoralen and ultraviolet A [PUVA])(n=60), oral MTX (n=82), ciclosporin (n=37), acitretin (n=19), fumaric acid esters (n=20), hydroxycarbamide (n=6), mycophenolate mofetil (n=2), and repeated in-patient admissions (n=2). Oral MTX was stopped due to nausea (n=43), ineffectiveness (n=13) or partial response (n=11), headache (n=3), increased liver enzymes (n=2), and lethargy (n=2). The median number of systemic agents used prior to SC MTX was 3 (mean 2.65, range 1 to 6 agents). The weekly dose of SC MTX varied between 7.5mg to 30 mg (mean 18.5mg, median 20mg) and had been used for 2 months to 67 months (mean 14 months; median 9 months). Folic acid supplementation was used in every patient. The patients were reviewed between 6 weeks to 3 months once treatment was fully established. Using a pre-determined "adjective list" (where specific adjectives were used to denote those who responded or did not respond to treatment), patients were classified as "responders" (n=59) or "non-responders" (n=26). CONCLUSION: This study suggests that SC MTX is an effective option in patients with CPP who have failed oral MTX and could be a worthwhile consideration prior to commencement of a biologic agent. Furthermore, the SC route may be a viable first choice of MTX administration. A randomised controlled trial comparing oral and SC MTX is required to validate these findings. PMID- 26954321 TI - Treatment of Imiquimod Resistant Epidermodysplasia Verruciformis With Ingenol Mebutate. AB - BACKGROUND: Epidermodysplasia verruciformis (EV) is a rare genetic disorder characterized by widespread human papillomavirus (HPV) associated lesions and an increase susceptibility to cutaneous malignancies. A host of medications traditionally used to treat warty lesions have been used with variable results and limited success. To our knowledge, we describe the first reported case of a patient with Imiquimod resistant EV successfully treated with topical ingenol mebutate (Picato). CASE: A patient with a 5 year history of EV failed to respond to a 6 week course of 5% imiquimod on the forehead and was subsequently treated with a 3 day course of 0.015% Picato gel which resulted in significant clinical improvement. A one month follow-up examination showed no reoccurrence of the lesions with the patient reporting continued satisfaction of the outcome. CONCLUSION: Our case provides insight into the potential use of ingenol mebutate for EV patients unresponsive to traditional medical treatments. PMID- 26954322 TI - Percutaneous Selective Neuromodulation via Monopolar Radiofrequency for Glabellar Lines: A Case Study. AB - INTRODUCTION: Injectable botulinum toxin is a safe, effective, and popular therapy that blocks neural impulses to achieve a desired effect. Using monopolar RF, percutaneous selective neuromodulation can achieve a similar but more persistent effect. METHODS: Bilateral treatment was performed on a woman (48 years of age) to ablate the angular nerves of the face, inhibiting muscular function and reduce the appearance of glabellar lines. The cannula was inserted at the mid-pupillary line and advanced toward the lateral border of the nose. After isolating the nerve via low-level stimulation, anesthetic was given through a port in the cannula and energy was applied; tissue temperature of 85 degrees C was maintained for 70 seconds. RESULTS: Full ablative lesioning of the angular nerve of the patient was achieved and function was therapeutically inhibited with minimal pain. Results have persisted for more than two years. PMID- 26954323 TI - Severe Small-Vessel Vasculitis Temporally Associated With Administration of Ustekinumab. AB - Vasculitis may be caused by infection, medications, systemic diseases, malignancy, or occur as an idiopathic condition. In cases of drug-induced vasculitis, it is essential to identify and discontinue the culprit medication. As novel agents are approved through clinical trials, some rare events, including vasculitis, may not become apparent until wider use, and rigorous post-marketing surveillance for new medications is important. Physicians should consider drug induced vasculitis on the differential for all new vasculitis diagnoses, and if the potential triggering medication is a novel medication, it is essential to rigorously investigate the potential for emerging cases of medication-associated vasculitis in all available scientific literature. PMID- 26954325 TI - Trans-Pacific Partnership Provisions in Intellectual Property, Transparency, and Investment Chapters Threaten Access to Medicines in the US and Elsewhere. AB - Brook Baker describes the potential harms to global health from the Trans Pacific Partnership Agreement and its failure to balance the interests of patients and the public with those of industry. PMID- 26954326 TI - Folding of ortho-Phenylenes. AB - In nature, the folding of oligomers and polymers is used to generate complex three-dimensional structures, yielding macromolecules with diverse functions in catalysis, recognition, transport, and charge- and energy-transfer. Over the past 20-30 years, chemists have sought to replicate this strategy by developing new foldamers: oligomers that fold into well-defined secondary structures in solution. A wide array of abiotic foldamers have been developed, ranging from non natural peptides to aromatics. The ortho-phenylenes represent a recent addition to the family of aromatic foldamers. Despite their structural simplicity (chains of benzenes connected at the ortho positions), it was not until 2010 that systematic studies of o-phenylenes showed that they reliably fold into helices in solution (and in the solid state). This conformational behavior is of fundamental interest: o-Arylene and o-heteroarylene structures are found embedded within many other systems, part of an emerging interest in sterically congested polyphenylenes. Further, o-phenylenes are increasingly straightforward to synthesize because of continuing developments in arene-arene coupling, the Asao Yamamoto benzannulation, and benzyne polymerization. In this Account, we discuss the folding of o-phenylenes with emphasis on features that make them unique among aromatic foldamers. Interconversion between their different backbone conformers is slow on the NMR time scale around room temperature. The (1)H NMR spectra of oligomers can therefore be deconvoluted to give sets of chemical shifts for different folding states. The chemical shifts are both highly sensitive to conformation and readily predicted using ab initio methods, affording critical information about the conformational distribution. The picture that emerges is that o-phenylenes fold into helices with offset stacking between every third repeat unit. In general, misfolding occurs primarily at the oligomer termini (i.e., "frayed ends"). Because of their structural simplicity, the folding can be described by straightforward models. The overall population can be divided into two enantiomeric pools, with racemization and misfolding as two distinct processes. Examination of substituent effects on folding reveals that the determinant of the relative stability of different conformers is (offset) aromatic stacking interactions parallel to the helical axis. That is, the folding of o-phenylenes is analogous to that of alpha-helices, with aromatic stacking in place of hydrogen bonding. The folding propensity can be tuned using well-known substituent effects on aromatic stacking, with moderate electron-withdrawing substituents giving nearly perfect folding. The combination of a simple folding mechanism and readily characterized conformational populations makes o-phenylenes attractive structural motifs for incorporation into more-complex architectures, an important part of the next phase of foldamer research. PMID- 26954324 TI - Rapid, Structure-Based Exploration of Pipecolic Acid Amides as Novel Selective Antagonists of the FK506-Binding Protein 51. AB - The FK506-binding protein 51 (FKBP51) is a key regulator of stress hormone receptors and an established risk factor for stress-related disorders. Drug development for FKBP51 has been impaired by the structurally similar but functionally opposing homologue FKBP52. High selectivity between FKBP51 and FKBP52 can be achieved by ligands that stabilize a recently discovered FKBP51 favoring conformation. However, drug-like parameters for these ligands remained unfavorable. In the present study, we replaced the potentially labile pipecolic ester group of previous FKBP51 ligands by various low molecular weight amides. This resulted in the first series of pipecolic acid amides, which had much lower molecular weights without affecting FKBP51 selectivity. We discovered a geminally substituted cyclopentyl amide as a preferred FKBP51-binding motif and elucidated its binding mode to provide a new lead structure for future drug optimization. PMID- 26954327 TI - Vibrationally resolved optical spectra and ultrafast electronic relaxation dynamics of diamantane. AB - We present theoretical simulations of the vibrationally resolved photoabsorption and photoemission spectra of diamantane combined with nonadiabatic dynamics simulations in order to identify the state responsible for the measured photoluminescence of diamantane and to determine the mechanism and the time scales of the electronic state relaxation. Diamantane is a prototype representative of the diamondoid class of hydrocarbons which have recently gained significant interest due to their unique electronic properties. This molecule is characterised by an almost dark first excited state, which therefore cannot be directly excited. Moreover, the calculated vertical transition from the geometrically relaxed first excited state to the ground state also bears no intensity. However, recent experiments suggest that the observed photoluminescence originates from the lowest excited state. We have performed spectral simulations in the frame of the Herzberg-Teller approximation for vibronic transitions, which goes beyond the Franck-Condon approximation of constant transition dipole moments and takes into account their linear dependence on the geometrical deformations. In this way, the available experimental spectrum could be fully reproduced, resolving the issue about the origin of the photoluminescence. Moreover, the photoemission from the first excited state also implies that ultrafast nonradiative processes have to take place after the initial excitation of the bright electronic states. We have determined the mechanism and time-scales of these relaxation processes by performing nonadiabatic dynamics simulations in the manifold of s- and p-type Rydberg excited states. The simulations demonstrate that the lowest excited electronic state of diamantane gains significant population from higher-lying states already after several hundreds of femtoseconds. Thus, our dynamics simulations combined with spectra calculated using the Herzberg-Teller approximation allow us to fully explain the observed photoabsorption and photoemission properties of diamantane. PMID- 26954328 TI - CT and MR imaging of thyroid carcinoma showing thymus-like differentiation (CASTLE): a report of ten cases. AB - OBJECTIVE: To study the CT and MR imaging features of carcinoma showing thymus like differentiation (CASTLE) and to raise awareness of this rare thyroid tumour. METHODS: The imaging appearances of 10 CASTLE tumours confirmed by surgical pathology were retrospectively reviewed and correlated with clinical and histological findings. RESULTS: Seven patients with newly diagnosed and three patients with recurrent tumours were identified (six males and four females). CASTLE tumours were commonly located in the lower neck between the inferior pole of the thyroid and the upper mediastinum. The average tumour size was 4.2 cm (range: 2.5-6 cm). On plain CT scans, most tumours were ill-defined nodular masses of uniform density. After enhancement, most cases showed mild enhancement, while heterogeneous enhancement could be seen in more than half the cases. On the MR images, tumours presented with homogeneous isointensity on T1 weighted images and they appeared to be slightly hyperintense on T2 weighted images. On post contrast images, marked enhancement was seen in two patients, and heterogeneous enhancement was seen in three cases. Aggressive local infringements mainly included the ipsilateral strap muscle, tracheoesophageal groove area and tracheal wall. The specimens stained positively for CD5 and CD117, indicating thymic differentiation. CONCLUSION: CASTLE has no characteristic imaging features when compared with other thyroid nodules, except for its unique location in the lower neck between the inferior pole of the thyroid and the upper mediastinum. CD5- and CD117-specific immunoreactivity is useful for diagnosis. ADVANCES IN KNOWLEDGE: We reported 10 cases of CT and MR images illustrating the features of CASTLE, and we raised the level of awareness of this rare malignant thyroid tumour. PMID- 26954330 TI - Prostate cancer: Proton therapy delays progression. PMID- 26954329 TI - A comparison of two post-processing analysis methods to quantify cerebral metabolites measured via proton magnetic resonance spectroscopy in HIV disease. AB - OBJECTIVE: Non-invasive biomarkers to monitor cerebral function in treated human immunodeficiency virus (HIV) disease are required. Cerebral metabolite ratios (CMRs) measured by proton-MR spectroscopy ((1)H-MRS) are a potential biomarker. Here, we compare two post-processing software packages to quantify CMRs. METHODS: Cerebral (1)H-MRS data from 11 HIV-positive subjects before and after antiretroviral therapy intensification with maraviroc were quantified using a java-based version of the MR user interface package (jMRUI) and the totally automatic robust quantitation in nuclear MR (TARQUIN). (1)H-MRS data included N acetylaspartate (NAA), creatine (Cr), choline (Cho) and myo-inositol (mI) from three cerebral locations. Differences in quantification and clinical associations of CMRs measured by the two packages were evaluated. RESULTS: Mean CMRs were generally lower when measured by TARQUIN than by jMRUI (NAA/Cr, Cho/Cr, mI/Cr ratios of 1.78, 0.83, 0.81 for jMRUI, and 1.27, 0.25, 0.81 for TARQUIN). Longitudinal changes were observed in CMRs in the basal ganglia voxel although these changes were not statistically significant [+7.1% (p = 0.18), +0.0% (p = 0.91) and -6.6% (p = 0.61) and +14.8% (p = 0.18), +17.9% (p = 0.07) and +34.8% (p = 0.17) for NAA/Cr, Cho/Cr and mI/Cr ratios measured by TARQUIN and jMRUI, respectively]. Plasma maraviroc concentration was associated with a decrease in mI/Cr ratio measured via TARQUIN (p = 0.049). CONCLUSION: Although CMRs differed when quantified by jMRUI vs TARQUIN, these differences were consistently observed across three cerebral locations, and clinical associations were evident by both methods. ADVANCES IN KNOWLEDGE: TARQUIN and jMRUI are viable options to use in the post-processing of cerebral MRS data acquired in HIV disease. PMID- 26954331 TI - Penile cancer: Ongoing search for molecular prognostic markers. PMID- 26954339 TI - Synthesis of Isoxazoline/Cyclic Nitrone-Featured Methylenes Using Unsaturated Ketoximes: A Dual Role of TEMPO. AB - A novel, metal-free, and regioselective approach for the synthesis of isoxazoline/cyclic nitrone-featured methylenes has been developed by the reaction of readily accessible beta,gamma- and gamma,delta-unsaturated ketoximes with TEMPO via tandem iminoxyl radical-promoted cyclization/TEMPO-mediated Cope-like elimination, respectively. This protocol utilizes commercially available TEMPO as the iminoxyl radical initiator as well as the beta-hydrogen acceptor in the Cope like elimination. PMID- 26954334 TI - Fast Interconversion of Hydrogen Bonding at the Hematite (001)-Liquid Water Interface. AB - The interface between transition-metal oxides and aqueous solutions plays an important role in biogeochemistry and photoelectrochemistry, but the atomistic structure is often elusive. Here we report on the surface geometry, solvation structure, and thermal fluctuations of the hydrogen bonding network at the hematite (001)-water interface as obtained from hybrid density functional theory based molecular dynamics. We find that the protons terminating the surface form binary patterns by either pointing in-plane or out-of-plane. The patterns exist for about 1 ps and spontaneously interconvert in an ultrafast, solvent-driven process within 50 fs. This results in only about half of the terminating protons pointing toward the solvent and being acidic. The lifetimes of all hydrogen bonds formed at the interface are shorter than those in pure liquid water. The solvation structure reported herein forms the basis for a better fundamental understanding of electron transfer coupled to proton transfer reactions at this important interface. PMID- 26954340 TI - Characteristics and Public Availability of Results of Clinical Trials on Rare Diseases Registered at Clinicaltrials.gov. PMID- 26954333 TI - Enhancing active surveillance of prostate cancer: the potential of exercise medicine. AB - Active surveillance (AS) is a strategy for the management of patients with low risk, localized prostate cancer, in which men undergo regular monitoring of serum PSA levels and tumour characteristics, using multiparametric MRI and repeat biopsy sampling, to identify signs of disease progression. This strategy reduces overtreatment of clinically insignificant disease while also preserving opportunities for curative therapy in patients whose disease progresses. Preliminary studies of lifestyle interventions involving basic exercise advice have indicated that exercise reduces the numbers of patients undergoing active treatment, as well as modulating the biological processes involved in tumour progression. Therefore, preliminary evidence suggests that lifestyle and/or exercise interventions might have therapeutic potential in this growing population of men with prostate cancer. However, several important issues remain unclear: the exact value of different types of lifestyle and exercise medicine interventions during AS; the biological mechanisms of exercise in delaying disease progression; and the influence of the anxieties and distress created by having a diagnosis of cancer without then receiving active treatment. Future studies are required to confirm and expand these findings and determine the relative contributions of each lifestyle component to specific end points and patient outcomes during AS. PMID- 26954332 TI - Active surveillance for prostate cancer: current evidence and contemporary state of practice. AB - Prostate cancer remains one of the most commonly diagnosed malignancies worldwide. Early diagnosis and curative treatment seem to improve survival in men with unfavourable-risk cancers, but significant concerns exist regarding the overdiagnosis and overtreatment of men with lower-risk cancers. To this end, active surveillance (AS) has emerged as a primary management strategy in men with favourable-risk disease, and contemporary data suggest that use of AS has increased worldwide. Although published surveillance cohorts differ by protocol, reported rates of metastatic disease and prostate-cancer-specific mortality are exceedingly low in the intermediate term (5-10 years). Such outcomes seem to be closely associated with programme-specific criteria for selection, monitoring, and intervention, suggesting that AS--like other management strategies--could be individualized based on the level of risk acceptable to patients in light of their personal preferences. Additional data are needed to better establish the risks associated with AS and to identify patient-specific characteristics that could modify prognosis. PMID- 26954341 TI - Photoinduced Electron Transfer in an Anthraquinone-[Ru(bpy)3](2+) Oligotriarylamine-[Ru(bpy)3](2+)-Anthraquinone Pentad. AB - A molecular pentad comprised of a central multielectron donor and two flanking photosensitizer-acceptor moieties was prepared in order to explore the possibility of accumulating two positive charges at the central donor, using visible light as an energy input. Photoinduced charge accumulation in purely molecular systems without sacrificial reagents is challenging, because of the multitude of energy-wasting reaction pathways that are accessible after excitation with two photons. As expected, the main photoproduct in our pentad is a simple electron-hole pair, and it is tricky to identify the desired two electron oxidation product on top of the stronger signal resulting from one electron oxidation. PMID- 26954342 TI - Cyclosporin A significantly improves preeclampsia signs and suppresses inflammation in a rat model. AB - Preeclampsia is associated with an increased inflammatory response. Immune suppression might be an effective treatment. The aim of this study was to examine whether Cyclosporin A (CsA), an immunosuppressant, improves clinical characteristics of preeclampsia and suppresses inflammation in a lipopolysaccharide (LPS) induced preeclampsia rat model. Pregnant rats were randomly divided into 4 groups: group 1 (PE) rats each received LPS via tail vein on gestational day (GD) 14; group 2 (PE+CsA5) rats were pretreated with LPS (1.0 MUg/kg) on GD 14 and were then treated with CsA (5mg/kg, ip) on GDs 16, 17 and 18; group 3 (PE+CsA10) rats were pretreated with LPS (1.0 MUg/kg) on GD 14 and were then treated with CsA (10mg/kg, ip) on GDs 16, 17 and 18; group 4 (pregnant control, PC) rats were treated with the vehicle (saline) used for groups 1, 2 and 3. Systolic blood pressure, urinary albumin, biometric parameters and the levels of serum cytokines were measured on day 20. CsA treatment significantly reduced LPS-induced systolic blood pressure and the mean 24-h urinary albumin excretion. Pro-inflammatory cytokines IL-6, IL-17, IFN-gamma and TNF-alpha were increased in the LPS treatment group but were reduced in (LPS+CsA) group (P<0.05). Anti inflammatory cytokine IL-4 was decreased in the LPS group but was increased in (LPS+CsA) group (P<0.05). Cyclosporine A improved preeclampsia signs and attenuated inflammatory responses in the LPS induced preeclampsia rat model which suggests that immunosuppressant might be an alternative management option for preeclampsia. PMID- 26954344 TI - Single-Nucleotide Polymorphisms of IL-17 Gene Are Associated with Asthma Susceptibility in an Asian Population. AB - BACKGROUND: The aim of this study was to examine the associations between the single-nucleotide polymorphisms (SNPs) of interleukin-17 (IL-17), including rs763780 (7488A/G), rs2275913 (-197G/A), and rs8193036 (-737C/T), and asthma susceptibility in an Asian population. MATERIAL/METHODS: From Oct 2013 to Dec 2014, 125 asthma patients enrolled in our hospital were selected as the case group. Another 132 healthy controls undergoing physical examinations in our hospital were enrolled as the control group. The genotype frequencies of IL-17 rs763780, rs2275913 and rs8193036 SNPs were detected using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Comprehensive Meta analysis 2.0 (CMA 2.0) software was applied for meta-analysis. RESULTS: Our results demonstrated that asthma patients presented with higher frequencies of GA genotype in rs2275913 and TT genotype in rs8193036 of IL-17 than healthy controls (both P<0.001). The genotype frequencies of IL-17 rs763780 between the asthma patients and healthy controls exhibited no significant differences (P>0.05). The comparisons on the rs2275913 and rs8193036 frequencies between the asthma patients and healthy controls were statistically significant in both allele and addictive models (all P<0.05). The frequency of IL-17 rs763780 between the asthma patients and healthy controls were statistically different in allele models (P<0.05), but not in addictive models (P>0.05). The overall results of our case control study were further confirmed by meta-analysis. CONCLUSIONS: Our results revealed that, in an Asian population, IL-17 rs763780, rs2275913, and rs8193036 SNPs may be associated with asthma susceptibility, and GA genotype in rs2275913 and TT genotype in rs8193036 of IL-17 may contribute to increased risk of asthma in Asians. PMID- 26954345 TI - Exploring effectiveness and effective components of self-management interventions for young people with chronic physical conditions: A systematic review. AB - OBJECTIVE: To systematically explore the effectiveness and effective components of self-management interventions. METHODS: Study selection criteria were: Original articles in English published between 2003 and 2015; focusing on youth with chronic conditions; describing self-management interventions; with clear outcome measures; using RCT design. The random effects analysis was applied in which standardized mean differences per study were calculated. RESULTS: 42 RCTs were included. Interventions focused on medical management, provided individually in clinical settings or at home by mono-disciplinary teams showed a trend in improving adherence. Interventions delivered individually at home by mono disciplinary teams showed a trend in improving dealing with a chronic condition. CONCLUSIONS AND PRACTICAL IMPLICATIONS: Adherence could be improved through interventions focused on medical management, provided individually in a clinical or home setting by a mono-disciplinary team. Interventions focused on dealing with a chronic condition might be provided individually, through telemedicine programs facilitating peer-support. These intervention elements seemed effective irrespective of diagnosis, and may therefore act as good starting points for further research into and for improvement of self-management support for youth with chronic conditions in pediatric care. Results underlined the need to systematically develop and evaluate self-management interventions, since this may provide more evidence for effectiveness and effective intervention components. PMID- 26954343 TI - High Mobility Group-Box 1 (HMGB1) levels are increased in amniotic fluid of women with intra-amniotic inflammation-determined preterm birth, and the source may be the damaged fetal membranes. AB - BACKGROUND: High Mobility Group Box-1 (HMGB1) is considered a prototype alarmin molecule. Upon its extracellular release, HMGB1 engages pattern recognition receptors and the Receptor for Advanced Glycation End-products (RAGE) followed by an outpouring of inflammatory cytokines, including interleukin (IL)-6. METHODS: We assayed the amniotic fluid (AF) levels of HMGB1 and IL-6 in 255 women that either had a normal pregnancy outcome or delivered preterm. Immunohistochemistry on fetal membranes was used for cellular localization and validation of immunoassay findings. HMGB1 also was analyzed in amniochorion tissue explants subjected to endotoxin. RESULTS: AF HMGB1 levels are not gestational age regulated but are increased in women with intra-amniotic inflammation and preterm birth. The likely source is the damaged amniochorion, as demonstrated by immunohistochemistry and explant experiments. CONCLUSIONS: Our research supports a role for HMGB1 in the inflammatory response leading to preterm birth. As a delayed phase cytokine, in utero exposure to elevated AF HMGB1 levels may have an impact on the newborn beyond the time of birth. PMID- 26954346 TI - Slow-Equilibration Approximation in Kinetic Size Exclusion Chromatography. AB - Kinetic size exclusion chromatography with mass spectrometry detection (KSEC-MS) is a solution-based label-free approach for studying kinetics of reversible binding of a small molecule to a protein. Extraction of kinetic data from KSEC-MS chromatograms is greatly complicated by the lack of separation between the protein and protein-small molecule complex. As a result, a sophisticated time consuming numerical approach was used for the determination of rate constants in the proof-of-principle works on KSEC-MS. Here, we suggest the first non-numerical (analytical) approach for finding rate constants of protein-small molecule interaction from KSEC-MS data. The approach is based on the slow-equilibration approximation, which is applicable to KSEC-MS chromatograms that reveal two peaks. The analysis of errors shows that the slow-equilibration approximation guarantees that the errors in the rate constants are below 20% if the ratio between the characteristic separation and equilibration times does not exceed 0.1. The latter condition can typically be satisfied for specific interactions such as receptor-ligand or protein-drug. The suggested analytical solution equips analytical scientists with a simple and fast tool for processing KSEC-MS data. Moreover, a similar approach can be potentially developed for kinetic analysis of protein-small molecule binding by other kinetic-separation methods such as nonequilibrium capillary electrophoresis of equilibrium mixtures (NECEEM). PMID- 26954347 TI - Impact of Functional Group Modifications on Designer Phenethylamine Induced Hyperthermia. AB - The popularity of designer phenethylamines such as synthetic cathinones ("bath salts") has led to increased reports of life-threatening hyperthermia. The diversity of chemical modifications has resulted in the toxicological profile of most synthetic cathinones being mostly uncharacterized. Here, we investigated the thermogenic effects of six recently identified designer phenethylamines (4 methylmethamphetamine, methylone, mephedrone, butylone, pentylone, and MDPV) and compared these effects to the established thermogenic agent 3,4 methylenedioxymethamphetamine (MDMA). Specifically, we determined the impact of a beta-ketone, alpha-alkyl, or pyrrolidine functional group on core-body temperature changes. Sprague-Dawley rats (n = 5-6) were administered a dose (30 mg/kg, sc) of a designer phenethylamine or MDMA, and core body temperature measurements were recorded at 30 min intervals for 150 min post treatment. MDMA elicited the greatest maximum temperature change (DeltaTmax), and this effect was significantly greater than that of its beta-ketone analogue, methylone. Temperature-area under the curves (TAUCs) and DeltaTmax were also significantly different between 4-methylmethamphetamine (4-MMA) and its beta-ketone analogue mephedrone. Lengthening the alpha-alkyl chain of methylone to produce butylone and pentylone significantly attenuated the thermogenic response on both TAUCs and DeltaTmax compared to those of methylone; however, butylone and pentylone were not different from each other. Pyrrolidine substitution on the N-terminus of pentylone produces 3,4-methylenedioxypyrovalerone (MDPV), which did not significantly alter core body temperature. Thermogenic comparisons of MDMA vs methylone and 4-MMA vs mephedrone indicate that oxidation at the benzylic position significantly attenuates the hyperthermic response. Furthermore, either extending the alpha-alkyl chain to ethyl and propyl (butylone and pentylone, respectively) or extending the alpha-alkyl chain and adding a pyrrolidine on the N-terminus (MDPV) significantly blunted the thermogenic effects of methylone. Overall, the present study provides the first structure-activity relationship in vivo toxicological analysis of designer phenethylamines. PMID- 26954348 TI - Clinical Outcome of a Wide-diameter Bone-anchored Hearing Implant and a Surgical Technique With Tissue Preservation. AB - OBJECTIVE: To investigate the clinical outcome of a surgical technique with tissue preservation for a wide bone-anchored hearing implant concerning postoperative complications, skin reactions, implant loss, and implant stability. STUDY DESIGN: Consecutive, prospective case series. SETTING: Tertiary referral center. PATIENTS: Twenty-four adult patients with normal skin quality were enrolled. INTERVENTION(S): Implantation of bone-anchored implant was performed using a one-stage linear-incision technique with tissue preservation surgery. MAIN OUTCOME MEASURES(S): Skin and soft tissue reactions according to Holgers grading system. Pain and numbness measured according to visual analogue scale. Implant stability quotient values were recorded using resonance frequency analysis. Follow-up at 10 days, 6 weeks, 6 months, and 1 year after surgery. RESULTS: Primary implant stability was good and a significant increase in implant stability quotient occurred during the first 10 days and continued to be stable throughout the 1-year observation period. No implants were lost. Skin and soft tissue reactions were few, no reaction (Holger grade 0) was observed in 88% of the follow-up examinations and no grade 4 reactions occurred. Pain and numbness were minimal. CONCLUSION: The wide implant showed good stability initially and throughout the observation period. Skin and soft tissue reactions were rare and minor. No implants were lost. PMID- 26954349 TI - Cadaveric Study of an Endoscopic Keyhole Middle Fossa Craniotomy Approach to the Superior Semicircular Canal. AB - OBJECTIVE: Demonstrate that an endoscopic keyhole approach to the middle cranial fossa is technically feasible for repair of semicircular canal dehiscence. STUDY DESIGN: Cadaveric technical feasibility/methods development study. SETTING: Tertiary care military medical center. PATIENTS: Three fresh cadaveric heads (six sides). INTERVENTION(S): Endoscopic minimally invasive approach to the middle cranial fossa using the Medtronic Fusion Guidance system. MAIN OUTCOME MEASURE(S): Ability to identify the surgical landmarks of the middle cranial fossa and successfully identify and instrument the superior semicircular canal. RESULTS: In every attempt, the arcuate eminence was successfully identified under endoscopic visualization and with the assistance of surgical navigation. The superior semicircular canal was unroofed, and its location confirmed visually and with the navigation system. The opened canal was then plugged with bone wax, bone pate, and covered with fascia. The 15-mm burr hole craniotomy provided ample room for one working instrument and a 4-mm 0-degree endoscope. CONCLUSION: The endoscopic keyhole approach to superior semicircular canal dehiscence is technically feasible in a human cadaveric model. Further studies will determine 1) if this approach is possible and safe in vivo, 2) is associated with improved surgical outcomes, and 3) if surgical navigation aids in this approach. PMID- 26954350 TI - Quantitative Analysis of Psychiatric Disorders in Intractable Peripheral Vertiginous Patients: A Prospective Study. AB - OBJECTIVE: To investigate the correlation between psychological disorder and vestibular dysfunction in patients suffering from intractable peripheral vertigo. STUDY DESIGN: Prospective study. SETTING: In-patients in a university hospital. METHODS: Prospective design of 26 intractable peripheral vertiginous patients with peripheral vestibular dysfunction and 20 controls recruited from the EENT hospital. Hospital Anxiety and Depression scale, Self-rating Anxiety scale, Self rating Depression scale, Symptom Checklist-90 were used in this study. All vertigo patients received intratympanic gentamicin/dexamethasone administration or endolymphatic sac decompression. Pre- and posttreatment scores were collected and compared. All the results were statistically analyzed using Stata 8.0. t test or rank-sum test and paired-sample t test or rank-sum test were performed. RESULTS: The outcomes of Hospital Anxiety and Depression scale, Self-rating Anxiety scale, Self-rating Depression scale, Symptom Checklist-90 were significantly greater in vertiginous group than that in normal controls (p < 0.05). The pretreatment scores of these four scales were greater than the posttreatment scores in vertiginous patients, especially in Class A and B groups (p < 0.05). The scores of more scales were demonstrated to be statistically different in patients with over 5 years of the disorder and among patient in stages 1 to 3 than in stage 4 (p < 0.05). No significant difference was noted between male and female participants in all the questionnaires used (p > 0.05). CONCLUSION: Increased anxiety/depression levels were noted in peripheral vertiginous patients compared with normal controls through psychiatric questionnaires, and then a significant decrease after the effective treatment of vertigo, suggesting that vertigo attack may contribute to psychological dysfunction. The intervention seemed to be more effective in lowering anxiety/depression levels among patients in earlier stage of Meniere's disease marked by pure-tone audiometry results. PMID- 26954351 TI - The active comparator, new user study design in pharmacoepidemiology: historical foundations and contemporary application. AB - Better understanding of biases related to selective prescribing of, and adherence to, preventive treatments has led to improvements in the design and analysis of pharmacoepidemiologic studies. One influential development has been the "active comparator, new user" study design, which seeks to emulate the design of a head to-head randomized controlled trial. In this review, we first discuss biases that may affect pharmacoepidemiologic studies and describe their direction and magnitude in a variety of settings. We then present the historical foundations of the active comparator, new user study design and explain how this design conceptually mitigates biases leading to a paradigm shift in pharmacoepidemiology. We offer practical guidance on the implementation of the study design using administrative databases. Finally, we provide an empirical example in which the active comparator, new user study design addresses biases that have previously impeded pharmacoepidemiologic studies. PMID- 26954353 TI - Four Common Simplifications of Multi-Criteria Decision Analysis do not hold for River Rehabilitation. AB - River rehabilitation aims at alleviating negative effects of human impacts such as loss of biodiversity and reduction of ecosystem services. Such interventions entail difficult trade-offs between different ecological and often socio-economic objectives. Multi-Criteria Decision Analysis (MCDA) is a very suitable approach that helps assessing the current ecological state and prioritizing river rehabilitation measures in a standardized way, based on stakeholder or expert preferences. Applications of MCDA in river rehabilitation projects are often simplified, i.e. using a limited number of objectives and indicators, assuming linear value functions, aggregating individual indicator assessments additively, and/or assuming risk neutrality of experts. Here, we demonstrate an implementation of MCDA expert preference assessments to river rehabilitation and provide ample material for other applications. To test whether the above simplifications reflect common expert opinion, we carried out very detailed interviews with five river ecologists and a hydraulic engineer. We defined essential objectives and measurable quality indicators (attributes), elicited the experts' preferences for objectives on a standardized scale (value functions) and their risk attitude, and identified suitable aggregation methods. The experts recommended an extensive objectives hierarchy including between 54 and 93 essential objectives and between 37 to 61 essential attributes. For 81% of these, they defined non-linear value functions and in 76% recommended multiplicative aggregation. The experts were risk averse or risk prone (but never risk neutral), depending on the current ecological state of the river, and the experts' personal importance of objectives. We conclude that the four commonly applied simplifications clearly do not reflect the opinion of river rehabilitation experts. The optimal level of model complexity, however, remains highly case study specific depending on data and resource availability, the context, and the complexity of the decision problem. PMID- 26954354 TI - Infrared Photodissociation Spectroscopy and Density Functional Theory Study of Carbon Suboxide Complexes [M(CO)4(C3O2)](+) (M = Fe, Co, Ni). AB - Infrared photodissociation spectra are measured for mass-selected cation complexes with a chemical formula [MC7O6](+) (M = Fe, Co, Ni) formed via pulsed laser evaporation of metal target in expansions of helium gas seeded by CO. The geometries of the complexes are determined by comparison of the experimental spectra with the simulated spectra from density functional calculations. All of these complexes are identified to have [M(CO)4(C3O2)](+) structures involving a carbon suboxide ligand, which binds the metal center in an eta(1) fashion. The antisymmetric CO stretching vibration of C3O2 is slightly red-shifted upon coordination. The donor-acceptor bonding interactions between C3O2 and the metal centers are analyzed using the EDA-NOCV method. The results show that M <- C3O2 sigma donation is stronger than the M -> C3O2 pi back-donation in these cation complexes. PMID- 26954356 TI - Cancer versus FM radio polarization types. AB - In 2002, a detailed analysis of skin melanoma in 289 Swedish municipalities showed a strong association with the number of horizontally polarized main FM transmitters covering a municipality. Basic antenna theory says that body resonance and standing waves cannot appear above a metal spring mattress unless the electric field is horizontally polarized. To test the hypothesis that body resonant radiation can cause increased cancer risk in other European countries, I collected and analysed reported data from 24 countries, among which six were using vertical polarization. The results showed a strong association between cancer risk and the use of horizontally polarized FM broadcasting radiation, whereas vertical polarization seemed to cause no health effects. This information should form the basis for initiating relevant corrective actions by responsible authorities. PMID- 26954355 TI - Cigarette Smoking Is Associated with a Lower Prevalence of Newly Diagnosed Diabetes Screened by OGTT than Non-Smoking in Chinese Men with Normal Weight. AB - Different studies have produced conflicting results regarding the association between smoking and diabetes mellitus, and detailed analysis of this issue in Chinese males based on nationwide samples is lacking. We explored the association between cigarette smoking and newly-diagnosed diabetes mellitus (NDM) in Chinese males using a population-based case-control analysis; 16,286 male participants without previously diagnosed diabetes were included. Prediabetes and NDM were diagnosed using the oral glucose tolerance test. The cohort included 6,913 non smokers (42.4%), 1,479 ex-smokers (9.1%) and 7,894 current smokers (48.5%). Age adjusted glucose concentrations (mmol/L) were significantly lower at fasting and 120 min in current smokers than non-smokers (5.25 vs. 5.30, 6.46 vs. 6.55, respectively, both P < 0.01). After adjustment for demographic and behavioral variables (age, region, alcohol consumption status, physical activity, education, and family history of diabetes), logistic regression revealed significant negative associations between smoking and NDM in males of a normal weight (BMI < 25 kg/m2: adjusted odds ratio [AOR] = 0.75, P = 0.007; waist circumference < 90 cm: AOR = 0.71, P = 0.001) and males living in southern China (AOR = 0.75, P = 0.009), but not in males who were overweight/obese, males with central obesity, or males living in northern China. Compared to non-smokers, current smokers were less likely to be centrally obese or have elevated BP (AOR: 0.82 and 0.74, both P < 0.05), and heavy smokers (>= 20 pack-years) were less likely to have elevated TG (AOR = 0.84, P = 0.012) among males of a normal weight. There were no significant associations between quitting smoking and metabolic disorders either among males of a normal weight or males who were overweight/obese. In conclusion, smokers have a lower likelihood of NDM than non-smokers among Chinese males with a lower BMI/smaller waist. PMID- 26954357 TI - The Effect of Attractive Interactions and Macromolecular Crowding on Crystallins Association. AB - In living systems proteins are typically found in crowded environments where their effective interactions strongly depend on the surrounding medium. Yet, their association and dissociation needs to be robustly controlled in order to enable biological function. Uncontrolled protein aggregation often causes disease. For instance, cataract is caused by the clustering of lens proteins, i.e., crystallins, resulting in enhanced light scattering and impaired vision or blindness. To investigate the molecular origins of cataract formation and to design efficient treatments, a better understanding of crystallin association in macromolecular crowded environment is needed. Here we present a theoretical study of simple coarse grained colloidal models to characterize the general features of how the association equilibrium of proteins depends on the magnitude of intermolecular attraction. By comparing the analytic results to the available experimental data on the osmotic pressure in crystallin solutions, we identify the effective parameters regimes applicable to crystallins. Moreover, the combination of two models allows us to predict that the number of binding sites on crystallin is small, i.e. one to three per protein, which is different from previous estimates. We further observe that the crowding factor is sensitive to the size asymmetry between the reactants and crowding agents, the shape of the protein clusters, and to small variations of intermolecular attraction. Our work may provide general guidelines on how to steer the protein interactions in order to control their association. PMID- 26954358 TI - Support leg action can contribute to maximal instep soccer kick performance: an intervention study. AB - This investigation assessed whether a Technique Refinement Intervention designed to produce pronounced vertical hip displacement during the kicking stride could improve maximal instep kick performance. Nine skilled players (age 23.7 +/- 3.8 years, height 1.82 +/- 0.06 m, body mass 78.5 +/- 6.1 kg, experience 14.7 +/- 3.8 years; mean +/- SD) performed 10 kicking trials prior to (NORM) and following the intervention (INT). Ground reaction force (1000 Hz) and three-dimensional motion analysis (250 Hz) data were used to calculate lower limb kinetic and kinematic variables. Paired t-tests and statistical parametric mapping examined differences between the two kicking techniques across the entire kicking motion. Peak ball velocities (26.3 +/- 2.1 m . s-1 vs 25.1 +/- 1.5 m . s-1) and vertical displacements of the kicking leg hip joint centre (0.041 +/- 0.012 m vs 0.028 +/- 0.011 m) were significantly larger (P < 0.025) when performed following INT. Further, various significant changes in support and kicking leg dynamics contributed to a significantly faster kicking knee extension angular velocity through ball contact following INT (70-100% of total kicking motion, P < 0.003). Maximal instep kick performance was enhanced following INT, and the mechanisms presented are indicative of greater passive power flow to the kicking limb during the kicking stride. PMID- 26954360 TI - Evaluation of Boys Town In-Home Family Services with Families Referred by Child Welfare. AB - This study evaluated the Boys Town In-Home Family Services model with families referred by child welfare for issues related to maltreatment. Participants were 135 parents (mean age = 32.15 years, SD = 9.13) who completed intake and discharge assessments. The target child ranged in age from one month to 17 years (M = 4.54, SD = 4.38). We had a high-risk sample (e.g., 57% and 41% of parents reported being victims of physical and sexual abuse, respectively; 24% of parents reported attempting suicide in their lifetimes). The intervention was implemented with a degree of fidelity consistent with model standards. Reduced levels of perceived stressors were found for several domains of functioning with the largest effects observed for family safety, parental capabilities, and environmental factors. Results serve as an important step in building the evidence base of a widely disseminated intervention. PMID- 26954361 TI - An overview of pedagogy and organisation in clinical interprofessional training units in Sweden and Denmark. AB - The purpose of this study was to provide an overview of the organization and pedagogy in Swedish and Danish interprofessional training units (ITUs) and to synthesize empirical findings from Swedish and Danish ITUs published in peer review journals. A questionnaire concerning organization and pedagogy was sent to twenty Swedish and Danish ITUs. After a bibliographic search aimed to find empirical studies from ITUs, twenty Swedish and eight Danish studies were included in the review. The questionnaires results showed that despite different wording, the overall aims for the ITUs were to provide students with the possibility of uniprofessional learning, interprofessional learning, and strengthening of professional identity. Furthermore, it appeared that there were different organizational and pedagogical approaches. The review revealed that differences in clinical tutors' affiliation and presence in the ITU were challenging. Also different pedagogical approaches were discussed. However, all articles showed that the goals for the ITUs in general were fulfilled. There is basis therefore to recommend the establishment of future clinical ITUs with the patient in the core and with the use of a student activating approach. PMID- 26954359 TI - The Effect of Diet and Exercise on Intestinal Integrity and Microbial Diversity in Mice. AB - BACKGROUND: The gut microbiota is now known to play an important role contributing to inflammatory-based chronic diseases. This study examined intestinal integrity/inflammation and the gut microbial communities in sedentary and exercising mice presented with a normal or high-fat diet. METHODS: Thirty six, 6-week old C57BL/6NTac male mice were fed a normal or high-fat diet for 12 weeks and randomly assigned to exercise or sedentary groups. After 12 weeks animals were sacrificed and duodenum/ileum tissues were fixed for immunohistochemistry for occludin, E-cadherin, and cyclooxygenase-2 (COX-2). The bacterial communities were assayed in fecal samples using terminal restriction fragment length polymorphism (TRFLP) analysis and pyrosequencing of 16S rRNA gene amplicons. RESULTS: Lean sedentary (LS) mice presented normal histologic villi while obese sedentary (OS) mice had similar villi height with more than twice the width of the LS animals. Both lean (LX) and obese exercise (OX) mice duodenum and ileum were histologically normal. COX-2 expression was the greatest in the OS group, followed by LS, LX and OX. The TRFLP and pyrosequencing indicated that members of the Clostridiales order were predominant in all diet groups. Specific phylotypes were observed with exercise, including Faecalibacterium prausnitzi, Clostridium spp., and Allobaculum spp. CONCLUSION: These data suggest that exercise has a strong influence on gut integrity and host microbiome which points to the necessity for more mechanistic studies of the interactions between specific bacteria in the gut and its host. PMID- 26954363 TI - Th17 cells in neuromyelitis optica spectrum disorder: a review. AB - Neuromyelitis optica spectrum disorder (NMOSD) has been identified as a central nervous system (CNS) autoimmune inflammatory disorder, which has been recognized as a B cell-mediated humoral immune disease. However, cases have been reported indicating that some of the neuromyelitis optica (NMO) patients have been resistant to B cell-related treatments. Recently, more and more evidence has shown that T cell-mediated immunity may take part in the pathogenesis of NMOSD, especially in the Th17 phenotype. In our PUBMED search, we used the following keywords: Th17 cell, Th17 cell-related cytokines, T cells, B cells, B cell related productions, NMO, NMOSD, recurrent/bilateral optic neuritis, recurrent transverse myelitis and longitudinally extensive transverse myelitis. We systemically reviewed the role of Th17 cells and Th17 cell-related cytokines in NMOSD. We found that Th17 cells and Th17-related cytokines, such as IL-6, IL 1beta, IL-17, IL-21, IL-22, IL-23 and TGF-beta, are not only directly involved in the pathogenesis but also collaborated with B cells and B cell-related antibody production to induce CNS lesions. Th17 cell-related therapy has also been reviewed in this article, and the data suggested that Th17 may be a new therapeutic target of NMOSD. PMID- 26954362 TI - Carcinoma-Associated Fibroblasts Lead the Invasion of Salivary Gland Adenoid Cystic Carcinoma Cells by Creating an Invasive Track. AB - Carcinoma-associated fibroblasts (CAFs) are critical in determining tumor invasion and metastasis. However the role of CAFs in the invasion of salivary gland adenoid cystic carcinoma (ACC) is poorly understood. In this study, we isolated primary CAFs from two ACC patients. ACC-derived CAFs expressed typical CAF biomarkers and showed increased migration and invasion activity. Conditioned medium collected from CAFs significantly promoted ACC cell migration and invasion. Co-culture of CAFs with ACC cells in a microfluidic device further revealed that CAFs localized at the invasion front and ACC cells followed the track behind the CAFs. Interfering of both matrix metalloproteinase and CXCL12/CXCR4 pathway inhibited ACC invasion promoted by CAFs. Overall, our study demonstrates that ACC-derived CAFs exhibit the most important defining feature of CAFs by promoting cancer invasion. In addition to secretion of soluble factors, CAFs also lead ACC invasion by creating an invasive track in the ECM. PMID- 26954364 TI - Risk Factors Associated with Discordant Ki-67 Levels between Preoperative Biopsy and Postoperative Surgical Specimens in Breast Cancers. AB - PURPOSE: The Ki-67 labelling index is significant for the management of breast cancer. However, the concordance of Ki-67 expression between preoperative biopsy and postoperative surgical specimens has not been well evaluated. This study aimed to find the correlation in Ki-67 expression between biopsy and surgical specimens and to determine the clinicopathological risk factors associated with discordant values. PATIENTS AND METHODS: Ki-67 levels were immunohistochemically measured using paired biopsy and surgical specimens in 310 breast cancer patients between 2008 and 2013. DeltaKi-67 was calculated by postoperative Ki-67 minus preoperative levels. The outliers of DeltaKi-67 were defined as [lower quartile of DeltaKi-67-1.5 * interquartile range (IQR)] or (upper quartile + 1.5 * IQR) and were evaluated according to clinicopathological parameters by logistic regression analysis. RESULTS: The median preoperative and postoperative Ki-67 levels were 10 (IQR, 15) and 10 (IQR, 25), respectively. Correlation of Ki-67 levels between the two specimens indicated a moderately positive relationship (coefficient = 0.676). Of 310 patients, 44 (14.2%) showed outliers of DeltaKi-67 (range, <=-20 or >=28). A significant association with poor prognostic factors was found among these patients. Multivariate analysis determined that significant risk factors for outliers of DeltaKi-67 were tumor size >1 cm, negative progesterone receptor (PR) expression, grade III cancer, and age <=35 years. Among 171 patients with luminal human epidermal growth factor receptor 2-negative tumors, breast cancer subtype according to preoperative or postoperative Ki-67 levels discordantly changed in 46 (26.9%) patients and a significant proportion of patients with discordant cases had >=1 risk factor. CONCLUSION: Ki-67 expression showed a substantial concordance between biopsy and surgical specimens. Extremely discordant Ki-67 levels may be associated with aggressive tumor biology. In patients with luminal subtype disease, clinical application of Ki-67 values should be cautious considering types of specimens and clinicopathological risk factors. PMID- 26954366 TI - Spectral plasmonic effect in the nano-cavity of dye-doped nanosphere-based photonic crystals. AB - We demonstrated three-dimensional PMMA-based photonic crystal (3D-PC) nanostructures attached to Au nanoparticles (AuNPs), which undergo self organization into super lattice planes and enhance the fluorescence properties. This new structure exhibited interesting tunable spectral, peak broadening plasmonic behavior because of strong plasmonic interaction at high laser powers. The presented work provides an important tool to improve the efficiency of dye laser applications. PMID- 26954365 TI - The role of diseases, risk factors and symptoms in the definition of multimorbidity - a systematic review. AB - Objective is to explore how multimorbidity is defined in the scientific literature, with a focus on the roles of diseases, risk factors, and symptoms in the definitions. DESIGN: Systematic review. METHODS: MEDLINE (PubMed), Embase, and The Cochrane Library were searched for relevant publications up until October 2013. One author extracted the information. Ambiguities were resolved, and consensus reached with one co-author. Outcome measures were: cut-off point for the number of conditions included in the definitions of multimorbidity; setting; data sources; number, kind, duration, and severity of diagnoses, risk factors, and symptoms. We reviewed 163 articles. In 61 articles (37%), the cut-off point for multimorbidity was two or more conditions (diseases, risk factors, or symptoms). The most frequently used setting was the general population (68 articles, 42%), and primary care (41 articles, 25%). Sources of data were primarily self-reports (56 articles, 42%). Out of the 163 articles selected, 115 had individually constructed multimorbidity definitions, and in these articles diseases occurred in all definitions, with diabetes as the most frequent. Risk factors occurred in 98 (85%) and symptoms in 71 (62%) of the definitions. The severity of conditions was used in 26 (23%) of the definitions, but in different ways. The definition of multimorbidity is heterogeneous and risk factors are more often included than symptoms. The severity of conditions is seldom included. Since the number of people living with multimorbidity is increasing there is a need to develop a concept of multimorbidity that is more useful in daily clinical work. Key points The increasing number of multimorbidity patients challenges the healthcare system. The concept of multimorbidity needs further discussion in order to be implemented in daily clinical practice. Many definitions of multimorbidity exist and most often a cut-off point of two or more is applied to a range of 4-147 different conditions. Diseases are included in all definitions of multimorbidity. Risk factors are often included in existing definitions, whereas symptoms and the severity of the conditions are less frequently included. PMID- 26954368 TI - Implementation and evaluation of an analytical method for a novel derivatizing agent to measure 4,4'-methylene diphenyl diisocyanate atmospheres. AB - Accurate measurement of 4,4'-methylene diphenyl diisocyanate (MDI) atmospheres is a challenge since the molecule is both chemically reactive and likely to be present in aerosol form when heated and sprayed because of its low vapor pressure. Meeting this challenge requires optimizing both the sampling device used and the derivatization agent employed to stabilize the isocyanate functional group. This study describes the use of a novel derivatization reagent for isocyanate sampling to address the challenge of MDI aerosol exposure sampling. Like most conventional derivatizing agents for isocyanates, 1,8-diaminonapthalene (DAN) reacts with isocyanate functional groups to form a urea. However, unlike other isocyanate derivatizing agents, the sample workup procedure with DAN includes a second step which yields a single analyte molecule, perimidone, for each isocyanate group. This feature gives DAN the unique ability to assess exposure to "total reactive isocyanate group" (TRIG). The analytical method implemented to quantitate the perimidone uses liquid chromatography coupled with tandem mass spectrometry. Positive mode ionization led to LOD and LOQ of 10 ng/mL and 34 ng/mL, respectively. The dynamic range was from 50-2000 ng/mL (with R(2) >= 0.990), which corresponds to TRIG concentrations in air from 0.07-3.04 ug/m(3), assuming 60 min of sampling at 10 L/min (based on use of the CIP-10M sampler). The intra-day and inter-day analytical precisions were <4% for all of the concentration levels tested, and the accuracy was within an appropriate range of 98 +/- 2%. Minimal matrix effect was observed, and a total recovery of 109% was obtained. The approach seems to be promising for TRIG measurements and further work is planned to establish DAN method behavior in samplers used for workplace monitoring. PMID- 26954367 TI - Evaluation of Tumor Cell Proliferation by Ki-67 Expression and Mitotic Count in Lymph Node Metastases from Breast Cancer. AB - Few studies have addressed the risk of recurrence by assessing proliferation markers in lymph node metastasis from breast cancer. Here, we aimed to examine Ki 67 expression and mitotic count in lymph nodes in comparison with primary tumors. A cohort of node positive breast cancer (n = 168) was studied as a part of the prospective Norwegian Breast Cancer Screening Program (1996-2009). The percentage of Ki-67 positivity was counted per 500 tumor cells in hot-spot areas (x630). Mitotic count was conducted in the most cellular and mitotic active areas in 10 high power fields (x400). Our results showed that Ki-67 and mitotic count were significantly correlated between primary tumor and lymph nodes (Spearman's correlation 0. 56 and 0.46, respectively) and were associated with most of the histologic features of the primary tumor. Univariate survival analysis (log-rank test) showed that high Ki-67 and mitotic count in the primary tumor and lymph node metastasis significantly predicted risk of recurrence. In multivariate analysis, mitotic count in the lymph node metastasis was an independent predictor of tumor recurrence. In conclusion, proliferation markers in lymph node metastases significantly predicted disease free survival in node positive breast cancer. PMID- 26954369 TI - Outbreak Caused by blaOXA-72-Producing Acinetobacter baumannii ST417 Detected in Clinical and Environmental Isolates. AB - We characterized an outbreak of imipenem-resistant Acinetobacter baumannii with clinical and environmental isolates from a tertiary care hospital in San Luis Potosi, Mexico. During a 4-month period, a total of 32 nonrepetitive imipenem resistant clinical isolates of A. baumannii were collected. All isolates were susceptible to colistin and tigecycline and resistant to cefepime, ceftazidime, ceftriaxone, imipenem, and meropenem. Genotyping by pulsed-field gel electrophoresis showed a major clone (A). Multilocus sequence type (MLST) analysis was performed, revealing sequence type (ST) 417 (ST417) and 208 (ST208). The blaIMP-, blaVIM-, blaGIM-, blaSIM-, blaNDM-type, and blaOXA-type (blaOXA-23 like, blaOXA-24-like, blaOXA-51-like, and blaOXA-58-like) genes were screened and showed that the blaOXA-51-like and blaOXA-24-like genes were present in all isolates. Sequencing and southern hybridization were performed, confirming the presence of the blaOXA-72 gene and its plasmid-borne nature. In addition, the blaOXA-72-XerC/XerD-like association was identified. These findings indicate that a clonal spread of blaOXA-72-producing A. baumannii ST417 had occurred throughout the hospital. The ST417 corresponded with a previous ST described in the United States. PMID- 26954370 TI - OXA-48 Producing Klebsiella pneumoniae in a Household Contact of a Previously Infected Patient: Person-to-Person Transmission or Coincidental Community Acquisition? AB - We reported a woman with urinary-tract infection caused by OXA-48 producing Klebsiella pneumoniae. Using molecular techniques, we showed that she might acquire this bacterium from another family member who lived in the same house. The two isolates, although different by pulsed-field gel electrophoresis and multilocus sequence typing, carried blaOXA-48 in a similar IncL/M plasmid. This case report shows that community spreading of carbapenemase producing Enterobacteriaceae occurs in the low endemic area not only in nosocomial setting but also in the community. PMID- 26954371 TI - Immunological and pleiotropic effects of individual beta-blockers and their relevance in cancer therapies. PMID- 26954372 TI - Tenofovir alafenamide as part of a salvage regimen in a patient with multi-drug resistant HIV and tenofovir-DF-associated renal tubulopathy. AB - We describe a patient with two recent episodes of tenofovir disoproxil fumarate (TDF)-associated acute kidney injury and six-class drug-resistant HIV infection who achieved and maintained viral suppression without worsening kidney function on a regimen including tenofovir alafenamide (TAF) through 48 weeks of therapy. The safety and efficacy of TAF in patients with TDF-associated renal tubulopathy and multiple drug resistant HIV has not yet been described. TAF may represent a useful option to maximally suppress HIV in patients with these complications. PMID- 26954373 TI - The Protective Effects of Social Factors on the Academic Functioning of Adolescents With ADHD. AB - There is considerable evidence that externalizing disorders such as attention deficit/hyperactivity disorder (ADHD) put youth at risk for a range of adverse academic outcomes. It is importantly to note that some youth avoid these negative outcomes, yet there is a gap in our understanding of these resilient youth. The purpose of this study was to longitudinally evaluate social acceptance and social skills as potential protective factors of the associations between inattentive, hyperactive/impulsive, and oppositional defiant behaviors with academic outcomes. Participants included a sample of 93 middle school students comprehensively diagnosed with ADHD. Parents and adolescents completed ratings of social skills and perceived social acceptance. School grades and teacher-rated academic impairment were assessed 18 months later as longitudinal academic functioning outcomes. Inattention and social acceptance were associated with academic outcomes 18 months later. Regression analyses revealed that parent- and adolescent-rated social acceptance demonstrated promotive effects for grades and against teacher-rated academic impairment. Further, social acceptance significantly interacted with inattention in predicting school grades, such that high parent- and adolescent-rated social acceptance significantly attenuated the relationship between inattention and poor grades, even after controlling for baseline grades and intelligence. The presence of social acceptance was especially critical for adolescents with high levels of inattention. Specifically, adolescents with high inattention and high social acceptance had a mean grade point average of 2.5, and adolescents with high inattention and low social acceptance had a mean grade point average of 1.5. These findings demonstrate that social acceptance may be an important intervention target for improving academic outcomes among adolescents with ADHD. PMID- 26954376 TI - Editorial. AB - It is fair to say that many fledgling healthcare researchers feel intimidated by the prospect of using statistics in their studies. Nurses and others who originally entered their profession because they wanted to care for others may initially feel uncomfortable about handling statistical material and find some of the terms confusing and alien. But, as the first article in this issue of Nurse Researcher notes, the relationship between nursing and statistics has a long history. PMID- 26954377 TI - Principles of statistical analysis in nursing and healthcare research. AB - In the first of three papers on statistical analysis, Nicola Crichton gives an overview of using statistical analysis in nursing and health care research. PMID- 26954378 TI - Nonparametric methods. AB - This paper by John Belcher aims to give a non-technical illustration of the applications of non-parametric tests and to list the types of medical data that can arise. (In a second paper on pages 26-40, the author presents an overview of time series analysis). PMID- 26954374 TI - A specific aptamer-cell penetrating peptides complex delivered siRNA efficiently and suppressed prostate tumor growth in vivo. AB - Specific and efficient delivery of siRNA into intended tumor cells remains as a challenge, even though RNAi has been exploited as a new strategy for prostate cancer therapy. This work aims to address both specificity and efficiency of SURVIVIN-siRNA delivery by constructing a therapeutic complex using combinatorial strategies. A fusion protein STD was first expressed to serve as a backbone, consisting of streptavidin, a cell-penetrating peptide called Trans-Activator of Transcription (TAT) and a double-stranded RNA binding domain. A biotinylated Prostate Specific Membrane Antigen (PSMA) specific aptamer A10 and SURVIVIN-siRNA were then linked to STD protein to form the therapeutic complex. This complex could specifically targeted PSMA(+) tumor cells. Compared to lipofectamine and A10-siRNA chimera, it demonstrated higher efficiency in delivering siRNA into target cells by 19.2% and 59.9%, and increased apoptosis by 16.8% and 26.1% respectively. Upon systemic administration, this complex also showed significant efficacy in suppressing tumor growth in athymic mice (p <0.001). We conclude that this therapeutic complex could specifically and efficiently deliver SURVIVIN siRNA to target cells and suppressed tumor growth in vivo, which indicates its potential to be used as a new strategy in prostate cancer therapy. PMID- 26954375 TI - Antinoceptive and Anti-inflammatory Activities of the Ethanolic Extract, Fractions and Flavones Isolated from Mimosa tenuiflora (Willd.) Poir (Leguminosae). AB - The bark of Mimosa tenuiflora (Willd.) Poiret (Leguminosae family), popularly known as "jurema preta" in Brazil, is used by the population of Contendas of Sincora (Bahia State, Brazil) for the treatment of coughs and wound healing. Thus, the aim of this study was to evaluate the antinociceptive and anti inflammatory activities of the bark ethanol extract (EEMT) and solvent soluble fractions (hexane-H, DCM-D, EtOAc-E and BuOH-B) of the extract in vivo. Additionally, we synthesized 5,7-dihidroxy-4'-methoxyflavanone (isosakuranetin) and isolated the compound sakuranetin, and both compounds were also tested. The anti-inflammatory and antinociceptive assays performed were: writhing test; nociception induced by intraplantar formalin injection; leukocyte recruitment to the peritoneal cavity; evaluation of vascular permeability (Evans blue test); and evaluation of mechanical hypernociception (von Frey test). Production of TNF alpha, IL-10, myeloperoxidase and the expression of ICAM-1 were also evaluated. Statistical analysis was performed by one-way ANOVA followed by the Bonferroni post-test (n = 8), with P < 0.05. The EEMT showed antinociceptive activities in writhing test (100-200 mg/kg), in the second phase of the formalin test (50-200 mg/kg), and in mechanical hypernociception (100 mg/kg). EEMT showed an anti inflammatory effect by reducing neutrophil migration to the peritoneal cavity and in the plantar tissue detected by the reduction of myeloperoxidase activity (100 mg/kg), reduction of IL-10 levels and expression of ICAM-1 in the peritoneal exudate and the mesentery (100 mg/kg), respectively. The four soluble EEMT fractions showed good results in tests for antinociceptive (H, D, E, B) and anti inflammation (H, D, E). Only sakuranetin showed reduction of the writhing and neutrophil migration (200 mg/kg). Thus, the EEMT and soluble fractions of M. tenuiflora bark demonstrated great antinociceptive and anti-inflammatory activities, as also sakuranetin. More studies should be conducted to elucidate the mechanism of action of this compound. To the best of our knowledge, this is the first report on the antinociceptive activity of the M. tenuiflora fractions and the bioactive isolated compound sakuranetin in vivo. PMID- 26954379 TI - An overview of time series analysis. AB - In this paper John Belcher provides an introduction to some basic ideas in the analysis of time series data. PMID- 26954380 TI - Engaging with cultures Reflections on entering the ethnographic field. AB - This paper, by Ian Hodgson, offers a reflection on the experience of starting an ethnographic study. It provides an overview of the study, addresses key elements in entering the field and suggests questions that require further investigation, while identifying those elements that are crucial to effective observation. PMID- 26954381 TI - The long and winding road Obtaining funding for qualitative research proposals. AB - In this article, John Cutcliffe and Chris Stevenson drew on their experience of seeking funding for qualitative studies in order to offer researchers some helpful tips. PMID- 26954382 TI - Development of competency based standards An application of the Delphi research technique. AB - This paper, by Ann Bonner and Glenn Stewart, describes the benefits and limitations of using the Delphi technique research method. The technique was applied to a study in Australia that sought to identify advanced practice competency standards within a nursing speciality. PMID- 26954388 TI - Relationship Among Body Fat Percentage, Body Mass Index, and All-Cause Mortality: A Cohort Study. AB - BACKGROUND: Prior mortality studies have concluded that elevated body mass index (BMI) may improve survival. These studies were limited because they did not measure adiposity directly. OBJECTIVE: To examine associations of BMI and body fat percentage (separately and together) with mortality. DESIGN: Observational study. SETTING: Manitoba, Canada. PARTICIPANTS: Adults aged 40 years or older referred for bone mineral density (BMD) testing. MEASUREMENTS: Participants had dual-energy x-ray absorptiometry (DXA), entered a clinical BMD registry, and were followed using linked administrative databases. Adjusted, sex-stratified Cox models were constructed. Body mass index and DXA-derived body fat percentage were divided into quintiles, with quintile 1 as the lowest, quintile 5 as the highest, and quintile 3 as the reference. RESULTS: The final cohort included 49 476 women (mean age, 63.5 years; mean BMI, 27.0 kg/m2; mean body fat, 32.1%) and 4944 men (mean age, 65.5 years; mean BMI, 27.4 kg/m2; mean body fat, 29.5%). Death occurred in 4965 women over a median of 6.7 years and 984 men over a median of 4.5 years. In fully adjusted mortality models containing both BMI and body fat percentage, low BMI (hazard ratio [HR], 1.44 [95% CI, 1.30 to 1.59] for quintile 1 and 1.12 [CI, 1.02 to 1.23] for quintile 2) and high body fat percentage (HR, 1.19 [CI, 1.08 to 1.32] for quintile 5) were associated with higher mortality in women. In men, low BMI (HR, 1.45 [CI, 1.17 to 1.79] for quintile 1) and high body fat percentage (HR, 1.59 [CI, 1.28 to 1.96] for quintile 5) were associated with increased mortality. LIMITATIONS: All participants were referred for BMD testing, which may limit generalizability. Serial measures of BMD and weight were not used. Some measures, such as physical activity and smoking, were unavailable. CONCLUSION: Low BMI and high body fat percentage are independently associated with increased mortality. These findings may help explain the counterintuitive relationship between BMI and mortality. PRIMARY FUNDING SOURCE: None. PMID- 26954389 TI - A photosensitizing decatungstate-based MOF as heterogeneous photocatalyst for the selective C-H alkylation of aliphatic nitriles. AB - The efficient photosensitizing of decatungstate-based MOF with 1D channels was achieved via in situ synthesis under solvothermal conditions for light driven acceleration of beta- or gamma-site C-H alkylation of aliphatic nitriles. The high catalytic efficiency, excellent size selectivity, high stability and good recyclability of the photocatalyst offer an environmentally-friendly route for widening the scope of accessible nitriles in both laboratory and industry. PMID- 26954390 TI - IgA directly inhibits antigen-dependent B cell activation following distinctive distribution of the antigen in mice. AB - CONTEXT: Serum IgA suppresses immune responses when exposed to antigens recognized by the antibody; however, the underlying mechanism remains unclear. OBJECTIVE: We herein clarified the relationships between changes in antigen distribution and antigen-dependent B cell activation in the presence or absence of IgA against the antigen in mice. MATERIALS AND METHODS: DBA/1J and HR-1 mice were intravenously injected with ovalbumin (OVA) and anti-OVA monoclonal IgA OA 4. The distribution of the antigen and B cell responses were measured. RESULTS: B cell activation by injected OVA, namely, increases in anti-OVA IgG production and the populations of B220(+)GL7(+) and B220(+)CD69(high) splenocytes, was diminished by the co-injection of OA-4. Co-injected OA-4 increased OVA in the serum as well as in the bile and gut. This was coincident with its decrease in the urine due to the inhibition of OVA monomer secretion through the formation of immune complexes. The apparent similarities in the association between fluorescein isothiocyanate (FITC)-OVA and splenic B cells in the presence and absence of OA-4 in vivo appeared to be attributed to compensation between the two effects of OA-4; an increase in serum OVA in vivo and inhibition of the association between OVA and B cells, as suggested by in vitro experiments. DISCUSSION: Based on these results, the stimulation of B cells by OVA may be directly reduced, at least partly, by the neutralization of OVA by OA-4. CONCLUSION: IgA may be an effective drug for the treatment of immune disorders due to its ability to blunt antigen-specific B cell activation. PMID- 26954391 TI - Bergenin ameliorates diabetic nephropathy in rats via suppressing renal inflammation and TGF-beta1-Smads pathway. AB - CONTEXT: Diabetic nephropathy (DN) is a serious complication of diabetes. Bergenin (BEG) was previously confirmed to be effective in treating type 2 diabetes in rats. OBJECTIVE: The objective of this study was to investigate the effects of BEG on renal function in diabetic rats, and meanwhile explore the molecular mechanism. METHODS: DN was induced in rats by a single intraperitoneal injection of streptozotocin. The renal function was evaluated by serum creatinine (SCr), blood urea nitrogen (BUN), urinary albumin and renal histopathology. The proliferation of mesangial cells (MCs) was assayed by 3-(4,5-dimethylthiazol-2 yl)-2,5-diphenyl-2H tetrazolium bromide. The production of inflammatory cytokines was detected by ELISA kits, and the levels of Smads were measured by western blotting. RESULTS AND CONCLUSION: In DN rats, there were significantly increased levels of SCr, BUN, urinary albumin, plasma glucose and renal index. The histological changes in diabetic kidney revealed noteworthy focal mesangial matrix expansion. In vitro experiment, high glucose markedly promoted MCs proliferation. However, treatment with BEG obviously normalized these functional parameters, improved diabetic histological changes in vivo and inhibited MCs' proliferation in vitro. Moreover, the levels of tumor necrosis factor-alpha, interleukin-1 (IL-1) and IL-6 in BEG-treated renal tissue and MCs were both reduced. Finally, it showed that BEG markedly reduced transforming growth factor beta1 (TGF-beta1) production, down-regulated p-Smad2/3 expression and promoted Smad7 expression both in vivo and in vitro. In conclusion, BEG exerts the effective protective role against kidney injuries of diabetic rat, in which the underlying mechanisms are associated with reducing renal inflammation and blocking TGF-beta1-Smads pathway. PMID- 26954392 TI - Celecoxib, a COX-2 inhibitor, synergistically potentiates the anti-inflammatory activity of docosahexaenoic acid in macrophage cell line. AB - BACKGROUND: The anti-inflammatory properties of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and non-steroidal anti-inflammatory drugs overlap in many ways. The aim of this study was to examine the individual and synergetic anti-inflammatory effects of celecoxib, EPA and DHA in RAW-264.7 cell line. METHODOLOGY: The cells were exposed to EPA, DHA, celecoxib, rosiglitazone, GW9662 alone or their combination, and stimulated with 5 MUg/mL lipopolysaccharide (LPS). Nitric oxide (NO), tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-6 and prostaglandin-E2 (PGE2) levels were estimated in the medium using enzyme-linked immunosorbent assays. The cyclooxygenase-2 (COX-2) and inducible Nitric Oxide Synthase (iNOS) expression were analyzed in the cell lysate by immunoblotting. Peroxisome proliferator-activated receptor gamma (PPARgamma) and nuclear factor-kappaB (NF-kappaB) transcription factor activation assays were performed in the nuclear extract. RESULTS: Combined treatment of DHA (50 MUM) and celecoxib (20 MUM) significantly inhibited LPS induced synthesis of NO, TNF alpha, IL-6 and PGE2 levels in the cells, compared to the individual treatments. In addition, DHA and celecoxib diminished the COX-2 and iNOS expression in the cells. This was associated with increased PPARgamma activity, supressed NF-kappaB activity in the nucleus. We determined whether GW9662, a specific PPARgamma inhibitor, could abolish the anti-inflammatory effect of DHA and celecoxib. GW9662 has abolished the DHA and celecoxib induced PPARgamma activation, but did not alter the NF-kappaB mediated anti-inflammatory effects induced by celecoxib and DHA. Interestingly, EPA did not exhibit any inhibitory effect on these parameters. CONCLUSION: Our results suggest that DHA and celecoxib exhibit anti inflammatory effect through inhibition of NF-kappaB, independent of PPARgamma. Co administration of celecoxib and DHA would be promising approach for the treatment of inflammatory diseases. PMID- 26954393 TI - Learning endobronchial ultrasound transbronchial needle aspiration - a 6-year experience at a single institution. AB - INTRODUCTION: Endobronchial ultrasound with transbronchial needle aspiration (EBUS-TBNA) has become an important diagnostic tool for the pulmonologist. Learning this procedure and maintaining technical skills requires continuous practice and evaluation. OBJECTIVES: The aims of the study were a retrospective evaluation of the diagnostic quality of the EBUS-technique and the learning profile of the endoscopy team during the first years (2007-2013) of experience in an unselected population. METHODS: EBUS-TBNA procedures were analysed for clinical data, including results from surgery or clinical/radiological follow-up for at least 6 months. Rapid on-site cytological evaluation (ROSE) was introduced on regular basis the forth year. RESULTS: A total of 711 EBUS-TBNA from 635 patients were included. The percentage of representative EBUS-TBNA initially decreased the first years (minimum 60,9%), before increased to a final result of 82,4%. There was a lower proportion of representative EBUS-TBNA in the benign group (76,8%) vs the malignant group (85,8%). A significant increase in the proportion of representative EBUS-TBNA was seen after ROSE had been introduced. The major indications were diagnosing/staging of lung cancer (54%) and mediastinal lymphadenopathy of unknown cause (25,7%). The sensitivity detecting malignancy was 94,9%, negative predictive value 81,2% and diagnostic accuracy 95,8%. During the study period the percentage of re-examinations with EBUS-TBNA declined from 18,0% to 8,2%. CONCLUSION: After an initial run-in period with declining results, the overall diagnostic yield of EBUS-TBNA increased and reached acceptable levels. These results underline the importance of continuously evaluation of our own results when new methods are implemented in clinical practice. PMID- 26954394 TI - Nutraceuticals in Migraine: A Summary of Existing Guidelines for Use. AB - BACKGROUND: The use of nutraceuticals or food/herbal products for health benefits is expanding in adults with migraine as they seek relief from pain in an effective and tolerable manner not always afforded by current conventional pharmacologic therapies. Guidelines from the American Academy of Neurology/American Headache Society, Canadian Headache Society, and European Federation of Neurological Societies have discussed nutraceuticals in varying degrees of detail with at times conflicting recommendations. CONCLUSION: This review serves to provide a summary of existing guidelines for the use of certain nutraceuticals including riboflavin, coenzyme Q10, magnesium, butterbur, feverfew, and omega-3 polyunsaturated fatty acids. The review will also discuss the regulation of nutraceuticals in North America and the current controversy regarding butterbur and its safety. PMID- 26954397 TI - Pinkerton Riot, Pittsburgh: Raymond Simboli. PMID- 26954404 TI - A PIECE OF MY MIND. Where Do You Put the Pain? PMID- 26954405 TI - Evaluation of the Cardiovascular Risk of Naltrexone-Bupropion: A Study Interrupted. PMID- 26954406 TI - Identifying Children and Adolescents at Risk for Persistent Postconcussion Symptoms. PMID- 26954408 TI - Effect of Naltrexone-Bupropion on Major Adverse Cardiovascular Events in Overweight and Obese Patients With Cardiovascular Risk Factors: A Randomized Clinical Trial. AB - IMPORTANCE: Few cardiovascular outcomes trials have been conducted for obesity treatments. Withdrawal of 2 marketed drugs has resulted in controversy about the cardiovascular safety of obesity agents. OBJECTIVE: To determine whether the combination of naltrexone and bupropion increases major adverse cardiovascular events (MACE, defined as cardiovascular death, nonfatal stroke, or nonfatal myocardial infarction) compared with placebo in overweight and obese patients. DESIGN, SETTING, AND PARTICIPANTS: Randomized, multicenter, placebo-controlled, double-blind noninferiority trial enrolling 8910 overweight or obese patients at increased cardiovascular risk from June 13, 2012, to January 21, 2013, at 266 US centers. After public release of confidential interim data by the sponsor, the academic leadership of the study recommended termination of the trial and the sponsor agreed. INTERVENTIONS: An Internet-based weight management program was provided to all participants. Participants were randomized to receive placebo (n=4454) or naltrexone, 32 mg/d, and bupropion, 360 mg/d (n=4456). MAIN OUTCOMES AND MEASURES: Time from randomization to first confirmed occurrence of a MACE. The primary analysis planned to assess a noninferiority hazard ratio (HR) of 1.4 after 378 expected events, with a confidential interim analysis after approximately 87 events (25% interim analysis) to assess a noninferiority HR of 2.0 for consideration of regulatory approval. RESULTS: Among the 8910 participants randomized, mean age was 61.0 years (SD, 7.3 years), 54.5% were female, 32.1% had a history of cardiovascular disease, and 85.2% had diabetes, with a median body mass index of 36.6 (interquartile range, 33.1-40.9). For the 25% interim analysis, MACE occurred in 59 placebo-treated patients (1.3%) and 35 naltrexone-bupropion-treated patients (0.8%; HR, 0.59; 95% CI, 0.39-0.90). After 50% of planned events, MACE occurred in 102 patients (2.3%) in the placebo group and 90 patients (2.0%) in the naltrexone-bupropion group (HR, 0.88; adjusted 99.7% CI, 0.57-1.34). Adverse effects were more common in the naltrexone bupropion group, including gastrointestinal events in 14.2% vs 1.9% (P < .001) and central nervous system symptoms in 5.1% vs 1.2% (P < .001). CONCLUSIONS AND RELEVANCE: Among overweight or obese patients at increased cardiovascular risk, based on the interim analyses performed after 25% and 50% of planned events, the upper limit of the 95% CI of the HR for MACE for naltrexone-bupropion treatment, compared with placebo, did not exceed 2.0. However, because of the unanticipated early termination of the trial, it is not possible to assess noninferiority for the prespecified upper limit of 1.4. Accordingly, the cardiovascular safety of this treatment remains uncertain and will require evaluation in a new adequately powered outcome trial. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01601704. PMID- 26954409 TI - Effect of Vitamin D Supplementation on Tibial Cartilage Volume and Knee Pain Among Patients With Symptomatic Knee Osteoarthritis: A Randomized Clinical Trial. AB - IMPORTANCE: Observational studies suggest that vitamin D supplementation is associated with benefits for knee osteoarthritis, but current trial evidence is contradictory. OBJECTIVE: To compare the effects of vitamin D supplementation vs placebo on knee pain and knee cartilage volume in patients with symptomatic knee osteoarthritis and low vitamin D levels. DESIGN, SETTING, AND PARTICIPANTS: A multicenter randomized, double-blind, placebo-controlled clinical trial in Tasmania and Victoria, Australia. Participants with symptomatic knee osteoarthritis and low 25-hydroxyvitamin D (12.5-60 nmol/L) were enrolled from June 2010 to December 2011. The trial was completed in December 2013. INTERVENTIONS: Participants were randomly assigned to receive monthly treatment with oral vitamin D3 (50,000 IU; n = 209) or an identical placebo (n = 204) for 2 years. MAIN OUTCOMES AND MEASURES: Primary outcomes were change in tibial cartilage volume (assessed using magnetic resonance imaging [MRI]) and change in the Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain score (0 [no pain] to 500 [worst pain]) from baseline to month 24. Secondary outcomes were cartilage defects and bone marrow lesions (assessed using MRI). RESULTS: Of 413 enrolled participants (mean age, 63.2 years; 50% women), 340 (82.3%) completed the study. The level of 25-hydroxyvitamin D increased more in the vitamin D group (40.6 nmol/L) than in the placebo group (6.7 nmol/L) (P < .001) over 2 years. There were no significant differences in annual change of tibial cartilage volume or WOMAC pain score. There were no significant differences in change of tibiofemoral cartilage defects or change in tibiofemoral bone marrow lesions. Adverse events (>= 1 per patient) occurred in 56 participants in the vitamin D group and in 37 participants in the placebo group (P = .04). [table: see text]. CONCLUSIONS AND RELEVANCE: Among patients with symptomatic knee osteoarthritis and low serum 25-hydroxyvitamin D levels, vitamin D supplementation, compared with placebo, did not result in significant differences in change in MRI-measured tibial cartilage volume or WOMAC knee pain score over 2 years. These findings do not support the use of vitamin D supplementation for preventing tibial cartilage loss or improving WOMAC knee pain in patients with knee osteoarthritis. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01176344; anzctr.org.au Identifier: ACTRN12610000495022. PMID- 26954411 TI - Association Between Hypertensive Disorders of Pregnancy and Later Risk of Cardiomyopathy. AB - IMPORTANCE: Women with hypertensive disorders of pregnancy, preeclampsia in particular, have an increased risk of cardiomyopathy during the peripartum period. Whether hypertensive disorders of pregnancy are also associated with cardiomyopathy later in life is unknown. OBJECTIVE: To determine whether hypertensive disorders of pregnancy are associated with cardiomyopathy beyond the peripartum period. DESIGN, SETTING, AND PARTICIPANTS: Nationwide register-based cohort study using Cox regression to compare rates of cardiomyopathy in women with and without a history of hypertensive disorders of pregnancy in a cohort of 1,075,763 women with at least 1 pregnancy ending in live birth or stillbirth in Denmark, 1978-2012, with follow-up through December 31, 2012. EXPOSURES: A hypertensive disorder of pregnancy (severe or moderate preeclampsia or gestational hypertension) registered in the National Patient Register. MAIN OUTCOMES AND MEASURES: Cardiomyopathy more than 5 months after delivery (outside the peripartum period) up to 34 years 7 months. RESULT: The women in the primary cohort had 2,067,633 eligible pregnancies during the study period, 76,108 of which were complicated by a hypertensive disorder of pregnancy. During follow-up, 1577 women (mean age, 48.5 years at cardiomyopathy diagnosis; 2.6% with multiple pregnancies) developed cardiomyopathy. Compared with women with normotensive pregnancies (18,211,603 person-years of follow-up; n = 1408 cardiomyopathy events, 7.7/100,000 person-years [95% CI, 7.3-8.2]), women with a history of hypertensive disorders of pregnancy had significantly increased rates of cardiomyopathy (in 173,062 person-years of follow-up among women with severe preeclampsia, n = 27 cardiomyopathy events; 15.6/100,000 person-years [95% CI, 10.7-22.7]; adjusted hazard ratio [HR], 2.20 [95% CI, 1.50-3.23]; in 697,447 person-years of follow-up among women with moderate preeclampsia, n = 102 cardiomyopathy events; 14.6/100,000 person-years [95% CI, 12.0-17.8]; adjusted HR, 1.89 [95% CI, 1.55-2.23]; in 213,197 person-years of follow-up among women with gestational hypertension, n = 40 cardiomyopathy events; 17.3/100,000 person years [95% CI, 12.7-23.6]; adjusted HR, 2.06 [95% CI, 1.50-2.82]). These increases persisted more than 5 years after the latest pregnancy. Mediation analyses suggested that only about 50% of the association was an indirect association through postpregnancy chronic hypertension. In this cohort, 11% of all cardiomyopathy events occurred in women with a history of hypertensive disorders of pregnancy. CONCLUSIONS AND RELEVANCE: Women with a history of hypertensive disorders of pregnancy, compared with women without such a history, had a small but statistically significant increased risk of cardiomyopathy more than 5 months after delivery. Further research is necessary to understand whether there is a causal mechanism behind this association. PMID- 26954410 TI - Clinical Risk Score for Persistent Postconcussion Symptoms Among Children With Acute Concussion in the ED. AB - IMPORTANCE: Approximately one-third of children experiencing acute concussion experience ongoing somatic, cognitive, and psychological or behavioral symptoms, referred to as persistent postconcussion symptoms (PPCS). However, validated and pragmatic tools enabling clinicians to identify patients at risk for PPCS do not exist. OBJECTIVE: To derive and validate a clinical risk score for PPCS among children presenting to the emergency department. DESIGN, SETTING, AND PARTICIPANTS: Prospective, multicenter cohort study (Predicting and Preventing Postconcussive Problems in Pediatrics [5P]) enrolled young patients (aged 5-<18 years) who presented within 48 hours of an acute head injury at 1 of 9 pediatric emergency departments within the Pediatric Emergency Research Canada (PERC) network from August 2013 through September 2014 (derivation cohort) and from October 2014 through June 2015 (validation cohort). Participants completed follow up 28 days after the injury. EXPOSURES: All eligible patients had concussions consistent with the Zurich consensus diagnostic criteria. MAIN OUTCOMES AND MEASURES: The primary outcome was PPCS risk score at 28 days, which was defined as 3 or more new or worsening symptoms using the patient-reported Postconcussion Symptom Inventory compared with recalled state of being prior to the injury. RESULTS: In total, 3063 patients (median age, 12.0 years [interquartile range, 9.2-14.6 years]; 1205 [39.3%] girls) were enrolled (n = 2006 in the derivation cohort; n = 1057 in the validation cohort) and 2584 of whom (n = 1701 [85%] in the derivation cohort; n = 883 [84%] in the validation cohort) completed follow up at 28 days after the injury. Persistent postconcussion symptoms were present in 801 patients (31.0%) (n = 510 [30.0%] in the derivation cohort and n = 291 [33.0%] in the validation cohort). The 12-point PPCS risk score model for the derivation cohort included the variables of female sex, age of 13 years or older, physician-diagnosed migraine history, prior concussion with symptoms lasting longer than 1 week, headache, sensitivity to noise, fatigue, answering questions slowly, and 4 or more errors on the Balance Error Scoring System tandem stance. The area under the curve was 0.71 (95% CI, 0.69-0.74) for the derivation cohort and 0.68 (95% CI, 0.65-0.72) for the validation cohort. CONCLUSIONS AND RELEVANCE: A clinical risk score developed among children presenting to the emergency department with concussion and head injury within the previous 48 hours had modest discrimination to stratify PPCS risk at 28 days. Before this score is adopted in clinical practice, further research is needed for external validation, assessment of accuracy in an office setting, and determination of clinical utility. PMID- 26954413 TI - Time-to-Event Analysis. PMID- 26954414 TI - Prevention, Diagnosis, and Treatment of Postthrombotic Syndrome. PMID- 26954415 TI - Privacy Policies of Android Diabetes Apps and Sharing of Health Information. PMID- 26954412 TI - Polypharmacy in the Aging Patient: A Review of Glycemic Control in Older Adults With Type 2 Diabetes. AB - IMPORTANCE: There is substantial uncertainty about optimal glycemic control in older adults with type 2 diabetes mellitus. OBSERVATIONS: Four large randomized clinical trials (RCTs), ranging in size from 1791 to 11,440 patients, provide the majority of the evidence used to guide diabetes therapy. Most RCTs of intensive vs standard glycemic control excluded adults older than 80 years, used surrogate end points to evaluate microvascular outcomes and provided limited data on which subgroups are most likely to benefit or be harmed by specific therapies. Available data from randomized clinical trials suggest that intensive glycemic control does not reduce major macrovascular events in older adults for at least 10 years. Furthermore, intensive glycemic control does not lead to improved patient-centered microvascular outcomes for at least 8 years. Data from randomized clinical trials consistently suggest that intensive glycemic control immediately increases the risk of severe hypoglycemia 1.5- to 3-fold. Based on these data and observational studies, for the majority of adults older than 65 years, the harms associated with a hemoglobin A1c (HbA1c) target lower than 7.5% or higher than 9% are likely to outweigh the benefits. However, the optimal target depends on patient factors, medications used to reach the target, life expectancy, and patient preferences about treatment. If only medications with low treatment burden and hypoglycemia risk (such as metformin) are required, a lower HbA1c target may be appropriate. If patients strongly prefer to avoid injections or frequent fingerstick monitoring, a higher HbA1c target that obviates the need for insulin may be appropriate. CONCLUSIONS AND RELEVANCE: High-quality evidence about glycemic treatment in older adults is lacking. Optimal decisions need to be made collaboratively with patients, incorporating the likelihood of benefits and harms and patient preferences about treatment and treatment burden. For the majority of older adults, an HbA1c target between 7.5% and 9% will maximize benefits and minimize harms. PMID- 26954416 TI - Laparoscopic Lavage vs Primary Resection for Perforated Diverticulitis. PMID- 26954417 TI - Laparoscopic Lavage vs Primary Resection for Perforated Diverticulitis. PMID- 26954418 TI - Laparoscopic Lavage vs Primary Resection for Perforated Diverticulitis--Reply. PMID- 26954419 TI - Radiation With or Without Androgen Deprivation Therapy for Localized Prostate Cancer. PMID- 26954420 TI - Radiation With or Without Androgen Deprivation Therapy for Localized Prostate Cancer--Reply. PMID- 26954421 TI - Targeted Text Messaging Support for Patients With Coronary Heart Disease. PMID- 26954422 TI - Targeted Text Messaging Support for Patients With Coronary Heart Disease--Reply. PMID- 26954423 TI - Errors in Text and Tables. PMID- 26954425 TI - Principles Underlying the Classification of Diseases of the Nervous System. PMID- 26954426 TI - JAMA PATIENT PAGE. Herbal Medications. PMID- 26954427 TI - Differentiation of Surface and Bulk Conductivities in Topological Insulators via Four-Probe Spectroscopy. AB - We show a new method to differentiate conductivities from the surface states and the coexisting bulk states in topological insulators using a four-probe transport spectroscopy in a multiprobe scanning tunneling microscopy system. We derive a scaling relation of measured resistance with respect to varying interprobe spacing for two interconnected conduction channels to allow quantitative determination of conductivities from both channels. Using this method, we demonstrate the separation of 2D and 3D conduction in topological insulators by comparing the conductance scaling of Bi2Se3, Bi2Te2Se, and Sb-doped Bi2Se3 against a pure 2D conductance of graphene on SiC substrate. We also quantitatively show the effect of surface doping carriers on the 2D conductance enhancement in topological insulators. The method offers a means to understanding not just the topological insulators but also the 2D to 3D crossover of conductance in other complex systems. PMID- 26954428 TI - Newly Identified Targets of Aspirin and Its Primary Metabolite, Salicylic Acid. AB - Salicylic acid (SA) is a plant hormone, which influences several physiological processes, and is a critical modulator of multiple levels of immunity in plants. Several high-throughput screens, which were developed to identify SA-binding proteins through which SA mediates its many physiological effects in plants, uncovered several novel targets of aspirin and its primary metabolite, SA, in humans. These include glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and high mobility group box 1 (HMGB1), two proteins associated with some of the most prevalent and devastating human diseases. In addition, natural and synthetic SA derivatives were discovered, which are much more potent than SA at inhibiting the disease-associated activities of these targets. PMID- 26954429 TI - Revealing the Binding Process of New 3-Alkylpyridine Marine Alkaloid Analogue Antimalarials and the Heme Group: An Experimental and Theoretical Investigation. AB - Synthetic 3-alkylpyridine marine alkaloid (3-APA) analogues have shown good antimalarial activity against Plasmodium falciparum. However, despite their structural originality, their molecular target was unknown. Herein, we report a proposal for the antimalarial mechanism of action of 3-APA analogues through interference with the process of hemozoin (Hz) formation. The interaction between 3-APA analogues and heme groups was investigated employing an in silico approach and biophysical techniques such as ultraviolet-visible light (UV-vis) titration and electrospray ionization-mass spectrometry (ESI-MS). The in silico approach was performed based on pure ab initio electronic structure methods in order to obtain insights at the molecular level concerning the binding process of antimalarial drugs at their target site, the heme group. In silico results showed that the formation of heme:3-APA complexes at a molecular ratio of 2:1 are more stable than 1:1 complexes. These results were further confirmed by experimental techniques, such as UV-vis and high-resolution mass spectrometry (ESI-TOF), for two of the most active 3-APA analogues. PMID- 26954430 TI - Polymorphism of Amyloid Fibrils In Vivo. AB - Polymorphism is a wide-spread feature of amyloid-like fibrils formed in vitro, but it has so far remained unclear whether the fibrils formed within a patient are also affected by this phenomenon. In this study we show that the amyloid fibrils within a diseased individual can vary considerably in their three dimensional architecture. We demonstrate this heterogeneity with amyloid fibrils deposited within different organs, formed from sequentially non-homologous polypeptide chains and affecting human or animals. Irrespective of amyloid type or source, we found in vivo fibrils to be polymorphic. These data imply that the chemical principles of fibril assembly that lead to such polymorphism are fundamentally conserved in vivo and in vitro. PMID- 26954431 TI - Effects of productivity on biodiversity in forest ecosystems across the United States and China. AB - In the global campaign against biodiversity loss in forest ecosystems, land managers need to know the status of forest biodiversity, but practical guidelines for conserving biodiversity in forest management are lacking. A major obstacle is the incomplete understanding of the relationship between site primary productivity and plant diversity, due to insufficient ecosystem-wide data, especially for taxonomically and structurally diverse forest ecosystems. We investigated the effects of site productivity (the site's inherent capacity to grow timber) on tree species richness across 19 types of forest ecosystems in North America and China through 3 ground-sourced forest inventory data sets (U.S. Forest Inventory and Analysis, Cooperative Alaska Forest Inventory, and Chinese Forest Management Planning Inventory). All forest types conformed to a consistent and highly significant (P < 0.001) hump-shaped unimodal relationship, of which the generalized coefficients of determination averaged 20.5% over all the forest types. That is, tree species richness first increased as productivity increased at a progressively slower rate, and, after reaching a maximum, richness started to decline. Our consistent findings suggest that forests of high productivity would sustain few species because they consist mostly of flat homogeneous areas lacking an environmental gradient along which a diversity of species with different habitats can coexist. The consistency of the productivity-biodiversity relationship among the 3 data sets we examined makes it possible to quantify the expected tree species richness that a forest stand is capable of sustaining, and a comparison between the actual species richness and the sustainable values can be useful in prioritizing conservation efforts. PMID- 26954432 TI - The potential for biodiversity offsetting to fund invasive species eradications on islands. PMID- 26954433 TI - The conservation paradox of endangered and invasive species. PMID- 26954434 TI - Marchantia. PMID- 26954435 TI - Biotremology. AB - Animal communication, including that among humans, is fascinating in its efficiency, diversity and its complexity. The evolution of a communication signal requires that the encoded content sent by an organism (sender) is detected and decoded by a receiver, who then must respond in such a way that the fitness of the sender is increased. The signal could be visual, such as bright coloration or some stereotypical movement that attracts attention through the sense of sight. It could be chemical, such as a pheromone we detect by smell or taste, or it could be tactile, involving direct physical touch. It could be an acoustic wave, detected by an auditory organ as sound and perceived through the sense of hearing, or it could be a vibrational wave detected by a vibration receiver of another sort. The medium through which the signal is transmitted could be any that exists on the Earth (solid, liquid or gas), and each type of medium influences the type of signal that is able to most efficiently move through it. PMID- 26954436 TI - Tissue Repair: How to Inflame Your Neighbours. AB - New work in Drosophila has identified a link between dying cells and compensatory proliferation of neighbouring survivor cells. Activation of initiator caspases in the dying cells stimulates the production of hydrogen peroxide, which orchestrates tissue repair via macrophages and TNF signalling. PMID- 26954437 TI - Zoology: The Walking Heads. AB - An analysis of Hox genes reveals that the body of the adorably weird tardigrades is essentially a truncated front end. This illustrates that loss and simplification are a hallmark of the evolution of animal body plans. PMID- 26954438 TI - Speciation: Genomic Archipelagos in a Crater Lake. AB - The opening stages of speciation remain poorly understood, especially from a genomic perspective. The genomes of newly discovered crater-lake cichlid fish shed light on the early phases of diversification and suggest that selection acts on multiple genomic regions. PMID- 26954439 TI - Visual Neuroscience: The Puzzle of Perceptual Stability. AB - Our world appears stable, although our eyes constantly shift its image across the retina. What brain mechanisms allow for this perceptual stability? A recent study has brought us a step closer to answering this millennial question. PMID- 26954440 TI - Evolution: Escaping the Inevitability of Ageing. AB - William Hamilton argued that even species inhabiting the farthest flung corners of the universe should age. However, a recent study shows that to find a species that escapes ageing, you only need to look as far as your local pond. PMID- 26954441 TI - Developmental Patterning: Putting the Squeeze on Mis-specified Cells. AB - Widely implicated in human disease, abnormal cellular cysts reflect dramatic defects in the maintenance of epithelial integrity. A new study reports that epithelial cysts may arise as a surprisingly general consequence of clonal defects in the specification of cell identity. PMID- 26954442 TI - Mitochondrial Dynamics: ER Actin Tightens the Drp1 Noose. AB - Drp1 is an oligomeric GTPase essential for mitochondrial division. A recent study has proposed a new model whereby machinery localized to the endoplasmic reticulum drives polymerization of actin, which then acts as a platform for Drp1 oligomerization and hydrolysis at mitochondrial constriction sites. PMID- 26954443 TI - Developmental Biology: Decapentaplegic Controls Growth at a Distance. AB - Decapentaplegic has long been thought to be a morphogen that controls patterning and growth in Drosophila wings, but hard evidence for the requisite long-range action has only now come from two new studies. PMID- 26954444 TI - Sexual Dimorphism: How Female Cells Win the Race. AB - Sexual dimorphisms are established by sex determination pathways and are maintained during regeneration of adult tissues. Two recent studies in Drosophila elucidate the contribution of cell-autonomous and endocrine mechanisms to the establishment and maintenance of growth dimorphism in larvae and the adult intestine. PMID- 26954445 TI - Snail Chirality: The Unwinding. AB - Most snails are coiled clockwise, but in some species rare genetic variants with reverse coiling occur. Now, a molecular determinant of coiling direction has been identified, the cytoskeletal regulator formin. PMID- 26954446 TI - Adhesively bonded versus non-bonded amalgam restorations for dental caries. AB - BACKGROUND: Dental caries (tooth decay) is one of the commonest diseases which afflicts mankind, and has been estimated to affect up to 80% of people in high income countries. Caries adversely affects and progressively destroys the tissues of the tooth, including the dental pulp (nerve), leaving teeth unsightly, weakened and with impaired function. The treatment of lesions of dental caries, which are progressing through dentine and have caused the formation of a cavity, involves the provision of dental restorations (fillings). This review updates the previous version published in 2009. OBJECTIVES: To assess the effects of adhesive bonding on the in-service performance and longevity of dental amalgam restorations. SEARCH METHODS: We searched the Cochrane Oral Health Group Trials Register (to 21 January 2016), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2015, Issue 12), MEDLINE via Ovid (1946 to 21 January 2016) and EMBASE via Ovid (1980 to 21 January 2016). We also searched the US National Institutes of Health Trials Registry (http://clinicaltrials.gov) and the WHO International Clinical Trials Registry Platform (www.who.int/ictrp/search/en) (both to 21 January 2016) for ongoing trials. No restrictions were placed on the language or date of publication when searching the electronic databases. SELECTION CRITERIA: Randomised controlled trials comparing adhesively bonded versus traditional non-bonded amalgam restorations in conventional preparations utilising deliberate retention, in adults with permanent molar and premolar teeth suitable for Class I and II amalgam restorations only. DATA COLLECTION AND ANALYSIS: Two review authors independently screened papers, extracted trial details and assessed the risk of bias in the included study. MAIN RESULTS: One trial with 31 patients who received 113 restorations was included. At two years, 50 out of 53 restorations in the non bonded group survived, and 55 of 60 bonded restorations survived with five unaccounted for at follow-up. Post-insertion sensitivity was not significantly different (P > 0.05) at baseline or two-year follow-up. No fractures of tooth tissue were reported and there was no significant difference between the groups or matched pairs of restorations in their marginal adaptation (P > 0.05). AUTHORS' CONCLUSIONS: There is no evidence to either claim or refute a difference in survival between bonded and non-bonded amalgam restorations. This review only found one under-reported trial. This trial did not find any significant difference in the in-service performance of moderately sized adhesively bonded amalgam restorations, in terms of their survival rate and marginal integrity, in comparison to non-bonded amalgam restorations over a two-year period. In view of the lack of evidence on the additional benefit of adhesively bonding amalgam in comparison with non-bonded amalgam, it is important that clinicians are mindful of the additional costs that may be incurred. PMID- 26954447 TI - Correction: Fat Metaplasia on Sacroiliac Joint Magnetic Resonance Imaging at Baseline Is Associated with Spinal Radiographic Progression in Patients with Axial Spondyloarthritis. PMID- 26954448 TI - Efficient Planar Perovskite Solar Cells with Reduced Hysteresis and Enhanced Open Circuit Voltage by Using PW12-TiO2 as Electron Transport Layer. AB - An electron transport layer is essential for effective operation of planar perovskite solar cells. In this Article, PW12-TiO2 composite was used as the electron transport layer for the planar perovskite solar cell in the device structure of fluorine-doped tin oxide (FTO)-glass/PW12-TiO2/perovskite/spiro OMeTAD/Au. A proper downward shift of the conduction band minimum (CBM) enhanced electron extraction from the perovskite layer to the PW12-TiO2 composite layer. Consequently, the common hysteresis effect in TiO2-based planar perovskite solar cells was significantly reduced and the open circuit voltage was greatly increased to about 1.1 V. Perovskite solar cells using the PW12-TiO2 compact layer showed an efficiency of 15.45%. This work can contribute to the studies on the electron transport layer and interface engineering for the further development of perovskite solar cells. PMID- 26954449 TI - Red blood cell non-ABO-identical transfusions are harmful: really? PMID- 26954450 TI - Ultramassive transfusion: give blood, save a life. PMID- 26954451 TI - TRANSFUSION MEDICINE ILLUSTRATED. Blood transfusion during the period of the Korean War in China. PMID- 26954453 TI - Lost in translation: signal and frequency amplification in animal modeling. PMID- 26954454 TI - Babesia screening: the importance of reporting and calibration in cost effectiveness models. PMID- 26954455 TI - Cost-effectiveness of a Babesia microti blood donation intervention based on real time prospective screening in endemic areas of the United States. PMID- 26954456 TI - Significant methemoglobinemia with bovine hemoglobin infusion in a case with severe autoimmune hemolytic anemia. PMID- 26954457 TI - Dealing with anti-CD38 (daratumumab) interference in blood compatibility testing. PMID- 26954458 TI - Reverse Water-Gas Shift or Sabatier Methanation on Ni(110)? Stable Surface Species at Near-Ambient Pressure. AB - The interaction of CO, CO2, CO + H2, CO2 + H2, and CO + CO2 + H2 with the nickel (110) single crystal termination has been investigated at 10(-1) mbar in situ as a function of the surface temperature in the 300-525 K range by means of infrared visible sum frequency generation (IR-vis SFG) vibrational spectroscopy and by near-ambient pressure X-ray photoelectron spectroscopy (NAP-XPS). Several stable surface species have been observed and identified. Besides atomic carbon and precursors for graphenic C phases, five nonequivalent CO species have been distinguished, evidencing the role of coadsorption effects with H and C atoms, of H-induced activation of CO, and of surface reconstruction. At low temperature, carbonate species produced by the interaction of CO2 with atomic oxygen, which stems from the dissociation of CO2 into CO + O, are found on the surface. A metastable activated CO2(-) species is also detected, being at the same time a precursor state toward dissociation into CO and O in the reverse water-gas shift mechanism and a reactive species that undergoes direct conversion in the Sabatier methanation process. Finally, the stability of ethylidyne is deduced on the basis of our spectroscopic observations. PMID- 26954459 TI - Proteomic profiling predicts drug response to novel targeted anticancer therapeutics. AB - Most recently approved anti-cancer drugs by the US FDA are targeted therapeutic agents and this represents an important trend for future anticancer therapy. Unlike conventional chemotherapy that rarely considers individual differences, it is crucial for targeted therapies to identify the beneficial subgroup of patients for the treatment. Currently, genomics and transcriptomics are the major 'omic' analytics used in studies of drug response prediction. However, proteomic profiling excels both in its advantages of directly detecting an instantaneous dynamic of the whole proteome, which contains most current diagnostic markers and therapeutic targets. Moreover, proteomic profiling improves understanding of the mechanism for drug resistance and helps finding optimal combination therapy. This article reviews the recent success of applications of proteomic analytics in predicting the response to targeted anticancer therapeutics, and discusses the potential avenues and pitfalls of proteomic platforms and techniques used most in the field. PMID- 26954460 TI - COMT genotype is associated with differential expression of muscarinic M1 receptors in human cortex. AB - Catechol-O-methyltransferase (COMT) genotype has been associated with varying levels of cognitive functioning and an altered risk of schizophrenia. COMT regulates the breakdown of catecholamines, particularly dopamine, which is thought critical in maintaining cognitive function and the aetiology of schizophrenia. This hypothesis gained support from reports that the VAL allele at rs4680 was associated with poorer performance on cognitive tests and a slightly increased risk of schizophrenia. More recently, genotype at rs4818, part of a hapblock with rs4680, has been shown to impact on cognitive ability more than genotype at rs4680 but, as yet, not the risk for schizophrenia. Here, we determined if COMT genotype at rs4680 or rs4818, as well as rs165519 and rs737865, two synonymous single nucleotide polymorphisms (SNPs) with no known functional consequences, were associated with an altered risk of schizophrenia and if genotype at the four COMT SNPs was related to expression of the cortical muscarinic M1 receptor (CHRM1) because the expression of the cortical CHRM1 has been reported to be lower in schizophrenia and is important in maintaining cognitive functioning in humans. We report that the variation in gene sequence at the four COMT SNPs studied was not associated with an altered the risk of schizophrenia but genotype at rs4680 and rs4818, but not rs165519 and rs737865, were associated with varying levels of cortical CHRM1 expression in the human dorsolateral prefrontal cortex (DLPFC). These data are the first to suggest that levels of CHRM1 in the human DLPFC are, in part, determined by COMT gene sequence. (c) 2016 Wiley Periodicals, Inc. PMID- 26954461 TI - Bone Healing and Hormonal Bioassay in Patients with Long-Bone Fractures and Concomitant Head Injury. AB - OBJECTIVE: The aim of this study is to investigate healing of fractures in patients with concomitant head injuries and to measure blood hormone levels to elucidate the mechanism of a possible accelerated osteogenesis. MATERIALS AND METHODS: One hundred and sixty-two patients were included in this study and divided into 3 cohorts: group A with head injuries only (n = 52); group B with head injuries as well as long-bone fractures (n = 50); group C with long-bone fractures only (n = 60). Fracture-healing parameters including time of appearance and thickness of the bridging callus, and blood hormonal assays were measured and compared using Student's t test. RESULTS: The mean time to healing was significantly lower in cohort B (6.9 +/- 2.9 weeks) than C (22.4 +/- 8.7 weeks; p = 0.001). The mean thickness of the healing callus was significantly higher in cohort B (26.3 +/- 9.7 mm) than C (8.1 +/- 5.9 mm; p = 0.002). The mean healing rate was also higher in cohort B (4.5 +/- 2.3 mm/week) than C (0.38 +/- 0.21 mm/week; p = 0.001). Blood hormonal assays in group B showed higher values of parathyroid hormone and growth hormone than in group C. However, adrenaline and noradrenaline values were lower in group B than in group C at all measured time intervals, and correspondingly leptin was lower in all groups (p = 0.001). Corticosteroid values were normal in group B compared to slightly higher values in group C, also at all measured time intervals. CONCLUSION: In this study, healing of fractures in patients with concomitant head injuries was accelerated, thereby indicating an involvement of a combined neurohormonal mechanism. PMID- 26954462 TI - Correlation between Methylation of Human Papillomavirus-16 L1 Gene and Cervical Carcinoma in Uyghur Women. AB - BACKGROUND: This study aims at determining the correlation between CpG methylation in human papillomavirus (HPV)-16 L1 and the persistent infections and development of cervical carcinoma in Uyghur women. METHODS: Among the 4,364 Uyghur women, specimens were collected from 145 (3.3%) HPV-16 single infected cases, which were divided into 5 groups: transient infection (n = 32), persistent infection (n = 21, 12 months), cervical intraepithelial neoplasia (CIN) grade 1 (CIN1, n = 21), CIN2-3 (n = 33) and invasive cervical cancer (n = 38) groups. Methylation level in HPV-16 L1 was quantified by pyrosequencing, and values in the prediction and diagnosis of CIN2+ lesions were evaluated with receiver operating characteristic curves. RESULTS: With the progression of the disease, increased methylation was detected at 13 CpG sites, and a high methylation level was associated with the risk of CIN2+. The strongest related site was 6650 (OR 9.89, 95% CI 3.57-27.44). The area under ROC curve (AUC) of methylation at each CpG site to differentiate between CIN2+ and 400 nm) and that the Fe2O3 sample synthesized in n-butyl alcohol exhibits the optimal photocatalytic activity. The synergistic photocatalysis for 4-Chlorophenol (4-CP) degradation and Cr(VI) reduction over above Fe2O3 sample is further investigated. The photocatalytic ratio of Cr(VI) reduction are enhanced from 24.8% to 70.2% while that of 4-CP oxidation are increased from 13.5% to 47.8% after 1 h visible light irradiation. The Fe2O3 sample keeps good degradation rates of mixed pollutants after 9 runs. The active oxygen intermediates O2(-), OH and H2O2 formed in the photoreaction process are discovered by ESR measurement and UV-vis test. The photocatalytic degradation mechanism is proposed accordingly. PMID- 26954473 TI - Coumarin-modified microporous-mesoporous Zn-MOF-74 showing ultra-high uptake capacity and photo-switched storage/release of U(VI) ions. AB - Driven by an energy crisis but consequently puzzled by various environmental problems, uranium, as the basic material of nuclear energy, is now receiving extensive attentions. In contrast to numerous sorbents applied in this field, metal-organic framework (MOFs), as a renovated material platform, has only recently been developed. How to improve the adsorption capacity of MOF materials towards U(VI) ions, as well as taking advantage of the nature of these MOFs to design photo-switched behaviour for photo-triggered storage/release of U(VI) ions are at present urgent problems and great challenges to be solved. Herein, we show a simple and facile method to target the goal. Through coordination-based post synthetic strategy, microporous- mesoporous Zn-MOF-74 was easily functionalized by grafting coumarin on coordinatively unsaturated Zn(II) centers, yielding a series of coumarin-modified Zn-MOF-74 materials. The obtained samples displayed ultra-high adsorption capacity for U(VI) ions from water at pH value of 4 with maximum adsorption capacities as high as 360 mg/g (the record value in MOFs) and a remarkable photo-switched capability of 50 mg/g at pH value of 4. To the best of knowledge, and in contrast to the well-known photo-switched behaviour towards CO2, dye (propidium iodide), as well as fluorescence observed in MOFs, this is the first study that shows a photo-switched behaviour towards radioactive U(VI) ions in aqueous solution. PMID- 26954474 TI - Benzothiazoles in indoor air from Albany, New York, USA, and its implications for inhalation exposure. AB - Benzothiazole and its derivatives (collectively referred to BTHs) are used widely in many consumer (e.g., textiles) and industrial (e.g., rubber) products. Very little is known about the occurrence of BTHs in indoor air and the inhalation exposure of humans to these substances. In this study, 81 indoor air samples collected from various locations in Albany, New York, USA, in 2014 were analyzed for BTHs by high-performance liquid chromatography-tandem mass spectrometry (HPLC MS/MS). BTHs were found in all indoor air samples, and the overall concentrations in bulk air (vapor plus particulate phases) were in the range of 4.36-2229 ng/m(3) (geometric mean: 32.7 ng/m(3)). The highest concentrations (geometric mean: 148 ng/m(3)) were found in automobiles, followed by homes (49.5)>automobile garages (46.0)>public places, e.g., shopping malls (24.2)>barbershops (18.9) >offices (18.8)>laboratories (15.1). The estimated geometric mean daily intake (EDI) of BTHs for infants, toddlers, children, teenagers, and adults through indoor air inhalation from homes was 27.7, 26.3, 17.9, 10.5, and 7.77 ng/kg bw/day, respectively. The estimated contribution of indoor air to total BTHs intake was approximately 10%. This is the first study on the occurrence of BTHs in indoor air. PMID- 26954472 TI - Enhanced bioreduction of iron and arsenic in sediment by biochar amendment influencing microbial community composition and dissolved organic matter content and composition. AB - Biochar derived from the pyrolysis at 500 degrees C with fresh biogas slurry and residue, was conducted to investigate its potential role in mediating the speciation and mobilization of As(V) and Fe(III) from arsenic-contaminated tailing mine sediment, with consideration of the changes in microbial populations and dissolved organic matter (DOM). The reduction of As(V) (10-13%) and Fe(III) (12-17%) were partly in response to biochar abiotically causing desorption and reduction effect, but were predominantly (87-90% and 83-88% for As(V) and Fe(III)) attributed to biochar stimulating biological reduction. The level of As(III) released from sediment upon biochar amendment (656.35+/-89.25 MUg L(-1)) was significantly higher than the level released without biochar amendment (98.06+/-19.38 MUg L(-1)) after 49 days incubation. Although a low level of Fe(II) (0.81+/-0.07 mg L(-1)) was determined in the solution when amending with biochar, most of released Fe(II) (166.25+/-40.25 mg L(-1)) was formed as biochar Fe(II)minerals composite. More importantly, biochar stimulated the DOM bioavailability in association with bacterial activities mediating As(V) and Fe(III) reduction. High-throughput sequencing results indicated biochar application shifted the soil microbial community and increased the relative abundance of As(V)-/Fe(III)-reducing bacteria, mostly Geobacter, Anaeromyxobacter, Desulfosporosinus and Pedobacter. The discovery of biochar bacteria-DOM consortium may broaden new understanding into speciation and mobilization of metals, which arouses attention to exploit feasible bioremediation for metal-contaminated sediment. PMID- 26954475 TI - Synergetic inhibition of thermochemical formation of chlorinated aromatics by sulfur and nitrogen derived from thiourea: Multielement characterizations. AB - Nitrogen and sulfur (N/S)-containing compounds inhibit the formation of polychlorinated dibenzo-p-dioxins (PCDDs) and furans (PCDFs) in thermal processes. However, few studies have examined the inhibition mechanisms of N/S containing compounds. In the present study, we focused on thiourea [(NH2)2CS] as such a compound and investigated its inhibition effects and mechanisms. The production of PCDD/Fs, polychlorinated biphenyls (PCBs), and chlorobenzenes (CBzs) were inhibited by >99% in the model fly ash in the presence of 1.0% thiourea after heating at 300 degrees C. Experimental results using real fly ash series were indicative of the thermal destruction of these chlorinated aromatics by thiourea. Multielement characterization using K-edge X-ray absorption fine structures of copper, chlorine, sulfur, nitrogen, and carbon revealed three possible inhibition paths, namely, (a) sulfidization of the copper catalyst to CuS, Cu2S, and CuSO4; (b) blocking the chlorination of carbon via the reaction of chlorine with N-containing compounds to generate ammonium chloride and other minor compounds; and (c) changing the carbon frame involved in attacking the carbon matrix by sulfur and nitrogen. Thus, thiourea plays a role as a sulfur and nitrogen donor to achieve multiple and synergistic inhibition of chlorinated aromatics. Our results suggest that other N/S-containing inhibitors function based on similar mechanisms. PMID- 26954476 TI - A solar light driven dual photoelectrode photocatalytic fuel cell (PFC) for simultaneous wastewater treatment and electricity generation. AB - In this paper, a novel dual heterojunction Photocatalytic Fuel Cell (PFC) system based on BiVO4/TiO2 nanotubes/FTO photoanode and ZnO/CuO nanowires/FTO photocathode has been designed. Compared with the electrodes in PFCs reported in earlier literatures, the proposed heterojunction not only enhances the visible light absorption but also offers a higher photoconversion efficiency. In addition, the nanostructured heterojunction owns a large surface area that ensures a large amount of active sites for organics degradation. The performance of the PFC base on the dual photoelectrodes was also studied herein. The results indicated that the PFC in ths paper exhibits a superior performance and its JV(max) reached 0.116 mw cm(-2), which is higher than that in most of reported PFCs with a Pt-free photocathode. When hazardous organic compounds such as methyl orange, Congo red and methylene blue were decomposed, the degradation rates obtained is to be 76%, 83%, and 90% respectively after 80 mins reaction. The proposed heterojunction photoelectrodes provided great potential for cost effective and high-efficiency organic pollutants degradation and electricity generation in a PFC system. PMID- 26954478 TI - UV/H2O2degradation of the antidepressants venlafaxine and O-desmethylvenlafaxine: Elucidation of their transformation pathway and environmental fate. AB - The aim of the present work is to investigate the removal and transformation of the antidepressants venlafaxine (VFX) and its main metabolite O desmethylvenlafaxine (DVFX) upon advanced oxidation with UV/H2O2 under lab conditions. High-resolution mass spectrometry (HRMS) analyses were carried out by means of ultra-high pressure liquid chromatography (UHPLC)-linear ion trap high resolution Orbitrap instrument (LTQ-Orbitrap-MS) in order to elucidate the different transformation products (TPs) generated. The depletion of both VFX and DVFX was very significant, with the 99.9% of both compounds eliminated after 5 and 30 min of reaction, respectively. Eleven TPs for VFX and six for DVFX were detected and their molecular structures elucidated by means of MS(2) and MS(3) scans, and the corresponding degradation pathways were proposed. The combined ecotoxicity at different treatment times was evaluated by means of bioluminescence inhibition assays with the marine bacteria Vibrio fischeri. Results showed an increase in the ecotoxicity during the UV/H2O2 experiment, especially at those reaction times where the total abundance of TPs was higher. PMID- 26954479 TI - Heterogeneous activation of H2O2 by defect-engineered TiO(2-x) single crystals for refractory pollutants degradation: A Fenton-like mechanism. AB - The heterogeneous catalyst plays a key role in Fenton-like reaction for advanced oxidation of refractory pollutants in water treatment. Titanium dioxide (TiO2) is a typical semiconductor with high industrial importance due to its earth abundance, low cost and no toxicity. In this work, it is found that TiO2 can heterogeneously activate hydrogen peroxide (H2O2, E degrees =1.78 eV), a common chemical oxidant, to efficiently generate highly-powerful hydroxyl radical, OH (E(0)=2.80 eV), for advanced water treatment, when its crystal shape, exposed facet and oxygen-stoichiometry are finely tuned. The defect-engineered TiO2 single crystals exposed by high-energy {001} facets exhibited an excellent Fenton like activity and stability for degrading typical refractory organic pollutants such as methyl orange and p-nitrophenol. Its defect-centered Fenton-like superiority is mainly attributed to the crystal oxygen-vacancy, single crystalline structure and exposed polar {001} facet. Our findings could provide new chance to utilize TiO2 for Fenton-like technology, and develop novel heterogeneous catalyst for advanced water treatment. PMID- 26954477 TI - Auxin effects on Pb phytoextraction from polluted soils by Tegetes minuta L. and Bidens pilosa L.: Extractive power of their root exudates. AB - The principal impediment for Pb uptake by plants is the Casparian strip in roots. It prevents metals reaching the xylem, thereby hampering translocation to the aerial organs. In the root apices, young root cells have thin cell walls and the Casparian strip is not completely developed, which could facilitate Pb uptake by roots at these vulnerable points. However, as the phytotoxic effects of Pb reduce root growth and enhance suberization, entry of Pb into the plant is avoided. We propose that the application of root growth promotors could be an important complement in the phytoextraction of Pb from polluted soils, due to their effects on produced biomass, Pb toxicity, and root exudate production. A greenhouse experiment was carried on to evaluate the auxin application effect on the Pb uptake of Bidens pilosa and Tagetes minuta. These species were sensitive to auxins, but the phytotoxic effect of Pb was not reversed by this treatment. Root exudates capable of extracting Pb were produced only when the species were grown in highly polluted soils, indicating a behavioral response to Pb exposure which is desirable for phytoremediation. PMID- 26954480 TI - Perceived health status and life satisfaction in old age, and the moderating role of social support. AB - OBJECTIVES: The aim of this study was on one hand to examine the associations between health impairment and life satisfaction, as well as social support and life satisfaction, and on the other, to analyze the moderating effect of social support with regard to health impairment and life satisfaction in a sample of community-dwelling older adults from urban areas of Granada, southern Spain. METHOD: This was a cross-sectional survey in which a sample of 406 older adults with ages between 65 and 99 years old (Mage = 74.88, SD = 6.75) was selected. Multiple stepwise regression analysis was used to assess the impact of health impairment and perceived social support on life satisfaction. Moderation analysis was performed using the bias-corrected and accelerated bootstrapping approach. RESULTS: Significant differences in life satisfaction scores were found by number and type of disease, restrictions in daily life activities and subjective health. Perceived health and perceived social support predicted life satisfaction. Besides global social support, emotional and affectionate support moderated the link between perceived health and life satisfaction. CONCLUSIONS: Older people who do not rate their health status positively and indicate low levels of social support have a higher risk of being dissatisfied with their lives and due to this they should receive special attention from gerontologists. PMID- 26954483 TI - C(sp(2))-H Functionalization of 2H-Indazoles at C3-Position via Palladium(II) Catalyzed Isocyanide Insertion Strategy Leading to Diverse Heterocycles. AB - Herein, we have reported an efficient Pd-catalyzed C-H functionalization of 2H indazole at C3-position via an isocyanide insertion strategy for the synthesis of unprecedented benzoxazinoindazoles, indazoloquinaoxalines and benzoxazinoindazolones for the first time. Our new method provides an operationally simple and versatile route for a selective synthesis of 2-(2H indazol-2-yl)phenols. Furthermore, we developed a sequential one-pot strategy for the synthesis of benzoxazinoindazolone under metal-oxidant-free conditions. We also achieved the isocyanide insertion between C(sp(2))-H and oxygen heteroatom for the first time. The key features of the present protocol are construction of 4 bonds in one-pot, synthesis of new skeletally diverse scaffolds, broad substrate scope, high yields and environmentally benign conditions. PMID- 26954481 TI - Intratracheal atomized surfactant provides similar outcomes as bolus surfactant in preterm lambs with respiratory distress syndrome. AB - BACKGROUND: Aerosolization of exogenous surfactant remains a challenge. This study is aimed to evaluate the efficacy of atomized poractant alfa (Curosurf) administered with a novel atomizer in preterm lambs with respiratory distress syndrome. METHODS: Twenty anaesthetized lambs, 127 +/- 1 d gestational age, (mean +/- SD) were instrumented before birth and randomized to receive either (i) positive pressure ventilation without surfactant (Control group), (ii) 200 mg/kg of bolus instilled surfactant (Bolus group) at 10 min of life or (iii) 200 mg/kg of atomized surfactant (Atomizer group) over 60 min from 10 min of life. All lambs were ventilated for 180 min with a standardized protocol. Lung mechanics, regional lung compliance (electrical impedance tomography), and carotid blood flow (CBF) were measured with arterial blood gas analysis. RESULTS: Dynamic compliance and oxygenation responses were similar in the Bolus and Atomizer groups, and both better than Control by 180 min (all P < 0.05; two-way ANOVA). Both surfactant groups demonstrated more homogeneous regional lung compliance throughout the study period. There were no differences in CBFConclusion:In a preterm lamb model, atomized surfactant resulted in similar gas exchange and mechanics as bolus administration. This study suggests evaluation of supraglottic atomization with this system when noninvasive support is warranted. PMID- 26954486 TI - Analysis of Prescribers' Notes in Electronic Prescriptions in Ambulatory Practice. AB - IMPORTANCE: The optional free-text Notes field in ambulatory electronic prescriptions (e-prescriptions) allows prescribers to communicate additional prescription-related information to dispensing pharmacists. However, populating this field with irrelevant or inappropriate information can create confusion, workflow disruptions, and potential patient harm. OBJECTIVES: To analyze the content of free-text prescriber notes in new ambulatory e-prescriptions and to develop recommendations to improve e-prescribing practices. DESIGN, SETTING, AND PARTICIPANTS: We performed a qualitative analysis of e-prescriptions containing free-text prescriber notes for conformance to the intended purpose of the free text field as established in the national e-prescribing standard. The study sample contained 26 341 new e-prescriptions randomly selected from 3 024 737 e prescriptions containing notes transmitted to community pharmacies across the United States during a 1-week period (November 10-16, 2013). The study e prescriptions were issued by 22 549 community-based prescribers using 492 different electronic health record (EHR) or e-prescribing software application systems. Data analysis was conducted from February 23, 2014, to November 4, 2015. MAIN OUTCOMES AND MEASURES: Reviewers classified free-text prescriber notes as appropriate, inappropriate (content for which a standard, structured data-entry field is available in the widely implemented national e-prescribing standard), or unnecessary (irrelevant to dispensing pharmacists). We developed and applied a classification scheme to further characterize and quantify types of appropriate and inappropriate content. RESULTS: Of the 26 341 free-text notes, 17 421 (66.1%) contained inappropriate content, 7522 (28.6%) contained appropriate content, and 1398 (5.3%) contained information considered to be unnecessary. Further characterization of inappropriate content resulted in 20 192 classification codes, of which 3841 codes (19.0%) were assigned because of patient directions that conflicted with directions included in the designated standard field intended for this purpose. Characterization of appropriate content resulted in 7785 classification codes, of which 3685 (47.3%) contained information that could be communicated using structured fields already approved in a yet-to-be implemented version of the e-prescribing standard. An additional 745 (9.6%) were prescription cancellation requests for which a separate e-prescribing message currently exists but is not widely supported by software vendors or used by prescribers. CONCLUSIONS AND RELEVANCE: The free-text Notes field in e prescriptions is frequently used inappropriately, suggesting the need for better prerelease usability testing, consistent end user training and feedback, and rigorous postmarketing evaluation and surveillance of EHR or e-prescribing software applications. Accelerated implementation of new e-prescribing standards and rapid adoption of existing ones could also reduce prescribers' reliance on free-text use in ambulatory e-prescriptions. PMID- 26954485 TI - Bone mineral density and intervertebral disc height in type 2 diabetes. AB - BACKGROUND: Studies of the effect of type 2 diabetes (T2D) on bone mineral density (BMD have produced conflicting results, possibly due to failure to adjust for potential confounding factors. Nonetheless, T2D has consistently been associated with increased fracture risk, suggesting that other factors might play a role. OBJECTIVE: This study assesses the relationship between T2D and BMD at the femoral neck and spine in diabetic and non-diabetic subjects, after adjusting for multiple covariates which may affect BMD. Intervertebral disc height was also investigated in view of its possible relation to fracture risk. METHODS: A cross sectional study of 100 patients with T2DM of at least 5 years duration and 86 non diabetic subjects was carried out. RESULTS: There were no significant differences in T scores in either the spine or femoral neck after adjustment for potential confounding variables between T2D subjects and controls. Diabetic patients had a statistically lower intervertebral disc height between the 2nd and 3rd lumbar vertebrae (D3) after adjustment for potential confounders (p=0.004). Urinary albumin:creatinine ratio, total cholesterol, LDL-cholesterol and cigarette smoking were independently associated with lower height of D3 in diabetic subjects. CONCLUSIONS: There is no significant independent association between T2D and BMD. However we found a novel association of significantly lower disc height in patients with T2D. This may contribute to the increased vertebral fracture risk in subjects with T2D. Further studies are needed to investigate the relationship of disc height, T2D and fracture risk. PMID- 26954484 TI - The effects of garlic extract upon endothelial function, vascular inflammation, oxidative stress and insulin resistance in adults with type 2 diabetes at high cardiovascular risk. A pilot double blind randomized placebo controlled trial. AB - BACKGROUND AND AIMS: Endothelial dysfunction, vascular inflammation and oxidative stress have been integrally linked to the pathogenesis of both type 2 diabetes and cardiovascular disease. Aged Garlic Extract (AGE), a potent antioxidant, has been shown in previous studies to attenuate these novel risk factors in a non diabetic population. AIMS: This study tested the hypothesis that AGE may improve endothelial function, oxidative stress, vascular inflammation and insulin resistance in high risk cardiovascular subjects with type 2 diabetes. METHODS: A double blind, placebo controlled crossover pilot study was performed in 26 subjects with type 2 diabetes who received 1200 mg of AGE or placebo daily for 4 weeks with a 4 week washout period. Plasma HsCRP was measured as a marker of inflammation. Plasma TAOS, blood GSH/GSSG and plasma LHP were measured as markers of oxidative stress/anti-oxidant defense. Insulin resistance was measured using the HOMA-IR method. Endothelial function was measured using change in the reflective index (RI) post-salbutamol using digital photoplethysmography and urinary albumin/creatinine ratio was measured as a biochemical surrogate. Measurements were taken at baseline and after intervention with AGE or placebo. RESULTS: Of the 26 patients studied (male 17, female 9), age was 61 +/- 8 years (mean +/- 1 SD), HbA1c 7.2 +/- 1.1%, BP 130/75 +/- 15.9/9.8 mmHg, total cholesterol 4.2 +/- 0.81 mmol/l, triglyceride 2.11 +/- 1.51 mmol/l, and HDL cholesterol 1.04 +/- 0.29 mmol/l. The majority of patients were being treated with metformin (59%), aspirin (50%) and statin (96%) therapy. 36% were treated with an ACEI. There were no changes in these therapies throughout the study. Treatment with AGE had no significant effect upon the above metabolic parameters including insulin resistance. Treatment with AGE also had no significant effect on markers of endothelial function (plethysmography), oxidative stress (TAOS, GSH/GSSG, LHP) or inflammation (HsCRP). CONCLUSION: In this group of type 2 diabetic patients at high cardiovascular risk, 4 weeks treatment with AGE did not significantly improve endothelial function, vascular inflammation, oxidative stress or insulin resistance. PMID- 26954482 TI - Cardiovascular and Renal Outcomes of Renin-Angiotensin System Blockade in Adult Patients with Diabetes Mellitus: A Systematic Review with Network Meta-Analyses. AB - BACKGROUND: Medications aimed at inhibiting the renin-angiotensin system (RAS) have been used extensively for preventing cardiovascular and renal complications in patients with diabetes, but data that compare their clinical effectiveness are limited. We aimed to compare the effects of classes of RAS blockers on cardiovascular and renal outcomes in adults with diabetes. METHODS AND FINDINGS: Eligible trials were identified by electronic searches in PubMed/MEDLINE and the Cochrane Database of Systematic Reviews (1 January 2004 to 17 July 2014). Interventions of interest were angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and direct renin (DR) inhibitors. The primary endpoints were cardiovascular mortality, myocardial infarction, and stroke-singly and as a composite endpoint, major cardiovascular outcome-and end stage renal disease [ESRD], doubling of serum creatinine, and all-cause mortality singly and as a composite endpoint, progression of renal disease. Secondary endpoints were angina pectoris and hospitalization for heart failure. In all, 71 trials (103,120 participants), with a total of 14 different regimens, were pooled using network meta-analyses. When compared with ACE inhibitor, no other RAS blocker used in monotherapy and/or combination was associated with a significant reduction in major cardiovascular outcomes: ARB (odds ratio [OR] 1.02; 95% credible interval [CrI] 0.90-1.18), ACE inhibitor plus ARB (0.97; 95% CrI 0.79 1.19), DR inhibitor plus ACE inhibitor (1.32; 95% CrI 0.96-1.81), and DR inhibitor plus ARB (1.00; 95% CrI 0.73-1.38). For the risk of progression of renal disease, no significant differences were detected between ACE inhibitor and each of the remaining therapies: ARB (OR 1.10; 95% CrI 0.90-1.40), ACE inhibitor plus ARB (0.97; 95% CrI 0.72-1.29), DR inhibitor plus ACE inhibitor (0.99; 95% CrI 0.65-1.57), and DR inhibitor plus ARB (1.18; 95% CrI 0.78-1.84). No significant differences were showed between ACE inhibitors and ARBs with respect to all-cause mortality, cardiovascular mortality, myocardial infarction, stroke, angina pectoris, hospitalization for heart failure, ESRD, or doubling serum creatinine. Findings were limited by the clinical and methodological heterogeneity of the included studies. Potential inconsistency was identified in network meta-analyses of stroke and angina pectoris, limiting the conclusiveness of findings for these single endpoints. CONCLUSIONS: In adults with diabetes, comparisons of different RAS blockers showed similar effects of ACE inhibitors and ARBs on major cardiovascular and renal outcomes. Compared with monotherapies, the combination of an ACE inhibitor and an ARB failed to provide significant benefits on major outcomes. Clinicians should discuss the balance between benefits, costs, and potential harms with individual diabetes patients before starting treatment. REVIEW REGISTRATION: PROSPERO CRD42014014404. PMID- 26954487 TI - Individual differences in flow proneness are linked to a dopamine D2 receptor gene variant. AB - Flow is a special mental state characterized by deep concentration that occurs during the performance of optimally challenging tasks. In prior studies, proneness to experience flow has been found to be moderately heritable. In the present study, we investigated whether individual differences in flow proneness are related to a polymorphism of the dopamine D2 receptor coding gene (DRD2 C957T rs6277). This polymorphism affects striatal D2 receptor availability, a factor that has been shown to be related to flow proneness. To our knowledge, this is the first study to investigate the association between this trait and a specific gene variant. In a sample of 236 healthy Hungarian adults, we found that CC homozygotes report higher flow proneness than do T allele carriers, but only during mandatory activities (i.e., studying and working), not during leisure time. We discuss implications of this result, e.g., the potential mediators of the relationship. PMID- 26954488 TI - Minding gaps on the skin: Opposite bisection biases on forehead and back of one's head. AB - Humans perceive the world from an egocentric perspective, while being able to mentally take a third person's perspective. Graphesthesia tasks revealed that letters written on the back of one's own head are consistently perceived from an embodied perspective, while the perspective on one's front is less consistent and often disembodied. We developed a cutaneous gap bisection task as a more discrete measure of the perspective on the body. In analogy to a visual pseudoneglect, we expected bisections to deviate toward the left ear when perceived from an embodied perspective. While this hypothesis was confirmed for gap bisections on the back, the results on the front suggest overall a disembodied perspective. Contrary to our expectation, this pattern was not predicted by the spontaneous perspective participants took in a graphesthesia task, indicating different cognitive mechanisms. We discuss these findings in the frame of the current literature on spatial attention and perspective taking. PMID- 26954489 TI - Decisions at the end of life made by relatives of institutionalized patients with dementia. AB - BACKGROUND: The wishes and preferences of patients with dementia should inform the decisions made about their future care. However, the decision-making that occurs at the end of life is a difficult experience for the families of patients. With regard to decision-making in the terminal stages, few studies have explored the experiences and feelings of caregivers of persons with dementia who are institutionalized. AIM: To describe the processes of decision-making used by families regarding treatments at the end of life of institutionalized patients with advanced stages of dementia. METHODS: Five focus groups were conducted in five nursing homes in Spain, representing a total of 84 familiars. RESULTS: Five categories that describe the context for decision-making were identified: the emotional effect, the "living death," the two faces of death, the values and objectives regarding treatments at the end of life, and the lack of knowledge about the progression of dementia. CONCLUSIONS: The participants have unresolved emotional needs resulting from both the disease and the institutionalization of a member of their family. The participants were unprepared to make end-of-life treatment decisions, and they lacked a consistent healthcare provider to provide informational and emotional support that would have helped with decision-making. The carers' own wishes and preferences were shaped by their perceptions and experiences of the dementia illness. PMID- 26954490 TI - The use of laser in hysteroscopic surgery. AB - The term laser, an acronym for light amplification by stimulated emission of radiation, covers a wide range of devices. Lasers are commonly described by the emitted wavelength that covers the entire light spectrum from infrared to ultraviolet and the active lasing medium. Currently, over forty different types of lasers have found application in medicine. Moreover, advances made by gynecologists in the field of operative hysteroscopy have developed a very great interest in the use of surgical lasers. Technical improvements in hysteroscopes and lasers have led several gynecologists to evaluate their use in the surgical treatment of intrauterine pathologies. This narrative review concerns the most common used lasers in hysteroscopic surgery with particular attention to the latest promising results of the laser technology. PMID- 26954491 TI - Comment on "Application of the Activity Framework for Assessing Aquatic Ecotoxicology Data for Organic Chemicals". PMID- 26954492 TI - American Pancreatic Association: 2015 Vay Liang and Frisca Go Award for Lifetime Achievement, APA Distinguished Service Award, and Other Awardees. PMID- 26954493 TI - The Standardization of Pancreatoduodenectomy: Where Are We? AB - Pancreaticoduodenectomy (PD) represents an important challenge for surgeons due to the complexity of the operation, requirement for technical skills and experience, and postoperative management involving important and life-threatening complications. Despite efforts to reduce mortality in high-volume centers, the morbidity rate is still high (approximately 40-50%). The PD standardization process of surgical aspects and preoperative and postoperative settings is essential to permit pancreatic surgeons to communicate in the same language, compare experiences and results, and to improve the short- and long-term outcomes. The aim of this article is to assess the state of the art practices for important matters of debate for PD (the role of mini invasive approach, the definition and the role of mesopancreas, the extent of lymphadenectomy, the different methods of reconstructions, the prophylactic drainage of the abdominal cavity), and to suggest possible future studies. PMID- 26954494 TI - Support Vector Machine Based on microRNA Expression Profiles to Predict Histological Origin of Ampullary Carcinoma: Case Report of a Patient Affected From Adenocarcinoma of the Papilla of Vater With Lynch Syndrome. AB - Adenocarcinomas of Vater's papilla (PVAC) may originate from either the pancreatic duct or the intestinal epithelium. Conflicting data have been reported about the frequency of the 2 anatomical entities and their influence on patients' prognosis. To ascertain the anatomical origin of PVAC in a family member of a Lynch syndrome kindred, we searched for microRNA (miRNA) expression profiles on resected tumor specimens. The support vector machine was trained on our previous miRNAs expression data sets of pancreatic and colorectal tissue samples and used to classify the site of origin of the tumor in our patient. The support vector machine worked by contrasting the profiles of miRNAs in patients with pancreatic ductal and colorectal cancers to that of our patient, which was finally classified as pancreatic ductal adenocarcinoma accordingly to alterations of 55 miRNAs. The PVAC might be originated from ductal epithelium rather than from the intestinal mucosa of the papilla in the case at issue. Alteration of miR-548b-3p, miR-551a, miR-21, miR-92a, miR-let-7i, and miR-181a* emerged as potentially associated with cancer genetic susceptibility in PVAC. PMID- 26954495 TI - MDM2 SNP 309G Allele Is Associated With Younger Age at Surgery in Chronic Pancreatitis Patients. PMID- 26954496 TI - Severe Tumor Lysis Syndrome in a Patient With Pancreatic Adenocarcinoma. PMID- 26954497 TI - Diabetes Mellitus and Pancreatic Cysts in African Americans. PMID- 26954498 TI - Effect of Workplace Counseling Interventions Launched by Workplace Health Promotion and Tobacco Control Centers in Taiwan: An Evaluation Based on the Ottawa Charter. AB - Workplace health promotion (WHP) is important to prevent work-related diseases, reduce workplace hazards, and improve personal health of the workers. Health promotion projects were launched through the centers of WHP funded by the Taiwan Bureau of Health Promotion since 2003. Hence, the aim of this study is to evaluate the impact of WHP programs intervention from 2003 to 2007. The intervention group consisted of 838 business entities which had ever undergone counseling of the three centers in northern, central, and southern Taiwan from 2003 to 2007. The control group was composed of 1000 business entities randomly selected from the business directories of the Ministry of Economic Affairs, Taiwan. The questionnaire survey included general company profiles and the assessment of workplace health according to the five action areas of the Ottawa Charter for Health Promotion. We have received 447 (53.3%) questionnaires from the intervention group and 97 questionnaires from the control group. The intervention group was more effective in using the external resources and medical consultation, and they had better follow-up rates of the abnormal results of annual health examinations. Compared to the control group, the intervention group had a significantly decreased smoking rate in 246 companies (61.2%) and a reduced second-hand smoke exposure in 323 companies (78.6%) (p<0.001). By means of the intervention of WHP programs, we can enhance the awareness of the enterprises and the employees to improve worksite health and to create a healthy work environment. PMID- 26954499 TI - Hierarchy of Dysfunction Related to Dressing Performance in Stroke Patients: A Path Analysis Study. AB - Previous reports indicated that various dysfunctions caused by stroke affect the level of independence in dressing. These dysfunctions can be hierarchical, and these effects on dressing performance can be complicated in stroke patients. However, there are no published reports focusing on the hierarchical structure of the relationships between the activities of daily living and balance function, motor and sensory functions of the affected lower limb, strength of the abdominal muscles and knee extension on the unaffected side, and visuospatial deficits. The purpose of this study was to elucidate the hierarchical and causal relationships between dressing performance and these dysfunctions in stroke patients. This retrospective study included 104 first-time stroke patients. The causal relationship between the dressing performance and age, time post stroke, balance function, motor and sensory functions of the affected lower limb, strength of the abdominal muscles and knee extension on the unaffected side, and visuospatial deficits were examined using path analysis. A hypothetical path model was created based on previous studies, and the goodness of fit between the data and model were verified. A modified path model was created that achieved an almost perfect fit to the data. Balance function and abdominal muscle strength have direct effects on dressing performance, with standardized direct effect estimates of 0.78 and 0.15, respectively. Age, motor and sensory functions of the affected lower limb, and strength of abdominal muscle and knee extension on the unaffected side have indirect effects on dressing by influencing balance function. Our results suggest that dressing performance depends strongly on balance function, and it is mainly influenced by the motor function of the affected lower limb. PMID- 26954500 TI - Effect of Rocking Movements on Respiration. AB - For centuries, rocking has been used to promote sleep in babies or toddlers. Recent research suggested that relaxation could play a role in facilitating the transition from waking to sleep during rocking. Breathing techniques are often used to promote relaxation. However, studies investigating head motions and body rotations showed that vestibular stimulation might elicit a vestibulo-respiratory response, leading to an increase in respiration frequency. An increase in respiration frequency would not be considered to promote relaxation in the first place. On the other hand, a coordination of respiration to rhythmic vestibular stimulation has been observed. Therefore, this study aimed to investigate the effect of different movement frequencies and amplitudes on respiration frequency. Furthermore, we tested whether subjects adapt their respiration to movement frequencies below their spontaneous respiration frequency at rest, which could be beneficial for relaxation. Twenty-one healthy subjects (24-42 years, 12 males) were investigated using an actuated bed, moving along a lateral translation. Following movement frequencies were applied: +30%, +15%, -15%, and -30% of subjects' rest respiration frequency during baseline (no movement). Furthermore, two different movement amplitudes were tested (Amplitudes: 15 cm, 7.5 cm; movement frequency: 0.3 Hz). In addition, five subjects (25-28 years, 2 males) were stimulated with their individual rest respiration frequency. Rocking movements along a lateral translation caused a vestibulo-respiratory adaptation leading to an increase in respiration frequency. The increase was independent of the applied movement frequencies or amplitudes but did not occur when stimulating with subjects' rest respiration frequency. Furthermore, no synchronization of the respiration frequency to the movement frequency was observed. In particular, subjects did not lower their respiration frequency below their resting frequency. Hence, it was not feasible to influence respiration in a manner that might be considered beneficial for relaxation. PMID- 26954501 TI - The Development of Metaphor Comprehension and Its Relationship with Relational Verbal Reasoning and Executive Function. AB - Our main objective was to analyse the different contributions of relational verbal reasoning (analogical and class inclusion) and executive functioning to metaphor comprehension across development. We postulated that both relational reasoning and executive functioning should predict individual and developmental differences. However, executive functioning would become increasingly involved when metaphor comprehension is highly demanding, either because of the metaphors' high difficulty (relatively novel metaphors in the absence of a context) or because of the individual's special processing difficulties, such as low levels of reading experience or low semantic knowledge. Three groups of participants, 11 year-olds, 15-year-olds and young adults, were assessed in different relational verbal reasoning tasks-analogical and class-inclusion-and in executive functioning tasks-updating information in working memory, inhibition, and shifting. The results revealed clear progress in metaphor comprehension between ages 11 and 15 and between ages 15 and 21. However, the importance of executive function in metaphor comprehension was evident by age 15 and was restricted to updating information in working memory and cognitive inhibition. Participants seemed to use two different strategies to interpret metaphors: relational verbal reasoning and executive functioning. This was clearly shown when comparing the performance of the "more efficient" participants in metaphor interpretation with that of the "less efficient" ones. Whereas in the first case none of the executive variables or those associated with relational verbal reasoning were significantly related to metaphor comprehension, in the latter case, both groups of variables had a clear predictor effect. PMID- 26954502 TI - On the selectivity of the Galphaq inhibitor UBO-QIC: A comparison with the Galphai inhibitor pertussis toxin. AB - Galphaq inhibitor UBO-QIC (FR900359) is becoming an important pharmacological tool, but its selectivity against other G proteins and their subunits, especially betagamma, has not been well characterized. We examined UBO-QIC's effect on diverse signaling pathways mediated via various G protein-coupled receptors (GPCRs) and G protein subunits by comparison with known Galphai inhibitor pertussis toxin. As expected, UBO-QIC inhibited Galphaq signaling in all assay systems examined. However, other non-Galphaq-events, e.g. Gbetagamma-mediated intracellular calcium release and inositol phosphate production, following activation of Gi-coupled A1 adenosine and M2 muscarinic acetylcholine receptors, were also blocked by low concentrations of UBO-QIC, indicating that its effect is not limited to Galphaq. Thus, UBO-QIC also inhibits Gbetagamma-mediated signaling similarly to pertussis toxin, although UBO-QIC does not affect Galphai-mediated inhibition or Galphas-mediated stimulation of adenylyl cyclase activity. However, the blockade by UBO-QIC of GPCR signaling, such as carbachol- or adenosine mediated calcium or inositol phosphate increases, does not always indicate inhibition of Galphaq-mediated events, as the betagamma subunits released from Gi proteins following the activation of Gi-coupled receptors, e.g. M2 and A1Rs, may produce similar signaling events. Furthermore, UBO-QIC completely inhibited Akt signaling, but only partially blocked ERK1/2 activity stimulated by the Gq coupled P2Y1R. Thus, we have revealed new aspects of the pharmacological interactions of UBO-QIC. PMID- 26954503 TI - Role of Gemcitabine and Pemetrexed as Maintenance Therapy in Advanced NSCLC: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. AB - BACKGROUND: Gemcitabine and pemetrexed have been used as maintenance therapy. However, few systematic reviews and meta-analyses have assessed their effects in the newest studies. This systematic review and meta-analysis were conducted to assess the role of gemcitabine and pemetrexed in the maintenance treatment of non small-cell lung carcinoma (NSCLC). METHODS: We performed a literature search using PubMed, EMBASE and Cochrane library databases from their inceptions to September 16, 2015. We also searched the American Society of Clinical Oncology (ASCO), European Society for Medical Oncology (ESMO), and National Comprehensive Cancer Network (NCCN) databases from 2008 to 2015. Two authors independently extracted the data. The Cochrane Collaboration's risk of bias graph was used to assess the risk of bias. The GRADE system was used to assess the grading of evidence, and a meta-analysis was conducted using Stata 11.0 software. RESULTS: Eleven randomized controlled trial (RCT) studies were collected. Ten studies were included in the meta-analysis and divided into the following 4 groups: gemcitabine vs. best supportive care (BSC)/observation, pemetrexed vs. BSC/placebo, pemetrexed + bevacizumab vs. bevacizumab and pemetrexed vs. bevacizumab. Gemcitabine exhibited significantly improved progression-free survival (PFS) compared with BSC (hazard ratio (HR) = 0.62, p = 0.000). Pemetrexed exhibited significantly improved PFS (HR = 0.54, p = 0.000) and OS (HR = 0.75, p = 0.000) compared with BSC. Pemetrexed + bevacizumab almost exhibited significantly improved PFS (HR = 0.71, p = 0.051) compared with bevacizumab. Pemetrexed exhibited no improvement in PFS or overall survival (OS) compared with bevacizumab. Regarding the grade, the GRADE system indicated that the gemcitabine group was "MODERATE", the pemetrexed group was "HIGH", and both the pemetrexed + bevacizumab vs. bevacizumab groups and pemetrexed vs. B groups were "LOW". CONCLUSIONS: Gemcitabine or pemetrexed compared with BSC/observation/placebo significantly improved PFS or OS. Whether pemetrexed + bevacizumab compared with bevacizumab alone significantly improves PFS requires further investigation. PMID- 26954507 TI - CLUSTOM-CLOUD: In-Memory Data Grid-Based Software for Clustering 16S rRNA Sequence Data in the Cloud Environment. AB - High-throughput sequencing can produce hundreds of thousands of 16S rRNA sequence reads corresponding to different organisms present in the environmental samples. Typically, analysis of microbial diversity in bioinformatics starts from pre processing followed by clustering 16S rRNA reads into relatively fewer operational taxonomic units (OTUs). The OTUs are reliable indicators of microbial diversity and greatly accelerate the downstream analysis time. However, existing hierarchical clustering algorithms that are generally more accurate than greedy heuristic algorithms struggle with large sequence datasets. To keep pace with the rapid rise in sequencing data, we present CLUSTOM-CLOUD, which is the first distributed sequence clustering program based on In-Memory Data Grid (IMDG) technology-a distributed data structure to store all data in the main memory of multiple computing nodes. The IMDG technology helps CLUSTOM-CLOUD to enhance both its capability of handling larger datasets and its computational scalability better than its ancestor, CLUSTOM, while maintaining high accuracy. Clustering speed of CLUSTOM-CLOUD was evaluated on published 16S rRNA human microbiome sequence datasets using the small laboratory cluster (10 nodes) and under the Amazon EC2 cloud-computing environments. Under the laboratory environment, it required only ~3 hours to process dataset of size 200 K reads regardless of the complexity of the human microbiome data. In turn, one million reads were processed in approximately 20, 14, and 11 hours when utilizing 20, 30, and 40 nodes on the Amazon EC2 cloud-computing environment. The running time evaluation indicates that CLUSTOM-CLOUD can handle much larger sequence datasets than CLUSTOM and is also a scalable distributed processing system. The comparative accuracy test using 16S rRNA pyrosequences of a mock community shows that CLUSTOM CLOUD achieves higher accuracy than DOTUR, mothur, ESPRIT-Tree, UCLUST and Swarm. CLUSTOM-CLOUD is written in JAVA and is freely available at http://clustomcloud.kopri.re.kr. PMID- 26954504 TI - A Human "eFP" Browser for Generating Gene Expression Anatograms. AB - Transcriptomic studies help to further our understanding of gene function. Human transcriptomic studies tend to focus on a particular subset of tissue types or a particular disease state; however, it is possible to collate into a compendium multiple studies that have been profiled using the same expression analysis platform to provide an overview of gene expression levels in many different tissues or under different conditions. In order to increase the knowledge and understanding we gain from such studies, intuitive visualization of gene expression data in such a compendium can be useful. The Human eFP ("electronic Fluorescent Pictograph") Browser presented here is a tool for intuitive visualization of large human gene expression data sets on pictographic representations of the human body as gene expression "anatograms". Pictographic representations for new data sets may be generated easily. The Human eFP Browser can also serve as a portal to other gene-specific information through link-outs to various online resources. PMID- 26954510 TI - Cellular respiration: replicating in vivo systems biology for in vitro exploration of human exposome, microbiome, and disease pathogenesis biomarkers. PMID- 26954511 TI - The Mutual Relationship Between Immigrants' Disrupted Everyday Activities and Their Health: A Grounded Theory of Experiences of Korean Immigrants Settling in New Zealand. AB - For Asian immigrants, immigration has the potential to disrupt all familiar routines. That is a threat to their health and well-being. This grounded theory study explored how immigrants adjust to a new environment by analyzing the experiences of 25 Korean immigrants in New Zealand. The findings suggest that immigration is a stress-inducing phenomenon that requires adjustment of valued activities and adversely affects their health. In response, participants worked on regaining control over disrupted activities by opting for two world perspectives. The study helps social workers to develop effective interventions and services for immigrants to better handle health problems. PMID- 26954509 TI - Cigarette Smoking and Tryptophan Hydroxylase 2 mRNA in the Dorsal Raphe Nucleus in Suicides. AB - Cigarette smoking is associated with suicide and mood disorders and stimulates serotonin release. Tryptophan hydroxylase (TPH2) synthesizes serotonin and is over-expressed in suicides. We determined whether smoking is associated with TPH2 mRNA in suicides and controls. TPH2 mRNA was measured postmortem in the dorsal raphe nucleus (DRN) of controls (N = 26, 17 nonsmokers and nine smokers) and suicides (N = 23, 5 nonsmokers and 18 smokers). Psychiatric history was obtained by psychological autopsy. TPH2 mRNA was greater in suicide nonsmokers than suicide smokers, control smokers and control nonsmokers (p = 0.006). There was more TPH2 mRNA throughout the DRN. Smoking interferes with the TPH2 mRNA increase observed in suicide nonsmokers. The absence of altered TPH2 expression in non suicide smokers suggests no pharmacological effect of smoking. PMID- 26954508 TI - Determinants of Amyloid Formation for the Yeast Termination Factor Nab3. AB - Low complexity protein sequences are often intrinsically unstructured and many have the potential to polymerize into amyloid aggregates including filaments and hydrogels. RNA-binding proteins are unusually enriched in such sequences raising the question as to what function these domains serve in RNA metabolism. One such yeast protein, Nab3, is an 802 amino acid termination factor that contains an RNA recognition motif and a glutamine/proline rich domain adjacent to a region with structural similarity to a human hnRNP. A portion of the C-terminal glutamine/proline-rich domain assembles into filaments that organize into a hydrogel. Here we analyze the determinants of filament formation of the isolated low complexity domain as well as examine the polymerization properties of full length Nab3. We found that the C-terminal region with structural homology to hnRNP-C is not required for assembly, nor is an adjacent stretch of 16 glutamines. However, reducing the overall glutamine composition of this 134-amino acid segment from 32% to 14% destroys its polymerization ability. Importantly, full-length wildtype Nab3 also formed filaments with a characteristic cross-beta structure which was dependent upon the glutamine/proline-rich region. When full length Nab3 with reduced glutamine content in its low complexity domain was exchanged for wildtype Nab3, cells were not viable. This suggests that polymerization of Nab3 is normally required for its function. In an extension of this idea, we show that the low complexity domain of another yeast termination factor, Pcf11, polymerizes into amyloid fibers and a hydrogel. These findings suggest that, like many other RNA binding proteins, termination factors share a common biophysical trait that may be important for their function. PMID- 26954512 TI - A perfluoroaromatic abiotic analog of H2 relaxin enabled by rapid flow-based peptide synthesis. AB - H2 relaxin is a pleiotropic peptide hormone with clinical potential. Here we report on the reaction and use of hexafluorobenzene as an intramolecular disulfide replacement between Cys10 and Cys15 in the A-chain of H2 relaxin. Using flow-based Fmoc solid-phase peptide synthesis methodology we were able to obtain high-quality H2 relaxin fragments that were previously reported as challenging to synthesize. Subsequent native chemical ligation and oxidative folding enabled total synthesis of both wild type H2 relaxin and a C6F4 linked analog. Cell-based activity assays revealed modest activity for the C6F4 linked H2 relaxin analog, albeit 100-fold reduced relative to wild type. This work demonstrates how perfluoroarylation-cysteine SNAr chemistry may be a useful tool for the selective replacement of native disulfide bonds in proteins. PMID- 26954513 TI - Test track evaluation of headlight glare associated with adaptive curve HID, fixed HID, and fixed halogen low beam headlights. AB - Adaptive curve headlights swivel with steering input and are linked to reduced insurance claims and improved visual performance. This study assessed glare experienced from adaptive curve high-intensity discharge (HID), fixed (non swiveling) HID and fixed halogen headlights - all tested in low beam mode. Twenty participants rated glare from vehicles' headlights using the DeBoer visual discomfort scale as a test driver drove towards them from five approaches on a test track. Participants rated the fixed halogen condition as less glaring than the adaptive curve and fixed HID conditions. There was no significant difference in ratings between the HID low-beam conditions. Collapsing across roadway approaches, the mean subjective ratings for the fixed halogen, adaptive curve HID and fixed HID low-beam conditions indicated 'satisfactory' levels of glare. Differences between subjective ratings were supported by illuminance data. Differences among the three low-beam systems appear minor, relative to their differences from a benchmark high-beam condition. Practitioner Summary: Insurance data indicates reduced claims associated with adaptive curve lighting. The current effort was to study how such lighting affects discomfort glare of oncoming drivers relative to conventional headlights. Participants rated halogen headlights as less glaring than fixed and adaptive curve HID low beams. Differences among systems were small and associated with acceptable levels of discomfort glare. PMID- 26954514 TI - Lifetime prevalence of non-suicidal self-injury in patients with eating disorders: a systematic review and meta-analysis. AB - BACKGROUND: Against a backdrop of increasing research, clinical and taxonomic attention in non-suicidal self-injury (NSSI), evidence suggests a link between NSSI and eating disorders (ED). The frequency estimates of NSSI in ED vary widely. Little is known about the sources of this variation, and no meta-analysis has quantified the association between ED and NSSI. METHOD: Using random-effects meta-analyses, meta-regression analyses, and 1816-6466 unique participants with various ED, we estimated the weighted average percentage of individuals with ED, those with anorexia nervosa (AN) and those with bulimia nervosa (BN) who are reported to have a lifetime history of NSSI across studies. We further examined predictors of NSSI in ED. RESULTS: The weighted average percentage of patients with a lifetime history of NSSI was 27.3% [95% confidence interval (CI) 23.8 31.0%] for ED, 21.8% (95% CI 18.5-25.6%) for AN, and 32.7% (95% CI 26.9-39.1%) for BN. The difference between BN and AN was statistically significant [odds ratio (OR) 1.77, 95% CI 1.14-2.77, p = 0.013]. The odds of NSSI increased by 24% for every 10% increase in the percentage of participants with histories of suicide attempts (OR 1.24, 95% CI 1.04-1.48, p = 0.020) and decreased by 26% for every 10% increase in the percentage of participants with histories of substance abuse (OR 0.74, 95% CI 0.58-0.95, p = 0.023). CONCLUSIONS: In the specific context of ED, NSSI is highly prevalent and correlates positively with attempted suicide, urging for NSSI-focused treatments. A novel finding is that NSSI is potentially antagonized by substance abuse. PMID- 26954515 TI - Site-specific conjugation of single domain antibodies to liposomes enhances photosensitizer uptake and photodynamic therapy efficacy. AB - Photodynamic therapy for therapy-resistant cancers will greatly benefit from targeted delivery of tumor photosensitizing agents. In this study, a strategy for the site-specific conjugation of single domain antibodies onto liposomes containing the photosensitizer zinc phthalocyanine was developed and tested. PMID- 26954516 TI - Salmonella Prevalence and Antimicrobial Susceptibility Among Dairy Farm Environmental Samples Collected in Texas. AB - Dairy cattle are a reservoir of several Salmonella serovars that are leading causes of human salmonellosis. The objectives of this study were to estimate the environmental prevalence of Salmonella on dairy farms in Texas and to characterize the antimicrobial susceptibility of the isolates. Eleven dairy farms throughout Texas were sampled from August through October 2013, using a cross sectional approach. Samples were collected from four locations within each farm (hospital pen, maternity pen, cow housing area, and calf housing area), and feces were collected from cull cows as available. Environmental and fecal samples were processed for Salmonella, and isolates were tested for susceptibility to 15 antimicrobial agents. Serovar characterization was performed on a subset of these isolates. Salmonella was isolated from 67.0% (236/352) of the environmental samples and 64.2% (43/67) of the cull cow fecal samples. Environmental samples from the maternity pen were significantly more likely to be Salmonella positive than samples from the cow and calf housing areas. Multidrug resistance was evident in 11.9% (27/226) of environmental isolates and 19.5% (8/41) of fecal isolates. Salmonella isolates from the calf housing area and maternity pen were significantly more likely to be multidrug resistant (MDR) than isolates from the cow housing area. The most common serovars found among the MDR isolates were Newport, Muenchen, and Typhimurium. These results help provide a focus for efforts to mitigate the burden of antimicrobial-resistant Salmonella at the preharvest level. PMID- 26954517 TI - Effectiveness of hepatitis B rapid tests toward linkage-to-care: results of a randomized, multicenter study. AB - OBJECTIVES: Worldwide, many infected individuals are unaware of their hepatitis B virus (HBV) status. We evaluated the effectiveness of HBV rapid testing in promoting linkage-to-care. METHODS: In 2012, volunteers were recruited from five Parisian centers. Participants were randomized 1 : 1 to receive standard serology (S) or rapid testing (VIKIA-HBsAg/Quick Profile anti-HBsAb) with confirmatory serology (R+S). The primary endpoint was percentage of individuals with appropriate linkage-to-care (nonimmunized individuals starting vaccination or HBsAg-positive individuals receiving medical evaluation). The secondary outcomes were percentage receiving HBV-test results and performance of HBV rapid tests. RESULTS: In total, 995 individuals were screened. Among the HBV-infection groups included in the primary endpoint (n=409), 20 (4.9%) received appropriate linkage to-care, with no difference between S and R+S groups (5.7 vs. 4.1%, P=0.5). Two of eight HBsAg-positive participants had a medical visit (1/6 and 1/2 in the S and R+S groups, respectively) and 18/401 (4.5%) nonimmunized participants initiated HBV-vaccination (11/205 and 7/196). Factors that tended to be associated with linkage-to-care were female sex, birth country of high HBV prevalence, and extended medical stay. Test results were not obtained in 4.7% of participants, which was significantly higher in the S arm (P=0.02). Both sensitivity and specificity were 100% for the VIKIA-HBsAg rapid test and 94.4 and 80.8%, respectively, for the anti-HBsAb Quick Profile rapid test. CONCLUSION: Despite a higher proportion of participants obtaining their results in the R+S arm and better performance of anti-HBsAb rapid tests than described previously, we found no evidence that HBV screening based initially on rapid tests leads to increased HBV-vaccination rates or medical evaluation. This strategy should be evaluated in more hard-to-reach populations. PMID- 26954519 TI - Hyperpolarizabilities of extended molecular mechanical systems. AB - We propose and evaluate algorithms for the calculation of molecular polarizabilities and hyperpolarizabilities of extended chemical systems. These algorithms are generalizations of the Silberstein-Applequist procedure involving interacting induced classical dipoles through the localized polarizabilities and hyperpolarizabilities. The models are evaluated in terms of interacting molecular units as well as interacting atomic units that result from the atomic decomposition scheme known as the LoProp transformation. We introduce a generalized LoProp scheme which applies to hyperpolarizabilities as well as to polarizabilities. The accuracy of the second-order Applequist method is tested for the first hyperpolarizability for the TIP3P water model using both Hartree Fock and density functional theory evaluated with different basis sets. Possible applications and ramifications of the scheme are discussed. PMID- 26954518 TI - Physical Fitness Among Swedish Military Conscripts and Long-Term Risk for Type 2 Diabetes Mellitus: A Cohort Study. AB - BACKGROUND: Early-life physical fitness has rarely been examined in relation to type 2 diabetes mellitus (DM) in adulthood because of the lengthy follow-up required. Elucidation of modifiable risk factors at young ages may help facilitate earlier and more effective interventions. OBJECTIVE: To examine aerobic capacity and muscle strength at age 18 years in relation to risk for type 2 DM in adulthood. DESIGN: National cohort study. SETTING: Sweden. PARTICIPANTS: 1 534 425 military conscripts from 1969 to 1997 (97% to 98% of all men aged 18 years nationwide) without prior type 2 DM. MEASUREMENTS: Aerobic capacity and muscle strength (measured in watts and newtons per kilogram of body weight, respectively) were examined in relation to type 2 DM identified from outpatient and inpatient diagnoses from 1987 to 2012 (maximum age, 62 years). RESULTS: 34 008 men were diagnosed with type 2 DM in 39.4 million person-years of follow-up. Low aerobic capacity and muscle strength were independently associated with increased risk for type 2 DM. The absolute difference in cumulative incidence of type 2 DM between the lowest and highest tertiles of both aerobic capacity and strength was 0.22% at 20 years of follow-up (95% CI, 0.20% to 0.25%), 0.76% at 30 years (CI, 0.71% to 0.81%), and 3.97% at 40 years (CI, 3.87% to 4.06%). Overall, the combination of low aerobic capacity and muscle strength was associated with a 3-fold risk for type 2 DM (adjusted hazard ratio, 3.07 [CI, 2.88 to 3.27]; P < 0.001), with a positive additive interaction (P < 0.001). These associations were seen even among men with normal body mass index. LIMITATION: This cohort did not include women and did not measure physical fitness at older ages. CONCLUSION: In this large cohort of Swedish male military conscripts, low aerobic capacity and muscle strength at age 18 years were associated with increased long-term risk for type 2 DM, even among those with normal body mass index. PRIMARY FUNDING SOURCE: National Institutes of Health. PMID- 26954520 TI - Survival of smear-positive multidrug resistant tuberculosis patients in Witbank, South Africa: A retrospective cohort study. AB - BACKGROUND: A retrospective cohort study was carried out to compare the survival between smear-positive patients and smear-negative multidrug resistant tuberculosis (MDR-TB) patients hospitalised in a specialised TB hospital in Witbank, South Africa. METHODS: A review of medical records of MDR-TB patients treated from 2001 to 2010 was carried out. Survival time was measured from a patient's date of hospitalisation to the date when the patient died, was last treated at the hospital or the end of the study (whichever came first). All patients who were alive until the end of the study period or lost to follow-up were censored and those who died were considered as failures. Survival patterns were estimated using Kaplan Meier plots, log rank tests and life tables. Cox proportional hazards regression analyses were also conducted. RESULTS: The mean age of the 442 MDR-TB patients in the study was 37.7 +/- 11.2 years. The incidence rates of mortality were 13.4 and 43.9 per 1000 person-months for smear negative and smear-positive MDR-TB patients, respectively. Cox proportional hazard regression showed that the predictors of death among MDR-TB patients include HIV co-infection (adjusted Hazard Rate, aHR = 1.89, 95% CI = 1.02-3.52), old age (above 60 years) (aHR = 2.05, 95% CI = 1.04-3.60) and smear positivity at diagnosis (aHR = 3.29, 95% CI = 2.39-4.64). CONCLUSION: The study showed that the probability of survival during the treatment is reduced in MDR-TB patients, who are smear-positive, HIV positive or older than 60 years. Special care should be given to these patients to improve survival. PMID- 26954525 TI - Visualizing the Motion of Graphene Nanodrums. AB - Membranes of suspended two-dimensional materials show a large variability in mechanical properties, in part due to static and dynamic wrinkles. As a consequence, experiments typically show a multitude of nanomechanical resonance peaks, which make an unambiguous identification of the vibrational modes difficult. Here, we probe the motion of graphene nanodrum resonators with spatial resolution using a phase-sensitive interferometer. By simultaneously visualizing the local phase and amplitude of the driven motion, we show that unexplained spectral features represent split degenerate modes. When taking these into account, the resonance frequencies up to the eighth vibrational mode agree with theory. The corresponding displacement profiles, however, are remarkably different from theory, as small imperfections increasingly deform the nodal lines for the higher modes. The Brownian motion, which is used to calibrate the local displacement, exhibits a similar mode pattern. The experiments clarify the complicated dynamic behavior of suspended two-dimensional materials, which is crucial for reproducible fabrication and applications. PMID- 26954522 TI - Maternal Depression Is Related to Reduced Error-Related Brain Activity in Child and Adolescent Offspring. AB - Chronic parental depression is associated with an increased likelihood of depression in offspring. One mechanism by which parental depression may increase risk is through physiological or cognitive tendencies in offspring. Error processing has been studied using the error-related negativity (ERN), an event related potential that occurs around the time someone commits an error, and has previously been shown to be heritable and blunted in depressed individuals. The current study examined the ERN as a potential biomarker of risk in a sample of never-depressed children whose mothers had a history of recurrent major depressive disorder (MDD), a single episode of MDD, or no lifetime history of any mood disorder. Seventy-eight mother-child dyads participated. The average age for children was 13.13 years (SD = 2.07) and 50% were female. Diagnostic interviews and self-report questionnaires were used to assess depression in both mothers and children. A flankers task was used to elicit the ERN and the correct response negativity (CRN) in children. Children of mothers with a history of recurrent MDD exhibited a reduced difference between the ERN and CRN compared to children of mothers with no depression history, even after controlling for children's current depression symptoms. Furthermore, current maternal depression symptoms related to a smaller difference between ERN and CRN in children. This pattern of findings suggests that blunted neural activity differentiating error from correct responses may be one mechanism by which recurrent maternal depression increases risk for depression in offspring and may be useful biomarker of risk. PMID- 26954523 TI - PD-1/PD-L1 expression in non-small-cell lung cancer and its correlation with EGFR/KRAS mutations. AB - This study was aimed to detect the correlation among EGFR/KRAS status and PD-1/PD L1 expression in non-small-cell lung cancer (NSCLC) patients. PD-1 and PD-L1 expressions were detected by immunohistochemistry in 100 surgically resected lung adenocarcinoma tissues and were statistically correlated with clinicopathological characteristics including EGFR and KRAS statuses. Besides, the overall survival (OS) times were analyzed. There was a statistical significances between PD-1 expression in tumor and KRAS status (P = 0.043), with a higher mutation rate in with lower PD-1 expression patients. There was a statistical significance between PD-L1 expression in tumor and EGFR status (P = 0.012), with a higher mutation rate in patients with lower PD-L1 expression. The OS of patients with EGFR mutation was significantly longer than those without EGFR mutation. The OS of patients with lower PD-L1 in tumor was significantly longer than those with higher PD-L1 expression. We found negative associations between PD-L1 expression in tumor and mutated EGFR status, as well as between PD-1 expression in tumor and mutated KRAS status. PMID- 26954526 TI - An overview of investigational Histone deacetylase inhibitors (HDACis) for the treatment of non-Hodgkin's lymphoma. AB - INTRODUCTION: Histone acetylation alters DNA transcription and protein expression. Aberrant acetylation is seen in tumor cells. Histone deacetylase inhibitors (HDACis) act by modifying gene expression and are the newest class of drugs shown to be promising in patients with several malignancies including relapsed and/or refractory lymphoma. Multiple HDACis are currently under various phases of clinical trials for the treatment of Non-Hodgkin's lymphoma (NHL). AREAS COVERED: This review discusses the mechanism of histone acetyl transferases (HAT's), histone deacetylases (HDAC's) and their role in B - and T-cell malignancies with a particular focus on the mechanism of action and clinical application of HDACis in NHL. Discussion includes: HDACi's like vorinostat, romidepsin, belinostat, panobinostat, entinostat and chidamide; pivotal clinical trials leading to the approval of HDACis in NHL; ongoing active clinical trials and combination therapies with novel agents. EXPERT OPINION: Relapsed and or refractory lymphoma poses a challenge to the clinician given the poor outcomes. HDACis show promising clinical activity in patients with relapsed/refractory NHL. Active pursuit of developing newer HDACis and clinical trials using combination therapies that help understand the molecular characteristics and synergistic actions of these agents is warranted. This would help improve efficacy, drug tolerability and expand the horizon of these novel agents. PMID- 26954528 TI - Author's Response to Caliskan. PMID- 26954530 TI - A Swollen, Red Areola in a Young Boy. PMID- 26954527 TI - Colorectal cancer risk and nitrate exposure through drinking water and diet. AB - Ingested nitrate leads to the endogenous synthesis of N-nitroso compounds (NOCs), animal carcinogens with limited human evidence. We aimed to evaluate the risk of colorectal cancer (CRC) associated with nitrate exposure in drinking water and diet. A case-control study in Spain and Italy during 2008-2013 was conducted. Hospital-based incident cases and population-based (Spain) or hospital-based (Italy) controls were interviewed on residential history, water consumption since age 18, and dietary information. Long-term waterborne ingested nitrate was derived from routine monitoring records, linked to subjects' residential histories and water consumption habits. Dietary nitrate intake was estimated from food frequency questionnaires and published food composition databases. Odd ratios (OR) were calculated using mixed models with area as random effect, adjusted for CRC risk factors and other covariables. Generalized additive models (GAMs) were used to analyze exposure-response relationships. Interaction with endogenous nitrosation factors and other covariables was also evaluated. In total 1,869 cases and 3,530 controls were analyzed. Average waterborne ingested nitrate ranged from 3.4 to 19.7 mg/day, among areas. OR (95% CIs) of CRC was 1.49 (1.24, 1.78) for >10 versus <=5 mg/day, overall. Associations were larger among men versus women, and among subjects with high red meat intake. GAMs showed increasing exposure-response relationship among men. Animal-derived dietary nitrate was associated with rectal, but not with colon cancer risk. In conclusion, a positive association between CRC risk and waterborne ingested nitrate is suggested, mainly among subgroups with other risk factors. Heterogeneous effects of nitrate from different sources (water, animal and vegetables) warrant further research. PMID- 26954532 TI - New Information About the Benefits of Drinking Water Compared With Sugar Sweetened Beverages. PMID- 26954534 TI - Intravenous Fluid Bolus Prior to Neonatal and Infant Lumbar Puncture: A Sonographic Assessment of the Subarachnoid Space After Intravenous Fluid Administration. AB - IMPORTANCE: Neonatal and infant lumbar puncture is a commonly performed procedure in emergency departments, yet traumatic and unsuccessful lumbar punctures occur 30% to 50% of the time. Dehydration may be a risk factor for unsuccessful lumbar punctures, but to our knowledge, no studies have investigated the use of intravenous (IV) fluid bolus prior to lumbar puncture. OBJECTIVE: To investigate the association of IV fluid bolus administration with the sonographic measure of the neonatal and infant lumbar subarachnoid space. We hypothesized that IV fluids would increase subarachnoid space size. DESIGN, SETTING, AND PARTICIPANTS: Prospective observational study conducted from August 2012 to April 2015.The study took place at the emergency department of the Children's Hospital Los Angeles, an urban pediatric emergency department with an annual census of 76,000 visits.A convenience sample of patients aged 0 to 3 months were enrolled if they had a clinical presentation consistent with pyloric stenosis. This population was used as a proxy because they are similar in age to patients undergoing lumbar puncture for evaluation of neonatal fever and are routinely given IV fluids for dehydration. EXPOSURES: Patients with a sonographic diagnosis of pyloric stenosis underwent additional ultrasonography evaluation to determine the size of the subarachnoid space before and after IV fluids. MAIN OUTCOMES AND MEASURES: Primary outcomes included the difference in the size of the subarachnoid space in millimeters squared before and 1 hour after administration of an IV fluid bolus in the emergency department. Interobserver consistency for the subarachnoid space measurement between attending radiologists was measured using intraclass correlation coefficient. The Wilcoxon signed-rank test was used to examine changes in subarachnoid space measurements (millimeters squared). RESULTS: The study sample consisted of 40 patients with a mean (SD) age of 37 (11.3) days (range, 15-71 days). The mean (SD) size of the subarachnoid space before and 1 hour after IV fluid bolus was 37.8 (11.1) mm(2) and 36.9 (11.2) mm(2) respectively (P = .42). The intraclass correlation coefficient ranged from 0.96 to 0.99 (95% CI, 0.90-0.99). CONCLUSIONS AND RELEVANCE: Intravenous fluid boluses were not associated with a significant increase in the sonographic measure of the neonatal and infant subarachnoid space. PMID- 26954536 TI - Nondisruptive Dissolution of Hyperpolarized (129)Xe into Viscous Aqueous and Organic Liquid Crystalline Environments. AB - Studies of hyperpolarized xenon-129 (hp-(129)Xe) in media such as liquid crystals and cell suspensions are in demand for applications ranging from biomedical imaging to materials engineering but have been hindered by the inability to bubble Xe through the desired media as a result of viscosity or perturbations caused by bubbles. Herein a device is reported that can be reliably used to dissolve hp-(129)Xe into viscous aqueous and organic samples without bubbling. This method is robust, requires small sample volumes (<60 MUL), is compatible with existing NMR hardware, and is made from readily available materials. Experiments show that Xe can be introduced into viscous and aligned media without disrupting molecular order. We detected dissolved xenon in an aqueous liquid crystal that is disrupted by the shear forces of bubbling, and we observed liquid crystal phase transitions in (MBBA). This tool allows an entirely new class of samples to be investigated by hyperpolarized-gas NMR spectroscopy. PMID- 26954535 TI - The cyclochlorotine mycotoxin is produced by the nonribosomal peptide synthetase CctN in Talaromyces islandicus ('Penicillium islandicum'). AB - Talaromyces islandicus ('Penicillium islandicum') is a widespread foodborne mold that produces numerous secondary metabolites, among them potent mycotoxins belonging to different chemical classes. A notable metabolite is the hepatotoxic and carcinogenic pentapeptide cyclochlorotine that contains the unusual amino acids beta-phenylalanine, 2-aminobutyrate and 3,4-dichloroproline. Although the chemical structure has been known for over five decades, nothing is known about the biosynthetic pathway of cyclochlorotine. Bioinformatic analysis of the recently sequenced genome of T. islandicus identified a wealth of gene clusters potentially coding for the synthesis of secondary metabolites. Here, we show by RNA interference-mediated gene silencing that a nonribosomal peptide synthetase, CctN, is responsible for the synthesis of cyclochlorotine. Moreover, we identified novel cyclochlorotine chemical variants, whose production also depended on cctN expression. Surprisingly, the halogenase required for cyclochlorotine biosynthesis is not encoded in the cct cluster. Nonetheless, our findings enabled us to propose a detailed model for cyclochlorotine biosynthesis. In addition, comparative genomics revealed that cct-like clusters are present in all of the sequenced Talaromyces strains indicating a high prevalence of cyclochlorotine production ability. PMID- 26954537 TI - Psychosocial Pathways Linking Adverse Childhood Experiences to Mental Health in Recently Deployed Canadian Military Service Members. AB - Multiple pathways have been suggested to account for the relationship of adverse childhood experiences (ACEs) and well-being in adulthood, including interpersonal difficulties, the underestimation of one's sense of mastery, and a greater propensity to experience stressors later in life. This study was conducted to examine the association between ACEs and mental health in Canadian Armed Forces (CAF) personnel, and the possible mediating roles of social support, mastery, and combat stressors in that relationship. The study consisted of a prospective analysis involving 3,319 CAF members upon their return from an overseas deployment. Results were that ACEs were associated with poorer mental health (beta = -.14, p < .001) and that approximately 42.6% of this relationship could be explained by the mediating effects of low social support, low mastery, and a greater number of combat stressors. The full model, including the covariates, ACEs, social support, mastery, and combat stressors as correlates of postdeployment mental health, was statistically significant with adjusted R(2) = .28, F(9, 3309) = 141.96, p < .001. On the whole, results suggested that social support, mastery, and life stressors may be possible targets for interventions to minimize the impact of ACEs on later mental health in military personnel. PMID- 26954538 TI - Cellular Engineering with Membrane Fusogenic Liposomes to Produce Functionalized Extracellular Vesicles. AB - Engineering of extracellular vesicles (EVs) without affecting biological functions remains a challenge, limiting the broad applications of EVs in biomedicine. Here, we report a method to equip EVs with various functional agents, including fluorophores, drugs, lipids, and bio-orthogonal chemicals, in an efficient and controlled manner by engineering parental cells with membrane fusogenic liposomes, while keeping the EVs intact. As a demonstration of how this method can be applied, we prepared EVs containing azide-lipids, and conjugated them with targeting peptides using copper-free click chemistry to enhance targeting efficacy to cancer cells. We believe that this liposome-based cellular engineering method will find utility in studying the biological roles of EVs and delivering therapeutic agents through their innate pathway. PMID- 26954539 TI - Mitotic Mysteries: The Case of HP1. AB - The role of Heterochromatin Protein-1 (HP1) during mitosis has been controversial. Two recent studies in Science and Developmental Cell, from Tanno et al. (2015) and Abe et al. (2016), suggest that the means of HP1 localization and its function at inner centromeres are altered in cancer cells with chromosomal instability. PMID- 26954533 TI - Family Presence During Pediatric Tracheal Intubations. AB - IMPORTANCE: Family-centered care, which supports family presence (FP) during procedures, is now a widely accepted standard at health care facilities that care for children. However, there is a paucity of data regarding the practice of FP during tracheal intubation (TI) in pediatric intensive care units (PICUs). Family presence during procedures in PICUs has been advocated. OBJECTIVE: To describe the current practice of FP during TI and evaluate the association with procedural and clinician (including physician, respiratory therapist, and nurse practitioner) outcomes across multiple PICUs. DESIGN, SETTING, AND PARTICIPANTS: Prospective cohort study in which all TIs from July 2010 to March 2014 in the multicenter TI database (National Emergency Airway Registry for Children [NEAR4KIDS]) were analyzed. Family presence was defined as a family member present during TI. This study included all TIs in patients younger than 18 years in 22 international PICUs. EXPOSURES: Family presence and no FP during TI in the PICU. MAIN OUTCOMES AND MEASURES: The percentage of FP during TIs. First attempt success rate, adverse TI-associated events, multiple attempts (>= 3), oxygen desaturation (oxygen saturation as measured by pulse oximetry <80%), and self reported team stress level. RESULTS: A total of 4969 TI encounters were reported. Among those, 81% (n = 4030) of TIs had documented FP status (with/without). The median age of participants with FP was 2 years and 1 year for those without FP. The average percentage of TIs with FP was 19% and varied widely across sites (0% 43%; P < .001). Tracheal intubations with FP (vs without FP) were associated with older patients (median, 2 years vs 1 year; P = .04), lower Paediatric Index of Mortality 2 score, and pediatric resident as the first airway clinician (23%, n = 179 vs 18%, n = 584; odds ratio [OR], 1.4; 95% CI, 1.2-1.7). Tracheal intubations with FP and without FP were no different in the first attempt success rate (OR, 1.00; 95% CI, 0.85-1.18), adverse TI-associated events (any events: OR, 1.06; 95% CI, 0.85-1.30 and severe events: OR, 1.04; 95% CI, 0.75-1.43), multiple attempts (>= 3) (OR, 1.03; 95% CI, 0.82-1.28), oxygen desaturation (oxygen saturation <80%) (OR, 0.97; 95% CI, 0.80-1.18), or self-reported team stress level (OR, 1.09; 95% CI, 0.92-1.31). This result persisted after adjusting for patient and clinician confounders. CONCLUSIONS AND RELEVANCE: Wide variability exists in FP during TIs across PICUs. Family presence was not associated with first attempt success, adverse TI-associated events, oxygen desaturation (<80%), or higher team stress level. Our data suggest that FP during TI can safely be implemented as part of a family-centered care model in the PICU. PMID- 26954540 TI - Tracking HSC Origin: From Bench to Placenta. AB - Reporting in Developmental Cell, Pereira et al. (2016) use in vitro lineage reprogramming insights to inform understanding of hematopoietic stem cell (HSC) development in vivo. They find Prom1(+)Sca1(+)CD34(+)CD45(-) hemogenic precursors, akin to fibroblast-derived hemato-vascular precursors, in mouse placenta and embryo. The cells mature into transplantable HSCs in culture. PMID- 26954541 TI - Chromatin Condensation and Enucleation in Red Blood Cells: An Open Question. AB - Differentiating erythroid cells undergo dramatic changes in morphology, with reduction in cell size, chromatin and nuclear condensation, and enucleation. In this issue of Developmental Cell, Zhao et al. (2016) show that these events are associated with the formation of transient, recurring nuclear openings and selective histone release mediated by caspase-3. PMID- 26954542 TI - You Are What You Eat... or Are You? AB - In this issue of Developmental Cell, Hosios et al. (2016) take a rigorous and quantitative approach to analyze metabolite acquisition and allocation in proliferating cultured mammalian cells. This work clarifies what we know while providing a new analytical framework to undergird future work on the metabolism of proliferating cells. PMID- 26954543 TI - Sticking Around: Short-Range Activity of Wnt Ligands. AB - Wnt ligands are secreted lipid-modified proteins that are essential for development and homeostasis. Published recently in Nature, Farin et al. (2016) report that Wnt3 acts at a short distance during growth of mouse intestinal organoids, suggesting that Wnt proteins remain membrane-bound to activate signaling at a short range from their source. PMID- 26954544 TI - HP1-Assisted Aurora B Kinase Activity Prevents Chromosome Segregation Errors. AB - Incorrect attachment of kinetochore microtubules is the leading cause of chromosome missegregation in cancers. The highly conserved chromosomal passenger complex (CPC), containing mitotic kinase Aurora B as a catalytic subunit, ensures faithful chromosome segregation through destabilizing incorrect microtubule attachments and promoting biorientation of chromosomes on the mitotic spindle. It is unknown whether CPC dysfunction affects chromosome segregation fidelity in cancers and, if so, how. Here, we show that heterochromatin protein 1 (HP1) is an essential CPC component required for full Aurora B activity. HP1 binding to the CPC becomes particularly important when Aurora B phosphorylates kinetochore targets to eliminate erroneous microtubule attachments. Remarkably, a reduced proportion of HP1 bound to CPC is widespread in cancers, which causes an impairment in Aurora B activity. These results indicate that HP1 is an essential modulator for CPC function and identify a molecular basis for chromosome segregation errors in cancer cells. PMID- 26954546 TI - Drosophila Schip1 Links Expanded and Tao-1 to Regulate Hippo Signaling. AB - Regulation of organ size is essential in animal development, and Hippo (Hpo) signaling is a major conserved mechanism for controlling organ growth. In Drosophila, Hpo and Warts kinases are core components of this pathway and function as tumor suppressors by inhibiting Yorkie (Yki). Expanded (Ex) is a regulator of the Hpo activity, but how they are linked is unknown. Here, we show that Schip1, a Drosophila homolog of the mammalian Schwannomin interacting protein 1 (SCHIP1), provides a link between Ex and Hpo. Ex is required for apical localization of Schip1 in imaginal discs. Schip1 is necessary for promoting membrane localization and phosphorylation of Hpo by recruiting the Hpo kinase Tao 1. Taking these findings together, we conclude that Schip1 directly links Ex to Hpo signaling by recruiting Tao-1. This study provides insights into the mechanism of Tao-1 regulation and a potential growth control function for SCHIP1 in mammals. PMID- 26954545 TI - Nuclear Condensation during Mouse Erythropoiesis Requires Caspase-3-Mediated Nuclear Opening. AB - Mammalian erythropoiesis involves chromatin condensation that is initiated in the early stage of terminal differentiation. The mechanisms of chromatin condensation during erythropoiesis are unclear. Here, we show that the mouse erythroblast forms large, transient, and recurrent nuclear openings that coincide with the condensation process. The opening lacks nuclear lamina, nuclear pore complexes, and nuclear membrane, but it is distinct from nuclear envelope changes that occur during apoptosis and mitosis. A fraction of the major histones are released from the nuclear opening and degraded in the cytoplasm. We demonstrate that caspase-3 is required for the nuclear opening formation throughout terminal erythropoiesis. Loss of caspase-3 or ectopic expression of a caspase-3 non-cleavable lamin B mutant blocks nuclear opening formation, histone release, chromatin condensation, and terminal erythroid differentiation. We conclude that caspase-3-mediated nuclear opening formation accompanied by histone release from the opening is a critical step toward chromatin condensation during erythropoiesis in mice. PMID- 26954547 TI - Hematopoietic Reprogramming In Vitro Informs In Vivo Identification of Hemogenic Precursors to Definitive Hematopoietic Stem Cells. AB - Definitive hematopoiesis emerges via an endothelial-to-hematopoietic transition in the embryo and placenta; however, the precursor cells to hemogenic endothelium are not defined phenotypically. We previously demonstrated that the induction of hematopoietic progenitors from fibroblasts progresses through hemogenic precursors that are Prom1(+)Sca1(+)CD34(+)CD45(-) (PS34CD45(-)). Guided by these studies, we analyzed mouse placentas and identified a population with this phenotype. These cells express endothelial markers, are heterogeneous for early hematopoietic markers, and localize to the vascular labyrinth. Remarkably, global gene expression profiles of PS34CD45(-) cells correlate with reprogrammed precursors and establish a hemogenic precursor cell molecular signature. PS34CD45(-) cells are also present in intra-embryonic hemogenic sites. After stromal co-culture, PS34CD45(-) cells give rise to all blood lineages and engraft primary and secondary immunodeficient mice. In summary, we show that reprogramming reveals a phenotype for in vivo precursors to hemogenic endothelium, establishing that direct in vitro conversion informs developmental processes in vivo. PMID- 26954549 TI - Localized LoxL3-Dependent Fibronectin Oxidation Regulates Myofiber Stretch and Integrin-Mediated Adhesion. AB - For muscles to function, myofibers have to stretch and anchor at the myotendinous junction (MTJ), a region rich in extracellular matrix (ECM). Integrin signaling is required for MTJ formation, and mutations affecting the cascade lead to muscular dystrophies in mice and humans. Underlying mechanisms for integrin activation at the MTJ and ECM modifications regulating its signaling are unclear. We show that lysyl oxidase-like 3 (LoxL3) is a key regulator of integrin signaling that ensures localized control of the cascade. In LoxL3 mutants, myofibers anchor prematurely or overshoot to adjacent somites, and are loose and lack tension. We find that LoxL3 complexes with and directly oxidizes Fibronectin (FN), an ECM scaffold protein and integrin ligand enriched at the MTJ. We identify a mechanism whereby localized LoxL3 secretion from myofiber termini oxidizes FN, enabling enhanced integrin activation at the tips of myofibers and ensuring correct positioning and anchoring of myofibers along the MTJ. PMID- 26954548 TI - Amino Acids Rather than Glucose Account for the Majority of Cell Mass in Proliferating Mammalian Cells. AB - Cells must duplicate their mass in order to proliferate. Glucose and glutamine are the major nutrients consumed by proliferating mammalian cells, but the extent to which these and other nutrients contribute to cell mass is unknown. We quantified the fraction of cell mass derived from different nutrients and found that the majority of carbon mass in cells is derived from other amino acids, which are consumed at much lower rates than glucose and glutamine. While glucose carbon has diverse fates, glutamine contributes most to protein, suggesting that glutamine's ability to replenish tricarboxylic acid cycle intermediates (anaplerosis) is primarily used for amino acid biosynthesis. These findings demonstrate that rates of nutrient consumption are indirectly associated with mass accumulation and suggest that high rates of glucose and glutamine consumption support rapid cell proliferation beyond providing carbon for biosynthesis. PMID- 26954550 TI - Repression of Pumilio Protein Expression by Rbfox1 Promotes Germ Cell Differentiation. AB - RNA-binding Fox (Rbfox) proteins have well-established roles in regulating alternative splicing, but specific Rbfox isoforms lack nuclear localization signals and accumulate in the cytoplasm. The potential splicing-independent functions of these proteins remain unknown. Here we demonstrate that cytoplasmic Drosophila Rbfox1 regulates germ cell development and represses the translation of mRNAs containing (U)GCAUG elements within their 3'UTRs. During germline cyst differentiation, Rbfox1 targets pumilio mRNA for destabilization and translational silencing, thereby promoting germ cell development. Mis-expression of pumilio results in the formation of germline tumors, which contain cysts that break down and dedifferentiate back to single, mitotically active cells. Together, these results reveal that cytoplasmic Rbfox family members regulate the translation of specific target mRNAs. In the Drosophila ovary, this activity provides a genetic barrier that prevents germ cells from reverting back to an earlier developmental state. The finding that Rbfox proteins regulate mRNA translation has implications for Rbfox-related diseases. PMID- 26954552 TI - The Effect of Quinidine, a Strong P-Glycoprotein Inhibitor, on the Pharmacokinetics and Central Nervous System Distribution of Naloxegol. PMID- 26954551 TI - Subsidising artemisinin-based combination therapy in the private retail sector. AB - BACKGROUND: Malaria causes ill health and death in Africa. Treating illness promptly with artemisinin-based combination therapy (ACT) is likely to cure people and avoid the disease progressing to more severe forms and death. In many countries, ACT use remains low. Part of the problem is that most people seek treatment from the retail sector where ACTs are expensive; this expense is a barrier to their use.The Global Fund and other international organisations are subsidising the cost of ACTs for private retail providers to improve access to ACTs. The subsidy was initially organised through a stand-alone initiative, called the Affordable Medicines Facility-malaria (AMFm), but has since been integrated into the Global Fund core grant management and financial processes. OBJECTIVES: To assess the effect of programmes that include ACT price subsidies for private retailers on ACT use, availability, price and market share. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2015, Issue 1, The Cochrane Library, including the Cochrane Effective Practice and Organisation of Care (EPOC) Group Specialised Register); MEDLINE (OvidSP), EMBASE (OvidSP), CINAHL (EbscoHost), EconLit (ProQuest), Global Health (OvidSP), Regional Indexes (Global Health Library, WHO), LILACS (Global Health Library, WHO), Science Citation Index and Social Sciences Citation Index (ISI Web of Science) and Health Management (ProQuest). All databases were searched February 2015, except for Health Management which was searched November 2013, without any date, language or publication status restrictions. We also searched the International Clinical Trials Registry Platform (ICTRP; WHO), ClinicalTrials.gov (NIH) and various grey literature sources. We also conducted a cited reference search for all included studies in ISI Web of Knowledge, checked references of identified articles and contacted authors to identify additional studies. SELECTION CRITERIA: Randomised trials, non-randomised trials, controlled before after studies and interrupted-time-series studies that compared the effects of ACT price subsidies for private retailers to no subsidies or alternative ACT financing mechanisms were eligible for inclusion. Two authors independently screened and selected studies for inclusion. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data, assessed study risk of bias and confidence in effect estimates (certainty of evidence) using Grading of Recommendations, Assessment, Development and Evaluation (GRADE). MAIN RESULTS: We included four trials (two cluster-randomised trials reported in three articles and two non-randomised cluster trials). Three trials assessed retail sector ACT subsidies combined with supportive interventions (retail outlet provider training, community awareness and mass media campaigns). One trial assessed vouchers provided to households to purchase subsidised ACTs. Price subsidies ranged from 80% to 95%. One trial enrolled children under five years of age; the other three trials studied people of all age groups. The studies were done in rural districts in East Africa (Kenya, Uganda and Tanzania).In this East Africa setting, these ACT subsidy programmes increased the percentage of children under five years of age receiving ACTs on the day, or following day, of fever onset by 25 percentage points (95% confidence interval (CI) 14.1 to 35.9 percentage points; 1 study, high certainty evidence). This suggests that in practice, among febrile children under five years of age with an ACT usage rate of 5% without a subsidy, subsidy programmes would increase usage by between 19% and 41% over a one year period.The ACT subsidy programmes increased the percentage of retail outlets stocking ACTs for children under five years of age by 31.9 percentage points (95% CI 26.3 to 37.5 percentage points; 1 study, high certainty evidence). Effects on ACT stocking for patients of any age is unknown because the certainty of evidence was very low.The ACT subsidy programmes decreased the median cost of ACTs for children under five years of age by US$ 0.84 (median cost per ACT course without subsidy: US$ 1.08 versus with subsidy: US$ 0.24; 1 study, high certainty evidence).The ACT subsidy programmes increased the market share of ACTs for children under five years of age by between 23.6 and 63.0 percentage points (1 study, high certainty evidence).The ACT subsidy programmes decreased the use of older antimalarial drugs (such as amodiaquine and sulphadoxine-pyrimethamine) among children under five years of age by 10.4 percentage points (95% CI 3.9 to 16.9 percentage points; 1 study, high certainty evidence).None of the three studies of ACT subsidies reported the number of patients treated who had confirmed malaria.Vouchers increased the likelihood that an illness is treated with an ACT by 16 to 23 percentage points; however, vouchers were associated with a high rate of over-treatment of malaria (only 56% of patients taking ACTs from the drug shop tested positive for malaria under the 92% subsidy; 1 study, high certainty evidence). AUTHORS' CONCLUSIONS: Programmes that include substantive subsidies for private sector retailers combined with training of providers and social marketing improved use and availability of ACTs for children under five years of age with suspected malaria in research studies from three countries in East Africa. These programmes also reduced prices of ACTs, improved market share of ACTs and reduced the use of older antimalarial drugs among febrile children under five years of age. The research evaluates drug delivery but does not assess whether the patients had confirmed (parasite-diagnosed) malaria. None of the included studies assessed patient outcomes; it is therefore not known whether the effects seen in the studies would translate to an impact on health. PMID- 26954553 TI - Reply to: Letter to the Editor "Effect of Quinidine, a Strong P-Glycoprotein Inhibitor, on the Pharmacokinetics and Central Nervous System Distribution of Naloxegol". PMID- 26954554 TI - Correction: MPX-004 and MPX-007: New Pharmacological Tools to Study the Physiology of NMDA Receptors Containing the GluN2A Subunit. PMID- 26954555 TI - Enclathration and Confinement of Small Gases by the Intrinsically 0D Porous Molecular Solid, Me,H,SiMe2. AB - The stable, guest-free crystal form of the simple molecular cavitand, Me,H,SiMe2, is shown to be intrinsically porous, possessing discrete, zero-dimensional (0D) pores/microcavities of about 28 A(3). The incollapsible 0D pores of Me,H,SiMe2 have been exploited for the enclathration and room temperature (and higher) confinement of a wide range of small gases. Over 20 isostructural x(gas/guest)@Me,H,SiMe2 (x <= 1) clathrates (guest = H2O, N2, Ar, CH4, Kr, Xe, C2H4, C2H6, CH3F, CO2, H2S, CH3Cl, CH3OCH3, CH3Br, CH3SH, CH3CH2Cl, CH2Cl2, CH3I, CH3OH, BrCH2Cl, CH3CH2OH, CH3CN, CH3NO2, I2), and a propyne clathrate (CH3CCH@Me,H,SiMe2.2CHCl3), have been prepared and characterized, and their single crystal structures determined. Gas enclathration is found to be highly selective for gases that can be accommodated by the predefined, though slightly flexible 0D pore. The structure determinations provide valuable insight, at subangstrom resolution, into the factors that govern inclusion selectivity, gas accommodation, and the kinetic stability of the clathrates, which has been probed by thermal gravimetric analysis. The activation (emptying) of several clathrates (guest = H2O, N2, CO2, Kr, CH3F) is shown to occur in a single-crystal-to-single crystal (SC -> SC) fashion, often requiring elevated temperatures. Akin to open pore materials, water vapor and CO2 gas are shown to be taken up by single crystals of empty Me,H,SiMe2 at room temperature, but sorption rates are slow, occurring over weeks to months. Thus, Me,H,SiMe2 exhibits very low, but measurable, gas permeability, despite there being no obvious dynamic mechanism to facilitate gas uptake. The unusually slow exchange kinetics has allowed the rates of gas (water vapor and CO2) sorption to be quantified by single crystal X-ray diffraction. The data are well fit to a simple three-dimensional diffusion model. PMID- 26954556 TI - Immunological Characterization of Dutch Sesame Seed-Allergic Patients. AB - BACKGROUND: Sesame seed is an allergen of growing importance worldwide. However, knowledge of the clinically relevant sesame allergen and its cross-reactivity with homologous allergens is limited. The aim of this study was the immunological characterization of Dutch sesame seed-allergic patients and evaluation of cross reactivity between sesame seed, tree nut and pollen allergens using different sources of allergen extracts. METHODS: Six patients with a medical history of sesame seed allergy were included, i.e. 5 with an anaphylactic reaction and 1 with an oral allergy syndrome (OAS). The immunological background of the sesame seed and tree nut IgE sensitization was characterized with Western blotting and a basophil activation test (BAT). The major sesame allergen was identified by nanoLC-MS/MS. Cross-reactivity was measured using an immuno-inhibition assay with the Phadia ImmunoCAP system. RESULTS: Oleosin was identified as the major allergen for the 5 patients with an anaphylactic reaction to sesame seed, but no cross-reactivity between sesame and tree nut proteins was observed. For the patient with OAS, IgE specific to oleosin was not detected but cross-reactivity between sesame seed and tree nut proteins was observed. The BAT and ImmunoCAP inhibition test added value to the clinical and immunological characterization of sesame seed-sensitized patients, distinguishing relevant and non-relevant sensitizations. CONCLUSIONS: Our immunological approach enabled us to fully characterize the sensitization pattern of 6 sesame seed-allergic patients. The different protein composition of commercially available allergen extracts influences the outcomes of the immunological assays and thus also the diagnosis to a large extent. PMID- 26954557 TI - Alteration of Motor Protein Expression Involved in Bidirectional Transport in Peripheral Blood Mononuclear Cells of Patients with Amyotrophic Lateral Sclerosis. AB - BACKGROUND: Sporadic amyotrophic lateral sclerosis (SALS) is a fatal motor neuron degenerative disease of unclear pathogenesis. Disturbances of intracellular transport are possible causes of the disease. OBJECTIVE: We evaluated the expression of motor proteins involved in the anterograde (kinesins KIF1B, KIF5C) and retrograde (KIFC3, dynactin subunits DCTN1 and DCTN3) intracellular transport in peripheral blood mononuclear cells (PBMCs). MATERIALS AND METHODS: PBMCs were obtained from 74 SALS patients with different clinical phenotypes, 65 blood donors (healthy control I), and 29 cases with other neurological diseases (disease control II) divided into subgroups IIA (atypical parkinsonism) and IIB (ALS-mimicking disorders). mRNA expression was studied by real-time qPCR, and protein level by Western blotting. RESULTS: In SALS, KIF5C and KIFC3 expression was significantly lower and DCTN1 higher than in control I, and dependent of age. KIF1B expression was significantly higher in SALS than in subgroup IIB, whereas DCTN1 and DCTN3 were higher in SALS than in subgroup IIA. All changes in the studied proteins were statistically significant in classic ALS but not in progressive muscular atrophy. CONCLUSION: In SALS, and especially in classic ALS, the changes in motor protein expression may alter bidirectional intracellular transport in PBMCs. More studies are needed to find out whether the levels of KIF5C and DCTN1 may be useful in ALS diagnosis, and whether KIF1B expression may discriminate ALS from ALS-mimicking disorders. PMID- 26954558 TI - Three Synchronous Atypical Metastases of Clear Cell Renal Carcinoma to the Maxillary Gingiva, Scalp and the Distal Phalanx of the Fifth Digit: A Case Report. AB - Oral cavity metastasis of malignant tumors is extremely rare and accounts for only 1% of all malignant oral tumors. Renal cell carcinoma (RCC) can metastasize to any part of the body, with a 15% risk of metastasis to the head and neck region when the disease is disseminated and a 1% risk when it is not. RCC also is the third most common infraclavicular neoplasm that metastasizes to the oral cavity, after lung carcinoma in men and breast carcinoma in women. In the maxillofacial region, the nasal cavity and paranasal sinuses are the most commonly affected sites, followed by the oral cavity. This report describes the case of a 51-year-old man with a history of clear RCC presenting with 3 synchronous atypical metastases of this tumor to the maxillary gingiva, scalp, and distal phalanx of the fifth digit. Clinical findings, diagnosis, pathology, and treatment of these lesions are discussed. Metastasis of RCC should always be included in the differential diagnosis when a new oral and maxillofacial lesion appears in a patient with a history of RCC because the metastatic lesions can often present in a broad spectrum of forms. The rapid growth of these lesions should alert clinicians to avoid any delays in biopsy examination and subsequent treatment, which is usually palliative, because prognosis is usually poor. PMID- 26954560 TI - Flapless Versus Traditional Dental Implant Surgery: Long-Term Evaluation of Crestal Bone Resorption. AB - PURPOSE: The literature reports that flapless compared with traditional implant surgery can be associated with several advantages, including the maintenance of peri-implant hard tissues. This study investigated vertical bone resorption during long-term follow-up after implant placement with flapless versus traditional surgery. MATERIAL AND METHODS: In this prospective, randomized controlled clinical trial, 40 patients underwent implant placement at the Maxillofacial Department Surgery of the Istituto Stomatologico Italiano Hospital in Milan, Italy. Patients were randomly assigned to the control or experimental group. The control group had implants placed with open flap surgery (traditional surgery), whereas the experimental group had implants placed with flapless surgery. The distance between the first implant thread and the marginal crestal bone level was measured at the basal, loading, and long-term control points. The basal recording was performed just after implant placement. The loading measurement was recorded at the time of implant loading, after 2 months of healing for the lower jaw and after 3 months of healing for the upper jaw, and the long-term control record was registered 36 months after implant placement. Statistical analysis was performed using mean values and standard deviations based on bone resorption in the 2 groups. To detect statistical differences, the Student t test was applied. Differences were considered significant if P values were less than .05. RESULTS: The control group (open flap surgery) was comprised of 19 patients, and the experimental group (flapless surgery) was comprised of 21 patients. No statistical differences were found in peri-implant bone resorption between the 2 groups at the basal, implant loading, and 3-year control recordings. CONCLUSION: According to this study, the approach to implant surgery does not seem to influence peri-implant bone resorption in humans, at least for the period measured in this study. PMID- 26954559 TI - Hydroxyapatite/Collagen Composite Is a Reliable Material for Malar Augmentation. AB - PURPOSE: To evaluate the long-term results of cheekbone augmentation using porous hydroxyapatite granules mixed with microfibrillar collagen in a large group of patients. MATERIALS AND METHODS: Four hundred thirty patients who underwent zygomatic augmentation and intermaxillary osteotomy were evaluated clinically, radiologically, and histologically. RESULTS: Complications were found in 13 patients (1.56%). There were no relevant radiologic differences in prosthesis volume after 1 month (T1) or after 24 months (T2) in any patient; there were no clinically relevant differences in 110 patients after 36 months. At T1, the prosthesis had a granular structure and the granules had not migrated; at T2, the prosthesis was staunchly adhering to the underlying bone. Over time, the radiopacity of the material increased. Histologic results of 19 biopsy specimens obtained from 8 patients 2 years after the procedure showed prominent ossification with low inflammation, confirming new bone formation over time. According to the visual analog scale, the patients were generally satisfied with the aspects that were considered. CONCLUSION: Hydroxyapatite and collagen composite used during malarplasty produced a successful outcome. Its main drawback is a learning curve that is longer than for more frequently used implantable biomaterials. PMID- 26954562 TI - Radiological and archaeological investigation of a mummy from Roman Egypt curated in the National Museum of Lithuania. AB - Among the collections belonging to the National Museum of Lithuania at Vilnius, resides an ancient Egyptian coffin containing a mummified human body. The coffin and its occupant are believed to have belonged to the King of Poland and to have been located in his palace at Warsaw. At the turn of the last century, Egyptologists dated the coffin to the end of the 21st dynasty (1070 BC-945 BC), and described the item as coming from Thebes, belonging to Hori, priest of Amun Ra. However, no investigation was ever carried out on the human body associated with the coffin. Within the framework of the Lithuanian Mummy Project, the preserved human remains underwent computed tomographic investigation in order to reconstruct the biological profile of the subject and to determine the embalming method employed. This led to the identification of a young adult male. Additionally, the mummy shroud was stylistically assessed in order to determine the mummy's chronology in Egyptian history. Interestingly, the body could be ascribed to the Roman period of Egypt (30 BC-395 AD) due to analogies with the burial shrouds of the Soter group. This indicates a reuse of the coffin at some point in history. PMID- 26954561 TI - Length of Stay After Childbirth in 92 Countries and Associated Factors in 30 Low- and Middle-Income Countries: Compilation of Reported Data and a Cross-sectional Analysis from Nationally Representative Surveys. AB - BACKGROUND: Following childbirth, women need to stay sufficiently long in health facilities to receive adequate care. Little is known about length of stay following childbirth in low- and middle-income countries or its determinants. METHODS AND FINDINGS: We described length of stay after facility delivery in 92 countries. We then created a conceptual framework of the main drivers of length of stay, and explored factors associated with length of stay in 30 countries using multivariable linear regression. Finally, we used multivariable logistic regression to examine the factors associated with stays that were "too short" (<24 h for vaginal deliveries and <72 h for cesarean-section deliveries). Across countries, the mean length of stay ranged from 1.3 to 6.6 d: 0.5 to 6.2 d for singleton vaginal deliveries and 2.5 to 9.3 d for cesarean-section deliveries. The percentage of women staying too short ranged from 0.2% to 83% for vaginal deliveries and from 1% to 75% for cesarean-section deliveries. Our conceptual framework identified three broad categories of factors that influenced length of stay: need-related determinants that required an indicated extension of stay, and health-system and woman/family dimensions that were drivers of inappropriately short or long stays. The factors identified as independently important in our regression analyses included cesarean-section delivery, birthweight, multiple birth, and infant survival status. Older women and women whose infants were delivered by doctors had extended lengths of stay, as did poorer women. Reliance on factors captured in secondary data that were self-reported by women up to 5 y after a live birth was the main limitation. CONCLUSIONS: Length of stay after childbirth is very variable between countries. Substantial proportions of women stay too short to receive adequate postnatal care. We need to ensure that facilities have skilled birth attendants and effective elements of care, but also that women stay long enough to benefit from these. The challenge is to commit to achieving adequate lengths of stay in low- and middle-income countries, while ensuring any additional time is used to provide high-quality and respectful care. PMID- 26954563 TI - Influenza immunology evaluation and correlates of protection: a focus on vaccines. AB - Vaccination is the most effective method of controlling seasonal influenza infections and preventing possible pandemic events. Although influenza vaccines have been licensed and used for decades, the potential correlates of protection induced by these vaccines are still a matter of discussion. Currently, inactivated vaccines are the most common and the haemagglutination inhibition antibody titer is regarded as an immunological correlate of protection and the best available parameter for predicting protection from influenza infection. However, the assay shows some limitations, such as its low sensitivity to B and avian strains and inter-laboratory variability. Additional assays and next generation vaccines have been evaluated to overcome the limitations of the traditional serological techniques and to elicit broad immune responses, underlining the need to revise the current correlates of protection. The aim of this review is to provide an overview of the current scenario regarding the immunological evaluation and correlates of protection of influenza vaccines. PMID- 26954564 TI - Preventability and Causes of Readmissions in a National Cohort of General Medicine Patients. AB - IMPORTANCE: Readmission penalties have catalyzed efforts to improve care transitions, but few programs have incorporated viewpoints of patients and health care professionals to determine readmission preventability or to prioritize opportunities for care improvement. OBJECTIVES: To determine preventability of readmissions and to use these estimates to prioritize areas for improvement. DESIGN, SETTING, AND PARTICIPANTS: An observational study was conducted of 1000 general medicine patients readmitted within 30 days of discharge to 12 US academic medical centers between April 1, 2012, and March 31, 2013. We surveyed patients and physicians, reviewed documentation, and performed 2-physician case review to determine preventability of and factors contributing to readmission. We used bivariable statistics to compare preventable and nonpreventable readmissions, multivariable models to identify factors associated with potential preventability, and baseline risk factor prevalence and adjusted odds ratios (aORs) to determine the proportion of readmissions affected by individual risk factors. MAIN OUTCOME AND MEASURE: Likelihood that a readmission could have been prevented. RESULTS: The study cohort comprised 1000 patients (median age was 55 years). Of these, 269 (26.9%) were considered potentially preventable. In multivariable models, factors most strongly associated with potential preventability included emergency department decision making regarding the readmission (aOR, 9.13; 95% CI, 5.23-15.95), failure to relay important information to outpatient health care professionals (aOR, 4.19; 95% CI, 2.17 8.09), discharge of patients too soon (aOR, 3.88; 95% CI, 2.44-6.17), and lack of discussions about care goals among patients with serious illnesses (aOR, 3.84; 95% CI, 1.39-10.64). The most common factors associated with potentially preventable readmissions included emergency department decision making (affecting 9.0%; 95% CI, 7.1%-10.3%), inability to keep appointments after discharge (affecting 8.3%; 95% CI, 4.1%-12.0%), premature discharge from the hospital (affecting 8.7%; 95% CI, 5.8%-11.3%), and patient lack of awareness of whom to contact after discharge (affecting 6.2%; 95% CI, 3.5%-8.7%). CONCLUSIONS AND RELEVANCE: Approximately one-quarter of readmissions are potentially preventable when assessed using multiple perspectives. High-priority areas for improvement efforts include improved communication among health care teams and between health care professionals and patients, greater attention to patients' readiness for discharge, enhanced disease monitoring, and better support for patient self management. PMID- 26954566 TI - Redrawing the US Obesity Landscape: Bias-Corrected Estimates of State-Specific Adult Obesity Prevalence. AB - BACKGROUND: State-level estimates from the Centers for Disease Control and Prevention (CDC) underestimate the obesity epidemic because they use self reported height and weight. We describe a novel bias-correction method and produce corrected state-level estimates of obesity and severe obesity. METHODS: Using non-parametric statistical matching, we adjusted self-reported data from the Behavioral Risk Factor Surveillance System (BRFSS) 2013 (n = 386,795) using measured data from the National Health and Nutrition Examination Survey (NHANES) (n = 16,924). We validated our national estimates against NHANES and estimated bias-corrected state-specific prevalence of obesity (BMI>=30) and severe obesity (BMI>=35). We compared these results with previous adjustment methods. RESULTS: Compared to NHANES, self-reported BRFSS data underestimated national prevalence of obesity by 16% (28.67% vs 34.01%), and severe obesity by 23% (11.03% vs 14.26%). Our method was not significantly different from NHANES for obesity or severe obesity, while previous methods underestimated both. Only four states had a corrected obesity prevalence below 30%, with four exceeding 40%-in contrast, most states were below 30% in CDC maps. CONCLUSIONS: Twelve million adults with obesity (including 6.7 million with severe obesity) were misclassified by CDC state-level estimates. Previous bias-correction methods also resulted in underestimates. Accurate state-level estimates are necessary to plan for resources to address the obesity epidemic. PMID- 26954565 TI - Callosal Abnormalities Across the Psychosis Dimension: Bipolar Schizophrenia Network on Intermediate Phenotypes. AB - BACKGROUND: The corpus callosum has been implicated in the pathogenesis of schizophrenia and bipolar disorder. However, it is unclear whether corpus callosum alterations are related to the underlying familial diathesis for psychotic disorders. We examined the corpus callosum and its subregion volumes and their relationship to cognition, psychotic symptoms, and age in probands with schizophrenia (SZ), psychotic bipolar disorder (PBD), and schizoaffective disorder; their first-degree relatives; and healthy control subjects. METHODS: We present findings from morphometric and neurocognitive analyses of 1381 subjects (SZ probands, n = 224; PBD probands, n = 190; schizoaffective disorder probands, n = 142; unaffected relatives, n = 483 [SZ relatives, n = 195; PBD relatives, n = 175; schizoaffective disorder relatives, n = 113]; control subjects, n = 342). Magnetization prepared rapid acquisition gradient-echo T1 scans across five sites were obtained using 3-tesla magnets. Image processing was done using FreeSurfer Version 5.1. Neurocognitive function was measured using the Brief Assessment of Cognition in Schizophrenia scale. RESULTS: Anterior and posterior splenial volumes were significantly reduced across the groups. The SZ and PBD probands showed robust and significant reductions, whereas relatives showed significant reductions of intermediate severity. The splenial volumes were positively but differentially correlated with aspects of cognition in the probands and their relatives. Proband groups showed a significant age-related decrease in the volume of the anterior splenium compared with control subjects. Among the psychosis groups, the anterior splenium in probands with PBD showed a stronger correlation with psychotic symptoms, as shown by the Positive and Negative Syndrome Scale. All five subregions showed significantly high familiality. CONCLUSIONS: The splenial volumes were significantly reduced across the psychosis dimension. However, this volume reduction impacts cognition and clinical manifestation of the illnesses differentially. PMID- 26954567 TI - Inhibition of CXCR4 by LY2624587, a Fully Humanized Anti-CXCR4 Antibody Induces Apoptosis of Hematologic Malignancies. AB - SDF-1 and CXCR4 are a chemokine and chemokine receptor pair playing critical roles in tumorigenesis. Overexpression of CXCR4 is a hallmark of many hematological malignancies including acute myeloid leukemia, chronic lymphocytic leukemia and non-Hodgkin's lymphoma, and generally correlates with a poor prognosis. In this study, we developed a humanized anti-CXCR4 monoclonal antibody, LY2624587 as a potent CXCR4 antagonist that was advanced into clinical study for cancer. LY2624587 blocked SDF-1 binding to CXCR4 with an IC50 of 0.26 nM, and inhibited SDF-1-induced GTP binding with a Kb of 0.66 nM. In human lymphoma U937 and leukemia CCRF-CEM cells expressing endogenous CXCR4, LY2624587 inhibited SDF-1-induced cell migration with IC50 values of 3.7 and 0.26 nM, respectively. This antibody also inhibited CXCR4 and SDF-1 mediated cell signaling including activation of MAPK and AKT in tumor cells expressing CXCR4. Bifocal microscopic and flow cytometry analyses revealed that LY2624587 mediated receptor internalization and caused CXCR4 down-regulation on the cell surface. In human hematologic cancer cells, LY2624587 caused dose dependent apoptosis in vitro and in vivo. In mouse xenograft models developed with human leukemia and lymphoma cells expressing high levels of CXCR4, LY2624587 exhibited dose dependent tumor growth inhibition and provided significant survival benefit in a disseminated lymphoma model. Collectively, we have demonstrated that CXCR4 inhibition by LY2624587 has the potential for the treatment of human hematological malignancies. PMID- 26954569 TI - The Effect of Radiotherapy on Ultrasound-Guided Fine Needle Aspiration Biopsy and the Ultrasound Characteristics of Neck Lymph Nodes in Oral Cancer Patients after Primary Treatment. AB - OBJECTIVES: To investigate the effect of radiotherapy (RT) on ultrasound-guided fine needle aspiration (USgFNA) and sonographic characteristics in the assessment of cervical lymph nodes (LNs) in oral squamous cell carcinoma (OSCC) patients after primary treatment. MATERIALS AND METHODS: 88 treated OSCC patients underwent 111 USgFNAs of the neck LNs after US evaluation. Among them, 48 USgFNAs were performed on 40 patients following RT and 63 USgFNAs on 48 patients without previous RT. The results of USgFNA and the US characteristics were compared between these two groups. RESULTS: USgFNA had a sensitivity of 88.0%, specificity of 91.4%, positive predictive value (PPV) of 88.0%, negative predictive value (NPV) of 91.4% and accuracy of 90.0% in patients without previous RT, and a sensitivity of 97.1%, specificity of 83.3%, PPV of 94.3%, NPV of 90.9% and accuracy of 93.5% in those with previous neck RT. The ranges of the short-axis and long-axis length were 13.3 +/- 8.0 mm (mean +/- SD) versus 17.8 +/- 9.1 mm, and 18.6 +/- 9.0 mm versus 24.4 +/- 10.9 mm for recurrent LNs from patients with, versus without, previous RT (both ps < 0.05), respectively. 76.5% (26/34) of the recurrent nodes after RT and 48% (12/25) of the recurrent nodes without previous RT exhibited an irregular margin (p < 0.05). Additionally, irradiated recurrent LNs had a significantly decreased percentage of discernable calcification compared with non-irradiated recurrent nodes (48% versus 20.6%, p < 0.05). CONCLUSIONS: RT had influence on sonographic characteristics but no influence on USgFNA in diagnosing recurrent LNs in treated OSCC patients. PMID- 26954568 TI - Social Rhythm and Mental Health: A Cross-Cultural Comparison. AB - BACKGROUND: Social rhythm refers to the regularity with which one engages in social activities throughout the week, and has established links with bipolar disorder, as well as some links with depression and anxiety. The aim of the present study is to examine social rhythm and its relationship to various aspects of health, including physical health, negative mental health, and positive mental health. METHOD: Questionnaire data were obtained from a large-scale multi national sample of 8095 representative participants from the U.S., Russia, and Germany. RESULTS: Results indicated that social rhythm irregularity is related to increased reporting of health problems, depression, anxiety, and stress. In contrast, greater regularity is related to better overall health state, life satisfaction, and positive mental health. The effects are generally small in size, but hold even when controlling for gender, marital status, education, income, country, and social support. Further, social rhythm means differ across Russia, the U.S., and Germany. Relationships with mental health are present in all three countries, but differ in magnitude. CONCLUSIONS: Social rhythm irregularity is related to mental health in Russia, the U.S., and Germany. PMID- 26954571 TI - Cardiovascular and perceptual stress of female basketball referees during women's International matches. AB - BACKGROUND: The current aims were to determine body composition (BC), and heart rate (HR) and rating of perceived effort (RPE) responses by female basketball referees during elite international competition. METHODS: Pre-competition, BC via skinfolds was assessed in 10 referees (38 +/- 3 yr) who officiated 11 matches. Referees' HR and exercise intensity (based upon maximum HR, HRmax) was recorded during each quarter of each match and RPE assessed post- match. Differences between quarters were examined via repeated measures ANOVA while correlations between RPE, HR, BC and experience were also considered. RESULTS: The average match HR was 86.2+/-5.0 HRmax with this being significantly lower during the 4th quarter compared to the 1st (p = 0.18) and 2nd quarters (p = 0.001), and significantly lower during the 3rd compared to the 2nd quarter (p = 0.005). The average post-match RPE was 12.5 +/- 1.6 with significant inverse correlations identified between post-match RPE and exercise intensity (average HR, %HRmax). Significant correlations were identified between the average match HR and BC (0.608, p = 0.016), and experience (-0.653, p = 0.008). CONCLUSION: The current investigation has demonstrated that elite female basketball referees experience significant cardiovascular and perceptual stress during international matches that may be influenced by referee experience and BC. These unique characteristics may aid in referee preparation for elite competition. PMID- 26954570 TI - Effects of Selected Egyptian Honeys on the Cellular Ultrastructure and the Gene Expression Profile of Escherichia coli. AB - The purpose of this study was to: (i) evaluate the antibacterial activities of three Egyptian honeys collected from different floral sources (namely, citrus, clover, and marjoram) against Escherichia coli; (ii) investigate the effects of these honeys on bacterial ultrastructure; and (iii) assess the anti-virulence potential of these honeys, by examining their impacts on the expression of eight selected genes (involved in biofilm formation, quorum sensing, and stress survival) in the test organism. The minimum inhibitory concentration (MIC) of the honey samples against E. coli ATCC 8739 were assessed by the broth microdilution assay in the presence and absence of catalase enzyme. Impacts of the honeys on the cellular ultrastructure and the expression profiles of the selected genes of E. coli were examined using transmission electron microscopy (TEM) and quantitative real-time polymerase chain reaction (qPCR) analysis, respectively. The susceptibility tests showed promising antibacterial activities of all the tested honeys against E. coli. This was supported by the TEM observations, which revealed "ghost" cells lacking DNA, in addition to cells with increased vacuoles, and/or with irregular shrunken cytoplasm. Among the tested honeys, marjoram exhibited the highest total antibacterial activity and the highest levels of peroxide-dependent activity. The qPCR analysis showed that all honey-treated cells share a similar overall pattern of gene expression, with a trend toward reduced expression of the virulence genes of interest. Our results indicate that some varieties of the Egyptian honey have the potential to be effective inhibitor and virulence modulator of E. coli via multiple molecular targets. PMID- 26954572 TI - Incidence of musculoskeletal sport injuries in a sample of male and female recreational paddle-tennis players. AB - BACKGROUND: Nowadays paddle-tennis is practiced by the Spanish population, not only in a professional or semi-professional way, but also as a recreational sport. As occurs in tennis, the repetition of specific actions and gestures in paddle-tennis could be a factor associated with one or more types of musculoskeletal injuries in this population. The aim of this research was to describe the incidence and location of musculoskeletal injuries in a sample of Spanish recreational paddle-tennis and to explore a possible causality injury model, focusing on gender contribution. METHODS: The sample was composed of 113 active paddle-tennis players, of whom 47.78% were men. The participants were asked about the injuries they had suffered during their paddle participation. Other variables such as age, physical position in the game and level of ability were taken into account. RESULTS: 85.4% of the players reported any sport paddle injury. The elbow and the lower back have been shown as the most common regions of injury, followed by knee and shoulder injuries. Female group reported a higher injury incidence due to playing paddle-tennis (OR=0.169; P=0.008). Significant differences also existed between the genders for calf injury location (OR=0.208; P=0.020). A global injury model explaining 22.5% of the variance has been observed. Gender seems to explain 7.4% of the variance. CONCLUSIONS: Being a medium-aged weighty right-handed woman seems to be the profile more likely to report paddle-tennis related musculoskeletal injuries. A lack of literature regarding paddle-tennis related injuries has been observed. It could be said that our results contribute substantially in this field. PMID- 26954573 TI - Perceived demands and postexercise physical dysfunction in CrossFit(r) compared to an ACSM based training session. AB - BACKGROUND: CrossFit(r) is considered an intense and extreme conditioning program (ECP) that can cause overtraining and injury. Exertional Rhabdomyolysis (ER) - breakdown of muscle tissue - after ECP has been reported in CrossFit(r) and might be linked to comparatively high rates of subjectively perceived exertion levels. Therefore, the present study aimed at recording symptoms of postexercise physical dysfunction (e.g., excessive muscle soreness, shortness of breath) following CrossFit(r) and ratings of perceived exertion (RPE) during CrossFit(r) compared with training according to the American College of Sports Medicine (ACSM) guidelines. METHODS: A validated questionnaire was completed by 101 CrossFit(r) (age: 35+/-8 years; weight: 79+/-16 kg) and 56 ACSM (age: 35+/-10 years; weight: 75+/-27 kg) participants. RESULTS: CrossFit(r) and ACSM groups, respectively, reported significantly different RPE levels of 7.3+/-1.7 and 5.5+/-1.4 (P<=0.001) and amounts of hard days per week of 4.0+/-1.1 and 3.5+/-1.4 (P=0.04). The five most frequent and hardest ECP workouts of the day (WODs) were Fran (47), Murph (27), Fight Gone Bad (10), Helen (9) and Filthy 50 (9). Presence of severe post exercise symptoms was notably higher in CrossFit(r) for excessive fatigue (42 vs. 8; P<0.001), muscle soreness (96 vs. 48; P=0.04), muscle swelling (19 vs. 4; P=0.048), shortness of breath (13 vs. 1; P=0.02), muscle pain to touch (31 vs. 4; P=0.001), and limited muscle movement during workout (37 vs. 9; P=0.007). CONCLUSIONS: CrossFit(r) leads to "very hard" perceived exertion causing detrimental post-exercise effects on muscle and ventilatory function in experienced athletes. Improved training progression with adequate recovery schedules are needed to prevent severe muscle injury, such as ER. PMID- 26954576 TI - Granular biochar compared with activated carbon for wastewater treatment and resource recovery. AB - Granular wood-derived biochar (BC) was compared to granular activated carbon (GAC) for the treatment and nutrient recovery of real wastewater in both batch and column studies. Batch adsorption studies showed that BC material had a greater adsorption capacity at the high initial concentrations of total chemical oxygen demand (COD-T) (1200 mg L(-1)), PO4 (18 mg L(-1)), and NH4 (50 mg L(-1)) compared to GAC. Conversely the BC material showed a lower adsorption capacity for all concentrations of dissolved chemical oxygen demand (COD-D) and the lower concentrations of PO4 (5 mg L(-1)) and NH4 (10 mg L(-1)). Packed bed column studies showed similar average COD-T removal rate for BC with 0.27 +/- 0.01 kg m( 3) d(-1) and GAC with 0.24 +/- 0.01 kg m(-3) d(-1), but BC had nearly twice the average removal rate (0.41 +/- 0.08 kg m(-3) d(-3)) compared to GAC during high COD-T concentrations (>500 mg L(-1)). Elemental analysis showed that both materials accumulated phosphorous during wastewater treatment (2.6 +/- 0.4 g kg( 1) and 1.9 +/- 0.1 g kg(-1) for BC and GAC respectively). They also contained high concentrations of other macronutrients (K, Ca, and Mg) and low concentrations of metals (As, Cd, Cr, Pb, Zn, and Cu). The good performance of BC is attributed to its macroporous structure compared with the microporous GAC. These favorable treatment data for high strength wastewater, coupled with additional life-cycle benefits, helps support the use of BC in packed bed column filters for enhanced wastewater treatment and nutrient recovery. PMID- 26954575 TI - Simultaneous nitrogen, phosphorous, and hardness removal from reverse osmosis concentrate by microalgae cultivation. AB - While reverse osmosis (RO) is a promising technology for wastewater reclamation, RO concentrate (ROC) treatment and disposal are important issues to consider. Conventional chemical and physical treatment methods for ROC present certain limitations, such as relatively low nitrogen and phosphorus removal efficiencies as well as the requirement of an extra process for hardness removal. This study proposes a novel biological approach for simultaneous removal of nitrogen, phosphorus, and calcium (Ca(2+)) and magnesium (Mg(2+)) ions from the ROC of municipal wastewater treatment plants by microalgal cultivation and algal biomass production. Two microalgae strains, Chlorella sp. ZTY4 and Scenedesmus sp. LX1, were used for batch cultivation of 14-16 days. Both strains grew well in ROC with average biomass production of 318.7 mg/L and lipid contents up to 30.6%, and nitrogen and phosphorus could be effectively removed with efficiencies of up to 89.8% and 92.7%, respectively. Approximately 55.9%-83.7% Ca(2+) could be removed from the system using the cultured strains. Mg(2+) removal began when Ca(2+) precipitation ceased, and the removal efficiency of the ion could reach up to 56.0%. The most decisive factor influencing Ca(2+) and Mg(2+) removal was chemical precipitation with increases in pH caused by algal growth. The results of this study provide a new biological approach for removing nitrogen, phosphorous, and hardness from ROC. The results suggest that microalgal cultivation presents new opportunities for applying an algal process to ROC treatment. The proposed approach serves dual purposes of nutrient and hardness reduction and production of lipid rich micro-algal biomass. PMID- 26954577 TI - Genetic Variation and Breeding Signature in Mass Selection Lines of the Pacific Oyster (Crassostrea gigas) Assessed by SNP Markers. AB - In breeding industries, a challenging problem is how to keep genetic diversity over generations. To investigate genetic variation and identify breeding signatures in mass selected lines of Pacific oyster (Crassostrea gigas), three sixth-generation selected lines and four wild populations were assessed using 103 single nucleotide polymorphism (SNP) markers. The genetic diversity data indicated that the selected lines exhibited a significant reduction in the observed heterozygosity and observed number of alleles per locus compared with the wild populations (P<=0.05), indicating the selected lines tended to lose genetic diversity contrasted with the wild populations. The unweighted pair-group method with arithmetic mean (UPGMA) analysis showed that the wild populations and selected lines were not separated into two groups. Using four outlier tests, a total of 17 loci were found under selection at two levels. The global outlier detection suggested that 4 common outlier loci were subject to selection using both the hierarchical island model and Bayesian likelihood approaches. At regional level, 3 SNPs were detected as outlier using at least two outlier tests and one outlier SNP (CgSNP309) was overlapped in the two wild-selected population comparisons. The candidate outlier SNPs provide valuable resources for future association studies in C. gigas. PMID- 26954578 TI - Can the Understory Affect the Hymenoptera Parasitoids in a Eucalyptus Plantation? AB - The understory in forest plantations can increase richness and diversity of natural enemies due to greater plant species richness. The objective of this study was to test the hypothesis that the presence of the understory and climatic season in the region (wet or dry) can increase the richness and abundance of Hymenoptera parasitoids in Eucalyptus plantations, in the municipality of Belo Oriente, Minas Gerais State, Brazil. In each eucalyptus cultivation (five areas of cultivation) ten Malaise traps were installed, five with the understory and five without it. A total of 9,639 individuals from 30 families of the Hymenoptera parasitoids were collected, with Mymaridae, Scelionidae, Encyrtidae and Braconidae being the most collected ones with 4,934, 1,212, 619 and 612 individuals, respectively. The eucalyptus stands with and without the understory showed percentage of individuals 45.65% and 54.35% collected, respectively. The understory did not represent a positive effect on the overall abundance of the individuals Hymenoptera in the E. grandis stands, but rather exerted a positive effect on the specific families of the parasitoids of this order. PMID- 26954580 TI - Labor market effects of intrauterine exposure to nutritional deficiency: Evidence from administrative data on Muslim immigrants in Denmark. AB - This paper examines whether nutritional disruptions experienced during the stage of fetal development impair an individual's labor market productivity later in life. We consider intrauterine exposure to the month of Ramadan as a natural experiment that might cause shocks to the inflow of nutrients essential for fetal development. Specifically, we use administrative data from Denmark to investigate the impact of exposure to Ramadan in utero on labor market outcomes of adult Muslim males, including employment status, annual salary, hourly wage rate, and hours of work. Our findings indicate that potential exposure to nutritional disruptions during a critical stage of fetal development is likely to have scarring effects on the fetus expressed as poor labor market outcomes later in life. Specifically, exposure to Ramadan around the 7th month of gestation results in a lower likelihood of employment and, to a lesser extent, a lower salary, and reduced labor supply. For example, the 7th month intrauterine exposure to Ramadan is associated with a 2.6 percentage points reduction in the likelihood of employment among Muslim males. We do not find an impact on the wage rate. Finally, we also document suggestive evidence that these results may partially be driven by increased disability and to a lesser extent by poor educational attainment among those who were exposed to Ramadan during this particular period in utero. PMID- 26954581 TI - Polar Order and Frustrated Antiferromagnetism in Perovskite Pb2MnWO6 Single Crystals. AB - Single crystals of the multiferroic double-perovskite Pb2MnWO6 have been synthesized and their structural, thermal, magnetic and dielectric properties studied in detail. Pure perovskite-phase formation and stoichiometric chemical composition of the as-grown crystals are confirmed by X-ray single-crystal and powder diffraction techniques as well as energy-dispersive X-ray and inductively coupled plasma mass spectrometry. Detailed structural analyses reveal that the crystals experience a structural phase transition from the cubic space group (s.g.) Fm3m to an orthorhombic structure in s.g. Pn21a at about 460 K. Dielectric data suggest that a ferrielectric phase transition takes place at that same temperature, in contrast to earlier results on polycrystalline samples, which reported a transition to s.g. Pnma and an antiferroelectric low-temperature phase. Magnetic susceptibility measurements indicate that a frustrated antiferromagnetic phase emerges below 8 K. Density functional theory based calculations confirm that the cationic order between Mn and W is favorable. The lowest total energy was found for an antiferromagnetically ordered state. However, analyses of the calculated exchange parameters revealed strongly competing antiferromagnetic interactions. The large distance between the magnetic atoms, together with magnetic frustration, is shown to be the main reason for the low value of the ordering temperature observed experimentally. We discuss the structure-property relationships in Pb2MnWO6 and compare these observations to reported results on related Pb2BWO6 perovskites with different B cations. PMID- 26954579 TI - Plasmodium vivax Tryptophan Rich Antigen PvTRAg36.6 Interacts with PvETRAMP and PvTRAg56.6 Interacts with PvMSP7 during Erythrocytic Stages of the Parasite. AB - Plasmodium vivax is most wide spread and a neglected malaria parasite. There is a lack of information on parasite biology of this species. Genome of this parasite encodes for the largest number of tryptophan-rich proteins belonging to 'Pv-fam a' family and some of them are potential drug/vaccine targets but their functional role(s) largely remains unexplored. Using bacterial and yeast two hybrid systems, we have identified the interacting partners for two of the P. vivax tryptophan-rich antigens called PvTRAg36.6 and PvTRAg56.2. The PvTRAg36.6 interacts with early transcribed membrane protein (ETRAMP) of P.vivax. It is apically localized in merozoites but in early stages it is seen in parasite periphery suggesting its likely involvement in parasitophorous vacuole membrane (PVM) development or maintenance. On the other hand, PvTRAg56.2 interacts with P.vivax merozoite surface protein7 (PvMSP7) and is localized on merozoite surface. Co-localization of PvTRAg56.2 with PvMSP1 and its molecular interaction with PvMSP7 probably suggest that, PvTRAg56.2 is part of MSP-complex, and might assist or stabilize the protein complex at the merozoite surface. In conclusion, the PvTRAg proteins have different sub cellular localizations and specific associated functions during intra-erythrocytic developmental cycle. PMID- 26954582 TI - Coupling and Decoupling Approach Enables Palladium-Catalyzed Aerobic Bimolecular Carbocyclizations of Enediynes to 2,6-Diacylnaphthalenes. AB - A formal palladium-catalyzed aerobic bimolecular carbocyclization reaction of (Z) hexa-1,5-diyn-3-ene scaffolds has been successfully developed for the construction of 2,6-diacylnaphthalenes, wherein copper salts play a critical role in accomplishing the oxygenative homo- and hetero-dimerization processes of readily accessible enediyne-carboxylic acids and esters, respectively. The enediyne dimerization protocol provides a flexible and regiospecific approach to a variety of functionalized naphthalenes with up to six differentiated substituents in good yields by using a directing-group-assisted coupling and decoupling strategy. Mechanistic studies indicated that the two oxygen atoms being selectively incorporated into the crossover-annulation products of enediynecarboxylic acid and ester directly originate from atmospheric molecular oxygen and H2O, respectively. PMID- 26954583 TI - Improving the Process of Enteral Nutrition Preparation With Milk Technicians: Perceptions of Cost, Time, and Quality. AB - BACKGROUND: Neonatal intensive care nurses have historically been responsible for preparing enteral feedings--a costly and time-consuming process that may require leaving the bedside. To address these concerns, the Milk Technician Program was implemented at a major military treatment facility. Milk technicians were specially trained and responsible for handling, storing, and preparing enteral feeds. PURPOSE: To determine effectiveness of the Milk Technician Program, changes in length of time required to first attain full feeds, cost of feeding preparation, adherence to feeding preparation procedures, and nurse and milk technician role variables were evaluated. METHODS: A pre-/postdesign was used to compare length of time to full enteral feedings and cost. A plan-do-study-act design was used to evaluate protocol adherence and to identify and evaluate nurse and milk technician role variables. Data were collected via surveys, direct observations, and retrospective chart reviews to determine the overall effectiveness of this intervention. RESULTS: The average time for extremely and very preterm infants (<28 to 31 weeks) to first reach full feeds decreased from 32 to 19 days, t (33.1) = 2.33, P = .026, d = 0.704. Estimated feeding preparation cost savings for all infants admitted to the unit was $767 per day. Observed milk technician adherence to preparation procedures was 95.5%. Most nurses reported that the program saved time (97%) and all milk technicians reported improved job satisfaction. Nurses expressed concerns about accuracy and safety of preparation. Milk technicians reported concerns with communication, supplies, and lack of perceived support. IMPLICATIONS FOR PRACTICE: Milk technicians offer significant benefit to infants and nurses in the neonatal intensive care unit, including reducing time for infants to reach full feeds, saving nurses' time, and reducing costs. IMPLICATIONS FOR RESEARCH: Further research is needed to identify ideal educational backgrounds for milk technicians and to directly measure the effect of milk technicians on hospital length of stay and infant growth parameters. PMID- 26954584 TI - Modalities of Mechanical Ventilation: Volume-Targeted Versus Pressure-Limited. AB - BACKGROUND: Respiratory distress syndrome remains the most common admission diagnosis in the neonatal intensive care unit. Healthcare providers have a clear appreciation for the potential harm to pulmonary structures that have been associated with mechanical ventilation (MV) in the preterm infant. Although life sustaining, the goal is to optimally ventilate while limiting trauma to the neonatal lung in order to preserve long-term cardiopulmonary and neurodevelopmental outcomes. PURPOSE: To describe, compare, and contrast 2 primary methods of neonatal MV, pressure-limited ventilation (PLV) and volume targeted ventilation (VTV), highlighting key considerations during therapy. METHODS: A comprehensive search of the literature was completed using the following databases: CINAHL, Cochrane, Google Scholar, and PubMed. Research articles that were published in English over the last 10 years were reviewed for key information to describe and support the topic. Expert content review was conducted prior to publication by respiratory care providers, neonatal nurse practitioners, staff nurses, and neonatologist. FINDINGS: Technology is rapidly evolving, with the newest mechanical ventilators providing the clinician with real-time data not previously available. Advanced microprocessors and feedback mechanisms can better support various ventilatory strategies including PLV and VTV. Renewed interest in volume ventilation has led many clinicians to ask about current evidence to support ventilatory modalities with regard to timing, settings, and short- and long-term effects. IMPLICATIONS FOR PRACTICE: The clinician understands that neonatal pulmonary status is frequently changing based on gestational age, current age, and physiologic influences. Evidence supporting recommendations for the described MV modalities of PLV and VTV is provided for both preterm and term neonates. IMPLICATIONS FOR RESEARCH: Comparison between MV strategies, specifically PLV and VTV, including short- and long-term neurodevelopmental outcomes, is needed. Recommendations regarding physiologic tidal volume for the extremely preterm infant are lacking. PMID- 26954585 TI - Noninvasive Ventilation in Premature Neonates. AB - BACKGROUND: The use of noninvasive ventilation is a constantly evolving treatment option for respiratory disease in the premature infant. The goals of these noninvasive ventilation techniques are to improve gas exchange in the premature infant's lungs and to minimize the need for intubation and invasive mechanical ventilation. PURPOSE: The goals of this article are to consider various uses of nasal interfaces, discuss skin care and developmental positioning concerns faced by the bedside nurse, and discuss the medical management aimed to reduce morbidity and mortality. This article explores the nursing role, the advances in medical strategies for noninvasive ventilation, and the team approach to noninvasive ventilation use in this population. SEARCH STRATEGY: Search strategy included a literature review on medical databases, such as EBSCOhost, CINAHL, PubMed, and NeoReviews. FINDINGS: Innovative products, nursing research on developmental positioning and skin care, and advanced medical management have led to better and safer outcomes for premature infants requiring noninvasive ventilation. IMPLICATIONS FOR PRACTICE: The medical focus of avoiding long-term mechanical ventilation would not be possible without the technology to provide noninvasive ventilation to these premature infants and the watchful eye of the nurse in terms of careful positioning, preventing skin breakdown and facial scarring, and a proper seal to maximize ventilation accuracy. IMPLICATIONS FOR RESEARCH: This article encourages nursing-based research to quantify some of the knowledge about skin care and positioning as well as research into most appropriate uses for noninvasive ventilation devices. PMID- 26954586 TI - Effect of Water on Molecular Mobility and Physical Stability of Amorphous Pharmaceuticals. AB - We investigated the influence of sorbed water concentration on the molecular mobility and crystallization behavior in a model amorphous drug and a solid dispersion. The temperature scaling (Tg/T) allowed us to simultaneously evaluate the effects of water content and temperature on the relaxation time. In the supercooled dispersions, once scaled, the relaxation times of the systems with different water content overlapped. Thus, the observed increase in mobility could be explained by the "plasticization" effect of water. This effect also explained the decrease in crystallization onset temperature brought about by water. That is, plasticization is the underlying mechanism governing the observed increase in mobility and physical instability in the supercooled state. Similar results were observed in the glassy drug substance. A single linear relationship was observed between crystallization time (time for 0.5% crystallization) and Tg/T in both dry and water containing systems. Since fragility is unaffected by modest amounts of water, much like crystallization time, the mobility in the glass is expected to scale with Tg. PMID- 26954588 TI - Are psychotherapeutic effects on family caregivers of people with dementia sustainable? Two-year long-term effects of a telephone-based cognitive behavioral intervention. AB - OBJECTIVES: Evaluation of long-term effects of an individualized short-term telephone intervention (seven sessions), based on a comprehensive cognitive behavioral therapy (CBT) approach. The study goal was to evaluate the maintenance of intervention effects regarding well-being, quality of life, and health at two years post treatment. METHOD: Participants (n = 105) were (partly) randomized after baseline assessment in a two-arm study (intervention, control group/usual care). Depressive symptoms were assessed with the German version of the Center for Epidemiologic Studies Depression Scale (CES-D). Caregivers' physical complaints were measured with the Giebetaener Beschwerdebogen (GBB-24), and quality of life with the World Health Organization quality of life -BREF (WHOQOL BREF). Emotional well-being and perceived health status were assessed using thermometer scaling. Data were analyzed by intention-to-treat analyses, including for those who terminated the intervention prematurely but still delivered data, using ANCOVAs. RESULTS: Long-term intervention effects were found for emotional well-being (p = 0.019). For the subgroup of caregivers who were still caring at home at follow-up, the intervention led to an increased health status (p = 0.023), fewer bodily complaints (global measure p= 0.014, rheumatic pain p = 0.027, heart trouble p = 0.042), and a higher quality of life (overall p = 0.044 and subscale environment p = 0.030). CONCLUSION: The short-term CBT intervention via telephone showed long-term effects two years after treatment on emotional well-being, health status, bodily complaints, and quality of life. PMID- 26954587 TI - miR-429 regulates the transition between Hypoxia-Inducible Factor (HIF)1A and HIF3A expression in human endothelial cells. AB - Hypoxia-inducible factors (HIF) are heterodimeric transcription factors that allow cells to adapt and survive during hypoxia. Regulation of HIF1A and HIF2A mRNA is well characterized, whereas HIF3A mRNA regulation and function are less clear. Using RNA-Seq analysis of primary human umbilical vein endothelial cells, we found two isoforms of HIF3A were expressed, HIF3A2 and HIF3A3. Comparing HIF3A expression profiles to HIF1A mRNA during 48 hours of hypoxia revealed that HIF1A message peaked at 4 hours, whereas HIF3A expression increased while HIF1A was decreasing. Given that HIF1A mRNA is regulated by miR-429, we tested miR-429 effects on both HIF3A isoforms and found that they too were regulated by miR-429. Analysis of a HIF-3 target, DNA-damage-inducible transcript 4, a key survival gene, indicated that DDIT4 mRNA is induced by HIF-3 and negatively regulated by miR-429 through miR-429's actions on HIF3A message. This provides a compelling model for how hypoxia-induced miR-429 regulates the switch between HIF-1 adaptive responses to HIF-3 survival responses by rapidly decreasing HIF1A levels while simultaneously slowing the progression of HIF3A expression until the miR-429 levels drop below normoxic levels. Since HIF-1 drives HIF3A and miR-429 expression, this establishes a regulatory network in which miR-429 plays a pivotal role. PMID- 26954589 TI - Epidemiologic Review of Carbapenem-Resistant Enterobacteriaceae, Duodenoscopes, and Endoscopic Ultrasonography in the Department of Veterans Affairs. PMID- 26954591 TI - Automated patient setup and gating using cone beam computed tomography projections. AB - In radiation therapy, fiducial markers are often implanted near tumors and used for patient positioning and respiratory gating purposes. These markers are then used to manually align the patients by matching the markers in the cone beam computed tomography (CBCT) reconstruction to those in the planning CT. This step is time-intensive and user-dependent, and often results in a suboptimal patient setup. We propose a fully automated, robust method based on dynamic programming (DP) for segmenting radiopaque fiducial markers in CBCT projection images, which are then used to automatically optimize the treatment couch position and/or gating window bounds. The mean of the absolute 2D segmentation error of our DP algorithm is 1.3 +/- 1.0 mm for 87 markers on 39 patients. Intrafraction images were acquired every 3 s during treatment at two different institutions. For gated patients from Institution A (8 patients, 40 fractions), the DP algorithm increased the delivery accuracy (96 +/- 6% versus 91 +/- 11%, p < 0.01) compared to the manual setup using kV fluoroscopy. For non-gated patients from Institution B (6 patients, 16 fractions), the DP algorithm performed similarly (1.5 +/- 0.8 mm versus 1.6 +/- 0.9 mm, p = 0.48) compared to the manual setup matching the fiducial markers in the CBCT to the mean position. Our proposed automated patient setup algorithm only takes 1-2 s to run, requires no user intervention, and performs as well as or better than the current clinical setup. PMID- 26954592 TI - Introduction. PMID- 26954590 TI - Quantifying Current Events Identifies a Novel Endurance Regulator. AB - In nongrowing microbes, proteome turnover is reduced and identification of newly synthesized, low-abundance proteins is challenging. Babin and colleagues recently utilized bio-orthogonal noncanonical amino acid tagging (BONCAT) to identify actively synthesized proteins in nongrowing Pseudomonas aeruginosa, discovering a regulator whose influences range from biofilm formation to secondary metabolism. PMID- 26954593 TI - History of the Concept of Disconnectivity in Schizophrenia. AB - Nearly 60 years ago Seymour Kety proposed that research on genetics and brain pathology, but not on neurochemistry, would ultimately lead to an understanding of the pathophysiology of schizophrenia. This article will demonstrate the prescience of Kety's proposal; advances in our knowledge of brain structure and genetics have shaped our current understanding of the pathophysiology of schizophrenia. Brain-imaging techniques have shown that schizophrenia is associated with cortical atrophy and ventricular enlargement, which progresses for at least a decade after the onset of psychotic symptoms. Cortical atrophy correlates with negative symptoms and cognitive impairment, but not with psychotic symptoms, in schizophrenia. Studies with the Golgi-staining technique that illuminates the entire neuron indicate that cortical atrophy is due to reduced synaptic connectivity on the pyramidal neurons and not due to actual loss of neurons. Results of recent genetic studies indicate that several risk genes for schizophrenia are within two degrees of separation from the N-methy-D aspartate receptor (NMDAR), a subtype of glutamate receptor that is critical to synapse formation and synaptic plasticity. Inactivation of one of these risk genes that encodes serine racemase, which synthesizes D-serine, an NMDAR co agonist, reproduces the synaptic pathology of schizophrenia. Thus, widespread loss of cortical synaptic connectivity appears to be the primary pathology in schizophrenia that is driven by multiple risk genes that adversely affect synaptogenesis and synapse maintenance, as hypothesized by Kety. PMID- 26954595 TI - Offspring of Parents with Schizophrenia: A Systematic Review of Developmental Features Across Childhood. AB - A significant body of longitudinal research has followed the offspring of parents with schizophrenia. This article presents a systematic review of 46 separate papers presenting the results of 18 longitudinal studies that have followed children who are at familial high risk of developing psychotic disorders. The studies suggest that these children do show distinct developmental patterns characterized by higher rates of obstetric complication, neurodevelopmental features such as motor and cognitive deficits, and distinctive social behavior. This review summarizes those findings according to child developmental stages. Twelve of the studies followed offspring into adulthood and examined psychiatric diagnoses. From 15% to 40% of children at familial high risk developed psychotic disorders in adulthood. Many also received other psychiatric diagnoses such as mood or anxiety disorders. This combination of results suggests that offspring of parents with schizophrenia are at high risk not just for schizophrenia but, more broadly, for poor developmental and general mental health outcomes. The clinical implications of the findings are discussed, as are new prognostic strategies and potential programs for selective prevention. PMID- 26954596 TI - The Longitudinal Course of Schizophrenia Across the Lifespan: Clinical, Cognitive, and Neurobiological Aspects. AB - Despite several decades of research, our knowledge of the long-term course of schizophrenia (SZ) is hampered by a lack of homogeneity of both research methods and phenotypic definitions of SZ's course. We provide a comprehensive review of the course of SZ by applying stringent methodological and diagnostic study selection criteria. We report on positive and negative symptoms, cognition, and findings obtained by neuroimaging. In addition, we perform a meta-analysis of longitudinal studies of cognition in humans. We selected 35 human studies focusing on a narrow SZ phenotype, employing a follow-up duration of six months or more and consistent methodology at the different measurement points. For the meta-analysis on global cognitive change, eight and four studies were used to compare SZ to healthy and psychiatric controls, respectively. We find that the course of SZ is characterized by a constancy or even improvement of positive and negative symptoms and by fairly stable cognitive impairment, reflecting structural frontal and temporal cortical pathology. Progressive changes of the frontal cortex appear to develop in parallel with changes in symptomatology and executive impairment. Despite stable differences in cognition between patients and controls over the time intervals studied, high heterogeneity in the magnitude of effect sizes is present, and age is identified as one of its potential sources. Meta-regression shows these magnitudes to depend on the age at study inclusion. For future research, a combination of longitudinal and cross-sectional research designs is warranted to better account for potential cohort effects. PMID- 26954598 TI - A Cognitive Neuroscience View of Voice-Processing Abnormalities in Schizophrenia: A Window into Auditory Verbal Hallucinations? AB - Auditory verbal hallucinations (AVH) are a core symptom of schizophrenia. Like "real" voices, AVH carry a rich amount of linguistic and paralinguistic cues that convey not only speech, but also affect and identity, information. Disturbed processing of voice identity, affective, and speech information has been reported in patients with schizophrenia. More recent evidence has suggested a link between voice-processing abnormalities and specific clinical symptoms of schizophrenia, especially AVH. It is still not well understood, however, to what extent these dimensions are impaired and how abnormalities in these processes might contribute to AVH. In this review, we consider behavioral, neuroimaging, and electrophysiological data to investigate the speech, identity, and affective dimensions of voice processing in schizophrenia, and we discuss how abnormalities in these processes might help to elucidate the mechanisms underlying specific phenomenological features of AVH. Schizophrenia patients exhibit behavioral and neural disturbances in the three dimensions of voice processing. Evidence suggesting a role of dysfunctional voice processing in AVH seems to be stronger for the identity and speech dimensions than for the affective domain. PMID- 26954599 TI - Cognitive Remediation for the Treatment of Cognitive Dysfunction in the Early Course of Psychosis. AB - The development of cognitive remediation programs has been a key step toward the creation of a treatment approach to address the cognitive-symptom domain in psychosis. Studies support the efficacy of cognitive remediation in producing moderate effects on cognition at the group level in patients with schizophrenia. Cognitive remediation may harness neuroplasticity in relevant systems that underpin the cognitive functions being addressed. Since neuroplasticity may be greater in people who (1) are younger and (2) have not yet experienced the consequences of long-term psychosis, cognitive remediation may be particularly effective in people in the early course of illness or in the prodrome, prior to the onset of frank symptoms. The present article reviews the evidence for implementing cognitive remediation in patients with recent-onset psychosis and people identified as being at high risk for developing schizophrenia, and also the evidence for cognitive remediation to modify neural targets. Promising findings suggest that cognitive remediation may be useful in addressing cognitive deficits in early-course and prodromal participants. Additionally, a growing literature using neuroimaging techniques demonstrates the ability of cognitive remediation paradigms to engage neural targets. PMID- 26954594 TI - Progress and Future Directions in Research on the Psychosis Prodrome: A Review for Clinicians. AB - LEARNING OBJECTIVES: After participating in this activity, learners should be better able to: ABSTRACT: The psychosis prodrome, or period of clinical and functional decline leading up to acute psychosis, offers a unique opportunity for identifying mechanisms of psychosis onset and for testing early-intervention strategies. We summarize major findings and emerging directions in prodromal research and provide recommendations for clinicians working with individuals suspected to be at high risk for psychosis. The past two decades of research have led to three major advances. First, tools and criteria have been developed that can reliably identify imminent risk for a psychotic disorder. Second, longitudinal clinical and psychobiological data from large multisite studies are strengthening individual risk assessment and offering insights into potential mechanisms of illness onset. Third, psychosocial and pharmacological interventions are demonstrating promise for delaying or preventing the onset of psychosis in help-seeking, high-risk individuals. The dynamic psychobiological processes implicated in both risk and onset of psychosis, including altered gene expression, cognitive dysfunction, inflammation, gray and white matter brain changes, and vulnerability-stress interactions suggest a wide range of potential treatment targets and strategies. The expansion of resources devoted to early intervention and prodromal research worldwide raises hope for investigating them. Future directions include identifying psychosis-specific risk and resilience factors in children, adolescents, and non-help-seeking community samples, improving study designs to test hypothesized mechanisms of change, and intervening with strategies that, in order to improve functional outcomes, better engage youth, address their environmental contexts, and focus on evidence-based neurodevelopmental targets. Prospective research on putatively prodromal samples has the potential to substantially reshape our understanding of mental illness and our efforts to combat it. PMID- 26954600 TI - Emerging Treatments in Schizophrenia: Highlights from Recent Supplementation and Prevention Trials. AB - In this column we examine the recent literature regarding adjunctive antipsychotic treatment of schizophrenia. We provide a brief introduction outlining the urgent need for new therapeutics, particularly for the treatment of negative and cognitive symptoms of schizophrenia. We then address (by mechanism of action) the most extensively studied adjunctive antipsychotic treatments. We conclude that adjunctive treatments targeting glutamatergic modulation, as well as supplementation with certain vitamins, have the strongest evidence for use in the treatment of schizophrenia. Further, larger randomized, controlled trials are needed, focusing on certain subgroups of patients and specific antipsychotic medications. PMID- 26954601 TI - Effect of Pneumococcal Conjugate Vaccine on the Natural Antibodies and Antibody Responses Against Protein Antigens From Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis in Children With Community-acquired Pneumonia. AB - BACKGROUND: Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis are common causative agents of respiratory infections. Pneumococcal conjugate vaccines have been introduced recently, but their effect on the natural immunity against protein antigens from these pathogens has not been elucidated. METHODS: This was an age-matched observational controlled study that evaluated the influence of 10-valent pneumococcal conjugate vaccines on the levels of antibodies and frequencies of antibody responses against proteins from S. pneumoniae, H. influenzae and M. catarrhalis in serum samples of children with community-acquired pneumonia. Eight pneumococcal proteins (pneumolysin, choline binding protein A, pneumococcal surface protein A families 1 and 2, pneumococcal choline-binding protein A, pneumococcal histidine triad protein D, serine/threonine protein kinase, protein required for cell wall separation of group B streptococcus), 3 proteins from H. influenzae (including protein D) and 5 M. catarrhalis proteins were investigated. RESULTS: The study group comprised 38 vaccinated children and 114 age-matched controls (median age: 14.5 vs. 14.6 months, respectively; P = 0.997), all with community-acquired pneumonia. There was no difference on clinical baseline characteristics between vaccinated and unvaccinated children. Vaccinated children had significantly lower levels of antibodies against 4 of the studied pneumococcal antigens (P = 0.048 for Ply, P = 0.018 for pneumococcal surface protein A, P = 0.001 for StkP and P = 0.028 for PcsB) and higher levels of antibodies against M. catarrhalis (P = 0.015). Nevertheless, the vaccination status did not significantly affect the rates of antibody responses against S. pneumoniae, H. influenzae and M. catarrhalis. CONCLUSIONS: In spite of the differences that have been found on the level of natural antibodies, no effect from pneumococcal vaccination was observed on the rate of immune responses associated with community-acquired pneumonia against protein antigens from S. pneumoniae, H. influenzae and M. catarrhalis. PMID- 26954603 TI - Coverage and Determinants of Uptake for Privately Funded Rotavirus Vaccine in a Canadian Birth Cohort, 2008-2013. AB - BACKGROUND: Rotavirus can lead to serious illness or death, even in developed countries. While vaccination can provide protection, many jurisdictions are still grappling with the issue of whether to introduce a universal publicly funded rotavirus vaccination program. This retrospective population-based study assessed rotavirus vaccine coverage, determinants of uptake, and compliance with the recommended schedule in a Canadian jurisdiction with a privately-funded rotavirus vaccination program. METHODS: Analysis of pharmaceutical dispensing, vital statistics, and administrative health data determined vaccine coverage and schedule compliance from 2008 to 2013. Multivariable logistic regression was used to assess characteristics of families purchasing vaccine. RESULTS: Vaccine coverage ranged from 1% to 4% between 2008-2013, with 52% of vaccinated children completing the full vaccine series; 7.9% and 3.8% of children received doses before and after the recommended ages, respectively. Children who received >=1 doses of the vaccine were more likely to have mothers who were married (adjusted odds ratio [aOR] 1.76, 95% CI1.64-1.88), fewer siblings (aOR 3.44, 95%CI 3.01 3.94), be non-First Nations (aOR 2.29, 95%CI 1.78-2.94), and be born prematurely (aOR 1.32, 95%CI 1.23-1.42). Income was a strong influence in urban areas, but not in rural regions, where coverage was lower overall. CONCLUSIONS: Vaccine coverage in a privately-funded model was very low and left high risk populations unprotected. Vaccine series completion and compliance with recommended scheduling was also suboptimal. PMID- 26954602 TI - Interferon-gamma-dependent Immunity in Bacillus Calmette-Guerin Vaccine Osteitis Survivors. AB - BACKGROUND: Inborn errors of interferon-gamma (IFN-gamma)-mediated immunity underlie disseminated disease caused by Mycobacterium bovis Bacillus Calmette Guerin (BCG) live vaccines. We hypothesized that some patients with osteitis after BCG vaccination may have an impaired IFN-gamma immunity. Our aim was to investigate interleukin (IL)-12 and IFN-gamma ex vivo production stimulated with BCG and BCG + IFN-gamma or BCG + IL-12, respectively, in BCG osteitis survivors. METHODS: Fresh blood samples were collected from 132 former BCG osteitis Finnish patients now aged 21-49 years, and IL-12 and IFN-gamma were measured in cell cultures with and without stimulation with BCG and with BCG + IFN-gamma or BCG + IL-12, respectively. As a pilot study, known disease-causing genes controlling IFN-gamma immunity (IFNGR1, IFNGR2, STAT1, IL12B, IL12RB1, ISG15, IRF8, NEMO and CYBB) were investigated in 20 selected patients by whole exome sequencing. RESULTS: By the limit of <5th percentile, ex vivo IL-12 concentration and increase in concentration was low in 5 and ex vivo IFN-gamma concentration and increase in concentration was low in 6 patients (including 2 samples with both IL 12 and IFN-gamma findings). By the limit of <10th percentile, an additional 6 and 4 patients were, respectively, detected (including 2 samples with both findings). With 2 exceptions, low concentrations and low increases in concentrations picked up the same cases. Mutations in known disease-causing IFN-gamma-related genes were not found in any of these patients. CONCLUSION: These findings call for searching of mutations in new genes governing IFN-gamma-dependent immunity to live BCG vaccine. PMID- 26954605 TI - Response to Comment on "Application of the Activity Framework for Assessing Aquatic Ecotoxicology Data for Organic Chemicals". PMID- 26954597 TI - Electrophysiological Endophenotypes for Schizophrenia. AB - Endophenotypes are quantitative, heritable traits that may help to elucidate the pathophysiologic mechanisms underlying complex disease syndromes, such as schizophrenia. They can be assessed at numerous levels of analysis; here, we review electrophysiological endophenotypes that have shown promise in helping us understand schizophrenia from a more mechanistic point of view. For each endophenotype, we describe typical experimental procedures, reliability, heritability, and reported gene and neurobiological associations. We discuss recent findings regarding the genetic architecture of specific electrophysiological endophenotypes, as well as converging evidence from EEG studies implicating disrupted balance of glutamatergic signaling and GABAergic inhibition in the pathophysiology of schizophrenia. We conclude that refining the measurement of electrophysiological endophenotypes, expanding genetic association studies, and integrating data sets are important next steps for understanding the mechanisms that connect identified genetic risk loci for schizophrenia to the disease phenotype. PMID- 26954607 TI - Two-dimensional tricycle arsenene with a direct band gap. AB - Based on a comprehensive investigation including ab initio phonon and finite temperature molecular dynamics calculations, we find that two-dimensional tricycle-shaped arsenene (T-As) is robust and even stable under high temperature. T-As is energetically comparable to previously reported chair-shaped arsenene (C As) and more stable than stirrup-shaped arsenene (S-As). In contrast to C-As and S-As, the monolayer T-As is a direct band gap semiconductor with an energy gap of 1.377 eV. Our results indicate that the electronic structure of T-As can be effectively modulated by stacking, strain, and patterning, which shows great potential of T-As in future nano-electronics. Moreover, by absorbing H or F atoms on the surface of T-As along a specific direction, nanoribbons with desired edge type and even width can be obtained, which is suitable for the fabrication of nano-devices. PMID- 26954606 TI - Discovery of new selective cytotoxic agents against Bcl-2 expressing cancer cells using ligand-based modeling. AB - Bcl-2 is an anti-apoptotic protein involved in cancer resistance to cytotoxic therapies making it an interesting target for inhibitors design. Towards this end, we implemented an elaborated ligand-based computational workflow that combines exhaustive pharmacophore modeling and quantitative structure-activity relationship (QSAR) analysis to explore the structural features required for potent Bcl-2 inhibitors employing 98 known Bcl-2 inhibitors. Genetic function algorithm (GFA) coupled with k nearest neighbor (kNN) or multiple linear regression (MLR) analyses were employed to generate predictive QSAR models based on optimal combinations of pharmacophores and physicochemical descriptors. The optimal QSAR-selected pharmacophore models were validated by receiver operating characteristic (ROC) curve analysis and by comparison with crystallographic structures of known inhibitors co-crystallized within Bcl-2 binding pocket. Optimal QSAR models and their associated pharmacophore hypotheses were validated by identification and experimental evaluation of new selective cytotoxic compounds against Bcl-2 expressing cancer cells. The hits were retrieved from the National Cancer Institute (NCI) structural database. Several potent hits were captured. The most potent hits illustrated IC50 values of 4.2 and 2.60 MUM against MDA-MB-231 cancer cell-line. PMID- 26954610 TI - High-resolution mass spectrometry: basic principles for using exact mass and mass defect for discovery analysis of organic molecules in blood, breath, urine and environmental media. PMID- 26954611 TI - Understanding the Relationship Between Suicidality and Psychopathy: An Examination of the Interpersonal-Psychological Theory of Suicidal Behavior. AB - A number of studies have reported a bifurcated relationship between psychopathy and suicidality, such that suicidality is positively related to Factor 2 (impulsive-antisocial lifestyle) of psychopathy but negatively related or unrelated to Factor 1 (affective-interpersonal deficits). The present study aims to expand these findings by investigating this relationship through the lens of the interpersonal-psychological theory of suicidal behavior across both undergraduate and forensic samples. We hypothesized that, although both Factors 1 and 2 would be associated with the acquired capability for suicide, Factor 2 would exhibit a unique relationship with suicidal desire (perceived burdensomeness and thwarted belongingness). Results were largely supportive of these hypotheses, although differences were noted across samples and measures. Findings highlight the importance of precision in the assessment of antisociality and suggest potential differences in the construct of psychopathy between non criminal and criminal samples. PMID- 26954612 TI - Costs of paying higher prices for equivalent effects on the Pharmaceutical Benefits Scheme. AB - Objective The aims of the present study were to illustrate and discuss the effects of the non-maintenance of equivalent prices when the comparators of pharmaceuticals listed on the Pharmaceutical Benefits Schedule (PBS) on a cost minimisation basis come off-patent and are subject to statutory price reductions, as well as further potential price reductions because of the effects of price disclosure. Methods Service use, benefits paid, and price data were analysed for a selected sample of pharmaceuticals recommended for listing on a cost minimisation basis between 2008 and 2011, and their comparators, to estimate the cost savings to the PBS of maintaining equivalent prices. Results Potential cost savings for 12 pharmaceuticals, including alternative compounds and combination products across nine therapeutic groups, ranged from A$570000 to A$40million to April 2015. Potential savings increased significantly following recent amendments to the price disclosure process. Conclusions Potential savings from maintaining equivalent prices for all pharmaceuticals listed on the PBS on a cost minimisation basis could be over A$500million per year. Actions to reduce these costs can be taken within existing policy frameworks, but legislative and political barriers may need to be addressed to minimise these costs, which are incurred by the taxpayer for no additional benefit. What is known about the topic? Pharmaceuticals listed on the PBS must provide value for money. Many pharmaceuticals achieve this by demonstrating equal effectiveness to an already listed pharmaceutical and requesting the same price as this comparator; that is, listing on a cost-minimisation basis. When the comparator moves off-patent, the price of the still-patented pharmaceutical is protected, whereas the off-patent drug is subject to price disclosure and often steep price reductions. What does this paper add? This paper adds to recent evidence on the costs to government of paying different prices for two or more pharmaceuticals that are equally effective. Between 2008 and 2011, the direct comparators for 68 pharmaceuticals listed on a cost-minimisation basis have moved onto the price disclosure list. Across 12 of these listings, the potential cost savings in the 10 months to April 2015 were A$73million. What are the implications for practitioners? The PBS costs the Australian government over A$9 billion per year. Annual savings over A$500million per year could be achieved by maintaining cost-minimisation across equally effective pharmaceuticals. This would improve the efficiency of the PBS at no risk to patients. Legislation is required to remove the existing F1 and F2 categorisation of listed pharmaceuticals, but the proposed changes would remove the need for therapeutic group premiums and simplify the pricing of PBS items. PMID- 26954609 TI - Testing candidate genes for attention-deficit/hyperactivity disorder in fruit flies using a high throughput assay for complex behavior. AB - Fruit flies are important model organisms for functional testing of candidate genes in multiple disciplines, including the study of human diseases. Here we use a high-throughput locomotor activity assay to test the response on activity behavior of gene disruption in Drosophila melanogaster. The aim was to investigate the impact of disruption of 14 candidate genes for human attention deficit/hyperactivity disorder (ADHD) on fly behavior. By obtaining a range of correlated measures describing the space of variables for behavioral activity we show, that some mutants display similar phenotypic responses, and furthermore, that the genes disrupted in those mutants had common molecular functions; namely processes related to cGMP activity, cation channels and serotonin receptors. All but one of the candidate genes resulted in aberrant behavioral activity, suggesting involvement of these genes in behavioral activity in fruit flies. Results provide additional support for the investigated genes being risk candidate genes for ADHD in humans. PMID- 26954613 TI - Frequency of Uveitis in the Central Tokyo Area (2010-2012). AB - PURPOSE: To investigate the frequency of conditions of newly arrived patients with uveitis from 2010 to 2012 and compare this frequency with that since 2004. METHODS: We retrospectively analyzed clinical records of patients who visited the outpatient clinic from January 2010 to December 2012, and compared them with those from 2004-2009. RESULTS: From 2010 to 2012, 695 new patients with uveitis visited Tokyo University Hospital, with a definite diagnosis made in 431 (62.0%). The most common diagnosis was scleritis (8.3%), followed by sarcoidosis (8.1%); herpetic iridocyclitis (5.5%); Behcet disease (4.6%); Vogt-Koyanagi-Harada disease (4.0%); acute anterior uveitis (3.7%); Posner-Schlossman syndrome (3.6%); intraocular malignant lymphoma (3.0%); and bacterial endophthalmitis (1.9%). The most frequent unclassified type of uveitis was sarcoidosis-suspected (14.8%). CONCLUSIONS: When compared with years 2004-2009, the present series showed an increasing trend of intraocular malignant lymphoma, bacterial endophthalmitis, and chronic iridocyclitis, and a notable increase in chronic iridocyclitis in young girls, with decreasing trends of scleritis and Vogt-Koyanagi-Harada disease. PMID- 26954614 TI - The Antibiofilm Effect of Ginkgo biloba Extract Against Salmonella and Listeria Isolates from Poultry. AB - Salmonella spp. and Listeria spp. are common foodborne pathogens in poultry and have caused a large number of outbreaks worldwide. Biofilm formation is common in the food industry and is also a mechanism of antimicrobial resistance. The aim of this work was to investigate the antimicrobial effect and mechanism of Ginkgo biloba extract against the biofilm formation of Salmonella and Listeria isolates from poultry at retail markets. Bacteria detection, isolation, and enumeration were carried out on 27 chicken and 29 ducks at retail markets. The effects of temperature and G. biloba extract against biofilm formation of Salmonella and Listeria isolates were measured using the crystal violet assay and swimming and swarming motilities. The monitoring results of Salmonella and Listeria in 56 poultry carcasses at retail markets in Korea showed that the prevalence of Salmonella spp. in poultry was low (5.4%), but the prevalence of Listeria spp (78.6%) was high. L. innocua was the predominant serotype (80%) in the isolated Listeria species. Temperature, strain, and surface affected the biofilm formation of Salmonella spp. and Listeria spp. L. innocua showed the best biofilm formation ability on a 96-well plate, while Salmonella Enteritidis formed the most biofilm on a glass slide. Biofilm formation abilities of Salmonella spp. and Listeria spp. were increased with the increase of temperature. G. biloba extract at 75 MUg/mL significantly inhibited biofilm formation of Salmonella spp. and Listeria spp (p < 0.05). The mechanism of the antibiofilm effect of the G. biloba extract showed that the motility reduction may be one of the mechanisms of G. biloba extract against some serotypes of Salmonella and Listeria, but not L. monocytogenes. The findings of this study provided the basis for the application of G. biloba extract as a food additive to promote the quality and safety of poultry products. PMID- 26954618 TI - Attitudes of West African Immigrants in the United States toward Substance Misuse: Exploring Culturally Informed Prevention and Treatment Strategies. AB - There is a lack of literature exploring substance misuse issues of the West African-born population in the United States. Thirty-four participants born in West Africa participated in one of three focus groups in a U.S. city to discuss their attitudes toward alcohol and drug use. Based on a qualitative analysis of the discussions, stigmatization of substance abusers and negative attitudes toward U.S. substance abuse treatment were identified as barriers to service utilization for West African immigrants. Community cohesion, importance of family, and a strong sense of spirituality were identified as essential resources to inform substance misuse prevention and treatment strategies. PMID- 26954619 TI - Physical Fitness and Risk for Type 2 Diabetes Mellitus: Reducing Risk at Any Weight. PMID- 26954620 TI - Long-Term Results of Bilateral Medial Rectus Muscle Recession in Children with Developmental Delay. AB - PURPOSE: To assess the long-term results of a reduced amount of medial rectus recession in children with esotropia and developmental delay. METHODS: A retrospective chart analysis of 42 children with developmental delay who had undergone surgery for esotropia during a 20-year period in a large referral center was performed. The pre- and postoperative angle of deviation was calculated for each subject as the mean of distant and near angles measured by a cover test or the Krimsky measurement. Surgical success was categorized as esotropia or exotropia of <=10 prism diopters (PD). The main outcome measure was a stable surgical result after several years of follow-up. RESULTS: The chart review identified 42 children who met inclusion criteria, with a mean age of 2.9 years (range, 0.8-10 years). The mean angle of esotropia prior to surgery was 44.29 +/- 13.9 PD (range 20-80 PD). All patients had bilateral medial rectus muscle recessions, with a mean surgical dosage of 5.04 +/- 0.62 mm per muscle, on average 0.66 mm less than the standard amount. The average postoperative follow up was 4.6 years (median 3.67 years, range 8 months-15 years). Twenty-four children (57%) achieved surgical success, 13 (31%) were undercorrected, and 5 (12%) were overcorrected. Ten of the 18 with an unsuccessful surgical outcome underwent a second procedure. The overall surgical success rate for all patients after all procedures was 71%. CONCLUSIONS: The main reason for surgical failure after bilateral medial rectus muscle recession (BMR) in developmentally delayed children remains residual esotropia. However, with time, more patients demonstrated consecutive exotropia. Although it is difficult to achieve a stable long-term ocular alignment in children with developmental delay, satisfactory results may be achieved with additional surgical procedures. The optimal amount of primary recession and whether to perform the surgical schedules according to the Parks tables or to reduce the amount of the recession when operating on children with developmental delay is still debatable. PMID- 26954621 TI - Phase I and II therapies targeting the androgen receptor for the treatment of castration resistant prostate cancer. AB - INTRODUCTION: Prostate cancer is the most common cancer in elderly males. Regardless of the initial hormonal treatment in metastatic disease, a significant proportion of patients develop castration resistant prostate cancer (CRPC). A better understanding of the molecular mechanisms behind castration resistance has led to the approval of oral medications such as abiraterone acetate and enzalutamide. Relevant research is accelerated with numerous agents being tested for the management of CRPC. AREAS COVERED: The authors present Phase I and II studies targeting the androgen receptor for the treatment of CRPC. Three groups of agents are identified according to the mechanism of action. These include the CYP-17 modulators (Orteronel, Galeterone, VT-464 and CFG-920), novel antiandrogens (Apatorsen, ARN-509, ODM-201, EZN-4176, AZD-3514) and bipolar androgen therapy. EXPERT OPINION: Further understanding of the mechanisms leading to castration resistance in prostate cancer can reveal potential targets for the development of novel anti-cancer agents. Except for the development of novel antiandrogens and CYP-17 modulators, bipolar androgen therapy is an interesting therapeutic approach. The combinations of the novel agents tested in Phase I and II studies with established agents is another field of interest. The real challenge is to distinguish a novel anti-cancer agent with acceptable tolerability and the best outcome. PMID- 26954608 TI - The Sexual Acceptability of Contraception: Reviewing the Literature and Building a New Concept. AB - How contraceptives affect women's sexual well-being is critically understudied. Fortunately, a growing literature focuses on sexual aspects of contraception, especially hormonal contraception's associations with libido. However, a more holistic approach to contraceptive sexual acceptability is needed to capture the full range of women's sexual experiences. We conducted a narrative literature review of this topic, working with an original sample of 3,001 citations published from 2005 to 2015. In Part 1, we draw from a subset of this literature (264 citations) to build a new conceptual model of sexual acceptability. Aspects include macro factors (gender, social inequality, culture, and structure), relationship factors (dyadic influences and partner preferences), and individual factors (sexual functioning, sexual preferences, such as dis/inhibition, spontaneity, pleasure, the sexual aspects of side effects, such as bleeding, mood changes, sexual identity and sexual minority status, and pregnancy intentions). In Part 2, we review the empirical literature on the sexual acceptability of individual methods (103 citations), applying the model as much as possible. Results suggest contraceptives can affect women's sexuality in a wide variety of positive and negative ways that extend beyond sexual functioning alone. More attention to sexual acceptability could promote both women's sexual well-being and more widespread, user-friendly contraceptive practices. PMID- 26954622 TI - Co(III)-Catalyzed Synthesis of Quinazolines via C-H Activation of N Sulfinylimines and Benzimidates. AB - C-H activation of arenes has been established as an important strategy for heterocycle synthesis via annulations between arenes and unsaturated coupling partners. However, nitriles failed to act as such a coupling partner. Dioxazolones have been employed as a synthon of nitriles, and subsequent coupling with arenes such as N-sulfinylimines and benzimidates bearing a functionalizable directing group provided facile access to two classes of quinazolines under Co(III)-catalysis. PMID- 26954623 TI - Lung cancer in never smokers in the UK Million Women Study. AB - To assess directly the effects of various risk factors on lung cancer incidence among never smokers, large prospective studies are needed. In a cohort of 1.2 million UK women without prior cancer, half (634,039) reported that they had never smoked. Mean age at recruitment was 55 (SD5) years, and during 14 (SD3) years of follow-up, 0.2% (1,469) of these never smokers developed lung cancer. Cox regression was used to estimate relative risks (RRs) of lung cancer for 34 potential risk factors, of which 31 were nonsignificant (p > 0.05). The remaining three risk factors were associated with a significantly increased incidence of lung cancer in never smokers: non-white vs. white ethnicity (RR = 2.34, 95% CI 1.55-3.52, p < 0.001), asthma requiring treatment vs. not (RR = 1.32, 1.10-1.58, p = 0.003) and taller stature (height >= 165 cm vs. <160 cm: RR = 1.16, 1.03 1.32, p = 0.02). There was little association with other sociodemographic, anthropometric or hormonal factors, or with dietary intakes of meat, fish, fruit, vegetables and fiber. The findings were not materially affected by restricting the analyses to adenocarcinomas, the most common histological type among never smokers. PMID- 26954625 TI - We are keen to contribute. AB - Consultation on the nursing associate (NA) role closes this month. We have been assured by Health Education England that the NA role will 'integrate the science and art of nursing through work-based collaborative experience to assimilate academic knowledge and practical learning'. PMID- 26954624 TI - Effect of N-Terminal Acylation on the Activity of Myostatin Inhibitory Peptides. AB - Inhibition of myostatin, which negatively regulates skeletal muscle growth, is a promising strategy for the treatment of muscle atrophic disorders, such as muscular dystrophy, cachexia and sarcopenia. Recently, we identified peptide A (H WRQNTRYSRIEAIKIQILSKLRL-NH2 ), the 23-amino-acid minimum myostatin inhibitory peptide derived from mouse myostatin prodomain, and highlighted the importance of its N-terminal tryptophan residue for the effective inhibition. In this study, we synthesized a series of acylated peptide derivatives focused on the tryptophan residue to develop potent myostatin inhibitors. As a result of the investigation, a more potent derivative of peptide A was successfully identified in which the N terminal tryptophan residue is replaced with a 2-naphthyloxyacetyl moiety to give an inhibitory peptide three times (1.19+/-0.11 MUm) more potent than parent peptide A (3.53+/-0.25 MUm). This peptide could prove useful as a new starting point for the development of improved inhibitory peptides. PMID- 26954626 TI - Designated nurse for children role must not be watered down. AB - RISING WORKLOADS are causing designated nurses for safeguarding children to struggle, new research suggests. PMID- 26954627 TI - Staff shortage affects care for families of seriously ill children. AB - THERE IS a 'worrying shortage' of children's nurses to care for seriously ill children, a charity has found. PMID- 26954628 TI - Online appointments for young people with diabetes. AB - YOUNG PEOPLE in London have been given online webcam appointments as part of a successful four-year pilot scheme to help them manage their diabetes care. PMID- 26954629 TI - Drop in one-to-one nursing linked with infant mortality. AB - A REDUCTION in one-to-one nursing in neonatal intensive care units has been linked in a new study to a higher death rate. PMID- 26954630 TI - WellChild appoints nurse lead. AB - CHILDREN'S NURSE Amika Challacombe has received funding from ITV's Text Santa appeal to become the charity WellChild's lead nurse for Yorkshire. PMID- 26954632 TI - Care for children is changing. AB - TRANSFORMING CARE has become a buzz phrase in the health service. Since NHS England's Five-Year Forward View was published in autumn 2014 a great deal of interest has been expressed in changing services to improve care and save money. PMID- 26954633 TI - Understanding the effects of eczema. AB - EMOTIONAL AND practical support is crucial for the families of children with eczema. This was the main feedback from a workshop organised by the charity Eczema Outreach Scotland for first-year nursing students at the University of Edinburgh. PMID- 26954638 TI - Research essentials. AB - TO MAXIMISE success, a research grant application should: ? Have a clear purpose with demonstrable and measurable outcomes. ? Be in line with government policies, healthcare agendas and health priorities. ? Meet objectives of the funding body and application criteria. PMID- 26954640 TI - Partnerships between parents and professionals should be developed. AB - The study by Smith et al (2015) was conducted in only one geographical area and among a single patient group; however, it does have wider resonance. Health care continues to change apace. Conditions that, until recently, would have resulted in severely shortened lifespan are now to a great extent ameliorated. However, this has had consequences, not only for the children, but also their families. PMID- 26954644 TI - Student voice - Join the battle. AB - BEING A nursing student in the current political climate can be alarming and exhausting. There is an uneasiness in the back of everyone's minds that the NHS is not the institution we thought it was, and that every day a new crack will appear in its foundations. It is as if, brick by brick, the NHS is being slowly dismantled, and the latest brick to be removed is actually a cornerstone: nursing student bursaries. PMID- 26954645 TI - Toilet training for children with autism. AB - Toilet training is one of the key developmental milestones of early childhood and there is growing evidence that it is now being initiated later than it was 50 years ago. This article explores the reasons why this is happening and considers the effect on children with autism and related conditions. It also examines the literature to discover the approaches to toilet training for this group. Research into this area has generally focused on small numbers of children and incorporated modified versions of Azrin and Foxx's ( 1971 ) rapid toilet training method. Suggestions are offered about the most appropriate advice to give parents and carers of children with autism and related disorders, and the importance of addressing toilet training at an early stage. PMID- 26954646 TI - Roles of nurses and parents caring for hospitalised children. AB - This article reviews the literature on nurses' and parents' self-perceived roles when caring for hospitalised children, focusing on research conducted since the Department of Health published the National Service Framework for Children: Standard for Hospital Services in 2003. Three main themes emerge from the review: nurses' perceptions, parents' perceptions, and negotiation. Clarification of what nurses and parents consider to be their respective roles when caring for hospitalised children is a prerequisite for negotiation of those roles. The family's background, life experiences and circumstances influence the effectiveness of negotiation between nurses and parents. The article explores potential barriers to negotiation, including poor communication and failure to provide information. Limitations of the research and the implications for practice are considered. PMID- 26954647 TI - Educating children and families about growth hormone deficiency and its management: part 2. AB - Growth hormone deficiency (GHD) is a long-term condition, therefore creating ongoing partnerships with families is a fundamental part of the role of a paediatric endocrine nurse specialist (PENS). Teaching children, young people and their families about GHD and exploring what it means to them and how they can manage their ongoing treatment is central to building positive relationships. Educating children about the management of their growth hormone treatment (GHT) is an ongoing process and professionals must respond to the changing needs for that information children may have as they grow and develop. Long-term relationships with families are strengthened by recognising and respecting the developing expertise of families as they gain confidence and competence to manage GHT. This article is the second of two parts. Part one was published in the February issue of Nursing Children and Young People and covered an overview of growth hormone, causes and clinical presentation of GHD, development and availability of GHT and the role of the PENS in building partnerships with parents. The focus of this article is the education role of the PENS and the importance of providing information that is appropriate to the child or young person's developmental age. PMID- 26954648 TI - Busting the Medical Trust? Professional Self-Regulation and the Imperatives of Competition. PMID- 26954649 TI - Commentary on "Busting the Medical Trust? Professional Self-Regulation and the Imperatives of Competition". PMID- 26954650 TI - Impact of Evidence-Based Guidelines on Outcomes of Hospitalized Patients With Clostridium difficile Infection. AB - OBJECTIVES: Clostridium difficile infection (CDI) is the most common healthcare associated infection in the United States. Clinical practice guidelines for the treatment of CDI were updated in 2010 by the Society for Healthcare Epidemiology of America and the Infectious Diseases Society of America. An institutional guideline for the classification and management of CDI in accordance with the 2010 Society for Healthcare Epidemiology of America/Infectious Diseases Society of America guideline was developed and provided to attending physicians and medical residents in multiple formats. METHODS: We sought to determine the impact of an evidence-based guideline for the treatment of CDI at a community teaching hospital. A retrospective chart review was conducted to identify length of stay (LOS), readmission rates, direct cost, mortality, and physician adherence to guidelines in patients with International Classification of Diseases, Ninth Edition codes and laboratory confirmation of CDI between February 1, 2013 and January 31, 2014. Endpoints included LOS after diagnosis of CDI, 30-day readmission rates, direct cost after diagnosis of CDI, and mortality. RESULTS: A total of 351 patient encounters were included in the study. Although not statistically significant, it was found that guideline-based therapy (n = 131) was associated with a lower median LOS (6 days vs 8 days; P = 0.06). Thirty-day hospital readmission (25.2% vs 29.5%; P = 0.39) and median cost after diagnosis of CDI ($7238.48 vs $8794.81; P = 0.10) also were lower but not statistically significant. Patients with mild-to-moderate infection were found to have a significantly lower median LOS (5 days vs 7 days; P = 0.03) and median cost after diagnosis ($5257.85 vs $7680.56; P = 0.03) when treated with guideline-based therapy. Overall physician adherence to guidelines was low, at 38%. CONCLUSIONS: Treatment with guideline-based therapy for CDI was associated with a trend toward a significantly lower LOS and cost. Barriers to physician adherence to guidelines still exist, despite education and guideline availability. Electronic health record-based order sets or clinical decision tools may improve recognition of and adherence to guidelines. PMID- 26954651 TI - Community Paramedicine and Mobile Integrated Health Care: Existing Resources Bringing New Benefits. PMID- 26954652 TI - Feasibility of Canine Therapy Among Hospitalized Pre-Heart Transplant Patients. AB - OBJECTIVES: Canine-assisted therapy (CAT) has been used in many settings with much success, yet no study has assessed its feasibility and receptiveness in hospitalized patients awaiting heart transplantation. METHODS: Patients admitted to our institution with a status I for heart transplantation during a 12-month period (April 2014-April 2015) were prospectively included in a feasibility pilot study. Patients were included if there was no history of transmittable disease or active infectious process and consented for study participation. Each patient was visited daily by a canine and quantitative and qualitative data regarding the visit were obtained. RESULTS: A total of 11 patients were included in the study. Most patients were men (n = 8, 72.7%) and the average age was 51.1 years. A total of 146 individual therapies took place, totaling 2718 minutes of CAT during the study period. Each patient had an average of 13.3 visits and each visit had an average duration of 14.7 minutes. Patient receptiveness, as measured by the CAT volunteer, averaged 9.9 (scale 0-10). No reports of infection transmission occurred. CONCLUSIONS: Our study found that CAT among hospitalized pre-heart transplant patients is feasible and is a welcomed adjunct to usual medical care. PMID- 26954653 TI - Stress Ulcer Prophylaxis in Hospitalized Patients, Subsequent Use in Primary Care, and Physicians' Opinions About Acid-Suppressive Therapy. AB - OBJECTIVES: Stress ulcer prophylaxis (SUP) is not indicated in most hospitalized patients. This study determined the prevalence of the use of proton pump inhibitors (PPI) and histamine receptor 2 blockers (H2B) in hospitalized patients, continued PPI/H2B use after discharge, and physicians' opinions about SUP. METHODS: A retrospective electronic chart review, as well as a national survey of residents and faculty in primary care residency programs to determine the appropriateness of SUP. RESULTS: Of 753 charts reviewed, 332 hospitalized patients with outpatient follow-up were included; 303 of them had either PPI or H2B ordered during hospitalization, but only 120 patients had an indication for SUP. Stepwise logistic regression results showed patients with a history of PPI/H2B use were 16.6 times more likely to receive SUP (odds ratio 16.6; 95% confidence interval 2.2-124.7). In addition, a PPI/H2B indication also significantly predicted SUP use (odds ratio 5.1; 95% confidence interval 1.2 22.2). A total of 171 completed surveys were received: 73% residents and 27% faculty. Only 24% reported being aware of SUP guidelines; 17% reported using electronic health record order set suggestions for SUP. CONCLUSIONS: More than 90% of hospitalized patients received SUP; less than half of them had an indication for needing SUP. A large number of patients discharged on PPI/H2B continued to receive it in the outpatient setting at 6 months follow-up. Only 24% of physicians reported using SUP based on guidelines. Physician education and evidence-based validation of electronic health record order sets are potential areas for improvement. PMID- 26954654 TI - Commentary on "Stress Ulcer Prophylaxis in Hospitalized Patients, Subsequent Use in Primary Care and Physicians' Opinions About Acid-Suppressive Therapy". PMID- 26954655 TI - Statin-Associated Diabetes Mellitus: Review and Clinical Guide. AB - A small but significant link between new-onset diabetes mellitus (NOD) and statin therapy was noted with rosuvastatin users in the Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin study. Since then multiple analyses have further confirmed this association, with most studies demonstrating a modest increase in NOD with statin therapy, especially among individuals with risk factors for developing diabetes mellitus. More recent observational analyses suggest a stronger correlation between statin use and NOD, however. A definitive mechanism confirming causation between statins and glucose impairment remains elusive, but many have been proposed. Although considered a class effect by the US Food and Drug Administration, most data indicate NOD is dependent upon the dose and potency of the statin, with certain agents appearing to be less diabetogenic. The consensus is that the benefits of statin therapy far outweigh the risk of NOD, especially among patients with high cardiovascular risk. Nonetheless, more studies are needed to better understand this association and long-term clinical implications. In the meantime, we provide clinicians with a practical guide to assist with clinical decision making when prescribing statin therapy. Overall, this article serves to provide the primary care physician with a timely review of the most clinically relevant data regarding statins and NOD, with hopes to ultimately optimize statin prescribing and limit any potential drug-induced glucose impairment. PMID- 26954656 TI - Light-Intensity Physical Activity and Medical Multimorbidity. AB - OBJECTIVES: No study has examined the association between objectively measured light-intensity physical activity (LIPA) and multimorbidity (>=2 chronic diseases) in a national sample of US adults. I undertook this examination. METHODS: Data from the 2005-2006 National Health and Nutrition Examination Survey were used (N = 2048 adults 20 years old and older). Physical activity was assessed via accelerometry, with multimorbidity assessed via physician diagnosis and biometric screening. RESULTS: In a multivariable linear regression and after adjustments, for every 60-minute/day increase in LIPA, participants had a lower multimorbidity index (betaadjusted = -0.09, 95% confidence interval -0.12 to 0.05, P < 0.001). In a multivariable logistic regression and after adjustments, for every 60-minute/day increase in LIPA, participants had 13% (odds ratioadjusted 0.87, 95% confidence interval 0.79-0.96, P = 0.01) reduced odds of being multimorbid (ie, having >=2 morbidities). CONCLUSIONS: LIPA, independent of moderate-to-vigorous physical activity, is associated with reduced odds of multimorbidity. As such, promotion of LIPA, as well as moderate-to-vigorous physical activity, may be a sensible strategy to help prevent and treat multimorbidity. PMID- 26954657 TI - Utility of the Shock Index and Other Risk-Scoring Tools in Patients with Gastrointestinal Bleeding. AB - Patients with upper gastrointestinal (GI) bleeding frequently require hospitalization and have a mortality rate that ranges from 6% to 14%. These patients need rapid clinical assessment to determine the urgency of endoscopy and the need for endoscopic treatment. Risk-scoring tools, such as the Rockall score and the Glasgow-Blatchford score, are commonly used in this assessment. These tools clearly help identify high-risk patients but do not necessarily have good predictive value in identifying important outcomes. Their diagnostic accuracy in identifying rebleeding and mortality ranges from poor to fair. The shock index (heart rate divided by systolic blood pressure) provides an integrated assessment of the cardiovascular status. It can be easily calculated during the initial evaluation of patients and monitoring after treatment. The shock index has been used in a few studies in patients with acute GI bleeding, including studies to determine which patients need emergency endoscopy, to predict complications after corrosive ingestions, to identify delayed hemorrhage following pancreatic surgery, and to evaluate the utility of angiograms to identify sites of GI bleeding. Not all studies have found the shock index to be useful in patients with GI bleeding, however. This may reflect the unpredictable natural history of various etiologies of GI bleeding, comorbidity that may influence blood pressure and/or heart rate, and inadequate data acquisition. The shock index needs more formal study in patients with GI bleeding admitted to medical intensive care units. Important considerations include the initial response to resuscitation, persistent bleeding following initial treatment, and rebleeding following a period of stabilization. In addition, it needs correlation with other risk scoring tools. PMID- 26954658 TI - Management of Cocaine-Induced Myocardial Infarction: 4-Year Experience at an Urban Medical Center. AB - OBJECTIVES: In 2008, the American Heart Association and the American College of Cardiology released guidelines for the management of cocaine-induced myocardial infarction (CIMI). We hypothesized that CIMI patients are likely to receive less invasive and more conservative management than patients with MI without history of cocaine use. METHODS: We conducted a retrospective analysis on patients younger than 65 years presenting with acute MI between April 1, 2008 and December 31, 2012. Patients were classified as cocaine-negative MI or CIMI based on either urine toxicology results or self-reported cocaine use. Categorical and continuous variables were compared using chi(2) or t test as appropriate. The primary outcome was cardiac catheterization or stress testing. The secondary outcome was a 30-day readmission rate for major adverse cardiovascular events. Multiple logistic regression models calculated odds ratios (ORs) for the primary outcomes adjusting for patient demographics and comorbidities. RESULTS: Of 378 MI patients, 4.2 % had CIMI. CIMI patients were younger (50 vs 54 years; P < 0.01) predominantly African American (56% vs 16%, P < 0.01), and mostly active smokers (88% vs 58%, P = 0.02). They were more likely to receive stress testing (adjusted OR 3.61, 95% confidence interval 1.04-12.53) and less likely to undergo cardiac catheterization (adjusted OR 0.12, 95% confidence interval 0.03-0.45). The 30-day readmission rate for major adverse cardiovascular events was higher in CIMI compared with cocaine-negative MI patients (38% vs 13%; P = 0.03). CONCLUSIONS: The use of cocaine in patients presenting with acute MI appears to impact management decisions of providers. Patient-centered postdischarge arrangements need better coordination for this patient group to optimize their follow-up care. PMID- 26954659 TI - Do Gestational Age Dating Criteria Matter in Medically Indicated Late Preterm, Early-Term, and Full-Term Inductions of Labor? AB - OBJECTIVES: To assess short-term neonatal respiratory morbidity from inductions of labor (IOL) in well-dated (WD) pregnancies (dating ultrasound [US] <20 0/7 weeks) versus non-well-dated (NWD) pregnancies when applying National Institutes of Health/Society for Maternal-Fetal Medicine/American College of Obstetricians and Gynecologists delivery recommendations at >=34 0/7 weeks. METHODS: Ours was a 1-year retrospective cohort of women with medically indicated IOL between 34 0/7 and 40 6/7 weeks with a live, cephalic, singleton gestation and no lethal anomaly. The primary outcome was a composite of neonatal respiratory morbidity (respiratory distress syndrome, transient tachypnea of the newborn, ventilator support, oxygen administration, and pneumonia). RESULTS: A total of 476 WD and 231 NWD women underwent IOL during the study period. The groups had similar maternal characteristics, indications for IOL, and mode of delivery. There was no difference in the rate of primary outcome (8.7% in NWD group vs 8.8% in WD group; P = 0.95). This finding persisted after control for parity, gestational age (GA) at first US, operator of the dating US, and exposure to antenatal corticosteroids and magnesium sulfate. When stratified by GA at delivery and GA at first US, these findings persisted even when the dating US was performed at >35 weeks. There were no differences in maternal or other neonatal outcomes between the WD and NWD pregnancies. CONCLUSIONS: In our cohort of medically indicated IOL, a dating US before 20 weeks was not associated with a difference in neonatal respiratory morbidity. PMID- 26954660 TI - Prevalence of Pancreatic Steatosis at a Pediatric Tertiary Care Center. AB - OBJECTIVES: Pancreatic steatosis in adults has been proposed to be associated with obesity; however, data on pancreatic steatosis in children are lacking. Our study aimed to measure the prevalence of pancreatic steatosis in children and to examine its association with obesity and nonalcoholic fatty liver disease. METHODS: This is a retrospective chart review study of 232 patients 2 to 18 years old who underwent abdominal computed tomographic imaging in the emergency department or inpatient ward within a 1-year time span and from whom demographics, anthropometrics, and medical history were obtained. Our radiologist determined mean Hounsfield unit (HU) measurements for the pancreas, liver, and spleen. A difference of -20 between the pancreas and spleen (psHU) and between the liver and spleen was used to determine fatty infiltration. RESULTS: Of the 232 patients, 11.5% had a psHU less than -20. The prevalence of pancreatic steatosis was more than double among obese children (19%) than that in nonobese groups (8%). There is a significant correlation between the psHU and liver-spleen HU (r = 0.50, P < 0.001). CONCLUSIONS: Pancreatic steatosis was identified in 10% of the study population and is associated with obesity. Also, pancreatic steatosis is significantly associated with nonalcoholic fatty liver disease. This is the first study assessing the prevalence of pancreatic steatosis in children. PMID- 26954662 TI - Chronic Trauma Effects on Personality Traits in Police Officers. AB - The impact of cumulative occupational exposure to traumatic events (TEs), posttraumatic stress (PTS) symptoms, and work environment stress on personality traits over time was examined in 38 police officers from an urban agency. California Psychological Inventory (CPI) personality trait scores from prehire evaluations were compared with follow-up CPI scores to test whether exposure to traumatic events was correlated with changes in traits from baseline to 5-10 years later. Measures of occupational TEs, PTS symptoms, and police work environment stress were administered. Mean trait scores declined on all CPI traits analyzed in the study. Trait change was evaluated using the Reliable Change Index; change in participants' scores unlikely to occur by chance ranged from 11% to 63% in the traits examined. All participants reported substantial TE exposure. PTS symptoms were correlated with steeper decline in 4 of 5 traits, with effect sizes ranging from r = -.47 to r = -.67. Scores on measures of job related TEs were negatively correlated with only one CPI trait (empathy) at T2 (r = -.31), and were unrelated to slope of trait change. Work environment stress was significantly related to gender, with female officers reporting higher levels of operational (r = .45) and organizational (r = .54) stress. PMID- 26954661 TI - Oxidative Conversion of a Europium(II)-Based T1 Agent into a Europium(III)-Based paraCEST Agent that can be Detected In Vivo by Magnetic Resonance Imaging. AB - The Eu(II) complex of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) tetra(glycinate) has a higher reduction potential than most Eu(II) chelates reported to date. The reduced Eu(II) form acts as an efficient water proton T1 relaxation reagent, while the Eu(III) form acts as a water-based chemical exchange saturation transfer (CEST) agent. The complex has extremely fast water exchange rate. Oxidation to the corresponding Eu(III) complex yields a well-defined signal from the paraCEST agent. The time course of oxidation was studied in vitro and in vivo by T1-weighted and CEST imaging. PMID- 26954663 TI - Highly Photoluminescent Molybdenum Oxide Quantum Dots: One-Pot Synthesis and Application in 2,4,6-Trinitrotoluene Determination. AB - As a well-studied transition-metal semiconductor material, MoOx has a wider band gap than molybdenum disulfide (MoS2), and its property varies dramatically for the existence of several different allotropes and suboxide phases of molybdenum oxides (MoOx, x < 3). In this manuscript, a one-pot method possessing the advantages of one pot, easily prepared, rapid, and environmentally friendly, has been developed for facile synthesis of highly photoluminescent MoOx quantum dots (MoOx QDs), in which commercial molybdenum disulfide (MoS2) powder and hydrogen peroxide (H2O2) are employed as the precursor and oxidant, respectively. The obtained MoOx QDs can be further utilized as an efficient photoluminescent probe, and a new turn-off sensor is developed for 2,4,6-trinitrotoluene (TNT) determination based on the fact that the photoluminescence of MoOx QDs can be quenched by the Meisenheimer complexes formed in the strong alkali solution through the inner filter effect (IFE). Under the optimal conditions, the decreased photoluminescence of MoOx QDs shows a good linear relationship to the concentration of TNT ranging from 0.5 to 240.0 MUM, and the limit of detection was 0.12 MUM (3sigma/k). With the present turn-off sensor, TNT in river water samples can be rapidly and selectively detected without tedious sample pretreatment processes. PMID- 26954664 TI - Metallogels through glyme coordination. AB - Glyme intercalation in copper-thiolate polymers is studied. The amorphous polymer network observed is significantly stronger than previously reported coinage metal thiolate supramolecular hydrogels synthesized without glyme. Glyme chain length and water content strongly influence mechanical and optical behavior. PMID- 26954665 TI - Correction: The Distribution of Prion Protein Allotypes Differs Between Sporadic and Iatrogenic Creutzfeldt-Jakob Disease Patients. PMID- 26954666 TI - Pharmacist-involved care for patients with heart failure and acute coronary syndrome: a systematic review with qualitative and quantitative meta-analysis. AB - WHAT IS KNOWN AND OBJECTIVE: Many trials have indicated that interventions by pharmacists resulted in beneficial outcomes with positive effects on cardiovascular diseases. The interventions through pharmacist-involved pharmaceutical care in patients with heart failure (HF) and acute coronary syndrome (ACS) were reviewed systemically and examined. METHODS: A systematic literature search was conducted to identify relevant articles describing pharmacist interventions in HF and ACS. Most studies were evaluated qualitatively, and the strength of evidence was graded according to the Agency for Healthcare Research and Quality (AHRQ) guidelines. Some of the studies were also assessed by a meta-analysis. RESULTS: A total of 26 studies containing data on 9415 patients were identified. For all studies, the strength of the body of evidence was reviewed and graded, and 14 studies among them were meta-analysed. The evidence was not strong enough to determine the effects of pharmaceutical care on major and patient-centred outcomes, except the prescription rates of angiotensin-converting-enzyme inhibitors (ACEI) with a high strength of evidence. In the meta-analysis, all-cause hospitalization [odds ratio (OR), 0.74; 95% confidence interval (CI), 0.58-0.94] was reduced and the prescription rates of angiotensin-converting-enzyme inhibitors (ACEI; OR 1.43; 95% CI, 1.07-1.91) and beta-blockers (OR 1.92; 95% CI, 1.24-2.96) were significantly higher in the pharmaceutical care group compared with the usual care group. WHAT IS NEW AND CONCLUSIONS: All-cause hospitalization showed improvement in the pharmaceutical care group. However, the strength of evidence for the majority of outcomes with pharmaceutical care, except direct performance measures such as prescription rates, was either insufficient or low. This could be explained by the presence of imprecision and inconsistency derived from the diversity of pharmaceutical care, the heterogeneity of patient populations or clinical settings. Moreover, it may indicate the necessity for homogeneous applicable criteria for assessment. A standardized consensus of the guidelines for pharmaceutical care service should be considered to improve homogeneity. PMID- 26954667 TI - Food Sensitization in Medically Resistant Chronic Rhinosinusitis with or without Nasal Polyposis. AB - BACKGROUND: Nasal polyposis is a common nasal mass with unknown etiology. It has been assumed that allergy predisposes to polyp formation. Our objective was to compare the prevalence of food sensitization in medically resistant chronic rhinosinusitis patients with or without nasal polyposis. METHODS: One hundred and fifty-five patients who fulfilled the inclusion and exclusion criteria were incorporated into this study. The results of their total serum IgE and food specific IgE levels were examined. RESULTS: The average age was 33 years (+/- 13) with 96 males and 59 females. The percentage of patients in each group that had a positive result for at least one tested allergen was 84% (88 patients in the sinusitis without polyposis group and 42 patients in nasal polyposis group). Patients without nasal polyposis reacted to an average of 4.6 foodstuffs, whereas patients with nasal polyposis reacted to 4.1. Egg white, sheefish and cherry were the most common type of sensitized food. There were no significant differences in the prevalence, type, number of positive food allergens and class level between the two groups. CONCLUSIONS: Food sensitization is common in medically resistant chronic rhinosinusitis. Since food sensitization prevalence, type and severity do not significantly differ between the two groups studied, food atopy is unlikely to be a major factor in nasal polyposis pathogenesis. PMID- 26954668 TI - Targeting Glycosphingolipid Metabolism to Treat Kidney Disease. AB - The enhanced expression of glucosylceramide-based glycosphingolipids (GSLs) is a hallmark of many forms of renal disease including diabetic nephropathy, polycystic kidney disease and renal cell carcinoma. A common feature of each of these renal disorders is the preference metabolism via aerobic glycolysis. While aerobic glycolysis is an inefficient way to generate ATP, aerobic glycolysis promotes the formation of substrates important for the production of biomass, including lipids, amino acids and nucleotides, through the pentose phosphate pathway. Two products that are essential for the synthesis of glucosylceramide and more complex GSLs are generated through the pentose phosphate pathway. These products are reducing equivalents in the form of NADPH and UDP-glucose. In experimental models of each of these disorders, inhibition of glucosylceramide synthase with eliglustat or related analogues reverses the disease phenotype suggesting that blocking GSL synthesis should be explored as a potential treatment strategy. PMID- 26954669 TI - A randomised controlled trial comparing continuous supraclavicular and interscalene brachial plexus blockade for open rotator cuff surgery. AB - Continuous interscalene block is an approved modality for postoperative pain control, but it may cause hemidiaphragmatic paresis. In this study we aimed to determine whether continuous supraclavicular block would provide postoperative analgesia comparable to that of continuous interscalene block and reduce the incidence of hemidiaphragmatic paresis. Patients scheduled for open rotator cuff repair were randomly allocated to receive continuous interscalene (n = 38) or supraclavicular block (n = 37). Both participants and assessing clinicians were blinded to the group allocation. The primary endpoint was the mean pain intensity 24 h after the surgery. Postoperative mean (SD) pain scores at 24 h were similar in the supraclavicular and interscalene groups (2.57 (1.71) vs 2.84 (1.75) respectively; p = 0.478). The incidence of complete or partial hemidiaphragmatic paresis was lower in the supraclavicular group at 1 h after admission to the postanaesthetic care unit and 24 h after the surgery [25 (68%) vs 38 (100%); p = 0.001 and 14 (38%) vs 27 (71%) respectively; p = 0.008]. Continuous supraclavicular block provided comparable analgesia compared with interscalene block with a reduced incidence of complete or partial hemidiaphragmatic paresis for 24 h following surgery. PMID- 26954670 TI - The mdx Mutation in the 129/Sv Background Results in a Milder Phenotype: Transcriptome Comparative Analysis Searching for the Protective Factors. AB - The mdx mouse is a good genetic and molecular murine model for Duchenne Muscular Dystrophy (DMD), a progressive and devastating muscle disease. However, this model is inappropriate for testing new therapies due to its mild phenotype. Here, we transferred the mdx mutation to the 129/Sv strain with the aim to create a more severe model for DMD. Unexpectedly, functional analysis of the first three generations of mdx129 showed a progressive amelioration of the phenotype, associated to less connective tissue replacement, and more regeneration than the original mdxC57BL. Transcriptome comparative analysis was performed to identify what is protecting this new model from the dystrophic characteristics. The mdxC57BL presents three times more differentially expressed genes (DEGs) than the mdx129 (371 and 137 DEGs respectively). However, both models present more overexpressed genes than underexpressed, indicating that the dystrophic and regenerative alterations are associated with the activation rather than repression of genes. As to functional categories, the DEGs of both mdx models showed a predominance of immune system genes. Excluding this category, the mdx129 model showed a decreased participation of the endo/exocytic pathway and homeostasis categories, and an increased participation of the extracellular matrix and enzymatic activity categories. Spp1 gene overexpression was the most significant DEG exclusively expressed in the mdx129 strain. This was confirmed through relative mRNA analysis and osteopontin protein quantification. The amount of the 66 kDa band of the protein, representing the post-translational product of the gene, was about 4,8 times higher on western blotting. Spp1 is a known DMD prognostic biomarker, and our data indicate that its upregulation can benefit phenotype. Modeling the expression of the DEGs involved in the mdx mutation with a benign course should be tested as a possible therapeutic target for the dystrophic process. PMID- 26954671 TI - Predictor Variables and Screening Protocol for Depressive and Anxiety Disorders in Cancer Outpatients. AB - BACKGROUND: Cancer patients are at increased risk of persistent depressive and anxiety symptoms and disorders compared to the general population. However, these issues are not always identified, which may worsen the prognosis and increase morbidity and mortality. Therefore, the objectives of this study are to identify predictor variables (demographic and clinical) for the development of mood and anxiety disorders in cancer outpatients and to propose a probabilistic screening protocol considering these variables and certain standardized screening instruments. METHODS: A total of 1,385 adults, of both genders, receiving outpatient cancer care were evaluated using a questionnaire and screening instruments. Thereafter, 400 of these subjects responded to the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (SCID-IV) by telephone to confirm or rule out the presence of a Current Major Depressive Episode (CMDE) or Anxiety Disorder (AD). RESULTS: Of the patients surveyed, 64% met the criteria for CMDE and 41% for AD. Female gender was found to be a risk factor for both disorders, and the presence of previous psychiatric history and marital status (divorced and widowed) were risk factors for anxiety disorders. When scoring above the recommended cutoff score, the screening instruments also indicated a risk of the studied disorders. Based on these findings, a screening protocol and nomograms were created for the quantification, combination and probabilistic estimate of risk, with accuracy indicators >0.68. CONCLUSION: The prevalence rates for the disorders under study are extremely high in cancer patients. The use of the proposed protocol and nomogram can facilitate rapid and wide screening, thus refining triage and supporting the establishment of criteria for referral to mental health professionals, so that patients can be properly diagnosed and treated. PMID- 26954672 TI - Are Isolated Indigenous Populations Headed toward Extinction? AB - At least 50 indigenous groups spread across lowland South America remain isolated and have only intermittent and mostly hostile interactions with the outside world. Except in emergency situations, the current policy of governments in Brazil, Colombia, and Peru towards isolated tribes is a "leave them alone" strategy, in which isolated groups are left uncontacted. However, these no contact policies are based on the assumption that isolated populations are healthy and capable of persisting in the face of mounting external threats, and that they can maintain population viability in the long-term. Here, we test this assumption by tracking the sizes and movements of cleared horticultural areas made by 8 isolated groups over the last 10-14 years. We used deforestation data derived from remote sensing Landsat satellite sensors to identify clearings, and those were then validated and assessed with high-resolution imagery. We found only a single example of a relatively large and growing population (c. 50 cleared ha and 400 people), whereas all of the other 7 groups exhibited much smaller villages and gardens with no sizable growth through time. These results indicated that the smaller groups are critically endangered, and it prompts an urgent re thinking of policies toward isolated populations, including plans for well organized contacts that may help save lives and rescue isolated indigenous populations from imminent extinction. PMID- 26954673 TI - Using Acoustics to Determine Eelgrass Bed Distribution and to Assess the Seasonal Variation of Ecosystem Service. AB - Eelgrass beds are an important source of primary production in coastal ecosystems. Understanding seasonal variation in the abundance and distribution of eelgrass is important for conservation, and the objectives of this study were to 1) monitor seasonal variation in eelgrass beds using an acoustic monitoring method (Quantitative echo sounder) and 2) broadly quantify the carbon circulation function. We obtained acoustic data of eelgrass beds in coastal areas north and east of Ikunojima Island. Surveys were conducted nine times over the 3-year period from 2011 to 2013 in order to monitor seasonal variation. Acoustic data were obtained and used to estimate the spatial distribution of eelgrass by geostatistical methods. To determine supporting services, we determined carbon sink and carbon fixation by eelgrass beds using data from the National Research Institute of Fisheries and Environment of Inland Sea (2011). The height and distribution of eelgrass beds were at a maximum in May and at a minimum in November of each year. Distribution trends were different between the north and east areas. Supporting services showed the same patterns throughout the year. The area of distribution was considered to be coincident with the life history of eelgrass. Distribution differed by area and changed yearly due to the effects of bottom characteristics and wind direction. Quantifying the supporting services of eelgrass beds was shown to be useful for managing the conservation of coastal ecosystems. PMID- 26954674 TI - Alteration of Antiviral Signalling by Single Nucleotide Polymorphisms (SNPs) of Mitochondrial Antiviral Signalling Protein (MAVS). AB - Genetic variation is associated with diseases. As a type of genetic variation occurring with certain regularity and frequency, the single nucleotide polymorphism (SNP) is attracting more and more attention because of its great value for research and real-life application. Mitochondrial antiviral signalling protein (MAVS) acts as a common adaptor molecule for retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs), which can recognize foreign RNA, including viral RNA, leading to the induction of type I interferons (IFNs). Therefore, MAVS is thought to be a crucial molecule in antiviral innate immunity. We speculated that genetic variation of MAVS may result in susceptibility to infectious diseases. To assess the risk of viral infection based on MAVS variation, we tested the effects of twelve non-synonymous MAVS coding-region SNPs from the National Center for Biotechnology Information (NCBI) database that result in amino acid substitutions. We found that five of these SNPs exhibited functional alterations. Additionally, four resulted in an inhibitory immune response, and one had the opposite effect. In total, 1,032 human genomic samples obtained from a mass examination were genotyped at these five SNPs. However, no homozygous or heterozygous variation was detected. We hypothesized that these five SNPs are not present in the Japanese population and that such MAVS variations may result in serious immune diseases. PMID- 26954675 TI - Determinants of Human African Trypanosomiasis Elimination via Paratransgenesis. AB - Human African trypanosomiasis (HAT), transmitted by tsetse flies, has historically infected hundreds of thousands of individuals annually in sub Saharan Africa. Over the last decade, concerted control efforts have reduced reported cases to below 10,000 annually, bringing complete elimination within reach. A potential technology to eliminate HAT involves rendering the flies resistant to trypanosome infection. This approach can be achieved through the introduction of transgenic Sodalis symbiotic bacteria that have been modified to produce a trypanocide, and propagated via Wolbachia symbionts, which confer a reproductive advantage to the paratransgenic tsetse. However, the population dynamics of these symbionts within tsetse flies have not yet been evaluated. Specifically, the key factors that determine the effectiveness of paratransgenesis have yet to be quantified. To identify the impact of these determinants on T.b. gambiense and T.b. rhodesiense transmission, we developed a mathematical model of trypanosome transmission that incorporates tsetse and symbiont population dynamics. We found that fecundity and mortality penalties associated with Wolbachia or recombinant Sodalis colonization, probabilities of vertical transmission, and tsetse migration rates are fundamental to the feasibility of HAT elimination. For example, we determined that HAT elimination could be sustained over 25 years when Wolbachia colonization minimally impacted fecundity or mortality, and when the probability of recombinant Sodalis vertical transmission exceeded 99.9%. We also found that for a narrow range of recombinant Sodalis vertical transmission probability (99.9-90.6% for T.b. gambiense and 99.9 85.8% for T.b. rhodesiense), cumulative HAT incidence was reduced between 30% and 1% for T.b. gambiense and between 21% and 3% for T.b. rhodesiense, although elimination was not predicted. Our findings indicate that fitness and mortality penalties associated with paratransgenic symbionts, as well as tsetse migration rates, are instrumental to HAT elimination, and should be a key focus in the development of paratransgenic symbionts. PMID- 26954677 TI - Genealogical Trees of Scientific Papers. AB - Many results have been obtained when studying scientific papers citations databases in a network perspective. Articles can be ranked according to their current in-degree and their future popularity or citation counts can even be predicted. The dynamical properties of such networks and the observation of the time evolution of their nodes started more recently. This work adopts an evolutionary perspective and proposes an original algorithm for the construction of genealogical trees of scientific papers on the basis of their citation count evolution in time. The fitness of a paper now amounts to its in-degree growing trend and a "dying" paper will suddenly see this trend declining in time. It will give birth and be taken over by some of its most prevalent citing "offspring". Practically, this might be used to trace the successive published milestones of a research field. PMID- 26954676 TI - Paxillin and Focal Adhesion Kinase (FAK) Regulate Cardiac Contractility in the Zebrafish Heart. AB - An orchestrated interplay of adaptor and signaling proteins at mechano-sensitive sites is essential to maintain cardiac contractility and when defective leads to heart failure. We recently showed that Integrin-linked Kinase (ILK), beta-Parvin and PINCH form the IPP-complex to grant tuned Protein Kinase B (PKB) signaling in the heart. Loss of one of the IPP-complex components results in destabilization of the whole complex, defective PKB signaling and finally heart failure. Two components of IPP, ILK and beta-Parvin directly bind to Paxillin; however, the impact of this direct interaction on the maintenance of heart function is not known yet. Here, we show that targeted gene inactivation of Paxillin results in progressive decrease of cardiac contractility and heart failure in zebrafish without affecting IPP-complex stability and PKB phosphorylation. However, we found that Paxillin deficiency leads to the destabilization of its known binding partner Focal Adhesion Kinase (FAK) and vice versa resulting in degradation of Vinculin and thereby heart failure. Our findings highlight an essential role of Paxillin and FAK in controlling cardiac contractility via the recruitment of Vinculin to mechano-sensitive sites in cardiomyocytes. PMID- 26954679 TI - Verticality Perceptions Associate with Postural Control and Functionality in Stroke Patients. AB - Deficits of postural control and perceptions of verticality are disabling problems observed in stroke patients that have been recently correlated to each other. However, there is no evidence in the literature confirming this relationship with quantitative posturography analysis. Therefore, the objectives of the present study were to analyze the relationship between Subjective Postural Vertical (SPV) and Haptic Vertical (HV) with posturography and functionality in stroke patients. We included 45 stroke patients. The study protocol was composed by clinical interview, evaluation of SPV and HV in roll and pitch planes and posturography. Posturography was measured in the sitting and standing positions under the conditions: eyes open, stable surface (EOSS); eyes closed, stable surface (ECSS); eyes open, unstable surface (EOUS); and eyes closed, unstable surface (ECUS). The median PV in roll plane was 0.34 degrees (-1.44 degrees to 2.54 degrees ) and in pitch plane 0.36 degrees (-2.72 degrees to 2.45 degrees ). The median of HV in roll and pitch planes were -0.94 degrees (-5.86 degrees to 3.84 degrees ) and 3.56 degrees (-0.68 degrees to 8.36 degrees ), respectively. SPV in the roll plane was correlated with all posturagraphy parameters in sitting position in all conditions (r = 0.35 to 0.47; p < 0.006). There were moderate correlations with the verticality perceptions and all the functional scales. Linear regression model showed association between speed and SPV in the roll plane in the condition EOSS (R2 of 0.37; p = 0.005), in the condition ECSS (R2 of 0.13; p = 0.04) and in the condition EOUS (R2 of 0.22; p = 0.03). These results suggest that verticality perception is a relevant component of postural control and should be systematically evaluated, particularly in patients with abnormal postural control. PMID- 26954678 TI - Impact of Molecular Diagnostics for Tuberculosis on Patient-Important Outcomes: A Systematic Review of Study Methodologies. AB - BACKGROUND: Several reviews on the accuracy of Tuberculosis (TB) Nucleic Acid Amplification Tests (NAATs) have been performed but the evidence on their impact on patient-important outcomes has not been systematically reviewed. Given the recent increase in research evaluating such outcomes and the growing list of TB NAATs that will reach the market over the coming years, there is a need to bring together the existing evidence on impact, rather than accuracy. We aimed to assess the approaches that have been employed to measure the impact of TB NAATs on patient-important outcomes in adults with possible pulmonary TB and/or drug resistant TB. METHODS: We first develop a conceptual framework to clarify through which mechanisms the improved technical performance of a novel TB test may lead to improved patient outcomes and outline which designs may be used to measure them. We then systematically review the literature on studies attempting to assess the impact of molecular TB diagnostics on such outcomes and provide a narrative synthesis of designs used, outcomes assessed and risk of bias across different study designs. RESULTS: We found 25 eligible studies that assessed a wide range of outcomes and utilized a variety of experimental and observational study designs. Many potentially strong design options have never been used. We found that much of the available evidence on patient-important outcomes comes from a small number of settings with particular epidemiological and operational context and that confounding, time trends and incomplete outcome data receive insufficient attention. CONCLUSIONS: A broader range of designs should be considered when designing studies to assess the impact of TB diagnostics on patient outcomes and more attention needs to be paid to the analysis as concerns about confounding and selection bias become relevant in addition to those on measurement that are of greatest concern in accuracy studies. PMID- 26954680 TI - Anti-Tumor Effects of Second Generation beta-Hydroxylase Inhibitors on Cholangiocarcinoma Development and Progression. AB - Cholangiocarcinoma (CCA) has a poor prognosis due to widespread intrahepatic spread. Aspartate beta-hydroxylase (ASPH) is a transmembrane protein and catalyzes the hydroxylation of aspartyl and asparaginyl residues in calcium binding epidermal growth factor (cbEGF)-like domains of various proteins, including Notch receptors and ligands. ASPH is highly overexpressed (>95%) in human CCA tumors. We explored the molecular mechanisms by which ASPH mediated the CCA malignant phenotype and evaluated the potential of ASPH as a therapeutic target for CCA. The importance of expression and enzymatic activity of ASPH for CCA growth and progression was examined using shRNA "knockdown" and a mutant construct that reduced its catalytic activity. Second generation small molecule inhibitors (SMIs) of beta-hydroxylase activity were developed and used to target ASPH in vitro and in vivo. Subcutaneous and intrahepatic xenograft rodent models were employed to determine anti-tumor effects on CCA growth and development. It was found that the enzymatic activity of ASPH was critical for mediating CCA progression, as well as inhibiting apoptosis. Mechanistically, ASPH overexpression promoted Notch activation and modulated CCA progression through a Notch1-dependent cyclin D1 pathway. Targeting ASPH with shRNAs or a SMI significantly suppressed CCA growth in vivo. PMID- 26954682 TI - Analysis of the Phialocephala subalpina Transcriptome during Colonization of Its Host Plant Picea abies. AB - BACKGROUND: Phialocephala subalpina belongs to the Phialocephala fortinii s.l. Acepphala applanata species complex (PAC) forming one of the major groups belonging to the dark septate endophytes (DSE). Depending on the strain, PAC was shown to form neutral to pathogenic associations with its host plant Picea abies. To understand PACs lifestyle we investigated the effect of presence/absence of Picea abies on the transcriptome of strain 6_70_1. MATERIALS AND METHODS: PAC strain 6_70_1 was grown in liquid Pachlewski media either induced by its host plant Picea abies or without host plant as a control. Mycelia were harvested in a time course (1, 2, 3, 4, 7, 11, 18 days) with and without induction by the host plant and the fungal transcriptome revealed by Illumina sequencing. Differential gene expression analysis over the time course comparing control and treatment at each time point using the 'edgeR glm approach' and a gene enrichment analysis using GO categories were performed. RESULTS: The three main functional groups within differentially expressed genes were 'metabolism', 'transport' and 'cell rescue, defense and virulence'. Additionally, genes especially involved in iron metabolism could be detected by gene set enrichment analysis. CONCLUSION: In conclusion, we found PAC strain 6_70_1 to be metabolically very active during colonization of its host plant Picea abies. A major shift in functional groups over the time course of this experiment could not be observed but GO categories which were found to be enriched showed different emphasis depending in the day post induction. PMID- 26954681 TI - Statin Safety in Chinese: A Population-Based Study of Older Adults. AB - BACKGROUND: Compared to Caucasians, Chinese achieve a higher blood concentration of statin for a given dose. It remains unknown whether this translates to increased risk of serious statin-associated adverse events amongst Chinese patients. METHODS: We conducted a population-based retrospective cohort study of older adults (mean age, 74 years) newly prescribed a statin in Ontario, Canada between 2002 and 2013, where 19,033 Chinese (assessed through a validated surname algorithm) were matched (1:3) by propensity score to 57,099 non-Chinese. This study used linked healthcare databases. FINDINGS: The follow-up observation period (mean 1.1, maximum 10.8 years) was similar between groups, as were the reasons for censoring the observation period (end of follow-up, death, or statin discontinuation). Forty-seven percent (47%) of Chinese were initiated on a higher than recommended statin dose. Compared to non-Chinese, Chinese ethnicity did not associate with any of the four serious statin-associated adverse events assessed in this study [rhabdomyolysis hazard ratio (HR) 0.61 (95% CI 0.28 to 1.34), incident diabetes HR 1.02 (95% CI 0.80 to 1.30), acute kidney injury HR 0.90 (95% CI 0.72 to 1.13), or all-cause mortality HR 0.88 (95% CI 0.74 to 1.05)]. Similar results were observed in subgroups defined by statin type and dose. CONCLUSIONS: We observed no higher risk of serious statin toxicity in Chinese than matched non Chinese older adults with similar indicators of baseline health. Regulatory agencies should review available data, including findings from our study, to decide if a change in their statin dosing recommendations for people of Chinese ethnicity is warranted. PMID- 26954684 TI - Dual Effect of Catecholamines and Corticosterone Crosstalk on Pineal Gland Melatonin Synthesis. AB - BACKGROUND/AIM: The nocturnal production of melatonin by the pineal gland is triggered by sympathetic activation of adrenoceptors and may be modulated by immunological signals. The effect of glucocorticoids on nocturnal melatonin synthesis is controversial; both stimulatory and inhibitory effects have been reported. During pathophysiological processes, an increased sympathetic tonus could result in different patterns of adrenoceptor activation in the pineal gland. Therefore, in this investigation, we evaluated whether the pattern of adrenergic stimulation of the pineal gland drives the direction of the glucocorticoid effect on melatonin production. METHODS: The corticosterone effect on the pineal hormonal production induced by beta-adrenoceptor or beta+alpha1 adrenoceptor activation was evaluated in cultured glands. We also investigated whether the in vivo lipopolysaccharide (LPS)-induced inhibition of melatonin is dependent on the interaction of glucocorticoids and the alpha1-adrenoceptor in adrenalectomized animals and on the in vivo blockade of glucocorticoid receptors (GRs) or the alpha1-adrenoceptor. RESULTS: Corticosterone potentiated beta adrenoceptor-induced pineal melatonin synthesis, whilst corticosterone-dependent inhibition was observed when melatonin production was induced by beta+alpha1 adrenoceptors agonists. The inhibitory effect of corticosterone is mediated by GR, as it was abolished in the presence of a GR antagonist. Moreover, LPS-induced reduction in melatonin nocturnal plasma content was reversed by adrenalectomy and by antagonizing GR or alpha1-adrenoceptors. CONCLUSIONS: The dual effect of corticosterone on pineal melatonin synthesis is determined by the activation pattern of adrenoceptors (beta or beta+alpha1) in the gland during GR activation, suggesting that increased activation of the sympathetic system and the hypothalamic-pituitary-adrenal axis are necessary for the control of melatonin production during defense responses. PMID- 26954685 TI - Proven Non-beta-Lactam Antibiotic Allergy in Children. AB - BACKGROUND: Parallel to the increasing use of non-beta-lactam (NBL) antibiotics, allergic reactions to this drug group seem to increase. Data about NBL antibiotic hypersensitivity in children are limited. The aim of this study is to evaluate characteristic reactions to NBL antibiotics in children. METHOD: Patients with suspected NBL allergy were assessed between 2011 and 2015. Characteristics of the reactions and results of skin and drug provocation tests (DPTs) were recorded. RESULTS: In total, 96 patients aged 75.15 +/- 56.77 months (range: 3-208) were assessed. Clarithromycin (63.6%) was the most common cause of reactions reported. After ingestion of NBL antibiotics, maculopapular rash, urticaria/angioedema and anaphylaxis presented in 48.9, 40.7 and 10.4% of the patients, respectively. Tests were performed in 85 patients. Intradermal tests were positive in 3 patients (clarithromycin, ciprofloxacin and cotrimoxazole) and DPT was positive in 1 patient (clarithromycin). Eleven patients could not be tested. Seven patients had severe anaphylaxis, and 4 patients with urticaria/angioedema had to take their medications at the time of the reaction so desensitization was performed. When only patients confirmed by tests were evaluated, NBL allergy was 4.7% (4/85) in our study group. However, when patients who could not be tested, but were regarded as suffering from drug hypersensitivity according to clinical findings, were included, the frequency of NBL allergy was 15.6% (15/96). CONCLUSION: Most of the children with suspected NBL do not have true hypersensitivity. The frequency of confirmed hypersensitivity is low, and thus a detailed history should be taken from patients with suspected NBL hypersensitivity and DPTs should be performed in patients without contraindications. PMID- 26954683 TI - Cyclin-Dependent Kinase CRK9, Required for Spliced Leader trans Splicing of Pre mRNA in Trypanosomes, Functions in a Complex with a New L-Type Cyclin and a Kinetoplastid-Specific Protein. AB - In eukaryotes, cyclin-dependent kinases (CDKs) control the cell cycle and critical steps in gene expression. The lethal parasite Trypanosoma brucei, member of the phylogenetic order Kinetoplastida, possesses eleven CDKs which, due to high sequence divergence, were generically termed CDC2-related kinases (CRKs). While several CRKs have been implied in the cell cycle, CRK9 was the first trypanosome CDK shown to control the unusual mode of gene expression found in kinetoplastids. In these organisms, protein-coding genes are arranged in tandem arrays which are transcribed polycistronically. Individual mRNAs are processed from precursor RNA by spliced leader (SL) trans splicing and polyadenylation. CRK9 ablation was lethal in cultured trypanosomes, causing a block of trans splicing before the first transesterification step. Additionally, CRK9 silencing led to dephosphorylation of RNA polymerase II and to hypomethylation of the SL cap structure. Here, we tandem affinity-purified CRK9 and, among potential CRK9 substrates and modifying enzymes, discovered an unusual tripartite complex comprising CRK9, a new L-type cyclin (CYC12) and a protein, termed CRK9 associated protein (CRK9AP), that is only conserved among kinetoplastids. Silencing of either CYC12 or CRK9AP reproduced the effects of depleting CRK9, identifying these proteins as functional partners of CRK9 in vivo. While mammalian cyclin L binds to CDK11, the CRK9 complex deviates substantially from that of CDK11, requiring CRK9AP for efficient CRK9 complex formation and autophosphorylation in vitro. Interference with this unusual CDK rescued mice from lethal trypanosome infections, validating CRK9 as a potential chemotherapeutic target. PMID- 26954686 TI - How a Kinase Inhibitor Withstands Gatekeeper Residue Mutations. AB - Mutations in the gatekeeper residue of kinases have emerged as a key way through which cancer cells develop resistance to treatment. As such, the design of gatekeeper mutation resistant kinase inhibitors is a crucial way forward in increasing the efficacy of a broad range of anticancer drugs. In this work we use atomistic simulations to provide detailed thermodynamic and structural insight into how two inhibitors of cSrc kinase, namely, a commercial drug and type I kinase inhibitor Dasatinib and the type II inhibitor RL45, respectively fail and succeed in being effective against the T338M gatekeeper residue mutation in the kinase binding site. Given the well-known limitations of atomistic simulations in sampling biomolecular systems, we use an enhanced sampling technique called free energy perturbation with replica exchange solute tempering (FEP/REST). Our calculations find that the type I inhibitor Dasatinib binds favorably to the wild type but unfavorably to T338M mutated kinase, while RL45 binds favorably to both. The predicted relative binding free energies are well within 1 kcal/mol accuracy compared to experiments. We find that Dasatinib's impotency against gatekeeper residue mutations arises from a loss of ligand-kinase hydrogen bonding due to T338M mutation and from steric hindrance due to the presence of an inflexible phenyl ring close to the ligand. On the other hand, in the type II binding RL45, the central phenyl ring has very pronounced flexibility. This leads to the inhibitor overcoming effects of steric clashes on mutation and maintaining an electrostatically favorable "edge-to-face" orientation with a neighboring phenylalanine residue. Our work provides useful insight into the mechanisms of mutation resistant kinase inhibitors and demonstrates the usefulness of enhanced sampling techniques in computational drug design. PMID- 26954687 TI - Population Structure and Antimicrobial Resistance Profiles of Streptococcus suis Serotype 2 Sequence Type 25 Strains. AB - Strains of serotype 2 Streptococcus suis are responsible for swine and human infections. Different serotype 2 genetic backgrounds have been defined using multilocus sequence typing (MLST). However, little is known about the genetic diversity within each MLST sequence type (ST). Here, we used whole-genome sequencing to test the hypothesis that S. suis serotype 2 strains of the ST25 lineage are genetically heterogeneous. We evaluated 51 serotype 2 ST25 S. suis strains isolated from diseased pigs and humans in Canada, the United States of America, and Thailand. Whole-genome sequencing revealed numerous large-scale rearrangements in the ST25 genome, compared to the genomes of ST1 and ST28 S. suis strains, which result, among other changes, in disruption of a pilus island locus. We report that recombination and lateral gene transfer contribute to ST25 genetic diversity. Phylogenetic analysis identified two main and distinct Thai and North American clades grouping most strains investigated. These clades also possessed distinct patterns of antimicrobial resistance genes, which correlated with acquisition of different integrative and conjugative elements (ICEs). Some of these ICEs were found to be integrated at a recombination hot spot, previously identified as the site of integration of the 89K pathogenicity island in serotype 2 ST7 S. suis strains. Our results highlight the limitations of MLST for phylogenetic analysis of S. suis, and the importance of lateral gene transfer and recombination as drivers of diversity in this swine pathogen and zoonotic agent. PMID- 26954689 TI - Safety profile of the 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV). AB - Safety and reactogenicity data were reviewed following 10 years of experience with the 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) in clinical development and from post-licensure settings. Analyses of pooled clinical trial data and post-marketing reports provided an overview of its safety profile and allowed assessment of rare adverse events that might not have been identified previously. The safety of PHiD-CV was also evaluated in children at higher risk for pneumococcal infection (preterm and HIV-infected or HIV-exposed infants), for different vaccination schedules and co administered pediatric vaccines, and with a focus on special categories of adverse events (febrile convulsions, apnea, Kawasaki disease and sudden deaths). Following the distribution of over 235 million doses, PHiD-CV has been well tolerated when co-administered with other pediatric vaccines to children aged less than 5 years from diverse ethnic and geographic backgrounds. Detailed examination of various aspects has confirmed its favorable benefit: risk profile. PMID- 26954688 TI - School Water, Sanitation, and Hygiene, Soil-Transmitted Helminths, and Schistosomes: National Mapping in Ethiopia. AB - BACKGROUND: It is thought that improving water, sanitation, and hygiene (WASH) might reduce the transmission of schistosomes and soil-transmitted helminths, owing to their life cycles. However, few large-scale studies have yet assessed the real extent of associations between WASH and these parasites. METHODOLOGY/PRINCIPAL FINDINGS: In the 2013-2014 Ethiopian national mapping of infections with these parasites, school WASH was assessed alongside infection intensity in children, mostly between 10 and 15 years of age. Scores were constructed reflecting exposure to schistosomes arising from water collection for schools, from freshwater sources, and the adequacy of school sanitation and hygiene facilities. Kendall's taub was used to test the WASH scores against the school-level arithmetic mean intensity of infection with each parasite, in schools with at least one child positive for the parasite in question. WASH and parasitology data were available for 1,645 schools. More frequent collection of water for schools, from open freshwater sources was associated with statistically significantly higher Schistosoma mansoni infection intensity (Kendall's taub = 0.097, 95% confidence interval, CI: 0.011 to 0.18), better sanitation was associated with significantly lower Ascaris lumbricoides intensity (Kendall's taub = -0.067, 95% CI: -0.11 to -0.023) and borderline significant lower hookworm intensity (Kendall's taub = -0.039, 95% CI: -0.090 to 0.012, P = 0.067), and better hygiene was associated with significantly lower hookworm intensity (Kendall's taub = -0.076, 95% CI: -0.13 to -0.020). However, no significant differences were observed when comparing sanitation and infection with S. mansoni or Trichuris trichiura, or hygiene and infection with A. lumbricoides or T. trichiura. CONCLUSIONS/SIGNIFICANCE: Improving school WASH may reduce transmission of these parasites. However, different forms of WASH appear to have different effects on infection with the various parasites, with our analysis finding the strongest associations between water and S. mansoni, sanitation and A. lumbricoides, and hygiene and hookworm. PMID- 26954690 TI - Principal Component Analysis of Multimodal Neuromelanin MRI and Dopamine Transporter PET Data Provides a Specific Metric for the Nigral Dopaminergic Neuronal Density. AB - The loss of dopaminergic (DA) neurons in the substantia nigra (SN) is a major pathophysiological feature of patients with Parkinson's disease (PD). As nigral DA neurons contain both neuromelanin (NM) and dopamine transporter (DAT), decreased intensities in both NM-sensitive MRI and DAT PET reflect decreased DA neuronal density. This study demonstrates that a more specific metric for the nigral DA neuronal density can be derived with multimodal MRI and PET. Participants were 11 clinically diagnosed PD patients and 10 age and gender matched healthy controls (HCs). Two quantities, the NM-related index (RNM) and the binding potential of the radiotracer [18F]FE-PE2I to DAT (BPND) in SN, were measured for each subject using MRI and PET, respectively. Principal component analysis (PCA) was applied to the multimodal data set to estimate principal components. One of the components, PCP, corresponds to a basis vector oriented in a direction where both BPND and RNM increase. The ability of BPND, RNM and PCP to discriminate between HC and PD groups was compared. Correlation analyses between the motor score of the unified Parkinson's disease rating scale and each metric were also performed. PCP, BPND and RNM for PD patients were significantly lower than those for HCs (F = 16.26, P<0.001; F = 6.05, P = 0.008; F = 7.31, P = 0.034, respectively). The differential diagnostic performance between the HC and PD groups as assessed by the area under the receiver-operating characteristic curve was best for PCP (0.94, 95% CI: 0.66-1.00). A significant negative correlation was found between the motor severity score and PCp (R = -0.70, P<0.001) and RNM (R = -0.52, P = 0.015), but not for BPND (R = -0.36, P = 0.110). PCA of multimodal NM-sensitive MRI and DAT PET data provides a metric for nigral DA neuronal density that will help illuminate the pathophysiology of PD in SN. Further studies are required to explore whether PCA is useful for other parkinsonian syndromes. PMID- 26954691 TI - NICE: A Computational Solution to Close the Gap from Colour Perception to Colour Categorization. AB - The segmentation of visible electromagnetic radiation into chromatic categories by the human visual system has been extensively studied from a perceptual point of view, resulting in several colour appearance models. However, there is currently a void when it comes to relate these results to the physiological mechanisms that are known to shape the pre-cortical and cortical visual pathway. This work intends to begin to fill this void by proposing a new physiologically plausible model of colour categorization based on Neural Isoresponsive Colour Ellipsoids (NICE) in the cone-contrast space defined by the main directions of the visual signals entering the visual cortex. The model was adjusted to fit psychophysical measures that concentrate on the categorical boundaries and are consistent with the ellipsoidal isoresponse surfaces of visual cortical neurons. By revealing the shape of such categorical colour regions, our measures allow for a more precise and parsimonious description, connecting well-known early visual processing mechanisms to the less understood phenomenon of colour categorization. To test the feasibility of our method we applied it to exemplary images and a popular ground-truth chart obtaining labelling results that are better than those of current state-of-the-art algorithms. PMID- 26954692 TI - The Use of Physiotherapy among Patients with Subacromial Impingement Syndrome: Impact of Sex, Socio-Demographic and Clinical Factors. AB - BACKGROUND: Physiotherapy with exercises is generally recommended in the treatment of patients with subacromial impingement syndrome (SIS). OBJECTIVE: We aimed to investigate the use of physiotherapy in patients with SIS in Danish hospital settings as part of initial non-surgical treatment and after SIS-related surgery and to evaluate to which extent sex, socio-demographic and clinical factors predict the use of physiotherapy. METHODS: Using national health registers, we identified 57,311 patients who had a first hospital contact with a diagnosis of ICD-10, groups M75.1-75.9, 1 July 2007 to 30 June 2011. Records of physiotherapy were extracted within 52 weeks after first contact (or until surgery), and for surgically treated patients within 26 weeks after surgery. Predictors of the use of physiotherapy after first contact and after surgery were analysed as time-to-event. RESULTS: Within 52 weeks after first contact, 43% of the patients had physiotherapy and 30% underwent surgery. Within 26 weeks after surgery, 80% had a record of physiotherapy. After first contact and after surgery, exercise was part of physiotherapy in 65% and 84% of the patients, respectively. A public hospital contact, physiotherapy before hospital contact, administrative region, female sex, a diagnosis of other or unspecified disorders (M75.8-M75.9), and surgical procedure predicted higher use of physiotherapy. Low education level predicted slightly lower use of physiotherapy after first contact, but not after surgery. CONCLUSION: In patients with SIS in Danish hospital settings, physiotherapy was more often used after surgery than as part of initial non-surgical treatment. The use of physiotherapy was less common among men than women, whereas unequal use of physiotherapy in relation to education level was not noticeable. The use of physiotherapy with exercises in initial non surgical treatment was relatively limited. PMID- 26954693 TI - Alterations in Cortical Sensorimotor Connectivity following Complete Cervical Spinal Cord Injury: A Prospective Resting-State fMRI Study. AB - Functional magnetic resonance imaging (fMRI) studies have demonstrated alterations during task-induced brain activation in spinal cord injury (SCI) patients. The interruption to structural integrity of the spinal cord and the resultant disrupted flow of bidirectional communication between the brain and the spinal cord might contribute to the observed dynamic reorganization (neural plasticity). However, the effect of SCI on brain resting-state connectivity patterns remains unclear. We undertook a prospective resting-state fMRI (rs-fMRI) study to explore changes to cortical activation patterns following SCI. With institutional review board approval, rs-fMRI data was obtained in eleven patients with complete cervical SCI (>2 years post injury) and nine age-matched controls. The data was processed using the Analysis of Functional Neuroimages software. Region of interest (ROI) based analysis was performed to study changes in the sensorimotor network using pre- and post-central gyri as seed regions. Two sampled t-test was carried out to check for significant differences between the two groups. SCI patients showed decreased functional connectivity in motor and sensory cortical regions when compared to controls. The decrease was noted in ipsilateral, contralateral, and interhemispheric regions for left and right precentral ROIs. Additionally, the left postcentral ROI demonstrated increased connectivity with the thalamus bilaterally in SCI patients. Our results suggest that cortical activation patterns in the sensorimotor network undergo dynamic reorganization following SCI. The presence of these changes in chronic spinal cord injury patients is suggestive of the inherent neural plasticity within the central nervous system. PMID- 26954694 TI - Molecular Diagnosis of Urinary Tract Infections by Semi-Quantitative Detection of Uropathogens in a Routine Clinical Hospital Setting. AB - BACKGROUND: The objective of our study was the development of a semi-quantitative real-time PCR to detect uropathogens. Two multiplex PCR reactions were designed to detect Escherichia coli, Klebsiella spp., Enterobacter spp., Citrobacter spp., Proteus mirabilis, Enterococcus faecalis, and Pseudomonas aeruginosa. 16S based PCR was performed in parallel to detect Gram-positive and Gram-negative bacteria. Firstly to identify non-targeted agents of infection in the same urine specimen, and secondly to quantify background flora. The method was evaluated in comparison with standard bacterial culture, and a commercial PCR kit for detection of uropathogens. FINDINGS: Analysis with a known panel of 116 clinical isolates yielded a PCR specificity of 100%. Analysis of urine specimens from 211 patients revealed a high correlation of PCR Cq values with both culture positivity and quantity. Concordance between PCR and culture was 98% when both methods yielded results. PCR was found to be more sensitive than culture. With a cut-off Cq value of 33, the negative predictive value of PCR was 94%. The 16S PCR confirmed most results. One specimen was positive by 16S PCR suggesting another cause of infection not detected by the specific PCR assays. CONCLUSION: We conclude that it is feasible to detect and identify uropathogens by multiplex real-time PCR assay. PMID- 26954695 TI - Patterns and prevalence of medication use across the menstrual cycle among healthy, reproductive aged women. AB - PURPOSE: The purpose of this study is to characterize the patterns of medication intake in healthy, reproductive-age women not using hormonal contraception. METHODS: Two hundered fifty-nine healthy, premenopausal women (18-44 years of age) enrolled in the BioCycle Study (2005-2007) were followed over two menstrual cycles. Women were excluded if they were currently using oral contraceptives or other chronic medications. Over-the-counter and prescription medication use among participants was evaluated daily throughout the study via a diary assessing type of medication, dosage, units, and frequency. Medications were categorized as allergy, antibiotics, central nervous system (CNS), cold and cough, gastrointestinal, musculoskeletal, and pain medication based on primary active ingredient. Medication use within each category was assessed across standardized 28-day cycles to evaluate differences in use across cycle phases (i.e., early, middle, and late). RESULTS: Medication use was reported by 73% of participants. The most and least frequently used medications, respectively, were pain (69%) and musculoskeletal medications (1%). Pain, CNS, and antibiotic medication use varied significantly across the cycle, with pain and CNS medication more frequently reported during menses and antibiotics more frequently during the luteal phase. Allergy, cold and cough, gastrointestinal, and musculoskeletal medication use did not vary across the cycle. CONCLUSIONS: Patterns of medication use among reproductive age women vary across the menstrual cycle for certain types of medications, particularly in pain (e.g., Ibuprofen), antibiotics (e,g, Amoxicillin), and CNS (e.g., Adderall) medications. Future studies involving use of these types of medication in premenopausal women may need to consider the relationship of their use to the menstrual cycle. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26954696 TI - You Don't See What I See: Individual Differences in the Perception of Meaning from Visual Stimuli. AB - Everyone has their own unique version of the visual world and there has been growing interest in understanding the way that personality shapes one's perception. Here, we investigated meaningful visual experiences in relation to the personality dimension of schizotypy. In a novel approach to this issue, a non clinical sample of subjects (total n = 197) were presented with calibrated images of scenes, cartoons and faces of varying visibility embedded in noise; the spatial properties of the images were constructed to mimic the natural statistics of the environment. In two experiments, subjects were required to indicate what they saw in a large number of unique images, both with and without actual meaningful structure. The first experiment employed an open-ended response paradigm and used a variety of different images in noise; the second experiment only presented a series of faces embedded in noise, and required a forced-choice response from the subjects. The results in all conditions indicated that a high positive schizotypy score was associated with an increased tendency to perceive complex meaning in images comprised purely of random visual noise. Individuals high in positive schizotypy seemed to be employing a looser criterion (response bias) to determine what constituted a 'meaningful' image, while also being significantly less sensitive at the task than those low in positive schizotypy. Our results suggest that differences in perceptual performance for individuals high in positive schizotypy are not related to increased suggestibility or susceptibility to instruction, as had previously been suggested. Instead, the observed reductions in sensitivity along with increased response bias toward seeing something that is not there, indirectly implicated subtle neurophysiological differences associated with the personality dimension of schizotypy, that are theoretically pertinent to the continuum of schizophrenia and hallucination-proneness. PMID- 26954697 TI - Siderophore Biosynthesis Governs the Virulence of Uropathogenic Escherichia coli by Coordinately Modulating the Differential Metabolism. AB - Urinary tract infections impose substantial health burdens on women worldwide. Urinary tract infections often incur a high risk of recurrence and antibiotic resistance, and uropathogenic E. coli accounts for approximately 80% of clinically acquired cases. The diagnosis of, treatment of, and drug development for urinary tract infections remain substantial challenges due to the complex pathogenesis of this condition. The clinically isolated UPEC 83972 strain was found to produce four siderophores: yersiniabactin, aerobactin, salmochelin, and enterobactin. The biosyntheses of some of these siderophores implies that the virulence of UPEC is mediated via the targeting of primary metabolism. However, the differential modulatory roles of siderophore biosyntheses on the differential metabolomes of UPEC and non-UPEC strains remain incompletely understood. In the present study, we sought to investigate how the differential metabolomes can be used to distinguish UPEC from non-UPEC strains and to determine the associated regulatory roles of siderophore biosynthesis. Our results are the first to demonstrate that the identified differential metabolomes strongly differentiated UPEC from non-UPEC strains. Furthermore, we performed metabolome assays of mutants with different patterns of siderophore deletions; the data revealed that the mutations of all four siderophores exerted a stronger modulatory role on the differential metabolomes of the UPEC and non-UPEC strains relative to the mutation of any single siderophore and that this modulatory role primarily involved amino acid metabolism, oxidative phosphorylation in the carbon fixation pathway, and purine and pyrimidine metabolism. Surprisingly, the modulatory roles were strongly dependent on the type and number of mutated siderophores. Taken together, these results demonstrated that siderophore biosynthesis coordinately modulated the differential metabolomes and thus may indicate novel targets for virulence-based diagnosis, therapeutics, and drug development related to urinary tract infections. PMID- 26954699 TI - Online Electronic Cigarette Marketing-Violation of Self-regulated Standards by Tobacco Companies. PMID- 26954698 TI - International Validity of the HOSPITAL Score to Predict 30-Day Potentially Avoidable Hospital Readmissions. AB - IMPORTANCE: Identification of patients at a high risk of potentially avoidable readmission allows hospitals to efficiently direct additional care transitions services to the patients most likely to benefit. OBJECTIVE: To externally validate the HOSPITAL score in an international multicenter study to assess its generalizability. DESIGN, SETTING, AND PARTICIPANTS: International retrospective cohort study of 117 065 adult patients consecutively discharged alive from the medical department of 9 large hospitals across 4 different countries between January 2011 and December 2011. Patients transferred to another acute care facility were excluded. EXPOSURES: The HOSPITAL score includes the following predictors at discharge: hemoglobin, discharge from an oncology service, sodium level, procedure during the index admission, index type of admission (urgent), number of admissions during the last 12 months, and length of stay. MAIN OUTCOMES AND MEASURES: 30-day potentially avoidable readmission to the index hospital using the SQLape algorithm. RESULTS: Overall, 117 065 adults consecutively discharged alive from a medical department between January 2011 and December 2011 were studied. Of all medical discharges, 16 992 of 117 065 (14.5%) were followed by a 30-day readmission, and 11 307 (9.7%) were followed by a 30-day potentially avoidable readmission. The discriminatory power of the HOSPITAL score to predict potentially avoidable readmission was good, with a C statistic of 0.72 (95% CI, 0.72-0.72). As in the derivation study, patients were classified into 3 risk categories: low (n = 73 031 [62.4%]), intermediate (n = 27 612 [23.6%]), and high risk (n = 16 422 [14.0%]). The estimated proportions of potentially avoidable readmission for each risk category matched the observed proportion, resulting in an excellent calibration (Pearson chi2 test P = .89). CONCLUSIONS AND RELEVANCE: The HOSPITAL score identified patients at high risk of 30-day potentially avoidable readmission with moderately high discrimination and excellent calibration when applied to a large international multicenter cohort of medical patients. This score has the potential to easily identify patients in need of more intensive transitional care interventions to prevent avoidable hospital readmissions. PMID- 26954700 TI - Potentiating the Anticancer Properties of Bisphosphonates by Nanocomplexation with the Cationic Amphipathic Peptide, RALA. AB - Bisphosphonates (BPs) are a class of bone resorptive drug with a high affinity for the hydroxyapatite structure of bone matrices that are used for the treatment of osteoporosis. However, clinical application is limited by a common toxicity, BP-related osteonecrosis of the jaw. There is emerging evidence that BPs possess anticancer potential, but exploitation of these antiproliferative properties is limited by their toxicities. We previously reported the utility of a cationic amphipathic fusogenic peptide, RALA, to traffic anionic nucleic acids into various cell types in the form of cationic nanoparticles. We hypothesized that complexation with RALA could similarly be used to conceal a BP's hydroxyapatite affinity, and to enhance bioavailability, thereby improving anticancer efficacy. Incubation of RALA with alendronate, etidronate, risedronate, or zoledronate provoked spontaneous electrostatic formation of cationic nanoparticles that did not exceed 100 nm in diameter and that were stable over a range of temperatures and for up to 6 h. The nanoparticles demonstrated a pH responsiveness, possibly indicative of a conformational change, that could facilitate release of the BP cargo in the endosomal environment. RALA/BP nanoparticles were more potent anticancer agents than their free BP counterparts in assays investigating the viability of PC3 prostate cancer and MDA-MB-231 breast cancer cells. Moreover, RALA complexation potentiated the tumor growth delay activity of alendronate in a PC3 xenograft model of prostate cancer. Taken together, these findings further validate the use of BPs as repurposed anticancer agents. PMID- 26954701 TI - Loss of FBXW7 is related to the susceptibility and poor prognosis of cervical squamous carcinoma. AB - OBJECTIVE: To investigate the relationship between F box/WD-40 domain protein 7 (FBXW7) and cervical squamous cancer. METHODS: We investigated the FBXW7 expression in 136 cervical squamous carcinoma cases through immunohistochemistry and Western-blot analysis to evaluate the clinical significance of FBXW7 and to elucidate the relationship of FBXW7 expression with progression-free survival (PFS) and overall survival (OS). RESULTS: Low FBXW7 expression was associated with high histologic grade, lymphovascular space invasion and lymph node metastasis, among other parameters. Patients with low FBXW7 expression exhibited poor OS and PFS. CONCLUSIONS: FBXW7 is related to the susceptibility and prognosis of cervical squamous carcinoma, indicating FBXW7 may be a potentially important target for the prediction of prognosis. PMID- 26954702 TI - Trajectories of PTSD Among Lower Manhattan Residents and Area Workers Following the 2001 World Trade Center Disaster, 2003-2012. AB - Group-based trajectory modeling was used to explore empirical trajectories of symptoms of posttraumatic stress disorder (PTSD) among 17,062 adult area residents/workers (nonrescue/recovery workers) enrolled in the World Trade Center (WTC) Health Registry using 3 administrations of the PTSD Checklist (PCL) over 9 years of observation. Six trajectories described PTSD over time: low-stable (48.9%), moderate-stable (28.3%), moderate-increasing (8.2%), high-stable (6.0%), high-decreasing (6.6 %), and very high-stable (2.0%). To examine factors associated with improving or worsening PTSD symptoms, groups with similar intercepts, but different trajectories were compared using bivariate analyses and logistic regression. The adjusted odds of being in the moderate-increasing relative to the moderate-stable group were significantly greater among enrollees reporting low social integration (OR = 2.18), WTC exposures (range = 1.34 to 1.53), job loss related to the September 11, 2001 disaster (OR = 1.41), or unmet mental health need/treatment (OR = 4.37). The odds of being in the high-stable relative to the high-decreasing group were significantly greater among enrollees reporting low social integration (OR = 2.23), WTC exposures (range = 1.39 to 1.45), or unmet mental health need/treatment (OR = 3.42). The influence of severe exposures, scarce personal/financial resources, and treatment barriers on PTSD trajectories suggest a need for early and ongoing PTSD screening postdisaster. PMID- 26954703 TI - Structural Environment and Stability of the Complexes Formed Between Calmodulin and Actinyl Ions. AB - Because of their presence in the nuclear fuel cycle, neptunium and uranium are two actinides of main interest in case of internal contamination. Complexation of U(VI) and Np(V) by the target protein calmodulin (CaM(WT)) was therefore studied herein. Both actinides have two axial oxygen atoms, which, charge aside, makes them very similar structurally wise. This work combines spectroscopy and theoretical density functional theory (DFT) calculations. Structural characterization was performed by extended X-ray absorption fine structure (EXAFS) at the L(III)-edge for each studied actinide. Models for the binding site of the protein were developed and then refined by using DFT to fit the obtained experimental EXAFS data. The effect of hydrolysis was also considered for both actinides (the uranyl experiment was performed at pH 3 and 6, while the neptunyl experiment was conducted at pH 7 and 9). The effect of the pH variation was apparent on the coordination sphere of the uranyl complexes, while the neptunyl complex characteristics remained stable under both studied conditions. The DFT calculations showed that at near physiological pH the complex formed by CaM(WT) with the neptunium ion is more stable than the one formed with uranyl. PMID- 26954704 TI - HLA-B51 Carriers are Susceptible to Ocular Symptoms of Behcet Disease and the Association between the Two Becomes Stronger towards the East along the Silk Road: A Literature Survey. AB - PURPOSE: Behcet disease (BD) is predominantly found between East Asia and the Mediterranean basin along the historic Silk Road. HLA-B51 is known to be strongly associated with BD. We investigated the association between HLA-B51 and the ocular manifestations of BD among various ethnic groups. METHODS: A literature survey was conducted, and 18 articles written in English were reviewed. RESULTS: A strong correlation was found between HLA-B51 and ocular lesions in the entire cohort discussed in the reviewed articles (OR = 1.76, p = 0.000057). HLA-B51 was shown to have a strong association with ocular manifestations of BD patients in East-Eurasian (OR = 2.40, p = 0.0030) and Middle-Eurasian (OR = 1.87, p = 0.0045), but not in West-Eurasian (OR = 1.28, p = 0.35) areas. This correlation seemed to become stronger towards the east. CONCLUSIONS: A meta-analysis showed that the correlation became stronger towards the east along the Silk Road. The study results may facilitate understanding of the etiology and characteristics of BD. PMID- 26954706 TI - Hydroxyethyl Starch or Saline for Fluid Resuscitation in Intensive Care. PMID- 26954705 TI - Long-Term Suicide Risk in Anxiety-The Lundby Study 1947-2011. AB - The objective of this study was to calculate the long-term risk of accomplished suicide in anxiety disorders, and to compare this with a healthy population. The Lundby Study is a prospective, longitudinal cohort study on a population of 3,563 subjects. Between 1947 and 1997, anxiety disorders were diagnosed in 300 subjects. Up to 2011 there were 68 suicides in all. The suicide risk was 3.3% for anxiety. For only anxiety, risk was increased (p = 0.008), but other diagnoses had a higher risk (p = 0.0001) compared with no diagnosis. Mean time from onset to suicide was 27 years. Risk of suicide in anxiety disorders seems elevated at an intermediate level. Suicide often occurs many years after onset of the disorder. PMID- 26954707 TI - Harmonization of Infliximab and Anti-Infliximab Assays Facilitates the Comparison Between Originators and Biosimilars in Clinical Samples. AB - BACKGROUND: The availability of an infliximab ELISA for measuring the originator drug Remicade and its biosimilars, such as Remsima and Inflectra (CT-P13), would facilitate the implementation of therapeutic drug monitoring of biosimilars and enhance the extrapolation of treatment stratification algorithms established for Remicade. A universal calibrator for all anti-infliximab antibody bridging assays allows harmonization of anti-drug antibody titers. METHODS: A panel of 55 mouse monoclonal antibodies raised against Remicade, including MA-IFX6B7 and MA IFX10F9, were evaluated for their reactivity toward the biosimilars using a sandwich-type ELISA and surface plasmon resonance. To analyze the similarity of detection of the biosimilars and Remicade in the infliximab ELISA, quality control samples were used. Bridging assays to determine anti-infliximab antibodies were developed according to the bridging ELISA of Remicade using MA IFX10F9 as calibrator. Serum of 36 patients treated with Remicade was analyzed for anti-infliximab antibodies toward Remicade, Remsima and Inflectra using their respective bridging ELISA. RESULTS: MA-IFX6B7 and MA-IFX10F9 exhibit equal reactivity toward Remicade, Remsima, and Inflectra. The infliximab ELISA quantifies the biosimilars equally well as Remicade. Quantification of anti infliximab antibodies in the serum of patients treated with Remicade revealed highly correlated titers between biosimilars and Remicade. CONCLUSIONS: The assay for therapeutic drug monitoring of Remicade can also be used to determine Remsima and Inflectra concentrations. Anti-drug antibody assays for biosimilars were developed. Anti-Remicade antibodies cross-react with infliximab biosimilars and reveal consistent negative/positive anti-drug antibody responses and highly correlated titers. PMID- 26954708 TI - Host Immune Response to Clostridium difficile Infection in Inflammatory Bowel Disease Patients. AB - BACKGROUND: Clostridium difficile infection (CDI) affects patients with inflammatory bowel disease (IBD). The aim of this study was to compare humoral response to C. difficile toxins in IBD patients and control outpatients. METHODS: We prospectively followed adult IBD patients and control subjects with serum and stool samples obtained at enrollment and during periods of CDI and tested by PCR. Semiquantitative serum levels of IgM, IgG, and IgA to C. difficile toxins A and B were measured. RESULTS: Overall, 119 stool and 117 serum samples were obtained from 150 subjects. Different levels of IgA to toxin A (P = 0.0016) and toxin B (P = 0.0468) were noted between different IBD groups. Toxin A IgA levels were higher in the Crohn's disease group (P = 0.0321) and ileal pouch anal anastomosis (IPAA) group (P = 0.001) compared with the ulcerative colitis (UC) group, and toxin B IgA levels were higher in the IPAA group compared with the UC group (P = 0.0309). There were lower levels of toxin A IgA in IBD patients compared with those in subjects without new CDI (P = 0.0488) and higher levels in IBD patients with compared with those in subjects without CDI history before enrollment (P = 0.016). There were nonsignificant lower toxin A IgG levels in IBD patients compared with those in subjects without prior CDI (P = 0.095) and higher levels in control subjects with a history of CDI compared with IBD patients with prior CDI (P = 0.049). CONCLUSIONS: Patients with UC have lower IgA levels to C. difficile toxins compared with those with Crohn's disease and those after IPAA. Patients with IBD with prior CDI failed to demonstrate any increase in antitoxin IgG. Our findings suggest that IBD patients may benefit from immunization strategies targeting C. difficile toxins. PMID- 26954709 TI - Microbiome Heterogeneity Characterizing Intestinal Tissue and Inflammatory Bowel Disease Phenotype. AB - Inflammatory bowel disease has been associated with differential abundance of numerous organisms when compared to healthy controls (HCs); however, few studies have investigated variability in the microbiome across intestinal locations and how this variability might be related to disease location and phenotype. In this study, we have analyzed the microbiome of a large cohort of individuals recruited at Mount Sinai Hospital in Toronto, Canada. Biopsies were taken from subjects with Crohn's disease, ulcerative colitis, and HC, and also individuals having undergone ileal pouch-anal anastomosis for treatment of ulcerative colitis or familial adenomatous polyposis. Microbial 16S rRNA was sequenced using the Illumina MiSeq platform. We observed a great deal of variability in the microbiome characterizing different sampling locations. Samples from pouch and afferent limb were comparable in microbial composition. When comparing sigmoid and terminal ileum samples, more differences were observed. The greatest number of differentially abundant microbes was observed when comparing either pouch or afferent limb samples to sigmoid or terminal ileum. Despite these differences, we were able to observe modest microbial variability between inflammatory bowel disease phenotypes and HCs, even when controlling for sampling location and additional experimental factors. Most detected associations were observed between HCs and Crohn's disease, with decreases in specific genera in the families Ruminococcaceae and Lachnospiraceae characterizing tissue samples from individuals with Crohn's disease. This study highlights important considerations when analyzing the composition of the microbiome and also provides useful insight into differences in the microbiome characterizing these seemingly related phenotypes. PMID- 26954711 TI - Effect of Limited Tenon Capsule and Intermuscular Membranes Dissection on the Outcome of Surgery in Patients with Horizontal Strabismus. AB - PURPOSE: The aim of the study was to evaluate the effect of limited dissection of Tenon capsule on the outcome of strabismus surgery. METHODS: Patients between the ages of 2 and 50 years with pure horizontal strabismus were enrolled in a prospective study. Patients were divided into two groups: case and control as a non-randomized study. The method of operation was similar in both groups except for the amount of sheath Tenon dissection. In the control group the intermuscular connections and Tenon capsule were cut as much as possible. In the study group, Tenon capsule, 3-4 mm posterior to the location of the sutures over the muscle (recessed or resected), were cut and intermuscular connections remained intact. RESULTS: The study enrolled 54 patients with 27 patients in each group. In both groups, after operation, regardless of the type of surgery, the angle of strabismus was reduced (P< 0.05). For patients who had undergone bimedial recession, the angle of strabismus was corrected to 2.6 +/- 0.4 prism diopters per mm (PD/mm) of muscle recession in the case group, and 2.2 +/- 0.9 in the control group (P=0.2). For patients who had undergone monocular recession and resection (R&R) for esotropia, the angle of strabismus was corrected 3.4 +/- 0.3 PD/mm of muscle recession or resection in the case group, and 3.2 +/- 0.2 in the control group (P=0.05). For patients who had undergone bilateral recession, the angle of strabismus was corrected 2.3 +/- 0.2 PD/mm of muscle recession in the case group, and 2.2 +/- 0.2 in the control group (P=0.03). For patients who had undergone R&R for exotropia, the angle of strabismus was corrected 3.1 +/- 0.5 PD/mm of muscle recession or resection in the case group, and 2.7 +/- 0.3 in the control group (P=0.02). CONCLUSION: Connective tissue ensheathments, whether disturbed or removed, do not ultimately affect the success of the strabismus surgery. PMID- 26954712 TI - Enhanced Resonance Energy Transfer and White-Light Emission from Organic Fluorophores and Lanthanides in Dendron-based Hybrid Hydrogel. AB - In this paper, we have investigated the use of poly(aryl ether) dendron-based gel as a medium for resonance energy transfer (RET) from organic donors (phenanthrene, naphthalene, and pyrene) to lanthanide [Eu(III) and Tb(III)] ions. The gel has been prepared through self-assembly of glucose-cored poly(aryl ether) dendrons in a dimethyl sulfoxide/water mixture (1:9 v/v). The efficiency of RET was calculated by metal-centered emission quantum yield measurements in the gel medium. While there was no resonance energy transfer observed between the donor acceptor pairs in solution, efficient RET has been observed in the gel medium. The metal-centered quantum yield values were 11.9% for phenanthrene-Eu(III), 3.9% for naphthalene-Eu(III), and 3.6% for pyrene-Eu(III) systems. Partial RET in the system has been utilized to generate white-light emission from the gel by incorporating an additional lanthanide ion, Tb(III), along with the organic donors and Eu(III). The CIE (Commission Internationale d'Eclairage) coordinates obtained for gels formed by phenanthrene-Tb(III)-Eu(III) (PTE), naphthalene Tb(III)-Eu(III) (NTE), and pyrene-Tb(III)-Eu(III) (PyTE) were (0.33, 0.32) for PTE, (0.35, 0.37) for NTE, and (0.35, 0.33) for PyTE. The correlated color temperatures (CCT) for white-light-emitting gels were calculated, and the values (5520 K for PTE, 4886 K for NTE, and 4722 K for PyTE) suggest that the system generates cool white light. PMID- 26954710 TI - Presence of Multidrug-Resistant Shiga Toxin-Producing Escherichia coli, Enteropathogenic E. coli and Enterotoxigenic E. coli, on Raw Nopalitos (Opuntia ficus-indica L.) and in Nopalitos Salads from Local Retail Markets in Mexico. AB - The presence of multidrug-resistant pathogenic bacteria in food is a significant public health concern. Diarrheagenic Escherichia coli pathotypes (DEPs) are foodborne bacteria. In Mexico, DEPs have been associated with diarrheal illness. There is no information about the presence of multidrug-resistant DEPs on fresh vegetables and in cooked vegetable salads in Mexico. "Nopalitos" (Opuntia ficus indica L.) is a Cactacea extensively used as a fresh green vegetable throughout Mexico. The presence of generic E. coli and multidrug-resistant DEPs on raw whole and cut nopalitos and in nopalitos salad samples was determined. One hundred raw whole nopalitos (without prickles) samples, 100 raw nopalitos cut into small square samples, and 100 cooked nopalitos salad samples were collected from markets. Generic E. coli was determined using the most probable number procedures. DEPs were identified using two multiplex polymerase chain reaction procedures. Susceptibility to 16 antibiotics was tested for the isolated DEP strains by standard test. Of the 100 whole nopalitos samples, 100 cut nopalitos samples, and 100 nopalitos salad samples, generic E. coli and DEPs were identified, respectively, in 80% and 10%, 74% and 10%, and 64% and 8%. Eighty-two DEP strains were isolated from positive nopalitos samples. The identified DEPs included Shiga toxin-producing E. coli (STEC), enteropathogenic E. coli (EPEC), and enterotoxigenic E. coli (ETEC). All isolated strains exhibited resistance to at least six antibiotics. To the best of our knowledge, this is the first report of the presence of multidrug-resistant and antibiotic resistance profiles of STEC, ETEC, and EPEC on raw nopalitos and in nopalitos salads in Mexico. PMID- 26954713 TI - Cerebellar Atrophy in Adult Survivors of Childhood Cerebellar Tumor. AB - OBJECTIVES: The cerebellum (CB) is known for its role in supporting processing speed (PS) and cognitive efficiencies. The CB often sustains damage from treatment and resection in pediatric patients with posterior fossa tumors. Limited research suggests that CB atrophy may be associated with the radiation treatment experienced during childhood. The purpose of the study was to measure cerebellar atrophy to determine its neurobehavioral correlates. METHODS: Brain magnetic resonance images were collected from 25 adult survivors of CB tumors and age- and gender-matched controls (M age= 24 years (SD=5), 52% female). Average age at diagnosis was 9 years (SD=5) and average time since diagnosis was 15 years (SD=5). PS was measured by the Symbol Digit Modality Test. To quantify atrophy, an objective formula was developed based on prior literature, in which Atrophy=[(CB White+CB Gray Volume)/Intracranial Vault (ICV)]controls-[(CB White+CB Gray+Lesion Size Volume)/ICV]survivors. RESULTS: Regression analyses found that the interaction term (age at diagnosis*radiation) predicts CB atrophy; regression equations included the Neurological Predictor Scale, lesion size, atrophy, and the interaction term and accounted for 33% of the variance in oral PS and 48% of the variance in written PS. Both interactions suggest that individuals with smaller CB lesion size but a greater degree of CB atrophy had slower PS, whereas individuals with a larger CB lesion size and less CB atrophy were less affected. CONCLUSION: The results of the current study suggest that young age at diagnosis and radiation is associated with CB atrophy, which interacts with lesion size to impact both written and oral PS. PMID- 26954714 TI - Identification of neutrophil-derived proteases and angiotensin II as biomarkers of cancer cachexia. AB - BACKGROUND: Cachexia is a metabolic disorder characterised by muscle wasting, diminished response to anti-cancer treatments and poor quality of life. Our objective was to identify blood-based biomarkers of cachexia in advanced cancer patients. Hence, we characterised the plasma cytokine and blood cell mRNA profiles of patients grouped in three cohorts: patients with cachexia, pre cachexia (no cachexia but high CRP levels: ? 5 mg l-1) and no cachexia (no cachexia and CRP: < 5 mg l-1). METHODS: A total of 122 newly diagnosed cancer patients with seven cancer types were studied prior to their initial therapy. Plasma levels of 22 cytokines were quantified using the bio-plex technology. mRNAs isolated from whole blood and expression profiles were determined by the chip array technology and Ingenuity Pathway Analysis (IPA) software. RESULTS: In comparison with non-cachectic individuals, both pre-cachectic and cachectic patients showed an increase (? 1.5-folds) in mRNA expression of neutrophil derived proteases (NDPs) and significantly elevated angiotensin II (Ang II) (P = 0.005 and P = 0.02, respectively), TGFbeta1 (P = 0.042 and P < 0.0001, respectively) and CRP (both P < 0.0001) in the plasma. Moreover, cachectic patients displayed a significant increase in IL-6 (P = 0.005), IL-8 (P = 0.001) and absolute neutrophil counts (P = 0.007). CONCLUSIONS: Ang II, TGFbeta1, CRP and NDP are blood biomarkers for cancer cachexia. These findings contribute to early diagnosis and prevention of cachexia. PMID- 26954715 TI - The impact of the 21-gene assay on adjuvant treatment decisions in oestrogen receptor-positive early breast cancer: a prospective study. AB - BACKGROUND: International guidelines, including NICE, recommend using the 21-gene Recurrence Score assay for guiding adjuvant treatment decisions in ER+, HER2 negative early breast cancer (BC). We investigated the impact of adding this assay to standard pathological tests on clinicians'/patients' treatment decisions and on patients' decisional conflict in the United Kingdom. METHODS: In this prospective multicentre study, eligibility criteria included: ER+ HER2-negative BC (N0/Nmic for patients ?50 years; ?3 positive lymph nodes for patients >50 years) and being fit for chemotherapy. Physicians'/patients' treatment choices and patients' decisional conflict were recorded pre- and post testing. RESULTS: The analysis included 137 patients. Overall, adjuvant treatment recommendations changed in 40.7% of patients, with the direction of the change consistent with the Recurrence Score results (net decrease in chemotherapy recommendation rate in low Recurrence Score patients and net increase in high Recurrence Score patients). Patients' choices were generally consistent with physicians' recommendations. Post-testing, patients' decisional conflict decreased significantly (P<0.0001). In the 67 patients meeting the NICE criteria for testing, the recommendation change rate was 49.3%. CONCLUSIONS: Recurrence Score testing significantly influenced treatment recommendations overall and in the subgroup of patients meeting the NICE criteria, suggesting that this test could substantially alter treatment patterns in the United Kingdom. PMID- 26954717 TI - Androgen deprivation in LNCaP prostate tumour xenografts induces vascular changes and hypoxic stress, resulting in promotion of epithelial-to-mesenchymal transition. AB - BACKGROUND: When single-agent androgen deprivation therapy (ADT) is administered for locally advanced prostate cancer, men usually relapse within 1-2 years with more malignant castrate-resistant disease. The reason for this is currently unknown. We now hypothesise that an initial treatment response that increases tumour hypoxia drives selection of more malignant tumours. METHODS: The LNCaP prostate tumour xenografts were analysed for physiological (oxygen and vasculature) and genetic (PCR array) changes during longitudinal treatment with ADT (bicalutamide, 6 or 2 mg kg-1 daily for 28 days). RESULTS: Bicalutamide caused an immediate (within 24 h) dose-dependent fall in oxygenation in LNCaP-luc prostate tumours with a nadir of <= 0.1% oxygen within 3-7 days; this was attributed to a significant loss of tumour microvessels (window chamber study). The hypoxic nadir persisted for 10-14 days. During the next 7 days, tumours regrew, oxygenation improved and the vasculature recovered; this was inhibited by the VEGF inhibitor B20.4.1.1. Gene expression over 28 days showed marked fluctuations consistent with the physiological changes. Accompanying the angiogenic burst (day 21) was a particularly striking increase in expression of genes associated with epithelial-to-mesenchymal transition (EMT). In particular, insulin-like growth factor 1 (IGF-1) showed increases in mRNA and protein expression. CONCLUSIONS: Hypoxic stress caused by ADT promotes EMT, providing a mechanism for the cause of malignant progression in prostate cancer. PMID- 26954716 TI - MYC functions are specific in biological subtypes of breast cancer and confers resistance to endocrine therapy in luminal tumours. AB - BACKGROUND: MYC is amplified in approximately 15% of breast cancers (BCs) and is associated with poor outcome. c-MYC protein is multi-faceted and participates in many aspects of cellular function and is linked with therapeutic response in BCs. We hypothesised that the functional role of c-MYC differs between molecular subtypes of BCs. METHODS: We therefore investigated the correlation between c-MYC protein expression and other proteins involved in different cellular functions together with clinicopathological parameters, patients' outcome and treatments in a large early-stage molecularly characterised series of primary invasive BCs (n=1106) using immunohistochemistry. The METABRIC BC cohort (n=1980) was evaluated for MYC mRNA expression and a systems biology approach utilised to identify genes associated with MYC in the different BC molecular subtypes. RESULTS: High MYC and c-MYC expression was significantly associated with poor prognostic factors, including grade and basal-like BCs. In luminal A tumours, c MYC was associated with ATM (P=0.005), Cyclin B1 (P=0.002), PIK3CA (P=0.009) and Ki67 (P<0.001). In contrast, in basal-like tumours, c-MYC showed positive association with Cyclin E (P=0.003) and p16 (P=0.042) expression only. c-MYC was an independent predictor of a shorter distant metastases-free survival in luminal A LN+ tumours treated with endocrine therapy (ET; P=0.013). In luminal tumours treated with ET, MYC mRNA expression was associated with BC-specific survival (P=0.001). In ER-positive tumours, MYC was associated with expression of translational genes while in ER-negative tumours it was associated with upregulation of glucose metabolism genes. CONCLUSIONS: c-MYC function is associated with specific molecular subtypes of BCs and its overexpression confers resistance to ET. The diverse mechanisms of c-MYC function in the different molecular classes of BCs warrants further investigation particularly as potential therapeutic targets. PMID- 26954718 TI - BH3 profiling and a toolkit of BH3-mimetic drugs predict anti-apoptotic dependence of cancer cells. AB - BACKGROUND: Anti-apoptotic BCL-2 family members antagonise apoptosis by sequestering their pro-apoptotic counterparts. The balance between the different BCL-2 family members forms the basis of BH3 profiling, a peptide-based technique used to predict chemosensitivity of cancer cells. Recent identification of cell permeable, selective inhibitors of BCL-2, BCL-XL and MCL-1, further facilitates the determination of the BCL-2 family dependency of cancer cells. METHODS: We use BH3 profiling in combination with cell death analyses using a chemical inhibitor toolkit to assess chemosensitivity of cancer cells. RESULTS: Both BH3 profiling and the inhibitor toolkit effectively predict chemosensitivity of cells addicted to a single anti-apoptotic protein but a combination of both techniques is more instructive when cell survival depends on more than one anti-apoptotic protein. CONCLUSIONS: The inhibitor toolkit provides a rapid, inexpensive and simple means to assess the chemosensitivity of tumour cells and in conjunction with BH3 profiling offers much potential in personalising cancer therapy. PMID- 26954721 TI - Structural properties of polymer-brush-grafted gold nanoparticles at the oil water interface: insights from coarse-grained simulations. AB - In this work, the structural properties of amphiphilic polymer-brush-grafted gold nanoparticles (AuNPs) at the oil-water interface were investigated by coarse grained simulations. The effects of grafting architecture (diblock, mixed and Janus brush-grafted AuNPs) and hydrophilicity of polymer brushes are discussed. Simulation results indicate that functionalized AuNPs present abundant morphologies including typical core-shell, Janus-type, jellyfish-like, etc., in a water or oil-water solvent environment. It is found that hydrophobic/weak hydrophilic polymer-brush-grafted AuNPs have better phase transfer performance, especially for AuNPs modified with hydrophobic chains as outer blocks and weak hydrophilic chains as inner blocks. This kind of AuNP can cross the interface region and move into the oil phase completely. For hydrophobic/strong hydrophilic polymer-brush-grafted AuNPs, they are trapped in the interface region instead of moving into any phase. The mechanism of phase transfer is ascribed to the flexibility and mobility of outer blocks. Besides, we study the desorption energy by PMF analysis. The results demonstrate that Janus brush-grafted AuNPs show the highest interfacial stability and activity, which can be further strengthened by increasing the hydrophilicity of grafted polymer brushes. This work will promote the industrial applications of polymer-brush-grafted NPs such as phase transfer catalysis and Pickering emulsion catalysis. PMID- 26954719 TI - Predicting microbiologically defined infection in febrile neutropenic episodes in children: global individual participant data multivariable meta-analysis. AB - BACKGROUND: Risk-stratified management of fever with neutropenia (FN), allows intensive management of high-risk cases and early discharge of low-risk cases. No single, internationally validated, prediction model of the risk of adverse outcomes exists for children and young people. An individual patient data (IPD) meta-analysis was undertaken to devise one. METHODS: The 'Predicting Infectious Complications in Children with Cancer' (PICNICC) collaboration was formed by parent representatives, international clinical and methodological experts. Univariable and multivariable analyses, using random effects logistic regression, were undertaken to derive and internally validate a risk-prediction model for outcomes of episodes of FN based on clinical and laboratory data at presentation. RESULTS: Data came from 22 different study groups from 15 countries, of 5127 episodes of FN in 3504 patients. There were 1070 episodes in 616 patients from seven studies available for multivariable analysis. Univariable analyses showed associations with microbiologically defined infection (MDI) in many items, including higher temperature, lower white cell counts and acute myeloid leukaemia, but not age. Patients with osteosarcoma/Ewings sarcoma and those with more severe mucositis were associated with a decreased risk of MDI. The predictive model included: malignancy type, temperature, clinically 'severely unwell', haemoglobin, white cell count and absolute monocyte count. It showed moderate discrimination (AUROC 0.723, 95% confidence interval 0.711-0.759) and good calibration (calibration slope 0.95). The model was robust to bootstrap and cross-validation sensitivity analyses. CONCLUSIONS: This new prediction model for risk of MDI appears accurate. It requires prospective studies assessing implementation to assist clinicians and parents/patients in individualised decision making. PMID- 26954722 TI - A Stable Heterocyclic Amino(phosphanylidene-sigma(4)-phosphorane) Germylene. AB - A new stable heterocyclic germylene, in which the divalent germanium atom lies between a nitrogen atom and a phosphanylidene phosphorane group, was synthesized. Experimental and theoretical studies revealed the peculiar effect of phosphanylidene phosphorane substituent, which is a stronger pi-donor towards germanium than an amino group is. Because of the weak phosphorus-germanium pi bond, this new germylene compound shows an enhanced reactivity compared to classical N-heterocyclic germylenes. PMID- 26954720 TI - Effects of High-Risk Kidneys on Scientific Registry of Transplant Recipients Program Quality Reports. AB - There is a perception that transplanting high-risk kidneys causes programs to be identified as underperforming, thereby increasing the frequency of discards and diminishing access to transplant. Thus, the Organ Procurement and Transplantation Network (OPTN) has considered excluding transplants using kidneys from donors with high Kidney Donor Profile Index (KDPI) scores (>=0.85) when assessing program performance. We examined whether accepting high-risk kidneys (KDPI >=0.85) for transplant yields worse outcome evaluations. Despite a clear relationship between KDPI and graft failure and mortality, there was no relationship between a program's use of high-KDPI kidneys and poor performance evaluations after risk adjustment. Excluding high-KDPI donor transplants from the June 2015 evaluations did not alter the programs identified as underperforming, because in every case underperforming programs also had worse-than-expected outcomes among lower-risk donor transplants. Finally, we found that hypothetically accepting and transplanting additional kidneys with KDPI similar to that of kidneys currently discarded would not adversely affect program evaluations. Based on the study findings, there is no evidence that programs that accept higher-KDPI kidneys are at greater risk for low performance evaluations, and risk aversion may limit access to transplant for candidates while providing no measurable benefit to program evaluations. PMID- 26954723 TI - Lower C-reactive protein and better hemodialysis survival are associated with regular exercise activity: Longitudinal outcomes from the ACTIVE-ADIPOSE special study. AB - Introduction Cross-sectional and longitudinal studies in the general population have shown that a physically active lifestyle may have anti-inflammatory properties, but evidence from studies conducted with maintenance hemodialysis (HD) patients is limited. Methods A multicenter prospective cohort of 755 HD participants aged 20-92 was evaluated in a USRDS special study 2009-2013. Kilocalories/week (kcal/week) of leisure time physical activity (LTPA) was estimated from the Minnesota Leisure Time Activity questionnaire. Predialysis serum samples were obtained concurrent with LTPA report date. Generalized estimating equations (GEE) examined association of participants' LTPA and log normalized CRP across 24 months. Cox proportional hazards models investigated LTPA and survival over a median follow-up of 718 days. Findings Baseline median CRP concentration was lower for participants with 500+ kcal/week LTPA vs. those with <500 kcal/week LTPA (3.4 mg/L vs. 4.6 mg/L; P = 0.03). Participants who reported lower LTPA (<500 kcal/week) at both baseline and 12 months had a borderline significant increase in CRP concentration (within-group change 4.8 [1.9-10.4] to 5.8 [1.6-15.7]; P = 0.08). Lower LTPA was associated with higher log CRP over 24 months in adjusted GEE analyses (beta coefficient = 0.16 [95% CI 0.02-0.31]; P = 0.03). 67/364 (18%) and 43/391 (11%) deaths occurred, respectively, among participants reporting <500 vs. 500+ kcal/week LTPA [adjusted mortality hazard ratio 1.63 (CI, 1.07, 2.47)]. Discussion The data suggest that increased estimated levels of LTPA, a physical activity/exercise opportunity widely applicable to HD patients, may be associated with lower CRP concentration as well as better survival outcome. PMID- 26954724 TI - Application of Electronic Nose for Measuring Total Volatile Basic Nitrogen and Total Viable Counts in Packaged Pork During Refrigerated Storage. AB - The objective of this study was to predict the total viable counts (TVC) and total volatile basic nitrogen (TVB-N) in pork using an electronic nose (E-nose), and to assess the freshness of chilled pork during storage using different packaging methods, including pallet packaging (PP), vacuum packaging (VP), and modified atmosphere packaging (MAP, 40% O2 /40% CO2 /20% N2 ). Principal component analysis (PCA) was used to analyze the E-nose signals, and the results showed that the relationships between the freshness of chilled pork and E-nose signals could be distinguished in the loadings plots, and the freshness of chilled pork could be distributed along 2 first principal components. Multiple linear regression (MLR) was used to correlate TVC and TVB-N to E-nose signals. High F and R2 values were obtained in the MLR output of TVB-N (F = 32.1, 21.6, and 24.2 for PP [R2 = 0.93], VP [R2 = 0.94], and MAP [R2 = 0.95], respectively) and TVC (F = 34.2, 46.4, and 7.8 for PP [R2 = 0.98], VP [R2 = 0.89], and MAP [R2 = 0.85], respectively). The results of this study suggest that it is possible to use the E-nose technology to predict TVB-N and TVC for assessing the freshness of chilled pork during storage. PMID- 26954725 TI - Copper-Catalyzed Intermolecular Hydroamination of Internal Alkynes with Anilines and Amines. AB - The copper-catalyzed regioselective intermolecular hydroamination of the aryl and trifluoromethyl group or electron-withdrawing group substituted internal alkynes with amines has been accomplished. The reaction was effectively catalyzed by the ligand-free Cu(OTf)2 and afforded the intended amine derivatives in good yields after treatment of NaBH3CN. PMID- 26954726 TI - Chemosignalling effects of human tears revisited: Does exposure to female tears decrease males' perception of female sexual attractiveness? AB - Gelstein et al. reported the results of three experiments suggesting a dampening influence of inhalation of female emotional tears on males' arousal and perception of female sexual attractiveness, specifically in non-sexual situations. This prompted the hypothesis that crying exerts its influence on others not only via the auditory and visual mode but also via chemosignals. In three studies, we attempted to replicate and extend Gelstein et al.'s findings by including an additional condition with irritant tears, by using pictures of sexually attractive women, and by testing related hypotheses on the pro-social effects of exposure to tears. All three studies, separately or combined in a meta analysis, failed to replicate the original inhibitory effects of tears. In addition, sniffing tears did not affect measures of connectedness, aggression and pro-social behaviour. It is concluded that the effects of female tears on male arousal and perception of female sexual attractiveness, if any, are very weak at best. Rather, it seems that crying exerts its strong inter-personal effects through the visual and auditory sensory channels. PMID- 26954727 TI - Modeling infection transmission in primate networks to predict centrality-based risk. AB - Social structure can theoretically regulate disease risk by mediating exposure to pathogens via social proximity and contact. Investigating the role of central individuals within a network may help predict infectious agent transmission as well as implement disease control strategies, but little is known about such dynamics in real primate networks. We combined social network analysis and a modeling approach to better understand transmission of a theoretical infectious agent in wild Japanese macaques, highly social animals which form extended but highly differentiated social networks. We collected focal data from adult females living on the islands of Koshima and Yakushima, Japan. Individual identities as well as grooming networks were included in a Markov graph-based simulation. In this model, the probability that an individual will transmit an infectious agent depends on the strength of its relationships with other group members. Similarly, its probability of being infected depends on its relationships with already infected group members. We correlated: (i) the percentage of subjects infected during a latency-constrained epidemic; (ii) the mean latency to complete transmission; (iii) the probability that an individual is infected first among all group members; and (iv) each individual's mean rank in the chain of transmission with different individual network centralities (eigenvector, strength, betweenness). Our results support the hypothesis that more central individuals transmit infections in a shorter amount of time and to more subjects but also become infected more quickly than less central individuals. However, we also observed that the spread of infectious agents on the Yakushima network did not always differ from expectations of spread on random networks. Generalizations about the importance of observed social networks in pathogen flow should thus be made with caution, since individual characteristics in some real world networks appear less relevant than they are in others in predicting disease spread. Am. J. Primatol. 78:767-779, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26954728 TI - The roles of autophagy in vascular smooth muscle cells. AB - Autophagy, which is an evolutionarily conserved mechanism and links to several cellular pathways, impacts vascular smooth muscle cells (VSMCs) survival and function. Activation of autophagy by intercellular and/or extracellular stimuli has protective effects on VSMCs against cell death, while on the contrary, overloading autophagy has been recognized as a deleterious process by excessive self-digestion. Alterations in autophagy has been documented in VSMC in response to various stimuli, resulting in modulation of VSMC functions, including proliferation, migration, matrix secretion, contraction/relaxation, and differentiation. Each of these changes in VSMC functions plays a critical role in the development of vascular diseases. Importantly, emerging evidence demonstrates that autophagy deficiency in VSMCs would contribute to atherosclerosis and restenosis, shedding novel light on therapeutic target of the vascular disorders. Herein, this review summarizes the recent progress associated with the roles of autophagy in VSMC and offers the perspectives to several challenges and future directions for further studies. PMID- 26954729 TI - Genetically engineered plants in the product development pipeline in India. AB - In order to proactively identify emerging issues that may impact the risk assessment and risk management functions of the Indian biosafety regulatory system, the Ministry of Environment, Forests and Climate Change sought to understand the nature and diversity of genetically engineered crops that may move to product commercialization within the next 10 y. This paper describes the findings from a questionnaire designed to solicit information about public and private sector research and development (R&D) activities in plant biotechnology. It is the first comprehensive overview of the R&D pipeline for GE crops in India. PMID- 26954730 TI - Illicit Cosmetic Silicone Injection: A Recent Reiteration of History. AB - The injection of liquid silicone for cosmetic augmentation has a history of both legal as well as illicit practice in the United States and worldwide. Recently, the American Society of Plastic Surgeons has launched a public awareness campaign through patient stories and various statements in response to the rise in deaths related to this illicit practice. A articular segment of the population that has become a target is the transgender patient group. A brief review is provided of the history of industrial liquid silicone injection, including the pathophysiology to fully describe and review silicone injection injury. Three cases of soft tissue cellulitis and wound necrosis treated at our institution are summarized and a treatment algorithm proposed based on literature review of treatment options and our own experience. PMID- 26954731 TI - The Clinical Application of Preexpanded and Prefabricated Super-Thin Skin Perforator Flap for Reconstruction of Post-Burn Neck Contracture. AB - OBJECTIVE: Based on our previous animal study, we applied the "bridging effect" to the neighboring axial flap through preexpansion and prefabrication of a skin perforator flap as a new method to reconstruct a large skin defect after release of severe neck burn scar contracture. METHODS: Twelve patients suffering from severe post-burn cervical contractures underwent reconstruction of large skin defects after surgical release of severe scar contractures with preexpanded and prefabricated super-thin skin perforator flaps supplied primarily by a number of perforators via the "bridging effect" from the branches of the adjacent arteries as 2-stage procedures. During the first-stage operation, 2 tissue expanders were placed accordingly, and this was followed by a subsequent second-stage procedure where an expanded super-thin skin perforator flap was transposed to reconstruct a large neck skin defect. Follow-up was between 6 months and 3 years in this series. RESULTS: All super-thin skin perforator flaps survived in this series with primary healing except one with a distal flap necrosis that was treated with a subsequent skin graft. All patients have had a good contour with improved range of motion in the neck. CONCLUSIONS: The preexpansion and prefabrication of a super-thin skin perforator flap can possibly improve the anastomoses between neighboring subdermal vascular plexuses and extend the supplying area of these vessels to the flap. This method may provide a favorable super-thin skin flap that can be used for reconstruction of large neck defects after release of post burn cervical scar contracture as demonstrated in this case series. PMID- 26954732 TI - Barbed Suture as a Treatment Approach in Complex Degloving Injuries. AB - In the late 19th century, French physician Morel-Lavallee was challenged with a group of patients who sustained similar patterns of degloving injuries, which today carry his eponym. In 1853, he reported a series of cases as well as proposed strategies for the management of these complex degloving injuries. Treatment strategies have not varied significantly over the years, and these lesions continue to plague surgeons today with failure rates in excess of 50%. We present 2 case series using barbed suture in the management of these complex injuries. PMID- 26954733 TI - Conditioned Media From Adipose-Derived Stromal Cells Accelerates Healing in 3 Dimensional Skin Cultures. AB - Wound healing involves a number of factors that results in the production of a "closed" wound. Studies have shown, in animal models, acceleration of wound healing with the addition of adipose-derived stromal cells (ADSC). The cause for the positive effect which these cells have on wound healing has not been elucidated. We have previously shown that addition of ADSC to the dermal equivalent in 3-dimensional skin cultures accelerates reepithelialization. We now demonstrate that conditioned media (CM) from cultured ADSC produced a similar rate of healing. This result suggests that a feedback from the 3-dimensional epithelial cultures to ADSC was not necessary to effect the accelerated reepithelialization. Mass spectrometry of CM from ADSC and primary human fibroblasts revealed differences in secretomes, some of which might have roles in the accelerating wound healing. Thus, the use of CM has provided some preliminary information on a possible mode of action. PMID- 26954735 TI - Abdominal Bulge After Retroperitoneal Dissection: The Definitive Management Using Bone Anchored Mesh. AB - BACKGROUND: Abdominal bulge after retroperitoneal dissection occurs at a rate of 1% to 56%. Injury to the T11 and T12 nerves is thought to result in abdominal musculature denervation, laxity, and symptomatic abdominal bulge. This complication has become more prevalent because the retroperitoneal approach for spinal surgery has become the preferred approach in specific lumbar and thoracic cases. Current repair techniques fail to address the etiology of abdominal wall laxity, and outcomes are poorly reported. Recurrence rates in lateral abdominal bulge repair are reported between 0% and 100%, and the complication rate is nearly 25%. We present a method of bone anchored fixation of mesh for abdominal wall reinforcement after the imbrication of the atrophied musculature, resulting in the definitive treatment of abdominal bulge after retroperitoneal dissection. METHODS: A retrospective review of 4 consecutive patients who underwent bony fixation of mesh using Mitek suture anchors (De Puy, Raynham, MA) for abdominal bulge after retroperitoneal dissection between February 2013 and September 2014 was performed. The preoperative, intraoperative, and postoperative records of 4 patients were reviewed and compared. RESULTS: There were no reported early recurrences and no perioperative morbidity or mortality related to the operation. Average follow-up was 12.8 months (range, 6-26 months); operative time, 157 minutes; postoperative length of stay, 3.5 days; and estimated blood loss was 50 mL. CONCLUSIONS: Reinforcement of the myofascial repair using bone anchored fixation of mesh represents a novel approach for the treatment of abdominal bulge after retroperitoneal dissection. Results demonstrate safety and no early recurrence. PMID- 26954734 TI - Refinements in the Techniques of 2-Stage Breast Reconstruction. AB - BACKGROUND: Two-stage breast reconstruction with tissue expanders is one of the most common plastic surgery procedures. Acellular dermal matrix (ADM) has become popular for its ability to improve expansion parameters and aesthetics, albeit with a higher complication profile. We present data that support redefining 2 stage reconstruction to include tissue expanders regardless of final reconstructive modality to act as a bridge. Furthermore, we show that cooperation with the ablative surgeon and technical refinements support ADM omission from the first stage of reconstruction. METHODS: We retrospectively reviewed charts from the senior author's (D.A.J.) private practice over a 10-year follow-up period. Inclusion criteria included all women over 18 years who underwent mastectomy and had a tissue expander placed immediately or in a delayed fashion and successfully completed tissue expansion and are finished with the second stage of reconstruction or awaiting second stage of reconstruction. Demographic data, tissue expander filling data, final reconstruction, aesthetic outcome, and complications were tabulated. RESULTS: A total of 118 women (165 breasts) met inclusion criteria. There were no statistically significant differences in initial fill volume (P = 0.094), number of visits until final expansion (P = 0.677), or final fill volume (P = 0.985) between the ADM and non-ADM cohorts. In addition, non-ADM patients had superior aesthetic scores with respect to defects other than scarring (P = 0.015), projection (P = 0.013), and inframammary fold quality (P = 0.009). Fifteen percent of women decided to change desired final reconstruction modality during the tissue expansion phase. CONCLUSIONS: This reconstructive algorithm emphasizes surgical cooperation between the ablative and reconstructive surgeon, improved technique, and patient education. This focus translates into maintained tissue expansion, aesthetically pleasing results, and allows for the omission of ADM from reconstruction. PMID- 26954736 TI - Double-Chamber Tissue Expanders Optimize Lower Pole Expansion in Immediate Breast Reconstruction Requiring Adjuvant Radiation Therapy. AB - INTRODUCTION: Tissue expander-based reconstruction in the irradiated breast has been associated with significant complications, including infection, skin breakdown and implant extrusion, and poor aesthetic outcome. These complications may be attributed to inadequate lower pole expansion causing increased pressure on the suture line. Achieving and maintaining adequate lower pole expansion in the reconstructed breast requiring adjuvant radiation therapy may reduce the pressure/strain on the suture line and preserve the natural appearance of the breast. We describe the effective use of a double-chamber tissue expander to control lower pole expansion in immediate breast reconstruction requiring adjuvant radiation therapy. METHODS: We performed a retrospective chart review of patients who underwent postoperative radiation therapy after immediate breast reconstruction using Sientra's double-chamber tissue expander, performed by a single plastic surgeon from 2012 to 2014. RESULTS: A total of 22 patients met our inclusion criteria. Seventeen patients had bilateral, and 5 patients had unilateral reconstruction (n = 39 total breasts). All patients were over expanded by 20% on the side affected by cancer before the start of radiation, which started by the sixth postoperative week. There was no expansion during radiation therapy. Two patients had further expansion after radiation therapy was completed. The tissue expanders were exchanged for shaped silicone gel implants 3 to 4 months after completion of radiation. A total of 2 complications occurred in 2 patients (9.0%) and 2 breasts (5.1%). These included an infection in one patient and a tissue expander leak in another. No patient developed Baker grade 3 or 4 capsular contracture, seroma, or device malposition. Good lower pole contour and projection was maintained in all breasts at 9 to 12 months of follow-up. CONCLUSIONS: The double-chamber tissue expander is effective in controlling shape, contour, and position of the breast following immediate tissue expander reconstruction requiring adjuvant radiation therapy, with decreased complication rates compared to standard expanders. These results suggest that double-chamber tissue expanders may be the preferred expander option in patients requiring adjuvant radiation therapy. Prospective clinical studies are needed to better evaluate the advantages of this reconstructive approach. PMID- 26954737 TI - Optimizing Safety, Predictability, and Aesthetics in Direct to Implant Immediate Breast Reconstruction: Evolution of Surgical Technique. AB - BACKGROUND: Although immediate breast reconstruction with the insertion of a permanent prosthesis rather than a tissue expander (direct to implant [DTI]) has become gradually more preferred and requested by patients, the technique has yet to be fully embraced by most plastic surgeons, presumably due to concerns of patient safety and perceived higher complication and revision rates, despite not being supported by the literature. OBJECTIVES: The authors review the senior author's protocol for patient selection and surgical technique in DTI reconstructions. A simple device is introduced which adds predictability and control in determining the inset suture line for the acellular dermal matrix and thus the position of the inframammary fold and lateral mammary fold, resulting in improved aesthetic outcomes, reduced complications, and reduced reoperation rates. METHODS: A retrospective review of our one surgeon experience with 134 DTI breast reconstructions in 77 patients between 2006 and 2015 is presented. The series is further subdivided into 74 reconstructions in 43 patients in whom their reconstruction was performed before the use of a patented 2-dimensional (2-D) template, and 60 reconstructions in 34 patients in whom the template was used. RESULTS: The overall complication rate requiring reoperation in the first 54 reconstructions was 50% versus 15% in the last 84. Failure of the reconstruction, defined by explantation, occurred in 11 of 74 reconstructions (14.9%) before the use of 2-D templates, and in 5 of 60 reconstructions (8.3%) in which templates were used, representing a 44% reduction. The revision rate specifically for implant malposition dropped from 18.6% before the use of templates to 2.9% after the incorporation of templates. Fifty-three reconstructions in 33 patients (40%) had no complications and no reoperations, correctly described as "one and done." CONCLUSIONS: Direct to implant reconstruction can be technically more demanding and exacting than 2-stage expander/implant reconstructions. A review of this single surgeon series confirms that despite a learning curve with a higher complication rate early in the series, in the setting of proper patient selection DTI immediate reconstruction is both safe and reliable, and can potentially have clinical, psychological, and aesthetic advantages for patients when compared with a 2-stage expander/implant reconstruction, with 40% of patients having 1 operation only. The use of a patented 2-D template has reduced complications and the rate of reoperation. PMID- 26954738 TI - Resorbable Construct for Subtotal Cranial Vault Remodeling. AB - INTRODUCTION: Pansynostosis can result in markedly thin calvarial bone resulting in poor quality and quantity of allograft for cranial vault expansion. Such scenarios can result in large calvarial defects and poorly stabilized constructs. Additionally, the osteoinductive properties of neonatal dura and paracranium in cranial vault reconstruction suggest the possibility of reconstructing extensive calvarial defects using minimal native calvarium given the appropriate scaffold. We report a case of subtotal cranial vault remodeling involving greater than 50% of the cranial vault using a custom poly DL lactic acid (Sonic Weld) resorbable plate construct and underlay calvarial bone grafting. METHODS: A 4-month-old male infant presented with a diagnosis of Cruzon syndrome and pansynostosis. Staged reconstruction was performed with the initial stage involving the posterior and middle cranial vault. Given the severity of the deformity, the native cranial bone was thinned with multiple defects such that it could not be used to provide structural integrity or sufficient surface coverage for cranial vault reconstruction. Useable bone comprised only a fraction of the surface area required to expand the posterior and midcranium. Resorbable poly DL lactic acid (Sonic Weld) plates were used to create a custom construct for reconstruction of the posterior and middle cranial vault. The construct was then seeded with usable fragments of the native calvarium and secured to the cranial base with resorbable pins. RESULTS: The construct resulted in maintained cranial shape throughout the postoperative period. Postoperative computed tomography imaging demonstrated osteogenesis throughout the construct with bridging of the fragmented calvarial grafts. Examination of the construct during anterior cranial vault remodeling demonstrated near complete resorption of the construct, stable posterior cranial vault, and minimal dural adhesions to the posterior cranium. At 11 months postoperatively, the patient continues to demonstrate appropriate cranial expansion and maintenance of posterior cranial shape. CONCLUSIONS: Fully resorbable constructs can provide effective structural support and a scaffold for osteogenisis in conjunction with minimal native calvarial bone grafts during reconstruction of large cranial vault defects in the infantile period. PMID- 26954740 TI - Evaluation Indicators of Aesthetic Effects on Hair Transplantation. AB - Hair transplantation involves the transplantation of hair, beard, eyebrows, eyelashes, and pubic hair. Based on our experience, the aesthetic result of hair transplantation mainly relies on 4 indicators, including selection of the donor site, direction and angle of grafted hairs, density, and survival rate of implanted hair follicles. We believe that good results can be achieved as long as attention is paid to the above 4 points. PMID- 26954739 TI - Should We Excise Native Breast Skin Envelope to Achieve Symmetric Scars in Bilateral Autologous Breast Reconstruction?--A Survey of Surgeon and Patient Preference. AB - BACKGROUND: Given the multiple possible scar patterns in autologous breast reconstruction and combinations of such patterns in bilateral reconstruction, the present study aimed to determine the importance of scar symmetry in achieving aesthetically pleasing results. METHODS: A survey was administered to 128 participants including plastic surgeons and female breast reconstruction patients. In part A of the survey, participants were provided with photos of bilateral autologous breast reconstructions, and scar placement was varied to represent bilateral (1) immediate, (2) delayed symmetric, (3) delayed asymmetric, and (4) a mixture of immediate and delayed free flap reconstructions. Participants were asked to rank the photos in order of best to worst aesthetic outcome. In part B, pairs of the same reconstruction before and after nipple areolar complex (NAC) reconstruction were presented, and participants were asked to assign a score to each photo according to aesthetic outcome. RESULTS: In part A, immediate reconstructions that included the smallest flap skin paddles ranked best among 52.5% +/- 30% of participants, followed by delayed symmetric reconstructions that ranked best in 46.7% +/- 29.6%. Mixed reconstructions ranked worst among 53.6% +/- 37.6% of participants, followed by delayed asymmetric reconstructions (42.5% +/- 37.9%). When NAC reconstruction was added to 1 set of the photos in part A, the same immediate reconstruction was ranked best, a significantly higher proportion of the time (36.3% increase, P < 0.001). This was accompanied by a significant decrease in top ranking for the delayed symmetric reconstruction (37.9% decrease, P < 0.001). In part B, addition of NAC increased each reconstruction's score by an average of 1.36 points on a 5-point scale with patients citing less improvement between the conditions (0.93 +/- 0.03) than plastic surgeons (1.13 +/- 0.49) (P = 0.03). CONCLUSIONS: More symmetric breast scars led to higher aesthetic ranking of bilateral autologous breast reconstructions. Participants in our survey preferred symmetric scars, even if achieving such a scar pattern would require excision of native breast skin and inclusion of more flap skin. Furthermore, NAC reconstruction alone improves aesthetic outcome, and improvement was most notable among immediate reconstructions. PMID- 26954741 TI - Price Transparency in the Online Age. AB - Plastic surgeons are sometimes hesitant to provide their pricing information online, due to several concerns. However, if implemented right, price transparency can be used as a lead generation tool that provides consumers with the pricing information they want and gives the physician the consumer's contact information for follow-up. This study took place during the author's first year in private practice in a new city. An interactive price transparency platform (ie, cost estimator) was integrated into his website, allowing consumers to submit a "wishlist" of procedures to check pricing on these procedures of interest. However, the consumer must submit their contact information to receive the desired breakdown of costs that are tailored based on the author's medical fees. During that first year, without any advertising expenditure, the author's website received 412 wishlists from 208 unique consumers. Consumers (17.8%) that submitted a wishlist came in for a consultation and 62% of those booked a procedure. The average value of a booked procedure was over US $4000 and cumulatively, all of the leads from this one lead source in that first year generated over US $92,000 in revenue. When compared with non-price-aware patients, price-aware patients were 41% more likely to book a procedure. Price transparency led to greater efficiency and reduced consultations that ended in "sticker shock." When prudently integrated into a medical practice, price transparency can be a great lead generation source for patients that are (1) paying out of pocket for medically necessary services due to a high-deductible health plan or (2) paying for services not typically covered by insurance, such as cosmetic services. PMID- 26954742 TI - Improvement of Split Skin Graft Quality Using a Newly Developed Collagen Scaffold as an Underlayment in Full Thickness Wounds in a Rat Model: Reply. PMID- 26954743 TI - Improvement of Split Skin Graft Quality Using a Newly Developed Collagen Scaffold as an Underlayment in Full Thickness Wounds in a Rat Model. PMID- 26954744 TI - The Modified Z-Epicanthoplasty-A Stepwise and Individualized Design. AB - PURPOSE: To describe a medial epicanthoplasty technique using a stepwise, customized design and to review the outcome in Asian patients after the treatment of medial epicanthal fold. DESIGN: Retrospective, noncomparative and interventional case series with the introduction of a new surgical technique. PARTICIPANTS: Forty-eight consecutive Asian patients with primary medial epicanthal fold. METHODS: Patient charts were reviewed from patients (mean age, 24.6 +/- 3.8 years; range, 19-40 years) with a stepwise z-epicanthoplasty. The intercanthal distance (ICD), interpupillary distance (IPD), and scar visibility were evaluated at regular intervals (preoperative, immediate postoperative, 3 months, 6 months, and 1 year after the operation). The ratio of the ICD to IPD (ICD ratio) was calculated, and the visibility of the surgical scar assessed. MAIN OUTCOME MEASURES: Postoperative improvement in ICD ratio and scar quality. RESULTS: The preoperative median ICD ratio was 0.60 (range, 0.57-0.66) and decreased to 0.57 (range, 0.52-0.60) postoperatively. The median ICD ratio reduction was 5.6% (range, 2.6-14.1%; P < 0.001, Wilcoxon signed-rank test). Forty patients (83.3%) had no visible scarring or scarring only visible under close inspection. Eight patients (16.7%) experienced a more apparent scar, but none of them developed a severe scar requiring revision. CONCLUSIONS: The modified z-epicanthoplasty using a stepwise design is a customized and effective technique for the treatment of the epicanthal fold. This method has a short learning curve, is widely applicable to various types of epicanthal fold, and has a high satisfaction rate with a stable long-term result. PMID- 26954745 TI - Fifth Dedicated CSPS Issue of Annals of Plastic Surgery. PMID- 26954746 TI - A Time Study of Plastic Surgery Residents. AB - BACKGROUND: Resident work hours are under scrutiny and have been subject to multiple restrictions. The studies supporting these changes have not included data on surgical residents. We studied the workday of a team of plastic surgery residents to establish prospective time-study data of plastic surgery (PRS) residents at a single tertiary-care academic medical center. METHODS: Five trained research assistants observed all residents (n = 8) on a PRS service for 10 weeks and produced minute-by-minute activity logs. Data collection began when the team first met in the morning and continued until the resident being followed completed all non-call activities. We analyzed our data from 3 perspectives: 1) time spent in direct patient care (DPC), indirect patient care, and didactic activities; 2) time spent in high education-value activities (HEAs) versus low education-value activities; and 3) resident efficiency. We defined HEAs as activities that surgeons must master; other activities were LEAs. We quantified resident efficiency in terms of time fragmentation and time spent waiting. RESULTS: A total of 642.4 hours of data across 50 workdays were collected. Excluding call, residents worked an average of 64.2 hours per week. Approximately 50.7% of surgical resident time was allotted to DPC, with surgery accounting for the largest segment of this time (34.8%). Time spent on HEAs demonstrated trended upward with higher resident level (P = 0.086). Time in spent in surgery was significantly associated with higher resident levels (P < 0.0001); 57.7% of activities require 4 minutes or less, suggesting that resident work was highly fragmented. Residents spent 10.7% of their workdays waiting for other services. CONCLUSIONS: In this first-time study of PRS residents, we found that compared with medicine trainees, surgical residents spent 3.23 times more time on DPC. High education-value activities comprised most of our residents' workdays. Surgery was the leading component of both DPC and HEAs. Our residents were highly efficient and fragmented, with the majority of all activities requiring 4 minutes or less. Residents spent a large portion of their time waiting for other services. In light of these data, we suggest that future changes to residency programs be pilot tested, with preimplantation and postimplementation time studies performed to quantify the changes' impact. PMID- 26954747 TI - Maximizing the Reach of the Pedicled Gastrocnemius Muscle Flap: A Comparison of 2 Surgical Approaches. AB - BACKGROUND: The medial gastrocnemius muscle flap is commonly used for the reconstruction of defects around the knee and proximal leg. The flap can be raised using either a medial or a posterior midline incision, although no studies have been done comparing the 2 different surgical approaches. METHODS: We compared the reach of the medial gastrocnemius muscle flap using either of the 2 incisions in a series of 25 fresh cadavers. All muscle flaps were elevated without division of the muscle origin. Muscle reach was calculated using the distance from a fixed bony point with the leg fully extended and the muscle under no tension. Muscle width measurements were used to calculate surface area of coverage. RESULTS: Muscle flaps elevated through the posterior midline incision group reached 2.02 cm farther than flaps through the medial incision (P < 0.05). This resulted in 20.3 cm increase in surface area for the posterior midline incision group over the medial incision group (P < 0.05). The posterior midline incision allowed for better visualization of the vascular pedicle and dissection of fascial attachments around the pes anserinus. CONCLUSIONS: The posterior midline incision for the elevation of the medial gastrocnemius pedicled muscle flap allows for a safe, thorough mobilization of the muscle resulting in increased muscle reach and increased surface area when compared with the medial incision. Furthermore, the posterior midline incision provides better access to the gastrocnemius muscle origin and the lateral muscle head. PMID- 26954748 TI - Tamoxifen-Related Thrombosis: An Experimental Study in Rat Venous Microvascular Anastomosis Model. AB - Tamoxifen is an estrogen receptor modulator and has been shown to increase risk for microvascular flap complications. This study aimed to investigate the clinical and histopathological effects of tamoxifen use in venous microvascular anastomosis model in rats. The role of vitamin E combination therapy and discontinuing tamoxifen therapy preoperatively were also evaluated.Forty rats were equally divided into 4 groups as follows: group 1 was given saline by oral gavage, group 2 was given tamoxifen citrate, group 3 was given tamoxifen citrate and vitamin E, and in group 4, tamoxifen citrate was given everyday except between days 12 and 16. In each group, femoral veins were dissected in each side and end-to-end anastomosis was performed in one side. Clinical and histopathological evaluations were performed. The ratio of total endothelial area to total vein area in a cross-sectional view of the vein was evaluated and compared.All veins with anastomosis in postoperative 15 minutes were found to be patent. In postoperative 1 week in groups 1 to 4, visible thrombus were present in 1, 3, 2, and 3 samples, respectively. Vitamin E group showed similar histopathological findings with control group. The ratio of endothelial layer to total vein cross-sectional area was increased in groups 2 and 4 in all samples. The increase was statistically significant between groups 2NA and 3NA (P = 0.023) and 2A and 1A (P = 0.006).Chronic tamoxifen consumption in the presence of anastomosis have led to prominent endothelial proliferation in rat femoral veins. Vitamin E combination therapy reversed this endothelial proliferation and should be focused in future studies. PMID- 26954749 TI - Analysis of Extended Deep Fat Pad Excision in Abdominoplasty. AB - BACKGROUND: Because abdominoplasty flap's major vascularization is suprafascial, some surgeons perform excision of the deep fat pad below Scarpa's fascia to achieve a better abdominal contour and balance the lower abdominal projection above and below the scar. The dimensions of this excised adipose flap and its correlations to both the classic abdominoplasty flap and patient biometrics have not been studied yet and are the aim of this article. Short-term complication outcomes are also reported. METHODS: We performed a prospective case series study, operating 74 consecutive women using an otherwise standard abdominoplasty technique, and recorded patient variables, flap dimensions, and complications. RESULTS: Average values are as follows: BMI, 27.35 kg/m; total flap weight, 1868 g; adipose flap weight, 157 g (corresponding to 9% extra flap weight); adipose flap height, 7.2 cm; and preserved infraumbilical deep fat pad thickness, 7.7 mm. Statistical analysis of correlations between variables was performed. CONCLUSIONS: Increased patient weight, umbilical perimeter, BMI, and width of the operative specimen can be used to predict a heavier extra adipose flap. The extra fat excision is safe, preventing inadvertent invasion of the abdominoplasty flap's suprafascial plane that can happen with liposuction. No flap necroses were observed. The use of this technique may prove useful to achieve a slimmer abdominal contour and harmonize it with the pubic region. PMID- 26954750 TI - Central Pedicle Reduction in Gigantomastia Without Free Nipple Graft. AB - BACKGROUND: Various pedicle techniques have been described in breast reduction surgery. However, in cases of massive hypertrophy, the free nipple graft technique is still being performed by some surgeons out of fear of losing the nipple-areolar complex (NAC). As such, we evaluated patients with severe gigantomastia who underwent the central pedicle horizontal scar reduction mammaplasty technique. METHODS: The records of 257 patients who underwent the central pedicle reduction technique were retrospectively reviewed. The demographic properties of the patients and the distances from the midclavicular point to the nipple were recorded. Patients whose distance from the midclavicular point to both nipple areolar complexes (NACs) was 38 cm or greater were included in this study. Resection weights and postoperative complications were evaluated. RESULTS: The distance from the midclavicular point to both NACs was 38 cm or greater in 53 patients (106 breasts). The age range of the patients was 17 to 73 years, and the mean body mass index was 39.6 kg/m. The range of distances from the midclavicular point to the nipple was 38 to 52 cm. The weight of the breast tissue excised ranged between 1450 and 2785 g. None of the patients experienced total nipple loss postoperatively, and all of the patients were satisfied with the aesthetic results. CONCLUSION: We were able to reduce all of the breasts safely, without using the free nipple grafting technique, even in very large breasts. This study shows that the central pedicle horizontal scar reduction technique is a very safe and effective method for use in massive reductions. Therefore, we strongly recommend using the central pedicle reduction mammaplasty technique in cases of gigantomastia. PMID- 26954751 TI - Highly crystalline covalent organic frameworks from flexible building blocks. AB - Two novel 2D covalent organic frameworks (TPT-COF-1 and TPT-COF-2) were synthesized from the flexible 2,4,6-triaryloxy-1,3,5-triazine building blocks on a gram scale, which show high crystallinity and large surface area. The controllable formation of highly ordered frameworks is mainly attributed to the self-assembly Piedfort unit of 2,4,6-triaryloxy-1,3,5-triazine. PMID- 26954752 TI - Probing the reactivity of pentaphenylborole with N-H, O-H, P-H, and S-H bonds. AB - The reactions of molecules containing E-H functionalities (E = Group 15 or 16 element) and pentaphenylborole were investigated revealing diverse outcomes. For aniline and water, protodeborylation ring opening reactions occurred via the N-H or O-H bonds. Pentaphenylborole reacted with water in a 1 : 1 or 2 : 1 ratio to yield the corresponding boroxane and diboroxane, respectively, whereas aniline reacted strictly in a 1 : 1 ratio. Interestingly, 1-naphthalenethiol reacted to produce a 1-bora-cyclopent-3-ene heterocycle. The reaction with a primary phosphine generated an adduct which was resilient, even at elevated temperatures. DFT calculations provide support for the observed reaction products, and identify the initial adduct as a key intermediate in determining the final product. In particular, ring opening may be linked to the lability of the hydrogen in the initial adduct. Collectively, these reactions provide insight into new reaction pathways, the stability of boroles, as well as mechanistic insight into previously reported transformations. PMID- 26954753 TI - Exploring Aboriginal patients' experiences of cardiac care at a major metropolitan hospital in Melbourne. AB - Objectives The aim of the present study was to explore Aboriginal patients' lived experiences of cardiac care at a major metropolitan hospital in Melbourne. Methods The study was a qualitative study involving in-depth interviews with a purposive sample of 10 Aboriginal patients who had been treated in the cardiology unit at the study hospital during 2012-13. A phenomenological approach was used to analyse the data. Results Eight themes emerged from the data, each concerning various aspects of participants' experiences: 'dislike of hospitals', 'system failures', 'engagement with hospital staff', 'experiences of racism', 'health literacy and information needs', 'self-identifying as Aboriginal', 'family involvement in care' and 'going home and difficulties adapting'. Most participants had positive experiences of the cardiac care, but hospitalisation was often challenging because of a sense of dislocation and disorientation. The stress of hospitalisation was greatly mediated by positive engagements with staff, but at times exacerbated by system failures or negative experiences. Conclusion Cardiac crises are stressful and hospital stays were particularly disorienting for Aboriginal people dislocated from their home land and community. What is known about the topic? Aboriginal people have higher mortality rates due to cardiovascular diseases compared with other Australians. Along with different factors contributing to the life expectancy gap, Aboriginal people also face significant barriers in the use of the healthcare system. What does this paper add? Aboriginal patients' lived experience of cardiac care at a major metropolitan hospital in Melbourne is explored in this paper. Different issues were revealed during their interaction with the hospital staff and the hospital system in conjunction with their cultural aspect of patient care. What are the implications for practitioners? Positive interactions with staff, ongoing support from family and community, culturally appropriate cardiac rehabilitation programs can improve the cardiac care experiences of Aboriginal patients. PMID- 26954754 TI - Motion-free endoscopic system for brain imaging at variable focal depth using liquid crystal lenses. AB - We present a motion-free system for microendoscopic imaging of biological tissues at variable focal depths. Fixed gradient index and electrically tunable liquid crystal lenses (TLCL) were used to build the imaging optical probe. The design of the TLCL enables polarization-independent and relatively low-voltage operation, significantly improving the energy efficiency of the system. A focal shift of approximately 74 +/- 3 um could be achieved by electrically controlling the TLCL using the driving frequency at a constant voltage. The potential of the system was tested by imaging neurons and spines in thick adult mouse brain sections and in vivo, in the adult mouse brain at different focal planes. Our results indicate that the developed system may enable depth-variable imaging of morpho-functional properties of neural circuitries in freely moving animals and can be used to investigate the functioning of these circuitries under normal and pathological conditions. PMID- 26954759 TI - Improved sensitivity for determining thiobarbituric acid reactive substances in ground beef. AB - To create expected differences in oxidation ground beef samples from grass-fed and grain-fed animals were utilized in six differing percentages with 4 different packaging types. Percentages of grass-fed and grain-fed ground beef (GB) consisted of 100% grain fed GB; 80% grain-fed: 20% grass-fed GB; 60% grain-fed: 40% grass-fed GB; 40% grain-fed: 60% grass-fed GB; 20% grain-fed: 80% grass-fed GB; and 100% grass-fed GB. Packaging treatments included: high oxygen (HO; 80% O2: 20% CO2), low oxygen (LO; 65% N2: 35% CO2), carbon monoxide (CO; 65% N2: 34.6% CO2: 0.4% CO), and overwrap (OV; polyvinyl chloride film wrapped over a styrofoam tray). The modified TBARS method showed greater sensitivity and increased differences between treatments with less variability. The original extraction method showed fewer differences between treatments with greater variability. Data suggest that the modified method of TBARS determination could provide researchers with a better assay to find differences while decreasing the amount of labor. PMID- 26954758 TI - Silencing Status Epilepticus-Induced BDNF Expression with Herpes Simplex Virus Type-1 Based Amplicon Vectors. AB - Brain-derived neurotrophic factor (BDNF) has been found to produce pro- but also anti-epileptic effects. Thus, its validity as a therapeutic target must be verified using advanced tools designed to block or to enhance its signal. The aim of this study was to develop tools to silence the BDNF signal. We generated Herpes simplex virus type 1 (HSV-1) derived amplicon vectors, i.e. viral particles containing a genome of 152 kb constituted of concatameric repetitions of an expression cassette, enabling the expression of the gene of interest in multiple copies. HSV-1 based amplicon vectors are non-pathogenic and have been successfully employed in the past for gene delivery into the brain of living animals. Therefore, amplicon vectors should represent a logical choice for expressing a silencing cassette, which, in multiple copies, is expected to lead to an efficient knock-down of the target gene expression. Here, we employed two amplicon-based BDNF silencing strategies. The first, antisense, has been chosen to target and degrade the cytoplasmic mRNA pool of BDNF, whereas the second, based on the convergent transcription technology, has been chosen to repress transcription at the BDNF gene. Both these amplicon vectors proved to be effective in down-regulating BDNF expression in vitro, in BDNF-expressing mesoangioblast cells. However, only the antisense strategy was effective in vivo, after inoculation in the hippocampus in a model of status epilepticus in which BDNF mRNA levels are strongly increased. Interestingly, the knocking down of BDNF levels induced with BDNF-antisense was sufficient to produce significant behavioral effects, in spite of the fact that it was produced only in a part of a single hippocampus. In conclusion, this study demonstrates a reliable effect of amplicon vectors in knocking down gene expression in vitro and in vivo. Therefore, this approach may find broad applications in neurobiological studies. PMID- 26954760 TI - Sequential model selection-based segmentation to detect DNA copy number variation. AB - Array-based CGH experiments are designed to detect genomic aberrations or regions of DNA copy-number variation that are associated with an outcome, typically a state of disease. Most of the existing statistical methods target on detecting DNA copy number variations in a single sample or array. We focus on the detection of group effect variation, through simultaneous study of multiple samples from multiple groups. Rather than using direct segmentation or smoothing techniques, as commonly seen in existing detection methods, we develop a sequential model selection procedure that is guided by a modified Bayesian information criterion. This approach improves detection accuracy by accumulatively utilizing information across contiguous clones, and has computational advantage over the existing popular detection methods. Our empirical investigation suggests that the performance of the proposed method is superior to that of the existing detection methods, in particular, in detecting small segments or separating neighboring segments with differential degrees of copy-number variation. PMID- 26954761 TI - What happens when drivers face hazards on the road? AB - The current study aims to obtain knowledge about the nature of the processes involved in Hazard Perception, using measurement techniques to separate and independently quantify these suspected sub-processes: Sensation, Situation Awareness (recognition, location and projection) and decision-making. It applies Signal Detection Theory analysis to Hazard Perception and Prediction Tasks. To enable the calculation of Signal Detection Theory parameters, video-recorded hazardous vs. quasi-hazardous situations were presented to the participants. In the hazardous situations it is necessary to perform an evasive action, for instance, braking or swerving abruptly, while the quasi-hazardous situations do not require the driver to make any evasive manoeuvre, merely to carry on driving at the same speed and following the same trajectory. A first Multiple Choice Hazard Perception and Prediction test was created to measure participants' performance in a What Happens Next? Task. The sample comprised 143 participants, 47 females and 94 males. Groups of non-offender drivers (learner, novice and experienced) and offender drivers (novice and experienced) were recruited. The Multiple Choice Hazard Perception and Prediction test succeeded in finding differences between drivers according to their driving experience. In fact, differences exist with regard to the level of hazard discrimination (d' prime) by drivers with different experience (learner, novice and experienced drivers) and profile (offenders and non-offenders) and these differences emerge from Signal Detection Theory analysis. In addition, it was found that experienced drivers show higher Situation Awareness than learner or novice drivers. On the other hand, although offenders do worse than non-offenders on the hazard identification question, they do just as well when their Situation Awareness is probed (in fact, they are as aware as non-offenders of what the obstacles on the road are, where they are and what will happen next). Nevertheless, when considering the answers participants provided about their degree of cautiousness, experienced drivers were more cautious than novice drivers, and non-offender drivers were more cautious than offender drivers. That is, a greater number of experienced and non offender drivers chose the answer "I would make an evasive manoeuvre such as braking gradually". PMID- 26954762 TI - The influence of daily sleep patterns of commercial truck drivers on driving performance. AB - Fatigued and drowsy driving has been found to be a major cause of truck crashes. Lack of sleep is the number one cause of fatigue and drowsiness. However, there are limited data on the sleep patterns (sleep duration, sleep percentage in the duration of non-work period, and the time when sleep occurred) of truck drivers in non-work periods and the impact on driving performance. This paper examined sleep patterns of 96 commercial truck drivers during non-work periods and evaluated the influence these sleep patterns had on truck driving performance. Data were from the Naturalistic Truck Driving Study. Each driver participated in the study for approximately four weeks. A shift was defined as a non-work period followed by a work period. A total of 1397 shifts were identified. Four distinct sleep patterns were identified based on sleep duration, sleep start/end point in a non-work period, and the percentage of sleep with reference to the duration of non-work period. Driving performance was measured by safety-critical events, which included crashes, near-crashes, crash-relevant conflicts, and unintentional lane deviations. Negative binomial regression was used to evaluate the association between the sleep patterns and driving performance, adjusted for driver demographic information. The results showed that the sleep pattern with the highest safety-critical event rate was associated with shorter sleep, sleep in the early stage of a non-work period, and less sleep between 1 a.m. and 5 a.m. This study also found that male drivers, with fewer years of commercial vehicle driving experience and higher body mass index, were associated with deteriorated driving performance and increased driving risk. The results of this study could inform hours-of-service policy-making and benefit safety management in the trucking industry. PMID- 26954763 TI - Pathologic deposition of non-amyloid immunoglobulin in the brain leading to mass effect and neurological deficits. AB - We report a 31-year-old man with multiple large, non-enhancing intracerebral lesions exerting significant mass effect. Following debulking, histopathological analysis revealed abundant amorphous non-amyloid eosinophilic material, while liquid chromatography mass spectrometry revealed kappa light chains and immunoglobulin A heavy chains, leading to the diagnosis of multiple intracerebral light-and-heavy chain aggregomas. Localized intracranial deposits of non-amyloid immunoglobulin may rarely mimic space-occupying intracranial neoplasms and should be considered in the differential diagnosis. PMID- 26954764 TI - Paricalcitol attenuates lipopolysaccharide-induced myocardial inflammation by regulating the NF-kappaB signaling pathway. AB - Vitamin D deficiency is associated with an increased risk of cardiovascular disease, diabetes, colon and breast cancer, infectious diseases and allergies. Vascular alterations are an important pathophysiological mechanism of sepsis. Experimental data suggest that paricalcitol, a vitamin D2 analogue, exerts beneficial effects on renal inflammation and fibrosis. In the present study, we aimed to investigate the effects of paricalcitol on lipopolysaccharide (LPS) induced myocardial inflammation and to elucidate the underlying mechanisms. We used primary cultured human umbilical vein endothelial cells for in vitro experiments, in which stimulation with tumor necrosis factor (TNF)-alpha was used to induce endothelial cell inflammation. For in vivo experiments, myocardial inflammation was induced by an intraperitoneal injection of 15 mg/kg LPS into C57BL6 mice pre-treated with or without 0.2 ug/kg paricalcitol. Treatment with paricalcitol suppressed the TNF-alpha-induced increase in the protein expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and fractalkine in endothelial cells. Treatment with paricalcitol also decreased the TNF-alpha-induced nuclear factor (NF)-kappaB binding activity. In a mouse model of LPS-induced myocardial inflammation, pre-treatment with paricalcitol prevented the LPS-induced increase in the expression of myocardial ICAM-1, phosphorylated p65 and myocardial TNF-alpha. Pre-treatment with paricalcitol also alleviated endotoxemia-induced microvascular leakage in the myocardium. The findings of our study suggest that paricalcitol exerts a protective effect against LPS-induced myocardial inflammation by regulating the expression of cell adhesion molecules and TNF-alpha, and by improving myocardial permeability. PMID- 26954766 TI - Physical Fitness During Adolescence and Long-Term Risk for Type 2 Diabetes Mellitus. PMID- 26954767 TI - Brain Abscess Drainage in a Case of Uncorrected Tetralogy of Fallot Under Scalp Block and Dexmedetomidine. PMID- 26954765 TI - Cumulative Violence Exposures: Black Women's Responses and Sources of Strength. AB - Black women with cumulative violence exposures (CVE) may have unique needs for health care and safety. Qualitative data was analyzed from interviews with nine Black women with CVE to explore factors that motivated women to leave abusive relationships, women's sources of strengths, and their responses to abuse. Quantitative data (N = 163) was analyzed to examine relationships between CVEs by intimate partner and health among Black women to further characterize the challenges these women face in making changes and finding their sources of strengths. Findings highlight the need to assess for CVE and identify multiple motivators for change, sources of strengths and coping strategies that could be potential points of intervention for women with CVE. PMID- 26954769 TI - Is a pulmonary rehabilitation program effective in COPD patients with chronic hypercapnic failure? AB - OBJECTIVES: Our study aimed to compare the effectiveness of a pulmonary rehabilitation (PR) program between hypercapnic and normocapnic patients with chronic obstructive pulmonary disease (COPD). METHODS: Hypercapnic (Group 1) and normocapnic (Group 2) patients with COPD who participated in this study underwent a comprehensive 8-week out-patient PR program. RESULTS: A total of 122 patients were enrolled in the study; (n:86, n:36 groups 1 and 2, respectively.) After PR, both groups had better symptom scores as well as physical, social and emotional functioning. In addition, the groups had reduced dyspnea, anxiety and depression scores. After PR, the hypercapnic group improved significantly more in exercise capacity (?6 MWT 50 m. vs 40 m.) compared with normocapnic patients (p=0.044). The hypercapnic group demonstrated a significant reduction in the PaCO2 levels after PR within (p<0.05) and between groups (p<0.0001). CONCLUSIONS: Given the significant reductions in pCO2 levels and significant increases in exercise capacity and QoL parameters after PR, the patients with chronic hypercapnic failure apparently benefited from the PR. PMID- 26954768 TI - Intraoperative Secondary Insults During Orthopedic Surgery in Traumatic Brain Injury. AB - BACKGROUND: Secondary insults worsen outcomes after traumatic brain injury (TBI). However, data on intraoperative secondary insults are sparse. The primary aim of this study was to examine the prevalence of intraoperative secondary insults during orthopedic surgery after moderate-severe TBI. We also examined the impact of intraoperative secondary insults on postoperative head computed tomographic scan, intracranial pressure (ICP), and escalation of care within 24 hours of surgery. MATERIALS AND METHODS: We reviewed medical records of TBI patients 18 years and above with Glasgow Coma Scale score <13 who underwent single orthopedic surgery within 2 weeks of TBI. Secondary insults examined were: systemic hypotension (systolic blood pressure<90 mm Hg), intracranial hypertension (ICP>20 mm Hg), cerebral hypotension (cerebral perfusion pressure<50 mm Hg), hypercarbia (end-tidal CO2>40 mm Hg), hypocarbia (end-tidal CO2<30 mm Hg in absence of intracranial hypertension), hyperglycemia (glucose>200 mg/dL), hypoglycemia (glucose<60 mg/dL), and hyperthermia (temperature >38 degrees C). RESULTS: A total of 78 patients (41 [18 to 81] y, 68% male) met the inclusion criteria. The most common intraoperative secondary insults were systemic hypotension (60%), intracranial hypertension and cerebral hypotension (50% and 45%, respectively, in patients with ICP monitoring), hypercarbia (32%), and hypocarbia (29%). Intraoperative secondary insults were associated with worsening of head computed tomography, postoperative decrease of Glasgow Coma Scale score by >=2, and escalation of care. After Bonferroni correction, association between cerebral hypotension and postoperative escalation of care remained significant (P<0.001). CONCLUSIONS: Intraoperative secondary insults were common during orthopedic surgery in patients with TBI and were associated with postoperative escalation of care. Strategies to minimize intraoperative secondary insults are needed. PMID- 26954770 TI - Nanometer-ranged attraction induced by multivalent ions between similar and dissimilar surfaces probed using an atomic force microscope (AFM). AB - Direct force measurements between positively charged amidine latex (AL) and negatively charged sulfate latex (SL) particles are carried out using an atomic force microscope (AFM). Forces between three different pairs, namely AL-AL, AL SL, and SL-SL, are measured in solutions containing multivalent cationic aliphatic hexamines (N6) and in simple monovalent KCl solutions. The classical theory of Derjaguin, Landau, Verwey, and Overbeek (DLVO) can rationalize the observed force profiles very well, provided the PB equation is solved for the appropriate asymmetric electrolyte and charge regulation effects are included in the analysis. However, the DLVO description is typically valid only at distances beyond several nanometers. At shorter distances, a short-ranged non-DLVO attraction is present, which can be modeled with an exponential force profile. In KCl solutions, the range of this attraction is around 0.3 nm. In N6 solutions, the range of this attraction is about 1.0 nm in the SL-SL system, 0.6 nm in the AL-SL system, and 0.3 nm in the AL-AL system. PMID- 26954771 TI - Poly(cyclohexylethylene)-block-Poly(lactide) Oligomers for Ultrasmall Nanopatterning Using Atomic Layer Deposition. AB - Poly(cyclohexylethylene)-block-poly(lactide) (PCHE-PLA) block polymers were synthesized through a combination of anionic polymerization, heterogeneous catalytic hydrogenation and controlled ring-opening polymerization. Ordered thin films of PCHE-PLA with ultrasmall hexagonally packed cylinders oriented perpendicularly to the substrate surface were prepared by spin-coating and subsequent solvent vapor annealing for use in two distinct templating strategies. In one approach, selective hydrolytic degradation of the PLA domains generated nanoporous PCHE templates with an average pore diameter of 5 +/- 1 nm corroborated by atomic force microscopy and grazing incidence small-angle X-ray scattering. Alternatively, sequential infiltration synthesis (SIS) was employed to deposit Al2O3 selectively into the PLA domains of PCHE-PLA thin films. A combination of argon ion milling and O2 reactive ion etching (RIE) enabled the replication of the Al2O3 nanoarray from the PCHE-PLA template on diverse substrates including silicon and gold with feature diameters less than 10 nm. PMID- 26954772 TI - Correction: An Open Receptor-Binding Cavity of Hemagglutinin-Esterase-Fusion Glycoprotein from Newly-Identified Influenza D Virus: Basis for Its Broad Cell Tropism. PMID- 26954773 TI - Wonders & Worries: evaluation of a child centered psychosocial intervention for families who have a parent/primary caregiver with cancer. AB - OBJECTIVE: Scant evidence exists to guide interventions for children who have a parent with cancer. This study evaluated the outcomes of a community based psychosocial intervention targeted to children dealing with parental or primary caregiver cancer. This curriculum provided an age-appropriate understanding of the illness, facilitated the expression of feelings, identified individual coping skills to help ease feelings related to parent's cancer, and enhanced the family's ability to communicate about the disease. METHODS: Families whose children participated in the six-week curriculum-based intervention completed a questionnaire that included demographic information, a five-item assessment of changes in parenting abilities, and a nine-item assessment of changes in children's behavioral issues. The prevalence of each reported item was determined through a secondary analyses of cross-sectional data derived from a multi-year sample of these survey results. RESULTS: A sample of 156 families responded to the survey between 2009 and 2014. A majority of families described improvement in all five areas of parenting abilities assessed including communication skills and confidence in parenting. Amelioration of multiple children's issues was reported including improved communication skills (87%), reduced anxiety (84%), increased feeling of security at home (90%), and improved school performance (73%). CONCLUSIONS: The results reported here suggest that this child centered psychosocial intervention promoted positive adaptation by actively supporting families and children while a parent/primary caregiver coped with a cancer diagnosis. Future research is planned utilizing a randomized controlled study design to formally evaluate the effectiveness and preventative impact of this manualized six-week curriculum. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26954775 TI - Serum and Muscle Metabolomics for the Prediction of Ultimate pH, a Key Factor for Chicken-Meat Quality. AB - Variations in muscle glycogen storage are highly correlated with variations in meat ultimate pH (pHu), a key factor for poultry meat quality. A total of two chicken lines were divergently selected on breast pHu to understand the biological basis for variations in meat quality (i.e., the pHu- and the pHu+ lines that are characterized by a 17% difference in muscle glycogen content). The effects of this selection on bird metabolism were investigated by quantifying muscle metabolites by high-resolution NMR ((1)H and (31)P) and serum metabolites by (1)H NMR. A total of 20 and 26 discriminating metabolites between the two lines were identified by orthogonal partial least-squares discriminant analysis (OPLS-DA) in the serum and muscle, respectively. There was over-representation of carbohydrate metabolites in the serum and muscle of the pHu- line, consistent with its high level of muscle glycogen. However, the pHu+ line was characterized by markers of oxidative stress and muscle catabolism, probably because of its low level of energy substrates. After OPLS-DA multiblock analysis, a metabolic set of 15 high-confidence biomarkers was identified that could be used to predict the quality of poultry meat after validation on an independent population. PMID- 26954774 TI - Misanalysis of Urinalysis: A Teachable Moment. PMID- 26954776 TI - Fostering Change from Within: Influencing Teaching Practices of Departmental Colleagues by Science Faculty with Education Specialties. AB - Globally, calls for the improvement of science education are frequent and fervent. In parallel, the phenomenon of having Science Faculty with Education Specialties (SFES) within science departments appears to have grown in recent decades. In the context of an interview study of a randomized, stratified sample of SFES from across the United States, we discovered that most SFES interviewed (82%) perceived having professional impacts in the realm of improving undergraduate science education, more so than in research in science education or K-12 science education. While SFES reported a rich variety of efforts towards improving undergraduate science education, the most prevalent reported impact by far was influencing the teaching practices of their departmental colleagues. Since college and university science faculty continue to be hired with little to no training in effective science teaching, the seeding of science departments with science education specialists holds promise for fostering change in science education from within biology, chemistry, geoscience, and physics departments. PMID- 26954777 TI - The ADAPAR Birth Cohort Study: Food Allergy Results at Five Years and New Insights. AB - BACKGROUND: Although food allergy (FA) is often a transient condition during childhood, when and in whom FA will resolve can be affected by many factors. In this study, we analyzed the data at 5 years on 33 children diagnosed with FA in the ADAPAR (Adana Pediatric Allergy Research) birth cohort study in southern Turkey. METHODS: Thirty-three infants detected as having FA at the end of their first year in the ADAPAR study were assessed every 6 months until the age of 5 years. Each follow-up included a clinical examination, questionnaire, blood sampling and a skin-prick test. RESULTS: Culprit allergens were cow's milk (n = 20), eggs (n = 17), chicken meat (n = 1) and bananas (n = 1). Of the 17 patients with egg allergy, 14 developed complete tolerance and 1 developed partial tolerance (i.e. tolerance to baked food). Of the 20 patients with milk allergy, complete tolerance was observed in 16 and partial tolerance in 1. The mean age of tolerance to egg was 22.4 +/- 7.5 months and to cow's milk, it was 20.9 +/- 1.1 months. Complete tolerance developed in 1 case allergic to chicken meat and in 1 case allergic to banana. Other allergic conditions were also determined: allergic rhinitis in 27.2%, atopic dermatitis in 21.2%, asthma in 9%, urticaria in 9% and drugs in 9%. CONCLUSIONS: Our results confirm early and high tolerance rates before school age in children with food allergies that started in infancy. This will help pediatricians to give more informed advice to parents of infants with cow's milk or hen's egg allergy. PMID- 26954778 TI - NADPH-Diaphorase Colocalizes with GPER and Is Modulated by the GPER Agonist G1 in the Supraoptic and Paraventricular Nuclei of Ovariectomized Female Rats. AB - Nitric oxide is produced in the brain by the neuronal nitric oxide synthase (nNOS) and carries out a wide range of functions by acting as a neurotransmitter like molecule. Gonadal hormones are involved in the regulation of the brain nitrergic system. We have previously demonstrated that estradiol, via classical estrogen receptors (ERs), regulates NOS activity in the supraoptic (SON) and paraventricular (PVN) nuclei of the hypothalamus, acting through both ERalpha and ERbeta. Magnocellular and parvocellular neurons in the SON and PVN also express the G protein-coupled ER (GPER). In this study, we have assessed whether GPER is also involved in the regulation of nicotinamide adenine dinucleotide phosphate (NADPH)-diaphorase in the SON and PVN. Adult female ovariectomized rats were treated with G1, a selective GPER agonist, or with G1 in combination with G15, a selective GPER antagonist. G1 treatment decreased NADPH-diaphorase expression in the SON and in all PVN subnuclei. The treatment with G1 + G15 effectively rescued the G1-dependent decrease in NADPH-diaphorase expression in both brain regions. In addition, the activation of extracellular signal-regulated kinase (ERK) 1/2, one of the kinases involved in the GPER-dependent intracellular signaling pathway and in NOS phosphorylation, was assessed in the same brain nuclei. Treatment with G1 significantly decreased the number of p-ERK 1/2-positive cells in the SON and PVN, while the treatment with G1 + G15 significantly recovered its number to control values. These findings suggest that the activation of GPER in the SON and PVN inhibits the phosphorylation of ERK 1/2, which induces a decrease in NADPH diaphorase expression. PMID- 26954780 TI - Correction: Evaluation in Cameroon of a Novel, Simplified Methodology to Assist Molecular Microbiological Analysis of V. cholerae in Resource-Limited Settings. PMID- 26954779 TI - Academic Outcomes 2 Years After Working Memory Training for Children With Low Working Memory: A Randomized Clinical Trial. AB - IMPORTANCE: Working memory training may help children with attention and learning difficulties, but robust evidence from population-level randomized controlled clinical trials is lacking. OBJECTIVE: To test whether a computerized adaptive working memory intervention program improves long-term academic outcomes of children 6 to 7 years of age with low working memory compared with usual classroom teaching. DESIGN, SETTING, AND PARTICIPANTS: Population-based randomized controlled clinical trial of first graders from 44 schools in Melbourne, Australia, who underwent a verbal and visuospatial working memory screening. Children were classified as having low working memory if their scores were below the 15th percentile on either the Backward Digit Recall or Mister X subtest from the Automated Working Memory Assessment, or if their scores were below the 25th percentile on both. These children were randomly assigned by an independent statistician to either an intervention or a control arm using a concealed computerized random number sequence. Researchers were blinded to group assignment at time of screening. We conducted our trial from March 1, 2012, to February 1, 2015; our final analysis was on October 30, 2015. We used intention to-treat analyses. INTERVENTION: Cogmed working memory training, comprising 20 to 25 training sessions of 45 minutes' duration at school. MAIN OUTCOMES AND MEASURES: Directly assessed (at 12 and 24 months) academic outcomes (reading, math, and spelling scores as primary outcomes) and working memory (also assessed at 6 months); parent-, teacher-, and child-reported behavioral and social emotional functioning and quality of life; and intervention costs. RESULTS: Of 1723 children screened (mean [SD] age, 6.9 [0.4] years), 226 were randomized to each arm (452 total), with 90% retention at 1 year and 88% retention at 2 years; 90.3% of children in the intervention arm completed at least 20 sessions. Of the 4 short-term and working memory outcomes, 1 outcome (visuospatial short-term memory) benefited the children at 6 months (effect size, 0.43 [95% CI, 0.25 0.62]) and 12 months (effect size, 0.49 [95% CI, 0.28-0.70]), but not at 24 months. There were no benefits to any other outcomes; in fact, the math scores of the children in the intervention arm were worse at 2 years (mean difference, -3.0 [95% CI, -5.4 to -0.7]; P = .01). Intervention costs were A$1035 per child. CONCLUSIONS AND RELEVANCE: Working memory screening of children 6 to 7 years of age is feasible, and an adaptive working memory training program may temporarily improve visuospatial short-term memory. Given the loss of classroom time, cost, and lack of lasting benefit, we cannot recommend population-based delivery of Cogmed within a screening paradigm. TRIAL REGISTRATION: anzctr.org.au Identifier: ACTRN12610000486022. PMID- 26954781 TI - Early Life History of the 'Irukandji' Jellyfish Carukia barnesi. AB - Adult medusae of Carukia barnesi were collected near Double Island, North Queensland Australia. From 73 specimens, 8 males and 15 females spawned under laboratory conditions. These gametes were artificially mixed which resulted in fertilized eggs. Post fertilization, most eggs developed to an encapsulated planula stage and then paused for between six days and six months prior to hatching as ciliated planulae. The paused stage planulae were negatively buoyant and adhered to substrate. The first planula was produced six days post fertilization, lacked larval ocelli, remained stationary, or moved very slowly for two days prior to metamorphosis into primary polyps. Mature polyps reproduced through asexual reproduction via lateral budding producing ciliated swimming polyps, which in turn settled and developed into secondary polyps. Medusae production for this species was in the form of monodisc strobilation, which left behind polyps able to continue asexual reproduction. PMID- 26954782 TI - COAGULASE-NEGATIVE STAPHYLOCOCCUS-INDUCED FROSTED BRANCH ANGIITIS AFTER INTRAVITREAL ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR INJECTION. AB - PURPOSE: To describe a case of frosted branch angiitis after intravitreal ranibizumab injection. METHODS: Retrospective chart review. RESULTS: A patient with a history of neovascular age-related macular degeneration underwent intravitreal ranibizumab injection and subsequently developed coagulase-negative Staphylococcus endophthalmitis with findings of frosted branch angiitis. CONCLUSION: Endophthalmitis presenting as frosted branch angiitis is a rare complication after intravitreal anti-vascular endothelial growth factor injection. Early recognition is critical to optimize outcomes. To our knowledge, this is the second reported case of frosted branch angiitis as a presentation of endophthalmitis with coagulase-negative Staphylococcus. PMID- 26954783 TI - An Efficacious Multi-Objective Fuzzy Linear Programming Approach for Optimal Power Flow Considering Distributed Generation. AB - This paper proposes a new formulation for the multi-objective optimal power flow (MOOPF) problem for meshed power networks considering distributed generation. An efficacious multi-objective fuzzy linear programming optimization (MFLP) algorithm is proposed to solve the aforementioned problem with and without considering the distributed generation (DG) effect. A variant combination of objectives is considered for simultaneous optimization, including power loss, voltage stability, and shunt capacitors MVAR reserve. Fuzzy membership functions for these objectives are designed with extreme targets, whereas the inequality constraints are treated as hard constraints. The multi-objective fuzzy optimal power flow (OPF) formulation was converted into a crisp OPF in a successive linear programming (SLP) framework and solved using an efficient interior point method (IPM). To test the efficacy of the proposed approach, simulations are performed on the IEEE 30-busand IEEE 118-bus test systems. The MFLP optimization is solved for several optimization cases. The obtained results are compared with those presented in the literature. A unique solution with a high satisfaction for the assigned targets is gained. Results demonstrate the effectiveness of the proposed MFLP technique in terms of solution optimality and rapid convergence. Moreover, the results indicate that using the optimal DG location with the MFLP algorithm provides the solution with the highest quality. PMID- 26954785 TI - Soluble biomarkers development in osteoarthritis: from discovery to personalized medicine. AB - CONTEXT: Specific soluble biomarkers could be a precious tool for diagnosis, prognosis and personalized management of osteoarthritic (OA) patients. OBJECTIVE: To describe the path of soluble biomarker development from discovery to clinical qualification and regulatory adoption toward OA-related biomarker qualification. METHODS AND RESULTS: This review summarizes current guidance on the use of biomarkers in OA in clinical trials and their utility at five stages, including preclinical development and phase 1 to phase 4 trials. It also presents all the available regulatory requirements. CONCLUSIONS: The path through the adoption of a specific soluble biomarker for OA is steep but is worth the challenge due to the benefit that it can provide. PMID- 26954784 TI - Biomarkers of (osteo)arthritis. AB - Arthritic diseases are a major cause of disability and morbidity, and cause an enormous burden for health and social care systems globally. Osteoarthritis (OA) is the most common form of arthritis. The key risk factors for the development of OA are age, obesity, joint trauma or instability. Metabolic and endocrine diseases can also contribute to the pathogenesis of OA. There is accumulating evidence to suggest that OA is a whole-organ disease that is influenced by systemic mediators, inflammaging, innate immunity and the low-grade inflammation induced by metabolic syndrome. Although all joint tissues are implicated in disease progression in OA, articular cartilage has received the most attention in the context of aging, injury and disease. There is increasing emphasis on the early detection of OA as it has the capacity to target and treat the disease more effectively. Indeed it has been suggested that this is the era of "personalized prevention" for OA. However, the development of strategies for the prevention of OA require new and sensitive biomarker tools that can detect the disease in its molecular and pre-radiographic stage, before structural and functional alterations in cartilage integrity have occurred. There is also evidence to support a role for biomarkers in OA drug discovery, specifically the development of disease modifying osteoarthritis drugs. This Special Issue of Biomarkers is dedicated to recent progress in the field of OA biomarkers. The papers in this Special Issue review the current state-of-the-art and discuss the utility of OA biomarkers as diagnostic and prognostic tools. PMID- 26954787 TI - Increasing the spectral shifts in LSPR biosensing using DNA-functionalized gold nanorods in a competitive assay format for the detection of interferon-gamma. AB - We demonstrate an approach that utilizes DNA-functionalized gold nanorods (AuNRs) in an indirect competitive assay format to increase the spectra shift in localized surface plasmon resonance (LSPR) biosensing. We use interferon gamma (IFN-gamma) as a model analyte to demonstrate the feasibility of our detection method. The LSPR chips with periodic gold nanodot arrays are fabricated using a thermal lithography process and are functionalized with IFN-gamma aptamers for detection. The DNA-functionalized AuNRs and IFN-gamma compete with each other to bind to the aptamers during detection, and the spectra shifts are mainly caused by the AuNRs rather than IFN-gamma. When using our approach, the target molecules do not need to be captured by two capture ligands simultaneously during detection and thus do not require multiple binding sites. Both experiments and finite difference time-domain (FDTD) simulations show that making the AuNRs as close to the chip surface as possible is very critical for increasing LSPR shifts, and the simulated results also show that the orientation of the AuNR affects the plasmon coupling between the gold nanodots on the chip surface and the nearby AuNRs. Although only the detection of IFN-gamma is demonstrated in this study, we expect that the LSPR biosensing method can be applied to label-free detection of a variety of molecules as long as suitable aptamers are available. PMID- 26954786 TI - Transcriptome Profiling of Two Asparagus Bean (Vigna unguiculata subsp. sesquipedalis) Cultivars Differing in Chilling Tolerance under Cold Stress. AB - Cowpea (V. unguiculata L. Walp.) is an important tropical grain legume. Asparagus bean (V. unguiculata ssp. sesquipedialis) is a distinctive subspecies of cowpea, which is considered one of the top ten Asian vegetables. It can be adapted to a wide range of environmental stimuli such as drought and heat. Nevertheless, it is an extremely cold-sensitive tropical species. Improvement of chilling tolerance in asparagus bean may significantly increase its production and prolong its supply. However, gene regulation and signaling pathways related to cold response in this crop remain unknown. Using Illumina sequencing technology, modification of global gene expression in response to chilling stress in two asparagus bean cultivars-"Dubai bean" and "Ningjiang-3", which are tolerant and sensitive to chilling, respectively-were investigated. More than 1.8 million clean reads were obtained from each sample. After de novo assembly, 88,869 unigenes were finally generated with a mean length of 635 bp. Of these unigenes, 41,925 (47.18%) had functional annotations when aligned to public protein databases. Further, we identified 3,510 differentially expressed genes (DEGs) in Dubai bean, including 2,103 up-regulated genes and 1,407 down-regulated genes. While in Ningjiang-3, we found 2,868 DEGs, 1,786 of which were increasing and the others were decreasing. 1,744 DEGs were commonly regulated in two cultivars, suggesting that some genes play fundamental roles in asparagus bean during cold stress. Functional classification of the DEGs in two cultivars using Mercator pipeline indicated that RNA, protein, signaling, stress and hormone metabolism were five major groups. In RNA group, analysis of TFs in DREB subfamily showed that ICE1-CBF3-COR cold responsive cascade may also exist in asparagus bean. Our study is the first to provide the transcriptome sequence resource for asparagus bean, which will accelerate breeding cold resistant asparagus bean varieties through genetic engineering, and advance our knowledge of the genes involved in the complex regulatory networks of this plant under cold stress. PMID- 26954788 TI - Quantitative determination of major capsaicinoids in serum by ELISA and time resolved fluorescent immunoassay based on monoclonal antibodies. AB - To monitor capsaicinoids in serum on-site, three new monoclonal antibodies (mAbs) were firstly proposed using a conjugate of 4-[(4-hydroxy-3-methoxybenzyl) amino] 4-oxobutanoic acid as the immunogen. Among them, the YQQD8 mAb showed the highest sensitivity and cross-reactivity to major capsaicinoids, such as capsaicin, dihydrocapsaicin and N-vanillylnonanamide. A competitive indirect enzyme-linked immunosorbent assay (icELISA) and a time-resolved fluorescent immunochromatographic assay (TRFICA) were established based on this mAb. The linear range was 1.1-27.0ngmL(-1) for icELISA and 1.9-62.5ngmL(-1) for TRFICA and the limit of detection (LOD) of TRFICA was 1.5ngmL(-1). To decrease the interference of sample components and increase accuracy, serum samples were diluted four times before assays. As a result, the linear range of serum samples was 4.6-107.9ngmL(-1) for icELISA and 7.6-250.0ngmL(-1) for TRFICA. Both icELISA and TRFICA showed good recoveries (91.0-112.8% for icELISA and 87.6-111.5% for TRFICA) and concordant results in spiked experiments. Overall, this is the first report of immunoassay based on the mAbs for quantitative determination of major capsaicinoids, and the results demonstrate that both methods can meet the demands of rapid on-site assay for capsaicinoids in serum samples. PMID- 26954790 TI - Amination of Diazocarbonyl Compounds: N-H Insertion under Metal-Free Conditions. AB - Transition-metal-free intermolecular N-H insertion of alpha-diazocarbonyl compounds is reported. Among the series of nitrogen sources examined, dibenzenesulfonimide was found to be the choice in terms of the yields and the reaction time. Primary mechanistic experiments suggest that a pathway involving a sequence of protonation and nucleophilic substitution was preferred. PMID- 26954789 TI - Ultrasensitive and rapid detection of miRNA with three-way junction structure based trigger-assisted exponential enzymatic amplification. AB - Aberrant expression of micro RNA (miRNA) is associated with development of cancers and diseases, so miRNA has become a tissue-based biomarker for cancer prognosis and diagnosis. Herein, a novel trigger-assisted exponential enzymatic amplification (T-EXPEA) method for ultrasensitive miRNA detection based on three way junction (3-WJ) structure driven has been reported, which can be used in potential applications in cancer prognosis and diagnoses. In this assay, target miRNA can unfold hairpin probe and start the reaction, and thus specifically form stable 3-WJ structure with helper. Then it can produce triggers under the synergetic polymerase and restriction endonucleases amplification. The produced triggers could be used to unfold molecular beacon (MB) and initiate T-EXPEA process. In the EXPEA part, the exponential triggers were generated to initiate new T-EXPEA and high enhancement fluorescence amplification efficiency was obtained. The feature of our strategy lies in the T-EXPEA combining with 3-WJ structure has been utilized for fluorescence miRNA detection. It is worth noting that the sequence of the triggers in T-EXPEA part is the same to that of triggers generated from the 3-WJ part. In addition, the design of restriction enzyme cutting sites using the same restriction enzyme (Nt.BbvCI) in hairpin probe and MB respectively, improved reaction efficiency cost-efficiently. This method can quantitatively detect sequence-specific miRNA in a dynamic range from 10 aM to 10 pM with a detection limit as low as 7.8 aM. PMID- 26954792 TI - Back to the future: Glimpses into the past. PMID- 26954793 TI - The philosophy of 'middle path' in neurosurgery. PMID- 26954794 TI - Cerebral dialysis for intracerebral glucose in traumatic brain injury. PMID- 26954795 TI - Cerebral microdialysis for assessing intracerebral hypoglycemia: Can it act as a prognostic marker in severe traumatic brain injury? PMID- 26954796 TI - Neuroimaging in tuberculous meningitis. AB - Tuberculous meningitis is a serious infection caused by Mycobacterium tuberculosis. Early diagnosis is the key to success of treatment. Neuroimaging plays a crucial role in the early and accurate diagnosis of tuberculous meningitis and its disabling complications. Magnetic resonance imaging is considered superior to computed tomography. Neuroimaging characteristics include leptomeningeal and basal cisternal enhancement, hydrocephalus, periventricular infarcts, and tuberculoma. Partially treated pyogenic meningitis, cryptococcal meningitis, viral encephalitis, carcinomatous, and lymphomatous meningitis may have many similar neuroimaging characteristics, and differentiation from tuberculous meningitis at times on the basis of neuroimaging characteristics becomes difficult. PMID- 26954797 TI - Scrutinizing brain magnetic resonance imaging patterns in Angelman syndrome. AB - BACKGROUND: Global developmental delay, lack of speech, and severe epilepsy are the characteristic hallmarks of Angelman syndrome (AS). The purpose of this study was to explore the utility of brain magnetic resonance imaging (MRI) as an ancillary tool for the diagnosis of AS. MATERIAL AND METHODS: Brain MRI images of nine laboratory-confirmed patients with AS from a neurorehabilitation center in Rio de Janeiro were reviewed. Each MRI was assessed by a set of two experienced neuroradiologists following a predefined protocol. RESULTS: The main neuroimaging findings revealed in our study were: Thinning of the corpus callosum in five patients; enlargement of lateral ventricles in four patients; and, cerebral atrophy with frontal and temporal predominance in one patient. All patients presented with an increased signal intensity in T2-weighted images and fluid attenuated inversion recovery (FLAIR) sequences. CONCLUSION: The lack of specific changes in the brain MRI of children with AS observed in this case series rendered brain MRI a less helpful complementary test. Thus, a definitive diagnosis of AS could only be established on molecular biology that was undertaken based on the clinical suspicion of AS. PMID- 26954798 TI - Elevated interictal serum galectin-3 levels in intractable epilepsy. AB - BACKGROUND: Intractable epilepsy is defined as the occurrence of seizures that cannot be controlled with medical treatment. The discovery of epilepsy biomarkers is increasingly attracting more attention from both clinical physicians as well as neuroscientists. Increased levels of soluble and/or cellular galectin-3 (Gal 3) have been associated with various diseases. However, the effects of Gal-3 in epilepsy are still unknown. In this study, we evaluated the association of higher interictal serum Gal-3 protein levels in patients diagnosed with intractable epilepsy. PATIENTS AND METHODS: A group of 38 patients with intractable epilepsy and 26 healthy age-matched control subjects were included in this study. A commercially available electrochemiluminescence immunoassay (ECLIA) kit was used to determine serum Gal-3 protein levels. RESULTS: Our results indicated that serum Gal-3 protein level in the patient group was 6.67 +/- 0.34 ng/ml, and in the age-matched control group was 5.40 +/- 0.34 ng/ml. The difference between the two groups was found to be statistically significant (P = 0.003). CONCLUSION: This study found a detectable elevation in serum Gal-3 concentration in patients with focal epilepsy. Given its secretory nature and detectable levels in the serum, Gal-3 could be a potential biomarker for intractable epilepsy. PMID- 26954799 TI - Galectin-3, an important yet unexplored molecule in drug resistant epilepsy. PMID- 26954800 TI - Diagnostic accuracy of Magnetic Resonance Parkinsonism Index in differentiating progressive supranuclear palsy from Parkinson's disease and controls in Indian patients. AB - AIMS AND OBJECTIVES: An assessment of the sensitivity and specificity of magnetic resonance (MR) imaging measurements of midbrain, pons, middle cerebellar peduncles (MCPs), and superior cerebellar peduncles (SCPs) and MR Parkinsonism Index (MRPI) in differentiating progressive supranuclear palsy (PSP) from Parkinson's disease (PD) and controls was performed. The correlation of these MR imaging measurements with the duration and severity of disease in the Indian patients using the PSP rating scale (PSPRS) was also performed. MATERIALS AND METHODS: Twenty-six consecutive patients were enrolled in this study, satisfying the diagnostic criteria by the National Institute for Neurological Disorders and Stroke, and the Society for PSP (NINDS-SPSP), along with 13 PD and 30 control patients. All PSP patients were assessed using the PSP rating scale and staging system. Radiologists were blinded to the clinical diagnoses. MRPI was calculated by multiplying the pons area/midbrain area ratio by MCP width/SCP width ratio. The midbrain/pons area (M/P) ratio was measured as the ratio of midbrain area to pons area. RESULTS: Mean MRPI in PSP patients (23.48 +/- 9.61) was significantly higher than that in PD patients (9.07 +/- 2.23) and controls (9.45 +/- 1.87). In this study, MRPI was 100% sensitive, specific, and accurate in differentiating PSP from PD and was 96.3% sensitive, 100% specific, and 98.21% accurate in differentiating PSP from controls. No correlation was found between the duration of disease, PSP rating scale, PSP staging system, and MRPI in the present study. MRPI was only marginally superior to the M/P ratio in differentiating between PSP and PD patients on an individual basis. No overlapping values were observed in the PSP and PD patients. CONCLUSION: Magnetic Resonance Parkinsonism Index is more sensitive, specific, and accurate in differentiating PSP from PD in the early stages on an individual basis. PMID- 26954801 TI - Metabonomic signature analysis in plasma samples of glioma patients based on (1)H nuclear magnetic resonance spectroscopy. AB - OBJECTIVE: The presence of a glioma is associated with increasing mortality. In this study, nuclear magnetic resonance (NMR) based metabonomics has been applied to investigate the metabolic signatures of a glioma in plasma. The purpose of this study was to assess the diagnostic potential of this approach and gain novel insights into the metabolism of glioma and its systemic effects. METHODS: Plasma samples were collected prospectively by centrifugation of blood samples from patients with a glioma (n = 70) or a control group (n = 70). NMR spectra of these plasma samples were analyzed using orthogonal partial least square discriminant analysis (OPLS-DA) to identify the potential biomarkers. RESULTS: The OPLS-DA model showed a good differentiation between the glioma and the control groups. A total of 20 metabolites were identified, which are closely correlating with the presence of a glioma. Compared to the control group, patients with a glioma were associated with lower concentrations of isoleucine, leucine, valine, lactate, alanine, glycoprotein, glutamate, citrate, creatine, myo-inositol, choline, tyrosine, phenylalanine, 1-methylhistidine, alpha-glucose, beta-glucose, and higher concentrations of very low density lipoprotein, low density lipoprotein (LDL), unsaturated lipid, and pyruvate. These 20 metabolites, which are involved in energy, fatty acid, and amino acid metabolism, may be associated with a human glioma. CONCLUSION: Our study is the first one to identify the plasma metabolites that have the potential to distinguish between patients with a glioma and healthy subjects. NMR-based metabonomics provides a good sensitivity and selectivity in differentiating the healthy control group from patients suffering form the disease. Plasma metabolic profiling may have a potential in diagnosing a glioma in the early phase and may help in enhancing our understanding of its underlying mechanisms. PMID- 26954802 TI - Can immediate postoperative random growth hormone levels predict long-term cure in patients with acromegaly? AB - BACKGROUND: Growth hormone (GH) levels following oral glucose tolerance test (OGTT) at 12 weeks or later after surgery have been accepted as the most reliable parameter for defining remission and/or cure in patients with acromegaly. However, the role of random GH in predicting remission in the immediate postoperative period using modern criteria is not known. This study was undertaken to evaluate the role of random GH levels in first 5 postoperative days as an early predictive tool for long-term remission of patients with acromegaly following transsphenoidal pituitary surgery (TSS). PATIENTS AND METHODS: Seventy five consecutive acromegaly patients with at least three postoperative OGTT values at 3, 6, and 12 months of follow-up were included in the study. GH levels were measured just before surgery, in the immediate postoperative period, at 6 h and on day 1 to day 5 after surgery. Remission was defined as normal age-specific insulin-like growth factor-1 and either basal fasting GH <1 ng/ml or a nadir GH following OGTT <0 .4 ng/ml at 3 months of surgery. RESULTS: Of the 75 patients with acromegaly who underwent TSS, long-term remission was achieved in 42 (56%) patients. GH values <=1.55 ng/ml at 6 h of surgery showed the highest predictive power for long-term remission, with a sensitivity of 81.2% and a specificity of 83.3%. The duration of disease and tumor volume had no effect on the 6 h GH value related prediction of cure. CONCLUSION: Early postoperative GH values may be used to predict long-term cure. A value of <=1.5 ng/ml at 6 h following surgery may predict long-term cure in two-thirds of the patients with acromegaly who undergo TSS. PMID- 26954803 TI - Intracerebral hypoglycemia and its clinical relevance as a prognostic indicator in severe traumatic brain injury: A cerebral microdialysis study from India. AB - CONTEXT: Traumatic brain injury (TBI) remains a major cause of morbidity and mortality worldwide. Largely, the prognosis is dependent on the nonmodifiable factors such as severity of the initial injury, Glasgow coma scale score, pupillary response, age, and presence of additional physiological derangements such as hypoxia or hypotension. However, secondary insults continue to take place after the initial injury and resuscitation. The study hypothesis in the present research article was that hypoglycemia is an independent outcome prognosticator in severe traumatic brain injury. The study aimed to assess the role of glucose monitoring in the brain parenchyma as an independent outcome prognosticator and also to study its association with plasma glucose levels. AIMS: The aim of the study was to analyze the relationship of intracerebral glucose measured by intraparenchymal cerebral microdialysis (CMD), and also to study its relationship with blood glucose levels. We also evaluated the relationship of these values to the outcome of patients. SETTINGS AND DESIGN: Prospective nonrandomized study conducted at a tertiary care trauma center in India. SUBJECTS AND METHODS: Twenty five patients with severe TBI, who underwent decompressive craniectomy, were prospectively monitored with CMD catheters. Twenty cases had unilateral catheters placed intraparenchymally (20 mm inside the brain parenchyma to accommodate 10 mm of the semipermeable catheter tip and another 10 mm of extra catheter length). Frontotemporal contusions were noted in 21 cases and an acute subdural hematoma (with/without associated contusions) were noted in 15 cases in the present series. Bilateral CMD catheters were placed during bifrontal decompressive craniectomies in five patients (two patients had peri-contusional catheters placement; these patients had bilateral frontal contusions); while, the remaining 3 patients had a contralateral catheter placement in the normal brain parenchyma [Table 1]. The position of the catheters was confirmed on postoperative computerized tomographic scan carried out in these subjects. However, bilateral catheter placement to compare the difference in cerebral biochemical values of glucose in the penumbric zone as well as the normal brain could not be done in all cases due to cost restraints. The relation between plasma glucose and CMD measured interstitial brain glucose concentrations, as well as the temporal pattern of CMD glucose was studied for 3-5 days following a decompressive craniectomy using a CMD analyzer at the patient's bedside at 1 hourly intervals. STATISTICAL ANALYSIS USED: All data were tabulated in Microsoft Excel 2011 and analyzed using SPSS version 21. To calculate the correlation between plasma and CMD glucose, Pearson's correlation was used with a two-tailed test of significance. Student's t-test was used to calculate the difference in means between the two groups. Significance was assumed at P <= 0.05. RESULTS: Fifteen patients (60%) had a good outcome in terms of the Glasgow Outcome Scale (GOS) at 3 months while the rest (10 patients) had a poor GOS at 3 months. There was a significant difference in the incidence of hyperglycemia (random blood sugar >10 mmol/L) between the two groups (P < 0.0001). The difference between the two groups while comparing episodes of hypoglycemia was also significant (P = 0.0026). The good outcome group had fewer episodes of brain hypoglycemia during the presence of systemic hypoglycemia (P = 0.0026). Neither the mean blood glucose values nor the mean cerebral glucose values predicted the outcome at 3 months. CONCLUSIONS: After decompressive craniectomy in severe TBI, there was a poor correlation between the plasma and CMD glucose concentration. A higher degree of variation was seen in the correlations for individual patients. Neither the mean blood glucose values nor the mean cerebral glucose values predicted the outcome at 3 months. The good outcome group had fewer episodes of both hyperglycemia and hypoglycemia. PMID- 26954804 TI - Comparison of the values of MRI diffusion kurtosis imaging and diffusion tensor imaging in cerebral astrocytoma grading and their association with aquaporin-4. AB - OBJECTIVE: To compare the value of MRI diffusion kurtosis imaging (DKI) and diffusion tensor imaging (DTI) in grading cerebral astrocytomas and to analyze the correlation of respective parameters with aquaporin-4 (AQP4) expression. METHODS: Sixty patients with cerebral astrocytoma, including low-grade astrocytomas (LGA, n = 25) and high-grade astrocytomas (HGA, n = 35), were studied. The values of DKI parameters (mean kurtosis [MK], radial kurtosis [Kr], and axial kurtosis [Ka]) and DTI parameters (fractional anisotropy, mean diffusivity [MD]) corrected by contralateral normal-appearing white matter in the solid parts of the tumors and peritumoral edema were compared. Receiver operating characteristic curves were used to identify the best parameters. Spearman correlation analysis was conducted to assess the correlation of AQP4 expression with each parameter value. RESULTS: MK, Ka, and Krvalues were significantly higher whereas MD values were significantly lower in the solid parts of HGA, as compared to those of LGA. MK value in peritumoral edematous tissue was significantly higher in HGA as compared to that in LGA. Ka (0.889) had the largest area under the curve (AUC), followed by MK (0.840), Kr (0.750), and MD (0.764). The AUC of Kaand MK was significantly higher than that of MD. Optimal thresholds for MK, Ka, Kr, and MD for differentiating the two groups were 0.490, 0.525, 0.432, and 1.493, respectively. The AQP4 expression in the solid parts of the tumors was significantly higher in HGAs. MK, Kr, Kavalues positively correlated with the AQP4 expression, whereas MD showed a slight negative correlation with AQP4. CONCLUSION: Use of DKI improved grading of cerebral astrocytomas when compared with DTI. DKI parameters appeared to reflect the level of AQP4 expression in astrocytomas. PMID- 26954805 TI - Diffusion kurtosis imaging for cerebral astrocytomas. PMID- 26954806 TI - Artificial atlanto-axial joints: On the "move". AB - The current management of atlantoaxial dislocation emphasizes on C1-2 reduction and fusion. The fusion of C1-2, however, hampers the neck movements significantly. The author has designed and developed artificial C1-2 joints that can mimic the natural joints to some extent. The concept and nuances of the design has been described. The joints have been fixed in dry cadaveric bones to demonstrate the possible movements. PMID- 26954807 TI - Molecular predictive and prognostic factors in ependymoma. AB - An ependymoma is an uncommon glial tumor, which arises from different parts of the neuroaxis. Considerable variation in presentation and survival in tumors in different locations after an optimum treatment indicates inherent molecular and genetic differences in tumorigenesis between them. A number of genetic aberrations have been identified to distinctly characterize different subgroups of ependymomas that include a posterior fossa tumor, a supratentorial tumor, and a pediatric tumor. These different groups have substantial genetic alterations, and also distinct demography, clinical characteristics, and prognosis. This article is intended to review the diverse molecular and genetic aberrations that may be helpful in prognostication and prediction of survival in patients suffering from an ependymoma. PMID- 26954808 TI - Prognostic factors in ependymal tumors: Molecular biology trumps histopathology. PMID- 26954809 TI - Adult brachial plexus injuries: Surgical strategies and approaches. AB - Traumatic brachial plexus injuries are devastating injuries commonly affecting the young population and leading to significant socioeconomic losses to the society. The results of brachial plexus surgery have been severely disappointing in the past. However, several technological advancements and newer surgical techniques, especially the advent of distal nerve transfers over recent years, have led to a paradigm shift in the outcome of patients with these injuries. The best time window for surgery is the first 3 months after injury, and the next best time is the next 3 months. The timing is a crucial factor as the neuromuscular junctions degenerate in 20-24 months. The presence of spontaneous fibrillations in a muscle on electromyography is an indication of denervated yet vital muscle. The restoration of elbow flexion is a priority followed closely by restoration of shoulder abduction and stabilization. The various surgical strategies in brachial plexus injuries should be directed toward accomplishing this goal. The global avulsion injuries have a poor outcome because of very limited source of donors in such types of injury whereas the partial injuries have a remarkable outcome in a majority of cases. This article presents the reader with the guidelines and management algorithms of repair strategy and various surgical approaches utilized in the surgical treatment of brachial plexus injuries. PMID- 26954810 TI - History of neurosurgery at Christian Medical College, Vellore: A pioneer's tale. AB - The Department of Neurological Sciences at Christian Medical College (CMC), Vellore was the first department to start neurosurgical and neurological services in India. Jacob Chandy started the department in 1949 against several odds. He started a formal training program in neurosurgery in 1958, for the first time in India, and went on to qualify several neurosurgeons, who in turn pioneered neurosurgical departments all over India. After 1970, K V Mathai and Jacob Abraham guided the department through some difficult times when there was a severe shortage of personnel and no faculty in the neurology section. Through their commitment and hard work, they continued not only the neurosurgery service but also looked after patients with neurological disorders. Mathew J Chandy, son of Jacob Chandy, joined them in 1980 and introduced micro-neurosurgery and several other neurosurgical techniques. Training of residents in micro neurosurgery began in the early 1980s. The last quarter of a century has been a period of rapid progress for neurosurgery at CMC. There has been an exponential rise in the number of surgeries, number of residents and number of publications. Research has always been an integral part of the activities of the department and several high impact articles have been published by the faculty and residents. The neurosurgical faculty at CMC has also contributed significantly to organized neurosurgery in India and internationally, with five of them serving as President of the Neurological Society of India, a society which had Jacob Chandy as its founder President. With this heritage, the neurosurgery section at CMC, Vellore is likely to continue to provide high quality ethical neurosurgical care to patients from all over India and overseas. PMID- 26954812 TI - Spinal cord atrophy: A rare complication of post- electrocution myelopathy. PMID- 26954813 TI - Epilepsy with PCDH19 mutation masquerading as benign partial epilepsy in infancy. PMID- 26954814 TI - Facial paretic migraine - A rare migraine variant. PMID- 26954815 TI - "Boomerang sign": An ominous-looking finding in reversible maladies. PMID- 26954817 TI - Postictal psychosis with self-amputation of foot in an epileptic patient: A report. PMID- 26954816 TI - Isolated acute bulbar palsy with anti-GM2 antibodies: A rare occurrence. PMID- 26954818 TI - Commentary: Self-mutilation in epilepsy: An unpleasantly, rare phenomenon. PMID- 26954819 TI - Expanding the clinical spectrum of myopathy, encephalopathy, lactic acidosis, and stroke-like (MELAS) episode: A case with A3243G mitochondrial DNA mutation presenting as MELAS and congenital melanocytic naevi overlap. PMID- 26954820 TI - A primary intrapetrous osteolytic meningioma in a child: A rare report and review of literature. PMID- 26954821 TI - Angiocentric glioma of hippocampus-report of a rare intractable epilepsy-related tumor. PMID- 26954822 TI - Granulomatous hypophysitis - A rare pathology: Review of three cases. PMID- 26954823 TI - Pure extra-axial supratentorial anaplastic ependymoma with no cortical attachment: A rare case. PMID- 26954824 TI - Straddling across the neural foramina with a leash of blood vessels: Mason's vegetant intravascular hemangioendothelioma mimicking a schwannoma. PMID- 26954825 TI - Ganglioglioma of the posterior third ventricle region: An unusual pathology in an uncommon location. PMID- 26954826 TI - Vanishing tumor of the tectal plate - stressing the need for a stringent radiological surveillance: A review of possible pathogenetic mechanisms. PMID- 26954827 TI - A case of fibrodysplasia ossificans progressiva: 20 years of follow-up. PMID- 26954828 TI - Giant trichilemmal cyst of the scalp. PMID- 26954829 TI - Three-dimensional constructive interference in steady-state magnetic resonance imaging diagnosis of isolated unilateral facial nerve hypoplasia. PMID- 26954830 TI - Madras Institute of Neurology. PMID- 26954831 TI - Arriving at natural history of a disease. PMID- 26954832 TI - Author's reply. PMID- 26954834 TI - Culture and dialogue in medical psychiatric narratives. PMID- 26954833 TI - Polarization-dependent interfacial coupling modulation of ferroelectric photovoltaic effect in PZT-ZnO heterostructures. AB - Recently, ferroelectric perovskite oxides have drawn much attention due to potential applications in the field of solar energy conversion. However, the power conversion efficiency of ferroelectric photovoltaic effect currently reported is far below the expectable value. One of the crucial problems lies in the two back-to-back Schottky barriers, which are formed at the ferroelectric electrode interfaces and blocking most of photo-generated carriers to reach the outside circuit. Herein, we develop a new approach to enhance the ferroelectric photovoltaic effect by introducing the polarization-dependent interfacial coupling effect. Through inserting a semiconductor ZnO layer with spontaneous polarization into the ferroelectric ITO/PZT/Au film, a p-n junction with strong polarization-dependent interfacial coupling effect is formed. The power conversion efficiency of the heterostructure is improved by nearly two orders of magnitude and the polarization modulation ratio is increased about four times. It is demonstrated that the polarization-dependent interfacial coupling effect can give rise to a great change in band structure of the heterostructure, not only producing an aligned internal electric field but also tuning both depletion layer width and potential barrier height at PZT-ZnO interface. This work provides an efficient way in developing highly efficient ferroelectric-based solar cells and novel optoelectronic memory devices. PMID- 26954835 TI - Failures of imagination: The refugee's narrative in psychiatry. AB - Refugees coming from war-torn areas sometimes face misunderstanding and frank incredulity when they encounter the psychiatric system. This failure of the clinical imagination reflects both reluctance to confront the enormity of patients' loss and cultural differences in self-presentation, self-understanding, memory and identity. This potential for incredulity is redoubled in the formal hearing before the Immigration and Refugee Board (IRB) where the claim for refugee status is adjudicated. Contemporary psychiatric practice is rooted in taking patients' stories at face value as accounts of their experience or reading through them to identify signs and symptoms of psychopathology. From this perspective any account reveals both the narrator's shifting experiential world and the current functioning of their cognitive machinery. Truth is 'experiential truth' and is relative to the narrator's social position, mental health and emotional state. In contrast, the IRB assesses the narrative of asylum seekers against the notion of a truthful story as fixed and isomorphic to a single historical sequence of events. From the perspective of the IRB members, any deviation from this fixed account is evidence of dissimulation designed to claim the valued status of refugee. The conflicting epistemologies of clinical psychiatry and the refugee hearing throw into relief the functions of social imagination in the construction, interpretation and assessment of the truth-value of narratives of identity and affliction. PMID- 26954836 TI - Hearts and minds: Agency and discourse on distress. AB - This paper is based on ethnographic fieldwork in south Bristol, United Kingdom, and on the south Atlantic island of St Helena. It addresses the relationship between the experience of psychosocial distress, the language used to express such distress and the socio-cultural constraints on both language and experience. Accounts of emotional distress were obtained from interviews with 36 informants in south Bristol and with 40 informants on St Helena. Informants in both settings shared a Euro-American discourse on the self in which emotional distress is conceived as a breakdown in human agency. This discourse is linked to narrative as a way of depicting and re-affirming individual agency. A prototypical concept of narrative is used in this paper to interpret accounts of emotional distress. This interpretation demonstrates the usefulness of the idea of narrative for understanding such experiences. PMID- 26954837 TI - Walking stories: Narratives of mental patients as magic a. AB - Mad stories are evocative and metaphoric. They are full of symbols, but we think that those symbols are used in very personal, even idiosyncratic ways. We consider them as incoherent and incomprehensible. They are not 'rational' and do not represent any 'normal' logic. They do not fit into categories. They escape every classification, save that of 'psychotic stories' or 'mad stories'. They are matters out of place. They are viewed as signs of madness and therefore show how much we should value health and normality. They often belong to the underground world in mental hospitals and clinical interaction. This world of stories is feared; therapists and psychiatric nurses often act as if this world does not exist. But when the stories become alive, i.e. acted out, they show their power. In this paper, the author would like to 'de-pathologise' the stories of psychiatric patients and show how they put culture at work and become the 'weapons of the weak' in order to control what usually remains beyond their control. The paper shows that a main dimension of power and force of the stories is their 'embodiment' (patients as walking stories), and argues that through these stories patients gain power to manipulate the course of events and the others' (i.e. professionals) responsive actions. PMID- 26954838 TI - Setting up the interlocutor: Two case-studies in the construction of self in 1930s Spain. AB - This paper considers two related but contrasting self-narratives of 1930s Spain, that of Hildegart Rodriguez, the youthful sex reformer who corresponded with Havelock Ellis, and that of Aurora Rodriguez Carballeira, her mother. The narrative of Aurora arises out of her arrest for the murder of Hildegart in 1933, and is composed partly of her account of herself at the murder trial, and partly by the case-notes compiled by the psychiatrists at Ciempozuelos. The self narrative of Hildegart consists primarily of her letters to Havelock Ellis, 1931 1933. The accepted view of Hildegart and her mother is that the latter was insane, and the former was sane. Yet the two of them display a comparable defensiveness in the way that they portray themselves to the world. In this paper I consider their respective accounts of themselves as the presentation of a 'life history', and use the model of the interlocutor to read the investments involved in the presentation of such a narrative. I examine first the discourse of Aurora, where her paranoia is clearly evident (despite certain textual complications), and then the discourse of Hildegart. In looking at the daughter's narrative I shall consider how there is an unconscious presentation of a medical narrative, and how--when read through a psychoanalytic lens--the discourse reveals that Hildegart also suffered some level of disturbance. PMID- 26954839 TI - Evolutionary narratives about mental disorders. AB - There is a growing interest, among psychiatrists and psychologists, in the evolutionary origins of clinical syndromes. Evolutionary explanations are organized around stories that connect syndromal features to environmental adaptations. The stories are based on a 'modular' vision of mind and human nature. This paper considers the credibility of evolutionary narratives intended to explain depression and homosexuality.|spagf|ro|epagf|. PMID- 26954840 TI - Why narrative? Why now? PMID- 26954841 TI - Development of a Wireless and Near Real-Time 3D Ultrasound Strain Imaging System. AB - Ultrasound elastography is an important medical imaging tool for characterization of lesions. In this paper, we present a wireless and near real-time 3D ultrasound strain imaging system. It uses a 3D translating device to control a commercial linear ultrasound transducer to collect pre-compression and post-compression radio-frequency (RF) echo signal frames. The RF frames are wirelessly transferred to a high-performance server via a local area network (LAN). A dynamic programming strain estimation algorithm is implemented with the compute unified device architecture (CUDA) on the graphic processing unit (GPU) in the server to calculate the strain image after receiving a pre-compression RF frame and a post compression RF frame at the same position. Each strain image is inserted into a strain volume which can be rendered in near real-time. We take full advantage of the translating device to precisely control the probe movement and compression. The GPU-based parallel computing techniques are designed to reduce the computation time. Phantom and in vivo experimental results demonstrate that our system can generate strain volumes with good quality and display an incrementally reconstructed volume image in near real-time. PMID- 26954842 TI - A System-on-Chip Solution for Point-of-Care Ultrasound Imaging Systems: Architecture and ASIC Implementation. AB - In this paper, we present a novel system-on-chip (SOC) solution for a portable ultrasound imaging system (PUS) for point-of-care applications. The PUS-SOC includes all of the signal processing modules (i.e., the transmit and dynamic receive beamformer modules, mid- and back-end processors, and color Doppler processors) as well as an efficient architecture for hardware-based imaging methods (e.g., dynamic delay calculation, multi-beamforming, and coded excitation and compression). The PUS-SOC was fabricated using a UMC 130-nm NAND process and has 16.8 GFLOPS of computing power with a total equivalent gate count of 12.1 million, which is comparable to a Pentium-4 CPU. The size and power consumption of the PUS-SOC are 27*27 mm(2) and 1.2 W, respectively. Based on the PUS-SOC, a prototype hand-held US imaging system was implemented. Phantom experiments demonstrated that the PUS-SOC can provide appropriate image quality for point-of care applications with a compact PDA size ( 200*120*45 mm(3)) and 3 hours of battery life. PMID- 26954843 TI - A MEMS Interface IC With Low-Power and Wide-Range Frequency-to-Voltage Converter for Biomedical Applications. AB - This paper presents an interface circuit for capacitive and inductive MEMS biosensors using an oscillator and a charge pump based frequency-to-voltage converter. Frequency modulation using a differential crossed coupled oscillator is adopted to sense capacitive and inductive changes. The frequency-to-voltage converter is designed with a negative feedback system and external controlling parameters to adjust the sensitivity, dynamic range, and nominal point for the measurement. The sensitivity of the frequency-to-voltage converter is from 13.28 to 35.96 mV/MHz depending on external voltage and charging current. The sensitivity ranges of the capacitive and inductive interface circuit are 17.08 to 54.4 mV/pF and 32.11 to 82.88 mV/mH, respectively. A capacitive MEMS based pH sensor is also connected with the interface circuit to measure the high acidic gastric acid throughout the digestive tract. The sensitivity for pH from 1 to 3 is 191.4 mV/pH with 550 MUV(pp) noise. The readout circuit is designed and fabricated using the UMC 0.18 MUm CMOS technology. It occupies an area of 0.18 mm (2) and consumes 11.8 mW. PMID- 26954844 TI - Luminescence Mechanistic Study of BaLaGa3O7:Nd Using Density Functional Theory Calculations. AB - BaLaGa3O7:Nd (BLGO:Nd) has been investigated as a laser crystal material for about three decades. In the present work, the luminescence mechanism of BLGO:Nd is clarified by density functional theory (DFT) calculations. Structural optimization was first performed on the constructed supercell to obtain the equilibrium geometry. On the basis of the optimized crystal, the electronic structures of the BLGO host (without and with single defects) and the BLGO:Nd phosphor (without and with neighboring defects) were comprehensively investigated. Three important features are revealed by theoretical analyses. First, single defects in BLGO have little effect on the light emission, although the impurity levels appeared within the band gap. Second, luminescence can be realized by the introduction of Nd ions. Calculations of optical properties demonstrated that parity-forbidden transitions among the 4f levels are partially allowed because the mixing of 4f and 5d configurations occurs at higher empty 4f levels. It is thus clear that the electronic transitions between occupied 4f and empty 4f-5d states are electric-dipole-allowed. Therefore, light emission in BLGO:Nd can be achieved in the electronic transition process of Nd 4f electrons > empty 4f-5d levels -> empty 5d levels -> Nd 4f levels. The neighboring intrinsic defects play only an auxiliary role in prolonging the decay time. Third, co-doping of Tb in BLGO:Nd is considered to be beneficial to luminescence in theory because of its shallow to deep distribution of impurity orbitals in the band gap. Therefore, BLGO:Nd co-doped with other lanthanide ions will offer guidelines in the search for the best luminescent materials. PMID- 26954845 TI - Unraveling a two-step oxidation mechanism in electrochemical Cu-MOF synthesis. AB - To employ the full potential of electrochemical (ec) synthesis to grow metal organic frameworks (MOFs) in more complex organizations at the mesoscale, it is vital to understand the underlying crystallization reaction pathway. For the MOF most typically grown electrochemically, CuBTC, we systematically investigated the role of oxygen species in the synthesis. PMID- 26954846 TI - Long-Term Survival Rates of Patients Undergoing Vitrectomy for Proliferative Diabetic Retinopathy. AB - PURPOSE: Reported 5-year survival rates in patients undergoing vitreous surgery for proliferative diabetic retinopathy (PDR) range from 68-95%. Studies relating survival rates to medical baseline characteristics predate the millennium. This study aimed to update data on life expectancy of patients undergoing vitrectomy for PDR and identify baseline factors which may influence survival. METHODS: A retrospective cohort study of consecutive patients who underwent their first pars plana vitrectomy for PDR between April 2004 and May 2005 was performed. Survival status on 1 May 2012 was the primary endpoint. The Kaplan-Meier life table method was used to determine survival rates. Univariate and multiple variable Cox proportional hazards regressions were used to identify risk factors for mortality. RESULTS: A total of 148 patients were included in the study, with a mean age of 54 years (range 20-80 years) at time of surgery. The 3-, 5- and 7 year survival rates were 94%, 86% and 77%, respectively (95% confidence interval, CI, 88-97%, 79-91% and 68-84%, respectively). Renal failure was the most common cause of death. The presence of limb ulcers at baseline was the most important prognostic indicator for mortality, with a hazard ratio of 3.13 (95% CI 1.46 6.71, p = 0.003) and a survival rate at 5 years reduced to 79%. CONCLUSION: The 5 year survival rate remains comparable to those reported 20 years ago despite a lowering in threshold for vitrectomy and increased health awareness. Limb ulcers are strongly associated with increasing mortality. Clinicians should remain mindful of the systemic associations of diabetes particularly in advanced retinal disease. PMID- 26954847 TI - Suicidal Behavior and Psychological Distress in University Students: A 12-nation Study. AB - This study investigated the prevalence of suicidal behavior and psychological distress in university students across 12 nations. A total of 5,572 university students from 12 countries were surveyed about suicide ideation, suicide attempts, and psychological distress by means of a self-administered questionnaire. Almost 29% of the samples reported having contemplated suicide and 7% reported attempting suicide. Of the total sample, 51.1% scored above the General Health Questionnaire-12 >= 3 cut-off points, 41.6% above the GHQ-12 >= 4 cut-off points, and 33.8% scored above the GHQ-12 >= 5 cut-off points. While odds of suicide ideation were elevated in Austria and the UK, reduced ORs were detected for China, Italy, Saudi Arabia, Tunisia, and Turkey. Similarly, while odds of suicide attempt were high in Jordan, Palestine, Saudi Arabia, and to some extent in Turkey, reduced ORs were observed for Austria, China, Italy, Japan and the United States. Elevated ORs for psychological distress were seen in Japan, Jordan, Palestine, Saudi Arabia, Tunisia, and Turkey but reduced ORs were noted in Austria, China, Iran, Italy, and the United States. Psychological distress was strongly associated with reports of suicide ideation and attempts. Suicide ideation, suicide attempt, and psychological distress are common in university students but their rates vary depending on the sociocultural context. Due attention should be devoted to the mental health needs of young adults enrolled in higher educational institutions and more cross-cultural research is warranted to better understand the etiology of the observed intersocietal variations in suicidal behavior and psychological distress. PMID- 26954848 TI - Discovery of 5-Chloro-1-(5-chloro-2-(methylsulfonyl)benzyl)-2-imino-1,2 dihydropyridine-3-carboxamide (TAK-259) as a Novel, Selective, and Orally Active alpha1D Adrenoceptor Antagonist with Antiurinary Frequency Effects: Reducing Human Ether-a-go-go-Related Gene (hERG) Liabilities. AB - A novel structural class of iminopyridine derivative 1 was identified as a potent and selective human alpha1D adrenoceptor (alpha1D adrenergic receptor; alpha1D AR) antagonist against alpha1A- and alpha1B-AR through screening of an in-house compound library. From initial structure-activity relationship studies, we found lead compound 9m with hERG K(+) channel liability. To develop analogues with reduced hERG K(+) channel inhibition, a combination of site-directed mutagenesis and docking studies was employed. Further optimization led to the discovery of (R)-9s and 9u, which showed antagonistic activity by a bladder strip test in rats with bladder outlet obstruction, as well as ameliorated cystitis-induced urinary frequency in rats. Ultimately, 9u was selected as a clinical candidate. This is the first study to show the utility of iminopyridine derivatives as selective alpha1D-AR antagonists and evaluate their effects in vivo. PMID- 26954850 TI - Effects of Bilateral Superior Oblique "Hang-Back" Recession in Treatment of A pattern Strabismus with Superior Oblique Overaction. AB - PURPOSE: To investigate the efficacy and safety of bilateral hang-back recession of superior oblique (SO) muscles in the treatment of A-pattern strabismus with superior oblique overaction (SOOA). METHODS: Thirty-one (31) patients (62 eyes) with A-pattern horizontal deviation and SOOA underwent hang-back recession of SO and retrospective analysis of the surgical amount of hang-back recession of SO, preoperative and postoperative A-pattern, ocular motility, and corrected objective torsion. Patients were evaluated before and 6 to 9 months after surgery. RESULTS: The average A-pattern horizontal deviation was 27.58 +/- 11.47 prism diopters (PD) before surgery and 3.48 +/- 3.70 PD after surgery (n=31, P<0.05). The mean corrected A-pattern was horizontal deviation 24.10 +/- 10.32 PD. The average scale of SOOA on a scale of +1 to +4 was +3.05 +/- 0.80 before surgery and +0.42 +/- 0.50 after surgery in 62 eyes (P<0.05). The mean corrected objective torsion was 4.91 degrees +/- 4.53 degrees . The surgical amount of SO hang-back recession ranged from 4 to 10 mm (mean: 7.62 +/- 1.18 mm), which was related to the preoperative A-pattern and corrected A-pattern. There were no surgical complications. CONCLUSIONS: SO hang-back recession is a safe and efficient option for A-pattern caused by SOOA. PMID- 26954849 TI - Interpretation of anthropogenic impacts (agriculture and urbanization) on tropical deltaic river network through the spatio-temporal variation of stable (N, O) isotopes of NO(-)3. AB - For the first time, the dual isotope approach was applied to trace the sources of impacts and to identify the governing biogeochemical processes in a river network in the tropical deltaic region of the Red River (Vietnam). Our long term surveys concluded that water in this river network was severely impacted by anthropogenic activities. Analysis has shown strong spatio-temporal variation of nitrate isotopes; ranges of delta(15)N-[Formula: see text] and delta(18)O-[Formula: see text] were from -5 to 15 0/00 and from -10 to 10 0/00, respectively. Average values of delta(15)N-[Formula: see text] and delta(18)O-[Formula: see text] in the dry season, when fertilizer is applied, were 3.54 and 3.15 0/00, respectively. In the rainy season, the values changed to 6.41 and -2.23 0/00, respectively. Denitrification and biological assimilation were active throughout the year, but were especially enhanced during fertilization time. Mineralization of domestic organic matter and consequent nitrification of mineralized [Formula: see text] were the dominant processes, particularly during the rainy period. PMID- 26954851 TI - High Stability Induced by the TiN/Ti Interlayer in Three-Dimensional Si/Ge Nanorod Arrays as Anode in Micro Lithium Ion Battery. AB - Three-dimensional (3D) Si/Ge-based micro/nano batteries are promising lab-on-chip power supply sources because of the good process compatibility with integrated circuits and Micro/Nano-Electro-Mechanical System technologies. In this work, the effective interlayer of TiN/Ti thin films were introduced to coat around the 3D Si nanorod (NR) arrays before the amorphous Ge layer deposition as anode in micro/nano lithium ion batteries, thus the superior cycling stability was realized by reason for the restriction of Si activation in this unique 3D matchlike Si/TiN/Ti/Ge NR array electrode. Moreover, the volume expansion properties after the repeated lithium-ion insertion/extraction were experimentally investigated to evidence the superior stability of this unique multilayered Si composite electrode. The demonstration of this wafer-scale, cost effective, and Si-compatible fabrication for anodes in Li-ion micro/nano batteries provides new routes to configurate more efficient 3D energy storage systems for micro/nano smart semiconductor devices. PMID- 26954853 TI - Sociodemographic disparities in choice of therapy and survival in advanced laryngeal cancer. AB - PURPOSE: To determine if sociodemographic factors are associated with treatment choice and survival in patients with advanced stage laryngeal cancer in the U.S. DESIGN/SETTING/SUBJECTS/METHODS: Population-based, non-concurrent cohort study of 5381 patients diagnosed with stage III or IV laryngeal squamous cell carcinoma from 1992-2009. Data was extracted from the Surveillance, Epidemiology, and End Results (SEER) database. MAIN OUTCOME(S) AND MEASURES: Choice of therapy (surgical vs. non-surgical) and disease-specific survival (DSS). RESULTS: Age >=60 years (odds ratio [OR]=0.78; 95% CI, 0.70-0.88) and more recent year of diagnosis (OR=0.89; 95% CI, 0.87-0.90) decreased the odds of receiving surgical therapy, while residing in a county with low median household income (OR=1.36; 95% CI, 1.17-1.57) increased the odds of receiving surgical therapy. Age >=60 years (hazard ratio [HR]=1.45; 95% CI, 1.33-1.59) and Black race (HR=1.14; 95% CI, 1.02-1.27) were negatively associated with DSS, while female sex (HR=0.81; 95% CI, 0.72-0.90) and married status (HR=0.69; 95% CI, 0.63-0.75) were positively associated with DSS. CONCLUSIONS AND RELEVANCE: For patients with advanced laryngeal cancer, younger age and residing in a low-income county increase the likelihood of receiving surgical therapy. Female sex and married status provide a survival benefit, while Black race appears to be a negative prognostic factor. This highlights the impact of sociodemographic factors on treatment strategies and outcomes and highlights areas for further research on health disparities. PMID- 26954852 TI - Pneumococcal Neuraminidase Substrates Identified through Comparative Proteomics Enabled by Chemoselective Labeling. AB - Neuraminidases (sialidases) are enzymes that hydrolytically remove sialic acid from sialylated proteins and lipids. Neuraminidases are encoded by a range of human pathogens, including bacteria, viruses, fungi, and protozoa. Many pathogen neuraminidases are virulence factors, indicating that desialylation of host glycoconjugates can be a critical step in infection. Specifically, desialylation of host cell surface glycoproteins can enable these molecules to function as pathogen receptors or can alter signaling through the plasma membrane. Despite these critical effects, no unbiased approaches exist to identify glycoprotein substrates of neuraminidases. Here, we combine previously reported glycoproteomics methods with quantitative proteomics analysis to identify glycoproteins whose sialylation changes in response to neuraminidase treatment. The two glycoproteomics methods-periodate oxidation and aniline-catalyzed oxime ligation (PAL) and galactose oxidase and aniline-catalyzed oxime ligation (GAL) rely on chemoselective labeling of sialylated and nonsialylated glycoproteins, respectively. We demonstrated the utility of the combined approaches by identifying substrates of two pneumococcal neuraminidases in a human cell line that models the blood-brain barrier. The methods deliver complementary lists of neuraminidase substrates, with GAL identifying a larger number of substrates than PAL (77 versus 17). Putative neuraminidase substrates were confirmed by other methods, establishing the validity of the approach. Among the identified substrates were host glycoproteins known to function in bacteria adherence and infection. Functional assays suggest that multiple desialylated cell surface glycoproteins may act together as pneumococcus receptors. Overall, this method will provide a powerful approach to identify glycoproteins that are desialylated by both purified neuraminidases and intact pathogens. PMID- 26954854 TI - Ceruminous adenocarcinoma: An analysis of the Surveillance Epidemiology and End Results (SEER) database. AB - OBJECTIVES: Ceruminous adenocarcinoma is a rare malignancy. However, due to the paucity of cases, this has been difficult to study. Using a population-based national database, patient demographics and survival trends were analyzed to further elucidate the management of this malignancy. METHODS: The SEER database was queried for patients diagnosed with ceruminous adenocarcinoma between 1973 and 2010. RESULTS: Twenty-two patients were identified in the database. The average age of diagnosis was between 60 and 64 years. All of the patients underwent surgical resection of the primary malignancy. Eight patients (36%) also had postoperative radiation. CONCLUSIONS: Ceruminous adenocarcinoma is uncommon but may not have as poor a prognosis as previously thought. Surgical resection alone appears to be a reasonable treatment option. Larger prospective studies are needed, but database analysis like this may provide clarity on the management of uncommon diseases. PMID- 26954855 TI - Stabilization of total ossicular replacement prosthesis using cartilage "shoe" graft. AB - PURPOSE: We aimed to determine the effect of a cartilage shoe graft placed between the foot of the TORP and the stapes footplate on hearing improvement and long-term displacement rates. MATERIALS AND METHODS: Patients who underwent TORP ossiculoplasty were divided into two groups. The TORP-alone group consisted of 32 patients who underwent TORP placement without cartilage shoe graft and served as the control group. The study group consisted of 56 patients who underwent placement of cartilage shoe graft together with TORP. Pure-tone audiometry was administered to all patients before and 3, 6 and 12 months after surgery. Indications for surgery, surgical technique used, postoperative complications, and air and bone conduction thresholds at 500, 1000, 2000 and 4000 Hz were recorded for all patients. RESULTS: No significant difference in postoperative air-bone gaps was observed between the groups. The number of patients with air bone gaps less than 20 dB was 14 (25%) in the study group and 8 (25%) in the control group. There was no significant difference in changes in air-bone gaps between the groups. Dislocation of the prosthesis was observed in 3 patients in the study group (5.3%) and 4 in the control group (12.5%). There was less dislocation of the prosthesis in the study group, but the difference was not statistically significant. CONCLUSION: Placement of a cartilage graft between the footplate of the stapes and the foot of the prosthesis may have positive effects on long-term hearing improvement and rates of prosthesis displacement. Further research with larger patient numbers is needed to identify the advantages of shoe graft. PMID- 26954856 TI - Endoscopic autologous cartilage injection for the patulous eustachian tube. AB - Patulous eustachian tube (PET) can have a significant negative impact on a patient's quality of life. Several methods of surgical management can be an option to treat PET, and our objective is to evaluate the safety and efficacy of autologous cartilage injection in patients with PET. Thirty-three ears of twenty five patients with chronic PET refractory to conservative treatment were enrolled to this study. Autologous tragal cartilage was harvested, and chopped into fine pieces to allow its injection using a 1 cc Bruening syringe. Endoscopic cartilage injection was performed submucosally into the anterior (0.5 mL) and posterior aspects (0.5 mL) of the nasopharyngeal ET under local anesthesia in an operating room. Patients were evaluated postoperatively by nasal endoscopy and by interview to document symptoms. Successful treatment was defined as complete relief or significant improvement plus satisfaction with treatment. The only complication that occurred was temporary otitis media with effusion in one ear. Inferior turbinate reduction was performed in three ears with accompanying nasal septal deviation or turbinate hypertrophy to allow better nasopharyngeal ET visualization. After autologous cartilage injection, the successful treatment rate, as determined by subjective autophony symptoms, was 69.7% (23/33). The average follow-up period was 25.2 months. Autologous cartilage injection is a minimally invasive technique that has been used by the authors to successfully treat patulous eustachian tube. The described procedure was found to provide a good overall success rate without long-term complications. PMID- 26954858 TI - Non tuberculous mycobacterial lesion of the parotid gland and facial skin in a 4year old girl: A proposed treatment strategy. AB - OBJECTIVE: We report a case of a parotid-facial caseating granulomatous infection caused by atypical mycobacteria (Mycobacterium avium) in an immuno-competent child. The size and depth of the lesion and its proximity to the facial nerve present a challenge for a purely surgical treatment strategy. An alternative treatment strategy is developed to avoid severe disfigurement. STUDY DESIGN/SUBJECT: Atypical mycobacterial infection of the parotid region in a 5 year old girl: timeline and definition of a planned combined treatment strategy with antibiotics and surgical excision. RESULTS/CONCLUSION: Cervicofacial infections caused by non-tuberculous mycobacteria (NTM) may present surgical challenges due to the size and depth of the lesion and its proximity to the facial nerve and major vascular structures. Even minor scars are highly visible and poorly tolerated. Close clinical monitoring combined with judicious treatment strategies is necessary for successful treatment and good cosmesis. Recent literature provides insufficient guidance in formulating the best treatment strategy for the individual patient. Comparisons of antibiotic therapy with variations of surgical excision are abundant but poorly formulated. Our case presented with a lesion involving skin, superficial and deep lobe of the parotid gland. Lesion was in immediate proximity to the distribution of the facial nerve through the parotid gland. The risk of surgical damage to the facial nerve in the acute phase of the inflammation and the required extent of skin excision were significant. We decided to start treatment with combination antimycobacterial antibiotics in close cooperation with the pediatric infectious disease specialists. We observed and documented the regress and executed a delayed surgical excision when the lesion was reduced to skin only. In our opinion this was the best treatment strategy that helped us avoid extensive dissection in the vicinity of the facial nerve as well as a parotidectomy. Excision of the involved skin with the deep portion was performed 6.5 months after initial diagnosis. PMID- 26954857 TI - Cochlear changes in serous labyrinthitis associated with silent otitis media: A human temporal bone study. AB - PURPOSE: To determine histopathological findings in the cochlea of human temporal bones with serous labyrinthitis. MATERIALS AND METHODS: We compared human temporal bones with serous labyrinthitis (20 cases) associated with silent otitis media and without serous labyrinthitis (20 cases) to study location of serous labyrinthitis, the degree of endolymphatic hydrops, number of spiral ganglion cells and hair cells, loss of fibrocytes in the spiral ligament, and areas of the spiral ligament and stria vascularis. RESULTS: The serous labyrinthitis caused significant loss of outer hair cells in the lower basal (P=0.006), upper basal (P=0.005), and lower middle (P=0.011) cochlear turns, and significant increase in the degree of endolymphatic hydrops than the control group (P=0.036). No significant difference was found in the loss of inner hair cells, in the number of spiral ganglion cells and fibrocytes in the spiral ligament, and in areas of the stria vascularis and spiral ligament (P>0.05). CONCLUSIONS: Serous labyrinthitis resulted in significant loss of outer hair cells and significant increase in the degree of endolymphatic hydrops. PMID- 26954859 TI - Intraoral midline mandibulotomy improves laryngeal access for transoral resection of laryngeal cancer. AB - Intraoral midline mandibulotomy is a technique that can be used to increase exposure for transoral endoscopic laser microsurgery (TLS). We describe the case of a 51 year old male with persistent T1 glottic carcinoma. At initial diagnosis, he had been referred for curative radiotherapy as laryngeal access was not sufficient for TLS. For treatment of his recurrence, we describe the technique of performing a midline mandibular osteotomy to improve access to the larynx allowing for safe and effective transoral endoscopic laser microsurgery. Surgical access to the larynx was greatly improved, and we were able to perform TLS in a case that would have otherwise not been amenable to TLS. An intraoral midline mandibulotomy can improve access to the larynx and allow for successful transoral resection of laryngeal cancer in patients with otherwise inaccessible tumors. PMID- 26954860 TI - Efficacy of balloon dilation in the treatment of symptomatic Eustachian tube dysfunction: One year follow-up study. AB - PURPOSE: Eustachian tube balloon dilation (ETBD) has been recently described as feasible treatment for patients with refractory Eustachian tube dysfunction (ETD). The aim of this study was to evaluate the efficacy of ETBD in the treatment of symptomatic Eustachian tube dysfunction (SETD) by subjective and objective analysis. MATERIALS AND METHODS: Forty patients who underwent ETBD were included in the study. Subjects' inclusion criteria were as follows: symptoms of ETD (aural fullness predominantly, with or without otalgia, muffle hearing and tinnitus), normal tympanic membrane, type A or C tympanograms, and without a history of any middle ear diseases. Main outcomes including subjective improvement, otoscopy, pure-tone audiometry, impedance audiometry, R-value in tubomanometry (TMM) at three pressure measurements (30, 40, and 50 mbar), Eustachian Tube Score (ETS) and the ability to perform a Valsalva maneuver were assessed preoperatively, 1 week, 3 months and 12 months postoperatively. RESULTS: All cases were dilated successfully. A significant effect of treatment was documented when measuring subjective improvement, impedance audiometry, R-value in TMM, ETS and the ability to perform a Valsalva maneuver 1 week, 3 months and 12 month postoperatively. Subjective symptoms were not relieved only in one patient. The overall success rate for all patients was 98%. CONCLUSIONS: ETBD can provide both short- and long-term benefits to those who are diagnosed SETD and refractory to medical management. SETD might be an optimal indication for ETBD in the treatment of ETD. PMID- 26954861 TI - Long-term radiological findings after endonasal endoscopic approach to the skull base. AB - OBJECTIVE: To study the long-term radiological findings after endonasal endoscopic approach to the skull base. MATERIAL AND METHODS: Prospective study that included 55 patients who underwent advance endoscopic skull base surgery. All patients were evaluated with MRI before, 3 months and 12 months after surgery. We used the Lund-Mackay staging system for chronic rhinosinusitis to evaluate the paranasal cavities and the sinonasal scoring system to assess sinonasal symptoms. RESULTS: Seventeen patients (30.9%) underwent extended endonasal approach that required a nasoseptal flap (NSF) for reconstruction of skull base. At baseline the mean total Lund-Mackay score was 0.63 +/- 1.2 (range 0-4), and at 3 and 12 months postoperatively the mean scores were 3.5 +/- 3.8 (range 0-14) and 2.0 +/- 2.5 (range 0-8) respectively. Patients who needed an NSF for reconstruction had a greater Lund-Mackay score (p<0.05). Moreover, NSF is correlated with sinonasal mucosal thickening and fluid retention at 3 months (r=0.45, p<0.01) and 12 months (r=0.4, p<0.01). Total 5-symptom score (T5SS) was similar between both groups at baseline. Patients with extended endoscopic approach reported more smell loss (40.1 +/- 26.2; p<0.05) and posterior nasal discharge (49.3 +/- 30.1; p<0.05) than TTEA patients (21.6 +/- 30.9 and 22.5 +/- 27.5 respectively). CONCLUSIONS: We observed that sinus opacity is still present after one year of advance endoscopic skull base surgery but symptoms seems to return to basal after 12 months of follow-up. PMID- 26954862 TI - Neuroendocrine adenoma of middle ear with new bone formation and review of literature. AB - Neuroendocrine adenoma of the middle ear has been described in literature as middle ear adenoma with neuroendocrine differentiation or carcinoid tumor. While there have been several case reports describing imaging features of carcinoid tumors of the ear and middle ear adenomas, in our literature review, we have not found a single case where bone formation is described as a prominent radiological feature. We report a first documented case of middle ear carcinoid tumor with new bone formation demonstrated on CT imaging and performed a review literature regarding the tumor. A differential diagnosis of neuroendocrine adenoma of the middle ear should be considered when there is prominent bone formation with a soft tissue mass in the middle ear on CT imaging. PMID- 26954863 TI - Adult onset xanthogranuloma presenting as laryngeal mass. AB - Histiocytic disorders can be classified according to the distribution pattern of the lesions and the organs involved. Non-Langerhans-cell histiocytosis is a rare group of diseases that have varied clinical presentations ranging from isolated masses to diffuse systemic eruptions. We discuss a patient who initially presented with a vocal cord lesion and was ultimately diagnosed with adult onset xanthogranuloma. PMID- 26954864 TI - Evaluation of iron and zinc levels in recurrent tonsillitis and tonsillar hypertrophy. AB - OBJECTIVES: The aim of this study is to look into the roles of iron and zinc metals in etiopathogenesis of recurrent tonsillitis and tonsillar hypertrophy by evaluating the levels of iron and zinc elements in the palatine tonsillar tissue. METHODS: In total, 40 patients who underwent a tonsillectomy to treat recurrent tonsillitis and tonsillar hypertrophy were included in the study. Patients were classified into two groups, recurrent tonsillitis and tonsillar hypertrophy, determined by the results of clinical and histopathological examination. The levels of iron and zinc elements were determined for each tonsillar tissue sample. RESULTS: There was a significant difference in the iron and zinc concentrations (p<0.001) between the tonsillar hypertrophy and recurrent tonsillitis groups. The levels of iron and zinc were significantly lower in the recurrent tonsillitis group. CONCLUSIONS: This study suggests that low tissue concentrations of iron and zinc may lead to recurrent tonsillitis. PMID- 26954865 TI - Pre-operative chemoradiation for sinonasal undifferentiated carcinoma of the anterior nasal cavity resected through a lateral nasal flap approach. AB - INTRODUCTION: Sinonasal undifferentiated carcinoma (SNUC) is an exceedingly rare and aggressive tumor that carries a poor prognosis due to its non-specific presentation and advanced stage at time of diagnosis. Early detection and treatment are vital, with chemotherapy, radiation, and surgery all being viable options. The literature is sparse and there is no consensus for optimal treatment. In surgical candidates, the otolaryngologist must have a vast skill set in order to resect the tumor with wide margins and reconstruct the defect in hopes of returning the patient to their pre-morbid state. METHODS: A 74-year-old female presented with a growing left nasal mass which was biopsied and found to be a sinonasal undifferentiated carcinoma originating from the anterior nasal cavity between the septum and upper lateral cartilage. The patient was treated with neo-adjuvant carboplatin with concurrent radiation, followed by resection through a lateral nasal flap. The defect was reconstructed with a contralateral septal hinge flap and septal cartilage graft with primary closure of the lateral nasal flap. RESULTS: Intraoperatively, no skin or cartilage invasion was noted and as such, nasal skin was spared and utilized for primary closure. At a follow up of 3 months, the patient had no evidence of recurrence and had a well healing repair site with satisfactory cosmesis. CONCLUSIONS: Despite the aggressive nature of SNUC tumors, neo-adjuvant chemo-radiation and surgical intervention with functionally and aesthetically minded reconstruction can provide patients with improved outcomes and decreased morbidity. PMID- 26954866 TI - Immediate obturator stabilization (ISO) in severely atrophic edentulous maxilla: Suspension wiring technique. PMID- 26954867 TI - Evaluation of growth curves in children after supraglottoplasty. AB - OBJECTIVES: To determine if monitoring weight growth curves is a sensitive objective parameter for evaluating operative outcomes after supraglottoplasty. STUDY DESIGN: Retrospective chart review. METHODS: An IRB approved retrospective review of patients who underwent supraglottoplasty from 2/28/2012 to 10/20/2014 by the otolaryngology department at a single institution was performed. Variables collected included age, race, sex, preoperative weight percentiles, and weight percentiles at 3 month, 12 month, and 3 year followup intervals. RESULTS: 20 patients met inclusion criteria. 15 (75%) patients were male and 5 (25%) were female. 9 (45%) patients were African American, 8 (40%) were Caucasian, and 3 (15%) were other. Average weight for age at surgery was 29.8 percentile. 6 (30%) had failure to thrive by weight. By 3 months postop average weight had increased by 7.67 percentile (p=0.09, 95% CI -1.62 to 17.0), by 12 months there was an observed increase of 19.1 percentile (p=0.06, 95% CI 0.47-37.8), and by 3 years the average weight had increased by 26.53 percentile (p=0.03, 95% CI 4.47-48.59). By three years postop the average weight had normalized (64.5 percentile). Among those who met preoperative failure to thrive criteria (average 0.11 percentile), weight gain was still dramatic with average weight percentile of 37.5 by 3 years postop. CONCLUSION: Patients undergoing supraglottoplasty are typically underweight for age. Statistically significant weight gain occurs in children after going supraglottoplasty. This intervention can normalize their growth chart growth patterns by 3 years postoperatively, even in children with failure to thrive. PMID- 26954868 TI - Three-week loading of the 4.5mm wide titanium implant in bone anchored hearing systems. AB - PURPOSE: The purpose of this study is to assess implant stability, implant loss, adverse skin reactions and quality of life benefit following surgical implantation and early processor loading (3-weeks post-implantation) of the Oticon Ponto 4.5 mm osseointegrated auditory implant. This study also investigates the relationship between the type of post-operative skin reactions and the gender, BMI and medical co-morbidities of participants. MATERIALS/METHODS: Using a prospective, multicenter design, thirty adult patients 18 years or older who met medical and audiological candidacy for an osseointegrated auditory bone-anchored hearing device were evaluated. They underwent simultaneous implantation of the Oticon 4.5mm wide implant and a 3.75 mm sleeper implant. Sound processor loading occurred at three weeks post implantation. Implant stability was measured using Radio Frequency Analysis (RFA) at surgery, 1, 3, 6, 12, 26 and 52 weeks. The Glasgow Benefit Inventory was used to assess quality of life benefit at 12 and 52 weeks following implantation. RESULTS: The results show a positive linear trend in implant stability measures in all subjects over time. There have been no implant losses with early 3-week loading. Skin reactions were limited to grade 0 and 1 of the modified Holger's grading scale. Due to the limited incidence of complications, no conclusion can be made regarding the relationship between patient demographic data and soft tissue reaction. CONCLUSION: Our findings confirm the safety and efficacy of early loading of the Oticon 4.5 mm wide implant. Participants showed satisfaction with the earlier use of their processor with no added complications after one year post-implantation. PMID- 26954869 TI - Bony ankylosis of hydroxyapatite prostheses in the middle ear. AB - BACKGROUND: Ossiculoplasty is a commonly performed middle ear procedure. Ossicular chain reconstruction (OCR) prostheses should be made of a biocompatible material; one such common material is hydroxyapatite (HA). METHODS: 2 patients were identified who had HA OCR prostheses which had fused to the middle ear bony structures. One HA OCR had fused to the fallopian canal in the tympanic segment and represented a management dilemma. The other fused to the scutum. CONCLUSION: Bony ankylosis of a HA containing OCR prosthesis should be considered in the differential diagnosis of a failed ossiculoplasty. Depending on the location of the fusion, special measures may be needed to free the prosthesis from the underlying middle ear structures. PMID- 26954870 TI - Sternocleidomastoid contour restoration: an added benefit of the anterolateral thigh free flap during facial reconstruction. AB - PURPOSE: To demonstrate the potential of the anterolateral thigh free flap for neck contour restoration. STUDY DESIGN: Retrospective chart review at a tertiary care medical center of patients who underwent radical parotidectomy with sternocleidomastoid sacrifice, with or without temporal bone resection, and reconstruction of both facial and cervical contour with the anterolateral thigh free flap between November 2011 and March 2015. Seven patients were included and demographics, flap viability, pathology and tumor staging, surgical intervention, adjunctive reanimation procedures, ischemia time, and pre-operative and post operative photos were recorded and analyzed. RESULTS: There were no flap failures and the mean ischemia time was 82 minutes. There were 2 recipient site complications. Post-operative neck symmetry was improved for all 7 patients. CONCLUSIONS: The adipofascial anterolateral thigh flap is useful for improving the aesthetic contour of the neck among patients undergoing sternocleidomastoid muscle resection/disinsertion following total parotidectomy with/without temporal bone resection. Contour restoration may be performed with minimal added morbidity and with relatively little additional operative time. This technique may be adapted for other complex facial and neck defects caused by ablative surgery. LEVEL OF EVIDENCE: 4. PMID- 26954871 TI - Adenoid cystic carcinoma of the lacrimal gland. AB - PURPOSE: This is a retrospective analysis of the 50-year University of Florida experience treating adenoid cystic carcinoma of the lacrimal gland with radiation therapy. MATERIALS AND METHODS: Between 1965 and 2015, 8 patients with adenoid cystic carcinoma of the lacrimal gland received radiation therapy with curative intent. Four patients received postoperative radiation therapy and 4 received definitive radiation therapy alone. The median follow-up was 3.3 years (range, 0.3 to 11.2 years). RESULTS: All 4 patients who received postoperative radiation therapy received 74.4 Gy. The 4 patients who received radiation therapy alone received a median dose of 72.3 Gy (range, 70.0 to 74.4 Gy). The overall survival rates at 5 and 10 years were 25% and 13%, respectively. The cause-specific survival rates at 5 and 10 years were 29% and 14%, respectively. The local control and freedom from metastases rates at 5 and 10 years were both 43%. Local recurrences occurred in 50% of patients, and distant metastatic disease occurred in 38% of patients. No patients experienced acute complications of treatment that warranted a treatment break. Two patients experienced bone exposure as late complications of treatment. CONCLUSIONS: The results of this study illustrate the propensity for adenoid cystic carcinoma of the lacrimal gland to recur both locally and with distant metastases despite aggressive local treatment measures. This study also demonstrates the relatively poor outcomes for individuals with this type of tumor. PMID- 26954872 TI - Type IV congenital laryngeal web: Case report and 15 year follow up. AB - A five day old patient with mild VACTERL syndrome had repair of a type IV congenital laryngeal web with successful decannulation 76 days later. Voice and respiratory outcome is good with follow up 15 years later. This case presents a rare clinical finding of a type IV laryngeal web successfully repaired with a keel and subsequent long term follow up during an era when it was suggested that repair be delayed until 18 months of age at the earliest. PMID- 26954873 TI - Successful Isavuconazole therapy in a patient with acute invasive fungal rhinosinusitis and acquired immune deficiency syndrome. AB - OBJECTIVES: To report a case of acute invasive Mucorales rhinosinusitis in a patient with acquired immune deficiency syndrome and diabetes mellitus. To provide a literature review on the role of Isavuconazole in the management of invasive Mucorales rhinosinusitis. METHODS: A literature review was conducted on August 9, 2015 using PubMed database. The keywords isavuconazole and invasive fungal rhinosinusitis were employed to identify original scientific manuscripts that describe the use of Isavuconazole in patients with invasive fungal rhinosinusitis or rhinocerebral mucormycosis. RESULTS: The initial search yielded 35 articles with only 1 article (case report) describing the clinical use of Isavuconazole in a patient with invasive Mucorales rhinosinusitis. CONCLUSIONS: Acute invasive fungal rhinosinusitis is a rare, life-threatening infection with mortality rates reported to range from 30-83%. Successful treatment depends on early surgical debridement, systemic anti-fungal therapy, and correction of predisposing conditions. Isavuconazole (Cresemba), a newly approved antifungal, is safe and clinically effective in treating invasive mucormycosis. This important new therapy should be considered for patients with invasive Mucorales rhinosinusitis that is refractory or intolerant to Amphotericin B. PMID- 26954874 TI - Direct application of bFGF without edge trimming on human subacute tympanic membrane perforation. AB - OBJECTIVE: To investigate the feasibility of direct application of basic fibroblast growth factor (bFGF) without edge trimming on human subacute traumatic tympanic membrane perforation (TMP). METHODS: A total of 29 patients with traumatic TMPs beyond 1 month after trauma were enrolled. Patients were placed into two groups: an observation group (n=17) and a bFGF-treated group (n=12). The bFGF-treated group was treated by direct application of bFGF, in which the margin of the perforation was not trimmed. All patients were followed at least once per week until the perforation was completely closed or for up to 6 months. The closure rate and closure time were estimated. RESULTS: At 6 months, 11/12 (91.7%) perforations achieved complete closure after bFGF treatment. The mean closure time was 18.1 +/- 11.4 days (range=3-65 days). Purulent otorrhea was found after treatment in five patients, but resolved after oral amoxicillin and ofloxacin ear drops. Of these five patients, four achieved complete closure. However, only 9/17 (52.9%) perforations achieved complete spontaneous closure in the observation group. FGF-treated groups had significantly improved closure rates compared to the observation group (91.7% vs. 52.9%, respectively, P=0.03). CONCLUSIONS: Although the margin of the perforation was not trimmed, direct application of bFGF on human subacute TMP was feasible, and it could significantly improve the closure rate of the subacute TMPs. The technique was simple and convenient. Thus, direct application of bFGF should be recommended pre-myringoplasty. PMID- 26954875 TI - Hearing loss patterns after cochlear implantation via the round window in an animal model. AB - PURPOSE: The mechanism and the type of hearing loss induced by cochlear implants are mostly unknown. Therefore, this study evaluated the impact and type of hearing loss induced by each stage of cochlear implantation surgery in an animal model. STUDY DESIGN: Original basic research animal study. SETTING: The study was conducted in a tertiary, university-affiliated medical center in accordance with the guidelines of the Institutional Animal Care and Use Committee. SUBJECTS AND METHODS: Cochlear implant electrode array was inserted via the round window membrane in 17 ears of 9 adult-size fat sand rats. In 7 ears of 5 additional animals round window incision only was performed, followed by patching with a small piece of periosteum (control). Hearing thresholds to air (AC) and bone conduction (BC), clicks, 1 kHz and 6 kHz tone bursts were measured by auditory brainstem evoked potential, before, during each stage of surgery and one week post-operatively. In addition, inner ear histology was performed. RESULTS: The degree of hearing loss increased significantly from baseline throughout the stages of cochlear implantation surgery and up to one week after (p<0.0001). In both operated groups, the greatest deterioration was noted after round window incision. Overall, threshold shift to air-conduction clicks, reached 61 dB SPL and the bone conduction threshold deteriorated by 19 dB SPL only. Similar losses were found for 1-kHz and 6-kHz frequencies. The hearing loss was not associated with significant changes in inner ear histology. CONCLUSIONS: Hearing loss following cochlear implantation in normal hearing animals is progressive and of mixed type, but mainly conductive. Changes in the inner-ear mechanism are most likely responsible for the conductive hearing loss. PMID- 26954876 TI - Oral dyclonine hydrochloride mucilage versus tetracaine spray in electronic flexible laryngoscopy: A prospective, randomized controlled trial. AB - BACKGROUND: Topical anesthesia is important for electronic flexible laryngoscopy (EFL) utilization. We hypothesized that oral dyclonine hydrochloride mucilage (ODHM) is superior to tetracaine spray (TS) in patients undergoing EFL examination. METHODS: This study included 932 patients randomized into either an ODHM or TS group, in which patients received either a single utilization of ODHM or TS administered via spray in three intervals. A 4.9 mm diameter flexible PENTAX-VNL-1570STK insertion tube placed into a Naso-Pharyngo-Laryngoscope (PENTAX Medical, Japan) was used in the procedure. Visual analogue scale (VAS) (0 10) was used to evaluate patient tolerance and procedure success by the operator, independently. Procedure time was also recorded. RESULTS: Both patients' and doctors' VAS scores were significantly higher in the ODHM group compared to the TS group. When subgroup analysis was made according to the procedure length (100 s), there was no significant difference in VAS between ODHM and TS groups in the short time procedure (<=100 s), while VAS in the ODHM group was higher compared to the TS in the long time procedure (>100 s), as assessed by both patients and doctors. CONCLUSION: A single use of ODHM seems to be superior to three doses of TS in patients undergoing EFL, specifically in procedures longer than 100seconds. PMID- 26954877 TI - Evaluation of syncope: focus on diagnosis and treatment of neurally mediated syncope. AB - Syncope, defined as a transient loss of consciousness secondary to global cerebral hypoperfusion, is common in the general population. The single most helpful "test" in the evaluation of patients with syncope is a thoughtful history, with recent evidence that structured histories are remarkably effective in arriving at a diagnosis. In addition to the history, physical examination, and electrocardiogram, arriving at a diagnosis of syncope can involve monitoring and provocative strategies. The majority of patients with syncope have neurally mediated syncope and a favourable prognosis. The management of neurally mediated syncope continues to largely revolve around education, avoidance of triggers, reassurance, and counter-pressure maneuvers. The evidence surrounding medical therapy in vasovagal syncope is not strong to date. Pacemaker therapy is reasonable in older patients with recurrent, unpredictable syncope with pauses, but should be considered as a last resort in younger patients. PMID- 26954878 TI - Bonding performance and interfacial characteristics of short fiber-reinforced resin composite in comparison with other composite restoratives. AB - The purpose of this study was to investigate the shear bond strength (SBS) and surface free-energy (SFE) of short fiber-reinforced resin composite (SFRC), using different adhesive systems, in comparison with other composite restoratives. The resin composites used were everX Posterior (EP), Clearfil AP-X (CA), and Filtek Supreme Ultra Universal Restorative (FS). The adhesive systems used were Scotchbond Multi-Purpose (SM), Clearfil SE Bond (CS), and G-Premio Bond (GB). Resin composite was bonded to dentin, and SBS was determined after 24 h of storage in distilled water and after 10,000 thermal cycles (TCs). The SFEs of the resin composites and the adhesives were determined by measuring the contact angles of three test liquids. The SFE values and SFE characteristics were not influenced by the type of resin composite, but were influenced by the type of adhesive system. The results of this study suggest that the bonding performance and interfacial characteristics of SFRC are the same as for other composite restoratives, but that these parameters are affected by the type of adhesive system. The bonding performance of SFRC was enhanced by thermal cycling in a manner similar to that for other composite restoratives. PMID- 26954879 TI - Microstructural Characterization of Aluminum-Carbon Nanotube Nanocomposites Produced Using Different Dispersion Methods. AB - This research focuses on characterization of the impact of dispersion methods on aluminum-carbon nanotubes (Al-CNTs) nanocomposite structure. Nanocomposites were produced by a conventional powder metallurgy process after the dispersion of the CNTs on the Al powders, using two approaches: (1) the dispersion of CNTs and mixture with Al powders were performed in a single step by ultrasonication; and (2) the CNTs were previously untangled by ultrasonication and then mixed with Al powders by ball milling. Microstructural characterization of Al-CNT nanocomposites was performed by optical microscopy, scanning and transmission electron microscopy, electron backscatter diffraction, and high-resolution transmission electron microscopy (HRTEM). Microstructural characterization revealed that the use of ball milling for mixing CNTs with Al powders promoted the formation of CNT clusters of reduced size, more uniformly dispersed in the matrix, and a nanocomposite of smaller grain size. However, the results of HRTEM and Raman spectroscopy show that ball milling causes higher damage to the CNT structure. The strengthening effect of the CNT is attested by the increase in hardness and tensile strength of the nanocomposites. PMID- 26954880 TI - A Tele-Behavioral Health Intervention to Reduce Depression, Anxiety, and Stress and Improve Diabetes Self-Management. AB - BACKGROUND: Depression is prevalent among individuals with diabetes and associated with suboptimal self-management. Little is known about the feasibility and potential impact of tele-behavioral therapy to improve depressive symptoms and self-management among diabetes patients. METHODS: This was a retrospective observational study of consecutive graduates enrolled in a national 8-week diabetes behavioral telehealth program between August 1, 2014, and January 31, 2015 (N = 466; mean age 56.8 +/- 5.0 years; 56% female). Participant characteristics (demographics, comorbidities) were obtained by standardized questionnaire. Depression, anxiety, and stress symptoms (DASS; validated Depression Anxiety and Stress Scale 21 survey), and glucose self-testing frequency and values (point-of-care monitor) were measured at program start and completion. Changes in DASS severity and glucose self-testing frequency were assessed by chi-square tests. Changes in DASS and blood glucose levels were evaluated by paired t-tests. RESULTS: At baseline, approximately one in three participants had elevated depression (32%), anxiety (33%), or stress (31%) scores. Significant reductions in average DASS, depression (-8.8), anxiety ( 6.9), and stress (-9.9), scores were observed at graduation among those with elevated baseline scores (p < 0.0001); most (>=80%) improved to less severe depression, anxiety, or stress categories. Improved glucose self-testing frequency (69% vs. 60% tested >=once per week; p = 0.0005) and significant reductions in mean morning glucose levels (-12.3 mg/dL; p = 0.0002) were observed from baseline to graduation. Participants with normal versus non-normal depression scores were more likely to have lower (=1 had significantly higher scores on all reported pain measures. Significant positive correlations were found between all pain measures, the total SNOT-22 score, and 3 SNOT-22 subdomains (sleep, psychological dysfunction, and ear/facial symptoms; R = 0.323 to 0.608, p < 0.05). CONCLUSION: Adult patients with CRS at risk for depression experience more pain and have overall worse disease-specific QOL. Further research investigating the complex interactions between depression and pain and the role it plays in CRS disease-specific QOL is warranted. PMID- 26954905 TI - Development of a symptom validity index to assist in identifying ADHD symptom exaggeration or feigning. AB - OBJECTIVE: Concerns have been identified regarding the ease with which students and young adults can feign or exaggerate symptoms of ADHD, and no formal measures exist to identify such behavior when it occurs. This article describes the development and initial validation of a new symptom validity measure designed to detect feigned or exaggerated ADHD symptom reporting. METHOD: Employing items from a commonly used self-report measure of ADHD (Conners' Adult ADHD Rating Scale [CAARS]) and select items from a scale measuring symptoms of dissociation, we assessed students diagnosed with ADHD, students with other diagnoses, and student volunteers with no psychopathology. RESULTS: This new measure (Exaggeration Index or EI) demonstrated excellent specificity (.97) and adequate sensitivity (.24) in discriminating between those who are suspected of or instructed to feign or exaggerate symptoms of ADHD and all other clinical groups. CONCLUSION: The results strongly suggest that the EI may be a useful adjunct to existing validity measures when identifying exaggerated or implausible symptoms of ADHD. PMID- 26954906 TI - Bayesian population size estimation using Dirichlet process mixtures. AB - We introduce a new Bayesian nonparametric method for estimating the size of a closed population from multiple-recapture data. Our method, based on Dirichlet process mixtures, can accommodate complex patterns of heterogeneity of capture, and can transparently modulate its complexity without a separate model selection step. Additionally, it can handle the massively sparse contingency tables generated by large number of recaptures with moderate sample sizes. We develop an efficient and scalable MCMC algorithm for estimation. We apply our method to simulated data, and to two examples from the literature of estimation of casualties in armed conflicts. PMID- 26954907 TI - Nonadiabatic Molecular Dynamics for Thousand Atom Systems: A Tight-Binding Approach toward PYXAID. AB - Excited state dynamics at the nanoscale requires treatment of systems involving hundreds and thousands of atoms. In the majority of cases, depending on the process under investigation, the electronic structure component of the calculation constitutes the computation bottleneck. We developed an efficient approach for simulating nonadiabatic molecular dynamics (NA-MD) of large systems in the framework of the self-consistent charge density functional tight binding (SCC-DFTB) method. SCC-DFTB is combined with the fewest switches surface hopping (FSSH) and decoherence induced surface hopping (DISH) techniques for NA-MD. The approach is implemented within the Python extension for the ab initio dynamics (PYXAID) simulation package, which is an open source NA-MD program designed to handle nanoscale materials. The accuracy of the developed approach is tested with ab initio DFT and experimental data, by considering intraband electron and hole relaxation, and nonradiative electron-hole recombination in a CdSe quantum dot and the (10,5) semiconducting carbon nanotube. The technique is capable of treating accurately and efficiently excitation dynamics in large, realistic nanoscale materials, employing modest computational resources. PMID- 26954908 TI - Current Epidemiology and Emerging Interventions for People With Co-occurring Mental Illness and Substance Use Disorders. PMID- 26954909 TI - Dual Diagnosis in an Aging Population: Prevalence of Psychiatric Disorders, Comorbid Substance Abuse, and Mental Health Service Utilization in the Department of Veterans Affairs. AB - OBJECTIVE: In the context of an aging baby boom cohort with higher rates of substance use disorders than previous cohorts, the abuse of substances and dual diagnosis represent growing areas of concern among older adults. The aims of this study were to determine the current treated prevalence of major psychiatric illnesses, substance use disorders, and dual diagnosis across multiple age groups in a national sample of mental health patients and to examine associated service utilization. METHODS: Using administrative data from specialty mental health clinics in the Department of Veterans Affairs (N = 911,725), treated prevalence of major psychiatric illnesses, substance use disorders, and dual diagnosis across multiple age groups were determined over a 1-year interval (FY 2009). Associated mental health service utilization was examined. RESULTS: Treated prevalence of almost all major psychiatric and substance use disorders decreased with age, while dementias increased with age. Across all major psychiatric illnesses, documented comorbid substance abuse decreased with age. Those with dual diagnoses had higher utilization of outpatient services compared to those without substance use disorders. With older age, patients had fewer outpatient visits and reduced likelihood of psychiatric hospitalization, but incurred more inpatient days per episode. CONCLUSIONS: Treated prevalence of substance use disorders and dual diagnosis decreases with age, falling to approximately 10% in those older than 65. Questions remain regarding the possibility of underdiagnosis of substance use disorders in the elderly. PMID- 26954910 TI - Prevalence and Sociodemographic Correlates of Mental Health Problems Among Emergency Department Patients With High-Risk and Dependent Alcohol Use Patterns. AB - OBJECTIVE: This study reports the prevalence of co-occurring mental health problems in a large convenience sample of emergency department (ED) patients with high-risk or dependent alcohol use patterns, as well as investigates associations between sociodemographic variables with co-occurring alcohol and mental health problems. METHODS: Health educators screened adult patients from 12 large Southern California hospital ED/trauma units, collecting data about alcohol use behavior, sociodemographic data, and past 30-day problems with depression, anxiety, and cognitive function. Participants (N = 1,369) scored within either high-risk (hazardous, nondependent) or severe-risk (likely dependent) alcohol use categories. Analyses examined associations between age, sex, annual family income, employment status, and race/ethnicity with past 30-day mental health problems. RESULTS: Overall, prevalence rates of 65%, 67%, and 50% were found for past 30-day problems with depression, anxiety, and cognitive function, respectively. Lower age was associated with anxiety problems only. Female gender was strongly associated with depression and anxiety. Higher income was associated with anxiety; lower income was associated with cognitive function problems. Employment status was strongly associated with all three mental health problems, with the unemployed having about double the risk of the employed. Race was associated with both depression and anxiety. CONCLUSIONS: Results suggest that emergency department patients with high-risk drinking patterns experience high rates of depression, anxiety, and cognitive function problems. Vulnerable groups may be identified based on sociodemographic characteristics. Incorporating standardized screening for mental health problems in the emergency department may be appropriate, especially among those presenting with alcohol-related problems. PMID- 26954911 TI - Prevalence of Substance Use in People With First-Episode Psychosis. AB - OBJECTIVE: People experiencing a first episode of psychosis often have co occurring substance use, which increases risk of prolonged psychosis and impairs recovery. This article examines the prevalence of substance use in people with first-episode psychosis. METHODS: The authors searched MEDLINE and other databases for articles published between 1990 and 2009 that described current or lifetime prevalence of substance use, misuse, abuse, or dependence in individuals with first-episode psychosis. RESULTS: Forty-four unique studies provided information. More than 25% of individuals with first-episode psychosis in reviewed studies indicated current or lifetime alcohol use, lifetime alcohol abuse/dependence, current or lifetime cannabis use, or lifetime cannabis abuse or dependence. For all substances, lifetime prevalence of abuse/dependence was higher than current abuse/dependence. CONCLUSIONS: Despite variation in assessment methods, findings were generally consistent. Individuals with first episode psychosis have lower current substance prevalence than lifetime prevalence, suggesting cessation of some substance use prior to seeking treatment for psychosis. PMID- 26954912 TI - Treatment With Acamprosate in Patients With Schizophrenia Spectrum Disorders and Comorbid Alcohol Dependence. AB - OBJECTIVE: Alcohol use disorders and schizophrenia frequently co-occur with rates higher than in the general population. There is no consensus on the best treatment for patients with these comorbid conditions. Several clinical trials have shown that acamprosate is superior to placebo in reducing drinking and is particularly effective in sustaining abstinence. No study to date has examined the efficacy of acamprosate in patients with alcohol dependence and comorbid schizophrenia. The aims of this study are to assess the efficacy of acamprosate when compared to placebo in reducing drinking and to examine its effects on schizophrenic symptoms. METHODS: This was a double-blind, randomized, 12-week treatment trial of acamprosate versus placebo. Twenty-three recently abstinent patients with diagnosed alcohol dependence and comorbid schizophrenia, schizoaffective disorder, or psychosis not otherwise specified were included in this study. RESULTS: All participants significantly decreased their drinking during medication treatment, although acamprosate was not superior to placebo in increasing consecutive days of abstinence. There was a significant difference favoring the acamprosate group on obsessive thoughts of drinking but no significant group X time interaction. Overall, medication treatment significantly reduced positive symptoms of schizophrenia, but there were no group differences. CONCLUSIONS: Acamprosate was not more effective than placebo in reducing drinking or symptoms of schizophrenia. It can be safely used in patients with alcohol dependence and comorbid schizophrenia spectrum disorders. PMID- 26954913 TI - The Trauma Recovery and Empowerment Model: A Quasi-Experimental Effectiveness Study. AB - OBJECTIVE: A quasi-experimental study tested the effectiveness of the Trauma Recovery and Empowerment Model (TREM), a group intervention for women trauma survivors, in comparison to services as usual. METHODS: Two hundred fifty-one women with histories of physical and/or sexual abuse and co-occurring serious mental illnesses and substance use disorders completed comprehensive study assessments at baseline and at 6 and 12 months. TREM groups were added to standard services at two community mental health agencies in Washington, DC (n = 153). Comparison group participants received usual services at two agencies in Baltimore, MD (n = 98). RESULTS: TREM participants showed greater reductions in alcohol and drug abuse severity, anxiety symptoms, and current stressful events, and they showed greater increases in perceived personal safety. There were no group differences in change for posttraumatic stress disorder and global mental health symptoms, physical and mental health-related quality of life, and exposure to interpersonal abuse. Changes in trauma recovery skills were associated positively with gains in study outcomes for TREM group participants. CONCLUSIONS: Despite design limitations, this study provides preliminary evidence for the effectiveness of the TREM intervention for a heterogeneous population of women trauma survivors with co-occurring disorders when added to usual services. PMID- 26954914 TI - Corrigendum. PMID- 26954915 TI - How Employed Physicians' Contracts May Threaten Their Patients and Professionalism. PMID- 26954916 TI - Let Them Take the Pebble From Your Hand. PMID- 26954917 TI - Nursing Bedside Dysphagia Screen: Is It Valid? PMID- 26954919 TI - Pharmacologic Management of Paroxysmal Sympathetic Hyperactivity After Brain Injury. AB - Paroxysmal sympathetic hyperactivity (PSH) is a result of acute brain injury that has been well known for many decades. However, the evidence for management of PSH is almost entirely anecdotal in nature. We reviewed case reports or series of pharmacotherapy management of PSH. These studies mentioned treatment options, but few studies exist to guide treatment strategies. For many years, the syndrome was not clearly understood; therefore, the therapy has focused on control of symptoms. In 2014, a Steering Committee came together to develop a conceptual definition and produced a consensus set of diagnostic criteria. Although understanding the diagnostic criteria is very well needed in management of patients with PSH, pharmacologic management is also crucial. Data describing the drug choices, dosing, and duration of therapy are also sparse. Recognition of appropriate medications is important because PSH is associated with morbidity, longer hospitalization, delaying transfer to rehabilitation units, and increasing cost. In this review article, we discussed the common medications used in the treatment of PSH. Treatment should target symptom abortion, prevention of symptoms, and refractory treatment. Symptom-abortive medications are indicated to control discrete breakthrough episodes, using medications such as morphine and short-acting benzodiazepines. Other medications used for prevention of symptoms and refractory treatment include long-acting benzodiazepines, nonselective beta blockers, alpha2 agonists, opioids, and GABA agonists. The mechanisms by which these agents improve symptoms of PSH remain speculative. However, a combination of medications from different classes seems the most effective approach in managing PSH symptoms. There is wide variability in clinical practice with regard to drug choices, dosing, and duration of therapy. Future research needs to be conducted using the new PSH assessment measure to appropriately apply drug management. PMID- 26954921 TI - The changing landscape in drug resistant-tuberculosis: an analysis of recent advances. PMID- 26954922 TI - [Not Available]. AB - Systematic improvement of quality of care at the end of life is still scarce. The regional palliative care service in Skane, which has eight units covering a population of almost 1.3 million inhabitants, has systematically used the Swedish Register of Palliative Care (SRPC, http://www.palliativ.se/ ) for care development. 9 out of 12 of the indicators improved significantly in 2014 compared to 2013. Through transparency of registered data and regular feedback to the department's units we have been able to encourage the exchange of experiences between the units, provide opportunities for internal and external benchmarking and also prioritize topics for teaching and training. The positive results must be interpreted with caution as this is a non-controlled follow-up. The exact correlation between recorded data and value for the patient is mainly unknown and requires further studies. PMID- 26954923 TI - [Not Available]. AB - As part of a mandate to provide continuing professional development (CPD) for paediatricians in western Sweden and to support patient safety, we have addressed the professional demands which are imposed on today's consultant paediatricians on call, by designing and implementing a CPD programme for this group. Learning objectives for specific learning modules were developed from a pre-course needs assessment among consultants. The implemented programme included a variety of learning, assessment and evaluation methods. Each specific learning module began with a reading assignment exploring the key concept. This prepared the participants for the case discussion, in which they would analyse, reflect and achieve a deeper level of understanding. We believe that the educational methods used and the approach of the programme are applicable to specialist training as well as to CPD programmes in general, as part of a lifelong learning process. PMID- 26954924 TI - [Not Available]. AB - We summarize an HTA report regarding patient values of drug-eluting stents and balloons for treatment of atherosclerotic disease in the lower extremities. We found 17 randomized controlled trials, 4 cohort studies and 13 case series. The total number of studied patients was substantial (about 3,000) but there was a strong heterogeneity regarding site of lesion, symptom pattern, device, drug used and outcome measures, making the analysis difficult and based on relatively small subgroups. We found low certainty of evidence (GRADE ++) for a reduced risk of restenosis in patients with critical ischemia and lesions below the knee, and also a modest beneficial effect on ischemic symptoms in a mixed patient population. However, we also identified a worrying safety signal, with increased risk for amputation in a group of patients with below-the-knee disease and critical ischemia. The results highlight the need for a structured system for validation of medical devices, a system analogous to that currently used for evaluation of new pharmacological products. PMID- 26954925 TI - [Not Available]. PMID- 26954926 TI - [Not Available]. AB - Exocrine pancreatic insufficiency may result in urgency and foul smelling steatorrhea that is difficult to flush. The simplest way of diagnosis is by observing the response to therapy with high dose pancreatic enzymes. We here describe two different cases of exocrine insufficiency in elderly patients who earlier had some form of pancreatic surgery. These cases illustrate the varying presentations of exocrine pancreatic insufficiency and how proper history taking can help to cure this debilitating condition. PMID- 26954927 TI - [Depression and evidence - Stockholm is not Sweden]. PMID- 26954928 TI - [A new wave of internship applications from foreign students]. PMID- 26954929 TI - [Misleading about viral infections, hand hygiene and hand disinfectants]. PMID- 26954930 TI - [The fact remains - evidence in psychiatry is complicated]. PMID- 26954931 TI - [The scientific community has a joint responsibility for the Macchiarini case]. PMID- 26954932 TI - [Not Available]. PMID- 26954933 TI - [Not Available]. PMID- 26954934 TI - The effect of quantitative and qualitative antiepileptic drug changes on cognitive recovery after epilepsy surgery. AB - PURPOSE: Epilepsy surgery is associated with a risk of cognitive deterioration, but improvement has also been reported. Improvements have mostly been attributed to seizure control, neglecting changes in drug treatment during the observation period. We evaluated whether changes of antiepileptic treatment affect cognitive outcome one year after epilepsy surgery. METHODS: This retrospective study evaluated the impact of quantitative and qualitative antiepileptic drug changes on postoperative outcome on cognition (executive functions, episodic memory) and mood in 116 epilepsy surgery patients, controlling the results for seizure outcome (seizure free yes/no) and site of surgery (87 temporal lobe, 29 extratemporal lobe resections). RESULTS: At baseline, 60% of all patients showed impairment in executive functions, 54% in memory, 49% in mood. Postoperatively, 65% of the patients were seizure free. Executive functions, memory, and mood improved in 22%, 10%, and 32%, respectively, and deteriorated in 15%, 21%, and 11%. Drugs were changed quantitatively (change of drug load) and qualitatively (optimization in regard to side effect profiles). According to MANCOVA and individual level analyses, executive functions changed significantly with altered drug load. This was confirmed by partial correlations when controlling for seizure outcome. Memory outcome was more strongly determined by site of surgery. Mood improved non-specifically. However, qualitative drug change had some positive effect on postoperative memory and mood. CONCLUSION: The data highlight the relevance of AED changes for cognitive outcome after epilepsy surgery. Drug load reduction and selection of drugs with favorable side effect profiles significantly release cognitive functions thereby supporting recovery after epilepsy surgery. PMID- 26954935 TI - Aptamer-integrated DNA nanostructures for biosensing, bioimaging and cancer therapy. AB - The combination of nanostructures with biomolecules leading to the generation of functional nanosystems holds great promise for biotechnological and biomedical applications. As a naturally occurring biomacromolecule, DNA exhibits excellent biocompatibility and programmability. Also, scalable synthesis can be readily realized through automated instruments. Such unique properties, together with Watson-Crick base-pairing interactions, make DNA a particularly promising candidate to be used as a building block material for a wide variety of nanostructures. In the past few decades, various DNA nanostructures have been developed, including one-, two- and three-dimensional nanomaterials. Aptamers are single-stranded DNA or RNA molecules selected by Systematic Evolution of Ligands by Exponential Enrichment (SELEX), with specific recognition abilities to their targets. Therefore, integrating aptamers into DNA nanostructures results in powerful tools for biosensing and bioimaging applications. Furthermore, owing to their high loading capability, aptamer-modified DNA nanostructures have also been altered to play the role of drug nanocarriers for in vivo applications and targeted cancer therapy. In this review, we summarize recent progress in the design of aptamers and related DNA molecule-integrated DNA nanostructures as well as their applications in biosensing, bioimaging and cancer therapy. To begin with, we first introduce the SELEX technology. Subsequently, the methodologies for the preparation of aptamer-integrated DNA nanostructures are presented. Then, we highlight their applications in biosensing and bioimaging for various targets, as well as targeted cancer therapy applications. Finally, we discuss several challenges and further opportunities in this emerging field. PMID- 26954936 TI - Complete Penile Necrosis in a Patient With Heparin-induced Thrombocytopenia: A Case Report. AB - Penile necrosis is a rare condition that has been mostly described in association with diabetes mellitus and end-stage renal disease. We report an unusual case of acute penile necrosis because of heparin-induced thrombocytopenia. A 75-year-old man presented with acute renal failure and experienced cardiac complications during the hospitalization. The patient was treated twice with intravenous heparin. He developed symptoms of penile necrosis 4 days after the reintroduction of heparin. At that moment, the platelet count dropped by 61%, and the analysis of heparin-pf4 antibodies was positive for heparin-induced thrombocytopenia. The patient underwent a total penectomy and a perineal urethrostomy. PMID- 26954938 TI - Positive Effect on Multiple Sclerosis With Treatment of Metabolic Syndrome. PMID- 26954937 TI - Self-other resonance, its control and prosocial inclinations: Brain-behavior relationships. AB - Humans seem to place a positive reward value on prosocial behavior. Evidence suggests that this prosocial inclination is driven by our reflexive tendency to share in the observed sensations, emotions and behavior of others, or "self-other resonance". In this study, we examine how neural correlates of self-other resonance relate to prosocial decision-making. Subjects performed two tasks while undergoing fMRI: observation of a human hand pierced by a needle, and observation and imitation of emotional facial expressions. Outside the scanner, subjects played the Dictator Game with players of low or high income (represented by neutral-expression headshots). Subjects' offers in the Dictator Game were correlated with activity in neural systems associated with self-other resonance and anticorrelated with activity in systems implicated in the control of pain, affect, and imitation. Functional connectivity between areas involved in self other resonance and top-down control was negatively correlated with subjects' offers. This study suggests that the interaction between self-other resonance and top-down control processes are an important component of prosocial inclinations towards others, even when biological stimuli associated with self-other resonance are limited. These findings support a view of prosocial decision-making grounded in embodied cognition. PMID- 26954940 TI - Fractionation of Source Materials Leads to a High Reproducibility of the SQ House Dust Mite SLIT-Tablets. AB - BACKGROUND: The production of house dust mite (HDM) allergen products for allergy immunotherapy has traditionally been based on purified mite bodies or whole-mite culture, which are quite different source materials with a limited possibility for adjusting the chemical composition. The SQ HDM SLIT-tablet is a fast dissolving pharmaceutical formulation that has been developed for sublingual immunotherapy (SLIT) of HDM respiratory allergic disease. OBJECTIVE: The objective of the present study was to establish a process for the production of drug substances for the SQ HDM SLIT-tablet offering a high reproducibility and independent control of the major allergens. METHODS: Process controls were documented in a comprehensive process parameter qualification. The analyses comprised composition by crossed immunoelectrophoresis, protein content by BCA, total IgE binding potency by Centaur assay, quantitative major allergen determination by radial immunodiffusion and ELISA, and the ranking of emPAI scores generated by mass spectrometry. RESULTS: Analysis of 20 batches of final product yielded a normalized mean and standard deviation for IgE binding potency of 100 +/- 4.5. The standard deviation in the contents of Der f 1 and Der p 1 were correspondingly 11.9 and 6.1, whereas the variation in the group 2 major allergen content was 6.4. All measured 95% confidence limits between batches were less than 12%. CONCLUSIONS: The production process for the SQ HDM SLIT-tablet based on the separation of source material into four fractions each enriched in one major allergen enables precise adjustment of the relative major allergen content and high reproducibility of the final product. PMID- 26954939 TI - Modifiable Neighborhood Features Associated With Adolescent Homicide. AB - IMPORTANCE: Homicide is a leading cause of adolescent mortality. To our knowledge, relatively little has been studied in terms of the association between environmental neighborhood features, such as streets, buildings, and natural surroundings, and severe violent injury among youth. OBJECTIVE: To assess associations between environmental neighborhood features and adolescent homicide in order to identify targets for future place-based interventions. DESIGN, SETTING, AND PARTICIPANTS: Population-based case-control study conducted in Philadelphia, Pennsylvania, from April 15, 2008, to March 31, 2014. We identified adolescents who died by homicide at 13 to 20 years of age from 2010 to 2012 while residing in Philadelphia. We used incidence-density sampling and random-digit dialing to recruit control participants ages 13 to 20 years matched on sex and indoor-outdoor location at the time of each index case participant's homicide. EXPOSURES: To obtain environmental data about modifiable features that were present in the immediate surroundings of our case and control participants, blinded field researchers used standardized techniques to photograph case and control participant outdoor locations. Photographic data were stitched together to create 360 degrees panoramic images that were coded for 60 elements of the visible environment. MAIN OUTCOME AND MEASURE: Adolescent homicide. RESULTS: We enrolled 143 homicide case participants (mean [SD] age, 18.4 [1.5] years) and 155 matched control participants (mean [SD] age, 17.2 [2.1] years) who were both outdoors at the time of the homicide. In adjusted analyses, multiple features of Philadelphia streets, buildings, and natural surroundings were associated with adolescent homicide. The presence of street lighting (odds ratio [OR], 0.24; 95% CI, 0.09-0.70), illuminated walk/don't walk signs (OR, 0.16; 95% CI, 0.03-0.92), painted marked crosswalks (OR, 0.17; 95% CI, 0.04-0.63), public transportation (OR, 0.13; 95% CI, 0.03-0.49), parks (OR, 0.09; 95% CI, 0.01-0.88), and maintained vacant lots (OR, 0.17; 95% CI, 0.03-0.81) were significantly associated with decreased odds of homicide. The odds of homicide were significantly higher in locations with stop signs (OR, 4.34; 95% CI, 1.40-13.45), security bars/gratings on houses (OR, 9.23; 95% CI, 2.45-34.80), and private bushes/plantings (OR, 3.44; 95% CI, 1.18-10.01). CONCLUSIONS AND RELEVANCE: Using a population-based case-control design, we identified multiple modifiable environmental features that might be targeted in future randomized intervention trials designed to reduce youth violence by improving neighborhood context. PMID- 26954941 TI - Increased Activity of the Immunoregulatory Enzyme Indoleamine-2,3-Dioxygenase with Consecutive Tryptophan Depletion Predicts Death in Patients with Neuroendocrine Neoplasia. AB - BACKGROUND/AIMS: Data from a considerable number of malignancies demonstrate that depletion of the essential amino acid tryptophan via induction of the immunoregulatory enzyme indoleamine-2,3-dioxygenase (IDO) serves as an important tumour escape strategy and is of prognostic importance. Here we investigate the predictive value of the activity of IDO as well as levels of tryptophan and respective downstream catabolites in a large cohort of patients with neuroendocrine neoplasms (NEN). METHODS: 142 consecutive Caucasian patients (62 male, aged 60.3 +/- 11.9 years) with histologically confirmed NEN were systematically analysed in a retrospective blinded end point analysis. Patients were followed up for a mean period of about 3.9 +/- 1.9 years. Clinical outcome, levels of established biomarkers, and tryptophan degradation markers (assessed using tandem mass spectrometry) including estimated IDO activity were recorded. Cox proportional hazards regression models were performed for the assessment of prognostic power. RESULTS: We found that baseline tryptophan levels were significantly lower and IDO activity was significantly increased in non survivors. The risk for death inclined stepwise and was highest in patients in the upper tertile of IDO activity. Cox proportional regression models identified IDO activity as an independent predictor of death. CONCLUSIONS: In this retrospective analysis, we observed that baseline activity of the immunoregulatory enzyme IDO was significantly increased in non-survivors. IDO activity was identified as an independent predictor of death in this cohort of NEN patients. Whether IDO activity or tryptophan depletion serves to guide future therapeutic interventions in NEN remains to be established. PMID- 26954943 TI - Cellular Stress Responses and Monitored Cellular Activities. AB - To survive, organisms require mechanisms that enable them to sense changes in the outside environment, introduce necessary responses, and resist unfavorable distortion. Consequently, through evolutionary adaptation, cells have become equipped with the apparatus required to monitor their fundamental intracellular processes and the mechanisms needed to try to offset malfunction without receiving any direct signals from the outside environment. It has been shown recently that eukaryotic cells are equipped with a special mechanism that monitors their fundamental cellular functions and that some pathogenic proteobacteria can override this monitoring mechanism to cause harm. The monitored cellular activities involved in the stressed intracellular response have been researched extensively in Caenorhabditis elegans, where discovery of an association between key mitochondrial activities and innate immune responses was named "cellular associated detoxification and defenses (cSADD)." This cellular surveillance pathway (cSADD) oversees core cellular activities such as mitochondrial respiration and protein transport into mitochondria, detects xenobiotics and invading pathogens, and activates the endocrine pathways controlling behavior, detoxification, and immunity. The cSADD pathway is probably associated with cellular responses to stress in human inflammatory diseases. In the critical care field, the pathogenesis of lethal inflammatory syndromes (e.g., respiratory distress syndromes and sepsis) involves the disturbance of mitochondrial respiration leading to cell death. Up-to-date knowledge about monitored cellular activities and cSADD, especially focusing on mitochondrial involvement, can probably help fill a knowledge gap regarding the pathogenesis of lethal inflammatory syndromes in the critical care field. PMID- 26954945 TI - Progesterone levels and days to luteolysis in mares treated with intrauterine fractionated coconut oil. AB - Intrauterine plant oil infusion, including fractionated coconut oil, has been previously found to be a safe, inexpensive, and reversible method of prolonging the luteal phase in mares when administered on Day 10 of the estrous cycle. Our objective was to understand the uteroovarian response to the administration of fractionated coconut oil infusion in the uterus of diestrous mares. We hypothesized that intrauterine coconut oil administration on Day 10 would prolong luteal life span in a dose-dependent fashion and would result in higher serum progesterone levels than untreated mares at the expected time of luteolysis. Light-horse mares (n = 18) were examined using transrectal palpation and ultrasonography to determine if they had a normal interovulatory interval and were then examined daily in estrus until the day of ovulation (Day 0) and then every other day during an estrous cycle. Jugular blood was drawn on Day 11, Day 13, Day 15, and Day 17, centrifuged, and serum stored until assayed for progesterone (P4; Siemens Coat-a-Count Progesterone RIA, Los Angeles, CA, USA). Mares were randomly assigned to treatment and studied over one to two estrous cycles with a rest cycle after each treatment cycle. Groups were: control (n = 5), fractionated coconut oil 1.0 mL (Miglyol 810; Sasol Oil, Witten, Germany) infused in the uterus with an artificial insemination pipette on Day 10 (Group 1; n = 5) and fractionated coconut oil 0.5 mL infused in the uterus with an embryo transfer gun, on Day 10 (Group 2; n = 5). All statistical analyses were performed using analytical software (Stata SE, version 13.1, College Station, TX, USA) at P < 0.05. Data were first evaluated using the Shapiro-Wilk test for normality. Differences between groups in days to luteolysis (DTL) were examined using analysis of variance and Bonferroni, and the effect of day and treatment on P4 levels were examined using the Kruskal-Wallis and Dunn's all pairwise test. There was a significant difference in DTL between the groups (P = 0.0083), with fewer DTL in Group 1 compared to control (P = 0.011) and to Group 2 (P = 0.034). There was a significant effect of day (P < 0.0001) on P4 levels with Day 11 P4 levels higher than Day 15 and Day 17 and Day 13 P4 levels higher than Day 15 or Day 17 (P < 0.03). There was a significant effect of treatment group (P = 0.0098) on P4 levels with control and Group 2 levels higher than Group 1 mares (P = 0.0012, P = 0.0495, respectively). We concluded that intrauterine administration of 1 mL of fractionated coconut oil lowered P4 levels in diestrus in a dose-dependent fashion and did not prolonged the luteal phase of the mares. PMID- 26954944 TI - Management of the pregnant mare and long-term consequences on the offspring. AB - The study of early developmental conditioning of health and disease in adulthood is particularly relevant in the horse, which is bred mainly to perform in demanding sport challenges. On the basis of this concept, the management of the broodmare could be considered an effective means to produce animals with the desired features. Knowledge on the Developmental Origins of Health and Disease in the equine species remains relatively scarce, with some experimental studies and one single epidemiologic study. Data highlight the determinant role of the maternal environment for postnatal body conformation, immune response, energy homeostasis, osteoarticular status and thyroidal, adrenocortical, and cardiovascular functions of the foal. Most research, however, focuses on the first months/years after birth. Long-term effects on the adult horse phenotype have not been investigated so far. PMID- 26954946 TI - Advanced tools in marine natural drug discovery. AB - Marine natural products (MNPs) remain promising drug sources with several marine derived drugs having been successfully approved. Nevertheless, it is never a smooth sailing to seek bioactive compounds from marine environments, during which many challenges are need to be faced to, for example, discovering unique marine resources, reviving unculturable organisms outside the marine environment, distinguishing novel compounds from the known ones, and disclosing the function of MNPs and optimizing their pharmacological use. Herein we review some advanced techniques and methodologies that can be employed to deal with above challenges with the intent of inspiring the forthcoming efforts in MNPs discovery pipelines. PMID- 26954942 TI - MiRNA-Mediated Macrophage Polarization and its Potential Role in the Regulation of Inflammatory Response. AB - Monocytes and macrophages are important components of the immune system, specialized in either removing pathogens as part of innate immunity or contributing to adaptive immunity through antigen presentation. Essential to such functions is classical activation (M1) and alternative activation (M2) of macrophages. M1 polarization of macrophages is characterized by production of pro inflammatory cytokines, antimicrobial and tumoricidal activity, whereas M2 polarization of macrophages is linked to immunosuppression, tumorigenesis, wound repair, and elimination of parasites. MiRNAs are small non-coding RNAs with the ability to regulate gene expression and network of cellular processes. A number of studies have determined miRNA expression profiles in M1 and M2 polarized human and murine macrophages using microarray and RT-qPCR arrays techniques. More specifically, miR-9, miR-127, miR-155, and miR-125b have been shown to promote M1 polarization while miR-124, miR-223, miR-34a, let-7c, miR-132, miR-146a, and miR 125a-5p induce M2 polarization in macrophages by targeting various transcription factors and adaptor proteins. Further, M1 and M2 phenotypes play distinctive roles in cell growth and progression of inflammation-related diseases such as sepsis, obesity, cancer, and multiple sclerosis. Hence, miRNAs that modulate macrophage polarization may have therapeutic potential in the treatment of inflammation-related diseases. This review highlights recent findings in miRNA expression profiles in polarized macrophages from murine and human sources, and summarizes how these miRNAs regulate macrophage polarization. Last, therapeutic potential of miRNAs in inflammation-related diseases through modulation of macrophage polarization is also discussed. PMID- 26954948 TI - Tuning Ionic Transport in Memristive Devices by Graphene with Engineered Nanopores. AB - Memristors, based on inherent memory effects in simple two-terminal structures, have attracted tremendous interest recently for applications ranging from nonvolatile data storage to neuromorphic computing based on non-von Neumann architectures. In a memristor, the ability to modulate and retain the state of an internal variable leads to experimentally observed resistive switching (RS) effects. Such phenomena originate from internal, microscopic ionic migration and associated electrochemical processes that modify the materials' electrical and other physical properties. To optimize the device performance for practical applications with large-size arrays, controlling the internal ionic transport and redox reaction processes thus becomes a necessity, ideally at the atomic scale. Here we show that the RS characteristics in tantalum-oxide-based memristors can be systematically tuned by inserting a graphene film with engineered nanopores. Graphene, with its atomic thickness and excellent impermeability and chemical stability, can be effectively integrated into the device stack and can offer unprecedented capabilities for the control of ionic dynamics at the nanoscale. In this device structure, the graphene film effectively blocks ionic transport and redox reactions; thereby the oxygen vacancies required during the RS process are allowed to transport only through the engineered nanosized openings in the graphene layer, leading to effective modulation of the device performance by controlling the nanopore size in graphene. The roles of graphene as an ion blocking layer in the device structure were further supported by transmission electron microscopy, energy-dispersive X-ray spectroscopy, and atomistic simulations based on first-principles calculations. PMID- 26954950 TI - Operative nuances of surgery for cortical arteriovenous malformations: A safe solution and permanent cure. PMID- 26954947 TI - Enhancing vaccine effectiveness with delivery technology. AB - Vaccines stand as a very powerful means of disease prevention and treatment. Fundamental to the success of vaccination is the efficient delivery of antigenic cargo needed to trigger an effective immune response. In this article, we will review recent advances in delivery technology with a focus on devices designed to optimally maximize responses to antigen cargo. Included with the review is an overview of traditional vaccine applications and how these approaches can benefit by well-designed delivery methods. PMID- 26954952 TI - A probable cavernoma in the medulla oblongata presenting as Opalski syndrome: A rare entity. PMID- 26954951 TI - Telemedicine and stroke: Stroke Emergency Mobile Unit - A new approach to stroke care. PMID- 26954953 TI - Spontaneous carotid-trigeminal cavernous fistula obliterated using a combination of coils and onyx. PMID- 26954954 TI - Isolated posterior circulation stroke following honey-bee sting. PMID- 26954955 TI - Varicella-zoster virus vasculopathy in a 75-year-old immunocompetent man. PMID- 26954956 TI - Management dilemmas of traumatic pseudoaneurysm of superficial temporal artery. PMID- 26954957 TI - Glioblastoma multiforme in association with a dural arteriovenous fistula. PMID- 26954958 TI - Vasospasm after iatrogenic subarachnoid hemorrhage. PMID- 26954960 TI - Bilateral medial medullary infarction with a "heart appearance" sign. PMID- 26954959 TI - Magnetic resonance imaging of ataxia-telangiectasia. PMID- 26954961 TI - Bilateral vertebral artery and internal carotid artery dissecting aneurysms due to syphilis. PMID- 26954962 TI - Traumatic aneurysms of the intracranial and cervical vessels: A review. AB - Traumatic intracranial aneurysms (TICA) are rare in occurrence, constituting less than 1% of the total cases of intracranial aneurysms. Cervical posttraumatic aneurysms arising from major blood vessels supplying the brain are also extremely rare. Their variable locations, morphological variations and the presence of concomitant head injury makes their diagnosis and treatment a challenge. In this review, we discuss the epidemiology, etiology, classification and management issues related to TICA as well as traumatic neck aneurysms and review the pertinent literature. PMID- 26954963 TI - Pathway to recovery. PMID- 26954964 TI - Endovascular reconstruction of aneurysms with a complex geometry. AB - Conventional endovascular coiling remains the mainstay of treatment for most aneurysms; however, it may not be suitable for aneurysms with a complex geometry and there remains the risk of recanalization. Aneurysms with an unfavorable morphology are difficult to treat through both endovascular and surgical means. Progress in endovascular technology has allowed for the emergence of newer strategies to treat aneurysms with a complex geometry. Better packing density in wide-necked and large aneurysms can be achieved through the balloon remodeling technique. Similarly, a self-expanding stent cannot only act as a scaffold that helps to retain coils but also aids in diverting the blood flow away from the aneurysm sac. Lately, focus has shifted from endosaccular occlusion to endoluminal reconstruction; flow diverters are being increasingly used to treat aneurysms with an unfavorable geometry. However, there is no clear consensus on the best endovascular management strategy in certain subset of aneurysms - large and giant internal carotid aneurysms, blister aneurysms, and fusiform/dissecting aneurysms of the vertebrobasilar artery. We present a review of literature and discuss the current evidence for the various endovascular strategies to treat complex aneurysms. PMID- 26954965 TI - Arterial spin labeling magnetic resonance perfusion study to evaluate the effects of age and gender on normal cerebral blood flow. AB - PURPOSE: Arterial spin labeling (ASL) is a noninvasive magnetic resonance (MR) perfusion technique to detect changes in blood flow. This study was undertaken to obtain a reference set of normal values of cerebral blood flow (CBF) in different age groups using three-dimensional pseudocontinuous ASL (3D PCASL) technique. The existence of an age-related decline in the gray matter (GM) and white matter (WM) CBF was evaluated. The gender-related CBF was also analyzed. MATERIALS AND METHODS: One hundred and sixty normal volunteers of varying age (6-72 years), arranged in 4 age groups, underwent MR perfusion imaging using 3D PCASL technique at 3 Tesla (T). Mean CBF values in global and regional GM and WM in different age groups were extracted from the quantitative perfusion map. RESULTS: A significant negative correlation was observed between the age and mean GM and WM CBF values (r = -0.80, P = 0.001; r = -0.59, P = 0.001, respectively). Similar results were also observed between age and various regional mean GM and WM CBF values (P = 0.001). No significant effect of gender on the GM CBF and WM CBF was found in any age group (P > 0.05). CONCLUSION: PCASL technique provides reliable quantitative parameters for the precise mapping of age-related perfusion changes occurring in the normal brain. PMID- 26954966 TI - Development and implementation of acute stroke care pathway in a tertiary care hospital in India: A cluster-randomized study. AB - BACKGROUND: In-hospital care of stroke patients can reduce the risk of death and disability. There is an emerging evidence for the routine use of care pathways (CPs) for acute stroke management. Our aim was to develop evidence-based CPs and test the hypothesis that acute stroke management by CPs is superior to that provided by conventional care. MATERIALS AND METHODS: An acute stroke CP was designed in accordance with the recent American Stroke Association (ASA)/American Heart Association (AHA) stroke guidelines and the Indian Academy of Neurology (IAN) stroke management guidelines in India. A total of 162 acute stroke patients, who were managed within 72 hours of onset of their symptoms, were enrolled prospectively in two groups-the stroke care pathway (CP) arm (n = 77) and the conventional care (CC) arm (n = 85). The incidence of aspiration pneumonia, complications during the hospital stay, and death or dependency at discharge and at 90 days were among the main outcomes of our study. RESULTS: The CP arm had a lower incidence of aspiration pneumonia (AP) in comparison with the CC arm (6.5% vs. 15.3%, risk ratio [RR] = 0.42, 95% confidence interval [CI] = 0.16-1.14, P = 0.062). The CP group had a decreased risk of requirement of mechanical ventilation (7.8% vs. 17.6%, odds ratio [OR] = 0.39, 95% CI = 0.14 1.07, P = 0.05). Barthel and modified Rankin Scale scores were similar in both the groups, but death at 90 days was significantly lesser in the CP arm (7.8% vs. 20%, P = 0.022). This benefit was most prominent in the Glasgow Coma Scale (GCS) subgroup scoring 9-15 (RR = 0.16, 95% CI = 0.03-0.71). There were no significant differences in the other outcome measures. CONCLUSION: Stroke CPs reduce the incidence of aspiration pneumonia, the need for mechanical ventilation, and the risk of death, when assessed at a follow-up of 90 days. PMID- 26954967 TI - Acute stroke care pathway: Will the journey be smooth? PMID- 26954968 TI - Stroke burden and stroke care system in Asia. AB - BACKGROUND: Stroke is a major cause of death and disability. Asia is the largest and mostly populated continent of the world. The Asian Stroke Advisory Panel (ASAP) consists of stroke neurologists from 12 different countries in 13 Asian regions. It has been established for 17 years, and holds regular meetings for reviewing the stroke activities in Asia. It also helps in conducting several multinational research projects. This study is one of the ASAP projects and aims to explore stroke care systems in member countries in Asia. METHODS: The survey is categorized into five main parts including the general country information, stroke epidemiology, stroke risk factors, stroke care systems, and national stroke professional societies. RESULTS: A higher proportion of ischemic stroke in comparison to hemorrhagic stroke was found in all countries. The overall incidence of stroke in Asia is between 116 and 483/100,000 per year.When compared to 1999, a 2-3-fold increase in the number of neurologists was observed in all countries. CONCLUSIONS: There is a favorable trend in all Asian countries regarding the need to increase the number of neurologists and facilities to effectively administer stroke care. PMID- 26954969 TI - Endovascular treatment of ruptured vertebrobasilar dissecting aneurysms: Review of 40 consecutive cases. AB - AIMS: To evaluate the safety and efficacy of endovascular intervention in the treatment of ruptured vertebrobasilar dissecting aneurysms (VBDAs) with the aim of developing endovascular treatment standards for this disorder. MATERIALS AND METHODS: The results of 40 consecutive patients with ruptured VBDAs, who were treated with internal trapping (n = 7), stent(s)-assisted coiling (n = 26), and solely stenting (n = 7) from January 2010 to June 2014, were retrospectively reviewed and analyzed. RESULTS: A treatment protocol for the ruptured VBDAs was created and proved to be effective. All 7 patients treated with internal trapping had satisfactory outcomes; none had treatment-related complications, rebleeding, or recanalization after treatment. Of the 26 patients treated with stent-assisted coiling, one patient suffered from an acute in-stent thrombosis during the operation, one had a small cerebral cortical infarction, one had rebleeding, and one had recanalization of his obliterated aneurysm after surgery. Of the seven patients treated solely with stenting, one patient had recanalization and two patients suffered rebleeding, of whom one patient died. CONCLUSIONS: The treatment protocol for ruptured VBDAs proposed in this study proved to be a simple and effective method in selecting the requisite treatment. If a proper endovascular strategy is in place, an effective treatment outcome for ruptured VBDAs can be obtained. PMID- 26954970 TI - Management of stroke: The triumphs and the travails. PMID- 26954971 TI - Cerebral aneurysm treatment in India: Results of a national survey regarding practice patterns in India. AB - BACKGROUND: The management of intracranial aneurysms (IAs) varies widely depending upon a number of factors. OBJECTIVE: To understand the variations in practice patterns in the treatment of IAs in India. METHODS: The survey consisted of 23 questions. Two group emails were sent to members of the Neurological Society of India and the Neurological Surgeons Society of India. Uni- and multivariate analysis was performed where appropriate. RESULTS: The response rate was 10.13% (150/1480). Fifty percent of the respondents used steroids in subarachnoid hemorrhage and 64% initiated triple-H therapy prophylactically. There was no significant difference in the use of steroids, antifibrinolytics, mannitol, or hypertonic saline and the choice of therapeutic intervention (clipping or endovascular therapy [EVT]) for anterior circulation aneurysms between physicians working at teaching and nonteaching hospitals. However, physicians in teaching and government hospitals were less likely to choose EVT for middle cerebral artery aneurysms as the first line of treatment (odds ratio [OR] 0.6 and 0.1, respectively). Physicians working at private hospitals were more likely to have EVT facilities than those working in government-owned hospitals. On multivariate analysis, physicians working in teaching hospitals preferred surgical clipping to EVT for posterior circulation aneurysms (OR = 0.7) and physicians at teaching hospitals performed >50 cases/year. CONCLUSION: Our study demonstrates the prevailing practice patterns in the management of IAs in India. Surgical clipping is the preferred treatment of choice for anterior circulation aneurysms and EVT for aneurysms along the posterior circulation. Corticosteroids and prophylactic "triple-H" therapy are still used by a large proportion of physicians. PMID- 26954972 TI - Stent-assisted coiling of ruptured wide-necked intracranial aneurysms: A single center experience of 218 consecutive patients. AB - BACKGROUND: Stent-assisted coiling (SAC) in the treatment of ruptured intracranial aneurysms (RIAs) remains controversial. AIMS: In this study, we report our experience of SAC of wide-necked RIAs and evaluate the risk factors contributing to periprocedural complications. MATERIALS AND METHODS: 218 patients underwent SAC for ruptured, wide-necked saccular intracranial aneurysms at our center between 2011 and 2014. Multivariate logistic regression analysis was performed to evaluate the risk factors contributing to the periprocedural complications. Follow-up angiography was available in 178 (84.8%) patients. Clinical outcome was measured using the Glasgow Outcome Scale (GOS) through telephonic interviews. RESULTS: Periprocedural complications occurred in 33 (15.1%) patients out of which 17 were thromboembolic (7.8%) and the remainder were hemorrhagic complications (n = 16, 7.3%). Multivariate logistic regression analysis showed that a positive history of hypertension (odds ratio [OR] 4.899, 95% confidence interval [CI] 1.266-18.951; P = 0.021), and daughter blebs (OR 12.165, 95% CI 3.247-45.577; P = 0.0001) were the major risk factors for the periprocedural hemorrhagic complications, but not for the thromboembolic complications. Angiographic follow-up (mean, 19.5 +/- 11.9 months) showed Raymond scale (RS) 1 in 158 (88.8%) patients and RS2 in 20 (11.2%) patients without any angiographic recurrence. At a mean clinical follow-up of 29.1 +/- 16.2 months, 201 out of the 210 surviving patients had a good functional outcome (GOS score of 4 or 5). CONCLUSIONS: SAC is an effective treatment option for selected ruptured wide-necked aneurysms, especially in patients who do not require external ventricle drainage for acute hydrocephalus. The periprocedural hemorrhagic complications tend to be more common in the hypertensive patients and in those with daughter blebs in the aneurysm sac. PMID- 26954973 TI - Moyamoya disease: Experience with direct and indirect revascularization in 70 patients from a nonendemic region. AB - INTRODUCTION: Moyamoya disease (MMD) is a chronic cerebrovascular disease characterized by stenosis/occlusion of bilateral terminal internal carotid arteries with the development of collaterals at base of the brain. We describe our experience of treating 70 patients (133 involved hemispheres, 108 hemispheres operated) surgically. PATIENTS AND METHODS: Surgically treated patients with MMD from 2006 to 2014 were reviewed retrospectively. There were 70 patients (54 pediatric, 36 females, range 2-46 years). Seven had a unilateral disease. One hundred and eight of 133 hemispheres underwent surgery; 58 underwent combined revascularization (superficial temporal artery - middle cerebral artery bypass and encephalo-duro-arterio-myo-synangiosis [EDAMS]); and, 50 underwent an indirect revascularization (EDAMS). 17/23 adult brain hemispheres and 41/85 pediatric hemispheres underwent combined revascularization. RESULTS: The median follow-up was 15.9 months (range 3-62 months). The mean modified Rankin scale score at presentation and follow-up were 2.27 +/- 1.034 and 1.80 +/- 1.269, respectively. There was an overall significant improvement in the clinical status in the operated patients (P < 0.001) at follow-up. The clinical improvement (admission to follow-up) was better in pediatric patients compared to the adults (P < 0.001 vs. 0.769). The combined revascularization gave better clinical improvement than the indirect one (P = 0.024 vs. 0.0312). There were three postoperative strokes and one death. The morbidity rate was 2.8%, and the mortality rate, 1.4%. Other patients were symptom-free at the latest follow-up. Angiographic outcome did not statistically correlate with age, anastomosis type, or Suzuki grade, though there was trend toward better angiographic outcomes in patients who underwent a combined revascularization. CONCLUSION: Both the combined and indirect revascularization procedures are effective in treating MMD. Pediatric patients had a better clinical improvement after surgery than the adult patients . Patients undergoing combined revascularization had a better clinical status compared to those who only underwent indirect revascularization. Combined revascularization surgery should be the surgical strategy in all age groups as it is feasible in a significant proportion of pediatric patients too. PMID- 26954974 TI - Post-traumatic subarachnoid hemorrhage: A review. AB - Head injury has been the leading cause of death and disability in people younger than 40 years and the incidence is rising continuously. Anticipation of the pathological consequences of post-traumatic subarachnoid hemorrhage (tSAH) and an outcome-oriented management are very important in these cases. To encounter the complications pertaining to traumatic brain injury (TBI) and tSAH, various classifications have been proposed and goal-oriented screening strategies have been offered. The role of serial computed tomography (CT) scans, perfusion studies, transcranial Doppler, magnetic resonance imaging (MRI), and angiographic studies as diagnostic tools, has been described. Recently, MRI fluid-attenuated inversion recovery (FLAIR), gradient reversal echo (GRE), and susceptibility weighted imaging (SWI) have emerged as excellent complimentary MRI sequences, and the authors of this article have evaluated their role in the diagnosis and prognostication of patients with tSAH. Numerous studies have been conducted on the various complications associated with tSAH such as vasospasm, hydrocephalus, and electrolyte disturbances and their management. This article discusses these aspects of tSAH and their management nuances. PMID- 26954975 TI - The influence of age and the initial clinical presentations of patients with an arteriovenous malformation on the risk of hemorrhage. AB - BACKGROUND AND PURPOSE: The major determinants of hemorrhage in an arteriovenous malformation (AVM) include its angioarchitecture, as well as the patient's age and clinical presentation. The aim of this study was to determine whether or not the risk of hemorrhage in an AVM differs based on the different clinical presentations and the initial age at diagnosis. METHODS: A consecutive case series of 496 patients having a brain AVM was retrospectively analyzed. The radiological evidence of hemorrhage was established in 84 of these cases after the initial diagnosis of AVM had been made. These cases were analyzed using univariate analysis and Kaplan-Meier curves with respect to age at diagnosis, the clinical presentation of patients harboring the AVM as well as the Spetzler Martin grade of the AVM. RESULTS: Hemorrage occurred in 84 patients with an AVM during a mean duration of 2.5 years (range, 1month-28 years). In univariate analysis, a subsequent hemorrhage within an AVM was associated with the following factors: When the patients initially presented with a hemorrhage, and, had a younger age (<30 years), female gender, and Spetzler-Martin III and IV grades. By analysis of the Kaplan-Meier curves, it was estimated that the annual hemorrhage rate was 12.3% in those cases who initially presented with hemorrhage, compared with 3.5% for those cases whose initial presentation was not associated with AVM bleed. In the latter category (i.e., patients who did not have hemorrhage as the initial presentation), the annual rate of subsequent hemorrhage was lower for those patients who initially presented with seizures than those who had other initial presentations (such as those having neurological deficits, headaches, or those incidentally detected to be having an AVM) (with the bleeding rate being 1.9% in those with seizures as the initial presentation vs. 4.6% for the other presentations or those with incidentally detected AVMs, P = 0.002). CONCLUSIONS: The subsequent occurrence of hemorrhage in an AVM was associated with the initial presentation of hemorrhage, a younger patient's age (<30 years), the female gender, and Spetzler-Martin grades III and IV. The risk of subsequent hemorrhage in patients with an initial presentation of a seizure was lower than the risk of hemorrhage that occurred with other presentations. Patients with an AVM who present with recurrent headaches, and those in whom the AVM has been detected incidentally, should also be kept under surveillance as they too manifest a risk of a subsequent hemorrhage. PMID- 26954976 TI - Complete middle cerebral artery block without brain infarction. AB - We report a patient with progressive supranuclear palsy and incidentally detected the absence of right middle cerebral artery (MCA) without any old or acute infarct in its territory. The magnetic resonance angiography and computed tomography angiography failed to detect any significant collateral circulation. We discuss the embryogenesis of brain circulation and offer a possible explanation for the nonvisualization of the right MCA in our patient. PMID- 26954977 TI - Computing the difference between life and death: Prerupture blood flow analysis of a fatal aneurysm bleed. AB - Although hemodynamics plays a key role in the genesis, expansion, and rupture of an aneurysm, quantified hemodynamic parameters for comparison have not been standardized for predicting the risk of rupture of intracranial aneurysms. Computational fluid dynamics is being increasingly used in near-realistic, patient-specific simulation of blood flow in intracranial aneurysms. A simulation was carried out on the computed tomography (CT) angiogram image of a patient harboring a giant internal carotid artery aneurysm. Since the CT angiogram was performed a few hours before the fatal rupture of the aneurysm, the study could give an insight into the hemodynamics of the aneurysm that tipped it to rupture. Wall shear stress, pressure distribution, and flow streamlines were obtained using computational methods. These objective results could form the basis of reference for future studies employing simulation techniques for predicting aneurysmal rupture. PMID- 26954978 TI - Preexisting mild sleep disturbance as a vulnerability factor for inflammation induced depressed mood: a human experimental study. AB - Sleep disturbance and depression are common, particularly in females, and sleep disturbance is a well-known risk factor for depression. Systemic inflammation has been suggested as a potential mechanism of this association. This study examined whether preexisting sleep disturbance acted as a vulnerability factor for depressed mood induced by an inflammatory challenge in healthy females vs males. In a randomized double-blind placebo-controlled design, volunteers aged 18-50 (N = 111; 67 females) were assigned to placebo or low-dose endotoxin. Before substance administration, sleep disturbance was assessed using the Pittsburgh Sleep Quality Index and dichotomized using median split (? 3 vs < 3). Self reported depressed mood (profile of mood states) and circulating proinflammatory cytokines (interleukin-6, tumor necrosis factor-alpha) were repeatedly assessed over 6 h. Among females, moderation of depressed mood by sleep disturbance was significant even after adjustment for covariates (X(2) = 12.73, df = 6, P < 0.05). There was a robust time-by-condition interaction in females with sleep disturbance (X(2) = 26.22, df = 6, P < 0.001), but not in females without sleep disturbance (X(2) = 8.65, df = 6, P = 0.19). Although cytokines increased equally in all females, the correlations between cytokines and depressed mood were significantly stronger in females with sleep disturbance. Among males, no moderating effect of sleep disturbance was observed. Inflammation-induced depressed mood was considerably more severe among females reporting mild sleep disturbance compared with those reporting no sleep disturbance, suggesting that even mild sleep disturbance may increase vulnerability for inflammation-induced depression in females. Furthermore, sleep disturbance appears to increase the vulnerability to depression by augmenting affective sensitivity to cytokines rather than by enhancing cytokine responses to inflammatory challenge in females. PMID- 26954979 TI - Reduced sleep duration mediates decreases in striatal D2/D3 receptor availability in cocaine abusers. AB - Neuroimaging studies have documented reduced striatal dopamine D2/D3 receptor (D2/D3R) availability in cocaine abusers, which has been associated with impaired prefrontal activity and vulnerability for relapse. However, the mechanism(s) underlying the decreases in D2/D3R remain poorly understood. Recent studies have shown that sleep deprivation is associated with a downregulation of striatal D2/D3R in healthy volunteers. As cocaine abusers have disrupted sleep patterns, here we investigated whether reduced sleep duration mediates the relationship between cocaine abuse and low striatal D2/D3R availability. We used positron emission tomography with [(11)C]raclopride to measure striatal D2/D3R availability in 24 active cocaine abusers and 21 matched healthy controls, and interviewed them about their daily sleep patterns. Compared with controls, cocaine abusers had shorter sleep duration, went to bed later and reported longer periods of sleep disturbances. In addition, cocaine abusers had reduced striatal D2/D3R availability. Sleep duration predicted striatal D2/D3R availability and statistically mediated the relationship between cocaine abuse and striatal D2/D3R availability. These findings suggest that impaired sleep patterns contribute to the low striatal D2/D3R availability in cocaine abusers. As sleep impairments are similarly observed in other types of substance abusers (for example, alcohol and methamphetamine), this mechanism may also underlie reductions in D2/D3R availability in these groups. The current findings have clinical implications suggesting that interventions to improve sleep patterns in cocaine abusers undergoing detoxification might be beneficial in improving their clinical outcomes. PMID- 26954982 TI - Health anthropology and urban health research. AB - We live in a rapidly urbanising world. According to the 2001 statistics of the United Nations,a the proportion of urban dwellers rose from 30% in 1950 to 47% in 2000 and will probably attain 60% in 2030. Almost 70% of these urban dwellers live in cities of developing regions. At the current rates of urbanisation, the number of city dwellers in the world will equal that of their rural counterparts by 2007. In the late 1980s, researchers became increasingly concerned about the combined impact of rapid urban growth and economic recession on the health of a majority of people in African and Asian cities. Several books established urban health research with a focus on developing countries as a multidisciplinary field of inquiry (Harpham et al., 1988; Salem &Jeannee, 1989). It is now widely recognised that urbanisation per se is not necessarily bad for health, but it becomes so if urban governments fail to establish and support necessary infrastructure and services to protect citizens from environmental hazards and from social, economic and political insecurity. PMID- 26954983 TI - Urban health in daily practice: livelihood, vulnerability and resilience in Dar es Salaam, Tanzania. AB - Health is the core value and ultimate goal of health development, yet we know very little about health conceptions in everyday life. Inspired by investigations into lay health concepts in Europe, our study explores experiences and meanings of health in a strikingly different context, namely, in a low-income neighbourhood of an African city. Grounded in ethnographic research in Dar es Salaam, we introduce the concept of 'health practice' and examine health definitions, explanations, and activities of urban Swahili women. Our findings show that representations of health form a set of experiences, meanings and embodied practice centring on the links between body, mind, and living conditions. We suggest that 'livelihood', 'vulnerability' and 'resilience' best capture women's main concerns of health practice in such a setting. All women face an emotional burden of being exposed to urban afflictions and an intellectual and practical burden of overcoming them, but some meet this challenge more successfully than others do. This approach tips the balance towards a positive view of health that has been neglected in medical anthropology. It also opens new lines of inquiry in urban health research by consequently following a resource orientation that acknowledges women's struggle to stay healthy and directs attention to their agency. PMID- 26954984 TI - Contextualizing mental health: gendered experiences in a Mumbai slum. AB - Urban mental health programmes in developing countries remain in their infancy. To serve low-income communities, research needs to consider the impact of common life experience in slums, including poverty, bad living conditions, unemployment, and crowding. Our study in the Malavani slum of Mumbai examines afflictions of the city affecting the emotional well-being and mental health of women and men with respect to gender. This is a topic for which mental health studies have been lacking, and for which psychiatric assumptions based on middle-class clinical experience may be most tenuous. This study employs ethnographic methods to show how environmental and social contexts interact in shaping local experience with reference to common mental health problems. Focusing on the social and environmental context of the mental health of communities, rather than psychiatric disorders affecting individuals, findings are broadly applicable and sorely needed to guide the development of locally appropriate community mental health programmes. Identified afflictions affecting mental health include not only access to health care, but also sanitation, addictions, criminality, domestic violence, and the so-called bar-girl culture. Although effective clinical interventions are required for mental health services to treat psychiatric disorders, they cannot directly affect the conditions of urban slums that impair mental health. PMID- 26954981 TI - Association of thalamic hyperactivity with treatment-resistant depression and poor response in early treatment for major depression: a resting-state fMRI study using fractional amplitude of low-frequency fluctuations. AB - Despite novel antidepressant development, 10-30% of patients with major depressive disorder (MDD) have antidepressant treatment-resistant depression (TRD). Although new therapies are needed, lack of knowledge regarding the neural mechanisms underlying TRD hinders development of new therapeutic options. We aimed to identify brain regions in which spontaneous neural activity is not only altered in TRD but also associated with early treatment resistance in MDD. Sixteen patients with TRD, 16 patients with early-phase non-TRD and 26 healthy control (HC) subjects underwent resting-state functional magnetic resonance imaging. To identify brain region differences in spontaneous neural activity between patients with and without TRD, we assessed fractional amplitude of low frequency fluctuations (fALFF). We also calculated correlations between the percent change in the Hamilton Rating Scale for Depression (HRSD17) scores and fALFF values in brain regions with differing activity for patients with and without TRD. Patients with TRD had increased right-thalamic fALFF values compared with patients without TRD. The percent change in HRSD17 scores negatively correlated with fALFF values in patients with non-TRD. In addition, patients with TRD showed increased fALFF values in the right inferior frontal gyrus (IFG), inferior parietal lobule (IPL) and vermis, compared with patients with non-TRD and HC subjects. Our results show that spontaneous activity in the right thalamus correlates with antidepressant treatment response. We also demonstrate that spontaneous activity in the right IFG, IPL and vermis may be specifically implicated in the neural pathophysiology of TRD. PMID- 26954985 TI - Cultural interpretations of an emerging health problem: blood pressure in Dar es Salaam, Tanzania. AB - This paper examines how a lower middle class community in an urban quarter of Dar es Salaam, Tanzania experiences the relatively new health problem of high blood pressure. Unlike previous research that focused on cultural risk factors or attempted to extract cultural models of hypertension, our study contributes to the growing body of literature that examines illness experience as a representation or embodiment of social suffering. The participants in this study use the local expressions 'BP' or 'presha' (from blood pressure) to refer to an illness that overlaps but is not synonymous with the biomedical conception of hypertension. The local concepts draw on biomedical notions of hypertension and, in addition, incorporate a range of afflictions into the symptomatology and aetiology that mirror their experiences of an increasingly harsh urban life. The concept of 'BP', therefore, is not bound to the body in a medical sense. As a broader and more complex syndrome, 'BP' is a somatic expression of emotional distress that links the body with the lived experience in this urban setting. Our approach of analysing cultural interpretations of 'BP' as an emerging health problem in this particular urban context calls for a more comprehensive response in diagnosis and treatment. PMID- 26954980 TI - What can rodent models tell us about apathy and associated neuropsychiatric symptoms in Parkinson's disease? AB - In addition to classical motor symptoms, Parkinson's disease (PD) patients display incapacitating neuropsychiatric manifestations, such as apathy, anhedonia, depression and anxiety. These hitherto generally neglected non-motor symptoms, have gained increasing interest in medical and scientific communities over the last decade because of the extent of their negative impact on PD patients' quality of life. Although recent clinical and functional imaging studies have provided useful information, the pathophysiology of apathy and associated affective impairments remains elusive. Our aim in this review is to summarize and discuss recent advances in the development of rodent models of PD related neuropsychiatric symptoms using neurotoxin lesion-based approaches. The data collected suggest that bilateral and partial lesions of the nigrostriatal system aimed at inducing reliable neuropsychiatric-like deficits while avoiding severe motor impairments that may interfere with behavioral evaluation, is a more selective and efficient strategy than medial forebrain bundle lesions. Moreover, of all the different classes of pharmacological agents, D2/D3 receptor agonists such as pramipexole appear to be the most efficient treatment for the wide range of behavioral deficits induced by dopaminergic lesions. Lesion-based rodent models, therefore, appear to be relevant tools for studying the pathophysiology of the non-motor symptoms of PD. Data accumulated so far confirm the causative role of dopaminergic depletion, especially in the nigrostriatal system, in the development of behavioral impairments related to apathy, depression and anxiety. They also put forward D2/D3 receptors as potential targets for the treatment of such neuropsychiatric symptoms in PD. PMID- 26954986 TI - Urban elderly with chronic illness: local understandings and emerging discrepancies in North Sulawesi, Indonesia. AB - Old-age research in developing countries is at its beginning in the social sciences and particularly in anthropology, which has focused on other vulnerable groups, but has not sufficiently addressed emerging health issues of elderly urban dwellers in developing countries. This study investigates the health status of aged people living in cities (i.e. the 'burden of disease'), and how urban elderly experience and give meaning to chronic illnesses in context (i.e. the 'burden of illness'). It correlates the conceptual framework of 'health transition' with prevailing theoretical concepts and models of medical anthropology. The research project was carried out in three cities of North Sulawesi Province; it encompasses elderly people (>= 60 years) suffering from one or more chronic illnesses. Elderly people experience chronic illnesses in three qualitative ways: illnesses that (1) disturb, (2) threaten, or (3) cause worry. The harsh urban setting reinforces these afflictions, and may lead to economic hardships and social destitution. The meaning of chronic illness of elderly varies distinctly from that of biomedicine and results in divergent health priorities. This article examines patterns of meaning developed by urban elderly with chronic illnesses, and explores how these emic classifications mirror afflictions of city life for these elderly in daily practice. PMID- 26954987 TI - "In the city, everybody only cares for himself": social relations and illness in Abidjan, Cote d'Ivoire. AB - Various studies on African solidarity, survival strategies and the 'therapy man agement group' [J. M. Janzen (1978) The Quest for Therapy in Lower Zaire, Berkeley, Los Angeles & London: University of California Press] have suggested that institutionalized relationships in the form of networks or groups afford an individual access to resources, also in case of illness. My study reconsiders these arguments in ethnographic research about everyday illness management. It focuses on a heterogeneous urban neighbourhood in Abidjan and analyses who offers help to whom, and what kind of help people offer to one another. The findings show that social networks play an important but at the same time restricted role in illness management. The main source of assistance in response to affliction is household members. Apart from emotional and moral support, relatives living outside the household and non-kin play only a minor role. The social network offers help only sporadically, and very often the sick person has to ask friends and family several times before she or he receives financial or practical support. The emphasis given to social networks in the existing literature is often overestimated, at least in the case of illness. These findings implicate the importance of strengthening informal and formal security systems, especially in an urban context of economic hardship and political insecurity. PMID- 26954988 TI - Engaging anthropology in urban health research: issues and prospects. AB - Urbanisation remains a challenge in the new millennium and will continue to have important implications for human health. This leads to lively debates in the field of international health, but with minimal engagement of anthropology. To stimulate active involvement, our paper highlights main issues addressed in this special issue and maps directions for future research. Our collection of papers addresses hot topics in urban health research, ranging from everyday health practice to mental health, chronic and degenerative illness, old age and social safety networks, and examines them from a complementary, anthropological perspective. Most priority concerns refer to four core issues commonly considered as characteris tics of urban life, namely, levels of environmental hazards, commodification, social fragmen tation and health service provision. We thus advocate for fresh perspectives, moving from a medical anthropology to a health anthropology, and from risk approaches to frameworks centring on affliction, vulnerability and resilience. Future research should concentrate on comparisons and longitudinal design to sharpen key distinctions, e.g. between rural, peri urban and urban, use dynamics, diversity and complexity as analytical frameworks and investigate emerging issues like trust and care. With an active engagement in and commitment to urban health research, anthropology can enhance conceptual clarity and contribute to locally relevant public health actions. PMID- 26954989 TI - Ising-like chain magnetism, Arrhenius magnetic relaxation, and case against 3D magnetic ordering in beta-manganese phthalocyanine (C32H16MnN8). AB - Previous magnetic studies in the organic semiconductor beta-manganese phthalocyanine (beta-MnPc) have reported it to be a canted ferromagnet below T(C) ~ 8.6 K. However, the recent result of the lack of a lambda-type anomaly in the specific heat versus temperature data near the quoted T(C) has questioned the presence of long-range 3-dimensional (3D) magnetic ordering in this system. In this paper, detailed measurements and analysis of the temperature (2 K-300 K) and magnetic field (up to 90 kOe) dependence of the dc and ac magnetic susceptibilities in a powder sample of beta-MnPc leads us to conclude that 3D long-range magnetic ordering is absent in this material. This is supported by the Arrott plots and the lack of a peak in the ac susceptibilities, chi' and chi", near the quoted T(C). Instead, the system can be best described as an Ising-like chain magnet with Arrhenius relaxation of the magnetization governed by an intra layer ferromagnetic exchange constant J/k(B) = 2.6 K and the single ion anisotropy energy parameter |D|/k(B) = 8.3 K. The absence of 3D long range order is consistent with the measured |D|/ > J. PMID- 26954990 TI - The psychometric properties of the Turkish Stroke and Aphasia Quality Of Life Scale-39. AB - The Stroke and Aphasia Quality Of Life Scale (SAQOL-39) is a widely used instrument in assessing the quality of life in aphasic patients. Our purpose was to translate the SAQOL-39 into the Turkish language (SAQOL-39/TR) and assess its reliability and validity in patients who had aphasia. SAQOL-39/TR was obtained using the 'translation-backward translation' method and administered to 40 patients with aphasia. The reliability studies were performed by means of internal consistency and test-retest reliability. The validation studies were carried out by means of construct validity using within-scale analyses and analyses against the external criteria. Correlation analysis was performed between scales and the Ege Aphasia Test, the Barthel index, the 12-item General Health Questionnaire and the Brunnstrom recovery stages (BRS) of the arm, hand, and lower extremity. In the results, the scores of the SAQOL-39 were not different between groups. Cronbach's alpha variables were good for all domains (0.80, 0.88, 0.89, 0.82, and 0.83). Test-retest reliability was also high (0.96, 0.97, 0.91, 0.70, and 0.96). There were significant correlations with coefficients ranging from 0.36 to 0.60 among the domains of scale and other measures. Moderate-high correlations were also seen with BRS-arm, BRS-hand, and BRS-lower extremity (r, 0.27-0.58). It was found that all domains were highly related with all domains of Ege aphasia test, except praxia (P<0.001). This study showed that the SAQOL-39/TR has acceptable validity and reliability in assessing the quality of life. However, similar results of the scale in patients with dysarthria suggest that the SAQOL-39 may not be specific to only aphasic patients. PMID- 26954991 TI - Cardiorespiratory fitness and cognitive functioning following short-term interventions in chronic stroke survivors with cognitive impairment: a pilot study. AB - This study, a quasi-experimental, one-group pretest-post-test design, evaluated the effects on cognitive functioning and cardiorespiratory fitness of 8-week interventions (aerobic exercise alone and aerobic exercise and cognitive training combined) in patients with chronic stroke and cognitive impairment living in the community (participants: n=14, 61.93+/-9.90 years old, 51.50+/-38.22 months after stroke, n=7 per intervention group). Cognitive functions and cardiorespiratory fitness were evaluated before and after intervention, and at a 3-month follow-up visit (episodic memory: revised-Hopkins Verbal Learning Test; working memory: Brown-Peterson paradigm; attention omission and commission errors: Continuous Performance Test; cardiorespiratory fitness: peak oxygen uptake during a symptom limited, graded exercise test performed on a semirecumbent ergometer). Friedman's two-way analysis of variance by ranks evaluated differences in score distributions related to time (for the two groups combined). Post-hoc testing was adjusted for multiple comparisons. Compared with before the intervention, there was a significant reduction in attention errors immediately following the intervention (omission errors: 14.6+/-21.5 vs. 8+/-13.9, P=0.01; commission errors: 16.4+/-6.3 vs. 10.9+/-7.2, P=0.04), and in part at follow-up (omission errors on follow-up: 3.4+/-4.3, P=0.03; commission errors on follow-up: 13.2+/ 7.6, P=0.42). These results suggest that attention may improve in chronic stroke survivors with cognitive impairment following short-term training that includes an aerobic component, without a change in cardiorespiratory fitness. Randomized controlled studies are required to confirm these findings. PMID- 26954992 TI - Evidence of threat to European economy and biodiversity following the introduction of an alien pathogen on the fungal-animal boundary. AB - Recent years have seen a global and rapid resurgence of fungal diseases with direct impact on biodiversity and local extinctions of amphibian, coral, or bat populations. Despite similar evidence of population extinction in European fish populations and the associated risk of food aquaculture due to the emerging rosette agent Sphaerothecum destruens, an emerging infectious eukaryotic intracellular pathogen on the fungal-animal boundary, our understanding of current threats remained limited. Long-term monitoring of population decline for the 8-year post-introduction of the fungal pathogen was coupled with seasonal molecular analyses of the 18S rDNA and histological work of native fish species organs. A phylogenetic relationship between the existing EU and US strains using the ribosomal internal transcribed spacer sequences was also carried out. Here, we provide evidence that this emerging parasite has now been introduced via Pseudorasbora parva to sea bass farms, an industry that represents over 400 M?? annually in a Mediterranean region that is already economically vulnerable. We also provide for the first time evidence linking S. destruens to disease and severe declines in International Union for Conservation of Nature threatened European endemic freshwater fishes (i.e. 80% to 90 % mortalities). Our findings are thus of major economic and conservation importance. PMID- 26954994 TI - Persister mechanisms in Borrelia burgdorferi: implications for improved intervention. PMID- 26954993 TI - Borrelia burgdorferi elongation factor EF-Tu is an immunogenic protein during Lyme borreliosis. AB - Borrelia burgdorferi, the etiological agent of Lyme disease, does not produce lipopolysaccharide but expresses a large number of lipoproteins on its cell surface. These outer membrane lipoproteins are highly immunogenic and have been used for serodiagnosis of Lyme disease. Recent studies have shown that highly conserved cytosolic proteins such as enolase and elongation factor Tu (EF-Tu) unexpectedly localized on the surface of bacteria including B. burgdorferi, and surface-localized enolase has shown to contribute to the enzootic cycle of B. burgdorferi. In this study, we studied the immunogenicity, surface localization, and function of B. burgdorferi EF-Tu. We found that EF-Tu is highly immunogenic in mice, and EF-Tu antibodies were readily detected in Lyme disease patients. On the other hand, active immunization studies showed that EF-Tu antibodies did not protect mice from infection when challenged with B. burgdorferi via either needle inoculation or tick bites. Borrelial mouse-tick cycle studies showed that EF-Tu antibodies also did not block B. burgdorferi migration and survival in ticks. Consistent with these findings, we found that EF-Tu primarily localizes in the protoplasmic cylinder of spirochetes and is not on the surface of B. burgdorferi. Taken together, our studies suggest that B. burgdorferi EF-Tu is not surfaced exposed, but it is highly immunogenic and is a potential serodiagnostic marker for Lyme borreliosis. PMID- 26954995 TI - A survey of the 2014 dengue fever epidemic in Guangzhou, China. AB - In 2014, a serious dengue outbreak in Guangzhou occurred, consisting of 37 354 laboratory confirmed cases of infection. In this study, the clinical picture of dengue fever due to dengue virus (DENV) type 1 in Guangzhou was described. Clinical and laboratory data collected by studying 726 sera of suspected clinical cases from hospitals and 328 sera of healthy persons from two residence communities were analyzed during the outbreak, and 484 patients were diagnosed with an acute dengue infection. Fever, headache, congestion of the throat, and myalgia were the most typical symptoms in DENV-infected patients. Thrombocytopenia, leukopenia, and an increase in liver enzymes were significantly more common in the infected patients than in the healthy controls. Fourteen cases of silent infection were discovered among the 328 healthy persons, suggesting a DENV inapparent infection rate of 4.27% among healthy individuals. The data obtained by analyzing 212 positive sera with three methods indicated different results with different detection methods. DENV RNA should be used for early diagnoses during days 1-6 after symptom onset, immunoglobulin M (IgM) can be easily recognized after four days have passed since symptom onset and DENV isolation has a peak positive rate during days 1-3 after the onset of symptoms. A phylogenetic analysis of viral NS1 gene sequences from this outbreak indicated that the predominant isolates could be categorized as DENV-1 genotype III and had the highest homology with the India genotypes from 2009 to 2011. However, this analysis also revealed a co-epidemic of the 2013 Zhongshan and 2003 Singapore genotypes, both belonging to DENV-1 genotype I, which suggested multiple geographic origins for the 2014 epidemic of dengue 1 strains in Guangzhou. PMID- 26954996 TI - Sepsis risk factors associated with HIV-1 patients undergoing surgery. AB - Recent developments in the treatment of HIV-1 have improved the disease prognosis from a terminal disease to a chronic disease. The number of HIV-1-infected patients who require surgery has become more common. The main threat to HIV-1 infected patients following surgery is the development of sepsis. In this study, we collected a large number of clinical recordings of HIV-1-infected patients from two hospitals in China, specializing in HIV-1 treatment in order to summarize the risk indicators of sepsis in HIV-1-infected patients. We compared the significant risk indicators between the sepsis and non-sepsis groups. Using logistic regression based on the indicators of four separate surgery-based diseases, we generally found that low CD4 and hypoalbuminemia counts prior to surgery were the significant risk factors for developing sepsis. The morbidity of sepsis in trauma patients was approximately 10 times higher than the dysfunction group, whereas the tumor and the infection groups were approximately 1.5 and 2 times higher, respectively. Based on the comparison between the sepsis and non sepsis groups for each surgery-based disease, we found that the severity of trauma is a critical risk factor for trauma patients; therefore, limiting the size of the wound during surgery is crucial. HIV-1-infected patients often develop postoperative sepsis due to immunodeficiency and complications due to the surgery. We hope that this study can help to reduce the risk of developing sepsis due to surgery and improve the survival rate of HIV-1-infected patients. PMID- 26954997 TI - Creating Pores on Graphene Platelets by Low-Temperature KOH Activation for Enhanced Electrochemical Performance. AB - KOH activation of microwave exfoliated graphite oxide (MEGO) is investigated in detail at temperatures of 450-550 degrees C. Out of the activation temperature range conventionally used for the preparation of activated carbons (>600 degrees C), the reaction between KOH and MEGO platelets at relatively low temperatures allows one to trace the structural transition from quasi-two-dimensional graphene platelets to three-dimensional porous carbon. In addition, it is found that nanometer-sized pores are created in the graphene platelets at the activation temperature of around 450 degrees C, leading to a carbon that maintains the platelet-like morphology, yet with a specific surface area much higher than MEGO (e.g., increased from 156 to 937 m(2) g(-1) ). Such a porous yet highly conducting carbon shows a largely enhanced electrochemical activity and thus improved electrochemical performance when being used as electrodes in supercapacitors. A specific capacitance of 265 F g(-1) (185 F cm(-3) ) is obtained at a current density of 1 A g(-1) in 6 m KOH electrolyte, which remains 223 F g(-1) (156 F cm(-3) ) at the current density of 10 A g(-1) . PMID- 26955000 TI - "a" interfacial parameter in Nicolais-Narkis model for yield strength of polymer particulate nanocomposites as a function of material and interphase properties. AB - In this paper, "a" interfacial parameter in Nicolais-Narkis model is expressed by thickness "ri" and strength "sigmai" of interphase between polymer and nanoparticles as well as material properties. "a" parameter is connected to "B1" interfacial parameter in modified Pukanszky model and the effects of "ri" and "sigmai" on "a" are explained. The negligible difference between "a" values calculated by fitting the experimental results to Nicolais-Narkis model and also, by "B1" results confirms the accurateness of the suggested relation between "a" and "B1" parameters. Additionally, an inverse relation is found between "a" and "B1" parameters for nanocomposites containing spherical nanoparticles. The results demonstrate that the slight levels of "ri" and "sigmai" data give a large value of "a" which indicates the poor interfacial adhesion. PMID- 26954998 TI - Homogeneous time-resolved G protein-coupled receptor-ligand binding assay based on fluorescence cross-correlation spectroscopy. AB - G protein-coupled receptors (GPCRs) mediate many important physiological functions and are considered as one of the most successful therapeutic target classes for a wide spectrum of diseases. Drug discovery projects generally benefit from a broad range of experimental approaches for screening compound libraries and for the characterization of binding modes of drug candidates. Owing to the difficulties in solubilizing and purifying GPCRs, assay formats have been so far mainly limited to cell-based functional assays and radioligand binding assays. In this study, we used fluorescence cross-correlation spectroscopy (FCCS) to analyze the interaction of detergent-solubilized receptors to various types of GPCR ligands: endogenous peptides, small molecules, and a large surrogate antagonist represented by a blocking monoclonal antibody. Our work demonstrates the suitability of the homogeneous and time-resolved FCCS assay format for a robust, high-throughput determination of receptor-ligand binding affinities and kinetic rate constants for various therapeutically relevant GPCRs. PMID- 26954999 TI - "Have no regrets:" Parents' experiences and developmental tasks in pregnancy with a lethal fetal diagnosis. AB - SIGNIFICANCE: Lethal fetal diagnoses are made in 2% of all pregnancies. The pregnancy experience is certainly changed for the parents who choose to continue the pregnancy with a known fetal diagnosis but little is known about how the psychological and developmental processes are altered. METHODS: This longitudinal phenomenological study of 16 mothers and 14 fathers/partners sought to learn the experiences and developmental needs of parents who continue their pregnancy despite the lethal diagnosis. The study was guided by Merleau-Ponty's philosophic view of embodiment. Interviews (N = 90) were conducted with mothers and fathers over time, from mid-pregnancy until 2-3 months post birth. Data analysis was iterative, through a minimum of two cycles of coding, theme identification, within- and cross-case analysis, and the writing of results. RESULTS: Despite individual differences, parents were quite consistent in sharing that their overall goal was to "Have no regrets" when all was said and done. Five stages of pregnancy were identified: Pre-diagnosis, Learning Diagnosis, Living with Diagnosis, Birth & Death, and Post Death. Developmental tasks of pregnancy that emerged were 1) Navigating Relationships, 2) Comprehending Implication of the Condition, 3) Revising Goals of Pregnancy, 4) Making the Most of Time with Baby, 5) Preparing for Birth and Inevitable Death, 6) Advocating for Baby with Integrity, and 7) Adjusting to Life in Absence of Baby. Prognostic certainty was found to be highly influential in parents' progression through developmental tasks. CONCLUSION: The framework of parents' pregnancy experiences with lethal fetal diagnosis that emerged can serve as a useful guide for providers who care for families, especially in perinatal palliative care. Providing patient-centered care that is matched to the stage and developmental tasks of these families may lead to improved care and greater parent satisfaction. PMID- 26955001 TI - Pumping Rate Study of a Left Ventricular Assist Device in a Mock Circulatory System. AB - The aim of this work was to investigate the hemodynamic influence of the change of pump rate on the cardiovascular system with consideration of heart rate and the resonant characteristics of the arterial system when a reliable synchronous triggering source is unavailable. Hemodynamic waveforms are recorded at baseline conditions and with the pump rate of left ventricular assist device (LVAD) at 55, 60, 66, and 70 beats per minute for four test conditions in a mock circulatory system. The total input work (TIW) and energy equivalent pressure (EEP) are calculated as metrics for evaluating the hemodynamic performance within different test conditions. Experimental results show that TIW and EEP achieve their maximum values, where the pump rate is equal to the heart rate. In addition, it demonstrates that TIW and EEP are significantly affected by changing pump rate of LVAD, especially when the pump rate is closing to the natural frequency of the arterial system. When a reliable synchronous triggering source is not available for LVAD, it is suggested that selecting a pump rate equal to the resonant frequency of the arterial system could achieve better supporting effects. PMID- 26955002 TI - The HeartMate II Risk Score: An Adjusted Score for Evaluation of All Continuous Flow Left Ventricular Assist Devices. AB - The aim of this study was to evaluate the performance of an adjusted HeartMate II risk score (HMRS) in Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS; n = 9,733) and in HeartWare Ventricular Assist Device (HVAD) bridge to transplant (BTT) trial patients (n = 360). Interagency Registry for Mechanically Assisted Circulatory Support data were used to calculate an adjusted HMRS, omitting center volume, for all patients on continuous-flow left ventricular assist device (LVAD) support. Ninety day mortality was then evaluated in INTERMACS and HVAD-BTT patients. Four risk groups were identified based on INTERMACS patient-adjusted HMRS: very low (<5%, 90 day mortality; score <0.20), low (5-10%, 90 day mortality; score 0.20-1.97), medium (10-20%, 90 day mortality; score 1.98-4.48), and high risk (>20%, 90 day mortality; score >4.48). Within INTERMACS, there were significant differences in survival between all-adjusted HMRS risk groups (p < 0.001 in pairwise comparisons). Controlling for known mortality correlates, the adjusted HMRS mortality hazard ratio was 1.19 (1.25 1.23) per unit HMRS increase. The HVAD cohort was a low-risk cohort with 90 day survivals for very low-, low-, and medium-risk patients of 100%, 97 +/- 1.1%, and 90 +/- 3.6%, respectively (p = 0.007). Patients in the very low- and low-risk group had significantly improved survival compared with medium-risk patients, respectively (both p < 0.05). The adjusted HMRS appropriately risk stratified a large cohort of INTERMACS patients and was predictive of survival in HeartWare supported patients. PMID- 26955003 TI - Gastrointestinal Congestion Dilates the Hepatic Artery Through the P38 MAPK Signal Transduction Pathway During Liver Transplantation. AB - During the neohepatic stage of liver transplantation, hemodynamics change markedly. The current study aimed to investigate whether gastrointestinal congestion caused by inferior vena cava and hepatic portal vein clamping can dilate the hepatic artery and to determine the associated mechanisms. Ring segments of the hepatic artery were treated with the plasma from gastrointestinal congestion or the superior vena cava. The fractions in gastrointestinal congestion and the superior vena cava plasma were tested, and the effect of these fractions on the tone of the hepatic artery ring was examined. Different signal transduction blockers and different inhibitors were then used to determine the exact signal transduction pathway involved. In addition, endothelial cell structure was observed by transmission electron microscopy after treatment with the gastrointestinal congestion plasma or the superior vena cava plasma. Gastrointestinal congestion plasma contained more inflammatory cytokines than superior vena cava plasma, and these cytokines could cause hepatic artery ring dilatation. A P38 mitogen-activated protein kinase (P38 MAPK) signal transduction pathway blocker and nitric oxide (NO), prostaglandin (PGI2), nuclear factor kappaB (NF-kappaB), and adenosine triphosphate (ATP)-sensitive K (KATP) channel inhibitors were able to significantly reverse the ring tension caused by gastrointestinal congestion plasma. The normal endothelium was also injured by treatment with gastrointestinal congestion plasma. The inflammatory cytokines in gastrointestinal congestion can cause hepatic artery ring dilatation through the P38 MAPK signal transduction pathway, and this phenomenon is also associated with NO, PGI2, NF-kappaB, and the KATP channel. These inflammatory cytokines can injure endothelial cells in the hepatic artery. PMID- 26955006 TI - Adventitial Cystic Disease of the Common Femoral Vein-A Rare Mimic of Deep Venous Thrombosis: A Case Report. PMID- 26955005 TI - Gain-of-function missense variant in SLC12A2, encoding the bumetanide-sensitive NKCC1 cotransporter, identified in human schizophrenia. AB - Perturbations of gamma-aminobutyric acid (GABA) neurotransmission in the human prefrontal cortex have been implicated in the pathogenesis of schizophrenia (SCZ), but the mechanisms are unclear. NKCC1 (SLC12A2) is a Cl(-)-importing cation-Cl(-) cotransporter that contributes to the maintenance of depolarizing GABA activity in immature neurons, and variation in SLC12A2 has been shown to increase the risk for schizophrenia via alterations of NKCC1 mRNA expression. However, no disease-causing mutations or functional variants in NKCC1 have been identified in human patients with SCZ. Here, by sequencing three large French Canadian (FC) patient cohorts of SCZ, autism spectrum disorders (ASD), and intellectual disability (ID), we identified a novel heterozygous NKCC1 missense variant (p.Y199C) in SCZ. This variant is located in an evolutionarily conserved residue in the critical N-terminal regulatory domain and exhibits high predicted pathogenicity. No NKCC1 variants were detected in ASD or ID, and no KCC3 variants were identified in any of the three neurodevelopmental disorder cohorts. Functional experiments show Y199C is a gain-of-function variant, increasing Cl(-) dependent and bumetanide-sensitive NKCC1 activity even in conditions in which the transporter is normally functionally silent (hypotonicity). These data are the first to describe a functional missense variant in SLC12A2 in human SCZ, and suggest that genetically encoded dysregulation of NKCC1 may be a risk factor for, or contribute to the pathogenesis of, human SCZ. PMID- 26955007 TI - Spiritual Meaning in Life and Values in Patients With Severe Mental Disorders. AB - Spirituality and meaning in life are key dimensions of recovery in psychiatric disorders. The aim of this study was to explore spiritual meaning in life in relation to values and mental health among 175 patients with schizophrenia, borderline personality disorder, bipolar disorder, and anorexia nervosa. For 26% of the patients, spirituality was essential in providing meaning in life. Depending on the diagnosis, considering spirituality as essential in life was associated with better social functioning; self-esteem; psychological and social quality of life; fewer negative symptoms; higher endorsement of values such as universalism, tradition (humility, devoutness), and benevolence (helpfulness); and a more meaningful perspective in life. These results highlight the importance of spirituality for recovery-oriented care. PMID- 26955008 TI - iBET: Immersive visualization of biological electron-transfer dynamics. AB - Recently, we presented a computational framework named VizBET to simulate and visualize biological electron-transfer (ET) dynamics. The visualization process was encapsulated as a plugin to the Visual Molecular Dynamics (VMD) software. However, the user's ability to understand complex, multidimensional ET pathways was severely limited when visualized in 2D on traditional computer monitors. To provide a more accurate representation with enhanced depth perception, we here present an extension of VizBET named iBET to render the VMD model of ET dynamics in a commodity virtual reality (VR) platform. The paper describes detailed procedures to export VMD models into the Unity game engine and render it in an Oculus Rift head mounted display. With the increasing availability of low-cost VR systems like the Rift and rich programmability of game engines, the iBET framework provides a powerful means to explore and understand not only biological ET processes but also a unique experiential tool for broad scientific communities. PMID- 26955010 TI - Measuring Blood Glucose Concentrations in Photometric Glucometers Requiring Very Small Sample Volumes. AB - Glucometers present an important self-monitoring tool for diabetes patients and, therefore, must exhibit high accuracy as well as good usability features. Based on an invasive photometric measurement principle that drastically reduces the volume of the blood sample needed from the patient, we present a framework that is capable of dealing with small blood samples, while maintaining the required accuracy. The framework consists of two major parts: 1) image segmentation; and 2) convergence detection. Step 1 is based on iterative mode-seeking methods to estimate the intensity value of the region of interest. We present several variations of these methods and give theoretical proofs of their convergence. Our approach is able to deal with changes in the number and position of clusters without any prior knowledge. Furthermore, we propose a method based on sparse approximation to decrease the computational load, while maintaining accuracy. Step 2 is achieved by employing temporal tracking and prediction, herewith decreasing the measurement time, and, thus, improving usability. Our framework is tested on several real datasets with different characteristics. We show that we are able to estimate the underlying glucose concentration from much smaller blood samples than is currently state of the art with sufficient accuracy according to the most recent ISO standards and reduce measurement time significantly compared to state-of-the-art methods. PMID- 26955009 TI - Health Worker mHealth Utilization: A Systematic Review. AB - This systematic review describes mHealth interventions directed at healthcare workers in low-resource settings from the PubMed database from March 2009 to May 2015. Thirty-one articles were selected for final review. Four categories emerged from the reviewed articles: data collection during patient visits, communication between health workers and patients, communication between health workers, and public health surveillance. Most studies used a combination of quantitative and qualitative methods to assess acceptability of use, barriers to use, changes in healthcare delivery, and improved health outcomes. Few papers included theory explicitly to guide development and evaluation of their mHealth programs. Overall, evidence indicated that mobile technology tools, such as smartphones and tablets, substantially benefit healthcare workers, their patients, and healthcare delivery. Limitations to mHealth tools included insufficient program use and sustainability, unreliable Internet and electricity, and security issues. Despite these limitations, this systematic review demonstrates the utility of using mHealth in low-resource settings and the potential for widespread health system improvements using technology. PMID- 26955012 TI - Compound Radar Approach for Breast Imaging. AB - Multistatic radar apertures record scattering at a number of receivers when the target is illuminated by a single transmitter, providing more scattering information than its monostatic counterpart per transmission angle. This paper considers the well-known problem of detecting tumor targets within breast phantoms using multistatic radar. To accurately image potentially cancerous targets size within the breast, a significant number of multistatic channels are required in order to adequately calibrate-out unwanted skin reflections, increase the immunity to clutter, and increase the dynamic range of a breast radar imaging system. However, increasing the density of antennas within a physical array is inevitably limited by the geometry of the antenna elements designed to operate with biological tissues at microwave frequencies. A novel compound imaging approach is presented to overcome these physical constraints and improve the imaging capabilities of a multistatic radar imaging modality for breast scanning applications. The number of transmit-receive (TX-RX) paths available for imaging are increased by performing a number of breast scans with varying array positions. A skin calibration method is presented to reduce the influence of skin reflections from each channel. Calibrated signals are applied to receive a beamforming method, compounding the data from each scan to produce a microwave radar breast profile. The proposed imaging method is evaluated with experimental data obtained from constructed phantoms of varying complexity, skin contour asymmetries, and challenging tumor positions and sizes. For each imaging scenario outlined in this study, the proposed compound imaging technique improves skin calibration, clearly detects small targets, and substantially reduces the level of undesirable clutter within the profile. PMID- 26955011 TI - Gait Rhythm Fluctuation Analysis for Neurodegenerative Diseases by Empirical Mode Decomposition. AB - Previous studies have indicated that gait rhythm fluctuations are useful for characterizing certain pathologies of neurodegenerative diseases such as Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD). However, no previous study has investigated the properties of frequency range distributions of gait rhythms. Therefore, in our study, empirical mode decomposition was implemented for decomposing the time series of gait rhythms into intrinsic mode functions from the high-frequency component to the low-frequency component sequentially. Then, Kendall's coefficient of concordance and the ratio for energy change for different IMFs were calculated, which were denoted as W and RE , respectively. Results revealed that the frequency distributions of gait rhythms in patients with neurodegenerative diseases are less homogeneous than healthy subjects, and the gait rhythms of the patients contain much more high-frequency components. In addition, parameters of W and RE can significantly differentiate among the four groups of subjects (HD, ALS, PD, and healthy subjects) (with the minimum p-value of 0.0000493). Finally, five representative classifiers were utilized in order to evaluate the possible capabilities of W and RE to distinguish the patients with neurodegenerative diseases from the healthy subjects. This achieved maximum area under the curve values of 0.949, 0.900, and 0.934 for PD, HD, and ALS detection, respectively. In sum, our study suggests that gait rhythm features extracted in the frequency domain should be given consideration seriously in the future neurodegenerative disease characterization and intervention. PMID- 26955014 TI - Multiscale Combinatorial Grouping for Image Segmentation and Object Proposal Generation. AB - We propose a unified approach for bottom-up hierarchical image segmentation and object proposal generation for recognition, called Multiscale Combinatorial Grouping (MCG). For this purpose, we first develop a fast normalized cuts algorithm. We then propose a high-performance hierarchical segmenter that makes effective use of multiscale information. Finally, we propose a grouping strategy that combines our multiscale regions into highly-accurate object proposals by exploring efficiently their combinatorial space. We also present Single-scale Combinatorial Grouping (SCG), a faster version of MCG that produces competitive proposals in under five seconds per image. We conduct an extensive and comprehensive empirical validation on the BSDS500, SegVOC12, SBD, and COCO datasets, showing that MCG produces state-of-the-art contours, hierarchical regions, and object proposals. PMID- 26955013 TI - 4-D Flow Control in Porous Scaffolds: Toward a Next Generation of Bioreactors. AB - Tissue engineering (TE) approaches that involve seeding cells into predetermined tissue scaffolds ignore the complex environment where the material properties are spatially inhomogeneous and evolve over time. We present a new approach for controlling mechanical forces inside bioreactors, which enables spatiotemporal control of flow fields in real time. Our adaptive approach offers the flexibility of dialing-in arbitrary shear stress distributions and adjusting flow field patterns in a scaffold over time in response to cell growth without needing to alter scaffold structure. This is achieved with a multi-inlet bioreactor and a control algorithm with learning capabilities to dynamically solve the inverse problem of computing the inlet pressure distribution required over the multiple inlets to obtain a target flow field. The new method constitutes a new platform for studies of cellular responses to mechanical forces in complex environments and opens potentially transformative possibilities for TE. PMID- 26955016 TI - Expanded Parts Model for Semantic Description of Humans in Still Images. AB - We introduce an Expanded Parts Model (EPM) for recognizing human attributes (e.g., young, short hair, wearing suits) and actions (e.g., running, jumping) in still images. An EPM is a collection of part templates which are learnt discriminatively to explain specific scale-space regions in the images (in human centric coordinates). This is in contrast to current models which consist of a relatively few (i.e., a mixture of) 'average' templates. EPM uses only a subset of the parts to score an image and scores the image sparsely in space, i.e., it ignores redundant and random background in an image. To learn our model, we propose an algorithm which automatically mines parts and learns corresponding discriminative templates together with their respective locations from a large number of candidate parts. We validate our method on three recent challenging datasets of human attributes and actions. We obtain convincing qualitative and state-of-the-art quantitative results on the three datasets. PMID- 26955017 TI - Adaptive Visual Tracking with Minimum Uncertainty Gap Estimation. AB - A novel tracking algorithm is proposed, which robustly tracks a target by finding the state that minimizes the likelihood uncertainty. Likelihood uncertainty is estimated by determining the gap between the lower and upper bounds of likelihood. By minimizing the gap between the two bounds, the proposed method identifies the confident and reliable state of the target. In this study, the state that provides the Minimum Uncertainty Gap (MUG) between likelihood bounds is shown to be more reliable than the state that provides the maximum likelihood only, especially when severe illumination changes, occlusions, and pose variations occur. A rigorous derivation of the lower and upper bounds of the likelihood for the visual tracking problem is provided to address this issue. Additionally, an efficient inference algorithm that uses Interacting Markov Chain Monte Carlo (IMCMC) approach is presented to find the best state that maximizes the average of the lower and upper bounds of likelihood while minimizing the gap between the two bounds. We extend our method to update the target model adaptively. To update the model, the current observation is combined with a previous target model with the adaptive weight, which is calculated according to the goodness of the current observation. The goodness of the observation is measured using the proposed uncertainty gap estimation of likelihood. Experimental results demonstrate that the proposed method robustly tracks the target in realistic videos and outperforms conventional tracking methods. PMID- 26955015 TI - Semantic Event Fusion of Different Visual Modality Concepts for Activity Recognition. AB - Combining multimodal concept streams from heterogeneous sensors is a problem superficially explored for activity recognition. Most studies explore simple sensors in nearly perfect conditions, where temporal synchronization is guaranteed. Sophisticated fusion schemes adopt problem-specific graphical representations of events that are generally deeply linked with their training data and focused on a single sensor. This paper proposes a hybrid framework between knowledge-driven and probabilistic-driven methods for event representation and recognition. It separates semantic modeling from raw sensor data by using an intermediate semantic representation, namely concepts. It introduces an algorithm for sensor alignment that uses concept similarity as a surrogate for the inaccurate temporal information of real life scenarios. Finally, it proposes the combined use of an ontology language, to overcome the rigidity of previous approaches at model definition, and a probabilistic interpretation for ontological models, which equips the framework with a mechanism to handle noisy and ambiguous concept observations, an ability that most knowledge-driven methods lack. We evaluate our contributions in multimodal recordings of elderly people carrying out IADLs. Results demonstrated that the proposed framework outperforms baseline methods both in event recognition performance and in delimiting the temporal boundaries of event instances. PMID- 26955018 TI - Hierarchical Clustering Multi-Task Learning for Joint Human Action Grouping and Recognition. AB - This paper proposes a hierarchical clustering multi-task learning (HC-MTL) method for joint human action grouping and recognition. Specifically, we formulate the objective function into the group-wise least square loss regularized by low rank and sparsity with respect to two latent variables, model parameters and grouping information, for joint optimization. To handle this non-convex optimization, we decompose it into two sub-tasks, multi-task learning and task relatedness discovery. First, we convert this non-convex objective function into the convex formulation by fixing the latent grouping information. This new objective function focuses on multi-task learning by strengthening the shared-action relationship and action-specific feature learning. Second, we leverage the learned model parameters for the task relatedness measure and clustering. In this way, HC-MTL can attain both optimal action models and group discovery by alternating iteratively. The proposed method is validated on three kinds of challenging datasets, including six realistic action datasets (Hollywood2, YouTube, UCF Sports, UCF50, HMDB51 & UCF101), two constrained datasets (KTH & TJU), and two multi-view datasets (MV-TJU & IXMAS). The extensive experimental results show that: 1) HC-MTL can produce competing performances to the state of the arts for action recognition and grouping; 2) HC-MTL can overcome the difficulty in heuristic action grouping simply based on human knowledge; 3) HC MTL can avoid the possible inconsistency between the subjective action grouping depending on human knowledge and objective action grouping based on the feature subspace distributions of multiple actions. Comparison with the popular clustered multi-task learning further reveals that the discovered latent relatedness by HC MTL aids inducing the group-wise multi-task learning and boosts the performance. To the best of our knowledge, ours is the first work that breaks the assumption that all actions are either independent for individual learning or correlated for joint modeling and proposes HC-MTL for automated, joint action grouping and modeling. PMID- 26955019 TI - Human Parsing with Contextualized Convolutional Neural Network. AB - In this work, we address the human parsing task with a novel Contextualized Convolutional Neural Network (Co-CNN) architecture, which well integrates the cross-layer context, global image-level context, semantic edge context, within super-pixel context and cross-super-pixel neighborhood context into a unified network. Given an input human image, Co-CNN produces the pixelwise categorization in an end-to-end way. First, the cross-layer context is captured by our basic local-to-global-to-local structure, which hierarchically combines the global semantic information and the local fine details across different convolutional layers. Second, the global image-level label prediction is used as an auxiliary objective in the intermediate layer of the Co-CNN, and its outputs are further used for guiding the feature learning in subsequent convolutional layers to leverage the global image-level context. Third, semantic edge context is further incorporated into Co-CNN, where the high-level semantic boundaries are leveraged to guide pixel-wise labeling. Finally, to further utilize the local super-pixel contexts, the within-super-pixel smoothing and cross-super-pixel neighbourhood voting are formulated as natural sub-components of the Co-CNN to achieve the local label consistency in both training and testing process. Comprehensive evaluations on two public datasets well demonstrate the significant superiority of our Co-CNN over other state-of-the-arts for human parsing. In particular, the F-1 score on the large dataset [1] reaches 81.72 percent by Co-CNN, significantly higher than 62.81 percent and 64.38 percent by the state-of-the-art algorithms, M CNN [2] and ATR [1], respectively. By utilizing our newly collected large dataset for training, our Co-CNN can achieve 85.36 percent in F-1 score. PMID- 26955020 TI - Deep Dynamic Neural Networks for Multimodal Gesture Segmentation and Recognition. AB - This paper describes a novel method called Deep Dynamic Neural Networks (DDNN) for multimodal gesture recognition. A semi-supervised hierarchical dynamic framework based on a Hidden Markov Model (HMM) is proposed for simultaneous gesture segmentation and recognition where skeleton joint information, depth and RGB images, are the multimodal input observations. Unlike most traditional approaches that rely on the construction of complex handcrafted features, our approach learns high-level spatio-temporal representations using deep neural networks suited to the input modality: a Gaussian-Bernouilli Deep Belief Network (DBN) to handle skeletal dynamics, and a 3D Convolutional Neural Network (3DCNN) to manage and fuse batches of depth and RGB images. This is achieved through the modeling and learning of the emission probabilities of the HMM required to infer the gesture sequence. This purely data driven approach achieves a Jaccard index score of 0.81 in the ChaLearn LAP gesture spotting challenge. The performance is on par with a variety of state-of-the-art hand-tuned feature-based approaches and other learning-based methods, therefore opening the door to the use of deep learning techniques in order to further explore multimodal time series data. PMID- 26955021 TI - Lung Pattern Classification for Interstitial Lung Diseases Using a Deep Convolutional Neural Network. AB - Automated tissue characterization is one of the most crucial components of a computer aided diagnosis (CAD) system for interstitial lung diseases (ILDs). Although much research has been conducted in this field, the problem remains challenging. Deep learning techniques have recently achieved impressive results in a variety of computer vision problems, raising expectations that they might be applied in other domains, such as medical image analysis. In this paper, we propose and evaluate a convolutional neural network (CNN), designed for the classification of ILD patterns. The proposed network consists of 5 convolutional layers with 2 * 2 kernels and LeakyReLU activations, followed by average pooling with size equal to the size of the final feature maps and three dense layers. The last dense layer has 7 outputs, equivalent to the classes considered: healthy, ground glass opacity (GGO), micronodules, consolidation, reticulation, honeycombing and a combination of GGO/reticulation. To train and evaluate the CNN, we used a dataset of 14696 image patches, derived by 120 CT scans from different scanners and hospitals. To the best of our knowledge, this is the first deep CNN designed for the specific problem. A comparative analysis proved the effectiveness of the proposed CNN against previous methods in a challenging dataset. The classification performance ( ~ 85.5%) demonstrated the potential of CNNs in analyzing lung patterns. Future work includes, extending the CNN to three dimensional data provided by CT volume scans and integrating the proposed method into a CAD system that aims to provide differential diagnosis for ILDs as a supportive tool for radiologists. PMID- 26955023 TI - Real-Time Model-Based Inversion in Cross-Sectional Optoacoustic Tomography. AB - Analytical (closed-form) inversion schemes have been the standard approach for image reconstruction in optoacoustic tomography due to their fast reconstruction abilities and low memory requirements. Yet, the need for quantitative imaging and artifact reduction has led to the development of more accurate inversion approaches, which rely on accurate forward modeling of the optoacoustic wave generation and propagation. In this way, multiple experimental factors can be incorporated, such as the exact detection geometry, spatio-temporal response of the transducers, and acoustic heterogeneities. The model-based inversion commonly results in very large sparse matrix formulations that require computationally extensive and memory demanding regularization schemes for image reconstruction, hindering their effective implementation in real-time imaging applications. Herein, we introduce a new discretization procedure for efficient model-based reconstructions in two-dimensional optoacoustic tomography that allows for parallel implementation on a graphics processing unit (GPU) with a relatively low numerical complexity. By on-the-fly calculation of the model matrix in each iteration of the inversion procedure, the new approach results in imaging frame rates exceeding 10 Hz, thus enabling real-time image rendering using the model based approach. PMID- 26955022 TI - Bayesian Community Detection in the Space of Group-Level Functional Differences. AB - We propose a unified Bayesian framework to detect both hyper- and hypo-active communities within whole-brain fMRI data. Specifically, our model identifies dense subgraphs that exhibit population-level differences in functional synchrony between a control and clinical group. We derive a variational EM algorithm to solve for the latent posterior distributions and parameter estimates, which subsequently inform us about the afflicted network topology. We demonstrate that our method provides valuable insights into the neural mechanisms underlying social dysfunction in autism, as verified by the Neurosynth meta-analytic database. In contrast, both univariate testing and community detection via recursive edge elimination fail to identify stable functional communities associated with the disorder. PMID- 26955024 TI - Pulmonary Nodule Detection in CT Images: False Positive Reduction Using Multi View Convolutional Networks. AB - We propose a novel Computer-Aided Detection (CAD) system for pulmonary nodules using multi-view convolutional networks (ConvNets), for which discriminative features are automatically learnt from the training data. The network is fed with nodule candidates obtained by combining three candidate detectors specifically designed for solid, subsolid, and large nodules. For each candidate, a set of 2-D patches from differently oriented planes is extracted. The proposed architecture comprises multiple streams of 2-D ConvNets, for which the outputs are combined using a dedicated fusion method to get the final classification. Data augmentation and dropout are applied to avoid overfitting. On 888 scans of the publicly available LIDC-IDRI dataset, our method reaches high detection sensitivities of 85.4% and 90.1% at 1 and 4 false positives per scan, respectively. An additional evaluation on independent datasets from the ANODE09 challenge and DLCST is performed. We showed that the proposed multi-view ConvNets is highly suited to be used for false positive reduction of a CAD system. PMID- 26955025 TI - In Vivo Estimation of Attenuation and Backscatter Coefficients From Human Thyroids. AB - Fine-needle aspiration (FNA) remains the gold standard for the diagnosis of thyroid cancer. However, currently, a large number of FNA biopsies result in negative or undetermined diagnosis, which suggests that better noninvasive tools are needed for the clinical management of thyroid cancer. Spectral-based quantitative ultrasound (QUS) characterizations may offer a better diagnostic management as previously demonstrated in mouse cancer models ex vivo. As a first step toward understanding the potential of QUS markers for thyroid disease management, this paper deals with the spectral-based QUS estimation of healthy human thyroids in vivo. Twenty volunteers were inspected by a trained radiologist using two ultrasonic imaging systems, which allowed them to acquire radio frequency data spanning the 3-16-MHz frequency range. Estimates of attenuation coefficient slope (ACS) using the spectral logarithmic difference method had an average value of [Formula: see text]) with a standard deviation of [Formula: see text]. Estimates of backscatter coefficient (BSC) using the reference-phantom method had an average value of [Formula: see text] over the useful frequency range. The intersubject variability when estimating BSCs was less than 1.5 dB over the analysis frequency range. Further, the effectiveness of three scattering models (i.e., fluid sphere, Gaussian, and exponential form factors) when fitting the experimentally estimated BSCs was assessed. The exponential form factor was found to provide the best overall goodness of fit ( R2 = 0.917), followed by the Gaussian ( R2 = 0.807) and the fluid-sphere models ( R2 = 0.752). For all scattering models used in this study, average estimates of the effective scatterer diameter were between 44 and 56 MUm. Overall, an excellent agreement in the estimated attenuation and BSCs with both scanners was exhibited. PMID- 26955027 TI - Guided Wave Tomography Based on Full-Waveform Inversion. AB - In this paper, a guided wave tomography method based on Full Waveform Inversion (FWI) is developed for accurate and high resolu- tion reconstruction of the remaining wall thickness in isotropic plates. The forward model is computed in the frequency domain by solving a full-wave equation in a two-dimensional acoustic model, accounting for higher order eects such as diractions and multiple scattering. Both numerical simulations and experiments were carried out to obtain the signals of a dispersive guided mode propagating through defects. The inversion was based on local optimization of a waveform mist func- tion between modeled and measured data, and was applied iteratively to discrete frequency components from low to high frequencies. The resulting wave velocity maps were then converted to thickness maps by the dispersion characteristics of selected guided modes. The results suggest that the FWI method is capable to reconstruct the thickness map of a irregularly shaped defect accurately on a 10 mm thick plate with the thickness error within 0.5 mm. PMID- 26955028 TI - A 7/24-GHz CMOS VCO with High Band Ratio Using a Current-Source Switching Topology. AB - In this paper, a 7/24-GHz dual-band voltage-controlled oscillator (DVCO) using a current-source switching topology is designed, implemented, and verified in a 0.18-MUm CMOS technology for C-band and K-band radar applications. The low- and high-frequency bands are obtained by the Colpitts mode oscillation and the cross coupled pairs (CCP) mode oscillation, respectively. Unlike conventional dual-band VCOs realized by resonator-switching topologies, the proposed VCO is based on the composite Colpitts and CCP architecture to avoid additional losses in the resonator, or lower its power consumption. The fabricated VCO occupies a chip area of 0.95*0.71 mm2 including all testing pads. Measurements show that the VCO operating in the Colpitts mode provides a phase noise of -112.5 dBc/Hz at 1 MHz offset from the 7.4-GHz oscillation frequency under 7.5-mW power consumption. When the VCO operating in the CCP mode, it provides a phase noise of -99.9 dBc/Hz at 1 MHz offset from the 24-GHz oscillation frequency with 9.7-mW power dissipation. Moreover, the DVCO achieves a high band ratio (fH/fL=24/7) of 3.43. To the authors' best knowledge, the design features the highest band ratio, low power dissipation, and comparable electrical performances among previously reported DVCOs. PMID- 26955026 TI - On the Feasibility of Quantifying Fibrous Cap Thickness With Acoustic Radiation Force Impulse (ARFI) Ultrasound. AB - Acute cerebrovascular accidents are associated with the rupture of vulnerable atherosclerotic plaques in the carotid arteries. Fibrous cap (FC) thickness has been shown to be an important predictor of plaque rupture but has been challenging to measure accurately with clinical noninvasive imaging modalities. The goals of this investigation were first, to evaluate the feasibility of using transcutaneous acoustic radiation force impulse (ARFI) ultrasound to quantify FC thickness and second, to optimize both imaging and motion-tracking parameters to support such measurements. FCs with varying thickness (0.1-1.0 mm) were simulated using a simple-layered geometry, and their mechanical response to an impulse of radiation force was solved using finite-element method (FEM) modeling. Ultrasound tracking of FEM displacements was performed in Field II utilizing three center frequencies (6, 9, and 12 MHz) and eight motion-tracking kernel lengths ( 0.5lambda-4lambda). Additionally, FC thickness in two carotid plaques imaged in vivo was measured with ARFI and compared to matched histology. The results of this study demonstrate that 1) tracking pulse frequencies around 12 MHz are necessary to resolve caps around 0.2 mm; 2) large motion-tracking kernel sizes introduce bias into thickness measurements and overestimate the true cap thickness; and 3) color saturation settings on ARFI peak displacement images can impact thickness measurement accuracy substantially. PMID- 26955029 TI - Misaligned Image Integration With Local Linear Model. AB - We present a new image integration technique for a flash and long-exposure image pair to capture a dark scene without incurring blurring or noisy artifacts. Most existing methods require well-aligned images for the integration, which is often a burdensome restriction in practical use. We address this issue by locally transferring the colors of the flash images using a small fraction of the corresponding pixels in the long-exposure images. We formulate the image integration as a convex optimization problem with the local linear model. The proposed method makes it possible to integrate the color of the long-exposure image with the detail of the flash image without causing any harmful effects to its contrast, where we do not need perfect alignment between the images by virtue of our new integration principle. We show that our method successfully outperforms the state of the art in the image integration and reference-based color transfer for challenging misaligned data sets. PMID- 26955030 TI - Robust Blur Kernel Estimation for License Plate Images From Fast Moving Vehicles. AB - As the unique identification of a vehicle, license plate is a key clue to uncover over-speed vehicles or the ones involved in hit-and-run accidents. However, the snapshot of over-speed vehicle captured by surveillance camera is frequently blurred due to fast motion, which is even unrecognizable by human. Those observed plate images are usually in low resolution and suffer severe loss of edge information, which cast great challenge to existing blind deblurring methods. For license plate image blurring caused by fast motion, the blur kernel can be viewed as linear uniform convolution and parametrically modeled with angle and length. In this paper, we propose a novel scheme based on sparse representation to identify the blur kernel. By analyzing the sparse representation coefficients of the recovered image, we determine the angle of the kernel based on the observation that the recovered image has the most sparse representation when the kernel angle corresponds to the genuine motion angle. Then, we estimate the length of the motion kernel with Radon transform in Fourier domain. Our scheme can well handle large motion blur even when the license plate is unrecognizable by human. We evaluate our approach on real-world images and compare with several popular state-of-the-art blind image deblurring algorithms. Experimental results demonstrate the superiority of our proposed approach in terms of effectiveness and robustness. PMID- 26955031 TI - An Approach to Streaming Video Segmentation With Sub-Optimal Low-Rank Decomposition. AB - This paper investigates how to perform robust and efficient video segmentation while suppressing the effects of data noises and/or corruptions, and an effective approach is introduced to this end. First, a general algorithm, called sub optimal low-rank decomposition (SOLD), is proposed to pursue the low-rank representation for video segmentation. Given the data matrix formed by supervoxel features of an observed video sequence, SOLD seeks a sub-optimal solution by making the matrix rank explicitly determined. In particular, the representation coefficient matrix with the fixed rank can be decomposed into two sub-matrices of low rank, and then we iteratively optimize them with closed-form solutions. Moreover, we incorporate a discriminative replication prior into SOLD based on the observation that small-size video patterns tend to recur frequently within the same object. Second, based on SOLD, we present an efficient inference algorithm to perform streaming video segmentation in both unsupervised and interactive scenarios. More specifically, the constrained normalized-cut algorithm is adopted by incorporating the low-rank representation with other low level cues and temporal consistent constraints for spatio-temporal segmentation. Extensive experiments on two public challenging data sets VSB100 and SegTrack suggest that our approach outperforms other video segmentation approaches in both accuracy and efficiency. PMID- 26955032 TI - Dynamic Facial Expression Recognition With Atlas Construction and Sparse Representation. AB - In this paper, a new dynamic facial expression recognition method is proposed. Dynamic facial expression recognition is formulated as a longitudinal groupwise registration problem. The main contributions of this method lie in the following aspects: 1) subject-specific facial feature movements of different expressions are described by a diffeomorphic growth model; 2) salient longitudinal facial expression atlas is built for each expression by a sparse groupwise image registration method, which can describe the overall facial feature changes among the whole population and can suppress the bias due to large intersubject facial variations; and 3) both the image appearance information in spatial domain and topological evolution information in temporal domain are used to guide recognition by a sparse representation method. The proposed framework has been extensively evaluated on five databases for different applications: the extended Cohn-Kanade, MMI, FERA, and AFEW databases for dynamic facial expression recognition, and UNBC-McMaster database for spontaneous pain expression monitoring. This framework is also compared with several state-of-the-art dynamic facial expression recognition methods. The experimental results demonstrate that the recognition rates of the new method are consistently higher than other methods under comparison. PMID- 26955033 TI - Minimizing the Number of Edges via Edge Concentration in Dense Layered Graphs. AB - Edge concentration in dense bipartite graphs is a technique for reducing the numbers of edges and edge crossings in graph drawings. The conventional method proposed by Newbery is designed to reduce the number of edge crossings; however, it does not always reduce the number of edges. Reducing the number of edges is also an important factor for improving the readability of graphs. However, no edge concentration method with the explicit purpose of minimizing the number of edges has previously been studied. In this study, we propose a novel, efficient heuristic method for minimizing the number of edges during edge concentration. We demonstrate the efficiency of the proposed method via a comparison using randomly generated graphs. We find that Newbery's method fails to reduce the number of edges when the number of vertices is large. By contrast, the proposed method achieves an average compression ratio of 47 to 82 percent for all generated graph groups. We also present a real-world application of the proposed method using a causality network of biological data. PMID- 26955034 TI - Critical Point Cancellation in 3D Vector Fields: Robustness and Discussion. AB - Vector field topology has been successfully applied to represent the structure of steady vector fields. Critical points, one of the essential components of vector field topology, play an important role in describing the complexity of the extracted structure. Simplifying vector fields via critical point cancellation has practical merit for interpreting the behaviors of complex vector fields such as turbulence. However, there is no effective technique that allows direct cancellation of critical points in 3D. This work fills this gap and introduces the first framework to directly cancel pairs or groups of 3D critical points in a hierarchical manner with a guaranteed minimum amount of perturbation based on their robustness, a quantitative measure of their stability. In addition, our framework does not require the extraction of the entire 3D topology, which contains non-trivial separation structures, and thus is computationally effective. Furthermore, our algorithm can remove critical points in any subregion of the domain whose degree is zero and handle complex boundary configurations, making it capable of addressing challenging scenarios that may not be resolved otherwise. We apply our method to synthetic and simulation datasets to demonstrate its effectiveness. PMID- 26955035 TI - Visual Analysis of Cloud Computing Performance Using Behavioral Lines. AB - Cloud computing is an essential technology to Big Data analytics and services. A cloud computing system is often comprised of a large number of parallel computing and storage devices. Monitoring the usage and performance of such a system is important for efficient operations, maintenance, and security. Tracing every application on a large cloud system is untenable due to scale and privacy issues. But profile data can be collected relatively efficiently by regularly sampling the state of the system, including properties such as CPU load, memory usage, network usage, and others, creating a set of multivariate time series for each system. Adequate tools for studying such large-scale, multidimensional data are lacking. In this paper, we present a visual based analysis approach to understanding and analyzing the performance and behavior of cloud computing systems. Our design is based on similarity measures and a layout method to portray the behavior of each compute node over time. When visualizing a large number of behavioral lines together, distinct patterns often appear suggesting particular types of performance bottleneck. The resulting system provides multiple linked views, which allow the user to interactively explore the data by examining the data or a selected subset at different levels of detail. Our case studies, which use datasets collected from two different cloud systems, show that this visual based approach is effective in identifying trends and anomalies of the systems. PMID- 26955036 TI - Adaptive Disentanglement based on Local Clustering in Small-World Network Visualization. AB - Small-world networks have characteristically low pairwise shortest-path distances, causing distance-based layout methods to generate hairball drawings. Recent approaches thus aim at finding a sparser representation of the graph to amplify variations in pairwise distances. Since the effect of sparsification on the layout is difficult to describe analytically, the incorporated filtering parameters of these approaches typically have to be selected manually and individually for each input instance. We here propose the use of graph invariants to determine suitable parameters automatically. This allows us to perform adaptive filtering to obtain drawings in which the cluster structure is most prominent. The approach is based on an empirical relationship between input and output characteristics that is derived from real and synthetic networks.Experimental evaluation shows the effectiveness of our approach and suggests that it can be used by default to increase the robustness of force directed layout methods. PMID- 26955037 TI - Finite-Time Lyapunov Exponents and Lagrangian Coherent Structures in Uncertain Unsteady Flows. AB - The objective of this paper is to understand transport behavior in uncertain time varying flow fields by redefining the finite-time Lyapunov exponent (FTLE) and Lagrangian coherent structure (LCS) as stochastic counterparts of their traditional deterministic definitions. Three new concepts are introduced: the distribution of the FTLE (D-FTLE), the FTLE of distributions (FTLE-D), and uncertain LCS (U-LCS). The D-FTLE is the probability density function of FTLE values for every spatiotemporal location, which can be visualized with different statistical measurements. The FTLE-D extends the deterministic FTLE by measuring the divergence of particle distributions. It gives a statistical overview of how transport behaviors vary in neighborhood locations. The U-LCS, the probabilities of finding LCSs over the domain, can be extracted with stochastic ridge finding and density estimation algorithms. We show that our approach produces better results than existing variance-based methods do. Our experiments also show that the combination of D-FTLE, FTLE-D, and U-LCS can help users understand transport behaviors and find separatrices in ensemble simulations of atmospheric processes. PMID- 26955038 TI - Improving Separability of Structures with Similar Attributes in 2D Transfer Function Design. AB - The 2D transfer function based on scalar value and gradient magnitude (SG-TF) is popularly used in volume rendering. However, it is plagued by the boundary overlapping problem: different structures with similar attributes have the same region in SG-TF space, and their boundaries are usually connected. The SG-TF thus often fails in separating these structures (or their boundaries) and has limited ability to classify different objects in real-world 3D images. To overcome such a difficulty, we propose a novel method for boundary separation by integrating spatial connectivity computation of the boundaries and set operations on boundary voxels into the SG-TF. Specifically, spatial positions of boundaries and their regions in the SG-TF space are computed, from which boundaries can be well separated and volume rendered in different colors. In the method, the boundaries are divided into three classes and different boundary-separation techniques are applied to them, respectively. The complex task of separating various boundaries in 3D images is then simplified by breaking it into several small separation problems. The method shows good object classification ability in real-world 3D images while avoiding the complexity of high-dimensional transfer functions. Its effectiveness and validation is demonstrated by many experimental results to visualize boundaries of different structures in complex real-world 3D images. PMID- 26955039 TI - Real-Time Detection and Monitoring of Acute Brain Injury Utilizing Evoked Electroencephalographic Potentials. AB - Rapid detection and diagnosis of a traumatic brain injury (TBI) can significantly improve the prognosis for recovery. Helmet-mounted sensors that detect impact severity based on measurements of acceleration or pressure show promise for aiding triage and transport decisions in active, field environments such as professional sports or military combat. The detected signals, however, report on the mechanics of an impact rather than directly indicating the presence and severity of an injury. We explored the use of cortical somatosensory evoked electroencephalographic potentials (SSEPs) to detect and track, in real-time, neural electrophysiological abnormalities within the first hour following head injury in an animal model. To study the immediate electrophysiological effects of injury in vivo, we developed an experimental paradigm involving focused ultrasound that permits continuous, real-time measurements and minimizes mechanical artifact. Injury was associated with a dramatic reduction of amplitude over the damaged hemisphere directly after the injury. The amplitude systematically improved over time but remained significantly decreased at one hour, compared with baseline. In contrast, at one hour there was a concomitant enhancement of the cortical SSEP amplitude evoked from the uninjured hemisphere. Analysis of the inter-trial electroencephalogram (EEG) also revealed significant changes in low-frequency components and an increase in EEG entropy up to 30 minutes after injury, likely reflecting altered EEG reactivity to somatosensory stimuli. Injury-induced alterations in SSEPs were also observed using noninvasive epidermal electrodes, demonstrating viability of practical implementation. These results suggest cortical SSEPs recorded at just a few locations by head-mounted sensors and associated multiparametric analyses could potentially be used to rapidly detect and monitor brain injury in settings that normally present significant levels of mechanical and electrical noise. PMID- 26955040 TI - Discriminative Manifold Learning Based Detection of Movement-Related Cortical Potentials. AB - The detection of voluntary motor intention from EEG has been applied to closed loop brain-computer interfacing (BCI). The movement-related cortical potential (MRCP) is a low frequency component of the EEG signal, which represents movement intention, preparation, and execution. In this study, we aim at detecting MRCPs from single-trial EEG traces. For this purpose, we propose a detector based on a discriminant manifold learning method, called locality sensitive discriminant analysis (LSDA), and we test it in both online and offline experiments with executed and imagined movements. The online and offline experimental results demonstrated that the proposed LSDA approach for MRCP detection outperformed the Locality Preserving Projection (LPP) approach, which was previously shown to be the most accurate algorithm so far tested for MRCP detection. For example, in the online tests, the performance of LSDA was superior than LPP in terms of a significant reduction in false positives (FP) (passive FP: 1.6 +/-0.9/min versus 2.9 +/-1.0/min, p = 0.002, active FP: 2.2 +/-0.8/min versus 2.7 +/-0.6/min , p = 0.03 ), for a similar rate of true positives. In conclusion, the proposed LSDA based MRCP detection method is superior to previous approaches and is promising for developing patient-driven BCI systems for motor function rehabilitation as well as for neuroscience research. PMID- 26955042 TI - Closed-Loop Control of Tremor-Predominant Parkinsonian State Based on Parameter Estimation. AB - A significant feature of Parkinson's disease (PD) is the inability of the thalamus to respond faithfully to sensorimotor information from the cerebral cortex. This may be the result of abnormal oscillations in the basal ganglia (BG). Deep brain stimulation (DBS) is regarded as an effective method to modulate these pathological brain rhythmic activities. However, the selection of DBS parameters is challenging because the mechanism is not well understood. This work proposes the design of a closed-loop control strategy to automatically adjust the parameters of a DBS waveform based on a computational model. By estimating the synaptic input from BG to the thalamic neuron model as feedback variable, we designed and compared various control algorithms to counteract the effects of pathological oscillatory inputs. We then obtained optimal DBS parameters to modulate the tremor-predominant Parkinsonian state. We showed that even a simple proportional controller provides higher fidelity of thalamic relay of sensorimotor information and lower energy expenditure, as compared with classical open-loop DBS. Integral action further enhances DBS performance. Additionally, a positive bias voltage further improves the relay ability of the thalamus with decreased stimulation energy expenditure. These findings were conducive to the development of a more effective DBS to further improve the treatment of the PD. PMID- 26955041 TI - Semiparametric Identification of Human Arm Dynamics for Flexible Control of a Functional Electrical Stimulation Neuroprosthesis. AB - We present a method to identify the dynamics of a human arm controlled by an implanted functional electrical stimulation neuroprosthesis. The method uses Gaussian process regression to predict shoulder and elbow torques given the shoulder and elbow joint positions and velocities and the electrical stimulation inputs to muscles. We compare the accuracy of torque predictions of nonparametric, semiparametric, and parametric model types. The most accurate of the three model types is a semiparametric Gaussian process model that combines the flexibility of a black box function approximator with the generalization power of a parameterized model. The semiparametric model predicted torques during stimulation of multiple muscles with errors less than 20% of the total muscle torque and passive torque needed to drive the arm. The identified model allows us to define an arbitrary reaching trajectory and approximately determine the muscle stimulations required to drive the arm along that trajectory. PMID- 26955043 TI - Gait Event Detection in Real-World Environment for Long-Term Applications: Incorporating Domain Knowledge Into Time-Frequency Analysis. AB - Detecting gait events is the key to many gait analysis applications that would benefit from continuous monitoring or long-term analysis. Most gait event detection algorithms using wearable sensors that offer a potential for use in daily living have been developed from data collected in controlled indoor experiments. However, for real-word applications, it is essential that the analysis is carried out in humans' natural environment; that involves different gait speeds, changing walking terrains, varying surface inclinations and regular turns among other factors. Existing domain knowledge in the form of principles or underlying fundamental gait relationships can be utilized to drive and support the data analysis in order to develop robust algorithms that can tackle real world challenges in gait analysis. This paper presents a novel approach that exhibits how domain knowledge about human gait can be incorporated into time frequency analysis to detect gait events from long-term accelerometer signals. The accuracy and robustness of the proposed algorithm are validated by experiments done in indoor and outdoor environments with approximately 93 600 gait events in total. The proposed algorithm exhibits consistently high performance scores across all datasets in both, indoor and outdoor environments. PMID- 26955045 TI - Modeling of Optimal Targeted Therapies Using Drug-Loaded Magnetic Nanoparticles for Liver Cancer. AB - To enhance locoregional therapies for liver cancer treatment, we propose in this study a mathematical model to optimize the transcatheter arterial delivery of therapeutical agents. To maximize the effect of the treatment and minimize adverse effects on the patient, different mathematical models of the tumor growth are considered in this study to find the optimal number of the therapeutic drug loaded magnetic nanoparticles to be administered. Three types of therapy models are considered, e.g., angiogenesis inhibition therapy, chemotherapy and radiotherapy. We use state-dependent Riccati equations (SDRE) as an optimal control methodology framework to the Hahnfeldt's tumor growth formulation. Based on this, design optimal rules are derived for each therapy to reduce the growth of a tumor through the administration of appropriate dose of antiangiogenic, radio- and chemo-therapeutic agents. Simulation results demonstrate the validity of the proposed optimal delivery approach, leading to reduced intervention time, low drug administration rates and optimal targeted delivery. PMID- 26955047 TI - A New Method for Predicting Protein Functions From Dynamic Weighted Interactome Networks. AB - Automated annotation of protein function is challenging. As the number of sequenced genomes rapidly grows, the overwhelming majority of proteins can only be annotated computationally. Under new conditions or stimuli, not only the number and location of proteins would be changed, but also their interactions. This dynamic feature of protein interactions, however, was not considered in the existing function prediction algorithms. Taking the dynamic nature of protein interactions into consideration, we construct a dynamic weighted interactome network (DWIN) by integrating protein-protein interaction (PPI) network and time course gene expression data, as well as proteins' domain information and protein complex information. Then, we propose a new prediction approach that predicts protein functions from the constructed dynamic weighted interactome network. For an unknown protein, the proposed method visits dynamic networks at different time points and scores functions derived from all neighbors. Finally, the method selects top N functions from these ranked candidate functions to annotate the testing protein. Experiments on PPI datasets were conducted to evaluate the effectiveness of the proposed approach in predicting unknown protein functions. The evaluation results demonstrated that the proposed method outperforms other competing methods. PMID- 26955046 TI - Optimizing Associative Experimental Design for Protein Crystallization Screening. AB - The goal of protein crystallization screening is the determination of the main factors of importance to crystallizing the protein under investigation. One of the major issues about determining these factors is that screening is often expanded to many hundreds or thousands of conditions to maximize combinatorial chemical space coverage for maximizing the chances of a successful (crystalline) outcome. In this paper, we propose an experimental design method called "Associative Experimental Design (AED)" and an optimization method includes eliminating prohibited combinations and prioritizing reagents based on AED analysis of results from protein crystallization experiments. AED generates candidate cocktails based on these initial screening results. These results are analyzed to determine those screening factors in chemical space that are most likely to lead to higher scoring outcomes, crystals. We have tested AED on three proteins derived from the hyperthermophile Thermococcus thioreducens, and we applied an optimization method to these proteins. Our AED method generated novel cocktails (count provided in parentheses) leading to crystals for three proteins as follows: Nucleoside diphosphate kinase (4), HAD superfamily hydrolase (2), Nucleoside kinase (1). After getting promising results, we have tested our optimization method on four different proteins. The AED method with optimization yielded 4, 3, and 20 crystalline conditions for holo Human Transferrin, archaeal exosome protein, and Nucleoside diphosphate kinase, respectively. PMID- 26955048 TI - Characterizing Nanoscale Transient Communication. AB - We consider the novel paradigm of nanoscale transient communication (NTC), where certain components of the small-scale communication link are physically transient. As such, the transmitter and the receiver may change their properties over a prescribed lifespan due to their time-varying structures. The NTC systems may find important applications in the biomedical, environmental, and military fields, where system degradability allows for benign integration into life and environment. In this paper, we analyze the NTC systems from the channel-modeling and capacity-analysis perspectives and focus on the stochastically meaningful slow transience scenario, where the coherence time of degeneration Td is much longer than the coding delay Tc. We first develop novel and parsimonious models to characterize the NTC channels, where three types of physical layers are considered: electromagnetism-based terahertz (THz) communication, diffusion-based molecular communication (DMC), and nanobots-assisted touchable communication (TouchCom). We then revisit the classical performance measure of epsilon-outage channel capacity and take a fresh look at its formulations in the NTC context. Next, we present the notion of capacity degeneration profile (CDP), which describes the reduction of channel capacity with respect to the degeneration time. Finally, we provide numerical examples to demonstrate the features of CDP. To the best of our knowledge, the current work represents a first attempt to systematically evaluate the quality of nanoscale communication systems deteriorating with time. PMID- 26955044 TI - Nanoparticle-Based Therapies for Wound Biofilm Infection: Opportunities and Challenges. AB - Clinical data from human chronic wounds implicates biofilm formation with the onset of wound chronicity. Despite the development of novel antimicrobial agents, the cost and complexity of treating chronic wound infections associated with biofilms remain a serious challenge, which necessitates the development of new and alternative approaches for effective anti-biofilm treatment. Recent advancement in nanotechnology for developing a new class of nanoparticles that exhibit unique chemical and physical properties holds promise for the treatment of biofilm infections. Over the last decade, nanoparticle-based approaches against wound biofilm infection have been directed toward developing nanoparticles with intrinsic antimicrobial properties, utilizing nanoparticles for controlled antimicrobials delivery, and applying nanoparticles for antibacterial hyperthermia therapy. In addition, a strategy to functionalize nanoparticles towards enhanced penetration through the biofilm matrix has been receiving considerable interest recently by means of achieving an efficient targeting to the bacterial cells within biofilm matrix. This review summarizes and highlights the recent development of these nanoparticle-based approaches as potential therapeutics for controlling wound biofilm infection, along with current challenges that need to be overcome for their successful clinical translation. PMID- 26955049 TI - 3D Genome Reconstruction with ShRec3D+ and Hi-C Data. AB - Hi-C technology, a chromosome conformation capture (3C) based method, has been developed to capture genome-wide interactions at a given resolution. The next challenge is to reconstruct 3D structure of genome from the 3C-derived data computationally. Several existing methods have been proposed to obtain a consensus structure or ensemble structures. These methods can be categorized as probabilistic models or restraint-based models. In this paper, we propose a method, named ShRec3D+, to infer a consensus 3D structure of a genome from Hi-C data. The method is a two-step algorithm which is based on ChromSDE and ShRec3D methods. First, correct the conversion factor by golden section search for converting interaction frequency data to a distance weighted graph. Second, apply shortest-path algorithm and multi-dimensional scaling (MDS) algorithm to compute the 3D coordinates of a set of genomic loci from the distance graph. We validate ShRec3D+ accuracy on both simulation data and publicly Hi-C data. Our test results indicate that our method successfully corrects the parameter with a given resolution, is more accurate than ShRec3D, and is more efficient and robust than ChromSDE. PMID- 26955050 TI - Leveraging FPGAs for Accelerating Short Read Alignment. AB - One of the key challenges facing genomics today is how to efficiently analyze the massive amounts of data produced by next-generation sequencing platforms. With general-purpose computing systems struggling to address this challenge, specialized processors such as the Field-Programmable Gate Array (FPGA) are receiving growing interest. The means by which to leverage this technology for accelerating genomic data analysis is however largely unexplored. In this paper, we present a runtime reconfigurable architecture for accelerating short read alignment using FPGAs. This architecture exploits the reconfigurability of FPGAs to allow the development of fast yet flexible alignment designs. We apply this architecture to develop an alignment design which supports exact and approximate alignment with up to two mismatches. Our design is based on the FM-index, with optimizations to improve the alignment performance. In particular, the n-step FM index, index oversampling, a seed-and-compare stage, and bi-directional backtracking are included. Our design is implemented and evaluated on a 1U Maxeler MPC-X2000 dataflow node with eight Altera Stratix-V FPGAs. Measurements show that our design is 28 times faster than Bowtie2 running with 16 threads on dual Intel Xeon E5-2640 CPUs, and nine times faster than Soap3-dp running on an NVIDIA Tesla C2070 GPU. PMID- 26955051 TI - DTL-RnB: Algorithms and Tools for Summarizing the Space of DTL Reconciliations. AB - Phylogenetic tree reconciliation is an important technique for reconstructing the evolutionary histories of species and genes and other dependent entities. Reconciliation is typically performed in a maximum parsimony framework and the number of optimal reconciliations can grow exponentially with the size of the trees, making it difficult to understand the solution space. This paper demonstrates how a small number of reconciliations can be found that collectively contain the most highly supported events in the solution space. While we show that the formal problem is NP-complete, we give a approximation algorithm, experimental results that indicate its effectiveness, and the new DTL-RnB software tool that uses our algorithms to summarize the space of optimal reconciliations (www.cs.hmc.edu/dtlrnb). PMID- 26955052 TI - Autumn Algorithm-Computation of Hybridization Networks for Realistic Phylogenetic Trees. AB - A minimum hybridization network is a rooted phylogenetic network that displays two given rooted phylogenetic trees using a minimum number of reticulations. Previous mathematical work on their calculation has usually assumed the input trees to be bifurcating, correctly rooted, or that they both contain the same taxa. These assumptions do not hold in biological studies and "realistic" trees have multifurcations, are difficult to root, and rarely contain the same taxa. We present a new algorithm for computing minimum hybridization networks for a given pair of "realistic" rooted phylogenetic trees. We also describe how the algorithm might be used to improve the rooting of the input trees. We introduce the concept of "autumn trees", a nice framework for the formulation of algorithms based on the mathematics of "maximum acyclic agreement forests". While the main computational problem is hard, the run-time depends mainly on how different the given input trees are. In biological studies, where the trees are reasonably similar, our parallel implementation performs well in practice. The algorithm is available in our open source program Dendroscope 3, providing a platform for biologists to explore rooted phylogenetic networks. We demonstrate the utility of the algorithm using several previously studied data sets. PMID- 26955053 TI - Robust Joint Graph Sparse Coding for Unsupervised Spectral Feature Selection. AB - In this paper, we propose a new unsupervised spectral feature selection model by embedding a graph regularizer into the framework of joint sparse regression for preserving the local structures of data. To do this, we first extract the bases of training data by previous dictionary learning methods and, then, map original data into the basis space to generate their new representations, by proposing a novel joint graph sparse coding (JGSC) model. In JGSC, we first formulate its objective function by simultaneously taking subspace learning and joint sparse regression into account, then, design a new optimization solution to solve the resulting objective function, and further prove the convergence of the proposed solution. Furthermore, we extend JGSC to a robust JGSC (RJGSC) via replacing the least square loss function with a robust loss function, for achieving the same goals and also avoiding the impact of outliers. Finally, experimental results on real data sets showed that both JGSC and RJGSC outperformed the state-of-the-art algorithms in terms of k -nearest neighbor classification performance. PMID- 26955054 TI - Rate of Convergence of the FOCUSS Algorithm. AB - Focal underdetermined system solver (FOCUSS) is a powerful method for basis selection and sparse representation, where it employs the [Formula: see text] norm with p ? (0,2) to measure the sparsity of solutions. In this paper, we give a systematical analysis on the rate of convergence of the FOCUSS algorithm with respect to p ? (0,2) . We prove that the FOCUSS algorithm converges superlinearly for and linearly for usually, but may superlinearly in some very special scenarios. In addition, we verify its rates of convergence with respect to p by numerical experiments. PMID- 26955055 TI - Systematical Approach for Detecting the Intention and Intensity of Feelings on Social Network. AB - Online posts not only represent the records of people's lives but also reveal their satisfaction with life and relationships as well as potential mental illnesses. The detection of (strong or general) negative as well as (strong or general) positive feelings of people from online posts can keep us from carelessly missing their important moments, difficult or great, due to the overloaded information in the daily life and lead to a better society. Therefore, in this paper, we build a Feeling Distinguisher system based on supervised Latent Dirichlet Allocation (sLDA), Latent Dirichlet Allocation, and SentiWordNet methodologies for detecting a person's intention and intensity of feelings through the analysis of his/her online posts. Experimental results on posts collected from five social network websites demonstrate the effectiveness of FeD. The performance of FeD is about 1.08-1.18 folds that of SVM and sLDA. PMID- 26955056 TI - Unified Generic Geometric-Decompositions for Consensus or Flocking Systems of Cooperative Agents and Fast Recalculations of Decomposed Subsystems Under Topology-Adjustments. AB - This paper considers a unified geometric projection approach for: 1) decomposing a general system of cooperative agents coupled via Laplacian matrices or stochastic matrices and 2) deriving a centroid-subsystem and many shape subsystems, where each shape-subsystem has the distinct properties (e.g., preservation of formation and stability of the original system, sufficiently simple structures and explicit formation evolution of agents, and decoupling from the centroid-subsystem) which will facilitate subsequent analyses. Particularly, this paper provides an additional merit of the approach: considering adjustments of coupling topologies of agents which frequently occur in system design (e.g., to add or remove an edge, to move an edge to a new place, and to change the weight of an edge), the corresponding new shape-subsystems can be derived by a few simple computations merely from the old shape-subsystems and without referring to the original system, which will provide further convenience for analysis and flexibility of choice. Finally, such fast recalculations of new subsystems under topology adjustments are provided with examples. PMID- 26955057 TI - Largest Matching Areas for Illumination and Occlusion Robust Face Recognition. AB - In this paper, we introduce a novel approach to face recognition which simultaneously tackles three combined challenges: (1) uneven illumination; (2) partial occlusion; and (3) limited training data. The new approach performs lighting normalization, occlusion de-emphasis and finally face recognition, based on finding the largest matching area (LMA) at each point on the face, as opposed to traditional fixed-size local areabased approaches. Robustness is achieved with novel approaches for feature extraction, LMA-based face image comparison and unseen data modeling. On the extended YaleB and AR face databases for face identification, our method using only a single training image per person, outperforms other methods using a single training image, and matches or exceeds methods which require multiple training images. On the labeled faces in the wild face verification database, our method outperforms comparable unsupervised methods. We also show that the new method performs competitively even when the training images are corrupted. PMID- 26955058 TI - A Wearable Virtual Usher for Vision-Based Cognitive Indoor Navigation. AB - Inspired by progresses in cognitive science, artificial intelligence, computer vision, and mobile computing technologies, we propose and implement a wearable virtual usher for cognitive indoor navigation based on egocentric visual perception. A novel computational framework of cognitive wayfinding in an indoor environment is proposed, which contains a context model, a route model, and a process model. A hierarchical structure is proposed to represent the cognitive context knowledge of indoor scenes. Given a start position and a destination, a Bayesian network model is proposed to represent the navigation route derived from the context model. A novel dynamic Bayesian network (DBN) model is proposed to accommodate the dynamic process of navigation based on real-time first-person view visual input, which involves multiple asynchronous temporal dependencies. To adapt to large variations in travel time through trip segments, we propose an online adaptation algorithm for the DBN model, leading to a self-adaptive DBN. A prototype system is built and tested for technical performance and user experience. The quantitative evaluation shows that our method achieves over 13% improvement in accuracy as compared to baseline approaches based on hidden Markov model. In the user study, our system guides the participants to their destinations, emulating a human usher in multiple aspects. PMID- 26955059 TI - Fuzzy Approximation-Based Global Pinning Synchronization Control of Uncertain Complex Dynamical Networks. AB - This paper is concerned with the global pinning synchronization problem of uncertain complex dynamical networks with communication constraints. First, an adaptive fuzzy controller is designed within a given compact set. In addition, a robust controller is introduced outside the compact set to pull back the system states. Then, a new pinning control scheme is given such that the global synchronization can be ensured. Moreover, via the Lyapunov theory and graph theory, the synchronization errors are proved to be asymptotically convergent. Especially, in an uncertainty-free environment, the proposed control scheme includes two easy-to-implement pinning control strategies as special cases, which improve the existing results from the view point of reducing the number of feedback controllers. Finally, two simulation examples are provided to validate the theoretical results. PMID- 26955060 TI - Joint Dictionary Learning for Multispectral Change Detection. AB - Change detection is one of the most important applications of remote sensing technology. It is a challenging task due to the obvious variations in the radiometric value of spectral signature and the limited capability of utilizing spectral information. In this paper, an improved sparse coding method for change detection is proposed. The intuition of the proposed method is that unchanged pixels in different images can be well reconstructed by the joint dictionary, which corresponds to knowledge of unchanged pixels, while changed pixels cannot. First, a query image pair is projected onto the joint dictionary to constitute the knowledge of unchanged pixels. Then reconstruction error is obtained to discriminate between the changed and unchanged pixels in the different images. To select the proper thresholds for determining changed regions, an automatic threshold selection strategy is presented by minimizing the reconstruction errors of the changed pixels. Adequate experiments on multispectral data have been tested, and the experimental results compared with the state-of-the-art methods prove the superiority of the proposed method. Contributions of the proposed method can be summarized as follows: 1) joint dictionary learning is proposed to explore the intrinsic information of different images for change detection. In this case, change detection can be transformed as a sparse representation problem. To the authors' knowledge, few publications utilize joint learning dictionary in change detection; 2) an automatic threshold selection strategy is presented, which minimizes the reconstruction errors of the changed pixels without the prior assumption of the spectral signature. As a result, the threshold value provided by the proposed method can adapt to different data due to the characteristic of joint dictionary learning; and 3) the proposed method makes no prior assumption of the modeling and the handling of the spectral signature, which can be adapted to different data. PMID- 26955061 TI - Relation between in Utero Arsenic Exposure and Birth Outcomes in a Cohort of Mothers and Their Newborns from New Hampshire. AB - BACKGROUND: Studies suggest that arsenic exposure influences birth outcomes; however, findings are mixed. OBJECTIVE: We assessed in utero arsenic exposure in relation to birth outcomes and whether maternal prepregnancy weight and infant sex modified the associations. METHODS: Among 706 mother-infant pairs exposed to low levels of arsenic through drinking water and diet, we assessed in utero arsenic exposure using maternal second-trimester urinary arsenic, maternal prepregnancy weight through self-report, and birth outcomes from medical records. RESULTS: Median (interquartile range) of total urinary arsenic [tAs; inorganic arsenic (iAs) + monomethylarsonic acid (MMA) + dimethylarsinic acid (DMA)] was 3.4 MUg/L (1.7-6.0). In adjusted linear models, each doubling of tAs was associated with a 0.10-cm decrease (95% CI: -0.19, -0.01) in head circumference. Results were similar for MMA and DMA. Ln(tAs) and ln(DMA) were positively associated with birth length in infant males only; among males, each doubling of tAs was associated with a 0.28-cm increase (95% CI: 0.09, 0.46) in birth length (pinteraction = 0.04). Results were similar for DMA. Additionally, arsenic exposure was inversely related to ponderal index, and associations differed by maternal weight. Each ln(tAs) doubling of tAs was associated with a 0.55-kg/m3 lower (95% CI: -0.82, -0.28, p < 0.001) ponderal index for infants of overweight/obese, but not normal-weight, mothers (pinteraction < 0.01). Finally, there was a significant interaction between maternal weight status, infant sex, and arsenic exposure on birth weight (pinteraction = 0.03). In girls born of overweight/obese mothers, each doubling of tAs was associated with a 62.9-g decrease (95% CI: -111.6, -14.2) in birth weight, though the association was null in the other strata. CONCLUSIONS: Low-level arsenic exposure may affect fetal growth, and the associations may be modified by maternal weight status and infant sex. CITATION: Gilbert-Diamond D, Emond JA, Baker ER, Korrick SA, Karagas MR. 2016. Relation between in utero arsenic exposure and birth outcomes in a cohort of mothers and their newborns from New Hampshire. Environ Health Perspect 124:1299-1307; http://dx.doi.org/10.1289/ehp.1510065. PMID- 26955062 TI - Long-Term Exposure to Ambient Fine Particulate Matter and Renal Function in Older Men: The Veterans Administration Normative Aging Study. AB - BACKGROUND: It is unknown if ambient fine particulate matter (PM2.5) is associated with lower renal function, a cardiovascular risk factor. OBJECTIVE: We investigated whether long-term PM2.5 exposure was associated with estimated glomerular filtration rate (eGFR) in a cohort of older men living in the Boston Metropolitan area. METHODS: This longitudinal analysis included 669 participants from the Veterans Administration Normative Aging Study with up to four visits between 2000 and 2011 (n = 1,715 visits). Serum creatinine was measured at each visit, and eGFR was calculated according to the Chronic Kidney Disease Epidemiology Collaboration equation. One-year exposure to PM2.5 prior to each visit was assessed using a validated spatiotemporal model that utilized satellite remote-sensing aerosol optical depth data. eGFR was modeled in a time-varying linear mixed-effects regression model as a continuous function of 1-year PM2.5, adjusting for important covariates. RESULTS: One-year PM2.5 exposure was associated with lower eGFRs; a 2.1-MUg/m3 interquartile range higher 1-year PM2.5 was associated with a 1.87 mL/min/1.73 m2 lower eGFR [95% confidence interval (CI): -2.99, -0.76]. A 2.1 MUg/m3-higher 1-year PM2.5 was also associated with an additional annual decrease in eGFR of 0.60 mL/min/1.73 m2 per year (95% CI: 0.79, -0.40). CONCLUSIONS: In this longitudinal sample of older men, the findings supported the hypothesis that long-term PM2.5 exposure negatively affects renal function and increases renal function decline. CITATION: Mehta AJ, Zanobetti A, Bind MC, Kloog I, Koutrakis P, Sparrow D, Vokonas PS, Schwartz JD. 2016. Long term exposure to ambient fine particulate matter and renal function in older men: the VA Normative Aging Study. Environ Health Perspect 124:1353-1360; http://dx.doi.org/10.1289/ehp.1510269. PMID- 26955063 TI - Secreted Phosphoprotein 1 and Sex-Specific Differences in Silica-Induced Pulmonary Fibrosis in Mice. AB - BACKGROUND: Fibrotic lung diseases occur predominantly in males, and reports describe better survival in affected females. Male mice are more sensitive to silica-induced lung fibrosis than silica-treated female mice. Secreted phosphoprotein 1 (SPP1, also known as osteopontin) increases in pulmonary fibrosis, and Spp1 transcription may be regulated by estrogen or estrogen receptor-related receptors. OBJECTIVE: We determined whether differences in silica-induced SPP1 levels contribute to sex differences in lung fibrosis. METHODS: Male and female mice were treated with 0.2 g/kg intratracheal silica, and lung injury was assessed 1, 3, or 14 days post-exposure. Gene-targeted (Spp1 /-) mice, control Spp1+/+ (C57BL/6J) mice, ovariectomized (OVX) female mice, and estrogen-treated male mice were treated with silica, and lung injury was assessed. RESULTS: Silica-induced SPP1 in lung tissue, bronchoalveolar lavage, and serum increased more in male than in female mice. Following silica treatment, bronchoalveolar lavage cell infiltrates decreased in female Spp1-/- mice compared with female Spp1+/+ mice, and lung hydroxyproline decreased in male Spp1-/- mice compared with male Spp1+/+ mice. OVX female mice had increased lung SPP1 expression in response to silica compared with silica-treated sham female mice. Silica-induced lung collagen and hydroxyproline (markers of fibrosis), and SPP1 levels decreased in estrogen-treated males compared with untreated males. CONCLUSION: These findings suggest that sex-specific differences in SPP1 levels contribute to the differential sensitivity of male and female mice to the development of silica-induced fibrosis. CITATION: Latoche JD, Ufelle AC, Fazzi F, Ganguly K, Leikauf GD, Fattman CL. 2016. Secreted phosphoprotein 1 and sex specific differences in silica-induced pulmonary fibrosis in mice. Environ Health Perspect 124:1199-1207; http://dx.doi.org/10.1289/ehp.1510335. PMID- 26955064 TI - An Informatics Approach to Evaluating Combined Chemical Exposures from Consumer Products: A Case Study of Asthma-Associated Chemicals and Potential Endocrine Disruptors. AB - BACKGROUND: Simultaneous or sequential exposure to multiple environmental stressors can affect chemical toxicity. Cumulative risk assessments consider multiple stressors but it is impractical to test every chemical combination to which people are exposed. New methods are needed to prioritize chemical combinations based on their prevalence and possible health impacts. OBJECTIVES: We introduce an informatics approach that uses publicly available data to identify chemicals that co-occur in consumer products, which account for a significant proportion of overall chemical load. METHODS: Fifty-five asthma associated and endocrine disrupting chemicals (target chemicals) were selected. A database of 38,975 distinct consumer products and 32,231 distinct ingredient names was created from online sources, and PubChem and the Unified Medical Language System were used to resolve synonymous ingredient names. Synonymous ingredient names are different names for the same chemical (e.g., vitamin E and tocopherol). RESULTS: Nearly one-third of the products (11,688 products, 30%) contained >= 1 target chemical and 5,229 products (13%) contained > 1. Of the 55 target chemicals, 31 (56%) appear in >= 1 product and 19 (35%) appear under more than one name. The most frequent three-way chemical combination (2 phenoxyethanol, methyl paraben, and ethyl paraben) appears in 1,059 products. Further work is needed to assess combined chemical exposures related to the use of multiple products. CONCLUSIONS: The informatics approach increased the number of products considered in a traditional analysis by two orders of magnitude, but missing/incomplete product labels can limit the effectiveness of this approach. Such an approach must resolve synonymy to ensure that chemicals of interest are not missed. Commonly occurring chemical combinations can be used to prioritize cumulative toxicology risk assessments. CITATION: Gabb HA, Blake C. 2016. An informatics approach to evaluating combined chemical exposures from consumer products: a case study of asthma-associated chemicals and potential endocrine disruptors. Environ Health Perspect 124:1155-1165; http://dx.doi.org/10.1289/ehp.1510529. PMID- 26955065 TI - Do reproduction and parenting influence personality traits? Insights from threespine stickleback. AB - Although one of the hallmarks of personality traits is their consistency over time, we might expect personality traits to change during life history shifts. Becoming a parent is a major life history event, when individuals undergo dramatic behavioural and physiological changes. Here we employ a longitudinal experiment to ask whether personality changes in response to the experience of parenting in male threespine sticklebacks, Gasterosteus aculeatus. Life history theory predicts that males should be less risk averse after successfully parenting, and the neuroendocrinology of parenting suggests that parenting could reorganize the hormonal landscape and behaviour of fathers. We randomly assigned males to either an experimental group (reproduced and parented) or a control group (did not reproduce and parent), and repeatedly measured a personality trait ('boldness') and 11-ketotestosterone levels (11-kT, the major androgen in fishes) in individual males. In the control group, males became bolder over time. However, in the experimental group, boldness did not change. Furthermore, 11-kT changed dramatically in the experimental group, and changes in 11-kT in parents were associated with boldness after parenting ceased. Our study is one of the first to assess proximate and ultimate explanations for changes in personality as a function of reproduction and parenting. PMID- 26955066 TI - A Structural Basis for How Motile Cilia Beat. AB - The motile cilium is a mechanical wonder, a cellular nanomachine that produces a high-speed beat based on a cycle of bends that move along an axoneme made of 9+2 microtubules. The molecular motors, dyneins, power the ciliary beat. The dyneins are compacted into inner and outer dynein arms, whose activity is highly regulated to produce microtubule sliding and axonemal bending. The switch point hypothesis was developed long ago to account for how sliding in the presence of axonemal radial spoke-central pair interactions causes the ciliary beat. Since then, a new genetic, biochemical, and structural complexity has been discovered, in part, with Chlamydomonas mutants, with high-speed, high-resolution analysis of movement and with cryoelectron tomography. We stand poised on the brink of new discoveries relating to the molecular control of motility that extend and refine our understanding of the basic events underlying the switching of arm activity and of bend formation and propagation. PMID- 26955068 TI - Biodiversity and Archeological Conservation Connected: Aragonite Shell Middens Increase Plant Diversity. AB - Natural and cultural heritage sites frequently have nonoverlapping or even conflicting conservation priorities, because human impacts have often resulted in local extirpations and reduced levels of native biodiversity. Over thousands of years, the predictable winter rains of northwestern Baja California have weathered calcium from the clam shells deposited by indigenous peoples in middens along the coast. The release of this calcium has changed soil properties, remediated sodic and saline soils, and resulted in a unique microhabitat that harbors plant assemblages very different from those of the surrounding matrix. Native plant biodiversity and landscape heterogeneity are significantly increased on the anthropogenic soils of these shell middens. Protection of this cultural landscape in the Anthropocene will further both archeological and biodiversity conservation in these anthropogenic footprints from the Holocene. Along these coasts, natural and cultural heritage priorities are overlapping and mutually beneficial. PMID- 26955067 TI - Linking the Primary Cilium to Cell Migration in Tissue Repair and Brain Development. AB - Primary cilia are unique sensory organelles that coordinate cellular signaling networks in vertebrates. Inevitably, defects in the formation or function of primary cilia lead to imbalanced regulation of cellular processes that causes multisystemic disorders and diseases, commonly known as ciliopathies. Mounting evidence has demonstrated that primary cilia coordinate multiple activities that are required for cell migration, which, when they are aberrantly regulated, lead to defects in organogenesis and tissue repair, as well as metastasis of tumors. Here, we present an overview on how primary cilia may contribute to the regulation of the cellular signaling pathways that control cyclic processes in directional cell migration. PMID- 26955069 TI - Farming for Ecosystem Services: An Ecological Approach to Production Agriculture. AB - A balanced assessment of ecosystem services provided by agriculture requires a systems-level socioecological understanding of related management practices at local to landscape scales. The results from 25 years of observation and experimentation at the Kellogg Biological Station long-term ecological research site reveal services that could be provided by intensive row-crop ecosystems. In addition to high yields, farms could be readily managed to contribute clean water, biocontrol and other biodiversity benefits, climate stabilization, and long-term soil fertility, thereby helping meet society's need for agriculture that is economically and environmentally sustainable. Midwest farmers-especially those with large farms-appear willing to adopt practices that deliver these services in exchange for payments scaled to management complexity and farmstead benefit. Surveyed citizens appear willing to pay farmers for the delivery of specific services, such as cleaner lakes. A new farming for services paradigm in US agriculture seems feasible and could be environmentally significant. PMID- 26955072 TI - Scientific Reproducibility, Human Error, and Public Policy. PMID- 26955071 TI - The Origin of Invasive Microorganisms Matters for Science, Policy, and Management: The Case of Didymosphenia geminata. AB - The value of distinguishing native from nonnative invasive species has recently been questioned. However, this dichotomy is important for understanding whether a species' successful dominance is caused by introductions, changing environmental conditions that facilitate an existing population, or both processes. We highlight the importance of knowing the origin of hard-to-detect invasive microorganisms for scientific research, management, and policy using a case study of recent algal blooms of the stalk-producing diatom Didymosphenia geminata. Nuisance blooms have been reported in rivers worldwide and have been hastily attributed to introductions. However, evidence indicates that blooms are probably not caused by introductions but, rather, by environmental conditions that promote excessive stalk production by this historically rare species. Effective responses to invasive microorganisms depend on knowing whether their proliferation is caused by being nonnative or is the result of changing environmental conditions that promote invasive characteristics of native species. PMID- 26955070 TI - Neurobiology of Caenorhabditis elegans Locomotion: Where Do We Stand? AB - Animals use a nervous system for locomotion in some stage of their life cycle. The nematode Caenorhabditis elegans, a major animal model for almost all fields of experimental biology, has long been used for detailed studies of genetic and physiological locomotion mechanisms. Of its 959 somatic cells, 302 are neurons that are identifiable by lineage, location, morphology, and neurochemistry in every adult hermaphrodite. Of those, 75 motoneurons innervate body wall muscles that provide the thrust during locomotion. In this Overview, we concentrate on the generation of either forward- or backward-directed motion during crawling and swimming. We describe locomotion behavior, the parts constituting the locomotion system, and the relevant neuronal connectivity. Because it is not yet fully understood how these components combine to generate locomotion, we discuss competing hypotheses and models. PMID- 26955073 TI - It's Good to Share: Why Environmental Scientists' Ethics Are Out of Date. AB - Although there have been many recent calls for increased data sharing, the majority of environmental scientists do not make their individual data sets publicly available in online repositories. Current data-sharing conversations are focused on overcoming the technological challenges associated with data sharing and the lack of rewards and incentives for individuals to share data. We argue that the most important conversation has yet to take place: There has not been a strong ethical impetus for sharing data within the current culture, behaviors, and practices of environmental scientists. In this article, we describe a critical shift that is happening in both society and the environmental science community that makes data sharing not just good but ethically obligatory. This is a shift toward the ethical value of promoting inclusivity within and beyond science. An essential element of a truly inclusionary and democratic approach to science is to share data through publicly accessible data sets. PMID- 26955074 TI - Ecological Networks in Stored Grain: Key Postharvest Nodes for Emerging Pests, Pathogens, and Mycotoxins. AB - Wheat is at peak quality soon after harvest. Subsequently, diverse biota use wheat as a resource in storage, including insects and mycotoxin-producing fungi. Transportation networks for stored grain are crucial to food security and provide a model system for an analysis of the population structure, evolution, and dispersal of biota in networks. We evaluated the structure of rail networks for grain transport in the United States and Eastern Australia to identify the shortest paths for the anthropogenic dispersal of pests and mycotoxins, as well as the major sources, sinks, and bridges for movement. We found important differences in the risk profile in these two countries and identified priority control points for sampling, detection, and management. An understanding of these key locations and roles within the network is a new type of basic research result in postharvest science and will provide insights for the integrated pest management of high-risk subpopulations, such as pesticide-resistant insect pests. PMID- 26955075 TI - Now Hiring! Empirically Testing a Three-Step Intervention to Increase Faculty Gender Diversity in STEM. AB - Workforce homogeneity limits creativity, discovery, and job satisfaction; nonetheless, the vast majority of university faculty in science, technology, engineering, and mathematics (STEM) fields are men. We conducted a randomized and controlled three-step faculty search intervention based in self-determination theory aimed at increasing the number of women faculty in STEM at one US university where increasing diversity had historically proved elusive. Results show that the numbers of women candidates considered for and offered tenure-track positions were significantly higher in the intervention groups compared with those in controls. Searches in the intervention were 6.3 times more likely to make an offer to a woman candidate, and women who were made an offer were 5.8 times more likely to accept the offer from an intervention search. Although the focus was on increasing women faculty within STEM, the intervention can be adapted to other scientific and academic communities to advance diversity along any dimension. PMID- 26955076 TI - Making Predictions in a Changing World: The Benefits of Individual-Based Ecology. AB - Ecologists urgently need a better ability to predict how environmental change affects biodiversity. We examine individual-based ecology (IBE), a research paradigm that promises better a predictive ability by using individual-based models (IBMs) to represent ecological dynamics as arising from how individuals interact with their environment and with each other. A key advantage of IBMs is that the basis for predictions-fitness maximization by individual organisms-is more general and reliable than the empirical relationships that other models depend on. Case studies illustrate the usefulness and predictive success of long term IBE programs. The pioneering programs had three phases: conceptualization, implementation, and diversification. Continued validation of models runs throughout these phases. The breakthroughs that make IBE more productive include standards for describing and validating IBMs, improved and standardized theory for individual traits and behavior, software tools, and generalized instead of system-specific IBMs. We provide guidelines for pursuing IBE and a vision for future IBE research. PMID- 26955077 TI - Strategic Actions to Value, Conserve, and Restore the Natural Capital of Megadiversity Countries: The Case of Mexico. AB - Decisionmakers need updated, scientifically sound and relevant information to implement appropriate policy measures and make innovative commitments to halt biodiversity loss and improve human well-being. Here, we present a recent science based synthesis on the biodiversity and ecosystem services of Mexico, intended to be a tool for policymakers. We describe the methodological approach used to undertake such an assessment and highlight the major findings. Organized into five volumes and originally written in Spanish (Capital Natural de Mexico), it summarizes the available knowledge on the components, structure, and functioning of the biodiversity of Mexico; the threats and trajectories of anthropogenic impact, together with its conservation status; and the policies, institutions, and instruments available for its sustainable management. We stress the lessons learned that can be useful for similar exercises in other megadiverse developing countries and identify major gaps and strategic actions to conserve the natural capital in light of the challenges of the Anthropocene. PMID- 26955078 TI - A Scientist's Guide to Achieving Broader Impacts through K-12 STEM Collaboration. AB - The National Science Foundation and other funding agencies are increasingly requiring broader impacts in grant applications to encourage US scientists to contribute to science education and society. Concurrently, national science education standards are using more inquiry-based learning (IBL) to increase students' capacity for abstract, conceptual thinking applicable to real-world problems. Scientists are particularly well suited to engage in broader impacts via science inquiry outreach, because scientific research is inherently an inquiry-based process. We provide a practical guide to help scientists overcome obstacles that inhibit their engagement in K-12 IBL outreach and to attain the accrued benefits. Strategies to overcome these challenges include scaling outreach projects to the time available, building collaborations in which scientists' research overlaps with curriculum, employing backward planning to target specific learning objectives, encouraging scientists to share their passion, as well as their expertise with students, and transforming institutional incentives to support scientists engaging in educational outreach. PMID- 26955079 TI - Predator-Free New Zealand: Conservation Country. AB - Eradications of invasive species from over 1000 small islands around the world have created conservation arks, but to truly address the threat of invasive species to islands, eradications must be scaled by orders of magnitude. New Zealand has eradicated invasive predators from 10% of its offshore island area and now proposes a vision to eliminate them from the entire country. We review current knowledge of invasive predator ecology and control technologies in New Zealand and the biological research, technological advances, social capacity and enabling policy required. We discuss the economic costs and benefits and conclude with a 50-year strategy for a predator-free New Zealand that is shown to be ecologically obtainable, socially desirable, and economically viable. The proposal includes invasive predator eradication from the two largest offshore islands, mammal-free mainland peninsulas, very large ecosanctuaries, plus thousands of small projects that will together merge eradication and control concepts on landscape scales. PMID- 26955080 TI - Global Protected Area Expansion: Creating More than Paper Parks. PMID- 26955081 TI - Toward a Mechanistic Understanding of Environmentally Forced Zoonotic Disease Emergence: Sin Nombre Hantavirus. AB - Understanding the environmental drivers of zoonotic reservoir and human interactions is crucial to understanding disease risk, but these drivers are poorly predicted. We propose a mechanistic understanding of human-reservoir interactions, using hantavirus pulmonary syndrome as a case study. Crucial processes underpinning the disease's incidence remain poorly studied, including the connectivity among natural and peridomestic deer mouse host activity, virus transmission, and human exposure. We found that disease cases were greatest in arid states and declined exponentially with increasing precipitation. Within arid environments, relatively rare climatic conditions (e.g., El Nino) are associated with increased rainfall and reservoir abundance, producing more frequent virus transmission and host dispersal. We suggest that deer mice increase their occupancy of peridomestic structures during spring-summer, amplifying intraspecific transmission and human infection risk. Disease incidence in arid states may increase with predicted climatic changes. Mechanistic approaches incorporating reservoir behavior, reservoir-human interactions, and pathogen spillover could enhance our understanding of global hantavirus ecology, with applications to other directly transmitted zoonoses. PMID- 26955083 TI - High Time for Conservation: Adding the Environment to the Debate on Marijuana Liberalization. AB - The liberalization of marijuana policies, including the legalization of medical and recreational marijuana, is sweeping the United States and other countries. Marijuana cultivation can have significant negative collateral effects on the environment that are often unknown or overlooked. Focusing on the state of California, where by some estimates 60%-70% of the marijuana consumed in the United States is grown, we argue that (a) the environmental harm caused by marijuana cultivation merits a direct policy response, (b) current approaches to governing the environmental effects are inadequate, and PMID- 26955084 TI - Do Ground-Dwelling Vertebrates Promote Diversity in a Neotropical Forest? Results from a Long-Term Exclosure Experiment. AB - Using a decade-long exclosure experiment in Panama, we tested the hypothesis that ground-dwelling vertebrate herbivores and seed predators are crucial determinants of tropical tree diversity and abundance within the understory. Our exclosure experiment is a community-level test of the Janzen-Connell hypothesis. Therefore, we predicted that vertebrate exclusion would (a) increase plant densities and (b) lower richness, diversity, and evenness. Excluding vertebrates caused a 38%-46% increase in plant densities, which, in contrast to our predictions, caused species richness to increase by 12%-15%. Because vertebrate exclusion causes plant species richness to increase, not decrease, vertebrates are unlikely to be causal agents of Janzen-Connell effects. We synthesized this and previous studies to explore why plant richness responds differently to defaunation and exclosures in tropical forests worldwide. Likely because of their contrasting effects on mesoconsumers, defaunation and exclosures cause decreases and increases in plant density respectively, which in turn cause corresponding changes in richness. PMID- 26955082 TI - Extracellular Vesicles: Composition, Biological Relevance, and Methods of Study. AB - The release of extracellular vesicles (EVs), including exosomes and microvesicles, is a phenomenon shared by many cell types as a means of communicating with other cells and also potentially removing cell contents. The cargo of EVs includes the proteins, lipids, nucleic acids, and membrane receptors of the cells from which they originate. EVs released into the extracellular space can enter body fluids and potentially reach distant tissues. Once taken up by neighboring and/or distal cells, EVs can transfer functional cargo that may alter the status of recipient cells, thereby contributing to both physiological and pathological processes. In this article, we will focus on EV composition, mechanisms of uptake, and their biological effects on recipient cells. We will also discuss established and recently developed methods used to study EVs, including isolation, quantification, labeling and imaging protocols, as well as RNA analysis. PMID- 26955085 TI - Threshold Responses to Soil Moisture Deficit by Trees and Soil in Tropical Rain Forests: Insights from Field Experiments. AB - Many tropical rain forest regions are at risk of increased future drought. The net effects of drought on forest ecosystem functioning will be substantial if important ecological thresholds are passed. However, understanding and predicting these effects is challenging using observational studies alone. Field-based rainfall exclusion (canopy throughfall exclusion; TFE) experiments can offer mechanistic insight into the response to extended or severe drought and can be used to help improve model-based simulations, which are currently inadequate. Only eight TFE experiments have been reported for tropical rain forests. We examine them, synthesizing key results and focusing on two processes that have shown threshold behavior in response to drought: (1) tree mortality and (2) the efflux of carbon dioxdie from soil, soil respiration. We show that: (a) where tested using large-scale field experiments, tropical rain forest tree mortality is resistant to long-term soil moisture deficit up to a threshold of 50% of the water that is extractable by vegetation from the soil, but high mortality occurs beyond this value, with evidence from one site of increased autotrophic respiration, and (b) soil respiration reaches its peak value in response to soil moisture at significantly higher soil moisture content for clay-rich soils than for clay-poor soils. This first synthesis of tropical TFE experiments offers the hypothesis that low soil moisture-related thresholds for key stress responses in soil and vegetation may prove to be widely applicable across tropical rain forests despite the diversity of these forests. PMID- 26955086 TI - Climate Warming and Soil Carbon in Tropical Forests: Insights from an Elevation Gradient in the Peruvian Andes. AB - The temperature sensitivity of soil organic matter (SOM) decomposition in tropical forests will influence future climate. Studies of a 3.5-kilometer elevation gradient in the Peruvian Andes, including short-term translocation experiments and the examination of the long-term adaptation of biota to local thermal and edaphic conditions, have revealed several factors that may regulate this sensitivity. Collectively this work suggests that, in the absence of a moisture constraint, the temperature sensitivity of decomposition is regulated by the chemical composition of plant debris (litter) and both the physical and chemical composition of preexisting SOM: higher temperature sensitivities are found in litter or SOM that is more chemically complex and in SOM that is less occluded within aggregates. In addition, the temperature sensitivity of SOM in tropical montane forests may be larger than previously recognized because of the presence of "cold-adapted" and nitrogen-limited microbial decomposers and the possible future alterations in plant and microbial communities associated with warming. Studies along elevation transects, such as those reviewed here, can reveal factors that will regulate the temperature sensitivity of SOM. They can also complement and guide in situ soil-warming experiments, which will be needed to understand how this vulnerability to temperature may be mediated by altered plant productivity under future climatic change. PMID- 26955088 TI - Notes From the Module Editor. PMID- 26955087 TI - Raman Spectroscopy: Incorporating the Chemical Dimension into Dermatological Diagnosis. AB - Raman spectroscopy provides chemical analysis of tissue in vivo. By measuring the inelastic interactions of light with matter, Raman spectroscopy can determine the chemical composition of a sample. Diseases that are visually difficult to visually distinguish can be delineated based on differences in chemical composition of the affected tissue. Raman spectroscopy has successfully found spectroscopic signatures for skin cancers and differentiated those of benign skin growths. With current and on-going advances in optics and computing, inexpensive and effective Raman systems may soon be available for clinical use. Raman spectroscopy provides direct analyses of skin lesions, thereby improving both disease diagnosis and management. PMID- 26955089 TI - Biostatistics Series Module 1: Basics of Biostatistics. AB - Although application of statistical methods to biomedical research began only some 150 years ago, statistics is now an integral part of medical research. A knowledge of statistics is also becoming mandatory to understand most medical literature. Data constitute the raw material for statistical work. They are records of measurement or observations or simply counts. A variable refers to a particular character on which a set of data are recorded. Data are thus the values of a variable. It is important to understand the different types of data and their mutual interconversion. Biostatistics begins with descriptive statistics that implies summarizing a collection of data from a sample or population. Categorical data are described in terms of percentages or proportions. With numerical data, individual observations within a sample or population tend to cluster about a central location, with more extreme observations being less frequent. The extent to which observations cluster is summarized by measures of central tendency while the spread can be described by measures of dispersion. The confidence interval (CI) is an increasingly important measure of precision. When we observe samples, there is no way of assessing true population parameters. We can, however, obtain a standard error and use it to define a range in which the true population value is likely to lie with a certain acceptable level of uncertainty. This range is the CI while its two terminal values are the confidence limits. Conventionally, the 95% CI is used. Patterns in data sets or data distributions are important, albeit not so obvious, component of descriptive statistics. The most common distribution is the normal distribution which is depicted as the well-known symmetrical bell-shaped Gaussian curve. Familiarity with other distributions such as the binomial and Poisson distributions is also helpful. Various graphs and plots have been devised to summarize data and trends visually. Some plots, such as the box-and-whiskers plot and the stem-and-leaf plot are used less often but provide useful summaries in select situations. PMID- 26955090 TI - Methodology Series Module 1: Cohort Studies. AB - Cohort design is a type of nonexperimental or observational study design. In a cohort study, the participants do not have the outcome of interest to begin with. They are selected based on the exposure status of the individual. They are then followed over time to evaluate for the occurrence of the outcome of interest. Some examples of cohort studies are (1) Framingham Cohort study, (2) Swiss HIV Cohort study, and (3) The Danish Cohort study of psoriasis and depression. These studies may be prospective, retrospective, or a combination of both of these types. Since at the time of entry into the cohort study, the individuals do not have outcome, the temporality between exposure and outcome is well defined in a cohort design. If the exposure is rare, then a cohort design is an efficient method to study the relation between exposure and outcomes. A retrospective cohort study can be completed fast and is relatively inexpensive compared with a prospective cohort study. Follow-up of the study participants is very important in a cohort study, and losses are an important source of bias in these types of studies. These studies are used to estimate the cumulative incidence and incidence rate. One of the main strengths of a cohort study is the longitudinal nature of the data. Some of the variables in the data will be time-varying and some may be time independent. Thus, advanced modeling techniques (such as fixed and random effects models) are useful in analysis of these studies. PMID- 26955091 TI - Pearls for Publishing Papers: Tips and Tricks. AB - With the stringent regulations from various academic bodies making it desirable for a post graduate resident to have submitted an original article prior to appearance for their exams or those working in teaching institutions to have published articles to claim credit for applying for promotions and private practitioners to increase their visibility on the academic front, paper, everyone is on a publishing spree. In this article, we attempt to elucidate the processes involved in publication; approaching it in a systematic and practical manner, incorporating some tips and tricks. This collection of pearls is aimed to serve as a beginner's guide to scientific writing and publications. The pearls cover assorted topics like- benefits of publications, collecting resources, various tools available and technical processes related to how a manuscript is processed. PMID- 26955092 TI - Rational Prescription for a Dermatologist. AB - The ultimate goal in dermatological therapy is to use the safest and least number of drugs in order to obtain the best possible effect in the shortest period and at reasonable cost. Rational drug use (RDU) is conventionally defined as the use of an appropriate, efficacious, safe and cost-effective drug given for the right indications in the right dose and formulation, at right time intervals. WHO estimates that more than half of all medicines are prescribed, dispensed or sold inappropriately, and that half of all patients fail to take them correctly as prescribed by the doctor. The process of Rational prescription for a Dermatologist (RPD) involves a series of steps such as defining the patient's illness, specifying the treatment objectives, using the principle of P-treatment, starting the treatment, providing appropriate information and monitoring the treatment. Reasons for irrational prescription could be physician related, patient related, industry related, regulations related. Practicing medicine irrationally can lead to disastrous events like increased morbidity and mortality, drain of resources, drug resistance etc. Principles to enhance the RDU in our practice and minimize errors of prescription are discussed in detail in this article. PMID- 26955093 TI - Proposing Melasma Severity Index: A New, More Practical, Office-based Scoring System for Assessing the Severity of Melasma. AB - BACKGROUND: Melasma Area and Severity Index (MASI), the scoring system in melasma, needs to be refined. AIMS AND OBJECTIVES: To propose a more practical scoring system, named as Melasma Severity Index (MSI), for assessing the disease severity and treatment response in melasma. MATERIALS AND METHODS: Four dermatologists were trained to calculate MASI and also the proposed MSI scores. For MSI, the formula used was 0.4 (a * p(2)) l + 0.4 (a * p(2)) r + 0.2 (a * p(2)) n where "a" stands for area, "p" for pigmentation, "l" for left face, "r" for right face, and "n" for nose. On a single day, 30 enrolled patients were randomly examined by each trained dermatologist and their MASI and MSI scores were calculated. Next, each rater re-examined every 6(th) patient for repeat MASI and MSI scoring to assess intra- and inter-rater reliability of MASI and MSI scores. Validity was assessed by comparing the individual scores of each rater with objective data from mexameter and ImageJ software. RESULTS: Inter-rater reliability, as assessed by intraclass correlation coefficient, was significantly higher for MSI (0.955) as compared to MASI (0.816). Correlation of scores with objective data by Spearman's correlation revealed higher rho values for MSI than for MASI for all raters. LIMITATIONS: Sample population belonged to a single ethnic group. CONCLUSIONS: MSI is simpler and more practical scoring system for melasma. PMID- 26955095 TI - Seasonal Variation in Contact Hypersensitivity to Parthenium in Patients of Parthenium Dermatitis. AB - BACKGROUND: Titer of contact hypersensitivity (TCH) is a measure of contact hypersensitivity to an allergen in an individual. Clinical severity of Parthenium dermatitis varies with season. However, the effect of seasonal variation on the TCH as determined by patch test to Parthenium has not been studied. OBJECTIVE: To study the effect of seasonal variation on TCH to Parthenium hysterophorus in patients with Parthenium dermatitis. MATERIALS AND METHODS: It was a prospective investigational study on clinically and patch test confirmed patients with airborne contact dermatitis to P. hysterophorus. The TCH values at baseline and after 6 months were recorded. The patients who were recruited in summers (April to September) and whose repeat patch test and TCH were determined in winters (October to March) were identified as Group I and those who were recruited in reverse order were identified as Group II. RESULTS: The study had 47 patients, of which 23 were in Group I and 24 in Group II. Mean TCH in Group, I (summer to winter) in period I (summer) was 0.11 +/- 0.28 whereas that in period II (winter), was 0.76+/- 0.41. Similarly, mean TCH in Group II (winter to summer) in period I (winter) and period II (summer) were 0.34+/- 0.44 and 0.166+/- 0.32, respectively. The difference in TCH values (95% confidence interval) in the two groups with a change of season was -0.41 (-0.58, -0.24) (P < 0.0001). CONCLUSIONS: TCH values in Parthenium dermatitis are lower in the summer season, indicating increased sensitivity to Parthenium allergen in summer. PMID- 26955094 TI - Cross-sectional Pilot Study of Antibiotic Resistance in Propionibacterium Acnes Strains in Indian Acne Patients Using 16S-RNA Polymerase Chain Reaction: A Comparison Among Treatment Modalities Including Antibiotics, Benzoyl Peroxide, and Isotretinoin. AB - BACKGROUND: Antibiotic resistance is a worldwide problem in acne patients due to regional prescription practices, patient compliance, and genomic variability in Propionibacterium acnes, though the effect of treatment on the resistance has not been comprehensively analyzed. AIMS: Our primary objective was to assess the level of antibiotic resistance in the Indian patients and to assess whether there was a difference in the resistance across common treatment groups. SUBJECTS AND METHODS: A cross-sectional, institutional based study was undertaken and three groups of patients were analyzed, treatment naive, those on antibiotics and patients on benzoyl peroxide (BPO) and/isotretinoin. The follicular content was sampled and the culture was verified with 16S rRNA polymerase chain reaction, genomic sequencing, and pulsed-field gel electrophoresis. Minimum inhibitory concentration (MIC) assessment was done for erythromycin (ERY), azithromycin (AZI), clindamycin (CL), tetracycline (TET), doxycycline (DOX), minocycline (MINO), and levofloxacin (LEVO). The four groups of patients were compared for any difference in the resistant strains. RESULTS: Of the 52 P. acnes strains isolated (80 patients), high resistance was observed to AZI (100%), ERY (98%), CL (90.4%), DOX (44.2%), and TETs (30.8%). Low resistance was observed to MINO (1.9%) and LEVO (9.6%). Statistical difference was seen in the resistance between CL and TETs; DOX/LEVO and DOX/MINO (P < 0.001). High MIC90 (>=256 MUg/ml) was seen with CL, macrolides, and TETs; moreover, low MIC90 was observed to DOX (16 MUg/ml), MINO (8 MUg/ml), and LEVO (4 MUg/ml). Though the treatment group with isotretinoin/BPO had the least number of resistant strains there was no statistical difference in the antibiotic resistance among the various groups of patients. CONCLUSIONS: High resistance was seen among the P. acnes strains to macrolides-lincosamides (AZI and CL) while MINO and LEVO resistance was low. PMID- 26955096 TI - Evaluation of National Leprosy Eradication Program after Integration into General Health System in Rajkot District, Gujarat from 2003 to 2014. AB - BACKGROUND: National Leprosy Eradication Program (NLEP) was launched in 1983 with the goal of elimination of leprosy as a public health problem. AIM: To evaluate the NLEP performance after integration into general health system from April 2003 to March 2014. MATERIAL AND METHODS: A retrospective record based study was conducted by obtaining data from Rajkot district leprosy center. Prevalence rate (PR), new case detection rate (NCDR), proportion of female cases, child cases, multibacillary (MB) cases, Grade II disability among new cases and release from treatment (RFT) cases were evaluated from April 2003 to March 2014 and analyzed by using Chi-square for trend analysis test. RESULTS: The PR of leprosy per 10,000 populations was significantly declined (P < 0.001) from 0.44 in 2003-2004 to 0.15 during March 2014. Reduction in NCDR trend was statistically significant (P < 0.001). The proportion of female cases among newly detected cases showed fluctuation from 36.23% in 2003-2004 to 37.10% in 2013-2014 (P > 0.05). The proportion of child cases also showed significantly declining trend from 12.08% in 2003-2004 to 6.70% in 2013-2014 (P < 0.05). Significant number of MB cases decreased from 122 (2003-2004) to 69 (2013-2014) (P < 0.001). Grade II disability proportion was 1.45% in the year 2003-2004, increased to 5.2% in 2009-2010 and then again decreased to 3.4% in 2013-2014 (P > 0.05). Proportion of patients RFT showed fluctuation from 66.66% (2003-2004) to 45.68% (2009-2010) and then 64.66% (2013-2014) (P < 0.001). CONCLUSION: The NLEP is having a favorable impact on the problem of leprosy by maintaining the elimination level of leprosy in Rajkot district over a decade. PMID- 26955097 TI - Comparison of Efficacy, Safety and Cost-effectiveness of Rupatadine and Olopatadine in Patients of Chronic Spontaneous Urticaria: A Randomized, Double blind, Comparative, Parallel Group Trial. AB - OBJECTIVE: To compare efficacy, safety and cost-effectiveness of rupatadine and olopatadine in patients of chronic spontaneous urticaria. MATERIALS AND METHODS: A 6-week, single-centered, randomized, double blind, parallel group comparative clinical study was conducted on patients with chronic spontaneous urticaria. Following inclusion and exclusion criteria, 60 patients were recruited and were randomized to two treatment groups and received the respective drugs for 6 weeks. At follow-up, parameters assessed were mean total symptom score (MTSS) calculated by adding the mean number of wheals (MNW) and the mean pruritus score (MPS), number of wheals, size of wheal, scale for interference of wheals with sleep (SIWS). RESULTS: Both the drugs significantly reduced the MTSS, number of wheals, size of wheal, scale for interference of wheals with sleep, but olopatadine was found to be superior. In olopatadine group, there was significantly higher reduction in MTSS (p = 0.01), Number of wheals (P < 0.05), Size of wheals (p < 0.05), Scale for intensity of erythema (p < 0.05) and change in eosinopils count (p = 0.015) than that of rupatadine. Incidence of adverse effects was found to be less in olopatadine group when compared with rupatadine group. Cost effectiveness ratio was less in olopatadine group as compared to rupatadine group throughout the treatment. CONCLUSIONS: Olopatadine is a better choice in chronic spontaneous urticaria in comparison to rupatadine due to its better efficacy, safety and cost effectiveness profile. PMID- 26955098 TI - Metastatic Vulvar Crohn's Disease-A Rare Case Report and Short Review of Literature. AB - Metastatic Crohn's disease (CD), a type of extraintestinal CD may present with gynecological manifestation which causes diagnostic dilemma and needs multidisciplinary approach. Vulvar lesions occur in very small number of cases with CD of which asymmetrical labial swelling and edema is the most common presentation. We report a case of hypertrophic exophytic variety of vulvar CD because of its rarity. PMID- 26955099 TI - Dermatoses due to Quackery: A Case Snippet and Concise Review of Literature. AB - A wide prevalence of socio-religious, cultural, and tribal practices in India often leads to a multitude of skin conditions, which can misled the dermatologists in arriving at a diagnosis. With increasing globalization and migration, the practice of indigenous customs and traditions are crossing boundaries, making it imperative for the dermatologists to be acquainted with the cutaneous side effects of these practices. Here, we report a unique case of thermal burn in a circumferential pattern over the umbilical region, a result of the placement of burning lamp over umbilicus to alleviate abdominal discomfort. PMID- 26955100 TI - Nonfamilial Multiple Trichoepithelioma: Few and Far Between. AB - Trichoepithelioma is a rare benign adnexal tumor which may be of solitary nonfamilial type or multiple familial trichoepitheliomas. Here, we describe a rare presentation of nonfamilial case of trichoepithelioma in a 50-year-old female with multiple skin colored facial papules and nodules over the face, upper back, and extremities. PMID- 26955101 TI - A 5-year Journey with Cutis Laxa in an Indian Child: The De Barsy Syndrome Revisited. AB - De Barsy syndrome (DBS), synonymously known as autosomal recessive cutis laxa type III, is an extremely rare condition clinically characterized by cutis laxa, a progeroid appearance, and ophthalmologic abnormalities. We present here an account of 5-year follow-up since the birth of an Indian boy with DBS, who had a few rare and unusual manifestations. In addition, our case probably represents the first reported case of DBS from India. PMID- 26955102 TI - Neglected Basal Cell Carcinoma on Scalp. AB - Giant basal cell carcinoma (BCC) is a very rare entity. Usually, they occur due to the negligence of the patient. Local or distant metastasis is present in most cases. Here, we present a case of giant BCC that clinically resembled squamous cell carcinoma and demonstrated no metastasis at presentation. PMID- 26955103 TI - Pilomatricoma Mimicking Ruptured Epidermal Cyst in a Middle Aged Woman. AB - Pilomatricoma is a benign tumor arising from the hair matrical cells. Most pilomatricomas appear in the first two decades of life as a solitary skin to a bluish colored nodule on head-neck area with an occasional sign of inflammation. Here, we present a case of pilomatricoma which appeared at 36 years of age with a history of recurrent inflammation and discharge mimicking ruptured epidermal cyst. PMID- 26955104 TI - Response Shift Bias in Pre- and Post-test Studies. PMID- 26955105 TI - Author's Reply. PMID- 26955106 TI - Lichen Myxedematosus: Strict Classification and Diagnostic Criteria are Still Lacking. PMID- 26955107 TI - Author's Reply: The curious case of prolactin hormone. PMID- 26955108 TI - Some Other Serendipitous Discoveries in Dermatology. PMID- 26955109 TI - Necrolytic Acral Erythema in the Absence of Hepatitis C Virus Infection. PMID- 26955110 TI - Dermatology Life Quality Index does not Reflect Quality of Life Status of Indian Vitiligo Patients. PMID- 26955111 TI - Toxic Epidermal Necrolysis Like Reaction due to Low-dose Methotrexate in a Case of Cutaneous Lupus Erythematosus: A Rare Occurrence. PMID- 26955112 TI - Focal Dermal Hypoplasia or Goltz Syndrome: A Rare Association with Keratoconus. PMID- 26955113 TI - "Nevoid Eruptive Keratoacanthoma" - Yet Another Atypical Manifestation of Generalized Keratoacanthoma. PMID- 26955114 TI - Keratoacanthoma Arising Over Margin of Porokeratosis of Mibelli: A New Association? PMID- 26955115 TI - Lichtenberg figure and lightning. PMID- 26955116 TI - Cutaneous Infarct and 4-Week Fever in a Young Man. PMID- 26955117 TI - Successful Treatment of Resistant Lichen Planus Pemphigoides with Cyclosporine: A New Hope. PMID- 26955118 TI - Persistent Skin-colored Papules Over Face in an Immunocompromised Patient. PMID- 26955119 TI - The Oxidant and Antioxidant Status in Pityriasis Rosea. AB - BACKGROUND: Pityriasis rosea (PR) is usually an asymptomatic and self-limiting papulosquamous skin disease with acute onset. The etiology has not been clarified yet. Recently, increased oxidative stress was found to play a role in etiopathogenesis of multiple cutaneous diseases with T cell-mediated immune response. However, there are no studies demonstrating the oxidative stress status in PR. AIM: The aim of the study is to determine the status of oxidative stress (OS) and paraoxonase (PON) 1/arylesterase enzyme activities in PR. MATERIALS AND METHODS: Study included 51 patients with active PR lesions, and 45 healthy volunteers. Serum levels of total oxidant status (TOS), total antioxidant status (TAS), and PON1/arylesterase (ARES) activity were determined and oxidative stress index (OSI) was calculated in all patients and controls. RESULTS: TAS levels and ARES activities in the patient group were significantly lower than the control group. On the other hand, TOS and OSI levels were significantly higher in patients compared with controls. There was no significant correlation between the duration of disease and TAS, TOS, OSI levels, and ARES activities. CONCLUSION: A systemic oxidative stress exists in PR, which suggests that OS may be involved in the etiopathogenesis of disease. PMID- 26955120 TI - The Evaluation of Endothelin-1 and Endothelin Receptor Type A Gene Polymorphisms in Patients with Vitiligo. AB - BACKGROUND: Endothelin-1 (EDN1) and EDN receptor type A (EDNRA) are implicated in melanocyte functions. AIM AND OBJECTIVES: This study examines the role of EDN1 (G5665T and T-1370G) and EDNRA (C + 70G and G-231A) polymorphisms as a risk factor for vitiligo, and evaluates the relationship between genotypes and clinical characteristics of vitiligo patients. MATERIALS AND METHODS: We analyzed genotype/allele distributions of EDN1 and EDNRA polymorphisms in 100 patients with vitiligo and 185 healthy controls by real-time polymerase chain reaction. RESULTS: There was no notable risk for vitiligo afflicted by studied polymorphisms. However, the presence of EDNRA +70 variant G allele was found to be related with decreased risk for development of generalized type of vitiligo (odds ratio [OR]: 0.42, 95% confidence interval [CI] = 0.21-0.86, pcorr = 0.03) and showed protective effect against associated diseases seen in vitiligo (OR: 0.49, 95% CI = 0.27-0.88, pcorr = 0.034). Haplotype analysis demonstrated a strong (disequilibrium coefficient = 0.73, r (2) = 0.405) linkage disequilibrium between EDN1 G5665T and T-1370G polymorphisms. The EDN1 5665/-1330 TT haplotype was over represented significantly in controls than in patients (P = 0.04). CONCLUSION: The studied polymorphisms do not seem to be a major risk for vitiligo. Haplotype analysis denoting protective effects against vitiligo may indicate an indirect interaction in the course of vitiligo. In addition, EDNRA + 70 polymorphism is protective against generalized type of vitiligo and associated diseases. PMID- 26955121 TI - Assessment of the Therapeutic Aspect of Systemic Non-Biologic Anti-Psoriatic Treatment Modalities Used in Combination with Methotrexate. AB - INTRODUCTION: Psoriasis is a common skin disease affecting 1% to 3% of the population worldwide. Combination therapy with traditional systemic anti psoriatic agents offers a promising method for managing severe or recalcitrant psoriasis. AIMS AND OBJECTIVES: Lack of documented data regarding the efficacy and safety of combination therapy with methotrexate and other anti-psoriatic drugs in Iranian patients prompted us to design a study to investigate this issue in an Iranian educational hospital. MATERIALS AND METHODS: Records of psoriatic patients in Razi Hospital were reviewed retrospectively from October 2008 to March 2012. Forty-six patients who had received methotrexate in combination with other systemic anti-psoriatic agents were included in this study. Response to treatment was evaluated by PASI. Adverse reactions and the type of combination were recorded for all patients. RESULTS: Methotrexate was most frequently administered in combination with acitretin (n = 21) followed by cyclosporine (n = 11), and NB-UVB and PUVA (n = 6). Combinations were effective in the majority of patients; 46% showed good response (21 patients), 26% showed moderate response (12 patients) and 28% (13 patients) showed poor response who therefore switched to another treatment. The treatments were generally tolerable. Thirty-two patients experienced adverse events although none was severe or required hospitalization. The relative frequencies of adverse reactions were different among groups of patients receiving various therapeutic regimens. CONCLUSIONS: Methotrexate-combination therapy can offer an effective therapeutic regimen. However, the patients should be monitored for potential adverse effects. More studies are needed to determine the long-term safety and efficacy of these combinations. PMID- 26955122 TI - Dermoscopic Changes of Melanocytic Nevi after Psoralen-Ultraviolet A and Narrow Band Ultraviolet B Phototherapy. AB - BACKGROUND: Phototherapy may alter the morphologic features of melanocytic nevi. Dermoscopy is a non-invasive method for evaluation of skin lesions, specifically melanocytic nevi. AIMS AND OBJECTIVES: This study was designed to evaluate the effects of narrowband ultraviolet B (NB-UVB) and psoralen-ultraviolet A (PUVA) therapy on the dermoscopic features of nevi. METHODS: A total of 74 melanocytic nevi were randomly selected from 20 patients. Out of those, 54 nevi received NB UVB, while 20 received PUVA. 50% of the nevi in each group were exposed to radiation, while the remaining nevi were covered with an opaque tape. All nevi were demoscopically evaluated before and after 30 or 60 sessions of phototherapy. RESULTS: Overall demoscopic changes were observed in 34/37 (91.8%) of the uncovered nevi compared to 16/37 (43.2%) of the covered nevi (P value 0.0001). The most common changes were new dot/globule formation (62.1%), darkening (32.4%), nevus enlargement (27%), and patchy pigmentation (18.8%). Compared to NB UVB, dermoscopic changes were more frequent in both covered and uncovered nevi of the PUVA group. (P values 0.041 and 0.0172, respectively). New dot/globule formation was observed more frequently in the covered and uncovered nevi of PUVA group. CONCLUSION: PUVA and NB-UVB induce dermoscopic changes in the majority of the irradiated nevi. However, PUVA is associated with higher frequency of dermoscopic changes in both covered and uncovered nevi. PMID- 26955123 TI - Extradigital Glomus Tumor Revisited: Painful Subcutaneous Nodules Located in Various Parts of the Body. AB - BACKGROUND: Glomus tumor is a common lesion of the subungual area of the hand fingers. However, glomus tumors located outside the hand region are rare and the diagnosis is often difficult due to their low incidence and lack of distinct clinical features in the physical examination. The presented article contains five cases of extradigital glomus tumors with a short review of the literature. PATIENTS AND METHODS: Five cases of extradigital glomus tumor were included in the study. All lesions were purple colored subcutaneous nodules with sharp pain by digital palpation. All lesions were examined with ultrasound imaging were operated under local anesthesia using loupe magnification. RESULTS: Among five patients, only one patient was female with a mean age of 35. Two lesions were located at the arm region, two at the crural region and one at the sternal area. The smallest nodule was 0.5 cm and the biggest lesion was 2 cm in diameter. In all the cases, the early postoperative period was uneventful without any surgical complication or acute recurrence. The postoperative 1(st) year examination of all patients revealed complete resolution of the pain and no recurrence was encountered. CONCLUSIONS: Glomus tumor should be kept in mind in the differential diagnosis of all painful subcutaneous lesions especially for those with purple reflection on the skin surface. In this manner, patients with extradigital glomus tumors may be diagnosed earlier and unnecessary and wrong treatments may be prevented. PMID- 26955124 TI - Prevalence of Topical Steroid Misuse Among Rural Masses. AB - BACKGROUND: A lot of cosmetic and Ayurvedic products containing unlabeled depigmenting agent and steroids are available readily over the counter sale. The side effects of these products are not documented and can lead to adverse effects of continuous usage. OBJECTIVE: By this study, we aimed to find out the true nature of the above problem and it's implication in the Indian rural scenario. METHODOLOGY: All patients attending dermatology department during the period of 3 months from May to June 2013 for skin diseases were enquired about unsupervised use of any cosmetic product on their facial skin, duration of use, any side effect experienced through the prescribed questionnaire. RESULTS: Total 50 patients were recruited for the study. Out of which, 48% were males and 52% were females. Seventy-four percent of people had applied topical products/steroids in an attempt of attainment of fair complexion, 14% for melasma, 8% for acne induced hyperpigmentation, and 4% for dark circles. About 80% people had obtained one or the other products over the counter sale, 8% had followed the attractive advertisements, 8% had started the application on the recommendation of friends/family while only 4% people had correctly gone through the proper channel to consult a dermatologist. CONCLUSION: The problem of topical products or steroids abuse is rampant and significant, and unless and until immediate steps are taken to root out this problem from our setup, the condition will become worse all the more. PMID- 26955125 TI - Contact Allergens Causing Hand Eczema in Ethnic Kashmiri Population: A Study of 7 years. AB - BACKGROUND: Hand eczema is one of the commonest eczemas encountered in dermatology practice. Contact allergens responsible for causing hand eczema vary from one geographical area of the world to another. AIM: The study tries to identify the commonest allergens causing hand eczema in ethnic Kashmiri population. MATERIAL AND METHODS: A total of 800 patients were patch tested at a sole patch testing facility for the local population over a 7-year period out of which 278 were diagnosed with hand eczema. The morphological type of hand eczema was noted and the patch testing results were analyzed. Past or present relevance of the patch-test result to the clinical diagnosis was also analyzed. RESULTS: Hand eczema was the most common type of eczema patch tested over the 7-year period, constituting 34.75% of the patch-tested population. A positive patch-test result was obtained in 135 patients (48.5%) out of which it was found to be clinically relevant in about 65% cases. Nickel and potassium dichromate were found to be the two commonest allergens causing hand eczema in our population with positive patch test reactions in 45 and 27 patients respectively. Females showed a much higher incidence of hand eczema as well as higher patch test positivity than males (54.1% vs. 38.1%). CONCLUSIONS: Hand eczema with a positive patch-test report was found to be much more common in females than males and nickel and potassium dichromate were seen to be the commonest allergens causing hand eczema in ethnic Kashmiri population. PMID- 26955126 TI - New Treatment Options for Mycosis Fungoides. AB - The article discusses imiquimod treatment for refractory early stage mycosis fungoides, with a review of the literature and three case studies. PMID- 26955127 TI - Vulvar Epidermal Inclusion Cyst as a Long-term Complication of Female Genital Mutilation. AB - We present a case report of a patient with epidermal inclusion cyst as a late complication of female genital mutilation (FGM). We describe the management of the patient, and a review of the literature. We report the clinical and pathological findings in a 37-year-old female patient from Nigeria, with a clitoral mass of 1 year duration. She declared to have an FGM since she was 5 years. The lesion was excised successfully with good cosmetic results. Histological examination revealed epidermal cyst with the presence of granular layer. An epidermal inclusion cyst can develop as a long-term consequence of FGM. PMID- 26955128 TI - A Case Report of Isotretinoin-induced Manic Psychosis. AB - Isotretinoin, an oral vitamin A derivative, used to treat severe treatment resistant acne. Psychiatric side effects of isotretinoin particularly depression and suicidal thoughts have been well documented. We report a case of isotretinoin induced manic psychosis in a young female without a family history and history of mental illness. PMID- 26955129 TI - Median Nail Dystrophy Involving the Thumb Nail. AB - Median canaliform dystrophy of Heller is a rare entity characterized by a midline or a paramedian ridge or split and canal formation in nail plate of one or both the thumb nails. It is an acquired condition resulting from a temporary defect in the matrix that interferes with nail formation. Habitual picking of the nail base may be responsible for some cases. Histopathology classically shows parakeratosis, accumulation of melanin within and between the nail bed keratinocytes. Treatment of median nail dystrophy includes injectable triamcinalone acetonide, topical 0.1% tacrolimus, and tazarotene 0.05%, which is many a times challenging for a dermatologist. Psychiatric opinion should be taken when associated with the depressive, obsessive-compulsive, or impulse-control disorder. We report a case of 19-year-old male diagnosed as median nail dystrophy. PMID- 26955130 TI - Plasma Cell Neoplasm Manifesting Initially as a Sub-Cutaneous Supra-Orbital Swelling. AB - Multiple myeloma is a plasma cell neoplasm seen usually in patients over 50 years of age. Some cases may be asymptomatic initially and are detected during a routine test like complete blood count. They only require a close follow-up and monitoring. However, around 1% of these monoclonal gammopathy of undetermined significance progress to multiple myeloma every year and then they need to be taken care of by chemotherapy, targeted therapy, bisphosphonates and 6 monthly urine and bone examinations. Here, we present a case of 35-year-old female with an initial symptom of a vague backache along with a left subcutaneous supra orbital swelling which was diagnosed as multiple myeloma by aspiration cytology and confirmed by ancillary tests. She has since been on treatment with bortezomib and prednisone and is responding well. PMID- 26955131 TI - Iatrogenic Cushing's Syndrome After Topical Steroid Therapy for Psoriasis. AB - Glucocorticoids are used for the treatment of many diseases, such as inflammatory, allergic, autoimmune, and neoplastic diseases. They can be used in the form of topical, oral, inhalable, rectal, and intra-articular agents. Many topical steroid-related iatrogenic Cushing's syndrome cases affecting especially children have been reported in the literature. Topical steroid-related Cushing's syndrome is rarely seen in adults. In this report, we present the case of a 32 year-old male patient with iatrogenic Cushing's syndrome related to long-term clobetasol propionate treatment for psoriasis. In the context of such treatment, the glucocorticoid withdrawal problem has to be overcome. At present there is no consensus on steroid withdrawal. Patients on long-term glucocorticoid treatment must be evaluated for potential adverse effects and withdrawal symptoms by their physician and their endocrinologist. PMID- 26955132 TI - A Fatal Case of "Bullous Erysipelas-like" Pseudomonas Vasculitis. AB - Erysipelas is a generally benign superficial bacterial skin infection, and its bullous form constitutes a rare and more severe variant. We describe the first and fatal case of "bullous erysipelas-like" septic vasculitis due to Pseudomonas bacteremi. A 69-year-old Chinese man presenting with diarrhea and septic shock initially began to rapidly develop sharply defined erythematous plaques with non hemorrhagic bullae over his lower limbs. Culture of the aspirate from the bullae was positive for Pseudomonas aeruginosa. This was also consistent with his blood cultures showing Pseudomonas bacteremia. Histology of the skin lesion showed microthrombi and neutrophilic infiltrates in blood vessels with Gram-negative bacilli extruding from the vessel walls, characteristic of septic vasculitis. The bullous erysipelas-like lesions seen in this patient represents a rare manifestation of both septic vasculitis and Pseudomonas infection. PMID- 26955133 TI - Lichen Sclerosus of Face: A Case Report and Review of Literature. AB - We present a case of lichen sclerosus (LS) involving face and review of the relevant literature since 1970. This article highlights the rarely reported manifestation of LS. Early diagnosis with dermoscopy or confocal microscopy and early treatment might help cure it, and it may have less malignant potential. PMID- 26955134 TI - Multiple Giant Pilar Cyst Distributed Over the Body Since Childhood. AB - Trichilemmal cyst or pilar cyst is defined as a cyst containing keratin and its breakdown products. It is usually situated on the scalp with a wall resembling external hair root sheath. In this case report we present a 55-year-old man with multiple giant pilar cysts that were distributed over the whole body since childhood. One of the cyst on the chest was transformed to squamous cell carcinoma (SCC). PMID- 26955135 TI - Transformation of Dermatofibrosarcoma Protuberans into a Fibrosarcoma. AB - Dermatofibrosarcoma protuberans is a rare cutaneous mesenchymal tumor characterized by a low potential of malignancy with a very low rate of metastasis but an important rate of local recurrence. Its transformation into a fibrosarcoma is exceptional, responsible for a higher metastatic potential. This transformation implies a closer surveillance. Through a case report and literature review, we will try to expose epidemiological, clinical, histological, therapeutic, and outcome particularities of this entity. PMID- 26955136 TI - Multiple Cutaneous Reticulohistiocytoma. AB - Multicentric reticulohistiocytosis is a rare non-Langerhans cell histiocytosis characterized in its full form by severe destructive arthritis, cutaneous nodules, and systemic manifestations. Cutaneous lesions may precede, accompany, or more commonly develop later than other features in this disease. We describe a case of multiple cutaneous reticulohistiocytoma without any systemic associations after thorough investigations. PMID- 26955138 TI - Painless Ulcers and Fissures of Toes: Hereditary Sensory Neuropathy, Not Leprosy. AB - Hereditary sensory neuropathies (HSN) are rare genetically determined neuropathies. They often manifest as painless injuries in children. We present HSN in a 5-year-old boy who presented with recurrent fissuring and ulceration involving both great toes. PMID- 26955137 TI - Dermatofibroma: Atypical Presentations. AB - Dermatofibroma is a common benign fibrohistiocytic tumor and its diagnosis is easy when it presents classical clinicopathological features. However, a dermatofibroma may show a wide variety of clinicopathological variants and, therefore, the diagnosis may be difficult. The typical dermatofibroma generally occurs as a single or multiple firm reddish-brown nodules. We report here two atypical presentations of dermatofibroma - Atrophic dermatofibroma and keloidal presentation of dermatofibroma. Clinical dermal atrophy is a common phenomenon in dermatofibromas as demonstrated by the dimpling on lateral pressure. However, this feature is exaggerated in the atrophic variant of dermatofibroma. Atrophic dermatofibroma is defined by dermal atrophy of more than 50% of the lesion apart from the usual features of common dermatofibroma. The keloidal variant of dermatofibroma should not be overlooked as a simple keloid. The findings of keloidal change in dermatofibromas may support that trauma is a possible cause of dermatofibroma. PMID- 26955139 TI - Bleomycin Containing Chemotherapeutic Regimen Induced Acquired Partial Lipodystrophy. AB - Bleomycin toxicity predominantly affects the skin and lungs. Cutaneous toxicity classically known to present with bleomycin are flagellate erythema and drug rash. We hereby report an isolated case of (bleomyicn)-induced acquired partial (lipodytrophy) having potential cosmetic implications in a young women prescribed postoperatively following a case of germ cell carcinoma of ovary (endodermal sinus tumor). PMID- 26955140 TI - Novel ALOX12B Mutation Identified in Parents following Single Nucleotide Polymorphism Microarray Testing of Banked DNA from a Fatal Case of Congenital Ichthyosis. AB - In genetically and phenotypically heterogeneous conditions like ichthyosis, it is clinically not possible to predict mutation in a specific gene. Sequential testing of all the causative genes is time consuming and expensive. In consanguineous families with autosomal recessive genetically heterogeneous disorders, it is possible to narrow down the candidate gene/genes by recognizing the regions of homozygosity by a single nucleotide polymorphism (SNP) array. Here, we present a fatal case of autosomal recessive severe congenital ichthyosis born to a consanguineous couple. Two candidate genes were recognized by SNP array on banked DNA of the subject. Sequencing of these candidate genes in parents found them to be carriers of the same variation, a novel heterozygous deletion of single nucleotide in exon 8 (c. 1067delT) of ALOX12B gene. The present case illustrates the utility of DNA banking, SNP array and testing of parents to arrive at a definitive molecular diagnosis, essential for genetic counseling, and prenatal testing. PMID- 26955141 TI - Amelanotic Melanoma in the Vicinity of Acquired Melanocytic Nevi and not Arising from Agminated Melanocytic Nevi: Masquerading as Pyogenic Granuloma. AB - Amelanotic melanoma (AMM) presenting as pyogenic granuloma and occurring in the vicinity of acquired melanocytic nevi is rare. Herein, we report such a manifestation in a 68-year-old male who presented with the painful red nodule and multiple pigmented patches involving the left great toe. Histopathological examination of skin biopsy taken from the nodule with an immunohistochemical study using HMB45 and S-100 confirmed the diagnosis of AMM. Biopsy from the pigmented patch near the nodule showed features of melanocytic nevus. Investigative work up revealed metastatic deposits in the left inguinal lymph node with no evidence of systemic involvement, placing him in malignant melanoma Stage IIIC of American Joint Committee on Cancer (AJCC) tumor node metastasis system. The development of AMM in the vicinity of acquired melanocytic nevi and manifesting as granuloma pyogenicum is unique in this case. PMID- 26955142 TI - Cellular Neurothekeoma on the Lip. PMID- 26955143 TI - Diagnostic Pitfalls of Neonatal Herpes Infection. PMID- 26955144 TI - Multiple Cutaneous Reticulohistiocytomas in a Middle-Aged Female. PMID- 26955145 TI - Pustular Psoriasis of Pregnancy with Acrodermatitis Continua of Hallopeau. PMID- 26955146 TI - White Streaks: Dermoscopic Sign of Distal Lateral Subungual Onychomycosis. PMID- 26955147 TI - Nevus Lipomatosus Cutaneous Superficialis: A Report of Two Cases. PMID- 26955148 TI - Multiple Giant Cutaneous Horns in a Renal Transplant Recipient. PMID- 26955149 TI - Asymptomatic Subcutaneous Nodules Heralding Recurrence of Gastric Adenocarcinoma. PMID- 26955150 TI - Post Herpes Zoster Trigeminal Trophic Syndrome in a Child: An Example of Immunocompromised District. PMID- 26955151 TI - Myeloma Associated Primary Systemic Amyloidosis. PMID- 26955152 TI - Interstitial Granulomatous Drug Reaction After Intranasal Desmopressin Administration. PMID- 26955154 TI - Angiolymphoid Hyperplasia with Eosinophilia Associated with Pregnancy - A Rare Report. PMID- 26955153 TI - Triangular Temporal Alopecia Revisited. PMID- 26955155 TI - Dermatoscopic Features of Hyper and Hypopigmented Lesions of Dowling Degos Disease. PMID- 26955156 TI - Histology Resembling Cutaneous T-Cell Lymphoma in Nodular Scabies: A Case Report. PMID- 26955157 TI - Recurrent Purpuric Patches on the Limbs of an 18-Year-Old-Female: Gardner-Diamond Syndrome. PMID- 26955158 TI - Giant Cerebriform Congenital Cellular Blue Nevus Presenting as Cutis Verticis Gyrata. PMID- 26955159 TI - Palisaded Encapsulated Neuroma in a Zosteriform Distribution. PMID- 26955160 TI - Squamous Cell Carcinoma in-situ and Basal Cell Carcinoma Arising From Seborrheic Keratosis in the Same Patient. PMID- 26955161 TI - Basosquamous Carcinoma Masquerading as Angiolymphoid Hyperplasia. PMID- 26955162 TI - Recurrence of Stewarty4Treves Syndrome in a Patient with Chronic Lymphedema Secondary to Breast Cancer. PMID- 26955163 TI - Idiopathic Acquired True Leukonychia Totalis. PMID- 26955164 TI - Periorbital Varicella Gangrenosa. PMID- 26955165 TI - Sacral Rheumatoid Nodule Mimicking Inflammatory Atheroma. PMID- 26955166 TI - Pigmentary Demarcation Lines in Pregnancy. PMID- 26955167 TI - Generalized Granuloma Annulare in a Cirrhotic Patient Treated with Narrowband Ultraviolet B Therapy. PMID- 26955168 TI - IgG4-related Skin Lesion with Mikulicz's Disease. PMID- 26955169 TI - Doxycycline Induced Generalized Bullous Fixed Drug Eruption. PMID- 26955170 TI - 73(rd) Annual Meeting, American Academy of Dermatology, San Francisco 2015. PMID- 26955171 TI - Road map of journal for coming years. PMID- 26955172 TI - Tuberculosis of spine: Research evidence to treatment guidelines. PMID- 26955173 TI - Modified Girdlestone arthroplasty and hip arthrodesis using the Ilizarov external fixator as a salvage method in the management of severely infected total hip replacement. AB - BACKGROUND: Resection arthroplasty or hip arthrodesis after total hip replacement (THR) can be used to salvage the limb in case with deep infection and severe bone loss. The Ilizarov fixator provides stability, axial correction, weight-bearing and good fusion rates. MATERIALS AND METHODS: We retrospectively assessed the outcomes of 37 patients with severe periprosthetic infection after THR treated between 1999 and 2011. The treatment included implant removal, debridement and a modified Girdestone arthroplasty (29 cases) or hip arthrodesis (seven cases) using the Ilizarov fixator. The Ilizarov fixation continued from 45 to 50 days in the modified arthroplasty group and 90 days in the arthrodesis group. One case was treated using the conventional resection arthroplasty bilaterally. RESULTS: Eighteen months after treatment, infection control was seen in 97.3% cases. Six hips were fused as one patient died in this group. Limb length discrepancy (LLD) averaged 5.5 cm. The Harris hip score ranged from 35 to 92 points. Hip joint motion ranged from 10 degrees to 30 degrees in the modified arthroplasty group. All subjects could walk independently or using support aids. No subluxation or LLD progression was observed. CONCLUSION: The modified Girdlestone arthroplasty and hip arthrodesis using the Ilizarov apparatus results in sufficient ability for ambulation and good infection control in cases of failed THR associated with severe infection. PMID- 26955174 TI - Total knee arthroplasty in valgus knees using minimally invasive medial-subvastus approach. AB - BACKGROUND: An ideal approach for valgus knees must provide adequate exposure with minimal complications due to approach per se. Median parapatellar approach is most commonly used approach in TKA including valgus knees. A medial subvastus approach is seldom used for valgus knees and has definite advantages of maintaining extensor mechanism integrity and minimal effect on patellar tracking. The present study was conducted to evaluate outcomes of total knee arthroplasty (TKA) and efficacy of subvastus approach in valgus knees in terms of early functional recovery, limb alignment and complications. MATERIALS AND METHODS: We retrospectively reviewed 112 knees with valgus deformity between January 2006 and December 2011. All patients were assessed postoperatively for pain using Visual Analog Scale (VAS) and quadriceps recovery in form of time to active straight leg raising (SLR) and staircase competency and clinical outcomes using American Knee Society (AKS) score and radiographic evaluation with average followup of 40 months (range 24-84 months). RESULTS: The mean VAS on postoperative day (POD) 1 and POD2 at rest was 2.73 and 2.39, respectively and after mobilization was 3.28 and 3.08, respectively (P < 0.001). The quadriceps recovery was very early and 92 (86.7%) patients were able to do active SLR by POD1 with mean time of 21.98 h while reciprocal gait and staircase competency was possible at 43.05 h. The AKS and function score showed significant improvement from preoperative mean score of 39 and 36 to 91 and 79 (P < 0.001), respectively, and the mean range of motion increased from 102 degrees preoperatively to 119 degrees at recent followup (P < 0.001). The mean tibiofemoral valgus was corrected from preoperative 16 degrees (range 10 degrees -35 degrees ) to 5 degrees (range 3 degrees -9 degrees ) valgus (P < 0.001). CONCLUSIONS: Mini-subvastus quadriceps approach provides adequate exposure and excellent early recovery for TKA in valgus knees, without increase in incidence of complications. PMID- 26955175 TI - Results of multiple ligament injured knees operated by three different strategies. AB - BACKGROUND: Multiple ligament injured knee is generally described for a scenario when at least 2 of the 4 major ligaments are ruptured. The most effective treatment for these injuries remains controversial. This study presents the clinical outcome of 3 surgical strategies based on personalized treatment. MATERIALS AND METHODS: Thirty two patients with multiple ligament injured knee were treated by 3 surgical strategies in the acute phase. (1) One-stage: Twelve patients treated by repair and reconstruction of all ruptured ligaments in a single operation. (2) Staged: Eleven patients treated by repair or reconstruction of the extraarticular (EA) ligaments and then intraarticular ligaments in 2(nd) stage. (3) EA ligament repair: Nine patients underwent only EA ligaments repair. RESULTS: The patients were followed up for an average of 34.7 +/- 12.1 months. Significant improvements in knee stabilities (P < 0.01), Lysholm score (P < 0.01) and International Knee Documentation Committee grade (P < 0.01) were noticed in all groups. Of the 32 patients, none had gross mal alignment or gait abnormalities at the latest followup. Comparing the 3 groups, a significant difference in Lysholm score was shown between the one stage group and the EA repair group (P = 0.040); additionally, significant differences were found in 2 subscales of knee injury and osteoarthritis outcome score (P < 0.05). CONCLUSION: Satisfactory clinical and functional outcomes could be achieved adopting the 3 surgical strategies based on personalized treatment. However, a combination of EA repair and intraarticular repair or reconstruction might be more reasonable options for the young and active patients. PMID- 26955177 TI - Effects of intraarticular (32)P colloid in the treatment of hemophilic synovitis of the knee: A short term clinical study. AB - BACKGROUND: Chronic synovitis is a consequence of recurrent intraarticular hemorrhage in patients with hemophilia. Eventually, synovitis leads to degeneration of the articular cartilage, with serious consequences that impact the quality-of-life in hemophiliacs. The aim of our study was to investigate the short term clinical effects of intraarticular injection of the radionuclide preparation(32)P colloid ((32)P-labelled colloidal chromic phosphate suspension) on recurrent intraarticular hemorrhages in patients with hemophilic synovitis of the knee. MATERIALS AND METHODS: Patients who met the inclusion criteria (n = 22) were enrolled in an open-label study between October 2011 and September 2012.(32)P colloid was injected into the knee joint and patients were followed up over 6 months after treatment. Hemorrhage frequency, visual analog scale pain score, hospital for special surgery knee score, knee circumference, upper knee circumference, knee diameter, and knee range of motion (ROM) were compared before and after treatment with intraarticular(32)P colloid injection. RESULTS: In 24 knees evaluated in 22 participating patients, there was a significant reduction in the number of hemorrhages after(32)P colloid treatment, along with significant pain relief. However, there were no statistically significant changes in the degree of joint swelling, degree of muscle atrophy and knee ROM between the pre and post treatment evaluations. CONCLUSION: The frequency of joint hemorrhage in patients with hemophilic knee synovitis can be significantly reduced and local symptoms can be improved in the short term by intraarticular injection of(32)P colloid. PMID- 26955176 TI - Prediction of quadruple hamstring graft diameter for anterior cruciate ligament reconstruction by anthropometric measurements. AB - BACKGROUND: The literature is scanty regarding the anthropometric predictors on the diameter of quadruple hamstring graft obtained in anterior cruciate ligament (ACL) reconstruction in Indian population. Minimum diameter of the graft for ACL reconstruction should be >7 mm to preclude failure. The objective of this study was to assess the prediction of the hamstring graft diameter by several anthropometric parameters including age, thigh circumference, weight, height and body mass index (BMI). MATERIALS AND METHODS: 46 consecutive patients who had undergone ACL reconstruction by the same surgeon using quadruple hamstring grafts were evaluated. The age, thigh circumference of the normal side, height, weight and BMI were recorded preoperatively and Pearson correlation was done using these parameters with graft diameter measured intraoperatively. Regression analysis in a stepwise manner was undertaken to assess the influence of individual anthropometric parameters on the graft diameter. RESULTS: There were 44 males and 2 females. Mean age was 29.4 years, mean height was 172.6 cm, mean weight was 70.9 kg, mean BMI was 23.8 kg/m(2), mean thigh circumference was 47.1 cm and mean graft diameter was 7.9 mm. There was a positive correlation individually between the thigh circumference and graft diameter obtained (r = 0.8, P < 0.01, n = 46), and between the height and graft diameter (r = 0.8, P < 0.01, n = 46). On the regression analysis thigh circumference and height were found to be significant predictors of graft diameter giving the following equation: Graft diameter (mm) = 0. 079 height (cm) +0.068 thigh circumference (cm) -9.031. CONCLUSION: Preoperatively using the above equation if graft diameter came out to be <7 mm then alternate options of graft material must be kept in mind in order to prevent failure. PMID- 26955178 TI - Subcutaneous versus intraarticular closed suction indwelling drainage after total knee arthroplasty: A randomised control trial. AB - BACKGROUND: Total knee arthroplasty (TKA) is widely accepted treatment for moderate or severe osteoarthritis and rheumatoid arthritis. Significant blood loss can be seen during the early postoperative period where a blood transfusion may be necessary. Closed suction drainage is known to prevent the formation of hematomas in the operative field, decrease tension on incisions, diminish delayed wound healing and reduce the risk of infection. Subcutaneous indwelling closed suction drainage method has been known to be beneficial and an alternative to the intraarticular indwelling method. This prospective randomized study was to compare the visible, hidden, total blood loss and postoperative hemodynamic change of subcutaneous and intraarticular indwelling closed suction drainage method after TKA. MATERIALS AND METHODS: One hundred and sixty patients with primary osteoarthritis who underwent unilateral TKA were enrolled; group A with subcutaneous (n = 78) and group B with intraarticular (n = 79) indwelling closed suction drainage method. Total blood loss, visible blood loss, internal blood loss, postoperative day 1, 5(th), 10(th) day hemoglobin, hematocrit levels were compared. Allogeneic blood transfusion rate and complications related to soft tissue hematoma formation were additionally compared. RESULTS: Allogenic transfusion requirements between subcutaneous drainage group and intraarticular drainage groups (6.4% vs. 24.1%) were significantly different (P = 0.002). Although the minor complications such as the incidence of bullae formation and the ecchymosis were higher in the subcutaneous indwelling group, the functional outcome at postoperative 2 year did not demonstrate the difference from intraarticular drainage group. CONCLUSION: Subcutaneous indwelling closed suction drainage method is a reasonable option after TKA for reduction of postoperative bleeding and transfusion rate. PMID- 26955179 TI - Comparison of postoperative pain after open and endoscopic carpal tunnel release: A randomized controlled study. AB - BACKGROUND: Results of open and endoscopic carpal tunnel surgery were compared with many studies done previously. To the best of our knowledge, difference in pain after endoscopic carpal tunnel release (ECTR) and open carpal tunnel release (OCTR) has not been objectively documented in literature. The aim of the study was to compare the pain intensity in the early postoperative period in patients undergoing OCTR versus those undergoing ECTR. MATERIALS AND METHODS: Fifty patients diagnosed with carpal tunnel syndrome were randomized into two groups using "random number generator" software (Research Randomizer, version 3.0); endoscopic surgery group [(21 female, 1 male; mean age 49 years (range 31-64 years)] and open surgery group [(25 female, 3 male; mean age 45.1 years (range 29 68 years)] and received carpal tunnel release. Surgery was performed under regional intravenous anesthesia. The patients' pain level was assessed at the 1(st), 2(nd), 4(th), and 24(th) postoperative hours using a visual analog scale (VAS) score. RESULTS: Mean age, gender and duration of symptoms were found similar for both groups. Boston functional scores were improved for both groups (P < 0.001, P < 0.001). Pain assessment at the postoperative 1(st), 2(nd), 4(th) and 24(th) hours revealed significantly low VAS scores in the endoscopic surgery group (P = 0.003, P < 0.001, P < 0.001, P < 0.001). Need for analgesic medication was significantly lower in the endoscopic surgery group (P < 0.001). CONCLUSION: Endoscopic carpal tunnel surgery is an effective treatment method in carpal tunnel release vis-a-vis postoperative pain relief. PMID- 26955180 TI - Results of two different surgical techniques in the treatment of advanced-stage Freiberg's disease. AB - BACKGROUND: Freiberg's disease is an osteochondrosis most commonly seen in adolescent women and characterized by pain, swelling and motion restriction in the second metatarsal. The early stages of this disease can be managed with semirigid orthoses, metatarsal bars and short leg walking cast. Number of operative methods are suggested which can be used depending on the pathophysiology of the disease, including abnormal biomechanics, joint congruence and degenerative process. We evaluated the outcomes of the patients with Freiberg's disease who were treated with dorsal closing-wedge osteotomy and resection of the metatarsal head. PATIENTS AND METHODS: 16 patients (11 female, 5 male) with a mean age of 24.5 (range 13-49 years) years who underwent dorsal closing wedge osteotomy or resection of the metatarsal head were included in this retrospective study. Second metatarsal was affected in 13 and third metatarsal in three patients. According to the Smillie's classification system, ten patients had type IV osteonecrosis and six patients had type V. The results of the patients were evaluated using the lesser metatarsophalangeal-interphalangeal (LMPI) scale. RESULTS: According to the LMPI scale, the postoperative scores for the osteotomy and excision groups were 86 (range 64-100) and 72.6 (range 60-85), respectively. In the osteotomy group, mean passive flexion restriction was 18 degrees (range 0 degrees -35 degrees ) and mean passive extension restriction was 12 degrees (range 0 degrees -25 degrees ). Mean metatarsal shortening was 2.2 mm (range 2-4 mm) in the osteotomy group as opposed to 9.8 mm (range 7-14 mm) in the excision group. Significant pain relief was obtained in both groups following the surgery. CONCLUSIONS: The decision of performing osteotomy or resection arthroplasty in the patients with advanced-stage Freiberg's disease should be based on the joint injury and the patients should be informed about the cosmetic problems like shortening which may arise from resection. PMID- 26955181 TI - Scoliosis may be the first symptom of the tethered spinal cord. AB - BACKGROUND: Tethered cord syndrome (TCS) is a progressive clinical entity that arises from abnormal spinal cord tension. Scoliosis may be a unique symptom in TCS. The aim of this study is to investigate prognosis after releasing the filum terminale in scoliosis due to TCS with/without findings in magnetic resonance imaging (MRI) and to draw attention to the importance of somatosensorial evoked potentials (SSEP) on the differential diagnosis of idiopathic scoliosis versus scoliosis due to TCS with normal appearance of filum terminale and conus medullaris. MATERIALS AND METHODS: Eleven female and seven male patients with progressive scoliosis were included in the study. They were evaluated radiologically, SSEP and urodynamical studies. Preoperative and postoperative anteroposterior full spine X-rays were obtained for measuring the Cobb's angle. MRI was performed in all cases for probable additional spinal abnormalities. All patients underwent filum terminale sectioning through a L5 hemilaminectomy. The resected filum terminale were subjected to histopathological examination. RESULTS: The mean Cobb angle was 31.6 degrees (range 18 degrees -45 degrees ). Eight patients (44.45%) had a normal appearance of filum terminale and normal level conus medullaris in MRI, but conduction delay and/or block was seen on SSEP. In the histopathological examination of filum terminale dense collagen fibers, hyaline degeneration and loss of elastic fibers were observed. Postoperatively none of the patients showed worsening of the Cobb angle. Three patients showed improvement of scoliosis. CONCLUSION: In TCS presented with scoliosis, untethering must be performed prior to the corrective spinal surgery. Absence of MRI findings does not definitely exclude TCS. SSEP is an important additional guidance in the diagnosis of TCS. After untethering, a followup period of 6 months is essential to show it untethering helps in stopping the progress of the scoliotic curve. In spite of non progression (curve stopped lesser than 45 degrees ) or even improvement of scoliosis, there may be no need for major orthopedic surgical intervention. PMID- 26955182 TI - Low dose short duration pulsed electromagnetic field effects on cultured human chondrocytes: An experimental study. AB - BACKGROUND: Pulsed electromagnetic field (PEMF) is used to treat bone and joint disorders for over 30 years. Recent studies demonstrate a significant effect of PEMF on bone and cartilage proliferation, differentiation, synthesis of extracellular matrix (ECM) and production of growth factors. The aim of this study is to assess if PEMF of low frequency, ultralow field strength and short time exposure have beneficial effects on in-vitro cultured human chondrocytes. MATERIALS AND METHODS: Primary human chondrocytes cultures were established using articular cartilage obtained from knee joint during joint replacement surgery. Post characterization, the cells were exposed to PEMF at frequencies ranging from 0.1 to 10 Hz and field intensities ranging from 0.65 to 1.95 MUT for 60 min/day for 3 consecutive days to analyze the viability, ECM component synthesis, proliferation and morphology related changes post exposure. Association between exposure doses and cellular effects were analyzed with paired't' test. RESULTS: In-vitro PEMF exposure of 0.1 Hz frequency, 1.95 MUT and duration of 60 min/day for 3 consecutive days produced the most favorable response on chondrocytes viability (P < 0.001), ECM component production (P < 0.001) and multiplication. Exposure of identical chondrocyte cultures to PEMFs of 0.65 MUT field intensity at 1 Hz frequency resulted in less significant response. Exposure to 1.3 MUT PEMFs at 10 Hz frequency does not show any significant effects in different analytical parameters. CONCLUSIONS: Short duration PEMF exposure may represent a new therapy for patients with Osteoarthritis (OA). PMID- 26955183 TI - The best location for proximal locking screw for femur interlocking nailing: A biomechanical study. AB - BACKGROUND: Proximal locking screw deformation and screw fracture is a frequently seen problem for femur interlocking nailing that affects fracture healing. We realized that there is lack of literature for the right level for the proximal locking screw. We investigated the difference of locking screw bending resistance between the application of screws on different proximal femoral levels. MATERIALS AND METHODS: We used a total of 80 proximal locking screws for eight groups, 10 screws for each group. Three-point bending tests were performed on four types of screws in two different trochanteric levels (the lesser trochanter and 20 mm proximal). We determined the yield points at three-point bending tests that a permanent deformation started in the locking screws using an axial compression testing machine. RESULTS: The mean yield point value of 5 mm threaded locking screws applied 20 mm proximal of lesser trochanter was 1022 +/- 49 (range 986 1057) (mean +/- standard deviation, 95% confidence interval). On the other hand, the mean yield point value of the same type of locking screws applied on the lesser trochanteric level was 2089 +/- 249 (range 1911-2268). Which means 103% increase of screw resistance between two levels (P = 0.000). In all screw groups, on the lesser trochanter line we determined 98-174% higher than the yield point values of the same type of locking screws in comparison with 20 mm proximal to the lesser trochanter (P = 0.000). CONCLUSION: According to our findings, there is twice as much difference in locking screw bending resistance between these two application levels. To avoid proximal locking screw deformation, locking screws should be placed in the level of the lesser trochanter in nailing of 1/3 middle and distal femur fractures. PMID- 26955184 TI - Results of cement augmentation and curettage in aneurysmal bone cyst of spine. AB - Aneurysmal bone cyst (ABC) is a vascular tumor of the spine. Management of spinal ABC still remains controversial because of its location, vascular nature and incidence of recurrence. In this manuscript, we hereby describe two cases of ABC spine treated by curettage, vertebral cement augmentation for control of bleeding and internal stabilization with two years followup. To the best of our knowledge, this is the first case report in the literature describing the role of cement augmentation in spinal ABC in controlling vascular bleeding in curettage of ABC of spine. Case 1: A 22 year old male patient presented with chronic back pain. On radiological investigation, there were multiple, osteolytic septite lesions at L3 vertebral body without neural compression or instability. Percutaneous transpedicular biopsy of L3 from involved pedicle was done. This was followed by cement augmentation through the uninvolved pedicle. Next, transpedicular complete curettage was done through involved pedicle. Case 2: A 15-year-old female presented with nonradiating back pain and progressive myelopathy. On radiological investigation, there was an osteolytic lesion at D9. At surgery, decompression, pedicle screw-rod fixation and posterolateral fusion from D7 to D11 was done. At D9 level, through normal pedicle cement augmentation was added to provide anterior column support and to control the expected bleeding following curettage. Transpedicular complete curettage was done through the involved pedicle with controlled bleeding at the surgical field. Cement augmentation was providing controlled bleeding at surgical field during curettage, internal stabilization and control of pain. On 2 years followup, pain was relieved and there was a stable spinal segment with well filled cement without any sign of recurrence in computed tomography scan. In selected cases of spinal ABC with single vertebral, single pedicle involvement; cement augmentation of vertebra through normal pedicle has an important role in surgery aimed for curettage of vertebra. PMID- 26955185 TI - Pathological fracture dislocation of the acetabulum in a patient with neurofibromatosis-1. AB - Skeletal neurofibromatosis (NF) commonly manifests as scoliosis and tibial dysplasias. NF affecting the pelvic girdle is extremely rare. Pathological fracture of the acetabulum leading to anterior hip dislocation in a patient with NF-1 has never been reported in the literature. The paper presents the clinical symptomatology, the course of management and the successful outcome of such a rare case of NF-1. Histopathological and immunohistochemistry studies showing abundant spindle cells, which are S-100 positive and of neural origin are the classical hallmarks of neurofibromatous lesions. Tumor resection and iliofemoral arthrodesis can be considered as a valid option in young patients with pathological fracture dislocation of the acetabulum. PMID- 26955186 TI - Safe corridors for K-wiring in phalangeal fractures. PMID- 26955187 TI - Author's reply. PMID- 26955189 TI - Stereocontrolled regeneration of olefins from epoxides. AB - Through treatment with NaI and trifluoroacetic anhydride, which presumably forms trifluoroacetyl iodide in situ, epoxides can be converted to olefins. This reaction now has been shown to tolerate remote olefins without loss of their individual stereochemistry. A reaction sequence involving regiospecific epoxidation of an isoprenoid alcohol, conversion of the alcohol to an azide, and cycloaddition with an acetylene, followed by conversion of the epoxide back to the original olefin, has allowed stereocontrolled preparation of triazole bisphosphonates with a farnesyl or a geranylgeranyl substituent. This strategy may be applicable selective protection of an alkene in other polyolefins, including substrates for metathesis reactions. PMID- 26955188 TI - Cognitive Predictors of Calculations and Number Line Estimation with Whole Numbers and Fractions among At-Risk Students. AB - The purpose of this study was to examine the cognitive predictors of calculations and number line estimation with whole numbers and fractions. At-risk 4th-grade students (N = 139) were assessed on 7 domain-general abilities (i.e., working memory, processing speed, concept formation, language, attentive behavior, and nonverbal reasoning) and incoming calculation skill at the start of 4th grade. Then, they were assessed on whole-number and fraction calculation and number line estimation measures at the end of 4th grade. Structural equation modeling and path analysis indicated that processing speed, attentive behavior, and incoming calculation skill were significant predictors of whole-number calculations whereas language, in addition to processing speed and attentive behavior, significantly predicted fraction calculations. In terms of number line estimation, nonverbal reasoning significantly predicted both whole-number and fraction outcome, with numerical working memory predicting whole-number number line estimation and language predicting fraction number line estimation. Findings are discussed in terms of distinctions between whole-number and fraction development and between calculations and number line learning. PMID- 26955190 TI - Thermal Signature Measurements for Ammonium Nitrate/Fuel Mixtures by Laser Heating. AB - Measurements were carried out to obtain thermal signatures of several ammonium nitrate/fuel (ANF) mixtures, using a laser-heating technique referred to as the laser-driven thermal reactor (LDTR). The mixtures were ammonium nitrate (AN)/kerosene, AN/ethylene glycol, AN/paraffin wax, AN/petroleum jelly, AN/confectioner's sugar, AN/cellulose (tissue paper), nitromethane/cellulose, nitrobenzene/cellulose, AN/cellulose/nitromethane, AN/cellulose/nitrobenzene. These mixtures were also compared with AN/nitromethane and AN/diesel fuel oil, obtained from an earlier investigation. Thermograms for the mixtures, as well as individual constituents, were compared to better understand how the sample thermal signature changes with mixture composition. This is the first step in development of a thermal-signature database, to be used along with other signature databases, to improve identification of energetic substances of unknown composition. The results indicated that each individual thermal signature was associated unambiguously with a particular mixture composition. The signature features of a particular mixture were shaped by the individual constituent signatures. It was also uncovered that the baseline signature was modified after an experiment due to coating of unreacted residue on the substrate surface and a change in the reactor sphere oxide layer. Thus, care was required to pre-oxidize the sphere prior to an experiment. A minimum sample mass (which was dependent on composition) was required to detect the signature characteristics. Increased laser power served to magnify signal strength while preserving the signature features. For the mixtures examined, the thermal response of each ANF mixture was found to be different, which was based on the mixture composition and the thermal behavior of each mixture constituent. PMID- 26955191 TI - Biodiversity of Trichoderma (Hypocreaceae) in Southern Europe and Macaronesia. AB - The first large-scale survey of sexual and asexual Trichoderma morphs collected from plant and fungal materials conducted in Southern Europe and Macaronesia including a few collections from French islands east of Africa yielded more than 650 specimens identified to the species level. Routine sequencing of tef1 revealed a genetic variation among these isolates that exceeds previous experience and ca. 90 species were recognized, of which 74 are named and 17 species newly described. Aphysiostroma stercorarium is combined in Trichoderma. For the first time a sexual morph is described for T. hamatum. The hitherto most complete phylogenetic tree is presented for the entire genus Trichoderma, based on rpb2 sequences. For the first time also a genus-wide phylogenetic tree based on acl1 sequences is shown. Detailed phylogenetic analyses using tef1 sequences are presented in four separate trees representing major clades of Trichoderma. Discussions involve species composition of clades and ecological and biogeographic considerations including distribution of species. PMID- 26955192 TI - Diversity and potential impact of Calonectria species in Eucalyptus plantations in Brazil. AB - Species in the genus Calonectria (Hypocreales) represent an important group of plant pathogenic fungi that cause serious losses to plant crops in tropical and subtropical climates. Calonectria leaf blight is currently one of the main impediments to Eucalyptus cultivation in Brazil, and various species of Calonectria have been associated with this disease. Since most previous identifications were solely based on morphological characters, much of the published literature needs to be re-evaluated. The aim of this study was thus to identify and determine the phylogenetic relationships among species that occur in the Eucalyptus growing regions of Brazil by using partial sequences of the beta tubulin, calmodulin, translation elongation factor 1-alpha and histone H3 gene regions. Based on extensive collections from soil and infected eucalypt leaf samples from plantations, phylogenetic inference revealed the Ca. pteridis complex to be the most common species complex present in Eucalyptus plantations in Brazil. By elucidating taxa in the Ca. pteridis, Ca. cylindrospora and Ca. candelabra species complexes, 20 novel Calonectria species were identified, and a new name in Calonectria provided for Cylindrocladium macrosporum as Ca. pseudopteridis. PMID- 26955193 TI - Novel taxa in the Fusarium fujikuroi species complex from Pinus spp. AB - The pitch canker pathogen Fusarium circinatum has caused devastation to Pinus spp. in natural forests and non-natives in commercially managed plantations. This has drawn attention to the potential importance of Fusarium species as pathogens of forest trees. In this study, we explored the diversity of Fusarium species associated with diseased Pinus patula, P. tecunumanii, P. kesiya and P. maximinoi in Colombian plantations and nurseries. Plants displaying symptoms associated with a F. circinatum-like infection (i.e., stem cankers and branch die-back on trees in plantations and root or collar rot of seedlings) were sampled. A total of 57 isolates were collected and characterised based on DNA sequence data for the translation elongation factor 1-alpha and beta-tubulin gene regions. Phylogenetic analyses of these data allowed for the identification of more than 10 Fusarium species. These included F. circinatum, F. oxysporum, species within the Fusarium solani species complex and seven novel species in the Fusarium fujikuroi species complex (formerly the Gibberella fujikuroi species complex), five of which are described here as new. Selected isolates of the new species were tested for their pathogenicity on Pinus patula and compared with that of F. circinatum. Of these, F. marasasianum, F. parvisorum and F. sororula displayed levels of pathogenicity to P. patula that were comparable with that of F. circinatum. These apparently emerging pathogens thus pose a significant risk to forestry in Colombia and other parts of the world. PMID- 26955194 TI - New species, hyper-diversity and potential importance of Calonectria spp. from Eucalyptus in South China. AB - Plantation forestry is expanding rapidly in China to meet an increasing demand for wood and pulp products globally. Fungal pathogens including species of Calonectria represent a serious threat to the growth and sustainability of this industry. Surveys were conducted in the Guangdong, Guangxi and Hainan Provinces of South China, where Eucalyptus trees in plantations or cuttings in nurseries displayed symptoms of leaf blight. Isolations from symptomatic leaves and soils collected close to infected trees resulted in a large collection of Calonectria isolates. These isolates were identified using the Consolidated Species Concept, employing morphological characters and DNA sequence comparisons for the beta tubulin, calmodulin, histone H3 and translation elongation factor 1-alpha gene regions. Twenty-one Calonectria species were identified of which 18 represented novel taxa. Of these, 12 novel taxa belonged to Sphaero-Naviculate Group and the remaining six to the Prolate Group. Southeast Asia appears to represent a centre of biodiversity for the Sphaero-Naviculate Group and this fact could be one of the important constraints to Eucalyptus forestry in China. The remarkable diversity of Calonectria species in a relatively small area of China and associated with a single tree species is surprising. PMID- 26955195 TI - Generic concepts in Nectriaceae. AB - The ascomycete family Nectriaceae (Hypocreales) includes numerous important plant and human pathogens, as well as several species used extensively in industrial and commercial applications as biodegraders and biocontrol agents. Members of the family are unified by phenotypic characters such as uniloculate ascomata that are yellow, orange-red to purple, and with phialidic asexual morphs. The generic concepts in Nectriaceae are poorly defined, since DNA sequence data have not been available for many of these genera. To address this issue we performed a multi gene phylogenetic analysis using partial sequences for the 28S large subunit (LSU) nrDNA, the internal transcribed spacer region and intervening 5.8S nrRNA gene (ITS), the large subunit of the ATP citrate lyase (acl1), the RNA polymerase II largest subunit (rpb1), RNA polymerase II second largest subunit (rpb2), alpha actin (act), beta-tubulin (tub2), calmodulin (cmdA), histone H3 (his3), and translation elongation factor 1-alpha (tef1) gene regions for available type and authentic strains representing known genera in Nectriaceae, including several genera for which no sequence data were previously available. Supported by morphological observations, the data resolved 47 genera in the Nectriaceae. We re evaluated the status of several genera, which resulted in the introduction of six new genera to accommodate species that were initially classified based solely on morphological characters. Several generic names are proposed for synonymy based on the abolishment of dual nomenclature. Additionally, a new family is introduced for two genera that were previously accommodated in the Nectriaceae. PMID- 26955196 TI - Phylogeny of tremellomycetous yeasts and related dimorphic and filamentous basidiomycetes reconstructed from multiple gene sequence analyses. AB - The Tremellomycetes (Basidiomycota) contains a large number of unicellular and dimorphic fungi with stable free-living unicellular states in their life cycles. These fungi have been conventionally classified as basidiomycetous yeasts based on physiological and biochemical characteristics. Many currently recognised genera of these yeasts are mainly defined based on phenotypical characters and are highly polyphyletic. Here we reconstructed the phylogeny of the majority of described anamorphic and teleomorphic tremellomycetous yeasts using Bayesian inference, maximum likelihood, and neighbour-joining analyses based on the sequences of seven genes, including three rRNA genes, namely the small subunit of the ribosomal DNA (rDNA), D1/D2 domains of the large subunit rDNA, and the internal transcribed spacer regions (ITS 1 and 2) of rDNA including 5.8S rDNA; and four protein-coding genes, namely the two subunits of the RNA polymerase II (RPB1 and RPB2), the translation elongation factor 1-alpha (TEF1) and the mitochondrial gene cytochrome b (CYTB). With the consideration of morphological, physiological and chemotaxonomic characters and the congruence of phylogenies inferred from analyses using different algorithms based on different data sets consisting of the combined seven genes, the three rRNA genes, and the individual protein-coding genes, five major lineages corresponding to the orders Cystofilobasidiales, Filobasidiales, Holtermanniales, Tremellales, and Trichosporonales were resolved. A total of 45 strongly supported monophyletic clades with multiple species and 23 single species clades were recognised. This phylogenetic framework will be the basis for the proposal of an updated taxonomic system of tremellomycetous yeasts that will be compatible with the current taxonomic system of filamentous basidiomycetes accommodating the 'one fungus, one name' principle. PMID- 26955197 TI - Phylogeny of yeasts and related filamentous fungi within Pucciniomycotina determined from multigene sequence analyses. AB - In addition to rusts, the subphylum Pucciniomycotina (Basidiomycota) includes a large number of unicellular or dimorphic fungi which are usually studied as yeasts. Ribosomal DNA sequence analyses have shown that the current taxonomic system of the pucciniomycetous yeasts which is based on phenotypic criteria is not concordant with the molecular phylogeny and many genera are polyphyletic. Here we inferred the molecular phylogeny of 184 pucciniomycetous yeast species and related filamentous fungi using maximum likelihood, maximum parsimony and Bayesian inference analyses based on the sequences of seven genes, including the small subunit ribosomal DNA (rDNA), the large subunit rDNA D1/D2 domains, the internal transcribed spacer regions (ITS 1 and 2) of rDNA including the 5.8S rDNA gene; the nuclear protein-coding genes of the two subunits of DNA polymerase II (RPB1 and RPB2) and the translation elongation factor 1-alpha (TEF1); and the mitochondrial gene cytochrome b (CYTB). A total of 33 monophyletic clades and 18 single species lineages were recognised among the pucciniomycetous yeasts employed, which belonged to four major lineages corresponding to Agaricostilbomycetes, Cystobasidiomycetes, Microbotryomycetes and Mixiomycetes. These lineages remained independent from the classes Atractiellomycetes, Classiculomycetes, Pucciniomycetes and Tritirachiomycetes formed by filamentous taxa in Pucciniomycotina. An updated taxonomic system of pucciniomycetous yeasts implementing the 'One fungus = One name' principle will be proposed based on the phylogenetic framework presented here. PMID- 26955198 TI - Multigene phylogeny and taxonomic revision of yeasts and related fungi in the Ustilaginomycotina. AB - The subphylum Ustilaginomycotina (Basidiomycota, Fungi) comprises mainly plant pathogenic fungi (smuts). Some of the lineages possess cultivable unicellular stages that are usually classified as yeast or yeast-like species in a largely artificial taxonomic system which is independent from and largely incompatible with that of the smut fungi. Here we performed phylogenetic analyses based on seven genes including three nuclear ribosomal RNA genes and four protein coding genes to address the molecular phylogeny of the ustilaginomycetous yeast species and their filamentous counterparts. Taxonomic revisions were proposed to reflect this phylogeny and to implement the 'One Fungus = One Name' principle. The results confirmed that the yeast-containing classes Malasseziomycetes, Moniliellomycetes and Ustilaginomycetes are monophyletic, whereas Exobasidiomycetes in the current sense remains paraphyletic. Four new genera, namely Dirkmeia gen. nov., Kalmanozyma gen. nov., Golubevia gen. nov. and Robbauera gen. nov. are proposed to accommodate Pseudozyma and Tilletiopsis species that are distinct from the other smut taxa and belong to clades that are separate from those containing type species of the hitherto described genera. Accordingly, new orders Golubeviales ord. nov. with Golubeviaceae fam. nov. and Robbauerales ord. nov. with Robbaueraceae fam. nov. are proposed to accommodate the sisterhood of Golubevia gen. nov. and Robbauera gen. nov. with other orders of Exobasidiomycetes. The majority of the remaining anamorphic yeast species are transferred to corresponding teleomorphic genera based on strongly supported phylogenetic affinities, resulting in the proposal of 28 new combinations. The taxonomic status of a few Pseudozyma species remains to be determined because of their uncertain phylogenetic positions. We propose to use the term pro tempore or pro tem. in abbreviation to indicate the single-species lineages that are temporarily maintained. PMID- 26955200 TI - Common but different: The expanding realm of Cladosporium. AB - The genus Cladosporium (Cladosporiaceae, Dothideomycetes), which represents one of the largest genera of dematiaceous hyphomycetes, has been intensively investigated during the past decade. In the process, three major species complexes (C. cladosporioides, C. herbarum and C. sphaerospermum) were resolved based on morphology and DNA phylogeny, and a monographic revision of the genus (s. lat.) published reflecting the current taxonomic status quo. In the present study a further 19 new species are described based on phylogenetic characters (nuclear ribosomal RNA gene operon, including the internal transcribed spacer regions ITS1 and ITS2, as well as partial actin and translation elongation factor 1-alpha gene sequences) and morphological differences. For a selection of the species with ornamented conidia, scanning electron microscopic photos were prepared to illustrate the different types of surface ornamentation. Surprisingly, during this study Cladosporium ramotenellum was found to be a quite common saprobic species, being widely distributed and occurring on various substrates. Therefore, an emended species description is provided. Furthermore, the host range and distribution data for several previously described species are also expanded. PMID- 26955201 TI - Revision of the Massarineae (Pleosporales, Dothideomycetes). AB - We here taxonomically revise the suborder Massarineae (Pleosporales, Dothideomycetes, Ascomycota). Sequences of SSU and LSU nrDNA and the translation elongation factor 1-alpha gene (tef1) are newly obtained from 106 Massarineae taxa that are phylogenetically analysed along with published sequences of 131 taxa in this suborder retrieved from GenBank. We recognise 12 families and five unknown lineages in the Massarineae. Among the nine families previously known, the monophyletic status of the Dictyosporiaceae, Didymosphaeriaceae, Latoruaceae, Macrodiplodiopsidaceae, Massarinaceae, Morosphaeriaceae, and Trematosphaeriaceae was strongly supported with bootstrap support values above 96 %, while the clades of the Bambusicolaceae and the Lentitheciaceae are moderately supported. Two new families, Parabambusicolaceae and Sulcatisporaceae, are proposed. The Parabambusicolaceae is erected to accommodate Aquastroma and Parabambusicola genera nova, as well as two unnamed Monodictys species. The Parabambusicolaceae is characterised by depressed globose to hemispherical ascomata with or without surrounding stromatic tissue, and multi-septate, clavate to fusiform, hyaline ascospores. The Sulcatisporaceae is established for Magnicamarosporium and Sulcatispora genera nova and Neobambusicola. The Sulcatisporaceae is characterised by subglobose ascomata with a short ostiolar neck, trabeculate pseudoparaphyses, clavate asci, broadly fusiform ascospores, and ellipsoid to subglobose conidia with or without striate ornamentation. The genus Periconia and its relatives are segregated from the Massarinaceae and placed in a resurrected family, the Periconiaceae. We have summarised the morphological and ecological features, and clarified the accepted members of each family. Ten new genera, 22 new species, and seven new combinations are described and illustrated. The complete ITS sequences of nrDNA are also provided for all new taxa for use as barcode markers. PMID- 26955203 TI - Spatiotemporal dynamics of distributed synthetic genetic circuits. AB - We propose and study models of two distributed synthetic gene circuits, toggle switch and oscillator, each split between two cell strains and coupled via quorum sensing signals. The distributed toggle switch relies on mutual repression of the two strains, and oscillator is comprised of two strains, one of which acts as an activator for another that in turn acts as a repressor. Distributed toggle switch can exhibit mobile fronts, switching the system from the weaker to the stronger spatially homogeneous state. The circuit can also act as a biosensor, with the switching front dynamics determined by the properties of an external signal. Distributed oscillator system displays another biosensor functionality: oscillations emerge once a small amount of one cell strain appears amid the other, present in abundance. Distribution of synthetic gene circuits among multiple strains allows one to reduce crosstalk among different parts of the overall system and also decrease the energetic burden of the synthetic circuit per cell, which may allow for enhanced functionality and viability of engineered cells. PMID- 26955199 TI - Towards an integrated phylogenetic classification of the Tremellomycetes. AB - Families and genera assigned to Tremellomycetes have been mainly circumscribed by morphology and for the yeasts also by biochemical and physiological characteristics. This phenotype-based classification is largely in conflict with molecular phylogenetic analyses. Here a phylogenetic classification framework for the Tremellomycetes is proposed based on the results of phylogenetic analyses from a seven-genes dataset covering the majority of tremellomycetous yeasts and closely related filamentous taxa. Circumscriptions of the taxonomic units at the order, family and genus levels recognised were quantitatively assessed using the phylogenetic rank boundary optimisation (PRBO) and modified general mixed Yule coalescent (GMYC) tests. In addition, a comprehensive phylogenetic analysis on an expanded LSU rRNA (D1/D2 domains) gene sequence dataset covering as many as available teleomorphic and filamentous taxa within Tremellomycetes was performed to investigate the relationships between yeasts and filamentous taxa and to examine the stability of undersampled clades. Based on the results inferred from molecular data and morphological and physiochemical features, we propose an updated classification for the Tremellomycetes. We accept five orders, 17 families and 54 genera, including seven new families and 18 new genera. In addition, seven families and 17 genera are emended and one new species name and 185 new combinations are proposed. We propose to use the term pro tempore or pro tem. in abbreviation to indicate the species names that are temporarily maintained. PMID- 26955204 TI - Valence, Implicated Actor, and Children's Acquiescence to False Suggestions. AB - Although adverse effects of suggestive interviewing on children's accuracy are well documented, it remains unclear as to whether these effects vary depending on the valence of and the actor implicated in suggestions. In this study, 124 3-8 year-olds participated in a classroom activity and were later questioned about positive and negative false details. The interviewer provided positive reinforcement when children acquiesced to suggestions and negative feedback when they did not. Following reinforcement or feedback, young children were comparably suggestible for positive and negative details. With age, resistance to suggestions about negative details emerged first, followed by resistance to suggestions about positive details. Across age, more negative feedback was required to induce acquiescence to negative than positive false details. Finally, children were less willing to acquiesce when they (versus the confederate) were implicated. Findings highlight the interactive effects of valence and children's age on their eyewitness performance in suggestive contexts. PMID- 26955205 TI - Design and development of self-healing dental composites. AB - The purpose of this project is to design and develop a clinically applicable self healing dental composite (SHDC). The value of resin-based dental restorations could be improved by increasing their service lives. One way to improve longevity is to obturate micro-cracks that form during or after the composite hardens in the dental cavity. Toward this end, we introduce here a new type of SHDC made with contemporary dental components plus two additional ingredients: a healing powder (HP, strongtium fluoroaluminosilicate particles) and a healing liquid (HL, aqueous solutions of polyacrylic acids) that is enclosed within silica microcapsules. As micro-cracks develop, they will break the microcapsules in their propagation path, thereby releasing HL. This liquid will then react with particles of HP exposed by the crack formation, forming an insoluble reaction product that fills and seals the cracks. The key factors to achieve this self healing of cracks are discussed. The elastic modulus of a SHDC appeared to be satisfactory. The healing process was confirmed by means of mechanical, morphological, and chemical methods. The SHDC restored micro-cracks without external intervention, thereby showing potential for increasing the service lives of dental restorations. Importantly, this SHDC contains only clinically-tested, biocompatible materials, making it readily applicable. PMID- 26955202 TI - Resolving the Phoma enigma. AB - The Didymellaceae was established in 2009 to accommodate Ascochyta, Didymella and Phoma, as well as several related phoma-like genera. The family contains numerous plant pathogenic, saprobic and endophytic species associated with a wide range of hosts. Ascochyta and Phoma are morphologically difficult to distinguish, and species from both genera have in the past been linked to Didymella sexual morphs. The aim of the present study was to clarify the generic delimitation in Didymellaceae by combing multi-locus phylogenetic analyses based on ITS, LSU, rpb2 and tub2, and morphological observations. The resulting phylogenetic tree revealed 17 well-supported monophyletic clades in Didymellaceae, leading to the introduction of nine genera, three species, two nomina nova and 84 combinations. Furthermore, 11 epitypes and seven neotypes were designated to help stabilise the taxonomy and use of names. As a result of these data, Ascochyta, Didymella and Phoma were delineated as three distinct genera, and the generic circumscriptions of Ascochyta, Didymella, Epicoccum and Phoma emended. Furthermore, the genus Microsphaeropsis, which is morphologically distinct from the members of Didymellaceae, grouped basal to the Didymellaceae, for which a new family Microsphaeropsidaceae was introduced. PMID- 26955208 TI - Shape critical properties of patterned Permalloy thin films. AB - The effects of shape and edges in magnetic elements with reduced dimensions on the magnetization reversal of cross- and framed cross-shaped Ni79Fe21 (30nm) films were studied. Remagnetization details in the stripes of the patterned structures, which had 3 MUm to 30 MUm widths and ~100 MUm lengths, were visualized by the magneto-optical indicator film technique. The magneto-optic images revealed three different types of the domain structure formation and evolution in the samples during their magnetization reversal: (i) spin rotation with growth and annihilation of a cross-tie structure in the stripes perpendicular to the applied field, (ii) nucleation and fast motion of special boundaries, which consist of a number of coupled vortices located along both edges of the stripes parallel to the applied field, and (iii) nonuniform magnetization rotation with macrodomain nucleation and domain wall motion in the large unpatterned part of the films. It was experimentally revealed that there exists a dependence of the critical field for nucleation and motion of domain walls in the parallel-to-field stripes on their width and frame width. In particular, an inverse proportionality between this nucleation field and stripe width was found. Both experimental and simulation results show that, in cases (i) and (ii), the magnetostatic fields, which are formed on the edges of the stripes and at their intersections, play a crucial role in the formation of spin inhomogeneities and switching of the samples. PMID- 26955206 TI - A meta-analysis of the Dimensional Change Card Sort: Implications for developmental theories and the measurement of executive function in children. AB - The Dimensional Change Card Sort (DCCS) is a widely used measure of executive function in children. In the standard version, children are shown cards depicting objects that vary on two dimensions (e.g., colored shapes such as red rabbits and blue boats), and are told to sort them first by one set of rules (e.g., shape) and then by another (e.g., color). Most 3-year-olds persist in sorting by the pre switch rules, whereas 5-year-olds switch flexibly. We conducted a meta-analysis of standard and experimental versions of the task (N = 69 reports, 426 conditions) to examine the influence of diverse task variations on performance. Age, how the test stimuli were labeled for the child, emphasis on conflict in the verbal introduction of the post-switch rules, and the number of pre-switch trials each independently predicted switching on the standard DCCS, whereas pre-switch feedback, practice, and task modality did not. Increasing the relative salience of the post-switch dimension was associated with higher rates of switching, and, conversely, decreasing post-switch salience was associated with lower rates of switching, and under both kinds of manipulation performance continued to be associated with age. Spatially separating the dimensional values was associated with higher rates of switching, and it was confirmed that the degree of spatial separation matters, with children benefiting most when the dimensional values are fully spatially segregated. Switch rates tended to be higher in versions on which children were prompted to label the stimuli compared to when the experimenter provided labels, and lower when reversal instructions were used in conjunction with the standard task stimuli. Theoretical and practical implications for the study and measurement of executive function in early childhood are discussed. PMID- 26955209 TI - Is dexmedetomidine a favorable agent for cerebral hemodynamics? PMID- 26955207 TI - Serum NT-proBNP Levels Are Not Related to Vitamin D Status in Young Patients with Congenital Heart Defects. AB - CONTEXT: Hypovitaminosis D frequently occurs in early life and increases with age. Vitamin D has been suggested to influence cardiac performance and N-terminal pro-type B natriuretic peptide (NT-proBNP) release in adults with heart failure. OBJECTIVES: To assess the vitamin D status and the impact of hypovitaminosis D on circulating NT-proBNP levels in young patients with congenital heart defects (CHD). DESIGN AND PATIENTS: This cross-sectional study included the assessment of serum 25-hydroxyvitamin D (25OHD), parathyroid function markers, and NT-proBNP levels in a series of 230 young in-patients (117 females, 113 males; 6.4 (4.0 9.1) years (median, interquartile range)) with CHD. RESULTS: Serum 25OHD levels <20 ng/mL were detected in 55.3% of patients. Optimal 25OHD levels (>30 ng/mL) occurred in 25% of patients. Serum 25OHD levels inversely correlated with age (r = -0.169, P = 0.013) and height standard deviation score (r = -0.269, P = 0.001). After correction for age, 25OHD negatively correlated with serum PTH levels (beta = -0.200, P = 0.002). PTH levels above the upper quartile (44 pg/mL) occurred in 32% of hypovitaminosis D patients. Serum NT-proBNP levels were not correlated with 25OHD and PTH levels. CONCLUSIONS: Half of the young CHD patients were diagnosed with 25OHD deficiency and a third of hypovitaminosis D patients experienced hyperparathyroidism. Nonetheless, serum NT-proBNP levels were not associated with hypovitaminosis D as well as hyperparathyroidism. PMID- 26955210 TI - Comparison of upper lip bite test and ratio of height to thyromental distance with other airway assessment tests for predicting difficult endotracheal intubation. AB - BACKGROUND: Various anatomical measurements and noninvasive clinical tests, singly or in various combinations can be performed to predict difficult intubation. Upper lip bite test (ULBT) and ratio of height to thyromental distance (RHTMD) are claimed to have high predictability. Hence, we have conducted this study to compare the predictive value of ULBT and RHTMD with the following parameters: Mallampati grading, inter-incisor gap, thyromental distance, sternomental distance, head and neck movements, and horizontal length of mandible for predicting difficult intubation. MATERIALS AND METHODS: In this single blinded, prospective, observational study involving 170 adult patients of either sex belonging to American Society of Anesthesiologists physical Status I III scheduled to undergo general anesthesia were recruited. All patients were subjected to the preoperative airway assessment and, the above parameters were recorded correlated with Cormack and Lehane grade and analyzed. The number of intubation attempts and use of intubation aids were also noted. RESULTS: ULBT and RHTMD had highest sensitivity (96.64%, 90.72%), specificity (82.35%, 80.39%), positive predictive value (92.74%, 91.53%), and negative predictive value (91.3%, 78.8%), respectively, compared to other parameters. While odds ratio and likelihood ratio >1 for all the tests. CONCLUSION: ULBT can be used as a simple bedside screening test for prediction of difficult intubation, but it should be combined with other airway assessment tests for better airway predictability. RHTMD can also be used as an acceptable alternative. PMID- 26955211 TI - Cerebral vascular effects of loading dose of dexmedetomidine: A Transcranial Color Doppler study. AB - BACKGROUND: Dexmedetomidine has been widely used in critical care settings because of its property of maintaining stable hemodynamics and inducing conscious sedation. The use of dexmedetomidine is in increasing trend particularly in patients with neurological disorders. Very few studies have focused on the cerebral hemodynamic effects of dexmedetomidine. This study is aimed to address this issue. METHODS: Thirty patients without any intracranial pathology were included in this study. Middle cerebral artery flow velocity obtained from transcranial color Doppler was used to assess the cerebral hemodynamic indices. Mean flow velocity (mFV), pulsatility index (PI), cerebral vascular resistant index (CVRi), estimated cerebral perfusion pressure (eCPP), and zero flow pressure (ZFP) were calculated bilaterally at baseline and after infusion of injection Dexmedetomidine 1 mcg/Kg over 10 min. RESULTS: Twenty-six patients completed the study protocol. After administration of loading dose of dexmedetomidine, mFV and eCPP values were significantly decreased in both hemispheres (P < 0.05); PI, CVRi, and ZFP values showed significant increase (P < 0.05) after dexmedetomidine infusion. CONCLUSION: Increase in PI, CVRi, and ZFP suggests that there is a possibility of an increase in distal cerebral vascular resistance (CVR) with loading dose of dexmedetomidine. Decrease in mFV and eCPP along with an increase in CVR may lead to a decrease in cerebral perfusion. This effect can be exaggerated in patients with preexisting neurological illness. Further studies are needed to evaluate the effect of dexmedetomidine on various other pathological conditions involving brain like traumatic brain injury and vascular malformations. PMID- 26955212 TI - Impact of dialysis practice patterns on outcomes in acute kidney injury in Intensive Care Unit. AB - AIM: Recent advances in dialysis therapy have made an impact on the clinical practice of renal replacement therapy (RRT) in acute kidney injury (AKI) in Intensive Care Unit (ICU). We studied the impact of RRT practice changes on outcomes in AKI in ICU over a period of 8 years. SUBJECTS AND METHODS: AKI patients requiring RRT in ICU referred to a nephrologist during two different periods (period-1: Between May 2004 and May 2007, n = 69; period-2: Between August 2008 and May 2011, n = 93) were studied. The major changes in the dialysis practice during the period-2, compared to period-1 were introduction of prolonged intermittent RRT (PIRRT), early dialysis for metabolic acidosis, early initiation of RRT for anuria and positive fluid balance and use of bicarbonate-based fluids for continuous RRT (CRRT) instead of lactate buffer. The primary study outcome was 28-day hospital mortality. RESULTS: The mean age was 53.8 +/- 16.1 years and 72.6% were male. Introduction of PIRRT resulted in 37% reduction in utilization of CRRT during period-2 (from 85.5% to 53.7%). The overall mortality was high (68%) but was significantly reduced during period-2 compared to period-1 (59% vs. 79.7%, P = 0.006). Metabolic acidosis but not the mode of RRT, was the significant factor which influenced mortality. CONCLUSIONS: Adaption of PIRRT resulted in 37% reduction of utilization of CRRT. The mortality rate was significantly reduced during the period of adaption of PIRRT, possibly due to early initiation of RRT in the latter period for indications such as anuria and metabolic acidosis. PMID- 26955213 TI - Measurement of muscle strength with handheld dynamometer in Intensive Care Unit. AB - BACKGROUND: Intensive Care Unit (ICU) acquired weakness is a common complication in critically ill patients affecting their prognosis. The handheld dynamometry is an objective method in detecting minimum muscle strength change, which has an impact on the physical function of ICU survivors. The minimal change in the force can be measured in units of weight such as pounds or kilograms. AIM OF THE STUDY: To detect the changes in peripheral muscle strength with handheld dynamometer in the early stage of ICU stay and to observe the progression of muscle weakness. METHODOLOGY: Three upper and three lower limb muscles force measured with handheld dynamometer during ICU stay. Data were analyzed using repeated measures ANOVA to detect changes in force generated by muscle on alternate days of ICU stay. RESULTS: There was a reduction in peripheral muscle strength from day 3 to day 5 as well from day 5 to day 7 of ICU stay (P < 0.01). The average reduction in peripheral muscle strength was 11.8% during ICU stay. CONCLUSION: This study showed a progressive reduction in peripheral muscle strength as measured by handheld dynamometer during early period of ICU stay. PMID- 26955214 TI - Illness severity and organ dysfunction scoring in Pediatric Intensive Care Unit. AB - The illness severity scoring systems provide objective measures for inter- and intra-unit comparisons with time and also provide useful information for comparing the severity of illness of patients, at the time of enrollment into clinical trials. These scores are an essential part of the improvement in clinical decisions and in stratifying patients with poor outcomes. Appropriate application of these models helps in decision-making at the right time and in decreasing mortality. However, it is also important to note that the choice of illness scores should accurately match the setting in which they are designed. In Indian setting, there is no Pediatric Intensive Care Unit illness severity score is designed until now as per our patient profile and resources. The purpose of this review article is to provide an idea regarding the evolution of illness severity scores in developed countries till date along with their utility. This review emphasizes the need for the development of pediatric illness severity score as per the local resources. PMID- 26955215 TI - Parenteral nutrition support: Beyond gut feeling? Quality control study of parenteral nutrition practices in a Tertiary Care Hospital. AB - BACKGROUND: Enteral nutrition (EN) is preferred over parenteral nutrition (PN) in hospitalized patients based on International consensus guidelines. Practice patterns of PN in developing countries have not been documented. OBJECTIVES: To assess practice pattern and quality of PN support in a tertiary hospital setting in Chennai, India. METHODS: Retrospective record review of patients admitted between February 2010 and February 2012. RESULTS: About 351,008 patients were admitted to the hospital in the study period of whom 29,484 (8.4%) required nutritional support. About 70 patients (0.24%) received PN, of whom 54 (0.18%) received PN for at least three days. Common indications for PN were major gastrointestinal surgery (55.6%), intolerance to EN (25.9%), pancreatitis (5.6%), and gastrointestinal obstruction (3.7%). CONCLUSIONS: The proportion of patients receiving PN was very low. Quality issues were identified relating to appropriateness of indication and calories and proteins delivered. This study helps to introspect and improve the quality of nutrition support. PMID- 26955216 TI - Bilateral acute angle closure glaucoma following a snake bite: Are we missing it? AB - INTRODUCTION: We report a case series of acute angle closure following snake bite, their clinical features, treatment, and the outcomes. MATERIALS AND METHODS: Ocular examination was done in all the snake bite victims admitted over 1-year period. The systemic status, presenting intraocular pressure (IOP), treatment instituted, and outcomes were recorded for all cases of acute angle closure. RESULTS: Six patients developed angle closure following snake bite. Average IOP was in the range of 32-56 mmHg. Treatment was initiated as for cases of acute angle closure. Two patients succumbed and the other four recovered, had normal IOP at follow-up. CONCLUSION: Acute angle closure glaucoma is a rare complication of snake bite. Timely detection and management will result in good visual prognosis. Treating physicians should be aware of this rare sight threatening complication so that a preliminary ophthalmic examination can be sought and the visual morbidity be prevented. PMID- 26955217 TI - Prone position and pressure control inverse ratio ventilation in H1N1 patients with severe acute respiratory distress syndrome. AB - AIM: To observe the 28 and 90 days mortality associated with prone position and assist control-pressure control (with inverse ratio) ventilation (ACPC-IRV). MATERIALS AND METHODS: All patients who were admitted to our medical Intensive Care Unit (ICU) who are positive for H1N1 viral infection with severe acute respiratory distress syndrome (ARDS) and requiring invasive mechanical ventilation in prone position were included in our prospective observational study. Six patients who are positive for H1N1 required invasive ventilation in prone position. These patients were planned to ventilate in prone for 16 h and in supine for 8 h daily until P/F ratio >150 with FiO2 of 0.6 or less and positive end-expiratory pressure <10 cm of H2 O. RESULTS: At admission, among these six patients the mean tidal volume generated was about 376.6 ml which was in the range of 6-8 ml/kg predicted body weight. The mean lung injury score was 3.79, mean PaO2 /FiO2 ratio was 52.66 and mean oxygenation index was 29.83. The mean duration of ventilation was 9.4 days (225.6 h). The ICU length of stay was 11.16 days. There was no mortality at 28 and 90 days. CONCLUSION: Early prone combined with ACPC-IRV in H1N1 patients having severe ARDS can be used as a rescue therapy and it should be confirmed by large observational studies. PMID- 26955218 TI - Strongyloides stercoralis hyperinfection in patient with autoimmune hepatitis and purpura fulminans. AB - Strongyloidiosis is usually an asymptomatic chronic nematodal disease. The term hyperinfection is used to denote autoinfection, a phenomenon in which the number of worms increases enormously. Development or exacerbation of gastrointestinal and pulmonary symptoms is seen, (A) and the detection of increased numbers of larvae in stool and or sputum is the hallmark. It is known to occur with a change in immune status of the host; this can occur due to immunosuppressants. Cytomegalovirus (CMV) is also known to suppress host immunity. Due to the nonspecific presentation, the diagnosis is frequently missed, and the outcome remains poor with 15-87% mortality despite therapy. We report here a case of Strongyloides stercoralis hyperinfection following immunosuppressive therapy for autoimmune hepatitis and concomitant CMV infection with purpura fulminance and frank sepsis, with fatal outcome. PMID- 26955219 TI - Stuck with pancytopenia in dengue fever: Evoke for hemophagocytic syndrome. AB - The hemophagocytic syndrome is an atypical and rare manifestation of dengue fever (DF). We describe a 15-year-old girl developing DF associated hemophagocytic syndrome who responded with supportive treatment. PMID- 26955220 TI - Cashew nut shell liquid poisoning. PMID- 26955221 TI - Central venous pressure and peripheral venous pressure, however correlated are still both in the gray-area. PMID- 26955222 TI - Musculoskeletal melioidosis: An under-diagnosed entity in developing countries. AB - BACKGROUND: Melioidosis is a saprophytic infectious disease caused by Gram negative soil-dwelling bacillus Burkholderia pseudomallei. MATERIALS & METHODS: We report three cases of musculoskeletal melioidosis that are presented to our department from 2011 to 2013. RESULTS: One of the patients died due to post septicemic ARDS. The other two patients have recovered fully and are followed up for minimum of 6 months. There were no recurrences. CONCLUSIONS: Though musculoskeletal infection due to melioidosis is not common in India, new cases are being reported from Karnataka, Goa and Southern Maharashtra. The need for diagnosing this entity is due to the fact that the septicemic form has a mortality rate that exceeds 90%, and though culture sensitivity report shows susceptibility to various antibiotics, the infection responds to only specific set of antibiotics i.e. intravenous ceftazidime and combination of trimethoprim and sulfamethoxazole. PMID- 26955223 TI - A new method for tibial torsion measurement by computerized tomography. AB - BACKGROUND: Computerized tomography (CT) is the gold standard technique for tibial torsion assessment. This study compared two methods of tibial torsion assessment and proposed a new method, which could be of value in cases of abnormal fibular changes. METHODS: The CT-scanograms of 60 participants were assessed by using two different techniques, differed in determination of the distal tibial axis. RESULTS: The interobserver reliability was 0.861 and 0.863 in the first and second methods, respectively. The intraobserver reliability in both measurement methods was 0.868. CONCLUSIONS: We proposed a reliable method, independent of the fibular midpoint, in assessment of tibial torsion by CT. PMID- 26955224 TI - The Scandinavian Total Ankle Replacement and the ideal biomechanical requirements of ankle replacements. AB - The complex anatomy of the articular bone surfaces, ligaments, tendon attachments and muscles makes the ankle joint difficult to replicate in prosthetic replacements. Ever since the early 1970s, which saw the dawn of the first total ankle replacements, there have been numerous other attempts at replicating the joint, often with poor clinical outcomes. The anatomy of the ankle is discussed, followed by evidence of the normal ankle biomechanics and the ideal requirements of an ankle replacement. We focus on the Scandinavian Total Ankle Replacement and evaluate whether these requirements have been met. PMID- 26955225 TI - Long-term follow-up of the Copeland mark III shoulder resurfacing hemi arthroplasty. AB - BACKGROUND: Shoulder humeral resurfacing is being performed in increasing numbers. We report the long-term outcome of patients with the Copeland mark III humeral resurfacing hemi-arthroplasty. METHODS: Ninety-five shoulder hemi arthroplasties were performed in 85 patients, from 1994 to 2003. Oxford Shoulder Score (OSS) and short form 12 (SF-12) questionnaires were administered. RESULTS: At 12-year follow-up, 49 patients were alive. The OSS was 35.2 and SF-12 score was 83. There were 3 revision operations and 95% survivorship at 18 years. CONCLUSION: This prosthesis has a low revision rate with few post-operative complications and good patient-reported outcome in an elderly population. PMID- 26955226 TI - Percutaneous repair of the Achilles tendon rupture in athletic population. AB - AIMS: This review was designed in order to study the percutaneous repair of Achilles tendon rupture in athletic population. We present a comprehensive description of clinical, functional outcomes, complications, with emphasis on patients' level, and time of return to sports. METHODS: We proceeded to a systematic search of Medline (PubMED), Cochrane, and Scopus databases using keywords "Achilles Tendon", "Percutaneous Repair", "Percutaneous suturing", "Subcutaneous repair", "Subcutaneous suturing", "Athletes", and "Athletic" to identify articles or abstracts written in English. RESULTS: Thirteen studies, including 670 patients, could be identified. A variety of percutaneous repair techniques were performed. Re-rupture rate was very low. The most frequent complication was sural nerve damage. Average functional outcomes were satisfying. Up to 91.4% continued practicing sports after surgery. Furthermore, 78-84% returned to the same or higher sports level. Average time of return was 18 weeks in 9 studies. CONCLUSION: Percutaneous repair of Achilles tendon rupture is an excellent perspective for athletic population. Low re-rupture rate and impressing level of return to sports allow athletes to continue their recreational activities or careers. PMID- 26955227 TI - "Reverse Bohlman" technique for the treatment of high grade spondylolisthesis in an adult population. AB - BACKGROUND/AIMS: Surgical techniques for effective high-grade spondylolisthesis (HGS) remain controversial. This study aims to evaluate radiographic/clinical outcomes in HGS patients treated using modified "Reverse Bohlman" (RB) technique. METHODS: Review of consecutive HGS patients undergoing RB at a single university center from 2006 to 2013. Clinical, surgical, radiographic parameters collected. RESULTS: Six patients identified: five with L5-S1 HGS with L4-L5 instability and one had an L4-5 isthmic spondylolisthesis and grade 1 L5-S1 isthmic spondylolisthesis. Two interbody graft failures and one L5-S1 pseudoarthrosis. Postoperative improvement of anterolisthesis (62.3% vs. 49.6%, p = 0.003), slip angle (10 vs. 5 degrees , p = 0.005), and lumbar lordosis (49 vs. 57.5 degrees , p = 0.049). CONCLUSIONS: RB technique for HGS recommended when addressing adjacent level instability/slip. PMID- 26955228 TI - Platelet-rich plasma versus open surgical release in chronic tennis elbow: A retrospective comparative study. AB - PURPOSE: To compare short and mid-term results in the treatment of chronic elbow tendinosis with platelet-rich plasma (PRP) or Nirschl surgical technique. METHOD: A retrospective study was conducted on patients with chronic lateral epicondylitis, treated by Nirschl surgical technique (50 elbows) or PRP (60 elbows). Outcome was evaluated with Visual Analog Score (VAS), Mayo Elbow Scores and grip strength measurements. RESULTS: VAS and Mayo Elbow Scores of the PRP group had improved as a mean of 83% (p = 0.0001), 74% (p = 0.0001) over baseline and 34.2 pounds gain of grip strength. CONCLUSION: The PRP seems to be better for pain relief and functionality in the short and mid-term periods. PMID- 26955230 TI - Fracture neck of femur - Still an unsolved issue. PMID- 26955229 TI - The management of greater trochanteric pain syndrome: A systematic literature review. AB - Greater trochanteric pain syndrome (GTPS) is a common cause of lateral hip pain. Most cases respond to conservative treatments with a few refractory cases requiring surgical intervention. For many years, this condition was believed to be caused by trochanteric bursitis, with treatments targeting the bursitis. More recently gluteal tendinopathy/tears have been proposed as potential causes. Treatments are consequently developing to target these proposed pathologies. At present there is no defined treatment protocol for GTPS. The purpose of this systematic literature review is to evaluate the current evidence for the effectiveness of GTPS interventions, both conservative and surgical. PMID- 26955231 TI - Zika virus Infection: New Threat in Global Health. PMID- 26955232 TI - Celebrating the Achievements and Fulfilling the Mission of the Korean Association of Medical Journal Editors. PMID- 26955233 TI - Catastrophic Health Expenditures for Households with Disabled Members: Evidence from the Korean Health Panel. AB - Persons with disabilities use more health care services due to ill health and face higher health care expenses and burden. This study explored the incidence of catastrophic health expenditures of households with persons with disabilities compared to that of those without such persons. We used the Korean Health Panel (KHP) dataset for the years 2010 and 2011. The final sample was 5,610 households; 800 (14.3%) of these were households with a person with a disability and 4,810 (85.7%) were households without such a person. Households with a person with a disability faced higher catastrophic health expenditures, spending about 1.2 to 1.4 times more of their annual living expenditures for out-of-pocket medical expenses, compared to households without persons with disabilities. Households having low economic status and members with chronic disease were more likely to face catastrophic health expenditures, while those receiving public assistance were less likely. Exemption or reduction of out-of-pocket payments in the National Health Insurance and additional financial support are needed so that the people with disabilities can use medical services without suffering financial crisis. PMID- 26955234 TI - Association between Short Maternal Height and Low Birth Weight: a Hospital-based Study in Japan. AB - Anthropometry measurements, such as height and weight, have recently been used to predict poorer birth outcomes. However, the relationship between maternal height and birth outcomes remains unclear. We examined the effect of shorter maternal height on low birth weight (LBW) among 17,150 pairs of Japanese mothers and newborns. Data for this analysis were collected from newborns who were delivered at a large hospital in Japan. Maternal height was the exposure variable, and LBW and admission to the neonatal intensive care unit were the outcome variables. Logistic regression models were used to estimate the associations. The shortest maternal height quartile (131.0-151.9 cm) was related to LBW (OR 1.91 [95% CI 1.64, 2.22]). The groups with the second (152.0-157.9 cm) and the third shortest maternal height quartiles (158.0-160.9 cm) were also related to LBW. A P trend with one quartile change also showed a significant relationship. The relationship between maternal height and NICU admission disappeared when the statistical model was adjusted for LBW. A newborn's small size was one factor in the relationship between shorter maternal height and NICU admission. In developed countries, shorter mothers provide a useful prenatal target to anticipate and plan for LBW newborns and NICU admission. PMID- 26955235 TI - Dual-Blocking of PI3K and mTOR Improves Chemotherapeutic Effects on SW620 Human Colorectal Cancer Stem Cells by Inducing Differentiation. AB - Cancer stem cells (CSCs) have tumor initiation, self-renewal, metastasis and chemo-resistance properties in various tumors including colorectal cancer. Targeting of CSCs may be essential to prevent relapse of tumors after chemotherapy. Phosphatidylinositol-3-kinase (PI3K) and mammalian target of rapamycin (mTOR) signals are central regulators of cell growth, proliferation, differentiation, and apoptosis. These pathways are related to colorectal tumorigenesis. This study focused on PI3K and mTOR pathways by inhibition which initiate differentiation of SW620 derived CSCs and investigated its effect on tumor progression. By using rapamycin, LY294002, and NVP-BEZ235, respectively, PI3K and mTOR signals were blocked independently or dually in colorectal CSCs. Colorectal CSCs gained their differentiation property and lost their stemness properties most significantly in dual-blocked CSCs. After treated with anti cancer drug (paclitaxel) on the differentiated CSCs cell viability, self-renewal ability and differentiation status were analyzed. As a result dual-blocking group has most enhanced sensitivity for anti-cancer drug. Xenograft tumorigenesis assay by using immunodeficiency mice also shows that dual-inhibited group more effectively increased drug sensitivity and suppressed tumor growth compared to single-inhibited groups. Therefore it could have potent anti-cancer effects that dual-blocking of PI3K and mTOR induces differentiation and improves chemotherapeutic effects on SW620 human colorectal CSCs. PMID- 26955236 TI - Multiple Human Papillomavirus Infection Is Associated with High-Risk Infection in Male Genital Warts in Ulsan, Korea. AB - Further understanding of male human papillomavirus (HPV) infection is necessary to prevent infection in men, as well as transmission to women. In our current study, we investigated patterns of HPV infection and genotype distributions in male genital warts using the Anyplex II HPV28 Detection kit. We reviewed the medical records of 80 male patients who presented to 5 neighborhood clinics in Ulsan, Korea, for the treatment of genital warts between April 2014 and January 2015. All patients underwent HPV genotyping. The prevalence and characteristics of HPV infection were analyzed, and the patterns of HPV infection according to age were assessed. Among the study patients, 13 (16.3%) were negative for HPV infection, 46 (57.3%) were infected with low-risk HPV, and 21 (26.3%) were infected with high-risk HPV. Patients with multiple HPV infection were more likely to have high-risk HPV infection (P = 0.001). The prevalence of HPV infection was much higher in samples obtained by tissue excision due to a definite lesion (P = 0.001). There were no differences in high-risk HPV infection (P = 0.459), multiple HPV infection (P = 0.185), and recurrence at diagnosis (P = 0.178) according to age. HPV-6 and HPV-11 were the most common type overall (39.7% and 13.8%, respectively). HPV-16 and HPV-18 were the most common high-risk infections (both 3.4%). HPV infection is not only commonly encountered in male genital warts, but is also accompanied by high-risk HPV and multiple infections. PMID- 26955237 TI - Predictors of Poor Retention in Care of HIV-infected Patients Receiving Antiretroviral Therapy in Korea: Five-Year Hospital-based Retrospective Cohort Study. AB - Poor retention in care (RIC) is associated with higher antiretroviral therapy (ART) failure and worse survival. Identifying high risk patients for poor RIC is important for targeted intervention. A retrospective cohort study was conducted at a tertiary care hospital in Korea. HIV-infected patients initiating ART during 2002-2008 were included. 5 year-RIC was measured by hospital visit constancy (HVC) at 5 years after initiating ART. Among 247 enrolled patients, 179 (72.5%) remained in care, 20 (8.1%) were transferred to other hospitals, 9 (3.6%) died and 39 (15.8%) were lost to follow-up. We compared the demographic, psychosocial, and clinical characteristics between the groups with 100% HVC (n = 166, 67.2%) and <= 50% HVC (n = 33, 13.4%). In multivariable analysis, ART-starting age <= 30 years (odds ratio [OR] 4.08 vs. > 50; 95% confidence interval [CI] 1.10-15.15, P = 0.036), no non-HIV related comorbidity (OR 2.94 vs. comorbidity >= 1; 95% CI 1.02-8.49, P = 0.046), baseline CD4 cell count > 300 cells/MUL (OR 3.58 vs. <= 200; 95% CI 1.33-9.65, P = 0.012) were significant predictable factors of poor RIC. HIV/AIDS care-givers should pay attention to young patients with higher baseline CD4 cell counts and no non-HIV related comorbidity. PMID- 26955238 TI - Urinary Albumin Excretion and Vascular Function in Rheumatoid Arthritis. AB - Rheumatoid arthritis (RA) is associated with significant cardiovascular (CV) morbidity and mortality. Increased urinary albumin excretion is a marker of CV risk. There are only few data on urinary albumin excretion in RA patients. Aim of the present study was to investigate urinary albumin excretion in RA patients and analyze, whether there is an association between urinary albumin excretion and vascular function as measured by the augmentation index (AIx). In a total of 341 participants (215 with RA, 126 without RA) urinary albumin-creatinine ratio (ACR) was determined and the AIx was measured. The Kolmogorov-Smirnov-test was used to cluster patient groups whose distributions of ACR can be considered to be equal. A crude analysis showed a median ACR of 6.6 mg/g in the RA group and 5.7 mg/g in patients without RA (P > 0.05). In order to account for diabetes (DM) we formed 4 distinct patient groups. Group 1: RA-/DM- (n = 74); group 2: RA+/DM- (n = 195); group 3: RA-/DM+ (n = 52); group 4: RA+/DM+ (n = 20). Clustering of these groups revealed two distinct patient groups: those without RA and DM, and those with either RA or DM or both. The latter group showed statistically significant higher ACR (median 8.1 mg/g) as the former (median 4.5 mg/g). We found no significant correlation between AIx and ACR. Urinary albumin excretion in patients with RA or DM or both is higher than in subjects without RA and DM. This can be seen as a sign of vascular alteration and increased CV risk in these patients. PMID- 26955239 TI - Elevated Erythrocyte Sedimentation Rate Is Predictive of Interstitial Lung Disease and Mortality in Dermatomyositis: a Korean Retrospective Cohort Study. AB - Interstitial lung disease (ILD) is a major cause of death in patients with dermatomyositis (DM). This study was aimed to examine the utility of the erythrocyte sedimentation rate (ESR) as a predictor of ILD and prognostic marker of mortality in patients with DM. One hundred-and-fourteen patients with DM were examined, including 28 with clinically amyopathic DM (CADM). A diagnosis of ILD was made based on high resolution computed tomography (HRCT) scans. The association between elevated ESR and pulmonary impairment and mortality was then examined. ILD was diagnosed in 53 (46.5%) of 114 DM patients. Cancer was diagnosed in 2 (3.8%) of 53 DM patients with ILD and in 24 (92.3%) of those without ILD (P < 0.001). The median ESR (50.0 mm/hour) in patients with ILD was significantly higher than that in patients without ILD (29.0 mm/hour; P < 0.001). ESR was inversely correlated with forced vital capacity (Spearman rho = - 0.303; P = 0.007) and carbon monoxide diffusing capacity (rho = - 0.319; P = 0.006). DM patients with baseline ESR >= 30 mm/hour had significantly higher mortality than those with ESR < 30 mm/hour (P = 0.002, log-rank test). Patients with a persistently high ESR despite immunosuppressive therapy was associated with higher mortality than those with a normalized ESR (P = 0.039, log-rank test). Elevated ESR is associated with increased mortality in patients with DM due to respiratory failure. Thus, monitoring ESR should be an integral part of the clinical care of DM patients. PMID- 26955240 TI - Ultrasonographic Characteristics of the Follicular Variant Papillary Thyroid Cancer According to the Tumor Size. AB - Follicular variant papillary thyroid cancer (FVPTC) is the second most common subtype after conventional PTC. We compared ultrasonographic (US) features of FVPTC to those of conventional PTC according to tumor size. We reviewed US findings, pathologic reports, and medical charts of 249 PTC patients with surgically proven disease (83 FVPTCs, 166 conventional PTCs) at our institution from January 2007 to December 2012. FVPTCs were divided into PTC-like and follicular neoplasm (FN)-like based on sonographic characteristics. PTC-like features were defined as having at least one malignant feature (taller-than-wide shape, infiltrative margin, marked hypoechogenicity, and micro-calcifications), whereas FN-like cancers showed oval solid features without malignant features. FVPTCs showed a higher rate of FN-like features than conventional PTCs. Of 166 conventional PTCs, 13 (7.8%) had FN-like features and 153 (92.2%) had PTC-like features, whereas of the 83 FVPTCs, 31 (37.3%) had FN-like features and 52 (62.7%) had PTC-like features. Macro-FVPTCs showed a higher rate of FN-like features than micro-FVPTCs (P < 0.001). Of 21 macro-FVPTCs, 18 (85.7%) had FN like features and 3 (14.3%) had PTC-like features, whereas of the 62 micro FVPTCs, 13 (21%) had FN-like features and 49 (79%) had PTC-like features. There were no differences in multifocality, extrathyroidal invasion, and lymph node metastasis between PTC-like FVPTCs and FN-like FVPTCs. FVPTCs showed fewer sonographic malignant features than conventional PTCs. In particular, FVPTCs larger than 1 cm had a more frequent benign sonographic appearance. Therefore, if fine-needle aspiration result is suspicious for PTC in a nodule larger than 1 cm with no suspicious US features, the possibility of FVPTC might be considered. PMID- 26955241 TI - Trends and Patterns of Hepatocellular Carcinoma Treatment in Korea. AB - Multiple therapeutic modalities are available for hepatocellular carcinoma (HCC) treatment. We aimed to evaluate the trends for HCC treatment in Korea. Recent trends and patterns in treatment modalities were assessed in HCC patients who first registered for the Health Insurance Review Assessment Service between 2008 and 2012. From 2009 to 2012, 57,690 patients were diagnosed with HCC. Transcatheter arterial chemoembolization (TACE) was the most common treatment modality for initial treatment. Curative treatment modalities like hepatic resection, liver transplantation, and local ablation therapy increased gradually. The 3 most common treatment modalities (hepatic resection, local ablation therapy, TACE) used after initial treatment in 2009 were studied. Following initial hepatic resection, 44.5% of patients required re-treatment. TACE was the most common modality (in 48.3% of cases), while 15.0% of patients received local ablation therapy. After local ablation therapy, 55.4% of patients were re treated, wherein 45.0% of patients received TACE and 31.5% received local ablation therapy. Following initial TACE, 73.9% patients were re-treated, most commonly with TACE (57.7%) followed by local ablation therapy (12.8%). While there were no significant differences between the initial and re-treatment modalities, various multiple treatments followed the initial treatment. The treatment modalities were interchangeable. PMID- 26955242 TI - The Risk of Abdominal Obesity according to the Degree of Non-Alcoholic Fatty Liver Disease in Korean Men. AB - Although non-alcoholic fatty liver disease has been reported as a cardiometabolic risk factor, the effect of non-alcoholic fatty liver is yet to be clarified on abdominal obesity. Therefore, this study was conducted to investigate the longitudinal relationship of non-alcoholic fatty liver on the development of abdominal obesity. The study participants were composed of 11,212 Korean men without abdominal obesity. They were followed up from 2005 to 2010 to be monitored for the development of abdominal obesity according to their degree of non-alcoholic fatty liver disease (normal, mild, and moderate to severe). Cox proportional hazard model was used to calculate the hazard ratios for abdominal obesity according to the degree of non-alcoholic fatty liver disease. While the average incidence was 15.5%, the incidence of abdominal obesity increased according to the degree of non-alcoholic fatty liver (normal: 11.6%, mild: 25.2%, moderate to severe: 41.0%, P < 0.001). Multivariable-adjusted hazard ratios for abdominal obesity independently increased proportionally to the degree of NAFLD (mild [1.07; 0.94-1.23], moderate to severe [1.58; 1.11-2.26], P for trend < 0.001). The risk of abdominal obesity increased proportionally to the degree of non-alcoholic fatty liver disease. This finding guarantees further studies to reveal the incidental relationship of abdominal obesity with non-alcoholic fatty liver disease. PMID- 26955243 TI - Correlations between the CagA Antigen and Serum Levels of Anti-Helicobacter pylori IgG and IgA in Children. AB - We tested correlations between anti-Helicobacter pylori IgG and IgA levels and the urease test, anti-CagA protein antibody, degree of gastritis, and age. In total, 509 children (0-15 years) were enrolled. Subjects were stratified as 0-4 years (n = 132), 5-9 years (n = 274), and 10-15 years (n = 103) and subjected to the urease test, histopathology, ELISA, and western blot using whole-cell lysates of H. pylori strain 51. The positivity rate in the urease test (P = 0.003), the degree of chronic gastritis (P = 0.021), and H. pylori infiltration (P < 0.001) increased with age. The median titer for anti-H. pylori IgG was 732.5 IU/mL at 0 4 years, 689.0 IU/mL at 5-9 years, and 966.0 IU/mL at 10-15 years (P < 0.001); the median titer for anti-H. pylori IgA was 61.0 IU/mL at 0-4 years, 63.5 IU/mL at 5-9 years, and 75.0 IU/mL at 10-15 years (P < 0.001). The CagA-positivity rate was 26.5% at 0-4 years, 36.5% at 5-9 years, and 46.6% at 10-15 years for IgG (P = 0.036), and 11.3% at 0-4 years, 18.6% at 5-9 years, and 23.3% at 10-15 years for IgA (P < 0.001). Anti-H. pylori IgG and IgA titers increased with the urease test grade, chronic gastritis degree, active gastritis, and H. pylori infiltration. Presence of CagA-positivity is well correlated with a high urease test grade and high anti-H. pylori IgG/IgA levels. PMID- 26955244 TI - Trends in Survival and Incidence of Bronchopulmonary Dysplasia in Extremely Preterm Infants at 23-26 Weeks Gestation. AB - The aim of this study was to investigate the relationship between survival and incidence of bronchopulmonary dysplasia (BPD) in extremely premature infants, and identify clinical factors responsible for this association. Medical records of 350 infants at 23-26 weeks gestation from 2000 to 2005 (period I, n = 137) and 2006 to 2010 (period II, n = 213) were retrospectively reviewed. The infants were stratified into 23-24 and 25-26 weeks gestation, and the survival, BPD incidence, and clinical characteristics were analyzed. BPD was defined as oxygen dependency at 36 weeks postmenstrual age. The overall survival rate was significantly improved in period II compared to period I (80.3% vs. 70.0%, respectively; P = 0.028), especially in infants at 23-24 weeks gestation (73.9% vs. 47.4%, respectively; P = 0.001). The BPD incidence in survivors during period II (55.0%) was significantly decreased compared to period I (67.7%; P = 0.042), especially at 25-26 weeks gestation (41.7% vs. 62.3%, respectively; P = 0.008). Significantly improved survival at 23-24 weeks gestation was associated with a higher antenatal steroid use and an improved 5-minute Apgar score. A significant decrease in BPD incidence at 25-26 weeks gestation was associated with early extubation, prolonged use of less invasive continuous positive airway pressure, and reduced supplemental oxygen. Improved perinatal and neonatal care can simultaneously lead to improved survival and decreased BPD incidence in extremely premature infants. PMID- 26955246 TI - Simplified Radiographic Damage Index for Affected Joints in Chronic Gouty Arthritis. AB - The aim of this study was to develop and validate a new radiographic damage scoring method (DAmagE index of GoUt; DAEGU) in chronic gout using plain radiography. Two independent observers scored foot x-rays from 15 patients with chronic gout according to the DAEGU method and the modified Sharp/van der Heijde (SvdH) method. The 10 metatarsophalangeal (MTP) and 2 interphalangeal (IP) joints of the first toes of both feet were scored to assess the degrees of erosion and joint space narrowing (JSN). The intraobserver and interobserver reliabilities were analyzed by calculating the intraclass correlation coefficient (ICC) and minimal detectable change (MDC). The correlation between the DAEGU and SvdH methods was analyzed by calculating the Spearman's rho correlation coefficients and Kappa coefficients. The DAEGU method was found to be highly reproducible (0.945-0.987 for the intraobserver and 0.993-0.996 for the interobserver ICC values). The erosion, JSN, and total scores exhibited strong positive correlations between the DAEGU and SvdH methods and also within each method (r = 0.860-0.969, P < 0.001 for all parameters). The DAEGU and SvdH methods were in very good agreement as determined by Kappa coefficient analysis [0.732 (0.387 1.000) for erosion and 1.000 (1.000-1.000) for JSN]. In conclusion, this study revealed that DAEGU method was a reliable and feasible tool in the assessment of radiographic damage in chronic gout. The DAEGU method may provide a more easy assessment of structural damage in chronic gout in the real clinical practice. PMID- 26955245 TI - Interleukin-6 Receptor Polymorphisms Contribute to the Neurological Status of Korean Patients with Ischemic Stroke. AB - To investigate the contribution of the interleukin-6 receptor (IL-6R) gene single nucleotide polymorphisms (SNPs) to the neurological status of Korean patients with ischemic stroke (IS), two SNPs of the IL-6R gene (rs4845617, 5 UTR; rs2228144, Ala31Ala) were selected. IS patients were classified into clinical phenotypes according to two well-defined scores: the National Institutes of Health Stroke Survey (NIHSS) and the Modified Barthel Index scores. There were 121 IS patients and 291 control subjects. The SNP rs4845617 significantly contributed to the neurological status of patients with IS (P = 0.011 in codominant model 2, P = 0.006 in recessive model, and P = 0.008 in log-additive model). Allele frequencies of rs4845617 and rs2228144 demonstrated no significant difference in IS patients and controls. The AG and GG haplotypes differed between the NIHSS 1 (NIHSS scores < 6) group and the NIHSS 2 (NIHSS scores >= 6) group in patients with IS (P = 0.014, P = 0.0024). These results suggest that rs4845617 of the IL-6R gene is associated with the neurologic status of Korean patients with IS. PMID- 26955248 TI - Epidemiology of Emergency Medical Services-Assessed Mass Casualty Incidents according to Causes. AB - To effectively mitigate and reduce the burden of mass casualty incidents (MCIs), preparedness measures should be based on MCIs' epidemiological characteristics. This study aimed to describe the epidemiological characteristics and outcomes of emergency medical services (EMS)-assessed MCIs from multiple areas according to cause. Therefore, we extracted the records of all MCIs that involved >= 6 patients from an EMS database. All patients involved in EMS-assessed MCIs from six areas were eligible for this study, and their prehospital and hospital records were reviewed for a 1-year period. The EMS-assessed MCIs were categorized as being caused by fire accidents (FAs), road traffic accidents (RTAs), chemical and biological agents (CBs), and other mechanical causes (MECHs). A total of 362 EMS-assessed MCIs were identified, with a crude incidence rate of 0.6-5.0/100,000 population. Among these MCIs, 322 were caused by RTAs. The MCIs involved 2,578 patients, and 54.3% of these patients were women. We observed that the most common mechanism of injury varied according to MCI cause, and that a higher number of patients per incident was associated with a longer prehospital time. The highest hospital admission rate was observed for CBs (16 patients, 55.2%), and most patients in RTAs and MECHs experienced non-severe injuries. The total number of deaths was 32 (1.2%). An EMS-assessed MCI database was established using the EMS database and medical records review. Our findings indicate that RTA MCIs create a burden on EMS and emergency department resources, although CB MCIs create a burden on hospitals' resources. PMID- 26955249 TI - Mammographic Breast Density Evaluation in Korean Women Using Fully Automated Volumetric Assessment. AB - The purpose was to present mean breast density of Korean women according to age using fully automated volumetric assessment. This study included 5,967 screening normal or benign mammograms (mean age, 46.2 +/- 9.7; range, 30-89 years), from cancer-screening program. We evaluated mean fibroglandular tissue volume, breast tissue volume, volumetric breast density (VBD), and the results were 53.7 +/- 30.8 cm(3), 383.8 +/- 205.2 cm(3), and 15.8% +/- 7.3%. The frequency of dense breasts and mean VBD by age group were 94.3% and 19.1% +/- 6.7% for the 30s (n = 1,484), 91.4% and 17.2% +/- 6.8% for the 40s (n = 2,706), 72.2% and 12.4% +/- 6.2% for the 50s (n = 1,138), 44.0% and 8.6% +/- 4.3% for the 60s (n = 89), 39.1% and 8.0% +/- 3.8% for the 70s (n = 138), and 39.1% and 8.0% +/- 3.5% for the 80s (n = 12). The frequency of dense breasts was higher in younger women (n = 4,313, 92.3%) than older women (n = 1,654, 59.8%). Mean VBD decreased with aging or menopause, and was about 16% for 46-year-old-Korean women, much higher than in other countries. The proportion of dense breasts sharply decreases in Korean women between 40 and 69 years of age. PMID- 26955247 TI - Is Routine Thromboprophylaxis Needed in Korean Patients Undergoing Unicompartmental Knee Arthroplasty? AB - This study was undertaken to determine the prevalence and the natural course of venous thromboembolism (VTE) without thromboprophylaxis to ascertain whether routine thromboprophylaxis is necessary following unicompartmental knee arthroplasty (UKA) in Korean patients. The medical records and multidetector row computed tomography (MDCT) imaging of the consecutive 77 UKAs in 70 patients were reviewed. In all patients, MDCTs were undertaken preoperatively and at 1-week after surgery, and VTE symptoms were evaluated. At postoperative 6-months, follow up MDCTs were undertaken in all patients in whom VTEs were newly detected after surgery. VTE lesions were newly detected in 18 (26%) of the 70 patients. However, none of the patients complained of VTE-related symptoms and MDCT demonstrated that all VTEs were small and involved limited portion without lower leg edema or pleuroparenchymal complication. At the 6-month follow up MDCT, all types of VTEs were shown to be completely resolved, regardless of their location. All of the VTE lesions maintained an asymptomatic status for 6-month after surgery. VTE following UKA in Korean patients who do not receive thromboprophylaxis seems to occur frequently, but all of the VTEs are clinically insignificant and all VTEs are spontaneously regressed. Routine thromboprophylaxis or thrombolytic treatment in Korean patients undergoing UKA may not be necessary. PMID- 26955250 TI - Genetic Variants in the Wnt Signaling Pathway Are Not Associated with Survival Outcome of Non-Small Cell Lung Cancer in a Korean Population. AB - Recently, genetic variants in the WNT signaling pathway have been reported to affect the survival outcome of Caucasian patients with early stage non-small cell lung cancer (NSCLC). We therefore attempted to determine whether these same WNT signaling pathway gene variants had similar impacts on the survival outcome of NSCLC patients in a Korean population. A total of 761 patients with stages I-IIIA NSCLC were enrolled in this study. Eight variants of WNT pathway genes were genotyped and their association with overall survival and disease-free survival were analyzed. None of the eight variants were significantly associated with overall survival or disease-free survival. There were no differences in survival outcome after stratifying the subjects according to age, gender, smoking status, and histological type. These results suggest that genetic variants in the WNT signaling pathway may not affect the survival outcome of NSCLC in a Korean population. PMID- 26955251 TI - Implementing the Use of Rapid HIV Tests in Public Health Centers in Seoul: Results of a Pilot Project, 2014. AB - To determine whether rapid HIV tests in public health centers might encourage voluntary HIV testing, a pilot project was conducted in four selected public health centers in Seoul, 2014. During the period April 10 to November 28 of pilot project, 3,356 rapid tests were performed, and 38 were confirmed as positive. The monthly average numbers of voluntary HIV tests and HIV-positive cases were up to nine-fold and six-fold larger, respectively, than those of the period before application of the rapid HIV test. Among 2,051 examinees that completed questionnaires, 90.3% were satisfied. In conclusion, the use of rapid HIV tests in public health centers promoted voluntary HIV testing and was satisfactory for examinees. PMID- 26955252 TI - Letter to the Editor: Publication Activity of Scientific Authors. PMID- 26955253 TI - The Author's Response: Educating Researchers and Editors: Contributing to Ethical Publication Activity. PMID- 26955254 TI - "Let's not forget our Raison d'etre". PMID- 26955255 TI - Effects of lower limb neurodynamic mobilization on intraneural fluid dispersion of the fourth lumbar nerve root: an unembalmed cadaveric investigation. AB - OBJECTIVES: Manual and physical therapists incorporate neurodynamic mobilisation (NDM) to improve function and decrease pain. Little is known about the mechanisms by which these interventions affect neural tissue. The objective of this research was to assess the effects of repetitive straight leg raise (SLR) NDM on the fluid dynamics within the fourth lumbar nerve root in unembalmed cadavers. METHODS: A biomimetic solution (Toluidine Blue Stock 1% and Plasma) was injected intraneurally, deep to the epineurium, into the L4 nerve roots of seven unembalmed cadavers. The initial dye spread was allowed to stabilise and measured with a digital calliper. Once the initial longitudinal dye spread stabilised, an intervention strategy (repetitive SLR) was applied incorporating NDMs (stretch/relax cycles) at a rate of 30 repetitions per minute for 5 minutes. Post intervention calliper measurements of the longitudinal dye spread were measured. RESULTS: The mean experimental posttest longitudinal dye spread measurement (1.1 +/- 0.9 mm) was significantly greater (P = 0.02) than the initial stabilised pretest longitudinal dye spread measurement. Increases ranged from 0.0 to 2.6 mm and represented an average of 7.9% and up to an 18.1% increase in longitudinal dye spread. DISCUSSION: Passive NDM in the form of repetitive SLR induced a significant increase in longitudinal fluid dispersion in the L4 nerve root of human cadaveric specimen. Lower limb NDM may be beneficial in promoting nerve function by limiting or altering intraneural fluid accumulation within the nerve root, thus preventing the adverse effects of intraneural oedema. PMID- 26955256 TI - The effect of manual therapy with augmentative exercises for neck pain: a randomised clinical trial. AB - OBJECTIVES: To compare the effect of manual therapy (MT) and an augmentative exercise programme (AEP) versus MT and general neck range of motion (ROM) on functional outcomes for patients with neck pain. A secondary objective was to examine changes in self-report measures and quantitative sensory testing (QST) following MT and AEP. METHODS: This was a randomised clinical trial. Seventy-two patients with neck pain were recruited. All patients received a single session of MT. Patients were randomly assigned to MT+AEP or MT+ROM. Clinical self-report outcome measures for disability and pain, and QST measures (pain and vibration thresholds) were collected at baseline, post MT treatment, at ~48 hours, and at ~96 hours. Repeated measures ANOVA and MANOVA were used to analyse within and between-group effects for clinical and QST measures. RESULTS: There were no between-group differences for disability, pain and QST measures. There was, however, a significant difference between groups for Global Rating of Change (GRoC) scores (P = 0.037). Patients in both groups showed improvements in pain, disability and trapezius pressure-pain threshold (PPT) (all P < 0.001). DISCUSSION: Augmentative exercise programme does not significantly improve disability, pain or QST measures in patients with chronic neck pain although it may enhance their GRoC scores. Over a 96-hour period, patients benefitted from MT plus exercise whether the exercise was general or specific. PMID- 26955257 TI - Effectiveness of trigger point dry needling for multiple body regions: a systematic review. AB - BACKGROUND: Trigger point dry needling (TDN) is commonly used to treat musculoskeletal pain related to myofascial trigger points (MTrPs). To date, no systematic review of high-quality randomised controlled trials (RCTs) investigating TDN to multiple body regions exists. PURPOSE: The aim of this review is to determine the effectiveness of TDN based on high-quality RCTs for all body regions. METHODS: To ensure thorough reporting, Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed as the methodological basis for this systematic review. PubMed, Physiotherapy Evidence Database (PEDro), Cinahl, Cochrane and reference lists were searched for the years 2000-2014 and the terms 'TDN', 'dry needling NOT trigger point', 'functional dry needling' and 'intramuscular manual therapy'. INCLUSION CRITERIA: RCTs with PEDro scores 6-10 investigating TDN. EXCLUSION CRITERIA: duplicates, non-human participants, non-English language, exclusive focus on acupuncture or medicinal injections. Three investigators searched databases, applied criteria, read and assigned PEDro scores to every RCT. Nineteen studies met the criteria. As compared to either baseline or control groups, significant differences were found for pain (14 studies), range of motion (ROM) (five studies) and at least one item on function and quality of life measures (six studies). LIMITATIONS: This review was limited by inclusion criteria, timeframe, language and databases searched. CONCLUSION: The majority of high-quality studies included in this review show measured benefit from TDN for MTrPs in multiple body areas, suggesting broad applicability of TDN treatment for multiple muscle groups. Further high-quality research is warranted to standardise TDN methods to determine clinical applicability. PMID- 26955258 TI - Low vs Standard Pressures in Gynecologic Laparoscopy: a Systematic Review. AB - BACKGROUND: The optimal intraperitoneal pressure during laparoscopy is not known. Recent literature found benefits of using lower pressures, but the safety of doing abdominal surgery with low peritoneal pressures needs to be assessed. This systematic review compares low with standard pneumoperitoneum during gynecologic laparoscopy. DATABASE: We searched Medline, Embase, and the Cochrane Library for randomized controlled trials comparing intraperitoneal pressures during gynecologic laparoscopy. Two authors reviewed references and extracted data from included trials. Risk ratios, mean differences, and standard mean differences were calculated and pooled using RevMan5. Of 2251 studies identified, three were included in the systematic review, for a total of 238 patients. We found a statistically significant but modest diminution in postoperative pain of 0.38 standardized unit based on an original 10-point scale (95% confidence interval [CI], -0.67 to -0.08) during the immediate postoperative period when using low intraperitoneal pressure of 8 mm Hg compared with >= 12 mm Hg and of 0.50 (95% CI, -0.80 to -0.21) 24 hours after the surgery. Lower pressures were associated with worse visualization of the surgical field (risk ratio, 10.31; 95% CI, 1.29 82.38). We found no difference between groups over blood loss, duration of surgery, hospital length of stay, or the need for increased pressure. CONCLUSION: Low intraperitoneal pressures during gynecologic laparoscopy cannot be recommended on the behalf of this review because improvement in pain scores is minimal and visualization of the surgical field is affected. The safety of this intervention as well as cost-effectiveness considerations need to be further studied. PMID- 26955260 TI - A new device to noninvasively estimate the intraocular pressure produced during ocular compression. AB - PURPOSE: To describe a noninvasive instrument that estimates intraocular pressure during episodes of external globe compression and to demonstrate the accuracy and reliability of this device by comparing it to the intraocular pressures simultaneously and manometrically measured in cannulated eyes. METHODS: A thin fluid-filled bladder was constructed from flexible and inelastic plastic sheeting and was connected to a pressure transducer with high pressure tubing. The output of the pressure transducer was sent to an amplifier and recorded. This device was validated by measuring induced pressure in the fluid-filled bladder while digital pressure was applied to one surface, and the other surface was placed directly against a human cadaver eye or in vivo pig eye. The human cadaver and in vivo pig eyes were each cannulated to provide a manometric intraocular pressure control. RESULTS: The measurements obtained with the newly described device were within ~5% of simultaneously measured manometric intraocular pressures in both a human cadaver and in vivo pig eye model for a pressure range of ~15-100 mmHg. CONCLUSION: This novel noninvasive device is useful for estimating the intraocular pressure transients induced during any form of external globe compression; this is a clinical setting where no other devices can be used to estimate intraocular pressure. PMID- 26955259 TI - Intragastric Balloon for Overweight Patients. AB - BACKGROUND AND OBJECTIVES: Current treatments for overweight adults include reduced-calorie diet, exercise, behavior modification, and selective use of medications. Many achieve suboptimal results with these measures and progress to obesity. Whether the intragastric balloon (IGB), a reversible device approved for treatment of obesity, is a safe and effective option in overweight adults is less well studied. We conducted a study to prospectively analyze the safety and effectiveness of IGB in overweight adults, to compare the results to a simultaneously studied cohort of obese patients, and to share procedural tips for safe IGB placement and removal. METHODS: One hundred thirty-nine patients were evaluated in this prospective, nonrandomized study. Twenty-six overweight [body mass index (BMI), 26-30)] and 113 obese (BMI > 30) patients underwent outpatient, endoscopic IGB placement under intravenous sedation. The IGB was filled with a 550-900 mL (average, 640 mL) solution of saline, radiological contrast, and methylene blue, with an approximate final proportion of 65:2:1. The patients were followed up at 1-2 weeks and then monthly for 6 months. At 6 months, they underwent IGB removal via an esophageal overtube to optimize safety, and then they were observed for 6 more months. RESULTS: IGB time was 190 +/- 36 d in the overweight patients and 192 +/- 43 d in the obese patients. Symptoms of IGB intolerance included nausea and pain, which were transiently present in 50-95% of patients for several days, and necessitated early IGB removal in 6% of patients. There were no procedure-related complications and no IGB-related esophagitis, erosion, perforation, or obstruction. The percentage of excess weight loss (EWL%) was 96 +/- 54% in the overweight group and 41 +/- 26% in the obese group (P < 0.001). CONCLUSION: In overweight adults failing standard treatments, IGB placement for 6 months had an acceptable safety profile and excellent weight loss. PMID- 26955261 TI - Microbiology of primary acquired nasolacrimal duct obstruction: simple epiphora, acute dacryocystitis, and chronic dacryocystitis. AB - PURPOSE: The aim of this study was to determine the microbiology of primary acquired nasolacrimal duct obstruction (PANDO) and its antimicrobial susceptibilities. METHODS: Ninety-three patients (100 eyes) diagnosed with PANDO, categorized as acute, chronic dacryocystitis, or simple epiphora, were prospectively enrolled. Lacrimal sac contents were cultured for aerobic and anaerobic bacteria and fungi. Cultured organisms were identified, and antimicrobial susceptibility testing was performed for aerobic bacteria. RESULTS: Seventy-nine of the 100 samples were culture positive. One hundred twenty-seven organisms were isolated, and 29 different species were identified. Most microorganisms were Gram-positive bacteria (45 samples or 57.0% of all positive culture samples), whereas Gram-negative bacteria, anaerobic bacteria, and fungi were found in 39 (49.4%), 24 (30.4%), and four samples (5.1%), respectively. The most frequently isolated group was coagulase-negative staphylococci (27.8%), followed by nonspore-forming Gram-positive rods (anaerobe) (17.7%) and Pseudomonas aeruginosa (15.2%). Of the 100 samples, five, 45, and 50 samples were obtained from patients with acute dacryocystitis, chronic dacryocystitis, and simple epiphora, respectively. Subgroup analysis showed that Gram-negative organisms were isolated more frequently from the chronic dacryocystitis subgroup than from the simple epiphora subgroup (P=0.012). Antimicrobial susceptibility testing demonstrated that ciprofloxacin was the most effective drug against all Gram-positive and Gram-negative organisms. CONCLUSION: Patients with PANDO, with or without clinical signs of lacrimal infection, were culture positive. Gram negative organisms were frequently isolated, which were different from previous studies. Ciprofloxacin was the most effective agent against all Gram-positive and Gram-negative organisms. PMID- 26955262 TI - Calycosin inhibits migration and invasion through modulation of transforming growth factor beta-mediated mesenchymal properties in U87 and U251 cells. AB - In this study, we investigated the potential anticancer effects of calycosin against human glioblastoma cells, including the impacts on cell proliferation, apoptosis, and cell cycle distribution. We further studied its inhibitory activity on migration and invasion in U87 and U251 cells. Furthermore, transforming growth factor beta-mediated reductions of mesenchymal-associated genes/activators, matrix metalloproteinases-2, and -9 were detected in this process. Administration of calycosin in a glioblastoma xenograft model showed that calycosin could not only reduce tumor volume but also suppress transforming growth factor beta as well as its downstream molecules. These results revealed calycosin as a potential antitumor agent in human glioblastoma. PMID- 26955264 TI - Failure to replicate the internal structure of Greek-specific thalassemia quality of life instrument in adult thalassemia patients in Sabah. AB - PURPOSE: To study the validity and reliability of the Malay version of the Specific Thalassemia Quality of Life Instrument (STQOLI) in Sabah's adult thalassemia patients. PATIENTS AND METHODS: This cross-sectional study was done at Thalassemia Treatment Centre, Queen Elizabeth Hospital in Sabah, Malaysia. Eighty-two adult thalassemia patients who fulfilled the inclusion and exclusion criteria were conveniently selected for participation in the study. The English version of STQOLI was translated into Malay by using forward and back translations. The content of the questionnaire was validated by the chief hematologist of the hospital. The construct validity of the 40-item questionnaire was assessed by principal component analysis with varimax rotation and the scale reliability was assessed by Cronbach's alpha. RESULTS: The study failed to replicate the internal structure of the Greek STQOLI. Instead, 12 factors have been identified from the exploratory factor analysis, which accounted for 72.2% of the variance. However, only eight factors were interpretable. The factors were iron chelation pump impact, transfusion impact, time spent on treatment and its impact on work and social life, sex life, side effects of treatment, cardiovascular problems, psychology, and iron chelation pill impact. The overall scale reliability was 0.913. CONCLUSION: This study was unable to replicate the internal structure of the Greek STQOLI in Sabah's adult thalassemia patients. Instead, a new structure has emerged that can be used as a guide to develop a questionnaire specific for adult thalassemia patients in Sabah. Future research should focus on the eight factors identified from this study. PMID- 26955263 TI - Comprehensive evaluation of formulation factors for ocular penetration of fluoroquinolones in rabbits using cassette dosing technique. AB - OBJECTIVE: Corneal permeability of drugs is an important factor used to assess the efficacy of topical preparations. Transcorneal penetration of drugs from aqueous formulation is governed by various physiological, physiochemical, and formulation factors. In the present study, we investigated the effect of formulation factors like concentration, pH, and volume of instillation across the cornea using cassette dosing technique for ophthalmic fluoroquinolones (FQs). MATERIALS AND METHODS: Sterile cocktail formulations were prepared using four congeneric ophthalmic FQs (ofloxacin, sparfloxacin, pefloxacin mesylate, and gatifloxacin) at concentrations of 0.025%, 0.5%, and 0.1%. Each formulation was adjusted to different pH ranges (4.5, 7.0, and 8.0) and assessed for transcorneal penetration in vivo in rabbit's cornea (n=4 eyes) at three different volumes (12.5, 25, and 50 MUL). Aqueous humor was aspirated through paracentesis after applying local anesthesia at 0, 5, 15, 30, 60, 120, and 240 minutes postdosing. The biosamples collected from a total of 27 groups were analyzed using liquid chromatography-tandem mass spectroscopy to determine transcorneal permeability of all four FQs individually. RESULTS: Increase in concentration showed an increase in penetration up to 0.05%; thereafter, the effect of concentration was found to be dependent on volume of instillation as we observed a decrease in transcorneal penetration. The highest transcorneal penetration of all FQs was observed at pH 7.0 at concentration 0.05% followed by 0.025% at pH 4.5. Lastly, increasing the volume of instillation from 12.5 to 50 MUL showed a significant fall in transcorneal penetration. CONCLUSION: The study concludes that formulation factors showed discernible effect on transcorneal permeation; therefore, due emphasis should be given on drug development and design of ophthalmic formulation. PMID- 26955266 TI - Relationship between frequent knee pain, obesity, and gait speed in older adults: data from the Osteoarthritis Initiative. AB - BACKGROUND: Knee pain (KP) causes gait difficulties in older adults and is associated with slow gait speed (GS). Obesity has negative effects on health. GS is an important indicator of health, well-being, and mean life span in older adults and is a strong predictor of future disability and mortality. The relationship between frequent KP, obesity, and GS in older adults remains unclear. Therefore, the present study aimed at examining the relationship between baseline frequent KP and obesity status on GS over time. We hypothesized that frequent KP, obesity, or both would be associated with decreased GS over time. METHODS: The data from the Osteoarthritis Initiative were used for this 6-year longitudinal cohort study. We studied 3,118 adults aged between 45 years and 79 years. We grouped the participants into the following four categories according to KP frequency and obesity status at baseline: 1) no KP and nonobese, 2) frequent KP and nonobese, 3) no KP and obese, and 4) frequent KP and obese. GS measurements were based on a 20 m walking test timed using a stopwatch; testing was performed at baseline and over a 6-year follow-up period. Walk pace (m/sec) was calculated as the average pace over two trials conducted at clinic visits. General linear mixed models were used to examine the relationships between frequent KP, obesity, and GS. RESULTS: After adjusting for all covariates, at baseline, all the nonobese group with frequent KP (beta=-0.06, 95% confidence interval [CI]: -0.07 to -0.04), the obese group with no KP (beta=-0.07, 95% CI: 0.1 to -0.04), and the obese group with frequent KP (beta=-0.08, 95% CI: -0.1 to 0.05) exhibited decreased GS compared with the nonobese and no KP group. However, the associations between frequent KP, obesity, and GS over time were not statistically significant. CONCLUSION: Frequent KP alone, obesity alone, and the combination of frequent KP and obesity were all associated with decreased GS in older adults. These associations did not change in any of the groups longitudinally; as such, the slopes corresponding to the data remained unchanged. PMID- 26955265 TI - Optimal nonpharmacological management of agitation in Alzheimer's disease: challenges and solutions. AB - Many patients with Alzheimer's disease will develop agitation at later stages of the disease, which constitutes one of the most challenging and distressing aspects of dementia. Recently, nonpharmacological therapies have become increasingly popular and have been proven to be effective in managing the behavioral symptoms (including agitation) that are common in the middle or later stages of dementia. These therapies seem to be a good alternative to pharmacological treatment to avoid unpleasant side effects. We present a systematic review of randomized controlled trials (RCTs) focused on the nonpharmacological management of agitation in Alzheimer's disease (AD) patients aged 65 years and above. Of the 754 studies found, eight met the inclusion criteria. This review suggests that music therapy is optimal for the management of agitation in institutionalized patients with moderately severe and severe AD, particularly when the intervention includes individualized and interactive music. Bright light therapy has little and possibly no clinically significant effects with respect to observational ratings of agitation but decreases caregiver ratings of physical and verbal agitation. Therapeutic touch is effective for reducing physical nonaggressive behaviors but is not superior to simulated therapeutic touch or usual care for reducing physically aggressive and verbally agitated behaviors. Melissa oil aromatherapy and behavioral management techniques are not superior to placebo or pharmacological therapies for managing agitation in AD. Further research in clinical trials is required to confirm the effectiveness and long-term effects of nonpharmacological interventions for managing agitation in AD. These types of studies may lead to the development of future intervention protocols to improve the well-being and daily functioning of these patients, thereby avoiding residential care placement. PMID- 26955267 TI - Mortality and economic burden of Krasnoyarsk region, Russia, caused by regular tobacco usage. AB - BACKGROUND: This study assesses mortality and economic burden due to the regular tobacco usage among the population of the Krasnoyarsk region of the Russian Federation. This territory was chosen for the analysis because of two factors: high smoking prevalence in the Krasnoyarsk region (46% among the adult population) and premature mortality of the working-age population, which leads to a significant burden to the federal budget of the Russian Federation. DATA SOURCES: In our work, three main causes of smoking-related deaths were considered: cardiovascular disease, lung cancer, and COPD. The working-age population was investigated (20-72 years old). The databases of mortality and population size of the territorial body of state statistics of the Krasnoyarsk region (data for 2013) were used as the information sources. METHODS: Joint application of population-attributable risk and disability-adjusted life years method allowed us to estimate medico-demographic and economic burden due to the tobacco-attributable premature mortality in the investigated population. RESULTS: We found that tobacco use-related economic burden is at least equal to 2% of the gross regional product of the Krasnoyarsk region in 2013. CONCLUSION: An assessment of economic tobacco use-related burden is important for determining the volume of necessary funding for development of smoking prevention programs, proper estimation of tobacco companies' taxation, and other measures for controlling tobacco use. Smoking cessation is a priority for prevention of the tobacco-related diseases and reduction of their burden on local economy. PMID- 26955268 TI - Explaining the link between access-to-care factors and health care resource utilization among individuals with COPD. AB - BACKGROUND: Limited accessibility to health care may be a barrier to obtaining good care. Few studies have investigated the association between access-to-care factors and COPD hospitalizations. The objective of this study is to estimate the association between access-to-care factors and health care utilization including hospital/emergency department (ED) visits and primary care physician (PCP) office visits among adults with COPD utilizing a nationally representative survey data. METHODS: We conducted a pooled cross-sectional analysis based upon a bivariate probit model, utilizing datasets from the 2011-2012 Behavioral Risk Factor Surveillance System linked with the 2014 Area Health Resource Files among adults with COPD. Dichotomous outcomes were hospital/ED visits and PCP office visits. Key covariates were county-level access-to-care factors, including the population weighted numbers of pulmonary care specialists, PCPs, hospitals, rural health centers, and federally qualified health centers. RESULTS: Among a total of 9,332 observations, proportions of hospital/ED visits and PCP office visits were 16.2% and 44.2%, respectively. Results demonstrated that access-to-care factors were closely associated with hospital/ED visits. An additional pulmonary care specialist per 100,000 persons serves to reduce the likelihood of a hospital/ED visit by 0.4 percentage points (pp) (P=0.028). In contrast, an additional hospital per 100,000 persons increases the likelihood of hospital/ED visit by 0.8 pp (P=0.008). However, safety net facilities were not related to hospital utilizations. PCP office visits were not related to access-to-care factors. CONCLUSION: Pulmonary care specialist availability was a key factor in reducing hospital utilization among adults with COPD. The findings of our study implied that an increase in the availability of pulmonary care specialists may reduce hospital utilizations in counties with little or no access to pulmonary care specialists and that since availability of hospitals increases hospital utilization, directing patients with COPD to pulmonary care specialists may decrease hospital utilizations. PMID- 26955269 TI - Determinants of successful completion of pulmonary rehabilitation in COPD. AB - BACKGROUND: Despite known benefits, a significant proportion of patients with COPD do not complete pulmonary rehabilitation (PR). Little is known regarding which factors promote successful completion of PR. METHODS: We analyzed data from a prospectively maintained database of subjects with COPD who attended a PR program at the University of Alabama at Birmingham, from 1996 to 2013. Subjects were categorized as either completers or non-completers, based on successful completion of at least 8 weeks of PR. Demographics and comorbidities were recorded. Short Form 36 Health Survey, Beck Depression Inventory-II, and San Diego Shortness of Breath Questionnaire were administered to all participants at baseline and on completion of PR to assess participants' perception of their health status, severity of depression, and dyspnea with performance of activities of daily living. Univariate and multivariable analyses were performed to identify predictors of successful completion of PR. RESULTS: Four hundred and forty subjects were included, of whom 229 completed PR. Forty-one percent were female, and 17% were African American. Compared with non-completers, completers had greater Short Form 36 Health Survey pain score, lower forced expiratory volume in the first second, and lower Beck Depression Inventory score, and included a lower percentage of current smokers. On multivariate analysis, cigarette smoking at enrollment was associated with lower likelihood of completion of PR (adjusted odds ratio 0.38, 95% confidence interval 0.16-0.90; P=0.02). CONCLUSION: Cigarette smoking was the sole independent predictor of PR dropout, and smoking cessation may warrant greater emphasis prior to enrollment. PMID- 26955270 TI - Development of a robust pH-sensitive polyelectrolyte ionomer complex for anticancer nanocarriers. AB - A polyelectrolyte ionomer complex (PIC) composed of cationic and anionic polymers was developed for nanomedical applications. Here, a poly(ethylene glycol) poly(lactic acid)-poly(ethylene imine) triblock copolymer (PEG-PLA-PEI) and a poly(aspartic acid) (P[Asp]) homopolymer were synthesized. These polyelectrolytes formed stable aggregates through electrostatic interactions between the cationic PEI and the anionic P(Asp) blocks. In particular, the addition of a hydrophobic PLA and a hydrophilic PEG to triblock copolyelectrolytes provided colloidal aggregation stability by forming a tight hydrophobic core and steric hindrance on the surface of PIC, respectively. The PIC showed different particle sizes and zeta potentials depending on the ratio of cationic PEI and anionic P(Asp) blocks (C/A ratio). The doxorubicin (dox)-loaded PIC, prepared with a C/A ratio of 8, demonstrated pH-dependent behavior by the deprotonation/protonation of polyelectrolyte blocks. The drug release and the cytotoxicity of the dox-loaded PIC (C/A ratio: 8) increased under acidic conditions compared with physiological pH, due to the destabilization of the formation of the electrostatic core. In vivo animal imaging revealed that the prepared PIC accumulated at the targeted tumor site for 24 hours. Therefore, the prepared pH-sensitive PIC could have considerable potential as a nanomedicinal platform for anticancer therapy. PMID- 26955271 TI - Thidiazuron-enhanced biosynthesis and antimicrobial efficacy of silver nanoparticles via improving phytochemical reducing potential in callus culture of Linum usitatissimum L. AB - Green synthesis of silver nanoparticles (AgNPs) by using plants is an emerging class of nanobiotechnology. It revolutionizes all domains of medical sciences by synthesizing chemical-free AgNPs for various biomedical applications. In this report, AgNPs were successfully synthesized by using whole plant extract (WPE) and thidiazuron-induced callus extract (CE) of Linum usitatissimum. The phytochemical analysis revealed that the total phenolic and flavonoid contents were higher in CE than that in WPE. Ultraviolet-visible spectroscopy of synthesized AgNPs showed a characteristic surface plasmon band in the range of 410-426 nm. Bioreduction of CE-mediated AgNPs was completed in a shorter time than that of WPE-mediated AgNPs. Scanning electron microscopy showed that both types of synthesized AgNPs were spherical in shape, but CE-mediated AgNPs were smaller in size (19-24 nm) and more scattered in distribution than that of WPE mediated AgNPs (49-54 nm). X-ray diffraction analysis confirmed crystalline nature (face-centered cubic) of both types of AgNPs. Fourier-transform infrared spectroscopy revealed that the polyphenols and flavonoids were mainly responsible for reduction and capping of synthesized AgNPs. Energy dispersive X-ray analysis further confirmed the successful synthesis of AgNPs. Moreover, the synthesized AgNPs were found to be stable over months with no change in the surface plasmon bands. More importantly, CE-mediated AgNPs displayed significantly higher bactericidal activity against multiple drug-resistant human pathogens than WPE mediated AgNPs. The present work highlighted the potent role of thidiazuron in in vitro-derived cultures for enhanced biosynthesis of chemical-free AgNPs, which can be used as nanomedicines in many biomedical applications. PMID- 26955272 TI - Pigment epithelial-derived factor gene loaded novel COOH-PEG-PLGA-COOH nanoparticles promoted tumor suppression by systemic administration. AB - Anti-angiogenesis has been proposed as an effective therapeutic strategy for cancer treatment. Pigment epithelium-derived factor (PEDF) is one of the most powerful endogenous anti-angiogenic reagents discovered to date and PEDF gene therapy has been recognized as a promising treatment option for various tumors. There is an urgent need to develop a safe and valid vector for its systemic delivery. Herein, a novel gene delivery system based on the newly synthesized copolymer COOH-PEG-PLGA-COOH (CPPC) was developed in this study, which was probably capable of overcoming the disadvantages of viral vectors and cationic lipids/polymers-based nonviral carriers. PEDF gene loaded CPPC nanoparticles (D NPs) were fabricated by a modified double-emulsion water-in-oil-in-water (W/O/W) solvent evaporation method. D-NPs with uniform spherical shape had relatively high drug loading (~1.6%), probably because the introduced carboxyl group in poly (D,L-lactide-co-glycolide) terminal enhanced the interaction of copolymer with the PEDF gene complexes. An excellent in vitro antitumor effect was found in both C26 and A549 cells treated by D-NPs, in which PEDF levels were dramatically elevated due to the successful transfection of PEDF gene. D-NPs also showed a strong inhibitory effect on proliferation of human umbilical vein endothelial cells in vitro and inhibited the tumor-induced angiogenesis in vivo by an alginate-encapsulated tumor cell assay. Further in vivo antitumor investigation, carried out in a C26 subcutaneous tumor model by intravenous injection, demonstrated that D-NPs could achieve a significant antitumor activity with sharply reduced microvessel density and significantly promoted tumor cell apoptosis. Additionally, the in vitro hemolysis analysis and in vivo serological and biochemical analysis revealed that D-NPs had no obvious toxicity. All the data indicated that the novel CPPC nanoparticles were ideal vectors for the systemic delivery of PEDF gene and might be widely used as systemic gene vectors. PMID- 26955275 TI - Suvorexant: a promising, novel treatment for insomnia. AB - Suvorexant a novel, orexin receptor antagonist was recently approved by the US Food and Drug Administration for the treatment of sleep onset and sleep maintenance insomnia in August 2014. Multiple animal and human studies support the efficacy, safety, and tolerability of suvorexant for patients of various profiles. Current recommendations advocate for a starting dose of 10 mg and a maximum dose of 20 mg, with cautious use in women, obese patients, and patients taking other CYP3A4 inhibitors. More head-to-head studies comparing suvorexant to other sedative-hypnotic therapies are needed to further delineate which patients will benefit the most from this medication over others. PMID- 26955273 TI - The potential applications of fibrin-coated electrospun polylactide nanofibers in skin tissue engineering. AB - Fibrin plays an important role during wound healing and skin regeneration. It is often applied in clinical practice for treatment of skin injuries or as a component of skin substitutes. We prepared electrospun nanofibrous membranes made from poly(l-lactide) modified with a thin fibrin nanocoating. Fibrin surrounded the individual fibers in the membrane and also formed a thin fibrous mesh on several places on the membrane surface. The cell-free fibrin nanocoating remained stable in the cell culture medium for 14 days and did not change its morphology. On membranes populated with human dermal fibroblasts, the rate of fibrin degradation correlated with the degree of cell proliferation. The cell spreading, mitochondrial activity, and cell population density were significantly higher on membranes coated with fibrin than on nonmodified membranes, and this cell performance was further improved by the addition of ascorbic acid in the cell culture medium. Similarly, fibrin stimulated the expression and synthesis of collagen I in human dermal fibroblasts, and this effect was further enhanced by ascorbic acid. The expression of beta1-integrins was also improved by fibrin, and on pure polylactide membranes, it was slightly enhanced by ascorbic acid. In addition, ascorbic acid promoted deposition of collagen I in the form of a fibrous extracellular matrix. Thus, the combination of nanofibrous membranes with a fibrin nanocoating and ascorbic acid seems to be particularly advantageous for skin tissue engineering. PMID- 26955274 TI - Financial stress during medical residency training: an experience from Iran. PMID- 26955276 TI - Tetrabenazine-induced oculogyric crisis - a rare complication in the treatment of Gilles de la Tourette syndrome. AB - Tetrabenazine is used in the treatment of chorea, tardive dyskinesia, tics, and dystonia. It rarely causes acute eyeball dystonia and the description of this complication in Gilles de la Tourette syndrome is limited. We provide a description of an acute oculogyric crisis caused by tetrabenazine in a patient with severe tics. The patient had never developed acute dystonic reactions, although he was previously exposed to numerous dopamine receptor-blocking agents. After 8 days of therapy with tetrabenazine at a dose of 62.5 mg daily, the patient developed involuntary movement of the eyeballs. Withdrawal of tetrabenazine caused resolution of all symptoms after a week. The purpose of this description is to draw attention to the potential of tetrabenazine to induce acute oculogyric crisis as well as the difficulty of differentiating drug-induced dystonia from dystonic tics in patients with Gilles de la Tourette syndrome. PMID- 26955277 TI - Is ketamine a lifesaving agent in childhood acute severe asthma? AB - Children with acute severe asthma exacerbation are at risk of developing respiratory failure. Moreover, conventional aggressive management might be futile in acute severe asthma requiring intubation and invasive ventilation. The aim of this review is to detail evidence on the use of ketamine in childhood asthma exacerbations. A search of the MEDLINE, EMBASE, and Cochrane databases was performed, using different combinations of the following terms: ketamine, asthma, use, exacerbation, and childhood. In addition, we searched the references of the identified articles for additional articles. We then reviewed titles and included studies that were relevant to the topic of interest. Finally, the search was limited to studies published in English and Spanish from 1918 to June 2015. Due to the scarcity in the literature, we included all published articles. The literature reports conflicting results of ketamine use for acute severe asthma in children. Taking into consideration the relatively good safety profile of the drug, ketamine might be a reasonable option in the management of acute severe asthma in children who fail to respond to standard therapy. Furthermore, pediatricians and pediatric emergency clinicians administering ketamine should be knowledgeable about the unique actions of this drug and its potential side effects. PMID- 26955278 TI - Male sex, height, weight, and body mass index can increase external pressure to calf region using knee-crutch-type leg holder system in lithotomy position. AB - BACKGROUND: Well-leg compartment syndrome (WLCS) is one of the catastrophic complications related to prolonged surgical procedures performed in the lithotomy position, using a knee-crutch-type leg holder (KCLH) system, to support the popliteal fossae and calf regions. Obesity has been implicated as a risk factor in the lithotomy position-related WLCS during surgery. In the present study, we investigated the relationship between the external pressure (EP) applied to the calf region using a KCLH system in the lithotomy position and selected physical characteristics. METHODS: Twenty-one young, healthy volunteers (21.4+/-0.5 years of age, eleven males and ten females) participated in this study. The KCLH system used was Knee Crutch((r)). We assessed four types of EPs applied to the calf region: box pressure, peak box pressure, contact pressure, and peak contact pressure, using pressure-distribution measurement system (BIG-MAT((r))). Relationships between these four EPs to the calf regions of both lower legs and a series of physical characteristics (sex, height, weight, and body mass index [BMI]) were analyzed. RESULTS: All four EPs applied to the bilateral calf regions were higher in males than in females. For all subjects, significant positive correlations were observed between all four EPs and height, weight, and BMI. CONCLUSION: EP applied to the calf region is higher in males than in females when the subject is supported by a KCLH system in the lithotomy position. In addition, EP increases with the increase in height, weight, and BMI. Therefore, male sex, height, weight, and BMI may contribute to the risk of inducing WLCS. PMID- 26955279 TI - Interprofessional team management in pediatric critical care: some challenges and possible solutions. AB - BACKGROUND: Aiming for and ensuring effective patient safety is a major priority in the management and culture of every health care organization. The pediatric intensive care unit (PICU) has become a workplace with a high diversity of multidisciplinary physicians and professionals. Therefore, delivery of high quality care with optimal patient safety in a PICU is dependent on effective interprofessional team management. Nevertheless, ineffective interprofessional teamwork remains ubiquitous. METHODS: We based our review on the framework for interprofessional teamwork recently published in association with the UK Centre for Advancement of Interprofessional Education. Articles were selected to achieve better understanding and to include and translate new ideas and concepts. FINDINGS: The barrier between autonomous nurses and doctors in the PICU within their silos of specialization, the failure of shared mental models, a culture of disrespect, and the lack of empowering parents as team members preclude interprofessional team management and patient safety. A mindset of individual responsibility and accountability embedded in a network of equivalent partners, including the patient and their family members, is required to achieve optimal interprofessional care. Second, working competently as an interprofessional team is a learning process. Working declared as a learning process, psychological safety, and speaking up are pivotal factors to learning in daily practice. Finally, changes in small steps at the level of the microlevel unit are the bases to improve interprofessional team management and patient safety. Once small things with potential impact can be changed in one's own unit, engagement of health care professionals occurs and projects become accepted. CONCLUSION: Bottom up patient safety initiatives encouraging participation of every single care provider by learning effective interprofessional team management within daily practice may be an effective way of fostering patient safety. PMID- 26955280 TI - Simulation-based assessments in health professional education: a systematic review. AB - INTRODUCTION: The use of simulation in health professional education has increased rapidly over the past 2 decades. While simulation has predominantly been used to train health professionals and students for a variety of clinically related situations, there is an increasing trend to use simulation as an assessment tool, especially for the development of technical-based skills required during clinical practice. However, there is a lack of evidence about the effectiveness of using simulation for the assessment of competency. Therefore, the aim of this systematic review was to examine simulation as an assessment tool of technical skills across health professional education. METHODS: A systematic review of Cumulative Index to Nursing and Allied Health Literature (CINAHL), Education Resources Information Center (ERIC), Medical Literature Analysis and Retrieval System Online (Medline), and Web of Science databases was used to identify research studies published in English between 2000 and 2015 reporting on measures of validity, reliability, or feasibility of simulation as an assessment tool. The McMasters Critical Review for quantitative studies was used to determine methodological value on all full-text reviewed articles. Simulation techniques using human patient simulators, standardized patients, task trainers, and virtual reality were included. RESULTS: A total of 1,064 articles were identified using search criteria, and 67 full-text articles were screened for eligibility. Twenty-one articles were included in the final review. The findings indicated that simulation was more robust when used as an assessment in combination with other assessment tools and when more than one simulation scenario was used. Limitations of the research papers included small participant numbers, poor methodological quality, and predominance of studies from medicine, which preclude any definite conclusions. CONCLUSION: Simulation has now been embedded across a range of health professional education and it appears that simulation-based assessments can be used effectively. However, the effectiveness as a stand-alone assessment tool requires further research. PMID- 26955282 TI - Neoadjuvant chemoradiotherapy or chemotherapy followed by surgery is superior to that followed by definitive chemoradiation or radiotherapy in stage IIIA (N2) nonsmall-cell lung cancer: a meta-analysis and system review. AB - BACKGROUND: Approximately 30% of all cases of nonsmall-cell lung cancer (NSCLC) are of a locally advanced (IIIA or IIIB) stage. However, surgical therapy for patients with stage IIIA (N2) NSCLC is associated with a disappointing 5-year survival rate. The optimal treatment for stage IIIA (N2) NSCLC is still in dispute. METHODS: A literature search was performed in the PubMed, Embase, and MEDLINE databases (last search updated in March 2015), and a meta-analysis of the available data was conducted. Two authors independently extracted data from each eligible study. RESULTS: A total of nine studies, including five randomized controlled trials and four retrospective studies, were enrolled in this meta analysis. Significant homogeneity (chi (2)=49.62, P=0.000, I (2)=81.9%) was detected between four of the studies, including a total of 11,948 selected cases. Among the nine studies that investigated overall survival, the pooled hazard ratio (HR) was 0.70 (95% confidence interval (CI): 0.56-0.87; P=0.000). Subgroup analyses were performed according to the study design and the extent of resection. We observed a statistically significant better outcome after lobectomy (pooled HR: 0.52; 95% CI: 0.47-0.58; P=0.000) than after pneumonectomy (pooled HR: 0.82; 95% CI: 0.69-0.98; P=0.028). Unfortunately, there was no significant difference between the randomized controlled studies, as the pooled HR was 0.94 (95% CI: 0.81-1.09; P=0.440). CONCLUSION: Neoadjuvant chemoradiotherapy or chemotherapy followed by surgery (particularly lobectomy) is superior to following these therapies with definitive chemoradiation or radiotherapy, particularly in patients undergoing lobectomy. PMID- 26955281 TI - The prevalence and prognostic significance of KRAS mutation subtypes in lung adenocarcinomas from Chinese populations. AB - BACKGROUND: We performed this retrospective study to identify the prevalence of KRAS mutation in Chinese populations and make a comprehensive investigation of the clinicopathological features of KRAS mutation in these patients. PATIENTS AND METHODS: Patients from 2007 to 2013 diagnosed with primary lung adeno-carcinoma who received a radical resection were examined for KRAS, EGFR, HER2, BRAF mutations, and ALK, RET, and ROS1 fusions. Clinicopathological features, including sex, age, tumor-lymph node-metastasis stage, tumor differentiation, smoking status, histological subtypes, and survival information were analyzed. RESULT: KRAS mutation was detected in 113 of 1,368 patients. Nine different subtypes of KRAS mutation were identified in codon 12, codon 13, and codon 61. KRAS mutation was more frequently found in male patients and former/current smoker patients. Tumors with KRAS mutation had poorer differentiation. Invasive mucinous adenocarcinoma predominant and solid predominant subtypes were more frequent in KRAS mutant patients. No statistical significance was found in relapse-free survival or overall survival between patients with KRAS mutation and patients with other mutations. CONCLUSION: In Chinese populations, we identified KRAS mutation in 8.3% (113/1,368) of the patients with lung adenocarcinoma. KRAS mutation defines a molecular subset of lung adenocarcinoma with unique clinicopathological features. PMID- 26955283 TI - Potential impact of (18)FDG-PET/CT on surgical approach for operable squamous cell cancer of middle-to-lower esophagus. AB - BACKGROUND: Fluorodeoxyglucose-positron emission tomography (PET)/computed tomography (CT) is reported to have a significant advantage over CT for staging esophageal cancer (EC). However, whether PET/CT may play a useful role in guiding surgical approach remains undetermined. METHODS: Patients with potentially resectable squamous cell EC were randomized into either PET/CT group or CT group. The surgical data and survival outcomes were compared. RESULTS: Compared to the CT group, the right-sided approach was more frequently used (42.6% versus 25.5%, P=0.065) in the PET/CT group in order to allow surgical access to radiographically suspicious lymph nodes inaccessible from the left, thus enabling the removal of more involved lymph nodes (2.83 versus 1.76; P=0.039) as well as their stations (1.65 versus 1.08; P=0.042). Although the overall survival between the two groups was similar, the PET/CT group had a longer disease-free survival (DFS) than the CT group (27.1 months versus 18.9 months; P=0.019), especially in the subgroup of node-positive patients (22.5 months versus 13.5 months; P=0.02). Preoperative imaging arm was the only prognostic factor found to independently influence DFS. CONCLUSION: For patients with middle-to-lower EC, surgical approaches directed by PET/CT may increase the likelihood of complete resection and affect DFS. PMID- 26955285 TI - Prognostic significance of platelet-to-lymphocyte ratio in non-small-cell lung cancer: a meta-analysis. AB - BACKGROUND: The platelet-to-lymphocyte ratio (PLR) is a useful predictive factor in several cancers. However, the prognostic value of PLR in patients with non small-cell lung cancer (NSCLC) is still indistinct. Therefore, it was necessary for us to perform a meta-analysis to assess the prognostic value of PLR in patients with NSCLC. METHODS: A systematic literature search was performed by using PubMed, EMBASE, and Web of Science databases for relevant studies until May 2015. Published studies investigating the association between PLR and overall survival (OS) and disease-free survival (DFS) were selected. Data from each eligible study were extracted. A meta-analysis was performed to analyze the prognostic value of PLR by using the hazard ratio (HR) and 95% confidence intervals (95% CI). RESULTS: A total of seven studies involving 1,554 patients were included in our meta-analysis. Our pooled results demonstrated that high PLR was associated with poor OS (HR: 1.60, 95% CI: 1.34-1.90, I (2)=22.3%, P heterogeneity = 0.259) and DFS (HR: 1.38, 95% CI: 1.11-1.73, I 2=0%, P heterogeneity = 0.482). Subgroup analysis between PLR and OS was performed in a further investigation. When the patients were segregated according to ethnicity, sample size, cutoff value, stage, and treatment modality, high PLR was also significantly correlated with OS. There was no significant heterogeneity among included studies. CONCLUSION: High PLR is associated with poor prognosis in patients with NSCLC. PLR may be a significant predictive biomarker in patients with NSCLC. PMID- 26955284 TI - Type I enteropathy-associated T-cell lymphoma in the colon of a 29-year-old patient and a brief literature review. AB - Enteropathy-associated T-cell lymphoma (EATL) is a rare gastrointestinal non Hodgkin's lymphoma, originating from intraepithelial T-lymphocyte, which is specifically associated with celiac disease. EATL most commonly presents in the sixth and seventh decades of life. We report a unique case of type I EATL in the colon with liver metastasis, which was presented with nonspecific radiological findings and at a very young age (29 years old) compared with previously published data. We suggest that EATL should be regarded as part of differential diagnosis in any patient presenting with abdominal pain, diarrhea, weight loss, and malabsorption because delay in treatment can result in an irreversible clinical outcome. PMID- 26955286 TI - Efficacy of surgical treatment using microwave coagulo-necrotic therapy for unresectable multiple colorectal liver metastases. AB - BACKGROUND: Five or more colorectal liver metastases (CRLM) are considered marginally resectable and cannot be treated solely by hepatic resection (Hr). This study investigated the long-term effectiveness of surgical treatment using microwave coagulo-necrotic therapy (MCN) and/or Hr for marginally resectable or unresectable multiple CRLM. METHODS: This study retrospectively analyzed 82 consecutive CRLM patients with >=5 CRLM who underwent MCN, Hr, or both, at our institution from 1994 to 2012. Presuming all CRLM were resected curatively, virtual remnant liver volume was calculated using preoperative computed tomography or magnetic resonance imaging. Virtual remnant liver volume <30% was defined as unresectable. Patients were divided into marginally resectable (Group Y; n=29) and unresectable (Group N; n=53). Overall and recurrence-free survival were assessed. RESULTS: Mean maximum tumor diameter and tumor number were 3.1 and 6.0 cm in Group Y and 3.3 and 11.3 cm in Group N. Surgical methods included MCN (n=16), MCN+Hr (n=9), and Hr (n=4) in Group Y, and MCN (n=28) and MCN+Hr (n=25) in Group N. One- and 2-year recurrence-free survival rates were 38.0% and 22.8% in Group Y, and 18.9% and 3.8% in Group N (P=0.01). However, 1-, 3-, and 5-year overall survival rates of Group N (86.8%, 44.6%, and 33.7%, respectively) were similar to those of Group Y (82.8%, 51.4%, and 33.3%, respectively; P= not significant each). CONCLUSION: MCN may improve survival for patients with unresectable multiple CRLM, similar to that in patients with marginally resectable multiple CRLM. PMID- 26955287 TI - Recurrent squamous cell carcinoma of the skin treated successfully with single agent cetuximab therapy. AB - Recurrent squamous cell carcinoma of the skin is a rare but difficult to treat condition. Frequently, the disease presents itself in elderly patients with poor performance status and bearing many comorbidities, thus the decision to administer systemic chemotherapy becomes difficult to make. In addition, current chemotherapeutic protocols response rates are far from satisfactory. Recently cetuximab, a chimeric antibody against epidermal growth factor receptor, is increasingly being reported as an alternative treatment. We therefore report this case of a recurrent squamous cell carcinoma of the skin in an elderly woman with poor performance status and who had an excellent clinical response to single agent cetuximab therapy with complete resolution of the disease and minimal toxicity during the course of the treatment to provide evidence for future prospective clinical trials. PMID- 26955288 TI - Quality-of-life indicators and falls due to vitamin D deficiency. AB - OBJECTIVE: To determine whether the number of falls and quality-of-life indicators relate to serum levels of vitamin D, parathyroid hormone (PTH), and calcium levels. DESIGN: A prospective study. PARTICIPANTS: Patients being admitted with a fall with or without sustaining a fragility fracture post fall. MEASUREMENTS: Measured frequency of falling, SF-12 questionnaire, serum concentrations of 25-hydroxyvitamin D, calcium, and PTH levels before and after treatment with vitamin D supplementation. RESULTS: The mean age (N=38) of the cohort was 80.2+/-12. In all, 76.3% of the cohort had sustained a fragility fracture after the fall. The cohort was vitamin D deficient with the pretreatment mean value of 24.2+/-17 nmol/L and posttreatment mean value of 99+/-40 nmol/L with a statistically significant mean difference of 74.7 nmol/L (confidence interval [CI] 61.27-88.3), P=0.001. The levels of calcium and PTH were statistically significant after treatment with a mean difference of 0.16 (CI 0.1 0.2), P=0.001, and 3.7 (CI -4.8 to -2.5), P=0.001, respectively. After treatment, the mean difference of physical component score (PCS) and mental component score for the whole cohort was 2.9 (CI -0.69 to 6.6), P=0.10, and 1.05 (CI -2.6 to 4.7), P=0.56, respectively. However, a subgroup analysis for cohort aged <=70 years provided a statistically significant effect on PCS with a mean difference of 8.9 (CI 1.3-16.4), P=0.03, but a statistically insignificant improvement in mental component score with a mean difference of 6.0 (CI -17 to -5.0), P=0.20. However, a statistically significant improvement in PCS SF-12 was observed in patients <=70 years of age 2.9 (1.3-16.4), P=0.03. The mean number of falls for the whole cohort pre- and posttreatment was 1.11+/-0.92 vs 0.97+/-0.99 (P=0.68), respectively. CONCLUSION: Patients who had fallen and sustained fragility fracture had lower serum 25-dihydroxyvitamin D and higher serum PTH levels. Our study demonstrates that there is no statistically significant improvement in the number of falls after treatment with vitamin D. Overall, vitamin D levels improved significantly, this is despite quality-of-life indicators showing a mean increase in PCS but not a statistically significant improvement. However, statistically significant improvement in PCS was observed in group aged <=70 years after vitamin D supplementation. PMID- 26955289 TI - Probiotics are effective at preventing Clostridium difficile-associated diarrhea: a systematic review and meta-analysis. AB - INTRODUCTION: Clostridium difficile infection (CDI) is the leading cause of antibiotic-associated diarrhea. CDI has increased in incidence and severity over the past decade, and is a growing worldwide health problem associated with substantial health care costs and significant morbidity and mortality. This meta analysis examines the impact of probiotics on the incidence of Clostridium difficile-associated diarrhea (CDAD) among children and adults, in both hospital and outpatient settings. METHODS: A comprehensive literature search of all published randomized control trials (RCTs) assessing the use of probiotics in the prevention of CDAD in patients receiving antibiotic therapy was conducted, and the incidence of CDAD was analyzed. RESULTS: Twenty-six RCTs involving 7,957 patients were analyzed. Probiotic use significantly reduced the risk of developing CDAD by 60.5% (relative risk [RR] =0.395; 95% confidence interval [CI], 0.294-0.531; P<0.001). Probiotics proved beneficial in both adults and children (59.5% and 65.9% reduction), especially among hospitalized patients. Lactobacillus, Saccharomyces, and a mixture of probiotics were all beneficial in reducing the risk of developing CDAD (63.7%, 58.5%, and 58.2% reduction). CONCLUSION: Probiotic supplementation is associated with a significant reduction in the risk of developing CDAD in patients receiving antibiotics. Additional studies are required to determine the optimal dose and strain of probiotic. PMID- 26955290 TI - A touchy subject: an assessment of cutaneous allodynia in a chronic migraine population. AB - BACKGROUND: Cutaneous allodynia (CA) is a common feature of migraine, which has a complex underlying pathophysiology that is not well understood. In addition to pain, photophobia, phonophobia, osmophobia, nausea, and vomiting, CA can contribute to the overall disability caused by migraine. The presence of CA can be established via a validated questionnaire. Validated questionnaires and other tests are rarely performed in clinical practice. As such, current prevalence estimates for CA may be an underestimation. METHODS: Utilizing a validated questionnaire, we assessed the presence of CA in consecutive patients (n=44) presenting with chronic migraine at a tertiary headache center. RESULTS: CA appears to be quite prevalent, at ~90%, among female patients with chronic migraine. CONCLUSION: CA prevalence in chronic migraine may be underestimated in the literature, and larger studies may better demonstrate a more accurate estimate of its prevalence. PMID- 26955292 TI - A comparative study to find out the relationship between the inner inter-canthal distance, interpupillary distance, inter-commissural width, inter-alar width, and the width of maxillary anterior teeth in Aryans and Mongoloids. AB - BACKGROUND: One of the most confusing and difficult aspects of complete denture prosthodontics is the selection of appropriately sized maxillary anterior denture teeth. Various guidelines have been suggested for determining the size of anterior teeth, but different opinions have been reported regarding their significance. In the study reported here, the relationships between facial measurements and the width of maxillary anterior teeth in two ethnic groups, namely Aryans and Mongoloids, were determined. OBJECTIVE: The aims of the study were to determine the inner inter-canthal distance (ICAD), inter-pupillary distance (IPD), inter-commissural width (ICOW), inter-alar width (IAW), and the combined width of maxillary anterior teeth (CW) in Aryans and Mongoloids and to determine the relationships between these measurements. MATERIALS AND METHODS: Impressions of the teeth of 170 dentulous subjects (85 males and 85 females) were made with alginate then Type IV gypsum product was poured in. Measurements of the cast maxillary anterior teeth at their widest dimension (contact areas) were made with the Boley gauge. ICAD, IPD, ICOW, and IAW distances were also measured with a Boley gauge. RESULTS: For all 170 subjects, 85 Aryans and 85 Mongoloids, Pearson's correlation coefficient (r) for IAW, IPD, ICOW, ICAD, and CW was calculated. In Aryans, highly significant (P<0.001) but weak correlations were found between CW and IAW, IPD, and ICOW. In Mongoloids, a highly significant (P<0.001) and weak correlation was found only between CW and IPD. CONCLUSION: Within the limitations of this study, the results suggest that the IAW, IPD, and ICOW for Aryans and IPD for Mongoloids can be used as a preliminary method for determining the width of the maxillary anterior teeth in edentulous patients. PMID- 26955291 TI - Probiotics and blood pressure: current insights. AB - Gut microbiota play a significant role in host metabolic processes, and recent metagenomic surveys have revealed that they are involved in host immune modulation and influence host development and physiology (organ development). Initially, probiotics are identified as potential therapeutics to treat gastrointestinal disorders and to revitalize the disturbed gut ecosystem. Currently, studies are exploring the potential for expanded uses of probiotics for improving the health conditions in metabolic disorders that increase the risk of developing cardiovascular diseases such as hypertension. Further investigations are required to evaluate targeted and effective use of the wide variety of probiotic strains in various metabolic disorders to improve the overall health status of the host. This review addresses the causes of hypertension and the hypotensive effect of probiotics, with a focus on their mechanistic action. PMID- 26955293 TI - Effect of aerobic exercise during pregnancy on antenatal depression. AB - BACKGROUND: Antenatal depression is not uncommon and is associated with a greater risk of negative pregnancy outcomes. AIM: Exploring the effect of exercise in preventing and treating antenatal depression. METHODS: This was a prospective interventional controlled study carried out in 100 pregnant women treated at the Ain-Shams Family Medicine Center and Maadi Outpatient Clinic, Cairo, Egypt. The participants were divided into two groups (n=50 in the exercise group and n=50 in the control group). The exercise group regularly attended supervised sessions for 12 weeks. The activities in each session included walking, aerobic exercise, stretching, and relaxation. The control group completed their usual antenatal care. The Center for Epidemiological Studies Depression Scale (CES-D) was used to assess depression symptoms at the first interview and immediately after the 12 week intervention. RESULTS: Compared to the control group, the exercise group showed significantly improved depressive symptoms as measured with the CES-D after the 12-week intervention on the CES-D (P=0.001). Within groups, the exercise group demonstrated a significant improvement of depressive symptoms from baseline to intervention completion, while the control group demonstrated no significant changes over time. CONCLUSION: Exercise during pregnancy was positively associated with reduced depressive symptoms. PMID- 26955294 TI - Chorea-acanthocytosis: a case report. AB - Neuroacanthocytosis is a group of rare disorders. We report a 36-year-old right handed female who presented with gradually progressive abnormal facial movements, generalized weakness, and lower-lip biting starting 4 years ago. On examination, she had lower-lip ulcer, orofacial dyskinesias, and peripheral neuropathy. Her peripheral blood smears showed acanthocytosis and magnetic resonance imaging revealed atrophied head of caudate nuclei and putaminal hyperintensities on T2 weighted and fluid attenuated inversion recovery images. Work-up for autoimmune and metabolic causes was negative. She was diagnosed with chorea-acanthocytosis, an entity under neuroacanthocytosis syndrome and the patient was offered symptomatic treatment. PMID- 26955296 TI - Anterior cruciate ligament reconstruction, rehabilitation, and return to play: 2015 update. AB - Anatomical discoveries and a growing appreciation of the knee as a complex organ are driving innovations in patient care decision-making following anterior cruciate ligament (ACL) injury. Surgeons are increasing their efforts to restore combined mechanical-neurosensory ACL function and placing more consideration on when to reconstruct versus repair native anatomical structures. Surgical options now include primary repair with or without reinforcing the injured ACL with suture-based internal bracing, and growing evidence supports biological augmentation using platelet-rich plasma and mesenchymal stem cells to enhance tissue healing. Physical therapists and athletic trainers are increasing their efforts to facilitate greater athlete cognitive engagement during therapeutic exercise performance to better restore nonimpaired neuromuscular control activation amplitude and timing. Knee brace design and use needs to evolve to better match these innovations and their influence on the rehabilitation plan timetable. There is a growing appreciation for the multifaceted characteristics of the rehabilitation process and how they influence neuromuscular, educational, and psychobehavioral treatment goal achievement. Multiple sources may influence the athlete during the return to sports process and clinical outcome measures need to be refined to better evaluate these influences. This update summarizes contemporary ACL surgical, medical, and rehabilitation interventions and future trends. PMID- 26955295 TI - Autophagy in hepatocellular carcinomas: from pathophysiology to therapeutic response. AB - Autophagy is an intracellular lysosomal degradation process performed by the cells to maintain energy balance. The autophagy response plays an important role in the progression of liver disease due to hepatitis virus infection, alcoholic liver disease, nonalcoholic fatty liver disease, liver cirrhosis, and hepatocellular carcinoma (HCC). An increased autophagy response also contributes to the pathogenesis of liver disease through modulation of innate and adaptive immune responses; a defective cellular autophagy response leads to the development of HCC. Recent progress in the field indicates that autophagy modulation provides a novel targeted therapy for human liver cancer. The purpose of this review is to update our understanding of how the cellular autophagy response impacts the pathophysiology of liver disease and HCC treatment. PMID- 26955298 TI - Improving medical graduates' training in palliative care: advancing education and practice. AB - The needs of an aging population and advancements in the treatment of both chronic and life-threatening diseases have resulted in increased demand for quality palliative care. The doctors of the future will need to be well prepared to provide expert symptom management and address the holistic needs (physical, psychosocial, and spiritual) of patients dealing with serious illness and the end of life. Such preparation begins with general medical education. It has been recommended that teaching and clinical experiences in palliative care be integrated throughout the medical school curriculum, yet such education has not become the norm in medical schools across the world. This article explores the current status of undergraduate medical education in palliative care as published in the English literature and makes recommendations for educational improvements which will prepare doctors to address the needs of seriously ill and dying patients. PMID- 26955297 TI - The epidemiology of acne vulgaris in late adolescence. AB - IMPORTANCE: Acne vulgaris is the most common skin condition affecting late adolescents across the globe. Although prior studies have evaluated epidemiologic patterns of acne vulgaris in various ethnicities and regions, adequate understanding of the worldwide burden of the disease associated with patients in their late adolescence (15-19-year olds) remains lacking. OBJECTIVE: To assess the global burden of the disease associated with acne vulgaris for late adolescents (15-19-year olds) and provide an overview of the epidemiology, pathophysiology, and treatment options for acne in this population. DESIGN: Database summary study. SETTING: Global Burden of Disease Study 2010 database. PARTICIPANTS: Global Burden of Disease regions comprised countries with prevalence of acne vulgaris between the ages of 15 and 19 years. MAIN OUTCOMES AND MEASURES: Geographic region-level disability-adjusted life year rates (per 100,000 persons) associated with acne vulgaris in years 1990 through 2010. Median percentage change in disability-adjusted life year rates was estimated for each region across the specified study period. CONCLUSION AND RELEVANCE: Acne vulgaris associated disease burden exhibits global distribution and has continued to grow in prevalence over time within this population. This continued growth suggests an unmet dermatologic need worldwide for this disorder and potential opportunities for improved access and delivery of dermatologic care. Our analysis of the literature reveals numerous opportunities for enhanced patient care. To that end, we highlight some of the effective and promising treatments currently available and address important factors, such as sex, nationality, genetics, pathophysiology, and diet, as they relate to acne vulgaris in late adolescence. PMID- 26955301 TI - Writing paper: Ladder and checklist. PMID- 26955300 TI - Mechanically Tunable Hollow Silica Ultrathin Nanoshells for Ultrasound Contrast Agents. AB - Perfluoropentane (PFP) gas filled biodegradable iron-doped silica nanoshells have been demonstrated as long-lived ultrasound contrast agents. Nanoshells are synthesized by a sol-gel process with tetramethyl orthosilicate (TMOS) and iron ethoxide. Substituting a fraction of the TMOS with R-substituted trialkoxysilanes produces ultrathin nanoshells with varying shell thicknesses and morphologies composed of fused nanoflakes. The ultrathin nanoshells had continuous ultrasound Doppler imaging lifetimes exceeding 3 hours, were twice as bright using contrast specific imaging, and had decreased pressure thresholds compared to control nanoshells synthesized with just TMOS. Transmission electron microscopy (TEM) showed that the R-group substituted trialkoxysilanes could reduce the mechanically critical nanoshell layer to 1.4 nm. These ultrathin nanoshells have the mechanical behavior of weakly linked nanoflakes but the chemical stability of silica. The synthesis can be adapted for general fabrication of three-dimensional nanostructures composed of nanoflakes, which have thicknesses from 1.4-3.8 nm and diameters from 2-23 nm. PMID- 26955302 TI - Operating room conflict resolution: Time to figure it out. PMID- 26955303 TI - Pain relief after ambulatory hand surgery: A comparison between dexmedetomidine and clonidine as adjuvant in axillary brachial plexus block: A prospective, double-blinded, randomized controlled study. AB - BACKGROUND: For ages various adjuvants have been tried to prolong axillary brachial plexus block. We compared the effect of adding dexmedetomidine versus clonidine to ropivacaine for axillary brachial plexus blockade. The primary endpoints were the onset and duration of sensory and motor block and duration of analgesia. MATERIALS AND METHODS: A total of 90 patients (20-40 years) posted for ambulatory elective hand surgery under axillary brachial plexus block were divided into two equal groups (groups ropivacaine dexmedetomidine [RD] and ropivacaine clonidine [RC]) in a randomized, double-blind fashion. In group RD (n = 45) 30 ml 0.5% ropivacaine + 100 MUg of dexmedetomidine and group RC (n = 45) 30 ml 0.5% ropivacaine + 75 MUg clonidine were administered in axillary plexus block. Sensory and motor block onset times and block durations, time to first analgesic use, total analgesic need, postoperative visual analog scale (VAS), hemodynamics and side-effects were recorded for each patient. RESULTS: Though with similar demographic profile in both groups, sensory and motor block in group RD (P < 0.05) was earlier than group RC. Sensory and motor block duration and time to first analgesic use were significantly longer and the total need for rescue analgesics was lower in group RD (P < 0.05) than group RC. Postoperative VAS value at 18 h were significantly lower in group RD (P < 0.05). Intraoperative hemodynamics were insignificantly lower in group RD (P < 0.05) without any appreciable side-effects. CONCLUSION: It can be concluded that adding dexmedetomidine to axillary plexus block increases the sensory and motor block duration and time to first analgesic use, and decreases total analgesic use with no side-effects. PMID- 26955304 TI - Multiple levels paravertebral block versus morphine patient-controlled analgesia for postoperative analgesia following breast cancer surgery with unilateral lumpectomy, and axillary lymph nodes dissection. AB - BACKGROUND: Postoperative pain after breast cancer surgery is not uncommon. Narcotic based analgesia is commonly used for postoperative pain management. However, the side-effects and complications of systemic narcotics is a significant disadvantage. Different locoregional anesthetic techniques have been tried including, single and multiple levels paravertebral block (PVB), which seems to have a significant reduction in immediate postoperative pain with fewer side-effects. The aim of this study was to compare unilateral multiple level PVB versus morphine patient-controlled analgesia (PCA) for pain relief after breast cancer surgery with unilateral lumpectomy and axillary lymph nodes dissection. MATERIALS AND METHODS: Forty patients scheduled for breast cancer surgery were randomized to receive either preoperative unilateral multiple injections PVB at five thoracic dermatomes (group P, 20 patients) or postoperative intravenous PCA with morphine (group M, 20 patients) for postoperative pain control. Numerical pain scale, mean arterial pressure, heart rate, Time to first analgesic demand, 24-h morphine consumption side-effects and length of hospital stay were recorded. RESULTS: PVB resulted in a significantly more postoperative analgesia, maintained hemodynamic, more significant reduction in nausea and vomiting, and shorter hospital stay compared with PCA patients. CONCLUSION: Multiple levels PVB is an effective regional anesthetic technique for postoperative pain management, it provides superior analgesia with less narcotics consumption, and fewer side effects compared with PCA morphine for patients with breast cancer who undergo unilateral lumpectomy, with axillary lymph nodes dissection. PMID- 26955305 TI - Effects of perineural administration of dexmedetomidine in combination with bupivacaine in a femoral-sciatic nerve block. AB - BACKGROUND AND AIM: Perineural administration of dexmedetomidine, a alpha2 adrenoceptor agonist, prolongs the duration of analgesia. We hypothesized that adding dexmedetomidine to bupivacaine would prolong postoperative analgesia after below knee surgery. MATERIALS AND METHODS: After ethical approval, 60 patients scheduled for below knee surgery under combined femoral-sciatic nerve block were randomly allocated into two groups to have their block performed using bupivacaine 0.5% alone (group B) or bupivacaine 0.5% combined with 100 MUg bupivacaine-dexmedetomidine (group BD). Motor and sensory block onset times; durations of blockades and analgesia were recorded. RESULTS: Sensory and motor block onset times were shorter by 20% in group BD than in group B (P < 0.01). Sensory and motor blockade durations were longer in group BD (+45% and +40%, respectively) than in group B (P < 0.01). Duration of analgesia was longer in group BD by 75% than in group B (P < 0.01). Systolic, diastolic arterial blood pressure levels, and heart rate were significantly less in group BD, six patients in group BD, and no patients in group B developed bradycardia (P < 0.05). CONCLUSION: The addition of dexmedetomidine 100 MUg to bupivacaine 0.5% during ultrasound-guided combined femoral and sciatic block for below knee surgery was associated with a prolonged duration of analgesia. However, this may be associated with significant bradycardia requiring treatment. PMID- 26955306 TI - Ultrasound-guided rectus sheath and transversus abdominis plane blocks for perioperative analgesia in upper abdominal surgery: A randomized controlled study. AB - BACKGROUND: Regional anesthetic techniques can be used to alleviate postoperative pain in patients undergoing major upper abdominal surgery. Our aim was to evaluate the efficacy of bilateral ultrasound (US)-guided rectus sheath (RS) and transversus abdominis plane (TAP) blocks for better perioperative analgesia. PATIENTS AND METHODS: It is a prospective, observer-blinded, randomized clinical study. 40 eligible patients undergoing elective liver resection or Whipple procedure were included. All patients received a standardized anesthetic technique. Group 1 (n = 20) received preincisional US-guided bilateral RS and TAP blocks using 20 ml volume of bupivacaine 0.25% for each, and group 2 (n = 20) received local wound infiltration at end of surgery with 40 ml of bupivacaine 0.25%. A standardized postoperative analgesic regimen composed of intravenous paracetamol and a morphine patient-controlled analgesia (PCA). The use of intraoperative fentanyl and recovery room morphine boluses, PCA-administered morphine, pain scores as well as number of patients' experienced postoperative nausea and vomiting in the ward at 6 and 24 h were recorded. RESULTS: Group 1 patients received a significantly lower cumulative intraoperative fentanyl, significantly lesser boluses of morphine in postanesthesia care unit, as well, significantly lower cumulative 24 h postoperative morphine dosage than the group 2 patients. Pain visual analog scale scores were significantly lower at both 6 and 24 h postoperatively in TAP group when compared with the no-TAP group. There were no complications related to the TAP block procedures. No signs or symptoms of local anesthetic systemic toxicity were detected. CONCLUSION: The combination of bilateral US-guided RS and TAP blocks provides excellent perioperative analgesia for major upper abdominal surgery. PMID- 26955307 TI - Use of an Android application "clinometer" for measurement of head down tilt given during subarachnoid block. AB - CONTEXT: Head down tilt is given to patients after sub arachnoid block for adjustment of height of block. However, the amount of tilt given is subjective and cannot be documented. AIMS: We used an android application named "clinometer" to measure exact degree of tilt given by anesthesiologists as their routine practice. SETTINGS AND DESIGN: This observational study, at a medical college hospital, was done in 130 patients given sub arachnoid block for lower abdominal surgeries. MATERIALS AND METHODS: We observed and documented vital data of patients and measured tilt given by application "clinometer." RESULTS: We observed that the application was easy to use and measured tilt each time. The result obtained can be documented, digitally saved and transferred. In 130 patients studied, we observed incidence of degree of tilt as follows: 6-8 degrees tilt in 38 patients (29.23%), 8-10 in 36 patients (27.69%), 10-12 in 30 patients (23.08%), 12-14 in 12 patients (9.23%) and 14-16 degrees tilt in 14 patients (10.77%). Use of application was received with enthusiasm by practicing anesthesiologists. Various possible uses of this application are discussed. PMID- 26955308 TI - Enhancing needle visualization during parasagittal approach in paravertebral block for patients undergoing simple mastectomy using in-plane, multiangle ultrasound needle guidance system. AB - BACKGROUND: Ultrasound-guided paravertebral blocks during breast surgeries with in-plane needle approaches can be challenging due to difficult needle visualization. The purpose of this study was to assess the usefulness of using a needle guide while performing in-plane parasagittal approach paravertebral block for breast surgery. PATIENTS AND METHODS: Eighty patients, American Society of Anesthesiologists physical status I-III, aged 20-40 years with breast mass scheduled for simple mastectomy surgery, were involved in prospective, controlled, randomized study, and were randomly divided by closed envelope method into two groups: Group I (n = 40): Scheduled for ultrasound-guided paravertebral block or group II (n = 40): Scheduled for ultrasound-guided paravertebral block using the needle guide. Both techniques compared as regards: (i) Needle visibility and block performance time; (ii) number of needle passes; (iii) duration of the block; (iv) doctor and patient satisfaction; and (v) incidence of complications. RESULTS: Needle visibility score was better in group II (2.92 +/- 0.26 vs. 1.9 +/- 0.44, P < 0.0001). Block performance time was shorter in group II (90.92 +/- 15 vs. 128.25 +/- 16s, P < 0.0001). A number of needle passes were less in group II (1.27 +/- 0.45 vs. 2.2 +/- 0.68, P < 0.0001). Doctor and patient satisfaction were better in group II (P = 0.015). No differences were found regarding the duration of the block and incidence of complications between groups. CONCLUSION: A needle guide can help reduce the time needed to perform a parasagittal in-plane thoracic paravertebral block, with a significant reduction in the block performance time, the number of needle passes, better needle visibility and better doctor and patient's satisfaction. However, there was no significant difference regarding the duration of the block or incidence of complications. PMID- 26955309 TI - Comparison of effects of ropivacaine with and without dexmedetomidine in axillary brachial plexus block: A prospective randomized double-blinded clinical trial. AB - BACKGROUND: Addition of dexmedetomidine to ropivacaine for peripheral nerve blocks has shown to improve the efficacy of ropivacaine by prolonging the duration of analgesia. This study was undertaken to evaluate the effects of ropivacaine alone and in combination with dexmedetomidine in the axillary block. MATERIALS AND METHODS: A total of 80 patients belonging to American Society of Anesthesiologists physical status I, II, and III, scheduled for elective forearm and/or hand surgeries were randomly allocated into one of the two groups to receive either 39 ml of 0.375% ropivacaine and 1 ml normal saline (Group R) or 39 ml of 0.375% ropivacaine and 1 MUg/kg dexmedetomidine diluted to 1 ml with normal saline (Group RD). RESULTS: There was a significant early the onset of sensory and the motor block in Group RD. Duration of sensory block in Group RD was 677.25 +/- 99.64 min and in Group R was 494.38 +/- 70.64 min and the difference was clinically significant (P < 0.001). Duration of motor block in Group RD was 712.88 +/- 89.32 min and in Group R was 526.25 +/- 70.229 min and was clinically significant. Duration of analgesia in Group RD was 764.38 +/- 110.275 min and that in Group R was 576.88 +/- 76.306 min and was clinically significant. There was a significant alteration in hemodynamics in Group RD when compared to Group R without any side effects. CONCLUSION: Dexmedetomidine as an adjuvant to ropivacaine provides quicker onset of anesthesia, longer duration of analgesia. It offers convenient, simple, effective mode of anesthesia, and postoperative analgesia for forearm and/or hand surgeries. PMID- 26955310 TI - Validation of acute physiologic and chronic health evaluation II scoring system software developed at The Aga Khan University, Pakistan. AB - OBJECTIVE: To assess the predictive performance of Acute Physiologic and Chronic Health Evaluation II (APACHE II) software available on the hospital intranet and analyze interrater reliability of calculating the APACHE II score by the gold standard manual method or automatically using the software. MATERIALS AND METHODS: An expert scorer not involved in the data collection had calculated APACHE II score of 213 patients admitted to surgical Intensive Care Unit using the gold standard manual method for a previous study performed in the department. The same data were entered into the computer software available on the hospital intranet (http://intranet/apacheii) to recalculate the APACHE II score automatically along with the predicted mortality. Receiver operating characteristic curve (ROC), Hosmer-Lemeshow goodness-of-fit statistical test and Pearson's correlation coefficient was computed. RESULTS: The 213 patients had an average APACHE II score of 17.20 +/- 8.24, the overall mortality rate was 32.8% and standardized mortality ratio was 1.00. The area under the ROC curve of 0.827 was significantly >0.5 (P < 0.01) and had confidence interval of 0.77-0.88. The goodness-of-fit test showed a good calibration (H = 5.46, P = 0.71). Interrater reliability using Pearson's product moment correlations demonstrated a strong positive relationship between the computer and the manual expert scorer (r = 0.98, P = 0.0005). CONCLUSION: APACHE II software available on the hospital's intranet has satisfactory calibration and discrimination and interrater reliability is good when compared with the gold standard manual method. PMID- 26955311 TI - Comparison of efficacy among various topical anesthetics: An approach towards painless injections in periodontal surgery. AB - BACKGROUND AND AIMS: Local anesthetics (LAs) are most commonly used agents in dentistry. They are used to prevent the pain and nociception generated during dental procedures. Since pain associated at the time of injection of LA is uncomfortable, most of the dentists are on pursuit of painless administration of LA injection and use of topical anesthetics prior to the injection has proven effective in reducing anxiety and pain to the patient. The aim of this study is to compare pain responses after application of three types of topical anesthetics with control in the patients referred for periodontal full mouth flap surgery. MATERIALS AND METHODS: A total of 83 patients (42 males and 41 females) participated in the study with age group ranging from 30 to 50 years. The present study is to evaluate the efficacy of three topical anesthetics (Precaine gel, Benzocaine topical paste and Lignocaine spray) before infiltration in altering visual analog scale (VAS) scores of pain during LA injection. The statistical analysis was performed using SPSS version 15.0 software. Repeated analysis of variance was performed to know the effect of each variable and reveal statistical significance. RESULTS: Results revealed that Precaine gel had least VAS score compared with other topical anesthetics. CONCLUSION: From the present study, it can be concluded that procaine gel is a better than other topical LA agents, as the number of studies on this subject is rare and clinical results are mixed, further studies are required with a larger sample before its routine application in our field. PMID- 26955312 TI - Effect of preoperative flupirtine on postoperative morphine sparing in patients undergoing total abdominal hysterectomy. AB - BACKGROUND: Flupirtine is a unique non-opioid, centrally acting analgesic with muscle relaxant properties. So far no study has evaluated, use of preoperative flupirtine on postoperative morphine sparing effect in patients undergoing total abdominal hysterectomy (TAH). MATERIALS AND METHODS: We performed a prospective, controlled, and randomized study in 50 female patients of American Society of Anesthesiologists physical status I-II, aged between 30 and 60 years scheduled for TAH under general anesthesia (GA). Patients were randomized to receive either single dose flupirtine 100 mg or placebo 1 h prior to surgery. A standard anesthetic and analgesic protocol was followed in both the groups. Postoperatively, a titrated loading dose of intravenous morphine 0.1 mg/kg was followed with patient-controlled analgesia with morphine (bolus of 0.01 mg/kg with a lockout time of 7 min). The primary outcome was cumulative morphine consumption at 48 h postoperatively. Secondary outcomes included hemodynamics, visual analog scale (VAS) at rest, VAS on cough, and any adverse effects. RESULTS: All enrolled 50 patients completed the follow-up. The cumulative mean morphine consumption (standard deviation [SD]) at 48 h (40.4 [6.0] vs. 47 [6.6] mg, P = 0.001) was reduced in-group flupirtine as compared with placebo. The cumulative mean VAS at rest (SD) (3 [0.7] vs. 3.7 [0.7], P = 0.001) and on cough (3 [0.9] vs. 3.8 [0.5], P = 0.002) were reduced in-group flupirtine as compared with placebo at 48 h postoperatively. CONCLUSION: Preoperative use of flupirtine exhibited morphine sparing effect in patients following TAH under GA at 48 h. PMID- 26955313 TI - Effect of addition of magnesium to local anesthetics for peribulbar block: A prospective randomized double-blind study. AB - BACKGROUND: Magnesium sulphate has been used along with local anesthetics in different regional blocks and found to be effective in decreasing the time of onset of the block and increasing the duration of the block. OBJECTIVE: To evaluate the effect of addition of magnesium sulfate to standard local anesthetics mixture on the time for onset of the globe and lid akinesia for peribulbar block in ophthalmic surgeries. MATERIALS AND METHODS: Sixty patients with American Society of Anesthesiologists status I to III undergoing ophthalmic surgery under peribulbar block were included in this study. Patients were randomized into two groups. Both the groups received 4.5 ml of 2% lidocaine, 4.5 ml of 0.5% bupivacaine with150 IU hyaluronidase. Group NS received normal saline 1 ml in the peribulbar block and Group MS, magnesium sulfate 50 mg in 1 ml normal saline. The onset of akinesia, satisfactory block and complications were observed by an independent observer. RESULTS: Demographic data was statistically similar. In the Group NS at 3, 5, 10 and 15 min after the block, complete akinesia was seen in 0, 2, 11 and 28 patients respectively. In the Group MS, at 3, 5, 10 and 15 min after the block, complete akinesia was seen in 13, 23, 27 and 28 patients respectively. Patients received magnesium sulfate showed the statistically significant rapid onset of lid and globe akinesia than the control group till 10 min (P < 0.000). None of the patients needed a supplementary block and had complications during the surgery. CONCLUSION: Addition of 50 mg of magnesium sulfate to the lidocaine-bupivacaine mixture for peribulbar block decreases the onset of akinesia without any obvious side effect. PMID- 26955314 TI - Elective surgery cancelation on day of surgery: An endless dilemma. AB - BACKGROUND: Cancelation of surgery is a constant agonizing dilemma for nearly all healthcare services that has been intensively investigated to find out its roots, consequences, and possible solutions. The rates of cancelation of surgery vary between centers and more so among surgical specialties with numerous reasons standing behind this phenomenon. PATIENTS AND METHODS: In the current study, analysis of monthly cancelation rates from January 2009 to December 2012, and assessment of establishing new operating rooms (ORs) using statistical process control charts was conducted. A detailed review of a total of 1813 cases canceled on the day of surgery from January to December 2012, to examine the various reasons of cancelation among surgical specialties. RESULTS: The average cancelation rate was 11.1%, which dropped to 9.0% after launching of new theaters. Four reasons explained about 80% of cancelations; Patients "no show" was the leading cause of cancelation (27%). One-fourth of cancelations (24.3%) were due to the need for further optimization, and the third most prominent cause of cancelation was a lack of OR time (19.5%). Unavailability of staff/equipment/implants accounted for only 0.7% of cancelations. The no show was the most common cause of cancelation among all surgical specialties ranging from 21% for plastic surgery to 32% in ophthalmic surgeries. CONCLUSION: It was confirmed that there is a unique profile of cancelation of surgery problem for every institute, an extension of infrastructure may not be the only solution. Control charts helped to enhance the general picture and are functional in monitoring and evaluating changes in the cancelation of surgery. PMID- 26955315 TI - Induced hypotension in ambulatory functional endoscopic sinus surgery: A comparison between dexmedetomidine and clonidine as premedication. A prospective, double-blind, and randomized study. AB - BACKGROUND: Functional endoscopic sinus surgery (FESS) is the mainstay of a therapeutic technique for nasal pathologies. This study is to compare the ability of preoperative dexmedetomidine versus clonidine for producing controlled hypotensive anesthesia during FESS in adults in an ambulatory care setting. MATERIALS AND METHODS: Sixty patients (25-50 years) posted for ambulatory FESS procedures under general anesthesia were randomly divided into Group C and D (n = 33 each) receiving dexmedetomidine 1 MUg/kg and clonidine 1.5 MUg/kg, respectively; both diluted in 100 ml saline solution 15 min before anesthetic induction. Nasal bleeding and surgeon's satisfaction score; amount and number of patients receiving fentanyl and nitroglycerine for analgesia and deliberate hypotension, duration of hypotension, post anesthesia care unit (PACU) and hospital stay; hemodynamic parameters and side effects were recorded for each patient. RESULTS: Number and dosage of nitroglycerine used was significantly (P = 0.034 and 0.0001 respectively) lower in Group D compared to that in Group C. Similarly, number of patients requiring fentanyl and dosage of same was significantly lower in Group D. But, the duration of controlled hypotension was almost similar in both the groups. Group D patients suffered from significantly less nasal bleeding and surgeon's satisfaction score was also high in this group. Discharge from PACU was significantly earlier in Group D, but hospital discharge timing was quite comparable among two groups. Intraoperative hemodynamics was significantly lower in Group D (P < 0.05) without any appreciable side effects. CONCLUSION: Dexmedetomidine found to be providing more effectively controlled hypotension and analgesia, and thus, allowing less nasal bleeding as well as more surgeons' satisfaction score. PMID- 26955317 TI - Role of oral care to prevent VAP in mechanically ventilated Intensive Care Unit patients. AB - Ventilator associated pneumonia (VAP) is the most common nosocomial infection in Intensive Care Unit. One major factor causing VAP is the aspiration of oral colonization because of poor oral care practices. We feel the role of simple measure like oral care is neglected, despite the ample evidence of it being instrumental in preventing VAP. PMID- 26955316 TI - Role of intraseptal anesthesia for pain-free dental treatment. AB - Pain control during the dental procedure is essentials and challenging. A complete efficacious pulp anesthesia has not been attained yet. The regional anesthesia such as inferior alveolar nerve block (IANB) only does not guarantee the effective anesthesia with patients suffering from irreversible pulpitis. This main aim of this review was to discuss various aspects of intraseptal dental anesthesia and its role significance in pain-free treatment in the dental office. In addition, reasons of failure and limitations of this technique have been highlighted. Literature search was conducted for peer-reviewed articles published in English language in last 30 years. Search words such as dental anesthesia, pain control, intraseptal, and nerve block were entered using a web of knowledge and Google scholar databases. Various dental local anesthesia techniques were reviewed. A combination of block anesthesia, buccal infiltration and intraligamentary injection resulted in deep anesthesia (P = 0.003), and higher success rate compared to IANB. For pain-free management of conditions such as irreversible pulpitis, buccal infiltration (4% articaine), and intraosseous injection (2% lidocaine) are better than intraligamentary and IANB injections. Similarly, nerve block is not always effective for pain-free root canal treatment hence, needing supplemental anesthesia. Intraseptal anesthesia is an efficient and effective technique that can be used in maxillary and mandibular adult dentition. This technique is also beneficial when used in conjunction to the regional block or local dental anesthesia. PMID- 26955319 TI - Fluoroscopy guided transforaminal epidural anesthesia in ankylosing spondylitis. AB - A 48-year-old male patient with a long-standing history of ankylosing spondylitis (AS) presented for ureteroscopic stone removal. On preoperative assessment, tracheal intubation was likely to be difficult due to decreased cervical spine mobility. Traditional neuraxial block was impossible due to the fusion of vertebral bodies. AS patients present the most serious array of intubation, which is secondary to decrease in cervical spine mobility and possible temporomandibular joint disease. Management of a case of AS can be very challenging when the airway and the central neuraxial blockade, both are difficult. Fluoroscopic assisted central neuraxial blockade may lead to predictable success in AS. We present a case report with severe AS where conventional techniques failed and C-arm assisted helped in successful epidural anesthesia for ureteroscopic stone removal. PMID- 26955318 TI - Anesthetic management of a patient with Weaver syndrome undergoing emergency evacuation of extra-dural hematoma: A case report and review of the literature. AB - Weaver syndrome is a rare disorder of unknown etiology characterized by skeletal overgrowth, distinctive craniofacial and digital abnormalities and advanced bone age. In general, craniofacial abnormalities that cause difficulty with tracheal intubation may improve, worsen, or remain unchanged as craniofacial structures mature. Furthermore, there is an estimated risk in these children of <=1.09% of rhabdomyolysis or malignant hyperpyrexia. We report a case of a boy with Weaver syndrome who underwent emergency evacuation of extra-dural hematoma under general anesthesia. PMID- 26955320 TI - Central bronchial carcinoid: Management of a case and anesthetic perspectives. AB - Obstructing lesions of the central airways present with a variety of symptoms and are often associated with pneumonia or asthma-like states. Anesthesia to these patients often presents challenges right from the preoperative stabilization of underlying lung condition, mask ventilation in the supine position to maintaining oxygenation and ventilation in the intraoperative and postoperative period. We present here a case of a young woman with a central bronchial tumor with significant airway obstruction with potential for major bleeding and subsequent anesthetic management without lung sacrificing measures and cardiopulmonary bypass assistance. PMID- 26955321 TI - Successful management of a refractory case of postoperative herniorrhaphy pain with extended duration pulsed radiofrequency. AB - Chronic postsurgical pain (CPSP) is a distressful condition following hernia surgery. A 25-year-old, 55 kg male patient presented with severe pain on the right side of the lower abdomen that radiated to the testicle and the inner side of the thigh. Patient was symptomatic since 5 months following inguinal herniorrhaphy surgery. The pain was not relieved with pharmacological and interventional nerve blocks. An ultrasound-guided ilioinguinal-iliohypogastric (II-IH) block with extended duration (42 degrees C, four cycles of 120 s each) pulsed radiofrequency (PRF) and a diagnostic genital branch of genitofemoral nerve (GGFN) block provided pain relief. After 1-month, an extended duration PRF in GGFN resulted in complete resolution of symptoms. During a regular follow-up of 9 months, patient reported an improved quality-of-life. We believe the successful management of CPSP following hernia repair with single extended duration PRF of II-IH and GGFN has not been described in the literature. PMID- 26955323 TI - Impacted tooth presenting as airway obstruction during spontaneous breathing trial. PMID- 26955322 TI - Anesthetic consideration in dystrophic epidermolysis bullosa. AB - Epidermolysis bullosa is a group of inherited rare skin disease, characterized by bullae formation in the skin or mucous membranes. The fundamental abnormality is collagen degeneration leads to splitting of various epidermal layers. Dystrophic epidermolysis bullosa (DEB) is one of the major forms of epidermolysis bullosa. These patients often admitted to the hospital for corrective surgeries, change of dressing, contracture release, and skin grafting. Anesthetic management of these cases is always a challenge. We are reporting a case of 5-year-old boy diagnosed as a case of DEB scheduled for upper lip contracture release, skin grafting and debridement of nonhealing scars under anesthesia. In this case, we have focused mainly on the anesthetic management, preparation of the monitoring, transportation, difficulties in establishing the venous accesses, and airway management. PMID- 26955324 TI - Complete airway obstruction with inferior turbinate avulsion after nasotracheal intubation. PMID- 26955325 TI - Sexual Behavior Increases Cell Proliferation in the Rostral Migratory Stream and Promotes the Differentiation of the New Cells into Neurons in the Accessory Olfactory Bulb of Female Rats. AB - We have previously demonstrated, that 15 days after female rats pace the sexual interaction, there is an increase in the number of new cells that reach the granular cell layer (GrL) of the accessory olfactory bulb (AOB). The aim of the present study was to evaluate, if the first sexual experience in the female rat increases cell proliferation in the subventricular zone (SVZ) and the rostral migratory stream (RMS). We also tested if this behavior promotes the survival of the new cells that integrate into the main olfactory bulb (MOB) and AOB 45 days after the behavioral test. Sexually, naive female rats were injected with the DNA synthesis marker 5'-bromo-2'-deoxyuridine (BrdU) on the day of the behavioral test. They were randomly divided into the following groups: Female rats placed alone in the mating cage (1); Females exposed to amyl acetate odor [banana scent, (2)]; Females that could see, hear, and smell the male but physical contact was not possible [exposed to male, (3)]; Female rats that could pace the sexual interaction (4); and females that mated without the possibility of pacing the sexual interaction (5). Animals were sacrificed 2 days after the behavioral test (proliferation) or 45 days later (survival). Our results show that 2 days after females were exposed to banana scent or to the male, they had a higher number of cells in the SVZ. Females, that mated in pace and no-paced conditions had more new cells in the RMS. At 45 days, no significant differences were found in the number of new cells that survived in the MOB or in the AOB. However, mating increased the percentage of new cells, that differentiated into neurons in the GrL of the AOB. These new cells expressed c-Fos after a second sexual encounter just before the females were sacrificed. No significant differences in plasma levels of estradiol and progesterone were observed between groups. Our results indicate that the first sexual experience increases cell proliferation in the RMS and mating 45 days later enhances the number of new cells that differentiate into neurons in the AOB. These new neurons are activated by sexual stimulation. PMID- 26955326 TI - Vascular Dynamics Aid a Coupled Neurovascular Network Learn Sparse Independent Features: A Computational Model. AB - Cerebral vascular dynamics are generally thought to be controlled by neural activity in a unidirectional fashion. However, both computational modeling and experimental evidence point to the feedback effects of vascular dynamics on neural activity. Vascular feedback in the form of glucose and oxygen controls neuronal ATP, either directly or via the agency of astrocytes, which in turn modulates neural firing. Recently, a detailed model of the neuron-astrocyte vessel system has shown how vasomotion can modulate neural firing. Similarly, arguing from known cerebrovascular physiology, an approach known as "hemoneural hypothesis" postulates functional modulation of neural activity by vascular feedback. To instantiate this perspective, we present a computational model in which a network of "vascular units" supplies energy to a neural network. The complex dynamics of the vascular network, modeled by a network of oscillators, turns neurons ON and OFF randomly. The informational consequence of such dynamics is explored in the context of an auto-encoder network. In the proposed model, each vascular unit supplies energy to a subset of hidden neurons of an autoencoder network, which constitutes its "projective field." Neurons that receive adequate energy in a given trial have reduced threshold, and thus are prone to fire. Dynamics of the vascular network are governed by changes in the reconstruction error of the auto-encoder network, interpreted as the neuronal demand. Vascular feedback causes random inactivation of a subset of hidden neurons in every trial. We observe that, under conditions of desynchronized vascular dynamics, the output reconstruction error is low and the feature vectors learnt are sparse and independent. Our earlier modeling study highlighted the link between desynchronized vascular dynamics and efficient energy delivery in skeletal muscle. We now show that desynchronized vascular dynamics leads to efficient training in an auto-encoder neural network. PMID- 26955327 TI - The Advantages of Structural Equation Modeling to Address the Complexity of Spatial Reference Learning. AB - BACKGROUND: Cognitive performance is a complex process influenced by multiple factors. Cognitive assessment in experimental animals is often based on longitudinal datasets analyzed using uni- and multi-variate analyses, that do not account for the temporal dimension of cognitive performance and also do not adequately quantify the relative contribution of individual factors onto the overall behavioral outcome. To circumvent these limitations, we applied an Autoregressive Latent Trajectory (ALT) to analyze the Morris water maze (MWM) test in a complex experimental design involving four factors: stress, age, sex, and genotype. Outcomes were compared with a traditional Mixed-Design Factorial ANOVA (MDF ANOVA). RESULTS: In both the MDF ANOVA and ALT models, sex, and stress had a significant effect on learning throughout the 9 days. However, on the ALT approach, the effects of sex were restricted to the learning growth. Unlike the MDF ANOVA, the ALT model revealed the influence of single factors at each specific learning stage and quantified the cross interactions among them. In addition, ALT allows us to consider the influence of baseline performance, a critical and unsolved problem that frequently yields inaccurate interpretations in the classical ANOVA model. DISCUSSION: Our findings suggest the beneficial use of ALT models in the analysis of complex longitudinal datasets offering a better biological interpretation of the interrelationship of the factors that may influence cognitive performance. PMID- 26955329 TI - An Unusual Case of Multiple Tendinous Xanthomas Involving the Extremities and the Ears. AB - Tendinous and subcutaneous xanthomas are nodular deposits of lipid-filled macrophages, which commonly form on the Achilles tendon, hands, feet, elbows, and knees. These nodules are frequently associated with familial hyperlipidemia, a group of diseases involving impaired cholesterol metabolism, and the accelerated development of atherosclerotic plaques. Since xanthomas may precede the diagnosis of hyperlipidemia, early identification can lead to preventative treatment that reduces the risk and morbidity of cardiovascular disease, including myocardial infarction. This case report presents a 43-year-old African-American male with multiple xanthomas involving the Achilles tendon, soles, hands, knees, elbows, and is associated with the unusual involvement of the ear. PMID- 26955328 TI - Erythromelanosis Follicularis Faciei: A Case Report and Review of the Literature. AB - Erythromelanosis follicularis faciei is a rare sporadic condition of unknown etiology characterized by reddish-brownish patches and follicular papules that appear commonly on the face and rarely on the neck. Herein, we report a 16-year old male who had asymptomatic facial skin lesions since early childhood. His family history revealed a similar case in his younger brother. His parents are not consanguineous. Skin examination revealed diffuse nonscaly brownish patches with erythematous background and multiple skin-colored, hypopigmented follicular papules on both cheeks. A summary of previous reports of erythromelanosis follicularis faciei in the literature is presented in this report. PMID- 26955331 TI - A Case of Basal Cell Carcinoma with Outer Hair Follicle Sheath Differentiation. AB - A 70-year-old Japanese man presented at our hospital with an asymptomatic, blackish, irregularly shaped plaque with a gray nodule in the periphery on his left lower leg. The lesion had been present for 10 years and had recently enlarged, associated with bleeding. Histopathologically, the tumor consisted of three distinct parts: The first part showed massive aggregation of basophilic basaloid cells with peripheral palisading and abundant melanin granules, and was diagnosed as solid-type basal cell carcinoma. The second part showed aggregation of clear cells with squamous eddies, and was diagnosed as proliferating trichilemmal tumor. The third part showed reticular aggregation of basaloid cells with infundibular cysts in the papillary dermis, and was diagnosed as infundibulocystic basal cell carcinoma. We diagnosed this tumor as basal cell carcinoma with various forms of hair follicle differentiation, including differentiation into the outer root sheath. PMID- 26955330 TI - A Case of Acute Generalized Pustular Psoriasis of von Zumbusch Triggered by Hypocalcemia. AB - Psoriasis is an autoimmune disease triggered by different conditions in genetically susceptible people. It is characterized by variable cutaneous manifestations including localized or disseminated pustules. Generalized pustular psoriasis (GPP) has two main clinical forms: von Zumbusch psoriasis, characterized by severe erythrodermia and scaling skin after the resolution of pustules, and the annular form. GPP may also present severe extracutaneous manifestations including pneumonitis, heart failure and hepatitis. Old reports showed a relationship between hypoparathyroidism and hypocalcemia as triggers for GPP highlighting the importance of adequate workup of the patient and possible therapeutic changes in acute situations. Here, we present a case of severe von Zumbusch psoriasis with life-threatening complications triggered by severe hypocalcemia secondary to hypoparathyroidism successfully treated with aggressive calcium reposition. PMID- 26955332 TI - Hair Follicle Nevus with Sebaceous Hyperplasia: A Dermoscopic Observation. AB - We herein report a case of hair follicle nevus, a rare hamartoma found on the face and showing follicular differentiation, which was associated with sebaceous hyperplasia. Dermoscopy of the lesion showed yellow globules surrounded by crown vessels/telangiectasias and scattered tiny hairs. Histopathological investigation revealed hyperplasia of the sebaceous glands and proliferation of well differentiated vellus hair follicles. These pathological findings were thought to correspond to the yellowish globules and tiny hairs observed under dermoscopy. Hair follicle nevus associated with sebaceous hyperplasia is extremely rare; however, dermoscopic examination can suggest an appropriate diagnosis. The present case proved the diagnostic usefulness of dermoscopy for cutaneous tumors with hair follicular and sebaceous glandular differentiation. PMID- 26955333 TI - Cerebral Amyloid Angiopathy Presenting with Synchronous Bilateral Intracerebral Macrohemorrhages. AB - Cerebral amyloid angiopathy (CAA) is the deposition of amyloid proteins in the cerebrovasculature, which can lead to intracerebral hemorrhage. Intracerebral hemorrhage in CAA often presents with microhemorrhages and, less frequently, with more devastating macrohemorrhages. We present a case of CAA-related synchronous bilateral intracerebral macrohemorrhage which, to our knowledge, has yet to be reported in the literature, and postulate its relationship to antiplatelet therapy and transient elevations in blood pressure. PMID- 26955334 TI - Cronobacter sakazakii DNA Detection in Cerebrospinal Fluid of a Patient with Amyotrophic Lateral Sclerosis Mimic Syndrome. AB - A 45-year-old male noticed progressive weakness of the right lower limb with gait disturbance. Over the following months, motor deficits worsened, spreading to the right upper limb. Electromyography showed active denervation in the upper and lower limb muscles. A diagnosis of amyotrophic lateral sclerosis (ALS) was made. About 2 years after symptom onset, gradual improvement occurred. Cerebrospinal fluid analysis performed about 3 years after the beginning of symptoms identified Cronobacter sakazakii. Since no other possible causes were identified, we suggest that an almost completely reversible ALS-like syndrome had been triggered by Cronobacter infection in our immunocompetent patient. PMID- 26955335 TI - Delayed Posthypoxic Leukoencephalopathy: Improvement with Antioxidant Therapy. AB - INTRODUCTION: Delayed posthypoxic leukoencephalopathy (DPHL) may result from a variety of hypoxic insults, including respiratory depression from an opiate overdose. The underlying pathophysiological mechanism of DPHL remains uncertain. We describe a patient with a typical case of DPHL who responded clinically to antioxidant treatment. METHODS: Clinical, serological, and radiographic investigations were undertaken in the evaluation of the patient. RESULTS: A 63 year-old man developed altered mental status 10 days following recovery from an opiate overdose and aspiration pneumonia that required intubation. The clinical course and brain imaging were consistent with DPHL. Initiation of antioxidant therapy with vitamin E, vitamin C, B-complex vitamins, and coenzyme Q10 coincided with the prompt reversal of clinical deterioration. CONCLUSIONS: The potential therapeutic effect of antioxidants on DPHL needs to be explored in future cases. If this relationship indeed holds true, it would be consistent with the hypothesis that formation of reactive oxygen species during reperfusion plays a role in the pathophysiology of this disorder. PMID- 26955336 TI - Recurrent Episodes of Stroke-Like Symptoms in a Patient with Charcot-Marie-Tooth Neuropathy X Type 1. AB - Charcot-Marie-Tooth disease (CMT), also known as hereditary motor sensory neuropathy, is a heterogeneous group of disorders best known for causing inherited forms of peripheral neuropathy. The X-linked form, CMTX1, is caused by mutations in the gap junction protein beta 1 (GJB1) gene, expressed both by peripheral Schwann cells and central oligodendrocytes. Central manifestations are known but are rare, and there are few case reports of leukoencephalopathy with transient or persistent neurological deficits in patients with this CMT subtype. Here, we report the case of a man with multiple male and female family members affected by neuropathy who carries a pathologic mutation in GJB1. He has experienced three transient episodes with variable neurological deficits over the course of 7 years with corresponding changes on magnetic resonance imaging (MRI). This case illustrates CMT1X as a rare cause of transient neurological deficit and demonstrates the evolution of associated reversible abnormalities on MRI over time. To the best of our knowledge, this report provides the longest period of serial imaging in a single patient with this condition in the English language literature. PMID- 26955337 TI - Choroidal Neovascularization Associated with Punctate Inner Choroidopathy: Combination of Intravitreal Anti-VEGF and Systemic Immunosuppressive Therapy. AB - PURPOSE: Choroidal neovascularization (CNV) associated with punctate inner choroidopathy (PIC) is a rare clinical entity, yet still a challenge for medical treatment. A case of a young myopic woman developing CNV secondary to unilateral PIC is presented. Clinical morphology, diagnostic procedure and follow-up are reported. CASE REPORT: A 29-year-old woman presented with multiple yellowish dots at the posterior pole. No other signs of inflammation could be seen. Angiography with fluorescein yielded hyperfluorescent signals in the affected areas with a diffuse leak, and SD-OCT showed a slightly elevated retinal pigment epithelial layer, consistent with the diagnosis of PIC. Additionally a classic CNV was observed. RESULTS: Anti-inflammatory therapy with local prednisolone acetate eye drops in combination with intravitreal injection of anti-vascular endothelial growth factor (VEGF, bevacizumab) yielded an increased best-corrected visual acuity. As CNV reappeared, systemic medication with prednisone and azathioprine in combination with two further intravitreal injections of anti-VEGF stabilized CNV and increased visual acuity again. CONCLUSION: Combined therapy of immunosuppression with intravitreal anti-VEGF injections can be considered as therapeutic strategy in the management of recurrent CNV associated with PIC. PMID- 26955338 TI - Periarteriolar-Sparing Retinal Edema in Acute Central Retinal Artery Occlusion. AB - A 56-year-old man was referred to our hospital about 48 h after sudden onset of painless central visual loss in his right eye (OD) on a winter morning. He had a more than 25-year history of systemic hypertension and smoking. Funduscopic observation showed striated retinal whitening in the macular region, faint cotton wool patches around the optic disc, and segmental narrowing of the retinal arteries near the optic disc edge. Based on the pattern of onset and fundus findings, he was diagnosed with vasospastic acute central retinal artery occlusion OD, and a venous drip injection of prostaglandin E1 was started immediately. Optical coherence tomography showed bands of high and low density in the inner retina arranged alternately in the edematous area; the bands corresponded to edematous and nonedematous areas, respectively, and geographically to venules and arterioles, respectively. The best-corrected visual acuity of 0.03 at referral improved to 0.5, and the striated retinal edema and most cotton-wool patches resolved 1 month after onset. The oxygen pressure gradient in the capillary networks due to differences in the distance from the arterioles may be the mechanism of this unique periarteriolar-sparing retinal edema pattern. PMID- 26955339 TI - Sudden Visual Deterioration as the First Symptom of Chronic Kidney Failure. AB - PURPOSE: We report here a unique case of a sudden loss of vision as the first symptom of an advanced chronic nephropathy. METHODS AND RESULTS: A 25-year-old man was referred to the Department of Ophthalmology with sudden visual deterioration presumptively diagnosed as bilateral retinitis. The patient had never been under any medical care before and had never had any clinical signs of any chronic disease. He underwent an ophthalmic examination with optical coherence tomography (OCT). Based on the clinical features, OCT scans and systemic blood pressure (BP) assessment (225/145 mm Hg), the patient was definitely diagnosed with hypertensive retinopathy and choroidopathy due to hypertensive crisis. After urgent diagnostic procedures, the patient was diagnosed with a chronic kidney disease at stage 5 in the course of chronic glomerulonephritis. Immediately, a renal replacement therapy was started and the patient was qualified for renal transplantation. CONCLUSION: Adolescents with an unclear picture of retinal lesions, who have neither a history nor clinical signs of a systemic disease, should undergo careful systemic screening with BP assessment. A sudden deterioration of vision may be the first symptom of a previously undiagnosed severe systemic disease (very rare chronic) that requires immediate treatment. PMID- 26955340 TI - Age-Related True Exfoliation of the Lens Capsule: Phacoemulsification Surgery Results. AB - Historically associated with glassblowers, true exfoliation of the crystalline lens involves a splitting or delamination of the capsule. We reviewed the phacoemulsification records of a single surgeon for patients with true exfoliation of the lens capsule. The incidence in our series was 2.2% (6 in 278 cases). The average age was 85.0 years. All patients had successful phacoemulsification outcomes, which may have been due to accurate recognition of the condition and appropriate surgical planning. Our findings support the notion that true exfoliation may be more often associated with advanced age rather than infrared radiation. PMID- 26955341 TI - Simultaneous Single Dexamethasone Implant and Ranibizumab Injection in a Case with Active Serpiginous Choroiditis and Choroidal Neovascular Membrane. AB - Intravitreal anti-vascular endothelial growth factor (VEGF) agents seem to be effective in choroidal neovascular membranes (CNV) in association with various entities of posterior uveitis. We herein report a 46-year-old woman who was treated with a simultaneous single intravitreal dexamethasone implant and ranibizumab administration for the treatment of unilateral extrafoveal CNV associated with an active serpiginous choroiditis. Simultaneously with the intravitreal therapy, oral mycophenolic acid (2 * 720 mg) was started, and oral cyclosporine (3 * 100 mg) was then added 2 months later. On the other hand, the fellow eye had been treated for subfoveal CNV but with an inactive disease 4 years previously and ended up with a final visual acuity of counting fingers despite treatment with a single session of photodynamic therapy and 3 subsequent intravitreal ranibizumab injections. Simultaneous administration of anti-VEGF agents and a dexamethasone implant can be a viable approach in eyes with CNV and active serpiginous choroiditis. PMID- 26955342 TI - Hypertensive Retinopathy as the First Manifestation of Advanced Renal Disease in a Young Patient: Report of a Case. AB - The purpose of this paper was to report the case of a 23-year-old patient suffering from bilateral acute visual loss who received the diagnosis of hypertensive retinopathy. After systemic evaluation, he was diagnosed with bilateral renal disease and chronic renal failure, requiring a kidney transplantation to manage the systemic illness, followed by gradual improvement of his visual acuity. PMID- 26955343 TI - Vitrectomy for Proliferative Diabetic Retinopathy Associated with Klinefelter Syndrome. AB - INTRODUCTION: We encountered a patient with Klinefelter syndrome (KS) who experienced poor outcomes after vitrectomy for proliferative diabetic retinopathy (PDR). CASE: A 44-year-old male with poorly controlled diabetes was diagnosed with KS by chromosome analysis. Ocular findings revealed severe PDR complicated with extensive preretinal hemorrhages and traction retinal detachment in his left eye, and pars plana vitrectomy was subsequently performed for treatment. RESULTS: A clotting hemorrhage developed during surgery and proved difficult to control. Due to postoperative bleeding and redetachment, the vitrectomy was repeated. At the second operation, we performed a silicone oil tamponade; however, the retina was redetached under the silicone oil, and the light perception vision ultimately disappeared. CONCLUSION: The patient, despite showing increased blood coagulability due to diabetes, presented severe coagulopathy, likely related to KS. In patients with KS and severe PDR, the potential difficulty of vitrectomy should always be kept in mind. PMID- 26955344 TI - Vitamin A Deficiency Presenting with 'Itchy Eyes'. AB - We present the case of an 88-year-old female living in metropolitan Melbourne, Australia who developed vitamin A deficiency manifesting as 'itchy eyes' due to a bizarre dietary habit. Slit lamp examination revealed Bitot's spots and a subsequent vitamin A serum level test revealed severe deficiency. An electroretinogram showed grossly reduced a- and b-wave amplitudes consistent with generalised rod and cone dysfunction - these parameters showed marked improvement 5 months post supplementation. This case highlights the presence of vitamin A deficiency in the developed world and that a careful dietary history should be taken when assessing a patient complaining of 'itchy eyes'. Timely diagnosis and treatment may result in dramatic resolution of symptoms and signs as well as prevention of serious morbidity. PMID- 26955345 TI - Breast Cancer Metastasis Presenting as Conjunctival Chemosis. AB - A 72-year-old woman presented with a painful right eye. A few weeks before, she had noticed a red, swollen area in the conjunctiva of the same eye. On slit lamp examination, it appeared as chemosis and vascular injection; artificial tears were prescribed. A month later, a firm mass developed on the superotemporal orbital rim, in the area of the lacrimal gland. A CT scan revealed infiltrative structures in both the left and right orbit, with contrast staining in the right lacrimal gland and near the left optic nerve. A biopsy was taken of the conjunctival swelling as well as of the lacrimal gland. Both tissues showed infiltration with lobular breast carcinoma metastases. PMID- 26955347 TI - Missed Diagnosis of an Intraorbital Foreign Body of Homemade Fireworks Origin: A Case Report. AB - PURPOSE: We report a rare case of traumatic injury to the eye caused by homemade fireworks in a Chinese juvenile patient with a metal ring left in the orbit after having been sutured at the Emergency Department. METHODS: An 11-year-old boy presented with a traumatic injury to the right eye from homemade fireworks. Following initial assessment involving maxillofacial computed tomography (CT) and suturing at the Emergency Department, he was transferred to our department for further evaluation because of his poor sight 1 day later. On examination, a skin laceration beneath the right eyebrow was noted, but the superior orbit was not fully visible on the maxillofacial CT performed 1 day previously. Therefore, an orbital CT scan was carried out on the second day, which showed a hyperdense ring embedded in the superior border of the orbital wall; the ring was surgically removed. On postoperative day 7, a fundus examination revealed resolving vitreous hemorrhage, blunt traumatic retinal detachment, and a large retinal tear superior to the macula. The patient refused to take surgery for retinal detachment into consideration. Therefore, we opted for oral steroids and careful observation. RESULTS: After 2 months' observation, the large retinal tear had healed and white fibrous scar tissue had developed, and the retinal detachment superior to the macula had reattached itself spontaneously. The patient's vision had further improved to 20/200. During 1 year of follow-up, he remained clinically stable. CONCLUSION: To avoid missing the diagnosis, a complete history of the mechanism of injury and accurate imaging still prove most useful. Complete removal of the foreign body by the emergency physician is necessary because of the ocular toxicity of an iron-containing foreign body. As evidenced by the current case, oral steroids and observation for a period of several months is a management of choice for traumatic retinal detachment and retinal tear superior to the macula associated with homemade fireworks in children. PMID- 26955346 TI - Diffuse Anterior Retinoblastoma with Sarcoidosis-Like Nodule. AB - BACKGROUND: Retinoblastomas account for 4% of malignancies in children, 1-2% of which are diffuse infiltrating retinoblastomas. Diffuse anterior retinoblastoma is rare and does not involve the retina. Here, we report on a diffuse anterior retinoblastoma with large sarcoidosis-like nodules on the iris that were responsive to anti-inflammatory therapy. CASE: We present a 6-year-old girl who had anterior uveitis with white nodules on the iris and posterior surface of the cornea in her right eye. The nodules initially responded well to anti inflammatory treatment. However, anterior segment optical coherence tomography (AS-OCT) showed that the nodules gradually grew, shrinking the iris. We then collected the aqueous humor for diagnosis. A biopsy revealed clusters of small cells with a high nuclear-to-cytoplasm ratio with partial rosette formation. Therefore, we diagnosed diffuse anterior retinoblastoma without retinal involvement and performed enucleation of the right eye. The histopathology demonstrated undifferentiated cells similar to those seen on the biopsy, and tumor cells invaded the iris stroma, posterior surface of the cornea, ciliary body, and sclera. After the enucleation, she underwent chemotherapy and remains alive. CONCLUSION: A differential diagnosis of retinoblastoma should be considered when white nodules refractory to anti-inflammatory therapy occur in the eye, even in the absence of obvious retinal masses. AS-OCT findings are useful in assessing retinoblastoma. PMID- 26955348 TI - A Case of Ampiginous Choroiditis. AB - PURPOSE: Presentation of a case report of a unilateral ampiginous choroiditis. METHODS: This is an observational case report. RESULTS: A 70-year-old woman was referred to us with unilateral scattered chorioretinal lesions. The multifocal pattern of the lesions and the angiographic features led to the diagnosis of ampiginous choroiditis. CONCLUSION: Ampiginous choroiditis is a primary inflammatory choriocapillaropathy with characteristics of both acute posterior multifocal placoid pigment epitheliopathy and serpiginous choroiditis. PMID- 26955349 TI - Bilateral Refractive Changes in Vascularized Pigment Epithelial Detachment Treated by Anti-VEGF Therapy. AB - We report the case of a patient bilaterally treated with anti-VEGF compounds for bilateral massive vascularized retinal pigment epithelial detachment (PED). During the years prior to treatment, PED growth was accompanied by gradual hypermetropization. After right intraocular injection of bevacizumab followed by three bilateral aflibercept injections, the PED flattened resulting in a rapid relative myopization. This case illustrates ocular refractive properties associated with PED and its response to treatment. This case also highlights the importance of assessing refraction in age-related macular degeneration patients experiencing substantial PED amplitude changes. PMID- 26955350 TI - Combined Central Retinal Artery and Vein Occlusion Associated with Factor V Leiden Mutation and Treated with Hyperbaric Oxygen. AB - BACKGROUND: Combined central retinal artery occlusion (CRAO) and central retinal vein occlusion (CRVO) is an uncommon retinal vascular disease which causes sudden visual acuity loss and is associated with poor prognosis and the development of severe complications. We report a very rare case of combined CRAO and CRVO in a patient with factor V Leiden (FVL) mutation (only 3 cases published). To our knowledge, this is the first case of combined CRAO and CRVO treated with hyperbaric oxygen therapy (HBOT). CASE AND RESULTS: A 49-year-old woman presented with complaints of sudden loss of vision in her left eye (LE), with best corrected visual acuity (BCVA) of 1/20. A complete ophthalmic evaluation with fundus angiography showed combined CRAO and CRVO. The patient was urgently treated with HBOT (she completed a total of 9 sessions in 7 days), with marked visual acuity and angiographic improvement (BCVA of 10/10). Forty-five days later, she developed a new LE CRVO, and BCVA decreased to 5/10 and later to <1/20 because of significant macular edema. A detailed investigation showed an abnormal resistance to activated protein C, and a genetic study showed homozygosity for FVL mutation. The patient was submitted to 3 monthly injections of 1.25 mg bevacizumab. After 10 months, the patient is in a stable condition with BCVA of 6/10. CONCLUSIONS: Combined CRAO and CRVO in young adults should be investigated thoroughly for embolic sources, thrombophilic disorders and local ocular conditions. This is the first case of this severe disease that was treated with HBOT, and the visual result was very good. PMID- 26955351 TI - Optical Coherence Tomography Findings in Anterior Chamber Ointment Globule after Phacoemulsification. AB - We present 2 cases of anterior chamber ointment with evidence of progressive endothelial cell loss. In both cases, an anterior segment optical coherence tomography (OCT) was similar to an OCT of a tobramycin-dexamethasone ointment placed on a pen tip. An anterior segment OCT also demonstrated the direct contact of the globule with the corneal endothelium. A gas chromatography/mass spectrometry analysis documented the similarity to tobramycin-dexamethasone ointment in 1 case. Anterior segment OCT can help in confirming the diagnosis. Corneal endothelial injury is a continuous process, and its clinical manifestation is related to the size of the globule, the initial endothelium count, and the duration of ointment contact, which is related to supine positioning. It is advisable to avoid ointments in the immediate postoperative period, especially in corneal wounds larger than 3 mm. PMID- 26955352 TI - Eplerenone in the Treatment of Polypoidal Choroidal Vasculopathy. AB - Overactivation of mineralocorticoid receptor pathways has been implicated in the pathophysiology of central serous chorioretinopathy (CSCR). Recently, mineralocorticoid receptor antagonists such as eplerenone have demonstrated success in treating subretinal fluid in CSCR. This case demonstrates a patient who was initially presumed to have subretinal fluid secondary to CSCR and was started on a trial of oral eplerenone. It quickly became evident that her subretinal fluid was secondary to a peripapillary polypoidal choroidal vasculopathy network, but she demonstrated a significant improvement with oral eplerenone. To the authors' knowledge, this is the first case of eplerenone use to treat polypoidal choroidal vasculopathy. PMID- 26955353 TI - Unilateral Direct Carotid Cavernous Fistula Causing Bilateral Ocular Manifestation. AB - Unilateral carotid cavernous fistula presents with ipsilateral ocular findings. Bilateral presentation is only seen in bilateral fistulas, usually associated with indirect (dural) carotid cavernous fistulas. Direct carotid cavernous fistulas are an abnormal communication between the internal carotid artery and the cavernous sinus. They typically begin with a traumatic disruption in the artery wall into the cavernous sinus, presenting with a classic triad of unilateral pulsatile exophthalmos, cranial bruit and episcleral venous engorgement. We report the case of a 38-year-old male with traumatic right carotid cavernous sinus fistula and bilateral ocular presentation successfully treated by interventional neuroradiology. PMID- 26955354 TI - En Face Optical Coherence Tomography Imaging of the Choroid in a Case with Central Serous Chorioretinopathy during the Course of Vogt-Koyanagi-Harada Disease: A Case Report. AB - Vogt-Koyanagi-Harada (VKH) disease and central serous chorioretinopathy (CSC) develop serous retinal detachment; however, the treatment of each disease is totally different. Steroids treat VKH but worsen CSC; therefore, it is important to distinguish these diseases. Here, we report a case with CSC which was diagnosed by en face optical coherence tomography (OCT) imaging during the course of VKH disease. A 50-year-old man was referred with blurring of vision in his right eye. Fundus examination showed bilateral optic disc swelling and macular fluid in the right eye. OCT showed thick choroid, and en face OCT images depicted blurry choroid without clear delineation of choroidal vessels. Combined with angiography findings, this patient was diagnosed with VKH disease and treated with steroids. Promptly, fundus abnormalities resolved with the reduction of the choroidal thickness and the choroidal vessels became visible on the en face images. During the tapering of the steroid, serous macular detachment in the right eye recurred several times. Steroid treatment was effective at first; however, at the fourth appearance of submacular fluid, the patient did not respond. At that time, the choroidal vessels on the en face OCT images were clear, which significantly differed from the images at the time of recurrence of VKH. Angiography also suggested CSC-like leakage. The tapering of the steroids was effective in resolving the fluid. Secondary CSC may develop in the eye with VKH after steroid treatment. En face OCT observation of the choroid may be helpful to distinguish each condition. PMID- 26955355 TI - High Sulfation and a High Molecular Weight Are Important for Anti-hepcidin Activity of Heparin. AB - Heparins are efficient inhibitors of hepcidin expression even in vivo, where they induce an increase of systemic iron availability. Heparins seem to act by interfering with BMP6 signaling pathways that control the expression of liver hepcidin, causing the suppression of SMAD1/5/8 phosphorylation. The anti-hepcidin activity persists also when the heparin anticoagulant property is abolished or reduced by chemical reactions of oxidation/reduction (glycol-split, Gs-Heparins) or by high sulfation (SS-Heparins), but the structural characteristics needed to optimize this inhibitory activity have not been studied in detail. To this aim we analyzed three different heparins (Mucosal Heparin, the Glycol split RO-82, the partially desulfated glycol-split RO-68 and the oversulfated SSLMWH) and separated them in fractions of molecular weight in the range 4-16 kD. Since the distribution of the negative charges in heparins contributes to the activity, we produced 2-O- and 6-O-desulfated heparins. These derivatives were analyzed for the capacity to inhibit hepcidin expression in hepatic HepG2 cells and in mice. The two approaches produced consistent results and showed that the anti-hepcidin activity strongly decreases with molecular weight below 7 kD, with high N acetylation and after 2-O and 6-O desulfation. The high sulfation and high molecular weight properties for efficient anti-hepcidin activity suggest that heparin is involved in multiple binding sites. PMID- 26955356 TI - Consequences of New Approach to Chemical Stability Tests to Active Pharmaceutical Ingredients. AB - There is a great need of broaden look on stability tests of active pharmaceutical ingredients (APIs) in comparison with current requirements contained in pharmacopeia. By usage of many modern analytical methods the conception of monitoring the changes of APIs during initial stage of their exposure to harmful factors has been developed. New knowledge must be acquired in terms of identification of each degradation products, especially volatile ones. Further research as toxicology prediction during in silico studies of determined and identified degradation products is necessary. In silico methods are known as computational toxicology or computer-assisted technologies which are used for predicting toxicology of pharmaceutical substances such as impurities or degradation products. This is a specialized software and databases intended to calculate probability of genotoxicity or mutagenicity of these substances through a chemical structure-based screening process and algorithm specific to a given software program. Applying of new analytical approach is proposed as the usage of PAT tools, XRD, HS-SPME GC-MS/MS, LC-MS/MS for stability testing. Described improvements should be taken into account in case of each drug existing already in the market as well as being implemented as new one. PMID- 26955358 TI - 15 Years of Microstate Research in Schizophrenia - Where Are We? A Meta-Analysis. AB - Schizophrenia patients show abnormalities in a broad range of task demands. Therefore, an explanation common to all these abnormalities has to be sought independently of any particular task, ideally in the brain dynamics before a task takes place or during resting state. For the neurobiological investigation of such baseline states, EEG microstate analysis is particularly well suited, because it identifies subsecond global states of stable connectivity patterns directly related to the recruitment of different types of information processing modes (e.g., integration of top-down and bottom-up information). Meanwhile, there is an accumulation of evidence that particular microstate networks are selectively affected in schizophrenia. To obtain an overall estimate of the effect size of these microstate abnormalities, we present a systematic meta analysis over all studies available to date relating EEG microstates to schizophrenia. Results showed medium size effects for two classes of microstates, namely, a class labeled C that was found to be more frequent in schizophrenia and a class labeled D that was found to be shortened. These abnormalities may correspond to core symptoms of schizophrenia, e.g., insufficient reality testing and self-monitoring as during auditory verbal hallucinations. As interventional studies have shown that these microstate features may be systematically affected using antipsychotic drugs or neurofeedback interventions, these findings may help introducing novel diagnostic and treatment options. PMID- 26955357 TI - Candida albicans and Pseudomonas aeruginosa Interaction, with Focus on the Role of Eicosanoids. AB - Candida albicans is commonly found in mixed infections with Pseudomonas aeruginosa, especially in the lungs of cystic fibrosis (CF) patients. Both of these opportunistic pathogens are able to form resistant biofilms and frequently infect immunocompromised individuals. The interaction between these two pathogens, which includes physical interaction as well as secreted factors, is mainly antagonistic. In addition, research suggests considerable interaction with their host, especially with immunomodulatory lipid mediators, termed eicosanoids. Candida albicans and Pseudomonas aeruginosa are both able to utilize arachidonic acid (AA), liberated from the host cells during infection, to form eicosanoids. The production of these eicosanoids, such as Prostaglandin E2, by the host and the pathogens may affect the dynamics of polymicrobial infection and the outcome of infections. It is of considerable importance to elucidate the role of host produced, as well as pathogen-produced eicosanoids in polymicrobial infection. This review will focus on in vitro as well as in vivo interaction between C. albicans and P. aeruginosa, paying special attention to the role of eicosanoids in the cross-talk between host and the pathogens. PMID- 26955359 TI - Assessment of Tobacco-Related Approach and Attentional Biases in Smokers, Cravers, Ex-Smokers, and Non-Smokers. AB - According to theories of addictive behaviors, approach and attentional biases toward smoking-related cues play a crucial role in tobacco dependence. Several studies have investigated these biases by using various paradigms in different sample types. However, this heterogeneity makes it difficult to compare and evaluate the results. The present study aimed to address this problem, via (i) a structural comparison of different measures of approach-avoidance and a measure of smoking-related attentional biases, and (ii) using within one study different representative samples in the context of tobacco dependence. Three measures of approach-avoidance were employed: an Approach Avoidance Task (AAT), a Stimulus Response Compatibility Task (SRC), and a Single Target Implicit Association Test (ST-IAT). To assess attentional biases, a modified Stroop task including smoking related words was administered. The study included four groups: n = 58 smokers, n = 57 non-smokers, n = 52 cravers, and n = 54 ex-smokers. We expected to find strong tobacco-related approach biases and attentional biases in smokers and cravers. However, the general pattern of results did not confirm these expectations. Approach responses assessed during the AAT and SRC did not differ between groups. Moreover, the Stroop did not show the expected interference effect. For the ST-IAT, cravers had stronger approach associations toward smoking related cues, whereas non-smokers showed stronger avoidance associations. However, no such differences in approach-avoidance associations were found in smokers and ex-smokers. To conclude, these data do not provide evidence for a strong role of implicit approach and attentional biases toward smoking-related cues in tobacco dependency. PMID- 26955360 TI - How Children's Mentalistic Theory Widens their Conception of Pictorial Possibilities. AB - An interpretative theory of mind enables young children to grasp that people fulfill varying intentions when making pictures. We tested the hypothesis that in middle childhood a unifunctional conception of artists' intention to produce a picture widens to include artists' intention to display their pictures to others. Children aged between 5 and 10 years viewed a brief video of an artist deliberately hiding her picture but her intention was thwarted when her picture was discovered and displayed. By 8 years of age children were almost unanimous that a picture-producer without an intention to show her work to others cannot be considered to be an artist. Further exploratory studies centered on aspects of picture-display involving normal public display as well as the contrary intentions of hiding an original picture and of deceitfully displaying a forgery. Interviews suggested that the concept of exhibition widened to take others' minds into account viewers' critical judgments and effects of forgeries on viewers' minds. The approach of interpolating probes of typical possibilities between atypical intentions generated evidence that in middle childhood the foundations are laid for a conception of communication between artists' minds and viewers' minds via pictorial display. The combination of hypothesis-testing and exploratory opening-up of the area generates a new testable hypothesis about how an increasingly mentalistic approach enables children to understand diverse possibilities in the pictorial domain. PMID- 26955361 TI - What's in a Name? Interlocutors Dynamically Update Expectations about Shared Names. AB - In order to refer using a name, speakers must believe that their addressee knows about the link between the name and the intended referent. In cases where speakers and addressees learned a subset of names together, speakers are adept at using only the names their partner knows. But speakers do not always share such learning experience with their conversational partners. In these situations, what information guides speakers' choice of referring expression? A speaker who is uncertain about a names' common ground (CG) status often uses a name and description together. This N+D form allows speakers to demonstrate knowledge of a name, and could provide, even in the absence of miscommunication, useful evidence to the addressee regarding the speaker's knowledge. In cases where knowledge of one name is associated with knowledge of other names, this could provide indirect evidence regarding knowledge of other names that could support generalizations used to update beliefs about CG. Using Bayesian approaches to language processing as a guiding framework, we predict that interlocutors can use their partner's choice of referring expression, in particular their use of an N+D form, to generate more accurate beliefs regarding their partner's knowledge of other names. In Experiment 1, we find that domain experts are able to use their partner's referring expression choices to generate more accurate estimates of CG. In Experiment 2, we find that interlocutors are able to infer from a partner's use of an N+D form which other names that partner is likely to know or not know. Our results suggest that interlocutors can use the information conveyed in their partner's choice of referring expression to make generalizations that contribute to more accurate beliefs about what is shared with their partner, and further, that models of CG for reference need to account not just for the status of referents, but the status of means of referring to those referents. PMID- 26955363 TI - What Klein's "Semantic Gradient" Does and Does Not Really Show: Decomposing Stroop Interference into Task and Informational Conflict Components. AB - The present study suggests that the idea that Stroop interference originates from multiple components may gain theoretically from integrating two independent frameworks. The first framework is represented by the well-known notion of "semantic gradient" of interference and the second one is the distinction between two types of conflict - the task and the informational conflict - giving rise to the interference (MacLeod and MacDonald, 2000; Goldfarb and Henik, 2007). The proposed integration led to the conclusion that two (i.e., orthographic and lexical components) of the four theoretically distinct components represent task conflict, and the other two (i.e., indirect and direct informational conflict components) represent informational conflict. The four components were independently estimated in a series of experiments. The results confirmed the contribution of task conflict (estimated by a robust orthographic component) and of informational conflict (estimated by a strong direct informational conflict component) to Stroop interference. However, the performed critical review of the relevant literature (see General Discussion), as well as the results of the experiments reported, showed that the other two components expressing each type of conflict (i.e., the lexical component of task conflict and the indirect informational conflict) were small and unstable. The present analysis refines our knowledge of the origins of Stroop interference by providing evidence that each type of conflict has its major and minor contributions. The implications for cognitive control of an automatic reading process are also discussed. PMID- 26955364 TI - High Current Anxiety Symptoms, But Not a Past Anxiety Disorder Diagnosis, are Associated with Impaired Fear Extinction. AB - Although impaired fear extinction has repeatedly been demonstrated in patients with anxiety disorders, little is known about whether these impairments persist after treatment. The current comparative exploratory study investigated fear extinction in 26 patients treated for their anxiety disorder in the years preceding the study as compared to 17 healthy control subjects. Fear-potentiated startle and subjective fear were measured in a cue and context fear conditioning paradigm within a virtual reality environment. Results indicated no differences in fear extinction between treated anxiety patients and control subjects. However, scores on the Beck Anxiety Inventory across all participants revealed impaired extinction of fear potentiated startle in subjects with high compared to low anxiety symptoms over the past week. Taken together, this exploratory study found no support for impaired fear extinction in treated anxiety patients, and implies that current anxiety symptoms rather than previous patient status determine the success of extinction. PMID- 26955365 TI - Preparation for Meaningful Work and Life: Urban High School Youth's Reflections on Work-Based Learning 1 Year Post-Graduation. AB - The challenges confronted by low-income high school students throughout school and across the transition to higher education and employment are well-documented in the US and many other nations. Adopting a positive youth development perspective (Lerner et al., 2005), this study reports findings from interviews with 18 low-income, racially and ethnically diverse graduates of an urban Catholic high school in the US. The interviews were designed to shed light on the post-high school experiences of urban high school graduates and to understand how students construct meaning about the value of school and work-based learning (WBL) in their preparation for meaningful work and life. The interviews highlight the perceived value of the academic and non-cognitive preparation students experienced through high school and WBL in relation to the challenges they encountered along the pathway to post-high school success and decent work. Overall, the findings suggest the potential of WBL for low-income youth in facilitating access to resources that build academic and psychological/non cognitive assets, while also illustrating the role of structural and contextual factors in shaping post-high school transitions and access to meaningful work and life opportunities. PMID- 26955366 TI - SiaA/D Interconnects c-di-GMP and RsmA Signaling to Coordinate Cellular Aggregation of Pseudomonas aeruginosa in Response to Environmental Conditions. AB - Pseudomonas aeruginosa has emerged as an important opportunistic human pathogen that is often highly resistant to eradication strategies, mediated in part by the formation of multicellular aggregates. Cellular aggregates may occur attached to a surface (biofilm), at the air-liquid interface (pellicle), or as suspended aggregates. Compared to surface attached communities, knowledge about the regulatory processes involved in the formation of suspended cell aggregates is still limited. We have recently described the SiaA/D signal transduction module that regulates macroscopic cell aggregation during growth with, or in the presence of the surfactant SDS. Targets for SiaA/D mediated regulation include the Psl polysaccharide, the CdrAB two-partner secretion system and the CupA fimbriae. While the global regulators c-di-GMP and RsmA are known to inversely coordinate cell aggregation and regulate the expression of several adhesins, their potential impact on the expression of the cupA operon remains unknown. Here, we investigated the function of SiaA (a putative ser/thr phosphatase) and SiaD (a di-guanylate cyclase) in cupA1 expression using transcriptional reporter fusions and qRT-PCR. These studies revealed a novel interaction between the RsmA posttranscriptional regulatory system and SiaA/D mediated macroscopic aggregation. The RsmA/rsmY/Z system was found to affect macroscopic aggregate formation in the presence of surfactant by impacting the stability of the cupA1 mRNA transcript and we reveal that RsmA directly binds to the cupA1 leader sequence in vitro. We further identified that transcription of the RsmA antagonist rsmZ is controlled in a SiaA/D dependent manner during growth with SDS. Finally, we found that the siaD transcript is also under regulatory control of RsmA and that overproduction of RsmA or the deletion of siaD results in decreased cellular cyclic di-guanosine monophosphate (c-di-GMP) levels quantified by a transcriptional reporter, demonstrating that SiaA/D connects c-di-GMP and RsmA/rsmY/Z signaling to reciprocally regulate cell aggregation in response to environmental conditions. PMID- 26955367 TI - Sepsis Patients with First and Second-Hit Infections Show Different Outcomes Depending on the Causative Organism. AB - OBJECTIVE: With improving rates of initial survival in severe sepsis, second-hit infections that occur following resolution of the primary insult carry an increasing burden of morbidity. However, despite the clinical relevance of these infections, no data are available on differential outcomes in patients with first and second-hit infections depending on the nature of the causative organism. This study aims to explore any differences in these subgroups. DESIGN: In a retrospective, observational cohort study, the United Kingdom Intensive Care National Audit & Research Centre (ICNARC) database was used to explore the outcomes of patient with first-hit infections leading to sepsis, and sepsis patients with second-hit infections grouped according to the Gram status of the causative organism. SETTING: General critical care units in England, Wales, and Northern Ireland participating in the ICNARC programme between 1 January, 2007 and 30 June, 2012. PATIENTS: Patient groups analyzed included 2119 patients with and 1319 patients without sepsis who developed an intensive care unit acquired infection in blood. Subgroups included patients with trauma, emergency neurosurgery, elective surgery, and cardiogenic shock. MEASUREMENTS AND MAIN RESULTS: Gram-negative organisms were associated with poorer outcomes in first hit infections. The 90-day mortality of patients who developed a Gram-negative infection was 43.6% following elective surgery and 27.9% following trauma. This compared with a mortality of 25.6 and 20.6%, respectively, in Gram-positive infections. Unexpectedly, an inverse relationship between Gram status and mortality was observed in second-hit infections. PATIENTS with an initial diagnosis of sepsis who developed secondary infections caused by Gram-negative organisms had a 90-day mortality of 40.4%, compared with 43.6% in Gram-positive infections. CONCLUSIONS: Our study identifies a fundamental difference in patient outcomes between first-hit and second-hit bacterial infections, which may be due to genetic, microbiological, immunological, and environmental factors. This finding has direct implications for risk stratification and defines future research priorities. PMID- 26955368 TI - Structural and Enzymatic Characterization of ABgp46, a Novel Phage Endolysin with Broad Anti-Gram-Negative Bacterial Activity. AB - The present study demonstrates the antibacterial potential of a phage endolysin against Gram-negative pathogens, particularly against multidrug resistant strains of Acinetobacter baumannii. We have cloned, heterologously expressed and characterized a novel endolysin (ABgp46) from Acinetobacter phage vb_AbaP_CEB1 and tested its antibacterial activity against several multidrug-resistant A. baumannii strains. LC-MS revealed that ABgp46 is an N-acetylmuramidase, that is also active over a broad pH range (4.0-10.0) and temperatures up to 50 degrees C. Interestingly, ABgp46 has intrinsic and specific anti-A. baumannii activity, reducing multidrug resistant strains by up to 2 logs within 2 h. By combining ABgp46 with several organic acids that act as outer membrane permeabilizing agents, it is possible to increase and broaden antibacterial activity to include other Gram-negative bacterial pathogens. In the presence of citric and malic acid, ABgp46 reduces A. baumannii below the detection limit (>5 log) and more than 4 logs Pseudomonas aeruginosa and Salmonella typhimurium strains. Overall, this globular endolysin exhibits a broad and high activity against Gram-negative pathogens, that can be enhanced in presence of citric and malic acid, and be used in human and veterinary medicine. PMID- 26955362 TI - Brain Oscillations in Sport: Toward EEG Biomarkers of Performance. AB - Brain dynamics is at the basis of top performance accomplishment in sports. The search for neural biomarkers of performance remains a challenge in movement science and sport psychology. The non-invasive nature of high-density electroencephalography (EEG) recording has made it a most promising avenue for providing quantitative feedback to practitioners and coaches. Here, we review the current relevance of the main types of EEG oscillations in order to trace a perspective for future practical applications of EEG and event-related potentials (ERP) in sport. In this context, the hypotheses of unified brain rhythms and continuity between wake and sleep states should provide a functional template for EEG biomarkers in sport. The oscillations in the thalamo-cortical and hippocampal circuitry including the physiology of the place cells and the grid cells provide a frame of reference for the analysis of delta, theta, beta, alpha (incl.mu), and gamma oscillations recorded in the space field of human performance. Based on recent neuronal models facilitating the distinction between the different dynamic regimes (selective gating and binding) in these different oscillations we suggest an integrated approach articulating together the classical biomechanical factors (3D movements and EMG) and the high-density EEG and ERP signals to allow finer mathematical analysis to optimize sport performance, such as microstates, coherency/directionality analysis and neural generators. PMID- 26955370 TI - RNA-Based Detection Does not Accurately Enumerate Living Escherichia coli O157:H7 Cells on Plants. AB - The capacity to distinguish between living and dead cells is an important, but often unrealized, attribute of rapid detection methods for foodborne pathogens. In this study, the numbers of enterohemorrhagic Escherichia coli O157:H7 after inoculation onto Romaine lettuce plants and on plastic (abiotic) surfaces were measured over time by culturing, and quantitative PCR (qPCR), propidium monoazide (PMA)-qPCR, and reverse transcriptase (RT)-qPCR targeting E. coli O157:H7 gapA, rfbE, eae, and lpfA genes and gene transcripts. On Romaine lettuce plants incubated at low relative humidity, E. coli O157:H7 cell numbers declined 10(7) fold within 96 h according to culture-based assessments. In contrast, there were no reductions in E. coli levels according to qPCR and only 100- and 1000-fold lower numbers per leaf by RT-qPCR and PMA-qPCR, respectively. Similar results were obtained upon exposure of E. coli O157:H7 to desiccation conditions on a sterile plastic surface. Subsequent investigation of mixtures of living and dead E. coli O157:H7 cells strongly indicated that PMA-qPCR detection was subject to false-positive enumerations of viable targets when in the presence of 100-fold higher numbers of dead cells. RT-qPCR measurements of killed E. coli O157:H7 as well as for RNaseA-treated E. coli RNA confirmed that transcripts from dead cells and highly degraded RNA were also amplified by RT-qPCR. These findings show that neither PMA-qPCR nor RT-qPCR provide accurate estimates of bacterial viability in environments where growth and survival is limited. PMID- 26955371 TI - Soil pH is a Key Determinant of Soil Fungal Community Composition in the Ny Alesund Region, Svalbard (High Arctic). AB - This study assessed the fungal community composition and its relationships with properties of surface soils in the Ny-Alesund Region (Svalbard, High Arctic). A total of thirteen soil samples were collected and soil fungal community was analyzed by 454 pyrosequencing with fungi-specific primers targeting the rDNA internal transcribed spacer (ITS) region. The following eight soil properties were analyzed: pH, organic carbon (C), organic nitrogen (N), ammonium nitrogen (NH4 (+)-N), silicate silicon (SiO4 (2-)-Si), nitrite nitrogen (NO2 (-)-N), phosphate phosphorus (PO4 (3-)-P), and nitrate nitrogen (NO3 (-)-N). A total of 57,952 reads belonging to 541 operational taxonomic units (OTUs) were found. of these OTUs, 343 belonged to Ascomycota, 100 to Basidiomycota, 31 to Chytridiomycota, 22 to Glomeromycota, 11 to Zygomycota, 10 to Rozellomycota, whereas 24 belonged to unknown fungi. The dominant orders were Helotiales, Verrucariales, Agaricales, Lecanorales, Chaetothyriales, Lecideales, and Capnodiales. The common genera (>eight soil samples) were Tetracladium, Mortierella, Fusarium, Cortinarius, and Atla. Distance-based redundancy analysis (db-rda) and analysis of similarities (ANOSIM) revealed that soil pH (p = 0.001) was the most significant factor in determining the soil fungal community composition. Members of Verrucariales were found to predominate in soils of pH 8 9, whereas Sordariales predominated in soils of pH 7-8 and Coniochaetales predominated in soils of pH 6-7. The results suggest the presence and distribution of diverse soil fungal communities in the High Arctic, which can provide reliable data for studying the ecological responses of soil fungal communities to climate changes in the Arctic. PMID- 26955369 TI - Antifungal Susceptibility in Serum and Virulence Determinants of Candida Bloodstream Isolates from Hong Kong. AB - Candida bloodstream infections (CBI) are one of the most common nosocomial infections globally, and they account for a high mortality rate. The increasing global prevalence of drug-resistant Candida strains has also been posing a challenge to clinicians. In this study, we comprehensively evaluated the biofilm formation and production of hemolysin and proteinase of 63 CBI isolates derived from a hospital setting in Hong Kong as well as their antifungal susceptibility both in the presence and in the absence of human serum, using standard methodology. Candida albicans was the predominant species among the 63 CBI isolates collected, and non-albicans Candida species accounted for approximately one third of the isolates (36.5%). Of them, Candida tropicalis was the most common non-albicans Candida species. A high proportion (31.7%) of the CBI isolates (40% of C. albicans isolates, 10% of C. tropicalis isolates, 11% of C. parapsilosis isolates, and 100% of C. glabrata isolates) were found to be resistant to fluconazole. One of the isolates (C. tropicalis) was resistant to amphotericin B. A rising prevalence of drug-resistance CBI isolates in Hong Kong was observed with reference to a previous study. Notably, all non-albicans Candida species, showed increased hemolytic activity relative to C. albicans, whilst C. albicans, C. tropicalis, and C. parapsilosis exhibited proteinase activities. Majority of the isolates were capable of forming mature biofilms. Interestingly, the presence of serum distorted the yeast sensitivity to fluconazole, but not amphotericin B. Taken together, our findings demonstrate that CBI isolates of Candida have the potential to express to varying extent their virulence attributes (e.g., biofilm formation, hemolysin production, and proteinase activity) and these, together with perturbations in their antifungal sensitivity in the presence of serum, may contribute to treatment complication in candidemia. The effect of serum on antifungal activity warrants further investigations, as it has direct clinical relevance to the treatment outcome in subjects with candidemia. PMID- 26955372 TI - Photosynthetic Acclimation of Symbiodinium in hospite Depends on Vertical Position in the Tissue of the Scleractinian Coral Montastrea curta. AB - Coral photophysiology has been studied intensively from the colony scale down to the scale of single fluorescent pigment granules as light is one of the key determinants for coral health. We studied the photophysiology of the oral and aboral symbiont band of scleractinian coral Montastrea curta to investigate if different acclimation to light exist in hospite on a polyp scale. By combined use of electrochemical and fiber-optic microsensors for O2, scalar irradiance and variable chlorophyll fluorescence, we could characterize the physical and chemical microenvironment experienced by the symbionts and, for the first time, estimate effective quantum yields of PSII photochemistry and rates of electron transport at the position of the zooxanthellae corrected for the in-tissue gradient of scalar irradiance. The oral- and aboral Symbiodinium layers received ~71% and ~33% of surface scalar irradiance, respectively, and the two symbiont layers experience considerable differences in light exposure. Rates of gross photosynthesis did not differ markedly between the oral- and aboral layer and curves of PSII electron transport rates corrected for scalar irradiance in hospite, showed that the light use efficiency under sub-saturating light conditions were similar between the two layers. However, the aboral Symbiodinium band did not experience photosynthetic saturation, even at the highest investigated irradiance where the oral layer was clearly saturated. We thus found a different light acclimation response for the oral and aboral symbiont bands in hospite, and discuss whether such response could be shaped by spectral shifts caused by tissue gradients of scalar irradiance. Based on our experimental finding, combined with previous knowledge, we present a conceptual model on the photophysiology of Symbiodinium residing inside living coral tissue under natural gradients of light and chemical parameters. PMID- 26955373 TI - Censored at the Nanoscale. PMID- 26955374 TI - The Dynamic Changes of the Plasma Membrane Proteins and the Protective Roles of Nitric Oxide in Rice Subjected to Heavy Metal Cadmium Stress. AB - The heavy metal cadmium is a common environmental contaminant in soils and has adverse effects on crop growth and development. The signaling processes in plants that initiate cellular responses to environmental stress have been shown to be located in the plasma membrane (PM). A better understanding of the PM proteome in response to environmental stress might provide new insights for improving stress tolerant crops. Nitric oxide (NO) is reported to be involved in the plant response to cadmium (Cd) stress. To further investigate how NO modulates protein changes in the plasma membrane during Cd stress, a quantitative proteomics approach based on isobaric tags for relative and absolute quantification (iTRAQ) was used to identify differentially regulated proteins from the rice plasma membrane after Cd or Cd and NO treatment. Sixty-six differentially expressed proteins were identified, of which, many function as transporters, ATPases, kinases, metabolic enzymes, phosphatases, and phospholipases. Among these, the abundance of phospholipase D (PLD) was altered substantially after the treatment of Cd or Cd and NO. Transient expression of the PLD fused with green fluorescent peptide (GFP) in rice protoplasts showed that the Cd and NO treatment promoted the accumulation of PLD in the plasma membrane. Addition of NO also enhanced Cd induced PLD activity and the accumulation of phosphatidic acid (PA) produced through PLD activity. Meanwhile, NO elevated the activities of antioxidant enzymes and caused the accumulation of glutathione, both which function to reduce Cd-induced H2O2 accumulation. Taken together, we suggest that NO signaling is associated with the accumulation of antioxidant enzymes, glutathione and PA which increases cadmium tolerance in rice via the antioxidant defense system. PMID- 26955375 TI - De novo Transcriptome Assembly of Floral Buds of Pineapple and Identification of Differentially Expressed Genes in Response to Ethephon Induction. AB - A remarkable characteristic of pineapple is its ability to undergo floral induction in response to external ethylene stimulation. However, little information is available regarding the molecular mechanism underlying this process. In this study, the differentially expressed genes (DEGs) in plants exposed to 1.80 mL.L(-1) (T1) or 2.40 mL.L(-1) ethephon (T2) compared with Ct plants (control, cleaning water) were identified using RNA-seq and gene expression profiling. Illumina sequencing generated 65,825,224 high-quality reads that were assembled into 129,594 unigenes with an average sequence length of 1173 bp. Of these unigenes, 24,775 were assigned to specific KEGG pathways, of which metabolic pathways and biosynthesis of secondary metabolites were the most highly represented. Gene Ontology (GO) analysis of the annotated unigenes revealed that the majority were involved in metabolic and cellular processes, cell and cell part, catalytic activity and binding. Gene expression profiling analysis revealed 3788, 3062, and 758 DEGs in the comparisons of T1 with Ct, T2 with Ct, and T2 with T1, respectively. GO analysis indicated that these DEGs were predominantly annotated to metabolic and cellular processes, cell and cell part, catalytic activity, and binding. KEGG pathway analysis revealed the enrichment of several important pathways among the DEGs, including metabolic pathways, biosynthesis of secondary metabolites and plant hormone signal transduction. Thirteen DEGs were identified as candidate genes associated with the process of floral induction by ethephon, including three ERF-like genes, one ETR-like gene, one LTI-like gene, one FT-like gene, one VRN1-like gene, three FRI-like genes, one AP1-like gene, one CAL-like gene, and one AG-like gene. qPCR analysis indicated that the changes in the expression of these 13 candidate genes were consistent with the alterations in the corresponding RPKM values, confirming the accuracy and credibility of the RNA-seq and gene expression profiling results. Ethephon mediated induction likely mimics the process of vernalization in the floral transition in pineapple by increasing LTI, FT, and VRN1 expression and promoting the up-regulation of floral meristem identity genes involved in flower development. The candidate genes screened can be used in investigations of the molecular mechanisms of the flowering pathway and of various other biological mechanisms in pineapple. PMID- 26955376 TI - A Potential Role of Flag Leaf Potassium in Conferring Tolerance to Drought Induced Leaf Senescence in Barley. AB - Terminal drought stress decreases crop yields by inducing abscisic acid (ABA) and premature leaf senescence. As potassium (K) is known to interfere with ABA homeostasis we addressed the question whether there is genetic variability regarding the role of K nutrition in ABA homeostasis and drought tolerance. To compare their response to drought stress, two barley lines contrasting in drought induced leaf senescence were grown in a pot experiment under high and low K supply for the analysis of flag leaves from the same developmental stage. Relative to the drought-sensitive line LPR, the line HPR retained more K in its flag leaves under low K supply and showed delayed flag leaf senescence under terminal drought stress. High K retention was further associated with a higher leaf water status, a higher concentration of starch and other primary carbon metabolites. With regard to ABA homeostasis, HPR accumulated less ABA but higher levels of the ABA degradation products phaseic acid (PA) and dehydro-PA. Under K deficiency this went along with higher transcript levels of ABA8'-HYDROXYLASE, encoding a key enzyme in ABA degradation. The present study provides evidence for a positive impact of the K nutritional status on ABA homeostasis and carbohydrate metabolism under drought stress. We conclude that genotypes with a high K nutritional status in the flag leaf show superior drought tolerance by promoting ABA degradation but attenuating starch degradation which delays flag leaf senescence. Flag leaf K levels may thus represent a useful trait for the selection of drought-tolerant barley cultivars. PMID- 26955377 TI - Boron Toxicity Causes Multiple Effects on Malus domestica Pollen Tube Growth. AB - Boron is an important micronutrient for plants. However, boron is also toxic to cells at high concentrations, although the mechanism of this toxicity is not known. This study aimed to evaluate the effect of boron toxicity on Malus domestica pollen tube growth and its possible regulatory pathway. Our results showed that a high concentration of boron inhibited pollen germination and tube growth and led to the morphological abnormality of pollen tubes. Fluorescent labeling coupled with a scanning ion-selective electrode technique detected that boron toxicity could decrease [Ca(2+)]c and induce the disappearance of the [Ca(2+)]c gradient, which are critical for pollen tube polar growth. Actin filaments were therefore altered by boron toxicity. Immuno-localization and fluorescence labeling, together with fourier-transform infrared analysis, suggested that boron toxicity influenced the accumulation and distribution of callose, de-esterified pectins, esterified pectins, and arabinogalactan proteins in pollen tubes. All of the above results provide new insights into the regulatory role of boron in pollen tube development. In summary, boron likely plays a structural and regulatory role in relation to [Ca(2+)]c, actin cytoskeleton and cell wall components and thus regulates Malus domestica pollen germination and tube polar growth. PMID- 26955378 TI - Citrus Plants: A Model System for Unlocking the Secrets of NO and ROS-Inspired Priming Against Salinity and Drought. AB - Plants treated with chemical compounds can develop an enhanced capacity to resist long after being subjected to (a)biotic stress, a phenomenon known as priming. Evidence suggests that reactive oxygen species (ROS) and reactive nitrogen species (RNS) coordinately regulate plant stress responses to adverse environmental conditions; however, the mechanisms underlying this function remain unknown. Based on the observation that pre-exposure of citrus (Citrus aurantium L.) roots to the NO donor sodium nitroprusside (SNP) or to H2O2 prior to NaCl application can induce acclimation against subsequent stress we characterized the changes occurring in primed citrus tissues using several approaches. Herein, using this experimental model system, we provide an overview of our current knowledge of the possible mechanisms associated with NO and H2O2 priming to abiotic stresses, particularly concerning salinity and drought. The data and ideas presented here introduce six aspects of priming behavior in citrus under abiotic stress that provide knowledge necessary to exploit priming syndrome in the context of sustainable agriculture. PMID- 26955379 TI - Disturbed Serotonergic Neurotransmission and Oxidative Stress in Elderly Patients with Delirium. AB - BACKGROUND: Oxidative stress and disturbances in serotonergic and dopaminergic neurotransmission may play a role in the pathophysiology of delirium. AIMS: In this study, we investigated levels of amino acids, amino acid ratios and levels of homovanillic acid (HVA) as indicators for oxidative stress and disturbances in neurotransmission. METHODS: Plasma levels of amino acids, amino acid ratios and HVA were determined in acutely ill patients aged >=65 years admitted to the wards of Internal Medicine and Geriatrics of the Erasmus University Medical Center and the ward of Geriatrics of the Havenziekenhuis, Rotterdam, The Netherlands. Differences in the biochemical parameters between patients with and without delirium were investigated by analysis of variance in models adjusted for age, gender and comorbidities. RESULTS: Of the 86 patients included, 23 had delirium. In adjusted models, higher mean phenylalanine/tyrosine ratios (1.34 vs. 1.14, p = 0.028), lower mean tryptophan/large neutral amino acids ratios (4.90 vs. 6.12, p = 0.021) and lower mean arginine levels (34.8 vs. 45.2 umol/l, p = 0.022) were found in patients with delirium when compared to those without. No differences were found in HVA levels between patients with and without delirium. CONCLUSION: The findings of this study suggest disturbed serotonergic neurotransmission and an increased status of oxidative stress in patients with delirium. PMID- 26955380 TI - The Quality of Pain Treatment in Community-Dwelling Persons with Dementia. AB - BACKGROUND/AIMS: Despite pervasive and debilitating pain among elders, it is underassessed and undertreated; and cognitive impairment can add challenges. We assessed the quality of pain care for community-dwelling elderly patients with dementia. METHODS: We phone interviewed 203 Veterans Affairs primary care outpatients with dementia and pain and reviewed medical records to score 15 quality indicators of pain assessment and management. RESULTS: Pain assessment was documented for 98%, and a standard pain scale was used for 94%. Modified pain scales were rarely used. Though 70% self-reported pain of 'quite bad' or worse, charts documented no pain in 64%. When pain was identified, treatment was offered to 80%; but only 59% had a follow-up assessment within 6 months. Nonpharmacological interventions were underused. CONCLUSION: Community-dwelling elders with dementia are underdiagnosed and undertreated for pain. PMID- 26955381 TI - Donepezil Adherence, Persistence and Time to First Discontinuation in a Three Year Follow-Up of Older People. AB - BACKGROUND: Donepezil is indicated for the management of mild to moderate dementia, particularly in Alzheimer's disease. Several studies have described low adherence rates with donepezil. AIM: To examine and measure donepezil adherence, persistence and time to first discontinuation in older New Zealanders. METHODS: An inception cohort of 1,999 new users of donepezil, aged 65 years or older, were identified from the Pharmaceutical Collections and National Minimum Dataset from 1 November 2010 to 31 December 2013. Kaplan-Meier curves and Cox regression analysis were used to estimate the cumulative probability and risk of time to first discontinuation of donepezil therapy. RESULTS: The mean age of the cohort was 79.5 +/- 6.4 years and included 42.7% females. Adherence was high (89.0%), while the proportion of donepezil dispensings (81.0-32.5%) declined between 6 and 36 months. Persistence between the 1st and 6th dispensing visit decreased by 19.0%, and 11.0% of the total cohort had a gap of 31 days or more. The adjusted risk of time to first discontinuation in the non-adherent group was 2.2 times (95% CI 1.9-2.6) that of the adherent group. CONCLUSIONS: The non-adherent new donepezil users, on average, discontinued faster than the adherent group. Time to first discontinuation in this study was higher compared to discontinuation rates observed in clinical trials. PMID- 26955382 TI - Exploring Visual Selective Attention towards Novel Stimuli in Alzheimer's Disease Patients. AB - BACKGROUND: Alzheimer's disease (AD) is associated with selective attention impairments, which could contribute to cognitive and functional deficits. Selective attention can be explored through examination of novelty preference. AIMS: In this study, we quantified novelty preference in AD patients by measuring visual scanning behaviour using an eye tracking paradigm. METHODS: Mild-to moderate AD patients and elderly controls viewed slides containing novel and repeated images simultaneously. The outcome measure was time spent on specific images, with novelty preference defined by greater relative fixation time (RFT) on novel versus repeated images. Cognitive status (Standardized Mini-Mental State Examination, SMMSE) and attention (Digit Span, DS) were also measured. RESULTS: AD patients (age 79.2 +/- 6.7 years, SMMSE 22.2 +/- 4.0, n = 41) and controls (age 76.2 +/- 6.4 years, SMMSE 28.1 +/- 2.0, n = 24) were similar in age, education and sex. Compared with controls, AD patients had lower RFT on novel than on repeated images (F1,63 = 11.18, p = 0.001). Further, reduced RFT was associated with lower scores on SMMSE (r63 = 0.288, p = 0.020) and DS (r63 = 0.269, p = 0.030). Within individuals, novelty preference was detected in 92.3% of patients and in 100% of controls. CONCLUSION: These findings suggest that novelty preference, measured by visual scanning behaviour, can differentiate cognitively healthy and impaired people and may offer a nonverbal, less cognitively demanding method of assessing selective attention. PMID- 26955383 TI - DAPHNE: A New Tool for the Assessment of the Behavioral Variant of Frontotemporal Dementia. AB - BACKGROUND: The diagnosis of behavioral variant of frontotemporal dementia (bvFTD) relies primarily on clinical features and remains challenging. The specificity of the recently revised criteria can be disappointing, justifying development of new clinical tools. OBJECTIVE: We produced a behavioral inventory named DAPHNE. This scale (adapted from Rascovsky's criteria) explores six domains: disinhibition, apathy, perseverations, hyperorality, personal neglect and loss of empathy. It is composed of ten items (five answer categories). The aim was (1) to assess the validity and reliability of DAPHNE and (2) to evaluate its contribution in differentiating patients. METHODS: Two scores were computed: DAPHNE-6 (screening) from the six domains and DAPHNE-40 (diagnosis) from the ten items. Reliability and reproducibility were assessed. External validity was studied with the Frontal Behavioral Inventory (FBI) and the Frontotemporal Behavioral Scale (FBS). Finally, the diagnostic performance of DAPHNE was compared to revised criteria, FBI and FBS. RESULTS: DAPHNE was administered to the caregivers of 89 patients, 36 with bvFTD, 22 with Alzheimer's disease, 15 with progressive supranuclear palsy and 16 with bipolar disorder. Reliability and reproducibility were excellent, as was external validity. DAPHNE-6 allowed bvFTD diagnosis (score >=4) with a sensitivity of 92%, while DAPHNE-40 (score >=15) had a specificity of 92%. CONCLUSION: We demonstrate excellent psychometric features for DAPHNE. This quick tool could help for both diagnosing and screening bvFTD. PMID- 26955384 TI - Non-Verbal and Verbal Fluency in Prodromal Huntington's Disease. AB - BACKGROUND: This study examines non-verbal (design) and verbal (phonemic and semantic) fluency in prodromal Huntington's disease (HD). An accumulating body of research indicates subtle deficits in cognitive functioning among prodromal mutation carriers for HD. METHODS: Performance was compared between 32 mutation carriers and 38 non-carriers in order to examine the magnitude of impairment across fluency tasks. The predicted years to onset (PYTO) in mutation carriers was calculated by a regression equation and used to divide the group according to whether onset was predicted as less than 12.75 years (HD+CLOSE; n = 16) or greater than 12.75 years (HD+DISTANT; n = 16). RESULTS: The results indicate that both non-verbal and verbal fluency is sensitive to subtle impairment in prodromal HD. HD+CLOSE group produced fewer items in all assessed fluency tasks compared to non-carriers. HD+DISTANT produced fewer drawings than non-carriers in the non verbal task. PYTO correlated significantly with all measures of non-verbal and verbal fluency. CONCLUSION: The pattern of results indicates that subtle cognitive deficits exist in prodromal HD, and that less structured tasks with high executive demands are the most sensitive in detecting divergence from the normal range of functioning. These selective impairments can be attributed to the early involvement of frontostriatal circuitry and frontal lobes. PMID- 26955386 TI - Knowledge-Driven Event Extraction in Russian: Corpus-Based Linguistic Resources. AB - Automatic event extraction form text is an important step in knowledge acquisition and knowledge base population. Manual work in development of extraction system is indispensable either in corpus annotation or in vocabularies and pattern creation for a knowledge-based system. Recent works have been focused on adaptation of existing system (for extraction from English texts) to new domains. Event extraction in other languages was not studied due to the lack of resources and algorithms necessary for natural language processing. In this paper we define a set of linguistic resources that are necessary in development of a knowledge-based event extraction system in Russian: a vocabulary of subordination models, a vocabulary of event triggers, and a vocabulary of Frame Elements that are basic building blocks for semantic patterns. We propose a set of methods for creation of such vocabularies in Russian and other languages using Google Books NGram Corpus. The methods are evaluated in development of event extraction system for Russian. PMID- 26955385 TI - The Influence of Patient Characteristics on Anticholinergic Events in Older People. AB - AIMS: To examine patient characteristics that predict adverse anticholinergic type events in older people. METHODS: This retrospective population-level study included 2,248 hospitalised patients. Individual data on medicines that are commonly associated with anticholinergic events (delirium, constipation and urinary retention) were identified. Patient characteristics examined were medicines with anticholinergic effects (ACh burden), age, sex, non anticholinergic medicines (non-ACM), Charlson comorbidity index scores and ethnicity. The Akaike information criterion was used for model selection. The data were analysed using logistic regression models for anticholinergic events using the software NONMEM. RESULTS: ACh burden was found to be a significant independent predictor for developing an anticholinergic event [adjusted odds ratio (aOR): 3.21, 95% CI: 1.23-5.81] for those taking an average of 5 anticholinergic medicines compared to those taking 1. Both non-ACM and age were also independent risk factors (aOR: 1.41, 95% CI: 1.31-1.51 and aOR: 1.08, 95% CI: 1.05-1.10, respectively). CONCLUSION: To our knowledge, this is the first study that has examined population-level data in a nonlinear model framework to predict anticholinergic-type adverse events. This study evaluated the relationship between important patient characteristics and the occurrence of anticholinergic-type events. These findings reinforce the clinical significance of reviewing anticholinergic medicines in older people. PMID- 26955387 TI - A Novel Particle Swarm Optimization Algorithm for Global Optimization. AB - Particle Swarm Optimization (PSO) is a recently developed optimization method, which has attracted interest of researchers in various areas due to its simplicity and effectiveness, and many variants have been proposed. In this paper, a novel Particle Swarm Optimization algorithm is presented, in which the information of the best neighbor of each particle and the best particle of the entire population in the current iteration is considered. Meanwhile, to avoid premature, an abandoned mechanism is used. Furthermore, for improving the global convergence speed of our algorithm, a chaotic search is adopted in the best solution of the current iteration. To verify the performance of our algorithm, standard test functions have been employed. The experimental results show that the algorithm is much more robust and efficient than some existing Particle Swarm Optimization algorithms. PMID- 26955388 TI - Comment on "Efficacy of 7-Day and 14-Day Triple Therapy Regimens for the Eradication of Helicobacter pylori: A Comparative Study in a Cohort of Romanian Patients". PMID- 26955389 TI - Advanced Studies in Clinical and Experimental Research in Gastroenterology. PMID- 26955390 TI - Hepatocellular Carcinoma in Pakistan: National Trends and Global Perspective. AB - Hepatocellular carcinoma (HCC) ranks second amongst all causes of cancer deaths globally. It is on a rise in Pakistan and might represent the most common cancer in adult males. Pakistan contributes significantly to global burden of hepatitis C, which is a known risk factor for HCC, and has one of the highest prevalence rates (>3%) in the world. In the absence of a national cancer registry and screening programs, prevalence of hepatitis and HCC only represents estimates of the real magnitude of this problem. In this review, we present various aspects of HCC in Pakistan, comparing and contrasting it with the global trends in cancer care. There is a general lack of awareness regarding risk factors of HCC in Pakistani population and prevalence of hepatitis C has increased. In addition, less common risk factors are also on a rise. Majority of patients present with advanced HCC and are not eligible for definitive treatment. We have attempted to highlight issues that have a significant bearing on HCC outcome in Pakistan. A set of strategies have been put forth that can potentially help reduce incidence and improve HCC outcome on national level. PMID- 26955392 TI - Towards Creating the Perfect In Vitro Cell Model. PMID- 26955391 TI - Pathogenesis and Diagnostic Approaches of Avian Infectious Bronchitis. AB - Infectious bronchitis (IB) is one of the major economically important poultry diseases distributed worldwide. It is caused by infectious bronchitis virus (IBV) and affects both galliform and nongalliform birds. Its economic impact includes decreased egg production and poor egg quality in layers, stunted growth, poor carcass weight, and mortality in broiler chickens. Although primarily affecting the respiratory tract, IBV demonstrates a wide range of tissues tropism, including the renal and reproductive systems. Thus, disease outcome may be influenced by the organ or tissue involved as well as pathotypes or strain of the infecting virus. Knowledge on the epidemiology of the prevalent IBV strains in a particular region is therefore important to guide control and preventions. Meanwhile previous diagnostic methods such as serology and virus isolations are less sensitive and time consuming, respectively; current methods, such as reverse transcription polymerase chain reaction (RT-PCR), Restriction Fragment Length Polymorphism (RFLP), and sequencing, offer highly sensitive, rapid, and accurate diagnostic results, thus enabling the genotyping of new viral strains within the shortest possible time. This review discusses aspects on pathogenesis and diagnostic methods for IBV infection. PMID- 26955393 TI - The Characteristics Variation of Hepatic Progenitors after TGF-beta1-Induced Transition and EGF-Induced Reversion. AB - Profibrogenesis cytokine, transforming growth factor- (TGF-) beta1, induces hepatic progenitors experiencing epithelial to mesenchymal transition (EMT) to matrix synthesis cells, even tumor initiating cells. Our previous data found that epidermal growth factor (EGF) blocks and reverses TGF-beta1-induced transition. The aim of this study is to determine the characteristic changes of hepatic progenitors after TGF-beta1-induced transition and EGF-induced reversion. Hepatic oval cells, rat hepatic progenitors, were isolated from rats fed a choline deficient diet supplemented with ethionine. TGF-beta1-containing medium was used for inducing EMT, while EGF-containing medium was used for reversing EMT. During TGF-beta1-induced transition and EGF-induced reversion, hepatic oval cells sustained their progenitor cell marker expression, including alpha-fetoprotein, albumin, and cytokeratin-19. The proliferation ability and differentiation potential of these cells were suppressed by TGF-beta1, while EGF resumed these capacities to the level similar to the control cells. RNA microarray analysis showed that most of the genes with significant changes after TGF-beta1 incubation were recovered by EGF. Signal pathway analysis revealed that TGF-beta1 impaired the pathways of cell cycle and cytochrome P450 detoxification, and EGF reverted TGF-beta1 effects through activating MAPK and PI3K-Akt pathway. EGF reverses the characteristics impaired by TGF-beta1 in hepatic oval cells, serving as a protective cytokine to hepatic progenitors. PMID- 26955394 TI - Colchicum autumnale in Patients with Goitre with Euthyroidism or Mild Hyperthyroidism: Indications for a Therapeutic Regulative Effect-Results of an Observational Study. AB - Introduction. Goitre with euthyroid function or with subclinical or mild hyperthyroidism due to thyroid autonomy is common. In anthroposophic medicine various thyroid disorders are treated with Colchicum autumnale (CAU). We examined the effects of CAU in patients with goitre of both functional states. Patients and methods. In an observational study, 24 patients with goitre having suppressed thyroid stimulating hormone (TSH) levels with normal or slightly elevated free thyroxine (fT4) and free triiodothyronine (fT3) (group 1, n = 12) or normal TSH, fT3, and fT4 (group 2, n = 12) were included. After 3 months and after 6 to 12 months of CAU treatment, we investigated clinical pathology using the Hyperthyroid Symptom Scale (HSS), hormone status (TSH, fT4, and fT3), and thyroidal volume (tV). Results. After treatment with CAU, in group 1 the median HSS decreased from 4.5 (2.3-11.8) to 2 (1.3-3) (p < 0.01) and fT3 decreased from 3.85 (3.5-4.78) to 3.45 (3.3-3.78) pg/mL (p < 0.05). In group 2 tV (13.9% (18.5% 6.1%)) and TSH (p < 0.01) were reduced. Linear regression for TSH and fT3 in both groups indicated a regulative therapeutic effect of CAU. Conclusions. CAU positively changed the clinical pathology of subclinical hyperthyroidism and thyroidal volume in patients with euthyroid goitre by normalization of the regulation of thyroidal hormones. PMID- 26955395 TI - Endoscopic ultrasound-guided fine-needle aspiration diagnosis of secondary tumors involving the pancreas: An institution's experience. AB - BACKGROUND: Pancreatic masses may seldom represent a metastasis or secondary involvement by lymphoproliferative disorders. Recognition of this uncommon occurrence may help render an accurate diagnosis and avoid diagnostic pitfalls during endoscopic ultrasound-guided fine needle aspiration (EUS-FNA). In this study, we review our experience in diagnosing secondary tumors involving the pancreas. MATERIALS AND METHODS: The electronic database of cytopathology archives was searched for cases of secondary tumors involving the pancreas at our institution and a total of 31 cases were identified. The corresponding clinical presentations, imaging study findings, cytological diagnoses, the results of ancillary studies, and surgical follow-up, if available, were reviewed. RESULTS: Nineteen of the patients were male and 12 female, with a mean age of 66 years. Twenty-three patients (74%) had a prior history of malignancy, with the latency ranging from 6 months to 19 years. The secondary tumors involving the pancreas included metastatic carcinoma (24 cases), metastatic sarcoma (3 cases), diffuse large B-cell lymphoma (2 cases), and plasma cell neoplasm (2 cases). The most common metastatic tumors were renal cell carcinoma (8 cases) and lung carcinoma (7 cases). Correct diagnoses were rendered in 29 cases (94%). The remaining two cases were misclassified as primary pancreatic carcinoma. In both cases, the patients had no known history of malignancy, and no ancillary studies were performed. CONCLUSIONS: Secondary tumors involving the pancreas can be accurately diagnosed by EUS-FNA. Recognizing uncommon cytomorphologic features, knowing prior history of malignancy, and performing ancillary studies are the keys to improve diagnostic performance and avoid diagnostic pitfalls. PMID- 26955396 TI - Primary ovarian non-Hodgkin lymphoma: Diagnosis of two cases on fine needle aspiration cytology. AB - Lymphoma of the female genital tract is a rare condition. Involvement of the ovary by non- Hodgkin lymphoma (NHL) is usually secondary to systemic disease and primary ovarian lymphomas are unusual. In most cases, the diagnosis is not suspected initially and is confirmed only after detailed histopathological evaluation. We describe two cases of primary ovarian NHL which were diagnosed on fine needle aspiration cytology (FNAC). One of the patients was a 40 years old female who presented with abdominal distension and lump. She was found to have bilateral adnexal masses on ultrasound and computed tomography (CT) scan. A USG guided fine needle aspiration of the ovarian masses was performed, following which a diagnosis of primary ovarian diffuse large B-cell lymphoma was established. The second patient was a 14 years old female who presented with pelvic lump, which was lobulated and mildly enhancing on contrast enhanced CT. A diagnosis of high grade NHL of ovaries was made on cytology. Subsequently, the lymphoma was characterized as Burkitt's on histopathological examination. Both the patients were started on R-CHOP chemotherapy regimen. FNAC serves as an extremely useful minimally invasive procedure for the diagnosis of ovarian lymphomas and early institution of appropriate chemotherapeutic regimens. PMID- 26955398 TI - Unparalleled Lithium and Sodium Superionic Conduction in Solid Electrolytes with Large Monovalent Cage-like Anions. AB - Solid electrolytes with sufficiently high conductivities and stabilities are the elusive answer to the inherent shortcomings of organic liquid electrolytes prevalent in today's rechargeable batteries. We recently revealed a novel fast ion-conducting sodium salt, Na2B12H12, which contains large, icosahedral, divalent B12H122- anions that enable impressive superionic conductivity, albeit only above its 529 K phase transition. Its lithium congener, Li2B12H12, possesses an even more technologically prohibitive transition temperature above 600 K. Here we show that the chemically related LiCB11H12 and NaCB11H12 salts, which contain icosahedral, monovalent CB11H12- anions, both exhibit much lower transition temperatures near 400 K and 380 K, respectively, and truly stellar ionic conductivities (> 0.1 S cm-1) unmatched by any other known polycrystalline materials at these temperatures. With proper modifications, we are confident that room-temperature-stabilized superionic salts incorporating such large polyhedral anion building blocks are attainable, thus enhancing their future prospects as practical electrolyte materials in next-generation, all-solid-state batteries. PMID- 26955399 TI - An Ethical Justification for Expanding the Notion of Effectiveness in Vaccine Post-Market Monitoring: Insights from the HPV Vaccine in Canada. AB - Health regulators must carefully monitor the real-world safety and effectiveness of marketed vaccines through post-market monitoring in order to protect the public's health and promote those vaccines that best achieve public health goals. Yet, despite the fact that vaccines used in collective immunization programmes should be assessed in the context of a public health response, post-market effectiveness monitoring is often limited to assessing immunogenicity or limited programmatic features, rather than assessing effectiveness across populations. We argue that post-market monitoring ought to be expanded in two ways to reflect a 'public health notion of post-market effectiveness', which incorporates normative public health considerations: (i) effectiveness monitoring should yield higher quality data and grant special attention to underrepresented and vulnerable populations; and (ii) the scope of effectiveness should be expanded to include a consideration of the various social factors that maximize (and minimize) a vaccine's effectiveness at the population level, paying particular attention to how immunization programmes impact related health gradients. We use the case of the human papillomavirus vaccine in Canada to elucidate how expanding post-market effectiveness monitoring is necessary to close the gap between clinical practice and public health, and to ensure that vaccines are effective in a morally relevant sense. PMID- 26955400 TI - Denoising Stimulated Raman Spectroscopic Images by Total Variation Minimization. AB - High-speed coherent Raman scattering imaging is opening a new avenue to unveiling the cellular machinery by visualizing the spatio-temporal dynamics of target molecules or intracellular organelles. By extracting signals from the laser at MHz modulation frequency, current stimulated Raman scattering (SRS) microscopy has reached shot noise limited detection sensitivity. The laser-based local oscillator in SRS microscopy not only generates high levels of signal, but also delivers a large shot noise which degrades image quality and spectral fidelity. Here, we demonstrate a denoising algorithm that removes the noise in both spatial and spectral domains by total variation minimization. The signal-to-noise ratio of SRS spectroscopic images was improved by up to 57 times for diluted dimethyl sulfoxide solutions and by 15 times for biological tissues. Weak Raman peaks of target molecules originally buried in the noise were unraveled. Coupling the denoising algorithm with multivariate curve resolution allowed discrimination of fat stores from protein-rich organelles in C. elegans. Together, our method significantly improved detection sensitivity without frame averaging, which can be useful for in vivo spectroscopic imaging. PMID- 26955401 TI - [Acute dilatation of the stomach: about 02 cases and literature review]. PMID- 26955402 TI - An infected false aneurysm of the subclavian artery in a 41-year old drug abuser. PMID- 26955403 TI - [Pseudoaneurysm of the femoral artery following a firearm wound]. PMID- 26955404 TI - [Spontaneous and isolated dissection of the celiac trunk]. PMID- 26955397 TI - Nanomedicines for Endothelial Disorders. AB - The endothelium lines the internal surfaces of blood and lymphatic vessels and has a critical role in maintaining homeostasis. Endothelial dysfunction is involved in the pathology of many diseases and conditions, including disorders such as diabetes, cardiovascular diseases, and cancer. Given this common etiology in a range of diseases, medicines targeting an impaired endothelium can strengthen the arsenal of therapeutics. Nanomedicine - the application of nanotechnology to healthcare - presents novel opportunities and potential for the treatment of diseases associated with an impaired endothelium. This review discusses therapies currently available for the treatment of these disorders and highlights the application of nanomedicine for the therapy of these major disease complications. PMID- 26955405 TI - [A case of advanced retinitis pigmentosa]. PMID- 26955406 TI - [Cholecystitis on stump: myth or reality?]. PMID- 26955407 TI - [Cover flap at the scarpa by plasty of sartorius muscle (Sartorius)]. PMID- 26955408 TI - [Ophthalmic zoster: a rare skin disease in children]. PMID- 26955409 TI - [Aneurysm of the superficial femoral artery linked to a salmonella infection]. PMID- 26955410 TI - [Term pegnancy on septate uterus: report of a case and review of the literature]. PMID- 26955411 TI - [Multinodular thyroid goiter revealing tuberculosis]. PMID- 26955412 TI - [Pseudotumoral sinonasal aspergillosis]. PMID- 26955413 TI - [Post-radiation ethmoidal mucocele]. PMID- 26955414 TI - [Closed tibia fracture associated with ipsilateral Chopart dislocation: a rare clinical entity]. PMID- 26955416 TI - [Sphenoid mucocele revealed by exophthalmia]. PMID- 26955415 TI - [Acetabular reconstruction in total hip replacement]. PMID- 26955417 TI - [Melkersson-Rosenthal syndrome]. PMID- 26955418 TI - Bruns Syndrome: a deadly sign. PMID- 26955419 TI - [Femoral-femoral bypass crossed with perineal under-scrotal tunneling for a serious infection of the Scarpa triangle]. PMID- 26955420 TI - [A psoas abscess complicating acute appendicitis]. PMID- 26955421 TI - [Primary tumors of the submandibular gland: report of 25 cases]. PMID- 26955423 TI - [Large cells diffuse B lymphoma of the ethmoid sinus]. PMID- 26955422 TI - [Arachnoid cyst: a cause of chronic low back pain not to ignore]. PMID- 26955424 TI - [Foreign body in the fallopian tube]. PMID- 26955425 TI - [Herpetic facial paralysis]. PMID- 26955426 TI - [Diabetes and heart attack: only a story of the heart?]. PMID- 26955428 TI - [Cholecystitis on stump]. PMID- 26955427 TI - [Formalized consensus: clinical practice recommendations for the management of acute low back pain of the African patient]. PMID- 26955429 TI - [Late post traumatic cerebrospinal rhinorrhea revealing a brain tumor]. PMID- 26955430 TI - Anti-Inflammatory Therapy Modulates Nrf2-Keap1 in Kidney from Rats with Diabetes. AB - This study addressed the relationship of proinflammatory cytokines and Nrf2-Keap1 system in diabetic nephropathy. The experimental groups were control, diabetic, and diabetic treated with mycophenolate mofetil (MMF). The renal function, proinflammatory and profibrotic cytokines, oxidative stress, morphology, and nephrin expression were assessed. Diabetic group showed impaired renal function in association with oxidative stress and decreased Nrf2 nuclear translocation. These results were associated with increased mesangial matrix index, interstitial fibrosis, and increased nephrin expression in cortex and urine excretion. Additionally, interleukin-1beta, IL-6, and transforming growth factor-beta1 were increased in plasma and kidney. MMF treatment conserved renal function, prevented renal structural alterations, and partially prevented the proinflammatory and profibrotic cytokines overexpression. Despite that MMF treatment induced nephrin overexpression in renal tissue, preventing its urinary loss. MMF salutary effects were associated with a partial prevention of oxidative stress, increased Nrf2 nuclear translocation, and conservation of antioxidant enzymes in renal tissue. In conclusion, our results confirm that inflammation is a key factor in the progression of diabetic nephropathy and suggest that treatment with MMF protects the kidney by an antioxidant mechanism, possibly regulated at least in part by the Nrf2/Keap1 system, in addition to its well-known anti-inflammatory effects. PMID- 26955432 TI - Microbiology of chronic suppurative otitis media at Queen Elizabeth Central Hospital, Blantyre, Malawi: A cross-sectional descriptive study. AB - BACKGROUND: Chronic suppurative otitis media (CSOM) is still a significant health problem in developing countries. Therefore, it was pertinent to determine the local Malawian microbiology in order to guide adequate treatment, avoid complications, and provide records for future reference. AIM: The study sought to determine the CSOM-causing microorganisms at Queen Elizabeth Central Hospital in Blantyre, Malawi, and establish their relationship signs and symptoms, and with the demographic pattern of the study. METHODS: This was a hospital-based cross sectional descriptive study carried out at the ENT outpatient clinic and the Microbiology Department of Queen Elizabeth Central Hospital.The sample comprised 104 patients with unilateral or bilateral active CSOM, who met the inclusion criteria. All patients were evaluated through a detailed history and clinical examination. Pus samples from draining ears were collected by aspiration with a sterile pipette. The specimens were immediately sent for microbiological analysis. Data were analyzed using SPSS.version 20. RESULTS: The study found that Proteus mirabilis, Pseudomonas aeruginosa, and Staphylococcus aureus were the most prevalent aerobic bacteria, while Bacteroides spp. and Peptostreptococcus spp. were the commonest anaerobic bacteria causing CSOM. These CSOM-causing microorganisms were predominant among males aged 18 years and below. Some CSOM causing microorganisms were-significantly more so than the others characteristically associated with each of the following clinical features: quantity of pus drainage, mode of onset, otalgia, hearing loss, location of tympanic membrane perforation, and mucosal appearance. PMID- 26955433 TI - Exploring fertility decisions among pregnant HIV-positive women on antiretroviral therapy at a health centre in Balaka, Malawi: A descriptive qualitative. AB - BACKGROUND: The proportions of women of reproductive age living with the human immunodeficiency virus (HIV) vary between different regions of the world, with significantly higher proportions in sub-Saharan Africa. Family planning is one of the major issues that couples and families affected with HIV must confront. We aimed to assess the cultural and social factors associated with childbearing and family planning knowledge, decision-making, and practices among HIV-positive pregnant women attending antenatal clinic at a health centre in Balaka, Malawi. METHODS: This was a qualitative descriptive study carried out at Kalembo Health Centre in Balaka. A purposive sampling technique was used to select pregnant women enroled in the antiretroviral therapy (ART) programme. A sample size of thirty-five women was decided upon after data saturation. Qualitative inquiry was used during data collection. Data were analysed using systematic text condensation, while numbers and percentages were generated using Microsoft Excel. RESULTS: Out of 35 participants, 20 were aged between 25 and 34 years, and 18 had been married at least three times. All 35 women wished to have their own biological child. Factors, reported by participants, that promote childbearing included: the desire to please their husbands, fear of losing their husbands to others if they did not bear children, the knowledge that ART would help prevent their children from acquiring the virus, the desire to prove to others that they can also bear children, and a lack of family planning leading to unplanned pregnancies. CONCLUSIONS: The factors that lead to pregnancies among women on ART in Balaka ranged from assured safety of the child from HIV, lack of contraception, to other factors related to their partners. The authors recognize and support the freedom for women to become pregnant and bear children, and, in the context of HIV infection, fertility and reproductive services should include a comprehensive approach towards addressing issues of HIV and AIDS and childbearing among infected women. PMID- 26955434 TI - Analysis of maternal and child health policies in Malawi: The methodological perspective. AB - The question of why most health policies do not achieve their intended results continues to receive a considerable attention in the literature. This is in the light of the recognized gap between policy as intent and policy as practice, which calls for substantial research work to understand the factors that improve policy implementation. Although there is substantial work that explains the reasons why policies achieve or fail to achieve their intended outcomes, there are limited case studies that illustrate how to analyze policies from the methodological perspective. In this article, we report and discuss how a mixed qualitative research method was applied for analyzing maternal and child health policies in Malawi. For the purposes of this article, we do not report research findings; instead we focus our dicussion on the methodology of the study and draw lessons for policy analysis research work. We base our disusssion on our experiences from a study in which we analyzed maternal and child health policies in Malawi over the period from 1964 to 2008. Noting the multifaceted nature of maternal and child health policies, we adopted a mixed qualitative research method, whereby a number of data collection methods were employed. This approach allowed for the capturing of different perspectives of maternal and child health policies in Malawi and for strengthening of the weaknesses of each method, especially in terms of data validity. This research suggested that the multidimensional nature of maternal and child health policies, like other health policies, calls for a combination of research designs as well as a variety of methods of data collection and analysis. In addition, we suggest that, as an emerging research field, health policy analysis will benefit more from case study designs because they provide rich experiences in the actual policy context. PMID- 26955431 TI - HCV and Oxidative Stress: Implications for HCV Life Cycle and HCV-Associated Pathogenesis. AB - HCV (hepatitis C virus) is a member of the Flaviviridae family that contains a single-stranded positive-sense RNA genome of approximately 9600 bases. HCV is a major causative agent for chronic liver diseases such as steatosis, fibrosis, cirrhosis, and hepatocellular carcinoma which are caused by multifactorial processes. Elevated levels of reactive oxygen species (ROS) are considered as a major factor contributing to HCV-associated pathogenesis. This review summarizes the mechanisms involved in formation of ROS in HCV replicating cells and describes the interference of HCV with ROS detoxifying systems. The relevance of ROS for HCV-associated pathogenesis is reviewed with a focus on the interference of elevated ROS levels with processes controlling liver regeneration. The overview about the impact of ROS for the viral life cycle is focused on the relevance of autophagy for the HCV life cycle and the crosstalk between HCV, elevated ROS levels, and the induction of autophagy. PMID- 26955435 TI - Maximizing HIV partner notification opportunities for index patients and their sexual partners in Malawi. AB - INTRODUCTION: HIV testing and counselling (HTC) is important to effect positive sexual behaviour change and is an entry point to treatment, care, and psychosocial support. One of the most practical initiatives to increase HTC is to encourage sexual partners of HIV-infected persons to test for HIV. However, partner notification strategies must be feasible in the healthcare setting and acceptable to the population. METHODS: We conducted a qualitative study during the pilot phase of an HIV partner notification trial to complement its assessment of feasibility and acceptability of methods of partner notification. We performed in-depth interviews with 16 consecutive HIV-positive index participants who consented and their 12 identifiable sexual partners. We also conducted two focus group discussions with healthcare workers to supplement the patient perspectives. In the main study, newly diagnosed HIV cases (index cases) were randomized to one of three methods of partner notification: passive, contract, and provider referral. Clients in the passive referral group were responsible for notifying their sexual partners themselves. Individuals in the contract referral group were given seven days to notify their partners, after which a healthcare provider contacted partners who had not reported for counselling and testing. In the provider group, a healthcare provider notified partners directly. RESULTS: Although most index participants and partners expressed a preference for passive notification, they also highlighted benefits for provider-assisted notification and the universal right for all HIV-exposed persons to know their HIV exposure and benefit from HIV testing and access antiretroviral treatment. Several participants mentioned couples counselling as a way to diffuse tension and get accurate information. All mentioned benefits to HIV testing, including the opportunity to change behaviour. CONCLUSIONS: Provider-assisted partner notification is not preferred, but it is acceptable and may complement the passive method of notification. Couples counselling should also be encouraged. PMID- 26955436 TI - The patient-provider relationship and antenatal care uptake at two referral hospitals in Malawi: A qualitative study. AB - BACKGROUND: Approximately 90% of Malawian women attend antenatal care at least once during their pregnancies; however, most mothers first present during months five and six and do not adhere to the World Health Organization's recommended four visits. The objective of this study was to explore the role the patient provider relationship has on antenatal care uptake. METHODS: A qualitative study, consisting of interviews with 20 urban pregnant mothers and eight health workers, was conducted from September to December 2014. Two large tertiary care hospitals in the Central and Southern regions of Malawi were selected as study sites. RESULTS: Several factors influenced antenatal care attendance. Significant barriers reported included the patient-provider relationship, clinic wait times, family and friend support, distance from home to the clinic, transportation, cost, and number of visits. The patient-provider relationship appears to have a large impact on antenatal clinic participation. Mothers indicated that health workers often mistreat or demean them during visits. Additionally, health workers revealed that, due to staff shortages, patients often do not receive the care they deserve. CONCLUSIONS: The results of this study suggest that, in addition to other factors, healthcare provider attitudes influence antenatal clinic attendance. Improving the patient-provider relationship may increase antenatal clinic attendance and decrease pregnancy complications during pregnancy. Professional development opportunities and quality improvement programmes are would help improve patient care and health outcomes while the continued staff shortages in the country are addressed. PMID- 26955437 TI - Semen profiles of young men involved as bicycle taxi cyclists in Mangochi District, Malawi: A case-control study. AB - AIM: The purpose of this study was to evaluate the semen profiles of bicycle taxi cyclists and healthy controls in Mangochi district, Malawi. METHODS: Semen samples were collected from young bicycle taxi cyclists after two to three days of sexual abstinence. A control group, comprising young men who were not bicycle taxi operators also submitted semen samples. Samples were left to liquefy for 30 minutes before measurements were conducted of volume, concentration, total motility, and progressive motility. This was followed by preparation of morphology slides. Light microscopy was used for sperm analysis. RESULTS: Semen parameters such as volume (1.66 +/- 0.18 mL vs. 3.64 +/- 0.17 mL; p = 0.0001), concentration (28.31 +/- 4.33 x 106/mL vs. 54.95 +/- 5.93 * 106/mL; p = 0.02) , total motility (56.98% +/- 8.22% vs. 56.98% +/- 8.22%; p = 0.03), progressive motility (22.57% +/- 3.35% vs. 59.69% +/- 4.82%; p = 0.004), and morphology (6.98% +/- 3.23% vs. 19.73% +/- 2.32%; p = 0.006) were significantly reduced in the bicycle taxi cyclists compared to the healthy controls. CONCLUSION: In this case-control study, bicycle taxi operators had lower semen volume, concentration, total motility, and progressive motility, as well as a higher concentration of abnormally shaped spermatocytes, compared to healthy controls. PMID- 26955438 TI - Clinicopathological comparisons of open vein harvesting and endoscopic vein harvesting in coronary artery bypass grafting patients in Mashhad. AB - INTRODUCTION: Harvesting of the greater saphenous vein is almost an inevitable part of coronary artery bypass grafting (CABG) operations, and it is done by two main techniques, i.e., conventional or open vein harvesting (OVH) and the minimally-invasive endoscopic vein harvesting (EVH). This study aimed to compare these two techniques in off-pump CABG procedures with respect to clinical and pathological outcomes. METHODS: This cohort study was conducted on CABG candidates during a one-year period from October 2013 through September 2014 in the Department of Cardiac Surgery at Mashhad University of Medical Sciences. Eighty-seven patients voluntarily underwent EVH, and another 86 patients matched for age, gender, and other cardiovascular risk factors were selected for OVH. They were followed up for six weeks, and the main outcome measures were infections of the wound, pain, duration of hospital stay, and the costs of hospitalization. Paired sample t-test, independent t-test, or their non parametric equivalents and the chi-squared test were used by SPSS version 17.0 for data analysis. RESULTS: The mean duration of time for vein harvesting was shorter in the EVH group (p < 0.001), and the pain score was lower (p = 0.04). No infections occurred at the site of the wound. The length of hospital stay was not significantly different for the two groups (OVH versus EVH: 8.5 +/- 3.3 versus 8.4 +/- 3.2 days; p-value: 0.08). Hospitalization costs were significantly higher in the EVH group (OVH versus EVH: 5.8 +/- 4.7 versus 7.3 +/- 2.0 million Tomman; p-value: 0.008), yet no difference was diagnosed with respect to endothelial damage in the vein grafts harvested by the EVH and OVH techniques. CONCLUSION: EVH is considered as a minimally invasive and safe vein harvesting technique in our Center, and it can reduce the harvesting time and post-operative pain. In addition, its efficiency was similar to that of OVH. PMID- 26955439 TI - Evaluation of mouse embryos produced in vitro after electromagnetic waves exposure; Morphometric study. AB - INTRODUCTION: Today, the use of electromagnetic waves in medical diagnostic devices, such as magnetic resonance imaging (MRI), has increased, and many of its biological effects have been reported. The aim of the present study was to assess the biological effects of 1.5 Tesla (T) magnetic resonance imaging (MRI) on fertility and reproductive parameters. METHODS: Eighty adult male and female NMRI mice (NMRI: Naval Medical Research Institute) of age 6-8 weeks were studied and randomly divided into two study and control groups. After confirmation of pregnancy, the mice in the study group were exposed to the MRI (1.5 T) machine's waves over the next three weeks, once a week for 36 minutes. One day and thirty five days after the last radiation, the mice were killed in order to do the in vitro fertilization (IVF) by neck beads' displacement and the impact on the evolution of embryos, and its quality was studied. Data were analyzed using SPSS version 20 and the significance level of less than 0.05 was considered. RESULTS: Embryo morphometry showed that the total diameter and the cytoplasm diameter of the study group embryos suffered significant reduction compared to the control group, 1 day after the last irradiation (p < 0.05), but the diameter of the perivitelline space of this group's embryos had a significant increase (p < 0.05). The qualitative results during 35 days after irradiation showed that morphologically parameters of the embryos in the study group had no significant differences from the control group. CONCLUSION: Exposure to MRI irradiation can transiently disturb the development of mouse embryos and fertility, but these effects are reversible 35 days after the last irradiation. PMID- 26955440 TI - Effects of Vocational Consultation on Relapse Rate and Hope among Drug Dependents in Bojnurd, Iran. AB - INTRODUCTION: Drug addiction is one of the most flagrant social damages that can easily enervate the socio-cultural foundation of a country as well as endanger human dynamism. One of the prevalent problems among most addicted people is their low hope and relapse of drug dependence. The aim of this study was to assess the effect of vocational consultation (for training on problem-solving skills) on hope and relapse rate of patients treated in methadone maintenance clinics. METHODS: This experiment was conducted on 60 drug abusers treated in a methadone maintenance program in drug addiction centers in Bojnurd, Iran, in 2014. The patients were randomly and equally allocated into two study and control groups. All patients completed the Miller Hope Questionnaire before and after the intervention. Ten sessions of vocational consultation were held for the study group while the control group received no special treatment. Patients were followed up on for relapses for six months. Data were analyzed using SPSS (version 16) and the paired-samples t-test technique. RESULTS: The results indicated that the mean and standard deviation of hope on the pre-test in the study group increased on the post-test (from M=175.5, SD=31.8, to M=198.5, SD=20.4), while in the control group the mean of hope decreased from the pre-test to past-test stage (M=184.7, SD=27.7, to M=183.3, SD=26.1), showing a significant relationship, t(56)= 5.657, p<0.05. The relapse rate was not significantly different in the two groups. CONCLUSION: The vocational consultation positively affects hope among drug dependents but did not affect their relapse rate during the six-month follow-up. Increasing the hope in these groups of patients may be effective in other aspects of treatment success in long-term follow-up. PMID- 26955441 TI - The potential role of cell surface complement regulators and circulating CD4+ CD25+ T-cells in the development of autoimmune myasthenia gravis. AB - INTRODUCTION: CD4+CD25+ regulatory T-lymphocytes (T-regs) and regulators of complement activity (RCA) involving CD55 and CD59 play an important role in the prevention of autoimmune diseases. However, their role in the pathogenesis of human autoimmune myasthenia gravis (MG) remains unclear. This study aimed to determine the frequency of peripheral blood T-regs and CD4+ T-helper (T-helper) cells and the red blood cells (RBCs) level of expression of CD55 and CD59 in MG patients. METHODS: Fourteen patients with MG in neurology outpatient clinics of Sohag University Hospital and Sohag General Hospital from March 2014 to December 2014, and 10 age-matched healthy controls participated in this case-control study. We did flowcytometric assessments of the percentage of peripheral T-regs and T-helper cells and the level of expression of CD55 and CD59 on RBCs in the peripheral blood of patients and controls. RESULTS: There was a statistically significant decrease in the percentage of peripheral blood T-regs and T-regs/T helper cell ratio in the MG patients group. Moreover, the level of expression of CD55, CD59, and dual expression of CD55/CD59 on RBCs were statistically significantly lower in MG patients than those of healthy controls. However, regression analysis indicated that there was no significant correlation between all the measured parameters and disease duration or staging. CONCLUSION: Functional defects in the T-regs and RCA may play a role in the pathogenesis of autoimmune MG and their functional modulation may represent an alternative therapeutic strategy for MG treatment. PMID- 26955442 TI - Epidemiological survey of pediatric food allergy in Mashhad in Northeast Iran. AB - INTRODUCTION: Food allergy is an increasing problem worldwide, but the foods responsible for food allergy are not the same in different countries, probably because of the role of genetic, cultural, and nutritional factors. The aim of this study was to determine the common food allergens in pediatric patients with different presentation of food allergy. METHODS: In this cross-sectional study, all of the patients were referred to pediatric allergy clinics affiliated with Mashhad University of Medical Sciences from September 2012 to August 2014. For patients with IgE-mediated food allergy that was diagnosed with clinical manifestations, the skin prick test was done. The results were analyzed by SPSS version 17 and statistical analysis was done with the chi-squared test and the t test. P values < 0.05 were considered statistically significant. RESULTS: Three hundred seventy-one patients (53.9% male, 46.1% female) with ages in the range of three months to 18 years were studied. The most frequent food allergen in all patients with decreasing prevalence were egg white (17.8%), pepper (15.8%), curry (14.3%), egg yolk (14%), cow's milk (10%), and tomato (7.8%). The most common presenting symptoms were respiratory (allergic rhinitis 45%, asthma 32%), dermatologic (atopic dermatitis 30%, urticaria 8.3%), colitis (17.5%), and gasteroesophagial reflux disease (GERD) (2%). According to the prevalence of food allergens in different age groups, we realized that, after the age of three years, the frequency of sensitization to egg white, egg yolk, cow's milk, wheat and cereals was decreased and allergy to pepper and curry was increased. CONCLUSION: The prevalence of culprit foods that produce food allergies depends on several factors, including age, presenting manifestation, and where the patient lives. As many food allergies are outgrown, patients should be reevaluated regularly to determine whether they have lost their reactivity or not. PMID- 26955443 TI - Explaining nutritional habits and behaviors of low socioeconomic status women in Sanandaj: a qualitative content analysis. AB - INTRODUCTION: Health and behavior are closely related subjects because disease is typically rooted in individuals' unhealthy behaviors and habits. This study aims to identify women's nutritional habits and behaviors in order to design interventions to promote nutritional literacy. METHODS: This qualitative research is part of a mixed method (quantitative-qualitative) study, conducted based on content analysis. Data were collected using semistructured interviews, group discussions, and in-depth interviews with married women, aged 18-50 years, who were referred to four health care centers in Sanandaj in 2013-2014. RESULTS: Nutritional habits and behaviors of participants were classified into two categories: representation of nutritional behavior based on consumption pattern and representation of nutritional behavior based on consumption method. For the former, eight consumption pattern subcategories were formed: meat, dairy, fast food, local foods, fruits and vegetables, soft drinks, and oils. The latter (representation of nutritional behavior based on consumption method), included two subcategories: consumption method in line with health and consumption method inconsistent with health. CONCLUSION: Results of this qualitative study provide a solid foundation for development and designing interventions to nutritional literacy promotion based on needs. The designed intervention to healthy nutritional behavior should be based on empowering women and providing facilitator factors of a healthy diet. While designing this study, with a holistic perspective, individual and social aspects of a healthy diet should be taken into account. PMID- 26955444 TI - The Effect of Occupational Noise Exposure on Blood and Biochemical Parameters: A Case Study of an Insulator Manufacturer in Iran. AB - INTRODUCTION: Occupational noise is among the most critical occupational hazards, which, in addition to hearing loss, can cause other adverse consequences on an individual's physical and mental health. Long-term exposure to noise can affect blood and biochemical parameters and subsequently lead to increased risk of cardiovascular disease. This study investigated the effect of occupational exposure to noise on blood and biochemical parameters of workers in an insulator manufacturing plant. METHODS: This case-control study was conducted on workers in the production section (49 people as a case group) and the administrative staff (10 people as a control group) in one insulator manufacturing plant from 2010 to 2014. To assess individual exposure of workers to noise, the noise dosimeter model TES-1355 was used. Noise dosimetry testing was done based on the exposure pattern of workers to noise in compliance with the Iranian national standard (the criterion level of 85 dBA and the exchange rate of Q = 3 dBA). Blood parameters such as blood glucose, cholesterol, red blood cells (RBC), white blood cells (WBC), hemoglobin (Hb), and hematocrit (Hct) were studied in production workers (case) and administrative staff (control) over five consecutive years. The data were analyzed by software (SPSS-22) using the t-test, Mann-Whitney test, Fisher exact test, and Greenhouse-Geisser test. RESULTS: No significant difference was found among the demographic data of the two groups (p > 0.05). Average of glucose and cholesterol levels in the two groups was statistically significant (p < 0.05) and blood glucose levels in the case group significantly reduced over time and cholesterol increased (p < 0.001). Mean difference of RBC number, WBC number, and serum levels of Hb and Hct was statistically significant between the two groups (p < 0.05). In addition, these hematological parameters increased among workers during these years. CONCLUSION: Occupational exposure to noise may have a significant effect on an individual's blood parameters, which will cause harmful effects on worker health. Therefore, industrialists must take preventive measures in the field of noise control. PMID- 26955445 TI - The effect of flexible acrylic resin on masticatory muscle activity in implant supported mandibular overdentures: a controlled clinical trial. AB - BACKGROUND: It is not yet clear from the current literature to what extent masticatory muscle activity is affected by the use of flexible acrylic resin in the construction of implant-supported mandibular overdentures. OBJECTIVE: To compare masticatory muscle activity between patients who were provided with implant-supported mandibular overdentures constructed from flexible acrylic resin and those who were provided with implant-supported mandibular overdentures constructed from heat-cured conventional acrylic resin. METHODS: In this clinical trial, 12 completely edentulous patients were selected and randomly allocated into two equal treatment groups. Each patient in Group 1 received two implants to support a mandibular overdenture made of conventional acrylic resin. In Group 2, the patients received two implants to support mandibular overdentures constructed from "Versacryl" flexible acrylic resin. The maxillary edentulous arch for patients in both groups was restored by conventional complete dentures. For all patients, masseter and temporalis muscle activity was evaluated using surface electromyography (sEMG). RESULTS: The results showed a significant decrease in masticatory muscle activity among patients with implant-supported mandibular overdentures constructed from flexible acrylic resin. CONCLUSION: The use of "Versacryl" flexible acrylic resin in the construction of implant-supported mandibular overdentures resulted in decreased masticatory muscle activity. PMID- 26955446 TI - The impact of butylphthalide on the hypothalamus-pituitary-adrenal axis of patients suffering from cerebral infarction in the basal ganglia. AB - BACKGROUND: Butylphthalide sodium chloride injection for patients with acute cerebral infarction has a certain effect. Although there are several proposed mechanisms of drug action, no related research on improving the inflammatory cytokines that regulate the body's immune system through the hypothalamus pituitary-adrenal axis has been published. OBJECTIVE: To determine the impact of butylphthalide and sodium chloride injection on the hypothalamus-pituitary adrenal (HPA) axis after acute cerebral infarction in the basal ganglia. METHODS: Patients were randomly divided into treatment and control groups; the treatment group received intravenous drips of butylphthalide, while the control group did not. The levels of adrenocorticotropic hormone (ACTH) and cortisol (COR), along with the National Institutes of Health Stroke Scale (NIHSS) scores of both groups were detected using the radioimmunoassay method. This was done at regular intervals after cerebral infarction in the basal ganglia was detected. RESULTS: Fourteen days after treatment, the levels of serum ACTH and COR in both groups were higher than normal. The NIHSS score and levels of ACTH and COR of the treatment group were significantly lower than those of the control group (p<0.05). The data was computed and analyzed using SPSS17.0 software. CONCLUSION: Butylphthalide treatment for patients suffering from acute basal ganglia infarction can reduce the adverse effects on the HPA axis, thus improving patient prognosis. PMID- 26955447 TI - Modified Use of Team-Based Learning to Teach Nursing Documentation. AB - INTRODUCTION: Nursing documentation is one of the main parts of clinical documentation. Poor knowledge of nurses in documentation methods could bring about problems for patients and nurses. It is very important to promote nurses' knowledge and skills in this regard through effective teaching methods. The aim of this study was to use Team-Based Learning (TBL) to teach nursing documentation for nurses. METHODS: TBL was implemented for 20 nurses participating in a nursing documentation workshop in Qazvin, Iran, in 2015. TBL consists of three main stages. The first stage is the learners' reading about the subject matter. The second stage is measuring the learners' knowledge about the subject matter they have studied using the Individual Readiness Assurance Test (IRAT). In the third stage, more profound learning is achieved by forming small groups and performing teamwork. Finally, participants' views and experiences about TBL were investigated using observations and interviews. RESULTS: The results showed that TBL method increases transfer of information and improves intrapersonal relationships and collaboration. All nurses were satisfied with the educational content and the TBL method. The strong points of this workshop included obtaining the viewpoints of the nurses, step-by-step integration of the contents of teamwork, consultation and active participation of all participants, high learning motivation, and creating a sense of competition. The nurses viewed TBL as a useful method to improve their reporting skills. CONCLUSION: Using new teaching methods based on teamwork could bring about achievements, including improvement of intrapersonal relationships and teamwork, which are requisites of nursing in addition to facilitating the learning of educational content. It is suggested that the TBL method be used to improve teaching and to increase nurses' skills and knowledge. PMID- 26955448 TI - Disaster Risk Assessment in Educational Hospitals of Qazvin Based on WHO Pattern in 2015. AB - INTRODUCTION: In addition to damaging communities and infrastructures, unexpected disasters affect service provider centers as well. Structural, non-structural, and functional components of hospitals could be affected when hazards or disasters occur, and they may be unable to admit casualties, have their own personnel and patients killed or injured, have their property destroyed. In such as case, they would increase the burden of death resulting from the disaster. Therefore, in this study, hospital safety was reviewed in two hospitals in Qazvin in 2015. METHODS: This cross-sectional descriptive study was conducted on two of the Rajaee and Velayat Hospitals in Qazvin. The tools used to assess for the hospitals' risk of experiencing a disaster were observation, interviews, and a checklist of hospital disaster risk assessment provided by the World Health Organization (WHO), including 5 sections and 145 indices for the safety assessment of hospitals. To determine the general weight, three main parts of the questionnaire, i.e., functional safety, non-structural safety, and structural safety, were given weights of 0.2, 0.3, and 0.5, respectively, according to the original version of the indices. Each index was scored as 0, 1, and 2 based on the low, medium, and high scores. The safety scores that were obtained were categorized in three groups, i.e., low safety (<= 34%), medium safety (34-66%), and high safety (> 66%). The data were analyzed using Excel 2007 software. RESULTS: Functional, structural, and non-structural safety scores were evaluated as 60.20% (medium safety), 67.61% (high safety), and 76.16% (high safety), respectively. General preparedness of the hospitals we studied were 71.90%, a high safety level. This high preparedness was related to the indices of availability of medicines, equipment, water supply, and other resources required in emergency conditions (85%), and the lowest preparedness was related to contingency plans of medical operations (19%). CONCLUSION: The preparedness of the two hospitals in the study was evaluated as being high. Considering the history of disasters in this Province, it would be effective to retrofit hospitals and compile written plans for administrative measures at the time of disasters. These measures must be consistent, and there should be safe installation of risky office and medical equipment. PMID- 26955449 TI - A Review of Nanoliposomal Delivery System for Stabilization of Bioactive Omega-3 Fatty Acids. AB - Currently, bioactive compounds are required in the design and production of functional foods, with the aim of improving the health status of consumers all around the world. Various epidemiological and clinical studies have demonstrated the salutary role of eicosapentaenoic acid (EPA, 22:6 n-3) and docosahexaenoic acid (DHA, 22:5 n-3) in preventing diseases and reducing mortality from cardiovascular diseases. The unsaturated nature of bioactive lipids leads to susceptibility to oxidation under environmental conditions. Oxidative deterioration of omega-3 fatty acids can cause the reduction in their nutritional quality and sensory properties. Encapsulation of these fatty acids could create a barrier against reaction with harmful environmental factors. Currently, fortification of foods containing bioactive omega-3 fatty acids has found great application in the food industries of different countries. Previous studies have suggested that nano-encapsulation has significant effects on the stability of physical and chemical properties of bioactive compounds. Considering the functional role of omega-3 fatty acids, this study has provided a literature review on applications of nanoliposomal delivery systems for encapsulation of these bioactive compounds. PMID- 26955450 TI - Chronic Gastritis in Morbidly Obese Patients with Sleeve Gastrectomy. AB - INTRODUCTION: Obesity is a condition that has significant impact on public health. Recent exciting studies have linked chronic gastritis and H. pylori infection to obesity. Chronic gastritis has shown increased prevalence in obesity, more particularly H. pylori-related gastritis. This study aimed to determine the prevalence of chronic gastritis in morbidly obese patients who were subjected to sleeve gastrectomy, with focus on H. pylori-related gastritis. The aim was to demonstrate any influence on chronic gastritis of the surgical procedure or its post-operative course. METHODS: One hundred six morbidly obese patients were subjected to vertical sleeve gastrectomy in King Abdulaziz University Hospital (KAUH) from March 2014 to April 2015. After full pre operative preparation, sleeve gastrectomy was carried out, followed by histological examination of the specimen to view the chronic gastritis and H. pylori-related cases. All epidemiological data of the patients, including age, gender, body mass index (BMI), as well as mean operative time, length of hospital stay, and post-operative complications were documented and analyzed by IBM-SPSS version 22. RESULTS: Female patients presented the higher prevalence, i.e., 66% among the group of patients with sleeve resection, while 33% had chronic gastritis and 8.5% had H. pylori-related gastritis. CONCLUSION: This study highlights the high prevalence of chronic gastritis in morbidly obese patients with reference to the high incidence of H. pylori-related gastritis among them, however no relationship was found between this infection and the post-operative outcome. PMID- 26955451 TI - Clinical versus Pathologic staging of Renal Tumors: Role of Multi-Detector CT Urography. AB - INTRODUCTION: Our ability to diagnose renal cell carcinoma (RCC) has increased in the past 30 years as a result of the extensive application of imaging techniques, such as ultrasonography, computed tomography, and magnetic resonance imaging. Multi-detector computed tomography (MDCT) remains the most appropriate imaging modality for the diagnosis and staging of RCC. The aim of this work was to compare the findings of MDCT with surgical pathology to determine the accuracy of delineating tumor size, localization, organ confinement, lymph node metastases, and the extent of tumor thrombus in the renal vein and inferior vena cava. METHODS: The clinical, surgical, and anatomo-pathologic records of 99 patients treated by nephrectomy (radical or partial) for solid renal tumors at Theodor Bilharz Research Institute and Nasser Institute from 2005 to 2011 were reviewed retrospectively. All cases were staged pre-operatively with abdominal MDCT (pre- and post-contrast enhancement) in addition to the routine biochemical, hematological, and radiological work-up. The tumors' histologic types were determined according to the WHO classification of renal tumors in adults in 2004, and staging was updated to the TNM 2010 system. Data were analyzed using the t test. RESULTS: The mean age was 52 (range 21-73). Seventy-eight patients were males, and 21 patients were females (Male/Female ratio: 3.7:1). There were no significant differences in the mean tumor size between radiographic and pathologic assessments in different tumor stages. The overall incidence of lymph node invasion in surgical specimens was 76%, whereas MDCT showed a positive incidence in 68.4% of cases (false negative result in 7 cases, 7.6%). CONCLUSION: Our findings indicated that MDCT urography is an accurate method to estimate renal tumor size, lymph node, vascular and visceral metastases preoperatively. Also, preoperative staging of renal tumors with MDCT represents a valuable and accurate tool. PMID- 26955452 TI - Circulating miRNAs as Predictor Markers for Activation of Hepatic Stellate Cells and Progression of HCV-Induced Liver Fibrosis. AB - INTRODUCTION: Liver fibrosis is the excessive accumulation of extracellular matrix that occurs by activation of hepatic stellate cells (HSCs), which has been identified as the major driver of liver fibrosis. Several studies confirmed that miRNAs have regulatory effects on the activation of HSCs by affecting the signaling pathways. The aim of this study was to develop non-invasive diagnostic markers by measuring different circulating miRNAs in serum as predictor markers for early diagnosis of liver fibrosis and its progression. METHODS: In this case control study, we enrolled 66 subjects with chronic hepatitis C (CHC) with early stage of fibrosis and 65 subjects with CHC with late-stage fibrosis. Also, 40 subjects were included as normal controls. The six main miRNAs, i.e., miR-138, miR-140, miR-143, miR-325, miR-328, and miR-349, were measured using the reverse transcription-polymerase chain reaction. RESULTS: In the cases of CHC both with early and late stage of fibrosis, the circulating levels of the six main miRNAs were significantly higher than the levels in the control group. ROC analysis indicated that the sensitivity and specificity of miR-138 were 89.3% and 71.43%, respectively, in the early stage of fibrosis. In the late stage, the sensitivity and specificity of miR-138 were 89.3 and 93.02%, respectively, whereas, for miR 143, they were 75.0 and 88.4%, respectively. CONCLUSIONS: Circulating miR-138 could serve as a non-invasive biomarker for the detection of early fibrosis. Also, miR-138 and miR-143 could be specific biomarkers for indicating the late stage of liver fibrosis. PMID- 26955453 TI - Influence of Sleep on Quality of Life Among Hospital Nurses. AB - INTRODUCTION: Sleep disorders are the cause of morbidity and mortality and can decrease functional capacity and quality of life. Nurses, especially those working irregular or night shifts, are at risk for developing sleep disorders. The present study aims to determine the relationship between sleep quality and health-related quality of life (HRQOL) as well as quantitative and subjective aspects of sleep quality in nurses. METHODS: This cross-sectional study was conducted on 1456 nurses working in 11 hospitals in Shiraz and Tehran (Iran) in 2014. Structured questionnaires (Pittsburg Sleep Quality Index [PSQI] and Medical Outcomes Study Short Form-36 Survey [SF-36]) were used to collect data on participants' demographic characteristics, sleep quality, and health-related quality of life. Chi-square and independent samples t-test were employed for statistical analysis. RESULTS: Mean age of participants was 30.81 +/- 7.8, and most of them were female (89.04%) and poor sleepers. Long-duration sleepers slept for more than 9.8 h/night, and they obtained higher scores than short-duration sleepers (<4.5 h/night) in all SF-36 domains. The study results showed that increased quality of life was significantly related to health-related quality of life. CONCLUSIONS: This study showed strong evidence that sleep disorders, such as poor quality and short duration of sleep, are negatively associated with HRQOL. Therefore, developing systemic strategies to cope with the problem seems to be necessary. PMID- 26955454 TI - Promoting Health Literacy Is A Necessary Action on the Outskirts Based on the Real Condition There. AB - INTRODUCTION: Health literacy refers to the degree to which individuals have the capacity to obtain, process, and understand the basic health information needed to make appropriate health decisions. The aim of this study was to determine the health literacy level in regions on the outskirts of Mashhad, Iran. METHODS: This cross-sectional study was undertaken in December 2014 on residents in the outskirts of Mashhad. We used a multistage sampling method, and data were collected via a questionnaire, conducted by trained interviewers. The data were analyzed using the t-test, the Mann-Whitney test, and the chi-squared test. RESULTS: We had 502 participants in this study. The mean age was 35.0 +/- 11.06 years. Sixty percent of participants (301) were female, and 86.3% (425) had high school diplomas or lower educational levels; the rest had higher educational levels. Television/radio and the Internet were the most and least frequently accessed and used media, respectively. There were significant correlations between the level of knowledge and response to questions in specific domains, such as weight, fasting blood sugar, and blood pressure (p < 0.001). The participants had no difficulty reading booklets (63%), physicians' prescriptions (59%), medical forms (56%), and guidance boards in hospitals (71%). People had no problems understanding most health/disease materials obtained via various routes (37%), but the health/disease materials published on the Internet/electronic resources (37%) and textbooks (64%) were difficult for them to understand. CONCLUSION: Health literacy is a complicated construct, and more comprehensive studies are needed to develop health-related information that can be understood by more of the general public. PMID- 26955455 TI - Evaluation of lemon fruit extract as an antioxidant agent against histopathological changes induced by cyclophosphamide in the testes of albino mice. AB - INTRODUCTION: The aim of this study was to determine the protective effects of lemon fruit extracts (LFE) against histopathological changes induced in the testes of male mice treated with cyclophosphamide (CP). METHODS: Thirty male mice were divided evenly into six groups: 1) group 1: the controls, 2) group 2: treated with LFE (10 ml/kg b wt.), 3) group 3: treated with CP (10 mg/kg b wt.), 4) group 4: treated with CP (20 mg/kg b wt.), 5) group 5: treated with LFE (10 ml/kg) + CP (10 mg/kg), 6) group 6: treated with LFE (10 ml/kg) + CP (20 mg/kg). RESULTS: Histological examination of the testes of mice treated with CP revealed histopathological changes, such as atrophy, degeneration, incomplete spermatogenic series in most seminiferous tubules, and spermatogenic necrosis with pyknotic nuclei. Advanced degree of improvement was seen in testes of mice treated with LFE co-administered with CP. Most of the seminiferous tubules restored their normal structure and spermatogenic layers appeared semi-normal with complete spermatogenic series. CONCLUSION: Lemon fruit extract in conjunction with drug treatment protects the testicular tissue against CP-induced testicular injury in mice. PMID- 26955456 TI - The role of medicinal plants in the treatment of diabetes: a systematic review. AB - INTRODUCTION: Diabetes is a serious metabolic disorder and plenty of medical plants are used in traditional medicines to treat diabetes. These plants have no side effects and many existing medicines are derived from the plants. The purpose of this systematic review is to study diabetes and to summarize the available treatments for this disease, focusing especially on herbal medicine. METHODS: Required papers about diabetes and effective plants were searched from the databases, including Science direct, PubMed, Wiley, Scopus, and Springer. Keywords in this study are "medicinal plants", "diabetes", "symptom", "herbal", and "treatment". Out of the 490 collected articles (published in the period between 1995 and 2015), 450 were excluded due to non-relevance or lack of access to the original article. RESULTS: Diabetes is mainly due to oxidative stress and an increase in reactive oxygen species that can have major effects. Many plants contain different natural antioxidants, in particular tannins, flavonoids, C and E vitamins that have the ability to maintain beta-cells performance and decrease glucose levels in the blood. CONCLUSION: According to published results, it can be said that medical plants are more affordable and have less side effects compared synthetic drugs, and are more effective in treatment of diabetes mellitus. PMID- 26955457 TI - Effects of some insecticides on longevity of the foragers honey bee worker of local honey bee race Apis mellifera jemenatica. AB - INTRODUCTION: Honeybees are constantly exposed to a wide range of vital and non vital pressures that may interact with each other and affect the health or survival of the insects. Pesticides are the main danger for the insects, and they subsequently have impacts on human and environmental health. METHODS: Field research was conducted in the apiary of Hada Al Sham Research Station, where the worker honeybees forager Apis mellifera jemenatica were selected to examine the effect of pesticides on workers' longevity. We used three insecticides, i.e., deltamethrin, malathion, and abamectin, in different concentrations. The longevity of worker honeybee foragers was calculated; the honeybees were supplied with water, food, natural protein, and sugar solution laced with selected insecticide by mouth under laboratory conditions. RESULTS: The longest period of insect longevity was 15.5 days when using deltamethrin concentrate at a concentration of 1.00 ppm; the lowest longevity was two days when using abamectin at a concentration 1.00 ppm. The longevity of the unexposed forager worker honeybees was 18 days, as the variation in the intensity of the effect of the insecticide on the bees appeared with the severity of the effect diminishing in the order of abamectin followed by malathion followed by deltamethrin. CONCLUSION: The study found that the type and concentration of the insecticides that are found in the honeybees' food had a significant impact on the time of survival of the insects. The longevity of a worker honeybee depends on the health and safety of all of the members of the beehive, and safe alternatives to insecticides must be used because of the danger imposed by the application of insecticides on the continuity of life of the entire society depends on the life of this layer bee community. PMID- 26955458 TI - The Effect of Green Tea Extract Supplementation on Liver Enzymes in Patients with Nonalcoholic Fatty Liver Disease. AB - BACKGROUND: Green tea is one of the most popular beverages in the world. It is believed to have beneficial effects in the prevention and treatment of many diseases, one of which is nonalcoholic fatty liver disease (NAFLD). The present study investigated the effects of consumption of green tea in NAFLD patients. METHODS: This study was a double-blind, placebo-controlled, randomized clinical trial. Ultrasonography was used to diagnose fatty liver in patients with alanine aminotransferase (ALT) >31 mg/dl and 41 mg/dl and aspartate aminotransferase (AST) >31 mg/dl and 47 g/dl in women and men, respectively and without other hepatic diseases. A total of 80 participants (20-50 years) with NAFLD were randomly allocated into two groups to receive either green tea extract (GTE) supplement (500 mg GTE tablet per day) or placebo for 90 days. At baseline and at the end of the intervention weight, serum ALT, AST, and alkaline phosphatase (ALP) were measured in fasting state, and dietary data were collected at baseline and end of the study. RESULTS: Green tea group showed significant reductions in ALT and AST levels after 12 weeks period (P < 0.001). The placebo group showed a reduction in ALT and AST levels at the end of the study, but it was no significant. ALP levels showed significant reductions in both groups after 12 weeks period (P < 0.001). CONCLUSIONS: According to the findings of this study, GTE supplementation decrease liver enzymes in patients with NAFLD. It can be claimed that GTE prescribed can be considered as a treatment to improve serum levels of liver enzymes in NAFLD patients. PMID- 26955459 TI - Co-education with Environmental Cues May Kindle Early Onset of Female Puberty. PMID- 26955460 TI - Effect of Cucurbita ficifolia and Probiotic Yogurt Consumption on Blood Glucose, Lipid Profile, and Inflammatory Marker in Type 2 Diabetes. AB - BACKGROUND: Control of blood sugar, hypertension, and dyslipidemia are key factors in diabetes management. Cucurbita ficifolia (pumpkin) is a vegetable which has been used traditionally as a remedy for diabetes in Iran. In addition, consumption of probiotics may have beneficial effects on people with Type 2 diabetes. The aim of this study was an investigation of the effects of C. ficifolia and probiotic yogurt consumption alone or at the same time on blood glucose and serum lipids in diabetic patients. METHODS: Eighty eligible participants randomly were assigned to four groups: 1 - green C. ficifolia (100 g); 2 - probiotic yogurt (150 g); 3 - C. ficifolia plus probiotic yogurt (100 g C. ficifolia plus 150 g yogurt); and 4 -control (dietary advice) for 8 weeks. Blood pressure, glycemic response, lipid profile, and high-sensitive C-reactive protein (hsCRP) were measured before and after the intervention. RESULTS: Total cholesterol (TC) decreased significantly in yogurt and yogurt plus C. ficifolia groups (within groups P = 0.010, and P < 0.001, respectively). C. ficifolia plus yogurt consumption resulted in a decrease in triglyceride (TG) and an increase in high-density lipoprotein cholesterol (HDL-C) (within groups P < 0.001 and P = 0.001, respectively). All interventions led to a significant decrease in blood sugar, hemoglobin A1c (HbA1c), hsCRP, and low-density lipoprotein cholesterol (LDL-C) level within groups. Blood pressure decreased significantly in Cucurbita group and yogurt group (within groups P < 0.001, and P = 0.001 for systolic blood pressure [SBP] and P < 0.001, and P = 0.004 for diastolic blood pressure [DBP], respectively). All variables changed between groups significantly except LDL-C level. CONCLUSIONS: Variables including TG, HDL-C, TC, fasting blood sugar, HbA1c, SBP, DBP, and hsCRP changed beneficially between groups. It seems that consumption of C. ficifolia and probiotic yogurt may help treatment of diabetic patients. PMID- 26955461 TI - The Trend in Histological Changes and the Incidence of Esophagus Cancer in Iran (2003-2008). AB - BACKGROUND: Esophageal cancer is the sixth cause of death in the world, there was a lack of population-based information on the trend and incidence rate of esophagus cancer, so this study aimed to determine the incidence and pathological changes of esophagus cancer in Iran. METHODS: In this study, data were extracted from annual cancer registry reports of Iranian ministry of health between 2003 and 2008. Standardized incidence rates were calculated using the world standard population, and incidence rate was calculated by age groups, sex, and histological type. Data on epidemiologic trend and histology were analyzed using Joinpoint software package. RESULTS: In this study, there were 18,177 recorded cases of esophagus cancer. Of all cases, 45.72% were females and 54.28% were males. Sex ratio was 1.19. The most common histological types related to squamous cell carcinoma NOS and adenocarcinoma NOS were 64.53% and 10.37%, respectively. The trend of annual changes of incidence rate significantly increased in both sexes. The annual percentage changes, the incidence rate was 7.9 (95% confidence interval [CI]: 3.3-12.6) for women and 9.6 (95% CI: 6.0-13.2) for men. The histology type of SCC, large cell, nonkeratinizing and SCC, keratinizing and SCC, NOS had a significant decreasing trend in total population (P < 0.05). CONCLUSIONS: According to this study, the trend of age-standardized incidence rate of esophagus cancer in Iran is rising. Hence, to prevent and control this cancer, it is necessary to investigate related risk factors and implement prevention programs in Iran. PMID- 26955462 TI - Diabetes Knowledge Translation Status in Developing Countries: A Mixed Method Study Among Diabetes Researchers in Case of Iran. AB - BACKGROUND: Despite considerable investment in research, the existing research evidence is frequently not implemented and/or leads to useless or detrimental care in healthcare. The knowledge-practice gap proposed as one of the main causes of not achieving the treatment goals in diabetes. Iran also is facing a difference between the production and utilization of the knowledge of diabetes. The aim of this study was to assess the status of diabetes knowledge translation (KT) in Iran. METHODS: This was a survey that executed in 2015 by concurrent mixed methods approach in a descriptive, cross-sectional method. The research population was 65 diabetes researchers from 14 diabetes research centers throughout Iran. The research was carried out via the self-assessment tool for research institutes (SATORI), a valid and reliable tool. Focus group discussions were used to complete this tool. The data were analyzed using quantitative (descriptive method by Excel software) and qualitative approaches (thematic analysis) based on SATORI-extracted seven themes. RESULTS: The mean of scores "the question of research," "knowledge production," "knowledge transfer," "promoting the use of evidence," and all aspects altogether were 2.48, 2.80, 2.18, 2.06, and 2.39, respectively. The themes "research quality and timeliness" and "promoting and evaluating the use of evidence" received the lowest (1.91) and highest mean scores (2.94), respectively. Except for the theme "interaction with research users" with a relatively mediocre scores (2.63), the other areas had scores below the mean. CONCLUSIONS: The overall status of diabetes KT in Iran was lower than the ideal situation. There are many challenges that require great interventions at the organizational or macro level. To reinforce diabetes KT in Iran, it should hold a more leading and centralized function in the strategies of the country's diabetes research system. PMID- 26955463 TI - Strategies to Prevent the Emergence of Radiation-Induced Malignancies. PMID- 26955464 TI - Air Pollution: Avicenna's Concept. PMID- 26955465 TI - Extracting drug-enzyme relation from literature as evidence for drug drug interaction. AB - BACKGROUND: Information about drug-drug interactions (DDIs) is crucial for computational applications such as pharmacovigilance and drug repurposing. However, existing sources of DDIs have the problems of low coverage, low accuracy and low agreement. One common type of DDIs is related to the mechanism of drug metabolism: a DDI relation may be caused by different interactions (e.g., substrate, inhibit) between drugs and enzymes in the drug metabolism process. Thus, information from drug enzyme interactions (DEIs) serves as important supportive evidence for DDIs. Further, potential DDIs present implicitly could be detected by inference and reasoning based on DEIs. METHODS: In this article, we propose a hybrid approach to combining machine learning algorithm with trigger words and syntactic patterns, for DEI relation extraction from biomedical literature. The extracted DEI relations are used for reasoning to infer potential DDI relations, based on a defined drug-enzyme ontology incorporating biological knowledge. RESULTS: Evaluation results demonstrate that the performance of DEI relation extraction is promising, with an F-measure of 84.97% on the in vivo dataset and 65.58% on the in vitro dataset. Further, the inferred DDIs achieved a precision of 83.19% on the in vivo dataset and 70.94% on the in vitro dataset, respectively. A further examination showed that the overlaps between our inferred DDIs and those present in DrugBank were 42.02% on the in vivo dataset and 19.23 % on the in vitro dataset, respectively. CONCLUSIONS: This paper proposed an effective approach to extract DEI relations from biomedical literature. Potential DDIs not present in existing knowledge bases were then inferred based on the extracted DEIs, demonstrating the capability of the proposed approach to detect DDIs with scientific evidence for pharmacovigilance and drug repurposing applications. PMID- 26955468 TI - The legacy of the Child Health and Nutrition Research Initiative (CHNRI). AB - Under the Global Forum for Health Research, the Child Health and Nutrition Research Initiative (CHNRI) began its operations in 1999 and became a Swiss foundation in 2006. The vision of CHNRI was to improve child health and nutrition of all children in low- and middle-income countries (LMIC) through research that informs health policy and practice. Specific objectives included expanding global knowledge on childhood disease burden and cost-effectiveness of interventions, promoting priority setting in research, ensuring inclusion of institutions and scientists in LMIC in setting priorities, promoting capacity development in LMIC and stimulating donors and countries to increase resources for research. CHNRI created a knowledge network, funded research through multiple rounds of a global competitive process and published research papers and policy briefs. A signature effort was to develop a systematic methodology for prioritizing health and nutrition research investments. The "CHNRI method" has been extensively applied to global health problems and is now the most commonly used method for prioritizing health research questions. PMID- 26937268 TI - CyAnimator: Simple Animations of Cytoscape Networks. AB - CyAnimator (http://apps.cytoscape.org/apps/cyanimator) is a Cytoscape app that provides a tool for simple animations of Cytoscape networks. The tool allows you to take a series of snapshots (CyAnimator calls them frames) of Cytoscape networks. For example, the first frame might be of a network shown from a "zoomed out" viewpoint and the second frame might focus on a specific group of nodes. Once these two frames are captured by the tool, it can animate between them by interpolating the changes in location, zoom, node color, node size, edge thickness, presence or absence of annotations, etc. The animations may be saved as a series of individual frames, animated GIFs, or H.264/MP4 movies. CyAnimator is available from within the Cytoscape App Manager or from the Cytoscape app store. PMID- 26955466 TI - Multimodal care for the management of musculoskeletal disorders of the elbow, forearm, wrist and hand: a systematic review by the Ontario Protocol for Traffic Injury Management (OPTIMa) Collaboration. AB - BACKGROUND: Musculoskeletal disorders of the elbow, forearm, wrist and hand are associated with pain, functional impairment and decreased productivity in the general population. Combining several interventions in a multimodal program of care is reflective of current clinical practice; however there is limited evidence to support its effectiveness. The purpose of our review was to investigate the effectiveness of multimodal care for the management of musculoskeletal disorders of the elbow, forearm, wrist and hand on self-rated recovery, functional recovery, or clinical outcomes in adults or children. METHODS: We conducted a systematic review of the literature and best evidence synthesis. We searched MEDLINE, EMBASE, CINAHL, PsycINFO, and the Cochrane Central Register of Controlled Trials from January 1990 to March 2015. Randomized controlled trials, cohort studies, and case-control studies were eligible. Random pairs of independent reviewers screened studies for relevance and critically appraised relevant studies using the Scottish Intercollegiate Guidelines Network criteria. Studies with a low risk of bias were synthesized following best evidence synthesis principles. RESULTS: We screened 5989 articles, and critically appraised eleven articles. Of those, seven had a low risk of bias; one addressed carpal tunnel syndrome and six addressed lateral epicondylitis. Our search did not identify any low risk of bias studies examining the effectiveness of multimodal care for the management of other musculoskeletal disorders of the elbow, forearm, wrist or hand. The evidence suggests that multimodal care for the management of lateral epicondylitis may include education, exercise (strengthening, stretching, occupational exercise), manual therapy (manipulation) and soft tissue therapy (massage). The evidence does not support the use of multimodal care for the management of carpal tunnel syndrome. CONCLUSIONS: The current evidence on the effectiveness of multimodal care for musculoskeletal disorders of the elbow, forearm, wrist and hand is limited. The available evidence suggests that there may be a role for multimodal care in the management of patients with persistent lateral epicondylitis. Future research is needed to examine the effectiveness of multimodal care and guide clinical practice. SYSTEMATIC REVIEW REGISTRATION NUMBER: CRD42014009093. PMID- 26955469 TI - Addressing the growing burden of non-communicable disease by leveraging lessons from infectious disease management. PMID- 26955470 TI - Management of childhood diarrhea among private providers in Uttar Pradesh, India. AB - BACKGROUND: In Uttar Pradesh (UP), India, a new initiative to introduce zinc and reinvigorate ORS for diarrhea treatment in the public and private sectors was rolled out in selected districts. We conducted an external evaluation of the program that included assessing the knowledge and practices of private sector providers 6 months after the initial program rollout. METHODS: We conducted interviews and direct observations among a randomly selected group of formal and informal private sector providers in 12 districts of UP. We calculated summary statistics for reported provider characteristics, diarrhea treatment knowledge and preferred treatments, as well as the treatments advised during consultation with a child with diarrhea. RESULTS: We interviewed 232 providers, of whom 67% reported receiving a diarrhea treatment training/drug detailing visit. In the interview, 14% of providers reported prescribing zinc to all children with diarrhea and 36% reported prescribing zinc to more than half of diarrhea cases. During direct observation, ORS and zinc were prescribed by 77.3% and 29.9% of providers, respectively. Treatments other than zinc and ORS were also commonly prescribed, including antibiotics (61.9%) and antidiarrheals (17.5%). CONCLUSION: Adequate treatment of childhood diarrhea with zinc and ORS remains a challenge among private sector providers in rural UP, India. Additional training and knowledge transfer activities are needed to curb the overprescription of antibiotics and antidiarrheals and to increase the confidence of private providers in advising zinc and ORS. In addition, policymakers and program implementers must ensure collaborative efforts to target and meaningfully engage informal private providers who play a major role in childhood diarrhea treatment in hard-to-reach areas. PMID- 26955471 TI - Moving global health forward in academic institutions. PMID- 26955472 TI - Verbal/Social Autopsy in Niger 2012-2013: A new tool for a better understanding of the neonatal and child mortality situation. AB - Niger, one of the poorest countries in the world, recently used for the first time the integrated verbal and social autopsy (VASA) tool to assess the biological causes and social and health system determinants of neonatal and child deaths. These notes summarize the Nigerien experience in the use of this new tool, the steps taken for high level engagement of the Niger government and stakeholders for the wide dissemination of the study results and their use to support policy development and maternal, neonatal and child health programming in the country. The experience in Niger reflects lessons learned by other developing countries in strengthening the use of data for evidence-based decision making, and highlights the need for the global health community to provide continued support to country data initiatives, including the collection, analysis, interpretation and utilization of high quality data for the development of targeted, highly effective interventions. In Niger, this is supporting the country's progress toward achieving Millennium Development Goal 4. A follow-up VASA study is being planned and the tool is being integrated into the National Health Management Information System. VASA studies have now been completed or are under way in additional sub-Saharan African countries, in each through the same collaborative process used in Niger to bring together health policy makers, program planners and development partners. PMID- 26955473 TI - Social determinants of child mortality in Niger: Results from the 2012 National Verbal and Social Autopsy Study. AB - BACKGROUND: Understanding the determinants of preventable deaths of children under the age of five is important for accelerated annual declines - even as countries achieve the UN's Millennium Development Goals and the target date of 2015 has been reached. While research has documented the extent and nature of the overall rapid decline in child mortality in Niger, there is less clear evidence to provide insight into the contributors to such deaths. This issue is the central focus of this paper. METHODS: We analyzed a nationally representative cross-sectional sample of 620 child deaths from the 2012 Niger Verbal Autopsy/Social Autopsy (VASA) Survey. We conducted a descriptive analysis of the data on preventive and curative care, guided by the coverage of proven indicators along the continuum of well child care and illness recognition and care-seeking for child illnesses encompassed by the BASICS/CDC Pathway to Survival model. RESULTS: Six hundred twenty deaths of children (1-59 months of age) were confirmed from the VASA survey. The majority of these children lived in households with precarious socio-economic conditions. Among the 414 children whose fatal illnesses began at age 0-23 months, just 24.4% were appropriately fed. About 24% of children aged 12-59 months were fully immunized. Of 601 children tracked through the Pathway to Survival, 62.4% could reach the first health care provider after about 67 minutes travel time. Of the 306 children who left the first health care provider alive, 161 (52.6%) were not referred for further care nor received any home care recommendations, and just 19% were referred to a second provider. About 113 of the caregivers reported cost (35%), distance (35%) and lack of transport (30%) as constraints to care-seeking at a health facility. CONCLUSION: Despite Niger's recent major achievements in reducing child mortality, the following determinants are crucial to continue building on the gains the country has made: improved socio-economic state of the poor in the country, investment in women's education, adoption of the a law to prevent marriage of young girls before 18 years of age, and implementation of health programs that encourage breastfeeding and complementary feeding, immunization, illness recognition, prompt and appropriate care-seeking, and improved referral rates. PMID- 26955474 TI - Verbal/social autopsy study helps explain the lack of decrease in neonatal mortality in Niger, 2007-2010. AB - BACKGROUND: This study was one of a set of verbal/social autopsy (VASA) investigations undertaken by the WHO/UNICEF-supported Child Health Epidemiology Reference Group to estimate the causes and determinants of neonatal and child deaths in high priority countries. The study objective was to help explain the lack of decrease in neonatal mortality in Niger from 2007 to 2010, a period during which child mortality was decreasing. METHODS: VASA interviews were conducted of a random sample of 453 neonatal deaths identified by the 2010 Niger National Mortality Survey (NNMS). Causes of death were determined by expert algorithm analysis, and the prevalence of household, community and health system determinants were examined along the continuum of maternal and newborn care, the Pathway to Survival for newborn illnesses, and an extended pathway for maternal complications. The social autopsy findings were compared to available data for survivors from the same cohort collected by the NNMS and the 2012 Niger Demographic and Health Survey. FINDINGS: Severe neonatal infection and birth asphyxia were the leading causes of early neonatal death in the community and facilities. Death in the community after delayed careseeking for severe infection predominated during the late neonatal period. The levels of nearly all demographic, antenatal and delivery care factors were in the direction of risk for the VASA study decedents. They more often resided rurally (P < 0.001) and their mothers were less educated (P = 0.03) and gave birth when younger (P = 0.03) than survivors' mothers. Their mothers also were less likely to receive quality antenatal care (P < 0.001), skilled attendance at birth (P = 0.03) or to deliver in an institution (P < 0.001). Nearly half suffered an obstetric complication, with more maternal infection (17.9% vs 0.2%), antepartum hemorrhage (12.5% vs 0.5%) and eclampsia/preeclampsia (9.5% vs 1.6%) than for all births in Niger. Their mothers also were unlikely to seek health care for their own complications (37% to 42%) as well as for the newborn's illness (30.6%). CONCLUSIONS: Niger should scale up its recently implemented package of high impact interventions to additional integrated health facilities and expand the package to provide antenatal care and management of labor and delivery, with support to reach a higher level facility when required. Community interventions are needed to improve illness recognition and careseeking for severe neonatal infection. PMID- 26955475 TI - Factors associated with burnout among residents in a developing country. AB - INTRODUCTION: Recent literature has focused on burnout as a specific job related distress syndrome among physicians and residents having adverse effects on patient care. Local data on burnout is lacking. MATERIALS & METHODS: An online self-administered questionnaire was sent via email to all residents (325) at our institute with and a response rate of 110 (34%) was achieved. Out of these 82 residents consented and completely filled the questionnaires and were included in the analysis. The questionnaire comprised of demographic variables, the Maslach burnout inventory and occupational risk factors. RESULTS: High levels of burnout on at least one subscale were reported by 61(74.4%) residents, in 2 components by 34(41.5%) whereas an alarming 10(12.2%) residents scored high on all three subscales. Among the individual subscales emotional exhaustion was most frequent in 49(59.8%). Among the departments Radiology reported the highest levels (100%) of burnout and low levels were reported by Pediatrics (45%). There was no difference between burnout levels among junior and senior residents. Dissatisfaction with workload, length of work hours, relationship with co-workers and lack of autonomy were significantly associated with high level of burnout. CONCLUSION: High levels of burnout are prevalent among trainee doctors in our part of the world which are comparable with international literature. Efforts to improve the work environment of residents may significantly reduce levels of burnout. PMID- 26955476 TI - Focused parathyroidectomy without intra-operative parathormone monitoring: The value of PTH assay in preoperative ultrasound guided fine needle aspiration washout. AB - BACKGROUND: The accurate identification of hyperfunctioning parathyroid (HP) gland is the only issue for definitive surgical treatment in primary hyperparathyroidism (pHPT). Various imaging and operative techniques have been proposed to confirm the localization of the diseased gland. Nevertheless, none of these methods proved to be the gold standard. The presented study aimed to assess the value of parathyroid hormone assay in preoperative ultrasound guided fine needle aspiration (FNA)-PTH washout fluid to verify the correct localisation for focused parathyroidectomy without intra-operative PTH monitoring. MATERIAL AND METHODS: The retrospective analysis of 57 patients with pHPT who underwent FNA PTH was conducted from a prospective database. Biochemical assessment together with radiological (ultrasonography) and nuclear (MIBI scan) imaging was reviewed. Associations between FNA-PTH washout values and localization technics were evaluated and compared in terms of operative findings. RESULTS: Focused parathyroidectomy without intraoperative PTH monitoring was performed to 45 patients with high FNA-PTH values. The median largest diameter of the target parathyroid lesion identified by ultrasonography was 13 mm (range, 6 to 36). The median serum PTH level was 190 pg/mL (range, 78 to 1709; reference range, 15 to 65) whereas the median washout PTH was 2500 pg/mL (range, 480 to 3389). According to operative findings high FNA-PTH levels correctly identified parathyroid adenoma in 40 cases (89% of sensitivity and 100% of specificity and positive predictive value) whereas MIBI scan localized the lesion in 36 of these cases (80% of sensitivity). CONCLUSIONS: The higher level of PTH in preoperative ultrasound guided FNA washout is a considerable data to predict the correct localization of HP, particularly in circumstances of greater values than the serum PTH level. However, although its specificity is high, in cases of coexisting nodular thyroid disease, associated additional HP might be missed at focused parathyroidectomy without PTH monitoring, leading to recurrent disease. PMID- 26955477 TI - Early combined parenteral and enteral nutrition for pancreaticoduodenectomy - Retrospective cohort analysis. AB - BACKGROUND: Suggested guidelines for nutritional support after pancreaticoduodenectomy are still controversial. Recent evidence suggests that combining enteral nutrition (EN) with parenteral nutrition (PN) improves outcome. For ten years, patients have been treated with Early Combined Parenteral and Enteral Nutrition (ECPEN) after PD. The aim of this study was to report on rationale, safety, effectiveness and outcome associated with this method. METHODS: Consecutive PD performed between 2003 and 2012 were analyzed retrospectively. Early EN and PN was standardized and started immediately after surgery. EN was increased to 40 ml/h (1 kcal/ml) over 24 h, while PN was supplemented based on a daily energy target of 25 kcal/kg. Standard enteral and parenteral products were used. RESULTS: Sixty-nine patients were nutritionally supplemented according to ECPEN. The median coverage of kcal per patients related to the total caloric requirements during the entire hospitalization (nutrition balance) was 93.4% (range: 100%-69.3%). The nutritional balance in patients with needle catheter jejunostomy (NCJ) was significantly higher than in the group with nasojejunal tube (97.1% vs. 91.6%; p < 0.0001). Mortality rate was 5.8%, while major complications (Clavien-Dindo 3-5) occurred in 21.7% of patients. Neither the presence of preoperative malnutrition nor the application of preoperative immunonutrition was associated with postoperative clinical outcome. CONCLUSION: This is the first European study of ECPEN after PD. ECPEN is safe and, especially in combination with NCJ, provides comprehensive coverage of caloric requirements during the postoperative phase. Clinical controlled trials are needed to investigate potential benefits of complete energy supplementation during the early postoperative phase after PD. PMID- 26955478 TI - An unusual case of intraabdominal abscess and acute abdomen caused by axial torsion of a Meckel's diverticulum. AB - BACKGROUND: Meckel's diverticulum (MD), the most common congenital anomaly of the gastrointestinal tract, is a true diverticulum. MD is mostly seen in pediatric age groups but may be seen in adults as well. Is twice common in men than women. Surgical treatment is required in symptomatic MD patients. We present a 21-year old female patient who was admitted with acute abdomen and underwent diverticulectomy with diagnosis of Meckel's diverticulum. PRESENTATION OF CASE: The 21-year-old female patient was admitted to emergency service with abdominal pain, nausea and vomiting. Physical examination revealed abdominal distention, rebound tenderness and defense. Abdominal radiography revealed air-fluid levels. White blood cell count was high. In the exploration, torsion of MD was observed and diverticulectomy was performed. Histopathologic analysis indicated the presence of MD. The patient recovered without complication, and was uneventfully discharged. DISCUSSION: MD is found in 2% of the general population. Common complications of MD include gastrointestinal bleeding, intestinal obstruction, perforation and diverticulitis. However, axial torsion of MD is a rare complication. Simple diverticulectomy is sufficient in the treatment of most MD cases; however, ileal resection may be required in some cases. Diagnosis of MD is established by histopathologic analysis. CONCLUSION: Although MD is known as a pediatric disease, it is likely to occur in adults as well. Axial torsion of Meckel's diverticulum should be kept in mind the adults presenting with symptoms of acute abdomen. PMID- 26955479 TI - Vitamin A status and body pool size of infants before and after consuming fortified home-based complementary foods. AB - BACKGROUND: Home fortification using sachets of micronutrient powder (e.g. "Sprinkles") is a food-based approach offering an alternative to high dose vitamin A (VA) supplements for infants. The primary objective was to investigate the impact of VA-home fortification on infant VA pool size. The secondary objective was to compare VA status of infants assessed by the modified relative dose response (MRDR) test before and the (13)C-retinol isotope dilution ((13)C RID) test in the same infants after vitamin A supplementation. METHODS: A randomized-controlled trial was conducted in 7-9 month old infants in Ghana. Eligible children were randomly allocated to receive a daily sachet of "Sprinkles" with or without VA for 5 months added to complementary foods. The MRDR test indirectly determined VA liver reserves at baseline and the (13)C-RID determined VA body pool at follow-up in the same cohort of children. RESULTS: At baseline, the MRDR values (95 % CI) for infants were comparable in the intervention and control groups: normal at 0.032 (SD 0.018) (0.025-0.038) and 0.031 (SD 0.018) (0.024-0.038), respectively. After intervention, total body stores (TBS) and liver retinol concentrations did not differ between intervention and control groups; TBS were 436 (SD 303) and 434 (SD 186) MUmol, respectively, and estimated liver concentrations were 0.82 (SD 0.53) and 0.79 (SD 0.36) MUmol/g liver, indicating adequate reserves in all children. CONCLUSIONS: Both the MRDR and (3)C-RID tests confirmed that the infants had adequate VA status before and after home fortification of their complementary foods. These tests offered more information than serum retinol concentrations alone, which predicted VA deficiency using current suggested cutoffs not corrected for inflammation status. PMID- 26955481 TI - Isolation of prostrate turfgrass mutants via screening of dwarf phenotype and characterization of a perennial ryegrass prostrate mutant. AB - Prostrate turf varieties are desirable because of their increased low mowing tolerance, heat resistance, traffic resistance and ground coverage compared with upright varieties. Mutation breeding may provide a powerful tool to create prostrate varieties, but there are no simple, straightforward methods to screen for such mutants. Elucidation of the molecular basis of the major 'green revolution' traits, dwarfism and semi-dwarfism, guided us to design a simple strategy for isolating dwarf mutants of perennial ryegrass (Lolium perenne L.). We have shown that gamma-ray-mediated dominant dwarf mutants can be easily screened for at the three-leaf stage. About 10% of dwarf mutant lines also displayed a prostrate phenotype at mature stages (>10 tillers). One prostrate line, Lowboy I, has been characterized in detail. Lowboy I had significantly shorter canopy, leaf blade and internode lengths compared with wild type. Lowboy I also exhibited greater tolerance to low mowing stress than wild type. Exogenous gibberellic acid (GA) restored Lowboy I to a wild-type phenotype, indicating that the dwarf and prostrate phenotypes were both due to GA deficiency. We further showed that phenotypes of Lowboy I were dominant and stably inherited through sexual reproduction. Prostrate turfgrass mutants are difficult to screen for because the phenotype is not observed at young seedling stages, therefore our method represents a simple strategy for easily isolating prostrate mutants. Furthermore, Lowboy I may provide an outstanding germplasm for breeding novel prostrate perennial ryegrass cultivars. PMID- 26955482 TI - The effects of dopamine on digit span in Parkinson's disease. AB - BACKGROUND: Parkinson's disease patients are at an elevated risk of developing cognitive impairment. Although cognitive impairment is one of the strongest predictors of quality of life, dopaminergic anti-parkinsonian medications are designed to target motor symptoms. However, there is substantial evidence that dopamine also impacts cognition, in particular working memory. It is therefore critical for movement disorders physicians to understand the potential dopaminergic effects on working memory when prescribing these medications. Verbal digit span tasks offer a potentially straightforward and quick assessment of baseline working memory. Moreover, Digit Span Backward was recently validated as a screening tool for mild cognitive impairment in Parkinson's disease when participants were medicated. Research indicates that the interaction between dopamine and working memory follows an Inverted-U shaped curve, but the effect of dopamine on Digit Span has not been well studied. Our study seeks to: (1) determine the validity of verbal Digit Spans for detecting cognitive impairment in Parkinson's disease patients both ON and OFF medications; and (2) ascertain the effects of dopaminergic medications on verbal Digit Span. METHODS: We recruited 64 Parkinson's disease patients and 22 age-and education-matched controls. Parkinson's patients completed Digit Span Backward and Digit Span Forward ON and OFF medications, while healthy controls completed them once. All participants were categorized by cognitive diagnosis using level-II consensus criteria. RESULTS: Digit Span Backward successfully identified mild cognitive impairment in Parkinson's disease, both ON and OFF medications. Combining patients with and without cognitive impairment, we found that dopamine significantly improved performance on Digit Span Backward, but not Forward. In a secondary analysis, we found this dopaminergic improvement was restricted to the Low baseline working memory group; the High baseline working memory group was unaffected. CONCLUSIONS: This study provides evidence for Digit Span Backward as a screening tool for working memory impairment in Parkinson's disease and for its utility in measuring baseline working memory. Moreover, it reveals a partial beneficial effect of dopamine on Digit Span in Parkinson's disease patients. PMID- 26955483 TI - Relationship between Daytime Sleepiness and Intrinsically Photosensitive Retinal Ganglion Cells in Glaucomatous Disease. AB - Patients with glaucoma showed to have higher daytime sleepiness measured by Epworth sleepiness scale. In addition, this symptom was associated with pupillary reflex and polysomnography parameters. These ipRGC functions might be impaired in patients with glaucoma, leading to worse quality of life. PMID- 26955485 TI - Comparing Single and Dual Console Systems in the Robotic Surgical Training of Graduating OB/GYN Residents in the United States. AB - Objective. To assess the impact of a single versus dual console robotic system on the perceptions of program directors (PD) and residents (RES) towards robotic surgical training among graduating obstetrics and gynecology residents. Design. An anonymous survey was developed using Qualtrics, a web-based survey development and administration system, and sent to obstetrics and gynecology program directors and graduating residents. Participants. 39 program directors and 32 graduating residents (PGY4). Results. According to residents perception, dual console is utilized in about 70% of the respondents' programs. Dual console system programs were more likely to provide a robotics training certificate compared to single console programs (43.5% versus 0%, p = 0.03). A greater proportion of residents graduating from a dual console program perform more than 20 robotic-assisted total laparoscopic hysterectomies, 30% versus 0% (p = 0.15). Conclusions. Utilization of dual console system increased the likelihood of obtaining robotic training certification without significantly increasing the case volume of robotic-assisted total laparoscopic hysterectomy. PMID- 26955484 TI - Neoadjuvant Chemotherapy in Locally Advanced and Borderline Resectable Nonsquamous Sinonasal Tumors (Esthesioneuroblastoma and Sinonasal Tumor with Neuroendocrine Differentiation). AB - INTRODUCTION: Sinonasal tumors are chemotherapy responsive which frequently present in advanced stages making NACT a promising option for improving resection and local control in borderline resectable and locally advanced tumours. Here we reviewed the results of 25 such cases treated with NACT. MATERIALS AND METHODS: Sinonasal tumor patients treated with NACT were selected for this analysis. These patients received NACT with platinum and etoposide for 2 cycles. Patients who responded and were amenable for gross total resection underwent surgical resection and adjuvant CTRT. Those who responded but were not amenable for resection received radical CTRT. Patients who progressed on NACT received either radical CTRT or palliative radiotherapy. RESULTS: The median age of the cohort was 42 years (IQR 37-47 years). Grades 3-4 toxicity with NACT were seen in 19 patients (76%). The response rate to NACT was 80%. Post-NACT surgery was done in 12 (48%) patients and radical chemoradiation in 9 (36%) patients. The 2-year progression free survival and overall survival were 75% and 78.5%, respectively. CONCLUSION: NACT in sinonasal tumours has a response rate of 80%. The protocol of NACT followed by local treatment is associated with improvement in outcomes as compared to our historical cohort. PMID- 26955486 TI - Prevalence of Low Back Pain among Undergraduate Physiotherapy Students in Nigeria. AB - Background. Low back pain (LBP) is a major cause of disability and the most common work-related musculoskeletal disorder among physiotherapists. This study examined the prevalence of low back pain among students undergoing training to become physiotherapists. Methods. Participants were 207 undergraduate clinical physiotherapy students at three universities in Nigeria. A modified version of a questionnaire used in a previous study was utilized to obtain demographic, educational activities, and LBP data. Prevalence of LBP was examined with descriptive statistics while factors associated with prevalence were explored using chi-square statistics. Results. More male students (53.1%) and those in the penultimate year of study (53.1%) participated in the study. Lifetime, 12-month, 1-month, and 7-day prevalence of LBP were 45.5%, 32.5%, 17.7%, and 11.5%, respectively. Prevalence of LBP was not significantly associated with any of the demographic variables. Educational activities, namely, "having techniques practiced on self for <=10 hours" and "treating patients for >=30 hours," a month prior to the study were significantly (P < 0.05) associated with higher 1-month and 7-day LBP prevalence, respectively. Conclusions. Although the prevalence of LBP was comparatively low, its association with educational activities emphasizes the need to incorporate effective LBP preventive strategies in the training of physiotherapy students. PMID- 26955488 TI - Synthesis of Polyformate Esters of Vegetable Oils: Milkweed, Pennycress, and Soy. AB - In a previous study of the characteristics of acyl derivatives of polyhydroxy milkweed oil (PHMWO), it was observed that the densities and viscosities of the respective derivatives decreased with increased chain length of the substituent acyl group. Thus from the polyhydroxy starting material, attenuation in viscosity of the derivatives relative to PHMWO was found in the order: PHMWO ? PAcMWE ? PBuMWE ? PPMWE (2332 : 1733 : 926.2 : 489.4 cSt, resp., at 40 degrees C), where PAcMWE, PBuMWE, and PPMWE were the polyacetyl, polybutyroyl, and polypentanoyl ester derivatives, respectively. In an analogous manner, the densities also decreased as the chain length increased although not as precipitously compared to the viscosity drop. By inference, derivatives of vegetable oils with short chain length substituents on the triglyceride would be attractive in lubricant applications in view of their higher densities and possibly higher viscosity indices. Pursuant to this, we have explored the syntheses of formyl esters of three vegetable oils in order to examine the optimal density, viscosity, and related physical characteristics in relation to their suitability as lubricant candidates. In the absence of ready availability of formic anhydride, we opted to employ the epoxidized vegetable oils as substrates for formyl ester generation using glacial formic acid. The epoxy ring-opening process was smooth but was apparently followed by a simultaneous condensation reaction of the putative alpha hydroxy formyl intermediate to yield vicinal diformyl esters from the oxirane. All three polyformyl esters milkweed, soy, and pennycress derivatives exhibited low coefficient of friction and a correspondingly much lower wear scar in the 4 ball antiwear test compared to the longer chain acyl analogues earlier studied. PMID- 26955487 TI - Differences in GPR30 Regulation by Chlorotriazine Herbicides in Human Breast Cells. AB - Over 200,000 cases of invasive breast cancer are diagnosed annually; herbicide contaminants in local water sources may contribute to the growth of these cancers. GPR30, a G protein coupled receptor, was identified as a potential orphan receptor that may interact with triazine herbicides such as atrazine, one of the most commonly utilized chlorotriazines in agricultural practices in the United States. Our goal was to identify whether chlorotriazines affected the expression of GPR30. Two breast cancer cell lines, MDA-MB-231 and MCF-7, as well as one normal breast cell line, MCF-10A, were treated with a 100-fold range of atrazine, cyanazine, or simazine, with levels flanking the EPA safe level for each compound. Using real-time PCR, we assessed changes in GPR30 mRNA compared to a GAPDH control. Our results indicate that GPR30 expression increased in breast cancer cells at levels lower than the US EPA drinking water contamination limit. During this treatment, the viability of cells was unaltered. In contrast, treatment with chlorotriazines reduced the expression of GPR30 in noncancerous MCF-10A cells. Thus, our results indicate that cell milieu and potential to metastasize may play a role in the extent of GPR30 response to pesticide exposure. PMID- 26955489 TI - Screening and Selection of Medium Components for Cyclodextrin Glucanotransferase Production by New Alkaliphile Microbacterium terrae KNR 9 Using Plackett-Burman Design. AB - Cyclodextrin glucanotransferase (CGTase, EC 2.4.1.19) production using new alkaliphile Microbacterium terrae KNR 9 was investigated by submerged fermentation. Statistical screening for components belonging to different categories, namely, soluble and raw starches as carbon sources, complex organic and inorganic nitrogen sources, minerals, a buffering agent, and a surfactant, has been carried out for CGTase production using Plackett-Burman factorial design. To screen out k (19), number of variables, k + 1 (20), number of experiments, were performed. Among the fourteen components screened, four components, namely, soluble starch, corn flour, yeast extract, and K2HPO4, were identified as significant with reference to their concentration effect and corresponding p value. Although soluble starch showed highest significance, comparable significance was also observed with corn flour and hence it was selected as a sole carbon source along with yeast extract and K2HPO4 for further media optimization studies. Using screened components, CGTase production was increased to 45% and 87% at shake flask level and laboratory scale fermenter, respectively, as compared to basal media. PMID- 26955490 TI - Mixed Adenoneuroendocrine Carcinoma Is a Rare but Important Tumour Found in the Oesophagus. AB - Mixed adenoneuroendocrine carcinoma (MANEC) is a rare tumour of the gastrointestinal tract that consists of a dual adenocarcinomatous and neuroendocrine differentiation, each component representing at least 30% of the tumour. We report a case of a 68-year-old man who presented with two-month history of postprandial pain and vomiting. Gastric endoscopy revealed a polypoid mass in the lower part of the oesophagus. In contrast to the majority of these tumours, this biopsy was immunohistochemically positive for chromogranin A, and synaptophysin and Ki-67 index was 50% and the tumour was diagnosed as poorly differentiated neuroendocrine carcinoma of the oesophagus. The patient underwent surgery and lower oesophagus resection was performed. Based on the histopathology and immunohistochemistry of the tumour in the oesophagogastrectomy specimen, a mixed adenoneuroendocrine carcinoma (MANEC) was diagnosed. The objective of this case report is to advocate for the focus on the MANEC diagnosis as such patients need to be referred to a centre of excellence with expertise in NET tumours, to have the correct diagnostic work-up, treatment, and secondary diagnostic procedures performed at progression, as this will have paramount influence of the choice of treatment. PMID- 26955491 TI - De Novo Interstitial Microdeletion at 1q32.1 in a 10-Year-Old Boy with Developmental Delay and Dysmorphism. AB - A 10-year-old boy was referred with developmental delay and dysmorphism. Genomewide aCGH microarray analysis detected a de novo 3.7 Mb deletion at 1q32.1: arr 1q32.1(199,985,888-203,690,832)x1 dn [build HG19]. This first report of a deletion in this region implies a critical role for dosage-sensitive genes within 1q32.1 in neurological development. This is consistent with previously reported duplications of this region in patients with a similar phenotype. PMID- 26955493 TI - Exactech Opteon Femoral Component Fracture 12 Years after Arthroplasty. AB - Arthroplasty implant fracture is a rare but critical complication that requires difficult revision surgery, often with poor results, patient disability, and significant cost. Several reports show component fracture either at the stem or at the neck interface after a relatively short postoperative course. We report such failure after 12 years, suggesting no safe period after which femoral implant fracture does not occur. PMID- 26955492 TI - Drug-Induced Acute Interstitial Nephritis with Nifedipine. AB - Background. Acute interstitial nephritis (AIN) is a frequent cause of Acute Kidney Injury (AKI). Drug hypersensitivity is the most common etiology and the list of drugs that can induce AIN is not exhaustive yet. Case Report. Here, we describe the case of a 43-year-old man who was treated with nifedipine (Adalate(r)) for Raynaud's syndrome. After nifedipine introduction, serum creatininemia progressively increased from 91 to 188 MUmol/L in a few months and AKI was diagnosed. Laboratory work-up results indicated the presence of tubular proteinuria and nonspecific inflammatory syndrome. Histological analysis found granulomatous interstitial nephropathy without necrosis in 20% of the kidney biopsy without immunofluorescent deposit. Nifedipine was stopped and corticosteroid treatment was started with a rapid but incomplete reduction of serum creatininemia level to 106 MUmol/L. Conclusion. This is the first case of AIN caused by nifedipine. PMID- 26955494 TI - Primary Aspergillosis of the Larynx. AB - Laryngeal aspergillosis is most commonly seen as a result of secondary invasion from the lungs and tracheobronchial tree in immunocompromised hosts. Primary aspergillosis of the larynx is, however, rare with few cases documented over the past fifty years. We report a case of a 73-year-old woman who presented with persistent hoarseness. She is a nonsmoker with a history of asthma and chronic bronchiectasis treated with bronchodilators, inhaled and oral corticosteroids, and nebulized tobramycin. Direct laryngoscopy with vocal cord stripping confirmed the diagnosis of invasive aspergillosis with no manifestations elsewhere. The patient was successfully treated with oral voriconazole with no signs of recurrence. Although several major risk factors contributing to the development of primary aspergillosis of the larynx have been discussed in the literature, there has been no mention of inhaled antibiotics causing this rare presentation to the best of our knowledge. We, therefore, highlight the use of inhaled tobramycin as a unique catalyst leading to the rapid onset of this rare presentation. PMID- 26955495 TI - Amlodipine and the Successful Management of Post-Electroconvulsive Therapy Agitation. AB - Electroconvulsive therapy (ECT) is a highly effective nonpharmacologic treatment for the management of depression and some other psychiatric disorders. Post-ECT agitation occurs in up to 12% of ECT treatments and is characterized by motor restlessness, irritability, disorientation, and panic-like behaviors. The severity of post-ECT agitation ranges from mild and self-limited to serious and severe forms requiring prompt medical intervention to protect the patient and the medical staff. In severe agitation medical management may be necessary which consists of using sedative agents, either benzodiazepines or propofol. The side effects of these sedative agents, especially in the elderly population, necessitate finding ways that could help the prevention of the occurrence of agitation after ECT treatments. We report a 68-year-old female with major depression who was referred for ECT. She experienced severe post-ECT agitation requiring medical intervention after all ECT treatments. Administering of oral amlodipine (5 mg) one hour before ECT treatment successfully prevented the occurrence of post-ECT agitation in this patient. We briefly discuss the possible underlying mechanisms and pathophysiology of amlodipine in the prevention of post ECT agitation. PMID- 26955496 TI - Mucous Membrane Pemphigoid with Tracheal Involvement. AB - 34-year-old African American female with history of pemphigoid presented with hemoptysis. Patient was found to have mucous membrane pemphigoid involving the oropharynx and extending to trachea, till just above main stem carina. Four other cases described mucosal pemphigoid involving the trachea. We hereby present a brief review of current consensus on management of mucous membrane pemphigoid with airway involvement. PMID- 26955497 TI - Left Inferior Vena Cava and Right Retroaortic Renal Vein. AB - Nowadays, incidental anatomical variants are frequent findings, due to the widespread diffusion of cross-sectional imaging. This case report illustrates a fairly uncommon anatomical variant, that is, the copresence of left inferior vena cava and retroaortic right renal vein reported in a 46-year-old lady, undergoing a staging CT for breast cancer. Although the patient was asymptomatic, the authors highlight potential risks related to the above-mentioned condition and the importance of correct identification and diagnosis of the findings. PMID- 26955498 TI - Fetal MRI Characteristics of Exencephaly: A Case Report and Literature Review. AB - We present the fetal MRI characteristics of exencephaly, a rare malformation of the cranium. The fetus was initially misdiagnosed as anencephaly at 14 weeks of estimated gestational age (EGA) and later mislabeled as acrania at 20 weeks of EGA by ultrasound. A confirmatory magnetic resonance imaging (MRI) at 29 weeks of EGA demonstrated findings consistent with exencephaly, which was confirmed after birth. To our knowledge, no full fetal MRI characteristics have been described. We hope to use this case to review the key MRI findings in differentiating exencephaly from other cranial vault defects and to help early diagnosis of exencephaly as the appropriate use of correct nomenclature allows better research while giving parents the most accurate and appropriate counseling. PMID- 26955499 TI - Quantitative nucleic features are effective for discrimination of intraductal proliferative lesions of the breast. AB - BACKGROUND: Intraductal proliferative lesions (IDPLs) of the breast are recognized as a risk factor for subsequent invasive carcinoma development. Although opportunities for IDPL diagnosis have increased, these lesions are difficult to diagnose correctly, especially atypical ductal hyperplasia (ADH) and low-grade ductal carcinoma in situ (LG-DCIS). In order to define the difference between these lesions, many molecular pathological approaches have been performed. However, still we do not have a molecular marker and objective histological index about IDPLs of the breast. METHODS: We generated full digital pathology archives from 175 female IDPL patients, including usual ductal hyperplasia (UDH), ADH, LG-DCIS, intermediate-grade (IM)-DCIS, and high-grade (HG)-DCIS. After total 2,035,807 nucleic segmentations were extracted, we evaluated nuclear features using step-wise linear discriminant analysis (LDA) and a support vector machine. RESULTS: High diagnostic accuracy (81.8-99.3%) was achieved between pathologists' diagnoses and two-group LDA predictions from nucleic features for IDPL discrimination. Grouping of nuclear features as size and shape-related or intranuclear texture-related revealed that the latter group was more important when distinguishing between normal duct, UDH, ADH, and LG DCIS. However, these two groups were equally important when discriminating between LG-DCIS and HG-DCIS. The Mahalanobis distances between each group showed that the smallest distance values occurred between LG-DCIS and IM-DCIS and between ADH and Normal. On the other hand, the distance value between ADH and LG DCIS was larger than this distance. CONCLUSIONS: In this study, we have presented a practical and useful digital pathological method that incorporates nuclear morphological and textural features for IDPL prediction. We expect that this novel algorithm is used for the automated diagnosis assisting system for breast cancer. PMID- 26955500 TI - How can we improve Science, Technology, Engineering, and Math education to encourage careers in Biomedical and Pathology Informatics? AB - The Computer Science, Biology, and Biomedical Informatics (CoSBBI) program was initiated in 2011 to expose the critical role of informatics in biomedicine to talented high school students.[1] By involving them in Science, Technology, Engineering, and Math (STEM) training at the high school level and providing mentorship and research opportunities throughout the formative years of their education, CoSBBI creates a research infrastructure designed to develop young informaticians. Our central premise is that the trajectory necessary to be an expert in the emerging fields of biomedical informatics and pathology informatics requires accelerated learning at an early age.In our 4(th) year of CoSBBI as a part of the University of Pittsburgh Cancer Institute (UPCI) Academy (http://www.upci.upmc.edu/summeracademy/), and our 2nd year of CoSBBI as an independent informatics-based academy, we enhanced our classroom curriculum, added hands-on computer science instruction, and expanded research projects to include clinical informatics. We also conducted a qualitative evaluation of the program to identify areas that need improvement in order to achieve our goal of creating a pipeline of exceptionally well-trained applicants for both the disciplines of pathology informatics and biomedical informatics in the era of big data and personalized medicine. PMID- 26955501 TI - Oxygen supply maps for hypoxic microenvironment visualization in prostate cancer. AB - BACKGROUND: Intratumoral hypoxia plays an important role with regard to tumor biology and susceptibility to radio- and chemotherapy. For further investigation of hypoxia-related changes, areas of certain hypoxia must be reliably detected within cancer tissues. Pimonidazole, a 2-nitroimindazole, accumulates in hypoxic tissue and can be easily visualized using immunohistochemistry. MATERIALS AND METHODS: To improve detection of highly hypoxic versus normoxic areas in prostate cancer, immunoreactivity of pimonidazole and a combination of known hypoxia related proteins was used to create computational oxygen supply maps of prostate cancer. Pimonidazole was intravenously administered before radical prostatectomy in n = 15 patients, using the da Vinci robot-assisted surgical system. Prostatectomy specimens were immediately transferred into buffered formaldehyde, fixed overnight, and completely embedded in paraffin. Pimonidazole accumulation and hypoxia-related protein expression were visualized by immunohistochemistry. Oxygen supply maps were created using the normalized information from pimonidazole and hypoxia-related proteins. RESULTS: Based on pimonidazole staining and other hypoxia.related proteins (osteopontin, hypoxia-inducible factor 1-alpha, and glucose transporter member 1) oxygen supply maps in prostate cancer were created. Overall, oxygen supply maps consisting of information from all hypoxia-related proteins showed high correlation and mutual information to the golden standard of pimonidazole. Here, we describe an improved computer-based ex vivo model for an accurate detection of oxygen supply in human prostate cancer tissue. CONCLUSIONS: This platform can be used for precise colocalization of novel candidate hypoxia-related proteins in a representative number of prostate cancer cases, and improve issues of single marker correlations. Furthermore, this study provides a source for further in situ tests and biochemical investigations. PMID- 26955502 TI - Diagnostic time in digital pathology: A comparative study on 400 cases. AB - BACKGROUND: Numerous validation studies in digital pathology confirmed its value as a diagnostic tool. However, a longer time to diagnosis than traditional microscopy has been seen as a significant barrier to the routine use of digital pathology. As a part of our validation study, we compared a digital and microscopic diagnostic time in the routine diagnostic setting. MATERIALS AND METHODS: One senior staff pathologist reported 400 consecutive cases in histology, nongynecological, and fine needle aspiration cytology (20 sessions, 20 cases/session), over 4 weeks. Complex, difficult, and rare cases were excluded from the study to reduce the bias. A primary diagnosis was digital, followed by traditional microscopy, 6 months later, with only request forms available for both. Microscopic slides were scanned at *20, digital images accessed through the fully integrated laboratory information management system (LIMS) and viewed in the image viewer on double 23" displays. A median broadband speed was 299 Mbps. A diagnostic time was measured from the point slides were made available to the point diagnosis was made or additional investigations were deemed necessary, recorded independently in minutes/session and compared. RESULTS: A digital diagnostic time was 1841 and microscopic 1956 min; digital being shorter than microscopic in 13 sessions. Four sessions with shorter microscopic diagnostic time included more cases requiring extensive use of magnifications over *20. Diagnostic time was similar in three sessions. CONCLUSIONS: A diagnostic time in digital pathology can be shorter than traditional microscopy in the routine diagnostic setting, with adequate and stable network speeds, fully integrated LIMS and double displays as default parameters. This also related to better ergonomics, larger viewing field, and absence of physical slide handling, with effects on both diagnostic and nondiagnostic time. Differences with previous studies included a design, image size, number of cases, specimen type, network speed, and participant's level of confidence and experience in digital reporting. Further advancements in working stations and gained experience in digital reporting are expected to improve diagnostic time and widen routine applications of digital pathology. PMID- 26955503 TI - Feature-based analysis of mouse prostatic intraepithelial neoplasia in histological tissue sections. AB - This paper describes work presented at the Nordic Symposium on Digital Pathology 2015, in Linkoping, Sweden. Prostatic intraepithelial neoplasia (PIN) represents premalignant tissue involving epithelial growth confined in the lumen of prostatic acini. In the attempts to understand oncogenesis in the human prostate, early neoplastic changes can be modeled in the mouse with genetic manipulation of certain tumor suppressor genes or oncogenes. As with many early pathological changes, the PIN lesions in the mouse prostate are macroscopically small, but microscopically spanning areas often larger than single high magnification focus fields in microscopy. This poses a challenge to utilize full potential of the data acquired in histological specimens. We use whole prostates fixed in molecular fixative PAXgeneTM, embedded in paraffin, sectioned through and stained with H&E. To visualize and analyze the microscopic information spanning whole mouse PIN (mPIN) lesions, we utilize automated whole slide scanning and stacked sections through the tissue. The region of interests is masked, and the masked areas are processed using a cascade of automated image analysis steps. The images are normalized in color space, after which exclusion of secretion areas and feature extraction is performed. Machine learning is utilized to build a model of early PIN lesions for determining the probability for histological changes based on the calculated features. We performed a feature-based analysis to mPIN lesions. First, a quantitative representation of over 100 features was built, including several features representing pathological changes in PIN, especially describing the spatial growth pattern of lesions in the prostate tissue. Furthermore, we built a classification model, which is able to align PIN lesions corresponding to grading by visual inspection to more advanced and mild lesions. The classifier allowed both determining the probability of early histological changes for uncategorized tissue samples and interpretation of the model parameters. Here, we develop quantitative image analysis pipeline to describe morphological changes in histological images. Even subtle changes in mPIN lesion characteristics can be described with feature analysis and machine learning. Constructing and using multidimensional feature data to represent histological changes enables richer analysis and interpretation of early pathological lesions. PMID- 26955504 TI - Data security in genomics: A review of Australian privacy requirements and their relation to cryptography in data storage. AB - The advent of next-generation sequencing (NGS) brings with it a need to manage large volumes of patient data in a manner that is compliant with both privacy laws and long-term archival needs. Outside of the realm of genomics there is a need in the broader medical community to store data, and although radiology aside the volume may be less than that of NGS, the concepts discussed herein are similarly relevant. The relation of so-called "privacy principles" to data protection and cryptographic techniques is explored with regards to the archival and backup storage of health data in Australia, and an example implementation of secure management of genomic archives is proposed with regards to this relation. Readers are presented with sufficient detail to have informed discussions - when implementing laboratory data protocols - with experts in the fields. PMID- 26955505 TI - Implementation of Epic Beaker Clinical Pathology at an academic medical center. AB - BACKGROUND: Epic Beaker Clinical Pathology (CP) is a relatively new laboratory information system (LIS) operating within the Epic suite of software applications. To date, there have not been any publications describing implementation of Beaker CP. In this report, we describe our experience in implementing Beaker CP version 2012 at a state academic medical center with a go live of August 2014 and a subsequent upgrade to Beaker version 2014 in May 2015. The implementation of Beaker CP was concurrent with implementations of Epic modules for revenue cycle, patient scheduling, and patient registration. METHODS: Our analysis covers approximately 3 years of time (2 years preimplementation of Beaker CP and roughly 1 year after) using data summarized from pre- and post implementation meetings, debriefings, and the closure document for the project. RESULTS: We summarize positive aspects of, and key factors leading to, a successful implementation of Beaker CP. The early inclusion of subject matter experts in the design and validation of Beaker workflows was very helpful. Since Beaker CP does not directly interface with laboratory instrumentation, the clinical laboratories spent extensive preimplementation effort establishing middleware interfaces. Immediate challenges postimplementation included bar code scanning and nursing adaptation to Beaker CP specimen collection. The most substantial changes in laboratory workflow occurred with microbiology orders. This posed a considerable challenge with microbiology orders from the operating rooms and required intensive interventions in the weeks following go-live. In postimplementation surveys, pathology staff, informatics staff, and end-users expressed satisfaction with the new LIS. CONCLUSIONS: Beaker CP can serve as an effective LIS for an academic medical center. Careful planning and preparation aid the transition to this LIS. PMID- 26955506 TI - Robotics: A Rehabilitation Modality. PMID- 26955507 TI - In silico motif analysis suggests an interplay of transcriptional and translational control in mTOR response. AB - The short 5'-terminal oligopyrimidine tract (TOP) of 5' UTRs is a well-known regulatory sequence motif of mRNAs that are subject to growth-dependent translation. Specifically, translation of TOP mRNAs is regulated by the mTOR signaling pathway that is involved in cell proliferation, cancer development and aging. High throughput data permit detailed study of specific features of the mRNA TOP motif and its DNA origins at transcription start sites (TSS). Recently, ribosome profiling was used to identify mRNA targets of the mTOR pathway in PC3 cells. A novel pyrimidine-rich translational element (PRTE) was reported to play a key role without positional preferences within the 5' UTRs, unlike 5' TOP, which are strictly located at the 5' ends. In this study, we couple recently reported ribosome profiling data on the mTOR mRNA targets with the annotation of TSS obtained by HeliScopeCAGE. We confirm the canonical TOP and strong positional preferences of respective oligopyrimidine tracts (OP) straddling the experimentally validated TSS regions at the DNA level. Such OP localization ensures that transcription from OP segments creates the 5'-terminal TOP in the corresponding mRNAs. We demonstrate that OP are not overrepresented in downstream regions of 5' UTRs of mTOR targets. Finally, we highlight several mTOR target genes with broad and multimodal TSS spanning dozens of nucleotides that are only partically covered with an OP. Therefore, in such cases only a fraction of all produced mRNAs carry a TOP regulatory motif and, thus, respond to mTOR via TOP mechanism. We hypothesize that the interplay between transcription and translation may play a crucial role in the regulation of the mTOR response. PMID- 26955508 TI - A new in vivo model using a dorsal skinfold chamber to investigate microcirculation and angiogenesis in diabetic wounds. AB - INTRODUCTION: Diabetes mellitus describes a dysregulation of glucose metabolism due to improper insulin secretion, reduced insulin efficacy or both. It is a well known fact that diabetic patients are likely to suffer from impaired wound healing, as diabetes strongly affects tissue angiogenesis. Until now, no satisfying in vivo murine model has been established to analyze the dynamics of angiogenesis during diabetic wound healing. To help understand the pathophysiology of diabetes and its effect on angiogenesis, a novel in vivo murine model was established using the skinfold chamber in mice. MATERIALS AND METHODS: Mutant diabetic mice (db; BKS.Cg-m+/+Lepr (db) /J), wildtype mice (dock7Lepr (db) +/+m) and laboratory BALB/c mice were examined. They were kept in single cages with access to laboratory chow with an 12/12 hour day/night circle. Lesions of the panniculus muscle (O 2 mm) were created in the center of the transparent window chamber and the subsequent muscular wound healing was then observed for a period of 22 days. Important analytic parameters included vessel diameter, red blood cell velocity, vascular permeability, and leakage of muscle capillaries and post capillary venules. The key parameters were functional capillary density (FCD) and angiogenesis positive area (APA). RESULTS: We established a model which allows high resolution in vivo imaging of functional angiogenesis in diabetic wounds. As expected, db mice showed impaired wound closure (day 22) compared to wounds of BALB/c or WT mice (day 15). FCD was lower in diabetic mice compared to WT and BALB/c during the entire observation period. The dynamics of angiogenesis also decreased in db mice, as reflected by the lowest APA levels. Significant variations in the skin buildup were observed, with the greatest skin depth in db mice. Furthermore, in db mice, the dermis:subcutaneous ratio was highly shifted towards the subcutaneous layers as opposed to WT or BALB/c mice. CONCLUSION: Using this new in vivo model of the skinfold chamber, it was possible to analyze and quantify microangiopathical changes which are essential for a better understanding of the pathophysiology of disturbed wound healing. Research in microcirculation is important to display perfusion in wounds versus healthy tissue. Using our model, we were able to compare wound healing in diabetic and healthy mice. We were also able to objectively analyze perfusion in wound edges and compare microcirculatory parameters. This model may be well suited to augment different therapeutic options. PMID- 26955509 TI - Combined approach for gynecomastia. AB - BACKGROUND: Gynecomastia is a deformity of male chest. Treatment of gynecomastia varied from direct surgical excision to other techniques (mainly liposuction) to a combination of both. Skin excision is done according to the grade. In this study, experience of using liposuction adjuvant to surgical excision was described. PATIENTS AND METHODS: Between September 2012 and April 2015, a total of 14 patients were treated with liposuction and surgical excision through a periareolar incision. Preoperative evaluation was done in all cases to exclude any underlying cause of gynecomastia. RESULTS: All fourteen patients were treated bilaterally (28 breast tissues). Their ages ranged between 13 and 33 years. Two patients were classified as grade I, and four as grade IIa, IIb or III, respectively. The first 3 patients showed seroma. Partial superficial epidermolysis of areola occurred in 2 cases. Superficial infection of incision occurred in one case and was treated conservatively. CONCLUSION: All grades of gynecomastia were managed by the same approach. Skin excision was added to a patient that had severe skin excess with limited activity and bad skin complexion. No cases required another setting or asked for 2(nd) opinion. PMID- 26955510 TI - Effect of Schneiderian membrane perforation on sinus lift graft outcome using two different donor sites: a retrospective study of 105 maxillary sinus elevation procedures. AB - BACKGROUND: Sinuslift is meanwhile an established method of bone augmentation in the posterior maxilla. Aim of the study was to evaluate the significance of intraoperative Schneiderian membrane perforations during maxillary sinus floor elevation surgery using autogenous bone harvested from two different donor sites using a Safescraper device on the success rate, graft survival and implant integration. METHODS: The investigators conducted a retrospective cohort study at the Department of Oral and Maxillofacial Surgery of Military Hospital Ulm composed of patients with severe maxillary atrophy who underwent sinus augmentation from January 2011 until December 2011. Ninety-nine consecutive patients (89 men, 10 women) with a mean age of 43.1 years underwent sinus graft procedures in a 2-stage procedure using the lateral wall approach, as described by Tatum (1986). Data on patient age, smoking status, donor site and surgical complications were recorded and the relationship between Schneiderian membrane perforation and complication rate was evaluated. Dental implants were inserted 4 months after grafting. RESULTS: A total of 105 sinus lift procedures were performed in 99 patients. Sixty-one patients (61.6%) underwent sinus elevation with autogenous bone from the buccal sinus wall, while 38 patients (38.4%) bone harvesting from the iliac crest. Intraoperative perforation of the Schneiderian membrane was observed in 11 of the 105 sinuses (10.4%). These perforations resulted in 4 (36.3%) of the cases in major postoperative complications accompanied by swelling and wound infection. Membrane perforations were slightly associated with the appearance of postoperative complications (p=0.0762). In 2.4% of all cases, regarding 2 patients the final rehabilitation with dental implants was not possible because of extensive bone resorption. CONCLUSION: Intraoperative complications performing sinus augmentation may lead to postoperative complications. With careful clinical and radiographic evaluation and appropriate treatment, the complications and risk for graft material displacement and implant loss can be eliminated. PMID- 26955511 TI - Measuring diagnostic safety of inpatients: time to set sail in uncharted waters. PMID- 26955512 TI - The challenges in defining and measuring diagnostic error. AB - Diagnostic errors have emerged as a serious patient safety problem but they are hard to detect and complex to define. At the research summit of the 2013 Diagnostic Error in Medicine 6th International Conference, we convened a multidisciplinary expert panel to discuss challenges in defining and measuring diagnostic errors in real-world settings. In this paper, we synthesize these discussions and outline key research challenges in operationalizing the definition and measurement of diagnostic error. Some of these challenges include 1) difficulties in determining error when the disease or diagnosis is evolving over time and in different care settings, 2) accounting for a balance between underdiagnosis and overaggressive diagnostic pursuits, and 3) determining disease diagnosis likelihood and severity in hindsight. We also build on these discussions to describe how some of these challenges can be addressed while conducting research on measuring diagnostic error. PMID- 26955513 TI - Characterizing "fibrofog": Subjective appraisal, objective performance, and task related brain activity during a working memory task. AB - The subjective experience of cognitive dysfunction ("fibrofog") is common in fibromyalgia. This study investigated the relation between subjective appraisal of cognitive function, objective cognitive task performance, and brain activity during a cognitive task using functional magnetic resonance imaging (fMRI). Sixteen fibromyalgia patients and 13 healthy pain-free controls completed a battery of questionnaires, including the Multiple Ability Self-Report Questionnaire (MASQ), a measure of self-perceived cognitive difficulties. Participants were evaluated for working memory performance using a modified N back working memory task while undergoing Blood Oxygen Level Dependent (BOLD) fMRI measurements. Fibromyalgia patients and controls did not differ in working memory performance. Subjective appraisal of cognitive function was associated with better performance (accuracy) on the working memory task in healthy controls but not in fibromyalgia patients. In fibromyalgia patients, increased perceived cognitive difficulty was positively correlated with the severity of their symptoms. BOLD response during the working memory task did not differ between the groups. BOLD response correlated with task accuracy in control subjects but not in fibromyalgia patients. Increased subjective cognitive impairment correlated with decreased BOLD response in both groups but in different anatomic regions. In conclusion, "fibrofog" appears to be better characterized by subjective rather than objective impairment. Neurologic correlates of this subjective experience of impairment might be separate from those involved in the performance of cognitive tasks. PMID- 26955514 TI - Emerging hubs in phantom perception connectomics. AB - Brain networks are small-world networks typically characterized by the presence of hubs, i.e. nodes that have significantly greater number of links in comparison to other nodes in the network. These hubs act as short cuts in the network and promote long-distance connectivity. Long-distance connections increase the efficiency of information transfer but also increase the cost of the network. Brain disorders are associated with an altered brain connectome which reflects either as a complete change in the network topology, as in, the replacement of hubs or as an alteration in the connectivity between the hubs while retaining network structure. The current study compares the network topology of binary and weighted networks in tinnitus patients and healthy controls by studying the hubs of the two networks in different oscillatory bands. The EEG of 311 tinnitus patients and 256 control subjects are recorded, pre-processed and source localized using sLORETA. The hubs of the different binary and weighted networks are identified using different measures of network centrality. The results suggest that the tinnitus and control networks are distinct in all the frequency bands but substantially overlap in the gamma frequency band. The differences in network topology in the tinnitus and control groups in the delta, theta and the higher beta bands are driven by a change in hubs as well as network connectivity; in the alpha band by changes in hubs alone and in the gamma band by changes in network connectivity. Thus the brain seems to employ different frequency band dependent adaptive mechanisms trying to compensate for auditory deafferentation. PMID- 26955515 TI - Brain network characterization of high-risk preterm-born school-age children. AB - Higher risk for long-term cognitive and behavioral impairments is one of the hallmarks of extreme prematurity (EP) and pregnancy-associated fetal adverse conditions such as intrauterine growth restriction (IUGR). While neurodevelopmental delay and abnormal brain function occur in the absence of overt brain lesions, these conditions have been recently associated with changes in microstructural brain development. Recent imaging studies indicate changes in brain connectivity, in particular involving the white matter fibers belonging to the cortico-basal ganglia-thalamic loop. Furthermore, EP and IUGR have been related to altered brain network architecture in childhood, with reduced network global capacity, global efficiency and average nodal strength. In this study, we used a connectome analysis to characterize the structural brain networks of these children, with a special focus on their topological organization. On one hand, we confirm the reduced averaged network node degree and strength due to EP and IUGR. On the other, the decomposition of the brain networks in an optimal set of clusters remained substantially different among groups, talking in favor of a different network community structure. However, and despite the different community structure, the brain networks of these high-risk school-age children maintained the typical small-world, rich-club and modularity characteristics in all cases. Thus, our results suggest that brain reorganizes after EP and IUGR, prioritizing a tight modular structure, to maintain the small-world, rich-club and modularity characteristics. By themselves, both extreme prematurity and IUGR bear a similar risk for neurocognitive and behavioral impairment, and the here defined modular network alterations confirm similar structural changes both by IUGR and EP at school age compared to control. Interestingly, the combination of both conditions (IUGR + EP) does not result in a worse outcome. In such cases, the alteration in network topology appears mainly driven by the effect of extreme prematurity, suggesting that these brain network alterations present at school age have their origin in a common critical period, both for intrauterine and extrauterine adverse conditions. PMID- 26955517 TI - Electrochemical degradation of trichloroethylene in aqueous solution by bipolar graphite electrodes. AB - In this study, we tested the use of the bipolar electrodes to enhance electrochemical degradation of trichloroethylene (TCE) in an undivided, flow through electrochemical reactor. The bipolar electrode forms when an electrically conductive material polarizes between feeder electrodes that are connected to a direct current source and, therefore, creates an additional anode/cathode pair in the system. We hypothesize that bipolar electrodes will generate additional oxidation/reduction zones to enhance TCE degradation. The graphite cathode followed by graphite anode sequence were operated without a bipolar electrode as well as with one and two bipolar graphite electrodes. The system without bipolar electrodes degraded 29% of TCE while the system with one and two bipolar electrodes degraded 38% and 66% of TCE, respectively. It was found that the removal mechanism for TCE in bipolar mode includes hydrodechlorination at the feeder cathode, and oxidation through reaction with peroxide. The results show that the bipolar electrodes presence enhance TCE removal efficiency and rate and imply that they can be used to improve electrochemical treatment of contaminated groundwater. PMID- 26955518 TI - Stereotactic laser ablation of the splenium for intractable epilepsy. AB - Partial or complete corpus callosotomies have been applied, traditionally via open surgical or radiosurgical approaches, for the treatment of epilepsy in patients with multifocal tonic, atonic, or myoclonic seizures. Minimally invasive methods, such as MRI-guided laser interstitial thermal ablation (MTLA), are being employed to functionally remove or ablate seizure foci in the treatment of epilepsy. This therapy can achieve effectiveness similar to that of traditional resection, but with reduced morbidity compared with open surgery. Here, we present a patient with a history of prior partial corpus callosotomy who continued to suffer from medically refractory epilepsy with bisynchronous onset. We report on the utilization of laser ablation of the splenium in this patient to achieve full corpus callosotomy. Adequate ablation of the splenial remnant was confirmed by postoperative MRI imaging, and at four-month follow-up, the patient's seizure frequency had dropped more than 50%. This is the first reported instance of laser ablation of the splenium to achieve full corpus callosotomy following a previous unsuccessful anterior callosotomy in a patient with intractable generalized epilepsy. PMID- 26955516 TI - Alpha desynchronization and fronto-parietal connectivity during spatial working memory encoding deficits in ADHD: A simultaneous EEG-fMRI study. AB - The underlying mechanisms of alpha band (8-12 Hz) neural oscillations are of importance to the functioning of attention control systems as well as to neuropsychiatric conditions that are characterized by deficits of that system, such as attention deficit hyperactivity disorder (ADHD). The objectives of the present study were to test if visual encoding-related alpha event-related desynchronization (ERD) correlates with fronto-parieto-occipital connectivity, and whether this is disrupted in ADHD during spatial working memory (SWM) performance. We acquired EEG concurrently with fMRI in thirty boys (12-16 yrs. old, 15 with ADHD), during SWM encoding. Psychophysiological connectivity analyses indicated that alpha ERD during SWM encoding was associated with both occipital activation and fronto-parieto-occipital functional connectivity, a finding that expands on prior associations between alpha ERD and occipital activation. This finding provides novel support for the interpretation of alpha ERD (and the associated changes in occipital activation) as a phenomenon that involves, and perhaps arises as a result of, top-down network interactions. Alpha ERD was associated less strongly with occipital activity, but associated more strongly with fronto-parieto-occipital connectivity in ADHD, consistent with a compensatory attentional response. Additionally, we illustrate that degradation of EEG data quality by MRI-amplified motion artifacts is robust to existing cleaning algorithms and is significantly correlated with hyperactivity symptoms and the ADHD Combined Type diagnosis. We conclude that persistent motion-related MR artifacts in EEG data can increase variance and introduce bias in interpretation of group differences in populations characterized by hypermobility -a clear limitation of current-state EEG-fMRI methodology. PMID- 26955519 TI - Microsurgical endoscopy-assisted anterior corpus callosotomy for drug-resistant epilepsy in an adult unresponsive to vagus nerve stimulation. AB - Because most of the corpus callosotomy (CC) series available in literature were published before the advent of vagus nerve stimulation (VNS), the efficacy of CC in patients with inadequate response to VNS remains unclear, especially in adult patients. We present the case of a 21-year-old female with medically refractory drop attacks that began at the age of 8 years, which resulted in the patient being progressively unresponsive to vagus nerve stimulation implanted at the age of 14 years. Corpus callosotomy was recommended to reduce the number of drop attacks. However, the patient had only mild cognitive impairments and no neurological deficits. For this reason, we were forced to plan a surgical approach able to maximize the disconnection for good seizure control while, at the same time, minimizing sequelae from disconnection syndromes and neurosurgical complications because in such cases of long-lasting epilepsy the gyri cinguli and the arteries can be tenaciously adherent and dislocated with all the normal anatomy altered. In this scenario, we opted for a microsurgical endoscopy assisted anterior two-thirds corpus callosotomy. The endoscopic minimally invasive approach proved to be quite adequate in this technically demanding case and confirmed that CC may offer advantages, with good results, even in adult patients with drop attacks who have had inadequate response to VNS. PMID- 26955520 TI - Arrhythmogenic Right Ventricular Cardiomyopathy: Electroarchitecture of the Substrate. PMID- 26955521 TI - Three cases of presumed pneumocystis pneumonia in patients receiving bortezomib therapy for multiple myeloma. AB - INTRODUCTION: This paper presents three probable cases of pneumocystis pneumonia in patients receiving bortezomib therapy for multiple myeloma. PRESENTATION OF CASES: Three patients receiving bortezomib therapy for multiple myeloma presented with dyspnoea, non-productive cough, and fevers. These patients deteriorated despite receiving broad-spectrum antibiotic therapy with piperacillin + tazobactam and azithromycin and an assortment of other antimicrobials but promptly responded to sulfamethoxazole + trimethoprim therapy. Only one of the patients exhibited a positive Pneumocystis jirovecii PCR test but testing was sub optimal. DISCUSSION: Although only one of the patients exhibited a positive sputum P. jirovecii PCR test, the diagnosis of PCP in these three patients is supported by their; clinical and radiological features consistent with PCP, deterioration despite receiving broad-spectrum antibiotic therapy, and prompt responses to sulfamethoxazole + trimethoprim therapy. In the patients with negative P. jirovecii PCR bronchoalveolar lavage specimens were not obtained as these patients were deemed too high risk to undergo the procedure. Although the three patients were also receiving dexamethasone therapy, the doses and durations were at the threshold of those expected to cause PCP. CONCLUSION: 26S proteosome inhibitor therapy for multiple myeloma may be a risk factor for PCP and clinicians should adopt a high level of suspicion for PCP in patients receiving these medications until conclusive evidence is obtained. PMID- 26955522 TI - Postoperative testicular abscess with bacteremia due to Actinomyces neuii. AB - Bacteremia due to Actinomyces neuii has been reported in the literature 14 times. A. neuii is an endogenous organism that has been cultured in clinical specimens of the genitourinary tract; we are reporting a unique case of A. neuii postoperative testicular abscess with bacteremia which was successfully treated with surgery and a short course of parenteral antimicrobials. PMID- 26955524 TI - Pancreatic panniculitis complicated by infection with Corynebacterium tuberculostearicum: A case report. AB - We present a case of pancreatic panniculitis in a patient with alcohol abuse where Corynebacterium tuberculostearicum was isolated from a pannicular nodule on the crus. The patient was started on linezolid treatment leading to regression of the patient's symptoms. Upon discontinuation of linezolid treatment progression of the skin symptoms progressed. PMID- 26955523 TI - Parinaud's oculoglandular syndrome associated with Sporothrix schenckii. AB - The Parinaud oculoglandular syndrome is a rare eye disease caused by different etiologic agents, including bacteria, viruses and fungi. It is characterized by a granulomatous conjunctivitis, accompanied by adjacent preauricular lymphadenopathy and can bring consequences if not treated promptly. We present a case of Parinaud oculoglandular syndrome caused by Sporothrix schenckii from the sporotrichosis epidemic in its zoonotic form occurring in Rio de Janeiro, Brazil. PMID- 26955525 TI - Clostridium subterminale septicemia in a patient with esophageal cancer. AB - Clostridium subterminale (C. subterminale) is a pathogenic species of Clostridium that has been infrequently isolated. We report a case of C. subterminale bacteremia causing sepsis in a patient with metastatic gastrointestinal malignancy. PMID- 26955526 TI - Anaerobiospirillum succiniciproducens sepsis in an autopsy patient: A troublesome diagnostic workup. AB - Anaerobiospirillum succiniciproducens is an uncommon yet potentially lethal gram negative bacterium typically affecting patients with comorbidities. We report a case of A. succiniciproducens infection in an autopsy patient who had hepatitis C and type 2 diabetes and describe the difficulties in the laboratory identification of this pathogen. PMID- 26955527 TI - Occult invasive aspergillosis infection following multivisceral transplantation. AB - Patients undergoing multivisceral transplantation are particularly susceptible to post-operative infections due to immunosuppression and the inclusion of bowel in the transplanted graft. These patients typically receive broad-spectrum antimicrobial and antifungal agents as prophylaxis and treatment. However, evidence for this is limited due to the small number of patients undergoing the procedure. We present a case of occult disseminated invasive aspergillosis infection in a patient who underwent multivisceral transplantation. PMID- 26955528 TI - Phthirus pubis as a cause of axillary pruritus. PMID- 26955529 TI - Cutaneous leishmaniasis with atypical clinical manifestations: Case report. AB - This case report alerts to the existence of atypical forms of cutaneous leishmaniasis (CL). A woman with nodular cutaneous lesions over a neck with papules and pustules located deep in the hypodermis that formed plaques with subcutaneous induration and satellite papules was confirmed to have CL. After confirmation, the patient was treated with remission of the lesions, scarring and thickening of the skin. PMID- 26955530 TI - A New Source for Your Patient-oriented Education. PMID- 26955531 TI - A Case Report of Primary Recurrent Malignant Melanoma of the Urinary Bladder. AB - Primary malignant melanoma of the urinary bladder is a rare neoplasm, with only 19 cases reported to date. We present a case report of an 84-year-old woman who underwent transurethral resection of a mucosal melanoma of bladder origin. She had no previous or concurrent diagnosis of cutaneous melanoma. The patient underwent transurethral resection of the tumor 5 months before presentation at our center with a recurrent, muscle-invasive tumor located in the bladder trigone, with evidence of bone metastasis. Malignant melanoma of the urinary bladder carries a poor prognosis and poses a therapeutic challenge to urologists who manage patients with this rare disease. PMID- 26955532 TI - Adenocarcinoma of the Ileal Conduit in a Patient Born With Classic Bladder Exstrophy. AB - Bladder exstrophy is a rare birth defect that typically requires patients to undergo multiple surgical procedures throughout the course of their childhood. Many ultimately undergo operations that use segments of bowel for the reconstruction and/or augmentation of the urinary tract, which imparts an increased risk of malignancy in these patients. We present the case of a 59-year old man with a history of bladder exstrophy managed with ureterosigmoidostomies revised to an ileal conduit who developed a large adenocarcinoma in the ileal conduit that extended into small bowel, sigmoid colon, and ureter. PMID- 26955533 TI - Spontaneous Extraperitoneal Bladder Rupture Because of Chronic Appendicitis. AB - A 62-year-old man presented to the emergency department with an episode of syncope after 2-3 weeks of diffuse abdominal pain, now complaining of a severe increase in pain concurrent with >24 hours of no urine output. His workup showed an idiopathic extraperitoneal rupture of the bladder on computed tomography, which was handled conservatively with Foley insertion. Repeated follow-up and imaging showed no resolution or etiology over 2 months. The patient underwent exploratory laparotomy that showed an elongated appendix with a chronic tip appendicitis that had induced bladder rupture by chronic inflammatory changes. After repair, the patient had no further complaints. PMID- 26955534 TI - Aggressive Renal Angiomyolipoma of the Lipomatous Variant With Inferior Vena Cava Thrombus: A Case Report and Review of the Literature. AB - Two variants of renal angiomyolipoma (AML)-classic and epithelioid-have been described. Although the epithelioid variant has been reported to demonstrate an aggressive clinical behavior, classic AML is usually benign. Herein, we report a case of a 42-year-old asymptomatic woman with a lipomatous variant of renal AML associated with an inferior vena cava thrombus managed with radical nephrectomy and caval thrombectomy. PMID- 26955535 TI - Fibrous Pseudotumor of the Penis - An Unusual Finding During Repair of Fractured Penis. AB - Fibrous pseudotumors of the testis and penis are a rare phenomenon, forming a spectrum of heterogeneous lesions. To the best of our knowledge, there has been only 1 previous report arising from the penis. We present a case of fibrous pseudotumor of the penis, incidentally found during the surgical repair of a fractured penis. These benign lesions have been described in the literature and are most commonly referred to as pseudotumors. They should be distinguished from potentially malignant lesions, including fibrosarcomas, squamous cell carcinoma, and polypoid urothelial carcinoma. Being aware of this pathology is important to prevent unnecessary radical surgery. PMID- 26955536 TI - Penile Abscess: A Case Report and Review of Literature. AB - A case of penile abscess after amphetamine injection into the penis is reported. A 45-year-old male patient was successfully treated with surgical drainage and antibiotics. There were no 3-month consequences of treatment at follow-up, and the patient maintained potency, without any penile deformity. The aetiology, diagnosis, and management of penile abscesses are discussed. PMID- 26955537 TI - Strange Vibes - Novel Presentation of Prostatitis. AB - Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) has significant variability in its presentation. In this study, we present 2 novel cases of prostatitis in which "buzz" is described as the primary pain symptom. These cases describe patients with the primary complaint of "cell phone-like buzzing" within the perineum, with accompanying urinary symptoms consistent with prostatitis. CP/CPPS is a multifactorial disease within which psychological, inflammatory, neurologic, and neuromuscular etiologies are at play. As in other disease descriptions, a buzzing sensation represents the interaction of multiple pathways that have significant overlay with CP/CPPS. As such, we believe buzzing might represent a new symptom of CP/CPPS. PMID- 26955538 TI - Sacral Neuromodulation for Bladder Atony - A Case Report. AB - In most cases, sacral neuromodulation is used as a treatment for urge incontinence and symptoms of urgency and frequency. It is most used in those who are refractory to traditional management. It is much less common to be used for bladder atony. In this report, we present a case of a 24-year-old woman with a history of urinary retention and bladder atony who failed medical management and subsequently had an InterStim sacral neuromodulator implanted. After implantation, she was able to discontinue intermittent catheterization and had a decrease in her postvoid residual from 848 to 72 mL. PMID- 26955539 TI - Placenta Percreta With Invasion into the Urinary Bladder. AB - Placenta percreta is a rare condition, which can lead to significant morbidity and potentially mortality. We present a case of a 38-year-old woman who presented at 24 weeks gestation with vaginal bleeding and was found to have complete placenta previa with placenta percreta invading the urinary bladder. Her hospital course was complicated by bilateral pulmonary emboli. She underwent an exploratory laparotomy, repeat Caesarean section, and total abdominal hysterectomy. Because of placental invasion into the bladder, the procedure was complicated by bladder and ureteral injuries for which urology carried out repair. Postoperatively, the patient had a persistent bladder leak until postoperative day #39. PMID- 26955540 TI - Giant Benign Prostatic Hyperplasia in a Pakistani Patient. AB - "Giant hyperplasia" of the prostate is a rare pathology of the prostate gland. We report one such case, in which a successful retropubic prostatectomy was performed on an elderly male patient in Pakistan. The weight of the resected prostate was 700 g, which is the eighth largest prostate with benign prostatic hyperplasia reported. PMID- 26955541 TI - Renal Squamous Cell Carcinoma Presented With Bone Metastasis and Coexistence With Xanthogranulomatous Pyelonephritis: A Case Report. AB - Squamous cell carcinoma (SCC) of the kidney is a rare entity. Coexistence of SCC with xanthogranulomatous pyelonephrits is exceedingly rare with only few reports in the literature. We report a case of a 45-year-old male patient with xanthogranulomatous pyelonephritis coexistence with renal SCC in one kidney, which proved radiologically and histopathologically. The patient presented to the medical care with bone metastasis. Full radiology workup is also provided which includes computed tomography, magnetic resonance imaging, and positron emission tomography-computed tomography. PMID- 26955542 TI - Prostate Stromal Tumor of Uncertain Malignant Potential: Case Report With 5-Year Follow-up. AB - Prostate stromal tumor of uncertain malignant potential is a term used to describe a specialized proliferation of stromal cells within the prostate. Most of these tumors tend to be benign, but some can present with local invasion or progress to prostatic stromal sarcoma with distant metastasis. We report a case of a 62-year-old male patient who presented to us with a diagnosis of stromal tumor of uncertain malignant potential. We have followed up the patient for 5 years with imaging, prostate-specific antigen checks, and annual prostate biopsies. PMID- 26955543 TI - Serial Ultrasonography Assessments of a Testicular Infarction Mimicking Testicular Tumor in a Behcet Disease Patient. AB - Behcet disease (BD), a vasculitic disease, may present with a broad range of systemic manifestations. Urologic complications are rarely described in the literature, but when they occur, they present as epididymo-orchitis. We describe a rare case of testicular infarction in a patient with BD followed up with serial ultrasound imaging. We highlight the diagnostic challenges when presented with testicular pain in a patient with BD and the potential consequences in the management. PMID- 26955544 TI - Internalization of Calcium Oxalate Calculi Developed in Narrow Cavities. AB - We describe the case of a patient with calcium oxalate monohydrate and calcium oxalate dihydrate calculi occluded in cavities. All those calculi were located inside narrow cavities covered with a thin epithelium that permits their visualization. Urinary biochemical analysis showed high calciuria, not hypercalciuria, hypocitraturia, and a ratio [calcium]/[citrate] >0.33. The existence of cavities of very low urodynamic efficacy was decisive in the formation of such calculi. It is important to emphasize that we observed a thin epithelium covering such cavities, demonstrating that this epithelium may be formed after the development of the calculi through a re-epithelialization process. PMID- 26955545 TI - Urethral Stone Disease Leading to Retention After Hair-bearing Neophalloplasty. AB - A 35-year-old male patient with a past history of traumatic penile amputation and subsequent penile reconstruction with a radial artery free flap phalloplasty presented to the urology clinic for urinary retention and complaint of a firm penile mass. The patient had been lost to follow-up for 2 years before this presentation. Patient had a suprapubic tube in place from initial surgery, with imaging showing 2 large uroliths encrusted around the end. Urethral stricture was suspected in the patient. On cystoscopy, an additional obstructing urolith was found in penile urethra, appearing to have formed in situ. PMID- 26955546 TI - A Case of Urethrocutaneous Fistula: A Forgotten Segment of a Broken Urethral Catheter. AB - A retained urethral catheter is a rare iatrogenic complication of which few cases have been reported in the literature. In this study, we describe a case of a forgotten urethral Foley catheter causing urethracutaneous fistula on scrotum. An 80-year-old man was referred for a small pus-draining cutaneous opening on the lower part of the scrotum. The distal segment of a broken Foley catheter was found, and it was located from urinary bladder to bulbous urethra with its tip penetrating the urethral mucosa. This catheter was removed using flexible cystoscopic forceps, and urethracutaneous fistula was well resolved with conservative therapy. PMID- 26955547 TI - A Domino Effect? The Spread of Implantation of Penile Foreign Bodies in the Prison System. AB - Subcutaneous penile insertion of foreign bodies is a practice performed globally but has mostly been reported outside of the United States. An incarcerated 29 year-old Caucasian male in a midwestern prison whittled a domino into a dog bone shape and placed it into his ventral penile subcutaneous tissue. He presented to our facility with erosion of the corners of the foreign body through his skin without evidence of infection. Self-insertion of foreign bodies into penile subcutaneous tissue by incarcerated American men for sexual enhancement is more widespread than previously reported. Erosion is a novel presentation. PMID- 26955548 TI - An Unexpected Foreign Body (a Thermometer) in the Bladder: A Case Report. AB - Foreign bodies in the bladder are rarely observed because of difficult access. These patients usually have a mental disorder, a background of intense sexual perversion, or inquisitiveness. A 48-year-old, deaf, and mentally retarded woman was referred to the nephrology clinic for severe anemia and impaired renal function. Imaging tests showed a mercury thermometer positioned in the bladder and a stone, 5 cm in diameter, around it. This had caused bilateral ureteral obstruction. The patient underwent an open cysteotomy. Obstructive uropathy is one of the causes of kidney failure; therefore, foreign bodies should be included in the differential diagnosis. PMID- 26955549 TI - Do Not Judge a Kidney by Its Pelvis: A Rare Case of an Unobstructed Dilated Renal Pelvis. AB - We present a rare case of an unobstructed dilated renal pelvis in a newborn female. Prenatal imaging documented a large abdominal cyst in a stable fetus. Postnatal imaging confirmed persistence of this large cyst but with an unclear etiology. The child was taken to surgery by the pediatric surgeons with concern for a possible harmful nonurologic diagnosis. Intraoperative findings were that of a severely dilated renal pelvis; however, in the absence of an expected ureteropelvic junction obstruction. Reduction pyeloplasty without interference of the ureteropelvic junction proved successful. PMID- 26955550 TI - Adenoma-carcinoma Sequence in the Bladder After Augmentation Cystoplasty. AB - We present a case of a 64-year-old woman showing multistep progression from adenoma to adenocarcinoma in the bladder 46 years after augmentation ileocystoplasty. She underwent augmentation ileocystoplasty for tuberculous contracted bladder at 18 years. After 44 years, tubulovillous adenomas were found and resected at the ileovesical anastomosis site. After 2 more years, bladder tumors recurred and revealed adenocarcinomas. Finally, radical cystectomy was required because of frequent recurrence and tumor extensiveness. To our knowledge, this is the first case demonstrating adenoma-carcinoma sequence histopathologically in the bladder after augmentation cystoplasty, indicating multistep carcinogenesis similar to intestinal carcinogenesis. PMID- 26955551 TI - Xp11 Translocation Renal Cell Carcinoma: Unusual Variant Masquerading as Upper Tract Urothelial Cell Carcinoma. AB - Xp11 translocation renal cell carcinoma (TRCC) is a rare subtype of renal cell carcinoma characterized by chromosomal translocations involving the TFE3 gene located at the Xp11.2 locus. Initial cases were more common in children, but cases in older adults have begun to accrue and suggest a relatively more aggressive course. We report a case of Xp11 TRCC in a 63-year-old female patient with initial presentation mimicking upper urinary tract urothelial cell carcinoma, with biopsy proving TRCC. She underwent a radical nephrectomy and paracaval lymph node dissection and is followed up with the intent to initiate vascular endothelial growth factor-targeted therapy in case of recurrence. PMID- 26955552 TI - Warty Condylomatous Squamous Cell Carcinoma of the Penis in a 19-Year-Old. AB - Warty carcinoma of the penis is an unusual neoplasm and a variant of penile squamous cell carcinoma. As with other types of penile cancer, risk factors include human papillomavirus infection, poor personal hygiene, and being uncircumcised. The typical case is an exophytic mass arising from the glans penis, frequently large (4-5 cm), and with invasion into corpus spongiosum. The diagnosis is typically made by tumor biopsy. Treatment depends on the stage of disease and includes partial vs total penectomy, with or without prophylactic or therapeutic bilateral lymphadenectomy. We present an unusual case of penile cancer in a 19-year-old patient. PMID- 26955553 TI - Chronic Cystitis Associated With Keratinizing Squamous Metaplasia Progressing to Squamous Papilloma. AB - We present a patient with extensive keratinizing squamous metaplasia that progressed to squamous papilloma over the course of follow-up. To our knowledge, this is the first published case of keratinizing squamous metaplasia with melanotic deposits of an unknown material with synchronous development of squamous papilloma. PMID- 26955554 TI - Primary Signet Ring Cell Adenocarcinoma of the Urinary Bladder: A Report of 2 Cases. AB - Primary signet ring cell carcinoma of the urinary bladder is a rare and aggressive histologic subtype of adenocarcinoma. In general, this tumor occurs in the middle age, and clinical presentation does not differ from transitional cell carcinomas. The prognosis is often poor, given the advanced stage at diagnosis. To our knowledge, <100 cases of signet ring cell adenocarcinoma of the urinary bladder have been reported. We report 2 cases with bladder linitis plastica primitive, and we draw attention to its pathologic, anatomoclinical, and evolution specificity to optimize its therapeutic management. PMID- 26955555 TI - Renal Angiomyxolipoma: Its First Appearance! AB - Angiomyxolipoma is considered a very rare subtype of lipoma, with the latter being the most common type of mesenchymal neoplasm. Only 17 cases have been described in English medical literature. Angiomyxolipomas have been described in many locations, mostly in the subcutaneous tissue. In this report, we present the first case of renal angiomyxolipoma ever encountered. Diagnosis was made after many differential diagnoses had been ruled out. Subsequent management and follow up are illustrated along with a discussion and review of literature. PMID- 26955556 TI - Urogenital and Rectal Multisystem Organ Injury After Detonation of an Explosive Substance in the Rectum of a Schizophrenic Man. AB - Penetrating injuries are caused by the injury of perineal area with gun or stab wounds, which may cause complex injuries or multiple organ injuries. Infections, bleeding, necrotizing fasciitis, ureterocutaneous fistulas, diverticulum, abscesses, narrowing, and incontinence may arise after urethral injuries. Although there are several case reports of urogenital system traumas in the literature, this case reports a schizophrenic patient who had a multisystem genitourinary and rectal trauma after self-detonation of an explosive in the rectum and managed with reconstructive surgery without any postoperative complications. Lower urinary tract anatomy was preserved and full continence was achieved after the surgical procedure. PMID- 26955557 TI - Testicular Dislocation After Scrotal Trauma: A Case Report and Brief Literature Review. AB - Traumatic dislocation of the testis is a rare event after blunt trauma of the scrotum or abdominopelvic injury. The diagnosis may be overlooked because of associated major injuries. In this study, we report on an adult who presented with a left traumatic dislocation of the testis after a falling astride injury. A brief literature review is also cited. PMID- 26955558 TI - The Efficacy of Bulbar Urethral Mobilization for Anastomotic Anterior Urethroplasty in a Case With Recurrent Anterior Urethral Stricture. AB - A 2-month-old boy was diagnosed with febrile urinary tract infection. Voiding cystourethrography showed bulbar and anterior urethral strictures, and endoscopic internal urethrotomy was performed. He developed febrile urinary tract infection again and revealed the recurrence of the anterior urethral stricture. Consequently, endoscopic internal urethrotomy was performed 4 times. Because the anterior urethral stricture had not improved, he was referred to us. Anterior urethroplasty was performed when he was 5 years. After excision of the scarred portions of the urethra, the defect of the urethra was 20 mm. Transperineal bulbar urethral mobilization was performed, and a single-stage end-to-end anterior urethroplasty without tension could be performed simultaneously. PMID- 26955559 TI - Spontaneous Urinary Bladder Perforation: An Unusual Presentation of Diabetes Mellitus. AB - Spontaneous urinary bladder perforation is a rare event, which requires immediate medical attention due to its extremely high morbidity and mortality. We report a case of a 36-year-old man who presented with acute-onset abdominal pain without any inciting events. His glucose level at the time of presentation was 1107 mg/dL. On initial abdominal imaging, it was believed that he had a large pelvic mass likely originating from the bladder. On further workup at our hospital, it was discovered that he had an intraperitoneal perforation after which he underwent an exploratory laparotomy and a cystorrhaphy. PMID- 26955560 TI - Xanthogranulomatous Pyelonephritis Can Simulate a Complex Cyst: Case Description and Review of Literature. AB - Xanthogranulomatous pyelonephritis is a rare and peculiar form of chronic pyelonephritis and is generally associated with renal lithiasis. Its incidence is higher in females. The peculiarity of this disease is that it requires a differential diagnosis, because it can often simulate dramatic pathologic conditions. In fact, in the literature are also described cases in association with squamous cell carcinoma of the kidney The radiologic clinical findings simulate renal masses, sometimes in association with caval thrombus. We describe a case of xanthogranulomatous pyelonephritis with radiologic aspects of a complex cyst of Bosniak class III in a man 40-year old. PMID- 26955561 TI - Unusual Presentation of Renal Vein Thrombosis in a Preterm Infant. AB - Neonatal renal vein thrombosis is the most common vascular condition in the newborn kidney, which could lead to serious complication in infants undergoing intensive care. In this study, we report the case of a preterm infant with left renal vein and inferior vena cava thrombosis, presented with gross hematuria, thrombocytopenia, transient hypertension, and adrenal hemorrhage. Supportive care was offered instead of heparin therapy or thrombolytic agents. In conclusion, our case teaches that, despite the lack of a clinically obvious shock event, renal vein thrombosis should be considered in a macrohematuric newborn without renal failure. PMID- 26955562 TI - Perioperative Anuria Resulting in the Diagnosis of Infrasphincteric Ectopic Ureter in an Adult Female. AB - Ectopic ureter, particularly in females, often presents at a young age as incontinence. Otherwise healthy girls who have continuous urinary wetting during day and night despite adequate toilet training should be held with a high level of suspicion for an extravesical infrasphincteric ectopic ureteral orifice. If such a diagnosis goes undiscovered, frequent reflux or obstruction may cause permanent damage to the renal unit, as in the patient discussed here. PMID- 26955563 TI - A New Adaptive Diffusive Function for Magnetic Resonance Imaging Denoising Based on Pixel Similarity. AB - Although there are many methods for image denoising, but partial differential equation (PDE) based denoising attracted much attention in the field of medical image processing such as magnetic resonance imaging (MRI). The main advantage of PDE-based denoising approach is laid in its ability to smooth image in a nonlinear way, which effectively removes the noise, as well as preserving edge through anisotropic diffusion controlled by the diffusive function. This function was first introduced by Perona and Malik (P-M) in their model. They proposed two functions that are most frequently used in PDE-based methods. Since these functions consider only the gradient information of a diffused pixel, they cannot remove noise in noisy images with low signal-to-noise (SNR). In this paper we propose a modified diffusive function with fractional power that is based on pixel similarity to improve P-M model for low SNR. We also will show that our proposed function will stabilize the P-M method. As experimental results show, our proposed function that is modified version of P-M function effectively improves the SNR and preserves edges more than P-M functions in low SNR. PMID- 26955565 TI - Computed Tomography Images De-noising using a Novel Two Stage Adaptive Algorithm. AB - In this paper, an optimal algorithm is presented for de-noising of medical images. The presented algorithm is based on improved version of local pixels grouping and principal component analysis. In local pixels grouping algorithm, blocks matching based on L (2) norm method is utilized, which leads to matching performance improvement. To evaluate the performance of our proposed algorithm, peak signal to noise ratio (PSNR) and structural similarity (SSIM) evaluation criteria have been used, which are respectively according to the signal to noise ratio in the image and structural similarity of two images. The proposed algorithm has two de-noising and cleanup stages. The cleanup stage is carried out comparatively; meaning that it is alternately repeated until the two conditions based on PSNR and SSIM are established. Implementation results show that the presented algorithm has a significant superiority in de-noising. Furthermore, the quantities of SSIM and PSNR values are higher in comparison to other methods. PMID- 26955564 TI - Computerized Analysis of Acoustic Characteristics of Patients with Internal Nasal Valve Collapse Before and After Functional Rhinoplasty. AB - Acoustic analysis of sounds produced during speech provides significant information about the physiology of larynx and vocal tract. The analysis of voice power spectrum is a fundamental sensitive method of acoustic assessment that provides valuable information about the voice source and characteristics of vocal tract resonance cavities. The changes in long-term average spectrum (LTAS) spectral tilt and harmony to noise ratio (HNR) were analyzed to assess the voice quality before and after functional rhinoplasty in patients with internal nasal valve collapse. Before and 3 months after functional rhinoplasty, 12 participants were evaluated and HNR and LTAS spectral tilt in /a/ and /i/ vowels were estimated. It was seen that an increase in HNR and a decrease in LTAS spectral tilt existed after surgery. Mean LTAS spectral tilt in vowel /a/ decreased from 2.37 +/- 1.04 to 2.28 +/- 1.17 (P = 0.388), and it was decreased from 4.16 +/- 1.65 to 2.73 +/- 0.69 in vowel /i/ (P = 0.008). Mean HNR in the vowel /a/ increased from 20.71 +/- 3.93 to 25.06 +/- 2.67 (P = 0.002), and it was increased from 21.28 +/- 4.11 to 25.26 +/- 3.94 in vowel /i/ (P = 0.002). Modification of the vocal tract caused the vocal cords to close sufficiently, and this showed that although rhinoplasty did not affect the larynx directly, it changes the structure of the vocal tract and consequently the resonance of voice production. The aim of this study was to investigate the changes in voice parameters after functional rhinoplasty in patients with internal nasal valve collapse by computerized analysis of acoustic characteristics. PMID- 26955566 TI - A Novel Method for Pulsometry Based on Traditional Iranian Medicine. AB - Arterial pulse measurement is one of the most important methods for evaluation of healthy conditions. In traditional Iranian medicine (TIM), physician may detect radial pulse by holding four fingers on the patient's wrist. By using this method, under standard condition, the detected pulses are subjective and erroneous, in case of weak and/or abnormal pulses, the ambiguity of diagnosis may rise. In this paper, we present an equipment which is designed and implemented for automation of traditional pulse detection method. By this novel system, the developed noninvasive diagnostic method and database based on the TIM are way forward to apply traditional medicine and diagnose patients with present technology. The accuracy for period measuring is 76% and systolic peak is 72%. PMID- 26955567 TI - A New Method to Segment the Multiple Sclerosis Lesions on Brain Magnetic Resonance Images. AB - Automatic segmentation of multiple sclerosis (MS) lesions in brain magnetic resonance imaging (MRI) has been widely investigated in the recent years with the goal of helping MS diagnosis and patient follow-up. In this research work, Gaussian mixture model (GMM) has been used to segment the MS lesions in MRIs, including T1-weighted (T1-w), T2-w, and T2-fluid attenuation inversion recovery. Usually, GMM is optimized by using expectation-maximization (EM) algorithm. The drawbacks of this optimization method are, it does not converge to optimal maximum or minimum and furthermore, there are some voxels, which do not fit the GMM model and have to be rejected. So, GMM is time-consuming and not too much efficient. To overcome these limitations, in this research study, at the first step, GMM was applied to segment only T1-w images by using 100 various starting points when the maximum number of iterations was considered to be 50. Then segmentation results were used to calculate the parameters of the other two images. Furthermore, FAST-trimmed likelihood estimator algorithm was applied to determine which voxels should be rejected. The output result of the segmentation was classified in three classes; White and Gray matters, cerebrospinal fluid, and some rejected voxels which prone to be MS. In the next phase, MS lesions were detected by using some heuristic rules. This new method was applied on the brain MRIs of 25 patients from two hospitals. The automatic segmentation outputs were scored by two specialists and the results show that our method has the capability to segment the MS lesions with dice similarity coefficient score of 0.82. The results showed a better performance for the proposed approach, in comparison to those of previous works with less time-consuming. PMID- 26955568 TI - Estimation of Organ Activity using Four Different Methods of Background Correction in Conjugate View Method. AB - To make an accurate estimation of the uptake of radioactivity in an organ using the conjugate view method, corrections of physical factors, such as background activity, scatter, and attenuation are needed. The aim of this study was to evaluate the accuracy of four different methods for background correction in activity quantification of the heart in myocardial perfusion scans. The organ activity was calculated using the conjugate view method. A number of 22 healthy volunteers were injected with 17-19 mCi of (99m)Tc-methoxy-isobutyl-isonitrile (MIBI) at rest or during exercise. Images were obtained by a dual-headed gamma camera. Four methods for background correction were applied: (1) Conventional correction (referred to as the Gates' method), (2) Buijs method, (3) BgdA subtraction, (4) BgdB subtraction. To evaluate the accuracy of these methods, the results of the calculations using the above-mentioned methods were compared with the reference results. The calculated uptake in the heart using conventional method, Buijs method, BgdA subtraction, and BgdB subtraction methods was 1.4 +/- 0.7% (P < 0.05), 2.6 +/- 0.6% (P < 0.05), 1.3 +/- 0.5% (P < 0.05), and 0.8 +/- 0.3% (P < 0.05) of injected dose (I.D) at rest and 1.8 +/- 0.6% (P > 0.05), 3.1 +/- 0.8% (P > 0.05), 1.9 +/- 0.8% (P < 0.05), and 1.2 +/- 0.5% (P < 0.05) of I.D, during exercise. The mean estimated myocardial uptake of (99m)Tc-MIBI was dependent on the correction method used. Comparison among the four different methods of background activity correction applied in this study showed that the Buijs method was the most suitable method for background correction in myocardial perfusion scan. PMID- 26955569 TI - Ethics committee minutes: Heart of ethics committee quality. PMID- 26955570 TI - Early access programs: Benefits, challenges, and key considerations for successful implementation. AB - Early access programs, (EAPs) are adopted by an increasing number of pharma companies due to several benefits offered by these programs. EAPs offer ethical, compliant, and controlled mechanisms of access to investigational drugs outside of the clinical trial space and before the commercial launch of the drug, to patients with life-threatening diseases having no treatment options available. In addition to the development of positive relationships with key opinion leaders (KOL), patients, advocacy groups and regulators, the data captured from the implementation of EAPs supports in the formulation of global commercialization strategies. This white paper outlines various circumstances to be considered for the implementation of EAPs named patient programs, the regulatory landscape, the benefits and challenges associated with implementing these programs and the key considerations for their successful implementation. PMID- 26955571 TI - Comparative effectiveness research and its utility in In-clinic practice. AB - One of the important components of patient-centered healthcare is comparative effectiveness research (CER), which aims at generating evidence from the real life setting. The primary purpose of CER is to provide comparative information to the healthcare providers, patients, and policy makers about the standard of care available. This involves research on clinical questions unanswered by the explanatory trials during the regulatory approval process. Main methods of CER involve randomized controlled trials and observational methods. The limitations of these two methods have been overcome with the help of new statistical methods. After the evidence generation, it is equally important to communicate the results to all the interested organizations. CER is beginning to have its impact in the clinical practice as its results become part of the clinical practice guidelines. CER will have far-reaching scientific and financial impact. CER will make both the treating physician and the patient equally responsible for the treatment offered. PMID- 26955572 TI - Sodium glucose co-transporter 2 inhibitors for glycemic control in type 2 diabetes mellitus: Quality of reporting of randomized controlled trials. AB - BACKGROUND: Sodium glucose co-transporter 2 inhibitors represent a novel class of antidiabetic drugs. The reporting quality of the trials evaluating the efficacy of these agents for glycemic control in type 2 diabetes mellitus has not been explored. Our aim was to assess the reporting quality of such randomized controlled trials (RCTs) and to identify the predictors of reporting quality. MATERIALS AND METHODS: A systematic literature search was conducted for RCTs published till 12 June 2014. Two independent investigators carried out the searches and assessed the reporting quality on three parameters: Overall quality score (OQS) using Consolidated Standards of Reporting Trials (CONSORT) 2010 statement, Jadad score and intention to treat analysis. Inter-rater agreements were compared using Cohen's weighted kappa statistic. Multivariable linear regression analysis was used to identify the predictors. RESULTS: Thirty-seven relevant RCTs were included in the present analysis. The median OQS was 17 with a range from 8 to 21. On Jadad scale, the median score was three with a range from 0 to 5. Complete details about allocation concealment and blinding were present in 21 and 10 studies respectively. Most studies lacked an elaborate discussion on trial limitations and generalizability. Among the factors identified as significantly associated with reporting quality were the publishing journal and region of conduct of RCT. CONCLUSIONS: The key methodological items remain poorly reported in most studies. Strategies like stricter adherence to CONSORT guidelines by journals, access to full trial protocols to gain valuable information and full collaboration among investigators and methodologists might prove helpful in improving the quality of published RCT reports. PMID- 26955573 TI - Clinical and economic outcomes of Acinetobacter vis a vis non-Acinetobacter infections in an Indian teaching hospital. AB - CONTEXT: Acinetobacter infections are a major nosocomial infection causing epidemics of infection in the Intensive Care Units (ICU). AIMS: This study estimates the clinical and economic outcomes of Acinetobacter infections and compares them with those of non-Acinetobacter bacterial infections. SETTINGS AND DESIGN: Prospective cross-sectional observational study carried out for 6 months in the medicine ICU of a tertiary care hospital. MATERIALS AND METHODS: Patients were divided in two groups, one group with Acinetobacter infections and the other with non-Acinetobacter infections. The data was collected for infection, length of stay (LOS), mortality and cost along with patient demographics from the hospital records for analysis. STATISTICAL ANALYSIS USED: The data was analyzed using Statistical Package for the Social Sciences Version 15.0. The LOS and cost of treatment (COT) for the two groups were compared using the nonparametric Mann Whitney U-test. RESULTS: A total of 220 patients were studied out of which 91 had Acinetobacter infections. The median LOS was 20 days in Group-A and 12 days in Group-B (P < 0.0001). The median COT was INR 125,862 in Group-A and INR 68,228 in the Group-B (P < 0.0001). Mortality in Group-A and Group-B was 32.97 and 32.56 (P = 0.949) respectively. CONCLUSION: The burden of Acinetobacter infections in ICUs is increasing with the increase in LOS and COT for the patients. The infection control team has to play a major role in reducing the rate of nosocomial infections. PMID- 26955574 TI - Coping and caregiving experience of parents of children and adolescents with type 1 diabetes: An exploratory study. AB - AIMS: To assess the coping strategies and the relationship of coping with subjective burden and positive caregiving consequences as perceived by the caregivers of children and adolescents with Type-1 diabetes. DESIGN: Cross sectional assessment. SETTING: Outpatient of Endocrinology Department. PARTICIPANTS: Forty-one parents of children and adolescents with Type-1 diabetes. MAIN OUTCOME MEASURE: Ways of coping checklist (WCC), involvement evaluation questionnaire (IEQ) and scale for assessment of positive aspects of caregiving experience (scale for positive aspects of caregiving experience) to study the coping, burden and positive aspects of caregiving respectively. RESULTS: On WCC, the highest score was obtained for seeking social support, followed by planful problem-solving. More frequent use of coping strategies of confrontation and escape-avoidance was associated with significantly higher score on the tension domain of IEQ. Those who more frequently used problem-solving and distancing had significantly higher scores on worrying-urging-I domain of IEQ. supervision domain of IEQ was associated with more frequent use of confrontation, self control, social support, escape-avoidance and positive reappraisal. More frequent use of distancing and problem-solving were associated with lower caregiving personal gains. More frequent use of problem-solving was associated with higher caregiver satisfaction and lower scores in the domain of self-esteem and social aspects of caring. CONCLUSION: Caregivers of patients with Type-1 diabetes predominantly use adaptive coping strategies. Higher use of certain coping strategies is associated with negative and positive caregiving consequences. PMID- 26955575 TI - Publication speed and advanced online publication: Are biomedical Indian journals slow? AB - OBJECTIVE: The aim of this study was to identify the publication speed (peer review time and publication time) of biomedical Indian journals and identify the journals having the facility of advance online publication (AOP). MATERIALS AND METHODS: Biomedical Indian journals were identified from the Journal Citation Report of 2013. Thirty original articles published between January 2012 and June 2014 were systematically selected from each journal. Information about the date of submission, revision, and acceptance were extracted from the full text of the articles. Median peer review time (submission to acceptance) and publication time (acceptance to AOP/electronic publication) were calculated for each journal. RESULTS: Of the 19 journals studied, 5 (26.3%), 15 (78.9%), and 6 (31.6%) journals did not mention details about date of submission, date of revision, and date of acceptance, respectively. The individual median peer review time of the journals ranged from 87 to 377.5 days and the combined median peer review time (interquartile range) was 143.5 days (105.5, 238). The individual median publication time ranged from 14 to 349 days. The publication time for journals with AOP was significantly lesser (29.5 [19.6, 50.6] vs. 146.5 [126.5, 202.5]; P = 0.02) compared to journals without AOP. Impact factor of the journal did not correlate with the publication speed. The facility of AOP was provided by 6 (31.6%) journals. CONCLUSIONS: Overall, the peer review time and publication time of biomedical Indian journals included in our study seems to be fairly long. Less than one-third of biomedical Indian journals provide the facility of AOP. PMID- 26955576 TI - Efficacy and safety of escitalopram versus desvenlafaxine in the treatment of major depression: A preliminary 1-year prospective randomized open label comparative trial. AB - AIM AND OBJECTIVE: To compare efficacy and safety of escitalopram with desvenlafaxine in the treatment of major depression. MATERIALS AND METHODS: A total of 60 patients of depression were randomized into two groups after meeting inclusion criterion. In the first 3 weeks, escitalopram 10 mg/day was given and then 20 mg/day for the next 3 weeks in group 1 (n = 30). Desvenlafaxine in the first 3 weeks was given 50 mg/day and 100 mg/day for the next 3 weeks in group 2 (n = 30). The parameters evaluated during the study were efficacy assessments byHamilton Scale of Rating Depression (HAM-D), Hamilton Rating Scale of Anxiety (HAM-A), and Clinical Global Impression (CGI). Safety assessments were done by UKU-scale. RESULTS: Escitalopram and desvenlafaxine significantly (P < 0.001), reduced HAM-D, HAM-A, and CGI scores from their respective base lines. However, on comparison failed show any statistical difference at 3 and 6 weeks of treatment. Escitalopram and desvenlafaxine were both found to be safe and well tolerated and there was not much difference between the two groups as evident from UKU Scale and their effect on various biochemical parameters. CONCLUSION: The present study demonstrated similar efficacy and safety in reducing depression and anxiety with both escitalopram and desvenlafaxine, but clinical superiority of one drug over the other cannot be concluded due to limitations of the small sample size. PMID- 26955577 TI - "Settlement Agreement" a new controversial agreement. PMID- 26955578 TI - Greetings from the desk of Editor-in-Chief. PMID- 26955579 TI - Scholarships, grants, and training opportunities for dermatology residents in India by Indian Association of Dermatologists, Venereologists and Leprologists. PMID- 26955580 TI - Position statement for the use of omalizumab in the management of chronic spontaneous urticaria in Indian patients. AB - Chronic spontaneous urticaria (CSU) affects 1% of the world population and also their quality of life, and 50% of these patients are refractory to H1 antihistamines. Omalizumab is a humanized monoclonal anti-IgE antibody that binds with free IgE antibodies and reduces the circulating levels of free IgE. This reduction in free IgE prevents mast-cell degranulation. The EAACI/GA2LEN/EDF/WAO guidelines recommend omalizumab as the third-line of therapy as an add-on to antihistamines. The recommended dose of omalizumab is 300 mg, 4 weekly in the management of CSU refractory to standard of care with H1-antihistamines in adults and adolescents >=12 years of age. In some patients, a dose of 150 mg may be acceptable. Omalizumab has a good safety profile. However, due to the biologic nature of the drug, all patients administered omalizumab must be observed for 2 h after administration for anaphylactoid reactions. There have been no studies on the effect of impaired renal or hepatic function on the pharmacokinetics of omalizumab. While no particular dose adjustment is recommended, omalizumab should be administered with caution in these patients. PMID- 26955581 TI - Photopatch and UV-irradiated patch testing in photosensitive dermatitis. AB - BACKGROUND: The photopatch test is used to detect photoallergic reactions to various antigens such as sunscreens and drugs. Photosensitive dermatitis can be caused due to antigens like parthenium, fragrances, rubbers and metals. The photopatch test does not contain these antigens. Therefore, the Indian Standard Series (ISS) along with the Standard photopatch series from Chemotechnique Diagnostics, Sweden was used to detect light induced antigens. AIM: To detect light induced antigens in patients with photosensitive dermatitis. METHODS: This study was done in a descriptive, observer blinded manner. Photopatch test and ISS were applied in duplicate on the patient's back by the standard method. After 24 hours, readings were recorded according to ICDRG criteria. One side was closed and other side irradiated with 14 J/cm(2) of UVA and a second set of readings were recorded after 48 hrs. RESULT: The highest positivity was obtained with parthenium, with 18 out of 35 (51%) patients showing a positive patch test reaction with both photoallergic contact dermatitis and photoaggravation. Four patients (11%) showed positive patch test reaction suggestive of contact dermatitis to potassium dichromate and fragrance mix. Six patients had contact dermatitis to numerous antigens such as nickel, cobalt, chinoform and para phenylenediamine. None of these patients showed photoaggravation on patch testing. CONCLUSION: Parthenium was found to cause photoallergy, contact dermatitis with photoaggravation and contact allergy. Hence, photopatch test and UV irradiated patch test can be an important tool to detect light induced antigens in patients with photosensitive dermatitis. PMID- 26955582 TI - Reticulin immunostaining revisited. AB - INTRODUCTION: Reticulin staining has been suggested as an inexpensive tool in the differential diagnosis of melanoma versus benign nevi. In the present study, reticulin immunostaining patterns in malignant melanomas, benign intradermal nevi, and blue nevi were observed. The concordance in evaluation of the pattern between observers was also done. MATERIALS AND METHODS: A retrospective search was performed in the computer database of the Ackerman Academy of Dermatopathology for "melanoma," "melanocytic nevus," and "blue nevus". Fifty-six melanomas (30 of nodular subtype and 26 of superficial spreading subtype), 54 benign compound nevi, and 27 blue nevi were selected for the study. Patterns of reticulin staining in the dermis and the basement membrane in these melanocytic lesions were evaluated and the concordance between the two groups of authors was assessed. Statistical evaluation was performed with the Statistica((r)) 10 program, Tulsa, OK. Concordance of the pattern evaluation was evaluated using Cohen's kappa coefficient. RESULTS: Melanomas show a variable basement membrane pattern some of which show flat, thin and smooth pattern. Benign nevi almost never showed this flat pattern at the basement membrane zone. In the dermis, melanomas showed reticulin fibers surrounding groups of melanocytic cells while nevi predominantly had reticulin fibers around individual cells. There was greater agreement in evaluating the dermal component compared to the basement membrane pattern. CONCLUSION: The dermal reticulin staining pattern may be of some value in the diagnosis of melanocytic lesions, but poor concordance in evaluation of the basement membrane zone pattern limits its usefulness. PMID- 26955583 TI - Purpura fulminans secondary to rickettsial infections: A case series. AB - Purpura fulminans (PF) is a descriptive term used to describe a heterogeneous group of disorders characterized by rapidly progressive purpuric lesions that may develop into extensive areas of skin necrosis, and peripheral gangrene. This rare disorder is associated with laboratory evidence of consumptive coagulopathy and is often fatal. PF is usually associated with many infections, most notably with meningococcal, staphylococcal, and streptococcal infections. However, there are very few reports of this entity with spotted fever and scrub typhus from India. Rickettsial infections are an underdiagnosed group of diseases presenting as acute febrile illness, with high mortality in untreated cases. Of the available tests, Weil-Felix is a handy and economical tool for early diagnosis of this fatal disease especially in resource poor settings. We present four infants with PF secondary to rickettsial fever diagnosed by the Weil-Felix test. PMID- 26955584 TI - Hansen's disease in association with immune reconstitution inflammatory syndrome. AB - Immune reconstitution inflammatory syndrome is characterized by a paradoxical worsening of an existing infection or disease process, soon after initiation of highly active antiretroviral therapy. The first case of leprosy presenting as immune reconstitution inflammatory syndrome was published in 2003. Here we report a case of Hansen's disease borderline tuberculoid presenting with type 1 lepra reaction 5 months after initiation of highly active antiretroviral therapy. PMID- 26955585 TI - Dowling-Degos disease with reticulate acropigmentation of Kitamura: Extended spectrum of a single entity. AB - Dowling-Degos disease (DDD) and reticulate acropigmentation of Kitamura (RAK) are rare genodermatoses inherited as an autosomal dominant trait with variable penetrance. They are considered to be part of a spectrum of reticulate pigmentary dermatoses, characterized by the presence of hyperpigmented macules coalescing in a reticular fashion. The authors describe a 28-year-old male patient having hyperpigmented macules on the axillae, neck and face, reticulate acropigmentation of dorsum of the hands, forearms and feet, palmar pitting, and comedo-like lesions over back. The patient showed the unique clinical as well as histopathological overlap of both the rare diseases (DDD and RAK), substantiating the hypothesis that they represent two different features of a single entity with variable phenotypic expression. PMID- 26955586 TI - Ecthyma gangrenosum in the periorbital region in a previously healthy immunocompetent woman without bacteremia. AB - Ecthyma gangrenosum (EG) is a cutaneous lesion classically associated with potentially fatal Pseudomonas septicemia in immunocompromised patients. Other bacterial and fungal pathogens have also been implicated. Although EG typically occurs in immunocompromised or neutropenic patients, it may occasionally affect a previously healthy person. The cutaneous findings are characteristic with small indurated papulovesicles progressing rapidly to necrotic ulcers with surrounding erythema and a central black Eschar. While lesions can occur at any site, most are commonly found over the buttocks, perineum, limbs, and axillae. We describe a case of EG in periorbital region in a previously healthy woman who responded to appropriate antibiotic treatment for Pseudomonas. It is very important to establish the diagnosis early so that appropriate systemic antibiotic therapy can be initiated to reduce morbidity and potential mortality. PMID- 26955587 TI - Cutaneous collagenous vasculopathy: A rare case report. AB - Cutaneous collagenous vasculopathy (CCV) is a distinct, rare, and underdiagnosed condition. We report a case of CCV in a 50-year-old woman presenting as asymptomatic, erythematous to hyperpigmented nonblanchable macules over both the lower extremities. The clinical differential diagnosis of the lesions was pigmented purpuric dermatoses (Schamberg's purpura) and cutaneous small vessel vasculitis. Histology of the lesions revealed dilated superficial dermal vessels with abundant pink hyaline material in the vessel wall, which stained with periodic acid Schiff stain. The patient was diagnosed as CCV. This condition remains largely underdiagnosed and is commonly mistaken for pigmented purpuric dermatosis or generalized essential telangiectasia. Emphasis on the differentiation of CCV from its clinical and histological mimicks is made. PMID- 26955589 TI - Loose anagen hair syndrome: Is there any association with atopic dermatitis? PMID- 26955588 TI - Subcutaneous emphysema mimicking angioedema. PMID- 26955590 TI - Alopecia universalis in a patient with Sheehan's syndrome. PMID- 26955592 TI - Tuberculosis verrucosa cutis with multifocal involvement. PMID- 26955591 TI - More angioedema from instant coffee, but not from caffeine. PMID- 26955593 TI - Tufted angioma. PMID- 26955594 TI - SkIndia Quiz 22: Scalp Tumor. PMID- 26955595 TI - Painful wart in the ear? PMID- 26955596 TI - Lymphangioma circumscriptum of the male genitalia. PMID- 26955597 TI - Erratum: Lymphomatoid contact dermatitis associated with textile dye at an unusual location. PMID- 26955598 TI - Avicenna Journal of Medicine: 5-year milestones. PMID- 26955599 TI - Analytic hierarchy process as module for productivity evaluation and decision making of the operation theater. AB - The analytic hierarchy process (AHP) is a theory of measurement through pairwise comparisons and relies on the judgments of experts to derive priority scales, these scales that measure intangibles in relative terms. The aim of the article was to develop a model for productivity measurement of the operation theater (OT), which could be applied as a model for quality improvement and decision making. AHP is used in this article to evolve such a model. The steps consist of identifying the critical success factors for measuring the productivity of OT, identifying subfactors that inflauence the critical factors, comparing the pairwise, deriving their relative importance and ratings, and calculating the cumulative effect according to the attributes in OT. The cumulative productivitycan be calculated by the end and can be compared Ideal productivity to measure the productive of OT in percentage fraction. Hence, the productivity could be calculated. Hence, AHP is a very useful model to measure the productivity in OT. PMID- 26955602 TI - Nanocosmeceuticals: A boon to personal care products. PMID- 26955601 TI - Image-guided ureteral reconstruction using rendezvous technique for complex ureteric transection after gunshot injuries. AB - Management of complex ureteric transection poses a significant clinical challenge, particularly after gunshot injuries due to marked distortion of anatomy and associated tissue loss. We report two cases of total ureteric transection due to gunshot injury successfully repaired using fluoroscopy-guided rendezvous procedure and double J stent placement. This minimally invasive approach may offer a safe and effective technique to repair complete ureteral transection and obviate the need for complex surgical procedures. PMID- 26955600 TI - The current approach of atrial fibrillation management. AB - Atrial fibrillation (AF) is the most commonly encountered arrhythmia in clinical practice. Aging populations coupled with improved outcomes for many chronic medical conditions has led to increases in AF diagnoses. AF is also known to be associated with an increased risk of adverse events such as transient ischemic attack, ischemic stroke, systemic embolism, and death. This association is enhanced in select populations with preexisting comorbid conditions such as chronic heart failure. The aim of this review is to highlight the advances in the field of cardiology in the management of AF in both acute and long-term settings. We will also review the evolution of anticoagulation management over the past few years and landmark trials in the development of novel oral anticoagulants (NOACs), reversal agents for new NOACs, nonpharmacological options to anticoagulation therapy, and the role of implantable loop recorder in AF management. PMID- 26955603 TI - Quantification of residual enrofloxacin and ciprofloxacin in feathers of broiler chickens by high-performance liquid chromatography-fluorescence after oral administration of the drugs. AB - Enrofloxacin (ENR) and ciprofloxacin (CIP) are drugs used in poultry feeding. In general, feathers that are incorporated in the food chain as a protein source for animal feed, have residues of these drugs. In order to study the pharmacokinetic of ENR/CIP residues in feathers of broiler chickens, to calculate the waiting times for these drugs, before human consumption, we developed the present research. Feathers of broiler chickens were enriched with ENR/CIP. After adding acetone, the mix was agitated and centrifuged and supernatant evaporated under nitrogen. The dry residue was suspended in a tetrahydrofuran solution and the supernatant was injected into the chromatographic system for analysis. Animals showed high levels of ENR/CIP in their feathers after administration of 10 mg/kg enrofloxacin dissolved in drinking water for 5 days. Both compounds were detected in feathers during 9 days. The analytical method developed in this paper to determine ENR and CIP in feathers of broiler chicken showed good linearity, selectivity, accuracy and precision in the analysis conditions. This technique could have important applications in the studies on residues of ENR/CIP in feathers, since the effect of this component in animal diets has not been considered yet. PMID- 26955605 TI - The effect of pomegranate mouthrinse on Streptococcus mutans count and salivary pH: An in vivo study. AB - Herbal mouthwashes have been considered to be a more advantageous option to their chemical counterparts, for a long-time. The use of pomegranate fruit dates from ancient times and reports of its therapeutic abilities have echoed throughout the ages. To evaluate the effect on the salivary pH and the Streptococcus mutans count in healthy subjects before and after pomegranate mouthrinse. Fifty healthy patients were randomly divided into two groups of 25 subjects each. Group A was treated with 0.2% chlorhexidine mouthrinse; while Group B was treated with pomegranate peel extract (PPE) mouthrinse and the saliva samples were collected at three different intervals: Prerinse, after 10 min, and 60 min. The salivary pH was measured using a digital pH meter and the S. mutans count was determined by the commercial system Dentocult SM. The statistical analyses used in this study are Mann-Whitney U-test and t-test. PPE mouthrinse had an inhibitory effect on S. mutans count in adults. There was also an increase in the salivary pH after 10 min of the mouthrinse. PPE mouthrinse may be considered as a potential anticariogenic mouthrinse. PMID- 26955604 TI - Thermodynamics of dissolution and infrared-spectroscopy of solid dispersions of phenacetin. AB - In this work enthalpies of dissolution in water of polyethylene glycols (PEGs) having an average molecular weight of 1000 and 1400, Pluronic-F127, phenacetin as well as the composites prepared from them were measured using solution calorimetry at 298.15 K. Intermolecular interaction energies of polymer phenacetin were calculated on the basis of an additive scheme. It was shown that for mixtures with high content of polymer (>90 wt%) Pluronic-F127 has the highest solubilizing effect, while for mixtures with (4-6):1 polymer: phenacetin ratio the best solubilizing agent is PEG-1400. Infrared-spectra showed a decrease of the number of self-associated molecules of phenacetin with increasing of polymer content in the composites. The obtained results enabled us to identify the features of intermolecular interactions of polymers with a model hydrophobic drug and may be used for optimizing the conditions for preparing solid dispersions based on hydrophilic polymers. PMID- 26955606 TI - Application of critical path analysis in clinical trials. AB - Clinical research operates in a strictly regulated environment under various management models, but a distinct management model of clinical trial (CT) still needs exploration and research. Critical path analysis (CPA) is a management approach can be used for monitoring, analysis, and prediction of success of its time-bound operational activities. A model CT was compiled with 78 activities, which were further merged into 35 major activities. After performing dependence analysis, the list was finalized with 25 activities which were taken in activity predecessor to create a network diagram and perform CPA considering patients, conduct, and outcome. Activities were inclusive, described the trial entirely with accuracy, and were in chronological and logical sequences. This approach does not replace an understanding of or adherence to the requirements contained in all applicable regulations, guidelines or standard operating procedures governing clinical studies but ensures the proper use of operational and decisional approaches including optimal resource management. As the need to meet deadlines becomes more important and the need to produce good, stable project plans, CPA is very useful for determining activities that can lead to project delay. With this approach, project may be effectively monitored, and realistic schedules can be maintained. PMID- 26955607 TI - Atorvastatin solid dispersion for bioavailability enhancement. AB - Atorvastatin calcium is a lipid-lowering agent. It has approximately 15% of bioavailability, remaining amount of drug showed adverse effect which is undesirable for patients. The objective of the study was to enhance the solubility and a dissolution profile of the atorvastatin (AT) calcium. Solid dispersion (SD) is a technique which enhances the solubility and a dissolution profile of poorly soluble drug. Various methods are being used for SDs such as microwave irradiation fusion, kneading, solvent evaporation, fusion, and dropping method. The authors have used here conventional fusion method using PEG 4000 as a hydrophilic carrier. The solubility of pure drug, physical mixture using PEG 4000 (1:3), and SD in phosphate buffer solutions (pH 6.8) was found to be 55.33 +/- 0.66, 81.89 +/- 2.35, and 93.66 +/- 1.35, respectively. Fourier transform infrared and differential scanning calorimetry study showed the significant peak shift of drug in SD. It indicated that the nature of drug had been changed from crystalline form to amorphous form due to conversion into SD formulation. The dissolution rate was significantly increased when the drug polyethylene glycol 4000 ratio was 1:3. The mean cumulative percentage drugs release from pure drug, physical mixture, marketed tablet, and SD at 1 h was 28.92 +/- 1.66%, 55.26 +/- 0.95%, 72.16 +/- 1.33%, and 91.66 +/- 1.65%, respectively. It was concluded that the solubility and dissolution profile of SD of AT calcium showed the enhancement of solubility and dissolution when compared with marketed preparations. PMID- 26955608 TI - Patient Satisfaction after Total Knee Arthroplasty. AB - Total knee arthroplasty (TKA) is one of the most successful and effective surgical options to reduce pain and restore function for patients with severe osteoarthritis. The purpose of this article was to review and summarize the recent literatures regarding patient satisfaction after TKA and to analyze the various factors associated with patient dissatisfaction after TKA. Patient satisfaction is one of the many patient-reported outcome measures (PROMs). Patient satisfaction can be evaluated from two categories, determinants of satisfaction and components of satisfaction. The former have been described as all of the patient-related factors including age, gender, personality, patient expectations, medical and psychiatric comorbidity, patient's diagnosis leading to TKA and severity of arthropathy. The latter are all of the processes and technical aspects of TKA, ranging from the anesthetic and surgical factors, type of implants and postoperative rehabilitations. The surgeon- and patient-reported outcomes have been shown to be disparate occasionally. Among various factors that contribute to patient satisfaction, some factors can be managed by the surgeon, which should be improved through continuous research. Furthermore, extensive discussion and explanation before surgery will reduce patient dissatisfaction after TKA. PMID- 26955609 TI - Imageless Navigation Versus Conventional Open Wedge High Tibial Osteotomy: A Meta Analysis of Comparative Studies. AB - PURPOSE: To summarize and compare radiological and clinical outcomes of open wedge high tibial osteotomy (HTO) using imageless computer-assisted navigation with conventional HTO. METHODS: A literature search of online register databases was conducted. The risk ratio (RR) of radiological outliers and mean differences in clinical outcomes were compared between navigated and conventional HTOs. Radiological results were evaluated by subgroup analyses according to the study period (concurrent/consecutive) and the use of locking fixation device. RESULTS: Seven comparative studies with a total sample size of 406 knees were included in this review. Radiographically, the mechanical axis [MA] was within the acceptable range (0 degrees -6 degrees ) in 83.7% of the navigation HTO group, showing significant difference from 62.1% of the conventional HTO group. Clinically, despite the forest plot demonstrating a general trend of favoring the navigation system, there were not sufficient studies to determine statistical significance in the meta-analysis. None of the subgroup analyses demonstrated significant differences in the RR of MA outliers. CONCLUSIONS: The present meta-analysis indicates that the use of navigation in open wedge HTO improves the precision of mechanical alignment by decreasing the incidence of outliers; however, the clinical benefit is not conclusive. Additionally, none of the subgroup analyses demonstrated significant difference in the RR of MA outliers. PMID- 26955610 TI - Changes in Femoral Posterior Condylar Offset, Tibial Posterior Slope Angle, and Joint Line Height after Cruciate-Retaining Total Knee Arthroplasty. AB - PURPOSE: Changes in the femoral posterior condylar offset (PCO), tibial posterior slope angle (PSA), and joint line height (JLH) after cruciate-retaining total knee arthroplasty (CR-TKA) were evaluated to determine their influence on the flexion angle. MATERIALS AND METHODS: A total of 125 CR-TKAs performed on 110 patients were retrospectively reviewed. Pre- and postoperative PCO, PSA, and JLH were compared using correlation analysis. Independent factors affecting the postoperative flexion angle of the knee were analyzed. RESULTS: The PCO was 28.2+/-2.0 mm (range, 24.5 to 33.1 mm) preoperatively and 26.7+/-1.8 mm (range, 22.2 to 31.2 mm) postoperatively (r=0.807, p<0.001). The PSA was 10.4 degrees +/ 4.9 degrees (range, 1.6 degrees to 21.2 degrees ) preoperatively and decreased to 4.9 degrees +/-2.0 degrees (2.2 degrees to 10.7 degrees ) postoperatively (r=-0.023, p=0.800). The JLH was 16.2+/-3.0 mm (range, 10.2 to 27.5 mm) preoperatively and 16.1+/-2.6 mm (range, 11.1 to 24.8 mm) postoperatively (r=0.505, p<0.001). None of the independent factors affected the flexion angle (p>0.291). CONCLUSIONS: Although the PCO and JLH did not change significantly after CR-TKA, the PSA decreased by 5.5 degrees with a small range of variation. Restoration of the PCO and JLH could promote optimization of knee flexion in spite of the decreased PSA after CR-TKA. PMID- 26955611 TI - Relationship between Mucoid Degeneration of the Anterior Cruciate Ligament and Posterior Tibial Slope in Patients with Total Knee Arthroplasty. AB - PURPOSE: The purpose was to analyze the relationship between posterior tibial slope (PTS) and mucoid degeneration of the anterior cruciate ligament (ACL) in patients with total knee arthroplasty. MATERIALS AND METHODS: Four hundred and twenty-four patients (24 males and 400 females; 636 knees) who received total knee arthroplasty for osteoarthritis were included. Their mean age was 68.9 years (range, 48 to 88 years). The patients were classified into three groups according to the status of ACL; normal ACL group (group I), mucoid degeneration of ACL group (group II) and ruptured or absent ACL group (group III). Plain lateral radiographs were used to measure the PTS and the values were compared among groups. RESULTS: There were no significant differences with regard to gender, age and left-to-right side ratio among groups (p>0.05). The mean PTS was 9.9 degrees (range, 0.6 degrees to 20.1 degrees ) in group I (161 knees), 10.8 degrees (range, 0.2 degrees to 21.8 degrees ) in group II (342 knees) and 12.3 degrees (range, 2 degrees to 22.2 degrees ) in group III (133 knees), which showed significant differences (p<0.001). CONCLUSIONS: The patients with mucoid degeneration of the ACL and those with ruptured or absent ACL had greater PTS than those with normal ACL. These findings suggest that an increased PTS may be one of the causative factors for mucoid degeneration of the ACL. PMID- 26955612 TI - Two- to Four-Year Follow-up Results of Total Knee Arthroplasty Using a New High Flexion Prosthesis. AB - PURPOSE: The purpose of this study was to evaluate minimum 2-year follow-up results of total knee arthroplasty (TKA) performed using a new high-flexion prosthesis design (LOSPA). MATERIALS AND METHODS: The 2- to 4-year results of 191 consecutive TKAs (177 patients) with the LOSPA posterior-stabilized prosthesis were evaluated. The patients were assessed clinically and radiographically using the Knee Society scoring system (KSS) and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). RESULTS: The mean range of motion (ROM) increased significantly from 117.4 degrees (range, 75 degrees to 140 degrees ) preoperatively to 126.7 degrees (range, 80 degrees to 144 degrees ) postoperatively (p<0.001). The mean KSS and WOMAC scores improved significantly from 121.4 (range, 42 to 185) and 56.1 (range, 23 to 88) preoperatively to 174.0 (range, 130 to 200) and 16.4 (range, 0 to 85) postoperatively, respectively (both, p<0.001). One knee required revision for deep infection. No knee had aseptic loosening or osteolysis. Radiolucent lines were noted in 15 knees (7.9%). CONCLUSIONS: The new high-flexion total knee prosthesis resulted in no early aseptic loosening of the component and improved postoperative ROM comparable to other high-flexion TKA prostheses at 2- to 4-year follow-ups. PMID- 26955613 TI - Radiological Stability after Revision of Infected Total Knee Arthroplasty Using Modular Metal Augments. AB - PURPOSE: To evaluate the radiological stability according to the number of modular augments after revision of infected total knee arthroplasty (TKA). MATERIALS AND METHODS: Between February 2006 and September 2013, 37 patients (39 knees) followed >=2 years after revision of infected TKA using modular metal augments for bone defects were reviewed retrospectively. We divided the patients into 3 groups according to the number of augments into group A (<=2 augments, 14 knees), group B (3-4 augments, 18 knees), and group C (5>= augments, 7 knees) and evaluated the width of radiolucent zones around the implant at the last follow up. RESULTS: There were 3 Anderson Orthopedic Research Institute type I, 33 type II, and 3 type III bone defects. The mean number of radiolucent zones of group A was 3 and the sum of width averaged 4.4 mm. In group B, the values were 4.8 and 6.2 mm, respectively. In group C, the values were 8.1 and 12.9 mm, respectively. The differences between the three groups were statistically significant. CONCLUSIONS: In revision TKA with modular metal augmentation caused by infected TKA, increased modularity can result in radiological instability. PMID- 26955614 TI - Correlation between Magnetic Resonance Imaging Characteristics of the Patellar Tendon and Clinical Scores in Osgood-Schlatter Disease. AB - PURPOSE: This study aims to evaluate magnetic resonance imaging (MRI) findings in young adults with symptomatic Osgood-Schlatter disease (OSD) and compare those in young adults without OSD. MATERIALS AND METHODS: We compared MRI findings between young adults with OSD (OS group, n=30) and the equivalent number of young adults without OSD (control group). Visual analog scale scores and Kujala scores were evaluated and correlation analysis was performed in the OS group. RESULTS: In the OS group, MRI revealed that the patellar tendon was attached to the tibia more widely, resulting in a reduced free tendon portion, and more proximally to the articular surface (p<0.001). The correlation analysis between MRI findings and clinical scores showed statistically significant correlations (p<0.01). In the OS group, 43% presented with patellar tendinopathy or bone marrow edema at the distal attachments. CONCLUSIONS: Compared to the control group, the relatively small free portion and relatively proximal attachment of the patellar tendon were observed with MRI in the OS group. The free portion of the patellar tendon was positively correlated with the clinical scores. Patellar tendinopathy was also frequently encountered in the OS group. PMID- 26955615 TI - Are "Patellofemoral Symptoms" Truly Related to the Patellofemoral Joint? AB - PURPOSE: The pattern of symptoms of knee osteoarthritis has been thought to be indicative of specific compartment involvement. This study investigated whether there was a true correlation between patellofemoral joint (PFJ) symptoms and unicompartmental patellofemoral arthritis. MATERIALS AND METHODS: A prospective analysis of 34 patients rendered to be suffering from PFJ osteoarthritis and subsequently undergoing unicompartmental patellofemoral arthroplasty (PFA) was performed. A control cohort of 32 patients suffering from medial tibiofemoral joint (MTFJ) osteoarthritis was included in the analysis. Four questions derived from the Oxford knee score questionnaire, traditionally deemed to be indicative of PFJ osteoarthritis, were combined to create a PFJ subscore and statistically analyzed for their potential relationship with PFJ osteoarthritis and outcomes following PFA. RESULTS: The PFJ subscore indicated slightly worse pathology in patients undergoing PFA compared to MTFJ replacement, but the difference was not significant (9.7 and 9.6, respectively; p=0.851). The improvement in PFJ symptoms was higher in those undergoing PFA compared to MTFJ surgery; however, the difference was not statistically significant (3.7 and 2.2 respectively, p=0.074). CONCLUSIONS: We were unable to prove that these symptoms were predictive of PFJ pathology in the preoperative setting, nor were they useful in interpreting which symptoms would likely improve following PFA. PMID- 26955616 TI - Magnetic Resonance Imaging Findings in Small Patella Syndrome. AB - Small patella syndrome (SPS) is characterized by aplasia or hypoplasia of the patella and pelvic girdle abnormalities, including bilateral absence or delayed ossification of the ischiopubic junction and infra-acetabular axe-cut notches. Here, we report a case of SPS in a 26-year-old female. Magnetic resonance image (MRI) showed a small patella with thick eccentric non-ossified patellar cartilage and femoral trochlear dysplasia with hypoplastic patellar undersurface. To our knowledge, this is the first report of MRI findings in SPS. MRI findings could be clinically relevant because elongation of the medial patellofemoral ligament and trochlear dysplasia with eccentric non-ossified patellar cartilage might lead to patellofemoral maltracking with an osteochondral lesion or acute dislocation or an extensor mechanism injury. Though the patient presented in this case report only had a gastrocnemius injury at the origin site, physicians should carefully examine abnormalities with MRI when an SPS patient has a trauma to the knee. PMID- 26955617 TI - Uncommon Primary Synovial Chondromatosis Involving Only the Infrapatellar Fat Pad in an Elderly Patient. AB - Primary synovial chondromatosis is a rare condition of idiopathic synovial chondrometaplasia and usually occurs during the third to fifth decades of life. Conversely, secondary synovial chondromatosis results from the growth of separated particles from articular cartilage or osteophytes in patients with joint diseases, such as degenerative osteoarthritis, and occurs mostly in elderly people. We describe here a 76-year-old male histopathologically confirmed as having primary synovial chondromatosis with no calcification of the infrapatellar fat pad (IFP) of the knee joint. To our knowledge, this is the first description of primary synovial chondromatosis of the knee joint confined to the IFP in a patient >60 years old. PMID- 26955618 TI - Lateral Knee Pain after Outside-in Anatomic Double-Bundle Anterior Cruciate Ligament Reconstruction Using the TightRope RT. AB - The anterior cruciate ligament (ACL) TightRope RT (TR) was recently introduced as a novel cortical suspension device for ACL reconstruction. It has an adjustable graft loop that gives the surgeon some advantages during ACL reconstruction. We report three patients who required removal of the TR after an outside-in anatomical ACL reconstruction because of lateral knee pain. We assumed that the knee pain was associated with friction between the TR button of the posterolateral bundle and iliotibial band (ITB). Placing the TR button close to the lateral epicondyle and tissue interposition between the TR button and lateral femoral cortex may be potential risk factors for ITB irritation. Therefore, we recommend not placing the TR button close to the top of the lateral epicondyle and reducing the tissue interposition between the TR button and lateral femoral cortex as much as possible. PMID- 26955619 TI - Hypoxia and Hypoxia-Inducible Factors in Leukemias. AB - Despite huge improvements in the treatment of leukemia, the percentage of patients suffering relapse still remains significant. Relapse most often results from a small number of leukemic stem cells (LSCs) within the bone marrow, which are able to self-renew, and therefore reestablish the full tumor. The marrow microenvironment contributes considerably in supporting the protection and development of leukemic cells. LSCs share specific niches with normal hematopoietic stem cells with the niche itself being composed of a variety of cell types, including mesenchymal stem/stromal cells, bone cells, immune cells, neuronal cells, and vascular cells. A hallmark of the hematopoietic niche is low oxygen partial pressure, indeed this hypoxia is necessary for the long-term maintenance of hematopoietic stem/progenitor cells. Hypoxia is a strong signal, principally maintained by members of the hypoxia-inducible factor (HIF) family. In solid tumors, it has been well established that hypoxia triggers intrinsic metabolic changes and microenvironmental modifications, such as the stimulation of angiogenesis, through activation of HIFs. As leukemia is not considered a "solid" tumor, the role of oxygen in the disease was presumed to be inconsequential and remained long overlooked. This view has now been revised since hypoxia has been shown to influence leukemic cell proliferation, differentiation, and resistance to chemotherapy. However, the role of HIF proteins remains controversial with HIFs being considered as either oncogenes or tumor suppressor genes, depending on the study and model. The purpose of this review is to highlight our knowledge of hypoxia and HIFs in leukemic development and therapeutic resistance and to discuss the recent hypoxia-based strategies proposed to eradicate leukemias. PMID- 26955621 TI - The use of urologic investigations among patients with traumatic spinal cord injuries. AB - OBJECTIVE: To assess the use of urologic investigations among traumatic spinal cord injury (TSCI) patients. METHODS: This is a retrospective cohort study from Ontario, Canada. We included all adult TSCI patients injured between 2002 and 2012. The primary outcome was the frequency of urodynamic testing, renal imaging, and cystoscopy. Primary exposure was the year of injury. The impact of age, sex, comorbidity, socioeconomic status, and lesion level was assessed with Cox regression models. RESULTS: One thousand five hundred and fifty one incident TSCI patients were discharged from a rehabilitation hospital. The median follow-up time of this cohort was 5.0 years (interquartile range =2.9-7.5). At least one urodynamics, renal imaging, or cystoscopy was performed during follow-up for 50%, 80%, and 48% of the cohort, respectively. The overall rate of these tests was 0.22, 0.60, and 0.22 per person-year of follow-up. The proportion of patients who had regular, yearly urodynamics (<2%), renal imaging (6%), or cystoscopy (<2%) was low. There were no significant linear trends in the use of these tests over the 10-year study period. Urodynamics were significantly less likely to be performed in patients over 65 years of age (hazard ratio [HR] =0.63, P<0.01) and those with a higher level of comorbidity (HR =0.72, P<0.01). Patients with quadriplegia were significantly less likely to receive any of the investigations compared to those with paraplegia. CONCLUSION: Renal imaging is done at least once for the majority of patients with TSCI; however, only half undergo urodynamics or cystoscopy. Few patients have regular urologic testing. The reality of urologic testing after TSCI is very different from urologist's ideals and practice guidelines. PMID- 26955620 TI - Phenotypic Characterization of a Novel Virulence-Factor Deletion Strain of Burkholderia mallei That Provides Partial Protection against Inhalational Glanders in Mice. AB - Burkholderia mallei (Bm) is a highly infectious intracellular pathogen classified as a category B biological agent by the Centers for Disease Control and Prevention. After respiratory exposure, Bm establishes itself within host macrophages before spreading into major organ systems, which can lead to chronic infection, sepsis, and death. Previously, we combined computational prediction of host-pathogen interactions with yeast two-hybrid experiments and identified novel virulence factor genes in Bm, including BMAA0553, BMAA0728 (tssN), and BMAA1865. In the present study, we used recombinant allelic exchange to construct deletion mutants of BMAA0553 and tssN (DeltaBMAA0553 and DeltaTssN, respectively) and showed that both deletions completely abrogated virulence at doses of >100 times the LD50 of the wild-type Bm strain. Analysis of DeltaBMAA0553- and DeltaTssN infected mice showed starkly reduced bacterial dissemination relative to wild type Bm, and subsequent in vitro experiments characterized pathogenic phenotypes with respect to intracellular growth, macrophage uptake and phagosomal escape, actin-based motility, and multinucleated giant cell formation. Based on observed in vitro and in vivo phenotypes, we explored the use of DeltaTssN as a candidate live-attenuated vaccine. Mice immunized with aerosolized DeltaTssN showed a 21 day survival rate of 67% after a high-dose aerosol challenge with the wild-type Bm ATCC 23344 strain, compared to a 0% survival rate for unvaccinated mice. However, analysis of histopathology and bacterial burden showed that while the surviving vaccinated mice were protected from acute infection, Bm was still able to establish a chronic infection. Vaccinated mice showed a modest IgG response, suggesting a limited potential of DeltaTssN as a vaccine candidate, but also showed prolonged elevation of pro-inflammatory cytokines, underscoring the role of cellular and innate immunity in mitigating acute infection in inhalational glanders. PMID- 26955622 TI - Gabapentin induces edema, hyperesthesia and scaling in a depressed patient; a diagnostic challenge. AB - Gabapentin is a common drug used as analgesic and anticonvulsant and also is prescribed for insomnia, depression, obsessive - compulsive disorder and panic attack. We report a case of a 48-year-old man who is prescribed gabapentin because of insomnia, headache, and depressed mood. In the first period of using the drug no complication has been seen. However in the next period, side-effects such as hyperesthesia, scaling and severe localized edema has been observed. After several laboratory tests and imaging, no reason was found for his edema. And after discontinuing gabapentin the pain and edema was quite relieved. We found out the brand of the drug has been switched in the second stage. The point which makes our study special is the incidence of side-effects such as severe edema, scaling and hyperesthesia for the first time because of using gabapentin and changing the drug combination. PMID- 26955623 TI - Effect of garlic powder consumption on body composition in patients with nonalcoholic fatty liver disease: A randomized, double-blind, placebo-controlled trial. AB - BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease that is becoming a public health problem in recent decades. Obesity and overweight play a key role in NAFLD pathogenesis. Thus, weight loss (especially body fat mass) is one component of therapeutic strategies in NAFLD. Results from experimental studies have shown that garlic (Allium sativum L.) can reduce body weight and body fat mass. However, the effect of garlic on body fat mass and weight in the human population, which is addressed in this study, is still obscure. MATERIALS AND METHODS: In this clinical trial, 110 subjects with NAFLD were randomly assigned to the intervention or the control group. The intervention group received two garlic tablets (containing 400 mg of garlic powder) daily while the control group received placebo tablets. Dietary intake and physical activity of participants were obtained by a validated questionnaire. Body composition was measured by bioelectrical impedance analysis. Data were analyzed using SPSS software version 16. RESULTS: In the intervention group, significant reductions were observed in body weight and body fat mass (P < 0.05). We also observed a significant reduction in body weight in the control group, but there were no significant changes in total body water and lean body mass in both groups (P > 0.05). In the intervention group, the percentage change in body weight was significantly greater than the control group (-2.6 vs. -0.7, P = 0.02). No serious side effects associated with the intervention were reported. CONCLUSION: Our trial suggests that garlic supplemfrom experimental studies have shown thatentation can reduce body weight and fat mass among subjects with NAFLD. PMID- 26955625 TI - Diagnostic validity of ultrasonography in evaluation of pulmonary thromboembolism. AB - BACKGROUND: Diagnosis of pulmonary embolism (PE) remains difficult due to its nonspecific symptoms and signs. Therefore, many patients die undiagnosed or untreated. We decided to study the sensitivity, specificity, and accuracy of ultrasonography in the diagnosis of pulmonary thromboembolism. MATERIALS AND METHODS: In this prospective study, 77 patients with clinically suspected PE in the emergency department of Isfahan Al-Zahra Hospital were enrolled from September 2011 to September 2012. At first, they were evaluated by thoracic ultrasonography (TUS) and then divided into four groups based on their TUS findings. Multi-slice computed tomography (MSCT) was the reference method in this study performed within 24 h from admission. MSCT scans were interpreted by a radiologist who was unaware of the TUS results. Sensitivity, specificity, positive predictive value (PPV), and negative predictive values (NPVs) of thoracic ultrasonography were determined. RESULTS: PE diagnosis was confirmed by MSCT in 25 patients and 54 hypoechoic lesions were detected by TUS with the average size of 16.4 mm * 11.1 mm. In our study, sensitivity, specificity, PPV, NPV, and accuracy of TUS for PE diagnosis were 84%, 94.2%, 87.5%, and 92.5%, respectively. CONCLUSION: TUS is an inexpensive, safe and easily available method for timely diagnosis and treatment of PE in emergency department and its NPV is high for cases with low scores for Wells criteria who had a normal or possible TUS findings. It is also specific in the diagnosis of PE in cases with high scores Wells criteria who have confirmed or probable TUS findings. PMID- 26955624 TI - Analysis and comparison of the effects of N-BiPAP and Bubble-CPAP in treatment of preterm newborns with the weight of below 1500 grams affiliated with respiratory distress syndrome: A randomised clinical trial. AB - BACKGROUND: Nowadays, establishment of nCPAP and surfactant administration is considered to be the first level of intervention for newborns engaged in the process of Respiratory Distress Syndrome (RDS). In order to decrease the side effects of the nCPAP management placed in noninvasive-non-cycled respiratory support. Noninvasive-cycled respiratory support mechanism have been developed such as N-BiPAP. Therefore, we compared N-BiPAP with Bubble-CPAP in a clinical trial. MATERIALS AND METHODS: This research was done as an on newborns weighing less than 1500 grams affiliated with RDS. A3 The total number of newborns was 70. Newborns were divided into two groups with the sample size of 35 patients in each, according to odd and even document numbers. One group was treated with N BiPAP and the other with Bubble-CPAP. Patients were compared according to the length of treatment with noninvasive respiratory support, length of oxygen intake, number of surfactant doses administered, need for invasive mechanical ventilation, apnea, patent ductus arteriosus (PDA), chronic lung disease, intraventricular hemorrhage, pneumothorax, and death. Data was recorded and compared. RESULTS: The average duration for noninvasive respiratory support and the average time of need to complementary oxygen was not significantly different in both groups (P value > 0.05). Need for invasive ventilation, also chronic lung disease, intraventricular hemorrhage (IVH), pneumothorax, need for the next dose of surfactant, and the death rate did also have no meaningful difference. (P value > 0.05). CONCLUSION: In this research N-BiPAP did not show any obvious clinical preference over the Bubble-CPAP in treatment of newborns weighing less than 1500 grams and affiliated with RDS. PMID- 26955626 TI - Endothelial dysfunction in patients with sudden sensorineural hearing loss. AB - BACKGROUND: Endothelial dysfunction probably has a role in the etiology of sudden sensorineural hearing loss (SSNHL). The aim of this study was determining of the relationship between endothelial dysfunction and SSNHL. MATERIALS AND METHODS: In a case-control study, 30 patients with SSNHL and 30 otherwise healthy age and sex matched controls were studied. Demographic data gathered included age, gender, family history of SSNHL, and history of smoking, cardiovascular disease, hypertension, diabetes, and dyslipidemia. Laboratory data included measurement of hemoglobin, fasting blood sugar (FBS) and lipid profile. Endothelial function was assessed by measuring flow-mediated dilation (FMD). RESULTS: The two groups were the same in age (47.9 +/- 9.3 and 48.1 +/- 9.6 years, P = 0.946) with female/male ratio of 1:1 in both groups. Diabetes and dyslipidemia were more frequent in patients than controls (20% vs. 0%, P = 0.024). Brachial artery diameter was greater in patients than controls before (4.24 +/- 0.39 vs. 3.84 +/- 0.23 mm, P < 0.001) and after ischemia (4.51 +/- 0.43 vs. 4.28 +/- 0.27 mm, P = 0.020), but FMD was lower in patients than controls (6.21 +/- 3.0 vs. 11.52 +/- 2.30%, P < 0.001). Binary logistic regression analysis showed that FMD was associated with SSNHL independent from FBS and lipid profile (odds ratio [95% confidence interval] =0.439 [0.260-0.740], P = 0.002). CONCLUSION: Endothelial dysfunction, among other cardiovascular risk factors, is associated with SSNHL. This association is independent from other cardiovascular risk factors including diabetes and dyslipidemia. PMID- 26955627 TI - Covering of fiber-reinforced composite bars by adhesive materials, is it necessary to improve the bond strength of lingual retainers? AB - OBJECTIVES: The objectives were to evaluate the shear bond strength (SBS) of fiber-reinforced composite (FRC) retainers when bonding them to teeth with and without covering the FRC bars using two different adhesive systems. MATERIALS AND METHODS: Hundred and twenty extracted human maxillary premolars were randomly divided into eight groups (n = 15). FRC bars (4 mm length, Everstick Ortho((r)), Stick Tech, Oy, Turku, Finland) were bonded to the proximal (distal) surfaces of the teeth using two different adhesives (Tetric Flow [TF, Ivoclar Vivadent, Switzerland] and resin-modified glass ionomer cement [RMGIC, ODP, Vista, CA, USA]) with and without covering with the same adhesive. Specimens were exposed to thermocycling (625 cycles per day [5-55 degrees C, intervals: 30 s] for 8 days). The SBS test was then performed using the universal testing machine (Zwick, GMBH, Ulm, Germany). After debonding, the remaining adhesive on the teeth was recorded by the adhesive remnant index (0-3). RESULTS: The lowest mean SBS (standard deviation) was found in the TF group without covering with adhesive (12.6 [2.11] MPa), and the highest bond strength was in the TF group with covering with adhesive (16.01 [1.09] MPa). Overall, the uncovered RMGIC (15.65 [3.57] MPa) provided a higher SBS compared to the uncovered TF. Covering of FRC with TF led to a significant increase in SBS (P = 0.001), but this was not true for RMGIC (P = 0.807). Thermal cycling did not significantly change the SBS values (P = 0.537). Overall, eight groups were statistically different (ANOVA test, F = 3.32, P = 0.034), but no significant differences in bond failure locations were found between the groups (Fisher's exact tests, P = 0.92). CONCLUSIONS: The present findings showed no significant differences between SBS of FRC bars with and without covering by RMGIC. However, when using TF, there was a significant difference in SBS measurements between covering and noncovering groups. Therefore, the use of RMGIC without covering FRC bars can be suggested, which can be validated with in vivo studies. PMID- 26955628 TI - Prevalence of snoring and facial profile type, malocclusion class and dental arch morphology among snorer and nonsnorer university population. AB - OBJECTIVES: The objectives of this study were to determine the prevalence of snoring in an adult male university population, and to test the null hypothesis that there is no difference in facial profile shape, malocclusion type, or palatal morphology among snorer and nonsnorer. MATERIALS AND METHODS: Berlin questionnaire was given to 840 students and employees aged 18-45 years (24 +/- 40). Both snorers and nonsnorers were assessed for the facial profile type, malocclusion type, and palatal morphology. Chi-square and Student's t-test were used to compare the difference between the two groups. RESULTS: The prevalence of snoring was 16.28%. The most frequent findings among snorer were straight profiles (52.0%), Class I malocclusion (74.7%), and V palatal shape (16.0%), respectively. The Chi-square test revealed a significant difference in terms of V shaped palatal morphology (P < 0.05); higher neck circumference (NC) (P < 0.007); upper arch length was significantly shorter (P < 0.038); and the inter- first upper premolar distance was significantly narrower (P < 0.013). CONCLUSION: The null hypothesis is rejected. Snoring in our university population is associated with V-shape palatal morphology, increased NC and decrease in the upper arch length, and inter- first upper premolar distance. PMID- 26955629 TI - Effect of acid etching on bond strength of nanoionomer as an orthodontic bonding adhesive. AB - AIMS: A new Resin Modified Glass Ionomer Cement known as nanoionomer containing nanofillers of fluoroaluminosilicate glass and nanofiller 'clusters' has been introduced. An in-vitro study aimed at evaluating shear bond strength (SBS) and adhesive remnant index (ARI) of nanoionomer under etching/unetched condition for use as an orthodontic bonding agent. MATERIAL AND METHODS: A total of 75 extracted premolars were used, which were divided into three equal groups of 25 each: 1-Conventional adhesive (Enlight Light Cure, SDS, Ormco, CA, USA) was used after and etching with 37% phosphoric acid for 30 s, followed by Ortho Solo application 2-nanoionomer (Ketac(TM) N100, 3M, ESPE, St. Paul, MN, USA) was used after etching with 37% phosphoric acid for 30 s 3-nanoionomer was used without etching. The SBS testing was performed using a digital universal testing machine (UTM-G-410B, Shanta Engineering). Evaluation of ARI was done using scanning electron microscopy. The SBS were compared using ANOVA with post-hoc Tukey test for intergroup comparisons and ARI scores were compared with Chi-square test. RESULTS: ANOVA (SBS, F = 104.75) and Chi-square (ARI, Chi-square = 30.71) tests revealed significant differences between groups (P < 0.01). The mean (SD) SBS achieved with conventional light cure adhesive was significantly higher (P < 0.05) (10.59 +/- 2.03 Mpa, 95% CI, 9.74-11.41) than the nanoionomer groups (unetched 4.13 +/- 0.88 Mpa, 95% CI, 3.79-4.47 and etched 9.32 +/- 1.87 Mpa, 95% CI, 8.58-10.06). However, nanoionomer with etching, registered SBS in the clinically acceptable range of 5.9-7.8 MPa, as suggested by Reynolds (1975). The nanoionomer groups gave significantly lower ARI values than the conventional adhesive group. CONCLUSION: Based on this in-vitro study, nanoionomer with etching can be successfully used as an orthodontic bonding agent leaving less adhesive remnant on enamel surface, making cleaning easier. However, in-vivo studies are needed to confirm the validity of present findings. PMID- 26955630 TI - Intensity of pain due to separators in adolescent orthodontic patients. AB - OBJECTIVE: To investigate the intensity of pain adolescent orthodontic patients experience following the insertion of separators. MATERIALS AND METHODS: Elastomeric separators were placed mesially and distally to the first molars in 62 adolescents (20 male, 42 female, age 12-15 years), and the participants were given self-administrated questionnaires to document perceived pain, pain upon chewing, and the severity of pain's affecting daily life, using a visual analog scale for seven days. RESULTS: The mean perceived pain scores out of 100 on the first 3 days were 54.6 +/- 32.7, 51.7 +/- 29.9, and 32.3 +/- 28.4, respectively; chewing pain scores were: 61.9 +/- 35.3, 52.6 +/- 30.4, and 39.5 +/- 32.1, respectively; the pain's affecting daily life scores were 24.9 +/- 35.5, 21.1 +/- 30.9, and 11.9 +/- 23.7, respectively. A Kruskal-Wallis test showed a statistically significant difference in the reported pain between the three studied parameters. A Mann-Whitney U-test showed an insignificant difference between male and female adolescents. CONCLUSION: Pain perception varies among adolescent patients, but it decreases significantly after the first 2 days, with no gender differences. PMID- 26955631 TI - Real-Time PCR Assay for the Identification of the Brown Marmorated Stink Bug (Halyomorpha halys). AB - The brown marmorated stink bug, Halyomorpha halys (Hemiptera: Pentatomidae), is a gregarious crop pest that has rapidly spread across the world in the last two decades. It is an excellent hitchhiker species, especially as an over-wintering adult. During this period it is often associated with non-biological commodities such as shipping containers and machinery that travel long distances. Inadequate identification keys and similarity to common species has assisted its spread across Europe, while accurate identification from immature stages or eggs is not possible. We developed a real-time TaqMan PCR assay for the accurate and sensitive detection of the brown marmorated stink bug from all life stages. The assay performance against required diagnostic criterion and within a quarantine framework are described. PMID- 26955632 TI - Macrophage Infiltration into the Glomeruli in Lipoprotein Glomerulopathy. AB - Lipoprotein glomerulopathy (LPG) is characterized by histopathological features showing intra-glomerular lipoprotein thrombi and type III hyperlipoproteinemia (HLP), with heterozygote mutation of apolipoprotein (apo) E gene. On the other hand, as another renal lipidosis with type III HLP, apoE2 homozygote-related glomerulopathy (apoE2-GN) showing foamy macrophages has been reported. The case of a 25-year-old man who had LPG by clinical behavior and gene analysis, but demonstrated atypical histopathological features with a substantial amount of foamy macrophage infiltration in the glomeruli, is presented. The combination of alleles for apoE Tokyo/Maebashi and classical apoE2 (Arg158Cys) was inferred to be the leading cause of the unique renal pathology with lipoprotein thrombi and foamy macrophages. In addition, foamy macrophages infiltrated some part of the apoE-positive region within the glomerulus, but did not exist in lipoprotein thrombi despite apoE positivity, suggesting that properties of apoE are crucial in the development of LPG rather than macrophage function. This case provides important information related to the pathogenesis of LPG and apoE2-GN. PMID- 26955633 TI - Suggested Cut-Off Values for Vitamin D as a Risk Marker for Total and Cardiac Death in Patients with Suspected Acute Coronary Syndrome. AB - BACKGROUND: Several studies have demonstrated an association between low vitamin D levels and cardiovascular risk. Vitamin D cut-off levels are still under debate. OBJECTIVES: To assess two cut-off levels, 40 and 70 nmol/L, respectively, for vitamin D measured as 25-hydroxyvitamin D in chest pain patients with suspected acute coronary syndrome. METHODS: We investigated 1853 patients from coastal-Norway and inland Northern-Argentina. A similar database was used for pooling of data. Two-year follow-up data including all-cause mortality, cardiac death, and sudden cardiac death in the total patient population were analyzed, applying univariate and multivariable analysis. RESULTS: Two hundred fifty-five patients with known vitamin D concentrations died. In the multivariable analysis, there was a decrease in total mortality above a cut-off level of 40 nmol/L and a decrease in cardiac death above a cut-off level of 70 nmol/L [HRs of 0.66 (95% CI, 0.50-0.88), p = 0.004 and 0.46 (95% CI, 0.22-0.94), p = 0.034, respectively]. CONCLUSION: Vitamin D cut-off levels of 40 and 70 nmol/L were related to total mortality and cardiac death, respectively. PMID- 26955634 TI - Rearing Laying Hens in Aviaries Reduces Fearfulness following Transfer to Furnished Cages. AB - Appropriate rearing is essential for ensuring the welfare and productivity of laying hens. Early experience has the potential to affect the development of fearfulness. This study tested whether rearing in aviaries, as opposed to cages, reduces the fearfulness of laying hens after transfer to furnished cages. Fear responses were recorded as avoidance of a novel object in the home cage. Lohmann Selected Leghorns were reared in an aviary system or conventional rearing cages and then transported to furnished cages at 16 weeks, before the onset of lay. Observations of a selection of birds were conducted at 19 (N = 50 independent cages) and 21 (N = 48 independent cages) weeks of age. At 19 and 21 weeks, cage reared birds showed higher levels of fearfulness indicated by spending more time away from the novel object compared to aviary-reared birds. These results suggest that rearing in an enriched aviary environment reduces fearfulness up to the fifth week after transfer to a new housing system, compared to rearing in cages. PMID- 26955635 TI - Selenium Accumulating Leafy Vegetables Are a Potential Source of Functional Foods. AB - Selenium deficiency in humans has been associated with various diseases, the risks of which can be reduced through dietary supplementation. Selenium accumulating plants may provide a beneficial nutrient for avoiding such illnesses. Thus, leafy vegetables such as Amaranthus hybridus, Amaranthus sp., Cucurbita maxima, Ipomoea batatas, Solanum villosum, Solanum scabrum, and Vigna unguiculata were explored for their capabilities to accumulate selenium when grown on selenium enriched soil and for use as a potential source of selenium enriched functional foods. Their selenium contents were determined by spectrophotometry using the complex of 3,3'-diaminobenzidine hydrochloride (DABH) as a chromogen. The mean concentrations in the leaves were found to range from 7.90 +/- 0.40 to 1.95 +/- 0.12 MUg/g dry weight (DW), with C. maxima accumulating the most selenium. In stems, the accumulated selenium content ranged from 1.12 +/ 0.10 MUg/g in Amaranthus sp. to 5.35 +/- 0.78 MUg/g DW in C. maxima and was hence significantly different (P < 0.01). The cancer cell line MDA-MB-231 was used in cytotoxicity assays to determine the anticancer potential of these extracts. With exception of S. scabrum and S. villosum, no cytotoxicity was detected for the selenium enriched vegetable extracts up to 100 MUg/mL concentration. Hence, following careful evaluation the studied vegetables may be considered as selenium enriched functional foods. PMID- 26955636 TI - Indigenous Starter Cultures to Improve Quality of Artisanal Dry Fermented Sausages from Chaco (Argentina). AB - Lactic acid bacteria (LAB) and coagulase negative cocci (CNC) were isolated from artisanal dry sausages sampled from the northeastern region of Chaco, Argentina. In order to evaluate their performance in situ and considering technological features of the isolated strains, two mixed selected autochthonous starter cultures (SAS) were designed: (i) SAS-1 (Lactobacillus sakei 487 + Staphylococcus vitulinus C2) and (ii) SAS-2 (L. sakei 442 + S. xylosus C8). Cultures were introduced into dry sausage manufacturing process at a local small-scale facility. Microbiological and physicochemical parameters were monitored throughout fermentation and ripening periods, while sensory attributes of the final products were evaluated by a trained panel. Lactic acid bacteria revealed their ability to colonize and adapt properly to the meat matrix, inhibiting the growth of spontaneous microflora and enhancing safety and hygienic profile of the products. Both SAS showed a beneficial effect on lipid oxidation and texture of the final products. Staphylococcus vitulinus C2, from SAS-1, promoted a better redness of the final product. Sensory profile revealed that SAS addition preserved typical sensory attributes. Introduction of these cultures could provide an additional tool to standardize manufacturing processes aiming to enhance safety and quality while keeping typical sensory attributes of regional dry fermented sausages. PMID- 26955637 TI - Increased Fracture Collapse after Intertrochanteric Fractures Treated by the Dynamic Hip Screw Adversely Affects Walking Ability but Not Survival. AB - In osteoporotic hip fractures, fracture collapse is deliberately allowed by commonly used implants to improve dynamic contact and healing. The muscle lever arm is, however, compromised by shortening. We evaluated a cohort of 361 patients with AO/OTA 31.A1 or 31.A2 intertrochanteric fracture treated by the dynamic hip screw (DHS) who had a minimal follow-up of 3 months and an average follow-up of 14.6 months and long term survival data. The amount of fracture collapse and shortening due to sliding of the DHS was determined at the latest follow-up and graded as minimal (<1 cm), moderate (1-2 cm), or severe (>2 cm). With increased severity of collapse, more patients were unable to maintain their premorbid walking function (minimal collapse = 34.2%, moderate = 33.3%, severe = 62.8%, and p = 0.028). Based on ordinal regression of risk factors, increased fracture collapse was significantly and independently related to increasing age (p = 0.037), female sex (p = 0.024), A2 fracture class (p = 0.010), increased operative duration (p = 0.011), poor reduction quality (p = 0.000), and suboptimal tip-apex distance of >25 mm (p = 0.050). Patients who had better outcome in terms of walking function were independently predicted by younger age (p = 0.036), higher MMSE marks (p = 0.000), higher MBI marks (p = 0.010), better premorbid walking status (p = 0.000), less fracture collapse (p = 0.011), and optimal lag screw position in centre-centre or centre-inferior position (p = 0.020). According to Kaplan-Meier analysis, fracture collapse had no association with mortality from 2.4 to 7.6 years after surgery. In conclusion, increased fracture collapse after fixation of geriatric intertrochanteric fractures adversely affected walking but not survival. PMID- 26955638 TI - Analysis and Identification of Aptamer-Compound Interactions with a Maximum Relevance Minimum Redundancy and Nearest Neighbor Algorithm. AB - The development of biochemistry and molecular biology has revealed an increasingly important role of compounds in several biological processes. Like the aptamer-protein interaction, aptamer-compound interaction attracts increasing attention. However, it is time-consuming to select proper aptamers against compounds using traditional methods, such as exponential enrichment. Thus, there is an urgent need to design effective computational methods for searching effective aptamers against compounds. This study attempted to extract important features for aptamer-compound interactions using feature selection methods, such as Maximum Relevance Minimum Redundancy, as well as incremental feature selection. Each aptamer-compound pair was represented by properties derived from the aptamer and compound, including frequencies of single nucleotides and dinucleotides for the aptamer, as well as the constitutional, electrostatic, quantum-chemical, and space conformational descriptors of the compounds. As a result, some important features were obtained. To confirm the importance of the obtained features, we further discussed the associations between them and aptamer compound interactions. Simultaneously, an optimal prediction model based on the nearest neighbor algorithm was built to identify aptamer-compound interactions, which has the potential to be a useful tool for the identification of novel aptamer-compound interactions. The program is available upon the request. PMID- 26955639 TI - Prognosis Risk of Urosepsis in Critical Care Medicine: A Prospective Observational Study. AB - This study aimed to investigate the clinical features of urosepsis and to raise awareness of this problem. Of the 112 sepsis patients enrolled, 36 were identified as having urosepsis. The bacteria involved in the infection leading to urosepsis included Escherichia coli, Proteus species, Enterococcus species, Klebsiella species, other Gram-positive cocci, and Pseudomonas aeruginosa. Although the organ/system dysfunction appeared earlier in the urosepsis patients than in the other sepsis patients (4.7 +/- 2.4 versus 7.2 +/- 4.5 hours, P < 0.001), the urosepsis patients presented with a better prognosis and lower 28-day mortality rate than the others (6% versus 37%). In the multivariate analysis, the type of sepsis (urosepsis, OR = 0.019, 95% CI = 0.001, 0.335, P = 0.007) and SOFA score (OR = 1.896, 95% CI = 1.012, 3.554, P = 0.046) remained significantly associated with the survival. The time of admission to the intensive care unit of 17 patients transferred from the Department of Urinary Surgery was significantly prolonged compared with those transferred from other departments (11.6 +/- 7.3 versus 7.2 +/- 4.9 hours, P < 0.05). In conclusion, urosepsis suggested a better prognosis, but attention needs to be paid in clinical practice, especially in urinary surgery. PMID- 26955640 TI - Uptake and Effects of the e-Vita Personal Health Record with Self-Management Support and Coaching, for Type 2 Diabetes Patients Treated in Primary Care. AB - We studied the use, uptake, and effects of e-Vita, a personal health record, with self-management support and personalized asynchronized coaching, for type 2 diabetes patients treated in primary care. Patients were invited by their practice nurse to join the study aimed at testing use and effects of a personal health record. Patients were followed up for 6 months. Uptake and usage were monitored using log data. Outcomes were self-reported diabetes self-care, diabetes-related distress, and emotional wellbeing. Patients' health status was collected from their medical chart. 132 patients agreed to participate in the study of which less than half (46.1%) did not return to the personal health record after 1st login. Only 5 patients used the self-management support program within the personal health record, 3 of whom asked a coach for feedback. Low use of the personal health record was registered. No statistical significant differences on any of the outcome measures were found between baseline and 6 month follow-up. This study showed minimal impact of implementing a personal health record including self-management support in primary diabetes care. Successful adoption of web-based platforms, as ongoing patient centered care, is hard to achieve without additional strategies aimed at enhancing patient motivation and engaging professionals. PMID- 26955641 TI - Diabetic Retinopathy Is Strongly Predictive of Cardiovascular Autonomic Neuropathy in Type 2 Diabetes. AB - A well-established, comprehensive, and simple test battery was used here to re evaluate risk factors for cardiovascular autonomic neuropathy (CAN) in type 2 diabetes. One hundred and seventy-four patients with type 2 diabetes were evaluated through the methods of deep breathing and Valsalva maneuver for correlation with factors that might influence the presence and severity of CAN. The Composite Autonomic Scoring Scale (CASS) was used to grade the severity of autonomic impairment, and CAN was defined as a CASS score >=2. Results showed that nephropathy, duration of diabetes, blood pressure, uric acid, and the presence of retinopathy and metabolic syndrome significantly correlated with the CASS score. Age may not be a risk factor for diabetic CAN. However, the effects of diabetes on CAN are more prominent in younger patients than in older ones. Diabetic retinopathy is the most significant risk factor predictive of the presence of CAN in patients with type 2 diabetes. PMID- 26955642 TI - Taurine Transporter Gene Expression in Mononuclear Blood Cells of Type 1 Diabetes Patients. AB - BACKGROUND: Taurine transporter gene expression (RNA-TauT) has a role in retinal cell function and is modulated in vitro and in vivo by hyperglycemia and/or oxidative stress. This study was aimed at testing whether RNA-TauT gene expression is modified in blood mononuclear peripheral cells (MPCs) of type 1 diabetic patients, is related to plasma markers of oxidative stress or endothelial dysfunction, or, finally, is related to presence of retinopathy. METHODS: RNA-TauT was measured in MPCs by real-time PCR-analysis in 35 type 1 diabetic patients and in 33 age- and sex-matched controls, additionally measuring plasma and cell taurine and markers of oxidative stress and endothelial dysfunction. RESULTS: RNA-TauT, expressed as 2(-DeltaDeltaCt), was significantly higher in MPCs of type 1 diabetic patients than in controls [median (interquartile range): 1.32(0.31) versus 1.00(0.15); P = 0.01]. In diabetic patients RNA-TauT was related to HbA1c (r = 0.42; P = 0.01) and inversely to plasma homocysteine (r = -0.39; P = 0.02) being additionally significantly higher in MPCs of patients without retinopathy [(n = 22); 1.36(0.34)] compared to those with retinopathy [(n = 13); 1.16(0.20)], independently from HbA1c or diabetes duration. CONCLUSIONS: RNA-TauT gene expression is significantly upregulated in MPCs of type 1 diabetes patients and is related to HbA1c levels and inversely to plasma homocysteine. Finally, in diabetes patients, RNA-TauT upregulation seems to be blunted in patients with retinopathy independently of their metabolic control or longer diabetes duration. PMID- 26955643 TI - Clinical Liver Disease Progression Among Hepatitis C-Infected Drug Users With CD4 Cell Count Less Than 200 Cells/mm(3) Is More Pronounced Among Women Than Men. AB - Background. Hepatitis C virus (HCV) infection is a leading cause of liver related morbidity and mortality in the United States, and injection drug users are at particularly high risk. Methods. This prospective observational cohort study assessed the rate of, and risk factors for, clinical liver disease progression in a cohort of HCV monoinfected and human immunodeficiency virus (HIV)/HCV coinfected drug users using unadjusted and multivariate Cox proportional hazards regression analyses. Results. Of 564 subjects including 421 (75%) with HIV/HCV coinfection and 143 with HCV monoinfection, 55 (10%) had clinical liver disease progression during follow-up with a rate of 25.3 events per 1000 person-years. In unadjusted analysis, there was an interaction between sex and HIV status. In sex-stratified multivariate analysis, HIV/HCV-coinfected women with CD4 <200 cells/mm(3) had 9.99 times the risk of liver disease progression as HCV-monoinfected women (confidence interval [CI], 1.84-54.31; P = .008), and white women had a trend towards increased risk of liver disease progression compared with non-white women (hazard ratio, 2.84; CI, .93-8.68; P = .07). Human immunodeficiency virus/HCV-coinfected men with CD4 <200 cells/mm(3) had 2.86 times the risk of liver disease progression as HCV-monoinfected men (CI, 1.23-6.65; P = .01). Conclusions. Hepatitis C virus-monoinfected and HIV/HCV coinfected drug users had high rates of clinical liver disease progression. In those with HIV infection, liver disease progression was associated with advanced immune suppression. This effect was strikingly more pronounced in women than in men. PMID- 26955644 TI - Insight Into Resistance Phenotypes of Emergent Non 13-valent Pneumococcal Conjugate Vaccine Type Pneumococci Isolated From Invasive Disease After 13-valent Pneumococcal Conjugate Vaccine Implementation in France. AB - Background. In 2010, the pneumococcal 13-valent conjugate vaccine (PCV13), containing 6 additional serotypes including the multidrug-resistant 19A, replaced the PCV7 in France. This study aimed at analyzing trends in antibiotic resistance in invasive pneumococcal disease (IPD) isolates in France after PCV13 introduction. Methods. A total of 5243 pneumococci isolated from IPD in 2008 2009 (late PCV7 era) and 2011-2012 (PCV13 era) were studied according to their serotype and antibiotic resistance profile. Multilocus sequence typing analysis was performed on strains of the predominant serotypes (12F and 24F) isolated from young children. Results. Overall, the prevalence of antibiotic resistance decreased in France (-21.5% for penicillin from 2008-2009 to 2011-2012), mainly driven by the decline of the 19A serotype. Among non-PCV13 serotypes that concomitantly emerged, serotypes 12F, 24F, 15A, and 35B were consistently associated with resistance to 1 or more antibiotics. In children under 2 years, serotypes 15A, 35B, and 24F accounted together for 37.8% and 31.9% of penicillin nonsusceptible and erythromycin-resistant isolates, respectively. Chloramphenicol and cotrimoxazole resistance were mainly associated with serotypes 12F and 24F, respectively. Genetic analysis showed that although emergence of serotype 12F pneumococci resulted from the expansion of various pre-existing lineages, increase in serotype 24F was related to the clonal expansion of the ST162 penicillin-susceptible cotrimoxazole-resistant lineage. Conclusions. We showed that decline of PCV13-related IPD was associated with a decline in antibiotic resistance in France, but that it likely favored the spread of several resistant nonvaccine serotypes. However, antibiotic resistance does not seem to be the only element that may drive this phenomenon. PMID- 26955645 TI - Ability to Work and Employment Rates in Human Immunodeficiency Virus (HIV)-1 Infected Individuals Receiving Combination Antiretroviral Therapy: The Swiss HIV Cohort Study. AB - Background. Limited data exist on human immunodeficiency virus (HIV)-infected individuals' ability to work after receiving combination antiretroviral therapy (cART). We aimed to investigate predictors of regaining full ability to work at 1 year after starting cART. Methods. Antiretroviral-naive HIV-infected individuals <60 years who started cART from January 1998 through December 2012 within the framework of the Swiss HIV Cohort Study were analyzed. Inability to work was defined as a medical judgment of the patient's ability to work as 0%. Results. Of 5800 subjects, 4382 (75.6%) were fully able to work, 471 (8.1%) able to work part time, and 947 (16.3%) were unable to work at baseline. Of the 947 patients unable to work, 439 (46.3%) were able to work either full time or part time at 1 year of treatment. Predictors of recovering full ability to work were non-white ethnicity (odds ratio [OR], 2.06; 95% confidence interval [CI], 1.20-3.54), higher education (OR, 4.03; 95% CI, 2.47-7.48), and achieving HIV-ribonucleic acid <50 copies/mL (OR, 1.83; 95% CI, 1.20-2.80). Older age (OR, 0.55; 95% CI, .42-.72, per 10 years older) and psychiatric disorders (OR, 0.24; 95% CI, .13 .47) were associated with lower odds of ability to work. Recovering full ability to work at 1 year increased from 24.0% in 1998-2001 to 41.2% in 2009-2012, but the employment rates did not increase. Conclusions. Regaining full ability to work depends primarily on achieving viral suppression, absence of psychiatric comorbidity, and favorable psychosocial factors. The discrepancy between patients' ability to work and employment rates indicates barriers to reintegration of persons infected with HIV. PMID- 26955647 TI - Optimal parameters for laccase-mediated destaining of Coomassie Brilliant Blue R 250-stained polyacrylamide gels. AB - The data presented in this article are related to the research article entitled "Destaining of Coomassie Brilliant Blue R-250-stained polyacrylamide gels with fungal laccase" [1]. Laccase is a class of multicopper oxidases that can catalyze oxidation of recalcitrant dyestuffs. This article describes optimal parameters for destaining of polyacrylamide gels, stained with Coomassie Brilliant Blue R 250, with laccase from basidiomycete Cerrena sp. strain HYB07. Effects of laccase activity, mediator type and concentration, temperature and time on destaining of polyacrylamide gels were evaluated with respect to gel background intensity and protein band signals, and the optimal destaining effects were obtained with 15 U mL(-1) laccase and 2 MUM ABTS at 37 degrees C after 2 h. PMID- 26955648 TI - Data supporting phylogenetic reconstructions of the Neotropical clade Gymnotiformes. AB - Data is presented in support of model-based total evidence (MBTE) phylogenetic reconstructions of the Neotropical clade of Gymnotiformes "Model-based total evidence phylogeny of Neotropical electric knifefishes (Teleostei, Gymnotiformes)" (Tagliacollo et al., 2016) [1]). The MBTE phylogenies were inferred using a comprehensive dataset comprised of six genes (5277 bp) and 223 morphological characters for an ingroup taxon sample of 120 of 218 valid species and 33 of the 34 extant genera. The data in this article include primer sequences for gene amplification and sequencing, voucher information and GenBank accession numbers, descriptions of morphological characters, morphological synapomorphies for the recognized clades of Gymnotiformes, a supermatrix comprised of concatenated molecular and morphological data, and computer scripts to replicate MBTE inferences. We also included here Maximum-likelihood and Bayesian topologies, which support two main gymnotiform clades: Gymnotidae and Sternopygoidei, the latter comprised of Rhamphichthyoidea (Rhamphichthyidae+Hypopomidae) and Sinusoidea (Sternopygidae+Apteronotidae). PMID- 26955646 TI - Stop signs in hippocampal insulin signaling: the role of insulin resistance in structural, functional and behavioral deficits. AB - In peripheral tissues insulin activates signaling cascades to facilitate glucose uptake from the blood into tissues like liver, muscle and fat. While insulin appears to play a minor role in the regulation of glucose uptake in the central nervous system (CNS), insulin is known to play a major role in regulating synaptic plasticity in brain regions like the hippocampus. The concept that insulin regulates hippocampal neuroplasticity is further supported from animal models of type 2 diabetes (T2DM) and Alzheimer's disease (AD). The goal of this review is to provide an overview of these studies, as well as the studies that have examined whether deficits in hippocampal insulin signaling are amenable to intervention strategies. PMID- 26955649 TI - Production of a recombinant capsid protein VP1 from a newly described polyomavirus (RacPyV) for downstream use in virus characterization. AB - Here we describe the methods for production of a recombinant viral capsid protein and subsequent use in an indirect enzyme linked immunosorbent assay (ELISA), and for use in production of a rabbit polyclonal antibody. These reagents were utilized in development and optimization of an ELISA, which established the extent of exposure of free ranging raccoons to a newly described polyomavirus (RacPyV) [1]. Production of a polyclonal antibody has allowed for further characterization of RacPyV, including immunohistochemistry and immunocytochemistry techniques, in order to answer questions about pathogenesis of this virus. PMID- 26955650 TI - BOLD data representing activation and connectivity for rare no-go versus frequent go cues. AB - The neural circuitry underlying response control is often studied using go/no-go tasks, in which participants are required to respond as fast as possible to go cues and withhold from responding to no-go stimuli. In the current task, response control was studied using a fully counterbalanced design in which blocks with a low frequency of no-go cues (75% go, 25% no-go) were alternated with blocks with a low frequency of go cues (25% go, 75% no-go); see also "Segregating attention from response control when performing a motor inhibition task: Segregating attention from response control" [1]. We applied a whole brain corrected, paired t-test to the data assessing for regions differentially activated by low frequency no-go cues relative to high frequency go cues. In addition, we conducted a generalized psychophysiological interaction analysis on the data using a right inferior frontal gyrus seed region. This region was identified through the BOLD response t-test and was chosen because right inferior gyrus is highly implicated in response inhibition. PMID- 26955651 TI - Experimental data for synthesis of bi-metalized chitosan particle for attenuating of an azo dye from wastewater. AB - In this data article, we introduce data acquired from new adsorbent, bi-metalized chitosan particle that is successfully synthesized and applied to remove the orange II dye, an azo dye, from textile wastewater. The adsorbent was meso- and macro-porous material with BET surface area of 12.69 m(2)/g and pHzpc 6.6. The simulated textile-wastewater can be significantly treated using a relatively low quantity of the adsorbent. Overall, the use of bi-metalized chitosan particle can be considered a promising method for eliminating the azo dye from wastewater effectively. Accordingly, these data will be useful for decolorizing of azo dyes from textile wastewater. PMID- 26955652 TI - Ensemble structure description of Lys63-linked diubiquitin. AB - The data described herein are related to the article entitled "Lys63-linked ubiquitin chain adopts multiple conformational states for specific target recognition" [1], and to the coordinates for the ensemble structure of Lys63 linked diubiquitin (PDB code 2N2K). A Lys63-linked diubiquitin exists in three conformational states with different orientations for the two subunits, each responsible for binding to a target protein and encoding a specific cell signal. An atomic entry in the ensemble structure file consists multiple lines, representing alternative locations of the atom and recapitulating the dynamics of the protein. Experimental details about obtaining strictly intramolecular paramagnetic restraints and determining the relative occupancies of the conformational states are presented. The experimental design and procedures in this Data article can be useful for characterizing the structure and dynamics of other multi-domain proteins. PMID- 26955653 TI - Data demonstrating the effects of build orientation and heat treatment on fatigue behavior of selective laser melted 17-4 PH stainless steel. AB - Axial fully-reversed strain-controlled ([Formula: see text]) fatigue experiments were performed to obtain data demonstrating the effects of building orientation (i.e. vertical versus horizontal) and heat treatment on the fatigue behavior of 17-4 PH stainless steel (SS) fabricated via Selective Laser Melting (SLM) (Yadollahi et al., submitted for publication [1]). This data article provides detailed experimental data including cyclic stress-strain responses, variations of peak stresses during cyclic deformation, and fractography of post-mortem specimens for SLM 17-4 PH SS. PMID- 26955654 TI - Inferior Vena Cava Reconstruction with Tubularized Bovine Pericardium. AB - A 32-year-old male presented with a large locally advanced sarcomatoid right renal cell carcinoma invading the duodenum and IVC. Due to persistent symptomatic gastrointestinal bleeding requiring repeat blood transfusion and the inability to utilize appropriate systemic chemotherapy, the patient was taken for palliative resection. En bloc pancreaticoduodenectomy, right nephrectomy and IVC resection were performed with reconstruction of the IVC with tubularized bovine pericardium. Widespread availability, ease and speed of tubularized graft creation, lack of morbidity to the patient and its inherent resistance to infection in contaminated fields make bovine pericardium an expedient reconstructive option in these challenging cases. PMID- 26955656 TI - Load Balancing in Cloud Computing Environment Using Improved Weighted Round Robin Algorithm for Nonpreemptive Dependent Tasks. AB - Cloud computing uses the concepts of scheduling and load balancing to migrate tasks to underutilized VMs for effectively sharing the resources. The scheduling of the nonpreemptive tasks in the cloud computing environment is an irrecoverable restraint and hence it has to be assigned to the most appropriate VMs at the initial placement itself. Practically, the arrived jobs consist of multiple interdependent tasks and they may execute the independent tasks in multiple VMs or in the same VM's multiple cores. Also, the jobs arrive during the run time of the server in varying random intervals under various load conditions. The participating heterogeneous resources are managed by allocating the tasks to appropriate resources by static or dynamic scheduling to make the cloud computing more efficient and thus it improves the user satisfaction. Objective of this work is to introduce and evaluate the proposed scheduling and load balancing algorithm by considering the capabilities of each virtual machine (VM), the task length of each requested job, and the interdependency of multiple tasks. Performance of the proposed algorithm is studied by comparing with the existing methods. PMID- 26955655 TI - Cerebrospinal fluid ratios with Abeta42 predict preclinical brain beta-amyloid accumulation. AB - INTRODUCTION: Biomarkers are urgently needed for the critical yet understudied preclinical stage of Alzheimer's disease (AD). METHODS: CSF collection, [C-11]PiB amyloid imaging, and MRI were acquired in n=104 cognitively healthy adults enriched with risk for sporadic AD. Image-derived cerebral beta-amyloid (Abeta) burden, measured concurrently and longitudinally, was regressed on CSF measures of Abeta, neural injury, and inflammation, as well as ratios with Abeta42. Linear mixed effects regression was used to model the effect of the CSF measures that predicted longitudinal brain amyloid accumulation on longitudinal cognitive decline, measured by memory test scores. RESULTS: At baseline, Abeta42/Abeta40 and all CSF ratios to Abeta42 were associated with PiB binding in AD-vulnerable regions. Longitudinally, Abeta42/Abeta40 and ratios of total tau, phosphorylated tau, neurofilament light protein, and monocyte chemoattractant protein-1 to Abeta42 were associated with increased beta-amyloid deposition over two years, predominantly in lateral parietal and temporal cortex. However, these CSF ratios were not significantly associated with cognitive decline, and the effect seems to be largely driven by Abeta42 in the denominator. DISCUSSION: These results corroborate previous findings that t-tau/Abeta42 and p-tau/Abeta42 are the strongest candidate biomarkers during the preclinical timeframe. They support a framework in which neural injury and amyloid deposition are likely occurring simultaneously. It may be that neurodegenerative processes influence progressive amyloid accumulation, even in the preclinical time frame. CSF biomarkers for non specific axonal injury and inflammation may provide more information at more advanced stages of the preclinical time course. PMID- 26955658 TI - Fluoroquinolone-related neuropsychiatric and mitochondrial toxicity: a collaborative investigation by scientists and members of a social network. AB - BACKGROUND: The 3 fluoroquinolone (FQ) antibiotics - ciprofoxacin, levofoxacin, and moxifoxacin - are commonly administered to oncology patients. Although these oral antibiotics are approved by the US Food and Drug Administration (FDA) for treatment of urinary tract infections, acute bacterial sinusitis, or bacterial infection in patients with chronic obstructive pulmonary disease, they are commonly prescribed off-label to neutropenic cancer patients for the prevention and treatment of infections associated with febrile neutropenia. New serious FQ associated safety concerns have been identified through novel collaborations between FQ-treated persons who have developed long-term neuropsychiatric (NP) toxicity, pharmacovigilance experts, and basic scientists. OBJECTIVE: To conduct basic science and clinical investigations of a newly identified adverse drug reaction, termed FQ-associated disability. METHODS: 5 groups of C57BL/6 mice receiving the antibiotic ciprofoxacin in 10-mg increments (10 mg/kg-50 mg/kg) and 1 group of control mice were evaluated. The Southern Network on Adverse Reactions (SONAR) and a social network of FQ-treated persons with long-term NP toxicity (the Floxed Network) conducted a web-based survey. The clinical toxicity manifestations reported by 94 respondents to the web-based survey of persons who had received 1 or more doses of an FQ prescribed for any indication (generally at FDA-approved dosages) and who subsequently experienced possible adverse drug reactions were compared with adverse event information included on the product label for levofoxacin and with FQ-associated adverse events reported to the FDA's MedWatch program. RESULTS: Mice treated with ciprofoxacin had lower grip strengths, reduced balance, and depressive behavior compared with the controls. For the survey, 93 of 94 respondents reported FQ-associated events including anxiety, depression, insomnia, panic attacks, clouded thinking, depersonalization, suicidal thoughts, psychosis, nightmares, and impaired memory beginning within days of FQ initiation or days to months of FQ discontinuation. The FDA Adverse Event Reporting System (FAERS) included 210,705 adverse events and 2,991 fatalities for FQs. Levofoxacin and ciprofoxacin toxicities were neurologic (30% and 26%, respectively), tendon damage (8% and 6%), and psychiatric (10% and 2%). In 2013, an FDA safety review reported that FQs affect mammalian topoisomerase II, especially in mitochondria. In 2013 and 2014, SONAR fled citizen petitions requesting black box revisions identifying neuropsychiatric toxicities and mitochrondrial toxicity as serious levofoxacin associated adverse drug reactions. In 2015, FDA advisors recommended that FQ product labels be revised to include information about this newly identified disability syndrome termed "FQ-associated disability" (FQAD). LIMITATIONS: Basic science studies evaluated NP toxicity for only 1 FQ, ciprofoxacin. CONCLUSION: Pharmacovigilance investigators, a social network, and basic scientists can collaborate on pharmacovigilance investigations. Revised product labels describing a new serious adverse drug reaction, levofoxacin-associated long-term disability, as recommended by an FDA advisory committee, are advised. PMID- 26955660 TI - A novel treatment approach prolonging survival in an uncommon metastatic primary bladder adenocarcinoma. AB - Primary bladder adenocarcinoma (PBA) is an epithelial malignancy with pure glandular differentiation, without evidence of typical urothelial (transitional cell) carcinoma. PBA is rare, accounting for 0.5%-2% of all malignant bladder neoplasms, and it is seen more frequently in men than in women and is commonly diagnosed in the sixth decade of life.1-3 Clinical presentation includes hematuria and symptoms of bladder irritation.2 PBA is common in schistosomiasis endemic regions and among patients with congenital bladder exstrophy (ectopia vesicae); it mostly arises in the trigone and posterior bladder wall.4 In contrast, urachal adenocarcinomas arise within urachal remnants (residual tissues from the embryonic allantoic stalk connecting the umbilicus and bladder), close to the dome and anterior wall of the bladder. Morphologically, PBA is classifed into enteric and nonenteric types, which includes mucinous, signetring cell variant, clear-cell type, hepatoid, and mixed forms.2 Currently, there is no standard of care in the management of PBA. We present the case of a patient with metastatic PBA with intestinal differentiation and wild-type KRAS, who was treated with colorectal cancer regimens. PMID- 26955659 TI - Prognostic value of complete remission with superior platelet counts in acute myeloid leukemia. AB - BACKGROUND: Complete remission (CR) in acute myeloid leukemia (AML) is defined as having <=5% leukemic blast cells in the bone marrow and return of normal hematopoiesis after the first induction cycle. There is a subset of patients, however, who achieve reduction of leukemic blast cells with a subnormal platelet count, designated as CR with incomplete platelet recovery (platelet count, <=100,000/mcL; normal, 150,000-450,000/mcL), which is associated with inferior outcomes when compared with CR. Furthermore, there is another subset of patients with CR but superior platelet counts (>=400,000/mcL) whose prognostic significance is unclear. OBJECTIVE: To establish whether CR with superior platelet counts is associated with better outcomes and can be used as a separate entity for prognostication. METHODS: A retrospective chart review of 104 cases of AML was conducted. The highest platelet count during days 25-35 from initiation of induction chemotherapy (designated as day 30 platelet count) was documented. A multivariate analysis for other factors such as age, sex, risk categories, day 14+ plasma cell count (average plasma cell percentage at days 14-21), infections, allogeneic bone marrow transplant, and remission status was done. RESULTS: Day 30 platelet count was found to be an independent predictor of survival in AML. On the multivariate analysis, the subgroup with superior platelet counts (>=400,000/mcL) was found to be associated with better outcomes. LIMITATIONS: Results need to be validated in a larger cohort. CONCLUSIONS: CR with superior platelet recovery (>=400,000/mcL) is a unique subcategory in itself and has prognostic significance. This may help better assess response to chemotherapeutic agents and aid in further decision-making regarding treatment. PMID- 26955657 TI - The use of 18F-2-fluorodeoxyglucose (FDG) to label antibody fragments for immuno PET of pancreatic cancer. AB - We generated 18F-labeled antibody fragments for PET imaging using a sortase mediated reaction to install a transcyclooctene (TCO)-functionalized short peptide onto proteins of interest, followed by reaction with a tetrazine-labeled 18F-2-deoxyfluoroglucose (FDG). The method is rapid, robust, and site-specific (radiochemical yields >25%, not decay corrected). The availability of 18F-2 deoxyfluoroglucose avoids the need for more complicated chemistries used to generate carbon-fluorine bonds. We demonstrate the utility of the method by detecting heterotopic pancreatic tumors in mice by PET, using anti-Class II MHC single domain antibodies. We correlate macroscopic PET images with microscopic two-photon visualization of the tumor. Our approach provides easy access to 18F labeled antibodies and their fragments at a level of molecular specificity that complements conventional18F-FDG imaging. PMID- 26955661 TI - An extremely indolent T-cell leukemia: an 18-year follow-up. AB - T-cell prolymphocytic leukemia (T-PLL) is a rare malignancy that comprises about 2% of all mature lymphoid neoplasms. Patients usually present with prominent peripheral blood lymphocytosis, splenomegaly, hepatomegaly, lymphadenopathy, B symptoms, and occasionally with skin lesions.1 The disease follows an aggressive clinical course with rapid progression and typically has a median survival of less than 1 year. In some cases, the disease is indolent for a period of time before becoming aggressive.2 In 2002, 7 years after initial diagnosis in 1995, the case discussed herein was reported as a rare, indolent form of T-PLL.3 We now present 11 additional years of follow-up of this case, during which time the patient remained asymptomatic with respect to his lymphoid neoplasm. PMID- 26955662 TI - Therapeutic plasma exchange in clinical practice: long-term single centre experience. AB - Therapeutic plasma exchange (TPE) is a powerful tool in the treatment of a whole host of diseases and there is hardly any organ for which TPE has not been shown to have some beneficial effects. In most instances, TPE is indicated only as a last resort treatment if all conservative measures have failed. However, there are lifethreatening conditions where TPE is the primary mode of acute treatment. Results from recent randomized prospective controlled trials caused a narrowing of the spectrum of indications for use of TPE, while advances in the various fields of medicine and technology have enabled wider clinical application of this procedure and generated several new indications. To define the current role of TPE, we retrospectively analysed changes in indications for TPE in our database, that contains information on all TPEs conducted during 27 years at University Hospital Centre Zagreb (a national referral centre for therapeutic apheresis, which covers approximately 90-95% of all TPEs performed in Croatia). The number of patients, including children and elderly people) who underwent this procedure and TPEs increased several-fold over 27 years of follow-up despite changes in the pattern of indications and the emergence of new, more selective therapeutic options (LDL-apheresis, immunoadsorption, etc.). With wider application of TPE, fear of its complications have diminished, which may be the reason for the more frequent treatment of very young children and very old patients. Our results derived from a large number of treatments indicate that TPE is a relatively safe method of treatment, providing it is carried out by experienced staff, and used for appropriate indications with all necessary precautions. Despite the development of more selective methods, TPE is still a widely applicable and useful procedure, possibly experiencing a renesance in this century. PMID- 26955663 TI - [Urological Cancer 2015]. PMID- 26955664 TI - [I. Docetaxel must be reconsidered in light of high cost-effectiveness in the treatment of prostate cancer]. PMID- 26955665 TI - [Recent topics in the treatments of renal cell carcinoma]. PMID- 26955666 TI - [III. Diagnosis and treatment for bladder cancer--recent topics]. PMID- 26955667 TI - [IV. Recent advance in treatment of testicular cancer--point to be noted]. PMID- 26955668 TI - [Enlightenment and Thinking of Winning The Nobel Prize in Medicine to Professor TU You-you]. PMID- 26955669 TI - [Development and Quality Evaluation of Evidence-based Clinical Practice Guidelines of Chinese Medicine]. AB - More attentions have been paid to the development of evidence-based clinical practice guidelines (ECPGs) of Chinese medicine (CM). International guideline evaluation instruments such as Appraisal of Guidelines for Research and Evaluation (AGREE I) has been gradually applied in ECPGs quality evaluation of CM. Nowadays, there are some certain methodological defects in partial ECPGs of Chinese medicine, with relatively low applicability and slowly update. It is suggested to establish technical specifications of CM-ECPGs in accordance with the characteristics of CM and international general specification, strengthen the quality evaluation of CM-ECPGs, attach great importance to the regularly update as well as popularization and application of CM-ECPGs. PMID- 26955671 TI - [Modernized History of Ancient Ophthalmology]. PMID- 26955670 TI - [Thinking and Problems of Peripheral Vascular Disease Research]. AB - It is necessary to study further syndrome differentiation based treatment of peripheral vascular disease. In order to improve the clinical effect and reduce the rate of amputation, early diagnosis and early intervention are important. Meanwhile, treatment of Chinese medicine should be combined with necessary surgical intervention. It should be important to supplement some details about blood stasis syndrome and activating blood and dissolving stasis therapy of peripheral vascular disease. The application of various Chinese medicine external therapies should not be ignored, especially promoting granulation and wound healing therapy. PMID- 26955672 TI - [Treatment of Rheumatoid Arthritis by Hebi Recipe: an Efficacy Observation]. AB - OBJECTIVE: To observe the auxiliary efficacy and safety of Hebi Recipe (HR)in treating early rheumatoid arthritis (RA). METHODS: Totally 63 early RA patients with Gan-Pi disharmony were randomly assigned to the treatment group [32 cases, treated by HR (one dose per day, taken in two portions for 24 successive weeks) plus Methotrexate (MTX)] and the control group (31 cases, treated by MTX alone). The dosage of MTX was increased from 7.5 mg to 12.5 mg, once per week, 24 weeks as one course of treatment. Efficacy for Chinese medical syndromes, American College of Rheumatology 20 (ACR20) improvement rate, disease activity score in 28 joints (DAS28), laboratory related indices [ESR, rheumatoid factor (RF), C reactive protein (CRP), anti-cyclic citrullinated peptide (CCP)], and related ultrasonic inspection items (synovium thickness, synovium blood flow classification, effusion of joint), and adverse reactions were observed. RESULTS: The total effective rate (83.9%, 26/31 cases) and ACR20 improvement rate (74.2%, 23/31 cases) were higher in the treatment group than in the control group [60.7% (17/28 cases), 46.4% (13/28 cases); P < 0.05]. Compared with before treatment in the same group, DAS28 score, ESR, RF, CRP, CCP, synovium thickness, synovium blood flow classification, effusion of joint all decreased in the two groups after treatment (P < 0.01, P < 0.05). Compared with the control group after treatment, ACR20 improvement rate, DAS28 score, ESR, RF, CRP, CCP, synovium thickness, synovium blood flow classification, effusion of joint all decreased in the treatment group (P < 0.01, P < 0.05). Liver dysfunction occurred in 1 case of the treatment group. One leucopenia and 2 liver dysfunction occurred in the control group. CONCLUSION: HR could effectively improve joints and systemic symptoms of early RA patients with Gan-Pi disharmony. PMID- 26955673 TI - [Effect of External Applying Compound Tripterygium wilfordii Hook F. on Joint Pain of Rheumatoid Arthritis Patients]. AB - OBJECTIVE: To observe the effectiveness and safety of external applying Compound Tripterygium wilfordii Hook F. (TwHF) in relieving joint pain in rheumatoid arthritis (RA) patients. METHODS: In this double-blinded, randomized multicenter trial, a total of 174 moderately active RA patients were enrolled and randomly assigned to the treatment group (treated with Compound TwHF, 87 cases) and the placebo control group (87 cases). Compound TwHF or placebo was externally applied in painful joints, 20 g each time, once per day for 8 weeks. Self-reported joint pain relief was taken as a primary effective indicator. Visual analogue scale for pain (VAS), disease activity score of 28 joints (DAS28), VAS for general health (GH) were evaluated before treatment, at week 4 and after treatment. Erythrocyte sedimentation rate (ESR) and hypersensitive C reactive protein (hs-CRP) were tested before and after treatment. Menstrual changes in females were observed during treatment. Skin irritation occurred during the recording process was assessed using skin irritation strength. Intention to treat (ITT) was statistically analyzed. RESULTS: The joint pain relief rate in the treatment group was 90.8% (79/87 cases), higher than that in the placebo control group (69.0%, 60/87 cases; P = 0.001). VAS pain score, DAS28, VAS for GH score were significantly improved in the two groups at week 4 of treatment and after treatment, as compared with before treatment (P < 0.01). ESR and hs-CRP levels significantly decreased in the treatment group after treatment (P < 0.05, P < 0.01). No difference was found in post-treatment VAS pain score, DAS28, VAS for GH score, ESR, or hs-CRP between the two groups (P > 0.05). Eight adverse events occurred in the treatment group (5 skin allergy, 1 intolerance of medical odor, and 2 mild liver injury), while 3 adverse events occurred in the placebo control group (2 skin allergy, 1 mild liver injury). There was no statistical difference in adverse event between the two groups (P > 0.05). No menstrual change occurred in the treatment group. CONCLUSION: External applying Compound TwHF was an effective and safe way to relieve-joint pain of RA patients, which could be taken as an adjuvant therapy. PMID- 26955674 TI - [Correlation Analysis of Apoptosis and Clinical Indicators in Rheumatoid Arthritis Patients]. AB - OBJECTIVE: To observe the expression of peripheral blood CD4+ T lymphocyte apoptosis gene in rheumatoid arthritis (RA) patients with cold dampness type (CDT), and to explore its correlation with clinical indicators of RA. METHODS: Sixteen RA patients with CDT (as the RA group) and 16 healthy subjects (as the normal control group) were recruited. CD4 T cell apoptosis rate was detected in the RA group and the normal control group using FCM. mRNA expressions of fas, fasL, caspase-3, caspase-8, bcl-2, and bax were detected using RT-PCR. Correlations between the expression of apoptosis gene and clinical activity indicators of RA (ESR, CRP, RF, CCP, integrals for Chinese medial symptoms, morning stiffness time, joint tenderness number, joint swelling number, DAS28-3) were analyzed. RESULTS: The apoptosis rate of CD4+ T was significantly lower in the RA group than in the control group [(2. 6 +/- 0.9) % vs. (7.7 +/- 1.3) %, P < 0.01]. mRNA expression levels of fas, fasL, caspase-8, caspase-3, and bax mRNA of CD4+ T significantly decreased, but bcl-2 mRNA expression increased in the RA group (P < 0.01). The apoptosis rate of CD4+ T was negatively correlated with ESR (P < 0.05). The mRNA expression of caspase-8 was negatively correlated with joint swelling number (P < 0.05). The mRNA expression of bcl-2 was negatively correlated with integrals for Chinese medial-symptoms and joint function classification (P < 0.01, P < 0.05). CONCLUSION: Apoptosis obstacle exists in peripheral blood CD4 +T lymphocyte of RA patients, and is closely related to disease activity. PMID- 26955675 TI - [Treatment of Steroid-induced Osteonecrosis of Femoral Head by Porous Tantalum Rod and Gugutou Huaisiyu Capsule]. AB - OBJECTIVE: To observe the curative effect of porous tantalum rod and Gugutou Huaisiyu Capsule (GHC) for steroid-induced osteonecrosis of femoral head (SONFH). METHODS: A total 60 hips of 50 SONFH patients were randomly assigned to the treatment group and the control group according to grouping time, 25 in each group (30 hips). Patients in the control group were implanted with porous tantalum rod, while those in the treatment group additionally took GHC (5 pills each time, three time per day for 2 successive months; and then twice per day for 4 successive months). Then all patients were followed-up to observe Harris hip score. The curative effect and the femoral head survival time were assessed. RESULTS: A total of 49 patients (59 hips) were followed-up. The Harris hip score of the two groups at the final follow-up was significantly improved after treatment, with statistical difference when compared with before treatment (P < 0.01). Besides, it was higher in the treatment group than in the control group. The curative effect and the survival time were superior in the treatment group, with statistical difference when compared with the control group (P < 0.05). CONCLUSIONS: Porous tantalum rod combined GHC got better effect in treating SONFH. It could significantly improve the function of affected hips and prolong the survival time of femoral head. PMID- 26955676 TI - [Analysis of Clinical Characteristics in 595 Patients with Herb-induced Liver Injury]. AB - OBJECTIVE: To observe clinical characteristics of herb-induced liver injury (HILI). METHODS: General conditions, medical history, clinical manifestations, biochemical indices, prognosis, and Roussed Uclaf Causality Assessment Method (RUCAM) scores were retrospectively analyzed in 595 inpatients at 302 Military Hospital between January 2009 and January 2014. RESULTS: There were 423 cases (accounting for 71.1%) were females with multiple onset age ranging 41 to 50 years old. The median time from starting Chinese herbs to the occurrence of liver injury (LI) was 30 days (15-75 days), and 511 cases (85.9%) were classified as hepatocellular injury. Chinese herbs inducing HILI were mainly used for skin disease (102 cases, 17.1%), osteoarticular disease (57 cases, 9.6%), and gastrointestinal disease (49 cases, 8.2%), covering 207 kinds of Chinese patent medicines. Polygonum multiflorum, Psoralea corylifolia, and Corydalis ambigua were often seen in Chinese prescriptions. In RUCAM scoring, 451 HILI patients (accounting for 74.1%) were very possibly associated with Chinese herbs. Liver failure occurred in 47 HILI patients (accounting for 7.9%), cirrhosis in 45 patients (accounting for 7.6%), chronic HILI in 80 patients (accounting for 13.4%), 27 (4.5%) died, and only 2 (0.3%) underwent liver transplantation. CONCLUSIONS: Chinese herbs could cause LI or even death. Attention should be paid to herbal hepatotoxicity and improving monitoring system of HILI. PMID- 26955677 TI - [Effect of Tai Ji Quan Training on Strength and Function of Lower Limbs in the Aged]. AB - OBJECTIVE: To observe the effect of Tai Ji Quan (TJQ) training on strength and function of lower limbs in the aged. METHODS: Sixty senile subjects were recruited and assigned to the TJQ group and the control group (imparting health knowledge)by random digit table. Patients in the TJQ group received 24-style TJQ training for 18 months (60 min each time, 5 times per week), while those in the control group were imparted with sarcopenia related causes, pathogeneses, prevention and control measures. The maximum isometric strength of bilateral iliopsoas, quadriceps femoris, tibialis anterior muscle, hamstrings; the time for 5 sitting-up tests and Time Up and Go Test (TUGT), one-leg standing time with closed eyes test; and the score of Berg balance scale were compared between the two groups. RESULTS: Compared with before treatment, muscle strength increased in the TJQ group with an average increased capacity (rate) as follows, bilateral iliopsoas 5.5 kg (16.9%), quadriceps femoris 5.5 kg (26.2%), and tibialis anterior muscle 8.5 kg (36.2%) (all P < 0.05). The time for TUGT and 5 sitting-up tests was shortened by 1.3 s (16.7%) and 0.9 s (14.5%) respectively in the TJQ group. The time for one-leg standing time with closed eyes test was increased by 8.4 s (left) and 9.1 s (right) respectively. The score of Berg balance scale increased by 4.3% (P < 0.05). Compared with the control group, bilateral quadriceps femoris and tibialis anterior muscle strength increased significantly (P < 0.01); the time for TUGT and 5 sitting-up tests, the time for one-leg standing time with closed eyes test, scores of Berg balance scale were all improved in the TJQ group after intervention (P < 0.05). CONCLUSION: TJQ training could improve strength of iliopsoas, quadriceps femoris, tibialis anterior muscle in the aged, elevate their balance and locomotor activities, and possibly prevent and treat sarcopenia. PMID- 26955678 TI - [Efficacy Observation of Ultrasonic Conductometric Acupoint Penetration of Wenhua Zhitong Recipe for Adenomyosis Patients]. AB - OBJECTIVE: To observe the efficacy of ultrasonic conductometric acupoint penetration of Wenhua Zhitong Recipe (WZR) in treating adenomyosis. METHODS: Totally 40 adenomyosis patients with Shen-deficiency blood stasis syndrome were randomly assigned to the treatment group and the control group, 20 in each group. Patients in the treatment group received ultrasonic conductometric acupoint penetration of WZR from the 2nd day before menstruation to the end of menstruation, while those in the control group took WZR. All patients received 3 consecutive menstrual cycles. Endometrial contents of cyclooxygenase-2 (COX-2) and oxytocin receptor (OTR) were determined using SP immunohistochemical staining method before and after treatment. Clinical effect, efficacy of Chinese medical syndrome, changes of uterus volume, and contents of carbohydrate antigen 125 (CA125) were observed before and after treatment. RESULTS: There was no statistical difference in the total clinical effect between the two groups (P = 0.357). Efficacies for relieving abdominal pain and lumbar soreness during menstruation were better in the treatment group than in the control group (P < 0.05). Uterus volume, endometrial levels and integrals of COX-2 and OTR decreased in the two groups after treatment (P < 0.05, P < 0.01). CONCLUSION: Ultrasonic conductometric acupoint penetration of WZR and oral administration of WZR both could effectively improve adenomyosis patients' symptoms such as Shen deficiency, and blood stasis, reduce the foci of uterus, and relieve the pain. PMID- 26955679 TI - [Treatment of Graves Hyperthyroidism by Jiakangling Capsule Combined with Reduction of 131I: an Efficacy Observation]. AB - OBJECTIVE: To observe the clinical efficacy of Jiakangling Capsule (JC) combined with reduction of 1311 in treatment of Graves hyperthyroidism. METHODS: Totally 387 Graves hyperthyroidism patients were randomly assigned to the treatment group (200 cases) and the control group (187 cases). Patients in the treatment group took JC combined with reduction of 131I. The 131I dosage per gram of thyroid tissue was 50-80 microCi. They additionally took JC one week after taking 1311 for one consecutive month. Patients in the control group took 131 routinely as one disposable treatment. The 131I dosage per gram of thyroid tissue was 70-120 microCi, without using JC or other anti-thyroid drugs. All patients were reexamined after 24-month treatment. Whether hyperthyroidism was cured, incurred, or permanent was observed. Efficacies of thyroglobulin antibody (TGAb) and thyroid microsome antibody (TMAb) were compared between the two groups. RESULTS: Compared with the control group, the incurred ratio increased in the treatment group [3.2% (6/187) vs. 16.0% (32/200), P < 0.01], the incurred ratio of strong positive TGAb and TMAb patients increased [3.5% (2/57) vs. 27.1% (16/59), P < 0.01], the permanent hypothyroidism ratio decreased [21.1% (12/57) vs. 3.4% (2/59), P < 0.05 ]. CONCLUSION: JC combined with reduction of 1311 was superior in treating Graves hyperthyroidism induced permanent hypothyroidism than routine 1311 treatment, especially for strong positive TGAb and TMAb patients. PMID- 26955680 TI - [Intervention of Yangfei Ziyin Decoction on Sjogren's Syndrome Model Mice]. AB - OBJECTIVE: To observe the effect of Yangfei Ziyin Decoction (YZD) on symptoms, serum levels of TNF-alpha, IL-6, and aquaporin-5 (AQP-5), and pathology of Sj6gren's syndrome (SS) model mice. METHODS: Totally 60 mice were divided into 6 groups according to random digit table, i.e., the model group, the normal control group, the high, medium, low dose YZD groups (administered with YZD at 36.7, 18.4, 9.2 g/kg, 0.2 mL/10 g), the Chinese patent medicine group [CPM, administered with total glucosides of paeony at 0.6 g/kg], 10 mice in each group. All intervention was performed for six successive days in a week, with an interval of one day, a total of 50 days. Body weight, salivary secretion, food and water intake were measured at day10, 20, 30, 40, and 50, respectively. At day 50 blood was collected. Submandibular gland, thymus, and spleen were weighed. Serum levels of TNF-alpha, IL-6, and AQP-5 were detected by ELISA. Pathological changes of submandibular gland were observed. Results Compared with the normal control group, there was no change in water intake of mice in the model group, but with reduced salivary secretion (P < 0.01, P < 0.05). Thymus/spleen/submandibular gland weight and index increased in the model group (P < 0.01, P < 0.05). Compared with the model group at the same time point, salivary secretion increased in the CPM group and 3 YZD groups (P < 0.01 , P < 0.05). Compared with the model group, thymus/spleen/submandibular gland weight and index decreased in the CPM group (P < 0.01, P < 0.05). Thymus/submandibular gland weight and index decreased in the low dose YZD group (P < 0.01, P < 0.05). Thymus/submandibular gland weight and index, and spleen index decreased in high and medium dose YZD groups (P < 0.01 , P < 0.05). Levels of TNF-alpha and IL-6 decreased, but AQP-5 level increased in the CPM group (P < 0.05). AQP-5 level increased in high and medium dose YZD groups (P < 0.01 , P < 0.05). In the model group alveoli and duct of salivary gland were destroyed, alveoli and duct were irregular, epithelial cells were degenerated, necrotic, and desquamated. Mild-to moderate lymphocytic infiltration occurred around submandibular gland. Pathological changes were alleviated in the CPM group and 3 YZD groups. CONCLUSION: YZD could improve clinical symptoms, serum levels of TNF-alpha, IL-6, AQP-5, and pathological changes of SS model mice. PMID- 26955682 TI - [Effect of Wenyang Decoction on the Differentiation of CD34+ Progenitor Cells in Occupational Asthma Model Rats]. AB - OBJECTIVE: To study the effect of Wenyang Decoction (WD) on the differentiation of CD34+ progenitor cells of occupational asthma (OA) model rats. METHODS: Fifty healthy male SD rats were randomly divided into five groups, i.e., the model group, the blank control group,the WD group,the Western medicine group,the combined group, 10 in each group. Prednisone suspension (10 mg/kg) was administered to rats in the Western medicine group by gastrogavage. WD (20 g/kg) was administered to rats in the WD group by gastrogavage. Prednisone suspension plus WD was administered to rats in the combined group by gastrogavage. Normal saline was administered to rats in the model group and the blank control group by gastrogavage. The general condition of rats was observed. Expression levels of peripheral blood IL-5 and eotaxin, eosinophils (EOS), CD34+, CC chemokine receptor 3 (CCR3+) in bone marrow suspension were detected by ELISA, Wirght Giemsa, and flow cytometry, respectively. RESULTS: Compared with the blank control group,expression levels of IL-5 and eotaxin in peripheral blood were significantly higher (P < 0.01), and the count of EOS and CD34+ cells, as well as CD34+ /CCR3+ significantly increased (P < 0.01) in the model group. Compared with the model group, expression levels of IL-5 and eotaxin, the count of EOS, CD34+ cells, CD34+ / CCR3+ were lowered in three treated groups (P < 0.01). Compared with the Western medicine group, the count of EOS and CD34+ / CCR3+ decreased in the combined group (P < 0.01). The count of EOS was significantly lower in the combined group than in the WD group (P < 0.01). CONCLUSION: WD could reduce levels of in vivo inflammatory factors, and restrain the differentiation and recruitment of EOS,thereby alleviating the differentiation of CD34 progenitor cells to EOS. PMID- 26955681 TI - [Inhibitory Effect of Feiji Recipe on IDO Induced Immune Escape on the Murine Model of Lewis Lung Carcinoma]. AB - OBJECTIVE: To study the effect of Feiji Recipe (FR) intervening indoleamine 2,3 dioxygenase (IDO) induced immune escape on the murine model of Lewis lung carcinoma. Methods Totally 48 C57BL/6 mice inoculated with Lewis lung cancer cells transfected with human (enhanced green fluorescent protein,EGFP)-IDO gene were divided into four groups according to radom digit table, i.e., the model group (administered with normal saline by gastrogavage) , the Chinese medicine group (treated with FR Decoction at the daily dose of 100 mg/g by gastrogavage), the 1-methyl-D-trytaphan (1-MT) group (administered with 1-MT mixed liquor at the daily dose of 100 mg/kg by gastrogavage), and the Paclitaxel group (treated with Paclitaxel at the daily dose of 15 mg/kg by peritoneal injection), 12 in each group. The intervention was started from the 2nd day of modeling. The survival time was observed in 24 of them. Ratios of CD4+ CD25+ FoxP3+ regulatory T cells (Treg) in the spleen were detected in the rest 24 mice by flow cytometry respectively. RESULTS: Compared with the model group, the survival time was significantly prolonged in the Chinese medicine group and the 1-MT group (P < 0.01); ratios of Treg cells remarkably decreased in the Chinese medicine group, the 1-MT group, and the Paclitaxel group (P < 0. 01). Compared with the Paclitaxel group, the survival time was significantly prolonged in the Chinese medicine group and the 1-MT group (P < 0.01); ratios of Treg cells decreased significantly in the 1-MT group (P < 0.05). CONCLUSION: FR could inhibit the proliferation of lung cancer cells and immune eseape, improve the immune function, and prolong the survival of tumor-bearing mice. PMID- 26955683 TI - [Effects of Xuefu Zhuyu Granule and Danlou Tablet on Anti-atherosclerosis Rats and Potential Mechanisms]. AB - OBJECTIVE: To observe anti-atherosclerotic effect of Xuefu Zhuyu Granule (XZU) and Danlou Tablet (DT) on blood lipids, platelet derived growth factor (PDGF), vascular smooth muscle cells (VSMCs) proliferation, extracellular signal regulated kinase (ERK) signal pathway in atherosclerosis (AS) model rats, and to explore their potential mechanisms. METHODS: Forty male Wistar rats were randomly divided into five groups, i.e., the normal control group, the model group, the Atorvastatin group, the DT group, the XZG group, 8 in each group. Rats in the normal control group were fed with basic forage for 12 weeks, while rats in the other four groups were fed with high fat forage plus intraperitoneal injection of vitamin D3 to build AS model. Then rats in the model control group, the Atorvastatin group, the DT group, the XZG group were administered with normal saline, Atorvastatin suspension (0.18 mg/mL), DT suspension (45 mg/mL), and XZG (1 g/mL) by gastrogavage for 8 successive weeks, respectively. After intervention serum levels of TC, TG, LDL-C, HDL-C, and PDGF were detected by ELISA. Pathological changes in thoracic aorta were observed by HE staining. Protein expression levels of ERK1/2 and pERK1/2 in thoracic aorta were measured by Western blot. RESULTS: Compared with the normal group, serum TC, TG, LDL-C, PDGF levels, and expression levels of ERK1/2 and pERK1/2 significantly increased (P <0. 05) in the model control group. HE staining showed irregular intimal thickness, accumulated endothelial foam cells, lipids deposited, disarranged media VSMCs, forming typical AS plaque. Compared with the model group, TC and PDGF levels decreased in all medicated groups (P < 0.05, P < 0.01). Serum levels of TG and LDL-C significantly decreased in the Atorvastatin group and the DT group (P < 0.01, P < 0.05). Expressions of ERK1/2 and pERK1/2 significantly decreased in the Atorvastatin group, the DT group, and the XZG group (P < 0.01). HE staining also showed typical AS plaque in three medicated groups, but with reduced pathological degree of endometrial hyperplasia and plaque area. CONCLUSIONS: XZG and DT could reduce the plaque area and attenuate pathological degree of AS in model rats, thereby postponing the progress of AS. Its mechanism might be achieved through reducing serum lipids and release of PDGF, inhibiting ERK signal pathway activation and VSMC proliferation. PMID- 26955684 TI - [Effect of Zishen Huoxue Recipe on Pathomorphology in Coronary Heart Disease Rats with Shen Deficiency Blood Stasis Syndrome]. AB - OBJECTIVE: To observe the effect of Zishen Huoxue Recipe (ZHR) on pathomorphology in coronary heart disease (CHD) rats with Shen deficiency blood stasis syndrome (SDBSS). METHODS: Totally 60 healthy Wistar rats were divided into the blank control group, the model group, high, middle, and low dose ZHR groups according to random digit table, 12 in each group. Myocardial ischemia SDBSS rat model was prepared by ligating the left anterior descending coronary artery and injecting hydrocortisone. ZHR physic liquor was administered to rats in high, middle, and low dose ZHR groups at the daily dose of 21.6, 10.8, 5.4 g/kg by gastrogavage for 7 successive days, equal volume of pure water was administered to rats in the blank control group and the model group by gastrogavage for 7 successive days. Rat heart was collected for pathomorphological observation under light microscope. RESULTS: In the model group the heart muscle fiber was swollen and deformed with widened space, loose and dropsy tissues. Blood vessels in myocardial mesenchymal were dilated, infiltrated with more inflammatory cells. Myocardial cells were markedly swollen, degenerated, or necrotic, with caryolysis or disappearance of partial nuclear. A large amount of collagen fibrous tissue became hyperplasia. Endocardial blood vessels were swollen and degenerated with infiltration of few inflammatory cells. Epicardium tissue and structure were destroyed and got hyperplasia. Swollen, degenerated, or necrotic vessels could be seen, with infiltration of more inflammatory cells and collagen deposition. Pathomorphological injuries were alleviated in each ZHR group. The higher ZHR concentration, the milder the injury degree of myocardial tissue, the more limited range of damage. CONCLUSION: ZHR could attenuate pathomorphological injuries of myocardial ischemia rats with SDBSS and regulate myocardial function, thus improving myocardial ischemia in CHD rats with SDBSS. PMID- 26955685 TI - [Effects of Salidroside on Tic Behavior of Tourette Syndrome Model Rats]. AB - OBJECTIVE: To observe the effect of salidroside on tic behavior and in vivo dopamine DA) and serotonin (5-HT) levels in Tourette syndrome (TS) model rats. METHODS: Forty rats were randomly divided into the blank control group, the TS model group, the haloperidol-treated group (0.5 mg/kg x d(-1)), and the salidroside-treated group (50 mg/kg x d(-1)), 10 in each group. TS rat model was induced by imino-dipropio-nitrile (IDPN). Peritoneal injection of haloperidol and salidroside was started from the 4th day of modeling in the haloperidol-treated group and the salidroside-treated group respectively. Normal saline was peritoneally injected to rats in the blank control group and the TS model group respectively. Stereotyped behavior was scored, and changes of DA and 5-HT levels in blood and striatum were measured before modeling, after modeling, and after intervention. RESULTS: Compared with the blank control group, the score of the tic behavior was elevated (P < 0.01) , levels of DA and 5-HT in plasma and striatum were reduced in the model group (P < 0.01, P < 0.05). Compared with the same group after modeling, the tic behavior score decreased and plasma DA levels increased in the two treated groups after intervention (P < 0.01). 5-HT content increased in the salidroside-treated group (P < 0.01). Compared with the model group after intervention, the tic behavior score was significantly reduced (P < 0.01), and DA levels in plasma and striatum were elevated (P < 0.01, P < 0.05) in the salidroside-treated group and the haloperidol-treated group. Compared with the haloperidol-treated group, the tic behavior score increased (P < 0.01), DA levels in plasma and striatum were lowered (P < 0.01, P < 0.05), the 5-HT level increased in plasma and striatum (P < 0.01, P < 0.05) in the salidroside-treated group. CONCLUSIONS: In the salidroside-treated group, the tic behavior was significantly reduced, and DA levels in plasma and striatum were elevated. Its mechanism might be related to regulating activities of dopamine neurons in striatum. PMID- 26955686 TI - [Effect of Baichanting Compound on Dopamine Contents in Parkinson's Disease Model Mice]. AB - OBJECTIVE: To observe the effect of Baichanting Compound (BC) on dopamine (DA) in striatum of Parkinson's disease (PD) mice, and to screen the optimal component proportion. METHODS: The PD model was established in 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) induced C57BL/6 mice. By using uniform design, they were intervened by three extracts of BC in different proportions [Acanthopanax senticosus extract (X1): white peony root extract (X2): Uncaria rhynchophylla extract (X3) = 30.00: 34.92: 82.50, 48.00: 19.98: 72.19, 18.00: 44.88: 61.88, 36.00: 29.94: 51.56, 54.00: 15.00: 41.25, 24.00: 39.90: 30.94, 42.00: 24.96: 20.63). Equal volume of 5% carboxymethylcellulose sodium was administered to mice in the model group and the normal group by gastrogavage. All medication was lasted for 20 successive days. The dopamine (DA) content was determined by ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS). Except 10 in the normal group, 20 PD model mice were screened and divided into the model group and the BC group (with the optimal proportion) according to random digit table. BC extract in optimal proportion was administered to mice in the BC group by gastrogavage, while equal volume of 5% carboxymethylcellulose sodium was administered to mice in the model group and the normal group by gastrogavage. All medication was lasted for 20 successive days. Praxiology was observed in each group. DA content in striatum was also detected. Results Compared with the normal group, the DA content in striatum decreased significantly in the model group (P < 0.01), suggesting a successful PD modeling. Compared with the model group, the DA content in striatum increased significantly in 1 and 2 groups (P<0.05). According to results of quadratic polynomial stepwise regression statistics, the regression equation obtained was: Y = 0.265 + 0.026 X 2 - 0.056 X 3 + 0.334 x 10(-3) x X1 x X3 + 0.691 x 10(-3) X X3(2). X3 extract was the main factor influencing the effectiveness (P < 0.01). The optimal proportion of BC was predicted by the regression equation: X1 = 54.00 mg/(kg x d), X2 = 44.88 mg/(kg x d), the X3 = 82.50 mg/(kg x d). The pole climbing time was shortened, times of autonomic activities increased, DA content was elevated, all with statistical difference in BC groups (P < 0.01, P < 0.05). CONCLUSION: BC could increase DA content in PD model mice with the optimal proportion as 54.00: 44.88: 82.50. PMID- 26955687 TI - [Effect of Huanglian Jiedu Decoction on Monocyte Development in apoE Gene Knockout Mice]. AB - OBJECTIVE: To observe monocyte (Mo) development in wild type C57BL/6 mice and apoE gene knockout (apoE(-/-)) mice, and to evaluate the immuno-regulatory effect of Huanglian Jiedu Decoction (HJD) on peripheral Mo development in apoE(-/-) mice. METHODS: Four, 8, 12, and 16 weeks old female C57BL/6 mice were set up as control groups of different ages, while 4, 8, 12, and 16 weeks old female apoE(-/ ) mice were set up as hyperlipidemia groups of different ages. Four-week old female C57BL/6 mice were recruited as a blank group. Four-week old female apoE(-/ ) mice were randomly divided into the control group, the Western medicine group, and the Chinese medicine group by paired comparison, 5 in each group. Equivalent clinical dose was administered to mice according to body weight. Mice in the Western medicine group were administered with Atrovastatin at the daily dose of 10 mg/kg by gastrogavage, while those in the Chinese medicine group were administered with HJD at the daily dose of 5 g/kg by gastrogavage. Body weight was detected each week. After 4 weeks blood lipids levels (such as TG, TC, LDL-C, and HDL-C), and the proportions of Mo and Ly6c(hi) were detected. RESULTS: Compared with 4-week-old homogenic mice, the proportion of Mo decreased in 16 week-old C57BL/6 mice (P < 0.05). Levels of TC and TG, and the proportion of Ly6c(hi) subtype increased, but the proportion of Mo de- creased in 8-week-old apoE(-/-) mice (P <0. 05). Levels of TC, TG, and LDL-C increased in 12-week-old apoE(-/-) mice (P < 0.05). Levels of TC, TG, LDL-C, and HDL-C increased in 16 week-old apoE(-/-) mice (P < 0.05, P < 0.01). Compared with 8-week-old homogenic mice, the proportion of Mo decreased in 16-week-old C57BL/6 mice (P < 0.05); levels of TC and LDL-C increased in 12-week-old apoE(-/-) mice (P < 0.05); levels of TC and HDL-C increased in 16-week-old apoE(-/-) mice (P < 0.05, P < 0.01). Compared with C57BL/6 mice of the same age, TC and TG increased, HDL-C decreased (P < 0.01) in 4-and 8-week-old apoE(-/-) mice (P < 0.01); levels of TC, TG, LDL-C increased, and HDL-C level decreased in 12- and 16-week-old apoE(-/-) mice (P < 0.05, P < 0.01); the proportion of Mo increased in 4-week-old apoE(-/-) mice (P < 0.05); proportions of Mo and Ly6c(hi) increased in 8-week-old apoE(-/-) mice (P < 0.05). Compared with the blank control group, levels of TC, TG, and LDL-C, proportions of Mo and Ly6c(hi) increased (P < 0.01, P < 0.05), but HDL-C level decreased (P <0. 01) in the control group after intervention. Compared with the control group, body weight gained less in the Western medicine group and the Chinese medicine group (P < 0.05); the proportion of Ly6c(hi) subtype decreased in the Chinese medicine group (P < 0.05). CONCLUSIONS: In development process blood lipids levels in apoE(-/-) mice are not only associated with age. Blood lipids levels induced growth changes in natural immune system are also correlated with age. In early stage of lipids development HJD intervention could correct this special immune disorder in apoE(-/-) mice. PMID- 26955688 TI - [Guiding Significance of "Mistreatment by Warming Therapy" in Treatment of Non small Cell Lung Cancer]. AB - "Mistreatment by warming therapy" refers to various symptoms/syndromes caused by improper use of fire methods mentioned in Treatise on Febrile Diseases, which are similar to damaged yin induced fire-heat syndrome (injury of yin, consumption of qi, loss of yin, consumption of body fluid) manifested after radiotherapy and/or chemotherapy in modern clinics. Better efficacy was obtained in treating various symptoms/syndromes by using nourishing yin purging fire method. In this paper authors focuses on exploring guiding significance of using "Mistreatment by warming therapy" in treating non-small cell lung cancer (NSCLC). PMID- 26955689 TI - [Experience of Professor SUN Xue-mei in Treatment of Primary Thrombocythemia]. AB - There is no radical cure for essential thrombocythemia currently. Professor SUN Xue-mei has extensive clinical experience in treating it by combined therapy of Chinese and Western medicine. In this paper, authors tried to summarize her experience from guiding ideology and therapeutic points. Authors insisted on the direction of integrative medicine on the basis of syndrome differentiation, paying attention to psychological counseling,and applied individual treatment in clinics. PMID- 26955690 TI - [Thinking and Methods for Demonstrating the Effectiveness of Chinese Herbal Compounds from the Perspective of Pharmacokinetics]. AB - To exert pharmacological effects, no matter therapeutic effect or toxic/side effect, it's necessary to achieve enough plasma concentration. Chinese medical compounds, which contain various ingredients, influence the metabolism of some active ingredients through the interaction of ingredients to improve curative effects or reduce toxic/side effects. Pharmacokinetics can be used to explore how Chinese medical compounds influence the in vivo metabolism of some active ingredients to achieve better curative effects. PMID- 26955691 TI - [Treating Ankylosing Spondylitis by Chinese Materia Medica Combined Recombinant Human TNF-alpha Receptor II-IgG Fusion Protein for Injection: Report of Two Patients]. PMID- 26955692 TI - [Regulatory Effect of Resveratrol on microRNA in Inflammation Reaction]. PMID- 26955693 TI - [The establishment of Chinese guidelines for management of severe sepsis and septic shock 2014, and comparison with former version of the guideline]. PMID- 26955694 TI - [Challenges to evidence-based medicine in an era of artificial intelligence]. PMID- 26955695 TI - [Effect of timing of initiation of renal replacement therapy on prognosis in septic patients with acute kidney injury: a Meta analysis]. AB - OBJECTIVE: To systemically review the effects of timing of initiation of renal replacement therapy (RRT) on prognosis in septic patients with acute kidney injury (AKI). METHODS: A systematic search for randomized controlled trials (RCTs) and other clinical studies focused on comparing varied timing of initiation of RRT in septic AKI patients was performed in English or Chinese from PubMed, Web of Science, EMBASE, CNKI, Wanfang data, VIP from January 2000 to July 2014. Data screened were extracted with Cochrane systemically review method, and enrolled literature was collected for Meta analysis with RevMan 5.2 software. Total mortality, 28-day mortality, the total length of hospital stay and intensive care unit (ICU) stay in septic AKI patients with early or late initiation of RRT was analyzed. Funnel plots were drawn to detect publication bias. RESULTS: Five retrospective comparative studies with a total of 885 patients were enrolled. Random effect model in Meta analysis showed that there was no significant difference in total mortality between early RRT group and late RRT group [65.7% (226/344) vs. 68.7% (239/348), odds ratio (OR) = 0.71, 95% confidence interval (95%CI) = 0.38-1.31, P = 0.27]. The funnel plot demonstrated publication bias. Fixed effect model showed that there was significant difference in 28-day mortality between early RRT group and late RRT group [43.4% (66/152) vs. 55.3% (94/170), OR = 0.59, 95% CI = 0.36-0.94, P = 0.03 ]. The funnel plot demonstrated publication bias too. The data of total length of hospital stay and ICU stay could not be Meta-analyzed because of different data distribution, but no differences in total length of hospital stay and ICU stay between early and late RRT groups for septic AKI patients were found. CONCLUSION: Early RRT could reduce the 28-day mortality in patients with septic AKI compared with late RRT, but it did not lower the total mortality. PMID- 26955696 TI - [Microbial characteristics in culture-positive sepsis and risk factors of polymicrobial infection in ICU]. AB - OBJECTIVE: To investigate the clinical characteristics and pathogenic microorganisms in culture-positive sepsis, to identify its risk factors, and evaluate the prognosis on polymicrobial infection in intensive care unit (ICU). METHODS: A descriptive retrospective study was conducted. Clinical data of patients aged >= 18 years, diagnosed as culture-positive sepsis, and admitted to six ICUs of Guangdong General Hospital from October 12th, 2012 to December 1st, 2014 were enrolled. Based on the number of isolated pathogens, patients were divided into polymicrobial infection group (>= two pathogens) and monomicrobial infection group (one pathogen) to investigate the clinical characteristics of patients with culture-positive sepsis and the causative pathogens. Multiple logistic regression was conducted to identify the risk factors for polymicrobial infection. Kaplan-Meier curve was plotted to analyze a 90-day survival rate from the onset of positive blood culture. RESULTS: 299 patients with positive blood culture were enrolled. A total of 450 strains of pathogens were isolated including 246 gram-positive cocci (54.67%), 167 gram-negative bacilli (37.11%) and 37 fungi (8.22%). Ninety-one patients had polymicrobial infection, and 208 with monomicrobial infection. Compared with monomicrobial infection group, patients suffering from polymicrobial infection had more advanced age (years: 73.19 +/- 18.02 vs. 60.83 +/- 18.06, t = -5.447, P = 0.000), also with higher incidence of cerebrovascular diseases [39.56% (36/91) vs. 17.79% (37/208), chi2 = 16.261, P = 0.000] or chronic renal insufficiency [15.38% (14/91) vs. 7.21% (15/208), chi2 = 4.828, P = 0.028], higher incidence of recent hospital stay (>= 2 days) within 90 days [73.63% (67/91) vs. 61.54% (128/208), chi2 = 4.078, P = 0.043], longer mechanical ventilation duration [days: 4 (0, 17) vs. 1 (0, 6), U = 7673.000, P = 0.006], longer length of hospital stay before blood was drawn for culture [days: 21 (7, 40) vs. 9 (3, 17), U = 6 441.500, P = 0.006], and higher incidence of pre-admission intravenous use of antibiotics [84.62% (77/91) vs. 66.83% (139/208), chi2 = 9.989, P = 0.002]. Multiple logistic regression analysis showed that advanced age [odd ratio (OR) = 1.032, 95% confidential interval (95% CI) = 1.015-1.050, P = 0.000], cerebrovascular diseases (OR = 2.247, 95%CI = 1.234-4.090, P = 0.008), prolonged mechanical ventilation (OR = 1.041, 95% CI = 1.014-1.069, P = 0.003), and recent hospital stay (>= 2 days) within 90 days (OR = 1.968, 95%CI = 1.079-3.592, P = 0.027) were the independent risk factors for polymicrobial infection. In the polymicrobial infection group, the length of ICU stay [days: 46 (22, 77) vs. 13 (7, 22), U = 3 148.000, P = 0.000] and hospital stay [days: 81 (47, 118) vs. 28 (17, 46), U = 3 620.000, P = 0.000] were significantly longer, and the ICU mortality [65.93% (60/91) vs. 43.75% (91/208), chi2 = 12.463, P = 0.000 ] and hospital mortality [68.13% (62/91) vs. 45.67% (95/208), chi2 = 12.804, P = 0.000] were significantly higher, and on the other hand the 90-day survival rate was significantly lower than that in the monomicrobial infection group (chi2 = 8.513, P = 0.004). CONCLUSIONS: The most common pathogen of ICU sepsis is gram-positive cocci. Independent risk factors for polymicrobial infections were found to be advanced age, occurrence of cerebrovascular disease, prolonged mechanical ventilation, and recent hospitalization. Polymicrobial infection is associated with longer length of ICU and hospital stay, as well as higher mortality. PMID- 26955697 TI - [A study on feasibility of emergency bedside ultrasound-guided central venous catheterization]. AB - OBJECTIVE: To evaluate the feasibility and clinical significance of emergency bedside ultrasound-guided central venous catheterization performed by emergency department doctors. METHODS: The clinical data of 216 patients, who underwent central venous catheterization in the Department of Emergency of Shengjing Hospital of China Medical University from January 2009 to June 2014 were retrospectively analyzed. All the patients received femoral vein puncture or internal jugular vein catheterization. The patients were divided into three groups according to the method of catheterization: 72 patients received emergency ultrasound-guided central venous catheterization by emergency doctors independently were assigned as A group, 72 patients underwent catheterization by emergency doctors after being demarcated by ultrasound doctors served as B group, and 72 patients who underwent catheterization method guided by traditional landmark served as C group. Success rate, time spent for catheterization, number of attempts for intubation, and incidence of complications were compared among three groups. RESULTS: As compared with that of groups B and C, a higher success rate [98.61% (71/72) vs. 83.33% (60/72), 73.61% (53/72), both P < 0.01] was found in group A, also with a shorter successful time for insertion of the catheter (minutes: 5.5 +/- 2.5 vs. 9.6 +/- 3.7, 16.6 +/- 7.2, both P < 0.05), less frequency of the catheter insertion (times: 1.0 +/- 0.0 vs. 1.8 +/- 0.7, 2.7 +/- 2.6, both P < 0.05), and lower incidence of changing puncture site due to insert failure [1.4% (1/72) vs. 8.3% (6/72), 20.8% (15/72), both P < 0.05], lower incidence of mechanical and infective complication [15.3% (11/72) vs. 41.7% (30/72), 59.7% (43/72), both P < 0.05], and also lower catheterization related infection risk [13.9% (10/72) vs. 15.3% (11/72), 12.5% (9/72), both P > 0.05]. CONCLUSION: Emergency bedside ultrasound-guided catheterization resulted in higher success rate and less related complication, therefore it can be recommended for widely application in emergency department treatment. PMID- 26955698 TI - [The value of passive leg raising test in predicting fluid responsiveness in patients with sepsis-induced cardiac dysfunction]. AB - OBJECTIVE: To assess the value of passive leg raising (PLR) test in predicting fluid responsiveness in patients with sepsis-induced cardiac dysfunction. METHODS: A prospective observational cohort study was conducted. Thirty-eight patients under mechanical ventilation suffering from sepsis-induced cardiac dysfunction admitted to Department of Surgical Intensive Care Unit of First Affiliated Hospital of Sun Yat-Sen University from September 2013 to July 2014 were enrolled. The patients were studied in four phases: before PLR (semi recumbent position with the trunk in 45 degrees ), PLR (the lower limbs were raised to a 45 degrees angle while the trunk was in a supine position), before volume expansion (VE, return to the semi-recumbent position), and VE with infusing of 250 mL 5% albumin within 30 minutes. Hemodynamic parameters were recorded in every phase. The patients were classified into two groups according to their response to VE: responders (at least a 15% increase in stroke volume, A SV(VE) >= 15%), and non-responders. The correlations among all changes in hemodynamic parameters were analyzed by linear correlation analysis, and the receiver operating characteristic curve (ROC) was plotted to assess the value of hemodynamic parameters before and after PLR in predicting fluid responsiveness. RESULTS: Of 38 patients, 25 patients were responders, and 13 non-responders. There was no significant difference in the baseline and hemodynamic parameters at semi-recumbent position between the two groups. The changes in SV and cardiac output (CO) after PLR (Delta SV(PLR) and Delta CO(PLR)) were significantly higher in responders than those of non-responders [ Delta SV(PLR): (14.7 +/- 5.7)% vs. (6.4 +/- 5.3)%, t = 4.304, P = 0.000; DeltaCO(PLR): (11.2 +/- 7.5)% vs. (3.4 +/- 2.3)%, t = 3.454, P = 0.001], but there was no significant difference in the changes in systolic blood pressure, mean arterial pressure, pulse pressure, and heart rate after PLR (Delta SBP(PLR), Delta MAP(PLR), Delta PP(PLR) and Delta HR(PLR)) between two groups. Delta SV(VE) in responders was significantly higher than that of the non-responders [(20.8 +/- 5.5) % vs. (5.0 +/- 3.7) %, t = 8.347, P = 0.000]. It was shown by correlation analysis that DeltaSV(PLR) was positively correlated with Delta SV(VE) (r = 0.593, P = 0.000), Delta CO(PLR) was positively correlated with DeltaSV(VE) (r = 0.494, P = 0.002). The area under ROC curve (AUC) of Delta SV(PLR) >= 8.1% for predicting fluid responsiveness was 0.860 +/- 0.062 (P = 0.000), with sensitivity of 92.0% and specificity of 70.0%; the AUC of Delta CO(PLR) >= 5.6% for predicting fluid responsiveness was 0.840 +/- 0.070 (P = 0.000), with sensitivity of 84.0% and specificity of 76.9%; the AUC of Delta MAP(PLR) >= 6.9% for predicting fluid responsiveness was 0.662 +/- 0.089, with sensitivity of 68.0% and specificity of 76.9%; the AUC of Delta SBP(PLR) >= 6.4% for predicting fluid responsiveness was 0.628 +/- 0.098, with sensitivity of 76.0% and specificity of 61.5%; the AUC of Delta PP(PLR) >= 6.2% for predicting fluid responsiveness was 0.502 +/- 0.094, with sensitivity of 56.0% and specificity of 53.8%; the AUC of Delta HR(PLR) >= -1.7% for predicting fluid responsiveness was 0.457 +/- 0.100, with sensitivity of 56.0% and specificity of 46.2%. CONCLUSION: In patients with sepsis-induced cardiac dysfunction, changes in SV and CO induced by PLR are accurate indices for predicting fluid responsiveness, but the changes in HR, MAP, SBP and PP cannot predict the fluid responsiveness. PMID- 26955699 TI - [Effect of early goal-directed therapy on mortality in patients with severe sepsis or septic shock: a Meta analysis]. AB - OBJECTIVE: To investigate whether early goal-directed therapy (EGDT) could improve the mortality rate in patients with severe sepsis or septic shock. METHODS: Articles were retrieved from PubMed, Cochrane Library, Embase data, Wanfang data, and CNKI from January 1980 to May 2015. Inclusion criteria included the subjects concerning patients with severe sepsis or septic shock reported as randomized controlled trial (RCT), clinical controlled trial (CCT), case-control studies, cohort studies with complete data, which endpoints were the short-term mortality [in-hospital, intensive care unit (ICU) or 28-day] and long-term mortality (60-day, 90-day or 1 year). RevMan 5.2 software was used for Meta analysis of effect of EGDT on mortality rate in patients with severe sepsis or septic shock, and funnel plot was drawn to evaluate the quality of enrolled literature. RESULTS: There were 12 studies meeting inclusive criteria including 5 528 patients, 4 RCTs, 3 case-control studies, 4 cohort studies, and 1 quasi experimental research. It was shown by Meta analysis that EGDT was associated with significant decrease in the short-term mortality [relative risk (RR) = 0.72, 95% confidence interval (95% CI) = 0.64-0.80, P < 0.000 01], but not associated with decrease of long-term mortality (RR = 0.99, 95% CI = 0.92-1.06, P = 0.81). The funnel plot showed that there was no publication bias. EGDT was recommended as grade C. CONCLUSIONS: EGDT was associated with significant improvement in short-term mortality but not with long-term mortality in patients with severe sepsis or septic shock. Grade C was recommended by our study. PMID- 26955700 TI - [The value of pro-adrenomedullin in early diagnosis of sepsis]. AB - OBJECTIVE: To explore the early diagnostic value of pro-adrenomedullin (pro-ADM) in sepsis. METHODS: A prospective study was conducted. Eighty-two patients with acute infection admitted to Department of Emergency of Shanxi Medical University Second Hospital from April 2013 to March 2014 were enrolled. According to the diagnostic criteria of sepsis, the patients with acute infection were divided into ordinary infection group [infection without systemic inflammatory response syndrome (SIRS), n = 25] and sepsis group (infection combined with SIRS, n = 57). According to degree of severity of sepsis, the latter group was subdivided into three subgroups: sepsis group (n = 22), severe sepsis group (n = 27) and septic shock group (n = 8). Twenty-four healthy persons were included to serve as healthy control group. The venous blood from all the research objects in hospital was collected within 24 hours. The levels of pro-ADM and procalcitonin ( PCT ) were determined by enzyme linked immunosorbent assay (ELISA), and acute physiology and chronic health evaluation II (APACHE II ) score was recorded. The relationship between pro-ADM and PCT and also APACHE II score was analyzed with Pearson correlation analysis. The receiver-operating characteristic curve (ROC) of pro-ADM and PCT were used to evaluate the diagnostic acuity of sepsis. RESULTS: The plasma levels of pro-ADM, PCT and APACHE II score in sepsis group were significantly higher than those in ordinary infection group and healthy control group [pro-ADM (ng/L): 66.69 +/- 1.73 vs. 53.43 +/- 2.70, 45.87 +/- 1.43; PCT (ng/L): 1 336.49 +/- 40.26 vs. 1 083.09 +/- 47.99, 959.04 +/- 37.53; APACHE II score: 14.60 +/- 0.81 vs. 8.10 +/- 1.14, 3.00 +/- 1.15, all P < 0.01]. With the aggravation of sepsis, the levels of pro-ADM, PCT and APACHE II score were gradually increased, and there were significant differences among sepsis, severe sepsis, and septic shock groups [pro-ADM (ng/L): 64.91 +/- 2.50, 73.56 +/- 2.80, 84.67 +/- 4.52; PCT (ng/L): 1 152.65 +/- 48.62, 1 233.93 +/- 63.06, 1 475.71 +/- 109.93; APACHE II score: 12.91 +/- 1.15, 14.55 +/- 1.14, 19.37 +/- 2.40, P < 0.05 or P < 0.01]. Pearson correlation analysis results showed that the level of pro ADM was positively related with PCT (r = 0.473, P = 0.006), and it was also positively correlated with APACHE II score (r = 0.707, P = 0.008). ROC curve analysis showed that area under the ROC curve (AUC) of pro-ADM for diagnosis of sepsis was 0.823 (P = 0.003). When the cutoff value was 59.40 ng/L, the sensitivity was 80.7%, the specificity was 68.0%, the positive predictive value was 85.2%, and the negative predictive value was 60.7%. AUC of the PCT for diagnosis of sepsis was 0.653 (P = 0.043). When the cutoff value was 1 194.67 ng/L, the sensitivity was 68.4%, the specificity was 64.0%, the positive predictive value was 81.8%, and the negative predictive value was 44.7%. It was proved that the pro-ADM had a higher diagnostic value for sepsis than PCT. CONCLUSION: The plasma levels of pro-ADM can be used as an early indicator in diagnosis and severity evaluation and prognosis in patients with sepsis. PMID- 26955701 TI - [Accuracy of procalcitonin for diagnosis of sepsis in adults: a Meta-analysis]. AB - OBJECTIVE: To assess the clinical value of procalcitonin (PCT ) in the diagnosis of sepsis in adults. METHODS: An extensive search for related literature from the Wanfang data, CNKI, VIP, Medline/PubMed, Embase/OvidSP and the Cochrane Library up to December 2014 was performed. The articles, including prospective observational studies or randomized controlled trials, regarding PCT for the diagnosing of sepsis were enrolled. Only patients older than 18 years were included. Patients with sepsis, severe sepsis, or septic shock served as the experimental group, and those with a systemic inflammatory response syndrome (SIRS) of non-infectious origin as control group. The language of literature included was English or Chinese. The quality of the studies was assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. Heterogeneity, pooled diagnostic odds ratio (DOR), pooled sensitivity, pooled specificity, pooled positive likelihood ratio, pooled negative likelihood ratio, the area under the summary receiver operating characteristic curve (SROC) and subgroup analysis were analyzed with the software of Metadisc 1.4. RESULTS: A total of 6 385 published reports were collected, and among them 24 met the inclusion criteria, including a total. of 3 107 patients. The studies showed substantial heterogeneity (I2 = 69.4%), and random effect model was used for Meta analysis, showing that the pooled DOR was 10.37 [95% confidence interval (95%CI) = 7.10-15.17]. No evidence of a threshold effect was found (Spearman correlation coefficient = 0.27, calculated by logarithm of sensitivity and logarithm of 1 specificity, P = 0.20). The DOR values of pooled and each study were not distributed along the same line in forest plots, and Cochran-Q = 78.33, P = 0.000 0, showing that there was heterogeneity in result from non threshold effect. Except for partial heterogeneity caused by non threshold effect, the result of Meta regression analysis including PCT detection method, categories of disease, research location and so on showed P values were all higher than 0.05. Thus, the heterogeneity could not be explained by Meta regression analysis. The pooled sensitivity was 74% (95% CI = 72%-76%), the pooled specificity was 70% (95% CI = 67%-72%), the pooled positive likelihood ratio was 2.79 (95% CI = 2.31-3.38), the pooled negative likelihood ratio was 0.34 (95% CI = 0.28-0.41), and the pooled AUC was 0.83 (95% CI = 0.79-0.87). AUC in medical patients was 0.80 (95% CI = 0.75-0.85), which was higher than that in surgical patients [0.71 (95% CI = 0.65 0.81)]. CONCLUSIONS: Our results indicate a moderate degree of value of PCT for diagnosis of sepsis in adult patients. The diagnostic accuracy in medical patients is higher than that in surgical patients. PCT is a good auxiliary biomarker for diagnosis of sepsis. PMID- 26955702 TI - [Effect of hemofiltration combined with hemoabsorption on improvement of immune function in septic patients with low expression of human leukocyte antigen DR]. AB - OBJECTIVE: To investigate the effect on improving immune function by hemofiltration combined with hemoabsorption in septic patients with low human leukocyte antigen DR (HLA-DR) expression. METHODS: A prospective randomized controlled trial was conducted. Sixty sepsis patients aged over 18 years, with HLA-DR expression lower than 30% were enrolled, and they were randomly divided into experimental group and control group, n = 30 in each group. The patients were treated with standard operating procedure for sepsis, and hemofiltration combined with hemoabsorption were added in addition in the experimental group within 1-3 days. The continuous venovenous hemofiltration (CVVH) mode was performed, with former dilution volume 4 L/h, and the hemofilter HF2000 was carried out with blood absorber HA-330H. The expression of HLA-DR in peripheral blood mononuclear cells was determined before the treatment and 3, 5, 7 days after treatment. Acute physiology and chronic health evaluation II (APACHE II) score, duration of mechanical ventilation, length of intensive care unit (ICU) stay, and 28-day survival rate were evaluated in both groups. RESULTS: The HLA-DR expression before treatment in experimental group and control group was both lower than 30%, and there was no statistical difference [(25.9 +/- 7.3)% vs. (26.4 +/- 6.7)%, P > 0.05]. The HLA-DR expression at 3, 5, 7 days after treatment in experimental group was gradually increased, and it was significantly higher than that of the control group [3 days: (38.9 +/- 8.6)% vs. (29.3 +/- 7.1)%, 5 days: (42.7 +/- 9.2)% vs. (31.4 +/- 6.5)%, 7 days: (40.9 +/- 8.5)% vs. (29.4 +/- 6.7)%, all P < 0.05]. There was no significant difference in APACHE II score before treatment between experimental group and control group (22.4 +/- 5.3 vs. 21.7 +/- 6.2, P > 0.05). APACHE II score at 3, 5, and 7 days after treatment was gradually decreased in experimental group, and it was obviously lower than that of the control group (3 days: 18.6 +/- 3.6 vs. 20.5 +/- 4.3, 5 days: 15.8 +/- 3.9 vs. 21.1 +/- 4.4, 7 days: 14.9 +/- 4.2 vs. 19.8 +/- 3.7, all P < 0.05). Compared with the control group, the duration of mechanical ventilation (days: 13.3 +/- 3.4 vs. 19.8 +/- 3.7, t = 6.432, P = 0.003) and length of ICU stay (days: 20.7 +/ 3.9 vs. 26.8 +/- 4.7, t = 5.452, P = 0.006) in experimental group were significantly shortened, and the 28-day survival rate was significantly elevated (83.3% vs. 73.3%, chi2 = 3.121, P = 0.016). CONCLUSION: Hemofiltration combined with hemoabsorption can improve the expression of HLA-DR in sepsis patients with low expression of HLA-DR, and it can improve immune function and prognosis of sepsis patients in certain degree. PMID- 26955703 TI - [Thrombocytopenia induced by lipopolysaccharide may be not related to coagulation and inflammatory response]. AB - OBJECTIVE: To explore the relationship between thrombocytopenia (TCP) induced by lipopolysaccharide (LPS) and coagulation or inflammatory response in mouse. METHODS: Forty-eight C57BL/6 mice were divided into control group, low-dose, and high-dose LPS treatment groups by random number table method, and each group was subdivided into 4-hour and 24-hour subgroups randomly, with 8 mice in each subgroup. 0.5 mg/kg or 50 mg/kg LPS was injected intraperitoneally in low-dose or high-does group respectively, and equal amount of normal saline was injected in control group. Blood was collected from endocanthal vein at the specified time point, platelet count (PLT) was counted, and the levels of thrombin antithrombin complex (TAT), D-dimer, fibrinogen degradation product (FDP), tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) were determined by enzyme linked immunosorbent assay (ELISA). RESULTS: Compared with control group, PLT ( x 10(9)/L) at 4 hours and 24 hours in low-dose and high-dose LPS groups was significantly decreased (4 hours: 660.65 +/- 180.48, 568.55 +/- 117.99 vs. 1 199.13 +/- 110.54; 24 hours: 505.63 +/- 218.92, 256.33 +/- 72.86 vs. 1 229.13 +/- 1 189.37, all P < 0.05), and the changes were more obvious in high-dose LPS group compared with those of the low-dose LPS group (all P < 0.05). Factorial analysis showed that the changes in PLT were related with LPS dosage and time (F1 = 135.660, P = 0.000; F2 = 12.120, P2 = 0.001). It was also found that there was an interactive effect of the dose of LPS and time on PLT (F = 5.580, P = 0.007). Compared with control group, TAT, TNF-alpha, and IL-6 at 4 hours and 24 hours in low-dose and high-dose LPS groups were significantly decreased [TAT (ng/L) at 4 hours: 1.10 +/- 0.59, 0.22 +/- 0.13 vs. 3.47 +/- 1.73; 24 hours: 1.18 +/- 0.68, 0.39 +/- 0.29 vs. 3.19 +/- 1.27; TNF-alpha (nmol/L) at 4 hours: 87.35 +/- 12.29, 93.70 +/- 5.25 vs. 101.59 +/- 10.96, 24 hours: 81.94 +/- 8.26, 93.23 +/- 4.71 vs. 102.84 +/- 10.56; IL-6 (ng/L) at 4 hours: 81.78 +/- 7.82, 78.59 +/- 9.06 vs. 110.88 +/- 9.66, 24 hours: 76.03 +/- 9.85, 71.34 +/- 3.69 vs. 110.88 +/- 10.35, all P < 0.05]. TAT at 4 hours and 24 hours in high-dose LPS group was further decreased, and TNF-alpha at 24 hours was increased as compared with those of low dose LPS group (all P < 0.05). TAT, TNF-alpha and IL-6 were influenced only by different dosage of LPS (TAT: F = 42.350, P = 0.000; TNF-alpha: F = 14.8 10, P = 0.000; IL-6: F = 81.910, P = 0.000), not time (TAT: F = 0.002, P = 0.967; TNF alpha: F = 0.342, P = 0.562; IL-6: F = 2.973, P = 0.092). Changes in TAT was not found to be related with the dose of LPS and its time of action, or levels of TNF alpha and IL-6 (TAT: F = 0.236, P = 0.791; TNF-alpha: F = 0.572, P = 0.569; IL-6: F = 0.774, P = 0.468). The dosage of LPS and time of admission showed no influence on D-dimer (F1 = 2.448, P = 0.099; F2 = 0.024; P2 = 0.877). The effect of different doses of LPS and time of administration showed no influence on FDP (F1 = 0.106, P = 0.900; F2 = 0.013, P2 = 0.908), and no interactive effects were found (D- dimer: F = 0.002, P = 0.998; FDP: F = 0.582, P = 0.563). CONCLUSION: LPS can induce TCP in mouse, but this effect may not related to the activation of coagulation system and excessive inflammatory response. PMID- 26955704 TI - [Esmolol improves clinical outcome and tissue oxygen metabolism in patients with septic shock through controlling heart rate]. AB - OBJECTIVE: To investigate whether esmolol could improve clinical outcome and tissue oxygen metabolism by controlling heart rate (HR) in patients with septic shock. METHODS: A single-center double-blinded randomized controlled trial was conducted. The patients suffering from septic shock received 6-hour early goal directed herapy (EGDT) with pulmonary artery wedge pressure >= 12 mmHg (1 mmHg = 0.133 kPa) or central venous pressure CVP) >= 12 mmHg requiring norepinephrine to maintain mean arterial pressure (MAP) >= 65 mmHg and HR >= 95 bpm admitted to intensive care unit (ICU) of Guangdong General Hospital from September 2013 to September 2014 were enrolled. They were randomly divided into esmolol group and control group by computer-based random number generator. All patients received conventional basic treatment, while those in the esmolol group received in addition persistent esmolol infusion by micro pump with dosage of 0.05 mg . kg( 1) . min(-1) with the dosage adjusted to maintain HR lower than 100 bpm within 24 hours. The patients in control group did not receive drug intervention for HR. The primary end-points consisted of length of stay in ICU and 28-day mortality. The secondary end-points included hemodynamic parameters [HR, MAP, CVP, cardiac index (CI), stroke volume index (SVI), systemic vascular resistance index (SVRI)] and tissue oxygen metabolism parameters [central venous oxygen saturation (ScvO2), lactate level (Lac)] before and 24, 48, 72 hours after the treatment. RESULTS: A total of 48 patients with septic shock were enrolled with 24 patients in esmolol group and 24 in control group. (1) The primary end-points: compared with control group, the length of stay in the ICU in the esmolol group was significantly shortened (days: 13.75 +/- 8.68 vs. 21.70 +/- 6.06, t = 3.680, P = 0.001), and 28-day mortality was significantly lowered [25.0% (6/24) vs. 62.5% (15/24 ), chi2 = 6.857, P = 0.009]. (2) The secondary end-points: there were no significant difference in the hemodynamic and tissue metabolism parameters before treatment between two groups. No significant difference was found between before and after treatment of all above parameters in control group. HR and Lac in the esmolol group were obviously declined, SVI, SVRI, SCvO2 were gradually increased, but no significant difference in MAP, CVP, and CI was found. Compared with the control group, HR in the esomolol group was significantly lowered (bpm: 84.4 +/- 3.5 vs. 111.2 +/- 7.2, P < 0.01), SVRI and ScvO2 were significantly increased from 24 hours [SVRI (kPa . s . L(-1) .m(-2)): 137.9 +/- 1.6 vs. 126.9 +/- 1.3, ScvO2: 0.652 +/- 0.017 vs. 0.620 +/- 0.017, both P < 0.01]; SVI was significantly increased (mL/m2: 39.9 +/- 2.2 vs. 36.8 +/- 1.7, P < 0.01) and Lac level significantly declined from 48 hours (mmol/L: 2.8 +/- 0.3 vs. 3.4 +/- 0.3, P < 0.01). CONCLUSION: The results demonstrate that HR controlled by a titrated esmolol infusion given to septic shock patients was associated with an improvement in tissue metabolism, reduction in the length of ICU stay and lowering of 28-day mortality. PMID- 26955705 TI - [Transcript assembly and quality assessment]. AB - The transcript assembly is essential for transcriptome studies trom next generation sequencing data. However, there are still many faults of algorithms in the present assemblers, which should be largely improved in the future. According to the requirement of reference genome or not, the transcript assembly could be classified into the genome-guided and de novo methods. The two methods have different algorithms and implementation processes. The quality of assembled transcripts depends on a large number of factors, such as the PCR amplification, sequencing techniques, assembly algorithm and genome character. Here, we reviewed the present tools of transcript assembly and various indexes for assessing the quality of assembled transcripts, which would help biologists to determine which assembler should be used in their studies. PMID- 26955706 TI - [Progress in the tumorigenic potential of iPSCs and methods to reduce it]. AB - Since Yamanaka successfully reprogrammed murine fibroblasts into iPSCs in 2006, iPSCs technology has drawn much attention worldwide. Although iPSCs provides tremendous possibilities for both basic research and regenerative medicine, it has meanwhile potential risks, e.g. tumorigenicity. Scientists, therefore, have made efforts in clarifying the mechanism of the cause for iPSCs tumorigenicity and the way how to reduce the risk. The results of some researches reveal some of tumorigenic factors, e.g. the partial similarity of gene expression profiles between cancer cells and iPSCs, the accumulation of the genetic damages in the course of reprogramming process, and mutation in the cellular culture. As a consequence, numerous methods for reducing iPSCs tumorigenicity have been explored, such as minimized use of the reprogramming factors at the controlled manner, and the selection of the expression vector or parental cells. In this paper, the cause of iPSCs tumorigenicity and the current achievements on preventing iPSCs tumorigenesis are reviewed. PMID- 26955707 TI - [Progress in microRNAs associated with major avian viruses]. AB - Recently, avian viral diseases have become one of the main models to study mechanisms of viral infections and pathogenesis. The study of regulatory relationships and mechanisms between viruses and microRNAs has also become the focus. In this review, we briefly summarize the general situations of microRNAs encoded by avian herpesviruses. Also, we analyze the regulatory relationships between tumorigenicity of avian herpesviruses and microRNAs. Additionally, the possible applications for prevention and treatment of viral diseases (such as infectious bursal disease, avian influenza and avian leucosis) using the regulatory mechanisms of microRNAs are also discussed. PMID- 26955708 TI - [Progress and application prospects of glutamine synthase in plants]. AB - Nitrogen is one of the most important nutrient elements for plants and a major limiting factor in plant growth and crop productivity. Glutamine synthase (GS) is a key enzyme involved in the nitrogen assimilation and recycling in plants. So far, members of the glutamine synthase gene family have been characterized in many plants such as Arabidopsis, rice, wheat, and maize. Reports show that GS are involved in the growth and development of plants, in particular its role in seed production. However, the outcome has generally been inconsistent, which are probably derived from the transcriptional and post-translational regulation of GS genes. In this review, we outlined studies on GS gene classification, QTL mapping, the relationship between GS genes and plant growth with nitrogen and the distribution characters, the biological functions of GS genes, as well as expression control at different regulation levels. In addition, we summarized the application prospects of glutamine synthetase genes in enhancing plant growth and yield by improving the nitrogen use efficiency. The prospects were presented on the improvement of nitrogen utility efficiency in crops and plant nitrogen status diagnosis on the basis of glutamine synthase gene regulation. PMID- 26955709 TI - [Construction of goat germ cell specific reporting system pVASA-EGFP]. AB - To monitor the trans-differentiation from adult stem cells to germ cells, we analyzed the vasa expression of goat testicular tissues in different ages and constructed the germ cell specific reporting vector pVASA-EGFP. The expression of vasa was verified by RT-PCR and immunofluorescence. The vector pVASA-EGFP was constructed by molecular technology, then transfected into goat bone mesenchymal stem cells (BMSCs) by Lipofectamine 2000. Moreover, we observed the expression of the vector through green fluorescent protein (GFP). Immunofluorescence results show that Vasa was expressed in all groups of goat testicular tissues, RT-PCR results show that the levels of vasa mRNA in 3-month group and 10-month group were significantly higher than that in 10-day group. Sequencing and restriction enzyme results show that the vector was successfully constructed. After transfection and RA treatment, GFP expression was observed, which proved the validity of our reporting system. All the results proved that vasa was expressed in different ages in goat testicular tissues, and the vector pVASA-EGFP is efficient in monitoring the trans-differentiation in vitro, which paves the way for further characterization and screening of the trans-differentiation of goat BMSCs. PMID- 26955710 TI - [Expression and characterization of porcine epidermal growth factor in Lactobacillus plantarum]. AB - Epidermal growth factor (EGF) is an epithelial cell growth factor that can stimulate intestinal development, repair the damage of epidermal cells as well as reduce the incidence of pathogen infection and diarrhea. In order to produce a recombinant Lactobacillus plantarum (L. plantarum) expressing porcine epidermal growth factor (pEGF), we constructed a recombinant vector stably expressing pEGF in L. plantarum strains. First, L. plantarum strain Lp-1 was isolated from intestinal contents of piglets. Then the functional domain of pEGF, M6 precursor protein signal peptide (SP) and super strong constitutive promoter (SCP) were connected with the backbone plasmid pIAbeta8 to construct the recombinant vector that was transformed into Lp-1 by electroporation. Afterwards, pEGF was expressed in Lp-1 and detected by Tricine-SDS-PAGE and ELISA. After orally irrigated early weaned BALB/c mice with the recombinant L. plantarum every morning and late afternoon for 10 consecutive days, body weight, villous height and crypt depth in the intestine were measured to examine the influence of the recombinant bacteria on the intestinal development of early-weaned mice in vivo. Finally, the results of our experiments demonstrated that pEGF was successfully expressed in Lp-1 and the molecular weight of pEGF was 6 kDa. In addition, the recombinant pEGF can enhanced the daily gain and exerted significance influence (P < 0.05) to the small intestinal morphology of early-weaned BALB/c mice. In conclusion, pEGF could be expressed in L. plantarum and the recombinant pEGF possesses good biological activity. PMID- 26955711 TI - [Immunological comparison of Efb and ClfA of Staphylococcus aureus isolated from bovine]. AB - To compare immunological characteristics of Extracellular fibrinogen-binding protein (Efb) and Clumping factor A (CfA) of Staphylococcus aureus, we constructed two prokaryotic expression vector pET28a-Efb and pET28a-ClfA. After prokaryotical expression and purification, Efb and ClfA were used to immunize experimental animal. After the second immunization the antisera were collected and the antibody titers, the bacteria binding activity and adhesion inhibition activity of these antisera were detected by enzyme linked immunosorbent assay, adhesion inhibition assay and challenge. Both Efb and ClfA had Fibrinogen binding activity whereas the former had better Fibronectin binding activity. The bacteria binding capability of antisera of rabbits immunized with ClfA was better than that with Efb (P < 0.01). Both antisera of Efb and ClfA could inhibit adherence activity of Staphylococcus aureus to Fibrinogen and Fibronectin adherence compare to the control group (P < 0.01), and Efb had better adhesion inhibition activity than ClfA. The antibody titer of immunized group could reach 1:40 500. After the second immunization, both Efb and ClfA had good protective efficacy. This result constitutes a good foundation for Staphylococcus aureus subunit vaccine development. PMID- 26955712 TI - [Overexpression of FKS1 to improve yeast autolysis-stress]. AB - With the development of high gravity brewing, yeast cells are exposed to multiple brewing-associated stresses, such as increased osmotic pressure, enhanced alcohol concentration and nutritional imbalance. These will speed up yeast autolysis, which seriously influence beer flavor and quality. To increase yeast anti autolytic ability, FKS1 overexpression strain was constructed by 18S rDNA. The concentration of beta-1,3-glucan of overexpression strain was 62% higher than that of wild type strain. Meantime, FKS1 overexpression strain increased anti stress ability at 8% ethanol, 0.4 mol/L NaCl and starvation stress. Under simulated autolysis, FKS1 showed good anti-autolytic ability by slower autolysis. These results confirms the potential of FKS1 overexpression to tackle yeast autolysis in high-gravity brewing. PMID- 26955713 TI - [Heterologous expression and substrate specificity of ketoreductase domain in bacillaene polyketide synthase]. AB - The ketoreductase (KR) domain in the first extending module of the polyketide synthase (PKS) catalyzes the reductions of both an alpha-keto group and a beta keto group in the biosynthesis of bacillaene, suggesting the intrinsic substrate promiscuity. In order to further investigate the substrate specificity, the KR domain (BacKR1) was heterologously overexpressed in Escherichia coli. In vitro enzymatic analysis showed that only one of the four diastereomers was formed in the reduction of the racemic (+/-)-2-methyl-3-oxopentanoyl-N-acetylcysteamine thioester catalyzed by BacKR1. In addition, BacKR1 was revealed to catalyze the reductions of cyclohexanone and p-chloroacetophenone, indicating the potential of KR domians of PKSs as biocatalysts. PMID- 26955714 TI - [Synergistic inhibitory effect of static magnetic field and antitumor drugs on Hepa1-6 cells]. AB - Chemotherapy as a routine method for clinical treatment of cancer has disadvantages such as significant toxicity and strong resistance. In order to improve the efficacy of the drugs and reduce the by-effects, we tried to combine static magnetic field (SMF) with cisplatin or adriamycin. The growth of Hepa1-6 cells treated with the static magnetic field (SMF) combined with cisplatin or adriamycin was significantly inhibited, as detected with MTT (3-(4,5-dimethyl-2 thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide) test. Combined treatment group cells underwent significant morphological changes as observed by HE (Hematoxylin and eosin) staining under optical microscope. Cell cycle analysis indicated that SMF increased the ratio of cells arrested in G2/M phase caused by cisplatin, and when treated with SMF combined with adriamycin, cells were almost arrested in G1 and G2/M phase. SCGE test showed that SMF can enhance the ability of cisplatin or adriamycin to promote cell DNA damage. Atomic force microscope observation found that the combination of antitumor drugs and magnetic field treatment induced larger and deeper holes on the cell membrane, and surface structure damage is serious. The combination of antitumor drugs and magnetic field technology effectively inhibits the growth of tumor cells, and reduces drug doses. The results implicate this method as potential cancer therapy. PMID- 26955715 TI - [Development of transgenic maize with anti-rough dwarf virus artificial miRNA vector and their disease resistance]. AB - Maize is one of the most important food crops. Rice black-streaked dwarf virus is a maize rough dwarf disease pathogen. The occurrence and transmission of maize rough dwarf disease brings great damage to maize production. The technology of using artificial miRNA to build antiviral plant has been proven effective in a variety of plants. However, such trials in maize have not been reported. We designed primers based on the sequence of maize zea-miR159a precursor and sequence of function protein genes and silencing RBSDV coding genes in RBSDV genome. We constructed amiRNA (artificial miRNA) gene for silencing RBSDV coding gene and gene silencing suppressor. We constructed pCAMBIA3301-121-amiRNA plant expression vector for transforming maize inbred lines Z31 by using agrobacterium mediated method. After molecular analysis of transgenic maize, homozygous lines with high miRNA expression were selected by molecular detection for a subsequent natural infection experiment. We studied the severity of maize rough dwarf disease according to a grading standard (grade 0 to 4). The experiment results showed that the disease resistance of transgenic homozygous maize with the anti rough dwarf virus amiRNA vector was better than that of wild type. Among the transgenic maize, S6-miR159 transgenic maize had high disease resistance. It is feasible to create new maize variety by the use of artificial miRNA. PMID- 26955716 TI - [Elution of urinary proteins preserved on nitrocellulose membrane with heating]. AB - The preservation of urinary proteins on a membrane plays a vital role in biomarker research, and the efficient elution of proteins preserved on nitrocellulose membrane (NC membrane) determines the application of this method. During the heating elution procedure, we raised the temperature to reduce the intense vortexing time, and kept gentle rotating while precipitation to prevent nitrocellulose reformation. We also used SDS-PAGE and LC-MS/MS to analyze the urinary proteins prepared by heating elution procedure, intense vortexing elution procedure and acetone precipitation method. There was no degradation of proteins prepared by heating elution procedure. Compared with proteins prepared by heating elution method and acetone precipitation method, the overlapping rates of the proteins was almost the same (92.6% versus 96.8%) and the ratios of CV values (< 20%) of the proteins were both high (85.2% and 94.4%). The heating elution procedure achieved good technical reproducibility, and was much simpler and more efficient than the previous one. It can facilitate the application of the preservation of urinary proteins on membrane. PMID- 26955717 TI - [Development of an aptamer/fluorescence dye PicoGreen-based method for detection of fumonisin B1]. AB - Fumonisin B1 (FB1) is a carcinogenic mycotoxin found in commodities such as corn and corn-originated products. An aptamer-based method for detection of FB1 was developed using the fluorescent dye PicoGreen, which can recognize and bind double-stranded DNA. A peak fluorescence of PicoGreen was obtained in 15 min in the presence of FB1 aptamer, which formed a double-stranded hybridizer DNA with its complementary strand. The excitation and emission wavelengths for PicoGreen detection were 480 nm and 520 nm, respectively. The sensitivity of this aptamer/PicoGreen-based method was 0.1 MUg/L. This method showed a good linearity for FB1 concentration ranging from 0.1 to 1 MUg/L. The entire detection procedure for FB1 could be completed within 40 min. No cross reactions were observed with any other mycotoxins against aflatoxin B1, ochratoxin A, citrinin and zearalenone, demonstrating high specificity towards FB1 aptamer. Agreement between commercial, antibody-based enzyme-linked immunosorbent assay (ELISA) kit and aptamer method was excellent with a kappa value of 0.857. Taken together, this aptamer/PicoGreen-based method is more cost-effective, time-saving and useful than ELISA for detection of FB1. PMID- 26955718 TI - [Breeding of high-producing LI-F lipopeptide Paenibacillus polymyxa by protoplast fusion and differential expression analysis of fusion strains]. AB - Auxotrophic strains of N1-37 (Phe-) and N2-27 (His-), screened from mutations of Paenibacillus polymyxa JSa-9 previously, were used as the parent strains to screen high-producing LI-F antibacterial lipopeptide fusion strain through protoplast fusion with polyethylene glycol as a promote agent. Fusion strain F5 15 was obtained. Then the product of LI-F antibacterial lipopeptide was quantified by HPLC, and the difference of expression of the key genes of lipopeptide synthase between wild strain JSa-9 and the fusion strain was analyzed by real-time PCR. LI-F antibacterial lipopeptide yield of the fusion strain F5-15 was 3.1-fold of the original strain JSa9's, and the expression levels of the target genes were 10.48, 2.48, 2.1 and 11.8 fold of the initial strain JSa-9, respectively. PMID- 26955719 TI - [Sudden cardiac death: resistance creates a stronger enemy, but vigilance is it's own reward]. PMID- 26955720 TI - [Is defibrillation testing necessary for implantable transvenous defibrillators]. PMID- 26955721 TI - [beta-receptor blocker therapy in inherited cardiac arrhythmias]. PMID- 26955722 TI - [Pathomechanisms of torsades de pointes]. PMID- 26955723 TI - [Chinese expert consensus on cardiacmagnetic resonance in cardiomyopathy]. PMID- 26955724 TI - [Mutation and clinical relevance in a large cohort of unrelated Chinese patients with hypertrophic cardiomyopathy]. AB - OBJECTIVE: To explore the genetic basis and phenotypic correlation with disease severity in a large cohort of Chinese patients with hypertrophic cardiomyopathy (HCM). METHODS: A total of 179 unrelated Chinese HCM patients admitted to our department from 2002 to 2011 were enrolled in this study. Direct gene sequencing of beta-myosin heavy chain (MYH7), myosin binding protein-C ( MYBPC3), and cardiac troponin T (TNNT2) were performed and clinical data were obtained in these patients. RESULTS: A total of 34 mutations were identified in 40 patients (22.3%), 79.4% (27/34) mutations occurred only once and a possible hot spot, A26 in MYH7, was found. Distribution of mutations was 52.9% (18/34) (MYBPC3), 35.3% (12/34) ( MYH7) and 11.8% (4/34) (TNNT2) respectively. Double mutations were identified in 2.2% (4/179) patients. Genotype-positive patients were associated with an earlier symptom onset, severer left ventricular hypertrophy, a higher incidence of syncope, and were more likely to have positive family history of HCM or sudden cardiac death (SCD) , and were more likely to progress into heart failure (24.2% vs. 5.0%, P = 0.002) and at a higher risk of SCD (9.1% vs. 0, P = 0.009) during the 6.5-year follow-up. No statistical difference in any clinical parameters and outcomes was found between patients carrying MYBPC3 and MYH7 mutations. Double mutations were associated with malignant clinical progression in this cohort. Different phenotype severity could be seen in HCM patients with same genotype (e. g. MYH7-1736T, TNNT2-R92W). CONCLUSION: MYBPC3 is the most predominant gene mutation in this HCM cohort. The presence of a sarcomere mutation in patients with HCM is associated with poor clinical outcome, although no specific genes or mutations can exactly predict the severity of clinical phenotypes. PMID- 26955725 TI - [Long-term outcome after cardioverter-defibrillator implantation in patients with Brugada syndrome]. AB - OBJECTIVE: To observe the long-term outcome of implantable cardioverter defibrillator (ICD) implantation in Brugada syndrome patients and to explore how to reduce the frequency of ICD nappropriate schocks. METHODS: This study included 14 symptomatic patients (mean age (44.3 +/- 8.3) years old; all males) with Brugada syndrome implanted with ICD in our hospital between 1998 and 2012, and these patients were followed up routinely every 6 months. The initial ICD parameters were set according o conventional experience. The ventricular tachycardia (VT) zone was programmed to ventricular rate 150-188 bpm/cycle length (CL) 400-320 ms and the ventricular fibrillation (VF) zone was programmed to ventricular rate >= 188 bpm/CL <= 320 ms. The total events were recorded by ICD. The ICD parameters revision was made by electrophysiological (EP) experts in case of inappropriate shocks. RESULTS: Patients were followed up for mean (43.0 +/- 28.3) months. A total of 297 VF/VT events were recorded by ICD. Electrophysiological experts found that 90% (178/198) episodes were true VF ( CL 130-250 ms) among of 198 VF episodes and 147 VF episodes were terminated by one shock and 21 VF events were terminated by two or more shocks, and the rest 10 VF terminated spontaneously. Only 9% (9/99) VT events were true VT (CL 320-360 ms) among of 99 VT episodes. Eight VT episodes were converted by antitachycardia pacing therapy (ATP) and the other one terminated spontaneously. The rest 90 VT episodes (91%) were supraventricular arrhythmias (SVT, CL 340-390 ms). About 90% inappropriate shocks can be reduced by Wavelet discrimination function and optimal programming (VF zone ventricular rate >= 222 bpm/CL <= 270 ms and/or VT zone ventricular rate 167-222 bpm/CL 270-360 ms ) according to the characteristics of arrhythmia of individual patient. CONCLUSION: ICD can effectively prevent sudden cardiac death and syncope in high-risk patients with Brugada syndrome. The most common complication is inappropriate shock due to SVT. Optimal ICD programming with Wavelet discrimination function can effectively reduce the frequency of inappropriate shock rate. PMID- 26955726 TI - [Impact of CHA2DS2 VASc score on substrate for persistent atrial fibrillation and outcome post catheter ablation of atrial fibrillation]. AB - OBJECTIVE: To explore if CHA2DS2 VASc score can predict substrate for persistent atrial fibrillation ( AF) and outcome post catheter ablation of AF. METHODS: From January 2011 to December 2012,116 patients underwent catheter ablation of persistent AF in our department and were enrolled in this study. CHA2DS2VASc score was calculated as follows: two points were assigned for a history of stroke or transient ischemic attack and age >= 75 and 1 point each was assigned for age >= 65, a history of hypertension, diabetes,recent cardiac failure, vessel disease, female. Left atrial geometry ( LA) was reconstructed with a 3.5 mm tip ablation catheter with fill-in threshold 10 in CARTO system. The mapping catheter was stabled at each endocardial location for at least 3 seconds for recording. The electrogram recordings at each endocardial location were analyzed with a custom software embedded in the CARTO mapping system. Interval confidence level (ICL) was used to characterize complex fractionated atrial electrograms (CFAEs) . As the default setting of the software, ICL more than or equal to 7 was considered sites with a highly repetitive CFAEs complex. CFAEs index was defined as the fraction of area of ICL more than or equal to 7 to the left atrial surface. The CFAEs index and outcome of catheter ablation among different CHA2DS2VASc groups were compared. RESULTS: Of the 116 patients, CHA2DS2VASc was 0 in 33 patients, 1 in 31 patients and >= 2 in 52 patients. Left atrial surface ((121.2 +/- 18.9) cm2, (133.6 +/- 23.8) cm2, (133.9 +/- 16.1) cm2, P = 0.008), left atrial volume ((103.6 +/- 24.8) ml, (118.3 +/- 27.8) ml, (120.9 +/- 20.9) ml, P = 0.005) and CFAEs index (44.6% +/- 22.4%, 54.2% +/- 22.2%, 58.7% +/- 23.1%, P = 0.023) increased in proportion with increasing CHA2DS2VASc. ICLmax, ICLmin and CFAEs spatial distribution were similar among the three groups. During the mean follow-up of (13 +/- 8) months, the recurrence rate were 36.4%, 35.5%, 55.8% among the three groups (P = 0.025). CONCLUSION: A high CHA2DS2VASc score is associated with extensive AF substrate and higher recurrence rate post catheter ablation of persistent AF. PMID- 26955727 TI - [Discrete potentials guided ablation for idiopathic outflow tract ventricular arrhythmias]. AB - OBJECTIVE: Discrete potentials (DPs) have been recorded and targeted as the site of ablation of the outflow tract arrhythmias. The aim of the present study was to investigate the significance of DPs with respect to mapping and ablation for idiopathic outflow tract premature ventricular contractions (PVCs) or ventricular tachycardias (VTs). METHODS: Seventeen out of 24 consecutive patients with idiopathic right or left ventricular outflow tract PVCs/VTs who underwent radiofrequency catheter ablation between September 2012 and December 2013 in our department were included. Intracardiac electrograms during the mapping and ablation were analyzed. RESULTS: During sinus rhythm, sharp high-frequency DPs that displayed double or multiple components were recorded following or buried in the local ventricular electrograms in all of the 17 patients, peak amplitude was (0.51 +/- 0.21) mV. The same potential was recorded prior to the local ventricular potential of the PVCs/VTs. Spontaneous reversal of the relationship of the DPs to the local ventricular electrogram was noted during the arrhythmias. The DPs were related to a region of low voltage showed by intracardiac high density contact mapping. At the sites with DPs, unipolar and bipolar ventricular voltage of sinus beats were lower compared with the adjacent regions without DPs (unipolar: (6.1 +/- 1.8) mV vs. (8.3 +/- 2.3) mV, P < 0.05; bipolar: (0.62 +/- 0.45) mV vs. (1.03 +/- 0.60) mV, P < 0.05). The targeted DPs were still present in 12 patients after successful elimination of the ectopies. Discrete potentials were not present in seven controls. CONCLUSIONS: Discrete potentials and related low-voltage regions were common in idiopathic outflow tract ventricular arrhythmias. Discrete potential- and substrate-guided ablation strategy could help to reduce the recurrence of idiopathic outflow tract arrhythmias. PMID- 26955728 TI - [Calpain-2 and calcineurin protein expression in right atrial appendages from patients underwent valve replacement with or without atrial fibrillation]. AB - OBJECTIVE: To investigate the relationship between the protein expression of calpain-2 and calcineurin (CaN) and atrial fibrillation (AF) in patient with valvular heart disease (VHD). METHODS: A total of 40 patients who underwent valve replacement surgery in our hospital from March 2013 to March 2014, right atrial appendages were excised during operation and patients were divided into sinus rhythm (SR) group (n = 17) and AF group (n = 23). The protein expression of calpain-2 and the alpha-isoform of CaN catalytic subunit (CnA) in the right atrial appendages were determined by Western blot. RESULTS: The protein levels of the full-length CnAa (60,000), the 45,000 fragment of CnAa without autoinhibitory domain, and calpain-2 were significantly upregulated in the AF group compared to the SR group (1.25 +/- 0.51 vs. 0.76 +/- 0.37, 1.08 +/- 0.37 vs. 0.76 +/- 0.25, and 0.82 +/- 0.44 vs. 0.51 +/- 0.19, respectively, all P < 0.05). CONCLUSION: Activated calpain-2-CaN signal pathway might be involved in the pathogenesis of AF. PMID- 26955729 TI - [Predict value of European system for cardiac operative risk evaluation II on 30 days operative mortality in patients with severe coronary artery disease undergoing active treatments]. AB - OBJECTIVE: To assess the predict value of European system for cardiac operative risk evaluation (EuroSCORE) II on early death in patients with severe coronary artery disease undergoing active treatment. METHODS: Consecutive 2 240 patients with three-vessel disease ( with or without left main disease) diagnosed by elevtive coronary angiogram between July 2011 and September 2012 were screened for this study, data from 1 892 patients who underwent active treatments (percutaneous coronary intervention or coronary artery bypass grafting) were analyzed retrospectivly. The predicted 30 days operative mortality calculated with EuroSCORE II was compared with the actual one. The calibration and discrimination of EuroSCORE II were tested with Hosmer-Lemeshow chi2 test and area under receiver operating characteristic (ROC) curve respectively. RESULTS: Age was 61.0 (54.0-68.0) years old and 75.8% (1,435/1,892) were male in this cohort, 58.0% (1,097/1,892) patients received percutaneous coronary intervention and 42.0% (795/1,892) patients received coronary artery bypass grafting. The overall 30 days operative mortality was 0.53% (10/1,892), 30 days operative mortality predicted by EuroSCORE II was 0.85% (95% CI:0. 44%-1.26%). The calibration (chi2 = 3.47 and P > 0.10) and discrimination (area under ROC curve was 0.75) of EuroSCORE II were satisfactory. CONCLUSION: EuroSCORE II could precisely predict 30 days operative mortality for three-vessel disease patients with or without left main disease undergoing active treatments. PMID- 26955730 TI - [Inhibition of microRNA195 attenuates high-glucose induced neonatal cardiomyocytes hypertrophy in vitro]. AB - OBJECTIVE: To investigate the effects of micro(mi) RNA-195 on high-glucose induced neonatal cardiomyocyte hypertrophy and to explore the related mechanism. METHODS: The potential target gene of miRNA-195 (Smad7) was predicted by TargetScan5. 1 software. Cardiomyocytes were isolated from neonatal SD rats and cells were then randomly divided into three groups: cells treated by culture medium containing 5 mmol/L glucose (control group) , by culture medium containing 25 mmol/L glucose (high glucose group) and treated by culture medium containing 25 mmol/L glucose and miRNA-195 inhibitor transfection (miRNA-195 inhibitor group). After 24, 48, or 72 h of in vitro culture, the morphology of cardiomyocytes was examined under phase contrast microscope. Micrographs were captured and the cell surface was calculated. The mRNA expressions of miRNA-195 and myosin heavy chain beta (beta-MHC), a biomarker for cardiomyocyte hypertrophy, in cardiomyocytes were detected by RT-PCR. The protein expression of Smad7 was determined by Western blot. The concentration of transforming growth factor-beta1 (TGF-beta1) in the supernatant of culture medium was measured by ELISA. RESULTS: Cross-sectional area of cardiomyocytes, expression of miRNA-195 and beta-MHC and secretion of TGF-beta1 were significantly increased in high glucose-treated cells (P < 0.05 vs. normal control). The protein expression of Smad7 was significantly downregulated in cells exposed to high glucose for 48 h (P < 0.05 vs. normal control). Downregulation of miRNA-195 partly reversed the high glucose-induced effects. The expression of Smad7 was negatively correlated with miRNA-195 in high glucose control group (correlation coefficient: -0.945, P < 0.05). CONCLUSION: Our results demonstrate that Smad7 could be the target gene of miRNA-195. miRNA-195 might play a crucial role in the development and progression of diabetic cardiomyopathy possibly through downregulating the expression of Smad7 and modulating TGF-beta/Smad pathways. PMID- 26955731 TI - [Effect of resveratrol on aniogtensin II induced cardiomyocytes hypertrophy and FoxO1/MnSOD signaling pathway]. AB - OBJECTIVE: To investigate the effect of resveratrol (RSV) on angiotensin II (Ang II) induced cardiomyocytes hypertrophy and FoxO1/MnSOD signaling pathway. METHODS: The cardiomyocytes isolated from neonatal Wistar rats were cultured with pancreatin and preplating technique and divided into five groups: control (CON), Ang II (1 x 10(-6) mol/L, Ang II), Ang II + RSV (10 umol/L), Ang II + RSV (25 umol/L), and Ang II + RSV (50 umol/L). 3H-Leucine incorporation method were used to determine the cardiomyocyte protein synthesis rate. Cell size was measured by phase contrast microscope. The gene expression of A type natriuretic factor (ANF) was detected by real-time PCR. Western blot was used to measure the expression of MnSOD, FoxO1 and acety-FoxO1. Immunoprecipitation was used to detect the interaction between Sirt1 and FoxO1. RESULTS: Cardiomyocyte protein synthesis rate in Ang II group was significantly higher in Ang II group than in the control group ((1,971 +/- 175) cpm vs. (1,216 +/- 136) cpm, P < 0.05), which could be significantly attenuated by RSV (10 umol/L, 25 umol/L, 50 umol/L, all P < 0.05), especially in Ang II + RSV (25 umol/L) group( (1,374 +/- 143) cpm). Cardiomyocytes size in Ang II group was significantly larger than control group ((29.3 +/- 3.2) um vs. (19.4 +/- 1.8) um, P < 0.05), which could be significantly reduced by cotreatment with RSV (10 umol/L, 25 umol/L, 50 umol/L, all P < 0.05), especially in Ang I + RSV (25 umol/L) group ((20.8 +/- 2.1) um). Ang II also significantly upregulated ANP mRNA expression of cardiomyocytes (4.4 +/- 0.4 vs. 1.0 +/- 0.1 in control group, P < 0.05), which could be significantly inhibited by cotreatment with RSV, especially in Ang II + RSV (25 umol/L) group (2.2 +/- 0.2). Ang II significantly decreased MnSOD expression of cardiomyocytes compared with control group (P < 0.05), which was reversed by RSV (25 umol/L). The binding level of Sirt1 and FoxO1 was significantly lower (1.00 +/- 0.11 vs. 1.63 +/- 0.16, P < 0.05), and the expression of acetylation of FoxO1 was significantly higher in Ang II group than in control group (1.48 +/- 0.16 vs. 1.00 +/- 0.13, P < 0.05), which was significantly reversed by cotreatment with RSV (25 umol/L). CONCLUSIONS: Resveratrol treatment can inhibit Ang II induced cardiomyocyte hypertrophy. This protective effect is associated with reduced FoxO1 acetylation and activation of Sirt1, suggesting that Sirt1 may serve as a potential therapeutic target of cardiomyocyte hypertrophy. PMID- 26955732 TI - [Effect of bone morphogenetic protein-2 on human heart valve interstitial cells calcification in vitro]. AB - OBJECTIVE: To establish human heart valve interstitial cells calcification culture model in vitro, and observe the effect of bone morphogenetic protein-2 (BMP-2) on calcification of human heart valve interstitial cells. METHODS: Human heart valve interstitial cells were cultured in vitro, and divided into control group: cells were cultured in conventional media plus recombinant human BMP-2 treatment and experimental group: besides above treaments, calcification inducers ( recombinant human BMP-2, beta-glycerophosphate, L-ascorbic acid, dexamethasone) were added to the culture media. The two group of cells were cultured for 14 days and were stained by Von Kossa, then the cell calcification was observed in this valvular interstitial cells calcification culture model in vitro. Protein expression of intercellular adhesion molecule 1 (ICAM-1), interleukin 8, BMP-2 and BMP-4 was determined by Western blot and BMP-2 secretion was measured by ELISA. RESULTS: In the control group, the structure of human heart valve interstitial cells was clear, and the spindle and radial growth shaped cellular morphology was visible, and Von Kossa staining was negative. In the experimental group, the nuclei become darker in color, and granular sediment distribution was seen surrounding cells, and Von Kossa staining was positive, the cells were forming nodules of calcification. The protein expression of ICAM-1, interleukin 8, BMP-2 and BMP-4 in the experimental was significantly higher than that of the control group (all P < 0.05). The expression of BMP-2 in the experimental group was also significantly higher than that in control group ((92.5 +/- 4.9) pg/ml vs. (22.2 +/- 1.9) pg/ml, P < 0.05). CONCLUSION: Human BMP-2, beta glycerophosphate, L-ascorbic acid, and dexamethasone can induce human heart valve interstitial cells calcification and enhance inflammation in vitro by stimulating the secretion of BMP-2. PMID- 26955733 TI - [Hydroxysafflor yellow A inhibits rat vascular smooth muscle cells proliferation possibly via blocking signal transduction of MEK-ERK1/2]. AB - OBJECTIVE: To elucidate the effect of hydroxysafflor yellow A ( HYSA) on the proliferation of vascular smooth muscle cells (VSMCs) and the related mechanism. METHODS: VSMCs derived from SD rats were treated with DMEC culture medium (Control), 10 ng/ml PDGF (PDGF group), pretreatment with HYSA at different doses (1, 5, 10, 20, 40, 60 umol/L) for 24 h then cotreatment with PDGF. After 24 h, MTT assay, Western blot and immunohistochemical staining were performed to evaluate the inhibitory effects of HYSA on VSMCs proliferation. RESULTS: HYSA inhibited PDGF induced VSMCs proliferation in a dose-dependent manner, dowregulated proliferating cell nuclear antigen (PCNA) expression and blocked PDGF activated PDGFR-MEK-ERK1/2 signaling pathway. CONCLUSIONS: HYSA inhibits VSMCs proliferation possibly via downregulating the expression of PCNA and blocking MEK-ERK1/2 signal transduction in VSMCs. PMID- 26955734 TI - [Prevalence of hypertension among "three minority ethnic groups" residents in Inner Mongolia Autonomous Region]. AB - OBJECTIVE: To survey the current situation of hypertension among "three minority ethnic groups" in Inner Mongolia Autonomous Region. METHODS: Hypertension epidemiological survey among Three Minority Ethnic Groups and Han nationality aged >= 18 years was performed from June to December 2010. RESULTS: The prevalence rate of hypertension among the surveyed population was 29. 4% (630/2 146) ( standardized prevalence was 34.6%). The prevalence rate of hypertension in male was 33. 8% (359/1 062) ( standardized prevalence was 39.9%), and the prevalence rate in female was 25.0% (271/1 084) (standardized prevalence was 26.6%) and the prevalence rate in male was higher than in female (P < 0.01). The prevalence rate of hypertension for the Oroqen nationality, Ewenki nationality and Daur nationality was 33.8% (92/272), 32.4% (170/524), and 30.2% (174/576) respectively (standardized prevalence was 33.7%, 33.1%, and 31.3%), and which was significantly higher than in the Han nationality (25.1% (194/774), P < 0.01) (standardized prevalence was 25.8%). The awareness, treatment and control rate of hypertension in the Oroqen nationality residents was 64.1% (59/92), 56.5% (52/92), 27.2% (25/92) (standardized rate was 63.5%, 56.8% and 27.4%), and 60.0% (102/170), 53.5% (91/170), 24.1% (41/170) ( standardized rate was 62.9%, 56.7%, 26.6%) in the Ewenki nationality residents, and 59.2% (103/174), 54.0% (94/174), 20.7% (36/174) (standardized rate was 50.3%, 54.7%, 21.4%) in the Daur nationality residents, and 65.0% (126/194), 57.7% (112/194), 27.3% (53/194) (standardized rate was 63.3%, 56.5%, 27.1%) in the Han nationality residents. Awareness rate, treatment rate and control rate were similar among different nationalities (all P > 0.05). CONCLUSION: The prevalence rate of hypertension among " three minority ethnic groups" residents in Inner Mongolia Autonomous Region is high and comprehensive prevention and therapy strategies are warranted to reduce the hypertension burden in these residents. PMID- 26955735 TI - [Distribution and major influencing factors of annual systolic blood pressure variability: results from a large cohort study]. AB - OBJECTIVE: To investigate the distribution and major influencing factors of annual systolic blood pressure variability from a large population cohort. METHODS: In this prospective cohort study, data from Kailuan Group employees who attended all 4 physical examinations ( taken in June 2006 to October 2007, June 2008 to October 2009, June 2010 to October 2011, June 2012 to October 2013, respectively) were analyzed (32 959 males and 10 401 females, mean age: (48.2 +/- 11.5) years old). Systolic blood pressure variability was defined as the standard deviation (SSD) and the coefficient of variation (SCV) of systolic blood pressure of 4 physical examinations. Multivariate linear regression analysis was used to determine the related influencing factors of SSD and SCV. RESULTS: (1) The mean of SSD and SCV for this cohort was 10.91 mmHg (1 mmHg = 0.133 kPa) and 8.34%, respectively. SSD and SCV increased in male and female with increasing age (both P < 0.001). (2) Multiple linear regression analysis showed that systolic blood pressure (beta = 0.225, P < 0.001), age (beta = 0.163, P < 0.001), fasting blood glucose (beta = 0.038, P < 0.001), the use of anti-hypertensive drugs (beta = 0.038, P < 0.001), sex (beta = 0.038, P < 0.001), smoking (beta = 0.025, P < 0.001), alcohol drinking (P = -0.022, P < 0.001), physical exercise (beta = 0.018, P = 0.001), high-sensitivity c-reactive protein (beta = 0.016, P = 0.001) body mass index (beta = -0.011, P = 0.018) were related to SSD. Age (beta = 0.139, P < 0.001), sex (beta = 0.055, P < 0.001), systolic blood pressure (beta = 0.047, P < 0.001), fasting blood glucose (P = 0.033, P < 0.001), drinking (beta = -0.030, P < 0.001), body mass index (beta = -0.026, P < 0.001), the use of anti- hypertensive drugs (beta = 0.026, P < 0.001), smoking (beta = 0.024, P < 0.001), physical exercise (beta = -0.015, P = 0. 001), high-sensitivity c-reactive protein (beta = 0. 014, P = 0. 001) were related to SCV. CONCLUSIONS: SSD and SCV increase with increasing age. Systolic blood pressure, age, fasting blood glucose, the use of anti-hypertensive drugs, sex, smoking, drinking, physical exercise, high-sensitivity c-reactive protein, body mass index are major influencing factors for SSD. Age, sex, systolic blood pressure, fasting blood glucose, alcohol drinking, body mass index, the use of anti-hypertensive drugs, smoking, physical exercise, high-sensitivity c-reactive protein are major influencing factors for SCV. PMID- 26955736 TI - [Acute aortic dissection, myocardial infarction and cerebral hemorrhage in a patient with Shone syndrome]. PMID- 26955737 TI - [A case of a fetal atrial flutter]. PMID- 26955738 TI - [Two cases of acute Stanford type B aortic dissection during pregnancy]. PMID- 26955739 TI - [A case of gestational hypertension complicating with tricuspid infective endocarditis]. PMID- 26955740 TI - [Research update on the origin of cardiac fibroblasts]. PMID- 26955741 TI - Reinforced Mechanical Properties and Tunable Biodegradability in Nanoporous Cellulose Gels: Poly(L-lactide-co-caprolactone) Nanocomposites. AB - Incorporation of nanofillers into aliphatic polyesters is a convenient approach to create new nanomaterials with significantly reinforced mechanical properties compared to the neat polymers or conventional composites. Nanoporous cellulose gels (NCG) prepared from aqueous alkali hydroxide/urea solutions can act as alternative reinforcement nanomaterials for polymers with improved mechanical properties. We report a simple and versatile process for the fabrication of NCG/poly(L-lactide-co-caprolactone) (NCG/P(LLA-co-CL) nanocomposites through in situ ring-opening polymerization of L-lactide (LLA) and epsilon-caprolactone (epsilon-CL) monomers in the NCG. The volume fraction of the NCG in the nanocomposites was tunable and ranged from 4.5% to 37%. Fourier transform infrared (FT-IR), X-ray diffraction (XRD), and differential scanning calorimetry (DSC) results indicated that P(LLA-co-CL) were synthesized within the NCG and partially grafted onto the surface of the cellulose nanofibrils. The glass transition temperature (Tg) of the NCG/P(LLA-co-CL) nanocomposites could be altered by varying the molar ratio of LLA/epsilon-CL and was affected by the volume fraction of NCG. Atomic force microscopy (AFM) and scanning electron microscopy (SEM) images confirmed that the interconnected nanofibrillar cellulose network structure of the NCG was finely distributed and preserved in the P(LLA-co CL) matrix after polymerization. The dynamic mechanical analysis (DMA) results showed remarkable reinforcement of the tensile storage modulus (E') of the P(LLA co-CL) nanocomposites in the presence of NCG, especially above the Tg of the P(LLA-co-CL). The modified percolation model agreed well with the mechanical properties of the NCG/P(LLA-co-CL) nanocomposites. The introduction of NCG into the P(LLA-co-CL) matrix improved the mechanical properties and thermal stability of the NCG/P(LLA-co-CL) nanocomposites. Moreover, the NCG/P(LLA-co-CL) nanocomposites have tunable biodegradability and biocompatibility and potential applications in tissue engineering repair, biomedical implants, and packing. PMID- 26955742 TI - Antihyperlipidemic activity of adenosine triphosphate in rabbits fed a high-fat diet and hyperlipidemic patients. AB - Context Recently, adenosine triphosphate (ATP) was occasionally found to decrease the triglyceride (TG) levels in several hyperlipidemic patients in our clinical practice. Objective The study investigates the anti-hyperlipidemic effects of ATP in a high-fat fed rabbit model and hyperlipidemic patients. Materials and methods Twenty-four rabbits were randomly divided into three groups of eight animals each as follows: normal diet, high-fat diet and high-fat diet + ATP group. ATP supplementation (40 mg/day) was started at the 20th day and lasted for 10 days. Serum concentrations of total cholesterol (TC), TG, LDL-C, HDL-C were measured on the 20th day and 30th day. Heart, liver and aorta were subjected histopathological examination. Twenty outpatients diagnosed primary hyperlipidemia took ATP at a dose of 60 mg twice a day for 1 week. Results Feeding rabbits with a high-fat diet resulted in a significant elevation of lipid parameters including TC, TG, LDL-C, VLDL-C compared to the normal diet group (p < 0.01). ATP treatment significantly decreased serum TG level (p < 0.01), whilst other parameters remained statistically unaltered. Meanwhile, ATP significantly reduced the thickness of fat layer in cardiac epicardium (p < 0.05) and pathological gradation of ballooning degeneration in hepatocytes (p < 0.05). After taking ATP for 1 week, hyperlipidemia patients exhibited a significant decrease of TG (p < 0.01), but other lipid parameters had no significant change. Discussion and conclusion The study indicates that ATP selectively decreases serum TG levels in high-fat diet rabbits and hyperlipidemic patients. Therefore, ATP supplementation may provide an effective approach to control TG level. PMID- 26955743 TI - Effect of glycine supplementation in low protein diets with amino acids from soy protein isolate or free amino acids on broiler growth and nitrogen utilisation. AB - Here, it was investigated whether substitution of amino acids (AA) from soy protein isolate with free AA in low crude protein diets influences the growth performance and N utilisation in broilers, and whether interactions with dietary glycine equivalent (Glyequi) concentration exist. Birds were distributed in two 2 * 2 factorial arrangements of 48 floor pens containing 10 birds each, plus 48 metabolism cages containing two birds each. Experimental feed was provided for ad libitum consumption from d 7 to 22. Diets contained either a soy protein isolate at 79 g/kg or a mix of free AA, which supplied the same amount of 18 proteinogenic AA. A mix of free glycine and l-serine was used to obtain low and high (12.0 and 20.5 g/kg dry matter) levels of dietary Glyequi. Substitution of soy protein isolate with free AA reduced the average daily gain and feed efficiency, mainly due to reduced feed intake. Efficiency of N accretion was not influenced by the AA source or Glyequi concentration on d 21, possibly due to the lower AA digestibility of soy protein isolate and higher urinary excretion of nitrogenous substances in the treatments with the AA mix. The average daily weight gain of the treatments with high Glyequi concentration was higher for both AA sources. This increase was due to higher average daily feed intake by broilers in the treatments with soy protein isolate and due to the increased feed efficiency in the treatments with the AA mix. Broilers exhibited different growth responses to dietary Glyequi between the AA sources; however, these responses could not be attributed to the different utilisation of Glyequi for uric acid synthesis. PMID- 26955744 TI - Epitaxial Brownmillerite Oxide Thin Films for Reliable Switching Memory. AB - Resistive switching memory, which is mostly based on polycrystalline thin films, suffers from wide distributions in switching parameters-including set voltage, reset voltage, and resistance-in their low- and high-resistance states. One of the most commonly used methods to overcome this limitation is to introduce inhomogeneity. By contrast, in this paper, we obtained uniform resistive switching parameters and sufficiently low forming voltage by maximizing the uniformity of an epitaxial thin film. To achieve this result, we deposited an SrFeOx/SrRuO3 heteroepitaxial structure onto an SrTiO3 (001) substrate by pulsed laser deposition, and then we deposited an Au top electrode by electron-beam evaporation. This device exhibited excellent bipolar resistance switching characteristics, including a high on/off ratio, narrow distribution of key switching parameters, and long data retention time. We interpret these phenomena in terms of a local, reversible phase transformation in the SrFeOx film between brownmillerite and perovskite structures. Using the brownmillerite structure and atomically uniform thickness of the heteroepitaxial SrFeOx thin film, we overcame two major hurdles in the development of resistive random-access memory devices: high forming voltage and broad distributions of switching parameters. PMID- 26955745 TI - Antioxidant activity of Inonotus obliquus polysaccharide and its amelioration for chronic pancreatitis in mice. AB - Inonotus obliquus polysaccharide (IOP) was extracted by water with a yield of 9.83% and purified by an anion-exchange DEAE cellulose column and Sephadex G-200 gel with a polysaccharide content of 98.6%. The scavenging activities for 2,2 diphenyl-1-picryl-hydrazyl (DPPH) and hydroxyl radicals of IOP were 82.3% and 81.3% respectively at a concentration of 5 mg/mL. IOP was composed of Man, Rha, Glu, Gal, Xyl and Ara in a molar ratio of 9.81:3.6:29.1:20.5:21.6:5.4 respectively. The gel permeation chromatography indicated that IOP was a homogeneous polysaccharide with molecular weight of 32.5 kDa. IOP helped to alleviate pancreatic acinar atrophy and weight loss for chronic pancreatitis (CP) mice induced by Diethyldithiocarbamate (DDC). The SOD level was increased most by IOP-H treatment (400 mg/kg body weight). MDA, IL-1beta and LDH were significantly decreased by IOP treatment, especially hydroxyproline, IFN-gamma and AMS levels were decreased 39.18%, 37.82% and 41.57% by IOP-H treatment respectively compared to MC group. In conclusion, IOP possessed strong antioxidant activity for scavenging free radicals in vitro and vivo which could be propitious to CP therapy in mice. PMID- 26955746 TI - Characterization, biomedical and agricultural applications of protease inhibitors: A review. AB - This review describes Protease Inhibitors (PIs) which target or inhibit proteases, protein digesting enzymes. These proteases play a crucial task in many biological events including digestion, blood coagulation, apoptosis etc. Regardless of their crucial roles, they need to be checked regularly by PIs as their excess may possibly damage host organism. On basis of amino acid composition of PIs where Protease-PI enzymatic reactions occur i.e. serine, cysteine, and aspartic acid, they are classified. Nowadays, various PIs are being worked upon to fight various parasitic or viral diseases including malaria, schistosomiasis, colds, flu', dengue etc. They prevent an ongoing process begun by carcinogen exposure by keeping a check on metastasis. They also possess potential to reduce carcinogen-induced, increased levels of gene amplification to almost normal levels. Some PIs can principally be used for treatment of hypertension and congestive heart failure by blocking conversion of angiotensin I to angiotensin II for example Angiotensin-converting enzyme inhibitors (ACEIs). Also PIs target amyloid beta-peptide (Abeta) level in brain which is prime responsible for development of Alzheimer's Disease (AD). Also, PIs inhibit enzymatic activity of HIV-1 Protease Receptor (PR) by preventing cleavage events in Gag and Gag-Pol that result in production of non-virulent virus particles. PMID- 26955747 TI - Synthesis of new thermo/pH sensitive drug delivery systems based on tragacanth gum polysaccharide. AB - In this study, new pH/temperature responsive graft copolymers were synthesized based on natural Tragacanth Gum (TG) carbohydrate and their controlled drug release was investigated. Amphiphilic alkyne terminated terpolymers (mPEG-PCL PDMAEMA-CCH)s consist of methylated poly(ethyleneglycol) (mPEG), polycaprolactone (PCL), and poly(dimethylaminoethylmethacrylate) (PDMAEMA) were synthesized by using ring opening polymerization (ROP) and atom transfer radical polymerization (ATRP), and then were grafted onto azide-functionalized TG molecules by click chemistry. Different techniques such as FT-IR, (1)H NMR, gel permeation chromatography (GPC), thermo-gravimetrical analysis (TGA) and scanning electron microscopy (SEM) were used to verify the successful synthesis of graft copolymers (TG-g-PDMAEMA-PCL-mPEG)s. The graft copolymers self-assembled to single micelles in aqueous solution and upon pH changes further assembled into micellar aggregates. These micelles were used to prepare quercetin loaded nanocarriers by probe sonication method. Size and morphology of the nanocarriers were studied by dynamic light scattering (DLS) and SEM. The in vitro release behavior of quercetin from these micelles showed pH-dependence. The results showed that release profile of quercetin best followed the first order model. PMID- 26955748 TI - Hyaluronic acid embedded cellulose acetate phthlate core/shell nanoparticulate carrier of 5-fluorouracil. AB - Aim of this research was to prepare hyaluronic acid-modified-cellulose acetate phthalate (HAC) core shell nanoparticles (NPs) of 5-fluorouracil (5-FU). HAC copolymer was synthesized and confirmed by fourier transform infrared (FTIR) and nuclear magnetic resonance (NMR) spectroscopy. HAC NPs with 5-FU were prepared using HAC copolymer and compared with 5-FU loaded cellulose acetate phthalate (CAP) NPs. NPs were characterized by atomic force microscopy (AFM), particle size, zeta potential, polydispersity index, entrapment efficiency, in-vitro release, differential scanning calorimetry (DSC) and X-ray diffraction (XRD). HAC NPs were found slower release (97.30% in 48h) than (99.25% in 8h) CAP NPs. In cytotoxicity studies, showed great cytotoxic potential of 5-FU loaded HAC NPs in A549, MDA-MD-435 and SK-OV-3 cancer cellline. HAC NPs showing least hemolytic than CAP NPs and 5-FU. Area under curve (AUC), maximum plasma concentration (Cmax), mean residence time (MRT) and time to reach maximum plasma concentration Tmax), were observed 4398.1+/-7.90MUgh/mL, 145.45+/-2.25MUg/L, 45.74+/-0.25h, 72+/-0.50h, respectively of HAC NPs and 119.92+/-1.78MUgh/mL, 46.38+/-3.42MUg/L, 1.2+/-0.25h, 0.5+/-0.02h were observed in plain 5-FU solution. In conclusion, HAC NPs is effective deliver carrier of 5-FU for lung cancer. PMID- 26955749 TI - Thermostabilization of Bacillus subtilis GH11 xylanase by surface charge engineering. AB - Aiming to improve thermostability of the mesophilic xylanase A from Bacillus subtilis (XynA), five single mutants (S22E, S27E, N32D, N54E and N181R) were used to construct a random combinatorial library, and screening of this library for thermostable XynA variants identified a double mutant (S22E/N32D). All 6 mutants were expressed in Escherichia coli (BL21) and purified. Xylanase activity showed all mutants have an optimum catalytic temperature (Topt) of 55 degrees C, and with the exception of the S27E mutant, a higher specific activity than the wild type XynA. The time for loss of 50% activity at 55 degrees C (t50) decreased in the order S22E/N32D>N181R>S22E>Wild-type>S27E=N32D~N54E. The values of the van't Hoff denaturation enthalpy change (DeltaHND), melting temperature (Tm) and heat capacity at constant pressure (DeltaCp) between the native and denatured states were estimated from thermal denaturation curves monitored by circular dichroism ellipticity changes. The decreasing order of Gibbs free energy change at 328K (DeltaG328) S22E/N32D>N181R>S22E>Wild-type>S27E~N54E>N32D correlates well with the thermotolerance results, and is dominated by changes in DeltaHND which is consistent with increased in hydrogen bonding in the thermostable mutants. PMID- 26955750 TI - The effect of surfactants on the dissolution behavior of amorphous formulations. AB - The optimal design of oral amorphous formulations benefits from the use of excipients to maintain drug supersaturation and thus ensures adequate absorption during intestinal transit. The use of surfactants for the maintenance of supersaturation in amorphous formulations has not been investigated in detail. The main aim of this study was to investigate the effect of surfactant on the dissolution behavior of neat amorphous drug and binary polymer based solid dispersion. Indomethacin was used as the model drug and the surfactants studied were polysorbate 80 and poloxamer 407. The presence of surfactants (alone or in combination with polymers) in the buffer was detrimental to the dissolution of neat amorphous indomethacin, suggesting that the surfactants promoted the crystallization of neat amorphous indomethacin. In contrast, the presence of surfactants (0.01% w/v) in the buffer resulted in a significant improvement on the dissolution behavior of binary polymer based solid dispersion. Incorporating the surfactant to the formulation to form ternary solid dispersion adversely affected the dissolution behavior. In conclusion, the use of surfactants (as wetting or solubilization agents) in dissolution studies of neat amorphous drugs requires prudent consideration. The design of amorphous formulations with optimal dissolution performance requires the appropriate selection of a combination of excipients and consideration of the method of introducing the excipients. PMID- 26955751 TI - Predicting biopharmaceutical performance of oral drug candidates - Extending the volume to dissolve applied dose concept. AB - The purpose of the study was to experimentally deduce pH-dependent critical volumes to dissolve applied dose (VDAD) that determine whether a drug candidate can be developed as immediate release (IR) tablet containing crystalline API, or if solubilization technology is needed to allow for sufficient oral bioavailability. pH-dependent VDADs of 22 and 83 compounds were plotted vs. the relative oral bioavailability (AUC solid vs. AUC solution formulation, Frel) in humans and rats, respectively. Furthermore, in order to investigate to what extent Frel rat may predict issues with solubility limited absorption in human, Frel rat was plotted vs. Frel human. Additionally, the impact of bile salts and lecithin on in vitro dissolution of poorly soluble compounds was tested and data compared to Frel rat and human. Respective in vitro - in vivo and in vivo - in vivo correlations were generated and used to build developability criteria. As a result, based on pH-dependent VDAD, Frel rat and in vitro dissolution in simulated intestinal fluid the IR formulation strategy within Pharmaceutical Research and Development organizations can be already set at late stage of drug discovery. PMID- 26955752 TI - Efficient unidirectional launching of surface plasmons by a cascade asymmetric groove structure. AB - Increasing the unidirectional launching efficiency of surface plasmon polaritons (SPPs) is crucial in plasmonics. Here, we demonstrate that this efficiency may be improved by cascading subwavelength unidirectional SPP launching units. A unidirectional SPP launching efficiency of at least 46% and an extinction ratio of 40 are experimentally demonstrated using a cascade asymmetric-groove structure. Meanwhile, the device is ultracompact, and has a lateral dimension of only 1.1 MUm. The proposed structure also presents a broadband response and is easy to fabricate. This high-performance wavelength-scale unidirectional SPP launcher represents an important development in practical SPP sources. PMID- 26955753 TI - Fatigue-Induced Changes in Movement Pattern and Muscle Activity During Ballet Releve on Demi-Pointe. AB - Fatigue in ballet dancers may lead to injury, particularly in the lower extremities. However, few studies have investigated the effects of fatigue on ballet dancers' performance and movement patterns. Thus, the current study examines the effect of fatigue on the balance, movement pattern, and muscle activities of the lower extremities in ballet dancers. Twenty healthy, female ballet dancers performed releve on demi-pointe before and after fatigue. The trajectory of the whole body movement and the muscle activities of the major lower extremity muscles were recorded continuously during task performance. The results show that fatigue increases the medial-lateral center of mass (COM) displacement and hip and trunk motion, but decreases the COM velocity and ankle motion. Moreover, fatigue reduces the activities of the hamstrings and tibialis anterior, but increases that of the soleus. Finally, greater proximal hip and trunk motions are applied to compensate for the effects of fatigue, leading to a greater COM movement. Overall, the present findings show that fatigue results in impaired movement control and may therefore increase the risk of dance injury. PMID- 26955754 TI - Mechanistic considerations of enantiorecognition on novel Cinchona alkaloid-based zwitterionic chiral stationary phases from the aspect of the separation of trans paroxetine enantiomers as model compounds. AB - The enantiomers of trans-paroxetine were separated on four chiral stationary phases (CSPs) based on chiral zwitterionic Cinchona alkaloids fused with (R,R)- or (S,S)-trans-2-aminocyclohexanesulfonic acid. The enantioseparations were carried out in polar-ionic or in hydro-organic mobile phases with MeOH/THF, MeCN/THF, MeCN/THF/H2O and MeOH/MeCN/THF containing organic acid and base additives, in the temperature range 0-50 degrees C. The effects of the mobile phase composition, the natures and concentrations of the additives and temperature on the separations were investigated. Thermodynamic parameters were calculated from plots of ln alpha vs 1/T. Delta(DeltaH degrees ) ranged between 3.0 and +1.5 kJ mol(-1), and Delta(DeltaS degrees ) between -8.8 and +5.9 J mol( 1)K(-1). The enantioseparation was generally enthalpically controlled, the retention factor and separation factor decreasing with increasing temperature, but entropically controlled separation was also observed. The elution sequences of the paroxetine enantiomers on the two pairs of pseudo-enantiomeric CSPs were investigated, and an attempt was made to explain the observed anomalies in silico in order to gain an insight into the underlying molecular recognition events between the four chiral selectors and the analyte enantiomers. PMID- 26955755 TI - A single marker choice strategy in simultaneous characterization and quantification of multiple components by rapid resolution liquid chromatography coupled with triple quadrupole tandem mass spectrometry (RRLC-QqQ-MS). AB - Single standard to determine multi-components (SSDMC) method has been accepted as an efficient technique for the quality control of Traditional Chinese medicines (TCMs), especially for overcoming the shortage of reference standards. HPLC-UV methods have been applied to establish SSDMC method for quantitative analysis in several plant medicines and Chinese patent medicines, however, no LC-MS methods have been used. The purpose of this study is to put forward an improved strategy for the choice of single marker in SSDMC using rapid resolution liquid chromatography coupled with triple quadrupole tandem mass spectrometry (RRLC-QqQ MS). Five different Panax genus plants, recorded in the Chinese Pharmacopeia 2015 edition, were used as research subjects. An improved SSDMC strategy for simultaneous characterization and determination of 18 bioactive saponins in five Panax plants was put forward, and which was validated to be more superior. Then, it was fully investigated with respect to linearity, LODs, LOQs, precision and accuracy. Coupling with multivariate statistical analysis, the established and validated SSDMC strategy could be successively used in discrimination of the five Panax genus plants. PMID- 26955756 TI - Optimization of ultrasound assisted dispersive liquid-liquid microextraction of six antidepressants in human plasma using experimental design. AB - A simple Ultrasounds Assisted-Dispersive Liquid Liquid Microextraction (UA-DLLME) method is presented for the simultaneous determination of six second-generation antidepressants in plasma by Ultra Performance Liquid Chromatography with Photodiode Array Detector (UPLC-PDA). The main factors that potentially affect to DLLME were optimized by a screening design followed by a response surface design and desirability functions. The optimal conditions were 2.5 mL of acetonitrile as dispersant solvent, 0.2 mL of chloroform as extractant solvent, 3 min of ultrasounds stirring and extraction pH 9.8.Under optimized conditions, the UPLC PDA method showed good separation of antidepressants in 2.5 min and good linearity in the range of 0.02-4 MUg mL(-1), with determination coefficients higher than 0.998. The limits of detection were in the range 4-5 ng mL(-1). The method precision (n=5) was evaluated showing relative standard deviations (RSD) lower than 8.1% for all compounds. The average recoveries ranged from 92.5% for fluoxetine to 110% for mirtazapine. The applicability of DLLME/UPLC-PDA was successfully tested in twenty nine plasma samples from antidepressant consumers. Real samples were analyzed by the proposed method and the results were successfully submitted to comparison with those obtained by a Liquid Liquid Extraction-Gas Chromatography - Mass Spectrometry (LLE-GC-MS) method. The results confirmed the presence of venlafaxine in most cases (19 cases), followed by sertraline (3 cases) and fluoxetine (3 cases) at concentrations below toxic levels. PMID- 26955757 TI - Partner concurrency and HIV infection risk in South Africa. AB - BACKGROUND: The relationship between concurrent sexual partnerships and HIV risk is not fully understood. Evidence on the relationship between partner concurrency (one's sexual partner has another partner) and individual HIV risk is limited. In this study, the relationship between reported sexual partner concurrency and the risk of HIV infection was explored among South Africans. METHODS: Data from the third South African national HIV survey were used. In this survey, performed in 2008, questionnaires and HIV tests were administered to a nationally representative sample of 15031 persons. Bivariate analysis and multiple logistic regression were used to evaluate the relationship between partner concurrency and HIV serostatus. Spearman's correlation was used to test the association between the prevalence of HIV and partner concurrency by race in women. RESULTS: The relationship between HIV prevalence and partner concurrency varied by race. At a cross-racial level there was a positive association between HIV prevalence and partner concurrency for women (rho=0.95, p=0.05). Among coloured, white, and Indian persons, HIV prevalence and partner concurrency rates were too low to allow further statistical testing. In the bivariate analysis, black African women who reported partner concurrency had a higher prevalence of HIV (36% (95% confidence interval (CI) 29.7-42.0) vs. 23% (95% CI 19.6-26.1), p<0.001). After controlling for demographic, social, biological, and behavioural variables, the association remained statistically significant (adjusted odds ratio (aOR) 1.4, p=0.04). The association was stronger among 15-29-year-old black African women (aOR 1.8, p=0.03) than among women aged 30 years and older (aOR 1.3, p=0.36). CONCLUSIONS: These results suggest that partner concurrency may increase the HIV infection risk for black South African women, and in particular, for younger women. PMID- 26955758 TI - Chronic Kidney Disease Impairs Bone Defect Healing in Rats. AB - Chronic kidney disease (CKD) has been regarded as a risk for bone health. The aim of this study was to evaluate the effect of CKD on bone defect repair in rats. Uremia was induced by subtotal renal ablation, and serum levels of BUN and PTH were significantly elevated four weeks after the second renal surgery. Calvarial defects of 5-mm diameter were created and implanted with or without deproteinized bovine bone mineral (DBBM). Micro-CT and histological analyses consistently revealed a decreased newly regenerated bone volume for CKD rats after 4 and 8 weeks. In addition, 1.4-mm-diameter cortical bone defects were established in the distal end of femora and filled with gelatin sponge. CKD rats exhibited significantly lower values of regenerated bone and bone mineral density (BMD) within the cortical gap after 2 and 4 weeks. Moreover, histomorphometric analysis showed an increase in both osteoblast number (N.Ob/B.Pm) and osteoclast number (N.Oc/B.Pm) in CKD groups due to hyperparathyroidism. Notably, collagen maturation was delayed in CKD rats as verified by Masson's Trichrome staining. These data indicate that declined renal function negatively affects bone regeneration in both calvarial and femoral defects. PMID- 26955759 TI - Mediterranean diet as a protection against asthma: Still another brick in building a causative association. PMID- 26955761 TI - TMEM16A contributes to angiotensin II-induced cerebral vasoconstriction via the RhoA/ROCK signaling pathway. AB - Calcium activated chloride channels (CaCCs) are critical in vascular smooth muscle function as they regulate proliferation/apoptosis of smooth muscle cells (SMCs) and vascular tone. Transmembrane protein 16A (TMEM16A) was demonstrated to encode CaCCs in basilar artery SMCs (BASMCs) and participate in basilar artery remodeling during hypertension. In addition, TMEM16A has recently been illustrated to contribute to pressure-induced myogenic response in cerebral vasculature. However, whether TMEM16A is involved in cerebral vasoconstriction that is stimulated by other vasoconstrictors remains unclear. The aim of the present study was to establish whether TMEM16A is involved in the progression of angiotensin II (Ang II)-induced basilar artery constriction and elucidate its potential role during hypertension. The study demonstrated that the specific inhibitor of TMEM16A, T16A-inhA01 attenuated Ang II-induced constriction in rat basilar arteries, and that this effect was weakened in parallel with the decline of TMEM16A expression in basilar arteries of 2-kidney, 2-clip hypertensive rats. Furthermore, it was found that 100 nM Ang II evoked a chloride current in cultured BASMCs with a basal 100-nM intracellular Ca2+ ([Ca2+]i) level. In addition, the current could be abolished by TMEM16A small interfering RNA pretreatment and Ang II receptor type 1 (AT1) receptor blocker, losartan, while Ang II failed to cause a further increase to Ca2+-dependent Cl- currents activated by 500 nM [Ca2+]i. In addition, in cultured BASMCs, Ang II induced phosphorylation of myosin phosphatase-targeting subunit 1, and myosin light chains were significantly enhanced by TMEM16A overexpression, which were reversed by Rho-associated protein kinase (ROCK) inhibitor, Y-27632, while TMEM16A silencing demonstrated an opposing result. Furthermore, Ang II-induced RhoA activation was enhanced by TMEM16A overexpression. In conclusion, the present study revealed that Ang II elicited a TMEM16A-mediated current and TMEM16A participated in Ang II-induced basilar constriction via the RhoA/ROCK signaling pathway. PMID- 26955762 TI - Pre-pregnancy body mass index (BMI) and macrosomia in a Canadian birth cohort. AB - OBJECTIVE: To compare demographic characteristics and maternal, fetal, neonatal, and pregnancy outcomes of term macrosomic infants of obese and non-obese mothers. METHODS: A sample of 1996 singleton, term deliveries was drawn from the All Our Babies Cohort, a prospective, community-based pregnancy cohort. Maternal self reported socio-demographic and anthropometric information was linked to the clinical data on pregnancy and birth events abstracted from electronic health records. Demographic, obstetrical characteristics and maternal, fetal, neonatal, and pregnancy outcomes of macrosomic infants in obese, overweight, and normal weight women were compared. Multinomial regression analysis assessed the risk factors of macrosomia in primiparous and multiparous women stratified by maternal pre-pregnancy BMI, controlling for confounding variables. RESULTS: Macrosomia affected 10% of pregnancies in the study. Mothers whose infants were macrosomic were more likely to be Caucasian, obese, have had previous deliveries, undergo induction of labour and delivery by emergency C-section, particularly for labour abnormalities. Macrosomic infants were more likely to be delivered postdates, have meconium stained liquor and require resuscitation at birth. There were no significant differences in birth and neonatal outcomes of macrosomic pregnancies between obese, overweight and normal weight women. Pre-pregnancy BMI and gestational age at delivery were risk factors for macrosomia in all women. Ethnicity and history of delivery of a macrosomic infant were additional independent risk factors in multiparas. CONCLUSIONS: Obesity in pregnancy increases the risk of delivery of a macrosomic infant in both primiparous and multiparous women. The maternal, fetal and neonatal outcomes of macrosomic pregnancies are similar in obese and normal weight women. PMID- 26955760 TI - Dual regulatory switch through interactions of Tcf7l2/Tcf4 with stage-specific partners propels oligodendroglial maturation. AB - Constitutive activation of Wnt/beta-catenin inhibits oligodendrocyte myelination. Tcf7l2/Tcf4, a beta-catenin transcriptional partner, is required for oligodendrocyte differentiation. How Tcf7l2 modifies beta-catenin signalling and controls myelination remains elusive. Here we define a stage-specific Tcf7l2 regulated transcriptional circuitry in initiating and sustaining oligodendrocyte differentiation. Multistage genome occupancy analyses reveal that Tcf7l2 serially cooperates with distinct co-regulators to control oligodendrocyte lineage progression. At the differentiation onset, Tcf7l2 interacts with a transcriptional co-repressor Kaiso/Zbtb33 to block beta-catenin signalling. During oligodendrocyte maturation, Tcf7l2 recruits and cooperates with Sox10 to promote myelination. In that context, Tcf7l2 directly activates cholesterol biosynthesis genes and cholesterol supplementation partially rescues oligodendrocyte differentiation defects in Tcf712 mutants. Together, we identify stage-specific co-regulators Kaiso and Sox10 that sequentially interact with Tcf7l2 to coordinate the switch at the transitions of differentiation initiation and maturation during oligodendrocyte development, and point to a previously unrecognized role of Tcf7l2 in control of cholesterol biosynthesis for CNS myelinogenesis. PMID- 26955764 TI - Imitators of preeclampsia: A review. AB - This review article describes disorders that may imitate preeclampsia (PET), preeclampsia with haemolysis, elevated liver enzymes and low platelets (HELLP syndrome) and eclampsia. PMID- 26955763 TI - Primary Care Pathway for Childhood Asthma: Protocol for a Randomized Cluster Controlled Trial. AB - BACKGROUND: Asthma is the most common chronic condition in children. For many, the disease is inadequately controlled, which can burden the lives of children and their families as well as the health care system. Improved use of the best available scientific evidence by primary care practitioners could reduce the need for hospital care and improve quality of life and asthma control, thereby reducing overall costs to society and families. OBJECTIVE: The Primary Care Pathway for Childhood Asthma aims to improve the management of children with asthma by (1) providing primary care practitioners with an electronic guide (a clinical pathway) incorporated into the patient's electronic medical record, and (2) providing train-the-trainer education to chronic disease management health professionals to promote the provision of asthma education in primary care. METHODS: The research will utilize a pragmatic cluster-controlled design, quantitative and qualitative research methodologies, and economic evaluation to assess the implementation of a pathway and education intervention in primary care. The intervention will be analyzed for effectiveness, and if the results are positive, a strategy will be developed to implement delivery to all primary care practices in Alberta. RESULTS: The research has been successfully funded and ethics approvals have been obtained. Practice recruitment began fall 2015, and we expect all study-related activities to be concluded by March 2018. CONCLUSIONS: The proposed pathway and education intervention has the potential to improve pediatric asthma management in Alberta. The intervention is anticipated to result in better quality of care for equal or lesser cost. CLINICALTRIAL: ClinicalTrials.gov NCT02481037; https://clinicaltrials.gov/ct2/show/NCT02481037 (Archived by WebCite at http://www.webcitation.org/6fPIQ02Ma). PMID- 26955765 TI - 3D power Doppler ultrasound in early diagnosis of preeclampsia. AB - INTRODUCTION: Preeclampsia is a known cause of maternal, fetal and neonatal morbidity and mortality. Thus, evaluation of the predicting value of comparing 3D power Doppler indices (3DPD) of uteroplacental circulation (UPC) in the first and second trimester in patients who developed preeclampsia (PE) and those who did not and testing the hypothesis that the parameters of vascularization and placenta flow intensity, as determined by three-dimensional ultrasound (3D), are different in normal pregnancies compared with preeclampsia, could be a suitable screening method. METHODS: A prospective observational study using 3D power Doppler were performed to evaluate the placental perfusion in 96 pregnant women who came to do the ultrasound routine between 11 and 14 weeks. The placental vascular index (VI), flow index (FI), blood vessels and blood flow index (VFI) by three-dimensional Doppler histogram were calculated. All patients repeated the exam between 16 and 20 weeks. The outcome was scored as normal or preeclamptic. RESULTS: Placental vascular indices including VI, FI and VFI were significantly lower in preeclamptic placentas compared with controls in the study performed in the second trimester (p<0.001). There was not any statistical difference in the patients examined in the first trimester. DISCUSSION: Our findings suggest that 3D-power Doppler assessment of placental vascular indices in the second trimester has the potential to detect women at risk for subsequent development of PE. PMID- 26955766 TI - Human chorionic gonadotropin, fetal sex and risk of hypertensive disorders of pregnancy: A nested case-control study. AB - OBJECTIVES: To assess whether human chorionic gonadotropin (HCG) and fetal sex are two independent risk factors for hypertensive pregnancy in the early second trimester of pregnancy. METHODS: This was a retrospective nested case-control study based on a cohort of 2521 singleton pregnancies, among whom we recruited 98 hypertensive pregnancies (subdivided into severe preeclampsia, n=34; mild preeclampsia, n=29 and gestational hypertension, n=35) and 196 normotensive pregnancies. Maternal serum HCG levels were measured at 15-20 weeks of gestation and fetal sex was determined from the neonatal record. Mann-Whitney U and chi square tests were performed to assess differences of HCG levels and fetal sex between groups. Logistic regressions were performed to evaluate the effect of HCG and fetal sex on hypertensive pregnancy. RESULTS: There were 35 male and 63 female fetuses in the hypertensive group, and 102 male and 94 female fetuses in the normotensive group (p=0.008). HCG (MoM) levels were significantly higher in only severe preeclamptic pregnancies (n=34) (p=0.013). There were no significant differences of the HCG (MoM) levels between male and female fetuses in each sub group. aOR for increased maternal HCG levels and female fetus were 2.4 (95% CI: 1.434-3.954) and 2.9 (95% CI: 1.227-6.661) respectively in severe preeclamptic pregnancies compared with normotensive pregnancies. CONCLUSIONS: There is a female preponderance in hypertensive pregnancies. Increased HCG levels and female fetus are two independent risk factors for severe preeclampsia in the early second-trimester of pregnancy. PMID- 26955767 TI - Is neutrophil/lymphocyte ratio a useful marker to predict the severity of pre eclampsia? AB - OBJECTIVE: To evaluate the relationship of neutrophil/lymphocyte ratio (NLR) with proteinuria and blood pressure level in patients with pre-eclampsia and to investigate whether or not NLR has a role in predicting the severity of pre eclampsia. STUDY DESIGN: The study comprised 30 healthy pregnant females (Group 1), 37 females with mild pre-eclampsia (Group 2) and 40 with severe pre-eclampsia (Group 3). All the study participants were statistically compared in respect of demographic data, proteinuria levels, and blood pressure levels. RESULT: Age, body mass index, and gestational weeks were similar in all the groups. Maternal NLR was determined to be significantly high in the pre-eclamptic patients (Groups 2 and 3) compared to the healthy pregnant patients (Group 1) (p=0.017). NLR was significantly higher in the severe pre-eclampsia group than in the mild pre eclampsia group (p=0.032). A significant positive correlation was determined in correlation analysis between NLR and proteinuria (p=0.013, r=0.319). There was also a significant and positive correlation between NLR and systolic/diastolic arterial pressure (p=0.007, r=0.285; p=0.044, r=0.213, respectively). CONCLUSION: In conclusion, while NLR was determined as significantly high in patients with pre-eclampsia, to be able to use this in the classification of the severity of pre-eclampsia, there is a need for further studies on a more extensive population. PMID- 26955768 TI - How important is the butyrylcholinesterase level for cesarean section? AB - OBJECTIVES: Butyrylcholinesterase (BChE), commonly known as pseudocholinesterase or non-neural cholinesterase, hydrolyzes neuromuscular blocker agents containing choline esters such as succinylcholine that is widely used in rapid sequence induction (RSI) for general anesthesia. The aim of this study is to compare plasma BChE levels and investigate the affects and relationship of succinylcholine on BChE levels in preeclamptic, gestational diabetic and healthy pregnants. STUDY DESIGN: We designed a prospective, controlled, pilot single center study. Thirty (n=30) pregnant women who were scheduled for cesarean section under general anesthesia (refusal of regional anesthesia) with RSI involved. Group 1 included ten (n=10) preeclamptic pregnancies, Group 2 included ten (n=10) gestational diabetic (GD) pregnancies and Group 3 included ten (n=10) healthy pregnancies. MAIN OUTCOME MEASURES: BChE levels of all patients were measured prior to the initiation of cesarean section. Train-of-four recovery of 90% (TOF T1) was used to monitor the degree of neuromuscular block beginning from the administration of succinylcholine. RESULTS: No statistically significant difference was found between the groups comparing BChE levels and the duration between tracheal intubation and formation of TOF T1 (p>0.05). CONCLUSIONS: As similar results were gathered from normal and high-risk pregnancies (preeclamptic pregnancy or gestational diabetic pregnancy) who underwent cesarean section under general anesthesia, we believe that succinylcholine is still neuromuscular agent of choice in cesarean section. PMID- 26955769 TI - Utero-placental cellular and nuclear expression of bradykinin B2 receptors in normal and preeclamptic pregnancies. AB - The bradykinin type 2 receptor (B2R), main effector of the pleiotropic kallikrein kinin system (KKS), has been localized in the key sites related to placentation in human, rat and guinea pig utero-placental units. The present study was directed to characterize the content, the cellular and subcellular localization of B2R in the villi and basal plate of placentas from normal and preeclamptic pregnancies by means of western blotting, immunohistochemistry and immunoelectron microscopy. The protein content of B2R was demonstrated in both placental zones. The villous placenta of normal and preeclamptic pregnancies expressed B2R in syncytiotrophoblast and fetal endothelium; the basal plate displayed B2R in extravillous trophoblasts and decidual cells. Lastly, immunogold electron microscopy revealed B2R in fetal endothelium, syncytiotrophoblast, extravillous cytotrophoblasts and decidual cells; in all cell types the receptor was mainly located in the cytosol and nucleus. The protein content of placental homogenates and the immunoreactivity in the different cells types did not differ between both study groups; however the abundance of nuclear immunogold B2R positive beads in extravillous trophoblasts was greater in the normal than in the preeclamptic placentas. The purpose of describing nuclear B2R in the utero-placental unit, and its increment in normal extravillous trophoblasts, is to stimulate the study of the functional pathways that may be relevant to understand the local role of the B2R in normal and preeclamptic gestation. PMID- 26955770 TI - Novel indexes of arrhythmogenesis in preeclampsia: QT dispersion, Tp-e interval, and Tp-e/QT ratio. AB - OBJECTIVE: There is increasing evidence that preeclampsia (PE) may also be a risk factor for future cardiovascular diseases (CVDs), including arrhythmia. In this study we aimed to evaluate the association between PE and ventricular repolarization using novel electrocardiogram markers: QT interval duration, Tp-e interval, and Tp-e/QT ratio. MATERIALS AND METHODS: In this controlled cross sectional study sixty-four pregnant women with PE (31 with mild and 33 with severe disease) and 32 healthy women with uncomplicated pregnancies in the third trimester were compared by measuring QT parameters, Tp-e interval, and Tp-e/QT ratio. RESULTS: Tp-e interval and Tp-e/QT ratio values were significantly higher in both the mild and severe PE groups compared to the healthy pregnant group. CONCLUSION: Prevention of CVD requires that patients be aware of their risk factors, be educated about their risk, and perhaps most importantly perceive them to be at risk. In this study, we documented that PE has a significant effect on ventricular repolarization. This alteration could, in part, explain the increased cardiovascular risk in women with a history of PE. This important association can be used to screen women for increased risk in order to better target counseling regarding lifestyle modifications and to follow up and manage women with a history of hypertensive disease of pregnancy more closely. PMID- 26955771 TI - Theobroma cacao increases cells viability and reduces IL-6 and sVCAM-1 level in endothelial cells induced by plasma from preeclamptic patients. AB - This study aims to investigate whether an ethanolic extract of Theobroma cacao bean is able to increase cell viability and decrease IL-6 and sVCAM-1 in endothelial cells induced by plasma from preeclamptic patients. Endothelial cells were obtained from human umbilical vascular endothelial cells. At confluency, endothelial cells were divided into six groups, which included control (untreated), endothelial cells exposed to plasma from normal pregnancy, endothelial cells exposed to 2% plasma from preeclamptic patients (PP), endothelial cells exposed to PP in the presence of ethanolic extract of T. cacao (PP+TC) at the following three doses: 25, 50, and 100 ppm. The analysis was performed in silico using the Hex 8.0, LigPlus and LigandScout 3.1 software. Analysis on IL-6 and sVCAM-1 levels were done by enzyme linked immunosorbent assay (ELISA). We found that seven of them could bind to the protein NFkappaB (catechin, leucoanthocyanidin, niacin, phenylethylamine, theobromine, theophylline, and thiamin). This increase in IL-6 was significantly (P<0.05) attenuated by both the 50 and 100 ppm treatments of T. cacao extract. Plasma from PP significantly increased sVCAM-1 levels compared to untreated cells. This increase in sVCAM-1 was significantly attenuated by all doses of the extract. In conclusion, T. cacao extract prohibits the increase in IL-6 and sVCAM-1 in endothelial cells induced by plasma from preeclamptic patients. Therefore this may provide a herbal therapy for attenuating the endothelial dysfunction found in preeclampsia. PMID- 26955772 TI - An analysis of the differences between early and late preeclampsia with severe hypertension. AB - Preeclampsia is clinically divided into early onset and late onset preeclampsia based on the gestational age at delivery. Although the diagnostic criteria are the same in each subgroup of preeclampsia, it has been suggested that the maternal and perinatal mortalities of early onset and late onset preeclampsia are different. However, studies that compare clinical parameters or laboratory biomarkers between early onset and late onset preeclampsia are limited. Data on 177 women with early or late preeclampsia with severe hypertension were collected from a University Teaching Hospital from January 2010 to January 2011 and analysed. Data included all the clinical parameters and laboratory biomarkers of liver and renal function. 63 women and 114 women were diagnosed with early and late preeclampsia with severe hypertension, respectively. There was no difference in the maternal age and the incidence of clinical symptoms including edema, vision disturbance, severe headache and stillbirth between two groups. There was a decrease in alkaline phosphatase levels in early preeclampsia with severe hypertension but other markers of liver function were not altered. However, renal function including blood urea nitrogen, creatinine and uric acid were significantly higher in early preeclampsia with severe hypertension. Umbilical artery systolic velocity/diastolic velocity ratio was significantly higher in early preeclampsia with severe hypertension. Our data demonstrates that the laboratory biomarkers of renal function differ between early and late preeclampsia with severe hypertension. The severity of renal dysfunction correlated with the time of delivery in preeclampsia with severe hypertension. PMID- 26955774 TI - The association of single nucleotide polymorphisms of the maternal cystathionine beta-synthase gene with early-onset preeclampsia. AB - OBJECTIVES: Preeclampsia (PE) is a pregnancy complication, characterized by hypertension and proteinuria. The transsulfuration pathway may be involved in its pathophysiology, since homocysteine, cystathionine and cysteine are increased in PE. Cystathionine-beta-synthase (CBS) is a key-enzyme in the pathway, converting homocysteine into cysteine via cystathionine. Another product of CBS is hydrogen sulfide (H2S), a vasodilatory, proangiogenic and cytoprotective gas that is thought to play a role in placental and vascular function during pregnancy. Since single nucleotide polymorphisms (SNPs) can affect CBS expression and/or function, we studied tag-SNPs in the CBS gene in PE patients. STUDY DESIGN: Controls (n=75), early-onset (n=45), and late-onset PE (n=52) cases were genotyped for six tag-SNPs in the CBS gene; rs12329764, rs2851391, rs234713, rs234706, rs1789953, and rs11203172. Plasma homocysteine, cysteine and cystathionine were determined during pregnancy. MAIN OUTCOME MEASURES: Early-onset PE, late-onset PE. RESULTS: Women with the minor allele of rs11203172 have a reduced risk for early-onset PE. Compared to women without the minor allele, normotensive pregnant women with the minor allele of rs11203172 and rs234713 have lower cysteine levels. Women with the minor allele of rs1789953 have increased levels of cysteine and cystathionine, compared to women without. CONCLUSION: The CBS tag-SNP rs11203172 is associated with a decreased risk for early-onset PE. Decreased cysteine concentrations in normotensive pregnant women carrying the minor allele of rs11203172, may be due to increased cysteine conversion to H2S by CBS. Higher H2S levels may positively affect placentation and vascular function during pregnancy and decrease their risk for PE. PMID- 26955773 TI - Extending the scope of pooled analyses of individual patient biomarker data from heterogeneous laboratory platforms and cohorts using merging algorithms. AB - BACKGROUND: A common challenge in medicine, exemplified in the analysis of biomarker data, is that large studies are needed for sufficient statistical power. Often, this may only be achievable by aggregating multiple cohorts. However, different studies may use disparate platforms for laboratory analysis, which can hinder merging. METHODS: Using circulating placental growth factor (PlGF), a potential biomarker for hypertensive disorders of pregnancy (HDP) such as preeclampsia, as an example, we investigated how such issues can be overcome by inter-platform standardization and merging algorithms. We studied 16,462 pregnancies from 22 study cohorts. PlGF measurements (gestational age ?20 weeks) analyzed on one of four platforms: R&D Systems, AlereTriage, RocheElecsys or AbbottArchitect, were available for 13,429 women. Two merging algorithms, using Z Score and Multiple of Median transformations, were applied. RESULTS: Best reference curves (BRC), based on merged, transformed PlGF measurements in uncomplicated pregnancy across six gestational age groups, were estimated. Identification of HDP by these PlGF-BRCs was compared to that of platform specific curves. CONCLUSIONS: We demonstrate the feasibility of merging PlGF concentrations from different analytical platforms. Overall BRC identification of HDP performed at least as well as platform-specific curves. Our method can be extended to any set of biomarkers obtained from different laboratory platforms in any field. Merged biomarker data from multiple studies will improve statistical power and enlarge our understanding of the pathophysiology and management of medical syndromes. PMID- 26955775 TI - Similarities and differences between the risk factors for gestational hypertension and preeclampsia: A population based cohort study in south China. AB - OBJECTIVES: To compare the risk factors for gestational hypertension (GH) and preeclampsia (PE) in the same population, which may provide clues to better understanding of their etiologic mechanisms. METHODS: We conducted a cohort study in Liuyang, China, during 2010-2011. Twelve potential risk factors were investigated, including maternal age, body mass index at first antenatal visit, gender of newborn, parity, abortion history, smoking history, family history of hypertension, gestational diabetes mellitus, pregnancy complications of diabetes mellitus/renal disease/cardiac disease, reproductive tract infection, season of delivery, and district level average per capita income. Logistic regression were used to estimate odds ratios for potential risk factors. RESULTS: Of 6223 pregnancies, 1.8% was complicated by PE, and 5.4% by GH. Maternal age older than 35, body mass index above 24, and pregnancy complicated with gestational diabetes mellitus increased the risk of both PE and GH, while with different effect sizes. Primiparity and deliver in winter and spring (compared with summer delivery) were risk factors for GH only. Pregnancy complicated with diabetes mellitus/renal disease/cardiac disease was risk factor for PE only. Significantly lower risk of GH was observed for women younger than 25 or with low body mass index in the first trimester. Mothers carrying a male fetus were more likely to develop PE. CONCLUSIONS: Risk factors for GH and PE were not exactly the same. Underling those differences might be their different etiology and mechanism. To confirm the similarities and differences been found in single study, it is important to conduct investigation in other population. PMID- 26955776 TI - Mid-pregnancy circulating immune biomarkers in women with preeclampsia and normotensive controls. AB - OBJECTIVES: To determine if mid-pregnancy circulating immune biomarkers are associated with preeclampsia. STUDY DESIGN: Nested case-control study of 410 preeclamptic women and 297 normotensive controls with primiparous singleton pregnancies enrolled in the Danish National Birth Cohort. The mean gestational age in our cohort is 16 weeks (range 9-26). MAIN OUTCOME MEASURES: Preeclampsia was defined by blood pressure ?140/90 mmHg and proteinuria ?3 g/24 h. Serum immune biomarkers included interleukin (IL)-6, IL-6 receptor, IL-4, IL-4 receptor, IL-5, IL-12, IL-2, TNF-alpha, TNF-beta, TNF-receptor, IL-1beta, IL 1alpha, IL-8, IL-10, IFN-gamma, IL-18, macrophage migration inhibitory factor, macrophage inflammatory protein, transforming growth factor-beta (TGF-beta), and RANTES. Associations with preeclampsia, term preeclampsia and preterm preeclampsia were determined using two logistic regression models; (1) biomarkers were dichotomized by the limit of detection (LOD); (2) on the continuous scale, non-detectable values were imputed by LOD/2 and transformed (base 2). All models were adjusted for body mass index and smoking. RESULTS: IL1beta was significantly associated with a decrease in the log odds of preeclampsia (p=0.0065), term preeclampsia (p=0.0230) and preterm preeclampsia (p=0.0068). Results were similar for IL4r and preeclampsia (p=0.0383). In the dichotomized models, detectable TNF beta was significantly associated with preeclampsia (ORadj 1.6, 95% CI 1.1-2.3) and term preeclampsia (OR 1.7, 95% CI 1.1-2.5) but not preterm preeclampsia. Detectable IL6 was significantly with term preeclampsia only (OR 1.5, 95% CI 1.1 2.2). CONCLUSION: Mid-pregnancy circulating IL1beta, IL4r, IL6, and TNFbeta were associated with preeclampsia. However, results were not consistent across statistical models. As the relationship is complex, future studies should explore cytokine clusters in preeclampsia risk. PMID- 26955777 TI - Elevated placental expression at the maternal-fetal interface but diminished maternal circulatory kisspeptin in preeclamptic pregnancies. AB - OBJECTIVE: To investigate the placental mRNA and protein expression of metastasis suppressor gene Kiss-1 and the transcript expression of its receptor GPR-54 across the maternal-fetal interface of healthy and preeclamptic pregnancies. To furthermore compare placental tissue kisspeptin expression to circulatory kisspeptin levels in these pregnancies. SETTING: Secondary and Tertiary Hospital Setting in Cape Town, South Africa. POPULATION: Patients with and without preeclampsia undergoing elective caesarean delivery. METHODS: The placenta, placental bed and decidua parietalis as well as maternal and cord blood in both healthy and preeclamptic pregnancies were simultaneously sampled at elective caesarean delivery. RT-PCR was utilised to determine mRNA expression while immunohistochemistry was employed to investigate protein expression in maternal fetal tissues. Circulating maternal and cord serum kisspeptin concentrations were determined using ELISA. MAIN OUTCOME MEASURES: Maternal-fetal tissue mRNA expression of Kiss-1 and GPR-54 as well as maternal/cord serum kisspeptin concentrations in healthy and preeclamptic pregnancies. RESULTS: There was high placental kisspeptin expression but low circulating serum kisspeptin levels in pregnancies complicated by preeclampsia. Kiss-1 mRNA and protein expression was minimal in the maternal tissues (placental bed and decidua parietalis) of both healthy and preeclamptic pregnancies. No difference was found in Kiss-1 receptor (GPR-54) mRNA expression across maternal-fetal tissues of healthy and preeclamptic pregnancies. CONCLUSIONS: Increased placental kisspeptin expression is consistent with reduced trophoblast invasiveness and may represent a molecular mechanism that explains the development of preeclampsia. Decreased circulating kisspeptin concentration has the potential to be utilised as a marker for placental dysfunction. PMID- 26955778 TI - Multimodal Video Colonoscope for Targeted Wide-Field Detection of Nonpolypoid Colorectal Neoplasia. PMID- 26955779 TI - Dual-Reactable Fluorescent Probes for Highly Selective and Sensitive Detection of Biological H2 S. AB - Hydrogen sulfide (H2 S) is an important endogenous signaling molecule with a variety of biological functions. Development of fluorescent probes for highly selective and sensitive detection of H2 S is necessary. We show here that dual reactable fluorescent H2 S probes could react with higher selectivity than single reactable probes. One of the dual-reactable probes gives more than 4000-fold turn on response when reacting with H2 S, the largest response among fluorescent H2 S probes reported thus far. In addition, the probe could be used for high throughput enzymatic assays and for the detection of Cys-induced H2 S in cells and in zebrafish. These dual-reactable probes hold potential for highly selective and sensitive detection of H2 S in biological systems. PMID- 26955780 TI - Synaptic abnormalities of mice lacking toll-like receptor (TLR)-9. AB - Motor, sensory, and autonomic abnormalities are reported for toll-like receptor 9 (TLR9) knock-out (KO) mice. However, a physiological role of TLR9 in the nervous system is largely unknown. Since altered synaptic transmission can contribute to sensory and motor abnormalities, we evaluated neuromuscular junction (NMJ) function and morphology of TLR9 KO mice. Triangularis sterni nerve-muscle preparations were dissected from TLR9 KO and age-matched control mice. Two electrode voltage clamp of the motor endplate revealed that the amplitude and frequency of miniature end plate currents (mEPCs) for TLR9 KO NMJs were significantly greater than control. In contrast, mean endplate current (EPC, 1Hz) amplitude was equivalent to control. The ratio of mean EPC to mean mEPC amplitude indicated a decline of quantal content (m) for TLR9 KO NMJs. Furthermore, m declined more rapidly than control in response to 50-Hz stimulus trains. A rightward shift of the mEPC amplitude distribution suggested formation of vesicles containing larger amounts of acetylcholine (ACh). Staining with rhodamine alpha-bungarotoxin revealed a significant decline of endplate size in TLR9 KO mice. This alteration may result from ACh-induced decline of acetylcholine receptor (AChR) expression resulting from increased frequency and amplitude of mEPCs. At the same time, excessive spontaneous vesicular ACh release may initiate retrograde suppression of excitation-secretion coupling. These data suggest a novel role of TLR9 in the development of the NMJ. PMID- 26955781 TI - Stimulating the proliferation, migration and lamellipodia of Schwann cells using low-dose curcumin. AB - Transplantation of peripheral glia is being trialled for neural repair therapies, and identification of compounds that enhance the activity of glia is therefore of therapeutic interest. We have previously shown that curcumin potently stimulates the activity of olfactory glia. We have now examined the effect of curcumin on Schwann cell (SC) activities including proliferation, migration and the expression of protein markers. SCs were treated with control media and with different concentrations of curcumin (0.02-20 MUM). Cell proliferation was determined by MTS assay and migration changes were determined by single live cell migration tracking. We found that small doses of curcumin (40 nM) dramatically increased the proliferation and migration in SCs within just one day. When compared with olfactory glia, curcumin stimulated SC proliferation more rapidly and at lower concentrations. Curcumin significantly increased the migration of SCs, and also increased the dynamic activity of lamellipodial waves which are essential for SC migration. Expression of the activated form of the MAP kinase p38 (p-p38) was significantly decreased in curcumin-treated SCs. These results show that curcumin's effects on SCs differ remarkably to its effects on olfactory glia, suggesting that subtypes of closely related glia can be differentially stimulated by curcumin. Overall these results demonstrate that the therapeutically beneficial activities of glia can be differentially enhanced by curcumin which could be used to improve outcomes of neural repair therapies. PMID- 26955782 TI - CART peptide and opioid addiction: Expression changes in male rat brain. AB - Previous studies have shown the prominence of cocaine- and amphetamine-regulated transcript (CART) peptide in rewarding and reinforcing effects of drugs of abuse specially psychostimulants. The data regarding the effects of different stages of opioid addiction on CART expression and the interconnection between CART and opioids are not much available. Here we have studied the changes in the expression level of CART mRNA and protein in various parts of the brain reward pathway in different stages of opioid addiction. Groups of male rats received acute low-dose (10mg/kg), acute high-dose (80mg/kg) and chronic escalating doses of morphine. In addition, withdrawal and abstinence states were evaluated after injection of naloxone (1mg/kg) and long-term maintenance of addicted animals, respectively. Expression of CART mRNA in the brain was measured by real-time PCR method. Western blotting was used to quantify the protein level. CART mRNA and protein were both up-regulated in high-dose morphine-administered animals and also in the withdrawal group in the nucleus accumbens (NAc), striatum and prefrontal cortex (PFC). In the addicted group, CART mRNA and protein were both down-regulated in NAc and striatum. In the abstinent group, CART mRNA was down regulated in NAc. In the hippocampus, the only observed change was the up regulation of CART mRNA in the withdrawal group. We suggest that the modulatory role of CART peptide in rewarding and reinforcing effects of opioids weakens when opioids are used for a long time and is stimulated when acute stress such as naloxone-induced withdrawal syndrome or acute high-dose administration of morphine occurs to the animal. PMID- 26955783 TI - Does medical intervention affect outcome in infants with trisomy 18 or trisomy 13? PMID- 26955784 TI - Observation of Single Pt Nanoparticle Collisions: Enhanced Electrocatalytic Activity on a Pd Ultramicroelectrode. AB - Single Pt nanoparticle (NP) collisions on an electrode surface were detected by using an electrocatalytic amplification method with a Pd ultramicroelectrode (UME). Pd is not a preferred material for UMEs for the detection of single Pt NP collisions, because Pd shows similar electrocatalytic activity compared with Pt for hydrazine oxidation, thus resulting in a high background current level. However, a Pt NP colliding on the Pd UME shows greatly enhanced activity compared with a Pt NP on an inert UME, such as a Au UME, which is usually used for the detection of single Pt NP collisions. The use of an electroactive UME material instead of an inert one facilitated the study of single-NP activity on the various solid supports, which is important in many NP applications. PMID- 26955785 TI - Spindle B-cell lymphoma: a rare variant of follicle center lymphoma. AB - Primary cutaneous follicle center lymphoma (PCFCL) is a common subtype of primary cutaneous B-cell lymphoma (PCBCL). The prognosis of this subtype is favorable and recurrence is observed in up to 50% of patients. The dissemination to lymph nodes or internal organs is rare. In this study, two cases of rare variant of PCFCL are reported. Both cases presented with multiple erythematous nodules, plaques and some annular configurations. Histopathological examination revealed dermal lymphocytic infiltrates consisting of admixed centrocytes and centroblasts. Interestingly, spindle-shaped cells with elongated nuclei, dispersed chromatin and scant cytoplasm were also detected. Immunohistochemical analysis revealed that all cells including the spindle cells were positive for CD20 and negative for CD3, CD43, CD10, CD34, CD68 and CD138. They were also negative for desmin and S-100. They consistently expressed nuclear bcl-6, but did not express bcl-2. The histopathological and immunohistochemical examination suggest a rare case of primary cutaneous spindle cell B-cell lymphoma (PCSBCL). Although few data is published about this rare subtype, PCSBCL is recently considered as a rare subtype of PCFCL. The prognosis and the nature of this peculiar subtype are not yet cleared. This indicates a great need for more investigations. PMID- 26955786 TI - Best Reviewers Award for 2015. PMID- 26955787 TI - Development and aging of superficial white matter myelin from young adulthood to old age: Mapping by vertex-based surface statistics (VBSS). AB - Superficial white matter (SWM) lies immediately beneath cortical gray matter and consists primarily of short association fibers. The characteristics of SWM and its development and aging were seldom examined in the literature and warrant further investigation. Magnetization transfer imaging is sensitive to myelin changes in the white matter. Using an innovative multimodal imaging analysis approach, vertex-based surface statistics (VBSS), the current study vertexwise mapped age-related changes of magnetization transfer ratio (MTR) in SWM from young adulthood to old age (30-85 years, N = 66). Results demonstrated regionally selective and temporally heterochronologic changes of SWM MTR with age, including (1) inverted U-shaped trajectories of SWM MTR in the rostral middle frontal, medial temporal, and temporoparietal regions, suggesting continuing myelination and protracted maturation till age 40-50 years and accelerating demyelination at age 60 and beyond, (2) linear decline of SWM MTR in the middle and superior temporal, and pericalcarine areas, indicating early maturation and less acceleration in age-related degeneration, and (3) no significant changes of SWM MTR in the primary motor, somatosensory and auditory regions, suggesting resistance to age-related deterioration. We did not observe similar patterns of changes in cortical thickness in our sample, suggesting the observed SWM MTR changes are not due to cortical atrophy. Hum Brain Mapp 37:1759-1769, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26955789 TI - Controlled Electromagnetically Induced Transparency and Fano Resonances in Hybrid BEC-Optomechanics. AB - Cavity-optomechanics, a tool to manipulate mechanical effects of light to couple optical field with other physical objects, is the subject of increasing investigations, especially with regards to electromagnetically induced transparency (EIT). EIT, a result of Fano interference among different atomic transition levels, has acquired a significant importance in many areas of physics, such as atomic physics and quantum optics. However, controllability of such multi-dimensional systems has remained a crucial issue. In this report, we investigate the controllability of EIT and Fano resonances in hybrid optomechanical system composed of cigar-shaped Bose-Einstein condensate (BEC), trapped inside high-finesse Fabry-Perot cavity with one vibrational mirror, driven by a single mode optical field and a transverse pump field. The transverse field is used to control the phenomenon of EIT. It is detected that the strength of transverse field is not only efficiently amplifying or attenuating out-going optical mode but also providing an opportunity to enhance the strength of Fano interactions which leads to the amplification of EIT-window. To observe these phenomena in laboratory, we suggest a certain set of experimental parameters. The results provide a route for tunable manipulation of optical phenomena, like EIT, which could be a significant step in quantum engineering. PMID- 26955788 TI - Adaptive bill morphology for enhanced tool manipulation in New Caledonian crows. AB - Early increased sophistication of human tools is thought to be underpinned by adaptive morphology for efficient tool manipulation. Such adaptive specialisation is unknown in nonhuman primates but may have evolved in the New Caledonian crow, which has sophisticated tool manufacture. The straightness of its bill, for example, may be adaptive for enhanced visually-directed use of tools. Here, we examine in detail the shape and internal structure of the New Caledonian crow's bill using Principal Components Analysis and Computed Tomography within a comparative framework. We found that the bill has a combination of interrelated shape and structural features unique within Corvus, and possibly birds generally. The upper mandible is relatively deep and short with a straight cutting edge, and the lower mandible is strengthened and upturned. These novel combined attributes would be functional for (i) counteracting the unique loading patterns acting on the bill when manipulating tools, (ii) a strong precision grip to hold tools securely, and (iii) enhanced visually-guided tool use. Our findings indicate that the New Caledonian crow's innovative bill has been adapted for tool manipulation to at least some degree. Early increased sophistication of tools may require the co-evolution of morphology that provides improved manipulatory skills. PMID- 26955790 TI - Quantifying variation in human scalp hair fiber shape and pigmentation. AB - OBJECTIVES: This study aims to evaluate the use of quantitative methods of measuring variation in scalp hair fiber shape and pigmentation and carry out exploratory data analysis on a limited sample of individuals from diverse populations in order to inform future avenues of research for the evolution of modern human hair variation. METHODS: Cross-sectional area and shape and average curvature of scalp hair fibers were quantified using ImageJ. Pigmentation was analyzed using chemical methods estimating total melanin content through spectrophotometric methods, and eumelanin and pheomelanin content through HLPC analysis of melanin-specific degradation products. RESULTS: The initial results reinforced findings from earlier, traditional studies. African and African Diaspora scalp hair was significantly curled, (East) Asian hair was significantly thick, and European hair was significantly lighter in color. However, pigmentation analyses revealed a high level of variability in the melanin content of non-European populations and analysis of curvature found a large range of variation in the average curvature of East African individuals. CONCLUSIONS: Overall, these results suggest the usefulness of chemical methods for the elucidation of nonperceptible differences in scalp hair color and highlight the need for improvements in our assessment and understanding of hair fiber curvature. Am J Phys Anthropol 160:341-352, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26955794 TI - Orofacial dyskinesia: caused by antidepressants? AB - A case report is presented of a 72 year old woman, who has been treated for a depression with amitriptyline. During the treatment an orofacial dyskinesia develloped. Data in the literature concerning a possible link between the manifestation of orofacial dyskinesia and treatment with antidepressants were mainly found to be case reports. A closer study of the total in all of 25 case reports reveals that the antidepressant is often at most one of more possible determinants of the movement disorder. Particularly, it was frequently noted that patients were treated with other drugs or that the use of other drugs was not specified. A controverse exists in the literature whether or not a so called spontaneous orofacial dyskinesia is found in high frequency in elderly people. For clinical practice the advice is given that, in case an orofacial dyskinesia arises during antidepressant treatment, attention should be paid to other provoking factors in the first place. PMID- 26955793 TI - The in-capillary DPPH-capillary electrophoresis-the diode array detector combined with reversed-electrode polarity stacking mode for screening and quantifying major antioxidants in Cuscuta chinensis Lam. AB - An in-capillary 2, 2-diphenyl-1-picrylhydrazyl (DPPH)-CE-the DAD (in-capillary DPPH-CE-DAD) combined with reversed-electrode polarity stacking mode has been developed to screen and quantify the active antioxidant components of Cuscuta chinensis Lam. The operation parameters were optimized with regard to the pH and concentration of buffer solution, SDS, beta-CDs, organic modifier, as well as separation voltage and temperature. Six antioxidants including chlorogenic acid, p-coumaric acid, rutin, hyperin, isoquercitrin, and astragalin were screened and the total antioxidant activity of the complex matrix was successfully evaluated based on the decreased peak area of DPPH by the established DPPH-CE-DAD method. Sensitivity was enhanced under reversed-electrode polarity stacking mode and 10- to 31-fold of magnitude improvement in detection sensitivity for each analyte was attained. The results demonstrated that the newly established in-capillary DPPH CE-DAD method combined with reversed-electrode polarity stacking mode could integrate sample concentration, the oxidizing reaction, separation, and detection into one capillary to fully automate the system. It was considered a suitable technique for the separation, screening, and determination of trace antioxidants in natural products. PMID- 26955795 TI - Narcolepsy, a "sleeping disorder"? AB - The narcoleptic syndrome in its most specific way is characterized by a set of clinical symptoms, including cataplexy, irresistable sleep episodes, hypnagogic hallucinations and sleepparalysis; the syndrome has been defined by the association of excessive day-time somnolence and REM-sleep abnormalities. In principle, anamnestic information is sufficient to establish the clinical diagnosis, although neuro-physiological and biochemical data(CSF monoamine metabolites and HLA-typology) are sometimes needed to support the diagnostic procedure. Treatment of excessive daytime somnolence is still primarily based upon CNS stimulants, while treatment of cataplexy and related symptoms rests on antidepressants with a primarily serotonergic mode of action. PMID- 26955791 TI - Silver nanoparticle-enriched diamond-like carbon implant modification as a mammalian cell compatible surface with antimicrobial properties. AB - The implant-bone interface is the scene of competition between microorganisms and distinct types of tissue cells. In the past, various strategies have been followed to support bony integration and to prevent bacterial implant-associated infections. In the present study we investigated the biological properties of diamond-like carbon (DLC) surfaces containing silver nanoparticles. DLC is a promising material for the modification of medical implants providing high mechanical and chemical stability and a high degree of biocompatibility. DLC surface modifications with varying silver concentrations were generated on medical-grade titanium discs, using plasma immersion ion implantation-induced densification of silver nanoparticle-containing polyvinylpyrrolidone polymer solutions. Immersion of implants in aqueous liquids resulted in a rapid silver release reducing the growth of surface-bound and planktonic Staphylococcus aureus and Staphylococcus epidermidis. Due to the fast and transient release of silver ions from the modified implants, the surfaces became biocompatible, ensuring growth of mammalian cells. Human endothelial cells retained their cellular differentiation as indicated by the intracellular formation of Weibel-Palade bodies and a high responsiveness towards histamine. Our findings indicate that the integration of silver nanoparticles into DLC prevents bacterial colonization due to a fast initial release of silver ions, facilitating the growth of silver susceptible mammalian cells subsequently. PMID- 26955796 TI - Postdexamethason intact and multisequentia ACTH in melancholia. AB - The dexamethasone suppression test has been carried out in 111 depressed inpatients. Fasting, 8 a.m. plasma levels of Cortisol and adrenocorticotropic hormone (ACTH) were determined before and after administration of 1 mg dexamethasone. In 64 subjects multisequential (1-17,1-24,1-39) ACTH, and in 47 subjects intact (1-39) ACTH has been determined. Patients with melancholia exhibited significantly higher postdexamethasone Cortisol and intact ACTH values as compared with minor and simple major depressives. Severity of illness was significantly and positively related to postdexamethasone intact ACTH - but not to multisequential ACTH. Cortisol nonsuppressors showed higher postdexamethasone (only intact) ACTH values than Cortisol suppressors. Both postdexamethasone ACTH values were significantly and positively related with the postdexamethasone Cortisol values. We have established that Cortisol nonsuppression during melancholia is determined by an augmented escape of ACTH from suppression by dexamethasone. Intact ACTH showed the most significant clinical relevance for depression and Cortisol nonsuppression. In the clinical practice we advize the use of postdexamethasone intact ACTH in stead of plasma Cortisol or multisequential ACTH. PMID- 26955797 TI - Psychofarmakologika V. AB - In deze rubriek zal worden ingegaan op recente observaties betreffende de psychofarmakologie in de breedst mogelijke zin. Vaak zullen zaken uit de literatuur worden behandeld. De gekozen onderwerpen dienen altijd klinische relevantie te hebben. Ook zal deze rubriek gaan over gewoontes die in psychofarmakologische behandeling of in onderzoek zijn geslopen die volgens de auteur lang niet altijd logisch zijn. Soms zal deze rubriek een oproep bevatten om te reageren op een bijdrage gepubliceerd in dit ofin een ander tijdschrift. Ook zal de lezer worden aangemoedigd hier zijn eigen ervaringen mee te delen. Het is niet de bedoeling in deze rubriek onderzoeken uitvoerig te rapporteren. Daarvoor staan andere pagina s van de Acta Neuropsychiatrica voor u open. PMID- 26955792 TI - Central nervous system involvement by multiple myeloma: A multi-institutional retrospective study of 172 patients in daily clinical practice. AB - The multicenter retrospective study conducted in 38 centers from 20 countries including 172 adult patients with CNS MM aimed to describe the clinical and pathological characteristics and outcomes of patients with multiple myeloma (MM) involving the central nervous system (CNS). Univariate and multivariate analyses were performed to identify prognostic factors for survival. The median time from MM diagnosis to CNS MM diagnosis was 3 years. Thirty-eight patients (22%) were diagnosed with CNS involvement at the time of initial MM diagnosis and 134 (78%) at relapse/progression. Upon diagnosis of CNS MM, 97% patients received initial therapy for CNS disease, of which 76% received systemic therapy, 36% radiotherapy and 32% intrathecal therapy. After a median follow-up of 3.5 years, the median overall survival (OS) from the onset of CNS involvement for the entire group was 7 months. Untreated and treated patients had median OS of 2 and 8 months, respectively (P < 0.001). At least one previous line of therapy for MM before the diagnosis of CNS disease and >1 cytogenetic abnormality detected by FISH were independently associated with worse OS. The median OS for patients with 0, 1 and 2 of these risk factors were 25 months, 5.5 months and 2 months, respectively (P < 0.001). Neurological manifestations, not considered chemotherapy-related, observed at any time after initial diagnosis of MM should raise a suspicion of CNS involvement. Although prognosis is generally poor, the survival of previously untreated patients and patients with favorable cytogenetic profile might be prolonged due to systemic treatment and/or radiotherapy. Am. J. Hematol. 91:575 580, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26955798 TI - Could spot urine analysis of calcium and uric acid help predict density of urinary stone in computerized tomography? A preliminary study. AB - BACKGROUD: This research studies if Hounsfield density of urinary stone can be predicted without computerized tomography (CT) caused by because increased radiation exposure in follow-up of patients. METHODS: The records of patients with renal or ureteral stone were analyzed retrospectively for the time period between November 2013 and April 2014. The inclusion criteria defined were: no multiple stones; stone size >=3 mm; presence of renal and ureteral stones; absence of staghorn stone. All CT images were assessed in abdominal windows by a single radiologist. Hounsfield Unit (HU) value of CT was used to interpret the density of the stone. The density of the stone was measured in the longest axis of the stone center (core) and the edges (periphery) of each stone. Biochemical analysis of spot urine calcium (Ca) and uric acid (UA) was done at the time of diagnosis. Correlation and linear regression analysis was performed. RESULTS: Forty patients were included the study and median age of patients is 22 (IQR 21 28). Since the unit was a military hospital, most patients admitted to hospital were young male conscripts with low median age. It has been found that spot urine uric acid and uric acid/Ca ratio is associated with stone density as HU (P=0.004, P<0.001). Although predictive value appeared low, linear regression model statistically predicted stone density as HU (P<0.001 R2=0.32). Stone size has proved to be positively correlated with stone density (P<0.001). CONCLUSIONS: Despite the predictive value of urine analysis model is low, it may be considered to predict HU attenuation of stone. Spot urine analysis of calcium and uric acid may be helpful for both diagnosis and follow-up. We believe that controlled studies with larger patient populations will provide further insights into this issue. PMID- 26955799 TI - Metal-center exchange of tetrahedral cages: single crystal to single crystal and spin-crossover properties. AB - An effective single crystal to single crystal transformation from a tetrahedral Ni cage to an FeNi cage was demonstrated. The iron(ii) centers of the FeNi cage can be induced to display spin crossover behaviors with an increasing amount of Fe(II) ions. The SCSC metal-center exchange provides a powerful approach to modify solid magnetic properties. PMID- 26955800 TI - Erratum: Pure-quartic solitons. PMID- 26955802 TI - Social health and dementia: the power of human capabilities. PMID- 26955801 TI - Engineering a multi-biofunctional composite using poly(ethylenimine) decorated graphene oxide for bone tissue regeneration. AB - Toward preparing strong multi-biofunctional materials, poly(ethylenimine) (PEI) conjugated graphene oxide (GO_PEI) was synthesized using poly(acrylic acid) (PAA) as a spacer and incorporated in poly(epsilon-caprolactone) (PCL) at different fractions. GO_PEI significantly promoted the proliferation and formation of focal adhesions in human mesenchymal stem cells (hMSCs) on PCL. GO_PEI was highly potent in inducing stem cell osteogenesis leading to near doubling of alkaline phosphatase expression and mineralization over neat PCL with 5% filler content and was ~50% better than GO. Remarkably, 5% GO_PEI was as potent as soluble osteoinductive factors. Increased adsorption of osteogenic factors due to the amine and oxygen containing functional groups on GO_PEI augment stem cell differentiation. GO_PEI was also highly efficient in imparting bactericidal activity with 85% reduction in counts of E. coli colonies compared to neat PCL at 5% filler content and was more than twice as efficient as GO. This may be attributed to the synergistic effect of the sharp edges of the particles along with the presence of the different chemical moieties. Thus, GO_PEI based polymer composites can be utilized to prepare bioactive resorbable biomaterials as an alternative to using labile biomolecules for fabricating orthopedic devices for fracture fixation and tissue engineering. PMID- 26955803 TI - Assessing the impact of meteorological factors on malaria patients in demilitarized zones in Republic of Korea. AB - BACKGROUND: The trend of military patients becoming infected with vivax malaria reemerged in the Republic of Korea (ROK) in 1993. The common explanation has been that infective Anopheles mosquitoes from the Democratic People's Republic of Korea have invaded Republic of Korea's demilitarized zone (DMZ). The aim of this study was to verify the relationship between meteorological factors and the number of malaria patients in the military in this region. METHODS: The authors estimated the effects of meteorological factors on vivax malaria patients from the military based on the monthly number of malaria cases between 2006 and 2011. Temperature, precipitation, snow depth, wind velocity, relative humidity, duration of sunshine, and cloud cover were selected as the meteorological factors to be studied. A systematic pattern in the spatial distribution of malaria cases was assessed using the Moran's Index. Granger causality tests and cross correlation coefficients were used to evaluate the relationship between meteorological factors and malaria patients in the military. RESULTS: Spatial analysis revealed significant clusters of malaria patients in the military in Republic of Korea in 2011 (Moran's I = 0.136, p-value = 0.026). In the six years investigated, the number of malaria patients in the military in Paju decreased, but the number of malaria patients in the military in Hwacheon and Chuncheon increased. Monthly average, maximum and minimum temperatures; wind velocity; and relative humidity were found to be predicting factors of malaria in patients in the military in Paju. In contrast, wind velocity alone was not able to predict malaria in Hwacheon and Chuncheon, however, precipitation and cloud cover were able to predict malaria in Hwacheon and Chuncheon. CONCLUSIONS: This study demonstrated that the number of malaria patients in the military is correlated with meteorological factors. The variation in occurrence of malaria cases was principally attributed to differences in meteorological factors by regions of Republic of Korea. PMID- 26955804 TI - The clinicopathological significance of Mortalin overexpression in invasive ductal carcinoma of breast. AB - BACKGROUND: Mortalin/GRP75 is a ubiquitous mitochondrial chaperone which related to the cytosolic heat shock protein 70 (HSP70), and plays a role in carcinogenesis. This study aims to investigate the Mortalin expression in breast cancer and its correlation with the outcome of the patients with breast cancer. METHODS: A total of 155 invasive ductal carcinoma of breast patients with strict follow-up, 52 ductal carcinoma in situ (DCIS) and 45 adjacent non-tumor breast tissues were selected for immunohistochemical (IHC) staining of Mortalin protein. The localization of Mortalin protein was detected in MDA-MB231 breast cancer cells using immunofluorescence (IF) staining. The correlations between overexpression of Mortalin and the clinical features of patients with breast cancer were evaluated using chi-square test and Fisher's exact tests. The survival rates were calculated by the Kaplan-Meier method, and the relationship between prognostic factors and patient survival was also analyzed by the Cox proportional hazard models. RESULTS: Mortalin protein showed a mainly cytoplasmic staining pattern in breast cancers by using IHC staining in paraffin embedded breast cancer tissues and IF staining in MDA-MB231 breast cancer cells. The strongly positive rate of Mortalin protein was 63.9% (99/155) in invasive ductal carcinoma of breast and was significantly higher than in DCIS 34.6% (18/52) and adjacent non-tumor tissues 15.6% (7/45). Overexpression of Mortalin was closely correlated with histological grade, clinical stage, lymph node metastasis, lower disease free survival (DFS) and overall survival (OS) rates of patients with breast cancer. Moreover, multivariate analysis suggested that Mortalin emerged as a significant independent prognostic factor along with clinical stage and Her2 expression status in patients with breast cancer. CONCLUSIONS: Mortalin is upregulated in breast cancer, and may be a useful poor prognostic biomarker as well as a potential therapeutic target for patients with breast cancer. PMID- 26955805 TI - Kordiimonas lipolytica sp. nov., isolated from seawater. AB - A Gram-stain-negative, aerobic, rod-shaped bacterium, designated M41T, was isolated from a surface seawater sample collected from the western Pacific Ocean. The isolate grew in medium containing 0.5-10.0 % (w/v) NaCl (optimally at 1.0-3.0 %) at 15-45 degrees C and pH 5.5-9.5. Positive for oxidase, catalase and nitrate reduction. The respiratory quinone is Q-10. The major fatty acids (>10 %) are iso C15:0, iso-C17:1omega9c and summed feature 3 (comprising C16:1omega7c and/or iso C15:0 2-OH). The major polar lipids are phosphatidylethanolamine, one unidentified phospholipid, one unidentified aminolipid, and three unidentified glycolipids.The genomic DNA G+C content is 56.3 mol %. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain M41T should be assigned to the genus Kordiimonas. The 16S rRNA gene sequence similarities between the isolate and the type strains of species of the genus Kordiimonas with validly published names were in the range 96.2- 98.6 %. Strain M41T exhibited average nucleotide identity (ANI) values of 81.7 and 72.3 % with respect to Kordiimonas. lacus S3-22T and Kordiimonasgwangyangensis JCM 12864T, respectively. The genome to-genome distance analysis revealed that strain M41T shared 51.4 % DNA-DNA relatedness with K. lacus S3-22T and 16.3 % with K. gwangyangensis JCM 12864T. On the basis of phenotypic and genotypic characteristics, strain M41T represents a novel species of the genus Kordiimonas, for which the name Kordiimonas lipolytica sp. nov. is proposed. The type strain is M41T (=CGMCC 1.15304T=JCM 30877T). An emended description of Kordiimonas lacus is also provided. PMID- 26955806 TI - Federally mandating motorcycle helmets in the United States. AB - BACKGROUND: Motorcycle helmets reduce both motorcycle-related fatalities and head injuries. Motorcycle crashes are a major public health concern which place economic stress on the U.S. healthcare system. DISCUSSION: Although statewide universal motorcycle helmet laws effectively increase helmet use, most state helmet laws do not require every motorcycle rider to wear a helmet. Herein, we propose and outline the solution of implementing federal motorcycle helmet law, while addressing potential counterarguments. CONCLUSIONS: The decision to ride a motorcycle without a helmet has consequences that affect more than just the motorcyclist. In an effort to prevent unnecessary healthcare costs, injuries, and deaths, public health efforts to increase helmet use through education and legislation should be strongly considered. Helmet use on motorcycles fits squarely within the purview of the federal government public health and economic considerations. PMID- 26955807 TI - Prognostic factors affecting the risk of thoracic progression in extensive-stage small cell lung cancer. AB - BACKGROUND: The efficacy of combined modality therapy is evaluated for patients with extensive-stage (ES) small cell lung cancer (SCLC). This study evaluated prognostic factors affecting the risk of thoracic progression in ES-SCLC patients likely to undergo thoracic radiotherapy combined chemotherapy. METHODS: A retrospective review of ES-SCLC patients who had received systemic chemotherapy at our hospital was performed. Tumor size, metastatic sites, and laboratory data at diagnosis were evaluated as potential prognostic factors. In ES-SCLC patients without pleural dissemination, the rate of thoracic progression after initial chemotherapy was assessed. RESULTS: Eighty-three of 96 consecutive ES-SCLC patients were analyzed. The overall response rate was 55 %, median progression free survival was 5.0 months (mo), and overall survival (OS) was 9.2 mo. Tumor size (19.4 mo for <=3 cm vs. 8.5 mo for >3 cm, p = 0.017) and the number of metastatic sites (12.9 mo for single sites vs. 7.1 mo for multiple sites, p = 0.015) were prognostic factors, in addition to known prognostic factors such as performance status and the levels of LDH and sodium. Cox proportional hazard model showed that the OS was significantly worse in patients with large (>3 cm) primary tumor size {HR 2.44 [95 % confidential interval (CI) 1.05-5.68], p = 0.038} and multiple metastatic sites [HR 1.81 (95 % CI 1.08-3.04), p = 0.026]. In 51 cases without pleural dissemination, the number of metastatic sites was associated with thoracic progression after initial chemotherapy (65 % for single sites vs. 36 % for multiple sites, p = 0.036). CONCLUSION: Large tumor size and multiple metastatic sites at diagnosis significantly predicted poor survival in ES-SCLC patients. Based on the high rate of thoracic progression in ES-SCLC patients with single site of distant metastasis, we should consider thoracic radiotherapy combined with chemotherapy for this population. PMID- 26955808 TI - Salmonella Typhimurium undergoes distinct genetic adaption during chronic infections of mice. AB - BACKGROUND: Typhoid fever caused by Salmonella enterica serovar Typhi (S. Typhi) is a severe systemic human disease and endemic in regions of the world with poor drinking water quality and sewage treatment facilities. A significant number of patients become asymptomatic life-long carriers of S. Typhi and serve as the reservoir for the disease. The specific mechanisms and adaptive strategies enabling S. Typhi to survive inside the host for extended periods are incompletely understood. Yet, elucidation of these processes is of major importance for improvement of therapeutic strategies. In the current study genetic adaptation during experimental chronic S. Typhimurium infections of mice, an established model of chronic typhoid fever, was probed as an approach for studying the molecular mechanisms of host-adaptation during long-term host association. RESULTS: Individually sequence-tagged wild type strains of S. Typhimurium 4/74 were used to establish chronic infections of 129X1/SvJ mice. Over the course of infections, S. Typhimurium bacteria were isolated from feces and from livers and spleens upon termination of the experiment. In all samples dominant clones were identified and select clones were subjected to whole genome sequencing. Dominant clones isolated from either systemic organs or fecal samples exhibited distinct single nucleotide polymorphisms (SNPs). One mouse appeared to have distinct adapted clones in the spleen and liver, respectively. Three mice were colonized in the intestines by the same clone containing the same non synonymous SNP in a transcriptional regulator, kdgR, of metabolic genes. This likely indicates transmission of this clone between mice. The mutation was tracked to have occurred prior to 2 weeks post infection in one of the three mice and had subsequently been transmitted to the other two mice. Re-infection with this clone confirmed that it is superior to the wild type for intestinal colonization. CONCLUSIONS: During 4 to 6 weeks of chronic infections, S. Typhimurium acquired distinct SNPs in known regulators of metabolic and virulence genes. One SNP, the kdgR-SNP was confirmed to confer selective advantage during chronic infections and constitute a true patho-adaptive mutation. Together, the results provide evidence for rapid genetic adaptation to the host of S. Typhimurium and validate experimental evolution in the context of host infection as a strategy for elucidating pathogen host interactions at the molecular level. PMID- 26955810 TI - Young people's parental discussion about sexual and reproductive health issues and its associated factors in Awabel woreda, Northwest Ethiopia. AB - BACKGROUND: In Ethiopia besides the very low health seeking behavior of young people, they do not have access to sexual and reproductive health information and even the existing health services are adult-centered. Furthermore, health providers are not well equipped in addressing young people sexual and reproductive health needs. Therefore, parent-young people discussion about sexual and reproductive health issues are crucial in increasing their awareness and reduces their risky sexual behaviors. This study was aimed to assess young people's parental discussion about sexual and reproductive health issues and its associated factors in Awabel woreda, Northwest Ethiopia. METHODS: A community based cross-sectional study was conducted among 781 young people aged 10-24 years in Awabel Woreda, Northwest Ethiopia. A pre-tested structured interview administered questionnaire was used for the data collection. The collected data were entered using Epi Data 3.1 and analyzed using SPSS for windows version 21. RESULTS: In the past 6 months, about one quarter, 25.3% of young people had a parental discussion about sexual and reproductive health issues. Young people who reside in urban areas were more likely to discuss on sexual and reproductive health issues with their parents [AOR = 2.44, 95% CI: 1.54-3.89]. Similarly, being male was more likely to have a parental discussion about sexual and reproductive health issues than females [AOR = 1.63, 95% CI: 1.11-2.38]. Furthermore, the odds of parent-young people discussion about SRH matters was more likely among young people aged 20-24 years [AOR = 4.57, 95% CI: 2.13-9.82], living with fathers [AOR = 2.46, 95% CI: 1.20-5.04] and had attained a primary level of education [AOR = 2.89, 95% CI: 1.22-6.87]. Parents lack of interest to discuss, feeling ashamed and culturally not acceptable to talk about sexual matters were found to deter young people's in discussing sexual and reproductive health matters. CONCLUSION: Parent-young people discussion about sexual and reproductive health is very low and there are different hindering factors. And therefore, young people's sexual and reproductive health programs or policies should be designed in addressing the cultural and societal factors besides the individual or behavioral factors. PMID- 26955812 TI - Beyond the Psychiatric Horizon: Preparing Residents for the Twenty-First Century. PMID- 26955809 TI - Preoperative radiochemotherapy versus immediate surgery for resectable and borderline resectable pancreatic cancer (PREOPANC trial): study protocol for a multicentre randomized controlled trial. AB - BACKGROUND: Pancreatic cancer is the fourth largest cause of cancer death in the United States and Europe with over 100,000 deaths per year in Europe alone. The overall 5-year survival ranges from 2-7 % and has hardly improved over the last two decades. Approximately 15 % of all patients have resectable disease at diagnosis, and of those, only a subgroup has a resectable tumour at surgical exploration. Data from cohort studies have suggested that outcome can be improved by preoperative radiochemotherapy, but data from well-designed randomized studies are lacking. Our PREOPANC phase III trial aims to test the hypothesis that median overall survival of patients with resectable or borderline resectable pancreatic cancer can be improved with preoperative radiochemotherapy. METHODS/DESIGN: The PREOPANC trial is a randomized, controlled, multicentric superiority trial, initiated by the Dutch Pancreatic Cancer Group. Patients with (borderline) resectable pancreatic cancer are randomized to A: direct explorative laparotomy or B: after negative diagnostic laparoscopy, preoperative radiochemotherapy, followed by explorative laparotomy. A hypofractionated radiation scheme of 15 fractions of 2.4 gray (Gy) is combined with a course of gemcitabine, 1,000 mg/m(2)/dose on days 1, 8 and 15, preceded and followed by a modified course of gemcitabine. The target volumes of radiation are delineated on a 4D CT scan, where at least 95 % of the prescribed dose of 36 Gy in 15 fractions should cover 98 % of the planning target volume. Standard adjuvant chemotherapy is administered in both treatment arms after resection (six cycles in arm A and four in arm B). In total, 244 patients will be randomized in 17 hospitals in the Netherlands. The primary endpoint is overall survival by intention to treat. Secondary endpoints are (R0) resection rate, disease-free survival, time to locoregional recurrence or distant metastases and perioperative complications. Secondary endpoints for the experimental arm are toxicity and radiologic and pathologic response. DISCUSSION: The PREOPANC trial is designed to investigate whether preoperative radiochemotherapy improves overall survival by means of increased (R0) resection rates in patients with resectable or borderline resectable pancreatic cancer. TRIAL REGISTRATION: Trial open for accrual: 3 April 2013 The Netherlands National Trial Register - NTR3709 (8 November 2012) EU Clinical Trials Register - 2012-003181-40 (11 December 2012). PMID- 26955811 TI - De novo assembly and analysis of the transcriptome of Ocimum americanum var. pilosum under cold stress. AB - BACKGROUND: Ocimum americanum var. pilosum is a chilling-sensitive, widely distributed plant that is consumed as a vegetable in central and southern China. To increase our understanding of cold stress responses in this species, we performed de novo transcriptome assembly for O. americanum var. pilosum and compared the transcriptomes of plants grown under normal and low temperatures. RESULTS: A total of 115,022,842 high quality, clean reads were obtained from four libraries (two replicates of control samples and two replicates of chilling treated samples) and were used to perform de novo transcriptome assembly. After isoforms were considered, 42,816 unigenes were generated, 30,748 of which were similar to known proteins as determined by a BLASTx search (E-value < =1.0E-05) against NCBI non-redundant, Swiss-Prot, Gene Ontology, KEGG, and Cluster of COG databases. Comparative analysis of transcriptomes revealed that 5179 unigenes were differentially expressed (with at least 2-fold changes, FDR < 0.01) in chilling-treated samples, and that 2344 and 2835 unigenes were up- and down regulated by chilling stress, respectively. Expression of the 10 most up regulated and the five most down-regulated unigenes was validated by qRT-PCR. To increase our understanding of these differentially expressed unigenes, we performed Gene ontology and KEGG pathway enrichment analyses. The CBF-mediated transcriptional cascade, a well-known cold tolerance pathway, was reconstructed using our de novo assembled transcriptome. CONCLUSION: Our study has generated a genome-wide transcript profile of O. americanum var. pilosum and a de novo assembled transcriptome, which can be used to characterize genes related to diverse biological processes. This is the first study to assess the cold responsive transcriptome in an Ocimum species. Our results suggest that cold temperature significantly affects genes related to protein translation and cellular metabolism in this chilling sensitive species. Although most of the CBF pathway genes have orthologs in O. americanum var. pilosum, none of the identified cold responsive (COR) gene orthologs was induced by cold, which is consistent with the lack of cold tolerance in this plant. PMID- 26955813 TI - The risk of imported malaria in security forces personnel returning from overseas missions in the context of prevention of re-introduction of malaria to Sri Lanka. AB - BACKGROUND: Sri Lanka is a malaria-free country. However it remains surrounded by countries with endemic malaria transmission. Since the last indigenous case of malaria was reported in October 2012, only imported malaria cases have been diagnosed with 36 cases detected in 2015, which includes 17 cases each of Plasmodium vivax and Plasmodium falciparum and two cases of Plasmodium ovale. METHODS: This study investigated the knowledge and practices regarding malaria chemoprophylaxis among all the Sri Lankan security forces personnel returning from peacekeeping missions in malaria endemic countries over a 7 month period. Adherence to other malaria prevention measures, occurrence of adverse events and incident cases of malaria were also recorded maintaining the anonymity of the respondents. Potential associations for non-compliance were studied. RESULTS: Interviews were carried out with 559 security forces personnel returning home from foreign deployments in malaria-endemic regions (males: 550, 98.4 %). The majority (553, 98.9 %) was well aware of the need for chemoprophylaxis during the overseas stay and its regular use as prescribed. The overall adherence to chemoprophylaxis was good with 78.7 % (440/559) reporting regular, as prescribed, use. Having better educational qualifications, being female, being prescribed mefloquine, having fever during deployment and belonging to a security force other than the army were significantly associated with poor compliance (p < 0.05). CONCLUSIONS: The study reveals that knowledge regarding malaria chemoprophylaxis among Sri Lankan security forces personnel serving abroad was good, a fact that may have contributed to absence/extremely low incidence of malaria during deployment. PMID- 26955814 TI - Left ventricular twist mechanics and its relation with aortic stiffness in chronic kidney disease patients without overt cardiovascular disease. AB - BACKGROUND: Recent studies hypothesized left ventricular (LV) twist as a potential biomarker for evaluation of sub clinical myocardial disease, however its relationship with aortic stiffness has yet to be investigated. Chronic kidney disease (CKD) has been identified as a risk factor for both myocardial and arterial disease. As such we sought to explore the relationship between aortic stiffness and LV twist in CKD patients without known cardiovascular disease (CVD). METHODS: In this prospective, observational study we enrolled 106 CKD patients (Stages 1 to 5) with normal LVEF as assessed by conventional echocardiography. Aortic stiffness was measured using aortic pulse wave velocity (aPWV). We defined increased aPWV as >=10 m/s. LV Twist was measured using two dimensional speckle tracking echocardiography. RESULTS: Patients with increased aPWV had higher LV twist (p = 0.002) but similar LVEF (p = 0.486). Aortic PWV correlated crudely with age (p < 0.001), the presence of diabetes (p < 0.001), hypertension (p < 0.001), eGFR (p < 0.001), LVMI (p = 0.01), e/e' (p < 0.001) and LV twist (p = 0.003). In multivariable analyses after adjusting for age, gender, cardiovascular risk factors and hypertensive medication, aPWV was independently associated with LV twist (beta = 0.163, p = 0.025). CONCLUSIONS: Aortic stiffness independently associates with LV Twist in asymptomatic CKD patients. These findings suggest a close interaction between LV twist mechanics and arterial remodeling even before CVD becomes clinically relevant. PMID- 26955815 TI - Hospitality Invites Sociability, Which Builds Cohesion: a Model for the Role of Main Streets in Population Mental Health. AB - The aim of this study was to investigate the contribution of main streets to community social cohesion, a factor important to health. Prior work suggests that casual contact in public space, which we call "sociability," facilitates more sustained social bonds in the community. We appropriate the term "hospitality" to describe a main street's propensity to support a density of such social interactions. Hospitality is a result of the integrity and complex contents of the main street and surrounding area. We examine this using a typology we term "box-circle-line" to represent the streetscape (the box), the local neighborhood (the circle), and the relationship to the regional network of streets (the line). Through field visits to 50 main streets in New Jersey and elsewhere, and a systematic qualitative investigation of main streets in a densely interconnected urban region (Essex County, New Jersey), we observed significant variation in main street hospitality, which generally correlated closely with sociability. Physical elements such as street wall, neighborhood elements such as connectivity, inter-community elements such as access and perceived welcome, and socio-political elements such as investment and racial discrimination were identified as relevant to main street hospitality. We describe the box-circle line as a theoretical model for main street hospitality that links these various factors and provides a viable framework for further research into main street hospitality, particularly with regard to geographic health disparities. PMID- 26955816 TI - Educational Needs of Oncology Practitioners in a Regional Cancer Center in the Middle East-Improving the Content of Smoking Cessation Training Programs. AB - Little is known with regard to perceptions and information needs of oncology practitioners in the Middle East as they pertain to smoking cessation (SC) support for cancer patients. We sought to assess these in a regional cancer center. A survey was distributed to oncology practitioners (physicians, nurses, pharmacists, and physio- and respiratory therapists) at King Hussein Cancer Center (Amman, Jordan) for self-completion. The survey included SC-related measures of perceptions, knowledge, and practices. Descriptive statistics and cross tabulations were performed to identify misperceptions and knowledge gaps that could be corrected through continuing education. Findings revealed, among 254 practitioners surveyed, low referral rates to the SC clinic. Negative perceptions about cancer patients who smoke existed (e.g., patients needing smoking to control anxiety; patients' willpower sufficient for quitting; patients not wanting to quit and not needing more information). Substantial knowledge gaps were prevalent with regard to the detrimental outcomes associated with continued tobacco use after a cancer diagnosis and with regard to approved SC medication choices. Our results are useful in identifying topics that need to be highlighted during training and educational efforts in the region and also reinforce the need to avail such efforts in order to improve SC-related knowledge and perceptions. PMID- 26955817 TI - Do hydrolysed infant formulas reduce the risk of allergic disease? PMID- 26955819 TI - The influence of respiratory motion on the cumulative SUV-volume histogram and fractal analyses of intratumoral heterogeneity in PET/CT imaging. AB - OBJECTIVE: The purpose of this study was to investigate the influence of respiratory motion on the evaluation of the intratumoral heterogeneity of FDG uptake using cumulative SUV-volume histogram (CSH) and fractal analyses. METHODS: We used an NEMA IEC body phantom with a homogeneous hot sphere phantom (HO) and two heterogeneous hot sphere phantoms (HE1 and HE2). The background radioactivity of (18)F in the NEMA phantom was 5.3 kBq/mL. The ratio of radioactivity was 4:2:1 for the HO and the outer rims of the HE1 and HE2 phantoms, the inner cores of the HE1 and HE2 phantoms, and background, respectively. Respiratory motion was simulated using a motion table with an amplitude of 2 cm. PET/CT data were acquired using Biograph mCT in motionless and moving conditions. The PET images were analyzed by both CSH and fractal analyses. The area under the CSH (AUC-CSH) and the fractal dimension (FD) was used as quantitative metrics. RESULTS: In motionless conditions, the AUC-CSHs of the HO (0.80), HE1 (0.75) and HE2 (0.65) phantoms were different. They did not differ in moving conditions (HO, 0.63; HE1, 0.65; HE2, 0.60). The FD of the HO phantom (0.77) was smaller than the FDs of the HE1 (1.71) and HE2 (1.98) phantoms in motionless conditions; however, the FDs of the HO (1.99) and HE1 (2.19) phantoms were not different from each other and were smaller than that of the HE2 (3.73) phantom in moving conditions. CONCLUSION: Respiratory motion affected the results of the CSH and fractal analyses for the evaluation of the heterogeneity of the PET/CT images. The influence of respiratory motion was considered to vary depending on the object size. PMID- 26955820 TI - MicroRNA-155 expression inversely correlates with pathologic stage of gastric cancer and it inhibits gastric cancer cell growth by targeting cyclin D1. AB - PURPOSE: MicroRNAs (miRs) have been frequently reported dysregulating in tumors and playing a crucial role in tumor development and progression. However, the expression of miR-155 and its role in gastric cancer (GC) are still obscure. METHODS: qRT-PCR was applied to detect miR-155 expression in 60 matched GC samples and four GC cell lines, and the relationship between miR-155 levels and clinicopathological features of GC was analyzed. Next, the effects of miR-155 on GC cell growth were evaluated by gain- and loss-of-function analysis. Finally, the target gene(s) of miR-155 in GC cells were explored. RESULTS: Our results revealed that miR-155 levels were significantly lower in both GC tissues and GC cell lines than in their normal controls, and its expression inversely correlated with tumor size and the pathologic stage. Moreover, our study showed that enforced expression of miR-155 impaired GC cell proliferation, promoted G1 phase arrest and induced apoptosis in vitro. In addition, we identified cyclin D1 as the direct target of miR-155, and knockdown of cyclin D1 partially phenocopied the role of miR-155 in GC cells. CONCLUSIONS: Our findings suggest that miR-155 may act as a potential diagnostic marker for early-stage GC and may represent a novel therapeutic target for GC treatment. PMID- 26955823 TI - Behind the Snoring. PMID- 26955821 TI - Social and Structural Determinants of Cervical Health among Women Engaged in HIV Care. AB - Cervical cancer prevention/control efforts among women living with HIV/AIDS (WLH) are socially and structurally challenging. Healthcare access and perceived HIV stigma and discrimination are factors that may challenge risk reduction efforts. This study examined socio-structural determinants of cervical cancer screening among women engaged in HIV care. One hundred forty-five WLH seeking health/social services from AIDS Service Organizations in the southeastern US completed a questionnaire assessing factors related to cervical cancer prevention/control. Ninety percent were African American, mean age 46.15 +/- 10.65 years. Eighty-one percent had a Pap test <1 year ago. Low healthcare access was positively associated with having a Pap test <1 year ago, (Odds ratio [OR] 3.80; 95 % Confidence interval [CI] 1.34-10.78). About 36 % reported >=2 Pap tests during the first year after HIV diagnosis. Lower educational attainment was positively associated with having >=2 Pap tests, OR 3.22; CI 1.08-9.62. Thirty-five percent reported more frequent Pap tests after diagnosis. Lower income was moderately associated with more frequent Pap tests post-diagnosis, OR 2.47; CI .98-6.23. Findings highlight the successes of HIV initiatives targeting socio-economically disadvantaged women and provide evidence that health policy aimed at providing and expanding healthcare access for vulnerable WLH has beneficial health implications. PMID- 26955822 TI - Ethnopharmacological survey of herbal remedies used for treatment of various types of cancer and their methods of preparations in the West Bank-Palestine. AB - BACKGROUND: Plants have been the primary source of medicines since life on earth; more than 50 % of existing cancer treatments are derived from plants. METHODS: An ethnopharmacological survey of herbal remedies used in cancer treatment was carried out in the West Bank/ Palestine. A questionnaire was distributed to one hundred and fifty herbalists, traditional healers and rural dwellers. Collected information included the names of plants, the used parts, types of cancers for which these plants were used and also their methods of preparation. To identify the most important species used, Factor of informant's consensus (F(ic)), Fidelity level (Fl) and the Use-value (UV) were calculated. RESULTS: Collected data has shown that 72 plants are utilized for treatment of cancer, belonging to 44 families; from them Compositae and Lamiaceae were the most common. Leaves and fruits were the most commonly used parts, while decoctions, infusions and syrups were the main methods of preparation. Lung cancer was the most common type of cancer treated with these plants and Ephedra alata was the most commonly used plant for treatment of cancer in Palestine. The Fic was high for all the plants; Fl was 100% for many plants, the highest UV (0.72) was for Ephedra alata. CONCLUSIONS: This study showed that many herbal remedies are still used by herbalists in Palestine for treatment of cancer; some of them have been approved scientifically while others are not. A combined effort between informants and scientific institutions working in this field can help in the discovery of new anticancer agents. Moreover, scientists must explore the most suitable method of extraction, formulation and dose determination in order to achieve the best benefits from these herbals. PMID- 26955824 TI - Thrombin Generation Assay and Its Application in the Clinical Laboratory. AB - BACKGROUND: A gap exists between in vivo and ex vivo coagulation when investigated by use of the coagulation tests prothrombin time (PT) and activated partial thromboplastin time (APTT). The thrombin generation assay (TGA) has been developed to fill this gap. CONTENT: TGA evaluates thrombin generation (resulting from the action of the procoagulant driver) and decay (resulting from the action of the anticoagulant driver), thus assessing the balance between the two. Coagulation of the test plasma (platelet poor or platelet rich) is activated by small amounts of tissue factor and phospholipids, and the reaction of thrombin generation is continuously monitored by means of a thrombin-specific fluorogenic substrate. Among the parameters derived from the thrombin-generation curve, the most important is the endogenous thrombin potential, defined as the net amount of thrombin that test plasmas can generate on the basis of the relative strength of the pro- and anticoagulant drivers. TGA is therefore the candidate assay to investigate hypo- or hypercoagulability. SUMMARY: From my analysis of the literature, I draw the following conclusions. There is strong evidence that TGA is helpful to elucidate coagulation mechanisms in various clinical conditions that until recently were poorly understood (chronic liver disease; diabetes; inflammatory bowel disease, myeloproliferative neoplasms, nonalcoholic fatty liver disease). TGA is a promising laboratory tool for investigating hemorrhagic coagulopathies and monitoring replacement therapy in hemophiliacs, predicting the risk of recurrent venous thromboembolism after a first event, and monitoring patients on parenteral or oral anticoagulants. These applications require clinical trials in which TGA results are combined with specific clinical end points. PMID- 26955825 TI - All doctors would benefit from a forum to reflect on practice. PMID- 26955826 TI - A 37-year-old woman found dead in a Jacuzzi: A case report. AB - One of the main problems in forensic medicine is the autopsy diagnosis of drowning, especially in the case of delay in the victim's recovery. The body of a 37-year-old woman was delivered to Kahrizak autopsy centre for post mortem. She was drowned in a public Jacuzzi because when she bent down to pick up her hairpin from the bottom of the Jacuzzi, her right arm became stuck in the drainage pipe and was sucked in. Unfortunately, she was not resuscitated after being pulled out of the Jacuzzi. The ambulance arrived too late, and she was already dead on arrival at the hospital. Her family pursued a claim against the managers and personnel of the pool for poor security management and failure to resuscitate. A forensic examination was needed to determine the manner of her death (natural, accidental, suicide and homicide). PMID- 26955827 TI - Emotional expressiveness and avoidance in narratives of unaccompanied refugee minors. AB - OBJECTIVE: The aim of this study was to examine a cohort of unaccompanied refugee minors (URMs) by means of psycholinguistic methods in order to obtain a more subtle picture of their degree of traumatization. METHODS: Twenty-eight participants were included in the Stress-Inducing Speech Task (SIST) consisting of a free association (FA) and a stress (STR) condition. Narratives were examined by means of (1) quantitative parameters (word count); (2) psycholinguistic variables (temporal junctures, TJs), narrative structure, referential activity (RA)-a measure of emotional expressivity; and (3) content analysis ratings. RESULTS: Word count was significantly lower than in age-matched norms. In the FA condition, TJs were lower, but in the STR condition, rates were comparable. RA was significantly higher in both conditions. Content analysis ratings showed that the experiences described by these youths were potentially traumatic in nature. CONCLUSIONS: This pattern of narrative shows a mixture of fulfilling the task demand, while containing an emotionally charged narrative. Narrative structure was absent in the FA condition, but preserved in the STR condition, as URMs struggled with the description of non-normative events. This indicates that these youths have not yet emotionally dealt with and fully integrated their trauma experiences. PMID- 26955828 TI - Low serum vitamin D is associated with axial length and risk of myopia in young children. AB - The aim of the study was to investigate the relationship between serum 25(OH)D levels and axial length (AL) and myopia in 6-year-old children. A total of 2666 children aged 6 years participating in the birth-cohort study Generation R underwent a stepwise eye examination. First, presenting visual acuity (VA) and AL were performed. Second, automated cycloplegic refraction was measured if LogMAR VA > 0.1. Serum 25-hydroxyvitamin D [25(OH)D] was determined from blood using liquid chromatography/tandem mass spectrometry. Vitamin D related SNPs were determined with a SNP array; outdoor exposure was assessed by questionnaire. The relationships between 25(OH)D and AL or myopia were investigated using linear and logistic regression analysis. Average 25(OH)D concentration was 68.8 nmol/L (SD +/- 27.5; range 4-211); average AL 22.35 mm (SD +/- 0.7; range 19.2-25.3); and prevalence of myopia 2.3 % (n = 62). After adjustment for covariates, 25(OH)D concentration (per 25 nmol/L) was inversely associated with AL (beta -0.043; P < 0.01), and after additional adjusting for time spent outdoors (beta -0.038; P < 0.01). Associations were not different between European and non-European children (beta -0.037 and beta -0.039 respectively). Risk of myopia (per 25 nmol/L) was OR 0.65 (95 % CI 0.46-0.92). None of the 25(OH)D related SNPs showed an association with AL or myopia. Lower 25(OH)D concentration in serum was associated with longer AL and a higher risk of myopia in these young children. This effect appeared independent of outdoor exposure and may suggest a more direct role for 25(OH)D in myopia pathogenesis. PMID- 26955829 TI - New insights on physical activity and amyotrophic lateral sclerosis. PMID- 26955830 TI - Trajectories of body mass index before the diagnosis of cardiovascular disease: a latent class trajectory analysis. AB - Patients with cardiovascular disease (CVD) are a heterogeneous group regarding their body mass index (BMI) levels at the time of diagnosis. To address the heterogeneity of CVD, we examined the trajectories of change in body mass index (BMI) and in other cardio-metabolic risk factors before CVD diagnosis. The study included 6126 participants from the prospective population-based Rotterdam Study, followed over 22 years with clinical examinations every 4 years. Latent class trajectory analysis and mixed-effect models were used to develop trajectories of BMI and other cardio-metabolic risk factors respectively. During follow-up, 1748 participants developed CVD, among whom we identified 3 distinct BMI trajectories. The majority of participants (n = 1534, 87.8 %) had steady BMI levels during follow-up, comprising the "stable weight" group. This group showed decrease in mean high-density lipoprotein (HDL) cholesterol over time. The second group, the "progressive weight gain" group (n = 112, 6.4 %), showed a progressive increase in BMI levels. In this group, mean waist circumference increased, mean HDL cholesterol decreased and mean fasting glucose levels were fluctuating over follow-up. In the third group, the "progressive weight loss" group (n = 102, 5.8 %), BMI levels decreased during follow-up. This group showed a decrease in mean waist circumference and in fasting glucose. In conclusion, the majority of individuals who developed CVD had a stable weight during follow-up, suggesting that BMI alone is not a good indicator for identifying middle-aged and elderly individuals at high risk of CVD. Waist circumference, HDL cholesterol, and glucose trajectories differed between the identified BMI subgroups, further highlighting that CVD is a heterogeneous disease with different pathophysiological pathways. PMID- 26955831 TI - [Anesthesiological approach to postpartum hemorrhage]. AB - Peripartum hemorrhage (PPH) is a frequent obstetric emergency situation with increasing incidence in the last decades. It requires a fast, coordinated and interdisciplinary management. This life-threatening situation is often recognized too late and not adequately treated (too little is done too late); therefore, it is important to be aware of the most important risk factors for PPH known as the 4 Ts (i.e. tonus, trauma, tissue and thrombin). Due to the special patient population there is only little evidence-based data on hemostatic therapy in this situation; therefore, the currently available studies on the therapy of PPH is discussed. PMID- 26955832 TI - Safe start at home: what parents of newborns need after early discharge from hospital - a focus group study. AB - BACKGROUND: The length of postpartum hospital stay is decreasing internationally. Earlier hospital discharge of mothers and newborns decreases postnatal care or transfers it to the outpatient setting. This study aimed to investigate the experiences of new parents and examine their views on care following early hospital discharge. METHODS: Six focus group discussions with new parents (n = 24) were conducted. A stratified sampling scheme of German and Turkish-speaking groups was employed. A 'playful design' method was used to facilitate participants communication wherein they used blocks and figurines to visualize their perspectives on care models The visualized constructions of care models were photographed and discussions were audio-recorded and transcribed verbatim. Text and visual data was thematically analyzed by a multi-professional group and findings were validated by the focus group participants. RESULTS: Following discharge, mothers reported feeling physically strained during recuperating from birth and initiating breastfeeding. The combined requirements of infant and self care needs resulted in a significant need for practical and medical support. Families reported challenges in accessing postnatal care services and lacking inter-professional coordination. The visualized models of ideal care comprised access to a package of postnatal care including monitoring, treating and caring for the health of the mother and newborn. This included home visits from qualified midwives, access to a 24-h helpline, and domestic support for household tasks. Participants suggested that improving inter-professional networks, implementing supervisors or a centralized coordinating center could help to remedy the current fragmented care. CONCLUSIONS: After hospital discharge, new parents need practical support, monitoring and care. Such support is important for the health and wellbeing of the mother and child. Integrated care services including professional home visits and a 24-hour help line may help meet the needs of new families. PMID- 26955833 TI - Roughness and wettability effect on histological and mechanical response of self drilling orthodontic mini-implants. AB - OBJECTIVES: Self-drilling orthodontic mini-implants can be used as temporary devices for orthodontic treatments. Our main goal was to evaluate surface characteristics, roughness and wettability, of surface modified mini-implants to increase their stability during orthodontic treatment without inducing bone fracture and tissue destruction during unscrewing. MATERIALS AND METHODS: Modified mini-implants by acid etching, grit-blasting and its combination were implanted in 20 New Zealand rabbits during 10 weeks. After that, the bone-to implant (BIC) parameter was determined and the torque during unscrewing was measured. The surface characteristics, roughness and wettability, were also measured, onto modified Ti c.p. discs. RESULTS: Acid-etched mini-implants (R a ~ 1.7 MUm, contact angle (CA) ~ 66 degrees ) significantly improved the bone-to implant parameter, 26 %, compared to as-machined mini-implants (R a ~ 0.3 MUm, CA ~ 68 degrees , BIC = 19 %) due to its roughness. Moreover, this surface treatment did not modify torque during unscrewing due to their statistically similar wettability (p > 0.05). Surface treatments with higher roughness and hydrophobicity (R a ~ 4.5 MUm, CA ~ 74 degrees ) lead to a greater BIC and to a higher removal torque during unscrewing, causing bone fracture, compared to as machined mini-implants. CONCLUSIONS: Based on these in vivo findings, we conclude that acid-etching surface treatment can support temporary anchoring of titanium mini-implants. CLINICAL RELEVANCE: This treatment represents a step forward in the direction of reducing the time prior to mini-implant loading by increasing their stability during orthodontic treatment, without inducing bone fracture and tissue destruction during unscrewing. PMID- 26955834 TI - Novel FGF10 mutation in autosomal dominant aplasia of lacrimal and salivary glands. AB - OBJECTIVE: Aplasia of lacrimal and salivary glands (ALSG) is a rare autosomal dominant inherited disease, characterized by aplasia, atresia, or hypoplasia of the lacrimal and salivary systems with variable expressivity. The purpose of this study was to identify genetic etiology of an ALSG family. MATERIALS AND METHODS: We recruited a Turkish family with ALSG and performed a mutational analysis, based on the candidate gene approach, to clarify the molecular genetic etiology. RESULTS: The candidate gene sequencing of the FGF10 gene identified a novel heterozygous nonsense mutation (c.237G > A, p.Trp79*) in the exon 1. CONCLUSION: The identified novel mutation would result in a haploinsufficiency of the FGF10, because of nonsense-mediated mRNA decay caused by a premature stop codon. This report further confirms that ALSG is caused by the haploinsufficiency of functional FGF10. CLINICAL RELEVANCE: Identification of the genetic etiology of the ALSG will help both the family members and dentist understand the nature of the disorder. Therefore, it will positively motivate oral health care to avoid further destruction of the tooth due to the lack of salivary production. PMID- 26955836 TI - Effect of alendronate on the progression of periodontitis induced by Porphyromonas gingivalis and Fusobacterium nucleatum: a study in rats. AB - OBJECTIVE: The study aimed to investigate the effect of alendronate (ALN) on the inhibition of alveolar bone loss in experimental periodontitis in Wistar rats. MATERIALS AND METHODS: Periodontitis was induced by oral inoculation of Porphyromonas gingivalis with Fusobacterium nucleatum. The rats (n = 80) were randomized as follows: negative control (n = 10); positive control (n = 10); ALN groups: test 8 (n = 10), test 12 (n = 10), and test 16 (n = 10); and placebo groups: control 8 (n = 10), control 12 (n = 10), and control 16 (n = 10). Two milligrams per kilogram of ALN or placebo was administered twice weekly for 8, 12, and 16 weeks. Bone loss was determined by morphological and histological analyses. One independent, blinded examiner (ICC, 0.91) performed the measurements. The distance from the cement enamel junction to the alveolar bone crest of the second lower molar was measured: distal-vestibular (d), furca (f), mesial-vestibular (h), and area. Histometry was performed on the second contralateral molar. Sections (6 MUm) were used to determine the furcation bone area (A-FB). The following statistical analyses were conducted: Mann-Whitney and Kruskal-Wallis. RESULTS: PC group developed periodontitis (p < 0.0001). Morphometric analysis determined that ALN was effective in T8 for linear measurements d, f, and h (p < 0.05). No significant differences occurred at test 8, test 12, and test 16. Analysis of A-FB revealed no significant differences between the ALN and placebo groups at 8 and 16 weeks (p > 0.05). ALN was effective against bone loss in relation to A-FB after 12 weeks (p < 0.0001). CONCLUSIONS: According to the methodology used, the results suggest that oral administration of ALN could influence alveolar bone loss in rats submitted to experimental periodontitis. CLINICAL RELEVANCE: ALN could be a potential therapeutic approach when associated with periodontal treatment. PMID- 26955838 TI - Erratum to: mGluR2/3 agonist LY379268 rescues NMDA and GABAA receptor level deficits induced in a two-hit mouse model of schizophrenia. PMID- 26955835 TI - Normoxic accumulation of HIF1alpha is associated with glutaminolysis. AB - OBJECTIVES: The stabilization of the transcription factor and prognostic tumor marker hypoxia-inducible factor 1alpha (HIF1alpha) is considered to be crucial for cellular metabolic adaptations to hypoxia. However, HIF1alpha has also been shown to accumulate under normoxic conditions, although this phenomenon is poorly understood. METHODS: We investigated the conditions for normoxic HIF1alpha stabilization in different tumor cell lines (e.g., two mammary carcinoma cell lines and three oral squamous cell carcinoma cell lines) via Western blot analysis or immunohistochemical staining. The transcriptional activity of HIF1 was demonstrated by analyzing the messenger RNA (mRNA) expression of the HIF1 target carbonic anhydrase 9 (CA9) via PCR. RESULTS: Our data demonstrate that the combined incubation of tumor cells with glutamine and growth factors (e.g., EGF, insulin, and serum) mediates the normoxic accumulation of HIF1alpha in vitro. Consequently, the inhibition of glutaminolysis by a glutaminase inhibitor blocked the normoxic accumulation of HIF1alpha. Additionally, the normoxic HIF1alpha protein displayed nuclear translocation and transcriptional activity, which was confirmed by the induction of CA9 mRNA expression. Furthermore, the normoxic accumulation of HIF1alpha was associated with impaired proliferation of tumor cells. Finally, ammonia, the toxic waste product of glutaminolysis, induced a normoxic accumulation of HIF1alpha to the same extent as glutamine. CONCLUSION: Our study suggests that HIF1alpha is involved in the regulation of glutamine metabolism and the cellular levels of the toxic metabolic waste product ammonia under normoxia. Hence, our results, together with data presented in the literature, support the hypothesis that HIF1alpha and its target genes play a crucial role in metabolic pathways, such as glutaminolysis and glycolysis, under both hypoxic and normoxic conditions. CLINICAL RELEVANCE: Therefore, the inhibition of HIF1alpha (and/or HIF1alpha target genes) could emerge as a promising therapeutic approach that would result in the accumulation of toxic metabolic waste products in tumor cells as well as the reduction of their nutrition and energy supply. PMID- 26955837 TI - Effect of hyperbaric oxygen therapy on tooth extraction sites in rats subjected to bisphosphonate therapy-histomorphometric and immunohistochemical analysis. AB - OBJECTIVE: This study aimed to investigate the effect of hyperbaric oxygen therapy (HBOT) on tooth extraction sites in rats treated with bisphosphonate. MATERIALS AND METHODS: Rats were treated with zoledronic acid, subjected to tooth extractions and allocated into groups: (1) 7 days of HBOT, (2) 14 days of HBOT, (3) 7-day control, and (4) 14-day control. The site of tooth extractions was analyzed by histomorphometry and immunohistochemistry. RESULTS: On macroscopic analysis, HBOT did not significantly affect bone exposure volume either at 7 or 14 days. On hematoxylin and eosin (H&E) analysis, the 14-day HBOT group showed less non-vital bone compared to both controls and 7-day HBOT group. HBOT significantly lowered expression of vascular endothelial growth factor (VEGF), receptor activator NF-kB ligand (RANKL), bone morphogenetic protein-2 (BMP-2), and osteoprotegerin (OPG) at 7 days, compared to control, whereas at 14 days, there was no significant difference for these variables. CONCLUSION: HBOT can reduce the amounts of non-vital bone microscopically detected in tooth extraction sites of rats subjected to bisphosphonate therapy. The effect seems to occur in a dose-dependent mode. Further studies are required to clarify the mechanisms accounting for this effect. CLINICAL RELEVANCE: Treatment of bisphosphonate related osteonecrosis of the jaw (BRONJ) has been a challenging task, where the effectiveness of HBOT is controversial. This study reports important effects of HBOT on the maxillae of rats subjected to bisphosphonate treatment, making an important contribution to the knowledge about the applicability of HBOT in BRONJ. PMID- 26955839 TI - Severity of dependence modulates smokers' functional connectivity in the reward circuit: a preliminary study. AB - RATIONALE: Nicotine dependence is characterized as a neural circuit dysfunction, particularly with regard to the reward circuit. Although dependence severity moderates cue reactivity in the brain regions involved in reward processing, the direction of its influence remains controversial. OBJECTIVES: Investigating the functional organization of the reward circuit may provide complementary information. Here, we used resting-state functional connectivity (rsFC) to evaluate the integrity of the reward circuit in smokers with different severities of nicotine dependence. METHODS: Totals of 65 smokers and 37 non-smokers underwent resting-state functional magnetic resonance imaging (fMRI). The smokers were divided into low-dependent (FTND < 5, n = 26) and high-dependent smoker groups (FTND >= 5, n = 39) based on their nicotine-dependence severity (as measured by the Fagerstrom test for nicotine dependence [FTND]). The region of interest (ROI)-wise rsFC within the reward circuit was compared between smokers and non-smokers as well as between low-dependent and high-dependent smokers and then correlated with smokers' FTND scores. RESULTS: Widespread rsFC attenuation was observed in the reward circuit of smokers compared with non-smokers. Compared with low-dependent smokers, high-dependent smokers showed greater rsFC between the right amygdala and the left nucleus accumbens (NAcc) as well as between the bilateral hippocampus. Furthermore, a positive correlation between the inter hippocampus rsFC and the severity of nicotine dependence (FTND) was detected among all smokers (r = 0.416, p = 0.001). CONCLUSIONS: Our results indicate a dysfunction of the reward circuit in nicotine-dependent individuals. Moreover, our study improves the understanding of the neuroplastic changes that occur during the development of nicotine dependence. PMID- 26955841 TI - Discovering Biology in Periodic Data through Phase Set Enrichment Analysis (PSEA). AB - Several tools use prior biological knowledge to interpret gene expression data. However, existing enrichment tools assume that variables are monotonic and incorrectly measure the distance between periodic phases. As a result, these tools are poorly suited for the analysis of the cell cycle, circadian clock, or other periodic systems. Here, we develop Phase Set Enrichment Analysis (PSEA) to incorporate prior knowledge into the analysis of periodic data. PSEA identifies biologically related gene sets showing temporally coordinated expression. Using synthetic gene sets of various sizes generated from von Mises (circular normal) distributions, we benchmarked PSEA alongside existing methods. PSEA offered enhanced sensitivity over a broad range of von Mises distributions and gene set sizes. Importantly, and unlike existing tools, the sensitivity of PSEA is independent of the mean expression phase of the set. We applied PSEA to 4 published datasets. Application of PSEA to the mouse circadian atlas revealed that several pathways, including those regulating immune and cell-cycle function, demonstrate temporal orchestration across multiple tissues. We then applied PSEA to the phase shifts following a restricted feeding paradigm. We found that this perturbation disrupts intraorgan metabolic synchrony in the liver, altering the timing between anabolic and catabolic pathways. Reanalysis of expression data using custom gene sets derived from recent ChIP-seq results revealed circadian transcriptional targets bound exclusively by CLOCK, independently of BMAL1, differ from other exclusive circadian output genes and have well-synchronized phases. Finally, we used PSEA to compare 2 cell-cycle datasets. PSEA increased the apparent biological overlap while also revealing evidence of cell-cycle dysregulation in these cancer cells. To encourage its use by the community, we have implemented PSEA as a Java application. In sum, PSEA offers a powerful new tool to investigate large-scale, periodic data for biological insight. PMID- 26955842 TI - Breast cancer stem cells programs: enter the (non)-code. AB - Breast tumors exhibit a hierarchical cellular organization driven by several subpopulations of cancer stem cells (CSCs). These breast CSC subpopulations are able to infinitely self-renew and to differentiate, giving rise to tumor heterogeneity. Accumulating evidence show that breast CSCs resist conventional therapies and i'nitiate tumor relapse. The development of anti-CSCs therapies may therefore greatly improve patient survival. A better elucidation of molecular circuitries involved in stemness would offer new relevant targets. Noncoding RNAs, especially microRNAs and long noncoding RNAs, are regulators of cell identity and are notably found deregulated in breast CSCs. This review will focus on noncoding RNAs involved in CSCs biology during breast cancer initiation, maintenance, therapeutic resistance and metastatic progression. Potential clinical applications using noncoding RNAs as biomarkers or therapies will be discussed. PMID- 26955840 TI - Alcohol-induced behavioral changes in zebrafish: The role of dopamine D2-like receptors. AB - RATIONALE: The dopaminergic system has been proposed to mediate alcohol-induced locomotor activity, yet the mechanisms underlying this behavioral response remain poorly understood. OBJECTIVES: This study was conducted to investigate the role of dopamine D2-like receptors in mediating alcohol-induced behavioral responses. METHODS: In experiment 1, we examined the effects of high concentrations (0, 2.5, 5, 10 MUM) of haloperidol on motor responses. In experiment 2, we examined the effects of low concentrations (0, 0.625, 1.25, 2.5 MUM) of haloperidol on anxiety like behavioral responses using the novel tank test. In experiment 3, we examined the effect of pre-treating zebrafish with different concentrations of haloperidol (0, 0.625, 2.5 MUM) and subsequently exposing them to 0 or 1 % alcohol. RESULTS: In experiment 1, haloperidol induced an inverted U-shaped concentration-dependent increase in locomotor activity. In experiment 2, haloperidol (2.5 MUM) reduced the absolute turn angle and freezing behavior in a new environment. In experiment 3, acute alcohol exposure significantly increased locomotor activity and decreased anxiety-like behavioral responses. Pre-treating zebrafish with the lower dose of haloperidol (0.625 MUM) abolished the alcohol-induced locomotor activity, without altering anxiety-like behavioral responses. However, pre treating with the higher dose of haloperidol (2.5 MUM) abolished both alcohol induced increase of locomotor activity and reduction of anxiety-like behavioral responses. CONCLUSION: The results suggest alcohol-induced locomotor hyperactivity in zebrafish is mediated via activation of dopamine D2-like receptors, whereas anxiety-like behavioral responses may only be altered by a high haloperidol concentration, at which dose the drug may affect receptors other than D2-R. PMID- 26955843 TI - Effects of Foot Strike and Step Frequency on Achilles Tendon Stress During Running. AB - Achilles tendon (AT) injuries are common in runners. The AT withstands high magnitudes of stress during running which may contribute to injury. Our purpose was to examine the effects of foot strike pattern and step frequency on AT stress and strain during running utilizing muscle forces based on a musculoskeletal model and subject-specific ultrasound-derived AT cross-sectional area. Nineteen female runners performed running trials under 6 conditions, including rearfoot strike and forefoot strike patterns at their preferred cadence, +5%, and -5% preferred cadence. Rearfoot strike patterns had less peak AT stress (P < .001), strain (P < .001), and strain rate (P < .001) compared with the forefoot strike pattern. A reduction in peak AT stress and strain were exhibited with a +5% preferred step frequency relative to the preferred condition using a rearfoot (P < .001) and forefoot (P=.005) strike pattern. Strain rate was not different (P > .05) between step frequencies within each foot strike condition. Our results suggest that a rearfoot pattern may reduce AT stress, strain, and strain rate. Increases in step frequency of 5% above preferred frequency, regardless of foot strike pattern, may also lower peak AT stress and strain. PMID- 26955844 TI - Nurses' Beliefs About Caring for Patients With Traumatic Brain Injury. AB - Patients with traumatic brain injury (TBI) and their families rely on health care providers, particularly nurses, to provide accurate information, yet inaccurate beliefs about TBI have been found among nurses. Although prior studies have assessed nurses' beliefs about TBI recovery and rehabilitation, none have assessed specific beliefs about the nursing role to care for these patients. The purpose of this study was to investigate nurses' beliefs and learning preferences about caring for patients with moderate-to-severe TBI. A cross-sectional survey was administered to 513 nurses at a Midwestern hospital between October and December 2014 (20.3% response rate). Latent class analysis was used. Findings showed that nurses had inaccurate beliefs about TBI relating to recovery and the nursing role, and had significant differences in learning preferences. These findings have implications for development of educational and training interventions specific to nurses to ensure that they have factual information about TBI and to clarify the nursing role. PMID- 26955846 TI - The Water to Water Cycles in Microalgae. AB - In oxygenic photosynthesis, light produces ATP plus NADPH via linear electron transfer, i.e. the in-series activity of the two photosystems: PSI and PSII. This process, however, is thought not to be sufficient to provide enough ATP per NADPH for carbon assimilation in the Calvin-Benson-Bassham cycle. Thus, it is assumed that additional ATP can be generated by alternative electron pathways. These circuits produce an electrochemical proton gradient without NADPH synthesis, and, although they often represent a small proportion of the linear electron flow, they could have a huge importance in optimizing CO2 assimilation. In Viridiplantae, there is a consensus that alternative electron flow comprises cyclic electron flow around PSI and the water to water cycles. The latter processes include photosynthetic O2 reduction via the Mehler reaction at PSI, the plastoquinone terminal oxidase downstream of PSII, photorespiration (the oxygenase activity of Rubisco) and the export of reducing equivalents towards the mitochondrial oxidases, through the malate shuttle. In this review, we summarize current knowledge about the role of the water to water cycles in photosynthesis, with a special focus on their occurrence and physiological roles in microalgae. PMID- 26955845 TI - Accelerated transformation of macrophage-derived foam cells in the presence of collagen-induced arthritis mice serum is associated with dyslipidemia. AB - OBJECTIVE: Atherosclerosis characterized by accumulation of foam cells in the arterial intimal layer is accelerated in rheumatoid arthritis (RA) patients. We and others have previously demonstrated that serum from RA patients and collagen induced arthritis (CIA) mice had proatherogenic features that might lead to progression of atherosclerosis. Here we further examined the effects of serum from CIA mice on the transformation of macrophage-derived foam cells, and investigated potential mechanism. METHODS: DBA/1j mice were used to establish CIA model. Murine peritoneal macrophages and macrophage cell line RAW264.7 were treated with different dilute concentrations of mice serum. RESULTS: CIA mice serum increased cholesterol influx and accumulation in murine macrophages, and markedly up-regulated scavenger receptor CD36 expression in the cells, but had no effect on intracellular lipid efflux. Neutralizing monocyte chemotactic protein (MCP)-1, the most significant altered cytokine we observed between normal and CIA mice serum to CIA mice could not reverse these effects. However, administering simvastatin to CIA mice could lower high-density lipoprotein-cholesterol (HDL-C) level and elevate oxidized low-density lipoprotein (ox-LDL) level in CIA mice serum, with attendant decreased lipid accumulation as well as CD36 expression in murine macrophages. CONCLUSION: Accelerated transformation of macrophage-derived foam cells via up-regulated CD36 expression is related to dyslipidemia rather than elevated inflammatory factor MCP-1 level in CIA mice serum. Decreased HDL-C and higher ox-LDL levels in CIA mice serum may link RA to atherosclerosis. PMID- 26955847 TI - Clinical and prognostic value of endothelin-1 and big endothelin-1 expression in children with pulmonary hypertension. AB - OBJECTIVE: Pulmonary arterial hypertension is known to be associated with increased expression of endothelin (ET)-1 and its precursor big ET-1. Therefore, we hypothesised that in children with pulmonary hypertension (PH) altered levels of ET-1 and big ET-1 may have clinical and prognostic impact. METHODS: Sixty-six children with different forms of PH (mean age 10.4+/-9.7 years) were included. Blood samples were taken from the pulmonary artery and a systemic artery. Levels of ET-1/big ET-1 were measured via ELISA method and compared with clinical and haemodynamic data. To assess prognostic relevance, Kaplan-Meier survival analysis was conducted with definition of end point as the composite of mortality, lung transplantation, use of intravenous prostanoids and Potts shunt creation. RESULTS: ET-1 levels ranged between 0.09 and 11.64 (mean 1.48+/-2.34) fmol/mL, and big ET-1 levels between 0.05 and 2.92 (mean 0.84+/-0.58) fmol/mL. No significant relationships were found between ET-1/big ET-1 levels and functional class as well as haemodynamic indices of PH severity. Mean follow-up after catheterisation was 63.2+/-44.1 months. While 31 of the 66 (47%) patients with PH reached a predefined end point, there was no significant relation between levels of ET-1/big ET-1 and patient outcome. CONCLUSIONS: Although children with PH had alterations in ET-1/big ET-1 expression, which may reflect changes in net release or lung clearance, levels of ET-1/big ET-1 showed no correlation with clinical and haemodynamic parameters, and were not able to predict outcome. PMID- 26955850 TI - Atomic-Scale Observations of Catalyst Structures under Reaction Conditions and during Catalysis. AB - Heterogeneous catalysis is a chemical process performed at a solid-gas or solid liquid interface. Direct participation of catalyst atoms in this chemical process determines the significance of the surface structure of a catalyst in a fundamental understanding of such a chemical process at a molecular level. High pressure scanning tunneling microscopy (HP-STM) and environmental transmission electron microscopy (ETEM) have been used to observe catalyst structure in the last few decades. In this review, instrumentation for the two in situ/operando techniques and scientific findings on catalyst structures under reaction conditions and during catalysis are discussed with the following objectives: (1) to present the fundamental aspects of in situ/operando studies of catalysts; (2) to interpret the observed restructurings of catalyst and evolution of catalyst structures; (3) to explore how HP-STM and ETEM can be synergistically used to reveal structural details under reaction conditions and during catalysis; and (4) to discuss the future challenges and prospects of atomic-scale observation of catalysts in understanding of heterogeneous catalysis. This Review focuses on the development of HP-STM and ETEM, the in situ/operando characterizations of catalyst structures with them, and the integration of the two structural analytical techniques for fundamentally understanding catalysis. PMID- 26955848 TI - Validation of presentation and 3 h high-sensitivity troponin to rule-in and rule out acute myocardial infarction. AB - OBJECTIVE: International guidelines to rule-in acute myocardial infarction (AMI) in patients presenting with chest pain to the emergency department (ED) recommend an algorithm using high-sensitivity cardiac troponin (hs-cTn) sampling on presentation and 3 h following presentation. We tested the diagnostic accuracy of this algorithm by pooling data from five distinct cohorts from three countries of prospectively recruited patients with independently adjudicated outcomes. METHOD: We measured high-sensitivity cardiac troponin I (hs-cTnI) and high-sensitivity cardiac troponin T (hs-cTnT) on presentation (0 h) and 3 h post-presentation samples in adult patients attending an ED with possible AMI to validate the European Society of Cardiology (ESC) Working Group on Acute Cardiac Care rule-in algorithm (ESC-rule-in). Specifically, (i) in patients with a 0 h hs-cTn concentration <=99th percentile and a 3 h hs-cTn >99th percentile, positive patients are those with an absolute change in troponin >=50% of the 99th percentile, and (ii) in patients with a 0 and 3 h hs-cTn >99th percentile, positive patients are those with a relative change in troponin of >=20%. We concurrently assessed the efficacy of the 0 and 3 h hs-cTn <99th percentile to rule-out AMI. RESULTS: 1061 patients with hs-cTnI and 985 with hs-cTnT were included. The ESC-rule-in positive predictive value (PPV) was 83.5% (95% CI 74.9% to 90.1%) for hs-cTnI and 72.0% (95% CI 62.1% to 80.5%) for hs-cTnT. Forty-six AMIs (34.9%) were not ruled in using hs-cTnI and 62 (46.2%) using hs-cTnT. The sensitivity of the 99th percentile to rule-out AMI was 93.2% (95% CI 87.5% to 96.8%) for hs-cTnI and 94.8% (95% CI 89.5% to 97.9%) for hs-cTnT. CONCLUSIONS: The ESC-rule-in algorithm has good PPV with hs-cTnI and reasonable with hs-cTnT and can rule-in over 50% of AMIs. However, the sensitivity of the 99th percentile to rule-out AMI is too low for clinical use. PMID- 26955849 TI - Protectin D1 reduces concanavalin A-induced liver injury by inhibiting NF-kappaB mediated CX3CL1/CX3CR1 axis and NLR family, pyrin domain containing 3 inflammasome activation. AB - Protectin D1 (PD1) is a bioactive product generated from docosahexaenoic acid, which may exert anti-inflammatory effects in various inflammatory diseases. However, the underlying molecular mechanism of its anti-inflammatory activity on concanavalin A (Con A)-induced hepatitis remains unknown. The aim of the present study was to investigate the protective effects of PD1 against Con A-induced liver injury and the underlying mechanisms via intravenous injection of PD1 prior to Con A administration. C57BL/6 mice were randomly divided into four experimental groups as follows: Control group, Con A group (30 mg/kg), 20 ug/kg PD1 + Con A (30 mg/kg) group and 10 ug/kg PD1 + Con A (30 mg/kg) group. PD1 pretreatment was demonstrated to significantly inhibit elevated plasma aminotransferase levels, high mobility group box 1 and liver necrosis, which were observed in Con A-induced hepatitis. Furthermore, compared with the Con A group, PD1 pretreatment prevented the production of pro-inflammatory cytokines, including tumor necrosis factor-alpha, interferon-gamma and interleukin-2, -1beta and -6. In addition, pretreatment with PD1 markedly downregulated cluster of differentiation (CD)4+, CD8+ and natural killer T (NKT) cell infiltration in the liver. PD1 pretreatment was observed to suppress the messenger RNA and protein expression levels of NLR family, pyrin domain containing 3 and Toll-like receptor (TLR) 4 in liver tissue samples. Further data indicated that PD1 pretreatment inhibited the activation of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) signaling pathway and chemokine (C-X3-C motif) ligand 1 (CX3CL1)/chemokine (C-X3-C motif) receptor 1 (CX3CR1) axis by preventing phosphorylation of nuclear factor of kappa light polypeptide gene enhancer in B cells inhibitor, alpha and NF-kappaB in Con A-induced liver injury. Therefore, these results suggest that PD1 administration protects mice against Con A-induced liver injury via inhibition of various inflammatory cytokines and, in part, by suppressing CD4+, CD8+ and NKT cell infiltration in the liver and the NF-kappaB activated CX3CL1/CX3CR1 signaling pathway. The beneficial effect of PD1 may be associated with the inhibition of TLR4 expression and the downregulation of NF kappaB activation. In conclusion, PD1 appears to be a potential natural bioproduct, and provide a promising strategy, for the prevention of hepatic injury in patients with chronic or acute liver disease. PMID- 26955853 TI - A Player Often Neglected: Electrochemical Comprehensive Analysis of Counter Electrodes for Quantum Dot Solar Cells. AB - The role played by the counter electrode (CE) in quantum dot sensitized solar cells (QDSSCs) is crucial: it is indeed responsible for catalyzing the regeneration of the redox electrolyte after its action to take back the oxidized light harvesters to the ground state, thus keeping the device active and stable. The activity of CE is moreover directly related to the fill factor and short circuit current through the resistance of the interface electrode-electrolyte that affects the series resistance of the cell. Despite that, too few efforts have been devoted to a comprehensive analysis of this important device component. In this work we combine an extensive electrochemical characterization of the most common materials exploited as CEs in QDSSCs (namely, Pt, Au, Cu2S obtained by brass treatment, and Cu2S deposited on conducting glass via spray) with a detailed characterization of their surface composition and morphology, aimed at systematically defining the relationship between their nature and electrocatalytic activity. PMID- 26955854 TI - Investigation of 6-O-methyl-scutellarein metabolites in rats by ultra-flow liquid chromatography/quadrupole-time-of-flight mass spectrometry. AB - Context Scutellarin (1) has been widely used in China to treat acute cerebral infarction and paralysis induced by cerebrovascular diseases. However, scutellarin (1) has unstable metabolic characteristics. Objective The metabolic profile of 6-O-scutellarein was studied to determine its metabolic stability in vivo. Materials and methods In this study, a method of UFLC/Q-TOF MS was used to study the 6-O-methyl-scutellarein metabolites in rat plasma, urine, bile and faeces after oral administration of 6-O-methyl-scutellarein (3). One hour after oral administration of 6-O-methyl-scutellarein (3) (34 mg/kg), approximately 1 mL blood samples were collected in EP tubes from all groups. Bile, urine and faeces samples were collected from eight SD rats during 0-24 h after oral administration. The mass defect filtering, dynamic background subtraction and information dependent acquisition techniques were also used to identify the 6-O methyl-scutellarein metabolites. Results The parent compound 6-O-methyl scutellarein (3) was found in rat urine, plasma, bile and faeces. The glucuronide conjugate of 6-O-methyl-scutellarein (M1, M2), diglucuronide conjugate of 6-O methyl-scutellarein (M3), sulphate conjugate of 6-O-methyl-scutellarein (M4), glucuronide and sulphate conjugate of 6-O-methyl-scutellarein (M5), methylated conjugate of 6-O-methyl-scutellarein (M6) were detected in rat urine. M1, M2 and M3 were detected in rat bile. M1 was found in rat plasma and M7 was detected in faeces. Discussion and conclusion Because the parent compound 6-O-methyl scutellarein (3) was found in rat urine, plasma, bile and faeces, we speculate that 6-O-methyl-scutellarein (3) had good metabolic stability in vivo. This warrants further study to develop it as a promising candidate for the treatment of ischemic cerebrovascular disease. PMID- 26955855 TI - Social memory associated with estrogen receptor polymorphisms in women. AB - The ability to recognize the identity of faces and voices is essential for social relationships. Although the heritability of social memory is high, knowledge about the contributing genes is sparse. Since sex differences and rodent studies support an influence of estrogens and androgens on social memory, polymorphisms in the estrogen and androgen receptor genes (ESR1, ESR2, AR) are candidates for this trait. Recognition of faces and vocal sounds, separately and combined, was investigated in 490 subjects, genotyped for 10 single nucleotide polymorphisms (SNPs) in ESR1, four in ESR2 and one in the AR Four of the associations survived correction for multiple testing: women carrying rare alleles of the three ESR2 SNPs, rs928554, rs1271572 and rs1256030, in linkage disequilibrium with each other, displayed superior face recognition compared with non-carriers. Furthermore, the uncommon genotype of the ESR1 SNP rs2504063 was associated with better recognition of identity through vocal sounds, also specifically in women. This study demonstrates evidence for associations in women between face recognition and variation in ESR2, and recognition of identity through vocal sounds and variation in ESR1. These results suggest that estrogen receptors may regulate social memory function in humans, in line with what has previously been established in mice. PMID- 26955857 TI - Risks and benefits of the skin-to-skin cesarean section - a retrospective cohort study. AB - OBJECTIVE: Comparing maternal and neonatal outcomes after conventional cesarean section (CS) versus a "natural" or "skin-to-skin" cesarean section (SSCS). METHODS: Retrospective cohort of women who underwent a SSCS (01-2013 until 12 2013) compared to conventional CS (08-2011 to 08-2012). CS before 37 weeks, under general anesthesia and in case of fetal distress were excluded. Main outcome measures were maternal blood loss, post-operative infection and admission; neonatal infection and admission; procedural outcomes. RESULTS: We analyzed 285 (44%) women in the SSCS-group and 365 (56%) in the conventional CS-group. There were no significant differences in surgical site infection (2.1% versus 1.6%; RR 1.1; 95%CI 0.64-2.0), or other maternal outcomes. Fewer neonates born after SSCS were admitted to the pediatric ward (9.5% versus 18%; RR 0.58; 95%CI 0.41-0.80) and fewer neonates had a suspected neonatal infection (2.0% versus 7.3%; RR 0.40; 95%CI 0.19-0.83). No differences were observed for other outcomes. Mean operation time was 4m42s longer in the SSCS-group compared to the conventional CS-group (58m versus 53m; 95%CI 2m44s-6m40s). Mean recovery time was 14m46s shorter (114m versus 129m; 95%CI 3m20s-26m). CONCLUSION: Adverse maternal and neonatal outcomes were not increased after skin-to-skin cesarean compared to conventional cesarean delivery. PMID- 26955856 TI - Stromal Cells in Dense Collagen Promote Cardiomyocyte and Microvascular Patterning in Engineered Human Heart Tissue. AB - Cardiac tissue engineering is a strategy to replace damaged contractile tissue and model cardiac diseases to discover therapies. Current cardiac and vascular engineering approaches independently create aligned contractile tissue or perfusable vasculature, but a combined vascularized cardiac tissue remains to be achieved. Here, we sought to incorporate a patterned microvasculature into engineered heart tissue, which balances the competing demands from cardiomyocytes to contract the matrix versus the vascular lumens that need structural support. Low-density collagen hydrogels (1.25 mg/mL) permit human embryonic stem cell derived cardiomyocytes (hESC-CMs) to form a dense contractile tissue but cannot support a patterned microvasculature. Conversely, high collagen concentrations (density >=6 mg/mL) support a patterned microvasculature, but the hESC-CMs lack cell-cell contact, limiting their electrical communication, structural maturation, and tissue-level contractile function. When cocultured with matrix remodeling stromal cells, however, hESC-CMs structurally mature and form anisotropic constructs in high-density collagen. Remodeling requires the stromal cells to be in proximity with hESC-CMs. In addition, cocultured cardiac constructs in dense collagen generate measurable active contractions (on the order of 0.1 mN/mm(2)) and can be paced up to 2 Hz. Patterned microvascular networks in these high-density cocultured cardiac constructs remain patent through 2 weeks of culture, and hESC-CMs show electrical synchronization. The ability to maintain microstructural control within engineered heart tissue enables generation of more complex features, such as cellular alignment and a vasculature. Successful incorporation of these features paves the way for the use of large scale engineered tissues for myocardial regeneration and cardiac disease modeling. PMID- 26955858 TI - Histopathological studies of the heart in three lines of broiler chickens. AB - The aim of this study was to analyse the morphological lesion pattern of the heart of broiler chickens (Cobb 500, Hubbard F15 and Ross 308) during fattening with no clinical signs of disease and to determine the most susceptible period for the occurrence of morphological lesions. The most frequently diagnosed lesions in each genetic line were degeneration of the fibres with vacuolation, congestion of cardiac muscle, oedema and vacuolisation of the Purkinje cells. The highest numbers of morphological lesions were observed on d 38, 31 and 10 of life. The lesions were most numerous in the septum, followed by the left and right ventricles. Ischaemic cardiomyocytes were also most numerous on d 38 of life and in the left ventricle. Overload of cardiac muscle, prolonged hypoxia and increasing body weight on d 38 are the likely reasons for the largest number of lesions and ischaemic fibres, which may lead to heart failure. PMID- 26955860 TI - On "Diagnostic value of aberrant gene methylation in stool samples for colorectal cancer or adenomas". PMID- 26955862 TI - Synthesis of nitrogen-doping carbon dots with different photoluminescence properties by controlling the surface states. AB - Surface states of carbon dots (CDs) are critical to the photoemission properties of CDs. By carefully adjusting the reaction conditions in a hydrothermal synthesis route, we have prepared a series of CDs with excitation-dependent emission (EDE) and excitation-independent emission (EIE) properties by controlling the content of nitrogen elements, confirming that the characteristic optical properties of CDs originate from their energy levels. It has been found that surface-passivation of the as-prepared CDs by nitrogen doping can improve the emission efficiency and be beneficial to EIE features due to the single electron transition resulting from the single functional groups. And the as prepared CDs can specifically bind with Hg(2+) with the emission quenched because of the electron transfer from the LUMO levels of CDs to Hg(2+). PMID- 26955861 TI - Exploring the relationship of decentering to health related concepts and cognitive and metacognitive processes in a student sample. AB - BACKGROUND: Decentering, a central change strategy of Mindfulness-Based Cognitive Therapy, is a process of stepping outside of one's own mental events leading to an objective and non-judging stance towards the self. The study aimed at investigating associated mechanisms of decentering. METHOD: The present study investigated the relation of decentering, operationalized by means of the German Version of the Experiences Questionnaire, to severity of depressive symptoms, assessed by the adaptive Rasch-based depression screening, and self-focussed attention, assessed by the Questionnaire of Dysfunctional and Functional Self Consciousness. Furthermore, the relationship between decentering and a) the ability to shift and allocate attention by means of the Stroop test, and b) metacognitive monitoring, i.e. the absolute difference between judged and real task performance, was investigated. These relationships were examined in 55 healthy students using Pearson's correlations. RESULTS: In line with our assumptions, higher decentering scores were significantly associated with lower scores on severity of depressive symptoms, with higher functional- and lower dysfunctional self-focussed attention. Contrary to our expectations, results neither indicated a relationship between decentering and attention ability, nor between decentering and metacognitive monitoring. CONCLUSIONS: The present results suggest that decentering is associated with concepts of mental health (i.e. less severity of depressive symptoms and higher functional self-focussed attention). Overall, the concept decentering seems to be mainly composed of self focussed aspects when investigated in a healthy sample without intervention. Further investigations of associated concepts of decentering should consider aspects of self-relevance and emotional valence. PMID- 26955864 TI - Dynamic foldamer chemistry. AB - Foldamers can be made more than pieces of static, conformationally uniform molecular architecture by designing into their structure the conformational dynamism characteristic of functional molecular machines. We show that these dynamic foldamers display biomimetic properties reminiscent of allosteric proteins and receptor molecules. They can translate chemical signals into conformational changes, and hence into chemical outputs such as control of reactivity and selectivity. Future developments could see dynamic foldamers operating in the membrane phase providing artificial mechanisms for communication and control that integrate synthetic chemistry into synthetic biology. PMID- 26955865 TI - Review on the Raman spectroscopy of different types of layered materials. AB - Two-dimensional layered materials, such as graphene and transition metal dichalcogenides (TMDs), have been under intensive investigation. The rapid progress of research on graphene and TMDs is now stimulating the exploration of different types of layered materials (LMs). Raman spectroscopy has shown its great potential in the characterization of layer numbers, interlayer coupling and layer-stacking configurations and will benefit the future explorations of other LMs. Lattice vibrations or Raman spectra of many LMs in bulk have been discussed since the 1960s. However, different results were obtained because of differences or limitations in the Raman instruments at early stages. The developments of modern Raman spectroscopy now allow us to revisit the Raman spectra of these LMs under the same experimental conditions. Moreover, to the best of our knowledge, there were limitations in detailed reviews on the Raman spectra of these different LMs. Here, we provide a review on Raman spectra of various LMs, including semiconductors, topological insulators, insulators, semi-metals and superconductors. We firstly introduce a unified method based on symmetry analysis and polarization measurements to assign the observed Raman modes and characterize the crystal structure of different types of LMs. Then, we revisit and update the positions and assignments of vibration modes by re-measuring the Raman spectra of different types of LMs and by comparing our results to those reported in previous papers. We apply the recent advances on the interlayer vibrations of graphene and TMDs to these various LMs and obtain their shear modulus. The observation of the shear modes of LMs in bulk facilitates an accurate and fast characterization of layer numbers during preparation processes in the future by a robust layer-number dependency on the frequencies of the shear modes. We also summarize the recent advances on the layer-stacking dependence on the intensities of interlayer shear vibrations. Finally, we review the recent advances on Raman spectroscopy in the characterization of anisotropic LMs, such as black phosphorus and rhenium diselenide. We believe that this review will benefit the future research studies on the fundamental physics and potential applications of these various LMs, particularly when they are reduced down to monolayers or multilayers. PMID- 26955863 TI - Combining the new injury severity score with an anatomical polytrauma injury variable predicts mortality better than the new injury severity score and the injury severity score: a retrospective cohort study. AB - BACKGROUND: Anatomy-based injury severity scores are commonly used with physiological scores for reporting severity of injury in a standardized manner. However, there is lack of consensus on choice of scoring system, with the commonly used injury severity score (ISS) performing poorly for certain sub groups, eg head-injured patients. We hypothesized that adding a dichotomous variable for polytrauma (yes/no for Abbreviated Injury Scale (AIS) scores of 3 or more in at least two body regions) to the New Injury Severity Score (NISS) would improve the prediction of in-hospital mortality in injured patients, including head-injured patients-a subgroup that has a disproportionately high mortality. Our secondary hypothesis was that the ISS over-estimates the risk of death in polytrauma patients, while the NISS under-estimates it. METHODS: Univariate and multivariable analysis was performed on retrospective cohort data of blunt injured patients aged 18 and over with an ISS over 9 from the Singapore National Trauma Registry from 2011-2013. Model diagnostics were tested using discrimination (c-statistic) and calibration (Hosmer-Lemeshow goodness-of-fit statistic). All models included age, gender, and comorbidities. RESULTS: Our results showed that the polytrauma and NISS model outperformed the other models (polytrauma and ISS, NISS alone or ISS alone) in predicting 30-day and in hospital mortality. The NISS underestimated the risk of death for patients with polytrauma, while the ISS overestimated the risk of death for these patients. When used together with the NISS and polytrauma, categorical variables for deranged physiology (systolic blood pressure of 90 mmHg or less, GCS of 8 or less) outperformed the traditional 'ISS and RTS (Revised Trauma Score)' model, with a c-statistic of greater than 0.90. This could be useful in cases when the RTS cannot be scored due to missing respiratory rate. DISCUSSION: The NISS and polytrauma model is superior to current scores for prediction of 30-day and in hospital mortality. We propose that this score replace the ISS or NISS in institutions using AIS-based scores. CONCLUSIONS: Adding polytrauma to the NISS or ISS improves prediction of 30-day mortality. The superiority of the NISS or ISS depends on the proportion of polytrauma and head-injured patients in the study population. PMID- 26955866 TI - Predicting long term cooperativity and specific modulators of receptor interactions in human transferrin from dynamics within a single microstate. AB - Transferrin (Tf) is an essential transport protein circulating iron in the blood and delivering it to tissues. It displays highly pH dependent cooperativity between the two lobes each carrying an iron, and forms a tight complex with the receptor during endocytosis and recycling back to the serum. We explore short term dynamics within selected microstates of human Tf to identify functional information relevant to long-term dynamics. While the variance-covariance matrix delineates cooperativity between the domains of Tf at serum pH which is lost at endosomal pH, its decomposition does not bring about additional information. We employ perturbation-response scanning (PRS) to extract essential components that contribute to a pre-selected conformational change. Since large-scale motions may require key residues to mediate correlated motions between different regions of the protein, we use PRS to predict those involved in the conformational transitions between the iron bound and free hTf. Physiological and endosomal conditions are mimicked to identify critical residues for holo -> apo and apo -> holo transitions. Iron binding motions are mainly orchestrated by residues at the synergistic anion uptake sites, a finding also corroborated by additional molecular dynamics simulations where these sites are perturbed by docking the anion. Iron release is not readily accessible at serum pH, while at endosomal pH single residue perturbations on any residue encourage the large transition that involves a complex twisting of the two domains relative to each other, simultaneously opening both lobes. The pH dependent change in the dynamics is traced to the altered electrostatic potential distribution along the surface. The examination of local dynamics in the hTf-receptor pair reveals cooperativity in the quaternary structure and explains resistance to iron release in the complex. Meanwhile, the analysis of the hTf complex with a bacterial receptor that has evolved to sequester iron identifies two regions contacting rapidly evolving residues that mechanically manipulate dissociation from the pathogen. PMID- 26955867 TI - Mechanistic and microkinetic analysis of CO2 hydrogenation on ceria. AB - We use density functional theory (DFT) calculations to investigate the mechanism of CO2 hydrogenation to methanol on a reduced ceria (110) catalyst, which has previously been shown to activate CO2. Two reaction channels to methanol are identified: (1) COOH pathway via a carboxyl intermediate and (2) HCOO pathway via a formate intermediate. While formaldehyde (H2CO) appears to be the key intermediate for methanol synthesis, other intermediates, including carbine diol, formic acid and methanol, are not feasible due to their high formation energies. Furthermore, direct formyl hydrogenation to formaldehyde is not feasible due to its high activation barrier. Instead, we find that conversion of H-formalin (H2COOH*) to formaldehyde is kinetically more favorable. The formaldehyde is then converted to methoxy (H3CO*), and finally hydrogenated to form methanol. Microkinetic analyses reveal the rate-limiting steps in the reaction network and establish that the HCOO route is the dominant pathway for methanol formation on this catalyst. PMID- 26955869 TI - Factors influencing the uptake of voluntary HIV counseling and testing in rural Ethiopia: a cross sectional study. AB - BACKGROUND: Voluntary counseling and testing (VCT) has been one of the key policy responses to the HIV/AIDS epidemic in Ethiopia. However, the utilization of VCT has been low in the rural areas of the country. Understanding factors influencing the utilization of VCT provides information for the design of context based appropriate strategies that aim to improve utilization. This study examined the effects of socio-demographic and behavioral factors, and health service characteristics on the uptake of VCT among rural adults in Ethiopian. METHODS/DESIGN: This study was designed as a cross sectional study. Data from 11,919 adults (6278 women aged 15-49 years and 5641 men aged 15-59 years) residing in rural areas of Ethiopia who participated in a national health extension program evaluation were used for this study. The participants were selected from ten administrative regions using stratified multi-stage cluster sampling. Multivariate logistic regression analysis was performed accounting for factors associated with the use of VCT service. RESULTS: Overall, men (28 %) were relatively more likely to get tested for HIV than women (23.7 %) through VCT. Rural men and women who were young and better educated, who perceived having small risk of HIV infection, who had comprehensive knowledge, no stigmatization attitude and discussed about HIV/AIDS with their partner, and model-family were more likely to undergone VCT. Regional state was also strongly associated with VCT utilization in both men and women. Rural women who belonged to households with higher socio-economic status, non-farming occupation, female-headed household and located near health facility, and who visited health extension workers and participated in community conversation were more likely to use VCT. Among men, agrarian lifestyle was associated with VCT use. CONCLUSIONS: Utilization of VCT in the rural communities is low, and socio-economic, behavioral and health service factors influence its utilization. For increasing the utilization of VCT service in rural areas, there is a need to target the less educated, women, poor and farming families with a focus on improving knowledge and reducing HIV/AIDS related stigma. Strategy should include promoting partner and community conversations, accelerating model-family training, and using alternative modes of testing. PMID- 26955870 TI - Improving gastric cancer preclinical studies using diverse in vitro and in vivo model systems. AB - BACKGROUND: "Biomarker-driven targeted therapy," the practice of tailoring patients' treatment to the expression/activity levels of disease-specific genes/proteins, remains challenging. For example, while the anti-ERBB2 monoclonal antibody, trastuzumab, was first developed using well-characterized, diverse in vitro breast cancer models (and is now a standard adjuvant therapy for ERBB2 positive breast cancer patients), trastuzumab approval for ERBB2-positive gastric cancer was largely based on preclinical studies of a single cell line, NCI-N87. Ensuing clinical trials revealed only modest patient efficacy, and many ERBB2 positive gastric cancer (GC) patients failed to respond at all (i.e., were inherently recalcitrant), or succumbed to acquired resistance. METHOD: To assess mechanisms underlying GC insensitivity to ERBB2 therapies, we established a diverse panel of GC cells, differing in ERBB2 expression levels, for comprehensive in vitro and in vivo characterization. For higher throughput assays of ERBB2 DNA and protein levels, we compared the concordance of various laboratory quantification methods, including those of in vitro and in vivo genetic anomalies (FISH and SISH) and xenograft protein expression (Western blot vs. IHC), of both cell and xenograft (tissue-sectioned) microarrays. RESULTS: The biomarker assessment methods strongly agreed, as did correlation between RNA and protein expression. However, although ERBB2 genomic anomalies showed good in vitro vs. in vivo correlation, we observed striking differences in protein expression between cultured cells and mouse xenografts (even within the same GC cell type). Via our unique pathway analysis, we delineated a signaling network, in addition to specific pathways/biological processes, emanating from the ERBB2 signaling cascade, as a potential useful target of clinical treatment. Integrated analysis of public data from gastric tumors revealed frequent (10 - 20 %) amplification of the genes NFKBIE, PTK2, and PIK3CA, each of which resides in an ERBB2-derived subpathway network. CONCLUSION: Our comprehensive bioinformatics analyses of highly heterogeneous cancer cells, combined with tumor "omics" profiles, can optimally characterize the expression patterns and activity of specific tumor biomarkers. Subsequent in vitro and in vivo validation, of specific disease biomarkers (using multiple methodologies), can improve prediction of patient stratification according to drug response or nonresponse. PMID- 26955871 TI - Prevalence, characterization, and antibiotic susceptibility of Vibrio parahaemolyticus isolated from retail aquatic products in North China. AB - BACKGROUND: Vibrio parahaemolyticus is a major foodborne pathogen, particularly in Asian countries. Increased occurrence of outbreaks of V. parahaemolyticus gastroenteritis in China indicates the need to evaluation of the prevalence of this pathogenic species. V. parahaemolyticus distribution in shellfish from the eastern coast of China has been reported previously. However, to date, the prevalence of V. parahaemolyticus in retail aquatic products in North China has not been determined. To investigate the prevalence of V. parahaemolyticus in aquatic products in North China, 260 aquatic product samples were obtained from retail markets in 6 provinces of North China from November to December in 2012 and July to August in 2013. RESULTS: V. parahaemolyticus was detected in 94 (36.2%) of the samples by the most probable number method. The density of V. parahaemolyticus ranged from 1.50 to 1100 MPN/g. V. parahaemolyticus was detected at a rate of 50.0% and 22.7% in summer and in winter, respectively. The density of V. parahaemolyticus was significantly higher in summer than in winter, with mean levels of 16.5 MPN/g and 5.0 MPN/g, respectively. Among 145 V. parahaemolyticus isolates examined, none of the isolates possessed tdh and trh. In multiplex PCR-based O-antigen serotyping of these 145 isolates, all serotypes, other than O6, O7, and O9, were detected, and serotype O2 was found to be the most prevalent (detected in 54 isolates). The 145 isolates were grouped into 7 clusters by enterobacterial repetitive intergenic consensus-polymerase chain reaction (ERIC-PCR) at a similarity coefficient of 0.66. The antimicrobial resistance patterns of these 145 isolates to 12 antimicrobial agents revealed that most of the isolates were resistant to streptomycin (86.2%), while fewer were resistant to ampicillin (49.6%), cefazolin (43.5%), cephalothin (35.9%), and kanamycin (22.1%). All of the examined isolates were susceptible to azithromycin and chloramphenicol. CONCLUSIONS: The findings of this study will help in defining appropriate monitoring programs, understanding of the dissemination of antibiotic resistant strains, and providing information for the assessment of exposure to this microorganism at the consumption level. PMID- 26955872 TI - New molecular settings to support in vivo anti-malarial assays. AB - BACKGROUND: Quantitative real-time PCR (qPCR) is now commonly used as a method to confirm diagnosis of malaria and to differentiate recrudescence from re infection, especially in clinical trials and in reference laboratories where precise quantification is critical. Although anti-malarial drug discovery is based on in vivo murine efficacy models, use of molecular analysis has been limited. The aim of this study was to develop qPCR as a valid methodology to support pre-clinical anti-malarial models by using filter papers to maintain material for qPCR and to compare this with traditional methods. METHODS: FTA technology (Whatman) is a rapid and safe method for extracting nucleic acids from blood. Peripheral blood samples from mice infected with Plasmodium berghei, P. yoelii, or P. falciparum were kept as frozen samples or as spots on FTA cards. The extracted genetic material from both types of samples was assessed for quantification by qPCR using sets of specific primers specifically designed for Plasmodium 18S rRNA, LDH, and CytB genes. RESULTS: The optimal conditions for nucleic acid extraction from FTA cards and qPCR amplification were set up, and were confirmed to be suitable for parasite quantification using DNA as template after storage at room temperature for as long as 26 months in the case of P. berghei samples and 52 months for P. falciparum and P. yoelii. The quality of DNA extracted from the FTA cards for gene sequencing and microsatellite amplification was also assessed. CONCLUSIONS: This is the first study to report the suitability of FTA cards and qPCR assay to quantify parasite load in samples from in vivo efficacy models to support the drug discovery process. PMID- 26955873 TI - Multi-contact functional electrical stimulation for hand opening: electrophysiologically driven identification of the optimal stimulation site. AB - BACKGROUND: Functional Electrical Stimulation (FES) is increasingly applied in neurorehabilitation. Particularly, the use of electrode arrays may allow for selective muscle recruitment. However, detecting the best electrode configuration constitutes still a challenge. METHODS: A multi-contact set-up with thirty electrodes was applied for combined FES and electromyography (EMG) recording of the forearm. A search procedure scanned all electrode configurations by applying single, sub-threshold stimulation pulses while recording M-waves of the extensor digitorum communis (EDC), extensor carpi radialis (ECR) and extensor carpi ulnaris (ECU) muscles. The electrode contacts with the best electrophysiological response were then selected for stimulation with FES bursts while capturing finger/wrist extension and radial/ulnar deviation with a kinematic glove. RESULTS: The stimulation electrodes chosen on the basis of M-waves of the EDC/ECR/ECU muscles were able to effectively elicit the respective finger/wrist movements for the targeted extension and/or deviation with high specificity in two different hand postures. CONCLUSIONS: A subset of functionally relevant stimulation electrodes could be selected fast, automatic and non-painful from a multi-contact array on the basis of muscle responses to subthreshold stimulation pulses. The selectivity of muscle recruitment predicted the kinematic pattern. This electrophysiologically driven approach would thus allow for an operator independent positioning of the electrode array in neurorehabilitation. PMID- 26955874 TI - Intracellular Ca(2+) and K(+) concentration in Brassica oleracea leaf induces differential expression of transporter and stress-related genes. AB - BACKGROUND: One of the most important members of the genus Brassica, cabbage, requires a relatively high level of calcium for normal growth (Plant Cell Environ 7: 397-405, 1984; Plant Physiol 60: 854-856, 1977). Localized Ca(2+) deficiency in cabbage leaves causes tip-burn, bringing about serious economic losses (Euphytica 9:203-208, 1960; Ann Bot 43:363-372, 1979; Sci Hortic 14:131-138, 1981). Although it has been known that the occurrence of tip-burn is related to Ca(2+) deficiency, there is limited information on the underlying mechanisms of tip-burn or the relationship between Ca(2+) and tip-burn incidence. To obtain more information on the genetic control of tip-burn symptoms, we focused on the identification of genes differentially expressed in response to increasing intracellular Ca(2+) and K(+) concentrations in B. oleracea lines derived from tip-burn susceptible, tip-burn resistant cabbages (B. oleracea var. capitata), and kale (B. oleracea var. acephala). RESULTS: We compared the levels of major macronutrient cations, including Ca(2+) and K(+), in three leaf segments, the leaf apex (LA), middle of leaf (LM), and leaf base (LB), of tip-burn susceptible, tip-burn resistant cabbages, and kale. Ca(2+) and K(+) concentrations were highest in kale, followed by tip-burn resistant and then tip-burn susceptible cabbages. These cations generally accumulated to a greater extent in the LB than in the LA. Transcriptome analysis identified 58,096 loci as putative non redundant genes in the three leaf segments of the three B. oleracea lines and showed significant changes in expression of 27,876 loci based on Ca(2+) and K(+) levels. Among these, 1844 loci were identified as tip-burn related phenotype specific genes. Tip-burn resistant cabbage and kale-specific genes were largely related to stress and transport activity based on GO annotation. Tip-burn resistant cabbage and kale plants showed phenotypes clearly indicative of heat shock, freezing, and drought stress tolerance compared to tip-burn susceptible cabbages, demonstrating a correlation between intracellular Ca(2+) and K(+) concentrations and tolerance of abiotic stress with differential gene expression. We selected 165 genes that were up- or down-regulated in response to increasing Ca(2+) and K(+) concentrations in the three leaf segments of the three plant lines. Gene ontology enrichment analysis indicated that these genes participated in regulatory metabolic processes or stress responses. CONCLUSIONS: Our results indicate that the genes involved in regulatory metabolic processes or stress responses were differentially expressed in response to increasing Ca(2+) and K(+) concentrations in the B. oleracea leaf. Our transcriptome data and the genes identified may serve as a starting point for understanding the mechanisms underlying essential macronutrient deficiencies in plants, as well as the features of tip-burn in cabbage and other Brassica species. PMID- 26955877 TI - Identification and Preclinical Evaluation of SC144, a Novel Pyrroloquinoxaline Derivative with Broad-Spectrum Anticancer Activity. AB - Design and discovery of new classes of anticancer agents with unique mechanisms of action is an urgent medical need. During the past several years, a series of salicylhydrazide class of compounds were reported to possess remarkable potency in a large panel of cancer cell lines from different tumor origins. In particular, the optimized lead compound, SC144, was further investigated and selected as a valuable drug candidate endowed with favorable pharmacokinetic and antiproliferative properties in various in vitro and in vivo xenograft models. This lead compound is active in cells resistant to conventional chemotherapies, synergistic with several standard-of-care drugs, and possesses an unique mechanism acting through the inhibition of the gp130-STAT3-survivin axis. Because of this novel mechanism, clinical development of SC144 will provide new therapeutic options for diverse cancers. PMID- 26955878 TI - Nanotechnology for the Environment and Medicine. AB - Nanotechnology encompasses the production and applications of physical, chemical, and biological systems at scales ranging from individual atoms or molecules to around 100 nanometres, as well as the integration of the resulting nanostructures into larger systems. Nanomaterials differ from bulk materials for their relatively larger surface-area-to-mass ratio, consequently they become more chemically reactive and can show different optical, magnetic and electrical behaviours. In recent years, engineered nanomaterials have gained a particular attention in some fields such as environmental protection (soil, air and water remediation/treatment) and medicine (bio-sensing, imaging, and drug delivery). Nanoparticles can be used to monitor in real-time some pollutants (including heavy metal ions, organic compounds, microbiological pathogens, etc.) present even at extremely low concentrations in different environments. The use of nanomaterials for waste remediation/treatment results in a technology more cost effective and rapid than current conventional approaches thanks to their enhanced surface area, transport properties, and sequestration characteristics. In addition, the integration of molecular biology and medicine with nanotechnology has resulted in new active nanostructures able to interact with biological systems. Nanocarriers based on carbon nanotubes, fumed silica (SiO2), titanium dioxide (TiO2), and magnetite and maghemite (Fe3O4, and gamma-Fe2O3) nanoparticles have a distinct advantage over other drug carriers as they can be opportunely designed to reach the desired targets. As a consequence, such nanostructures can represent an important platform for enhanced medical imaging and controlled drug delivery. Here, some applications of nanomaterials as water purifying agents and drug delivery systems are reported. PMID- 26955876 TI - Conversion of nanoscale topographical information of cluster-assembled zirconia surfaces into mechanotransductive events promotes neuronal differentiation. AB - BACKGROUND: Thanks to mechanotransductive components cells are competent to perceive nanoscale topographical features of their environment and to convert the immanent information into corresponding physiological responses. Due to its complex configuration, unraveling the role of the extracellular matrix is particularly challenging. Cell substrates with simplified topographical cues, fabricated by top-down micro- and nanofabrication approaches, have been useful in order to identify basic principles. However, the underlying molecular mechanisms of this conversion remain only partially understood. RESULTS: Here we present the results of a broad, systematic and quantitative approach aimed at understanding how the surface nanoscale information is converted into cell response providing a profound causal link between mechanotransductive events, proceeding from the cell/nanostructure interface to the nucleus. We produced nanostructured ZrO2 substrates with disordered yet controlled topographic features by the bottom-up technique supersonic cluster beam deposition, i.e. the assembling of zirconia nanoparticles from the gas phase on a flat substrate through a supersonic expansion. We used PC12 cells, a well-established model in the context of neuronal differentiation. We found that the cell/nanotopography interaction enforces a nanoscopic architecture of the adhesion regions that affects the focal adhesion dynamics and the cytoskeletal organization, which thereby modulates the general biomechanical properties by decreasing the rigidity of the cell. The mechanotransduction impacts furthermore on transcription factors relevant for neuronal differentiation (e.g. CREB), and eventually the protein expression profile. Detailed proteomic data validated the observed differentiation. In particular, the abundance of proteins that are involved in adhesome and/or cytoskeletal organization is striking, and their up- or downregulation is in line with their demonstrated functions in neuronal differentiation processes. CONCLUSION: Our work provides a deep insight into the molecular mechanotransductive mechanisms that realize the conversion of the nanoscale topographical information of SCBD-fabricated surfaces into cellular responses, in this case neuronal differentiation. The results lay a profound cell biological foundation indicating the strong potential of these surfaces in promoting neuronal differentiation events which could be exploited for the development of prospective research and/or biomedical applications. These applications could be e.g. tools to study mechanotransductive processes, improved neural interfaces and circuits, or cell culture devices supporting neurogenic processes. PMID- 26955880 TI - Cardiac Arrhythmias in Patients with Chronic Kidney Disease: Implications of Renal Failure for Antiarrhythmic Drug Therapy. AB - The kidney has numerous complex interactions with the heart, including shared risk factors (e.g., hypertension, dyslipidemia, etc.) and mutual amplification of morbidity and mortality. Both cardiovascular diseases and chronic kidney disease (CKD) may cause various alterations in cardiovascular system, metabolic homeostasis and autonomic nervous system that may facilitate the occurrence of cardiac arrhythmias. Also, pre-existent or incident cardiac arrhythmias such as atrial fibrillation (AF) may accelerate the progression of CKD. Patients with CKD may experience various cardiac rhythm disturbances including sudden cardiac death. Contemporary management of cardiac arrhythmias includes the use of antiarrhythmic drugs (AADs), catheter ablation and cardiac implantable electronic devices (CIEDs). Importantly, AADs are not used only as the principal treatment strategy, but also as an adjunct therapy in combination with CIEDs, to facilitate their effects or to minimize inappropriate device activation in selected patients. Along with their principal antiarrhythmic effect, AADs may also induce cardiac arrhythmias and the risk for such proarrhythmic effect(s) is particularly increased in patients with reduced left ventricular systolic function or in the setting of electrolyte imbalance. Moreover, CKD itself can induce profound alterations in the pharmacokinetics and pharmacodynamics of many drugs including AADs, thus facilitating the drug accumulation and increased exposure. Hence, the use of AADs in patients with CKD may be challenging. In this review article, we provide an overview of the characteristics of arrhythmogenesis in patients with CKD with special emphasis on the complexity of pharmacokinetics and risk for proarrhythmias when using AADs in patients with cardiac arrhythmias and CKD. PMID- 26955879 TI - Clarification of the molecular pathway of Taiwan local pomegranate fruit juice underlying the inhibition of urinary bladder urothelial carcinoma cell by proteomics strategy. AB - BACKGROUND: Pomegranate fruit has been shown to exhibit the inhibitory activity against prostate cancer and lung cancer in vitro and in vivo, which might be a resource for chemoprevention and chemotherapy of cancer. Our previous documented findings indicated that treatment of urinary bladder urothelial carcinoma cell with the ethanol extract isolated from the juice of pomegranate fruit grown in Taiwan could inhibit tumor cell. In this study we intended to uncover the molecular pathway underlying anti-cancer efficacy of Taiwan pomegranate fruit juice against urinary bladder urothelial carcinoma. METHODS: We exploited two dimensional gel electrophoresis coupled with tandem mass spectrometry to find the de-regulated proteins. Western immunoblotting was used to confirm the results collected from proteomics study. RESULTS: Comparative proteomics indicated that 20 proteins were differentially expressed in ethanol extract-treated T24 cells with 19 up-regulated and 1 down-regulated proteins. These de-regulated proteins were involved in apoptosis, cytoskeleton regulation, cell proliferation, proteasome activity and aerobic glycolysis. Further studies on signaling pathway demonstrated that ethanol extract treatment might inhibit urinary bladder urothelial carcinoma cell proliferation through restriction of PTEN/AKT/mTORC1 pathway via profilin 1 up-regulation. It also might evoke cell apoptosis through Diablo over-expression. CONCLUSIONS: The results of this study provide a global picture to further investigate the anticancer molecular mechanism of pomegranate fruit. PMID- 26955882 TI - Energy-requiring uptake of prostasomes and PC3 cell-derived exosomes into non malignant and malignant cells. AB - Epithelial cells lining the prostate acini release, in a regulated manner (exocytosis), nanosized vesicles called prostasomes that belong to the exosome family. Prostate cancer cells have preserved this ability to generate and export exosomes to the extracellular space. We previously demonstrated that human prostasomes have an ATP-forming capacity. In this study, we compared the capacity of extracellular vesicles (EVs) to generate ATP between normal seminal prostasomes and exosomes secreted by PC3 cells (PC3 exosomes), a prostate cancer cell line. Proteomic analyses identified enzymes of the glycolytic chain in both prostasomes and PC3 exosomes, and we found that both of them were capable of generating ATP when supplied with substrates. Notably, the net production of extracellular ATP was low for prostasomes due to a high ATPase activity contrary to an elevated net ATP level for PC3 exosomes because of their low ATPase activity. The uptake of the 2 types of EVs by normal prostate epithelial cells (CRL2221) and prostate cancer cells (PC3) was visualized and measured, demonstrating differential kinetics. Interestingly, this uptake was dependent upon an ongoing glycolytic flux involving extracellular ATP formation by EVs and/or intracellular ATP produced from the recipient cells. We conclude that the internalization of EVs into recipient cells is an energy-requiring process also demanding an active V-ATPase and the capacity of EVs to generate extracellular ATP may play a role in this process. PMID- 26955881 TI - Plasma VEGF-related polymorphisms are implied in autoimmune thyroid diseases. AB - Autoimmune thyroid diseases (AITD), including Graves' disease (GD) and Hashimoto thyroiditis (HT), are complex multifactorial diseases. Vascular endothelial growth factor (VEGF) is implicated in various inflammatory diseases, especially autoimmune diseases. Our aim was to elucidate the relationships between plasma VEGF levels and four genome-wide association study-identified single nucleotide polymorphisms (SNPs) related to VEGF with AITD in Tunisian patients. A total of 364 healthy controls and 389 patients with AITD were genotyped for the SNPs rs6921438, rs4416670, rs6993770 and rs10738760. Levels of thyroid hormones and antibodies were quantified simultaneously with plasma VEGF after a period of six months of treatment. We found that the minor alleles of rs10738760 and rs6921438 are associated with the presence of GD. A allele of rs10738760 polymorphism is associated with increased plasma levels of free tri-iodothyronin (FT3) while no relationship was found with circulating VEGF plasma levels after six months of treatment. We also showed that the T allele of rs4416670 polymorphism was associated with increased risk of hyperthyroidism in patients treated for six months, independently of their initial diagnosis. There was no significant association between the SNPs and the risk for HT compared with controls. This study shows that AITD are influenced by 3 SNPs linked to VEGF circulating levels. Whereas rs10738760 appeared specific to GD and FT3 production after six months of treatment, rs6921438 and rs4416670 were implicated in the risk for GD. This study opens new ways to test pharmacogenomics concepts in the future especially in GD in which recurrence prognosis is still challenging. PMID- 26955883 TI - Health care providers' perceived barriers to and need for the implementation of a national integrated health care standard on childhood obesity in the Netherlands a mixed methods approach. AB - BACKGROUND: In 2010, a national integrated health care standard for (childhood) obesity was published and disseminated in the Netherlands. The aim of this study is to gain insight into the needs of health care providers and the barriers they face in terms of implementing this integrated health care standard. METHODS: A mixed-methods approach was applied using focus groups, semi-structured, face-to face interviews and an e-mail-based internet survey. The study's participants included: general practitioners (GPs) (focus groups); health care providers in different professions (face-to-face interviews) and health care providers, including GPs; youth health care workers; pediatricians; dieticians; psychologists and physiotherapists (survey). First, the transcripts from the focus groups were analyzed thematically. The themes identified in this process were then used to analyze the interviews. The results of the analysis of the qualitative data were used to construct the statements used in the e-mail-based internet survey. Responses to items were measured on a 5-point Likert scale and were categorized into three outcomes: 'agree' or 'important' (response categories 1 and 2), 'disagree' or 'not important'. RESULTS: Twenty-seven of the GPs that were invited (51 %) participated in four focus groups. Seven of the nine health care professionals that were invited (78 %) participated in the interviews and 222 questionnaires (17 %) were returned and included in the analysis. The following key barriers were identified with regard to the implementation of the integrated health care standard: reluctance to raise the subject; perceived lack of motivation and knowledge on the part of the parents; previous negative experiences with lifestyle programs; financial constraints and the lack of a structured multidisciplinary approach. The main needs identified were: increased knowledge and awareness on the part of both health care providers and parents/children; a social map of effective intervention; structural funding; task rearrangements; a central care coordinator and structural information feedback from the health care providers involved. CONCLUSIONS: The integrated health care standard stipulate that the care of overweight or obese children be provided using an integrated approach. The barriers and needs identified in this study can be used to define strategies to improve the implementation of the integrated health care standard pertaining to overweight and obese children in the Netherlands. PMID- 26955884 TI - Glycyrrhizic acid prevents enteritis through reduction of NF-kappaB p65 and p38MAPK expression in rat. AB - Glycyrrhizic acid has a variety of biological properties, including a protective function in the liver, and anti-inflammatory, anti-ulcer, anti-anaphylaxis, anti oxidant, immunoregulatory, antiviral and anticancer activities. The efficacy of glycyrrhizic acid can be increased when combined with other medicines. In the present study, the potential protective effects of glycyrrhizic acid against enteritis in rats, and its role in regulating anti-inflammation, anti-oxidation, angiogenic and apoptotic mechanisms were investigated using enzyme-linked immunosorbent and bicinchoninic acid assays, and reverse transcription quantitative polymerase chain reaction and western blotting analyses. Adult male Sprague-Dawley rats were injected with 20 mg/kg methotrexate (MTX) to establish enteritis. Additionally, rats with MTX-induced enteritis were peritoneally injected with 200 mg glycyrrhizic acid for 9 weeks. The current study demonstrated that glycyrrhizic acid could alleviate MTX-induced increases of tumor necrosis factor-alpha, interleukin (IL)-1beta and IL-6 levels, and raise IL 10 levels, in rats with enteritis. Treatment with glycyrrhizic acid significantly reduced D-lactate and intercellular adhesion molecule-1 gene expression (P<0.01), but did not inhibit diamine oxidase activity in MTX-induced enteritis. Pretreatment with glycyrrhizic acid significantly suppressed the promotion of p38 mitogen-activated protein kinase (p38MAPK), nuclear factor-kappaB p65 (NF-kappaB p65) protein expression, interferon-gamma protein concentration, and caspase-3 and cycloxygenase-2 activity in MTX-induced enteritis (P<0.01). The findings of the current study suggest that glycyrrhizic acid may prevent enteritis by reducing NF-kappaB p65 and p38MAPK expression levels, which may inform future therapeutic strategies for the treatment of enteritis. PMID- 26955886 TI - Trans-Atlantic exchanges have shaped the population structure of the Lyme disease agent Borrelia burgdorferi sensu stricto. AB - The origin and population structure of Borrelia burgdorferi sensu stricto (s.s.), the agent of Lyme disease, remain obscure. This tick-transmitted bacterial species occurs in both North America and Europe. We sequenced 17 European isolates (representing the most frequently found sequence types in Europe) and compared these with 17 North American strains. We show that trans-Atlantic exchanges have occurred in the evolutionary history of this species and that a European origin of B. burgdorferi s.s. is marginally more likely than a USA origin. The data further suggest that some European human patients may have acquired their infection in North America. We found three distinct genetically differentiated groups: i) the outgroup species Borrelia bissettii, ii) two divergent strains from Europe, and iii) a group composed of strains from both the USA and Europe. Phylogenetic analysis indicated that different genotypes were likely to have been introduced several times into the same area. Our results demonstrate that irrespective of whether B. burgdorferi s.s. originated in Europe or the USA, later trans-Atlantic exchange(s) have occurred and have shaped the population structure of this genospecies. This study clearly shows the utility of next generation sequencing to obtain a better understanding of the phylogeography of this bacterial species. PMID- 26955888 TI - Enhanced Electron Extraction Capability of Polymer Solar Cells via Employing Electrostatically Self-Assembled Molecule on Cathode Interfacial Layer. AB - In this paper, high-performance inverted polymer solar cells (PSCs) with a modified cathode buffer layer, titanium dioxide:polyethylenimine (TiO2:PEI), are demonstrated. The TiO2-O-PEI transport layer was fabricated by electrostatically self-assembled monolayers (ESAM) of PEI molecules. Protonated amine functional groups of PEI can combine protons (H(+)) hydrolyzing from its aqueous solution. Also, PEI could produce ESAM on the surface of hydroxylated TiO2 because of its cationic characteristics. The incorporation of the TiO2-O-PEI layer enhances the photocurrent and power conversion efficiency (PCE) due to the improved interfacial electron transport and extraction of the TiO2-O-PEI surface and the increased light absorption of the active layer. The enhanced PCE, low-cost materials, and solution process of TiO2-O-PEI buffer layers provide a promising method for highly efficient PSCs. PMID- 26955885 TI - Genome-wide association analysis identifies novel loci for chronotype in 100,420 individuals from the UK Biobank. AB - Our sleep timing preference, or chronotype, is a manifestation of our internal biological clock. Variation in chronotype has been linked to sleep disorders, cognitive and physical performance, and chronic disease. Here we perform a genome wide association study of self-reported chronotype within the UK Biobank cohort (n=100,420). We identify 12 new genetic loci that implicate known components of the circadian clock machinery and point to previously unstudied genetic variants and candidate genes that might modulate core circadian rhythms or light-sensing pathways. Pathway analyses highlight central nervous and ocular systems and fear response-related processes. Genetic correlation analysis suggests chronotype shares underlying genetic pathways with schizophrenia, educational attainment and possibly BMI. Further, Mendelian randomization suggests that evening chronotype relates to higher educational attainment. These results not only expand our knowledge of the circadian system in humans but also expose the influence of circadian characteristics over human health and life-history variables such as educational attainment. PMID- 26955887 TI - Inter-molecular beta-sheet structure facilitates lung-targeting siRNA delivery. AB - Size-dependent passive targeting based on the characteristics of tissues is a basic mechanism of drug delivery. While the nanometer-sized particles are efficiently captured by the liver and spleen, the micron-sized particles are most likely entrapped within the lung owing to its unique capillary structure and physiological features. To exploit this property in lung-targeting siRNA delivery, we designed and studied a multi-domain peptide named K-beta, which was able to form inter-molecular beta-sheet structures. Results showed that K-beta peptides and siRNAs formed stable complex particles of 60 nm when mixed together. A critical property of such particles was that, after being intravenously injected into mice, they further associated into loose and micron-sized aggregates, and thus effectively entrapped within the capillaries of the lung, leading to a passive accumulation and gene-silencing. The large size aggregates can dissociate or break down by the shear stress generated by blood flow, alleviating the pulmonary embolism. Besides the lung, siRNA enrichment and targeted gene silencing were also observed in the liver. This drug delivery strategy, together with the low toxicity, biodegradability, and programmability of peptide carriers, show great potentials in vivo applications. PMID- 26955889 TI - Identification of Human Juvenile Chondrocyte-Specific Factors that Stimulate Stem Cell Growth. AB - Although regeneration of human cartilage is inherently inefficient, age is an important risk factor for osteoarthritis. Recent reports have provided compelling evidence that juvenile chondrocytes (from donors below 13 years of age) are more efficient at generating articular cartilage as compared to adult chondrocytes. However, the molecular basis for such a superior regenerative capability is not understood. To identify the cell-intrinsic differences between juvenile and adult cartilage, we have systematically profiled global gene expression changes between a small cohort of human neonatal/juvenile and adult chondrocytes. No such study is available for human chondrocytes although young and old bovine and equine cartilage have been recently profiled. Our studies have identified and validated new factors enriched in juvenile chondrocytes as compared to adult chondrocytes including secreted extracellular matrix factors chordin-like 1 (CHRDL1) and microfibrillar-associated protein 4 (MFAP4). Network analyses identified cartilage development pathways, epithelial-mesenchymal transition, and innate immunity pathways to be overrepresented in juvenile-enriched genes. Finally, CHRDL1 was observed to aid the proliferation and survival of bone marrow-derived human mesenchymal stem cells (hMSC) while maintaining their stem cell potential. These studies, therefore, provide a mechanism for how young cartilage factors can potentially enhance stem cell function in cartilage repair. PMID- 26955890 TI - Role of food-derived antioxidant agents against acetaminophen-induced hepatotoxicity. AB - Context Acetaminophen (APAP), also known as paracetamol and N-acetyl p aminophenol, is one of the most frequently used drugs for analgesic and antipyretic purposes on a worldwide basis. It is safe and effective at recommended doses but has the potential for causing hepatotoxicity and acute liver failure (ALF) with overdose. To solve this problem, different strategies have been developed, including the use of compounds isolated from food, which have been studied to characterize their efficacy as natural dietary antioxidants. Objective The objective of this study is to show the beneficial effects of a variety of natural compounds and their use against acetaminophen-induced hepatotoxicity. Methods PubMed database was reviewed to compile data about natural compounds with hepatoprotective effects against APAP toxicity. Results and conclusion As a result, the health-promoting properties of 13 different food derived compounds with protective effect against APAP-induced hepatotoxicity were described as well as the mechanisms involved in hepatoprotection. PMID- 26955892 TI - The association of platelets with failed patent ductus arteriosus closure after a primary course of indomethacin or ibuprofen: a systematic review and meta analysis. AB - OBJECTIVE: To conduct a meta-analysis of the association of platelet counts and pharmacotherapeutic failure in preterms with a patent ductus arteriosus (PDA). METHODS: MEDLINE, Embase, Science Citation Index, abstracts and conference proceedings were searched, and principal authors contacted. Included studies reported indomethacin or ibuprofen use for PDA closure, compared a group which failed treatment versus a group which did not and reported the association between platelet counts and indomethacin or ibuprofen failure. Two reviewers independently screened results and assessed methodological quality using the Newcastle-Ottawa Scale. Results are expressed as mean difference in platelet counts and summary odds ratios (OR) using a random effects model. RESULTS: 1105 relevant studies were identified; eight involving 1087 preterms were included. Platelet counts were significantly lower in infants who failed pharmacotherapy (Meandifference:-30.88 * 109/L; 95% CI:-45.69 * 109,-16.07 * 109/L; I2 = 24%; pheterogeneity = 0.24). Similar results were obtained based on either pharmacotherapeutic agent. Treatment failure was also significantly associated with pre-treatment thrombocytopenia (summary OR:1.75; 95% CI:1.23-2.49, I2 = 36%, pheterogeneity = 0.20). CONCLUSIONS: Platelet counts are significantly lower in preterms who fail primary treatment for PDA. Pre-treatment thrombocytopenia is associated with higher odds of failure. Further cohort studies reporting platelet counts in prostaglandin inhibitor failure are needed for meta-analyses to firmly establish or refute a stronger association. PMID- 26955891 TI - Lung ventilation strategies for acute respiratory distress syndrome: a systematic review and network meta-analysis. AB - To identify the best lung ventilation strategy for acute respiratory distress syndrome (ARDS), we performed a network meta-analysis. The Cochrane Central Register of Controlled Trials, EMBASE, MEDLINE, CINAHL, and the Web of Science were searched, and 36 eligible articles were included. Compared with higher tidal volumes with FiO2-guided lower positive end-expiratory pressure [PEEP], the hazard ratios (HRs) for mortality were 0.624 (95% confidence interval (CI) 0.419 0.98) for lower tidal volumes with FiO2-guided lower PEEP and prone positioning and 0.572 (0.34-0.968) for pressure-controlled ventilation with FiO2-guided lower PEEP. Lower tidal volumes with FiO2-guided higher PEEP and prone positioning had the greatest potential to reduce mortality, and the possibility of receiving the first ranking was 61.6%. Permissive hypercapnia, recruitment maneuver, and low airway pressures were most likely to be the worst in terms of all-cause mortality. Compared with higher tidal volumes with FiO2-guided lower PEEP, pressure-controlled ventilation with FiO2-guided lower PEEP and lower tidal volumes with FiO2-guided lower PEEP and prone positioning ventilation are associated with lower mortality in ARDS patients. Lower tidal volumes with FiO2 guided higher PEEP and prone positioning ventilation and lower tidal volumes with pressure-volume (P-V) static curve-guided individual PEEP are potential optimal strategies for ARDS patients. PMID- 26955893 TI - Autosomal recessive MFN2-related Charcot-Marie-Tooth disease with diaphragmatic weakness: Case report and literature review. AB - Pathogenic variants in the mitofusin 2 gene (MFN2) are the most common cause of autosomal dominant Charcot-Marie-Tooth (CMT2) disease, which is typically characterized by axonal sensorimotor neuropathy. We report on a 7-month-old white female with hypotonia, motor delay, distal weakness, and motor/sensory axonal neuropathy in which next-generation sequencing analysis identified compound heterozygous pathogenic variants (c.2054_2069_1170del and c.392A>G) in MFN2. A review of the literature reveals that sporadic and familial cases of compound heterozygous or homozygous pathogenic MFN2 variants have been infrequently described, which indicates that MFN2 can also be inherited in a recessive manner. This case highlights several clinical findings not typically associated with MFN2 pathogenic variants, including young age of onset and rapidly progressing diaphragmatic paresis that necessitated tracheostomy and mechanical ventilation, and adds to the growing list of features identified in autosomal recessive MFN2 related CMT2. Our patient with MFN2-related CMT2 expands the clinical and mutational spectrum of individuals with autosomal recessive CMT2 and identifies a new clinical feature that warrants further observation. (c) 2016 Wiley Periodicals, Inc. PMID- 26955894 TI - Anti-predator behaviour of adult red-legged partridge (Alectoris rufa) tutors improves the defensive responses of farm-reared broods. AB - The aim of this work was to improve natural anti-predator behaviour of farm reared gamebirds. We evaluated the anti-predator behaviour of reared red-legged partridge Alectoris rufa chicks kept in brooder houses in large groups (>350 chicks), trained and not trained by parent red-legged partridges acting as experienced tutors. The experiment consisted of two conditioned tests (a raptor model and a human) and two control tests, which were conducted during three consecutive phases of life (1-4, 15-17 and 30-32 d after hatching). The motor anti-predator behaviour, its duration, the intensity of response in chicks and alarm calls elicited by adults were recorded. Tutors elicited aerial alarm calls (76% of tests) and showed prolonged crouching (59% of tests) in response to the raptor model whereas uttering the ground alarm call (73% of tests) and showing vigilance behaviour (78% of tests) was the main pattern during the human test. Trained and not trained chicks showed similar motor behaviour in response to the raptor model (crouching) and the human test (escaping), but frequency of strong responses (all chicks responding) from chicks trained with tutors was double that of chicks trained without them, and chicks trained with tutors showed a higher frequency of long responses (41-60 s). This study indicates that anti-predator training programmes before release may improve behaviour of farm-reared partridges which may confer benefits to survival of birds. PMID- 26955896 TI - Fe3 O4 Anisotropic Nanostructures in Hydrogels: Efficient Catalysts for the Rapid Removal of Organic Dyes from Wastewater. AB - Fe3 O4 anisotropic nanostructures that exhibit excellent catalytic performance are rarely used to catalyze Fenton-like reactions because of the inevitable drawbacks resulting from traditional preparation methods. In this study, a facile, nontoxic, water-based approach is developed for directly regulating a series of anisotropic morphologies of Fe3 O4 nanostructures in a hydrogel matrix. In having the advantages of both the catalytic activity of Fe3 O4 and the adsorptive capacity of an anionic polymer network, the hybrid nanocomposites have the capability to effect the rapid removal of cationic dyes, such as methylene blue, from water samples. Perhaps more interestingly, hybrid nanocomposites loaded with Fe3 O4 nanorods exhibit the highest catalytic activity compared to those composed of nanoneedles and nanooctahedra, revealing the important role of nanostructure morphology. By means of scanning electrochemical microscopy, it is revealed that Fe3 O4 nanorods can efficiently catalyze H2 O2 decomposition and thus generate more free radicals ((.) OH, (.) HO2 ) for methylene blue degradation, which might account for their high catalytic activity. PMID- 26955897 TI - An unusual presentation of dermatofibrosarcoma protuberans with pleomorphic sarcomatous transformation: potential pitfall and diagnostic strategy. AB - Dermatofibrosarcoma protuberans (DFSP) is a low grade, superficial sarcoma characterized by a proliferation of monomorphous, spindle cells arranged in a storiform pattern and infiltrating the subcutaneous tissue. The tumor is typically CD34 positive, and shows the characteristic COL1A1-PDGFB fusion gene, detectable either by florescent in situ hybridization (FISH) and polymerase chain reaction (PCR). We describe a case of DFSP with a focus of peculiar pleomorphic sarcomatous transformation. The focus constituted the entire bioptic tissue that was initially excised, raising considerable diagnostic problems for pathologist. The use of FISH as an ancillary technique allowed the right diagnosis. PMID- 26955898 TI - Actinic keratosis: correlation between clinical and histological classification systems. AB - BACKGROUND: There are several clinical and histological classification systems for grading actinic keratosis (AK) lesions. The Olsen clinical classification scheme grades AK lesions according to their thickness and degree of hyperkeratosis (grades 1-3). The Roewert-Huber histological classification system grades AK lesions based on the extent of epidermal atypical keratinocytes (AK I III). OBJECTIVE: The aim of this study was to determine whether there is a correlation between these clinical and histological AK classification schemes. METHODS: One AK lesion from patients in three pivotal clinical studies and routine practice was assessed clinically and histologically. A match in grading was defined as Olsen grade 1 being classified histologically as AK I, Olsen grade 2 as AK II and Olsen grade 3 as AK III. RESULTS: Of the 892 lesions included, 29.0% were classified as Olsen grade 1, 59.6% as Olsen grade 2 and 11.3% as Olsen grade 3; 19.2% were histologically classified as AK I, 69.6% as AK II and 11.2% as AK III. Only 480 lesions (53.8%) had a matching clinical and histological classification. Of these matches, most were 'Olsen grade 2 = AK II' (83.1%). The Spearman's rank correlation coefficient for clinical and histological classification was r = 0.0499 (P = 0.137). CONCLUSIONS: Clinical classification of AK lesions using the system of Olsen does not accurately match histological classification of the same lesions using the system of Roewert-Huber. Consequently, it is not possible to draw conclusions about the histology of AK lesions from their clinical appearance. This finding reinforces the need to treat all AK lesions as well as field cancerization. PMID- 26955895 TI - Effects of a mindfulness-based weight loss intervention in adults with obesity: A randomized clinical trial. AB - OBJECTIVE: To determine whether adding mindfulness-based eating and stress management practices to a diet-exercise program improves weight loss and metabolic syndrome components. METHODS: In this study 194 adults with obesity were randomized to a 5.5-month program with or without mindfulness training and identical diet-exercise guidelines. Intention-to-treat analyses with multiple imputation were used for missing data. The primary outcome was 18-month weight change. RESULTS: Estimated effects comparing the mindfulness to control arm favored the mindfulness arm in (a) weight loss at 12 months, -1.9 kg (95% CI: 4.5, 0.8; P = 0.17), and 18 months, -1.7 kg (95% CI: -4.7, 1.2; P = 0.24), though not statistically significant; (b) changes in fasting glucose at 12 months, -3.1 mg/dl (95% CI: -6.3, 0.1; P = 0.06), and 18 months, -4.1 mg/dl (95% CI: -7.3, 0.9; P = 0.01); and (c) changes in triglyceride/HDL ratio at 12 months, -0.57 (95% CI: -0.95, -0.18; P = 0.004), and 18 months, -0.36 (95% CI: -0.74, 0.03; P = 0.07). Estimates for other metabolic risk factors were not statistically significant, including waist circumference, blood pressure, and C-reactive protein. CONCLUSIONS: Mindfulness enhancements to a diet-exercise program did not show substantial weight loss benefit but may promote long-term improvement in some aspects of metabolic health in obesity that requires further study. PMID- 26955899 TI - Between- and within-site variability of fMRI localizations. AB - This study provides first data about the spatial variability of fMRI sensorimotor localizations when investigating the same subjects at different fMRI sites. Results are comparable to a previous patient study. We found a median between site variability of about 6 mm independent of task (motor or sensory) and experimental standardization (high or low). An intraclass correlation coefficient analysis using data quality measures indicated a major influence of the fMRI site on variability. In accordance with this, within-site localization variability was considerably lower (about 3 mm). We conclude that the fMRI site is a considerable confound for localization of brain activity. However, when performed by experienced clinical fMRI experts, brain pathology does not seem to have a relevant impact on the reliability of fMRI localizations. Hum Brain Mapp 37:2151 2160, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26955900 TI - An easy and effective method for synthesis and radiolabelling of risedronate as a model for bone imaging. AB - This study aimed to provide an easy method for synthesis of 1-hydroxy-2-(3 pyridyl) ethylidene bisphosphonic acid monosodium (sod. risedronate) with a high yield of 71%. The synthesized risedronate was labeled with technetium-99 m using two different reducing agents (SnCl2 .2H2 O and NaBH4 ) where NaBH4 gave stable complex and higher radiochemical yield more than SnCl2 .2H2 O. The results showed that, the radiochemical purity of (99m) Tc(NaBH4 )-risedronate was 99.2 +/- 0.6% and its stability was up to 6 h. Biodistribution study showed high uptake and long retention of (99m) Tc(NaBH4 )-risedronate in bone starting from 15 min (29 +/- 2.5% ID/organ) up to 4 h (35.1 +/- 3.2 ID/organ) post injection. This research could introduce an easy and effective method for synthesis and labeling of risedrionate and affording a good tracer for bone imaging. PMID- 26955859 TI - Cause of Death and Predictors of All-Cause Mortality in Anticoagulated Patients With Nonvalvular Atrial Fibrillation: Data From ROCKET AF. AB - BACKGROUND: Atrial fibrillation is associated with higher mortality. Identification of causes of death and contemporary risk factors for all-cause mortality may guide interventions. METHODS AND RESULTS: In the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) study, patients with nonvalvular atrial fibrillation were randomized to rivaroxaban or dose-adjusted warfarin. Cox proportional hazards regression with backward elimination identified factors at randomization that were independently associated with all-cause mortality in the 14 171 participants in the intention to-treat population. The median age was 73 years, and the mean CHADS2 score was 3.5. Over 1.9 years of median follow-up, 1214 (8.6%) patients died. Kaplan-Meier mortality rates were 4.2% at 1 year and 8.9% at 2 years. The majority of classified deaths (1081) were cardiovascular (72%), whereas only 6% were nonhemorrhagic stroke or systemic embolism. No significant difference in all cause mortality was observed between the rivaroxaban and warfarin arms (P=0.15). Heart failure (hazard ratio 1.51, 95% CI 1.33-1.70, P<0.0001) and age >=75 years (hazard ratio 1.69, 95% CI 1.51-1.90, P<0.0001) were associated with higher all cause mortality. Multiple additional characteristics were independently associated with higher mortality, with decreasing creatinine clearance, chronic obstructive pulmonary disease, male sex, peripheral vascular disease, and diabetes being among the most strongly associated (model C-index 0.677). CONCLUSIONS: In a large population of patients anticoagulated for nonvalvular atrial fibrillation, ~7 in 10 deaths were cardiovascular, whereas <1 in 10 deaths were caused by nonhemorrhagic stroke or systemic embolism. Optimal prevention and treatment of heart failure, renal impairment, chronic obstructive pulmonary disease, and diabetes may improve survival. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov/. Unique identifier: NCT00403767. PMID- 26955901 TI - Rapamycin-associated lymphoedema in an infant with Kasabach-Merritt phenomenon. PMID- 26955902 TI - Clinical monitoring of smooth surface enamel lesions using CP-OCT during nonsurgical intervention. AB - INTRODUCTION: Studies have shown that cross-polarization optical coherence tomography (CP-OCT) can be used to image the internal structure of carious lesions in vivo. The objective of this study was to show that CP-OCT can be used to monitor changes in the internal structure of early active carious lesions on smooth surfaces during non-surgical intervention with fluoride. METHODS: Lesions on the smooth surfaces of teeth were imaged using CP-OCT on 17 test subjects. Lesion structural changes were monitored during fluoride varnish application at 6 week intervals for 30 weeks. The lesion depth (Ld ), integrated reflectivity (DeltaR), and surface zone thickness (Sz ) were monitored. RESULTS: A distinct transparent surface zone that may be indicative of lesion arrestment was visible in CP-OCT images on 62/63 lesions before application of fluoride varnish. The lesion depth and internal structure were resolved for all the lesions. The overall change in the mean values for Ld , DeltaR, and Sz for all the lesions was minimal and was not significant during the study (P > 0.05). Only 5/63 lesions manifested a significant increase in Sz during intervention. CONCLUSION: Even though it appears that most of the lesions manifested little change with fluoride varnish application in the 30 weeks of the study, CP-OCT was able to measure the depth and internal structure of all the lesions including the thickness of the important transparent surface zone located at the surface of the lesions, indicating that CP-OCT is ideally suited for monitoring lesion severity in vivo. Lasers Surg. Med. 48:915-923, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26955904 TI - Effect of acute high-intensity exercise in normobaric hypoxia on Thoroughbred skeletal muscle. AB - BACKGROUND: We examined the effect of transient hypoxic exposure during high intensity exercise on satellite cell activation and angiogenesis in Thoroughbred skeletal muscle. METHODS: Six Thoroughbreds horses (6.3+/-0.8 years old) ran on a treadmill in normoxia (N; FIO2=21%) and hypoxia (H; FIO2=16%) at the same speed for the same duration, and oxygen consumption and plasma lactate and hemoglobin concentrations were measured. In addition, muscle biopsy samples were obtained from gluteus medius muscle before exercise and immediately, 4 hours, 24 hours, 3 days and 7 days after exercise, and immunohistochemical analysis and relative quantitative analysis of mRNA expression using real-time RT-PCR were performed. RESULTS: Oxygen consumption during exercise in H was 29% lower than that in N, and plasma lactate concentration in H was 47% higher than that in N. The mRNA expressions of satellite cell activation-related factors slightly increased, but the mRNA expressions of factors related to angiogenesis and mitochondrial biogenesis slightly decreased. Fluorescence-stained basal lamina evaluation in stacked images 7 days after exercise showed no difference in capillary density between the two groups. CONCLUSIONS: These results suggest that transient hypoxic exposure during exercise increases the contribution of the glycolytic energy supply and promotes satellite cell activation, but does not facilitate angiogenesis and mitochondrial biogenesis. PMID- 26955903 TI - Relation between glenohumeral internal rotation deficit and valgus laxity of the elbow in high school baseball pitchers. AB - BACKGROUND: There are few literatures describing the association between glenohumeral internal rotation deficits (GIRD) and valgus laxity of the elbow on the throwing side of high school pitchers with and without a history of elbow symptom. METHODS: The passive range of motion of glenohumeral internal and external rotation on bilateral side shoulders was measured in 75 high-school baseball pitchers during the preseason. Using ultrasonography, the width of the ulnohumeral joint of the elbow was measured at 30 degrees of flexion, both at rest and with valgus stress in the pitching side. Comparisons of glenohumeral internal rotation deficits and the difference between the width of ulnohumeral joint space with and without valgus stress on the throwing side were made between 75 high-school pitchers with and without a history of elbow symptom. RESULTS: Participants with a history of elbow symptom exhibited a greater difference between the width of ulnohumeral joint with and without valgus stress in the throwing side than participants with no history of elbow symptom (P<0.05). No difference in glenohumeral internal rotation deficits was found in participants with and without a history of elbow symptom. In all participants, significant association was found between glenohumeral internal rotation deficits on the pitching side and the difference from the width of the ulnohumeral joint with and without valgus stress (P=0.04, r=0.23). CONCLUSIONS: Elbow valgus instability was associated with elbow joint pain in high-school pitchers. Although GIRD was not significantly different between the two groups, GIRD and elbow valgus instability might be related to the throwing side in high-school pitchers. PMID- 26955905 TI - Distribution of plantar pressure during jogging barefoot or in minimalistic shoes in people who used to run in cushioned shoes. AB - BACKGROUND: In recent years, an increasing number of runners prefer jogging barefoot or in minimalistic shoes. The aim of this study was to compare the distribution of plantar pressure during jogging barefoot, in minimalistic shoes, or in shoes with cushioned soles, as these forces modulate the risk of injury. METHODS: The study included nine men aged between 24 and 25 years, who engaged in long-distance running. The plantar pressure of three foot zones (forefoot, midfoot, and hindfoot) was examined with WIN-POD electronic podometer during running barefoot, in minimalistic shoes, or in shoes with cushioned soles. RESULTS: Individuals who ran barefoot showed the greatest forefoot pressure, followed by those running in minimalistic shoes and cushioned shoes. In contrast, the heel pressure in individuals running in cushioned shoes was significantly greater than in those using minimalistic shoes or running barefoot. CONCLUSIONS: Switching from running in cushioned shoes to jogging barefoot is associated with the accumulation of greatest pressure in the forefoot and midfoot. The accumulation of the greatest pressure at the insertion of plantar aponeurosis can lead to the injuries of musculoskeletal system, in particular plantar aponeurositis. Even distribution of pressure among various parts of the foot in persons running in minimalistic shoes is associated with lower risk of injury than in the case of running barefoot. PMID- 26955906 TI - A pilot lifestyle intervention study: effects of an intervention using an activity monitor and Twitter on physical activity and body composition. AB - BACKGROUND: This pilot study aimed to examine the effects of a lifestyle intervention comprising an activity monitor and the concurrent use of Twitter, on physical activity (PA) and body composition. METHODS: Seventeen healthy volunteers (36+/-3 years) were randomly assigned to normal (N, N.=8) or Twitter (T, N.=9) intervention groups for six weeks. Participants in both groups wore an activity monitor but those in the T group also tweeted daily about their PA. An observer read the tweets from each participant and provided feedback. Body composition was determined using bioelectrical impedance analysis before and after the intervention. RESULTS: Significantly more daily steps and PA at an intensity of >=3 metabolic equivalents (METs) were recorded by the T than the N during six weeks. The number of steps and PA did not significantly change over time in the N, but significantly increased in the T from weeks one to six (8170+/ 1130 to 12,934+/-1400 steps/day and 2.6+/-0.5 to 5.0+/-0.8 METs.h/day). In addition, significantly more body fat was lost in the T, than in the N (-1.1+/ 0.2 vs. -0.1+/-0.3 kg), and the changes in PA significantly correlated with the changes in body fat (r=-0.713). CONCLUSIONS: Lifestyle intervention can increase daily PA and reduce body fat more effectively when using an activity monitor and Twitter than an activity monitor alone. PMID- 26955908 TI - Speciation of nanoscale objects by nanoparticle imprinted matrices. AB - The toxicity of nanoparticles is not only a function of the constituting material but depends largely on their size, shape and stabilizing shell. Hence, the speciation of nanoscale objects, namely, their detection and separation based on the different species, similarly to heavy metals, is of outmost importance. Here we demonstrate the speciation of gold nanoparticles (AuNPs) and their electrochemical detection using the concept of "nanoparticles imprinted matrices" (NAIM). Negatively charged AuNPs are adsorbed as templates on a conducting surface previously modified with polyethylenimine (PEI). The selective matrix is formed by the adsorption of either oleic acid (OA) or poly(acrylic acid) (PAA) on the non-occupied areas. The AuNPs are removed by electrooxidation to form complementary voids. These voids are able to recognize the AuNPs selectively based on their size. Furthermore, the selectivity could be improved by adsorbing an additional layer of 1-hexadecylamine, which deepened the voids. Interestingly, silver nanoparticles (AgNPs) were also recognized if their size matched those of the template AuNPs. The steps in assembling the NAIMs and the reuptake of the nanoparticles were characterized carefully. The prospects for the analytical use of NAIMs, which are simple, of small dimension, cost-efficient and portable, are in the sensing and separation of nanoobjects. PMID- 26955907 TI - Neoadjuvant chemotherapy does not impair liver regeneration following hepatectomy or portal vein embolization for colorectal cancer liver metastases. AB - BACKGROUND AND OBJECTIVES: Treatment strategies for colorectal cancer liver metastasis (CRCLM) such as major hepatectomy and portal vein embolization (PVE) rely on liver regeneration. We aim to investigate the effect of neoadjuvant chemotherapy on liver regeneration occurring after PVE and after major hepatectomy. METHODS: CRCLM patients undergoing PVE or major resection were identified retrospectively from our database. Liver regeneration data (expressed as future liver remnant [FLR] and percentage of liver regeneration [%LR]), total liver volume (TLV) and clinical characteristics were collected. RESULTS: Between 2003 and 2013, 226 patients were included (85 major resection, 141 PVE). The median chemotherapy cycles was six in both groups. The median time interval between the last chemotherapy and the intervention was 51 days in the PVE group and 79 days in the hepatectomy group. In the PVE group, chemotherapy was not associated with altered liver regeneration (number of cycles [P = 0.435], timing [P = 0.563], or chemotherapy agent [P = 0.116]). Similarly in the major hepatectomy group, preoperative chemotherapy (number of cycles [P = 0.114]; agent [P = 0.061], timing [P = 0.126]) were not significantly associated with differences in liver regeneration (P = 0.592). In both groups, the predicted FLR% was inversely correlated with the %LR (P < 0.001). CONCLUSION: Chemotherapy does not affect liver regeneration following PVE or major resection. J. Surg. Oncol. 2016;113:449-455. (c) 2016 Wiley Periodicals, Inc. PMID- 26955909 TI - Nanostructural evolution of one-dimensional BaTiO3 structures by hydrothermal conversion of vertically aligned TiO2 nanotubes. AB - The use of TiO2 nanotube (NT) arrays as templates for hydrothermal conversion of one-dimensional barium titanate (BaTiO3) structures is considered a promising synthesis approach, even though the formation mechanisms are not yet fully understood. Herein we report a nanostructural study by means of XRD and (HR)TEM of high aspect ratio TiO2-NTs hydrothermally converted into BaTiO3. The nanostructure shows two different and well-defined regions: at the top the conversion involves complete dissolution of NTs and subsequent precipitation of BaTiO3 crystals by homogeneous nucleation, followed by the growth of dendritic structures by aggregation and oriented attachment mechanisms. Instead, at the bottom, the low liquid/solid ratio, due to the limited amount of Ba solution that infiltrates the NTs, leads to the rapid crystallization of such a solution into BaTiO3, thus allowing the NTs to act as a template for the formation of highly oriented one-dimensional nanostructures. The in-depth analysis of the structural transformations that take place during the formation of the rod-like arrays of BaTiO3 could help elucidate the conversion mechanism, thus paving the way for the optimization of the synthesis process in view of new applications in energy harvesting devices, where easy and low temperature processing, controlled composition, morphology and functional properties are required. PMID- 26955910 TI - The unique axon trajectory of the accessory nerve is determined by intrinsic properties of the neural tube in the avian embryo. AB - The accessory nerve is a cranial nerve, composed of only motor axons, which control neck muscles. Its axons ascend many segments along the lateral surface of the cervical spinal cord and hindbrain. At the level of the first somite, they pass ventrally through the somitic mesoderm into the periphery. The factors governing the unique root trajectory are unknown. Ablation experiments at the accessory nerve outlet points have shown that somites do not regulate the trajectory of the accessory nerve fibres. Factors from the neural tube that may control the longitudinal pathfinding of the accessory nerve fibres were tested by heterotopic transplantations of an occipital neural tube to the cervical and thoracic level. These transplantations resulted in a typical accessory nerve trajectory in the cervical and thoracic spinal cord. In contrast, cervical neural tube grafts were unable to give rise to the typical accessory nerve root pattern when transplanted to occipital level. Our results show that the formation of the unique axon root pattern of the accessory nerve is an intrinsic property of the neural tube. PMID- 26955911 TI - The use of cyclooxygenase-2 inhibitors for improvement of efficacy of radiotherapy in cancers. AB - Cyclooxygenase-2 (COX-2) is overexpressed in cancer cells and is associated with carcinogenesis and maintenance of progressive tumour growth as well as resistance of cancer cells to ionising radiation (IR). COX-2 inhibitors can attenuate tumour growth and expression of markers of cell proliferation as well as induce apoptosis in tumour cells. These agents can have a synergistic effect with IR in the killing of cancer cells. In this review, we discuss the rational basis and molecular mechanisms regarding the usefulness of COX-2 inhibitors in cancer therapy, and also their potential role in increasing the therapeutic index of chemoradiation by protecting normal cells and sensitising tumour cells to radiotherapy. PMID- 26955913 TI - Does early communication mediate the relationship between motor ability and social function in children with cerebral palsy? AB - BACKGROUND: Children diagnosed with neurodevelopmental conditions such as cerebral palsy (CP) are at risk of experiencing restrictions in social activities negatively impacting their subsequent social functioning. Research has identified motor and communication ability as being unique determinants of social function capabilities in children with CP, to date, no research has investigated whether communication is a mediator of the relationship between motor ability and social functioning. AIMS: To investigate whether early communication ability at 24 months corrected age (ca.) mediates the relationship between early motor ability at 24 months ca. and later social development at 60 months ca. in a cohort of children diagnosed with cerebral palsy (CP). METHOD: A cohort of 71 children (43 male) diagnosed with CP (GMFCS I=24, 33.8%, II=9, 12.7%, III=12, 16.9%, IV=10, 14.1%, V=16, 22.5%) were assessed at 24 and 60 months ca. Assessments included the Gross Motor Function Measure (GMFM), the Communication and Symbolic Behaviour Scales-Developmental Profile (CSBS-DP) Infant-Toddler Checklist and the Paediatric Evaluation of Disability Inventory (PEDI). A mediation model was examined using bootstrapping. RESULTS: Early communication skills mediated the relationship between early motor abilities and later social functioning, b=0.24 (95% CI=0.08-0.43 and the mediation model was significant, F (2, 68)=32.77, p<0.001, R(2)=0.49. CONCLUSIONS AND IMPLICATION: Early communication ability partially mediates the relationship between early motor ability and later social function in children with CP. This demonstrates the important role of early communication in ongoing social development. Early identification of communication delay and enriched language exposure is crucial in this population. PMID- 26955912 TI - Evaluation of group versus individual physiotherapy following lower limb intra muscular Botulinum Toxin-Type A injections for ambulant children with cerebral palsy: A single-blind randomized comparison trial. AB - This study aimed to evaluate efficacy of group (GRP) versus individual (IND) physiotherapy rehabilitation following lower limb intramuscular injections of Botulinum Toxin-Type A (BoNT-A) for ambulant children with cerebral palsy (CP). Following lower limb BoNT-A injections, 34 children were randomly allocated to GRP (n=17; mean age 7y8m SD 2.0; 13 males; Gross Motor Function Classification System (GMFCS) I=5, II=8, III=4) or IND physiotherapy (n=17; mean age 8y7m SD 2.0; 11 males; GMFCS I=9, II=5, III=3). Primary outcomes were the Canadian Occupational Performance Measure (COPM) and Edinburgh Visual Gait Score (EVGS) assessed at baseline, 10 and 26 weeks post intervention. There were no baseline differences between groups. GRP intervention had greater, but not clinically meaningful, improvement in COPM satisfaction (estimated mean difference EMD 1.7, 95% CI 0.4-3.1; p<0.01) at 26 weeks. Both groups demonstrated clinically significant improvements in COPM performance and satisfaction, but minimal change in quality of gait (EVGS). Six hours of direct physiotherapy (either GRP or IND) with an additional indirect dose (median 16 episodes) of individualized home programme activities following lower limb BoNT-A injections, however, was inadequate to drive clinically meaningful changes in lower limb motor outcomes. PMID- 26955914 TI - Part C early intervention utilization in preterm infants: Opportunity for referral from a NICU follow-up clinic. AB - OBJECTIVE: Early Intervention (EI) services promote development for preterm infants. In the state of Illinois, Child and Family Connections (CFC) is the intake agency that determines qualification for EI services. In Illinois, all extremely low birth weight (ELBW) infants are eligible for and referred to CFC at discharge from the Neonatal Intensive Care Unit (NICU). This study investigated: (1) patterns of CFC and EI enrollment, and; (2) predictors of CFC enrollment, need for CFC referral, and high EI therapy use among preterm infants seen in a NICU follow-up clinic. METHODS: 405 preterm infants, including 169 ELBW infants, were seen in a NICU follow-up clinic at 4-, 8- and 20-months corrected age. CFC/EI data were collected at each visit. Multiple regression analyses adjusted for the effect of medical, sociodemographic and neurodevelopmental risk factors on CFC/EI outcome. RESULTS: Despite the high rate of EI utilization and routine care by primary pediatricians, up to 28% of ELBW infants required a CFC referral from a NICU follow-up clinic. Medical and neurodevelopmental risk factors were associated with CFC enrollment while medical, sociodemographic and neurodevelopmental risk factors were associated with need for CFC referral. CONCLUSION: NICU follow-up clinics facilitate appropriate CFC/EI services for preterm infants. PMID- 26955915 TI - [Tobacco dependence treatment guidelines]. AB - Tobacco dependence causes every sixth death in the Czech Republic and is associated with diseases of the whole body. Treatment of tobacco dependence should be a standard part of clinical care to the extent of time available--from brief intervention at each clinical contact with patients up to intensive treatment. It includes psycho-socio-behavioural support and pharmacotherapy. It should apply to all professions in clinical medicine--as recommended by WHO mainly doctors, nurses, pharmacists and dentists, and should be covered within health care systems. Economically, it is one of the most cost-effective interventions in medicine. In our population over 15 years about 30% smokes (about 2.2 million people), diagnosis F17 relates to approximately 1.75 million people (about 80% of smokers). PMID- 26955916 TI - Polaronic effects at finite temperatures in the B850 ring of the LH2 complex. AB - Energy transfer and relaxation dynamics in the B850 ring of LH2 molecular aggregates are described, taking into account the polaronic effects, by a stochastic time-dependent variational approach. We explicitly include the finite temperature effects in the model by sampling the initial conditions of the vibrational states randomly. This is in contrast to previous applications of the variational approach, which consider only the zero-temperature case. The method allows us to obtain both the microscopic dynamics at the single-wavefunction level and the thermally averaged picture of excitation relaxation over a wide range of temperatures. Spectroscopic observables such as temperature dependent absorption and time-resolved fluorescence spectra are calculated. Microscopic wavefunction evolution is quantified by introducing the exciton participation (localization) length and the exciton coherence length. Their asymptotic temperature dependence demonstrates that the environmental polaronic effects range from exciton self-trapping and excitonic polaron formation at low temperatures to thermally induced state delocalization and decoherence at high temperatures. While the transition towards the polaronic state can be observed on the wavefunction level, it does not produce a discernible effect on the calculated spectroscopic observables. PMID- 26955918 TI - Chemical signals might mediate interactions between females and juveniles of Latrodectus geometricus (Araneae: Theridiidae). AB - Studies related to communication on spiders show that, as in other invertebrates, the interactions between conspecifics are also made through chemical signals. Therefore, in order to assess whether the composition of cuticular compounds might be involved in interactions that occur during the days after the emergence of juveniles in Latrodectus geometricus, we conducted behavioral and cuticular chemical profiles analysis of females and juveniles of different ages. The results show that females, regardless of their reproductive state, tolerate juveniles of other females with up to 40 days post-emergence and attack juveniles of 80 days post-emergence. Cuticlar chemical analysis shows that while the profile of juveniles is similar to adult's profile, they can remain in the web without being confused with threat or prey. Also, cuticular chemical profiles vary between different populations probably due to genetic and environmental differences or similarities between them. Finally, females in incubation period are able to detect the presence of eggs within any egg sac, but cannot distinguish egg sacs produced by conspecifics from the ones they had produced. PMID- 26955919 TI - Oxatub[4]arene: a molecular "transformer" capable of hosting a wide range of organic cations. AB - The molecular "transformer", oxatub[4]arene, was found to be able to host a wide range of organic cations. The strong binding ability is believed to originate from its four interconvertible and deep-cavity conformers. The binding behavior of such adaptable receptors may provide implications for molecular recognition in nature. PMID- 26955917 TI - Childhood exposure to polybrominated diphenyl ethers and neurodevelopment at six years of age. AB - Mixtures of polybrominated diphenyl ethers (PBDEs) are present in indoor environments. Studies of the developmental effects of exposure to these chemicals in large prospective mother-child cohorts are required, with data on prenatal exposure and long-term follow-up of the children. We aimed to investigate the relationship between prenatal and childhood exposure to PBDEs and neurodevelopment at the age of six years. We determined the levels of PBDEs and other neurotoxicants in cord blood and dust collected from the homes of children for 246 families included in the PELAGIE mother-child cohort in France. We assessed two cognitive domains of the six-year-old children using the Wechsler Intelligence Scale for Children-IV. Verbal comprehension scores were lower in children from homes with higher concentrations of BDE99 (betaDetects=median_vs_NonDetects=-5.4; -9.9, -1.0; p trend=0.02) and of BDE209 (beta2nd_vs_1st_tertile=-1.8; 95% CI: -6.1, 2.5; beta3rd_vs_1st_tertile=-3.2; 7.5, 1.2; p trend=0.15) in dust, particularly for boys (p trend=0.02 and 0.04, respectively). Working memory scores seemed to be lower in children with higher BDE99 concentrations in dust (p trend=0.10). No association was observed with cord blood levels of BDE209. Our findings are in agreement with those of four previous studies suggesting adverse cognitive outcomes among children associated with early-life exposure to penta-BDE mixtures, and provide new evidence for the potential neurotoxicity of BDE209. Several countries are in the process of banning the use of PBDE mixtures as flame-retardants. However, these compounds are likely to remain present in the environment for a long time to come. PMID- 26955920 TI - A comparative computational study of lithium and sodium insertion into van der Waals and covalent tetracyanoethylene (TCNE)-based crystals as promising materials for organic lithium and sodium ion batteries. AB - We present a comparative ab initio study of Li and Na insertion into molecular (van der Waals) crystals of TCNE (tetracyanoethylene) as well as in covalent Li/Na-TCNE crystals. We confirm the structure of the previously synthesized (covalent) Li-TCNE crystal and predict the existence of its Na-TCNE analogue. In the molecular crystals, we compute the maximum voltages to be 3.5 V for Li and 3.3 V for Na, with theoretical capacities of 1247 mA h g(-1) for Li and 416 mA h g(-1) for Na. In the covalent crystals, the maximum voltages are 2.2 V for Li and 2.7 V for Na, and theoretical capacities are 394 mA h g(-1) for Li and 176 mA h g(-1) for Na. Significantly, up to a capacity of 416 mA h g(-1) for both Li and Na in the molecular crystal and 197 mA h g(-1) for Li and 176 mA h g(-1) for Na in the covalent crystal, the insertion of Li and Na would not lead to reactions with common electrolytes. We show that volumetric capacities of organic electrodes need not be low compared to their inorganic counterparts, contrary to popular belief: the molecular TCNE crystal has been computed to achieve the values of 1845 mA h cm(-3) for Li and 615 mA h cm(-3) for Na, respectively. Tetracyanoethylene-based molecular and covalent crystals could therefore become efficient organic cathode and anode materials for Li and Na ion batteries. PMID- 26955922 TI - Collaborative Work or Individual Chores: The Role of Family Social Organization in Children's Learning to Collaborate and Develop Initiative. AB - In many communities, children learn about family and community endeavors as they collaborate and become involved in community activities. This chapter analyzes how parents promote collaboration and learning to collaborate at home in an Indigenous and in a non-Indigenous Mexican community. We examine variation among parents with different extent of experience with schooling and concepts regarding child development and relate these to patterns of child collaboration at home among Mexican Indigenous and urban families. Drawing on interviews with 34 mothers in the P'urhepecha community of Cheran, Michoacan, and 18 interviews in the cosmopolitan city of Guadalajara, Mexico, we argue that the social nature of participation may be a key feature of learning to collaborate and pitch in in families and communities where school has not been a central institution of childhood over generations. PMID- 26955921 TI - A Cultural Paradigm--Learning by Observing and Pitching In. AB - We discuss Learning by Observing and Pitching In (LOPI) as a cultural paradigm that provides an interesting alternative to Assembly-Line Instruction for supporting children's learning. Although LOPI may occur in all communities, it appears to be especially prevalent in many Indigenous and Indigenous-heritage communities of the Americas. We explain key features of this paradigm, previewing the chapters of this volume, which examine LOPI as it occurs in the lives of families and communities. In this introductory chapter, we focus especially on one feature of the paradigm that plays an important role in its uptake and maintenance in families, institutions, and communities-the nature of assessment. We consider the power of the dominant paradigm and the challenges in making paradigm shifts. PMID- 26955923 TI - Children's Everyday Learning by Assuming Responsibility for Others: Indigenous Practices as a Cultural Heritage Across Generations. AB - This chapter uses a comparative approach to examine the maintenance of Indigenous practices related with Learning by Observing and Pitching In in two generations- parent generation and current child generation--in a Central Mexican Nahua community. In spite of cultural changes and the increase of Western schooling experience, these practices persist, to different degrees, as a Nahua cultural heritage with close historical relations to the key value of cuidado (stewardship). The chapter explores how children learn the value of cuidado in a variety of everyday activities, which include assuming responsibility in many social situations, primarily in cultivating corn, raising and protecting domestic animals, health practices, and participating in family ceremonial life. The chapter focuses on three main points: (1) Cuidado (assuming responsibility for), in the Nahua socio-cultural context, refers to the concepts of protection and "raising" as well as fostering other beings, whether humans, plants, or animals, to reach their potential and fulfill their development. (2) Children learn cuidado by contributing to family endeavors: They develop attention and self motivation; they are capable of responsible actions; and they are able to transform participation to achieve the status of a competent member of local society. (3) This collaborative participation allows children to continue the cultural tradition and to preserve a Nahua heritage at a deeper level in a community in which Nahuatl language and dress have disappeared, and people do not identify themselves as Indigenous. PMID- 26955924 TI - Supporting Children's Initiative: Appreciating Family Contributions or Paying Children for Chores. AB - Collaborative initiative is an important aspect of Learning by Observing and Pitching In (LOPI), and many interrelated family and community practices in LOPI may support children's initiative. In this chapter, we examine two cultural ways of supporting children's helpfulness and responsibility that draw on different cultural paradigms for organizing children's participation in everyday work in U.S. Mexican-heritage and European American communities. European American university students reported having received allowances as a contractual enticement to do assigned chores. In contrast, although U.S. Mexican-heritage university students reported having received pocket money from their families, this was as a gift, noncontingent on completed chores or good behavior. They reported that this noncontingent support for children's responsibility focuses children on collaborating with the family, and contributing to shared work with initiative, consistent with LOPI, in which children are integrated in family and community endeavors and are eager to contribute. The chapter challenges traditional dichotomies in motivational theory that attempt to specify the "source" of children's motivation to learn and help within either individuals or social contexts. PMID- 26955925 TI - Adults' Orientation of Children--And Children's Initiative to Pitch In--To Everyday Adult Activities in a Tsotsil Maya Community. AB - This chapter examines how 2-year-old children attempt to actively participate in adult work in a Mayan community in Chiapas, Mexico, and how adults contribute and accommodate to the contributions. As children enter into activities and adults orient and reorient the activity to direct the children, teaching from expert to novice is generated by children's agency in co-participatory interactions. The chapter enriches the LOPI model by focusing on the structure of participation and communication, social and community organization, and the evaluation that occurs in the activity itself. PMID- 26955926 TI - Respect and Autonomy in Children's Observation and Participation in Adults' Activities. AB - This chapter examines Peruvian Quechua children's learning by observing and pitching in. The children concentrate attentively when they observe the activities of the adults and they exercise autonomy in the context of adults' encouragement of measured behaviors while always showing respectful silence in the presence of their elders. PMID- 26955927 TI - Mayan Children's Creation of Learning Ecologies by Initiative and Cooperative Action. AB - This chapter examines Mayan children's initiatives in creating their own learning environments in collaboration with others as they engage in culturally relevant endeavors of family and community life. To this end, I carry out a fine-grained ethnographic and linguistic analysis of the interactional emergence of learning ecologies. Erickson defines learning ecology as a socioecological system where participants mutually influence one another through verbal and nonverbal actions, as well as through other forms of semiotic communication (2010, 254). In analyzing learning ecologies, I adopt a "theory of action" approach, taking into account multimodal communication (e.g., talk, gesture, gaze, body positioning), participants' sociospatial organization, embodied action, objects, tools, and other culturally relevant materials brought together to build action (Goodwin, 2000, 2013; Hutchins, 1995). I use microethnographic analysis (Erickson, 1992) to bring to the surface central aspects of children's agentive roles in learning through "cooperative actions" (Goodwin, 2013) and "hands-on" experience (Ingold, 2007) the skills of competent members of their community. I examine three distinct Learning Ecologies created by children's initiatives among the Mayan children that I observed: (i) children requesting guidance to collaborate in a task, (ii) older children working on their own initiative with subsequent monitoring and correction from competent members, and (iii) children with near competence in a task with occasional monitoring and no guidance. I argue that these findings enrich and add power to models of family- and community-based learning such as Learning by Observing and Pitching In (Rogoff, 2014). PMID- 26955928 TI - Children's Avoidance of Interrupting Others' Activities in Requesting Help: Cultural Aspects of Considerateness. AB - To be able to collaborate skillfully, people need to coordinate well with others, taking into account how their actions fit with those of their partners. This is a key aspect of an approach to learning called Learning by Observing and Pitching In, hypothesized to be common in many Indigenous-heritage communities of the Americas. This chapter considers cultural values that emphasize considerateness and awareness of how one's actions impact others such as the Mexican cultural value of respeto and cultural differences in children's efforts to avoid interrupting others' activity. US Mexican-heritage children showed more evidence of avoiding interrupting the ongoing activity of an adult when they requested help, compared with European American children from families with extensive schooling experience. Most of the Mexican-heritage children's requests for help that gave evidence of avoiding interruption were made nonverbally, which may facilitate unobtrusive requests. There were no significant differences among children from two US Mexican-heritage backgrounds varying in experience with Western schooling and likely experience with Indigenous-American practices, suggesting that the Mexican cultural value of respeto and associated considerateness is widespread even among US Mexican-heritage families with extensive experience with Western schooling and life in the United States. PMID- 26955930 TI - Dia de los Muertos: Learning About Death Through Observing and Pitching In. AB - The chapter explores how young children in the state of Puebla, Mexico are socialized with respect to death by observing and pitching in during the annual celebration for dia de los muertos. This chapter focuses on observations made of children's participation in practices related to dia de los muertos and their experiences with death as explored through ethnographic interviews of preschool children and adults from the cities of Cholula and Puebla. We found that children were included in all aspects of dia de los muertos and participated by hanging out, observing, pitching in, and listening. Parents (and grandparents) viewed this active participation as crucial for children to acquire the skills and traditions necessary to be responsible adults in their culture. The current research provides new perspectives regarding the study of children and death within the field of developmental psychology by focusing on how multiple modes of participation are an integral part of young children's socialization with death. PMID- 26955929 TI - Young Children's Attention to What's Going On: Cultural Differences. AB - This chapter examines children' attention to surrounding events in which they are not directly involved, a way of learning that fits with the cultural approach of Learning by Observing and Pitching In. Research in instructional settings has found that attention to surrounding events is more common among Indigenous Guatemalan Mayan and some US Mexican-heritage children than among middle-class children from several ethnic backgrounds. We examine this phenomenon in a quasi naturalistic setting to see if the cultural variation in young children's attention to surrounding events in which they were not directly involved extends beyond instructional settings. During a home visit focused on their younger sibling, 19 Guatemalan Mayan and 18 middle-class European American 3- to 5-year olds were nearby but not addressed, as their mother helped their toddler sibling operate novel objects. The Guatemalan Mayan children more frequently attended to this nearby interaction and other third-party activities, whereas the middle class European American children more often attended to their own activities in which they were directly involved or they fussed or showed off. The results support the idea that in some Indigenous communities of the Americas where young children are included in a broad range of family and community endeavors, children may be especially inclined to attend to ongoing events, even if they are not directly involved or addressed, compared to European American children whose families have extensive experience in Western school ways. PMID- 26955931 TI - Conceptions of Educational Practices Among the Nahuas of Mexico: Past and Present. AB - Historical documents and recent fieldwork indicate that, since the sixteenth century, there is robust continuity in central beliefs about learning among Nahuatl families. Nahuatl documents from nearly five centuries ago and current Nahuatl adults consider guidance and teaching to be accompaniment of the learner, more than direct action, because nobody can enter the minds and personalities of others. Learning by observing and pitching in is valued: The adults can organize good conditions of apprenticeship, they can indicate the good direction and the goal, serve as examples, and protect the learner. Across centuries, Nahuatl educational practices consist of facilitating observation by copresence, early training for attentive engagement, hiding nothing, and not preventing children from trying, as well as persuading children to be responsible, to work, and to adopt a calm attitude for paying close attention. PMID- 26955932 TI - Learning to Inhabit the Forest: Autonomy and Interdependence of Lives from a Mbya Guarani Perspective. AB - This chapter examines the ideas of reciprocity, respect, autonomy, and interdependence of lives and the impact of these on children's learning. Using an ecological perspective that recognizes humans' relationship with other living beings that inhabit the forest, this chapter is based on ethnographic research conducted in two Mbya-Guarani communities (Argentina). Respect and reciprocity are key for children to develop as part of the community and the forest and they are related to children's well-being and health. I describe Mbya perspectives on children's growth and development, emphasizing the balance between interdependence and autonomy as complementary goals and values, providing examples of environmentally relevant skills to grow up in the forest. These skills are associated with particular ways of inhabiting the forest, including learning how to walk in it and developing entendimiento (understanding). These make possible children's integration in community life through their participation and collaboration in daily activities. I attempt to articulate these ideas with the theoretical framework of Learning by Observing and Pitching In, especially concerning ways of organizing and supporting children's learning processes in the context of their engagement with multiaged and more experienced group of people. PMID- 26955933 TI - Learning and Human Dignity Are Built Through Observation and Participation in Work. AB - This chapter focuses on how children learn through work in ongoing family and community endeavors in an Indigenous Mexican (Mixe) community, where cultural values emphasize that human dignity is derived from work and from collaboration with the work of other people, animals, and the natural world. The chapter highlights the central role that work plays in children's learning, and how attentive and more casual observation and accomplishment of endeavors are important tools that children employ in learning. PMID- 26955934 TI - Learning by Observing, Pitching in, and Being in Relations in the Natural World. AB - This chapter describes a central tenet of Indigenous American social interaction, which emphasizes mutuality in collaboration and caring in Indigenous communities. This includes interactions with an agentive natural world, in which more-than human beings act as participants in the lives of humans and vice versa. We argue that research on children's learning should take a broader view of interactional partners to include the natural world. PMID- 26955935 TI - Using History to Analyze the Learning by Observing and Pitching In Practices of Contemporary Mesoamerican Societies. AB - The analysis of Indigenous learning practices in Mexico and the United States typically relies on ethnography, oral history, and participant observation as the methodology for understanding the socialization processes of Mesoamerican societies. In this chapter, we consider the importance of using historical analysis as an added methodology for understanding the Indigenous learning practices by considering three case studies of Indigenous communities in Mexico, where a consideration of historical patterns have proven fruitful for understanding the contemporary Learning by Observing and Pitching In (LOPI) practices. These communities include the Nahua people of the state of Puebla, the P'urhepecha communities of the state of Michoacan, and the Nahua people of the Texcoco area to the southeast of Mexico City. We conclude that a consideration of the cultural patterns that have developed in Mesoamerican societies across time would benefit contemporary researchers as one component of their LOPI research. PMID- 26955936 TI - "My Teacher Is Going to Think They're Crazy": Responses to LOPI Practices in U.S. First-Grade Classrooms. AB - This chapter explores how children and adults have been responding when they watch first graders in the United States using their agency in classrooms that value and permit children to Learn by Observing and Pitching In (LOPI). First, I explore how video-cued ethnography helped to capture on film practices in classrooms that support LOPI through the Agency and Young Children Project. Then, I detail what happened when I showed these films to first-grade (age 6-8) children of Latina/o immigrants, elementary school administrators, teachers, and parents as a means to elicit ideas, perspectives, and concerns about the early education of young Latina/o children of immigrants. Findings from the initial analysis indicate that deficit views of immigrant families in the United States may prevent teachers and administrators from supporting LOPI. PMID- 26955937 TI - Learning by Observing and Pitching In and the Connections to Native and Indigenous Knowledge Systems. AB - This chapter opens a broader dialogue of Learning by Observing and Pitching-In (LOPI) with Native and Indigenous Studies, and Native and Indigenous Education, drawing particular attention to how LOPI can provide a model for better understanding Indigenous pedagogy in Indigenous Knowledge Systems (IKS). As Battiste (2002) pointed out, "Indigenous pedagogy values a person's ability to learn independently by observing, listening, participating with a minimum of intervention and instruction." Like LOPI, IKS include ways of knowing and ways of being in the world, with life-long processes and responsibilities that model competent and respectful behavior. The chapter explores similarities and differences between IKS and LOPI by analyzing each perspective's scope, defining features, and foundational origins, as well as what each contributes to our understanding of Native and Indigenous communities, especially in terms of learning and incorporation into adulthood and family and community life. PMID- 26955938 TI - Children's Participation in Ceremonial Life in Bali: Extending LOPI to Other Parts of the World. AB - This chapter extends a model of how children in Indigenous communities of the Americas Learn by Observing and Pitching In (LOPI; Rogoff, 2014) to another region of the world, by examining which aspects of the model can be applied to the ways in which Balinese children learn with their peers and adults. We describe clear parallels in the role of observation and communication, the social organization of endeavors, and children's motivation to participate as they learn the music of gamelan (the traditional orchestra) that is used in religious ceremonies. PMID- 26955939 TI - Use of an ultrathin gastroscope to guide endotracheal intubation for endoscopy. PMID- 26955940 TI - Structural effects of a carbon matrix in non-precious metal O2-reduction electrocatalysts. AB - Developing non-precious metal electrocatalysts (NPMCs) for the oxygen reduction reaction (ORR) is of paramount importance for commercial implementation of several clean energy techniques (e.g. proton exchange membrane fuel cells). However, limited understanding of the ORR catalytic mechanism of NPMCs greatly hinders the progress in the precise fabrication of NPMCs at the molecular or atomic level. Recently, an increasing number of studies have demonstrated the crucial role of a carbon matrix in exposing, stabilizing, and activating the catalytic sites, thus providing a platform to identify the nature of NPMCs. Herein, the unique structural effects of a carbon matrix in NPMCs are first reviewed to inspire the development of more advanced NPMCs for the ORR. PMID- 26955942 TI - Deposition of C-terminally truncated Abeta species Abeta37 and Abeta39 in Alzheimer's disease and transgenic mouse models. AB - In Alzheimer's disease (AD) a variety of amyloid beta-peptides (Abeta) are deposited in the form of extracellular diffuse and neuritic plaques (NP), as well as within the vasculature. The generation of Abeta from its precursor, the amyloid precursor protein (APP), is a highly complex procedure that involves subsequent proteolysis of APP by beta- and gamma-secretases. Brain accumulation of Abeta due to impaired Abeta degradation and/or altered ratios between the different Abeta species produced is believed to play a pivotal role in AD pathogenesis. While the presence of Abeta40 and Abeta42 in vascular and parenchymal amyloid have been subject of extensive studies, the deposition of carboxyterminal truncated Abeta peptides in AD has not received comparable attention. In the current study, we for the first time demonstrate the immunohistochemical localization of Abeta37 and Abeta39 in human sporadic AD (SAD). Our study further included the analysis of familial AD (FAD) cases carrying the APP mutations KM670/671NL, E693G and I716F, as well as a case of the PSEN1 DeltaExon9 mutation. Abeta37 and Abeta39 were found to be widely distributed within the vasculature in the brains of the majority of studied SAD and FAD cases, the latter also presenting considerable amounts of Abeta37 containing NPs. In addition, both peptides were found to be present in extracellular plaques but only scarce within the vasculature in brains of a variety of transgenic AD mouse models. Taken together, our study indicates the importance of C-terminally truncated Abeta in sporadic and familial AD and raises questions about how these species are generated and regulated. PMID- 26955943 TI - Non-technical skills evaluation in the critical care air ambulance environment: introduction of an adapted rating instrument--an observational study. AB - BACKGROUND: In the isolated and dynamic health-care setting of critical care air ambulance transport, the quality of clinical care is strongly influenced by non technical skills such as anticipating, recognising and understanding, decision making, and teamwork. However there are no published reports identifying or applying a non-technical skills framework specific to an intensive care air ambulance setting. The objective of this study was to adapt and evaluate a non technical skills rating framework for the air ambulance clinical environment. METHODS: In the first phase of the project the anaesthetists' non-technical skills (ANTS) framework was adapted to the air ambulance setting, using data collected directly from clinician groups, published literature, and field observation. In the second phase experienced and inexperienced inter-hospital transport clinicians completed a simulated critical care air transport scenario, and their non-technical skills performance was independently rated by two blinded assessors. Observed and self-rated general clinical performance ratings were also collected. Rank-based statistical tests were used to examine differences in the performance of experienced and inexperienced clinicians, and relationships between different assessment approaches and assessors. RESULTS: The framework developed during phase one was referred to as an aeromedical non-technical skills framework, or AeroNOTS. During phase two 16 physicians from speciality training programmes in intensive care, emergency medicine and anaesthesia took part in the clinical simulation study. Clinicians with inter-hospital transport experience performed more highly than those without experience, according to both AeroNOTS non-technical skills ratings (p = 0.001) and general performance ratings (p = 0.003). Self-ratings did not distinguish experienced from inexperienced transport clinicians (p = 0.32) and were not strongly associated with either observed general performance (r(s) = 0.4, p = 0.11) or observed non-technical skills performance (r(s) = 0.4, p = 0.1). DISCUSSION: This study describes a framework which characterises the non-technical skills required by critical care air ambulance clinicians, and distinguishes higher and lower levels of performance. CONCLUSION: The AeroNOTS framework could be used to facilitate education and training in non-technical skills for air ambulance clinicians, and further evaluation of this rating system is merited. PMID- 26955944 TI - Effects of weather factors on dengue fever incidence and implications for interventions in Cambodia. AB - BACKGROUND: Dengue viruses and their mosquito vectors are sensitive to their environment. Temperature, rainfall and humidity have well-defined roles in the transmission cycle. Therefore changes in these conditions may contribute to increasing incidence. The aim of this study was to examine the relationship between weather factors and dengue incidence in three provinces in Cambodia, in order to strengthen the evidence basis of dengue control strategies in this high burden country. METHODS: We developed negative binomial models using monthly average maximum, minimum, mean temperatures and monthly cumulative rainfall over the period from January 1998 to December 2012. We adopted piecewise linear functions to estimate the incidence rate ratio (IRR) between dengue incidence and weather factors for simplicity in interpreting the coefficients. We estimated the values of parameters below cut-points defined in terms of the results of sensitivity tests over a 0-3 month lagged period. RESULTS: Mean temperature was significantly associated with dengue incidence in all three provinces, but incidence did not correlate well with maximum temperature in Banteay Meanchey, nor with minimum temperature in Kampong Thom at a lag of three months in the negative binomial model. The monthly cumulative rainfall influence on the dengue incidence was significant in all three provinces, but not consistently over a 0-3 month lagged period. Rainfall significantly affected the dengue incidence at a lag of 0 to 3 months in Siem Reap, but it did not have an impact at a lag of 2 to 3 months in Banteay Meanchey, nor at a lag of 2 months in Kampong Thom. CONCLUSIONS: The association between dengue incidence and weather factors also apparently varies by locality, suggesting that a prospective dengue early warning system would likely be best implemented at a local or regional scale, rather than nation-wide in Cambodia. Such spatial down-scaling would also enable dengue control measures to be better targeted, timed and implemented. PMID- 26955945 TI - Birth rates among male cancer survivors and mortality rates among their offspring: a population-based study from Sweden. AB - BACKGROUND: With improvements in treatment of cancer, more men of fertile age are survivors of cancer. This study evaluates trends in birth rates among male cancer survivors and mortality rates of their offspring. METHODS: From the Swedish Multi generation Register and Cancer Register, we identified 84,752 men <=70 years with a history of cancer, for which we calculated relative birth rates as compared to the background population(Standardized Birth Ratios, SBRs). We also identified 126,696 offspring of men who had cancer, and compared their risks of death to the background population(Standardized Mortality Ratio, SMRs). Independent factors associated with reduced birth rates and mortality rates were estimated with Poisson modelling. RESULTS: Men with a history of cancer were 23 % less likely to father a child compared to the background population(SBR 0.77, 95 % Confidence Interval[CI] 0.75-0.79). Nulliparous men were significantly more likely to father a child after diagnosis (SBR 0.81, 95 % CI 0.79-0.83) compared to parous men (SBR 0.68, 95 % CI 0.66-0.74). Cancer site(prostate), onset of cancer during childhood or adolescence, parity status at diagnosis(parous), current age(>40 years) and a recent diagnosis were significant and independent predictors of a reduced probability of fathering a child after diagnosis. Of the 126,696 children born to men who have had a diagnosis of cancer, 2604(2.06 %) died during follow up. The overall mortality rate was similar to the background population(SMR of 1.00, 95 %CI 0.96-1.04) and was not affected by the timing of their birth in relation to father's cancer diagnosis. CONCLUSION: Male cancer survivors are less likely to father a child compared to the background population. This is influenced by cancer site, age of onset and parity status at diagnosis. However, their offspring are not at an increased risk of death. PMID- 26955947 TI - Characterization and analysis of an infectious bronchitis virus strain isolated from southern China in 2013. AB - BACKGROUND: Infectious bronchitis is a severe disease caused by infectious bronchitis virus (IBV) that affects fowl flocks worldwide. The understanding of the mechanisms involved in IBV evolution and variation would provide important theoretical basis for prevention and control of the disease in the future. METHODS: IBV strain GD was isolated from southern China in 2013 and the complete genome sequencing and phylogenetic analysis were performed. RESULTS: The genome of approximately 27,680 nt comprised six genes, with insertions and mutations in most of the structural genes. The S1 gene showed the highest identity to strain TW2575/98 isolated in Taiwan, and was distantly related to the H120 vaccine strain. Phylogenetic analysis showed that the S1 gene of strain GD was also related to that of TW-type strains. Recombination analysis indicated that strain GD was a chimera whose putative parental strains belonged to the QX- and TW-type subgroups. CONCLUSIONS: An increasing number of TW-type strains have been isolated from China in recent years, which is in agreement with our findings, suggesting the emergence and increased prevalence of new TW-type strains in southern China. PMID- 26955946 TI - Evidence for the role of transposons in the recruitment of cis-regulatory motifs during the evolution of C4 photosynthesis. AB - BACKGROUND: C4 photosynthesis evolved from C3 photosynthesis and has higher light, water, and nitrogen use efficiencies. Several C4 photosynthesis genes show cell-specific expression patterns, which are required for these high resource-use efficiencies. However, the mechanisms underlying the evolution of cis-regulatory elements that control these cell-specific expression patterns remain elusive. RESULTS: In the present study, we tested the hypothesis that the cis-regulatory motifs related to C4 photosynthesis genes were recruited from non-photosynthetic genes and further examined potential mechanisms facilitating this recruitment. We examined 65 predicted bundle sheath cell-specific motifs, 17 experimentally validated cell-specific cis-regulatory elements, and 1,034 motifs derived from gene regulatory networks. Approximately 7, 5, and 1,000 of these three categories of motifs, respectively, were apparently recruited during the evolution of C4 photosynthesis. In addition, we checked 1) the distance between the acceptors and the donors of potentially recruited motifs in a chromosome, and 2) whether the potentially recruited motifs reside within the overlapping region of transposable elements and the promoter of donor genes. The results showed that 7, 4, and 658 of the potentially recruited motifs might have moved via the transposable elements. Furthermore, the potentially recruited motifs showed higher binding affinity to transcription factors compared to randomly generated sequences of the same length as the motifs. CONCLUSIONS: This study provides molecular evidence supporting the hypothesis that transposon-driven recruitment of pre-existing cis regulatory elements from non-photosynthetic genes into photosynthetic genes plays an important role during C4 evolution. The findings of the present study coincide with the observed repetitive emergence of C4 during evolution. PMID- 26955949 TI - Reminiscence functions scale: factorial structure and its relation with mental health in a sample of Spanish older adults. AB - BACKGROUND: The reminiscence functions scale (RFS) is a 43-item self-report instrument designed to assess the use of reminiscence for different functions. This study aims, on one hand, to analyze the factorial structure and the psychometric properties of the RFS and, on the other, to examine the relationship between the functions of reminiscence and mental health. METHODS: RFS scale and measures of depressive symptomology, despair, and life satisfaction were administered to a sample of persons over the age of sixty (n = 364). RESULTS: After eliminating three conflictive items from the original scale, the confirmatory factor analysis results present a factorial structure comprising eight traditional factors and adequate reliability scores (from 0.73 to 0.87). Using structural equation modeling, we find that these reminiscence factors are organized in three second-order factors (self-positive, self-negative, and prosocial). Results show that the self-positive factor relates negatively and the self-negative factor relates positively with symptoms of mental health problems. CONCLUSIONS: These results, on one hand, confirm that the RFS scale is a useful instrument to assess reminiscence functions in a sample of Spanish older adults and, on the other, that the three-factor model of reminiscence is a better predictor of mental health than the alternative four-factor model. PMID- 26955950 TI - Introduction. PMID- 26955951 TI - The use of thyroid hormone in the treatment of depression: a review. AB - The writers of this paper made an inventory of the studies on the use of thyroid hormone in the treatment of depression. Fifteen clinical trials (353 patients), published between 1969 and 1987. were found, that can be described, as to their design, in two seperate groups: One group (7 studies) administers thyroid hormone simultaneously with a tricyclic antidepressant to reach a faster effect of the antidepressant. The other group (8 studies) adds thyroid hormone to a tricyclic antidepressant in patients who fail to respond to this treatment, with the aim to convert therapeutic failure to success. After studying the literature we think we are able to conclude that it can be usefull to combine the antidepressant with thyroid hormone in view of the fact that, in a number of depressed patients, it shortens the duration of the illness. The augmentation of tricyclics by thyroid hormone needs further study. PMID- 26955952 TI - Psychomotor retardation in depression, a pilot study. AB - Several studies have demonstrated that psychomotor retardation is an important sign of the major depressive episode, both from a diagnostic point of view and as a predictor of treatment outcome. However, it is uncertain to what extent psychomotor retardation is specific for the major depressive episode. A heterogeneous group of psychiatric patients (n=26) was studied using a rating scale developed specifically to assess psychomotor retardation (RRS). The 13 patients suffering from a major depressive episode had a significantly higher RRS score than patients with another diagnosis. Furthermore, in the depressive subjects the severity of the depression (measured by means of Hamilton's depression rating scale) appeared to correlate with the severity of the psychomotor retardation. Cognitive features of psychomotor retardation were mainly responsible for the more severe psychomotor retardation in the depressive patients. Surprisingly. Hamilton's depression scale which was used in this study does not pay much attention to these aspects. PMID- 26955948 TI - Plasmodium falciparum: multifaceted resistance to artemisinins. AB - Plasmodium falciparum resistance to artemisinins, the most potent and fastest acting anti-malarials, threatens malaria elimination strategies. Artemisinin resistance is due to mutation of the PfK13 propeller domain and involves an unconventional mechanism based on a quiescence state leading to parasite recrudescence as soon as drug pressure is removed. The enhanced P. falciparum quiescence capacity of artemisinin-resistant parasites results from an increased ability to manage oxidative damage and an altered cell cycle gene regulation within a complex network involving the unfolded protein response, the PI3K/PI3P/AKT pathway, the PfPK4/eIF2alpha cascade and yet unidentified transcription factor(s), with minimal energetic requirements and fatty acid metabolism maintained in the mitochondrion and apicoplast. The detailed study of these mechanisms offers a way forward for identifying future intervention targets to fend off established artemisinin resistance. PMID- 26955953 TI - Alcoholism and dementia. AB - The controversy concerning the concept 'alcoholic dementia' is reviewed in brief. Evidence from neuroradiological and neuropathological studies contribute little to the solution of this controversy, if dementia is considered as a clinical syndrome. From clinical descriptions it can be concluded that a sub-population of alcoholics suffers from a syndrome typified by psychologic disturbances other than amnesia alone. These patients fulfill the criteria for the syndromal diagnosis of 'dementia'. The nosologic concept of 'alcoholic dementia' implies a direct neurotoxic effect of alcohol and it raises questions concerning pathogenetic mechanisms which can not be answered. The DSM-III-R category 'dementia associated with alcoholism' represents a solution for this controversy, because it gives a correct and complete (radically syndromal) clinical description without making assumptions on the relative contribution of multiple factors causing cognitive disturbances in alcoholics. PMID- 26955954 TI - Lithium als adjuvans bij een therapie-resistente depressie: een casus. AB - Lithium was added to imipramine in case of a 55-year old depressed woman who didn't respond to imipramine alone. There was a clear improvement within a few days on 900 mg lithium carbonate a day (lithium plasmalevel 0.9 mmol/l). However when after two weeks the lithium dose was reduced to 600 mg a day (lithium plasmalevel 0.5 mmol/l), an almost immediate relapse followed. On resuming lithium in the old dose the depression disappeared again. After four weeks the second attempt at reducing and eventually stopping the lithium appeared to be successful. Half a year after cessation of lithium imipramine was also stopped. More than a year afterwards there hasn't been a depression again. In this case, after a fast potentiation of imipramine by lithium, a relapse followed when the lithium dose was reduced. It seems to be that even a high and successful starting dose of lithium needs to be continued for some time in order to prevent a relapse. PMID- 26955955 TI - Psychofarmakologikum VI. AB - Inleiding In deze rubriek zal worden ingegaan op recente observaties betreffende de psychofarmakologie in de breedst mogelijke zin. Vaak zullen zaken uit de Literatuur worden behandeld. De gekozen onderwerpen dienen altijd klinische relevantie te hebben. Ook zal deze rubriek gaan over gewoontes die in psychofarmakologische behandeling of in onderzoek zijn geslopen die volgens de auteur lang niet altijd logisch zijn. Soms zal deze rubriek een oproep bevatten om te reageren op een bijdrage gepubliceerd in dit of in een ander tijdschrift. Ook zal de lezer worden aangemoedigd hier zijn eigen ervaringen mee te delen. Het is niet de bedoeling in deze rubriek onderzoeken uitvoerig te rapporteren. Daarvoor staan andere pagina's van de Acta Neuropsychiatrica voor u open. PMID- 26955957 TI - Evaluation of recombinant multi-epitope proteins for diagnosis of goat schistosomiasis by enzyme-linked immunosorbent assay. AB - BACKGROUND: Schistosomiasis is a huge threat to human and animal health. Apart from bovines, goats play an important role in the transmission of schistosomiasis in some endemic areas of China. An accessible, quality-assured goat schistosomiasis diagnostic technique is needed. Recently, our laboratory identified two recombinant diagnostic antigens, SjPGM and SjRAD23 via an immuno proteomic method. The application of these two recombinant antigens to develop a higher sensitivity and specificity technique for the sheep schistosomiasis diagnosis is urgently needed. METHODS: Epitopes of SjPGM and SjRAD23 were predicted and three polypeptides, two from SjRAD23 and one from SjPGM, were selected. Recombinant plasmids containing two to three DNA sequences encoding predicted polypeptides or large hydrophilic region of Sj23 (LHD-Sj23) were constructed and expressed. Eight recombinant schistosome antigens including four multi-epitope proteins and four recombinant single-molecule antigens as well as SEA, were assessed by ELISA in 91 sera from schistosome-infected goats, 44 sera from non-infected goats, 37 sera from Orientobilharzia-infected goats, and 12 from Haemonchus contortus-infected goats. RESULTS: ELISA tests showed that three multi-epitope proteins had higher sensitivity than the four single-molecule antigens (rSjRAD23, rSjPGM, rBSjRAD23-1, rBSj23) and the multi-epitope protein rBSjPGM-BSjRAD23-1-BSj23 had the highest sensitivity (97.8 %, 89/91) and maintained good specificity (100 %, 44/44) as well as low cross-reactivity with haemonchosis (8.33 %, 3/12) and orientobilharziasis (13.51 %, 5/37) in the diagnosis of goat schistosomiasis. In contrast, when SEA was applied as a diagnosis antigen, it had 100 % (91/91) sensitivity, 75 % (33/44) specificity, 25 and 83.78 % cross-reactivity with haemonchosis (3/12) and orientobilharziasis (31/37), respectively. CONCLUSIONS: The application of recombinant multi-epitope proteins may increase the sensitivity of diagnosis technique and retain high specificity of single-molecule antigens for schistosomiasis, and the recombinant antigen rBSjPGM-BSjRAD23-1-BSj23 has the potential to be used as a diagnosis antigen for goat schistosomiasis. PMID- 26955960 TI - Heterogeneous grain-scale response in ferroic polycrystals under electric field. AB - Understanding coupling of ferroic properties over grain boundaries and within clusters of grains in polycrystalline materials is hindered due to a lack of direct experimental methods to probe the behaviour of individual grains in the bulk of a material. Here, a variant of three-dimensional X-ray diffraction (3D XRD) is used to resolve the non-180 degrees ferroelectric domain switching strain components of 191 grains from the bulk of a polycrystalline electro ceramic that has undergone an electric-field-induced phase transformation. It is found that while the orientation of a given grain relative to the field direction has a significant influence on the phase and resultant domain texture, there are large deviations from the average behaviour at the grain scale. It is suggested that these deviations arise from local strain and electric field neighbourhoods being highly heterogeneous within the bulk polycrystal. Additionally, the minimisation of electrostatic potentials at the grain boundaries due to interacting ferroelectric domains must also be considered. It is found that the local grain-scale deviations average out over approximately 10-20 grains. These results provide unique insight into the grain-scale interactions of ferroic materials and will be of value for future efforts to comprehensively model these and related materials at that length-scale. PMID- 26955958 TI - Antiproliferation of Cryptocarya concinna-derived cryptocaryone against oral cancer cells involving apoptosis, oxidative stress, and DNA damage. AB - BACKGROUND: Cryptocarya-derived crude extracts and their compounds have been reported to have an antiproliferation effect on several types of cancers but their impact on oral cancer is less well understood. METHODS: We examined the cell proliferation effect and mechanism of C. concinna-derived cryptocaryone (CPC) on oral cancer cells in terms of cell viability, apoptosis, reactive oxygen species (ROS), mitochondrial depolarization, and DNA damage. RESULTS: We found that CPC dose-responsively reduced cell viability of two types of oral cancer cells (Ca9-22 and CAL 27) in MTS assay. The CPC-induced dose-responsive apoptosis effects on Ca9-22 cells were confirmed by flow cytometry-based sub-G1 accumulation, annexin V staining, and pancaspase analyses. For oral cancer Ca9-22 cells, CPC also induced oxidative stress responses in terms of ROS generation and mitochondrial depolarization. Moreover, gammaH2AX flow cytometry showed DNA damage in CPC-treated Ca9-22 cells. CPC-induced cell responses in terms of cell viability, apoptosis, oxidative stress, and DNA damage were rescued by N acetylcysteine pretreatment, suggesting that oxidative stress plays an important role in CPC-induced death of oral cancer cells. CONCLUSIONS: CPC is a potential ROS-mediated natural product for anti-oral cancer therapy. PMID- 26955956 TI - NANOMEDICINE: will it offer possibilities to overcome multiple drug resistance in cancer? AB - This review is written with the purpose to review the current nanomedicine literature and provide an outlook on the developments in utilizing nanoscale drug constructs in treatment of solid cancers as well as in the potential treatment of multi-drug resistant cancers. No specific design principles for this review have been utilized apart from our active choice to avoid results only based on in vitro studies. Few drugs based on nanotechnology have progressed to clinical trials, since most are based only on in vitro experiments which do not give the necessary data for the research to progress towards pre-clinical studies. The area of nanomedicine has indeed spark much attention and holds promise for improved future therapeutics in the treatment of solid cancers. However, despite much investment few targeted therapeutics have successfully progressed to early clinical trials, indicating yet again that the human body is complicated and that much more understanding of the fundamentals of receptor interactions, physics of nanomedical constructs and their circulation in the body is indeed needed. We believe that nanomedical therapeutics can allow for more efficient treatments of resistant cancers, and may well be a cornerstone for RNA based therapeutics in the future given their general need for shielding from the harsh environment in the blood stream. PMID- 26955959 TI - In vivo treatment of rat arterial adventitia with interleukin-1beta induces intimal proliferation via the JAK2/STAT3 signaling pathway. AB - Previous studies have indicated that adventitial inflammation is involved in the development of atherosclerosis. The aim of this study was to investigate the effect of arterial adventitia inflammation induced by interleukin (IL)-1beta on intimal proliferation and the mechanisms involved in this process. The left common carotid artery adventitia of male rats in the experimental and control groups (25 rats/group) was wrapped with agar containing or without a sustained release suspension of 2.5 ug IL-1beta, respectively. Five animals in each group were randomly selected for sacrifice at 2 h, 8 h, 24 h, 48 h, and 1 week post treatment. Hematoxylin and eosin staining was performed for to analyze the morphology of the adventitia. The expression of janus kinase (JAK)2, signal transducer and activator of transcription (STAT)3, phosphorylated (p-)JAK2 and p STAT3 were detected by western blot analysis or immunohistochemistry staining. A model of adventitial inflammation was successfully created by wrapping IL-1beta around the rat carotid artery. IL-1beta treatment induced vascular smooth muscle cell proliferation and migration as well as intimal proliferation. In addition, the expression of p-JAK2 and p-STAT3 increased after IL-1beta treatment. Furthermore, an inhibitor of JAK2/STAT3 pathway, AG490, suppressed IL-1beta induced intimal proliferation and phosphorylation of JAK2 and STAT3. Thus, the JAK2/STAT3 signaling pathway is involved in intimal proliferation caused by vascular adventitial inflammation. Inhibiting the JAK2/STAT3 signaling pathway may be a novel method for the clinical treatment of artery atherosclerosis. PMID- 26955962 TI - Hydrophobic and Metallophobic Surfaces: Highly Stable Non-wetting Inorganic Surfaces Based on Lanthanum Phosphate Nanorods. AB - Metal oxides, in general, are known to exhibit significant wettability towards water molecules because of the high feasibility of synergetic hydrogen-bonding interactions possible at the solid-water interface. Here we show that the nano sized phosphates of rare earth materials (Rare Earth Phosphates, REPs), LaPO4 in particular, exhibit without any chemical modification, unique combination of intrinsic properties including remarkable hydrophobicity that could be retained even after exposure to extreme temperatures and harsh hydrothermal conditions. Transparent nanocoatings of LaPO4 as well as mixture of other REPs on glass surfaces are shown to display notable hydrophobicity with water contact angle (WCA) value of 120 degrees while sintered and polished monoliths manifested WCA greater than 105 degrees . Significantly, these materials in the form of coatings and monoliths also exhibit complete non-wettability and inertness towards molten metals like Ag, Zn, and Al well above their melting points. These properties, coupled with their excellent chemical and thermal stability, ease of processing, machinability and their versatile photo-physical and emission properties, render LaPO4 and other REP ceramics utility in diverse applications. PMID- 26955963 TI - Anti-EGFR Therapy: Strategies in Head and Neck Squamous Cell Carcinoma. AB - Epidermal growth factor receptor (EGFR) is a tyrosine kinase receptor that activates downstream signaling pathways, including the Ras-MEK-Erk and PI3K-AKT pathways, leading to cell proliferation, resistance to apoptosis, angiogenesis and the ability to metastasize. EGFR overexpression is a significant finding in cancer, particularly in head and neck cancer, where it is also associated with a poor prognosis. In recent years, several molecules have been designed to inhibit EGFR activation. Among the many available anti-EGFR drugs, only cetuximab was approved for the treatment of head and neck cancers. However, no predictive biomarkers of cetuximab response are currently known. In the present review, we provide an updated assessment of EGFR biology and its clinical impact in head and neck cancers. A special emphasis is placed on novel patents of EGFR-inhibitors that are anticipated to diversify the anti-EGFR therapies available to treat head and neck cancers. In particular, we outline a new class of irreversible multi target inhibitors (e.g. afatinib, icotinib, CUDC-101), which may significantly contribute to new head and neck cancer therapies. PMID- 26955964 TI - Application of Nanotechnology in the Diagnosis and Therapy of Hepatocellular Carcinoma. AB - Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide. However, the inherent limitations of traditional surgery and insensitivity to radiation and chemotherapy result in failing treatment and poor prognosis. In recent years, the development and advances of nanotechnology has brought new hope for the diagnosis and treatment of HCC. This article reviews the development of nanoparticles used for cancer detection, diagnosis and treatment due to their large specific surface area and unique optical, electronic and magnetic properties. Moreover, studies have shown that after intended surface modification, nano-carriers can achieve active targeting effect, which improves the efficiency of chemotherapeutic drugs and decreases their side effects. In this review, we provide an overview of these studies results, patents about novel nanomaterials and conclude with a discussion about future development. PMID- 26955961 TI - The Gq signalling pathway inhibits brown and beige adipose tissue. AB - Brown adipose tissue (BAT) dissipates nutritional energy as heat via the uncoupling protein-1 (UCP1) and BAT activity correlates with leanness in human adults. Here we profile G protein-coupled receptors (GPCRs) in brown adipocytes to identify druggable regulators of BAT. Twenty-one per cent of the GPCRs link to the Gq family, and inhibition of Gq signalling enhances differentiation of human and murine brown adipocytes. In contrast, activation of Gq signalling abrogates brown adipogenesis. We further identify the endothelin/Ednra pathway as an autocrine activator of Gq signalling in brown adipocytes. Expression of a constitutively active Gq protein in mice reduces UCP1 expression in BAT, whole body energy expenditure and the number of brown-like/beige cells in white adipose tissue (WAT). Furthermore, expression of Gq in human WAT inversely correlates with UCP1 expression. Thus, our data indicate that Gq signalling regulates brown/beige adipocytes and inhibition of Gq signalling may be a novel therapeutic approach to combat obesity. PMID- 26955965 TI - Hospitalizations among HIV controllers and persons with medically controlled HIV in the U.S. Military HIV Natural History Study. AB - INTRODUCTION: HIV controllers (HICs) experience relatively low-level viraemia and CD4 preservation without antiretroviral therapy (ART), but also immune activation that may predispose to adverse clinical events such as cardiovascular disease and hospitalization. The objective of this study was to characterize the rates and reasons for hospitalization among HICs and persons with medically controlled HIV. METHODS: Subjects with consistently well-controlled HIV were identified in the U.S. Military HIV Natural History Study. ART prescription and HIV-1 RNA data were used to categorize subjects as HICs or medically controlled as defined by >= 3 HIV-1 RNA measurements <= 2000 or <= 400 copies/mL, respectively, representing the majority of measurements spanning >= 12 months. Hospitalizations were tallied and assigned diagnostic categories. All-cause hospitalization rates were compared between groups using negative binomial regression. RESULTS AND DISCUSSION: Of 3106 subjects followed from 2000 to 2013, 221 were HICs, including 33 elite (1.1%) and 188 viraemic (6.0%) controllers, who contributed 882 person-years (PY) of observation time. An additional 870 subjects with medically controlled HIV contributed 4217 PY. Mean hospitalization rates were 9.4/100 PY among HICs and 8.8/100 PY among medically controlled subjects. Non-AIDS-defining infections were the most common reason for hospitalization (2.95/100 PY and 2.70/100 PY, respectively) and rates of cardiovascular hospitalization were similar in both groups (0.45/100 PY and 0.76/100 PY). There was no difference in hospitalization rate for HICs compared with subjects with medically controlled HIV (adjusted incidence rate ratio 1.15 [95% confidence interval 0.80 to 1.65]). CONCLUSIONS: All-cause and cardiovascular hospitalization rates did not differ between HICs and persons with medically controlled HIV. Non-AIDS defining infections were common in this young, healthy, predominantly male cohort of military personnel and beneficiaries. PMID- 26955966 TI - Towards the Molecular Foundations of Glutamatergic-targeted Antidepressants. AB - BACKGROUND: Depression affects over 120 million individuals of all ages and is the leading cause of disability worldwide. The lack of objective diagnostic criteria, together with the heterogeneity of the depressive disorder itself, makes it challenging to develop effective therapies. The accumulation of preclinical data over the past 20 years derived from a multitude of models using many divergent approaches, has fueled the resurgence of interest in targeting glutamatergic neurotransmission for the treatment of major depression. OBJECTIVE: The emergence of mechanistic studies are advancing our understanding of the molecular underpinnings of depression. While clearly far from complete and conclusive, they offer the potential to lead to the rational design of more specific therapeutic strategies and the development of safer and more effective rapid acting, long lasting antidepressants. METHODS: The development of comprehensive omics-based approaches to the dysregulation of synaptic transmission and plasticity that underlies the core pathophysiology of MDD are reviewed to illustrate the fundamental elements. RESULTS: This review frames the rationale for the conceptualization of depression as a "pathway disease". As such, it culminates in the call for the development of novel state-of-the-art " omics approaches" and neurosystems biological techniques necessary to advance our understanding of spatiotemporal interactions associated with targeting glutamatergic-triggered signaling in the CNS. CONCLUSION: These technologies will enable the development of novel psychiatric medications specifically targeted to impact specific, critical intracellular networks in a more focused manner and have the potential to offer new dimensions in the area of translational neuropsychiatry. PMID- 26955967 TI - Neuroprotection by Estrogen and Progesterone in Traumatic Brain Injury and Spinal Cord Injury. AB - In recent years there has been a growing body of clinical and laboratory evidence demonstrating the neuroprotective effects of estrogen and progesterone after traumatic brain injury (TBI) and spinal cord injury (SCI). In humans, women have been shown to have a lower incidence of morbidity and mortality after TBI compared with age-matched men. Similarly, numerous laboratory studies have demonstrated that estrogen and progesterone administration is associated with a mortality reduction, improvement in neurological outcomes, and a reduction in neuronal apoptosis after TBI and SCI. Here, we review the evidence that supports hormone-related neuroprotection and discuss possible underlying mechanisms. Estrogen and progesterone-mediated neuroprotection are thought to be related to their effects on hormone receptors, signaling systems, direct antioxidant effects, effects on astrocytes and microglia, modulation of the inflammatory response, effects on cerebral blood flow and metabolism, and effects on mediating glutamate excitotoxicity. Future laboratory research is needed to better determine the mechanisms underlying the hormones' neuroprotective effects, which will allow for more clinical studies. Furthermore, large randomized clinical control trials are needed to better assess their role in human neurodegenerative conditions. PMID- 26955969 TI - Health care contact following a new incident neck or low back pain episode in the general population; the HUNT study. AB - BACKGROUND: Low back and neck pain are commonly reported in the general population and represent frequent causes for health care consultations. The main aim of this study was to describe the determinants of health care contact during a 1-year period in a general population with recent onset spinal pain. METHODS: From 9056 participants in a general health survey in Norway we identified 219 persons reporting a recent onset (<1 month) of low back or neck pain. Questionnaires were given at 1 (baseline), 2, 3, 6 and 12 months after pain debut. The main outcome was self-reported health care contact due to spinal pain. Associations between health care contact and pain-related factors, other somatic and mental health factors, pain-related work limitations, physical activity and sociodemographic factors were explored. RESULTS: Conventional health care was sought by 93 persons (43 %) at least once throughout the year following the onset of pain. 18 persons (8 %) sought alternative health care only and 108 persons (49 %) sought no kind of health care. Baseline reports of coexisting low back and neck pain of equal intensity, poor self-reported health, symptoms of anxiety or depression, obesity and smoking were all associated with an increased tendency to seek conventional health care. Pain intensity and pain-related work limitations at each occasion were strongly associated with concurrent health care contact throughout the year. Higher education was associated with a reduced tendency to contact health care and no association was found for physical activity. CONCLUSION: The main finding in this study was that people from the general population who seek health-care for a new incident of neck or low back pain report more symptoms of mental distress, poorer self-reported health and more intense pain with stronger work limitations compared to those who do not. The findings suggest that identification of complementary symptoms is highly relevant in the examination of spinal pain patients, even for those with recent onset of symptoms. PMID- 26955968 TI - Molecular and Cellular Mechanisms of Rapid-Acting Antidepressants Ketamine and Scopolamine. AB - Major depressive disorder (MDD) is a prevalent neuropsychiatric disease that causes profound social and economic burdens. The impact of MDD is compounded by the limited therapeutic efficacy and delay of weeks to months of currently available medications. These issues highlight the need for more efficacious and faster-acting treatments to alleviate the burdens of MDD. Recent breakthroughs demonstrate that certain drugs, including ketamine and scopolamine, produce rapid and long-lasting antidepressant effects in MDD patients. Moreover, preclinical work has shown that the antidepressant actions of ketamine and scopolamine in rodent models are caused by an increase of extracellular glutamate, elevated BDNF, activation of the mammalian target of rapamycin complex 1 (mTORC1) cascade, and increased number and function of spine synapses in the prefrontal cortex (PFC). Here we review studies showing that both ketamine and scopolamine elicit rapid antidepressant effects through converging molecular and cellular mechanisms in the PFC. In addition, we discuss evidence that selective antagonists of NMDA and muscarinic acetylcholine (mACh) receptor subtypes (i.e., NR2B and M1-AChR) in the PFC produce comparable antidepressant responses. Furthermore, we discuss evidence that ketamine and scopolamine antagonize inhibitory interneurons in the PFC leading to disinhibition of pyramidal neurons and increased extracellular glutamate that promotes the rapid antidepressant responses to these agents. Collectively, these studies indicate that specific NMDA and mACh receptor subtypes on GABAergic interneurons are promising targets for novel rapid-acting antidepressant therapies. PMID- 26955971 TI - Tuning Superconductivity in FeSe Thin Films via Magnesium Doping. AB - In contrast to its bulk crystal, the FeSe thin film or layer exhibits better superconductivity performance, which recently attracted much interest in its fundamental research as well as in potential applications around the world. In the present work, tuning superconductivity in FeSe thin films was achieved by magnesium-doping technique. Tc is significantly enhanced from 10.7 K in pure FeSe films to 13.4 K in optimized Mg-doped ones, which is approximately 1.5 times higher than that of bulk crystals. This is the first time achieving the enhancement of superconducting transition temperature in FeSe thin films with practical thickness (120 nm) via a simple Mg-doping process. Moreover, these Mg doped FeSe films are quite stable in atmosphere with Hc2 up to 32.7 T and Tc(zero) up to 12 K, respectively, implying their outstanding potential for practical applications in high magnetic fields. It was found that Mg enters the matrix of FeSe lattice, and does not react with FeSe forming any other secondary phase. Actually, Mg first occupies Fe-vacancies, and then substitutes for some Fe in the FeSe crystal lattices when Fe-vacancies are fully filled. Simultaneously, external Mg-doping introduces sufficient electron doping and induces the variation of electron carrier concentration according to Hall coefficient measurements. This is responsible for the evolution of superconducting performance in FeSe thin films. Our results provide a new strategy to improve the superconductivity of 11 type Fe-based superconductors and will help us to understand the intrinsic mechanism of this unconventional superconducting system. PMID- 26955970 TI - Effects of Monoamine Oxidase Inhibition on the Reinforcing Properties of Low-Dose Nicotine. AB - The Food and Drug Administration (FDA) has the authority to regulate cigarette smoke constituents, and a reduction in nicotine content might benefit public health by reducing the prevalence of smoking. Research suggests that cigarette smoke constituents that inhibit monoamine oxidase (MAO) may increase the reinforcing value of low doses of nicotine. The aim of the present experiments was to further characterize the impact of MAO inhibition on the primary reinforcing and reinforcement enhancing effects of nicotine in rats. In a series of experiments, rats responded for intravenous nicotine infusions or a moderately reinforcing visual stimulus in daily 1-h sessions. Rats received pre-session injections of known MAO inhibitors. The results show that (1) tranylcypromine (TCP), a known MAO inhibitor, increases sensitivity to the primary reinforcing effects of nicotine, shifting the dose-response curve for nicotine to the left, (2) inhibition of MAO-A, but not MAO-B, increases low-dose nicotine self administration, (3) partial MAO-A inhibition, to the degree observed in chronic cigarette smokers, also increases low-dose nicotine self-administration, and (4) TCP decreases the threshold nicotine dose required for reinforcement enhancement. The results of the present experiments suggest cigarette smoke constituents that inhibit MAO-A, in the range seen in chronic smokers, are likely to increase the primary reinforcing and reinforcement enhancing effects of low doses of nicotine. If the FDA reduces the nicotine content of cigarettes, then variability in constituents that inhibit MAO-A could impact smoking. PMID- 26955972 TI - Concurrent and Sustained Delivery of FGF2 and FGF9 from Electrospun Poly(ester amide) Fibrous Mats for Therapeutic Angiogenesis. AB - Therapeutic angiogenesis has emerged as a potential strategy to treat ischemic vascular diseases. However, systemic or local administration of growth factors is usually inefficient for maintaining the effective concentration at the site of interest due to their rapid clearance or degradation. In this study, we report a differential and sustained release of an angiogenic factor, fibroblast growth factor-2 (FGF2), and an arteriogenic factor, fibroblast growth factor-9 (FGF9), from alpha-amino acid-derived biodegradable poly(ester amide) (PEA) fibers toward targeting neovessel formation and maturation. FGF2 and FGF9 were dual loaded using a mixed blend and emulsion electrospinning technique and exhibited differential and sustained release from PEA fibers over 28 days with preserved bioactivity. In vitro angiogenesis assays showed enhanced endothelial cell (EC) tube formation and directed migration of smooth muscle cells (SMCs) to platelet derived growth factor (PDGF)-BB and stabilized EC/SMC tube formation. FGF2/FGF9 loaded PEA fibers did not induce inflammatory responses in vitro using human monocytes or in vivo after their subcutaneous implantation into mice. Histological examination showed that FGF2/FGF9-loaded fibers induced cell niche recruitment around the site of implantation. Furthermore, controlled in vivo delivery of FGF9 to mouse tibialis anterior (TA) muscle resulted in a dose dependent expansion of mesenchymal progenitor-like cell layers and extracellular matrix deposition. Our data suggest that the release of FGF2 and FGF9 from PEA fibers offers an efficient differential and sustained growth factor delivery strategy with relevance to therapeutic angiogenesis. PMID- 26955973 TI - PEGylated substrates of NSP4 protease: A tool to study protease specificity. AB - Herein we present the synthesis of a novel type of peptidomimetics composed of repeating diaminopropionic acid residues modified with structurally diverse heterobifunctional polyethylene glycol chains (abbreviated as DAPEG). Based on the developed compounds, a library of fluorogenic substrates was synthesized. Further library deconvolution towards human neutrophil serine protease 4 (NSP4) yielded highly sensitive and selective internally quenched peptidomimetic substrates. In silico analysis of the obtained peptidomimetics revealed the presence of an interaction network with distant subsites located on the enzyme surface. PMID- 26955974 TI - Relationship between thioredoxin and thioredoxin-binding protein in patients with gestational diabetes mellitus. AB - OBJECTIVE: This study examined the clinical and biological significance of thioredoxin (Trx) and thioredoxin-binding protein (TrxBP), which are redox-active proteins that control multiple biological functions, in gestational diabetes. METHODS: We measured serum concentrations of Trx, TrxBP, insulin and other blood parameters, as well as insulin resistance and glucose tolerance in pregnant women with or without gestational dieabetes mellitus (GDM) (34/34) at the early second trimester. RESULTS: Contrary to diabetes patients, serum TrxBP levels were lower in women with GDM than healthy pregnant controls. The serum insulin concentrations were higher in GDM, but the difference was not statistically significant. Furthermore, the intracellular redox potential ratio (Trx/TrxBP) of GDM patients was higher than that of the control group. CONCLUSION: During pregnancy, the mother is potentially subjected to glucotoxicity as well as oxidative stress (OS) to help the foetus absorb more nutrients. Our results suggest that the Trx/TrxBP system may mediate a compensating mechanism. Reduced TrxBP levels and consequent enhanced Trx activity may alleviate OS and protect the foetus from hypoglycaemia. We hypothesise that the decrease in TrxBP levels is not a consequence of GDM, but rather is an instance of the active functional role of TrxBP in maternal development, unifying redox regulation and glucose metabolism. PMID- 26955976 TI - The new ACEM Fellowship Examination: Lessons learnt. PMID- 26955975 TI - Prepubertal children exposed to concentrated disadvantage: An exploratory analysis of inflammation and metabolic dysfunction. AB - OBJECTIVE: It is unclear whether physiologic and metabolic biomarkers are associated with chronic stressors evidenced during early childhood. METHODS: Cross-sectional data were obtained from a cohort of healthy, prepubertal (Tanner stage < 2) children (n = 96; age: 8.06 [7.8] years; M = 51 [53%]; F = 45 [47%]; African-American = 26 [27%]; Caucasian = 70 [73%]; with obesity = 21 [22%]; without obesity = 75 [78%]) from the MET study. Body mass index z-score (z_BMI), total body fat (BF), visceral adipose tissue (VAT), intrahepatic and intramyocellular lipids, and insulin resistance (HOMA-IR) were measured. Chronic stress was assessed using neighborhood concentrated disadvantage index (CDI) for the U.S. Census tracts in which participants resided. Spearman's rank correlations were used to examine relationships, accounting for sex and race. RESULTS: CDI was not positively associated with inflammatory and metabolic markers of dysfunction. However, z_BMI (-0.234, P = 0.023), BF (-0.228, P = 0.028, n = 95), and VAT (-0.241, P = 0.042, n = 74) were significantly negatively associated with CDI. When stratifying by race, these relationships remained significant in Caucasian children only. CONCLUSIONS: These findings suggest chronic stress during early childhood is not associated with inflammatory and metabolic biomarkers, typically observed in adults. Therefore, exposure to stress during this critical developmental period may remain latent and emerge during a later developmental stage. PMID- 26955977 TI - A call for specific geriatric data on cervical cancers. PMID- 26955978 TI - Study provides insufficient evidence of a link between clarithromycin and myocardial infarction. PMID- 26955979 TI - Transforming the ACPSEM for a sustainable future. PMID- 26955980 TI - [Concept and results of the German Research Network on Schizophrenia]. AB - BACKGROUND: The German Research Network on Schizophrenia (GRNS) was funded by the Federal Ministry of Education and Research (BMBF) from 1999 to 2011. The aim was to obtain a better horizontal and vertical networking of German research and care facilities on schizophrenia, in order to investigate open research questions, to transfer the results into clinical practice and improve care and quality of life in patients with schizophrenia. OBJECTIVES/METHODS: This paper describes the concept and operations of the GRNS as well as its results on the basis of selected research projects. RESULTS: The GRNS comprised about 25 clinical trials of high practical relevance, which were closely interrelated regarding content, methodology and organization. The trials primarily served the development and evaluation of new and established diagnostic and therapeutic approaches, the assessment of the status quo of clinical care, as well as its improvements, together with the investigation of basic scientific questions. Many substantial results to highly relevant issues were obtained, which led or will lead to an improvement in mental health care. CONCLUSIONS: Quantitative and qualitative evaluation parameters, such as scientific publications and obtaining additional grants, as well as promotion of young scientists, public relations activities, congress activities and the foundation of a European Schizophrenia Association, document the successful work of the network. Successful funding requests will allow us to continue cooperative schizophrenia research in Germany as initiated by the GRNS, without necessarily always binding these activities formally to the GRNS. PMID- 26955983 TI - Structure and rheology of gel nanostructures from a vitamin C-based surfactant. AB - The structure and rheology behaviour of gels produced by water dispersions of a vitamin C-derived surfactant (ascorbyl-6-O-dodecanoate) were investigated by means of SAXS and rheology experiments for the first time. The gel state is formed upon heating and is due to an anisotropic expansion of the tightly compact lamellar structure. The phase transition involves primarily the melting of the alkyl chains and a significant increment in the interlamellar water layer. In particular, our results show that in the gel the hydrophobic chains are in a liquid-like state, as in the core of a micelle, while the head groups release their acidic proton, become negatively charged and determine the onset of strong electrostatic interactions between facing lamellae. The full hydration of the anionic head groups and the uptake of a significant amount of water increase the interlamellar thickness and stabilise the gel structure. Rheology and SAXS measurements together provide an updated picture for the gel state. Moreover, for the first time we show the presence of a concentration threshold, above which the self-assembled aggregates interact more strongly and deplete some of the water that is retained in the interlamellar region. PMID- 26955981 TI - Oil removal and effects of spilled oil on active microbial communities in close to salt-saturation brines. AB - Abiotic and biotic processes associated with the degradation of a light petroleum in brines close to the salt-saturation (~31 %) and the effect of labile organic matter (LOM) supply (casaminoacids/citrate; 0.2 and 0.1 % w/v, respectively) were followed during an incubation of 30 days. After 4-week incubation at 40 degrees C under light/dark cycles, a 24 % of abiotic degradation was observed in untreated brines. The stimulation of native brines community with LOM addition allowed an additional 12.8 % oil attenuation due to biodegradation processes. Successional changes in the active microbial community structure due to the oil contamination (16S rRNA DGGE approach) showed the selection of one phylotype affiliated to Salinibacter and the disappearance of Haloquadratum walsbyi in untreated brines. In LOM-amended microcosms, phylotypes related to Salinibacter, Haloarcula, Haloterrigena and Halorhabdus were selected. An effect of hydrocarbon contamination was only observed in the bacterial community with the inhibition of two dominant proteobacterial phylotypes. This study further confirms that short term and moderate oil biodegradation is possible in LOM-stimulated brines. Biodegradation should be much more reduced under in situ conditions. Self cleaning capacities of close to saturation hypersaline lakes appears, therefore very limited compared to non-extreme haline environments. PMID- 26955982 TI - Psychoeducation Improves Compliance and Outcome in Schizophrenia Without an Increase of Adverse Side Effects: A 7-Year Follow-up of the Munich PIP-Study. AB - Psychoeducation improves adherence and motivates patients to accept a maintenance therapy as recommended by the guidelines. This would mean a daily consumption of at least 300 chlorpromazine (CPZ) units in the long run and should lead to an increase of the antipsychotic dosage in comparison to patients with treatment as usual (TAU). This raises 2 important questions: whether more side effects are provoked and do the patients have a corresponding benefit with a better outcome. A total of 41 patients with a diagnosis of schizophrenic or schizoaffective disorder were randomized at study entry, either to bifocal psychoeducation (21), or to standard treatment (20). They were compared concerning compliance, type of medication, dosage (CPZ equivalents), motor side effects and number of days in hospital. The average daily antipsychotic medication 2 and 7 years after index discharge was 365 and 354 CPZ-units respectively in the intervention group (IG), but 247 and 279, respectively in the control group (CG). The extent of motor side effects was slightly smaller in the IG, but they showed a small and statistically not significant increase in the rate of tardive dyskinesia (TD) after 7 years. At the 7-year follow-up the patients in the IG had spent 74.7 days in hospital compared to 243.4 days for the patients in the CG (P < .05). The course of illness was significantly better in the IG without increasing motor side-effects. Therefore, psychoeducation should be integrated more systematically into the routine treatment. These data are part of a previous study, published 2007, with a sample size of 48 patients. Seven patients-3 of the IG and 4 of the CG-could not be included, because they were not able to complete the very complex "Computer-based kinematic analysis of motor performance." In this article all conclusions are referred to the new sample size, therefore some results are slightly different in comparison to the previous data. PMID- 26955985 TI - Methotrexate-associated EBV-positive vasculitis in the skin: a report of two cases simulating rheumatoid vasculitis. AB - Rheumatoid vasculitis (RV) is one of the most serious extra-articular complications of rheumatoid arthritis (RA), generally treated with a high dose of immunosuppressive drugs. Recently, we encountered two cases of ulcerative vasculitis in methotrexate (MTX)-prescribed RA patients, which simulated RV; however, Epstein-Barr virus (EBV)-encoded RNA in situ hybridization on their skin biopsies revealed many EBV-positive lymphocytes (over 50 cells/high-power field) within the vessel walls and perivascular stroma, which led us to the diagnosis of EBV-related vasculitis instead of RV. Subsequently, both ulcers regressed after the discontinuation of MTX and no recurrence was noted during the follow-up period. To prevent unnecessary treatment, EBV-positive vasculitis should be added in the differential diagnosis of lymphocytic vasculitis observed in MTX administered RA patients. PMID- 26955996 TI - The Impact of Balanced Counseling on Contraceptive Method Choice and Determinants of Long Acting and Reversible Contraceptive Continuation in Nepal. AB - Introduction Long-acting reversible contraceptives (LARCs) reduce rates of unintended pregnancies and repeat abortion. Uptake and continuation rates of LARCs are very low in Nepal, despite free provision from most health facilities. We sought to establish the effectiveness of a new approach to LARC promotion in Nepal. Methods We examined change in contraceptive method mix in Nepal using service data resulting from introduction of a balanced counseling (BC) approach to family planning (FP). All staff located at nine randomly selected FP sites were trained and began applying BC in April and May 2014. Women who accepted LARCs from a participating facility were re-contacted at 1, 3, 6 and 12 months. We estimated the LARC continuation rate and assessed determinants of continuation using descriptive analysis, Kaplan-Meier survival curves and univariate and multivariate Cox proportional hazard analysis. Results A total of 5744 women received BC between April and July 2014. 1580 women (27.5 %) took up LARCs, raising its contribution to contraceptive method mix at [organization] to 40 %, significantly higher than the 15 % recorded in 2013. 913 women were followed-up, and the LARC continuation rate at 12 months was 82 %. Women's reported satisfaction with LARC [AHR 0.23; 95 % CI 0.14-0.39, p = 0.000] was the single strongest determinant of LARC continuation after adjusting for all background characteristics. Discussion The findings suggest BC is an effective approach for increasing LARC uptake in Nepal. The rate of LARC continuation and its determinants are important inputs to strategies for improved delivery of FP services. PMID- 26955997 TI - Moderate and Vigorous Intensity Exercise During Pregnancy and Gestational Weight Gain in Women with Gestational Diabetes. AB - Objectives To estimate the associations of moderate and vigorous intensity exercise during pregnancy with the rate of gestational weight gain (GWG) from gestational diabetes (GDM) diagnosis to delivery, overall and stratified by prepregnancy overweight/obesity. Methods Prospective cohort study with physical activity reported shortly after the GDM diagnosis and prepregnancy weight and post-diagnosis GWG obtained from electronic health records (n = 1055). Multinomial logistic regression models in the full cohort and stratified by prepregnancy overweight/obesity estimated associations of moderate and vigorous intensity exercise with GWG below and above the Institute of Medicine's (IOM) prepregnancy BMI-specific recommended ranges for weekly rate of GWG in the second and third trimesters. Results In the full cohort, any participation in vigorous intensity exercise was associated with decreased odds of GWG above recommended ranges as compared to no participation [odds ratio (95 % confidence interval): 0.63 (0.40, 0.99)], with a significant trend for decreasing odds of excess GWG with increasing level of vigorous intensity exercise. Upon stratification by prepregnancy overweight/obesity, significant associations were only observed for BMI >= 25.0 kg/m(2): any vigorous intensity exercise, as compared to none, was associated with 54 % decreased odds of excess GWG [0.46 (0.27, 0.79)] and significant trends were detected for decreasing odds of GWG both below and above the IOM's recommended ranges with increasing level of vigorous exercise (both P <= 0.03). No associations were observed for moderate intensity exercise. Conclusions for Practice In women with GDM, particularly overweight and obese women, vigorous intensity exercise during pregnancy may reduce the odds of excess GWG. PMID- 26955999 TI - Rigid, Bistable Molecular Shuttles Combining T-shaped Benzimidazolium and Y shaped Imidazolium Recognition Sites. AB - Two different recognition sites, one a T-shaped 2,4,7-triphenylbenzimidazolium and the other a Y-shaped 2,4,5-triphenylimidazolium are combined to construct a rigid bistable [2]rotaxane molecular shuttle on which the position of a 24 membered crown ether macrocycle can be controlled by acid-base chemistry. Molecular shuttling in both the neutral and dicationic versions were studied. PMID- 26955998 TI - Intimate Partner Violence Associated with Postpartum Depression, Regardless of Socioeconomic Status. AB - Objective This study examined whether socioeconomic status moderated the association between intimate partner violence (IPV) and postpartum depression among a community-based sample of women. Defining the role of poverty in the risk of postpartum depression for IPV victims enables prioritization of health promotion efforts to maximize the effectiveness of existing maternal-infant resources. Methods This cross-sectional telephone-survey study interviewed 301 postpartum women 2 months after delivery, screening them for IPV and depression [using Edinburgh Postnatal Depression Scale (EPDS)]. Socioeconomic status was defined by insurance (Medicaid-paid-delivery or not). This analysis controlled for the following covariates, collected through interview and medical-record review: demographics, obstetric history, prenatal health and additional psychosocial risk factors. After adjusting for significant covariates, multiple linear regression was conducted to test whether socioeconomic status confounded or moderated IPV's relationship with EPDS-score. Results Ten percent of participants screened positive for postpartum depression, 21.3 % screened positive for current or previous adult emotional or physical abuse by a partner, and 32.2 % met poverty criteria. IPV and poverty were positively associated with each other (chi(2) (1) = 11.76, p < .001) and with EPDS score (IPV: beta 3.2 (CI 2.0, 4.5) p < .001, poverty: beta 1.3 (CI 0.2, 2.4) p = .017). In the multiple linear regression, IPV remained significantly associated, but poverty did not (IPV: adjusted beta 3.1 (CI 1.8, 4.3) p < .001, poverty: adjusted beta 0.8 (CI 0.3, 1.9) p = .141), and no statistically significant interaction between IPV and poverty was found. Conclusions Study findings illustrated that IPV was strongly associated with postpartum depression, outweighing the influence of socioeconomic status upon depression for postpartum women. PMID- 26956000 TI - Consequences of hyperthyroidism in male and female fertility: pathophysiology and current management. AB - Thyroid hormone acts on the oocytes, sperm and embryo during fertilization, implantation and placentation. Both hypothyroidism and hyperthyroidism may influence fertility. However, evidence of the association of hyperthyroidism with infertility is scarce and sometimes conflicting. Thyroid hormone influences human reproduction via a variety of mechanisms at both the central and the peripheral level. Infertility may occur in hyperthyroid men and women, but it is usually reversible upon restoration of euthyroidism. This review aims to summarize the available data on the association of hyperthyroidism and infertility in both men and women and to provide practical suggestions for the management of these patients. PMID- 26956003 TI - Giant Primary Yolk Sac Tumor of the Liver. PMID- 26956002 TI - Detection of Sulfatase Enzyme Activity with a CatalyCEST MRI Contrast Agent. AB - A chemical exchange saturation transfer (CEST) MRI contrast agent has been developed that detects sulfatase enzyme activity. The agent produces a CEST signal at delta=5.0 ppm before enzyme activity, and a second CEST signal appears at delta=9.0 ppm after the enzyme cleaves a sulfate group from the agent. The comparison of the two signals improved detection of sulfatase activity. PMID- 26956001 TI - Thalassobaculum fulvum sp. nov., isolated from deep seawater. AB - A novel Gram-stain-negative, rod-shaped (1.0-1.2*2.0-8.0 um), non-motile without flagella strain, designated HSF7T, was isolated from deep seawater. Strain HSF7T was able to grow at 20-40 degrees C (optimum 35 degrees C), pH 5.5-9.0 (optimum pH 6.5) and 0-10 % (w/v) NaCl (optimum 2 %). The G+C content of the genomic DNA was 69 mol%. Bacteriochlorophyll a and poly-beta-hydroxybutyrate (PHB) granules were not found. The major fatty acids were C18 : 1omega7c (69.3 %), C16 : 0 (9.1 %) and C19 : 0 cyclo omega8c (6.6 %). The polar lipids were phosphatidylglycerol, three unknown aminophospholipids, an unknown phospholipid, an unknown aminolipid and two unknown lipids. The only isoprenoid quinone was Q-10. 16S rRNA gene sequence analysis revealed that strain HSF7T was most closely related toThalassobaculum salexigens DSM 19539T, Thalassobaculum litoreum DSM 18839T, Nisaeadenitrificans DSM 18348T and Oceanibaculum indicum MCCC 1A02083Twith pairwise sequence similarities of 95.56 %, 95.21 %, 93.64 % and 92.65 %, respectively. On the basis of genotypic, phenotypic, phylogenetic and chemotaxonomic characteristics, strain HSF7T represents a novel species of the genus Thalassobaculum, or which the name Thalassobaculum fulvum sp. nov. is proposed. The type strain is HSF7T(=KCTC 42651T=MCCC 1K01158T). PMID- 26956004 TI - Intra-pancreatic Distal Bile Duct Carcinoma is Morphologically, Genetically, and Clinically Distinct from Pancreatic Ductal Adenocarcinoma. AB - PURPOSE: Differentiating intra-pancreatic distal bile duct carcinoma invading the pancreas from pancreatic ductal adenocarcinomas (PDAC) surrounding the distal common bile duct (CBD) can be challenging. Our aim is to identify clinical, morphological, and genetic features characteristic of intra-pancreatic distal bile duct carcinoma. METHODS: Clinicopathologic data of 550 patients undergoing a pancreaticoduodenectomy between September 1990 and May 2008 were reviewed. KRAS status was assessed with mass-spectrometric genotyping. RESULTS: Ninety-seven patients with intra-pancreatic adenocarcinomas surrounding the CBD were identified; slides were available for 80. Two relationships with the CBD were recognized as follows: type I (n = 42): cancer grew concentrically around the CBD and type II (n = 38): cancer grew asymmetrically around the CBD. Type I adenocarcinomas were associated with high-grade biliary dysplasia (45 vs. 13 %; p = 0.003); type II were associated with high-grade pancreatic intra-epithelial neoplasia (PanIN-2 or -3) (39 vs. 9 %; p = 0.003). Type I tumors had a better median survival (46 months) compared to type II (23 months) or other PDAC (20 months) (p < 0.001). Mutated KRAS was identified in 3/26 (11 %) type I and 20/21 (95 %) type II cancers (p < 0.001). There may be poorer survival in the presence of a KRAS mutation than wild-type KRAS (22.9 vs. 41.6 months; p = 0.3). CONCLUSIONS: Distal periductal adenocarcinomas fall into two distinct groups with biologic, morphologic and genetic differences. Those growing symmetrically around the CBD are more likely to be intra-pancreatic distal bile duct carcinomas and are associated with improved survival whereas cancers with asymmetric growth are more likely to have KRAS mutations and to be PDACs. These findings facilitate a more accurate histopathological diagnosis, which could improve patient selection for therapeutic trials. PMID- 26956006 TI - Gastric Schwannoma. PMID- 26956005 TI - Investigating Transitional Care to Decrease Post-pancreatectomy 30-Day Hospital Readmissions for Dehydration or Failure to Thrive. AB - BACKGROUND: Current literature emphasizes post-operative complications as a leading cause of post-pancreatectomy readmissions. Transitional care factors associated with potentially preventable conditions such as dehydration and failure to thrive (FTT) may play a significant role in readmission after pancreatectomy and have not been studied. METHODS: Thirty-one post-pancreatectomy patients, who were readmitted for dehydration or FTT between 2009 and 2014, were compared to 141 nonreadmitted patients. Medical record review and a questionnaire based survey, specifically designed to assess transitional care, were used to identify predictors of readmissions for dehydration or FTT. Logistic regression models were used to evaluate outcomes. RESULTS: On multivariable analysis, the strongest predictors of readmission for dehydration and FTT were the patient's lower educational level (P = 0.0233), the absence of family during the delivery of discharge instructions (P = 0.0098), episodic intermittent nausea at discharge (P = 0.0019), uncertainty about quantity, quality, or frequency of fluid intake (P = 0.0137), and the inability or failure to adhere to the clinician's instructions in the outpatient setting (P = 0.0048). CONCLUSION: Transitional care-related factors are found to be associated with post-pancreatectomy readmission for dehydration and FTT. Using these results to identify high-risk patients and implement focused preventive measures combining efficient communication and optimal inpatient and outpatient management could potentially decrease readmission rates. PMID- 26956007 TI - What is the Learning Curve for Laparoscopic Major Hepatectomy? AB - BACKGROUND: Laparoscopic liver resection is rapidly expanding with more than 9500 cases performed worldwide. While initial series reported non-anatomic resection of benign peripheral hepatic lesions, approximately 50-65 % of laparoscopic liver resections are now being done for malignant tumors, primarily hepatocellular carcinoma (HCC) or colorectal cancer liver metastases (mCRC). METHODS: We performed a literature review of published studies evaluating outcomes of major laparoscopic liver resection, defined as three or more Couinaud segments. RESULTS: Initial fears of adverse oncologic outcomes or tumor seeding have not been demonstrated, and dozens of studies have reported comparable 5-year disease free and overall survival between laparoscopic and open resection of HCC or mCRC in case-cohort and propensity score-matched analyses. Increased experience has led to laparoscopic anatomic liver resections including laparoscopic major hepatectomy. A steep learning curve of 45-60 cases is evident for laparoscopic hepatic resection. CONCLUSION: Laparoscopic major hepatectomy is safe and effective in the treatment of benign and malignant liver tumors when performed in specialized centers with dedicated teams. Comparable to other complex laparoscopic surgeries, laparoscopic major hepatectomy has a learning curve of 45 60 cases. PMID- 26956008 TI - Current Evidence in Image-Guided Liver Surgery. PMID- 26956009 TI - Characterization of DNA methyltransferase and demethylase genes in Fragaria vesca. AB - DNA methylation is an epigenetic modification essential for gene regulations in plants, but understanding on how it is involved in fruit development, especially in non-climacteric fleshy fruit, is limited. The diploid woodland strawberry (Fragaria vesca) is an important model for non-climacteric fruit crops. In this study, we identified DNA methyltransferase genes and demethylase genes in Fragaria vesca and other angiosperm species. In accordance with previous studies, our phylogenetic analyses of those DNA methylation modifiers support the clustering of those genes into several classes. Our data indicate that whole genome duplications and tandem duplications contributed to the expansion of those DNA methylation modifiers in angiosperms. We have further demonstrated that some DNA methylase and demethylase genes reach their highest expression levels in strawberry fleshy fruits when turning from white to red, suggesting that DNA methylation might undergo a dramatic change at the onset of fleshy fruit-ripening process. In addition, we have observed that expression of some DNA demethylase genes increases in response to various abiotic stresses including heat, cold, drought and salinity. Collectively, our study indicates a regulatory role of DNA methylation in the turning stage of non-climacteric fleshy fruit and responses to environment stimuli, and would facilitate functional studies of DNA methylation in the growth and development of non-climacteric fruits. PMID- 26956011 TI - Improving the precision of sample-based forest damage inventories through two phase sampling and post-stratification using remotely sensed auxiliary information. AB - Many countries have a national forest inventory (NFI) designed to produce statistically sound estimates of forest parameters. However, this type of inventory may not provide reliable results for forest damage which usually affects only small parts of the forest in a country. For this reason, specially designed forest damage inventories are performed in many countries, sometimes in coordination with the NFIs. In this study, we evaluated a new approach for damage inventory where existing NFI data form the basis for two-phase sampling for stratification and remotely sensed auxiliary data are applied for further improvement of precision through post-stratification. We applied Monte Carlo sampling simulation to evaluate different sampling strategies linked to different damage scenarios. The use of existing NFI data in a two-phase sampling for stratification design resulted in a relative efficiency of 50 % or lower, i.e., the variance was at least halved compared to a simple random sample of the same size. With post-stratification based on simulated remotely sensed auxiliary data, there was additional improvement, which depended on the accuracy of the auxiliary data and the properties of the forest damage. In many cases, the relative efficiency was further reduced by as much as one-half. In conclusion, the results show that substantial gains in precision can be obtained by utilizing auxiliary information in forest damage surveys, through two-phase sampling, through post stratification, and through the combination of these two approaches, i.e., post stratified two-phase sampling for stratification. PMID- 26956012 TI - Soil quality assessment using GIS-based chemometric approach and pollution indices: Nakhlak mining district, Central Iran. AB - This paper is a comprehensive assessment of the quality of soil in the Nakhlak mining district in Central Iran with special reference to potentially toxic metals. In this regard, an integrated approach involving geostatistical, correlation matrix, pollution indices, and chemical fractionation measurement is used to evaluate selected potentially toxic metals in soil samples. The fractionation of metals indicated a relatively high variability. Some metals (Mo, Ag, and Pb) showed important enrichment in the bioavailable fractions (i.e., exchangeable and carbonate), whereas the residual fraction mostly comprised Sb and Cr. The Cd, Zn, Co, Ni, Mo, Cu, and As were retained in Fe-Mn oxide and oxidizable fractions, suggesting that they may be released to the environment by changes in physicochemical conditions. The spatial variability patterns of 11 soil heavy metals (Ag, As, Cd, Co, Cr, Cu, Mo, Ni, Pb, Sb, and Zn) were identified and mapped. The results demonstrated that Ag, As, Cd, Mo, Cu, Pb, Sb, and Zn pollution are associated with mineralized veins and mining operations in this area. Further environmental monitoring and remedial actions are required for management of soil heavy metals in the study area. The present study not only enhanced our knowledge regarding soil pollution in the study area but also introduced a better technique to analyze pollution indices by multivariate geostatistical methods. PMID- 26956010 TI - Thioridazine inhibits gene expression control of the cell wall signaling pathway (CWI) in the human pathogenic fungus Paracoccidioides brasiliensis. AB - Paracoccidioides brasiliensis is a thermodimorphic fungus associated with paracoccidioidomycosis (PCM), the most common systemic mycosis in Latin America. PCM treatment involves a long-term chemotherapeutic approach and relapses occur at an alarming frequency. Moreover, the emergence of strains with increased drug resistance phenotypes puts constant pressure on the necessity to develop new alternatives to treat systemic mycoses. In this work, we show that the phenothiazine (PTZ) derivative thioridazine (TR) inhibits in vitro growth of P. brasiliensis yeasts at micromolar concentrations. We employed microarray hybridization to examine how TR affects gene expression in this fungus, identifying ~1800 genes that were modulated in response to this drug. Dataset evaluation showed that TR inhibits the expression of genes that control the onset of the cell wall integrity (CWI) response, hampering production of all major structural polysaccharides of the fungal cell wall (chitin, alpha-glucan and beta glucan). Although TR and other PTZs have been shown to display antimicrobial activity by various mechanisms, inhibition of CWI signaling has not yet been reported for these drugs. Thus, TR may provide a novel approach to treat fungal infections by targeting cell wall biogenesis. PMID- 26956013 TI - Rapid assessment of total and polycyclic aromatic contents in heavy oils. AB - The monitoring of the content of polycyclic aromatic hydrocarbons (PAHs) is important for evaluating heavy oil products, especially those most likely to cause environmental impacts. In this study, a comparison between samples of heavy petroleum fractions, using different methods, was carried out. The calculation of carbon distribution and polycyclic aromatic contents was compared with other methods using Fourier transform infrared spectroscopy (FTIR). Therefore, it was possible to quickly estimate the aromatic content by the FTIR method, and the results showed consistency with those obtained through traditional methods. A rapid method, using extraction with dimethyl sulfoxide followed by FTIR measurements, was proposed and shown as particularly useful and reliable for a quick quantification of the PAH content, when compared to the traditional IP 346 method. Furthermore, the difference in total aromatic and PAH concentrations may be more clearly established. This rapid method may be used for the evaluation of PAH content in samples obtained from studies for their removal from complex heavy oil fractions. PMID- 26956015 TI - Effect of an organizational change in a prehospital trauma care protocol and trauma transport directive in a large urban city: a before and after study. AB - BACKGROUND: Trauma systems and regionalized trauma care have been shown to improve outcome in severely injured trauma patients. The aim of this study was to evaluate the implementation of a prehospital trauma care protocol and transport directive, and to determine its effects on the number of primary admissions and secondary trauma transfers in a large Scandinavian city. METHODS: We performed a retrospective observational study based on local trauma registries and hospital and ambulance records in Stockholm County; patients > 15 years of age with an Injury Severity Score (ISS) > 15 transported to any emergency care hospitals in the Stockholm area were included for the years 2006 and 2008. We also included secondary transferred patients to the regional trauma center during 2006, 2008, and 2013. RESULTS: A total of 693 primarily admitted trauma patients were included for the years 2006 and 2008. For the years 2006, 2008 and 2013, we included 114 secondarily transported trauma patients. The number of primary patient transports to the trauma center increased during the years by 20.2%, (p < 0.001); patients primarily transported to the trauma center had a significantly higher Injury Severity Score in 2008 than in 2006, and the number of patients transported secondarily to the trauma center in 2006 was higher compared to 2008 and to 2013 (p < 0.001, all 3 years). DISCUSSION: Our data indicate that implementation of a prehospital trauma care protocol may have an effect on transportation of severely injured trauma patients. A decrease in secondarily transported trauma patients to the regional trauma center was noted after 1 year and persisted at 7 years after the organizational change. Patients primarily admitted to the trauma center after the change had more severe injuries than patients transported to other emergency hospitals in the area even if 20 % of patients were not admitted primarily to a trauma center. This does not imply that the transport directives or the criteria were not followed but rather reveals the difficulties and uncertainties of field triage. CONCLUSIONS: With the introduction of a prehospital trauma transport directive in a large urban city, an increase in patients transported to the regional trauma center and a decrease in secondary transfers were detected, but a considerable number of severely injured patients were still transported to local hospitals. PMID- 26956016 TI - High risk of drug-induced microscopic colitis with concomitant use of NSAIDs and proton pump inhibitors. AB - BACKGROUND: Microscopic colitis (MC) is a chronic bowel disorder characterised by watery diarrhoea. Nonsteroidal anti-inflammatory drugs (NSAIDs), proton pump inhibitors (PPIs), selective serotonin reuptake inhibitors (SSRIs) and statins have been associated with MC. However, underlying mechanisms remain unclear. AIM: To study the association between exposure to these drugs and MC, with attention to time of exposure, duration, dosage and combined exposure, and to test hypotheses on underlying pharmacological mechanisms. METHODS: A case-control study was conducted using the British Clinical Practice Research Datalink. MC cases (1992-2013) were matched to MC-naive controls on age, sex and GP practice. Drug exposure was stratified according to time of exposure, duration of exposure or dosage. Conditional logistic regression analysis was applied to calculate adjusted odds ratios (AORs). RESULTS: In total, 1211 cases with MC were matched to 6041 controls. Mean age was 63.4 years, with 73.2% being female. Current use of NSAIDs (AOR 1.86, 95% CI 1.39-2.49), PPIs (AOR 3.37, 95% CI 2.77-4.09) or SSRIs (AOR 2.03, 95% CI 1.58-2.61) was associated with MC compared to never or past use. Continuous use for 4-12 months further increased the risk of MC. Strongest associations (fivefold increased risk) were observed for concomitant use of PPIs and NSAIDs. Statins were not associated with MC. CONCLUSIONS: Current exposure to NSAIDs, PPIs or SSRIs and prolonged use for 4-12 months increased the risk of MC. Concomitant use of NSAIDs and PPIs showed the highest risk of MC. Acid suppression related dysbiosis may contribute to the PPI effect, which may be exacerbated by NSAID-related side-effects. PMID- 26956018 TI - Worker Alienation and Compensation at the Savannah River Site. AB - Corporations operating U.S. nuclear weapons plants for the federal government began tracking occupational exposures to ionizing radiation in 1943. However, workers, scholars, and policy makers have questioned the accuracy and completeness of radiation monitoring and its capacity to provide a basis for workers' compensation. We use interviews to explore the limitations of broad scale, corporate epidemiological surveillance through worker accounts from the Savannah River Site nuclear weapons plant. Interviewees report inadequate monitoring, overbearing surveillance, limited venues to access medical support and exposure records, and administrative failure to report radiation and other exposures at the plant. The alienation of workers from their records and toil is relevant to worker compensation programs and the accuracy of radiation dose measurements used in epidemiologic studies of occupational radiation exposures at the Savannah River Site and other weapons plants. PMID- 26956017 TI - Occupational Hazards in the Thai Healthcare Sector. AB - Healthcare personnel work in vulnerable conditions that can adversely impact physical and/or mental health. This paper aims to synthesize the state of knowledge on work-related illnesses, injuries, and risks experienced by Thai healthcare workers. We found that Thai healthcare personnel, like others worldwide, are at risk for injury related to needle sticks and sharp instruments; infectious diseases due to biological hazards exposure such as airborne pathogens and patient secretions; muscle pain due to workload and long duration of work; and psychological disorders related to stressful working conditions. Because detailed surveillance data are limited for the Thai healthcare workforce, we recommend that additional surveillance data on Thai healthcare workers' health outcomes be collected. Future research efforts should also focus on evidence based interventions in order to develop methods to prevent and treat occupational health injuries and illnesses acquired in the workplace for Thai healthcare sector workers. PMID- 26956019 TI - Retrospective analysis of population-based causes of death and life expectancy in urban Western China from 2003 to 2012. AB - BACKGROUND: Hitherto, a population-based analysis of the cause of death in urban areas of Western China has not been undertaken over an extended period. The aims of this study were to calculate the overall and annual cause-specific mortality rates by age and sex in urban areas of Western China from 2003 to 2012 and to evaluate the quality of the data. METHODS: We used Excel software, cause-of-death registrations, and International Classification of Diseases, 10th revision, codes to calculate the overall and yearly cause-specific crude mortality rates by age and sex, the Chinese age-standardized mortality rate, and life expectancies. RESULTS: In the Jiulongpo District from 2003 to 2012, there was an increase in the number of death case reports in the census-registered population, a decrease in the number of omitted deaths, and rise in the crude mortality rate. Except for 2003, the Chinese age-standardized mortality rate was the lowest in 2012 (330.83/100,000) and highest in 2005 (390.08/100,000). Life expectancy increased from 78.36 years in 2005 to 81.67 years in 2012. CONCLUSIONS: With the development of its social economy, the Chinese government and public attach greater importance to cause-of-death surveillance. The quality of cause-of-death registrations has gradually increased, crude mortality rates have risen, the Chinese age-standardized mortality rate has fallen, and life expectancies have increased. PMID- 26956020 TI - Comparative characterization of two GDP-mannose dehydrogenase genes from Saccharina japonica (Laminariales, Phaeophyceae). AB - BACKGROUND: Saccharina japonica is an important commercial brown seaweed, its main product is alginate, which is used in food, textile and by the cosmetic and pharmaceutical industries. GDP-mannose dehydrogenase (GMD) is the key enzyme involved in the synthesis of alginate. However, little is known about GMD in S. japonica. Here we report comparative biochemical analysis of two GMD genes in S. japonica. RESULTS: Two GMD genes from S. japonica (Sjgmd1, Sjgmd2) were cloned. The open reading frame lengths of Sjgmd1, Sjgmd2 are 963 bp and 948 bp, respectively. Alignment analysis showed that the two SjGMD sequences shared 79.38 % identity. Both proteins possess the GGxCLPKDV and GxGxVG sequence motifs characteristic of the short-chain dehydrogenase/reductase superfamily. The optimum temperatures for SjGMDs were 30 degrees C (SjGMD1) and 20 degrees C (SjGMD2), and the optimum pH values were 8.0 (SjGMD1) and 8.25 (SjGMD2). Kinetic analysis demonstrated the Km values for the substrate GDP-mannose were 289 MUM (SjGMD1) and 177 MUM (SjGMD2), and the Km values for the cofactor NAD(+) were 139 MUM (SjGMD1) and 195 MUM (SjGMD2). The metal iron Zn(2+) is a potent inhibitor of SjGMD1 and SjGMD2. Real-time PCR analysis showed that heat and desiccation treatments resulted in a significant increase in Sjgmd1 and Sjgmd2 transcript abundance, suggesting that the SjGMDs are directly involved in the acclimitisation of S. japonica to abiotic stresses. CONCLUSION: Our work identified two novel genes encoding GMD in S. japonica, comparatively characterized their structural characteristics and enzyme kinetics, and revealed the function of GMD in the stress adaptability of S. japonica. The knowledge obtained here enriched our understanding of the alginate synthesis mechanism in S. japonica, and may promote further research on functional differences between GMD genes. PMID- 26956021 TI - Mapping the genomic mosaic of two 'Afro-Bolivians' from the isolated Yungas valleys. AB - BACKGROUND: Unraveling the ancestry of 'Afro-American' communities is hampered by the complex demographic processes that took place during the Transatlantic Slave Trade (TAST) and the (post-)colonization periods. 'Afro-Bolivians' from the subtropical Yungas valleys constitute small and isolated communities that live surrounded by the predominant Native American community of Bolivia. By genotyping >580,000 SNPs in two 'Afro-Bolivians', and comparing these genomic profiles with data compiled from more than 57 African groups and other reference ancestral populations (n = 1,161 in total), we aimed to disentangle the complex admixture processes undergone by 'Afro-Bolivians'. RESULTS: The data indicate that these two genomes constitute a complex mosaic of ancestries that is approximately 80 % of recent African origin; the remaining ~20 % being European and Native American. West-Central Africa contributed most of the African ancestry to 'Afro-Bolivians', and this component is related to populations living along the Atlantic coast (i.e. Senegal, Ghana, Nigeria). Using tract length distribution of genomic segments attributable to distinct ancestries, we could date the time of admixture in about 400 years ago. This time coincides with the maximum importation of slaves to Bolivia to compensate the diminishing indigenous labor force needed for the development of the National Mint of Potosi. CONCLUSIONS: Overall, the data indicate that the genome of 'Afro-Bolivians' was shaped by a complex process of admixture occurring in America among individuals originating in different West Central African populations; their genomic mosaics received additional contributions of Europeans and local Native Americans (e.g. Aymaras). PMID- 26956022 TI - Prospective, single-center cohort study analyzing the efficacy of complete laparoscopic resection on recurrent hepatocellular carcinoma. AB - BACKGROUND: Laparoscopic hepatectomy is increasingly being used to treat hepatocellular carcinoma (HCC). However, few studies have examined the treatment of recurrent HCC in patients who received a prior hepatectomy. The present prospective study compared the clinical efficacy of laparoscopic surgery with conventional open surgery in HCC patients with postoperative tumor recurrence. METHODS: We conducted a prospective study of 64 patients, all of whom had undergone open surgery once before, who were diagnosed with recurrent HCC between June 2014 and November 2014. The laparoscopic group (n = 31) underwent laparoscopic hepatectomy, and the control group (n = 33) underwent conventional open surgery. Operation time, intraoperative blood loss, surgical margins, postoperative pain scores, postoperative time until the patient could walk, anal exsufflation time, length of hospital stay, and inpatient costs were compared between the two groups. The patients were followed up for 1 year after surgery, and relapse-free survival was compared between the two groups. RESULTS: All surgeries were successfully completed. No conversion to open surgery occurred in the laparoscopic group, and no serious postoperative complications occurred in either group. No significant difference in inpatient costs was found between the laparoscopic group and the control group (P = 0.079), but significant differences between the two groups were observed for operation time (116.7 +/- 37.5 vs. 148.2 +/- 46.7 min, P = 0.031), intraoperative blood loss (117.5 +/- 35.5 vs. 265.9 +/- 70.3 mL, P = 0.012), postoperative time until the patient could walk (1.6 +/- 0.6 vs. 2.2 +/- 0.8 days, P < 0.05), anal exsufflation time (2.1 +/- 0.3 vs. 2.8 +/- 0.7 days, P = 0.041), visual analogue scale pain score (P < 0.05), postoperative hepatic function (P < 0.05), and length of hospital stay (4.5 +/- 1.3 vs. 6.0 +/- 1.2 days, P = 0.014). During the 1-year postoperative follow-up period, 6 patients in each group had recurrent HCC on the side of the initial operation, but no significant difference between groups was observed in the recurrence rate or relapse-free survival. In the laparoscopic group, operation time, postoperative time until the patient could walk, anal exsufflation time, and inpatient costs were not different (P > 0.05) between the patients with contralateral HCC recurrence (n = 18) and those with ipsilateral HCC recurrence (n = 13). However, intraoperative blood loss was significantly less (97.7 +/- 14.0 vs. 186.3 +/- 125.6 mL, P = 0.012) and the hospital stay was significantly shorter (4.2 +/- 0.7 vs. 6.1 +/- 1.7 days, P = 0.021) for the patients with contralateral recurrence than for those with ipsilateral recurrence. CONCLUSIONS: For the patients who previously underwent conventional open surgical resection of HCC, complete laparoscopic resection was safe and effective for recurrent HCC and resulted in a shorter operation time, less intraoperative blood loss, and a faster postoperative recovery than conventional open surgery. Laparoscopic resection was especially advantageous for the patients with contralateral HCC recurrence. PMID- 26956023 TI - A Global Charter for the Public's Health-the public health system: role, functions, competencies and education requirements. PMID- 26956024 TI - Ambient particulate matter and microRNAs in extracellular vesicles: a pilot study of older individuals. AB - BACKGROUND: Air pollution from particulate matter (PM) has been linked to cardiovascular morbidity and mortality; however the underlying biological mechanisms remain to be uncovered. Gene regulation by microRNAs (miRNAs) that are transferred between cells by extracellular vesicles (EVs) may play an important role in PM-induced cardiovascular risk. This study sought to determine if ambient PM2.5 levels are associated with expression of EV-encapsulated miRNAs (evmiRNAs), and to investigate the participation of such evmiRNAs in pathways related to cardiovascular disease (CVD). METHODS: We estimated the short- (1-day), intermediate- (1-week and 1-month) and long-term (3-month, 6-month, and 1-year) moving averages of ambient PM2.5 levels at participants' addresses using a validated hybrid spatio-temporal land-use regression model. We collected 42 serum samples from 22 randomly selected participants in the Normative Aging Study cohort and screened for 800 miRNAs using the NanoString nCounter(r) platform. Mixed effects regression models, adjusted for potential confounders were used to assess the association between ambient PM2.5 levels and evmiRNAs. All p-values were adjusted for multiple comparisons. In-silico Ingenuity Pathway Analysis (IPA) was performed to identify biological pathways that are regulated by PM associated evmiRNAs. RESULTS: We found a significant association between long term ambient PM2.5 exposures and levels of multiple evmiRNAs circulating in serum. In the 6-month window, ambient PM2.5 exposures were associated with increased levels of miR-126-3p (0.74 +/- 0.21; p = 0.02), miR-19b-3p (0.52 +/- 0.15; p = 0.02), miR-93-5p (0.78 +/- 0.22; p = 0.02), miR-223-3p (0.74 +/- 0.22; p = 0.02), and miR-142-3p (0.81 +/- 0.21; p = 0.03). Similarly, in the 1-year window, ambient PM2.5 levels were associated with increased levels of miR-23a-3p (0.83 +/- 0.23; p = 0.02), miR-150-5p (0.90 +/- 0.24; p = 0.02), miR-15a-5p (0.70 +/- 0.21; p = 0.02), miR-191-5p (1.20 +/- 0.35; p = 0.02), and let-7a-5p (1.42 +/ 0.39; p = 0.02). In silico pathway analysis on PM2.5-associated evmiRNAs identified several key CVD-related pathways including oxidative stress, inflammation, and atherosclerosis. CONCLUSIONS: We found an association between long-term ambient PM2.5 levels and increased levels of evmiRNAs circulating in serum. Further observational studies are warranted to confirm and extend these important findings in larger and more diverse populations, and experimental studies are needed to elucidate the exact roles of evmiRNAs in PM-induced CVD. PMID- 26956026 TI - Reconstructive algorithms in the pediatric population. AB - Reconstruction of oncologic defects in the pediatric population is a unique challenge. Differences in patient comorbidities, size of the reconstructive components, response of the skeletally immature body to surgery and radiation, compliance, and overall recovery potential make the pediatric patient cohort distinct from the adult population. Considering that patients are enjoying longer life spans, it behooves the surgeon to reconstruct oncologic defects with durable and long-lasting tissue. Determining when to implement each of the reconstructive tools is based upon principles embodied by the reconstructive ladder and taking into account the defect-specific characteristics, including location and type of tissues involved. Within the setting of multi-disciplinary care, reconstruction can be associated with good long-term functional and aesthetic outcomes. J. Surg. Oncol. 2016;113:940-945. (c) 2016 Wiley Periodicals, Inc. PMID- 26956025 TI - The effect of moderate intensity exercise in the postprandial period on the inflammatory response to a high-fat meal: an experimental study. AB - BACKGROUND: Consuming a high-fat meal (HFM) may lead to postprandial lipemia (PPL) and inflammation. Postprandial exercise has been shown to effectively attenuate PPL. However, little is known about the impact of postprandial exercise on systemic inflammation and whether PPL and inflammation are associated. The purpose of this study was to determine whether moderate intensity exercise performed 60 min following a true-to-life HFM would attenuate PPL and inflammation. METHODS: Thirty-nine young adults (18-40 year) with no known metabolic disease were randomized to either a control group (CON) who remained sedentary during the postprandial period or an exercise (EX) group who walked at 60 % VO2peak to expend ~ 5 kcal/kgbw one-hour following the HFM. Participants consumed a HFM of 10 kcal/kgbw and blood draws were performed immediately before, 2 h and 4 h post-HFM. RESULTS: At baseline, there were no differences between EX and CON groups for any metabolic or inflammatory markers (p > 0.05). Postprandial triglycerides (TRG) increased from baseline to 4 h in the EX and CON groups (p < 0.001), with no differences between groups (p = 0.871). High density lipoprotein cholesterol (HDL-C) decreased in both groups across time (p < 0.001) with no differences between groups (p = 0.137). Interleukin-6 (IL-6) was significant as a quadratic function over time (p = 0.005), decreasing from baseline to 2 h then increasing and returning to baseline at 4 h in all participants with no difference between groups (p = 0.276). Tumor necrosis factor-alpha (TNF-alpha) was not different from baseline to 4 h between groups (p > 0.05). There was an increase in soluble vascular adhesion molecule (sVCAM-1) from baseline to 4 h (p = 0.027) for all participants along with a group x time interaction (p = 0.020). Changes in TRG were associated with changes in interleukin-10 (IL-10) from 0 to 2 h (p = 0.007), but were not associated with changes in any other inflammatory marker in the postprandial period (p > 0.05). CONCLUSIONS: Despite significant increases in PPL following a HFM, moderate intensity exercise in the postprandial period did not mitigate the PPL nor the inflammatory response to the HFM. These results indicate that in populations with low metabolic risk, PPL and inflammation following a HFM may not be directly related. PMID- 26956027 TI - Developing fibre optic Raman probes for applications in clinical spectroscopy. AB - Raman spectroscopy has been shown by various groups over the last two decades to have significant capability in discriminating disease states in bodily fluids, cells and tissues. Recent development in instrumentation, optics and manufacturing approaches has facilitated the design and demonstration of various novel in vivo probes, which have applicability for myriad of applications. This review focusses on key considerations and recommendations for application specific clinical Raman probe design and construction. Raman probes can be utilised as clinical tools able to provide rapid, non-invasive, real-time molecular analysis of disease specific changes in tissues. Clearly the target tissue location, the significance of spectral changes with disease and the possible access routes to the region of interest will vary for each clinical application considered. This review provides insight into design and construction considerations, including suitable probe designs and manufacturing materials compatible with Raman spectroscopy. PMID- 26956030 TI - Full protection of swine against foot-and-mouth disease by a bivalent B-cell epitope dendrimer peptide. AB - Foot-and-mouth disease virus (FMDV) causes a highly contagious disease of cloven hoofed animals. We have reported (Cubillos et al., 2008) that a synthetic dendrimeric peptide consisting of four copies of a B-cell epitope [VP1(136-154)] linked through thioether bonds to a T-cell epitope [3A(21-35)] of FMDV [B4T(thi)] elicits potent B- and T-cell specific responses and confers solid protection in pigs to type C FMDV challenge. Herein we show that downsized versions of this peptide bearing two copies of a B-cell epitope from a type O isolate and using thioether [B2T(thi)] or maleimide [B2T(mal)] conjugation chemistries for their synthesis elicited in swine similar or higher B and T-cell specific responses than tetravalent B4T(thi). Moreover, while partial protection was observed in animals immunized with B4T(thi) (60%) and B2T(thi) (80%), B2T(mal) conferred full (100%) protection against FMDV challenge, associated to high levels of circulating IgG2 and mucosal IgGA, and entirely prevented virus shedding. Interestingly, B2T(mal) is also the most advantageous option in terms of synthetic practicality. Taken together, the results reported here point out to B2T(mal) as a highly valuable, cost-effective FMDV candidate vaccine. PMID- 26956029 TI - Understanding differences in HIV/HCV prevalence according to differentiated risk behaviors in a sample of PWID in rural Puerto Rico. AB - BACKGROUND: Blood contained in needles and injection equipment has been identified as a vector for HIV and HCV transmission among people who inject drugs (PWID). Yet, there is often a wide discrepancy in prevalence for both viruses. While microbiological differences between viruses influence prevalence, other variables associated with the way drugs are acquired and used, also play a role. METHODS: Respondent-driven sampling (RDS) methods recruited a sample of 315 current intravenous drug users in rural Puerto Rico. Information about type and frequency of use, HIV and HVC risk behaviors (sharing needles, cookers, cotton, and water), sexual behaviors, and alcohol use was collected. HIV and HCV statuses were assessed via rapid antibody tests. T tests compare means of participants who tested positive (reactive) to those who tested negative. Logistic regression analyses were used to validate the association of the risk factors involved. RESULTS: Tests showed a significant difference in HIV (6%) and HCV (78.4%) prevalence among a population of current PWID. The main risk behaviors in HCV transmission are the sharing of injection "works", (e.g., cookers, cotton, and water). Sharing works occurred more than twice as often as the sharing of needles, and HCV+ and HCV- individuals reported the same needle sharing habits. CONCLUSIONS: Washing and rinsing injection works with water seems to prevent HIV transmission, but it is unable to prevent HCV infection. While education about the need to clean injection equipment with bleach might be beneficial, equipment sharing--and the subsequent risk of HVC--might be unavoidable in a context where participants are forced to pool resources to acquire and use intravenous drugs. PMID- 26956031 TI - Morphological classification of penetrating artery pontine infarcts and association with risk factors and prognosis: The SPS3 trial. AB - BACKGROUND: Pontine infarcts are common and often attributed to small vessel disease ("small deep infarcts") or basilar branch atherosclerosis ("wedge shaped"). A well-described morphological differentiation using magnetic resonance images has not been reported. Furthermore, whether risk factors and outcomes differ by morphology, or whether infarct morphology should guide secondary prevention strategy, is not well characterized. METHODS: All participants in the Secondary Prevention of Small Subcortical Strokes Study with magnetic resonance imaging -proven pontine infarcts were included. Infarcts were classified as well circumscribed small deep (small deep infarct, i.e. lacunar), paramedian, atypical paramedian, or other based on diffusion-weighted imaging, T2/fluid-attenuated inversion recovery, and T1-magnetic resonance images. Inter-rater reliability was high (90% agreement, Cohen's kappa = 0.84). Clinical and radiologic features independently associated with small deep infarct versus paramedian infarcts were identified (multivariable logistic regression). Differences in stroke risk and death were assessed using Cox proportional hazards. RESULTS: Of the 3020 patients enrolled, 644 had pontine infarcts; 619 images were available: 302(49%) small deep infarct, 245 (40%) paramedian wedge, 35 (6%) atypical paramedian, and 37 (6%) other. Among vascular risk factors, only smoking (OR 2.1, 95% CI 1.3-3.3) was independently associated with small deep infarct versus paramedian infarcts; on neuroimaging, old lacunes on T1/fluid-attenuated inversion recovery (OR 1.8, 1.3-2.6) and intracranial stenosis (any location) >=50% (OR 0.62, 0.41-0.96). Small deep infarct versus paramedian was not predictive of either recurrent stroke or death, and there was no interaction with assigned treatment. CONCLUSIONS: Pontine infarcts can be reliably classified based on morphology using clinical magnetic resonance images. Few risk factors differed between small deep infarct and paramedian infarcts with no differences in recurrent stroke or mortality. There was no difference in response to different antiplatelet or blood pressure treatment strategies between these two groups. REGISTRATION: http://www.clinicaltrials.gov/NCT00059306. PMID- 26956032 TI - Swipe out Stroke: Feasibility and efficacy of using a smart-phone based mobile application to improve compliance with weight loss in obese minority stroke patients and their carers. AB - RATIONALE: Swipe out Stroke (SOS) examines the use of a smartphone-based mobile application to reduce obesity in high-risk minority stroke patients. At record high levels in the United States, obesity disproportionately affects minorities and is highly correlated with cerebrovascular disease. Unfortunately, structured weight loss programs are expensive, and compliance significantly decreases upon program completion. Mobile health (mHealth) technology is an innovative, cost effective way to bridge this gap. Minorities spend over 4.5 billion dollars annually on consumer electronics, making studies that utilize mHealth applications ideal for health promotion and disease prevention. AIMS AND DESIGN: SOS is a prospective, randomized-controlled trial with open blinded endpoint comparing an mHealth based dietary intervention to usual care to facilitate weight reduction. Ischemic and hemorrhagic stroke survivors and their carers are recruited from the acute care service of a Houston-based comprehensive stroke center. A neurorehabilitation physician or vascular neurologist meets with participants during the index hospitalization, a baseline clinic visit, followed by visits at 1, 3, and 6 month intervals. The SOS Team focuses on feasible modifications to the Southern dietary pattern (fried foods, fatty foods, added fats, eggs, processed meats, such as bacon and ham, organ meats (e.g., liver), and sweetened drinks) and caloric restriction to facilitate a 5% reduction in total body weight. Practical barriers to adherence are addressed, such as access to transportation, financial limitations, and depression. STUDY OUTCOMES: The primary dependent measure is a reduction of total body weight. Secondary outcomes include systolic blood pressure, hemoglobin A1c, low-density lipoprotein, triglycerides, and Factor VIII. CONCLUSION: SOS will determine whether a Phase III effectiveness trial of a smartphone-based mobile application to address obesity-related health disparities is warranted throughout the Southeastern United States (Stroke Belt). PMID- 26956033 TI - Dextran sulfate inhibits acute Toxoplama gondii infection in pigs. AB - BACKGROUND: Toxoplasma gondii is a highly prevalent protozoan that can infect all warm-blooded animals, including humans. Its definitive hosts are Felidae and its intermediate hosts include various other mammals and birds, including pigs. It is found in the meat of livestock which is a major source of human infection. Hence the control of toxoplasmosis in pigs is important for public health. We previously showed that dextran sulfate (DS), especially DS10 (dextran sulfate MW 10 kDa), is effective against T. gondii infection both in vitro and in mice. In this study, we asked whether DS affects T. gondii infection of pigs, one of the main animal sources of toxoplasmosis transmission to humans. METHODS: Fourteen day-old male pigs (n = 10) were infected with T. gondii and then immediately treated with different doses of DS10; clinical, pathological, and immunological analyses were performed 5 days post-infection. RESULTS: DS10 had an inhibitory effect on toxoplasmosis in pigs. Intravenous injection of DS10 prevented the symptoms of toxoplasmosis and reduced the parasite burden and inflammation induced by T. gondii infection. High-dose DS10 (500 MUg per head) caused reversible hepatocellular degeneration of the liver; middle-dose DS10 (50 MUg per head) was effective against toxoplasmosis in pigs without causing this side effect. CONCLUSIONS: Our data suggest that middle-dose DS10 led to minimal clinical symptoms of T. gondii infection and caused little hepatocellular degeneration in our pig model, thereby demonstrating its potential as a new treatment for toxoplasmosis. These data should be very beneficial to those interested in the control of toxoplasmosis in pigs. PMID- 26956034 TI - Paediatric cardiology fellowship training: effect of work-hour regulations on scholarly activity. AB - BACKGROUND: In 2003, work-hour regulations were implemented by the Accreditation Council for Graduate Medical Education. Much has been published regarding resident rest and quality of life as well as patient safety. There has been no examination on the effect of work-hour restrictions on academic productivity of fellows in training. Paediatric subspecialty fellows have a scholarly requirement mandated by the American Board of Pediatrics. We have examined the impact of work hour restrictions on the scholarly productivity of paediatric cardiology fellows during their fellowship. METHODS: We conducted a literature search for all paediatric cardiology fellows between 1998 and 2007 at a single academic institution as first or senior authors on papers published during their 3-year fellowship and 3 years after completion of their categorical fellowship (n=63, 30 fellows before 2003 and 33 fellows after 2003). The numbers of first- or senior author fellow publications before and after 2003 were compared. We also collected data on final paediatric cardiology subspecialty career choice. RESULTS: There was no difference in the number of fellow first-author publications before and after 2003. Before work-hour restrictions, the mean number of publications per fellow was 2.1 (+/-2.2), and after work-hour restrictions it was 2.0 (+/-1.8), (p=0.89). By subspecialty career choice, fellows who select electrophysiology, preventative cardiology, and heart failure always published within the 6-year time period. CONCLUSIONS: Since the implementation of work-hour regulations, total number of fellow first-authored publications has not changed. The role of subspecialty choice may play a role in academic productivity of fellows in training. PMID- 26956035 TI - Incidence of BRCA1 somatic mutations and response to neoadjuvant chemotherapy in Chinese women with triple-negative breast cancer. AB - BACKGROUND: The prevalence of BRCA1 somatic mutations status in triple-negative breast cancer (TNBC) has not been well documented. The aims of this study were to determine the frequency of BRCA1 somatic mutations and to investigate the association between BRCA1 deleterious somatic mutation status and response to neoadjuvant chemotherapy in women with TNBC. METHODS: Two hundred and five TNBC patients without BRCA1 germline mutations were enrolled in this study. Fresh tumor tissues were available for this cohort of 205 patients, including 112 patients with fresh core needle biopsy tumor tissues before treatment and 93 patients with fresh tumor tissues procured after surgery. BRCA1 somatic mutations were determined in the tumor samples using PCR-direct sequencing assay. Among the 112 patients with core needle biopsy samples, 97 patients received neoadjuvant chemotherapy. RESULTS: Eight patients (3.9%) carried a BRCA1 pathogenic somatic mutation in this cohort of 205 TNBC patients. These eight BRCA1 deleterious somatic mutations included five frameshift or nonsense mutations (c.191_212del22, c.1664delA, c.4674_4675+17del, c.3671_3672insTTCC, c.1162A>T), one splicing site mutation (c.134+2T>G) and two missense mutations (c.5511G>C and c.286G>A). No significant differences in tumor characteristics between BRCA1 deleterious somatic mutation carriers and non-carriers were observed. The pCR (pathologic complete response) rate was 32.0% in the 97 patients who received neoadjuvant chemotherapy. BRCA1 deleterious somatic mutation carriers (n=5) had a higher pCR rate than did non-carriers (n=92) (BRCA1 carriers vs non-carriers, 60.0% vs 30.4%, P=0.32), although it did not reach a significance due to a small sample size. CONCLUSIONS: A small subset of TNBC patients carried a BRCA1 deleterious somatic mutation; BRCA1 somatic mutation carriers are likely to respond to neoadjuvant chemotherapy. PMID- 26956036 TI - Constitutive expression of PPARgamma inhibits proliferation and migration of gastric cancer cells and down-regulates Wnt/beta-Catenin signaling pathway downstream target genes TERT and ENAH. AB - BACKGROUND: Peroxisome proliferator-activated receptor gamma (PPARgamma) is a member of the PPAR nuclear hormone receptor superfamily, which plays a crucial role in carcinogenesis. Wnt/beta-Catenin signaling pathway has been well certified to contribute to the progression of gastric malignancies. beta-Catenin mediates transcriptional regulation by forming a complex with LEF/TCF transcription factors, resulting in activation of downstream target genes such as TERT, ENAH. In this study, we aimed at detecting the effect of PPARgamma on TERT, ENAH and explaining the further mechanisms of PPARgamma on tumor suppression. METHODS: The pEGFP-N1-PPARgamma recombinant plasmid has already been constructed by researchers in our laboratory. We stably transfected it into three gastric cancer (GC) cell lines (MKN-28, SGC-7901 and BGC-823). CCK-8 and transwell assay were employed to analyze the capability of cell proliferation and metastasis. The mRNA and protein levels were evaluated by real-time PCR and western blot analysis. RESULTS: After transfected with PPARgamma overexpression plasmid, the ability of cell proliferation and migration declined significantly (p<0.05). The expression of PPARgamma increased (p<0.05) and beta-Catenin was inhibited obviously (p<0.05) in the group of pEGFP-N1-PPARgamma plasmid transfection. Meanwhile, the mRNA or protein levels of TERT and ENAH were suppressed (p<0.05) in pEGFP-N1-PPARgamma plasmid transfection group compared with control groups. CONCLUSION: PPARgamma might inhibit the proliferation and migration of GC cell lines through suppressing the expression of TERT and ENAH. PPARgamma played an important role as a physiological regulator and might be a target for the treatment of GC. PMID- 26956037 TI - Chronic myeloid leukemia incidence, survival and accessibility of tyrosine kinase inhibitors: a report from population-based Lithuanian haematological disease registry 2000-2013. AB - BACKGROUND: Currently available chronic myeloid leukaemia (CML) survival reports have originated from more affluent countries. Herein we report the entire country data on incidence and survival of CML, as well as penetrance of tyrosine kinase inhibitors (TKIs) in Lithuania. METHODS: We analyzed all patients (N = 601) from the national haematological disease monitoring system who were diagnosed with CML between 2000 and 2013. Crude (CR) and age-standardized (weighted) (ASW(R)) incidence and mortality rates, as well as 1-, 5-, and 10-year relative survival rates (RSR) were calculated. Information on TKI penetration is also reported. RESULTS: Throughout the entire 2000-2013 period the median age at diagnosis of CML patients was 62 years. The respective incidence and mortality CRs were 1.28 and 0.78, both characterized by decreasing trends over the observation period. A 5-year RSR increased from 0.33 [95 % CI, 0.27-0.40] in 2000-2004 to 0.55 [95 % CI, 0.47-0.63] in 2005-2009. However, the respective 5-year RSRs for patients aged 65-74 and >=75 were only 0.33 [95 % CI, 0.24-0.42] and 0.18 [95 % CI 0.07 0.23] during the entire study period. TKI penetrance for CML patients grew from 1.5 % in 2000-2004 to 30.6 % in 2005-2009 and 69.1 % in 2010-2013. TKI penetrance was low in the older age groups (60 % for the 65-74 and 19 % for the >=75 patient group, in 2010-2013). CONCLUSION: Relative CML survival in Lithuania steadily improved and paralleled the increase in TKI treatment availability. Patients above 64 years rarely received TKIs and their relative survival remained low throughout the observation period. The latency of TKI availability may have influenced the survival trends. PMID- 26956038 TI - Variations in SXT elements in epidemic Vibrio cholerae O1 El Tor strains in China. AB - Vibrio cholerae O1 El Tor biotype strains are responsible for three multiyear epidemics of cholera in China during the seventh ongoing pandemic. The presence of the integrative conjugative element SXT is strongly correlated with resistance to nalidixic acid, tetracycline, and trimethoprim-sulfamethoxazole in these strains. Here, we sequenced the conserved genes of the SXT element, including eex, setR, and int, from 59 V. cholerae O1 El Tor strains and extracted and assembled the intact SXT sequences from the 11 genome sequenced strains. These elements had characteristics distinct from those of previously reported integrative conjugative elements (ICEs). They could be clearly divided into two types based on the clustering of conserved genes and gene structures of the elements, showing their possibly independent derivation and evolution. These two types were present before and after 2005, respectively, demonstrating the type substitution that occurred in 2005. Four to six antibiotic-resistant genes were found on the SXT elements, including genes resistant to tetracycline, trimethoprim-sulfamethoxazole, and multiple drugs. In summary, our findings demonstrated the roles of the SXT element in the emergence of multidrug resistance in epidemic O1 El Tor V. cholerae strains in China. PMID- 26956040 TI - Testing the effects of a message framing intervention on intentions towards hearing loss prevention in adolescents. AB - Adolescent hearing loss is a public health problem that has eluded effective intervention. A persuasive message strategy was tested for its effectiveness on adolescents' intention to listen to music at a reduced volume. The messages manipulated both type of message frame [positive consequences of listening to music at a reduced volume (gain-framed) versus negative consequences of not listening to music at a reduced volume (loss-framed)] and type of temporal context (short-term versus long-term consequences). Participants were recruited from four vocational and secondary education schools in the Netherlands and message exposure took place online during class hours. Two weeks prior to message exposure, adolescents provided data on intention and risk perception towards hearing loss and use of (digital) music players. After message exposure, 194 adolescents (mean age = 14.71 years, SD = 1.00, 37.8% males) provided immediate follow-up data on intention. Results revealed that intention to listen to music at a reduced volume increased in those exposed to a loss-framed message with short-term consequences. No changes were found in the other conditions. Messages that emphasize negative short-term consequences of not listening to music at a moderate volume have the ability to influence adolescents' intention towards hearing loss prevention. PMID- 26956039 TI - Population-based evaluation of the 'LiveLighter' healthy weight and lifestyle mass media campaign. AB - The Western Australian (WA) 'LiveLighter' (LL) mass media campaign ran during June-August and September-October 2012. The principal campaign ad graphically depicts visceral fat of an overweight individual ('why' change message), whereas supporting ads demonstrate simple changes to increase activity and eat healthier ('how' to change message). Cross-sectional surveys among population samples aged 25-49 were undertaken pre-campaign (N= 2012) and following the two media waves (N= 2005 and N= 2009) in the intervention (WA) and comparison state (Victoria) to estimate the population impact of LL. Campaign awareness was 54% after the first media wave and overweight adults were more likely to recall LL and perceive it as personally relevant. Recall was also higher among parents, but equal between socio-economic groups. The 'why' message about health-harms of overweight rated higher than 'how' messages about lifestyle change, on perceived message effectiveness which is predictive of health-related intention and behaviour change. State-by-time interactions showed population-level increases in self referent thoughts about the health-harms of overweight (P < 0.05) and physical activity intentions (P < 0.05). Endorsement of stereotypes of overweight individuals did not increase after LL aired. LL was associated with some population-level improvements in proximal and intermediate markers of campaign impact. However, sustained campaign activity will be needed to impact behaviour. PMID- 26956042 TI - Photonic hybrid crystals constructed from in situ host-guest nanoconfinement of a light-emitting complex in metal-organic framework pores. AB - We report the concept underpinning the facile nanoconfinement of a bulky luminous guest molecule in the pores of a metal-organic framework (MOF) host, which yields a hybrid host ? guest nanomaterial with tunable opto-electronic characteristics and enhanced photostability. Utilizing an in situ host-guest confinement strategy enabled by molecular self-assembly, we show that the highly emitting ZnQ [Zn-(bis 8-hydroxyquinoline)] guest complexes could be rapidly encapsulated within the sodalite nanocages of zeolitic imidazolate framework (ZIF-8) host crystals. The nature of optical and electronic transitions phenomena of the guest-encapsulated ZIF-8 ? ZnQ has been elucidated by means of fluorescence and absorption spectroscopy measurements, and substantiated further via theoretical molecular orbital calculations revealing the plausible host-guest charge transfer mechanism involved. Evidence suggests that its photophysical properties are not only strongly determined by the host-guest co-operative bonding interactions within the environment of the confined MOF nanocage, but also can be engineered to manipulate its emission color chromaticity or to shield light-sensitive emitting guests against rapid photochemical degradation. PMID- 26956041 TI - Building young women's knowledge and skills in female condom use: lessons learned from a South African intervention. AB - Partner negotiation and insertion difficulties are key barriers to female condom (FC) use in sub-Saharan Africa. Few FC interventions have provided comprehensive training in both negotiation and insertion skills, or focused on university students. In this study we explored whether training in FC insertion and partner negotiation influenced young women's FC use. 296 female students at a South African university were randomized to a one-session didactic information-only minimal intervention (n= 149) or a two-session cognitive-behavioral enhanced intervention (n= 147), which received additional information specific to partner negotiation and FC insertion. Both groups received FCs. We report the 'experiences of' 39 randomly selected female students who participated in post intervention qualitative interviews. Two-thirds of women reported FC use. Most women (n= 30/39) applied information learned during the interventions to negotiate with partners. Women reported that FC insertion practice increased their confidence. Twelve women failed to convince male partners to use the FC, often due to its physical attributes or partners' lack of knowledge about insertion. FC educational and skills training can help facilitate use, improve attitudes toward the device and help women to successfully negotiate safer sex with partners. Innovative strategies and tailored interventions are needed to increase widespread FC adoption. PMID- 26956043 TI - Cycloartanes from Oxyanthus pallidus and derivatives with analgesic activities. AB - BACKGROUND: The leaves of Oxyanthus pallidus Hiern (Rubiaceae) are extensively used in the west region of Cameroon as analgesic. These leaves are rich in cycloartanes, a subclass of triterpenes known to possess analgesic and anti inflammatory properties. The present study aimed at evaluating the analgesic properties of three cycloartanes isolated from Oxyanthus pallidus leaves as well as their aglycones and acetylated derivatives. METHODS: Three cycloartanes OP3, OP5 and OP6 obtained by successive chromatography of the crude methanol extract of the leaves were hydrolysed to yield respective aglycone AOP1, AOP2, AOP3 and acetylated to HOP1, HOP2 and HOP3 respectively. Formalin-induced pain model was used to evaluate the acute anti-nociceptive properties of these cycloartanes (5 mg/kg, p.o) in mice and to determine the structure-activity relationship. Acute (24 h) and chronic (10 days) anti-hyperalgesic and anti-inflammatory activities of OP5 were evaluated at the doses of 2.5 and 5 mg/kg/day administered orally. OP6 was also evaluated in acute experiments. The antioxidant and hepato protective activities of OP5 were evaluated at the end of the chronic treatment. RESULTS: The mixture and the individual isolated cycloartanes significantly inhibited both phases of formalin-induced pain with percentage inhibition ranging from 13 to 78%. Acid hydrolysis did not significantly affect their antinociceptive activities while acetylation significantly reduced the effects of these compounds during the second phase of pain. OP5 and OP6 induced acute anti hyperalgesic activity in formalin-induced mechanical hyperalgesia but not an anti inflammatory effect. Repeated administration of OP5 for 10 days did not induce any anti-hyperalgesic effect. The evaluation of in vivo antioxidant properties showed that OP5 significantly reduced malondialdehyde and increased superoxide dismutase levels in liver without significantly affecting other oxidative stress and hepatotoxic parameters. Chronic administration of OP5 did not cause gastric ulceration. CONCLUSION: Cycloartanes isolated from Oxyanthus pallidus possess analgesic effects but lack anti-inflammatory activities. This analgesic effect especially on inflammatory pain may be due to the presence of hydroxyl group in front of the plane. OP5 is devoid of ulcerogenic effect and possess antioxidant properties that might be of benefit to its analgesic properties. PMID- 26956044 TI - Positive feedback regulation between IL10 and EGFR promotes lung cancer formation. AB - The role of IL10 in the tumorigenesis of various cancer types is still controversial. Here, we found that increased IL10 levels are correlated with a poor prognosis in lung cancer patients. Moreover, IL10 levels were significantly increased in the lungs and serum of EGFRL858R- and Kras4bG12D-induced lung cancer mice, indicating that IL10 might facilitate lung cancer tumorigenesis. IL10 knockout in EGFRL858R and Kras4bG12D mice inhibited the development of lung tumors and decreased the levels of infiltrating M2 macrophages and tumor promoting Treg lymphocytes. We also showed that EGF increases IL10 expression by enhancing IL10 mRNA stability, and IL10 subsequently activates JAK1/STAT3, Src, PI3K/Akt, and Erk signaling pathways. Interestingly, the IL10-induced recruitment of phosphorylated Src was critical for inducing EGFR through the activation of the JAK1/STAT3 pathway, suggesting that Src and JAK1 positively regulate each other to enhance STAT3 activity. Doxycycline-induced EGFRL858R mice treated with gefitinib and anti-IL10 antibodies exhibited poor tumor formation. In conclusion, IL10 and EGFR regulate each other through positive feedback, which leads to lung cancer formation. PMID- 26956045 TI - The TGF-beta pathway is activated by 5-fluorouracil treatment in drug resistant colorectal carcinoma cells. AB - TGF-beta pathway is generally associated with the processes of metastasis, angiogenesis and EMT in cancer. Very little is known, however, about the role of TGF-beta in cancer drug resistance. In this work, we show a specific activation of the TGF-beta pathway in consequence of chemotherapeutic treatment in in vivo and in vitro models of colorectal carcinoma. 5-Fluorouracil (5FU) was able to stimulate the activation of SMAD3 and the transcription of specific genes such as ACVRL1, FN1 and TGFB1. On the other hand, the specific inhibition of TGF-betaRI was able to repress the 5FU-induced genes transcription and to restore the sensitivity of chemoresistant cells to the toxic action of the drug, by decreasing the expression of BCL2L1 and ID1 genes. The role of the TGF-beta molecule in the chemoresistant colon carcinoma cells' response to 5FU was further demonstrated by conditioned medium (CM) experiments: CM from 5FU-treated chemoresistant cells was able to protect chemosensitive cells against the toxic action of 5FU. In conclusion, these findings showed the pivotal role of TGF-beta pathway in colon cancer mechanisms of drug resistance suggesting new possible approaches in diagnosis and treatment of colon cancer patients. PMID- 26956046 TI - The synergic antitumor effects of paclitaxel and temozolomide co-loaded in mPEG PLGA nanoparticles on glioblastoma cells. AB - To get better chemotherapy efficacy, the optimal synergic effect of Paclitaxel (PTX) and Temozolomide (TMZ) on glioblastoma cells lines was investigated. A dual drug-loaded delivery system based on mPEG-PLGA nanoparticles (NPs) was developed to potentiate chemotherapy efficacy for glioblastoma. PTX/TMZ-NPs were prepared with double emulsification solvent evaporation method and exhibited a relatively uniform diameter of 206.3 +/- 14.7 nm. The NPs showed sustained release character. Cytotoxicity assays showed the best synergistic effects were achieved when the weight ratios of PTX to TMZ were 1:5 and 1:100 on U87 and C6 cells, respectively. PTX/TMZ-NPs showed better inhibition effect to U87 and C6 cells than single drug NPs or free drugs mixture. PTX/TMZ-NPs (PTX: TMZ was 1:5(w/w)) significantly inhibited the tumor growth in the subcutaneous U87 mice model. These results indicate that coordinate administration of PTX and TMZ combined with NPs is an efficient method for glioblastoma. PMID- 26956047 TI - Modulation of chemokines in the tumor microenvironment enhances oncolytic virotherapy for colorectal cancer. AB - An oncolytic poxvirus such as vvDD-CXCL11 can generate potent systemic antitumor immunity as well as targeted oncolysis, yet the antitumor effect is limited probably due to limited homing to and suppressed activity of tumor-specific adaptive immune cells in the tumor microenvironment (TME). We reasoned that a chemokine modulating (CKM) drug cocktail, consisting of IFN-alpha, poly I:C, and a COX-2 inhibitor, may skew the chemokine (CK) and cytokine profile into a favorable one in the TME, and this pharmaceutical modulation would enhance both the trafficking into and function of antitumor immune cells in the TME, thus increasing therapeutic efficacy of the oncolytic virus. In this study we show for the first time in vivo that the CKM modulates the CK microenvironment but it does not modulate antitumor immunity by itself in a MC38 colon cancer model. Sequential treatment with the virus and then CKM results in the upregulation of Th1-attracting CKs and reduction of Treg-attracting CKs (CCL22 and CXCL12), concurrent with enhanced trafficking of tumor-specific CD8+ T cells and NK cells into the TME, thus resulting in the most significant antitumor activity and long term survival of tumor-bearing mice. This novel combined regimen, with the oncolytic virus (vvDD-CXCL11) inducing direct oncolysis and eliciting potent antitumor immunity, and the CKM inducing a favorable chemokine profile in the TME that promotes the trafficking and function of antitumor Tc1/Th1 and NK cells, may have great utility for oncolytic immunotherapy for cancer. PMID- 26956048 TI - Diagnostic and clinical relevance of the autophago-lysosomal network in human gliomas. AB - Recently, the conserved intracellular digestion mechanism 'autophagy' has been considered to be involved in early tumorigenesis and its blockade proposed as an alternative treatment approach. However, there is an ongoing debate about whether blocking autophagy has positive or negative effects in tumor cells. Since there is only poor data about the clinico-pathological relevance of autophagy in gliomas in vivo, we first established a cell culture based platform for the in vivo detection of the autophago-lysosomal components. We then investigated key autophagosomal (LC3B, p62, BAG3, Beclin1) and lysosomal (CTSB, LAMP2) molecules in 350 gliomas using immunohistochemistry, immunofluorescence, immunoblotting and qPCR. Autophagy was induced pharmacologically or by altering oxygen and nutrient levels. Our results show that autophagy is enhanced in astrocytomas as compared to normal CNS tissue, but largely independent from the WHO grade and patient survival. A strong upregulation of LC3B, p62, LAMP2 and CTSB was detected in perinecrotic areas in glioblastomas suggesting micro-environmental changes as a driver of autophagy induction in gliomas. Furthermore, glucose restriction induced autophagy in a concentration-dependent manner while hypoxia or amino acid starvation had considerably lesser effects. Apoptosis and autophagy were separately induced in glioma cells both in vitro and in vivo. In conclusion, our findings indicate that autophagy in gliomas is rather driven by micro environmental changes than by primary glioma-intrinsic features thus challenging the concept of exploitation of the autophago-lysosomal network (ALN) as a treatment approach in gliomas. PMID- 26956049 TI - Anti-apoptotic ARC protein confers chemoresistance by controlling leukemia microenvironment interactions through a NFkappaB/IL1beta signaling network. AB - To better understand how the apoptosis repressor with caspase recruitment domain (ARC) protein confers drug resistance in acute myeloid leukemia (AML), we investigated the role of ARC in regulating leukemia-mesenchymal stromal cell (MSC) interactions. In addition to the previously reported effect on AML apoptosis, we have demonstrated that ARC enhances migration and adhesion of leukemia cells to MSCs both in vitro and in a novel human extramedullary bone/bone marrow mouse model. Mechanistic studies revealed that ARC induces IL1beta expression in AML cells and increases CCL2, CCL4, and CXCL12 expression in MSCs, both through ARC-mediated activation of NFkappaB. Expression of these chemokines in MSCs increased by AML cells in an ARC/IL1beta-dependent manner; likewise, IL1beta expression was elevated when leukemia cells were co-cultured with MSCs. Further, cells from AML patients expressed the receptors for and migrated toward CCL2, CCL4, and CXCL12. Inhibition of IL1beta suppressed AML cell migration and sensitized the cells co-cultured with MSCs to chemotherapy. Our results suggest the existence of a complex ARC-regulated circuit that maintains intimate connection of AML with the tumor microenvironment through NFkappaB/IL1beta-regulated chemokine receptor/ligand axes and reciprocal crosstalk resulting in cytoprotection. The data implicate ARC as a promising drug target to potentially sensitize AML cells to chemotherapy. PMID- 26956050 TI - Antitumor effect of the novel sphingosine kinase 2 inhibitor ABC294640 is enhanced by inhibition of autophagy and by sorafenib in human cholangiocarcinoma cells. AB - Sphingosine kinase 2 (Sphk2) has an oncogenic role in cancer. A recently developed first-in-class Sphk2 specific inhibitor ABC294640 displays antitumor activity in many cancer models. However, the role of Sphk2 and the antitumor activity of its inhibitor ABC294640 are not known in cholangiocarcinoma. We investigated the potential of targeting Sphk2 for the treatment of cholangiocarcinoma. We found that Sphk2 is overexpressed in five established human cholangiocarcinoma cell lines (WITT, HuCCT1, EGI-1, OZ and HuH28) and a new patient-derived cholangiocarcinoma cell line (LIV27) compared to H69 normal cholangiocytes. Inhibition of Sphk2 by ABC294640 inhibited proliferation and induced caspase-dependent apoptosis. Furthermore, we found that ABC294640 inhibited STAT3 phosphorylation, one of the key signaling pathways regulating cholangiocarcinoma cell proliferation and survival. ABC294640 also induced autophagy. Inhibition of autophagy by bafilomycin A1 or chloroquine potentiated ABC294640-induced cytotoxicity and apoptosis. In addition, ABC294640 in combination with sorafenib synergistically inhibited cell proliferation of cholangiocarcinoma cells. Strong decreases in STAT3 phosphorylation were observed in WITT and HuCCT1 cells exposed to the ABC294640 and sorafenib combination. These findings provide novel evidence that Sphk2 may be a rational therapeutic target in cholangiocarcinoma. Combinations of ABC294640 with sorafenib and/or autophagy inhibitors may provide novel strategies for the treatment of cholangiocarcinoma. PMID- 26956051 TI - Biomarkers of evasive resistance predict disease progression in cancer patients treated with antiangiogenic therapies. AB - Numerous antiangiogenic agents are approved for the treatment of oncological diseases. However, almost all patients develop evasive resistance mechanisms against antiangiogenic therapies. Currently no predictive biomarker for therapy resistance or response has been established. Therefore, the aim of our study was to identify biomarkers predicting the development of therapy resistance in patients with hepatocellular cancer (n = 11), renal cell cancer (n = 7) and non small cell lung cancer (n = 2). Thereby we measured levels of angiogenic growth factors, tumor perfusion, circulating endothelial cells (CEC), circulating endothelial progenitor cells (CEP) and tumor endothelial markers (TEM) in patients during the course of therapy with antiangiogenic agents, and correlated them with the time to antiangiogenic progression (aTTP). Importantly, at disease progression, we observed an increase of proangiogenic factors, upregulation of CEC/CEP levels and downregulation of TEMs, such as Robo4 and endothelial cell specific chemotaxis regulator (ECSCR), reflecting the formation of torturous tumor vessels. Increased TEM expression levels tended to correlate with prolonged aTTP (ECSCR high = 275 days vs. ECSCR low = 92.5 days; p = 0.07 and for Robo4 high = 387 days vs. Robo4 low = 90.0 days; p = 0.08). This indicates that loss of vascular stabilization factors aggravates the development of antiangiogenic resistance. Thus, our observations confirm that CEP/CEC populations, proangiogenic cytokines and TEMs contribute to evasive resistance in antiangiogenic treated patients. Higher TEM expression during disease progression may have clinical and pathophysiological implications, however, validation of our results is warranted for further biomarker development. PMID- 26956052 TI - Survival kinase genes present prognostic significance in glioblastoma. AB - Cancer biomarkers with a strong predictive power for diagnosis/prognosis and a potential to be therapeutic targets have not yet been fully established. Here we employed a loss-of-function screen in glioblastoma (GBM), an infiltrative brain tumor with a dismal prognosis, and identified 20 survival kinase genes (SKGs). Survival analyses using The Cancer Genome Atlas (TCGA) datasets revealed that the expression of CDCP1, CDKL5, CSNK1E, IRAK3, LATS2, PRKAA1, STK3, TBRG4, and ULK4 stratified GBM prognosis with or without temozolomide (TMZ) treatment as a covariate. For the first time, we found that GBM patients with a high level of NEK9 and PIK3CB had a greater chance of having recurrent tumors. The expression of CDCP1, IGF2R, IRAK3, LATS2, PIK3CB, ULK4, or VRK1 in primary GBM tumors was associated with recurrence-related prognosis. Notably, the level of PIK3CB in recurrent tumors was much higher than that in newly diagnosed ones. Congruent with these results, genes in the PI3K/AKT pathway showed a significantly strong correlation with recurrence rate, further highlighting the pivotal role of PIK3CB in the disease progression. Importantly, 17 SKGs together presented a novel GBM prognostic signature. SKGs identified herein are associated with recurrence rate and present prognostic significance in GBM, thereby becoming attractive therapeutic targets. PMID- 26956053 TI - Insulin receptor substrate 1 is a substrate of the Pim protein kinases. AB - The Pim family of serine/threonine protein kinases (Pim 1, 2, and 3) contribute to cellular transformation by regulating glucose metabolism, protein synthesis, and mitochondrial oxidative phosphorylation. Drugs targeting the Pim protein kinases are being tested in phase I/II clinical trials for the treatment of hematopoietic malignancies. The goal of these studies was to identify Pim substrate(s) that could help define the pathway regulated by these enzymes and potentially serve as a biomarker of Pim activity. To identify novel substrates, bioinformatics analysis was carried out to identify proteins containing a consensus Pim phosphorylation site. This analysis identified the insulin receptor substrate 1 and 2 (IRS1/2) as potential Pim substrates. Experiments were carried out in tissue culture, animals, and human samples from phase I trials to validate this observation and define the biologic readout of this phosphorylation. Our study demonstrates in both malignant and normal cells using either genetic or pharmacological inhibition of the Pim kinases or overexpression of this family of enzymes that human IRS1S1101 and IRS2S1149 are Pim substrates. In xenograft tumor experiments and in a human phase I clinical trial, a pan-Pim inhibitor administered in vivo to animals or humans decreased IRS1S1101 phosphorylation in tumor tissues. This phosphorylation was shown to have effects on the half-life of the IRS family of proteins, suggesting a role in insulin or IGF signaling. These results demonstrate that IRS1S1101 is a novel substrate for the Pim kinases and provide a novel marker for evaluation of Pim inhibitor therapy. PMID- 26956055 TI - KCNE2 and gastric cancer: bench to bedside. PMID- 26956054 TI - Nickel chloride (NiCl2) induces endoplasmic reticulum (ER) stress by activating UPR pathways in the kidney of broiler chickens. AB - It has been known that overexposure to Ni can induce nephrotoxicity. However, the mechanisms of underlying Ni nephrotoxicity are still elusive, and also Ni- and Ni compound-induced ER stress has been not reported in vivo at present. Our aim was to use broiler chickens as animal model to test whether the ER stress was induced and UPR was activated by NiCl2 in the kidney using histopathology, immunohistochemistry and qRT-PCR. Two hundred and eighty one-day-old broiler chickens were divided into 4 groups and fed on a control diet and the same basal diet supplemented with 300 mg/kg, 600mg/kg and 900mg/kg of NiCl2 for 42 days. We found that dietary NiCl2 in excess of 300 mg/kg induced ER stress, which was characterized by increasing protein and mRNA expression of ER stress markers, e.g., GRP78 and GRP94. Concurrently, all the three UPR pathways were activated by dietary NiCl2. Firstly, the PERK pathway was activated by increasing eIF2a and ATF4 mRNA expression. Secondly, the IRE1 pathway was activated duo to increase in IRE1 and XBP1 mRNA expression. And thirdly, the increase of ATF6 mRNA expression suggested that ATF6 pathway was activated. The findings clearly demonstrate that NiCl2 induces the ER stress through activating PERK, IRE1 and ATF6 UPR pathways, which is proved to be a kind of molecular mechanism of Ni- or/and Ni compound induced nephrotoxicity. PMID- 26956057 TI - Undergraduate nursing students' perspectives on clinical assessment at transition to practice. AB - BACKGROUND: Assessment of clinical competence requires explicitly defined standards meeting the national standards of the nursing profession. This is a complex process because of the diverse nature of nursing practice. OBJECTIVES: To explore the perceptions of final-year undergraduate nursing students regarding clinical assessment at transition to practice. METHODS: An exploratory qualitative approach was adopted. Twenty-four students participated in three focus group discussions. Thematic analysis was conducted. FINDINGS: Five themes emerged: the need for a valid and reliable clinical assessment tool, the need for a flexible style of reflection and specific feedback, the dynamic clinical learning environment, students' efforts in learning and assessment, and the unclear support system for preceptors. CONCLUSIONS: Workload, time, resource availability, adequate preparation of preceptors, and the provision of valid and reliable clinical assessment tools were deemed to influence the quality of students' clinical learning and assessment. Nursing leadership in hospitals and educational institutions has a joint responsibility in shaping the clinical learning environment and providing clinical assessments for the students. PMID- 26956058 TI - Study and application of noncatalyzed photoinduced conjugation of azides and cycloocta-1,2,3-selenadiazoles. AB - The non-catalyzed cycloaddition of eight structurally different azides with cyclooctyne generated in situ by the photolysis of cycloocta-1,2,3-selenadiazole gives 1,2,3-triazole derivatives as the main products. The application of this reaction was demonstrated by the photoconjugation reaction of cycloocta-1,2,3 selenadiazole with an avidin-modified biotin complex to introduce a new strategy in the non-catalyzed synthesis of bioconjugates. PMID- 26956056 TI - Anti-tumor Necrosis Factor Alpha (Infliximab) Attenuates Apoptosis, Oxidative Stress, and Calcium Ion Entry Through Modulation of Cation Channels in Neutrophils of Patients with Ankylosing Spondylitis. AB - Ankylosing Spondylitis (AS) is known to be associated with increased neutrophil activation and oxidative stress, however, the mechanism of neutrophil activation is still unclear. We have hypothesized that the antioxidant and anti-tumor necrosis factor properties of infliximab may affect intracellular Ca(2+) concentration in the neutrophils of AS patients. The objective of this study was to investigate the effects of infliximab on calcium signaling, oxidative stress, and apoptosis in neutrophils of AS patients. Neutrophils collected from ten patients with AS and ten healthy controls were used in the study. In a cell viability test, the ideal non-toxic dose and incubation time of infliximab were found as 100 MUM and 1 h, respectively. In some experiments, the neutrophils were incubated with the voltage-gated calcium channel (VGCC) blockers verapamil + diltiazem (V + D) and the TRPM2 channel blocker 2-aminoethyl diphenylborinate (2 APB). Intracellular Ca(2+) concentration, lipid peroxidation, apoptosis, caspase 3, and caspase 9 values were high in neutrophils of AS patients and were reduced with infliximab treatment. Reduced glutathione level and glutathione peroxidase activity were low in the patients and increased with infliximab treatment. The intracellular Ca(2+) concentrations were low in 2-APB and V + D groups. In conclusion, the current study suggests that infliximab is useful against apoptotic cell death and oxidative stress in neutrophils of patients with AS, which seem to be dependent on increased levels of intracellular Ca(2+) through activation of TRPM2 and VGCC. PMID- 26956059 TI - The cumulative effect of genetic polymorphisms on depression and brain structural integrity. AB - In major depressive disorder (MDD), the need to study multiple-gene effect on brain structure is emerging. Our aim was to assess the effect of accumulation of specific SERT, BDNF and COMT gene functional polymorphisms on brain structure in MDD patients. Seventy-seven MDD patients and 66 controls underwent a clinical assessment, genetic testing and MRI scan. Compared with controls, patients were more BDNF-Val homozygotes, COMT-Met carriers and SERT-L' carriers. Thus, subjects were split into three groups: 1. High-frequency susceptibility polymorphism group (hfSP, subjects with all three SPs); 2. Intermediate-frequency SP group (ifSP, two SPs); and 3. Low-frequency SP group (lfSP, one/none SP). Cortical thickness, volumetry of hippocampus, amygdala and subcortical structures, and white matter (WM) tract integrity were assessed. Compared to controls, hfSP patients showed thinning of the middle frontal cortex bilaterally, left frontal pole, and right lateral occipital cortex, and smaller hippocampal volume bilaterally; and both hfSP and lfSP patient groups showed thinning of the left inferior parietal cortex and reduced WM integrity of the corpus callosum. Compared to patients, hfSP controls showed greater integrity of the fronto-occipital cortices and corpus callosum. We showed that cortical prefrontal and occipital damage of MDD patients is modulated by the SP accumulation, while damage to the parietal cortex and corpus callosum seem to be independent of genetic accumulation. HfSP controls may experience protective mechanisms leading to a preserved integrity of critical cortical and WM regions. Investigating the effect of multiple genes is promising to understand the pathological mechanisms underlying MDD. Hum Brain Mapp 37:2173 2184, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26956060 TI - Reappraisal of Hydatigera taeniaeformis (Batsch, 1786) (Cestoda: Taeniidae) sensu lato with description of Hydatigera kamiyai n. sp. AB - The common cat tapeworm Hydatigera taeniaeformis is a complex of three morphologically cryptic entities, which can be differentiated genetically. To clarify the biogeography and the host spectrum of the cryptic lineages, 150 specimens of H. taeniaeformis in various definitive and intermediate hosts from Eurasia, Africa and Australia were identified with DNA barcoding using partial mitochondrial cytochrome c oxidase subunit 1 gene sequences and compared with previously published data. Additional phylogenetic analyses of selected isolates were performed using nuclear DNA and mitochondrial genome sequences. Based on molecular data and morphological analysis, Hydatigera kamiyai n. sp. Iwaki is proposed for a cryptic lineage, which is predominantly northern Eurasian and uses mainly arvicoline rodents (voles) and mice of the genus Apodemus as intermediate hosts. Hydatigera taeniaeformis sensu stricto (s.s.) is restricted to murine rodents (rats and mice) as intermediate hosts. It probably originates from Asia but has spread worldwide. Despite remarkable genetic divergence between H. taeniaeformis s.s. and H. kamiyai, interspecific morphological differences are evident only in dimensions of rostellar hooks. The third cryptic lineage is closely related to H. kamiyai, but its taxonomic status remains unresolved due to limited morphological, molecular, biogeographical and ecological data. This Hydatigera sp. is confined to the Mediterranean and its intermediate hosts are unknown. Further studies are needed to classify Hydatigera sp. either as a distinct species or a variant of H. kamiyai. According to previously published limited data, all three entities occur in the Americas, probably due to human mediated introductions. PMID- 26956062 TI - IBS: Snail venom for gut pain? PMID- 26956061 TI - Laminin gamma2 knockout mice rescued with the human protein exhibit enamel maturation defects. AB - The epithelial ameloblasts are separated from the maturing enamel by an atypical basement membrane (BM) that is enriched in laminin 332 (LM-332). This heterotrimeric protein (alpha3, beta3 and gamma2 chains) provides structural integrity to BMs and influences various epithelial cell processes including cell adhesion and differentiation. Mouse models that lack expression of individual LM 332 chains die shortly after birth. The lethal phenotype of laminin gamma2 knockout mice can be rescued by human laminin gamma2 (LAMC2) expressed using a doxycycline-inducible (Tet-on) cytokeratin 14 promoter-rtTA. These otherwise normal-looking rescued mice exhibit white spot lesions on incisors. We therefore investigated the effect of rescue with human LAMC2 on enamel maturation and structuring of the atypical BM. The maturation stage enamel organ in transgenic mice was severely altered as compared to wild type controls, a structured BM was no longer discernible, dystrophic matrix appeared in the maturing enamel layer, and there was residual enamel matrix late into the maturation stage. Microtomographic scans revealed excessive wear of occlusal surfaces on molars, chipping of enamel on incisor tips, and hypomineralization of the enamel layer. No structural alterations were observed at other epithelial sites, such as skin, palate and tongue. These results indicate that while this humanized mouse model is capable of rescue in various epithelial tissues, it is unable to sustain structuring of a proper BM at the interface between ameloblasts and maturing enamel. This failure may be related to the atypical composition of the BM in the maturation stage and reaffirms that the atypical BM is essential for enamel maturation. PMID- 26956063 TI - Colorectal cancer: Surgery for colorectal cancer - standardization required. PMID- 26956065 TI - Alcoholic liver disease: New UK alcohol guidelines and Dry January: enough to give up boozing? PMID- 26956064 TI - Timing of catheter drainage in infected necrotizing pancreatitis. AB - Acute pancreatitis is the most common gastrointestinal indication for hospital admission, and infected pancreatic and/or extrapancreatic necrosis is a potentially lethal complication. Current standard treatment of infected necrosis is a step-up approach, consisting of catheter drainage followed, if necessary, by minimally invasive necrosectomy. International guidelines recommend postponing catheter drainage until the stage of 'walled-off necrosis' has been reached, a process that typically takes 4 weeks after onset of acute pancreatitis. This recommendation stems from the era of primary surgical necrosectomy. However, postponement of catheter drainage might not be necessary, and earlier detection and subsequent earlier drainage of infected necrosis could improve outcome. Strong data and consensus among international expert pancreatologists are lacking. Future clinical, preferably randomized, studies should focus on timing of catheter drainage in patients with infected necrotizing pancreatitis. In this Perspectives, we discuss challenges in the invasive treatment of patients with infected necrotizing pancreatitis, focusing on timing of catheter drainage. PMID- 26956067 TI - Fabrication and morphology tuning of graphene oxide nanoscrolls. AB - Here we report the synthesis of graphene oxide nanoscrolls (GONS) with tunable dimensions via low and high frequency ultrasound solution processing techniques. GONS can be visualized as a graphene oxide (GO) sheet rolled into a spiral-wound structure and represent an alternative to traditional carbon nano-morphologies. The scrolling process is initiated by the ultrasound treatment which provides the scrolling activation energy for the formation of GONS. The GO and GONS dimensions are observed to be a function of ultrasound frequency, power density, and irradiation time. Ultrasonication increases GO and GONS C-C bonding likely due to in situ thermal reduction at the cavitating bubble-water interface. The GO area and GONS length are governed by two mechanisms; rapid oxygen defect site cleavage and slow cavitation mediated scission. Structural characterization indicates that GONS with tube and cone geometries can be formed with both narrow and wide dimensions in an industrial-scale time window. This work paves the way for GONS implementation for a variety of applications such as adsorptive and capacitive processes. PMID- 26956068 TI - Struggles for Equal Rights and Social Justice as Unrepresented and Represented in Psychological Research. AB - Issues of equality and social justice remain important concerns for contemporary societies. Struggles for equal rights and fair treatment continue in both organized movements and in acts of everyday life. We first consider trends in psychological research that fail to address such struggles and may even impede theoretical understanding of the complex processes of thought and action involved when individuals confront situations of welfare, justice, and rights. Then, we consider research, which attempts to address these issues. We review studies on the development of moral judgments and on understandings of equality and distributive justice. We also discuss research that accounts for the varying social contexts of individual lives and conceives of human behavior as engaged in moral judgments, which often produce resistance and opposition to injustice. In conclusion, we call for more attention in psychological research to issues of equity and social justice. PMID- 26956066 TI - Clostridium difficile infection: epidemiology, diagnosis and understanding transmission. AB - Clostridium difficile infection (CDI) continues to affect patients in hospitals and communities worldwide. The spectrum of clinical disease ranges from mild diarrhoea to toxic megacolon, colonic perforation and death. However, this bacterium might also be carried asymptomatically in the gut, potentially leading to 'silent' onward transmission. Modern technologies, such as whole-genome sequencing and multi-locus variable-number tandem-repeat analysis, are helping to track C. difficile transmission across health-care facilities, countries and continents, offering the potential to illuminate previously under-recognized sources of infection. These typing strategies have also demonstrated heterogeneity in terms of CDI incidence and strain types reflecting different stages of epidemic spread. However, comparison of CDI epidemiology, particularly between countries, is challenging due to wide-ranging approaches to sampling and testing. Diagnostic strategies for C. difficile are complicated both by the wide range of bacterial targets and tests available and the need to differentiate between toxin-producing and non-toxigenic strains. Multistep diagnostic algorithms have been recommended to improve sensitivity and specificity. In this Review, we describe the latest advances in the understanding of C. difficile epidemiology, transmission and diagnosis, and discuss the effect of these developments on the clinical management of CDI. PMID- 26956069 TI - Toward an Intersectional Approach in Developmental Science: The Role of Race, Gender, Sexual Orientation, and Immigrant Status. AB - Developmental theory and research have often focused on a single social identity category, for example, race or sexual orientation, and examined the consequences of that category on life outcomes. Yet intersectional models of social disadvantage (eg, Cole, 2009; Crenshaw, 1995; King, 1988) suggest that social categories combine to shape the experiences and life outcomes of individuals across life domains. In this chapter, we review empirical research that offers insight into the intersectionality of social identities across three critical developmental periods, namely, middle childhood, adolescence, and emerging adulthood. We also consider the consequences of intersecting identities across several life domains, including intergroup relations and political and civic engagement. Recognizing that the body of work on social identities is expansive, we focus our review on race/ethnicity, gender, sexual orientation, and immigrant status. In each developmental stage, we discuss what we know, drawing from the limited empirical literature, and offer suggestions on where we need to go moving forward. We conclude that research that focuses on as a single category and ignores the specific domain of development provides an incomplete and inaccurate picture that will hinder efforts to develop culturally appropriate and clinically effective prevention and intervention programs to meet the needs of our diverse children and youth living in the United States. PMID- 26956070 TI - Social Inequality in Population Developmental Health: An Equity and Justice Issue. AB - The conceptual framework for this chapter focuses on outcomes in developmental health as a key indicator of equity. Not all disparities in developmental health are indicators of a failure of equity and justice, but those that are clearly linked to social patterns in theoretically coherent and empirically substantial ways serve as a powerful diagnostic tool. They are especially diagnostic when they point to social factors that are remediable, especially in comparison to societies in which such social disparities are sharply lower (Keating, Siddiqi, & Nguyen, 2013). In this chapter, I review the theoretical links and empirical evidence supporting this central claim and propose that there is strong evidence for the following critical links: (a) there is a compelling empirical connection between disparities in social circumstances and disparities in developmental health outcomes, characterized as a social gradient effect; (b) "drilling down" reveals the core biodevelopmental mechanisms that yield the social disparities that emerge across the life course; (c) in turn, life course effects on developmental health have an impact on societies and populations that are revealed by "ramping up" the research to consider international comparisons of population developmental health; and (d) viewing this integrated evidence through the lens of equity and justice helps to break the vicious cycle that reproduces social inequality in a distressingly recurring fashion. PMID- 26956072 TI - A Right to Disclose: LGBTQ Youth Representation in Data, Science, and Policy. AB - There has been growing attention to sexual orientation and gender identity (SOGI) in child and adolescent development, public discourse, and research. A strong tension is clear: The right for participation, and thus representation in data, science, and policy, is often understood as conflicting with the right for protection, that is, safety from disclosure of a marginalized orientation or identity. Both participation and protection rights are also closely tied to young people's rights to privacy (or lack thereof). We review recent scholarship on SOGI in developmental sciences in light of this tension. We focus on schooling as a salient developmental context for all youth, a place that is historically unsafe for lesbian, gay, bisexual, transgender, queer, and questioning (LGBTQ) youth, and a context where researchers have identified gaps of knowledge as well as strategies for improvement. Our review focuses on the politics and processes of SOGI inclusion in education data collection efforts in the United States, an area where SOGI data collection is scarce in comparison to other systems of care, such as health. We suggest that one solution to the dilemma would be that youth have the right to disclose their SOGI information to whom and when they choose. We offer strategies on how to hold these tensions in balance and move toward SOGI inclusive research and data collection so that LGBTQ youth can be represented in data, science, and policy. PMID- 26956071 TI - Gender Stereotypes and Discrimination: How Sexism Impacts Development. AB - In this chapter, we summarize and integrate some of the latest developmental science research on gender stereotypes and discrimination in childhood and adolescence. We focus on five forms of sexism: (a) stereotypes and discrimination against boys regarding their school behaviors and disciplinary actions; (b) stereotypes and discrimination against girls in science, technology, engineering, and mathematics (STEM) domains; (c) stereotypes and discrimination in sports; (d) peer gendered harassment, including sexual harassment and teasing because of gender atypicality or nonconformity; and (e) sexualized gender stereotypes that sexually objectify girls and assume boys are sexually voracious. First, we document each type of sexism and examine children's awareness and perceptions of that bias, including their own self-reports and attributions. We examine the implications of this sexism for children and adolescents' developmental health (i.e., social, academic, and psychological well-being). We then draw connections between these various areas of research, focusing on how these different forms of sexism interact to reduce equity and justice among children and negatively impact positive developmental outcomes. The chapter concludes with suggestions for future research. PMID- 26956073 TI - Just Good Developmental Science: Trust, Identity, and Responsibility in Ethnic Minority Recruitment and Retention. AB - Given the noted difficulty of recruiting and retaining ethnic and racial minority populations into various kinds of research endeavors (e.g., basic, prevention, intervention, health), they remain underrepresented and thus underserved by the research community as compared to other US groups. As developmental scientists, we often ask questions that imply longitudinal research designs, and thus, issues of attentiveness and responsiveness are paramount to the successful engagement (i.e., recruitment) and sustainability (i.e., retention) of our research with ethnic/racial minority samples. The goal of this chapter is to advance an ongoing dialogue about much of the work researchers of ethnic/racial minority child and youth development do in order to effectually recruit and retain youth and families but that is not often obvious to colleagues and readers of the final products. We frame our discussion with three key broadly significant themes: the role of trust, researcher identity and insider/outsider status, and responsibility. Perhaps most importantly, throughout the chapter, we provide concrete examples of the ways in which developmental scientists are transforming potential recruitment and retention challenges into opportunities in their own research programs. PMID- 26956074 TI - Youth-Led Participatory Action Research: Developmental and Equity Perspectives. AB - Youth-led participatory action research (YPAR) is an approach to scientific inquiry and social change grounded in principles of equity that engages young people in identifying problems relevant to their own lives, conducting research to understand the problems, and advocating for changes based on research evidence. This chapter provides an introduction to YPAR followed by consideration of the (a) developmental relevance of YPAR for marginalized youth, (b) implications of YPAR for developmental science research on inequities experienced by youth, and (c) potential opportunities and impact of YPAR for improving key developmental settings such as schools and youth-serving organizations. Resources for conducting YPAR projects are discussed, as well as the need for potential integration of YPAR and other participatory approaches to engaging youth and their expertise-at a significant enough scale to have a meaningful impact on policies and practices that affect youth development. PMID- 26956075 TI - A Mixed Methods Approach to Equity and Justice Research: Insights from Research on Children's Reasoning About Economic Inequality. AB - Mixed methods research approaches are gaining traction across various social science disciplines, including among developmental scientists. In this chapter, we discuss the utility of a mixed methods research approach in examining issues related to equity and justice. We incorporate a brief overview of quantitative and qualitative monomethod research approaches in our larger discussion of the advantages, procedures, and considerations of employing a mixed methods design to advance developmental science from an equity and justice perspective. To better illustrate the theoretical and practical significance of a mixed methods research approach, we include examples of research conducted on children and adolescents' conceptions of economic inequality as one example of developmental science research with an equity and justice frame. PMID- 26956076 TI - Preface. PMID- 26956077 TI - Biological psychiatry marching towards the future and the perils of progress. AB - The study of the biological determinants of abnormal behavior is not anymore psychiatry's stepchild, but a respected branch of that discipline. There is every reason to be optimistic over the future of biological psychiatry. The brain sciences are developing with astounding speed and the systematic attention for psychiatric-diagnosis and differential diagnosis renders biological psychiatry an unprecedented vitality. One should, however, not ignore some disquieting prospects. The following points of concern are discussed: the alarming shortage of young research psychiatrists; the deficiencies in the teaching of biological psychiatry; the hesitancy to utilize the fruits of brain and behavior research in clinical practice; the shortcomings in psychiatric diagnosing; nosological tunnel vision and, finally, the danger of overrating biological psychiatry with the inevitable disappointment reaction that will follow. The scientific maturation of psychiatry is contingent on a balanced development of its constituents. PMID- 26956078 TI - Cognitive neurobiology of schizophreni. AB - Schizophrenia is a neurobiological developmental disorder of basic neuro integrative functions, resulting in failures of cognitive selfregulation. Neurophysiological and psychophysiological dysfunctions should be considered in connection with the ubiquitous cognitive dysfunctions. Schizophrenic patients have problems with the integration of information, resulting in deficits of perceptual organization, and in 'metacognitive' deficits of executive functions in the area of behavior and experience. The biological basis of these cognitive functions is in the frontal cortex, but the primary dysfunction seems to be a subcortical one. Negative symptoms can be understood as a secondary exhaustion mechanism, and partly as an adaptive process, corresponding with energetic deficits in information processing. Psychophysiological studies of regional cerebral blood flow, positron emission tomography, electrophysiological recordings and measures of eye tracking point to frontal dysfunction and hypoactivation in patients with negative symptoms. This agrees well with the results of cognitive studies. Psychophysiologists and cognitive psychologists are studying different aspects of the same systems disorder. PMID- 26956079 TI - Measuring sleep (dys)function by polysomnography. AB - A vigilance state is characterized by a particular activity state of the motorIautonomic and psychiclcognitive functional systems. S-W screening is possible through poly graphic monitoring of physiological variables and signals. Quantification of these signals introduces a set of parameters allowing the characterisation of the sleep (dys)function. There is no consensus regarding the choice or definition of these parameters. A particular cluster is presented and their informative value with respect to clinical practice and research is discussed. PMID- 26956080 TI - Intervertebral disc regeneration using platelet-rich plasma-containing bone marrow-derived mesenchymal stem cells: A preliminary investigation. AB - Platelet-rich plasma (PRP) is a promising strategy for intervertebral disc degeneration (IDD). However, the short half-life of growth factors released from PRP cannot continuously stimulate the degenerated discs. Thus, the present study hypothesized that the combined use of PRP and bone marrow-derived mesenchymal stem cells (BMSCs) may repair the early degenerated discs in the long term for their synergistic reparative effect. In the present study, following the induction of early IDD by annular puncture in rabbits, PRP was prepared and mixed with BMSCs (PRP-BMSC group) for injection into the early degenerated discs. As controls, phosphate-buffered saline (PBS; PBS group) and PRP (PRP group) were similarly injected. Rabbits without any intervention served as a control group. At 8 weeks following treatment, histological changes of the injected discs were assessed. Magnetic resonance imaging (MRI) was used to detect the T2-weighted signal intensity of the targeted discs at weeks 1, 2 and 8 following treatment. Annular puncture resulted in disc narrowing and decreased T2-weighted signal intensity. At weeks 1 and 3, MRI examinations showed regenerative changes in the PRP-BMSC group and PRP group, whereas the PBS group exhibited a continuous degenerative process of the discs. At 8 weeks post-injection, the PRP-BMSCs induced a statistically significant restoration of discs, as shown by MRI (PRP BMSCs, vs.PRP and PBS; P<0.05), which was also confirmed by histological evaluations. Thus, compared with PRP, the administration of PRP-containing BMSCs resulted in a superior regenerative effect on the early degenerated discs, which may be a promising therapeutic strategy for the restoration of early degenerated discs. PMID- 26956081 TI - Safety and tolerability of regadenoson for myocardial perfusion imaging - first Danish experience. AB - OBJECTIVES: Evaluating safety and tolerability of the selective A2A receptor agonist, regadenoson, in patients referred for single photon emission computed tomography myocardial perfusion imaging (MPI). DESIGN: Observational study of patients referred for MPI stress testing using a 400 MUg regadenoson (Rapiscan((r))) bolus. Hemodynamic variables and severity of adverse events (AE) were recorded before, during, and after administration. RESULTS: A total of 232 patients were included. One or more AE were reported in 90% of patients; the AEs were graded mostly mild to moderate in severity, resolved spontaneously, and were mainly dyspnea, headache, and chest pain. No advanced heart block or bronchospasm were seen. Transient ST-segment changes developed in 10 patients. The maximum increase in heart rate was 19 +/- 11 beats/minute. The mean systolic blood pressure decreased from 144 to 139 mmHg (p < 0.0001). Medical intervention was required in three patients: one case with severe hypotension and two cases with chest pain that was relieved with sublingual nitroglycerin. One patient died the day after stress MPI for reasons considered unrelated to regadenoson. CONCLUSION: Regadenoson for MPI is easy to use with a high frequency of AEs, which are generally mild in severity, transient, and resolve spontaneously. PMID- 26956083 TI - Organized Aggregation Makes Insoluble Perylene Diimide Efficient for the Reduction of Aryl Halides via Consecutive Visible Light-Induced Electron-Transfer Processes. AB - The consecutive photo-induced electron-transfer (conPET) process found with perylene diimide (PDI) overcomes the limitation of visible-light photocatalysis and sheds light on effective solar energy conversion. By the incorporation of PDI into a metal-organic polymer Zn-PDI, a heterogeneous approach was achieved to tackle the poor solubility and strong tendency to aggregate of PDIs that restricted the exploitation of this outstanding homogeneous process. The interplay between metal-PDI coordination and pi...pi stacking of the organized PDI arrays in Zn-PDI facilitates the conPET process for the visible light-driven reduction of aryl halides by stabilizing the radical-anion intermediate and catalyst-substrate interacted moiety. These synergistic effects between the PDI arrays and Zn sites further render Zn-PDI photoactivity for fundamental oxidation of benzyl alcohols and amines. The tunable and modular nature of the two dimensional metal-organic polymers makes the catalyst-embedding strategy promising for the development of ideal photocatalysts toward the better utilization of solar energy. PMID- 26956084 TI - Object-based Encoding in Visual Working Memory: Evidence from Memory-driven Attentional Capture. AB - Visual working memory (VWM) adopts a specific manner of object-based encoding (OBE) to extract perceptual information: Whenever one feature-dimension is selected for entry into VWM, the others are also extracted. Currently most studies revealing OBE probed an 'irrelevant-change distracting effect', where changes of irrelevant-features dramatically affected the performance of the target feature. However, the existence of irrelevant-feature change may affect participants' processing manner, leading to a false-positive result. The current study conducted a strict examination of OBE in VWM, by probing whether irrelevant features guided the deployment of attention in visual search. The participants memorized an object's colour yet ignored shape and concurrently performed a visual-search task. They searched for a target line among distractor lines, each embedded within a different object. One object in the search display could match the shape, colour, or both dimensions of the memory item, but this object never contained the target line. Relative to a neutral baseline, where there was no match between the memory and search displays, search time was significantly prolonged in all match conditions, regardless of whether the memory item was displayed for 100 or 1000 ms. These results suggest that task-irrelevant shape was extracted into VWM, supporting OBE in VWM. PMID- 26956085 TI - Disorder-mediated crowd control in an active matter system. AB - Living active matter systems such as bacterial colonies, schools of fish and human crowds, display a wealth of emerging collective and dynamic behaviours as a result of far-from-equilibrium interactions. The dynamics of these systems are better understood and controlled considering their interaction with the environment, which for realistic systems is often highly heterogeneous and disordered. Here, we demonstrate that the presence of spatial disorder can alter the long-term dynamics in a colloidal active matter system, making it switch between gathering and dispersal of individuals. At equilibrium, colloidal particles always gather at the bottom of any attractive potential; however, under non-equilibrium driving forces in a bacterial bath, the colloids disperse if disorder is added to the potential. The depth of the local roughness in the environment regulates the transition between gathering and dispersal of individuals in the active matter system, thus inspiring novel routes for controlling emerging behaviours far from equilibrium. PMID- 26956086 TI - A Novel Acetylcholinesterase Biosensor: Core-Shell Magnetic Nanoparticles Incorporating a Conjugated Polymer for the Detection of Organophosphorus Pesticides. AB - To construct a sensing interface, in the present work, a conjugated polymer and core-shell magnetic nanoparticle containing biosensor was constructed for the pesticide analysis. The monomer 4,7-di(furan-2-yl)benzo[c][1,2,5]thiadiazole (FBThF) and core-shell magnetic nanoparticles were designed and synthesized for fabrication of the biosensing device. The magnetic nanoparticles were first treated with silica and then modified using carboxyl groups, which enabled binding of the biomolecules covalently. For the construction of the proposed sensor a two-step procedure was performed. First, the poly(FBThF) was electrochemically generated on the electrode surface. Then, carboxyl group modified magnetic nanoparticles (f-MNPs) and acetylcholinesterase (AChE), the model enzyme, were co-immobilized on the polymer-coated surface. Thereby, a robust and novel surface, conjugated polymer bearing magnetic nanoparticles with pendant carboxyl groups, was constructed, which was characterized using Fourier transform infrared spectrometer, cyclic voltammetry, scanning electron microscopy, and contact angle measurements. This novel architecture was then applied as an immobilization platform to detect pesticides. To the best of our knowledge, a sensor design that combines both conjugated polymer and magnetic nanoparticles was attempted for the first time, and this approach resulted in improved biosensor characteristics. Hence, this approach opens a new perspective in the field of enzyme immobilization and sensing applications. Paraoxon and trichlorfon were selected as the model toxicants. To obtain best biosensor performance, optimization studies were performed. Under optimized conditions, the biosensor in concern revealed a rapid response (5 s), a low detection limit (6.66 * 10(-3) mM), and high sensitivity (45.01 MUA mM(-1) cm(-2)). The KM(app) value of poly(FBThF)/f-MNPs/AChE were determined as 0.73 mM. Furthermore, there was no considerable activity loss for 10 d for poly(FBThF)/f-MNPs/AChE biofilm. PMID- 26956087 TI - MAKING SENSE OF BIG DATA. AB - As data sets grow in size, new computational tools are needed. Jeffrey Perkel looks at the ins and outs of data analysis. PMID- 26956082 TI - Lipidomics profile of a NAPE-PLD KO mouse provides evidence of a broader role of this enzyme in lipid metabolism in the brain. AB - A leading hypothesis of N-acyl ethanolamine (NAE) biosynthesis, including the endogenous cannabinoid anandamide (AEA), is that it depends on hydrolysis of N acyl-phosphatidylethanolamines (NAPE) by a NAPE-specific phospholipase D (NAPE PLD). Thus, deletion of NAPE-PLD should attenuate NAE levels. Previous analyses of two different NAPE-PLD knockout (KO) strains produced contradictory data on the importance of NAPE-PLD to AEA biosynthesis. Here, we examine this hypothesis with a strain of NAPE-PLD KO mice whose lipidome is uncharacterized. Using HPLC/MS/MS, over 70 lipids, including the AEA metabolite, N-arachidonoyl glycine (NAGly), the endocannabinoid 2-arachidonyl glycerol (2-AG) and prostaglandins (PGE(2) and PGF(2alpha)), and over 60 lipoamines were analyzed in 8 brain regions of KO and wild-type (WT) mice. Lipidomics analysis of this third NAPE-PLD KO strain shows a broad range of lipids that were differentially affected by lipid species and brain region. Importantly, all 6 NAEs measured were significantly reduced, though the magnitude of the effect varied by fatty acid saturation length and brain region. 2-AG levels were only impacted in the brainstem, where levels were significantly increased in KO mice. Correspondingly, levels of arachidonic acid were significantly decreased exclusively in brainstem. NAGly levels were significantly increased in 4 brain regions and levels of PGE(2) increased in 6 of 8 brain regions in KO mice. These data indicate that deletion of NAPE-PLD has far broader effects on the lipidome than previously recognized. Therefore, behavioral characteristics of suppressing NAPE-PLD activity may be due to a myriad of effects on lipids and not simply due to reduced AEA biosynthesis. PMID- 26956088 TI - Exploiting translational coupling for the selection of cells producing toxic recombinant proteins from expression vectors. AB - High rates of plasmid instability are associated with the use of some expression vectors in Escherichia coli, resulting in the loss of recombinant protein expression. This is due to sequence alterations in vector promoter elements caused by the background expression of the cloned gene, which leads to the selection of fast-growing, plasmid-containing cells that do not express the target protein. This phenomenon, which is worsened when expressing toxic proteins, results in preparations containing very little or no recombinant protein, or even in clone loss; however, no methods to prevent loss of recombinant protein expression are currently available. We have exploited the phenomenon of translational coupling, a mechanism of prokaryotic gene expression regulation, in order to select cells containing plasmids still able to express recombinant proteins. Here we designed an expression vector in which the cloned gene and selection marker are co-expressed. Our approach allowed for the selection of the recombinant protein-expressing cells and proved effective even for clones encoding toxic proteins. PMID- 26956089 TI - Head-to-head comparison of protocol modifications for the generation of collagen induced arthritis in a specific-pathogen free facility using DBA/1 mice. AB - Collagen-induced arthritis (CIA) is a widely used mouse model for studying inflammatory arthritis (IA). However, CIA induction protocols differ between laboratories, and direct comparison between protocol variations has not been reported. To address this issue, DBA/1 mice housed in conventional and specific pathogen free (SPF) facilities were administered various combinations of two doses of collagen type II (CII) in complete (CFA) or incomplete Freund's adjuvant (IFA); some mice were also injected with lipopolysaccharide (LPS) and/or additional CII at specific intervals. Mice were evaluated for IA over the subsequent 2 months. Depending directly on the combination of CII, CFA, IFA, and LPS used, the incidence of IA ranged between 20%-100%, and severity extended from mild to severe even in an SPF environment. Our results demonstrate for the first time in head-to-head comparisons that specific variations in the use of CII, CFA, IFA, and LPS can induce a range of arthritic disease intensity and severity in an SPF facility. Thus, distinct experimental settings can be designed for robust assessment of factors that either exacerbate or inhibit arthritis pathogenesis. Furthermore, by achieving 100% incidence in an SPF facility, the protocols provide a practical and humane benefit by reducing the number of mice necessary for experimental assessment. PMID- 26956090 TI - Improved lysis of single bacterial cells by a modified alkaline-thermal shock procedure. AB - Single-cell genomics (SCG) is a recently developed tool to study the genomes of unculturable bacterial species. SCG relies on multiple-strand displacement amplification (MDA), PCR, and next-generation sequencing (NGS); however, obtaining sufficient amounts of high-quality DNA from samples is a major challenge when performing this technique. Here we present an improved bacterial cell lysing procedure that combines incubation in an alkaline buffer with a thermal shock (freezing/heating) treatment to yield highly intact genomic DNA with high efficiency. This procedure is more efficient in lysing Bacillus subtilis and Synechocystis cells compared with two other frequently used lysis methods. Furthermore, 16S ribosomal RNA gene and overall genome recovery were found to be improved by this method using single cells from a Utah desert soil community or Escherichia coli single cells, respectively. The efficiency of genome recovery for E. coli single cells using our procedure is comparable with that of the REPLI-g Single Cell (sc) Kit, but our method is much more economical. By providing high-quality genome templates suitable for downstream applications, our procedure will be a promising improvement for SCG research. PMID- 26956091 TI - Gain-of-function reporters for analysis of mRNA 3'-end formation: Design and optimization. AB - The concept of mRNA 3'-end formation as a static, minimally regulated housekeeping process has undergone a paradigm shift. Many recent studies have shown that accurate and efficient 3'-end formation of mRNA is highly regulated and that dysregulation of this process is a hallmark of several diseases. While there are many global analysis methods for monitoring altered mRNA processing, methods for investigating specific RNA 3'-end processing events in cells have not significantly changed. Here we describe a facile gain-of-function cellular reporter for the analysis of mRNA 3'-end formation as an alternative to approaches that are technically challenging or use radioactivity. We also offer suggestions for optimization of our approach and enhancement of its reproducibility. PMID- 26956092 TI - Streamlined scanning for enhancer elements in Drosophila melanogaster. AB - Enhancer elements in most eukaryotic organisms are often positioned at a great distance away from the transcription start site of the gene they regulate. Complex three-dimensional chromatin organization and insulators usually guide and limit the range of an enhancer's regulatory activity to a specific genetic locus. Rigorous testing of an entire genomic locus is often required in order to uncover the complete set of cis-regulatory modules (CRMs) regulating a gene, especially those with complex and dynamic expression patterns. Here we report a fast and efficient method for enhancer element identification by scanning large genomic regions using transgenic reporter genes. PMID- 26956093 TI - Antimicrobial cocktails to control bacterial and fungal contamination in Chlamydomonas reinhardtii cultures. AB - Chlamydomonas reinhardtii is a unicellular green alga widely used for research in photosynthesis, cell cycle regulation, ciliary biogenesis, and other physiological processes. Sterile cultures are needed for these studies, but contamination from bacteria and fungi occurs frequently. Although the One-shot Solution cocktail consisting of carbendazim, ampicillin, and cefotaxime has been developed for removing these contaminants from algal cultures, it is not always effective. Here we report two new antimicrobial cocktails for treating mixed bacterial and fungal contamination of Chlamydomonas cultures. A combination of the bactericide nalidixic acid with one of two fungicides, azoxystrobin or tebuconazole, was more effective than the One-shot Solution cocktail. In some of our tests, we find that alternating use of our new cocktails with One-shot Solution is needed to remove obstinate contaminants. PMID- 26956094 TI - Higher risk of urothelial carcinoma in the upper urinary tract than in the urinary bladder in hemodialysis patients. AB - Purpose This study used the a nationwide population-based retrospective cohort study with the claims data from the Taiwan National Health Insurance Research Database to investigate the risk of urothelial carcinoma (UC) for hemodialysis (HD) patients. Methods The study population consisted of 2689 patients with end stage renal disease (ESRD) newly diagnosed in 2000-2002 and underwent maintenance HD. Then, 21,449 reference patients were collected without HD randomly selected and matched with sex and age. The exclusion criteria were previous long-term analgesics and Chinese medication usage. Incidence density rates of UC in upper urinary tract (UTUC) and bladder (UBUC) were estimated for both cohorts by the end of 2012. Hazard ratios (HRs) of UC were measured in association with HD, covariates, and comorbidity. Results The incidence of UC was significantly higher in the HD cohort than in the reference cohort for both UT (21.8 vs. 0.65 per 10,000 person-years) and UB (17.7 vs. 3.55 per 10,000 person-years). The multivariate Cox proportional hazard regression analysis showed that the HRs of UTUC in HD cohort was 33.3 (95% CI = 15.9-69.5) and 5.14 for UBUC (95% CI = 3.24 8.15). The risk increased further for HD patients with comorbidity of hematuria, urinary tract infection (UTI) or hydronephrosis. Conclusion Patients with ESRD on HD are at a high risk of developing UC, especially UTUC in Taiwan. They will be paid more frequent to check urine analysis, urine cytology, and upper urinary tract survey. PMID- 26956096 TI - Correlation of p-doping in CVD Graphene with Substrate Surface Charges. AB - Correlations between the level of p-doping exhibited in large area chemical vapour deposition (CVD) graphene field effect transistor structures (gFETs) and residual charges created by a variety of surface treatments to the silicon dioxide (SiO2) substrates prior to CVD graphene transfer are measured. Beginning with graphene on untreated thermal oxidised silicon, a minimum conductivity (sigma(min)) occurring at gate voltage V(g) = 15 V (Dirac Point) is measured. It was found that more aggressive treatments (O2 plasma and UV Ozone treatments) further increase the gate voltage of the Dirac point up to 65 V, corresponding to a significant increase of the level of p-doping displayed in the graphene. An electrowetting model describing the measured relationship between the contact angle (theta) of a water droplet applied to the treated substrate/graphene surface and an effective gate voltage from a surface charge density is proposed to describe biasing of V(g) at sigma(min) and was found to fit the measurements with multiplication of a correction factor, allowing effective non-destructive approximation of substrate added charge carrier density using contact angle measurements. PMID- 26956095 TI - Vitronectin-Based, Biomimetic Encapsulating Hydrogel Scaffolds Support Adipogenesis of Adipose Stem Cells. AB - Soft tissue defects are relatively common, yet currently used reconstructive treatments have varying success rates, and serious potential complications such as unpredictable volume loss and reabsorption. Human adipose-derived stem cells (ASCs), isolated from liposuction aspirate have great potential for use in soft tissue regeneration, especially when combined with a supportive scaffold. To design scaffolds that promote differentiation of these cells down an adipogenic lineage, we characterized changes in the surrounding extracellular environment during adipogenic differentiation. We found expression changes in both extracellular matrix proteins, including increases in expression of collagen-IV and vitronectin, as well as changes in the integrin expression profile, with an increase in expression of integrins such as alphaVbeta5 and alpha1beta1. These integrins are known to specifically interact with vitronectin and collagen-IV, respectively, through binding to an Arg-Gly-Asp (RGD) sequence. When three different short RGD-containing peptides were incorporated into three-dimensional (3D) hydrogel cultures, it was found that an RGD-containing peptide derived from vitronectin provided strong initial attachment, maintained the desired morphology, and created optimal conditions for in vitro 3D adipogenic differentiation of ASCs. These results describe a simple, nontoxic encapsulating scaffold, capable of supporting the survival and desired differentiation of ASCs for the treatment of soft tissue defects. PMID- 26956097 TI - A shared respite--The meaning of place for family well-being in families living with chronic illness. AB - Living with chronic illness is a family affair that involves ongoing changes and challenges in everyday life. When life changes, the environment is important for family health and well-being. The relation between a place and a family is rarely described, and therefore the aim of this study was to explore the meaning of place for family well-being in families living with chronic illness. A qualitative design was chosen. Data were collected by photovoice combined with narrative family research interviews with 10 families living with chronic illness. A phenomenological hermeneutic analysis was used to interpret the data. The results showed that the meaning of place for family well-being in families living with chronic illness can be described as "a shared respite." This main theme included three subthemes: "a place for relief," "a place for reflection," and "a place for re-creation." These results were further understood by means of the concept place security. Feeling well means having place security in these families. Through knowledge about the meaning of place for family well-being, health care personnel can stimulate families living with chronic illness to find respite in places that contribute to well-being, both in familiar and new places. PMID- 26956098 TI - Nanostructured lipid carriers as semisolid topical delivery formulations for diflucortolone valerate. AB - CONTEXT: Topical treatment of skin disease needs to be strategic to ensure high drug concentration in the skin with minimum systemic absorption. OBJECTIVE: The aim of this study was to produce semisolid nanostructured lipid carrier (NLC) formulations, for topical delivery of the corticosteroid drug, diflucortolone valerate (DFV), with minimum systemic absorption. METHOD: NLC formulations were developed using a high shear homogenization combined with sonication, using Precirol(r) ATO5 or Tristearin(r) as the solid lipid, CapryolTM or isopropyl myristate as the liquid lipid and Poloxamer(r) 407 as surfactant. The present study addresses the influence of different formulations composition as solid lipid, liquid lipid types and concentrations on the physicochemical properties and drug release profile from NLCs. RESULTS AND DISCUSSION: DFV-loaded NLC formulations possessed average particle size ranging from 160.40 nm to 743.7 nm with narrow polydispersity index. The encapsulation efficiency was improved by adding the lipid-based surfactants (Labrasol(r) and Labrafil(r) M1944CS) to reach 68%. The drug release from the investigated NLC formulations showed a prolonged release up to 12 h. The dermatopharmacokinetic study revealed an improvement in drug deposition in the skin with the optimized DFV-loaded NLC formulation, in contrast to a commercial formulation. CONCLUSION: NLC provides a promising nanocarrier system that work as reservoir for targeting topical delivery of DFV. PMID- 26956099 TI - Mindfulness in a weight loss intervention: Some utility and some challenges. PMID- 26956101 TI - The Efficacy of Topiramate in Benign Paroxysmal Torticollis of Infancy: Report of Four Cases. AB - Benign paroxysmal torticollis (BPT) is a rare paroxysmal dyskinesia and 1 of the childhood periodic syndromes presenting with recurrent stereotypic episodes of torticollis, usually accompanied with some of the nonheadache features of migraine such as vomiting and ataxia. Although the nature of BPT may seem benign, its recurrent episodes can mimic attacks of epilepsy and expose the infant to unnecessary hospitalization and adverse effects of inappropriate medications. There is no approved medication for the disease, but a few studies have suggested that cyproheptadine is useful. However, use of this agent has not been confirmed as effective for these patients, and the safe dosage for children aged <2 years has not yet been established. We report 4 patients who exhibited a successful response to treatment with topiramate (their episodes of BPT stopped). Considering the underlying relation of BPT with migraine, the satisfactory response of our patients to topiramate, and the safety of this medication in neonates and children, topiramate seems to be an effective and safe medication for the reduction and elimination of BPT episodes. In addition, 1 of our case subjects (patient 4) confirmed this finding by exhibiting an explicit dependence in the regularity and duration of her attacks with topiramate. Topiramate seems to be an effective medication for the prophylaxis of BPT episodes. Further studies and clinical trials are recommended. PMID- 26956100 TI - Evaluation of chemical castration with calcium chloride versus surgical castration in donkeys: testosterone as an endpoint marker. AB - BACKGROUND: For the last few years, researchers have been interested in developing a method for chemical sterilization which may be a better alternative to surgical castration. An ideal chemical sterilant would be one that effectively arrests spermatogenesis and androgenesis as well as libido with absence of toxic or other side effects. Calcium chloride in various solutions and concentrations has been tested in many animal species, but few studies have been evaluated it in equines as a chemical sterilant. So, the objective of this study was to evaluate the clinical efficacy of chemical castration with 20% calcium chloride dissolved in absolute ethanol in comparison with surgical castration in donkeys based on the changes in the serum testosterone level and the histopathological changes in treated testes. METHODS: Twelve clinically healthy adult male donkeys were used in this study. Donkeys were divided randomly and equally into two groups: a surgical (S) group (n = 6) and a chemical (C) group (n = 6). Animals in the (S) group were subjected to surgical castration while those in the (C) group received a single bilateral intratesticular injection of 20% calcium chloride dissolved in absolute ethanol (20 ml/testis). Animals were kept under clinical observation for 60 days. Changes in animals' behavior and gross changes in external genitalia were monitored daily. Serum concentrations of testosterone were measured prior to treatment and at 15, 30, 45 and 60 days post-treatment. Testicles in the (C) group were examined histopathologically at the end of the experiment. RESULTS: Chemical castration with intratesticular calcium chloride vs. surgical castration failed to reduce serum concentrations of testosterone throughout the whole duration of the study; however it induced orchitis that was evident by focal necrotic areas in seminiferous tubules, cellular infiltration of neutrophils, proliferative intertubular fibrosis with a compensatory proliferation of Leydig cells. Donkeys tolerated the intratesticular injection of calcium chloride. There were no detectable changes in the general health status of the animals with the exception of swelling in external genitalia, scrotal ulcerations and fistulas. Food and water consumption and the gait of animals remained unaffected. CONCLUSION: Intratesticular calcium chloride can't be considered an effective method for chemical castration in donkeys. PMID- 26956102 TI - Development of Guidelines for Skeletal Survey in Young Children With Intracranial Hemorrhage. AB - BACKGROUND AND OBJECTIVE: As evidenced by the variation and disparities in evaluation, there is uncertainty in determining which young children with intracranial hemorrhage (ICH) should undergo evaluation with skeletal survey (SS) for additional injuries concerning for abuse. We aimed to develop guidelines for performing initial SS in children <24 months old presenting with ICH by combining available evidence from the literature with expert opinion. METHODS: Using the RAND/UCLA Appropriateness Method, a multispecialty panel of 12 experts used the literature and their own clinical expertise to rate the appropriateness of performing SS for 216 scenarios characterizing children <24 months old with ICH. After a moderated discussion of initial ratings, the scenarios were revised. Panelists re-rated SS appropriateness for 74 revised scenarios. For the 63 scenarios in which SS was deemed appropriate, the panel rated the necessity of SS. RESULTS: Panelists concluded that SS is appropriate for 85% (63), uncertain for 15% (11), and inappropriate for 0% of scenarios. Panelists determined that SS is necessary in all scenarios deemed appropriate. SS was deemed necessary for infants <6 months old and for children <24 months old with subdural hemorrhage that is not tiny and under a skull fracture. For children 6 to 23 months old with epidural hemorrhage, necessity of SS depended on the child's age, history of trauma, signs/symptoms, and ICH characteristics. CONCLUSIONS: The resulting clinical guidelines call for near-universal evaluation in children <24 months old presenting with ICH. Detailed, validated guidelines that are successfully implemented may decrease variation and disparities in care. PMID- 26956103 TI - Pathogen-Specific Clustering of Nosocomial Blood Stream Infections in Very Preterm Infants. AB - BACKGROUND AND OBJECTIVES: Nosocomial infections in NICUs tend to cluster, sometimes as devastating outbreaks, but pathogen-specific transmission probabilities are unknown. We aimed to quantify the pathogen-specific risk of a blood stream infection (BSI) in preterm infants after an index case with that pathogen in the same department. METHODS: Data of 44 818 infants below 1500 g birth weight of the German NICU surveillance system (2000-2011) were used to calculate the probability of a BSI in the presence or absence of another infant in the same unit with a same-pathogen BSI. RESULTS: The relative risk was similar for the more common pathogens, Enterococcus spp (4.3; 95% confidence interval: 2.7-6.9; n = 243), Enterobacter spp (7.9, 5.4-11.4; n = 246), Escherichia coli (7.9; 5.1-12.1; n = 210), Candida albicans (8.7; 5.0-15.4; n = 138), Staphylococcus aureus (9.5; 7.6-12.1; n = 407) and Klebsiella spp (13.1; 9.0 19.1; n = 190) but markedly elevated for Serratia spp (77.5; 41.1-146.1; n = 58) and Pseudomonas aeruginosa (64.5; 25.7-162.1; n = 38). Rates of BSI per 100 exposed infants ranged between 2.21 (Enterococcus) and 8.15 (Serratia). The same pattern emerged after adjustments were made for patients' characteristics or when the analysis was restricted to positive blood cultures during the preceding 30 days. CONCLUSIONS: Although BSIs with P aeruginosa or Serratia spp in preterm infants are rare, they are associated with a markedly elevated risk of secondary same-pathogen BSI and should prompt intensified active surveillance and infection control measures. PMID- 26956104 TI - Preparing for the ACEM Fellowship Examination: FAC'EM without fear, a medical educator's perspective. PMID- 26956106 TI - Special Issue in Memory of Prof. Dr. Luis Eduardo Diaz: Current Topics in Pharmaceutical Biotechnology. PMID- 26956105 TI - Safety of eribulin mesylate and concomitant radiotherapy for metastatic breast cancer: a single-center experience. AB - AIM: This study evaluates, for the first time, the safety of eribulin in metastatic breast cancer patients concomitantly treated with palliative radiotherapy (RT). Patients & materials: A total of 17 patients were pretreated for metastatic breast cancer. Patients received eribulin mesylate and bone RT. RESULTS: The most frequent grade 3 hematologic adverse events were neutropenia (56%) and anemia (20%). Mean pain score decreased from 2 (baseline) to 0.7 (end of observation). Analgesic score remained stable (1.8 vs 1.6). Bone pain scores dropped within a few weeks and remained below baseline values throughout the analysis. The overall response rate was 29%, and the clinical benefit rate was 59%. CONCLUSION: Eribulin is characterized by a manageable safety profile also when combined with palliative RT. PMID- 26956107 TI - Healing or Not Healing. AB - Healing process might be considered as a byproduct of the mechanisms underlying the biological defense system consisting of hemostasis and clotting, the innate immune system, and fibrogenesis. But there is no biological process that does not potentially entail high costs through trade-offs with other life-history parameters and that might be seen as collateral damage. Depending on the balance among the robust and flexible modular defense system, which will be deployed in many different arrays, the structural outcome of the healing process will not resolve with a unitary outcome. Drawing on the regenerative potential of platelets, plasma biomolecules and fibrin matrix, several systems of producing autologous platelets-and plasma derived products (APPDPs) have been developed and aimed at enhancing the natural in vivo tissue regenerative capacity of damaged tissues. Despite the care with which the medical staff elaborate and apply autologous platelets-and plasma derived products, some pitfalls arise regarding the composition of autologous plasma-and platelet derived products, the modalities of their application, and the in vitro versus in vivo evaluations, all of which can deeply influence tissue healing - a process which is already unpredictable, without a unitary mechanism that might be deployed in many different structural and functional arrays which culminate in the tissue repair. A biological approach to the application of autologous platelets-and plasma derived products is crucial to obtaining optimum functional healing outcomes in addition to avoiding poor clinical results and reaching misleading conclusions. PMID- 26956108 TI - Insect Larvae: A New Platform to Produce Commercial Recombinant Proteins. AB - In Biotechnology, the expression of recombinant proteins is a constantly growing field and different hosts are used for this purpose. Some valuable proteins cannot be produced using traditional systems. Insects from the order Lepidoptera infected with recombinant baculovirus have appeared as a good choice to express high levels of proteins, especially those with post-translational modifications. Lepidopteran insects, which are extensively distributed in the world, can be used as small protein factories, the new biofactories. Species like Bombyx mori (silkworm) have been analyzed in Asian countries to produce a great number of recombinant proteins for use in basic and applied science and industry. Many proteins expressed in this larva have been commercialized. Several recombinant proteins produced in silkworms have already been commercialized. On the other hand, species like Spodoptera frugiperda, Heliothis virescens, Rachiplusia nu, Helicoverpa zea and Trichoplusia ni are widely distributed in both the occidental world and Europe. The expression of recombinant proteins in larvae has the advantage of its low cost in comparison with insect cell cultures. A wide variety of recombinant proteins, including enzymes, hormones and vaccines, have been efficiently expressed with intact biological activity. The expression of pharmaceutically proteins, using insect larvae or cocoons, has become very attractive. This review describes the use of insect larvae as an alternative to produce commercial recombinant proteins. PMID- 26956110 TI - Potential Application of Plant-derived Bioengineered Human VEGF for Tissue Regeneration. AB - The design and development of novel biological drugs are among the most exciting new areas of biotechnology which are gaining the attention of scientists. In the last few decades several fabrication processes have been proposed and developed for the production of recombinant growth factors. However, traditional production processes have several limitations in terms of scale- up, cost-efficiency and purity grade of the proteins. In the present study, we propose for the first time the proof-of-concept of large-scale production of growth factors in plants as a new alternative to other production processes. We have decided to select vascular endothelial growth factor (VEGF) as model assuming its key role in cell survival and regenerative medicine. Results show that the present protocol is efficient to scale up a purification procedure of rh VEGF isoform 165 in Nicotiana benthamiana plants. Our procedure resulted in dimeric VEGF protein with high purity degree and yield, which showed full biological activity over endothelial and epithelial cells, suggesting great potential for its use in regenerative medicine. This protein could be exploited not only in tissue repair and regeneration but also as a biologically active ingredient in dermocosmetics. PMID- 26956109 TI - Innovative Immobilization Matrices. AB - We present a brief survey of some of the recent work of Professor Luis E. Diaz, performed together with his students and collaborators at the University of Buenos Aires. Dr Luis E. Diaz has been involved in research on biochemical and pharmaceutical sciences solving scientific and industry problems for over 40 years until he passed away. Prof. Diaz scientific interests included various topics from NMR spectroscopy to biomedicine but fundamentally he focused in various aspects of chemistry (analytical, organic, inorganic and environmental). This is not a complete survey but a sampling of prominent projects related to sol gel chemistry with a focus on some of his recent publications. PMID- 26956112 TI - The Unbiased Search of Biomarkers in Neurodegenerative Diseases. AB - A clear link exists between the extension of life expectancy throughout the world and the increased incidence of age-related neurodegenerative disorders. Diseases like Alzheimer's and Parkinson's are chronic diseases with devastating consequences for patients and their families. They also represent a major economic cost for society. Therapeutic progress has been made mainly by alleviating some of the symptoms of these diseases, but currently no cure is available. Attempts to develop new therapies have been hampered mainly because of gaps in our current knowledge about the pathogenic mechanism underlying neurodegeneration, making difficult the identification of targets for new drug development, and also because of the lack of biomarkers essential for early diagnosis, patient stratification and follow up of treatment. Taking advantage of the latest technical developments, proteomics and peptidomics based approaches are being used to identify new cellular pathophysiological pathways as well as biomarkers in biological fluids. Here we will review the results, mainly published in the last five years, of unbiased proteomics and peptidomics approaches for biomarker research using biological fluids of Alzheimer's, Parkinson's and Amyotrophic Lateral Sclerosis patients. PMID- 26956111 TI - Nanotoxicological Effects of SiO2 Nanoparticles on Spodoptera frugiperda Sf9 Cells. AB - The application of silica nanoparticles (NPs) in the biomedical field experienced a great development. The driving forces for these and future developments are the possibility to design NPs with homogeneous size and structure amenable to specific grafting. Moreover, it is possible to tune the characteristics of the NPs to meet the requirements of each specific cell and desired application. Herein, we analyzed the effect of silica NPs of various sizes and surface charge on the viability of Spodoptera frugiperda cells (Sf9 cell line) with the aim of extending the knowledge of possible toxicity of the NPs in the environment and development of new tools for insect control. Moreover, these results will also contribute to develop more effective systems for gene vectors delivery and recombinant proteins expression. Bare silica NPs of 14 nm, 380 nm and 1430 nm as well as amine-modified silica NPs of 131 nm and 448 nm were obtained by the Stober method. The NPs were characterized by DLS and zeta potential measurements. The cell viability was assessed by the MTT test. It was observed that the 14 nm NPs possess the highest toxic effect. Indeed, after 24 h, the viability of the cells exposed to the lower concentration of NPs (0.12 mg/ml) was about 40% of the value obtained for the control cells not exposed to NPs. Moreover, the exposure to other negative charged NPs also causes a lower activity when compared with the control. Alternatively, lower concentrations of positive charged NPs (i.e.: 0.12 or 0.6 mg/ml) demonstrated to stimulate the proliferation of the cells and higher concentrations (i.e.: 7.2 mg/ml) did not present significant differences with the control. In conclusion, we have demonstrated that the NPs possess an effect that is highly influenced by the size, charge and concentration. Although, silica NPs are being used in the biomedical field, these results contribute to further understanding the risk that could be associated to nanoparticles and how these can be modified in order to meet the requirements of each desired application. PMID- 26956113 TI - Response to Magnus and Wilfond. PMID- 26956114 TI - Developing and validating a new national remote health advice syndromic surveillance system in England. AB - Background: Public Health England (PHE) coordinates a suite of real-time national syndromic surveillance systems monitoring general practice, emergency department and remote health advice data. We describe the development and informal evaluation of a new syndromic surveillance system using NHS 111 remote health advice data. Methods: NHS 111 syndromic indicators were monitored daily at national and local level. Statistical models were applied to daily data to identify significant exceedances; statistical baselines were developed for each syndrome and area using a multi-level hierarchical mixed effects model. Results: Between November 2013 and October 2014, there were on average 19 095 NHS 111 calls each weekday and 43 084 each weekend day in the PHE dataset. There was a predominance of females using the service (57%); highest percentage of calls received was in the age group 1-4 years (14%). This system was used to monitor respiratory and gastrointestinal infections over the winter of 2013-14, the potential public health impact of severe flooding across parts of southern England and poor air quality episodes across England in April 2014. Conclusions: This new system complements and supplements the existing PHE syndromic surveillance systems and is now integrated into the routine daily processes that form this national syndromic surveillance service. PMID- 26956116 TI - Can genetic evidence help us understand why height and weight relate to social position? PMID- 26956117 TI - Erratum to: Low ambient oxygen prevents atherosclerosis. PMID- 26956118 TI - SIRT1 inhibits differentiation of monocytes to macrophages: amelioration of synovial inflammation in rheumatoid arthritis. AB - Monocyte-to-macrophage differentiation plays a central role in the pathophysiology of rheumatoid arthritis (RA)-associated inflammation because it results in the secretions of various inflammatory mediators in inflamed synovium, and thus, this differentiation is viewed as a clinical target. We aimed to determine whether SIRT1 inhibits the differentiation of monocytes from RA patients into macrophages by suppressing PU.1 phosphorylation. Monocytes from synovial fluid of RA patients (RAMCs), THP-1 monocytes, and mouse bone marrow derived monocytes (BMDCs) were studied. The phorbol 12-myristate 13-acetate (PMA) stimulated RA monocyte adherence was significantly inhibited by resveratrol (a SIRT1 activator), and this inhibition by resveratrol was prevented by pretreating cells with sirtinol (a SIRT1 inhibitor). Furthermore, resveratrol pretreatment inhibited PMA-induced expressions of macrophage surface markers (CD11b, CD14, and CD36) and PMA-induced NF-kappaB transcriptional activation and, thus, suppressed the secretions of proinflammatory cytokines (TNF-alpha, IL-1beta, and IL-6). In SIRT1 transgenic (Tg) mice, monocyte differentiation was inhibited and NF-kappaB transcriptional activity was suppressed and the expressions of TNF-alpha, IL 1beta, and IL-6 were decreased at the protein and mRNA levels versus control C57BL/6 mice. Furthermore, SIRT1 activation by resveratrol suppressed PMA-induced phosphorylation and the nuclear translocation of PU.1 and, thus, inhibited monocyte differentiation. In conclusion, SIRT1 appears to inhibit monocyte to macrophage differentiation by suppressing PU.1 phosphorylation and inflammatory signaling, which suggests SIRT1 plays a critical role in the regulation of synovial inflammation in RA. KEY MESSAGE: SIRT1 overexpression inhibits monocyte to macrophage differentiation. SIRT1 suppresses PU.1 phosphorylation. Inactivation of PU.1 phosphorylation inhibits monocyte differentiation. SIRT1 regulates inflammation by inhibiting NF-kappaB during monocyte differentiation. PMID- 26956119 TI - Inferring Phylogenetic Relationships of Indian Citron (Citrus medica L.) based on rbcL and matK Sequences of Chloroplast DNA. AB - Phylogenetic relationships of Indian Citron (Citrus medica L.) with other important Citrus species have been inferred through sequence analyses of rbcL and matK gene region of chloroplast DNA. The study was based on 23 accessions of Citrus genotypes representing 15 taxa of Indian Citrus, collected from wild, semi wild, and domesticated stocks. The phylogeny was inferred using the maximum parsimony (MP) and neighbor-joining (NJ) methods. Both MP and NJ trees separated all the 23 accessions of Citrus into five distinct clusters. The chloroplast DNA (cpDNA) analysis based on rbcL and matK sequence data carried out in Indian taxa of Citrus was useful in differentiating all the true species and species/varieties of probable hybrid origin in distinct clusters or groups. Sequence analysis based on rbcL and matK gene provided unambiguous identification and disposition of true species like C. maxima, C. medica, C. reticulata, and related hybrids/cultivars. The separation of C. maxima, C. medica, and C. reticulata in distinct clusters or sub-clusters supports their distinctiveness as the basic species of edible Citrus. However, the cpDNA sequence analysis of rbcL and matK gene could not find any clear cut differentiation between subgenera Citrus and Papeda as proposed in Swingle's system of classification. PMID- 26956121 TI - A Mobilising Concept? Unpacking Academic Representations of Responsible Research and Innovation. AB - This paper makes a plea for more reflexive attempts to develop and anchor the emerging concept of responsible research and innovation (RRI). RRI has recently emerged as a buzzword in science policy, becoming a focus of concerted experimentation in many academic circles. Its performative capacity means that it is able to mobilise resources and spaces despite no common understanding of what it is or should be 'made of'. In order to support reflection and practice amongst those who are interested in and using the concept, this paper unpacks understandings of RRI across a multi-disciplinary body of peer-reviewed literature. Our analysis focuses on three key dimensions of RRI (motivations, theoretical conceptualisations and translations into practice) that remain particularly opaque. A total of 48 publications were selected through a systematic literature search and their content was qualitatively analysed. Across the literature, RRI is portrayed as a concept that embeds numerous features of existing approaches to govern and assess emerging technologies. Our analysis suggests that its greatest potential may be in its ability to unify and provide political momentum to a wide range of long-articulated ethical and policy issues. At the same time, RRI's dynamism and resulting complexity may represent its greatest challenge. Further clarification on what RRI has to offer in practice beyond what has been offered to date-is still needed, as well as more explicit engagement with research and institutional cultures of responsibility. Such work may help to realise the high political expectations that are attached to nascent RRI. PMID- 26956123 TI - Histopathology of keratotic papules of the limbs in frontal fibrosing alopecia. AB - Frontal fibrosing alopecia (FFA) is a scarring type of alopecia that presents clinically as progressive frontotemporal hairline regression and eyebrow loss, mainly in postmenopausal women. An additional common finding is keratotic papules on the face or (less commonly) on the trunk and extremities. The histopathology of the facial keratotic papules associated with FFA is the same as that of lichen planopilaris. There are very few FFA cases with biopsies from extrafacial sites and no cases of folliculocentric keratotic papules with biopsies from extrafacial sites. In the current report, we describe the histopathology of one such keratotic papule from the arm of a 75-year-old woman with FFA and show that the morphology is that of lichen planopilaris and that the papules are identical to those found in Graham-Little-Piccardi syndrome. PMID- 26956120 TI - Functional analysis of the binding model of microbial inulinases using docking and molecular dynamics simulation. AB - Recently inulinase has regained interest due to its usage in the production of fructooligosaccharides, biofuels, and in pharmaceutical industries. Inulinases properties are experimentally reported by nomerous studies but their characteristics are just partially explained by only a few computational investigations. In the present study we have investigated exoinulinase and endoinulinase from different microbial sources toward their catalytic activity. Docking and molecular dynamic (MD) simulation were carried out for microbial endoinulinase and exoinulinase docked with 1-kestose and fructose-6-phosphate respectively. Pseudomonas mucidolens (-7.42 kcal mol(-1) binding energy), docked with fructose-6-phosphate, was recorded as the most favorable binding energy, Pseudomonas mucidolens made hydrogen bonds with fructose-6-phosphate and the amino acids involved were arginine 286, tryptophan 158, and isoleucine 87. After the simulation only tryptophan 158 remained bonded and additionally valine 156 made hydrogen bonds with fructose-6-phosphate. Aspergillus niger docked with 1 kestose was bonded with the involvement of threonine 271, aspartate 285, threonine 288, and proline 283, after the simulation aspartate 285 was retained till the end of the simulation. The present study thus refers to the indication of depicting binding analysis of microbial inulinases. PMID- 26956124 TI - The association of weight, weight variability and socioeconomic situation among children. AB - BACKGROUND/OBJECTIVES: We studied the association of body weight and weight variability among populations from different geographic, historic and socioeconomic background. SUBJECTS/METHODS: We reanalyzed data from 833 growth studies of 78 different countries from 1920 to 2013. We used data from two age groups-infants (age 2 years) and juvenile (age 7 years)-and divided the studies into two geographic-socioeconomic groups. RESULTS: Multiple regressions showed significant interactions between weight, sex, historic year of study, continent and within-study standard deviation. Multiple regression revealed R(2)=0.256 (P<0.001) at age 2 years and R(2)=0.478 (P<0.001) at age 7 years. Although infants and juveniles in more affluent countries are heavier than children in less affluent countries (P<0.001), the within-study standard deviation of the two geographic-socioeconomic groups differs at age 7 years (P<0.001) but not at age 2 years (P>0.15). CONCLUSIONS: The general impression that prosperous conditions lead to growth improvements in height and weight appears to be true only at a large scale: wealthy countries have tall and heavy children. At small scale, the situation is different. Whereas economic and nutritional improvements can exhibit substantial effects in weight gains, the discrepancy between the within population variation in height and weight strongly suggests that height gains and weight gains are subject to different regulations. PMID- 26956125 TI - Multiple imputation as one tool to provide longitudinal databases for modelling human height and weight development. AB - BACKGROUND/OBJECTIVES: Besides large efforts regarding field work, provision of valid databases requires statistical and informational infrastructure to enable long-term access to longitudinal data sets on height, weight and related issues. SUBJECTS/METHODS: To foster use of longitudinal data sets within the scientific community, provision of valid databases has to address data-protection regulations. It is, therefore, of major importance to hinder identifiability of individuals from publicly available databases. To reach this goal, one possible strategy is to provide a synthetic database to the public allowing for pretesting strategies for data analysis. The synthetic databases can be established using multiple imputation tools. Given the approval of the strategy, verification is based on the original data. RESULTS: Multiple imputation by chained equations is illustrated to facilitate provision of synthetic databases as it allows for capturing a wide range of statistical interdependencies. Also missing values, typically occurring within longitudinal databases for reasons of item non response, can be addressed via multiple imputation when providing databases. CONCLUSIONS: The provision of synthetic databases using multiple imputation techniques is one possible strategy to ensure data protection, increase visibility of longitudinal databases and enhance the analytical potential. PMID- 26956115 TI - Deep Brain Stimulation for Movement Disorders of Basal Ganglia Origin: Restoring Function or Functionality? AB - Deep brain stimulation (DBS) is highly effective for both hypo- and hyperkinetic movement disorders of basal ganglia origin. The clinical use of DBS is, in part, empiric, based on the experience with prior surgical ablative therapies for these disorders, and, in part, driven by scientific discoveries made decades ago. In this review, we consider anatomical and functional concepts of the basal ganglia relevant to our understanding of DBS mechanisms, as well as our current understanding of the pathophysiology of two of the most commonly DBS-treated conditions, Parkinson's disease and dystonia. Finally, we discuss the proposed mechanism(s) of action of DBS in restoring function in patients with movement disorders. The signs and symptoms of the various disorders appear to result from signature disordered activity in the basal ganglia output, which disrupts the activity in thalamocortical and brainstem networks. The available evidence suggests that the effects of DBS are strongly dependent on targeting sensorimotor portions of specific nodes of the basal ganglia-thalamocortical motor circuit, that is, the subthalamic nucleus and the internal segment of the globus pallidus. There is little evidence to suggest that DBS in patients with movement disorders restores normal basal ganglia functions (e.g., their role in movement or reinforcement learning). Instead, it appears that high-frequency DBS replaces the abnormal basal ganglia output with a more tolerable pattern, which helps to restore the functionality of downstream networks. PMID- 26956126 TI - Antiobesity effect of Pediococcus pentosaceus LP28 on overweight subjects: a randomized, double-blind, placebo-controlled clinical trial. AB - BACKGROUND/OBJECTIVES: The population of the obese is increasing worldwide. Prevention and improvement of obesity are indispensable for decreasing the risk of metabolic disorders. We have recently shown that obesity and fatty liver are reduced by a plant-derived lactic acid bacterium, Pediococcus pentosaceus LP28 (LP28), in high-fat diet-induced obese mice. The aim of the present clinical study is to prove that LP28 is effective for reducing body fat and body weight, as shown in the experiment using mice. SUBJECTS/METHODS: The clinical trial was carried out as a double-blind, randomized, placebo-controlled study comprising 62 subjects (20-70 years of age, BMI 25-30 kg/m(2)). These subjects were randomly assigned to three groups that received living LP28, heat-killed LP28 or a placebo powder, administered orally once a day for 12 weeks. RESULTS: Heat-killed LP28 reduced BMI (0.45 kg/m(2), 95% CI (0.04, 0.86), P=0.035), body fat percentage (1.11%, (0.39, 1.82), P=0.002), body fat mass (1.17 kg (0.43, 1.92), P=0.004) and waist circumference (2.84 cm (0.74, 4.93), P=0.009) when compared with a placebo group. Fasting plasma glucose, HbA1c, fasting insulin, HOMA-IR and serum lipids levels did not change by either living LP28 or heat-killed LP28 intake. CONCLUSIONS: Heat-killed LP28 displays an antiobesity effect that reduces BMI, body fat and waist circumference, suggesting that the plant-derived lactic acid bacterium LP28 would be a promising preventive of metabolic syndrome. PMID- 26956128 TI - Phthalocyanine-Gold Nanoparticle Hybrids: Modulating Quenching with a Silica Matrix Shell. AB - An asymmetrically substituted zinc phthalocyanine (ZnPc) with a terminal dithiolane group is anchored to Au nanoparticles (NPs) directly or through an interposed silica matrix. Transient absorption spectroscopy shows that the quenching of the ZnPc excited state by AuNPs occurs through a photoinduced electron transfer, the efficiency of which is modulated by the presence of the insulating silica matrix. PMID- 26956127 TI - Vitamin-D status is not a confounder of the relationship between zinc and diarrhoea: a study in 6-24-month-old underweight and normal-weight children of urban Bangladesh. AB - BACKGROUND/OBJECTIVE: The role of micronutrients particularly zinc in childhood diarrhoea is well established. Immunomodulatory functions of vitamin-D in diarrhoea and its role in the effect of other micronutrients are not well understood. This study aimed to investigate whether vitamin-D directly associated or confounded the association between other micronutrient status and diarrhoeal incidence and severity in 6-24-month underweight and normal-weight children in urban Bangladesh. SUBJECTS/METHODS: Multivariable generalised estimating equations were used to estimate incidence rate ratios for incidence (Poisson) and severity (binomial) of diarrhoea on cohorts of 446 normal-weight and 466 underweight children. Outcomes of interest included incidence and severity of diarrhoea, measured daily during a follow-up period of 5 months. The exposure of interest was vitamin-D status at enrolment. RESULTS: Normal-weight and underweight children contributed 62 117 and 62 967 day observation, with 14.2 and 12.8 days/child/year of diarrhoea, respectively. None of the models showed significant associations of vitamin-D status with diarrhoeal morbidity. In the final model, zinc-insufficient normal-weight children had 1.3 times more days of diarrhoea than sufficient children (P<0.05). Again zinc insufficiency and mother's education (1-5 and >5 years) had 1.8 and 2.3 times more risk of severe diarrhoea. In underweight children, older age and female had 24-63 and 17% fewer days of diarrhoea and 52-54 and 31% fewer chances of severe diarrhoea. CONCLUSION: Vitamin-D status was not associated with incidence and severity of diarrhoea in study children. Role of zinc in diarrhoea was only evident in normal weight children. Our findings demonstrate that vitamin-D is not a confounder of the relationship between zinc and diarrhoea. PMID- 26956129 TI - Chemoenzymatic Synthesis of Pleiogenone A: An Antiproliferative Trihydroxyalkylcyclohexenone Isolated from Pleiogynium timorense. AB - The first total synthesis of polyhydroxylated cyclohexenone 1, isolated from Pleiogynium timorense and named pleiogenone A, is reported that also serves as a proof of structure and absolute configuration. Enzymatic dihydroxylation of benzoic acid with R. eutrophus B9 provided enantiomerically pure diene diol 6. Elaboration of the carboxylate moiety to the alkyl side chain was followed by singlet oxygen cycloaddition to furnish an endoperoxide whose reduction with thiourea led to cyclitol 19. Several protective operations were required before oxidation and the final extension of the side chain by a Wittig reaction. After final deprotection of the acetonide functionality the desired pleiogenone A (1) was obtained in 14 operations from benzoic acid. PMID- 26956130 TI - Association of methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphism with autism: evidence of genetic susceptibility. AB - Autism (MIM 209850) is a heterogeneous neurodevelopmental disease that manifests within the first 3 years of life. Numerous articles reported that dysfunctional folate-methionine pathway enzymes may play an important role in the pathophysiology of autism. Methylenetetrahydrofolate reductase (MTHFR) is a critical enzyme of this pathway and MTHFR C677T polymorphism reported as risk factor for autism in several case control studies. However, controversial reports were also published. Hence the present meta-analysis was designed to investigate the relationship of the MTHFR C677T polymorphism with the risk of autism. Electronic databases were searched for case control studies with following search terms - 'MTHFR', 'C677T', in combination with 'Autism'. Pooled OR with its corresponding 95 % CI was calculated and used as association measure to investigate the association between MTHFR C677T polymorphism and risk of autism. Total of thirteen studies were found suitable for the inclusion in the present meta-analysis, which comprises 1978 cases and 7257 controls. Meta-analysis using all four genetic models showed significant association between C677T polymorphism and autism (ORTvs.C = 1.48; 95 % CI: 1.18-1.86; P = 0.0007; ORTT + CT vs. CC = 1.70, 95 % CI = 0.96-2.9, p = 0.05; ORTT vs. CC = 1.84, 95 % CI = 1.12-3.02, p = 0.02; ORCT vs.CC = 1.60, 95 % CI = 1.2-2.1, p = 0.003; ORTT vs.CT+CC = 1.5, 95 % CI = 1.02-2.2, p = 0.03). In total 13 studies, 9 studies were from Caucasian population and 4 studies were from Asian population. The association between C677T polymorphism and autism was significant in Caucasian (ORTvs.C = 1.43; 95 % CI = 1.1-1.87; p = 0.009) and Asian population (ORTvs.C = 1.68; 95 % CI = 1.02 2.77; p = 0.04) using allele contrast model. In conclusion, present meta-analysis strongly suggested a significant association of the MTHFR C677T polymorphism with autism. PMID- 26956133 TI - Erratum to: PAD4, LSD1 and EDS1 regulate drought tolerance, plant biomass production, and cell wall properties. PMID- 26956131 TI - Interpreting the results of chemical stone analysis in the era of modern stone analysis techniques. AB - INTRODUCTION AND OBJECTIVE: Stone analysis should be performed in all first-time stone formers. The preferred analytical procedures are Fourier-transform infrared spectroscopy (FT-IR) or X-ray diffraction (XRD). However, due to limited resources, chemical analysis (CA) is still in use throughout the world. The aim of the study was to compare FT-IR and CA in well matched stone specimens and characterize the pros and cons of CA. METHODS: In a prospective bi-center study, urinary stones were retrieved from 60 consecutive endoscopic procedures. In order to assure that identical stone samples were sent for analyses, the samples were analyzed initially by micro-computed tomography to assess uniformity of each specimen before submitted for FTIR and CA. RESULTS: Overall, the results of CA did not match with the FTIR results in 56 % of the cases. In 16 % of the cases CA missed the major stone component and in 40 % the minor stone component. 37 of the 60 specimens contained CaOx as major component by FTIR, and CA reported major CaOx in 47/60, resulting in high sensitivity, but very poor specificity. CA was relatively accurate for UA and cystine. CA missed struvite and calcium phosphate as a major component in all cases. In mixed stones the sensitivity of CA for the minor component was poor, generally less than 50 %. CONCLUSIONS: Urinary stone analysis using CA provides only limited data that should be interpreted carefully. Urinary stone analysis using CA is likely to result in clinically significant errors in its assessment of stone composition. Although the monetary costs of CA are relatively modest, this method does not provide the level of analytical specificity required for proper management of patients with metabolic stones. PMID- 26956132 TI - Lipotoxicity as a trigger factor of renal disease. AB - In the last few decades, rapid changes in lifestyle have led to an alarming increase in the prevalence of obesity and obesity-associated complications. Obese patients are at increased risk of developing hypertension, heart disease, insulin resistance, dyslipidemia, type 2 diabetes and kidney disease. The surplus of calories is normally stored as triglycerides in adipose tissue. However, excess lipids can also accumulate ectopically in other organs, including the kidney, contributing to their damage through toxic processes named lipotoxicity. The kidney is negatively affected by dyslipidemia, lipid accumulation and changes in circulating adipokines that bring about alterations in renal lipid metabolism and promote insulin resistance, generation of reactive oxygen species and endoplasmic reticulum stress, ultimately leading to alterations in the glomerular filtration barrier and renal failure. This review focuses on the pathogenic molecular mechanisms associated with renal lipotoxicity, and presents new insights about potential new therapeutic targets and biomarkers such as microRNAs and long non coding RNAs, of relevance for the early detection of lipid-associated kidney disease. PMID- 26956134 TI - Co-overexpression of Brassica juncea NPR1 (BjNPR1) and Trigonella foenum-graecum defensin (Tfgd) in transgenic peanut provides comprehensive but varied protection against Aspergillus flavus and Cercospora arachidicola. AB - KEY MESSAGE: Coexpression of two antifungal genes ( NPR1 and defensin ) in transgenic peanut results in the development of resistance to two major fungal pathogens, Aspergillus flavus and Cercospora arachidicola. Fungal diseases have been one of the principal causes of crop losses with no exception to peanut (Arachis hypogeae L.), a major oilseed crop in Asia and Africa. To address this problem, breeding for fungal disease resistance has been successful to some extent against specific pathogens. However, combating more than one fungal pathogen via breeding is a major limitation in peanut. In the present study, we demonstrated the potential use of co-overexpression of two genes, NPR1 and defensin isolated from Brassica juncea and Trigonella foenum-graecum respectively; that offered resistance towards Aspergillus flavus in peanut. The transgenic plants not only resisted the mycelial growth but also did not accumulate aflatoxin in the seeds. Resistance was also demonstrated against another pathogen, Cercospora arachidicola at varied levels; the transgenic plants showed both reduction in the number of spots and delay in the onset of disease. PCR, Southern and Western blot analysis confirmed stable integration and expression of the transgenes in the transgenic plants. The combinatorial use of the two pathogen resistance genes presents a novel approach to mitigate two important fungal pathogens of peanut. PMID- 26956135 TI - Topoisomerase II-associated protein PAT1H1 is involved in the root stem cell niche maintenance in Arabidopsis thaliana. AB - KEY MESSAGE: PAT1H1, one of the homologues of Topoisomerase II-associated protein, is involved in the maintenance of root stem cell niche through the interaction with NINJA. The root stem cell niche, which possesses four mitotically inactive quiescent cells (QC) and the surrounding mitotically active stem cells, is critical for root development in Arabidopsis thaliana. However, the molecular regulation of the maintenance of root stem cell niche identity is still not fully understood. Here we show that one of the homologues of Topoisomerase II-associated protein, here named as PAT1H1, could regulate root stem cell niche identity. The pat1h1 mutant showed higher frequency of QC cell division and root distal stem cell (DSC) differentiation. With a high expression in roots, PAT1H1 was found to interact with the jasmonic acid (JA) signalling negative regulator Novel Interactor of JAZ (NINJA) and thus regulate root DSC niche identity. Consistent with the active QC cell division, which rarely occurs in wild-type controls, the pat1h1 mutant displayed higher expression of CYCB1 in the root stem cell niche. Together our data reveals that PAT1H1 maintains root stem cell niche stability through the interaction with NINJA and the regulation of cell division. PMID- 26956136 TI - Tumebacillus soli sp. nov., isolated from non-rhizosphere soil. AB - A Gram-stain-positive, strictly aerobic, motile, spore-forming, rod-shaped bacterial strain, CAU 11108T, was isolated from soil in Danghangpo, Republic of Korea, and its taxonomic position was investigated using a polyphasic approach. The bacterium grew optimally at 37 degrees C, at pH 8, and in the presence of 1 % (w/v) NaCl. Phylogenetic analysis based on 16S rRNA gene sequence similarity revealed that strain CAU 11108T formed a distinct lineage within the genus Tumebacillus and was most closely related to Tumebacillus luteolus U13T (98.2 %). The strain contained menaquinone-7 (MK-7) as the major respiratory quinone and iso-C15 : 0 and anteiso-C15 : 0 as the major fatty acids. The DNA G+C content was 54.6 mol%. On the basis of phenotypic differentiation, phylogenetic and chemotaxonomic data, strain CAU 11108T represents a novel species of the genus Tumebacillus, for which the name Tumebacillus soli sp. nov. is proposed. The type strain is CAU 11108T (=KCTC 33141T=CECT 8918T). PMID- 26956137 TI - Capsule Commentary on Meredith et al., Impact of Collaborative Care for Underserved Patients with PTSD in Primary Care: A Randomized Controlled Trial. PMID- 26956138 TI - Capsule Commentary on Koroukian et al., Combinations of Chronic Conditions, Functional Limitations, and Geriatric Syndromes that Predict Health Outcomes. PMID- 26956139 TI - Capsule Commentary on Post et al., Rating the Quality of Entrustable Professional Activities: Content Validation and Associations with the Clinical Context. PMID- 26956141 TI - Enhancement of electricity production in a mediatorless air-cathode microbial fuel cell using Klebsiella sp. IR21. AB - A novel dissimilatory iron-reducing bacteria, Klebsiella sp. IR21, was isolated from the anode biofilm of an MFC reactor. Klebsiella sp. IR21 reduced 27.8 % of ferric iron to ferrous iron demonstrating that Klebsiella sp. IR21 has electron transfer ability. Additionally, Klebsiella sp. IR21 generated electricity forming a biofilm on the anode surface. When a pure culture of Klebsiella sp. IR21 was supplied into a single chamber, air-cathode MFC fed with a mixture of glucose and acetate (500 mg L(-1) COD), 40-60 mV of voltage (17-26 mA m(-2) of current density) was produced. Klebsiella sp. IR21 was also utilized as a biocatalyst to improve the electrical performance of a conventional MFC reactor. A single chamber, air-cathode MFC was fed with reject wastewater (10,000 mg L(-1) COD) from a H2 fermentation reactor. The average voltage, current density, and power density were 142.9 +/- 25.74 mV, 60.5 +/- 11.61 mA m(-2), and 8.9 +/- 3.65 mW m( 2), respectively, in the MFC without inoculation of Klebsiella sp. IR21. However, these electrical performances of the MFC were significantly increased to 204.7 +/ 40.24 mV, 87.5 +/- 17.20 mA m(-2), and 18.6 +/- 7.23 mW m(-2), respectively, with inoculation of Klebsiella sp. IR21. The results indicate that Klebsiella sp. IR21 can be utilized as a biocatalyst for enhancement of electrical performance in MFC systems. PMID- 26956142 TI - Global Host Partner Perspectives: Utilizing a Conceptual Model to Strengthen Collaboration with Host Partners for International Nursing Student Placements. AB - OBJECTIVES: Collaboration in international nursing student placements requires equitable partnerships between global partners to address areas of shared importance, such as equity and justice in health promotion. This qualitative study was the first to use the Leffers and Mitchell Conceptual Model for Partnership and Sustainability in Global Health to elicit global host partners' perspectives regarding effective collaboration for Canadian community health nursing placements in the Dominican Republic. DESIGN AND SAMPLE: Focus group and semi-structured interview methodology was conducted with Dominican Republic (Dominican and Haitian) host partners (n = 23) about the engagement processes and host partner factors for effective partnership. RESULTS: Dominican (83%) and Haitian (17%) participants, comprised similar numbers of male and female adults aged 18-60 years (mean age = 36 years), represented the full range of the Dominican Republic host partners (e.g., teachers, health professionals). Interpretive analysis revealed themes that included (1) the unique role of the cultural broker; (2) relational collaboration in a collective society; (3) reciprocal approaches that honor local expertise; and (4) contextual socioeconomic and cultural factors that influence partnerships. CONCLUSIONS: Future research and implications at the individual, community, and policy levels are discussed. PMID- 26956140 TI - Training Primary Care Physicians to Employ Self-Efficacy-Enhancing Interviewing Techniques: Randomized Controlled Trial of a Standardized Patient Intervention. AB - BACKGROUND: Primary care providers (PCPs) have few tools for enhancing patient self-efficacy, a key mediator of myriad health-influencing behaviors. OBJECTIVE: To examine whether brief standardized patient instructor (SPI)-delivered training increases PCPs' use of self-efficacy-enhancing interviewing techniques (SEE IT). DESIGN: Randomized controlled trial. PARTICIPANTS: Fifty-two family physicians and general internists from 12 primary care offices drawn from two health systems in Northern California. INTERVENTIONS: Experimental arm PCPs received training in the use of SEE IT training during three outpatient SPI visits scheduled over a 1 month period. Control arm PCPs received a single SPI visit, during which they viewed a diabetes treatment video. All intervention visits (experimental and control) were timed to last 20 min. SPIs portrayed patients struggling with self care of depression and diabetes in the first 7 min, then delivered the appropriate intervention content during the remaining 13 min. MAIN MEASURES: The primary outcome was provider use of SEE IT (a count of ten behaviors), coded from three audio-recorded standardized patient visits at 1-3 months, again involving depression and diabetes self-care. Two five-point scales measured physician responses to training: Value (7 items: quality, helpfulness, understandability, relevance, feasibility, planned use, care impact), and Hassle (2 items: personal hassle, flow disruption). KEY RESULTS: Pre-intervention, study PCPs used a mean of 0.7 behaviors/visit, with no significant between-arm difference (P = 0.23). Post-intervention, experimental arm PCPs used more of the behaviors than controls (mean 2.7 vs. 1.0 per visit; adjusted difference 1.7, 95 % CI 1.1-2.2; P < 0.001). Experimental arm PCPs had higher training Value scores than controls (mean difference 1.05, 95 % CI 0.68-1.42; P < 0.001), and similarly low Hassle scores. CONCLUSIONS: Primary care physicians receiving brief SPI-delivered training increased their use of SEE IT and found the training to be of value. Whether patients visiting SEE IT-trained physicians experience improved health behaviors and outcomes warrants study. CLINICALTRIALS. GOV IDENTIFIER: NCT01618552. PMID- 26956144 TI - A novel p.Val244Leu mutation in MFN2 leads to Charcot-Marie-Tooth disease type 2. AB - BACKGROUND: Charcot-Marie-Tooth (CMT) disease is one of the most common hereditary peripheral neuropathy. The major clinical features of CMT are progressive muscle weakness of distal extremities and sensory loss. MFN2 encodes a GTPase dynamin-like protein mitofusin 2 and plays an essential role in mitochondrial functions. In previous studies, MFN2 mutations have been linked to neurological disorders including CMT type 2 (CMT2). Here, we report a novel mutation in MFN2 which leads to CMT 2. CASE PRESENTATION: We report a 4-year-old Chinese boy with CMT symptoms including foot-drop gait, running difficulties, frequent falls, slowly progressive atrophy of lower legs with a mildly foot deformity. Nerve conduction velocity study (NCVS) found that no compound motor action potential (CMAP) was elicited in the nervi suralis and tibial nerve. Moreover, the sensory nerve action potential (SNAP) of the nervi suralis was not elicited, which means the peripheral nerves of his lower limbs were damaged. Targeted next-generation sequencing identified a novel heterozygous mutation c.730G > C (p.Val244Leu) in MFN2 in the patient but not in his parents, suggesting that this mutation likely occurred de novo. c.730G > C (p.Val244Leu) in MFN2 is a likely pathogenic mutation for CMT2. CONCLUSION: The c.730G > C (p.Val244Leu) mutation in MFN2 is a likely pathogenic mutation for CMT2. PMID- 26956143 TI - Evaluation of TP53 Pro72Arg and MDM2 SNP285-SNP309 polymorphisms in an Italian cohort of LFS suggestive patients lacking identifiable TP53 germline mutations. AB - Li-Fraumeni syndrome (LFS) is a rare genetic cancer predisposition disease, partly determined by the presence of a TP53 germline mutation; lacking thereof, in presence of a typical LFS phenotype, defines a wide group of 'LFS Suggestive' patients. Alternative LFS susceptibility genes have been investigated without promising results, thus suggesting other genetic determinants involvement in cancer predisposition. Hence, this study explores the single and combined effects of cancer risk, age of onset and cancer type of three single nucleotide polymorphisms (SNPs)-TP53 Pro72Arg, MDM2 SNP285 and SNP309-already described as modifiers on TP53 mutation carriers but not properly investigated in LFS Suggestive patients. This case-control study examines 34 Italian LFS Suggestive lacking of germline TP53 mutations and 95 tumour-free subjects. A significant prevalence of homozygous MDM2 SNP309 G in the LFS Suggestive group (p < 0.0005) confirms its contribute to cancer susceptibility, also highlighted in LFS TP53 positive families. Conversely its anticipating role on tumour onset has not been confirmed, as in our results it was associated with the SNP309 T allele. A strong combined outcome with a 'dosage' effect has also been reported for TP53 P72 and MDM2 SNP309 G allele on cancer susceptibility (p < 0.0005). Whereas the MDM2 SNP285 C allele neutralizing effect on MDM2 SNP309 G variant is not evident in our population. Although it needs further evaluations, obtained results strengthen the role of MDM2 SNP309 as a genetic factor in hereditary predisposition to cancer, so improving LFS Suggestive patients management. PMID- 26956145 TI - Production of Isotonic, Sterile, and Kinetically Stable Lipid-Core Nanocapsules for Injectable Administration. AB - Lipid-core nanocapsules (LNC) were designed and prepared as a colloidal system for drug targeting to improve the stability of drugs and allow their controlled release. For parenteral administration, it is necessary to ensure formulation sterility. However, sterilization of nanotechnological devices using an appropriate technique that keeps the supramolecular structure intact remains a challenge. This work aimed to evaluate the effect of autoclaving on the physicochemical characteristics of LNC. Formulations were prepared by the self assembling method, followed by isotonization and sterilization at varying times and temperatures. The isotonicity was confirmed by determining the freezing temperature, which was -0.51 degrees C. The formulation was broadly characterized, and the diameter of the particles was determined utilizing complementary methods. To evaluate the chemical stability of poly(epsilon caprolactone), its molecular weight was determined by size exclusion chromatography. The physicochemical characteristics (average diameter, viscosity, and physical stability) of the formulation were similar before and after adding glycerol and conducting the sterilization at the highest temperature (134 degrees C) and the shorter exposure time (10 min). After autoclaving, the sterility test was performed and showed no detectable microbial growth. Multiple light scattering demonstrated that the formulations were kinetically stable, and the mean diameter was constant for 6 months, corroborating this result. The polymer was chemically stable in the sterilized formulation. Isotonic and sterile LNC aqueous suspensions were produced using glycerol and autoclaving. Briefly, the results open an opportunity to produce an isotonic and sterile LNC aqueous dispersion applicable as nanomedicine for intravenous administration in clinical trials. PMID- 26956146 TI - LOOKING BACK ON 5 YEARS OF HORIZON SCANNING IN ONCOLOGY. AB - OBJECTIVES: The regularly structured adaptation of health technology assessment (HTA) programs is of utmost importance to sustain the relevance of the products for stakeholders and to justify investment of scarce financial resources. This study describes internal adjustments and external measures taken to ensure the Horizon Scanning Programme in Oncology (HSO) is current. METHODS: Formal evaluation methods comprising a survey, a download, an environmental analysis, and a Web site questionnaire were used to evaluate user satisfaction. RESULTS: The evaluation showed that users were satisfied with HSO outputs in terms of timeliness, topics selected, and depth of information provided. Discussion of these findings with an expert panel led to changes such as an improved dissemination strategy and the introduction of an additional output, that is, the publication of a league table of emerging oncology drugs. The rather high level of international usage and the environmental analysis highlighted a considerable overlap in topics assessed and, thus, the potential for international collaboration. As a consequence, thirteen reports were jointly published based on eleven "calls for collaboration." To further facilitate collaboration and the usability of reports for other agencies, HSO reports will be adjusted according to tools developed at a European level. CONCLUSIONS: Evaluation of the impact of HTA programs allows the tailoring of outputs to fit the needs of the target population. However, within a fast developing HTA community, estimates of impact will increasingly be determined by international collaborative efforts. Refined methods and a broader definition of impact are needed to ultimately capture the efficiency of national HTA programs. PMID- 26956147 TI - A mortality prediction rule for non-elderly patients with community-acquired pneumonia. AB - BACKGROUND: No mortality prediction rule is suited for non-elderly patients with community-acquired pneumonia. Therefore, we tried to create a mortality prediction rule that is simple and suitable for non-elderly patients with community-acquired pneumonia. METHODS: Because of low mortality at young age, we used information from an administrative database that included A-DROP data. We analysed the rate and risk factors for in-hospital community-acquired pneumonia associated death among non-elderly patients and created a mortality prediction rule based on those risk factors. RESULTS: We examined 49,370 hospitalisations for patients aged 18-64 years with community-acquired pneumonia. The 30-day fatality rate was 1.5%. Using regression analysis, five risk factors were selected: patient requires help for feeding, the existence of malignancy, confusion, low blood pressure, and age 40-64 years. Each risk factor of our proposed mortality risk scoring system received one point. A total point score for each patient was obtained by summing the points. The negative likelihood ratio for the score 0 group was 0.01, and the positive likelihood ratio for the score >=4 group was 19.9. The area under the curve of the risk score for non elderly (0.86, 95% confidence interval: 0.84-0.87) was higher than that of the A DROP score (0.72, 95% confidence interval: 0.70-0.74) (P < 0.0001). CONCLUSIONS: Our newly proposed mortality risk scoring system may be appropriate for predicting mortality in non-elderly patients with community-acquired pneumonia. It showed a possibility of a better prediction value than the A-DROP and is easy to use in various clinical settings. PMID- 26956149 TI - Rapid screening of Alternaria mycotoxins using MALDI-TOF mass spectrometry. AB - BACKGROUND: Members of the Alternaria genus produce various toxins whose occurrence in agricultural commodities is a major concern for humans and the environment. The present study developed a simple and efficient matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) method for the rapid detection of Alternaria toxins. RESULTS: A new method for the detection of alternariol (AOH), alternariol monomethyl ether (AME) and tentoxin (TEN) by MALDI-TOF MS was developed. Different solid phase extraction (SPE) clean-up methods were tried to optimize the purification of wheat matrix, and an optimal extraction method was designed to recover the three Alternaria toxins. In addition, various MALDI matrices were examined and alpha-cyano-4 hydroxycinnamic acid (CHCA) matrix gave good repeatability for all three Alternaria toxins. CONCLUSION: This is the first study to report the detection of three important Alternaria toxins concurrently using MALDI-TOF MS and opens up the possibility of rapid screening of Alternaria toxins in several other cereals and food products. (c) 2016 Her Majesty the Queen in Right of Canada Journal of the Science of Food and Agriculture (c) 2016 Society of Chemical Industry. PMID- 26956148 TI - Azilsartan compared to ACE inhibitors in anti-hypertensive therapy: one-year outcomes of the observational EARLY registry. AB - BACKGROUND: Azilsartan medoxomil (AZL-M), has been demonstrated to be more effective than the other sartans currently in use; however, there is insufficient information available comparing it with ACE-inhibitors. Therefore, we aimed to compare the efficacy, safety, and tolerability of AZL-M with that of ACE inhibitors in a real life clinical setting. METHODS: The EARLY registry is a prospective, observational, national, multicentre registry with a follow-up period of 12 months. There were two principal objectives: 1) documentation of the achievement of target BP values set according to recent national and international guidelines, and 2) description of the safety profile of AZL-M. RESULTS: A total of 3 849 patients with essential arterial hypertension were recruited from primary care offices in Germany. Patients who initiated monotherapy at baseline comprising either AZL-M or an ACE-inhibitor were included at a ratio of seven to three. Results demonstrated that a blood pressure target of <140/90 mmHg was achieved by a significantly greater proportion of patients in the AZL-M group (61.1 %) compared with the ACE-inhibitor group (56.4 %; p < 0.05; OR, 1.21; 95 % CI, 1.03-1.42), with this finding maintained after adjusting for differences in baseline characteristics. AZL-M appeared to have an equivalent safety profile to the ACE-inhibitors, with a similar incidence of adverse events in the two patient groups (p = 0.73). CONCLUSIONS: These data add to the results of previous randomized controlled clinical trials suggesting that, compared with other agents that target the renin-angiotensin system, AZL-M provides statistically significant albeit small improvements in blood pressure control. PMID- 26956150 TI - Results of a multicentre UK-wide retrospective study evaluating the efficacy of pixantrone in relapsed, refractory diffuse large B cell lymphoma. AB - Relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) in those unfit or ineligible for autologous stem cell transplantation is associated with a poor outcome and new treatment approaches are needed. Pixantrone is a novel aza anthracenedione which is structurally similar to anthracyclines and is licenced in R/R DLBCL and National Institute for Health and Care Excellence (NICE) approved following the PIX301 trial. No data exist post-NICE approval. We performed a UK-wide retrospective multi-centre study of 92 R/R DLBCL who received pixantrone. Eighty-five per cent had refractory disease and 72% had an international prognostic index (IPI) 3-5 at commencement of pixantrone. The median progression-free survival (PFS) was 2.0 months (95% confidence interval (CI) 1.5-2.4) and the median overall survival was 3.4 months (95% CI 2.7-4.5). The overall response rate was 24% (complete response 10%; partial response 14%). We demonstrate that pixantrone has limited activity in a cohort of high risk, predominantly refractory DLBCL. Multivariate Cox regression revealed that patients who relapsed >12 months after first line treatment, those with fewer prior lines of therapy and relapsed (non-refractory) DLBCL had improved PFS. The major population of unmet need are those with refractory DLBCL who are poorly represented within trials and in whom pixantrone appears less efficacious compared to relapsed DLBCL. PMID- 26956151 TI - Synthesis and characterisation of bismacrocyclic DO3A-amide derivatives - an approach towards metal-responsive PARACEST agents. AB - Three new bismacrocyclic Ln(3+) chelates consisting of triamide derivatives of cyclen with glycine, methyl and tert-butyl substituents (, respectively) linked to an acyclic EGTA-derived calcium chelator were synthesised as potential MRI contrast agents (EGTA - ethylene glycol-bis(2-aminoethylether)-N,N,N',N' tetraacetic acid). Eu(3+) and Yb(3+) complexes of were investigated as chemical exchange saturation transfer (CEST) agents. Moderate to minor CEST effects were observed for , and complexes in the absence of Ca(2+), with negligible changes upon addition of this metal ion. Luminescence steady-state emission and lifetime experiments did not reveal any changes in the coordination environment of the complexes, while the number of inner-sphere water molecules remained constant in the absence and presence of Ca(2+). The protonation constants of and and stability constants of their complexes with Ca(2+), Mg(2+) and Zn(2+) were determined by means of potentiometric titrations. The results show that the charge of the complex dramatically affects the protonation constants of the EGTA binding unit. The stability constants of the complexes formed with Ca(2+), Mg(2+) and Zn(2+) are several orders of magnitude lower than those of EGTA. These findings indicate that the nature of Ln(3+) chelates and their charge are the main reasons for the observed results and weaker response of these EGTA-derived triamide derivatives compared to their tricarboxylate analogues. PMID- 26956152 TI - Heritable gene expression differences between apomictic clone members in Taraxacum officinale: Insights into early stages of evolutionary divergence in asexual plants. AB - BACKGROUND: Asexual reproduction has the potential to enhance deleterious mutation accumulation and to constrain adaptive evolution. One source of mutations that can be especially relevant in recent asexuals is activity of transposable elements (TEs), which may have experienced selection for high transposition rates in sexual ancestor populations. Predictions of genomic divergence under asexual reproduction therefore likely include a large contribution of transposable elements but limited adaptive divergence. For plants empirical insight into genome divergence under asexual reproduction remains limited. Here, we characterize expression divergence between clone members of a single apomictic lineage of the common dandelion (Taraxacum officinale) to contribute to our knowledge of genome evolution under asexuality. RESULTS: Using RNA-Seq, we show that about one third of heritable divergence within the apomictic lineage is driven by TEs and TE-related gene activity. In addition, we identify non-random transcriptional differences in pathways related to acyl-lipid and abscisic acid metabolisms which might reflect functional divergence within the apomictic lineage. We analyze SNPs in the transcriptome to assess genetic divergence between the apomictic clone members and reveal that heritable expression differences between the accessions are not explained simply by genome wide genetic divergence. CONCLUSION: The present study depicts a first effort towards a more complete understanding of apomictic plant genome evolution. We identify abundant TE activity and ecologically relevant functional genes and pathways affecting heritable within-lineage expression divergence. These findings offer valuable resources for future work looking at epigenetic silencing and Cis regulation of gene expression with particular emphasis on the effects of TE activity on asexual species' genome. PMID- 26956153 TI - Antidepressant actions of lateral habenula deep brain stimulation differentially correlate with CaMKII/GSK3/AMPK signaling locally and in the infralimbic cortex. AB - High frequency deep brain stimulation (DBS) of the lateral habenula (LHb) reduces symptoms of depression in severely treatment-resistant individuals. Despite the observed therapeutic effects, the molecular underpinnings of DBS are poorly understood. This study investigated the efficacy of high frequency LHb DBS (130Hz; 200MUA; 90MUs) in an animal model of tricyclic antidepressant resistance. Further, we reported DBS mediated changes in Ca(2+)/calmodulin-dependent protein kinase (CaMKIIalpha/beta), glycogen synthase kinase 3 (GSK3alpha/beta) and AMP activated protein kinase (AMPK) both locally and in the infralimbic cortex (IL). Protein expressions were then correlated to immobility time during the forced swim test (FST). Antidepressant actions were quantified via FST. Treatment groups comprised of animals treated with adrenocorticotropic hormone alone (ACTH; 100MUg/day, 14days, n=7), ACTH with active DBS (n=7), sham DBS (n=8), surgery only (n=8) or control (n=8). Active DBS significantly reduced immobility in ACTH treated animals (p<0.05). For this group, western blot results demonstrated phosphorylation status of LHb CaMKIIalpha/beta and GSK3alpha/beta significantly correlated to immobility time in the FST. Concurrently, we observed phosphorylation status of CaMKIIalpha/beta, GSK3alpha/beta, and AMPK in the IL to be negatively correlated with antidepressant actions of DBS. These findings suggest that activity dependent phosphorylation of CaMKIIalpha/beta, and GSK3alpha/beta in the LHb together with the downregulation of CaMKIIalpha/beta, GSK3alpha/beta, and AMPK in the IL, contribute to the antidepressant actions of DBS. PMID- 26956154 TI - Who benefits most from influenza vaccination policy: a study among the elderly in Beijing, China. AB - BACKGROUND: Influenza continues to have a major impact on vulnerable populations worldwide, particularly among the elderly (>= 60 years of age). Vaccination for targeted groups is recommended by the WHO as the most effective way to control influenza infections. Since 2009, the Beijing municipal government has provided influenza vaccination to the elderly at no out-of-pocket cost to reduce influenza threats and improve related health equality. The study aims to evaluate the equality of the policy, and to analyze factors that bring influences to equality. METHODS: Based on data from a household survey, concentration index (CI) was calculated to measure the socioeconomic inequality in influenza vaccination. A Logit regression model was used to decompose CI, in which the contribution of each determinant was calculated and the percentages of these contribution were obtained. RESULTS: Free influenza vaccination at point of use shows significant pro-poor distribution among the elderly in Beijing (CI = -0.115). After the decomposition of CI, the elderly with lower income, higher education, and living in rural areas were more likely to get the influenza vaccination, in which place of residence (contribution percentage = 57 %) held the most contribution of variance. CONCLUSIONS: Beijing's free influenza vaccination strategy at point of use could provide the poor elderly with equal opportunities to receive preventive health service, showing a significant pro-poor distribution. The poor elderly, who live in rural areas with high education, benefit most from the policy. Further policy interventions should target the population living in urban areas in order to improve the utilization of public health services and health equality. PMID- 26956155 TI - The influence of family violence and child marriage on unmet need for family planning in Jordan. AB - BACKGROUND: Risk for unmet need for contraception is associated with men's perpetration of intimate partner violence (IPV) against women and may be influenced by violence perpetrated by other family members (family violence, FV). Women who married as minors may be most vulnerable to the potential compounding effect of IPV and FV on unmet need. AIM: Using nationally representative data from the 2012 Jordan Population and Family Health Survey we examined unmet need by exposure to IPV and FV by women's age at marriage (<18, 18+ years). DESIGN: Logistic regression was used to test whether IPV and FV were independently associated with unmet need, by age at marriage. Interaction terms (IPV*FV) were tested in both models. Stratification by FV was employed to clarify the interpretation of significant interactions. RESULTS: IPV increased the odds of unmet need by 87% [adjusted odds ratio (AOR) 1.87; 95% confidence interval (95% CI) 1.13-3.10] and 76% (AOR 1.76; 95% CI 1.30-2.38) among women who married prior to and after the age of 18 years, respectively. Women married as minors who experienced IPV and FV had a four-fold higher likelihood of having an unmet need (AOR 6.75; 95% CI 1.95-23.29) compared to those experiencing only IPV (AOR 1.49; 95% CI 0.84-2.38). No interaction between IPV and FV was detected for women married at or above majority. CONCLUSIONS: Laws that prohibit child marriage should be strengthened and health sector screening for violence experience could help identify women at risk of unmet need and improve women's reproductive agency. PMID- 26956157 TI - Mechanism of action of cariprazine. AB - Cariprazine is a new therapeutic agent recently approved for the treatment of both schizophrenia and manic or mixed episodes associated with bipolar disorder, and is under investigation for the treatment of both bipolar depression and major depressive disorder. PMID- 26956156 TI - Surface modification-mediated biodistribution of 13C-fullerene C60 in vivo. AB - BACKGROUND: Functionalization is believed to have a considerable impact on the biodistribution of fullerene in vivo. However, a direct comparison of differently functionalized fullerenes is required to prove the hypothesis. The purpose of this study was to investigate the influences of surface modification on the biodistribution of fullerene following its exposure via several routs of administration. METHODS: (13)C skeleton-labeled fullerene C60 ((13)C-C60) was functionalized with carboxyl groups ((13)C-C60-COOH) or hydroxyl groups ((13)C C60-OH). Male ICR mice (~25 g) were exposed to a single dose of 400 MUg of (13)C C60-COOH or (13)C-C60-OH in 200 MUL of aqueous 0.9% NaCl solution by three different exposure pathways, including tail vein injection, gavage and intraperitoneal exposure. Tissue samples, including blood, heart, liver, spleen, stomach, kidneys, lungs, brain, large intestine, small intestine, muscle, bone and skin were subsequently collected, dissected, homogenized, lyophilized, and analyzed by isotope ratio mass spectrometry. RESULTS: The liver, bone, muscle and skin were found to be the major target organs for C60-COOH and C60-OH after their intravenous injection, whereas unmodified C60 was mainly found in the liver, spleen and lung. The total uptakes in liver and spleen followed the order: C60 > > C60-COOH > C60-OH. The distribution rate over 24 h followed the order: C60 > C60-OH > C60-COOH. C60-COOH and C60-OH were both cleared from the body at 7 d post exposure. C60-COOH was absorbed in the gastrointestinal tract following gavage exposure and distributed into the heart, liver, spleen, stomach, lungs, intestine and bone tissues. The translocation of C60-OH was more widespread than that of C60-COOH after intraperitoneal injection. CONCLUSIONS: The surface modification of fullerene C60 led to a decreased in its accumulation level and distribution rate, as well as altering its target organs. These results therefore demonstrate that the chemical functionalization of fullerene had a significant impact on its translocation and biodistribution properties. Further surface modifications could therefore be used to reduce the toxicity of C60 and improve its biocompatibility, which would be beneficial for biomedical applications. PMID- 26956158 TI - Frail older adults with minor fractures show lower health-related quality of life (SF-12) scores up to six months following emergency department discharge. AB - BACKGROUND: Minor fractures (e.g. wrist, ankle) are risk factors for lower physical health-related quality of life (HRQoL) in seniors. Recent studies found that measures of frailty were associated with decreased physical and mental HRQoL in older people. As most people with minor fractures go to emergency departments (EDs) for treatment, measuring their frailty status in EDs may help stratify their level of HRQoL post-injury and provide them with appropriate health care and services after discharge. This study thus examines the HRQoL of seniors visiting EDs for minor fractures at 3 and 6 months after discharge, according to their frailty status. METHODS: This prospective sub-study was conducted within the larger Canadian Emergency Team Initiative (CETI) cohort. Independent seniors (>=65 years) were recruited in 7 Canadian EDs after treatment for various minor fractures. Frailty status in the ED phase was assessed by the Canadian Study of Health and Aging--Clinical Frailty Scale (CSHA-CFS). The SF-12 questionnaire was completed at 3 and 6 months after ED discharge to ascertain HRQoL. Demographic and clinical data were collected. Linear mixed models were used to test for differences between frailty levels and HRQoL outcomes, controlling for confounding variables and repeated measures over time. RESULTS: The sample comprised 334 participants with minor fractures. Prevalence of frailty was as follows: 56.6 % very fit-well; 32.3 % well with treated comorbidities-apparently vulnerable; and 11.1 % mildly-moderately frail. After adjusting for confounding variables, the frailest group showed significantly lower mean HRQoL scores than the fittest group on the physical scale at 3 months (49.3 +/- 3.7 vs 60.9 +/- 2.0) and 6 months (48.7 +/- 3.8 vs 61.1 +/- 1.8), as well as on the mental scale at 3 months (59.5 +/- 4.4 vs 69.6 +/- 1.9). Analyses exploring differences in proportion of patients with HRQoL < 50/100 between the three groups produced similar results. CONCLUSIONS: Older adults with minor fractures who were frail had lower physical and mental HRQoL scores at 3 and 6 months after ED discharge than their fittest counterparts. Measuring the frailty status of older adults who suffered a minor fracture in ED might help clinical decision-making at the time of discharge by providing them with appropriate health care and services to improve their HRQoL in the following months. PMID- 26956159 TI - The role of helper lipids in the intracellular disposition and transfection efficiency of niosome formulations for gene delivery to retinal pigment epithelial cells. AB - In this work, we carried out a comparative study of four different niosome formulations based on the same cationic lipid and non-ionic tensoactive. The niosomes prepared by oil-in-water emulsion technique (o/w) only differed in the helper lipid composition: squalene, cholesterol, squalane or no helper lipid. Niosomes and nioplexes elaborated upon the addition of pCMS-EGFP reporter plasmid were characterized in terms of size, zeta potential and polydispersity index. The capacity of the niosomes to condense, release and protect the DNA against enzymatic degradation was evaluated by agarose gel electrophoresis. In vitro experiments were carried out to evaluate transfection efficiency and cell viability in retinal pigment epithelial cells. Moreover, uptake and intracellular trafficking studies were performed to further understand the role of the helper lipids in the transfection process. Interestingly, among all tested formulations, niosomes elaborated with squalene as helper lipid were the most efficient transfecting cells. Such transfection efficiency could be attributed to their higher cellular uptake and the particular entry pathways used, where macropinocytosis pathway and lysosomal release played an important role. Therefore, these results suggest that helper lipid composition is a crucial step to be considered in the design of niosome formulation for retinal gene delivery applications since clearly modulates the cellular uptake, internalization mechanism and consequently, the final transfection efficiency. PMID- 26956161 TI - Effect of acupuncture on sleep quality and hyperarousal state in patients with primary insomnia: study protocol for a randomised controlled trial. AB - INTRODUCTION: Primary insomnia (PI) is commonly defined as a state of having disturbed daytime activities due to poor night-time sleep quality. Studies have demonstrated that it is a disorder of 24 h hyperarousal, expressed in terms of physiological, cognitive and cortical activation. Acupuncture is considered to be beneficial to restore the normal sleep-wake cycle. The aim of the trial is to assess the therapeutic effects of acupuncture on sleep quality and hyperarousal state in patients with PI. METHODS AND ANALYSIS: This study is a randomised, patient-assessor-blinded, sham controlled trial. -88 eligible patients with PI will be randomised in a ratio of 1:1 to the intervention group (real acupuncture) and control group (sham acupuncture, superficial insertion at irrelevant acupuncture points). Acupuncture intervention will be given to all participants three times a week for 4 weeks, followed up for 8 weeks.The primary outcome measures are the Pittsburgh Sleep Quality Index (PSQI) and Hyperarousal scale (HAS). The secondary outcomes are Fatigue scale-14 (FS-14), polysomnography (PSG), heart rate variability (HRV) and Morning Salivary Cortisol Level (MSCL). Outcomes will be evaluated at baseline, post-treatment period and 8 weeks follow up. All main analyses will be carried out on the basis of the intention-to-treat principle. ETHICS/DISSEMINATION: This protocol has been approved by the Medical Ethical Committee of Beijing Traditional Chinese Medicine Hospital (Beijing TCM Hospital) on 5 January 2015. The permission number is 2014BL-056-02. The study will present data concerning the clinical effects of treating primary insomnia with acupuncture. The results will help to demonstrate if acupuncture is an effective therapy for improving sleep quality in association with a decreased hyperarousal level as a possible underlying mechanism. The findings from this study will be shared with the healthcare professionals, general public and relevant organisations through publication of manuscripts and conference presentations. TRIAL REGISTRATION NUMBER: ISRCTN16079489; Pre-results. PMID- 26956160 TI - Comparison of cognitive and neuropsychiatric profiles in hospitalised elderly medical patients with delirium, dementia and comorbid delirium-dementia. AB - OBJECTIVES: Differentiation of delirium and dementia is a key diagnostic challenge but there has been limited study of features that distinguish these conditions. We examined neuropsychiatric and neuropsychological symptoms in elderly medical inpatients to identify features that distinguish major neurocognitive disorders. SETTING: University teaching hospital in Ireland. PARTICIPANTS AND MEASURES: 176 consecutive elderly medical inpatients (mean age 80.6 +/- 7.0 years (range 60-96); 85 males (48%)) referred to a psychiatry for later life consultation-liaison service with Diagnostic and Statistical Manual of Mental Disorders (DSM) IV delirium, dementia, comorbid delirium-dementia and cognitively intact controls. Participants were assessed cross-sectionally with comparison of scores (including individual items) for the Revised Delirium Rating Scale (DRS-R98), Cognitive Test for Delirium (CTD) and Neuropsychiatric Inventory (NPI-Q). RESULTS: The frequency of neurocognitive diagnoses was delirium (n=50), dementia (n=32), comorbid delirium-dementia (n=62) and cognitively intact patients (n=32). Both delirium and comorbid delirium-dementia groups scored higher than the dementia group for DRS-R98 and CTD total scores, but all three neurocognitively impaired groups scored similarly in respect of total NPI-Q scores. For individual DRS-R98 items, delirium groups were distinguished from dementia groups by a range of non-cognitive symptoms, but only for impaired attention of the cognitive items. For the CTD, attention (p=0.002) and vigilance (p=0.01) distinguished between delirium and dementia. No individual CTD item distinguished between comorbid delirium-dementia and delirium. For the NPI-Q, there were no differences between the three neurocognitively impaired groups for any individual item severity. CONCLUSIONS: The neurocognitive profile of delirium is similar with or without comorbid dementia and differs from dementia without delirium. Simple tests of attention and vigilance can help to distinguish between delirium and other presentations. The NPI-Q does not readily distinguish between neuropsychiatric disturbances in delirium versus dementia. Cases of suspected behavioural and psychological symptoms of dementia should be carefully assessed for possible delirium. PMID- 26956162 TI - Prospective observational cohort study of patients with weaning failure admitted to a specialist weaning, rehabilitation and home mechanical ventilation centre. AB - OBJECTIVES: According to National Health Service England (NHSE) specialist respiratory commissioning specification for complex home ventilation, patients with weaning failure should be referred to a specialist centre. However, there are limited data reporting the clinical outcomes from such centres. SETTING: Prospective observational cohort study of patients admitted to a UK specialist weaning, rehabilitation and home mechanical ventilation centre between February 2005 and July 2013. PARTICIPANTS: 262 patients admitted with a median age of 64.2 years (IQR 52.6-73.2 years). 59.9% were male. RESULTS: 39.7% of patients had neuromuscular and/or chest wall disease, 21% were postsurgical, 19.5% had chronic obstructive pulmonary disease (COPD), 5.3% had obesity-related respiratory failure and 14.5% had other diagnoses. 64.1% of patients were successfully weaned, with 38.2% weaned fully from ventilation, 24% weaned to nocturnal non invasive ventilation (NIV), 1.9% weaned to nocturnal NIV with intermittent NIV during the daytime. 21.4% of patients were discharged on long-term tracheostomy ventilation. The obesity-related respiratory failure group were most likely to wean (relative risk (RR) for weaning success=1.48, 95% CI 1.35 to 1.77; p<0.001), but otherwise weaning success rates did not significantly vary by diagnostic group. The median time-to-wean was 19 days (IQR 9-33) and the median duration of stay was 31 days (IQR 16-50), with no difference observed between the groups. Weaning centre mortality was 14.5%, highest in the COPD group (RR=2.15, 95% CI 1.19 to 3.91, p=0.012) and lowest in the neuromuscular and/or chest wall disease group (RR=0.34, 95% CI 0.16 to 0.75, p=0.007). Of all patients discharged alive, survival was 71.7% at 6 months and 61.8% at 12 months postdischarge. CONCLUSIONS: Following NHSE guidance, patients with weaning delay and failure should be considered for transfer to a specialist centre where available, which can demonstrate favourable short-term and long-term clinical outcomes. PMID- 26956163 TI - Are you ready? Exploring readiness to engage in exercise among people living with HIV and multimorbidity in Toronto, Canada: a qualitative study. AB - OBJECTIVES: Our aim was to explore readiness to engage in exercise among people living with HIV and multimorbidity. DESIGN: We conducted a descriptive qualitative study using face-to-face semistructured interviews with adults living with HIV. SETTING: We recruited adults (18 years or older) who self-identified as living with HIV and 2 or more additional health-related conditions from a specialty hospital in Toronto, Canada. PARTICIPANTS: 14 participants with a median age of 50 years and median number of 9 concurrent health-related conditions participated in the study. The majority of participants were men (64%) with an undetectable viral load (71%). OUTCOME MEASURES: We asked participants to describe their readiness to engage in exercise and explored how contextual factors influenced their readiness. We analysed interview transcripts using thematic analysis. RESULTS: We developed a framework to describe readiness to engage in exercise and the interplay of factors and their influence on readiness among adults with HIV and multimorbidity. Readiness was described as a diverse, dynamic and fluctuating spectrum ranging from not thinking about exercise to routinely engaging in daily exercise. Readiness was influenced by the complex and episodic nature of HIV and multimorbidity comprised of physical impairments, mental health challenges and uncertainty from HIV and concurrent health conditions. This key factor created a context within which 4 additional subfactors (social supports, perceptions and beliefs, past experience with exercise, and accessibility) may further hinder or facilitate an individual's position along the spectrum of readiness to exercise. CONCLUSIONS: Readiness to engage in exercise among people living with HIV is a dynamic and fluctuating construct that may be influenced by the episodic nature of HIV and multimorbidity and 4 subfactors. Strategies to facilitate readiness to exercise should consider the interplay of these factors in order to enhance physical activity and subsequently improve health outcomes of people with HIV and multimorbidity. PMID- 26956164 TI - Tweeting links to Cochrane Schizophrenia Group reviews: a randomised controlled trial. AB - OBJECTIVE: To assess the effects of using health social media on web activity. DESIGN: Individually randomised controlled parallel group superiority trial. SETTING: Twitter and Weibo. PARTICIPANTS: 170 Cochrane Schizophrenia Group full reviews with an abstract and plain language summary web page. INTERVENTIONS: Three randomly ordered slightly different 140 character or less messages, each containing a short URL to the freely accessible summary page sent on specific times on one single day. This was compared with no messaging. OUTCOME: The primary outcome was web page visits at 1 week. Secondary outcomes were other metrics of web activity at 1 week. RESULTS: 85 reviews were randomised to each of the intervention and control arms. Google Analytics allowed 100% follow-up within 1 week of completion. Intervention and control reviews received a total of 1162 and 449 visits, respectively (IRR 2.7, 95% CI 2.2 to 3.3). Fewer intervention reviews had single page only visits (16% vs 31%, OR 0.41, 0.19 to 0.88) and users spent more time viewing intervention reviews (geometric mean 76 vs 31 s, ratio 2.5, 1.3 to 4.6). Other secondary metrics of web activity all showed strong evidence in favour of the intervention. CONCLUSIONS: Tweeting in this limited area of healthcare increases 'product placement' of evidence with the potential for that to influence care. TRIAL REGISTRATION NUMBER: ISRCTN84658943. PMID- 26956165 TI - Mortality and use of psychotropic medication in patients with stroke: a population-wide, register-based study. AB - OBJECTIVES: The study sought to describe whether psychotropic medication may have long-term side effects in patients with stroke compared with controls. SETTING: Use of national register data from healthcare services were identified from the Danish National Patient Registry in Denmark. Information about psychotropic medication use was obtained from the Danish Register of Medicinal Product Statistics. OBJECTIVES: We aimed to evaluate all-cause mortality in relation to the use of benzodiazepines, antidepressants and antipsychotics in patients with stroke and matched controls. PARTICIPANTS: Patients with a diagnosis of stroke and either no drug use or preindex use of psychotropic medication (n=49,968) and compared with control subjects (n=86,100) matched on age, gender, marital status and community location. PRIMARY OUTCOME MEASURE: All-cause mortality. RESULTS: All-cause mortality was higher in patients with previous stroke compared with control subjects. Mortality HRs were increased for participants prescribed serotonergic antidepressant drugs (HR=1.699 (SD=0.030), p=0.001 in patients; HR=1.908 (0.022), p<0.001 in controls, respectively), tricyclic antidepressants (HR=1.365 (0.045), p<0.001; HR=1.733 (0.022), p<0.001), benzodiazepines (HR=1.643 (0.040), p<0.001; HR=1.776 (0.053), p<0.001), benzodiazepine-like drugs (HR=1.776 (0.021), p<0.001; HR=1.547 (0.025), p<0.001), first-generation antipsychotics (HR=2.001 (0.076), p<0.001; HR=3.361 (0.159), p<0.001) and second-generation antipsychotics (HR=1.645 (0.070), p<0.001; HR=2.555 (0.086), p<0.001), compared with no drug use. Interaction analysis suggested statistically significantly higher mortality HRs for most classes of psychotropic drugs in controls compared with patients with stroke. CONCLUSIONS: All-cause mortality was higher in patients with stroke and controls treated with benzodiazepines, antidepressants and antipsychotics than in their untreated counterparts. Our findings suggest that care should be taken in the use and prescription of such drugs, and that they should be used in conjunction with adequate clinical controls. PMID- 26956167 TI - A Targeted DNAzyme-Nanocomposite Probe Equipped with Built-in Zn(2+) Arsenal for Combined Treatment of Gene Regulation and Drug Delivery. AB - As catalytic nucleic acids, DNAzymes have been extensively used in the design of sensing platforms. However, their potentials as intelligent drug carriers for responsive drug release in gene therapy and chemotherapy were rarely explored. Herein, we report a dual-functional probe composed of gold nanoparticles (GNPs), catalytic Zn(2+)-dependent DNAzyme, anticancer drug doxorubicin (Dox), targeted AS1411 aptamer and acid-decomposable ZnO quantum dots (ZnO QDs) to achieve intracellular gene regulation and drug delivery in a controlled manner. By means of aptamer-guided targeting and receptor-mediated endocytosis, the probes were specifically internalized into the HeLa cells and trapped in the acidic endo /lysosomes, where the ZnO QDs as the built-in Zn(2+) arsenal were promptly dissolved to offer Zn(2+), leading to the activation of DNAzyme to cleave the substrate strands, and subsequent drug release. Meanwhile, as designed, one part of the cleaved substrate, hybridized with the overexpressed miR-21 in the target cells, thereby declining its intracellular level. Taken together, the down regulation of miR-21 has a synergistic effect with Dox to efficiently eradicate the cancer cells. Thus, the favorable biocompatibility, cancer cell specificity and combined treatment make the probe promising for therapy of multidrug resistant cancer and in vivo application. PMID- 26956166 TI - Effect of vitamin D replacement on maternal and neonatal outcomes: a randomised controlled trial in pregnant women with hypovitaminosis D. A protocol. AB - INTRODUCTION: The vitamin D recommended doses during pregnancy differ between societies. The WHO guidelines do not recommend routine prenatal supplementation, but they underscore the fact that women with the lowest levels may benefit most. The effects of routine supplementation during pregnancy on maternal and neonatal clinical outcomes have not been investigated in the Middle East, where hypovitaminosis D is prevalent. Our hypothesis is that in Middle Eastern pregnant women, a vitamin D dose of 3000 IU/day is required to reach a desirable maternal 25-hydroxyvitamin D [25(OH)D] level, and to positively impact infant bone mineral content (BMC). METHODS AND ANALYSIS: This is a multicentre blinded randomised controlled trial. Pregnant women presenting to the Obstetrics and Gynaecology clinics will be approached. Eligible women will be randomised to daily equivalent doses of cholecalciferol, 600 IU or 3000 IU, from 15 to 18 weeks gestation until delivery. Maternal 25(OH)D and chemistries will be assessed at study entry, during the third trimester and at delivery. Neonatal anthropometric variables and 25(OH)D level will be measured at birth, and bone and fat mass assessment by dual energy X-ray absorptiometry scan at 1 month. A sample size of 280 pregnant women is needed to demonstrate a statistically significant difference in the proportion of women reaching a 25(OH)D level >= 50 nmol/L at delivery, and a difference in infant BMC of 6 (10)g, for a 90% power and a 2.5% level of significance. The proportions of women achieving a target 25(OH)D level will be compared between the two arms, using chi(2). An independent t test will be used to compare mean infant BMC between the two arms. The primary analysis is an intention-to-treat analysis of unadjusted results. ETHICS AND DISSEMINATION: The protocol has been approved by the Institutional Review Board at the American University of Beirut Lebanon (IM.GEHF.22). The trial results will be published in peer-reviewed medical journals and presented at scientific conferences. TRIAL REGISTRATION NUMBER: NCT02434380. PMID- 26956169 TI - Synthesis and biological evaluation of peptide-conjugated phthalocyanine photosensitizers with highly hydrophilic modifications. AB - The selectivity of targeted photosensitizer delivery is a constant challenge for photodynamic therapy (PDT). Herein, with the aim of optimizing the affinity, selectivity and activity of peptide-conjugated photosensitizers for PDT therapy and fluorescence imaging, we designed a solid-phase strategy for the efficient synthesis of peptide-phthalocyanine (Pc) conjugates with two types of highly hydrophilic modifications to the Pc rings. The peptide conjugation clearly increased the photodynamic efficacy and selectivity of Pcs against cancer cells with different receptor expression levels. A highly hydrophilic modification to the Pc rings can block non-specific interactions between the Pcs and biological molecules while minimally influencing peptide ligand affinity with target receptors. Compared with the triethyleneglycol monomethyl ether group modification, the glycerol group modification exhibited a stronger capability to decrease the Pc aggregation tendency in aqueous medium, reduce non-specific binding and non-specific, light-induced cytotoxicity towards cells with low receptor expression in vitro; increased targeting selectivity was observed in the in vivo distribution experiments via the obvious reduction of background signals. Highly hydrophilic modifications to the Pc rings may be very useful for improving targeting selectivity for PDT with the construction of peptide-conjugated photosensitizers. PMID- 26956171 TI - Building better boxes for theories of health behavior: a comment on Williams and Rhodes (2016). PMID- 26956170 TI - Bimatoprost, latanoprost, and tafluprost induce differential expression of matrix metalloproteinases and tissue inhibitor of metalloproteinases. AB - BACKGROUND: Differences in the increase in matrix metalloproteinase (MMP) and decrease in tissue inhibitor of metalloproteinase (TIMP) activity may contribute to the different characteristics observed clinically on decreased intraocular pressure in patients with glaucoma or ocular hypertension. The purpose of this study was to investigate differences in the expression profiles of MMPs and TIMPs induced by the prostaglandin analogs bimatoprost, latanoprost, and tafluprost in human non-pigmented ciliary epithelial cells (HNPCECs). METHODS: HNPCECs were cultured for 24 h with 0, 10, 100, or 1000 MUM of the free acid forms of bimatoprost, latanoprost, and tafluprost. We measured the expression levels of MMPs and TIMPs using real-time polymerase chain reaction, and compared the results. Enzyme activities of MMP-2 and -9 in conditioned media were measured by gelatin zymography. RESULTS: All prostaglandin analogs we examined dose dependently increased expression levels of MMP-1, -2, -3, -9, and -17, whereas expression levels of TIMP-1 and -2 decreased with increasing concentrations of each analog. Each prostaglandin analog induced different levels of increases in MMPs and decreases in TIMPs. CONCLUSIONS: Unique expression profiles of MMPs and TIMPs induced by bimatoprost, latanoprost, and tafluprost, as shown in HNPCECs, may contribute to clinically different effects on intraocular pressure decreases in patients with glaucoma or ocular hypertension. PMID- 26956172 TI - Thrombocytopenia is associated with a dysregulated host response in critically ill sepsis patients. AB - Preclinical studies have suggested that platelets influence the host response during sepsis. We sought to assess the association of admission thrombocytopenia with the presentation, outcome, and host response in patients with sepsis. Nine hundred thirty-one consecutive sepsis patients were stratified according to platelet counts (very low <50 * 10(9)/L, intermediate-low 50 * 10(9) to 99 * 10(9)/L, low 100 * 10(9) to 149 * 10(9)/L, or normal 150 * 10(9) to 399 * 10(9)/L) on admission to the intensive care unit. Sepsis patients with platelet counts <50 * 10(9)/L and 50 * 10(9) to 99 * 10(9)/L presented with higher Acute Physiology and Chronic Health Evaluation scores and more shock. Both levels of thrombocytopenia were independently associated with increased 30-day mortality (hazard ratios with 95% confidence intervals 2.00 [1.32-3.05] and 1.72 [1.22 2.44], respectively). To account for baseline differences besides platelet counts, propensity matching was performed, after which the association between thrombocytopenia and the host response was tested, as evaluated by measuring 17 plasma biomarkers indicative of activation and/or dysregulation of pathways implicated in sepsis pathogenesis and by whole genome blood leukocyte expression profiling. In the propensity matched cohort, platelet counts < 50 * 10(9)/L were associated with increased cytokine levels and enhanced endothelial cell activation. All thrombocytopenic groups showed evidence of impaired vascular integrity, whereas coagulation activation was similar between groups. Blood microarray analysis revealed a distinct gene expression pattern in sepsis patients with <50 * 10(9)/L platelets, showing reduced signaling in leukocyte adhesion and diapedesis and increased complement signaling. These data show that admission thrombocytopenia is associated with enhanced mortality and a more disturbed host response during sepsis independent of disease severity, thereby providing clinical validity to animal studies on the role of platelets in severe infection. PMID- 26956173 TI - Surface-enhanced Raman scattering detection of silver nanoparticles in environmental and biological samples. AB - Growing concerns over the potential release and threat of silver nanoparticles (AgNPs) to environmental and biological systems urge researchers to investigate their fate and behavior. However, current analytical techniques cannot meet the requirements for rapidly, sensitively and reliably probing AgNPs in complex matrices. Surface-enhanced Raman spectroscopy (SERS) has shown great capability for rapid detection of AgNPs based on an indicator molecule that can bind on the AgNP surface. The objective of this study was to exploit SERS to detect AgNPs in environmental and biological samples through optimizing the Raman indicator for SERS. Seven indicator molecules were selected and determined to obtain their SERS signals at optimal concentrations. Among them, 1,2-di(4-pyridyl)ethylene (BPE), crystal violet and ferric dimethyl-dithiocarbamate (ferbam) produced the highest SERS intensities. Further experiments on binding competition between each two of the three candidates showed that ferbam had the highest AgNPs-binding ability. The underlying mechanism lies in the strong binding affinity of ferbam with AgNPs via multiple sulfur atoms. We further validated ferbam to be an effective indicator for SERS detection of as low as 0.1mg/L AgNPs in genuine surface water and 0.57 mg/L in spinach juice. Moreover, limited interference on SERS detection of AgNPs was found from environmentally relevant inorganic ions, organic matter, inorganic particles, as well as biologically relevant components, demonstrating the ferbam-assisted SERS is an effective and sensitive method to detect AgNPs in complex environmental and biological samples. PMID- 26956174 TI - Spatial patterns and environmental controls of particulate organic carbon in surface waters in the conterminous United States. AB - Carbon cycling in inland waters has been identified as an important, but poorly constrained component of the global carbon cycle. In this study, we compile and analyze particulate organic carbon (POC) concentration data from 1145 U.S. Geological Survey (USGS) gauge stations to investigate the spatial variability and environmental controls of POC concentration. We observe substantial spatial variability in POC concentration (1.43 +/- 2.56 mg C/L, mean +/- one standard deviation), with the Upper Mississippi River basin and the Piedmont region in the eastern U.S. having the highest POC concentration. Further, we employ generalized linear models (GLMs) to analyze the impacts of sediment transport and algae growth as well as twenty-one other environmental factors on the POC variability. Suspended sediment and chlorophyll-a explain 26% and 17% of the variability in POC concentration, respectively. At the national level, the twenty-one environmental factors combined can explain ca. 40% of the spatial variance in POC concentration. At the national scale, urban area and soil clay content show significant negative correlations with POC concentration, whereas soil water content and soil bulk density correlate positively with POC. In addition, total phosphorus concentration and dam density correlate positively with POC concentration. Furthermore, regional scale analyses reveal substantial variation in environmental controls of POC concentration across eighteen major water resource regions in the U.S. The POC concentration and associated environmental controls also vary non-monotonically from headwaters to large rivers. These findings indicate complex interactions among multiple factors in regulating POC concentration over different spatial scales and across various sections of the river networks. This complexity, together with the large unexplained uncertainty, highlights the need for considering non-linear interplays of multiple environmental factors and developing appropriate methodologies to track the transformation and transport of POC along the terrestrial-aquatic interfaces. PMID- 26956175 TI - Will a rising sea sink some estuarine wetland ecosystems? AB - Sea-level rise associated with climate change presents a major challenge to plant diversity and ecosystem service provision in coastal wetlands. In this study, we investigate the effect of sea-level rise on benthos, vegetation, and ecosystem diversity in a tidal wetland in west Wales, the UK. Present relationships between plant communities and environmental variables were investigated through 50 plots at which vegetation (species and coverage), hydrological (surface or groundwater depth, conductivity) and soil (matrix chroma, presence or absence of mottles, organic content, particle size) data were collected. Benthic communities were sampled at intervals along a continuum from saline to freshwater. To ascertain future changes to the wetlands' hydrology, a GIS-based empirical model was developed. Using a LiDAR derived land surface, the relative effect of peat accumulation and rising sea levels were modelled over 200 years to determine how frequently portions of the wetland will be inundated by mean sea level, mean high water spring and mean high water neap conditions. The model takes into account changing extents of peat accumulation as hydrological conditions alter. Model results show that changes to the wetland hydrology will initially be slow. However, changes in frequency and extent of inundation reach a tipping point 125 to 175 years from 2010 due to the extremely low slope of the wetland. From then onwards, large portions of the wetland become flooded at every flood tide and saltwater intrusion becomes more common. This will result in a reduction in marsh biodiversity with plant communities switching toward less diverse and occasionally monospecific communities that are more salt tolerant. While the loss of tidal freshwater wetland is in line with global predictions, simulations suggest that in the Teifi marshes the loss will be slow at first, but then rapid. While there will be a decrease in biodiversity, the model indicated that at least for one ecosystem service, carbon storage, there is potential for an increase in the near future. PMID- 26956176 TI - Estimating agro-ecosystem carbon balance of northern Japan, and comparing the change in carbon stock by soil inventory and net biome productivity. AB - Soil C sequestration in croplands is deemed to be one of the most promising greenhouse gas mitigation options for agriculture. We have used crop-level yields, modeled heterotrophic respiration (Rh) and land use data to estimate spatio-temporal changes in regional scale net primary productivity (NPP), plant C inputs, and net biome productivity (NBP) in northern Japan's arable croplands and grasslands for the period of 1959-2011. We compared the changes in C stocks derived from estimated NBP and using repeated inventory datasets for each individual land use type from 2005 to 2011. For the entire study region of 2193 ha, overall annual plant C inputs to the soil constituted 37% of total region NPP. Plant C inputs in upland areas (excluding bush/fallow) could be predicted by climate variables. Overall NBP for all land use types increased from -1.26MgCha( 1)yr(-1) in 1959-0.26 Mg Cha(-1)yr(-1) in 2011. However, upland and paddy fields showed a decreased in NBP over the period of 1959-2011, under the current C input scenario. From 1988, an increase in agricultural abandonment (bush/fallow) and grassland cover caused a slow increase in the regional C pools. The comparison of carbon budgets using the NBP estimation method and the soil inventory method indicated no significant difference between the two methods. Our results showed C loss in upland crops, paddy fields and sites that underwent land use change from paddy field to upland sites. We also show C gain in grassland from 2005 to 2011. An underestimation of NBP or an overestimation of repeated C inventories cannot be excluded, but either method may be suitable for tracking absolute changes in soil C, considering the uncertainty associated with these methods. PMID- 26956178 TI - Regulating wild boar populations is "somebody else's problem"! - Human dimension in wild boar management. AB - As a part of the ongoing game survey of the German federal state of Lower Saxony (WTE), we conducted inquiries into wild boar management and distribution, as well as hunters' attitudes, in order to determine the reasons for the increase of wild boar populations and to inform our game management strategy. According to hunters' reports within the WTE, increases in distribution and population continue and a reduction of the wild boar population has been deemed necessary on a large scale. In the home region, however, it seems to be "somebody else's problem" (SEP), according to hunters' opinions. The majority of hunters are not able to regulate the population and this could be a reason that wild boar numbers continue to increase. Cooperation and comprehensive hunting with efficient hunting methods seems to be the most promising solution, as non-hunting methods are unpopular amongst hunters. The hunters seem to be aware of the problems, solutions and contributing factors; however, most hunters do not feel responsible and see the management of wild boar, again, as a SEP. Regional conditions, as well as hunters' willingness and capacity to manage wild boar will have to be incorporated into management concepts. PMID- 26956177 TI - Nitrogen accumulation and partitioning in a High Arctic tundra ecosystem from extreme atmospheric N deposition events. AB - Arctic ecosystems are threatened by pollution from recently detected extreme atmospheric nitrogen (N) deposition events in which up to 90% of the annual N deposition can occur in just a few days. We undertook the first assessment of the fate of N from extreme deposition in High Arctic tundra and are presenting the results from the whole ecosystem (15)N labelling experiment. In 2010, we simulated N depositions at rates of 0, 0.04, 0.4 and 1.2 g Nm(-2)yr(-1), applied as (15)NH4(15)NO3 in Svalbard (79( degrees )N), during the summer. Separate applications of (15)NO3(-) and (15)NH4(+) were also made to determine the importance of N form in their retention. More than 95% of the total (15)N applied was recovered after one growing season (~90% after two), demonstrating a considerable capacity of Arctic tundra to retain N from these deposition events. Important sinks for the deposited N, regardless of its application rate or form, were non-vascular plants>vascular plants>organic soil>litter>mineral soil, suggesting that non-vascular plants could be the primary component of this ecosystem to undergo measurable changes due to N enrichment from extreme deposition events. Substantial retention of N by soil microbial biomass (70% and 39% of (15)N in organic and mineral horizon, respectively) during the initial partitioning demonstrated their capacity to act as effective buffers for N leaching. Between the two N forms, vascular plants (Salix polaris) in particular showed difference in their N recovery, incorporating four times greater (15)NO3( ) than (15)NH4(+), suggesting deposition rich in nitrate will impact them more. Overall, these findings show that despite the deposition rates being extreme in statistical terms, biologically they do not exceed the capacity of tundra to sequester pollutant N during the growing season. Therefore, current and future extreme events may represent a major source of eutrophication. PMID- 26956179 TI - Extensive organohalogen contamination in wildlife from a site in the Yangtze River Delta. AB - The environmental and human health concerns for organohalogen contaminants (OHCs) extend beyond the 23 persistent organic pollutants (POPs) regulated by the Stockholm Convention. The current, intense industrial production and use of chemicals in China and their bioaccumulation makes Chinese wildlife highly suitable for the assessment of legacy, novel and emerging environmental pollutants. In the present study, six species of amphibians, fish and birds were sampled from paddy fields in the Yangtze River Delta (YRD) were screened for OHCs. Some extensive contamination was found, both regarding number and concentrations of the analytes, among the species assessed. High concentrations of chlorinated paraffins were found in the snake, Short-tailed mamushi (range of 200-340 MUg g(-)(1)lw), Peregrine falcon (8-59 MUg g(-1)lw) and Asiatic toad (97 MUg g(-)(1)lw). Novel contaminants and patterns were observed; octaCBs to decaCB made up 20% of the total polychlorinated biphenyls (PCBs) content in the samples and new OHCs, substituted with 5-8 chlorines, were found but are not yet structurally confirmed. In addition, Dechlorane 602 (DDC-DBF) and numerous other OHCs (DDTs, hexachlorocyclohexanes (HCHs), polybrominated diphenyl ethers (PBDEs), hexbromocyclododecane (HBCDD), chlordane, heptachlor, endosulfan and Mirex) were found in all species analyzed. These data show extensive chemical contamination of wildlife in the YRD with a suite of OHCs with both known and unknown toxicities, calling for further in-depth studies. PMID- 26956180 TI - Contaminants in two West Greenland caribou populations. AB - Two caribou populations in West Greenland were sampled and the kidneys, liver and muscle analyzed for contaminants, including aluminum, arsenic, cadmium, copper, lead, mercury, selenium and zinc. Although close in proximity, the two populations are topographically separated by an ice cap, which creates different climates and vegetation types in each region. Contaminant levels reflected the differing diets of the two caribou populations. To the south in the wetter lichen rich region, caribou had significantly more aluminum, arsenic, cadmium, lead, mercury, selenium and zinc, likely due to atmospheric deposition on lichens. To the north in the dry desert steppe where grasses predominate, caribou had higher levels of copper. Cows collected in late winter had significantly less hepatic copper, lead and mercury if pregnant, indicating placental transfer of these elements. Our results suggest that hepatic copper levels <200 MUg g(-1) dry weight may result in copper depletion in pregnant cows and hepatic mercury concentrations above 0.5 MUg g(-1) dry weight may negatively affect fertility in caribou cows. Hepatic mercury levels were negatively correlated with cow body weight, suggesting an adverse effect on body condition. Element concentrations found in tissues from these caribou are not considered to be of a health concern for those consuming this traditional food. PMID- 26956181 TI - Evidence-based review of oral traditional Chinese medicine compound recipe administration for treating weight drop-induced experimental traumatic brain injury. AB - BACKGROUND: Recently, a number of studies conducted and published in China have suggested that traditional Chinese medicine compound recipe (TCMCR) may be beneficial in the treatment of experimental traumatic brain injury (TBI). In this study, we conducted a systematic review and meta-analysis of the efficacy of TCMCR in TBI model with weight drop method to provide robust evidence on the effects of TCMCR and to determine whether TCMCR can be recommended for routine treatment or considered as a standard treatment for TBI. METHODS: We identified eligible studies by searching five electronic databases on April 1, 2014, and pooled the data using the random-effects model. Results were reported in terms of standardized mean difference (SMD). We also calculated statistical heterogeneity, evaluated the studies' methodological quality and investigated the presence of publication bias. RESULTS: Totally, 187 relevant publications were searched from databases, 25 of which met our inclusion criteria. The overall methodological quality of the most studies was poor, and there was evidence of statistical heterogeneity among studies along with small-study effects. Meta-analysis showed statistically significant effects indicating that TCMCR has a beneficial effect on TBI. CONCLUSIONS: Despite the limitations, we concluded that TCMCR may reduce brain water content, improve BBB permeability, and decrease TNF-alpha/NO expression after experimental TBI in terms of overall efficacy. However, our review also indicates that more well-designed and well-reported animal studies are needed. PMID- 26956182 TI - Abnormalities of the executive control network in multiple sclerosis phenotypes: An fMRI effective connectivity study. AB - The Stroop interference task is a cognitively demanding task of executive control, a cognitive ability that is often impaired in patients with multiple sclerosis (MS). The aim of this study was to compare effective connectivity patterns within a network of brain regions involved in the Stroop task performance between MS patients with three disease clinical phenotypes [relapsing remitting (RRMS), benign (BMS), and secondary progressive (SPMS)] and healthy subjects. Effective connectivity analysis was performed on Stroop task data using a novel method based on causal Bayes networks. Compared with controls, MS phenotypes were slower at performing the task and had reduced performance accuracy during incongruent trials that required increased cognitive control. MS phenotypes also exhibited connectivity abnormalities reflected as weaker shared connections, presence of extra connections (i.e., connections absent in the HC connectivity pattern), connection reversal, and loss. In SPMS and the BMS groups but not in the RRMS group, extra connections were associated with deficits in the Stroop task performance. In the BMS group, the response time associated with correct responses during the congruent condition showed a positive correlation with the left posterior parietal -> dorsal anterior cingulate connection. In the SPMS group, performance accuracy during the congruent condition showed a negative correlation with the right insula -> left insula connection. No associations between extra connections and behavioral performance measures were observed in the RRMS group. These results suggest that, depending on the phenotype, patients with MS use different strategies when cognitive control demands are high and rely on different network connections. Hum Brain Mapp, 37:2293-2304, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26956183 TI - Longitudinal Analysis of Microbiota in Microalga Nannochloropsis salina Cultures. AB - Large-scale open microalgae cultivation has tremendous potential to make a significant contribution to replacing petroleum-based fuels with biofuels. Open algal cultures are unavoidably inhabited with a diversity of microbes that live on, influence, and shape the fate of these ecosystems. However, there is little understanding of the resilience and stability of the microbial communities in engineered semicontinuous algal systems. To evaluate the dynamics and resilience of the microbial communities in microalgae biofuel cultures, we conducted a longitudinal study on open systems to compare the temporal profiles of the microbiota from two multigenerational algal cohorts, which include one seeded with the microbiota from an in-house culture and the other exogenously seeded with a natural-occurring consortia of bacterial species harvested from the Pacific Ocean. From these month-long, semicontinuous open microalga Nannochloropsis salina cultures, we sequenced a time-series of 46 samples, yielding 8804 operational taxonomic units derived from 9,160,076 high-quality partial 16S rRNA sequences. We provide quantitative evidence that clearly illustrates the development of microbial community is associated with microbiota ancestry. In addition, N. salina growth phases were linked with distinct changes in microbial phylotypes. Alteromonadeles dominated the community in the N. salina exponential phase whereas Alphaproteobacteria and Flavobacteriia were more prevalent in the stationary phase. We also demonstrate that the N. salina associated microbial community in open cultures is diverse, resilient, and dynamic in response to environmental perturbations. This knowledge has general implications for developing and testing design principles of cultivated algal systems. PMID- 26956184 TI - Comparison of antibody assays for detection of autoantibodies to Ro 52, Ro 60 and La associated with primary Sjogren's syndrome. AB - Anti-Ro(52/60) and anti-La constitute the hallmark autoantibodies in primary Sjogren's syndrome, being present in 40-70% of sera. Several anti-Ro/La assays exist, but antibody detection appears to be assay-specific, thus the aim of this study was to compare several anti-Ro/La assays. In total, 96 sera from individuals with primary Sjogren's syndrome and 114 healthy controls were tested for anti-Ro 52/60 and anti-La in 17 immunoassays. Especially the immunoassays used for detection of anti-Ro 52 differed in their sensitivity (48-79%), while only small differences in sensitivities were observed for the anti-Ro 60 (69-77%) anti-La (39-44%) assays. Concordances of 65%, 79% and 73% for the anti-Ro 52, anti-Ro 60 and anti-La assays were found, respectively. The majority of the assays yielded high specificities, primarily ranging from 97 to 100%, except from a single anti-Ro 60 assay, which yielded a specificity of 79%. Occasionally, reactivity levels were increased in a few assays, indicating that false-positive results can be obtained when applying assays of reduced specificity. In general, the commercial assays appeared to perform better than the in-house analyses. When correcting the in-house assays for background reactivity, sensitivities were reduced by approximately 7%, 17%, and 19% for anti-Ro 52, anti-Ro 60 and anti-La assays, respectively, illustrating the pitfalls when applying immunoassays for detection of autoantibodies, which in theory may apply to commercial assays as well. Finally, increased total sensitivities were obtained when combining assays. These studies contribute to clarify the clinical utility of immunoassays for detection of autoantibodies of Ro 52, Ro 60 and La and illustrate that the most efficient strategy to maximize antibody sensitivity is to combine several assays. PMID- 26956185 TI - The effects of microvesicles on endothelial progenitor cells are compromised in type 2 diabetic patients via downregulation of the miR-126/VEGFR2 pathway. AB - Our previous study showed that circulating microvesicles (cMVs) of diabetic mice have negative effects on the function of endothelial progenitor cells (EPCs). Whether this is true in diabetic patients deserves further study. In this study, the effects of cMVs and EPC-derived MVs (EPC-MVs) on EPC migration, apoptosis, and reactive oxygen species (ROS) production in healthy controls, well controlled, and uncontrolled diabetic patients were investigated. The levels of miR-126 and vascular endothelial growth factor receptor 2 (VEGFR2) in cMVs, EPC MVs, and/or EPCs were analyzed. Moreover, miR-126 inhibitor or mimic was applied to EPCs to modulate the miR-126 level in EPC-MVs. We found the following: 1) the circulating EPC level was reduced but the circulating EPC-MV level increased in uncontrolled diabetic patients; 2) the cMVs and EPC-MVs of healthy controls had beneficial effects on EPCs (migration, apoptosis, ROS), whereas the effects were reversely changed in the cMVs and EPC-MVs of uncontrolled diabetic patients; and 3) the cMVs and EPC-MVs of uncontrolled diabetic patients carried less miR-126 and had downregulated VEGFR2 expression in EPCs. Manipulating the miR-126 level in EPC-MVs with inhibitor or mimic changed their function. The effects of cMVs and EPC-MVs are compromised in diabetes due to the reduction of their carried miR 126, which might provide a therapy target for diabetic vascular complications. PMID- 26956187 TI - Skeletal inflammation and attenuation of Wnt signaling, Wnt ligand expression, and bone formation in atherosclerotic ApoE-null mice. AB - ApoE-null (ApoE-KO) mice fed a high-fat diet (HFD) develop atherosclerosis, due in part to activation of vascular inflammation by oxidized low-density lipoprotein. Since bone loss also occurs in these mice, we used them to investigate the impact of oxidized lipids on bone homeostasis and to search for underlying pathogenic pathways. Four-month-old female ApoE-KO mice fed a HFD for three months exhibited increased levels of oxidized lipids in bone, as well as decreased femoral and vertebral trabecular and cortical bone mass, compared with ApoE-KO mice on normal diet. Despite HFD-induced increase in expression of Alox15, a lipoxygenase that oxidizes LDL and promotes atherogenesis, global deletion of this gene failed to ameliorate the skeletal impact of HFD. Osteoblast number and function were dramatically reduced in trabecular and cortical bone of HFD-fed mice, whereas osteoclast number was modestly reduced only in trabecular bone, indicating that an imbalance in favor of osteoclasts was responsible for HFD-induced bone loss. These changes were associated with decreased osteoblast progenitors and increased monocyte/macrophages in the bone marrow as well as increased expression of IL-1beta, IL-6, and TNF. HFD also attenuated Wnt signaling as evidenced by reduced expression of Wnt target genes, and it decreased expression of pro-osteoblastogenic Wnt ligands. These results suggest that oxidized lipids decrease bone mass by increasing anti-osteoblastogenic inflammatory cytokines and decreasing pro-osteoblastogenic Wnt ligands. PMID- 26956186 TI - Estradiol modulates myosin regulatory light chain phosphorylation and contractility in skeletal muscle of female mice. AB - Impairment of skeletal muscle function has been associated with changes in ovarian hormones, especially estradiol. To elucidate mechanisms of estradiol on skeletal muscle strength, the hormone's effects on phosphorylation of the myosin regulatory light chain (pRLC) and muscle contractility were investigated, hypothesizing an estradiol-specific beneficial impact. In a skeletal muscle cell line, C2C12, pRLC was increased by 17beta-estradiol (E2) in a concentration dependent manner. In skeletal muscles of C57BL/6 mice that were E2 deficient via ovariectomy (OVX), pRLC was lower than that from ovary-intact, sham-operated mice (Sham). The reduced pRLC in OVX muscle was reversed by in vivo E2 treatment. Posttetanic potentiation (PTP) of muscle from OVX mice was low compared with that from Sham mice, and this decrement was reversed by acute E2 treatment, demonstrating physiological consequence. Western blot of those muscles revealed that low PTP corresponded with low pRLC and higher PTP with greater pRLC. We aimed to elucidate signaling pathways affecting E2-mediated pRLC using a kinase inhibitor library and C2C12 cells as well as a specific myosin light chain kinase inhibitor in muscles. PI3K/Akt, MAPK, and CamKII were identified as candidate kinases sensitive to E2 in terms of phosphorylating RLC. Applying siRNA strategy in C2C12 cells, pRLC triggered by E2 was found to be mediated by estrogen receptor-beta and the G protein-coupled estrogen receptor. Together, these results provide evidence that E2 modulates myosin pRLC in skeletal muscle and is one mechanism by which this hormone can affect muscle contractility in females. PMID- 26956188 TI - Glucagon-like peptide-1 does not have acute effects on central or renal hemodynamics in patients with type 2 diabetes without nephropathy. AB - During acute administration of native glucagon-like peptide-1 (GLP-1), we previously demonstrated central hemodynamic effects in healthy males, whereas renal hemodynamics, despite renal uptake of GLP-1 in excess of glomerular filtration, was unaffected. In the present study, we studied hemodynamic effects of GLP-1 in patients with type 2 diabetes under fixed sodium intake. During a 3-h infusion of GLP-1 (1.5 pmol.kg(-1).min(-1)) or saline, intra-arterial blood pressure and heart rate were measured continuously, concomitantly with cardiac output estimated by pulse contour analysis. Renal plasma flow, glomerular filtration rate, and uptake/release of hormones and ions were measured using Fick's Principle after catheterization of a renal vein. Urine collection was conducted throughout the experiments at voluntary voiding, and patients remained supine during the experiments. During the GLP-1 infusion, systolic and diastolic blood pressure and cardiac output remained unchanged, whereas heart rate increased significantly. Arterio-venous gradients for GLP-1 exceeded glomerular filtrations significantly, but renal plasma flow and glomerular filtration rate as well as renal sodium and lithium excretion were not affected. In conclusion, acute administration of GLP-1 in patients with type 2 diabetes leads to a positive chronotropic effect, but in contrast to healthy individuals, cardiac output does not increase in patients with type 2 diabetes. Renal hemodynamics and sodium excretion are not affected. PMID- 26956189 TI - Novel and prevalent CYP11B1 gene mutations in Turkish patients with 11-beta hydroxylase deficiency. AB - 11beta-Hydroxylase deficiency is the second most frequent type of congenital adrenal hyperplasia and is more common in those of Turkish descent than in other populations. The purpose of this study is to examine the spectrum of CYP11B1 gene mutations in Turkish patients with 11beta-hydroxylase deficiency. Twenty-eight patients from 24 families, ages ranging from 0.1 to 7 years, were included in the study. Clinical diagnosis was based on virilization and high levels of 11 deoxycortisol. Twenty-six cases exhibited the classical and 2 cases the non classical form. Mutation screening of 9 CYP11B1 exons was performed by direct DNA sequence analysis, specifically amplifying CYP11B1 gene fragments while avoiding simultaneous amplification of homologous CYP11B2 gene sequences. Seventeen different mutations were detected, 6 of which are novel (p.Gln189Hisfs*70, p.Glu198Gly, p.Thr318Lys, p.Gly446Ser, IVS8+5G>C and exon 3-5 del). All of the identified mutations resulted in the classical form with severe virilization, except for the p.Gly446Ser mutation, which caused a late-onset type of 11beta hydroxylase deficiency. The c.954G>A;p.Thr318Thr mutation was the most common in our cohort, with an allele frequency of 14.6%.Of the CYP11B1 gene mutations detected, 75% were found in exons 3, 5 and 7 and the half of the mutations were nonsense, splice site, deletion or insertion mutations, causing severe virilization in female patients. The findings are important for genetic counseling and the prenatal diagnosis of Turkish patients with 11beta-hydroxylase deficiency. PMID- 26956190 TI - Apparent mineralocorticoid excess. AB - Apparent mineralocorticoid excess is a syndrome reflecting the absent or impaired activity of the enzyme 11beta-hydroxysteroid dehydrogenase Type 2. It may be mild when the mutant enzyme retains some activity, or severe when activity is absolutely or essentially absent. Diagnosis relies on a triad of hypertension, hypokalemia and suppressed plasma aldosterone levels, plus an abnormal urinary cortisol to cortisone ratio, either free steroid or metabolites. Treatment is symptomatic in the mild form - correction of hypertension and hypokalemia - but needs to be prompt, vigorous and sustained in the severe form, which usually presents in neonates/infancy. Elucidation of the pathogenesis of apparent mineralocorticoid excess is an example of 'reverse translation', in that it proved prismatic for the demonstration of the physiologic mechanisms underlying the selective activation of epithelial mineralocorticoid receptors by aldosterone. PMID- 26956191 TI - Novel cases of Tunisian patients with mutations in the gene encoding 17beta hydroxysteroid dehydrogenase type 3 and a founder effect. AB - 17beta-Hydroxysteroid dehydrogenase type 3 (17beta-HSD3) is expressed almost exclusively in the testis and converts Delta4-androstene-3,17-dione to testosterone. Mutations in the HSD17B3 gene causing 17beta-HSD3 deficiency are responsible for a rare recessive form of 46, XY Disorders of Sex Development (46, XY DSD). We report novel cases of Tunisian patients with 17beta-HSD3 deficiency due to previously reported mutations, i.e. p.C206X and p.G133R, as well as a case with the novel compound heterozygous mutations p.C206X and p.Q176P. Moreover, the previously reported polymorphism p.G289S was identified in a heterozygous state in combination with a novel non-coding variant c.54G>T, also in a heterozygous state, in a male patient presenting with micropenis and low testosterone levels. The identification of four different mutations in a cohort of eight patients confirms the generally observed genetic heterogeneity of 17beta-HSD3 deficiency. Nevertheless, analysis of DNA from 272 randomly selected healthy controls from the same geographic area (region of Sfax) revealed a high carrier frequency for the p.C206X mutation of approximately 1 in 40. Genotype reconstruction of the affected pedigree members revealed that all p.C206X mutation carriers harbored the same haplotype, indicating inheritance of the mutation from a common ancestor. Thus, the identification of a founder effect and the elevated carrier frequency of the p.C206X mutation emphasize the importance to consider this mutation in the diagnosis and genetic counseling of affected 17beta-HSD3 deficiency pedigrees in Tunisia. PMID- 26956192 TI - Development of Biliary and Enteral Stents by the Korean Gastrointestinal Endoscopists. AB - Stenting in the gastrointestinal tract is a common procedure used for palliation of obstruction in the enteral and biliary tract. Today, stenting of malignant and benign strictures is performed at almost every major tertiary hospital in Korea. Moreover, Korea has become a major global supplier of cutting edge technology in the field of self-expanding metal stents. However, the history of stenting in Korea is relatively short and was far behind that of other nations such as Japan and Germany. The authors are humbled and gratified to have been able to observe the development and application of these stents in Korea, first hand. In this article, the authors review the overall history of stenting with a specific focus on the development of stenting in Korea. The development of esophageal, gastroduodenal, biliary, and colonic stents in Korea are reviewed in this article from a chronological and historical point of view, and a personal account of some of the significant moments of stent development in Korea are described. PMID- 26956193 TI - Fecal Microbiota Transplantation: Current Applications, Effectiveness, and Future Perspectives. AB - Fecal microbiota transplantation (FMT) is the infusion of liquid filtrate feces from a healthy donor into the gut of a recipient to cure a specific disease. A fecal suspension can be administered by nasogastric or nasoduodenal tube, colonoscope, enema, or capsule. The high success rate and safety in the short term reported for recurrent Clostridium difficile infection has elevated FMT as an emerging treatment for a wide range of disorders, including Parkinson's disease, fibromyalgia, chronic fatigue syndrome, myoclonus dystopia, multiple sclerosis, obesity, insulin resistance, metabolic syndrome, and autism. There are many unanswered questions regarding FMT, including donor selection and screening, standardized protocols, long-term safety, and regulatory issues. This article reviews the efficacy and safety of FMT used in treating a variety of diseases, methodology, criteria for donor selection and screening, and various concerns regarding FMT. PMID- 26956197 TI - Single potassium niobate nano/microsized particles as local mechano-optical Brownian probes. AB - Perovskite alkaline niobates, due to their strong nonlinear optical properties, including birefringence and the capability to produce second-harmonic generation (SHG) signals, attract a lot of attention as potential candidates for applications as local nano/microsized mechano-optical probes. Here, we report on an implementation of photonic force microscopy (PFM) to explore the Brownian motion and optical trappability of monocrystalline potassium niobate (KNbO3) nano/microsized particles having sizes within the range of 50 to 750 nm. In particular, we exploit the anisotropic translational diffusive regime of the Brownian motion to quantify thermal fluctuations and optical forces of singly trapped KNbO3 particles within the optical trapping volume of a PFM microscope. We also show that, under near-infrared (NIR) excitation of the highly focused laser beam of the PFM microscope, a single optically-trapped KNbO3 particle reveals a strong SHG signal manifested by a narrow peak (lambda(em) = 532 nm) at half the excitation wavelength (lambda(ex) = 1064 nm). Moreover, we demonstrate that the thus induced SHG emission can be used as a local light source that is capable of optically exciting molecules of an organic dye, Rose Bengal (RB), which adhere to the particle surface, through the mechanism of luminescence energy transfer (LET). PMID- 26956198 TI - Tissue-Engineered Vocal Fold Mucosa Implantation in Rabbits. AB - OBJECTIVE: To assess phonatory function and wound healing of a tissue-engineered vocal fold mucosa (TE-VFM) in rabbits. An "artificial" vocal fold would be valuable for reconstructing refractory scars and resection defects, particularly one that uses readily available autologous cells and scaffold. This work implants a candidate TE-VFM after resecting native epithelium and lamina propria in rabbits. STUDY DESIGN: Prospective animal study. SETTING: Research laboratory. SUBJECTS AND METHODS: Rabbit adipose-derived stem cells were isolated and cultured in three-dimensional fibrin scaffolds to form TE-VFM. Eight rabbits underwent laryngofissure, unilateral European Laryngologic Society type 2 cordectomy, and immediate reconstruction with TE-VFM. After 4 weeks, larynges were excised, phonated, and examined by histology. RESULTS: Uniform TE-VFM implants were created, with rabbit mesenchymal cells populated throughout fibrin hydrogels. Rabbits recovered uneventfully after implantation. Phonation was achieved in all, with mucosal waves evident at the implant site. Histology after 4 weeks showed resorbed fibrin matrix, continuous epithelium, and mildly increased collagen relative to contralateral unoperated vocal folds. Elastic fiber appearance was highly variable. Inflammatory cell infiltrate was limited to animals receiving sex-mismatched implants. CONCLUSION: TE-VFMs were successfully implanted into 8 rabbits, with minor evidence of scar formation and immune reaction. Vibration was preserved 4 weeks after resecting and reconstructing the complete vocal fold cover layer. Further studies will investigate the mechanism and durability of improvement. TE-VFM with autologous cells is a promising new approach for vocal fold reconstruction. PMID- 26956195 TI - Molecular circuitry of stem cell fate in skeletal muscle regeneration, ageing and disease. AB - Satellite cells are adult myogenic stem cells that repair damaged muscle. The enduring capacity for muscle regeneration requires efficient satellite cell expansion after injury, their differentiation to produce myoblasts that can reconstitute damaged fibres and their self-renewal to replenish the muscle stem cell pool for subsequent rounds of injury and repair. Emerging studies indicate that misregulation of satellite cell fate and function can contribute to age associated muscle dysfunction and influence the severity of muscle diseases, including Duchenne muscular dystrophy (DMD). It has also become apparent that satellite cell fate during muscle regeneration and ageing, and in the context of DMD, is governed by an intricate network of intrinsic and extrinsic regulators. Targeted manipulation of this network may offer unique opportunities for muscle regenerative medicine. PMID- 26956199 TI - Utility of Fine-Needle Aspiration Biopsy in the Evaluation of Pediatric Head and Neck Masses. AB - OBJECTIVES: Fine-needle aspiration biopsy (FNAB) has a well-established role in the evaluation of an adult head and neck mass (HNM) but remains underused in children. The objectives of this study were to assess the diagnostic accuracy, safety profile, use of anesthesia, and influence on surgical decision making of FNAB of HNM in the pediatric population. STUDY DESIGN: Case series with chart review. SETTING: Tertiary care children's hospital. SUBJECTS AND METHODS: In total, 257 consecutive patients with HNM who underwent 338 FNABs from July 2007 to July 2014 were reviewed. Patients ranged in age from 0 to 21 years (mean, 9.3 years); lesions ranged in size from 0.3 to 12.5 cm (mean, 2.4cm). Fine-needle aspiration biopsies were performed in the interventional radiology suite, operating room, clinic, or ward. RESULTS: The most common patient final diagnoses included reactive lymphadenopathy (n = 99, 38.5%), benign thyroid colloid nodule (n = 31, 12.1%), malignancies (n = 21, 8.2%), and atypical mycobacterial infection (n = 15, 5.8%). On surgical histopathologic and clinical follow-up, overall sensitivity of FNAB was 94.6% and specificity was 97.7%. The complication rate was 2.1%, and general anesthesia or sedation was used for 73% of FNAB. Surgery occurred only 9 times following the 191 patients with negative FNAB results, indicating that 95.3% of unnecessary surgeries were avoided with the assistance of the FNAB result. CONCLUSIONS: Fine-needle aspiration biopsy is an accurate and safe diagnostic tool for guiding management of persistent lymphadenopathy, thyroid nodules, and other HNM in pediatric patients. Negative FNABs can often obviate the need for surgical intervention. PMID- 26956194 TI - Mitonuclear communication in homeostasis and stress. AB - Mitochondria participate in crucial cellular processes such as energy harvesting and intermediate metabolism. Although mitochondria possess their own genome--a vestige of their bacterial origins and endosymbiotic evolution--most mitochondrial proteins are encoded in the nucleus. The expression of the mitochondrial proteome hence requires tight coordination between the two genomes to adapt mitochondrial function to the ever-changing cellular milieu. In this Review, we focus on the pathways that coordinate the communication between mitochondria and the nucleus during homeostasis and mitochondrial stress. These pathways include nucleus-to-mitochondria (anterograde) and mitochondria-to nucleus (retrograde) communication, mitonuclear feedback signalling and proteostasis regulation, the integrated stress response and non-cell-autonomous communication. We discuss how mitonuclear communication safeguards cellular and organismal fitness and regulates lifespan. PMID- 26956196 TI - Nuclear DNA damage signalling to mitochondria in ageing. AB - Mitochondrial dysfunction is a hallmark of ageing, and mitochondrial maintenance may lead to increased healthspan. Emerging evidence suggests a crucial role for signalling from the nucleus to mitochondria (NM signalling) in regulating mitochondrial function and ageing. An important initiator of NM signalling is nuclear DNA damage, which accumulates with age and may contribute to the development of age-associated diseases. DNA damage-dependent NM signalling constitutes a network that includes nuclear sirtuins and controls genomic stability and mitochondrial integrity. Pharmacological modulation of NM signalling is a promising novel approach for the prevention and treatment of age associated diseases. PMID- 26956200 TI - Outcomes and Prognostic Factors of Radiation-Induced and De Novo Head and Neck Squamous Cell Carcinomas. AB - OBJECTIVE: We sought to compare clinical outcomes, pathological features, treatment patterns, and survival outcomes between radiation-induced squamous cell carcinoma (RISCC) and de novo SCC (DNSCC) of the head and neck, as well as identify prognostic factors in these patients. STUDY DESIGN: Case-control study. SETTING: Tertiary medical center. SUBJECTS AND METHODS: Retrospective case control analysis of 34 RISCCs and 136 DNSCCs matched by age at diagnosis, sex, smoking status, and primary tumor site. RESULTS: Median latency of RISCC development was 13 years. Radiation-induced squamous cell carcinomas were more likely to present with node-negative disease than DNSCCs (70.6% vs 42.9%; P = .024). A greater proportion of DNSCCs was treated with curative intent (92.6% vs 79.4%; P = .048) and achieved no residual disease posttreatment (82.2% vs 41.2%; P < .001) compared with RISCCs. Patients with RISCC had poorer overall survival (OS) (median, 1.67 vs 5.03 years; P = .018) and disease-specific survival (DSS) (median, 1.67 vs 8.65 years; P = .001) than those with DNSCC. Among patients who underwent curative treatment with no residual disease after treatment, there were, however, no survival differences between RISCC and DNSCC. CONCLUSION: In our cohort, RISCCs have a poorer prognosis than DNSCCs. However, those able to undergo curative treatment and have no residual disease after treatment have comparable survival outcomes. Locoregional control of these tumors appears paramount in achieving the best outcomes for patients with RISCC. PMID- 26956201 TI - Oat-cell carcinoma of the tongue. PMID- 26956203 TI - Thyroid function and psychiatric disorders. AB - To answer the question if it is possible for specific psychiatric illnesses to influence the thyroxine-concentration, a group of 376 patients admitted to a psychiatric hospital was studied retrospectively. 13.5% had an elevated thyroxine concentration and only 0.6% had a low concentration. Of the group of 145 men, 22.8% was found to have an elevated thyroxine-concentration. In the group of 196 women we found 6.6% to be elevated. A low thyroxine was found in only 0.5% of the women and 0.7% of the men. In the group with an elevated thyroxine the psychiatric diagnoses of schizophrenia and psychotic disorders NOS are more common (19.6% and 17.4% respectively) than in the group with a normal thyroxine (4.4% and 6.5% respectively). PMID- 26956202 TI - The clinical significance of atypical antipsychotics. AB - A concise review is given of the importance of the atypical antipsychotic drugs clozapine, sulpiride, remoxipride and raclopride. Both the concept of atypicality and the pharmacological profile of these compounds is discussed. The newly developed atypical antipsychotic remoxipride has been studied in several double blind studies. In virtually all of these studies a reduced propensity for the induction of extrapyramidal symptoms was found. These findings implicate that atypical antipsychotics may also not induce tardive dyskinesia. In addition to the treatment of acute schizophrenia, these compounds might be of use in the treatment of treatment resistent schizophrenia (clozapine), tardive dyskinesia and psychosis during the course of Parkinson's disease. PMID- 26956204 TI - Influence of Propofol on the Mood - a comparative study. AB - The influence of propofol on mood was evaluated, considering the potential use of propofol as an anesthetic for electroconvulsive therapy. The mood state of 80 psychologically healthy subjects was assessed before and from 1/2 hour till 4 hours after surgery under anesthesia with either propofol or methohexitone. The mood was assessed with the Profile of Mood States (POMS). The propofol group was more elated from one hour until 4 hours after anesthesia (p<0,01 )(factor 1). 1 hour after anesthesia the propofol group was continuously more composed than the methohexitone group (p<0,01) (factor 4) and after two hours the propofol group was more agreeable (p<0,05) (factor 2). Moreover, patients, who received propofol, were less tired (factor 3) and confused (factor 5). It can be concluded that, compared with methohexitone, propofol has a favorable influence on different aspects of mood. PMID- 26956205 TI - Psychofarmacologics. PMID- 26956206 TI - Cancer Stem Cell-Based Models of Colorectal Cancer Reveal Molecular Determinants of Therapy Resistance. AB - Colorectal cancer (CRC) therapy mainly relies on the use of conventional chemotherapeutic drugs combined, in a subset of patients, with epidermal growth factor receptor [EGFR]-targeting agents. Although CRC is considered a prototype of a cancer stem cell (CSC)-driven tumor, the effects of both conventional and targeted therapies on the CSC compartment are largely unknown. We have optimized a protocol for colorectal CSC isolation that allowed us to obtain CSC-enriched cultures from primary tumor specimens, with high efficiency. CSC isolation was followed by in vitro and in vivo validation, genetic characterization, and drug sensitivity analysis, thus generating panels of CSC lines with defined patterns of genetic mutations and therapy sensitivity. Colorectal CSC lines were polyclonal and maintained intratumor heterogeneity in terms of somatically acquired mutations and differentiation state. Such CSC-enriched cultures were used to investigate the effects of both conventional and targeted therapies on the CSC compartment in vivo and to generate a proteomic picture of signaling pathways implicated in sensitivity/resistance to anti-EGFR agents. We propose CSC lines as a sound preclinical framework to test the effects of therapies in vitro and in vivo and to identify novel determinants of therapy resistance. SIGNIFICANCE: Colorectal cancer stem cells (CSCs) have been shown to be responsible for tumor propagation, metastatic dissemination, and relapse. However, molecular pathways present in CSCs, as well as mechanisms of therapy resistance, are mostly unknown. Taking advantage of genetically characterized CSC lines derived from colorectal tumors, this study provides an extensive analysis of CSC response to EGFR-targeted therapy in vivo and an overview of factors implicated in therapy response or resistance. Furthermore, the implementation of a biobank of molecularly annotated CSC lines provides an innovative resource for future investigations in colorectal cancer. PMID- 26956208 TI - Obesity Determines the Immunophenotypic Profile and Functional Characteristics of Human Mesenchymal Stem Cells From Adipose Tissue. AB - Adipose tissue is a major source of mesenchymal stem cells (MSCs), which possess a variety of properties that make them ideal candidates for regenerative and immunomodulatory therapies. Here, we compared the immunophenotypic profile of human adipose-derived stem cells (hASCs) from lean and obese individuals, and explored its relationship with the apparent altered plasticity of hASCs. We also hypothesized that persistent hypoxia treatment of cultured hASCs may be necessary but not sufficient to drive significant changes in mature adipocytes. hASCs were obtained from subcutaneous adipose tissue of healthy, adult, female donors undergoing abdominal plastic surgery: lean (n=8; body mass index [BMI]: 23+/-1 kg/m2) and obese (n=8; BMI: 35+/-5 kg/m2). Cell surface marker expression, proliferation and migration capacity, and adipogenic differentiation potential of cultured hASCs at two different oxygen conditions were studied. Compared with lean-derived hASCs, obese-derived hASCs demonstrated increased proliferation and migration capacity but decreased lipid droplet accumulation, correlating with a higher expression of human leukocyte antigen (HLA)-II and cluster of differentiation (CD) 106 and lower expression of CD29. Of interest, adipogenic differentiation modified CD106, CD49b, HLA-ABC surface protein expression, which was dependent on the donor's BMI. Additionally, low oxygen tension increased proliferation and migration of lean but not obese hASCs, which correlated with an altered CD36 and CD49b immunophenotypic profile. In summary, the differences observed in proliferation, migration, and differentiation capacity in obese hASCs occurred in parallel with changes in cell surface markers, both under basal conditions and during differentiation. Therefore, obesity is an important determinant of stem cell function independent of oxygen tension. SIGNIFICANCE: The obesity-related hypoxic environment may have latent effects on human adipose tissue-derived mesenchymal stem cells (hASCs) with potential consequences in mature cells. This study explores the immunophenotypic profile of hASCs obtained from lean and obese individuals and its potential relationship with the altered plasticity of hASCs observed in obesity. In this context, an altered pattern of cell surface marker expression in obese-derived hASCs in both undifferentiated and differentiated stages is demonstrated. Differences in proliferation, migration, and differentiation capacity of hASCs from obese adipose tissue correlated with alterations in cell surface expression. Remarkably, altered plasticity observed in obese-derived hASCs was maintained in the absence of hypoxia, suggesting that these cells might be obesity conditioned. PMID- 26956207 TI - Concise Review: Endothelial Progenitor Cells in Regenerative Medicine: Applications and Challenges. AB - Endothelial progenitor cells (EPCs) are currently being studied as candidate cell sources for revascularization strategies. Significant advances have been made in understanding the biology of EPCs, and preclinical studies have demonstrated the vasculogenic, angiogenic, and beneficial paracrine effects of transplanted EPCs in the treatment of ischemic diseases. Despite these promising results, widespread clinical acceptance of EPCs for clinical therapies remains hampered by several challenges. The present study provides a concise summary of the different EPC populations being studied for ischemic therapies and their known roles in the healing of ischemic tissues. The challenges and issues surrounding the use of EPCs and the current strategies being developed to improve the harvest efficiency and functionality of EPCs for application in regenerative medicine are discussed. SIGNIFICANCE: Endothelial progenitor cells (EPCs) have immense clinical value for cardiovascular therapies. The present study provides a concise description of the EPC subpopulations being evaluated for clinical applications. The current major lines of investigation involving preclinical and clinical evaluations of EPCs are discussed, and significant gaps limiting the translation of EPCs are highlighted. The present report could be useful for clinicians and clinical researchers with interests in ischemic therapy and for basic scientists working in the related fields of tissue engineering and regenerative medicine. PMID- 26956209 TI - Enhanced Osteogenesis of Adipose-Derived Stem Cells by Regulating Bone Morphogenetic Protein Signaling Antagonists and Agonists. AB - Although adipose-derived stem cells (ASCs) are an attractive cell source for bone tissue engineering, direct use of ASCs alone has had limited success in the treatment of large bone defects. Although bone morphogenetic proteins (BMPs) are believed to be the most potent osteoinductive factors to promote osteogenic differentiation of ASCs, their clinical applications require supraphysiological dosage, leading to high medical burden and adverse side effects. In the present study, we demonstrated an alternative approach that can effectively complement the BMP activity to maximize the osteogenesis of ASCs without exogenous application of BMPs by regulating levels of antagonists and agonists to BMP signaling. Treatment of ASCs with the amiloride derivative phenamil, a positive regulator of BMP signaling, combined with gene manipulation to suppress the BMP antagonist noggin, significantly enhanced osteogenic differentiation of ASCs through increased BMP-Smad signaling in vitro. Furthermore, the combination approach of noggin suppression and phenamil stimulation enhanced the BMP signaling and bone repair in a mouse calvarial defect model by adding noggin knockdown ASCs to apatite-coated poly(lactic-coglycolic acid) scaffolds loaded with phenamil. These results suggest novel complementary osteoinductive strategies that could maximize activity of the BMP pathway in ASC bone repair while reducing potential adverse effects of current BMP-based therapeutics. SIGNIFICANCE: Although stem cell-based tissue engineering strategy offers a promising alternative to repair damaged bone, direct use of stem cells alone is not adequate for challenging healing environments such as in large bone defects. This study demonstrates a novel strategy to maximize bone formation pathways in osteogenic differentiation of mesenchymal stem cells and functional bone formation by combining gene manipulation with a small molecule activator toward osteogenesis. The findings indicate promising stem cell-based therapy for treating bone defects that can effectively complement or replace current osteoinductive therapeutics. PMID- 26956212 TI - Healthcare academic informatics and IT vendors - A modest proposal for a collaborative focus. PMID- 26956211 TI - Sasanquasaponin promotes cellular chloride efflux and elicits cardioprotection via the PKCepsilon pathway. AB - Sasanquasaponin (SQS) is an active component of Camellia oleifera Abel. A recent study by our group demonstrated that SQS was able to inhibit ischemia/reperfusion induced elevation of the intracellular chloride ion concentration ([Cl-]i) and exerted cardioprotective effects; however, the underlying intracellular signal transduction mechanisms have yet to be elucidated. As protein kinase C epsilon (PKCepsilon) is able to mediate Cl- homeostasis, the present study investigated its possible involvement in the effects of SQS on cardiomyocytes subjected to ischemia/reperfusion injury. Cardiomyocytes were pre-treated with or without SQS or SQS plus epsilonV1-2, a selective PKCepsilon inhibitor, followed by simulated ischemia/reperfusion (sI/R). The effects on cell viability, PKCepsilon phosphorylation levels, [Cl-]i, mitochondrial membrane potential and reactive oxygen species (ROS) production were assessed using an MTS assay, western blot analysis, colorimetric assays and flow cytometry. The results revealed that treatment with SQS prior to sI/R increased the viability of cardiomyocytes, and efficiently attenuated lactate dehydrogenase and creatine phosphokinase release induced by sI/R. In addition, SQS promoted PKCepsilon phosphorylation and inhibited sI/R-induced elevation of [Cl-]i, paralleled by the attenuation of mitochondrial membrane potential loss and ROS generation. However, when the cardiomyocytes were treated with epsilonV1-2 prior to SQS pre-conditioning, the cardioprotection induced by SQS was reduced and the inhibitory effects of SQS on sI/R-induced elevation of [Cl-]i, production of ROS and loss of mitochondrial membrane potential were also attenuated. These findings indicated that SQS may inhibit sI/R-induced elevation of [Cl-]i through the PKCepsilon signaling pathway to elicit cardioprotection in cultured cardiomyocytes. PMID- 26956210 TI - Impaired Angiogenic Potential of Human Placental Mesenchymal Stromal Cells in Intrauterine Growth Restriction. AB - Human placental mesenchymal stromal cells (pMSCs) have never been investigated in intrauterine growth restriction (IUGR). We characterized cells isolated from placental membranes and the basal disc of six IUGR and five physiological placentas. Cell viability and proliferation were assessed every 7 days during a 6 week culture. Expression of hematopoietic, stem, endothelial, and mesenchymal markers was evaluated by flow cytometry. We characterized the multipotency of pMSCs and the expression of genes involved in mitochondrial content and function. Cell viability was high in all samples, and proliferation rate was lower in IUGR compared with control cells. All samples presented a starting heterogeneous population, shifting during culture toward homogeneity for mesenchymal markers and occurring earlier in IUGR than in controls. In vitro multipotency of IUGR derived pMSCs was restricted because their capacity for adipocyte differentiation was increased, whereas their ability to differentiate toward endothelial cell lineage was decreased. Mitochondrial content and function were higher in IUGR pMSCs than controls, possibly indicating a shift from anaerobic to aerobic metabolism, with the loss of the metabolic characteristics that are typical of undifferentiated multipotent cells. SIGNIFICANCE: This study demonstrates that the loss of endothelial differentiation potential and the increase of adipogenic ability are likely to play a significant role in the vicious cycle of abnormal placental development in intrauterine growth restriction (IUGR). This is the first observation of a potential role for placental mesenchymal stromal cells in intrauterine growth restriction, thus leading to new perspectives for the treatment of IUGR. PMID- 26956213 TI - Analysis of clinical prognostic variables for Chronic Lymphocytic Leukemia decision-making problems. AB - INTRODUCTION: Chronic Lymphocytic Leukemia (CLL) is a disease with highly heterogeneous clinical course. A key goal is the prediction of patients with high risk of disease progression, which could benefit from an earlier or more intense treatment. In this work we introduce a simple methodology based on machine learning methods to help physicians in their decision making in different problems related to CLL. MATERIAL AND METHODS: Clinical data belongs to a retrospective study of a cohort of 265 Caucasians who were diagnosed with CLL between 1997 and 2007 in Hospital Cabuenes (Asturias, Spain). Different machine learning methods were applied to find the shortest list of most discriminatory prognostic variables to predict the need of Chemotherapy Treatment and the development of an Autoimmune Disease. RESULTS: Autoimmune disease occurrence was predicted with very high accuracy (>90%). Autoimmune disease development is currently an unpredictable severe complication of CLL. Chemotherapy Treatment has been predicted with a lower accuracy (80%). Risk analysis showed that the number of false positives and false negatives are well balanced. CONCLUSIONS: Our study highlights the importance of prognostic variables associated with the characteristics of platelets, reticulocytes and natural killers, which are the main targets of the autoimmune haemolytic anemia and immune thrombocytopenia for autoimmune disease development, and also, the relevance of some clinical variables related with the immune characteristics of CLL patients that are not taking into account by current prognostic markers for predicting the need of chemotherapy. Because of its simplicity, this methodology could be implemented in spreadsheets. PMID- 26956214 TI - Bcl-2 is a critical mediator of intestinal transformation. AB - Intestinal tumour formation is generally thought to occur following mutational events in the stem cell pool. However, active NF-kappaB signalling additionally facilitates malignant transformation of differentiated cells. We hypothesized that genes shared between NF-kappaB and intestinal stem cell (ISCs) signatures might identify common pathways that are required for malignant growth. Here, we find that the NF-kappaB target Bcl-2, an anti-apoptotic gene, is specifically expressed in ISCs in both mice and humans. Bcl-2 is dispensable in homeostasis and, although involved in protecting ISCs from radiation-induced damage, it is non-essential in tissue regeneration. Bcl-2 is upregulated in adenomas, and its loss or inhibition impairs outgrowth of oncogenic clones, because Bcl-2 alleviates apoptotic priming in epithelial cells following Apc loss. Furthermore, Bcl-2 expression in differentiated epithelial cells renders these cells amenable to clonogenic outgrowth. Collectively, our results indicate that Bcl-2 is required for efficient intestinal transformation following Apc-loss and constitutes a potential chemoprevention target. PMID- 26956215 TI - Mechanical oscillations enhance gene delivery into suspended cells. AB - Suspended cells are difficult to be transfected by common biochemical methods which require cell attachment to a substrate. Mechanical oscillations of suspended cells at certain frequencies are found to result in significant increase in membrane permeability and potency for delivery of nano-particles and genetic materials into the cells. Nanomaterials including siRNAs are found to penetrate into suspended cells after subjecting to short-time mechanical oscillations, which would otherwise not affect the viability of the cells. Theoretical analysis indicates significant deformation of the actin-filament network in the cytoskeleton cortex during mechanical oscillations at the experimental frequency, which is likely to rupture the soft phospholipid bilayer leading to increased membrane permeability. The results here indicate a new method for enhancing cell transfection. PMID- 26956217 TI - Tailoring Conformation-Induced Chromism of Polythiophene Copolymers for Nucleic Acid Assay at Resource Limited Settings. AB - Here we report on the design and synthesis of cationic water-soluble thiophene copolymers as reporters for colorimetric detection of microRNA (miRNA) in human plasma. Poly(3-alkoxythiophene) (PT) polyelectrolytes with controlled ratios of pendant groups such as triethylamine/1-methyl imidazole were synthesized for optimizing interaction with target miRNA sequence (Tseq). Incorporation of specific peptide nucleic acid (PNA) sequences with the cationic polythiophenes yielded distinguishable responses upon formation of fluorescent PT-PNA-Tseq triplex and weakly fluorescent PT-Tseq duplex, thereby enabling selective detection of target miRNA. Unlike homopolymers of PT (hPT), experimental results indicate the possibility of utilizing copolymers of PT (cPT) with appropriate ratios of pendant groups for miRNA assay in complex matrices such as plasma. As an illustration, colorimetric responses were obtained for lung cancer associated miRNA sequence (mir21) in human plasma, with a detection limit of 10 nM, illustrating the feasibility of proposed methodology for clinical applications without involving sophisticated instrumentation. The described methodology therefore possesses high potential for low-cost nucleic acid assays in resource limited settings. PMID- 26956218 TI - Cyclocarya paliurus extract alleviates diabetic nephropathy by inhibiting oxidative stress and aldose reductase. AB - Diabetes is the leading cause of end-stage renal disease because diabetic nephropathy (DN) develops in 30-40% of the patients. This study investigated the protective effect of the aqueous extract from leaves of Cyclocarya paliurus (Batal.) Iljinsk (ACP) on DN by inhibiting oxidative stress and aldose reductase (AR) activity. ACP was obtained by hot water extraction. The in vitro antioxidant capability and AR inhibition of ACP were investigated by employing various established systems. DN rats were used to assess the reno-protective effect of ACP. Results showed that the polysaccharide and total polyphenol contents of ACP were (479.3 +/- 19.8) mg/g and (38.3 +/- 2.3) mg/g, respectively. ACP exhibited strong antioxidant ability and AR inhibition in vitro and in vivo; furthermore, the inhibition mechanism of ACP in AR takes the form of uncompetitive inhibition. In addition, the animals treated with ACP showed significant amelioration of blood glucose, serum biomarkers related to renal function, urinary protein excretion, and histopathological changes in the kidney. The results suggest that ACP has a potential role in ameliorating renal damage involved in DN. PMID- 26956219 TI - Two gonad-infecting species of Philometra (Nematoda: Philometridae) from groupers (Serranidae) off Tunisia, with a key to Philometra species infecting serranid gonads. AB - Based on light and scanning electron microscopical studies of nematode specimens (males and mature females) collected from the ovary of groupers (Serranidae, Perciformes) in the Mediterranean Sea off Tunisia (near Tunis and Sfax), two gonad-infecting species of Philometra Costa, 1845 (Nematoda, Philometridae) are reported: Philometra inexpectata n. sp. from the mottled grouper Mycteroperca rubra and P. jordanoi (Lopez-Neyra, 1951) from the dusky grouper Epinephelus marginatus. Identification of both fish species was confirmed by molecular barcoding. The new species is mainly characterized by the length of equally long spicules (147-165 MUm), the gubernaculum (63-93 MUm long) bearing at the tip two dorsolateral lamellar parts separated from each other by a smooth median field, a V-shaped mound on the male caudal extremity, the presence of a pair of large caudal papillae located posterior to the cloaca and by the body length of the males (1.97-2.43 mm). Philometra inexpectata n. sp. is the fifth known gonad infecting philometrid species parasitizing serranid fishes in the Mediterranean region. The males of P. jordanoi were examined by scanning electron microscopy for the first time; this detailed study revealed some new taxonomically important morphological features, such as the number and arrangement of cephalic and caudal papillae, presence of amphids and phasmids and mainly the lamellate structures at the posterior end of the gubernaculum. A key to gonad-infecting species of Philometra parasitic in serranid fishes is provided. PMID- 26956216 TI - Dexamethasone Release from Within Engineered Cartilage as a Chondroprotective Strategy Against Interleukin-1alpha. AB - While significant progress has been made toward engineering functional cartilage constructs with mechanical properties suitable for in vivo loading, the impact on these grafts of inflammatory cytokines, chemical factors that are elevated with trauma or osteoarthritis, is poorly understood. Previous work has shown dexamethasone to be a critical compound for cultivating cartilage with functional properties, while also providing chondroprotection from proinflammatory cytokines. This study tested the hypothesis that the incorporation of poly(lactic co-glycolic acid) (PLGA) (75:25) microspheres that release dexamethasone from within chondrocyte-seeded agarose hydrogel constructs would promote development of constructs with functional properties and protect constructs from the deleterious effects of interleukin-1alpha (IL-1alpha). After 28 days of growth culture, experimental groups were treated with IL-1alpha (10 ng/mL) for 7 days. Reaching native equilibrium moduli and proteoglycan levels, dexamethasone-loaded microsphere constructs exhibited tissue properties similar to microsphere-free control constructs cultured in dexamethasone-supplemented culture media and were insensitive to IL-1alpha exposure. These findings are in stark contrast to constructs containing dexamethasone-free microspheres or no microspheres, cultured without dexamethasone, where IL-1alpha exposure led to significant tissue degradation. These results support the use of dexamethasone delivery from within engineered cartilage, through biodegradable microspheres, as a strategy to produce mechanically functional tissues that can also combat the deleterious effects of local proinflammatory cytokine exposure. PMID- 26956220 TI - Guerrerostrongylus marginalis n. sp. (Trichostrongyloidea: Heligmonellidae) from the Guianan arboreal mouse (Oecomys auyantepui) from French Guiana. AB - Based on the number and arrangement of cuticular ridges and configuration of the dorsal ray, nematode specimens collected from the small intestine of eight Guianan arboreal mice, Oecomys auyantepui (Rodentia: Sigmodontinae), in French Guiana are herein described and characterized. Guerrerostrongylus marginalis n. sp. (Heligmosomoidea: Heligmonellidae) shows a synlophe consisting of more than 40 ridges and a unique bursal arrangement with ray 8 (externo-dorsal) extending to the edge of the bursal margin, and appearing more prominent than the dorsal ray. This bursal arrangement is common in members of Hassalstrongylus Durette Desset, 1971, but uncommon in the other four species in Guerrerostrongylus Sutton & Durette-Desset, 1991. The placement of the new species in Guerrerostrongylus is based on the number and nature of cuticular ridges and the ray arrangement and symmetry of the caudal bursa. Diagnostic characteristics of Guerrerostrongylus marginalis n. sp. include the length of ray 8 relative to bursal margin, the relative size of the spicules and vestibule, and the number of eggs in the uterus. We propose an amendment to the generic diagnosis of Guerrerostrongylus to modify the characters of the long rays 6 (postero-lateral), rays 8 (externo dorsal), and dorsal ray as diagnostic, since at least ray 6 appears to be short in two different species in the genus, namely G. ulysi Digiani, Notarnicola & Navone, 2012 and G. marginalis n. sp. PMID- 26956221 TI - Sero-epidemiological survey of Crimean-Congo hemorrhagic fever virus in Tunisia. AB - Crimean-Congo hemorrhagic fever (CCHF) is a tick-borne disease associated with a high case fatality rate and transmitted mainly by Hyalomma marginatum. The geographical distribution of H. marginatum covers most of the Western Mediterranean basin. We aimed to investigate whether CCHF virus (CCHFv) is circulating in Tunisia. Samples from unexplained acute febrile patients (n = 181) and a high risk group of humans, mainly slaughter workers (n = 38), were collected in the summer of 2014 and analyzed for exposure to CCHFv using serological tests and real-time RT-PCR. Ticks were collected from Northern and Southern Tunisia during May-June 2014 and examined for the presence of CCHFv by real-time RT-PCR. Of the 181 febrile patients, 5 showed only high titers of IgM suggesting a recent exposure to CCHFv. Among 38 slaughter workers, 2 had IgG anti CCHFv responses yielding a seroprevalence of 5.2%. No CCHFv was detected in ticks and sera. Our results provide evidence of human exposure to CCHFv in Tunisia. PMID- 26956222 TI - A novel small-molecule inhibitor of influenza A virus acts by suppressing PA endonuclease activity of the viral polymerase. AB - The RNA-dependent RNA polymerase of influenza A virus comprises conserved and independently-folded subdomains with defined functionalities. The N-terminal domain of the PA subunit (PA(N)) harbors the endonuclease function so that it can serve as a desired target for drug discovery. To identify a class of anti influenza inhibitors that impedes PA(N) endonuclease activity, a screening approach that integrated the fluorescence resonance energy transfer based endonuclease inhibitory assay with the DNA gel-based endonuclease inhibitory assay was conducted, followed by the evaluation of antiviral efficacies and potential cytotoxicity of the primary hits in vitro and in vivo. A small-molecule compound ANA-0 was identified as a potent inhibitor against the replication of multiple subtypes of influenza A virus, including H1N1, H3N2, H5N1, H7N7, H7N9 and H9N2, in cell cultures. Combinational treatment of zanamivir and ANA-0 exerted synergistic anti-influenza effect in vitro. Intranasal administration of ANA-0 protected mice from lethal challenge and reduced lung viral loads in H1N1 virus infected BALB/c mice. In summary, ANA-0 shows potential to be developed to novel anti-influenza agents. PMID- 26956224 TI - Development and Validation of the Rappel Indice-24: Behavioral and Brain Morphological Evidence. AB - The primary goals of the present study were to develop and validate the Rappel Indice 24 (RI-24), a shorter version of the original Rappel Indice, which includes 48 items (RI-48), and to identify the specific brain regions that were correlated with scores on the RI-24. Using these clinical scales, the present study evaluated 91 elderly Korean participants who were classified into 3 groups: normal control (NC; n = 34), patients with mild cognitive impairment (MCI; n = 29), and patients with Alzheimer disease (AD; n = 28). Of the 91 participants, 77 also underwent magnetic resonance imaging scans. The RI-24 delayed cued recall (DCR) scores significantly differed among the NC, MCI, and AD groups. A receiver operating characteristic curve analysis revealed that the RI-24 was very sensitive (89%) and specific (91%) for the detection of AD. Furthermore, although the time needed to administer the RI-24 was half that needed for the RI-48, the 24-item version showed a high correlation (r= .85 for the DCR score) with the 48 item version. In terms of brain morphological characteristics, voxel-based morphometry analyses revealed a significant positive correlation between DCR score and gray matter volume in the parahippocampal gyrus (r= .468), which plays a role in cued recall. Taken together, the present findings indicate that the RI 24 is a sensitive and reliable test for the detection of memory impairments in patients with MCI and AD despite its brief administration time. PMID- 26956223 TI - Substrate specificity and function of acetylpolyamine amidohydrolases from Pseudomonas aeruginosa. AB - BACKGROUND: Pseudomonas aeruginosa, a Gram-negative, aerobic coccobacillus bacterium is an opportunistic human pathogen and worldwide the fourth most common cause of hospital-acquired infections which are often high mortality such as ventilator-associated pneumoniae. The polyamine metabolism of P. aeruginosa and particularly the deacetylation of acetylpolyamines has been little studied up to now. Results with other bacterial pathogens e.g., Y. pestis suggest that polyamines may be involved in the formation of biofilms or confer resistance against certain antibiotics. RESULTS: To elucidate the role of acetylpolyamines and their enzymatic deacetylation in more detail, all three putative acetylpolyamine amidohydrolases (APAHs) from P. aeruginosa have been expressed in enzymatic active form. The APAHs PA0321 and PA1409 are shown to be true polyamine deacetylases, whereas PA3774 is not able to deacetylate acetylated polyamines. Every APAH can hydrolyze trifluoroacetylated lysine-derivatives, but only PA1409 and much more efficiently PA3774 can also process the plain acetylated lysine substrate. P. aeruginosa is able to utilize acetylcadaverine and acetylputrescine as a carbon source under glucose starvation. If either the PA0321 or the PA1409 but not the PA3774 gene is disrupted, the growth of P. aeruginosa is reduced and delayed. In addition, we were able to show that the APAH inhibitors SAHA and SATFMK induce biofilm formation in both PA14 and PAO1 wildtype strains. CONCLUSIONS: P. aeruginosa has two functional APAHs, PA0321 and PA1409 which enable the utilization of acetylpolyamines for the metabolism of P. aeruginosa. In contrast, the physiological role of the predicted APAH, PA3774, remains to be elucidated. Its ability to deacetylate synthetic acetylated lysine substrates points to a protein deacetylation functionality with yet unknown substrates. PMID- 26956225 TI - Hypofractionated radiation treatment in early breast cancer: Results in a New Zealand setting. AB - AIMS: High-quality evidence supports that hypofractionated radiation treatment (HFRT) is as effective and safe in early breast cancer as conventionally fractionated radiation treatment. HFRT with fewer treatments has potential benefits for both patients and radiation departments. Despite this, concerns about local control and toxicity with HFRT persist, such that many eligible patients do not receive HFRT. The local recurrence rates and acute toxicity after HFRT was analyzed in our center in Christchurch, New Zealand. METHODS: An audit was undertaken of all early breast cancer (T1-2 and N0-1) patients treated with HFRT from Jan 21, 2004, to December 31, 2006, dating from the adoption of HFRT in our department. Sixty-eight percent of the patients during this time received HFRT (274/402). Acute toxicity was prospectively recorded and local, regional and distant recurrences were documented. RESULTS: A total of 274 patients were analyzed with a median follow-up of 7 years (range 0.55-9.5 years). Eleven of 274 patients had local recurrence only. The local recurrence-free survival was 97.2% and 95.8% at 7 years. The skin, lethargy and breast pain acute toxicity was less than grade 3, except for one patient experiencing grade 3 breast pain. CONCLUSION: Low local recurrence rates and acceptably low acute toxicity were achieved in a local setting with HFRT, comparable to results achieved in large randomized controlled trials. HFRT is a valid option for eligible patients and its use should be encouraged. PMID- 26956226 TI - Maternal obesity, gestational diabetes, breastfeeding and childhood overweight at age 2 years. AB - BACKGROUND: Maternal obesity, excessive gestational weight gain (EGWG), gestational diabetes mellitus (GDM) and breastfeeding are four important factors associated with childhood obesity. OBJECTIVES: The objective of the study was to assess the interplay among these four factors and their independent contributions to childhood overweight in a cohort with standard clinical care. METHODS: The cohort included 15 710 mother-offspring pairs delivered in 2011. Logistic regression was used to assess associations between maternal exposures and childhood overweight (body mass index >85th percentile) at age 2 years. RESULTS: Mothers with pre-pregnancy obesity or overweight were more likely to have EGWG, GDM and less likely to breastfeed >=6 months. Mothers with GDM had 40-49% lower EGWG rates and similar breastfeeding rates compared with mothers without GDM. Analysis adjusted for exposures and covariates revealed an adjusted odds ratio (95% confidence interval) associated with childhood overweight at age 2 years of 2.34 (2.09-2.62), 1.50 (1.34-1.68), 1.23 (1.12-1.35), 0.95 (0.83-1.10) and 0.76 (0.69-0.83) for maternal obesity, overweight, EGWG, GDM and breastfeeding >=6 months vs. <6 months, respectively. CONCLUSIONS: In this large clinical cohort, GDM was not associated with, but maternal pre-pregnancy obesity or overweight and EGWG were independently associated with an increased risk, and breastfeeding >=6 months was associated with a decreased risk of childhood overweight at age 2 years. PMID- 26956228 TI - The effects of cancer therapy on women's fertility: what do we know now? AB - Due to the improvements of cancer treatment, the survival rate of cancer increased over the last decades. One of the detrimental side effects of cytotoxic treatment is the impairment or loss of fertility. Having a family is one of the important aspects for long-time survivors. The impact of gynecologic cancer on fertility depends on the site and kind of the cancer disease, the oncologic therapeutic regimen and additional the age of the patient. In cancer of the internal genital organs, fertility-preserving surgery techniques should be used, if possible. In case, that cytotoxic treatment has to be applied, fertility preservation techniques should be implemented into the oncologic treatment. PMID- 26956227 TI - Epidemiological analysis of bovine ephemeral fever in 2012-2013 in the subtropical islands of Japan. AB - BACKGROUND: Bovine ephemeral fever (BEF) is a febrile disease of cattle that is transmitted by arthropod vectors such as mosquitoes and Culicoides biting midges. An outbreak of BEF recently occurred in Ishigaki Island and surrounding islands that are located southwest of Japan. In this study, an epidemiological analysis was conducted to understand the temporal and spatial characteristics of the outbreak. Factors associated with the disease spread within Ishigaki Island were investigated by hierarchical Bayesian models. The possibility of between-island transmission by windborne vectors and transmission by long-distance migration of infected vectors were examined using atmospheric dispersion models. RESULTS: In September 2012, the first case of the disease was detected in the western part of Ishigaki Island. In 1 month, it had rapidly spread to the southern part of the island and to surrounding islands, and led to 225 suspected cases of BEF during the outbreak. The dispersion model demonstrated the high possibility of between island transmission by wind. Spatial analysis showed that paddy fields, farmlands, and slope gradients had a significant impact on the 1-km cell-level incidence risk. These factors may have influenced the habitats and movements of the vectors with regard to the spread of BEF. A plausible incursion event of infected vectors from Southeast Asia to Ishigaki Island was estimated to have occurred at the end of August. CONCLUSION: This study revealed that the condition of a terrain and land use significantly influenced disease transmission. These factors are important in assessing favorable environments for related vectors. The results of the dispersion model indicated the likely transmission of the infected vectors by wind on the local scale and on the long-distance scale. These findings would be helpful for developing a surveillance program and developing preventive measures against BEF. PMID- 26956229 TI - Revascularization vs. Optimal Medical Therapy in Women with NSTE-ACS. AB - BACKGROUND: There is conflicting evidence regarding the benefit of an early invasive strategy vs. a conservative strategy in women with non-ST-elevation acute coronary syndrome (NSTE-ACS). METHODS: We searched English-language studies on MEDLINE and the Cochrane Database of Systematic Reviews from 2000 to December 2015. Results from major available studies and meta-analysis comparing outcomes of an early invasive strategy vs. a conservative strategy or medical therapy vs. revascularization in women with NSTE-ACS were considered. RESULTS: Available data on the comparative effectiveness and safety of different management strategies in NSTE-ACS women derive from observational registries and pre-specified gender sub analyses of randomized trials comparing early routine invasive with a selective invasive strategy. While some post-hoc analysis of randomized trials showed that an early invasive strategy did not reduce the risk of future events among women, in contrast to its beneficial effect in men, others showed similar benefits of a routine early invasive vs. a conservative strategy in men and women. Several important differences between these trials may explain the lack of benefits from a routine invasive strategy compared with a conservative strategy. Overall evidence showed better outcomes with a routine invasive strategy, especially for women at higher risk and those with positive biomarkers. Differently, women with negative biomarkers and those at lower risk appeared to benefit most from a conservative approach. CONCLUSION: The benefit of an early invasive strategy is restricted to women at higher risk. Further research is warranted to define the optimal management of women with NSTE-ACS. PMID- 26956230 TI - Risk Factors for Myocardial Infarction in Women and Men: A Review of the Current Literature. AB - BACKGROUND: Cardiovascular disease has been the leading cause of death in both sexes in developed countries for decades. In general, men and women share the same cardiovascular risk factors. However, in recent trials including both men and women sexspecific analyses have raised awareness of sex differences in cardiovascular risk factors due to both biological and cultural differences. RESULTS: Women experience their first myocardial infarction (MI) 6-10 years later than men and a protective effect of their natural estrogen status prior to menopause has been suggested. Female sex hormones have been associated with a less atherogenic lipid profile and a more healthy fat distribution. These differences are attenuated following menopause. Regarding life style the prevalence of smoking is highest in men but female smokers have a relatively higher cardiovascular risk than male smokers. Men are more physically active than women while women have healthier dietary habits. Genetic factors also affect cardiovascular risk but no sex differences have been seen. Increased cardiovascular risk attributed to psychosocial distress is similar in men and women, but since women are more prone to psychosocial distress their burden of disease is greater. Compared with a healthy population the relative risk of MI in a diabetic population is higher in women than in men. No sex difference exists in the prevalence of hypertension but it has an earlier onset in men. CONCLUSION: Sex differences in cardiovascular risk are becoming more apparent and paying attention to this is pivotal when addressing risk factors in preventive efforts. PMID- 26956231 TI - Atypical Chest Pain in ACS: A Trap Especially for Women. AB - Not all acute coronary syndromes (ACS) exhibit the classic symptoms of chest pain. The diagnosis of ACS in patients without typical chest pain is often challenging. These patients are at increased risk for delayed or incorrect diagnosis, less aggressive treatment and high in-hospital mortality. The association between diabetes mellitus and absence of chest pain in ischemic heart disease is established. As well, it is known that women, more frequently than men, have atypical presentation. However, there is a lack of standardization in characterizing the population of patients with ACS and atypical presentation. The identification of other factors influencing and/or related with the absence of chest pain in ACS could be helpful for patients' outcomes. The object of our study was to examine the current literature on the clinical features, other than female gender and diabetes, associated with the atypical presentation of ACS. We found that patients with non-ST-elevation ACS more frequently than patients with ST-elevation myocardial infarction have atypical presentation. Atypical symptoms in aged population are common both among female and male. Subjects with history of comorbidities, specifically heart failure, chronic kidney disease, chronic obstructive pulmonary disease and stroke are less likely to report chest pain as chief complain of ACS. PMID- 26956232 TI - Atheroma Burden and Morphology in Women. AB - BACKGROUND: Ischemic heart disease is the major cause of death in women. Men and women have many similarities in relation to cardiovascular risk factors, but they differ in the pathophysiology, clinical presentation and outcomes in the setting of coronary artery disease and myocardial ischemia. Over the last years, due to innovative imaging technologies and more specific diagnostic strategies, increasing number of clinical studies report on specific-gender characteristics on plaque composition and burden, associated to acute coronary syndromes, and also on coronary vascular dysfunction as a major cause of clinical symptoms in women with apparently normal arteries. METHODS: Here we performed a review of the literature focused on atheroma burden in women that includes information provided in original articles (basic and clinical oriented), cohort studies, trial and registry data, metaanalysis and other systematic reviews. RESULTS AND CONCLUSIONS: The Studies published over the last 30 years provide a new view about the pathophysiology and presentation of ischemic heart disease in women. However, many questions remain to be addressed by future research. The mechanisms behind the delay on disease presentation in women over the fertile period and the paradoxical fact that young women have more adverse outcomes after an ischemic event need to be identified. A better understanding of these issues is expected to derive in better strategies for prevention and management of ischemic heart disease in women. PMID- 26956234 TI - Combined effects of engineered tendon matrix and GDF-6 on bone marrow mesenchymal stem cell-based tendon regeneration. AB - OBJECTIVES: To examine whether an engineered tendon matrix (ETM) environment and growth and differentiation factor-6 (GDF-6) have synergistic effects on the tenogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) and the quality of tendon repair. RESULTS: ETM and GDF-6 promote tenogenic differentiation of BMSCs in vitro. Implantation of GDF-6-incorporated ETM containing BMSCs into a tendon injury model significantly improved the histological and mechanical properties of the repaired tendon. CONCLUSIONS: GDF-6 incorporated ETM containing BMSCs represents a promising strategy for tendon injury repair. PMID- 26956233 TI - Into the black and back: the ecology of brain investment in Neotropical army ants (Formicidae: Dorylinae). AB - Shifts to new ecological settings can drive evolutionary changes in animal sensory systems and in the brain structures that process sensory information. We took advantage of the diverse habitat ecology of Neotropical army ants to test whether evolutionary transitions from below- to above-ground activity were associated with changes in brain structure. Our estimates of genus-typical frequencies of above-ground activity suggested a high degree of evolutionary plasticity in habitat use among Neotropical army ants. Brain structure consistently corresponded to degree of above-ground activity among genera and among species within genera. The most above-ground genera (and species) invested relatively more in visual processing brain tissues; the most subterranean species invested relatively less in central processing higher-brain centers (mushroom body calyces). These patterns suggest a strong role of sensory ecology (e.g., light levels) in selecting for army ant brain investment evolution and further suggest that the subterranean environment poses reduced cognitive challenges to workers. The highly above-ground active genus Eciton was exceptional in having relatively large brains and particularly large and structurally complex optic lobes. These patterns suggest that the transition to above-ground activity from ancestors that were largely subterranean for approximately 60 million years was followed by re-emergence of enhanced visual function in workers. PMID- 26956235 TI - Squalene isolated from Schizochytrium mangrovei is a peroxisome proliferator activated receptor-alpha agonist that regulates lipid metabolism in HepG2 cells. AB - OBJECTIVE: Peroxisome proliferator-activated receptor-alpha (PPARalpha) is a nuclear receptor that has critical roles in the treatment of atherosclerosis, hyperlipidemia and hepatic steatosis. RESULTS: Squalene is a novel nature PPARalpha agonist, identified from reporter gene assay and qPCR analysis. Cultured hepatocytes stimulated with squalene exhibited significantly decreased cellular triacylglycerols and cholesterol concentrations, while cellular uptake of fatty acids was increased. Quantitative PCR analysis revealed that expression of genes related to fatty acid uptake, fatty acid oxidation, ketogenesis and reverse cholesterol transport metabolism were upregulated, while that of genes related to fatty acid synthesis were suppressed in cell treated with squalene. CONCLUSION: Squalene is hypolipidemic by activation of PPARalpha via a ligand mediated mechanism that regulates the expression of lipid metabolism genes in hepatocytes. PMID- 26956236 TI - Boosting fatty acid synthesis in Rhodococcus opacus PD630 by overexpression of autologous thioesterases. AB - OBJECTIVES: To explore the role of thioesterases in Rhodococcus opacus PD630 by endogenously overexpression in this bacteria for increased lipid production. RESULTS: Overexpression of four thioesterases from R. opacus PD630 in E. coli led to a 2- to 8-fold increase in C16:1 and C18:1 fatty acids while, when overexpressed in R. opacus PD630, only two recombinants had significant effect on the quantities and compositions of total fatty acid. The contents of total fatty acids (FAs) in two recombinants, pJTE2 (OPAG_00508 thioesterase) and pJTE4 (WP_012687673.1 thioesterase), were 400-460 mg/g (CDW) which is 1.5 times of wild type strain PD630 (300-350 mg/g CDW), and 20-30 % (w/w) more than that of the control strain PDpJAM2 (330-370 mg/g CDW). The contents of 17:1 and 18:1 fatty acids increased by about 27 and 35 %, respectively, in pJTE2 and by 35 and 20 %, respectively, in pJTE4 compared with the control strain. CONCLUSIONS: The engineered strains showed improved production of lipid (as total fatty acids), and could also tailor the composition of the fatty acid profile when cultured in mineral salts medium using glucose as sole carbon source. PMID- 26956237 TI - Expression, characterization and mutagenesis of a novel glutamate decarboxylase from Bacillus megaterium. AB - OBJECTIVES: To search for a novel glutamate decarboxylase (GAD) with an optimum pH towards near-neutrality in order to improve production of gamma-aminobutyric acid (GABA) in recombinant hosts. RESULTS: A novel glutamate decarboxylase, BmGAD, from Bacillus megaterium was overexpressed and purified. BmGAD was approximately 53 kDa by SDS-PAGE analysis. Its optimum activity was at pH 5 and 50 degrees C. BmGAD had a specific activity of 59 +/- 5.2 U mg(-1) at pH 6, which is the highest value reported so far. The apparent Km and Vmax values of BmGAD were 8 +/- 0.5 mM and 150 +/- 4.7 U mg(-1), respectively. Through site directed mutagenesis, two BmGAD mutants (E294R and H467A) showed higher Vmax values than that of wild-type, with the values of 210 +/- 6.9 and 180 +/- 4.1 U mg(-1) at pH 5 and 50 degrees C, respectively. CONCLUSIONS: The unusual high activity of BmGAD at pH 6 makes it an attractive GABA-producing candidate in industrial application. PMID- 26956238 TI - Discovery of novel feruloyl esterase activity of BioH in Escherichia coli BL21(DE3). AB - OBJECTIVES: To characterize a novel feruloyl esterase from Escherichia coli BL21 DE3. RESULTS: The gene encoding BioH was cloned and overexpressed in E. coli. The protein was purified and its catalytic activity was assessed. BioH exhibited feruloyl esterase activity toward a broad range of substrates, and the corresponding kinetic constants for the methyl ferulate, ethyl ferulate, and methyl p-coumarate substrates were: K m values of 0.48, 6.3, and 1.9 mM, respectively, and k cat /K m values of 9.3, 3.8, and 3.8 mM(-1) s(-1), respectively. CONCLUSIONS: Feruloyl esterase from E. coli was expressed for the first time. BioH was confirmed to be a feruloyl esterase. PMID- 26956239 TI - Blunt aortic trauma in a patient with the Ehlers-Danlos syndrome type VI. AB - A 24-year-old male with the Ehlers-Danlos syndrome (EDS) type VI (ocular scoliotic) who was kicked in the abdomen presented to the emergency room (ER) with abdominal pain. He was found to have a blunt traumatic aortic injury. The patient was treated nonoperatively. He was stable and discharged home on the eighth day. The patient returned to the ER several days later hypotensive and tachycardic. The patient was taken immediately to the operating room, but vascular repair was not possible. The patient expired. We discuss the challenges of taking care of a patient with EDS and offer suggestions that might improve future patient's outcome. PMID- 26956241 TI - Crisis in general practice: the problem of "independent" contractor status. PMID- 26956242 TI - 17th Annual Hernia Repair : March 30-April 2, 2016 Washington DC, USA. PMID- 26956240 TI - Aspects of Hyperglycemia Contribution to Arterial Stiffness and Cardiovascular Complications in Patients With Type 1 Diabetes. AB - Controlling the blood glucose level is of outmost importance for the prevention of the micro- and macrovascular diabetic complications observed in patients with type 1 diabetes (T1D). Although the pathogenesis behind the complex cascade of complications is far from solved, one possible mechanism could be a negative effect of glucose on the arteries resulting in a stiffening of the arteries and ultimately in vascular complications. Intriguingly, patients with T1D have been shown to suffer from premature arterial aging compared to nondiabetic subjects-an association that is even more evident in the presence of diabetic complications such as diabetic nephropathy. Arterial stiffness has in several patient populations been shown to independently predict cardiovascular disease. However, interventional studies aimed at attenuating arterial stiffness to reduce cardiovascular disease in T1D are yet to come. Moreover, most of the data on pharmacological treatments of arterial stiffening are directed toward pathophysiological pathways other than hyperglycemia. Interestingly, the sodium glucose transport-2 (SGLT2) inhibitor empagliflozin was recently shown to reduce both blood pressure and arterial stiffness in patients with type 2 diabetes. Whether, these effects can also be replicated in patients with T1D is an intriguing question. Tight metabolic and antihypertensive control are still of central importance for the prevention and the treatment of diabetic complications. However, the need for a noninvasive intermediate marker to identify at risk patients for aggressive treatment is evident. One such tool might be arterial stiffness linking diabetes to increased cardiovascular risk. Future research efforts exploring large-scale databases will play a key role in the identification of other clinically useful markers. PMID- 26956243 TI - Pigmented desmoplastic trichilemmoma. AB - Desmoplastic trichilemmoma (DT), the pseudomalignant variant of conventional trichilemmoma described by Hunt et al in 1990, displays a superficial lobular growth pattern of glycogen-rich cells with peripheral nuclear palisading surrounded by a thickened basement membrane. DT differs from its conventional counterpart by showing a central hyalinized area with epithelial cords and strands mimicking invasive carcinoma. We report a case that fully satisfies the criteria for DT and, in addition, shows an extensive melanocytic cell component and prominent melanin deposition. To our knowledge, a pigmented variant of DT has not been reported and should be recognized in order to appropriately face the differential diagnosis with malignant pigmented tumors particularly pigmented basal cell carcinoma (BCC). PMID- 26956247 TI - Does Preadmission Cutaneous Chlorhexidine Preparation Reduce Surgical Site Infections After Total Knee Arthroplasty? AB - BACKGROUND: Many preventive methodologies seek to reduce the risk of surgical site infections after total knee arthroplasty (TKA), including the use of preoperative chlorhexidine baths and cloths. Although we have demonstrated in previous studies that this may be an efficacious method for infection prevention, our study was underpowered and we therefore set out to evaluate this with a larger sample size. QUESTIONS/PURPOSES: (1) Does a preadmission chlorhexidine cloth skin preparation protocol decrease the risk of surgical site infection in patients undergoing TKA? (2) When stratified using the National Healthcare Safety Network (NHSN) risk categories, which categories are associated with risk reduction from the preadmission chlorhexidine preparation protocol? METHODS: In our study, all patients (3717 total) who had undergone primary or revision TKA at a single institution between January 1, 2007, and December 31, 2013, were identified, of whom 991 patients used the chlorhexidine cloths before surgery and 2726 patients did not. All patients were provided cloths with instructions before surgery; however, as a result of a lack of compliance, we were able to substratify patients into treatment and control cohorts. Additionally, we substratified patients by NHSN risk category to determine differences in infection between the two cohorts (cloth versus no cloth). Patient medical records and an infection-tracking database were reviewed to determine the development of periprosthetic infection (patients who had superficial infections were excluded from our study) in both groups after 1 year surveillance. We then calculated relative risk reductions with use of chlorhexidine gluconate and stratified results based on NHSN risk category. RESULTS: Use of a preoperative chlorhexidine cloth skin preparation protocol is associated with reduced relative risk of periprosthetic infection after TKA (infections with protocol: three of 991 [0.3%]; infections in control: 52 of 2726 [1.9%]; relative risk [RR]: 6.3 [95% confidence interval [CI], 1.9-20.1]; p = 0.002). When stratified by NHSN risk category, periprosthetic infection risk reduction was seen in the medium risk category (protocol: one of 402 [0.3%]; control: 25 of 1218 [2.0%]; RR, 8.3 [CI, 1.1-60.7]; p = 0.038), but no significant difference was detected in the low and medium-risk groups (RR, 2.1 [CI, 0.5-9.6; p = 0.33] and RR, 11.3 [CI, 0.7 186.7; p = 0.09]). CONCLUSIONS: A prehospital chlorhexidine gluconate wipe protocol appears to reduce the risk of periprosthetic infections after TKA, primarily in those patients with medium and high risk. Although future multicenter randomized trials will need to confirm these preliminary findings, the intervention is inexpensive and is unlikely to be risky and therefore might be considered on the basis of this retrospective, comparative study. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 26956248 TI - Can Preoperative Patient-reported Outcome Measures Be Used to Predict Meaningful Improvement in Function After TKA? AB - BACKGROUND: Despite the overall effectiveness of total knee arthroplasty (TKA), a subset of patients do not experience expected improvements in pain, physical function, and quality of life as documented by patient-reported outcome measures (PROMs), which assess a patient's physical and emotional health and pain. It is therefore important to develop preoperative tools capable of identifying patients unlikely to improve by a clinically important margin after surgery. QUESTIONS/PURPOSES: The purpose of this study was to determine if an association exists between preoperative PROM scores and patients' likelihood of experiencing a clinically meaningful change in function 1 year after TKA. METHODS: A retrospective study design was used to evaluate preoperative and 1-year postoperative Knee injury and Osteoarthritis Outcome Score (KOOS) and SF-12 version 2 (SF12v2) scores from 562 patients who underwent primary unilateral TKA. This cohort represented 75% of the 750 patients who underwent surgery during that time period; a total of 188 others (25%) either did not complete PROM scores at the designated times or were lost to follow-up. Minimum clinically important differences (MCIDs) were calculated for each PROM using a distribution-based method and were used to define meaningful clinical improvement. MCID values for KOOS and SF12v2 physical component summary (PCS) scores were calculated to be 10 and 5, respectively. A receiver operating characteristic analysis was used to determine threshold values for preoperative KOOS and SF12v2 PCS scores and their respective predictive abilities. Threshold values defined the point after which the likelihood of clinically meaningful improvement began to diminish. Multivariate regression was used to control for the effect of preoperative mental and emotional health, patient attributes quantified by SF12v2 mental component summary (MCS) scores, on patients' likelihood of experiencing meaningful improvement in function after surgery. RESULTS: Threshold values for preoperative KOOS and SF12v2 PCS scores were a maximum of 58 (area under the curve [AUC], 0.76; p < 0.001) and 34 (AUC, 0.65; p < 0.001), respectively. Patients scoring above these thresholds, indicating better preoperative function, were less likely to experience a clinically meaningful improvement in function after TKA. When accounting for mental and emotional health with a multivariate analysis, the predictive ability of both KOOS and SF12v2 PCS threshold values improved (AUCs increased to 0.80 and 0.71, respectively). Better preoperative mental and emotional health, as reflected by a higher MCS score, resulted in higher threshold values for KOOS and SF12v2 PCS. CONCLUSIONS: We identified preoperative PROM threshold values that are associated with clinically meaningful improvements in functional outcome after TKA. Patients with preoperative KOOS or SF12v2 PCS scores above the defined threshold values have a diminishing probability of experiencing clinically meaningful improvement after TKA. Patients with worse baseline mental and emotional health (as defined by SF12v2 MCS score) have a lower probability of experiencing clinically important levels of functional improvement after surgery. The results of this study are directly applicable to patient-centered informed decision-making tools and may be used to facilitate discussions with patients regarding the expected benefit after TKA. LEVEL OF EVIDENCE: Level III, prognostic study. PMID- 26956249 TI - Erratum to: Ceramic Heads Decrease Metal Release Caused by Head-taper Fretting and Corrosion. PMID- 26956251 TI - Somatic mosaicism due to a reversion variant causing hemi-atrophy: a novel variant of dystrophinopathy. AB - We describe a case of hemi-atrophy in a young adult male, with a positive family history of three maternal uncles with Duchenne muscular dystrophy (DMD). The patient showed progressive weakness localized to the left side, an abnormal electromyography, and creatine kinase levels >3000 IU/l. Muscle biopsy showed both dystrophin-positive and -negative myofibers. An out-of-frame duplication variant in DMD, that is, c.(93+1_94-1)_(649+1_650-1)dup(p.?) resulting in duplication of exons 3-7 was inherited, but the muscle biopsy showed dystrophin mRNA with and without the duplication. Dystrophin quantification using mass spectrometry showed 25% normal dystrophin protein levels in the muscle biopsy from the stronger right side. Sex chromosome aneuploidy was ruled out. We conclude that the patient inherited the duplication variant, but early in development an inner cell mass underwent a somatic recombination event removing the duplication and restoring dystrophin expression. To our knowledge, this is the first report of a reversion leading to somatic mosaicism in DMD. PMID- 26956250 TI - The genomic architecture of NLRP7 is Alu rich and predisposes to disease associated large deletions. AB - NLRP7 is a major gene responsible for recurrent hydatidiform moles. Here, we report 11 novel NLRP7 protein truncating variants, of which five deletions of more than 1-kb. We analyzed the transcriptional consequences of four variants. We demonstrate that one large homozygous deletion removes NLRP7 transcription start site and results in the complete absence of its transcripts in a patient in good health besides her reproductive problem. This observation strengthens existing data on the requirement of NLRP7 only for female reproduction. We show that two other variants affecting the splice acceptor of exon 6 lead to its in-frame skipping while another variant affecting the splice donor site of exon 9 leads to an in-frame insertion of 54 amino acids. Our characterization of the deletion breakpoints demonstrated that most of the breakpoints occurred within Alu repeats and the deletions were most likely mediated by microhomology events. Our data define a hotspot of Alu instability and deletions in intron 5 with six different breakpoints and rearrangements. Analysis of NLRP7 genomic sequences for repetitive elements demonstrated that Alu repeats represent 48% of its intronic sequences and these repeats seem to have been inserted into the common NLRP2/7 primate ancestor before its duplication into two genes. PMID- 26956246 TI - Nociceptin/Orphanin FQ Receptor Structure, Signaling, Ligands, Functions, and Interactions with Opioid Systems. AB - The NOP receptor (nociceptin/orphanin FQ opioid peptide receptor) is the most recently discovered member of the opioid receptor family and, together with its endogenous ligand, N/OFQ, make up the fourth members of the opioid receptor and opioid peptide family. Because of its more recent discovery, an understanding of the cellular and behavioral actions induced by NOP receptor activation are less well developed than for the other members of the opioid receptor family. All of these factors are important because NOP receptor activation has a clear modulatory role on mu opioid receptor-mediated actions and thereby affects opioid analgesia, tolerance development, and reward. In addition to opioid modulatory actions, NOP receptor activation has important effects on motor function and other physiologic processes. This review discusses how NOP pharmacology intersects, contrasts, and interacts with the mu opioid receptor in terms of tertiary structure and mechanism of receptor activation; location of receptors in the central nervous system; mechanisms of desensitization and downregulation; cellular actions; intracellular signal transduction pathways; and behavioral actions with respect to analgesia, tolerance, dependence, and reward. This is followed by a discussion of the agonists and antagonists that have most contributed to our current knowledge. Because NOP receptors are highly expressed in brain and spinal cord and NOP receptor activation sometimes synergizes with mu receptor-mediated actions and sometimes opposes them, an understanding of NOP receptor pharmacology in the context of these interactions with the opioid receptors will be crucial to the development of novel therapeutics that engage the NOP receptor. PMID- 26956252 TI - Mayans: a Y chromosome perspective. AB - In spite of the wealth of available cultural and archeological information as well as general interest in the Mayans, little is known about their genetics. In this study, for the first time, we attempt to alleviate this lacuna of knowledge by comprehensively investigating the Y chromosome composition of contemporary Mayan populations throughout their domain. To accomplish this, five geographically targeted and ethnically distinct Mayan populations are investigated using Y-SNP and Y-STR markers. FINDINGS: overall, the Mayan populations as a group are highly homogeneous, basically made up of only two autochthonous haplogroups, Q1a2a1a1*-M3 and Q1a2a1*-L54. Although the Y-STR data illustrates diversity, this diversity, for the most part, is uniformly distributed among geographically distant Mayan populations. Similar haplotypes among populations, abundance of singletons and absence of population partitioning within networks among Mayan populations suggest recent population expansion and substantial gene flow within the Mayan dominion, possibly due to the development of agriculture, the establishment of interacting City-State systems and commerce. PMID- 26956254 TI - Supplementation during pregnancy: beliefs and science. AB - Pregnancy represents a challenge from a nutritional perspective, because micronutrient intake during the periconceptional period and in pregnancy affects fetal organ development and the mother's health. Inappropriate diet/nutrition in pregnancy can lead to numerous deficiencies including iron deficiency and may impair placental function and play a role in miscarriage, intrauterine growth restriction, preterm delivery, and preeclampsia. This article reviews the risks associated with nutrient deficiencies in pregnant women and presents an overview of recommendations for dietary supplementation in pregnancy, focusing on oral iron supplementation. Risk factor detection, including dietary patterns and comorbidities, is paramount in optimal pregnancy management. Dietary habits, which can lead to deficiencies (e.g., iron, folate, vitamin D, and calcium) and result in negative health consequences for the mother and fetus/newborn, need to be investigated. Prenatal care should be personalized, accounting for ethnicity, culture, education, information level about pregnancy, and dietary and physical habits. Clinicians should make a plan for appropriate supplementation and prophylaxis/treatment of nutritional and other needs, and consider adequate intake of calcium, iodine, vitamin D, folate, and iron. Among the available oral iron supplements, prolonged-released ferrous sulfate (ferrous sulfate-polymeric complex) presents the lowest incidence of overall and gastrointestinal adverse events, with positive implications for compliance. PMID- 26956253 TI - Mosaic CREBBP mutation causes overlapping clinical features of Rubinstein-Taybi and Filippi syndromes. AB - Rubinstein-Taybi syndrome (RTS, OMIM 180849) and Filippi syndrome (FLPIS, OMIM 272440) are both rare syndromes, with multiple congenital anomalies and intellectual deficit (MCA/ID). We present a patient with intellectual deficit, short stature, bilateral syndactyly of hands and feet, broad thumbs, ocular abnormalities, and dysmorphic facial features. These clinical features suggest both RTS and FLPIS. Initial DNA analysis of DNA isolated from blood did not identify variants to confirm either of these syndrome diagnoses. Whole-exome sequencing identified a homozygous variant in C9orf173, which was novel at the time of analysis. Further Sanger sequencing analysis of FLPIS cases tested negative for CKAP2L variants did not, however, reveal any further variants. Subsequent analysis using DNA isolated from buccal mucosa revealed a mosaic variant in CREBBP. This report highlights the importance of excluding mosaic variants in patients with a strong but atypical clinical presentation of a MCA/ID syndrome if no disease-causing variants can be detected in DNA isolated from blood samples. As the striking syndactyly observed in the present case is typical for FLPIS, we suggest CREBBP analysis in saliva samples for FLPIS syndrome cases in which no causal CKAP2L variant is detected. PMID- 26956255 TI - Effect of obesity and weight loss on ventricular repolarization: a systematic review and meta-analysis. AB - We performed a systematic review and meta-analysis of the effects of obesity +/- overweight and weight loss on the corrected QT interval (QTc) and QT or QTc dispersion (indices of ventricular repolarization). Mean difference for both QTc and QT or QTc dispersion with 95% confidence intervals (CIs) was calculated comparing obese +/- overweight subjects and normal weight controls and QTc and QT or QTc dispersion before and after weight loss from diet +/- exercise or bariatric surgery. A total of 22 studies fulfilled the selection criteria. Compared with normal weight controls, there was a significantly longer QTc in obese +/- overweight subjects (mean difference of 21.74 msec, 95% CI: 18.76 to 22.32) and significantly longer QT or QTc dispersion (mean difference of 15.17 msec, 95% CI: 13.59 to 16.74). Weight loss was associated with a significant decrease in QTc (mean difference -25.77 msec, 95% CI: -28.33-23.21) and QT or QTc dispersion (mean difference of -13.46 msec, 95% CI: -15.60 to -11.32 in obese +/- overweight subjects. Thus, obesity +/- overweight is associated with significant prolongation of QTc and QT or QTC dispersion. Weight loss in obese +/- overweight subjects produces significant decreases in these variables. (c) 2016 World Obesity. PMID- 26956256 TI - Alkaline Earth-Olefin Complexes with Secondary Interactions. AB - Strontium and calcium (alkaline earth: Ae) olefin complexes stabilised by secondary Ae???F-C and beta-agostic Ae???H-Si interactions are presented. Olefin coordination onto the alkaline earths is plain in the solid state, and it is thermodynamically favoured over the coordination of THF. The existence of the Ae???olefin interactions is corroborated by solution NMR data and DFT computations. The coordination mode of the olefin varies with steric effects and, if enforced, olefin dissociation can be compensated by the other non-covalent interactions, as supported by DFT computations. PMID- 26956257 TI - Outcome in Childhood Stroke. PMID- 26956259 TI - Impaired Arm Function and Finger Dexterity in a Nonhuman Primate Model of Stroke: Motor and Cognitive Assessments. AB - BACKGROUND AND PURPOSE: Ischemic stroke is the leading cause of upper extremity motor impairments. Although several well-characterized experimental stroke models exist, modeling of upper extremity motor impairments, which are unique to primates, is not well established. Cortical representation of dexterous movements in nonhuman primates is functionally and topographically similar to that in humans. In this study, we characterize the African green monkey model of focal ischemia reperfusion with a defined syndrome, impaired dexterous movements. METHODS: Cerebral ischemia was induced by transient occlusion of the M3 segment of the left middle cerebral artery. Motor and cognitive functions after stroke were evaluated using the object retrieval task with barrier-detour. Postmortem magnetic resonance imaging and histopathology were performed to map and characterize the infarct. RESULTS: The middle cerebral artery occlusion consistently produced a necrotic infarct localized in the sensorimotor cortex in the middle cerebral artery territory. The infarction was reproducible and resulted in significant loss of fine motor function characterized by impaired dexterity. No significant cognitive impairment was detected. Magnetic resonance imaging and histopathology demonstrated consistent and significant loss of tissue on the left parietal cortex by the central sulcus covering the sensorimotor area. The results suggest that this species has less collateralization, which closely resembles humans. CONCLUSIONS: The reported nonhuman primate model produces a defined and reproducible syndrome relevant to our understanding of ischemic stroke, cortical representation, and sensorimotor integration controlling dexterous movements. This model will be useful in basic and translational research addressing loss of arm function and dexterity. PMID- 26956258 TI - Association Between Time to Reperfusion and Outcome Is Primarily Driven by the Time From Imaging to Reperfusion. AB - BACKGROUND AND PURPOSE: A progressive decline in the odds of favorable outcome as time to reperfusion increases is well known. However, the impact of specific workflow intervals is not clear. METHODS: We studied the mechanical thrombectomy group (n=103) of the prospective, randomized REVASCAT (Randomized Trial of Revascularization With Solitaire FR Device Versus Best Medical Therapy in the Treatment of Acute Stroke due to Anterior Circulation Large Vessel Occlusion Presenting Within Eight Hours of Symptom Onset) trial. We defined 3 workflow metrics: time from symptom onset to reperfusion (OTR), time from symptom onset to computed tomography, and time from computed tomography (CT) to reperfusion. Clinical characteristics, core laboratory-evaluated Alberta Stroke Program Early CT Scores (ASPECTS) and 90-day outcome data were analyzed. The effect of time on favorable outcome (modified Rankin scale, 0-2) was described via adjusted odds ratios (ORs) for every 30-minute delay. RESULTS: Median admission National Institutes of Health Stroke Scale was 17.0 (14.0-20.0), reperfusion rate was 66%, and rate of favorable outcome was 43.7%. Mean (SD) workflow times were as follows: OTR: 342 (107) minute, onset to CT: 204 (93) minute, and CT to reperfusion: 138 (56) minute. Longer OTR time was associated with a reduced likelihood of good outcome (OR for 30-minute delay, 0.74; 95% confidence interval [CI], 0.59-0.93). The onset to CT time did not show a significant association with clinical outcome (OR, 0.87; 95% CI, 0.67-1.12), whereas the CT to reperfusion interval showed a negative association with favorable outcome (OR, 0.72; 95% CI, 0.54-0.95). A similar subgroup analysis according to admission ASPECTS showed this relationship for OTR time in ASPECTS<8 patients (OR, 0.56; 95% CI, 0.35-0.9) but not in ASPECTS>=8 (OR, 0.99; 95% CI, 0.68-1.44). CONCLUSIONS: Time to reperfusion is negatively associated with favorable outcome, being CT to reperfusion, as opposed to onset to CT, the main determinant of this association. In addition, OTR was strongly associated to outcome in patients with low ASPECTS scores but not in patients with high ASPECTS scores. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01692379. PMID- 26956261 TI - Aphasia 1 Week After Carotid Endarterectomy: Hypoperfusion or Hyperperfusion? PMID- 26956262 TI - Erratum to: The optimal regimen of bevacizumab for recurrent glioblastoma: does dose matter? PMID- 26956260 TI - Fibroblast Growth Factor 23 Is Associated With Subclinical Cerebrovascular Damage: The Northern Manhattan Study. AB - BACKGROUND AND PURPOSE: Elevated fibroblast growth factor 23 (FGF23) regulates phosphate homeostasis and is linked with mortality, cardiovascular events, and stroke. However, the role of FGF23 as a risk factor for subclinical cerebrovascular damage is unclear. METHODS: We used multivariable linear and logistic regression to evaluate associations between FGF23, continuously and by quartiles, with white matter hyperintensity volume, expressed as percent intracranial volume (%ICV), and subclinical brain infarction (SBI) in a community based stroke-free sample. RESULTS: There were 1170 stroke-free Northern Manhattan Study (NOMAS) participants with FGF23 levels and quantitative magnetic resonance imaging data on white matter hyperintensity volume and SBI. Participants with FGF23 levels in the top quartile (range=85-1425 RU/mL) had greater white matter hyperintensity volume (beta=0.19 %ICV; 95% CI, 0.04-0.33 %ICV; P=0.01) compared with those in the lowest quartile (range=15-49 RU/mL), adjusted for demographics, vascular risk factors, and estimated glomerular filtration rate. These findings remained significant in those without evidence of chronic kidney disease (estimated glomerular filtration rate <60 mL/min per 1.73 m(2)). Elevated FGF23 was not associated with SBI overall after adjusting for demographic factors and estimated glomerular filtration rate, but sex modified the effect of FGF23 on odds of SBI (P for interaction=0.03). FGF23 was associated with significantly greater odds of SBI only in men (odds ratio, 1.7; 95% CI, 1.1-2.7; P=0.03) after full adjustment. CONCLUSIONS: These cross-sectional community-based data from a diverse urban sample show an association between elevated FGF23 and small vessel disease and magnetic resonance imaging-defined brain infarction in men, independent of chronic kidney disease. Data on elevated FGF23 and subclinical cerebrovascular damage progression are needed. PMID- 26956264 TI - The performance of silicon photomultipliers in Cherenkov TOF PET. PMID- 26956265 TI - Measurement of the point spread function of a pixelated detector array. PMID- 26956263 TI - Preservation of KIT genotype in a novel pair of patient-derived orthotopic xenograft mouse models of metastatic pediatric CNS germinoma. AB - Metastatic intracranial germinoma is difficult to treat. Although the proto oncogene KIT is recognized as one of the most frequent genetic abnormalities in CNS germinoma, the development of new target therapeutic agents for CNS germinoma is hampered by the lack of clinically-relevant animal models that replicate the mutated or over-expressed KIT. CNS germinoma tumor cells from five pediatric patients were directly implanted into the brains of Rag2/severe combined immune deficiency mice. Once established, the xenograft tumors were sub-transplanted in vivo in mouse brains. Characterization of xenograft tumors were performed through histologic and immunohistochemical staining, and KIT mutation analysed with quantitative pyro-sequencing. Expression of putative cancer stem cell markers (CD133, CD15, CD24, CD44, CD49f) was analyzed through flow cytometry. Two patient derived orthotopic xenograft (PDOX) models (IC-6999GCT and IC-9302GCT) were established from metastatic germinoma and serially sub-transplanted five times in mouse brains. Similar to the original patient tumors, they both exhibited faint expression (+) of PLAP, no expression (-) of beta-HCG and strong (+++) expression of KIT. KIT mutation (D816H), however, was only found in IC-9320GCT. This mutation was maintained during the five in vivo tumor passages with an increased mutant allele frequency compared to the patient tumor. Expression of putative cancer stem cell markers CD49f and CD15 was also detected in a small population of tumor cells in both models. This new pair of PDOX models replicated the key biological features of pediatric intracranial germinoma and should facilitate the biological and pre-clinical studies for metastatic intracranial germinomas. PMID- 26956266 TI - A novel method for gamma photons depth of interaction discrimination on monolithic LYSO crystals for brain PET/MRI. PMID- 26956267 TI - A practical depth-of-interaction PET/MR detector with dichotomous-orthogonal symmetry decoding. PMID- 26956245 TI - Endothelin. AB - The endothelins comprise three structurally similar 21-amino acid peptides. Endothelin-1 and -2 activate two G-protein coupled receptors, ETA and ETB, with equal affinity, whereas endothelin-3 has a lower affinity for the ETA subtype. Genes encoding the peptides are present only among vertebrates. The ligand receptor signaling pathway is a vertebrate innovation and may reflect the evolution of endothelin-1 as the most potent vasoconstrictor in the human cardiovascular system with remarkably long lasting action. Highly selective peptide ETA and ETB antagonists and ETB agonists together with radiolabeled analogs have accurately delineated endothelin pharmacology in humans and animal models, although surprisingly no ETA agonist has been discovered. ET antagonists (bosentan, ambrisentan) have revolutionized the treatment of pulmonary arterial hypertension, with the next generation of antagonists exhibiting improved efficacy (macitentan). Clinical trials continue to explore new applications, particularly in renal failure and for reducing proteinuria in diabetic nephropathy. Translational studies suggest a potential benefit of ETB agonists in chemotherapy and neuroprotection. However, demonstrating clinical efficacy of combined inhibitors of the endothelin converting enzyme and neutral endopeptidase has proved elusive. Over 28 genetic modifications have been made to the ET system in mice through global or cell-specific knockouts, knock ins, or alterations in gene expression of endothelin ligands or their target receptors. These studies have identified key roles for the endothelin isoforms and new therapeutic targets in development, fluid-electrolyte homeostasis, and cardiovascular and neuronal function. For the future, novel pharmacological strategies are emerging via small molecule epigenetic modulators, biologicals such as ETB monoclonal antibodies and the potential of signaling pathway biased agonists and antagonists. PMID- 26956268 TI - Evaluation of algorithms for photon depth of interaction estimation for the TRIMAGE PET component. PMID- 26956269 TI - Evaluation of DC/DC switching power regulation with small-scale integrated inductors for PET/MR. PMID- 26956270 TI - The SAFIR project: an innovative high rate preclinical PET/MR detector towards dynamic multimodal imaging. PMID- 26956272 TI - Successful demonstration of simultaneous PET/MR Imaging with a RF-penetrable PET insert. PMID- 26956271 TI - Small animal PET based on 16x16 TSV-MPPCs and monolithic crystals. PMID- 26956273 TI - Imaging performance of a full-ring prototype PET-MRI system based on four-layer DOI-PET detectors integrated with a RF coil. PMID- 26956274 TI - A single-mode data acquisition architecture for PET/MRI. PMID- 26956276 TI - Imaging the attenuation coefficients of positron beams in matter: positron attenuation tomography. PMID- 26956275 TI - Development of compact DOI-measurable PET detectors for simultaneous PET/MR Imaging. PMID- 26956277 TI - Development of a PET Insert for simultaneously small animal PET/MRI. PMID- 26956278 TI - Long-term stability of the MR system of the Philips Ingenuity TF. PMID- 26956279 TI - Geometric optimization of an ultralow-dose high-resolution pediatric PET scanner based on monolithic scintillators with dSiPM readout. PMID- 26956280 TI - Respiratory Motion Compensation for Simultaneous PET/MR based on strongly undersampled radial MR data. PMID- 26956281 TI - Improved parameter-estimation with combined PET-MRI kinetic modelling. PMID- 26956282 TI - Tissue probability-based AC for neurological PET/MR using SPM8. PMID- 26956283 TI - Automatic derivation of an MR-PET image-based input function for quantification of 18F-FET. PMID- 26956284 TI - Cross calibration of the Siemens mMR: easily acquired accurate PET phantom measurements, long term stability and reproducibility. PMID- 26956285 TI - Pseudo-CT generation in brain MR-PET attenuation correction: comparison of several multi-atlas methods. PMID- 26956286 TI - SPAD array chips with full frame readout for crystal characterization. PMID- 26956287 TI - Simultaneous reconstruction of attenuation and activity for non-TOF PET/MR using MR prior information. PMID- 26956288 TI - CT synthesis in the head & neck region for PET/MR attenuation correction: an iterative multi-atlas approach. PMID- 26956289 TI - A multi-modal fusion scheme for the enhancement of PET/MR viewing. PMID- 26956290 TI - Simultaneous reconstruction of attenuation and activity in ToF PET/MRI with additional transmission data. PMID- 26956291 TI - Do carotid MR surface coils affect PET quantification in PET/MR imaging? PMID- 26956292 TI - Multi-modality image reconstruction for dual-head small-animal PET. PMID- 26956294 TI - Ultra fast, accurate PET image reconstruction for the Siemens hybrid MR/BrainPET scanner using raw LOR data. PMID- 26956293 TI - A theoretical comparison of position estimation methods for determining the interaction position of gamma rays in monolithic scintillators. PMID- 26956295 TI - Attenuation correction for hybrid MR/PET scanners: a comparison study. PMID- 26956296 TI - PET/MR attenuation correction in brain imaging using a continuous bone signal derived from UTE. PMID- 26956297 TI - Development of an MR-compatible DOI-PET detector module. PMID- 26956298 TI - Alternating-direction method of multipliers estimation of attenuation and activity distributions in time-of-flight flat-panel positron emission tomography. PMID- 26956299 TI - Comparison of different tube-of-response (TOR) models for resolution recovery in PET image reconstruction for the Philips Ingenuity TF PET/MR. PMID- 26956300 TI - Rapid workflow of mMR PET list-mode data processing using CUDA. PMID- 26956301 TI - Respiratory and cardiac motion correction in dual gated PET/MR imaging. PMID- 26956302 TI - Establishment of an open database of realistic simulated data for evaluation of partial volume correction techniques in brain PET/MR. PMID- 26956303 TI - Validation of a simultaneous PET/MR system model for PET simulation using GATE. PMID- 26956304 TI - Assessment of the quality of brain regions and neuroimaging metrics as biomarkers of Alzheimer's Disease. PMID- 26956305 TI - Evaluation of a partial ring design for the INSERT SPECT/MRI system. PMID- 26956306 TI - MRC-SPECT-DF: an MR-Compatible SPECT system with Dual-FOV collimation design for microscopic SPECT imaging. PMID- 26956307 TI - SiPM-MAROC gamma-camera prototype with monolithic NaI(Tl) scintillator. PMID- 26956308 TI - 3D photon impact determination in monolithic crystals based on autocorrelation filters and RTP methods. PMID- 26956309 TI - Measuring the mutual effects between a CZT detector and MRI for the development of a simultaneous MBI/MRI insert. PMID- 26956310 TI - Analysis and reduction of eddy current effects induced by tesseral end zonal gradient coils in different collimator geometries for SPECT/MRI integration. PMID- 26956311 TI - Compatibility of metal additive manufactured tungsten collimator for SPECT/MRI integration. PMID- 26956312 TI - Lymph node imaging using novel simultaneous PET/MRI and dual-modality imaging agent. PMID- 26956314 TI - Evaluation of PET performance and MR compatibility of a preclinical PET/MR insert with digital silicon photomultiplier technology. PMID- 26956313 TI - First results from a high-resolution small animal PET insert for PET/MRI imaging. PMID- 26956315 TI - Initial reconstruction results from a simulated adaptive small animal C shaped PET/MR insert. PMID- 26956316 TI - Monte Carlo study of scattered and random coincidences for MADPET-4. PMID- 26956318 TI - Measuring cardiac efficiency using PET/MRI. PMID- 26956317 TI - PET/MR: improvement of the UTE MU-maps using modified MLAA. PMID- 26956319 TI - Evaluation of large-area, low-noise, arrays of SiPMs. PMID- 26956320 TI - Dynamic brain PET/MR using TOF reconstruction. PMID- 26956321 TI - Congruency of tumour volume delineated by FET PET and MRSI. PMID- 26956322 TI - Image artifacts from MR-based attenuation correction in dedicated PET/MR breast coil for PET/MR mammography. PMID- 26956323 TI - Dedicated brain PET system of PET/MR for brain research. PMID- 26956324 TI - Whole-body simultaneous time-of-flight PET-MRI: early experience with clinical studies. PMID- 26956325 TI - Imaging patients with breast and prostate cancers using combined 18F NaF/18F FDG and TOF simultaneous PET/ MRI. PMID- 26956326 TI - Simultaneous functional imaging using fPET and fMRI. PMID- 26956327 TI - Stability of MR brain-perfusion measurement using arterial spin labeling. PMID- 26956328 TI - Impact of atlas-CT-based bone anatomy compensation on MR-based attenuation correction for brain PET imaging in a time-of-flight PET/MRI system: A direct comparison to a patient-CT-based approach. PMID- 26956329 TI - Assess PET/MR in diagnosis of disease in comparison with PET/CT. PMID- 26956330 TI - A compact PET detector module using SiPMs and MVT digitizers. PMID- 26956331 TI - Simultaneous acquisition of dynamic PET-MRI: arterial input function using DSC MRI and [18F]-FET. PMID- 26956332 TI - Simultaneous trimodal MR-PET-EEG imaging for the investigation of resting state networks in humans. PMID- 26956333 TI - Resolution improvement of brain PET images using prior information from MRI: clinical application on refractory epilepsy. PMID- 26956334 TI - Assessment of PET & ASL metabolism in the hippocampal subfields of MCI and AD using simultaneous PET-MR. PMID- 26956335 TI - Quantitative impact of Dixon MUmap variability in dual-time-point brain PET/MR. PMID- 26956336 TI - Brain connectivity study of brain tumor patients using MR-PET data: preliminary results. PMID- 26956337 TI - Clinical evaluation of PET image quality as a function of acquisition time in a new TOF-PET/MR compared to TOF-PET/CT - initial results. PMID- 26956338 TI - The potential of TOF PET-MRI for reducing artifacts in PET images. PMID- 26956339 TI - A close link between metabolic activity and functional connectivity in the resting human brain. PMID- 26956340 TI - Determination of position and shape of flexible mri surface coils using the Microsoft Kinect for attenuation correction in PET/MRI. PMID- 26956341 TI - Performance evaluation of two SiPMs arrays coupled to pixelated scintillations for PET/MR applications. PMID- 26956342 TI - Preliminary evaluation of MRI-derived input function for quantitative measurement of glucose metabolism in an integrated PET-MRI. PMID- 26956343 TI - Epileptogenic focus localization: a new approach. PMID- 26956344 TI - Corticospinal MRI tractography in space-occupying brain lesions by diffusion tensor and kurtosis imaging methods. PMID- 26956345 TI - Correlation between arterial spin labeling MRI and dynamic FDG on PET-MR in Alzheimer's disease and non-Alzhiemer's disease patients. PMID- 26956346 TI - [18F]FDG PET/MRI of patients with chronic pain alters management: early experience. PMID- 26956347 TI - Authentically radiolabelled Mn(II) complexes as bimodal PET/MR tracers. PMID- 26956348 TI - First results with SiPM tiles for TOF PET based on FBK RGB-HD technology. PMID- 26956349 TI - PET/MR and SPECT/MR multimodal imaging constructs: Direct radiolabelling of silica shell iron oxide nanorods for use in liver imaging and potential for hyperthermia therapy. PMID- 26956350 TI - New nontoxic double information magnetic and fluorescent MRI agent. PMID- 26956351 TI - Initial in vitro and in vivo assessment of Au@DTDTPA-RGD nanoparticles for Gd-MRI and 68Ga-PET dual modality imaging. PMID- 26956352 TI - Evaluation of a SiPM array detector coupled to a LFS-3 pixellated scintillator for PET/MR applications. PMID- 26956353 TI - Biocompatible branched copolymer nanoparticles prepared by RAFT polymerization as MRI/PET bimodal tracers. PMID- 26956355 TI - Systematic review of red yeast rice compared with simvastatin in dyslipidaemia. AB - WHAT IS KNOWN AND OBJECTIVE: Red yeast rice is believed to be a useful alternative in the management of dyslipidaemia. However, the comparative effectiveness of red yeast rice and simvastatin for the management of dyslipidaemia is unknown. This review assesses the efficacy and safety of red yeast rice versus simvastatin in dyslipidaemia. METHODS: Electronic databases were searched up to May 2015 without publication date and language restriction. The Cochrane Risk of Bias Assessment Tool was used to assess the quality of included trials. Changes in total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides were examined. RESULTS AND DISCUSSION: Ten randomized controlled trials involving 905 Chinese subjects with dyslipidaemia were systematically reviewed. Overall, red yeast rice and simvastatin did not show any statistically significant difference in any of the outcomes examined. WHAT IS NEW AND CONCLUSION: A number of small trials show that red yeast rice and simvastatin produce similar lipid-lowering effects. Larger trials with increased methodological rigour and trials with clinical outcomes are necessary for more robust inferences. PMID- 26956354 TI - Evidence of selection signatures that shape the Persian cat breed. AB - The Persian cat is mainly characterized by an extremely brachycephalic face as part of the standard body conformation. Despite the popularity, world-wide distribution, and economic importance of the Persian cat as a fancy breed, little is known about the genetics of their hallmark morphology, brachycephaly. Over 800 cats from different breeds including Persian, non-Persian breeds (Abyssinian, Cornish Rex, Bengal, La Perm, Norwegian Forest, Maine Coon, Manx, Oriental, and Siamese), and Persian-derived breeds (British Shorthair, Scottish Fold, Selkirk Rex) were genotyped with the Illumina 63 K feline DNA array. The experimental strategy was composed of three main steps: (i) the Persian dataset was screened for runs of homozygosity to find and select highly homozygous regions; (ii) selected Persian homozygous regions were evaluated for the difference of homozygosity between Persians and those considered non-Persian breeds, and, (iii) the Persian homozygous regions most divergent from the non-Persian breeds were investigated by haplotype analysis in the Persian-derived breeds. Four regions with high homozygosity (H > 0.7) were detected, each with an average length of 1 Mb. Three regions can be considered unique to the Persian breed, with a less conservative haplotype pattern in the Persian-derived breeds. Moreover, two genes, CHL1 and CNTN6 known to determine face shape modification in humans, reside in one of the identified regions and therefore are positional candidates for the brachycephalic face in Persians. In total, the homozygous regions contained several neuronal genes that could be involved in the Persian cat behavior and can provide new insights into cat domestication. PMID- 26956356 TI - Concerns and Structural Barriers Associated with WIC Participation among WIC Eligible Women. AB - OBJECTIVES: To examine sociodemographic status, psychosocial concerns, and structural barriers associated with women's participation in the USDA's Women, Infants, and Children (WIC) program among those eligible for the program. DESIGN AND SAMPLE: A total of 1,634 White, African-American, Hispanic, and Asian/Pacific Islander (A/PI) women from the New York City area completed the Pregnancy Risk Assessment Monitoring System (PRAMS) from 2004 to 2007, a population-based survey. MEASURES: Data on WIC eligibility and participation, sociodemographic details, unintended pregnancy, social support, and structural barriers were evaluated. RESULTS: Hispanics and Blacks were 4.1 and 2.4 times more likely to participate, respectively, in the WIC program relative to Whites. Mothers reporting unplanned pregnancies, fewer social supports, and more structural barriers (e.g., transportation) were less likely to participate in WIC. Race stratified analyses revealed race/ethnic differences in the pattern of barriers; unintended pregnancy and structural problems were barriers associated with WIC participation particularly for A/PI. CONCLUSIONS: WIC-eligible women with unintended pregnancies and fewer social supports tend to participate in WIC, but those who experience more structural barriers are less likely to participate. A/PI women may face specific challenges to WIC participation. Careful attention is needed to understand the unique attitudes and behaviors in the process of participating in WIC. PMID- 26956357 TI - Effect of insulin supplementation on in vitro maturation of pre-antral follicles from adult and pre-pubertal mice. AB - This study was aimed to determine the impact of insulin concentrations on in vitro pre-antral follicle growth, survival, antrum formation rate, and retrieval of mature oocytes in mice. Mice pre-antral follicle growth were recorded on days 2, 4, 6, 8, 10, and 12 in alpha-modified essential media (alpha-MEM) supplemented with insulin concentrations of 6, 8, and 10 MUg/ml along with 10% FBS, 100 mIU/ml follicle stimulating hormone, 10 mIU/ml luteinizing hormone, 100 MUg/ml penicillin, and 50 MUg/ml streptomycin. After 12 d of growth in vitro, follicles were allowed to mature for 16-18 h in alpha-MEM supplemented with 1.5 IU/ml human chorionic gonadotrophin (hCG) and 5 ng/ml epidermal growth factor (EGF). The initial diameter (54.86 +/- 2.5 MUm) of mice oocyte progressively increased in all the three insulin concentration groups and attained a maximum size on day 12 (71.90 +/- 2.8 MUm). Supplementation with higher concentrations of insulin (both 8 and 10 MUg/ml) significantly enhanced antrum formation without effecting the oocyte diameter and percent retrieval of mature oocyte in all the three concentration groups. Both in vitro cultured as well as in vivo collected follicles and oocytes showed similar localization and expression of oocyte maturation markers SAS1B and GDF9. Insulin concentration of 8 MUg/ml was found to be optimal for in vitro follicle culture of adult mice (42-49 d). Optimized follicle culture conditions were also assessed successfully with pre-pubertal mice (12-14 d); however, adult mice showed higher follicle survival, antrum formation, and more mature oocytes production in comparison to pre-pubertal mice. PMID- 26956358 TI - IGF-2/IGF-1R signaling has distinct effects on Sox1, Irx3, and Six3 expressions during ES cell derived-neuroectoderm development in vitro. AB - Insulin-like growth factors (IGFs) are involved in growth and tissue development, including diseases such as type-2 diabetes and cancers. However, their roles in lineage specification, especially in early mammalian neural development, are poorly understood. Here, we analyzed the protein expression of IGF-2 in early mouse embryo, and it was preferentially detected in anterior mesodermal tissue, adjacent to the neural plate. We utilized a self-organizing neural tissue culture system and analyzed the direct effect of IGF-2 on the general neural marker Sox1. Interestingly, using recombinant IGF-2 and a chemical inhibitor of its receptor (IGF-1R), we found that the IGF-2/IGF-1R pathway positively regulated Sox1 expression in embryonic stem (ES) cell-derived neural tissue. Furthermore, to visualize the expression patterns of other neural markers, we used reporter ES cell lines and we found that the IGF-2/IGF-1R signaling upregulated the expression of the posterior neural marker Irx3. In contrast, the anterior neural marker Six3 was downregulated by IGF-2/IGF-1R signaling. Together, our results demonstrate that IGF-2/IGF-1R signaling has different effects on neural marker expression, which may influence the early regional identity of ES cell-derived neural tissues. PMID- 26956359 TI - Comparison of vitrified outcomes between human early blastocysts and expanded blastocysts. AB - We compared the vitrified outcomes between early and expanded blastocysts with or without laser drilling. The grade III embryos from the patients undergoing in vitro fertilization-embryo transfer (IVF-ET) in our reproductive center from September 2009 to February 2015 were incubated into early blastocysts and expanded blastocysts. The early blastocysts and expanded blastocysts were, respectively, divided into laser group (vitrification after laser drilling), non laser group (direct vitrification), and control group (fresh non-vitrified blastocysts). After thawing, the blastular anabiosis rate, expansion rate, hatching rate, and apoptosis were observed in each group and then were compared amongst groups. This study indicated that the blastular expansion rate (all P < 0.01) and hatching rate (all P < 0.01) were significantly lower, but the blastular apoptosis (all P < 0.05) was significantly higher in both laser and non laser groups than in the control group in the early blastocysts. In the expanded blastocysts, the blastular anabiosis rate was significantly higher in the laser group than in the non-laser group (P < 0.01), and the blastular expansion rate was significantly higher, but the blastular apoptosis was significantly lower in both laser group and control group than in the non-laser group (all P < 0.05). The blastular expansion rate (all P < 0.01) and hatching rate (all P < 0.01) were significantly higher, but the blastular apoptosis (all P < 0.05) was significantly lower in the expanded laser group than in both early laser and early non-laser groups. We conclude that vitrification for laser-drilling expanded blastocysts can achieve the best outcomes. PMID- 26956360 TI - Pedobacter humicola sp. nov., a member of the genus Pedobacter isolated from soil. AB - An aerobic, Gram-stain-negative, oxidase-negative, catalase-positive, non-motile, non-spore-forming, rod-shaped, light pink-pigmented bacterium, designated strain R135T, was isolated from soil in Hwaseong, South Korea. Flexirubin-type pigments were absent. Phylogenetic analysis based on the 16S rRNA gene sequence revealed that strain R135T formed a lineage within the family Sphingobacteriaceae of the phylum Bacteroidetes. It was distinct from various species of the genus Pedobacter, including P. terrae DS-57T (98.13 % sequence similarity), P. alluvionis NWER-II11T (97.76 %), P. suwonensis 15-52T (97.71 %), P. kyungheensis KACC 16221T (97.37 %), P. roseus CG-GP80T (97.24 %), P. soli 15-51T (97.23 %) and P. sandarakinus DS-27T (97.09 %). The major isoprenoid quinone was menaquinone-7 (MK-7), and the major polar lipid was phosphatidylethanolamine. The major cellular fatty acids were summed feature 3 (C16 : 1omega7c and/or C16 : 1omega6c), iso-C15 : 0, iso-C17 : 0 3-OH and C16 : 0. The DNA G+C content of strain R135T was 40.4 mol%. Levels of DNA-DNA hybridization similarities between strain R135Tand other members of the genus Pedobacter ranged from 25 % to 43 %. On the basis of phenotypic, genotypic and phylogenetic analysis, strain R135T represents a novel species of the genus Pedobacter, for which the name Pedobacter humicola sp. nov. is proposed. The type strain is R135T (=KEMB 9005-332T=KACC 18452T=JCM 31010T). PMID- 26956361 TI - A comparison of two endoscopic closures: over-the-scope clip (OTSC) versus KING closure (endoloop + clips) in a randomized long-term experimental study. AB - BACKGROUND: Both over-the-scope clip (OTSC) and KING (endoloop + clips) closures provide reliable and safe full-thickness endoscopic closure. Nevertheless, OTSC clip demonstrated significantly inferior histological healing in the short-term follow-up. AIM: To compare OTSC versus KING closure of a perforation with regard to long-term effectiveness and macroscopic and histological quality of healing. METHODS: We performed a randomized experimental study with 16 mini-pigs (mean weight 43.2 +/- 11.2 kg). A standardized perforation was performed on the anterior sigmoid wall. KING closure (n = 8) was attained by approximation of an endoloop fixed to the margins of a perforation with endoclips. OTSC closure (n = 8) was performed by deploying OTSC (OVESCO) over the defect. Pigs underwent a control sigmoidoscopy 8 months after the closure to assess the macroscopic quality of healing. Then, autopsy was performed and the rectosigmoid was sent for histopathological assessment. RESULTS: All closures were completed successfully without air leaks. The duration of closure was similar in both techniques (OTSC 17.8 +/- 7.6 min vs. KING 19.6 +/- 8.8 min). At autopsy, all KING closures (100 %) were healed with a flat scar without signs of leakage. Microscopically, no inflammatory changes were observed after KING closure. In the OTSC group, microscopic ulcers were present in two pigs (25 %), cryptal abscesses in three pigs (38 %) and significant neutrophil accumulation in all eight pigs (P < 0.01). Giant cell granulomas, dysplasia or abundant scarification was not observed in either group. CONCLUSIONS: Both OTSC and KING closures offer a long-term reliable seal of a gastrointestinal perforation without stenosis or fistulas. KING closure provides long-term histologically superior healing. PMID- 26956362 TI - IMPLEMENTATION OF HEALTH TECHNOLOGY ASSESSMENT WORK IN A HOSPITAL IN KAZAKHSTAN. AB - OBJECTIVES: The aim of this study was to implement health technology assessment (HA) in the First General City Hospital in Astana, Kazakhstan. METHODS: We organized trainings to familiarize hospital staff with the purpose and details of HTA. An HTA committee was established, with representation from hospital physicians and managers, and criteria for prioritization of health technologies determined. Clinical departments of the hospital were asked to prepare applications for new technologies for their services. RESULTS: The HTA committee reviewed five applications and selected a technology from one of these, on single incision laparoscopic surgery (SILS), for assessment. A short HTA report on SILS was prepared, covering its safety, clinical effectiveness, and cost effectiveness. The report was used to support a request to the Department of Health for additional funding to implement this technology within the hospital. This funding was approved and SILS was established in several hospital departments. CONCLUSIONS: This successful initial experience with HTA has paved the way for its routine use by the hospital for informing decisions on the procurement and use of new health technologies. PMID- 26956363 TI - The effect of calcitriol on high mobility group box 1 expression in periodontal ligament cells during orthodontic tooth movement in rats. AB - High mobility group box 1 (HMGB1) is a late inflammatory cytokine that plays an important role in periodontal tissue remodeling during orthodontic tooth movement. Calcitriol (1,25-dihydroxyvitamin D3 [1alpha,25 (OH)2D3]) is a systemic calcium-regulating hormone shown to downregulate expression of multiple proinflammatory cytokines in human periodontal ligament cells in response to orthodontic force. The purpose of this study was to investigate the effect of 1alpha,25(OH)2D3 on the expression of HMGB1 in periodontal ligament (PDL) cells during orthodontic tooth movement. Seven-week-old male Wistar rats were used for experimentation. Tooth movement was assessed using a nickel-titanium coil spring to apply mechanical loading to the tooth for 5 days. This was followed by administration of either 1alpha,25(OH)2D3 or normal saline by gavage every other day for up to 28 days. Immunohistochemistry was used to analyze the expression of tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-6 and HMGB1. After discontinuation of orthodontic force, expression of the early inflammatory cytokines IL-6 and TNF-alpha were time-dependently reduced in the 1alpha,25(OH)2D3 group compared with the control group at each time point. Similarly, expression of HMGB1 was decreased over time in both the 1alpha,25(OH)2D3 and normal saline groups, and 1alpha,25(OH)2D3 administration enhanced this decline. These findings indicate that administration of 1alpha,25(OH)2D3 might provide a favorable microenvironment for orthodontic tooth movement by downregulating expression of HMGB1 in PDL cells. PMID- 26956364 TI - Chondrogenic cells respond to partial-thickness defects of articular cartilage in adult rats: an in vivo study. AB - The purpose of this study was to establish a partial-thickness articular cartilage defects model in adult rats and explore the respond of chondrogenic cells to the cartilage injury. Forty-five adult Sprague-Dawley rats were divided into operated group, sham-operated group and control group. Partial-thickness cartilage defects were created on the weight-bearing region of femoral condyles by a converted ophthalmic knife. Rats were exposed to 5-bromo-2'-deoxyuridine (BrdU) for five consecutive days and were sacrificed 1, 2 and 4 weeks after surgery. Evaluations of macroscopic and histological changes were made. Chondrocyte apoptosis was evaluated by TUNEL assay. Immunofluorescence staining of CD105 and BrdU, double staining of CD105/integrin alpha5beta1 and CD105 positive cells counting were performed for evaluations of cells around the defects. Cartilage softening and fibrillation with chondrocyte apoptosis were observed around the injury site after surgery. Results of histological scores indicated no significant difference between one time point and a successive time point for either group. CD105-positive cells and BrdU-label-retaining cells were observed around the linear injury. And cells counting showed the number of CD105 positive cells increased at later time points (P < 0.05). Immunofluorescence double staining demonstrated co-localization of CD105 and integrin alpha5beta1 in activated cells around the defects. We establish a partial-thickness cartilage defects model in adult rats and demonstrate this injury may lead to activation of putative progenitor cells. In addition, the activated cells express integrin alpha5beta1 specially, which may help in early discovery of osteoarthritis. PMID- 26956366 TI - Selection of promising sweet potato clones using projective mapping. AB - BACKGROUND: Increasing demand for sweet potato in regions with temperate climates has triggered interest in the development of new cultivars. Breeding of this crop should consider sensory characteristics in order to meet consumers' expectations. This requires the application of simple and cost-effective methodologies that allow quality evaluation from a sensory perspective. RESULTS: With the objective of identifying the key sensory characteristics of different sweet potato genotypes, two commercial cultivars and seven clones were evaluated during three consecutive years using projective mapping by an untrained consumer panel. This methodology allowed the discrimination of the genotypes, identifying similarities and differences among groups based on sensory terms selected by the assessors. Genotypes were differentiated in terms of texture and flavor characteristics (firmness, moisture, smoothness, creaminess, flavor intensity, sweetness and bitterness). Materials for future crossings were identified. CONCLUSIONS: The evaluation of the sensory characteristics of sweet potato clones and cultivars using projective mapping is a quick, cost-effective and reliable tool for the selection of new advanced sweet potato clones with superior sensory characteristics compared to the reference cultivars INIA Arapey and Cuari. (c) 2016 Society of Chemical Industry. PMID- 26956365 TI - Interferon-gamma increased epithelial barrier function via upregulating claudin-7 expression in human submandibular gland duct epithelium. AB - Tight junctions (TJs) are necessary for salivary gland function and may serve as indicators of salivary gland epithelial dysfunction. IgG4-related disease (IgG4 RD) is a newly recognized fibro-inflammatory condition which disrupts the TJ associated epithelial barrier. The salivary glands are one of the most frequently involved organs in IgG4-RD, however, changes of the TJ associated epithelial barrier in salivary gland duct epithelium is poorly understood. Here, we investigated the regulation and function of TJs in human submandibular gland ductal epithelial cells (HSDECs) in normal and IgG4-RD. We examined submandibular gland (SMG) tissue from eight control individuals and 22 patients with IgG4-RD and established an HSDEC culture system. Immunohistochemistry, immunocytochemistry, western blotting, and measurement of transepithelial electrical resistance (TER) were performed. Claudin-4, claudin-7, occludin, and JAM-A were expressed at the apical side of the duct epithelium in submandibular gland (SMG) tissue and at the cell borders in HSDECs of normal and IgG4-RD. The expression and distribution of TJs in SMG tissue were not different in control individuals and patients with IgG4-RD in vivo and in vitro. Although interferon gamma (IFNgamma) generally disrupts the integrity and function of TJs, as manifested by decreased epithelial barrier function, IFNgamma markedly increased the epithelial barrier function of HSDECs via upregulation of claudin-7 expression in HSDECs from patients with IgG4-RD. This is the first report showing an IFNgamma-dependent increase in epithelial barrier function in the salivary gland duct epithelium. Our results provide insights into the functional significance of TJs in salivary gland duct epithelium in physiological and pathological conditions, including IgG4-RD. PMID- 26956368 TI - Charge transfer complexes of fullerenes containing C60- and C70- radical anions with paramagnetic Co(II)(dppe)2Cl+ cations (dppe: 1,2 bis(diphenylphosphino)ethane). AB - The reduction of Co(II)(dppe)Cl2 with sodium fluorenone ketyl produces a red solution containing the Co(I) species. The dissolution of C60 in the obtained solution followed by the precipitation of crystals with hexane yields a salt {Co(I)(dppe)2(+)}(C60(-)).2C6H4Cl2 and a novel complex {Co(dppe)2Cl}(C60) (). With C70, only the crystals of {Co(dppe)2Cl}(C70).0.5C6H4Cl2 () are formed. Complex contains zig-zag fullerene chains whereas closely packed double chains are formed from fullerenes in . According to the optical spectra and magnetic data charge transfer occurs in both and with the formation of the Co(II)(dppe)2Cl(+) cations and the C60(-) or C70(-) radical anions. In spite of the close packing in crystals, C60(-) or C70(-) retain their monomeric form at least down to 100 K. The effective magnetic moments of and of 1.98 and 2.27MUB at 300 K, respectively, do not attain the value of 2.45MUB expected for the system with two non-interacting S = 1/2 spins at full charge transfer to fullerenes. Most probably diamagnetic {Co(I)(dppe)2Cl}(0) and neutral fullerenes are partially preserved in the samples which can explain the weak magnetic coupling of spins and the absence of fullerene dimerization in both complexes. The EPR spectra of and show asymmetric signals approximated by several lines with g factors ranging from 2.0009 to 2.3325. These signals originate from the exchange interaction between the paramagnetic Co(II)(dppe)2Cl(+) cations and the fullerene(-) radical anions. PMID- 26956367 TI - Characteristics and risk factors for 28-day mortality of hospital acquired fungemias in ICUs: data from the EUROBACT study. AB - BACKGROUND: To characterize and identify prognostic factors for 28-day mortality among patients with hospital-acquired fungemia (HAF) in the Intensive Care Unit (ICU). METHODS: A sub-analysis of a prospective, multicenter non-representative cohort study conducted in 162 ICUs in 24 countries. RESULTS: Of the 1156 patients with hospital-acquired bloodstream infections (HA-BSI) included in the EUROBACT study, 96 patients had a HAF. Median time to its diagnosis was 20 days (IQR 10.5 30.5) and 9 days (IQR 3-15.5) after hospital and ICU admission, respectively. Median time to positivity of blood culture was longer in fungemia than in bacteremia (48.7 h vs. 38.1 h; p = 0.0004). Candida albicans was the most frequent fungus isolated (57.1%), followed by Candida glabrata (15.3%) and Candida parapsilosis (10.2%). No clear source of HAF was detected in 33.3% of the episodes and it was catheter-related in 21.9% of them. Compared to patients with bacteremia, HAF patients had a higher rate of septic shock (39.6% vs. 21.6%; p = 0.0003) and renal dysfunction (25% vs. 12.4%; p = 0.0023) on admission and a higher rate of renal failure (26% vs. 16.2%; p = 0.0273) at diagnosis. Adequate treatment started within 24 h after blood culture collection was less frequent in HAF patients (22.9% vs. 55.3%; p < 0.001). The 28-day all cause fatality was 40.6%. According to multivariate analysis, only liver failure (OR 14.35; 95% CI 1.17-175.6; p = 0.037), need for mechanical ventilation (OR 8.86; 95% CI 1.2 65.24; p = 0.032) and ICU admission for medical reason (OR 3.87; 95% CI 1.25 11.99; p = 0.020) were independent predictors of 28-day mortality in HAF patients. CONCLUSIONS: Fungi are an important cause of hospital-acquired BSI in the ICU. Patients with HAF present more frequently with septic shock and renal dysfunction on ICU admission and have a higher rate of renal failure at diagnosis. HAF are associated with a significant 28-day mortality rate (40%), but delayed adequate antifungal therapy was not an independent risk factor for death. Liver failure, need for mechanical ventilation and ICU admission for medical reason were the only independent predictors of 28-day mortality. PMID- 26956369 TI - Heterologous Expression and Functional Analysis of Rice GLUTAMATE RECEPTOR-LIKE Family Indicates its Role in Glutamate Triggered Calcium Flux in Rice Roots. AB - BACKGROUND: Tremendous progress has been made in understanding the functions of the GLUTAMATE RECEPTOR-LIKE (GLR) family in Arabidopsis. Still, the functions of OsGLRs in rice, especially the ion channel activities, are largely unknown. RESULTS: Using the aequorin-based luminescence imaging system, we screened the specificity of amino acids involved in the induction of Ca(2+) flux in rice roots. Of all the amino acids tested, glutamate (Glu) was the only one to trigger Ca(2+) flux significantly in rice roots. Detailed analysis showed a dose response of Ca(2+) increase to different concentrations of Glu. In addition, the Ca(2+) spike response to Glu was rapid, within 20 s after the application. A desensitization assay and pharmacological tests showed that the Glu-triggered Ca(2+) flux is mediated by OsGLRs. Whole genome analysis identified 13 OsGLR genes in rice, and these genes have various expression patterns in different tissues. Subcellular localization studies showed that all the OsGLRs examined are likely localized to the plasma membrane. Bacteria growth assays showed that at least OsGLR2.1 and OsGLR3.2 have the potential to mediate ion uptake in bacteria. Further analysis using Fura-2-based Ca(2+) imaging revealed a Glu-triggered Ca(2+) increase in OsGLR2.1-expressing human embryonic kidney (HEK) cells. CONCLUSIONS: Our work provides a molecular basis for investigating mechanisms of Glu-triggered Ca(2+) flux in rice. PMID- 26956370 TI - Developmental origins of infant stress reactivity profiles: A multi-system approach. AB - BACKGROUND: This study tested the hypothesis that maternal physiological and psychological variables during pregnancy discriminate between theoretically informed infant stress reactivity profiles. METHODS: The sample comprised 254 women and their infants. Maternal mood, salivary cortisol, respiratory sinus arrhythmia (RSA), and salivary alpha-amylase (sAA) were assessed at 15 and 32 weeks gestational age. Infant salivary cortisol, RSA, and sAA reactivity were assessed in response to a structured laboratory frustration task at 6 months of age. Infant responses were used to classify them into stress reactivity profiles using three different classification schemes: hypothalamic-pituitary-adrenal (HPA)-axis, autonomic, and multi-system. Discriminant function analyses evaluated the prenatal variables that best discriminated infant reactivity profiles within each classification scheme. RESULTS: Maternal stress biomarkers, along with self reported psychological distress during pregnancy, discriminated between infant stress reactivity profiles. CONCLUSIONS: These results suggest that maternal psychological and physiological states during pregnancy have broad effects on the development of the infant stress response systems. (c) 2016 Wiley Periodicals, Inc. Dev Psychobiol 58: 578-599, 2016. PMID- 26956371 TI - The use of inhaled antibiotic therapy in the treatment of ventilator-associated pneumonia and tracheobronchitis: a systematic review. AB - BACKGROUND: Ventilator-associated respiratory infections (tracheobronchitis, pneumonia) contribute significant morbidity and mortality to adults receiving care in intensive care units (ICU). Administration of broad-spectrum intravenous antibiotics, the current standard of care, may have systemic adverse effects. The efficacy of aerosolized antibiotics for treatment of ventilator-associated respiratory infections remains unclear. Our objective was to conduct a systematic review of the efficacy of aerosolized antibiotics in the treatment of ventilator associated pneumonia (VAP) and tracheobronchitis (VAT), using the Cochrane Collaboration guidelines. METHODS: We conducted a search of three databases (PubMed, Web of Knowledge and the Cochrane Collaboration) for randomized, controlled trials studying the use of nebulized antibiotics in VAP and VAT that measured clinical cure (e.g., change in Clinical Pulmonary Infection Score) as an outcome measurement. We augmented the electronic searches with hand searches of the references for any narrative review articles as well as any article included in the systematic review. Included studies were examined for risk of bias using the Cochrane Handbook's "Risk of Bias" assessment tool. RESULTS: Six studies met full inclusion criteria. For the systemic review's primary outcome (clinical cure), two studies found clinically and statistically significant improvements in measures of VAP cure while four found no statistically significant difference in measurements of cure. No studies found inferiority of aerosolized antibiotics. The included studies had various degrees of biases, particularly in the performance and detection bias domains. Given that outcome measures of clinical cure were not uniform, we were unable to conduct a meta-analysis. CONCLUSIONS: There is insufficient evidence for the use of inhaled antibiotic therapy as primary or adjuvant treatment of VAP or VAT. Additional, better-powered randomized-controlled trials are needed to assess the efficacy of inhaled antibiotic therapy for VAP and VAT. PMID- 26956372 TI - Complete genome sequence of Streptococcus thermophilus MN-BM-A01, a strain with high exopolysaccharides production. AB - Streptococcus thermophilus MN-BM-A01 (ST MN-BM-A01) (CGMCC No. 11383) was a strain isolated from Yogurt Block in Gansu, China. The yogurt fermented with this strain has good flavor, acidity, and viscosity. Moreover, ST MN-BM-A01 could produce a high level of EPS which can confer the yogurt with improved rheological properties. We reported the complete genome sequence of ST MN-BM-A01 that contains 1,876,516bp encoding 1704 coding sequences (CDSs), 67 tRNA genes and 6 rRNA operons. The genomic sequence indicated that this strain included a 35.3-kb gene cluster involved in EPS biosynthesis. PMID- 26956374 TI - Sort-seq under the hood: implications of design choices on large-scale characterization of sequence-function relations. AB - BACKGROUND: Sort-seq is an effective approach for simultaneous activity measurements in a large-scale library, combining flow cytometry, deep sequencing, and statistical inference. Such assays enable the characterization of functional landscapes at unprecedented scale for a wide-reaching array of biological molecules and functionalities in vivo. Applications of sort-seq range from footprinting to establishing quantitative models of biological systems and rational design of synthetic genetic elements. Nearly as diverse are implementations of this technique, reflecting key design choices with extensive impact on the scope and accuracy the results. Yet how to make these choices remains unclear. Here we investigate the effects of alternative sort-seq designs and inference methods on the information output using mathematical formulation and simulations. RESULTS: We identify key intrinsic properties of any system of interest with practical implications for sort-seq assays, depending on the experimental goals. The fluorescence range and cell-to-cell variability specify the number of sorted populations needed for quantitative measurements that are precise and unbiased. These factors also indicate cases where an enrichment-based approach that uses a single sorted population can offer satisfactory results. These predications of our model are corroborated using re-analysis of published data. We explore implications of these results for quantitative modeling and library design. CONCLUSIONS: Sort-seq assays can be streamlined by reducing the number of sorted populations, saving considerable resources. Simple preliminary experiments can guide optimal experiment design, minimizing cost while maintaining the maximal information output and avoiding latent biases. These insights can facilitate future applications of this highly adaptable technique. PMID- 26956375 TI - Response to Enhanced Cognitive Behavioural Therapy in an Adolescent with Anorexia Nervosa. AB - BACKGROUND: Few studies have examined the acceptability and usefulness of enhanced cognitive behavioural therapy (CBT-E) for adolescents with eating disorders (EDs). AIM: To investigate whether CBT-E was an acceptable and efficacious treatment for an adolescent presenting to a routine clinical service with an ED. METHOD: Daily self-monitoring records were completed during a baseline (A) and intervention (B) phase in addition to routine outcome measures. RESULTS: There were reductions in both ED behaviours and "feeling fat", and increases in weight after 11 CBT-E sessions. Progress was only partially maintained at 8-month follow-up. CONCLUSION: CBT-E may be an acceptable and useful intervention for adolescents with EDs. PMID- 26956373 TI - Can the buck always be passed to the highest level of clustering? AB - BACKGROUND: Clustering commonly affects the uncertainty of parameter estimates in epidemiological studies. Cluster-robust variance estimates (CRVE) are used to construct confidence intervals that account for single-level clustering, and are easily implemented in standard software. When data are clustered at more than one level (e.g. village and household) the level for the CRVE must be chosen. CRVE are consistent when used at the higher level of clustering (village), but since there are fewer clusters at the higher level, and consistency is an asymptotic property, there may be circumstances under which coverage is better from lower- rather than higher-level CRVE. Here we assess the relative importance of adjusting for clustering at the higher and lower level in a logistic regression model. METHODS: We performed a simulation study in which the coverage of 95 % confidence intervals was compared between adjustments at the higher and lower levels. RESULTS: Confidence intervals adjusted for the higher level of clustering had coverage close to 95 %, even when there were few clusters, provided that the intra-cluster correlation of the predictor was less than 0.5 for models with a single predictor and less than 0.2 for models with multiple predictors. CONCLUSIONS: When there are multiple levels of clustering it is generally preferable to use confidence intervals that account for the highest level of clustering. This only fails if there are few clusters at this level and the intra cluster correlation of the predictor is high. PMID- 26956376 TI - Antiulcer mechanisms of Vernonia condensata Baker: A medicinal plant used in the treatment of gastritis and gastric ulcer. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The leaves from Vernonia condensata Baker are broadly used in folk medicine for the treatment of gastric ulcers and dyspepsia. The Brazilian Public Health System (SUS) describes this species as having the potential to serve as a new herbal product with therapeutic benefits. AIM OF THE STUDY: The purpose of the study was to evaluate the gastroprotective activity and gastric healing properties of a crude ethanolic extract from leaves of V. condensata (CEEV) in different animal models. MATERIALS AND METHODS: In order to assess the gastroprotective potential of CEEV, ulcer models were established using ethanol and indomethacin. The gastric healing effect was then evaluated in the acetic acid-induced ulcer model, where the tissue was used to assess oxidative levels (reduced glutathione and lipid hydroperoxide levels, as well as superoxide dismutase and catalase activity), inflammatory [myeloperoxidase (MPO)] parameters, and mucin content. Furthermore, the ligature pylorus model, with and without secretagogue stimuli, was employed to investigate the mechanism of action of CEEV. In addition, H(+)K(+)-ATPase activity, MPO activity, and antioxidant activity through the DPPH assay were examined through in vitro trials. Phytochemical analyses were also performed. The ethanol/HCl-induced gastric ulcer method was employed to verify the gastroprotective effect of the main compound in CEEV. RESULTS: CEEV (30 and 300mg/kg, p.o) exhibited gastroprotective activity and prevented both gastric lesions induced by ethanol or indomethacin in rats. The gastric healing effect of CEEV (300mg/kg, p.o. taken twice a day for a duration of seven days) was confirmed by examining the macroscopic and microscopic appearance of chronic gastric ulcers induced by acetic acid in rats. The restorative effect of CEEV was accompanied by a significant increase in mucin content (PAS staining) and by a reduction in oxidative stress and inflammatory parameters at the site of the ulcer. Moreover, CEEV (300mg/kg), administered via an intraduodenal route, significantly reduced the volume, pH, total acidity and pepsin activity of gastric content in the pylorus ligature model in rats. The gastric acid antisecretory effect of CEEV was maintained even in the presence of cholinergic and gastrinergic, but not histaminergic, stimuli. In vitro, CEEV (1 10ug/ml) was able to scavenge free radical DPPH, but did not promote inhibitory effects on MPO or H(+),K(+)-ATPAse activity. Phytochemical analysis of CEEV indicated that luteolin is the main compound present in the extract. However, luteolin (1, 3 and 10mg/kg, p.o or 1mg/kg, i.p.) did not promote gastroprotection against ethanol/HCl in mice. It is also important to mention that oral administration of CEEV did not produce any sign of acute toxicity in animals. CONCLUSIONS: V. condensata extract demonstrates gastroprotective effects through the inhibition of gastric secretion via cholinergic and gastrinergic pathways. Furthermore, it exhibits cytoprotective effects, involving antioxidant activity, an increase in mucin content and inhibition of neutrophil migration. Thus, this medicinal plant may be a suitable natural source for the prevention and treatment of gastric lesions. PMID- 26956377 TI - Full Polarization Conical Dispersion and Zero-Refractive-Index in Two-Dimensional Photonic Hypercrystals. AB - Photonic conical dispersion has been found in either transverse magnetic or transverse electric polarization, and the predominant zero-refractive-index behavior in a two-dimensional photonic crystal is polarization-dependent. Here, we show that two-dimensional photonic hypercrystals can be designed that exhibit polarization independent conical dispersion at the Brillouin zone center, as two sets of triply-degenerate point for each polarization are accidentally at the same Dirac frequency. Such photonic hypercrystals consist of periodic dielectric cylinders embedded in elliptic metamaterials, and can be viewed as full-polarized near zero-refractive-index materials around Dirac frequency by using average eigen-field evaluation. Numerical simulations including directional emissions and invisibility cloak are employed to further demonstrate the double-zero-index characteristics for both polarizations in the photonic hypercrystals. PMID- 26956378 TI - Erratum to: A round robin approach to the analysis of bisphenol a (BPA) in human blood samples. PMID- 26956380 TI - A descriptive analysis of batting backlift techniques in cricket: Does the practice of elite cricketers follow the theory? AB - One of the first principles of cricket batsmanship that is coached from a young age is to play with a straight bat. Limited studies to date have examined whether top international batsmen use this traditionally described technique. Accordingly, we performed a descriptive, observational study of the backlift technique adopted by 65 of the most successful batsmen of all time, based on their career averages, strike rate and runs scored. The batsmen were divided into two groups depending on whether they played the game before or after 1954. Surprisingly, more than 70% of these successful batsmen did not adopt the traditionally taught technique. Instead, they adopted a more looped action in which the initial movement of the bat was in the direction of the slips, and in extreme cases it was either towards the gully/point region or to have the face of the bat directed towards the off-side. This suggests that traditionally taught batting coaching techniques may hinder, rather than enhance future cricketing performance. Since the vast majority of cricketers are not coached in this technique, this finding probably indicates that this looped technique is likely a contributing factor to effective batsmanship. PMID- 26956379 TI - Immunohistochemical and molecular detection of the expression of FGF23 in phosphaturic mesenchymal tumors including the non-phosphaturic variant. AB - BACKGROUND: Phosphaturic mesenchymal tumors (PMTs) are rare neoplasms that are often associated with tumor-induced osteomalacia (TIO) due to excessive serum levels of fibroblast growth factor 23 (FGF23). PMTs share overlapping histologic features with other types of tumors; thus, accurate pathological diagnosis may be challenging. We performed an immunohistochemical examination of FGF23 expression in PMTs and other types of tumors, together with pertinent molecular analyses. METHODS: Seven PMTs (5 with TIO and 2 without TIO) and 46 other types of bone and soft tissue tumors were retrieved, and immunohistochemistry was performed using a commercially available anti-FGF23 antibody. In addition, FGF23 mRNA expression was detected by reverse transcription-polymerase chain reaction (RT-PCR), using RNA extracted from formalin-fixed, paraffin-embedded tissues. RESULTS: Immunohistochemical analysis of FGF23 expression showed distinct, punctate staining in the cytoplasm in 5 PMTs with TIO, whereas FGF23 expression was negative in the 2 PMTs without TIO and the other 46 tumors. FGF23 mRNA expression was detected in all 4 PMTs examined, as well as in 1 chondromyxoid fibroma and 1 myxoid liposarcoma. The real-time RT-PCR data showed that the relative expression levels of the FGF23 mRNA tended to be higher in PMTs with TIO than in PMTs without TIO, or in the chondromyxoid fibroma specimen. CONCLUSIONS: Our data suggested that the feasibility of immunohistochemical detection of FGF23 may depend on the level of secreted FGF23 from tumor cells. Thus, immunohistochemistry for FGF23 is an useful diagnostic adjunct for PMT, although its utility appears to be limited in cases without TIO. PMID- 26956381 TI - Misdiagnosis of primary hepatic marginal zone B cell lymphoma of mucosa associated lymphoid tissue type, a case report. AB - BACKGROUND: Extra-nodal marginal zone B cell lymphoma of mucosa-associated lymphoid tissue originating in the liver is less common. CASE PRESENTATION: We described the clinical presentation, immunohistochemistry, and immunophenotypes of this lymphoma, which was misdiagnosed with tiny hepatic carcinoma in a 44-year old woman with hepatitis C; the patient underwent left lateral sectionectomy. The immunophenotype identified the most of the lymphoid cells as positive CD20, CD34, Ki67, CD3, CD4, CD79a, CD45RO, MUM-1, and CD5 and negative CD10, CD15, CD30, ACT, CK, CRO, DES, and HMB45. The diagnosis of primary hepatic mucosa-associated lymphoid tissue (MALT) was made by histology after surgery; the patient went through the excellent recovery with no chemotherapy and is disease free for 27 months. CONCLUSIONS: Primary hepatic MALT is less common with incidental finding; local resection is beneficial due to its oncological indolence. PMID- 26956382 TI - Initial combination therapy versus step-up therapy in treatment to the target of remission in daily clinical practice in early rheumatoid arthritis patients: results from the DREAM registry. AB - BACKGROUND: Treat to target (T2T) is widely accepted as the standard of care for patients with rheumatoid arthritis (RA) and has been shown to be more effective than traditional routine care. The objective of this study was to compare the effectiveness of two T2T strategies in patients with early RA: a step-up approach starting with methotrexate (MTX) monotherapy (cohort I) versus an initial disease modifying antirheumatic drug combination approach (cohort II). METHODS: A total of 128 patients from cohort II were case-control-matched with 128 patients from cohort I on gender, age, and baseline disease activity. Twelve-month follow-up data were available for 121 patients in both cohorts. The primary outcome was the proportion of patients having reached at least one 28-joint Disease Activity Score (DAS28) score <2.6 (remission) during 12 months of follow-up. Secondary outcomes were time until remission was achieved and mean DAS28 scores at 6- and 12-month follow-up. RESULTS: After 12 months of follow-up, remission was reached at least once in 77.3 % of the patients in cohort II versus 71.9 % in cohort I (P = 0.31). Median time until first remission was 17 weeks in cohort II versus 27 weeks in cohort I (P = 0.04). A significant time by strategy interaction was found in mean DAS28 scores. Post hoc analysis revealed a significant difference in mean DAS28 scores between both cohorts at 6 months (P = 0.04), but not at 12 months (P = 0.36). CONCLUSIONS: The initial combination strategy resulted in a comparable remission rate after 1 year but a significantly shorter time until remission. At 6 months, mean DAS28 scores were lower in patients with initial combination treatment than in those with step-up therapy. At 12 months, no significant differences remained in mean DAS28 scores or the proportion of patients in remission. PMID- 26956383 TI - Impact of offering cycle training in schools upon cycling behaviour: a natural experimental study. AB - BACKGROUND: England's national cycle training scheme, 'Bikeability', aims to give children in England the confidence to cycle more. There is, however, little evidence on the effectiveness of cycle training in achieving this. We therefore examined whether delivering Bikeability was associated with cycling frequency or with independent cycling. METHODS: We conducted a natural experimental study using information on children aged 10-11 years participating in the nationally representative Millennium Cohort Study. We identified Cohort participants whose schools had offered Bikeability in 2011-2012 using operational Bikeability delivery data (children in London excluded, as delivery data not available). Our natural experimental design capitalised on the fact that Cohort participants were surveyed at different times during 2012 and were also offered Bikeability at different times during 2012. This allowed us to compare cycling levels between children whose schools delivered Bikeability before their survey interview ('intervention group', N = 2563) and an otherwise comparable group of children whose schools delivered Bikeability later in the year ('control group', N = 773). Parents reported whether their child had completed formal cycle training; their child's cycling frequency; whether their child ever made local cycling trips without an adult; and other child and family factors. We used Poisson regression with robust standard errors to examine whether cycling behaviour differed between the intervention and control groups. RESULTS: Children whose school had offered Bikeability were much more likely to have completed cycle training than the control group (68% vs. 28%, p < 0.001). There was, however, no evidence that delivering Bikeability in school was associated with cycling more often (49.0% cycling at least once per week in the intervention group vs. 49.6% in the control group; adjusted risk ratio 0.99, 95% CI 0.89, 1.10). There was likewise no evidence of an association with cycling independently (51.5% in the intervention group vs. 50.1% in the control group; adjusted risk ratio 0.97, 95% CI 0.89, 1.06). CONCLUSIONS: Offering high-quality cycle training free at the point of delivery in English schools encourages children to do cycle training, but we found no evidence of short-term effects on cycling frequency or independent cycling. Future evaluation should investigate longer-term effects on these and other stated Bikeability objectives such as increasing cycling safety. PMID- 26956386 TI - Mass spectrometry for the detection of bioterrorism agents: from environmental to clinical applications. AB - In the current context of international conflicts and localized terrorist actions, there is unfortunately a permanent threat of attacks with unconventional warfare agents. Among these, biological agents such as toxins, microorganisms, and viruses deserve particular attention owing to their ease of production and dissemination. Mass spectrometry (MS)-based techniques for the detection and quantification of biological agents have a decisive role to play for countermeasures in a scenario of biological attacks. The application of MS to every field of both organic and macromolecular species has in recent years been revolutionized by the development of soft ionization techniques (MALDI and ESI), and by the continuous development of MS technologies (high resolution, accurate mass HR/AM instruments, novel analyzers, hybrid configurations). New possibilities have emerged for exquisite specific and sensitive detection of biological warfare agents. MS-based strategies for clinical application can now address a wide range of analytical questions mainly including issues related to the complexity of biological samples and their available volume. Multiplexed toxin detection, discovery of new markers through omics approaches, and identification of untargeted microbiological or of novel molecular targets are examples of applications. In this paper, we will present these technological advances along with the novel perspectives offered by omics approaches to clinical detection and follow-up. PMID- 26956384 TI - Role of trophic factors GDNF, IGF-1 and VEGF in major depressive disorder: A comprehensive review of human studies. AB - RATIONALE: The neurotrophin hypothesis of major depressive disorder (MDD) postulates that this illness results from aberrant neurogenesis in brain regions that regulates emotion and memory. Notwithstanding this theory has primarily implicated BDNF in the neurobiology of MDD. Recent evidence suggests that other trophic factors namely GDNF, VEGF and IGF-1 may also be involved. PURPOSE: The present review aimed to critically summarize evidence regarding changes in GDNF, IGF-1 and VEGF in individuals with MDD compared to healthy controls. In addition, we also evaluated the role of these mediators as potential treatment response biomarkers for MDD. METHODS: A comprehensive review of original studies studies measuring peripheral, central or mRNA levels of GDNF, IGF-1 or VEGF in patients with MDD was conducted. The PubMed/MEDLINE database was searched for peer reviewed studies published in English through June 2nd, 2015. RESULTS: Most studies reported a reduction in peripheral GDNF and its mRNA levels in MDD patients versus controls. In contrast, IGF-1 levels in MDD patients compared to controls were discrepant across studies. Finally, most studies reported high peripheral VEGF levels and mRNA expression in MDD patients compared to healthy controls. CONCLUSIONS: GDNF, IGF-1 and VEGF levels and their mRNA expression appear to be differentially altered in MDD patients compared to healthy individuals, indicating that these molecules might play an important role in the pathophysiology of depression and antidepressant action of therapeutic interventions. PMID- 26956387 TI - Fast detection of Piscirickettsia salmonis in Salmo salar serum through MALDI-TOF MS profiling. AB - Piscirickettsia salmonis is a pathogenic bacteria known as the aetiological agent of the salmonid rickettsial syndrome and causes a high mortality in farmed salmonid fishes. Detection of P. salmonis in farmed fishes is based mainly on molecular biology and immunohistochemistry techniques. These techniques are in most of the cases expensive and time consuming. In the search of new alternatives to detect the presence of P. salmonis in salmonid fishes, this work proposed the use of MALDI-TOF-MS to compare serum protein profiles from Salmo salar fish, including experimentally infected and non-infected fishes using principal component analysis (PCA). Samples were obtained from a controlled bioassay where S. salar was challenged with P. salmonis in a cohabitation model and classified according to the presence or absence of the bacteria by real time PCR analysis. MALDI spectra of the fish serum samples showed differences in its serum protein composition. These differences were corroborated with PCA analysis. The results demonstrated that the use of both MALDI-TOF-MS and PCA represents a useful tool to discriminate the fish status through the analysis of salmonid serum samples. PMID- 26956385 TI - Neck circumference as a predictor of metabolic syndrome, insulin resistance and low-grade systemic inflammation in children: the ACFIES study. AB - BACKGROUND: The current study aims to evaluate the association between neck circumference (NC) and several cardio-metabolic risk factors, to compare it with well-established anthropometric indices, and to determine the cut-off point value of NC for predicting children at increased risk of metabolic syndrome, insulin resistance and low-grade systemic inflammation. METHODS: A total of 669 school children, aged 8-14, were recruited. Demographic, clinical, anthropometric and biochemical data from all patients were collected. Correlations between cardio metabolic risk factors and NC and other anthropometric variables were evaluated using the Spearman's correlation coefficient. Multiple linear regression analysis was applied to further examine these associations. We then determined by receiver operating characteristic (ROC) analyses the optimal cut-off for NC for identifying children with elevated cardio-metabolic risk. RESULTS: NC was positively associated with fasting plasma glucose and triglycerides (p = 0.001 for all), and systolic and diastolic blood pressure, C-reactive protein, insulin and HOMA-IR (p < 0.001 for all), and negatively with HDL-C (p = 0.001). Whereas, other anthropometric indices were associated with fewer risk factors. CONCLUSIONS: NC could be used as clinically relevant and easy to implement indicator of cardio-metabolic risk in children. PMID- 26956388 TI - Identification of transformation products from beta-blocking agents formed in wetland microcosms using LC-Q-ToF. AB - Identification of degradation products from trace organic compounds, which may retain the biological activity of the parent compound, is an important step in understanding the long-term effects of these compounds on the environment. Constructed wetlands have been successfully utilized to remove contaminants from wastewater effluent, including pharmacologically active compounds. However, relatively little is known about the transformation products formed during wetland treatment. In this study, three different wetland microcosm treatments were used to determine the biotransformation products of the beta-adrenoreceptor antagonists atenolol, metoprolol and propranolol. LC/ESI-Q-ToF run in the MS(E) and MS/MS modes was used to identify and characterize the degradation products through the accurate masses of precursor and product ions. The results were compared with those of a reference standard when available. Several compounds not previously described as biotransformation products produced in wetlands were identified, including propranolol-O-sulfate, 1-naphthol and the human metabolite N-deaminated metoprolol. Transformation pathways were significantly affected by microcosm conditions and differed between compounds, despite the compounds' structural similarities. Altogether, a diverse range of transformation products in wetland microcosms were identified and elucidated using high resolving MS. This work shows that transformation products are not always easily predicted, nor formed via the same pathways even for structurally similar compounds. PMID- 26956390 TI - Structures of [M(Ura-H)(H2 O)n ](+) (M = Mg, Ca, Sr, Ba; n = 1-3) complexes in the gas phase by IRMPD spectroscopy and theoretical studies. AB - The structures of singly and doubly (and for Mg, triply) hydrated group 2 metal dications bound to deprotonated uracil were explored in the gas phase using infrared multiple photon dissociation spectroscopy in the mid-infrared region (1000-1900 cm(-1) ) and the O-H/N-H stretching region (2700-3800 cm(-1) ) in a Fourier transform ion cyclotron resonance mass spectrometer. The infrared multiple photon dissociation spectra were then compared with the computed IR spectra for various isomers. Calculations were performed using B3LYP with the 6 31 + G(d,p) basis set for all atoms except Ba(2+) and Sr(2+) , for which the LANL2DZ or the def2-TZVPP basis sets with relativistic core potentials were used. Atoms-in-molecules analysis was conducted for all lowest energy structures. The lowest energy isomers in all cases are those in which the one uracil is deprotonated at the N3 position, and the metal is coordinated to the N3 and O4 of uracil. Regardless of the degree of solvation, all water molecules are bound to the metal ion and participate in a hydrogen bond with a carbonyl of the uracil moiety. PMID- 26956391 TI - Competitive homolytic and heterolytic decomposition pathways of gas-phase negative ions generated from aminobenzoate esters. AB - An alkyl-radical loss and an alkene loss are two competitive fragmentation pathways that deprotonated aminobenzoate esters undergo upon activation under mass spectrometric conditions. For the meta and para isomers, the alkyl-radical loss by a homolytic cleavage of the alkyl-oxygen bond of the ester moiety is the predominant fragmentation pathway, while the contribution from the alkene elimination by a heterolytic pathway is less significant. In contrast, owing to a pronounced charge-mediated ortho effect, the alkene loss becomes the predominant pathway for the ortho isomers of ethyl and higher esters. Results from isotope labeled compounds confirmed that the alkene loss proceeds by a specific gamma hydrogen transfer mechanism that resembles the McLafferty rearrangement for radical cations. Even for the para compounds, if the alkoxide moiety bears structural motifs required for the elimination of a more stable alkene molecule, the heterolytic pathway becomes the predominant pathway. For example, in the spectrum of deprotonated 2-phenylethyl 4-aminobenzoate, m/z 136 peak is the base peak because the alkene eliminated is styrene. Owing to the fact that all deprotonated aminobenzoate esters, irrespective of the size of the alkoxy group, upon activation fragment to form an m/z 135 ion, aminobenzoate esters in mixtures can be quantified by precursor ion discovery mass spectrometric experiments. PMID- 26956392 TI - Fullerene separation and identification by traveling wave ion mobility mass spectrometry in laser desorption processes during asphaltene analysis. PMID- 26956389 TI - Travelling-wave ion mobility and negative ion fragmentation of high-mannose N glycans. AB - The isomeric structure of high-mannose N-glycans can significantly impact biological recognition events. Here, the utility of travelling-wave ion mobility mass spectrometry for isomer separation of high-mannose N-glycans is investigated. Negative ion fragmentation using collision-induced dissociation gave more informative spectra than positive ion spectra with mass-different fragment ions characterizing many of the isomers. Isomer separation by ion mobility in both ionization modes was generally limited, with the arrival time distributions (ATD) often showing little sign of isomers. However, isomers could be partially resolved by plotting extracted fragment ATDs of the diagnostic fragment ions from the negative ion spectra, and the fragmentation spectra of the isomers could be extracted by using ions from limited areas of the ATD peak. In some cases, asymmetric ATDs were observed, but no isomers could be detected by fragmentation. In these cases, it was assumed that conformers or anomers were being separated. Collision cross sections of the isomers in positive and negative fragmentation mode were estimated from travelling-wave ion mobility mass spectrometry data using dextran glycans as calibrant. More complete collision cross section data were achieved in negative ion mode by utilizing the diagnostic fragment ions. Examples of isomer separations are shown for N-glycans released from the well-characterized glycoproteins chicken ovalbumin, porcine thyroglobulin and gp120 from the human immunodeficiency virus. In addition to the cross-sectional data, details of the negative ion collision-induced dissociation spectra of all resolved isomers are discussed. PMID- 26956393 TI - Chiral recognition between L-alanine peptides and tryptophan enantiomers probed by ultraviolet photodissociation in the gas phase. PMID- 26956395 TI - Glycosylation Quality Control by the Golgi Structure. AB - Glycosylation is a ubiquitous modification that occurs on proteins and lipids in all living cells. Consistent with their high complexity, glycans play crucial biological roles in protein quality control and recognition events. Asparagine linked protein N-glycosylation, the most complex glycosylation, initiates in the endoplasmic reticulum and matures in the Golgi apparatus. This process not only requires an accurate distribution of processing machineries, such as glycosyltransferases, glycosidases, and nucleotide sugar transporters, but also needs an efficient and well-organized factory that is responsible for the fidelity and quality control of sugar chain processing. In addition, accurate glycosylation must occur in coordination with protein trafficking and sorting. These activities are carried out by the Golgi apparatus, a membrane organelle in the center of the secretory pathway. To accomplish these tasks, the Golgi has developed into a unique stacked structure of closely aligned, flattened cisternae in which Golgi enzymes reside; in mammalian cells, dozens of Golgi stacks are often laterally linked into a ribbon-like structure. Here, we review our current knowledge of how the Golgi structure is formed and why its formation is required for accurate glycosylation, with the focus on how the Golgi stacking factors GRASP55 and GRASP65 generate the Golgi structure and how the conserved oligomeric Golgi complex maintains Golgi enzymes in different Golgi subcompartments by retrograde protein trafficking. PMID- 26956398 TI - Imaging of rectus femoris proximal tendinopathies. AB - The rectus femoris is the most commonly injured muscle of the anterior thigh among athletes, especially soccer players. Although the injury pattern of the muscle belly is well documented, less is known about the anatomy and specific lesions of the proximal tendons. For each head, three distinctive patterns may be encountered according to the location of the injury, which can be at the enthesis, within the tendon, or at the musculotendinous junction. In children, injuries correspond most commonly to avulsion of the anteroinferior iliac spine from the direct head and can lead to subspine impingement. Calcific tendinitis and traumatic tears may be encountered in adults. Recent studies have shown that traumatic injuries of the indirect head may be underdiagnosed and that injuries of both heads may have a surgical issue. Finally, in the case of tears, functional outcome and treatment may vary if the rupture involves one or both tendons and if the tear is partial or complete. Thus, it is mandatory for the radiologist to know the different ultrasound and magnetic resonance imaging (MRI) patterns of these lesions in order to provide accurate diagnosis and treatment. The purpose of this article is to recall the anatomy of the two heads of rectus femoris, describe a reliable method of assessment with ultrasound and MRI and know the main injury patterns, through our own experience and literature review. PMID- 26956397 TI - Efficacy and acceptability of an "App on sick newborn care" in physicians from newborn units. AB - BACKGROUND: There has been an increased emphasis on institutional births, and thus an increasing clinical work load for health care professionals in the recent past. Hence, continuing education, training, ongoing supervision, and mentorship of health care professionals working in these health facilities with easy access to guidelines in a cost effective manner has become a challenging task. With the increased emphasis on institutional births, and an increasing clinical work load, continuing education and training of health care professional managing these health facilities, their ongoing supervision, mentorship, with ready availability of guidelines in a cost effective manner becomes imperative and is a challenging task. Training opportunities can be linked to mobile electronic devices and 'Apps' to improve the care of seriously ill newborn. The aim of this study was to evaluate the efficacy of an innovative point of care tool- Android based App- 'AIIMS-WHO CC STPs' on the knowledge, skill scores, and satisfaction among Special Newborn Care Unit (SNCU) physicians managing sick neonates. METHODS: The baseline knowledge and skill scores of pediatricians working in SNCUs in the state of Tamil Nadu, India (n = 32) were assessed by 25 multiple choice questions (MCQs) and by five Objective Structured Clinical Examination (OSCE) skill stations. The training was conducted in a single-day workshop using the app on four modules followed by post-training assessment of knowledge and skill scores after 3 weeks using the same. The satisfaction was assessed by mixed method approach using Likert's scale and focus group discussion (FGD) after 3 weeks. RESULTS: The mean knowledge scores [19.4 (2.6) vs. 10.7 (3.2); maximum marks (MM) 25, mean difference 8.7 (95 % CI 7.6 to 9.9)], and the composite mean skill scores [55.2 (5.8) and 42 (6.2), MM 75, mean difference 13.2 (95 % CI 10.4 to 15.9)] improved after training. The median (IQR) satisfaction score with the course was 4 (4 to 5) (Likert's scale). Focus group discussion revealed that the physicians were overall satisfied using the device. They expressed overall satisfaction on the teaching methodology using wall charts, simulators, and device. CONCLUSION: Training SNCU physicians on Android based App- 'AIIMS-WHO CC STPs' improved their knowledge and skills. This app may have a potential role as a supplement to other modalities in training doctors for improving newborn care. PMID- 26956396 TI - Aberrant excitatory rewiring of layer V pyramidal neurons early after neocortical trauma. AB - Lesioned neuronal circuits form new functional connections after a traumatic brain injury (TBI). In humans and animal models, aberrant excitatory connections that form after TBI may contribute to the pathogenesis of post-traumatic epilepsy. Partial neocortical isolation ("undercut" or "UC") leads to altered neuronal circuitry and network hyperexcitability recorded in vivo and in brain slices from chronically lesioned neocortex. Recent data suggest a critical period for maladaptive excitatory circuit formation within the first 3days post UC injury (Graber and Prince 1999, 2004; Li et al. 2011, 2012b). The present study focuses on alterations in excitatory connectivity within this critical period. Immunoreactivity (IR) for growth-associated protein (GAP)-43 was increased in the UC cortex 3days after injury. Some GAP-43-expressing excitatory terminals targeted the somata of layer V pyramidal (Pyr) neurons, a domain usually innervated predominantly by inhibitory terminals. Immunocytochemical analysis of pre- and postsynaptic markers showed that putative excitatory synapses were present on somata of these neurons in UC neocortex. Excitatory postsynaptic currents from UC layer V Pyr cells displayed properties consistent with perisomatic inputs and also reflected an increase in the number of synaptic contacts. Laser scanning photostimulation (LSPS) experiments demonstrated reorganized excitatory connectivity after injury within the UC. Concurrent with these changes, spontaneous epileptiform bursts developed in UC slices. Results suggest that aberrant reorganization of excitatory connectivity contributes to early neocortical hyperexcitability in this model. The findings are relevant for understanding the pathophysiology of neocortical post-traumatic epileptogenesis and are important in terms of the timing of potential prophylactic treatments. PMID- 26956399 TI - Nitrogen cycling in an extreme hyperarid environment inferred from delta(15)N analyses of plants, soils and herbivore diet. AB - Climate controls on the nitrogen cycle are suggested by the negative correlation between precipitation and delta(15)N values across different ecosystems. For arid ecosystems this is unclear, as water limitation among other factors can confound this relationship. We measured herbivore feces, foliar and soil delta(15)N and delta(13)C values and chemically characterized soils (pH and elemental composition) along an elevational/climatic gradient in the Atacama Desert, northern Chile. Although very positive delta(15)N values span the entire gradient, soil delta(15)N values show a positive correlation with aridity as expected. In contrast, foliar delta(15)N values and herbivore feces show a hump shaped relationship with elevation, suggesting that plants are using a different N source, possibly of biotic origin. Thus at the extreme limits of plant life, biotic interactions may be just as important as abiotic processes, such as climate in explaining ecosystem delta(15)N values. PMID- 26956401 TI - Teledermatology: From the Tempest of Debate to Calmer Waters. PMID- 26956400 TI - Rational design of a comprehensive cancer therapy platform using temperature sensitive polymer grafted hollow gold nanospheres: simultaneous chemo/photothermal/photodynamic therapy triggered by a 650 nm laser with enhanced anti-tumor efficacy. AB - Combining multi-model treatments within one single system has attracted great interest for the purpose of synergistic therapy. In this paper, hollow gold nanospheres (HAuNs) coated with a temperature-sensitive polymer, poly(oligo(ethylene oxide) methacrylate-co-2-(2-methoxyethoxy)ethyl methacrylate) (p(OEGMA-co-MEMA)), co-loaded with DOX and a photosensitizer Chlorin e6 (Ce6) were successfully synthesized. As high as 58% DOX and 6% Ce6 by weight could be loaded onto the HAuNs-p(OEGMA-co-MEMA) nanocomposites. The grafting polymer brushes outside the HAuNs play the role of "gate molecules" for controlled drug release by 650 nm laser radiation owing to the temperature-sensitive property of the polymer and the photothermal effect of HAuNs. The HAuNs-p(OEGMA-co-MEMA)-Ce6 DOX nanocomposites with 650 nm laser radiation show effective inhibition of cancer cells in vitro and enhanced anti-tumor efficacy in vivo. In contrast, control groups without laser radiation show little cytotoxicity. The nanocomposite demonstrates a way of "killing three birds with one stone", that is, chemotherapy, photothermal and photodynamic therapy are triggered simultaneously by the 650 nm laser stimulation. Therefore, the nanocomposites show the great advantages of multi-modal synergistic effects for cancer therapy by a remote-controlled laser stimulus. PMID- 26956403 TI - Neuropeptides as psychotropic drugs. AB - Neuropeptides are endogenous substances present in nerve cells and involved in nervous system functions. Neuropeptides are synthetized in large precursor proteins and several are formed in the same precursor. Neuropeptides affect learning and memory processes, social, sexual and maternal behavior, pain and addiction, body temperature, food and water intake e.a. In addition, neuropeptides possess trophic influences on the nervous system, neuroleptic-like andpsychostimulant-like activities. Disturbances in classical neurotransmitter activity as found in Parkinson's disease, psychoses, and dementia, may also be caused by disturbances in neuropeptide activity. In fact, alterations in the concentration of a number of neuropeptides in schizophrenia, depression, and dementia have been found. Much work has been done during the last decade on the influence of neuropeptides in schizophrenia, autism, depression, and in various disorders associated with memory disturbances. These studies concern neuropeptides related to adrenocorticotropic hormone (ACTH) and melanocyte stimulating hormone (MSH), vasopressin- and endorphin-type neuropeptides, thyrotropic releasing hormone (TRH), and the C-terminal part of oxytocin Pro-Leu Gly-NH2 (PLG). Several of these exert positive effects but in not more than 25% the response is clinically relevant. This may have to do with the severity of the disease and its chronicity. The modest effects may also be caused by the poor bioavailability of peptides and insufficient pharmacotherapeutic experience regarding dose, and duration of treatment. PMID- 26956402 TI - An Update on Neurofibromatosis Type 1: Not Just Cafe-au-Lait Spots and Freckling. Part II. Other Skin Manifestations Characteristic of NF1. NF1 and Cancer. AB - Neurofibromatosis type 1 (NF1) is the most common neurocutaneous syndrome and probably the one best known to dermatologists. Although the genetic locus of NF1 was identified on chromosome 17 in 1987, diagnosis of the disease is still based primarily on clinical observations. The 7 diagnostic criteria of the National Institutes of Health, which were established in 1988, include 3 skin manifestations (cafe-au-lait spots, freckling on flexural areas, and cutaneous neurofibromas). The age at which these diagnostic lesions appear is variable: onset can be late in some patients while others never develop certain symptoms. Definitive diagnosis may therefore be delayed by years. Although the appearance of the characteristic cafe-au-lait spots and freckling in the early years of childhood are very suggestive of the disease, these signs are not pathognomonic and, in isolation, do not constitute sufficient evidence to establish a definitive diagnosis. Thus, other diagnoses should be considered in patients whose only symptoms are cafe-au-lait spots and freckling. By contrast, the presence of multiple cutaneous neurofibromas or at least 1 plexiform neurofibroma is a very specific indication of NF1. Identification of the different types of neurofibroma allows us to confirm the diagnosis and initiate appropriate management. PMID- 26956404 TI - Aphasia and apraxia in dementia: cognitive regression or focal symptoms? AB - A review is given of the neuropsychological conceptualizations of aphasia and apraxia in SDAT. In the beginning of this century localisationism was prevailing. Later, developmental and cognitive psychology gave an important impetus to reconsider these symptoms in an holistic framework. More recently, since the application of new brain imaging techniques, there is a revival of localizing conceptualizations. PMID- 26956405 TI - Dystonie reactions and hallucinations: a rare adverse-effect? AB - Dystonie reactions and hallucinations: a rare adverse-effect? One of the intriguing side-effects of neuroleptics is the acute dystonie reaction like oculogyric crises. It is seldom mentioned that the dystonie reaction may be combined with hallucinations. This combination of acute dystonia with hallucinations may be explained by overstimulation of dopamine-receptors in the striatal neurons. Awareness of these hallucinations as a complication of neuroleptics is essential to prevent that neuroleptic dose will be increased; instead it must be lowered. Prevention of the dystonia is critical. These side effects may be suppressed with anti-parkinsonian drugs. Information to the patient in due time may prevent anxiety about the side effects. PMID- 26956406 TI - Dementia and Amyotrophic Lateral Sclerosis. AB - Dementia and Amyotrophic Lateral Sclerosis The case-histories of two patients are presented with Amyo-trofic Lateral Sclerosis and dementia (ALS-D), followed by a discussion of recent literature on this topic. This condition can be considered as the interface between non-Alzheimer frontal lobe dementia and amyotrophic lateral sclerosis. The nosological classification of the ALS-D complex has not been established yet. PMID- 26956408 TI - Letters to the editor. PMID- 26956407 TI - Psychofarmakologika VIII. AB - Inleiding In deze rubriek zal worden ingegaan op recente observaties betreffende de psychofarmakologie in de breedst mogelijke zin. Vaak zullen zaken uit de literatuur worden behandeld. De gekozen onderwerpen dienen altijd klinische relevantie te hebben. Ook zal deze rubriek gaan over gewoontes die in psychofarmakologische behandeling of in onderzoek zijn geslopen die volgens de auteur lang niet altijd logisch zijn. Soms zal deze rubriek een oproep bevatten om te reageren op een bijdrage gepubliceerd in dit of in een ander tijdschrift. Ook zal de lezer worden aangemoedigd hier zijn eigen ervaringen mee te delen. Het is niet de bedoeling in deze rubriek onderzoeken uitvoerig te rapporteren. Daarvoor staan andere pagina's van de Acta Neuropsychiatrica voor u open. PMID- 26956409 TI - Prevalence and possible causes of hypouricemia at a tertiary care hospital. AB - BACKGROUND/AIMS: We aimed to investigate the prevalence and possible causes of hypouricemia in the Korean population and to compare our findings with published results of other populations. METHODS: We examined the serum uric acid levels of 30,757 subjects who had their uric acid values measured at least once during a 1 year period. All individuals with hypouricemia (serum uric acid < 2.0 mg/dL, n = 424) were reviewed with respect to medical drug history and concomitant diseases previously identified as being associated with hypouricemia. RESULTS: The prevalence of hypouricemia was 4.14% (299/7,223) among inpatients and 0.53% (125/23,534) among outpatients, for an overall prevalence of 1.39% (424/30,757). Possible causes associated with hypouricemia were found to be solid or hematologic malignancies (n = 86), diabetes mellitus (n = 56), and therapeutic drugs (n = 29). The medications were allopurinol (n = 11), angiotensin II receptor blockers (n = 10), salicylates (n = 6), febuxostat (n = 1), and warfarin (n = 1). In the remaining 226 individuals, the cause of hypouricemia was not identified. CONCLUSIONS: Hypouricemia is relatively common in the Korean population compared to those of other countries. The possible causes associated with hypouricemia are related to underlying diseases and medications. PMID- 26956410 TI - Interleukin-12B is upregulated by decoy receptor 3 in rheumatoid synovial fibroblasts. AB - Decoy receptor 3 (DcR3) competitively binds to three ligands, Fas ligand, lymphotoxin-related inducible ligand that competes for glycoprotein D binding to herpesvirus entry mediator on T cells and tumor necrosis factor-like ligand 1A (TL1A), to prevent their effects. Recent studies have suggested that DcR3 directly affects cells as a ligand. Using a microarray assay, our group newly identified interleukin (IL)-12B, which encodes the p40 subunit common to IL-12 and IL-23, as one of the genes for which expression in fibroblast-like synoviocytes from patients with rheumatoid arthritis (RA-FLS) is induced by DcR3. The present study demonstrated that IL-12B mRNA expression was upregulated by DcR3-Fc in RA-FLS in a dose-dependent manner, but not in OA-FLS. IL-12B p40 protein in RA-FLS was increased when stimulated with DcR3-Fc. Pre-treatment with anti-TL1A antibody suppressed the upregulation of IL-12B mRNA in RA-FLS stimulated with DcR3-Fc. DcR3 mRNA expression in RA-FLS was induced by IL-23, but not by IL-12. These results indicated that DcR3 may increase IL-12 or IL-23 by inducing IL-12B p40 expression via membrane-bound TL1A on RA-FLS and that IL-23 reciprocally induces DcR3 expression in RA-FLS. DcR3 and IL-23 may interact in a feedback loop that aggravates local inflammation in patients with RA. PMID- 26956412 TI - Quantum dots increased fat storage in intestine of Caenorhabditis elegans by influencing molecular basis for fatty acid metabolism. AB - Caenorhabditis elegans is a useful model animal for fat storage study. In nematodes, CdTe quantum dots (QDs) induced an increase in fat storage in intestine that is partially due to prolonged defecation cycle length, and not attributed to altered feeding or cadmium ion released from CdTe QDs. Moreover, CdTe QDs altered the molecular basis of both synthesis and degradation of fatty acid; however, CdTe QDs did not influence that of degradation of phospholipids. CdTe QDs increased expression of fasn-1 and pod-2 genes encoding enzymes required for fatty acid synthesis, and decreased expression of acs-2 and ech-1 genes encoding enzymes required for fatty acid beta-oxidation. The altered molecular basis of fatty acid synthesis or degradation by CdTe QDs acted in intestine to regulate fat storage. Our study highlights the potential of CdTe QDs in influencing lipid metabolism in certain organs or tissues in animals. PMID- 26956413 TI - Osteoconductive composite graft based on bacterial synthesized hydroxyapatite nanoparticles doped with different ions: From synthesis to in vivo studies. AB - To repair damaged bone tissues, osteoconductive bone graft substitutes are required for enhancement of the regenerative potential of osteoblast cells. Nanostructured hydroxyapatite is a bioactive ceramic used for bone tissue engineering purposes. In this study, carbonate hydroxyapatite (cHA) and zinc magnesium substituted hydroxyapatite (Zn-Mg-HA) nanoparticles were synthesized via biomineralization method using Enterobacter aerogenes. The structural phase composition and the morphology of the samples were analyzed using appropriate powder characterization methods. Next, a composite graft was fabricated by using polyvinyl alcohol and both cHA and Zn-Mg-HA samples. In vivo osteogenic potential of the graft was then investigated in a rabbit tibial osteotomy model. Histological, radiological and morphological studies showed that the graft was mineralized by the newly formed bone tissue without signs of inflammation or infection after 4 weeks of implantation. These histomorphometric results suggest that the fabricated graft can function as a potent osteoconductive bone tissue substitute. PMID- 26956415 TI - Selective advantage of trisomic human cells cultured in non-standard conditions. AB - An abnormal chromosome number, a condition known as aneuploidy, is a ubiquitous feature of cancer cells. A number of studies have shown that aneuploidy impairs cellular fitness. However, there is also evidence that aneuploidy can arise in response to specific challenges and can confer a selective advantage under certain environmental stresses. Cancer cells are likely exposed to a number of challenging conditions arising within the tumor microenvironment. To investigate whether aneuploidy may confer a selective advantage to cancer cells, we employed a controlled experimental system. We used the diploid, colorectal cancer cell line DLD1 and two DLD1-derived cell lines carrying single-chromosome aneuploidies to assess a number of cancer cell properties. Such properties, which included rates of proliferation and apoptosis, anchorage-independent growth, and invasiveness, were assessed both under standard culture conditions and under conditions of stress (i.e., serum starvation, drug treatment, hypoxia). Similar experiments were performed in diploid vs. aneuploid non-transformed human primary cells. Overall, our data show that aneuploidy can confer selective advantage to human cells cultured under non-standard conditions. These findings indicate that aneuploidy can increase the adaptability of cells, even those, such as cancer cells, that are already characterized by increased proliferative capacity and aggressive tumorigenic phenotypes. PMID- 26956416 TI - Guidelines for Dual Energy X-Ray Absorptiometry Analysis of Trabecular Bone-Rich Regions in Mice: Improved Precision, Accuracy, and Sensitivity for Assessing Longitudinal Bone Changes. AB - Trabecular bone is frequently studied in osteoporosis research because changes in trabecular bone are the most common cause of osteoporotic fractures. Dual energy X-ray absorptiometry (DXA) analysis specific to trabecular bone-rich regions is crucial to longitudinal osteoporosis research. The purpose of this study is to define a novel method for accurately analyzing trabecular bone-rich regions in mice via DXA. This method will be utilized to analyze scans obtained from the International Space Station in an upcoming study of microgravity-induced bone loss. Thirty 12-week-old BALB/c mice were studied. The novel method was developed by preanalyzing trabecular bone-rich sites in the distal femur, proximal tibia, and lumbar vertebrae via high-resolution X-ray imaging followed by DXA and micro computed tomography (micro-CT) analyses. The key DXA steps described by the novel method were (1) proper mouse positioning, (2) region of interest (ROI) sizing, and (3) ROI positioning. The precision of the new method was assessed by reliability tests and a 14-week longitudinal study. The bone mineral content (BMC) data from DXA was then compared to the BMC data from micro-CT to assess accuracy. Bone mineral density (BMD) intra-class correlation coefficients of the new method ranging from 0.743 to 0.945 and Levene's test showing that there was significantly lower variances of data generated by new method both verified its consistency. By new method, a Bland-Altman plot displayed good agreement between DXA BMC and micro-CT BMC for all sites and they were strongly correlated at the distal femur and proximal tibia (r=0.846, p<0.01; r=0.879, p<0.01, respectively). The results suggest that the novel method for site-specific analysis of trabecular bone-rich regions in mice via DXA yields more precise, accurate, and repeatable BMD measurements than the conventional method. PMID- 26956418 TI - Impaired endothelial barrier function in apolipoprotein M-deficient mice is dependent on sphingosine-1-phosphate receptor 1. AB - Apolipoprotein M (ApoM) transports sphingosine-1-phosphate (S1P) in plasma, and ApoM-deficient mice (Apom(-/-)) have ~50% reduced plasma S1P levels. There are 5 known S1P receptors, and S1P induces adherens junction formation between endothelial cells through the S1P1 receptor, which in turn suppresses vascular leak. Increased vascular permeability is a hallmark of inflammation. The purpose of this study was to explore the relationships between vascular leakage in ApoM deficiency and S1P1 function in normal physiology and in inflammation. Vascular permeability in the lungs was assessed by accumulation of dextran molecules (70 kDa) and was increased ~40% in Apom(-/-) mice compared to WT (C57Bl6/j) mice. Reconstitution of plasma ApoM/S1P or treatment with an S1P1 receptor agonist (SEW2871) rapidly reversed the vascular leakage to a level similar to that in WT mice, suggesting that it is caused by decreased plasma levels of S1P and reduced S1P1 stimulation. In a carrageenan-induced model of inflammation, Apom(-/-) mice had increased vascular leakage compared with that in WT mice. Adenoviral overexpression of ApoM in Apom(-/-) mice decreased the vascular leakage compared to adenoviral overexpression of green fluorescent protein. The study suggests that vascular leakage of albumin-sized particles in ApoM deficiency is S1P- and S1P1-dependent and this dependency exacerbates the response to inflammatory stimuli.-Christensen, P. M., Liu, C. H., Swendeman, S. L., Obinata, H., Qvortrup, K., Nielsen, L B., Hla, T., Di Lorenzo, A., Christoffersen, C. Impaired endothelial barrier function in apolipoprotein M-deficient mice is dependent on sphingosine-1-phosphate receptor 1. PMID- 26956417 TI - Leishmania-encoded orthologs of macrophage migration inhibitory factor regulate host immunity to promote parasite persistence. AB - Leishmania major encodes 2 orthologs of the cytokine macrophage migration inhibitory factor (MIF), whose functions in parasite growth or in the host parasite interaction are unknown. To determine the importance of Leishmania encoded MIF, both LmMIF genes were removed to produce an mif(-/-) strain of L. major This mutant strain replicated normally in vitro but had a 2-fold increased susceptibility to clearance by macrophages. Mice infected with mif(-/-) L. major, when compared to the wild-type strain, also showed a 3-fold reduction in parasite burden. Microarray and functional analyses revealed a reduced ability of mif(-/-) L. major to activate antigen-presenting cells, resulting in a 2-fold reduction in T-cell priming. In addition, there was a reduction in inflammation and effector CD4 T-cell formation in mif(-/-) L. major-infected mice when compared to mice infected with wild-type L. major Notably, effector CD4 T cells that developed during infection with mif(-/-) L. major demonstrated statistically significant differences in markers of functional exhaustion, including increased expression of IFN-gamma and IL-7R, reduced expression of programmed death-1, and decreased apoptosis. These data support a role for LmMIF in promoting parasite persistence by manipulating the host response to increase the exhaustion and depletion of protective CD4 T cells.-Holowka, T., Castilho, T. M., Baeza Garcia, A., Sun, T., McMahon-Pratt, D., Bucala, R. Leishmania-encoded orthologs of macrophage migration inhibitory factor regulate host immunity to promote parasite persistence. PMID- 26956420 TI - Effects of maternal exposure to aflatoxin B1 during pregnancy on fertility output of dams and developmental, behavioral and reproductive consequences in female offspring using a rat model. AB - A suboptimal in utero environment can have detrimental effects on the pregnancy and long-term adverse "programing" effects on the offspring. Aflatoxin B1 is one of the potent reproductive toxicants and currently detected in both milk and tissues. This article focuses on the effects of prenatal exposure to graded doses of aflatoxin B1 on the pregnancy outcomes of dams and postnatal developments of the female offspring, since these issues have ethological relevance in both animals and humans. Pregnant Wistar rats were injected intramuscularly with vehicle or aflatoxin B1 (10, 20, 50 or 100 MUg/kg body weight/day) on days 12-19 of gestation. At parturition, newborns were observed for clinical signs of toxicity and survival. The female offspring were examined through a battery of tests in order to evaluate their developmental, behavioral and reproductive end points. All animals were born alive. The litter size of the aflatoxin B1 treated rats was comparable to the controls. However, the birth weight of the pups in the experimental group was significantly lower when compared to controls. Significant and persistent lags in cliff avoidance, negative geotaxis, surface rightening activity and ascending wire mesh, with a delay in elapsed time for vaginal opening were detected in the female progeny exposed to aflatoxin B1 during embryonic development. The locomotor activity and exploratory behavior in experimental females were significantly decreased than that of controls. Embryonic exposure to aflatoxin B1 also resulted in prolonged stress response, irregular estrus and suppressed fertility output in the progeny at their adulthood. These results indicate that in utero exposure to aflatoxin B1 severely compromised postnatal development of neonatal rats and caused irregular estrus that was accompanied by suppressed fertility output. PMID- 26956421 TI - Brain activity underlying tool-related and imitative skills after major left hemisphere stroke. AB - Apraxia is a debilitating cognitive motor disorder that frequently occurs after left hemisphere stroke and affects tool-associated and imitative skills. However, the severity of the apraxic deficits varies even across patients with similar lesions. This variability raises the question whether regions outside the left hemisphere network typically associated with cognitive motor tasks in healthy subjects are of additional functional relevance. To investigate this hypothesis, we explored regions where functional magnetic resonance imaging activity is associated with better cognitive motor performance in patients with left hemisphere ischaemic stroke. Thirty-six patients with chronic (>6 months) large left hemisphere infarcts (age +/- standard deviation, 60 +/- 12 years, 29 male) and 29 control subjects (age +/- standard deviation, 72 +/- 7, 15 male) were first assessed behaviourally outside the scanner with tests for actual tool use, pantomime and imitation of tool-use gestures, as well as for meaningless gesture imitation. Second, functional magnetic resonance imaging activity was registered during the passive observation of videos showing tool-associated actions. Voxel wise linear regression analyses were used to identify areas where behavioural performance was correlated with functional magnetic resonance imaging activity. Furthermore, lesions were delineated on the magnetic resonance imaging scans for voxel-based lesion-symptom mapping. The analyses revealed two sets of regions where functional magnetic resonance imaging activity was associated with better performance in the clinical tasks. First, activity in left hemisphere areas thought to mediate cognitive motor functions in healthy individuals (i.e. activity within the putative 'healthy' network) was correlated with better scores. Within this network, tool-associated tasks were mainly related to activity in supramarginal gyrus and ventral premotor cortex, while meaningless gesture imitation depended more on the anterior intraparietal sulcus and superior parietal lobule. Second, repeating the regression analyses with total left hemisphere lesion volume as additional covariate demonstrated that tool-related skills were further supported by right premotor, right inferior frontal and left anterior temporal areas, while meaningless gesture imitation was also driven by the left dorso-lateral prefrontal cortex. In summary, tool-related and imitative skills in left hemisphere stroke patients depend on the activation of spared left hemisphere regions that support these abilities in healthy individuals. In addition, cognitive motor functions rely on the activation of ipsi- and contralesional areas that are situated outside this 'healthy' network. This activity may explain why some patients perform surprisingly well despite large left brain lesions, while others are severely impaired. PMID- 26956414 TI - Meta-analysis of genome-wide association studies discovers multiple loci for chronic lymphocytic leukemia. AB - Chronic lymphocytic leukemia (CLL) is a common lymphoid malignancy with strong heritability. To further understand the genetic susceptibility for CLL and identify common loci associated with risk, we conducted a meta-analysis of four genome-wide association studies (GWAS) composed of 3,100 cases and 7,667 controls with follow-up replication in 1,958 cases and 5,530 controls. Here we report three new loci at 3p24.1 (rs9880772, EOMES, P=2.55 * 10(-11)), 6p25.2 (rs73718779, SERPINB6, P=1.97 * 10(-8)) and 3q28 (rs9815073, LPP, P=3.62 * 10( 8)), as well as a new independent SNP at the known 2q13 locus (rs9308731, BCL2L11, P=1.00 * 10(-11)) in the combined analysis. We find suggestive evidence (P<5 * 10(-7)) for two additional new loci at 4q24 (rs10028805, BANK1, P=7.19 * 10(-8)) and 3p22.2 (rs1274963, CSRNP1, P=2.12 * 10(-7)). Pathway analyses of new and known CLL loci consistently show a strong role for apoptosis, providing further evidence for the importance of this biological pathway in CLL susceptibility. PMID- 26956422 TI - Increased cortical grey matter lesion detection in multiple sclerosis with 7 T MRI: a post-mortem verification study. AB - The relevance of cortical grey matter pathology in multiple sclerosis has become increasingly recognized over the past decade. Unfortunately, a large part of cortical lesions remain undetected on magnetic resonance imaging using standard field strength. In vivo studies have shown improved detection by using higher magnetic field strengths up to 7 T. So far, a systematic histopathological verification of ultra-high field magnetic resonance imaging pulse sequences has been lacking. The aim of this study was to determine the sensitivity of 7 T versus 3 T magnetic resonance imaging pulse sequences for the detection of cortical multiple sclerosis lesions by directly comparing them to histopathology. We obtained hemispheric coronally cut brain sections of 19 patients with multiple sclerosis and four control subjects after rapid autopsy and formalin fixation, and scanned them using 3 T and 7 T magnetic resonance imaging systems. Pulse sequences included T1-weighted, T2-weighted, fluid attenuated inversion recovery, double inversion recovery and T2*. Cortical lesions (type I-IV) were scored on all sequences by an experienced rater blinded to histopathology and clinical data. Staining was performed with antibodies against proteolipid protein and scored by a second reader blinded to magnetic resonance imaging and clinical data. Subsequently, magnetic resonance imaging images were matched to histopathology and sensitivity of pulse sequences was calculated. Additionally, a second unblinded (retrospective) scoring of magnetic resonance images was performed. Regardless of pulse sequence, 7 T magnetic resonance imaging detected more cortical lesions than 3 T. Fluid attenuated inversion recovery (7 T) detected 225% more cortical lesions than 3 T fluid attenuated inversion recovery (Z = 2.22, P < 0.05) and 7 T T2* detected 200% more cortical lesions than 3 T T2* (Z = 2.05, P < 0.05). Sensitivity of 7 T magnetic resonance imaging was influenced by cortical lesion type: 100% for type I (T2), 11% for type II (FLAIR/T2), 32% for type III (T2*), and 68% for type IV (T2). We conclude that ultra-high field 7 T magnetic resonance imaging more than doubles detection of cortical multiple sclerosis lesions, compared to 3 T magnetic resonance imaging. Unfortunately, (subpial) cortical pathology remains more extensive than 7 T magnetic resonance imaging can reveal. PMID- 26956419 TI - Contribution of the anaphylatoxin receptors, C3aR and C5aR, to the pathogenesis of pulmonary fibrosis. AB - Complement activation, an integral arm of innate immunity, may be the critical link to the pathogenesis of idiopathic pulmonary fibrosis (IPF). Whereas we have previously reported elevated anaphylatoxins-complement component 3a (C3a) and complement component 5a (C5a)-in IPF, which interact with TGF-beta and augment epithelial injury in vitro, their role in IPF pathogenesis remains unclear. The objective of the current study is to determine the mechanistic role of the binding of C3a/C5a to their respective receptors (C3aR and C5aR) in the progression of lung fibrosis. In normal primary human fetal lung fibroblasts, C3a and C5a induces mesenchymal activation, matrix synthesis, and the expression of their respective receptors. We investigated the role of C3aR and C5aR in lung fibrosis by using bleomycin-injured mice with fibrotic lungs, elevated local C3a and C5a, and overexpression of their receptors via pharmacologic and RNA interference interventions. Histopathologic examination revealed an arrest in disease progression and attenuated lung collagen deposition (Masson's trichrome, hydroxyproline, collagen type I alpha 1 chain, and collagen type I alpha 2 chain). Pharmacologic or RNA interference-specific interventions suppressed complement activation (C3a and C5a) and soluble terminal complement complex formation (C5b-9) locally and active TGF-beta1 systemically. C3aR/C5aR antagonists suppressed local mRNA expressions of tgfb2, tgfbr1/2, ltbp1/2, serpine1, tsp1, bmp1/4, pdgfbb, igf1, but restored the proteoglycan, dcn Clinically, compared with pathologically normal human subjects, patients with IPF presented local induction of C5aR, local and systemic induction of soluble C5b-9, and amplified expression of C3aR/C5aR in lesions. The blockade of C3aR and C5aR arrested the progression of fibrosis by attenuating local complement activation and TGF-beta/bone morphologic protein signaling as well as restoring decorin, which suggests a promising therapeutic strategy for patients with IPF.-Gu, H., Fisher, A. J., Mickler, E. A., Duerson, F., III, Cummings, O. W., Peters-Golden, M., Twigg, H. L., III, Woodruff, T. M., Wilkes, D. S., Vittal, R. Contribution of the anaphylatoxin receptors, C3aR and C5aR, to the pathogenesis of pulmonary fibrosis. PMID- 26956423 TI - A subcutaneous cellular implant for passive immunization against amyloid-beta reduces brain amyloid and tau pathologies. AB - Passive immunization against misfolded toxic proteins is a promising approach to treat neurodegenerative disorders. For effective immunotherapy against Alzheimer's disease, recent clinical data indicate that monoclonal antibodies directed against the amyloid-beta peptide should be administered before the onset of symptoms associated with irreversible brain damage. It is therefore critical to develop technologies for continuous antibody delivery applicable to disease prevention. Here, we addressed this question using a bioactive cellular implant to deliver recombinant anti-amyloid-beta antibodies in the subcutaneous tissue. An encapsulating device permeable to macromolecules supports the long-term survival of myogenic cells over more than 10 months in immunocompetent allogeneic recipients. The encapsulated cells are genetically engineered to secrete high levels of anti-amyloid-beta antibodies. Peripheral implantation leads to continuous antibody delivery to reach plasma levels that exceed 50 ug/ml. In a proof-of-concept study, we show that the recombinant antibodies produced by this system penetrate the brain and bind amyloid plaques in two mouse models of the Alzheimer's pathology. When encapsulated cells are implanted before the onset of amyloid plaque deposition in TauPS2APP mice, chronic exposure to anti-amyloid beta antibodies dramatically reduces amyloid-beta40 and amyloid-beta42 levels in the brain, decreases amyloid plaque burden, and most notably, prevents phospho tau pathology in the hippocampus. These results support the use of encapsulated cell implants for passive immunotherapy against the misfolded proteins, which accumulate in Alzheimer's disease and other neurodegenerative disorders. PMID- 26956424 TI - Rates of ICU Transfers After a Scheduled Night-Shift Interprofessional Huddle. AB - OBJECTIVES: To evaluate a scheduled interprofessional huddle among pediatric residents, nursing staff, and cardiologists on the number of high-risk transfers to the ICU. METHODS: A daily, night-shift huddle intervention was initiated between the in-house pediatric residents and nursing staff covering the cardiology ward patients with the at-home attending cardiologist. Retrospective cohort chart review identified high-risk transfers from the inpatient floor to the ICU over a 24-month period (eg, inotropic support, intubation, and/or respiratory support within 1 hour of ICU transfer). Satisfaction with the intervention and the impact of the intervention on team-based communication and resident education was collected using a retrospective pre-post survey. RESULTS: Ninety-three patients were identified as unscheduled transfers from the ward team to the ICU. Overall, 21 preintervention transfers were considered high risk, whereas only 8 patients were considered high risk after the intervention (P=.004). During the night shift, high risk transfers decreased from 8 of 17 (47%) to 3 of 21 patients (14%) (P=.03). Interprofessional communication improved with 12 of 14 nurses and 24 of 25 residents reporting effective communication after the intervention (P<.0001) compared with only 1 nurse and 15 residents reporting a positive experience before the intervention. Overall, all 3 provider groups stated an improved experience covering a high-risk cardiology patient population. CONCLUSIONS: Implementation of an interprofessional huddle may contribute to decreasing high-risk transfers to the ICU. Initiating a daily huddle was well received and allowed for open lines of communication across all provider groups. PMID- 26956426 TI - The Role of Specific Alcohol-Related Problems in Predicting Depressive Experiences in a Cross-Sectional National Household Survey. AB - AIMS: This study examines the type of alcohol-related problems that commonly occur before the onset of depressive experiences to shed light on the mechanisms underlying the alcohol-depression comorbidity relationship. METHODS: Data were from the 1992 USA National Longitudinal Alcohol Epidemiologic Survey. Analytical sample comprised of drinkers with a prior to past year (PPY) history of alcohol related problems with or without any experiences of depressed mood in the past year (PY). The prevalence of PPY alcohol-related problems was examined, as well as the ability of specific alcohol problems to predict PY experiences of depressed mood. The type of depressed mood experienced by drinkers with PPY history of alcohol-related problems was compared to those without. RESULTS: All but one alcohol-related problem PPY was more frequently endorsed among drinkers with PY experiences of depressed mood. Controlling for confounders, five alcohol related problems experienced PPY were significantly predictive of depressed mood PY: tolerance, drinking longer than intended, inability to perform important social and occupational roles/obligations, as well as drinking in physically hazardous situations. Drinkers with alcohol-related problems PPY more frequently experienced difficulties with concentration, energy, and thoughts of death, than those without. CONCLUSIONS: Alcohol-related problems are likely associated with depressive experiences through a complex network, whereby experiences of physical dependence and negative consequences increase the likelihood of negative affect. Novel study designs are necessary to fully understand the complex mechanisms underlying this comorbidity. PMID- 26956425 TI - Phosphorus Doping in Si Nanocrystals/SiO2 multilayers and Light Emission with Wavelength compatible for Optical Telecommunication. AB - Doping in semiconductors is a fundamental issue for developing high performance devices. However, the doping behavior in Si nanocrystals (Si NCs) has not been fully understood so far. In the present work, P-doped Si NCs/SiO2 multilayers are fabricated. As revealed by XPS and ESR measurements, P dopants will preferentially passivate the surface states of Si NCs. Meanwhile, low temperature ESR spectra indicate that some P dopants are incorporated into Si NCs substitutionally and the incorporated P impurities increase with the P doping concentration or annealing temperature increasing. Furthermore, a kind of defect states will be generated with high doping concentration or annealing temperature due to the damage of Si crystalline lattice. More interestingly, the incorporated P dopants can generate deep levels in the ultra-small sized (~2 nm) Si NCs, which will cause a new subband light emission with the wavelength compatible with the requirement of the optical telecommunication. The studies of P-doped Si NCs/SiO2 multilayers suggest that P doping plays an important role in the electronic structures and optoelectronic characteristics of Si NCs. PMID- 26956427 TI - Longitudinal Effects of Acculturation on Alcohol Use among Vietnamese and Cambodian Immigrant Women in the USA. AB - AIMS: Recent studies indicate that alcohol use is increasing among Asian American populations and that acculturation impacts alcohol use among immigrants in the USA. We investigated the longitudinal relationship between three domains of acculturation (traditionalism, biculturalism, assimilation) and alcohol use among 302 Vietnamese and Cambodian women in Washington State. METHODS: Data were obtained from the Cross Cultural Families Project (CCF), a 5-year longitudinal investigation of a random sample of Vietnamese and Cambodian immigrant families living in Washington State. Alcohol use was measured with a three item scale assessing frequency and quantity of use, and binge drinking. Acculturation was measured with the Suinn-Lew Asian Self-Identity Acculturation Scale. Linear mixed effects regression models were estimated to assess the impact of acculturation on alcohol use among the overall sample and among a sub-sample of only women who consumed any alcohol. RESULTS: A majority of the sample, 73.2%, reported no alcohol use. In the overall sample, none of the three acculturation domains were significantly associated with drinking. Among a sub-sample of only those who reported any alcohol use, however, a greater degree of traditional cultural identification (beta = -0.94, SE= 0.44, P= 0.03) and a greater degree of biculturalism (beta = -1.33, SE= 0.53, P =0.01) were associated with lower levels of use. CONCLUSIONS: Our findings suggest that acculturation did not impact alcohol use prevalence but that it did affect the drinking pattern among alcohol consumers. Clinicians should be cognizant that certain aspects of cultural identification are important contributors to drinking behavior among alcohol consumers in these populations. PMID- 26956428 TI - Chemical Treatment of Low-k Dielectric Surfaces for Patterning of Thin Solid Films in Microelectronic Applications. AB - A protocol has been developed to selectively process low-k SiCOH dielectric substrates in order to activate or deactivate them toward the deposition of thin solid films by chemical (CVD or ALD) means. The original SiCOH surfaces are hydrophobic, an indication that they are alkyl- rather than silanol-terminated and that, consequently, they are fairly unreactive. However, the chemical mechanical polishing (CMP) sometimes done during microelectronics fabrication renders them hydrophilic and reactive. It was shown here that silylation of the CMP-treated surfaces with any of a number of well-known silylation agents such as HMDS, ODTS, or OTS caps the reactive silanol surface groups and turns them back to being hydrophilic and unreactive. Further exposure of any of the passivated surfaces to a combination of ozone and UV radiation reinstates their hydrophilicity and chemical activity. Importantly, it was also demonstrated that all these changes could be induced without altering the original mechanical, optical, or electrical properties of the samples: atomic force microscopy (AFM) images show no increase in roughness, ellipsometry measurements yield the same values for the index of refraction and dielectric constant, and infrared absorption spectroscopy attests to the preservation of the organic fragments present in the original SiCOH samples. The chemical selectivity of the resulting surfaces was tested for the atomic layer deposition (ALD) of HfO2 films, which could be grown only on the UV/O3 treated substrates. PMID- 26956430 TI - Accurate and interpretable nanoSAR models from genetic programming-based decision tree construction approaches. AB - The number of engineered nanomaterials (ENMs) being exploited commercially is growing rapidly, due to the novel properties they exhibit. Clearly, it is important to understand and minimize any risks to health or the environment posed by the presence of ENMs. Data-driven models that decode the relationships between the biological activities of ENMs and their physicochemical characteristics provide an attractive means of maximizing the value of scarce and expensive experimental data. Although such structure-activity relationship (SAR) methods have become very useful tools for modelling nanotoxicity endpoints (nanoSAR), they have limited robustness and predictivity and, most importantly, interpretation of the models they generate is often very difficult. New computational modelling tools or new ways of using existing tools are required to model the relatively sparse and sometimes lower quality data on the biological effects of ENMs. The most commonly used SAR modelling methods work best with large datasets, are not particularly good at feature selection, can be relatively opaque to interpretation, and may not account for nonlinearity in the structure property relationships. To overcome these limitations, we describe the application of a novel algorithm, a genetic programming-based decision tree construction tool (GPTree) to nanoSAR modelling. We demonstrate the use of GPTree in the construction of accurate and interpretable nanoSAR models by applying it to four diverse literature datasets. We describe the algorithm and compare model results across the four studies. We show that GPTree generates models with accuracies equivalent to or superior to those of prior modelling studies on the same datasets. GPTree is a robust, automatic method for generation of accurate nanoSAR models with important advantages that it works with small datasets, automatically selects descriptors, and provides significantly improved interpretability of models. PMID- 26956429 TI - Transglutaminase 2 contributes to a TP53-induced autophagy program to prevent oncogenic transformation. AB - Genetic alterations which impair the function of the TP53 signaling pathway in TP53 wild-type human tumors remain elusive. To identify new components of this pathway, we performed a screen for genes whose loss-of-function debilitated TP53 signaling and enabled oncogenic transformation of human mammary epithelial cells. We identified transglutaminase 2 (TGM2) as a putative tumor suppressor in the TP53 pathway. TGM2 suppressed colony formation in soft agar and tumor formation in a xenograft mouse model. The depletion of growth supplements induced both TGM2 expression and autophagy in a TP53-dependent manner, and TGM2 promoted autophagic flux by enhancing autophagic protein degradation and autolysosome clearance. Reduced expression of both CDKN1A, which regulates the cell cycle downstream of TP53, and TGM2 synergized to promote oncogenic transformation. Our findings suggest that TGM2-mediated autophagy and CDKN1A-mediated cell cycle arrest are two important barriers in the TP53 pathway that prevent oncogenic transformation. PMID- 26956431 TI - HLA-E polymorphism and soluble HLA-E plasma levels in chronic hepatitis B patients. AB - Chronic hepatitis B virus (HBV) infection occurs in association to a deregulation of immune system. Human leukocyte antigen E (HLA-E) is an immune-tolerant nonclassical HLA class I molecule that could be involved in HBV progression. To measure soluble (s) HLA-E in patients with chronic HBV hepatitis (CHB). We tested the potential association of HLA-E*01:01/01:03 A > G gene polymorphism to CHB. Our cohort consisted of 93 Tunisian CHB patients (stratified in CHB with high HBV DNA levels and CHB with low HBV DNA levels) and 245 healthy donors. Plasma sHLA-E was determined using enzyme-linked immunosorbent assay (ELISA). Genotyping was performed using polymerase chain reaction sequence-specific primer. No association between HLA-E*01:01/01:03 A > G polymorphism and HBV DNA levels in CHB patients was found. G/G genotype is less frequent in CHB patients without significance. sHLA-E is significantly enhanced in CHB patients compared with healthy controls (P = 0.0017). Stratification according to HBV DNA levels showed that CHB patients with low HBV DNA levels have higher sHLA-E levels compared with CHB patients with high HBV DNA levels. CHB patients with G/G genotype have enhanced sHLA-E levels compared with other genotypes (P = 0.037). This significant difference is maintained only for CHB women concerning G/G genotypes (P = 0.042). Finally, we reported enhanced sHLA-E in CHB patients with advanced stages of fibrosis (P = 0.032). We demonstrate, for the first time, the association of sHLA-E to CHB. Owing to the positive correlation of HLA E*01:01/01:03 A > G polymorphism and the association of sHLA-E to advanced fibrosis stages, HLA-E could be a powerful predictor for CHB progression. Further investigations will be required to substantiate HLA-E role as a putative clinical biomarker of CHB. PMID- 26956432 TI - Biweekly dose-dense gemcitabine-oxaliplatin and dexamethasone for relapsed/refractory aggressive non-Hodgkin lymphoma: A multicenter, single-arm, phase II trial. AB - AIM: We performed a phase II study to evaluate the efficacy of combination chemotherapy consisting of gemcitabine, dexamethasone and oxaliplatin (GemDOx) as a biweekly regimen and salvage therapy in patients with relapsed or refractory aggressive non-Hodgkin lymphoma (NHL). METHODS: Gemcitabine (1000 mg/m(2) ) and oxaliplatin (85 mg/m(2) ) were administered intravenously on days 1 and 15, and dexamethasone (40 mg) was administered orally on days 1-4. RESULTS: Twenty-nine patients were enrolled, and most patients had diffuse large B-cell lymphoma (n = 18). The median age of the patients and median prior number of chemotherapy cycles were 53 (range, 26-74) years and 1 (range, 1-4) cycle, respectively. Only 17 (58.6%) and 9 (31.0%) patients completed two or more and four or more cycles, respectively, and the median number of received cycles was two (range, 1-8). Overall response rates were 27.6% (complete response in 13.8%) among intent-to treat patients and 47.1% (complete response in 23.5%) among patients who had received at least two GemDOx cycles. Median progression-free survival and median overall survival were 3.9 and 20.5 months, respectively. The most-frequent grade 3 or 4 toxicity was neutropenia (22.9%), and no grade 3 or 4 peripheral neurotoxicity was noted. CONCLUSION: GemDOx chemotherapy, therefore, showed modest activity against relapsed or refractory aggressive NHL, although toxicities were acceptable. PMID- 26956433 TI - Improving cell mixture deconvolution by identifying optimal DNA methylation libraries (IDOL). AB - BACKGROUND: Confounding due to cellular heterogeneity represents one of the foremost challenges currently facing Epigenome-Wide Association Studies (EWAS). Statistical methods leveraging the tissue-specificity of DNA methylation for deconvoluting the cellular mixture of heterogenous biospecimens offer a promising solution, however the performance of such methods depends entirely on the library of methylation markers being used for deconvolution. Here, we introduce a novel algorithm for Identifying Optimal Libraries (IDOL) that dynamically scans a candidate set of cell-specific methylation markers to find libraries that optimize the accuracy of cell fraction estimates obtained from cell mixture deconvolution. RESULTS: Application of IDOL to training set consisting of samples with both whole-blood DNA methylation data (Illumina HumanMethylation450 BeadArray (HM450)) and flow cytometry measurements of cell composition revealed an optimized library comprised of 300 CpG sites. When compared existing libraries, the library identified by IDOL demonstrated significantly better overall discrimination of the entire immune cell landscape (p = 0.038), and resulted in improved discrimination of 14 out of the 15 pairs of leukocyte subtypes. Estimates of cell composition across the samples in the training set using the IDOL library were highly correlated with their respective flow cytometry measurements, with all cell-specific R (2)>0.99 and root mean square errors (RMSEs) ranging from [0.97 % to 1.33 %] across leukocyte subtypes. Independent validation of the optimized IDOL library using two additional HM450 data sets showed similarly strong prediction performance, with all cell-specific R (2)>0.90 and R M S E<4.00 %. In simulation studies, adjustments for cell composition using the IDOL library resulted in uniformly lower false positive rates compared to competing libraries, while also demonstrating an improved capacity to explain epigenome-wide variation in DNA methylation within two large publicly available HM450 data sets. CONCLUSIONS: Despite consisting of half as many CpGs compared to existing libraries for whole blood mixture deconvolution, the optimized IDOL library identified herein resulted in outstanding prediction performance across all considered data sets and demonstrated potential to improve the operating characteristics of EWAS involving adjustments for cell distribution. In addition to providing the EWAS community with an optimized library for whole blood mixture deconvolution, our work establishes a systematic and generalizable framework for the assembly of libraries that improve the accuracy of cell mixture deconvolution. PMID- 26956434 TI - Short epitope-based synthetic peptides for serodiagnosis of human strongyloidiasis. AB - Strongyloidiasis is one of the major intestinal infections in humans, and a neglected tropical disease whose diagnosis still poses a challenge. We hypothesized that diagnostic tests based on short peptides containing major epitopes may represent a promising strategy to improve strongyloidiasis detection due to reduced cross-reactivity and higher sensitivity. Our aim was to evaluate two synthetic peptides selected by phage display (C10 and D3) as potential tools for serodiagnosis of strongyloidiasis, and to predict their putative antigen target. To investigate their diagnostic potential, we have tested different panels of serum samples (n=120) by enzyme linked immunosorbent assay (ELISA) to detect specific IgG, and their diagnostic parameters were calculated. Similarities with proteins from Strongyloides stercoralis were searched and conformational epitopes were predicted and aligned to known protein structures. Both C10 and D3 achieved sensitivity of 95%, and specificities were 89.2% and 92.5%, respectively. D3 presented the highest diagnostic efficiency (93.3%). Epitope prediction for both C10 and D3 led to the alignment with the cytochrome c oxidase subunit 1 structure. In brief, we propose two synthetic peptides as new biomarkers for serodiagnosis of strongyloidiasis, which can be promptly used for ELISA and in future field sensor platforms. PMID- 26956435 TI - Efficient derivation of dopaminergic neurons from SOX1- floor plate cells under defined culture conditions. AB - BACKGROUND: Parkinson's disease (PD) is a severe neurodegenerative disease associated with loss of dopaminergic neurons. Derivation of dopaminergic neurons from human embryonic stem cells (hESCs) could provide new therapeutic options for PD therapy. Dopaminergic neurons are derived from SOX(-) floor plate (FP) cells during embryonic development in many species and in human cell culture in vitro. Early treatment with sonic hedgehog (Shh) has been reported to efficiently convert hESCs into FP lineages. METHODS: In this study, we attempted to utilize a Shh-free approach in deriving SOX1(-) FP cells from hESCs in vitro. Neuroectoderm conversion from hESCs was achieved with dual inhibition of the BMP4 (LDN193189) and TGF-beta signaling pathways (SB431542) for 24 h under defined culture conditions. RESULTS: Following a further 5 days of treatment with LDN193189 or LDN193189 + SB431542, SOX1(-) FP cells constituted 70-80 % of the entire cell population. Upon treatment with Shh and FGF8, the SOX1(-) FP cells were efficiently converted to functional Nurr1(+) and TH(+) dopaminergic cells (patterning), which constituted more than 98 % of the entire cell population. However, when the same growth factors were applied to SOX1(+) cells, only less than 4 % of the cells became Nurr1(+), indicating that patterning was effective only if SOX1 expression was down-regulated. After transplanting the Nurr1(+) and TH(+) cells into a hemiparkinsonian rat model, significant improvements were observed in amphetamine induced ipslateral rotations, apomorphine induced contra lateral rotations and Rota rod motor tests over a duration of 8 weeks. CONCLUSIONS: Our findings thus provide a convenient approach to FP development and functional dopaminergic neuron derivation. PMID- 26956436 TI - Longitudinal Effects of Sexual Assault Victims' Drinking and Self-Blame on Posttraumatic Stress Disorder. AB - Alcohol plays a major role in sexual assaults, but few studies have examined its impact on recovery outcomes, particularly in longitudinal studies. In a longitudinal study of 1,013 adult sexual assault survivors, we investigated the effects of victim drinking on posttraumatic stress disorder (PTSD), as well as the mediating role of characterological and behavioral self-blame attributions. In line with some prior research, victims who were drinking before their assault experienced less PTSD, but more self-blame than those who were not. Characterological, but not behavioral self-blame was related to increased PTSD symptoms. Thus, although drinking was overall related to less PTSD, it was also associated with increased PTSD via self-blame attributions, highlighting the danger of blaming victims of alcohol-related rapes for their assaults. Implications for future research and clinical work with survivors of alcohol related sexual assaults are drawn. PMID- 26956438 TI - [Not Available]. PMID- 26956437 TI - Multiple Reaction Monitoring for Direct Quantitation of Intact Proteins Using a Triple Quadrupole Mass Spectrometer. AB - Methods that can efficiently and effectively quantify proteins are needed to support increasing demand in many bioanalytical fields. Triple quadrupole mass spectrometry (QQQ-MS) is sensitive and specific, and it is routinely used to quantify small molecules. However, low resolution fragmentation-dependent MS detection can pose inherent difficulties for intact proteins. In this research, we investigated variables that affect protein and fragment ion signals to enable protein quantitation using QQQ-MS. Collision induced dissociation gas pressure and collision energy were found to be the most crucial variables for optimization. Multiple reaction monitoring (MRM) transitions for seven standard proteins, including lysozyme, ubiquitin, cytochrome c from both equine and bovine, lactalbumin, myoglobin, and prostate-specific antigen (PSA) were determined. Assuming the eventual goal of applying such methodology is to analyze protein in biological fluids, a liquid chromatography method was developed. Calibration curves of six standard proteins (excluding PSA) were obtained to show the feasibility of intact protein quantification using QQQ-MS. Linearity (2-3 orders), limits of detection (0.5-50 MUg/mL), accuracy (<5% error), and precision (1%-12% CV) were determined for each model protein. Sensitivities for different proteins varied considerably. Biological fluids, including human urine, equine plasma, and bovine plasma were used to demonstrate the specificity of the approach. The purpose of this model study was to identify, study, and demonstrate the advantages and challenges for QQQ-MS-based intact protein quantitation, a largely underutilized approach to date. PMID- 26956440 TI - Polymorphous sweat gland carcinoma: a report of two cases. AB - Polymorphous sweat gland carcinoma (PSGC) is a rare adnexal neoplasm with characteristic variegated histopathologic findings and low-grade clinical behavior. First described in 1994, only 11 cases have been reported in the literature. It is named for the multiplicity of architectural patterns that may be present: solid, tubular, trabecular, pseudopapillary and cylindromatous. Owing to the multiple architectural patterns, the differential diagnosis is broad, including metastatic adenocarcinoma and other adnexal neoplasms with ductular differentiation. We present two new cases of PSGC and review the literature on this rare tumor. PMID- 26956441 TI - Disorder in Milk Proteins: alpha -Lactalbumin. Part A. Structural Properties and Conformational Behavior. AB - This is a first part of the two-part article that continues a series of reviews on the abundance and roles of intrinsic disorder in milk proteins. We introduce here alpha-lactalbumin, a small (Mr 14 200), simple, acidic (pI 4-5), Ca(2+) binding protein that might constitute up to 20% of total milk protein. Although function (it is one of the two components of lactose synthase that catalyzes the final step of the lactose biosynthesis in the lactating mammary gland), structure (protein has two domains, a large alpha -helical domain and a small beta -sheet domain connected by a calcium binding loop), and folding mechanisms (alpha lactalbumin is well-known as a classic example of the molten globule state) of this model globular protein are relatively well understood, alpha-lactalbumin continues to surprise researchers and clearly continues to have high discovery potential. The goal of this review is to summarize some recent advances in the field of alpha-lactalbumin research and to analyze the peculiarities of the "intrinsic disorder code" of this protein. PMID- 26956439 TI - Ferrous iron content of intravenous iron formulations. AB - The observed biological differences in safety and efficacy of intravenous (IV) iron formulations are attributable to physicochemical differences. In addition to differences in carbohydrate shell, polarographic signatures due to ferric iron [Fe(III)] and ferrous iron [Fe(II)] differ among IV iron formulations. Intravenous iron contains Fe(II) and releases labile iron in the circulation. Fe(II) generates toxic free radicals and reactive oxygen species and binds to bacterial siderophores and other in vivo sequestering agents. To evaluate whether differences in Fe(II) content may account for some observed biological differences between IV iron formulations, samples from multiple lots of various IV iron formulations were dissolved in 12 M concentrated HCl to dissociate and release all iron and then diluted with water to achieve 0.1 M HCl concentration. Fe(II) was then directly measured using ferrozine reagent and ultraviolet spectroscopy at 562 nm. Total iron content was measured by adding an excess of ascorbic acid to reduce Fe(III) to Fe(II), and Fe(II) was then measured by ferrozine assay. The Fe(II) concentration as a proportion of total iron content [Fe(III) + Fe(II)] in different lots of IV iron formulations was as follows: iron gluconate, 1.4 and 1.8 %; ferumoxytol, 0.26 %; ferric carboxymaltose, 1.4 %; iron dextran, 0.8 %; and iron sucrose, 10.2, 15.5, and 11.0 % (average, 12.2 %). The average Fe(II) content in iron sucrose was, therefore, >=7.5-fold higher than in the other IV iron formulations. Further studies are needed to investigate the relationship between Fe(II) content and increased risk of oxidative stress and infections with iron sucrose. PMID- 26956442 TI - Hydroxypyridinones with enhanced iron chelating properties. Synthesis, characterization and in vivo tests of 5-hydroxy-2-(hydroxymethyl)pyridine-4(1H) one. AB - The synthesis of 5-hydroxy-2-(hydroxymethyl)pyridin-4(1H)-one (P1) is presented, together with the evaluation of its coordination ability towards Fe(3+), studied by a combination of chemical, computational, and animal approaches. The use of complementary analytical techniques has allowed us to give evidence of the tautomeric changes of P1 as a function of pH, and to determine their influence on the coordinating ability of P1 towards Fe(3+). The pFe(3+) value 22.0 of P1-iron complexes is noticeably higher than that of deferiprone (20.6), one of the three clinical chelating agents in therapeutic use for iron overload diseases. This is due on one side to the tautomeric change to the catechol form, and on the other to the lower protonation constant of the OH group. Bio-distribution studies on mice allowed us to confirm in vivo the efficacy of P1. Furthermore the coordinating ability toward Al(3+), Cu(2+) and Zn(2+) has been studied to evaluate the possible use of P1 against a second toxic metal ion (Al(3+)), and to envisage its potential influence on the homeostatic equilibria of essential metal ions. The chelating ability of P1 toward these ions, not higher than that of the corresponding deferiprone, contributes to render P1 a more selective iron chelator. PMID- 26956443 TI - Examining the relationship between HbA1c and diabetes risk models in a European population indicates a lower threshold to identify 'high risk' is required. AB - This study examined whether changes in HbA1c values are reflected in the risk scores and categories of four validated risk-assessment tools (QDiabetes, Leicester Risk Assessment, Finnish Diabetes Risk Score and Cambridge Risk Score). Retrospective analysis was performed on 651 individuals with no prior diagnosis of cardiovascular disease or diabetes who participated in a UK workplace-based risk-assessment initiative. There were significant positive correlations (p < 0.01) revealed between HbA1c values and predicted risk scores: QDiabetes (r = 0.362), Leicester Risk Assessment (r = 0.315), Finnish Diabetes Risk Score (r = 0.202) and Cambridge Risk Score (r = 0.335). HbA1c values increased within risk prediction categories, and at 'high-risk' categories, median HbA1c values were at least 39 mmol mol(-1) (5.7%) irrespective of gender or risk-assessment model. Overall, an association is present between increases in HbA1c scores and predicted risk of type 2 diabetes. Furthermore, the 'high-risk' median HbA1c values in each of the risk assessments are more akin to the lower American recommendations rather than those suggested by the UK expert group. PMID- 26956445 TI - Public supports commercial access to patient records when public benefit is clear. PMID- 26956444 TI - Prevalence of rheumatic diseases in Raramuri people in Chihuahua, Mexico: a community-based study. AB - This study aimed to determine the prevalence of musculoskeletal (MSK) pain and rheumatic diseases in the Raramuri population (also known as Tarahumaras) who are an indigenous group in the northern state of Chihuahua in Mexico. We used the Community-Oriented Program for Control of Rheumatic Diseases (COPCORD) methodology. An analytical cross-sectional study was conducted including indigenous Raramuri aged >=18 years from communities settled in Chihuahua City. Subjects with positive MSK pain were evaluated by primary care physicians and rheumatologists. Demographic and occupational factors such as gender and job type associated with rheumatic disease were investigated. A total of 380 indigenous Raramuri (mean age 33.6 +/- 13.1 years; 37.9 % male) were interviewed. Seventy six individuals (20 %) reported MSK pain in the last 7 days. Pain intensity was reported as "severe" and "the most severe" in 30 % of the cases. Fifty-six individuals (14.7 %) reported pain in the past and 86 (22.6 %) had either past or current pain. The prevalence of rheumatic diseases was 10.5 %. Diagnosed diseases were osteoarthritis (6.6 %), low back pain (1.6 %), spondyloarthritis (0.8 %), rheumatoid arthritis (0.5 %), non-specific arthritis (0.5 %), rheumatic regional pain syndromes (0.3 %), and fibromyalgia (0.3 %). Rheumatic disease was associated with the following variables: age (odds ratio (OR) 1.04, 95 % confidence interval (CI) 1.02-1.08; p = 0.006), family history of rheumatic symptoms (OR 6.9; 95 % CI 2.6-18.7; p < 0.001), and Health Assessment Questionnaire-Disability Index (OR 28.9; 95 % CI 2.8-289.7; p < 0.001). A high prevalence of non-traumatic MSK pain suggests the need for a rheumatic disease prevention program in the Raramuri people in Chihuahua, Mexico. PMID- 26956448 TI - Zika virus outbreak: 'a perfect storm'. PMID- 26956446 TI - Profiling of Leptospira interrogans, L. santarosai, L. meyeri and L. borgpetersenii by SE-AFLP, PFGE and susceptibility testing--a continuous attempt at species and serovar differentiation. AB - Leptospirosis is a widespread systemic zoonosis, considered as reemerging in certain developing countries. Although the cross agglutinin absorption test is still considered the standard method for Leptospira identification, it presents several disadvantages. The aim of this study was to characterize Leptospira spp. isolated from various hosts by genotyping and broth microdilution susceptibility testing in an attempt to differentiate Leptospira species, serogroups and serovars. Forty-seven isolates were studied. They were previously serotyped, and species confirmation was performed by 16S rRNA sequencing. Single-enzyme amplified fragment length polymorphism (SE-AFLP) and pulsed-field gel electrophoresis (PFGE) analysis enabled the distinction of L. interrogans from L. santarosai, L. meyeri and L. borgpetersenii in two main clusters. Among L. interrogans, it was possible to differentiate into two new clusters the serogroup Icterohaemorrhagiae from the serogroups Canicola and Pomona. L. santarosai isolates presented higher genetic variation than the other species in both techniques. Interestingly, the minimum inhibitory concentration (MIC) cluster analysis also provided Leptospira serogroup differentiation. Further studies are necessary regarding serovar Bananal isolates, as they presented the highest MIC values for most of the antimicrobials tested. All studied techniques successfully distinguished Leptospira species and serogroups. Despite being library-dependent methods, these approaches are less labor intensive and more economically viable, particularly SE-AFLP, and can be implemented in most reference laboratories worldwide to enable faster Leptospira typing. PMID- 26956449 TI - First Case of a Compound Heterozygosity for Two Nondeletional alpha-Thalassemia mutations, Hb Constant Spring and Hb Quong Sze. AB - Nondeletional alpha-thalassemia (alpha-thal) is the result of point mutations in critical regions of the alpha-globin genes, affecting mRNA processing, mRNA translation, or alpha-globin stability. Hb Constant Spring (Hb CS, HBA2: c.427T > C) is the most common nondeletional alpha-thal that results from a nucleotide substitution at the termination codon of the alpha2-globin gene. Hb Quong Sze (Hb QS, HBA2: c.377T > C) is another nondeletional alpha-thal in South China with the missense mutation at codon 125 of the alpha2-globin gene making this hemoglobin (Hb) variant highly unstable. Although homozygosity for Hb CS (alpha(CS)alpha/alpha(CS)alpha) or Hb QS (alpha(QS)alpha/alpha(QS)alpha) has been reported, clinical pictures vary from severe hemolysis that developed early in life to only mild anemia, no clinical phenotypic data of compound heterozygosity for Hb CS/Hb QS (alpha(CS)alpha/alpha(QS)alpha) has been described. In this report we describe an adult case with such a compound heterozygosity who presented with a mild alpha-thal. PMID- 26956452 TI - Assessing Quantitative Changes in Intrinsic Thalamic Networks in Blast and Nonblast Mild Traumatic Brain Injury: Implications for Mechanisms of Injury. AB - In the global war on terror, the increased use of improvised explosive devices has resulted in increased incidence of blast-related mild traumatic brain injury (mTBI). Diagnosing mTBI is both challenging and controversial due to heterogeneity of injury location, trauma intensity, transient symptoms, and absence of focal biomarkers on standard clinical imaging modalities. The goal of this study is to identify a brain biomarker that is sensitive to mTBI injury. Research suggests the thalamus may be sensitive to changes induced by mTBI. A significant number of connections to and from various brain regions converge at the thalamus. In addition, the thalamus is involved in information processing, integration, and regulation of specific behaviors and mood. In this study, changes in task-free thalamic networks as quantified by graph theory measures in mTBI blast (N = 186), mTBI nonblast (N = 80), and controls (N = 21) were compared. Results show that the blast mTBI group had significant hyper connectivity compared with the controls and nonblast mTBI group. However, after controlling for post-traumatic stress symptoms (PTSS), the blast mTBI group was not different from the controls, but the nonblast mTBI group showed significant hypo-connectivity. The results suggest that there are differences in the mechanisms of injury related to mTBI as reflected in the architecture of the thalamic networks. However, the effect of PTSS and its relationship to mTBI is difficult to distinguish and warrants more research. PMID- 26956454 TI - Charles Dickens' favourite child and a new kind of ray. PMID- 26956453 TI - Optometric use of a teleophthalmology service in rural Western Australia: comparison of two prospective audits. AB - BACKGROUND: Lions Outback Vision provides a telehealth service ('the telehealth service') to rural and remote communities in Western Australia aiming to deliver timely ophthalmic care to this underserved population. A number of barriers to its use were identified by an initial prospective audit. A multifaceted intervention was designed to increase the use of the telehealth service by optometrists. METHODS: Optometrists referred patients from rural and remote Western Australia to the telehealth service. Two five-month prospective audits of the telehealth service were compared. The first, in 2012, was prior to the implementation of the intervention. The second, in 2014, was during the period of the intervention, which included logistical support, remuneration to optometrists, a more user-friendly referral pathway and awareness raising. The outcome measures were the number of consultations conducted during the two audit periods and other quantitative changes to the telehealth service. RESULTS: After implementation of the intervention, use of the telehealth service increased 3.5 fold. A greater percentage of referrals were for non-urgent conditions (145 [69 per cent] versus 16 [32 per cent], p < 0.001) and less consultations recommended follow up with an ophthalmologist in clinic (42 [20 per cent] versus 17 [28 per cent], p = 0.04). Imaging studies were frequently used to supplement information provided by the referrer to the specialist during both audit periods. CONCLUSIONS: Optometrists used the telehealth service more frequently after the implementation of an intervention that addressed the barriers to its use. This has a number of potential benefits to rural and remote ocular health service provision in Australia. PMID- 26956447 TI - Talaromyces (Penicillium) marneffei infection in non-HIV-infected patients. AB - Talaromyces (Penicillium) marneffei is an important pathogenic thermally dimorphic fungus causing systemic mycosis in Southeast Asia. The clinical significance of T. marneffei became evident when the human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome epidemic arrived in Southeast Asia in 1988. Subsequently, a decline in the incidence of T. marneffei infection among HIV-infected patients was seen in regions with access to highly active antiretroviral therapy and other control measures for HIV. Since the 1990s, an increasing number of T. marneffei infections have been reported among non-HIV infected patients with impaired cell-mediated immunity. Their comorbidities included primary adult-onset immunodeficiency due to anti-interferon-gamma autoantibodies and secondary immunosuppressive conditions including other autoimmune diseases, solid organ and hematopoietic stem cell transplantations, T lymphocyte-depleting immunsuppressive drugs and novel anti-cancer targeted therapies such as anti-CD20 monoclonal antibodies and kinase inhibitors. Moreover, improved immunological diagnostics identified more primary immunodeficiency syndromes associated with T. marneffei infection in children. The higher case-fatality rate of T. marneffei infection in non-HIV-infected than HIV-infected patients might be related to delayed diagnosis due to the lack of clinical suspicion. Correction of the underlying immune defects and early use of antifungals are important treatment strategies. Clinicians should be familiar with the changing epidemiology and clinical management of T. marneffei infection among non-HIV-infected patients. PMID- 26956455 TI - COST-EFFECTIVENESS OF TREATMENTS FOR MILD-TO-MODERATE OBSTRUCTIVE SLEEP APNEA IN FRANCE. AB - OBJECTIVES: Untreated obstructive sleep apnea-hypopnea syndrome (OSAHS) is associated with excessive daytime sleepiness, increased risk of cardiovascular (CV) disease, and road traffic accidents (RTAs), which impact survival and health related quality of life. This study, funded by the French National Authority for Health (HAS), aimed to assess the cost-effectiveness of different treatments (i.e., continuous positive airway pressure [CPAP], dental devices, lifestyle advice, and no treatment) in patients with mild-to-moderate OSAHS in France. METHODS: A Markov model was developed to simulate the progression of two cohorts, stratified by CV risk, over a lifetime horizon. Daytime sleepiness and RTAs were taken into account for all patients while CV events were only considered for patients with high CV risk. RESULTS: For patients with low CV risk, incremental cost-effectiveness ratio (ICER) of dental devices versus no treatment varied between 32,976 EUR (moderate OSAHS) and 45,579 EUR (mild OSAHS) per quality adjusted life-year (QALY), and CPAP versus dental devices, above 256,000 EUR/QALY. For patients with high CV risk, CPAP was associated with a gain of 0.62 QALY compared with no treatment, resulting in an ICER of 10,128 EUR/QALY. CONCLUSION: The analysis suggests that it is efficient to treat all OSAHS patients with high CV risk with CPAP and that dental devices are more efficient than CPAP for mild-to-moderate OSAHS with low CV risk. However, out-of-pocket costs are currently much higher for dental devices than for CPAP (i.e., 3,326 EUR versus 2,430 EUR) as orthodontic treatment is mainly non-refundable in France. PMID- 26956456 TI - [Anterior segment findings with far-reaching consequences]. PMID- 26956457 TI - Antigenic Drift of A/H3N2/Virus and Circulation of Influenza-Like Viruses During the 2014/2015 Influenza Season in Poland. AB - Morbidity rates of influenza could be greatly reduced due to vaccination. However, the virus is able to evolve through genetic mutations, which is why vaccines with updated composition are necessary every season. Their effectiveness depends on whether there is a good antigenic match between circulating viruses and vaccine strains. In Poland, the 2014/2015 influenza epidemic started in week 5 (January/February) of 2015 and continued until week 17 (April) of 2015. The influenza activity was moderate with the highest incidence of influence-like illness at week 10/2015 (March). During that season, antigenic drift of influenza virus A/H3N2/ occurred causing higher rates of A/H3N2/ infections. Among the 2416 tested specimens, 22.6 % of influenza cases were positive for A/H3N2/, while A/H1N1/pdm09 constituted 14.6 % cases. Influenza A viruses were detected in co circulation with influenza B viruses; the latter amounted to 34.1 % of all influenza detections. Other detected causes of influenza-like illness consisted of respiratory syncytial virus (RSV), being predominant, and, sporadically, human coronavirus, parainfluenza 1-3, rhinovirus, and adenovirus. Despite low vaccine effectiveness of solely one component, A/H3N2/, the vaccine could mitigate or shorten the length of influenza infection and reduce the number of severe outcomes and mortality. Thus, vaccination against influenza remains the most effective way to prevent illness and possibly fatal outcomes. PMID- 26956458 TI - In Silico Modelling of Transdermal and Systemic Kinetics of Topically Applied Solutes: Model Development and Initial Validation for Transdermal Nicotine. AB - PURPOSE: The purpose was to develop a mechanistic mathematical model for predicting the pharmacokinetics of topically applied solutes penetrating through the skin and into the blood circulation. The model could be used to support the design of transdermal drug delivery systems and skin care products, and risk assessment of occupational or consumer exposure. METHODS: A recently reported skin penetration model [Pharm Res 32 (2015) 1779] was integrated with the kinetic equations for dermis-to-capillary transport and systemic circulation. All model parameters were determined separately from the molecular, microscopic and physiological bases, without fitting to the in vivo data to be predicted. Published clinical studies of nicotine were used for model demonstration. RESULTS: The predicted plasma kinetics is in good agreement with observed clinical data. The simulated two-dimensional concentration profile in the stratum corneum vividly illustrates the local sub-cellular disposition kinetics, including tortuous lipid pathway for diffusion and the "reservoir" effect of the corneocytes. CONCLUSIONS: A mechanistic model for predicting transdermal and systemic kinetics was developed and demonstrated with published clinical data. The integrated mechanistic approach has significantly extended the applicability of a recently reported microscopic skin penetration model by providing prediction of solute concentration in the blood. PMID- 26956459 TI - Melatonin Delivery: Transdermal and Transbuccal Evaluation in Different Vehicles. AB - PURPOSE: Melatonin (MLT) could be candidate drug for treatment of several diseases because of its high antioxidant and anticarcinogenic activity and its important biological roles. The aim of this study was to assess the influence of different vehicles on the permeation of MLT through buccal and skin tissues. METHODS: Formulations were characterized in terms of rheology, drug release and permeation through human skin as well as porcine buccal mucosa. Irradiation experiments were also performed. RESULTS: The lowest amount of MLT released was from oral adhesive paste Orabase(r) (OB) and the highest from the emulsion system Montanov(r) 68 (M68). Skin permeation revealed high pattern for Carbopol(r) 940 (C940) and M68, and poor for poloxamer 407 (P407) and Pluronic(r) lecithin organogel (PLO). Statistical differences of MLT remaining in skin between M68 vs C940 (p < 0.05) and M68 vs PLO (p < 0.05) were observed. Transmucosal results showed that sodium carboxymethylcellulose (NaCMC) was the best and OB the worst vehicle. P407 and PLO followed similar behaviour. Photostability studies revealed high percentage of degradation of MLT in solution which was also similar when was loaded in OB. The rest of formulations showed low rates of degradation. CONCLUSIONS: C940 or M68 and NaCMC can be proposed as formulations for a potential systemic effect of MLT by skin and buccal mucosa routes, respectively. However, if the intended objective is to obtain local action in the skin and buccal mucosa, the proposed formulations are M68 or P407 and PLO. PMID- 26956460 TI - A new genotype of flax (Linum usitatissimum L.) with decreased susceptibility to fat oxidation: consequences to hematological and biochemical profiles of blood indices. AB - BACKGROUND: Flaxseed is an alternative to marine products that provide the traditional dietary sources of omega-fatty acids. A new genotype of flax, W92, is rich in natural antioxidants as well as having a reduced content of alpha linolenic acid and therefore shows decreased susceptibility to fat oxidation. The objective of this study was to evaluate the effect of a diet supplemented with W92 flaxseed on hematological and biochemical blood indices. RESULTS: A positive impact of diet with the addition of flaxseed was observed on erythrocyte indices, including red blood cell (RBC), hematocrit (HCT), mean corpuscular hemoglobin (MCH) and mean corpuscular hemoglobin concentration (MCHC) values. There were no significant differences for white blood cell (WBC), total protein and glucose values. Aspartate aminotransferase and alanine aminotransferase estimations in serum were also carried out and no obvious toxicity to the liver was shown. Moreover, a lipid profile was performed in serum samples and a decrease in total cholesterol and low-density lipoprotein cholesterol (LDL-C), accompanied by an increase in high-density lipoprotein cholesterol (HDL-C), was observed in rabbits fed flaxseed diets. CONCLUSION: Based on the results obtained, it appeared that the inclusion of a new genetically modified type of flaxseed in the diet altered cholesterol metabolism and could reduce the possibility of cardiovascular diseases. Diet enrichment with W92 flaxseed may be a solution to the health issues that are a result of improper diet in humans and animals. (c) 2016 Society of Chemical Industry. PMID- 26956462 TI - A rat model of vascular dementia for evaluating Chinese medicine prescriptions. AB - OBJECTIVE: To develop a new model of vascular dementia for evaluating Chinese medicine prescriptions. METHODS: Eighty-eight male Wistar rats were randomly divided into 4 groups. At d00, d42, d70, d98 (ni=20, 20, 24, 24) during fatty feeding, rats in each group were further divided into 10 or 12 subgroups (ni=2), respectively. Lacunar stroke were replicated with the injection of thrombi which coagulated artificially from itself blood. The median lethal doses (LD50) were regressed from accumulative mortality in each geometric thrombus doses (k=0.75, 0.5, 0.85, 0.85), respectively. The degree of vascular dementia was evaluated as exploratory, learning and memorizing abilities. The median effective dose of thrombus for replicating rat model was regressed from dementia scores which were derived from the abilities. The linear correlation was regressed between the values of LD50 or effective dose (ED50) and the durations (days) of hypercholesterolemia. This model of vascular dementia was pathologically confirmed as the neural injuries from lacunar stroke in rats. RESULTS: The hypercholesterolemia was indicated as elevated total cholesterol, triglyeerides low-density lipoprotein cholesterol, and decreased high-density lipoprotein cholesterol. The values of LD50 with its 95% confidence intervals (CI) were 1525.0 (1361.0-1709.0), 584.3 (490.1-696.6), 168.7 (163.7-173.8), or 62.4 (59.5 65.4) mg/mL, at d00, d42, d70, and d98, respectively. There is a linear regression between the values of LD50 and the durations of hypercholesterolemia (y=-15.33x+1390.0, r=0.963, P<0.05). The values of ED50 with its 95% CI were 528.8 (340.5-821.4), 217.0 (20.84-2259.0), 96.3 (23.4-402.6), or 47.0 (43.7-50.6) mg/mL from dementia score, at d00, d42, d70, and d98, respectively. There is a linear regression between the values of ED50 and the durations of hypercholesterolemia (y=-4.992x+484.2, r=0.965, P<0.05). The neural injuries were demonstrated as neural degeneration and necrosis. CONCLUSIONS: For evaluating Chinese medicine, a model of vascular dementia in rats is set up with the lacunar stroke from self-thrombosis during hypercholesterolemia. This model from lacunar stroke is useful to investigate the pathogenesis and treatment of vascular dementia. PMID- 26956461 TI - Antioxidative effect of luteolin pretreatment on simulated ischemia/reperfusion injury in cardiomyocyte and perfused rat heart. AB - OBJECTIVE: To investigate the antioxidative effect and mechanism of luteolin on rat cardiomyocytes and isolated hearts followed by simulated ischemia/reperfusion (SI/R) injury. METHODS: The left ventricular cardiomyocytes and the isolated hearts from adult rats were subjected to SI/R injury. The experiment groups included control, SI/R, luteolin + SI/R (Lut + SI/R), vitamin E (Vit E) + SI/R, and LY294002 + luteolin + SI/R (LY + Lut + SI/R) groups. Cell viability, shortening amplitude, lactate dehydrogenase (LDH) release, superoxide dismutase (SOD) activity, the production of reactive oxygen species (ROS) and malondialdehyde (MDA), expression levels of Akt, phosphorylated Akt, NOX2 (gp91phox), NOX2 mRNA, mitogen-activated protein kinase (p38 MAPK) and phosphorylated p38MAPK were all measured after 3-h simulated ischemia and 2-h simulated reperfusion procedure in cardiomyocytes. Vit E was used as a standard control. The contractile function of isolated hearts was further observed after they were subjected to 30-min global ischemia and 120-min reperfusion. RESULTS: Pretreatment with 8-MUmol/L luteolin substantially increased cell viability and shortening amplitude, while reducing evidence of oxidative stress-induced damage in the cells. In addition, the expression of NOX2, NOX2 mRNA and phosphorylation of p38MAPK were all downregulated. Furthermore, pretreatment with 40-MUmol/L luteolin improved the recovery of myocardial contractile function following SI/R induced injury, and luteolin markedly increased phosphorylation of Akt. However, all of the above effects were partially inhibited by the phosphatidylinositol 3 kinase (PI3K) inhibitor, LY294002. CONCLUSIONS: Luteolin prevents SI/R-induced myocardial damage by reducing oxidative stress-induced injury in isolated rat hearts and cardiomyocytes, and the cardioprotection induced by luteolin was partially mediated by the PI3K/Akt pathway. PMID- 26956463 TI - Risk factors and clinical features in ischemic stroke patients with different tongue conditions. AB - OBJECTIVE: To investigate the risk factors and clinical features in ischemic stroke patients with different tongue conditions. METHODS: A total of 168 successive acute ischemic stroke inpatients (within 7 days of stroke onset) were recruited. Patients were assigned to groups according to tongue color (pink, pale, red, purple), tongue coating (no coating, thin coating, thick coating) and sublingual vessel (normal, abnormal). Risk factors and clinical features including National Institutes of Health Stroke Scale (NIHSS), modified Rankin Scale (mRS) and Barthel Index (BI), clinical classification, laboratory data and pulmonary infection complications were compared. RESULTS: There were no significant differences in risk factors and clinical features among groups with different tongue colors. The incidence of smoking (4.5%) was lower in the no coating group compared with the thin (30.0%) and thick (39.3%) coating groups (P<0.017). NIHSS (19.05+/-10.68) in the no coating group was higher than the thin (6.40+/-6.18) and thick (7.41+/-7.05) coating groups (P<0.017), BI (20.91+/ 29.99) was lower than the thin (67.61+/-28.78) and thick (63.02+/-33.54) coating groups (P<0.017), and the percentage of mRS >3 (90.9%) was higher than the thin (42.2%) and thick (42.9%) coating groups (P<0.017). The percentage of partial anterior circulation infarction patients in the no coating group was higher than the thin coating group (77.3% vs. 42.2%), and the percentage of lacunar infarction patients was lower than the thin coating group (4.5% vs. 37.8%, P<0.017). NIHSS in the abnormal sublingual vessel group was lower than the normal group (5.28+/-4.38 vs. 10.57+/-9.58, P=0.000), and BI was higher than the normal group (67.61+/-29.29 vs. 54.64+/-36.23, P=0.015). CONCLUSION: Tongue conditions of acute stroke patients were relevant to clinical features. PMID- 26956464 TI - Curcumin reduces cardiac fibrosis by inhibiting myofibroblast differentiation and decreasing transforming growth factor beta1 and matrix metalloproteinase 9 / tissue inhibitor of metalloproteinase 1. AB - OBJECTIVE: To study the effect of curcumin on fibroblasts in rats with cardiac fibrosis. METHODS: The rats were randomly divided into 4 groups (n=12 in each group): the normal control, isoproterenol (ISO), ISO combined with low-dose curcumin (ISO+Cur-L), and ISO combined with high-dose curcumin (ISO+Cur-H) groups. ISO+Cur-L and ISO+Cur-H groups were treated with curcumin (150 or 300 mg*kg-1*day-1) for 28 days. The primary culture of rat cardiac fibroblast was processed by trypsin digestion method in vitro. The 3rd to 5th generation were used for experiment. Western blot method was used to test the expression of collagen type I/III, alpha-smooth muscle actin (alpha-SMA), transforming growth factor (TGF)-beta1, matrix metalloproteinase (MMP)-9 and tissue inhibitor of metalloproteinase (TIMP)-1. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was applied to test the proliferation of fibroblast. RESULT: Curcumin significantly decreased interstitial and perivascular myocardial collagen deposition and cardiac weight index with reducing protein expression of collagen type I/III in hearts (P<0.05). In addition, curcumin directly inhibited angiotensin (Ang) II-induced fibroblast proliferation and collagen type I/III expression in cardiac fibroblasts (P<0.05). Curcumin also inhibited fibrosis by inhibiting myofibroblast differentiation, decreased TGF-beta1, MMP-9 and TIMP-1 expression (P<0.05) but had no effects on Smad3 in Ang II incubated cardiac fibroblasts. CONCLUSIONS: Curcumin reduces cardiac fibrosis in rats and Ang II induced fibroblast proliferation by inhibiting myofibroblast differentiation, decreasing collagen synthesis and accelerating collagen degradation through reduction of TGF-beta1, MMPs/TIMPs. The present findings also provided novel insights into the role of curcumin as an antifibrotic agent for the treatment of cardiac fibrosis. PMID- 26956465 TI - Characterization of the antioxidant fraction of Trapa japonica pericarp and its hepatic protective effects in vitro and in vivo. AB - The ethanolic extract of Trapa japonica pericarp (TJP) and its various fractions were evaluated for their antioxidant potential. The ethyl acetate fraction (EF) from TJP exhibited significant antioxidant and protective effects against tert butylhydroperoxide (t-BHP)-induced oxidative damage in vitro and in vivo. In vitro experimental results showed that the EF suppressed t-BHP-induced damage in Chang cells by inhibiting reactive oxygen species generation and regulating the mitochondrial membrane potential. Furthermore, western blot analysis showed that the EF effectively inhibited t-BHP-induced apoptosis by suppressing caspase-3, caspase-7, caspase-8, and caspase-9. In the in vivo study, the EF significantly prevented serum increases in glutamate oxaloacetate transaminase and glutamate pyruvate transaminase and hepatic malondialdehyde levels caused by t-BHP. Furthermore, the EF markedly increased hepatic superoxide dismutase, catalase, and glutathione levels. Histopathological examinations further confirmed that the EF could protect the liver from t-BHP-induced oxidative injury. These findings indicate that the EF could be developed as a therapy or to prevent hepatic injury. PMID- 26956466 TI - Is serum CRP level a reliable inflammatory marker in pediatric nephrotic syndrome? AB - BACKGROUND: This study tested the hypothesis that during massive proteinuria, C reactive protein (CRP) may be lost into the urine along with other proteins, making serum CRP (sCRP) level an unreliable marker of infection severity in nephrotic syndrome (NS). METHODS: Children with active NS (n = 23) were compared with two matched control groups: patients with febrile non-renal infectious disease (n = 30) and healthy subjects (n = 16). Laboratory measurements included sCRP, urine protein, creatinine, IgG, and protein electrophoresis. Urinary CRP (uCRP) was measured by ELISA. RESULTS: Sixty-nine patients were enrolled: 23 patients with NS, 30 patients with non-renal febrile infectious diseases, and 16 healthy children. Median uCRP concentrations were 0 mcg/gCr (0-189.7) in NS, 11 mcg/gCr (0-286) in the febrile group, and 0 mcg/gCr (0-1.8) in the healthy group. The uCRP/creatinine ratio was similar in the NS and healthy groups (p > 0.1) and significantly higher in the febrile group than the other two groups (p < 0.0001). There was no association of uCRP concentration with severity of proteinuria or IgG excretion. CONCLUSIONS: NS in children is not characterized by significant loss of CRP into the urine. Therefore, sCRP may serve as a reliable marker of inflammation in this setting. The significant urinary excretion of CRP in children with transient non-renal infectious disease might be attributable to CRP synthesis in renal epithelial cells. PMID- 26956467 TI - Campaigns and counter campaigns: reactions on Twitter to e-cigarette education. AB - BACKGROUND: Social media present opportunities for public health departments to galvanise interest in health issues. A challenge is creating content that will resonate with target audiences, and determining reactions to educational material. Twitter can be used as a real-time surveillance system to capture individuals' immediate reactions to education campaigns and such information could lead to better campaigns in the future. A case study testing Twitter's potential presented itself when the California Department of Public Health launched its 'Still Blowing Smoke' media campaign about the potential harmful effects of e-cigarettes. Pro-e-cigarette advocacy groups, in response, launched a counter campaign titled 'Not Blowing Smoke'. This study tracked the popularity of the two campaigns on Twitter, analysed the content of the messages and determined who was involved in these discussions. METHODS: The study period was from 22 March 2015 to 27 June 2015. A stratified sampling procedure supplied 2192 tweets for analysis. Content analysis identified pro, anti and neutral e-cigarette tweets, and five additional themes: Marketing Elements, Money, Regulation/propaganda, Health, and Other. Metadata were analysed to obtain additional information about Twitter accounts. RESULTS: 'Not Blowing Smoke' was referenced more frequently than 'Still Blowing Smoke' on Twitter. Messages commonly objected to government regulation of e-cigarettes, refuted claims that e cigarette manufactures were aligned with big tobacco, and touted the health benefits of e-cigarette use. E-cigarette companies and vape shops used campaign slogans to communicate with customers on Twitter. CONCLUSIONS: Findings showed the time dynamics of Twitter and the possibility for real-time monitoring of education campaigns. PMID- 26956468 TI - LPS-induced neonatal stress in mice affects the response profile to an inflammatory stimulus in an age and sex-dependent manner. AB - The aim of this study is to evaluate the response to an inflammatory stimulus in mice exposed to LPS-induced neonatal stress at different ages and sexes. Balb/c mice were submitted to intraperitoneal injections on postnatal days 3 and 10 with lipopolysaccharide (nLPS) or saline solution (nSal). At 21 or 60 days, either saline solution was injected or an inflammatory stimulus was induced by the injection of 1% carrageenan. Inflammatory cytokines, reactive oxygen species, and neutrophil extracellular traps (NETs) production were measured in peritoneal fluid. LPS-induced neonatal stress can reduce inflammatory cytokines in males and females. An increase in NETs production was observed when 60 day nLPS animals were compared to 21 day mice in both sexes. The ROS production was not affected by neonatal stress. The results shown here indicate that LPS-induced neonatal stress can alter cytokine production in response to inflammatory stimuli at different ages, in a sex-dependent effect. (c) 2016 Wiley Periodicals, Inc. Dev Psychobiol 58: 600-613, 2016. PMID- 26956469 TI - CSTMP Exerts Anti-Inflammatory Effects on LPS-Induced Human Renal Proximal Tubular Epithelial Cells by Inhibiting TLR4-Mediated NF-kappaB Pathways. AB - (E)-2-(2-chlorostyryl)-3,5,6-trimethylpyrazine (CSTMP), a novel stilbene derivative, have been shown to have cytoprotective effects against H2O2-induced oxidative stress in human endothelial cells. However, little is known about its anti-inflammatory effects in lupus nephritis (LN). In the present study, we investigated the anti-inflammatory effects of CSTMP on lipopolysaccharide (LPS) induced human renal proximal tubular epithelial cells (hRPTECs) and elucidated its molecular mechanisms. CSTMP significantly attenuated the cytotoxicity and suppressed the release of proinflammatory mediators, including iNOS, COX-2, TNF alpha, IL-6, IL-8, CCL-2, ICAM-1, IL-1beta, and MCP-1 in LPS-induced hRPTECs. In addition, CSTMP decreased the expression of TLR4 and its adapter molecules (MyD88, phosphorylation of TAK1, TRAF6, and IRAK1) and abolished its interactions with these adapter molecules in LPS-induced hRPTECs, resulting in an inhibition of the TLR4/MyD88/TAK1/ TRAF6/IRAK1 complex. Moreover, CSTMP also attenuated phosphorylation of IkappaB and IKK-alpha/beta, and P50-NF-kappaB and P65-NF kappaB translocation to nucleus in LPS-induced hRPTECs. These findings provided new insights to understand the mode of action of CSTMP in treatment of inflammatory diseases, such as LN. PMID- 26956470 TI - Propofol Protects Rats and Human Alveolar Epithelial Cells Against Lipopolysaccharide-Induced Acute Lung Injury via Inhibiting HMGB1 Expression. AB - High-mobility group box 1 (HMGB1) plays a key role in the development of acute lung injury (ALI). Propofol, a general anesthetic with anti-inflammatory properties, has been suggested to be able to modulate lipopolysaccharide (LPS) induced ALI. In this study, we investigated the effects of propofol on the expression of HMGB1 in a rat model of LPS-induced ALI. Rats underwent intraperitoneal injection of LPS to mimic sepsis-induced ALI. Propofol bolus (1, 5, or 10 mg/kg) was infused continuously 30 min after LPS administration, followed by infusion at 5 mg/(kg . h) through the left femoral vein cannula. LPS increased wet to dry weight ratio and myeloperoxidase activity in lung tissues and caused the elevation of total protein and cells, neutrophils, macrophages, and neutrophils in bronchoalveolar lavage fluid (BALF). Moreover, HMGB1 and other cytokine levels were increased in BALF and lung tissues and pathological changes of lung tissues were excessively aggravated in rats after LPS administration. Propofol inhibited all the above effects. It also inhibited LPS-induced toll-like receptor (TLR)2/4 protein upexpression and NF-kappaB activation in lung tissues and human alveolar epithelial cells. Propofol protects rats and human alveolar epithelial cells against HMGB1 expression in a rat model of LPS-induced ALI. These effects may partially result from reductions in TLR2/4 and NF-kappaB activation. PMID- 26956471 TI - Does Inflammation Mediate the Association Between Obesity and Insulin Resistance? AB - In adult obesity, low-grade systemic inflammation is considered an important step in the pathogenesis of insulin resistance (IR). The association between obesity and inflammation is less well established in adolescents. Here, we ascertain the importance of inflammation in IR among obese adolescents by utilizing either random forest (RF) classification or mediation analysis approaches. The inflammation balance score, composed of eight pro- and anti-inflammatory makers, as well as most of the individual inflammatory markers differed significantly between lean and overweight/obese. In contrast, adiponectin was the only individual marker selected as a predictor of IR by RF, and the balance score only revealed a medium-to-low importance score. Neither adiponectin nor the inflammation balance score was found to mediate the relationship between obesity and IR. These findings do not support the premise that low-grade systemic inflammation is a key for the expression of IR in the human. Prospective longitudinal studies should confirm these findings. PMID- 26956472 TI - IL-10-Expressing Th2 Cells Contribute to the Elevated Antibody Production in Rheumatoid Arthritis. AB - Rheumatoid arthritis (RA) is a common autoimmune disease associated with progressive disability, systemic complications, and early death. Multiple lines of evidence have placed adaptive immune responses in the center of RA pathogenesis. However, the functional roles of T helper cells are insufficiently described. Here, we examined the Th2 cell subsets and their functions in RA patients. A downregulation of IL-4(+) cells in CD4(+) T cells were observed in RA patients, indicating a downregulation of Th2 cells, and these results were confirmed by using and CXCR3 and CCR6 surface markers. We then found that CXCR3( )CCR6(-) Th2 cells can be separated into IL-4(+) (single positive), IL-10(+) (single positive), and IL-4(+)IL-10(+) (double positive) subsets. Further results showed that CXCR5 only expressed on IL-10+ Th2 cells. The CXCR5(+) and CXCR5(-) Th2 cells each exhibited distinctive features in helping B cell antibody secretion. CXCR5(+) Th2 cells were more potent at stimulating total Ig and IgM secretion, while CXCR5(-) Th2 cells were more potent at stimulating IgE. IL-10 was required for helping B cell total Ig, IgM, and IgE production, while IL-4 was required for total Ig and IgE. The frequencies of IL-10(+) and IL-4(+)IL-10(+) Th2 cells were positively correlated with rheumatoid factor titer in vivo. Together, our study demonstrated distinctive subsets within Th2 cells, each with different impacts on antibody production and RA disease. PMID- 26956473 TI - Tiger frog virus ORF080L protein interacts with LITAF and impairs EGF-induced EGFR degradation. AB - Tiger frog virus (TFV) belongs to the genus Ranavirus, family Iridoviridae, and causes severe mortality in commercial cultures in China. TFV ORF080L is a gene homolog of lipopolysaccharide-induced TNF-alpha factor (LITAF), which is a regulator in endosome-to-lysosome trafficking through its function in the endosomal sorting complex required for transport machinery. The characteristics and biological roles of TFV ORF080L were identified. TFV ORF080L was predicted to encode an 84-amino acid peptide (VP080L). It had high-sequence identity with mammalian LITAF, but lacked the N-terminus of LITAF, which contains two PPXY motifs. Transcription and protein level analyses showed that TFV ORF080L was a late viral gene. Localization in the virons also showed that TFV VP080L was a viral structural protein. Immunofluorescence staining showed that TFV ORF080L was predominantly colocalized with plasma membrane and partly distributed with the late endosome in infected HepG2 cells. SiRNA-mediated TFV ORF080L silencing decreased viral reproduction. Moreover, TFV ORF080L interacted with human/zebrafish LITAF and impaired EGF-induced EGFR degradation, thereby indicating that TFV ORF080L played a role in endosome-to-lysosome trafficking. These findings suggested that TFV ORF080L might negate the function of cellular LITAF to impair endosomal sorting and trafficking. Results provide a clue to the link between the dysregulated endosomal trafficking and iridovirus pathogenesis. PMID- 26956474 TI - Lack of cortistatin or somatostatin differentially influences DMBA-induced mammary gland tumorigenesis in mice in an obesity-dependent mode. AB - BACKGROUND: Somatostatin (SST) and cortistatin (CORT), two structurally and functionally related peptides, share a family of widespread receptors (sst1-5) to exert apparently similar biological actions, including endocrine/metabolic regulation and suppression of tumor cell proliferation. However, despite their therapeutic potential, attempts to apply SST-analogs to treat breast cancer have yielded unsatisfactory results. Actually, the specific roles of SST and CORT in mammary gland tumorigenesis (MGT), particularly in relation to metabolic dysregulation (i.e. obesity), remain unknown. METHODS: The role of endogenous SST and CORT in carcinogen-induced MGT was investigated under normal (lean) and obesity conditions. To that end, SST- and CORT-knockout (KO) mice and their respective littermate-controls, fed low-fat (LF) or high-fat (HF) diets, were treated with 7,12-dimethyl-benza-anthracene (DMBA) once a week (wk) for 3 wk, and MGT was monitored for 25 wk. Additionally, we examined the effect of SST or CORT removal in the development of the mammary gland. RESULTS: Lack of SST did not alter DMBA-induced MGT incidence under lean conditions; conversely, lack of endogenous CORT severely aggravated DMBA-induced MGT in LF-fed mice. These differences were not attributable to altered mammary gland development. HF-diet modestly increased the sensitivity to DMBA-induced carcinogenesis in control mice, whereas, as observed in LF-fed CORT-KO, HF-fed CORT-KO mice exhibited aggravated tumor incidence, discarding a major influence of obesity on these CORT actions. In marked contrast, HF-fed SST-KO mice exhibited much higher tumor incidence than LF-fed SST-KO mice, which could be associated with higher mammary complexity. CONCLUSIONS: Endogenous SST and CORT distinctly impact on DMBA induced MGT, in a manner that is strongly dependent on the metabolic/endocrine milieu (lean vs. obese status). Importantly, CORT, rather than SST, could represent a major inhibitor of MGT under normal/lean-conditions, whereas both neuropeptides would similarly influence MGT under obesity conditions. The mechanisms mediating these different effects likely involve mammary development and hormones, but the precise underlying factors are still to be fully elucidated. However, our findings comprise suggestive evidence that CORT-like molecules, rather than classic SST-analogs, may help to identify novel tools for the medical treatment of breast cancer. PMID- 26956477 TI - Food insecurity among people who inject drugs in Los Angeles and San Francisco. AB - OBJECTIVE: We estimated the prevalence of food insecurity among people who inject drugs (PWID) in Los Angeles and San Francisco and explored correlates of food insecurity. DESIGN: A cross-sectional study that measured 30 d food insecurity using the US Adult Food Security Survey ten-item Module developed by the US Department of Agriculture. Food insecurity was defined as including low and very low food security. SETTING: Two cities in the state of California, USA. SUBJECTS: Male and female active PWID (n 777). RESULTS: Among participants, 58 % reported food insecurity and 41 % reported very low food security. Food-insecure PWID were more likely to report being homeless (prevalence ratio (PR)=1.20; 95 % CI 1.05, 1.37), chest pain in the past 12 months (PR=1.19; CI 1.06, 1.35), acquiring syringes from someone who goes to a syringe exchange programme (PR=1.27; 95 % CI 1.13, 1.43) and feeling at risk for arrest for possession of drug paraphernalia (PR=1.30; 95 % CI 1.15, 1.46). CONCLUSIONS: Current food insecurity was common among PWID in these two cities, yet few factors were independently associated with food insecurity. These data suggest that broad strategies to improve food access for this high-risk population are urgently needed. PMID- 26956476 TI - Focal cartilage defects in the knee - a randomized controlled trial comparing autologous chondrocyte implantation with arthroscopic debridement. AB - BACKGROUND: Focal cartilage injuries in the knee might have devastating effect due to the predisposition of early onset osteoarthritis. Various surgical treatment options are available, however no statistically significant differences have been found between the different surgical treatments. This supports the suggestion that the improvement might be a result of the post-operative rehabilitation rather than the surgery itself. Autologous chondrocyte implantation (ACI) has become a recognized treatment option for larger cartilage lesions in the knee. Although ACI has been compared to other surgical treatment such as microfracture and mosaicplasty, it has never been directly compared to simple arthroscopic debridement and rehabilitation alone. In this study we want to increase clinical and economic knowledge about autologous chondrocyte implantation compared to arthroscopic debridement and physical rehabilitation in the short and long run. METHODS/DESIGN: We will conduct a randomized controlled trial to compare ACI with simple arthroscopic debridement (AD) and physiotherapy for the treatment of cartilage lesions in the knee. The study will include a total of 82 patients, both men and non-pregnant women, with a full thickness cartilage defect in the weight bearing area of the femoral condyles or trochlea larger than 2 cm2. The lesion must be symptomatic, with a Lysholm score less than 75. The two treatment groups will receive identical rehabilitation protocol according to a modification of Wondrasch et al., which is an active rehabilitation and education program divided into 3 phases: accommodation, rehabilitation and return to activity. The patients will be followed for 24 months, with additional late follow-ups at 5 and 10 years to monitor the potential onset of osteoarthtitis. The primary outcome measure will be the difference in the KOOS knee-related quality of life (QoL) subscore in the ACI group compared to the AD group at 2 years. A combination of self-explanatory questionnaires, clinical parameters, clinical hop tests and radiographs and Magnetic Resonance Imaging (MRI) will be used as secondary endpoints. DISCUSSION: This is the first study with a high level of evidence to compare ACI with simple debridement and physiotherapy for the treatment of isolated symptomatic full thickness lesions of the knee. TRIAL REGISTRATION: ClinicalTrial NCT02636881 (21 December 2015). PMID- 26956478 TI - Withanolide A offers neuroprotection, ameliorates stress resistance and prolongs the life expectancy of Caenorhabditis elegans. AB - Withanolide A (steroidal lactone) forms the major constituent of the most popular herbal drug in Ayurvedic medicine, Ashwagandha. It has been used since ancient times as an alternative medicine for the treatment of a variety of age related disorders. Here we provide multiple lines of evidence indicating that Withanolide A improves healthspan, delays age-associated physiological changes and also extends the lifespan of Caenorhabditis elegans. We also report several neuroprotective benefits of this natural product, including its anti amyloidogenic effects, alleviation of alpha-synuclein aggregation and neuroprotection through modulation of neural mediators like acetylcholine. We observed that Withanolide A mediates lifespan extension and promotes stress resistance via insulin/insulin-like growth factor signaling pathway. Such findings could be helpful to develop a therapeutic medicine from this natural product for the prevention or reversal of age-related ailments and to improve the survival of patients suffering from Alzheimer's or Parkinson's disease. PMID- 26956475 TI - Influence of Immune Myeloid Cells on the Extracellular Matrix During Cancer Metastasis. AB - The extracellular matrix (ECM) is one of the most important components within the tumor microenvironment that supports cancer development and metastasis. Under normal physiological conditions, the ECM is a tightly regulated network providing structural and biochemical support. However, the ECM becomes highly disorganized during neoplastic progression and consequently, stimulates cancer cell transformation, growth and spread. Cancer development and progression is also known to greatly benefit from the support of immune myeloid cells, which have multiple pro-tumorigenic functions including promoting tumor growth, migration and invasion, stimulating angiogenesis and suppressing anti-tumor responses. An increasing number of studies have shown that myeloid cells alter the ECM to support metastatic cancer progression and in turn, the ECM can influence the function of infiltrating myeloid cells. However, the exact nature of this relationship, such as the mechanisms employed and their molecular targets remains unclear. This review discusses evidence for the reciprocal dependence of myeloid cells and the tumor ECM for efficient tumor development and explores potential mechanisms involved in these interactions. A better understanding of this relationship has exciting implications for the development of new therapeutic treatments for metastatic cancer. PMID- 26956479 TI - Deficits in coordinated motor behavior and in nigrostriatal dopaminergic system ameliorated and VMAT2 expression up-regulated in aged male rats by administration of testosterone propionate. AB - The effects of testosterone propionate (TP) supplements on the coordinated motor behavior and nigrostriatal dopaminergic (NSDA) system were analyzed in aged male rats. The present study showed the coordinated motor behavioral deficits, the reduced activity of NSDA system and the decreased expression of vesicular monoamine transporter 2 (VMAT2) in 24 month-old male rats. Long term TP treatment improved the motor coordination dysfunction with aging. Increased tyrosine hydroxylase and dopamine transporter, as well as dopamine and its metabolites were found in the NSDA system of TP-treated 24 month-old male rats, indicative of the amelioratory effects of TP supplements on NSDA system of aged male rats. The enhancement of dopaminergic (DAergic) activity of NSDA system by TP supplements might underlie the amelioration of the coordinated motor dysfunction in aged male rats. TP supplements up-regulated VMAT2 expression in NSDA system of aged male rats. Up-regulation of VMAT2 expression in aged male rats following chronic TP treatment might be involved in the maintenance of DAergic function of NSDA system in aged male rats. PMID- 26956480 TI - Short range magnetic exchange interaction favors ferroelectricity. AB - Multiferroics, where two or more ferroic order parameters coexist, is one of the hottest fields in condensed matter physics and materials science. To search multiferroics, currently most researches are focused on frustrated magnets, which usually have complicated magnetic structure and low magnetic ordering temperature. Here, we argue that actually simple interatomic magnetic exchange interaction already contains a driving force for ferroelectricity, thus providing a new microscopic mechanism for the coexistence and strong coupling between ferroelectricity and magnetism. We demonstrate this mechanism by showing that even the simplest antiferromagnetic insulator like MnO, could display a magnetically induced ferroelectricity under a biaxial strain. In addition, we show that such mechanism also exists in the most important single phase multiferroics, i.e. BiFeO3, suggesting that this mechanism is ubiquitous in systems with superexchange interaction. PMID- 26956481 TI - Focus Issue: The ins and outs of ORAI in immune cells. AB - This Focus Issue highlights research into cell-specific regulation of store operated calcium entry through the ORAI/STIM channel complex. Understanding the properties of these channels and how ORAI activity is regulated will lead to a better molecular view of immune cell function and diseases involving the immune system. PMID- 26956482 TI - Sterol hindrance of Orai activation. AB - Orai channels at the plasma membrane mediate store-operated Ca(2+) entry in response to Ca(2+) depletion of the endoplasmic reticulum. Orai channels are gated by stromal-interacting molecule proteins, which act as Ca(2+) sensors, and the association of these proteins is enhanced in cholesterol-rich lipid rafts. In research published in Science Signaling, Derler et al. report that cholesterol inhibits Orai function through direct association with the channel amino terminus. PMID- 26956483 TI - The CAR that drives Ca2+ to Orai1. AB - How Ca(2+) permeates the Orai1 channel and the mechanism by which the channel achieves high Ca(2+) selectivity remain critical questions in understanding store operated Ca(2+) influx. In research published in Science Signaling, Frischauf et al. identified a Ca(2+)-accumulating region (CAR) in the extracellular opening of Orai1, which explains how concentrating Ca(2+) at the mouth of Orai1 facilitates channel permeation and contributes to selectivity. PMID- 26956484 TI - Cell type-specific glycosylation of Orai1 modulates store-operated Ca2+ entry. AB - N-glycosylation of cell surface proteins affects protein function, stability, and interaction with other proteins. Orai channels, which mediate store-operated Ca(2+) entry (SOCE), are composed of N-glycosylated subunits. Upon activation by Ca(2+) sensor proteins (stromal interaction molecules STIM1 or STIM2) in the endoplasmic reticulum, Orai Ca(2+) channels in the plasma membrane mediate Ca(2+) influx. Lectins are carbohydrate-binding proteins, and Siglecs are a family of sialic acid-binding lectins with immunoglobulin-like repeats. Using Western blot analysis and lectin-binding assays from various primary human cells and cancer cell lines, we found that glycosylation of Orai1 is cell type-specific. Ca(2+) imaging experiments and patch-clamp experiments revealed that mutation of the only glycosylation site of Orai1 (Orai1N223A) enhanced SOCE in Jurkat T cells. Knockdown of the sialyltransferase ST6GAL1 reduced alpha-2,6-linked sialic acids in the glycan structure of Orai1 and was associated with increased Ca(2+) entry in Jurkat T cells. In human mast cells, inhibition of sialyl sulfation altered the N-glycan of Orai1 (and other proteins) and increased SOCE. These data suggest that cell type-specific glycosylation influences the interaction of Orai1 with specific lectins, such as Siglecs, which then attenuates SOCE. In summary, the glycosylation state of Orai1 influences SOCE-mediated Ca(2+) signaling and, thus, may contribute to pathophysiological Ca(2+) signaling observed in immune disease and cancer. PMID- 26956485 TI - A calcium-redox feedback loop controls human monocyte immune responses: The role of ORAI Ca2+ channels. AB - In phagocytes, pathogen recognition is followed by Ca(2+) mobilization and NADPH oxidase 2 (NOX2)-mediated "oxidative burst," which involves the rapid production of large amounts of reactive oxygen species (ROS). We showed that ORAI Ca(2+) channels control store-operated Ca(2+) entry, ROS production, and bacterial killing in primary human monocytes. ROS inactivate ORAI channels that lack an ORAI3 subunit. Staphylococcal infection of mice reduced the expression of the gene encoding the redox-sensitive Orai1 and increased the expression of the gene encoding the redox-insensitive Orai3 in the lungs or in bronchoalveolar lavages. A similar switch from ORAI1 to ORAI3 occurred in primary human monocytes exposed to bacterial peptides in culture. These alterations in ORAI1 and ORAI3 abundance shifted the channel assembly toward a more redox-insensitive configuration. Accordingly, silencing ORAI3 increased the redox sensitivity of the channel and enhanced oxidation-induced inhibition of NOX2. We generated a mathematical model that predicted additional features of the Ca(2+)-redox interplay. Our results identified the ORAI-NOX2 feedback loop as a determinant of monocyte immune responses. PMID- 26956487 TI - Associations between patients' risk attitude and their adherence to statin treatment - a population based questionnaire and register study. AB - BACKGROUND: Poor adherence to medical treatment may have considerable consequences for the patients' health and for healthcare costs to society. The need to understand the determinants for poor adherence has motivated several studies on socio-demographics and comorbidity. Few studies focus on the association between risk attitude and adherence. The aim of the present study was to estimate associations between patients' adherence to statin treatment and different dimensions of risk attitude, and to identify subgroups of patients with poor adherence. METHODS: Population-based questionnaire and register-based study on a sample of 6393 persons of the general. Danish population aged 20-79. Data on risk attitude were based on 4 items uncovering health-related as well as financial dimensions of risk attitude. They were collected through a web-based questionnaire and combined with register data on redeemed statin prescriptions, sociodemographics and comorbidity. Adherence was estimated by proportion of days covered using a cut-off point at 80 %. RESULTS: For the dimension of health related risk attitude, "Preference for GP visit when having symptoms", risk neutral and risk-seeking patients had poorer adherence than the risk-averse patients, OR 0.80 (95 %-CI 0.68-0.95) and OR 0.83 (95 %-CI 0.71-0.98), respectively. No significant association was found between adherence and financial risk attitude. Further, patients in the youngest age group and patients with no CVD were less adherent to statin treatment. CONCLUSION: We find some indication that risk attitude is associated with adherence to statin treatment, and that risk-neutral and risk-seeking patients may have poorer adherence than risk-averse patients. This is important for clinicians to consider when discussing optimal treatment decisions with their patients. The identified subgroups with the poorest adherence may deserve special attention from their GP regarding statin treatment. PMID- 26956486 TI - The adhesion molecule PECAM-1 enhances the TGF-beta-mediated inhibition of T cell function. AB - Transforming growth factor-beta (TGF-beta) is an immunosuppressive cytokine that inhibits the proinflammatory functions of T cells, and it is a major factor in abrogating T cell activity against tumors. Canonical TGF-beta signaling results in the activation of Smad proteins, which are transcription factors that regulate target gene expression. We found that the cell surface molecule platelet endothelial cell adhesion molecule-1 (PECAM-1) facilitated noncanonical (Smad independent) TGF-beta signaling in T cells. Subcutaneously injected tumor cells that are dependent on TGF-beta-mediated suppression of immunity for growth grew more slowly in PECAM-1(-/-) mice than in their wild-type counterparts. T cells isolated from PECAM-1(-/-) mice demonstrated relative insensitivity to the TGF beta-dependent inhibition of interferon-gamma (IFN-gamma) production, granzyme B synthesis, and cellular proliferation. Similarly, human T cells lacking PECAM-1 demonstrated decreased sensitivity to TGF-beta in a manner that was partially restored by reexpression of PECAM-1. Co-incubation of T cells with TGF-beta and a T cell-activating antibody resulted in PECAM-1 phosphorylation on an immunoreceptor tyrosine-based inhibitory motif (ITIM) and the recruitment of the inhibitory Src homology 2 (SH2) domain-containing tyrosine phosphatase-2 (SHP-2). Such conditions also induced the colocalization of PECAM-1 with the TGF-beta receptor complex as identified by coimmunoprecipitation, confocal microscopy, and proximity ligation assays. These studies indicate a role for PECAM-1 in enhancing the inhibitory functions of TGF-beta in T cells and suggest that therapeutic targeting of the PECAM-1-TGF-beta inhibitory axis represents a means to overcome TGF-beta-dependent immunosuppression within the tumor microenvironment. PMID- 26956488 TI - Antiobesity Action of ACAM by Modulating the Dynamics of Cell Adhesion and Actin Polymerization in Adipocytes. AB - Coxsackie virus and adenovirus receptor-like membrane protein (CLMP) was identified as the tight junction-associated transmembrane protein of epithelial cells with homophilic binding activities. CLMP is also recognized as adipocyte adhesion molecule (ACAM), and it is upregulated in mature adipocytes in rodents and humans with obesity. Here, we present that aP2 promoter-driven ACAM transgenic mice are protected from obesity and diabetes with the prominent reduction of adipose tissue mass and smaller size of adipocytes. ACAM is abundantly expressed on plasma membrane of mature adipocytes and associated with formation of phalloidin-positive polymerized form of cortical actin (F-actin). By electron microscopy, the structure of zonula adherens with an intercellular space of ~10-20 nm was observed with strict parallelism of the adjoining cell membranes over distances of 1-20 MUm, where ACAM and gamma-actin are abundantly expressed. The formation of zonula adherens may increase the mechanical strength, inhibit the adipocyte hypertrophy, and improve the insulin sensitivity. PMID- 26956489 TI - Methylglyoxal-Induced Endothelial Cell Loss and Inflammation Contribute to the Development of Diabetic Cardiomyopathy. AB - The mechanisms for the development of diabetic cardiomyopathy remain largely unknown. Methylglyoxal (MG) can accumulate and promote inflammation and vascular damage in diabetes. We examined if overexpression of the MG-metabolizing enzyme glyoxalase 1 (GLO1) in macrophages and the vasculature could reduce MG-induced inflammation and prevent ventricular dysfunction in diabetes. Hyperglycemia increased circulating inflammatory markers in wild-type (WT) but not in GLO1 overexpressing mice. Endothelial cell number was reduced in WT-diabetic hearts compared with nondiabetic controls, whereas GLO1 overexpression preserved capillary density. Neuregulin production, endothelial nitric oxide synthase dimerization, and Bcl-2 expression in endothelial cells was maintained in the hearts of GLO1-diabetic mice and corresponded to less myocardial cell death compared with the WT-diabetic group. Lower receptor for advanced glycation end products and tumor necrosis factor-alpha (TNF-alpha) levels were also observed in GLO1-diabetic versus WT-diabetic mice. Over a period of 8 weeks of hyperglycemia, GLO1 overexpression delayed and limited the loss of cardiac function. In vitro, MG and TNF-alpha were shown to synergize in promoting endothelial cell death, which was associated with increased angiopoietin 2 expression and reduced Bcl-2 expression. These results suggest that MG in diabetes increases inflammation, leading to endothelial cell loss. This contributes to the development of diabetic cardiomyopathy and identifies MG-induced endothelial inflammation as a target for therapy. PMID- 26956491 TI - A Proposal Regarding Best Practices for Validating the Identity of Genetic Stocks and the Effects of Genetic Variants. PMID- 26956493 TI - Correction. PMID- 26956490 TI - Predicting chemical bioavailability using microarray gene expression data and regression modeling: A tale of three explosive compounds. AB - BACKGROUND: Chemical bioavailability is an important dose metric in environmental risk assessment. Although many approaches have been used to evaluate bioavailability, not a single approach is free from limitations. Previously, we developed a new genomics-based approach that integrated microarray technology and regression modeling for predicting bioavailability (tissue residue) of explosives compounds in exposed earthworms. In the present study, we further compared 18 different regression models and performed variable selection simultaneously with parameter estimation. RESULTS: This refined approach was applied to both previously collected and newly acquired earthworm microarray gene expression datasets for three explosive compounds. Our results demonstrate that a prediction accuracy of R(2) = 0.71-0.82 was achievable at a relatively low model complexity with as few as 3-10 predictor genes per model. These results are much more encouraging than our previous ones. CONCLUSION: This study has demonstrated that our approach is promising for bioavailability measurement, which warrants further studies of mixed contamination scenarios in field settings. PMID- 26956492 TI - Correction. PMID- 26956494 TI - From the Editor's Desk. PMID- 26956496 TI - Left ventricular systolic function in Nigerian children infected with HIV/AIDS: a cross-sectional study. AB - BACKGROUND: Cardiac complications contribute significantly to morbidity and mortality in children with HIV/AIDS. These rates have been under-reported in sub Saharan African children. METHODS: This was an observational, cross-sectional Doppler echocardiographic study of ventricular systolic function, performed at a tertiary clinic on children with HIV/AIDS. RESULTS: Left ventricular systolic dysfunction was present in 27.0% of the children with HIV infection and 81.2% of those with AIDS. The mean fractional shortening in the AIDS group (31.6 +/- 9.5%) was significantly lower than in the HIV-infected group (35.3 +/- 10.5%, p = 0.001). A significant correlation was found with CD4(+) cell count and age, and these were the best predictors of left ventricular systolic dysfunction in the stepwise multiple regression analysis (r = 0.396, p = 0.038; r = -0.212, p = 0.025, respectively). CONCLUSION: Left ventricular systolic dysfunction is common in Nigerian children with HIV/AIDS. PMID- 26956497 TI - The change in right ventricular systolic function according to the revascularisation method used, following acute ST -segment elevation myocardial infarction. AB - OBJECTIVE: The level of right ventricular (RV) systolic function has prognostic importance in right ventricular ST-segment elevation myocardial infarction (RV STEMI). This study aimed to evaluate the changes in RV systolic function in patients with RV-STEMI according to the revascularisation method used for their management. METHODS: The first group consisted of 132 patients who received primary percutaneous coronary intervention (PPCI). The 78 patients who had received thrombolytic therapy (TT) in external centres before referral to our centre for PCI within three to 12 hours of RV-STEMI were included in the second group. All patients were evaluated by conventional and two-dimensional speckle tracking echocardiography. RESULTS: There were 172 male patients and their mean age was 63.7 +/- 11.8 years. There were no significant differences between the two groups with regard to right ventricular systolic parameters at admission and at the one-month follow-up visit. The echocardiographic changes between admission and the one-month follow up were investigated for the patients included in the study groups. Mean values of each parameter observed at the one-month follow up were significantly increased compared to those at admission within each group. CONCLUSION: Our study demonstrated that PCI within three to 12 hours following TT provided similar benefits on right ventricular systolic function compared to PPCI in patients with RV-STEMI. PMID- 26956495 TI - Filamin C: a novel component of the KCNE2 interactome during hypoxia. AB - AIM: KCNE2 encodes for the potassium voltage-gated channel, KCNE2. Mutations in KCNE2 have been associated with long-QT syndrome (LQTS). While KCNE2 has been extensively studied, the functions of its C-terminal domain remain inadequately described. Here, we aimed to elucidate the functions of this domain by identifying its protein interactors using yeast two-hybrid analysis. METHODS: The C-terminal domain of KCNE2 was used as bait to screen a human cardiac cDNA library for putative interacting proteins. Co-localisation and co immunoprecipitation analyses were used for verification. RESULTS: Filamin C (FLNC) was identified as a putative interactor with KCNE2. FLNC and KCNE2 co localised within the cell, however, a physical interaction was only observed under hypoxic conditions. CONCLUSION: The identification of FLNC as a novel KCNE2 ligand not only enhances current understanding of ion channel function and regulation, but also provides valuable information about possible pathways likely to be involved in LQTS pathogenesis. PMID- 26956498 TI - Intimomedial mucoid degeneration causing aortic and renal artery aneurysms in a young adult. AB - Intimomedial mucoid degeneration (IMMD) is characterised by aneurysm formation following mucin deposition in the intima and media, with elastic tissue degeneration of the arterial wall. We present a case of a young adult who developed a diffusely aneurysmal aorta and its major branches, which was histopathologically confirmed as intimomedial mucoid degeneration, and a review of the literature. This case report attempts to raise the awareness of the reader to this rare cause of aortic aneurysm and to the bleeding diathesis associated with IMMD that may complicate surgery. PMID- 26956500 TI - Leadless pacing: an advance in cardiac pacing. PMID- 26956499 TI - First reported cases: renal denervation with second-generation multi-electrode catheter via brachial and radial access. AB - Renal denervation is a minimally invasive procedure that aims to reduce brain kidney sympathetic cross-talk. Despite the negative results of the recent SYMPLICITY HTN-3 trial, the procedure is considered safe and has been associated with many beneficial effects, including the reversal of hypertensive heart disease substrate and the prevention of cardiac arrhythmia. The first-generation radiofrequency catheter system featured a monopolar catheter that required sequential singlepoint energy application, followed by rotation, partial withdrawal of the catheter and re-application of energy. The latest generation device features four electrodes configured in a helical arrangement that can simultaneously ablate in four quadrants of the vessel circumference. Renal denervation via brachial or radial arterial access with the second-generation system has not been described before. PMID- 26956501 TI - WOX3 in the scene: intimacy with hormones. PMID- 26956502 TI - The tonoplast--where sweetness is dispensable. PMID- 26956503 TI - Duplicate MADS genes with split roles. PMID- 26956504 TI - Flower development: the evolutionary history and functions of the AGL6 subfamily MADS-box genes. AB - AGL6 is an ancient subfamily of MADS-box genes found in both gymnosperms and angiosperms. Its functions remained elusive despite the fact that the MADS-box genes and the ABC model have been studied for >20 years. Nevertheless, recent discoveries in petunia, rice, and maize support its involvement in the 'E' function of floral development, very similar to the closely related AGL2 (SEPALLATA) subfamily which has been well characterized. The known functions of AGL6 span from ancient conserved roles to new functions acquired in specific plant families. The AGL6 genes are involved in floral meristem regulation, in floral organs, and ovule (integument) and seed development, and have possible roles in both male and female germline and gametophyte development. In grasses, they are also important for the development of the first whorl of the flower, whereas in Arabidopsis they may play additional roles before floral meristem formation. This review covers these recent insights and some other aspects that are not yet fully elucidated, which deserve more studies in the future. PMID- 26956505 TI - Genome-wide analyses for dissecting gene regulatory networks in the shoot apical meristem. AB - Shoot apical meristem activity is controlled by complex regulatory networks in which components such as transcription factors, miRNAs, small peptides, hormones, enzymes and epigenetic marks all participate. Many key genes that determine the inherent characteristics of the shoot apical meristem have been identified through genetic approaches. Recent advances in genome-wide studies generating extensive transcriptomic and DNA-binding datasets have increased our understanding of the interactions within the regulatory networks that control the activity of the meristem, identifying new regulators and uncovering connections between previously unlinked network components. In this review, we focus on recent studies that illustrate the contribution of whole genome analyses to understand meristem function. PMID- 26956506 TI - Volatile emission in dry seeds as a way to probe chemical reactions during initial asymptomatic deterioration. AB - The nature and kinetics of reactions in dry seeds determines how long the seeds survive. We used gas chromatography to assay volatile organic compounds (VOCs) emitted from seeds of three unrelated species as a means to non-invasively probe chemical changes during very dry, dry, and humid storage (seeds were dried to 5.5, 33, and 75% relative humidity at room temperature). VOCs emitted from seeds stored in humid conditions reflected fermentation-type reactions, with methanol and ethanol being predominant in Lactuca sativa and Carum carvi, and acetaldehyde and acetone being predominant in Eruca vesicaria. Dried C. carvi seeds continued to emit fermentation-type products, although at slower rates than the seeds stored in humid conditions. In contrast, drying caused a switch in VOC emission in L. sativa and E. vesicaria seeds towards higher emission of pentane and hexanal, molecules considered to be byproducts from the peroxidation of polyunsaturated fatty acids. Longevity correlated best with the rate of fermentation-type reactions and appeared unrelated to the rate of lipid peroxidation. Emission of VOCs decreased when seed species were mixed together, indicating that seeds adsorbed VOCs. Adsorption of VOCs did not appear to damage seeds, as longevity was not affected in seed mixtures. Collectively, the study shows similarity among species in the types of reactions that occur in dry seeds, but high diversity in the substrates, and hence the byproducts, of the reactions. Moreover, the study suggests that the most abundant VOCs arise from degradation of storage reserves within seed cells, and that these reactions and their byproducts are not, in themselves, damaging. PMID- 26956507 TI - Tissue-Specific Cultured Human Pericytes: Perivascular Cells from Smooth Muscle Tissue Have Restricted Mesodermal Differentiation Ability. AB - Microvascular pericytes (PCs) are considered the adult counterpart of the embryonic mesoangioblasts, which represent a multipotent cell population that resides in the dorsal aorta of the developing embryo. Although PCs have been isolated from several adult organs and tissues, it is still controversial whether PCs from different tissues exhibit distinct differentiation potentials. To address this point, we investigated the differentiation potentials of isogenic human cultured PCs isolated from skeletal (sk-hPCs) and smooth muscle tissues (sm hPCs). We found that both sk-hPCs and sm-hPCs expressed known pericytic markers and did not express endothelial, hematopoietic, and myogenic markers. Both sk hPCs and sm-hPCs were able to differentiate into smooth muscle cells. In contrast, sk-hPCs, but not sm-hPCs, differentiated in skeletal muscle cells and osteocytes. Given the reported ability of the Notch pathway to regulate skeletal muscle and osteogenic differentiation, sk-hPCs and sm-hPCs were treated with N-[N (3,5- difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT), a known inhibitor of Notch signaling. DAPT treatment, as assessed by histological and molecular analysis, enhanced myogenic differentiation and abolished osteogenic potential of sk-hPCs. In contrast, DAPT treatment did not affect either myogenic or osteogenic differentiation of sm-hPCs. In summary, these results indicate that, despite being isolated from the same anatomical niche, cultured PCs from skeletal muscle and smooth muscle tissues display distinct differentiation abilities. PMID- 26956508 TI - In vitro selection of Staphylococcus aureus mutants resistant to tigecycline with intermediate susceptibility to vancomycin. AB - BACKGROUND: Tigecycline (TIG) is an antibiotic belonging to the glycylcyclines class and appears to be a good choice to fight infections caused by Staphylococcus aureus. To date, TIG exhibits good activity against this microorganism. The aim of this work was to obtain in vitro mutants of S. aureus resistant to TIG and evaluate possible changes in their susceptibility patterns to other antibiotics. RESULTS: Two mutants of S. aureus resistant to TIG (MIC = 16 ug/mL) were selected in vitro from clinical isolates of methicillin-resistant S. aureus. In both mutants, corresponding to different lineage (ST5 and ST239), an increase of efflux activity against TIG was detected. One mutant also showed a reduced susceptibility to vancomycin, corresponding to the VISA phenotype (MIC = 4 ug/mL), with a loss of functionality of the agr locus. The emergence of the VISA phenotype was accompanied by an increase in oxacillin and cefoxitin MICs. CONCLUSIONS: This study demonstrates that, under selective pressure, the increase of efflux activity in S. aureus is one of the mechanisms that may be involved in the emergence of tigecycline resistance. The emergence of this phenotype may eventually be associated to changes in susceptibility to other antibiotics such oxacillin and vancomycin. PMID- 26956509 TI - Grading of prostatic adenocarcinoma: current state and prognostic implications. AB - BACKGROUND: Despite significant changes in the clinical and histologic diagnosis of prostate cancer, the Gleason grading system remains one of the most powerful prognostic predictors in prostate cancer. The correct diagnosis and grading of prostate cancer is crucial for a patient's prognosis and therapeutic options. However, this system has undergone significant revisions and continues to have deficiencies that can potentially impact patient care. MAIN BODY: We describe the current state of grading prostate cancer, focusing on the current guidelines for the Gleason grading system and recent changes from the 2014 International Society of Urological Pathology Consensus Conference on Gleason Grading of Prostatic Carcinoma. We also explore the limitations of the current Gleason grading system and present a validated alternative to the Gleason score. The new grading system initially described in 2013 in a study from Johns Hopkins Hospital and then validated in a multi-institutional study, includes five distinct Grade Groups based on the modified Gleason score groups. Grade Group 1 = Gleason score <=6, Grade Group 2 = Gleason score 3 + 4 = 7, Grade Group 3 = Gleason score 4 + 3 = 7, Grade Group 4 = Gleason score 8, Grade Group 5 = Gleason scores 9 and 10. CONCLUSION: As this new grading system is simpler and more accurately reflects prostate cancer biology, it is recommended by the World Health Organization (WHO) to be used in conjunction with Gleason grading. PMID- 26956510 TI - Elevated systemic galectin-1 levels characterize HELLP syndrome. AB - Galectin-1 (gal-1), a member of a family of conserved beta-galactoside-binding proteins, has been shown to exert a key role during gestation. Though gal-1 is expressed at higher levels in the placenta from HELLP patients, it is still poorly understood whether systemic gal-1 levels also differ in HELLP patients. In the present study, we evaluated the systemic expression of gal-1, together with the angiogenic factors, placental growth factor (PlGF) and soluble fms-like tyrosine kinase 1 (sFlt-1) in conjunction with HELLP syndrome severity. Systemic levels of gal-1 and sFlt-1 were elevated in patients with both early- and late onset HELLP syndrome as compared to healthy controls. In contrast, peripheral PlGF levels were decreased in early- and late-onset HELLP. A positive correlation between systemic gal-1 levels and sFlt-1/PlGF ratios was found in early onset HELLP patients. Our results show that HELLP syndrome is associated with increased circulating levels of gal-1; integrating systemic gal-1 measurements into the diagnostic analyses of pregnant women may provide more effective prediction of HELLP syndrome development. PMID- 26956513 TI - 'Those who cannot remember the past are condemned to repeat it'. PMID- 26956511 TI - Optimized total thoracoscopic and laparoscopic esophagectomy for esophageal cancer. AB - BACKGROUND: Total thoracoscopic and laparoscopic esophagectomy (TLE) has attracted attention with the advantage of better operative field and minimal wound for the esophageal cancer. However, various severe complications are also reported during the TLE such as cervical anastomotic leakage, chylothorax, and tracheal injury. The aim of this study was to introduce a new optimized TLE procedure for the esophageal cancer and assess its safety and clinical effects. METHODS: We retrospectively collected the clinical data of 30 patients with esophageal cancer who underwent optimized TLE procedures between January 2014 and December 2014. The optimized TLE procedures mainly include as follows: (1) 50 ml of sesame oil-milk mixture (1:1) is injected via gastric tube after endotracheal intubation; (2) patients are intubated with a single lumen endotracheal tube; (3) patients were positioned at 150 degrees in the left prone position rather than lateral decubitus position; and (4) duodenal feeding tube was not placed intraoperatively and however triple lumen nasojejunal feeding tube was placed on the second postoperative day under imaging guidance. Operation time, amount of blood loss, number of dissected nodes, length of hospital stays, and complications were recorded. RESULTS: The mean operation time of the optimized TLE group was 202.13 +/- 13.74 min. The mean visible blood loss of the optimized TLE group was 300.00 +/- 120.12 ml. The postoperative hospital stays in the optimized TLE group were 16.27 +/- 4.51 days. The number of dissected nodes in the optimized TLE group was 13.57 +/- 2.76. The postoperative complications for the optimized TLE procedure were seen in one case (3.3%). CONCLUSIONS: The method of optimized TLE is an effective, reliable, and safe procedure for the treatment of esophageal cancer, which provide favorable outcomes in terms of operation time, blood loss, length of hospital stays, the number the dissected nodes, and reduced incidence of postoperative complications compared to previous literatures. Further studies with a large number of samples are warranted. PMID- 26956514 TI - Airway device research in pediatric anesthesia: More than just Device A vs Device B? PMID- 26956515 TI - Creation of an integrated outcome database for pediatric anesthesia. AB - Outcome analysis is essential to health care quality improvement efforts. Pediatric anesthesia faces unique challenges in analyzing outcomes. Anesthesia most often involves a one-time point of care interaction where work flow precludes detailed feedback to care givers. In addition, pediatric outcome evaluations must take into account patients' age, development, and underlying illnesses when attempting to establish benchmarks. The deployment of electronic medical records, including preoperative, operative, and postoperative data, offers an opportunity for creating datasets large and inclusive enough to overcome these potential confounders. At our institution, perioperative data exist in five distinct environments. In this study, we describe a method to integrate these datasets into a single web-based relational database that provides researchers and clinicians with regular anesthesia outcome data that can be reviewed on a daily, weekly, or monthly basis. Because of its complexity, the project also entailed the creation of a 'dashboard,' allowing tracking of data trends and rapid feedback of measured metrics to promote and sustain improvements. We present the first use of such a database and dashboard for pediatric anesthesia professionals as well as successfully demonstrating its capabilities to perform as described above. PMID- 26956516 TI - Continuous ventilation during flexible fiberscopic-assisted intubation via supraglottic airways. PMID- 26956517 TI - Successful arterial cannulation in neonates: the 'hanging drop' technique. PMID- 26956518 TI - Dynamic needle tip positioning-para vessel approach. PMID- 26956519 TI - Assessment of hemodynamics with esophageal Doppler in a 3-year-old child undergoing major craniofacial surgery. PMID- 26956520 TI - Which medical and social decision topics are important after early diagnosis of Alzheimer's Disease from the perspectives of people with Alzheimer's Disease, spouses and professionals? AB - BACKGROUND: The relevance of early decision making will rise with increasing availability of early detection of Alzheimer's disease (AD) using brain imaging or biomarkers. RESULTS: Five people with mild AD, six relatives and 13 healthcare professionals with experience in the management of AD were interviewed in a qualitative study regarding medical and social decision topics that emerge after early diagnosis of Alzheimer's disease. Medical treatment, assistance in everyday life and legal issues emerged as the main decision topics after an early diagnosis of AD. People with AD mostly got in contact with the health and social care system through the initiative of their spouses. They were usually aware of their illness and most received antidementia drugs and/or behavioural interventions. Following diagnosis people with AD received support by their spouses. Healthcare professionals were aware of the risk of excessive demand on relatives due to supporting their family member with AD. In the opinion of healthcare professionals legal issues should be arranged in time before patients lose their decisional capacity. In addition, people with AD and spouses reported various coping strategies, in particular "carry on as normal" after diagnosis but mostly are reluctant to actively plan for future stages of the disease. CONCLUSIONS: Due to the common desire to "carry on as usual" after a diagnosis of AD, many people with AD and spouses may miss the opportunity to discuss and decide on important medical and social topics. A structured approach e.g. a decision aid might support people with AD and spouses in their decision making process and thereby preserve persons' with AD autonomy before they lose the capacity in decision-making. PMID- 26956521 TI - Analysis of cellular and humoral immune responses against cytomegalovirus in patients with autoimmune Addison's disease. AB - BACKGROUND: Autoimmune Addison's disease (AAD) is caused by multiple genetic and environmental factors. Variants of genes encoding immunologically important proteins such as the HLA molecules are strongly associated with AAD, but any environmental risk factors have yet to be defined. We hypothesized that primary or reactivating infections with cytomegalovirus (CMV) could represent an environmental risk factor in AAD, and that CMV specific CD8(+) T cell responses may be dysregulated, possibly leading to a suboptimal control of CMV. In particular, the objective was to assess the HLA-B8 restricted CD8(+) T cell response to CMV since this HLA class I variant is a genetic risk factor for AAD. METHODS: To examine the CD8(+) T cell response in detail, we analyzed the HLA-A2 and HLA-B8 restricted responses in AAD patients and healthy controls seropositive for CMV antibodies using HLA multimer technology, IFN-gamma ELISpot and a CD107a based degranulation assay. RESULTS: No differences between patients and controls were found in functions or frequencies of CMV-specific T cells, regardless if the analyses were performed ex vivo or after in vitro stimulation and expansion. However, individual patients showed signs of reactivating CMV infection correlating with poor CD8(+) T cell responses to the virus, and a concomitant upregulation of interferon regulated genes in peripheral blood cells. Several recently diagnosed AAD patients also showed serological signs of ongoing primary CMV infection. CONCLUSIONS: CMV infection does not appear to be a major environmental risk factor in AAD, but may represent a precipitating factor in individual patients. PMID- 26956522 TI - Kaempferol targets Krt-14 and induces cytoskeletal mineralization in osteoblasts: A mechanistic approach. AB - Kaempferol (KEM) has been observed to stimulate Krt-14 protein which subsequently contributes to matrix maturation and mineralization in rat primary osteoblast cells. Incorporation of Krt-14 siRNA results in reduced mRNA and protein expression after 48h post transfection and remained low for 9days. At day 9 Krt 14 siRNA significantly reduced mineralization without concomitant change in the cell number. ColI and OCN gene expression was reduced in Krt-14 siRNA-treated osteoblast cells. Soluble osteocalcin and collagen levels were markedly decreased in conditioned medium as well as in acid-salt soluble cell-ECM layer treated with Krt-14 siRNA compared to control siRNA treated cells corroborated at the ultrastructral level by AFM. Further, knockdown of Krt-14 and inhibitors against AMPK and mTOR, repressed the activation of mTOR and mineralization attenuated by KEM confirmed the role of Krt-14 in mineralization. These findings strongly suggest that Krt-14 regulates osteoblast mineralization by organizing osteoblast derived ECM. PMID- 26956523 TI - Long-term administration of angiotensin (1-7) prevents heart and lung dysfunction in a mouse model of type 2 diabetes (db/db) by reducing oxidative stress, inflammation and pathological remodeling. AB - Congestive heart failure is one of the most prevalent and deadly complications of type 2 diabetes that is frequently associated with pulmonary dysfunction. Among many factors that contribute to development and progression of diabetic complications is angiotensin II (Ang2). Activation of pathological arm of renin angiotensin system results in increased levels of Ang2 and signaling through angiotensin type 1 receptor. This pathway is well recognized for its role in induction of oxidative stress (OS), inflammation, hypertrophy and fibrosis. Angiotensin (1-7) [A(1-7)], through activation of Mas receptor, opposes the actions of Ang2 which can result in the amelioration of diabetic complications; enhancing the overall welfare of diabetic patients. In this study, 8 week-old db/db mice were administered A(1-7) daily via subcutaneous injections. After 16 weeks of treatment, echocardiographic assessment of heart function demonstrated significant improvement in cardiac output, stroke volume and shortening fraction in diabetic animals. A(1-7) also prevented cardiomyocyte hypertrophy, apoptosis, lipid accumulation, and decreased diabetes-induced fibrosis and OS in the heart tissue. Treatment with A(1-7) reduced levels of circulating proinflammatory cytokines that contribute to the low grade inflammation observed in diabetes. In addition, lung pathologies associated with type 2 diabetes, including fibrosis and congestion, were decreased with treatment. OS and macrophage infiltration were also reduced in the lungs after treatment with A(1-7). Long-term administration of A(1-7) to db/db mice is effective in improving heart and lung function in db/db mice. Treatment prevented pathological remodeling of the tissues and reduced OS, fibrosis and inflammation. PMID- 26956525 TI - Scalable fabrication of high-quality, ultra-thin single crystal diamond membrane windows. AB - High quality, ultra-thin single crystal diamond (SCD) membranes that have a thickness in the sub-micron range are of extreme importance as a materials platform for photonics, quantum sensing, nano/micro electro-mechanical systems (N/MEMS) and other diverse applications. However, the scalable fabrication of such thin SCD membranes is a challenging process. In this paper, we demonstrate a new method which enables high quality, large size (~4 * 4 mm) and low surface roughness, low strain, ultra-thin SCD membranes which can be fabricated without deformations such as breakage, bowing or bending. These membranes are easy to handle making them particularly suitable for fabrication of optical and mechanical devices. We demonstrate arrays of single crystal diamond membrane windows (SCDMW), each up to 1 * 1 mm in dimension and as thin as ~300 nm, supported by a diamond frame as thick as ~150 MUm. The fabrication method is robust, reproducible, scalable and cost effective. Microwave plasma chemical vapour deposition is used for in situ creation of single nitrogen-vacancy (NV) centers into the thin SCDMW. We have also developed SCD drum head mechanical resonator composed of our fully clamped and freely suspended membranes. PMID- 26956524 TI - Changes in mean serum lipids among adults in Germany: results from National Health Surveys 1997-99 and 2008-11. AB - BACKGROUND: Monitoring of serum lipid concentrations at the population level is an important public health tool to describe progress in cardiovascular disease risk control and prevention. Using data from two nationally representative health surveys of adults 18-79 years, this study identified changes in mean serum total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) in relation to changes in potential determinants of serum lipids between 1997-99 and 2008-11 in Germany. METHODS: Sex-specific multivariable linear regression analyses were performed with serum lipids as dependent variables and survey wave as independent variable and adjusted for the following covariables: age, fasting duration, educational status, lifestyle, and use of medication. RESULTS: Mean TC declined between the two survey periods by 13 % (5.97 mmol/l vs. 5.19 mmol/l) among men and by 12 % (6.03 mmol/l vs. 5.30 mmol/l) among women. Geometric mean TG decreased by 14 % (1.66 mmol/l vs. 1.42 mmol/l) among men and by 8 % (1.20 mmol/l vs. 1.10 mmol/l) among women. Mean HDL-C remained unchanged among men (1.29 mmol/l vs. 1.27 mmol/l), but decreased by 5 % among women (1.66 mmol/l vs. 1.58 mmol/l). Sports activity and coffee consumption increased, while smoking and high alcohol consumption decreased only in men. Processed food consumption increased and wholegrain bread consumption decreased in both sexes, and obesity increased among men. The use of lipid-lowering medication, in particular statins nearly doubled over time in both sexes. Among women, hormonal contraceptive use increased and postmenopausal hormone therapy halved over time. The changes in lipid levels between surveys remained significant after adjusting for covariables. CONCLUSION: Serum TC and TG considerably declined over one decade in Germany, which can be partly explained by increased use of lipid lowering medication and improved lifestyle among men. The decline in serum lipids among women, however, remains unexplained. PMID- 26956526 TI - A High-Throughput, Multi-Cell Phenotype Assay for the Identification of Novel Inhibitors of Chemotaxis/Migration. AB - Chemotaxis and cell migration are fundamental, universal eukaryotic processes essential for biological functions such as embryogenesis, immunity, cell renewal, and wound healing, as well as for pathogenesis of many diseases including cancer metastasis and chronic inflammation. To identify novel chemotaxis inhibitors as probes for mechanistic studies and leads for development of new therapeutics, we developed a unique, unbiased phenotypic chemotaxis-dependent Dictyostelium aggregation assay for high-throughput screening using rapid, laser-scanning cytometry. Under defined conditions, individual Dictyostelium secrete chemoattractants, migrate, and aggregate. Chemotaxis is quantified by laser scanning cytometry with a GFP marker expressed only in cells after chemotaxis/multi-cell aggregation. We applied the assay to screen 1,280 known compounds in a 1536-well plate format and identified two chemotaxis inhibitors. The chemotaxis inhibitory activities of both compounds were confirmed in both Dictyostelium and in human neutrophils in a directed EZ-TAXIscan chemotaxis assay. The compounds were also shown to inhibit migration of two human cancer cell lines in monolayer scratch assays. This test screen demonstrated that the miniaturized assay is extremely suited for high-throughput screening of very large libraries of small molecules to identify novel classes of chemotaxis/migratory inhibitors for drug development and research tools for targeting chemotactic pathways universal to humans and other systems. PMID- 26956527 TI - A review of immune amplification via ligand clustering by self-assembled liquid crystalline DNA complexes. AB - We examine how the interferon production of plasmacytoid dendritic cells is amplified by the self-assembly of liquid-crystalline antimicrobial peptide/DNA complexes. These specialized dendritic cells are important for host defense because they quickly release large quantities of type I interferons in response to infection. However, their aberrant activation is also correlated with autoimmune diseases such as psoriasis and lupus. In this review, we will describe how polyelectrolyte self-assembly and the statistical mechanics of multivalent interactions contribute to this process. In a more general compass, we provide an interesting conceptual corrective to the common notion in molecular biology of a dichotomy between specific interactions and non-specific interactions, and show examples where one can construct exquisitely specific interactions using non specific interactions. PMID- 26956528 TI - Multiscale coarse-grained modelling of chromatin components: DNA and the nucleosome. AB - To model large biomolecular systems, such as cell and organelles an atomistic description is not currently achievable and is not generally practical. Therefore, simplified coarse-grained (CG) modelling becomes a necessity. One of the most important cellular components is chromatin, a large DNA-protein complex where DNA is highly compacted. Recent progress in coarse graining modelling of the major chromatin components, double helical DNA and the nucleosome core particle (NCP) is presented. First, general principles and approaches allowing rigorous bottom-to-top generation of interaction potentials in the CG models are presented. Then, recent CG models of DNA are reviewed and their adequacy is benchmarked against experimental data on the salt dependence of DNA flexibility (persistence length). Furthermore, a few recent CG models of the NCP are described and their application for studying salt-dependent NCP-NCP interaction is discussed. An example of a multiscale approach to CG modelling of chromatin is presented where interactions and self-assembly of thousands of NCPs in solution are observed. PMID- 26956529 TI - Characterisation of dihydroazulene and vinylheptafulvene derivatives using Raman spectroscopy: The CN-stretching region. AB - The effect of adding electron donating and withdrawing groups on the dihydroazulene (DHA)/vinylheptafulvene (VHF) photochromic system has been investigated using Raman spectroscopy in CS2 solutions. The photoswitching between DHA and VHF is often characterised with UV-Vis spectroscopy. However, Raman spectroscopy can also be used for this purpose and give structural insight, as the light induced ring-opening from DHA to VHF causes changes in the CN stretching frequencies. The CN-stretching frequencies in DHA and VHF are isolated and optimal for the identification of DHA and VHF. The DHA system is also investigated in the solid state. PMID- 26956531 TI - Neuropeptides and anxiety disorders. AB - In this review article four neuropeptides: adrenocorticotrope hormone (ACTH), corticotrope releasing hormone (CRH), neuropeptide- Y(NPY) and cholecystokinin (CCK) are discussed with respect to their possible role in the pathogenesis of anxiety disorders. First the presumable working mechanism of these peptides in the brain is mentioned. In addition, the relationship of these peptides and anxiety is outlined using neuroanatomical and electrophysiological research data. Subsequently, animal experiments and human research findings are discussed. Most of the research findings so far are obtained from animal data. Only with respect to CCK, there is increasing evidence, also from human studies, that this peptide might play a role in the pathogenesis of anxiety disorders. The putative role of the other peptides remains to be estab lished in future research. PMID- 26956530 TI - Protein-binding, cytotoxicity in vitro and cell cycle arrest of ruthenium(II) polypyridyl complexes. AB - The cytotoxic activity of two Ru(II) complexes against A549, BEL-7402, HeLa, PC 12, SGC-7901 and SiHa cell lines was investigated by MTT method. Complexes 1 and 2 show moderate cytotoxicity toward BEL-7402 cells with an IC50 value of 53.9 +/- 3.4 and 39.3 +/- 2.1 MUM. The effects of the complexes inducing apoptosis, cellular uptake, reactive oxygen species and mitochondrial membrane potential in BEL-7402 cells have been studied by fluorescence microscopy. The percentages of apoptotic and necrotic cells and cell cycle arrest were studied by flow cytometry. The BSA-binding behaviors were investigated by UV/visible and fluorescent spectra. PMID- 26956532 TI - An ethological approach of depression. AB - Within the framework of interactional theories of depression it was examined whether the interaction of 31 severely depressed patients and a psychiatrist was related to the course of depression during hospitalization. Interactional processes were defined on the basis of directly observed behaviour displayed during an interview and by the use of ethological methods. The behavioural structure of such interaction could be described by 6-7 factors. Some of these factors could predict the clinical course of depression, over an interval of tien weeks. The patients who would not improve displayed before treatment (just after admission) more involvement (i.e., looking, gesticulating) coinciding with more general activation (leg and hand movements) than the patients who would improve. The psychiatrist displayed relatively high levels of involvement (encouragement: hm, hm, yes, yes, and yes-nodding) and low levels of general activation (hand movements) in his interaction with patients who would not improve. The results provide support for interactional theories of depression. PMID- 26956534 TI - Letter to the editor. PMID- 26956533 TI - Preclinical evidence for the role of serotonin receptor-subtypes in depression. AB - Serotonin (5-HT) plays an important role in depression and specific 5-HT reuptake blockers appear to be clinically important antidepressants. It is unclear however, which serotonergic mechanism is involved in the antidepressant effect, certainly when regarding the existence of at least seven 5-HT receptor subtypes. By testing different 5-HT ligands in two animal models of depression (forced swimming and DRL72-S test) and comparison with data from literature, evidence is provided for potential antidepressant qualities of 5-HT1A receptor-agonists and 5 HT1C receptor-antagonists. Compounds binding to 5-HT1B, 5-HT2 and 5-HT3 receptors do not have an antidepressant profile. Results of clinical research support the predicted antidepressive effects of 5-HT1A receptor-agonists. PMID- 26956537 TI - Erratum to: EANM '15 Annual Congress of the European Association of Nuclear Medicine, October 10-14, 2015, Hamburg, Germany. PMID- 26956535 TI - A large-scale mass casualty simulation to develop the non-technical skills medical students require for collaborative teamwork. AB - BACKGROUND: There is little research on large-scale complex health care simulations designed to facilitate student learning of non-technical skills in a team-working environment. We evaluated the acceptability and effectiveness of a novel natural disaster simulation that enabled medical students to demonstrate their achievement of the non-technical skills of collaboration, negotiation and communication. METHODS: In a mixed methods approach, survey data were available from 117 students and a thematic analysis undertaken of both student qualitative comments and tutor observer participation data. RESULTS: Ninety three per cent of students found the activity engaging for their learning. Three themes emerged from the qualitative data: the impact of fidelity on student learning, reflexivity on the importance of non-technical skills in clinical care, and opportunities for collaborative teamwork. Physical fidelity was sufficient for good levels of student engagement, as was sociological fidelity. We demonstrated the effectiveness of the simulation in allowing students to reflect upon and evidence their acquisition of skills in collaboration, negotiation and communication, as well as situational awareness and attending to their emotions. Students readily identified emerging learning opportunities though critical reflection. The scenarios challenged students to work together collaboratively to solve clinical problems, using a range of resources including interacting with clinical experts. CONCLUSIONS: A large class teaching activity, framed as a simulation of a natural disaster is an acceptable and effective activity for medical students to develop the non-technical skills of collaboration, negotiation and communication, which are essential to team working. The design could be of value in medical schools in disaster prone areas, including within low resource countries, and as a feasible intervention for learning the non technical skills that are needed for patient safety. PMID- 26956539 TI - Constitutive expression of Wnt/beta-catenin target genes promotes proliferation and invasion of liver cancer stem cells. AB - Wnt/beta-catenin is an important signaling pathways involved in the tumorgenesis, progression and maintenance of cancer stem cells (CSCs). In the present study, the role of Wnt/beta-catenin signaling in CSC-mediated tumorigenesis and invasion in liver CSCs was investigated. A small population of cancer stem-like side population (SP) cells (3.6%) from liver cancer samples were identified. The cells were highly resistant to drug treatment due to the enhanced expression of drug efflux pumps, such as ABC subfamily G member 2, multidrug resistance protein 1 and ATP-binding cassette subfamily B member 5. Furthermore, using TOPflash and reverse transcription-quantitative polymerase chain reaction analysis, Wnt/beta catenin signaling and the transcriptional regulation of Wnt/beta-catenin target genes including dickkopf Wnt signaling pathway inhibitor 1, axis inhibition protein 2 and cyclin D1 were observed to be markedly upregulated in liver cancer SP cells. As a consequence, SP cells possessed infinite cell proliferation potential and the ability to generating tumor spheres. In addition, upon reducing Wnt/beta-catenin signaling, the rates of proliferation, tumor sphere formation and tumor invasion of SP cells were markedly reduced. Therefore, these data suggest that Wnt/beta-catenin signaling is a potential therapeutic target to reduce CSC-mediated tumorigenicity and invasion in liver cancer. PMID- 26956540 TI - Serum nitric oxide is associated with the risk of chronic kidney disease in women: Tehran lipid and glucose study. AB - Background and aim This study was conducted to investigate the association between serum nitric oxide metabolites (NOx) and the risk of chronic kidney disease (CKD). Methods We recruited 3462 and 2504 participants of the Tehran Lipid and Glucose Study (TLGS), for a cross-sectional and prospective analysis, respectively. Serum NOx concentrations were measured at baseline (2006-2008), and demographics, anthropometrics and biochemical variables were evaluated at baseline and again after 3 years (2009-2011). Estimated glomerular filtration rate (eGFR) and CKD were defined. Association between serum NOx and CKD in the cross-sectional phase and the predictability of NOx in CKD occurrence were assessed using multivariable logistic regression models with adjustment for confounders. Results Mean age of participants was 45.0 +/- 15.9 years at baseline and 40.5% were male. The prevalence of CKD was 17.9% (13.4% in men, 21.0% in women) at baseline, at which point, marginally significant odds of CKD in the highest tertile of serum NOx in men (OR = 1.53, 95% CI = 0.96-2.45, p for trend = 0.047) and a significant odds of CKD in women (OR = 2.48, 95% CI = 1.76-3.49, p for trend = 0.001) were observed. After a 3-year follow-up, in women, risk of CKD was higher in the highest compared to the lowest NOx tertiles (OR = 1.86, 95% CI = 1.10-3.14, p for trend = 0.032) but no significant association was observed in men. Conclusion Serum NOx level was found to be an independent predictor of CKD in women; it could be a valuable surrogate for prediction of renal dysfunction in women and help to identify high-risk subjects. PMID- 26956538 TI - Diagnostic imaging to detect and evaluate response to therapy in bone metastases from prostate cancer: current modalities and new horizons. AB - Different therapeutic options for the management of prostate cancer (PC) have been developed, and some are successful in providing crucial improvement in both survival and quality of life, especially in patients with metastatic castration resistant PC. In this scenario, diverse combinations of radiopharmaceuticals (for targeting bone, cancer cells and receptors) and nuclear medicine modalities (e.g. bone scan, SPECT, SPECT/CT, PET and PET/CT) are now available for imaging bone metastases. Some radiopharmaceuticals are approved, currently available and used in the routine clinical setting, while others are not registered and are still under evaluation, and should therefore be considered experimental. On the other hand, radiologists have other tools, in addition to CT, that can better visualize bone localization and medullary involvement, such as multimodal MRI. In this review, the authors provide an overview of current management of advanced PC and discuss the choice of diagnostic modality for the detection of metastatic skeletal lesions in different phases of the disease. In addition to detection of bone metastases, the evaluation of response to therapy is another critical issue, since it remains one of the most important open questions that a multidisciplinary team faces when optimizing the management of PC. The authors emphasize the role of nuclear modalities that can presently be used in clinical practice, and also look at future perspectives based on relevant clinical data with novel radiopharmaceuticals. PMID- 26956541 TI - CHoosing Options for Insomnia in Cancer Effectively (CHOICE): Design of a patient centered comparative effectiveness trial of acupuncture and cognitive behavior therapy for insomnia. AB - Insomnia is a prevalent and persistent side effect of cancer, which if left unaddressed, can be unremitting and negatively influence physical and mental well being. Acupuncture and Cognitive Behavioral Therapy (CBT) are commonly used non pharmacological treatments that are efficacious for treating insomnia in cancer patients; however, little is known about the comparative effectiveness of these options. The goal of personalized medicine is to determine which treatments are most effective for which individuals, and patient preference for treatment is a particularly important contributor to adherence and outcomes. Here we describe the design of a clinical trial that begins to determine how best to personalize the treatment of insomnia for cancer survivors. This project is a randomized controlled comparative effectiveness trial with a nested qualitative study comparing acupuncture and CBT for insomnia and co-morbid symptoms in a heterogeneous sample of 160 cancer survivors. The primary aim is to determine which treatment is associated with the largest reduction in insomnia severity. The secondary aim is to examine the demographic, clinical, and psychological characteristics that predict and/or moderate treatment effect. Patients will receive ten treatments of acupuncture or 7 sessions of CBT over eight weeks and complete validated patient-reported outcome measures of sleep and co-morbid symptoms at baseline, mid-treatment, post-treatment, and at three-months to assess durability of effect. The results of the proposed study have the potential to improve healthcare outcomes by helping cancer survivors and their caregivers make informed and evidence-based decisions, leading to patient-centered and personalized care for cancer survivors with insomnia. PMID- 26956542 TI - Understanding of the Effects of Ionic Strength on the Bimolecular Rate Constant between Structurally Identified Redox Enzymes and Charged Substrates Using Numerical Simulations on the Basis of the Poisson-Boltzmann Equation. AB - To understand electrostatic interactions in biomolecules, the bimolecular rate constants (k) between redox enzymes and charged substrates (in this study, redox mediators in the electrode reaction) were evaluated at various ionic strengths (I) for the mediated bioelectrocatalytic reaction. The k value between bilirubin oxidase (BOD) and positively charged mediators increased with I, while that between BOD and negatively charged mediators decreased with I. The opposite trend was observed for the reaction of glucose oxidase (GOD). In the case of noncharged mediators, the k value was independent of I for both BOD and GOD. These results reflect the electrostatic interactions between the enzymes and the mediators. Furthermore, we estimated k/k degrees (k degrees being the thermodynamic rate constant) by numerical simulation (finite element method) based on the Poisson Boltzmann (PB) equation. By considering the charges of individual atoms involved in the amino acids around the substrate binding sites in the enzymes, the simulated k/k degrees values well reproduced the experimental data. In conclusion, k/k degrees can be predicted by PB-based simulation as long as the crystal structure of the enzyme and the substrate binding site are known. PMID- 26956543 TI - Editing of mouse and human immunoglobulin genes by CRISPR-Cas9 system. AB - Applications of the CRISPR-Cas9 system to edit the genome have widely expanded to include DNA gene knock-out, deletions, chromosomal rearrangements, RNA editing and genome-wide screenings. Here we show the application of CRISPR-Cas9 technology to edit the mouse and human immunoglobulin (Ig) genes. By delivering Cas9 and guide-RNA (gRNA) with retro- or lenti-virus to IgM(+) mouse B cells and hybridomas, we induce class-switch recombination (CSR) of the IgH chain to the desired subclass. Similarly, we induce CSR in all human B cell lines tested with high efficiency to targeted IgH subclass. Finally, we engineer mouse hybridomas to secrete Fab' fragments instead of the whole Ig. Our results indicate that Ig genes in mouse and human cells can be edited to obtain any desired IgH switching helpful to study the biology of normal and lymphoma B cells. We also propose applications that could transform the technology of antibody production. PMID- 26956544 TI - Redox homeostasis protects mitochondria through accelerating ROS conversion to enhance hypoxia resistance in cancer cells. AB - Mitochondria are the powerhouses of eukaryotic cells and the main source of reactive oxygen species (ROS) in hypoxic cells, participating in regulating redox homeostasis. The mechanism of tumor hypoxia tolerance, especially the role of mitochondria in tumor hypoxia resistance remains largely unknown. This study aimed to explore the role of mitochondria in tumor hypoxia resistance. We observed that glycolysis in hypoxic cancer cells was up-regulated more rapidly, with far lesser attenuation in aerobic oxidation, thus contributing to a more stable ATP/ADP ratio. In hypoxia, cancer cells rapidly convert hypoxia-induced O(2)(-) into H2O2. H2O2 is further decomposed by a relatively stronger antioxidant system, causing ROS levels to increase lesser compared to normal cells. The moderate ROS leads to an appropriate degree of autophagy, eliminating the damaged mitochondria and offering nutrients to promote mitochondria fusion, thus protects mitochondria and improves hypoxia tolerance in cancer. The functional mitochondria could enable tumor cells to flexibly switch between glycolysis and oxidative phosphorylation to meet the different physiological requirements during the hypoxia/re-oxygenation cycling of tumor growth. PMID- 26956545 TI - Location of metastases in cancer of unknown primary are not random and signal familial clustering. AB - Cancer of unknown primary (CUP) is a fatal disease diagnosed through metastases. It shows intriguing familial clustering with certain defined primary cancers. Here we examine whether metastatic location in CUP patients is related to primary non-CUP cancers in relatives based on the Swedish Cancer Registry. Standardized incidence ratios (SIRs) were calculated for CUP patients defined by metastatic location depending on cancer in their first degree relatives. SIRs for CUP were high in association with liver (3.94), ovarian (3.41), lung (2.43) and colorectal cancers (1.83) in relatives. The SIR was 1.63 for CUP with metastases in the abdomen when a relative was diagnosed with ovarian cancer. CUP with liver metastases associated with liver (1.44) cancer in relatives. CUP with head and neck region metastases associated with relatives' esophageal (2.87) cancer. CUP metastases in the thorax associated with a relative's cancers in the upper aerodigestive tract (2.14) and lung (1.74). The findings, matching metastatic location in CUP and primary cancer in relatives, could be reconciled if these cases of CUP constitute a phenotypically modified primary lacking tissue identification, resulting from epitope immunoediting. Alternatively, CUP metastases arise in a genetically favored tissue environment (soil) promoting growth of both primary cancers and metastases (seeds). PMID- 26956546 TI - Single concentration loss of activity assay provides an improved assessment of drug-drug interaction risk compared to IC50-shift. AB - 1. The utility of two abbreviated, higher-throughput assays [IC50-shift and the loss of activity (LOA) assay] to evaluate time-dependent inhibition (TDI) of 24 structurally related compounds was compared. 2. Good correlation (R(2) = 0.90) between % inhibition and kinact/KI suggested that the LOA assay has utility as an indicator of TDI potential. Weaker correlation was observed for the shifted IC50 (IC50(T = 30)) (R(2) = 0.61) and the fold-shift in IC50 (R(2) = 0.17). 3. Primary mechanism for poor correlation was depletion of active enzyme at concentrations > 1 MUM leading to greater than predicted inhibition in the IC50-shift assay. 4. Previously reported strong correlations between IC50(T = 30) and kinact/KI were found to be dependent on potent TDI compounds with kinact/KI > 30; correlation was reduced for moderate inhibitors (kinact/KI < 30). LOA assay maintained good correlation even when strong TDI compounds were excluded. 5. LOA assay (% Inhibition at 30 min, 10 MUM) was a good predictor of in vivo DDI (AUCr), providing a graded response with low potential for false negatives or positives. IC50-shift assay had bias for over-predicting in vivo DDI and was more likely to identify false positives. PMID- 26956547 TI - Evaluation of Thiol Raman Activities and pKa Values Using Internally Referenced Raman-Based pH Titration. AB - Thiols, including organothiol and thiol-containing biomolecules, are among the most important classes of chemicals that are used broadly in organic synthesis, biological chemistry, and nanosciences. Thiol pKa values are key indicators of thiol reactivity and functionality. Reported herein is an internally referenced Raman-based pH titration method that enables reliable quantification of thiol pKa values for both mono- and dithiols in water. The degree of thiol ionization is monitored directly using the peak intensity of the S-H stretching feature in the 2600 cm(-1) region relative to an internal reference peak as a function of the titration solution's pH. The thiol pKa values and Raman activity relative to its internal reference were then determined by curve fitting the experimental data with equations derived on the basis of the Henderson-Hasselbalch equation. Using this Raman titration method, we determined for the first time the first and second thiol pKa values for 1,2-benzenedithiol in water. This Raman-based method is convenient to implement, and its underlying theory is easy to follow. It should therefore have broad application for thiol pKa determinations and verification. PMID- 26956548 TI - Acute systemic exposure to silver-based nanoparticles induces hepatotoxicity and NLRP3-dependent inflammation. AB - Nanoparticles (NPs) are increasingly being commercialized for use in biomedicine. NP toxicity following acute or chronic exposure has been described, but mechanistic insight into this process remains incomplete. Recent evidence from in vitro studies suggested a role for NLRP3 in NP cytotoxicity. In this study, we investigated the effect of systemic administration of composite inorganic NP, consisting of Ag:Cu:B (dose range 1-20 mg/kg), on the early acute (4-24 h post exposure) and late phase response (96 h post-exposure) in normal and NLRP3 deficient mice. Our findings indicate that systemic exposure (>=2 mg/kg) was associated with acute liver injury due to preferential accumulation of NP in this organ and resulted in elevated AST, ALT and LDH levels. Moreover, within 24 h of NP administration, there was a dose-dependent increase in intraperitoneal neutrophil recruitment and upregulation in gene expression of several proinflammatory mediators, including TNF-alpha, IL-1beta and S100A9. Histological analysis of liver tissue revealed evidence of dose-dependent hepatocyte necrosis, increase in sinusoidal Kupffer cells, lobular granulomas and foci of abscess formation which were most pronounced at 24 h following NP administration. NP deposition in the liver led to a significant upregulation in gene expression of S100A9, an endogenous danger signal recognition molecule of phagocytes, IL-1beta and IL-6. The extent of proinflammatory cytokine activation and hepatotoxicity was significantly attenuated in mice deficient in the NLRP3 inflammasome, demonstrating the critical role of this innate immune system recognition receptor in the response to NP. PMID- 26956549 TI - Fine needle aspiration cytology of cystic primary adult granulosa cell tumor of the ovary: Potential diagnostic pitfalls with other cystic ovarian lesions. AB - INTRODUCTION: Fine needle aspiration(FNA) of cystic adult granulosa cell tumors(CAGCT) has been sporadically reported in the literature. We undertook a retrospective study to further elucidate the cytologic features on FNA material in order to avoid possible misinterpretation with other primary tumors of ovary. MATERIALS AND METHODS: During 1992 and 2014, FNA of five cases of CAGCT were recorded. RESULTS: The patient's age ranged from 28 to 62 years. One was bilateral and all cases involved right side of ovary. The size of tumor was 5.5 to 10 cm. FNA of the five CAGCT show similar cytologic features except one case. Four cases contained a background composed of histiocytic cells and debris material. The tumor cells were small with round to oval nuclei and fine chromatin pattern, inconspicuous nucleoli, scanty cytoplasm with rare intranuclear longitudinal grooves. Tumor cells were arranged in small groups as well as single cells were appreciated some of which were deprived of cytoplasm. Microfollicular or rosette pattern were vague, some of which contain amorphous material resembling Call-Exner bodies. In addition, two cases also showed prominent papillary component and one of which was misdiagnosed for serous papillary carcinoma. All five cases were surgically resected and CAGCT was confirmed. CONCLUSIONS: FNA of CAGCT of ovary can be a challenging diagnosis as classic cytologic features may not be present and can be confused with benign follicular cyst especially when the ultrasound study favor benign cystic lesion. Rarely this tumor may show prominent papillary component and can be confused for a more clinically aggressive tumor such as papillary serous carcinoma. Diagn. Cytopathol. 2016;44:461-465. (c) 2016 Wiley Periodicals, Inc. PMID- 26956550 TI - RNA transcript sequencing reveals inorganic sulfur compound oxidation pathways in the acidophile Acidithiobacillus ferrivorans. AB - Acidithiobacillus ferrivorans is an acidophile implicated in low-temperature biomining for the recovery of metals from sulfide minerals. Acidithiobacillus ferrivorans obtains its energy from the oxidation of inorganic sulfur compounds, and genes encoding several alternative pathways have been identified. Next generation sequencing of At. ferrivorans RNA transcripts identified the genes coding for metabolic and electron transport proteins for energy conservation from tetrathionate as electron donor. RNA transcripts suggested that tetrathionate was hydrolyzed by the tetH1 gene product to form thiosulfate, elemental sulfur and sulfate. Despite two of the genes being truncated, RNA transcripts for the SoxXYZAB complex had higher levels than for thiosulfate quinone oxidoreductase (doxDAgenes). However, a lack of heme-binding sites in soxX suggested that DoxDA was responsible for thiosulfate metabolism. Higher RNA transcript counts also suggested that elemental sulfur was metabolized by heterodisulfide reductase (hdrgenes) rather than sulfur oxygenase reductase (sor). The sulfite produced as a product of heterodisulfide reductase was suggested to be oxidized by a pathway involving the sat gene product or abiotically react with elemental sulfur to form thiosulfate. Finally, several electron transport complexes were involved in energy conservation. This study has elucidated the previously unknown At. ferrivorans tetrathionate metabolic pathway that is important in biomining. PMID- 26956552 TI - How Ovarian Cancer Evades Immune Scrutiny. AB - Although dendritic cells are abundant in ovarian tumors, scientists have been puzzled that these cells aren't immunostimulatory. New research reveals a role for the protein SATB1, which is transiently required during ovarian-associated dendritic cell maturation-its unremitting expression in these cells drives them to acquire an inflammatory, immunosuppressive phenotype. PMID- 26956551 TI - Transdermal testosterone pretreatment in poor responders undergoing ICSI: a randomized clinical trial. AB - STUDY QUESTION: Does pretreatment with transdermal testosterone increase the number of cumulus-oocyte complexes (COCs) retrieved by more than 1.5 in poor responders undergoing intracytoplasmic sperm injection (ICSI), using recombinant follicle stimulating hormone (FSH) and gonadotrophin releasing hormone agonists (GnRHa)? SUMMARY ANSWER: Testosterone pretreatment failed to increase the number of COCs by more than 1.5 as compared with no pretreatment in poor responders undergoing ICSI (difference between medians: 0.0, 95% CI: -1.0 to +1.0). WHAT IS KNOWN ALREADY: Androgens are thought to play an important role in early follicular development by enhancing ovarian sensitivity to FSH. In a recent meta analysis, testosterone pretreatment resulted in an increase of 1.5 COCs as compared with no pretreatment. However, this effect was based on the analysis of only two randomized controlled trials (RCTs) including 163 patients. Evidently, there is a need for additional RCTs that will allow firmer conclusions to be drawn. STUDY DESIGN, SIZE, DURATION: The present RCT was designed to detect a difference of 1.5 COCs (sample size required = 48 patients). From 02/2014 until 04/2015, 50 poor responders fulfilling the Bologna criteria have been randomized (using a randomization list) to either testosterone pretreatment for 21 days ( ITALIC! n = 26) or no pretreatment ( ITALIC! n = 24). PARTICIPANTS/MATERIALS, SETTING, METHODS: All patients underwent a long follicular GnRHa protocol. Recombinant FSH stimulation was started on Day 22 following GnRHa initiation. In the testosterone pretreatment group, a daily dose of 10 mg of testosterone gel was applied transdermally for 21 days starting from GnRHa initiation. Results are expressed as median (interquartile range). MAIN RESULTS AND THE ROLE OF CHANCE: No differences in baseline characteristics were observed between the two groups compared. Testosterone levels [median (interquartile range)] were significantly higher in the testosterone pretreatment on the day of initiation of FSH stimulation [114 (99.5) ng/dl versus 20 (20) ng/dl, respectively, ITALIC! P < 0.001]. Duration of FSH stimulation [median (interquartile range)] was similar between the groups compared [12.5 (3.0) days versus 12 (3.0) days, respectively, ITALIC! P = 0.52]. The number of COCs retrieved [median (interquartile range)] was not different between the testosterone pretreatment and the no pretreatment groups [3.5 (4.0) versus 3.0 (3.0), 95% CI for the median: 2.0-5.0 versus 2.7 4.3, respectively; difference between medians: 0.0, 95% CI: +1.0 to -1.0). Similarly no differences were observed regarding fertilization rates [median (interquartile range)] [66.7% (32.5) versus 66.7% (42.9), respectively, ITALIC! P = 0.97] and live birth rates per randomized patient (7.7% versus 8.3%, respectively, rate difference: -0.6%, 95% CI: -19.0 to +16.9). LIMITATIONS, REASONS FOR CAUTION: The study was not powered to detect differences less than 1.5 COCs, although it is doubtful whether these differences would be clinically relevant. Moreover, due to sample size restrictions, no conclusions can be drawn regarding the probability of live birth. WIDER IMPLICATIONS OF THE FINDINGS: The results of this randomized clinical trial, suggesting that pretreatment with 10 mg of transdermal testosterone for 21 days does not improve ovarian response by more than 1.5 oocytes, could be used to more accurately consult patients with poor ovarian response. However, an improvement in IVF outcome using a higher dose of testosterone or a longer pretreatment period cannot be excluded. STUDY FUNDING/COMPETING INTEREST: The study was partially funded by a Scholarship from the Academy of Athens. C.A.V. reports personal fees and non-financial support from Merck, Sharp and Dome, personal fees and non-financial support from Merck Serono, personal fees and non-financial support from IPSEN Hellas S.A., outside the submitted work. B.C.T. reports grants from Merck Serono, grants from Merck Sharp & Dohme, personal fees from Merck Serono, personal fees from Merck Sharp & Dohme, personal fees from IBSA & Ferring, outside the submitted work. TRIAL REGISTRATION NUMBER: NCT01961336. TRIAL REGISTRATION DATE: 10 October 2013. DATE OF FIRST PATIENT'S ENROLLMENT: 02/2014. PMID- 26956553 TI - Comparative analysis of pathways to early intervention services and duration of untreated psychosis in two Canadian cities. AB - AIM: Understanding pathways to early intervention services for psychosis in the local context is crucial, as the structure and organization of services need to be considered. This study compared pathways to early intervention services in two Canadian cities. METHODS: Data on pathways to care and duration of untreated psychosis were collected from 171 people admitted to early intervention services in Toronto (n = 150) and Hamilton (n = 21). We compared the cities on several indicators of pathway to care and duration of untreated psychosis. RESULTS: Pathways to care were more complex in Toronto, where people saw a greater number of health care services (median = 6, interquartile range = 3-9) than those in Hamilton (median = 3, IQR = 1-4). General practitioner involvement was higher in Toronto (56.0% vs. 33.3%). We did not find differences in the median duration of untreated psychosis. CONCLUSIONS: Pathways to early intervention services could be streamlined, and general practitioners may be a target for strategies to improve pathways to care. PMID- 26956555 TI - Flavone C-glycosides from Trichuriella monsoniae (L.f.) Bennet. AB - In the first phytochemical investigation of Trichuriella monsoniae, three known flavonoidal C-glycosides, isoswertisin 1, 2"-O-beta-d-galactosyl isoswertisin 2 and 2"-O-beta-d-xylosyl isoswertisin 3 were isolated from the methanolic extract of the whole plant. Their structures were elucidated by extensive NMR spectroscopic studies including 2D NMR and HRMS, and the structure of 2 was supported by single crystal X-ray data studies. Further, NMR assignments for 3 are being reported for the first time. PMID- 26956554 TI - Associations Between the Serum Metabolome and All-Cause Mortality Among African Americans in the Atherosclerosis Risk in Communities (ARIC) Study. AB - Early and accurate identification of people at high risk of premature death may assist in the targeting of preventive therapies in order to improve overall health. To identify novel biomarkers for all-cause mortality, we performed untargeted metabolomics in the Atherosclerosis Risk in Communities (ARIC) Study. We included 1,887 eligible ARIC African Americans, and 671 deaths occurred during a median follow-up period of 22.5 years (1987-2011). Chromatography and mass spectroscopy identified and quantitated 204 serum metabolites, and Cox proportional hazards models were used to analyze the longitudinal associations with all-cause and cardiovascular mortality. Nine metabolites, including cotinine, mannose, glycocholate, pregnendiol disulfate, alpha-hydroxyisovalerate, N-acetylalanine, andro-steroid monosulfate 2, uridine, and gamma-glutamyl leucine, showed independent associations with all-cause mortality, with an average risk change of 18% per standard-deviation increase in metabolite level (P < 1.23 * 10(-4)). A metabolite risk score, created on the basis of the weighted levels of the identified metabolites, improved the predictive ability of all cause mortality over traditional risk factors (bias-corrected Harrell's C statistic 0.752 vs. 0.730). Mannose and glycocholate were associated with cardiovascular mortality (P < 1.23 * 10(-4)), but predictive ability was not improved beyond the traditional risk factors. This metabolomic analysis revealed potential novel biomarkers for all-cause mortality beyond the traditional risk factors. PMID- 26956556 TI - A NMF based approach for integrating multiple data sources to predict HIV-1-human PPIs. AB - BACKGROUND: Predicting novel interactions between HIV-1 and human proteins contributes most promising area in HIV research. Prediction is generally guided by some classification and inference based methods using single biological source of information. RESULTS: In this article we have proposed a novel framework to predict protein-protein interactions (PPIs) between HIV-1 and human proteins by integrating multiple biological sources of information through non negative matrix factorization (NMF). For this purpose, the multiple data sets are converted to biological networks, which are then utilized to predict modules. These modules are subsequently combined into meta-modules by using NMF based clustering method. The integrated meta-modules are used to predict novel interactions between HIV-1 and human proteins. We have analyzed the significant GO terms and KEGG pathways in which the human proteins of the meta-modules participate. Moreover, the topological properties of human proteins involved in the meta modules are investigated. We have also performed statistical significance test to evaluate the predictions. CONCLUSIONS: Here, we propose a novel approach based on integration of different biological data sources, for predicting PPIs between HIV-1 and human proteins. Here, the integration is achieved through non negative matrix factorization (NMF) technique. Most of the predicted interactions are found to be well supported by the existing literature in PUBMED. Moreover, human proteins in the predicted set emerge as 'hubs' and 'bottlenecks' in the analysis. Low p-value in the significance test also suggests that the predictions are statistically significant. PMID- 26956557 TI - Luminescent coordination polymers for the VIS and NIR range constituting LnCl3 and 1,2-bis(4-pyridyl)ethane. AB - A series of 14 lanthanide containing coordination polymers LnCl3 with 1,2-bis(4 pyridyl)ethane (bpe) was synthesized from either thiazole or pyridine. Depending on the ligand content, a structural diversity from 3D-frameworks [LnCl3(bpe)2].thz, Ln = Ce-Lu, to 1D-strands [La2Cl6(bpe)2(thz)6] and [LnCl3(bpe)(py)2].(bpe/py), Ln = Gd, Er, was obtained and characterized by X-ray single crystal diffraction, powder diffraction, differential thermal analysis and thermogravimetry (DTA/TG), IR-spectroscopy and photoluminescence spectroscopy. The compounds exhibit a variety of luminescence properties and different phenomena. This includes ligand centred fluorescence, metal-centred 5d-4f/4f-4f emission in the visible and the NIR range, antenna effects via Dexter and Forster energy transfer mechanisms, excitation dependent emission with a correlating shift of the chromaticity coordinates and inner filter effects by combined re absorption/emission. PMID- 26956558 TI - Diet-induced obesity alters myeloid cell populations in naive and injured lung. AB - BACKGROUND: There are pulmonary consequences to obesity, including increased prevalence of asthma, greater susceptibility to influenza, and possibly reduced susceptibility to lung injury. Although it is well established that obesity is associated with alterations to the immune system, little is known about obesity associated changes to pulmonary immune cells. OBJECTIVES: We hypothesized that obesity would alter the inflammatory milieu in the unchallenged lung and circulation; thereby contributing to altered susceptibility to lung injury. METHODS: We used a murine model of diet-induced obesity and evaluated bone marrow and blood leukocytes at 3 months, and pulmonary leukocytes at 3 and 6 months for changes in their adhesion and chemokine receptors, markers of activation states, and cell numbers. We also evaluated the inflammatory response to LPS in obese mice. RESULTS: In the lung, diet-induced obesity was associated with increased leukocyte numbers over-time. Adhesion receptors were increased in a cell- and site-specific fashion, and there was an evolution of macrophage and neutrophil polarization toward M1 and N1, respectively. After LPS-challenge, obesity was associated with increased neutrophil recruitment to the lung with impaired migration into the alveolar space. Associated with these changes, obesity increased LFA-1 and ICAM-1 neutrophil expression and altered CXCL1 gradients. CONCLUSION: Our results highlight the effects of diet-induced obesity on the murine blood and lung leukocyte populations, including increases in adhesion receptor expression that may contribute to altered recruitment or retention within the lung. Translation of these findings to people with obesity will be critical for determining the basic inflammatory underpinnings of pulmonary disease susceptibility. PMID- 26956560 TI - Inhibitory cueing effects following manual and saccadic responses to arrow cues. AB - With two cueing tasks, in the present study we examined output-based inhibitory cueing effects (ICEs) with manual responses to arrow targets following manual or saccadic responses to arrow cues. In all experiments, ICEs were observed when manual localization responses were required to both the cues and targets, but only when the cue-target onset asynchrony (CTOA) was 2,000 ms or longer. In contrast, when saccadic responses were made in response to the cues, ICEs were only observed with CTOAs of 2,000 ms or less-and only when an auditory cue-back signal was used. The present study also showed that the magnitude of ICEs following saccadic responses to arrow cues decreased with time, much like traditional inhibition-of-return effects. The magnitude of ICEs following manual responses to arrow cues, however, appeared later in time and had no sign of decreasing even 3 s after cue onset. These findings suggest that ICEs linked to skeletomotor activation do exist and that the ICEs evoked by oculomotor activation can carry over to the skeletomotor system. PMID- 26956561 TI - Clear cell atypical fibroxanthoma: a case report and review of the literature. AB - Atypical fibroxanthoma (AFX) is a group of cutaneous tumors characterized by a population of fusiform, epithelioid and pleomorphic cells. Clinically, AFX is commonly found on the head and neck of older adults as a solitary ulcerated nodule. Clear cell atypical fibroxanthoma is a very rare variant of AFX, with only 13 cases reported to date. The differential diagnoses often include dermal neoplasms composed of clear cells, such as squamous cell carcinoma, basal cell carcinoma, metastatic renal cell carcinoma and balloon cell malignant melanoma. These diagnoses can be ruled out by the typical immunohistochemical profile of clear cell AFX, which is negative for specific epithelial and melanocytic markers. Herein, we describe a rare and unusual case of clear cell AFX arising on the ear of a relatively young adult patient. Histologically, the dermis was completely replaced by an atypical population of vacuolated cells with numerous atypical mitoses. Immunohistochemical stains were negative forpancytokeratin, CK5/6, CK7, and p63 S100 and Melan-A stains. CD10 and CD68 stains were positive, making the findings consistent with the diagnosis of clear cell atypical fibroxanthoma. PMID- 26956559 TI - A unified framework for hybrid breeding and the establishment of heterotic groups in wheat. AB - KEY MESSAGE: Global wheat genetic diversity can be used in a unified framework to support and accelerate hybrid breeding and the development of heterotic groups in wheat. Hybrid wheat breeding has great potential to increase the global wheat grain yield level particularly in view of the increasing abiotic and biotic stress challenges as well as variable climatic conditions. For the long-term success of hybrid wheat breeding and the maximum exploitation of heterosis, high yielding heterotic patterns must be established. Here, we propose a unified framework for hybrid breeding and the establishment of heterotic groups in autogamous crops and exemplify it for hybrid wheat breeding in Germany. A key component is the establishment of genetic distance between heterotic groups and in this context, we assessed genetic diversity in a global collection of 1110 winter wheat varieties released during the past decades in 35 countries but with a focus on European origin. Our analyses revealed the absence of major population structure but nevertheless suggest genetically distinct subgroups with potential for hybrid wheat breeding. Taking our molecular results and additional phenotypic data together, we propose how global genetic diversity can be used to accelerate and support reciprocal recurrent selection for the development of genetically distinct heterotic groups in hybrid wheat breeding. PMID- 26956562 TI - Testing Multiple Psychological Processes for Common Neural Mechanisms Using EEG and Independent Component Analysis. AB - Temporal independent component analysis (ICA) is applied to an electrophysiological signal mixture (such as an EEG recording) to disentangle the independent neural source signals-independent components-underlying said signal mixture. When applied to scalp EEG, ICA is most commonly used either as a pre processing step (e.g., to isolate physiological processes from non-physiological artifacts), or as a data-reduction step (i.e., to focus on one specific neural process with increased signal-to-noise ratio). However, ICA can be used in an even more powerful way that fundamentally expands the inferential utility of scalp EEG. The core assumption of EEG-ICA-namely, that individual independent components represent separable neural processes-can be leveraged to derive the following inferential logic: If a specific independent component shows activity related to multiple psychological processes within the same dataset (e.g., elicited by different experimental events), it follows that those psychological processes involve a common, non-separable neural mechanism. As such, this logic allows testing a class of hypotheses that is beyond the reach of regular EEG analyses techniques, thereby crucially increasing the inferential utility of the EEG. In the current article, this logic will be referred to as the 'common independent process identification' (CIPI) approach. This article aims to provide a tutorial into the application of this powerful approach, targeted at researchers that have a basic understanding of standard EEG analysis. Furthermore, the article aims to exemplify the usage of CIPI by outlining recent studies that successfully applied this approach to test neural theories of mental functions. PMID- 26956563 TI - Molecular Characterization of beta-Thalassemia in the Czech and Slovak Populations: Mediterranean, Asian and Unique Mutations. AB - beta-Thalassemia (beta-thal) is considered rare in Central Europe. As in other malaria-free regions, the presence of beta-thal in Central Europe reflects historical and recent immigration, and demographic changes that have influenced the genetic variability of the current populations living in this area. This study assesses the frequency and spectrum of mutations on the beta-globin gene in Czech and Slovak subjects with clinical symptoms of thalassemia. The results of the initial part of this research were published more than two decades ago; the aim of this study was to update these original reports. During the period from 2002 to 2015, 400 cases from Czech and Slovak hematological centers were analyzed. Twenty-nine beta-thal mutations, identified in 356 heterozygotes from 218 unrelated families, involve five unique mutations including a recently described insertion of a transposable L1 element into the beta-globin gene. One mutation described here is reported for the first time. Most of the mutations were of Mediterranean origin and accounted for 82.0% of cases. All but one case studied were heterozygous carriers, manifesting beta-thal minor, with rare exceptions represented by the rare (beta(0)) codons 46/47 (+G) (HBB: c.142_142dupG) mutation associated with an alpha-globin gene quadruplication and by dominantly inherited beta-thal with a more severe phenotype. One double heterozygous beta-thal patient was a recent immigrant from Moldavia. The list of deltabeta-thal alleles (26 carriers, 16 families) contains Hb Lepore and two types of deltabeta(0)-thal deletions. In the past, genetic drift and migration as well as recent immigrations were responsible for the introduction of Mediterranean alleles, while several mutations described in single families were of local origin. PMID- 26956564 TI - In search of genetic constraints limiting the evolution of egg size: direct and correlated responses to artificial selection on a prenatal maternal effector. AB - Maternal effects are an important force in nature, but the evolutionary dynamics of the traits that cause them are not well understood. Egg size is known to be a key mediator of prenatal maternal effects with an established genetic basis. In contrast to theoretical expectations for fitness-related traits, there is a large amount of additive genetic variation in egg size observed in natural populations. One possible mechanism for the maintenance of this variation is through genetic constraints caused by a shared genetic basis among traits. Here we created replicated, divergent selection lines for maternal egg investment in Japanese quail (Coturnix japonica) to quantify the role of genetic constraints in the evolution of egg size. We found that egg size responds rapidly to selection, accompanied by a strong response in all egg components. Initially, we observed a correlated response in body size, but this response declined over time, showing that egg size and body size can evolve independently. Furthermore, no correlated response in fecundity (measured as the proportion of days on which a female laid an egg) was observed. However, the response to selection was asymmetrical, with egg size plateauing after one generation of selection in the high but not the low investment lines. We attribute this pattern to the presence of genetic asymmetries, caused by directional dominance or unequal allele frequencies. Such asymmetries may contribute to the evolutionary stasis in egg size observed in natural populations, despite a positive association between egg size and fitness. PMID- 26956565 TI - Frequent, geographically structured heteroplasmy in the mitochondria of a flowering plant, ribwort plantain (Plantago lanceolata). AB - Recent research has convincingly documented cases of mitochondrial heteroplasmy in a small set of wild and cultivated plant species. Heteroplasmy is suspected to be common in flowering plants and investigations of additional taxa may help understand the mechanisms generating heteroplasmy as well as its effects on plant phenotypes. The role of mitochondrial heteroplasmy is of particular interest in plants as cytoplasmic male sterility is controlled by mitochondrial genotypes, sometimes leading to co-occurring female and hermaphroditic individuals (gynodioecy). Paternal leakage may be important in the evolution of mating systems in such populations. We conducted a genetic survey of the gynodioecious plant Plantago lanceolata, in which heteroplasmy has not previously been reported, and estimated the frequencies of mitochondrial genotypes and heteroplasmy. Sanger sequence genotyping of 179 individuals from 15 European populations for two polymorphic mitochondrial loci, atp6 and rps12, identified 15 heteroplasmic individuals. These were distributed among 6 of the 10 populations that had polymorphisms in the target loci and represented 8% of all sampled individuals and 15% of the individuals in those 6 populations. The incidence was highest in Northern England and Scotland. Our results are consistent with geographic differences in the incidence of paternal leakage and/or the rates of nuclear restoration of male fertility. PMID- 26956566 TI - Focal interictal epileptiform discharges in idiopathic generalized epilepsy. AB - Are idiopathic generalized epilepsies (IGEs) truly generalized? Do IGEs represent a continuum or rather distinct syndromes? Focal changes in the electroencephalography (EEG) have been reported in IGEs. The aim of this work is to investigate focal interictal epileptiform discharges (IEDs) in IGEs, and their relation to clinical variables. Forty-one IGE patients (classified according to ILAE, 2001) were recruited from a tertiary center (age 23 +/- 10.938 years). Their files were reviewed and they were subjected to clinical examination and interictal EEG. Patients with focal IEDs were compared to those without focal IEDs. Nine patients had juvenile myoclonic epilepsy (JME) and 32 had idiopathic epilepsy with generalized tonic-clonic seizures only (EGTCSA). Focal IEDs were found in 20 patients, mostly in the frontal (45.5 %) and temporal (31.8 %) distribution. Patients with focal IEDs were treated with a larger number of combined antiepileptic drugs (AEDs) (p value = 0.022). No significant difference was found between the two groups regarding age, sex, age at onset, epilepsy syndrome, seizure frequency, family history, AEDs used (sodium valproate and carbamazepine) and their doses. Seventeen EGTCSA patients had focal IEDs. They were treated with larger number of combined AEDs (p value = 0.0142). No significant difference was found between the EGTCSA patients with and those without focal IEDs regarding age, sex, age at onset, seizure frequency, family history and AEDs doses. Caution must be applied in the interpretation of interictal focal IEDs. These focal changes may be related to prognosis, however this needs further investigation. PMID- 26956567 TI - Biological underpinnings of psychogenic nonepileptic seizures: directions for future research. AB - Psychogenic nonepileptic seizures (PNES) are relatively common occurrences in epilepsy centers, but their pathophysiology is still poorly understood. Research that elucidates the pathophysiology of PNES, including their neurobiological basis and biomarkers, may have important clinical implications. The literature provides some evidence that genetic factors, intrinsic factors, and environmental factors probably play a significant role as the biological underpinnings of PNES. Researchers may be able to learn more about the pathophysiology of PNES by investigating the effects of each of these factors on functional and structural brain connectivity. PMID- 26956569 TI - Delayed presentation of a peripapillary combined hamartoma of the retina and retinal pigment epithelium. PMID- 26956570 TI - Incorporating Pets into Acute Inpatient Rehabilitation: A Case Study. AB - PURPOSE: The use of animals in various healthcare settings dates as far back as the 19th century, and is still a widely practiced intervention even today. The use of animals in the acute rehabilitation setting is a common practice that benefits both the patient's therapy progression and allows the opportunity for financial reimbursement for the facility. As acute rehabilitation facilities continue to cope with ever changing rules and guidelines, the use of alternate modalities can help the facility overcome difficult challenges while focusing on the needs of the patients. The use of animal assisted therapy is illustrated with a stroke patient at an acute rehabilitation facility who benefited from implementing a pet therapy regimen when regular therapy modalities were not helping. CLINICAL RELEVANCE: Incorporating animal assisted therapy in acute rehabilitation settings is described to obtain greater satisfaction for patients and staff and to facilitate reimbursement for rehabilitation settings. PMID- 26956568 TI - Intimate partner violence during pregnancy and the risk for adverse infant outcomes: a systematic review and meta-analysis. AB - BACKGROUND: Intimate partner violence (IPV) is of particular concern during pregnancy when not one, but two lives are at risk. Previous meta-analyses have suggested an association between IPV and adverse birth outcomes; however, many large studies have since been published, illustrating the need for updated pooled effect estimates. OBJECTIVES: To evaluate the relationship between IPV during pregnancy and the risk of preterm birth (PTB), low-birthweight (LBW), and small for-gestational-age (SGA) infants. SEARCH STRATEGY: We searched PubMed and SCOPUS (from inception until May 2015), and the reference lists of the relevant studies. SELECTION CRITERIA: Observational studies comparing the rates of at least one adverse birth outcome (SGA, LBW, or PTB) in women who experienced IPV during pregnancy and those who did not. DATA COLLECTION AND ANALYSIS: Data extracted from 50 studies were pooled and pooled odds ratios were calculated using random effects models. MAIN RESULTS: Intimate partner violence (IPV) was significantly associated with PTB (OR 1.91, 95% CI 1.60-2.29) and LBW (OR 2.11, 95% CI 1.68 2.65), although a large level of heterogeneity was present for both (I(2) = 84 and 91%, respectively). The association with SGA was less pronounced and marginally significant (OR 1.37, 95% CI 1.02-1.84), although fewer studies were available for meta-analysis (n = 7). CONCLUSIONS: Our meta-analysis indicates that women who experienced IPV during pregnancy are at increased risk of having a PTB, and an LBW or an SGA infant. More studies examining the association between IPV and SGA are needed. TWEETABLE ABSTRACT: Meta-analysis of IPV during pregnancy finds increased risk for preterm birth, LBW and SGA infants. PMID- 26956571 TI - Bringing Evidence-Based Sexual Health Programs to Adolescents in Black Churches: Applying Knowledge From Systematic Adaptation Frameworks. AB - Previous studies have documented Black churches' receptivity to implementing adolescent sexual health programs within their congregations. Some authors have argued for new sexual health programs to be designed specifically for churches, similar to the development of school- and community-based interventions. However, strategies and curricula used in secular settings may also be effective in influencing sexual behaviors among youth in churches. The current study examined the ways in which the phases of two theorized intervention adaptation frameworks were reflected in the desired key components of a church-based sexual health program. Participants in this community-based participatory research project were youth, parents, and faith leaders from nine Black churches in Baltimore, Maryland. Our findings suggest that the priorities of church stakeholders are consistent, rather than discordant, with the current paradigms of evidence-based sexual health programs and intervention adaptation. Future research and practical implications are discussed. PMID- 26956572 TI - Iron intake, serum iron indices and risk of colorectal adenomas: a meta-analysis of observational studies. AB - To provide a quantitative assessment of the association between iron intake, serum iron indices and the risk of colorectal adenoma (CRA), we summarised the evidence from observational studies. Relevant studies were identified in MEDLINE and EMBASE until 31 March 2015. Summary relative risks (SRRs) with 95% confidence intervals (CIs) were pooled with a random-effects model. A total of 10 articles, involving 3318 subjects with CRA, were used in this meta-analysis. The SRR of CRA was 0.83 (95% CI: 0.71-0.98; Pheterogeneity = 0.694, I2 = 0) for the highest versus the lowest level of dietary iron intake. The SRR was 0.93 (95% CI: 0.62 1.42) for total (dietary and supplemental) iron intake, 1.23 (95% CI: 1.03-1.48) for haem iron intake and 0.73 (95% CI: 0.54-0.97) for supplemental iron intake. Serum iron indices were not associated with CRA risk (serum ferritin: SRR = 1.16, 95% CI: 0.81-1.66; serum iron: SRR = 1.02, 95% CI: 0.75-1.38; serum transferrin saturation: SRR = 1.01; 95% CI: 0.82-1.50). Increased intake of haem iron is associated with significantly increased risk of CRA, whereas intake of non-haem or supplemental iron is inversely associated with risk of CRA. Limited data indicate null associations between serum iron indices and CRA risk. PMID- 26956573 TI - INTELLIGENCE AND TRANSPARENCY IN HEALTH TECHNOLOGY ASSESSMENT. AB - Current thinking about the methodology of health technology assessment (HTA) seems to be dominated by two fundamental tensions: [1] between maintaining a tight focus on quality-adjusted life-years and broadening its concern out to pay attention to a broader range of factors, and [2] between thinking of the evaluative dimensions that matter as being objectively important factors or as ones that are ultimately of merely subjective importance. In this study, I will argue that health is a tremendously important all-purpose means to enjoying basic human capabilities, but a mere means, and not an end. The ends to which health is a means are manifold, requiring all those engaged in policy making to exercise intelligence in a continuing effort to identify them and to think through how they interrelate. Retreating to the subjective here would be at odds with the basic idea of HTA, which is to focus on certain objectively describable dimensions of what matters about health and to collect empirical evidence rigorously bearing on what produces improvements along those dimensions. To proceed intelligently in doing HTA, it is important to stay open to reframing and refashioning the ends we take to apply to that arena. The only way for that to happen, as an exercise of public, democratic policy making, is for the difficult value questions that arise when ends clash not to be buried in subjective preference information, but to be front-and-center in the analysis. PMID- 26956574 TI - Production, Optimization, and Characterization of Organic Solvent Tolerant Cellulases from a Lignocellulosic Waste-Degrading Actinobacterium, Promicromonospora sp. VP111. AB - High costs of natural cellulose utilization and cellulase production are an industrial challenge. In view of this, an isolated soil actinobacterium identified as Promicromonospora sp. VP111 showed potential for production of major cellulases (CMCase, FPase, and beta-glucosidase) utilizing untreated agricultural lignocellulosic wastes. Extensive disintegration of microcrystalline cellulose and adherence on it during fermentation divulged true cellulolytic efficiency of the strain. Conventional optimization resulted in increased cellulase yield in a cost-effective medium, and the central composite design (CCD) analysis revealed cellulase production to be limited by cellulose and ammonium sulfate. Cellulase activities were enhanced by Co(+2) (1 mM) and retained up to 60 degrees C and pH 9.0, indicating thermo-alkaline tolerance. Cellulases showed stability in organic solvents (25 % v/v) with log P ow >= 1.24. Untreated wheat straw during submerged fermentation was particularly degraded and yielded about twofold higher levels of cellulases than with commercial cellulose (Na-CMC and avicel) which is especially economical. Thus, this is the first detailed report on cellulases from an efficient strain of Promicromonospora that was non-hemolytic, alkali-halotolerant, antibiotic (erythromycin, kanamycin, rifampicin, cefaclor, ceftazidime) resistant, multiple heavy metal (Mo(+6) = W(+6) > Pb(+2) > Mn(+2) > Cr(+3) > Sn(+2)), and organic solvent (n-hexane, isooctane) tolerant, which is industrially and environmentally valuable. PMID- 26956575 TI - Antifouling Activity of Lipidic Metabolites Derived from Padina tetrastromatica. AB - An attempt has been made to identify the potential seaweed for antifouling property due to the growing need for environmentally safe antifouling systems. The antibacterial, antimicroalgal, and antimussel foot adherence potentials of methanol, dichloromethane, and hexane extracts of the chosen seaweeds such as Padina tetrastromatica, Caulerpa taxifolia, and Amphiroa fragilissima have been compared against copper sulfate. Among the extracts, the maximum antibacterial activities were exhibited by the methanol extract of P. tetrastromatica. The minimum inhibitory concentration (MIC) of the methanolic extract of P. tetrastromatica was found to be 10 and 1 MUg/ml against test biofilm bacteria and diatoms, respectively. The antimussel foot adherence assay indicated that the extract had inhibited the foot adherence of the green mussels Perna viridis with the effective concentration (EC50) of 25.51 +/- 0.03 MUg/ml, and lethal concentration for 50 % mortality (LC50) was recorded at 280.22 +/- 0.12 MUg/ml. Based on the prolific results, the crude methanolic extract of P. tetrastromatica was subjected to purification using silica gel column and thin-layer chromatography (TLC). Then, the active compounds of the bioassay-guided fraction (F13) were identified using gas chromatography coupled with mass spectroscopy (GC MS), and it was observed that fatty acids were the major components, which may be responsible for the antifouling properties. PMID- 26956576 TI - [Pneumology and Sports: An Outpatient Endurance Training with Sports Medical Guidance as an Effective Non-pharmacological Therapy in Pneumology - a Feasibility Study]. AB - BACKGROUND: In the process of medical rehabilitation muscular endurance training is the main focus. Unfortunately, outpatient rehabilitation opportunities are limited and specialized pulmonary exercise groups ("lung sport groups") rarely available. Therefore we developed an outpatient endurance sports program for patients with respiratory diseases and evaluated its effectiveness. METHODS: In this feasibility study 31 patients (50 +/- 15 years) with diverse respiratory diseases were included. By professional functional exercise testing (incl. CPET and lactate measurement according to the standards of DGP and DGSP) the patients optimal training zone was determined and an individualized 12 week lasting aerobic endurance training with >= 3 sessions of 20 - 60 min/week realized. RESULTS: After completion of the exercise training program a significant improvement in dyspnoea (Borg-Scale: 65.7 +/- 12.2 vs. 62.2 +/- 12.6, p = 0.013), body constitution (BMI: 25.7 +/- 3.3 vs. 24.3 +/- 3.2 kg/m(2), p = 0.018; portion of body fat: 24.8 +/- 5.8 vs. 23.8 +/- 6.4 %, p = 0.043) as well as physical capacity (VO2 at 4 mmol/l Laktat: 24.2 +/- 6.9 vs. 26.5 +/- 7.6 ml/min/kg, p < 0.01; performance at 4 mmol/l Laktat: running/walking (n = 14) + 1.1 km/h, p = 0.018 and biking/bicycle ergometer (n = 17) + 8.7 Watt, p = 0.019) was recorded. These positive developments were also observed in mental and physical quality of life (quality of life questionnaire SF-36: physical score + 9.7 points, mental score + 4.5 points). CONCLUSION: The evaluated exercise program can easily be trained by the patient in a self-dependent setting and was seen to be an effective sports medical treatment in patients with diverse pulmonary diseases. PMID- 26956577 TI - Artificial Neural Network for Total Laboratory Automation to Improve the Management of Sample Dilution. AB - Diluting a sample to obtain a measure within the analytical range is a common task in clinical laboratories. However, for urgent samples, it can cause delays in test reporting, which can put patients' safety at risk. The aim of this work is to show a simple artificial neural network that can be used to make it unnecessary to predilute a sample using the information available through the laboratory information system. Particularly, the Multilayer Perceptron neural network built on a data set of 16,106 cardiac troponin I test records produced a correct inference rate of 100% for samples not requiring predilution and 86.2% for those requiring predilution. With respect to the inference reliability, the most relevant inputs were the presence of a cardiac event or surgery and the result of the previous assay. Therefore, such an artificial neural network can be easily implemented into a total automation framework to sensibly reduce the turnaround time of critical orders delayed by the operation required to retrieve, dilute, and retest the sample. PMID- 26956578 TI - A Wide Linearity Range Method for the Determination of Lenalidomide in Plasma by High-Performance Liquid Chromatography: Application to Pharmacokinetic Studies. AB - A wide linearity range analytical method for the determination of lenalidomide in patients with multiple myeloma for pharmacokinetic studies is required. Plasma samples were ultrasonicated for protein precipitation. A solid-phase extraction was performed. The eluted samples were evaporated to dryness under vacuum, and the solid obtained was diluted and injected into the high-performance liquid chromatography (HPLC) system. Separation of lenalidomide was performed on an Xterra RP C18 (250 mm length * 4.6 mm i.d., 5 um) using a mobile phase consisting of phosphate buffer/acetonitrile (85:15, v/v, pH 3.2) at a flow rate of 0.5 mL . min-1 The samples were monitored at a wavelength of 311 nm. A linear relationship with good correlation coefficient (r = 0.997, n = 9) was found between the peak area and lenalidomide concentrations in the range of 100 to 950 ng . mL-1 The limits of detection and quantitation were 28 and 100 ng . mL-1, respectively. The intra- and interassay precisions were satisfactory, and the accuracy of the method was proved. In conclusion, the proposed method is suitable for the accurate quantification of lenalidomide in human plasma with a wide linear range, from 100 to 950 ng . mL-1 This is a valuable method for pharmacokinetic studies of lenalidomide in human subjects. PMID- 26956580 TI - Sialendoscopy: Getting started, how long does it take? AB - OBJECTIVES/HYPOTHESIS: Dilation of the salivary gland papilla for access is well recognized as one of the major rate-limiting steps to sialendoscopy and has been shown to be a major challenge for beginners. The purpose of this study was to demonstrate that an algorithm involving multiple techniques for salivary duct access in sialendoscopy results in excellent success rates and acceptable operative times. STUDY DESIGN: A retrospective, observational review of 61 patients who underwent sialendoscopy of the parotid or submandibular gland, for a total of 65 papillas accessed (31 parotid, 34 submandibular) with seven different trainees utilizing a standard protocol for duct access, was performed. The time interval from the case start to endoscopic visualization of the ductal lumen was measured. Average values for time to duct access were then calculated. RESULTS: The papilla was identified in all but one case without difficulty. Five submandibular gland cases required sialodochotomy for access. The average time to duct access was 4.2 +/- 4.7 minutes (range: 0.67-25 minutes). Exclusion of four difficult cases with access times over 15 minutes yielded an average access time of 3.2 +/- 2.2 minutes. CONCLUSION: This standardized protocol demonstrates high rates of success for salivary duct access via the papilla in a short time interval with infrequent need for sialodochotomy, even in the hands of novice surgeons. LEVEL OF EVIDENCE: 4. Laryngoscope, 126:1083-1085, 2016. PMID- 26956579 TI - Hydrolysed formula and risk of allergic or autoimmune disease: systematic review and meta-analysis. AB - OBJECTIVE: To determine whether feeding infants with hydrolysed formula reduces their risk of allergic or autoimmune disease. DESIGN: Systematic review and meta analysis, as part of a series of systematic reviews commissioned by the UK Food Standards Agency to inform guidelines on infant feeding. Two authors selected studies by consensus, independently extracted data, and assessed the quality of included studies using the Cochrane risk of bias tool. DATA SOURCES: Medline, Embase, Web of Science, CENTRAL, and LILACS searched between January 1946 and April 2015. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Prospective intervention trials of hydrolysed cows' milk formula compared with another hydrolysed formula, human breast milk, or a standard cows' milk formula, which reported on allergic or autoimmune disease or allergic sensitisation. RESULTS: 37 eligible intervention trials of hydrolysed formula were identified, including over 19,000 participants. There was evidence of conflict of interest and high or unclear risk of bias in most studies of allergic outcomes and evidence of publication bias for studies of eczema and wheeze. Overall there was no consistent evidence that partially or extensively hydrolysed formulas reduce risk of allergic or autoimmune outcomes in infants at high pre-existing risk of these outcomes. Odds ratios for eczema at age 0-4, compared with standard cows' milk formula, were 0.84 (95% confidence interval 0.67 to 1.07; I(2)=30%) for partially hydrolysed formula; 0.55 (0.28 to 1.09; I(2)=74%) for extensively hydrolysed casein based formula; and 1.12 (0.88 to 1.42; I(2)=0%) for extensively hydrolysed whey based formula. There was no evidence to support the health claim approved by the US Food and Drug Administration that a partially hydrolysed formula could reduce the risk of eczema nor the conclusion of the Cochrane review that hydrolysed formula could allergy to cows' milk. CONCLUSION: These findings do not support current guidelines that recommend the use of hydrolysed formula to prevent allergic disease in high risk infants. REVIEW REGISTRATION: PROSPERO CRD42013004252. PMID- 26956581 TI - Clinical and oncologic outcomes of totally robotic total mesorectal excision for rectal cancer: initial results in a center for minimally invasive surgery. AB - PURPOSE: A robotic system was mainly designed to allow precise dissection in deep and narrow spaces. We report the clinical and oncologic outcomes of totally robotic total mesorectal excision for rectal cancer. METHODS: Between July 2009 and January 2012, 60 consecutive patients undergoing robotic surgery for rectal cancer at the Eulji University Hospital were included. RESULTS: The mean total operation time, docking time, and surgeon console time were 466.8 +/- 115.6, 7.5 +/- 6.7, and 261 +/- 87.5 min, respectively. Oral intake of diet was started at 3.3 +/- 0.9 days and the mean hospital stay was 8.6 +/- 2.4 days. All 60 procedures were technically successful without the need for conversion to open or laparoscopic surgery. Complications included anastomotic leakage, anastomotic stricture, postoperative bleeding, ileus, and perineal wound infection in 3 (5 %), 1 (1.7 %), 2 (3.3 %), 2 (3.3 %), and 1 (1.7 %) patient, respectively. The mean distal resection margin and total number of lymph nodes harvested was 3.1 +/ 1.7 cm and 20.1 +/- 11.5, respectively. During the mean follow-up period of 48.5 months (range, 7-75), the 4-year overall and disease-free survival rates were 87.7 and 72.8 %, respectively. CONCLUSIONS: A totally robotic approach for rectal cancer operations was a time-consuming procedure, although we already had a lot experience in laparoscopic colorectal surgery. However, the dexterity of the robotic surgery could enable the surgeon to expand the choice of surgical methods according to the condition of the rectal cancer without the need for conversion. PMID- 26956582 TI - Monitoring protein synthesis in single live cancer cells. AB - Protein synthesis is generally under sophisticated and dynamic regulation to meet the ever-changing demands of a cell. Global up or down-regulation of protein synthesis and the shift of protein synthesis location (as shown, for example, during cellular stress or viral infection) are recognized as cellular responses to environmental changes such as nutrient/oxygen deprivation or to alterations such as pathological mutations in cancer cells. Monitoring protein synthesis in single live cells can be a powerful tool for cancer research. Here we employed a microfluidic platform to perform high throughput delivery of fluorescent labeled tRNAs into multiple myeloma cells with high transfection efficiency (~45%) and high viability (>80%). We show that the delivered tRNAs were actively recruited to the ER for protein synthesis and that treatment with puromycin effectively disrupted this process. Interestingly, we observed the scattered distribution of tRNAs in cells undergoing mitosis, which has not been previously reported. Fluorescence lifetime analysis detected extensive FRET signals generated from tRNAs labeled as FRET pairs, further confirming that the delivered tRNAs were used by active ribosomes for protein translation. Our work demonstrates that the microfluidic delivery of FRET labeled tRNAs into living cancer cells can provide new insights into basic cancer metabolism and has the potential to serve as a platform for drug screening, diagnostics, or personalized medication. PMID- 26956583 TI - Delineation of Steroid-Degrading Microorganisms through Comparative Genomic Analysis. AB - Steroids are ubiquitous in natural environments and are a significant growth substrate for microorganisms. Microbial steroid metabolism is also important for some pathogens and for biotechnical applications. This study delineated the distribution of aerobic steroid catabolism pathways among over 8,000 microorganisms whose genomes are available in the NCBI RefSeq database. Combined analysis of bacterial, archaeal, and fungal genomes with both hidden Markov models and reciprocal BLAST identified 265 putative steroid degraders within only Actinobacteria and Proteobacteria, which mainly originated from soil, eukaryotic host, and aquatic environments. These bacteria include members of 17 genera not previously known to contain steroid degraders. A pathway for cholesterol degradation was conserved in many actinobacterial genera, particularly in members of the Corynebacterineae, and a pathway for cholate degradation was conserved in members of the genus Rhodococcus. A pathway for testosterone and, sometimes, cholate degradation had a patchy distribution among Proteobacteria. The steroid degradation genes tended to occur within large gene clusters. Growth experiments confirmed bioinformatic predictions of steroid metabolism capacity in nine bacterial strains. The results indicate there was a single ancestral 9,10-seco steroid degradation pathway. Gene duplication, likely in a progenitor of Rhodococcus, later gave rise to a cholate degradation pathway. Proteobacteria and additional Actinobacteria subsequently obtained a cholate degradation pathway via horizontal gene transfer, in some cases facilitated by plasmids. Catabolism of steroids appears to be an important component of the ecological niches of broad groups of Actinobacteria and individual species of Proteobacteria. IMPORTANCE: Steroids are ubiquitous growth substrates for environmental and pathogenic bacteria, and bacterial steroid metabolism has important pharmaceutical and health applications. To date, the genetics and biochemistry of microbial steroid degradation have mainly been studied in a few model bacteria, and the diversity of this metabolism remains largely unexplored. Here, we provide a bioinformatically derived perspective of the taxonomic distribution of aerobic microbial steroid catabolism pathways. We identified several novel steroid degrading bacterial groups, including ones from marine environments. In several cases, we confirmed bioinformatic predictions of metabolism in cultures. We found that cholesterol and cholate catabolism pathways are highly conserved among certain actinobacterial taxa. We found evidence for horizontal transfer of a pathway to several proteobacterial genera, conferring testosterone and, sometimes, cholate catabolism. The results of this study greatly expand our ecological and evolutionary understanding of microbial steroid metabolism and provide a basis for better exploiting this metabolism for biotechnology. PMID- 26956584 TI - Toll-Like Receptor 3/TRIF-Dependent IL-12p70 Secretion Mediated by Streptococcus pneumoniae RNA and Its Priming by Influenza A Virus Coinfection in Human Dendritic Cells. AB - A functional immune response is crucial to prevent and limit infections with Streptococcus pneumoniae. Dendritic cells (DCs) play a central role in orchestrating the adaptive and innate immune responses by communicating with other cell types via antigen presentation and secretion of cytokines. In this study, we set out to understand how pneumococci activate human monocyte-derived DCs to produce interleukin-12 (IL-12) p70, an important cytokine during pneumococcal infections. We show that IL-12p70 production requires uptake of bacteria as well as the presence of the adaptor molecule TRIF, which is known to transfer signals of Toll-like receptor 3 (TLR3) or TLR4 from the endosome into the cell. While TLR4 is redundant for IL-12p70 production in DCs, we found that TLR3 is required to induce full IL-12p70 secretion. Influenza A virus (IAV) infection of DCs did not induce IL-12p70 but markedly upregulated TLR3 expression that during coinfection with S. pneumoniae significantly enhanced IL-12p70 secretion. Finally, we show that pneumococcal RNA can act as a bacterial stimulus for TLR3 and that it is a key signal to induce IL-12p70 production during challenge of DCs with pneumococci. IMPORTANCE: Streptococcus pneumoniae, a common colonizer of the nose, is the causative agent of severe and deadly diseases. A well-orchestrated immune response is vital to prevent and limit these diseases. Dendritic cells (DCs) reside in the mucosal linings of the lungs and sample antigens. They are activated by pathogens to present antigens and secrete cytokines. While many studies focus on murine models, we focused our work on human monocyte-derived DCs. We found that pneumococcal RNA is an important stimulus in DCs to activate the endosomal receptor TLR3, a receptor previously not identified to sense pneumococci, and its adaptor molecule TRIF. This leads to secretion of the cytokine interleukin-12 (IL-12). Severe pneumococcal pneumonia occurs closely after influenza A virus (IAV) infection. We show that IAV infection upregulates TLR3 in DCs, which sensitizes the cells to endosomal pneumococcal RNA. This new insight contributes to unlock the interplay between pneumococci, IAV, and humans. PMID- 26956585 TI - Kisameet Clay Isolated from the Central Coast of British Columbia, Canada, Demonstrates Broad-Spectrum Antimicrobial Activity. AB - Clay minerals are naturally occurring layered phyllosilicates which consist of fine particles and possess antimicrobial activity. In a recent article, Behroozian et al. obtained Kisameet clay (KC) from Kisameet, from the central coast of British Columbia, Canada, northwest of Vancouver and assessed its antimicrobial activity versus 16 selected ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.) possessing a variety of different resistance profiles [S. Behroozian, S. L. Svensson, and J. Davies, mBio 7(1):e01842-15, 2016, http://dx.doi.org/10.1128/mBio.01842-15]. KC demonstrated complete bacterial eradication of Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Staphylococcus aureus within 24 h. For Enterobacter spp., the organisms were eradicated with 1% KC within 5 h, while for Enterococcus faecium, it took 48 h to kill all organisms. Although many questions need to be answered, these exciting findings highlight the importance of testing natural substances/products from around the globe to assess whether they possess antimicrobial activity and potential for usage as topical, oral, or systemic agents for the treatment of multidrug-resistant pathogens. PMID- 26956588 TI - Impact of Intervention Measures on MRSA Clonal Type and Carriage Site Prevalence. PMID- 26956589 TI - The Fast-Evolving phy-2 Gene Modulates Sexual Development in Response to Light in the Model Fungus Neurospora crassa. AB - Rapid responses to changes in incident light are critical to the guidance of behavior and development in most species. Phytochrome light receptors in particular play key roles in bacterial physiology and plant development, but their functions and regulation are less well understood in fungi. Nevertheless, genome-wide expression measurements provide key information that can guide experiments that reveal how genes respond to environmental signals and clarify their role in development. We performed functional genomic and phenotypic analyses of the two phytochromes in Neurospora crassa, a fungal model adapted to a postfire environment that experiences dramatically variable light conditions. Expression of phy-1 and phy-2 was low in early sexual development and in the case of phy-2 increased in late sexual development. Under light stimulation, strains with the phytochromes deleted exhibited increased expression of sexual development-related genes. Moreover, under red light, the phy-2 knockout strain commenced sexual development early. In the evolution of phytochromes within ascomycetes, at least two duplications have occurred, and the faster-evolving phy 2 gene has frequently been lost. Additionally, the three key cysteine sites that are critical for bacterial and plant phytochrome function are not conserved within fungal phy-2 homologs. Through the action of phytochromes, transitions between asexual and sexual reproduction are modulated by light level and light quality, presumably as an adaptation for fast asexual growth and initiation of sexual reproduction of N. crassa in exposed postfire ecosystems. IMPORTANCE: Environmental signals, including light, play critical roles in regulating fungal growth and pathogenicity, and balance of asexual and sexual reproduction is critical in fungal pathogens' incidence, virulence, and distribution. Red light sensing by phytochromes is well known to play critical roles in bacterial physiology and plant development. Homologs of phytochromes were first discovered in the fungal model Neurospora crassa and then subsequently in diverse other fungi, including many plant pathogens. Our study investigated the evolution of red light sensors in ascomycetes and confirmed-using the model fungus Neurospora crassa-their roles in modulating the asexual-sexual reproduction balance in fungi. Our findings also provide a key insight into one of the most poorly understood aspects of fungal biology, suggesting that further study of the function of phytochromes in fungi is critical to reveal the genetic basis of the asexual-sexual switch responsible for fungal growth and distribution, including diverse and destructive plant pathogens. PMID- 26956591 TI - Staphylococcus aureus Clumping Factor A Remains a Viable Vaccine Target for Prevention of S. aureus Infection. AB - In a recent article, X. Li et al. [mBio 7(1):e02232-15, 2016, http://dx.doi.org/10.1128/mBio.02232-15] investigate the utility of a vaccine composed of the Staphylococcus aureus protein clumping factor A (ClfA) in protecting mice from S. aureus infection. ClfA, one of the first proteins to be identified as a potential vaccine antigen for S. aureus prophylaxis, is currently a component of several investigational vaccines. The authors conclude that ClfA may not be effective for S. aureus prophylaxis. In contrast, previously published papers reporting positive data suggested that ClfA was potentially an important vaccine target to prevent invasive S. aureus disease. This commentary addresses the observed differences between the findings of Li et al. and those from other publications, highlighting the importance for preclinical vaccine antigen assessments to reflect the biological role of said antigen in virulence and, consequently, the importance of choosing appropriate preclinical disease models to test such antigens. PMID- 26956590 TI - Genomic Analysis of Salmonella enterica Serovar Typhimurium Characterizes Strain Diversity for Recent U.S. Salmonellosis Cases and Identifies Mutations Linked to Loss of Fitness under Nitrosative and Oxidative Stress. AB - Salmonella enterica serovar Typhimurium is one of the most common S. enterica serovars associated with U.S. foodborne outbreaks. S. Typhimurium bacteria isolated from humans exhibit wide-ranging virulence phenotypes in inbred mice, leading to speculation that some strains are more virulent in nature. However, it is unclear whether increased virulence in humans is related to organism characteristics or initial treatment failure due to antibiotic resistance. Strain diversity and genetic factors contributing to differential human pathogenicity remain poorly understood. We reconstructed phylogeny, resolved genetic population structure, determined gene content and nucleotide variants, and conducted targeted phenotyping assays for S. Typhimurium strains collected between 1946 and 2012 from humans and animals in the United States and abroad. Strains from recent U.S. salmonellosis cases were associated with five S. Typhimurium lineages distributed within three phylogenetic clades, which are not restricted by geography, year of acquisition, or host. Notably, two U.S. strains and four Mexican strains are more closely related to strains associated with human immunodeficiency virus (HIV)-infected individuals in sub-Saharan Africa than to other North American strains. Phenotyping studies linked variants specific to these strains in hmpA and katE to loss of fitness under nitrosative and oxidative stress, respectively. These results suggest that U.S. salmonellosis is caused by diverse S. Typhimurium strains circulating worldwide. One lineage has mutations in genes affecting fitness related to innate immune system strategies for fighting pathogens and may be adapting to immunocompromised humans by a reduction in virulence capability, possibly due to a lack of selection for its maintenance as a result of the worldwide HIV epidemic. IMPORTANCE: Nontyphoidal Salmonella bacteria cause an estimated 1.2 million illnesses annually in the United States, 80 million globally, due to ingestion of contaminated food or water. Salmonella Typhimurium is one of the most common serovars associated with foodborne illness, causing self-limiting gastroenteritis and, in approximately 5% of infected patients, systemic infection. Although some S. Typhimurium strains are speculated to be more virulent than others, it is unknown how strain diversity and genetic factors contribute to differential human pathogenicity. Ours is the first study to examine the diversity of S. Typhimurium associated with recent cases of U.S. salmonellosis and to provide some initial correlation between observed genotypes and phenotypes. Definition of specific S. Typhimurium lineages based on such phenotype/genotype correlations may identify strains with greater capability of associating with specific food sources, allowing outbreaks to be more quickly identified. Additionally, defining simple correlates of pathogenesis may have predictive value for patient outcome. PMID- 26956592 TI - An aptamer-antibody complex (oligobody) as a novel delivery platform for targeted cancer therapies. AB - Aptamers have recently emerged as reliable and promising targeting agents in the field of biology. However, their therapeutic potential has yet to be completely assessed due to their poor pharmacokinetics for systemic administration. Here, we describe a novel aptamer-antibody complex, designated an "oligobody" (oligomer+antibody) that may overcome the therapeutic limitations of aptamers. To provide proof-of-principle study, we investigated the druggability of oligobody in vivo using cotinine conjugated t44-OMe aptamer, which is specific for the sequence of pegaptanib, and an anti-cotinine antibody. The antibody part of oligobody resulted in extended in vivo pharmacokinetics of the aptamer without influencing its binding affinity. Moreover, the aptamer of oligobody penetrated deeply into the tumor tissues whereas the anti-VEGF antibody did not. Finally, the systemic administration of this oligobody reduced the tumor burden in a xenograft mouse model. Together, these results suggested that our oligobody strategy may represent a novel platform for rapid, low-cost and high-throughput cancer therapy. PMID- 26956593 TI - Sequential co-delivery of miR-21 inhibitor followed by burst release doxorubicin using NIR-responsive hollow gold nanoparticle to enhance anticancer efficacy. AB - Previous literature and our study showed the delivery sequence of microRNA inhibitor and chemotherapeutic compounds achieve distinct therapeutic anticancer efficacy. Yet, it is challenging to use nanoparticle to achieve sequential drug delivery. In the current study, we designed sequential co-delivery system using a near-infrared-radiation (NIR) responsive hollow gold nanoparticle (HGNPs) to achieve sequential release of microRNA inhibitor (miR-21i)/doxirubicin(Dox) in order to achieve synergistic efficacy. PAMAM modified HGNPs was used to encapsulate miR-21i and Dox. Upon entering tumor cells, miRNA-21i was released first to sensitize the cancer cells, the subsequent burst release of Dox was achieved by NIR triggered collapse of HGNPs. This sequential delivery of miRNA 21i and Dox produced a synergistic apoptotic response, thereby enhancing anticancer efficacy by 8-fold and increasing anti-cancer stem cell activity by 50 fold. The sequential delivery of miR-21i and Dox using HGNPs under NIR after intravenous administration showed high tumor accumulation and significantly improved efficacy, which was 4-fold compared to free Dox group. These data suggested that the sequential co-delivery of miR-21i followed by burst release Dox using NIR-responsive HGNPs sensitized cancer cells to chemotherapeutic compound, which provided a novel concept for co-delivery miRNA inhibitors and chemotherapeutic compounds to enhance their efficacy. PMID- 26956594 TI - Taxonomic description and genome sequence of Salinicoccus sediminis sp. nov., a halotolerant bacterium isolated from marine sediment. AB - A Gram-staining-positive, coccoid, halotolerant bacterial strain, designated SV 16T, was isolated from marine sediment and subjected to a polyphasic taxonomic study. The strain exhibited phenotypic properties that included chemotaxonomic characteristics consistent with its classification in the genus Salinicoccus. Growth occurred at temperatures in the range 25-37 degrees C (optimum 30 degrees C), at pH 7.0-11.0 (optimum pH 8.0) and at NaCl concentrations of up to 25.0% (optimum 15.0%). The highest level of 16S rRNA gene sequence similarity was with Salinicoccus carnicancri CrmT (98.6%) followed by Salinicoccus halodurans W24T (96.6%). The predominant polar lipids were diphosphatidylglycerol, phosphatidylinositol and phosphatidylglycerol. The major cellular fatty acids were iso-C15:0, anteiso-C15:0, iso-C17:0 and anteiso-C17:0. The draft genome of strain SV-16T consisted of 2,591,284 bp with a DNA G+C content of 48.7 mol%. On the basis of the phenotypic characteristics and genotypic distinctiveness of strain SV-16T, it should be classified within a novel species of the genus Salinicoccus, for which the name Salinicoccus sediminis sp. nov. is proposed. The type strain is SV-16T ( = MTCC 11832T = DSM 28797T). PMID- 26956595 TI - Xanthomarina gelatinilytica gen. nov., sp. nov., isolated from seawater. AB - A novel Gram-stain-negative, rod-shaped, yellow-pigmented, non-sporulating, non motile bacterium, designated strain AK20T, was isolated from seawater collected from Kochi city, Kerala state, India. Colonies on marine agar were circular, yellow, shiny, translucent, 2-3 mm in diameter, convex and with entire margin. Flexirubin-type pigment was present. The fatty acids were dominated by iso branched units with a high abundance of iso-C15:0, iso-C15:1 G, iso-C17:0 3-OH, summed feature 3 (C16:1omega7c and/or iso-C15:0 2-OH) and iso-C15:0 3-OH. Polar lipids included phosphatidylethanolamine, two unidentified aminophospholipids, two unidentified phospholipids and four unidentified lipids. Menaquinone 6 (MK-6) was the predominant respiratory quinone. The DNA G+C content of strain AK20T was 38.8 mol%. Phylogenetic analysis based on 16S rRNA gene sequences revealed that strain AK20T was closely related to Formosa spongicola A2T and Bizionia paragorgiae KMM 6029T (pair-wise sequence similarities of 95.9 and 95.7%, respectively), forming a distinct branch within the family Flavobacteriaceae and clustering with the clade comprising species of the genus Bizionia. Based on phenotypic and chemotaxonomic characteristics and phylogenetic analysis, strain AK20T is different from the existing genera in the family Flavobacteriaceae, and is therefore considered to represent a novel species of a new genus, for which the name Xanthomarina gelatinilytica gen. nov., sp. nov. is proposed. The type strain of Xanthomarina gelatinilytica is AK20T ( = MTCC 11705T = JCM 18821T). PMID- 26956597 TI - Alteromonas naphthalenivorans sp. nov., a polycyclic aromatic hydrocarbon degrading bacterium isolated from tidal-flat sediment. AB - A Gram-staining-negative and halotolerant bacterium, designated SN2T, capable of biodegrading polycyclic aromatic hydrocarbons, was isolated from a tidal flat contaminated with crude oil in Korea. Cells were strictly aerobic, catalase- and oxidase-positive, motile rods, with a single polar flagellum. Growth was observed at 4-37 degrees C (optimum, 25-30 degrees C) at pH 6.0-9.0 (optimum, pH 7.0 7.5) and in the presence of 0.5-9.0% (w/v) NaCl (optimum, 2.0%). Only ubiquinone 8 was detected as the isoprenoid quinone, and summed feature 3 (comprising C16:1omega7c and/or iso-C15:0 2-OH), C16:0, C18:1omega7c and C12:0 were observed as the major cellular fatty acids. The major polar lipids consisted of phosphatidylethanolamine, phosphatidylglycerol, a glycolipid, an aminolipid and three unidentified lipids. The DNA G+C content was 43.5 mol%. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain SN2T formed a phylogenetic lineage with Alteromonas stellipolaris and Alteromonas addita within the genus Alteromonas, which was consistent with multilocus phylogenetic and MALDI-TOF MS analyses. Strain SN2T was most closely related to the type strains of A. stellipolaris, A. addita and Alteromonas macleodii, with 16S rRNA gene sequence similarities of 99.5, 99.3 and 98.4% and DNA-DNA relatedness of 48.7 +/- 6.6, 24.9 +/- 7.5 and 27.9 +/- 8.4%, respectively. In conclusion, strain SN2T represents a novel species of the genus Alteromonas, for which the name Alteromonas naphthalenivorans sp. nov. is proposed. The type strain is SN2T ( = KCTC 11700BPT = JCM 17741T =KACC 18427T). PMID- 26956596 TI - Spirosoma aerolatum sp. nov., isolated from a motor car air conditioning system. AB - A Gram-stain-negative, yellow-pigmented bacterial strain, designated PR1012KT, was isolated from a motor car evaporator core collected in Korea. Cells of the strain were facultatively anaerobic, non-spore-forming and rod-shaped. The strain grew at 10-40 degrees C (optimum, 25 degrees C), at pH 6.5-8.0 (optimum, pH 7.0 8.0) and in the presence of 0-1% (w/v) NaCl. Phylogenetically, the strain was closely related to members of the genus Spirosoma (97.50-90.74% 16S rRNA gene sequence similarities) and showed highest sequence similarity to Spirosoma panaciterrae DSM 21099T (97.50%). Its predominant fatty acids included summed feature 3 (C16:1omega7c and/or C16:1omega6c), C16:1omega5c, iso-C15:0 and summed feature 4 (iso-C17:1 I and/or anteiso B) and it had MK-7 as the major menaquinone. The polar lipids present included phosphatidylethanolamine, one unknown aminophospholipid, two unknown aminolipids and five unknown polar lipids. The DNA G+C content of this strain was 54 mol%. Based on phenotypic, genotypic and chemotaxonomic data, strain PR1012KT represents a novel species in the genus Spirosoma, for which the name Spirosoma aerolatum sp. nov. is proposed. The type strain is PR1012KT ( = KACC 17939T = NBRC 110794T). PMID- 26956598 TI - Step-and-Repeat Nanoimprint-, Photo- and Laser Lithography from One Customised CNC Machine. AB - The conversion of a computer numerical control machine into a nanoimprint step and-repeat tool with additional laser- and photolithography capacity is documented here. All three processes, each demonstrated on a variety of photoresists, are performed successfully and analysed so as to enable the reader to relate their known lithography process(es) to the findings. Using the converted tool, 1 cm(2) of nanopattern may be exposed in 6 s, over 3300 times faster than the electron beam equivalent. Nanoimprint tools are commercially available, but these can cost around 1000 times more than this customised computer numerical control (CNC) machine. The converted equipment facilitates rapid production and large area micro- and nanoscale research on small grants, ultimately enabling faster and more diverse growth in this field of science. In comparison to commercial tools, this converted CNC also boasts capacity to handle larger substrates, temperature control and active force control, up to ten times more curing dose and compactness. Actual devices are fabricated using the machine including an expanded nanotopographic array and microfluidic PDMS Y-channel mixers. PMID- 26956599 TI - ZnO Nanoparticles/Reduced Graphene Oxide Bilayer Thin Films for Improved NH3 Sensing Performances at Room Temperature. AB - ZnO nanoparticles and graphene oxide (GO) thin film were deposited on gold interdigital electrodes (IDEs) in sequence via simple spraying process, which was further restored to ZnO/reduced graphene oxide (rGO) bilayer thin film by the thermal reduction treatment and employed for ammonia (NH3) detection at room temperature. rGO was identified by UV-vis absorption spectra and X-ray photoelectron spectroscope (XPS) analyses, and the adhesion between ZnO nanoparticles and rGO nanosheets might also be formed. The NH3-sensing performances of pure rGO film and ZnO/rGO bilayer films with different sprayed GO amounts were compared. The results showed that ZnO/rGO film sensors exhibited enhanced response properties, and the optimal GO amount of 1.5 ml was achieved. Furthermore, the optimal ZnO/rGO film sensor showed an excellent reversibility and fast response/recovery rate within the detection range of 10-50 ppm. Meanwhile, the sensor also displayed good repeatability and selectivity to NH3. However, the interference of water molecules on the prepared sensor is non ignorable; some techniques should be researched to eliminate the effect of moisture in the further work. The remarkably enhanced NH3-sensing characteristics were speculated to be attributed to both the supporting role of ZnO nanoparticles film and accumulation heterojunction at the interface between ZnO and rGO. Thus, the proposed ZnO/rGO bilayer thin film sensor might give a promise for high performance NH3-sensing applications. PMID- 26956601 TI - Optical and Vibrational Spectra of CsCl-Enriched GeS2-Ga2S3 Glasses. AB - Optical and FTIR spectroscopy was employed to study the properties of 80GeS2 20Ga2S3-CsCl chalcohalide glasses with CsCl additives in a temperature range of 77-293 K. It is shown that CsCl content results in the shift of fundamental absorption edge in the visible region. Vibrational bands in FTIR spectra of (80GeS2-20Ga2S3)100 - x (SsCl) x (x = 5, 10, and 15) are identified near 2500 cm( 1), 3700 cm(-1),, around 1580 cm(-1), and a feature at 1100 cm(-1). Low energy shifts of vibrational frequencies in glasses with a higher amount of CsCl can be caused by possible thermal expansion of the lattice and nanovoid agglomeration formed by CsCl additives in the inner structure of the Ge-Ga-S glass. PMID- 26956600 TI - Electro-Optical Properties of Low-Temperature Growth Indium-tin-oxide Nanowires Using Polystyrene Spheres as Catalyst. AB - Polystyrene sphere was chosen as a catalyst to fabricate indium-tin-oxide (ITO) nanowires (NWs) with a low-temperature (280-300 degrees C) electron-beam deposition process, bearing high purity. The ITO NWs with diameter of 20-50 nm and length of ~2 um were obtained. X-ray diffraction and high-resolution transmission electron microscope show high crystal quality. The transmittance is above 90 % at a wavelength 400 nm or more, superior to the ITO bulk film. Owing to the unique morphology gradient of the ITO NWs, the effective refractive index of ITO NWs film is naturally graded from the bottom to the top. The ITO NWs have been used on LED devices (lambda = 450 nm), which improved the light output power by 31 % at the current of 150 mA comparing to the one without NWs and did not deteriorate the electrical properties. Such ITO NWs open opportunity in LED devices to further improve light extraction efficiency. PMID- 26956602 TI - Water-Vapor Sorption Processes in Nanoporous MgO-Al2O3 Ceramics: the PAL Spectroscopy Study. AB - The water-vapor sorption processes in nanoporous MgO-Al2O3 ceramics are studied with positron annihilation lifetime (PAL) spectroscopy employing positron trapping and positronium (Ps)-decaying modes. It is demonstrated that the longest lived components in the four-term reconstructed PAL spectra with characteristic lifetimes near 2 and 60-70 ns can be, respectively, attributed to ortho positronium (o-Ps) traps in nanopores with 0.3- and 1.5-1.8-nm radii. The first o Ps decaying process includes "pick-off" annihilation in the "bubbles" of liquid water, while the second is based on o-Ps interaction with physisorbed water molecules at the walls of the pores. In addition, the water vapor modifies structural defects located at the grain boundaries in a vicinity of pores, this process being accompanied by void fragmentation during water adsorption and agglomeration during water desorption after drying. PMID- 26956603 TI - Can Nucleobase Pairs Offer a Possibility of a Direct 3D Self-assembly? AB - BACKGROUND: The nucleobase pairs are characterized by their conformational diversity in the wild. Yet a modern nanobiotechnology utilizes their planar conformations only, developing what can be called a "planar approach". It is well established that the most energetically favorable conformations of the complementary nucleobase pairs are planar and correspond to the classical Watson Crick nucleobase pairs. PRESENTATION OF THE HYPOTHESIS: The point of interest lies in a study of a conformational capacity of the nucleobase pairs to expand the diversity of a spatial configuration and to produce the complex 3D objects from the non-planar conformations. If such a goal could be achieved, then that could definitely open the perspectives for a novel "stereo approach". TESTING THE HYPOTHESIS: For the first time, basing on the first principles, we reveal an ability of the heteroassociates of the m(1)Cyt . m(1)Thy to form up to ten observable molecular complexes under standard conditions. The first three of them have population of ~90 % at standard conditions and are highly non-planar. The most energetically favorable structure has a T-shape, while the next two have an L-shape. At the same time, we show the lack of any experimental data covering a self-assembly of the m(1)Cyt . m(1)Thy base pairs. IMPLICATIONS OF THE HYPOTHESIS: We present a theoretical evidence of the fact that the conformational capacity of the nucleobase pairs is much richer from the perspective of their self-assembly than it is considered in the modern nanobiotechnology. The capability of a modified cytosine and a modified thymine to create significantly non-planar structures opens a way for the innovative "stereo approach" to construction of the nanobiotechnological devices. We believe that a modern nanobiotechnological basis can and should be extended with the new nucleic base pairs with innate ability for non-planar structures. We would like to especially emphasize a prognostic role of our algorithm in obtaining the new results. PMID- 26956604 TI - Editor's choice, Volume 117. PMID- 26956605 TI - The Ebola epidemic and public health response. AB - INTRODUCTION: An unprecedented global effort has been required to tackle the Ebola outbreak in West Africa. In this paper, we describe the contribution of Public Health England (PHE) in West Africa and the UK. SOURCES OF DATA: Public Health England AREAS OF AGREEMENT: The epidemic has been a humanitarian crisis for the three worst affected countries. PHE contributions have included expertise in outbreak control and microbiology services in West Africa, and UK preparedness for an imported case. AREAS OF CONTROVERSY: National and international systems require change to enhance the response to the next international public health crisis. GROWING POINTS: Legacy planning following the epidemic will be crucial, supporting the recovery of the health and public health systems in West Africa and ensuring that the knowledge gained during this outbreak is put to best use. AREAS TIMELY FOR DEVELOPING RESEARCH: Ongoing PHE-associated research includes efforts to understand the pathogenicity of Ebola virus disease, improve diagnostic capability, explore therapeutic options and develop new vaccines. PMID- 26956606 TI - Evaluation of choroidal thickness in psoriasis using optical coherence tomography. AB - The purpose of this study was to evaluate choroidal thickness (CT) in patients with psoriasis using enhanced depth imaging optical coherence tomography (EDI OCT) and to determine its relationship with psoriasis activity indices. In this prospective study, EDI-OCT images were obtained in consecutive patients with psoriasis and in age-gender-matched healthy individuals. Comprehensive ophthalmic examination and EDI-OCT evaluation were performed. CT was measured in the subfoveal area. Correlation analyses were performed to identify the relationship of the CT with disease duration and clinical disease activity score. In total, 65 individuals were evaluated in this study, 35 with psoriasis and 30 controls. The mean disease duration of the patients with psoriasis was 15.7 +/- 8.8 years (0.3 34 years). There was no difference between groups with respect to age and gender (p = 0.695 and p = 0.628, respectively). Five of the 35 patients with psoriasis had anterior uveitis. None of the patients with psoriasis had signs of posterior uveitis. CT was significantly higher in the psoriasis group than that of control subjects (p < 0.001). The mean central foveal thickness was comparable between groups (p = 0.672). There was also no significant correlation between EDI-OCT, disease activity score, and disease duration (p < 0.05). Choroidal thickness is increased in psoriasis patients. Large serial and comparative studies are necessary to evaluate EDI-OCT, an examination that may be helpful in understanding the effects of psoriasis on the eye and its pathophysiology. PMID- 26956607 TI - Intraocular pressure in infants and its association with hormonal changes with vaginal birth versus cesarean section. AB - To investigate cord arterial blood sample and the relationship between birth stress and intraocular pressure in infants at 5 min after delivery. The IOP measurements were taken using Tonopen-Avia tonometer to 158 newborns (158 eyes) at 5th min after birth, in a university hospital. Cord blood was collected within 3 min after delivery. Intraocular pressure, gender, gestation period, mode of delivery, and birth weight of newborns were noted from medical records. Sixty-two babies were delivered by normal vaginal delivery (NVD) and 96 by cesarian section (C/S). Mean IOP of NVD and C/S groups were 19.56 +/- 3.84 and 17.42 +/- 3.50, respectively. There was significant difference of mean IOP between two groups. (p < 0.001) There were significant differences between two groups regarding APGAR score (p < 0.001) and cord blood adrenaline (p = 0.003), noradrenaline (p = 0.008), and cortisol (p < 0.001) levels. There was no difference between infant corneal thickness measurements (p = 0.698). In correlation analyses, there is a strong negative correlation between the labor type and postpartum measurements except corneal thickness. Correlation analyses of the 5th min intraocular pressure of the groups individually revealed significant correlation in the NVD group. The conclusion is that the intraocular pressure of newborn infants was higher in NVD delivery compare to C/S. Blood hormonal changes in different anesthesia types and physical stress was thought as the main reason of this result. PMID- 26956609 TI - Postural Instability in Prodromal Spinocerebellar Ataxia Type 2: Insights into Cerebellar Involvement Before Onset of Permanent Ataxia. PMID- 26956610 TI - Simultaneous optimization of power and duration of radio-frequency pulse in PARACEST MRI. AB - Chemical exchange saturation transfer (CEST) MRI is increasingly used to probe mobile proteins and microenvironment properties, and shows great promise for tumor and stroke diagnosis. The CEST effect is complex and depends not only on the CEST agent concentration, exchange rates, the characteristic of the magnetization transfer (MT), and the relaxation properties of the tissue, but also varies with the experimental conditions such as radio-frequency (RF) pulse power and duration. The RF pulse is one of the most important factors that promote the CEST effect for biological properties such as pH, temperature and protein content, especially for contrast agents with intermediate to fast exchange rates. The CEST effect is susceptible to the RF duration and power. The present study aims at determining the optimal power and the corresponding optimal duration (that maximize the CEST effect) using an off-resonance scheme through a new definition of the CEST effect. This definition is formulated by solving the Bloch-McConnell equation through the R1rho method (based on the eigenspace solution) for both of the MT and CEST effects as well as their interactions. The proposed formulations of the optimal RF pulse power and duration are the first formulations in which the MT effect is considered. The extracted optimal RF pulse duration and power are compared with those of the MTR asymmetry model in two- and three-pool systems, using synthetic data that are similar to the muscle tissue. To validate them further, the formulations are compared with the empirical formulation of the CEST effect and other findings of the previous researches. By extending our formulations, the optimal power and the corresponding optimal duration (in the biological systems with many chemical exchange sites) can be determined. PMID- 26956608 TI - Quantitative CRISPR interference screens in yeast identify chemical-genetic interactions and new rules for guide RNA design. AB - BACKGROUND: Genome-scale CRISPR interference (CRISPRi) has been used in human cell lines; however, the features of effective guide RNAs (gRNAs) in different organisms have not been well characterized. Here, we define rules that determine gRNA effectiveness for transcriptional repression in Saccharomyces cerevisiae. RESULTS: We create an inducible single plasmid CRISPRi system for gene repression in yeast, and use it to analyze fitness effects of gRNAs under 18 small molecule treatments. Our approach correctly identifies previously described chemical genetic interactions, as well as a new mechanism of suppressing fluconazole toxicity by repression of the ERG25 gene. Assessment of multiple target loci across treatments using gRNA libraries allows us to determine generalizable features associated with gRNA efficacy. Guides that target regions with low nucleosome occupancy and high chromatin accessibility are clearly more effective. We also find that the best region to target gRNAs is between the transcription start site (TSS) and 200 bp upstream of the TSS. Finally, unlike nuclease proficient Cas9 in human cells, the specificity of truncated gRNAs (18 nt of complementarity to the target) is not clearly superior to full-length gRNAs (20 nt of complementarity), as truncated gRNAs are generally less potent against both mismatched and perfectly matched targets. CONCLUSIONS: Our results establish a powerful functional and chemical genomics screening method and provide guidelines for designing effective gRNAs, which consider chromatin state and position relative to the target gene TSS. These findings will enable effective library design and genome-wide programmable gene repression in many genetic backgrounds. PMID- 26956611 TI - The effect of providing lipid-based nutrient supplements on morbidity in rural Malawian infants and young children: a randomized controlled trial. AB - OBJECTIVE: Safety of home fortificants in children is uncertain in areas where infections are common. We tested the hypothesis that provision of lipid-based nutrient supplements (LNS) containing Fe does not increase infectious morbidity in children. DESIGN: Randomized controlled trial. Infants were randomised to receive 10, 20 or 40 g LNS/d; or no supplement until age 18 months. All LNS contained 6 mg Fe/d. Morbidity outcomes (serious adverse events, non-scheduled visits and guardian-reported morbidity episodes) were compared between control and intervention groups using a non-inferiority margin of 20 %. SETTING: Namwera and Mangochi catchment areas in rural Malawi. SUBJECTS: Infants aged 6 months (n 1932). RESULTS: The enrolled 1932 infants contributed 1306 child-years of follow up. Baseline characteristics were similar across groups. Compared with the control group, the relative risk (95 % CI) of serious adverse events was 0.71 (0.48, 1.07), 0.67 (0.48, 0.95) and 0.91 (0.66, 1.25) in 10, 20 and 40 g LNS/d groups, respectively. The incidence rate ratio (95 % CI) of non-scheduled visits due to malaria was 1.10 (0.88, 1.37), 1.08 (0.89, 1.31) and 1.21 (1.00, 1.46), and of guardian-reported morbidity episodes was 1.04 (0.96, 1.11), 1.03 (0.97, 1.10) and 1.04 (0.97, 1.10), in the respective LNS groups. CONCLUSIONS: Provision of 10 and 20 g LNS/d containing 6 mg Fe/d did not increase morbidity in the children. Provision of 40 g LNS/d did not affect guardian-reported illness episodes but may have increased malaria-related non-scheduled visits. PMID- 26956612 TI - A simple, accurate and universal method for quantification of PCR. AB - BACKGROUND: Research into gene expression enables scientists to decipher the complex regulatory networks that control fundamental biological processes. Quantitative real-time PCR (qPCR) is a powerful and ubiquitous method for interrogation of gene expression. Accurate quantification is essential for correct interpretation of qPCR data. However, conventional relative and absolute quantification methodologies often give erroneous results or are laborious to perform. To overcome these failings, we developed an accurate, simple to use, universal calibrator, AccuCal. RESULTS: Herein, we show that AccuCal quantification can be used with either dye- or probe-based detection methods and is accurate over a dynamic range of >=10(5) copies, for amplicons up to 500 base pairs (bp). By providing absolute quantification of all genes of interest, AccuCal exposes, and circumvents, the well-known biases of qPCR, thus allowing objective experimental conclusions to be drawn. CONCLUSION: We propose that AccuCal supersedes the traditional quantification methods of PCR. PMID- 26956614 TI - Localised pericardial effusion mimicking anterior myocardial infarction following coronary angiography. AB - The diagnosis of pericarditis is important, especially in patients assumed to have acute coronary syndrome. Distinguishing these two conditions is vital but not always easy. Accurate diagnosis is essential to provide appropriate treatment as soon as possible and to avoid inappropriate invasive procedures. By highlighting this distinction, we report a case of pericarditis that occurred after percutaneous coronary intervention and mimicked acute coronary syndrome. PMID- 26956613 TI - Sepsis-induced elevation in plasma serotonin facilitates endothelial hyperpermeability. AB - Hyperpermeability of the endothelial barrier and resulting microvascular leakage are a hallmark of sepsis. Our studies describe the mechanism by which serotonin (5-HT) regulates the microvascular permeability during sepsis. The plasma 5-HT levels are significantly elevated in mice made septic by cecal ligation and puncture (CLP). 5-HT-induced permeability of endothelial cells was associated with the phosphorylation of p21 activating kinase (PAK1), PAK1-dependent phosphorylation of vimentin (P-vimentin) filaments, and a strong association between P-vimentin and ve-cadherin. These findings were in good agreement with the findings with the endothelial cells incubated in serum from CLP mice. In vivo, reducing the 5-HT uptake rates with the 5-HT transporter (SERT) inhibitor, paroxetine blocked renal microvascular leakage and the decline in microvascular perfusion. Importantly, mice that lack SERT showed significantly less microvascular dysfunction after CLP. Based on these data, we propose that the increased endothelial 5-HT uptake together with 5-HT signaling disrupts the endothelial barrier function in sepsis. Therefore, regulating intracellular 5-HT levels in endothelial cells represents a novel approach in improving sepsis associated microvascular dysfunction and leakage. These new findings advance our understanding of the mechanisms underlying cellular responses to intracellular/extracellular 5-HT ratio in sepsis and refine current views of these signaling processes during sepsis. PMID- 26956615 TI - Wnt5a Supports Osteogenic Lineage Decisions in Embryonic Stem Cells. AB - The specification of pluripotent stem cells into the bone-forming osteoblasts has been explored in a number of studies. However, the current body of literature has yet to adequately address the role of Wnt glycoproteins in the differentiation of pluripotent stem cells along the osteogenic lineage. During mouse embryonic stem cell (ESC) in vitro osteogenesis, the noncanonical WNT5a is expressed early on. Cells either sorted by their positive WNT5a expression or when supplemented with recombinant WNT5a (rWNT5a) during a 2-day window showed significantly enhanced osteogenic yield. Mechanistically, rWNT5a supplementation upregulated protein kinase C (PKC), calcium/calmodulin-dependent kinase II (CamKII) and c-Jun N terminal kinase (JNK) activity while antagonizing the key effector of canonical Wnt signaling: beta-catenin. Conversely, when recombinant WNT3a (rWNT3a) or other positive regulators of beta-catenin were employed during this same time window there was a decrease in osteogenic marker expression. However, if rWNT3a was supplemented during a time window following rWNT5a treatment, osteogenic differentiation was enhanced both in murine and human ESCs. Elucidating the role of these WNT ligands in directing the early stages of osteogenesis has the potential to considerably improve tissue engineering protocols and applications for regenerative medicine. PMID- 26956616 TI - Understanding non-performance reports for instrumental activity of daily living items in population analyses: a cross sectional study. AB - BACKGROUND: Concerns about using Instrumental Activities of Daily Living (IADLs) in national surveys come up frequently in geriatric and rehabilitation medicine due to high rates of non-performance for reasons other than health. We aim to evaluate the effect of different strategies of classifying "does not do" responses to IADL questions when estimating prevalence of IADL limitations in a national survey. METHODS: Cross-sectional analysis of a nationally representative sample of 13,879 non-institutionalized adult Medicare beneficiaries included in the 2010 Medicare Current Beneficiary Survey (MCBS). Sample persons or proxies were asked about difficulties performing six IADLs. Tested strategies to classify non-performance of IADL(s) for reasons other than health were to 1) derive through multiple imputation, 2) exclude (for incomplete data), 3) classify as "no difficulty," or 4) classify as "difficulty." IADL stage prevalence estimates were compared across these four strategies. RESULTS: In the sample, 1853 sample persons (12.4 % weighted) did not do one or more IADLs for reasons other than physical problems or health. Yet, IADL stage prevalence estimates differed little across the four alternative strategies. Classification as "no difficulty" led to slightly lower, while classification as "difficulty" raised the estimated population prevalence of disability. CONCLUSIONS: These analyses encourage clinicians, researchers, and policy end-users of IADL survey data to be cognizant of possible small differences that can result from alternative ways of handling unrated IADL information. At the population-level, the resulting differences appear trivial when applying MCBS data, providing reassurance that IADL items can be used to estimate the prevalence of activity limitation despite high rates of non-performance. PMID- 26956618 TI - Resistance training programs on bone related variables and functional independence of postmenopausal women in pharmacological treatment: A randomized controlled trial. AB - INTRODUCTION: Osteoporosis is a chronic disease that leads to bone fragility and is associated with fracture risks and serious consequences for mobility. OBJECTIVE: To verify the effects of two linear programs of resistance training (RT) on bone mineral density (BMD), functional autonomy (FA), muscular strength and quality of life (QoL) of postmenopausal women in pharmacological treatment. STUDY DESIGN: Randomized controlled trial, code: RBR-6bqsw8. METHODS: 52 volunteers were distributed into three groups, according to randomly parallel form: RT3times-per-week (RT3, n=20); RT2times-per-week (RT2, n=16) and control group (CG, n=16). The following assessment tools were used: bone mineral density (BMD) by dual X-ray absorptiometry, 'Latin America Group for maturity' (GDLAM) protocol for FA, 10RM test for leg exercises and the 'Osteoporosis Assessment Questionnaire' (OPAQ) for QoL. The physical activities were planned for 13 months in cycles with different intensities. A two-way ANOVA with Bonferroni post-hoc test were used. RESULTS: The results showed that the RT3/week was significantly more efficient (p<0.05) compared with RT2/week, including: All BMD variables, FA (Delta%=29.3%), leg press at 45 degrees (Delta%=24.97%) and OPAQ (Delta%=20.23%). In addition, both RT3 and RT2 groups were more efficient (p<0.05) compared with CG, including: total BMD (Delta%=0.09%) and (Delta%=0.06%); FA (Delta%=7.1%) and RT2 (Delta%=3.78%); Leg press at 45 degrees (Delta%=84.1%) and (Delta%=59.1%); keen extension (Delta%=15.28%) and (Delta%=20.37%); OPAQ (Delta%=57.61%) and (Delta%=37.37%), respectively. CONCLUSION: The study showed that both experimental groups presented favorable results for BMD, strength, FA and QoL. However, the RT3 showed the best results compared to other groups after 13 months of intervention. PMID- 26956617 TI - A Colletotrichum graminicola mutant deficient in the establishment of biotrophy reveals early transcriptional events in the maize anthracnose disease interaction. AB - BACKGROUND: Colletotrichum graminicola is a hemibiotrophic fungal pathogen that causes maize anthracnose disease. It progresses through three recognizable phases of pathogenic development in planta: melanized appressoria on the host surface prior to penetration; biotrophy, characterized by intracellular colonization of living host cells; and necrotrophy, characterized by host cell death and symptom development. A "Mixed Effects" Generalized Linear Model (GLM) was developed and applied to an existing Illumina transcriptome dataset, substantially increasing the statistical power of the analysis of C. graminicola gene expression during infection and colonization. Additionally, the in planta transcriptome of the wild type was compared with that of a mutant strain impaired in the establishment of biotrophy, allowing detailed dissection of events occurring specifically during penetration, and during early versus late biotrophy. RESULTS: More than 2000 fungal genes were differentially transcribed during appressorial maturation, penetration, and colonization. Secreted proteins, secondary metabolism genes, and membrane receptors were over-represented among the differentially expressed genes, suggesting that the fungus engages in an intimate and dynamic conversation with the host, beginning prior to penetration. This communication process probably involves reception of plant signals triggering subsequent developmental progress in the fungus, as well as production of signals that induce responses in the host. Later phases of biotrophy were more similar to necrotrophy, with increased production of secreted proteases, inducers of plant cell death, hydrolases, and membrane bound transporters for the uptake and egress of potential toxins, signals, and nutrients. CONCLUSIONS: This approach revealed, in unprecedented detail, fungal genes specifically expressed during critical phases of host penetration and biotrophic establishment. Many encoded secreted proteins, secondary metabolism enzymes, and receptors that may play roles in host-pathogen communication necessary to promote susceptibility, and thus may provide targets for chemical or biological controls to manage this important disease. The differentially expressed genes could be used as 'landmarks' to more accurately identify developmental progress in compatible versus incompatible interactions involving genetic variants of both host and pathogen. PMID- 26956620 TI - Changes in intracuff pressure of cuffed endotracheal tubes while positioning for adenotonsillectomy in children. AB - BACKGROUND: When using cuffed endotracheal tubes (cETTs), changes in head and neck position can lead to changes in intracuff pressure. AIM: The aim of this study was to assess the combined effect of neck extension, shoulder roll placement, and Crowe-Davis retractor use during adenotonsillectomy on the intracuff pressure of cETTs in children. METHODS: Patients <18 years of age undergoing adenotonsillectomy under general anesthesia following the placement of a cETT were included in the study. After inflation of the cuff to seal the trachea, using the leak test, baseline intracuff pressure was recorded and then continuously monitored. After neck extension, placement of a shoulder roll, insertion of the Crow-Davis retractor, suspension from a Mayo stand, and positioning for surgery, the intracuff pressure was recorded again. RESULTS: The study cohort included 84 patients, ranging in age from 0.9 to 17 years (5.7 +/- 3.9 years). In 46 patients (54.8%), the intracuff pressure increased from baseline after positioning for adenotonsillectomy. In 12 of these patients (14.3%), the intracuff pressure was >30 cm H2O. The intracuff pressure decreased in 28 patients (33.3%), while no change was noted in 10 patients (11.9%). Overall, the general trend was an increase in intracuff pressure from 15.9 +/- 7.8 cm H2O to 18.9 +/- 11.6 cm H2O. CONCLUSION: Both increases and decreases in the intracuff pressure may occur following positioning of the pediatric patient for adenotonsillectomy. An increase in intracuff pressure may result in a higher risk of damage to the tracheal mucosa. A decrease in the intracuff pressure can result in an air leak resulting in inadequate ventilation, increased risk of aspiration, and even predispose to airway fire if oxygen-enriched gases are used. Continuous intracuff pressure monitoring or rechecking the intracuff pressure after positioning for adenotonsillectomy may be indicated. PMID- 26956621 TI - The 4KEEPS study: identifying predictors of sustainment of multiple practices fiscally mandated in children's mental health services. AB - BACKGROUND: Research to date has largely focused on predictors of adoption and initial implementation of evidence-based practices (EBPs), yet sustained implementation is crucial to deliver a return on investments in dissemination. Furthermore, most studies focus on single EBPs, limiting opportunities to study the fit between practice characteristics EBPs and implementation contexts. METHODS/DESIGN: This observational study will characterize implementation sustainment and identify organizational and therapist characteristics that predict sustainment of multiple practices being implemented within a fiscal mandate in the largest public mental health system in the USA. Specific aims are to (1) characterize sustainment outcomes (volume/penetration, EBP concordant care); (2) use mixed methods to characterize inner context (agency- and therapist level) factors and early implementation conditions; and (3) identify inner context factors and early implementation conditions that predict sustainment outcomes. This study will undertake original data collection and analysis of existing data sources to achieve its aims. Archived reports and documents will be used to characterize early implementation conditions in 102 agencies. Administrative claims data will be used to characterize volume and penetration outcomes over 8 years. Therapist and program manager surveys will be administered to characterize sustained EBP concordant care and inner context determinants of sustainment. An in-depth study in a subset of agencies will yield interview data and recordings of treatment sessions for validation of the EBP concordant care scale. DISCUSSION: This project will yield new understanding of whether and how multiple EBPs can be sustained in public mental health systems undergoing a policy-driven community implementation effort. We will produce generalizable models for characterizing sustainment, including feasible and flexible measurement of practice across multiple EBPs. The findings will inform the development of implementation interventions to promote sustained delivery of EBPs to maximize their public health impact. PMID- 26956619 TI - ERK mediated upregulation of death receptor 5 overcomes the lack of p53 functionality in the diaminothiazole DAT1 induced apoptosis in colon cancer models: efficiency of DAT1 in Ras-Raf mutated cells. AB - BACKGROUND: p53 is a tumour suppressor protein that plays a key role in many steps of apoptosis, and malfunctioning of this transcription factor leads to tumorigenesis. Prognosis of many tumours also depends upon the p53 status. Most of the clinically used anticancer compounds activate p53 dependent pathway of apoptosis and hence require p53 for their mechanism of action. Further, Ras/Raf/MEK/ERK axis is an important signaling pathway activated in many cancers. Dependence of diaminothiazoles, compounds that have gained importance recently due to their anticancer and anti angiogenic activities, were tested in cancer models with varying p53 or Ras/Raf mutational status. METHODS: In this study we have used p53 mutated and knock out colon cancer cells and xenograft tumours to study the role of p53 in apoptosis mediated by diaminothiazoles. Colon cancer cell lines with varying mutational status for Ras or Raf were also used. We have also examined the toxicity and in vivo efficacy of a lead diaminothiazole 4-Amino 5-benzoyl-2-(4-methoxy phenylamino)thiazole (DAT1) in colon cancer xenografts. RESULTS: We have found that DAT1 is active in both in vitro and in vivo models with nonfunctional p53. Earlier studies have shown that extrinsic pathway plays major role in DAT1 mediated apoptosis. In this study, we have found that DAT1 is causing p53 independent upregulation of the death receptor 5 by activating the Ras/Raf/MEK/ERK signaling pathway both in wild type and p53 suppressed colon cancer cells. These findings are also confirmed by the in vivo results. Further, DAT1 is more efficient to induce apoptosis in colon cancer cells with mutated Ras or Raf. CONCLUSIONS: Minimal toxicity in both acute and subacute studies along with the in vitro and in vivo efficacy of DAT1 in cancers with both wild type and nonfunctional p53 place it as a highly beneficial candidate for cancer chemotherapy. Besides, efficiency in cancer cells with mutations in the Ras oncoprotein or its downstream kinase Raf raise interest in diaminothiazole class of compounds for further follow-up. PMID- 26956623 TI - Breast segmentectomy with rotation mammoplasty as an oncoplastic approach to extensive ductal carcinoma in situ. AB - BACKGROUND: The aim of this study was to assess the usefulness of the breast segmentectomy with rotation mammoplasty (BSRMP) in conserving therapy for an extensive ductal carcinoma in situ (DCIS) with or without an invasive component. METHODS: Thirty-six women with DCIS visible as large area of microcalcifications distributed out of the retroareolar area regardless of the quadrant were studied prospectively. All the patients underwent BSRMP and axillary procedure (31 sentinel node biopsy, 5 axillary dissection) followed by radiotherapy. In each case, follow-up was carried out carefully and special effort was made to identify postoperative complications. Cosmetic result was judged 6 months after radiotherapy by the patient herself and two surgeons being rated as poor, mediocre, medium, good or excellent. RESULTS: Operation was completed without any difficulties in all the cases. Appropriate BSRMP was easily done after the skin marking. Regardless of the type of axillary approach, it was conveniently performed. Wound was healed by primary adhesion; skin or breast tissue necrosis did not develop. Neither haematoma nor surgical site infection was observed. In none of the patient, centralisation of the nipple-areola complex (NAC) was needed. Three patients (8.3%) with close margins (1 mm or less) successfully underwent subsequent re-excision. The scar did not result in any impairment of arm movement. Cosmetic outcome was evaluated by the women as excellent and good in 55 (87%) and 8 (13%) cases, respectively, while by the surgeons as excellent, good and medium in 52 (82%), 8 (13%), and 3 cases (5%), respectively. CONCLUSIONS: BSRMP is a simple and safe technique achieving good cosmetic results without NAC centralisation and giving the wide and easy access to axilla for both sentinel node biopsy and lymphadenectomy. It can be helpful in cases of extensive, radially spreading tumours (in particular DCIS or invasive cancers with intraductal component), eccentric lesions, or superficially located cancers when the neighbouring skin is excised. However, due to its limitations (long incision, difficult subsequent mastectomy, possibility of scar placement in the visible area of decollete), a careful patients' selection should be done. Further studies are needed to assess long-term cosmetic outcomes including delayed post radiotherapy effects. PMID- 26956622 TI - Reproducibility of axon reflex-related vasodilation assessed by dynamic thermal imaging in healthy subjects. AB - INTRODUCTION: Small nerve fiber dysfunction is an early feature of diabetic neuropathy. There is a strong clinical need for a non-invasive method to assess small nerve fiber function. Small nerve fibers mediate axon reflex-related vasodilation and play an important role in thermoregulation. Assessing the reflex vasodilation after local heating might elucidate some aspects of small fiber functioning. In this study, we determined the reproducibility of the reflex vasodilation after short local heating in healthy subjects, assessed with thermal imaging and laser Doppler imaging. METHODS: Healthy subjects underwent six heating rounds in one session (protocol I, N=10) or spread over two visits (protocol II, N=20). Reflex vasodilation was elicited by heating the skin to 42 degrees C with an infrared lamp. Skin temperature and skin blood flow were recorded during heating and recovery with a thermal imaging camera and a laser Doppler imager. Skin temperature curves were fitted with a mathematical model to describe the heating and recovery phase with time constant tau (tauHeat and tauCool1). RESULTS: The reproducibility of tau within a session was moderate to excellent (intra-class correlation coefficient 0.42-0.86) and good (0.71-0.72) between different sessions. Within one session the differences in tauHeat were small (bias+/-SD -1.3+/-18.9s); the bias between two visits was -1.2+/-12.2s. For tauCool1 the differences were also small, 1.4+/-6.6s within a session and between visits -1.4+/-11.6s. CONCLUSIONS: The heat induced axon reflex-related vasodilation, assessed with thermal imaging and laser Doppler imaging, was reproducible both within a session and between different sessions. Tau describes the temporal profile in one parameter and represents the effects of all changes including blood flow and as such, is an indicator of the vasodilator function. TauHeat and tauCool1 can accurately describe the dynamics of the axon reflex related vasodilator response in the heating and recovery phase respectively. PMID- 26956625 TI - Fabrication of perovskite films using an electrostatic assisted spray technique: the effect of the electric field on morphology, crystallinity and solar cell performance. AB - An electric field assisted spray deposition method is employed for improving the perovskite film morphology, crystallinity, and surface coverage, and for further fabricating an efficient solar cell. By applying different voltages ranging from 0.5 to 2.0 kV during spray deposition, we observed a large variation in the film morphology and surface coverage compared to those fabricated without an electric field, which is due to improved atomization from the Coulomb fission process. The optimized applied voltage of 1.5 kV during spraying led to completion of the reaction between CH3NH3I and PbI2 on a hot substrate for pure phase CH3NH3PbI3 thin film formation with improved grain growth and surface coverage. The cells fabricated using perovskite films showed clear applied voltage dependence in the energy conversion process and alleviation in J-V hysteresis; with 1.5 kV applied voltage the average cell efficiency of 8.9% was obtained compared to films fabricated without applying voltage providing only 6.5%. The best efficiencies are 10.9% and 7.37% for applied voltages of 1.5 kV and 0 kV, respectively. The enhancement in efficiency with applied voltage is due to the formation of more uniform and dense films with large perovskite crystals, which resulted in efficient electron transportation (enhanced photocurrent and modified series and shunt resistances) by minimizing the charge carrier recombination at grain boundaries (resulting in enhanced open circuit voltage). With further optimization of the perovskite film thickness by adjusting the CH3NH3I spray volume, the average cell efficiency of ~11.0% was obtained. PMID- 26956624 TI - Computer vision syndrome among computer office workers in a developing country: an evaluation of prevalence and risk factors. AB - BACKGROUND: Computer vision syndrome (CVS) is a group of visual symptoms experienced in relation to the use of computers. Nearly 60 million people suffer from CVS globally, resulting in reduced productivity at work and reduced quality of life of the computer worker. The present study aims to describe the prevalence of CVS and its associated factors among a nationally-representative sample of Sri Lankan computer workers. METHODS: Two thousand five hundred computer office workers were invited for the study from all nine provinces of Sri Lanka between May and December 2009. A self-administered questionnaire was used to collect socio-demographic data, symptoms of CVS and its associated factors. A binary logistic regression analysis was performed in all patients with 'presence of CVS' as the dichotomous dependent variable and age, gender, duration of occupation, daily computer usage, pre-existing eye disease, not using a visual display terminal (VDT) filter, adjusting brightness of screen, use of contact lenses, angle of gaze and ergonomic practices knowledge as the continuous/dichotomous independent variables. A similar binary logistic regression analysis was performed in all patients with 'severity of CVS' as the dichotomous dependent variable and other continuous/dichotomous independent variables. RESULTS: Sample size was 2210 (response rate-88.4%). Mean age was 30.8 +/- 8.1 years and 50.8% of the sample were males. The 1-year prevalence of CVS in the study population was 67.4%. Female gender (OR: 1.28), duration of occupation (OR: 1.07), daily computer usage (1.10), pre-existing eye disease (OR: 4.49), not using a VDT filter (OR: 1.02), use of contact lenses (OR: 3.21) and ergonomics practices knowledge (OR: 1.24) all were associated with significantly presence of CVS. The duration of occupation (OR: 1.04) and presence of pre-existing eye disease (OR: 1.54) were significantly associated with the presence of 'severe CVS'. CONCLUSIONS: Sri Lankan computer workers had a high prevalence of CVS. Female gender, longer duration of occupation, higher daily computer usage, pre-existing eye disease, not using a VDT filter, use of contact lenses and higher ergonomics practices knowledge all were associated with significantly with the presence of CVS. The factors associated with the severity of CVS were the duration of occupation and presence of pre-existing eye disease. PMID- 26956627 TI - Effects of optineurin mutants on SH-SY5Y cell survival. AB - Mutations in the optineurin gene (OPTN) have been found to be associated with glaucoma and amyotrophic lateral sclerosis (ALS). However, the mechanism by which this single gene mutation leads to neurodegeneration in those two diseases remains unrevealed. To study the roles of wild-type (WT) OPTN and its pathogenic mutants in neuronal survival, here we overexpressed SH-SY5Y cells with WT OPTN or its four mutants (E50K, M98K, Q398X and E478G), and detected their effects on neuronal viability under normal or oxidative stress conditions. We found that overexpression of WT OPTN or its glaucoma-linked mutants (E50K and M98K) causes little harm in SH-SY5Y cells, while ALS-associated OPTN mutants (Q398X and E478G) leads to remarkably increased oxidative status and decreased antioxidase activity, which might result in severe mitochondrial dysfunction and neuronal injury. Further investigation suggests that overexpression of WT OPTN promotes endogenous antioxidase activation in the SH-SY5Y cells under oxidative stress and increases neuronal survival. Nevertheless, this neuroprotective effect of WT OPTN is abolished by its four mutants. Our results indicate that oxidative stress may play a central role in the pathogenesis of glaucoma and ALS caused by OPTN mutation. PMID- 26956626 TI - Bortezomib-mediated downregulation of S-phase kinase protein-2 (SKP2) causes apoptotic cell death in chronic myelogenous leukemia cells. AB - BACKGROUND: Proteasome inhibitors are attractive cancer therapeutic agents because they can regulate apoptosis-related proteins. Bortezomib also known as Velcade((r)), a proteasome inhibitor that has been approved by the food and drug administration for treatment of patients with multiple myeloma, and many clinical trials are ongoing to examine to the efficacy of bortezomib for the treatment of other malignancies. Bortezomib has been shown to induce apoptosis and inhibit cell growth of many cancer cells. In current study, we determine whether bortezomib induces cell death/apoptosis in CML. METHODS: Cell viability was measured using MTT assays. Apoptosis was measured by annexin V/PI dual staining and DNA fragmentation assays. Immunoblotting was performed to examine the expression of proteins. Colony assays were performed using methylcellulose. RESULTS: Treatment of CML cells with bortezomib results in downregulation of S phase kinase protein 2 (SKP2) and concomitant stabilization of the expression of p27Kip1. Furthermore, knockdown of SKP2 with small interference RNA specific for SKP2 caused accumulation of p27Kip1. CML cells exposed to bortezomib leads to conformational changes in Bax protein, resulting in loss of mitochondrial membrane potential and leakage of cytochrome c to the cytosol. In the cytosol, cytochrome c causes sequential activation of caspase-9, caspase-3, PARP cleavage and apoptosis. Pretreatment of CML cells with a universal inhibitor of caspases, z-VAD-fmk, prevents bortezomib-mediated apoptosis. Our data also demonstrated that bortezomib treatment of CML downregulates the expression of inhibitor of apoptosis proteins. Finally, inhibition of proteasome pathways by bortezomib suppresses colony formation ability of CML cells. CONCLUSIONS: Altogether, these findings suggest that bortezomib suppresses the cell proliferation via induction of apoptosis in CML cells by downregulation of SKP2 with concomitant accumulation of p27Kip1, suggesting that proteasomal pathway may form novel therapeutic targets for better management of CML. PMID- 26956630 TI - Monoamines and CSF: relevance to neuropsychiatric disorders. AB - Over the past 25 years much effort has been put into the research of the relationship between neuropsychiatric disorders and the concentrations of CSF monoamine metabolites. Most of this research has beenfocused on the relation between CSF-concentrations of 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) and specific symptomatological entities, particularly schizophrenia, Alzheimer's dementia and endogenous depression. It appeared that specific relations between diseases and CSF-concentrations of monoamine metabolites cannot be longer maintained and that a more functional psychopathology should be considered as the future research strategy. PMID- 26956629 TI - Lacosamide tolerability in adult patients with partial-onset seizures: Impact of planned reduction and mechanism of action of concomitant antiepileptic drugs. AB - OBJECTIVE: We evaluated the impact of planned dose reduction and mechanism of action of concomitant AEDs on tolerability in adults with partial-onset seizures undergoing lacosamide (LCM) titration. METHODS: Data were collected at baseline and 3-6 and 12-24 months post-LCM initiation. Subjects were categorized as having planned reduction of concomitant AEDs or not; AEDs were categorized as traditional sodium channel blockers (TSCB) or non-TSCB (NTSCB). Groups with/without planned reduction were compared on the presence and number of treatment-emergent adverse events (TEAEs) using chi-square tests or logistic regression and on time to LCM discontinuation with time-to-event methods controlling for standardized (STD) AED dose, a measure of concomitant AED load. Similar analyses were performed comparing subjects taking TSCB and NTSCB agents and used to identify relationships with >=50% decreases in seizure frequency. RESULTS: One hundred six adults (mean age 41.4 +/- 13.4; 50% male) underwent LCM titration from June 2009-2011 with complete data. Reduction of concomitant AEDs was planned at the time of LCM initiation in 59 (55.7%) subjects. Fewer subjects with planned reduction had TEAEs (49.2% vs. 68.1%; p=0.05), and these subjects had a lower risk of TEAEs (OR 0.36; p=0.019) after adjusting for STD AED dose. The hazard ratio (95% CI) for LCM discontinuation was 0.46 (0.23, 0.94) in subjects with planned reduction of concomitant AEDs vs. others (p=0.033) and 3.29 (1.01, 10.70) in subjects taking TSCB vs. NTSCB agents (p=0.048). Among all cases, those who ever had TEAEs had significantly higher STD dose at both follow up visits (p=0.033 and p=0.023, respectively). Seizure outcomes were not significantly different between groups at the last follow-up assessment. SIGNIFICANCE: Planned reduction of concomitant AEDs during LCM initiation and the use of NTSCB agents only are associated with a reduced risk of TEAEs and LCM discontinuation in adults with partial-onset seizures. This study extends prior observations by considering total AED load in the assessment of tolerability and supports the benefits of early reduction of concomitant AEDs during LCM initiation. PMID- 26956631 TI - Manic episode, thyroid gland function and lithium. AB - This paper addresses the issue of (recurrent) mania in relation to an increased T4-value, whether or not influenced by lithium. Lithium has an anti-TSH-effect on the thyroid gland by inhibiting the intracellular enzyme adenylate cyclase. This might cause hypothyroidism. Moreover, lithium is also known to have a direct stabilizing effect on (behavioral manifestations) of dopamine receptor supersensitivity. The hypothesis regarding the relation between thyroid function and affective disturbances is that the altered thyroid function may cause a change in the availability of the central dopamine receptors. Dopamine is known to be able to cause a manic state. TSH and TRH are also involved in this mechanism. It is, therefore, very likely that an increased thyroid function, whether or not caused by discontinuation of lithium-therapy, could induce a (recurrent) mania. PMID- 26956632 TI - Clinical evaluation of antidepressant drugs; Guidelines from authorities. AB - Food and Drug Administration, World Health Organisation and Committee on Proprietary Medicinal Products have published guidelines with recommendations how to conduct clinical trials. The guidelines for the clinical evaluation of antidepressant drugs contain a great variety of recommendations how to design phase I, phase II and phase III trials. Especially the pharmaceutical industry will follow these guidelines as much as possible to make the chances to register a new chemical entity as optimal as possible. While FDA and CPMP guidelines are primarily meant to be read by representatives from the pharmaceutical industries, the WHO guidelines give mainly information for clinicians. For the psychiatrist with interest in clinical research on antidepressants it is mandatory to know about the existence of these different guidelines. Fundamental differences between the guidelines do not exist; the methodological and ethical problems concerning placebo-use and relapse-recurrence problems are especially emphasized in the CPMP-guidelines. PMID- 26956628 TI - Dependence of fluorescent protein brightness on protein concentration in solution and enhancement of it. AB - Fluorescent proteins have been widely used in biology because of their compatibility and varied applications in living specimens. Fluorescent proteins are often undesirably sensitive to intracellular conditions such as pH and ion concentration, generating considerable issues at times. However, harnessing these intrinsic sensitivities can help develop functional probes. In this study, we found that the fluorescence of yellow fluorescent protein (YFP) depends on the protein concentration in the solution and that this dependence can be enhanced by adding a glycine residue in to the YFP; we applied this finding to construct an intracellular protein-crowding sensor. A Forster resonance energy transfer (FRET) pair, involving a cyan fluorescent protein (CFP) insensitive to protein concentration and a glycine-inserted YFP, works as a genetically encoded probe to evaluate intracellular crowding. By measuring the fluorescence of the present FRET probe, we were able to detect dynamic changes in protein crowding in living cells. PMID- 26956633 TI - The effect of stress and psychosocial variables on natural killer cells: a review. AB - In this review we discuss the results of studies about the effect of stress, depression, anxiety, social support and various psychosocial treatments on numbers and activity of Natural Killer (NK) cells. In general a suppressive effect is observed among depressive persons and persons who react to stressfull events with feelings of helplessness and anxiety. Lack of social support also seems to engender immunosuppression including NK suppression. Various forms of psychosocial care seem to be able to undo these negative consequences. However, the real clinical relevance of these findings is still a matter of dispute. PMID- 26956634 TI - Psychofarmakologika IX. AB - Inleiding In deze rubriek zal worden ingegaan op recente observaties betreffende de psychofarmakologie in de breedst mogelijke zin. Vaak zullen zaken uit de literatuur worden behandeld. De gekozen onderwerpen dienen altijd klinische relevantie te hebben. Ook zal deze rubriek gaan over gewoontes die in psychofarmakologische behandeling of in onderzoek zijn geslopen die volgens de auteur lang niet altijd logisch zijn. Soms zal deze rubriek een oproep bevatten om te reageren op een bijdrage gepubliceerd in dit of in een ander tijdschrift. Ook zal de lezer worden aangemoedigd hier zijn eigen ervaringen mee te delen. Het is niet de bedoeling in deze rubriek onderzoeken uitvoerig te rapporteren. Daarvoor staan andere pagina's van de Acta Neuropsychiatrica voor u open. PMID- 26956635 TI - Safety, Efficacy, and Complications of Pericardiocentesis by Real-Time Echo Monitored Procedure. AB - Pericardiocentesis is useful in the diagnosis and treatment of pericardial effusive disease. To date, a number of methods have been developed to reduce complications and increase the success rate of the procedure. The aim of the present study was to evaluate the efficacy and the safety of echocardiography guided pericardiocentesis under continuous echocardiographic monitoring in the management of pericardial effusion. We prospectively performed 161 pericardiocentesis procedures in 141 patients admitted from 1993 to 2015 in 3 centers. This procedure was performed for tamponade or large pericardial effusion in 157 cases and for diagnosis in 4 cases. A percutaneous puncture was performed where the largest amount of fluid was detected. To perform a real-time echo guided procedure, a multi-angle bracket was mounted on the echocardiographic probe to support the needle and enable its continuous visualization during the puncture. The procedure was successful in 160 of 161 cases (99%). Two major complications occurred (1.2%): 1 mediastinal hematoma that required surgical drainage in a patient on anticoagulant therapy and 1 pleuropericardial shunt requiring thoracentesis. Seven minor complications occurred (4.3%): 1 pleuropericardial shunt, 1 case of transient AV type III block, 3 vasovagal reactions (1 with syncope), and 2 cases of acute pulmonary edema managed with medical therapy. No punctures of any cardiac chamber occurred, and emergency surgical drainage was not required in any case. In conclusion, echocardiography guided pericardiocentesis under continuous visualization is effective, safe, and easy to perform, even in hospitals with low volumes of procedures with or without cardiac surgery. PMID- 26956636 TI - Relation of Gamma-Glutamyl Transferase to Cardiovascular Events in Patients With Acute Coronary Syndromes. AB - The prognostic value of gamma-glutamyl transferase (GGT) in patients with acute coronary syndromes (ACS) has been incompletely investigated. We investigated this clinically relevant question in 2,534 consecutive patients with ACS who underwent percutaneous coronary intervention (PCI). GGT activity was measured before PCI procedure in all patients. Statin therapy at hospital discharge was prescribed in 94% of the patients. The primary outcome was 3-year mortality. Patients were divided into 3 groups: the group with GGT in the first tertile (GGT <28 U/L; n = 848 patients), the group with GGT in the second tertile (GGT 28 to <50 U/L; n = 843 patients), and the group with GGT in the third tertile (GGT >=50 U/L; n = 843 patients). The primary outcome (all-cause deaths) occurred in 250 patients: 70 deaths (9.7%) among patients of the first, 69 deaths (9.0%) among patients of the second, and 111 deaths (14.8%) among patients of the third GGT tertile (adjusted hazard ratio [HR] 1.24, 95% CI 1.08 to 1.42, p = 0.002) and cardiac and noncardiac deaths occurred in 157 (63%) and 93 patients (37%), respectively. GGT was associated with the increased risk of noncardiac mortality (adjusted HR 1.35 [1.09 to 1.66], p = 0.005) but not cardiac mortality (adjusted HR 1.16 [0.97 to 1.38], p = 0.098; all 3 risk estimates were calculated per SD increase in the logarithmic scale of GGT activity). In conclusion, in contemporary patients with ACS treated with PCI and on statin therapy, elevated GGT activity was associated with the increased risk of all-cause and noncardiac mortality but not with the risk of cardiac mortality. PMID- 26956637 TI - Comparison of Trends in Incidence, Revascularization, and In-Hospital Mortality in ST-Elevation Myocardial Infarction in Patients With Versus Without Severe Mental Illness. AB - Patients with severe mental illness (SMI), including schizophrenia and bipolar disorder, are at elevated risk of ST-elevation myocardial infarction (STEMI) but have previously been reported as less likely to receive revascularization. To study the persistence of these findings over time, we examined trends in STEMI incidence, revascularization, and in-hospital mortality for patients with and without SMI in the National Inpatient Sample from 2003 to 2012. We further used multivariate logistic regression analysis to assess the odds of revascularization and in-hospital mortality. SMI was present in 29,503 of 3,058,697 (1%) of the STEMI population. Patients with SMI were younger (median age 58 vs 67 years), more likely to be women (44% vs 38%), and more likely to have several co morbidities, including diabetes, chronic pulmonary disease, substance abuse, and obesity (p <0.001 for all). Over time, STEMI incidence significantly decreased in non-SMI (p for trend <0.001) but not in SMI (p for trend 0.14). Revascularization increased in all subgroups (p for trend <0.001) but remained less common in SMI. In-hospital mortality decreased in non-SMI (p for trend = 0.004) but not in SMI (p for trend 0.10). After adjustment, patients with SMI were less likely to undergo revascularization (odds ratio 0.59, 95% CI 0.52 to 0.61, p <0.001), but SMI was not associated with increased in-hospital mortality (odds ratio 0.97, 95% CI 0.93 to 1.01, p = 0.16). In conclusion, in contrast to the overall population, the incidence of STEMI is not decreasing in patients with SMI. Despite changes in the care of STEMI, patients with SMI remain less likely to receive revascularization therapies. PMID- 26956638 TI - Drug-Related Hyponatremic Encephalopathy: Rapid Clinical Response Averts Life Threatening Acute Cerebral Edema. AB - BACKGROUND: Drug-induced hyponatremia characteristically presents with subtle psychomotor symptoms due to its slow onset, which permits compensatory volume adjustment to hypo-osmolality in the central nervous system. Due mainly to the syndrome of inappropriate antidiuretic hormone secretion (SIADH), this condition readily resolves following discontinuation of the responsible pharmacological agent. Here, we present an unusual case of life-threatening encephalopathy due to adverse drug-related effects, in which a rapid clinical response facilitated emergent treatment to avert life-threatening acute cerebral edema. CASE REPORT: A 63-year-old woman with refractory depression was admitted for inpatient psychiatric care with a normal physical examination and laboratory values, including a serum sodium [Na+] of 144 mEq/L. She had a grand mal seizure and became unresponsive on the fourth day of treatment with the dual serotonin and norepinephrine reuptake inhibitor [SNRI] duloxetine while being continued on a thiazide-containing diuretic for a hypertensive disorder. Emergent infusion of intravenous hypertonic (3%) saline was initiated after determination of a serum sodium [Na+] of 103 mEq/L with a urine osmolality of 314 mOsm/kg H20 and urine [Na+] of 12 mEq/L. Correction of hyposmolality in accordance with current guidelines resulted in progressive improvement over several days, and she returned to her baseline mental status. CONCLUSIONS: Seizures with life threatening hyponatremic encephalopathy in this case likely resulted from co occurring SIADH and sodium depletion due to duloxetine and hydrochlorothiazide, respectively. A rapid clinical response expedited diagnosis and emergent treatment to reverse life-threatening acute cerebral edema and facilitate a full recovery without neurological complications. PMID- 26956640 TI - The ABCG2 Efflux Transporter in the Mammary Gland Mediates Veterinary Drug Secretion across the Blood-Milk Barrier into Milk of Dairy Cows. AB - In human and mice ATP-binding cassette efflux transporter ABCG2 represents the main route for active drug transport into milk. However, there is no detailed information on the role of ABCG2 in drug secretion and accumulation in milk of dairy animals. We therefore examined ABCG2-mediated drug transport in the bovine mammary gland by parallel pharmacokinetic studies in lactating Jersey cows and in vitro flux studies using the anthelmintic drug monepantel (MNP) as representative bovine ABCG2 (bABCG2) drug substrate. Animals received MNP (Zolvix, Novartis Animal Health Inc.) once (2.5 mg/kg per os) and the concentrations of MNP and the active MNP metabolite MNPSO2 were assessed by high-performance liquid chromatography. Compared with the parent drug MNP, we detected higher MNPSO2 plasma concentrations (expressed as area under the concentration-versus-time curve). Moreover, we observed MNPSO2 excretion into milk of dairy cows with a high milk-to-plasma ratio of 6.75. In mechanistic flux assays, we determined a preferential time-dependent basolateral-to-apical (B > A) MNPSO2 transport across polarized Madin-Darby canine kidney II cells-bABCG2 monolayers using liquid chromatography coupled with tandem mass spectrometry analysis. The B > A MNPSO2 transport was significantly inhibited by the ABCG2 inhibitor fumitremorgin C in bABCG2- but not in mock-transduced MDCKII cells. Additionally, the antibiotic drug enrofloxacin, the benzimidazole anthelmintic oxfendazole and the macrocyclic lactone anthelmintic moxidectin caused a reduction in the MNPSO2(B > A) net efflux. Altogether, this study indicated that therapeutically relevant drugs like the anthelmintic MNP represent substrates of the bovine mammary ABCG2 transporter and may thereby be actively concentrated in dairy milk. PMID- 26956639 TI - Cardiometabolic risk in young adults from northern Mexico: Revisiting body mass index and waist-circumference as predictors. AB - BACKGROUND: A body mass index (BMI) >=30 kg/m(2) and a waist circumference (WC) >=80 cm in women (WCF) or >=90 cm in men (WCM) are reference cardiometabolic risk markers (CMM) for Mexicans adults. However, their reliability to predict other CMM (index tests) in young Mexicans has not been studied in depth. METHODS: A cross-sectional descriptive study evaluating several anthropometric, physiological and biochemical CMM from 295 young Mexicans was performed. Sensitivity (Se), specificity (Sp) and Youden's index (J) of reference BMI/WC cutoffs toward other CMM (n = 14) were obtained and their most reliable cutoffs were further calculated at Jmax. RESULTS: Prevalence, incidence and magnitude of most CMM increased along the BMI range (p < 0.01). BMI explained 81 % of WC's variance [Se (97 %), Sp (71 %), J (68 %), Jmax (86 %), BMI = 30 kg/m(2)] and 4-50 % of other CMM. The five most prevalent (>=71 %) CMM in obese subjects were high WC, low HDL-C, and three insulin-related CMM [Fasting insulin, HOMA-IR, and QUICKI]. For a BMI = 30 kg/m(2), J ranged from 16 % (HDL-C/LDL-C) to 68 % (WC), being moderately reliable (Jmax = 61-67) to predict high uric acid (UA), metabolic syndrome (MetS) and the hypertriglyceridemic-waist phenotype (HTGW). Corrected WCM/WCF were moderate-highly reliable (Jmax = 66-90) to predict HTGW, MetS, fasting glucose and UA. Most CMM were moderate-highly predicted at 27 +/- 3 kg/m(2) (CI 95 %, 25-28), 85 +/- 5 cm (CI 95 %, 82-88) and 81 +/- 6cm (CI 95 %, 75-87), for BMI, WCM and WCF, respectively. CONCLUSION: BMI and WC are good predictors of several CMM in the studied population, although at different cutoffs than current reference values. PMID- 26956641 TI - Mechanistic Modeling to Predict Midazolam Metabolite Exposure from In Vitro Data. AB - Methods to predict the pharmacokinetics of drugs in humans from in vitro data have been established, but corresponding methods to predict exposure to circulating metabolites are unproven. The objective of this study was to use in vitro methods combined with static and dynamic physiologically based pharmacokinetic (PBPK) models to predict metabolite exposures, using midazolam and its major metabolites as a test system. Intrinsic clearances (CLint) of formation of individual metabolites were determined using human liver microsomes. Metabolic CLintof hydroxymidazolam metabolites via oxidation and glucuronidation were also determined. Passive diffusion intrinsic clearances of hydroxymidazolam metabolites were determined using sandwich cultured human hepatocytes and the combination of this term along with the metabolic CLint, and liver blood flow was used to estimate the fraction of the metabolite that can enter the systemic circulation after formation in the liver. The metabolite/parent drug area under the plasma concentration-time curve ratio (AUCm/AUCp) was predicted using a static model relating the fraction of midazolam clearance to each metabolite, the clearance rates of midazolam and hydroxymidazolam metabolites, and the availability of the metabolites. Additionally, the human disposition of midazolam metabolites was simulated using a SimCYP PBPK model. Both approaches yielded AUCm/AUCpratios that were in agreement with the in vivo ratios. This study shows that in vivo midazolam metabolite exposure can be predicted from in vitro data and PBPK modeling. This study emphasized the importance of metabolite systemic availability from its tissue of formation, which remains a challenge to quantitative prediction. PMID- 26956642 TI - Peer tutoring in a medical school: perceptions of tutors and tutees. AB - BACKGROUND: Peer tutoring has been described as "people from similar social groupings who are not professional teachers helping each other to learn and learning themselves by teaching". Peer tutoring is well accepted as a source of support in many medical curricula, where participation and learning involve a process of socialisation. Peer tutoring can ease the transition of the junior students from the university class environment to the hospital workplace. In this paper, we apply the Experienced Based Learning (ExBL) model to explore medical students' perceptions of their experience of taking part in a newly established peer tutoring program at a hospital based clinical school. METHODS: In 2014, all students at Sydney Medical School - Central, located at Royal Prince Alfred Hospital were invited to voluntarily participate in the peer tutoring program. Year 3 students (n = 46) were invited to act as tutors for Year 1 students (n = 50), and Year 4 students (n = 60) were invited to act as tutors for Year 2 students (n = 51). Similarly, the 'tutees' were invited to take part on a voluntary basis. Students were invited to attend focus groups, which were held at the end of the program. Framework analysis was used to code and categorise data into themes. RESULTS: In total, 108/207 (52 %) students participated in the program. A total of 42/106 (40 %) of Year 3 and 4 students took part as tutors; and of 66/101 (65 %) of Year 1 and 2 students took part as tutees. Five focus groups were held, with 50/108 (46 %) of students voluntarily participating. Senior students (tutors) valued the opportunity to practice and improve their medical knowledge and teaching skills. Junior students (tutees) valued the opportunity for additional practice and patient interaction, within a relaxed, small group learning environment. CONCLUSION: Students perceived the peer tutoring program as affording opportunities not otherwise available within the curriculum. The peer teaching program provided a framework within the medical curriculum for senior students to practice and improve their medical knowledge and teaching skills. Concurrently, junior students were provided with a valuable learning experience that they reported as being qualitatively different to traditional teaching by faculty. PMID- 26956643 TI - Dual-energy CT of pancreatic adenocarcinoma: reproducibility of primary tumor measurements and assessment of tumor conspicuity and margin sharpness. AB - PURPOSE: To determine the inter- and intra-reader agreement of size, conspicuity, and margin sharpness of pancreatic adenocarcinoma on monochromatic, polychromatic, and iodine map dual-energy CT (DECT) images. METHODS: Retrospective review of DECT images from 61 patients with untreated pancreatic adenocarcinoma was performed by three radiologists independently. Pancreatic parenchymal phase images were generated as 50 and 70 keV, 140 kVp quality control (QC), and iodine map images. These were analyzed in a blinded randomized order during four reading sessions separated by 5-7 days. For each image set, readers recorded the longest axial and perpendicular primary tumor dimensions, and qualitatively scored tumor conspicuity and edge sharpness on 5-point scales. Linear mixed model was used to estimate and compare tumor measurements, tumor conspicuity, and tumor edge sharpness scores between readers and image sets. Kappa statistics were used to determine inter-observer agreement for tumor conspicuity and edge sharpness. RESULTS: The range of tumor measures (mean of longest dimension +/- standard deviation) was 3.18 +/- 1.41 to 3.83 +/- 1.57 cm. Reproducibility of tumor measurements was very high with mild variability (s (2) = 0.01-0.10) between readers for the different image sets. Inter-observer agreement values for tumor conspicuity (kappa = 0.01-0.17) and edge sharpness (kappa = 0.12-0.25) were low for all image sets, although two of three readers scored tumor conspicuity and edge sharpness higher on monochromatic and iodine map DECT images than on 140 kVp QC images (p < 0.05). CONCLUSIONS: Pancreatic adenocarcinoma measurements were highly reproducible on DECT images, and subjective reader preference trended toward monochromatic and iodine images rather than polychromatic images. PMID- 26956644 TI - Imatinib Inhibits the Renewal and Tumorigenicity of CT-26 Colon Cancer Cells after Cytoreductive Treatment with Doxorubicin. AB - Conventional anti-cancer drugs preferentially eliminate differentiated cancer cells but those cells that are spared (i.e. cancer stem cells: CSC), initiate recurrence. We tested whether drugs that target receptor tyrosine kinases (RTKs) involved in developmental signaling cascades and activated in CSC, could be used to silence and/or to eliminate colorectal cancer cells refractory to conventional treatment with cytoreductive drugs. A sequential treatment model was thereby developed with doxorubicin (DOX) and imatinib. CT-26 mouse colon carcinoma cells were pre-treated with DOX to select DOX-refractory cells with CSC properties, which were then subsequently treated with RTK inhibitor imatinib, where their regrowth was found to be inhibited. Under both normoxic and hypoxic conditions, imatinib potently inhibited clonogenicity of DOX-refractory CT-26 cells. Treatment with DOX did not eliminate tumorigenic CT-26 cells, since CT-26 cells pre-exposed to DOX in vitro, when inoculated subcutaneously, induced tumors in 90 % of mice, as opposed to a 100 % rate in the case of chemonaive CT-26 cells. In mice inoculated with chemonaive CT-26 cells, tumor formation was not prevented by imatinib. However, imatinib prevented tumor formation in 50 % of mice inoculated with CT-26 cells pre-exposed to DOX in vitro, with the remaining 50 % mice showing delayed tumor formation. These results suggest that the sequential use of the drug imatinib, as a drug targeting cancer cells expressing stem cell features after conventional cytoreductive treatment, is a promising future strategy for preventing tumor recurrence. PMID- 26956645 TI - Mitochondria single nucleotide variation across six blood cell types. AB - It has been shown that heteroplasmic mitochondrial DNA variants can be tissue specific. However, whether mitochondrial DNA variants are specific by blood cell types has not been investigated. Motivated by this question and using mitochondria sequences extracted from RNAseq data from six distinct blood cell types (neutrophil, monocyte, myeloid dendritic, natural killer, T and B), we thoroughly compared SNPs and heteroplasmies among these cell types. Each cell type from each subject was sequenced at four time points used as biological replicates. We found that mitochondria content is low in neutrophil compared to the other five blood cell types. Subsequent analysis on the other five blood cell types showed that at the SNP level, there was no discrepancy. At the heteroplasmy level, we observed good concordances among all blood cell types. However, the allele frequencies of the heteroplasmy differed between blood cell types for certain heteroplasmic sites. Furthermore, we identified five tri-allelic sites (1610, 2617, 8303, 12146, 13710) that are likely caused by RNA editing. Three out of these five sites are located at the ninth position of tRNA genes, and are likely resulting from post-transcriptional methylation. PMID- 26956646 TI - Reversible Stochastically Gated Diffusion-Influenced Reactions. AB - An approximate but accurate theory is developed for the kinetics of reversible binding of a ligand to a macromolecule when either can stochastically fluctuate between reactive and unreactive conformations. The theory is based on a set of reaction-diffusion equations for the deviations of the pair distributions from their bulk values. The concentrations are shown to satisfy non-Markovian rate equations with memory kernels that are obtained by solving an irreversible geminate (i.e., two-particle) problem. The relaxation to equilibrium is not exponential but rather a power law. In the Markovian limit, the theory reduces to a set of ordinary rate equations with renormalized rate constants. PMID- 26956647 TI - E-selectin-targeting delivery of microRNAs by microparticles ameliorates endothelial inflammation and atherosclerosis. AB - E-selectin is a surface marker of endothelial cell (EC) inflammation, one of the hallmarks of atherogenesis. Thus, we tested the hypothesis that delivery of microRNA (miR)-146a and miR-181b with an E-selectin-targeting multistage vector (ESTA-MSV) to inflamed endothelium covering atherosclerotic plaques inhibits atherosclerosis. Cy5-conjugated miR-146a and miR-181b were packaged in polyethylene glycol-polyethyleneimine (PEG/PEI) nanoparticles and loaded into ESTA-MSV microparticles. Both miRs were downregulated in tumor necrosis factor (TNF)-alpha-treated ECs. Transfection of TNF-alpha-treated mouse aortas and cultured ECs with miRs was more efficient with ESTA-MSV than with the PEG/PEI. Likewise, miR-146a/-181b packaged in ESTA-MSV efficiently suppressed the chemokines, CCL2, CCL5, CCL8, and CXCL9, and monocyte adhesion to ECs. Complementary in vivo tests were conducted in male apolipoprotein E-deficient mice fed a Western diet and injected intravenously with the particles prepared as above biweekly for 12 weeks. Treatment with miRs packaged in ESTA-MSV but not in PEG/PEI reduced atherosclerotic plaque size. Concurrently, vascular inflammation markers, including macrophages in aortic root lesions and chemokine expression in aortic tissues were reduced while the vascular smooth muscle cells and collagen increased in plaques from ESTA-MSV/miRs-treated vs. vehicle-treated mice. Our data supported our hypothesis that ESTA-MSV microparticle-mediated delivery of miR-146a/-181b ameliorates endothelial inflammation and atherosclerosis. PMID- 26956648 TI - Emotion Regulation and Perceptions of Hostile and Constructive Criticism in Romantic Relationships. AB - Perceptions of hostile criticism (PHC) from close others are associated with poor individual functioning and low relationship satisfaction, whereas perceptions of constructive criticism (PCC) are associated with better relationship satisfaction. There is little empirical knowledge, however, regarding individual factors that contribute to such perceptions. The present study examined associations of overall emotion regulation difficulties, as well as the specific use of expressive suppression and cognitive reappraisal, with PHC and PCC. Both partners of 63 community couples completed global self-report measures. Sixty-one couples also completed similar measures immediately following each of three discussions during a laboratory session. Multilevel modeling analyses of global data indicated that individuals' reports of PHC were higher when they used more suppression and when both they and their partners reported greater difficulty in emotion regulation. Results with discussion-specific data were similar: Participants reported higher PHC in discussions when both they and their partners reported using more suppression or when they had more difficulties in emotion regulation during the discussions. Individuals reported higher levels of PCC when their partners reported using less suppression, both globally and in discussions. Finally, participants also reported higher levels of PCC in discussions when they reported using more reappraisal. PMID- 26956649 TI - Predicting Response to Therapist-Assisted Internet-Delivered Cognitive Behavior Therapy for Depression or Anxiety Within an Open Dissemination Trial. AB - Therapist-assisted Internet-delivered cognitive behavior therapy (ICBT) is efficacious for treating anxiety and depression, but predictors of response to treatment when delivered in clinical practice are not well understood. In this study, we explored demographic, clinical, and program variables that predicted modules started and symptom improvement (i.e., Generalized Anxiety Disorder-7 or Patient Health Questionnaire-9 total scores over pre-, mid-, and posttreatment) within a previously published open dissemination trial (Hadjistavropoulos et al., 2014). The sample consisted of 195 patients offered 12 modules of therapist assisted ICBT for depression or generalized anxiety; ICBT was delivered by therapists working in six geographically dispersed clinics. Consistent across ICBT for depression or generalized anxiety, starting fewer modules was associated with more phone calls from therapists reflecting that therapists tended to call patients who did not start modules as scheduled. Also consistent for both ICBT programs, greater pretreatment condition severity and completion of more modules was associated with superior ICBT-derived benefit. Other predictors of response to treatment varied across the two programs. Younger age, lower education, taking psychotropic medication, being in receipt of psychiatric care and lower comfort with written communication were associated with either fewer program starts or lower symptom improvement in one of the two programs. It is concluded that monitoring response to ICBT may be particularly important in patients with these characteristics. Research directions for identifying patients who are less likely to benefit from ICBT are discussed. PMID- 26956650 TI - Stepped Care Versus Direct Face-to-Face Cognitive Behavior Therapy for Social Anxiety Disorder and Panic Disorder: A Randomized Effectiveness Trial. AB - The aim of this study was to assess the effectiveness of a cognitive behavioral therapy (CBT) stepped care model (psychoeducation, guided Internet treatment, and face-to-face CBT) compared with direct face-to-face (FtF) CBT. Patients with panic disorder or social anxiety disorder were randomized to either stepped care (n=85) or direct FtF CBT (n=88). Recovery was defined as meeting two of the following three criteria: loss of diagnosis, below cut-off for self-reported symptoms, and functional improvement. No significant differences in intention-to treat recovery rates were identified between stepped care (40.0%) and direct FtF CBT (43.2%). The majority of the patients who recovered in the stepped care did so at the less therapist-demanding steps (26/34, 76.5%). Moderate to large within groups effect sizes were identified at posttreatment and 1-year follow-up. The attrition rates were high: 41.2% in the stepped care condition and 27.3% in the direct FtF CBT condition. These findings indicate that the outcome of a stepped care model for anxiety disorders is comparable to that of direct FtF CBT. The rates of improvement at the two less therapist-demanding steps indicate that stepped care models might be useful for increasing patients' access to evidence based psychological treatments for anxiety disorders. However, attrition in the stepped care condition was high, and research regarding the factors that can improve adherence should be prioritized. PMID- 26956651 TI - Direct and Indirect Effects of Behavioral Parent Training on Infant Language Production. AB - Given the strong association between early behavior problems and language impairment, we examined the effect of a brief home-based adaptation of Parent child Interaction Therapy on infant language production. Sixty infants (55% male; mean age 13.47+/-1.31 months) were recruited at a large urban primary care clinic and were included if their scores exceeded the 75th percentile on a brief screener of early behavior problems. Families were randomly assigned to receive the home-based parenting intervention or standard pediatric primary care. The observed number of infant total (i.e., token) and different (i.e., type) utterances spoken during an observation of an infant-led play and a parent-report measure of infant externalizing behavior problems were examined at pre- and post intervention and at 3- and 6-month follow-ups. Infants receiving the intervention demonstrated a significantly higher number of observed different and total utterances at the 6-month follow-up compared to infants in standard care. Furthermore, there was an indirect effect of the intervention on infant language production, such that the intervention led to decreases in infant externalizing behavior problems from pre- to post-intervention, which, in turn, led to increases in infant different utterances at the 3- and 6-month follow-ups and total utterances at the 6-month follow-up. Results provide initial evidence for the effect of this brief and home-based intervention on infant language production, including the indirect effect of the intervention on infant language through improvements in infant behavior, highlighting the importance of targeting behavior problems in early intervention. PMID- 26956654 TI - Mindfulness-Based Exposure Strategies as a Transdiagnostic Mechanism of Change: An Exploratory Alternating Treatment Design. AB - The present study explored whether distress reduction in response to strong negative emotions, a putative transdiagnostic mechanism of action, is facilitated by mindfulness strategies. Seven patients (mean age=31.14years, SD=12.28, range 19-48 years, 43% female, 86% Caucasian) with heterogeneous anxiety disorders (i.e., panic disorder with or without agoraphobia, social anxiety, generalized anxiety) were assigned a randomized order of weeklong blocks utilizing either mindfulness- or avoidance-based strategies while ascending a 6-week emotion exposure hierarchy. Participants completed three exposures per block and provided distress and avoidance use ratings following each exposure. Anxiety severity, distress aversion, and distraction/suppression tendencies were also assessed at baseline and the conclusion of each block. Visual, descriptive, and effect size results showing exposures utilizing mindfulness were associated with higher overall distress levels, compared with those utilizing avoidance. Within blocks, the majority of participants exhibited declining distress levels when employing mindfulness strategies, as opposed to more static distress levels in the avoidance condition. Systematic changes in anxiety severity, distress aversion, and distraction/suppression were not observed. These results suggest mindfulness strategies may be effective in facilitating emotion exposure; however, a minimum dosage may be necessary to overcome initial distress elevation. Potential transdiagnostic change mechanisms and clinical implications are discussed. PMID- 26956652 TI - Feasibility of Pairing Behavioral Activation With Exercise for Women With Type 2 Diabetes and Depression: The Get It Study Pilot Randomized Controlled Trial. AB - Major depressive disorder is often comorbid with diabetes and associated with worse glycemic control. Exercise improves glycemic control and depression, and thus could be a parsimonious intervention for patients with comorbid diabetes and major depression. Because patients with diabetes and comorbid depression are often sedentary and lack motivation to exercise, we developed a group exercise intervention that integrates strategies from behavioral activation therapy for depression to increase motivation for and enjoyment of exercise. We conducted a 6 month pilot randomized controlled trial to test the feasibility of the behavioral activation exercise intervention (EX) for women with diabetes and depression. Of the 715 individuals who contacted us about the study, 29 participants were randomized to the EX condition or an enhanced usual care condition (EUC), which represents 4.1% of participants who initially contacted us. Inclusion criteria made recruitment challenging and limits the feasibility of recruiting women with diabetes and depression for a larger trial of the intervention. Retention was 96.5% and 86.2% at 3 and 6months. Participants reported high treatment acceptability; use of behavioral activation strategies and exercise class attendance was acceptable. No condition differences were observed for glycemic control, depressive symptoms, and physical activity, though depressive symptoms and self-reported physical activity improved over time. Compared to participants in the EUC condition, participants in the EX condition reported greater exercise enjoyment and no increase in avoidance behavior over time. Using behavioral activation strategies to increase exercise is feasible in a group exercise setting. However, whether these strategies can be delivered in a less intensive manner to a broader population of sedentary adults, for greater initiation and maintenance of physical activity, deserves further study. PMID- 26956653 TI - Cognitive-Behavioral Therapy for Adolescent Body Dysmorphic Disorder: A Pilot Study. AB - Body dysmorphic disorder (BDD) is a relatively common and severe disorder that typically onsets in adolescence, but often goes unrecognized. Despite BDD's severity and early onset, treatment outcome research on adolescent BDD is scarce. Cognitive-behavioral therapy is the gold-standard psychosocial treatment for BDD in adults and has shown promise in adolescents. The current study examined the development and testing of a new CBT for adolescents with BDD. We tested feasibility, acceptability, and treatment outcome in a sample of 13 adolescents (mean age 15.23years, range: 13-17) with primary BDD. Treatment was delivered in 12-22 weekly individual sessions. Standardized clinician ratings and self-report measures were used to assess BDD and related symptoms pre- and posttreatment and at 3- and 6-months follow-up. At posttreatment, BDD and related symptoms (e.g., insight, mood) were significantly improved. Scores on the Yale-Brown Obsessive Compulsive Scale for BDD indicated a 50% (intent-to-treat) and 68% (completer) improvement in BDD symptoms. Seventy-five percent of adolescents who started treatment and 100% of completers were considered treatment responders. Treatment gains were maintained at follow-up. High patient satisfaction ratings and patient feedback indicated that treatment was acceptable. This represents the largest study of a psychosocial treatment for adolescent BDD. PMID- 26956655 TI - Pushed by Symptoms, Pulled by Values: Promotion Goals Increase Motivation in Therapeutic Tasks. AB - While many therapies focus on the reduction of disturbing symptoms, others pursue behavior consistent with personally held values. Based on regulatory focus theory (Higgins, 1997), reducing symptoms is a type of prevention goal while pursuing values is a promotion goal. In the current study, 123 undergraduate students elicited a negative, self-focused emotion-laden cognition. They were then randomly assigned to construe their negative thought as either (a) an impediment to valued behaviors, (b) a cause of unpleasant symptoms, or to one of two control conditions: (c) distraction or (d) no intervention. Then, participants in all groups completed a series of repetitive therapeutic tasks that targeted their elicited negative cognitions. Results showed that participants who construed treatment in terms of valued behavior promotion spent more time on a therapeutic task than all other groups. The group in the unpleasant symptom promotion condition did not differ from either control group. The motivational advantage of value promotion was not accounted for by differences in mood. The present findings suggest that clients may be better motivated through value promotion goals, as opposed to symptom prevention goals. PMID- 26956656 TI - Imagery Rescripting for Body Dysmorphic Disorder: A Multiple-Baseline Single-Case Experimental Design. AB - Individuals with body dysmorphic disorder (BDD) often experience negative distorted images of their appearance, and research suggests these may be linked to memories of adverse events such as bullying or teasing. This study evaluates imagery rescripting (ImR) as an intervention for BDD. In this article, we present a multiple-baseline single-case experimental design testing imagery rescripting as a brief, stand-alone intervention, with six individuals with BDD that related to aversive memories. The impact of the intervention was assessed by self reported daily measures of symptom severity (preoccupation with appearance, appearance-related checking behaviors, appearance-related distress, and strength of belief that their main problem is their appearance) and standardized clinician ratings of BDD severity (Yale-Brown Obsessive Compulsive Scale modified for BDD). Four out of six of the participants responded positively to the intervention, with clinically meaningful improvement in symptomatology. Overall response was rapid; improvements began within the first week post-ImR intervention. From a small sample it is cautiously concluded that imagery rescripting may show promise as a module in cognitive-behavioral therapy for BDD, and is worthy of further investigation. PMID- 26956657 TI - Examining the Link Between Hoarding Symptoms and Cognitive Flexibility Deficits. AB - Executive functioning deficits have been found to underlie primary symptoms of hoarding, such as difficulty discarding belongings and significant clutter. Cognitive flexibility-the ability to inhibit irrelevant material and attend flexibly between different mental sets-may be impaired as well, as individuals experience difficulty staying on task and are often distracted by specific possessions that tend to evoke an exaggerated emotional response. The present study investigated cognitive flexibility deficits via eye-tracking technology as a novel approach. Participants (N=69) with high and low self-reported hoarding symptoms were asked to respond to a series of auditory cues requiring them to categorize a small target number superimposed on one of three distractor image types: hoarding, nature, or a blank control. Across a range of behavioral and eye tracking outcomes (including reaction time, accuracy rate, initial orientation to distractors, and viewing time for distractors), high hoarding participants consistently demonstrated greater cognitive inflexibility compared to the low hoarding group. However, high hoarding participants did not evidence context dependent deficits based on preceding distractor types, as performance did not significantly differ as a function of hoarding versus nature distractors. Current findings indicate a pervasive, more global deficit in cognitive flexibility. Those with hoarding may encounter greater difficulty disengaging from previous stimuli and attending to a given task at hand, regardless of whether the context of the distractor is specifically related to hoarding. Implications and future directions for clarifying the nature of cognitive inflexibility are discussed. PMID- 26956658 TI - Electrocortical Evidence of Enhanced Performance Monitoring in Social Anxiety. AB - Self-focused attention is thought to be a key feature of social anxiety disorder. Yet few studies have used event-related potentials (ERPs) to examine whether socially anxious individuals display greater monitoring of their performance and attention to their errors. Similarly, only a few studies have used ERPs to examine how social anxiety is related to processing of performance feedback. Individuals with high (n=26) and low (n=28) levels of social anxiety completed a trial-and-error learning task. Self-focus was manipulated using false heart-rate feedback during a random subset of trials. Performance feedback was given using emotional and neutral faces in a positive context (correct=happy face; incorrect=neutral face) and negative context (correct=neutral face; incorrect=disgust face) in order to investigate biased interpretation and attention to feedback. Socially anxious subjects displayed enhanced amplitude of the ERN and CRN, suggesting greater response monitoring, and enhanced Pe amplitude, suggesting greater processing of errors relative to the low social anxiety group. No group differences were observed with respect to feedback processing. Before learning stimulus-response mappings in the negative context, the FRN was larger for self-focus compared to standard trials and marginally larger for socially anxious subjects compared to controls. These findings support cognitive models and suggest avenues for future research. PMID- 26956659 TI - FAM21 directs SNX27-retromer cargoes to the plasma membrane by preventing transport to the Golgi apparatus. AB - The endosomal network maintains cellular homeostasis by sorting, recycling and degrading endocytosed cargoes. Retromer organizes the endosomal sorting pathway in conjunction with various sorting nexin (SNX) proteins. The SNX27-retromer complex has recently been identified as a major endosomal hub that regulates endosome-to-plasma membrane recycling by preventing lysosomal entry of cargoes. Here, we show that SNX27 directly interacts with FAM21, which also binds retromer, within the Wiskott-Aldrich syndrome protein and SCAR homologue (WASH) complex. This interaction is required for the precise localization of SNX27 at an endosomal subdomain as well as for recycling of SNX27-retromer cargoes. Furthermore, FAM21 prevents cargo transport to the Golgi apparatus by controlling levels of phosphatidylinositol 4-phosphate, which facilitates cargo dissociation at the Golgi. Together, our results demonstrate that the SNX27-retromer-WASH complex directs cargoes to the plasma membrane by blocking their transport to lysosomes and the Golgi. PMID- 26956661 TI - Cytologic separation of branchial cleft cyst from metastatic cystic squamous cell carcinoma: A multivariate analysis of nineteen cytomorphologic features. AB - BACKGROUND: The separation of branchial cleft cysts from metastatic cystic squamous cell carcinomas in adults can be clinically and cytologically challenging. Diagnostic accuracy for separation is reported to be as low as 75% prompting some authors to recommend frozen section evaluation of suspected branchial cleft cysts before resection. We evaluated 19 cytologic features to determine which were useful in this distinction. METHODS: Thirty-three cases (21 squamous carcinoma and 12 branchial cysts) of histologically confirmed cystic lesions of the lateral neck were graded for the presence or absence of 19 cytologic features by two cytopathologists. The cytologic features were analyzed for agreement between observers and underwent multivariate analysis for correlation with the diagnosis of carcinoma. RESULTS: Interobserver agreement was greatest for increased nuclear/cytoplasmic (N/C) ratio, pyknotic nuclei, and irregular nuclear membranes. Recursive partitioning analysis showed increased N/C ratio, small clusters of cells, and irregular nuclear membranes were the best discriminators. CONCLUSION: The distinction of branchial cleft cysts from cystic squamous cell carcinoma is cytologically difficult. Both digital image analysis and p16 testing have been suggested as aids in this separation, but analysis of cytologic features remains the main method for diagnosis. In an analysis of 19 cytologic features, we found that high nuclear cytoplasmic ratio, irregular nuclear membranes, and small cell clusters were most helpful in their distinction. Diagn. Cytopathol. 2016;44:561-567. (c) 2016 Wiley Periodicals, Inc. PMID- 26956660 TI - Response of Human Osteoblast to n-HA/PEEK--Quantitative Proteomic Study of Bio effects of Nano-Hydroxyapatite Composite. AB - Nano-sized hydroxyapatite (n-HA) is considered as a bio-active material, which is often mixed into bone implant material, polyetheretherketone (PEEK). To reveal the global protein expression modulations of osteoblast in response to direct contact with the PEEK composite containing high level (40%) nano-sized hydroxyapatite (n-HA/PEEK) and explain its comprehensive bio-effects, quantitative proteomic analysis was conducted on human osteoblast-like cells MG 63 cultured on n-HA/PEEK in comparison with pure PEEK. Results from quantitative proteomic analysis showed that the most enriched categories in the up-regulated proteins were related to calcium ion processes and associated functions while the most enriched categories in the down-regulated proteins were related to RNA process. This enhanced our understanding to the molecular mechanism of the promotion of the cell adhesion and differentiation with the inhibition of the cell proliferation on n-HA/PEEK composite. It also exhibited that although the calcium ion level of incubate environment hadn't increased, merely the calcium fixed on the surface of material had influence to intracellular calcium related processes, which was also reflect by the higher intracellular Ca(2+) concentration of n-HA/PEEK. This study could lead to more comprehensive cognition to the versatile biocompatibility of composite materials. It further proves that proteomics is useful in new bio-effect discovery. PMID- 26956662 TI - Characterization of feline cytochrome P450 2B6. AB - 1. Little is known about drug metabolism in carnivores. Although the domestic cat (Felis catus) is an obligate carnivore and is the most common companion animal, usage and dosage of many drugs are determined according to information obtained from humans and dogs. We determined the complete cDNA sequence of CYP2B6 from the feline lung. 2. Feline CYP2B6 consists of 494 deduced amino acids, showing highest identity with the dog CYP2B ortholog, followed by those of horse, pig, primate and human. 3. Feline CYP2B6 transcripts were expressed predominantly in the lung and slightly in the small intestine but not in the liver without significant sex-dependent differences. Western blot analysis with an anti-human CYP2B6 antibody confirmed the presence of CYP2B protein in the lung but not in the liver. 4. Feline CYP2B6 proteins heterologously expressed in Escherichia coli metabolized several substrates specific to human CYP2B6, including 7-ethoxy-4 (trifluoromethyl) coumarin (EFC). The metabolic activity was strongly inhibited by medetomidine and atipamezole, potent inhibitors of canine CYP2B11 (now officially CYP2B6) as well as by ticlopidine and sertraline, inhibitors selective to human CYP2B6. 5. The results suggest that feline CYP2B6 is a functional CYP2B ortholog that plays a role in the local defense mechanism in the cat respiratory system and intestine. PMID- 26956663 TI - Potential clinical implication of (18) F-FDG PET/CT in diagnosis of periprosthetic infection and its comparison with (18) F-Fluoride PET/CT. AB - INTRODUCTION: The differentiation between septic and aseptic loosening of prosthetic hip joint is a major challenge for the clinician. This study assessed and compared the diagnostic accuracy of (18) F- flouro-deoxyglucose positron emission tomography/computed tomography ((18) F-FDG PET/CT) with (18) F-fluoride PET/CT for diagnosis of infection in the painful hip prosthesis. METHODS: In this prospective study, we included the patients with painful hip prostheses with radiological or clinical suspicion of loosening, those who had given the written consent and scheduled for clinical and diagnostic evaluation before revision arthroplasty. To rule out the nature of loosening (septic vs. aseptic), all the patients underwent (18) F-Fluoride PET/CT and (18) F-FDG PET/CT. The reference standard for periprosthetic infection was based on histopathology and/or microbial culture and/or intraoperative findings. RESULTS: We prospectively evaluated 42 patients of hip prostheses before revision arthroplasty. Visual and semi-quantitative analysis of both the positron emission tomography (PET) images was done and the results were compared with a reference standard. The sensitivity, specificity, positive predictive value (PPV), negative predictive values (NPV) and accuracy of (18) F-FDG PET/CT were 93.7%, 92.3%, 88.2%, 96% and 92.8% respectively. The sensitivity, specificity, PPV, NPV and accuracy of (18) F fluoride PET/CT were 75%, 96.1%, 92.3%, 86% and 88.1% respectively. FDG PET/CT has higher sensitivity, NPV and accuracy as compared to compared to Fluoride PET/CT and comparable specificity and PPV. CONCLUSIONS: Fluoride PET/CT had shown slightly higher specificity than FDG-PET/CT, but the overall diagnostic performance of FDG-PET/CT in periprosthetic infection is optimal in routine clinical practice and better than fluoride PET/CT. PMID- 26956664 TI - A new sesquiterpenoid from Saussurea lappa roots. AB - A new sesquiterpenoid, 10alpha-methoxyartemisinic acid (1) was isolated from Saussurea lappa roots along with two known compounds, costunolide (2) and dehydrocostus lactone (3) by high-speed countercurrent chromatography with purities of 85, 95 and 98%, respectively. Their structures were determined on the basis of spectral data including 1D and 2D NMR and HREIMS. PMID- 26956665 TI - Banana MaMADS Transcription Factors Are Necessary for Fruit Ripening and Molecular Tools to Promote Shelf-Life and Food Security. AB - Genetic solutions to postharvest crop loss can reduce cost and energy inputs while increasing food security, especially for banana (Musa acuminata), which is a significant component of worldwide food commerce. We have functionally characterized two banana E class (SEPALLATA3 [SEP3]) MADS box genes, MaMADS1 and MaMADS2, homologous to the tomato (Solanum lycopersicum) RIN-MADS ripening gene. Transgenic banana plants repressing either gene (via antisense or RNA interference [RNAi]) were created and exhibited specific ripening delay and extended shelf-life phenotypes, including delayed color development and softening. The delay in fruit ripening is associated with a delay in climacteric respiration and reduced synthesis of the ripening hormone ethylene; in the most severe repressed lines, no ethylene was produced and ripening was most delayed. Unlike tomato rin mutants, banana fruits of all transgenic repression lines responded to exogenous ethylene by ripening normally, likely due to incomplete transgene repression and/or compensation by other MADS box genes. Our results show that, although MADS box ripening gene necessity is conserved across diverse taxa (monocots to dicots), unlike tomato, banana ripening requires at least two necessary members of the SEPALLATA MADS box gene group, and either can serve as a target for ripening control. The utility of such genes as tools for ripening control is especially relevant in important parthenocarpic crops such as the vegetatively propagated and widely consumed Cavendish banana, where breeding options for trait improvement are severely limited. PMID- 26956668 TI - The growth mechanism and ferroelectric domains of diisopropylammonium bromide films synthesized via 12-crown-4 addition at room temperature. AB - Diisopropylammonium bromide (DIPAB) has attracted great attention as a molecular ferroelectric with large spontaneous polarization and high Curie temperature. It is hard to grow the ferroelectric phase DIPAB because of the appearance of the non-ferroelectric phase DIPAB at room temperature. Here, a ferroelectric thin film of DIPAB was successfully fabricated on a Si substrate using a spin coating method from aqueous solution via 12-crown-4 addition at room temperature. The ferroelectric DIPAB film with a thickness of hundreds of nanometers is distributed discontinuously on the substrate in narrow strips. The direction of polarization is along the narrow strip. Piezoresponse force microscopy (PFM) shows that the ferroelectric films have two kinds of domain structures: noncharged antiparallel stripe domains and charged head-to-head (H-H)/tail-to tail (T-T) type domains. 12-crown-4 has been proved to play important roles in forming the H-H/T-T type domains. The Chynoweth method shows that the DIPAB films synthesized in this way show a better pyroelectric effect than DIPAB crystals. PMID- 26956667 TI - Light Modulates the Biosynthesis and Organization of Cyanobacterial Carbon Fixation Machinery through Photosynthetic Electron Flow. AB - Cyanobacteria have evolved effective adaptive mechanisms to improve photosynthesis and CO2 fixation. The central CO2-fixing machinery is the carboxysome, which is composed of an icosahedral proteinaceous shell encapsulating the key carbon fixation enzyme, Rubisco, in the interior. Controlled biosynthesis and ordered organization of carboxysomes are vital to the CO2-fixing activity of cyanobacterial cells. However, little is known about how carboxysome biosynthesis and spatial positioning are physiologically regulated to adjust to dynamic changes in the environment. Here, we used fluorescence tagging and live-cell confocal fluorescence imaging to explore the biosynthesis and subcellular localization of beta-carboxysomes within a model cyanobacterium, Synechococcus elongatus PCC7942, in response to light variation. We demonstrated that beta-carboxysome biosynthesis is accelerated in response to increasing light intensity, thereby enhancing the carbon fixation activity of the cell. Inhibition of photosynthetic electron flow impairs the accumulation of carboxysomes, indicating a close coordination between beta-carboxysome biogenesis and photosynthetic electron transport. Likewise, the spatial organization of carboxysomes in the cell correlates with the redox state of photosynthetic electron transport chain. This study provides essential knowledge for us to modulate the beta-carboxysome biosynthesis and function in cyanobacteria. In translational terms, the knowledge is instrumental for design and synthetic engineering of functional carboxysomes into higher plants to improve photosynthesis performance and CO2 fixation. PMID- 26956666 TI - The Pseudomonas fluorescens Siderophore Pyoverdine Weakens Arabidopsis thaliana Defense in Favor of Growth in Iron-Deficient Conditions. AB - Pyoverdines are siderophores synthesized by fluorescent Pseudomonas spp. Under iron-limiting conditions, these high-affinity ferric iron chelators are excreted by bacteria in the soil to acquire iron. Pyoverdines produced by beneficial Pseudomonas spp. ameliorate plant growth. Here, we investigate the physiological incidence and mode of action of pyoverdine from Pseudomonas fluorescens C7R12 on Arabidopsis (Arabidopsis thaliana) plants grown under iron-sufficient or iron deficient conditions. Pyoverdine was provided to the medium in its iron-free structure (apo-pyoverdine), thus mimicking a situation in which it is produced by bacteria. Remarkably, apo-pyoverdine abolished the iron-deficiency phenotype and restored the growth of plants maintained in the iron-deprived medium. In contrast to a P. fluorescens C7R12 strain impaired in apo-pyoverdine production, the wild type C7R12 reduced the accumulation of anthocyanins in plants grown in iron deficient conditions. Under this condition, apo-pyoverdine modulated the expression of around 2,000 genes. Notably, apo-pyoverdine positively regulated the expression of genes related to development and iron acquisition/redistribution while it repressed the expression of defense-related genes. Accordingly, the growth-promoting effect of apo-pyoverdine in plants grown under iron-deficient conditions was impaired in iron-regulated transporter1 and ferric chelate reductase2 knockout mutants and was prioritized over immunity, as highlighted by an increased susceptibility to Botrytis cinerea This process was accompanied by an overexpression of the transcription factor HBI1, a key node for the cross talk between growth and immunity. This study reveals an unprecedented mode of action of pyoverdine in Arabidopsis and demonstrates that its incidence on physiological traits depends on the plant iron status. PMID- 26956670 TI - Skin involvement as the first manifestation of breast implant-associated anaplastic large cell lymphoma. AB - Breast implant-associated anaplastic large cell lymphoma (ALCL) is a newly described clinical and pathologic entity that typically presents as seroma in the fibrous scar around the implant. Less frequently, it presents as a solid peri implant mass, and there have been no reports to date of cutaneous lesions as the presenting manifestation. We report the case of a 56-year-old woman with a history of bilateral breast reconstruction following breast cancer of the right breast who consulted with several papules on the right breast suggestive of metastasis. Histopathology showed a proliferation of large epithelioid lymphocytes with highly pleomorphic cells and nuclei. The neoplastic cells were CD15 and CD30 positive and ALK-1 negative. The epithelial markers were all negative except for epithelial membrane antigen (EMA), which was weakly positive. Molecular analysis showed monoclonal T-cell receptor gamma gene rearrangement, confirming a diagnosis of breast implant-associated ALCL. The non-specific morphology of the skin lesions, the epithelioid nature of the neoplastic cells and the expression of EMA can lead to an erroneous diagnosis of skin metastases from a poorly differentiated adenocarcinoma of the breast. We recommend immunohistochemical staining for CD30 and ALK-1 for patients with breast implants who develop anaplastic lesions. PMID- 26956671 TI - Iodosylbenzene and iodylbenzene adducts of cerium(IV) complexes bearing chelating oxygen ligands. AB - Reactions of [Ce(IV)(LOEt)2Cl2] (LOEt(-) = [Co(eta(5)-C5H5){P(O)(OEt)2}3](-)) and [Ce(MU-O){N(Pr(i)2PO)2}4Cl2] with PhIO afford the lambda3-iodane complexes [Ce(IV)(LOEt)2{OI(Cl)Ph}2] and [Ce{N(Pr(i)2PO)2}3{OI(Cl)Ph}], respectively, whereas that between [Ce(IV)(LOEt)2Cl2] and PhIO2 or excess PhIO yields the lambda5-iodane adduct [Ce(IV)(LOEt)2{OI(O)ClPh}2]. The crystal structures of the Ce(IV)lambda3- and lambda5-iodane complexes have been determined and their oxo transfer reactivities have been investigated. PMID- 26956669 TI - CRM1 Inhibition Promotes Cytotoxicity in Ewing Sarcoma Cells by Repressing EWS FLI1-Dependent IGF-1 Signaling. AB - Ewing sarcoma (EWS) is an aggressive bone malignancy that mainly affects children and young adults. The mechanisms by which EWS (EWSR1) fusion genes drive the disease are not fully understood. CRM1 (XPO1) traffics proteins from the nucleus, including tumor suppressors and growth factors, and is overexpressed in many cancers. A small-molecule inhibitor of CRM1, KPT-330, has shown therapeutic promise, but has yet to be investigated in the context of EWS. In this study, we demonstrate that CRM1 is also highly expressed in EWS. shRNA-mediated or pharmacologic inhibition of CRM1 in EWS cells dramatically decreased cell growth while inducing apoptosis, cell-cycle arrest, and protein expression alterations to several cancer-related factors. Interestingly, silencing of CRM1 markedly reduced EWS-FLI1 fusion protein expression at the posttranscriptional level and upregulated the expression of the well-established EWS-FLI1 target gene, insulin like growth factor binding protein 3 (IGFBP3), which inhibits IGF-1. Accordingly, KPT-330 treatment attenuated IGF-1-induced activation of the IGF-1R/AKT pathway. Furthermore, knockdown of IGFBP3 increased cell growth and rescued the inhibitory effects on IGF-1 signaling triggered by CRM1 inhibition. Finally, treatment of EWS cells with a combination of KPT-330 and the IGF-1R inhibitor, linsitinib, synergistically decreased cell proliferation both in vitro and in vivo Taken together, these findings provide a strong rationale for investigating the efficacy of combinatorial inhibition of CRM1 and IGF-1R for the treatment of EWS. Cancer Res; 76(9); 2687-97. (c)2016 AACR. PMID- 26956672 TI - Sickle Cell Crisis Complicated by Synthetic Cannabinoid Abuse: A Case Report. AB - We describe a case of delirium occurring in a hospitalized sickle cell patient. Following admission for a typical pain crisis, the patient continued to report unrelieved pain with marked agitation for several days, despite escalating doses of opioid analgesia, and ultimately required intubation following development of acute chest syndrome (ACS). After some delay, it was discovered that he had been using a synthetic cannabinoid (K2) which may have precipitated his pain crisis and, with hindsight, explained his prolonged period of delirium. Delayed recognition was due to multiple factors, notably the absence of an index of suspicion for this novel drug, the presence of alternate explanations for the patient's altered mental status, and the fact that reliable laboratory screening for synthetic cannabinoids is currently not widely available. PMID- 26956673 TI - CoeViz: a web-based tool for coevolution analysis of protein residues. AB - BACKGROUND: Proteins generally perform their function in a folded state. Residues forming an active site, whether it is a catalytic center or interaction interface, are frequently distant in a protein sequence. Hence, traditional sequence-based prediction methods focusing on a single residue (or a short window of residues) at a time may have difficulties in identifying and clustering the residues constituting a functional site, especially when a protein has multiple functions. Evolutionary information encoded in multiple sequence alignments is known to greatly improve sequence-based predictions. Identification of coevolving residues further advances the protein structure and function annotation by revealing cooperative pairs and higher order groupings of residues. RESULTS: We present a new web-based tool (CoeViz) that provides a versatile analysis and visualization of pairwise coevolution of amino acid residues. The tool computes three covariance metrics: mutual information, chi-square statistic, Pearson correlation, and one conservation metric: joint Shannon entropy. Implemented adjustments of covariance scores include phylogeny correction, corrections for sequence dissimilarity and alignment gaps, and the average product correction. Visualization of residue relationships is enhanced by hierarchical cluster trees, heat maps, circular diagrams, and the residue highlighting in protein sequence and 3D structure. Unlike other existing tools, CoeViz is not limited to analyzing conserved domains or protein families and can process long, unstructured and multi-domain proteins thousands of residues long. Two examples are provided to illustrate the use of the tool for identification of residues (1) involved in enzymatic function, (2) forming short linear functional motifs, and (3) constituting a structural domain. CONCLUSIONS: CoeViz represents a practical resource for a quick sequence-based protein annotation for molecular biologists, e.g., for identifying putative functional clusters of residues and structural domains. CoeViz also can serve computational biologists as a resource of coevolution matrices, e.g., for developing machine learning-based prediction models. The presented tool is integrated in the POLYVIEW-2D server (http://polyview.cchmc.org/) and available from resulting pages of POLYVIEW-2D. PMID- 26956675 TI - Radiation-related risks of non-cancer outcomes in the atomic bomb survivors. AB - Risks of non-cancer outcomes after exposure to atomic bomb (A-bomb) radiation have been evaluated among the Life Span Study (LSS) cohort and its subcohort, the Adult Health Study (AHS). Information regarding non-cancer outcomes in the LSS is obtained from death certificates. In the AHS, members undergo clinical examinations biennially to determine their health status. Many AHS studies have been limited to participants attending the clinic over a limited period, and therefore have varying degrees of inferential utility; as such, care is required for comparison with the LSS results. Disease structure of non-cancer diseases in Japan has changed over the long follow-up period since the end of World War II. The health status of the A-bomb survivors may be associated with the hardships of living in a devastated city and impoverished country following the prolonged war effort, in addition to the direct effects of radiation exposure. Radiation related risk of cardiovascular disease may have increased due to radiation related increased risk of hypertension and other secondary associations, and the risk of atherosclerotic disorders has also been reported recently. These results should be interpreted with caution because of changes in disease definitions over the follow-up period. The radiation-related risk of non-cancer respiratory diseases also appears to have increased over the follow-up period, but the shapes of the dose-response curves have shown little consistency. PMID- 26956676 TI - Evidence for variation in human radiosensitivity and its potential impact on radiological protection. AB - Radiological protection standards generally assume that all members of the population are equally sensitive to the adverse health effects associated with radiation exposure, recognising the age- and sex-related differences in sensitivity to radiation-induced cancer. It has become very clear over recent years that genetic and lifestyle factors can play important roles in the susceptibility of individuals to a range of diseases; as such, the same may apply to radiation-associated diseases. Evidence is accumulating from studies at many levels of biological organisation - cells, experimental organisms, and humans - that a range of radiosensitivity exists between individuals in the population. Consideration of improvements in radiological protection practices to take account of such differences will require the availability of robust and accurate ways to assess the sensitivity of an individual or population subgroup. In addition, there will need to be careful consideration of the ethical aspects relating to use of individual sensitivity information. These ethical considerations are very likely to be exposure context dependent, and require careful risk-benefit balance consideration before practical application. PMID- 26956674 TI - The activation of M3 mAChR in airway epithelial cells promotes IL-8 and TGF-beta1 secretion and airway smooth muscle cell migration. AB - BACKGROUND: Muscarinic acetylcholine receptors (mAChRs) have been identified in airway epithelium, and epithelium-derived chemokines can initiate the migration of airway smooth muscle (ASM) cells. However, the mAChRs that are expressed in airway epithelium and the mechanism underlying the regulation of ASM cell migration are not clear. The aim of this study was to test whether the effects of the epithelium-derived chemokines on ASM cell migration could be modulated by mAChRs. METHOD: Human epithelial cells (A549 cells) were stimulated with cigarette smoke extract (CSE) or the mAChRs agonist carbachol. IL-8 and TGF-beta1 production were measured by ELISA, and human ASM cell migration was measured using the transwell migration assay and scratch assay. The mRNA levels of the mAChRs subtypes and the acetylcholine concentrations were measured using RT-PCR and LC-MS/MS, respectively. RESULTS: ASM cell migration toward CSE-stimulated A549 cells was markedly reduced by Ac-RRWWCR-NH2 (IL-8 inhibitor) and SB431542 (TGF-beta1 inhibitor). CSE-induced ASM cell migration was also suppressed by the mAChRs antagonist tiotropium. Interestingly, carbachol-stimulated A549 cells also induced ASM cell migration; this migration event was suppressed by tiotropium, Ac RRWWCR-NH2 and SB431542. In addition, the effects of CSE on ASM cell migration were significantly and cooperatively enhanced by carbachol compared to CSE alone. Carbachol-induced ASM cell migration was reduced by selective inhibitors of PI3K/Akt (LY294002) and p38 (SB203580), suggesting that it occurred through p38 and Akt phosphorylation, which was inhibited by the M3 mAChR antagonist 4-DAMP. CONCLUSIONS: These findings indicate that M3 mAChR may be important therapeutic target for obstructive airway diseases, as it regulates the effects of the epithelial-derived chemokines on ASM cell migration, which results in lung remodeling. PMID- 26956677 TI - ICRP Publication 131: Stem cell biology with respect to carcinogenesis aspects of radiological protection. AB - Current knowledge of stem cell characteristics, maintenance and renewal, evolution with age, location in 'niches', and radiosensitivity to acute and protracted exposures is reviewed regarding haematopoietic tissue, mammary gland, thyroid, digestive tract, lung, skin, and bone. The identity of the target cells for carcinogenesis continues to point to the more primitive and mostly quiescent stem cell population (able to accumulate the protracted sequence of mutations necessary to result in malignancy), and, in a few tissues, to daughter progenitor cells. Several biological processes could contribute to the protection of stem cells from mutation accumulation: (1) accurate DNA repair; (2) rapid induced death of injured stem cells; (3) retention of the intact parental strand during divisions in some tissues so that mutations are passed to the daughter differentiating cells; and (4) stem cell competition, whereby undamaged stem cells outcompete damaged stem cells for residence in the vital niche. DNA repair mainly operates within a few days of irradiation, while stem cell replications and competition require weeks or many months depending on the tissue type. This foundation is used to provide a biological insight to protection issues including the linear-non-threshold and relative risk models, differences in cancer risk between tissues, dose-rate effects, and changes in the risk of radiation carcinogenesis by age at exposure and attained age. PMID- 26956678 TI - Eight decades of ICRP recommendations in medicine: a perspective. AB - Medicine has been intimately associated with ionising radiation since the discovery of x rays in 1895; the first adverse effects of radiation were observed in persons working in research and on medical staff using x rays. Consequently, in 1925, the first International Congress of Radiology considered the need for a protection committee, which was established at its second congress in Stockholm in 1928 and is known today as the International Commission on Radiological Protection (ICRP). The first ICRP recommendations in 1928 were devoted to the protection of medical staff in the use of x rays for diagnosis and radiotherapy, and radium for radiotherapy. Later, ICRP devoted increased attention to the protection of patients, starting in 1970 with Publication 16 on protection of the patient in x-ray diagnosis, followed by three reports on the broad areas of radiation medicine: diagnostic radiology, radiation therapy, and nuclear medicine. A major change was made at the end of the 20(th) Century with the introduction of a series of short reports, focussed on specific problems and addressing specific medical practices. Since then, as many as 20 reports have been published on issues such as prevention of accidental exposure in radiotherapy, avoidance of radiation injuries from interventional procedures, managing radiation dose in digital radiology and computed tomography, protection in paediatric radiology, and many others. PMID- 26956679 TI - Te Ira Tangata: a Zelen randomised controlled trial of a culturally informed treatment compared to treatment as usual in Maori who present to hospital after self-harm. AB - PURPOSE: Indigenous people have high rates of suicide and self-harm compared to other population groups. AIM: The aim of this trial was to see if a package of interventions delivered in a culturally appropriate way improved outcomes at one year in Maori who presented with intentional self-harm to emergency departments. METHODS: Participants were Maori who presented with intentional self-harm to emergency departments in New Zealand. The study design was a double consent Zelen randomised controlled trial. The intervention included regular postcards, problem solving therapy, patient support, risk management, improved access to primary care and cultural assessment in addition to usual care. The control group received usual care. The main outcome measure was the self-rated change in scores on the Beck Hopelessness Scale at one year. RESULTS: 182 people were randomized to the intervention group 95 of whom consented to take part in the study. 183 people were randomized to the control group 72 of whom consented to take part in the study. For those who consented comparing the intervention group with the control group there was a statistically significant greater change in hopelessness scores at 3 months (difference -1.7 95 % CI -3.4 to -0.01, p = 0.05) but not at one year (difference -1.6 95 % CI -3.4 to 0.3, p = 0.11). Maori who consented and received the intervention were also significantly less likely to present to hospital for non-self-harm reasons in the year after the index episode (44.2 vs. 61.1 %, p = 0.03). Those participants randomised to the intervention were less likely to re-present with self-harm at 3 months (10.4 vs. 18 %, p = 0.04) but not at 12 months compared to the control group. CONCLUSIONS: In Maori who presented to hospital with intentional self-harm a culturally informed intervention had an effect on hopelessness and re-presentation with self-harm in the short term but not at 12 months. There was a significant decrease in hospital presentations for non-self harm over the next year. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry ACTRN12609000952246. PMID- 26956680 TI - Stimulus needs are a moving target: 240 additional matched literal and metaphorical sentences for testing neural hypotheses about metaphor. AB - As the cognitive neuroscience of metaphor has evolved, so too have the theoretical questions of greatest interest. To keep pace with these developments, in the present study we generated a large set of metaphoric and literal sentence pairs ideally suited to addressing the current methodological and conceptual needs of metaphor researchers. In particular, the need has emerged to distinguish metaphors along three dimensions: the grammatical class of their base terms, the sensorimotor features of their base terms, and the syntactic form in which the base terms appear. To meet this need, we generated nominal metaphors (and matched literal sentences) using entity nouns as the base terms, with the intention that they be used in concert with already published sets of predicate metaphors or nominal metaphors using event nouns. Using the results of three norming experiments, we provide 120 pairs of closely matched metaphoric and literal sentences that are characterized along 14 dimensions: 11 at the sentence level (length, frequency, concreteness, familiarity, naturalness, imageability, figurativeness, interpretability, ease of interpretation, valence, and valence judgment reaction time), and three related to the base term (visual, motion, and auditory imagery). These items extend previously published stimuli, filling an extant gap in metaphor research and allowing for tests of new behavioral and neural hypotheses about metaphor. PMID- 26956681 TI - Affective meanings of 1,469 Bengali concepts. AB - This article provides semantic differential ratings of 1,469 concepts in Bengali, a language spoken by about 250 million individuals in eastern India and Bangladesh. These data were collected from 20 male and 20 female Calcutta respondents who rated stimuli on three culturally universal affective dimensions: evaluation-potency-activity (EPA). This study employs pan-respondent component analyses as a means of examining the respondents' usage of the standard EPA scales. The pan-respondent component analyses indicate that some respondents used the rating scales in unexpected ways, recording their feelings about one component of concepts' EPA with ratings on a scale intended to measure a different dimension. When scores were based only on respondents who used the scales appropriately, several interesting patterns were found. For respondents of both genders, potency scores have a curvilinear relation with evaluation, such that very good and very bad concepts are mostly seen as very potent, whereas evaluatively neutral concepts are seen as somewhat impotent or just slightly potent. A moderate linear correlation exists between activity and evaluation, and a modest positive relation exists between potency and activity. Gender correlations are high on evaluation, .93, but much lower for potency scores, with a correlation of .55, and even lower for activity, .30. In this article we examine several explanations for why scales denoting potency and activity were reinterpreted as indicating goodness by certain respondents, and consider the matter of including data collected from respondents who used scales in this way. PMID- 26956682 TI - A menu-driven software package of Bayesian nonparametric (and parametric) mixed models for regression analysis and density estimation. AB - Most of applied statistics involves regression analysis of data. In practice, it is important to specify a regression model that has minimal assumptions which are not violated by data, to ensure that statistical inferences from the model are informative and not misleading. This paper presents a stand-alone and menu-driven software package, Bayesian Regression: Nonparametric and Parametric Models, constructed from MATLAB Compiler. Currently, this package gives the user a choice from 83 Bayesian models for data analysis. They include 47 Bayesian nonparametric (BNP) infinite-mixture regression models; 5 BNP infinite-mixture models for density estimation; and 31 normal random effects models (HLMs), including normal linear models. Each of the 78 regression models handles either a continuous, binary, or ordinal dependent variable, and can handle multi-level (grouped) data. All 83 Bayesian models can handle the analysis of weighted observations (e.g., for meta-analysis), and the analysis of left-censored, right-censored, and/or interval-censored data. Each BNP infinite-mixture model has a mixture distribution assigned one of various BNP prior distributions, including priors defined by either the Dirichlet process, Pitman-Yor process (including the normalized stable process), beta (two-parameter) process, normalized inverse Gaussian process, geometric weights prior, dependent Dirichlet process, or the dependent infinite-probits prior. The software user can mouse-click to select a Bayesian model and perform data analysis via Markov chain Monte Carlo (MCMC) sampling. After the sampling completes, the software automatically opens text output that reports MCMC-based estimates of the model's posterior distribution and model predictive fit to the data. Additional text and/or graphical output can be generated by mouse-clicking other menu options. This includes output of MCMC convergence analyses, and estimates of the model's posterior predictive distribution, for selected functionals and values of covariates. The software is illustrated through the BNP regression analysis of real data. PMID- 26956683 TI - Effect of yeast-derived products and distillers dried grains with solubles (DDGS) on growth performance and local innate immune response of broiler chickens challenged with Clostridium perfringens. AB - This study evaluated the effect of yeast-derived products on growth performance, gut lesion score, intestinal population of Clostridium perfringens, and local innate immunity of broiler chickens challenged with C. perfringens. One-day-old broiler chickens were randomly assigned to eight dietary treatments providing six replicate pens of 55 birds each per treatment. Dietary treatments consisted of Control diets without and with C. perfringens challenge, and diets containing bacitracin methylene disalicylate (BMD, 55 g/tonne), nucleotides (150 g/tonne), yeast cell wall (YCW, 300 g/tonne), and a commercial product Maxi-Gen Plus (1 kg/tonne) fed to chickens challenged with C. perfringens. Diets containing 10% distillers dried grains with solubles without and with C. perfringens challenge were also used. Birds were orally challenged with C. perfringens (10(8) colony forming units (cfu)/bird) on day 14. On day 21, intestinal samples were collected for gene expression analysis. Pathogen challenge significantly (P < 0.05) impaired feed intake, body weight gain, and feed conversion ratio (FCR) shortly after the challenge (14-21 days). Increased C. perfringens counts and intestinal lesion scores were observed for challenged birds except the BMD-containing diet. Over the entire trial (1-35 days), no difference in growth performance was observed except the BMD diet which improved FCR over the Control, challenged group. Birds receiving nucleotides showed increased expression of toll-like receptors and cytokines interleukin (IL)-4 and IL-18 compared to the Control, challenged group. Expression of macrophage mannose receptor and IL-18 was upregulated in birds receiving YCW. Increased expression of cytokines and receptors involved in innate immunity in broilers receiving nucleotides and YCW suggests the immunomodulatory properties of these products under pathogen challenge conditions. PMID- 26956685 TI - Research in the Rehabilitation Unit Presents Challenges to Nurse Researchers. AB - PURPOSE: Gathering data from patients on a rehabilitation unit poses challenges for nurse researchers. DESIGN: A case study is presented that describes ways the researchers attempted to meet these challenges while conducting their study. METHODS: The case study presents the approaches that the investigators took to undertake the study and then described the ways in which these approaches could have been improved. FINDINGS: Their successes and failures are described. CONCLUSIONS: Suggestions are made for future investigators. CLINICAL RELEVANCE: Clinical nursing research is required to develop an evidence base for practice in the rehabilitation unit. An analysis of the challenges and possible methods of overcoming these challenges is useful to both future investigators and nurses in practice to insure that studies can be carried out effectively. PMID- 26956684 TI - Assigning cause of maternal death: a comparison of findings by a facility-based review team, an expert panel using the new ICD-MM cause classification and a computer-based program (InterVA-4). AB - OBJECTIVE: To compare methodology used to assign cause of and factors contributing to maternal death. DESIGN: Reproductive Age Mortality Study. SETTING: Malawi. POPULATION: Maternal deaths among women of reproductive age. METHODS: We compared cause of death as assigned by a facility-based maternal death review team, an expert panel using the International Classification of Disease, 10th revision (ICD-10) cause classification for deaths during pregnancy, childbirth and the puerperium (ICD-MM) and a computer-based probabilistic program (InterVA-4). MAIN OUTCOME MEASURES: Number and cause of maternal deaths. RESULTS: The majority of maternal deaths occurred at a health facility (94/151; 62.3%). The estimated maternal mortality ratio was 363 per 100 000 live births (95% CI 307-425). There was poor agreement between cause of death assigned by a facility based maternal death review team and an expert panel (kappa = 0.37, 86 maternal deaths). The review team considered 36% of maternal deaths to be indirect and caused by non-obstetric complications (ICD-MM Group 7) whereas the expert panel considered only 17.4% to be indirect maternal deaths with 33.7% due to obstetric haemorrhage (ICD-MM Group 3). The review team incorrectly assigned a contributing condition rather than cause of death in up to 15.1% of cases. Agreement between the expert panel and InterVA-4 regarding cause of death was good (kappa = 0.66, 151 maternal deaths). However, contributing conditions are not identified by InterVA-4. CONCLUSIONS: Training in the use of ICD-MM is needed for healthcare providers conducting maternal death reviews to be able to correctly assign underlying cause of death and contributing factors. Such information can help to identify what improvements in quality of care are needed. TWEETABLE ABSTRACT: For maternal deaths assigning cause of death is best done by an expert panel and helps to identify where quality of care needs to be improved. PMID- 26956686 TI - Double Switch Procedure and Surgical Alternatives for the Treatment of Congenitally Corrected Transposition of the Great Arteries. AB - BACKGROUND: We present our experience with the double switch operation in sixteen patients with congenitally corrected transposition of the great arteries. METHODS: We enrolled 16 patients with congenitally corrected transposition of the great arteries operated by a single surgeon between 1995 and 2015. The mean age was 25 months (range 4 to 72 months) and the mean body weight was 8.9 kg (range 4.3 to 19 kg) at the time of operation. RESULTS: We encountered seven patients with moderate to severe tricuspid regurgitation, five of which had Ebstein anomaly. We performed a combination of atrial and arterial switch procedures in 11 cases, one of which had a concomitant coarctation of the aorta that was repaired along with the double switch procedure. Atrial switch and the Rastelli procedures were performed in three cases with concomitant pulmonary stenosis. A combination of arterial switch, Hemi-Mustard procedure, and bidirectional cavopulmonary anastomosis was performed in two cases. During a mean follow-up period of 67 months (range three months to 18 years), we encountered one early postoperative mortality related to intracerebral bleeding. All but one of the patients are now in NYHA class I-II. CONCLUSIONS: Congenitally corrected transposition of the great arteries is a rare congenital cardiac anomaly in which the results of the anatomical repair with double switch operation appear to be superior to that achieved by a physiological repair. PMID- 26956687 TI - Author's response on Arria (2016): Intention matters--using the terminology 'pharmacological neuroenhancement' as a behavioural definition based on the assumed functionality. PMID- 26956688 TI - Multifocal Cerebral and Bilateral Middle Cerebellar Peduncle Infarctions in CADASIL. PMID- 26956690 TI - Contraception in the Developing World: Special Considerations. AB - The United States Agency for International Development (USAID) estimates that there are 225 million women and girls with unmet contraceptive need yearly. Unmet need for contraception is defined as women who desire a delay in childbearing and are not using a modern method of contraception. It is projected that providing contraception to these women would avert 36 million abortions, 70,000 maternal deaths, and 52 million unintended pregnancies overall. In the past 30 years, there has been an increase both in population and in contraception use in the developing world. As a result, it is estimated that in 2015 there were 500 million contraceptive users in developing countries, which is nearly double the prevalence in 2000. Unfortunately, women and girls in developing nations still face many obstacles in obtaining modern methods of contraception. Particular challenges in the developing world include lack of access due to inadequate number of trained providers, fewer method options, and "stock-outs" of contraceptive supplies. Innovative strategies for decreasing unmet need will have to address these challenges, and will necessarily involve programmatic solutions such as community-based distribution and social marketing campaigns. Additionally, increasing uptake of long-acting reversible contraceptive methods will be essential for achieving the goal of decreasing unmet need. PMID- 26956691 TI - Emerging Technologies to Prevent Pregnancy and Sexually Transmitted Infections in Women. AB - Worldwide, there continues to be a large unmet need for family planning and sexually transmitted infection (STI) prevention methods. Multipurpose prevention technology (MPT) is a general term encompassing any single prevention methodology targeting more than one STI (including HIV) and/or pregnancy. While innovation has been slow over the past several decades, recent scientific advances have resulted in new products entering clinical trials. This review focuses primarily on multipurpose technologies that are designed to prevent pregnancy and HIV. To examine the current state of MPTs, we outline key discoveries of biologic mechanisms that influence susceptibility of the female genital tract to HIV and STIs, and review the effects of hormonal contraception on HIV susceptibility. We discuss the state of currently available HIV prevention strategies for women, and their interactions with hormonal contraceptive products. Finally, we describe MPTs currently in preclinical and clinical trials and propose ongoing questions requiring research to help advance the field. PMID- 26956689 TI - Adjuvant capecitabine plus oxaliplatin after D2 gastrectomy in Japanese patients with gastric cancer: a phase II study. AB - BACKGROUND: Adjuvant chemotherapy with XELOX (capecitabine plus oxaliplatin) has been shown to be beneficial following resection of gastric cancer in South Korean, Chinese, and Taiwanese patients. This phase II study (J-CLASSIC-PII) was undertaken to evaluate the feasibility of XELOX in Japanese patients with resected gastric cancer. METHODS: Patients with stage II or III gastric cancer who underwent curative D2 gastrectomy received adjuvant XELOX (eight 3-week cycles of oral capecitabine, 1000 mg/m2 twice daily on days 1-14, plus intravenous oxaliplatin 130 mg/m2 on day 1). The primary endpoint was dose intensity. Secondary endpoints were safety, proportion of patients completing treatment, and 1-year disease-free survival (DFS) rate. RESULTS: One hundred patients were enrolled, 76 of whom completed the study as planned. The mean dose intensity was 67.2 % (95 % CI, 61.9-72.5 %) for capecitabine and 73.4 % (95 % CI, 68.4-78.4 %) for oxaliplatin, which were higher than the predefined age-adjusted threshold values of 63.4 % and 69.4 %, respectively, and the study therefore met its primary endpoint. The 1-year DFS rate was 86 % (95 % CI, 77-91 %). No new safety signals were identified. CONCLUSIONS: The feasibility of adjuvant XELOX in Japanese patients with resected gastric cancer is similar to that observed in South Korean, Chinese, and Taiwanese patients in the Capecitabine and Oxaliplatin Adjuvant Study in Stomach Cancer (CLASSIC) study. Based on findings from this study and the CLASSIC study, the XELOX regimen can be considered an adjuvant treatment option for Japanese gastric cancer patients who have undergone curative resection. PMID- 26956692 TI - Cassing Hammond, MD. PMID- 26956693 TI - Innovations in Contraception. PMID- 26956694 TI - Visual, auditive and somatosensory pathways alterations in geriatric rhesus monkeys (Macaca mulatta). AB - BACKGROUND: Synapses loss during aging is associated to neurophysiologic alterations that impair organism's health span, thus making the study and prevention of sensory decline relevant for healthy aging and welfare. Therefore the aim of this study was to obtain normative data related to the electrophysiological responses of the different neurosensory components in the visual, auditory and somatosensory pathways in healthy geriatric rhesus monkeys in captivity. METHODS: Twenty-four rhesus monkeys were divided in two groups: (i) Geriatric monkeys, 20-30 years of age, and (ii) Young monkeys, 7 years of age. Evoked potentials were obtained from the visual, auditory and somatosensory pathways. RESULTS: Regardless the sensory pathways evaluated, a significant delay in nerve conduction was observed in the geriatric group in comparison to the young group. CONCLUSIONS: Evoked potentials allowed identifying changes generated during aging in rhesus monkeys and normative data for this species were obtained. PMID- 26956695 TI - Comment on "The promise of microfluidic artificial lungs" by J. A. Potkay, Lab Chip, 2014, 14, 4122-4138. AB - This comment on an article that appeared in this journal (Potkay, Lab Chip, 2014, 14, 4122-4138) presents an alternative view on the feasibility and clinical application of current microfluidic artificial lungs. PMID- 26956696 TI - Zinc Attenuates Tubulointerstitial Fibrosis in Diabetic Nephropathy Via Inhibition of HIF Through PI-3K Signaling. AB - Evidence has demonstrated that hypoxia may have a central pathogenic mechanism in the development of diabetic nephropathy (DN). Epithelial-to-mesenchymal transition (EMT) of mature tubular epithelial cells in kidney is a contributor to the renal accumulation of matrix protein in DN and is highly associated with the progression of tubulointerstitial fibrosis. Zinc (Zn) has anti-fibrosis effects in liver and lungs. In the present study, we aimed to investigate the effect of Zn on renal tubulointerstitial fibrosis especially under hypoxic conditions and its association with DN. We found that Zn treatment blockaded tubular EMT and attenuated renal tubulointerstitial fibrosis by downregulation of hypoxia inducible factor alpha (HIF-1alpha) in the kidneys of diabetic streptozotocin treated mice. High glucose (HG)/hypoxic conditions stimulated EMT in renal tubular cells as indicated by the significant decrease in epithelial marker E cadherin and ZO-1 while the increase in mesenchymal markers alpha-smooth muscle actin (alpha-SMA). Zn supplement mainly prevented HG/hypoxic-induced HIF-1alpha accumulation and EMT marker changes. In co-treatment Zn with PI3K/Akt/GSK-3beta signaling pathway, inhibitor LY294002 prevented HG/hypoxic-induced HIF-1alpha increase and EMT changes, suggesting that Zn may mediate HG/hypoxic-induced EMT through PI3K/Akt/GSK-3beta pathway. Therefore, we concluded that Zn had an important anti-fibrosis role under HG/hypoxic conditions, and a novel mechanism contributing to Zn protection on renal tubular epithelial cells from HG/hypoxia induced EMT through activation of PI3K/Akt/GSK-3beta signaling pathway, which subsequently leads to the downregulation of the expression of HIF-1alpha. PMID- 26956697 TI - Multiple myeloma exosomes establish a favourable bone marrow microenvironment with enhanced angiogenesis and immunosuppression. AB - Multiple myeloma (MM) pathogenesis and progression largely rely on the cells and extracellular factors in the bone marrow (BM) microenvironment. Compelling studies have identified tumour exosomes as key regulators in the maintenance and education of the BM microenvironment by targeting stromal cells, immune cells, and vascular cells. However, the role of MM exosomes in the modification of the BM microenvironment and MM progression remains unclear. Here, we explored the functions of MM exosomes in angiogenesis and immunosuppression in vitro and in vivo. Murine MM exosomes carrying multiple angiogenesis-related proteins enhanced angiogenesis and directly promoted endothelial cell growth. Several pathways such as signal transducer and activator of transcription 3 (STAT3), c-Jun N-terminal kinase, and p53 were modulated by the exosomes in endothelial and BM stromal cells. These exosomes promoted the growth of myeloid-derived suppressor cells (MDSCs) in naive mice through activation of the STAT3 pathway and changed their subsets to similar phenotypes to those seen in MM-bearing mice. Moreover, MM exosomes up-regulated inducible nitric oxide synthase and enhanced the immunosuppressive capacity of BM MDSCs in vivo. Our data show that MM exosomes modulate the BM microenvironment through enhancement of angiogenesis and immunosuppression, which will further facilitate MM progression. Copyright (c) 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 26956698 TI - Sofosbuvir/velpatasvir improves patient-reported outcomes in HCV patients: Results from ASTRAL-1 placebo-controlled trial. AB - BACKGROUND & AIMS: The new pan-genotypic regimen [sofosbuvir (SOF) and velpatasvir (VEL)] for hepatitis C virus (HCV) has been associated with high efficacy. The aim of this study was to assess patient-reported outcomes (PROs) of this regimen. METHODS: The PRO data (CLDQ-HCV, SF-36, FACIT-F, WPAI) came from the ASTRAL-1 study, a multicenter multinational blinded placebo-controlled phase 3 clinical trial of a fixed dose combination of SOF 400mg and VEL 100mg for patients with genotype 1, 2, 4, 5, and 6 compared to placebo for 12weeks. RESULTS: 624 patients received active treatment [618 achieved sustained virologic response (SVR)], and 116 received placebo. The baseline PRO scores were similar. By treatment week 4, patients receiving SOF/VEL experienced improvements in general health (on average, +2.3points), emotional well-being (+3.4), FACIT-F (+1.3), and all domains of CLDQ-HCV (+2.1 to +7.3) (all p<0.005). On the other hand, the only PRO that improved in patients receiving placebo was the worry domain of CLDQ-HCV: +4.6 (p=0.002). By the end of treatment, improvement in PRO scores with SOF/VEL continued, and no improvement was noted in the placebo. Improvement in PROs were also noted 12 and 24weeks post-treatment: +3.7, on average, in patients with SVR-12 after SOF/VEL vs. -2.6, on average, in the placebo arm (p<0.005). Multivariate analysis showed that treatment-emergent changes in PROs were predicted by receiving SOF/VEL for some summary PRO score (p<0.005). CONCLUSIONS: This placebo-controlled trial shows that patients treated with SOF/VEL experience significant improvement of their PROs during treatment and after achieving SVR. LAY SUMMARY: In patients with chronic hepatitis C infection, health-related quality of life and work productivity are often impaired due to HCV-related fatigue. Treatment of hepatitis C with interferon based regimens, which was the standard of care for all HCV patients until recently, had substantial and potentially debilitating side effects. These regimens caused additional impairment in health-related quality of life and work productivity during treatment and shortly after treatment cessation. The newly developed interferon-free combination of sofosbuvir and velpatasvir has been shown to improve health-related quality of life during treatment, and lead to an improvement in a number of indicators of patient-reported outcomes after successful clearance of HCV and achieving sustained virologic response. PMID- 26956700 TI - Nikolay Ivanovich Pirogov (1810-1881): A pioneering Russian surgeon and medical scientist. AB - Nikolay Pirogov qualified as a physician from Moscow University in 1828 and then studied surgery and anatomy at University of Dorpat. He developed new surgical techniques, including the eponymous osteoplastic foot amputation. His application of scientifically based techniques extended surgery from a craft to a science. During the Crimean War he initiated the deployment of women as nurses and used triage for dealing with mass casualties. His textbook on field surgery became the standard reference on the subject and his principles remained virtually unchanged until the Second World War. Pirogov died on 5 December 1881 at his estate in Vishnya. PMID- 26956699 TI - Multiple abiotic stress tolerance in Vigna mungo is altered by overexpression of ALDRXV4 gene via reactive carbonyl detoxification. AB - Vigna mungo (blackgram) is an important leguminous pulse crop, which is grown for its protein rich edible seeds. Drought and salinity are the major abiotic stresses which adversely affect the growth and productivity of crop plants including blackgram. The ALDRXV4 belongs to the aldo-keto reductase superfamily of enzymes that catalyze the reduction of carbonyl metabolites in the cells and plays an important role in the osmoprotection and detoxification of the reactive carbonyl species. In the present study, we developed transgenic plants of V. mungo using Agrobacterium mediated transformation. The transgene integration was confirmed by Southern blot analysis whereas the expression was confirmed by RT PCR, Western blot and enzyme activity. The T1 generation transgenic plants displayed improved tolerance to various environmental stresses, including drought, salt, methyl viologen and H2O2 induced oxidative stress. The increased aldose reductase activity, higher sorbitol content and less accumulation of the toxic metabolite, methylglyoxal in the transgenic lines under non-stress and stress (drought and salinity) conditions resulted in increased protection through maintenance of better photosynthetic efficiency, higher relative water content and less photooxidative damage. The accumulation of reactive oxygen species was remarkably decreased in the transgenic lines as compared with the wild type plants. This study of engineering multiple stress tolerance in blackgram, is the first report to date and this strategy for trait improvement is proposed to provide a novel germplasm for blackgram production on marginal lands. PMID- 26956701 TI - Interlinked mental and physical health problems cost NHS more than L11bn a year. PMID- 26956702 TI - Comment on Brock and Blake: debating brain drain. AB - In this response I focus largely on Brock's arguments for the right of developing nations to restrict emigration of health workers. Brock claims that the conditions she specifies for this restriction are fair and reasonable, but I dispute whether it is possible to meet those conditions given fundamental inequalities in power. In the end, there are far more powerful agents than health workers who are responsible for causing and solving the 'brain drain' issue. PMID- 26956703 TI - Understanding the role of family dynamics, perceived norms, and lung cancer worry in predicting second-hand smoke avoidance among high-risk lung cancer families. AB - Reducing exposure to environmental tobacco smoke significantly reduces lung cancer risk. We used family communication patterns theory and the theory of planned behavior to examine whether perceived norms and lung cancer worry more strongly influenced intentions to avoid environmental tobacco smoke in families higher in conformity and conversation orientations. Results from 52 individuals in 17 high-risk lung cancer families showed injunctive norms were positively related to intentions when families conformed and conversed more. Lung cancer worry was positively related to intentions in high conformity families and negatively related to intentions in low conformity families. Findings can benefit interventions to reduce environmental tobacco smoke exposure. PMID- 26956704 TI - Gender differences in psychological factors shaping smoking decisions of Chilean adolescents. AB - This study examined gender differences in how internalizing and externalizing symptoms affect adolescents' decisions about smoking in Chile, where girls smoke at some of the highest rates in the world. In multivariate logistic regression analyses with 607 adolescents, internalizing symptoms, such as depressed mood and anxiety, predicted smoking among girls more than boys, with girls who were low in internalizing symptoms being more likely to smoke than those who were high in internalizing symptoms. In Chile's high-risk context, internalizing symptoms may be indirectly protective for girls by decreasing their exposure to peer pressure and related influences that encourage cigarette use. PMID- 26956705 TI - Tumebacillus lipolyticus sp. nov., isolated from river water. AB - An aerobic, endospore-forming, alkali-tolerant, Gram-stain-positive, non-motile, rod-shaped bacterium, designated strain NIO-S10T, was isolated from a surface water sample collected from the Godavari River, Kapileswarapuram, India. Colonies on nutrient agar were circular, 3-4 mm in diameter, creamish and raised after incubation for 36 h at 37 degrees C. Growth occurred at 20-40 degrees C, at pH 6-9 and in the presence of 0-2 % (w/v) NaCl. Strain NIO-S10T was positive for oxidase, caseinase, DNase, gelatinase, lipase and urease activities, and negative for catalase, aesculinase, amylase and cellulase activities. The fatty acids were dominated by branched and saturated fatty acids, with a high abundance of iso-C15 : 0, anteiso-C15 : 0 and C18 : 0.The cell-wall peptidoglycan contained meso diaminopimelic acid as the diagnostic diamino acid, and MK-7 was the major menaquinone. The DNA G+C content of strain NIO-S10T was 54.4 mol%. A blast sequence similarity search based on 16S rRNA gene sequences indicated that Tumebacillus ginsengisoli Gsoil 1105T was the nearest phylogenetic neighbour to strain NIO-S10T, with a pairwise sequence similarity of 94.9 %. Phylogenetic analysis showed that strain NIO-S10T was clustered with members of the genus Tumebacillus and together with members of the genus Effusibacillus. Based on phenotypic characteristics and phylogenetic inference, strain NIO-S10T represents a novel species of the genus Tumebacillus, for which the name Tumebacillus lipolyticus sp. nov. is proposed. The type strain is NIO-S10T ( = KCTC 32289T = MTCC 12483T). PMID- 26956706 TI - Open and closed distal anastomosis for acute type A aortic dissection repair. AB - OBJECTIVES: The current consensus favours an open distal anastomosis for aortic dissection repair. A small number of experiences have compared early and long term outcomes between closed and open distal anastomosis in the setting of acute aortic dissection. METHODS: We reviewed our experience in 204 patients who underwent repair of spontaneous acute type A aortic dissection between January 2000 and December 2013. Open distal repair was performed in 109 patients, whereas 95 patients received a closed anastomosis. The clinical presentation, anatomical characteristics of aortic dissection, surgical techniques and the outcomes were analysed in the overall population and in the subgroup of patients (n = 100; open = 39, closed = 61) with Type 1 DeBakey dissection and a proximal intimal tear. Twenty-six preoperative and operative variables were studied to determine their impact on hospital mortality and postoperative neurological deficits. Imaging follow-up was available in 83 patients. RESULTS: A more extensive involvement of the aortic arch characterized the open repair group. No differences in terms of mortality, morbidity and survival rates were observed between the two groups of patients. Open repair with cerebral perfusion was associated with a better neurological outcome. Patients who underwent an open distal anastomosis showed a significant higher rate of complete thrombosis of the false lumen. CONCLUSIONS: An open repair does not increase the risk of early mortality and positively affect the evolution of the false lumen in distal unresected aortic segments. The use of cerebral perfusion reduces the risk of perioperative neurological injury. PMID- 26956707 TI - Repair of complicated type B dissection with an aberrant right subclavian artery. AB - OBJECTIVES: An aberrant right subclavian artery (ARSA) is one of most common congenital anomalies, but the coexistence of type B dissection and an ARSA is extremely rare. Repair of type B dissection poses a technical challenge due to an ARSA. We retrospectively reviewed our experience of surgical treatment of a complicated type B dissection with an ARSA. METHODS: From August 2010 to March 2014, 7 patients with chronic type B dissection with an ARSA underwent the stented elephant trunk procedure under hypothermic cardiopulmonary bypass in our centre. The mean age was 45 +/- 7 (range, 32-54) years. Total arch replacement was performed in 2 patients. Revascularization of the ARSA was done in 5 of 7 patients. RESULTS: There were no in-hospital deaths. The mean time of mechanical ventilation and stay in the intensive care unit was 22 +/- 11 and 53 +/- 11 h, respectively. Neurological deficit, visceral ischaemia or injury to the spinal cord was not observed. Right upper-limb ischaemia was not observed in patients without ARRA revascularization during follow-up. CONCLUSIONS: In patients not undergoing descending aortic replacement, the stented elephant trunk method is our preferred procedure for this anomaly via a median sternotomy. Repair of type B dissection and revascularization of the ARSA were achieved in a single stage using this technique. Satisfactory surgical results and follow-up outcomes were obtained. There was no right upper-limb ischaemia or neurological deficit in patients without ARSA revascularization, but revascularization of the ARSA is recommended for this vessel anomaly. PMID- 26956708 TI - Practice variation in treatment of suspected asymptomatic bacteriuria prior to cardiac surgery: are there differences in postoperative outcome? A retrospective cohort study. AB - OBJECTIVES: It is unclear whether postoperative infections can be prevented by treating asymptomatic bacteriuria, or whether, on the other hand, such treatment will increase the risk of more serious infection by pathogenic bacteria different from the ones causing bacteriuria. This study aimed to support future treatment decisions for preoperative cardiothoracic surgery patients with asymptomatic bacteriuria, by examining current preoperative practice, in relation to postoperative outcome. METHODS: A retrospective cohort study was conducted. All patients who underwent cardiothoracic surgery in 2011-2013 using extracorporeal circulation in St. Antonius Hospital Nieuwegein, and who preoperatively had nitrituria and/or leucocyturia were included. Exclusion criteria were C-reactive protein level higher than 10 mg/l, emergency surgery, critical preoperative state and/or antibiotic treatment because of other infections. Outcomes were postoperative infections and length of stay. Furthermore, we compared culture results of preoperative urine with postoperative infection sites in order to study the hypothesis of haematogenous spread. RESULTS: One thousand and two patients with leucocyturia or nitrituria were eligible, of whom 3.9% had been treated with antibiotics preoperatively (AB+). Of the 96.1% of patients who had not been treated (AB-), 8.3% had an infection postoperatively, compared with 5.1% in the treatment (AB+) group. This was not statistically significant {odds ratio, corrected for EuroSCORE, 0.53 [95% confidence interval (CI) 0.12-2.24, P = 0.39]}. Length of stay, corrected for EuroSCORE, between the treated (AB+) and the non-treated (AB-) group did not differ, with a hazard ratio of 1.05 (95% CI 0.63-1.75, P = 0.85). As regards bacterial culture results, none of patients not treated with antibiotics preoperatively (AB-) seemed to have a postoperative infection due to haematogenous spread of bacteria from the urinary tract present preoperatively. CONCLUSIONS: The risk of haematogenous spread of bacteria seems to be non-existent in this large cohort of non-treated patients, under our local clinical practice. Based on this current, best available evidence, it seems therefore safe not to treat patients with asymptomatic bacteriuria prior to cardiothoracic surgery. This could also imply that it is safe not to perform routine preoperative urine testing. PMID- 26956709 TI - Treatment of stand-alone atrial fibrillation with a right thoracoscopic approach employing a microwave or monopolar radiofrequency energy source: long-term results. AB - OBJECTIVES: Minimally invasive surgery for atrial fibrillation (AF) has rapidly evolved recently. The long-term efficacy of most of these procedures is poorly known. METHODS: Between 2006 and 2010, 38 drug-resistant, symptomatic patients with stand-alone AF underwent unilateral, thoracoscopic, off-pump ablation. The mean age was 60 +/- 8.2 (range 42-75) years and the mean AF duration was 46 +/- 62 (range 3-240) months. Sixteen patients (42%) had paroxysmal, 9 (24%) had persistent and 13 (34%) had long-standing persistent AF. A box lesion was created using a microwave (26 patients) or monopolar radiofrequency (12 patients) system. Patients were prospectively followed with repeat electrocardiograms (ECGs) and ECG Holters. Additional catheter ablation was offered to patients with recurrence of arrhythmia. RESULTS: All procedures were completed as planned with one conversion to sternotomy, zero mortality and minimal in-hospital complications. The mean follow-up duration was 70 +/- 19 (range 20-88) months. Arrhythmia-free survival rates after the procedure were 50, 44.4, 24.1 and 10.8% at 6, 12, 36 and 60 months, respectively, with most recurrences in the first 6 months. Twelve patients underwent additional catheter ablation(s); from the last intervention, 75% of them were in sinus rhythm (SR) with a mean follow-up of 31 +/- 23 (range 4 86) months. Overall, at the end of follow-up, only 3 patients were still in SR without any arrhythmia recurrence. Major complications (cerebral, peripheral embolism or bleeding) occurred in 5 patients. CONCLUSIONS: Unilateral, thoracoscopic AF ablation is safe and technically feasible. However, the results of the microwave and monopolar radiofrequency devices were less than satisfactory, with a gradual decline in arrhythmia-free survival over a very long term follow-up. PMID- 26956710 TI - Only-child and non-only-child exhibit differences in creativity and agreeableness: evidence from behavioral and anatomical structural studies. AB - Different family composition and size inevitably make only-children different from non-only-children. Previous studies have focused on the differences in behaviors, such as cognitive function and personality traits, between the only child and the non-only-child. However, there are few studies that have focused on the topic of whether different family environments influence children's brain structural development and whether behavior differentially has its neural basis between only-child and non-only-child status. Thus, in the present study, we investigated the differences in cognition (e.g., intelligence and creativity) and personality and the anatomical structural differences of gray matter volume (GMV) using voxel-based morphometry (VBM) between only-children and non-only-children. The behavioral results revealed that only-children exhibited higher flexibility scores (a dimension of creativity) and lower agreeableness scores (a dimension of personality traits) than non-only-children. Most importantly, the GMV results revealed that there were significant differences in the GMV between only-children and non-only-children that occurred mainly in the brain regions of the supramarginal gyrus, which was positively correlated with flexibility scores; the medial prefrontal cortex (mPFC), which was positively correlated with agreeableness scores; and the parahippocampal gyrus. These findings may suggest that family environment (i.e., only-child vs. non-only-child), may play important roles in the development of the behavior and brain structure of individuals. PMID- 26956711 TI - Making sense of genomes of parasitic worms: Tackling bioinformatic challenges. AB - Billions of people and animals are infected with parasitic worms (helminths). Many of these worms cause diseases that have a major socioeconomic impact worldwide, and are challenging to control because existing treatment methods are often inadequate. There is, therefore, a need to work toward developing new intervention methods, built on a sound understanding of parasitic worms at molecular level, the relationships that they have with their animal hosts and/or the diseases that they cause. Decoding the genomes and transcriptomes of these parasites brings us a step closer to this goal. The key focus of this article is to critically review and discuss bioinformatic tools used for the assembly and annotation of these genomes and transcriptomes, as well as various post-genomic analyses of transcription profiles, biological pathways, synteny, phylogeny, biogeography and the prediction and prioritisation of drug target candidates. Bioinformatic pipelines implemented and established recently provide practical and efficient tools for the assembly and annotation of genomes of parasitic worms, and will be applicable to a wide range of other parasites and eukaryotic organisms. Future research will need to assess the utility of long-read sequence data sets for enhanced genomic assemblies, and develop improved algorithms for gene prediction and post-genomic analyses, to enable comprehensive systems biology explorations of parasitic organisms. PMID- 26956712 TI - Associations between frequency of food shopping at different store types and diet and weight outcomes: findings from the NEWPATH study. AB - OBJECTIVE: The present study aimed to: (i) examine associations between food store patronage and diet and weight-related outcomes; and (ii) explore consumer motivations for visiting different types of food store. DESIGN: A stratified probability sample of residents completed household and individual-level surveys in 2009/2010 on food purchasing patterns and motivations, dietary intake, waist circumference (WC), weight and height. Diet quality was calculated using the Healthy Eating Index for Canada from a subset of participants (n 1362). Generalized estimating equations were created in 2015 to examine how frequency of patronizing different types of food store was associated with diet quality, intake of fruits and vegetable, mean intake of energy (kcal) sodium and saturated fat, WC and BMI. SETTING: Three mid-sized urban municipalities in Ontario, Canada. SUBJECTS: A representative sample of residents (n 4574). RESULTS: Participants who shopped frequently at food co-ops had significantly better diet quality (beta=5.3; 99 % CI 0.3, 10.2) than those who did not. BMI and WC were significantly lower among those who frequently shopped at specialty shops (BMI, beta=-2.1; 99 % CI -3.0, -1.1; WC, beta=-4.8; 99 % CI -7.0, -2.5) and farmers' markets (BMI, beta=-1.4; 99 % CI -2.3, -0.5; WC, beta=-3.8; 99 % CI -6.0, -1.6) compared with those who did not. Relative importance of reasons for food outlet selection differed by large (price, food quality) v. small (proximity, convenient hours) shopping trip and by outlet type. CONCLUSIONS: Findings contribute to our understanding of food store selection and have implications for potentially relevant retail food intervention settings. PMID- 26956713 TI - Dynasplint Trismus System exercises for trismus secondary to head and neck cancer: a prospective explorative study. AB - PURPOSE: The Dynasplint Trismus System (DTS) can be used to treat trismus secondary to head and neck cancer. We conducted a prospective study with the following aims: (1) to determine the effects of DTS exercises on changes in mouth opening, pain, mandibular function, quality of life (QoL), and symptomatology and (2) to analyze the patients' perception on DTS exercises, including user satisfaction, experiences, comfort, and compliance. METHODS: The patients were instructed to exercise with the DTS for at least 16 weeks. Changes in mouth opening, pain, mandibular function, QoL, and symptomatology were evaluated, as well as the patients' perception of DTS exercises. RESULTS: Eighteen consecutive patients were included. Baseline mouth opening was 22.6 mm (sd 7.6). After the patients completed the DTS exercise program, mouth opening increased (7.1 mm, sd 4.7) and perceived difficulty of opening the mouth improved significantly (p < 0.05). No significant effects were found in mandibular function, QoL, and overall symptomatology. The patients' perception was diverse. They reported effectiveness and positive feelings of the results and would recommend DTS exercises to other patients. About half of them thought DTS exercises were burdensome. CONCLUSIONS: Mouth opening increased significantly after the DTS exercise program, relative to baseline. About one third of the gained increase was lost in the follow-up period. In general, the patients were satisfied about the effects and the DTS exercise program. PMID- 26956714 TI - Role of Moesin in Advanced Glycation End Products-Induced Angiogenesis of Human Umbilical Vein Endothelial Cells. AB - Disorders of angiogenesis are related to microangiopathies during the development of diabetic vascular complications, but the effect of advanced glycation end products (AGEs) on angiogenesis and the mechanism has not been completely unveiled. We previous demonstrated that moesin belonging to the ezrin-radixin moesin (ERM) protein family protein played a critical role in AGE-induced hyper permeability in human umbilical vein endothelial cells (HUVECs). Here, we investigated the impact of moesin on AGE-induced HUVEC proliferation, migration, and tubulogenesis. Silencing of moesin decreased cell motility and tube formation but not cell proliferation. It also attenuated cellular F-actin reassembly. Further, phosphorylation of threonine at the 558 amino acid residue (Thr 558) in moesin suppressed AGE-induced HUVEC proliferation, migration, and tube formation, while the activating mutation of moesin at Thr 558 enhanced HUVEC angiogenesis. Further, the inhibition of either RhoA activity by adenovirus or ROCK activation with inhibitor Y27632 decreased AGE-induced moesin phosphorylation and subsequently suppressed HUVEC angiogenesis. These results indicate that the Thr 558 phosphorylation in moesin mediates endothelial angiogenesis. AGEs promoted HUVEC angiogenesis by inducing moesin phosphorylation via RhoA/ROCK pathway. PMID- 26956715 TI - Classifying Autism Spectrum Disorders by ADI-R: Subtypes or Severity Gradient? AB - To reduce phenotypic heterogeneity of Autism spectrum disorders (ASD) and add to the current diagnostic discussion this study aimed at identifying clinically meaningful ASD subgroups. Cluster analyses were used to describe empirically derived groups based on the Autism Diagnostic Interview-revised (ADI-R) in a large sample of n = 463 individuals with ASD aged 3-21. Three clusters were observed. Most severely affected individuals regarding all core symptoms were allocated to cluster 2. Cluster 3 comprised moderate symptom severity of social communication impairments (SCI) and less stereotyped repetitive behavior (RRB). Minor SCI and relatively more RRB characterized cluster 1. This study offers support for both, a symptom profile, and a gradient model of ASD within the spectrum due to the sample included. PMID- 26956716 TI - Brief Report: Coaching Adolescents with Autism Spectrum Disorder in a School Based Multi-Sport Program. AB - While physical activity (PA) is often overwhelming for people with ASD, appropriate engagement strategies can result in increased motivation to participate and associated physical and psychosocial benefits. In this framework, the multi-sport Supporting Success program aims to inform good-practice coaching strategies for community coaches to engage with adolescents with ASD in order to foster socialisation. The project employs a community development approach and a Participatory Action Research (PAR) design. Methods include ongoing consultation, focus groups, briefing/debriefing sessions and questionnaire surveys. Preliminary findings indicate that coaching strategies and program design are fundamental variables in the use of sport/PA to help adolescents with ASD to develop social skills and share positive experiences with peers, coaches, educators and local community members. PMID- 26956717 TI - Sensitization of hepatocellular carcinoma cells to irradiation by miR-34a through targeting lactate dehydrogenase-A. AB - Radiation is a therapeutic strategy for the treatment of cancer, and is also used for the treatment of hepatocellular carcinoma. MicroRNAs (miRs) are endogenous, non-coding single-stranded RNA molecules, which regulate gene expression at the post-transcriptional level. In the present study, the roles of miR-34a-mediated glycolysis in radiation sensitivity were investigated. By establishing a radioresistant liver cancer cell line, the present study compared the expression level of miR-34a from radiosensitive and radioresistant cells using the reverse transcription-quantitative polymerase chain reaction. The glucose uptake and lactate production were also compared between the two types of cells. The results demonstrated that miR-34a acted as a tumor suppressor in human hepatocellular cancer cells. Following comparison of radiosensitive and radioresistant cancer cells, the results of the present study demonstrated that miR-34a was negatively correlated with radiation resistance; and levels of miR-34a were significantly downregulated in the HepG2 radioresistant cells. Furthermore, the rate of glycolysis in the radioresistant cells was elevated, and there was evidence that glucose uptake and lactate production increased. Lactate dehydrogenase A (LDHA), which is a key enzyme in the glycolysis signaling pathway, was found to be a target of miR-34a in hepatocellular cancer cells. Notably, the overexpression of miR-34a re-sensitized HepG2 radioresistant cells to radiation treatment by inhibiting LDHA. The results of the present study revealed a negative correlation between miR-34a and glycolysis, caused by the targeting of LDHA-34a, providing a novel mechanism for miR-34a-mediated radioresistance. PMID- 26956718 TI - CD30 Receptor-Targeted Lentiviral Vectors for Human Induced Pluripotent Stem Cell Specific Gene Modification. AB - Cultures of induced pluripotent stem cells (iPSCs) often contain cells of varying grades of pluripotency. We present novel lentiviral vectors targeted to the surface receptor CD30 (CD30-LV) to transfer genes into iPSCs that are truly pluripotent as demonstrated by marker gene expression. We demonstrate that CD30 expression is restricted to SSEA4(high) cells of human iPSC cultures and a human embryonic stem cell line. When CD30-LV was added to iPSCs during routine cultivation, efficient and exclusive transduction of cells positive for the pluripotency marker Oct-4 was achieved, while retaining their pluripotency. When added during the reprogramming process, CD30-LV solely transduced cells that became fully reprogrammed iPSCs as confirmed by co-expression of endogenous Nanog and the reporter gene. Thus, CD30-LV may serve as novel tool for the selective gene transfer into PSCs with broad applications in basic and therapeutic research. PMID- 26956719 TI - The ethics of sustainable genomic research in Africa. AB - Michael Parker and Dominic Kwiatkowski discuss important ethical considerations for sustainable genomics research in Africa. PMID- 26956720 TI - Body fat rather than weight should be considered when assessing a patient's health, study finds. PMID- 26956721 TI - Endoscopic ultrasound-guided choledochoduodenostomy with a lumen-apposing, self expandable fully covered metal stent for palliative biliary drainage. AB - In addition to the poor prognosis associated with pancreatic adenocarcinoma, it can also lead to several other conditions including obstructive jaundice that can affect a patient's quality of life. This is a major concern in non-operative patients where palliation is considered the main therapeutic goal. Traditionally, there are several ways to pursue palliative biliary drainage including endoscopic methods, a variety of surgical procedures, and percutaneous techniques. Generally, endoscopic methods such as endoscopic retrograde cholangiopancreatography (ERCP) with transpapillary stent placement are considered first-line therapies. Unfortunately, ERCP is not always possible due to several potential reasons. Although endoscopic ultrasound-guided biliary puncture has been well described for several years, there are limitations to its usefulness in biliary drainage, in part due to complication concerns. However, more recently a lumen-apposing, self-expandable fully covered metal stent has been employed for such situations. We describe two cases in which this type of stent was used in patients for palliative biliary drainage in pancreatic adenocarcinoma where standard ERCP was not feasible. In both cases, stent deployment was successful without immediate complications related to the procedure or the stent. Furthermore, the main goal of these therapies was palliation and in both cases the patient chose this procedure for quality of life reasons. In the future, randomized trials are needed to better define the long term effectiveness and safety of these stents compared to more standard therapies. PMID- 26956722 TI - Metabolic engineering of Escherichia coli for the production of hydroxy fatty acids from glucose. AB - BACKGROUND: Hydroxy fatty acids (HFAs) are valuable chemicals for a broad variety of applications. However, commercial production of HFAs has not been established so far due to the lack of low cost routes for their synthesis. Although the microbial transformation pathway of HFAs was extensively studied decades ago, these attempts mainly focused on converting fatty acids or vegetable oils to their hydroxyl counterparts. The use of a wider range of feedstocks to produce HFAs would reduce the dependence on oil crops and be expected to cut down the manufacturing cost. RESULTS: In this study, the industrially important microorganism Escherichia coli was engineered to produce HFAs directly from glucose. Through the coexpression of the acetyl-CoA carboxylase (ACCase) and the leadless acyl-CoA thioesterase ('TesA), and knockout of the endogenous acyl-CoA synthetase (FadD), an engineered E. coli strain was constructed to efficiently synthesize free fatty acids (FFAs). Under shake-flask conditions, 244.8 mg/L of FFAs were obtained by a 12 h induced culture. Then the fatty acid hydroxylase (CYP102A1) from Bacillus megaterium was introduced into this strain and high level production of HFAs was achieved. The finally engineered strain BL21DeltafadD/pE-A1'tesA&pA-acc accumulated up to 58.7 mg/L of HFAs in the culture broth. About 24 % of the FFAs generated by the thioesterase were converted to HFAs. Fatty acid composition analysis showed that the HFAs mainly consisted of 9-hydroxydecanoic acid (9-OH-C10), 11-hydroxydodecanoic acid (11-OH C12), 10-hydroxyhexadecanoic acid (10-OH-C16) and 12-hydroxyoctadecanoic acid (12 OH-C18). Fed-batch fermentation of this strain further increased the final titer of HFAs to 548 mg/L. CONCLUSIONS: A robust HFA-producing strain was successfully constructed using glucose as the feedstock, which demonstrated a novel strategy for bioproduction of HFAs. The results of this work suggest that metabolically engineered E. coli has the potential to be a microbial cell factory for large scale production of HFAs. PMID- 26956723 TI - Anesthetic care and perioperative complications in children with Sanfilipo Syndrome Type A. AB - BACKGROUND: Patients with mucopolysaccharidoses (MPS) are generally considered high risk for anesthesia care, owing to disease-related factors. Sanfilippo syndrome type A (MPS IIIA) is the most frequently occurring MPS. Anesthesia specific information for MPS IIIA is not readily available in the literature. OBJECTIVES: To report post hoc analyses on anesthesia care and outcomes from a 2 year study of the natural history of patients with untreated MPS IIIA (NCT01047306). METHODS: Subjects were >=1 year of age, developmental age >=1 year, and without significant central nervous system impairment (other than that due to MPS IIIA) or issues that would preclude study procedures. Procedures requiring general anesthesia included brain/abdominal magnetic resonance imaging, lumbar puncture, and echocardiography. Sedation, intubation, and extubation procedures as well as postoperative airway problems were recorded at baseline and 6, 12, and 24 months of age. RESULTS: Twenty-five patients (baseline age, 13-220 months) received a total of 94 general anesthetics. Patients successfully received oral sedation prior to 76 of 94 anesthetics. No patients required airway intervention or oxygen supplementation during sedation. All anesthesia providers described facemask ventilation and endotracheal intubations as 'easy'. All subjects were successfully extubated after completion of the procedures. No patients required reintubation. Six (24%) patients had episodes of postoperative airway problems: wheezing (7/94, 7.4%), croup (6/94, 6.4%), and laryngospasm (2/94, 2.1%). CONCLUSION: We found no change in the modified Cormack-Lehane intubation grades in 25 Sanfilippo syndrome type A children over the 2-year study period. PMID- 26956725 TI - Does the organisational model of dementia case management make a difference in satisfaction with case management and caregiver burden? An evaluation study. AB - BACKGROUND: In the Netherlands, various organisational models of dementia case management exist. In this study the following four models are distinguished, based on differences in the availability of the service and in the case management function: Model 1: the case management service is available from first dementia symptoms + is always a separate specialist function; Model 2: the case management service is only available after a formal dementia diagnosis + is always a separate specialist function; Model 3: the case management service is available from first dementia symptoms + is often a combined function; Model 4: the case management service is only available after a formal dementia diagnosis + is often a combined function. The objectives of this study are to give insight into whether satisfaction with dementia case management and the development of caregiver burden depend on the organisational model. METHODS: A survey was carried out in regional dementia care networks in the Netherlands among 554 informal carers for people with dementia at the start of case management (response of 85 %), and one year later. Descriptive statistics and multilevel models were used to analyse the data. RESULTS: The satisfaction with the case manager was high in general (an average of 8.0 within a possible range of 1 to 10), although the caregiver burden did not decrease in the first year after starting with case management. No differences were found between the four organisational models regarding the development of caregiver burden. However, statistically significant differences (p < 0.05) were found regarding satisfaction: informal carers in the organisational model where case management is only available after formal diagnosis of dementia and is often a combined function had on average the lowest satisfaction scores. Nevertheless, the satisfaction of informal carers within all organisational models was high (ranging from 7.51 to 8.40 within a range of 1 to 10). CONCLUSIONS: Organisational features of case management seem to make little or no difference to the development in caregiver burden and the satisfaction of informal carers. Future research is needed to explore whether the individual characteristics of the case managers themselves are associated with case management outcomes. PMID- 26956724 TI - Transcriptomic responses of the basidiomycete yeast Sporobolomyces sp. to the mycotoxin patulin. AB - BACKGROUND: Patulin is a mycotoxin produced by Penicillium expansum, the causal agent of blue mold of stored pome fruits, and several other species of filamentous fungi. This mycotoxin has genotoxic, teratogenic and immunotoxic effects in mammals, and its presence in pome fruits and derived products represents a serious health hazard. Biocontrol agents in the Pucciniomycotina, such as the yeasts Sporobolomyces sp. strain IAM 13481 and Rhodosporidium kratochvilovae strain LS11, are able to resist patulin and degrade it into the less toxic compounds desoxypatulinic acid and ascladiol. RESULTS: In this investigation we applied a transcriptomic approach based on RNAseq to annotate the genome of Sporobolomyces sp. IAM 13481 and then study the changes of gene expression in Sporobolomyces sp. exposed to patulin. Patulin treatment leads to ROS production and oxidative stress that result in the activation of stress response mechanisms controlled by transcription factors. Upregulated Sporobolomyces genes were those involved in oxidation-reduction and transport processes, suggesting the activation of defense mechanisms to resist patulin toxicity and expel the mycotoxin out of the cells. Other upregulated genes encoded proteins involved in metabolic processes such as those of the glutathione and thioredoxin systems, which are essential to restore the cellular redox homeostasis. Conversely, patulin treatment decreased the expression of genes involved in the processes of protein synthesis and modification, such as transcription, RNA processing, translation, protein phosphorylation and biosynthesis of amino acids. Also, genes encoding proteins involved in transport of ions, cell division and cell cycle were downregulated. This indicates a reduction of metabolic activity, probably due to the high energy requirement by the cells or metabolic arrest while recovering from the insult caused by patulin toxicity. CONCLUSIONS: Complex mechanisms are activated in a biocontrol yeast in response to patulin. The genes identified in this study can pave the way to develop i) a biodetoxification process of patulin in juices and ii) a biosensor for the rapid and cost-effective detection of this mycotoxin. PMID- 26956726 TI - A tailored intervention to implement guideline recommendations for elderly patients with depression in primary care: a pragmatic cluster randomised trial. AB - BACKGROUND: Elderly patients with depression are underdiagnosed, undertreated and run a high risk of a chronic course. General practitioners adhere to clinical practice guidelines to a limited degree. In the international research project Tailored Implementation for Chronic Diseases, we tested the effectiveness of tailored interventions to improve care for patients with chronic diseases. In Norway, we examined this approach to improve adherence to six guideline recommendations for elderly patients with depression targeting healthcare professionals, patients and administrators. METHODS: We conducted a cluster randomised trial in 80 Norwegian municipalities. We identified determinants of practice for six recommendations and subsequently tailored interventions to address these determinants. The interventions targeted healthcare professionals, administrators and patients and consisted of outreach visits, a website presenting the recommendations and the underlying evidence, tools to manage depression in the elderly and other web-based resources, including a continuous medical education course for general practitioners. The primary outcome was mean adherence to the recommendations. Secondary outcomes were improvement in depression symptoms as measured by patients and general practitioners. We offered outreach visits to all general practitioners and practice staff in the intervention municipalities. We used electronic software that extracted eligible patients from the general practitioners' lists. We collected data by interviewing general practitioners or sending them a questionnaire about their practice for four patients on their list and by sending a questionnaire to the patients. RESULTS: One hundred twenty-four of the 900 general practitioners (14 %) participated in the data collection, 51 in the intervention group and 73 in the control group. We interviewed 77 general practitioners, 47 general practitioners completed the questionnaire, and 134 patients responded to the questionnaire. Amongst the general practitioners who provided data, adherence to the recommendations was 1.6 percentage points higher in the intervention group than in the control group (95 % CI -6 to 9). CONCLUSIONS: The effectiveness of our tailored intervention to implement recommendations for elderly patients with depression in primary care is uncertain, due to the low response rate in the data collection. However, it is unlikely that the effect was large. It remains uncertain how best to improve adherence to evidence-based recommendations and thereby improve the quality of care for these patients. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01913236 . PMID- 26956727 TI - Voltage-sensor conformation shapes the intra-membrane drug binding site that determines gambierol affinity in Kv channels. AB - Marine ladder-shaped polyether toxins are implicated in neurological symptoms of fish-borne food poisonings. The toxin gambierol, produced by the marine dinoflagellate Gambierdiscus toxicus, belongs to the group of ladder-shaped polyether toxins and inhibits Kv3.1 channels with nanomolar affinity through a mechanism of gating modification. Binding determinants for gambierol localize at the lipid-exposed interface of the pore forming S5 and S6 segments, suggesting that gambierol binds outside of the permeation pathway. To explore a possible involvement of the voltage-sensing domain (VSD), we made different chimeric channels between Kv3.1 and Kv2.1, exchanging distinct parts of the gating machinery. Our results showed that neither the electro-mechanical coupling nor the S1-S3a region of the VSD affect gambierol sensitivity. In contrast, the S3b S4 part of the VSD (paddle motif) decreased gambierol sensitivity in Kv3.1 more than 100-fold. Structure determination by homology modeling indicated that the position of the S3b-S4 paddle and its primary structure defines the shape and?or the accessibility of the binding site for gambierol, explaining the observed differences in gambierol affinity between the channel chimeras. Furthermore, these findings explain the observed difference in gambierol affinity for the closed and open channel configurations of Kv3.1, opening new possibilities for exploring the VSDs as selectivity determinants in drug design. PMID- 26956729 TI - Epstein Barr Virus and Mycobacterium avium subsp. paratuberculosis peptides are recognized in sera and cerebrospinal fluid of MS patients. AB - Mycobacterium avium subsp. paratuberculosis (MAP) and Epstein-Barr virus (EBV) epitopes elicit a consistent humoral response in serum of multiple sclerosis patients, but the cross reactivity against the homologous myelin basic protein (MBP) and human interferon regulatory factor 5 (IRF5) has not been searched within the Cerebral Spinal Fluid (CSF). We evaluated in sera and CSF of patients with MS and with other neurological diseases (OND) the humoral response against EBV/MAP peptides and the IRF5/MBP. Our data showed that EBV and MAP peptides are able to induce a specific humoral immune response in MS patients compared to OND controls both in serum and in CSF. An intrathecal specific synthesis of IgG against MBP and their EBV and MAP homologous as indicated by the antibody index was observed in MS patients. The humoral response against EBV, MAP, MBP and IRF5 was significantly higher in MS patients compared to OND both in serum and in CSF. The higher presence of antibodies against MBP and their MAP and EBV homologous in CSF during relapses suggests a possible role of the pathogens in enhancing inflammation. PMID- 26956730 TI - A validated active contour method driven by parabolic arc model for detection and segmentation of mitochondria. AB - Recent studies reveal that mitochondria take substantial responsibility in cellular functions that are closely related to aging diseases caused by degeneration of neurons. These studies emphasize that the membrane and crista morphology of a mitochondrion should receive attention in order to investigate the link between mitochondrial function and its physical structure. Electron microscope tomography (EMT) allows analysis of the inner structures of mitochondria by providing highly detailed visual data from large volumes. Computerized segmentation of mitochondria with minimum manual effort is essential to accelerate the study of mitochondrial structure/function relationships. In this work, we improved and extended our previous attempts to detect and segment mitochondria from transmission electron microcopy (TEM) images. A parabolic arc model was utilized to extract membrane structures. Then, curve energy based active contours were employed to obtain roughly outlined candidate mitochondrial regions. Finally, a validation process was applied to obtain the final segmentation data. 3D extension of the algorithm is also presented in this paper. Our method achieved an average F-score performance of 0.84. Average Dice Similarity Coefficient and boundary error were measured as 0.87 and 14nm respectively. PMID- 26956731 TI - Shear-induced amyloid fibrillization: the role of inertia. AB - Agitation of protein is known to induce deleterious effects on protein stability and structure, with extreme agitation sometimes resulting in complete aggregation into amyloid fibrils. Many mechanisms have been proposed to explain how protein becomes unstable when subjected to flow, including alignment of protein species, shear-induced unfolding, simple mixing, or fragmentation of existing fibrils to create new seeds. Here a shearing flow was imposed on a solution of monomeric human insulin via a rotating Couette device with a small hydrophobic fluid interface. The results indicate that even very low levels of shear are capable of accelerating amyloid fibril formation. Simulations of the flow suggest that the shear enhances fibrillization kinetics when flow inertia is non-negligible and the resulting meridional circulation allows for advection of bulk protein to the hydrophobic interface. PMID- 26956732 TI - Aromatic character of planar boron-based clusters revisited by ring current calculations. AB - The planarity of small boron-based clusters is the result of an interplay between geometry, electron delocalization, covalent bonding and stability. These compounds contain two different bonding patterns involving both sigma and pi delocalized bonds, and up to now, their aromaticity has been assigned mainly using the classical (4N + 2) electron count for both types of electrons. In the present study, we reexplored the aromatic feature of different types of planar boron-based clusters making use of the ring current approach. B3(+/-), B4(2-), B5(+/-), B6, B7(-), B8(2-), B9(-), B10(2-), B11(-), B12, B13(+), B14(2-) and B16(2-) are characterized by magnetic responses to be doubly sigma and pi aromatic species in which the pi aromaticity can be predicted using the (4N + 2) electron count. The triply aromatic character of B12 and B13(+) is confirmed. The pi electrons of B18(2-), B19(-) and B20(2-) obey the disk aromaticity rule with an electronic configuration of [1sigma(2)1pi(4)1delta(4)2sigma(2)] rather than the (4N + 2) count. The double aromaticity feature is observed for boron hydride cycles including B@B5H5(+), Li7B5H5 and M@BnHn(q) clusters from both the (4N + 2) rule and ring current maps. The double pi and sigma aromaticity in carbon-boron planar cycles B7C(-), B8C, B6C2, B9C(-), B8C2 and B7C3(-) is in conflict with the Huckel electron count. This is also the case for the ions B11C5(+/-) whose ring current indicators suggest that they belong to the class of double aromaticity, in which the pi electrons obey the disk aromaticity characteristics. In many clusters, the classical electron count cannot be applied, and the magnetic responses of the electron density expressed in terms of the ring current provide us with a more consistent criterion for determining their aromatic character. PMID- 26956728 TI - Bit1 knockdown contributes to growth suppression as well as the decreases of migration and invasion abilities in esophageal squamous cell carcinoma via suppressing FAK-paxillin pathway. AB - BACKGROUND: There is growing evidence that Bit1 exerts different roles in the development and progression of human cancers. Although Bit1 was highly exhibited in ESCC tissues in our previous study, its roles and molecular mechanisms implicated in development and progression of ESCC remain unknown. METHODS: Bit1 protein expression in ESCC cell lines and normal esophageal epithelial cell was detected by Western blotting. Bit1 protein expression mediated by Bit1 shRNA was investigated by Western blotting. MTT, migration assay, invasion experiment, ELISA and Flow cytometry were utilized to determine the effects of Bit1 knockdown on cell proliferation, migration, invasion and apoptosis, respectively. A xenograft model was used to examine in vivo tumourigenicity, and immunohistochemistry and TUNEL were utilized to evaluate the related protein expression and apoptosis. Gene microarray was determined by Agilent SurePrint G3 Human GE 8 * 60 K Microarray, the interaction of Bit1 and FAK proteins were detected by Immunoprecipitation and the key protein expressions of FAK-paxillin pathway were detected by Western blotting. RESULTS: We found Bit1 expression in all human ESCC cell lines tested was significantly higher than that in normal esophageal epithelial cell Het-1A (P < 0.05), in which EC9706 presented the highest Bit1 level. Bit1 protein level was significantly downregulated at day 1 after transfection with specific shRNA against Bit1 (P < 0.05). At days 2 and 3, Bit1 level reached the lowest value after transfection with Bit1 shRNA. Moreover, Bit1 depletion contributed to growth inhibition in vitro and in vivo, reduced cell migration and invasion abilities, and induced cell apoptosis in EC9706 and TE1 cells. More importantly, Bit1 downregulation significantly lowered Bcl-2 and MMP-2 levels in EC9706 xenografted tumor tissues, meanwhile triggered apoptosis after treatment with different doses of Bit1 shRNA. Further gene microarray revealed that 23 genes in Bit1-RNAi group were markedly downregulated, whereas 16 genes were obviously upregulated. Notably, Bit1 intrinsically interacted with FAK protein in EC9706 cells. Moreover, paxillin was downregulated at mRNA and protein levels in Bit1 shRNA group, coupled with the decreases of FAK mRNA and protein expressions. CONCLUSION: Bit1 may be an important regulator in cell growth, apoptosis, migration and invasion of ESCC via targeting FAK-paxillin pathway, and thereby combinative manipulation of Bit1 and FAK-paxillin pathway may be the novel and promising therapeutic targets for the patients with ESCC. PMID- 26956733 TI - The ALPPS procedure as a novel "liver-first" approach in treating liver metastases of colon cancer: the first experience in Greek Cypriot area. AB - BACKGROUND: Despite recent advances in multimodality and multidisciplinary treatment of colorectal liver metastases, many patients suffer from extensive bilobar disease, which prevents the performance of a single procedure due to an insufficient future liver remnant (FLR). We present a novel indication for associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) as a "liver-first" approach when inadequate FLR was faced preoperatively, in a patient with extensive bilobar liver metastatic disease of colon cancer origin. CASE PRESENTATION: A 51-year-old lady was referred to our center due to a stage IV colon cancer with extensive bilobar liver disease and synchronous colon obstruction. During the multidisciplinary tumor board, it was recommended to proceed first in a palliative loop colostomy (at the level of transverse colon) operation and afterwards to offer her palliative chemotherapy. After seven cycles of chemotherapy, the patient was re-evaluated by CT scans that revealed an excellent response (>30%), but the metastatic liver disease was still considered inoperable. Moreover, with the completion of 12 cycles, the indicated restaging process showed further response. Subsequent to a thorough review by the multidisciplinary team, it was decided to proceed to the ALPPS procedure as a feasible means to perform extensive or bilobar liver resections, combined with a decreased risk of tumor progression in the interim. CONCLUSIONS: All in all, ALPPS can offer a feasible but surgically demanding liver-first approach with satisfactory short-term results in selected patients. Larger studies are mandatory to evaluate short- and long-term results of the procedure on survival, morbidity, and mortality. PMID- 26956734 TI - Prosthetic heart valve selection in women of childbearing age with acquired heart disease: a case report. AB - BACKGROUND: The problem of prosthetic heart valve selection in fertile women with acquired heart defects remains crucial in modern cardiology. Mechanical heart valves require lifelong indirect anticoagulant therapy, which has significant fetal toxicity and is unacceptable for women planning pregnancy. Bioprosthetic heart valves are the best choice for fertile women; however, their durability is limited, and reoperations are required. CASE PRESENTATION: We describe the clinical case of a 21-year-old Russian woman with infectious endocarditis who underwent heart valve replacement with an epoxy-treated mitral valve prosthesis. CONCLUSIONS: Epoxy-treated bioprosthetic heart valves can be used without long term anticoagulant therapy because of their optimal hemodynamic functional parameters. Moreover, their high thromboresistance and resistance to infection improve patients' quality of life in their late postoperative period. We recommend these valves both in older persons and in young patients including women who are planning pregnancy. PMID- 26956736 TI - The TRH-test in depression: a review. AB - The TRH-test in depression: a review This paper reviews the literature on the thyrotropin releasing hormone (TRH)-test in depressive patients. The TRH-test appears to exhibit some use as an external validating criterion for the clinical diagnosis of major depression and, in particular melancholia versus minor depression once the clinical diagnosis depression is made. However, the clinical use of this test is hampered by the low sensitivity (+/-50%) and by the fact that abnormal tests occur in non-depressive states such as borderline personality disorder, schizophrenia, and anxiety disorders. The TRH-test may be used as a predictor for a positive response to biological therapies. In addition, the test has some value for the outcome of a depressive episode. The pathophysiology underpinning an abnormal TRH-test may be determined by noradrenergic (central and peripheric) or serotonergic (central) dysfunctions, thyroid hormone and cortisol hypersecretion, phenomena that are pertinent to severe depression. Recently, it has been established that an abnormal depression-linked TRH-test reflects lower basal thyroid secreting hormone (TSH) secretion. The determination of basal TSH may, in the future, replace TRH-testing. PMID- 26956737 TI - Congenital malformations caused by psychotropic drugs in pregnancy. AB - After a description of the harmful effects of psychotropic drugs as well as of the moments of vulnerability to any teratogenic effect, this paper reviews prospective, retrospective and epidemiological studies of the teratogenic effects of anticonvulsants (phenytoin, valproic acid, carbamazepine and barbiturates), lithium, anti-psychotics, benzodiazepines and anti-depressive agents. It is found that the results of these studies are not unequivocal. Only lithium and valproic acid are shown to be teratogenic. In cases where malformations of the fetus are observed, the treatment often consisted in a combination of various psychotropic drugs. The review is completed with data on the psychopharmacological problems during delivery and their side-effects on the newborn. PMID- 26956738 TI - Interrater reliability of the Hamilton Rating Scale for Depression. AB - Interrater reliability of the Hamilton Rating Scale for Depression Interrater reliability of the Dutch version of the Hamilton Rating Scale for Depression (HRSD 17 items) was investigated. Although sufficient, a kappa of .65, found for all raters, was not very high. Specifically item 2 (feelings of guilt) and item 11 (psychic anxiety) seemed difficult to judge. The most experienced raters achieved the highest kappas as well on the total score of the HRSD. It is concluded that this version of the HRSD, if administered by experienced raters, is a reasonably reliable instrument to obtain a certain 'cut-off score (for instance in-exclusion criterium) as well as to measure the change in severity of the depression during treatment. PMID- 26956735 TI - HPV infection and vaccination in Systemic Lupus Erythematosus patients: what we really should know. AB - Patients with Systemic Lupus Erythematosus (SLE) are at increased risk for infections. Vaccination is a powerful tool to prevent infections, even in immunocompromised patients. Most non-live vaccines are immunogenic and safe in patients with SLE, even if antibody titres are frequently lower than those of healthy controls. Human papillomavirus (HPV) infections are more prevalent in SLE patients when compared to the healthy population. Low-risk types of this virus cause anogenital warts, while high risk types are strongly related to pre malignant cervical abnormalities and cervical cancer. HPV vaccines have been developed to prevent these conditions. Although little is known about HPV vaccination in SLE, few studies in patients with autoimmune rheumatic diseases (AIRDs) have shown that HPV vaccines are safe, and capable to induce an immunogenic response in this group of patients. To date, available data suggest that HPV vaccines can be given safely to SLE patients. Given the increased incidence of cervical abnormalities due to HPV in SLE patients, this vaccination should be encouraged. PMID- 26956739 TI - Neuroleptics: preclinical and clinical differences. AB - Neuroleptics: preclinical and clinical differences In this review we propose that the clinical and preclinical effects of neuroleptic drugs justify a distinction between classical and atypical neuroleptic drugs. Binding, biochemical, electrophysiological and behavioural studies have revealed clearcut differences between classical neuroleptics (like haloperidol and fluphenazine) and atypical neuroleptics (such as clozapine, thioridazine and remoxipride). These large differences are likely due to differences in the workingmechanisms. In view of the clinical relevance of these findings it is therefore both justified and essential to subdivide the neuroleptics in two distinct groups: the classical neuroleptics and the atypical neuroleptics. PMID- 26956740 TI - Apoptosis Factors of Lens Epithelial Cells Responsible for Cataractogenesis in Vitrectomized Eyes with Silicone Oil Tamponade. AB - BACKGROUND: The aim of this study was to determine the expression of apoptotic factors Bax, Bcl-2, and Caspase-3 in lens epithelial cells (LECs) from cataracts secondary to pars plana vitrectomy with silicone oil (SO) tamponade. We also investigated the impact of SO emulsification on the expression of apoptotic factors. MATERIAL/METHODS: Anterior capsulotomy specimens of 20 eyes in 20 patients with cataract secondary to SO tamponade (Group 2), were collected. Another 20 eyes of 20 patients with age-related cataract (Group 1) were recruited as controls. The anterior capsule specimens were obtained from the patients during cataract surgery, frozen and later analyzed with respect to immunohistochemical stains of Bax, Bcl-2, and Caspase-3 using a confocal microscope. RESULTS: Age, sex, and laterality did not show any difference between the 2 groups. There was a greater increase in Bax and Caspase-3 expression in LEC in Group 2 than in Group 1 (P(Bax)<0.0001, P(Caspase-3)<0.0001). The Bcl-2 expression decreased in Group 2, although the difference was not significant (P=0.616). The changes of apoptosis factors are not associated to SO emulsification (P(Bax)=0.354, P(Bcl-2)=0.728, P(Caspase-3)=0.939). CONCLUSIONS: The caspase-3-dependent apoptosis of LECs increased in complicated cataract patients with SO endotamponade. The Bax played a critical role in regulating apoptosis of LECs in vitrectomized eyes with SO tamponade. The SO emulsification had no significant impact on the expression of apoptosis factors. PMID- 26956741 TI - Drug addiction stigma in relation to methadone maintenance treatment by different service delivery models in Vietnam. AB - BACKGROUND: The rapid expansion of methadone maintenance treatment (MMT) services has significantly improved health status and quality of life of patients. However, little is known about its impacts on addiction-related stigma and associated factors. METHODS: A cross-sectional survey was conducted in 2013 in Vietnam's capital, Hanoi, and Nam Dinh province among 1016 methadone maintenance patients; 26.6 % at provincial AIDS centers (PAC) and 73.4 % at district health centers (DHC), respectively. Drug addiction history and related stigma, health status, MMT-related covariates, and sociodemographic characteristics were interviewed. RESULTS: More than one-sixth of the sample reported experiencing felt or enacted stigma, including Blame or Judgement (17.2 %), Shame (19.9 %), or Others' fear of HIV transmission (17.1 %). These proportions were higher in PACs than in DHCs, which are integrated with other HIV or general health care services. Very few patients reported being discriminated at the workplace (2.5 %) or at health care services (1.7 %); however, 15.6 % of patients at PACs and 10.6 % of patients at DHCs reported discrimination in their communities. Drug users taking MMT for longer periods were less likely to report felt stigma. Other factors associated with stigma against MMT patients included the lack of comprehensive services, higher education, presence of pain/discomfort, and anxiety/depression, self-reported HIV positive, and number of previous drug rehabilitation episodes. CONCLUSION: The study shows a high level of stigma against MMT patients and emphasizes the necessity to integrate MMT with comprehensive health and support services. Mass communication campaigns to reduce stigma against people with drug addiction and HIV/AIDS, as well as vocational trainings and jobs referrals for MMT patients, are needed to maximize the benefits of MMT programs in Vietnam. PMID- 26956742 TI - Induced hypernatraemia is protective in acute lung injury. AB - BACKGROUND: Sucrose induced hyperosmolarity is lung protective but the safety of administering hyperosmolar sucrose in patients is unknown. Hypertonic saline is commonly used to produce hyperosmolarity aimed at reducing intra cranial pressure in patients with intracranial pathology. Therefore we studied the protective effects of 20% saline in a lipopolysaccharide lung injury rat model. 20% saline was also compared with other commonly used fluids. METHODS: Following lipopolysaccharide-induced acute lung injury, male Sprague Dawley rats received either 20% hypertonic saline, 0.9% saline, 4% albumin, 20% albumin, 5% glucose or 20% albumin with 5% glucose, i.v. During 2h of non-injurious mechanical ventilation parameters of acute lung injury were assessed. RESULTS: Hypertonic saline resulted in hypernatraemia (160 (1) mmol/l, mean (SD)) maintained through 2h of ventilation, and in amelioration of lung oedema, myeloperoxidase, bronchoalveolar cell infiltrate, total soluble protein and inflammatory cytokines, and lung histological injury score, compared with positive control and all other fluids (p <= 0.001). Lung physiology was maintained (conserved PaO2, elastance), associated with preservation of alveolar surfactant (p <= 0.0001). CONCLUSION: Independent of fluid or sodium load, induced hypernatraemia is lung protective in lipopolysaccharide-induced acute lung injury. PMID- 26956744 TI - Shifting Sands. PMID- 26956743 TI - In vivo estimates of NO and CO conductance for haemoglobin and for lung transfer in humans. AB - Membrane conductance (Dm) and capillary lung volume (Vc) derived from NO and CO lung transfer measurements in humans depend on the blood conductance (theta) values of both gases. Many theta values have been proposed in the literature. In the present study, measurements of CO and NO transfer while breathing 15% or 21% O2 allowed the estimation of thetaNO and the calculation of the optimal equation relating 1/thetaCO to pulmonary capillary oxygen pressure (PcapO2). In 10 healthy subjects, the mean calculated thetaNO value was similar to the thetaNO value previously reported in the literature (4.5mmHgmin(-1)) provided that one among three thetaCO equations from the literature was chosen. Setting 1/thetaCO=a.PcapO2+b, optimal values of a and b could be chosen using two methods: 1) by minimizing the difference between Dm/Vc ratios for any PcapO2, 2) by establishing a linear equation relating a and b. Using these methods, we are proposing the equation 1/thetaCO=0.0062.PcapO2+1.16, which is similar to two equations previously reported in the literature. With this set of theta values, DmCO reached the morphometric range. PMID- 26956745 TI - Behavioral Outcomes of Supervisory Education in the Association for Clinical Pastoral Education: A Qualitative Research Study. AB - This study advances the work of developing a theory for educating Clinical Pastoral Education (CPE) Supervisors by describing the behaviors which result from the successful completion of CPE supervisory education. Twenty-eight Association for Clinical Pastoral Education (ACPE) Certification Commissioners were interviewed to identify the behaviors demonstrated by Supervisory Education Students (Candidates) which influenced the decision to certify them at the level of Associate Supervisor. Specific behavioral descriptors are listed for each ACPE supervisory competency. PMID- 26956746 TI - 'Out of the Whirlwind': Clinical Pastoral Education and Climate Change. AB - This article traces the development of an innovative program of Clinical Pastoral Education (CPE), conducted in 2013 in Victoria, Australia. Interns were placed in environmental contexts; the program's aim was to enhance the eco-ministry identity of interns as they attended to the anxieties and concerns of people affected by ecological change, as well as listening to the cries and groans of Earth. In this sense, pastoral care acknowledges the environment and our human presence within it as of religious and spiritual concern. The theological and supervisory rationales of the program are outlined and include a careful alignment of parallel competencies with the existing objectives and standards required for accreditation. Guidelines for sacred practice in nature, place/case study and the more-than-human verbatims are described, and an illustrative example of such a verbatim is also included. PMID- 26956747 TI - The Spiral Staircase: A Narrative Approach to Pastoral Conversation. AB - The following is a patient-centered pastoral conversation paradigm to be used by chaplains, pastors, or any other spiritual care provider, in engaging in healing conversation with patients, clients, or parishioners. It is based on the intimate, interpathic incarnation of oneself into another's story. PMID- 26956748 TI - Predictors of Clergy's Ability to Fulfill a Suicide Prevention Gatekeeper Role. AB - Catholic, Jewish and Protestant clergy (n = 801) completed a survey to identify predictors of clergy's ability to fulfill a suicide gatekeeper role. Exploratory backward stepwise regression identified predictors of risk identification including suicide knowledge, religion, conducting suicide funerals, having an attitude that people have a right to die, age, and race. Predictors of ability to intervene include suicide knowledge, training, religion, right to die attitude, and ethnicity. Recommendations include more suicide training and clergy self care. PMID- 26956749 TI - Spiritual Care and CPE: 2nd Year Experience. AB - The aim of this article is to provide the experience of one chaplain resident in a clinical pastoral education program specializing in women and infants health and the intersection of professional spiritual care for this particular patient population. Spiritual care can be an elusive, non-tangible form of professional healthcare, and so within the clinical setting the chaplain is called to act as spiritual care provider, emotions facilitator, grief counselor, cultural and religious expert and administrative specialist in decedent care. Gaining a better perspective on the contributions the clinical chaplain makes in healthcare allows other clinicians (nurses and physicians) to better serve and provide quality holistic care to patients and their families during moments of great emotional, spiritual and psychosocial loss and grief. Both nursing and physician staff must be aware of the relevance, importance and complementary role of the spiritual care provider (clinical chaplain) in the provision of quality holistic healthcare. PMID- 26956750 TI - 'Paramedical' Healing in Hospitals: The Expansion of Spiritual Care in Seoul. AB - Emotional and spiritual healing stand at the center of the activity of Catholic pastoral caregivers attending to the sick in non-Catholic hospitals in Seoul. In this paper I explore how these agents understand their practice as part of a holistic human healing, positioning their work side by side with medical healing. I also examine how their role is both confirmed and challenged against the backdrop of the growing commercialization of the health care industry under the neoliberal paradigm. PMID- 26956751 TI - Spiritual Care Education and Rural Systems in Swan River. AB - The provision of spiritual care, and the training of spiritual care providers, must be embedded within the larger systems (economic, social, generational, and environmental) and communities within which clients reside. This study analyzes the results of a systems approach to CPE training that focused on the rural context of Swan River, Manitoba. It addresses the need for new approaches to contextualizing CPE training and for understanding the uniqueness of rural contexts in particular. PMID- 26956752 TI - Ethics, Politics, and Religion in Public Health Care: A Manifesto for Health Care Chaplains in Canada. AB - Health care chaplaincy positions in Canada are significantly threatened due to widespread health care cutbacks. Yet the current time also presents a significant opportunity for spiritual care providers. This article argues that religion and spirituality in Canada are undergoing significant changes. The question for Canadian health care chaplains is, then: how well equipped are they to understand these changes in health care settings and to engage them? This article attempts to go part way toward an answer. PMID- 26956753 TI - Art at the Bedside: Reflections on Use of Visual Imagery in Hospital Chaplaincy. AB - 'Art at the Bedside' is the name given to a hospital visitation program during which works of art loaded onto a computer are used to start conversations with patients and their families. The article traces the genesis of the program that evolved from the author's dual training in art museum education and hospital chaplaincy through the evolution of the practice, now in its sixth year. Reflections on the practice itself are the focus of this article, from identifying the kinds of responses frequently elicited by the artwork to understanding how these works of art seem to forge immediate connections between the patient and the facilitator. Ultimately posed in this reflection is whether the 'Art at the Bedside' experience might suggest a future for the integration of the visual arts more broadly into hospital - and related - chaplaincy. PMID- 26956754 TI - The Need to Be Seen. AB - When we recognize our common humanity, suspend judgment and embrace the intrinsic value and worth of every individual, we elevate those we serve, and we elevate ourselves. Whether or not we are able to offer cure, we are always capable of fulfilling our mission to heal. PMID- 26956755 TI - The Haircut. AB - The article describes my experience - and the lessons learned - with a terminally ill patient in 1977 as a clinical pastoral education chaplain intern. PMID- 26956756 TI - No Child Left in the Morgue: Standing in as Hope's Family. AB - This personal reflection expresses a chaplaincy department's feelings as they became the surrogate family for a child whose body was abandoned by its mother in the hospital morgue. PMID- 26956757 TI - The Gift Relationship: Discovering Gift Exchange in Interpersonal Practice. AB - Encountering the deeper flows of human experience and glimpsing the touch of the divine on the human soul offer guides and companions rich reflective content for their ongoing formation. This is a precious gift which pilgrims constantly place before their companions, though at times it remains 'unwrapped'. Through offering a supervision narrative, this paper provides a phenomenological description of such a gift exchange. PMID- 26956758 TI - Promises, Promises. AB - Presenting a pledge to another establishes expectation in the recipient for the commitment to be fulfilled, particularly when a promise is devoid of coercion. Defaulting on a commitment may damage relationships between people and may predispose the disenchanted recipient to distrust those who proffer succeeding commitments. God's advocates who have been disappointed by God's evident under delivery may experience a crisis of faith, exemplified in attachment distress, when disappointment intimates God has over-promised his providence, which questions the nature and, ultimately, the relevance of God. PMID- 26956759 TI - In the Media. PMID- 26956765 TI - Composition and Diversity of Avian Communities Using a New Urban Habitat: Green Roofs. AB - Green roofs on buildings are becoming popular and represent a new component of the urban landscape. Public benefits of green roof projects include reduced stormwater runoff, improved air quality, reduced urban heat island effects, and aesthetic values. As part of a city-wide plan, several green roofs have been constructed at Chicago's O'Hare International Airport (ORD). Like some other landscaping features, green roofs on or near an airport might attract wildlife and thus increase the risk of bird-aircraft collisions. During 2007-2011, we conducted a series of studies to evaluate wildlife use of newly constructed green roofs and traditional (gravel) roofs on buildings at ORD. These green roofs were 0.04-1.62 ha in area and consisted of primarily stonecrop species for vegetation. A total of 188 birds were observed using roofs during this research. Of the birds using green roofs, 66, 23, and 4 % were Killdeer, European Starlings, and Mourning Doves, respectively. Killdeer nested on green roofs, whereas the other species perched, foraged, or loafed. Birds used green roofs almost exclusively between May and October. Overall, avian use of the green roofs was minimal and similar to that of buildings with traditional roofs. Although green roofs with other vegetation types might offer forage or cover to birds and thus attract potentially hazardous wildlife, the stonecrop-vegetated green roofs in this study did not increase the risk of bird-aircraft collisions. PMID- 26956764 TI - A "Diabetes Acute Care Day" for medical students increases their knowledge and confidence of diabetes care: a pilot study. AB - BACKGROUND: Evidence suggests that junior doctors lack the confidence and skills to manage acute/inpatient diabetes. We investigated the impact of the introduction of a "Diabetes Acute Care Day" on undergraduate medical students' knowledge and confidence in acute/inpatient diabetes. METHODS: Participants attended four short lectures on the basics of diabetes, diabetic emergencies, inpatient diabetes management and peri-operative/procedure care followed by case based learning tutorials on diabetic ketoacidosis (DKA), hyperosmolar hyperglycaemic state (HHS) and hypoglycaemia using capillary blood glucose charts to interpret and practice subsequent insulin prescription and adjustment. Participants were asked to complete multiple-choice questions and confidence questionnaires using a visual analogue score pre and post participation. RESULTS: One hundred forty-four students completed the pre-course survey and 196 completed the post-course survey. Mean confidence using a visual analogue score increased in all areas with a mean at baseline of 46.9 mm rising to 71.2 mm post participation (p < 0.001). The largest increases were in the management of HHS, patients on subcutaneous and intravenous insulin and perioperative/procedure care. The mean mark obtained in the pre-test multiple choice questions (MCQs) was 2.72 (27.2 %) and increased to 4.74 (47.4 %) on the post-score MCQs (p < 0.001). 56.9 % of participants answered all 10 pre-test MCQs with the mean number of questions answered = 4.71 rising to 82.0 % of students answered all ten questions and the mean number of questions answered = 9.56 in the post-test MCQs. CONCLUSIONS: An intensive "Diabetes Acute Care Day" consisting of themed live lectures and case-based learning tutorials is an effective way to increase medical students' knowledge and confidence in acute/inpatient diabetes. Further development and evaluation of this educational intervention is required to assess the impact of on patient care in the clinical setting post graduation. PMID- 26956769 TI - Proton Inventory and Dynamics in the Nia-S to Nia-C Transition of a [NiFe] Hydrogenase. AB - Hydrogenases (H2ases) represent one of the most striking examples of biological proton-coupled electron transfer (PCET) chemistry, functioning in facile proton reduction and H2 oxidation involving long-range proton and electron transport. Spectroscopic and electrochemical studies of the [NiFe] H2ases have identified several catalytic intermediates, but the details of their interconversion are still a matter of debate. Here we use steady state and time-resolved infrared spectroscopy, sensitive to the CO ligand of the active site iron, as a probe of the proton inventory as well as electron and proton transfer dynamics in the soluble hydrogenase I from Pyrococcus furiosus. Subtle shifts in infrared signatures associated with the Nia-C and Nia-S states as a function of pH revealed an acid-base equilibrium associated with an ionizable amino acid near the active site. Protonation of this residue was found to correlate with the photoproduct distribution that results from hydride photolysis of the Nia-C state, in which one of the two photoproduct states becomes inaccessible at low pH. Additionally, the ability to generate Nia-S via PCET from Nia-C was weakened at low pH, suggesting prior protonation of the proton acceptor. Kinetic and thermodynamic analysis of electron and proton transfer with respect to the various proton inventories was utilized to develop a chemical model for reversible hydride oxidation involving two intermediates differing in their hydrogen bonding character. PMID- 26956766 TI - CD200Fc reduces TLR4-mediated inflammatory responses in LPS-induced rat primary microglial cells via inhibition of the NF-kappaB pathway. AB - OBJECTIVE: Based on recent information, CD200Fc, a CD200R1 agonist, could attenuate the inflammatory response of microglial cells in autoimmune diseases and neuro-degeneration. However, the exact molecular mechanisms responsible for the anti-inflammatory activity of CD200Fc in microglial cells have not been elucidated. In the present study, we investigated the anti-inflammatory effects and the molecular mechanisms of CD200Fc in lipopolysaccharide (LPS)-stimulated rat primary microglial cells. METHODS: The cell viability was measured by MTT assay. The LPS-induced cytokines release (IL-1beta, IL-6, TNF-alpha, iNOS, MCP-1, and COX-2) was monitored by ELISA or real-time PCR, while NF-kappaB-related signals (MyD88, p-TAK1, TRIF, p-TBK1, p-IRF3, p-IkappaB, and NF-kappaB-P65) were assessed by real-time PCR, western blot and/or Immunofluorescent staining. RESULTS: CD200Fc and/or LPS exerted no significant cytotoxicity on microglial cells. LPS reduced the CD200R1 expression in microglial cells, and this effect was attenuated by CD200Fc. In addition, CD200Fc inhibited LPS-induced expression of TLR4 and its adapter molecules (MyD88 and p-TAK1, TRIF, p-TBK1, and p-IRF3), and abolished its interactions with MyD88, TAK1, and TRIF in microglial cells. CD200Fc also attenuated LPS-induced protein expression of p-IkappaB and NF-kappaB P65 translocation to nucleus in microglial cells. Moreover, CD200Fc suppressed the LPS-induced release of inflammatory mediators in microglial cells, including IL-1beta, IL-6, TNF-alpha, iNOS, MCP-1, and COX-2. CONCLUSION: These results indicated that CD200Fc displayed an anti-inflammatory effect in LPS-induced microglial cells by blocking TLR4-mediated NF-kappaB activation. PMID- 26956768 TI - Distinct Metabolic Signature of Human Bladder Cancer Cells Carrying an Impaired Fanconi Anemia Tumor-Suppressor Signaling Pathway. AB - Metabolic profiling has great potential to help the diagnosis and prognosis of cancer patients. Fanconi Anemia (FA) tumor-suppressor signaling has been instrumental in understanding human tumorigenesis. However, this instrumental understanding has never been demonstrated at the metabolic level. Here, we show that impaired FA signaling can lead cells to exhibit metabolic signatures of tumorigenesis. This is consistent with our original studies of the roles of FA signaling in suppressing non-FA tumorigenesis at functional and genetic levels. Using ultraperformance liquid chromatography-mass spectroscopy and gas chromatography-mass spectrometry, we characterized metabolic alterations in bladder cancer cells carrying an intact or impaired FA pathway. The latter was obtained by ectopically expressing FAVL (FAVL-high), which we previously found to be capable of inactivating FA signaling. A total of 18 metabolites, end products of cell proliferation or apoptosis, were significantly different between FAVL high and -low cells. Methionine, phenylalanine, and threonine, resulting from a tumorigenic process, were substantially increased in FAVL-high cells. With this study, we achieved genomic, functional, and metabolomic characterization of the roles of FA signaling in the development of human cancer. Furthermore, this study provides novel insights into how to translate FA basic research into strategies for producing effective biomarkers in human cancer diagnosis and prognosis. PMID- 26956767 TI - The immunomodulatory properties of human bone marrow-derived mesenchymal stromal cells are defined according to multiple immunobiological criteria. AB - OBJECTIVE: Human bone marrow-derived mesenchymal stromal cells (hBM-MSCs) are well known to modulate T cells. However, the molecular mechanisms that mark hBM MSCs immunomodulation of T cells are not fully resolved. MATERIALS AND METHODS: hBM-MSCs harvested from sternum or iliac crest of five healthy donors and characterized in accordance with the International Society of Cellular Therapy (ISCT) guidelines are co-cultured with T cells. Additionally, modulatory effects of MSCs on T-cell viability, proliferation, cytokine profile, co-stimulatory pathway, activation and immunomodulation are also determined. RESULTS: hBM-MSCs significantly reduced the expression of T-cell activation marker CD38 as well as co-stimulatory markers CD134 and CD154, whilst that of CD27 remained unchanged. BrdU, CFSE and Ki67 proliferation assays showed that hBM-MSCs reduced T-cell proliferation. Moreover, viability of T cells remained unchanged when co-cultured with hBM-MSCs. Finally, T cells when co-cultured with hBM-MSCs showed increased secretion of IL-10 and IL-11. CONCLUSION: Collectively, hBM-MSCs are able to modulate the main steps involved in T-cell response toward a tolerogenic state. Thus, establishing immunobiological criteria defining the immunosuppressive effect of hBM-MSCs is of importance to reach efficient immunotherapeutic intervention. PMID- 26956770 TI - Antitumour activity of 2-dihydroailanthone from the bark of Ailanthus altissima against U251. AB - Context The bark of Ailanthus altissima (Mill.) Swingle (Simaroubaceae) is traditionally used to treat ascariasis, diarrhoea, spermatorrhoea, bleeding and gastrointestinal diseases. Objective The objective of this study is to investigate the antitumour activity and mechanism of 2-dihydroailanthone isolated from A. altissima. Materials and methods The U251 cells were treated with 1.00, 4.00 and 8.00 MUg/mL of 2-dihydroailanthone for 48 h and the normal cells treated with 20.00 MUg/mL of 2-dihydroailanthone were tested as well. Proliferation inhibition of 2-dihydroailanthone on the cells was tested by MTT. Apoptosis and cell-cycle distribution in U251 cells with 1.00, 3.00 and 5.80 MUg/mL of 2 dihydroailanthone for 48 h were determined by flow cytometry, respectively. The expression of the apoptosis-related genes and proteins was analysed by RT-PCR and Western blot method, respectively. Results MTT assay revealed that 2 dihydroailanthone inhibited U251 cells proliferation. The cell viability of U251 cells was 62.82, 31.34 and 25.58%, and that of three normal cells was 72.75, 82.74 and 44.92%, respectively. Flow cytometry assay showed that 2 dihydroailanthone induced apoptosis and G0/G1 phase cycle arrest towards U251 cells. The late apoptotic cells were 11.37, 21.73 and 33.83%, and the cells cycle distributed in the G0/G1 accounted for 48.85, 62.77 and 64.40%, respectively. The Western blot and RT-PCR assay showed that up-regulation of pro-apoptotic bax protein and down-regulation of anti-apoptotic bcl-2 protein as well as their mRNA on U251 cells might be related to the apoptosis induction and proliferation inhibition. Conclusion An important bioactive component, 2-dihydroailanthone, has antitumour effects, enlightening a novel source of phytomedicines in tumour therapy. PMID- 26956771 TI - Oxidation Effects in Rare Earth Doped Topological Insulator Thin Films. AB - The breaking of time-reversal symmetry (TRS) in topological insulators is a prerequisite for unlocking their exotic properties and for observing the quantum anomalous Hall effect (QAHE). The incorporation of dopants which exhibit magnetic long-range order is the most promising approach for TRS-breaking. REBiTe3, wherein 50% of the Bi is substitutionally replaced by a RE atom (RE = Gd, Dy, and Ho), is a predicted QAHE system. Despite the low solubility of REs in bulk crystals of a few %, highly doped thin films have been demonstrated, which are free of secondary phases and of high crystalline quality. Here we study the effects of exposure to atmosphere of rare earth-doped Bi2(Se, Te)3 thin films using x-ray absorption spectroscopy. We demonstrate that these RE dopants are all trivalent and effectively substitute for Bi(3+) in the Bi2(Se, Te)3 matrix. We find an unexpected high degree of sample oxidation for the most highly doped samples, which is not restricted to the surface of the films. In the low-doping limit, the RE-doped films mostly show surface oxidation, which can be prevented by surface passivation, encapsulation, or in-situ cleaving to recover the topological surface state. PMID- 26956773 TI - Recovery of Interdependent Networks. AB - Recent network research has focused on the cascading failures in a system of interdependent networks and the necessary preconditions for system collapse. An important question that has not been addressed is how to repair a failing system before it suffers total breakdown. Here we introduce a recovery strategy for nodes and develop an analytic and numerical framework for studying the concurrent failure and recovery of a system of interdependent networks based on an efficient and practically reasonable strategy. Our strategy consists of repairing a fraction of failed nodes, with probability of recovery gamma, that are neighbors of the largest connected component of each constituent network. We find that, for a given initial failure of a fraction 1 - p of nodes, there is a critical probability of recovery above which the cascade is halted and the system fully restores to its initial state and below which the system abruptly collapses. As a consequence we find in the plane gamma - p of the phase diagram three distinct phases. A phase in which the system never collapses without being restored, another phase in which the recovery strategy avoids the breakdown, and a phase in which even the repairing process cannot prevent system collapse. PMID- 26956774 TI - Fine-needle aspiration cytology of non-neoplastic adrenal pathology. AB - BACKGROUND: The incidence of many fungal and parasitic lesions are on the rise over the last few decades. In this study, we have analyzed the spectrum of non malignant lesions in adrenal gland diagnosed on fine-needle aspiration biopsy (FNAB) in a tertiary health care center. METHODS: FNAB of the adrenal gland was done under CT (4 cases) and ultrasound guidance (11 cases). In six cases, the lesions were present in both the adrenal glands. Special stains were done whenever needed. No complications were encountered in any of the FNAB procedure. Detailed cytomorphological study was done along with clinical history. RESULTS: There were total of 15 cases comprising of 5 tuberculosis, 5 Histoplasma, 2 acute inflammation, 2 granulomatous inflammation, and 1 myelolipoma. Acid fast bacilli positive on Ziehl Neelsen stain were labeled as mycobacterial infection possibly tuberculosis. The capsule of Histoplasma was bright pink on Periodic Acid Schiff stain. CONCLUSIONS: FNAB is an easy, reliable, and minimally invasive method to diagnose and categorize the various benign non-neoplastic diseases of adrenal gland. Diagn. Cytopathol. 2016;44:472-476. (c) 2016 Wiley Periodicals, Inc. PMID- 26956772 TI - Spacer-free BODIPY fluorogens in antimicrobial peptides for direct imaging of fungal infection in human tissue. AB - Fluorescent antimicrobial peptides are promising structures for in situ, real time imaging of fungal infection. Here we report a fluorogenic probe to image Aspergillus fumigatus directly in human pulmonary tissue. We have developed a fluorogenic Trp-BODIPY amino acid with a spacer-free C-C linkage between Trp and a BODIPY fluorogen, which shows remarkable fluorescence enhancement in hydrophobic microenvironments. The incorporation of our fluorogenic amino acid in short antimicrobial peptides does not impair their selectivity for fungal cells, and enables rapid and direct fungal imaging without any washing steps. We have optimized the stability of our probes in human samples to perform multi-photon imaging of A. fumigatus in ex vivo human tissue. The incorporation of our unique BODIPY fluorogen in biologically relevant peptides will accelerate the development of novel imaging probes with high sensitivity and specificity. PMID- 26956775 TI - Insecticidal activity of a novel fatty acid amide derivative from Streptomyces species against Helicoverpa armigera. AB - Helicoverpa armigera, an important pest causes serious damage to grain legumes. The main objective of this study was to isolate and identify the metabolite against H. armigera from a previously characterised Streptomyces sp. CAI-155. The culture filtrate of CAI-155 was extracted using Diaion HP-20 and the active fractions were fractionated on Silica and C18 column chromatography. The C18 active fraction was further fractionated on Silica gel 60 F254 thin layer chromatography (TLC). The most active fraction (Rf 0.64) purified from TLC led to the identification of a novel metabolite N-(1-(2,2-dimethyl-5-undecyl-1,3 dioxolan-4-yl)-2-hydroxyethyl)stearamide by spectral studies. The purified metabolite showed 70-78% mortality in 2nd instar H. armigera by diet impregnation assay, detached leaf assay and greenhouse assay. The LD50 and LD90 values of the purified metabolite were 627 and 2276 ppm, respectively. Hence, this novel metabolite can be exploited for pest management in future. PMID- 26956776 TI - Poorer divided attention in children born very preterm can be explained by difficulty with each component task, not the executive requirement to dual-task. AB - Children born very preterm (VP, <= 32 weeks) exhibit poor performance on tasks of executive functioning. However, it is largely unknown whether this reflects the cumulative impact of non-executive deficits or a separable impairment in executive-level abilities. A dual-task paradigm was used in the current study to differentiate the executive processes involved in performing two simple attention tasks simultaneously. The executive-level contribution to performance was indexed by the within-subject cost incurred to single-task performance under dual-task conditions, termed dual-task cost. The participants included 77 VP children (mean age: 7.17 years) and 74 peer controls (mean age: 7.16 years) who completed Sky Search (selective attention), Score (sustained attention) and Sky Search DT (divided attention) from the Test of Everyday Attention for Children. The divided attention task requires the simultaneous performance of the selective- and sustained-attention tasks. The VP group exhibited poorer performance on the selective- and divided-attention tasks, and showed a strong trend toward poorer performance on the sustained-attention task. However, there were no significant group differences in dual-task cost. These results suggest a cumulative impact of vulnerable lower-level cognitive processes on dual-tasking or divided attention in VP children, and fail to support the hypothesis that VP children show a separable impairment in executive-level abilities. PMID- 26956777 TI - High-Oxygen-Balance Furazan Anions: A Good Choice for High-Performance Energetic Salts. AB - 3,4-Diaminofurazan was conveniently converted into energetic salts of 3,4 dinitraminofurazan that were paired with nitrogen-rich cations in fewer than three steps. Seven energetic salts were prepared and fully characterized by multinuclear ((1) H, (13) C) NMR and IR spectroscopy, differential scanning calorimetry (DSC), and elemental analysis. In addition, the structures of the ammonium salt (2), hydrazinium salt (4), hydroxylammonium salt (5), aminoguanidinium salt (7), diaminoguanidinium salt (8) and triaminoguanidinium salt of 3,4-dinitraminofurazan (9) were further confirmed by single-crystal X-ray diffraction. The densities of these salts were between 1.673 (8) and 1.791 g cm( 3) (5), whilst their oxygen balances were between -48.20 % (9) and -6.25 % (5). These salts showed high thermal stabilities, with decomposition temperatures between 179 (5) and 283 degrees C (6). Their sensitivities towards impact and friction were measured by BAM equipment to be between <1 J (9) and >40 J (6-8) and 64 N (9) and >360 N (6), respectively. The detonation performance of these compounds, which was calculated by using the EXPLO5 program, revealed detonation pressures of between 28.0 (6) and 40.5 GPa (5) and detonation velocities of between 8404 (6) and 9407 m s(-1) (5). PMID- 26956779 TI - Dengue epidemics in two distinct periods reveal distinct epidemiological, laboratorial and clinical aspects in a same scenario: analysis of the 2010 and 2013 epidemics in Mato Grosso do Sul, Brazil. AB - BACKGROUND: Dengue is a major problem in Brazil. Epidemiological and clinical aspects were characterized in patients from two epidemics which occurred in Mato Grosso do Sul, Brazil. METHODS: Dengue cases were classified according to the 2009 WHO criteria, tested by serological and molecular biology tests and analysed for nonstructural protein 1 (NS1) antigenemia. RESULTS: Dengue was confirmed in 78.7% (48/61) and 75.6% (118/156) of the cases studied in 2010 and 2013, respectively. DENV-1 and DENV-2 were the serotypes involved in the 2010 epidemic and DENV-4 in the 2013 one. Most of the cases were classified as dengue without warning; however, severe dengue was observed in 18.7% (9/48) of the cases in 2010 and less observed in DENV-4 cases. NS1 levels were higher in patients with dengue with warning signs and severe dengue in 2010. Circulating aspartate aminotransferase (AST) and alanine transferase (ALT) were altered in all groups, independently of the infecting serotype or epidemic. Patients with DENV-1 and DENV-2 presented significant lower monocyte counts when compared to patients with DENV-4. An inverse correlation was found between platelet count, leucocytes, monocytes and NS1 levels. CONCLUSIONS: Epidemics caused by the prevalence of distinct DENV serotypes had different impacts and clinical characteristics in a same scenario and, despite the occurrence of secondary infections, the DENV-4 emergence was not associated with severe cases. PMID- 26956778 TI - Emergence or improved detection of Japanese encephalitis virus in the Himalayan highlands? AB - The emergence of Japanese encephalitis virus (JEV) in the Himalayan highlands is of significant veterinary and public health concern and may be related to climate warming and anthropogenic landscape change, or simply improved surveillance. To investigate this phenomenon, a One Health approach focusing on the phylogeography of JEV, the distribution and abundance of the mosquito vectors, and seroprevalence in humans and animal reservoirs would be useful to understand the epidemiology of Japanese encephalitis in highland areas. PMID- 26956780 TI - Selenium-substituted polymers for improved photovoltaic performance. AB - Four isostructural donor-acceptor alternating polymers of benzodithiophene (BDT)/naphthodifuran (NDF) and benzoselenadiazole (BSe)/benzothiadiazole (BT) have been developed and evaluated for organic photovoltaics. The substitution of one-atom (Se for S) in the accepting units exerts remarkable impact on the optoelectronic properties of polymers. Extended absorption, narrowed bandgap and higher HOMO energy levels were observed for Se-containing polymers in comparison to their S-containing counterparts. Theoretical calculations confirmed the measurable effect on energy levels as found in experimental studies. Bulk heterojuction solar cells based on the BDT-BSe copolymer and [6,6]-phenyl-C71 butyric acid methyl ester (1 : 2, w/w) blend films deliver the best PCE of 5.40%. BSe-based polymers showed enhanced photovoltaic performances than BT-based polymers. The device performance is found to be strongly dependent on the processing conditions and morphology of the active layers. PMID- 26956782 TI - Effect of early administration of probiotics on gut microflora and feeding in pre term infants: a randomized controlled trial. AB - BACKGROUND: This study aimed to evaluate the effect of early probiotic administration on gut microflora and influence on feeding in pre-term infants. METHODS: A double-blind, randomized, controlled clinical study was conducted to assess the effect of probiotics [live, combined lactobacillus and bifidobacterium (LCB)] supplementation in pre-term infants. Sixty hospitalized pre-term babies were randomly assigned to two groups: a probiotics-supplemented group and the control group. The primary endpoint was measurement of lactobacillus and bifidobacterium in the gut. The secondary outcome was the rate of feeding intolerance. RESULTS: In the first weekend, the quantity of gut lactobacillus and bifidobacterium was significantly higher in the probiotics-supplemented group than in the control group [7.84 +/- 0.35 versus 6.39 +/- 0.53 (log copy number/g wet fecal weight), p = 0.013; 8.52 +/- 0.23 versus 7.01 +/- 0.48, p = 0.024, respectively]. In the second weekend, the amount of gut lactobacillus and bifidobacterium in the probiotics-supplemented group remained significantly higher (8.62 +/- 0.28 versus 7.34 +/- 0.59, p = 0.036 and 9.45 +/- 0.64 versus 7.85 +/- 0.43, p = 0.007, respectively). Fewer patients in the probiotics supplemented group developed a feeding intolerance (13.3% versus 46.7%, p = 0.013). CONCLUSIONS: Probiotic supplementation in the hospitalized pre-term infants in the first 2 weeks of life resulted in higher amounts of lactobacillus and bifidobacterium in the gut and a concomitant lower rate of feeding intolerance. PMID- 26956781 TI - Histopathologic diagnosis of multifactorial alopecia. AB - Establishing a definitive diagnosis for any form of alopecia can be challenging. Adding to the diagnostic complexity is the fact that many patients have more than one form of alopecia contributing to their hair loss. We conducted a review of 1360 consecutive scalp biopsy specimens submitted for the evaluation of scalp hair loss over a 16-month period, demonstrating that 12.5% of cases had a combination of diagnoses (multifactorial alopecia) accounting for their hair loss. An approach to the histopathologic diagnosis of multifactorial alopecia, particularly multiple forms of alopecia found in a single biopsy, is here presented. PMID- 26956783 TI - MnBr2/18-crown-6 coordination complexes showing high room temperature luminescence and quantum yield. AB - The reaction of manganese(ii) bromide and the crown ether 18-crown-6 in the ionic liquid [(n-Bu)3MeN][N(Tf)2] under mild conditions (80-130 degrees C) resulted in the formation of three different coordination compounds: MnBr2(18-crown-6) (), Mn3Br6(18-crown-6)2 () and Mn3Br6(18-crown-6) (). In general, the local coordination and the crystal structure of all compounds are driven by the mismatch between the small radius of the Mn(2+) cation (83 pm) and the ring opening of 18-crown-6 as a chelating ligand (about 300 pm). This improper situation leads to different types of coordination and bonding. MnBr2(18-crown-6) represents a molecular compound with Mn(2+) coordinated by two bromine atoms and only five oxygen atoms of 18-crown-6. Mn3Br6(18-crown-6)2 falls into a [MnBr(18 crown-6)](+) cation - with Mn(2+) coordinated by six oxygen atoms and Br - and a [MnBr(18-crown-6)MnBr4](-) anion. In this anion, Mn(2+) is coordinated by five oxygen atoms of the crown ether as well as by two bromine atoms, one of them bridging to an isolated (MnBr4) tetrahedron. Mn3Br6(18-crown-6), finally, forms an infinite, non-charged [Mn2(18-crown-6)(MnBr6)] chain. Herein, 18-crown-6 is exocyclically coordinated by two Mn(2+) cations. All compounds show intense luminescence in the yellow to red spectral range and exhibit remarkable quantum yields of 70% (Mn3Br6(18-crown-6)) and 98% (Mn3Br6(18-crown-6)2). The excellent quantum yield of Mn3Br6(18-crown-6)2 and its differentiation from MnBr2(18-crown 6) and Mn3Br6(18-crown-6) can be directly correlated to the local coordination. PMID- 26956784 TI - The role of 99m Tc-RBC scintigraphy in lower gastrointestinal hemorrhage. AB - Given the controversy surrounding the use of 99m Tc-RBC scintigraphy (TRBCS) in lower gastrointestinal hemorrhage (LGIH), we examined how often it was performed and whether it led to specific therapy. We performed a retrospective cohort study of 565 admissions with a primary diagnosis of LGIH. We obtained detailed clinical data on all subjects, focusing in particular on outcomes after TRBCS. 199 TRBCS studies were performed during 166 patient admissions (a patient admission was defined as an incident LGIH episode in a single patient). Of the 166 patient admissions in which TRBCS was performed, the scan was positive in approximately half (84/166; 51%); if TRBCS themselves were considered, they were positive 42% (84/199) of the time. Of the 84 admissions with a positive TRBCS, angiography was performed 54 times. Among this group, angiography revealed bleeding in only 20 patients (11 patients underwent embolization and 9 had hemostatic therapy). Out of 64 patients with a positive TRBCS who underwent colonoscopy, only 3 patients underwent endoscopic hemostatic therapy. Surgery was performed in 20 patients after a positive TRBCS (including in 17/54 patients after angiogram) and hemostasis was achieved in 16. Angiography, surgery and therapeutic colonoscopy were more commonly performed after positive than after a negative TRBCS. Patients who underwent angiography within 4 h of a positive TRBCS were neither more likely to have active bleeding found nor to undergo successful embolization. Not all patients with a positive TRBCS underwent angiography, and an abnormal TRBCS did not appear to predict successful angiographic therapy; further, a positive TRBCS was not predictive of subsequent definitive therapy. Because TRBCS appears to be followed up inconsistently, the data bring into question its routine use in clinical practice, and specifically raise the possibility that it is overused in patients with LGIH. PMID- 26956785 TI - Identification and characterization of human dendritic cell subsets in the steady state: a review of our current knowledge. AB - Dendritic cells (DC) are generally categorized as a group of rare antigen presenting cells that are to the crucial development of immune responses to pathogens and also of tolerance to self-antigens. Therefore, having the ability to identify DC in specific tissues and to test their functional abilities in the steady state are scientific gaps needing attention. Research on primary human DC is lacking due to their rarity and the difficulty of obtaining tissue samples. However, recent findings have shown that several different DC subsets exist, and that these subsets vary both by markers expressed and functions depending on their specific microenvironment. After discriminating from other cell types, DC can be split into myeloid and plasmacytoid fractions. While plasmacytoid DC express definite markers, CD123 and BDCA-2, myeloid DC encompass several different subsets with overlapping markers expressed. Such markers include the blood DC antigens BDCA-1 and BDCA-3, along with Langerin, CD1a and CD14. Marker specificity is further reduced when accounting for microenvironmental differences, as observed in the blood, primary lymphoid tissues, skin and lungs. The mixed leukocyte reaction (MLR) has been used to measure the strength of antigen presentation by specific DC subsets. Surface markers and MLR require standardization to enable consistent identification of and comparisons between DC subsets. To alleviate these issues, researchers have begun comparing DC subsets at the transcriptional level. This has allowed degrees of relatedness to be determined between DC in different microenvironments, and should be a continued area of focus in years to come. PMID- 26956786 TI - Detection of chromosomal changes in chronic lymphocytic leukemia using classical cytogenetic methods and FISH: application of rich mitogen mixtures for lymphocyte cultures. AB - One of the research methods of prognostic value in chronic lymphocytic leukemia (CLL) is cytogenetic analysis. This method requires the presence of appropriate B cell mitogens in cultures in order to obtain a high mitotic index. The aim of our research was to determine the most effective methods of in vitro B-cell stimulation to maximize the number of metaphases from peripheral blood cells of patients with CLL for classical cytogenetic examination, and then to correlate the results with those obtained using fluorescence in situ hybridization (FISH). The study group involved 50 consecutive patients with CLL. Cell cultures were maintained with the basic composition of culture medium and addition of respective stimulators. We used the following stimulators: Pokeweed Mitogen (PWM), 12-O-tetradecanoylphorbol 13-acetate (TPA), ionophore, lipopolysaccharide (LPS), and CpG-oligonucleotide DSP30. We received the highest mitotic index when using the mixture of PWM+TPA+I+DSP30. With classical cytogenetic tests using banding techniques, numerical and structural aberrations of chromosomes were detected in 46 patients, and no change was found in only four patients. Test results clearly confirmed the legitimacy of using cell cultures enriched with the mixture of cell stimulators and combining classical cytogenetic techniques with the FISH technique in later patient diagnosing. PMID- 26956787 TI - Increased expression of vascular endothelial growth factor is associated with hypertrophic ligamentum flavum in lumbar spinal canal stenosis. AB - Lumbar spinal canal stenosis (LSCS) is the most common spinal disorder in elderly patients, causing low back and leg pain, radiculopathy, and cauda equina syndrome. Vascular endothelial growth factor (VEGF) is a potent regulator of many cellular functions including proliferation, differentiation, wound healing, and angiogenesis. The present study aimed to investigate the pattern of VEGF expression in the ligamentum flavum (LF) of patients with LSCS. 24 patients with LSCS were recruited in this prospective study. We quantified and localized VEGF expression in LF tissues obtained during surgery. VEGF messenger RNA and protein expression in LF were determined using reverse transcription PCR (RT-PCR), and quantitative real-time PCR, immunohistochemistry, and ELISA. VEGF expression was significantly higher in the hypertrophic LF group than in the non-pathological LF group (p<0.01) as quantified by quantitative real-time PCR. Further ELISA analysis showed that the average concentration of VEGF in the hypertrophic LF was significantly elevated compared with that of controls (p<0.01). There was no correlation between the tissue VEGF expression of non-pathological LF and patient age in patients with LSCS. Moreover, the immunohistochemical study revealed that VEGF was positively stained on fibroblasts, inflammatory cells, and endothelial cells representing neovascularization within hypertrophic LF compared to the non pathological LF of controls. The increased expression of VEGF was associated with the degenerative changes of hypertrophic LF, suggesting that VEGF could contribute to one of the mechanisms of pathogenesis in lumbar spinal stenosis. PMID- 26956789 TI - Studies on novel HIF activators, A-503451s.I. Producing organism, fermentation, isolation and structural elucidation. AB - In the course of our screening for activators of hypoxia-inducible factor (HIF), A-503451 A and virantmycin were isolated from the cultured broth of an actinomycete strain, Streptomyces sp. SANK 60101. From the same culture, the non active homologs A-503451 B and D were also isolated. A-503451 A and virantmycin activated HIF-dependent reporter gene expression with EC50 values of 8 and 17 ng ml-1, respectively. They are highly potent activators of HIF and thus may be therapeutically useful for erythropoiesis and neural cell protection. PMID- 26956788 TI - Synthesis of the ABCDEF and FGHI ring system of yessotoxin and adriatoxin. AB - Yessotoxin and adriatoxin are members of the polycyclic ether family of marine natural products. Outlined in this article is our synthetic approach to two subunits of these targets. Central to our strategy is a coupling sequence that employs an olefinic-ester cyclization reaction. As outlined, this sequence was used in two coupling sequences. First, it was used to merge the A, B- and E, F bicyclic precursors and in the process generate the C- and D-rings. Second, it was used to couple the F- and I-rings while building the eight-membered G-ring and subsequently the H-ring pyran. PMID- 26956791 TI - Furan-iminium cation cyclization (FIC) in a total synthesis of manzamine alkaloids. PMID- 26956790 TI - Inhibition of protein SUMOylation by natural quinones. PMID- 26956792 TI - The use of fluorescently-tagged apoptolidins in cellular uptake and response studies. AB - The apoptolidins are glycomacrolide microbial metabolites reported to be selectively cytotoxic against tumor cells. Using fluorescently tagged active derivatives we demonstrate selective uptake of these four tagged glycomacrolides in cancer cells over healthy human blood cells. We also demonstrate the utility of these five fluorescently tagged glycomacrolides in fluorescent flow cytometry to monitor cellular uptake of the six glycomacrolides and cellular response. PMID- 26956793 TI - Pairwise antibiotic interactions in Escherichia coli: triclosan, rifampicin and aztreonam with nine other classes of antibiotics. AB - Previous investigations have shown that analyzing pairwise interactions between 22 antibiotics in Escherichia coli enable the grouping of drugs into nine functional classes. Our aim is to significantly expand this drug network by adding three clinically relevant antibiotics, two of which have distinct mechanisms of action not previously represented. Here, we examine triclosan, rifampicin and aztreonam, by testing them pairwise against themselves and one antibiotic from each of the nine classes. Network analysis shows that triclosan, rifampicin and aztreonam each form distinct functional groups of their own. This is particularly surprising for aztreonam, which is a cell wall synthesis inhibitor but did not cluster with other cell wall synthesis inhibitors. Furthermore, of the 30 pairs tested, we found several previously unreported synergies that could potentially be used in multidrug therapies. The distinct functional groups suggest that there may be properties of these drugs that are different from other drugs even with similar mechanism of action, and that, when considering drug combinations, aztreonam in particular is not simply interchangeable with other cell wall synthesis inhibitors. PMID- 26956794 TI - Biosynthesis of the alpha-nitro-containing cyclic tripeptide psychrophilin. PMID- 26956795 TI - Synthesis of the phorboxazoles-potent, architecturally novel marine natural products. AB - The phorboxazoles have attracted the attention of synthetic chemists around the globe due to their potent biological activity and novel structure. A review of the recent synthetic efforts as well as new phorboxazole analogs is discussed. PMID- 26956796 TI - Hangtaimycin, a peptide secondary metabolite discovered from Streptomyces spectabilis CPCC 200148 by chemical screening. PMID- 26956797 TI - Studies on novel HIF activators, A-503451sII: biological activities of A-503451A. AB - In the course of our screening, we discovered a novel compound, A-503451A, as a potent hypoxia-inducible factor (HIF) activator. In human hepatocarcinoma HepG2 cells, A-503451A induced HIF-mediated luciferase reporter gene expression and stabilized HIF-1alpha protein. A-503451A increased the mRNA expression levels and the protein secretion of HIF-dependent genes, vascular endothelial growth factor and erythropoietin. Addition of excess ferric chloride to the culture medium suppressed the HIF-induction activity of A-503451A. A-503451A did not have iron chelating activity in vitro, but decreased the intracellular labile iron pool concentration. These data indicate that A-503451A is a unique HIF activator. PMID- 26956798 TI - Synthetic studies toward citrinadin A: construction of the pentacyclic core. AB - This manuscript describes the preparation of an advanced intermediate toward the total synthesis of citrinadin A, featuring a [3+2] cycloaddition employing in situ generation of the dipole. PMID- 26956800 TI - Evolutionary history of host use, rather than plant phylogeny, determines gene expression in a generalist butterfly. AB - BACKGROUND: Although most insect species are specialized on one or few groups of plants, there are phytophagous insects that seem to use virtually any kind of plant as food. Understanding the nature of this ability to feed on a wide repertoire of plants is crucial for the control of pest species and for the elucidation of the macroevolutionary mechanisms of speciation and diversification of insect herbivores. Here we studied Vanessa cardui, the species with the widest diet breadth among butterflies and a potential insect pest, by comparing tissue specific transcriptomes from caterpillars that were reared on different host plants. We tested whether the similarities of gene-expression response reflect the evolutionary history of adaptation to these plants in the Vanessa and related genera, against the null hypothesis of transcriptional profiles reflecting plant phylogenetic relatedness. RESULT: Using both unsupervised and supervised methods of data analysis, we found that the tissue-specific patterns of caterpillar gene expression are better explained by the evolutionary history of adaptation of the insects to the plants than by plant phylogeny. CONCLUSION: Our findings suggest that V. cardui may use two sets of expressed genes to achieve polyphagy, one associated with the ancestral capability to consume Rosids and Asterids, and another allowing the caterpillar to incorporate a wide range of novel host plants. PMID- 26956799 TI - Profilin modulates sarcomeric organization and mediates cardiomyocyte hypertrophy. AB - AIMS: Heart failure is often preceded by cardiac hypertrophy, which is characterized by increased cell size, altered protein abundance, and actin cytoskeletal reorganization. Profilin is a well-conserved, ubiquitously expressed, multifunctional actin-binding protein, and its role in cardiomyocytes is largely unknown. Given its involvement in vascular hypertrophy, we aimed to test the hypothesis that profilin-1 is a key mediator of cardiomyocyte-specific hypertrophic remodelling. METHODS AND RESULTS: Profilin-1 was elevated in multiple mouse models of hypertrophy, and a cardiomyocyte-specific increase of profilin in Drosophila resulted in significantly larger heart tube dimensions. Moreover, adenovirus-mediated overexpression of profilin-1 in neonatal rat ventricular myocytes (NRVMs) induced a hypertrophic response, measured by increased myocyte size and gene expression. Profilin-1 silencing suppressed the response in NRVMs stimulated with phenylephrine or endothelin-1. Mechanistically, we found that profilin-1 regulates hypertrophy, in part, through activation of the ERK1/2 signalling cascade. Confocal microscopy showed that profilin localized to the Z-line of Drosophila myofibrils under normal conditions and accumulated near the M-line when overexpressed. Elevated profilin levels resulted in elongated sarcomeres, myofibrillar disorganization, and sarcomeric disarray, which correlated with impaired muscle function. CONCLUSION: Our results identify novel roles for profilin as an important mediator of cardiomyocyte hypertrophy. We show that overexpression of profilin is sufficient to induce cardiomyocyte hypertrophy and sarcomeric remodelling, and silencing of profilin attenuates the hypertrophic response. PMID- 26956802 TI - Genotyping of infectious laryngotracheitis virus using allelic variations from multiple genomic regions. AB - Live attenuated vaccines are extensively used worldwide to control the outbreak of infectious laryngotracheitis. Virulent field strains showing close genetic relationship with the infectious laryngotracheitis virus (ILTV) vaccines of chicken embryo origin have been detected in the poultry industry. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis, a reliable molecular epidemiological method, of multiple genomic regions was performed. The PCR-RFLP is a time-consuming method that requires considerable amount of intact viral genomic DNA to amplify genomic regions greater than 4 kb. In this study, six variable genomic regions were selected and amplified for sequencing. The multi-allelic PCR-sequence genotyping showed better discrimination power than that of previous PCR-sequencing schemes using single or two target regions. The allelic variation patterns yielded 16 strains of ILTV classified into 14 different genotypes. Three Korean field strains, 550/05/Ko, 0010/05/Ko and 40032/08/Ko, were found to have the same genotype as the commercial vaccine strain, Laryngo Vac (Zoetis, Florham Park, NJ, USA). Three other Korean field strains, 40798/10/Ko, 12/07/Ko, and 30678/14/Ko, showed recombined allelic patterns. The multi-allelic PCR-sequencing method was proved to be an efficient and practical procedure to classify the different strains of ILTV. The method could serve as an alternate diagnostic and differentiating tool for the classification of ILTV, and contribute to understanding of the epidemiology of the disease at a global level. PMID- 26956803 TI - Pelvic organ function before and after laparoscopic bowel resection for rectosigmoid endometriosis: a prospective, observational study. AB - OBJECTIVE: To assess urinary, sexual, and bowel function before and after laparoscopic bowel resection for rectosigmoid endometriosis. DESIGN: Prospectively collected data regarding the function of the pelvic organs. SETTING: Tertiary endometriosis referral unit, Aarhus University Hospital. SAMPLE: A cohort of 128 patients who underwent laparoscopic bowel resection for endometriosis. METHODS: The International Consultation on Incontinence Questionnaire (ICIQ), Sexual Function-Vaginal Changes Questionnaire (SVQ), and the Low Anterior Resection Syndrome (LARS) questionnaire were answered before and after surgery. Non-invasive urodynamic testing was performed. MAIN OUTCOME MEASURES: Pre- and postoperative function of the pelvic organs was compared, and risk factors for improved/impaired function were identified. RESULTS: A total of 96.1% of the women completed the 1-year follow-up. A significant decrease (P = 0.002) in bladder filling problems (F-score) was observed 1 year after surgery, primarily caused by a significant decrease in bladder pain (P = 0.0001). No change for urodynamic parameters was observed. A significant increase in overall sexual satisfaction (P = 0.0001) and decrease in worries about sexual life (P = 0.001) was seen 1 year after surgery. Frequency of defecation was significantly increased 1 year after surgery (P = 0.0001), but the overall bowel function measured by LARS score was unchanged. Patients with anastomotic leakage had a significantly higher risk (odds ratio, OR 5.40; P = 0.002) of increased incontinence problems (I-score) 1 year after surgery. CONCLUSION: A significant and clinically relevant improvement in urinary and sexual function 1 year after laparoscopic bowel resection for endometriosis was found. Except for anastomotic leakage, this could be observed independent of any patient- or treatment-related factor. Apprehension about impairment of urinary and sexual function should not be a contraindication for bowel resection in endometriosis patients. TWEETABLE ABSTRACT: Rectal resection for endometriosis does not impair urinary and sexual function 1 year after surgery. PMID- 26956804 TI - An Exercise Counseling Intervention in Minority Adults With Heart Failure. AB - PURPOSE: The primary aim of this study was to assess the feasibility of an exercise counseling intervention for adults of diverse race/ethnicity with heart failure (HF) and to assess its potential for improving overall physical activity, functional capacity, and HF self-care. DESIGN: This study was a quasi experimental, prospective, longitudinal cohort design. METHODS: Twenty adults were enrolled and completed the 6-minute walk and standardized instruments, followed by exercise counseling using motivational interviewing. Each received an accelerometer, hand weights, and a diary to record self-care behaviors. Participants were followed via phone for 12 weeks to collect step-counts, review symptoms, and plan the following week's step goal. FINDINGS: Results indicate that this intervention was feasible for most participants and resulted in improvements in physical activity, functional capacity, and self-care behaviors. CONCLUSION/CLINICAL RELEVANCE: Brief exercise counseling may be an appropriate option to improve outcomes for stable patients with HF and may be tailored to fit different settings. PMID- 26956805 TI - ARAS: an automated radioactivity aliquoting system for dispensing solutions containing positron-emitting radioisotopes. AB - BACKGROUND: Automated protocols for measuring and dispensing solutions containing radioisotopes are essential not only for providing a safe environment for radiation workers but also to ensure accuracy of dispensed radioactivity and an efficient workflow. For this purpose, we have designed ARAS, an automated radioactivity aliquoting system for dispensing solutions containing positron emitting radioisotopes with particular focus on fluorine-18 ((18)F). METHODS: The key to the system is the combination of a radiation detector measuring radioactivity concentration, in line with a peristaltic pump dispensing known volumes. RESULTS: The combined system demonstrates volume variation to be within 5 % for dispensing volumes of 20 MUL or greater. When considering volumes of 20 MUL or greater, the delivered radioactivity is in agreement with the requested amount as measured independently with a dose calibrator to within 2 % on average. CONCLUSIONS: The integration of the detector and pump in an in-line system leads to a flexible and compact approach that can accurately dispense solutions containing radioactivity concentrations ranging from the high values typical of [(18)F]fluoride directly produced from a cyclotron (~0.1-1 mCi MUL(-1)) to the low values typical of batches of [(18)F]fluoride-labeled radiotracers intended for preclinical mouse scans (~1-10 MUCi MUL(-1)). PMID- 26956801 TI - Forkhead box transcription factor 1: role in the pathogenesis of diabetic cardiomyopathy. AB - Diabetic cardiomyopathy (DCM) is a disorder of the heart muscle in people with diabetes that can occur independent of hypertension or vascular disease. The underlying mechanism of DCM is incompletely understood. Some transcription factors have been suggested to regulate the gene program intricate in the pathogenesis of diabetes prompted cardiac injury. Forkhead box transcription factor 1 is a pleiotropic transcription factor that plays a pivotal role in a variety of physiological processes. Altered FOXO1 expression and function have been associated with cardiovascular diseases, and the important role of FOXO1 in DCM has begun to attract attention. In this review, we focus on the FOXO1 pathway and its role in various processes that have been related to DCM, such as metabolism, oxidative stress, endothelial dysfunction, inflammation and apoptosis. PMID- 26956806 TI - Should a Mechanical or Biological Prosthesis Be Used for a Tricuspid Valve Replacement? A Meta-Analysis. AB - BACKGROUND AND AIM OF THE STUDY: The prosthesis of choice for a tricuspid valve replacement is still unkown. This meta-analysis was undertaken to review the results of mechanical and bioprosthetic valves in the tricuspid position. METHODS: We identified all relevant studies published in the past 20 years (from January 1, 1995 to December 31, 2014) through the Embase, Current Contents, and PubMed databases. The hazard ratio and its 95% confidence limits were utilized to evaluate time-to-event related effects of surgical procedures. The Q-statistic, Index of Inconsistency test, funnel plots, and Egger's test were used to assess the degree of heterogeneity and publication bias. Random effects models were used, and study quality was also assessed. RESULTS: In our meta-analysis, 22 studies published from 1995 to 2014 were reviewed and 2630 patients and 14,694 follow-up years were analyzed. No statistically significant difference was identified between mechanical and biological valves in terms of survival, reoperation, and prosthetic valve failure. The respective pooled hazard ratio estimates were 0.95 (0.79 to 1.16, p = 0.62, I(2) = 29%), 1.20 (0.84 to 1.71, p = 0.33, I(2) = 0%), and 0.35 (0.06 to 2.01, p = 0.24, I(2) = 0%). A higher risk of thrombosis was found in mechanical tricuspid valve prostheses (3.86, 1.38 to 10.82, p = 0.01, I(2) = 0%). CONCLUSIONS: No statistically significant difference was identified between mechanical and biological valves in terms of survival, reoperation, or prosthetic valve failure, but mechanical tricuspid valve prostheses had a higher risk of thrombosis. doi: 10.1111/jocs.12730 (J Card Surg 2016;31:294-302). PMID- 26956807 TI - Deficit in rewarding mechanisms and prefrontal left/right cortical effect in vulnerability for internet addiction. AB - OBJECTIVE: The present research explored the cortical correlates of rewarding mechanisms and cortical 'unbalance' effect in internet addiction (IA) vulnerability. METHODS: Internet Addiction Inventory (IAT) and personality trait (Behavioural Inhibition System, BIS; Behavioural Activation System, BAS) were applied to 28 subjects. Electroencephalographic (EEG, alpha frequency band) and response times (RTs) were registered during a Go-NoGo task execution in response to different online stimuli: gambling videos, videogames or neutral stimuli. Higher-IAT (more than 50 score, with moderate or severe internet addiction) and lower-IAT (<50 score, with no internet addiction). RESULTS: Alpha band and RTs were affected by IAT, with significant bias (reduced RTs) for high-IAT in response to gambling videos and videogames; and by BAS, BAS-Reward subscale (BAS R), since not only higher-IAT, but also BAS and BAS-R values determined an increasing of left prefrontal cortex (PFC) activity (alpha reduction) in response to videogames and gambling stimuli for both Go and NoGo conditions, in addition to decreased RTs for these stimuli categories. CONCLUSION: The increased PFC responsiveness and the lateralisation (left PFC hemisphere) effect in NoGo condition was explained on the basis of a 'rewarding bias' towards more rewarding cues and a deficit in inhibitory control in higher-IAT and higher-BAS subjects. In contrast lower-IAT and lower-BAS predicted a decreased PFC response and increased RTs for NoGo (inhibitory mechanism). These results may support the significance of personality (BAS) and IAT measures for explaining future internet addiction behaviour based on this observed 'vulnerability'. PMID- 26956808 TI - Pregnancy denial or concealement: A case report highlighting risks and forensic aspects. PMID- 26956809 TI - Informal care for people with chronic psychotic symptoms: four case studies in a San community in South Africa. AB - Despite the internationally recognised importance of informal care, especially in settings with limited services, few studies focus on the informal care for people with mental health problems in low- and middle-income countries. Making informal care visible is important for understanding the challenges and identifying the needs to be addressed. This ethnographic case study explored the dynamics of informal care for people with chronic psychotic symptoms in a group of San living in poor socioeconomic circumstances in a township near Kimberley, Northern Cape, South Africa. Data were collected in 2013 and 2014 and included semi-structured interviews, informal conversations and observations. Using local terminology, four individuals with chronic psychotic symptoms were identified and selected during the research process. A total of 33 semi-structured interviews took place with their caregivers. Data were analysed using descriptive, interpretive and pattern coding to identify core themes and interrelations across the four cases. Results indicate that informal care is characterised by shared and fragmented care structures. Care was shared among family members from various households and unrelated community members. This allowed for an adaptive process that responded to local dynamics and the care recipients' needs. However, informal care was fragmented as it was generally uncoordinated, which increased the recipients' vulnerability as caregivers could redirect care-giving responsibility and withdraw care. Specific challenges for providing care were related to poverty and care resistance. To improve the living conditions of people suffering from psychosis-related mental health problems, community-based mental healthcare should broaden its scope and incorporate local strengths and challenges. PMID- 26956810 TI - Fluorescein Sodium-Guided Surgery of Malignant Brain Tumors: History, Current Concepts, and Future Project. AB - Fluorescein sodium (FL)-guided resection has become an important and beneficial treatment method for malignant brain tumors. FL-guided resection improves the rate of gross total resection in high-grade gliomas (HGG) and cerebral metastases (CM). FL sensitively visualizes the disruption of the blood-brain barrier in the area surrounding malignant lesions, similar to contrast-enhanced T1-weighted MR sequences. This review of the current literature summarizes the history of FL in neurosurgery from 1946 until today. We discuss the molecular mechanism of FL accumulation in cerebral malignant tumors and provide an overview of the current practice of using FL and applying a dedicated surgical microscope filter. Additionally, we outline and discuss ongoing trials and future projects. PMID- 26956811 TI - Etiology of Pituitary Tumors: A Case Control Study. AB - AIM: Pituitary tumors are generally benign, but may be associated with some morbidities. The aim of this study was to identify the risk factors for pituitary tumors. MATERIAL AND METHODS: A population-based case-control study on the potential risk factors of pituitary tumors was conducted in China. The personal interview technique was used to gather information on medical and reproductive history, taste, and cigarette smoking from 204 pituitary tumor cases and 246 controls aged between 6 and 82 years. RESULTS: The risk of tumor was reduced when the interviewee was a worker. The risk was raised with spicy taste, mobile phone use, duration of use, characteristics, and taking vitamins. No significant association was observed with gender, age, education, marriage, speed of eating, fat intake, other tastes (salt, sour, sweet), medical and reproductive history, female sex hormones, cigarette smoking, tea drinking, wine drinking, menses, and oral contraceptive use, whether the interviewee was a farmer. CONCLUSION: Increased risk for pituitary tumors is related with spicy taste, mobile phone use, duration of use, characteristics, taking vitamins and possibly a reduced risk is related with the interviewee being a worker. Further investigations are needed to clarify the causes of these associations. PMID- 26956812 TI - Middle Turbinate Mucosal Flap in Endoscopic Skull Base Reconstruction. AB - AIM: To explore the indications, operation techniques and benefits of pedicled middle turbinate mucosal flap in endoscopic skull base reconstruction. MATERIAL AND METHODS: The patients, who underwent endonasal endoscopic surgery from October 2009 to June 2010 in our department, were involved in this study. Multi layer skull base reconstruction was performed in four cases by pedicled middle turbinate mucosal flap combined with fascia lata, artificial dura mater, fat and other reconstruction materials. The results of surgery were assessed in the follow-up period. RESULTS: No reconstruction-associated complications, such as cerebrospinal fluid leakage or infection were observed in four cases during the follow-up period for more than one year. All patients showed excellent recovery. CONCLUSION: Pedicled middle turbinate mucosal flap for skull base reconstruction has the advantages of fast healing and low incidence of cerebrospinal fluid leakage. It provides satisfactory skull base reconstruction. PMID- 26956813 TI - Burr Hole Evacuation of Extradural Hematoma in Mass Trauma. A Life Saving and Time Saving Procedure: Our Experience in the Earthquake of 2005. AB - AIM: To observe the outcome of burr hole evacuation of extradural hematoma (EDH) in mass head injury. MATERIAL AND METHODS: This study included patients of any age who sustained head injury in the earthquake of October 8, 2005, were diagnosed as EDH on computed tomography (CT) scan and were admitted in the neurosurgery ward over a period of 3 days. All patients were followed by serial CT scans and neurological assessments. RESULTS: A total of 36 patients were included in this study. There were 25 male and 11 female patients and the age range was from 5 years to 50 years. All cases were the victim of the earthquake. All patients underwent surgery for evacuation of EDH through a single burr hole. One patient required craniotomy for EDH due to neurological deterioration on the second postoperative day, and 1 patient died. CONCLUSION: As EDH is potentially fatal lesion, evacuation of EDH through a single burr hole has good outcome with less chances of recurrence and complications in mass head injured patients as seen with earthquakes. PMID- 26956814 TI - Combination of Curcumin with an Anti-Transferrin Receptor Antibody Suppressed the Growth of Malignant Gliomas In vitro. AB - AIM: Transferrin receptor (TfR) has been used as a target for the molecular cancer therapy due to its higher expression in a variety of tumors. Anti-TfR antibodies combined with chemotherapeutic drugs has showed great potential as a possible cancer therapeutic strategy. In our study, we investigated the anti tumor effects of anti-TfR monoclonal antibody (mAb) alone or in combination with curcumin in vitro. MATERIAL AND METHODS: We detected the apoptosis, proliferation and cell cycle of glioma cells after treated with anti-TfR mAb and curcumin alone or the combinations by flow cytometer. RESULTS: Anti-TfR mAb or curcumin could inhibit proliferation of tumor cells. Anti-TfR mAb marked S phase arrest and curcumin induced G2/M arrest in tumor cells. When anti-TfR mAb and curcumin were used simultaneously, a synergistic effect was detected in relation to tumor growth inhibition and the induction of cells necrosis. CONCLUSION: These results provided a potential role of anti-TfR mAb-containing curcumin in the treatment for gliomas. PMID- 26956816 TI - Stent-Assisted Coil Embolization of Ruptured Supraclinoid Blood Blister-Like Aneurysm of Internal Carotid Artery. AB - AIM: To report angiographic and clinical results obtained in patients with supraclinoid segment blood blister-like aneurysms (BBLAs) of the internal carotid artery treated with stent-assisted coil embolization. MATERIAL AND METHODS: A retrospective review of patients, who were treated for a ruptured supraclinoid BBLAs of the internal carotid artery (ICA) from 2004 to 2010, was performed. Clinical data, including hospital records, operative reports, and angiograms, were analyzed. Outcome was assessed using the modified Rankin scale (mRS). RESULTS: Thirteen ruptured supraclinoid BBLAs in 13 patients were treated with stent-assisted coil embolization without any complication. Six patients recovered without any neurological deficits and three patients had mild neurological deficits (mRS 1 in one and 2 in two patients) due to late ischemic deficit. Three patients died of rebleeding and one died of intracranial infection after ventricular puncture for hydrocephalus. CONCLUSION: In our experience, the natural history of supraclinoid BBLAs is dismal. Some of the lesions rebled after stent-assisted coil embolization. PMID- 26956815 TI - Endovascular Treatment of Rare Vascular Complications of Percutaneous Balloon Compression for Trigeminal Neuralgia. AB - AIM: To present the clinical features and outcomes of rare vascular complications of percutaneous balloon compression (PBC) for trigeminal neuralgia. These complications were treated by the endovascular technique. MATERIAL AND METHODS: In this retrospective study, 5 patients with trigeminal neuralgia were treated by PBC, who complicated vascular incidence between December 2000 and May 2011. The complications included 3 internal carotid cavernous fistulae (CCF) and 2 external carotid artery system fistulae. These complications were treated by endovascular coil embolism and balloon occlusion techniques. RESULTS: Five patients (100%) had pain free after the PBC. All the complications were cured and symptoms were gradually improved. There was no recurrence of trigeminal neuralgia or vascular complication symptoms during the follow-up period (mean 20 months, range 7-52 months). CONCLUSION: Endovascular treatment is effective and safe for the rare iatrogenic vascular complications of the PBC procedure. Neurosurgeons should be made aware of this complication. Timely diagnosis and expedient treatment should be ensured as early as possible in order to decrease further danger. PMID- 26956817 TI - Endovascular Treatment of Intracranial Ophthalmic Segment Aneurysms: A Series and Literature Review. AB - AIM: To present the outcomes and follow-up results of endovascular coil embolization in patients with ophthalmic segment aneurysms (OSAs). MATERIAL AND METHODS: The data of 42 patients with 44 OSAs (7 ruptured and 37 unruptured), who underwent treatment using endovascular techniques between January 2007 and November 2010, were retrospectively reviewed. RESULTS: The angiographic occlusion of the aneurysms was complete for 37 aneurysms (84.1%), near complete for 4 aneurysms (9.1%) and incomplete occlusion for 3 aneurysms (6.8%). There were 2 (4.5%) symptomatic procedure-related complications (ischemic events). One patient died of massive cerebral infarction caused by a large dissecting OSA. A favorable outcome was achieved in 97.6 % (41 of 42) of the patients at the time of follow up. No sign of bleeding or re-bleeding was observed in any patient during the follow-up period (1 to 44 months, mean 14.2 months). Minor aneurysm recanalization occurred in 2 (4.5%) cases. The OSA-associated visual disorders completely recovered in 9 (64.3%) patients. CONCLUSION: Endovascular treatment is a safe and effective treatment modality for intracranial OSAs. PMID- 26956818 TI - Proposal of Classification of Aneurysms Coexisting with AVM and Possible Treatment Strategies. AB - AIM: To describe the classification of aneurysms coexisting with arteriovenous malformations (AVMs) and their endovascular treatment. MATERIAL AND METHODS: Based on the basis of radiological findings and clinical features, 59 aneurysms coexisting with AVMs were classified into four different types: intranidal, flow related (proximal and distal), and unrelated. These aneurysms were treated by endovascular techniques with or without AVM embolization. Clinical outcome was assessed using the modified Rankin Scale (mRS). RESULTS: 59 aneurysms coexisting with AVMs were found in 39 patients. There were 11 unrelated aneurysms, 18 proximal flow-related aneurysms, 11 distal flow-related aneurysms and 19 intranidal aneurysms. In the 11 unrelated aneurysms, 4 were caused subarachnoid hemorrhage. In 11 distal flow-related aneurysms near the AVM, 7 caused a major hemorrhage. Six of the 19 intranidal aneurysms presented with hemorrhage. In contrast, only 3 of the 14 proximal flow-related aneurysms on major feeding arteries caused hemorrhage. CONCLUSION: Aneurysms coexisting with AVMs could be classified into four types and this classification may provide a rationale for endovascular treatment. PMID- 26956819 TI - Neurosurgical Site Infection Prevention: Single Institute Experience. AB - AIM: To estimate the effect of a multimodal prevention program on controlling surgical site infection (SSI) risk among neurosurgical patients. MATERIAL AND METHODS: This prospective study was conducted among adult patients who have undergone neurosurgical procedures in a tertiary-care university-affiliated hospital during January 2008 to December 2013 since the implementation of an infection control program. SSI cases among inpatients were identified by daily active searches, whereas post-discharge surveillance was performed for outpatients through telephone contact 30-35 days after surgery, according to the definition proposed by the Center for Disease Control. The variation of SSI rate during the study period was analyzed by Cochran-Armitage trend test. RESULTS: Overall, a total of 3042 patients were enrolled and 112 SSI cases were identified during the studied period. SSI more likely occurred in patients with older age (t=5.16, p < 0.01), undergoing emergency operations (x2=50.5, p < 0.01), having higher American Society of Anesthesiologists (ASA) scores (x2=7.2, p=0.01) and clean contaminated wound or above (x2=53.8, p < 0.01). The annual incidence rate of SSI was 6.21%, 5.01%, 3.89%, 3.06%, 2.38% and 2.28%, respectively, showing a significant decreasing trend (z=3.96, p < 0.01). CONCLUSION: The results provide evidence of a significant decreasing trend in the SSI rate following the infection prevention program, demonstrating the role of multimodal approach in controlling SSI. PMID- 26956820 TI - CO2 Laser Soldering for the Reconstruction of Dural Defects in the Minipig Model. AB - AIM: To explore the feasibility and reliability of CO2 laser soldering on the reconstruction of dura mater in the minipig model. MATERIAL AND METHODS: Ten minipigs were divided into 2 groups as Group A (n=5) and Group B (n=5). Bilateral fronto-parietal craniotomy was performed and 2 cm * 1 cm dural defect created under general anesthesia. Then, the defect was repaired with autologous temporalis fascia by CO2 laser soldering. After pressure and watertightness testing, the minipigs of group A were sacrificed immediately. Minipigs in Group B were followed for 4 weeks, with daily monitoring of behavior, food intake, skin incision and neurological condition. Animals of Group B were also subjected to the same tests as group A. Then, they were also sacrificed. The reconstructed area and underlying brain tissue were fixed in paraformaldehyde and submitted for histological analysis. RESULTS: No neural impairment, hydrops or empyema, and no cerebrospinal fluid leak in the dura-fascia interface were observed in Group B. The mean burst pressures were higher than the mean intracranial crest pressure in groups A and B. This difference was significant (P=0.010, P=0.000, respectively). The physiological intracranial pressure of ten minipigs ranged between 4.53 and 6.47 mmHg. No thermal injury was observed in either group. CONCLUSION: CO2 laser soldering for dural defect reconstruction was feasible and reliable. PMID- 26956822 TI - Prediction of Lumbar Disc Herniation Patients' Satisfaction with the Aid of an Artificial Neural Network. AB - AIM: To identify key determinants of lumbar disc herniation (LDH) patients' satisfaction and to evaluate the efficiency of an artificial neural network (ANN) model to prognosticate satisfaction derived from the hospital stay in this specific patient group. MATERIAL AND METHODS: A single item question was used to assess patient satisfaction. Principal component analysis evaluated several aspects of care (15 items). An ANN encompassed all variables and its prediction ability was tested. The ANN performance was correlated to a binary logistic regression (BLR) model. RESULTS: Higher levels of satisfaction were reported by females, older patients, Greeks, and patients with elementary education staying in not rural areas. A history of a single previous hospitalisation was correlated with more satisfaction. The accuracy of ANN was 96% for satisfaction prediction outperforming the BLR model. CONCLUSION: Satisfactory health services are influenced by sex, age, nationality, and number of prior admissions. The self perceived health state plays also a crucial role. The current study is the first one reporting on the capability of an ANN to accurately predict the satisfaction levels of LDH patients. PMID- 26956821 TI - Evaluation of Computed Tomography Perfusion Imaging in a Rat Acute Cerebral Ischemia-Reperfusion Model. AB - AIM: This study aims to apply computed tomography perfusion imaging (CTPI) technology under in vivo conditions in order to explore its reliability and accuracy in evaluating the rat acute cerebral ischemia-reperfusion model (RACIRM). MATERIAL AND METHODS: The thread embolism method was used in 48 rats to create the RACIRM. Rats were divided into 2 groups as ischemia group and ischemia reperfusion group. We then compared and evaluated the results of CTPI, 2,3,5 triphenyl tetrazolium chloride (TTC) staining, and hematoxylin and eosin (HE) staining of both groups. RESULTS: There were no significant differences in the volumes of hypoperfusion regions in the cerebral blood flow (CBF) and cerebral blood volume (CBV) of each group at each CTPI time point and these volumes were not significantly different from the corresponding findings on the TTC-stained infarct regions. The mean transit time (MTT) did show a significant difference, as did the volumes observed in both the MTT ischemic region and TTC-stained infarct region. The CTPI parameters exhibited correlation with the infarct volumes calculated in TTC staining, among which CBV exhibited the highest correlation. CONCLUSION: CTPI could rapidly, accurately, and non-invasively evaluate the site, size, and hemodynamic changes in the cerebral ischemia reperfusion animal model. PMID- 26956823 TI - A Novel Classification and Minimally Invasive Treatment of Degenerative Lumbar Spinal Stenosis. AB - AIM: We conducted a novel classification system of degenerative lumbar spinal stenosis (DLSS) based on clinical manifestations and imaging (computed tomography and magnetic resonance imaging) features. We chose different minimally invasive surgical procedures according to our system. Clinical parameters and radiological findings will be assessed in the article. MATERIAL AND METHODS: A retrospective study was conducted on 96 patients undergoing minimally invasive surgery for DLSS. We chose different surgical procedures according to our novel classification system based on clinical manifestations, imaging features, and concurrence with other spinal diseases. Clinical parameters and radiological findings were assessed pre- and postoperatively. RESULTS: The mean follow up period was 24 months (range, 15~36 months). There was a statistically significant improvement in the Visual Analogue Scale (VAS) score of low back pain and leg pain after surgery (p < 0.05). According to the Japanese Orthopaedic Association (JOA) scores, the operation efficacy was excellent in 57 cases, good in 36 cases, and fair in 3 cases. According to Bridwell's criterion, the fusion rate was 96% (48/50) in patients who underwent fusion surgery. There were no cages or pedicle screws related complications. CONCLUSION: Minimally invasive surgical treatment of DLSS has satisfactory outcomes according to the novel classification, but further long-term, prospective, randomized controlled studies involving a larger study group are needed to validate the long-term efficacy. PMID- 26956825 TI - Evaluation of the Association Between Matrix Metalloproteinase 11 and Intervertebral Disc Disease. AB - AIM: The intervertebral disc starts to degenerate when a human being begins to stand and learn to walk. It is known that many extrinsic, intrinsic and genetic factors play a role in disc degeneration. In this study, we examined whether the matrix metalloproteinase 11 might be associated with intervertebral disc degeneration. MATERIAL AND METHODS: Fifty-six patients with lumbar disc herniations who were operated at Goztepe Education and Research Hospital, Neurosurgery Clinic between September 2008 and December 2009 were prospectively reviewed. History and complaints were obtained from the case reports. Neuroradiological evaluation was performed with magnetic resonance imaging. Surgical findings of cases were reported in the operation notes. Microscopic posterior hemipartial laminectomy and discectomy were performed in all cases. Degenerated herniated disc material of all cases extracted during surgery was evaluated with immunohistochemical staining in Marmara University, Institute of Neurological Sciences, Pathology Laboratory. RESULTS: Comparing the immunohistochemical staining of cases who were 50 years or younger and cases who were over 50 years old, statistical significance was determined. CONCLUSION: Matrix metalloproteinase 11 has a role in degenerating intervertebral disc disease, but it is not the only factor. Matrix metalloproteinase 11 might be a genetic factor in young-middle aged patients. PMID- 26956824 TI - Dynamic Radiographic Results of Different Semi-Rigid Fusion Devices for Degenerative Lumbar Spondylolisthesis: "Dynamic Rod" vs. "Dynamic Screw Head". AB - AIM: To assess the clinical outcomes and compare the segmental range of motion (ROM) at the implanted L4-L5 level, the cranial and caudal adjacent levels, and the ROM of the whole lumbar spine after semi-rigid lumbar fusion with 2 different devices. MATERIAL AND METHODS: Patients with neurogenic claudication, due to grade 1 spondylolisthesis and spinal stenosis at levels L4-L5, were treated either Bio-flex(r) (n = 28) and Cosmic(r) (n = 23); discectomy was not performed at any level. The clinical outcomes were compared between the 2 groups. All patients underwent neutral, flexion, and extension radiography before the surgery and after 2 years postoperatively. ROM was assessed at the level of L4-L5, L3-L4, L5-S1, and at the whole lumbar spine. RESULTS: According to clinical outcomes, 82% and 78% of patients in the BioFlex and Cosmic groups, respectively, had a good or excellent result. In both groups, there was significant reduction of the segmental ROM at the implanted L4-L5 level (p = 0.039 and 0.011). CONCLUSION: These outcomes may play a role in decreasing the risk of ASD after dynamic stabilization, at least 2 years after surgery. PMID- 26956826 TI - The Correlation Study of C5 Nerve Root Palsy and Common Body Position in Posterior Total Laminectomy Decompression and Instrumentation. AB - AIM: To compare both the clinical characteristics and incidence of postoperative cervical nerve root palsy in cervical spondylosis patients treated by posterior total laminectomy, decompression and instrumentation with two different common body positions, traction bed and plaster bed. MATERIAL AND METHODS: One hundred and thirty-three patients, with a mean age of 49.5 years suffering from multilevel cervical spondylosis and treated by laminectomy from 2007 to 2009, were reviewed. RESULTS: Overall 30 of 133 (22.56%) patients had C5 palsy, of which 14 (19.44%) out of 72 patients were in the plaster bed group, while 16 of 61 (26.23%) patients were in the traction bed group. The difference was statistically significant (P < 0.05). CONCLUSION: The cervical curvature index (CCI) reflected both the change of cervical height and the change of the overall cervical curvature. CCI was related with the incidence of C5 nerve root palsy postoperatively. The patients in the traction bed group had a higher nerve root palsy rate and change in cervical alignment because of over traction. PMID- 26956827 TI - Experimental Endoscopic Cordotomy in the Sheep Model. AB - AIM: Interventional pain therapies are usually based on destruction of the related pain-conducting pathways. Current procedures targeting pain have replaced conventional pain treatment modalities while being less invasive. In this study, we investigated the feasibility of the endoscopic percutaneous cordotomy process on the sheep cervical spinal cord. MATERIAL AND METHODS: Seven male sheep, Akkaraman(r) genus, were operated on in the study. The guide was introduced at C1 to C2 vertebrae. The interlaminar area was exposed by a dilator, the dura was identified, and then the working cannula was inserted into the subarachnoid space. The target point of cordotomy was defined by endoscopic visualization as the midpoint between the dentate ligament and ventral root entry zone. After determination of the target point, a carbon dioxide laser (CDL) probe was introduced through the cannula. Ablative lesioning was performed by CDL. Hindlimb withdrawal thresholds were measured using the "Sample Pain Scale". The lesion was demonstrated by magnetic resonance imaging and histopathological examination. RESULTS: Three sheep had ipsilateral hemiparesis and the response to firm pressure test was not performed on them. Among the remaining four sheep, the pain tolerance test showed that one sheep was at stage 0, two at stage 1, and the last one at stage 3. CONCLUSION: Cordotomy might be successfully performed with the endoscopic technique in the sheep model and this should encourage future studies regarding minimal invasive procedures for intractable pain. PMID- 26956828 TI - Prevention of Epidural Fibrosis in Rats by Local Administration of Mitomycin C or Daunorubicin. AB - AIM: Epineural adhesion after peripheral nerve surgery is common. The purpose of this study was to evaluate the macroscopic and histopathologic effects of topical mitomycin C and daunorubicin on epineural scar formation. MATERIAL AND METHODS: In this study, we used 15 rats (30 nerves). Two test groups and one control group were created. Sciatic nerve exposure was created bilaterally in each group (30 nerve examinations in total). In experimental group 1, cotton pads that had absorbed mitomycin C (0.5 mg/ml) were placed onto the nerves for 5 minutes while in experimental group 2, cotton pads that had absorbed daunorubicin (0.2 mg/ml) were placed onto the nerves for 5 minutes and cotton pads that had absorbed saline were applied to the control group. Eight weeks after the first surgery, surgical dissection was performed for the evaluation of neurolysis sites. Epineural adhesions were classified utilizing a numerical grading layout. RESULTS: We did not find any adverse effect with topically applied mitomycin C and daunorubicin. Within the 3 groups, no significant difference was seen in skin and fascia-muscle cavity closure (p > 0.05). Macroscopically, mitomycin C and daunorubicin decreased the adhesion of sciatic nerve to adjacent structures. There was intensive epineural scar formation in the control group. Scar tissue thickness and fibroblast/fibrocyte cell number were less in the two test groups compared with the control group (p < 0.001). There was no statistical difference between the two test groups. CONCLUSION: Epineural scar formation after peripheral nerve surgery may be reduced by using topical application of mitomycin C and daunorubicin. PMID- 26956829 TI - Microsurgical Outcome of Post-traumatic Peripheral Nerve Injuries: An Experience of 23 Cases and Review of Literature. AB - AIM: The present study aimed to evaluate the microsurgical outcome in post traumatic peripheral nerve injuries and its correlation with time since injury and the type of the operative procedure performed. MATERIAL AND METHODS: All the patients admitted to our center with the diagnosis of post-traumatic peripheral nerve injury were included in the study. The data of all patients was retrospectively analysed from the computerized database of our hospital. The time period of the study was from January 2008 to March 2011. RESULTS: A total of 23 patients were included in the study. The interval between injury and surgery was 28.8 weeks (range: 1 day - 70 weeks). The most common mode of injury was road traffic accidents (39%, n=9). The mean follow up was 24.7 +/- 11.3 months (range 9-45 months). Six (60%) patients had a good outcome. There was no statistically significant correlation between outcome and time since injury or type of operative procedure performed (p > 0.05). CONCLUSION: Post-traumatic peripheral nerve injury is a rare form of nerve injury. There is no correlation between the surgical outcome and time since injury. Some of the nerves have a better outcome as compared to others. PMID- 26956830 TI - Post-Traumatic Tension Pneumocephalus: Series of Four Patients and Review of the Literature. AB - Tension pneumocephalus is an uncommon and life-threatening neurological condition. It requires emergent and immediate attention to prevent fatal complications. Head injury is the most common cause of tension pneumocephalus. Air can gain access into the cranium either through a fracture involving paranasal sinus or the middle ear cavity or even more rarely in association with a compound depressed fracture of the skull vault. Its management includes simple twist drill and aspiration of intracranial air with or without placement of an under water seal. 100% oxygen should be administered by a non-breatheable mask which hastens the resorption of air. The authors report a series of 4 cases of post-traumatic tension pneumocephalus, highlighting its management, and review the pertinent literature. PMID- 26956831 TI - The Penumbra System for the Treatment of Acute Ischemic Stroke: Report of Two Cases. AB - Mortality associated with the occlusion of large vessels in acute ischemic stroke is particularly high despite best available medical therapy. Early and safe revascularization of the primary occlusion is correlated with good clinical result. We report two patients with acute ischemic stroke in whom the mechanical device Penumbra System was used for thrombolysis and embolectomy. The Penumbra System provided the revascularization of the primary occlusion site in the two patients and complete revascularization was obtained. Improvement was observed in both cases on the National Institutes of Health Stroke Scale and on modified Rankin scale scores at 1 and 30 days post-procedure. Neither of the patients had intracranial hemorrhage. The Penumbra System is a valuable device as a treatment for acute ischemic stroke secondary to large vessel occlusion. PMID- 26956832 TI - Image-Guided Endoscopic Endonasal Transmaxillary Transpterygoid Approach to Meckel's Cave. AB - The aim of this report was to summarize our preliminary experience on the resection of tumors located in Meckel's cave via the endoscopic endonasal transmaxillary transpterygoid approach with image-guided system and to investigate the feasibility and efficacy of this approach. Two patients who had tumors in left Meckel's cave underwent surgical treatment using the image-guided endoscopic endonasal transmaxillary transpterygoid approach. This particular technique has advantages of no brain retraction, direct vision of tumor resection and protection of surrounding neurovascular structures. Neuronavigation increases the safety of the endoscopic approach. PMID- 26956833 TI - Familial Aggregation of Chiari Malformation: Presentation, Pedigree, and Review of the Literature. AB - This article reports the largest familial aggregation of Chiari malformation in a single family to date as reported in the literature. This study is a retrospective case series of a family of whom five individuals have a confirmed case of Chiari malformation and three additional individuals have Chiari signs and symptoms. This contribution further supports the implication of genetics in the transmission of Chiari malformation. The family reported in this study also has a significant incidence of Ehlers-Danlos. Three sisters, including a set of twins, presented with confirmed cases of Chiari malformation and four of the five children of the twin sisters presented with confirmed or suspected Chiari malformation. Of note, the non-twin sister has three children who are unaffected. This report provides further evidence for a shared loci between the Chiari malformation and Ehlers-Danlos. PMID- 26956834 TI - Bilateral Thalamic Glioma: Case Report and Review of the Literature. AB - Bilateral thalamic glioma is extremely rare and the incidence cannot be adequately expressed. We present the case of a 72 years old male suffering from the rapid deterioration of cognitive function to moderately severe dementia in a short period of time. Magnetic resonance studies demonstrated a bilateral thalamic glioma with a minimal focal gadolinium uptake in the left thalamus. Biopsy was performed and pathology report was of anaplastic astrocytoma, WHO grade III. Radiotherapy was proposed but was rejected by the patient's relatives. The patient deceased 57 days later. We performed an extensive review of the literature and by updating the previous described series we can state that to the best of our knowledge this is the 60th case described in the literature and the second eldest patient presented. Patients suffering from this disease present a poor prognosis, the longest survival described being of 3 years in patients diagnosed with grade II bilateral thalamic glioma. Adjuvant therapy in form of radiotherapy to the thalami is most commonly used but the benefits are unclear. The natural progression of WHO grade III bilateral thalamic glioma left untreated, as can be seen from our case, has an even poorer outcome. PMID- 26956835 TI - To TEM or not to TEM: past, present and probable future perspectives of the transanal endoscopic microsurgery platform. PMID- 26956837 TI - A microfluidic platform with pH imaging for chemical and hydrodynamic stimulation of intact oral biofilms. AB - A microfluidic platform with a fluorescent nanoparticle-based sensor is demonstrated for real-time, ratiometric pH imaging of biofilms. Sensing is accomplished by a thin patterned layer of covalently bonded Ag@SiO2+FiTC nanoparticles on an embedded planar glass substrate. The system is designed to be sensitive, responsive and give sufficient spatial resolution to enable new micro scale studies of the dynamic response of oral biofilms to well-controlled chemical and hydrodynamic stimulation. Performance under challenging operational conditions is demonstrated, which include long-duration exposure to sheer stresses, photoexcitation and pH sensor biofouling. After comprehensive validation, the device was used to monitor pH changes at the attachment surface of a biofilm of the oral bacteria, Streptococcus salivarius. By controlling flow and chemical concentration conditions in the microchannel, biochemical and mass transport contributions to the Stephan curve could be probed individually. This opens the way for the analysis of separate contributions to dental caries due to localized acidification directly at the biofilm tooth interface. PMID- 26956836 TI - Preliminary results of video-assisted anal fistula treatment (VAAFT) in children. AB - BACKGROUND: Anal fistula is a common acquired anorectal disorder in children. Treatment methods that have been used are associated with inconsistent results and possible serious complications. In 2011 a minimally invasive approach, video assisted anal fistula treatment (VAAFT) was described for adult patients. The aim of the present study was to assess the first series of pediatric patients treated with VAAFT. METHODS: All patients who underwent VAAFT between August 2013 and May 2015 were included. Demographics, clinical features, preoperative imaging, surgical details, outcome, and medium-term data were prospectively collected for each patient. RESULTS: Thirteen procedures were performed in nine patients. The male to female ratio was 8:1, and the median age was 9.6 years. Five fistulas were idiopathic, three iatrogenic, and one associated with Crohn's disease. Eight complete VAAFT procedures were performed. The remaining five procedures were either fistuloscopy and cutting seton placement or fistuloscopy and electrocoagulation, both without mucosal sleeve. The median length of surgery was 41 min. The median hospital stay was 24 h, and the median length of follow-up was 10 months. Resolution of the fistula was observed in all patients who underwent a complete VAAFT. In four out of five patients who underwent an incomplete procedure (without mucosal sleeve), the fistula recurred. No incontinence or soiling was reported in the medium term. CONCLUSIONS: VAAFT proved to be feasible and safe in children. It also proved to be versatile as it could be applied to fistulas of different etiologies. The key to success seems to be an adequate mucosal sleeve. Older children and adolescents benefit most from VAAFT which is a valid alternative to available surgical procedures. PMID- 26956838 TI - Stromal beta-catenin overexpression contributes to the pathogenesis of renal dysplasia. AB - Renal dysplasia, the leading cause of renal failure in children, is characterized by disrupted branching of the collecting ducts and primitive tubules, with an expansion of the stroma, yet a role for the renal stroma in the genesis of renal dysplasia is not known. Here, we demonstrate that expression of beta-catenin, a key transcriptional co-activator in renal development, is markedly increased in the expanded stroma in human dysplastic tissue. To understand its contribution to the genesis of renal dysplasia, we generated a mouse model that overexpresses beta-catenin specifically in stromal progenitors, termed beta-cat(GOF-S) . Histopathological analysis of beta-cat(GOF) (-S) mice revealed a marked expansion of fibroblast cells surrounding primitive ducts and tubules, similar to defects observed in human dysplastic kidneys. Characterization of the renal stroma in beta-cat(GOF) (-S) mice revealed altered stromal cell differentiation in the expanded renal stroma demonstrating that this is not renal stroma but instead a population of stroma-like cells. These cells overexpress ectopic Wnt4 and Bmp4, factors necessary for endothelial cell migration and blood vessel formation. Characterization of the renal vasculature demonstrated disrupted endothelial cell migration, organization, and vascular morphogenesis in beta-cat(GOF) (-S) mice. Analysis of human dysplastic tissue demonstrated a remarkably similar phenotype to that observed in our mouse model, including altered stromal cell differentiation, ectopic Wnt4 expression in the stroma-like cells, and disrupted endothelial cell migration and vessel formation. Our findings demonstrate that the overexpression of beta-catenin in stromal cells is sufficient to cause renal dysplasia. Further, the pathogenesis of renal dysplasia is one of disrupted stromal differentiation and vascular morphogenesis. Taken together, this study demonstrates for the first time the contribution of stromal beta-catenin overexpression to the genesis of renal dysplasia. Copyright (c) 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 26956839 TI - Neurologic outcome after cardiac arrest: What you see at hospital discharge may or may not be what you get. PMID- 26956840 TI - Benefits of cardiac sonography performed by a non-expert sonographer in patients with non-traumatic cardiopulmonary arrest. AB - The purpose of this study was to evaluate a rapid cardiac ultrasound assessment performed by trained non-expert sonographers integrated into the advanced cardiac life support (ACLS). MATERIAL AND METHODS: This study was prospectively performed in 179 patients (104 males and 75 females) who underwent cardiopulmonary resuscitation (CPR) in an emergency department (ED) during two calendar years (2013 and 2014). Two senior doctors, who had received emergency cardiac ultrasonography training, performed cardiac ultrasound through the apical, subxiphoid, or parasternal windows. Ultrasound evaluation and pulse controls were performed simultaneously. SPSS 18.0 was used for statistical analysis. RESULTS: A total of 63.7% (114) of the cardiopulmonary arrest incidents occurred out of the hospital. Only 13 patients had a femoral pulse during the initial evaluation, while 166 showed no femoral pulse. Initial monitoring showed a regular rhythm in 53 patients, ventricular fibrillation in 18 patients, and no rhythms in 108 patients. The first evaluation with ultrasound detected an effective heart rate in 26 patients and ventricular fibrillation in 14 patients, while no effective heart rate was observed in 139 patients. In addition, ultrasound revealed pericardial tamponade in seven patients and right ventricular enlargement in four cases. Global hypokinesia was detected in four patients and hypovolemia was observed in another four patients. CONCLUSION: The use of real-time ultrasonography during resuscitation with real-time femoral pulse check can help facilitate the distinguishing of pea-type arrest, ascertain the cause of the arrest, infer a suitable treatment, and optimize medical management decisions regarding CPR termination. PMID- 26956841 TI - Dispatch-assisted CPR instructions: Time to measure and improve. PMID- 26956842 TI - CPR induced consciousness: It's time for sedation protocols for this growing population. PMID- 26956843 TI - Bone resorption following weight loss surgery is associated with treatment procedure and changes in secreted Wnt antagonists. AB - To assess if altered bone turnover following bariatric surgery is related to metabolic consequences of the surgical procedure or weight loss. We evaluated serum markers reflecting bone turnover and metabolic pathways at baseline and after 1-year in a controlled non-randomized clinical trial comparing Roux-en-Y gastric bypass surgery (n = 74) with lifestyle intervention (n = 63) on obesity related comorbidities. The decrease in body mass index (BMI) was larger in the surgery (-14.0 kg/m(2)) compared to lifestyle (-3.7 kg/m(2)). Markedly increased bone turnover was observed following surgery compared to lifestyle intervention and was correlated with change in BMI. Stepwise multivariable regression analysis revealed that group (beta = 0.31, p < 0.01), and changes in BMI (beta = -0.28, p < 0.01), dickkopf-1 (beta = 0.20, p < 0.001) and sclerostin (beta = 0.11, p < 0.05) were predictors of change in the bone resorption marker N-terminal telopeptide. Our data support that mechanisms related to the procedure itself and changes in secreted Wnt antagonists may contribute to increased bone turnover following bariatric surgery. PMID- 26956844 TI - Impact of vitamin D receptor polymorphisms in centenarians. AB - Vitamin D is a seco-sterol produced endogenously in the skin or obtained from certain foods. It exerts its action through binding to intracellular vitamin D receptor (VDR). Lately, the role of vitamin D has been revised regarding its potential advantage on delaying the process of aging. The aim of this study was to assess the contribution of VDR gene polymorphisms in healthy aging and longevity. We evaluated the frequency of four polymorphisms of the VDR gene (FokI, BsmI, ApaI, and TaqI) in centenarians (102 subjects, mean age: 102.3 +/- 0.3 years), compared to septuagenarians (163 subjects, mean age: 73.0 +/- 0.6 years) and we analyzed a variety of pathophysiologically relevant functions in centenarians. BsmI and ApaI provided a significant association with longevity: there was a highly significant difference in the frequency of BsmI genotypes (p = 0.037), ApaI genotypes (p = 0.022), and ApaI alleles (p = 0.050) in centenarians versus septuagenarians. Furthermore, we found a significant correlation of all the VDR gene polymorphisms in centenarians with some measured variables such as hand grip strength, body mass index, blood pressure, HDL cholesterol, and mini mental state examination. We also found a correlation with the prevalence of medical history of hypertension, acute myocardial infarction, angina, venous insufficiency, dementia, chronic obstructive pulmonary disease, and arthrosis. In conclusion, this study proposes a new scenario in which the variability of the VDR gene is relevant in the aging process and emphasizes the role of VDR genetic background in determining healthy aging. PMID- 26956845 TI - Evidence for elevated (LIMK2 and CFL1) and suppressed (ICAM1, EZR, MAP2K2, and NOS3) gene expressions in metabolic syndrome. AB - The metabolic syndrome (MetS) is a common multicomponent condition including abdominal obesity, dyslipidemia, hypertension, and hyperglycaemia. The aim of this study was to investigate the associations of the expression of a panel of signalling genes with the MetS in a Turkish population. A total of 54 MetS patients and 42 healthy controls with similar age and sex were included to this study. mRNA from blood samples was extracted, and real-time polymerase chain reaction was performed for gene expressions using a BioMark 96.96 dynamic array system. We observed marked increases in LIM kinase 2 (LIMK2) and cofilin 1 (CFL1) gene expressions in MetS patients. However, there were significant decreases in intercellular adhesion molecules 1 (ICAM1), ezrin (EZR), mitogen-activated protein kinase kinase 2 (MAP2K2), and nitric oxide synthase 3 (NOS3) gene expressions in MetS patients. Additionally, no marked changes were noted in other 15 genes studied. This is the first study to provide evidence that activation of LIMK2/CFL1 pathway may play an important role in MetS. PMID- 26956846 TI - The PPARgamma2 P12A polymorphism is not associated with all-cause mortality in patients with type 2 diabetes mellitus. AB - The high mortality risk of patients with type 2 diabetes mellitus may well be explained by the several comorbidities and/or complications. Also the intrinsic genetic component predisposing to diabetes might have a role in shaping the risk of diabetes-related mortality. Among type 2 diabetes mellitus SNPs, rs1801282 is of particular interest because (i) it is harbored by peroxisome proliferator activated receptor-gamma2 (PPARgamma2), which is the target for thiazolidinediones which are used as antidiabetic drugs, decreasing all-cause mortality in type 2 diabetes mellitus, and (ii) it is associated with insulin resistance and related traits, risk factors for overall mortality in type 2 diabetes mellitus. We investigated the role of PPARgamma2 P12A, according to a dominant model (PA + AA vs. PP individuals) on incident all-cause mortality in three cohorts of type 2 diabetes mellitus, comprising a total of 1672 patients (462 deaths) and then performed a meta-analysis of ours and all available published data. In the three cohorts pooled and analyzed together, no association between PPARgamma2 P12A and all-cause mortality was observed (HR 1.02, 95 % CI 0.79-1.33). Similar results were observed after adjusting for age, sex, smoking habits, and BMI (HR 1.09, 95 % CI 0.83-1.43). In a meta-analysis of ours and all studies previously published (n = 3241 individuals; 666 events), no association was observed between PPARgamma2 P12A and all-cause mortality (HR 1.07, 95 % CI 0.85-1.33). Results from our individual samples as well as from our meta-analysis suggest that the PPARgamma2 P12A does not significantly affect all-cause mortality in patients with type 2 diabetes mellitus. PMID- 26956848 TI - Bioinformatic and Expression Analysis of Ventricular Septal Defect-associated Long Non-coding RNA TUC40-. AB - OBJECTIVE: To explore the potential role of TUC40- in human and mouse embryonic heart development. METHODS: Bioinformatics databases including NCBI,UCSC,and Uniprot and software including Clustal,DNAMAN,and MEGA 6 were used to collect information of TUC40- and uc.40-. The expression profile at key time points of heart development was investigated by strand-specific quantitative real time polymerase chain reaction. RESULTS: Uc.40- was conservative in sequence, genomic location, and transcription factor binding sites across human and mouse. Pbx1/TUC40- showed negative trend during embryonic mouse heart maturation. CONCLUSIONS: Various levels of conservation of uc.40- suggests similar functions of TUC40- in these two species. TUC40- may play its roles in human and mouse embryonic heart development by regulating Pbx1. PMID- 26956849 TI - Culture and Identification of Bone Marrow Mesenchymal Stem Cells from Enhanced Green Fluorescent Protein-transgenic Rats. AB - OBJECTIVE: To isolate, culture, and identify bone marrow mesenchymal stem cells (BMSCs) from enhanced green fluorescent protein (EGFP)-transgenic rats in vitro. METHODS: Bone marrows were isolated from tibia and femur of healthy EGFP transgenic rats of specific pathogen free (SPF) grade. Then,the whole bone marrow adherent method was used for isolation,culture,and purification of BMSCs. The morphological change was noted by continuous observation under inverted fluorescence microscope. The growth curve of cells was drawn through the method of CCK-8 and the proliferation compared with wild type BMSCs. The surface markers of BMSCs were detected by flow cytometry. The BMSCs were induced to differentiate into osteoblasts, adipocytes, and chondrocytes lineages. The EGFP-BMSCs were transplanted into the rats intravenously, and the expression of GFP was detected. RESULTS: BMSCs stably expressing EGFP gene were obtained successfully, with the fusiform-shaped appearance and the forming of circinate cell colonies. The growth curve of EGFP-MSCs showed the characteristic of active proliferation, showing no significant difference compared with the wild-type BMSCs. The expression rates of the surface markers of BMSCs CD29, CD90, CD34, CD49d, and CD45 were 99.4%, 96.4%, 0.171%, 0.049%, and 0.038%. The GFP were detected in lung 3 days after transplantation. After osteogenic, adipogenic, and chondrogenic induction, oil red-O and alizarin red positive signals and toluidine blue positive cells were detected. CONCLUSIONS: High-purity BMSCs stably expressing green fluorescent protein gene can be cultured using the whole bone marrow adherent method. EGFP does not affect the stem cell properties and expresses stably after transplantation. The cells can be used as seed cells for subsequent research. PMID- 26956850 TI - Comparisons of Emu Necrotic Femoral Head Micro Structure Repaired in Two Different Methods. AB - OBJECTIVE: To compare emu necrotic femoral head micro structure repaired in two different methods. METHODS: Fifteen adult emus were divided into 3 groups (all n=5), and the right femoral head was selected to research. The first group was the control group; in the second group, femoral head necrosis was made by cryogen with liquid nitrogen; and in the third group, femoral head necrosis was made by local pure ethanol injection. Right femurs were taken for micro CT examination,then femoral head micro structures were compared among these three groups. RESULTS: No infection or unexpected death was found in all groups. Compared with normal group, necrotic femoral heads in cryogen group showed that bone mineral density significantly reduced after repaire (P=0.015), trabecular space significantly reduced (P=0.001), bone volume fraction significantly enlarged (P=0.036), bone surface/volume fraction (P=0.032) and trabecular numbers (P=0.002) significantly enlarged; trabecular thickness showed no significant difference (P=0.060). Compared with control group, necrotic femoral heads in ethanol group showed that bone mineral density significantly enlarged after repaire (P=0.001), trabecular thickness (P=0.003) and bone surface/volume fraction (P=0.022) significantly enlarged, trabecular space (P=0.001) and bone volume fraction (P=0.001) significantly reduced; the trabecular numbers showed no significant difference (P=0.143). Compared with ethanol group, necrotic femoral heads in cryogen group showed significant lower bone mineral density after repair (P=0.001), significantly lower bone volume fraction (P=0.001), significantly lower trabecular thickness (P=0.001), significantly higher bone surface/volume fraction (P=0.022) and higher trabecular numbers (P=0.003); the trabecular space showed no significant difference (P=0.398). CONCLUSION: Different repair methods make reconstructed femoral head weight bearing area have different bone structure and bone mineral density, along with different bone trabecular quality. PMID- 26956851 TI - Effect of Connexin43 on Mechanical Tension-stimulated Osteogenic Transcription Factors of Human Periodontal Ligament Fibroblasts. AB - OBJECTIVE: To investigate the expression and effect of Connexin43 (Cx43) on tensile tension-stimulated osteogenic transcription factors of human periodontal ligament fibroblasts (hPDLFs). METHODS: After hPDLFs were treated with 5% elongation tension for 1 h, 2 h, 4 h, 8 h, and 24 h, we examined the expressions of Cx43, Osterix, and RUNX2 at the mRNA level. After Cx43 expression was suppressed by siRNA or 18alpha-GA, the changes The mRNA in hPDLFs of Osterix and RUNX2 were observed. RESULTS: The expressions of Cx43, Osterix, and RUNX2 mRNA in hPDLFs increased in a time-dependent fashion following tensile strain (all P<0.05), with the highest level at 5% elongation for 24 h. After Cx43 expression was blocked by two different methods, the increasing expressions of Osterix and RUNX2 were inhibited. CONCLUSIONS: 5% cyclic tension upregulates Cx43 expression and promotes the expression of Osterix and RUNX2 in a time-dependent manner. Cx43 may be involved in the osteogenic response of hPDLFs to mechanical tension. PMID- 26956847 TI - The metabolic vascular syndrome - guide to an individualized treatment. AB - In ancient Greek medicine the concept of a distinct syndrome (going together) was used to label 'a group of signs and symptoms' that occur together and 'characterize a particular abnormality and condition'. The (dys)metabolic syndrome is a common cluster of five pre-morbid metabolic-vascular risk factors or diseases associated with increased cardiovascular morbidity, fatty liver disease and risk of cancer. The risk for major complications such as cardiovascular diseases, NASH and some cancers develops along a continuum of risk factors into clinical diseases. Therefore we still include hyperglycemia, visceral obesity, dyslipidemia and hypertension as diagnostic traits in the definition according to the term 'deadly quartet'. From the beginning elevated blood pressure and hyperglycemia were core traits of the metabolic syndrome associated with endothelial dysfunction and increased risk of cardiovascular disease. Thus metabolic and vascular abnormalities are in extricable linked. Therefore it seems reasonable to extend the term to metabolic-vascular syndrome (MVS) to signal the clinical relevance and related risk of multimorbidity. This has important implications for integrated diagnostics and therapeutic approach. According to the definition of a syndrome the rapid global rise in the prevalence of all traits and comorbidities of the MVS is mainly caused by rapid changes in life-style and sociocultural transition resp. with over- and malnutrition, low physical activity and social stress as a common soil. PMID- 26956852 TI - Effect of High MiR-146a Expression on the Inflammatory Reaction in BV2 Cells. AB - OBJECTIVE: To explore the effect of MiR-146a regulator function on the inflammatory response in neuroglia cell (microglia). METHODS: BV2 cells were transfected by MiR-146a mimics,and then stimulated by lipopolysaccharide (LPS). MiR-146a expression was measured by real-time polymerase chain reaction (real time PCR). Interleukin (IL)-6 and tumor necrosis factor alpha (TNFalpha) were measured by enzyme-linked immunosorbent assay (ELISA). Furthermore, IL-1 receptor associated kinase 1 (IRAK1) and TNF receptor-associated factor 6 (TRAF6) were detected by PCR and Western blotting. RESULTS: Compared to the normal control group, MiR-146a expression was significantly elevated by transfection with MiR 146a mimics (t=5.846, P=0.0021). The expression levels of IRAK1, TRAF6, TNFalpha, and IL-6 significantly increased in the LPS-stimulated BV2 cells compared to the non-stimulated BV2. The enhancement of MiR-146a resulted in significantly decreased IL-6 (t=5.200, P=0.0003) and TNFalpha (t=9.812, P<0.0001) secretion. The mRNA (t=5.353, P=0.0007) and protein (t=6.980, P=0.0009) levels of TRAF6, but not IRAK1, also significantly decreased. CONCLUSION: MiR-146a may negatively suppress the inflammatory response of BV2 cells by regulating the expression of IRAF6 molecules in the TLR4 signaling pathway. PMID- 26956853 TI - Protection of Nerve Injury with Exosome Extracted from Mesenchymal Stem Cell. AB - OBJECTIVE: To investigate the protective effect of Exosomes from human adipose derived mesenchymal stem cells (hAMSCs) in neural injury induced by glutamate and its possible mechanism. METHODS: Characteristics of Exosomes from hAMSCs were identified by electron microscopy and Western blot analysis. Cytokines that might play a major role in the protective effect were tested by enzyme-linked immunosorbent assay (ELISA). The protective action of Exosome and its possible signaling pathway were researched by the in vitro neural injury induced by glutamate, including control group (without Glu), Glu group (dealing with Glu), Glu+Exo group (dealing with Glu +100 ng/ml Exo), Glu+Exo+Akt group (dealing with Glu+100 ng/ml Exo+10 MUmol/L Akt), Glu+Exo+Erk group (dealing with 100 ng/ml Glu+100 ng/ml Exo+10 MUmol/L Erk), and Glu+Exo+TrkB group (dealing with Glu+100 ng/ml Exo +10 MUmol/L TrkB). RESULTS: Exosomes from hAMSCs had similar sizes to those isolated from other kinds of cells, and expressed the characteristic proteins such as CD63, CD81, HSP70, and HSP90. Cytokines that had neurotrophic effects on Exosomes were mainly insulin-like growth factor and hepatocyte growth factor, with the concentration being 9336.49+/-258.63 and 58,645.50+/-16,014.62, respectively; brain derived neurotrophic factor, nerve growth factor,and vascular endothelial growth factor had lower levels, with the concentration being 1928.25+/-385.47, 1136.94+/-5.99, and 33.34+/-9.43, respectively. MTS assay showed that the PC12 cell survival rates were 0.842+/-0.047, 0.306+/-0.024, 0.566+/-0.026, 0.461+/-0.016, 0.497+/-0.003, and 0.515+/-0.034 in the control group, Glu group, Glu+Exo group, Glu+Exo+Akt group, Glu+Exo+Erk group, and Glu+Exo+TrkB group; obviously, it was significantly lower in Glu group than in control group (P=0.02), significantly higher in Glu+Exo group than in Glu group (P=0.01), and significantly lower in Glu+Exo+Akt group than in Glu+Exo group (P=0.01). CONCLUSION: Exosomes secreted from hAMSCs have protective effect against neuron damage induced by glutamate, which may be mediated through activating the PI3/K-Akt signalling pathway. PMID- 26956854 TI - Correlation between Pituitary Stalk Interruption Syndrome and Prokineticin Receptor 2 and Prokineticin 2 Mutations. AB - OBJECTIVE: To analyze the correlation between pituitary stalk interruption syndrome (PSIS) and prokineticin receptor 2 (PROKR2) and prokineticin 2 (RROK2) mutations. METHODS: PROKR2 and RROK2 genotypes were identified by multiplex polymerase chain reaction analysis with exon-flanking primers and by automated sequencing techniques with peripheral blood DNA samples from 59 patients with PSIS. RESULTS: Of these 59 PSIS patients, 6 showed intragenic deletions at the PROKR2 locus. Of them, 5 patients exhibited intragenic subsititution of exon 2 (c.991G>A), and the remaining one patient exhibited intragenic subsititution of exon 2 (c.1057C>T). No PROK2 mutation was found in these PSIS patients. CONCLUSION: PROKR2 may be the susceptibility gene of PSIS. PMID- 26956855 TI - In Vivo Confocal Microscopic Evaluation of Corneal Endothelial Dysfunction Induced by Phacoemulcification in Rhesus Monkey Models. AB - OBJECTIVE: To observe the characteristic morphological changes of corneal endothelial dysfunction induced by phacoemulcification in rhesus monkey models under confocal microscope. METHODS: The corneal endothelial dysfunction models were established by phacoemulcification power on the central corneal of 7 to 9 mm diameter in the right eyes of 4 rhesus monkeys (the modeling group). The left eyes of 4 rhesus monkeys were set as blank control group. The structural changes in different corneal layers were evaluated by slit lamp microscope and in vivo confocal microscope before surgery and 1, 2, 3, and 4 weeks after surgery. SPSS 19.0 software was applied to analyze data. Paired-t test was used to compare the number of nerve plexus in Bowman's layer and corneal endothelial cell density. Analysis of variance (ANOVA) was used to analyze corneal thickness. RESULTS: After phacoemulcification, the changes of cornea occurred gradually in the endothelial layer, stroma, Bowman's membrane, and basal epithelial layer. In the early stage, the interspace of corneal endothelial cells enlarged and few activated stromal cells were detected in the stroma. The cell morphology of stroma altered. The thickness of stroma increased. Two weeks after surgery, the nerve plexus in Bowman's layer decreased and edema of stroma and endothelial layer increased. Three weeks after surgery, the interspace of basal epithelial cells increased with a few Langerhans' cells infiltration and edema of stroma and endothelial layer increased. Four weeks after the surgery, a large amount of Langerhans' cells presented in basal epithelial layer. Only a few nerve lexus could be seen in Bowman's layer. The stroma and endothelial cells had severe edema. A large number of activated stromal cells could be found in stromal layer. Two weeks after the surgery, the number of nerve plexus in Bowman's layer (t=6.9192, P=0.002) and corneal endothelial cell density (t=7.8936, P<0.0001) in the modeling group were significantly lower than that in control group. Compared with corneal thickness in control group, it was significantly larger in the modeling group at 1 (t=28.31, P<0.0001), 2 (t=63.56, P<0.0001), 3 (t=123.22, P<0.0001), and 4 weeks (t=180.80, P<0.0001) after the surgery. CONCLUSIONS: The changes in corneal endothelial dysfunction induced by phacoemulcification in rhesus monkey models can be clearly shown under in vivo confocal microscope. Gradual increase of endothelial cells interspace, activated stromal cells, increase of Langerhans' cells, and decrease of plexus in Bowman's layer are the main changes. PMID- 26956856 TI - Therapeutic Effect of Carboxyamidotriazole on Adjuvant Arthritis in Rats. AB - OBJECTIVE: To study the effect of carboxyamidotriazole (CAI) on adjuvant arthritis (AA) in rats. METHODS: The rats were randomly divided into normal group,two vehicle groups (polyethylene glycol 400 control and normal sodium control group), CAI-treated groups (10, 20, and 40 mg/kg) and positive control dexamethasone group. Freund's completed adjuvant was used to induce AA in rats. The arthritis index (AI) was scored, and X-ray check of the hind limbs and histopathological examination were performed. The levels of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and IL-6 in the inflamed paw tissues were measured. RESULTS: The administration of CAI significantly decreased the AI, restored the body weights, and ameliorated the radiological and histopathological features of joint destruction in AA rats (P<0.05, P<0.01). In addition, CAI reduced the TNF-alpha, IL-1beta, and IL-6 levels in the inflamed paw tissues (P<0.05, P<0.01). CONCLUSION: CAI has therapeutic effect on AA rats, which may be achieved by decreasing the pro-inflammatory cytokines at the site of inflammation. PMID- 26956857 TI - Enhancing Effect of Chiral Enhancer Linalool on Skin Permeation of Naproxen. AB - OBJECTIVE: To investigate the permeation-enhancing effect of dl-linalool, d linalool, and l-linalool on model drugs across excised rat skin and the effect of linalool on the ceramides in stratum corneum lipids. METHODS: In vitro skin permeation studies were performed with Valia-Chien diffusion cells, and the permeation samples were analyzed by high performance liquid chromatography with chiral stationary phase. Infrared spectroscopy was used to investigate the effect of linalool on stratum corneum lipids. RESULTS: When the donor vehicles added with 1% dl-linalool, 1% d-linalool, or 1% l-linalool, the steady-state skin permeation rate of naproxen was (2.47+/-0.63), (1.53+/-0.54), (1.73+/-0.48) MUg.cm(-2).h(-1), respectively, which is 2.49, 1.55, and 1.75 times (all P<0.05) compared with control group [(0.99+/-0.42)MUg.cm(-2).h(-1)], and the differences were statistically significant (all P<0.05). The permeation-enhancing effect of dl-linalool on naproxen was found significantly greater than that of d-linalool and l-linalool (both P<0.05). Compared with the control group, the stratum corneum treated with dl-linalool shifted to higher wave number on 2.09 cm(-1) of asymmetric CH2 stretching vibrations in attenuated total reflection-fourier transform infrared spectroscopy analysis. However, stratum corneum treated with d linalool and l-linalool did not display this phenomenon. CONCLUSION: The disturbing degree of dl-linalool on stratum corneum lipids (ceramides) is different from that of linalool enantiomers, suggesting their different enhancing effect on the same drug. PMID- 26956858 TI - Efficacy and Safety of Tiotropium in the Treatment of Severe Persistent Asthma:Meta-analysis. AB - OBJECTIVE: To evaluate the efficacy and safety of tiotropium in treatment of severe persistent asthma. METHODS: Reports of randomized controlled trials (RCTs) describing tiotropium for treatment of severe persistent asthma published from January 1946 to February 2015 were searched in Cochrane Library, ClinicalTrials.gov, PubMed, Ovid Medline, CNKI, and CSJD. The data of the included RCTs were extracted and the data quality was evaluated. Meta-analyses were performed with Revman 5.3 software. RESULTS: Five RCTs including 1433 patients were analyzed. Meta-analysis of the data showed that compared with the placebo group, tiotropium treatment significantly improved the patients' peak forced expiratory volume in one second (FEV1) [weighted mean difference (WMD): 0.13 L, 95% confidence interval (CI): 0.10-0.16 L, P<0.00001], trough FEV1 (WMD: 0.09 L, 95%CI: 0.06-0.12 L, P<0.00001), peak forced vital capacity (FVC) (WMD: 0.10 L, 95%CI: 0.06-0.14 L, P<0.00001), trough FVC (WMD: 0.12 L, 95%CI: 0.08-0.17 L, P<0.00001), morning peak expiratory flow (PEF) (WMD: 9.21 L/min, 95%CI: 4.2 14.23 L/min, P=0.0003), evening PEF (WMD: 22.06 L/min, 95%CI 13.05-31.08 L/min, P<0.00001). The scores of asthma control questionnaire (ACQ) (WMD: 0.01, 95% CI: 0.07-0.09, P=0.86) or asthma quality of life questionnaire (AQLQ)(WMD: 0.06, 95% CI:-0.18-0.06, P=0.33) were not affected by tiotropium. No significant difference with adverse events between tiotropium group and placebo group were reported in these included studies (P>0.05). CONCLUSIONS: Tiotropium for severe persistent asthma treatment can improve FEV1, FVC, and PEF but may not improve the quality of life of the patients. Tiotropium is well tolerated and can be an add-on therapy for severe persistent asthma. PMID- 26956859 TI - KLF17 Expression in Colorectal Carcinoma and Its Clinical Significance. AB - OBJECTIVE: To detect KLF17 expression in colorectal carcinoma (CRC) and to evaluate its effect on the prognosis of colorectal carcinoma. METHODS: Immunohistochemistry was performed to detect the expression of KLF17 in CRC and matched pericarcinous tissue,and the relationship between KLF17 expression and disease-free survival (DFS) was analyzed. RESULTS: Of 73 CRC patients, KLF17 expression was positive in 32 patients and negative in 41 patients. KLF17 expression rate was significantly lower in CRC tissue than in pericarcinous tissue (chi(2)=12.418, P=0.001). The DFS of KLF17-positive stage III colon cancer patients was (56.3+/-7.2) months (95% CI: 42-70 months), which was significantly longer than that [(32.3+/-5.5) months (95% CI: 22-43 months)] of KLF17-negative patients (P=0.039). CONCLUSION: KLF17 expression decreases in CRC tissue, and a positivie KLF17 expression predicts a better prognosis in stage III CRC patients. PMID- 26956860 TI - Effect of Transsphenoidal Adenectomy on Glucose Tolerance Status in Patients with Growth Hormone-secreting Pituitary Adenoma. AB - OBJECTIVE: To explore the effect of transsphenoidal adenectomy on glucose tolerance status in patients with growth hormone (GH)-secreting pituitary adenoma. METHODS: The clinical data of 105 patients with GH-secreting pituitary adenoma who underwent transsphenoidal adenectomy in our department in 2013 were retrospectively analyzed. The glucose tolerance status, GH level, and insulin like growth factor-1 (IGF-1) level before and after surgery were compared. RESULTS: Among these 105 patients, the blood glucose tolerance status included normal glucose tolerance (NGT) in 47 cases (44.8%), early carbohydrate metabolism disorders (ECMDs) in 26 cases (24.8%), and diabetes mellitus (DM) in 32 cases (30.5%) before surgery. After the surgery, the fasting blood glucose (P=0.006, P=0.017) and postprandial blood glucose (P=0.000, P=0.000) in the ECMDs and DM groups were significantly improved. Also, the random GH (P=0.001, P=0.004, P=0.001), nadir GH (P=0.000, P=0.001, P=0.001), and IGF-1 (P=0.005, P=0.000, P=0.000) significantly decreased during the follow-up period in NGT, ECMDs and DM groups. Compared with ECMDs and DM groups, the decrease in fasting blood glucose (P=0.029, P=0.000), postprandial blood glucose (P=0.003, P=0.000), and serum IGF 1 (P=0.048, P=0.000) were more significant in DM group. CONCLUSIONS: Transsphenoidal adenectomy can improve the blood glucose, GH, and IGF-1 levels in patients with growth hormone-secreting pituitary adenoma. Meanwhile,the surgery has a better effect in improving the glucose tolerance status and IGF-1 in patients with preoperatively confirmed DM. PMID- 26956861 TI - Clinical Characteristics and Prognosis of Peripartum Cardiomyopathy in 28 Patients. AB - OBJECTIVE: To analyze the clinical features and prognosis of patients with peripartum cardiomyopathy (PPCM). METHODS: The clinical data of 28 PPCM patients with PPCM diagnosed in Peking Union Medical College Hospital from January 1983 to December 2014 were retrospectively analyzed and followed up for at least 6 months or to death or cardiac transplantation. RESULTS: All patients were presented with heart failure. Mean baseline left ventricular ejection fraction (LVEF) was (36.2+/-11.8)%. After a median follow-up of 27 months, 16 of the 21 patients (76%) showed improvement in LVEF and 5 patients (24%) did not have improvement in their LVEF. Only 1 patient died. There were significant differences between improved and non-improved patients in baseline LVEF (P=0.007), baseline left ventricular end-diastolic dismension (LVEDD) (P=0.040), follow-up LVEF (P<0.001), and follow-up LVEDD (P<0.001). Cox regression analysis showed that higher LVEF (RR: 0.89, 95%CI: 0.83-0.96, P=0.002) and smaller LVEDD (RR: 0.90, 95%CI: 0.83 0.99, P=0.026) were predictors of improvement in LVEF. CONCLUSIONS: Early diagnosis and regular treatment helps to improve the prognosis of PPCM. Patients with higher LVEF and smaller LVEDD appear to be the most likely to recover. PMID- 26956862 TI - Response to (131)I Therapy in Non-metastatic Differentiated Thyroid CancerPatients with Preablative Stimulated Thyroglobulin above 10 ng/ml. AB - OBJECTIVE: To evaluate the response of (131)I therapy and to explore the influencing factors in non-metastatic differentiated thyroid cancer (DTC) patients with preablative stimulated thyroglobulin (ps-Tg) above 10 ng/ml. METHODS: The study included 157 DTC patients who had undergone total or near total thyroidectomy and subsequent (131)I therapy with ps-Tg>10 ng/ml, and they were divided into 3 groups as excellent response (ER, 49 cases), acceptable response (AR, 36 cases), and incomplete response (IR, 72 cases) according to the response to (131)I therapy. We compared the clinicopathologic features and ps-Tg levels among 3 groups, as well as ps-Tg levels between IR and non-IR groups. The ROC curve was employed to evaluate the predictive value of ps-Tg levels in (131)I therapy responses. RESULTS: The three groups showed significant difference in ps Tg levels (H=35.142, P<0.001), gender (chi(2)=6.82, P=0.033), extrathyroid invasion (H=31.380, P<0.001), and lymph metastases (H=14.375, P=0.001). The ps-Tg level in IR is higher than that in non-IR (U=1384.5, P<0.001), while it was not significantly different between ER and AR (U=771.5, P=0.326). The diagnostic critical point (DCP) of ps-Tg to differentiate IR and non-IR was 28.3 ng/ml (sensitivity 57.5%, specificity 87.1%), with a corresponding area under the ROC curve (AUC) of 0.774 (95%CI: 0.701-0.847). CONCLUSIONS: Near-half (45.86%) non metastatic DTC patients with ps-Tg above 10 ng/ml are more susceptible to IR. The level of ps-Tg>28.3 ng/ml may be a useful and sensitive diagnostic marker for predicting incomplete response. PMID- 26956863 TI - Clinical Outcome of (131)I Therapy in Differentiated Thyroid Cancer with Preablative Thyroglobulin below 10 ng/ml. AB - OBJECTIVE: To investigate the clinical outcome of (131)I therapy in differentiated thyroid cancer (DTC) with preablative stimulated thyroglobulin (ps Tg) below 10 ng/ml and the value of ps-Tg for predicting clinical outcome. METHODS: Totally 167 DTC patients with ps-Tg below 10 ng/ml were included and divided into three groups [excellent response (ER, n=131), acceptable response (AR, n=34), and incomplete response (IR, n=2)] according to the response to initial (131)I therapy. One-way analysis of variance, chi(2) test, and Kruskal Wallis test were used to evaluate the statistical differences of clinicopathological features, recurrence risk, and ps-Tg value among the three groups. The ps-Tg value between ER group and non-ER group were compared by Mann Whitney rank-sum test. The ROC curve and optimal cut-off point were analyzed to evaluate the clinical value of ps-Tg for predicting disease-free status. RESULTS: There was significant difference in ps-Tg level (H=14.305, P=0.001) among three groups but not in age (F=0.831, P=0.755), sex (chi(2)=0.178, P=0.915), cervical lymph node metastases (chi(2)=1.475, P=0.478), TNM stage (H=1.063, P=0.588), and recurrence risk (H=2.947, P=0.229). The median level of ps-Tg in ER group was 2.20 ng/ml (1.10, 4.40), which was significantly lower than 4.40 ng/ml (2.70, 5.90) of non-ER groups (U=1424.50, P=0.000). Area under the ROC curve was 0.717. The cut-off value of ps-Tg was 2.35 ng/ml,with a sensitivity of 83.33%, specificity of 53.43%, and negative predictive value of 92.11%. CONCLUSION: The serum ps-Tg value is a sensitive marker for predicting the disease-free status in DTC patients with ps-Tg below 10 ng/ml. PMID- 26956864 TI - Computed Tomographic and Pathological Features of Primary Pulmonary Sarcomatoid Carcinoma. AB - OBJECTIVE: To investigate the computed tomographic (CT) and pathological features of primary pulmonary sarcomatoid carcinoma (PSC). METHODS: The clinical data and CT images of 20 patients with pathologically confirmed PSC were retrospectively analyzed. RESULTS: Solitary pulmonary mass was identified in 18 patients and multiple pulmonary masses in 2 patients, amounting to 22 masses. There were 17 peripheral masses and 5 central masses, including 11 masses larger than 5 cm. The smooth margin was identified in 9 masses, deep lobulation and/or spinous protuberance in 11 masses, and ill-defined margin in 2 masses. Pleural indentation was identified in 2 masses and pleural thickening with wide basement was identified in 14 masses. On plain CT, cavity was observed in 5 masses, hypo density in 7 masses, and homogeneous density in 10 masses. On contrast-enhanced CT scanning, irregular ring/patchy enhancement were shown in 15 masses and slightly homogenous enhancement in 2 masses. Of all patients, 6 patients had unilateral or bilateral hilar and/or mediastinal lymphadenopathy. There were 16 pleomorphic carcinomas and 4 spindle cell carcinomas. Immunohistochemically, anti pan cytokeratin antibody was positive in 13 patients, cytokeratin was positive in 8 patients, Vimentin was positive in 15 patients, epithelial membrane antigen was positive in 1 patient, and thyroid transcription factor-1 was positive in 8 patients. CONCLUSION: PSC has some specific CT features; however, the final confirmation of PSC still depends on pathological and immunohistochemical examinations. PMID- 26956865 TI - Colony Stimulating Factor 3 Mutations and Myeloid Malignancies. AB - Granulocyte colony stimulating factor (G-CSF) plays a major role in the proliferation, differentiation, and activation of neutrophil cell line hematopoietic cells. G-CSF exert the function depending on its binding to colony stimulating factor 3 receptor (CSF3R), a homo-dimer receptor located on the surface of effector cells. Some recent studies have demonstrated that CSF3R mutations play a significant role in many diseases. Some of the hematopoietic diseases, especially myeloid malignancies (e.g. chronic neutrophilic leukemia) are related to the presence of various CSF3R mutations, which leads to abnormal G CSF signal pathways. Also, the downstream kinases can be the treatment targets for these diseases. This review summarizes CSF3R mutations, mechanisms of mutations, and their contributions to the myeloid malignancies, with an attempt to further reveal the pathogenesis of myeloid malignancies, inform the diagnosis and clinical treatment of the myeloid malignancies, and provide clues for the research and development of new molecular target drugs. PMID- 26956866 TI - Pathogenesis of Castleman's Disease. AB - Castleman's disease (CD) is a rare lymphoproliferative disorder that comprises at least two distinct clinical subtypes (unicentric and multicentric). Three pathologic variants (hyaline vascular variant, plasma cell variant, and mixed variant) have been recognized. In addition to interleukin-6 and human herpes virus 8, some other cytokines and viruses may also be involved in the pathogenesis of CD. This review summarizes the recent advances in the underlying pathogenesis of CD, with an attempt to provide evidence for new treatment options that may change the current treatment strategies and improve patients' outcomes. PMID- 26956867 TI - Research Advances in Biomarkers for Demyelinating Optic Neuritis. AB - Optic neuritis refers to all inflammatory diseases in the optic nerve. The most common type is demyelinating optic neuritis. Biomarkers can indicate its pathophysiological process and thus are useful in disease diagnosis and treatment. This article reviews the known biomarkers for demyelinating optic neuritis. PMID- 26956868 TI - Short term, low dose fluoxetine blocks estrous cycle-linked changes in responsiveness to diazepam in female rats. AB - Anxiety behavior in female Wistar rats was assessed at different stages of the estrous cycle using the elevated plus maze (EPM). No differences were observed at any cycle stage. Pretreatment with diazepam (1 mg kg(-1) intraperitoneal (i.p.)) 30 min before testing produced an anxiolytic effect (significant increase in percentage of time in the open arms compared to control group in the same cycle phase) in animals in proestrus, estrus, and early diestrus but had no effect in rats in late diestrus. Locomotor activity (total arm entries) was unchanged at any cycle phase. When rats in the late diestrus phase were pretreated with the selective serotonin reuptake inhibitor fluoxetine (1.75 mg kg(-1) i.p. on the afternoon of early diestrus and again in the morning of late diestrus) diazepam produced an anxiolytic effect (increase percentage time in the open arms). This dose is sufficient to raise brain allopregnanolone concentration without affecting 5-hydroxytryptamine (5-HT) systems. We propose that insensitivity to diazepam in late diestrus is due to increased expression of benzodiazepine insensitive alpha4 subunit-containing gamma-aminobutyric acid A (GABAA) receptors triggered by a sharp decrease in brain allopregnanolone concentration. Pretreatment with fluoxetine to raise brain allopregnanolone concentration during late diestrus prevents the withdrawal effect. PMID- 26956869 TI - Annular, scaly, erythematous rash on the buttocks and thighs. PMID- 26956872 TI - The DSM and learning difficulties: formulating a genealogy of the learning disabled subject. AB - The article examines the manner in which the learning-disabled subject is created as an object within contemporary psychiatric discourse by means of a genealogical analysis of the learning-disorders in the Diagnostic and Statistical Manual of Mental Disorders (DSM). It investigates how this pathology was formed historically in the text, what metamorphoses it underwent, and their epistemic significance. First, the theoretical underpinnings of the sociological discourse on DSM are presented, giving a brief background of the DSM status in the Israeli context. Many problematic characteristics in the text are unveiled, by means of critiques from sociology, anthropology and discourse studies. Second, the changing definitions and conceptualizations of learning-disorders in the seven editions of the Manual and the accompanying case studies (1952-2013) are examined. It becomes apparent that the disorders have undergone changes that have enabled the biomedical paradigm to triumph. The implications of these transformations are addressed. PMID- 26956873 TI - Erratum to: Predictive value of serum HER2 ECD in patients with HER2-positive advanced gastric cancer treated with trastuzumab plus chemotherapy. PMID- 26956871 TI - Recurrent neomorphic mutations of MTOR in central nervous system and testicular germ cell tumors may be targeted for therapy. AB - Germ cell tumors constitute a heterogeneous group that displays a broad spectrum of morphology. They often arise in testes; however, extragonadal occurrence, in particular brain, is not uncommon, and whether they share a common pathogenesis is unknown. We performed whole exome sequencing in 41 pairs of central nervous system germ cell tumors (CNS GCTs) of various histology and their matched normal tissues. We then performed targeted sequencing of 41 selected genes in a total of 124 CNS GCTs, 65 testicular germ cell tumors (tGCTs) and 8 metastatic GCTs to the CNS. The results showed that mutually exclusive mutations of genes involved in the MAPK pathway were most common (48.4 %), typically in KIT (27.4 %), followed by those in the PI3K pathway (12.9 %), particularly in MTOR (6.5 %), among the 124 CNS GCTs. Pure germinomas and non-germinomatous germ cell tumors (NGGCTs), as well as CNS and testicular GCTs, showed similar mutational profiles, suggesting that GCTs share a common molecular pathogenesis. Mutated MTOR identified in CNS GCTs upregulated phosphorylation of the AKT pathway proteins including AKT and 4EBP1 in nutrient-deprived conditions and enhanced soft-agar colony formation; both events were suppressed in a dose-dependent manner by addition of the MTOR inhibitor pp242. Our findings indicate that the dominant genetic drivers of GCTs regardless of the site of origin are activation of the MAPK and/or PI3K pathways by somatic point mutations. Mutated MTOR represents a potential target for novel targeted therapies for refractory GCTs. PMID- 26956874 TI - Structural insights of a PI3K/mTOR dual inhibitor with the morpholino-triazine scaffold. AB - Stimulation of the PI3K/Akt/mTOR pathway, which controls cell proliferation and growth, is often observed in cancer cell. Inhibiting both PI3K and mTOR in this pathway can switch off Akt activation and hence, plays a powerful role for modulating this pathway. PKI-587, a drug containing the structure of morpholino triazines, shows a dual and nano-molar inhibition activity and is currently in clinical trial. To provide an insight into the mechanism of this dual inhibition, pharmacophore and QSAR models were developed in this work using compounds based on the morpholino-triazines scaffold, followed by a docking study. Pharmacophore model suggested the mechanism of the inhibition of PI3Kalpha and mTOR by the compounds were mostly the same, which was supported by the docking study showing similar docking modes. The analysis also suggested the importance of the flat plane shape of the ligands, the space surrounding the ligands in the binding pocket, and the slight difference in the shape of the binding sites between PI3Kalpha and mTOR. PMID- 26956875 TI - A multicenter randomized controlled open-label trial to assess the efficacy of compound kushen injection in combination with single-agent chemotherapy in treatment of elderly patients with advanced non-small cell lung cancer: study protocol for a randomized controlled trial. AB - BACKGROUND: With the aging of the global population, an increasing number of elderly are diagnosed with advanced non-small cell lung cancer. Although systematic chemotherapy has been one of the primary treatments for advanced non small cell lung cancer worldwide, the elderly cannot always tolerate standard platinum-based doublet chemotherapy, thus resulting in treatment failure. To reduce toxicity, single-agent chemotherapy is often used to treat the elderly with non-small cell lung cancer; however, this may increase the risk of treatment failure due to an inadequate dose. It has been shown that compound kushen injection in combination with chemotherapy can enhance the efficacy and reduce the toxicity. The aim of this trial is to assess the clinical effectiveness and safety of compound kushen injection in combination with single-agent chemotherapy versus platinum-based doublet chemotherapy in the treatment of elderly patients with advanced non-small cell lung cancer. METHODS: This multicenter study will be an open-label, randomized controlled trial. Three hundred seventy elderly patients with advanced non-small cell lung cancer will be randomly divided into experimental (n = 185) and control groups (n = 185) to receive compound kushen injection in combination with single-agent chemotherapy or standard platinum based doublet chemotherapy for two cycles. After two cycles, the disease control rate, objective response rate, clinical symptoms, quality of life, Karnofsky Performance Status, and side effects will be assessed. Follow-up evaluations will be performed every 8 weeks to evaluate the progression-free and overall survival. DISCUSSION: Before the trial was designed, compound kushen injection was shown to be effective for lung cancer through basic experiments and clinical trials. This study will determine whether or not the efficacy of compound kushen injection in combination with single-agent chemotherapy is comparable to that of platinum based doublet chemotherapy, and whether or not the toxicity of compound kushen injection in combination with single-agent chemotherapy is lower than that of platinum-based doublet chemotherapy. TRIAL REGISTRATION: ChiCTR-IPR-14005484 (16 November 2014). PMID- 26956877 TI - Optimizing radiation dose and imaging time with conventional myocardial perfusion SPECT: Technical aspects. PMID- 26956876 TI - Comparison of biventricular ejection fractions using cadmium-zinc-telluride SPECT and planar equilibrium radionuclide angiography. AB - BACKGROUND: We compared biventricular ejection fractions (EFs) from gated blood pool single-photon emission computed tomography (SPECT) using a cadmium-zinc telluride camera (CZT-SPECT) with planar equilibrium radionuclide angiography (ERNA) using a NaI gamma camera (NaI-planar). We also evaluated whether imaging time can be reduced without compromising image quality using the CZT camera. METHODS: Forty-eight patients underwent NaI-planar and CZT-SPECT on the same day. CZT-SPECT datasets were re-projected at an LAO orientation similar to ERNA acquisition, forming CZT-repro planar datasets. The resulting biventricular volumetric measurements and EFs were compared. RESULTS: LVEF calculated from CZT SPECT and CZT-repro correlated better with NaI-planar (r = 0.93 and 0.99, respectively) than RVEF (r = 0.76 and 0.82, respectively). Excellent intra-class correlation and low bias in intra-observer comparisons were observed for the biventricular EFs derived from three datasets. A wider limit of agreement in CZT SPECT-derived LVEFs, lower correlation and significant bias for NaI-planar, and CZT-repro-derived RVEFs was found in the inter-observer analyses. Nonetheless, the imaging time can be reduced to 4 minutes without increasing variability in EFs using the CZT camera (P = NS). CONCLUSIONS: LVEFs calculated from CZT-SPECT and CZT-repro correlated well with NaI-planar. CZT camera may reduce imaging time while preserving image quality in the assessment of biventricular EFs. PMID- 26956878 TI - Mervyn Deitel-Biography. PMID- 26956879 TI - High-resolution Impedance Manometry after Sleeve Gastrectomy: Increased Intragastric Pressure and Reflux are Frequent Events. AB - INTRODUCTION AND PURPOSE: Sleeve gastrectomy (SG) is gaining ground in the field of bariatric surgery. Data are scarce on its impact on esophagogastric physiology. Our aim was to evaluate the impact of SG on esophagogastric motility with high-resolution impedance manometry (HRIM) and to assess the usefulness of HRIM in patients with upper gastrointestinal (GI) symptoms after SG. METHODS: A retrospective analysis of 53 cases of HRIM performed after SG was conducted. Upper GI symptoms at the time of HRIM were scored. HRIM was analyzed according to the Chicago classification v3.0. A special attention was devoted to the occurrence of increased intragastric pressure (IIGP) after water swallows and reflux episodes as detected with impedance. A measurement of sleeve volume and diameter was performed with CT scan in a subgroup of patients. RESULTS: IIGP occurred very frequently in patients after SG (77 %) and was not associated with any upper GI symptoms, specific esophageal manometric profile, or impedance reflux. Impedance reflux episodes were also frequently observed after SG (52 %): they were significantly associated with gastroesophageal reflux (GER) symptoms and ineffective esophageal motility. The sleeve volume and diameters were also significantly smaller in patients with impedance reflux episodes (p < 0.01). CONCLUSION: SG significantly modified esophagogastric motility. IIGP is frequent, not correlated to symptoms, and should be regarded as a HRIM marker of SG. Impedance reflux episodes were also frequent, associated with GER symptoms and esophageal dysmotility. HRIM may thus have a clinical impact on the management of patients with upper GI symptoms after SG. PMID- 26956882 TI - MiR-106b exhibits an anti-angiogenic function by inhibiting STAT3 expression in endothelial cells. AB - BACKGROUND: Recent discoveries of the atherosclerosis-related miRNAs shed new light on the treatment of cardiovascular diseases. Of note, miR-106b ~ 25 cluster and miR-17 ~ 92 cluster are paralogs. Up till now, plenty of researches have shown the role of miR-17 ~ 92 cluster in tumor and atherosclerosis, but miR-106b ~ 25 cluster has stayed mysterious in atherosclerosis field. This study was designed to investigate how miR-106b functions in the atherosclerosis-related angiogenesis and to explore the functioning processes of miR-106b, so as to seek out a new target for the treatment of atherosclerosis. METHODS: Up and down regulation of miR-106b expression was achieved through transfection in HUVECs so as to investigate the function of miR-106b. Next we predicted the target genes of miR-106b and detected them using qRT-PCR and Western blot technique. At last, luciferase assay was conducted to verify the direct target gene of miR-106b. Data are expressed as mean +/- SEM. Two treatment groups were compared by Mann-Whitney U test or student's t-test. Results were considered statistically significant when P < 0.05. RESULTS: The results showed miR-106b up-regulation groups formed less tubes than control groups while the down-regulation groups showed the opposite. Meanwhile, no obvious effect on apoptosis was observed in endothelial cells. Next we predicted the target genes of miR-106b and finally settled down to MAPK14 (Mitogen-Activated Protein Kinase), STAT3 (Signal Transducers and Activators of Transcription 3), JAK1(Janus Kinase 1) and VEGFA(Vascular Endothelial Growth Factor A) as candidate target genes. Our results revealed over expressed miR-106b represses STAT3 expression, while miR-106b inhibition resulted in STAT3 up-regulation. Ultimately, luciferase assay confirmed STAT3 mRNA is the direct target of miR-106b. CONCLUSIONS: Our research demonstrated that miR-106b modulate angiogenesis in endothelial cells through affecting expression of STAT3, which occurs by direct target action. Therefore, we affirmed that miR-106b exerts an anti-angiogenic effect in endothelial cells via STAT3-involved signaling pathway, via directly targeting STAT3. PMID- 26956883 TI - Modulation of CYP3A4 activity alters the cytotoxicity of lipophilic phycotoxins in human hepatic HepaRG cells. AB - The aim of this study was to investigate (i) the cytotoxic effects of lipophilic phycotoxins, including okadaic acid (OA) and dinophysistoxin-1 and -2 (DTX-1 and DTX-2), pectenotoxin-2 (PTX-2), yessotoxin (YTX), spirolide (SPX), and azaspiracids-1, -2 and -3 (AZA-1, AZA-2 and AZA-3), in human HepaRG cells using a multiparametric high content analysis approach, (ii) the ability of nine lipophilic phycotoxins to act as PXR agonists in a HepG2-PXR cell line, (iii) their potential to induce CYP450 activity, and (iv) the role of CYP3A4 in cytotoxicity induced by lipophilic phycotoxins. Our results indicate that while OA, DTX-1 and DTX-2 activated PXR-dependent transcriptional activity in HepG2 cells, no increase of CYP450 (1A2, 3A4, 2C9, 2C19) activities were observed in HepaRG cell following a 72h treatment with these toxins. Multiparametric analysis showed that OA, DTX-1, DTX-2, and PTX-2 were highly cytotoxic in HepaRG cells; inducing cell loss, activation of caspase-3 and gamma-H2AX formation. However, no toxicity was observed for YTX, SPX, and AZAs. Moreover, we found that inhibition of CYP3A4 activity by ketoconazole enhances the toxic effects of OA, DTX-1, DTX 2, and PTX-2 in HepaRG cells. Taken together, these results suggest that CYP3A4 mediated metabolism of some lipophilic phycotoxins decreases their in vitro toxicity. PMID- 26956880 TI - Reproductive and genital health and risk of cervical human papillomavirus infection: results from the Ludwig-McGill cohort study. AB - BACKGROUND: There are inconsistencies in the literature on reproductive and genital health determinants of human papillomavirus (HPV) infection, the primary cause of cervical cancer. We examined these factors in the Ludwig-McGill Cohort Study, a longitudinal, repeated-measurements investigation on the natural history of HPV infection. METHODS: We analyzed a cohort subset of 1867 women with one complete year of follow-up. We calculated odds ratios (OR) and 95% confidence intervals (CI) for reproductive and genital health characteristics from questionnaire and laboratory data in relation to 1-year period prevalence of HPV infection. Two outcomes were measured; the first based on phylogenetic grouping of HPV types based on tissue tropism and oncogenicity (Alphapapillomavirus Subgenus 1: species 1, 8, 10 and 13; Subgenus 2: species 5, 6, 7, 9, 11; Subgenus 3: species 3, 4 and 14) and the second based on transient or persistent HPV infections. RESULTS: Lifetime (Subgenus 3 OR = 2.00, CI: 1.23-3.24) and current (Subgenus 3 OR =2.00, CI: 1.15-3.47) condom use and use of contraceptive injections (Subgenus 1 OR = 1.96, CI: 1.22-3.16, Subgenus 2 OR = 1.34, CI: 1.00 1.79) were associated with increased risk of HPV infection. Intrauterine device use was protective (Subgenus 1 OR = 0.48, CI: 0.30-0.75, Subgenus 2 OR = 0.78, CI: 0.62-0.98). These factors were not associated with persistence of HPV infection. Tampon use, previous gynecologic infections and cervical inflammation were associated with an overall increased risk of HPV infection. CONCLUSIONS: Cervical HPV infection was associated with reproductive and genital health factors. Further studies are necessary to confirm the low to moderate associations observed. PMID- 26956884 TI - Magnitude of dental caries, missing and filled teeth in Malawi: National Oral Health Survey. AB - BACKGROUND: Oral health problems are significant cause of morbidity particularly in sub-Saharan Africa. In Malawi, routine health management information system data over the years showed that oral health problems were one of the top ten reasons for outpatient attendance. However, to date, no national oral survey has been carried out to determine the prevalence of oral health problems. METHODS: A national population-based cross-sectional survey was conducted in 2013. A total of 130 enumeration areas (EAs) were randomly selected and from each EA, 40 participants were randomly selected as per WHO STEPS survey protocol. Eligible participants were 12, 15, 35-44 and 65-74 year old. A multi-stage sampling design was used to obtain a national representative sample of these age groups. Oral examination was based on WHO diagnostic criteria (2010). RESULTS: A total of 5400 participants were enrolled in the survey. Of these: 3304 (61.3 %) were females, 2090 (38.7 %) were males; 327 (6.9 %) were from urban and 4386 (93.1 %) from rural areas; 1115 (20.6 %), 993 (17.3 %), 2306 (42.7 %) and 683 (12.6 %) were aged 12, 15, 35-44, 65-74 years respectively. Among 12 year-old, 15 year-old, 35 44 and 65-74 year age groups, prevalence of dental caries was 19.1, 21.9, 49.0 and 49.2 % respectively, overall 37.4 %. Prevalence of missing teeth was 2.7, 5.2, 47.7 and 79.9 %, overall 35.2 %. Prevalence of filled teeth was 0.2 %, 1.3 %, 8.7 %, 12.7 %, overall 6.5 %. Prevalence of bleeding gums was 13.0, 11.8, 30.8 and 36.1 %, overall 23.5 %. Toothache, dental caries and missing teeth were more common in females than males; 46.5 % vs 37.9 %, 40.5 % vs 32.4 %, 37.7 % vs 30.1 % respectively, all p < 0.05. Prevalence of dental caries and missing teeth in urban areas were as high as in the rural areas; 33.3 % vs 37.4 % and 30.9 % vs 33.7 % respectively, all p > 0.05. The mean number of decayed, missing and filled teeth (DMFT) in 12, 15, 35-44, 65-74 year old was 0.67, 0.71, 3.11 and 6.87 respectively. Self- reported brushing of teeth was poor with only 35.2 % of people brushed their teeth twice a day and tobacco smoking was high, particularly among adult males where one in five (22.9 %) was a smoker. CONCLUSION: This study demonstrated that oral health problems are major public health problems in Malawi. One in five (21 %) adolescents aged 12-15 years and half (49 %) of adults aged 35 years or more had dental caries, half (48 %) and 80 % of the population aged 35-44, 65-74 years had missing teeth respectively. Toothache, dental caries and missing teeth were more prevalent in females than males and prevalence in urban was as high as in rural areas. Oral hygiene was poor with less than 40 % of the population brush their teeth twice a day and tobacco smoking was high, particularly in men where prevalence was 23 %. These findings could be used to develop evidence-informed national policy, action and resource mobilization plan and community based interventions to reduce the prevalence of oral health problems in Malawi. PMID- 26956881 TI - Wnt3a upregulates brain-derived insulin by increasing NeuroD1 via Wnt/beta catenin signaling in the hypothalamus. AB - BACKGROUND: Insulin plays diverse roles in the brain. Although insulin produced by pancreatic beta-cells that crosses the blood-brain barrier is a major source of brain insulin, recent studies suggest that insulin is also produced locally within the brain. However, the mechanisms underlying the production of brain derived insulin (BDI) are not yet known. RESULTS: Here, we examined the effect of Wnt3a on BDI production in a hypothalamic cell line and hypothalamic tissue. In N39 hypothalamic cells, Wnt3a treatment significantly increased the expression of the Ins2 gene, which encodes the insulin isoform predominant in the mouse brain, by activating Wnt/beta-catenin signaling. The concentration of insulin was higher in culture medium of Wnt3a-treated cells than in that of untreated cells. Interestingly, neurogenic differentiation 1 (NeuroD1), a target of Wnt/beta catenin signaling and one of transcription factors for insulin, was also induced by Wnt3a treatment in a time- and dose-dependent manner. In addition, the treatment of BIO, a GSK3 inhibitor, also increased the expression of Ins2 and NeuroD1. Knockdown of NeuroD1 by lentiviral shRNAs reduced the basal expression of Ins2 and suppressed Wnt3a-induced Ins2 expression. To confirm the Wnt3a induced increase in Ins2 expression in vivo, Wnt3a was injected into the hypothalamus of mice. Wnt3a increased the expression of NeuroD1 and Ins2 in the hypothalamus in a manner similar to that observed in vitro. CONCLUSION: Taken together, these results suggest that BDI production is regulated by the Wnt/beta catenin/NeuroD1 pathway in the hypothalamus. Our findings will help to unravel the regulation of BDI production in the hypothalamus. PMID- 26956885 TI - Genome-enabled prediction using probabilistic neural network classifiers. AB - BACKGROUND: Multi-layer perceptron (MLP) and radial basis function neural networks (RBFNN) have been shown to be effective in genome-enabled prediction. Here, we evaluated and compared the classification performance of an MLP classifier versus that of a probabilistic neural network (PNN), to predict the probability of membership of one individual in a phenotypic class of interest, using genomic and phenotypic data as input variables. We used 16 maize and 17 wheat genomic and phenotypic datasets with different trait-environment combinations (sample sizes ranged from 290 to 300 individuals) with 1.4 k and 55 k SNP chips. Classifiers were tested using continuous traits that were categorized into three classes (upper, middle and lower) based on the empirical distribution of each trait, constructed on the basis of two percentiles (15-85 % and 30-70 %). We focused on the 15 and 30 % percentiles for the upper and lower classes for selecting the best individuals, as commonly done in genomic selection. Wheat datasets were also used with two classes. The criteria for assessing the predictive accuracy of the two classifiers were the area under the receiver operating characteristic curve (AUC) and the area under the precision recall curve (AUCpr). Parameters of both classifiers were estimated by optimizing the AUC for a specific class of interest. RESULTS: The AUC and AUCpr criteria provided enough evidence to conclude that PNN was more accurate than MLP for assigning maize and wheat lines to the correct upper, middle or lower class for the complex traits analyzed. Results for the wheat datasets with continuous traits split into two and three classes showed that the performance of PNN with three classes was higher than with two classes when classifying individuals into the upper and lower (15 or 30 %) categories. CONCLUSIONS: The PNN classifier outperformed the MLP classifier in all 33 (maize and wheat) datasets when using AUC and AUCpr for selecting individuals of a specific class. Use of PNN with Gaussian radial basis functions seems promising in genomic selection for identifying the best individuals. Categorizing continuous traits into three classes generally provided better classification than when using two classes, because classification accuracy improved when classes were balanced. PMID- 26956886 TI - Dementia plan for England is unveiled. PMID- 26956887 TI - Two successive pregnancies in a patient during 14 years of hemodialysis: a case report. AB - BACKGROUND: The incidence of pregnancy in women with end-stage renal disease seems to be increasing. Improvements in dialysis, obstetrical care, and antenatal fetal monitoring over the past two decades appear to have increased fertility rates and successful pregnancies in dialysis-dependent women. A pregnancy with a successful outcome despite the long dialysis period, as in the patient described here, is very rarely reported in the literature. CASE PRESENTATION: I report a case of a 34-year-old white Kurdish woman who had had two uncomplicated pregnancies while on hemodialysis, with delivery of healthy babies. The first pregnancy occurred in the eighth year of her hemodialysis and ended in the 32nd week of gestation with healthy vaginal delivery of a 1900-g baby. The second pregnancy occurred in the 14th year of her hemodialysis and ended in the 30th week of gestation, with vaginal delivery of a 1400-g baby. The second baby, who had respiratory problems, was discharged after 45 days of intensive care. CONCLUSIONS: Although pregnancy during the hemodialysis is risky, the outcomes of the pregnancies could be improved by an intensive hemodialysis regimen, appropriate anemia management, strict blood pressure follow-up, and correct evaluation of the dry weight. PMID- 26956889 TI - Bending the rules: a novel approach to placement and retrospective experience with the 5 French Arndt endobronchial blocker in children <2 years. AB - BACKGROUND: One-lung ventilation (OLV) is frequently employed to improve surgical exposure during video-assisted thoracoscopic surgery (VATS) and thoracotomy in adults and children. Because of their small size, children under the age of 2 years are not candidates for some of the methods typically used for OLV in adults and older children, such as a double-lumen endotracheal (DLT) tube or intraluminal use of a bronchial blocker. Due to this, the clinician is left with few options. One of the most robust approaches to OLV in infants and small children has been the extraluminal placement of a 5 French (5F) Arndt endobronchial blocker (AEB). AIM: The aim of this retrospective study was to examine and describe our experience with placement and management of an extraluminal 5F AEB for thoracic surgery in children <2 years of age. METHODS: We retrospectively examined the anesthetic records for details of AEB placement, arterial blood gas (ABG) data, and intraoperative analgesic prescription in 15 children under the age of 2 years undergoing OLV with a 5F AEB for thoracic surgery at our institution from January 2010 through January 2016. RESULTS: We were able to successfully achieve lung isolation in 14 of 15 patients using a 5F AEB that was bent 35-45 degrees 1.5 cm proximal to the inflatable cuff. In 13 of 15 patients, we were able to place the AEB into final position with the aid of video-assisted fiberoptic bronchoscopy. In two patients, fluoroscopy was required to place the 5F AEB into the left mainstem due to poor visualization of the carina and rapid desaturation during bronchoscopy. In one of these patients, even though the blocker appeared to be correctly placed by fluoroscopy, adequate lung isolation was not observed. Intraoperatively, we observed significant degrees of hypercarbia in most patients without oxygen desaturation. Analgesic regimens lacked consistency and varied among patients. Open thoracotomy procedures tended to receive more aggressive narcotic regimens than video-assisted thoracoscopic surgery (VATS) procedures. Fourteen of 15 patients were extubated in the immediate postoperative period. CONCLUSIONS: Our technique of placing a 35-45 degrees bend in the AEB, extraluminal placement, and observed manipulation with a video-assisted flexible fiberoptic bronchoscope (FFB) within the trachea can be used to achieve consistent lung isolation in patients <2 undergoing thoracic surgery. When the use of a FFB proves unsuccessful, fluoroscopy can provide an alternative solution to successful placement. Significant respiratory derangements without long-term sequelae will occur in a majority of these patients during OLV. Several different approaches to intraoperative analgesia did not impede extubation in the early postoperative period. PMID- 26956888 TI - Transcriptomes of Plant Gametophytes Have a Higher Proportion of Rapidly Evolving and Young Genes than Sporophytes. AB - Reproductive traits in plants tend to evolve rapidly due to various causes that include plant-pollinator coevolution and pollen competition, but the genomic basis of reproductive trait evolution is still largely unknown. To characterize evolutionary patterns of genome wide gene expression in reproductive tissues in the gametophyte and to compare them to developmental stages of the sporophyte, we analyzed evolutionary conservation and genetic diversity of protein-coding genes using microarray-based transcriptome data from three plant species, Arabidopsis thaliana, rice (Oryza sativa), and soybean (Glycine max). In all three species a significant shift in gene expression occurs during gametogenesis in which genes of younger evolutionary age and higher genetic diversity contribute significantly more to the transcriptome than in other stages. We refer to this phenomenon as "evolutionary bulge" during plant reproductive development because it differentiates the gametophyte from the sporophyte. We show that multiple, not mutually exclusive, causes may explain the bulge pattern, most prominently reduced tissue complexity of the gametophyte, a varying extent of selection on reproductive traits during gametogenesis as well as differences between male and female tissues. This highlights the importance of plant reproduction for understanding evolutionary forces determining the relationship of genomic and phenotypic variation in plants. PMID- 26956890 TI - The design, fate and impact of a hospital-wide training program in evidence-based medicine for physicians - an observational study. AB - BACKGROUND: Many doctors fail to practice Evidence-Based Medicine (EBM) effectively, in part due to insufficient training. We report on the design, fate and impact of a short learner-centered EBM train-the-trainer program aimed at all 2400 doctors at the Karolinska University Hospital in Sweden on the heels of a tumultuous merger, focusing particularly on whether it affected the doctors' knowledge, attitudes and skills regarding EBM. METHODS: We used a validated EBM instrument in a before-and-after design to assess the impact of the training. Changes in responses were analyzed at the individual level using the Wilcoxon matched pairs test. We also reviewed documentation from the program - including the modular EBM training schedule and the template for participants' Critically Appraised Topic reports - to describe the training's content, design, conduct, and fate. RESULTS: The training, designed to be delivered in modules of 45 min totaling 1.5 days, failed to reach most doctors at the hospital, due to cost cutting pressures and competing demands. Among study participants (n = 174), many reported suboptimal EBM knowledge and skills before the training. Respondents' strategies for solving clinical problems changed after the training: the proportion of respondents reporting to use (or intend to use) secondary sources "Often/very often" changed from 5 % before the training to 76 % after the training; in parallel, reliance on textbooks and on colleagues fell (48 to 23 % and 79 to 65 %, respectively). Participants' confidence in assessing scientific articles increased and their attitudes toward EBM became more positive. The proportion of correct answers in the EBM knowledge test increased from 52 to 71 %. All these changes were statistically significant at p < 0.05. CONCLUSIONS: Many study participants, despite working at a university hospital, lacked basic EBM knowledge and skills and used the scientific literature suboptimally. The kind of short learner-centered EBM training evaluated here brought significant improvements among the minority of hospital doctors who were able to participate and, if applied widely, could contribute to better, safer and more cost-effective care. PMID- 26956891 TI - Downregulation of selenium-binding protein 1 is associated with poor prognosis in lung squamous cell carcinoma. AB - BACKGROUND: We found that selenium-binding protein 1 (SBP1) was progressively decreased in the human bronchial epithelial carcinogenic processes. Knockdown of SBP1 in immortalized human bronchial epithelial cell line 16HBE cells significantly increased the efficiency of B[a]P-induced cell transformation. However, the relationship between SBP1 expression and clinicopathological factors of patients has not been defined completely. The specific role of SBP1 in prognosis of lung squamous cell carcinoma (LSCC) is still unknown. METHODS: Tissue samples from 82 patients treated by pulmonary lobectomy for LSCC were used. Immunohistochemistry and western blotting were used to detect the expressions of SBP1 protein. The relationships between the expression level of SBP1 and the clinicopathological features of patients were analyzed. Cox proportional hazard regression analysis and Kaplan-Meier method were used to perform survival analysis. RESULTS: Expressions of SBP1 proteins were significantly lower in LSCC tissues than that in the corresponding normal bronchial epithelium (NBE) tissues (P = 0.000). In LSCC, The expression levels of SBP1 had not correlated with patients' age, gender, smoking state, primary tumor stages (T), TNM clinical stages, and distant metastasis (M) (P > 0.05). However, downregulation of SBP1 was significantly associated with higher lymph node metastasis and lower overall survival rate (P < 0.05). Cox regression analysis indicated low expressions of SBP1 can be an independent prognostic factor for poor overall survival in LSCC patients (P = 0.002). CONCLUSIONS: Downregulation of SBP1 may play a key role in the tumorigenic process of LSCC. SBP1 may be a novel potential prognostic factor of LSCC. PMID- 26956895 TI - A Facile Strategy to Prepare Dendrimer-stabilized Gold Nanorods with Sub-10-nm Size for Efficient Photothermal Cancer Therapy. AB - Gold (Au) nanoparticles are promising photothermal agents with the potential of clinical translation. However, the safety concerns of Au photothermal agents including the potential toxic compositions such as silver and copper elements in their structures and the relative large size-caused retention and accumulation in the body post-treatment are still questionable. In this article, we successfully synthesized dendrimer-stabilized Au nanorods (DSAuNRs) with pure Au composition and a sub-10-nm size in length, which represented much higher photothermal effect compared with dendrimer-encapsulated Au nanoparticles due to their significantly enhanced absorption in the near-infrared region. Furthermore, glycidol-modified DSAuNRs exhibited the excellent biocompatibility and further showed the high photothermal efficiency of killing cancer cells in vitro and retarding tumor growth in vivo. The investigation depicted an optimal photothermal agent with the desirable size and safe composition. PMID- 26956896 TI - Atorvastatin attenuates atherosclerotic plaque destabilization by inhibiting endoplasmic reticulum stress in hyperhomocysteinemic mice. AB - Endoplasmic reticulum (ER) stress has been suggested to play a role in the progression of plaque vulnerability and the occurrence of acute complications of coronary atherosclerosis. Atorvastatin is known to exert pleiotropic effects on the cardiovascular system. The present study aimed to examine the stabilizing effects of atorvastatin on vulnerable plaques within hyperhomocysteinemic apolipoprotein E-deficient (ApoE-/-) mice, and to investigate the potential mechanisms underlying ER stress in ApoE-/- mice and macrophages. In the present study, ApoE-/- mice were administrated methionine or atorvastatin, and were sacrificed after 2 months. Necrotic core size, collagen content and inflammatory cytokine infiltration were subsequently measured in the aortic lesions, in order to investigate plaque stability. Treatment with atorvastatin decreased the number and size of necrotic cores, increased collagen content, and downregulated tumor necrosis factor (TNF)-alpha and matrix metalloproteinase (MMP)-9 mRNA expression, as compared with the methionine group. Immunohistochemical analysis indicated that atorvastatin administration prevented ER stress activation in aortic lesions of hyperhomocysteinemic mice. Furthermore, macrophages were challenged with homocysteine (Hcy) in the presence or absence of atorvastatin and thapsigargin (an ER stress inducer). Atorvastatin suppressed Hcy-induced ER stress, and downregulated TNF-alpha and MMP-9 mRNA expression in the macrophages. Conversely, thapsigargin attenuated the inhibitory effects of atorvastatin against Hcy induced TNF-alpha and MMP-9 expression. These results indicated that hyperhomocysteinemia may promote atherosclerotic plaque development and instability. In addition, atorvastatin was able to improve atherosclerotic plaque stability in hyperhomocysteinemic mice by inhibiting ER stress. PMID- 26956898 TI - Keratin 14 Expression in Epithelial Progenitor Cells of the Developing Human Cornea. AB - A healthy and transparent cornea is essential for exquisite vision. During adulthood, its epithelium is constantly replenished through the activity of its stem cells (SCs). Precisely when these cells develop and their distribution across the ocular surface remain incompletely characterized in man. We postulated that the human fetal cornea harbors SCs that can be identified with keratin (K) 14 and alphav-integrin, two markers we and others previously used to identify their adult counterparts. Immunofluorescence, cell culture, quantitative real time polymerase chain reaction (qRT-PCR), and colony-forming assays were performed on fetal and adult biomaterial to locate progenitors and establish their phenotypic and functional properties. K14 was used to map the spatiotemporal distribution of precursor cell activity across the developing cornea, divulging a dynamic pattern of vertical and horizontal consolidated expression with increasing gestational age. K14 was coexpressed with alphav integrin in fetal and adult corneas and cultured corneolimbal epithelium, and colony-forming efficiency (an indicator of SC activity) was similar in cells from both sources. Finally, fetal cells were adherent, grew well, and maintained a K14 phenotype on contact lenses, a substrate we previously used to deliver cells to patients with blinding corneal disease. This study provides valuable insights into the development of the cornea, including the formation of the SC repository, the distribution of these cells across the ocular surface, and a preliminary attempt at harnessing, phenotyping, and functionally characterizing these cells. Future studies will focus on isolating fetal SCs to determine their utility as an alternative cell therapy for patients suffering from corneal blindness. PMID- 26956893 TI - Tumor-associated macrophages and anti-tumor therapies: complex links. AB - Myeloid cells infiltrating the tumor microenvironment, especially tumor associated macrophages (TAMs), are essential providers of cancer-related inflammation, a condition known to accelerate tumor progression and limit the response to anti-tumor therapies. As a matter of fact, TAMs may have a dual role while interfering with cancer treatments, as they can either promote or impair their functionality. Here we review the connection between macrophages and anticancer therapies; moreover, we provide an overview of the different strategies to target or re-program TAMs for therapeutic purposes. PMID- 26956899 TI - Thumb carpometacarpal osteoarthritis: are we closer to gold standards? PMID- 26956897 TI - Estimating the severity distribution of disease in South Korea using EQ-5D-3L: a cross-sectional study. AB - BACKGROUND: There is a paucity of data on the distribution of disease severity. In this study, we estimated disease severity distributions in South Korea using two EQ-5D-3L population surveys. METHODS: A total of 110 health states for 35 diseases with 2-5 severity levels (e.g., mild, moderate, severe) were included in this study. A general population of 360 participants from the areas surrounding Seoul and Gyunggi evaluated these health states using EQ-5D-3L via face-to-face interviews and a paper questionnaire. The EQ-5D indices were used to measure the severity levels of health states and used as the cutoff points for the disease severity distributions. Finally, these cutoff points were applied to disease prevalence data with EQ-5D-3L, which were obtained from the Korean National Health and Nutrition Examination Surveys (KNHNES) and Korean Community Health Survey, in order to estimate the disease severity distributions. RESULTS: The severity distributions of 8 diseases were estimated, including asthma, angina, stroke, chronic obstructive pulmonary disease, major depressive disorder, musculoskeletal problems in the legs, anemia, and allergic rhinitis and conjunctivitis. For example, the EQ-5D indices for chronic obstructive pulmonary disease severity were 0.929, 0.742, and 0.620, and the cut-off points were 0.835 (between mild and moderate) and 0.681 (between moderate and severe). Using these cutoff points, the distributions of chronic obstructive pulmonary disease severity were 66.5 % (mild), 23.3 % (moderate), and 10.1 % (severe) according to KNHNES. CONCLUSIONS: The estimated severity distributions in this study can be used as a valid calculation of the disease burden in the general population. PMID- 26956900 TI - Evolving Management of Zenker's Diverticulum in the Endoscopic Era: A North American Experience. AB - BACKGROUND: Open surgical cricopharyngeal myotomy(CM) is considered standard of care for Zenker's diverticulum(ZD). Trans-oral CM has been described using a rigid stapling device for two decades; however, this remains problematic for severely kyphotic patients. This problem can be overcome with flexible endoscopy utilizing an electrosurgical needle knife. We sought to compare clinical outcomes between these techniques to stratify patient selection. METHODS: Patients undergoing ZD treatment from 1992 to 2015 were reviewed. Demographics, diverticulum size, post-operative complications, and length of stay (LOS) were compared between open cricopharyngeal myotomy (OpenCM), rigid trans-oral stapling myotomy (RigidCM), and flexible endoscopic myotomy (FlexCM). Dysphagia scores (DS, 0:best-4:worst) and pneumonia incidence were assessed pre-operatively and post-operatively. RESULTS: 62 patients underwent OpenCM (39/62(63 %)) or endoscopic CM (23/62(37 %) (8 RigidCM/15 FlexCM)). CM significantly reduced dysphagia for all approaches [OpenCM:2(2-3)-0(0-0); RigidCM:2(2-2)-0(0-0); FlexCM:3(3-3)-0(0-0)]. FlexCM patients had significantly worse pre-operative DS. Endoscopic CM was attempted and completed in 23/35(66 %) patients. Reasons for OpenCM conversion included inability to position the diverticular retractor due to patient body habitus (RigidCM), and the inability to position the overtube due to small ZD (FlexCM). Major post-operative complications were rare and similar in all groups. Medium-to-long-term post-myotomy pneumonia was comparable between groups. LOS (days) was reduced for FlexCM (1(1-2)) versus RigidCM (3(2-6)) and OpenCM (4(3-7)). CONCLUSIONS: CM is highly effective for treating ZD. Open and endoscopic approaches offer comparable outcomes and dysphagia resolution. FlexCM is efficacious for large ZD and can be performed in most patients irrespective of body habitus. FlexCM represents an excellent approach for large ZD, while OpenCM should be reserved for small ZD for which an overtube cannot be positioned. PMID- 26956894 TI - Sweet complementarity: the functional pairing of glycans with lectins. AB - Carbohydrates establish the third alphabet of life. As part of cellular glycoconjugates, the glycans generate a multitude of signals in a minimum of space. The presence of distinct glycotopes and the glycome diversity are mapped by sugar receptors (antibodies and lectins). Endogenous (tissue) lectins can read the sugar-encoded information and translate it into functional aspects of cell sociology. Illustrated by instructive examples, each glycan has its own ligand properties. Lectins with different folds can converge to target the same epitope, while intrafamily diversification enables functional cooperation and antagonism. The emerging evidence for the concept of a network calls for a detailed fingerprinting. Due to the high degree of plasticity and dynamics of the display of genes for lectins the validity of extrapolations between different organisms of the phylogenetic tree yet is inevitably limited. PMID- 26956901 TI - The C-reactive Protein to Albumin Ratio Predicts Long-Term Outcomes in Patients with Pancreatic Cancer After Pancreatic Resection. AB - BACKGROUND: The C-reactive protein to albumin (CRP/Alb) ratio, a novel inflammation-based prognostic score, is associated with outcomes in septic patients. The prognostic value of CRP/Alb ratio has not been established in cancer patients. The aim of this study is to evaluate the significance of CRP/Alb ratio in therapeutic outcome after pancreatic resection for pancreatic cancer. METHODS: The study comprised 113 patients who had undergone pancreatic resection for pancreatic cancer between April 2001 and December 2011. We retrospectively investigated the relation between CRP/Alb ratio and disease-free as well as overall survival. RESULTS: The optimal cut-off level of the CRP/Alb ratio was 0.03. For disease-free survival, preoperative biliary drainage (p = 0.011), advanced tumor-node-metastasis (TNM) classification (p = 0.002), and higher CRP/Alb ratio (p = 0.049) by univariate analysis, and advanced TNM classification (p = 0.003) by multivariate analysis, were independent and significant predictors of cancer recurrence. For overall survival, preoperative biliary drainage (p = 0.012), advanced TNM classification (p = 0.001), and higher CRP/Alb ratio (p = 0.023) by univariate analysis, and advanced TNM classification (p = 0.003) and higher CRP/Alb ratio (p = 0.035) by multivariate analysis, were independent and significant predictors of poor patient outcome. CONCLUSIONS: The CRP/Alb ratio may be an independent and significant indicator of poor long-term outcomes in patients with pancreatic cancer after pancreatic resection. PMID- 26956902 TI - Feasibility of Nipple-Sparing Mastectomy with Immediate Breast Reconstruction in Breast Cancer Patients with Tumor-Nipple Distance Less Than 2.0 cm. AB - BACKGROUND AND OBJECTIVE: Debate continues concerning the oncological risk of nipple-sparing mastectomy (NSM) with immediate breast reconstruction (IBR) if the tumor-nipple distance (TND) is less than 2.0 cm. In this retrospective study, we analyzed oncological outcomes after NSM with IBR for the treatment of breast cancer to determine the risk posed by NSM in cases in which magnetic resonance imaging (MRI) showed a TND <2.0 cm but intraoperative frozen biopsy results were negative for tumor cells at the nipple base. MATERIALS AND METHODS: We conducted a retrospective review of patients with breast cancer who underwent NSM with IBR at Samsung Medical Center between 2008 and 2014. Preoperative MRI was done in all cases to define the TND, and frozen biopsy specimens were obtained intraoperatively. RESULTS: Among the 266 NSMs performed, TND was <2.0 cm in 145 cases (54.5 %) and >=2.0 cm in 121 cases (45.5 %). Median follow-up was 25.6 months. There were no significant differences between the two patient groups with respect to disease-free survival or local recurrence-free survival. CONCLUSION: Our results suggest that NSM can be a feasible treatment option when the intraoperative frozen biopsy is negative for tumor cells even with a TND <2.0 cm in MRI. PMID- 26956903 TI - Minimally Invasive Versus Open Pancreatic Surgery in Patients with Multiple Endocrine Neoplasia Type 1. AB - OBJECTIVE: The role of minimally invasive pancreatic surgery for pancreatic neuroendocrine neoplasms (pNENs) in patients with multiple endocrine neoplasia type 1 (MEN1) is not well defined. The aim of this study was to compare the outcome of minimally invasive versus open pancreatic resections in patients with MEN1. MATERIALS AND METHODS: Prospectively collected data of MEN1 patients who underwent a primary distal pancreatic resection and/or enucleation for non functioning pNENs or insulinoma were retrospectively analyzed regarding the outcome of minimally invasive or open pancreatic resections. RESULTS: Thirty three patients underwent primary pancreatic resection for either organic hyperinsulinism (n = 9, 27 %) or non-functioning pNENs >1 cm in size (n = 24, 73 %) between 1987 and 2015. 21 (64 %) patients underwent an open surgical (group 1) and 12 patients (36 %) a minimally invasive approach, either laparoscopic (n = 8) or robotic assisted (n = 4) (group 2). Both groups were comparable regarding age, gender, number, and size of pancreatic tumors. In both groups, the hyperinsulinism of all patients (9/9,100 %) could be cured and all NF-pNENs >1 cm could be resected. Group 2 had a significant shorter operative time (200 vs. 260 min; p = 0.036), less intraoperative blood loss (120 vs. 280 ml; p < 0.001), and a shorter hospital stay (11 vs. 15.5 days; p = 0.034). The rate of patients with postoperative complications, especially postoperative pancreatic fistulas, was not different between groups (62 % group 1 vs. 67 % group 2, p = 0.74). CONCLUSION: Minimally invasive distal pancreatic resections and enucleations are feasible and safe in MEN1 patients with insulinoma or non-functioning pNENs. PMID- 26956904 TI - High Probability of an Underlying Colorectal Cancer Among Patients Treated for Acute Diverticulitis. A Population-Based Cohort Follow-Up Study. AB - INTRODUCTION: Patients treated conservatively for acute diverticulitis (AD) are recommended colonic assessment to rule out an underlying Colorectal cancer (CRC). This has been questioned in patients with a CT diagnosis of uncomplicated AD. We analyzed the frequency of CRC and compared the characteristics of the CRC patients with controls. METHOD: A cohort of patients treated conservatively for AD during 2005-2011 was identified through an administrative database. Patients diagnosed with CRC within 1 year after the index admission and four randomly selected controls were identified. The patients' files were reviewed to verify the diagnosis and obtain information about the clinical characteristics and the management. A blinded review was performed of CT examinations. The expected number of CRC was calculated from age, sex, and period-specific incidence data. The characteristics of the CRC patients were compared with the controls in a nested case-control study. RESULTS: 890 patients (298 men and 592 women) were treated conservatively for AD. 12 patients were diagnosed with CRC within 1 year, and ten of them in the sigmoid, giving a Standardized Incidence Ratio of 20.0 (95 % CI 10.2-35.7, p<0.001) for sigmoidal cancer. All CRC patients were aged over 70 years. The cancer was missed in six CT scans at the primary reading and in five at the blinded review. CONCLUSION: Patients conservatively treated for AD are at high risk for an underlying CRC, especially if older than 70 years, which motivates routine follow-up. A CT diagnosis of uncomplicated AD does not rule out CRC. PMID- 26956905 TI - Propensity Score Analysis of an Enhanced Recovery Programme in Upper Gastrointestinal Cancer Surgery. AB - INTRODUCTION: The aim of this study was to examine the influence of an enhanced recovery programme (ERP) on outcomes of upper gastrointestinal (UGI) cancer surgery by means of propensity score-matched analysis. METHODS: Three hundred consecutive patients diagnosed with UGI cancer were studied prospectively before and after the introduction of an ERP. Multiple regression models, including propensity scores, were developed to assess confounding variables associated with undergoing surgery, and the risk adjusted association between treatment and length of hospital stay (LOHS). RESULTS: After regression for confounding factors, a cohort of 252 patients was available of whom 160 received ERP [median age 66 years (IQR 58-73), 119 male, 81 oesophageal, 79 gastric cancer] and 92 control [66 years (IQR 58-74), 74 male, 58 oesophageal, 34 gastric cancer]. ERP operative morbidity (Clavien-Dindo >=3) and mortality were 13.8 and 3.1 % compared with 17.4 (p = 0.449) and 2.2 % (p = 0.658) in controls. Median ERP critical care and total LOS were 1 (IQR 0-1) and 13 (IQR 10-17) days, compared with 1 (IQR 1-2, p = 0.009) and 16 (IQR 13-26, p < 0.001) days. Multivariable analysis revealed ERP (HR 1.477, 95 % CI 1.084-2.013, p = 0.013), tumour location (HR 2.420, 95 % CI 1.624-3.606, p < 0.001), operative procedure (HR 1.143, 95 % CI 1.032-1.265, p = 0.010), and operative morbidity (HR 0.277, 95 % CI 0.179 0.429, p < 0.001) to be associated with LOHS. CONCLUSION: An ERP in UGI cancer surgery was feasible, safe, and effective. PMID- 26956906 TI - Effects of inhibiting PI3K-Akt-mTOR pathway on lipid metabolism homeostasis in goose primary hepatocytes. AB - Phosphatidylinositol-3 kinases (PI3K)-Protein kinase B (Akt)-mammalian target of rapamycin (mTOR) pathway plays an important role in the synthesis and secretion of triacylglycerol. However, the mechanism of PI3K-Akt-mTOR pathway in regulating lipid metabolism of goose liver was poorly understood. The purpose of this study was to determine how PI3K-Akt-mTOR pathway regulating lipid metabolic homeostasis in goose hepatocytes. Goose primary hepatocytes were treated with different PI3K Akt-mTOR signal inhibitors (LY294002, rapamycin and NVP-BEZ235) for 24 h. The results showed that these inhibitors evidently inhibited PI3K-Akt-mTOR downstream signaling. Meanwhile, these PI3K-Akt-mTOR inhibitors reduced intracellular lipid accumulation, decreased the mRNA expression and protein content of genes involved in the de novo fatty acid synthesis, while increased the transcriptional and protein level of key factors involved in fatty acid oxidation and very low density lipoprotein (VLDL) assembly and secretion. CONCLUSION: These findings suggested that the reduction of lipids accumulation induced-by inhibiting PI3K Akt-mTOR pathway was closely linked to the decrease of lipogenesis, the increase of fatty acids oxidation, and the increase of VLDL assembly and secretion in goose hepatocytes. PMID- 26956907 TI - The neural correlates of processing scale-invariant environmental sounds at birth. AB - Sensory systems are thought to have evolved to efficiently represent the full range of sensory stimuli encountered in the natural world. The statistics of natural environmental sounds are characterized by scale-invariance: the property of exhibiting similar patterns at different levels of observation. The statistical structure of scale-invariant sounds remains constant at different spectro-temporal scales. Scale-invariance plays a fundamental role in how efficiently animals and human adults perceive acoustic signals. However, the developmental origins and brain correlates of the neural encoding of scale invariant environmental sounds remain unexplored. Here, we investigate whether the human brain extracts the statistical property of scale-invariance. Synthetic sounds generated by a mathematical model to respect scale-invariance or violate it were presented to newborns. In alternating blocks, the two sound types were presented together in an alternating fashion, whereas in non-alternating blocks, only one type of sound was presented. Newborns' brain responses were measured using near-infrared spectroscopy. We found that scale-invariant and variable scale sounds were discriminated by the newborn brain, as suggested by differential activation in the left frontal and temporal areas to alternating vs. non-alternating blocks. These results indicate that newborns already detect and encode scale-invariance as a characteristic feature of acoustic stimuli. This suggests that the mathematical principle of efficient coding of information guides the auditory neural code from the beginning of human development, a finding that may help explain how evolution has prepared the brain for perceiving the natural world. PMID- 26956909 TI - Global signal modulation of single-trial fMRI response variability: Effect on positive vs negative BOLD response relationship. AB - In functional magnetic resonance imaging (fMRI), the relationship between positive BOLD responses (PBRs) and negative BOLD responses (NBRs) to stimulation is potentially informative about the balance of excitatory and inhibitory brain responses in sensory cortex. In this study, we performed three separate experiments delivering visual, motor or somatosensory stimulation unilaterally, to one side of the sensory field, to induce PBR and NBR in opposite brain hemispheres. We then assessed the relationship between the evoked amplitudes of contralateral PBR and ipsilateral NBR at the level of both single-trial and average responses. We measure single-trial PBR and NBR peak amplitudes from individual time-courses, and show that they were positively correlated in all experiments. In contrast, in the average response across trials the absolute magnitudes of both PBR and NBR increased with increasing stimulus intensity, resulting in a negative correlation between mean response amplitudes. Subsequent analysis showed that the amplitude of single-trial PBR was positively correlated with the BOLD response across all grey-matter voxels and was not specifically related to the ipsilateral sensory cortical response. We demonstrate that the global component of this single-trial response modulation could be fully explained by voxel-wise vascular reactivity, the BOLD signal standard deviation measured in a separate resting-state scan (resting state fluctuation amplitude, RSFA). However, bilateral positive correlation between PBR and NBR regions remained. We further report that modulations in the global brain fMRI signal cannot fully account for this positive PBR-NBR coupling and conclude that the local sensory network response reflects a combination of superimposed vascular and neuronal signals. More detailed quantification of physiological and noise contributions to the BOLD signal is required to fully understand the trial-by trial PBR and NBR relationship compared with that of average responses. PMID- 26956908 TI - Subject-level measurement of local cortical coupling. AB - The human cortex is highly folded to allow for a massive expansion of surface area. Notably, the thickness of the cortex strongly depends on cortical topology, with gyral cortex sometimes twice as thick as sulcal cortex. We recently demonstrated that global differences in thickness between gyral and sulcal cortex continue to evolve throughout adolescence. However, human cortical development is spatially heterogeneous, and global comparisons lack power to detect localized differences in development or psychopathology. Here we extend previous work by proposing a new measure - local cortical coupling - that is sensitive to differences in the localized topological relationship between cortical thickness and sulcal depth. After estimation, subject-level coupling maps can be analyzed using standard neuroimaging analysis tools. Capitalizing on a large cross sectional sample (n=932) of youth imaged as part of the Philadelphia Neurodevelopmental Cohort, we demonstrate that local coupling is spatially heterogeneous and exhibits nonlinear development-related trajectories. Moreover, we uncover sex differences in coupling that indicate divergent patterns of cortical topology. Developmental changes and sex differences in coupling support its potential as a neuroimaging phenotype for investigating neuropsychiatric disorders that are increasingly conceptualized as disorders of brain development. R code to estimate subject-level coupling maps from any two cortical surfaces generated by FreeSurfer is made publicly available along with this manuscript. PMID- 26956911 TI - Innovative Design of Ca-Sensitive Paramagnetic Liposomes Results in an Unprecedented Increase in Longitudinal Relaxivity. AB - Bioresponsive MRI contrast agents sensitive to Ca(II) fluctuations may play a critical role in the development of functional molecular imaging methods to study brain physiology or abnormalities in muscle contraction. A great challenge in their chemistry is the preparation of probes capable of inducing a strong signal variation that could be detected in a robust way. To this end, the incorporation of small molecular weight bioresponsive agents into nanocarriers can improve the overall properties in a few ways: (i) the agent can be delivered into the tissue of interest, increasing the local concentration; (ii) its biokinetic properties and retention time will improve; (iii) the high molecular weight and size of the nanocarrier may cause additional changes in the MRI signal and raise the chances for their detection in functional experiments. In this work, we report the preparation of the new class of liposome-based, Ca-sensitive MRI agents. We synthesized a novel amphiphilic ligand which was incorporated into the liposome bilayer. A remarkable increase of ~420% in longitudinal relaxivity r1, from 7.3 mM(-1) s(-1) to 38.1 mM(-1) s(-1) at 25 degrees C and 21.5 MHz in the absence and presence of Ca(II), respectively, was achieved by the most active liposomal formulation. To the best of our knowledge, this is the highest change in r1 observed for Ca-sensitive agents at physiological pH and can be explained by simultaneous Ca-triggered increase in hydration and reduction of local motion of Gd(III) complex, which can be followed at low magnetic fields. PMID- 26956910 TI - Computational modelling of movement-related beta-oscillatory dynamics in human motor cortex. AB - Oscillatory activity in the beta range, in human primary motor cortex (M1), shows interesting dynamics that are tied to behaviour and change systematically in disease. To investigate the pathophysiology underlying these changes, we must first understand how changes in beta activity are caused in healthy subjects. We therefore adapted a canonical (repeatable) microcircuit model used in dynamic causal modelling (DCM) previously used to model induced responses in visual cortex. We adapted this model to accommodate cytoarchitectural differences between visual and motor cortex. Using biologically plausible connections, we used Bayesian model selection to identify the best model of measured MEG data from 11 young healthy participants, performing a simple handgrip task. We found that the canonical M1 model had substantially more model evidence than the generic canonical microcircuit model when explaining measured MEG data. The canonical M1 model reproduced measured dynamics in humans at rest, in a manner consistent with equivalent studies performed in mice. Furthermore, the changes in excitability (self-inhibition) necessary to explain beta suppression during handgrip were consistent with the attenuation of sensory precision implied by predictive coding. These results establish the face validity of a model that can be used to explore the laminar interactions that underlie beta-oscillatory dynamics in humans in vivo. Our canonical M1 model may be useful for characterising the synaptic mechanisms that mediate pathophysiological beta dynamics associated with movement disorders, such as stroke or Parkinson's disease. PMID- 26956912 TI - Cellular uptake and intracellular fate of protein releasing bacterial amyloids in mammalian cells. AB - Bacterial Inclusion Bodies (IBs) are amyloidal protein deposits that functionally mimic secretory granules from the endocrine system. When formed by therapeutically relevant proteins, they complement missing intracellular activities in jeopardized cell cultures, offering an intriguing platform for protein drug delivery in substitutive therapies. Despite the therapeutic potential of IBs, their capability to interact with eukaryotic cells, cross the cell membrane and release their functional building blocks into the cytosolic space remains essentially unexplored. We have systematically dissected the process by which bacterial amyloids interact with mammalian cells. An early and tight cell membrane anchorage of IBs is followed by cellular uptake of single or grouped IBs of variable sizes by macropinocytosis. Although an important fraction of the penetrating particles is led to lysosomal degradation, biologically significant amounts of protein are released into the cytosol. In addition, our data suggest the involvement of the bacterial cell folding modulator DnaK in the release of functional proteins from these amyloidal reservoirs. The mechanisms supporting the internalization of disintegrable protein nanoparticles revealed here offer clues to implement novel approaches for protein drug delivery based on controlled protein packaging as bacterial IBs. PMID- 26956913 TI - Characterising the material properties at the interface between skin and a skin vaccination microprojection device. AB - The rapid emergence of micro-devices for biomedical applications over the past two decades has introduced new challenges for the materials used in the devices. Devices like microneedles and the Nanopatch, require sufficient strength to puncture skin often with sharp-slender micro-scale profiles, while maintaining mechanical integrity. For these technologies we sought to address two important questions: 1) On the scale at which the device operates, what forces are required to puncture the skin? And 2) What loads can the projections/microneedles withstand prior to failure. First, we used custom fabricated nanoindentation micro-probes to puncture skin at the micrometre scale, and show that puncture forces are ~0.25-1.75mN for fresh mouse skin, in agreement with finite element simulations for our device. Then, we used two methods to perform strength tests of Nanopatch projections with varied aspect ratios. The first method used a nanoindenter to apply a force directly on the top or on the side of individual silicon projections (110MUm in length, 10MUm base radius), to measure the force of fracture. Our second method used an Instron to fracture full rows of projections and characterise a range of projection designs (with the method verified against previous nanoindentation experiments). Finally, we used Cryo Scanning Electron Microscopy to visualise projections in situ in the skin to confirm the behaviour we quantified, qualitatively. STATEMENT OF SIGNIFICANCE: Micro-device development has proliferated in the past decade, including devices that interact with tissues for biomedical outcomes. The field of microneedles for vaccine delivery to skin has opened new material challenges both in understanding tissue material properties and device material. In this work we characterise both the biomaterial properties of skin and the material properties of our microprojection vaccine delivery device. This study directly measures the micro scale puncture properties of skin, whilst demonstrating clearly how these relate to device design. This will be of strong interest to those in the field of biomedical microdevices. This includes work in the field of wearable and semi implantable devices, which will require clear understanding of tissue behaviour and material characterisation. PMID- 26956914 TI - Second harmonic generation from gold meta-molecules with three-fold symmetry. AB - The unique optical properties of arrays of metallic nanoparticles are of great interest for many applications such as in optical data storage, sensing applications, optoelectronic devices or as platforms to increase the detection limit in spectroscopic measurements. Nonlinear optical phenomena can also be altered by metallic nanostructures opening new possible applications. In this work, arrays composed of non-centrosymmetric individual structures with three fold axial symmetry made of gold are designed and fabricated using electron beam lithography. The nonlinear optical properties of these structures are investigated using second-harmonic generation microscopy (SHGM) with a femtosecond excitation source set near the plasmon resonance frequency. Modeling of the electromagnetic field distribution around the metallic structures is performed using the Finite Difference Time Domain (FDTD) method, highlighting the confinement of the SHG signal and its polarization dependence. Polarization resolved measurements are conducted to correlate the SHG signal with the structure and symmetry of the individual nanostructures. Since both two-photon induced photoluminescence (TPPL) and SHG signals are produced upon excitation of these structures, lifetime measurements are performed to further evaluate the magnitude of these two effects. PMID- 26956915 TI - Paracetamol-induced nephrotoxicity and oxidative stress in rats: the protective role of Nigella sativa. AB - Context Nigella sativa L. (Ranunculaceae) (NS) is traditionally used to treat many conditions such as inflammation. Objective This study evaluates the effects of NS seeds ethanol extract in paracetamol-induced acute nephrotoxicity in rats. Materials and methods Forty-eight female Wistar Albino rats were divided into eight groups: I = sham; II = sham + 1000 mg/kg NS; III = sham + 140 mg/kg (N acetyl cysteine) NAC; IV = 2 g/kg paracetamol; V = 2 g/kg paracetamol + 140 mg/kg NAC; VI, VII and VIII = 2 g/kg paracetamol + 250, 500 and 1000 mg/kg NS, respectively. Paracetamol administration (oral) was carried out 1 h after NS and NAC administrations (oral), and all animals were sacrificed 24 h later. Results Paracetamol administration significantly increased serum urea (88.05 U/L) and creatinine (0.80 U/L) when compared with the sham group (49.80 and 0.31 U/L, respectively). However, serum urea level was reduced to 65.60, 56.00 and 54.18 U/L, with 250, 500 and 1000 mg/kg doses of the extract, respectively. Also, serum creatinine level was reduced to 0.64, 0.57 and 0.52 U/L with 250, 500 and 1000 mg/kg doses of the extract, respectively. NS administration increased superoxide dismutase and glutathione, and decreased malondialdehyde levels in the kidneys. Kidney histopathological examinations showed that NS administration antagonized paracetamol-induced kidney pathological damage. Discussion and conclusions The results suggest NS has a significant nephroprotective activity on paracetamol induced nephrotoxicity. It may be suggested that the antiinflammatory and antioxidant effects of NS ethanolic extract originated from different compounds of its black seeds. PMID- 26956916 TI - Novel EGFR-targeted strategy with hybrid peptide against oesophageal squamous cell carcinoma. AB - Epidermal growth factor receptor (EGFR) is a key molecule in the pathophysiology of oesophageal squamous cell carcinoma (OSCC). However, EGFR-targeted agents such as anti-EGFR antibody or tyrosine kinase inhibitors for OSCC have not demonstrated any clinical benefits. Recently, a novel chemotherapeutic agent, EGFR(2R)-lytic hybrid peptide, a composite of EGFR-binding peptide and lytic peptide fragments, has been shown to exhibit a potent anti-tumour effect against cancers that express high EGFR levels. In this study, we investigated the validity of employing EGFR(2R)-lytic hybrid peptide against OSCC cells both in vitro and in vivo. Additionally, the toxicity of this peptide was assessed in mice. We found high EGFR expression levels on the cell surface of OSCC cells, and the EGFR-binding peptide fragment showed high affinity for OSCC cells. A potent cytotoxic effect was induced within 30 minutes by the exposure of OSCC cells to EGFR(2R)-lytic hybrid peptide. Furthermore, EGFR(2R)-lytic hybrid peptide markedly suppressed the tumour growth of OSCC cells in a xenograft model. Moreover, it did not cause any identifiable adverse effects in mice. Taken together, EGFR(2R)-lytic hybrid peptide was shown to be a valid therapeutic agent against OSCC, providing a crucial rationale regarding novel EGFR-targeted therapies against OSCC. PMID- 26956917 TI - Interleukin-31 expression and relation to disease severity in human asthma. AB - Interleukin 31 (IL-31) is a novel T helper type 2 effector cytokine that plays an important role in the pathogenesis of allergic diseases. However, its role in human asthma remains unclear. The aim of this study was to measure IL-31 levels in the serum, bronchoalveolar lavage fluid (BALF) and bronchial tissue of asthmatics and healthy subjects, and identify its possible correlation to disease severity. We quantified IL-31 levels in the serum of patients with asthma (n = 44), as well as in controls (n = 22). Of these subjects, 9 asthmatics and five controls underwent bronchoscopy with endobronchial biopsy and BALF collection. Our data showed that serum and BALF IL-31 levels were significantly elevated in patients with asthma compared with controls. Expressions of IL-31 and IL-31 receptor (IL-31RA and OSMR) were more prominent in the bronchial tissue in severe compared to mild asthma and controls. Serum IL-31 levels correlated positively with Th2 related cytokines (IL-5, IL-13, and TSLP), asthma severity or total serum immunoglobulin E (IgE), and inversely with asthma control and the forced expiratory volume in 1 second (FEV1). The current data may provide insight into the underlying pathogenesis of asthma, in which IL-31 has an important pathogenic role. PMID- 26956918 TI - Dislocation "Bubble-Like-Effect" and the Ambient Temperature Super-plastic Elongation of Body-centred Cubic Single Crystalline Molybdenum. AB - With our recently developed deformation device, the in situ tensile tests of single crystal molybdenum nanowires with various size and aspect ratio were conducted inside a transmission electron microscope (TEM). We report an unusual ambient temperature (close to room temperature) super-plastic elongation above 127% on single crystal body-centred cubic (bcc) molybdenum nanowires with an optimized aspect ratio and size. A novel dislocation "bubble-like-effect" was uncovered for leading to the homogeneous, large and super-plastic elongation strain in the bcc Mo nanowires. The dislocation bubble-like-effect refers to the process of dislocation nucleation and annihilation, which likes the nucleation and annihilation process of the water bubbles. A significant plastic deformation dependence on the sample's aspect ratio and size was revealed. The atomic scale TEM observations also demonstrated that a single crystal to poly-crystal transition and a bcc to face-centred cubic phase transformation took place, which assisted the plastic deformation of Mo in small scale. PMID- 26956919 TI - Nitrate reductase-mediated NO production enhances Cd accumulation in Panax notoginseng roots by affecting root cell wall properties. AB - Panax notoginseng (Burk) F. H. Chen is a traditional medicinal herb in China. However, the high capacity of its roots to accumulate cadmium (Cd) poses a potential risk to human health. Although there is some evidence for the involvement of nitric oxide (NO) in mediating Cd toxicity, the origin of Cd induced NO and its function in plant responses to Cd remain unknown. In this study, we examined NO synthesis and its role in Cd accumulation in P. notoginseng roots. Cd-induced NO production was significantly decreased by application of the nitrate reductase inhibitor tungstate but not the nitric oxide synthase inhibitor L-NAME (N(G)-methyl-l-arginine acetate), indicating that nitrate reductase is the major contributor to Cd-induced NO production in P. notoginseng roots. Under conditions of Cd stress, sodium nitroprusside (SNP, an NO donor) increased Cd accumulation in root cell walls but decreased Cd translocation to the shoot. In contrast, the NO scavenger cPTIO (2-(4-carboxyphenyl)-4,4,5,5 tetramethylimidazoline-1-oxyl-3-oxide) and tungstate both significantly decreased NO-increased Cd retention in root cell walls. The amounts of hemicellulose 1 and pectin, together with pectin methylesterase activity, were increased with the addition of SNP but were decreased by cPTIO and tungstate. Furthermore, increases or decreases in hemicellulose 1 and pectin contents as well as pectin methylesterase activity fit well with the increased or decreased retention of Cd in the cell walls of P. notoginseng roots. The results suggest that nitrate reductase-mediated NO production enhances Cd retention in P. notoginseng roots by modulating the properties of the cell wall. PMID- 26956920 TI - Strategies for meloxicam delivery to and across the skin: a review. AB - Although meloxicam (MX) is relatively safer than other NSAIDs, adverse effects relating to the gastro-intestinal tract are still a problem when administrated MX at high doses and on the long-term treatment. Drug delivery via skin provides an attractive alternative to oral administration, but is limited by the first layer of the skin-stratum corneum. Studies have been focused on developing effective methods to break the barrier of stratum corneum for enhancing delivery of MX to and across the skin. Strategies including formulation optimizing, chemical modification and physical enhancements to transiently reduce stratum corneum barrier function have been introduced. This article reviews the current state of the techniques in the delivery of MX to and across the skin, and it also includes the profiles of pharmacokinetic and safety related with skin delivery of MX. PMID- 26956922 TI - Structural prediction of ultrahard semi-titanium boride (Ti2B) using the frozen phonon method. AB - The dynamical stability, crystal structure, and mechanical properties of semi titanium boride (Ti2B) are extensively studied using the pseudopotential plane wave method within first-principles calculations. Soft transverse acoustic phonon modes are identified in the material, which has been assumed for a long time to have an Al2Cu-type structure with a I4/mcm space group. Using the frozen-phonon method, a tetragonal I4/m structure is uncovered to be energetically more stable and have similar diffraction patterns compared to the previously assumed Al2Cu type structure. Phonon dispersion and elastic constant calculations reveal the dynamical and mechanical stability of the I4/m structure of Ti2B at ambient pressure. The calculated high elastic constants, modulus, and ideal strength show that Ti2B possesses outstanding mechanical properties. PMID- 26956921 TI - Analytical Performance and Validation of a Bioassay for Thyroid-Blocking Antibodies. AB - BACKGROUND AND OBJECTIVE: A cell-based bioassay for the measurement of thyroid blocking autoantibodies (TBAb) has been recently reported. The analytical performance and validation of this bioassay is assessed and described. METHODS: Chinese hamster ovary cells expressing a chimeric thyrotropin receptor were treated with bovine (b) TSH and different concentrations of an immunoglobulin G (IgG) monoclonal human TBAb (K1-70). TBAb was measured as a function of luciferase activity relative to bTSH alone and expressed as percent inhibition. Results obtained in the chimeric cell line were compared with those of a wild type cell line. Analytical performance studies were subsequently performed with the chimeric cell line only. RESULTS: Immunodepletion of K1-70 IgG by using a protein G-Sepharose column showed that positive percent inhibition in the TBAb bioassay was detectable from K1-70 IgG only. The limit of blank was determined to be 12.2%. The limit of detection was 14% inhibition, equivalent to 0.4 ng/mL K1 70, while the limit of quantitation was 22% (coefficient of variation [CV] 12%) equivalent to 0.625 ng/mL K1-70. The dynamic range was between 14 +/- 3.7 (mean % inhibition +/- standard deviation) and 101 +/- 2.6, equivalent to 0.4-10 ng/mL K1 70. The linear range was between 22 +/- 2.6 and 93 +/- 0.6 inhibition, equivalent to 0.625-5 ng/mL K1-70. The upper limit of the 99th percent reference range was 34% inhibition. In two laboratories, CV values for the intra- and inter-assay precisions for K1-70 ranged from 2% to 12% and from 1.7% to 14.5%, respectively. For patient sera, the CV values for the intra- and inter-assay precisions ranged from 3% to 9% and from 3% to 11%, respectively. No interference was found when follicle-stimulating hormone, luteinizing hormone, and human chorionic gonadotrophin were tested in the TBAb bioassay. The median of % inhibition values in 40 TBAb positive sera from patients with autoimmune thyroid disease were 93.5 (range 25-103) and 92 (range 64-107) for the wild type and chimeric cell lines, respectively. Further, all 40 samples of patients with various non-thyroidal autoimmune diseases were TBAb negative. CONCLUSIONS: This TBAb bioassay exhibits excellent analytical performance and high level of reproducibility. PMID- 26956923 TI - Safety and Biodistribution Evaluation in Cynomolgus Macaques of rAAV2tYF-PR1.7 hCNGB3, a Recombinant AAV Vector for Treatment of Achromatopsia. AB - AGTC is developing rAAV2tYF-PR1.7-hCNGB3, a recombinant adeno-associated virus (rAAV) vector expressing the human CNGB3 gene, for treatment of achromatopsia, an inherited retinal disorder characterized by markedly reduced visual acuity, extreme light sensitivity and absence of color discrimination. We report here results of a study evaluating the safety and biodistribution of rAAV2tYF-PR1.7 hCNGB3 in cynomolgus macaques. Three groups of animals (n=2 males and 2 females per group) received a subretinal injection in one eye of 300 uL containing either vehicle or rAAV2tYF-PR1.7-hCNGB3 at one of two concentrations (4 * 1011 or 4 * 1012 vg/mL) and were evaluated over a 3 month period prior to being euthanized. Administration of rAAV2tYF-PR1.7-hCNGB3 was associated with a dose-related anterior and posterior segment inflammatory response that was greater than that observed in eyes injected with the vehicle control. Most manifestations of inflammation improved over time except that vitreous cells persisted in vector-treated eyes until the end of the study. One animal in the lower vector dose group was euthanized on Study Day 5 based on a clinical diagnosis of endophthalmitis. There were no test article-related effects on intraocular pressure, visual evoked potential responses, hematology or clinical chemistry parameters, or gross necropsy observations. Histopathological examination demonstrated minimal mononuclear infiltrates in all vector-injected eyes. Serum anti-AAV antibodies developed in all vector-injected animals. No animals developed antibodies to CNGB3. Biodistribution studies demonstrated high levels of vector DNA in the injected eye but minimal or no vector DNA in any other tissue. These results support the use of rAAV2tYF-PR1.7-hCNGB3 in clinical studies in patients with achromatopsia caused by CNGB3 mutations. PMID- 26956925 TI - Limited data suggest that otherwise healthy school-aged children with obstructive sleep disordered breathing have some benefit from adenotonsillectomy compared with non-surgical treatment. PMID- 26956926 TI - The Poggendorff illusion driven by real and illusory contour: Behavioral and neural mechanisms. AB - The Poggendorff illusion refers to the phenomenon that the human brain misperceives a diagonal line as being apparently misaligned once the diagonal line is interrupted by two parallel edges, and the size of illusion is negatively correlated with the angle of interception of the oblique, i.e. the sharper the oblique angle, the larger the illusion. This optical illusion can be produced by both real and illusory contour. In this fMRI study, by parametrically varying the oblique angle, we investigated the shared and specific neural mechanisms underlying the Poggendorff illusion induced by real and illusory contour. At the behavioral level, not only the real but also the illusory contours were capable of inducing significant Poggendorff illusion. The size of illusion induced by the real contour, however, was larger than that induced by the illusory contour. At the neural level, real and illusory contours commonly activated more dorsal visual areas, and the real contours specifically activated more ventral visual areas. More importantly, examinations on the parametric modulation effects of the size of illusion revealed the specific neural mechanisms underlying the Poggendorff illusion induced by the real and the illusory contours, respectively. Left precentral gyrus and right middle occipital cortex were specifically involved in the Poggendorff illusion induced by the real contour. On the other hand, bilateral intraparietal sulcus (IPS) and right lateral occipital complex (LOC) were specifically involved in the Poggendorff illusion induced by the illusory contour. Functional implications of the above findings were further discussed. PMID- 26956927 TI - Jumping to conclusions in untreated patients with Parkinson's disease. AB - BACKGROUND: Jumping to conclusions due to impulsivity has been shown to be a sensitive marker for dopamine dysregulation and addictive behaviour patterns in treated patients with Parkinson's disease (PD). It is unknown whether drug naive PD patients, who have never received dopaminergic therapy also have deficits in information sampling. METHODS: Twenty five de novo PD patients and twenty matched healthy controls were recruited and tested on the beads task, which is a validated information sampling task to assess reflection impulsivity and a temporal discounting questionnaire. RESULTS: Patients gathered significantly less information and made more irrational choices than matched controls. There was, however, no group difference on the temporal discounting questionnaire. CONCLUSIONS: Poor information sampling and irrational decision making may be an inherent component of the neuropsychological deficit in Parkinson's disease. These findings suggest that underlying impulsivity detected by a metric task is common in de novo PD. PMID- 26956928 TI - Long-term episodic memory decline is associated with olfactory deficits only in carriers of ApoE-e4. AB - The E4 allele of the Apolipoprotein E gene is a genetic risk factor for late onset dementia of the Alzheimers' type (DAT), which is characterized by loss of both episodic memory and olfactory functions. Little is known about the possible role of E4 in the association between ongoing episodic memory decline and olfactory deficits in the general population, but such information is relevant in determining the relevance of olfaction as a marker of DAT risk. The present study was based on a large, population-based sample (n=1087, aged 45-90 years, of which 324 were E4-carriers). Episodic memory change rates were established using data collected every 5 years for a 10-20 year interval leading up to an olfactory assessment using the Scandinavian Odor Identification Test at the last wave of data collection. Participants were classified according to whether or not their episodic memory ability declined more rapidly than the age-typical norm (by >1SD). Our main result is that only in E4-carriers was episodic memory decline associated with odor identification impairment. In individuals without E4, odor identification was unrelated to episodic memory decline status. Follow-up analyses indicated that this moderation by E4 was due to the olfactory nature of the identification test, and that the effect was not caused by 63 individuals with dementia. Our results suggest that the E4 determines the functional association between ongoing episodic memory decline and olfaction. These findings are consistent with the notion that E4-carriers with DAT, compared to non carriers, display a cortical atrophy pattern that is more focused on mediotemporal lobe regions supporting olfactory and episodic memory functions. Olfactory and memory assessments might provide complementary information on mediotemporal atrophy prior to clinical dementia onset, but the E4 should be considered when using olfactory assessment as an early-stage indicator. PMID- 26956929 TI - Shape Engineering of Oxide Nanoparticles for Heterogeneous Catalysis. AB - The fabrication of oxide particles with tunable sizes and shapes at the nanoscale is one of the most crucial issues for the design and development of highly efficient heterogeneous catalysts. The shape of oxide nanoparticles has been demonstrated to affect their catalytic properties remarkably. Tuning the shape of oxide particles allows preferential exposure of specific reactive facets; this can maximize the number of active sites available to the reactants, which can improve the activity and also mediate the reaction route to a specific channel to achieve higher selectivity for a particular chemical reaction. In addition, the shape of the oxide particles affects their interaction with metal particles or clusters, and this involves interfacial strain and charge transfer. Metal particles or clusters dispersed on the reactive or polar facets of the oxide support often provide superior catalytic performance, primarily because of strong metal-support interactions. However, the geometric and electronic features of the metal-oxide interface may change during the course of the reaction, induced by chemisorption of reactive molecules at elevated temperatures, which should be taken into account in proposing a structure-reactivity relationship. PMID- 26956931 TI - Effects of socio-demographic variables on performance on the Cambridge neuropsychological automated tests for the assessment of dementia and Portuguese norms for older adults living in retirement homes. AB - OBJECTIVE: This study aimed to analyze the effects of age, education, gender, computer experience, institutionalization time, and psychotropic drug use on performance on four tests of the Cambridge Neuropsychological Test Automated Battery (CANTAB) which are recommended for the assessment of dementia (Rapid Visual Information Processing [RVP], Paired Associates Learning [PAL], Spatial Working Memory [SWM], and Reaction Time [RTI]), and to provide norms for Portuguese older persons without neuropsychiatric diagnoses who are living in retirement homes. METHOD: The normative sample included 128 adults aged 69-96 years who had no neuropsychiatric diagnosis and who had lived in retirement homes for 3-232 months. The CANTAB was administered, at the latest, one week after a screening session that comprised an interview and the administration of pencil and-paper tests. RESULTS: The simultaneous multiple linear regression models were significant (p < .05) for all tests except the RTI five-choice movement time measure. The total variance explained by the socio-demographic variables was smaller for the CANTAB measures (4-14%) than for the pencil-and-paper tests (10 33%). Significant effects involving age or gender were observed for RVP, PAL, and SWM. A marginally significant computer experience effect was found for the RTI simple movement time measure. We additionally observed significant effects of education, age, gender, and computer experience on several pencil-and-paper tests. CONCLUSIONS: Our findings suggest that different socio-demographic variables influence distinct tests and measures of the same test, and that the associations between computer experience and several pencil-and-paper tests may be mediated by possible cognitive skills developed through computer use. PMID- 26956932 TI - Risk factors for stillbirth in a socio-economically disadvantaged urban Australian population. AB - INTRODUCTION: Several risk factors for stillbirth have been extensively investigated. Some risk factors are more common in socio-economically disadvantaged regions. The aim of this study was to identify risk factors for stillbirth in the Northern suburbs of Adelaide, one of the most socio economically disadvantaged urban areas in Australia. MATERIAL AND METHODS: A retrospective case control study (two controls per case) of all women with a singleton pregnancy resulting in a stillbirth during the decade 2002-2012. RESULTS: One hundred and thirty stillbirths were registered over these 10 years. Using univariate analysis, the following risk factors were identified: obesity >=40 body mass index (BMI) (OR 4.75), non-Caucasian ethnicity (odds ratio [OR] 2.737), pre-existing diabetes (p <0.000), polycystic ovary syndrome (PCOS) (OR 5.250), in vitro fertilisation (IVF) (OR 4.000), booking systolic blood pressure (SBP) >= 140 (OR 5.000) and booking diastolic blood pressure (DBP) >= 80 (OR 3.111). Many of these factors have complex interrelationships. Multivariate analysis identified the following independent risk factors: BMI >=40 (OR 3.940), ethnic minorities (mainly indigenous Australians) (OR 2.255) and social issues (OR 3.079). PCOS had an independent effect to some extent, but this was clearly confounded by BMI. CONCLUSION: These Australian data confirm the presence of several potentially modifiable risk factors for stillbirth, within this socio economically disadvantaged region. Modifying these risk factors, in particular obesity, is a big challenge not only for maternity and primary care providers, but for overall society. PMID- 26956930 TI - MICU1 regulation of mitochondrial Ca(2+) uptake dictates survival and tissue regeneration. AB - Mitochondrial Ca(2+) uptake through the recently discovered Mitochondrial Calcium Uniporter (MCU) is controlled by its gatekeeper Mitochondrial Calcium Uptake 1 (MICU1). However, the physiological and pathological role of MICU1 remains unclear. Here we show that MICU1 is vital for adaptation to postnatal life and for tissue repair after injury. MICU1 knockout is perinatally lethal in mice without causing gross anatomical defects. We used liver regeneration after partial hepatectomy as a physiological stress response model. Upon MICU1 loss, early priming is unaffected, but the pro-inflammatory phase does not resolve and liver regeneration fails, with impaired cell cycle entry and extensive necrosis. Ca(2+) overload-induced mitochondrial permeability transition pore (PTP) opening is accelerated in MICU1-deficient hepatocytes. PTP inhibition prevents necrosis and rescues regeneration. Thus, our study identifies an unanticipated dependence of liver regeneration on MICU1 and highlights the importance of regulating MCU under stress conditions when the risk of Ca(2+) overload is elevated. PMID- 26956933 TI - Theoretical study on the surface stabilities, electronic structures and water adsorption behavior of the Ta3N5(110) surface. AB - A recent experiment revealed that the Ta3N5 semiconductor with orientation along the (110) surface exhibited improved photoelectrochemical activities, but the role of the (110) surface in the improved photoelectrochemical activity remains unclear. In this study, density functional theory calculations were performed to investigate the surface stabilities, surface electronic structures and water splitting behavior of the Ta3N5(110) surface with and without oxygen impurities. The results showed that, on the clean and oxygen impurity containing (110) surfaces, the energy barriers of water splitting were as low as 0.05 and 0.06 eV, respectively, suggesting that the Ta3N5(110) surface is a promising candidate for water splitting. The lower energy barriers of water splitting on the Ta3N5(110) surface may be ascribed to the easy migration of the H atom from the surface Ta atom to the nearby N atom. Furthermore, the surface energies and surface electronic structures revealed that the Ta3N5(110) surface contained less oxygen impurities, which is in accordance with the experimental observations. PMID- 26956934 TI - Elevator pitch. PMID- 26956935 TI - Residential mobility impacts exposure assessment and community socioeconomic characteristics in longitudinal epidemiology studies. AB - Epidemiologic studies commonly use residential locations to estimate environmental exposures or community-level characteristics. The impact of residential mobility on these characteristics, however, is rarely considered. The objective of this analysis was to examine the effect of residential mobility on estimates of traffic-related air pollution (TRAP), greenspace, and community level characteristics. All residential addresses were reported from birth through age seven for children enrolled in the Cincinnati Childhood Allergy and Air Pollution Study. Exposure to TRAP at each address was estimated using a land use model. Greenspace was estimated using satellite imagery. Indices of neighborhood deprivation and race were created based on socioeconomic-census tract measures. Exposure estimates using the birth record address, the last known address, and the annual address history were used to determine exposure estimation error and bias in the association with asthma at age seven. Overall, 54% of the cohort moved at least once prior to age seven. Each move was separated by a median of 4 miles and associated with a median decrease of 4.4% in TRAP exposure, a 5.3% increase in greenspace, an improved deprivation index, and no change in the race index. Using the birth record address or the last known address instead of the annual address history resulted in exposure misclassification leading to a bias toward the null when associating the exposures with asthma. Using a single address to estimate environmental exposures and community-level characteristics over a time period may result in differential assessment error. PMID- 26956936 TI - Predictors and respiratory depositions of airborne endotoxin in homes using biomass fuels and LPG gas for cooking. AB - Recent studies have highlighted the presence of endotoxin in indoor air and its role in respiratory morbidities. Burning of household fuels including unprocessed wood and dried animal dung could be a major source of endotoxin in homes. We measured endotoxin levels in different size fractions of airborne particles (PM10, PM2.5, and PM1), and estimated the deposition of particle-bound endotoxin in the respiratory tract. The study was carried out in homes burning solid biomass fuel (n=35) and LPG (n=35). Sample filters were analyzed for endotoxin and organic carbon (OC) content. Household characteristics including temperature, relative humidity, and carbon dioxide levels were also recorded. Multivariate regression models were used to estimate the contributing factors for airborne endotoxin. Respiratory deposition doses were calculated using a computer-based model. We found a higher endotoxin concentration in PM2.5 fractions of the particle in both LPG (median: 110, interquartile range (IQR) 100-120 EU/m3) and biomass (median: 350, IQR: 315-430 EU/m3) burning homes. In the multivariate adjusted model, burning of solid biomass fuel (beta: 67; 95% CI: 10.5-124) emerged as the most significant predictor followed by OC (beta: 4.7; 95% CI: 2.7 6.8), RH (beta: 1.6; 95% CI: 0.76-2.4), and PM2.5 (beta: 0.45; 95% CI: 0.11-0.78) for airborne endotoxin (P<0.05). We also observed an interaction between PM organic carbon content and household fuel in predicting the endotoxin levels. The model calculations showed that in biomass burning homes, total endotoxin deposition was higher among infants (59%) than in adult males (47%), of which at least 10% of inhaled endotoxin is deposited in the alveolar region of the lung. These results indicate that fine particles are significant contributors to the deposition of endotoxin in the alveolar region of the lung. Considering the paramount role of endotoxin exposure, and the source and timing of exposure on respiratory health, additional studies are warranted to guide evidence-based public health interventions. PMID- 26956937 TI - Cadmium exposure and risk of lung cancer: a meta-analysis of cohort and case control studies among general and occupational populations. AB - The association between cadmium exposure and risk of lung cancer is still unclear. We quantitatively reviewed the observational studies that investigated the association between cadmium exposure and lung cancer risk in both general and occupational populations published through April 2015. The final data set is comprised of three cohort studies in the general population totaling 22,551 participants (354 events) with a mean follow-up of 15 years, five occupational cohort studies including 4205 individuals (180 events) with an average follow-up of 31 years, and three occupational case-control studies including 4740 cases and 6268 controls. Comparing the highest to the lowest category of cadmium exposure, the weighted relative risk and 95% confidence interval of lung cancer in the general population was 1.42 (95% CI (0.91, 2.23)); the weighted risk estimates (95% CIs) of lung cancer in three occupational cohort studies and three case control studies were 0.68 (95% CI (0.33, 1.41)) and 1.61 (95% CI (0.94, 2.75)), respectively. No linear association was found. When comparing participants exposed to cadmium with non-exposed based on available data, the association became statistically significant. According to findings from this meta-analysis, the possibility that cadmium exposure may increase risk of lung cancer cannot be completely ruled out in either general or occupational population. PMID- 26956938 TI - Toddler's behavior and its impacts on exposure to polybrominated diphenyl ethers. AB - Children have higher polybrominated diphenyl ether (PBDE) body burdens than adults, which may be related to hand-to-mouth behavior. We investigate associations between children's behavior, including hand-to-mouth contacts, and markers of PBDE exposure. In addition, we investigate associations between characteristics of the home environment and exposure. Eighty-three children aged 12-36 months were recruited from North Carolina (2009-2010). Children provided blood and handwipes samples, which were analyzed for PBDEs. Parents completed questionnaires, providing demographic, behavioral, and environmental data. More active children had higher levels of PBDEs on their hands and in their bodies. For example, children who spent more time sleeping had lower exposures to PBDEs; each additional hour of sleep resulted in a 30% decrease in handwipe BDE-99 levels (P<0.001) and a 15% decrease in serum (P=0.03). After accounting for handwipe PBDE levels, children who licked their fingers while eating had higher serum PBDEs. Other behaviors were not consistently associated with serum levels. Playing with plastic toys was associated with higher handwipe levels of PBDEs, while frequent vacuuming decreased handwipe PBDE levels. Characteristics of the home environment generally were not associated with serum PBDEs. Our results suggest that certain aspects of children's behavior and their environment impact exposure to PBDEs. PMID- 26956940 TI - Revisiting histopathologic findings in Goltz syndrome. AB - Goltz syndrome (focal dermal hypoplasia) is an X-linked dominant disorder that is classically associated with yellowish papules representing fat herniation (superficial adipocytes). We report a series of three cases, with clinicopathologic correlation of biopsies from Blaschkoid streaks. A range of histopathologic features, including some underreported findings (increased papillary dermal blood vessels, decreased thickness of the dermis, and adipocytes high in the dermis), are reproducible and can strongly point to the correct diagnosis of Goltz syndrome. PMID- 26956939 TI - Bisphenol A exposure and children's behavior: A systematic review. AB - Bisphenol A (BPA) is an endocrine disrupting chemical used to synthesize polycarbonate plastics and epoxy resins. Previous research suggests that exposure to it can alter children's behavior. The objective of this study is to conduct a systematic review of the existing literature, examining associations between prenatal and childhood BPA exposure and behavior in children up to 12 years of age. We searched electronic bibliographic databases (MEDLINE, PubMed, EMBASE, PsycINFO, CINAHL, and ERIC), reference lists of included articles, and conference abstracts (American Psychiatric Association, American Academy of Neurology, Pediatric Academic Societies, and International Society of Environmental Epidemiology). We included original studies reporting on the association between prenatal and childhood BPA exposure that measured BPA metabolites in urine and children's behavioral outcomes. From 2811 citations, 11 articles met our inclusion criteria. Descriptive analyses indicated that prenatal exposure to maternal BPA concentrations were related to higher levels of anxiety, depression, aggression, and hyperactivity in children. BPA exposure in childhood was associated with higher levels of anxiety, depression, hyperactivity, inattention, and conduct problems. Limited observational evidence suggests an association between both prenatal and childhood exposure to BPA and adverse behavioral outcomes in children. Prospective cohort studies are needed to clarify these associations. PMID- 26956941 TI - Application potential of mesenchymal stem cells from euthanased dogs: evaluation of the pathogen transmission risk. PMID- 26956942 TI - The Effect of Reflexology Applied to Patients with Chronic Obstructive Pulmonary Disease on Dyspnea and Fatigue. AB - PURPOSE: The purpose of this study was to determine the effect of reflexology on reducing dyspnea and fatigue in patients with chronic obstructive pulmonary disease (COPD). DESIGN/METHODS: The study was conducted as a pretest-posttest experimental design. The population of the study consisted of 60 patients (30 in experimental group and 30 in control group). Patient Description Form, Baseline Dyspnea Index (BDI) and Visual Analogue Scale-Fatigue (VAS-F) were used to collect the data. RESULTS: The difference between pretest-posttest dyspnea and fatigue mean scores of patients in the experimental group was statistically significant (p < .01). The difference between pretest-posttest dyspnea and fatigue mean scores of patients in the control group was statistically insignificant (p > .05). CONCLUSION: It was determined that the reflexology reduced dyspnea and fatigue in patients with COPD. CLINICAL RELEVANCE: Complementary methods such as reflexology should be used with pharmacological methods to reduce dyspnea and fatigue of COPD patients. PMID- 26956943 TI - Human Xq28 inversion polymorphism: From sex linkage to Genomics--A genetic mother lode. AB - An inversion polymorphism of the filamin and emerin genes at the tip of the long arm of the human X-chromosome serves as the basis of an investigative laboratory in which students learn something new about their own genomes. Long, nearly identical inverted repeats flanking the filamin and emerin genes illustrate how repetitive elements can lead to alterations in genome structure (inversions) through nonallelic homologous recombination. The near identity of the inverted repeats is an example of concerted evolution through gene conversion. While the laboratory in its entirety is designed for college level genetics courses, portions of the laboratory are appropriate for courses at other levels. Because the polymorphism is on the X-chromosome, the laboratory can be used in introductory biology courses to enhance understanding of sex-linkage and to test for Hardy-Weinberg equilibrium in females. More advanced topics, such as chromosome interference, the molecular model for recombination, and inversion heterozygosity suppression of recombination can be explored in upper-level genetics and evolution courses. DNA isolation, restriction digests, ligation, long PCR, and iPCR provide experience with techniques in molecular biology. This investigative laboratory weaves together topics stretching from molecular genetics to cytogenetics and sex-linkage, population genetics and evolutionary genetics. PMID- 26956945 TI - 'It pushed me back into the human race': evaluative findings from a community Christmas event. AB - Many older people in Britain spend Christmas day alone. The Christmas period may be especially difficult for older people who are socially isolated, living with dementia or who have physical impairments, and may feel particularly marginalised at this time of year. This paper draws on evaluative research findings from a community Christmas event held in December 2014 at the University of Salford for older people and their carers who would be on their own on Christmas day. A multi method approach was employed, seven guests took part in semi-structured interviews to explore their experiences and perceptions of the event, seven staff and student volunteers participated in a group interview to explore and discuss their participation in the event. Data collection took place during April and May 2015. Interview transcripts were subjected to thematic analysis. Three overarching themes were identified from the interviews: 'reasons for participants attending the event', 'a different Christmas day: the impact on guests and volunteers', and 'learning, planning and moving forwards'. The findings illustrate that a range of people participated in the Christmas day event for a variety of reasons. The event itself had a positive impact, including the shared experience of social belonging, for all involved. There are tangible longer term benefits as a result of the event, such as ongoing contact between participants and the development of supportive networks in the local community. PMID- 26956946 TI - Epidemiologic aspects of necrotic enteritis in broiler chickens - disease occurrence and production performance. AB - Since future conventional broiler production can no longer rely upon in-feed antimicrobials (anticoccidials and antibiotic growth promoters), understanding the most important non-antimicrobial factors influencing occurrence of necrotic enteritis (NE) in poultry will become urgent. Solid population-based data on NE occurrence are scarce. Additionally, data on cholangiohepatitis (CPH) at slaughter is a useful indirect measurement of NE occurrence. Existing data suggest that coccidiosis and nutritional factors are among the most important determinants of NE occurrence. Dietary cereal contents and dietary level of animal proteins can both influence NE occurrence, but cereal composition may be more important because cereals constitute a larger portion of the diet. Losses associated with NE vary depending on the severity of the disease, but data indicate that the farmers' profit may be reduced on average with as much as one third during an epidemic of clinical disease. PMID- 26956944 TI - Policy analysis for deciding on a malaria vaccine RTS,S in Tanzania. AB - BACKGROUND: Traditionally, it has taken decades to introduce new interventions in low-income countries. Several factors account for these delays, one of which is the absence of a framework to facilitate comprehensive understanding of policy process to inform policy makers and stimulate the decision-making process. In the case of the proposed introduction of malaria vaccines in Tanzania, a specific framework for decision-making will speed up the administrative process and shorten the time until the vaccine is made available to the target population. METHODS: Qualitative research was used as a basis for developing the Policy Framework. Interviews were conducted with government officials, bilateral and multilateral partners and other stakeholders in Tanzania to assess malaria treatment policy changes and to draw lessons for malaria vaccine adoption. RESULTS: The decision-making process for adopting malaria interventions and new vaccines in general takes years, involving several processes: meetings and presentations of scientific data from different studies with consistent results, packaging and disseminating evidence and getting approval for use by the Ministry of Health and Social Welfare (MOHSW). It is influenced by contextual factors; Promoting factors include; epidemiological and intervention characteristics, country experiences of malaria treatment policy change, presentation and dissemination of evidence, coordination and harmonization of the process, use of international scientific evidence. Barriers factors includes; financial sustainability, competing health and other priorities, political will and bureaucratic procedures, costs related to the adoption and implementations of interventions, supply and distribution and professional compliance with anti malarial drugs. CONCLUSION: The framework facilitates the synthesis of information in a coherent way, enabling a clearer understanding of the policy process, thereby speeding up the policy decision-making process and shortening the time for a malaria vaccine to become available. PMID- 26956947 TI - A case-control study to identify risk factors for acute salmonellosis in New Zealand dairy herds, 2011-2012. AB - In late 2011 the New Zealand Ministry for Primary Industries reported an increase in confirmed laboratory diagnoses of salmonellosis in dairy herds. To identify risk factors for herd-level outbreaks of salmonellosis we conducted a case control study of New Zealand dairy herds in 2011-2012. In a multivariable analysis, use of continuous feed troughs [adjusted odds ratio (aOR) 6.2, 95% confidence interval (CI) 2.0-20], use of pelletized magnesium supplements (aOR 10, 95% CI 3.3-33) and use of palm kernel meal as a supplementary feed (aOR 8.7, 95% CI 2.5-30) were positively associated with a herd-level outbreak of salmonellosis between 1 July 2011 and 31 January 2012. We conclude that supplementary feeds used on dairy farms (regardless of type) need to be stored and handled appropriately to reduce the likelihood of bacterial contamination, particularly from birds and rodents. Magnesium supplementation in the pelletized form played a role in triggering outbreaks of acute salmonellosis in New Zealand dairy herds in 2011-2012. PMID- 26956948 TI - Sperm competition-induced plasticity in the speed of spermatogenesis. AB - BACKGROUND: Sperm competition between rival ejaculates over the fertilization of ova typically selects for the production of large numbers of sperm. An obvious way to increase sperm production is to increase testis size, and most empirical work has focussed on this parameter. Adaptive plasticity in sperm production rate could also arise due to variation in the speed with which each spermatozoon is produced, but whether animals can respond to relevant environmental conditions by modulating the kinetics of spermatogenesis in this way has not been experimentally investigated. RESULTS: Here we demonstrate that the simultaneously hermaphroditic flatworm Macrostomum lignano exhibits substantial plasticity in the speed of spermatogenesis, depending on the social context: worms raised under higher levels of sperm competition produce sperm faster. CONCLUSIONS: Our findings overturn the prevailing view that the speed of spermatogenesis is a static property of a genotype, and demonstrate the profound impact that social environmental conditions can exert upon a key developmental process. We thus identify, to our knowledge, a novel mechanism through which sperm production rate is maximised under sperm competition. PMID- 26956949 TI - [Physiological and Pathological Development of calcaneal apophysis in Children]. AB - BACKGROUND: The apophysis of the calcaneal bone forms an insertional region for the strong plantarflexors with the Achillis tendon and serves as an origin for the plantar aponeurosis and the short intrinsic foot muscles. Both components create a tendinous sling whithin which the apophysis acts as a pivot, which functions when it runs a straight course and its tension is adequate. This mechanism results in combined tractional and compressional forces which work together with the ground reaction forces during gait as molding elements of the calcaneous bone. Every longer lasting change in the magnitude and distribution of these forces can be followed by structural adaptations especially during the growth period. Furthermore the calcaneal apophysis functions as a connecting link between the ankle and thigh bones on one side and the mid- and forefoot region on the other side. When studying the causal relationships which influence the apophyseal growth and shape intrinsic and extrinsic components must be distinguished. CLINICAL DIAGNOSTICS: Every analysis of calcaneal pathologies should use clinical and instrumented diagnostics. Any classification must separate between bony and soft tissue elements and consider structural and functional influences in three planes. If an exact classification can be established an individual hypothesis must be formulated out of which therapeutic measures can be developed. THERAPY: Treatment must focus on the pathologic changes of shape as well as on functional aspects. A thorough knowledge of the normal development and function of the calcaneal apophysis serves as a basis for further understanding and treating pathologic changes of this hitherto only sparsely investigated functional region. PMID- 26956950 TI - [Acute tibial tubercle avulsion fractures]. AB - BACKGROUND: The tear-off of the apophysis of the proximal tibia is a rare injury (< 1 % of all apophysal lesions). It mainly affects male adolescents (14,6 years). Main causes are concentric and eccentric stress during sport activity. Morbus Osgood-Schlater seems to be a predisposing factor. AIM: Up-to-date survey of pathogenesis, diagnostics and treatment strategies. MATERIAL AND METHODS: Literature research (level III and IV studies) as well as own results. RESULTS: The affected patients are mostly male (97 %), type III fractures are most frequently seen (48 %). Accompanying injuries are not to be missed (10 %). The treatment usually consists of surgery by means of an open reposition and internal refixation, recently also minimal invasi. The results are mainly very good to good, approximately 95 % reach their old level of activity again. Almost one third of the patients develop a mostly slight complication. CONCLUSION: The acute tear-off of the apophysis of the proximal tibia is an infrequent disease. In dislocated injuries the standard procedure is the open reposition and the internal fixation. Lesions within the knee are particularly to be expected in intraarticular fractures und must not be missed. A very good to good result is to be expected with correct treatment, momentous complications are all together rare. PMID- 26956951 TI - Early Eating Behaviours and Food Acceptance Revisited: Breastfeeding and Introduction of Complementary Foods as Predictive of Food Acceptance. AB - Current dietary advice for children is that they should eat at least five portions of fruit and vegetables a day (Department of Health. National Diet and Nutrition Survey, 2014). However, many parents report that children are reluctant to eat vegetables and often fail to comply with the five-a-day rule. In fact, in surveys carried out in areas in the UK, the number of children eating according to the five-a-day rule has been found to be as low as 16 % (Cockroft et al. Public Health Nutr 8(7):861-69, 2005). This narrative review looks at those factors which contribute to food acceptance, especially fruit and vegetables, and how acceptance might be enhanced to contribute to a wider dietary range in infancy and later childhood. The questions we address are whether the range of foods accepted is determined by the following: innate predispositions interacting with early experience with taste and textures, sensitive periods in infancy for introduction, breastfeeding and the pattern of introduction of complementary foods. Our conclusions are that all of these factors affect dietary range, and that both breastfeeding and the timely introduction of complementary foods predict subsequent food acceptance. PMID- 26956952 TI - Cholesterol oxidation products and their biological importance. AB - The main biological cause of oxysterols is the oxidation of cholesterol. They differ from cholesterol by the presence of additional polar groups that are typically hydroxyl, keto, hydroperoxy, epoxy, or carboxyl moieties. Under typical conditions, oxysterol concentration is maintained at a very low and precisely regulated level, with an excess of cholesterol. Like cholesterol, many oxysterols are hydrophobic and hence confined to cell membranes. However, small chemical differences between the sterols can significantly affect how they interact with other membrane components, and this in turn can have a substantial effect on membrane properties. In this spirit, this review describes the biological importance and the roles of oxysterols in the human body. We focus primarily on the effect of oxysterols on lipid membranes, but we also consider other issues such as enzymatic and nonenzymatic synthesis processes of oxysterols as well as pathological conditions induced by oxysterols. PMID- 26956953 TI - Early-stage sea lice recruits on Atlantic salmon are freshwater sensitive. AB - Sea lice are significant parasites of marine and brackish farmed fishes. Freshwater bathing is a potential control option against numerous sea lice species, although has been viewed as futile against those that are capable of tolerating freshwater for extended periods. By comparing freshwater survival times across host-attached stages of Lepeophtheirus salmonis (Kroyer), a key parasite in Atlantic salmon farming, we show the first attached (copepodid) stage undergoes 96-100% mortality after 1 h in freshwater, whereas later attached stages can tolerate up to 8 days. Thus, regular freshwater bathing methods targeting the more susceptible attached copepodid stage may successfully treat against L. salmonis and potentially other sea lice on fish cultured in marine and brackish waters. PMID- 26956954 TI - Discharge Diuretic Dose and 30-Day Readmission Rate in Acute Decompensated Heart Failure. AB - BACKGROUND: Loop diuretics play a crucial role in symptom management in patients with fluid overload. There is a paucity of data regarding optimal diuretic dose at hospital discharge for acute decompensated heart failure (ADHF) patients requiring loop diuretics. OBJECTIVE: To compare all-cause 30-day readmission in ADHF patients on chronic loop diuretics who had an increase in loop diuretic dose at discharge (relative to their preadmission dose) with patients without a change or a decrease in loop diuretic dose at discharge. METHODS: This was a multicenter, retrospective cohort study. Institutional review board approval was obtained. Patients admitted with a primary discharge diagnosis of heart failure, evidence of fluid overload, and reduced ejection fraction were included. Patients were divided into 2 groups based on total daily loop diuretic dose at discharge: those discharged on an increased dose and those discharged on a dose less than or equal to their preadmission dose. RESULTS: A total of 131 patient admissions met inclusion criteria; 50 had an increase in loop diuretic dose at discharge, and 81 were discharged with no change or a decrease in diuretic dose. Patients in the increased dose group had an all-cause 30-day readmission rate of 20% compared with 38% of patients with no change or a decrease in diuretic dose (adjusted odds ratio = 0.320; 95% CI = 0.117-0.873). CONCLUSION: In patients admitted for ADHF with reduced ejection fraction and evidence of fluid overload, an increase in loop diuretic dose at discharge was associated with a reduced rate of 30-day hospital readmission. PMID- 26956956 TI - [Research progress on chronic colitis and molecular mechanism of carcinogenesis]. PMID- 26956955 TI - Identification of novel inhibitors of DDR1 against idiopathic pulmonary fibrosis by integrative transcriptome meta-analysis, computational and experimental screening. AB - Idiopathic pulmonary fibrosis (IPF) is a kind of a chronic and fatal lung disease leading to progressive lung function decline. Although several RNA microarray studies on IPF patients have been reported, their results were merely specific to each study with distinct platforms or sample types. In the current study, an integrative transcriptome meta-analysis of IPF was performed to explore regulated pathways, based on four independent expression profiling microarrays of IPF datasets, including 73 samples from IPF tissues or lung fibroblast cells. The results suggested the discoidin domain receptor 1 (DDR1) and downstream c-Jun N terminal kinases (JNK) pathway may play important roles in the progression of IPF. To our knowledge, discoidin domain receptor 1 (DDR1) is a kind of receptor tyrosine kinase (RTK) with a unique ability to bind both fibrillar and non fibrillar collagens. Based on the crystallographic structures of DDR1, the combination of molecular dynamics simulation and a hybrid protocol of a virtual screening method, comprised of PBVS (multicomplex-pharmacophore based virtual screening) and DBVS (docking based virtual screening) methods were used for retrieving novel DDR1 inhibitors from the SPECS database. Twelve hit compounds were selected from the hit compounds and shifted to experimental validations, and the most potent compound was evaluated for its anti-IPF capacity on murine IPF models. Thus, these results may provide valuable information for further discovery of potential lead compounds for IPF therapy. PMID- 26956957 TI - [Consensus on diagnosis on congenital intestinal aganglionosis]. PMID- 26956958 TI - [Clinicopathologic features of succinate dehydrogenase-deficient gastrointestinal stromal tumor]. AB - OBJECTIVE: To investigate clinicopathologic features of succinate dehydrogenase deficient gastrointestinal stromal tumors (SDH-deficient GIST). METHODS: Immunohistochemical EnVision technique was used to assess the expression of succinate dehydrogenase subunit B (SDHB) in 192 cases of GIST. Cases of SDH deficient GIST were further evaluated for the presence of CKIT exons 9, 11, 13 and 17 mutations and PDGFRA exons 12 and 18 mutations with clinical followed-up data. RESULTS: Seven of the 192 cases showed SDHB-deficiency (3.6%, 7/192). The patients ranged in age from 35 to 84 years (median=56 years; mean=60 years). Four were male and three were female. Six tumors involved stomach and one involved mesentery. Histopathologic features of SDHB-deficient GIST included four cases of mixed-cell type and three of epithelioid cell type. The tumors commonly involved muscularis propria of the stomach as multiple nodules, creating a plexiform pattern. The tumors had high cellularity with cytoplasmic vacuolization. Five cases developed lymph node metastases including one also metastasizing to liver and pancreas. Two cases showed no evidence of metastasis. None of the 7 cases of the SDHB-deficient GIST had CKIT exons 9, 11, 13 and 17 mutations and PDGFRA exons 12 and 18 mutations. Three of the seven SDHB-deficient GIST cases had followed-up data: two did not recur and one died after 24 months of surgery of unknown cause. CONCLUSION: SDHB-deficient GIST has characteristic clinicopathologic features with wide-type CKIT gene and a favorable prognosis. PMID- 26956959 TI - [Intraductal papillary mucinous neoplasm of pancreas: analysis of the clinicopathologic features and prognosis]. AB - OBJECTIVE: To study the clinicopathologic and immunohistochemical features, and the prognosis of intraductal papillary mucinous neoplasms (IPMN) of the pancreas. METHODS: The clinical findings, morphologic features, immunophenotype and prognosis were investigated in 61 cases of IPMN. RESULTS: Of these 61 cases, 33 were in the pancreatic head and 14 were in the body and tail, and 14 in the entire pancreas. The average patients' age was 61.8 years. The initial symptom was abdominal pain in 37 cases, and the tumors were detected at routine checkup in 14 cases. The imaging examination showed dilated ducts and/or cystic and solid masses. Grossly, 32 cases were multi-loculated cystic masses containing mucin and papillary areas; 13 cases were solid. Microscopically, the IPMN showed four patterns, including gastric-type (16 cases), intestinal-type (21 cases), pancreatobiliary-type (21 cases) and eosinophilic-type (3 cases). The IPMN cohort included 13, 13 and 6 IPMN with low, intermediate and high-grade dysplasia respectively, and 29 IPMN associated with invasive carcinoma. The IPMN associated carcinomas were mainly ductal adenocarcinoma (23/29, 79.3%), followed by colloid carcinoma (4/29, 13.8%) and undifferentiated carcinoma (2/29, 6.9%). Immunohistochemically, IPMN expressed MUC5AC (51/57, 89.4%), MUC2 (21/57, 36.8%), and MUC1 (13/46, 28.3%). The mean postoperative follow-up period was 32 months (range 12-112 months). Six of 61 patients were lost to follow-up. Overall 5-year survival rate was 76%. The 5-year survival rate of IPMN with low, intermediate or high-grade dysplasia was 100%, and recurrence was local in 3 patients. The 3-year survival rate of IPMN associated with invasive carcinoma was 55%. 12 of 13 patients died within 2 years after operation. CONCLUSIONS: IPMN is a common cystic neoplasm of the pancreas located in the ducts. The pathologic types and classifications are clearly defined. MUC stains are helpful for the diagnosis and papillary typing. IPMN with invasive carcinoma was associated with significantly worse survival than IPMN with dysplasia. PMID- 26956960 TI - [Hepatic angiomyolipoma: a clinicopathologic features and prognosis analysis of 182 cases]. AB - OBJECTIVE: To study the clinicopathological characteristics of hepatic angiomyolipoma (HAML) and to evaluate the correlation between clinicopathological parameters and tumor subtypes. METHODS: Retrospective analysis of clinicopathological features was conducted in 182 cases of HAML. RESULTS: HAML patients were predominantly female (M:F=1:4) and most commonly presented with non specific symptoms. The median age at diagnosis was 46 years, ranged from 17 to 77 years. Tumor diameter was ranged from 0.3 to 32.0 cm with an average of 5.0 cm. Majority of the tumor was epithelioid type (112/165, 67.9%). Extramedullary hematopoiesis, multinucleated giant cells, intranuclear inclusions, nucleolus, cellular atypia, invasive growth pattern, multiple masses, hyperpigmentation and purpura-like changes mostly occurred in the epithelioid type (P<0.05). Extramedullary hematopoiesis was commonly seen in HAML, the significance of which was still uncertain. CONCLUSIONS: Most of HAML are epithelioid type, characterized by a proliferation of predominantly epithelioid cells, in which extramedullary hematopoiesis is commonly seen. Some morphologic features that may predict malignant such as necrosis, mitotic figures, and tumor emboli are only found in the epithelioid HAML. Mitotic activity, tumor necrosis, tumor thrombus, giant cells, periportal invasion, multiple lesions and tumors size over 10 cm are closely related with tumor recurrence and metastasis. PMID- 26956961 TI - [Histologic detection of cytomegalovirus and its application in gastrointestinal cytomegalovirus infection]. AB - OBJECTIVE: To investigate the clinical and pathologic features of gastrointestinal cytomegalovirus (CMV) disease, and the histological detection of CMV. METHODS: Forty-one gastrointestinal tissues were obtained from 35 patients suspected for gastrointestinal CMV disease. The pathologic changes of these specimens were evaluated by immunohistochemistry and in situ hybridization for CMV, and these were compared to serologic detection methods. RESULTS: CMV was detected in 23/41 tissues. There were 32 serologic CMV DNA tests at the time of biopsies or operations. Compared with histological detection, the sensitivity and specificity of serologic CMV DNA tests were 73.7% and 69.2% respectively. CONCLUSIONS: Gastrointestinal histological detection of CMV has important clinical application. HE staining combined with immunohistochemistry and/or in situ hybridization detection is a reliable method to detect CMV. PMID- 26956962 TI - [Combined hepatocellular-cholangiocarcinoma (cholangiolocellular type) with stem cell features: a clinicopathologic analysis of 26 cases]. AB - OBJECTIVE: To study the clinicopathologic features of combined hepatocellular cholangiocarcinoma (cholangiolocellular type, CLC type) with stem cell features and its relationship to hepatic progenitor cells (HPCs). METHODS: Clinical and histologic features of 26 cases of combined hepatocellular-cholangiocarcinoma (CLC type) were reviewed. Histochemistry was performed to confirm the type of mucin and immunohistochemical study was carried out for hepatocytic markers (Hep Par-1 and AFP) and biliary/HPCs markers (CK7, CK9, EMA, EpCAM, NCAM, CKIT). RESULTS: The age of patients ranged from 51 to 82 years (mean 64 years). All 26 cases contained CLC and hepatocellular carcinoma components. CLC area was composed of mixtures of small monotonous glands with abundant fibrous stroma and lymphocytic infiltrate. Tumor cells were cuboidal, smaller in size than normal hepatocytes, with basophilic cytoplasm and round nuclei. All cases, especially at the tumor boundary, showed HCC-like trabecular areas characterized by mildly atypical tumor cells with abundant eosinophilic cytoplasm and little stroma. Out of 26 cases, 21 showed definite glandular formation with mucin production, representing intrahepatic cholangiocarcinoma areas. The three distinct areas showed transitional zones merging with each other. The surrounding liver tissue showed cirrhosis and chronic hepatitis with varying degrees of fibrosis and periportal ductular reaction. Immunohistochemistry showed that biliary/HPC markers (CK7, CK9, EMA, EpCAM, NCAM and CKIT) were strongly positive in CLC area in almost all cases, similar to the staining pattern of ductular reaction. In HCC like areas, CK7 and CK19 were positive in all cases and the expression rates of EMA, EpCAM, NCAM, CKIT, AFP, Hep Par-1 were 80.8% (21/26), 88.5% (23/26), 84.6% (22/26), 88.5% (23/26), 46.2% (12/26) and 53.8% (14/26) respectively, similar to the staining pattern of intermediate hepatocytes. In ICC areas, CK7, CK9, EMA and EpCAM were positive in all cases without the expression of NCAM and CKIT. CONCLUSION: The clinicopathologic findings and immunohistochemical results in this study highly suggest a hepatic progenitor cell origin of combined hepatocellular-cholangiocarcinoma (CLC type). PMID- 26956964 TI - [Autopsy findings of 19 cases of pulmonary vein abnormalities associated with fetal cardiac anomalies]. AB - OBJECTIVE: To improve the diagnostic accuracy of fetal pulmonary venous abnormalities through the analysis of the fetal pulmonary vein anatomy. METHODS: 234 cases of congenital cardiac abnormalities were detected by echocardiography during pregnancy in An Zhen Hospital, Capital Medical University from May 2010 to August 2015. Autopsy was then performed. The type of fetal pulmonary venous malformation, cardiac abnormalities, systemic venous malformations, and other internal organs deformities were documented. RESULTS: There were ninteen cases of pulmonary venous malformations among the 234 cases of fetal congenital heart disease. These included two cases of congenital pulmonary venous hypoplasia (CPVH) or atresia, four cases of partial anomalous pulmonary venous drainage (PAPVD), seven cases of total anomalous pulmonary venous drainage (TAPVD), five cases of atresia of common pulmonary vein (CPV), one case of congenital pulmonary venous hypoplasia with total anomalous pulmonary venous drainage. There were eleven cases with single ventricle, eight cases with right aortic arch, seven cases with single atrium and six cases with pulmonary valve stenosis. Eleven cases had pulmonary hypoplasia and nine cases had abnormal spleen. CONCLUSIONS: There are many variations in pulmonary venous abnormalities associated with severe and complex cardiac abnormalities and internal organs malformation. Care should be exercised during autopsy examination to look for all branches of the pulmonary vein. PMID- 26956965 TI - [Clinicopathologic analysis of angiofibroma of soft tissue: report of 3 cases]. PMID- 26956963 TI - [IgG4-related sialodacryoadenitis and chronic rhinosinusitis: a clinicopathologic analysis of 13 cases]. AB - OBJECTIVE: To study the clinicopathologic characteristics of IgG4-related sialodacryoadenitis and chronic rhinosinusitis (CRS). METHODS: A total of 13 patients (patient group) were evaluated clinically and biopsy specimens from the lacrimal/salivary glands (n=12) and nasal mucosa (n=8) were reviewed and immunohistochemistry was performed to assess IgG-and IgG4-positive cells. Similarly, nine patients with IgG4-related sialodacryoadenitis without CRS and 10 patients with common CRS were included as controls. RESULTS: There were 8 male patients and 5 female patients. The age of patients ranged from 32 to 71 years (mean 50.2 years). The patient group had higher serum IgG4 concentration than that of the control group (P<0.05). Lymphoplasmacytic infiltration, lymphoid follicle formation and sclerosis were prominent in lacrimal/salivary glands in both groups; however the magnitude of IgG4-positive plasmacytic infiltration in the patient group was significantly higher than that of the control group (P<0.05). Similarly, evaluation of nasal mucosa revealed greater lymphocytic and plasmacytic infiltration, and lymphoid follicle formation, together with significantly higher amount of IgG4-positive plasma cell infiltration in the patient group compared to the common CRS group (P<0.05). CONCLUSIONS: IgG4 related disease (IgG4-RD) simultaneously involving lacrimal/salivary glands and nasal cavity/paranasal sinuses is rare and characterized by a combination of IgG4 positive plasma cell infiltration involving lacrimal/salivary glands and nasal mucosa along with an increased serum level of IgG4. As a systemic disease, early and accurate diagnosis is therefore of great importance, and unnecessary surgery should be avoided. PMID- 26956966 TI - [Primary mesenteric Castleman disease complicated follicular dendritic cell sarcoma: report of a case]. PMID- 26956967 TI - [Endometrial carcinoma with trophoblastic differentiation: report of a case]. PMID- 26956968 TI - [Clinicopathologic features of the newly understood and rare gastric disease]. PMID- 26956969 TI - [Intraductal papillary mucinous neoplasms of the pancreas: analysis of clinicopathologic features and prognosis]. PMID- 26956970 TI - [Advances in the study of cMET in gastric cancer]. PMID- 26956971 TI - [Advances in molecular biology of esophageal squamous cell carcinoma]. PMID- 26956972 TI - Erratum to: Loss of glucocorticoid receptor activation is a hallmark of BRCA1 mutated breast tissue. AB - Erratum to: Breast Cancer Res Treat (2013),142:283-296,DOI 10.1007/s10549-013 2722-8. In the original publication of the article, the blot corresponding to the total P38 protein content for the conditions siCtl and siBRCA1 in Fig. 7a was incorrectly laid out. The corrected Fig. 7a is given in this erratum.The PMID- 26956973 TI - Tristetraprolin mediates the anti-proliferative effects of metformin in breast cancer cells. AB - Metformin, which is a drug commonly prescribed to treat type 2 diabetes, has anti proliferative effects in cancer cells; however, the molecular mechanisms underlying this effect remain largely unknown. The aim is to investigate the role of tristetraprolin (TTP), an AU-rich element-binding protein, in anti proliferative effects of metformin in cancer cells. p53 wild-type and p53 mutant breast cancer cells were treated with metformin, and expression of TTP and c-Myc was analyzed by semi-quantitative RT-PCR, Western blots, and promoter activity assay. Breast cancer cells were transfected with siRNA against TTP to inhibit TTP expression or c-Myc and, after metformin treatment, analyzed for cell proliferation by MTS assay. Metformin induces the expression of tristetraprolin (TTP) in breast cancer cells in a p53-independent manner. Importantly, inhibition of TTP abrogated the anti-proliferation effect of metformin. We observed that metformin decreased c-Myc levels, and ectopic expression of c-Myc blocked the effect of metformin on TTP expression and cell proliferation. Our data indicate that metformin induces TTP expression by reducing the expression of c-Myc, suggesting a new model whereby TTP acts as a mediator of metformin's anti proliferative activity in cancer cells. PMID- 26956974 TI - MSCs and inflammation: new insights into the potential association between ALCL and breast implants. AB - Possible association between anaplastic large cell lymphoma (ALCL) and breast implants has been suggested. In this context, formation of the periprosthetic capsule has been reported as a cause of inflammation, which plays a key role in tumor onset. Tumors take advantage of inflammation to influence and interfere with the host immune response by secreting multiple factors, and their onset and survival is in turn affected by the paracrine effects from mesenchymal stem cells (MSCs). In this study, we tried to clarify how inflammation can modify the immunobiology and the exerted paracrine effect of MSCs. MSCs derived from both inflamed (I-MSCs) and control (C-MSCs) tissues were isolated and co-cultured with an ALCL cell line. Proliferation rate and the expression of selected cytokines were tested. I-MSCs secrete higher levels of cytokine related to chronic inflammation than C-MSCs. After co-cultures with KI-JK cells, C- and I-MSCs show the same variation in the cytokine expression, with an increase of IL2, IL4, IL5, IL10, IL13, TNF-alpha, TGF-beta, and G-CSF. Proliferation of ALCL cells was not influenced by co-cultures. Our results state that (i) inflamed microenvironment affects the immunobiology of MSCs modifying the profile of the expressed cytokines, and (ii) the paracrine effects exerted by MSCs on ALCL cells are not influenced by inflammation. Moreover, it seems that ALCL cells are able to manipulate MSCs' immunoregulatory properties to evade the host immune control. Nevertheless, this ability is not associated with inflammation and the question about BIA-ALCL is not proved by our experiments. PMID- 26956975 TI - Toll-like receptor signalling in regenerative myogenesis: friend and foe. AB - Skeletal muscle regeneration in normal and diseased muscle is regulated by multiple factors and cells present in the injured muscle micro-environment. In addition to muscle progenitor cells, several immunocytes participate in the regenerative response. Among them, macrophages are one of the most important components of the immune response that governs the step-wise progression of muscle regeneration. The initial role of macrophages is to phagocytose muscle cell debris and later, through their transition to an anti-inflammatory phenotype, they promote regeneration. However, in several genetic muscle disorders, continuous muscle injury disrupts the balance between pro-inflammatory and anti-inflammatory macrophages, leading to an overall inflammatory milieu and inhibition of muscle regeneration. Accumulating evidence suggests that Toll-like receptor (TLR)-mediated signalling plays an important role in the regulation of macrophage phenotypes during regenerative myogenesis in response to both acute and chronic muscle injury. Here, we discuss the role of TLR signalling in regulating macrophage phenotypes and skeletal muscle regeneration in healthy and diseased muscle. Copyright (c) 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 26956977 TI - Post-mortem Takotsubo cardiomyopathy diagnosis: the challenge is open! PMID- 26956976 TI - Abnormal Tilt Perception During Centrifugation in Patients with Vestibular Migraine. AB - Vestibular migraine (VM), defined as vestibular symptoms caused by migraine mechanisms, is very common but poorly understood. Because dizziness is often provoked in VM patients when the semicircular canals and otolith organs are stimulated concurrently (e.g., tilting the head relative to gravity), we measured tilt perception and eye movements in patients with VM and in migraine and normal control subjects during fixed-radius centrifugation, a paradigm that simultaneously modulates afferent signals from the semicircular canals and otoliths organs. Twenty-four patients (8 in each category) were tested with a motion paradigm that generated an inter-aural centrifugal force of 0.36 G, resulting in a 20 degrees tilt of the gravito-inertial force in the roll plane. We found that percepts of roll tilt developed slower in VM patients than in the two control groups, but that eye movement responses, including the shift in the eye's rotational axis, were equivalent in all three groups. These results demonstrate a change in vestibular perception in VM that is unaccompanied by changes in vestibular-mediated eye movements and suggest that either the brain's integration of canal and otolith signals or the dynamics of otolith responses are aberrant in patients with VM. PMID- 26956978 TI - Cardiac troponin T determination by a highly sensitive assay in postmortem serum and pericardial fluid. AB - PURPOSE: The main objective of this study was to test, for the first time, a highly sensitive cardiac troponin T (cTnThs) assay in postmortem serum and pericardial fluid and to evaluate cardiac troponin T (cTnT) levels and their stability after death at different postmortem intervals, in an attempt to determine the viability of the cTnThs assay in the postmortem diagnosis of the cause of death. METHODS: cTnT levels were determined in serum and pericardial fluid samples taken from 58 cadavers at known postmortem intervals, whose causes of death were categorized into the following groups: (1) sudden cardiac deaths, (2) multiple trauma, (3) mechanical asphyxia, and (4) other natural deaths. cTnT was determined by inmunoassay, using the Troponin T highly sensitive STAT assay (Roche((r))). RESULTS: Average cTnT levels measured by a highly sensitive assay in postmortem serum were markedly higher than clinical serum levels. Moreover, similar results, higher cTnT levels in postmortem pericardial fluid, were obtained when compared to levels found in pericardial fluid taken from two living patients during coronary artery bypass surgery. cTnT levels in both postmortem fluids remained stable for up to 34 h after death. No differences in cTnT levels in either postmortem fluid by sex and age were detected. Levels of cTnT found in pericardial fluid in the other natural deaths group were significantly lower than the cTnT levels found in that postmortem fluid from any of the other causes of death groups. CONCLUSION: It is therefore reasonable to conclude that determination of cTnT by a highly sensitive assay in pericardial fluid can provide forensic pathologists with a complementary test to the diagnosis of cause of death. PMID- 26956979 TI - Neuroticism and extraversion in relation to physiological stress reactivity during adolescence. AB - The current study examined mean level and change in extraversion and neuroticism across adolescence in relation to physiological stress reactivity to social evaluation. Adolescents (n=327) from the Dutch general population reported on personality measures at five annual assessments. At age 17 years, adolescents participated in a psychosocial stress procedure characterized by social evaluation during which cortisol, heart rate, pre-ejection period (PEP) and heart rate variability were assessed. Dual latent growth curve models were fitted in which the intercepts (mean level) and slopes (change) of personality across adolescence predicted the intercepts (baseline) and slopes (reactivity) of the physiological stress measures. Most comparisons revealed no relation between personality and stress reactivity. Adolescents with higher mean level scores on extraversion did show lower cortisol reactivity. Adolescents with higher mean level neuroticism scores showed higher PEP reactivity. Our findings lend partial support for a relation between personality and physiological stress reactivity. PMID- 26956980 TI - A new graft material for myringoplasty: bacterial cellulose. AB - We aimed to determine the success rate of bacterial cellulose (BC) myringoplasty in tympanic membrane (TM) perforation. We reviewed the clinical records of 12 patients (16 ears) who underwent BC myringoplasty for long-standing TM perforations (>6 months) between March 2012 and January 2015. The mean duration of postoperative follow-up was 12.8 (range 6-24) months. In all patients, the perforation involved less than 50 % of the tympanic membrane, and the air-bone gap was <=30 dB on the operative side. The age, gender, preoperative air average, bone average, air-bone gap, perforation size and location, and postoperative TM microscopic examinations of the patients were recorded. Following the BC myringoplasty, complete coverage of the perforation occurred in the first 6 months in 13 of 16 ears (81.3 %), although retraction occurred in two of these ears within 6 months. In three ears (18.8 %), the perforation persisted during the first postoperative month. The pre- and postoperative average air threshold was 19.56 (range 7-75) and 15.69 (range 5-75) dB, respectively. The pre- and postoperative average air-bone gap was 9.25 (range 0-25) and 5.63 (0-25) dB, respectively. Both the air threshold and air-bone gap improved postoperatively (both p = 0.008). No complications such as infection and granulation tissue formation were detected in any patient. BC is a safe graft material that is inexpensive, easy-to-use, and provides a high success rate in small tympanic membrane perforations. However, further studies of large tympanic membrane perforations with more samples and long-term follow-up are required. PMID- 26956981 TI - Pharyngocutaneous fistula: the incidence and the risk factors. AB - A pharyngocutaneous fistula is the most common complication following laryngectomy. A wide range of potential risk factors has been suggested. The purpose of this study was to determine the incidence and risk factors for the fistula at the Department of Otorhinolaryngology and Head and Neck Surgery in Ljubljana, Slovenia between 2007 and 2012. Charts from patients treated for head and neck cancer by laryngectomy were retrospectively reviewed. Comprehensive clinicopathologic data were collected including potential risk factors related to the patient, disease, surgery and postoperative period. The patients were categorised into the group with the fistula (a study group) and without it (a control group). The incidence of the fistula was calculated and the groups were statistically compared according to potential risk factors using the Chi square test, Fisher exact test, T test, Mann-Whitney U test and binary logistic regression analysis. Hundred fifty-eight patients were included. The incidence of the fistula was 30.4 %. In the primary laryngectomy group the incidence was 22.6 %, whereas in the salvage laryngectomy group 44.6 % (p = 0.006). The independent predictors for the fistula were history of head and neck cancer (p = 0.001), invasion of piriform sinus (p = 0.020) and surgical wound infection (p < 0.001). The timing of surgical wound infection could be of some importance. In the PCF group, it started on the 5th postoperative day, whereas in the control group on the 7th postoperative day (p = 0.063). Decreasing the rate of surgical wound infection could diminish the fistula rate. PMID- 26956982 TI - True bilateral nasopharyngeal angiofibroma: report and review. AB - This report describes the third case of a true bilateral Juvenile nasopharyngeal angiofibroma (JNA), i.e. two separate JNA arising from both sides simultaneously. The associated multiple recurrences in such a case have not yet been reported. A 21-year-man underwent transpalatal excision and recurred twice. The last 'neo occurrence' encountered after 2 years was at a different site and was subsequently managed by post-embolization endoscopic resection. A complete report of its clinico-radiological features and management outcome is discussed. PMID- 26956983 TI - Clean intermittent catheterization revisited. AB - Catheterization is the insertion of a hollow flexible tube (called a catheter) to drain the urine from the bladder and is probably one of the oldest urologic procedures, dating back 3000 years. Since 1972, when urologist Dr Jack Lapides described a procedure for performing clean intermittent catheterization, this method of bladder management has become lifesaving for an individual who cannot empty their bladder independently. If the bladder is not emptied regularly, elevated storage pressures can develop which may put the upper tracts at risk of subsequent deterioration. Intermittent catheterization (IC) has become the first line and preferred method of drainage in patients with neurogenic lower urinary tract dysfunction, as long as dexterity or available caregiver support and body habitus allow access. However, over the past 20 years, an evolution has occurred in the technology of catheters used for IC. But with these advances, so has controversy arisen. This article is a review of the current application of IC, the current technology in catheter material and systems, differences between reusable and one-time, or single-use catheters, the cost benefit of doing IC, and the infectious benefit. PMID- 26956985 TI - Medicinal Chemistry of Hepatitis C Virus: Current and Future Perspective. PMID- 26956984 TI - Height, body mass index, and socioeconomic status: mendelian randomisation study in UK Biobank. AB - OBJECTIVE: To determine whether height and body mass index (BMI) have a causal role in five measures of socioeconomic status. DESIGN: Mendelian randomisation study to test for causal effects of differences in stature and BMI on five measures of socioeconomic status. Mendelian randomisation exploits the fact that genotypes are randomly assigned at conception and thus not confounded by non genetic factors. SETTING: UK Biobank. PARTICIPANTS: 119,669 men and women of British ancestry, aged between 37 and 73 years. MAIN OUTCOME MEASURES: Age completed full time education, degree level education, job class, annual household income, and Townsend deprivation index. RESULTS: In the UK Biobank study, shorter stature and higher BMI were observationally associated with several measures of lower socioeconomic status. The associations between shorter stature and lower socioeconomic status tended to be stronger in men, and the associations between higher BMI and lower socioeconomic status tended to be stronger in women. For example, a 1 standard deviation (SD) higher BMI was associated with a L210 (?276; $300; 95% confidence interval L84 to L420; P=6 * 10(-3)) lower annual household income in men and a L1890 (L1680 to L2100; P=6 * 10(-15)) lower annual household income in women. Genetic analysis provided evidence that these associations were partly causal. A genetically determined 1 SD (6.3 cm) taller stature caused a 0.06 (0.02 to 0.09) year older age of completing full time education (P=0.01), a 1.12 (1.07 to 1.18) times higher odds of working in a skilled profession (P=6 * 10(-7)), and a L1130 (L680 to L1580) higher annual household income (P=4 * 10(-8)). Associations were stronger in men. A genetically determined 1 SD higher BMI (4.6 kg/m(2)) caused a L2940 (L1680 to L4200; P=1 * 10(-5)) lower annual household income and a 0.10 (0.04 to 0.16) SD (P=0.001) higher level of deprivation in women only. CONCLUSIONS: These data support evidence that height and BMI play an important partial role in determining several aspects of a person's socioeconomic status, especially women's BMI for income and deprivation and men's height for education, income, and job class. These findings have important social and health implications, supporting evidence that overweight people, especially women, are at a disadvantage and that taller people, especially men, are at an advantage. PMID- 26956986 TI - Medical specialty certification in the United States-a false idol? AB - PURPOSE: Recent changes to medical specialty certification in the USA have prompted the process to come under intense scrutiny. METHODS: We review the history of board certification and the changes made to the process. As part of this review, we examine both literature and public record to examine the motives behind the changes made. We then review the legal challenges and changes under way to modify the current ABMS board re-certification process. RESULTS: In 1917, the first board certification was a lifetime designation, voluntary, and managed by unpaid board members with a focus to enhance quality for patients. Corresponding to the implementation of time-limited certification, $55 million of physician testing fees were transferred from the American Board of Internal Medicine to its Foundation between 1989 and 1999. From 2000 through 2007, and additional $20.66 million were transferred from the ABIM to its Foundation culminating in the purchase of a $2.3 million luxury condominium in December 2007. CONCLUSIONS: Significant financial conflicts of interest for the implementation of time-limited specialty certification exited and continue to plague the medical profession. The specialty boards and the organizations that created them should remove all requirements for time-limited board certification and resort to conventional self-selected ACGME-approved CME programs for ongoing education. PMID- 26956989 TI - Erratum to: Tachyarrhythmia in patients with congenital heart disease: inevitable destiny. PMID- 26956988 TI - Self-Consent for HIV Prevention Research Involving Sexual and Gender Minority Youth: Reducing Barriers Through Evidence-Based Ethics. AB - This project examined the attitudes of sexual and gender minority youth (SGMY) toward guardian permission for a pre-exposure prophylaxis (PrEP) adherence trial and their preparedness to provide informed, rational, and voluntary self-consent. Sixty sexually active SGMY (ages 14-17) participated in online survey and asynchronous focus group questions after watching a video describing a PrEP adherence study. Youth responses highlighted guardian permission as a significant barrier to research participation, especially for those not "out" to families. Youth demonstrated understanding of research benefits, medical side effects, confidentiality risks, and random assignment and felt comfortable asking questions and declining participation. Reasoning about participation indicated consideration of health risks and benefits, personal sexual behavior, ability to take pills every day, logistics, and post-trial access to PrEP. Results demonstrate youth's ability to self-consent to age- and population-appropriate procedures, and underscore the value of empirical studies for informing institutional review board (IRB) protections of SGMY research participants. PMID- 26956987 TI - The functional and clinical outcomes of exercise training following a very low energy diet for severely obese women: study protocol for a randomised controlled trial. AB - BACKGROUND: Clinical practice guidelines globally recommend lifestyle modification including diet and exercise training as first-line treatment for obesity. The clinical benefits of exercise training in adults with obesity is well-documented; however, there is no strong evidence for the effectiveness of exercise training for weight loss in class II and class III obesity. The purpose of the randomised controlled trial described in this protocol article is to examine the effect of exercise training, in addition to a very low energy diet (VLED), in clinically severe obese women for changes in body composition, physical function, quality of life, and markers of cardiometabolic risk. METHODS/DESIGN: Sixty women, aged 18-50 years with a body mass index (BMI) greater than 34.9 kg.m(2) and at least one obesity-related co-morbidity, will be recruited for this 12-month study. Participants will be randomised to either exercise plus energy restriction (n = 30), or energy restriction alone (n = 30). All participants will follow an energy-restricted individualised diet incorporating a VLED component. The exercise intervention group will also receive exercise by supervised aerobic and resistance training and a home-based exercise programme totalling 300 minutes per week. Primary outcome measures include body composition and aerobic fitness. Secondary outcome measures include: physical function, cardiometabolic risk factors, quality of life, physical activity, and mental health. All outcome measures will be conducted at baseline, 3, 6 and 12 months. DISCUSSION: Previous research demonstrates various health benefits of including exercise training as part of a healthy lifestyle at all BMI ranges. Although clinical practice guidelines recommend exercise training as part of first-line treatment for overweight and obesity, there are few studies that demonstrate the effectiveness of exercise in class II and class III obesity. The study aims to determine whether the addition of exercise training to a VLED provides more favourable improvements in body composition, physical function, quality of life, and markers of cardiometabolic risk for women with clinically severe obesity, compared to VLED alone. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ( ACTRN12611000694910 ). Date registered: 4 July 2011. PMID- 26956990 TI - Massive obesity and hyperphagia in posterior bilateral periventricular heterotopias: case report. AB - BACKGROUND: Bilateral posterior periventricular nodular heterotopia PNH is a complex malformation of cortical development with imaging features distinguishing it from classic bilateral PNH associated with filamin (FLNA) mutations. It distinctively consists of variably sized nodules of neurons along the trigones and temporal or occipital horns of the lateral ventricles and spectrum of developmental disorders of the mid-/hindbrain. This association suggests that pPNH is part of a more diffuse process of posterior or infrasylvian brain developmental abnormalities other than just a disorder of neuronal migration. CASE PRESENTATION: This report describes the first case of an Italian young girl featuring pPNH and severe hyperphagic obesity. At the time of our first examination at age 3 years of age she was severely obese (body mass index, BMI 45.9 Kg/m(2)) and food-seeking behavior in the free-living situation was reported by the relatives. She showed normal linear growth and cognition, but mildly dysmorphic facial traits including deeply-set eyes, prominent zygomatic bones, downturned mouth corners and low-set ears. Over the years, the patient progressively developed further massive weight gain (at age 9 years, her BMI was 60.4 Kg/m(2)) and hyperphagia was confirmed by an ad libitum test meal. During follow-up, she presented limitations in walking capacity and in physical functioning due to the disabling obesity. On the basis of distinctive neuro radiological findings pPNH was diagnosed, in absence of history of seizures. CONCLUSION: The present case may contribute to the expansion of the phenotypic expressions of this distinctive complex malformation. PMID- 26956993 TI - A U-shaped relationship between alcohol consumption and cardiometabolic index in middle-aged men. AB - BACKGROUND: Cardiometabolic index (CMI) is a new index for discriminating diabetes. The purpose of this study was to determine whether CMI is affected by habitual alcohol drinking. METHODS: The subjects were 21572 men (35-60 years) receiving annual health checkups. They were divided by average daily ethanol consumption into non-, light (< 22 g), moderate (>= 22 and < 44 g), heavy (>= 44 and < 66 g) and very heavy (>= 66 g) drinkers. Relationship between alcohol intake and CMI was investigated with adjustment for age and histories of smoking and regular exercise. RESULTS: Log-transformed CMI was significantly lower in light, moderate and heavy drinkers than in nondrinkers and was lowest in light drinkers, while there was no significant difference in log-transformed CMI of nondrinkers and very heavy drinkers. Odds ratio vs. nondrinkers for high CMI was significantly lower than the reference level of 1.00 in light, moderate and heavy drinkers and was lowest in light drinkers but was not significantly different from the reference level in very heavy drinkers. Odds ratio of subjects with vs. those without high CMI for hyperglycemia was significantly higher than the reference level in all of the alcohol groups and was significantly lower in moderate drinkers but was not significantly different in the other drinker groups when compared with the nondrinker group. CONCLUSION: There is a U-shaped relationship between alcohol consumption and CMI, and moderate drinking but not excessive drinking attenuates the association between CMI and hyperglycemia. PMID- 26956991 TI - Sleep disturbance as detected by actigraphy in pre-pubertal juvenile monkeys receiving therapeutic doses of fluoxetine. AB - Sleep disturbance is a reported side effect of antidepressant drugs in children. Using a nonhuman primate model of childhood selective serotonin reuptake inhibitor (SSRI) therapy, sleep was studied quantitatively with actigraphy. Two 48-h sessions were recorded in the home cage environment of juvenile male rhesus monkeys at two and three years of age, after one and two years of treatment with a therapeutic dose of the SSRI fluoxetine, and compared to vehicle treated controls. A third session was conducted one year after discontinuation of treatment at four years of age. During treatment, the fluoxetine group demonstrated sleep fragmentation as indexed by a greater number of rest-activity transitions compared to controls. In addition fluoxetine led to more inactivity during the day as indexed by longer duration of rest periods and the reduced activity during these periods. The fluoxetine effect on sleep fragmentation, but not on daytime rest, was modified by the monkey's genotype for polymorphisms of monoamine oxidase A (MAOA), an enzyme that metabolizes serotonin. After treatment, the fluoxetine effect on nighttime rest-activity transitions persisted, but daytime activity was not affected. The demonstration in this nonhuman primate model of sleep disturbance in connection with fluoxetine treatment and specific genetic polymorphisms, and in the absence of diagnosed psychopathology, can help inform use of this drug in children. PMID- 26956994 TI - Auditory functional magnetic resonance in awake (nonsedated) and propofol-sedated children. AB - BACKGROUND: Functional Magnetic Resonance Imaging (fMRI) is often used in preoperative assessment before epilepsy surgery, tumor or cavernous malformation resection, or cochlear implantation. As it requires complete immobility, sedation is needed for uncooperative patients. OBJECTIVE: The aim of this study was to compare the fMRI cortical activation pattern after auditory stimuli in propofol sedated 5- to 8-year-old children with that of similarly aged nonsedated children. METHODS: When possible, children underwent MRI without sedation, otherwise it was induced with i.v. propofol 2 mg.kg(-1) and maintained with i.v. propofol 4-5 mg.kg(-1) .h(-1) . Following diagnostic MRI, fMRi was carried out, randomly alternating two passive listening tasks (a fairy-tale and nonsense syllables). RESULTS: We studied 14 awake and 15 sedated children. During the fairy-tale task, the nonsedated children's blood-oxygen-level-dependent (BOLD) signal was bilaterally present in the posterior superior temporal gyrus (STG), Wernicke's area, and Broca's area. Sedated children showed similar activation, with lesser extension to Wernicke's area, and no activation in Broca's area. During the syllable task, the nonsedated children's BOLD signal was bilaterally observed in the STG and Wernicke's area, in Broca's area with leftward asymmetry, and in the premotor area. In sedated children, cortical activation was present in the STG, but not in the frontal lobes. BOLD signal change areas in sedated children were less extended than in nonsedated children during both the fairy tale and syllable tasks. Modeling the temporal derivative during both the fairy tale and syllable tasks, nonsedated children showed no response while sedated children did. CONCLUSIONS: After auditory stimuli, propofol-sedated 5- to 8-year old children exhibit an fMRI cortical activation pattern which is different from that in similarly aged nonsedated children. PMID- 26956997 TI - Model of THz Magnetization Dynamics. AB - Magnetization dynamics can be coherently controlled by THz laser excitation, which can be applied in ultrafast magnetization control and switching. Here, transient magnetization dynamics are calculated for excitation with THz magnetic field pulses. We use the ansatz of Smit and Beljers, to formulate dynamic properties of the magnetization via partial derivatives of the samples free energy density, and extend it to solve the Landau-Lifshitz-equation to obtain the THz transients of the magnetization. The model is used to determine the magnetization response to ultrafast multi- and single-cycle THz pulses. Control of the magnetization trajectory by utilizing the THz pulse shape and polarization is demonstrated. PMID- 26956996 TI - Cas3 is a limiting factor for CRISPR-Cas immunity in Escherichia coli cells lacking H-NS. AB - BACKGROUND: CRISPR-Cas systems provide adaptive immunity to mobile genetic elements in prokaryotes. In many bacteria, including E. coli, a specialized ribonucleoprotein complex called Cascade enacts immunity by" an interference reaction" between CRISPR encoded RNA (crRNA) and invader DNA sequences called "protospacers". Cascade recognizes invader DNA via short "protospacer adjacent motif" (PAM) sequences and crRNA-DNA complementarity. This triggers degradation of invader DNA by Cas3 protein and in some circumstances stimulates capture of new invader DNA protospacers for incorporation into CRISPR as "spacers" by Cas1 and Cas2 proteins, thus enhancing immunity. Co-expression of Cascade, Cas3 and crRNA is effective at giving E. coli cells resistance to phage lysis, if a transcriptional repressor of Cascade and CRISPR, H-NS, is inactivated (Deltahns). We present further genetic analyses of the regulation of CRISPR-Cas mediated phage resistance in Deltahns E. coli cells. RESULTS: We observed that E. coli Type I-E CRISPR-Cas mediated resistance to phage lambda was strongly temperature dependent, when repeating previously published experimental procedures. Further genetic analyses highlighted the importance of culture conditions for controlling the extent of CRISPR immunity in E. coli. These data identified that expression levels of cas3 is an important limiting factor for successful resistance to phage. Significantly, we describe the new identification that cas3 is also under transcriptional control by H-NS but that this is exerted only in stationary phase cells. CONCLUSIONS: Regulation of cas3 is responsive to phase of growth, and to growth temperature in E. coli, impacting on the efficacy of CRISPR-Cas immunity in these experimental systems. PMID- 26956998 TI - Suppression of A549 cell proliferation and metastasis by calycosin via inhibition of the PKC-alpha/ERK1/2 pathway: An in vitro investigation. PMID- 26956995 TI - When parents face the death of their child: a nationwide cross-sectional survey of parental perspectives on their child's end-of life care. AB - BACKGROUND: Parents facing the death of their child have a strong need for compassionate professional support. Care services should be based on empirical evidence, be sensitive to the needs of the families concerned, take into account the heterogeneity within the medical field of paediatrics, and fit into the local health care system. We need to better understand the perspectives of parents facing the death of their child in order to guide further development and evaluation of specialised paediatric palliative and end-of-life (EOL) care services. METHODS: Questionnaire survey to assess the EOL care perspectives of a Swiss population-based sample of bereaved parents who had lost a child due to a cardiac, neurological or oncological condition, or during the neonatal period in the years 2011 or 2012. The parental perspective was assessed with a newly developed and tested instrument that was structured according to six evidence based quality domains. Responses regarding parental experiences and perceived satisfaction are described. Differences between the four diagnostic groups are analysed using a generalized estimation equation to account for the dyadic data structure. RESULTS: Of 307 eligible families, 267 could be contacted and 135 (51%) consented to participate in this questionnaire survey. Our findings show positive parental experiences of their child's EOL care and high perceived satisfaction with the care their child received. Parents of a child with cancer rated their experiences highest in most of the six quality domains and reported the highest satisfaction with care. The lowest scores were mainly reported by parents from the neurology group, with the exception of the shared decision making domain, where parents of neonates reported significantly less positive experiences. CONCLUSIONS: Although positive in general, our study results suggest some areas for improvement. The integration of specialised paediatric palliative care has the potential to minimise lost opportunities to support and assist parents. PMID- 26956999 TI - Painless legs and moving toes syndrome associated with a sacral Tarlov cyst: a case report. AB - BACKGROUND: Painless legs and moving toes syndrome is a very rare syndrome characterized by continuous and involuntary movement of the toes. The etiology of the disease is not clear though it has been linked to a wide range of neuronal insults including proximal root compression and neuropathy. A previous study has reported bilateral painful legs and moving toes syndrome in a patient with a sacral Tarlov cyst. In this report we present a case of unilateral painless legs and moving toes syndrome in a woman with a sacral Tarlov cyst. CASE PRESENTATION: A 50-year-old Mediterranean woman presented with a 1-year history of involuntary sustained movement of her right toes. Her physical examination and laboratory findings did not show any remarkable abnormality. Her lumbosacral magnetic resonance imaging scan showed a sacral Tarlov cyst. Our patient was given gabapentin, 100 mg per day as a starting dose, and showed modest improvement. Our patient preferred not to continue with the treatment as her symptoms were not disabling and she was only concerned about the cosmetic appearance. CONCLUSIONS: This report presents a new case of a very rare syndrome called painless legs and moving toes syndrome, which is possibly a variant of painful legs and moving toes syndrome. This is considered to be the first case of unilateral painless legs and moving toes syndrome that is associated with a sacral Tarlov cyst. Although the disease etiology is still unknown and the presence of the cyst can be accidental, neurologists should be aware that Tarlov cyst is a possible cause. In addition, patients with the painless variant who are not disabled by movement of the toes may not require treatment. PMID- 26957000 TI - OH-PRED: prediction of protein hydroxylation sites by incorporating adapted normal distribution bi-profile Bayes feature extraction and physicochemical properties of amino acids. AB - Hydroxylation of proline or lysine residues in proteins is a common post translational modification event, and such modifications are found in many physiological and pathological processes. Nonetheless, the exact molecular mechanism of hydroxylation remains under investigation. Because experimental identification of hydroxylation is time-consuming and expensive, bioinformatics tools with high accuracy represent desirable alternatives for large-scale rapid identification of protein hydroxylation sites. In view of this, we developed a supporter vector machine-based tool, OH-PRED, for the prediction of protein hydroxylation sites using the adapted normal distribution bi-profile Bayes feature extraction in combination with the physicochemical property indexes of the amino acids. In a jackknife cross validation, OH-PRED yields an accuracy of 91.88% and a Matthew's correlation coefficient (MCC) of 0.838 for the prediction of hydroxyproline sites, and yields an accuracy of 97.42% and a MCC of 0.949 for the prediction of hydroxylysine sites. These results demonstrate that OH-PRED increased significantly the prediction accuracy of hydroxyproline and hydroxylysine sites by 7.37 and 14.09%, respectively, when compared with the latest predictor PredHydroxy. In independent tests, OH-PRED also outperforms previously published methods. PMID- 26957001 TI - Renal and retroperitoneal metastasis from prostate adenocarcinoma: a case report. AB - BACKGROUND: Diffuse renal and retroperitoneal metastasis of prostatic origin is an uncommon spread pattern of prostate cancer. CASE PRESENTATION: We described a 74-year-old male patient who was admitted because of dysuria and nocturia. Physical examination and imaging study indicated prostate mass, and laboratory analysis revealed elevated prostate specific antigen (PSA). The diagnosis of prostate cancer was established after biopsy. In the further evaluation, diffuse renal and retroperitoneal metastasis of prostate cancer was confirmed. Radiotherapy combined with endocrine therapy was given. CONCLUSIONS: Our present case emphasized that the routine metastatic work-up was quite necessary, since a small proportion of men with advanced prostate cancer might experience metastases in atypical sites. PMID- 26957003 TI - MRI and FDG-PET/CT imaging in gynecological malignancies: the radiation oncology perspective. AB - MRI and FDG-PET imaging plays an important role in diagnosis, monitoring and follow-up of gynecological cancer. The goal of this paper was to summarize data of the literature about sensitivity and specificity of MRI and FDG-PET/CT for detection of primary tumor, lymph nodes invasion and metastases in cervix and endometrial cancer and to discuss their implication for radiation treatment planning and monitoring. PMID- 26957002 TI - The predictive validity of a situational judgement test and multiple-mini interview for entry into postgraduate training in Australia. AB - BACKGROUND: Evidence for the predictive validity of situational judgement tests (SJTs) and multiple-mini interviews (MMIs) is well-established in undergraduate selection contexts, however at present there is less evidence to support the validity of their use in postgraduate settings. More research is also required to assess the extent to which SJTs and MMIs are complementary for predicting performance in practice. This study represents the first longitudinal evaluation of the complementary roles and predictive validity of an SJT and an MMI for selection for entry into postgraduate General Practice (GP) specialty training in Australia. METHODS: Longitudinal data was collected from 443 GP registrars in Australia who were selected into GP training in 2010 or 2011. All 17 Regional Training Providers in Australia were asked to participate; performance data were received from 13 of these. Data was collected for participants' end-of-training assessment performance. Outcome measures include GP registrars' performance on the Royal Australian College of General Practitioners (RACGP) applied knowledge test, key feature problems and an objective structured clinical exam. RESULTS: Performance on the SJT, MMI and the overall selection score significantly predicted all three end-of-training assessments (r = .12 to .54), indicating that both of the selection methods, as well the overall selection score, have good predictive validity. The SJT and MMI provide incremental validity over each other for two of the three end-of-training assessments. CONCLUSIONS: The SJT and MMI were both significant positive predictors of all end-of-training assessments. Results provide evidence that they are complementary in predicting end-of training assessment scores. This research adds to the limited literature at present regarding the predictive validity of postgraduate medical selection methods, and their comparable effectiveness when used in a single selection system. A future research agenda is proposed. PMID- 26957004 TI - European scheme to develop drugs for diseases with no treatment launched. PMID- 26957005 TI - Reciprocal signals between microglia and neurons regulate alpha-synuclein secretion by exophagy through a neuronal cJUN-N-terminal kinase-signaling axis. AB - BACKGROUND: Secretion of proteopathic alpha-synuclein (alpha-SNC) species from neurons is a suspected driving force in the propagation of Parkinson's disease (PD). We have previously implicated exophagy, the exocytosis of autophagosomes, as a dominant mechanism of alpha-SNC secretion in differentiated PC12 or SH-SY5Y nerve cells. Here we have examined the regulation of exophagy associated with different forms of nerve cell stress relevant to PD. RESULTS: We identify cJUN-N terminal kinase (JNK) activity as pivotal in the secretory fate of autophagosomes containing alpha-SNC. Pharmacological inhibition or genetic (shRNA) knockdown of JNK2 or JNK3 decreases alpha-SNC secretion in differentiated PC12 and SH-SY5Y cells, respectively. Conversely, expression of constitutively active mitogen activated protein kinase kinase 7 (MKK7)-JNK2 and -JNK3 constructs augment secretion. The transcriptional activity of cJUN was not required for the observed effects. We establish a causal relationship between increased alpha-SNC release by exophagy and JNK activation subsequent to lysosomal fusion deficiency (overexpression of Lewy body-localized protein p25alpha or bafilomycin A1). JNK activation following neuronal ER or oxidative stress was not correlated with exophagy, but of note, we demonstrate that reciprocal signaling between microglia and neurons modulates alpha-SNC secretion. NADPH oxidase activity of microglia cell lines was upregulated by direct co-culture with alpha-SNC-expressing PC12 neurons or by passive transfer of nerve cell-conditioned medium. Conversely, inflammatory factors secreted from activated microglia increased JNK activation and alpha-SNC secretion several-fold in PC12 cells. While we do not identify these factors, we extend our observations by showing that exposure of neurons in monoculture to TNFalpha, a classical pro-inflammatory mediator of activated microglia, is sufficient to increase alpha-SNC secretion in a mechanism dependent on JNK2 or JNK3. In continuation hereof, we show that also IFNbeta and TGFbeta increase the release of alpha-SNC from PC12 neurons. CONCLUSIONS: We implicate stress kinases of the JNK family in the regulation of exophagy and release of alpha-SNC following endogenous or exogenous stimulation. In a wider scope, our results imply that microglia not only inflict bystander damage to neurons in late phases of inflammatory brain disease but may also be active mediators of disease propagation. PMID- 26957007 TI - Maternal knowledge, outcome expectancies and normative beliefs as determinants of cessation of exclusive breastfeeding: a cross-sectional study in rural Kenya. AB - BACKGROUND: Despite the importance of multiple psychosocial factors on nutrition related behavior, very few studies have explored beyond the role of mothers' knowledge and perception of child-focused outcomes on the duration of exclusive breastfeeding in Africa. Our objective was to determine the relationships among mothers' knowledge, outcome expectancies, normative beliefs, and cessation of exclusive breastfeeding in rural Kenya. METHODS: A cross-sectional survey was conducted among 400 mothers of children, 0-24 months old, in rural Kenya. Early child-feeding practices, knowledge of breastfeeding recommendations, beliefs associated with impact of exclusive breastfeeding on child- and mother-focused outcomes and perception of acceptability of exclusive breastfeeding by important others were examined. Cox regression analysis was used to assess the relationship between independent variables of interest and cessation of exclusive breastfeeding. RESULTS: Being knowledgeable of breastfeeding-related recommendations, positive beliefs on the impact of exclusive breastfeeding on child- focused outcomes, having a more positive perception of the impact of exclusive breastfeeding on mother-focused outcomes and a more positive perception of acceptability of exclusive breastfeeding by important others were associated with significantly lower risks of premature cessation of exclusive breastfeeding. CONCLUSION: In addition to knowledge levels, mothers' beliefs play an important role in mothers' decisions to practice exclusive breastfeeding. Mother's beliefs on the impact of exclusive breastfeeding on the mother's health, physical appearance and ability to engage in other activities were shown to have the strongest relationship with premature cessation of exclusive breastfeeding. Addressing these beliefs has the potential to contribute to more effective exclusive breastfeeding promotion efforts in rural Kenya. PMID- 26957009 TI - Re: "A System Dynamics Model of Serum Prostate-Specific Antigen Screening for Prostate Cancer". PMID- 26957006 TI - Predictive and prognostic value of admission neutrophil-to-lymphocyte ratio in patients with CHD. AB - BACKGROUND AND AIM: The aim of this study was to examine the association between the admission neutrophil-to-lymphocyte ratio (N/L ratio) with coronary heart disease (CHD), separately from acute coronary syndrome (ACS) and stable angina (SA). A further aim was to investigate the clinical value of the N/L ratio in predicting in-hospital CHD events and the long-term prognosis of patients with CHD. PATIENTS AND METHODS: In all, 942 patients were enrolled and classified into a CHD group (comprising an ACS group and an SA group) and a normal group. Laboratory data including regular blood test results were obtained at baseline. The relationship between the N/L ratio and CHD, ACS, Gensini score, and multivessel lesions was analyzed by logistic regression. Receiver operating characteristics (ROC) curve analysis was used to identify the value of the N/L ratio in the diagnosis of CHD, ACS, and the severity of CHD. We divided the patients into four groups according to the N/L ratio quartiles and compared the differences in major adverse cardiac events (MACEs) that occurred in hospital and in the 4.26 +/- 0.57-year follow-up out of hospital. RESULTS: Patients with an elevated N/L ratio had a significantly increased risk of CHD [odds ratio (OR) = 1.697, 95 % confidence interval (CI) = 1.483-1.942], and an elevated N/L ratio was closely related to a higher risk of ACS (OR = 1.652, 95 % CI = 1.434-1.902). The admission N/L ratio (0.664; 95 % CI = 1.942-1.616) showed a greater ROC area than the WBC and LDL-C values. Patients with a higher N/L ratio in both the SA group and the ACS group had a higher incidence of in-hospital and out-of-hospital MACEs, including long-term mortality and occurrence of new-onset heart failure or re-occurrence of heart failure. An elevated N/L ratio on admission was also found to be a significant indicator of 4.26-year MACEs. CONCLUSION: The admission N/L ratio was significantly associated with CHD and may become a risk predictor in the prognosis of patients with CHD. PMID- 26957010 TI - Review: Opportunities and challenges for small populations of dairy cattle in the era of genomics. AB - In modern dairy cattle breeding, genomic breeding programs have the potential to increase efficiency and genetic gain. At the same time, the requirements and the availability of genotypes and phenotypes present a challenge. The set-up of a large enough reference population for genomic prediction is problematic for numerically small breeds but also for hard to measure traits. The first part of this study is a review of the current literature on strategies to overcome the lack of reference data. One solution is the use of combined reference populations from different breeds, different countries, or different research populations. Results reveal that the level of relationship between the merged populations is the most important factor. Compiling closely related populations facilitates the accurate estimation of marker effects and thus results in high accuracies of genomic prediction. Consequently, mixed reference populations of the same breed, but from different countries are more promising than combining different breeds, especially if those are more distantly related. The use of female reference information has the potential to enlarge the reference population size. Including females is advisable for small populations and difficult traits, and maybe combined with genotyping females and imputing those that are un-genotyped. The efficient use of imputation for un-genotyped individuals requires a set of genotyped related animals and well-considered selection strategies which animals to choose for genotyping and phenotyping. Small populations have to find ways to derive additional advantages from the cost-intensive establishment of genomic breeding schemes. Possible solutions may be the use of genomic information for inbreeding control, parentage verification, within-herd selection, adjusted mating plans or conservation strategies. The second part of the paper deals with the issue of high-quality phenotypes against the background of new, difficult and hard to measure traits. The use of contracted herds for phenotyping is recommended, as additional traits, when compared to standard traits used in dairy cattle breeding can be measured at set moments in time. This can be undertaken even for the recording of health traits, thus resulting in complete contemporary groups for health traits. Future traits to be recorded and used in genomic breeding programs, at least partly will be traits for which traditional selection based on widespread phenotyping is not possible. Enabling phenotyping of sufficient numbers to enable genomic selection will rely on cooperation between scientists from different disciplines and may require multidisciplinary approaches. PMID- 26957011 TI - Correlation of Peripheral Vein Tumour Marker Levels, Internal Iliac Vein Tumour Marker Levels and Radical Prostatectomy Specimens in Patients with Prostate Cancer and Borderline High Prostate-Specific Antigen: A Pilot Study. AB - PURPOSE: To correlate prostate-specific antigen (PSA), free to total PSA percentage (fPSA%) and prostatic acid phosphatase (PAP) levels from peripheral and pelvic venous samples with prostatectomy specimens in patients with prostate adenocarcinoma and borderline elevation of PSA. MATERIALS AND METHODS: In this prospective institutional review board approved study, 7 patients with biopsy proven prostate cancer had a venous sampling procedure prior to prostatectomy (mean 3.2 days, range 1-7). Venous samples were taken from a peripheral vein (PVS), the right internal iliac vein, a deep right internal iliac vein branch, left internal iliac vein and a deep left internal iliac vein branch. Venous sampling results were compared to tumour volume, laterality, stage and grade in prostatectomy surgical specimens. RESULTS: Mean PVS PSA was 4.29, range 2.3-6 ng/ml. PSA and PAP values in PVS did not differ significantly from internal iliac or deep internal iliac vein samples (p > 0.05). fPSA% was significantly higher in internal iliac (p = 0.004) and deep internal iliac (p = 0.003) vein samples compared to PVS. One of 7 patients had unilateral tumour only. This patient, with left-sided tumour, had a fPSA% of 6, 6, 6, 14 and 12 in his peripheral, right internal iliac, deep right internal iliac branch, left internal iliac and deep left internal iliac branch samples respectively. There were no adverse events. CONCLUSION: fPSA%, unlike total PSA or PAP, is significantly higher in pelvic vein compared to peripheral vein samples when prostate cancer is present. Larger studies including patients with higher PSA values are warranted to further investigate this counterintuitive finding. PMID- 26957012 TI - Enzymatic Degradation of Polysaccharide-Based Layer-by-Layer Structures. AB - The lack of knowledge on the degradation of layer-by-layer structures is one of the causes hindering its translation to preclinical assays. The enzymatic degradation of chitosan/hyaluronic acid films in the form of ultrathin films, freestanding membranes, and microcapsules was studied resorting to hyaluronidase. The reduction of the thickness of ultrathin films was dependent on the hyaluronidase concentration, leading to thickness and topography variations. Freestanding membranes exhibited accelerated weight loss up to 120 h in the presence of the enzyme, achieving complete degradation. Microcapsules with around 5 MUm loaded simultaneously with FITC-BSA and hyaluronidase showed that the coencapsulation of such enzyme and protein mixture led to a FITC-BSA release four times higher than in the absence of hyaluronidase. The results suggest that the degradation of LbL devices may be tuned via embedded enzymes, namely, in the controlled release of active agents in biomedical applications. PMID- 26957013 TI - Mathematical model suitable for efficient simulation of thin semi-flexible polymers in complex environments. AB - We present an alternative approach to simulations of semi-flexible polymers. In contrast with the usual bead-rod compromise between bead-spring and rigid rod models, we use deformable cylindrical segments as basic units of the polymer. The length of each segment is not preserved with end points diffusing under constraints keeping the polymer chain nature intact. The model allows the simulation of tension transport and elasticity properties. In particular we describe a new cooperative regime in the relaxation of the polymer from its fully elongated configuration. PMID- 26957014 TI - Healing effects of sumac (Rhus coriaria) in streptozotocin-induced diabetic rats. AB - Context Sumac [Rhus coriaria L. (RC) (Anacardiaceae)] is used as a folk medicine in the treatment of diabetes in Turkey. Objective This study investigates the in vivo healing and protective effects of lyophilized extract sumac against streptozotocin (STZ)-induced diabetic complications. Materials and methods Toxicity test was conducted in three different dosages (250, 500 and 1000 mg/kg of plant extracts, respectively). Six groups of seven rats each were used in experiments. Groups were designed as Normal control, Diabetic (DM), DM + AC-20 mg/kg, DM + Extract-100 mg/kg, DM + Extract 250 mg/kg and DM + Extract 500 mg/kg group. Experimental diabetes [50 mg/kg, intraperitoneal (i.p.)] was induced by STZ. The effects of oral administration of the extract for 21 d on the level of serum glucose, insulin, C-peptide, lipid profile (LP), hepatic and renal damage biomarkers (HRDB), diabetic serum biomarkers (DSB), glycosylated haemoglobin (HbA1c), antioxidant defence system constituents (ADSCs), malondialdehyde (MDA) and alpha-glucosidase activity in small intestine tissue were evaluated. Results The extract decreased the levels of blood glucose in diabetic groups (an average of 31%). Triglyceride, total cholesterol, high-density lipoprotein and low density lipoprotein levels were balanced by plant extract (500 mg/kg) supplementation in the diabetic group. Decreased levels of aspartate aminotransferase (89%), alanine aminotransferase (91%), lactate dehydrogenase (35%), alkaline phosphatase (47%), creatinine (25%) and urea (29%) were detected in plant extract (500 mg/kg) supplemented diabetic group. Additionally, a considerable increase in the HRDB, DSB, LP, MDA and fluctuated ADSC levels were restored in RC-extract supplemented groups. Conclusion RC lyophilized extract has a healing effect on diabetes and diabetes-related complications. PMID- 26957015 TI - Diversification of Bromelioideae (Bromeliaceae) in the Brazilian Atlantic rainforest: A case study in Aechmea subgenus Ortgiesia. AB - Aechmea subgenus Ortgiesia comprises ca. 20 species distributed in Brazil, Argentina, Paraguay, and Uruguay, with a center of diversity in the Brazilian Atlantic rainforest. We examined interspecific relationships of Ortgiesia based on Amplified Fragment Length Polymorphisms (AFLP). Ninety-six accessions belonging to 14 species of Ortgiesia were sampled, and genotyped with 11 AFLP primer combinations. The neighbor joining (NJ) tree depicted two main genetic groups within Aechmea subgenus Ortgiesia, and four subgroups. The NJ tree showed short internal branches, indicating an overall shallow genetic divergence among Ortgiesia species as expected for the recently radiated subfamily Bromelioideae. Our results suggest that hybridization and/or incomplete lineage sorting may have hampered the reconstruction of interspecific relationships in Aechmea subgenus Ortgiesia. The mapping of petal color (yellow, blue, pink, or white), inflorescence type (simple or compound), and inflorescence shape (ellipsoid, subcylindric, cylindric, or pyramidal) against the NJ tree indicated that these characters are of limited taxonomic use in Aechmea subgenus Ortgiesia due to homoplasy. An analysis of the current distribution of Ortgiesia identified the southern region of the Brazilian Atlantic rainforest, between latitudes of 26 degrees and 27 degrees S, as the center of diversity for the subgenus. PMID- 26957016 TI - The role of biopsy for small renal masses. AB - The incidence of small renal masses (SRMs) has been increasing due to the more liberal use of abdominal imaging. This increased detection has driven the attention of clinicians to the characterization of these lesions and toward a better understanding of their natural history. To this end, renal tumour biopsies (RTBs) have a crucial role as they provide vital pathological information. The improved quality and accuracy of RTBs provide urologists with a very truthful tool to support and guide treatment decisions. The future of RTB will combine pathological, molecular and genetic information that will, improve our knowledge about these lesions and open the potential for risk-adapted personalized medicine. PMID- 26957017 TI - Adipocytes enhance murine pancreatic cancer growth via a hepatocyte growth factor (HGF)-mediated mechanism. AB - INTRODUCTION: Obesity accelerates the development and progression of pancreatic cancer, though the mechanisms underlying this association are unclear. Adipocytes are biologically active, producing factors such as hepatocyte growth factor (HGF) that may influence tumor progression. We therefore sought to test the hypothesis that adipocyte-secreted factors including HGF accelerate pancreatic cancer cell proliferation. MATERIAL AND METHODS: Murine pancreatic cancer cells (Pan02 and TGP-47) were grown in a) conditioned medium (CM) from murine F442A preadipocytes, b) HGF-knockdown preadipocyte CM, c) recombinant murine HGF at increasing doses, and d) CM plus HGF-receptor (c-met) inhibitor. Cell proliferation was measured using the MTT assay. ANOVA and t-test were applied; p < 0.05 considered significant. RESULTS: Wild-type preadipocyte CM accelerated Pan02 and TGP-47 cell proliferation relative to control (59 +/- 12% and 34 +/- 12%, p < 0.01, respectively). Knockdown of preadipocyte HGF resulted in attenuated proliferation vs. wild type CM in Pan02 cells (35 +/- 5% vs. 68 +/- 14% greater than control; p < 0.05), but proliferation in TGP-47 cells remained unchanged. Recombinant HGF dose-dependently increased Pan02, but not TGP-47, proliferation (p < 0.05). Inhibition of HGF receptor, c-met, resulted in attenuated proliferation versus control in Pan02 cells, but not TGP-47 cells. CONCLUSIONS: These experiments demonstrate that adipocyte-derived factors accelerate murine pancreatic cancer proliferation. In the case of Pan02 cells, HGF is responsible, in part, for this proliferation. PMID- 26957019 TI - Behaviour of one-step spray-coated carbon nanotube supercapacitor in ambient light harvester circuit with printed organic solar cell and electrochromic display. AB - A printed energy harvesting and storage circuit powered by ambient office lighting and its use to power a printed display is reported. The autonomous device is composed of three printed electronic components: an organic photovoltaic module, a carbon-nanotubes-only supercapacitor and an electrochromic display element. Components are fabricated from safe and environmentally friendly materials, and have been fabricated using solution processing methods, which translate into low-cost and high-throughput manufacturing. A supercapacitor made of spray-coated carbon nanotube based ink and aqueous NaCl electrolyte was charged using a printed organic photovoltaic module exposed to office lighting conditions. The supercapacitor charging rate, self-discharge rate and display operation were studied in detail. The supercapacitor self-discharge rate was found to depend on the charging rate. The fully charged supercapacitor was used as a power source to run the electrochromic display over 50 times. PMID- 26957020 TI - Quantum chemical clarification of the alkyl chain length threshold of nonionic surfactants for monolayer formation at the air/water interface. AB - A theoretical basis is provided for the experimental fact that for various surfactant classes the alkyl chain length threshold varies for the formation of condensed monolayers. The existence of the alkyl chain length threshold for a surfactant enabling the formation of monolayers is determined by the entropy increment to the Gibbs' energy, assessed by using the quantum chemical semiempiric method PM3. The value of the clusterization threshold is not stipulated by the surfactant solubility in water, rather by the electron-donor and electron-seeking properties of the head groups. These properties in turn impact the value of the solubility threshold for surfactants. The value of the clusterization threshold depends quadratically on the substituent constants, i.e. it is independent of whether the functional group is a donor or an acceptor of electrons. Rather it depends only on the donor or the acceptor 'force' of the substituent. The square-law dependence of the surface clusterization threshold of the amphiphile on the solubility threshold is evidenced. PMID- 26957018 TI - Plant Phenotyping using Probabilistic Topic Models: Uncovering the Hyperspectral Language of Plants. AB - Modern phenotyping and plant disease detection methods, based on optical sensors and information technology, provide promising approaches to plant research and precision farming. In particular, hyperspectral imaging have been found to reveal physiological and structural characteristics in plants and to allow for tracking physiological dynamics due to environmental effects. In this work, we present an approach to plant phenotyping that integrates non-invasive sensors, computer vision, as well as data mining techniques and allows for monitoring how plants respond to stress. To uncover latent hyperspectral characteristics of diseased plants reliably and in an easy-to-understand way, we "wordify" the hyperspectral images, i.e., we turn the images into a corpus of text documents. Then, we apply probabilistic topic models, a well-established natural language processing technique that identifies content and topics of documents. Based on recent regularized topic models, we demonstrate that one can track automatically the development of three foliar diseases of barley. We also present a visualization of the topics that provides plant scientists an intuitive tool for hyperspectral imaging. In short, our analysis and visualization of characteristic topics found during symptom development and disease progress reveal the hyperspectral language of plant diseases. PMID- 26957022 TI - Hazard identification and risk characterization of bisphenols A, F and AF to aquatic organisms. AB - Production of bisphenol A (BPA) analogues such as bisphenol F (BPF) and bisphenol AF (BPAF) has recently increased, due to clear evidence of adverse effects of BPA on humans and wildlife. Bisphenols (BPs) have already been released into aquatic environment without previous available information about potential adverse effects of BPs and their potential risk to aquatic ecosystems. In this study, lethal and sublethal effects of BPF and BPAF to bacteria, algae, crustacea and fish embryos were investigated and the results were compared to the adverse effects obtained for BPA. We found that BPAF was the most toxic compound to Daphnia magna, Danio rerio and Desmodesmus subspicatus; the lowest 72 h EC50 (median effective concentration) and 21 d NOEC (no observed effect concentration) values were determined at 2.2 mg/L regarding zebrafish hatching success and 0.23 mg/L of BPAF obtained for growth and reproduction of water fleas, respectively. In most cases, BPA was more toxic to D. magna, D. rerio and D. subspicatus in comparison to BPF, but pigmentation of zebrafish embryos after 48 h of exposure and reproduction of water fleas after 21-day D. magna reproductive test exposure to BPF were much more impaired. Risk quotients (measured environmental concentration/21 d NOEC) showed that BPA, BPF and BPAF are recently not chronically hazardous to the survival, reproduction and growth of water fleas in surface waters. On the other hand, we importantly show that currently present BPAF concentrations in surface waters could cause a potential ecological risk to aquatic organisms. In the near future, higher concentrations of BPF and BPAF in surface waters are anticipated and for this reason further testing using test systems with various aquatic species and endpoints are needed to provide additional information about toxic impacts of BPF and BPAF on aquatic biota. PMID- 26957021 TI - The RecQ DNA helicase Rqh1 constrains Exonuclease 1-dependent recombination at stalled replication forks. AB - DNA double-strand break (DSB) repair by homologous recombination (HR) involves resection of the break to expose a 3' single-stranded DNA tail. In budding yeast, resection occurs in two steps: initial short-range resection, performed by Mre11 Rad50-Xrs2 and Sae2; and long-range resection catalysed by either Exo1 or Sgs1 Dna2. Here we use genetic assays to investigate the importance of Exo1 and the Sgs1 homologue Rqh1 for DNA repair and promotion of direct repeat recombination in the fission yeast Schizosaccharomyces pombe. We find that Exo1 and Rqh1 function in alternative redundant pathways for promoting survival following replication fork breakage. Exo1 promotes replication fork barrier-induced direct repeat recombination but intriguingly limits recombination induced by fork breakage. Direct repeat recombination induced by ultraviolet light depends on either Exo1 or Rqh1. Finally, we show that Rqh1 plays a major role in limiting Exo1-dependent direct repeat recombination induced by replication fork stalling but only a minor role in constraining recombination induced by fork breakage. The implications of our findings are discussed in the context of the benefits that long-range resection may bring to processing perturbed replication forks. PMID- 26957023 TI - Microneedle delivery of trivalent influenza vaccine to the skin induces long-term cross-protection. AB - A painless self-immunization method with effective and broad cross-protection is urgently needed to prevent infections against newly emerging influenza viruses. In this study, we investigated the cross-protection efficacy of trivalent influenza vaccine containing inactivated A/PR/8/34 (H1N1), A/Hong Kong/68 (H3N2) and B/Lee/40 after skin vaccination using microneedle patches coated with this vaccine. Microneedle vaccination of mice in the skin provided 100% protection against lethal challenges with heterologous pandemic strain influenza A/California/04/09, heterogeneous A/Philippines/2/82 and B/Victoria/287 viruses 8 months after boost immunization. Cross-reactive serum IgG antibody responses against heterologous influenza viruses A/California/04/09, A/Philippines/2/82 and B/Victoria/287 were induced at high levels. Hemagglutination inhibition titers were also maintained at high levels against these heterogeneous viruses. Microneedle vaccination induced substantial levels of cross-reactive IgG antibody responses in the lung and cellular immune responses, as well as cross-reactive antibody-secreting plasma cells in the spleen. Viral loads in the lung were significantly (p < 0.05) reduced. All mice survived after viral challenges. These results indicate that skin vaccination with trivalent vaccine using a microneedle array could provide protection against seasonal epidemic or new pandemic strain of influenza viruses. PMID- 26957024 TI - Understanding the effect of the nature of the nucleobase in the loops on the stability of the i-motif structure. AB - The nature and the length of loops connecting cytosine tracts in i-motif structures may affect their stability. In this work, the influence of the nature of the nucleobases located in two of the loops of an intramolecular i-motif is studied using spectroscopy, separation techniques, and multivariate data analysis. The insertion of bases other than thymine induces an additional acid base equilibrium with pKa ~ 4.5. The presence of two guanine bases in the loops, placed opposite to each other, decreases the thermal stability of the structure. In contrast, thymine and cytosine bases in these positions stabilize the structure. PMID- 26957028 TI - The Diversification of Evolutionarily Conserved MAPK Cascades Correlates with the Evolution of Fungal Species and Development of Lifestyles. AB - The fungal kingdom displays an extraordinary diversity of lifestyles, developmental processes, and ecological niches. The MAPK (mitogen-activated protein kinase) cascade consists of interlinked MAPKKK, MAPKK, and MAPK, and collectively such cascades play pivotal roles in cellular regulation in fungi. However, the mechanism by which evolutionarily conserved MAPK cascades regulate diverse output responses in fungi remains unknown. Here we identified the full complement of MAPK cascade components from 231 fungal species encompassing 9 fungal phyla. Using the largest data set to date, we found that MAPK family members could have two ancestors, while MAPKK and MAPKKK family members could have only one ancestor. The current MAPK, MAPKK, and MAPKKK subfamilies resulted from duplications and subsequent subfunctionalization during the emergence of the fungal kingdom. However, the gene structure diversification and gene expansion and loss have resulted in significant diversity in fungal MAPK cascades, correlating with the evolution of fungal species and lifestyles. In particular, a distinct evolutionary trajectory of MAPK cascades was identified in single-celled fungi in the Saccharomycetes. All MAPK, MAPKK, and MAPKKK subfamilies expanded in the Saccharomycetes; genes encoding MAPK cascade components have a similar exon intron structure in this class that differs from those in other fungi. PMID- 26957029 TI - Maintenance of a Protein Structure in the Dynamic Evolution of TIMPs over 600 Million Years. AB - Deciphering the events leading to protein evolution represents a challenge, especially for protein families showing complex evolutionary history. Among them, TIMPs represent an ancient eukaryotic protein family widely distributed in the animal kingdom. They are known to control the turnover of the extracellular matrix and are considered to arise early during metazoan evolution, arguably tuning essential features of tissue and epithelial organization. To probe the structure and molecular evolution of TIMPs within metazoans, we report the mining and structural characterization of a large data set of TIMPs over approximately 600 Myr. The TIMPs repertoire was explored starting from the Cnidaria phylum, coeval with the origins of connective tissue, to great apes and humans. Despite dramatic sequence differences compared with highest metazoans, the ancestral proteins displayed the canonical TIMP fold. Only small structural changes, represented by an alpha-helix located in the N-domain, have occurred over the evolution. Both the occurrence of such secondary structure elements and the relative solvent accessibility of the corresponding residues in the three dimensional structures raises the possibility that these sites represent unconserved element prone to accept variations. PMID- 26957030 TI - Plastid Phylogenomic Analyses Resolve Tofieldiaceae as the Root of the Early Diverging Monocot Order Alismatales. AB - The predominantly aquatic order Alismatales, which includes approximately 4,500 species within Araceae, Tofieldiaceae, and the core alismatid families, is a key group in investigating the origin and early diversification of monocots. Despite their importance, phylogenetic ambiguity regarding the root of the Alismatales tree precludes answering questions about the early evolution of the order. Here, we sequenced the first complete plastid genomes from three key families in this order:Potamogeton perfoliatus(Potamogetonaceae),Sagittaria lichuanensis(Alismataceae), andTofieldia thibetica(Tofieldiaceae). Each family possesses the typical quadripartite structure, with plastid genome sizes of 156,226, 179,007, and 155,512 bp, respectively. Among them, the plastid genome ofS. lichuanensisis the largest in monocots and the second largest in angiosperms. Like other sequenced Alismatales plastid genomes, all three families generally encode the same 113 genes with similar structure and arrangement. However, we detected 2.4 and 6 kb inversions in the plastid genomes ofSagittariaandPotamogeton, respectively. Further, we assembled a 79 plastid protein-coding gene sequence data matrix of 22 taxa that included the three newly generated plastid genomes plus 19 previously reported ones, which together represent all primary lineages of monocots and outgroups. In plastid phylogenomic analyses using maximum likelihood and Bayesian inference, we show both strong support for Acorales as sister to the remaining monocots and monophyly of Alismatales. More importantly, Tofieldiaceae was resolved as the most basal lineage within Alismatales. These results provide new insights into the evolution of Alismatales as well as the early-diverging monocots as a whole. PMID- 26957031 TI - Three Dimensional Organization of Genome Might Have Guided the Dynamics of Gene Order Evolution in Eukaryotes. AB - In eukaryotes, genes are nonrandomly organized into short gene-dense regions or "gene-clusters" interspersed by long gene-poor regions. How these gene-clusters have evolved is not entirely clear. Gene duplication may not account for all the gene-clusters since the genes in most of the clusters do not exhibit significant sequence similarity. In this study, using genome-wide data sets from budding yeast, fruit-fly, and human, we show that: 1) long-range evolutionary repositioning of genes strongly associate with their spatial proximity in the nucleus; 2) presence of evolutionary DNA break-points at involved loci hints at their susceptibility to undergo long-range genomic rearrangements; and 3) correlated epigenetic and transcriptional states of engaged genes highlight the underlying evolutionary constraints. The significance of observation 1, 2, and 3 are particularly stronger for the instances of inferred evolutionary gain, as compared with loss, of linear gene-clustering. These observations suggest that the long-range genomic rearrangements guided through 3D genome organization might have contributed to the evolution of gene order. We further hypothesize that the evolution of linear gene-clusters in eukaryotic genomes might have been mediated through spatial interactions among distant loci in order to optimize co-ordinated regulation of genes. We model this hypothesis through a heuristic model of gene order evolution. PMID- 26957032 TI - Lu-177 labelled peptide treatment for radioiodine refractory differentiated thyroid carcinoma. AB - Differentiated thyroid carcinoma (DTC) has good prognosis but 5% of the patients already have distant metastasis at the diagnosis. Tumour cells can lose their iodine uptake ability and enter a state of dedifferentiation. Treatment for differentiated thyroid carcinoma that is not suitable for the local surgery and unresponsive to radioactive iodine uptake is not always easy for physicians. We present a case of a 64-year-old man who had total thyroidectomy surgery and central lymph node dissection with diagnosis of multinodular goitre disease. Histopathological evaluation was papillary thyroid cancer with tall cell variant. Treatment using 150 mCi radioiodine was administered to the patient three times but could not effect a cure. We performed Ga-68 labelled DOTATE (synthetic somatostatin analogue peptide). This provided a good outcome. As evident from our case, Lu-177 radionuclide labelled synthetic somatostatin analogue peptides have therapeutic effect on radioiodine refractory DTC, as an alternative treatment modality. PMID- 26957033 TI - Fractured tracheostomy tube presenting as a foreign body in a paediatric patient. AB - Tracheostomy tube fracture and aspiration into the tracheobronchial tree leading to airway obstruction is a dangerous complication after tracheostomy. We report a case of a fractured tracheostomy tube in a 6-year-old child who had been maintained on a tracheostomy tube for the past 5 years. The tracheostomy tube got fractured at the junction of the tube and neck plate, and impacted in the trachea and right main bronchus. Rigid bronchoscopy performed through the tracheostomy stoma to retrieve the fractured tracheostomy tube and the anaesthetic management during the period are discussed. PMID- 26957034 TI - Metastatic pancreatic cancer presenting as linitis plastica of the stomach. AB - Metastatic disease from pancreatic carcinoma involving the stomach is an unusual event, and the pattern of spread in the form of linitis plastica, to our knowledge, has not been reported previously. Local recurrence after curative resection for pancreatic cancer is the most common pattern of disease. We report a case of metastatic pancreatic adenocarcinoma presenting as linitis plastica of the stomach 4 years after curative resection. A 52-year-old man presented with epigastric pain and melaena 4 years after undergoing a Whipple's procedure for a poorly-differentiated pancreatic adenocarcinoma, stage IB; T2N0M0. CT imaging of the abdomen revealed thickening of the gastric wall, and subsequent oesophagogastroduodenoscopy (OGD) revealed diffuse friable erythaematous tissue. The biopsy specimen obtained during the OGD revealed a poorly differentiated adenocarcinoma, with similar appearance to the prior specimen obtained from the pancreas. PMID- 26957035 TI - Unusual renal tumour: multilocular cystic renal cell carcinoma. AB - Multilocular cystic renal cell carcinoma (MCRCC) is a rare presentation of renal cell carcinoma. Most patients are asymptomatic and frequently MCRCCs are detected incidentally. MCRCCs have good prognosis because of their low malignant potential. We report a case of a 39-year-old woman who presented with mild right flank pain and normal laboratory data. On imaging examinations, a Bosniak III cystic lesion was detected in the lower third of the right kidney. She underwent right partial nephrectomy and histopathology showed a multilocular cystic renal cell carcinoma Fuhrman grade 1. In this article, we also present a review of the literature on MCRCC, highlight the correlation of the pathological and imaging characteristics of these low aggressive renal lesions, and underscore the importance of their recognition to prevent unnecessary radical surgery. PMID- 26957036 TI - Eosinophilic colitis. AB - A 57-year-old man, diagnosed with colon cancer stage III in July/2010, underwent surgery and received adjuvant chemotherapy with FOLFOX 4 (5-fluorouracil; calcium folinate and oxaliplatin), which ended in March/2011 after 12-cycles. It was then decided to maintain periodical surveillance. About 1 year later, the patient developed several episodes of diarrhoea, mainly during the night, and presented persistent peripheral eosinophilia in the blood count (range 585-1300 eosinophils/uL). Colonoscopy was performed, with the histological result showing eosinophilic infiltration of the colon, compatible with eosinophilic colitis. The patient was treated with a short course of budesonide, achieving resolution of symptoms, and has remained asymptomatic. PMID- 26957037 TI - Daily feeding regimen impacts pig growth and behavior. AB - A primary swine production goal is to increase efficiency of lean tissue gains. While many swine production systems currently utilize ad libitum feeding, recent research suggests that altering feeding patterns may impact feed efficiency. Therefore, the objective of this study was to compare two feeding patterns and evaluate their impact on whole body tissue accretion, feeding behavior and activity in growing pigs. Forty eight individually housed gilts (55.9+/-5.2kg on test BW) were assigned into one of two feeding treatments: 1) Free access to the feeder (Free Access) or 2) twice daily access where gilts were allowed to eat ad libitum between 08:00-09:00h and again from 17:00-18:00h (2*). Pig performance was recorded weekly for 55days and average daily gain (ADG), average daily feed intake (ADFI), and gain:feed (G:F) was calculated. Body composition was assessed in 12 gilts per treatment using dual X-ray absorptiometry (DXA) at day -3 and 55 of treatment, and tissue accretion rates were calculated. Gilt behaviors were assessed via video analysis during week 7 and included time spent eating, feeding rate, enrichment interaction, postural changes, standing, sitting, and lying behaviors. Gilts fed 2* had lower ADG and ADFI compared to Free Access gilts (P<=0.01); however, no treatment difference in G:F was observed (P=0.83). At day 55 gilts fed 2* had a lower fat:protein compared to Free Access gilts (P=0.05). Fat, lean, and protein accretion rates were lower in gilts fed 2* compared to those fed Free Access (P=0.01). Gilts fed 2* ate less frequently and for a shorter duration of time, interacted with enrichment more frequently (P<=0.005), and tended to have less frequent postural changes compared to Free Access gilts (P=0.08). No treatment differences were observed in duration of time spent standing, sitting, or lying (P>=0.39). Although feed regimen did not alter feed efficiency, these data indicate that twice daily feeding reduced gilt adiposity and growth without altering the pig's behavioral expression of hunger. Therefore, twice daily feeding may be a method of increasing percent of lean tissue without negatively impacting gilt welfare. PMID- 26957039 TI - The influence of visual mental imagery size on metamemory accuracy in judgment of learning. AB - Many studies have found the font size of to-be-remembered words has a significant influence on judgments of learning (JOLs). However, few studies have investigated whether JOLs are affected by the mental imagery size of to-be-remembered words, even when the font sizes themselves are kept identical in study materials. This study investigated whether the visual mental imagery size influences the participants' JOLs and what the underlying mechanisms are. In Experiments 1 and 2, participants learned words with identical font sizes, mentally generated large or small imageries and then made JOLs. We found that JOLs under the large imagery condition were significantly higher than those under the small imagery condition, but actual recall performance exhibited no significant difference. In Experiment 3, participants pressed a button immediately after mental imagery generation and showed that it took significantly longer to generate large imageries than to generate small imageries, and the difference in JOLs between two conditions was no longer significant. In Experiment 4, we used a questionnaire to investigate the contribution of beliefs and found that participants believed large imageries were easier to remember. These findings indicate that imagery size has a significant impact on JOLs, in which beliefs may play a leading role. PMID- 26957040 TI - Reply to the 'Comment on "The promise of microfluidic artificial lungs"' by G. Wagner, A. Kaesler, U. Steinseifer, T. Schmitz-Rode and J. Arens, Lab Chip, 2016, 16. AB - This response explores and discusses the critiques of Wagner et al. in their "Comment on 'The promise of microfluidic artificial lungs' by Joseph A. Potkay, Lab Chip, 2014, 14, 4122-4138". PMID- 26957038 TI - Re-patterning of H3K27me3, H3K4me3 and DNA methylation during fibroblast conversion into induced cardiomyocytes. AB - Direct conversion of fibroblasts into induced cardiomyocytes (iCMs) offers an alternative strategy for cardiac disease modeling and regeneration. During iCM reprogramming, the starting fibroblasts must overcome existing epigenetic barriers to acquire the CM-like chromatin pattern. However, epigenetic dynamics along this reprogramming process have not been studied. Here, we took advantage of our recently generated polycistronic system and determined the dynamics of two critical histone marks, H3K27me3 and H3K4me3, in parallel with gene expression at a set of carefully selected cardiac and fibroblast loci during iCM reprogramming. We observed reduced H3K27me3 and increased H3K4me3 at cardiac promoters as early as day 3, paralleled by a rapid significant increase in their mRNA expression. In contrast, H3K27me3 at loci encoding fibroblast marker genes did not increase until day 10 and H3K4me3 progressively decreased along the reprogramming process; these changes were accompanied by a gradual decrease in the mRNA expression of fibroblast marker genes. Further analyses of fibroblast-enriched transcription factors revealed a similarly late deposition of H3K27me3 and decreased mRNA expression of Sox9, Twist1 and Twist2, three important players in epithelial mesenchymal transition. Our data suggest early rapid activation of the cardiac program and later progressive suppression of fibroblast fate at both epigenetic and transcriptional levels. Additionally, we determined the DNA methylation states of representative cardiac promoters and found that not every single CpG was equally demethylated during early stages of iCM reprogramming. Rather, there are specific CpGs, whose demethylation states correlated tightly with transcription activation, that we propose are the major contributing CpGs. Our work thus reveals a differential re-patterning of H3K27me3, H3K4me3 at cardiac and fibroblast loci during iCM reprogramming and could provide future genome-wide epigenetic studies with important guidance such as the appropriate time window and loci to be utilized as positive and negative controls. PMID- 26957041 TI - Risk of neurodevelopmental impairment for outborn extremely preterm infants in an Australian regional network. AB - OBJECTIVE: To compare neurodevelopmental outcomes at 2-3 years in extremely premature outborn and inborn infants. DESIGN: Population-based retrospective cohort study. SETTING: Geographically defined area of New South Wales (NSW) and the Australian Capital Territory (ACT) served by a network of 10 neonatal intensive care units (NICUs). PATIENTS: All premature infants <29 weeks gestation born between 1998 and 2004 in the setting. INTERVENTION: At 2-3 years, corrected age, 1473 children were assessed with either the Griffiths Mental Developmental Scales (GMDS) or the Bayley Scales of Infant Development (BSID-II). MAIN OUTCOME MEASURE: Moderate/severe functional disability (FD) defined as: developmental delay (GMDS general quotient (GQ) or BSID-II mental developmental index (MDI)) > 2 standard deviations (SD) below the mean; cerebral palsy (CP) requiring aids; sensorineural or conductive deafness (requiring amplification); or bilateral blindness (visual acuity <6/60 in better eye). RESULTS: At 2-3 years, moderate/severe functional disability does not appear to be significantly different between outborn and inborn infants (adjusted OR 0.782; 95% CI 0.424 1.443). However, there were a significant number of outborn infants lost to follow up (23.3% versus 42.9%). CONCLUSION: In this cohort, at 2-3 years follow up neurodevelopmental outcome does not appear to be significantly different between outborn and inborn infants. These results should be interpreted with caution given the limitation of this study. PMID- 26957042 TI - The impact of Salmonella Enteritidis on lipid accumulation in chicken hepatocytes. AB - Salmonella enterica serovar Enteritidis (SE) is a public health concern and infected chickens serve as a reservoir that potentially transmits to humans through food. Although SE seldom causes systemic disease in chickens, virulent SE strains can colonize in intestines and lead a persistent infection of the liver. The liver is the primary organ for lipid metabolism in chickens and the site for production and assembly of main components in yolk. We performed a time-course experiment using LMH-2A cells that were infected with SE and co-incubated with beta-oestradiol to evaluate if SE infection affected lipid metabolism and subsequently changed lipoprotein formation for egg yolk. The results indicated that lipid accumulation significantly increased in infected LMH-2A cells while the viability of these cells was only slightly decreased. The mRNA expressions of lipid transportation and most lipogenetic genes including sterol regulatory element binding protein 1, acetyl-CoA carboxylase, fatty-acid synthase, long chain-fatty-acid-CoA ligase 1, peroxisome proliferator-activated receptor-gamma, and very-low-density lipoproteins (VLDLs) II were significantly up-regulated while the expression of lipogenetic-related stearoyl-CoA denaturase 1 was down regulated. Moreover, decline in lipid transportation of hepatocytes was evidenced by the down-regulation of oestrogen receptor alpha which promotes VLDLy formation, an increase of intra-cellular accumulation of Apoprotein B (ApoB) protein, and a decrease of cellular excretion of VLDL protein. Conclusively, SE infection could elevate lipid synthesis and reduce lipid transportation in the chicken hepatocytes. These changes may lead excessive lipid accumulation in liver and slower lipoprotein deposition in yolk. PMID- 26957045 TI - Exfoliating and Dispersing Few-Layered Graphene in Low-Boiling-Point Organic Solvents towards Solution-Processed Optoelectronic Device Applications. AB - With normal organic surfactants, graphene can only be dispersed in water and cannot be dispersed in low-boiling-point organic solvents, which hampers its application in solution-processed organic optoelectronic devices. Herein, we report the exfoliation of graphite into graphene in low-boiling-point organic solvents, for example, methanol and acetone, by using edge-carboxylated graphene quantum dots (ECGQD) as the surfactant. The great capability of ECGQD for graphene dispersion is due to its ultralarge pi-conjugated unit that allows tight adhesion on the graphene surface through strong pi-pi interactions, its edge carboxylated structure that diminishes the steric effects of the oxygen containing functional groups on the basal plane of ECGQD, and its abundance of carboxylic acid groups for solubility. The graphene dispersion in methanol enables the application of graphene:ECGQD as a cathode interlayer in polymer solar cells (PSCs). Moreover, the PSC device performance of graphene:ECGQD is better than that of Ca, the state-of-the-art cathode interlayer material. PMID- 26957044 TI - Malaria incidence and entomological findings in an area targeted for a cluster randomized controlled trial to prevent malaria in Ethiopia: results from a pilot study. AB - BACKGROUND: This study was part of the work to prepare for a cluster-randomized controlled trial to evaluate the effect of combining indoor residual spraying and long-lasting insecticidal nets on malaria incidence. A pilot study was done to estimate the variations of malaria incidence among villages, combined with entomological collections and an assessment of susceptibility to insecticides in malaria vectors. METHODS: A cohort of 5309 residents from four kebeles (the lowest government administrative unit) in 996 households was followed from August to December 2013 in south-central Ethiopia. Blood samples were collected by a finger prick for a microscopic examination of malaria infections. A multilevel mixed effect model was applied to measure the predictors of malaria episode. Adult mosquitoes were collected using light traps set indoors close to a sleeping person, pyrethrum spray sheet catches and artificial outdoor pit shelters. Enzyme linked immunosorbent assays were used to detect the sources of mosquito blood meals, while mosquito longevity was estimated based on parity. The World Health Organization's tube bioassay test was used to assess the insecticide susceptibility status of malaria vectors to pyrethroids and carbamates. RESULTS: The average incidence of malaria episode was 4.6 per 10,000 person weeks of observation. The age group from 5 to 14 years (IRR = 2.7; 95 % CI 1.1-6.6) and kebeles near a lake or river (IRR = 14.2, 95 % CI 3.1-64) were significantly associated with malaria episode. Only 271 (27.3 %) of the households owned insecticide-treated nets. Of 232 adult Anopheles mosquitoes collected, Anopheles arabiensis (71.1 %) was the predominant species. The average longevity of An. arabiensis was 14 days (range: 7-25 human blood index days). The overall human blood index (0.69) for An. arabiensis was higher than the bovine blood index (0.38). Statistically significant differences in Anopheline mosquitoes abundance were observed between the kebeles (P = 0.001). Anopheles arabiensis was susceptible to propoxur, but resistant to pyrethroids. However, An. pharoensis was susceptible to all pyrethroids and carbamates tested. CONCLUSIONS: This study showed a high variation in malaria incidence and Anopheles between kebeles. The observed susceptibility of the malaria vectors to propoxur warrants using this insecticide for indoor residual spraying, and the results from this study will be used as a baseline for the trial. PMID- 26957043 TI - Open-gate mutants of the mammalian proteasome show enhanced ubiquitin-conjugate degradation. AB - When in the closed form, the substrate translocation channel of the proteasome core particle (CP) is blocked by the convergent N termini of alpha-subunits. To probe the role of channel gating in mammalian proteasomes, we deleted the N terminal tail of alpha3; the resulting alpha3DeltaN proteasomes are intact but hyperactive in the hydrolysis of fluorogenic peptide substrates and the degradation of polyubiquitinated proteins. Cells expressing the hyperactive proteasomes show markedly elevated degradation of many established proteasome substrates and resistance to oxidative stress. Multiplexed quantitative proteomics revealed ~ 200 proteins with reduced levels in the mutant cells. Potentially toxic proteins such as tau exhibit reduced accumulation and aggregate formation. These data demonstrate that the CP gate is a key negative regulator of proteasome function in mammals, and that opening the CP gate may be an effective strategy to increase proteasome activity and reduce levels of toxic proteins in cells. PMID- 26957046 TI - Gingival recession and oral health-related quality of life: a population-based cross-sectional study in Brazil. AB - OBJECTIVES: To assess the association between gingival recession (GR) and oral health-related quality of life (OHRQoL) in a Brazilian population of adults. METHODS: A representative sample from Porto Alegre city was drawn in 2011 using a multistage probability sampling strategy. For this study, 740 individuals, 35-59 years of age and with >=6 teeth, were included. GR was assessed by two calibrated examiners at four sites in all present teeth. The Oral Health Impact Profile (OHIP-14) was used to assess OHRQoL. OHIP-14 was dichotomized using 'fairly often' as the cutoff point for a negative impact. Multiple logistic regression models were fitted to define which descriptors of GR were associated with the dichotomous outcome of OHIP-14, including dentine hypersensitivity in separate models, adjusting for age, gender, socioeconomic status, smoking, dental care, and missing teeth. RESULTS: Mean OHIP was significantly higher for individuals with >=1 tooth with GR >=2, >=3, >=4, and >=5 mm. Individuals with >=1 tooth with GR >=2 mm had approximately two times higher chance of having a negative impact than individuals without GR of this threshold [odds ratio (OR) = 1.99, 95% confidence interval (CI) 1.05-3.78]. When buccal and proximal sites were analyzed separately, the presence of GR was significantly associated with worst quality of life only in anterior and not in posterior teeth. GR in the lower arch had no impact on OHRQoL. GR >=2 mm affected only physical pain (OR = 2.61; 95% CI 1.06 6.42), whereas GR >=4 mm affected functional limitation, physical pain, psychological discomfort, physical and psychological disabilities, with ORs ranging from 1.43 to 1.91. Dentine hypersensitivity alone was not associated with OHRQoL, but it modified the association between GR and OHIP when present concomitantly with GR, mainly in buccal sites. CONCLUSIONS: OHRQoL is poorer in this adult population in the presence of GR, mainly in upper and anterior teeth. Dentine hypersensitivity and esthetics were found to be factors linking GR to OHRQoL. PMID- 26957047 TI - Health Systems Research in a Complex and Rapidly Changing Context: Ethical Implications of Major Health Systems Change at Scale. AB - This paper discusses health policy and systems research in complex and rapidly changing contexts. It focuses on ethical issues at stake for researchers working with government policy makers to provide evidence to inform major health systems change at scale, particularly when the dynamic nature of the context and ongoing challenges to the health system can result in unpredictable outcomes. We focus on situations where 'country ownership' of HSR is relatively well established and where there is significant involvement of local researchers and close ties and relationships with policy makers are often present. We frame our discussion around two country case studies with which we are familiar, namely China and South Africa and discuss the implications for conducting 'embedded' research. We suggest that reflexivity is an important concept for health system researchers who need to think carefully about positionality and their normative stance and to use such reflection to ensure that they can negotiate to retain autonomy, whilst also contributing evidence for health system change. A research process informed by the notion of reflexive practice and iterative learning will require a longitudinal review at key points in the research timeline. Such review should include the convening of a deliberative process and should involve a range of stakeholders, including those most likely to be affected by the intended and unintended consequences of change. PMID- 26957048 TI - Role of Accurate Methodology in Demonstrating the Safety and Efficacy of Chondroitin Sulfate. PMID- 26957050 TI - JEB Editorial 2016. PMID- 26957049 TI - Epidemiological studies in hypertension: more relevant than ever. PMID- 26957051 TI - Corrigendum. PMID- 26957052 TI - Enhanced risk of illness during the 1918 influenza pandemic after previous influenza-like illnesses in three military populations. AB - The reasons for the unprecedented mortality during the 1918 influenza pandemic remain poorly understood. We examined morbidity records from three military cohorts from years prior to and during the 1918 pandemic period to assess the effects of previous respiratory illnesses on experiences during the pandemic. Clinical registers and morbidity lists were examined to identify all medical encounters for acute respiratory illnesses in students at two U.S. military officer training academies and Australian soldiers deployed in Europe. Influenza like illness prior to the major pandemic wave of 1918 predisposed Australian soldiers [relative risk (RR) 1.37, 95% confidence interval (CI) 1.18-1.60, P < 0.0001] and US officer trainees at West Point (RR 3.10, 95% CI 2.13-4.52, P < 0.0001) and Annapolis (RR 2.03, 95% CI 1.65-2.50, P < 0.0001) to increased risks of medically treated illnesses in late 1918. The findings suggest that susceptibility to and/or clinical expressions of the 1918 pandemic influenza virus depended on previous experiences with respiratory infectious agents. The findings are consistent with observations during the 2009 pandemic in Canada and may reflect antibody-dependent enhancement of influenza infection. PMID- 26957053 TI - Pretreatment of rats with increased bioavailable berberine attenuates cerebral ischemia-reperfusion injury via down regulation of adenosine-5'monophosphate kinase activity. AB - Berberine (BBR) exhibits multiple beneficial biological effects. However, poor bioavailability of BBR has limited its clinical application. We previously demonstrated that solid dispersion of BBR with sodium caprate (HGSD) remarkably improves its bioavailability. We examined whether this increased bioavailability of BBR could protect the brain from ischemia-reperfusion (IR) induced injury. Rats treated with HGSD, SC and saline for 7 days then subjected to cerebral ischemia reperfusion by middle cerebral artery occlusion for 2h followed 12h reperfusion. Neurological deficit scores, infarct size, SOD, MDA and NO levels were examined. P-AMPK, Bax, cleaved-Caspase-3 in brain was determined. To further probe for the mechanism of beneficial effect of HGSD, PC12 cells were incubated with serum from control or HGSD pretreated animals, incubated with 300MUM H2O2 to induce apoptosis. Caspase-3 activity and cell apoptosis was evaluated. HGSD pretreatment significantly attenuated neurological deficit scores, reduced infarct size, increased SOD and decreased MDA and NO after cerebral IR injury compared to controls. Meanwhile, HGSD pretreatment significantly reduced expression of p-AMPK, Bax, cleaved-Caspase-3 after cerebral IR injury. Sodium caprate (100mg/kg/d) pretreatment alone did not exhibit any of these beneficial effects. PC12 cell apoptosis was attenuated when cells were cultured with HGSD serum compared to control. The presence of AMPK activator (AICAR) attenuated whereas AMPK inhibitor (Compound C) augmented the protective effect of HGSD serum on PC12 cell apoptosis.The results indicate that HGSD-pretreatment of rats protects the brain from ischemia-reperfusion injury and the mechanism is due to its anti-apoptotic effect mediated by decreased activation of AMPK. PMID- 26957054 TI - Piracetam prevents memory deficit induced by postnatal propofol exposure in mice. AB - Postnatal propofol exposure impairs hippocampal synaptic development and memory. However, the effective agent to alleviate the impairments was not verified. In this study, piracetam, a positive allosteric modulator of AMPA receptor was administered following a seven-day propofol regime. Two months after propofol administration, hippocampal long-term potentiation (LTP) and long-term memory decreased, while intraperitoneal injection of piracetam at doses of 100mg/kg and 50mg/kg following last propofol exposure reversed the impairments of memory and LTP. Mechanically, piracetam reversed propofol exposure-induced decrease of BDNF and phosphorylation of mTor. Similar as piracetam, BDNF supplementary also ameliorated propofol-induced abnormalities of synaptic plasticity-related protein expressions, hippocampal LTP and long-term memory. These results suggest that piracetam prevents detrimental effects of propofol, likely via activating BDNF synthesis. PMID- 26957055 TI - The effect of urapidil, an alpha-1 adrenoceptor antagonist and a 5-HT1A agonist, on the vascular tone of the porcine coronary and pulmonary arteries, the rat aorta and the human pulmonary artery. AB - Urapidil (Eupressyl((r))) an antihypertensive drug acting as an alpha1 antagonist and a 5-HT1A agonist, may be of special interest in the treatment of hypertension associated with preeclamptic toxaemia and hypoxia-induced pulmonary arterial vasoconstriction. However, the effect of urapidil on vascular tone has been poorly investigated. Vascular reactivity was evaluated using pulmonary and coronary arteries from 36 pigs, aortae from 22 rats and 9 human pulmonary artery samples suspended in organ chambers. Concentration-relaxation curves either to urapidil, 5-HT, or the 5-HT1A receptor agonist 8-OH-DPAT were constructed after pre-contraction of rings. Pig pulmonary and coronary artery rings were contracted with U46619, a thromboxane mimetic, rat aortic rings with either endothelin-1 or phenylephrine, and human pulmonary artery rings with U46619 or phenylephrine. Urapidil markedly inhibited phenylephrine-induced contractions in rat aortic rings with and without endothelium with a more pronounced effect observed in rings without endothelium. Both 5-HT and 8-OH-DPAT failed to induce relaxation in rat aortic rings with an intact endothelium. 5-HT, but not urapidil and 8-OH DPAT, induced a concentration-dependent relaxation in the porcine coronary and pulmonary artery rings with an intact endothelium (P<0.05). 5-HT and phenylephrine but not urapidil caused concentration-dependent contractions in human pulmonary artery rings. The present findings, while confirming that urapidil is a potent inhibitor of alpha1-adrenoceptor-induced contraction, do not support the role of 5-HT1A receptor activation in the control of the vascular tone of the different types of arteries tested in response to urapidil. In addition, they indicate that urapidil seems to preferentially target arteries with endothelial dysfunction. PMID- 26957057 TI - Primary adenocarcinoma of the lung--histological subtypes and outcome after surgery, using the IASLC/ATS/ERS classification of lung adenocarcinoma. AB - Adenocarcinoma is the most common histological type of lung carcinoma. Recently the histologic classification of adenocarcinomas in the lung was modified to better reflect biologic properties and prognosis. We reviewed the histology of all primary lung adenocarcinomas operated on in Iceland during a 20-year period and assessed the impact of histology on survival. This nationwide study included 285 patients (mean age 67 years, 57% female), who underwent resection in Iceland from 1991 to 2010. Tumors were reclassified according to the current IASLC/ATS/ERS classification system. Overall survival was estimated by the Kaplan Meier method and Cox regression analysis used to evaluate prognostic factors of overall mortality. Acinar predominant adenocarcinoma was the most common histological subtype (46%) followed by solid-predominant (SPA) with mucin production comprised (23%). Non-invasive carcinomas were rare. A difference in survival between the histological adenocarcinoma subtypes was not seen (p = 0.32) and multivariate analysis showed that advanced stage and age predicted worse outcome, but histologic subtyping of adenocarcinoma did not. In this nation-wide study there was not a statistical difference in survival according to adenocarcinoma subtypes and the histological subtype did not predict mortality. Preinvasive and minimally invasive adenocarcinomas were rare. PMID- 26957056 TI - Differential regulation of the beta-adrenoceptor density and cyclic AMP level with age and sex in turkey cardiac chambers. AB - Decreased responses of the heart to beta-adrenoceptor stimulation with aging have been shown to occur merely in selected heart chambers in relation to increased catecholamine levels. However, there are no systematic studies that investigate all cardiac chambers with regard to receptor density and cAMP (adenosine 3', 5' cyclic monophosphate) responses. We used meat-type turkey poults (British United Turkey (B.U.T.) Big 6) with increasing age because their heart seems to decrease in weight in relation to body weight and they are often used as an animal model for heart failure. The receptor density and distribution were quantified by radioligand binding analysis using (-)-[(125)I]-iodocyanopindolol and beta adrenoceptor subtype-specific antagonists (ICI 118.551 and CGP 20712 A) in membranes of four cardiac chambers (right and left atria and ventricles) of 6 week-, 12-week-, 16/21-week-, and 57-week-old B.U.T. BIG 6 turkeys. Receptor function was determined by measuring basal and stimulated cAMP production. In both sexes, the beta-adrenoceptor density decreased significantly in all chambers with age without altered beta-adrenoceptor subtype distribution. The receptor affinity (KD) to the radioligand was similar in hearts of all age groups. beta adrenoceptor-(isoproterenol and guanosine 5'-triphosphate), G-protein-(NaF) and catalytic unit of adenylate cyclase (forskolin, Mn(2+)) mediated cAMP responses were not chamber-dependent. Indeed, the cAMP level was significantly lower in 57 week-old hearts than in 6-week-, 12-week-, 16/21-week-old hearts. These data suggest that with increasing age and body weight, the beta-adrenoceptor signal transduction pathway was highly blunted in all cardiac chambers, occurring by decreased receptor density and cAMP responses. PMID- 26957059 TI - [Emphasis on standardized diagnosis and treatment of bronchial asthma in children]. PMID- 26957060 TI - [Development and Prospect of Chinese pediatric respiratory medicine]. PMID- 26957058 TI - Altered ratios of pro- and anti-angiogenic VEGF-A variants and pericyte expression of DLL4 disrupt vascular maturation in infantile haemangioma. AB - Infantile haemangioma (IH), the most common neoplasm in infants, is a slowly resolving vascular tumour. Vascular endothelial growth factor A (VEGF-A), which consists of both the pro- and anti-angiogenic variants, contributes to the pathogenesis of IH. However, the roles of different VEGF-A variants in IH progression and its spontaneous involution is unknown. Using patient-derived cells and surgical specimens, we showed that the relative level of VEGF-A165 b was increased in the involuting phase of IH and the relative change in VEGF-A isoforms may be dependent on endothelial differentiation of IH stem cells. VEGFR signalling regulated IH cell functions and VEGF-A165 b inhibited cell proliferation and the angiogenic potential of IH endothelial cells in vitro and in vivo. The inhibition of angiogenesis by VEGF-A165 b was associated with the extent of VEGF receptor 2 (VEGFR2) activation and degradation and Delta-like ligand 4 (DLL4) expression. These results indicate that VEGF-A variants can be regulated by cell differentiation and are involved in IH progression. We also demonstrated that DLL4 expression was not exclusive to the endothelium in IH but was also present in pericytes, where the expression of VEGFR2 is absent, suggesting that pericyte-derived DLL4 may prevent sprouting during involution, independently of VEGFR2. Angiogenesis in IH therefore appears to be controlled by DLL4 within the endothelium in a VEGF-A isoform-dependent manner, and in perivascular cells in a VEGF-independent manner. The contribution of VEGF-A isoforms to disease progression also indicates that IH may be associated with altered splicing. (c) 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. PMID- 26957061 TI - [Guideline for the diagnosis and optimal management of asthma in children(2016)]. PMID- 26957062 TI - [Ten years comparison of diagnosis and treatment of asthma in urban children in China]. AB - OBJECTIVE: To compare the changes of diagnosis, treatment and control of 0-14 years old urban asthma children during 10 years. METHOD: The questionnaires were given to diagnosed asthmatic children during the national epidemiological survey of asthma in children in 2000 and 2010 to understand the diagnosis and treatment of asthma and the status of the disease control. Children with asthma of a total of 36 cities were involved in this study, and the diagnosed asthma children in recent 2 years were 6,128 and 8 174, separately. Data were stored using epi-info software by double entry, V19.0 of SPSS was used to do the statistical analysis , chi(2) test was used. RESULT: The proportion of correct diagnosis of asthma before investigation in 2010 was 64.6%, while it was 70.7% in 2010, which showed a significant increase (chi(2) = 59.3, P < 0.01). Diagnosis rate of asthma onset within 1 year was separately 50.8% and 78.6% in 2000 and 2010. The early diagnostic rate was significantly higher in 2010 than that in 2000 (chi(2) = 817.7, P < 0.01). In 2000 and 2010 children with asthma medication in the use of inhaled corticosteroids was 36.3% and 61.7%, it increased by 0.7 times in 2010 (chi(2) = 907.5, P < 0.01). Systemic corticosteroids utilization rate was separately 74.2% and 39.1% (chi(2) = 1 730.6, P < 0.01). Beta 2 agonists utilization rate was separately 71.8% and 73.4%, showing a slight rise (chi(2) = 4.3, P < 0.05). Antibiotics usage was separately 97.4% and 76.0%, compared to a decrease of 21.4% (chi(2) = 1 274.2, P < 0.01). In the survey of 2000 and 2010, children with acute asthma attacks within recent 1 year were separately 86.3% and 77.0% (chi(2) = 194.0, P<0.01), hospitalizations for asthma attack were separately 54.0% and 47.3% (chi(2) = 61.7, P < 0.01), rate of absence from school due to asthma less than 10 days was separately 47.5% and 71.4% (chi(2) = 682.6, P < 0.01). CONCLUSION: The rates of correct diagnosis and early diagnosis of asthma in urban Chinese children within 1 year had a significant increase compared with a decade ago. Inhaled corticosteroids therapy had increased by 0.7 times than before while systemic corticosteroids utilization rate significantly decreased. Antibiotics usage had a decrease of 22.0% but they were still overused. Asthma control was significantly improved, but acute exacerbations and hospitalizations of asthma children still accounts for a large proportion although they both had a great improvement. PMID- 26957063 TI - [Clinical analysis of 16 cases of invasive pulmonary aspergillosis in children]. AB - OBJECTIVE: To investigate the diagnosis and treatment of invasive pulmonary aspergillosis (IPA) in children. METHOD: The clinical data of 16 cases of proven or probable IPA who had been in our Hospital from January 2006 to June 2014 were retrospectively analyzed. RESULT: Among the 16 patients, 11 were males and 5 were females. One child had proven IPA and 15 children had probable IPA. Host risk included long duration use of multiple broad-spectrum antibiotics in 16 cases, neutropenia in 9 cases, invasive mechanical ventilation in 3 cases, primary immunodeficiency disease in 2 cases, long-term use of glucocorticoids in 2 cases, measles in 2 cases, and congenital pulmonary hypoplasia in 1 case. Fever, cough and expectoration were present in all the children with IPA. At the time of diagnosis, the halo sign and subpleural wedge consolidation shadows were more common in neutropenia group (5/9, 7/9) than those in non-neutropenia group(0/7, 1/7)(P<0.05). The cavities and"air-crescent sign"were more common after 15 days to 1 month when the children had been treated with anti-aspergillosis drugs than that at the onset of diagnosis of IPA (P<0.05). The positive rate of serum galactomannan (GM) test was higher than that of sputum culture and serum G test (P<0.05). Thirteen children received voriconazole, in 7 of the children the treatment was effective. CONCLUSION: Neutropenia were the common host risk factors in children with IPA. Subpleural wedge consolidation shadows, the halo sign and the"air-crescent"sign were highly suggestive of the diagnosis of IPA in children. Subpleural wedge consolidation shadows and the halo sign were more common in neutropenia group than in non-neutropenia group in the early stage of the course. Serum GM test played an important role in the diagnosis of IPA in children. Voriconazole was effective in majority of the children with IPA. PMID- 26957064 TI - [Electroencephalographic features of anti-N-methyl-D-aspartate receptor encephalitis in children]. AB - OBJECTIVE: To investigate electroencephalographic (EEG) characteristics of anti-N methyl-D-aspartate receptor (anti-NMDAR) encephalitis in children. METHOD: Clinical data of 28 children diagnosed as anti-NMDAR encephalitis were retrospectively analyzed for EEG characteristics in different periods and severity of disease and outcome. RESULT: Among the 28 patients with anti-NMDAR encephalitis, 15 were males and 13 were females. Their age at disease onset ranged from 1 year 3 months to 12 years 4 months. Patients were divided into mild group (5 cases) and severe group (23 cases). In the different stage of the disease, occipital background activity of the EEG was preserved in more than half of patients. Accompanied by the evolution of disease course, the occipital background activity and slow waves gradually recovered to normal. In the peak phase of disease, occipital background activity in the awake state was preserved in 4/5 patients of the mild group and 9/17 patients of the severe group. Alpha and theta band rhythms in non-rapid eye movement (NREM) sleep existed in 77% (17/22) patients. EEG monitoring showed delta brushes in 2 cases, and the delta brushes were mixed with background fast waves in one case; 71% (20/28) patients had epileptiform discharges in EEG during the course, and among them, 6 patients had secondary epilepsy. CONCLUSION: The background activity in the awake state and abnormal diffuse slow waves of EEG were evolved and gradually recovered during the course of the disease. Regardless milder or severe illness condition, occipital background activity was still preserved during different stages in most patients. Alpha and theta rhythms in NREM sleep might represent a relatively overt EEG characteristic. The presence of delta brush in EEG was rare, and sometimes they were difficult to be distinguished from fast wave activities caused by drugs. The presence of epileptiform discharges in EEG suggested the possibility of secondary epilepsy. PMID- 26957065 TI - [Clinical analysis of 8 cases of neonatal septicemia caused by Candida haemulonii in neonatal intensive care unit]. AB - OBJECTIVE: To study the clinical characteristics, antibiotics sensitivity, outcome and risk factors of neonatal septicemia caused by Candida haemulonii. METHOD: A retrospective analysis was performed on clinical characteristics and antibiotics sensitivity after 8 cases of neonatal septicemia caused by Candida haemulonii were identified; each of these patients had at least one positive result of bacterial culture for Candida haemulonii. RESULT: The 8 cases born at gestational age of 178-260 d, weighing 835-2 055 g, developed the infection from May to July at 10-34 d after hospitalization. Among the 8 patients, 7 were cured, 1 died during hospitalization after the treatments were given up because of serious complications. The 8 patients with septicemia caused by Candida haemulonii had similar clinical chariacteristics to those of other neonatal candidemia, such as apnea, fever, abdominal distension, jaundice etc. They had abnormal auxiliary examination with increased C-reactive protein (CRP), declined platelet (PLT) count to different degrees. All of the 8 patients had peripherally inserted central catheter (PICC) and broad-spectrum antibiotics were applied. C. haemulonii as an emergent fungal pathogen had varying degrees of resistance to fluconazole, amphotericin B, itraconazole, or ketone, but was susceptible to voriconazole. CONCLUSION: The characteristics of neonatal septicemia caused by Candida haemulonii were similar to those caused by other candida, and the main risk factors are the low birth weight, PICC, and usage of broad-spectrum antibiotics. It mainly occurred in May to July which is hot and humid season. PMID- 26957066 TI - [Analysis of clinical characteristics of hypoxic hepatitis in children]. AB - OBJECTIVE: To explore the etiology and clinical characteristics of hypoxic hepatitis (HH) in children. METHOD: Clinical data of 7 patients with HH in Shenzhen Children's Hospital from January 2011 to March 2014 were retrospectively reviewed. RESULT: Seven cases diagnosed as HH, age from 4 months to 11 years, were admitted to pediatric intensive care unit (PICU), and accounted for 0.32% of patients in PICU during the same period. The primary causes of HH were respiratory failure and cardiac shock caused by severe hand-foot-and-mouth disease, fulminant myocarditis, infant muggy syndrome . Serologic tests for hepatitis B virus, hepatitis C virus, as well as serum antibody and DNA for Epstein-Barr virus and cytomegalovirus were all negative. There was an increase of alanine aminotransferase (ALT) (>=20 time supper limit of normal (ULN), the highest ALT was more than 130 times ULN in all the patients, which was decreased to 2 times ULN from peak within 10 days. There was a significant relationship between ALT and aspartate aminotransferase(AST)in 3 cases(r=1.000, 1.000, and 0.833, respectively, P<0.05), ALT and lactate dehydrogenase (LDH)in 2 cases(r=1.000 and 0.886, respectively, P<0.05), ALT and blood urea nitrogen(BUN)in 1 case(r=1.000, P<0.05), and ALT and creatine kinase(CK)in 1 case(r=0.964, P<0.05). The ALT, AST and LDH returned to normal soon after the primary diseases were controlled. CONCLUSION: Severe heart failure, hypoxemia, shock, etc. are the leading primary diseases causing HH. The sharp increase in ALT, AST and LDH is the typical laboratory manifestion in HH after the onset, which may decline to normal shortly after the treatment, sometimes complicated with reversible change in BUN or CK. PMID- 26957067 TI - [Clinical and molecular characteristics of a child with familial adenomatous polyposis]. AB - OBJECTIVE: To explore the clinical features and molecular mutation of early-onset familial adenomatous polyposis(FAP) in childhood. METHOD: The clinical features, endoscopic findings, pathology and therapeutic effect of sulindac during 11 years follow-up in a child with FAP were retrospectively reviewed . Adenomatous polyposis coli (APC) gene mutation analysis was performed by PCR and first generation sequencing. RESULT: This 6-year-old girl was admitted for intermittent bloody stool during the last one and a half years. Colonoscopy showed hundreds of polyps in the rectum and colon. Pathological examination revealed tubular adenomas with high grade dysplasia. During the follow-up period of 11 years, the child presented intermittent mucous bloody stool. Endoscopy showed the number of polyps in colon and rectum increased to thousands, and found multiple polyps in gastric fundus and body.She was treated with sulindac at the age of 13. Then the number of polyps and the grade of pathology showed a slight improvement and no carcinoma was seen on biopsy. She has not accepted surgery until now. Gene sequencing of this child revealed 5 bp deletion at codon 1,309 of exon 15 (c.3927_3931delAAAGA) of tumor suppressor gene, whereas none of her parents had the same mutation. And no polyps were found on her parents colonoscopy. CONCLUSION: This child with FAP had an early onset of this disease, and clinical conditions were exacerbated with age. Sulindac was partially effective in controlling size and number of polyps. The site of mutation in this case was consistent with classic FAP, and without family history, the mutation may be a sporadic one. PMID- 26957068 TI - [Copy number variations in pediatric ETV6/RUNX1 positive acute lymphoblastic leukemia]. AB - OBJECTIVE: To evaluate the copy number variations (CNVs) in pediatric ETV6/RUNX1 gene positive acute lymphoblastic leukemia(ALL) and its correlation with clinical features and prognosis. METHOD: Totally 141 children (<14 years of age) with newly diagnosed ETV6/RUNX1 positive ALL in Institute of Hematology and Blood Diseases Hospital, were included from January 2006 to November 2012. The CNVs were analyzed by multiplex ligation-dependent probe amplification (MLPA). The survival rate between the patients with CNVs were explored. Overall survival (OS) and event-free survival (EFS) were estimated by the Kaplan-Meier method and compared with the log-rank test. RESULT: Among the 141 cases, 55.3% (n=78) were boys and 44.7% (n=63) were girls and the median age was 4 (1-13) years. The estimated 5-year DFS rate for the patients was (84+/-4)%. The estimated 5-year OS rate for the patients was (85+/-4)%. Ninety-five patients were tested MLPA. CNVs were detected in 73 cases (76.8%). CNVs of genes EBF1(15.8%), CDKN2A/2B(18.9%), PAX5(21.1%), ETV6(54.8%), BTG1(10.5%) were detected in more than 10% of the patients. Among the 95 patients, EBF1 deletions were found in 9 patients and EBF1 amplifications were found in 6 patients; 5-year recurrence-free survival (RFS) was statistically significant among 3 groups (chi(2)=9.809, P=0.007) . PAX5 deletions were found in 13 patients and PAX5 amplifications were found in 7 patients; the difference in 5-year RFS was statistically significant between 3 groups(chi(2)=7.622, P=0.022). ETV6 deletions were found in 39 patients and ETV6 amplifications were found in 13 patients; the difference in 5-year RFS was statistically significant among the 3 groups (chi(2)=11.045, P=0.004). CONCLUSION: The CNVs had prognostic relevance in ETV6/RUNX1 positive ALL. PMID- 26957069 TI - [Clinical analysis of three cases with infant botulism and review of literature]. AB - OBJECTIVE: To analyze the clinical characteristics and diagnosis of three cases with infant botulism. METHOD: Clinical data of three clinically diagnosed cases with infant botulism in May 2015 in Peking University First Hospital were retrospectively analyzed. Literature search at databases of PubMed, Wanfang, China National Knowledge Infrastructure and VIP with the key words"infant AND botulism". The date of literature retrieval was from the database founding to November 2015. The characteristics of infant botulism were summarized through review of literature. RESULT: Three patients were infants of 4-8 months of age, and all had acute onsets of anorexia and poor response. All of them had normal psychomotor development previously, and without clear history of exposure to poisons. The main findings on physical examination were reduced muscle strength and hypotonia, dullness or disappeared pupillary light reflex, reduced facial expression, weak crying and dysphagia. Unexpectedly their states of consciousness were relatively normal. Finally, through identification and PCR genotyping of bacteria in stool, 2 cases were confirmed as Clostridium (C.) botulinum type B infection. Totally 446 reports were retrieved from foreign language literature and 52 reports from Chinese literature. More than 3,000 cases of infant botulism cases were reported in the world. Rare cases were reported in China and only 1 case was reported in 2000. CONCLUSION: Most cases of infant botulism had no clear exposure history. The main clinical manifestations are hypotonia, cranial nerve paralysis, flaccid paralysis, but different patients may have different presentations. Detection of C. Botulinum and its toxin in stool can help to confirm the diagnosis. Infant botulism is relatively rare in China, which may be related to the insufficient understanding and inspection level of the disease. It might be underestimated in China. PMID- 26957070 TI - [Peroneal myoatrophy type 4H FGD4 new gene mutation in one case and literature review]. AB - OBJECTIVE: To explore the clinical and gene mutation characteristics of children with peroneal myoatrophy FGD4 mutations. METHOD: The clinical data of a patient with peroneal myoatrophy with novel FGD4 gene mutations were collected, the related literature was searched from China National Knowledge Infrastructure, Wanfang Data Knowledge Service Platform, National Center for Biotechnology Information and PubMed (up to December 2014) by using search terms"muscular disorders, atrophic""peripheral nervous system diseases""genes". The clinical features and treatment of the patients with FGD4 gene mutations were studied. RESULT: The patient was a 10-years-old boy, he was presented to our clinic due to lower extremity weakness for 3 years, worsening for one year with normal family history and birth history. When he was 6 years old, his feet turned inward as he walked, at 7 years of age, his toes pointed toward the ground, the heel could not touch the ground, the right foot was more serious. During the recent year his symptoms were worsened, manifested as clubfoot, foot drop, arched feet, crane legs, difficult in squatting, walking with swaying gait, easy to fall. He was brought to a number of domestic general hospitals' neurology clinic, he was clearly diagnosed as peroneal myoatrophy, but failed to make typing. Electromyography (EMG) showed neurogenic damage (peripheral neuropathy - motor and sensory fibers are involved). Target gene sequencing showed that the child had FGD4 genes compound heterozygous mutation: c. 338A> G and c. 1730G> A, where the former was inherited from his father, the latter inherited from his mother, it was a new mutation unreported previously. Literature search retrieved six reports (all in English literature) with FGD4 10 cases with mutations, which were expressed as peroneal myoatrophy, but were homozygous mutation. CONCLUSION: This study found the FGD4 4th and the 14th exons' c. 338A> G and c. 1730G> A heterozygous mutations, and this mutations may lead to peroneal myoatrophy. PMID- 26957071 TI - [Platelet-rich plasma closed successfully patent ductus arteriosus in preterm infant: report of one case]. PMID- 26957072 TI - [Screening and molecular diagnosis for a rare genotype of beta-thalassemia intermedia]. PMID- 26957073 TI - [Megacystis microcolon intestinal hypoperistalsis syndrome: report of 2 cases]. PMID- 26957074 TI - [Significance of the application of point-of-care lung ultrasound in neonatal lung diseases]. PMID- 26957075 TI - [Progress in the genetics of bronchopulmonary dysplasia]. PMID- 26957076 TI - [Progress on the current status and therapy of the carbapenem-resistant Klebsiella pneumoniae infection]. PMID- 26957077 TI - [Mechanism of angioneurins' protective effect against premature brain injury: a summary of research progress]. PMID- 26957078 TI - A model of dopamine regulation of glutamatergic synapse on medium size spiny neurons. AB - Spiny neurons of striatum receive glutamatergic synapses on dendritic spines on the neck of which project dopaminergic synapses. Dopamine modulates, by D1 type receptors, the glutamatergic synapses by inducing the phosphorylation of AMPA and NMDA receptors which produces an increased amplitude response. Herein we present a model where, in addition to phosphorylation, the direct modulation by dopamine of the spine resistance can cooperate in producing the observed effect on some of these synapses. PMID- 26957079 TI - A qualitative study of the barriers and enablers to fertility-awareness education in general practice. AB - AIMS: To understand the barriers and enablers to fertility-awareness education in general practice. BACKGROUND: Most women along with their primary care practitioners - general practitioners and practice nurses - believe that women should be educated about fertility-awareness when first reporting trouble conceiving. To date, no in-depth study has examined the enablers and challenges of this type of education in general practice. DESIGN: A descriptive exploratory qualitative study using deductive content analysis. METHODS: General practitioners (N = 11) and practice nurses (N = 20) were recruited from general practices in three socioculturally diverse areas in Victoria, Australia. Data were collected through semistructured interviews based on the 12 domains of a theoretical behaviour change framework from April-August 2012. The participants' responses were organized into themes that fall under the framework domains. FINDINGS: The biggest barriers to fertility-awareness education in general practice were short consultations and time constraints faced by general practitioners together with a lack of patient educational materials and remuneration to support its delivery. The biggest enablers were a greater use of nurses trained in fertility-awareness in a collaborative team care arrangement with general practitioners. CONCLUSION: This study has identified several important barriers and enablers to fertility-awareness education in general practice. Translation into practice of our findings is imperative as the first step in establishing a primary care model in fertility-awareness. This would fill an important gap in the primary care of infertile women and build capacity in general practice to reduce infertility through women's enhanced fertility knowledge. PMID- 26957080 TI - Ten things that nurses should know about ECMO. PMID- 26957081 TI - A novel Markov Blanket-based repeated-fishing strategy for capturing phenotype related biomarkers in big omics data. AB - BACKGROUND: We propose a novel Markov Blanket-based repeated-fishing strategy (MBRFS) in attempt to increase the power of existing Markov Blanket method (DASSO MB) and maintain its advantages in omic data analysis. RESULTS: Both simulation and real data analysis were conducted to assess its performances by comparing with other methods including chi(2) test with Bonferroni and B-H adjustment, least absolute shrinkage and selection operator (LASSO) and DASSO-MB. A serious of simulation studies showed that the true discovery rate (TDR) of proposed MBRFS was always close to zero under null hypothesis (odds ratio = 1 for each SNPs) with excellent stability in all three scenarios of independent phenotype-related SNPs without linkage disequilibrium (LD) around them, correlated phenotype related SNPs without LD around them, and phenotype-related SNPs with strong LD around them. As expected, under different odds ratio and minor allel frequency (MAFs), MBRFS always had the best performances in capturing the true phenotype related biomarkers with higher matthews correlation coefficience (MCC) for all three scenarios above. More importantly, since proposed MBRFS using the repeated fishing strategy, it still captures more phenotype-related SNPs with minor effects when non-significant phenotype-related SNPs emerged under chi(2) test after Bonferroni multiple correction. The various real omics data analysis, including GWAS data, DNA methylation data, gene expression data and metabolites data, indicated that the proposed MBRFS always detected relatively reasonable biomarkers. CONCLUSIONS: Our proposed MBRFS can exactly capture the true phenotype-related biomarkers with the reduction of false negative rate when the phenotype-related biomarkers are independent or correlated, as well as the circumstance that phenotype-related biomarkers are associated with non-phenotype related ones. PMID- 26957083 TI - Lasiothyris luminosa (Razowski & Becker) (Lepidoptera: Tortricidae): a New Grapevine Pest in Northeastern Brazil. AB - The little-known Neotropical tortricid moth Lasiothyris luminosa (Razowski & Becker) is reported for the first time as a grapevine pest in northeastern Brazil. A diagnosis based on morphological characters including the genitalia is provided for both sexes, together with a preliminary description of economic damage caused by the larval stage on flowers and fruits. In addition, we sequenced a partial region of the cytochrome oxidase subunit I gene from specimens from the region and reconstructed phylogenetic relationships using representative lineages of closely related tortricids as terminals. PMID- 26957082 TI - High Diversity of Drosophilidae in High-Altitude Wet Forests in Northeastern Brazil. AB - The high-altitude wet forests of northeastern Brazil, locally known as "Brejos de Altitude," are enclaves of the Atlantic Forest situated above 500 m, surrounded by dryland vegetation, the Caatinga. The aim of this study was to characterize drosophilid communities in these upland forests, since few ecological studies on drosophilid communities have been conducted in northeastern Brazil. Four sites were investigated in three different times of the year throughout standardized traps. The results reveal the presence of 55 different species in a total of 13,064 specimens collected. The data were evaluated using ecological diversity measurements and compared with those obtained for other environments in the same geographic region. As for species composition, the Bonito upland forest, in a boundary forest location, stood out as having high species richness. PMID- 26957084 TI - Scale Insects (Hemiptera: Coccoidea) on Myrciaria dubia (Myrtaceae) in Brazil. AB - Commercial cultivation of the fruit tree Myrciaria dubia (Myrtaceae) is being developed in Brazil but phytophagous insects, including scale insects (Hemiptera: Coccoidea), can become pests in plantations. The coccids Ceroplastes jamaicensis White, Coccus viridis (Green), Parasaissetia nigra (Nietner), Pseudokermes vitreus (Cockerell) (Coccidae), and the diaspidid Pseudaonidia trilobitiformis (Green) were collected on M. dubia in the municipality of Belem and Tome-Acu, state of Para (PA), metropolitan and Northeast Para mesoregions, Brazil. A key to species of Coccoidea recorded on M. dubia, based on adult females, is provided. Photographs for all scale insects reported on M. dubia are provided. Ceroplastes jamaicensis is recorded for the first time for Brazil and is herein reported for the first time associated with this host. PMID- 26957086 TI - Taxonomic and Functional Resilience of Grasshoppers (Orthoptera, Caelifera) to Fire in South Brazilian Grasslands. AB - Fire is a frequent disturbance in grassland ecosystems enabling variability in habitat characteristics and creating important environmental filters for community assembly. Changes in vegetation have a large influence on herbivore insect assemblages. Here, we explored the responses of grasshoppers to disturbance by fire in grasslands of southern Brazil through a small-scale experiment based in paired control and burned plots. The resilience of grasshoppers was assessed by monitoring changes to their abundance, taxonomic, and functional parameters along time. Burned patches have been already recolonized by grasshoppers 1 month after fire and did not differ in terms of abundance and richness from control areas in any evaluated time within 1 year. Simpson diversity decreased 1 month after fire due to the increased dominance of Dichroplus misionensis (Carbonell) and Orphulella punctata (De Geer). In this period, grasshoppers presented in average a smaller body and a larger relative head size; these are typically nymph characteristics, which are possibly indicating a preference of juveniles for the young high-quality vegetation, or a diminished vulnerability to predation in open areas. Further, at 6 months after fire grasshoppers with smaller relative hind femur and thus lower dispersal ability seemed to be benefitted in burned patches. Finally, 1 year after fire grasshoppers became more similar to each other in relation to their set of traits. This study demonstrates how taxonomic and functional aspects of grasshopper assemblages can be complementary tools to understand their responses to environmental change. PMID- 26957087 TI - Passipassalus brevicornis n. sp.: a New Passalidae (Coleoptera) from Brazilian Amazonian, with a Key to the Species of Passipassalus Reyes-Castillo & Fonseca. AB - Passipassalus brevicornis n. sp. is described from two specimens from Tefe and Coari, Amazonas, Brazil. This species represents the fifth species recognized of Passipassalus and differs from the other species of the genus mainly by having an apex of central tubercle of median frontal structure not free, frontal fossae with some scarce setae, metasternal fossae with scarce setae, humeri fully pubescent, and marginal groove over anterior ventral edge of femur I marked and complete. Additionally, a key to the species of Passipassalus is given. PMID- 26957085 TI - Olfactory Response and Host Plant Feeding of the Central American Locust Schistocerca piceifrons piceifrons Walker to Common Plants in a Gregarious Zone. AB - The Central American locust (CAL) Schistocerca piceifrons piceifrons Walker is one of the most harmful plant pests in the Yucatan Peninsula, where an important gregarious zone is located. The olfactory response and host plant acceptance by the CAL have not been studied in detail thus far. In this work, the olfactory response of the CAL to odor of various plant species was evaluated using an olfactometer test system. In addition, the host plant acceptance was assessed by the consumption of leaf area. Results showed that the CAL was highly attracted to odor of Pisonia aculeata. Evaluation of host plant acceptance showed that the CAL fed on Leucaena glauca and Waltheria americana, but not on P. aculeata or Guazuma ulmifolia. Analysis of leaf thickness, and leaf content of nitrogen (N) and carbon (C) showed that the CAL was attracted to plant species with low leaf C content. PMID- 26957088 TI - Mammalian target of rapamycin complex (mTOR) pathway modulates blood-testis barrier (BTB) function through F-actin organization and gap junction. AB - mTOR (mammalian target of rapamycin) is one of the most important signaling molecules in mammalian cells which regulates an array of cellular events, ranging from cell metabolism to cell proliferation. Based on the association of mTOR with the core component proteins, such as Raptor or Rictor, mTOR can become the mTORC1 (mammalian target of rapamycin complex 1) or mTORC2, respectively. Studies have shown that during the epithelial cycle of spermatogenesis, mTORC1 promotes remodeling and restructuring of the blood-testis barrier (BTB) in vitro and in vivo, making the Sertoli cell tight junction (TJ)-permeability barrier "leaky"; whereas mTORC2 promotes BTB integrity, making the Sertoli cell TJ-barrier "tighter". These contrasting effects, coupled with the spatiotemporal expression of the core signaling proteins at the BTB that confer the respective functions of mTORC1 vs. mTORC2 thus provide a unique mechanism to modulate BTB dynamics, allowing or disallowing the transport of biomolecules and also preleptotene spermatocytes across the immunological barrier. More importantly, studies have shown that these changes to BTB dynamics conferred by mTORC1 and mTORC2 are mediated by changes in the organization of the actin microfilament networks at the BTB, and involve gap junction (GJ) intercellular communication. Since GJ has recently been shown to be crucial to reboot spermatogenesis and meiosis following toxicant-induced aspermatogenesis, these findings thus provide new insightful information regarding the integration of mTOR and GJ to regulate spermatogenesis. PMID- 26957089 TI - Does the T1 subdivision correlate with the risk of recurrence of papillary thyroid cancer? AB - BACKGROUND: Based on the AJCC seventh TNM classification, T1 intraglandular tumors are subdivided into T1a (<=10 mm) and T1b (11-20 mm), but the differences in prognosis remain controversial. The present study aimed to determine the clinicopathological features and outcomes of T1a and T1b patients. METHODS: A retrospective study of 2518 T1 patients, including 1840 T1a (73 %) and 678 (27 %) T1b patients who underwent surgery for PTC from 1978 to 2014, was conducted. In patients with a preoperative or operative diagnosis of PTC, a total thyroidectomy (TT) with prophylactic (macroscopically N0) or therapeutic (evident N1) lymph node dissection (LND) was performed. Other patients had a TT or partial thyroidectomy without LND. The mean follow-up time was 8.9 +/- 8.8 years (median, 6.5 years; range, 1-36.4 years). RESULTS: A TT was performed in 2273 patients (90 %), including 1184 (52 %) with LND. Other patients (n = 245) had a single lobectomy with isthmectomy. Multifocality, bilaterality, number of tumors, sum of the largest size of all foci, vascular invasion, and (in patients with LND) LN metastases were significantly more frequent in T1b than in T1a patients. Of the 1184 patients with LND, 278 had LN metastases (N1, 23 %), including 136/680 T1a (20 %) and 142/504 (28 %) T1b patients (p = 0.002). These LN metastases were diagnosed after a prophylactic LND in 86/609 T1a (14 %) and 93/440 T1b (21 %) patients (p = 0.001). Recurrences were more frequent in T1b (n = 26, 3.8 %) than in T1a patients (n = 35, 1.9 %, p = 0.005). In the multivariate analysis, independent prognostic factors for recurrence in both groups were the number of tumors, the sum of the largest size of all foci and, in patients who had LND, LN metastases and extranodal extension. For N0-x patients, the recurrence rate was significantly higher in the T1b than in the T1a group (2.4 vs. 0.9 %, respectively, p = 0.005), although this rate was similar in N1 patients (16.2 % for T1a and 9.2 % for T1b patients, p = 0.1). The 5-year disease-free survival rates for T1a and T1b patients were 98.3 and 96.6 %, respectively (p = 0.01). CONCLUSION: For PTC patients, T1b had poorer clinicopathological features and increased risk of recurrence than T1a. PMID- 26957091 TI - Catalog of genetic progression of human cancers: non-Hodgkin lymphoma. AB - The recent application of next-generation sequencing technologies lead to significant improvements in our understanding of genetic underpinnings of non Hodgkin lymphomas with identification of an unexpectedly high number of novel mutation targets across the different B-cell lymphoma entities. These recently discovered molecular lesions are expected to have a major impact on development of novel biomarkers and targeted therapies as well as patient stratification based on the underlying genetic profile. This review will cover the major discoveries in B-cell lymphomas using next-generation sequencing technologies over the last few years, highlighting alterations associated with relapse and progression of these diseases. PMID- 26957090 TI - Medication overuse headache in Europe and Latin America: general demographic and clinical characteristics, referral pathways and national distribution of painkillers in a descriptive, multinational, multicenter study. AB - BACKGROUND: Medication overuse headache (MOH) is a very disabling and costly disorder due to indirect costs, medication and healthcare utilization. The aim of the study was to describe general demographic and clinical characteristics of MOH, along with the national referral pathways and national painkillers distribution in several European and Latin American (LA) Countries. METHODS: This descriptive cross-sectional observational study included 669 patients with MOH referred to headache-centers in Europe and LA as a part of the COMOESTAS project. Information about acute medication and healthcare utilization were collected by extensive questionnaires, supplemented with structured patient interviews. RESULTS: Triptans were overused by 31 % European patients and by 6 % in LA (p < 0.001), whereas ergotamines were overused by 4 % in Europe and 72 % in LA (p < 0.001). Simple analgesics were overused by 54 % in Europe and by 33 % in LA (p < 0.001), while combination-analgesics were more equally overused (24 % in Europe and 29 % in LA). More European patients (57 %) compared with LA patients (27 %) visited general practitioners (p < 0.001), and 83 % of European patients compared to 38 % in LA consulted headache specialists (p < 0.001). A total of 20 % in Europe and 30 % in LA visited emergency rooms (p = 0.007). CONCLUSION: There are marked variations between LA and Europe in healthcare pathways and in acute medication overuse regarding patients with MOH. This should be considered when planning prevention campaigns against MOH. PMID- 26957092 TI - Molecular characterization of echovirus 30 isolates from Poland, 1995-2015. AB - Echovirus 30 (E30) is one of the most frequently identified enterovirus and a major cause of meningitis in children and adults. To investigate the genetic variability and relationship of E30 isolated from specimens of aseptic meningitis cases that occurred in Poland over a period of 20 years, sequences of VP1 gene were determined and genetic analysis was performed. From 1995 to 2015, 124 E30 were isolated using RD cells, and 58 isolates were sequenced and characterized by phylogenetic analysis of partial VP1 region (793 nt). In general, nucleotide sequence divergence in pairwise comparisons among Polish E30 isolates ranged from 0.0 to 15.0 %. The phylogenetic analysis revealed that E30 circulating in Poland since 1995 belong to two unique groups: Group I, characterized by high divergence (up to 13.1 %), segregated in four subgroups, and showed strong temporal circulation of E30. Group II, detected in Poland in 2013-2014, was closely correlated with two meningitis outbreaks and formed a separate genetically homogeneous group. Phylogenetic analysis revealed that strains from Poland had the closest genetic relationship with not only the isolates previously identified in Europe (Belarus, France, Germany, Italy, Russia) but also those in other parts of the world (Australia, China). Sequences of outbreak isolates were grouped in group II together with those from Russia and China isolated during 2010-2013. The identification of five distinct viral lineages during 1995-2015 confirmed the high E30 genetic diversity which may be an essential precondition for the emergence of new strains responsible for further potential aseptic meningitis outbreaks. PMID- 26957093 TI - A recombinant rabies virus carrying GFP between N and P affects viral transcription in vitro. AB - Several studies have demonstrated the rabies virus to be a perfect potential vaccine vector to insert foreign genes into the target genome. For this study, a green fluorescent protein (GFP) gene was cloned into the rabies virus (RABV) genome between the N and P gene. CT dinucleotide was inserted as intergenic region. The recombinant high egg passage Flury strain (HEP-Flury) of RABV, carrying GFP (rHEP-NP-GFP), was generated in BHK-21 cells using reverse genetics. According to the viral growth kinetics assay, the addition of GFP between N and P gene has little effect on the viral growth compared to the parental strain HEP Flury. Quantitative real-time PCR (qPCR) indicated that rHEP-NP-GFP showed different viral gene transcription, especially for G gene, compared to HEP-Flury. The same is true for one other recombinant RABV carrying GFP between G and L gene in NA cells. In addition, parent HEP-Flury showed more expression of innate immune-related molecules in NA cells. Compared to HEP-Flury, Western blotting (WB) indicated that insertion of a foreign gene following N gene enhanced the expression of M and G proteins. According to the qPCR and WB, GFP expression levels of rHEP-NP-GFP were significantly higher than rHEP-GFP. This study indicates HEP-Flury as valid vector to express exogenous genes between N and P. PMID- 26957094 TI - Translating Inhibitory Fc Receptor Biology into Novel Therapeutic Approaches. AB - Innate and adaptive immune responses represent well balanced reactions aimed at resolving microbial infections without causing major collateral damage to the host. Disturbances in this system either due to enhanced activating or decreased inhibitory signaling pathways may lead to excessive immune activation resulting in tissue damage, the induction of autoimmune disease and/or chronic inflammation. On the molecular level this balance is achieved by the integration of inhibitory and activating signals, which are delivered by pairs of activating and inhibitory cell surface receptors expressed on innate and adaptive immune cells. The regulation of immunoglobulin G activity through cellular Fc receptors is a prime example for this type of regulation. This is not only relevant for the regulation of antibody-mediated effector functions through innate immune effector cells but also for the regulation of B cell activation and antibody production itself. PMID- 26957095 TI - Accelerated Premalignant Polyposis and Second Colon Cancers: Incriminating Immunosuppression, Radiotherapy, and Systemic Chemotherapy Agents. AB - BACKGROUND: Cancer survivors are known to be at increased risk for second primary cancers. In addition, immunosuppression and previous cancer treatments such as radiotherapy and systemic chemotherapy are linked with increased risk of both colonic adenomas and adenocarcinomas. AIM: We performed a systematic review searching for manuscripts discussing second colon cancers, accelerated polyposis, immunosuppression, radiation, and chemotherapy. We sought to identify a link between immunosuppression and increased risks specific to premalignant polyposis and second colon cancers. FINDINGS: We identified multiple studies demonstrating associations between radiotherapy, systemic chemotherapy, and immunosuppression with a higher propensity for second colon adenomas and adenocarcinomas. When compared to the general population, these risks were more profound and the rate at which these second malignancies developed was significantly increased. CONCLUSIONS: We believe that timing for colonoscopic surveillance in these patients should be different from the general population in order to identify promptly these rapidly progressive neoplasms. Screening for second malignancies should be considered early after remission of the primary cancer is documented, especially when a prolonged survival or a cure is anticipated. We also recommend consideration be given to increasing the frequency of colonoscopy in these cohorts. Future studies are required in order to establish the optimal time interval for surveillance colonoscopy in these high-risk individuals. PMID- 26957096 TI - Sacroiliac joint fusion for low back pain: a systematic review and meta-analysis. AB - BACKGROUND CONTEXT: Although pain is generally regarded as originating in the lumbar spine, it has been estimated that in 15-30 % of patients, LBP originates from the sacroiliac joint (SIJ). PURPOSE: To determine whether sacroiliac joint fusion (SIJF) for LBP is effective in reducing pain when the SIJ is known to be the pain generator. STUDY DESIGN/SETTING: Systematic review and meta-analysis. METHODS: A systematic literature review and meta-analysis was performed of observational studies describing outcome of SIJF in patients with LBP. Outcome measures were VAS pain, ODI, SF-36 PCS/MCS and Majeed score. The following databases were searched: PubMed, Web of Science, Embase, Medline and Google scholar. The methodological quality of selected studies was assessed using the National Heart Lung and Blood Institute case series quality assessment tool. Meta analysis was used to combine the studies for each outcome and forest plots were prepared. Outcomes were expressed as mean difference (MD). RESULTS: Six studies were included in the meta-analysis with a mean follow-up of 17.6 months. All outcomes showed statistical and clinical improvement (VAS pain MD: 54.8; 95 % CI 48.6, 61.0; n = 380; p < 0.001, ODI MD: 14.5; 95 % CI 8.4, 20.6; n = 102; p < 0.001, SF-36 PCS MD: -19.5; 95 % CI -24.7, -14.2; n = 140; p < 0.001, SF-36 MCS MD: -8.5; 95 % CI -12.9, -4.1; n = 198; p < 0.001 and Majeed score MD: -35.4; 95 % CI -48.5, -22.2; n = 140; p < 0.001). CONCLUSIONS: SIJF appears to be a satisfactory procedure for alleviating pelvic girdle pain. PMID- 26957097 TI - Percutaneous pedicle screw placements: accuracy and rates of cranial facet joint violation using conventional fluoroscopy compared with intraoperative three dimensional computed tomography computer navigation. AB - PURPOSE: The goal of this study was to compare the accuracy and cranial facet joint violation rates between percutaneous pedicle screw placements using conventional fluoroscopy and intraoperative 3-D CT (O-arm) computer navigation. METHODS: We reviewed 194 pedicle screw of 28 consecutive patients who underwent minimally invasive lumbar or thoracic spinal stabilization. The accuracy of screw placement was evaluated according to two criteria published by Neo et al. and Upendra et al. Facet joint violation was evaluated according to the classification described by Babu et al. RESULTS: Upon Neo grading, CFT group had 19.4 % (14/72) pedicle breach rate and CT-IGN group had a 5.7 % (7/122) pedicle breach rate (p < 0.005). The same sets of screws were also assessed using the outcome-based classification established by Upendra. There were no screw caused neurovascular injuries (type 3 = 0) in both groups. The results showed that 87.5 % (63/72) screws had acceptable placements (type I) and 12.5 % (9/72) had unacceptable placements (type II) in CFT group. In contrast, 94.3 % (115/122) screw had acceptable placements (type I) and only 5.7 % (7/122) had unacceptable placements (type II) in CT-IGN group. Additionally, CFT group had a significantly higher facet joint violation rate of 30.5 % (11/36) than CT-IGN group that had a 3.8 % (3/79) violation rate (p < 0.005). CONCLUSION: This study indicated the use of intraoperative CT imaging (O-arm) navigation in PPS placement have very beneficial implications for MIS. PMID- 26957098 TI - Adjacent segment degeneration and revision surgery after circumferential lumbar fusion: outcomes throughout 15 years of follow-up. AB - PURPOSE: This retrospective study analyzes long-term outcomes (15 years) of circumferential lumbar fusion (CF) for degenerative spine disease using instrumented PLIF. The occurrence of adjacent segment degeneration (ASD) and the reintervention rate was specially focused. METHODS: A series of 73 patients who underwent CF (1-3 levels) was reviewed. Patients were evaluated preoperatively, at 2, 5, 10 and 15 years after surgery with static and dynamic radiographic studies, CT scan and MRI. Patients completed also the Oswestry-Disability index (ODI), the VAS score, and the patient self-satisfaction questionnaire. RESULTS: At 2-year follow-up, there was a decrease in the average ODI score (from 72.3 +/- 16.4 preop to 30.5 +/- 6.2). At 10- and 15-year follow-up, ODI scores return to preoperative scores in patients without revision surgery. The 82.8 % of patients referred an excellentgood self-satisfaction rate at this time. At 5-year follow up, seven patients (9.6 %) required reoperation because of symptomatic ASD. At 10 year follow-up, reoperated patients increased to 24.6 % (18 cases). Excellent and good self-satisfaction rate decreased to 41.1 % at this time. Radiological ASD was then detected in 37 cases (50.7 %). At 15-year follow-up, nine patients were lost and a total of 24 (37.5 %) required a new surgical treatment because of ASD. The occurrence of revision surgery because of symptomatic ASD was highly dependent of the age of patients at the first surgery and the number of fused levels. CONCLUSION: Circumferential lumbar fusion provides good clinical results at short-term follow-up. From 2- to 15-year follow-up, outcome worsened significantly. The high rate of ASD occurrence and reintervention questions the reliability of this technique for lumbar fusion. PMID- 26957099 TI - Compensatory modulation for severe global sagittal imbalance: significance of cervical compensation on quality of life in thoracolumbar kyphosis secondary to ankylosing spondylitis. AB - PURPOSE: To investigate the cervical compensation pattern and to clarify relationships between cervical compensation and quality of life (QOL) in ankylosing spondylitis (AS) patients with thoracolumbar kyphosis. METHODS: A cross-sectional study of consecutive AS patients with thoracolumbar kyphosis was performed. Forty-four patients with hyperlordotic cervical spine were assigned to group A and sixteen with kyphotic cervical spine in group B. Sagittal parameters were measured and compared, including T1 slope, cervical lordosis (CL), cervical sagittal vertical axis (C-SVA), global SVA and global kyphosis (GK). Independent factors for cervical compensation were identified. To exclude confounding variables while comparing QOL between patients with hyperlordotic and kyphotic cervical spine, 31 patients were selected as group A-1, similar to 13 patients in group B-1 in the distribution of matching variables such as age, gender, course of disease, GK, global SVA and radiographic progression assessment for AS. The QOL was assessed by Neck Disability Index (NDI) and other indices. RESULTS: Mean C-SVA was significantly lower in group A than in group B, whereas mean T1 slope, global SVA and GK were significantly larger in group A. T1 slope (36.0 %) was the independent factor for CL. T1 slope was correlated with CL, GK and global SVA in group A. Group A-1 showed lower NDI score. CL (59.6 %) independently affects NDI. CONCLUSION: Notable cervical compensation exists in AS patients with thoracolumbar kyphosis. The cervical compensation responsive to global imbalance was mediated by T1 slope. AS patients with hyperlordotic cervical spine present with better QOL than patients with kyphotic cervical spine. PMID- 26957100 TI - Validity and utility of monopolar spinal cord stimulation in pediatric scoliosis surgery. AB - PURPOSE: To assess the validity and utility of monopolar stimulation (between a peridural needle and a large adhesive anode placed in the sternal area) for intraoperative monitoring in scoliosis surgery. METHODS: This procedure was assessed during 41 operations involving either arthrodesis with posterior instrumentation or a Vertical Expandable Prosthetic Titanium Rib (VEPTR). Responses evoked by monopolar stimulation were compared with those evoked by bipolar stimulation between two epidural needle electrodes. Potentials evoked by monopolar stimulation in the upper limbs were compared with those evoked in the lower limbs during the same stimulation procedure. RESULTS: Monopolar stimulation yielded equivalent and, if anything, more stable responses in the lower limbs. Recording in the upper limbs was satisfactory and allowed a decrease in responses to be detected in two patients. Acceptable thresholds for changes in amplitude relative to baseline were 40 % for upper limbs and 30 % for lower limbs. CONCLUSIONS: Monopolar stimulation can be used to monitor the spinal cord during surgery for scoliosis correction. This procedure is more convenient for the surgeon and allows for the combined recording of responses in all four limbs, which can be useful in the case of surgical techniques such as those involving a VEPTR. PMID- 26957101 TI - Paraspinal muscle asymmetry and fat infiltration in patients with symptomatic disc herniation. AB - PURPOSE: To investigate asymmetry in size and composition of the multifidus and erector spinae in patients with posterolateral disc herniation and concordant radicular symptoms, and determine whether symptom duration is associated with degree of asymmetry. METHODS: Thirty-three patients diagnosed with posterolateral disc herniation at L4-L5 verified on imaging and concordant leg pain were included. Multifidus and erector spinae cross-sectional area (CSA), functional cross-sectional area (FCSA, fat-free area), signal intensity and ratio of FCSA to total CSA were measured bilaterally from T 2-weighted axial magnetic resonance imaging (MRI) at L3-L4, L4-L5, L5-S1 and S1 levels. RESULTS: No side-to-side differences in multifidus CSA, FCSA, and ratio of FCSA/CSA reached statistical significance at any spinal level. The multifidus signal intensity at L5-S1 was significantly greater (more fatty infiltration) on the side of the disc herniation. The erector spinae FCSA (lean muscle mass) at L5-S1 was found to be significantly smaller on the side of the herniation and the ratio of FCSA/CSA was smaller (more fatty infiltration) on the side of the herniation at L4-L5 and L5 S1. The degree of muscle asymmetry was not associated with symptoms duration. CONCLUSIONS: There was no significant asymmetry of the multifidus at spinal level above, same or level below the disc herniation. Instead, variations in muscle composition were observed, with greater fat infiltration on the side and at spinal levels adjacent to the disc herniation. Muscle asymmetry was not correlated with symptom duration. PMID- 26957102 TI - Pain control following posterior spine fusion: patient-controlled continuous epidural catheter infusion method yields better post-operative analgesia control compared to intravenous patient controlled analgesia method. A retrospective case series. AB - PURPOSE: Pain management following posterior spinal fusion surgeries is a challenging topic. Continuous epidural analgesia (CEA) technique has been invented to resolve some deleterious effects related with conventional intravenous patient-controlled analgesia (IV-PCA) method. However, studies for effectiveness and safety of CEA are scarce in adult population. Our aim was to compare effectiveness and safety of patient-controlled CEA with conventional IV PCA method in adult patient population. METHODS: Chart review of patients, scheduled for elective posterior spine fusion to treat spinal stenosis, degenerative disc disease, spondylolisthesis or spinal instability from May 2012 to March 2015, was performed. Patients with spinal infection, cancer, inflammatory disease, and ASA higher than class III, allergy to analgesic medications were excluded from the study. One hundred and nine patients were enrolled into the study. 80 out of 109 patients (40 in CEA group, 40 in IV-PCA group) were matched for age, gender, BMI, type of surgery, level of fusions. Visual Analog Scale scores (VAS) and Ramsay Sedation Scale (RSS) scores were evaluated following surgeries until post-operative 24th hour. RESULTS: There were 58 female patients (72.5 %). The mean age of the patients was 59.85 years (range 24-82 years). When VAS and RSS scores were compared between the groups, there were statistically significant differences between the groups in respect of VAS scores at every time point following surgery (lower in CEA group), whereas there was no significant difference between the groups in respect of RSS scores. More additional analgesia medication was needed in IV-PCA group (16 vs. 5 patients), which was significantly higher than CEA group (p = 0.029). CONCLUSIONS: Patient controlled CEA method is as safe as IV-PCA method and is even more effective than that in controlling immediate post-operative pain in patients treated with posterior spinal fusion. PMID- 26957104 TI - The AGREE Reporting Checklist: a tool to improve reporting of clinical practice guidelines. PMID- 26957105 TI - Multi-Pulse Excitation for Underwater Analysis of Copper-Based Alloys Using a Novel Remote Laser-Induced Breakdown Spectroscopy (LIBS) System. AB - In this work, the use of multi-pulse excitation has been evaluated as an effective solution to mitigate the preferential ablation of the most volatile elements, namely Sn, Pb, and Zn, observed during laser-induced breakdown spectroscopy (LIBS) analysis of copper-based alloys. The novel remote LIBS prototype used in this experiments featured both single-pulse (SP-LIBS) and multi pulse excitation (MP-LIBS). The remote instrument is capable of performing chemical analysis of submersed materials up to a depth of 50 m. Laser-induced breakdown spectroscopy analysis was performed at air pressure settings simulating the conditions during a real subsea analysis. A set of five certified bronze standards with variable concentration of Cu, As, Sn, Pb, and Zn were used. In SP LIBS, signal emission is strongly sensitive to ambient pressure. In this case, fractionation effect was observed. Multi-pulse excitation circumvents the effect of pressure over the quantitative analysis, thus avoiding the fractionation phenomena observed in single pulse LIBS. The use of copper as internal standard minimizes matrix effects and discrepancies due to variation in ablated mass. PMID- 26957103 TI - The Cedar Project WelTel mHealth intervention for HIV prevention in young Indigenous people who use illicit drugs: study protocol for a randomized controlled trial. AB - BACKGROUND: Despite successes in preventing and treating HIV, Indigenous people in Canada continue to face disproportionately high rates of HIV infection. Programs that support healing from lifetime trauma, support connection to culture, and reduce drug-related harms are critical to preventing HIV among young Indigenous people who use drugs. The Cedar Project WelTel mHealth intervention proposed here is a structured mobile-phone initiative to connect young Indigenous people who use drugs with Cedar Case Managers in a community-based setting. The intervention consists of a package of supports, including a mobile phone and cellular plan, weekly two-way text messaging, and support from Cedar Case Managers. METHODS: The Cedar Project WelTel mHealth study is a multi-site Zelen pre-randomized trial to measure the effect of a two-way supportive text-message intervention to reduce HIV vulnerability among young Indigenous people who use illicit drugs in two Canadian cities. The trial is nested within the Cedar Project, an ongoing cohort study addressing HIV and hepatitis C vulnerability among young Indigenous people who use drugs in Vancouver and Prince George, British Columbia. The Cedar Project Partnership, an independent body of Indigenous Elders, leaders, and health/social service experts, governs all aspects of the study. Two hundred participants will be followed over a 16-month period, with HIV propensity score at 6 months as the primary outcome. Secondary outcomes include HIV propensity at 1 year, HIV risk, resilience, psychological distress, access to drug-related services, and connection to culture measured at 6 months and 1 year. Primary analysis is by intention to treat. DISCUSSION: Culturally safe interventions that address barriers to HIV prevention while supporting the strength of young Indigenous people who use drugs are urgently needed. Despite presenting a tremendous opportunity to connect young, highly transient Indigenous people who use drugs to prevention services, supportive two way mHealth programs have yet to be tested for HIV prevention in a community based setting with this population. TRIAL REGISTRATION: ClinicalTrials.gov NCT02437123 https://clinicaltrials.gov/show/NCT02437123 (registered 4 May 2015). Protocol version: 24 July 2015. PMID- 26957106 TI - Advances in Drug Discovery for the Treatment of Cancer: Many Approaches, One Goal. PMID- 26957108 TI - Consequences of randomized clinical trial design decisions need to be clarified. PMID- 26957107 TI - Stress Hyperglycemia During Surgery and Anesthesia: Pathogenesis and Clinical Implications. AB - Numerous studies have demonstrated an association between hyperglycemia in the perioperative period and adverse clinical outcomes. Many patients who experience hyperglycemia while hospitalized do not have a known history of diabetes and experience a transient phenomenon often described as "stress hyperglycemia" (SH). We discuss the epidemiology and pathogenesis of SH as well as evidence to date regarding predisposing factors and outcomes. Further research is needed to identify the long-term sequelae of SH as well as perioperative measures that may modulate glucose elevations and optimal treatment strategies. PMID- 26957109 TI - A Systematic Review of Predictors of, and Reasons for, Adherence to Online Psychological Interventions. AB - PURPOSE: A key issue regarding the provision of psychological therapy in a self guided online format is low rates of adherence. The aim of this systematic review was to assess both quantitative and qualitative data on the predictors of adherence, as well as participant reported reasons for adhering or not adhering to online psychological interventions. METHODS: Database searches of PsycINFO, Medline, and CINAHL identified 1721 potentially relevant articles published between 1 January 2000 and 25 November 2015. A further 34 potentially relevant articles were retrieved from reference lists. Articles that reported predictors of, or reasons for, adherence to an online psychological intervention were included. RESULTS: A total of 36 studies met the inclusion criteria. Predictors assessed included demographic, psychological, characteristics of presenting problem, and intervention/computer-related predictors. Evidence suggested that female gender, higher treatment expectancy, sufficient time, and personalized intervention content each predicted higher adherence. Age, baseline symptom severity, and control group allocation had mixed findings. The majority of assessed variables however, did not predict adherence. CONCLUSIONS: Few clear predictors of adherence emerged overall, and most results were either mixed or too preliminary to draw conclusions. More research of predictors associated with adherence to online interventions is warranted. PMID- 26957110 TI - GS-9857 in patients with chronic hepatitis C virus genotype 1-4 infection: a randomized, double-blind, dose-ranging phase 1 study. AB - GS-9857, an inhibitor of the hepatitis C virus (HCV) nonstructural protein (NS) 3/4A, demonstrates potent activity against HCV genotypes 1-6 and improved coverage against commonly encountered NS3 resistance-associated variants (RAVs). In this study, the safety, tolerability, antiviral activity and pharmacokinetics (PK) of GS-9857 were evaluated in patients with chronic HCV genotype 1-4 infection. Patients with genotype 1-4 infection received placebo or once-daily GS 9857 at doses ranging from 50 to 300 mg for 3 days under fasting conditions. GS 9857 was well tolerated; all reported adverse events (AEs) were mild or moderate in severity. Diarrhoea and headache were the most commonly reported AEs. Grade 3 or 4 laboratory abnormalities were observed in 17% of patients receiving GS-9857; there were no Grade 3 or 4 abnormalities in alanine aminotransferase, aspartate aminotransferase or alkaline phosphatase levels. GS-9857 demonstrated potent antiviral activity in patients with chronic HCV infection, achieving mean and median maximum reductions in HCV RNA of >=3 log10 IU/mL following administration of a 100-mg dose in patients with HCV genotype 1a, 1b, 2, 3 or 4 infection. The antiviral activity of GS-9857 was unaffected by the presence of pretreatment NS3 RAVs. In patients with genotype 1-4 infection, GS-9857 exhibited linear PK and was associated with a median half-life of 29-42 h, supporting once-daily dosing. Thus, the tolerability, efficacy and pharmacokinetic profile of GS-9857 support its further evaluation for treatment of patients with chronic HCV infection. PMID- 26957111 TI - A prospective comparison of telemedicine versus in-person delivery of an interprofessional education program for adults with inflammatory arthritis. AB - Introduction We evaluated two modes of delivery of an inflammatory arthritis education program ("Prescription for Education" (RxEd)) in improving arthritis self-efficacy and other secondary outcomes. Methods We used a non-randomized, pre post design to compare videoconferencing (R, remote using telemedicine) versus local (I, in-person) delivery of the program. Data were collected at baseline (T1), immediately following RxEd (T2), and at six months (T3). Self-report questionnaires served as the data collection tool. Measures included demographics, disorder-related, Arthritis Self-Efficacy Scale (SE), previous knowledge (Arthritis Community Research and Evaluation Unit (ACREU) rheumatoid arthritis knowledge questionnaire), coping efficacy, Illness Intrusiveness, and Effective Consumer Scale. Analysis included: baseline comparisons and longitudinal trends (R vs I groups); direct between-group comparisons; and Generalized Estimating Equations (GEE) analysis. Results A total of 123 persons attended the program (I: n = 36; R: n = 87) and 111 completed the baseline questionnaire (T1), with follow-up completed by 95% ( n = 117) at T2 and 62% ( n = 76) at T3. No significant baseline differences were found across patient characteristics and outcome measures. Both groups (R and I) showed immediate effect (improved arthritis SE, mean change (95% confidence interval (CI)): R 1.07 (0.67, 1.48); I 1.48 (0.74, 2.23)) after the program that diminished over six months (mean change (95% CI): R 0.45 (-0.1, 0.1); I 0.73 (-0.25, 1.7)). For each of the secondary outcomes, both groups showed similar trends for improvement (mean change scores (95% CI)) over time. GEE analysis did not show any meaningful differences between groups (R vs I) over time. Discussion Improvements in arthritis self-efficacy and secondary outcomes displayed similar trends for I and R participant groups. PMID- 26957112 TI - Acalabrutinib (ACP-196): a selective second-generation BTK inhibitor. AB - More and more targeted agents become available for B cell malignancies with increasing precision and potency. The first-in-class Bruton's tyrosine kinase (BTK) inhibitor, ibrutinib, has been in clinical use for the treatment of chronic lymphocytic leukemia, mantle cell lymphoma, and Waldenstrom's macroglobulinemia. More selective BTK inhibitors (ACP-196, ONO/GS-4059, BGB-3111, CC-292) are being explored. Acalabrutinib (ACP-196) is a novel irreversible second-generation BTK inhibitor that was shown to be more potent and selective than ibrutinib. This review summarized the preclinical research and clinical data of acalabrutinib. PMID- 26957113 TI - Two overlapping two-component systems in Xanthomonas oryzae pv. oryzae contribute to full fitness in rice by regulating virulence factors expression. AB - Two-component signal transduction systems (TCSs) are widely used by bacteria to adapt to the environment. In the present study, StoS (stress tolerance-related oxygen sensor) and SreKRS (salt response kinase, regulator, and sensor) were found to positively regulate extracellular polysaccharide (EPS) production and swarming in the rice pathogen Xanthomonas oryzae pv. oryzae (Xoo). Surprisingly, the absence of stoS or sreKRS did not attenuate virulence. To better understand the intrinsic functions of StoS and SreKRS, quantitative proteomics isobaric tags for relative and absolute quantitation (iTRAQ) was employed. Consistent with stoS and sreK mutants exhibiting a similar phenotype, the signalling circuits of StoS and SreKRS overlapped. Carbohydrate metabolism proteins and chemotaxis proteins, which could be responsible for EPS and swarming regulation, respectively, were reprogrammed in stoS and sreK mutants. Moreover, StoS and SreKRS demonstrated moderate expression of the major virulence factor, hypersensitive response and pathogenicity (Hrp) proteins through the HrpG-HrpX circuit. Most importantly, Xoo equipped with StoS and SreKRS outcompetes strains without StoS or SreKRS in co infected rice and grows outside the host. Therefore, we propose that StoS and SreKRS adopt a novel strategy involving the moderation of Hrp protein expression and the promotion of EPS and motility to adapt to the environment. PMID- 26957114 TI - Targeted inhibition of survivin with YM155 promotes apoptosis of hypoxic human pulmonary arterial smooth muscle cells via the upregulation of voltage-dependent K+ channels. AB - Hypoxic pulmonary hypertension (PH) is a common disease characterized by a disturbance to the balance of apoptosis and cell proliferation in pulmonary artery smooth muscle cells (PASMCs). The anti-apoptotic protein, survivin, has been observed to be upregulated in pulmonary arteries (PAs) of chronic hypoxia induced PH rats. The present study aimed to investigate the therapeutic potential of sepantronium bromide (YM155), a selective survivin inhibitor, on hypoxic human PASMCs and examine the potential underlying mechanisms. Cultured human PASMCs (HPASMCs) were randomly divided into the following groups: i) Normoxia (N); ii) normoxia + 100 nmol/l YM155 (NY100); iii) hypoxia (H); iv) hypoxia + 1 nmol/l YM155 (HY1); v) hypoxia + 10 nmol/l YM155 (HY10); and hypoxia + 100 nmol/l YM155 (HY100) groups. The cells were exposed to the different conditions for 24 h, according to the group. Cell viability was then determined using a Cell Counting Kit-8 assay, and apoptosis was detected using a terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling assay. The expression levels of survivin were determined using reverse transcription quantitative polymerase chain reaction (RT-qPCR), immunocytochemistry and Western blot analyses. The expression levels of the voltage-dependent K+ (Kv) channels, Kv1.5 and Kv2.1, were measured using RT-qPCR and Western blotting. Cell proliferation in the hypoxic PASMCs was significantly increased by hypoxia, however, apoptosis of the HPASMCs was suppressed, the expression of survivin were upregulated and the expression levels of Kv1.5 and Kv2.1 were downregulated. YM155 treatment ameliorated the hypoxia-induced increase in cell proliferation and expression of survivin in a concentration-dependent manner, increased apoptosis, and increased the expression levels of Kv1.5 and Kv2.1 (P<0.05). By contrast, YM155 treatment in normoxic HPASMCs had no significant effects on proliferation, apoptosis, or the expression levels of survivin and Kv channels in the PASMCs. The present study is the first, to the best of our knowledge, to demonstrate that YM155, a selective survivin inhibitor, has a beneficial therapeutic effect on hypoxic HPASMCs, and that YM155 induces a pro-apoptotic effect by downregulating the apoptosis inhibitor, survivin, possibly through a Kv channel-mediated mechanism. PMID- 26957115 TI - Abundance and functional roles of intrinsic disorder in the antimicrobial peptides of the NK-lysin family. AB - NK-lysins are antimicrobial peptides (AMPs) that participate in the innate immune response and also have several pivotal roles in various biological processes. Such multifunctionality is commonly found among intrinsically disordered proteins. However, NK-lysins have never been systematically analyzed for intrinsic disorder. To fill this gap, the amino acid sequences of NK-lysins from various species were collected from UniProt and used for the comprehensive computational analysis to evaluate the propensity of these proteins for intrinsic disorder and to investigate the potential roles of disordered regions in NK-lysin functions. We analyzed abundance and peculiarities of intrinsic disorder distribution in all-known NK-lysins and showed that many NK-lysins are expected to have substantial levels of intrinsic disorder. Curiously, high level of intrinsic disorder was also found even in two proteins with known 3D-strucutres (NK-lysin from pig and human granulysin). Many of the identified disordered regions can be involved in protein-protein interactions. In fact, NK-lysins are shown to contain three to eight molecular recognition features; i.e. short structure-prone segments which are located within the long disordered regions and have a potential to undergo a disorder-to-order transition upon binding to a partner. Furthermore, these disordered regions are expected to have several sites of various posttranslational modifications. Our study shows that NK-lysins, which are AMPs with a set of prominent roles in the innate immune response, are expected to abundantly possess intrinsically disordered regions that might be related to multifunctionality of these proteins in the signal transduction pathways controlling the host response to pathogenic agents. PMID- 26957116 TI - Effects of Bacillus licheniformis on the growth performance and expression of lipid metabolism-related genes in broiler chickens challenged with Clostridium perfringens-induced necrotic enteritis. AB - BACKGROUND: Necrotic enteritis (NE), caused by Clostridium perfringens, has cost the poultry industry $2 billion in losses. This study aimed to investigate the effect of Bacillus licheniformis as dietary supplement on the growth, serum antioxidant status, and expression of lipid-metabolism genes of broiler chickens with C. perfringens-induced NE. METHODS: A total of 240 one-day-old broilers were randomly grouped into four: a negative control, an NE experimental model (PC), chickens fed a diet supplemented with 30 % of fishmeal from day 14 onwards and challenged with coccidiosis vaccine (FC), and NE group supplied with feed containing 1.0 * 10(6) CFU/g B. licheniformis (BL). RESULTS: Body weight gain, feed conversion ratio, serum antioxidant status, and lipid-metabolism-gene expression were analyzed. In the PC group, FCR increased significantly whereas serum catalase and glutathione peroxidase activity decreased compared with NC group. Dietary B. licheniformis supplementation improved FCR and oxidative stress in experimental avian NE. Using Bacillus licheniformis as a direct-fed microbial (DFM) could also significantly upregulate catabolism-related genes, namely, peroxisome proliferator-activated receptor-alpha and carnitine palmitoyltransferase-1, in livers and changed the expression of lipid-anabolism genes. CONCLUSION: These results suggested that dietary B. licheniformis supplementation can enhance growth and antioxidant ability, as well as change the expression of genes related to fatty-acid synthesis and oxidation in the livers of NE-infected broilers. PMID- 26957117 TI - Closed-loop ventilation mode (IntelliVent(r)-ASV) in intensive care unit: a randomized trial. AB - BACKGROUND: Closed-loop modes automatically adjust ventilation settings, delivering individualized ventilation over short periods of time. The objective of this randomized controlled trial was to compare safety, efficacy and workload for the health care team between IntelliVent(r)-ASV and conventional modes over a 48-hour period. METHODS: ICU patients admitted with an expected duration of mechanical ventilation of more than 48 hours were randomized to IntelliVent(r) ASV or conventional ventilation modes. All ventilation parameters were recorded breath-by-breath. The number of manual adjustments assesses workload for the healthcare team. Safety and efficacy were assessed by calculating the time spent within previously defined ranges of non-optimal and optimal ventilation, respectively. RESULTS: Eighty patients were analyzed. The median values of ventilation parameters over 48 hours were similar in both groups except for PEEP (7[4] cmH2O versus 6[3] cmH2O with IntelliVent(r)-ASV and conventional ventilation, respectively, P=0.028) and PETCO2 (36+/-7 mmHg with IntelliVent(r) ASV versus 40+/-8 mmHg with conventional ventilation, P=0.041). Safety was similar between IntelliVent(r)-ASV and conventional ventilation for all parameters except for PMAX, which was more often non-optimal with IntelliVent(r) ASV (P=0.001). Efficacy was comparable between the 2 ventilation strategies, except for SpO2 and VT, which were more often optimal with IntelliVent(r)-ASV (P=0.005, P=0.016, respectively). IntelliVent(r)-ASV required less manual adjustments than conventional ventilation (P<0.001) for a higher total number of adjustments (P<0.001). The coefficient of variation over 48 hours was larger with IntelliVent(r)-ASV in regard of maximum pressure, inspiratory pressure (PINSP), and PEEP as compared to conventional ventilation. CONCLUSIONS: IntelliVent(r)-ASV required less manual intervention and delivered more variable PEEP and PINSP, while delivering ventilation safe and effective ventilation in terms of VT, RR, SpO2 and PETCO2. PMID- 26957118 TI - Right ventricle dilation as a prognostic factor in refractory acute respiratory distress syndrome requiring veno-venous extracorporeal membrane oxygenation. AB - BACKGROUND: The aim of this study was to assess the incidence and prognostic role of echocardiographic abnormalities in consecutive patients with refractory acute respiratory distress syndrome (ARDS) before veno-venous extracorporeal membrane oxygenation (VV-ECMO). METHODS: In this study 74 consecutive patients with refractory ARDS underwent echocardiography (transthoracic, transesophageal or both, according to the best acoustic window). Baseline characteristics were collected for all patients and the simplified acute physiology score was calculated. At echocardiography the following parameters were considered: left ventricle (LV) ejection fraction, right ventricle (RV) size and function (by means of tricuspid annular plane excursion [TAPSE]) and systolic pulmonary arterial pressure. RESULTS: At echocardiography, 25 patients showed normal findings (33.8%), 32 patients exhibited isolated pulmonary hypertension (43.2%) and the remaining 17 patients showed RV dilation and pulmonary hypertension (23%). A reduced LVEF (<50%) was observed in 14 patients (18.9%), while RV dysfunction (as indicated by TAPSE<16 mm) was documented in 21 patients (28.4%). The in-Intensive Care Unit [ICU] mortality rate was 41.8%. At stepwise regression analysis the following variables were independent predictor for in-ICU mortality (when adjusted for TAPSE<16 mm): RV end diastolic area/LV end diastolic area (OR 0.21, 95%CI 0.062-0.709, P=0.012), Body Mass Index (BMI) (OR 0.87, 95%CI 0.802 0.958, P=0.004) CONCLUSIONS: In consecutive patients with refractory ARDS, echocardiographic alterations were common, mainly represented by systolic pulmonary hypertension associated or not with RV dilatation. Moreover, RV dilatation and BMI were independent predictors of in-ICU mortality. On clinical grounds, our findings strongly suggest that echocardiography helps to risk stratifying patients with refractory ARDS requiring VV-ECMO. PMID- 26957119 TI - Acute kidney injury after cardiac arrest: a systematic review and meta-analysis of clinical studies. AB - INTRODUCTION: The prevalence of and the risk factors for acute kidney injury (AKI) after cardiac arrest (CA), and the association of AKI with outcome have not been systematically investigated so far. EVIDENCE ACQUISITION: In this systematic review and meta-analysis, studies on adult patients (dating from January 1966 to August 2015) published as full-text articles were screened. Two authors independently extracted data and assessed study quality using the Quality Assessment Tool of the U.S. National Institute of Health. Data were summarized using weighted means. EVIDENCE SYNTHESIS: Eight studies (total 1693 patients; 68% males) were included. The incidence of AKI was 37%. In six studies where a standard AKI definition (RIFLE, AKIN or KDIGO) was used, the incidence for AKI stage 1 or higher was 52%. AKI occurred at a median of 1-2 days from cardiac arrest in 6/8 studies. Renal replacement therapy (RRT) was used in 239 AKI patients (33%), of whom five (2%) still needed RRT at 30 days after CA. An initial non-shockable rhythm, a longer duration of arrest, higher creatinine levels on admission, and the presence of shock or higher blood lactate after resuscitation were significant predictors of AKI occurrence. Hospital mortality was significantly higher in AKI vs. non-AKI patients (OR 2.63 [1.86-3.68]; P<0.0001). CONCLUSIONS: post-arrest AKI has an early onset, occurs in more than 50% of CA patients, and it is associated with increased mortality. Decreased renal function on admission, an initial non-shockable rhythm and both pre-arrest and post-arrest markers of hypoperfusion are associated with increased risk of AKI in this setting. PMID- 26957121 TI - The size of the population potentially in need of palliative care in Germany--an estimation based on death registration data. AB - BACKGROUND: No data exist on the size of the population potentially in need of palliative care in Germany. The aim of this study is to estimate the size of the German population that may benefit from palliative care. METHOD: Based on existing population-based methods (Rosenwax and Murtagh), German death registration data were analyzed and contrasted with international results. The data include all death cases in 2013 in Germany. RESULTS: According to the method Rosenwax defined, between 40.7% (minimal estimate) and 96.1% (maximal estimate) of death cases could benefit from palliative care. The estimation, based on Murtagh's refined method, results in 78.0% of death cases potentially being eligible for palliative care. The percentage of potential palliative care candidates is conditioned by age. Based on the Murtagh Method, in the age category between 30 and 39 years, a potential demand for palliative care can be found for 40.4% percent of all deaths occurring in this age category, with this number increasing to 80.3% in the age bracket of 80 years and over. CONCLUSION: An estimation of the size of the population in need is essential for healthcare planning. Therefore, our data serve as a guide and starting point for further research. PMID- 26957120 TI - Borrelia burgdorferi induces a type I interferon response during early stages of disseminated infection in mice. AB - BACKGROUND: Lyme borrelia genotypes differ in their capacity to cause disseminated disease. Gene array analysis was employed to profile the host transcriptome induced by Borrelia burgdorferi strains with different capacities for causing disseminated disease in the blood of C3H/HeJ mice during early infection. RESULTS: B. burgdorferi B515, a clinical isolate that causes disseminated infection in mice, differentially regulated 236 transcripts (P < 0.05 by ANOVA, with fold change of at least 2). The 216 significantly induced transcripts included interferon (IFN)-responsive genes and genes involved in immunity and inflammation. In contrast, B. burgdorferi B331, a clinical isolate that causes transient skin infection but does not disseminate in C3H/HeJ mice, stimulated changes in only a few genes (1 induced, 4 repressed). Transcriptional regulation of type I IFN and IFN-related genes was measured by quantitative RT PCR in mouse skin biopsies collected from the site of infection 24 h after inoculation with B. burgdorferi. The mean values for transcripts of Ifnb, Cxcl10, Gbp1, Ifit1, Ifit3, Irf7, Mx1, and Stat2 were found to be significantly increased in B. burgdorferi strain B515-infected mice relative to the control group. In contrast, transcription of these genes was not significantly changed in response to B. burgdorferi strain B331 or B31-4, a mutant that is unable to disseminate. CONCLUSIONS: These results establish a positive association between the disseminating capacity of B. burgdorferi and early type I IFN induction in a murine model of Lyme disease. PMID- 26957123 TI - Neoadjuvant imatinib treatment and laparoscopic anus-preserving surgery for a large gastrointestinal stromal tumor of the rectum. AB - BACKGROUND: Resection of a gastrointestinal stromal tumor (GIST) of the rectum can be difficult because of the particular location in the pelvis, and a large rectal GIST often requires abdominoperineal resection. Recent reports demonstrate that neoadjuvant imatinib treatment improves surgical outcomes in patients with a rectal GIST, and there are only a few reports of the effectiveness of laparoscopic surgery for a rectal GIST. CASE PRESENTATION: A 46-year-old man was found to have a rectal GIST that measured 80 mm and was located on the anterior wall of the lower rectum. After 6 months treatment with imatinib, the tumor decreased in size to 37 mm, and laparoscopic low anterior resection was performed. The patient is currently alive without any evidence of recurrence 37 months after surgery. CONCLUSIONS: Neoadjuvant imatinib should be a treatment of choice for a large rectal GIST. When marked tumor shrinkage is achieved, laparoscopic surgery may be the preferred procedure. PMID- 26957122 TI - Human bone marrow-derived and umbilical cord-derived mesenchymal stem cells for alleviating neuropathic pain in a spinal cord injury model. AB - BACKGROUND: Stem cell therapy can be used for alleviating the neuropathic pain induced by spinal cord injuries (SCIs). However, survival and differentiation of stem cells following their transplantation vary depending on the host and intrinsic factors of the cell. Therefore, the present study aimed to determine the effect of stem cells derived from bone marrow (BM-MSC) and umbilical cord (UC MSC) on neuropathic pain relief. METHODS: A compression model was used to induce SCI in a rat model. A week after SCI, about 1 million cells were transplanted into the spinal cord. Behavioral tests, including motor function recovery, mechanical allodynia, cold allodynia, mechanical hyperalgesia, and thermal hyperalgesia, were carried out every week for 8 weeks after SCI induction. A single unit recording and histological evaluation were then performed. RESULTS: We show that BM-MSC and UC-MSC transplantations led to improving functional recovery, allodynia, and hyperalgesia. No difference was seen between the two cell groups regarding motor recovery and alleviating the allodynia and hyperalgesia. These cells survived in the tissue at least 8 weeks and prevented cavity formation due to SCI. However, survival rate of UC-MSC was significantly higher than BM-MSC. Electrophysiological evaluations showed that transplantation of UC-MSC brings about better results than BM-MSCs in wind up of wide dynamic range neurons. CONCLUSIONS: The results of the present study show that BM-MSC and UC-MSC transplantations alleviated the symptoms of neuropathic pain and resulted in subsequent motor recovery after SCI. However, survival rate and electrophysiological findings of UC-MSC were significantly better than BM-MSC. PMID- 26957124 TI - Towards tailored teaching: using participatory action research to enhance the learning experience of Longitudinal Integrated Clerkship students in a South African rural district hospital. AB - BACKGROUND: The introduction of Stellenbosch University's Longitudinal Integrated Clerkship (LIC) model as part of the undergraduate medical curriculum offers a unique and exciting training model to develop generalist doctors for the changing South African health landscape. At one of these LIC sites, the need for an improvement of the local learning experience became evident. This paper explores how to identify and implement a tailored teaching and learning intervention to improve workplace-based learning for LIC students. METHODS: A participatory action research approach was used in a co-operative inquiry group (ten participants), consisting of the students, clinician educators and researchers, who met over a period of 5 months. Through a cyclical process of action and reflection this group identified a teaching intervention. RESULTS: The results demonstrate the gaps and challenges identified when implementing a LIC model of medical education. A structured learning programme for the final 6 weeks of the students' placement at the district hospital was designed by the co-operative inquiry group as an agreed intervention. The post-intervention group reflection highlighted a need to create a structured programme in the spirit of local collaboration and learning across disciplines. The results also enhance our understanding of both students and clinician educators' perceptions of this new model of workplace-based training. CONCLUSIONS: This paper provides practical strategies to enhance teaching and learning in a new educational context. These strategies illuminate three paradigm shifts: (1) from the traditional medical education approach towards a transformative learning approach advocated for the 21(st) century health professional; (2) from the teaching hospital context to the district hospital context; and (3) from block-based teaching towards a longitudinal integrated learning model. A programme based on balancing structured and tailored learning activities is recommended in order to address the local learning needs of students in the LIC model. We recommend that action learning sets should be developed at these LIC sites, where the relevant aspects of work place based learning are negotiated. PMID- 26957125 TI - Graphical displays for effective reporting of evidence quality tables in research syntheses. AB - BACKGROUND: When generating guidelines, quality of the evidence is tabulated to capture its several domains, often using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. We developed a graphic display to capture deficiencies, outliers and similarities across comparisons contained in GRADE tables. METHODS: Based on a systematic literature review capturing the effects of 32 different therapeutic comparisons on dysmenorrhoea, we synthesised evidence quality in tables and graphs. We evaluated time taken to accurately assess evident quality and preference for tables vs. graphs. RESULTS: The plots provided visually striking displays of strengths and weaknesses of the evidence across the spectrum of comparisons on a single page. Equivalent tabulated information spread over 4 pages. Participants preferred and interpreted graphs quicker and more accurately than tables. CONCLUSIONS: The graphic approach we developed makes interpreting evidence easier. Large tables are dry and cumbersome to read and assimilate. When guideline statements are accompanied by these plots, they have the scope for improving the credibility of the recommendations made, as the strength of the evidence used can be clearly seen. Further empirical research will establish the place for graphic displays. PMID- 26957126 TI - Low-Carbon Fuel and Chemical Production by Anaerobic Gas Fermentation. AB - World energy demand is expected to increase by up to 40% by 2035. Over this period, the global population is also expected to increase by a billion people. A challenge facing the global community is not only to increase the supply of fuel, but also to minimize fossil carbon emissions to safeguard the environment, at the same time as ensuring that food production and supply is not detrimentally impacted. Gas fermentation is a rapidly maturing technology which allows low carbon fuel and commodity chemical synthesis. Unlike traditional biofuel technologies, gas fermentation avoids the use of sugars, relying instead on gas streams rich in carbon monoxide and/or hydrogen and carbon dioxide as sources of carbon and energy for product synthesis by specialized bacteria collectively known as acetogens. Thus, gas fermentation enables access to a diverse array of novel, large volume, and globally available feedstocks including industrial waste gases and syngas produced, for example, via the gasification of municipal waste and biomass. Through the efforts of academic labs and early stage ventures, process scale-up challenges have been surmounted through the development of specialized bioreactors. Furthermore, tools for the genetic improvement of the acetogenic bacteria have been reported, paving the way for the production of a spectrum of ever-more valuable products via this process. As a result of these developments, interest in gas fermentation among both researchers and legislators has grown significantly in the past 5 years to the point that this approach is now considered amongst the mainstream of emerging technology solutions for near term low-carbon fuel and chemical synthesis. PMID- 26957128 TI - Need for evidence on telehealth providers. PMID- 26957127 TI - Development of Anaerobic High-Rate Reactors, Focusing on Sludge Bed Technology. AB - In the last 40 years, anaerobic sludge bed reactor technology has evolved from localized laboratory-scale trials to worldwide successful implementations in a variety of industries. High-rate sludge bed reactors are characterized by a very small footprint and high applicable volumetric loading rates. Best performances are obtained when the sludge bed consists of highly active and well settleable granular sludge. Sludge granulation provides a rich microbial diversity, high biomass concentration, high solids retention time, good settling characteristics, reduction in both operation costs and reactor volume, and high tolerance to inhibitors and temperature changes. However, sludge granulation cannot be guaranteed on every type of industrial wastewater. Especially in the last two decades, various types of high-rate anaerobic reactor configurations have been developed that are less dependent on the presence of granular sludge, and many of them are currently successfully used for the treatment of various kinds of industrial wastewaters worldwide. This study discusses the evolution of anaerobic sludge bed technology for the treatment of industrial wastewaters in the last four decades, focusing on granular sludge bed systems. PMID- 26957129 TI - Do work-related factors contribute to differences in doctor-certified sick leave? A prospective study comparing women in health and social occupations with women in the general working population. AB - BACKGROUND: Doctor -certified sick leave is prevalent in the health and social sector. We examined whether the higher risk of doctor-certified sick leave in women in health and social occupations compared to women in other occupations was explained by particular work-related psychosocial and mechanical risk factors. METHODS: A randomly drawn cohort aged 18-69 years from the general population in Norway was surveyed in 2009 (n = 12,255, response at baseline = 60.9 %), and was followed up in the national registry of social transfer payments in 2010. Eligible respondents were women registered with an active employee relationship for >=100 actual working days in 2009 and 2010 (n = 3032). Using this sample, we compared health and social workers (n = 661) with the general working population (n = 2371). The outcome of interest was long-term sick leave (LTSL) >=21 working days during 2010. Eight psychosocial and eight mechanical factors were evaluated. RESULTS: After adjusting for age, previous LTSL, education and working hours/week, women in health and social occupations had a higher risk for LTSL compared with women in the general working population (OR = 1.42, 95 % CI = 1.13 1.79; p = 0.003). After adjusting for psychosocial and mechanical factors, 70 % of the excess risk for LTSL was explained compared with the initial model. The main contributory factors to the increased risk were threats of violence and violence, emotional demands and awkward lifting. CONCLUSIONS: Psychosocial and mechanical factors explained much of the excess risk for LTSL in women in health and social occupations compared with working women in general. Psychosocial risk factors were the most important contributors. PMID- 26957130 TI - Immunocastrated male pigs: effect of 4 v. 6 weeks time post second injection on performance, carcass quality and meat quality. AB - Immunocastration or vaccination against boar taint can be used as alternative for surgical castration of male piglets. The vaccine is administrated twice. After the second vaccination (V2), the pigs behave like barrows instead of boars and their feed intake increases which may result in a lower lean meat percentage. The timing of V2 is therefore crucial to find the right balance between the advantages of entire males and barrows. In this study, we evaluated the effect of time post second injection within the advised time frame (4 v. 6 weeks before slaughter) on behaviour, performance, carcass and meat quality of immunocastrated male pigs. In total, 180 animals (hybrid sow*Pietrain): 60 gilts, 60 male pigs vaccinated 6 weeks before slaughter (IM-6) and 60 male pigs vaccinated 4 weeks before slaughter (IM-4), all slaughtered at comparable slaughter weights. After 20 weeks of age, IM-6 showed more inactive behaviour at the expense of playing and aggressive behaviour. Daily feed intake (DFI), daily gain (DG) and feed conversion ratio (FCR) did not differ significantly between IM-6 and IM-4. Gilts had a lower DFI and DG in the late finishing phase and a higher FCR overall compared with both IM groups. Gilts showed a higher lean meat content compared with both IM groups. Earlier vaccination increased dressing percentage, which could partly be explained by the lower weight of the gastrointestinal tract, but not by testes weight. Meat quality traits and palatability did not differ significantly between IM-6 and IM-4. Vaccination of immunocastrates at 6 compared with 4 weeks before slaughter improved the calmness in the stable and the dressing percentage, while maintaining performance and carcass characteristics. PMID- 26957132 TI - Stuck in Unhealthy Places: How Entering, Exiting, and Remaining in Poor and Nonpoor Neighborhoods Is Associated with Obesity during the Transition to Adulthood. AB - Adolescents from poor versus nonpoor neighborhoods are more likely to become obese during the transition to adulthood. It is unclear whether this pertains to all adolescents from poor neighborhoods or only those who remain in disadvantaged settings. Further, it is unknown how neighborhood poverty entries and exits are associated with obesity. Using census and interview data from 12,164 National Longitudinal Study of Adolescent Health participants, I find that those who consistently live in poor neighborhoods are more likely to become or remain obese by adulthood than those who never live in poor neighborhoods. Exiting severe neighborhood poverty curtails this risk, while entering and remaining in neighborhood poverty in adulthood increases it. These patterns are more pronounced for young women and robust to adjustments for health behaviors and selection bias. Findings support accumulation of risks and social mobility perspectives and highlight how previous and current neighborhood contexts are relevant for health. PMID- 26957133 TI - How Initial Prevalence Moderates Network-based Smoking Change: Estimating Contextual Effects with Stochastic Actor-based Models. AB - We use an empirically grounded simulation model to examine how initial smoking prevalence moderates the effectiveness of potential interventions designed to change adolescent smoking behavior. Our model investigates the differences that result when manipulating peer influence and smoker popularity as intervention levers. We demonstrate how a simulation-based approach allows us to estimate outcomes that arise (1) when intervention effects could plausibly alter peer influence and/or smoker popularity effects and (2) across a sample of schools that match the range of initial conditions of smoking prevalence in U.S. schools. We show how these different initial conditions combined with the exact same intervention effects can produce substantially different outcomes-for example, effects that produce smoking declines in some settings can actually increase smoking in others. We explore the form and magnitude of these differences. Our model also provides a template to evaluate the potential effects of alternative intervention scenarios. PMID- 26957131 TI - Sex Differences in Effects of Ketamine on Behavior, Spine Density, and Synaptic Proteins in Socially Isolated Rats. AB - BACKGROUND: The mechanistic underpinnings of sex differences in occurrence of depression and efficacy of antidepressant treatments are poorly understood. We examined the effects of isolation stress (IS) and the fast-acting antidepressant ketamine on anhedonia and depression-like behavior, spine density, and synaptic proteins in male and female rats. METHODS: We used a chronic social IS paradigm to test the effects of ketamine (0, 2.5 mg/kg, and 5 mg/kg) on behavior and levels of synaptic proteins synapsin-1, postsynaptic density protein 95, and glutamate receptor 1 in male rats and female rats in diestrus. Medial prefrontal cortex spine density was also examined in male rats and female rats that received ketamine during either the diestrus or the proestrus phase of their estrous cycle. RESULTS: Male rats showed anhedonia and depression-like behavior after 8 weeks of IS, concomitant with decreases in spine density and levels of synapsin 1, postsynaptic density protein 95, and glutamate receptor 1 in the medial prefrontal cortex; these changes were reversed by a single injection of ketamine (5 mg/kg). After 11 weeks of IS, female rats showed depression-like behavior but no signs of anhedonia. Although both doses of ketamine rescued depression-like behavior in female rats, the decline observed in synaptic proteins and spine density in IS and in diestrus female rats could not be reversed by ketamine. Spine density was higher in female rats during proestrus than in diestrus. CONCLUSIONS: Our findings implicate a role for synaptic proteins synapsin-1, postsynaptic density protein 95, and glutamate receptor 1 and medial prefrontal cortex spine density in the antidepressant effects of ketamine in male rats subjected to IS but not in female rats subjected to IS, suggesting dissimilar underlying mechanisms for efficacy of ketamine in the two sexes. PMID- 26957134 TI - Multiple Chronic Conditions, Spouse's Depressive Symptoms, and Gender within Marriage. AB - Multiple chronic conditions (i.e., multimorbidity) increase a person's depressive symptoms more than having one chronic condition. Little is known regarding whether multimorbidity similarly increases the depressive symptoms of one's spouse and whether this depends on type of condition, gender, or both spouses' health status. Analysis of multiple waves of the Health and Retirement Study reveals husband's number of chronic conditions is positively related to wife's depressive symptoms when both spouses are chronically ill. The association between wife's chronic conditions and husband's depressive symptoms is weaker and less robust. Type of chronic condition also matters but which type depends on the gender and health status of both spouses. By highlighting key contexts where chronic conditions are connected to spousal depressive symptoms, this study identifies areas of vulnerability and urges researchers and clinicians to consider multimorbidity when designing and implementing interventions, along with gender, both spouses' chronic conditions, and condition type. PMID- 26957136 TI - Policy Brief. PMID- 26957135 TI - Marital Histories and Heavy Alcohol Use among Older Adults. AB - We develop a gendered marital biography approach-which emphasizes the accumulating gendered experiences of singlehood, marriage, marital dissolution, and remarriage-to examine the relationship between marital statuses and transitions and heavy alcohol use. We test this approach using individual-level (n = 10,457) and couple-level (n = 2,170) longitudinal data from the Health and Retirement Study, and individual-level (n = 46) and couple-level (n = 42) in depth interview data. Quantitative results show that marriage, including remarriage, reduces men's but increases women's drinking relative to being never married and previously married, whereas divorce increases men's but decrease women's drinking, with some variation by age. Our qualitative findings reveal that social control and convergence processes underlie quantitative results. We call attention to how men's and women's heavy drinking trajectories stop, start, and change direction as individuals move through their distinctive marital biography. PMID- 26957137 TI - Work Disability among Women: The Role of Divorce in a Retrospective Cohort Study. AB - We assess how divorce through midlife affects the subsequent probability of work limiting health among U.S. women. Using retrospective marital and work disability histories from the Survey of Income and Program Participation matched to Social Security earnings records, we identify women whose first marriage dissolved between 1975 and 1984 (n = 1,214) and women who remain continuously married (n = 3,394). Probit and propensity score matching models examine the cumulative probability of a work disability over a 20-year follow-up period. We find that divorce is associated with a significantly higher cumulative probability of a work disability, controlling for a range of factors. This association is strongest among divorced women who do not remarry. No consistent relationships are observed among divorced women who remarry and remained married. We find that economic hardship, work history, and selection into divorce influence, but do not substantially alter, the lasting impact of divorce on work-limiting health. PMID- 26957138 TI - Religious Attendance and the Mobility Trajectories of Older Mexican Americans: An Application of the Growth Mixture Model. AB - Although several studies have examined the association between religious involvement and physical functioning, there is no consistent empirical evidence concerning the true nature of the association. The Hispanic population is also surprisingly understudied in previous work. In this article, we employ seven waves of data from the Hispanic Established Populations for the Epidemiologic Study of the Elderly to examine the association between religious attendance and performance-based mobility trajectories among older Mexican Americans. Growth mixture estimates reveal three latent classes of mobility trajectories: (1) high, (2) moderate, and (3) low. Multinomial logistic regression estimates show that the odds of being classified as having low mobility (versus high and moderate mobility) are lower for respondents who attend religious services than for respondents who never attend. Religious attendance does not distinguish between moderate and high mobility. Our regression results confirm that religious attendance is associated with favorable mobility trajectories among older Mexican Americans. PMID- 26957139 TI - Bioactive glycosides from the roots of Ilex asprella. AB - Context The roots of Ilex asprella (Hook. et Arn.) Champ. ex Benth. (Aquifoliaceae) are widely used in Chinese medicine to treat influenza, amygdalitis, pertussis, etc. Their mechanism of action is still unknown, which raises the need to identify new bioactive compounds in this plant. Objective In this study, we isolated a novel saponin containing sulphonic groups, namely, asprellcoside A (1) and a known phenolic glycoside compound (2) from the roots of Ilex asprella and evaluated their bioactivities. Materials and methods Molecular structures were elucidated by analysing their spectral and chemical properties. The viability of A549 cells was tested using a MTT assay. Ability of the compounds to inhibit viruses was determined using the neuraminidase activity assay. Their anti-inflammatory effects were tested using the IP-10 activity assay using various concentrations (compound 1: 0.6, 0.2, 0.6, 1.70, 5.00 and 15.00 MUM; compound 2: 0.4, 1.2, 3.6, 11.0, 33.0 and 100 MUM). Their inhibitory effect on platelet aggregation induced by adenosine diphosphate (ADP) in rabbit plasma was determined at 60 and 80 MUM. Results Both compounds inhibit influenza virus strain A/PuertoRico/8/1934 (H1N1) strongly with EC50 values of 4.1 and 1.7 MUM, respectively. Both compounds inhibit the secretion of IP-10 with EC50 values of 6.6 and 2.5 MUM, respectively. Compound 1 alone inhibited platelet aggregation significantly, with the rate of suppression being 47 +/- 8 and 38 +/- 3%, at 60 and 80 MUM, respectively. Conclusions The results suggest that both compounds may be valid therapeutics against influenza virus infection and that compound 1 may be a novel agent for treating thrombosis. PMID- 26957140 TI - Size-Limited Penetration of Nanoparticles into Porcine Respiratory Mucus after Aerosol Deposition. AB - We investigated the rheological properties and the penetration of differently sized carboxylated nanoparticles in pig pulmonary mucus, on different distance and time scales. Nanoparticles were either mechanically mixed into the mucus samples or deposited as an aerosol, the latter resembling a more physiologically relevant delivery scenario. After mechanical dispersion, 500 nm particles were locally trapped; a fraction of carboxylated tracer particles of 100 or 200 nm in diameter could however freely diffuse in these networks over distances of approximately 20 MUm. In contrast, after aerosol deposition on top of the mucus layer only particles with a size of 100 nm were able to penetrate into mucus, suggesting the presence of smaller pores at the air-mucus interface compared to within mucus. These findings are relevant to an understanding of the fate of potentially harmful aerosol particles, such as pathogens, pollutants, and other nanomaterials after incidental inhalation, as well as for the design of pulmonary drug delivery systems. PMID- 26957141 TI - Cardiovascular safety assessments in the cynomolgus monkey: Unmasking potential background arrhythmias in general toxicity studies. AB - INTRODUCTION: We describe experience with an unexpectedly high background incidence of atrioventricular block (AVB) observed in Mauritian cynomolgus monkeys (MCM) during preclinical safety assessment for bitopertin, a glycine transporter-1 inhibitor. METHODS: Preclinical ECGs were reviewed to assess potential effects on cardiac conductivity, specifically AVB. RESULTS: Bitopertin administration in Chinese/Vietnamese monkeys (CVM; n=46) or MCM (n=64, from all relevant studies) revealed dose-dependent hypoactivity with a lack of expected increases in heart rate in response to chair-restraint during ECG recordings. Instances of 2 degrees AVB were detected post-dose in two repeat-dose studies in MCM. AVB was generally restricted to animals showing a lower than expected increase in heart rate during restraint compared to placebo conditions (111-161 to 220-250bpm). A subsequent study in MCM prescreened for AVB found pre-existing 2 degrees AVB in 15.4% of animals. After exclusion of these animals, no incidences of AVB were identified over 36weeks of bitopertin treatment. No evidence of AVB was observed in CVM in a 14-day study with continuous ECG recordings or in any clinical studies to date. DISCUSSION: Bitopertin-treatment was not associated with a direct effect on AV conduction in AVB naive MCM. Pre test detection of AVB in MCM was likely due to the unmasking of pre-existing AVB through a slowed heart rate. The background incidence of AVB in the current MCM cohort was much higher than has been previously reported. These data suggest that ECG prescreening of unrestrained, nonstressed animals is recommended for the accurate assessment of possible treatment-related increases in AVB, especially in MCM. PMID- 26957142 TI - We are being myopic about myopia control. PMID- 26957143 TI - Proteomics, photosynthesis and salt resistance in crops: An integrative view. AB - Salinity is a stressful condition that causes a significant decrease in crop production worldwide. Salt stress affects several photosynthetic reactions, including the modulation of several important proteins. Despite these effects, few molecular-biochemical markers have been identified and evaluated for their importance in improving plant salt resistance. Proteomics is a powerful tool that allows the analysis of multigenic events at the post-translational level that has been widely used to evaluate protein modulation changes in plants exposed to salt stress. However, these studies are frequently fragmented and the results regarding photosynthesis proteins in response to salinity are limited. These constraints could be related to the low number of important photosynthetic proteins differently modulated in response to salinity, as has been commonly revealed by conventional proteomics. In this review, we present an evaluation and perspective on the integrated application of proteomics for the identification of photosynthesis proteins to improve salt resistance. We propose the use of phospho , thiol- and redox-proteomics, associated with the utilization of isolated chloroplasts or photosynthetic sub-organellar components. This strategy may allow the characterization of essential proteins, providing a better understanding of photosynthesis regulation. Furthermore, this may contribute to the selection of molecular markers to improve salt resistance in crops. PMID- 26957144 TI - Proteomic approach reveals that starch degradation contributes to anthocyanin accumulation in tuberous root of purple sweet potato. AB - A comparative proteomic approach was carried out to investigate anthocyanin biosynthesis in the tuberous roots of yellow sweet potato (YSP) and purple sweet potato (PSP) cultivars. More than 800 proteins were reproducibly detected through two-dimensional electrophoresis (2-DE), of which 50 proteins with 39 more and 11 less accumulated in PSP were identified through matrix-assisted laser desorption ionization-time of flight/time of flight mass spectrometry (MALDI-TOF/TOF-MS). Most of the analyzed proteins are annotated to be involved in starch metabolism and glycolysis. The more abundant starch phosphorylase (SP) and phosphoglucomutase (PGM) in PSP promoted the synthesis of precursors for anthocyanin synthesis. The results implied that starch degradation provided abundant substrates for anthocyanin biosynthesis in tuberous roots of PSP. 24kDa vacuolar protein (VP24) is related to anthocyanin transport and accumulation in vacuoles. Vacuole-associated annexin protein, VCaB42, is correlated with tonoplast biogenesis. Synergistic action of the two proteins is probably involved in the microautophagy and the intravacuolar trapping of anthocyanins. Interestingly, both VCaB42 and VP24 were more accumulated in PSP, suggesting that anthocyanins generated in the cytosol were transported into and became stored in the vacuoles of PSP. The present study provides new insights into the mechanism of tuberous root-specific anthocyanin accumulation in PSP. BIOLOGICAL SIGNIFICANCE: Sweet potato ranks as the seventh most important crop worldwide. Purple sweet potato, a special sweet potato cultivar, has been extensively investigated because large amounts of anthocyanin accumulate in its tuberous roots. Anthocyanin is well known for its free radical-scavenging activity and beneficial effects on human health. Its biosynthetic pathway has been well characterized in model plants. Although large-scale systematic studies have been performed to identify the proteins present in sweet potato, information on the regulation of anthocyanin synthesis in sweet potato is insufficient. Our proteome study demonstrated that starch degradation may contribute to anthocyanin accumulation in purple sweet potato. To our knowledge, this study is the first to propose that starch degradation may provide precursors of anthocyanin biosynthesis in sweet potato. PMID- 26957145 TI - Ultra-sensitive droplet digital PCR for detecting a low-prevalence somatic GNAQ mutation in Sturge-Weber syndrome. AB - Droplet digital PCR (ddPCR), a method for measuring target nucleic acid sequence quantity, is useful for determining somatic mutation rates using TaqMan probes. In this study, the detection limit of copy numbers of test DNA by ddPCR was determined based on Poisson distribution. Peptide nucleic acid (PNA), which strongly hybridises to target lesions, can inhibit target amplification by PCR. Therefore, by combination of PCR with PNA and ddPCR (PNA-ddPCR), the detection limit could be lowered. We reanalysed a somatic GNAQ mutation (c.548G > A) in patients with Sturge-Weber syndrome (SWS) using ddPCR and PNA-ddPCR. Importantly, among three patients previously found to be mutation negative by next-generation sequencing, two patients had the GNAQ mutation with a mutant allele frequency of less than 1%. Furthermore, we were able to find the same mutation in blood leukocyte or saliva DNA derived from four out of 40 SWS patients. Vascular anomalies and blood leukocytes originate from endothelial cells and haemangioblasts, respectively, which are both of mesodermal origin. Therefore, blood leukocytes may harbour the GNAQ mutation, depending on the time when the somatic mutation is acquired. These data suggest the possibility of diagnosis using blood DNA in some patients with SWS. PMID- 26957146 TI - Atomic-Scale Engineering of Abrupt Interface for Direct Spin Contact of Ferromagnetic Semiconductor with Silicon. AB - Control and manipulation of the spin of conduction electrons in industrial semiconductors such as silicon are suggested as an operating principle for a new generation of spintronic devices. Coherent injection of spin-polarized carriers into Si is a key to this novel technology. It is contingent on our ability to engineer flawless interfaces of Si with a spin injector to prevent spin-flip scattering. The unique properties of the ferromagnetic semiconductor EuO make it a prospective spin injector into silicon. Recent advances in the epitaxial integration of EuO with Si bring the manufacturing of a direct spin contact within reach. Here we employ transmission electron microscopy to study the interface EuO/Si with atomic-scale resolution. We report techniques for interface control on a submonolayer scale through surface reconstruction. Thus we prevent formation of alien phases and imperfections detrimental to spin injection. This development opens a new avenue for semiconductor spintronics. PMID- 26957149 TI - Communication: Enhanced dissociative chemisorption of CO2 via vibrational excitation. AB - A fully coupled global nine-dimensional potential energy surface for the dissociative chemisorption of CO2 on Ni(100) is constructed from ~18,000 density functional points. It reveals a complex reaction pathway dominated by two near iso-energetic transition states. The dissociation probabilities obtained by quasi classical trajectories on the potential energy surface reproduced experimental trends, and indicate that vibrational excitations of CO2 significantly promote the dissociation. Using the sudden vector projection model, the behavior of the reactivity is rationalized by couplings with the reaction coordinate at each transition state. These results offer plausible rationalization for the observed enhancement of CO2 dissociation in non-thermal plasmas by metal surfaces. PMID- 26957148 TI - Topographical and functional anatomy of trapezius muscle innervation by spinal accessory nerve and C2 to C4 nerves of cervical plexus. AB - The aim of this study was to determine the existence and the frequency of communicating branches between the spinal accessory nerve (SAN) and the C2, C3 and C4 roots of the cervical plexus. The present study also aimed to elucidate whether these branches contain motor fibers or not. Dissection of the cervical region was performed on twelve adult cadavers. A powered operating microscope was necessary to dissect the SAN and its branches and also to dissect C2, C3 and C4 nerve branches. In a second step, data from 13 patients who underwent 25 modified neck dissections under trapezius muscle's monitoring were collected. At the end of surgery, intraoperative stimulation on the SAN, C2, C3 and C4 nerve branches was performed. Registered potentials in the three parts of the trapezius muscle, using the NIM Medtronic system, were analyzed. During cadaver dissection, 18 (78 %) communicating branches were identified between the SAN and C2, 11 (48 %) between the SAN and C3, 12 (52 %) between the SAN and C4. Intraoperative stimulation of the SAN and its branch for the trapezius muscle provided a significant electroneurographic response in the three parts of the trapezius muscle in all subjects. Intraoperative stimulation of C3 led to recordable contractions of the trapezius muscle in 5 (20 %) modified neck surgeries, stimulation of C4 led to recordable contractions during 5 (20 %) modified neck dissections. One case of contraction was recorded after intraoperative stimulation of C2 (7 %). Although we were able to identify at least one communicating branch between the SAN and the roots of the cervical plexus in each cadaver dissection, the cervical plexus is not always involved in trapezius motor innervation. Intraoperative electroneurography demonstrated that a motor input from the cervical plexus to the trapezius muscle was provided in only 32 % of cases. Therefore, SAN trunk and C3-C4 roots should be carefully preserved during modified neck dissection to protect trapezius and shoulder functions. PMID- 26957150 TI - Communication: Generalized canonical purification for density matrix minimization. AB - A Lagrangian formulation for the constrained search for the N-representable one particle density matrix based on the McWeeny idempotency error minimization is proposed, which converges systematically to the ground state. A closed form of the canonical purification is derived for which no a posteriori adjustment on the trace of the density matrix is needed. The relationship with comparable methods is discussed, showing their possible generalization through the hole-particle duality. The appealing simplicity of this self-consistent recursion relation along with its low computational complexity could prove useful as an alternative to diagonalization in solving dense and sparse matrix eigenvalue problems. PMID- 26957147 TI - In vivo reprogramming reactive glia into iPSCs to produce new neurons in the cortex following traumatic brain injury. AB - Traumatic brain injury (TBI) results in a significant amount of cell death in the brain. Unfortunately, the adult mammalian brain possesses little regenerative potential following injury and little can be done to reverse the initial brain damage caused by trauma. Reprogramming adult cells to generate induced pluripotent stem cell (iPSCs) has opened new therapeutic opportunities to generate neurons in a non-neurogenic regions in the cortex. In this study we showed that retroviral mediated expression of four transcription factors, Oct4, Sox2, Klf4, and c-Myc, cooperatively reprogrammed reactive glial cells into iPSCs in the adult neocortex following TBI. These iPSCs further differentiated into a large number of neural stem cells, which further differentiated into neurons and glia in situ, and filled up the tissue cavity induced by TBI. The induced neurons showed a typical neuronal morphology with axon and dendrites, and exhibited action potential. Our results report an innovative technology to transform reactive glia into a large number of functional neurons in their natural environment of neocortex without embryo involvement and without the need to grow cells outside the body and then graft them back to the brain. Thus this technology offers hope for personalized regenerative cell therapies for repairing damaged brain. PMID- 26957151 TI - Supersampling method for efficient grid-based electronic structure calculations. AB - The egg-box effect, the spurious variation of energy and force due to the discretization of continuous space, is an inherent vexing problem in grid-based electronic structure calculations. Its effective suppression allowing for large grid spacing is thus crucial for accurate and efficient computations. We here report that the supersampling method drastically alleviates it by eliminating the rapidly varying part of a target function along both radial and angular directions. In particular, the use of the sinc filtering function performs best because as an ideal low pass filter it clearly cuts out the high frequency region beyond allowed by a given grid spacing. PMID- 26957152 TI - Mixed semiclassical initial value representation time-averaging propagator for spectroscopic calculations. AB - A mixed semiclassical initial value representation expression for spectroscopic calculations is derived. The formulation takes advantage of the time-averaging filtering and the hierarchical properties of different trajectory based propagation methods. A separable approximation is then introduced that greatly reduces (about an order of magnitude) the computational cost compared with a full Herman-Kluk time-averaging semiclassical calculation for the same systems. The expression is exact for the harmonic case and it is tested numerically for a Morse potential coupled to one or two additional harmonic degrees of freedom. Results are compared to full Herman-Kluk time-averaging calculations and exact quantum wavepacket propagations. We found the peak positions of the mixed semiclassical approximations to be always in very good agreement with full quantum calculations, while overtone peak intensities are lower with respect to the exact ones. Given the reduced computational effort required by this new mixed semiclassical approximation, we believe the present method to make spectroscopic calculations available for higher dimensional systems than accessible before. PMID- 26957153 TI - Diffusion Monte Carlo study on temporal evolution of entropy and free energy in nonequilibrium processes. AB - A computational scheme to describe the temporal evolution of thermodynamic functions in stochastic nonequilibrium processes of isothermal classical systems is proposed on the basis of overdamped Langevin equation under given potential and temperature. In this scheme the associated Fokker-Planck-Smoluchowski equation for the probability density function is transformed into the imaginary time Schrodinger equation with an effective Hamiltonian. The propagator for the time-dependent wave function is expressed in the framework of the path integral formalism, which can thus represent the dynamical behaviors of nonequilibrium molecular systems such as those conformational changes observed in protein folding and ligand docking. The present study then employs the diffusion Monte Carlo method to efficiently simulate the relaxation dynamics of wave function in terms of random walker distribution, which in the long-time limit reduces to the ground-state eigenfunction corresponding to the equilibrium Boltzmann distribution. Utilizing this classical-quantum correspondence, we can describe the relaxation processes of thermodynamic functions as an approach to the equilibrium state with the lowest free energy. Performing illustrative calculations for some prototypical model potentials, the temporal evolutions of enthalpy, entropy, and free energy of the classical systems are explicitly demonstrated. When the walkers initially start from a localized configuration in one- or two-dimensional harmonic or double well potential, the increase of entropy usually dominates the relaxation dynamics toward the equilibrium state. However, when they start from a broadened initial distribution or go into a steep valley of potential, the dynamics are driven by the decrease of enthalpy, thus causing the decrease of entropy associated with the spatial localization. In the cases of one- and two-dimensional asymmetric double well potentials with two minimal points and an energy barrier between them, we observe a nonequilibrium behavior that the system entropy first increases with the broadening of the initially localized walker distribution and then it begins to decrease along with the trapping at the global minimum of the potential, thus leading to the minimization of the free energy. PMID- 26957154 TI - On the accuracy of surface hopping dynamics in condensed phase non-adiabatic problems. AB - We perform extensive benchmark comparisons of surface hopping dynamics with numerically exact calculations for the spin-boson model over a wide range of energetic and coupling parameters as well as temperature. We find that deviations from golden-rule scaling in the Marcus regime are generally small and depend sensitively on the energetic bias between electronic states. Fewest switches surface hopping (FSSH) is found to be surprisingly accurate over a large swath of parameter space. The inclusion of decoherence corrections via the augmented FSSH algorithm improves the accuracy of dynamical behavior compared to exact simulations, but the effects are generally not dramatic, at least for the case of an environment modeled with the commonly used Debye spectral density. PMID- 26957155 TI - Efficient sampling over rough energy landscapes with high barriers: A combination of metadynamics with integrated tempering sampling. AB - In order to efficiently overcome high free energy barriers embedded in a complex energy landscape and calculate overall thermodynamics properties using molecular dynamics simulations, we developed and implemented a sampling strategy by combining the metadynamics with (selective) integrated tempering sampling (ITS/SITS) method. The dominant local minima on the potential energy surface (PES) are partially exalted by accumulating history-dependent potentials as in metadynamics, and the sampling over the entire PES is further enhanced by ITS/SITS. With this hybrid method, the simulated system can be rapidly driven across the dominant barrier along selected collective coordinates. Then, ITS/SITS ensures a fast convergence of the sampling over the entire PES and an efficient calculation of the overall thermodynamic properties of the simulation system. To test the accuracy and efficiency of this method, we first benchmarked this method in the calculation of phi - psi distribution of alanine dipeptide in explicit solvent. We further applied it to examine the design of template molecules for aromatic meta-C-H activation in solutions and investigate solution conformations of the nonapeptide Bradykinin involving slow cis-trans isomerizations of three proline residues. PMID- 26957156 TI - Multiconfigurational quantum propagation with trajectory-guided generalized coherent states. AB - A generalized version of the coupled coherent states method for coherent states of arbitrary Lie groups is developed. In contrast to the original formulation, which is restricted to frozen-Gaussian basis sets, the extended method is suitable for propagating quantum states of systems featuring diversified physical properties, such as spin degrees of freedom or particle indistinguishability. The approach is illustrated with simple models for interacting bosons trapped in double- and triple-well potentials, most adequately described in terms of SU(2) and SU(3) bosonic coherent states, respectively. PMID- 26957157 TI - Range-separated time-dependent density-functional theory with a frequency dependent second-order Bethe-Salpeter correlation kernel. AB - We present a range-separated linear-response time-dependent density-functional theory (TDDFT) which combines a density-functional approximation for the short range response kernel and a frequency-dependent second-order Bethe-Salpeter approximation for the long-range response kernel. This approach goes beyond the adiabatic approximation usually used in linear-response TDDFT and aims at improving the accuracy of calculations of electronic excitation energies of molecular systems. A detailed derivation of the frequency-dependent second-order Bethe-Salpeter correlation kernel is given using many-body Green-function theory. Preliminary tests of this range-separated TDDFT method are presented for the calculation of excitation energies of the He and Be atoms and small molecules (H2, N2, CO2, H2CO, and C2H4). The results suggest that the addition of the long range second-order Bethe-Salpeter correlation kernel overall slightly improves the excitation energies. PMID- 26957158 TI - A multi-state trajectory method for non-adiabatic dynamics simulations. AB - A multi-state trajectory approach is proposed to describe nuclear-electron coupled dynamics in nonadiabatic simulations. In this approach, each electronic state is associated with an individual trajectory, among which electronic transition occurs. The set of these individual trajectories constitutes a multi state trajectory, and nuclear dynamics is described by one of these individual trajectories as the system is on the corresponding state. The total nuclear electron coupled dynamics is obtained from the ensemble average of the multi state trajectories. A variety of benchmark systems such as the spin-boson system have been tested and the results generated using the quasi-classical version of the method show reasonably good agreement with the exact quantum calculations. Featured in a clear multi-state picture, high efficiency, and excellent numerical stability, the proposed method may have advantages in being implemented to realistic complex molecular systems, and it could be straightforwardly applied to general nonadiabatic dynamics involving multiple states. PMID- 26957159 TI - Construction of the landscape for multi-stable systems: Potential landscape, quasi-potential, A-type integral and beyond. AB - Motivated by the famous Waddington's epigenetic landscape metaphor in developmental biology, biophysicists and applied mathematicians made different proposals to construct the landscape for multi-stable complex systems. We aim to summarize and elucidate the relationships among these theories from a mathematical point of view. We systematically investigate and compare three different but closely related realizations in the recent literature: the Wang's potential landscape theory from steady state distribution of stochastic differential equations (SDEs), the Freidlin-Wentzell quasi-potential from the large deviation theory, and the construction through SDE decomposition and A-type integral. We revisit that the quasi-potential is the zero noise limit of the potential landscape, and the potential function in the third proposal coincides with the quasi-potential. We compare the difference between local and global quasi-potential through the viewpoint of exchange of limit order for time and noise amplitude. We argue that local quasi-potentials are responsible for getting transition rates between neighboring stable states, while the global quasi potential mainly characterizes the residence time of the states as the system reaches stationarity. The difference between these two is prominent when the transitivity property is broken. The most probable transition path by minimizing the Onsager-Machlup or Freidlin-Wentzell action functional is also discussed. As a consequence of the established connections among different proposals, we arrive at the novel result which guarantees the existence of SDE decomposition while denies its uniqueness in general cases. It is, therefore, clarified that the A type integral is more appropriate to be applied to the decomposed SDEs rather than its primitive form as believed by previous researchers. Our results contribute to a deeper understanding of landscape theories for biological systems. PMID- 26957160 TI - Understanding and improving the efficiency of full configuration interaction quantum Monte Carlo. AB - Within full configuration interaction quantum Monte Carlo, we investigate how the statistical error behaves as a function of the parameters which control the stochastic sampling. We define the inefficiency as a measure of the statistical error per particle sampling the space and per time step and show there is a sizeable parameter regime where this is minimised. We find that this inefficiency increases sublinearly with Hilbert space size and can be reduced by localising the canonical Hartree-Fock molecular orbitals, suggesting that the choice of basis impacts the method beyond that of the sign problem. PMID- 26957161 TI - SparseMaps--A systematic infrastructure for reduced-scaling electronic structure methods. III. Linear-scaling multireference domain-based pair natural orbital N electron valence perturbation theory. AB - Multi-reference (MR) electronic structure methods, such as MR configuration interaction or MR perturbation theory, can provide reliable energies and properties for many molecular phenomena like bond breaking, excited states, transition states or magnetic properties of transition metal complexes and clusters. However, owing to their inherent complexity, most MR methods are still too computationally expensive for large systems. Therefore the development of more computationally attractive MR approaches is necessary to enable routine application for large-scale chemical systems. Among the state-of-the-art MR methods, second-order N-electron valence state perturbation theory (NEVPT2) is an efficient, size-consistent, and intruder-state-free method. However, there are still two important bottlenecks in practical applications of NEVPT2 to large systems: (a) the high computational cost of NEVPT2 for large molecules, even with moderate active spaces and (b) the prohibitive cost for treating large active spaces. In this work, we address problem (a) by developing a linear scaling "partially contracted" NEVPT2 method. This development uses the idea of domain based local pair natural orbitals (DLPNOs) to form a highly efficient algorithm. As shown previously in the framework of single-reference methods, the DLPNO concept leads to an enormous reduction in computational effort while at the same time providing high accuracy (approaching 99.9% of the correlation energy), robustness, and black-box character. In the DLPNO approach, the virtual space is spanned by pair natural orbitals that are expanded in terms of projected atomic orbitals in large orbital domains, while the inactive space is spanned by localized orbitals. The active orbitals are left untouched. Our implementation features a highly efficient "electron pair prescreening" that skips the negligible inactive pairs. The surviving pairs are treated using the partially contracted NEVPT2 formalism. A detailed comparison between the partial and strong contraction schemes is made, with conclusions that discourage the strong contraction scheme as a basis for local correlation methods due to its non invariance with respect to rotations in the inactive and external subspaces. A minimal set of conservatively chosen truncation thresholds controls the accuracy of the method. With the default thresholds, about 99.9% of the canonical partially contracted NEVPT2 correlation energy is recovered while the crossover of the computational cost with the already very efficient canonical method occurs reasonably early; in linear chain type compounds at a chain length of around 80 atoms. Calculations are reported for systems with more than 300 atoms and 5400 basis functions. PMID- 26957162 TI - Using full configuration interaction quantum Monte Carlo in a seniority zero space to investigate the correlation energy equivalence of pair coupled cluster doubles and doubly occupied configuration interaction. AB - Over the past few years, pair coupled cluster doubles (pCCD) has shown promise for the description of strong correlation. This promise is related to its apparent ability to match results from doubly occupied configuration interaction (DOCI), even though the latter method has exponential computational cost. Here, by modifying the full configuration interaction quantum Monte Carlo algorithm to sample only the seniority zero sector of Hilbert space, we show that the DOCI and pCCD energies are in agreement for a variety of 2D Hubbard models, including for systems well out of reach for conventional configuration interaction algorithms. Our calculations are aided by the sign problem being much reduced in the seniority zero space compared with the full space. We present evidence for this and then discuss the sign problem in terms of the wave function of the system which appears to have a simplified sign structure. PMID- 26957163 TI - Prospects for quantum computing with an array of ultracold polar paramagnetic molecules. AB - Arrays of trapped ultracold molecules represent a promising platform for implementing a universal quantum computer. DeMille [Phys. Rev. Lett. 88, 067901 (2002)] has detailed a prototype design based on Stark states of polar (1)Sigma molecules as qubits. Herein, we consider an array of polar (2)Sigma molecules which are, in addition, inherently paramagnetic and whose Hund's case (b) free rotor pair-eigenstates are Bell states. We show that by subjecting the array to combinations of concurrent homogeneous and inhomogeneous electric and magnetic fields, the entanglement of the array's Stark and Zeeman states can be tuned and the qubit sites addressed. Two schemes for implementing an optically controlled CNOT gate are proposed and their feasibility discussed in the face of the broadening of spectral lines due to dipole-dipole coupling and the inhomogeneity of the electric and magnetic fields. PMID- 26957164 TI - Dynamics of photoexcited Ba(+) cations in (4)He nanodroplets. AB - We present a joint experimental and theoretical study on the desolvation of Ba(+) cations in (4)He nanodroplets excited via the 6p <- 6s transition. The experiments reveal an efficient desolvation process yielding mainly bare Ba(+) cations and Ba(+)Hen exciplexes with n = 1 and 2. The speed distributions of the ions are well described by Maxwell-Boltzmann distributions with temperatures ranging from 60 to 178 K depending on the excitation frequency and Ba(+) Hen exciplex size. These results have been analyzed by calculations based on a time dependent density functional description for the helium droplet combined with classical dynamics for the Ba(+). In agreement with experiment, the calculations reveal the dynamical formation of exciplexes following excitation of the Ba(+) cation. In contrast to experimental observation, the calculations do not reveal desolvation of excited Ba(+) cations or exciplexes, even when relaxation pathways to lower lying states are included. PMID- 26957165 TI - Interplay between structure and transport properties of molten salt mixtures of ZnCl2-NaCl-KCl: A molecular dynamics study. AB - Molten mixtures of network-forming covalently bonded ZnCl2 and network-modifying ionically bonded NaCl and KCl salts are investigated as high-temperature heat transfer fluids for concentrating solar power plants. Specifically, using molecular dynamics simulations, the interplay between the extent of the network structure, composition, and the transport properties (viscosity, thermal conductivity, and diffusion) of ZnCl2-NaCl-KCl molten salts is characterized. The Stokes-Einstein/Eyring relationship is found to break down in these network forming liquids at high concentrations of ZnCl2 (>63 mol. %), while the Eyring relationship is seen with increasing KCl concentration. Further, the network modification due to the addition of K ions leads to formation of non-bridging terminal Cl ions, which in turn lead to a positive temperature dependence of thermal conductivity in these melts. This new understanding of transport in these ternary liquids enables the identification of appropriate concentrations of the network formers and network modifiers to design heat transfer fluids with desired transport properties for concentrating solar power plants. PMID- 26957166 TI - Analysis of structural correlations in a model binary 3D liquid through the eigenvalues and eigenvectors of the atomic stress tensors. AB - It is possible to associate with every atom or molecule in a liquid its own atomic stress tensor. These atomic stress tensors can be used to describe liquids' structures and to investigate the connection between structural and dynamic properties. In particular, atomic stresses allow to address atomic scale correlations relevant to the Green-Kubo expression for viscosity. Previously correlations between the atomic stresses of different atoms were studied using the Cartesian representation of the stress tensors or the representation based on spherical harmonics. In this paper we address structural correlations in a 3D model binary liquid using the eigenvalues and eigenvectors of the atomic stress tensors. This approach allows to interpret correlations relevant to the Green Kubo expression for viscosity in a simple geometric way. On decrease of temperature the changes in the relevant stress correlation function between different atoms are significantly more pronounced than the changes in the pair density function. We demonstrate that this behaviour originates from the orientational correlations between the eigenvectors of the atomic stress tensors. We also found correlations between the eigenvalues of the same atomic stress tensor. For the studied system, with purely repulsive interactions between the particles, the eigenvalues of every atomic stress tensor are positive and they can be ordered: lambda1 >= lambda2 >= lambda3 >= 0. We found that, for the particles of a given type, the probability distributions of the ratios (lambda2/lambda1) and (lambda3/lambda2) are essentially identical to each other in the liquids state. We also found that lambda2 tends to be equal to the geometric average of lambda1 and lambda3. In our view, correlations between the eigenvalues may represent "the Poisson ratio effect" at the atomic scale. PMID- 26957167 TI - Departure of microscopic friction from macroscopic drag in molecular fluid dynamics. AB - Friction coefficient of the Langevin equation and drag of spherical macroscopic objects in steady flow at low Reynolds numbers are usually regarded as equivalent. We show that the microscopic friction can be different from the macroscopic drag when the mass is taken into account for particles with comparable scale to the surrounding fluid molecules. We illustrate it numerically by molecular dynamics simulation of chloride ion in water. Friction variation by the atomistic mass effect beyond the Langevin regime can be of use in the drag reduction technology as well as the electro or thermophoresis. PMID- 26957168 TI - A common neighbor analysis of crystallization kinetics and excess entropy of charged spherical colloids. AB - The topological analysis tool known as the common neighbor analysis (CNA) is used for the first time in this work to analyze crystallization kinetics and excess entropy of charge-stabilized colloidal suspensions. For this purpose, Brownian dynamics computer simulations are implemented to investigate the crystallization kinetics of homogeneously melted colloidal crystals that are composed of hard core-screened-Coulomb interacting particles. The results are in agreement with recent static structure factor measurements that could indicate the presence of icosahedral units in the metastable melt, and with the fact that weakly screened charged colloids crystallize into body-centered-cubic (bcc) ordering. A two-step crystallization pathway is found, in which the population of bcc-subunit CNA pairs satisfactorily obeys a Verhulst model. Moreover, the CNA helped to unveil that the excess entropy obeys a quasi-universal functional form, relating the behavior of colloidal, molecular, and metallic liquid systems. The work contributes to the scientific understanding of the crystallization pathway of charged colloids, and to the development of new ways to assess the degree of crystalline order, starting from the excess entropy. PMID- 26957169 TI - Path-integral and Ornstein-Zernike study of quantum fluid structures on the crystallization line. AB - Liquid neon, liquid para-hydrogen, and the quantum hard-sphere fluid are studied with path integral Monte Carlo simulations and the Ornstein-Zernike pair equation on their respective crystallization lines. The results cover the whole sets of structures in the r-space and the k-space and, for completeness, the internal energies, pressures and isothermal compressibilities. Comparison with experiment is made wherever possible, and the possibilities of establishing k-space criteria for quantum crystallization based on the path-integral centroids are discussed. In this regard, the results show that the centroid structure factor contains two significant parameters related to its main peak features (amplitude and shape) that can be useful to characterize freezing. PMID- 26957170 TI - Passivation of surface states of alpha-Fe2O3(0001) surface by deposition of Ga2O3 overlayers: A density functional theory study. AB - There is a big debate in the community regarding the role of surface states of hematite in the photoelectrochemical water splitting. Experimental studies on non catalytic overlayers passivating the hematite surface states claim a favorable reduction in the overpotential for the water splitting reaction. As a first step towards understanding the effect of these overlayers, we have studied the system Ga2O3 overlayers on hematite (0001) surfaces using first principles computations in the PBE+U framework. Our computations suggest that stoichiometric terminations of Ga2O3 overlayers are energetically more favored than the bare surface, at ambient oxygen chemical potentials. Energetics suggest that the overlayers prefer to grow via a layer-plus-island (Stranski-Krastanov) growth mode with a critical layer thickness of 1-2 layers. Thus, a complete wetting of the hematite surface by an overlayer of gallium oxide is thermodynamically favored. We establish that the effect of deposition of the Ga2O3 overlayers on the bare hematite surface is to passivate the surface states for the stoichiometric termination. For the oxygen terminated surface which is the most stable termination under photoelectrochemical conditions, the effect of deposition of the Ga2O3 overlayer is to passivate the hole-trapping surface state. PMID- 26957171 TI - Iron phthalocyanine on Cu(111): Coverage-dependent assembly and symmetry breaking, temperature-induced homocoupling, and modification of the adsorbate surface interaction by annealing. AB - We have examined the geometric and electronic structures of iron phthalocyanine assemblies on a Cu(111) surface at different sub- to mono-layer coverages and the changes induced by thermal annealing at temperatures between 250 and 320 degrees C by scanning tunneling microscopy, x-ray photoelectron spectroscopy, and x-ray absorption spectroscopy. The symmetry breaking observed in scanning tunneling microscopy images is found to be coverage dependent and to persist upon annealing. Further, we find that annealing to temperatures between 300 and 320 degrees C leads to both desorption of iron phthalocyanine molecules from the surface and their agglomeration. We see clear evidence of temperature-induced homocoupling reactions of the iron phthalocyanine molecules following dehydrogenation of their isoindole rings, similar to what has been observed for related tetrapyrroles on transition metal surfaces. Finally, spectroscopy indicates a modified substrate-adsorbate interaction upon annealing with a shortened bond distance. This finding could potentially explain a changed reactivity of Cu-supported iron phthalocyanine in comparison to that of the pristine compound. PMID- 26957172 TI - The interplay of covalency, hydrogen bonding, and dispersion leads to a long range chiral network: The example of 2-butanol. AB - The assembly of complex structures in nature is driven by an interplay between several intermolecular interactions, from strong covalent bonds to weaker dispersion forces. Understanding and ultimately controlling the self-assembly of materials requires extensive study of how these forces drive local nanoscale interactions and how larger structures evolve. Surface-based self-assembly is particularly amenable to modeling and measuring these interactions in well defined systems. This study focuses on 2-butanol, the simplest aliphatic chiral alcohol. 2-butanol has recently been shown to have interesting properties as a chiral modifier of surface chemistry; however, its mode of action is not fully understood and a microscopic understanding of the role non-covalent interactions play in its adsorption and assembly on surfaces is lacking. In order to probe its surface properties, we employed high-resolution scanning tunneling microscopy and density functional theory (DFT) simulations. We found a surprisingly rich degree of enantiospecific adsorption, association, chiral cluster growth and ultimately long range, highly ordered chiral templating. Firstly, the chiral molecules acquire a second chiral center when adsorbed to the surface via dative bonding of one of the oxygen atom lone pairs. This interaction is controlled via the molecule's intrinsic chiral center leading to monomers of like chirality, at both chiral centers, adsorbed on the surface. The monomers then associate into tetramers via a cyclical network of hydrogen bonds with an opposite chirality at the oxygen atom. The evolution of these square units is surprising given that the underlying surface has a hexagonal symmetry. Our DFT calculations, however, reveal that the tetramers are stable entities that are able to associate with each other by weaker van der Waals interactions and tessellate in an extended square network. This network of homochiral square pores grows to cover the whole Au(111) surface. Our data reveal that the chirality of a simple alcohol can be transferred to its surface binding geometry, drive the directionality of hydrogen bonded networks and ultimately extended structure. Furthermore, this study provides the first microscopic insight into the surface properties of this important chiral modifier and provides a well-defined system for studying the network's enantioselective interaction with other molecules. PMID- 26957173 TI - Co on Fe3O4(001): Towards precise control of surface properties. AB - A novel approach to incorporate cobalt atoms into a magnetite single crystal is demonstrated by a combination of x-ray spectro-microscopy, low-energy electron diffraction, and density-functional theory calculations. Co is deposited at room temperature on the reconstructed magnetite (001) surface filling first the subsurface octahedral vacancies and then occupying adatom sites on the surface. Progressive annealing treatments at temperatures up to 733 K diffuse the Co atoms into deeper crystal positions, mainly into octahedral ones with a marked inversion level. The oxidation state, coordination, and magnetic moments of the cobalt atoms are followed from their adsorption to their final incorporation into the bulk, mostly as octahedral Co(2+). This precise control of the near-surface Co atoms location opens up the way to accurately tune the surface physical and magnetic properties of mixed spinel oxides. PMID- 26957174 TI - Importance of hydrophobic traps for proton diffusion in lyotropic liquid crystals. AB - The diffusion of protons in self-assembled systems is potentially important for the design of efficient proton exchange membranes. In this work, we study proton dynamics in a low-water content, lamellar phase of a sodium-carboxylate gemini surfactant/water system using computer simulations. The hopping of protons via the Grotthuss mechanism is explicitly allowed through the multi-state empirical valence bond method. We find that the hydronium ion is trapped on the hydrophobic side of the surfactant-water interface, and proton diffusion then proceeds by hopping between surface sites. The importance of hydrophobic traps is surprising because one would expect the hydronium ions to be trapped at the charged headgroups. The physics illustrated in this system should be relevant to the proton dynamics in other amphiphilic membrane systems, whenever there exist exposed hydrophobic surface regions. PMID- 26957175 TI - Structure and dynamics of water at the mackinawite (001) surface. AB - We present a molecular dynamics investigation of the properties of water at the interface with the mackinawite (001) surface. We find water in the first layer to be characterised by structural properties which are reminiscent of hydrophobic substrates, with the bulk behaviour being recovered beyond the second layer. In addition, we show that the mineral surface reduces the mobility of interfacial water compared to the bulk. Finally, we discuss the important differences introduced by simulating water under conditions of high temperature and pressure, a scenario relevant to geochemistry. PMID- 26957176 TI - Raman and nuclear magnetic resonance investigation of alkali metal vapor interaction with alkene-based anti-relaxation coating. AB - The use of anti-relaxation coatings in alkali vapor cells yields substantial performance improvements compared to a bare glass surface by reducing the probability of spin relaxation in wall collisions by several orders of magnitude. Some of the most effective anti-relaxation coating materials are alpha-olefins, which (as in the case of more traditional paraffin coatings) must undergo a curing period after cell manufacturing in order to achieve the desired behavior. Until now, however, it has been unclear what physicochemical processes occur during cell curing, and how they may affect relevant cell properties. We present the results of nondestructive Raman-spectroscopy and magnetic-resonance investigations of the influence of alkali metal vapor (Cs or K) on an alpha olefin, 1-nonadecene coating the inner surface of a glass cell. It was found that during the curing process, the alkali metal catalyzes migration of the carbon carbon double bond, yielding a mixture of cis- and trans-2-nonadecene. PMID- 26957177 TI - Phase diagrams of charged colloidal rods: Can a uniaxial charge distribution break chiral symmetry? AB - We construct phase diagrams for charged rodlike colloids within the second-virial approximation as a function of rod concentration, salt concentration, and colloidal charge. Besides the expected isotropic-nematic transition, we also find parameter regimes with a coexistence between a nematic and a second, more highly aligned nematic phase including an isotropic-nematic-nematic triple point and a nematic-nematic critical point, which can all be explained in terms of the twisting effect. We compute the Frank elastic constants to see if the twist elastic constant can become negative, which would indicate the possibility of a cholesteric phase spontaneously forming. Although the twisting effect reduces the twist elastic constant, we find that it always remains positive. In addition, we find that for finite aspect-ratio rods the twist elastic constant is also always positive, such that there is no evidence of chiral symmetry breaking due to a uniaxial charge distribution. PMID- 26957178 TI - Adsorption of highly charged Gaussian polyelectrolytes onto oppositely charged surfaces. AB - In many biological processes highly charged biopolymers are adsorbed onto oppositely charged surfaces of macroions and membranes. They form strongly correlated structures close to the surface which cannot be explained by the conventional Poisson-Boltzmann theory. In this work strong coupling theory is used to study the adsorption of highly charged Gaussian polyelectrolytes. Two cases of adsorptions are considered, when the Gaussian polyelectrolytes are confined (a) by one charged wall, and (b) between two charged walls. The effects of salt and the geometry of the polymers on their adsorption-depletion transitions in the strong coupling regime are discussed. PMID- 26957179 TI - Sequential programmable self-assembly: Role of cooperative interactions. AB - We propose a general strategy of "sequential programmable self-assembly" that enables a bottom-up design of arbitrary multi-particle architectures on nano- and microscales. We show that a naive realization of this scheme, based on the pairwise additive interactions between particles, has fundamental limitations that lead to a relatively high error rate. This can be overcome by using cooperative interparticle binding. The cooperativity is a well known feature of many biochemical processes, responsible, e.g., for signaling and regulations in living systems. Here we propose to utilize a similar strategy for high precision self-assembly, and show that DNA-mediated interactions provide a convenient platform for its implementation. In particular, we outline a specific design of a DNA-based complex which we call "DNA spider," that acts as a smart interparticle linker and provides a built-in cooperativity of binding. We demonstrate versatility of the sequential self-assembly based on spider-functionalized particles by designing several mesostructures of increasing complexity and simulating their assembly process. This includes a number of finite and repeating structures, in particular, the so-called tetrahelix and its several derivatives. Due to its generality, this approach allows one to design and successfully self assemble virtually any structure made of a "GEOMAG" magnetic construction toy, out of nanoparticles. According to our results, once the binding cooperativity is strong enough, the sequential self-assembly becomes essentially error-free. PMID- 26957180 TI - Influence of mutations at the proximal histidine position on the Fe-O2 bond in hemoglobin from density functional theory. AB - Four mutated hemoglobin (Hb) variants and wild type hemoglobin as a reference have been investigated using density functional theory methods focusing on oxygen binding. Dispersion-corrected B3LYP functional is used and found to provide reliable oxygen binding energies. It also correctly reproduces the spin distribution of both bound and free heme groups as well as provides correct geometries at their close vicinity. Mutations in hemoglobin are not only an intrigued biological problem and it is also highly important to understand their effects from a clinical point of view. This study clearly shows how even small structural differences close to the heme group can have a significant effect in reducing the oxygen binding of mutated hemoglobins and consequently affecting the health condition of the patient suffering from the mutations. All of the studied mutated Hb variants did exhibit much weaker binding of molecular oxygen compared to the wild type of hemoglobin. PMID- 26957181 TI - Folding and escape of nascent proteins at ribosomal exit tunnel. AB - We investigate the interplay between post-translational folding and escape of two small single-domain proteins at the ribosomal exit tunnel by using Langevin dynamics with coarse-grained models. It is shown that at temperatures lower or near the temperature of the fastest folding, folding proceeds concomitantly with the escape process, resulting in vectorial folding and enhancement of foldability of nascent proteins. The concomitance between the two processes, however, deteriorates as temperature increases. Our folding simulations as well as free energy calculation by using umbrella sampling show that, at low temperatures, folding at the tunnel follows one or two specific pathways without kinetic traps. It is shown that the escape time can be mapped to a one-dimensional diffusion model with two different regimes for temperatures above and below the folding transition temperature. Attractive interactions between amino acids and attractive sites on the tunnel wall lead to a free energy barrier along the escape route of the protein. It is suggested that this barrier slows down the escape process and consequently promotes correct folding of the released nascent protein. PMID- 26957182 TI - Publisher's Note: "Study of infrared emission spectroscopy for the B(1)Deltag A(1)Piu and B('1)Sigmag (+)-A(1)Piu systems of C2" [J. Chem. Phys. 144, 064301 (2016)]. PMID- 26957183 TI - Erratum: "Energy of the quasi-free electron in H2, D2, and O2: Probing intermolecular potentials within the local Wigner-Seitz model" [J. Chem. Phys. 143, 224303 (2015)]. PMID- 26957184 TI - Erratum: "Fluids in porous media. III. Scaled particle theory" [J. Chem. Phys. 134, 074503 (2011)]. PMID- 26957185 TI - Erratum: "Equilibrium simulation of trp-cage in the presence of protein crowders" [J. Chem. Phys. 143, 175102 (2015)]. PMID- 26957187 TI - A novel technique of Roux-en-Y gastric bypass reversal for postprandial hyperinsulinemic hypoglycaemia: A case report. AB - BACKGROUND: We describe an evaluation of the effects of partial Roux-en-Y gastric bypass (RYGB) reversal on postprandial hyperinsulinaemic hypoglycaemia, insulin and GLP-1 levels. CASE SUMMARY: A 37 year old man was admitted with neuroglycopenia (plasma-glucose 1.6mmol/l) 18 months after RYGB, with normal 72h fasting test and abdominal CT. Despite dietary modifications and medical treatment, the hypoglycaemic episodes escalated in frequency. Feeding by a gastrostomy tube positioned in the gastric remnant did not prevent severe episodes of hypoglycaemia. A modified reversal of the RYGB was performed. Mixed meal tests were done perorally (PO), through the gastrostomy tube 1 (GT1), 4 weeks (GT2) after placement and 4 weeks after reversal (POr), with assessment of glucose, insulin and GLP-1 levels. RESULTS: Plasma-glucose increased to a maximum of 9.6, 5.4, 6.5 and 5.8mmol/l at the PO, GT1, GT2 and POr tests respectively. The corresponding insulin levels were 2939, 731, 725 and 463pmol/l. A decrease of plasma-glucose followed: 2.2, 3.0, 3.9 and 2.9mmol/l respectively and insulin levels were suppressed at 150min: 45, 22, 21 and 14pmol/l, respectively. GLP-1 levels increased in the PO test (60min: 122pmol/l, 21 fold of basal), but was attenuated in the two latter tests (12-23pmol/l at 60min). CONCLUSIONS: Reduction of plasma-glucose, insulin and GLP-1 excursions and symptoms were seen after gastric tube placement and partial RYGB reversal. This attenuation of GLP-1 response to feeding could reflect an adaptation to nutrients. PMID- 26957186 TI - Adapting Technological Interventions to Meet the Needs of Priority Populations. AB - Cardiovascular diseases (CVD) comprise the leading cause of mortality worldwide, accounting for 3 in 10 deaths. Individuals with certain risk factors, including tobacco use, obesity, low levels of physical activity, type 2 diabetes mellitus, racial/ethnic minority status and low socioeconomic status, experience higher rates of CVD and are, therefore, considered priority populations. Technological devices such as computers and smartphones are now routinely utilized in research studies aiming to prevent CVD and its risk factors, and they are also rampant in the public and private health sectors. Traditional health behavior interventions targeting these risk factors have been adapted for technology-based approaches. This review provides an overview of technology-based interventions conducted in these priority populations as well as the challenges and gaps to be addressed in future research. Researchers currently possess tremendous opportunities to engage in technology-based implementation and dissemination science to help spread evidence-based programs focusing on CVD risk factors in these and other priority populations. PMID- 26957188 TI - Synchronous thymoma and oligodendroglioma: A rare association. AB - INTRODUCTION: Patients with thymoma are found to have another systemic illness and a broadly increased risk for secondary malignancies. We present the case of a 53-year-old female patient who harbored two synchronous primary malignant neoplasms-an anaplastic oligodendroglioma of the right frontal lobe and an anterior mediastinal thymoma. PRESENTATION OF CASE: A 53-year-old female patient presented in her first hospital admission with nausea, chest pain and non pulsatile bitemporal headache. Continued headache and nausea along with negative cardiac findings prompted radiological evaluation including chest CT scan and brain CT scan which revealed simultaneous anterior mediastinal mass and frontal lobe calcification respectively. The patient underwent craniotomy and the pathological diagnosis was anaplastic oligodendriglioma. The anterior mediastinal tumor resection was performed three months later, while the patient had no newly onset of any symptoms necessitating more investigation. DISCUSSION: Multiple primary malignancies have been diagnosed by the following criteria: each tumor must have an obvious picture of malignancy, each must be separate and discrete and the probability that one was a metastatic lesion from the other must be excluded. Treatment strategies in cases of double malignancy involve treating the malignancy that is more advanced first. In our case we concluded that synchronous double malignancy can be treated successfully according to the above mentioned criteria. CONCLUSION: Clinicians should be aware of the possibility of synchronous malignancies in order to use screening procedures in patients with reported increased risk of double malignancy. Such clinical alertness may lead to a better outcome for double primary tumor cases. PMID- 26957189 TI - Myeloid sarcoma: An unusual and rare laryngeal presentation. AB - INTRODUCTION: Myeloid Sarcoma (MS) or Granulocytic Sarcoma is an uncommon laryngeal malignancy. It may arise from myelodysplastic syndromes, malignancy or de novo. Presentation in the larynx is rare and some may present with Acute Myeloid Leukaemia (AML) whereby the later may be asymptomatic. CASE PRESENTATION: A 44-year-old South East Asian lady presented with a six months history of hoarseness, shortness of breath, reduced exercise tolerance, weight loss and laryngeal irritation. Symptoms progressed to coughing with liquids two months prior. On examination, she had a resting biphasic stridor and laryngoscopy revealed right immobile vocal cord with a firm right ventricle mass extending into the right paraglottic space. She was pale and haematology investigations revealed microcytic hypochromic anaemia. Magnetic Resonance Imaging (MRI) of the neck and thorax showed thickening of the right false cord, true cord and aryepiglottic fold. A biopsy taken during endolaryngeal microsurgery (ELMS) confirmed myeloid sarcoma of the right ventricle and para glottic mass. Further investigation revealed a background of AML and she then underwent chemotherapy. DISCUSSION: MS is a rarity with only nine reported cases between the years of 1954 until 2015. Immunohistochemistry and immunophenotyping are definite for diagnosis confirmation as MS cells often exhibit myeloperoxidase (MPO), lymphocyte common antigen (LCA) and CD117 markers. MS is treated with are chemotherapy (either systemic or intrathecal), radiotherapy, surgical excision or in combination. Systemic chemotherapy has better efficacy and prognosis as compared to localised treatment of radiotherapy or surgical excision. However, there has yet to be a definitive chemotherapy protocol. Prognosis is poor with a 5-year survival rate of 48%. CONCLUSION: Although laryngeal MS is a rare phenomenon, early recognition is key and patients should always be investigated for an underlying myeloproliferative or dysplastic disease. PMID- 26957190 TI - Brain lesion correlates of fatigue in individuals with traumatic brain injury. AB - The purpose of this study was to investigate the neurological correlates of both subjective fatigue as well as objective fatigability in individuals with traumatic brain injury (TBI). The study has a cross-sectional design. Participants (N = 53) with TBI (77% male, mean age at injury 38 years, mean time since injury 1.8 years) underwent a structural magnetic resonance imaging (MRI) scan and completed the Fatigue Severity Scale (FSS), while a subsample (N = 36) was also tested with a vigilance task. While subjective fatigue (FSS) was not related to measures of brain lesions, multilevel analyses showed that a change in the participants' decision time was significantly predicted by grey matter (GM) lesions in the right frontal lobe. The time-dependent development of the participants' error rate was predicted by total brain white matter (WM) lesion volumes, as well as right temporal GM and WM lesion volumes. These findings could be explained by decreased functional connectivity of attentional networks, which results in accelerated exhaustion during cognitive task performance. The disparate nature of objectively measurable fatigability on the one hand and the subjective experience of fatigue on the other needs further investigation. PMID- 26957191 TI - Doxorubicin conjugated functionalizable carbon dots for nucleus targeted delivery and enhanced therapeutic efficacy. AB - Carbon dots (CDs) have shown great potential in imaging and drug/gene delivery applications. In this work, CDs functionalized with a nuclear localization signal peptide (NLS-CDs) were employed to transport doxorubicin (DOX) into cancer cells for enhanced antitumor activity. DOX was coupled to NLS-CDs (DOX-CDs) through an acid-labile hydrazone bond, which was cleavable in the weakly acidic intracellular compartments. The cytotoxicity of DOX-CD complexes was evaluated by the MTT assay and the cellular uptake was monitored using flow cytometry and confocal laser scanning microscopy. Cell imaging confirmed that DOX-CDs were mainly located in the nucleus. Furthermore, the complexes could efficiently induce apoptosis in human lung adenocarcinoma A549 cells. The in vivo therapeutic efficacy of DOX-CDs was investigated in an A549 xenograft nude mice model and the complexes exhibited an enhanced ability to inhibit tumor growth compared with free DOX. Thus, the DOX-CD conjugates may be exploited as promising drug delivery vehicles in cancer therapy. PMID- 26957192 TI - Neonatal anthropometry at 3400 m above sea level compared with INTERGROWTH 21st standards. AB - OBJECTIVE: To determine the 3rd, 10th, 50th, 90th and 97th percentile of weight, length and head circumference (HC) of male and female neonates born at 3400 m above sea level and compare with published INTERGROWTH 21st standards. METHODS: Observational, transverse analytical study conducted in the National Hospital Adolfo Guevara Velazco of the ESSALUD hospital system in Cusco, Peru, at 3400 m altitude, during the period of January 2005 to December 2010. Using inclusion criteria, 7635 newborns were selected. The 3rd, 10th, 50th, 90th and 97th percentiles for the anthropometric measurements of birthweight, length and HC were determined for each sex and the results analyzed via polynomial regression for each percentile in order to compare the results with INTERGROWTH 21st standards. RESULTS: No statistically significant difference was observed with the exception of female HC at the 97th percentile when compared with the INTERGROWTH 21st standards. CONCLUSIONS: Based on tables generated in the present study, neonatal anthropometric percentiles at term at 3400 m above sea level demonstrate no appreciable difference with INTERGROWTH 21st standards with the exception of female HC at the 97th percentile. PMID- 26957193 TI - Editorial: Strategies to Defeat HIV. PMID- 26957194 TI - Anti-HIV Factors: Targeting Each Step of HIV's Replication Cycle. AB - BACKGROUND: Similar to other animal viruses, HIV-1 relies on the contributions of the cellular machinery to ensure efficient virus propagation. However, human cells have evolved refined mechanisms to block key steps of the virus life-cycle, thereby suppressing viral replication. These cellular proteins are generally known as restriction factors, and they provide an early antiviral defense. So far, five potent restriction factors have been shown to effectively block HIV and/or SIV replication. These are TRIM5 proteins, SAMHD-1, members of the APOBEC3 (A3) family, Mx2 and Tetherin/BST-2. RESULTS: Here, we review the antiviral mechanisms of these and other antiviral factors, their interaction with the innate immune responses, and how their functions might be exploited to clear and prevent HIV infection. CONCLUSION: Since the majority of vaccine approaches against HIV have failed so far, it is imperative to start looking at alternative strategies for vaccine and therapy development. By better understanding how HIV hijacks the cellular machinery for its own benefit in completing its life-cycle, and how the virus adapts to circumvent our intrinsic immunity, we will be better equipped to design compounds that specifically interrupt virus replication and spread. PMID- 26957195 TI - The Early Bird Catches the Worm--Can Evolution Teach us Lessons in Fighting HIV? AB - BACKGROUND: Human immunodeficiency virus 1 (HIV-1) infection is the primary cause of the acquired immunodeficiency syndrome (AIDS). Worldwide, approximately 37 million people are infected (UNAIDS, 2014), most of them in developing countries. A vaccine is not available and current treatment strategies and diagnostics are expensive and require appropriate medical infrastructure. As a lentivirus of the family Retroviridae, HIV-1 reverse transcribes its RNA into double stranded DNA that integrates into the host genome during infection, establishing a stably integrated provirus that serves as a template for the production of progeny virus. The earliest steps during infection are critical for onset of disease, progression and clinical outcome. METHODS: Here we review the current literature of known interactions between host cell factors and HIV-1 in the early infection steps and discuss them as possible targets for new treatment strategies. RESULTS: Targeting the earliest interactions of the virus with host cell factors is an attractive way to prevent provirus formation, underlined by the evolution of multiple antiviral host cell barriers at this stage. HIV-1 has to overcome these restrictions by either counteracting them directly or by escape mutations. At the same time, viral fitness requires preservation of viral structures that interact with host components, thereby avoiding recognition of viral nucleic acids, like reverse transcription intermediates, by innate pattern recognition receptors. CONCLUSION: Future drug development, improvement of existing drugs acting in the earliest stages of the HIV-1 replication cycle as well as specifically targeting interactions of viral components with host cell factors required for HIV-1 infection will likely advance current therapy strategies. PMID- 26957196 TI - Apobec3G-Based Strategies to Defeat HIV Infection. AB - BACKGROUND: To suppress HIV infection, host cells have evolved numerous defenses that generally belong to the innate and adaptive immune responses. Over the last decade, extensive efforts have been focused on understanding HIV restriction factors and mechanisms of evasion. The host protein APOBEC3G (A3G) was identified as a member of cytidine deaminase family in 2002, and it was shown that, in the absence of HIV encoded Vif, A3G can block the replication of HIV-1 by introducing viral hypermutations during reverse transcription, also conferring innate immunity to the virus. Hence, therapeutic exploitation of A3G as an antiviral therapy has received an increasing amount of attention. Recent studies have developed a series of strategies to abolish the interaction between Vif and A3G or facilitate A3G expression, thus enhancing active A3G formation and delivering A3G into virion. CONCLUSION: Here we present a review that discuss the role of A3G as a host innate immunity factor and its application in HIV therapy. PMID- 26957197 TI - SAMHD1 in Retroviral Restriction and Innate Immune Sensing--Should We Leash the Hound? AB - BACKGROUND: The antiviral restriction factor SAM domain and HD domain-containing protein 1 (SAMHD1) is a dNTP triphosphohydrolase and thereby contributes to the regulation of intracellular dNTP levels. SAMHD1 blocks retroviral infection at the level of reverse transcription in myeloid cells and resting CD4+ T cells and is counteracted by the accessory protein Vpx, which is encoded by human immunodeficiency virus 2 (HIV-2) and several simian immunodeficiency virus (SIV) strains. Recently, it has been shown that the antiviral activity of SAMHD1 in myeloid dendritic cells (DC) hampers the induction of an efficient immune response directed against HIV-1. CONCLUSION: Within this review, we will summarize recent advances on the biology of SAMHD1 and its function as an antiviral restriction factor. In addition, we will discuss its role in autoimmunity and the antiviral immune response directed against HIV-1 and will evaluate the possibility of modulating SAMHD1 activity to generate an enhanced antiretroviral immune response. PMID- 26957199 TI - Mucosal Vaccination for Prevention of HIV Infection and AIDS. AB - BACKGROUND: Most of HIV infections occur via the genital tract or the rectum and HIV replicates at high levels in lymphoid organs and intestinal mucosa, likely requiring a more diversified immunity than pathogens restricted to a single mucosal site, such as the gastrointestinal tract for Vibrio cholera, or the respiratory airways for the influenza virus. RESULTS: Numerous AIDS vaccine candidates are under development and a general observation obtained from preclinical trials in non-human primates that failed to provide sterilizing immunity is that some infection protection or delayed onset of disease is observed in the presence of anti-SIV immunity. Recent clinical trials support difficulties to reproduce in humans the results observed in simian models, but at least one of them indicated that some protection of infection can be achieved. However, given the limited efficacy observed in the RV144 trial and concerns voiced in its statistical interpretation, preclinical trials should explore more effective immunogens, whether new or as combinations of existing ones, and mucosal routes of vaccinations in addition to the systemic routes, with the goal to maximize vaccination-mediated protection. CONCLUSION: The rationale for generating both strong mucosal and systemic immunity comes from animal experiments, recent clinical trials, and other successful vaccines currently in use. Mucosal responses against SIV have been induced with a variety of SIV antigens and via different mucosal routes with a spectrum of effects on protection. This review covers the rational and the experimental data that support the validity to explore mucosal immunization for HIV infection and AIDS prevention. PMID- 26957200 TI - Antibody-Based Preventive and Therapeutic Strategies Against HIV. AB - BACKGROUND: Over the years, numerous studies have been carried out demonstrating the role of antibodies in HIV control leading to the development of antibody based therapeutic and prophylactic strategies. OBJECTIVE: The objective of this review is to provide updated information on the role of antibodies in the prevention and control of HIV infection and the strategies against HIV that have been designed based on this information. RESULTS: Passive transfer of anti-HIV antibodies in animal models has proven the efficacy of certain antibodies in the prevention and treatment of infection. The capacity of antibodies to control the virus was first attributed to their neutralizing capacity. However, we now know that there are other Fc-mediated antibody activities associated with virus protection. When it comes to better understanding protection against HIV, we ought to pay particular attention to mucosal immune responses. The evidence accumulated so far indicates that an effective vaccine against HIV should generate both mucosal IgAs and systemic IgGs. Due to the problematic induction of protective anti-HIV antibodies, several groups have developed alternative approaches based on antibody delivery via gene therapy vectors. Experiments in animal models with these vectors have shown impressive protection levels and this strategy is now being clinically trialed. CONCLUSION: Taking into account all the information included in this review, it seems evident that anti-HIV-1 antibodies play an important role in virus control and prevention. This review aims to give an overview of the strategies used and the advances in antibody-based preventive and therapeutic strategies against HIV-1. PMID- 26957198 TI - Tetherin/BST-2: Restriction Factor or Immunomodulator? AB - BACKGROUND: Cell-mediated immune (CMI) responses are critical for the control of HIV-1 infection and their importance was highlighted by the existence of viral proteins, particularly Vpu and Nef, that antagonize these responses. Pandemic HIV 1 Vpu counteracts Tetherin/BST-2, a host factor that could prevent the release of HIV-1 virions by tethering virions on the cell surface, but a link between Tetherin and HIV-1 CMI responses has not yet been demonstrated in vivo. In vitro, the virological and immunological impact of Tetherin-mediated accumulation of virions ranged from enhanced or diminished cell-to-cell spread to enhanced recognition by virus-specific antibodies for natural killer cellmediated lysis. However, Tetherin-restricted virions could be internalized through an endocytosis motif in the Tetherin cytoplasmic tail. METHODS: Given the uncertainties on which in vitro results manifest in vivo and the dearth of knowledge on how Tetherin influences retroviral immunity, in vivo retrovirus infections in mice encoding wild-type, null and endocytosis-defective Tetherin were performed. Here, we review and highlight the results from these in vivo studies. RESULTS: Current data suggests that endocytosis-defective Tetherin functions as a potent innate restriction factor. By contrast, endocytosis-competent Tetherin, the form found in most mammals including humans and the form counteracted by HIV-1 Vpu, was linked to stronger CMI responses in mice. CONCLUSION: We propose that the main role of endocytosis-competent Tetherin is not to directly restrict retroviral replication, but to promote a more effective CMI response against retroviruses. PMID- 26957203 TI - The role of host genetic factors and host immunity in necrotic enteritis. AB - The increasing number of legislative restrictions and the voluntary withdrawal of antibiotic growth promoters worldwide will continue to impact poultry health and production. The rising incidence of Clostridium infections and development of necrotic enteritis (NE) in commercial chickens has been associated with the withdrawal of antibiotics. High-throughput genomic analysis of intestinal tissues from NE-afflicted chickens showed alterations in the local immunity and gut microbiota. Therefore, a better understanding of host- and environmentally related factors on Clostridium perfringens infections will be necessary for the development of effective sustainable strategies aimed to reduce the negative consequences of NE. In this short review, we summarize the current knowledge on the role of host genomics and immunity in NE. The limited progress in understanding the complexity of host-pathogen interactions in NE underscores the urgent need for more fundamental research in host immunity against Clostridium pathogens in order to develop effective control strategies against NE. PMID- 26957201 TI - HIV-1 Capsid Inhibitors as Antiretroviral Agents. AB - BACKGROUND: The infectious human immunodeficiency virus (HIV) particle is characterized by a conical capsid that encloses the viral RNA genome. The capsid is essential for HIV-1 replication and plays crucial roles in both early and late stages of the viral life cycle. Early on, upon fusion of the viral and cellular membranes, the viral capsid is released into the host cell cytoplasm and dissociates in a process known as uncoating, tightly associated with the reverse transcription of the viral genome. During the late stages of viral replication, the Gag polyprotein, precursor of the capsid protein, assemble at the plasma membrane to form immature non-infectious viral particles. After a maturation step by the viral protease, the capsid assembles to form a fullerene-like conical shape characteristic of the mature infectious particle. Mutations affecting the uncoating process, or capsid assembly and maturation, have been shown to hamper viral infectivity. The key role of capsid in viral replication and the absence of approved drugs against this protein have promoted the development of antiretrovirals. Screening based on the inhibition of capsid assembly and virtual screening for molecules binding to the capsid have successfully identified a number of potential small molecule compounds. Unfortunately, none of these molecules is currently used in the clinic. CONCLUSION: Here we review the discovery and the mechanism of action of the small molecules and peptides identified as capsid inhibitors, and discuss their therapeutic potential. PMID- 26957204 TI - Tracking the shape-dependent sintering of platinum-rhodium model catalysts under operando conditions. AB - Nanoparticle sintering during catalytic reactions is a major cause for catalyst deactivation. Understanding its atomic-scale processes and finding strategies to reduce it is of paramount scientific and economic interest. Here, we report on the composition-dependent three-dimensional restructuring of epitaxial platinum rhodium alloy nanoparticles on alumina during carbon monoxide oxidation at 550 K and near-atmospheric pressures employing in situ high-energy grazing incidence x ray diffraction, online mass spectrometry and a combinatorial sample design. For platinum-rich particles our results disclose a dramatic reaction-induced height increase, accompanied by a corresponding reduction of the total particle surface coverage. We find this restructuring to be progressively reduced for particles with increasing rhodium composition. We explain our observations by a carbon monoxide oxidation promoted non-classical Ostwald ripening process during which smaller particles are destabilized by the heat of reaction. Its driving force lies in the initial particle shape which features for platinum-rich particles a kinetically stabilized, low aspect ratio. PMID- 26957205 TI - Thrombin-Mediated Direct Activation of Proteinase-Activated Receptor-2: Another Target for Thrombin Signaling. AB - Thrombin is known to signal to cells by cleaving/activating a G-protein-coupled family of proteinase-activated receptors (PARs). The signaling mechanism involves the proteolytic unmasking of an N-terminal receptor sequence that acts as a tethered receptor-activating ligand. To date, the recognized targets of thrombin cleavage and activation for signaling are PAR1 and PAR4, in which thrombin cleaves at a conserved target arginine to reveal a tethered ligand. PAR2, which like PAR1 is also cleaved at an N-terminal arginine to unmask its tethered ligand, is generally regarded as a target for trypsin but not for thrombin signaling. We now show that thrombin, at concentrations that can be achieved at sites of acute injury or in a tumor microenvironment, can directly activate PAR2 vasorelaxation and signaling, stimulating calcium and mitogen-activated protein kinase responses along with triggeringbeta-arrestin recruitment. Thus, PAR2 can be added alongside PAR1 and PAR4 to the targets, whereby thrombin can affect tissue function. PMID- 26957202 TI - Inhibition of HIV Entry by Targeting the Envelope Transmembrane Subunit gp41. AB - BACKGROUND: The transmembrane subunit of the HIV envelope protein, gp41 is a vulnerable target to inhibit HIV entry. There is one fusion inhibitor T20 (brand name: Fuzeon, generic name: enfuvirtide) available by prescription. However, it has several drawbacks such as a high level of development of drug resistance, a short-half life in vivo, rapid renal clearance, low oral bioavailability, and it is only used as a salvage therapy. Therefore, investigators have been studying a variety of different modalities to attempt to overcome these limitations. METHODS: Comprehensive literature searches were performed on HIV gp41, inhibition mechanisms, and inhibitors. The latest structural information was collected, and multiple inhibition strategies targeting gp41 were reviewed. RESULTS: Many of the recent advances in inhibitors were peptide-based. Several creative modification strategies have also been performed to improve inhibitory efficacy of peptides and to overcome the drawbacks of T20 treatment. Small compounds have also been an area of intense research. There is a wide variety in development from those identified by virtual screens targeting specific regions of the protein to natural products. Finally, broadly neutralizing antibodies have also been important area of research. The inaccessible nature of the target regions for antibodies is a challenge, however, extensive efforts to develop better neutralizing antibodies are ongoing. CONCLUSION: The fusogenic protein, gp41 has been extensively studied as a promising target to inhibit membrane fusion between the virus and target cells. At the same time, it is a challenging target because the vulnerable conformations of the protein are exposed only transiently. However, advances in biochemical, biophysical, structural, and immunological studies are coming together to move the field closer to an understanding of gp41 structure and function that will lead to the development of novel drugs and vaccines. PMID- 26957208 TI - Postirradiation pseudosclerodermatous panniculitis with involvement of breast parenchyma: a dramatic example of a rare entity and a pitfall in diagnosis. AB - Postirradiation pseudosclerodermatous panniculitis is a rare complication of external beam radiotherapy. This inflammatory process typically presents as an erythematous indurated plaque in a previously irradiated region of skin. To date, 13 cases have been reported worldwide. We present a case of a 70-year-old female who received breast irradiation following conservation surgery for invasive breast carcinoma. In her third year of follow-up, she developed an enlarging mass, involving the subcutis and underlying breast tissue, associated with mammographically detected coarse calcifications and density, at the surgical site. This was deemed highly suspicious of recurrent malignancy. Following several benign needle core biopsies, she had an excision of the mass. This revealed a lobular panniculitis and irradiation-induced vascular changes affecting subcutaneous fat and underlying breast tissue. This is the 14th reported case of this rare entity. It is unique in the degree of involvement, affecting breast parenchyma as well as subcutaneous fat, and in its corresponding dramatic clinical and radiographic manifestations. PMID- 26957207 TI - Phenylene-Bridged Core-Modified Planar Aromatic Octaphyrin: Aromaticity, Photophysical and Anion Receptor Properties. AB - The synthesis of a planar expanded meso porphyrin with an intramolecular para phenylene-bridged core is reported. The planarity of the octaphyrin macrocycle was confirmed by single-crystal X-ray structural analysis, in which the bridged para-phenylene unit deviated by 27 degrees from the mean macrocyclic plane. Spectroscopic analyses and theoretical calculations suggested that the macrocycle was Huckel aromatic and followed a major [34 pi] single-conjugation pathway, which indicated that the bridging para-phenylene unit was not involved in the macrocyclic conjugation. Analysis of the photophysical properties of this system by steady-state absorption/fluorescence spectroscopy and transient absorption spectroscopy revealed moderate enhancement in the parameters of the octaphyrin as compared to its non-bridged octaphyrin congeners, which was attributed to the planarity and rigidity of the macrocycle as imposed by the bridging para phenylene unit. Preliminary anion-binding studies revealed that the protonated macrocycle bound selectively with chloride ions through N-H???Cl hydrogen-bonding interactions. PMID- 26957209 TI - Hidden entropic contribution in the thermodynamics of molecular complexation. AB - It has become an axiom that the thermodynamic analysis of non-covalent molecular complexation is intrinsically model-dependent, i.e. the set of implicitly or explicitly introduced assumptions may strongly affect the thermodynamic parameters. This review deals with the entropy change accompanying molecular complexation, which results in the formation of ordered structures. In simple terms the key question may be formulated as follows: 'If the molecular complexation leads to the formation of supramolecular structures, then, the system entropy changes due to ordering. So, how is this factor accounted for in standard models of molecular complexation and does it have any effect on the magnitude of measured thermodynamic parameters of complexation?' The structure of the review is made as a collection of cases in which the hidden entropy change has been recognized among the most influential factors. PMID- 26957206 TI - Inhibition of the Motor Protein Eg5/Kinesin-5 in Amyloid beta-Mediated Impairment of Hippocampal Long-Term Potentiation and Dendritic Spine Loss. AB - Alzheimer's disease (AD) is characterized by neurofibrillary tangles, amyloid plaques, and neurodegeneration. However, this pathology is preceded by increased soluble amyloid beta (Abeta) 1-42 oligomers that interfere with the glutamatergic synaptic plasticity required for learning and memory, includingN-methyl-d aspartate receptor (NMDAR)-dependent long-term potentiation (LTP). In particular, soluble Abeta(1-42) acutely inhibits LTP and chronically causes synapse loss. Many mechanisms have been proposed for Abeta-induced synaptic dysfunction, but we recently found that Abeta(1-42) inhibits the microtubule motor protein Eg5/kinesin-5. Here we compared the impacts of Abeta(1-42) and monastrol, a small molecule Eg5 inhibitor, on LTP in hippocampal slices and synapse loss in neuronal cultures. Acute (20-minute) treatment with monastrol, like Abeta, completely inhibited LTP at doses >100 nM. In addition, 1 nM Abeta(1-42) or 50 nM monastrol inhibited LTP #x223c;50%, and when applied together caused complete LTP inhibition. At concentrations that impaired LTP, neither Abeta(1-42) nor monastrol inhibited NMDAR synaptic responses until #x223c;60 minutes, when only #x223c;25% inhibition was seen for monastrol, indicating that NMDAR inhibition was not responsible for LTP inhibition by either agent when applied for only 20 minutes. Finally, 48 hours of treatment with either 0.5-1.0MUM Abeta(1-42) or 1 5MUM monastrol reduced the dendritic spine/synapse density in hippocampal cultures up to a maximum of #x223c;40%, and when applied together at maximal concentrations, no additional spine loss resulted. Thus, monastrol can mimic and in some cases occlude the impact of Abetaon LTP and synapse loss, suggesting that Abetainduces acute and chronic synaptic dysfunction in part through inhibiting Eg5. PMID- 26957210 TI - Trends in US President's Malaria Initiative-funded indoor residual spray coverage and insecticide choice in sub-Saharan Africa (2008-2015): urgent need for affordable, long-lasting insecticides. AB - This article reports the changing pattern of US President's Malaria Initiative funded IRS in sub-Saharan Africa between 2008 and 2015. IRS coverage in sub Saharan Africa increased from <2 % of the at-risk population in 2005, to 11 % or 78 million people in 2010, mainly as a result of increased funding from PMI. The scaling up of IRS coverage in sub-Saharan Africa has been successful in several epidemiological settings and contributed to reduced malaria transmission rates. However, the spread and intensification of pyrethroid resistance in malaria vectors led many control programmes to spray alternative insecticides. Between 2009 and 2013, pyrethroid spraying decreased from 87 % (13/15) of PMI-funded countries conducting IRS to 44 % (7/16), while bendiocarb use increased from 7 % (1/15) to 56 % (9/16). Long-lasting pirimiphos-methyl CS received WHOPES recommendation in 2013 and was scheduled to be sprayed in 85 % (11/13) of PMI funded countries conducting IRS in 2015. The gradual replacement of relatively inexpensive pyrethroids, firstly with bendiocarb (carbamate) and subsequently with pirimiphos methyl CS (organophosphate), has contributed to the downscaling of most PMI-funded IRS programmes. Overall, there was a 53 % decrease in the number of structures sprayed between years of peak coverage and 2015, down from 9.04 million to 4.26 million structures. Sizeable reductions in the number of structures sprayed were reported in Madagascar (56 %, 576,320-254,986), Senegal (64 %, 306,916-111,201), Tanzania (68 %, 1,224,095-389,714) and Zambia (63 %, 1,300,000-482,077), while in Angola, Liberia and Malawi PMI-funded spraying was suspended. The most commonly cited reason was increased cost of pesticides, as vector resistance necessitated switching from pyrethroids to organophosphates. There are worrying preliminary reports of malaria resurgence following IRS withdrawal in parts of Benin, Tanzania and Uganda. The increase in malaria cases following the end of the Global Malaria Eradication Programme in 1969 highlights the fragility of such gains when control efforts are weakened. At present there are several countries reliant on organophosphates and carbamates for IRS, and increasing incipient resistance is a serious threat that could result in IRS no longer being viable. A portfolio of new cost-effective insecticides with different modes of action is urgently needed. PMID- 26957211 TI - Epigallocatechin-3-gallate ameliorates autoimmune arthritis by reciprocal regulation of T helper-17 regulatory T cells and inhibition of osteoclastogenesis by inhibiting STAT3 signaling. AB - The green tea polyphenol epigallocatechin-3-gallate is a potent antioxidant. Here, we describe the effects of epigallocatechin-3-gallate on T cell differentiation and osteoclast differentiation in an animal model of arthritis. Mice with collagen-induced arthritis were injected intraperitoneally with epigallocatechin-3-gallate, 3 times/wk after the primary immunization. Surface markers of T helper 17 cells and regulatory T cells were analyzed by flow cytometry. Flow cytometry, Western blotting, and enzyme-linked immunosorbent assays were used to evaluate the effect of epigallocatechin-3-gallate on cell signaling in the collagen-induced arthritis model. Epigallocatechin-3-gallate decreased the arthritis index and showed protective effects against joint destruction in collagen-induced arthritis mice. The expression of cytokines, oxidative stress proteins, and phosphorylated-signal transducer and activator of transcription-3, 705 and 727, were significantly less in mice treated with epigallocatechin-3-gallate than it was in controls. Epigallocatechin-3-gallate reduced the expression of osteoclast markers in vitro and in vivo relative to the control, and the antiosteoclastic activity was observed in epigallocatechin-3 gallate-treated, interferon-gamma knockout mice. The proportion of forkhead box protein 3-positive regulatory T cells was increased in the spleens of mice treated with epigallocatechin-3-gallate compared with control mice, whereas the proportion of T helper 17 cells was reduced. In vitro, the expression of nuclear respiratory factor 2, heme oxygenase-1, and extracellular signal-regulated kinase was increased significantly by epigallocatechin-3-gallate. We demonstrated that the administration of epigallocatechin-3-gallate attenuated the symptoms of arthritis, inhibited osteoclastogenesis and T helper 17 cell activation, and increased the number of regulatory T cells. At the molecular level, the antiarthritic effects of epigallocatechin-3-gallate may be due to induction of phosphorylated-extracellular signal-regulated kinase, nuclear respiratory factor 2, and heme oxygenase-1 and inhibition of signal transducer and activator of transcription-3 activation. PMID- 26957212 TI - Characterization of neutrophil function in Papillon-Lefevre syndrome. AB - Papillon-Lefevre syndrome is a rare, inherited, autosomal-recessive disease, characterized by palmoplantar keratosis and severe prepubertal periodontitis, leading to premature loss of all teeth. Papillon-Lefevre syndrome is caused by a mutation in the cathepsin C gene, resulting in complete loss of activity and subsequent failure to activate immune response proteins. Periodontitis in Papillon-Lefevre syndrome is thought to arise from failure to eliminate periodontal pathogens as a result of cathepsin C deficiency, although mechanistic pathways remain to be elucidated. The aim of this study was to characterize comprehensively neutrophil function in Papillon-Lefevre syndrome. Peripheral blood neutrophils were isolated from 5 patients with Papillon-Lefevre syndrome, alongside matched healthy control subjects. For directional chemotactic accuracy, neutrophils were exposed to the chemoattractants MIP-1alpha and fMLP and tracked by real-time videomicroscopy. Reactive oxygen species generation was measured by chemiluminescence. Neutrophil extracellular trap formation was assayed fluorometrically, and proinflammatory cytokine release was measured following overnight culture of neutrophils with relevant stimuli. Neutrophil serine protease deficiencies resulted in a reduced ability of neutrophils to chemotax efficiently and an inability to generate neutrophil extracellular traps. Neutrophil extracellular trap-bound proteins were also absent in Papillon-Lefevre syndrome, and Papillon-Lefevre syndrome neutrophils released higher levels of proinflammatory cytokines in unstimulated and stimulated conditions, and plasma cytokines were elevated. Notably, neutrophil chemoattractants MIP-1alpha and CXCL8 were elevated in Papillon-Lefevre syndrome neutrophils, as was reactive oxygen species formation. We propose that relentless recruitment and accumulation of hyperactive/reactive neutrophils (cytokines, reactive oxygen species) with increased tissue transit times into periodontal tissues, alongside a reduced antimicrobial capacity, create a locally destructive chronic inflammatory cycle in Papillon-Lefevre syndrome. PMID- 26957213 TI - IL-1beta differently stimulates proliferation and multinucleation of distinct mouse bone marrow osteoclast precursor subsets. AB - Osteoclasts are bone-resorbing cells and targets for treating bone diseases. Previously, we reported that distinct murine osteoclast precursor subsets, such as early blasts (CD31(hi) Ly-6C(-)), myeloid blasts (CD31(+) Ly-6C(+)), and monocytes (CD31(-) Ly-6C(hi)), respond differently to the osteoclastogenesis inducing cytokines, macrophage colony-stimulating factor, and receptor activator for nuclear factor kappaB ligand. It is unknown, however, how these cell types respond to the osteoclast-stimulating inflammatory cytokine interleukin 1beta. This study aims to investigate the effect of interleukin 1beta on osteoclastogenesis derived from different mouse bone marrow precursors. Early blasts, myeloid blasts, and monocytes were sorted from mouse bone marrow cells using flow cytometry. Cells were cultured on plastic or on bone slices in the presence of macrophage colony-stimulating factor and receptor activator for nuclear factor kappaB ligand, without or with interleukin 1beta (0.1-10 ng/ml). We found that interleukin 1beta stimulated multinucleation and bone resorption of osteoclasts derived from the 3 precursors at different rates. The most large osteoclasts (>20 nuclei) and highest level of bone resorption (16.3%) was by myeloid blast-derived osteoclasts. Interleukin 1beta particularly accelerated proliferation of early blasts and the most small osteoclasts (3-5 nuclei) formed on plastic. Life span varied among osteoclasts derived from different precursors: large osteoclasts (>2400 um(2)) formed most rapidly (75 h) from myeloid blasts but had a short life span (30 h). Monocytes needed the longest time (95 h) for the generation of such large osteoclasts, but these cells had a longer life span (50 h). Our results indicate that the different bone marrow osteoclast precursors are differently stimulated by interleukin 1beta with respect to proliferation, multinucleation, life span, and bone resorption. PMID- 26957214 TI - TLR9 stability and signaling are regulated by phosphorylation and cell stress. AB - Innate sensing of pathogens elicits protective immune responses through pattern recognition receptors, including Toll-like receptors. Although signaling by Toll like receptors is regulated at multiple steps, including localization, trafficking, proteolytic cleavage, and phosphorylation, the significance of post translational modifications and cellular stress response on Toll-like receptor stability and signaling is still largely unknown. In the present study, we investigated the role of cytoplasmic tyrosine motifs in Toll-like receptor-9 stability, proteolytic cleavage, and signaling. We demonstrated that tyrosine phosphorylation is essential for mouse Toll-like receptor-9 protein stability and signaling. Upon inhibition of tyrosine kinases with piceatannol, Toll-like receptor-9 tyrosine phosphorylation induced by CpG deoxyribonucleic acid was inhibited, which correlated with decreased signaling. Furthermore, inhibition of Src kinases with 1-tert-Butyl-3-(4-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4 amine also inhibited response to CpG deoxyribonucleic acid. Toll-like receptor-9 protein stability was also sensitive to autophagy, the cellular stress response pathway, and infection by a deoxyribonucleic acid virus. Whereas autophagy induced by rapamycin or low serum levels caused a preferential loss of the mature p80 proteolytic cleavage product, infection with herpes simplex virus-1 and induction of cell stress with tunicamycin caused preferential loss of full-length Toll-like receptor-9, which is localized to the endoplasmic reticulum. Our data reveal new information about the stability and signaling of Toll-like receptor-9 and suggest that immune evasion mechanisms may involve targeted loss of innate sensing receptors. PMID- 26957215 TI - Defensin gene variation and HIV/AIDS: a comprehensive perspective needed. AB - Both alpha- and beta-defensins have anti-human immunodeficiency virus activity. These defensins achieve human immunodeficiency virus inhibition through a variety of mechanisms, including direct binding with virions, binding to and modulation of host cell-surface receptors with disruption of intracellular signaling, and functioning as chemokines or cytokines to augment and alter adaptive immune responses. Polymorphisms in the defensin genes have been associated with susceptibility to human immunodeficiency virus infection and disease progression. However, the roles that these defensins and their genetic polymorphisms have in influencing human immunodeficiency virus/acquired immunodeficiency syndrome outcomes are not straightforward and, at times, appear contradictory. Differences in populations, study designs, and techniques for genotyping defensin gene polymorphisms may have contributed to this lack of clarity. In addition, a comprehensive approach, where both subfamilies of defensins and their all inclusive genetic polymorphism profiles are analyzed, is lacking. Such an approach may reveal whether the human immunodeficiency virus inhibitory activities of alpha- and beta-defensins are based on parallel or divergent mechanisms and may provide further insights into how the genetic predisposition for susceptibility or resistance to human immunodeficiency virus/acquired immunodeficiency syndrome is orchestrated between these molecules. PMID- 26957216 TI - Measurement of beta-Glucan in Mushrooms and Mycelial Products. AB - A robust and reliable method has been developed for the measurement of beta glucan in mushroom and mycelial products. Total glucan (plus free glucose and glucose from sucrose) was measured using controlled acid hydrolysis with H2SO4 and the glucose released specifically was measured using glucose oxidase/peroxidase reagent. alpha-Glucan (starch/glycogen) plus free glucose and glucose from sucrose were specifically measured after hydrolysis of starch/glycogen to glucose with glucoamylase and sucrose to glucose plus fructose with invertase and the glucose specifically measured with GOPOD reagent. beta Glucan was determined by the difference. Several acid and enzyme-based methods for the hydrolysis of the beta-glucan were compared, and the best option was the method using H2SO4. For most samples, similar beta-glucan values were obtained with both the optimized HCl and H2SO4 PROCEDURES: However, in the case of certain samples, specifically Ganoderma lucidum and Poria cocus, the H2SO4 procedure resulted in significantly higher values. Hydrolysis with 2 N trifluoroacetic acid at 120 degrees C was found to be much less effective than either of the other two acids evaluated. Assays based totally on enzymatic hydrolysis, in general, yielded much lower values than those obtained with the H2SO4 procedure. PMID- 26957217 TI - Is Anterior Cruciate Ligament Reconstruction Effective in Preventing Secondary Meniscal Tears and Osteoarthritis? AB - BACKGROUND: Reconstruction of anterior cruciate ligament (ACL) tears may potentially prevent the development of secondary meniscal injuries and arthritis. PURPOSE/HYPOTHESIS: The purpose of this study was to (1) evaluate the protective benefit of ACL reconstruction (ACLR) in preventing subsequent meniscal tears or arthritis, (2) determine if earlier ACLR (<1 year after injury) offers greater protective benefits than delayed reconstruction (>=1 year after injury), and (3) evaluate factors predictive of long-term sequelae after ACLR. The hypothesis was that the incidence of secondary meniscal tears, arthritis, and total knee arthroplasty (TKA) would be higher in patients treated nonoperatively after ACL tears than patients treated with surgical reconstruction. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: This retrospective study included a population-based incidence cohort of 964 patients with new-onset, isolated ACL tears between 1990 and 2000 as well as an age- and sex-matched cohort of 964 patients without ACL tears. A chart review was performed to collect information related to the initial injury, treatment, and outcomes. A total of 509 patients were treated with early ACLR, 91 with delayed ACLR, and 364 nonoperatively. All patients were retrospectively followed (range, 2 months to 25 years) to determine the development of subsequent meniscal tears, arthritis, or TKA. RESULTS: At a mean follow-up of 13.7 years, patients treated nonoperatively after ACL tears had a significantly higher likelihood of developing a secondary meniscal tear (hazard ratio [HR], 5.4; 95% CI, 3.8-7.6), being diagnosed with arthritis (HR, 6.0; 95% CI, 4.3-8.4), and undergoing TKA (HR, 16.7; 95% CI, 5.0-55.2) compared with patients treated with ACLR. Similarly, patients treated with delayed ACLR had a higher likelihood of developing a secondary meniscal tear (HR, 3.9; 95% CI, 2.2 6.9) and being diagnosed with arthritis (HR, 6.2; 95% CI, 3.4-11.4) compared with patients treated with early ACLR. Age >21 years at the time of injury, articular cartilage damage, and medial/lateral meniscal tears were predictive of arthritis after ACLR. CONCLUSION: Patients treated with ACLR have a significantly lower risk of secondary meniscal tears, symptomatic arthritis, and TKA when compared with patients treated nonoperatively after ACL tears. Similarly, early ACLR significantly reduces the risk of subsequent meniscal tears and arthritis compared with delayed ACLR. PMID- 26957218 TI - Risk of Noncontact Anterior Cruciate Ligament Injuries Is Not Associated With Slope and Concavity of the Tibial Plateau in Recreational Alpine Skiers: A Magnetic Resonance Imaging-Based Case-Control Study of 121 Patients. AB - BACKGROUND: Anatomic features of the tibial plateau (ie, posterior slope and medial concavity) have been associated with an increased risk of anterior cruciate ligament (ACL) injuries. However, it remains unclear whether these findings translate to ACL injuries sustained during recreational alpine skiing. PURPOSE: To investigate the association in recreational alpine skiers between prominent morphological features of the tibial plateau (slope and concavity) and the risk of sustaining an ACL injury during a noncontact incident. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: Magnetic resonance imaging data of 121 recreational alpine skiers (74 female, 47 male) after a noncontact knee injury were used for this study. Of these patients, 80 (71% female [n = 57]) had a complete unilateral ACL tear (rupture group), and 41 (41% female [n = 17]) had no indications of an ACL injury (intact group). Two blinded independent examiners measured the slopes of the tibial plateau in the sagittal and coronal planes along with the maximum depth of the medial tibial plateau. Measurements were compared between sexes and between groups using t tests. Logistic regression was used to assess the associations between quantified anatomic indices and the risk of ACL injuries. RESULTS: Within 121 study patients, female skiers had greater odds of an ACL tear compared with male skiers (odds ratio, 3.5; 95% CI, 1.6-7.8; P < .001). Female skiers were more likely to have a greater lateral tibial slope (LTS) (P = .02) and medial tibial slope (MTS) (P = .02) with a shallower medial tibial depth (MTD) (P = .02) compared with male skiers. No differences between sexes were observed in the coronal tibial slope (CTS) (P = .97). Male and female skiers as a combined group showed no associations between quantified anatomic indices and the risk of sustaining an ACL tear (P > .10). Likewise, no significant differences were observed between the intact versus rupture group in any of the quantified anatomic indices (P > .10). Similar findings were observed when the analyses were repeated on male and female skiers separately. CONCLUSION: Despite differences between sexes in knee anatomy and the injury risk, the sagittal and coronal slopes (LTS, MTS, CTS), as well as the concavity of the medial tibial plateau (MTD), were not associated with the risk of an ACL tear during a noncontact injury among recreational alpine skiers. PMID- 26957219 TI - A Novel Silk Fiber-Based Scaffold for Regeneration of the Anterior Cruciate Ligament: Histological Results From a Study in Sheep. AB - BACKGROUND: Because of ongoing problems with anterior cruciate ligament (ACL) reconstruction, new approaches in the treatment of ACL injuries, particularly strategies based on tissue engineering, have gained increasing research interest. To allow for ACL regeneration, a structured scaffold that provides a mechanical basis, has cells from different sources, and comprises mechanical as well as biological factors is needed. Biological materials, biodegradable polymers, and composite materials are being used and tested as scaffolds. The optimal scaffold for ACL regeneration should be biocompatible and biodegradable to allow tissue ingrowth but also needs to have the right mechanical properties to provide immediate mechanical stability. HYPOTHESES: The study hypotheses were that (1) a novel degradable silk fiber-based scaffold with mechanical properties similar to the native ACL will be able to initiate ligament regeneration after ACL resection and reconstruction under in vivo conditions and (2) additional cell seeding of the scaffold with autologous stromal vascular fraction-containing adipose-derived stem cells will increase regenerative activity. STUDY DESIGN: Controlled laboratory study. METHODS: A total of 33 mountain sheep underwent ACL resection and randomization to 2 experimental groups: (1) ACL reconstruction with a scaffold alone and (2) ACL reconstruction with a cell-seeded scaffold. Histological evaluation of the intra-articular portion of the reconstructed/regenerated ligament was performed after 6 and 12 months. RESULTS: After 6 months, connective tissue surrounded the silk scaffold with ingrowth in some areas. The cell-seeded scaffolds had a significant lower silk content compared with the unseeded scaffolds and demonstrated a higher content of newly formed tissue. After 12 months, the density of the silk fibers decreased significantly, and the ingrowth of newly formed tissue increased in both groups. No differences between the 2 groups regarding silk fiber degradation and regenerated tissue were detected at 12 months. CONCLUSION: The novel silk fiber based scaffold was able to stimulate ACL regeneration under in vivo conditions. Additional cell seeding led to increased tissue regeneration and decreased silk fiber content at 6 months, whereas these differences were not present at 12 months. CLINICAL RELEVANCE: ACL regeneration using a silk fiber-based scaffold with and without additional cell seeding may provide a new treatment option after joint injuries. PMID- 26957221 TI - Aortic Stenosis Gradients and a Case for Quality Improvement. PMID- 26957220 TI - Implementing a Continuous Quality Improvement Program in a High-Volume Clinical Echocardiography Laboratory: Improving Care for Patients With Aortic Stenosis. AB - BACKGROUND: The management of aortic stenosis rests on accurate echocardiographic diagnosis. Hence, it was chosen as a test case to examine the utility of continuous quality improvement (CQI) approaches to increase echocardiographic data accuracy and reliability. A novel, multistep CQI program was designed and prospectively used to investigate whether it could minimize the difference in aortic valve mean gradients reported by echocardiography when compared with cardiac catheterization. METHODS AND RESULTS: The Duke Echo Laboratory compiled a multidisciplinary CQI team including 4 senior sonographers and MD faculty to develop a mapped CQI process that incorporated Intersocietal Accreditation Commission standards. Quarterly, the CQI team reviewed all moderate- or greater severity aortic stenosis echocardiography studies with concomitant catheterization data, and deidentified individual and group results were shared at meetings attended by cardiologists and sonographers. After review of 2011 data, the CQI team proposed specific amendments implemented over 2012: the use of nontraditional imaging and Doppler windows as well as evaluation of aortic gradients by a second sonographer. The primary outcome measure was agreement between catheterization- and echocardiography-derived mean gradients calculated by using the coverage probability index with a prespecified acceptable echocardiography-catheterization difference of <10 mm Hg in mean gradient. Between January 2011 and January 2014, 2093 echocardiograms reported moderate or greater aortic stenosis. Among cases with available catheterization data pre- and post-CQI, the coverage probability index increased from 54% to 70% (P=0.03; 98 cases, year 2011; 70 cases, year 2013). The proportion of patients referred for invasive valve hemodynamics decreased from 47% pre-CQI to 19% post-CQI (P<0.001). CONCLUSIONS: A laboratory practice pattern that was amenable to reform was identified, and a multistep modification was designed and implemented that produced clinically valuable performance improvements. The new protocol improved aortic stenosis mean gradient agreement between echocardiography and catheterization and was associated with a measurable decrease in referrals of patients for invasive studies. PMID- 26957222 TI - A Six-Week Resistance Training Program Does Not Change Shear Modulus of the Triceps Brachii. AB - We investigated the effect of a 6-week resistance training program on the shear modulus of the triceps brachii (TB). Twenty-three young men were randomly assigned to either the training (n = 13) or control group (n = 10). Before and after conducting the resistance training program, the shear modulus of the long head of the TB was measured at the point 70% along the length of the upper arm from the acromial process of the scapula to the lateral epicondyle of the humerus using shear wave ultrasound elastography. Muscle thickness of the long head of the TB was also determined at the same site by ultrasonography used during both tests. A resistance exercise was performed 3 days a week for 6 weeks using a dumbbell mass-adjusted to 80% of the 1-repetition maximum (1RM). The training effect on the muscle thickness and 1RM was significant. Nevertheless, the muscle shear modulus was not significantly changed after the training program. From the perspective of muscle mechanical properties, the present results indicate that significant adaptation must occur to make the TB more resistant to subsequent damaging bouts during the 6-week training program to target the TB. PMID- 26957224 TI - Evaluation of the insertion torque, implant stability quotient and drilled hole quality for different drill design: an in vitro Investigation. AB - OBJECTIVE: The purpose of the present study was to compare the insertion torque and implant stability quotient between different drill design for implant site preparation. MATERIALS AND METHODS: Synthetic blocks of bone (type I density) were used for drilling procedures. Three groups were evaluated: Group G1 - drilling with a single bur for a 4.2 mm conical implant; Group G2 and Group G3 - drilling with three consecutive burs for a 4.1 mm cylindrical implant and for a 4.3 mm conical implant respectively. For each group, 15 drilling procedures were performed without irrigation for 10-mm in-depth. The drilled hole quality (HQ) after the osteotomy for implant site preparation was measured in the five-first holes through a fully automated roundness/cylindricity instrument at three levels (top, middle, and bottom of the site). The insertion torque value (ITV) was achieved with a computed torquimeter and the implant stability quotient (ISQ) values were measured using a resonance frequency apparatus. RESULTS: The single drill (group 1) achieved a significantly higher ITV and ISQ than the multiple drills for osteotomy (groups 2 and 3). Group 1 and 3 displayed significantly better HQ than group 2. CONCLUSIONS: Within the limitations of the study, the results suggest that the hole quality, in addition to the insertion torque, may significantly affect implant primary stability. PMID- 26957223 TI - Evaluating the Safety of Retroviral Vectors Based on Insertional Oncogene Activation and Blocked Differentiation in Cultured Thymocytes. AB - Insertional oncogenesis due to retroviral (RV) vector integration has caused recurrent leukemia in multiple gene therapy trials, predominantly due to vector integration effects at the LMO2 locus. While currently available preclinical safety models have been used for evaluating vector safety, none have predicted or reproduced the recurrent LMO2 integrations seen in previous X-linked severe combined immunodeficiency (X-SCID) and Wiskott-Aldrich clinical gene therapy trials. We now describe a new assay for assessing vector safety that recapitulates naturally occurring insertions into Lmo2 and other T-cell proto oncogenes leading to a preleukemic developmental arrest in primary murine thymocytes cultured in vitro. This assay was used to compare the relative oncogenic potential of a variety of gamma-RV and lentiviral vectors and to assess the risk conferred by various transcriptional elements contained in these genomes. Gamma-RV vectors that contained full viral long-terminal repeats were most prone to causing double negative 2 (DN2) arrest and led to repeated cases of Lmo2 pathway activation, while lentiviral vectors containing these same elements were significantly less prone to activate proto-oncogenes or cause DN2 arrest. This work provides a new preclinical assay that is especially relevant for assessing safety in SCID disorders and provides a new tool for designing safer RV vectors. PMID- 26957225 TI - A concept analysis of proactive behaviour in midwifery. AB - AIM: To report an analysis of the concept of proactive behaviour and apply the findings to midwifery. BACKGROUND: Proactive behaviour is a universal phenomenon generalizable to multiple professions. The purpose of this work was to establish a link with midwifery. DESIGN: Concept analysis by Walker and Avant's method. DATA SOURCES: Literature was searched in PubMed, ERIC, NARCIS, Emerald and reference lists of related journal articles with a timeline of 1990 - April 2015 in the period of November 2014 - June 2015. Next key words were combined by the use of Boolean operators: 'proactive behaviour', 'midwifery', 'midwife', 'proactivity' and 'proactive'. Fifteen studies were included. METHODS: A focused review of scientific publications in midwifery, health care, healthcare education and social sciences, which highlighted the concept of proactive behaviour. RESULTS: In the studied literature, several attributes of proactive behaviour were cited. These attributes were narrowed by applying it on a midwifery model case, borderline case and contrary case. Related concepts were elaborated and distinguished of the concept of proactive behaviour in midwifery. Proactive behaviour is triggered by different individual and contextual antecedents and has consequences at multiple levels. CONCLUSION: A midwife who behaves proactive would not look at changes as a boundary, persistently improves things she experienced as wrong, anticipates future barriers and looks for viable alternatives to carry out her work as efficiently and effectively as possible. Various individual and/or contextual antecedents trigger proactive behaviour in midwifery, and this behaviour could cause multiple future benefits for the constant evolving reproductive health care. PMID- 26957226 TI - Intracellular imaging of Qdots-labeled DNA in cyanobacteria. AB - In this contribution, they have attempted to develop a labeling technique for in vivo imaging of functionally active plasmid DNA in cyanobacterial cells through its decoration with semiconductor quantum dots (Qdots) as fluorescent nanoprobes. For that purpose biotinylated plasmid slr2060 DNA was conjugated with Qdots streptavidine. The intact DNA was visualized in a single green color by light microscopy. These Qdots-DNA conjugates were capable of expressing the acyltransferase enzyme. Qdots-DNA conjugates and confocal microscope imaging technique were adopted to visualize the gene transport across the membrane of the live cyanobacteria cell in real time. Long-term kinetic study enabled to reveal the steps of extracellular and intracellular microenvironment for plasmid transportation into the live cell. To confirm these processes a confocal microscope and indicator plate assay test were applied in tandem. In this contribution, Qdots-labeled plasmid DNA was utilized for the first time for long term intracellular imaging studies in cyanobacteria species PCC6803. The results showed that the Qdots-labeled plasmid DNA detection could be used as a powerful labeling technique for visualization of exogenous DNA entry and tracking into living cells by confocal microscopy. PMID- 26957227 TI - Synergistic effect of atorvastatin and Cyanidin-3-glucoside on angiotensin II induced inflammation in vascular smooth muscle cells. AB - Statins have often been used in atherosclerosis treatment because of its pleiotropic effects on inflammation. However, some adverse effects of high doses of statin show reverse effects after withdrawal. Cyanidin-3-glucoside (C3G) is a powerful anti-inflammation and antioxidant that has been of interest for use in combination with low doses of statin, which may be alternative treatment for atherosclerosis. The objective is to investigate the synergistic effect of atorvastatin and C3G in angiotensin II (Ang II)-induced inflammation in vascular smooth muscle cells. Human aortic smooth muscle cells (HASMCs) were exposed to Ang II with or without atorvastatin and C3G alone, or in combination. The results revealed that the combination of atorvastatin and C3G produces synergism against inflammation and oxidative stress. The mechanism of the combination of atorvastatin and C3G suppressed the translocation of the p65 subunit of NF-kappaB from cytosol to nucleus, and attenuated the expression of proteins including inducible nitric oxide synthase, intracellular adhesion molecule 1(ICAM-1), and vascular cell adhesion molecule 1(VCAM-1), in addition to nitric oxide (NO) production. Moreover, C3G exerts the antioxidative properties of atorvastatin through down-regulating NOX1 and promoting the activity of the Nrf2(-)ARE signaling pathway and downstream proteins including heme oxygenase (HO-1), NAD(P)H:quinoneoxidoreductase 1 (NQO-1), and glutamate-cysteine ligase catalytic subunit (gamma-GCLC), besides increasing the activity of superoxide dismutase (SOD) enzymes. Taken together, these results suggest that a combination of low dose statins and C3G might serve as a potential regulator of the atherosclerosis process which is mediated by attenuating oxidative stress, thereby inhibiting NF kappaB and activating Nrf2 signaling pathways induced by Ang II. PMID- 26957228 TI - Spinal D1-like dopamine receptors modulate NMDA receptor-induced hyperexcitability and NR1 subunit phosphorylation at serine 889. AB - Activation of the N-methyl-d-aspartate receptor (NMDAR) in dorsal horn neurons is recognized as a fundamental mechanism of central sensitization and pathologic pain. This study assessed the influence of dopaminergic, D1-like receptor mediated input to the spinal dorsal horn on NMDAR function. Spinal superfusion with selective NMDAR agonist cis-ACPD significantly increased C-fiber-evoked field potentials in rats subjected to spinal nerve ligation (SNL), but not in sham-operated rats. Simultaneous application of D1LR antagonist SCH 23390 dramatically reduced hyperexcitability induced by cis-ACPD. Furthermore, cis-ACPD induced hyperexcitability seen in nerve-ligated rats could be mimicked in unin jured rats during stimulation of D1LRs by agonist SKF 38393 at subthreshold concentration. Phosphorylation of NMDAR subunit NR1 at serine 889 at postsynaptic sites was found to be increased in dorsal horn neurons 90 min after SNL, as assessed by increased co-localization with postsynaptic marker PSD-95. Increased NR1 phosphorylation was attenuated in the presence of SCH 23390 in the spinal superfusate. The present results support that D1LRs regulate most basic determinants of NMDAR function in dorsal horn neurons, suggesting a potential mechanism whereby dopaminergic input to the dorsal horn can modulate central sensitization and pathologic pain. PMID- 26957229 TI - Associations between a locus downstream DRD1 gene and cerebrospinal fluid dopamine metabolite concentrations in psychosis. AB - Dopamine activity, mediated by the catecholaminergic neurotransmitter dopamine, is prominent in the human brain and has been implicated in schizophrenia. Dopamine targets five different receptors and is then degraded to its major metabolite homovanillic acid (HVA). We hypothesized that genes encoding dopamine receptors may be associated with cerebrospinal fluid (CSF) HVA concentrations in patients with psychotic disorder. We searched for association between 67 single nucleotide polymorphisms (SNPs) in the five dopamine receptor genes i.e., DRD1, DRD2, DRD3, DRD4 and DRD5, and the CSF HVA concentrations in 74 patients with psychotic disorder. Nominally associated SNPs were also tested in 111 healthy controls. We identified a locus, located downstream DRD1 gene, where four SNPs, rs11747728, rs11742274, rs265974 and rs11747886, showed association with CSF HVA concentrations in psychotic patients. The associations between rs11747728, which is a regulatory region variant, and rs11742274 with HVA remained significant after correction for multiple testing. These associations were restricted to psychotic patients and were absent in healthy controls. The results suggest that the DRD1 gene is implicated in the pathophysiology of psychosis and support the dopamine hypothesis of schizophrenia. PMID- 26957230 TI - Antidepressant-like effects of sodium butyrate and its possible mechanisms of action in mice exposed to chronic unpredictable mild stress. AB - Sodium butyrate (NaB) has exhibited neuroprotective activity. This study aimed to explore that NaB exerts beneficial effects on chronic unpredictable mild stress (CUMS)-induced depression-like behaviors and its possible mechanisms. The behavioral tests including sucrose preference test (SPT), open field test (OFT), tail suspension test (TST) and forced swimming test (FST) were to evaluate the antidepressant effects of NaB. Then changes of Nissl's body in the hippocampus, brain serotonin (5-HT) concentration, brain-derived neurotrophic factor (BDNF) and tight junctions (TJs) proteins level were assessed to explore the antidepressant mechanisms. Our results showed that CUMS caused significant depression-like behaviors, neuropathological changes, and decreased brain 5-HT concentration, TJs protein levels and BDNF expression in the hippocampus. However, NaB treatment significantly ameliorated behavioral deficits of the CUMS induced mice, increased 5-HT concentration, increased BDNF expression, and up regulated Occludin and zonula occludens-1(ZO-1) protein levels in the hippocampus, which demonstrated that NaB could partially restore CUMS-induced blood-brain barrier (BBB) impairments. Besides, the pathologic changes were alleviated. In conclusion, these results demonstrated that NaB significantly improved depression-like behaviors in CUMS-induced mice and its antidepressant actions might be related with, at least in part, the increasing brain 5-HT concentration and BDNF expression and restoring BBB impairments. PMID- 26957231 TI - The histopathological comparison on the destruction of the periodontal tissue between normal junctional epithelium and long junctional epithelium. AB - BACKGROUND AND OBJECTIVE: The barrier function of long junctional epithelium is thought to be important after periodontal initial therapy and periodontal surgery. Although the difference between long junctional epithelium and normal junctional epithelium regarding their resistance to destruction of periodontal tissue has been investigated, the mechanism still remains unclear. Using our rat experimental periodontitis model in which loss of attachment and resorption of alveolar bone is induced by the formation of immune complexes, we investigated the resistance of periodontal tissue containing long junctional epithelium and normal junctional epithelium to destruction. MATERIAL AND METHODS: Rats were divided into four groups. In the immunized long junctional epithelium (I-LJE) group, rats were immunized with lipopolysaccharide (LPS), and curettage and root planing procedures were performed on the palatal gingiva of the maxillary first molars to obtain reattachment by long junctional epithelium. In the immunized normal junctional epithelium (I-JE) group, rats were immunized without curettage and root planing procedures. In the nonimmunized long junctional epithelium (nI LJE) group, rats were not immunized but curettage and root-planing procedures were performed. In the control group, neither immunization nor curettage and root planing was performed. In all rats, periodontal inflammation was induced by topical application of LPS into the palatal gingival sulcus of maxillary first molars. The rats were killed at baseline and after the third and fifth applications of LPS. Attachment loss and the number of inflammatory cells and osteoclasts in the four groups were compared histopathologically and histometrically. RESULTS: After the third application of LPS in the I-LJE group, attachment loss showed a greater increase than in control and nI-LJE groups, and inflammatory cell infiltration and osteoclasts were increased more than in the other groups. After the fifth application of LPS, attachment loss was greater and there was a higher degree of inflammatory cell infiltration in nI-LJE and I-LJE groups than in control and I-JE groups. CONCLUSION: Our findings suggest that the destruction of periodontal tissue is increased in tissue containing long junctional epithelium compared with normal junctional epithelium and that the immunized condition accelerates the destruction by forming immune complexes. PMID- 26957232 TI - The impact of laser-assisted hatching on the outcome of frozen human embryo transfer cycles. AB - Biochemical modifications of zona pellucida (ZP) result in zona hardening. Zona hardening (ZH) is induced by several factors such as advancing maternal age, in vitro culture conditions and cryopreservation and adversely effects implantation. The objective of the clinical study was to determine whether or not laser assisted hatching (LAH) applied on day 3 frozen embryos improves the outcome of frozen embryo transfer (FET) cycles in patients with recurrent implantation failure and/or advanced female age. In total, 413 patients of different ages with recurrent implantation failure (maximum three cycles) were involved into the study. Patients were allocated randomly into LAH and control groups. On the day of FET, after thawing and just before FET, the ZP was thinned using a laser system. In the control group no treatment was applied on frozen embryo before transfer. The main outcome measures were clinical pregnancy rate. Overall, the results indicate a tendency that LAH increased (P = 0.08) clinical pregnancy. However, for patients older than 37 years, LAH increased pregnancy rates significantly (P = 0.03). In the LAH and control groups, the age of patients and the number of transferred embryos influenced pregnancy rates (P = 0.01). For patients older than 37 years, no effect of number of transferred embryos was detected (P = 0.14). The incidence of multiple pregnancies also increased in the LAH group (P = 0.01). In conclusion, in older woman, to overcome the negative effect of zona hardening, LAH could be performed on frozen embryos as a routine strategy before FET in frozen cycles in order to increase the possibility of pregnancy formation. PMID- 26957233 TI - [Actively promote nutrition and health surveillance, achieve the national nutrition and health goals]. AB - The results of Chinese Nutrition and Health Surveillance (2010-2012) showed that the anemia prevalence in China reduced significantly compared with 2002, and people's nutrition and health status have improved. Unbalanced diet still exist, such as low intake of vegetables and fruits, and high intake of salt. The serum total cholesterol level and the prevalence of hypercholesterolemia and borderline high cholesterolemia were high among urban adults, and more attention should be paid for high serum total cholesterol level among older adults. These results are significant to the development of nutrition and health intervention strategy, carry out nutrition intervention and the achievement of national nutrition and health goals. PMID- 26957234 TI - [Scheme of the 2010-2012 Chinese nutrition and health surveillance]. PMID- 26957235 TI - [Serum total cholesterol status among urban residents aged 18 and above in China from 2010 to 2012]. AB - OBJECTIVE: To analyze the serum total cholesterol level and the prevalence of hypercholesterolemia and borderline high cholesterolemia among urban-resident adults in China from 2010 to 2012. METHODS: Data were from Chinese Nutrition and Health Surveillance in 2010-2012. Multi-stage stratified proportion to the population cluster random sampling method was conducted to determine 54 042 adult residents in 34 big cities and 41 small and medium-sized cities. Serum total cholesterol was measured by cholesterol oxidase method. Hypercholesterolemia and borderline high cholesterolemia were evaluated by Guidelines on Prevention and Treatment of Blood Lipid Abnormality in Chinese Adults 2007 edition. Standardized cholesterol level (x +/- Sx) and prevalence of hypercholesterolemia and borderline high cholesterolemia were calculated through weighted complex sampling processing by population data released by the National Bureau of Statistics in 2009. RESULTS: The mean level of urban-resident adults's erum total cholesterol was (4.58 +/- 0.05)mmol/L, (4.58 +/- 0.05)mmol/L for both male and female. The cholesterol concentration level in big cities and small and medium-sized cities were (4.66 +/- 0.04)mmol/L and (4.57 +/- 0.06) mmol/L, respectively. It increased with age gradually from the minimum level, which was (4.18 +/- 0.05)mmol/L in aged 18 to 29 group, till reached the maximum, which was (4.94 +/- 0.05)mmol/L in aged 60 to 69 group, and then it declined to (4.92 +/- 0.06)mmol/L in aged 70 group. The prevalence of hypercholesterolemia and borderline high cholesterolemia were 5.6%(95%CI:4.5%-6.6%) and 24.7%(95%CI:21.6%-27.9%) totally; 5.1% (95%CI:4.1% 6.1%) and 24.4% (95%CI:21.0%-27.6%) for male, 6.0% (95%CI:4.7%-7.3%) and 25.1%(95%CI:21.8%-28.4%) for female; 6.0%(95%CI: 5.0%-7.0%) and 27.7%(95%CI:24.9% 30.6%) in big cities, while 5.5%(95%CI: 4.2%-6.7%) and 24.2%(95%CI:20.5%-27.9%) in small and medium-sized cities. The minimum prevalence of hypercholesterolemia was in aged 18 to 29 group and maximum in aged 70 group, which were 2.2%(95%CI: 1.4%-3.0%) and 10.3%(95%CI: 7.1%-13.4%), respectively; while the lowest borderline high cholesterolemia prevalence was in aged 18 to 29 group and the highest in aged 60 to 69 year group, which were 12.9%(95%CI: 10.4%-15.4%) and 37.6% (95%CI: 33.6%-41.6%), respectively. CONCLUSION: The serum total cholesterol level and the prevalence of hypercholesterolemia and borderline high cholesterolemia were high among urban adults in China from 2010 to 2012, and more attention should be paid for high serum total cholesterol level among older adults. PMID- 26957236 TI - [Study on the anemia status of Chinese urban residents in 2010-2012]. AB - OBJECTIVE: The level of blood hemoglobin and the anemia status of Chinese urban residents in 2010-2012 was analyzed. METHODS: All the data in this study came from the China Nutrition and Health Survey in 2010-2012. By using multi-stage stratified sampling and population proportional stratified random sampling method, 74 276 residents aged above 6 from 34 metropolis and 41 middle-sized and small cities were included in this study. The concentration of blood hemoglobin was determined by cyanmethemoglobin method. Anemia was judged by the anemia standard recommended by WHO, combined with elevation correction standard. The level of blood hemoglobin, the prevalence of anemia and the 95%CI value were analyzed by using the complex sampling weighted processing, combined with the population figures released by the National Bureau of Statistics in 2009. RESULTS: In 2010-2012, the level of blood hemoglobin of Chinese city population was(144.16 +/- 0.78)g/L, (152.88 +/- 0.94)g/L for male and(135.01 +/- 0.71)g/L for female, while (145.65 +/- 1.22)g/L for metropolis and (143.90 +/- 0.89)g/L for small and medium-sized. The anemia prevalence of Chinese city population (pregnant women were not included) was 9.7%(95%CI: 9.4%-10.1%), 6.8%(95%CI: 6.4% 7.3%) for male and 12.8%(95%CI: 12.2%-13.4%) for female, while 8.5%(95% CI: 8.0% 9.0%) for metropolis and 10.0%(95%CI: 9.5%-10.4%) for small and medium-sized. The anemia prevalence of 18-44 women (15.4%, 95%CI: 14.3%-16.6%) was the highest among all the age-groups, and the average anemia prevalence of people more than 60 years-old (including) (12.5%, 95%CI: 11.8%-13.2%) was higher than the other age-groups. CONCLUSION: The anemia prevalence of Chinese city population in 2010 2012 was obviously decreased in comparison of 10 years ago, while, more attention and improvement measures should be take upon women at reproductive age and the elder people. PMID- 26957237 TI - [Salt intake among Chinese adults in 2010-2012]. AB - OBJECTIVE: To analyze the mean population intake of salt in Chinese adults in 2010-2012. METHODS: Data were from the Chinese Nutrition and Health Surveillance in 2010-2012. The samples were selected through the method of probability proportion to size (PPS). The study objects were 55 531 adults aged 18 and over from 150 sites in 31 provinces, autonomous regions or municipalities in China. The information of oil, salt and other condiments for household was from the 3 d food weighed record. The average of salt intake for individuals was calculated based on the energy percentage in one family. The results presented the level of salt intake (x +/- Sx) by analyzing the different demography characteristics. The results were calculated using complex weighting by the population data from National Bureau of Statistics in 2009. RESULTS: The intake of salt was (9.6 +/- 0.3) g/d and it was higher in men ((10.4 +/- 0.4) g/d) than that in women ((8.8 +/- 0.3) g/d). The intake in the age group of 40-49, 50-59 and 60-69 was (9.9 +/- 0.5) g/d, (10.3 +/- 0.4) g/d and (9.9 +/- 0.3) g/d, respectively. The adults in rural ((10.2 +/- 0.3) g/d) had a higher salt intake than that of urban ((9.0 +/- 0.5) g/d). An average of salt intake was increased gradually in big city ((7.9 +/ 0.3) g/d), medium /small city ((9.2 +/- 0.6) g/d) , general rural ((9.9 +/- 0.4) g/d) and poor rural ((10.8 +/- 0.7)g/d). CONCLUSION: The mean salt intake among Chinese adults was still in a very high level. Something should be done to reduce the salt intake for the government and policy-makers. PMID- 26957238 TI - [Consumption of fruits and vegetables in Chinese adults from 2010 to 2012]. AB - OBJECTIVE: To analyze the consumption of fruits and vegetables of Chinese adults. METHODS: Data were collected from 2010-2012 China National Nutrition and Health Surveillance. Information on fruits and vegetables consumption was collected by using the 24 h recall method for 3 consecutive days. Using the multi-stage stratified cluster randomization sampling method. The participants selected were more than 18 years old of 150 counties from 31 provinces in China. Age and sex standardization was performed based on the China 2009 population published by National Statistics Bureau. The average consumption of vegetables or fruits after weight adjustment for complex sampling was reported to analyze the consumption of fruits and vegetables of Chinese adults (x +/- Sx). RESULTS: The average daily consumptions of vegetables and fruits for Chinese residents were (255 +/- 6) and (36 +/- 3)g/d, respectively. The total consumptions of fruits and vegetables were (291 +/- 7)g/d, (295 +/- 8)g/d for male, (286 +/- 7)g/d for female. Rates on intake of vegetables in Chinese adults during the three survey days were 99.0% 99.8%.Rates on intake of fruits of urban and rural residents were 36.9%-51.5% and 21.3%-30.3%,respectively.The proportion of people whose total amount of vegetables and fruits intake reached 400 g/d were 24%-28% and 13%-23% in urban and rural areas, respectively. In urban and rural areas, the proportion of adults whose consumption reached Chinese dietary guidelines recommended level were 22% 26% and 14%-19% in vegetables, 2%-5% and 1%-2% in fruit, respectively. CONCLUSION: The consumptions of vegetables and fruits were inadequate in Chinese adults. PMID- 26957239 TI - [Mediating effect of insulin related indices on the association between body fat with blood pressure among overweight adults]. AB - OBJECTIVE: To examine the contribution of insulin related indices on the association between body fat and blood pressure among overweight adults. METHODS: From April to May 2014, based on convenience sampling, we recruited overweight and obese volunteer participants aged 20-55 years living in Beijing at least 1 year through a strict examination by doctors in a physical examination center. In this study, we excluded the participants who reported suffering from any severe heart, lung, liver or kidney organic diseases, and abnormal development, disabilities, and secondary obesity caused by other disease. Also participants with use of antihypertensive drugs, hypoglycemic drugs and lipid lowering drugs were excluded for this study. A total of 1 221 participants were investigated in this study. With a simple self-designed questionnaire, the birthdates, sex, drug use, and disease history were examined. Participants' blood pressure (BP), percentage of body fat (PBF), glucose and fasting insulin level were measured. Mediation analysis was used to analyze the total effect of PBF on BP (c), the association between PBF and insulin related indices (a), and the mediation effect of serum fasting insulin level/HOMA-IR/HOMA-%S on relation between PBF and systolic/diastolic blood pressure (SBP/DBP). RESULTS: PBF was positively associated with SBP (c=0.25 +/- 0.05 and 0.19 +/- 0.03 for male and female, respectively, P<0.001). In males, PBF was positively associated with fasting insulin level and HOMA-IR (a=0.28 +/- 0.05 and 0.24 +/- 0.05, P<0.001), and negatively associated with HOMA-%S (a=-0.29 +/- 0.05, P<0.001); in females, PBF was positively associated with fasting insulin level, HOMA-IR (a=0.21 +/- 0.04 and 0.20 +/- 0.04, P<0.001), and negatively associated with HOMA-%S (a=-0.13 +/- 0.04, P<0.001). In further mediation analysis for female participants, fasting insulin level/HOMA-IR/HOMA-%S played mediation roles in the relation between PBF and SBP, with ratio of mediation of 13.78%,18.3%, and 5.98%. Fasting insulin level/HOMA-IR also mediated the relation between PBF and DBP, with mediation ratio of 11.98% and 14.13%. CONCLUSION: In overweight/obese female participants, insulin related indices mediated the relation between PBF and BP. PMID- 26957240 TI - [Prevalence of dyslipidemia among residents aged 18-69 years in Shandong province of China, 2011]. AB - OBJECTIVE: To investigate the prevalence and distribution characteristics of dyslipidemia among Shandong residents aged 18-69 years. METHODS: The levels of triglyceride (TG), low density lipoprotein-cholesterol (LDL-C), high density lipoprotein-cholesterol (HDL-C), and total cholesterol (TC) were determined in fasting serum of 5 ml venous blood for subjects aged 18-69 years who were selected by multi-stage stratified cluster random sampling from 20 counties in July, 2011 in 140 counties of Shandong province. The prevalence of dyslipidemia, hypercholesterolemia, high blood LDL-C, low blood HDL-C and hypertriglyceridemia were analyzed by the complex weighting. The prevalence of dyslipidemia, hypercholesterolemia, high blood LDL-C, low blood HDL-C and hypertriglyceridemia were compared for different characteristics by Rao-Scott chi(2). RESULTS: The prevalence of dyslipidemia among 15 350 subjects was 22.70% (3 572), with higher in males (26.91% (2 110/7 683)) than in females (18.41% (1 462/7 667)). The prevalence of hypercholesterolemia was 3.39% (n=582), with higher in Eastern Shandong (4.59% (185/3 704)). The prevalence of high blood LDL-C was 0.56% (n=94), with higher in Eastern Shandong (0.79% (32/3 074)). The prevalence of low blood HDL-C was 11.41% (n=1 789). The prevalence of hypertriglyceridemia was 13.02% (n=2 059), higher in urban residents (16.54% (814/4 804)) than in rural (11.52% (1 245/10 546)) (chi(2)=71.54, P<0.001). The difference between the prevalence of low blood HDL-C and hypertriglyceridemia was not significant among Eastern Shandong, Central-South and Northwest. CONCLUSION: Dyslipidemia rate was higher among adult residents in Shandong province. The rate was higher for men than for women. The prevalence of hypercholesterolemia and high blood LDL-C were higher in Eastern Shandong than the other areas. The hypertriglyceridemia and low blood HDL-C were two major types of dyslipidemia. PMID- 26957241 TI - [Study on skeletal muscle mass of 1 836 check-up adults and its association with age in Qiqihar]. AB - OBJECTIVE: To analyze the correlation between skeletal muscle mass and age among check-up adults. METHODS: The study objects were those who aged 18-87 years old and came to a city hospital of Qiqihar for health examination from December, 2013 to September, 2014, excepted those with coronary heart disease, infectious disease, endocrine system disease, hypertension, anemia, cancer, liver disease, kidney disease and those carrying with heart pacemaker. A total of 1 836 respondents were finally enrolled into analysis. Appendicular Skeletal Muscle (ASM) was measured by a Body Composition Analyzer, and relative skeletal muscle index (RSMI) was calculated. The relationship among ASM, RSMI and age was assessed by linear regression analysis. The difference of height, weight, BMI, waist-hip-ratio (WHR), total muscle mass and percentage of body fat between genders were tested by t-test. The difference of ASM and total skeletal muscle mass between genders and among age groups was tested by multi-factor variance analysis. The difference of the muscle decline between genders was compared by Chi-square test. RESULTS: The total muscle mass in males was (52.22 +/- 6.65) kg, which was significantly higher than that in females ((38.05 +/- 4.39) kg) (t=28.20, P<0.001). ASM in 18-29, 30-39, 40-49, 50-59, 60-69, 70-87 years was (24.64 +/- 3.23), (24.00 +/- 3.12), (24.35 +/- 3.03), (23.33 +/- 2.97), (22.54 +/ 2.91) and (21.40 +/- 3.36) kg (F=16.12, P<0.001) in males, respectively, and (16.48 +/- 3.14), (16.72 +/- 1.93), (16.75 +/- 1.93), (16.84 +/- 2.28), (16.52 +/ 2.35) and(14.70 +/- 2.37)kg (F=4.38, P=0.001) in females, respectively. ASM in males ((23.72 +/- 3.16) kg) was higher than that in females ((16.65 +/- 2.25) kg) (t=55.97, P<0.001). There was a negative correlation between age and ASM in males after 50 years old, the regression equation was y=28.31-0.09x (P<0.001). While a negative correlation between age and ASM in females occurred after 60 years old, the regression equation was y=27.69-0.18x (P<0.001). The prevalence of low ASM was 16.85% (124/736) in females, which was significantly higher than that in males (8.73%, 96/1 100) (chi(2)=27.57, P<0.001). CONCLUSION: A negative correlation was found between age and ASM in males after 50 years old and in females after 60 years old. The prevalence of low RSMI in females was significantly higher than that in males. PMID- 26957242 TI - [Association of SNP of leukocyte differentiation antigen-CD40 gene and its serum level with ischemic stroke]. AB - OBJECTIVE: To investigate the association of SNP of CD40 gene and its serum levels with ischemic stroke (IS). METHODS: A total of 202 IS patients from a hospital of Baise city were enrolled in case group from May 2013 to November 2014. At the same time, 109 healthy people who had physical check-ups in the outpatient department at the same hospital were enrolled in the control group. All participants were from Guangxi Zhuang Autonomous Region and unrelated to each other. 3 ml venous blood were collected on the premise of informed consent. The single nucleotide polymorphisms of CD40 gene rs1883832 C/T, rs13040307 C/T, rs752118 C/T and rs3765459 G/A were analyzed using a Snapshot SNP genotyping assays, and the serum levels of CD40 were tested by ELISA. t-test was used to compare the serum levels of CD40 between the case and control group, and the genotypes at different locuses in case group; chi(2) test was used to compare the distribution differences of the CD40 gene locuses in different genotypes and allele between the case group and the control group; alleles was established as independent variables, the occurrence of the IS as dependent variable, and expressed relative risk with OR (95%CI) value. RESULTS: In the case group, the frequency of CC, CT and TT genotypes in CD40 gene rs1883832 C/T were 21.78% (44/202), 49.51% (100/202) and 28.71% (58/202), respectively, and 33.17% (66/199), 48.74% (97/199), 18.09% (36/199) in the control group, respectively, the differences between the two groups was significant (chi(2)=9.57, P=0.008). The CD40 serum levels were (62.7 +/- 24.5) pg/ml in the case group, which was higher than that in the control group (45.3 +/- 17.2) pg/ml (t=8.97, P<0.001). The serum levels of TT and CT genotypes in CD40 gene were (65.9 +/- 26.3) and (64.3 +/- 25.9) pg/ml, respectively, and the differences were significant when comparing with CC genotype (t equaled 5.34 and 5.03, respectively, P<0.001). The risk of developing IS was 1.56 times higher in 1883832 T allele carriers than that in rs1883832 C allele carriers (OR=1.56, 95% CI: 1.18-2.06); Combined genotype analysis displayed that CD40 gene rs1883832 C/T, rs13040307 C/T, rs752118 C/T and rs3765459 G/A polymorphisms showed strong linkage disequilibrium, the case group TCCA haplotype was tested to be associated with a significantly increased risk of IS as compared with that in the control group(OR=2.49; 95%CI: 1.13-5.48). CONCLUSION: CD40 gene rs1883832 C/T polymorphism and its TCCA haplotype were possibly associated with ischemic stroke, and the susceptibility gene for ischemic stroke may be rs1883832 T allele. PMID- 26957243 TI - [Effect of SiO2 nanoparticles exposure on microRNA expression level in human bronchial epithelial cells]. AB - OBJECTIVE: To investigate the effect of short and long term exposure to SiO2 nanoparticles on microRNA expression level in human bronchial epithelial cells(16HBE cells). METHODS: The 16HBE cells were exposed to 5, 10, 15, 20, 25, 30 and 40 MUg/ml SiO2 nanoparticles for 24 h to detect the cell viability by using CCK-8 assay. The inhibition rate of proliferation activity and half inhibitory concentration (IC50) were calculated. The 16HBE cells were exposed to 10 MUg/ml SiO2 nanoparticles for 10 and 30 generations, named P10 and P30, and the control P0 was set. The cells were treated with SiO2 nanoparticles at 0, 1/4 IC50, 1/2 IC50 and IC50 concentration and MUm-SiO2 at IC50 concentration for 24 h, and the control serum-free culture medium was set. Agilent miRNAs microarray chip was used to screen differentially expressed miRNAs in P10, P30 and P0 groups. The expression level of miRNA was detected by reverse transcription fluorescence quantitative polymerase chain reaction (qRT-PCR). RESULTS: The inhibition rate of proliferation activity of 5, 10, 15, 20, 25,30,40 MUg/ml group were (-3.33 +/- 3.80)%, (20.40 +/- 11.73)%, (39.08 +/- 5.53)%, (55.10 +/- 5.78)%, (66.42 +/- 9.60)%, (71.67 +/- 7.34)%, (81.43 +/- 5.37)%, respectively; F=129.11, P<0.001. The IC50 (95%CI) was 18.35 (15.82-20.72) MUg/ml. The expression level of miRNA-494-3p in P0, P10 and P30 were 1.00, 0.45 +/- 0.08, 0.28 +/- 0.07, respectively; F=60.77, P<0.001. miRNA-19a-3p were 1.00, 2.27 +/- 0.45, 1.06 +/- 0.19, respectively; F=30.05, P<0.001. miRNA-148b-3p were 1.00, 1.78 +/- 0.29, 0.88 +/- 0.19, respectively; F=30.23, P<0.001. Compared to control group, the expression level of miRNA-494-3p in 5, 10, 20 MUg/ml SiO2 nanoparticles groups and 20 MUg/ml MUm-SiO2 group were 0.99 +/- 0.04, 1.38 +/- 0.19, 2.13 +/- 0.14, 0.81 +/- 0.25, respectively; F=57.03, P<0.001. miRNA-19a-3p were 0.91 +/- 0.03, 1.12 +/- 0.03, 0.53 +/- 0.01, 0.86 +/- 0.01, respectively; F=408.78, P<0.001. miRNA-148b-3p were 0.95 +/- 0.02, 1.22 +/- 0.00, 0.54 +/- 0.02, 1.15 +/- 0.04 respectively; F=264.14, P<0.001. CONCLUSION: Short and long term exposure to SiO2 nanoparticles can affect the expression level of miRNAs in 16HBE cells. The expressions of miRNA-494-3p after long and short period exposure are different. PMID- 26957244 TI - [Avian influenza virus in various environments and risk factors for the contamination of live poultry markets during winter and spring season in Zhejiang province]. AB - OBJECTIVE: To evaluate the prevalence of avian influenza virus in various environment and the influence factors for subtype H7 prevalence in live poultry markets. METHODS: We collected environmental samples from various environments across 11 cities of Zhejiang province between October 2014 and March 2015. Cage surface swabs, chopping board surface swabs, feces, water for cleaning, drinking water and swabs of other surfaces were collected. A total of 6 457 samples were collected, including 4 487 samples from poultry markets, 820 samples from poultry farms, 715 samples from backyard poultry pens, 118 samples from poultry processing factories, 118 samples from wild bird habitats and 86 samples from other sites. The chi-squared test was used to compare virus prevalence among sample types, sites types, and poultry markets types. Binary logistic regression was used to analyze factors on H7 subtype prevalence in poultry markets. RESULTS: Of 6 457 samples, 32.54% (2 101) samples were positive for avian influenza, with 3.67% (237) positive for H5 subtype, 12.02%(776) positive for H7 subtype, 11.77%(760) positive for H9 subtype. Of 237 live poultry markets, 33.8% (80) were positive for H7 subtype. The prevalence of influenza A in poultry processing factories was the highest at 43.72% (101/231) (chi(2)=737.80, P<0.001). Poultry markets were contaminated most seriously by subtype H5/H7/H9 with the prevalence of 27.55% (1 236/4 487) (chi(2)=436.37, P<0.001). Compared with markets with 1 type of poultry, OR was 4.58 (95%CI: 1.63-12.87) for markets with >=2 types of poultry. CONCLUSION: Live poultry markets and poultry processing factories were contaminated most seriously by avian influenza. The types of poultry might be the factor which influenced the subtype H7 prevalence in poultry markets. PMID- 26957245 TI - [Analysis of pathogenic features and infection status of human parainfluenza virus type 3 among children in Hangzhou]. AB - OBJECTIVE: To determine the level of genetic variation of human parainfluenza virus type 3 (HPIV-3), and to describe infection and co-infection characteristics of HPIV-3 in children. METHODS: Single respiratory samples from 856 pediatric patients with acute respiratory tract infection (ARI) in Hangzhou were collected from December 2009 to March 2013. All samples were screened for HPIV-3 by real time RT-PCR and followed by HN sequencing and phylogenetic analysis. In all RSV positive specimens, we screened for the other pathogens, and co-infection characteristics were evaluated. RESULTS: A total of 9.6% of 856 samples were positive for HPIV-3, the nucleotide among the strains ranged from 96.9% to 100%. All Hangzhou strains were placed in C3 subgroup based on HN gene analysis. 49% (n=41) of all HPIV-3-positive children with ARI were found to be co-infected with at least one of the other pathogen. The highest co-infection rate of HPIV-3 was with HRV (n=17). Children in the younger groups (<=12 months old) were significantly more prone to be co-infected with other pathogen (chi(2)=4.78, P=0.029). Pneumonia infection rate was significantly higher in the mono-infection group than the co-infection group (chi(2)=3.92, P=0.048). CONCLUSION: HPIV-3 was an important pathogen in children with ARI in Hangzhou. HN gene variation rate was low, but showed a more local pattern. The co-infections with other respiratory viruses were popular. Except for pneumonia, no significant differences in other clinical presentation between the HPIV-3 mono-infection and co-infection groups were observed. PMID- 26957246 TI - [Characteristics of drug resistance and molecular typing research for Salmonella Enteritidis isolated in Henan province from 2011 to 2013]. AB - OBJECTIVE: To investigate the antimicrobial resistance status and pulsed field gel electrophoresis (PFGE) patterns of Salmonella Enteritidis (S.Enteritidis) strains in Henan province. METHODS: S. Enteritidis strains were isolated from seven sentinel hospitals from March 2011 to December 2013. According to molecular typing and Salmonella (Kirby-Bauer, K-B) drug susceptibility testing method published by the international PulseNet bacterial infectious disease monitoring network and USA Clinical and Laboratory Standards Institute (CLSI), we analyzed drug sensitivity of 8 kinds antibiotics and PFGE molecule characteristics of 120 S. Enteritidis isolates from seven sentinel hospitals. RESULTS: Among 120 strains of S. Enteritidis, 77 were isolated from male patients, 43 from female patients. A total of 78 strains S. Enteritidis were isolated from young children ranged from 0 to 5 years old (65.0%), including 57 strains isolated from 6 months to 2 years old (47.5%). The isolated time mainly centralized on May to October of the year, 11 strains isolated in March-April (9.2%), 48 were in May-July (40.0%),54 in August-October (45.0%), 7 in other months, with a typical summer seasonal characteristics. The resistance rate of 120 strains S. Enteritidis to ampicillin was 50.0% (n=60); to ceftazidime was 14.2% (n=17), to cefotaxime was 18.3% (n=22); to cefepime was 5.8% (n=7); to nalidixic acid was 61.7% (n=74); to ciprofloxacin was 8.3% (n=10), to norfloxacin was 5.8% (n=7); to gentamicin was 42.5% (n=51); to streptomycin was 21.7% (n=26); to chloramphenicol was 30.0% (n=36); resistance to methicillin benzyl ammonium was 11.7% (n=14), compound sulfamethoxazole resistance rate was 71.7% (n=86); the tetracycline resistant rate was 47.5% (n=57). All 120 strains of S. Enteritidis had different levels of resistance to 8 kinds of antibiotics, all strains were multidrug resistant strains, 28 isolates were resistant to 3-4 kinds of antibiotics (23.3%), 38 isolates were resistant to 5-6 kinds of antibiotics (31.7%), 39 isolates were resistant to 7-8 kinds of antibiotics (32.5%). All 120 strains of S. Enteritidis were divided into 44 molecular patterns by digestion with XbaI and pulsed field gel electrophoresis. each pattern contained 1-35 strains with similarity ranged from 54.3%-100%. EN14 and EN19 were the main PFGE types, including 35 and 29 strains respectively. CONCLUSION: The status of drug resistance of clinical isolates of Salmonella in Henan province was rather serious, PFGE patterns showed advantages and partial strain's corresponding resistant spectrum have certain relevance and the same aggregation relationship. PMID- 26957247 TI - [Role of Toll-like receptor 7 in the production of inflammatory cytokines in EV A71-infected human Jurkat T cells]. AB - OBJECTIVE: To investigate the expression of Toll-like receptor (TLR) mRNA in enterovirus 71(EV-A71) infected human Jurkat T cells and clarify the role of TLRs in the pathogenesis of EV-A71 infection-induced inflammation. METHODS: EV-A71 strains were isolated from feces of children patients with hand, foot and mouth disease in 2014 by Shenzhen Center for Disease Control and Prevention. Human Jurkat T cells were infected with 200 MUl EV-A71 at 10(3) cell culture infective dose 50%(CCID50)/ml. The expression of TLR1-TLR10 mRNA in human Jurkat T cells was assessed at different exposure time by RT-PCR. Levels of TLR7 mRNA expression were detected by real-time PCR, and levels of myeloid differentiation factor 88 (MyD88) by western blot. The cytokine secretion of interleukin (IL)-6, IL-8 and Tumor Necrosis Factor alpha (TNF-alpha) was analyzed by ELISA assay. RESULTS: The relative expression level of TLR7 mRNA in human Jurkat T cells were 1.26 +/- 0.15, 1.75 +/- 0.20, 2.26 +/- 0.23 and 3.74 +/- 0.62 in 6, 12, 24 and 48 h after EV-A71 infection, which the differences were significant with mock-infected group(t values were -2.96, -6.38, -9.57, -7.71; P<0.05). Western blot showed that the protein expression levels of MyD88 had increased 1.34 times and 2.17 times in 24 h and 48 h after EV-A71 infection compared with mock-infected group. After infected for 24 h and 48 h, the levels of IL-6 were (302.86 +/- 38.11), (179.70 +/- 14.50) pg/ml, which were significantly higher than mock-infected group (176.42 +/- 9.60), (179.70 +/- 14.50) pg/ml (t values were -5.57, -18.54, P<0.05). The levels of TNF-alpha in EV-A71 infected group (100.81 +/- 9.81) pg/ml was higher than that in mock-infected group (56.19 +/- 6.94) pg/ml, and the difference was significant (t=-6.43, P=0.003). CONCLUSION: TLR7 is the main pattern recognition receptor responsible for EV-A71 recognition in immune cells, which then leads to the activation of TLR7 downstream signaling and the production of proinflammatory cytokines. PMID- 26957248 TI - [Rapid detection of diethylstilbestrol using a quartz crystal microbalance with gold nanoparticals amplification]. AB - OBJECTIVE: To develop a quartz crystal microbalance (QCM) immunosensor with high sensitivity and selectivity for the rapid detection of diethylstilbestrol. METHODS: Dextran was used as reducing agent for preparing gold nanoparticles (AuNPs) with the size of 40 nm. The AuNPs were coupled with anti-DES antibody after amination. A monolayer was generated after immersing the quartz crystal into the solution of 5 mmol/L 11-mercaptoundecanoic acid(MUA) for 16 hours. After the monolayer was activated by 1-ethyl-3-(3-dimethylaminopropry) carbodiimide hydrochloride (EDC.HCl) and N-hydrosuccinimide (NHS), 20 MUl of 2.2 mg/ml DES-HS BSA was dropped onto the surface of crystal to prepare a sensitive membrane which can recognize DES specifically. Then, 50 MUl of 1 mol/L ethanolamine (pH 8.5) was used to seal the carboxylic groups to make the sensitive membrane which could identify DES specifically. QCM immunosensor was used as detection platform to optimize the reaction conditions. Under the optimized conditions, 10 MUl of 28 MUg/ml AuNPs-antibody was mixed with 10 MUl of 0.03-2.5 MUg/ml DES, and the mixture was added on the sensitive membrane. QCM immunosensor was used to detect the signals and the standard curve was obtained at the same time. The detection limit was calculated based on the standard curve. The specificity was evaluated by testing DES and its analogues with the same concentration. RESULTS: The optimized concentration for the immobilization of DES-HS-BSA on the surface of QCM was 2.2 mg/ml. The optimized concentration for coupling anti-DES antibody with AuNPs was 7 MUg/ml and 15 nmol/L, respectively. The optimized concentration of AuNPs-antibody was 14 MUg/ml. The logarithm of DES concentration was proportional to the frequency shift in the range of 0.16-500 ng/ml, Deltaf= 24.170 lgCDES+69.71, R(2)=0.998. The detection limit of this method was 0.13 ng/ml. DES analogues could not influence the detection of DES obviously, so the sensor had good specificity. CONCLUSION: The quartz crystal microbalance immunosensor with gold nanoparticals amplification could detect DES sensitively and rapidly. PMID- 26957249 TI - [Incidence and trend change of oophoroma in 11 tumor registration stations, Chongqing]. PMID- 26957250 TI - [Hepatitis E virus (HEV) infection analysis of patients with maintenance haemodialysis]. PMID- 26957251 TI - [Epidemiological serosurvey of hepatitis B in national disease surveillance points of Henan province in 2014]. PMID- 26957252 TI - [Alteration on household salt consumption status and urinary iodine concentration of a primary school children in Shanghai, 2012-2014]. PMID- 26957253 TI - [Advances on research of human exposure to triclosan]. AB - Triclosan, a broad-spectrum antimicrobial agent, was reported to have been widely detected in various human biological samples such as urine, blood and human milk among foreign populations. In China, limited reports have been found on human exposure to triclosan, and the reported urinary triclosan concentrations were significantly lower than that of American populations. Besides, the potential influencing factors still remain unclear regarding human exposure to triclosan, but evidences suggest that those in middle age and with higher household income and higher social class tend to have higher urinary triclosan concentrations. Furthermore, triclosan exposure tend to differ by sex, geography, heredity, metabolism and life style. PMID- 26957255 TI - Effect of 5-fluorouracil mobilized bone marrow regenerative cells transplantation on brain injury following focal cerebral ischemia in rats. PMID- 26957256 TI - The importance of selection criteria for the evaluation of Heart Rate Variability in women. PMID- 26957257 TI - The curative effects of LPN combined LCA in treating with middle and advanced renal cancer. AB - OBJECTIVE: To discuss the curative effects of laparoscopy partial nephrectomy (LPN) combined with laparoscopy cryoablation (LCA) in treating renal cancer. PATIENTS AND METHODS: A total of 58 patients that were diagnosed with phase III IV renal cancer in the Hospital from February 2013 to October 2014 were enrolled in this study. After obtaining the approval of Ethics Committee of the Hospital as well as the informed consent of the patients and their relatives, the patients were randomly divide into two groups: control group consisted of 24 patients, who were treated with LPN + chemo radiotherapy and the observation group consisted of 34 patients, who were treated with LPN in combination of LCA + chemo radiotherapy. RESULTS: The rate of successful operation was significantly higher in the observation group than in control group and the prevalence of per procedural complications in observation group was significantly lower than that of control group, and these differences had statistical significance (p < 0.05). Glomerular filtration rate (eGFR) after operation and 6-month follow-up in observation group was significantly higher than that in control group, and the level of serum creatinine (sCr) was significantly lower compared to the control group and the differences had statistical significance (p < 0.05). Follow-up survival rate of patients in the observation group was significantly higher than that of control group, recurrence rate and recurrence time of patients in the observation group was significantly lower than those of control group and the difference had statistical significance (p < 0.05). CONCLUSIONS: LPN combined LCA therapy was quite effective in treating with middle and advanced renal cancer. Compared with pure LPN therapy, LPN combined LCA therapy could significantly improve the surgical effects, retain the functions of the renal unit and improve the patients' prognosis. PMID- 26957258 TI - Effect of complete hilar versus only renal artery clamping on renal histomorphology following ischemia/reperfusion injury in an experimental model. AB - OBJECTIVE: To evaluate the effect of temporary complete hilar versus only renal artery clamping with different duration of warm ischemia on renal functions, and possibly identify a "safe" clamping type and duration of renal ischemia. MATERIALS AND METHODS: Fifty male rabbits have been incorporated to study. Rabbits were subjected to ischemia/reperfusion injury by temporary vascular clamping. Reagents were randomized to 3 experimental groups (only renal artery clamping, complete hilar clamping, sham surgery) and sub-groups were determined according to different clamping times (30 and 60 minutes). Median laparotomy and left renal hilus dissection were performed to sham group. Only artery or complete hilar clamping was performed for 30 or 60 minutes by microvascular bulldog clamps to other reagents. Rabbits were sacrificed 10 days after primary surgery and left nephrectomy performed. Nephrectomy materials were evaluated for the level of nitric-oxide synthase (NOS) immunoreactivity, malondialdehyde (MDA) level and superoxide dismutase (SOD) activity and an electron microscopic examination was performed. RESULTS: NOS immunoreactivity was correlated with the temporary clamping time. We also observed that complete hilar vascular clamping entails an increase on NOS immunoreactivity. MDA levels were similar for all experimental surgery groups (p = 0.42). The SOD activity was decreased among all subgroups compared with sham surgery. But the significant decrease occurred in 30 minutes only artery and 30 minutes complete hilar clamping groups in proportion to sham surgery (p = 0.026 and p = 0.019, respectively). CONCLUSIONS: This current study suggested that only renal artery clamping under 30 minutes is more appropriate during renal surgical procedures requiring temporary vascular clamping. PMID- 26957260 TI - Impression cytological study for ocular surface disorders of late stage eye burns. AB - OBJECTIVE: This study aims to explore the ocular surface of late stage eye burns by impression cytology (IC) and analyze the cytological changes and their relationship to ocular surface abnormalities. PATIENTS AND METHODS: 68 eyes with late stage eye burns (thermal burn: 28 eyes; alkali burn: 26 eyes; acid burn: 14 eyes), procured from 68 patients (aged ranges from 17 to 70 years old). Ocular surface abnormalities were assessed under slit lamp and graded. These were broadly classified as eyelid, corneal, conjunctival, and tear film abnormalities. Impression cytological examination was taken by cellulose acetate filter paper for all eyes. Samples were analyzed and scored under light microscope, including the status of epithelial cells, goblet cells, mucus and inflammatory cells. All the results and data were compared and analyzed by SPSS software (version 16.0). RESULTS: According to the IC results, loosed cell-to-cell density and nuclear abnormality, keratinization, reduced goblet cell amount, disorder of mucus, and existing of inflammatory cells were observed in almost all the cases. The IC results were significantly correlated to the ocular surface injury severity (r=0.458, p<0.01). The ocular surface injury severity mostly contains three aspects: the corneal neovascularization scales, the present or absent of recurrent epithelial erosion and the tear film break-up time. Eyes with the foreword three symptoms were inclined to have higher IC scores. The epithelial cell-to-cell density, goblet cell and mucus amount were all correlated to tear film break-up time. However, inflammatory cell density showed no significant correlation to the conjunctival hyperemia grade. But inflammatory cell density correlated to the corneal opacity grade and epithelial stability status. CONCLUSIONS: IC examinations could reflect the cytological disorders and relative injury severity of the ocular surface in late stage eye burns. It provides further information which will be useful in surgery and therapy. PMID- 26957254 TI - Glycosylation and other PTMs alterations in neurodegenerative diseases: Current status and future role in neurotrauma. AB - Traumatic brain injuries (TBIs) present a chief public health threat affecting nations worldwide. As numbers of patients afflicted by TBI are expected to rise, the necessity to increase our understanding of the pathophysiological mechanism(s) as a result of TBI mounts. TBI is known to augment the risk of developing a number of neurodegenerative diseases (NDs) such as Alzheimer's disease (AD) and Parkinson's disease (PD). Hence, it is rational to assume that a common mechanistic ground links the pathophysiology of NDs to that of TBIs. Through this review, we aim to identify the protein-protein interactions, differential proteins expression, and PTMs, mainly glycosylation, that are involved in the pathogenesis of both ND and TBI. OVID and PubMed have been rigorously searched to identify studies that utilized advanced proteomic platforms (MS based) and systems biology tools to unfold the mechanism(s) behind ND in an attempt to unveil the mysterious biological processes that occur postinjury. Various PTMs have been found to be common between TBI and AD, whereas no similarities have been found between TBI and PD. Phosphorylated tau protein, glycosylated amyloid precursor protein, and many other modifications appear to be common in both TBI and AD. PTMs, differential protein profiles, and altered biological pathways appear to have critical roles in ND processes by interfering with their pathological condition in a manner similar to TBI. Advancement in glycoproteomic studies pertaining to ND and TBI is urgently needed in order to develop better diagnostic tools, therapies, and more favorable prognoses. PMID- 26957261 TI - A new cyclic RGD peptide dimer for integrin alphavbeta3 imaging. AB - OBJECTIVE: To design a new Arg-Gly-Asp (RGD) peptide that can specifically bind integrin alphavbeta3 and evaluate the possibility of using 131I-labeled peptide for imaging alphavbeta3-positive tumors. MATERIALS AND METHODS: The structure of the RGD monomer was selected using V-life software. Based on the RGD monomer, a dimer of cyclic RGD [c(RGD)2] linked by Tyr-(D)Ser-Lys-(D)Ser-Ser with a Gly-Gly (D)Ala-Gly side chain on the lysine residue was synthesized. 131I-c(RGD)2 was synthesized using the chloramine-T (ChT) method, and the octanol-water partition coefficient was experimentally measured. To evaluate its binding affinity and selectivity, its equilibrium dissociation constant (Kd) with U87 MG glioma cells was measured in vitro, while whole body imaging and biodistribution were assessed in vivo in mice bearing U87 MG xenografts. RESULTS: The optimal structure of the monomer was cyclic [-Cys-Arg-Gly-Asp-(D)Ser-Cys-]. The 131I-c(RGD)2 molecule exhibited good stability and was highly hydrophilic. The Kd value was (3.87 +/- 0.05) * 10(-9) M, suggesting a high alphavbeta3-binding affinity and specificity. The tumors were clearly visualized at 3 and 6 h post-injection. Biodistribution data of the 131I-c(RGD)2 molecule showed rapid clearance from the blood and predominant accumulation in the tumor and kidney. The tumor-to-normal tissue (T/NT) ratio increased over time. At 24 h post-injection, the tumor-to-liver, tumor-to-muscle, and tumor-to-blood ratios were 4.92, 4.29, and 5.00, respectively. CONCLUSIONS: These results suggest that the 131I-c(RGD)2 molecule may serve as a promising tracer for the detection of alphavbeta3-positive tumors. PMID- 26957262 TI - The effect of permissive hypotension in combined traumatic brain injury and blunt abdominal trauma: an experimental study in swines. AB - OBJECTIVE: Optimal hemodynamic resuscitation strategy of the trauma patient with uncontrolled hemorrhage and severe head injury in the pre-hospital setting remains a special challenge. Permissive hypotension prior to definite surgical haemostasis promotes coagulation, decreases blood loss and favors survival. However, hypotension is associated with poor outcome in severe head injury. The purpose of this experimental animal study was to assess the impact of permissive hypotension on survival, hemodynamic profile and brain oxygenation parameters before and/or after definite surgical haemostasis. PATIENTS AND METHODS: Six-week old pigs (n=12) underwent general anesthesia and brain injury was produced by the fluid percussion model. Animals were instrumented to measure hemodynamic parameters and cerebral blood flow. All animals (n=12) were subjected to laparotomy and a surgical knot was placed through the abdominal aorta wall. Uncontrolled hemorrhage was simulated by pulling out the intentionally left protruding free ends of the suture (goal MAP=30 mmHg). Animals were randomly divided into two groups; group A (n=6) was subjected to aggressive fluid resuscitation (goal SAP >80 mmHg) and group B (n=6) was left hypotensive (permissive hypotension). Animals who survived one hour of hypotensive shock underwent definite surgical haemostasis and were resuscitated for one hour. We measured survival, hemodynamic and brain oxygenation parameters at different time points before and after surgical haemostasis. RESULTS: All animals from Group A and 50% from Group B died before surgical haemostasis. In surviving animals (Group B, 50%, p=0.033), MAP, CO, rCBF, SjO2 and AVDO2 were restored to pre procedural levels. CONCLUSIONS: Permissive hypotension by delaying fluid resuscitation up to definite surgical haemostasis improves survival, hemodynamics and allows restoration of cerebral oxygenation in severe head injury. PMID- 26957259 TI - A correlation between selenium and carnitine levels with hypo-osmotic swelling test for sperm membrane in low-grade varicocele patients. AB - OBJECTIVE: The hypo-osmotic swelling (HOS) test predicts membrane integrity by determining the ability of the sperm membrane to maintain equilibrium between the sperm cell and its environment. The aim of our study was to determine the correlation between selenium and carnitine levels in the seminal fluid with HOS test for sperm membrane in low-grade varicocele patients. PATIENTS AND METHODS: Study numbered 64 examinees who suffered from low-grade varicocele and were divided into two groups, according to fertility potential and HOS test outcome. The study also included a control group of 64 healthy subjects, with no varicocele. RESULTS: From the Shapiro-Wilk's test, it is clear that carnitine distribution differs significantly from normal (0.938, p = 0.03). In distribution of selenium, Kolmogorov-Smirnov test clearly shows statistically significant deviation from the normal curve (z = 0.225, p < 0.000), likewise Shapiro-Wilk's statistic (0.787, p < 0.000). According to the results, the second group had significantly higher levels of carnitine and selenium than the first group of examinees (p < 0.05); therefore, when we compared epididymal markers with HOS tests outcomes, we found significant differences between the two groups. There were no significant differences between second group and healthy subjects (p > 0.05). CONCLUSIONS: HOS test outcome in varicocele patients is directly proportional to the carnitine and selenium levels, which could play a major role in both determining fertility parameters and in the treatment of its impairment. This result is important for sub-clinical varicocele in infertile patients with normal semen analysis, since there is no evidence of benefit from any treatment so far. PMID- 26957263 TI - A potential clinical usefulness of measuring serum bilirubin levels in patients with polymyositis. AB - OBJECTIVE: Accumulated data have indicated that bilirubin has antiinflammatory, antioxidative, and immunosuppressive properties. Polymyositis (PM) belongs to an autoimmune disease characterized by chronic inflammation in skeletal muscle. Until now, to the best of our knowledge, there are no literature investigating bilirubin levels in patients with PM. Therefore, the aim of this investigation was to assess a relationship between bilirubin and PM. PATIENTS AND METHODS: Our study included newly diagnosed 77 patients with PM who were admitted to the Affiliated Hospital of Youjiang Medical University for Nationalities (Guangxi, China) and 108 healthy subjects as controls. Clinical characteristics and laboratory parameters of patients were analyzed, retrospectively. RESULTS: The serum concentrations of total bilirubin (TB), conjugate bilirubin (CB), unconjugated bilirubin (UCB) were significantly lower in patients with PM than healthy controls. Serum concentrations of TB were negatively correlated with erythrocyte sedimentation rate (ESR), creatine kinase (CK) and lactic dehydrogenase (LDH) in patients with PM (r=-0.494, p<0.001; r=-0.274, p=0.017; r= 0.282, p=0.014), and serum concentrations of UCB were negatively correlated with ESR and CK in PM patients (r=-0.424, p<0.001; r=-0.234, p=0.041). Both serum TB and UBC concentrations were positively correlated with manual muscle test (MMT) score in patients with PM (r=0.328, p=0.004; r=0.333, p=0.004). In multiple linear regression analysis, serum UBC levels were independently associated with MMT score (r=0.239, p=0.003). CONCLUSIONS: We observed significantly lower serum concentrations of TB, CB and UCB in patients with PM, and suggested a potential association between serum concentrations of UBC and disease activity in PM patients. PMID- 26957264 TI - Relationship between leptin and regulatory T cells in systemic lupus erythematosus: preliminary results. AB - OBJECTIVE: Crescent literature data demonstrated a role of adipokines in immune responses, particularly leptin is involved in wide spectrum of pro-inflammatory functions. Several evidences suggested that leptin is able to inhibit T regulatory cells proliferation and function in vitro models. In the present study, we investigate the relationship between leptin and circulating T regulatory cells (Tregs) in patients affected by systemic lupus erythematosus (SLE). PATIENTS AND METHODS: 13 SLE patients and 11 healthy controls were enrolled. Metabolic syndrome and cardiovascular parameters were evaluated. Serum leptin levels were detected by commercial ELISA kit and circulating regulatory T cells were determined by FACS analysis as CD4+CD25highFOP3+ lymphocytes. RESULTS: Metabolic syndrome, defined by ATPIII criteria, was more prevalent in SLE compared to controls (38.4% vs. 0%, p = 0.04), as well as arterial hypertension (38.4% vs. 0%, p = 0.04). We did not find significant differences in mean leptin levels among SLE and controls (13.13 +/- 1.51 ng/ml vs. 9.48 +/- 8.67 ng/ml, p = 0.6). Mean Tregs percentage of total CD4 were 1.27 +/- 0.9 in SLE vs. 2.8 +/- 1.2 in healthy controls (p = 0.001). We found a negative correlation between leptin levels and Tregs percentage of total CD4 in SLE patients (r = 0.4, p = 0.01). CONCLUSIONS: Our results suggest a role of leptin in the regulation of circulating T regulatory cells amount in human SLE. PMID- 26957265 TI - Expression of CD27, CD28 and IL-17A in peripheral blood from patients with colorectal carcinoma. AB - OBJECTIVE: To compare the different expressions of CD27, CD28, IL-17A, IFN-gamma and TNF-alpha in the peripheral blood sampled from patients with colorectal carcinoma and healthy volunteers. PATIENTS AND METHODS: Vdelta2 T cells were isolated from the peripheral blood mononuclear cells (PBMCs) of patients with the colorectal carcinoma (CRC, n = 30) and healthy controls (HC, n = 21). The proportion of CD27, CD28, IL-17A, IFN-gamma and TNF-alpha of Vdelta2 T cells was detected by the flow cytometry. RESULTS: We found that the proportion of IL-17A of Vdelta2 T cells in PBMCs was higher in the CRC vs. the HC group (p < 0.05). A significant positive correlation was observed between the expression of IFN-gamma and TNF-alpha of Vdelta2 T cells. In the CRC patients, the proportions of IL-17A of CD27- Vdelta2 T cells and CD28+ Vdelta2 T cells were higher than those of CD27+ Vdelta2 T cells and CD28- Vdelta2 T cells, whereas the expression of IFN gamma and TNF-alpha of CD27-Vdelta2 T cells was lower than that of CD27+ Vdelta2 T cells. CONCLUSIONS: Vdelta2 T cells from PBMCs had higher expression of IL-17A in CRC patients than that in the HC group. The expression of IFN-gamma and TNF alpha of Vdelta2 T cells from PBMCs was positively correlated. The cytokine profiles of peripheral Vdelta2 T cells were likely determined by a CD27 and CD28 involving mechanism. PMID- 26957266 TI - Preoperative neutrophil-to-lymphocyte ratio (NLR) may be predictive of pathologic stage in patients with bladder cancer larger than 3 cm. AB - OBJECTIVE: Bladder cancer (BCa) is the most common malignancy of the urinary tract. In this study, we aimed to evaluate the ability of preoperative neutrophil to-lymphocyte ratio (NLR) to predict pathologic stage of at the time of first transurethral resection of bladder tumor (TUR-BT) in patients with BCa larger than 3 cm. PATIENTS AND METHODS: Records of consecutive patients undergoing TUR BT for BCa with a diameter >3 cm were reviewed. A total of 222 patients were eligible for analysis, and were divided into two groups: 162 patients in non muscle-invasive BCa (NMIBC) group and 60 patients in muscle-invasive BCa (MIBC) group. Differences in preoperative blood parameters and NLR were evaluated between groups with an unequal variance t-test. RESULTS: In the NMIBC group, 59 patients had low-grade and 103 high-grade papillary urothelial carcinomas. 60 patients had T2 stage carcinoma. The mean age of the patients was 71.8 and 75.7 years, and mean NLR was 3.44 +/- 2.03 and 4.6 +/- 2.8 in NMIBC and MIBC groups, respectively. In terms of NLR, there was a statistically significant difference between the NMIBC and MIBC groups (p = 0.005). CONCLUSIONS: Our results showed that NLR might act as a significant predictive biomarker on the staging of BCa. Also, NLR could be used as a cost-effective, simple, common usable biomarker in urology clinic practice. PMID- 26957267 TI - Study on the relationship between miR-520g and the development of breast cancer. AB - OBJECTIVE: Breast cancer (BC) is one of the most common malignant tumors occurred in women. There is no sensitive and specific marker for early diagnosis, treatment and prognosis of breast cancer. It is suggested that miRNA may be a potential tumor marker for breast cancer. Mir-520g is considered to be associated with many tumors. This study aims to test the expression of mir-520g in peripheral blood of BC patients and healthy control. We also explored the relationship between mir-520g and several prognostic factors in breast cancer patients. PATIENTS AND METHODS: The peripheral blood of 86 cases with breast cancer (including 18 cases with stage 0, 24 cases of phase I, 20 cases of stage II, 24 cases of stage III) and 26 cases of healthy subjects were collected. The miR-520g level was measured by real-time quantitative PCR (RT qPCR) method. The correlation between plasma miR-520g level and the clinical stage, molecular subtype, receptors' expression and other factors related to the prognosis of the patients were examined. RESULTS: Plasma mir-520g expression levels were significantly higher in BC patients with lymph node metastatic and low differentiation degree grade (p = 0.033 and 0.016), and plasma miR-520g expression was significantly higher in breast cancer patients with mammary gland invasion (p < 0.01) and low expressed p53 (p = 0.0039). CONCLUSIONS: Highly expressed mir-520g is associated with lymph node metastasis and low differentiation of breast cancer, and also is associated with mammary gland invasion in breast cancer. This study suggests that mir-520g may be associated with some important prognostic factors in breast cancer patients, and may have a potential value for breast cancer marker. PMID- 26957268 TI - Identification of key genes involved in HER2-positive breast cancer. AB - OBJECTIVE: As an invasive cancer, breast cancer is the most common tumour in women and is with high mortality. To study the mechanisms of HER2-positive breast cancer, we analyzed microarray of GSE52194. MATERIALS AND METHODS: GSE52194 was downloaded from Gene Expression Omnibus including 5 HER2-positive breast cancer samples and 3 normal breast samples. Using cuffdiff software, differentially expressed genes (DEGs) and differentially expressed long non-coding RNAs (DE lncRNAs) were screened. Functions of the DEGs were analyzed by Gene Ontology (GO) and pathway enrichment analyses. Then, protein-protein interaction (PPI) network of the DEGs was constructed using Cytoscape and modules of the PPI network were screened by CFinder. Moreover, lncRNA-DEG pairs were screened. RESULTS: Total 209 lncRNA transcriptions were predicted, and 996 differentially expressed transcriptions were screened. Besides, FOS had interaction relationships with EGR1 and SOD2 separately in module E and F of the PPI network for the DEGs. Moreover, there were many lncRNA-DEG pairs (e.g. TCONS_00003876-EGR1, TCONS_00003876-FOS, lnc-HOXC4-3:1-FOS, lnc-HOXC4-3:1-BCL6B, lnc-TEAD4-1:1-FOS and lnc-TEAD4-1:1-BCL6B), meanwhile, co-expressed DEGs of TCONS_00003876, lnc-HOXC4 3:1 and lnc-TEAD4-1:1 were enriched in p53 signaling pathway, MAPK signaling pathway and cancer-related pathways, respectively. CONCLUSIONS: ANXA1, EGR1, BCL6, SOD2, FOS, TCONS_00003876, lnc-HOXC4-3:1 and lnc-TEAD4-1:1 might play a role in HER2-positive breast cancer. PMID- 26957269 TI - Low level of low-density lipoprotein cholesterol is related with increased hemorrhagic transformation after acute ischemic cerebral infarction. AB - OBJECTIVE: The prevalence of hemorrhagic transformation (HT) after acute ischemic infarction varies greatly. Risk factors of HT include ageing, severity of stroke, baseline hypertension, high NIH Stroke Scale (NIHSS) scores, hyperglycemia and cardioembolic infarction and low levels of low-density lipoprotein (LDL). We investigated the relationship between LDL, lipid profile and HT after acute ischemic infarction and suggested precautions for HT management. PATIENTS AND METHODS: Three hundred and forty-eight patients with acute infarction were included in the study. Fasting lipid profile was examined on the next morning following hospitalization. Either MRI GRE-T2*WI or CT was performed, one week after hospitalization to detect any cerebral microbleed (CMB) and hemorrhagic transformation. The lipid profiles examined included total cholesterol (TCH), triglyceride (TG), LDL and high-density lipoprotein (HDL). RESULTS: Among all the patients, HT was noted in 35 patients and non-HT in 313. As compared with non-HT group, HT group had lower levels of TCH, HDL and LDL, lower rates of leukoaraiosis and CMB, but higher scores of NIHSS, higher rates of diabetes mellitus, atrial fibrillation and urokinase thrombolysis. The multivariate binary logistic regression showed that cardioembolic infarction, infarction with undetermined etiology, high scores of NIHSS and diabetes were the risk factors of HT, while the protective factor was LDL (OR=0.654, 95% CI: 0.430-0.996, p=0.048). CONCLUSIONS: Low level of LDL is likely associated with increased HT after acute ischemic infarct, so for those patients with low level of LDL, high scores of NIHSS and cardioembolic infarction at admission, aggressive lipid- lowering treatment should be prescribed cautiously to prevent the incidence of HT. PMID- 26957270 TI - Proanthocyanidins affects the neurotoxicity of Abeta25-35 on C57/bl6 mice. AB - OBJECTIVE: To investigate the influence of procyanidins on the impairment of memory. MATERIALS AND METHODS: Thirty male C57bl/6 mice were divided into five groups: low, middle, and high concentration, model, and control groups. Intracerebroventricular injection of beta-amyloid25-35 in C57bl/6 mice caused an impairment of learning and memory. Next day, intragastric administration of procyanidins in the treatment group mice: (lower, middle and high concentration). Hoechst staining observed apoptosis of neuronal nuclei in the hippocampus. Immunohistochemistry determined synaptic remodeling reaction and the expression level of glial inflammatory response. RESULTS: Compared with the model group, the proportion of neuronal apoptosis decreased in the hippocampal CA1 region of the treatment group. The Synaptic (SYN) density was increased, and the level of activated astrocytes and microglia expression in the hippocampus was decreased. CONCLUSIONS: Procyanidins have a protective influence on Abeta25-35 mice hippocampus neuron, reducing nerve cell damage and eases learning and memory deficit. PMID- 26957271 TI - Onset of ulcerative colitis after thyrotoxicosis: a case report and review of the literature. AB - OBJECTIVE: Ulcerative colitis is a chronic disease that could be triggered by acute stressful events, such as gastrointestinal infections or emotional stress. PATIENTS AND METHODS: We reported the case of the onset of an ulcerative colitis after a thyrotoxicosis crisis and reviewed the literature about the relationships between thyroid dysfunctions and ulcerative colitis. RESULTS: A 38-year-old woman was diagnosed with ulcerative colitis after her third thyrotoxicosis crisis, two years after the diagnosis of Graves' disease. In this case, thyrotoxicosis acted as a trigger for ulcerative colitis onset. CONCLUSIONS: Hyperthyroidism could be a trigger able to elicit ulcerative colitis in susceptible patients. PMID- 26957272 TI - Irisin/FNDC5--An updated review. AB - OBJECTIVE: The irisin, recently identified novel molecule, has been shown to be secreted from fibronectin type III domain containing 5 (FNDC5) of skeletal muscle by an unknown protease. It has been proposed that this molecule plays an important role in converting the white adipose tissue to brown adipose tissue and regulating the energy expenditure. Apart from this, its expression and role in various other conditions such as inflammation, hippocampal neurogenesis, aging and other metabolic conditions have been reported. However, due to conflicting results, several issues have been raised regarding its expression, cleavage, circulating levels, detection, excretion, designation, etc. MATERIALS AND METHODS: Complete literature survey was performed using PubMed database search to gather available information regarding FNDC5/irisin. RESULTS AND CONCLUSIONS: The present review discussed on the discovery of irisin, its possible role in physiological and pathological conditions and controversies. It also discussed the current challenges and future perspectives. PMID- 26957273 TI - Blood and sputum biomarkers in COPD and asthma: a review. AB - Chronic obstructive pulmonary disease (COPD) and asthma are lung inflammatory diseases that represent major public health problems. The primary, and often unique, method to evaluate lung function is spirometry, which reflects disease severity rather than disease activity. Moreover, its measurements strictly depend on patient's compliance, physician's expertise and data interpretation. The limitations of clinical history and pulmonary function tests have encouraged focusing on new possible tracers of diseases. The increase of the inflammatory response in the lungs represents an early pathological event, so biological markers related to inflammation may play key roles in earlier diagnosis, evaluation of functional impairment and prognosis. Biomarkers are measurable indicators associated with the presence and/or severity of a biological or pathogenic process, which may predict functional impairment, prognosis and response to therapy. The traditional approach based on invasive techniques (bronchoalveolar lavage and biopsies) may be replaced, at least in part, by using less invasive methods to collect specimens (sputum and blood), in which biomarkers could be measured. Proteomics, by the association between different protein profiles and pathogenic processes, is gaining an important role in pulmonary medicine allowing a more precise discrimination between patients with different outcomes and response to therapy. The aim of this review was to evaluate the use of biomarkers of airway inflammation in the context of both research and clinical practice. PMID- 26957274 TI - Effects of radiological extent on neutrophil/lymphocyte ratio in pulmonary sarcoidosis. AB - OBJECTIVE: Determining the severity of sarcoidosis is based on the clinical and radiological findings of the disease and the changes in pulmonary function test results. On the other hand; studies are ongoing for objective and easy markers in this respect. Neutrophil/lymphocyte ratio (NLR) is shown as a good prognostic marker for inflammation due to tissue damage in recent clinical trials. In this study, we aimed to identify the possible relationship between NLR and radiological extent of sarcoidosis. PATIENTS AND METHODS: Data of 122 patients included in the study were evaluated retrospectively in terms of age, gender, complete blood count parameters, erythrocyte sedimentation rate (ESR) and radiological findings at the time of diagnosis. RESULTS: Mean NLR and ESR were significantly different between radiological stages according to chest radiography and also total HRCT score (THS) groups according to parenchymal involvement in thorax tomography (p <0.05). Mean NLR was found to be 1.28 in stage 0, 1.65 in stage 1, 2.88 in stage 2,5.47 in stage 3 and 8.48 in stage 4; 1.63 in THS group 1, 2.01 in group 2, 3.47 in group 3 and 5.46 in group 4. There were statistically significant positive correlations between NLR and WBC, NLR and THS, NLR and ESR, THS and ESR, ESR and platelet, WBC and #neutrophil, WBC and #lymphocyte. CONCLUSIONS: Our findings suggest that NLR might be used as a prognostic marker in pulmonary sarcoidosis. PMID- 26957275 TI - Functional role of NKX2-5 and Smad6 expression in developing rheumatic heart disease. AB - OBJECTIVE: Rheumatic heart disease (RHD) results due to the cross reaction of the host immune system when it develops immunity against group A streptococcal infection. This autoimmune disease progress with different pathological conditions and the genes associated with it are still less understood. MATERIALS AND METHODS: To understand the role of NKX2-5 and Smad-6 in developing an RHD, we successfully developed RHD model using BALB/c mice and we evaluate the expression of NKX2-5 and Smad-6 in different conditions. RESULTS: The disease conditions are confirmed through histological sectioning of RHD heart tissue with its associated Aschoff bodies. The histological of control heart tissue in the absence of NKX2-5 looks abnormal with an enlarged nucleus and in the absence of Smad-6 the solid nature of heart tissue loosens. The mice developed a complex form of acute RHD with tissue hardening in the absence of either NKX2-5 or Smad-6 which are confirmed in NKX2-5 or Smad-6 null mice. Immunohistochemical studies reveal that the NKX2-5 and Smad-6 expression get down regulated on developing with RHD. Through experiments, we detected that both Nkx2-5 and Smad-6 are both inter dependable and it negatively regulated each other by inhibiting them. In the absence of NKX2-5 or Smad-6, a severe form of RHD is observed together with down regulation of either NKX2-5 or Smad-6. CONCLUSIONS: The present investigation of NKX2-5 and Smad-6 in RHD provides a new insight of data that helps to understand the disease pathogenesis. PMID- 26957276 TI - Relationship between B-type natriuretic peptide and short-term prognosis in non diabetic patients with ST-segment elevation myocardial infarction. AB - OBJECTIVE: To investigate the differences of the B-type natriuretic peptide (BNP) levels in serum or plasma of the STEMI patients with different infarction sites. To explore the relationship between the BNP level and the short-term prognosis in patients with ST-segment elevation myocardial infarction (STEMI). PATIENTS AND METHODS: A total of 216 STEMI patients were enrolled in this study from June 2012 to June 2014. All patients received coronary angiography (CAG). Based on electrocardiography (ECG) and CAG results, patients were divided into three groups. Group A included 80 patients with anterior/lateral wall myocardial infarction, group B included 76 patients with inferior/posterior wall myocardial infarction and group C included 60 patients with right ventricular myocardial infarction. We enrolled 53 patients with normal CAG results as Group D. BNP levels were compared among these groups. and according to BNP levels, all patients were subdivided into normal BNP group (< 100 ng/mL, n = 53), mild-higher BNP group (100-400 ng/mL, n = 105) and marked-higher BNP group (>= 400 ng/mL, n = 58). The occurrence of major adverse cardiovascular events (MACE) including secondary heart failure, severe arrhythmia, post-infarction angina, recurrent myocardial infarction, and cardiac death within 6 months after disease onset were assessed. RESULTS: BNP levels showed a gradually decreasing trend in groups A, B, C and D (p < 0.05). Significant differences in left ventricular ejection fraction (LVEF) were found among normal BNP group, mild-high BNP group and marked-higher BNP group (p < 0.05). The MACE occurrence presented no statistical differences between normal BNP group and mild-higher BNP group (p > 0.05). The MACE prevalence in marked-higher BNP group was significantly higher than normal BNP group and mild-higher BNP group (p < 0.05). CONCLUSIONS: BNP levels can be used as a clinical indicator to predict short-term prognosis in STEMI patients. PMID- 26957277 TI - Evaluation of heart rate variability and night-time blood pressure measurements in patients with idiopathic sudden sensorineural hearing loss. AB - OBJECTIVE: The aim of this study is to investigate the role of the autonomic nervous system in the etiology of idiopathic sudden sensorineural hearing loss (ISSHL) by measuring heart rate variability (HRV) and night-time blood pressure levels. PATIENTS AND METHODS: A total of 58 patients, 31 ISSHL patients (group 1) and 27 healthy volunteers (control group; group 2), were included in this study. Clinical and ambulatory blood pressure measurements and Holter electrocardiography were performed in both groups. After these evaluations, HRV parameters and night-time blood pressure values were determined. RESULTS: Mean systolic blood pressure (SBP) and mean diastolic blood pressure (DBP) measured at night-time were higher in group 1 compared to group 2 (p < 0.05). Heart rate variability parameters were lower in group 1 than in group 2. CONCLUSIONS: In patients with ISSHL, elevated blood pressure at night-time and reduced heart rate variability suggest that autonomic nervous system dysfunction might play a role in the etiopathogenesis of the disease. The measurements of ambulatory blood pressure and heart rate variability can reveal more enlightening data in the determination of the etiology of ISSHL and guiding the treatment. PMID- 26957278 TI - Infection with Plasmodium chabaudi diminishes plasma immune complexes and ameliorates the histopathological alterations in different organs of female BWF1 lupus mice. AB - OBJECTIVE: To determine the effect of Plasmodium chabaudi infection on the plasma level of circulating immune complexes (CICs), haemoglobin (Hb) content, urine profile, and histological features of female BWF1 mice, the murine model of systemic lupus erythematosus (SLE). MATERIALS AND METHODS: A total of 30 female BWF1 lupus mice were randomly divided into three groups as follows: group (I) control group (P. chabaudi uninfected); group (II) lupus mice infected with live P. chabaudi; group (III) lupus mice infected with irradiated P. chabaudi. Urine samples were daily collected from the second week-post infection. Mice from the three groups were killed at day 14 post-infection and heparinized blood was collected for further haemoglobin contents and plasma analysis. Paraffin-embedded kidney, liver, lung, heart, brain, ovary and skin tissues were stained with Hematoxylin and Eosin (H&E) and examined under light microscope. RESULTS: Our results reveal that infection of lupus mice with live P. chabaudi was associated with an increase in urinary Hb and a decrease in plasma Hb and CIC levels. Interestingly, infection of lupus mice with live P. chabaudi ameliorates the histopathological alterations mediated by lupus disease in kidney tissues. Although no parasite sequestration was observed in any of the investigated organs, P. chabaudi pigment deposition was observed in the liver of both live and irradiated P. chabaudi infected groups. CONCLUSIONS: This study in lupus prone BWF1 mice indicated that gamma-irradiated P. chabaudi infection has the desired lupus ameliorating effect without negative effects of malaria which assist the understanding of different responses to plasmodium sp. infection in human lupus patients. PMID- 26957279 TI - Effects of hemodialysis and hemoperfusion on inflammatory factors and nuclear transcription factors in peripheral blood cell of multiple organ dysfunction syndrome. AB - OBJECTIVE: To investigate the effects of hemodialysis (HD) and hemoperfusion (HP) on inflammatory factors and nuclear transcription factors in peripheral blood cell of multiple organ dysfunction syndrome (MODS) patients. PATIENTS AND METHODS: 92 cases of MODS patients undergoing maintained hemodialysis in our hospital were randomly divided into the control group and observation group. The control group was treated with conventional hemodialysis (HD), the observation group was treated with hemoperfusion combined therapy (HD+HP) based on the control group. The levels of serum creatinine (SCR), serum total cholesterol (TC), blood urea nitrogen (BUN) and serum albumin (Alb) were compared and analyzed between two groups before and after treatment. The levels of NK-kappaB p65 in the white cell of peripheral blood were compared between two groups before and after treatment by Western blot. The levels of inflammatory factors TNF-alpha and IL-6 in peripheral blood were detected between two groups before and after treatment using ELISA method. RESULTS: Compared with the control group, the levels of Scr, BUN and TC were significantly decreased, while the level of Alb was significantly increased (p < 0.05). The level of cytoplasm NK-kappaB p65 protein in peripheral blood was significantly increased in the observation group, while the level of nuclear NK-kappaB p65 in peripheral blood was significantly decreased (p < 0.05). CONCLUSIONS: Hemodialysis combined with hemoperfusion in treating MODS patients could significantly improve the biochemical indicators, effectively remove the inflammatory mediums, and significantly inhibit the activation of NK-kappaB. PMID- 26957280 TI - Treatment of infantile hemangioma by intralesional injection of propranolol combined with compound betamethasone. AB - OBJECTIVE: To explore the effective and convenient methods of infantile hemangioma treatment. PATIENTS AND METHODS: From October 2010 to June 2014, 31 infantile hemangioma patients admitted to our hospital, were administered propranolol combined with betamethasone injection treatment of lesions. RESULTS: All patients were followed for 6 months-2 years. In treated patients, 24 patients with tumor had complete or nearly complete remission while 6 patients showed partial regression. In 1 patient the tumor had no evident change. Adverse reactions of the therapy included local tissue atrophy, ulcer and anorexia, mild diarrhea in the early treatment. Ulcer wound healed after dressing change. CONCLUSIONS: Treatment of infantile hemangioma lesions with an injection of propranolol combined with betamethasone showed good efficacy. The method is safe and reliable with clear curative effect, convenient, less complicated, and especially suitable for patients with a small area infantile hemangioma. PMID- 26957281 TI - Allopurinol ameliorates cardiac function in non-hyperuricaemic patients with chronic heart failure. AB - OBJECTIVE: This study sought to observe the effects of allopurinol on the cardiac function of non-hyperuricaemic patients with chronic heart failure and determine the safety of allopurinol for clinical applications. PATIENTS AND METHODS: A group of 125 consecutive cases of non-hyperuricaemic patients with chronic heart failure who were treated at Chongqing Emergency Medical Centre between July 2011 and June 2012 were enrolled and were randomly divided into allopurinol (300 mg/day) group (n=62) and control group (n=63). During the six months treatment period, levels of cardiac function, brachial artery endothelial function, inflammatory cytokines, and biochemical markers were routinely examined. RESULTS: After three months of allopurinol treatment, patients exhibited an increase in flow-mediated vasodilatation (FMD) of brachial artery, whereas, after six months of treatment, the cardiac function classification was improved; plasma levels of brain natriuretic peptide and tumour necrosis factor-a were decreased; left ventricular internal diameter was diminished; and the ejection fraction was increased (p<0.01 for all the parameters) in patients. Serum uric acid level was decreased during the treatment period for both groups, with no significant difference between the two groups. Liver and kidney dysfunction was not observed among the study participants, and no significant increase in creatine kinase level was detected for either treatment group. CONCLUSIONS: For non hyperuricaemic patients with chronic heart failure, the addition of six months of allopurinol therapy was safe and effective. Moreover, in these patients, allopurinol treatment not only can significantly ameliorate the left ventricular function and reduce the level of inflammatory factors but could also improve endothelial function. PMID- 26957282 TI - A novel phospholipid delivery system of curcumin (Meriva(r)) preserves muscular mass in healthy aging subjects. AB - OBJECTIVE: Curcumin is known to interrupt pro-inflammatory signalling and increases anti-oxidant protection, thus inhibiting the expression of inflammatory cytokines and the expression and function of inducible inflammatory enzymes. Together, these effects contribute to limit the onset and the progression of sarcopenia, due to the major role played by inflammation in the pathophysiology of this disease. This registry study evaluates the effects of Meriva(r) supplementation in otherwise healthy elderly subjects. PATIENTS AND METHODS: This was a registry, supplement study, conducted in healthy subjects > 65 years with apparent loss of strength and tiredness who freely decided to start one of the following interventions: (1) standard management (exercise, balanced diet including proteins) (n = 33); (2) standard management + Meriva(r) one tablet/day (n = 31); (3) standard management + Meriva(r) one tablet/day + other supplementation (n = 22). A number of functional and biochemical parameters were evaluated at baseline and after three months (hand grip, weight lifting, time/distance before feeling tired after cycling, walking and climbing stairs; general fitness, proteinuria, oxidative stress, Karnofsky scale; left ventricular ejection fraction). RESULTS: Significant improvements in all parameters, with respect to baseline values, were observed in the two supplementation groups (p < 0.05 for all comparisons). On the other hand, no improvement was observed in the standard management-only group. At three months, inter-group comparison revealed a statistical advantage in all parameters for both supplementation groups compared with the standard management-only group (p < 0.05 for all comparisons). CONCLUSIONS: Our registry study shows that the addition of Meriva(r) - either or not combined with other nutritional supplements - to standardized diet and exercise plan contributes to improve strength and physical performance in elderly subjects, potentially preventing the onset of sarcopenia. PMID- 26957283 TI - The protective effects of pomegranate on liver and remote organs caused by experimental obstructive jaundice model. AB - OBJECTIVE: We aimed to investigate the protective potential of pomegranate extract on the liver and remote organs in rats with obstructive jaundice. MATERIALS AND METHODS: The rats were split into 4 groups. In Group 1 (G1) (sham group) rats, the common bile duct was mobilized without any ligation. Group 2 (G2) received a combination of the sham operation and synchronous treatment with pomegranate. Group 3 (G3) received common bile duct ligation (CBDL). Group 4 (G4) were subjected to CBDL and treatment with pomegranate. After 8 days, we measured total oxidative status (TOS) and antioxidant capacity in the rats' liver tissue and remote organs, and evaluated blood levels of malondialdehyde and total antioxidant capacity (TAC). RESULTS: G3 rats showed significantly raised malondialdehyde level as compared to G1 rats (p < 0.001). Following the pomegranate therapy, a decrease in malondialdehyde was observed (p = 0.015). TAC levels were significantly raised in the G3 rats compared to the G1 rats (p = 0.004). TAC levels dropped after pomegranate therapy (p = 0.011). CBDL caused elevated TOS levels in the liver and remote organs, with a statistically significant increase in the lung tissue (p = 0.002). TOS levels in the CBDL groups decreased after pomegranate treatment (p < 0.001). CONCLUSIONS: This study reveals the marked protective effect of pomegranate on the liver and remote organs in obstructive jaundice. PMID- 26957284 TI - Selenium protects reproductive system and foetus development in a rat model of gestational lead exposure. AB - OBJECTIVE: Lead is a common environmental contaminant. Lead accumulation in the body is especially dangerous for pregnant women and newborns. Selenium is a trace element which may rectify the damaging effects of lead. Here we tested potential protective effects of selenium against gestational lead exposure. MATERIALS AND METHODS: Pregnant SD rats were exposed to 200 mg/L of lead acetate (given with water), with or without sodium selenite supplementation (2-8 mg/kg/day via intragastric administration). Pregnant rats not exposed to lead or selenium served as control animals. The outcomes in pregnant rats were serum lead and selenium levels, reproductive hormone (follicle-stimulating hormone, luteinizing hormone, prolactin, oestradiol, progesterone) levels, and uterine and ovarian morphological changes. The outcomes in the offspring were sex differentiation, survival rates (day 21 after birth), weight (days 0-35 after birth), weight of reproductive organs, and puberty onset (foreskin separation or vaginal opening). RESULTS: Selenium supplementation dose-dependently decreased serum lead levels, rectified reproductive hormone levels, and attenuated reproductive morphological changes caused by lead exposure. Lead exposure did not affect sex differentiation, but significantly (p < 0.05 vs. control animals) decreased the offspring weight on days 0-28 and the weight of their reproductive organs. Furthermore, lead exposure delayed the onset of puberty. These pathological changes were dose-dependently rectified or attenuated by selenium supplementation. CONCLUSIONS: Gestational lead exposure causes damages to the reproductive system of pregnant rats, and negatively modulates growth and reproductive system development of the offspring. These adverse effects are rectified or attenuated by selenium supplementation. PMID- 26957285 TI - Bioinformatics-based design of novel antigenic B-cell linear epitopes of Deinagkistrodon acutus venom. AB - OBJECTIVE: With the help of bioinformatics analysis, we wished to develop a novel antivenom against the Deinagkistrodon (D.) acutus snake venom using B-cell linear epitopes of three primary toxins (serine protease, metalloprotease, and phospholipase A2). MATERIALS AND METHODS: cDNA sequences of three toxins of D. acutus venom were retrieved from the NCBI database. B-cell linear epitopes were predicted using DNAStar and the website server software provided by IEDB. Then, the sequences of the predicted epitopes were artificially synthesized and inserted into the vector pET-32a-c(+). Recombinant antigen peptide was expressed and purified. BALB/c mice were immunized with the recombinant antigen peptide. The immunoprotective effect of this novel antivenom was measured by neutralization of venom haemorrhagic activity. RESULTS: Six epitopes were obtained by bioinformatics analysis. ELISA analysis showed that antibody titre was >8,000 against snake venom and >64,000 against the recombinant peptide. Neutralization assays confirmed that the developed antivenom could effectively reduce the haemorrhagic activity of snake venom. CONCLUSIONS: Six B-cell linear epitopes of D. acutus snake venom were predicted by bioinformatics analysis and successfully utilized to produce a novel antivenom. PMID- 26957287 TI - Developing a complex systems perspective for medical education to facilitate the integration of basic science and clinical medicine. AB - RATIONALE, AIMS AND OBJECTIVES: The purpose of medical education is to produce competent and capable professional practitioners who can combine the art and science of medicine. Moreover, this process must prepare individuals to practise in a field in which knowledge is increasing and the contexts in which that knowledge is applied are changing in unpredictable ways. The 'basic sciences' are important in the training of a physician. The goal of basic science training is to learn it in a way that the material can be applied in practice. Much effort has been expended to integrate basic science and clinical training, while adding many other topics to the medical curriculum. This effort has been challenging. The aims of the paper are (1) to propose a unifying conceptual framework that facilitates knowledge integration among all levels of living systems from cell to society and (2) illustrate the organizing principles with two examples of the framework in action - cybernetic systems (with feedback) and distributed robustness. METHODS: Literature related to hierarchical and holarchical frameworks was reviewed. RESULTS: An organizing framework derived from living systems theory and spanning the range from molecular biology to health systems management was developed. The application of cybernetic systems to three levels (regulation of pancreatic beta cell production of insulin, physician adjustment of medication for glycaemic control and development and action of performance measures for diabetes care) was illustrated. Similarly distributed robustness was illustrated by the DNA damage response system and principles underlying patient safety. CONCLUSIONS: Each of the illustrated organizing principles offers a means to facilitate the weaving of basic science and clinical medicine throughout the course of study. The use of such an approach may promote systems thinking, which is a core competency for effective and capable medical practice. PMID- 26957286 TI - Graded perturbations of metabolism in multiple regions of human brain in Alzheimer's disease: Snapshot of a pervasive metabolic disorder. AB - Alzheimer's disease (AD) is an age-related neurodegenerative disorder that displays pathological characteristics including senile plaques and neurofibrillary tangles. Metabolic defects are also present in AD-brain: for example, signs of deficient cerebral glucose uptake may occur decades before onset of cognitive dysfunction and tissue damage. There have been few systematic studies of the metabolite content of AD human brain, possibly due to scarcity of high-quality brain tissue and/or lack of reliable experimental methodologies. Here we sought to: 1) elucidate the molecular basis of metabolic defects in human AD-brain; and 2) identify endogenous metabolites that might guide new approaches for therapeutic intervention, diagnosis or monitoring of AD. Brains were obtained from nine cases with confirmed clinical/neuropathological AD and nine controls matched for age, sex and post-mortem delay. Metabolite levels were measured in post-mortem tissue from seven regions: three that undergo severe neuronal damage (hippocampus, entorhinal cortex and middle-temporal gyrus); three less severely affected (cingulate gyrus, sensory cortex and motor cortex); and one (cerebellum) that is relatively spared. We report a total of 55 metabolites that were altered in at least one AD-brain region, with different regions showing alterations in between 16 and 33 metabolites. Overall, we detected prominent global alterations in metabolites from several pathways involved in glucose clearance/utilization, the urea cycle, and amino-acid metabolism. The finding that potentially toxigenic molecular perturbations are widespread throughout all brain regions including the cerebellum is consistent with a global brain disease process rather than a localized effect of AD on regional brain metabolism. PMID- 26957288 TI - Vertebral body morphology is associated with incident lumbar vertebral fracture in postmenopausal women. The OFELY study. AB - We investigate the predictive role of vertebral anterior cortical curvature and height heterogeneity in the occurrence of vertebral fractures in postmenopausal women. Women who will fracture had shorter vertebral height, greater heterogeneity of height than those who will not fracture, and their anterior vertebral body edge was less concave. INTRODUCTION: Vertebral morphology has been demonstrated to be associated with further risk of fracture. The aim of this study was to analyze vertebral anterior cortical curvature (Ct.curv) and vertebral height heterogeneity in postmenopausal women before the occurrence of a vertebral fracture. METHODS: This case-control study included 29 postmenopausal women who have underwent incident lumbar vertebral fractures (mean age 71 +/- 9 years, mean time to fractures 9 +/- 4 years), age-matched with 57 controls. From lateral X-rays of lumbar spine radiographs (T12 to L4), the following parameters were measured: (1) the posterior, middle, and anterior vertebral heights; (2) the heterogeneity of heights evaluated by the coefficient of variation of these three variables; (3) antero-posterior width, a 2D estimator of cross-sectional area; and (4) Ct.curv. RESULTS: Mean vertebral heights were significantly lower among women who fractured than in controls (p < 0.05). The anterior and middle heights were significantly lower at L4 and L3 levels in fracture group (p = 0.02). The heterogeneity of vertebral height was significantly greater in the fracture group (p = 0.003). In addition, fractured patients had a significantly higher Ct.curv on L3 (p = 0.04). After adjustment for bone mineral density (BMD), only the heterogeneity of vertebral height remained significant (p = 0.005). CONCLUSION: The current case-control study confirmed the association between vertebral height and occurrence of future vertebral fracture in postmenopausal women. The vertebrae with the smallest Ct.curv tended to fracture less often, and the heterogeneity of vertebral heights was associated with future fracture independently of BMD. An additional validation in a prospective study would be needed to confirm these initial results. PMID- 26957290 TI - Paracetamol 325 mg/tramadol 37.5 mg effect on pain during needle electromyography: a double-blind crossover clinical trial. AB - Needle insertion during electromyography (EMG) may cause varying levels of pain that could lead to inaccurate assessment and premature termination of the procedure. The aim of this study is to compare paracetamol 325 mg/tramadol 37.5 mg with placebo in relieving pain before EMG. This is a randomized, crossover, placebo-controlled, double-blind clinical trial; forty-four healthy individuals, including 27 males with a mean age of 35.3 years (range 18-59 years), entered this study. The needles were inserted unilaterally 2 h after administration of two analgesic tablets of paracetamol 325 mg/tramadol 37.5 mg or two placebo tablets. The pain was scored through a 100-mm visual analog scale (VAS) immediately and 2 h after the procedure. The side effects were also recorded. Within a week, the procedure was repeated on the other upper limb, changing the treatment and placebo. The immediate and 2-h VAS scores were notably lower after administration of treatment compared to placebo (immediate pain: 17.5 +/- 12.8 vs. 32.1 +/- 16.0, P < 0.001; and 2-h pain: 1.6 +/- 5.6 vs. 5.8 +/- 7.9, P = 0. 002). There was a higher prevalence of side effects when treatment was used (48 vs. 9 %, P < 0.001). Although most symptoms were mild, transient and resolved without medical interventions, on one occasion a volunteer experienced brief loss of consciousness and one subject had severe vertigo that required hospitalization and fluid therapy. Paracetamol 325 mg/tramadol 37.5 mg administration prior to EMG could effectively alleviate pain. Further application of this medication in patients with neuromuscular disorders would warrant additional clinical trials, particularly considering the adverse events. PMID- 26957291 TI - Constructing a Computer-Aided Differential Diagnosis Engine from Open-Source APIs. AB - This paper describes the design and implementation of an application that parses and analyzes radiology report text to provide a radiologic differential diagnosis. The system was constructed using a combination of freely available web based APIs and originally developed during the Society for Imaging Informatics in Medicine (SIIM) 2014 Hackathon. Continued development has refined and increased the accuracy of the algorithm. This project demonstrates the power and possibilities of combining existing technologies to solve unique problems as well as the stimulus of the hackathon setting to spur innovation. PMID- 26957292 TI - A Business Analytics Software Tool for Monitoring and Predicting Radiology Throughput Performance. AB - Business analytics (BA) is increasingly being utilised by radiology departments to analyse and present data. It encompasses statistical analysis, forecasting and predictive modelling and is used as an umbrella term for decision support and business intelligence systems. The primary aim of this study was to determine whether utilising BA technologies could contribute towards improved decision support and resource management within radiology departments. A set of information technology requirements were identified with key stakeholders, and a prototype BA software tool was designed, developed and implemented. A qualitative evaluation of the tool was carried out through a series of semi-structured interviews with key stakeholders. Feedback was collated, and emergent themes were identified. The results indicated that BA software applications can provide visibility of radiology performance data across all time horizons. The study demonstrated that the tool could potentially assist with improving operational efficiencies and management of radiology resources. PMID- 26957289 TI - Decoding Lamarck-transgenerational control of metabolism by noncoding RNAs. AB - The concept of epigenetic transgenerational inheritance (ETI) posits that lifetime experiences in parents, particularly fathers, alter the phenotypic trajectory of their progeny independently of Mendelian genetics. Based on evidence from population studies and laboratory-controlled studies in syngenic animals, this long-term discredited so-called Lamarckian inheritance gained prominent attention. This article aims to summarize the current knowledge about ETI in lower and in higher organisms as well as in human cohorts and elaborates on epigenetic principles potentially underlying this nongenetic mode of heredity. Special attention is given to-small and long-noncoding RNAs in male gametes that recently emerged as a molecular sensor of organismal metabolic states which can ultimately relay information across the germline barrier by translating environmental cues into (epigenetic) changes in zygotic gene expression. PMID- 26957293 TI - Exploring Attitudes of Children 12-17 Years of Age Toward Electronic Cigarettes. AB - The purpose of this study is to explore electronic cigarettes (EC) use among youth. Focus group sessions with youth (aged 12-17) were held to explore their knowledge and attitudes about EC use. Content analysis techniques were used. There has been an increase in the visibility and accessibility of EC in the past few years among youth. Compared with conventional cigarettes (CC), youth indicated that they would be more willing to use EC under their peer influence. This was motivated by the perception that EC were less harmful. Among youth EC are perceived as less harmful, easier to access and use than CC. Youth do not appear to have received much education about EC. However, they were not convinced that EC were risk free. Clear and unambiguous education about the risk of engaging in any form of smoking/vaping and enforcement of access restrictions appear to be required. PMID- 26957294 TI - Distinctive Pattern of Serum Elements During the Progression of Alzheimer's Disease. AB - Element profiling is an interesting approach for understanding neurodegenerative processes, considering that compelling evidences show that element toxicity might play a crucial role in the onset and progression of Alzheimer's disease (AD). Aim of this study was to profile 22 serum elements in subjects with or at risk of AD. Thirtyfour patients with probable AD, 20 with mild cognitive impairment (MCI), 24 with subjective memory complaint (SMC) and 40 healthy subjects (HS) were included in the study. Manganese, iron, copper, zinc, selenium, thallium, antimony, mercury, vanadium and molybdenum changed significantly among the 4 groups. Several essential elements, such as manganese, selenium, zinc and iron tended to increase in SMC and then progressively to decrease in MCI and AD. Toxic elements show a variable behavior, since some elements tended to increase, while others tended to decrease in AD. A multivariate model, built using a panel of six essential elements (manganese, iron, copper, zinc, selenium and calcium) and their ratios, discriminated AD patients from HS with over 90% accuracy. These findings suggest that essential and toxic elements contribute to generate a distinctive signature during the progression of AD, and their monitoring in elderly might help to detect preclinical stages of AD. PMID- 26957296 TI - Erratum to: 'Effectiveness of a behavioral incentive scheme linked to goal achievement: study protocol for a randomized controlled trial'. PMID- 26957295 TI - Impaired function of the intestinal barrier in a novel sub-health rat model. AB - Sub-health is a state featuring a deterioration in physiological function between health and illness, and the sub-health condition has surfaced as life-threatening in humans. The aim of the present study was to establish a sub-health model in rats, and investigate the function of the intestinal barrier in the sub-health rats and rats following intervention. To establish a sub-health model, the rats were subjected to a high-fat and sugar diet, motion restriction and chronic stress. Their serum glucose and triglyceride levels, immune function and adaptability were then measured. The levels of diamine oxidase and D-lactic acid in the plasma were analyzed as markers of the intestinal permeability. The protein and mRNA expression levels of anti-apoptotic YWHAZ in the colonic tissue was detected using immunohistochemical and reverse transcription-quantitative polymerase chain reaction analyses In the present study, the sub-health rat model was successfully established, and sub-health factors increased the intestinal permeability and reduced the expression of YWHAZ. Providing sub-health rats with normal living conditions did not improve the function of the intestinal barrier. In conclusion, the results of the present study demonstrated that intestinal disorders in the sub-health rat model may result from the damage caused by reduce intestinal barrier function as well as the decreased expression levels of YWHAZ. Additionally, rats in the sub-health condition did not recover following subsequent exposure to normal living conditions, suggesting that certain exercises or medical intervention may be necessary to improve sub-health symptoms. PMID- 26957297 TI - Erratum to: An Analysis of Training, Generalization, and Maintenance Effects of Primary Care Triple P for Parents of Preschool-Aged Children with Disruptive Behavior. PMID- 26957298 TI - Genetic variability of human adenovirus type 8 causing epidemic and sporadic cases of keratoconjunctivitis. AB - Human adenovirus type 8 (HAdV-8) is a main aetiological agent of keratoconjunctivitis. It has been reported from both epidemic and sporadic cases. The aim of our study was to investigate the genetic characteristics and chronological pattern of HAdV-8 strains that have been circulating in Tunisia over a 14-year period. Fourteen HAdV-8 isolates from a keratoconjunctivitis outbreak that occurred in 2000 and from sporadic cases between 2001 and 2013 were studied. Nucleotide sequences from the hexon, fiber and penton base genes were determined, including hypervariable regions of the hexon (loops 1 and 2), the fiber (knob) and the penton base (HVR 1 and RGD loops). The sequences were compared to each other and to those of HAdV-8 strains. The Tunisian sequences were unique when compared to the previously published sequences. Also, despite a relatively low degree of genetic variation in the three genomic regions, phylogenetic analysis and alignment of amino acid sequences showed that the sequence from the year 2000 and two other sequences from the year 2013 were similar to each other and differed from the isolates that circulated in the intervening year by two main amino acid changes in the loop 1 hexon gene and the knob-fiber gene. Our results confirm the genetic variability of HAdV-8 and document the chronological changes of circulating genetic variants. PMID- 26957299 TI - Adenosine Monophosphate-Activated Protein Kinase Abates Hyperglycaemia-Induced Neuronal Injury in Experimental Models of Diabetic Neuropathy: Effects on Mitochondrial Biogenesis, Autophagy and Neuroinflammation. AB - Impaired adenosine monophosphate kinase (AMPK) signalling under hyperglycaemic conditions is known to cause mitochondrial dysfunction in diabetic sensory neurons. Facilitation of AMPK signalling is previously reported to ameliorate inflammation and induce autophagic response in various complications related to diabetes. The present study assesses the role of AMPK activation on mitochondrial biogenesis, autophagy and neuroinflammation in experimental diabetic neuropathy (DN) using an AMPK activator (A769662). A769662 (15 and 30 mg/kg, i.p) was administered to Sprague-Dawley rats (250-270 g) for 2 weeks after 6 weeks of streptozotocin (STZ) injection (55 mg/kg, i.p.). Behavioural parameters (mechanical/thermal hyperalgesia) and functional characteristics (motor/sensory nerve conduction velocities (MNCV and SNCV) and sciatic nerve blood flow (NBF)) were assessed. For in vitro studies, Neuro2a (N2A) cells were incubated with 25 mM glucose to simulate high glucose condition and then studied for mitochondrial dysfunction and protein expression changes. STZ administration resulted in significant hyperglycaemia (>250 mg/dl) in rats. A769662 treatment significantly improved mechanical/thermal hyperalgesia threshold and enhanced MNCV, SNCV and NBF in diabetic animals. A769662 exposure normalised the mitochondrial superoxide production, membrane depolarisation and markedly increased neurite outgrowth of N2A cells. Further, AMPK activation also abolished the NF-kappaB-mediated neuroinflammation. A769662 treatment increased Thr-172 phosphorylation of AMPK results in stimulated PGC-1alpha-directed mitochondrial biogenesis and autophagy induction. Our study supports that compromised AMPK signalling in hyperglycaemic conditions causes defective mitochondrial biogenesis ultimately leading to neuronal dysfunction and associated deficits in DN and activation of AMPK can be developed as an attractive therapeutic strategy for the management of DN. PMID- 26957300 TI - Monocarboxylate Transporter 1 in the Medial Prefrontal Cortex Developmentally Expresses in Oligodendrocytes and Associates with Neuronal Amounts. AB - Lactate is an energy substrate in adult brain especially when glucose is withdrawn or only lactate is present as main energy source. Besides, the most abundant lactate transporter in brain-monocarboxylate transporter 1 (MCT1)-was recognized recently. Despite this, MCT1 expressions in central nervous system (CNS) have not been clearly understood. Medial prefrontal cortex (mPFC), taking part in many higher executive functions in brain, is chosen here for observing MCT1 expressions in mice in 12 months. As results showed, MCT1 is gradually increased from an initial level at the 1st week to a high level at the 6th week and then gradually decreased to a low level at the 12th month. Besides, neuronal amounts change in a similar trend as MCT1 that neurons at the 6th week are more than that of at the 1st week and the 12th month. Also, MCT1 expressions are highly correlated with neuronal amounts, while MCT1 does not localize within neurons, instead localize around axons. On the other hand, MCT1 does localize to oligodendrocytes (OLs) without localizing to other glial cells (astrocytes and microglias). Importantly, the amounts of OLs change in a similar trend as MCT1, while the amounts of other glial cells do not change obviously in the mPFC in vivo in 12 months. These results demonstrate that the changeable expressions of MCT1 in the mPFC in vivo in 12 months may be mainly contributed by OLs and associate with the neuronal amounts. Above all, it infers that in vivo, MCT1 which is changeably expressed in OLs may further affect neuronal amounts in the mPFC in 12 months. PMID- 26957301 TI - L-theanine, a Component of Green Tea Prevents 3-Nitropropionic Acid (3-NP) Induced Striatal Toxicity by Modulating Nitric Oxide Pathway. AB - L-theanine is unique amino acid which readily crosses blood brain barrier and possesses neuroprotective potential against neurodegenerative disorders including Huntington disease (HD). HD is characterized by selective loss of GABAergic medium spiny neurons. 3-nitropropionic acid (3-NP) induces a spectrum of HD-like neuropathology in rat striatum and widely used as experimental tool to study HD. Therefore, the present study was intended to investigate the effect of L-theanine against 3-NP-induced striatal toxicity and to explore its possible mechanism. Rats were administered with 3-NP for 21 days. L-theanine was given once a day, 1 h prior to 3-NP treatment for 21 days and L-NAME (10 mg/kg, i.p.), NO inhibitor and L-arginine (50 mg/kg; i.p.), NO precursor were administered 1 h prior to L theanine treatment. Body weight and behavioral observation were made on weekly basis. On the 22nd day, animals were sacrificed, and the striatum was isolated for biochemical (LPO, GSH, and nitrite), pro-inflammatory cytokines and neurochemical analysis. 3-NP treatment significantly altered body weight, locomotor activity, motor coordination, mitochondrial complex-II activity, oxidative defense, pro-inflammatory mediators, and striatal neurotransmitters level. L-theanine pre-treatment (25 and 50 mg/kg/day, p.o.) significantly prevented these alterations. In addition, concurrent treatment of L-NAME with L theanine (25 mg/kg/day, p.o.) significantly enhanced protective effect of L theanine (25 mg/kg/day, p.o.) whereas concurrent treatment of L-arginine with L theanine (50 mg/kg/day, p.o.) significantly ameliorated the protective effect of L-theanine (50 mg/kg/day, p.o.). The neuroprotective potential of L-theanine involves inhibition of detrimental nitric oxide production and prevention of neurotransmitters alteration in the striatum. PMID- 26957302 TI - Associations Between Hepatic Functions and Plasma Amyloid-Beta Levels Implications for the Capacity of Liver in Peripheral Amyloid-Beta Clearance. AB - Amyloid-beta (Abeta) plays a pivotal role in the pathogenesis of Alzheimer's disease (AD). Clearance of Abeta is a promising therapeutic strategy for AD. We have previously demonstrated that peripheral organs play important roles in the clearance of brain-derived Abeta. In the present study, we recruited 46 patients with liver cirrhosis and 46 normal controls and found that plasma Abeta40 and Abeta42 levels were significantly higher in the cirrhosis patients than in the normal controls. Notably, cirrhosis patients with hepatitis B virus (HBV) infection had higher plasma Abeta40 and Abeta42 levels than HBV-negative cirrhosis patients. Besides, cirrhosis patients had significantly higher plasma levels of interleukin-1beta (IL-1beta) and IL-6. Plasma tumor necrosis factor alpha (TNF-alpha) and interferon-gamma (IFN-gamma) levels were not significantly different between the groups. Moreover, we found significant correlations of hepatic functions with plasma Abeta40 and Abeta42 levels. Plasma IL-6 levels were also significantly correlated with plasma Abeta40 levels. However, in the linear regression model, we found significant correlation of plasma Abeta40 levels with hepatic functions, but not with plasma IL-6 levels. Our results indicate that the hepatic dysfunctions might result in decreased peripheral Abeta clearance by the liver. Protecting hepatic functions might be helpful for the clearance of brain derived Abeta in the blood. PMID- 26957303 TI - Modulation of Diabetes-Induced Oxidative Stress, Apoptosis, and Ca2+ Entry Through TRPM2 and TRPV1 Channels in Dorsal Root Ganglion and Hippocampus of Diabetic Rats by Melatonin and Selenium. AB - Neuropathic pain and hippocampal injury can arise from the overload of diabetes induced calcium ion (Ca2+) entry and oxidative stress. The transient receptor potential (TRP) melastatin 2 (TRPM2) and TRP vanilloid type 1 (TRPV1) are expressed in sensory neurons and hippocampus. Moreover, activations of TRPM2 and TRPV1 during oxidative stress have been linked to neuronal death. Melatonin (MEL) and selenium (Se) have been considered potent antioxidants that detoxify a variety of reactive oxygen species (ROS) in neurological diseases. In order to better characterize the actions of MEL and Se in diabetes-induced peripheral pain and hippocampal injury through modulation of TRPM2 and TRPV1, we tested the effects of MEL and Se on apoptosis and oxidative stress in the hippocampal and dorsal root ganglion (DRG) neurons of streptozotocin (STZ)-induced diabetic rats. Fifty-eight rats were divided into six groups. The first group was used as control. The second group was used as the diabetic group. The third and fourth groups received Se and MEL, respectively. Intraperitoneal Se and MEL were given to diabetic rats in the fifth and sixth groups. On the 14th day, hippocampal and DRG neuron samples were freshly taken from all animals. The neurons were stimulated with a TRPV1 channel agonist (capsaicin) and a TRPM2 channel agonist (cumene hydroperoxide). We observed a modulator role of MEL and Se on intracellular free Ca2+ concentrations, current densities of TRPM2 and TRPV1 channels, apoptosis, caspase 3, caspase 9, mitochondrial depolarization, reduced glutathione, glutathione peroxidase, lipid peroxidation, and intracellular ROS production values in the neurons. In addition, procaspase 3 and 9 activities in western blot analyses of the brain cortex were also decreased by MEL and Se treatments. In conclusion, in our diabetes experimental model, TRPM2 and TRPV1 channels are involved in the Ca2+ entry-induced neuronal death and modulation of this channel activity by MEL and Se treatment may account for their neuroprotective activity against apoptosis and Ca2+ entry. Graphical Abstract Possible molecular pathways of involvement of melatonin and selenium in diabetes induced apoptosis, oxidative stress, and calcium accumulation through TRPM2 and TRPV1 channels in the hippocampus and DRG neurons of rats. The TRPM2 channel is activated by ADP-ribose and oxidative stress although it is inhibited by ACA. The TRPV1 channel is activated by oxidative stress and capsaicin and it is blocked by capsazepine (CPZ). Diabetes can result in augmented ROS release in hippocampal and DRG neurons through polyol reactions, leading to Ca2+ uptake through TRPM2 and TRPV1 channels. Mitochondria were reported to accumulate Ca2+ provided intracellular Ca2+ rises, thereby leading to the depolarization of mitochondrial membranes and release of apoptosis-inducing factors such as caspase 3 and caspase 9. Melatonin and selenium reduce TRPM2 and TRPV1 channel activation through the modulation of polyol oxidative reactions and selenium-dependent glutathione peroxidase (GSH-Px) antioxidant pathways. PMID- 26957304 TI - Triptolide Promotes the Clearance of alpha-Synuclein by Enhancing Autophagy in Neuronal Cells. AB - Parkinson's disease (PD) is an aging-associated neurodegenerative disease with a characteristic feature of alpha-synuclein accumulation. Point mutations (A53T, A30P) that increase the aggregation propensity of alpha-synuclein result in familial early onset PD. The abnormal metabolism of alpha-synuclein results in aberrant level changes of alpha-synuclein in PD. In pathological conditions, alpha-synuclein is degraded mainly by the autophagy-lysosome pathway. Triptolide (T10) is a monomeric compound isolated from a traditional Chinese herb. Our group demonstrated for the first time that T10 possesses potent neuroprotective properties both in vitro and in vivo PD models. In the present study, we reported T10 as a potent autophagy inducer in neuronal cells, which helped to promote the clearance of various forms of alpha-synuclein in neuronal cells. We transfected neuronal cells with A53T mutant (A53T) or wild-type (WT) alpha-synuclein plasmids and found T10 attenuated the cytotoxicity induced by pathogenic A53T alpha synuclein overexpression. We observed that T10 significantly reduced both A53T and WT alpha-synuclein level in neuronal cell line, as well as in primary cultured cortical neurons. Excluding the changes of syntheses, secretion, and aggregation of alpha-synuclein, we further added autophagy inhibitor or proteasome inhibitor with T10, and we noticed that T10 promoted the clearance of alpha-synuclein mainly by the autophagic pathway. Lastly, we observed increased autophagy marker LC3-II expression and autophagosomes by GFP-LC3-II accumulation and ultrastructural characterization. However, the lysosome activity and cell viability were not modulated by T10. Our study revealed that T10 could induce autophagy and promote the clearance of both WT and A53T alpha-synuclein in neurons. These results provide evidence of T10 as a promising mean to treat PD and other neurodegenerative diseases by reducing pathogenic proteins in neurons. PMID- 26957305 TI - Molecular Diagnostic and Prognostic Subtyping of Gliomas in Tunisian Population. AB - It has become increasingly evident that morphologically similar gliomas may have distinct clinical phenotypes arising from diverse genetic signatures. To date, glial tumours from the Tunisian population have not been investigated. To address this, we correlated the clinico-pathology with molecular data of 110 gliomas by a combination of HM450K array, MLPA and TMA-IHC. PTEN loss and EGFR amplification were distributed in different glioma histological groups. However, 1p19q co deletion and KIAA1549:BRAF fusion were, respectively, restricted to Oligodendroglioma and Pilocytic Astrocytoma. CDKN2A loss and EGFR overexpression were more common within high-grade gliomas. Furthermore, survival statistical correlations led us to identify Glioblastoma (GB) prognosis subtypes. In fact, significant lower overall survival (OS) was detected within GB that overexpressed EGFR and Cox2. In addition, IDH1R132H mutation seemed to provide a markedly survival advantage. Interestingly, the association of IDHR132H mutation and EGFR normal status, as well as the association of differentiation markers, defined GB subtypes with good prognosis. By contrast, poor survival GB subtypes were defined by the combination of PTEN loss with PDGFRa expression and/or EGFR amplification. Additionally, GB presenting p53-negative staining associated with CDKN2A loss or p21 positivity represented a subtype with short survival. Thus, distinct molecular subtypes with individualised prognosis were identified. Interestingly, we found a unique histone mutation in a poor survival young adult GB case. This tumour exceptionally associated the H3F3A G34R mutation and MYCN amplification as well as 1p36 loss and 10q loss. Furthermore, by exhibiting a remarkable methylation profile, it emphasised the oncogenic power of G34R mutation connecting gliomagenesis and chromatin regulation. PMID- 26957307 TI - GMP-grade alpha-TEA lysine salt: a 28-Day oral toxicity and toxicokinetic study with a 28-Day recovery period in Beagle dogs. AB - BACKGROUND: Alpha-tocopheryloxyacetic acid (alpha-TEA) is a semi-synthetic derivative of naturally occurring vitamin E (alpha-tocopherol) that can be delivered via an oral route. Preclinical in vitro and in vivo data demonstrated that alpha-TEA is a potent anti-tumor agent with a safe toxicity profile in mice. We report a comprehensive study to evaluate the toxokinetics of good manufacturing practice (GMP)-grade alpha-TEA in dogs after daily oral administration for 28 days, followed by a 28-day recovery period. METHODS: Male and female beagle dogs received capsules of alpha-TEA Lysine Salt at doses of 100, 300, 1500 mg/kg/day. alpha-TEA plasma levels were determined by high performance liquid chromatography (HPLC) with mass spectrometric detection. During the treatment, animals were observe for clinical signs, food consumption, body weight, and subjected to ophthalmoscopic, and electrocardiographic assessments. At the end of the dosing period, blood was taken and toxicokinetic analyses and histopathology assessments were performed when animals were necropsied. RESULTS: Our findings showed that there was no alpha-TEA-related mortality or moribundity. At the highest dose, increases in white blood cells and fibrinogen levels were observed. These levels returned to normal at the end of the recovery period. Histopathological evaluation of major organs revealed no significant lesions related to alpha-TEA-treatment. CONCLUSION: We demonstrate that for designing clinical trials in patients, the highest non-severely toxic dose (HNSTD) of alpha-TEA is 1500 mg/kg/day in Beagle dogs and this data informed the design of dose-escalation studies of alpha-TEA in patients with advanced cancer. PMID- 26957306 TI - Neural Control of Non-vasomotor Organs in Hypertension. AB - Hypertension affects over 25 % of the population with the incidence continuing to rise, due in part to the growing obesity epidemic. Chronic elevations in sympathetic nerve activity (SNA) are a hallmark of the disease and contribute to elevations in blood pressure through influences on the vasculature, kidney, and heart (i.e., neurogenic hypertension). In this regard, a number of central nervous system mechanisms and neural pathways have emerged as crucial in chronically elevating SNA. However, it is important to consider that "sympathetic signatures" are present, with differential increases in SNA to regional organs that are dependent upon the disease progression. Here, we discuss recent findings on the central nervous system mechanisms and autonomic regulatory networks involved in neurogenic hypertension, in both non-obesity- and obesity-associated hypertension, with an emphasis on angiotensin-II, salt, oxidative and endoplasmic reticulum stress, inflammation, and the adipokine leptin. PMID- 26957309 TI - Comprehensive benchmarking reveals H2BK20 acetylation as a distinctive signature of cell-state-specific enhancers and promoters. AB - Although over 35 different histone acetylation marks have been described, the overwhelming majority of regulatory genomics studies focus exclusively on H3K27ac and H3K9ac. In order to identify novel epigenomic traits of regulatory elements, we constructed a benchmark set of validated enhancers by performing 140 enhancer assays in human T cells. We tested 40 chromatin signatures on this unbiased enhancer set and identified H2BK20ac, a little-studied histone modification, as the most predictive mark of active enhancers. Notably, we detected a novel class of functionally distinct enhancers enriched in H2BK20ac but lacking H3K27ac, which was present in all examined cell lines and also in embryonic forebrain tissue. H2BK20ac was also unique in highlighting cell-type-specific promoters. In contrast, other acetylation marks were present in all active promoters, regardless of cell-type specificity. In stimulated microglial cells, H2BK20ac was more correlated with cell-state-specific expression changes than H3K27ac, with TGF-beta signaling decoupling the two acetylation marks at a subset of regulatory elements. In summary, our study reveals a previously unknown connection between histone acetylation and cell-type-specific gene regulation and indicates that H2BK20ac profiling can be used to uncover new dimensions of gene regulation. PMID- 26957308 TI - Gene Expression Profiling of Evening Fatigue in Women Undergoing Chemotherapy for Breast Cancer. AB - Moderate-to-severe fatigue occurs in up to 94% of oncology patients undergoing active treatment. Current interventions for fatigue are not efficacious. A major impediment to the development of effective treatments is a lack of understanding of the fundamental mechanisms underlying fatigue. In the current study, differences in phenotypic characteristics and gene expression profiles were evaluated in a sample of breast cancer patients undergoing chemotherapy (CTX) who reported low (n = 19) and high (n = 25) levels of evening fatigue. Compared to the low group, patients in the high evening fatigue group reported lower functional status scores, higher comorbidity scores, and fewer prior cancer treatments. One gene was identified as upregulated and 11 as downregulated in the high evening fatigue group. Gene set analysis found 24 downregulated and 94 simultaneously up- and downregulated pathways between the two fatigue groups. Transcript origin analysis found that differential expression (DE) originated primarily from monocytes and dendritic cell types. Query of public data sources found 18 gene expression experiments with similar DE profiles. Our analyses revealed that inflammation, neurotransmitter regulation, and energy metabolism are likely mechanisms associated with evening fatigue severity; that CTX may contribute to fatigue seen in oncology patients; and that the patterns of gene expression may be shared with other models of fatigue (e.g., physical exercise and pathogen-induced sickness behavior). These results suggest that the mechanisms that underlie fatigue in oncology patients are multifactorial. PMID- 26957311 TI - Abolishing unnecessary bureaucracy in general practice. PMID- 26957310 TI - 2C-Cas9: a versatile tool for clonal analysis of gene function. AB - CRISPR/Cas9-mediated targeted mutagenesis allows efficient generation of loss-of function alleles in zebrafish. To date, this technology has been primarily used to generate genetic knockout animals. Nevertheless, the study of the function of certain loci might require tight spatiotemporal control of gene inactivation. Here, we show that tissue-specific gene disruption can be achieved by driving Cas9 expression with the Gal4/UAS system. Furthermore, by combining the Gal4/UAS and Cre/loxP systems, we establish a versatile tool to genetically label mutant cell clones, enabling their phenotypic analysis. Our technique has the potential to be applied to diverse model organisms, enabling tissue-specific loss-of function and phenotypic characterization of live and fixed tissues. PMID- 26957312 TI - Metformin sensitizes sorafenib to inhibit postoperative recurrence and metastasis of hepatocellular carcinoma in orthotopic mouse models. AB - BACKGROUND: Sorafenib is recognized as a standard treatment for advanced hepatocellular carcinoma (HCC). However, many patients have to adopt dose reduction or terminate the use of sorafenib because of side effects. In addition, a large number of patients are resistant to sorafenib. Thus, it is essential to investigate the underlying mechanisms of the resistance to sorafenib and seek potential strategy to enhance its efficacy. METHODS: The protein expression of hypoxia-inducible factors (HIF)-2alpha, 30-kDa HIV Tat-interacting protein (TIP30), E-cadherin, N-cadherin, and pAMPK was detected by Western blot. Cell viability assays were performed to study the influence of metformin and sorafenib on cell proliferation. Annexin V-FITC apoptosis assays were used to detect the influence of metformin and sorafenib on cell apoptosis. The relationship between HIF-2alpha and TIP30 was studied using gene silencing approach and chromatin immunoprecipitation assay. To investigate the effect of metformin and sorafenib on postoperative recurrence and lung metastasis of HCC in tumor-bearing mice, the mice were orally treated either with metformin or sorafenib once a day for continuous 37 days after the operation to remove the lobe where the tumor was implanted. CD31, Ki67, and TUNEL were examined by immunohistochemistry. RESULTS: Our study demonstrated that metformin synergized with sorafenib reduced HIF 2alpha expression as examined by Western blot. Gene silencing approach indicated TIP30 was upregulated after knocking-down of HIF-2alpha and chromatin immunoprecipitation assay revealed that HIF-2alpha could bind to TIP30 promoter under hypoxic condition. Cell Counting Kit-8 (CCK8) cell viability assay and Annexin V-FITC apoptosis assay showed that metformin in combination with sorafenib suppressed cell proliferation and promoted cell apoptosis. Besides, combined therapy suppressed epithelial-mesenchymal transition (EMT) process both in vitro and in vivo. Moreover, metformin in combination with sorafenib significantly minimized postoperative recurrence and lung metastasis of HCC in orthotopic mouse model. Combined therapy inhibited CD31 and Ki67 expression but promoted TUNEL expression. CONCLUSIONS: Metformin may potentially enhance the effect of sorafenib to inhibit HCC recurrence and metastasis after liver resection by regulating the expression of HIF-2alpha and TIP30. PMID- 26957313 TI - Atherogenic index of plasma and risk of cardiovascular disease among Cameroonian postmenopausal women. AB - BACKGROUND: The paucity of data regarding the relationship between atherogenic index of plasma (AIP) and risk of cardiovascular disease (CVD) in postmenopausal women living in sub-Saharan Africa prompted us to conduct this study which aimed at assessing the interplay between AIP and risk of CVD among Cameroonian postmenopausal women. METHODS: This was a cross-sectional study conducted among 108 postmenopausal women in Yaounde, Cameroon. Risk of CVD was calculated using the Framingham risk score, (FRS), and the AIP was derived as log (triglycerides/high-density lipoproteins cholesterol). RESULTS: Mean age of participants equaled 56.4 +/- 6.9 years. AIP values ranged from -0.40 to 0.85 with a mean of 0.21 +/- 0.27. There was a positive and significant correlation between AIP and body mass index (r = 0.234; p = 0.015), systolic blood pressure (r = 0.350; p < 0.001), diastolic blood pressure (r = 0.365; p < 0.001), fasting plasma glucose (r = 0.314; p = 0.001), uric acid (r = 0.374; p < 0.001), and total cholesterol (r = 0.374; p < 0.001), but not with age (r = -0.104; p = 0.284). The FRS varied between 1.2 % and >30 % with a mean of 13.4 +/- 8.7 %. In univariable model, AIP significantly influenced the risk of CVD (beta = 11.94; p < 0.001; R(2) = 0.136). But in the multivariable model, after adjusting for confounders, AIP did not impact the risk of CVD anymore (adjusted beta = 1.98; p = 0.487; R(2) = 0.486). CONCLUSION: AIP may not be an independent factor impacting the risk of CVD among Cameroonian postmenopausal women. More studies are needed to better elucidate the interaction between AIP and risk of CVD in our setting. PMID- 26957314 TI - A qualitative study exploring midlife women's stages of change from domestic violence towards freedom. AB - BACKGROUND: Domestic Violence (DV) remains a significant global health problem for women in contemporary society. Existing literature on midlife women's experiences of domestic violence is limited and focuses on health implications. Leaving a violent relationship is a dynamic process that often requires multiple attempts and separations prior to final termination. The aim of this study was to explore the process of leaving a violent relationship for midlife women. METHODS: This qualitative study involved fifteen women aged between 40-55 who had accessed residential and non-residential community support services for domestic violence within the UK. Community-based support agencies provided these women with access to letters of invitation and participant information sheet explaining the study. The women notified agency staff who contacted the research team to arrange a mutually convenient time to meet within a safe place for both the women and researchers. It was stressed to all potential participants that no identifiable information would be shared with the agency staff. Women were considered survivors of DV if they defined themselves as such. Data were gathered through semi structured interviews, transcribed verbatim and thematically analysed. RESULTS: Midlife women appear to differ from younger women by transitioning quickly though the stages of change, moving rapidly through the breaking free onto the maintenance stage. This rapid transition is the resultant effect of living with long-term violence causing a shift in the women's perception towards the violent partner, with an associated reclamation of power from within the violent relationship. A realisation that rapid departure from the violence may be critical in terms of personal safety, and the realisation that there was something 'wrong' within the relationship, a 'day of dawning' that had not been apparent previously appears to positively affect the trajectory of leaving. CONCLUSIONS: Midlife women appeared to navigate through the stages of change in a rapid linear process, forging ahead and exiting the relationship with certainty and without considering options. Whilst these findings appear to differ from younger women's process of leaving, further research is needed to explore and understand the optimum time for intervention and support to maximise midlife women's opportunities to escape an abusive partner, before being reflected appropriately in policy and practice. PMID- 26957316 TI - Zika Virus and Global Implications for Reproductive Health Reforms. PMID- 26957315 TI - One-lung flooding reduces the ipsilateral diaphragm motion during mechanical ventilation. AB - BACKGROUND: Diaphragm motion during spontaneous or mechanical respiration hinders image-guided percutaneous interventions of tumours in lung and upper abdomen. Motion-tracking methods can be applied but increase procedure complexity and procedure time. One-lung flooding (OLF) generates a suitable acoustic pathway to lung tumours and likely suppress diaphragm motion. The aim of this study was to quantify the effect of OLF on ipsilateral diaphragm motion during contralateral one-lung ventilation. METHODS: To measure the diaphragm motion, M-mode ultrasonography of the right hemidiaphragm was performed during spontaneous breathing and mechanical ventilation, as well as after right-side lung flooding, in three pigs. Diaphragm motion was analysed using magnetic resonance images during left-side lung flooding and mechanical ventilation, in four pigs. RESULTS: Double-lung ventilation increased the diaphragm movement in comparison with spontaneous breathing (17.8 +/- 4.4 vs. 12.2 +/- 3.4 mm, p = 0.014). Diaphragm movement on the flooded side during contralateral one-lung ventilation was significantly reduced compared to that during double-lung ventilation (3.9 +/- 1.0 vs. 17.8 +/- 4.4 mm, p = 0.041). By analysing the magnetic resonance images, the hemidiaphragm on the flooded side showed an average displacement of 4.2 mm, a maximum displacement of 15 mm close to the ventilated lung and no displacement at the lateral side. CONCLUSION: OLF leads to a drastic reduction of diaphragm motion on the ipsilateral side which implies that targeting and motion compensation algorithms for interventions like high-intensity focused ultrasound ablation of intrapulmonary and hepatic lesions might not be required. PMID- 26957317 TI - Iris metastasis of gastric adenocarcinoma. AB - BACKGROUND: Iris metastasis in patients with gastric cancer is extremely rare. Herein, it is aimed to report on a patient with gastric adenocarcinoma and iris metastasis. CASE PRESENTATION: A 65-year-old patient with the history of gastric cancer was admitted for eye pain and eye redness on his left eye. There was ciliary injection, severe +4 cells with hypopyon in the anterior chamber and a solitary, friable, yellow-white, fleshy-creamy vascularized 2 mm * 4 mm mass on the upper nasal part of the iris within the left eye. The presented patient's mass lesion in the iris fulfilled the criteria of the metastatic iris lesion's appearance. The ocular metastasis occurred during chemotherapy. CONCLUSIONS: Iris metastasis can masquerade as iridocyclitis with pseudohypopyon or glaucoma. In patients with a history of gastric cancer that present with an iris mass, uveitis, and high intraocular pressure, ocular metastasis of gastric cancer should be a consideration. PMID- 26957318 TI - Identification of novel surfactin derivatives from NRPS modification of Bacillus subtilis and its antifungal activity against Fusarium moniliforme. AB - BACKGROUND: Bacillus subtilis strain PB2-L1 produces the lipopeptide surfactin, a highly potent biosurfactant synthesized by a large multimodular nonribosomal peptide synthetase (NRPS). In the present study, the modules SrfA-A-Leu, SrfA-B Asp, and SrfA-B-Leu from surfactin NRPS in B. subtilis BP2-L1 were successfully knocked-out using a temperature-sensitive plasmid, pKS2-mediated-based, homologous, recombination method. RESULTS: Three novel surfactin products were produced, individually lacking amino acid Leu-3, Asp-5, or Leu-6. These surfactins were detected, isolated, and characterized by HPLC and LC-FTICR-MS/MS. In comparison with native surfactin, [?Leu(3)]surfactin and [?Leu(6)]surfactin showed evidence of reduced toxicity, while [?Asp(5)]surfactin showed stronger inhibition than native surfactin against B. pumilus and Micrococcus luteus. These results showed that the minimum inhibitory concentration of [?Leu(6)]surfactin for Fusarium moniliforme was 50 MUg/mL, such that [?Leu(6)]surfactin could lead to mycelium projection, cell damage, and leakage of nucleic acids and protein. These factors all contributed to stimulating apoptosis in F. moniliforme. CONCLUSIONS: The present results revealed that [?Leu(6)]surfactin showed a significant antifungal activity against F. moniliforme and might successfully be employed to control fungal food contamination and improve food safety. PMID- 26957319 TI - PREventing Maternal And Neonatal Deaths (PREMAND): a study protocol for examining social and cultural factors contributing to infant and maternal deaths and near misses in rural northern Ghana. AB - BACKGROUND: While Ghana is a leader in some health indicators among West African nations, it still struggles with high maternal and neonatal morbidity and mortality rates, especially in the northern areas. The clinical causes of mortality and morbidity are relatively well understood in Ghana, but little is known about the impact of social and cultural factors on maternal and neonatal outcomes. Less still is understood about how such factors may vary by geographic location, and how such variability may inform locally-tailored solutions. METHODS/DESIGN: Preventing Maternal And Neonatal Deaths (PREMAND) is a three year, three-phase project that takes place in four districts in the Upper East, Upper West, and Northern Regions of Ghana. PREMAND will prospectively identify all maternal and neonatal deaths and 'near-misses', or those mothers and babies who survive a life threatening complication, in the project districts. Each event will be followed by either a social autopsy (in the case of deaths) or a sociocultural audit (in the case of near-misses). Geospatial technology will be used to visualize the variability in outcomes as well as the social, cultural, and clinical predictors of those outcomes. Data from PREMAND will be used to generate maps for local leaders, community members and Government of Ghana to identify priority areas for intervention. PREMAND is an effort of the Navrongo Health Research Centre and the University of Michigan Medical School. DISCUSSION: PREMAND uses an innovative, multifaceted approach to better understand and address neonatal and maternal morbidity and mortality in northern Ghana. It will provide unprecedented access to information on the social and cultural factors that contribute to deaths and near-misses in the project regions, and will allow such causal factors to be situated geographically. PREMAND will create the opportunity for local, regional, and national stakeholders to see how these events cluster, and place them relative to traditional healer compounds, health facilities, and other important geographic markers. Finally, PREMAND will enable local communities to generate their own solutions to maternal and neonatal morbidity and mortality, an effort that has great potential for long-term impact. PMID- 26957320 TI - Diagnostic support for selected neuromuscular diseases using answer-pattern recognition and data mining techniques: a proof of concept multicenter prospective trial. AB - BACKGROUND: Diagnosis of neuromuscular diseases in primary care is often challenging. Rare diseases such as Pompe disease are easily overlooked by the general practitioner. We therefore aimed to develop a diagnostic support tool using patient-oriented questions and combined data mining algorithms recognizing answer patterns in individuals with selected neuromuscular diseases. A multicenter prospective study for the proof of concept was conducted thereafter. METHODS: First, 16 interviews with patients were conducted focusing on their pre diagnostic observations and experiences. From these interviews, we developed a questionnaire with 46 items. Then, patients with diagnosed neuromuscular diseases as well as patients without such a disease answered the questionnaire to establish a database for data mining. For proof of concept, initially only six diagnoses were chosen (myotonic dystrophy and myotonia (MdMy), Pompe disease (MP), amyotrophic lateral sclerosis (ALS), polyneuropathy (PNP), spinal muscular atrophy (SMA), other neuromuscular diseases, and no neuromuscular disease (NND). A prospective study was performed to validate the automated malleable system, which included six different classification methods combined in a fusion algorithm proposing a final diagnosis. Finally, new diagnoses were incorporated into the system. RESULTS: In total, questionnaires from 210 individuals were used to train the system. 89.5 % correct diagnoses were achieved during cross validation. The sensitivity of the system was 93-97 % for individuals with MP, with MdMy and without neuromuscular diseases, but only 69 % in SMA and 81 % in ALS patients. In the prospective trial, 57/64 (89 %) diagnoses were predicted correctly by the computerized system. All questions, or rather all answers, increased the diagnostic accuracy of the system, with the best results reached by the fusion of different classifier methods. Receiver operating curve (ROC) and p value analyses confirmed the results. CONCLUSION: A questionnaire-based diagnostic support tool using data mining methods exhibited good results in predicting selected neuromuscular diseases. Due to the variety of neuromuscular diseases, additional studies are required to measure beneficial effects in the clinical setting. PMID- 26957321 TI - Editorialists' reply to Blake. PMID- 26957322 TI - Complementary school garden, nutrition, water, sanitation and hygiene interventions to improve children's nutrition and health status in Burkina Faso and Nepal: a study protocol. AB - BACKGROUND: Malnutrition and intestinal parasitic infections are common among children in Burkina Faso and Nepal. However, specific health-related data in school-aged children in these two countries are scarce. In the frame of a larger multi-stakeholder project entitled "Vegetables go to School: Improving Nutrition through Agricultural Diversification" (VgtS), a study has been designed with the objectives to: (i) describe schoolchildren's health status in Burkina Faso and Nepal; and to (ii) provide an evidence-base for programme decisions on the relevance of complementary school garden, nutrition, water, sanitation and hygiene (WASH) interventions. METHODS/DESIGN: The studies will be conducted in the Centre Ouest and the Plateau Central regions of Burkina Faso and the Dolakha and Ramechhap districts of Nepal. Data will be collected and combined at the level of schools, children and their households. A range of indicators will be used to examine nutritional status, intestinal parasitic infections and WASH conditions in 24 schools among 1144 children aged 8-14 years at baseline and a 1 year follow-up. The studies are designed as cluster randomised trials and the schools will be assigned to two core study arms: (i) the 'complementary school garden, nutrition and WASH intervention' arm; and the (ii) 'control' arm with no interventions. Children will be subjected to parasitological examinations using stool and urine samples and to quality-controlled anthropometric and haemoglobin measurements. Drinking water will be assessed for contamination with coliform bacteria and faecal streptococci. A questionnaire survey on nutritional and health knowledge, attitudes and practices (KAP) will be administered to children and their caregivers, also assessing socioeconomic, food-security and WASH conditions at household level. Focus group and key-informant interviews on children's nutrition and hygiene perceptions and behaviours will be conducted with their caregivers and school personnel. DISCUSSION: The studies will contribute to fill a data gap on school-aged children in Burkina Faso and Nepal. The data collected will also serve to inform the design of school-based interventions and will contribute to deepen the understanding of potential effects of these interventions to improve schoolchildren's health in resource constrained settings. Key findings will be used to provide guidance for the implementation of health policies at the school level in Burkina Faso and Nepal. TRIAL REGISTRATION: ISRCTN30840 (date assigned: 17 July 2015). PMID- 26957323 TI - Effects of curcumin on synapses in APPswe/PS1dE9 mice. AB - Significant losses of synapses have been demonstrated in studies of Alzheimer's disease (AD), but structural and functional changes in synapses that depend on alterations of the postsynaptic density (PSD) area occur prior to synaptic loss and play a crucial role in the pathology of AD. Evidence suggests that curcumin can ameliorate the learning and memory deficits of AD. To investigate the effects of curcumin on synapses, APPswe/PS1dE9 double transgenic mice (an AD model) were used, and the ultra-structures of synapses and synapse-associated proteins were observed. Six months after administration, few abnormal synapses were observed upon electron microscopy in the hippocampal CA1 areas of the APPswe/PS1dE9 double transgenic mice. The treatment of the mice with curcumin resulted in improvements in the quantity and structure of the synapses. Immunohistochemistry and western blot analyses revealed that the expressions of PSD95 and Shank1 were reduced in the hippocampal CA1 areas of the APPswe/PS1dE9 double transgenic mice, but curcumin treatment increased the expressions of these proteins. Our findings suggest that curcumin improved the structure and function of the synapses by regulating the synapse-related proteins PSD95 and Shank1. PMID- 26957324 TI - All together now: Analogies between chimera state collapses and epileptic seizures. AB - Conceptually and structurally simple mathematical models of coupled oscillator networks can show a rich variety of complex dynamics, providing fundamental insights into many real-world phenomena. A recent and not yet fully understood example is the collapse of coexisting synchronous and asynchronous oscillations into a globally synchronous motion found in networks of identical oscillators. Here we show that this sudden collapse is promoted by a further decrease of synchronization, rather than by critically high synchronization. This strikingly counterintuitive mechanism can be found also in nature, as we demonstrate on epileptic seizures in humans. Analyzing spatiotemporal correlation profiles derived from intracranial electroencephalographic recordings (EEG) of seizures in epilepsy patients, we found a pronounced decrease of correlation at the seizure onsets. Applying our findings in a closed-loop control scheme to models of coupled oscillators in chimera states, we succeed in both provoking and preventing outbreaks of global synchronization. Our findings not only advance the understanding of networks of coupled dynamics but can open new ways to control them, thus offering a vast range of potential new applications. PMID- 26957325 TI - Element substitution by living organisms: the case of manganese in mollusc shell aragonite. AB - Determining the manganese concentration in shells of freshwater bivalves provides a unique way to obtain information about climate and environmental changes during time-intervals that pre-date instrumental data records. This approach, however, relies on a thorough understanding of how manganese is incorporated into the shell material -a point that remained controversial so far. Here we clarify this issue, using state-of-the-art X-ray absorption and X-ray emission spectroscopy in combination with band structure calculations. We verify that in the shells of all studied species manganese is incorporated as high-spin Mn(2+), i.e. manganese always has the same valence as calcium. More importantly, the unique chemical sensitivity of valence-to-core X-ray emission enables us to show that manganese is always coordinated by a CO3-octahedron. This, firstly, provides firm experimental evidence for manganese being primarily located in the inorganic carbonate. Secondly, it indicates that the structure of the aragonitic host is locally altered such that manganese attains an octahedral, calcitic coordination. This modification at the atomic level enables the bivalve to accommodate many orders of magnitude more manganese in its aragonitic shell than found in any non biogenic aragonite. This outstanding feature is most likely facilitated through the non-classical crystallization pathway of bivalve shells. PMID- 26957326 TI - Distinctive clinical features of Dhat syndrome with comorbid sexual dysfunction. PMID- 26957327 TI - Research by psychiatry residents in Indian scenario: Challenges and opportunities. PMID- 26957328 TI - Violence against the adolescents of Kolkata: A study in relation to the socio economic background and mental health. AB - This study attempts to understand the nature of violence suffered by the adolescents of Kolkata (erstwhile Calcutta) and to identify its relation with their socio-economic background and mental health variables such as anxiety, adjustment, and self-concept. It is a cross-sectional study covering a total of 370 adolescents (182 boys and 188 girls) from six higher secondary schools in Kolkata. The data was gathered by way of a semi-structured questionnaire and three standard psychological tests. Findings revealed that 52.4%, 25.1%, and 12.7% adolescents suffered psychological, physical, and sexual violence in the last year. Older adolescents (aged 17-18 years) suffered more psychological violence than the younger ones (15-16 years) (p<0.05). Sixty nine (18.6%) adolescent students stood witness to violence between adult members in the family. More than three-fifth (61.9%) adolescents experienced at least one type of violence, while one-third (32.7%) experienced physical or sexual violence or both. Whatever its nature is, violence leaves a scar on the mental health of the victims. Those who have been through regular psychological violence reported high anxiety, emotional adjustment problem, and low self-concept. Sexual abuse left a damaging effect on self-concept (p<0.05), while psychological violence or the witnessing of violence prompted high anxiety scores (p<0.05), poor emotional adjustment (p<0.05), and low self-concept (p<0.05). This study stresses the need to provide individual counselling services to the maltreated adolescents of Kolkata so that their psychological traumas can heal and that they can move on in life with new hopes and dreams. PMID- 26957329 TI - Postural sway and flexibility in patients with schizophrenia-spectrum disorders: A cross-sectional study. AB - Coordinated bodily balance is necessary to prevent falls, where postural sway and/or body inflexibility should be relevant. We aimed to assess postural sway and flexibility in patients with schizophrenia and identify clinical characteristics. Postural sway (length and range of trunk motion, and Romberg ratio) and flexibility (anteflexion in sitting) were measured in schizophrenia. The Positive and Negative Syndrome Scale (PANSS) and the Drug Induced Extrapyramidal Symptoms Scale (DIEPSS) were used for the assessment of psychopathology and extrapyramidal symptoms, respectively. Characteristics associated with postural sway and flexibility were examined with regression analysis. A total of 100 patients (68 men, mean +/- S.D. age: 49.3 +/- 13.8 years, PANSS score: 83.4 +/- 15.1, DIEPSS score: 2.2 +/- 2.2) participated in this study. The anteflexion in sitting was not significantly correlated with length of trunk motion, range of trunk motion, or Romberg ratio. Postural instability was associated with higher DIEPSS overall severity score and PANSS positive symptoms. A significant correlation was also found between less flexibility and increased PANSS negative symptoms. In conclusion, flexibility and postural stability might be regarded as separate elements of physical fitness in schizophrenia. Prospective exercise intervention would be worthy of investigation to enhance postural stability and flexibility in an effort to prevent falls. PMID- 26957330 TI - Acute polymorphic psychosis as a presenting feature of Hashimoto's encephalopathy. PMID- 26957331 TI - Tools to facilitate the teaching and enhance the practice of psychopharmacology. PMID- 26957332 TI - Right to information act, 2005 and privacy in public mental health sector in India. PMID- 26957333 TI - Leadership and management skills for psychiatry trainees: An integral part of curriculum? PMID- 26957334 TI - Telemental health: Need and application in Indian setting. PMID- 26957335 TI - Cardiovascular diseases among patients with schizophrenia. AB - The presence of comorbid physical illnesses especially, cardiovascular diseases (CVD) in schizophrenia is a growing area of concern in recent years. In order to reduce disease burden, to improve quality of life and to provide holistic care, it is important to know about the relationship between schizophrenia and CVD. The objective of this review is to explore the extent of CVD problems, relevant risk factors and potential measures for early diagnosis and prevention of CVD among patients with schizophrenia. Worldwide studies show that patients with schizophrenia have a higher mortality and lower life expectancy than the general population. CVD is the leading cause of increased mortality in schizophrenia. Common CVD risk factors in schizophrenia include metabolic syndrome, sedentary behaviour, tobacco smoking, effects of antipsychotics, long chain omega-3 fatty acid deficiency and shared genetics between CVD and schizophrenia. The potential methods for early detection and prevention of CVD in schizophrenia are also discussed. Though the patients with schizophrenia form a high risk group for CVD, consensus guidelines for early detection and prevention of CVD in schizophrenia are lacking. Comorbidity of CVD in schizophrenia needs more serious attention by clinicians and researchers. PMID- 26957336 TI - Prevalence and correlates of heart disease among adults in Singapore. AB - Heart disease is one of the leading causes of morbidity and mortality worldwide and it has been well established that it is associated with both mental and physical conditions. This paper describes the prevalence of heart disease with mental disorders and other chronic physical conditions among the Singapore resident population. Data were from the Singapore Mental Health Study which was a representative, cross-sectional epidemiological survey undertaken with 6616 Singapore residents, between December 2009 and December 2010. The Composite International Diagnostic Interview Version 3.0 was used to establish the diagnosis of mental disorders, while a chronic medical conditions checklist was used to gather information on 15 physical conditions, including various forms of heart disease. Health-related quality of life was measured using the Euro-Quality of Life Scale (EQ-5D). The lifetime prevalence of heart disease was 2.8%. Socio demographic correlates of heart disease included older age, Indian ethnicity, secondary education (vs. tertiary) and being economically inactive. After adjusting for socio-demographic variables and other comorbid physical and mental disorders, the prevalence of major depressive disorder and bipolar disorder were significantly higher among those with heart disease, as were diabetes, arthritis, kidney failure and lung disease. These findings highlight important associations between heart disease and various socio-demographic correlates, mental disorders and physical conditions. Given the high prevalence of mood disorders among heart disease patients, timely and appropriate screening and treatment of mental disorders among this group is essential. PMID- 26957337 TI - Clinical characteristics of children presenting with history of sexual abuse to a tertiary care centre in India. AB - OBJECTIVES: To study the clinical features of children with history of sexual abuse. METHOD: A chart review of 40 children (<16 years) with history of Child Sexual Abuse (CSA) evaluated at the Department of Child and Adolescent Psychiatry at NIMHANS during a three year period. RESULTS: 52.5% (N=21) of the children came from broken families. The most common form of abuse was contact penetrative (67.5%) followed by contact non-penetrative abuse (30%). Seventy-Five percent (N=30) had a psychiatric diagnosis at baseline and 37.5% of these children had comorbidities. The commonest diagnoses were Depressive Disorder (35%) followed by Stress related disorders--PTSD and Acute Stress Disorder (25%). Children abused multiple times were more likely to have psychiatric illness following CSA. Children abused by multiple perpetrators were more likely to have depression, psychiatric comorbidity and more prone to exhibit sexualized behaviour. Sixty five percent of children did not follow up 8 weeks after the initial consultation. DISCUSSION: Psychiatric morbidity is high in the population of children with history of CSA. It is necessary to assess the risk factors, circumstances of abuse along with psychiatric morbidity in order provide flexible and tailor made interventions for this population. In order to ensure the best possible care for these families, focused and time limited intervention that respect the needs of the child and addresses the ground realities of the circumstances of the family and the health system are the need of the day. PMID- 26957338 TI - Internet and smartphone application usage in eating disorders: A descriptive study in Singapore. AB - Eating disorders are associated with significant morbidity and mortality. The Internet is a popular medium for individuals with eating disorders to discuss and reinforce their affliction. However, the available literature on Internet usage and eating disorders is scarce, especially in the area of social media and smartphone application ("app") usage. This study looked at the Internet and smartphone app usage patterns of participants who presented with an eating disorder in Singapore, and whether it corresponded to severity of illness. Individuals who presented to the Eating Disorders clinic at the Singapore General Hospital completed a self-reported questionnaire on Internet and app usage. They also completed the EDE-Q, EAT-26 and CIA 3.0. 55 participants completed the study. 41.8% had anorexia nervosa, 34.5% had bulimia nervosa, and 9.1% were ED NOS. 41.8% felt that apps helped to perpetuate their illness while 32.7% felt that the apps were helpful for recovery. Overall, any smartphone application usage was associated with younger age and greater eating disorder psychopathology and psychosocial impairment. While 30.9% had encountered eating disorder-related content on Facebook, only 12.7% visited Facebook groups related to eating disorders. For YouTube, "Cooking and Food" and "Beauty and Fashion" videos were among the top 3 types of videos that participants watched. In conclusion, Internet and smartphone app usage is significant, and they are associated with greater severity of illness. It is necessary to include interventions in this aspect as part of treatment of eating disorders. PMID- 26957339 TI - Inpatient suicide in a psychiatric hospital: Fourteen years' observation. PMID- 26957340 TI - Mental health in Aceh--Indonesia: A decade after the devastating tsunami 2004. AB - The province of Aceh has suffered enormously from the perennial armed conflict and the devastating Tsunami in 2004. Despite the waves of external aid and national concern geared toward improving healthcare services as part of the reconstruction and rehabilitation efforts after the Tsunami, mental health services still require much attention. This paper aims to understand the mental healthcare system in Aceh Province, Indonesia; its main focus is on the burden, on the healthcare system, its development, service delivery and cultural issues from the devastating Tsunami in 2004 until the present. We reviewed those published and unpublished reports from the local and national government, from international instances (UN bodies, NGOs) and from the academic literature pertaining to mental health related programs conducted in Aceh. To some extent, mental health services in Aceh have been improved compared to their condition before the Tsunami. The development programs have focused on procurement of policy, improvement of human resources, and enhancing service delivery. Culture and religious beliefs shape the pathways by which people seek mental health treatment. The political system also determines the development of the mental health service in the province. The case of Aceh is a unique example where conflict and disaster serve as the catalysts toward the development of a mental healthcare system. Several factors contribute to the improvement of the mental health system, but security is a must. Whilst the Acehnese enjoy the improvements, some issues such as stigma, access to care and political fluctuations remain challenging. PMID- 26957341 TI - Adjunctive ondansetron in schizophrenia--A pilot study. PMID- 26957342 TI - Pattern and correlates of agitation in an acute psychiatry in-patient setting in a teaching hospital. AB - Agitation among psychiatry inpatients can be a distressing and burdensome entity for patients, caregivers and staff. It has been poorly studied in low-middle income countries such as India both within acute care as well as long stay settings. 272 psychiatry admissions had 19.9% prevalence of agitation with the most common form being non goal directed physical agitation (13.6%). Episodes of agitation were most likely to occur on the 3rd or 2nd day of admission. Substance abuse [O.R.=2.51(1.05-5.99)] and the presence of persecutory delusions [O.R.=2.62(1.34-5.15)] were independently associated with agitation. It is difficult to predict violence in acutely ill individuals and there is evidence that the emergence of more serious aggression may be preceded by milder forms of agitation. Therefore, there is a need to identify various forms of agitation and its correlates. An understanding of these factors may assist in planning appropriate interventions that could improve patient outcomes and reduce the burden on caregivers. PMID- 26957343 TI - Predicting obsessions and compulsions according to superego and ego characteristics: A comparison between scrupulosity and non-religious obsessive compulsive symptoms. AB - Obsessive Compulsive Disorder (OCD) is characterized by intrusive images or impulses and/or ritualistic and rigid behaviors. Symptoms of OCD have different contents including contamination, harming and symmetry. Religion is one of the themes that has been observed in the context of OCD frequently. The aim of the present study was to examine the power of superego and ego characteristics in predicting scrupulosity and non-religious obsessions and compulsions, as well as comparing the two sets of obsessive-compulsive symptoms. Sixty six Iranian (19 men, 47 women) participated in the study. All participants were asked to complete Maudsley Obsessive-Compulsive Inventory, Penn Inventory of Scrupulosity, Perfectionism Cognitions Inventory, the Multidimensional Anger Inventory, and Ego Strength Scale. Results showed that perfectionism and anger were positively correlated with scrupulosity and non-religious obsessive-compulsive symptoms. Ego control was negatively correlated with scrupulosity, while ego resiliency was not correlated with any of these two sets of symptoms. Regression analysis indicated that among these variables, anger was the best predictor of non-religious obsessive-compulsive symptoms, while perfectionism and ego control were the best predictors of scrupulosity. PMID- 26957344 TI - Non-fatal self-poisoning across age groups, in Sri Lanka. AB - Attempted or non-fatal self-poisoning in common in Sri Lanka, but little is known about variation of psychiatric morbidity and suicidal intent across differing ages. The aim of this study was to investigate factors associated with non-fatal self-poisoning in Sri Lanka across three different age groups (namely 14-24 years, 25-34 years and >= 35 years). It was anticipated that the findings of the study would inform and guide development of preventive interventions for non fatal self-poisoning in this country. 935 participants were interviewed within one week of admission to hospital for medical management of non-fatal self poisoning, over a consecutive 14-month period. Socio-demographic factors, types of poison ingested, triggers and psychiatric morbidity was examined as a function of age. Results showed that a majority (83%) of participants were aged below 35 years. Younger participants aged <25 years were significantly more likely to ingest medicinal overdoses, compared to older persons (aged 25-34 years, and >= 35 years), who were more likely to ingest pesticides. Recent interpersonal conflict was a proximal trigger seen in all age groups, but suicidal intent, depression and alcohol use disorders increased with age. The overall study findings indicate that most who carry out acts of non-fatal self-poisoning in Sri Lanka are young (aged <35 years). Interpersonal conflict as a trigger is common to all age groups, but psychiatric morbidity and suicidal intent is higher in the older age groups, as is pesticide ingestion. Age specific interventions may be efficacious in the prevention of non-fatal self-poisoning in Sri Lanka. PMID- 26957345 TI - Use of amisulpride in treating adolescent onset schizophrenia associated with stuttering priapism induced by multiple antipsychotics. PMID- 26957346 TI - Mentoring for junior medical faculty: Existing models and suggestions for low resource settings. AB - Globally, there is increasing recognition about the positive benefits and impact of mentoring on faculty retention rates, career satisfaction and scholarly output. However, emphasis on research and practice of mentoring is comparatively meagre in low and middle income countries. In this commentary, we critically examine two existing models of mentorship for medical faculty and offer few suggestions for an integrated hybrid model that can be adapted for use in low resource settings. PMID- 26957347 TI - Heart disease and mortality in patients with serious mental illness: Prevention is key. PMID- 26957349 TI - Mesoporous and carbon hybrid structures from layered molecular precursors for Li ion battery application: the case of beta-In2S3. AB - A new method was demonstrated to construct mesoporous and carbon hybrid structures of beta-In2S3 from the thermal decomposition of layered molecular precursors. When applied to LIBs, they all exhibit good cycling stability and excellent rate performance due to the great uniformity of mesopores and pyrolysis carbon distributed in the materials. PMID- 26957348 TI - Decreased fracture rate, pharmacogenetics and BMD response in 79 Swedish children with osteogenesis imperfecta types I, III and IV treated with Pamidronate. AB - BACKGROUND: Osteogenesis imperfecta (OI) is an inherited heterogeneous bone fragility disorder, usually caused by collagen I mutations. It is well established that bisphosphonate treatment increases lumbar spine (LS) bone mineral density (BMD), as well as improves vertebral geometry in severe OI; however, fracture reduction has been difficult to prove, pharmacogenetic studies are scarce, and it is not known at which age, or severity of disease, treatment should be initiated. MATERIALS AND METHODS: COL1A1 and COL1A2 were analyzed in 79 children with OI (type I n=33, type III n=25 and type IV n=21) treated with Pamidronate. Data on LS BMD, height, and radiologically confirmed non-vertebral and vertebral fractures were collected prior to, and at several time points during treatment. RESULTS: An increase in LS BMD Z-score was observed for all types of OI, and a negative correlation to Delta LS BMD was observed for both age and LS BMD Z-score at treatment initiation. Supine height Z-scores were not affected by Pamidronate treatment, The fracture rate was reduced for all OI types at all time points during treatment (overall p<0.0003, <0.0001 and 0.0003 for all OI types I, III and IV respectively). The reduced fracture rate was maintained for types I and IV, while an additional decrease was observed over time for type III. The fracture rate was reduced also in individuals with continued low BMD after >4yrs Pamidronate. Twice as many boys as girls with OI type I were treated with Pamidronate, and the fracture rate the year prior treatment was 2.2 times higher for boys (p=0.0236). Greater Delta LS BMD, but smaller Delta fracture numbers were observed on Pamidronate for helical glycine mutations in COL1A1 vs. COL1A2. Vertebral compression fractures did not progress in any individual during treatment; however, they did not improve in 9%, and these individuals were all >11years of age at treatment initiation (p<0.0001). CONCLUSION: Pamidronate treatment in children with all types of OI increased LS BMD, decreased fracture rate, and improved vertebral compression fractures. Fracture reduction was prompt and maintained during treatment, irrespective of age at treatment initiation and collagen I mutation type. PMID- 26957351 TI - A liposomal steroid nano-drug for treating systemic lupus erythematosus. AB - BACKGROUND: Glucocorticoids have been known for years to be the most effective therapy in systemic lupus erythematosus. Their use, however, is limited by the need for high doses due to their unfavorable pharmacokinetics and biodistribution. We have previously developed a novel liposome-based steroidal (methylprednisolone hemisuccinate (MPS)) nano-drug and demonstrated its specific accumulation in inflamed tissues, as well as its superior therapeutic efficacy over that of free glucocorticoids (non-liposomal) in the autoimmune diseases, including the adjuvant arthritis rat model and the experimental autoimmune encephalomyelitis mouse model. OBJECTIVES: In the present work we have evaluated the therapeutic effect of the above liposome-based steroidal (MPS) nano-drug in the MRL-lpr/lpr murine model of SLE and compared it with similar doses of the free MPS. METHODS: MRL-lpr/lpr mice were treated with daily injections of free MPS or weekly injections of 10% dextrose, empty nano-liposomes or the steroidal nano-drug and the course of their disease was followed up to the age of 24 weeks. RESULTS: Treatment with the steroidal nano-drug was found to be significantly superior to the free MPS in suppressing anti-dsDNA antibody levels, proliferation of lymphoid tissue and renal damage, and in prolonging survival of animals. CONCLUSION: This significant superiority of our liposome based steroidal nano drug administered weekly compared with daily injections of free methylprednisolone hemisuccinate in suppressing murine lupus indicates this glucocorticoid nano-drug formulation may be a good candidate for the treatment of human SLE. PMID- 26957350 TI - Immune Infertility Should Be Positively Diagnosed Using an Accurate Method by Monitoring the Level of Anti-ACTL7a Antibody. AB - Infertility is currently a major public health problem. Anti-sperm antibodies (ASAs) markedly reduce sperm quality, which can subsequently lead to male and/or female infertility. The accurate detection of ASAs derived from specific spermatozoa is, therefore, clinically useful. We have focused on the spermatozoa specific expression protein ACTL7a for many years and have developed an enzyme linked immunosorbent assay (ELISA) to detect the concentration of anti-ACTL7a antibodies in fertile sera (n = 267) and infertile sera (n = 193). Infertile sera were collected from the positive sera of tray agglutination tests (TAT), which is a routine ASA screening methodology. We found that the concentration of anti ACTL7a antibodies was significantly higher in the infertile sera (than in the fertile sera, P < 0.0001) and much higher in the TAT >= 16 infertile sera. The ELISA was much better for male sera detection (AUC = 0.9899). If we set the standard at a strongly positive value (calculated by ROC curve), the positive predictive value of the antibody detection reached 100 percent, with a false positive rate of zero. The developed ELISA method for anti-ACTL7a antibody detection is therefore sensitive, accurate, and easy to perform, making it an excellent potential tool for future clinical use. PMID- 26957352 TI - Possible risk factors associated with greater damage in systemic lupus erythematosus patients: an Egyptian multicenter study. AB - OBJECTIVES: Systemic lupus erythematosus (SLE) is a prototypic multisystem autoimmune disorder. The total damage in a patient with SLE may result from SLE itself or from any other pathologic process. The aim of this study was to assess risk factors of greater damage in a sample of Egyptian SLE patients. METHODS: This Egyptian multicenter retrospective study included 100 SLE patients: 64 patients from Cairo University Hospitals and 36 patients from Zagazig University Hospitals. The Systemic Lupus International Collaborative Clinics (SLICC)/American College of Rheumatology (ACR) Damage Index (ACR-DI) was used to document the damage in each patient. RESULTS: The total SLICC/ACR-DI score ranged from 0 to 8. A higher DI score was found in hypertensive patients, compared to normotensive patients; and among those with positive anti-phospholipid antibodies, compared to those with negative anti-phospholipid antibodies. This difference was statistically significant (p < 0.01). Also, a higher DI score was found in cyclophosphamide users, compared to non-users; and in those with proteinuria and seizures, compared to those without; and the difference was statistically significant (p < 0.05). There was a significant positive correlation between the DI and patient age (p < 0.05). CONCLUSIONS: Damage in SLE cannot be prevented completely, as SLE disease is considered an aggressive disease treated by aggressive medications, but rheumatologists should try to minimize damage as much as possible to maintain the patients' health, functioning and general wellbeing. PMID- 26957353 TI - Systemic lupus erythematosus in Nepal: A review. AB - Nepal is a small country that is landlocked between India and China. Several ethnic groups live within the 147,181 km(2) of this country. Geographic diversity ranges from the high Himalayas to the flatlands of the Ganges plains. Lupus nephritis (LN), a complication of systemic lupus erythematosus (SLE), is a common kidney problem in Nepal; but the real incidence and prevalence of SLE in Nepal is largely not known. Here, it more commonly affects people (mostly women) living in the southern flatlands, but SLE is reported to be uncommon further south in India. Even though the disease appears to be common, good quality research is uncommon in Nepali literature. This article was written to provide a review of the articles published to date about SLE in Nepal and to discuss the gaps in knowledge that require further evaluation. PMID- 26957355 TI - A new perspective of the structural complexity of HCMV-specific T-cell responses. AB - BACKGROUND: In studies exploring the effects of HCMV infection on immune system aging ('immunosenescence'), after organ transplantation or in other settings, HCMV-specific T-cell responses are often assessed with respect to purportedly 'immunodominant' protein subunits. However, the response structure in terms of recognized antigens and response hierarchies (architecture) is not well understood and actual correlates of immune protection are not known. METHODS: We explored the distribution of T-cell response sizes and dominance hierarchies as well as response breadth in 33 HCMV responders with respect to >200 HCMV proteins. RESULTS: At the individual responder level HCMV-specific T-cell responses were generally arranged in clear dominance hierarchies; interestingly, the number of proteins recognized by an individual correlated closely with the size of their biggest response. Target-specificity varied considerably between donors and across hierarchy levels with the presence, size, and hierarchy position of responses to purportedly 'immunodominant' targets being unpredictable. CONCLUSIONS: Predicting protective immunity based on isolated HCMV subunit-specific T-cell responses is questionable in light of the complex architecture of the overall response. Our findings have important implications for T-cell monitoring, intervention strategies, as well as the application of animal models to the understanding of human infection. PMID- 26957354 TI - Motivation and Treatment Credibility Predicts Dropout, Treatment Adherence, and Clinical Outcomes in an Internet-Based Cognitive Behavioral Relaxation Program: A Randomized Controlled Trial. AB - BACKGROUND: In previous research, variables such as age, education, treatment credibility, and therapeutic alliance have shown to affect patients' treatment adherence and outcome in Internet-based psychotherapy. A more detailed understanding of how such variables are associated with different measures of adherence and clinical outcomes may help in designing more effective online therapy. OBJECTIVE: The aims of this study were to investigate demographical, psychological, and treatment-specific variables that could predict dropout, treatment adherence, and treatment outcomes in a study of online relaxation for mild to moderate stress symptoms. METHODS: Participant dropout and attrition as well as data from self-report instruments completed before, during, and after the online relaxation program were analyzed. Multiple linear and logistical regression analyses were conducted to predict early dropout, overall attrition, online treatment progress, number of registered relaxation exercises, posttreatment symptom levels, and reliable improvement. RESULTS: Dropout was significantly predicted by treatment credibility, whereas overall attrition was associated with reporting a focus on immediate consequences and experiencing a low level of intrinsic motivation for the treatment. Treatment progress was predicted by education level and treatment credibility, whereas number of registered relaxation exercises was associated with experiencing intrinsic motivation for the treatment. Posttreatment stress symptoms were positively predicted by feeling external pressure to participate in the treatment and negatively predicted by treatment credibility. Reporting reliable symptom improvement after treatment was predicted by treatment credibility and therapeutic bond. CONCLUSIONS: This study confirmed that treatment credibility and a good working alliance are factors associated with successful Internet-based psychotherapy. Further, the study showed that measuring adherence in different ways provides somewhat different results, which underscore the importance of carefully defining treatment adherence in psychotherapy research. Lastly, the results suggest that finding the treatment interesting and engaging may help patients carry through with the intervention and complete prescribed assignments, a result that may help guide the design of future interventions. TRIAL REGISTRATION: Clinicaltrials.gov NCT02535598; http://clinicaltrials.gov/ct2/show/NCT02535598 (Archived by WebCite at http://www.webcitation.org/6fl38ms7y). PMID- 26957356 TI - Severe Helicobacter pylori gastritis-related thrombocytopenia and iron deficiency anemia in an adolescent female. PMID- 26957357 TI - Longitudinal changes of endocrine and bone disease in adults with beta thalassemia major receiving different iron chelators over 5 years. AB - In this study, we compared the long-term effects of different iron chelation regimens (deferoxamine, deferiprone, deferoxamine + deferiprone, and deferasirox) in preventing or reversing endocrinopathy (diabetes mellitus, hypothyroidism, or hypogonadism) and bone disease (measured through DEXA) in 165 adults with beta thalassemia major (TM) (mean age 39.9 +/- 8.3 years, 43 % males). After five consecutive years of therapy, patients on deferasirox had the highest decrease in the prevalence of any endocrinopathy compared to other chelators which either had no change (deferiprone and deferoxamine) or had an increase (deferoxamine + deferiprone), p = 0.015. This was attributed to a lower proportion of patients on deferasirox developing new-onset endocrinopathy and higher proportion showing reversal of disease, compared to other chelators. A serum ferritin level of >1300 ng/mL predicted the development of new endocrinopathy (p = 0.025) while a level of <200 ng/mL predicted reversal of existing endocrinopathy (p = 0.147). A significant increase in mean BMD T-score (p < 0.001) and a considerable decrease in osteoporosis prevalence were observed in patients receiving deferasirox but not other chelators. Iron chelation therapy with deferasirox has a role in the prevention of endocrinopathy and reversal of existing disease. PMID- 26957358 TI - New mechanism of lymphoma-induced bone marrow aplasia. PMID- 26957359 TI - Erratum: RSV-specific airway resident memory CD8+ T cells and differential disease severity after experimental human infection. PMID- 26957360 TI - Facile Syntheses of N-Heterocyclic Carbene Precursors through I2 - or NIS Promoted Amidiniumation of N-Alkenyl Formamidines. AB - We have developed I2 - or N-iodosuccinimide (NIS)-mediated amidiniumation of N alkenyl formamidines for the syntheses of cyclic formamidinium salts, some of which could be directly used as N-heterocyclic carbene (NHC) precursors. Treatment of iodine-containing formamidinium salts with Al2 O3 led to the formation of cyclic formamidinium salts with an unsaturated backbone. A rhodium(I) complex ligated by a representative NHC was prepared by the reaction of [Rh(cod)Cl]2 (cod=1,5-cyclooctadiene) with the free carbene obtained in situ from deprotonation of the corresponding formamidinium salts. The NHCs prepared in situ can also react with S8 to afford the corresponding thiones. PMID- 26957361 TI - Eruptive angiokeratomas and porokeratosis in the setting of sclerodermatous graft vs.-host disease. AB - Porokeratosis and angiokeratomas are both seen in the setting of chronic graft vs.-host disease (GVHD), but rarely occur together. We present a case of a patient with lichen planus-like (LPL) and sclerodermatous chronic GVHD manifesting after allogeneic bone marrow transplant with concomitant eruptive angiokeratomas and porokeratosis. PMID- 26957362 TI - Accuracy and postoperative assessment of pedicle screw placement during scoliosis surgery with computer-assisted navigation: a meta-analysis. AB - BACKGROUND: Accurate insertion of pedicle screws in scoliosis patients is a challenge for surgeons. Computer-assisted navigation techniques might help improve the accuracy of screw placement, thereby avoiding complications. Thus, the objective of this present work is to compare the accuracy and postoperative assessment of pedicle screw placement in scoliosis patients using a computer assisted navigation technique and using a conventional free-hand method. METHODS: A search of the PubMed, Cochrane, and Web of Science databases was executed. In vivo comparative studies that assessed the accuracy and postoperative evaluation of pedicle screw placement in scoliosis patients with or without navigation techniques were chosen and analyzed. RESULTS: The accuracy of pedicle screw insertion was significantly increased when using the navigation system, although the average operative time and correction rate was not significantly different from that with non-navigated surgery. CONCLUSION: The navigation technique improves the accuracy of pedicle screw placement during scoliosis surgery without prolonging the operative time or decreasing the deformity correction effect. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26957365 TI - Amputee Locomotion: Ground Reaction Forces During Submaximal Running With Running Specific Prostheses. AB - Individuals with lower extremity amputation must adapt the mechanical interactions between the feet and ground to account for musculoskeletal function loss. However, it is currently unknown how individuals with amputation modulate three-dimensional ground reaction forces (GRFs) when running. This study aimed to understand how running with running-specific prostheses influences three dimensional support forces from the ground. Eight individuals with unilateral transtibial amputations and 8 control subjects ran overground at 2.5, 3.0, and 3.5 m/s. Ten force plates measured GRFs at 1000 Hz. Peak and average GRFs and impulses in each plane were compared between limbs and groups. Prosthetic limbs generated reduced vertical impulses, braking forces and impulses, and mediolateral forces while generating similar propulsive impulses compared with intact and control limbs. Intact limbs generated greater peak and average vertical forces and average braking forces than control subjects' limbs. These data indicate that the nonamputated limb experiences elevated mechanical loading compared with prosthetic and control limbs. This may place individuals with amputation at greater risk of acute injury or joint degeneration in their intact limb. Individuals with amputation adapted to running-specific prosthesis force production limitations by generating longer periods of positive impulse thus producing propulsive impulses equivalent to intact and control limbs. PMID- 26957364 TI - Operational strategies of anti-malarial drug campaigns for malaria elimination in Zambia's southern province: a simulation study. AB - BACKGROUND: Malaria elimination requires reducing both the potential of mosquitoes to transmit parasites to humans and humans to transmit parasites to mosquitoes. To achieve this goal in Southern province, Zambia a mass test and treat (MTAT) campaign was conducted from 2011-2013 to complement high coverage of long-lasting insecticide-treated nets (LLIN). To identify factors likely to increase campaign effectiveness, a modelling approach was applied to investigate the simulated effect of alternative operational strategies for parasite clearance in southern province. METHODS: OpenMalaria, a discrete-time, individual-based stochastic model of malaria, was parameterized for the study area to simulate anti-malarial drug administration for interruption of transmission. Simulations were run for scenarios with a range of artemisinin-combination therapies, proportion of the population reached by the campaign, targeted age groups, time between campaign rounds, Plasmodium falciparum test protocols, and the addition of drugs aimed at preventing onward transmission. A sensitivity analysis was conducted to assess uncertainty of simulation results. Scenarios were evaluated based on the reduction in all-age parasite prevalence during the peak transmission month one year following the campaign, compared to the currently implemented strategy of MTAT 19 % population coverage at pilot and 40 % coverage during the first year of implementation in the presence of 56 % LLIN use and 18 % indoor residual spray coverage. RESULTS: Simulation results suggest the most important determinant of success in reducing prevalence is the population coverage achieved in the campaign, which would require more than 1 year of campaign implementation for elimination. The inclusion of single low-dose primaquine, which acts as a gametocytocide, or ivermectin, which acts as an endectocide, to the drug regimen did not further reduce parasite prevalence one year following the campaign compared to the currently-implemented strategy. Simulation results indicate a high proportion of low-density infections were missed by rapid diagnostic tests that would be treated and cleared with mass drug administration (MDA). CONCLUSIONS: The optimal implementation strategy for MTAT or MDA will vary by background level of prevalence, by rate of infections imported to the area, and by ability to operationally achieve high population coverage. Overall success with new parasite clearance strategies depends on continued coverage of vector control interventions to ensure sustained gains in reduction of disease burden. PMID- 26957363 TI - Classification based on mutations of TERT promoter and IDH characterizes subtypes in grade II/III gliomas. AB - BACKGROUND: Grade II and III gliomas have variable clinical behaviors, showing the distinct molecular genetic alterations from glioblastoma (GBM), many of which eventually transform into more aggressive tumors. Since the classifications of grade II/III gliomas based on the genetic alterations have been recently emerging, it is now a trend to include molecular data into the standard diagnostic algorithm of glioma. METHODS: Here we sequenced TERT promoter mutational status (TERTp-mut) in the DNA of 377 grade II/III gliomas and analyzed the clinical factors, molecular aberrations, and transcriptome profiles. RESULTS: We found that TERTp-mut occurred in 145 of 377 grade II and III gliomas (38.5%), mutually exclusive with a TP53 mutation (TP53-mut; P < .001) and coincident with a 1p/19q co-deletion (P = .002). TERTp-mut was an independent predictive factor of a good prognosis in all patients (P = .048). It has been an independent factor associated with a good outcome in the IDH mutation (IDH-mut) subgroup (P = .018), but it has also been associated with a poor outcome in the IDH wild-type (IDH-wt) subgroup (P = .049). Combining TERTp-mut and IDH-mut allowed the grade II/III malignancies to be reclassified into IDH-mut/TERTp-mut, IDH-mut only, TERTp-mut only, and IDH-wt/TERTp-wt. 1p/19q co-deletion, TP53-muts, Ki-67 expression differences, and p-MET expression differences characterized IDH-mut/TERTp-mut, IDH-mut only, TERTp-mut only, and IDH-wt/TERTp-wt subtypes, respectively. CONCLUSIONS: Our results showed that TERTp-mut combined with IDH-mut allowed simple classification of grade II/III gliomas for stratifying patients and clarifying diagnostic accuracy by supplementing standard histopathological criteria. PMID- 26957366 TI - Validation of the RIDASCREEN((r))FAST Milk Kit. AB - The RIDASCREEN((r))FAST Milk test is a sandwich ELISA for the rapid quantification of milk proteins in various foods. The specific antibodies target casein and beta-lactoglobulin. Samples are extracted and can then be analyzed in less than 40 min. The calibration curve covers a range from 2.5 to 67.5 mg/kg milk protein. The assay was validated with cookies, infant formula, chocolate dessert, ice cream, and sausages. All negative samples were found well below the LOQ of 2.5 mg/kg. Recoveries of the spiked samples were mostly in the range of 80 120%. The LOD of the ELISA was found below 1 mg/kg. The analysis of 39 different substances of interest revealed that no cross-reactivity above the LOQ occurred. Ruggedness testing proved that variations in incubation temperature, reagent volume, incubation time, extraction temperature, and extraction time had no significant influence. The stability at 4-8 degrees C of three independent lots was investigated and found to exceed 18 months. Very good lot-to-lot consistency and no significant loss of the analytical capacity over the shelf life were observed. Incurred cookies and chocolate dessert samples were prepared and analyzed by an independent laboratory; mean recoveries of 94.4 and 102.2% and mean SDs of 10.9 and 6.3%, respectively, were found. For the 0 mg/kg level for both materials, all samples tested returned values of <2.5 mg/kg. Therefore, the analytical performance claims of the manufacturer were confirmed. PMID- 26957367 TI - Beta-catenin is essential for ameloblast movement during enamel development. AB - Beta-catenin is a multifunctional protein that plays key roles in cadherin-based cell adherens junctions and in the Wnt signaling pathway. The canonical Wnt/beta catenin pathway can regulate transcription factors that control cell movement/invasion. We investigated whether beta-catenin regulates ameloblast movement through canonical Wnt signaling. The morphological and physical properties of enamel were assessed in enamel from control and beta-catenin conditional knockout (cKO) mice. Ameloblast-lineage cells (ALC) were used to investigate the potential roles of beta-catenin in cell migration and in E cadherin expression. Compared with controls, incisors from beta-catenin cKO mice were short, blunt, and where enamel was present, it was soft and malformed. Scanning electron microscopy revealed a dysplastic rod pattern within the enamel of incisors from beta-catenin cKO mice, and Vickers microhardness measurements confirmed that mice with beta-catenin ablated from their enamel organ had enamel that was significantly softer than normal. Amelogenesis was disrupted in the absence of beta-catenin and the ameloblasts did not differentiate properly. We further demonstrated that migration of ALCs was inhibited in vitro and that E cadherin expression was significantly up-regulated when ALCs were treated with the beta-catenin inhibitor, ICG-001. Beta-catenin ablation causes enamel malformation in mice and this phenotype may occur, in part, by a lack of ameloblast differentiation and/or movement necessary to form the decussating enamel rod structure. PMID- 26957368 TI - Scanning electron microscopy reveals severe external root resorption in the large periapical lesion. AB - The present study was designed to investigate the relationships between clinicopathological findings and the resorptive conditions of root apices of teeth with periodontitis. The samples included 21 root apices with large periapical radiolucent lesions. The preoperative computed tomography (CT) and intraoperative findings were correlated with the presence, extension, and the progression pattern of periapical resorption using a scanning electron microscope. The subjects' age, gender, chief complaint, type of tooth, percussion test results, size of periapical lesion using CT, and intraoperative findings were recorded. All apicoectomies were performed under an operative microscope for endodontic microsurgery. A significant large size was observed in cystic lesions compared with granulomatous lesions. The cementum surface at the periphery of the lesion was covered with globular structures (2-3 MUm in diameter). Cementum resorption started as small defect formations at the surface. As the defect formation progressed, a lamellar structure appeared at the resorption area, and the size of globular structures became smaller than that of globules at the surface. Further resorption produced typical lacuna formation, which was particularly observed in fracture cases. The most morphologically severe destructive pattern of dentin resorption was observed in large cystic lesions. This study is the first report to elucidate the relationships between three clinical types of undesirable periapical lesions: (1) undertreatment, (2) periapical fracture, (3) macro-level resorption, and the microstructure of external root resorption including from small defects at the cementum surface to a significant destructive pattern inside the dentin. Microsc. Res. Tech. 79:495 500, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26957370 TI - The pectic disaccharides lepidimoic acid and beta-d-xylopyranosyl-(1->3)-d galacturonic acid occur in cress-seed exudate but lack allelochemical activity. AB - BACKGROUND AND AIMS: Cress-seed (Lepidium sativum) exudate exerts an allelochemical effect, promoting excessive hypocotyl elongation and inhibiting root growth in neighbouring Amaranthus caudatus seedlings. We investigated acidic disaccharides present in cress-seed exudate, testing the proposal that the allelochemical is an oligosaccharin-lepidimoic acid (LMA; 4-deoxy-beta-l-threo hex-4-enopyranuronosyl-(1->2)-l-rhamnose). METHODS: Cress-seed exudate was variously treated [heating, ethanolic precipitation, solvent partitioning, high voltage paper electrophoresis and gel-permeation chromatography (GPC)], and the products were bioassayed for effects on dark-grown Amaranthus seedlings. Two acidic disaccharides, including LMA, were isolated and characterized by electrophoresis, thin-layer chromatography (TLC) and nuclear magnetic resonance (NMR) spectroscopy, and then bioassayed. KEY RESULTS: Cress-seed exudate contained low-Mr, hydrophilic, heat-stable material that strongly promoted Amaranthus hypocotyl elongation and inhibited root growth, but that separated from LMA on electrophoresis and GPC. Cress-seed exudate contained ~250 umLMA, whose TLC and electrophoretic mobilities, susceptibility to mild acid hydrolysis and NMR spectra are reported. A second acidic disaccharide, present at ~120 um, was similarly characterized, and shown to be beta-d-xylopyranosyl-(1->3)-d galacturonic acid (Xyl->GalA), a repeat unit of xylogalacturonan. Purified LMA and Xyl->GalA when applied at 360 and 740 um, respectively, only slightly promoted Amaranthus hypocotyl growth, but equally promoted root growth and thus had no effect on the hypocotyl:root ratio, unlike total cress-seed exudate. CONCLUSIONS: LMA is present in cress seeds, probably formed by rhamnogalacturonan lyase action on rhamnogalacturonan-I during seed development. Our results contradict the hypothesis that LMA is a cress allelochemical that appreciably perturbs the growth of potentially competing seedlings. Since LMA and Xyl->GalA slightly promoted both hypocotyl and root elongation, their effect could be nutritional. We conclude that rhamnogalacturonan-I and xylogalacturonan (pectin domains) are not sources of oligosaccharins with allelochemical activity, and the biological roles (if any) of the disaccharides derived from them are unknown. The main allelochemical principle in cress-seed exudate remains to be identified. PMID- 26957371 TI - Outcomes of Health System Structures, Highly Pertinent Clinical Information, Idea Stimulators, Clinical Reviews, and Prediction Tools: JABFM Exemplified. AB - This issue exemplifies the types of articles that JABFM publishes to advance family medicine. We have articles on the implications of health system organizational structures. Three of these are international articles at the level of the national health system (1 from China) and systematic local health interventions (1 from Canada and 1 from Netherlands). Inside the United States, where there are more family physicians, there is less obesity, and designation as a Patient Centered Medical Home is related to increased rates of colorectal cancer screening. Review articles on common clinical topics discuss treatments that are changing (acne in pregnancy) or lack consensus (distal radial fractures). We have articles on making life easier in the office, such as for predicting Vitamin D levels, osteoporosis, and pre-diabetes in normal weight adults. There are articles to raise awareness of the "newest" testing or treatments, that is, auditory brainstem implants. "Reminder" articles highlight known entities that need to be reinforced to prevent over-/underdiagnosis or treatment, for example, "cotton fever." Another article discusses the increased risk for postoperative complications with sleep apnea. We also provide "thought" pieces, in this case about the terminology we are using to extend our concept of patient-centered medical homes. PMID- 26957369 TI - Intracellular signaling pathway regulation of myelination and remyelination in the CNS. AB - The restoration of myelin sheaths on demyelinated axons remains a major obstacle in the treatment of multiple sclerosis (MS). Currently approved therapies work by modulating the immune system to reduce the number and rate of lesion formation but are only partially effective since they are not able to restore lost myelin. In the healthy CNS, myelin continues to be generated throughout life and spontaneous remyelination occurs readily in response to insults. In patients with MS, however, remyelination eventually fails, at least in part as a result of a failure of oligodendrocyte precursor cell (OPC) differentiation and the subsequent production of new myelin. A better understanding of the molecular mechanisms and signaling pathways that drive the process of myelin sheath formation is therefore important in order to speed the development of novel therapeutics designed to target remyelination. Here we review data supporting critical roles for three highly conserved intracellular signaling pathways: Wnt/beta-catenin, PI3K/AKT/mTOR, and ERK/MAPK in the regulation of OPC differentiation and myelination both during development and in remyelination. Potential points of crosstalk between the three pathways and important areas for future research are also discussed. PMID- 26957372 TI - The Impact of Debt on Young Family Physicians: Unanswered Questions with Critical Implications. PMID- 26957373 TI - Over Half of Graduating Family Medicine Residents Report More Than $150,000 in Educational Debt. AB - Primary care workforce shortages are thought to result not only from lower remuneration than other specialties but also from increasing amounts of debt at graduation. A census of 3083 graduating family medicine residents found that 58% reported having >$150,000 in educational debt and 26% reported having >$250,000 levels that may deter students' interest in primary care and constrain the practice location choices of those who do choose primary care. PMID- 26957374 TI - Access to Primary Care in US Counties Is Associated with Lower Obesity Rates. AB - BACKGROUND: Obesity causes substantial morbidity and mortality in the United States. Evidence shows that primary care physician (PCP) supply correlates positively with improved health, but its association with obesity in the United States as not been adequately characterized. Our purpose was to characterize the association between PCP supply in US counties and adult obesity. METHODS: We performed a multivariate logistic regression analysis to examine the relationship between county-level PCP supply and individual obesity status. We controlled for individual variables, including sex, race, marital status, income, and insurance status, and county-level variables, including rurality and poverty. RESULTS: Higher county-level PCP supply was associated with lower adult obesity after controlling for common confounders. Individuals living in counties with the most robust PCP supply were about 20% less likely to be obese (P <= .01) than those living in counties with the lowest PCP supply. CONCLUSIONS: While the observed association between the supply of PCPs and lower rates of obesity may not be causal, the association warrants further investigation. This may have important implications for restructuring the physician workforce in the context of the current PCP shortage and implementation of the Affordable Care Act and the patient-centered medical home. PMID- 26957375 TI - Colorectal Cancer Screening Rates Increased after Exposure to the Patient Centered Medical Home (PCMH). AB - OBJECTIVE: The patient-centered medical home (PCMH) includes comprehensive chronic illness and preventive services, including identifying patients who are overdue for colorectal cancer screening (CRCS). The association between PCMH implementation and CRCS during the Systems of Support to Increase Colorectal Cancer Screening Trial (SOS) is described. METHODS: The SOS enrolled 4664 patients from 21 clinics from August 2008 to November 2009. Patients were randomized to usual care, mailed fecal kits, kits plus brief assistance, or kits plus assistance and navigation. A PCMH model that included a workflow for facilitating CRCS was implemented at all study clinics in late 2009. Patients enrolled early had little exposure to the PCMH, whereas patients enrolled later were exposed during most of their first year in the trial. Logistic regression models were used to assess the association between PCMH exposure and CRCS. RESULTS: Usual care patients with >=8 months in the PCMH had higher CRCS rates than those with <=4 months in the PCMH (adjusted difference, 10.1%; 95% confidence interval, 5.7-14.6). SOS interventions led to significant increases in CRCS, but the magnitude of effect was attenuated by exposure to the PCMH (P for interaction = .01). CONCLUSION: Exposure to a PCMH was associated with higher CRCS rates. Automated mailed and centrally delivered stepped interventions increased CRCS rates, even in the presence of a PCMH. PMID- 26957376 TI - Improving Continuity of Care Reduces Emergency Department Visits by Long-Term Care Residents. AB - INTRODUCTION: Care by DesignTM (CBD) (Canada), a model of coordinated team-based primary care, was implemented in long-term care facilities (LTCFs) in Halifax, Nova Scotia, Canada, to improve access to and continuity of primary care and to reduce high rates of transfers to emergency departments (EDs). METHODS: This was an observational time series before and after the implementation of CBD (Canada). Participants are LTCF residents with 911 Emergency Health Services calls from 10 LTCFs, representing 1424 beds. Data were abstracted from LTCF charts and Emergency Health Services databases. The primary outcome was ambulance transports from LTCFs to EDs. Secondary outcomes included access (primary care physician notes in charts) and continuity (physician numbers and contacts). RESULTS: After implementation of CBD (Canada), transports from LTCFs to EDs were reduced by 36%, from 68 to 44 per month (P = .01). Relational and informational continuity of care improved with resident charts with >=10 physician notes, increasing 38% before CBD to 55% after CBD (P = .003), and the median number of chart notes increased from 7 to 10 (P = .0026). Physicians contacted before 911 calls and onsite assessment increased from 38% to 54% (P = .01) and 3.7% to 9.2% (P = .03), respectively, before CBD to after CBD. CONCLUSION: A 34% reduction in overall transports from LTCFs to EDs is likely attributable to improved onsite primary care, with consistent physician and team engagement and improvements in continuity of care. PMID- 26957377 TI - Multicomponent Program to Reduce Functional Decline in Frail Elderly People: A Cluster Controlled Trial. AB - BACKGROUND: The increasing number of community-dwelling frail elderly people poses a challenge to general practice. We evaluated the effectiveness of a general practitioner-led extensive, multicomponent program integrating cure, care, and welfare for the prevention of functional decline. METHODS: We performed a cluster controlled trial in 12 general practices in Nijmegen, the Netherlands. Community-dwelling frail elderly people aged >=70 years were identified with the EASY-Care two-step older persons screening instrument. In 6 general practices, 287 frail elderly received care according to the CareWell primary care program. This consisted of proactive care planning, case management, medication reviews, and multidisciplinary team meetings with a general practitioner, practice and/or community nurse, elderly care physician, and social worker. In another 6 general practices, 249 participants received care as usual. The primary outcome was independence in functioning during (instrumental) activities of daily living (Katz-15 index). Secondary outcomes were quality of life [EuroQol (EQ5D+C) instrument], mental health and health-related social functioning (36-item RAND Short Form survey instrument), institutionalization, hospitalization, and mortality. Outcomes were assessed at baseline and at 12 months, and were analyzed with linear mixed-model analyses. RESULTS: A total of 204 participants (71.1%) in the intervention group and 165 participants (66.3%) in the control group completed the study. No differences between groups regarding independence in functioning and secondary outcomes were found. CONCLUSION: We found no evidence for the effectiveness of a multifaceted integrated care program in the prevention of adverse outcomes in community-dwelling frail elderly people. Large-scale implementation of this program is not advocated. PMID- 26957378 TI - Lack of Agreement on Distal Radius Fracture Treatment. AB - INTRODUCTION: Variation in clinical practice resulting from the absence of evidence-based treatment protocols has negative implications on both the cost and the quality of medical care. The objective of this study was to assess whether a standard of care for the treatment of extra-articular nondisplaced distal radius fracture has developed despite the lack of a conclusive recommendation from the American Academy of Orthopaedic Surgeons. METHODS: A case-vignette survey was conducted. Treatment type and duration of casting selections were analyzed. The cost implications of responses were assessed. Participants were practicing orthopedists primarily in the mid-Atlantic region of the United States. Orthopedists (n = 494) were recruited via E-mail and at the American Academy of Orthopaedic Surgeons Annual Meeting held in Chicago in March 2013. Inclusion criteria required that participants be graduates of an accredited medical school and be practicing orthopedists at the time of survey distribution. The main outcome measure was surgical or nonsurgical intervention. RESULTS: Nonsurgical treatment was selected by 60% of respondents, with surgery preferred by 37%. Duration of casting responses varied from 2 to 12 weeks. Among nonsurgical responses, 69% indicated 6 weeks as their preferred duration of casting (95% confidence interval, 64.9-73.1%). Surgery imposes a 76% greater total cost to society than nonsurgical treatments. CONCLUSIONS: Our findings suggest the absence of a consensus strategy for the treatment of extra-articular nondisplaced distal radius fractures. Implications of variance in treatment on cost and quality support the need for established, evidence-based guidelines or further clinical trials to assist in the management of this common fracture. PMID- 26957379 TI - Probability of Vitamin D Deficiency by Body Weight and Race/Ethnicity. AB - INTRODUCTION: While most physicians recognize that vitamin D status varies by skin color because darker skin requires more light to synthesize vitamin D than lighter skin, the importance of body weight to vitamin D status is a newer, less recognized, finding. The purpose of this study was to use nationally representative US data to determine the probability of vitamin D deficiency by body weight and skin color. METHODS: Using data for individuals age >=6 years from the 2001 to 2010 cycles of the US National Health and Nutrition Examination Survey, we calculated the effect of skin color, body weight, and age on vitamin D status. We determined the probability of deficiency within the normal range of body weight for 3 race/ethnicity groups at 3 target levels of 25-hydroxyvitamin D. RESULTS: Darker skin colors and heavier body weights are independently and significantly associated with poorer vitamin D status. We report graphically the probability of vitamin D deficiency by body weight and skin color at vitamin D targets of 20 and 30 ng/mL. CONCLUSION: The effects of skin color and body weight on vitamin D status are large both statistically and clinically. Knowledge of these effects may facilitate diagnosis of vitamin D deficiency. PMID- 26957380 TI - Comparison of Clinical Risk Tools for Predicting Osteoporosis in Women Ages 50 64. AB - OBJECTIVE: The objective of this study was to compare the performance of the US Preventive Services Task Force (USPSTF) recommended WHO Fracture Risk Assessment Tool (FRAX) threshold score of 9.3% (calculated without femoral neck bone density) with the Simple Calculated Osteoporosis Risk Estimate (SCORE), Osteoporosis Self-Assessment Tool (OST), and the Osteoporosis Risk Assessment Instrument (ORAI) to identify osteoporosis in younger women. METHODS: We conducted a retrospective review of women ages 50 to 64 years who underwent dual energy radiographic absorptiometry (DXA) at our institution over a 6-month period. Scores for the FRAX, ORAI, OST, and SCORE tools were calculated using various thresholds: FRAX >=9.3%, SCORE >=6, OST <2, and ORAI >=9. Sensitivity, specificity, and area under the receiver-operating characteristic curve for detection of densitometric osteoporosis by DXA for each tool were compared. RESULTS: A total of 290 women were identified. Of these, 284 (97.9%) were white, and the mean +/- standard deviation age was 56.6 +/- 3.4 years. Fifty (17.2%) had osteoporosis of the lumbar spine and/or femoral neck on DXA. Sensitivity, specificity, and area under the receiver-operating characteristic curve for identifying densitometric osteoporosis at the femoral neck and/or spine were 36%, 73%, and 0.55 for FRAX; 74%, 42%, and 0.58 for SCORE; 56%, 69%, and 0.63 for the OST; and 52%, 67%, and 0.60 for the ORAI, respectively. CONCLUSIONS: DXA screening based on the USPSTF-recommended FRAX threshold score of 9.3% has a low sensitivity to identify densitometric osteoporosis in women ages 50 to 64. Lowering the threshold score would increase sensitivity but would also increase the number of women sent for screening DXA. Use of the validated SCORE tool would improve sensitivity to identify osteoporosis in this age group. PMID- 26957381 TI - Underuse of Primary Care in China: The Scale, Causes, and Solutions. AB - Strengthening the primary care system and promoting utilization of primary care are the major targets of China's ambitious health reforms to meet its people's escalating health care needs. However, the changing trend of primary care utilization 4 years before and after 2009, when the health reforms started, is against the government's stated goal. The percentage of outpatient visits in primary care significantly declined from 63% in 2005 to 59% in 2013 (P = .002). In Western China it went down from 66% in 2010 to 62% in 2013 (P = .017) and slightly dropped in Eastern and Central China. Causes are multiple and include major historic and institutional factors such as severe maldistribution of human resources and lack of primary care practitioners (PCPs), lack of a functional gate-keeping mechanism, the low educational attainment of PCPs, and the detrimental elements of health reforms. Immediate measures need to be taken to improve the situation. These include taking irrational hospital expansion under strict control through enhancing the government's accountability for health care industry regulation, strategies to recruit and retain a quality primary care workforce, empowering PCPs as gatekeepers in the system, timely evaluation of the impact of health reforms on primary care, and modifying damaging policies. PMID- 26957382 TI - Maximizing the Patient-Centered Medical Home (PCMH) by Choosing Words Wisely. AB - BACKGROUND: Culture is transmitted through language and reflects a group's values, yet much of the current language used to describe the new patient centered medical home (PCMH) is a carryover from the traditional, physician centric model of care. This language creates a subtle yet powerful force that can perpetuate the status quo, despite transformation efforts. This article describes new terminology that some innovative primary care practices are using to support the transformational culture of the PCMH. METHODS: Data come from the Agency for Healthcare Research and Quality-funded Working Conference for PCMH Innovation 2013, which convened 10 innovative practices and interdisciplinary content experts to discuss innovative practice redesign. Session and interview transcripts were analyzed using a grounded theory approach to identify patterns and explore their significance. RESULTS: Language innovations are used by 5 practices. Carefully selected terms facilitate creative reimagining of traditional roles and spaces through connotations that highlight practice goals. Participants felt that the language used was important for reinforcing substantive changes. CONCLUSIONS: Reworking well-established vernacular requires openness to change. True transformation does not, however, occur through a simple relabeling of old concepts. New terminology must represent values to which practices genuinely aspire, although caution is advised when using language to support cultural and clinical change. PMID- 26957383 TI - Treatment of Acne in Pregnancy. AB - Acne vulgaris is a common disease of the pilosebaceous unit and affects adolescents and adults. Because high-quality guidelines regarding treatment of acne in pregnancy are scarce, management of this condition can be challenging. We describe the safety profile of common therapies and outline approaches based on available evidence. Topical azelaic acid or benzoyl peroxide can be recommended as baseline therapy. A combination of topical erythromycin or clindamycin with benzoyl peroxide is recommended for inflammatory acne. Oral erythromycin or cephalexin is generally considered safe for moderate to severe inflammatory acne when used for a few weeks. A short course of oral prednisolone may be useful for treating fulminant nodular cystic acne after the first trimester. In general, topical and oral antibiotics should not be used as monotherapy, but combined with topical benzoyl peroxide to decrease bacterial resistance. Oral retinoids are teratogenic and absolutely contraindicated for women who are pregnant or considering pregnancy. Although some complementary therapies including micronutrients and nonpharmacologic treatments seem to be well tolerated, limited data exist regarding their safety and efficacy, and they are not currently recommended during pregnancy. The risk-to-benefit ratio, efficacy, acceptability, and costs are considerations when choosing a treatment for acne in pregnancy. PMID- 26957384 TI - Obstructive Sleep Apnea: Preoperative Screening and Postoperative Care. AB - The incidence of obstructive sleep apnea (OSA) has reached epidemic proportions, and it is an often unrecognized cause of perioperative morbidity and mortality. Profound hypoxic injury from apnea during the postoperative period is often misdiagnosed as cardiac arrest due to other causes. Almost a quarter of patients entering a hospital for elective surgery have OSA, and >80% of these cases are undiagnosed at the time of surgery. The perioperative period puts patients at high risk of apneic episodes because of drug effects from sedatives, narcotics, and general anesthesia, as well as from the effects of postoperative rapid eye movement sleep changes and postoperative positioning in the hospital bed. For adults, preoperative screening using the STOP or STOP-Bang questionnaires can help to identify adult patients at increased risk of OSA. In the pediatric setting, a question about snoring should be part of every preoperative examination. For patients with known OSA, continuous positive airway pressure should be continued postoperatively. Continuous pulse oximetry monitoring with an alarm system can help to prevent apneic catastrophes caused by OSA in the postoperative period. PMID- 26957385 TI - Cotton Fever: A Condition Self-Diagnosed by IV Drug Users. AB - The presentation of fever in an intravenous drug user prompts diagnostic testing targeted at identifying infectious etiologies. However, an alternate diagnosis exists in "cotton fever." While few reports describe this phenomenon in the peer reviewed literature, the diagnosis is well recognized among the intravenous drug user community. Although its etiology is not well understood, cotton fever seems to be a self-limited, febrile response to the intravenous administration of a drug filtered through cotton. Educating clinicians regarding cotton fever may limit unnecessary hospital admissions and improve our ability to care for this population. PMID- 26957386 TI - Low Grip Strength and Prediabetes in Normal-Weight Adults. AB - INTRODUCTION: Detection of prediabetes is an important step in diabetes prevention in primary care. Risk stratification of healthy-weight individuals for detection of prediabetes is necessary to avoid missed opportunities for diabetes prevention. METHODS: Using data from the 2011 to 2012 National Health and Nutrition Examination Survey, we studied the relationship between combined handgrip strength, a proxy for lean muscle mass, and prediabetes among adults aged >=20 years without diagnosed or undiagnosed diabetes who had a healthy body mass index (18.5-24.9 kg/m(2); unweighted n = 1340, weighted n = 58,360,690). Prediabetes was defined as having a glycohemoglobin level between 5.7% and 6.4%. RESULTS: Of the healthy-weight adults, 20.5% had prediabetes. Combined mean grip strength was lower for individuals with prediabetes than those with normoglycemia in the full sample (63.8 vs 70.9 kg; P = .004). Similar results were seen among both men (87.9 vs 82.1 kg; P = .03) and women (51.8 vs 56.5 kg; P = .001) in subgroup analysis. CONCLUSIONS: Grip strength is associated with prediabetes among healthy-weight US adults. Grip strength may have utility as an indicator for screening healthy-weight individuals for prediabetes. PMID- 26957387 TI - Prediabetes Diagnosis and Treatment in Primary Care. AB - BACKGROUND: The increasing prevalence of diabetes is a major health problem. The detection and treatment of prediabetes can delay the onset of diabetes and presents an important diabetes prevention strategy. METHODS: Using data from the 2012 National Ambulatory Medical Care Survey, we studied visits by adults aged >=45 years without diagnosed diabetes who had an HbA1c test within 90 days of the visit (n = 518 unweighted visits; n = 11,167,004 weighted visits). HbA1c results were categorized into normal, prediabetes, and diabetes, and we examined patient characteristics (age, sex, race, payer type, body mass index) and treatment of prediabetes. RESULTS: Among visiting adults, 54.6% had a normal HbA1c value, 33.6% had prediabetes, and 11.9% had diabetes. Of those patient visits with HbA1c consistent with prediabetes, the number of patients diagnosed with prediabetes was too low for a reliable population estimate. Indication of treatment in the medical record (lifestyle modification counseling and/or metformin) was present in 23.0% of those with diagnosed or undiagnosed prediabetes. The most common treatment was lifestyle modification counseling. CONCLUSIONS: Our findings show that there are missed opportunities for diabetes prevention in primary care. Providers need to change their approach to prediabetes and play a more effective role in preventing diabetes. PMID- 26957388 TI - Pediatric Auditory Brainstem Implant Surgery: A New Option for Auditory Habilitation in Congenital Deafness? AB - INTRODUCTION: The auditory brainstem implant (ABI) is a neuroprosthetic device that provides sound sensations to individuals with profound hearing loss who are not candidates for a cochlear implant (CI) because of anatomic constraints. Herein we describe the ABI for family physicians. METHODS: PubMed was searched to identify articles relevant to the ABI, as well as articles that contain outcomes data for pediatric patients (age <18 years) who have undergone ABI surgery. RESULTS: The ABI was originally developed for patients with neurofibromatosis type 2 (NF2) who become deaf from bilateral vestibular schwannomas. Over the past decade, indications for an ABI have expanded to adult patients without tumors (without NF2) who cannot receive a CI and children with no cochlea or cochlear nerve. Outcomes among NF2 ABI users are modest compared to cochlear implant patients, but recent studies from Europe suggest that some non-tumor adult and pediatric ABI users achieve speech perception. CONCLUSION: The ABI is a reasonable surgical option for children with profound hearing loss due to severe cochlear or cochlear nerve deformities. Continued prospective data collection from several clinical trials in the U.S. will provide greater understanding on long term outcomes that focus on speech intelligibility. PMID- 26957389 TI - Re: Electronic Health Record Challenges, Workarounds, and Solutions Observed in Practices Integrating Behavioral Health and Primary Care. PMID- 26957390 TI - Re: Patient Preferences for Receiving Reports of Test Results. PMID- 26957391 TI - Synergism of the IGRs Methoprene and Pyriproxyfen Against Larval Cat Fleas (Siphonaptera: Pulicidae). AB - Insect growth regulators (IGRs) methoprene and pyriproxyfen are widely used as topical treatments to pets or applied to the indoor environment to control cat fleas, Ctenocephalides felis (Bouche). The toxicity of methoprene, pyriproxyfen, and combinations of both IGRs to cat flea larvae was determined. The LC50 of methoprene and pyriproxyfen applied to larval rearing medium was 0.39 and 0.19 ppm, respectively. Combinations of methoprene:pyriproxyfen in ratios of 1:1, 5:1, 10:1, and 20:1 produced LC50s of 0.06, 0.09, 0.19, and 0.13 ppm, respectively. The pyriproxyfen synergized the activity of methoprene as indicated by the combination indices (CI). The ratio of methoprene:pyriproxyfen (40:1) provided an LC50 of 0.42 ppm and the pyriproxyfen was not synergistic. Combinations of pyriproxyfen:methoprene in ratios of 5:1, 10:1, and 20:1 provided LC50s of 0.14, 0.20, 0.20 ppm, respectively, and the methoprene did not synergize the activity of pyriproxyfen. The dose-reduction indices (DRIs) indicated that the concentrations of IGRs in the combinations of methoprene:pyriproxyfen (ratios of 20:1 or less) could be reduced by at least one-third of the amount required by methoprene alone to provide similar larval mortality. Combinations of methoprene and pyriproxyfen may be effective in increasing the residual activity on pets and assist in reducing the likelihood of insecticide resistance developing to IGRs. PMID- 26957393 TI - Adult Congenital Heart Surgery: A Thing of Beauty .... PMID- 26957392 TI - Detection of SFTS Virus in Ixodes nipponensis and Amblyomma testudinarium (Ixodida: Ixodidae) Collected From Reptiles in the Republic of Korea. AB - A survey of reptile-associated ticks and their infection status with severe fever with thrombocytopenia syndrome (SFTS) virus was conducted to determine the relative abundance and distribution among lizards, skinks, and snakes in the Republic of Korea (ROK). In total, 132 reptiles, including 49 lizards (two species), 15 skinks (one species), and 68 snakes (eight species) were collected. In total, 84 ixodid ticks belonging to two genera (Ixodes and Amblyomma) were collected from 28/132 (21.2%) lizards, skinks, and snakes. Ixodes nipponensis Kitaoka & Saito was only collected from lizards and skinks, while Amblyomma testudinarium Koch was only collected from snakes. Takydromus wolteri had the highest tick index (0.7; total number ticks/total number collected hosts) among lizards and skinks, while Rhabdophis tigrinus had the highest tick index (2.2) among the snakes. Ixodes nipponensis larvae and nymphs accounted for 11.1% and 88.9%, respectively, of all ticks collected from lizards and skinks, while only A. testudinarium nymphs were collected from snakes. Nymphs of both species of ticks were collected from lizards and skinks from April to October, while I. nipponensis larvae were collected only from September to October. Ixodes nipponensis larvae and nymphs were preferentially attached to the lateral trunk (83.3%) and the foreleg axillae (16.7%) of lizards and skinks. SFTS virus was detected in both I. nipponensis and A. testudinarium collected from lizards and snakes. Phylogenetic analysis of SFTS viruses of ticks collected from two lizards and one snake demonstrated close relationships with SFTS virus strains observed from humans and ticks in the ROK, China, and Japan. These results implicate lizards and snakes as potential hosts of SFTS virus. PMID- 26957394 TI - Advancing Cardiac Critical Care: A Call for Training, Collaboration, and Family Engagement. AB - The evolution and development of pediatric cardiac critical care as a distinct subspecialty have occurred rapidly over the past 20 years. As the field has grown, models for education, training, and care delivery have changed as well. This review will highlight the current state of education, training, and parental involvement in care delivery for pediatric cardiac critical care as initially. PMID- 26957395 TI - Well-Being and Agency in Parents of Children With Congenital Heart Disease: A Survey in Chile. AB - BACKGROUND: Parents of children having congenital heart diseases (CHDs) develop symptoms of depression, distress, anxiety, and hopelessness more frequently than parents of healthy children. Associated with the described symptoms, parents may experience a lack of control and disempowerment, which decreases the parent's agency, a construct from development studies, and which may have negative consequences on adherence to treatment. The primary aim of this study was to assess the effect of medical treatment on well-being and agency in parents of children having CHDs, in Chile, and to compare it with reference values. METHODS: Forty parents of children having CHDs (before surgery and before hospital discharge) and 115 parents of healthy children were surveyed. The following scales were applied to this population: the General Health Questionnaire, the Basic Psychological Needs Scales, the Self-Determination Scale, the Beck Hopelessness Scale, and a socioeconomic survey. RESULTS: Children's surgery decreased parents' hopelessness (3.13 +/- 0.35 and 2.18 +/- 0.40, P = .04), and no significant differences were found in the remaining scales. Parents of children with CHDs scored significantly worse than parents of healthy children on the General Health Questionnaire (13.82 +/- 1.03 and 9.21 +/- 0.64, P = .001). This difference was not found using the others scales. CONCLUSION: Children's surgery has a positive effect on parent's hopelessness, but it does not have any impact on their well-being nor agency. Parents of children with CHD have a decreased well-being compared to parents of healthy children but have a similar level of agency. Socioeconomic level and gender may influence this association. PMID- 26957396 TI - Diaphragmatic Fenestration for Resistant Pleural Effusions After Univentricular Palliation. AB - OBJECTIVE: Persistent pleural effusions are a major source of morbidity after univentricular repair. These are often refractory to conventional conservative therapy. We adopted a strategy of diaphragmatic fenestration (DF) in such patients and report the results. METHODS: Between January 2002 and 2014, we performed DF in 12 patients using an original technique that was first described by us. The medical records of all these patients were studied. Preoperative characteristics, amount and duration of effusions, and time to removal of chest tubes following DF were studied. RESULTS: Mean age was 101 +/- 57.9 months (range: 38-180 months), and mean body weight was 18.8 +/- 5.8 kg (range: 11-28 kg). Five had a bidirectional Glenn, four had lateral tunnel Fontan, and three had an extracardiac Fontan as initial procedure. The average pleural drainage prior to DF was 352.5 +/- 152 mL/24 h (18.75 mL/kg/24 h) for a median period of 33 days (bidirectional Glenn 216 +/- 85 mL/24 h [16.5 mL/kg/24 h] for 30 days and total cavopulmonary connection 450 +/- 104 mL/24 h [22.5 mL/kg/24 h] for 36 days). All patients underwent DF. Additionally, five patients underwent thoracic duct ligation on the left side. Postoperative chest drainage after DF was 25 mL/d for a median of 4 days, and the chest tubes could be removed in a median of 5.5 days (mean 7 days). There were no complications related to DF. CONCLUSIONS: In patients with persistent pleural effusions following univentricular palliation, DF is an attractive option when conventional therapies have failed. This original technique of DF is simple, reproducible, cost-effective, and free of any known complications. PMID- 26957397 TI - The Kidney in Critical Cardiac Disease: Proceedings From the 10th International Conference of the Pediatric Cardiac Intensive Care Society. AB - The field of cardiac intensive care continues to advance in tandem with congenital heart surgery. The focus of intensive care unit care has now shifted to that of morbidity reduction and eventual elimination. Acute kidney injury (AKI) after cardiac surgery is associated with adverse outcomes, including prolonged intensive care and hospital stays, diminished quality of life, and increased long-term mortality. Acute kidney injury occurs frequently, complicating the care of both postoperative patients and those with heart failure. Patients who become fluid overloaded and/or require dialysis are at high risk of mortality, but even minor degrees of AKI portend a significant increase in mortality and morbidity. Clinicians continue to seek methods of early diagnosis and risk stratification of AKI to prevent its adverse sequelae. Previous conventional wisdom that survivors of AKI fully recover renal function without subsequent consequences may be flawed. PMID- 26957398 TI - "Just-In-Time" Simulation Training Using 3-D Printed Cardiac Models After Congenital Cardiac Surgery. AB - BACKGROUND: High-fidelity simulation using patient-specific three-dimensional (3D) models may be effective in facilitating pediatric cardiac intensive care unit (PCICU) provider training for clinical management of congenital cardiac surgery patients. METHODS: The 3D-printed heart models were rendered from preoperative cross-sectional cardiac imaging for 10 patients undergoing congenital cardiac surgery. Immediately following surgical repair, a congenital cardiac surgeon and an intensive care physician conducted a simulation training session regarding postoperative care utilizing the patient-specific 3D model for the PCICU team. After the simulation, Likert-type 0 to 10 scale questionnaire assessed participant perception of impact of the training session. RESULTS: Seventy clinicians participated in training sessions, including 22 physicians, 38 nurses, and 10 ancillary care providers. Average response to whether 3D models were more helpful than standard hand off was 8.4 of 10. Questions regarding enhancement of understanding and clinical ability received average responses of 9.0 or greater, and 90% of participants scored 8 of 10 or higher. Nurses scored significantly higher than other clinicians on self-reported familiarity with the surgery (7.1 vs. 5.8; P = .04), clinical management ability (8.6 vs. 7.7; P = .02), and ability enhancement (9.5 vs. 8.7; P = .02). Compared to physicians, nurses and ancillary providers were more likely to consider 3D models more helpful than standard hand off (8.7 vs. 7.7; P = .05). Higher case complexity predicted greater enhancement of understanding of surgery (P = .04). CONCLUSION: The 3D heart models can be used to enhance congenital cardiac critical care via simulation training of multidisciplinary intensive care teams. Benefit may be dependent on provider type and case complexity. PMID- 26957399 TI - How Suitable Are Registry Data for Recurrence Risk Calculations? Validation of Diagnoses on 1,593 Families With Congenital Heart Disease. AB - BACKGROUND: Congenital heart disease (CHD) occurs in approximately 1% of all live births, and 3% to 8% of these have until now been considered familial cases, defined as the occurrence of two or more affected individuals in a family. The validity of CHD diagnoses in Danish administrative registry data has only been studied previously in highly selected patient populations. These studies identified high positive predictive values (PPVs) and recurrence risk ratios (RRRs-ratio between probabilities of CHD given family history of CHD and no family history). However, the RRR can be distorted if registry data are used indiscriminately. Here, we investigated the consequences of misclassifications for the RRR using validated diagnoses on Danish patients with familial CHD. METHODS: Danish citizens are assigned a civil registration number (CPR number) at birth or immigration, which acts as a unique identifier in the Danish registries, thus enabling connection of information from several registries. Utilizing the CPR number, we identified Danish patients with familial CHD and reviewed each patient's file. We compared diagnoses from the registries with those manually assigned, which enabled calculation of the PPVs of diagnoses in the Danish registries, and from this, we deduced the false discovery rate (FDR). To measure the consequences on the RRR, the FDR was applied to a simulated data set with true RRR values of 2 and 10. RESULTS: We validated diagnoses of 2,442 patients from 1,593 families. Of these, 874 patients were misclassified corresponding to an FDR of 36%. Applying this FDR on the simulated data sets, we found that the RRR decreased from 2 and 10 to 1.4 and 5.1, respectively. Lastly, we estimated that 11% of all cases with CHD were familial. CONCLUSION: We found that approximately one of nine of all cases with CHD are familial, and we also found that 36% of individuals with CHD in administrative medical registries are misclassified, which distort the RRR in simulated scenarios. PMID- 26957400 TI - Transforming Data Into Information. PMID- 26957401 TI - Postoperative Abdominal NIRS Values Predict Low Cardiac Output Syndrome in Neonates. AB - BACKGROUND: The development of low cardiac output syndrome (LCOS) after cardiopulmonary bypass (CPB) occurs in up to 25% of neonates and is associated with increased morbidity. Invasive cardiac output monitors such as pulmonary artery catheters have limited availability and are costly. Near-infrared spectroscopy (NIRS) is a noninvasive tool for monitoring regional oxygenation in neonates in the cardiac intensive care unit (CICU). We hypothesize that anterior abdominal NIRS may aid in the early identification of LCOS after cardiac surgery. METHODS: Prospective observational study from October 2013 to October 2014 of all neonates with congenital heart disease admitted to the CICU following CPB. Abdominal NIRS values were continuously recorded upon CICU admission and for the subsequent 24-hour period. The primary outcome was the development of LCOS. Low cardiac output syndrome was defined as the presence of metabolic lactic acidosis (pH < 7.3 and lactate > 4) or addition of a new vasoactive agent or a vasoactive inotropic score > 15. Autoregressive time series models were constructed for each patient based on the continuously recorded NIRS values, and patients were stratified by development of LCOS. RESULTS: Twenty-seven neonates met inclusion criteria, of whom 11 developed LCOS. Neonates who developed LCOS had lower constant NIRS values (49% vs. 66%, P < .001). Constant NIRS values less than 58% best predicted development of LCOS with a sensitivity of 100% and specificity of 69%. CONCLUSION: Lower constant anterior abdominal NIRS values in the early postoperative period may allow early identification of neonates at risk for LCOS. PMID- 26957402 TI - Evaluation of Adults With Congenital Heart Disease. AB - The clinical approach to adults with congenital heart diseases (ACHDs) is unique in cardiovascular medicine because these patients encompass a broad range of presentations. Each patient, despite having similar diagnosis, will be anatomically and physiologically unlike others within ACHD population, in relation to the type of repair, age at repair, associated defects, with specific long-term risk factors and complications. Furthermore, as many patients will not complain of symptoms, clinical evaluation and diagnostic testing must also be based on the underlying main diagnostic category, with complete standardized lesion-specific clinical protocols, investigating all known risk factors specific for each congenital heart disease and performed as part of screening for significant long-term complications. The first part of this review will focus on clinical history, physical examination, and the most important diagnostic testing in ACHD population. The second part of the article will focus on some clinical issues we have to face in our daily practice, such as heart failure, cyanosis, and pulmonary hypertension. Furthermore, as survival rates of ACHD population continue to improve and patients with this condition live longer, we will briefly report on a new clinical concern regarding the impact of acquired morbidities like coronary artery disease that appear to be of greater importance in defining outcome in older patients with ACHD. PMID- 26957403 TI - Fontan Conversion: Literature Review and Lessons Learned Over 20 Years. AB - Early survival after the Fontan operation has improved significantly leading to a lifetime of Fontan circulation for patients. There is a natural progression of pulmonary artery pressure during the human lifetime that is easily tolerated in two-ventricle physiology but is deleterious for single-ventricle physiology. Obstructions in the venous to pulmonary artery pathway and pulmonary venous return or ventricular outflow, atrioventricular valve dysfunction (regurgitation), pulmonary arteriovenous malformations, venous thrombosis, and the development of atrial arrhythmias can lead to reduced functional status. These complications have been demonstrated in older patients with largely atriopulmonary connections owing to time accrual and unfavorable flow characteristics. Various surgical and catheter interventions aimed at reducing morbidity and mortality have been attempted to treat these identifiable abnormalities. The purpose of this article is to review the extant literature on Fontan Conversion and to assess the lessons learned over 20 years. PMID- 26957404 TI - Noncardiac Challenges in the Cardiac ICU: Feeding, Growth and Gastrointestinal Complications, Anticoagulation, and Analgesia. AB - Outcomes following cardiac intensive care unit (CICU) admission are influenced by many factors including initial cardiac diagnosis, surgical complexity, and burden of critical illness. Additionally, the presence of noncardiac issues may have a significant impact on outcomes and the patient experience during and following an intensive care unit stay. This review focuses on three common noncardiac areas which impact outcomes and patient experience in and beyond the CICU: feeding and growth, pain and analgesia, and anticoagulation. Growth failure and feeding dysfunction are commonly encountered in infants requiring cardiac surgery and have been associated with worse surgical and developmental outcomes. Recent studies most notably in the single ventricle population have demonstrated improved weight gain and outcomes when feeding protocols are implemented. Children undergoing cardiac surgery may experience both acute and chronic pain. Emerging research is investigating the impact of sedatives and analgesics on neurodevelopmental outcomes and quality of life. Improved pain scores and standardized management of pain and withdrawal may improve the patient experience and outcomes. Effective anticoagulation is a critical component of perioperative care but may be complicated by inflammation, multiorgan dysfunction, and patient factors. Advances in monitoring of anticoagulation and emerging therapies are reviewed. PMID- 26957405 TI - Sinus Node Dysfunction After Extracardiac Conduit and Lateral Tunnel Fontan Operation: The Importance of the Type of Prior Superior Cavopulmonary Anastomosis. AB - This review summarizes the influence of the type of prior superior cavopulmonary anastomosis in the studies that report a difference in the occurrence of sinus node dysfunction among extracardiac conduit Fontan and lateral tunnel Fontan operations along with clinical implications. PMID- 26957406 TI - The New AHA/ACC Guidelines for Competitive Sports Participation in Young Athletes With Anomalous Coronary Arteries: The Evolution of Change. PMID- 26957407 TI - [Not Available]. PMID- 26957408 TI - [Not Available]. PMID- 26957409 TI - [Not Available]. PMID- 26957410 TI - [Mechanical circulatory treatment of advanced heart failure]. AB - Heart failure is one of the most common causes of morbidity and mortality worldwide. When patients cease to respond adequately to optimal medical therapy mechanical circulatory support has been promising. The advent of mechanical circulatory support devices has allowed significant improvements in patient survival and quality of life for those with advanced or end-stage heart failure. We provide a general overview of current mechanical circulatory support devices encompassing options for both short- and long-term ventricular support. PMID- 26957411 TI - [Nasal fractures in adults]. AB - The risk of complications warrants treatment of most dislocated nasal fractures. Other injuries including other facial fractures and septal haematoma must be treated if present at the initial presentation. The usual treatment for a simple nasal fracture is closed reduction in local anaesthesia after five to seven days. Complicated cases require open reduction in general anaesthesia. Later revision of the deviated nose may become necessary in patients suffering from complications such as persistent nasal stenosis and/or deformity. PMID- 26957412 TI - [Weak evidence for the use of graduated elastic compression stockings by laparoscopic day surgery]. AB - Deep vein thrombosis and pulmonary embolism are well-known complications after surgery. Despite the widespread use of graduated elastic compression stockings as a mechanical prophylaxis method against thromboembolic complications, data supporting their use for patients under-going laparoscopic surgery for benign conditions are sparse. In this paper, we address the evidence for the effectiveness of the stockings as a method of prophylaxis in laparoscopic day surgery. PMID- 26957413 TI - Inhibition of gingipains and Porphyromonas gingivalis growth and biofilm formation by prenyl flavonoids. AB - BACKGROUND AND OBJECTIVE: Porphyromonas gingivalis is considered a major pathogen of chronic periodontitis, which also may be implicated with systemic diseases such as atherosclerosis. Secreted cysteine proteases, gingipains Rgp and Kgp, are essential for P. gingivalis virulence. Some polyphenols and flavonoids are known to inhibit gingipain activity and interfere with biofilm formation by P. gingivalis. Many bioactive compounds have been isolated from Epimedium species, but availability of these compounds on gingipains and P. gingivalis is still unclear. Therefore, the aim of this study was to evaluate natural products from medical plants to develop a new therapeutic agent against periodontal disease. MATERIAL AND METHODS: Prenylated flavonoids were isolated from Epimedium species plant using column chromatographies. The inhibitory effect of the prenylated flavonoids against protease activity of gingipains were examined using purified gingipains and fluorogenic substrates. Anti-P. gingivalis activity was evaluated to analyze planktonic growth and biofilm formation in brain heart infusion medium in the presence of the prenylated flavonoids. RESULTS: We isolated 17 prenylated flavonoids (Limonianin, Epimedokoreanin B, etc.) from Epimedium species. We found that some prenylated flavonoids inhibited gingipain activity in a non-competitive manner with Ki values at MUm order. The prenylated flavonoids also hindered growth and biofilm formation of P. gingivalis, in a manner independent of gingipain inhibition by the compounds. CONCLUSION: The results indicated an inhibitory effect of the prenylated flavonoids against P. gingivalis and would provide useful information for future development of periodontitis treatment that suppresses gingipains, P. gingivalis growth and biofilm formation. PMID- 26957414 TI - Parallel data acquisition of in-source fragmented glycopeptides to sequence the glycosylation sites of proteins. AB - Glycosylation plays important roles in maintaining protein stability and controlling biological processes. In recent years, the correlation between aberrant glycoproteins and many diseases has been reported. Hence, qualitative and quantitative analyses of glycoproteins are necessary to understand physiological processes. LC-MS/MS analysis of glycopeptides is faced with the low glycopeptide signal intensities and low peptide sequence identification. In our study, in-source fragmentation (ISF) was used in conjunction with LC-MS/MS to facilitate the parallel acquisition of peptide backbone sequence and glycan composition information. In ISF method, the identification of glycosylation sites depended on the detection of Y1 ion (ion of peptide backbone with an N acetylglucosamine attached). To attain dominant Y1 ions, a range of source fragmentation voltages was studied using fetuin. A 45 V ISF voltage was found to be the most efficient voltage for the analysis of glycoproteins. ISF was employed to study the glycosylation sites of three model glycoproteins, including fetuin, alpha1-acid glycoprotein and porcine thyroglobulin. The approach was then used to analyze blood serum samples. Y1 ions of glycopeptides in tryptic digests of samples were detected. Y1 ions of glycopeptides with different sialic acid groups are observed at different retention times, representing the various numbers of sialic acid moieties associated with the same peptide backbone sequence. With ISF facilitating the peptide backbone sequencing of glycopeptides, identified peptide sequence coverage was increased. For example, identified fetuin sequence percentage was improved from 39 to 80% in MASCOT database searching compared to conventional CID method. The formation of Y1 ions and oxonium ions in ISF facilitates glycopeptide sequencing and glycan composition identification. PMID- 26957415 TI - Uptake of free, calcium-bound and liposomal encapsulated nitrogen containing bisphosphonates by breast cancer cells. AB - PURPOSE: We have examined the uptake routes by which breast cancer cells internalize different formulations of nitrogen containing bisphosphonates (N BPs). METHODS: Cell viability was assessed with the tetrazolium colorimetric test (MTT assay) after treatment with different N-BP formulations in the presence or absence of inhibitors for different endocytosis mechanisms. Intracellular formation of isopentenyl pyrophosphate (IPP) and triphosphoric acid 1-adenosin-5' yl ester 3-(3-methylbut-3-enyl) ester (ApppI), were quantified with mass spectrometry (ES-LTQ-MS) as surrogate markers for N-BP efficacy. Direct quantification intracellular [(14)C]-labeled zoledronic acid was done with liquid scintillation counting. RESULTS: The main uptake route for all the different formulations of nitrogen containing bisphosphonates was shown to be dynamin dependent endocytosis, which was significantly enhanced with calcium. This uptake mechanism was mostly caveolin and clathrin independent in MCF7 cells, but more clathrin dependent in T47D cells. Liposome encapsulation of the drug shifted the uptake mechanism to be more dependent on caveolin in both the cell lines. The cytotoxicity of N-BPs and the concentrations of formed intracellular ApppI and IPP were significantly increased by calcium chelation and liposome encapsulation, the latter being the most potent formulation. CONCLUSION: Nitrogen containing bisphosphonates require active endocytosis for cellular uptake and in the breast cancer cells the mechanism is uniformly dynamin dependent for all the formulations tested. This differs e.g. from the previous observations on macrophages, which mostly utilize macropinocytosis. Liposomal formulation was found to prolong the duration of the drug effect in cells. PMID- 26957416 TI - Histone demethylase JMJD3 at the intersection of cellular senescence and cancer. AB - Cellular senescence is defined by an irreversible growth arrest and is an important biological mechanism for suppression of tumor formation. Although deletion/mutation to DNA sequences is one mechanism by which cancer cells can escape senescence, little is known about the epigenetic factors contributing to this process. Histone modifications and chromatin remodeling related to the function of a histone demethylase, jumonji domain-containing protein 3 (JMJD3; also known as KDM6B), play an important role in development, tissue regeneration, stem cells, inflammation, and cellular senescence and aging. The role of JMJD3 in cancer is poorly understood and its function may be at the intersection of many pathways promoted in a dysfunctional manner such as activation of the senescence associated secretory phenotype (SASP) observed in aging. PMID- 26957417 TI - Temporal Trends in the Risk Profile of Patients Undergoing Outpatient Percutaneous Coronary Intervention: A Report from the National Cardiovascular Data Registry's CathPCI Registry. AB - BACKGROUND: Because of recent changes in criteria for coverage for inpatient hospital stays, most nonacute percutaneous coronary intervention (PCI) procedures are reimbursed on an outpatient basis regardless of underlying patient risk. Downstream effects of these changes on the risk profile of patients undergoing outpatient PCI have not been evaluated. METHODS AND RESULTS: Using the American College of Cardiology National Cardiovascular Data Registry's CathPCI Registry, we assessed temporal trends in risk profiles and rates of hospital admission among 999 279 patients undergoing PCI qualifying for outpatient reimbursement. We estimated mortality and bleeding risk using validated models from the registry. From 2009 to 2014, the proportion of outpatients not admitted to a hospital after PCI increased from 32.8% to 66.3% (P<0.001). Patients who were admitted after PCI were older, had greater comorbidities, and experienced more post-PCI complications (all P<0.001). Among those not admitted, the proportion of patients at high risk for predicted mortality increased significantly from 17.0% to 19.8% during the study period (P<0.001). In contrast, 16.7% of patients admitted after PCI were at low risk for mortality. CONCLUSIONS: Among patients undergoing PCI procedures that qualify for outpatient reimbursement, there has been a temporal decrease in postprocedure hospital admission. Concomitantly, the proportion of these outpatients at high risk for mortality has significantly increased over time. These data suggest that current reimbursement classification could be improved by incorporating patient risk to appropriately match the necessary resources to the needed level of care. PMID- 26957419 TI - Inpatient or Outpatient Status for Elective Percutaneous Coronary Intervention: Doctor, "You Gotta Let Me Know, Should I Stay or Should I Go?". PMID- 26957418 TI - Comparison of Immediate With Delayed Stenting Using the Minimalist Immediate Mechanical Intervention Approach in Acute ST-Segment-Elevation Myocardial Infarction: The MIMI Study. AB - BACKGROUND: Delayed stent implantation after restoration of normal epicardial flow by a minimalist immediate mechanical intervention aims to decrease the rate of distal embolization and impaired myocardial reperfusion after percutaneous coronary intervention. We sought to confirm whether a delayed stenting (DS) approach (24-48 hours) improves myocardial reperfusion, versus immediate stenting, in patients with acute ST-segment-elevation myocardial infarction undergoing primary percutaneous coronary intervention. METHODS AND RESULTS: In the prospective, randomized, open-label minimalist immediate mechanical intervention (MIMI) trial, patients (n=140) with ST-segment-elevation myocardial infarction <=12 hours were randomized to immediate stenting (n=73) or DS (n=67) after Thrombolysis In Myocardial Infarction 3 flow restoration by thrombus aspiration. Patients in the DS group underwent a second coronary arteriography for stent implantation a median of 36 hours (interquartile range 29-46) after randomization. The primary end point was microvascular obstruction (% left ventricular mass) on cardiac magnetic resonance imaging performed 5 days (interquartile range 4-6) after the first procedure. There was a nonsignificant trend toward lower microvascular obstruction in the immediate stenting group compared with DS group (1.88% versus 3.96%; P=0.051), which became significant after adjustment for the area at risk (P=0.049). Median infarct weight, left ventricular ejection fraction, and infarct size did not differ between groups. No difference in 6-month outcomes was apparent for the rate of major cardiovascular and cerebral events. CONCLUSIONS: The present findings do not support a strategy of DS versus immediate stenting in patients with ST-segment-elevation infarction undergoing primary percutaneous coronary intervention and even suggested a deleterious effect of DS on microvascular obstruction size. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01360242. PMID- 26957420 TI - An Efficient Lanthanide-Dependent DNAzyme Cleaving 2'-5'-Linked RNA. AB - RNA can form two types of linkage. In addition to the predominant 3'-5' linkage, 2'-5'-linked RNA is also important in biology, medicine, and prebiotic studies. Here, in vitro selection was used to isolate a DNAzyme that specifically cleaves 2'-5' RNA by using Ce(3+) as the metal cofactor, but leaves the 3'-5' counterpart intact. This Ce5 DNAzyme requires trivalent light lanthanide ions and shows a rate of 0.16 min(-1) in the presence of 10 MUm Ce(3+) ; the activity decreases with heavier lanthanide ions. This is the fastest DNAzyme reported for this reaction, and it might enable applications in chemical biology. As a proof-of concept, using this DNAzyme, the reactions between phosphorothioate-modified RNA and strongly thiophilic metals (Hg(2+) and Tl(3+) ) were studied as a function of pH. PMID- 26957422 TI - Reincarnated medicines: using out-dated drugs for novel indications. PMID- 26957421 TI - Imaging- and physiology-guided percutaneous coronary intervention without contrast administration in advanced renal failure: a feasibility, safety, and outcome study. AB - AIMS: The feasibility, safety, and clinical utility of percutaneous coronary intervention (PCI) without radio-contrast medium in patients with advanced chronic kidney disease (CKD) are unknown. In this series, we investigated a specific strategy for 'zero contrast' PCI with the aims of preserving renal function and preventing the need for renal replacement therapy (RRT) in patients with advanced CKD. METHODS AND RESULTS: A total of 31 patients with advanced CKD [creatinine = 4.2 mg/dL, inter-quartile range (IQR) 3.1-4.8, estimated glomerular filtration rate = 16 +/- 8 mL/min/1.73 m2] who had clinical indication for PCI based on a prior minimal contrast coronary angiogram were included. Zero contrast PCI was performed at least 1 week after diagnostic angiography using real-time intravascular ultrasound (IVUS) guidance, with pre- and post-PCI measurements of fractional flow reserve and coronary flow reserve to confirm physiological improvement. This approach resulted in successful PCI, no major adverse cardiovascular events and preservation of renal function without the need for RRT within a follow-up time of 79 days (IQR 33-207) in all patients. CONCLUSION: In patients with advanced CKD who require revascularization, PCI may safely be performed without contrast using IVUS and physiological guidance with high procedural success and without complications. PMID- 26957423 TI - Assessing suspected angina: requiem for coronary computed tomography angiography or exercise electrocardiogram? PMID- 26957425 TI - Sex differences in the Simon task help to interpret sex differences in selective attention. AB - In the last decade, a number of studies have reported sex differences in selective attention, but a unified explanation for these effects is still missing. This study aims to better understand these differences and put them in an evolutionary psychological context. 418 adult participants performed a computer-based Simon task, in which they responded to the direction of a left or right pointing arrow appearing left or right from a fixation point. Women were more strongly influenced by task-irrelevant spatial information than men (i.e., the Simon effect was larger in women, Cohen's d = 0.39). Further, the analysis of sex differences in behavioral adjustment to errors revealed that women slow down more than men following mistakes (d = 0.53). Based on the combined results of previous studies and the current data, it is proposed that sex differences in selective attention are caused by underlying sex differences in core abilities, such as spatial or verbal cognition. PMID- 26957426 TI - Emission and distribution of PCDD/Fs and CBzs from two co-processing RDF cement plants in China. AB - An analysis of the emission and distribution characteristics of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) and chlorobenzenes (CBzs) from two cement kilns (CK1 and CK2) is done. Six measurements in CK1 showed an increase of PCDD/F emission from 76 to 97 pg I-TEQ/Nm(3) after feeding 10 ton/h RDF (refuse derived fuel). For CK2, the effect of increasing the RDF substitution rates from 0 to 21 t/h on the emission of PCDD/Fs was investigated. The correlation analysis indicated that replacing parts of the conventional fuel with RDF could not increase the emission of PCDD/Fs. Furthermore, the gas/particle partitions of PCDD/Fs and CBzs in stack gas were investigated, indicating that PCDD/Fs and CBzs were more associated in gas phase, especially for the lower chlorinated ones. Moreover, the bag filter fly ash was characterized by its particle distribution, XRD- and EDS-analysis. Additionally, the level of PCDD/Fs in outflowing fly ash escalates for smaller particle size. In order to evaluate the environmental effect on inhabitants, the levels of PCDD/Fs were also determined in samples of ambient air collected in the vicinity of CK2 (~200 m). PMID- 26957424 TI - Next-generation genotyping of hypervariable loci in many individuals of a non model species: technical and theoretical implications. AB - BACKGROUND: Across species, diversity at the Major Histocompatibility Complex (MHC) is critical to disease resistance and population health; however, use of MHC diversity to quantify the genetic health of populations has been hampered by the extreme variation found in MHC genes. Next generation sequencing (NGS) technology generates sufficient data to genotype even the most diverse species, but workflows for distinguishing artifacts from alleles are still under development. We used NGS to evaluate the MHC diversity of over 300 captive and wild ring-tailed lemurs (Lemur catta: Primates: Mammalia). We modified a published workflow to address errors that arise from deep sequencing individuals and tested for evidence of selection at the most diverse MHC genes. RESULTS: In addition to evaluating the accuracy of 454 Titanium and Ion Torrent PGM for genotyping large populations at hypervariable genes, we suggested modifications to improve current methods of allele calling. Using these modifications, we genotyped 302 out of 319 individuals, obtaining an average sequencing depth of over 1000 reads per amplicon. We identified 55 MHC-DRB alleles, 51 of which were previously undescribed, and provide the first sequences of five additional MHC genes: DOA, DOB, DPA, DQA, and DRA. The additional five MHC genes had one or two alleles each with little sequence variation; however, the 55 MHC-DRB alleles showed a high dN/dS ratio and trans-species polymorphism, indicating a history of positive selection. Because each individual possessed 1-7 MHC-DRB alleles, we suggest that ring-tailed lemurs have four, putatively functional, MHC-DRB copies. CONCLUSIONS: In the future, accurate genotyping methods for NGS data will be critical to assessing genetic variation in non-model species. We recommend that future NGS studies increase the proportion of replicated samples, both within and across platforms, particularly for hypervariable genes like the MHC. Quantifying MHC diversity within non-model species is the first step to assessing the relationship of genetic diversity at functional loci to individual fitness and population viability. Owing to MHC-DRB diversity and copy number, ring-tailed lemurs may serve as an ideal model for estimating the interaction between genetic diversity, fitness, and environment, especially regarding endangered species. PMID- 26957427 TI - Metallothionein modulation in relation to cadmium bioaccumulation and age dependent sensitivity of Chironomus riparius larvae. AB - The goal of this study was to contribute to understanding of the mechanisms behind sensitivity differences between early and late instar larvae of Chironomus riparius and to address the influence of the differences in standard testing approaches on the toxicity evaluation. A 10-day contact sediment toxicity test was carried out to assess sensitivity to cadmium exposure in relation to different age and laboratory culture line origin of test organisms. Chironomid larvae of early (OECD 218 method) and late instar (US-EPA600/R-99/064 method) differed substantially in sensitivity of traditional endpoints (OECD: LOEC 50 and 10 MUg Cd/g dry weight (dw); US-EPA: LOEC > 1000 and 100 MUg Cd/g dw for survival and growth, respectively). Bioaccumulated cadmium and metallothioneins (MTs) concentrations were analyzed to investigate the role of MTs in reduced sensitivity to cadmium in late instar larvae. Metallothioneins were induced after treatment to greater Cd concentrations, but their levels in relation to cadmium body burdens did not fully explain low sensitivity of late instars to cadmium, which indicates some other effective way of detoxification in late instars. This study brings new information related to the role of MTs in age-dependent toxicant sensitivity and discusses the implications of divergence in data generated by chironomid sediment toxicity tests by standardized methods using different instars. PMID- 26957428 TI - Ameliorative effect of flaxseed oil against thiacloprid-induced toxicity in rats: hematological, biochemical, and histopathological study. AB - The present study was carried out to evaluate the hematological, biochemical, and histopathological changes due to thiacloprid toxicity, and the potential protective role of flaxseed oil in male Wistar albino rats. Subacute thiacloprid intoxication induced a significant increase in RBCs, Hb, PCV, and WBCs count, and bone marrow micronucleus (MN) formation. Moreover, there was a significant increase in serum biochemical parameters related to hepatic injury: alanine aminotransferase (ALT) and alkaline phosphatase (ALP). Serum total protein and albumin levels were significantly reduced. Thiacloprid increases tumor necrosis factor-alpha (TNF-alpha) and interleukine-2(IL-2). There was a significant decrease in glutathione-S-transferase, while the lipid peroxidation (MDA) and cytochrome P450 activity were significantly increased. Flaxseed oil coadministration partially retrieved the changes in all studied parameters. Thiacloprid induced histopathological liver damage, which was minimized as a result of flaxseed oil treatment. In general, it was concluded that, flaxseed oil able to protect against thiacloprid-induced hepatoxicity. PMID- 26957430 TI - An assessment of the physicochemical properties and toxicity potential of carwash effluents from professional carwash outlets in Gauteng Province, South Africa. AB - The assessment of the quality of carwash effluents has received scant attention as a potential source of public and environmental health hazard in South Africa as demonstrated by the lack of literature in this subject. The physicochemical quality and potential ramifications of carwash effluents on receiving waterbodies were investigated in this study. Grab effluent samples were collected from six carwash outlets in Gauteng Province of South Africa and analysed for selected physicochemical qualities including biological oxygen demand (BOD), oil and grease, total petroleum hydrocarbons-gasoline range organics (TPH-GRO), pH, dissolved oxygen (DO), total solids (TS) and total dissolved solids (TDS), electrical conductivity (EC), nutrients (nitrates, nitrites and phosphates), anionic surfactants and heavy metals (zinc [Zn], copper [Cu], lead [Pb] and chromium [Cr]). Further, the toxicity potential of the effluent samples was assessed using organisms from four trophic levels ranging from Selenastrum capricornutum (primary producer), Daphnia magna (primary consumer), Poecilia reticulata (secondary-tertiary consumer) and Vibrio fischeri (decomposer). High pollutant levels were observed in all effluents with BOD ranging from 27 +/- 2.1 to 650 +/- 4.9 mg/l, TDS from 362 +/- 8.5 to 686 +/- 8.5 mg/l, GRO-TPH from 0.01 +/- 0.0 to 7.6 +/- 0.2 mg/l, DO from 0.0 to 0.1 mg/l, Zn from 0.79 +/- 0.08 to 20 +/- 2.12 mg/l, Cu from 0.77 +/- 0.03 to 13 +/- 0.71 mg/l and oil and grease from 12 +/- 2.8 to 43 +/- 2.1 mg/l. Ammonium concentrations ranged from 0.4 +/- 0.1 to 75 +/- 6.4 mg/l; turbidity from 109 +/- 0.7 to 4000 +/- 29.7 mg/l, anionic surfactants from 1.4 +/- 0.1 to 5.8 +/- 0.3 mg/l and TPH from <0.01 to 7.6 mg/l. Toxicity assessment assays resulted in 100 % mortality for fish and Daphnia after 96 and 24 h, respectively, and significant bioluminescence and growth reduction in V. fischeri and algae after 15 min and 72 h, respectively. Most of the measured physicochemical parameters were in concentrations above the Environmental Management Agency (EPA) stipulated guidelines. Additionally, the effluents demonstrated acute toxicity against all four test species. PMID- 26957429 TI - Osmoregulation and antioxidant production in maize under combined cadmium and arsenic stress. AB - An investigation was carried out to examine the combined and individual effects of cadmium (Cd) and arsenic (As) stress on osmolyte accumulation, antioxidant activities, and reactive oxygen species (ROS) production at different growth stages (45, 60, 75, 90 days after sowing (DAS)) of two maize cultivars viz., Dong Dan 80 and Run Nong 35. The Cd (100 MUM) and As (200 MUM) were applied separately as well as in combination (Cd + As) at 30 DAS. Results revealed pronounced variations in the behavior of antioxidants, osmolytes, and ROS in both maize cultivars under the influence of Cd and As stress. Activities of enzymatic (SOD, POD, CAT and APX, GPX, GR) and non-enzymatic (GSH and AsA) antioxidants, generation of ROS, and accumulation of osmolytes were enhanced with the passage of time; therefore, the maximum values for these attributes were observed at 90 DAS for both cultivars. Exposure of plants to Cd or As stress considerably enhanced the antioxidant activities, ROS, and osmolyte accumulation compared with control, while combined application of Cd + As was more devastating in reducing plant biomass of both maize cultivars. Among cultivars, Dong Dan 80 was better able to negate the heavy metal-induced oxidative damage, which was associated with higher antioxidant activities, greater osmolytes accumulation, and lower ROS production in this cultivar. PMID- 26957431 TI - Dissipation of six fungicides in greenhouse-grown tomatoes with processing and health risk. AB - Greenhouse studies were conducted to evaluate the dissipation rate kinetics and estimate the behavior of selected pesticides after washing, peeling, simmering, and canning of tomato expressed as processing factor (PF). Two varieties (Marissa and Harzfeuer) were treated by six fungicides: azoxystrobin, boscalid, chlorothalonil, cyprodinil, fludioxonil, and pyraclostrobin at single and double dose and risk assessment defined as hazard quotient was performed. The QuEChERS method was used for sample preparation followed by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). The dissipation of fungicides approximately fitted to a first-order kinetic model, with half-life values ranging from 2.49 and 2.67 days (cyprodinil) to 5.00 and 5.32 days (chlorothalonil) for Marissa and Harzfeuer variety, respectively. Results from processing studies showed that treatments have significant effects on the removal of the studied fungicides for both varieties. The PFs were generally less than 1 (between 0.01 and 0.90) and did not depend on variety. The dietary exposure assessed based on initial deposits of application at single and double dose on tomatoes and concentration after each process with PF correction showed no concern to consumer health. Our results would be a useful tool for monitoring of fungicides in tomatoes and provide more understanding of residue behavior and risk posed by these fungicides. PMID- 26957432 TI - Evaluation of metal mobility from copper mine tailings in northern Chile. AB - This work shows the results obtained on a copper mine tailing in the Antofagasta Region, Chile. The tailing was classified as saline-sodic with high concentrations of metals, especially Cu and Fe, with pH 8.4. Our objectives were to (1) compare the physicochemical properties of the tailing with surrounding soils of the mine under study, and (2) evaluate the effect of two amendments (CaCO3 and compost) and their mixtures on Cu(2+), Mn, Fe, Zn, Mg(2+), and K(+) and Ca(2+), SO4 (2-), NO3 (-), and PO4 (3-) leaching. The data obtained were submitted to variance and covariance analysis. The results from the comparison between both substrates showed that in general, the tailing presented greater content of metals. Regarding tailing leaching, pH, electrical conductivity (EC), and concentration of the elements of interest were measured. The statistical analysis showed that Cu(2+) leaching and immobilization of Fe occurred to the greatest extent with compost. The EC decreased throughout the experiment with irrigation and increased upon treatment with compost. The major interactions found among the chemical parameters were (1) tailings without treatment, Cu(2+)/Fe and NO3 (-)/SO4 (2-); (2) tailings treated with CaCO3, Cu(2+)/K(+); (3) tailings treated with compost, NO3 (-)/SO4 (-2) and EC/Cu(2+); and (4) tailings treated with both amendments, EC/Fe and Cu(2+)/Fe. The ANOVA showed that the number of irrigations and the amendments statistically significantly affected the copper mobility and the organic amendment significantly influenced the iron mobility. PMID- 26957433 TI - Summative peer marking? PMID- 26957435 TI - White-Nose Syndrome Disease Severity and a Comparison of Diagnostic Methods. AB - White-nose syndrome is caused by the fungus Pseudogymnoascus destructans and has killed millions of hibernating bats in North America but the pathophysiology of the disease remains poorly understood. Our objectives were to (1) assess non destructive diagnostic methods for P. destructans infection compared to histopathology, the current gold-standard, and (2) to evaluate potential metrics of disease severity. We used data from three captive inoculation experiments involving 181 little brown bats (Myotis lucifugus) to compare histopathology, quantitative PCR (qPCR), and ultraviolet fluorescence as diagnostic methods of P. destructans infection. To assess disease severity, we considered two histology metrics (wing area with fungal hyphae, area of dermal necrosis), P. destructans fungal load (qPCR), ultraviolet fluorescence, and blood chemistry (hematocrit, sodium, glucose, pCO2, and bicarbonate). Quantitative PCR was most effective for early detection of P. destructans, while all three methods were comparable in severe infections. Correlations among hyphae and necrosis scores, qPCR, ultraviolet fluorescence, blood chemistry, and hibernation duration indicate a multi-stage pattern of disease. Disruptions of homeostasis occurred rapidly in late hibernation. Our results provide valuable information about the use of non destructive techniques for monitoring, and provide novel insight into the pathophysiology of white-nose syndrome, with implications for developing and implementing potential mitigation strategies. PMID- 26957437 TI - Erratum to: Company Policies on Working Hours and Night Work in Relation to Older Workers' Work Ability and Work Engagement: Results From a Dutch Longitudinal Study with 2 Year Follow-Up. PMID- 26957436 TI - Protecting Free-Living Dormice: Molecular Identification of Cestode Parasites in Captive Dormice (Muscardinus avellanarius) Destined for Reintroduction. AB - The success of any population translocation programme relies heavily on the measures implemented to control and monitor the spread of disease. Without these measures, programmes run the risk of releasing immunologically naive species or, more dangerously, introducing novel infectious agents to native populations. As a precaution, a reintroduction programme for the common or hazel dormouse, Muscardinus avellanarius, in England screens dormice before release following captive breeding. Using PCR sequencing of a range of genes, we tested whether the same species of tapeworm(s) were present in captive and free-living dormice. Whilst only Rodentolepis straminea were identified in free-living dormice, cestode ova found in a captive individual produced a molecular match closely related to Hymenolepis microstoma and a previously unrecorded Rodentolepis species. To prevent putting at risk the free-living population, we recommended the continued treatment of dormice showing tapeworm infection before release. Our work demonstrates how molecular techniques can be used to inform reintroduction programmes, reduce risk from disease and increase chances of reintroduction success. PMID- 26957434 TI - Effect of bexarotene on differentiation of glioblastoma multiforme compared with ATRA. AB - Glioblastoma multiforme (GBM) is the most aggressive malignant brain tumor. Since differentiation can attenuate or halt the growth of tumor cells, an image-based phenotypic screening was performed to find out drugs inducing morphological differentiation of GBMs. Bexarotene, a selective retinoid X receptor agonist, showed strong inhibition of neurospheroidal colony formation and migration of cultured primary GBM cells. Bexarotene treatment reduced nestin expression, while significantly increasing glial fibrillary acidic protein (GFAP) expression. The effect of bexarotene on gene expression profile was compared with the activity of all-trans retinoic acid (ATRA), a well-known differentiation inducer. Both drugs largely altered the gene expression pattern into a tumor-ameliorating direction. These drugs increased the gene expression levels of Kruppel-like factor 9 (KLF9), regulator of G-protein signaling 4 (RGS4), growth differentiation factor 15 (GDF15), angiopoietin-like protein 4 (ANGPTL4), and lowered the level of chemokine receptor type 4 (CXCR4). However, transglutaminase 2 (TG2) induction, an adverse effect of ATRA, was much weaker in bexarotene treated primary GBM cells. Consistently, the TG2 enzymatic activity was negligibly affected by bexarotene treatment. It is important to control TG2 overexpression since its upregulation is correlated with tumor transformation and drug resistance. Bexarotene also showed in vivo tumoricidal effects in a GBM xenograft mouse model. Therefore, we suggest bexarotene as a more beneficial differentiation agent than ATRA for GBM. PMID- 26957438 TI - If you cannot move, send messengers: how cells organize space. PMID- 26957439 TI - HBsAg loss in a New Zealand community study with 28-year follow-up: rates, predictors and long-term outcomes. AB - BACKGROUND AND AIMS: HBsAg seroclearance is the most desired endpoint in chronic hepatitis B (CHB) but occurs uncommonly. Recent studies have shown baseline HBsAg levels to be predictive of HBsAg loss up to 10 years. We report the 28-year rates of HBsAg loss and outcomes in the Kawerau study cohort from New Zealand, and assess the predictive value of baseline HBsAg levels to predict long-term HBsAg loss. METHODS: The 1984 Kawerau community study identified 572 CHB patients, followed up for 28 years (41 % HBeAg-positive, median age 17 years, range 1-71 years). In 2012, surviving individuals attended a local clinic for an interview, blood tests and transient elastography. RESULTS: 384/218 (74 %) surviving individuals attended the clinic in 2012. Spontaneous HBsAg loss occurred in 145 (33 %) after 12,702 person-years of follow-up (1.14 per 100 person-years). Liver stiffness measurements were significantly lower if HBsAg loss occurred <50 years (mean 6.1 kPa) versus >50 years (mean 11.6 kPa), p = 0.0002. No HCC occurred following HBsAg loss (median follow-up 72 months). Predictors of HBsAg loss were older age and lower baseline HBsAg level (HR for HBsAg loss at 28 years 2.7 (95 % CI 1.7-4.2), 6.7 (95 % CI 3.9-11.4) and 9.4 (95 % CI 5.2-16.9), respectively, for HBsAg 1000-9999, 100-999 and <100 IU/mL compared to HBsAg >10,000 IU/mL at baseline, (p < 0.0001). Baseline HBsAg was a superior predictor of HBsAg loss compared to HBV DNA at all time-points: AUROC at 15 years: 0.87 (95 % CI 0.82 0.93) versus 0.73 (95 % CI 0.66-0.80) (p < 0.0001) and AUROC at 28 years: 0.74 (95 % CI 0.69-0.79) versus 0.67 (95 % CI 0.62-0.72) (p = 0.0007). The optimal cut off HBsAg level to predict HBsAg seroclearance at 28 years is HBsAg <10,000 IU/mL (sensitivity 72 %, specificity 64 %, NPV 88 %). CONCLUSIONS: Rates of HBsAg loss in our community cohort were high, and occurred earlier than previously reported. Earlier HBsAg loss was associated with less severe liver fibrosis. Baseline HBsAg level was a good predictor of long-term HBsAg loss up to 28 years and superior to HBV DNA. PMID- 26957441 TI - Child Welfare, Juvenile Justice, Mental Health, and Education Providers' Conceptualizations of Trauma-Informed Practice. AB - This study systematically examined child-service providers' conceptualizations of trauma-informed practice (TIP) across service systems, including child welfare, juvenile justice, mental health, and education. Eleven focus groups and nine individual interviews were conducted, totaling 126 child-service providers. Conventional content analysis was used to analyze the qualitative data with interrater reliability analyses indicating near perfect agreement between coders. Qualitative analysis revealed that child-service providers identified traumatic stress as an important common theme among children and families served as well as the interest in TIP in their service systems. At the same time, child-service providers generally felt knowledgeable about what they define TIP to be, although they articulated wide variations in the degree to which they are taught skills and strategies to respond to their traumatized clients. The results of this study suggest a need for a common lexicon and metric with which to advance TIP within and across child-service systems. PMID- 26957442 TI - Guest Editorial: How to Be Human? Some Answers and New Questions. PMID- 26957443 TI - Humanity and Social Responsibility, Solidarity, and Social Rights. AB - This article discusses the suggestion of having the notion of solidarity as the foundational value for welfare scheme reforms. Solidarity is an emerging concept in bioethical deliberations emphasizing the need for value-oriented discussion in revising healthcare structures, and the notion has been contrasted with liberal justice and rights. I suggest that this contrast is unnecessary, flawed, and potentially counterproductive. As necessary as the sense of solidarity is in a society, it is an insufficient concept to secure the goals related to social responsibility. The discussion on solidarity is also based on a questionable sense of nostalgia. Furthermore, solidarity and liberal justice share essential objectives concerning welfare schemes; therefore, the question arises whether the proper comparison should in the first place be within justice and solidarity. PMID- 26957444 TI - Issues on Luck Egalitarianism, Responsibility, and Intercultural Healthcare Policies. AB - This article analyzes the criteria for the distribution of healthcare services through different justice theories such as utilitarianism and liberalism, pointing out the problems that arise when providing services to a culturally diverse population. The international epidemiological setting is a favorable one for discussing personal responsibility and luck egalitarianism; however, some provisions have to be made so that healthcare institutions do not treat ethnic, cultural, religious, and linguistic minorities unfairly. The article concludes by proposing that accommodations and culturally sensible attention should be provided when possible, without affecting the equal opportunity of others to access these services. PMID- 26957440 TI - CUDC-101, a Novel Inhibitor of Full-Length Androgen Receptor (flAR) and Androgen Receptor Variant 7 (AR-V7) Activity: Mechanism of Action and In Vivo Efficacy. AB - Castration-resistant prostate cancer (CRPC) is an androgen receptor (AR) dependent disease expected to cause the death of more than 27,000 Americans in 2015. There are only a few available treatments for CRPC, making the discovery of new drugs an urgent need. We report that CUDC-101 (an inhibitor od HER2/NEU, EGFR and HDAC) inhibits both the full length AR (flAR) and the AR variant AR-V7. This observation prompted experiments to discover which of the known activities of CUDC-101 is responsible for the inhibition of flAR/AR-V7 signaling. We used pharmacologic and genetic approaches, and found that the effect of CUDC-101 on flAR and AR-V7 was duplicated only by other HDAC inhibitors, or by silencing the HDAC isoforms HDAC5 and HDAC10. We observed that CUDC-101 treatment or AR-V7 silencing by RNAi equally reduced transcription of the AR-V7 target gene, PSA, without affecting viability of 22Rv1 cells. However, when cellular proliferation was used as an end point, CUDC-101 was more effective than AR-V7 silencing, raising the prospect that CUDC-101 has additional targets beside AR-V7. In support of this, we found that CUDC-101 increased the expression of the cyclin dependent kinase inhibitor p21, and decreased that of the oncogene HER2/NEU. To determine if CUDC-101 reduces growth in a xenograft model of prostate cancer, this drug was given for 14 days to castrated male SCID mice inoculated with 22Rv1 cells. Compared to vehicle, CUDC-101 reduced xenograft growth in a statistically significant way, and without macroscopic side effects. These studies demonstrate that CUDC-101 inhibits wtAR and AR-V7 activity and growth of 22Rv1 cells in vitro and in vivo. These effects result from the ability of CUDC-101 to target not only HDAC signaling, which was associated with decreased flAR and AR-V7 activity, but multiple additional oncogenic pathways. These observations raise the possibility that treatment of CRPC may be achieved by using similarly multi-targeted approaches. PMID- 26957445 TI - Vulnerability. AB - Collating the concepts of vulnerability through five regional perspectives on bioethics from the United States, Europe, Latin America, Africa, and Asia, this article proposes a means of integration between the different approaches in order to seek a theoretical and normative basis for the field of global bioethics. It argues that only through opening continuous, critical, and self-critical dialogue within the international bioethical community will it be possible to achieve a sufficiently global understanding of vulnerability that is capable of identifying the means needed for addressing the conditions that leave certain groups and individuals more susceptible to "wounding" than others. PMID- 26957446 TI - The Person in a State of Sickness. AB - In this article, we discuss the ideas of Eric J. Cassell about the patient professional relationship. We argue that his approach combines in an interesting way features from the literature on patient autonomy and paternalistic practices. We suggest that these seemingly paternalistic features of practicing medicine, which are widely either ignored or condemned in bioethical discussion, are of vital significance in medical practice. In the first sections of the article, we describe the main features of Cassell's understanding of the sick person and his version of personalized medicine. We pay particular attention to his notion of information control and compare his ideas about conversation with patients to Hans-Georg Gadamer's analysis of patient-professional dialogue. In the latter part of the article, we explore through a couple of examples the implications these ideas have for medical practice. PMID- 26957447 TI - Turning the Tables. AB - In bioethics, the concept of vulnerability is applied almost exclusively to research participants and patients. We turn the tables and apply the concept to nurses caring for anorexia nervosa (AN) sufferers. In doing so, and using results from a qualitative research study undertaken in the UK, we show that AN nurses face a significant probability of incurring identifiable harms (inauthentic relationships and nonreciprocal relationships). Some recommendations on how these harms can be avoided or mitigated are given, but further research is needed. PMID- 26957448 TI - Undignified Arguments. AB - Something strange has happened to the concept of dignity in bioethics. After a long period in which U.S. pragmatist and U.K. consequentialist philosophers have argued that the concept is useless and vacuous, and in which they have been reasonably successful in expunging it from mainstream English-language academic bioethics, dignity has suddenly become popular again in debates about the legalization of physician-assisted dying (PAD). And, even stranger, it is deployed not by conservatives but by liberals. In the debates about PAD, liberal proponents of legalization seem to accept without question that there is such a state or process as "death with dignity," which is juxtaposed to "undignified dying." It also seems to be accepted that both of these states can be fairly easily identified and that they carry great moral weight. This article provides an analysis of the current resurgence of "undignified" arguments and argues on the basis of that analysis (1) that a proper understanding of the concept of dignity shows that the previous reductive arguments against dignity are partially incomplete and therefore partially misguided and (2) that, despite dignity having meaning, the idea of an undignified death cannot carry the moral weight it is given by proponents of the legalization of PAD. PMID- 26957449 TI - Natural Good Theories and the Value of Human Dignity. AB - One of the widely recognized facts about human dignity is its vastly divergent applicability-from highly controversial issues in bioethics to broader topics in political philosophy. A group of theories that this article subsumes under the header "natural good theories" appears to be especially fitted for normatively multifaceted notions like dignity. However, the heavy normative weight the concept of dignity has to bear due to the central position it occupies within these theories creates its own difficulties. As is shown in a discussion of Martha Nussbaum's capability conception of dignity, dignity appears to be unable to mirror the special normative relevance people want to assign to it in cases of great moral misconduct. The article provides a suggestion on how to solve this problem by means of paradigmatic cases that work as material constraints regarding the exact boundaries of dignity violations. PMID- 26957450 TI - Artificial Intelligence. AB - It seems natural to think that the same prudential and ethical reasons for mutual respect and tolerance that one has vis-a-vis other human persons would hold toward newly encountered paradigmatic but nonhuman biological persons. One also tends to think that they would have similar reasons for treating we humans as creatures that count morally in our own right. This line of thought transcends biological boundaries-namely, with regard to artificially (super)intelligent persons-but is this a safe assumption? The issue concerns ultimate moral significance: the significance possessed by human persons, persons from other planets, and hypothetical nonorganic persons in the form of artificial intelligence (AI). This article investigates why our possible relations to AI persons could be more complicated than they first might appear, given that they might possess a radically different nature to us, to the point that civilized or peaceful coexistence in a determinate geographical space could be impossible to achieve. PMID- 26957451 TI - Discoursive Humanity as a Transcendental Basis for Cognitive (Dis)Ability Ethics and Policies. AB - This article explicates two approaches to the basis of moral worth and status: Eva Kittay's relational view and Jeff McMahan's psychological personhood view. It is argued that these theories alone do not provide adequate support for the conclusions Kittay and McMahan want to draw concerning individuals whose entitlement to fundamental protections can be challenged-infants with severe cognitive disabilities and infants without the support of their families and social environments. The real justification can in each case be found in deeply held convictions regarding entities that must and entities that must not be included in the core community of moral equals. Philosophical discussions about these convictions would be more useful for the advancement of our moral thinking than vain attempts to show that the absolute truth lies on either side of the ongoing debate. PMID- 26957452 TI - Organ Transplantation for Individuals with Neurodevelopmental Disorders. AB - In 1996, Sandra Jensen became the first person with Down syndrome to receive a heart-lung transplant. Although it took place almost 20 years ago, her experience continues to shed light on contemporary challenges that individuals with neurodevelopmental disorders face in securing access to transplantation. While overt discrimination has decreased, barriers persist in physician referrals, center-specific decisionmaking regarding wait-listing, and the provision of accommodations for optimizing the assessment and medical management of these individuals. These issues arise from the persistent biases and assumptions of individuals as well as those of a healthcare system that is inadequately positioned to optimally serve the medical needs of the growing number of individuals with functional impairments. More data and greater transparency are needed to understand the nature and extent of ongoing access problems; however, long-term solutions will require changes at the healthcare professional, regional transplant center, and national levels. PMID- 26957453 TI - Bright New World. PMID- 26957454 TI - Vulnerability and Trustworthiness. AB - Although recent literature on professionalism in healthcare abounds in recommended character traits, attitudes, or behaviors, with a few exceptions, the recommendations are untethered to any serious consideration of the contours and ethical demands of the healing relationship. This article offers an approach based on the professional's commitment to trustworthiness in response to the vulnerability of those seeking professional help. Because our willingness and ability to trust health professionals or healthcare institutions are affected by our personality, culture, race, age, prior experiences with illness and healthcare, and socioeconomic and political circumstances-"the social determinants of trust"-the attitudes and behaviors that actually do gain trust are patient and context specific. Therefore, in addition to the commitment to cultivating attitudes and behaviors that embody trustworthiness, professionalism also includes the commitment to actually gaining a patient's or family's trust by learning, through individualized dialogue, which conditions would win their justified trust, given their particular history and social situation. PMID- 26957455 TI - Using a Scoring Rubric to Assess the Writing of Bioethics Students. AB - Educators in bioethics have struggled to find valid and reliable assessments that transcend the "reproduction of knowledge" to target more important skill sets. This manuscript reports on the process of developing and grading a minimal competence comprehensive examination in a bioethics master's degree program. We describe educational theory and practice for the creation and deployment of scoring rubrics for high-stakes performance assessments that reduce scoring inconsistencies. The rubric development process can also benefit the program by building consensus among stakeholders regarding program goals and student outcomes. We describe the Structure of the Observed Learning Outcome taxonomy as a mechanism for rubric design and provide an example of how we applied that taxonomy to define pass/fail cut scores. Details about domains of assessment and writing descriptors of performance are also presented. Despite the laborious work required to create a scoring rubric, we found the effort to be worthwhile for our program. PMID- 26957456 TI - How Should Health Data Be Used? AB - Electronic health records, data sharing, big data, data mining, and secondary use are enabling exciting opportunities for improving health and healthcare while also exacerbating privacy concerns. Two court cases about selling prescription data, the Sorrell case in the U.S. and the Source case in the U.K., raise questions of what constitutes "privacy" and "public interest"; they present an opportunity for ethical analysis of data privacy, commodifying data for sale and ownership, combining public and private data, data for research, and transparency and consent. These interwoven issues involve discussion of big data benefits and harms and touch on common dualities of the individual versus the aggregate or the public interest, research (or, more broadly, innovation) versus privacy, individual versus institutional power, identification versus identity and authentication, and virtual versus real individuals and contextualized information. Transparency, flexibility, and accountability are needed for assessing appropriate, judicious, and ethical data uses and users, as some are more compatible with societal norms and values than others. PMID- 26957457 TI - The Case. AB - KS is a 76-year-old Burmese woman who presented to the hospital with right-sided weakness that had begun two days prior. Although KS had been diagnosed earlier with dementia and had a medical history of stroke, she was living at a nursing home and was able to walk on her own and use her right arm to feed herself. Since her last stroke three years ago, she had also developed aphasia, and her speech has been minimal. During her current hospitalization, KS was found to have a cerebral hemorrhage, but after consultation with neurosurgery, the team determined that no medical interventions were available, and a higher level of care was not required. She also presented with other medical conditions, including severe hypertension, chronic kidney disease, and depression. The patient's blood pressure has remained high. She has now failed a swallow evaluation and is refusing the insertion of a nasogastric feeding tube. The patient has a younger sister who believes, from a cultural perspective, that only the patient should make her medical decisions. As a result, she feels helpless in assisting the team. The medical team has asked for an ethics consultation to direct the patient's care and to guide decisionmaking. PMID- 26957458 TI - Commentary: The Reluctant Surrogate. AB - An individual's hesitance or outright refusal to function as a substitute decisionmaker creates a number of challenges for treating teams, as is highlighted by the case of KS. It is not uncommon for individuals who suddenly find themselves in the role of substitute decisionmaker (SDM) to experience feelings of inadequacy or of being overwhelmed. The natural apprehension that comes with realizing, or being informed, that you are now responsible for providing or refusing consent on behalf of a loved one is often exacerbated by the accompanying circumstances. Even though there are movements afoot to encourage and support advance care planning and the inclusion of those who will become SDMs in conversations about values and wishes, there is still much work to be done. Although the case as presented does not provide information regarding what, if any, processes have taken place prior to the current hospital admission with regard to including the patient's sister in discussions about future circumstances, it is clear that the sister feels unprepared to assume the role being thrust upon her. What, then, does a clinical ethics consultation have to offer in such situations? The following discussion highlights three ways in which ethics consultation can be of value to both the treating team and the identified SDM: ethics consultation (1) helps the care team and SDM navigate the regulatory landscape, (2) supports the treating team, and (3) supports the SDM. PMID- 26957459 TI - Commentary: Looking beyond Treatment Refusal. AB - This case illustrates the dilemma that occurs when a patient refuses treatment. When a patient refuses recommended interventions, it can cause much distress among the medical team and family. On the surface, the ethical issue appears to be in regard to treatment refusal. However, when we look deeper, it becomes evident that the question is truly about whether the patient has the ability to make this treatment decision, given her worsening dementia, recent hemorrhage, and depression. In this case, an essential component of an ethics consultation would be to assess this patient's decisionmaking capacity to determine if her refusals are informed. This case has another level of complexity. If the patient does not have decisionmaking capacity, then who would be willing to serve in the role of surrogate decisionmaker? The case raises several ethical questions and thus makes directing a patient's care and decisionmaking challenging. PMID- 26957460 TI - Commentary: Cultural Issues in Decisionmaking. AB - This case presents several fundamental ethical issues. The first issue is the patient's refusal of treatment (a nasogastric tube [NGT] insertion). Second, the patient's refusal of a seemingly beneficial treatment, combined with her medical history, ultimately necessitates an assessment of her decisionmaking capacity. Third, the sister's reluctance to participate in decisionmaking requires a discussion of appropriate surrogate decisionmakers. Finally, the main ethical component to this case is a cultural one, which should be addressed appropriately. PMID- 26957461 TI - What Actually Happened. AB - The medical team found the patient to lack medical decisionmaking capacity. However, the team felt that the patient was still able to respond appropriately to some situations. KS had displayed a consistent refusal of all medical treatments that made her uncomfortable or caused pain. During her sister's visits, the patient would be much more receptive to eating. A meeting was planned with the patient's sister in which the ethicist explained that the patient was not able to make her own decisions. The patient's sister agreed that she would honor the patient's wishes but would let the team make any decisions outside of what she knew about the patient's preferences. The patient's sister agreed and was willing to be at the patient's bedside as much as she could to encourage her eating. If the patient's condition worsened, it was discussed that the team honor the patient's wishes and not force a feeding tube on her. The patient's code status was also addressed, and KS's sister felt comfortable in communicating to the team that the patient would not want to be resuscitated if medical treatments would not be able to improve her current quality of life. A natural passing away would be most amenable to the patient. The patient was discharged to her nursing home with a physician order for life-sustaining treatment (POLST) form signed by the sister documenting a do-not-resuscitate code status with comfort-focused treatments. PMID- 26957462 TI - Re: Implementation of a split-bolus single-pass CT protocol at a UK major trauma centre to reduce excess radiation dose in trauma pan-CT. A reply. PMID- 26957463 TI - Editorial: Understanding Consumer Expectations and Reducing Asymmetry Between Consumers and Producers: A Challenge for Food Producers in a Monopolistic Competition Market. PMID- 26957464 TI - The Strategy of Voluntary Certification in Italian Olive Oil Industry: Who and Why? AB - BACKGROUND: The phenomenon of asymmetric information is central in the agri-food sector, in which often there is not full information transparency about product quality. This condition is particularly complex considering the high-end products. In particular, there are specific attributes (credence attributes) that are not assessable by consumers. For these reasons, a clear information about certification can give to consumers the possibility to make a rational choice. A company can choose voluntarily to participate in certification programs that can be viewed also as a simplification of some organization issues. Often the incentives to participate in voluntary programs arise from the need to have a positive economic performance of the firm. On the one hand, the firm may have benefits from the technical assistance of the certification, which allows it to reduce costs of controlling particular sensible steps of the process. On the other hand, the firm may provide a new certification label, in order to ensure a greater transparency of its processes. METHODS: The research aims to understand the characteristics of firms oriented to use voluntary certifications as a tool to reduce information asymmetries between producers and final consumers. In particular, we want to consider two contexts of analysis: a structural one, considering some specific internal aspects and investment choices of the firms (typology, size, extraction system, storage system, material investments, immaterial investments); a second one that takes into account some decisions related to market relationships (sale to consumers, sale to HoReCa, sale to wholesalers, sale to purchasing groups, sale to GDO, export activity). The study concerns small and medium olive oil company of Southern Italy. We apply two logit models in order to show the determinants in the choice to introduce a voluntary certification. RESULTS: The results show significant values in both the two dimensions considered. Among the first one, there are significances in immaterial company investments but also in physical assets related to the olive oil process. There are several scientific developments relevant to the olive oil process and some of these patents have been reviewed in this paper. Regarding the physical assets, the storage system is a clear representation of the asset importance in the decision to participate in the certification program. Furthermore, the presence of considerable immaterial investments is important in the certification decision, which confirms the idea that voluntary certification can be viewed as a strategic tool. In the second part of analysis there are significances in some distribution channels (direct sale to final consumer, to wholesalers and to purchasing groups) as well as in the export activity. CONCLUSION: This work aims to contribute to the debate about the addressing of quality policy for a reduction of asymmetric information in the high-end products. Because of small dimensions of firms in Southern Italy, not always we can find conditions about the presence of specific assets. Indeed, the small dimensions of the companies make quality investments complicated. The incentive to invest, both in terms of control of product and in terms of immaterial investment, can help in a participation in voluntary certification programs. Further, it is important to investigate the three distribution channels resulting from the research because of their importance in terms of information asymmetry. PMID- 26957465 TI - Trends and Perspectives of the Information Asymmetry Between Consumers and Italian Traditional Food Producers. AB - BACKGROUND: Contemporary food market offers plenty of different food products from all over the world. However, as people have more disposable income, they are more discerning with regards to quality, and certified food has a reputation as being more wholesome and more healthy. In other words, food quality issues become crucial in a consumer's choice. Nevertheless, the question arises - that what should be considered as a food quality, and which quality criteria consumers are ready to pay more? There are many certified products within the variety of agricultural food, and for understanding which products are more preferable for a consumer, it is necessary to know, what do labels mean and what do they guarantee. Absence or lack of this knowledge promotes the information asymmetry between consumers and food producers. Italian traditional food was chosen as an example, due to its crucial meaning for authentical development of the rural areas and particular culture heritage. METHODS: To analyze phenomenon of an information asymmetry within the labeled food market were studied the next theoretical issues: dimensions of traditional food and its labeling; consumer's behavior and attitudes towards traditional food; features and consequences of an information asymmetry. The empirical side highlights the contemporary tendencies of the Italian quality food market. RESULTS: As the main reason of information asymmetry is the lack of information for consumers, the paper offers for food producers to use knowledge management as the main tool to smooth an information asymmetry. An implementation of knowledge management includes two directions: development of the appropriate communication strategy and application of the Internet of Things to provide on the food packing the sufficient information for consumers. In that direction, many recent patents have been developed. CONCLUSION: The findings of this paper confirm the importance of the literature review for understanding the reasons of an information asymmetry. The offered pathways for reducing of this phenomenon will increase the share of the traditional food products on the Italian food market, thereby sustaining the local producers. PMID- 26957466 TI - The Case of Cruse Affair for the Bordeaux Wines (Winegate) and Its Consequences on the Burgundy Wine Industry. AB - BACKGROUND: The aim of the study is to show how the Cruse affair known as the "Winegate" has changed the wine industry in Burgundy. Cruse, one of the major Bordeauxsellers, was caught by the Customs Office in 1973 and condemned for fraud involving 20'000 hl of Bordeaux wine. This affair has generated a loss of trust between consumers and producers and also between small wine-growers who were selling their wine to the Negociants. METHODS: The objective of this study is to focus on the consequences that this affair has generated for Burgundy growers and Negociants. The method used is the analysis of historical documents (press articles and books on Bordeaux wines) to understand through a review the Cruise affair and its consequences. RESULTS: Under consumer but also retailer pressure, more and more winegrowers in Burgundy decided to bottle the production of their estate and sell it under their own label. To a certain extent, this new development entailed a competition with Negociants. The structure of estates moved from farm style companies to small SME's in charge of vinification, ageing, selling and exporting. Finally, some recent patents related to the wine fraud and mechanisms to create the trust in the wine chain, with specific regard to intelligent label and distribution, have been considered. PMID- 26957467 TI - The Seven Challenges for Transitioning into a Bio-based Circular Economy in the Agri-food Sector. AB - BACKGROUND: Closed-loop agri-food supply chains have a high potential to reduce environmental and economic costs resulting from food waste disposal. This paper illustrates an alternative to the traditional supply chain of bread based on the principles of a circular economy. METHODS: Six circular interactions among seven actors (grain farmers, bread producers, retailers, compostable packaging manufacturers, insect breeders, livestock farmers, consumers) of the circular filiere are created in order to achieve the goal of "zero waste". In the model, two radical technological innovations are considered: insects used as animal feed and polylactic acid compostable packaging. RESULTS: The main challenges for the implementation of the new supply chain are identified. Finally, some recent patents related to bread sustainable production, investigated in the current paper, are considered. CONCLUSION: Recommendations are given to academics and practitioners interested in the bio-based circular economy model approach for transforming agri-food supply chains. PMID- 26957468 TI - Reducing Information Gap and Increasing Market Orientation in the Agribusiness Sector: Some Evidences from Apulia Region. AB - BACKGROUND: Market orientation plays a crucial role in reinforcing firm's competitive advantage; nevertheless, marketing myopia can negatively affect a clear perception of the market. METHODS: An organization that defines itself by product rather than by market terms is probably affected by marketing myopia, a narrowness of mind towards any newness - newness respect to firms' convincement and routines - coming from the external environment. In that context some scientific relevant developments that comes from recent patents have been considered. This paper explores the determinants of marketing myopia in the Apulia wine business (South Italy). RESULTS: The aim of this paper is to describe how experiential research based on Consumer Science research tools, can facilitate a better market knowledge. Experimental sessions carried out in 2013 in Apulia with a group of professionals from the oil and wine sectors clearly demonstrate how country of origin effect can improve marketing myopia. CONCLUSION: Through a protocol based on an "academicians - practitioners" model, professionals can be facilitated in their strategy formulation. PMID- 26957469 TI - The Multidisciplinary Issue of Obesity: Epidemiological Studies, Company Strategies and Policy Actions: A Systematic and Methodological Review of the Research Approaches. AB - BACKGROUND: The work is a review of studies carried out in recent years on the epidemic of obesity. The issue of obesity includes several disciplines: medical health, socio-economic impacts and policy actions. METHODS: This review focuses on the three main areas of study: the first area is about patent epidemiological researches, the second one analyzes the companies that focus on research and development towards less obesogenic foods and the third one investigates on the policies actions adopted by European governments to address the problem of obesity. RESULTS: This study underlined a more strong scientific production relative to US and UK countries compared with the southern countries of the world where the attention of scientists and politicians to the obesity is lower due to the problems of food security rather than to those of inappropriate lifestyle. CONCLUSION: The study of the cause and effects of this phenomenon through epidemiological researches is a good tool to counteract obesity. However, the development of policies controlling and contrasting obesogenic food production is fundamental like greater communication to consumers on the risks of obesity and foods processing. PMID- 26957470 TI - Clinical academics' postdoctoral career development: what about gender inequality? PMID- 26957473 TI - Prioritising prevention and health promotion. PMID- 26957471 TI - Assessment of the Effects of Age, Gender, and Exercise Training on the Cardiac Sympathetic Nervous System Using Positron Emission Tomography Imaging. AB - BACKGROUND: Using positron emission tomography (PET) imaging, we sought to determine whether normal age or exercise training cause changes in the cardiac sympathetic nervous system function in male or female healthy volunteers. METHODS: Healthy sedentary participants underwent PET studies before and after 6 months of supervised exercise training. Presynaptic uptake by the norepinephrine transporter-1 function was measured using PET imaging of [(11)C]-meta hydroxyephedrine, a norepinephrine analog, and expressed as a permeability surface area product (PSnt in mL/min/mL). Postsynaptic function was measured as beta-adrenergic receptor density (beta'max in pmol/mL tissue) by imaging the beta receptor antagonist [(11)C]-CGP12177. Myocardial blood flow (MBF in mL/min/mL tissue) was measured by imaging [(15)O]-water. RESULTS: At baseline, there was no age difference in beta'max or MBF but PSnt declined with age (1.12+/-0.11 young vs 0.87+/-0.06 old, p = .036). Before training, women had significantly greater MBF (0.87+/-0.03 vs 0.69+/-0.03, p < .0001) and PSnt (1.14+/-0.08 vs 0.75+/-0.07, p < .001) than men. Training increased VO2 max by 13% (p < .0001), but there were no training effects on beta'max, PSnt, or MBF. Greater MBF in females and a trend to increased PSnt post-training persisted. CONCLUSION: With age, presynaptic uptake as measured by PSnt declines, but there were no differences in beta'max. Endurance training significantly increased VO2 max but did not cause any changes in the measures of cardiac sympathetic nervous system function. These findings suggest that significant changes do not occur or that current PET imaging methods may be inadequate to measure small serial differences in a highly reproducible manner. PMID- 26957472 TI - Assessing Daily Physical Activity in Older Adults: Unraveling the Complexity of Monitors, Measures, and Methods. AB - At the 67th Gerontological Society of America Annual Meeting, a preconference workshop was convened to discuss the challenges of accurately assessing physical activity in older populations. The advent of wearable technology (eg, accelerometers) to monitor physical activity has created unprecedented opportunities to observe, quantify, and define physical activity in the real world setting. These devices enable researchers to better understand the associations of physical activity with aging, and subsequent health outcomes. However, a consensus on proper methodological use of these devices in older populations has not been established. To date, much of the validation research regarding device type, placement, and data interpretation has been performed in younger, healthier populations, and translation of these methods to older populations remains problematic. A better understanding of these devices, their measurement properties, and the data generated is imperative to furthering our understanding of daily physical activity, its effects on the aging process, and vice versa. The purpose of this article is to provide an overview of the highlights of the preconference workshop, including properties of the different types of accelerometers, the methodological challenges of employing accelerometers in older study populations, a brief summary of ongoing aging related research projects that utilize different types of accelerometers, and recommendations for future research directions. PMID- 26957475 TI - Spermatogonial cells: mouse, monkey and man comparison. AB - In all mammals, spermatogonia are defined as constituting the mitotic compartment of spermatogenesis including stem, undifferentiated and differentiating cell types, possessing distinct morphological and molecular characteristics. Even though the real nature of the spermatogonial stem cell and its regulation is still debated the general consensus holds that in steady-state spermatogenesis the stem cell compartment needs to balance differentiation versus self-renewal. This review highlights current understanding of spermatogonial biology, the kinetics of amplification and the signals directing spermatogonial differentiation in mammals. The focus will be on relevant similarities and differences between rodents and non human and human primates. PMID- 26957476 TI - Mediastinal Gray Zone Lymphoma: A Wider Category Than We Think? AB - AIM: To identify aggressively behaving classical Hodgkin lymphoma (CHL) of mediastinum and primary mediastinal B-cell lymphoma (PMBCL) and to classify them as mediastinal gray zone lymphoma(MGZL) and to define a minimum immunopanel for the diagnosis of MGZL. MATERIALS AND METHODS: Ninety-two mediastinal B-cell lymphomas were reviewed with a wide immunopanel and were classified as CHL, PMBCL, or MGZL. CHL with an expression of 3 or 4 transcription factors performed worse, and hence the CHL with >=3 transcription factors were classified as MGZL CHL. In PMBCL, the cases with a weak or negative CD20 and positive CD15 as well as those cases showing cyclin E positivity with a negative or focal LCA and any one of the transcription factors were classified as MGZL-PMBCL. RESULTS: The MGZL cases expanded from 9 to 28 cases after using an extended immunopanel. CHL and PMBCL had a disease-free survival rate of 86.8% and 69.2% and an overall survival rate of 97.4% and 80.8%, respectively. MGZL-CHL and MGZL-PMBCL had a disease-free survival rate of 33% and 40% and an overall survival rate of 66.7% and 60%, respectively. CONCLUSION: Thus, the MGZL may be a wider category than we think and hence the use of a wide immunopanel is recommended to identify the aggressively behaving mediastinal B-cell lymphomas. PMID- 26957474 TI - Multiple LINEs of retrotransposon silencing mechanisms in the mammalian germline. AB - Retrotransposons play an important role in genome evolution but pose acute challenges to host genome integrity, particularly in early stage germ cells where epigenetic control is relaxed to permit genome-wide reprogramming. In most species, the inability to silence retrotransposons in the germline is usually associated with sterility. LINE1 is the most abundant retrotransposon type in the mammalian genome. Mammalian germ cells employ multiple mechanisms to suppress retrotransposon activity, including small non-coding piRNAs, DNA methylation, and repressive histone modifications. Novel factors contributing to the epigenetic silencing of retrotransposons in the germline continue to be identified. Recent studies have provided insight into how epigenetic changes associated with retrotransposon activation impact on fertility. PMID- 26957477 TI - Toward a Mixed-Methods Research Approach to Content Analysis in The Digital Age: The Combined Content-Analysis Model and its Applications to Health Care Twitter Feeds. AB - BACKGROUND: Twitter's 140-character microblog posts are increasingly used to access information and facilitate discussions among health care professionals and between patients with chronic conditions and their caregivers. Recently, efforts have emerged to investigate the content of health care-related posts on Twitter. This marks a new area for researchers to investigate and apply content analysis (CA). In current infodemiology, infoveillance and digital disease detection research initiatives, quantitative and qualitative Twitter data are often combined, and there are no clear guidelines for researchers to follow when collecting and evaluating Twitter-driven content. OBJECTIVE: The aim of this study was to identify studies on health care and social media that used Twitter feeds as a primary data source and CA as an analysis technique. We evaluated the resulting 18 studies based on a narrative review of previous methodological studies and textbooks to determine the criteria and main features of quantitative and qualitative CA. We then used the key features of CA and mixed-methods research designs to propose the combined content-analysis (CCA) model as a solid research framework for designing, conducting, and evaluating investigations of Twitter-driven content. METHODS: We conducted a PubMed search to collect studies published between 2010 and 2014 that used CA to analyze health care-related tweets. The PubMed search and reference list checks of selected papers identified 21 papers. We excluded 3 papers and further analyzed 18. RESULTS: Results suggest that the methods used in these studies were not purely quantitative or qualitative, and the mixed-methods design was not explicitly chosen for data collection and analysis. A solid research framework is needed for researchers who intend to analyze Twitter data through the use of CA. CONCLUSIONS: We propose the CCA model as a useful framework that provides a straightforward approach to guide Twitter-driven studies and that adds rigor to health care social media investigations. We provide suggestions for the use of the CCA model in elder care related contexts. PMID- 26957478 TI - Estrogen receptor-alpha as a predictive biomarker in endometrioid endometrial cancer. AB - BACKGROUND: We sought to validate the prognostic significance of estrogen receptor alpha (ERalpha) expression and to investigate the relationship between ESR1 mutation status and outcomes in a large cohort of patients with endometrial cancer. We also investigated the predictive value of ERalpha for lymph node involvement in a large surgically staged cohort. METHODS: A tumor microarray (TMA) was constructed including only pure endometrioid adenocarcinomas, stained with ER50 monoclonal antibody, and assessed using digital image analysis. For mutation analysis, somatic DNA was extracted and sequenced for ESR1 gene hotspot regions. Differences in patient and tumor characteristics, recurrence and survival between ERalpha positive and negative, mutated and wild-type tumors were evaluated. RESULTS: Sixty (18.6%) tumors were negative for ERalpha. Absence of ERalpha was significantly associated with stage and grade, but not with disease free or overall survival. ERalpha was a strong predictor of lymph node involvement (RR: 2.37, 95% CI: 1.12-5.02). Nineteen of 1034 tumors (1.8%) had an ESR1 hotspot mutation; twelve in hotspot 537Y, four in 538D and three in 536L. Patients with an ESR1 mutation had a significantly lower BMI, but were comparable in age, stage and grade, and progression-free survival. CONCLUSION: Patients with ERalpha negative endometrioid endometrial cancer are more often diagnosed with higher grade and advanced stage disease. Lymph node involvement is more common with lack of ERalpha expression, and may be able to help triage which patients should undergo lymphadenectomy. Mutations in ESR1 might explain why some low risk women with low BMI develop endometrial cancer. PMID- 26957479 TI - The health-related quality of life journey of gynecologic oncology surgical patients: Implications for the incorporation of patient-reported outcomes into surgical quality metrics. AB - OBJECTIVE: To report the changes in patient-reported quality of life for women undergoing gynecologic oncology surgeries. METHODS: In a prospective cohort study from 10/2013-10/2014, women were enrolled pre-operatively and completed comprehensive interviews at baseline, 1, 3, and 6months post-operatively. Measures included the disease-specific Functional Assessment of Cancer Therapy General (FACT-GP), general Patient Reported Outcome Measure Information System (PROMIS) global health and validated measures of anxiety and depression. Bivariate statistics were used to analyze demographic groups and changes in mean scores over time. RESULTS: Of 231 patients completing baseline interviews, 185 (80%) completed 1-month, 170 (74%) 3-month, and 174 (75%) 6-month interviews. Minimally invasive (n=115, 63%) and laparotomy (n=60, 32%) procedures were performed. Functional wellbeing (20 -> 17.6, p<0.0001) decreased at 1-month, and recovered by 3 and 6months. Emotional wellbeing increased (16.3 -> 20.1, p<0.0001) and anxiety decreased (54.2 -> 49.0, p<0.0001) at 1-month, and were stable at 3 and 6months. Physical wellbeing scales were not sensitive to surgery. These patterns were consistent across procedure type, cancer diagnosis, and adjuvant therapy administration. In an exploratory analysis of the interaction of QOL and quality, patients with increased postoperative healthcare resource use were noted to have higher baseline levels of anxiety. CONCLUSIONS: For women undergoing gynecologic oncology procedures, temporary declines in functional wellbeing are balanced by improvements in emotional wellbeing and decreased anxiety symptoms after surgery. Not all commonly used QOL surveys are sensitive to changes during the perioperative period and may not be suitable for use in surgical quality metrics. PMID- 26957480 TI - Biological role and clinical implications of homeobox genes in serous epithelial ovarian cancer. AB - Homeobox (HOX) genes are a family of transcription factors that are essential regulators of development. HOX genes play important roles in normal reproductive physiology, as well as in the development and progression of serous carcinomas, the predominant and most aggressive subtype of epithelial ovarian cancer (EOC). This review discusses aberrant HOX gene expression in serous EOC and its impact on tumor development and progression. Further identification of HOX target genes may facilitate the development of novel diagnostic and therapeutic strategies to improve the prognosis of patients with serous EOC. PMID- 26957482 TI - Sway Area and Velocity Correlated With MobileMat Balance Error Scoring System (BESS) Scores. AB - The Balance Error Scoring System (BESS) is often used for sport-related concussion balance assessment. However, moderate intratester and intertester reliability may cause low initial sensitivity, suggesting that a more objective balance assessment method is needed. The MobileMat BESS was designed for objective BESS scoring, but the outcome measures must be validated with reliable balance measures. Thus, the purpose of this investigation was to compare MobileMat BESS scores to linear and nonlinear measures of balance. Eighty-eight healthy collegiate student-athletes (age: 20.0 +/- 1.4 y, height: 177.7 +/- 10.7 cm, mass: 74.8 +/- 13.7 kg) completed the MobileMat BESS. MobileMat BESS scores were compared with 95% area, sway velocity, approximate entropy, and sample entropy. MobileMat BESS scores were significantly correlated with 95% area for single-leg (r = .332) and tandem firm (r = .474), and double-leg foam (r = .660); and with sway velocity for single-leg (r = .406) and tandem firm (r = .601), and double-leg (r = .575) and single-leg foam (r = .434). MobileMat BESS scores were not correlated with approximate or sample entropy. MobileMat BESS scores were low to moderately correlated with linear measures, suggesting the ability to identify changes in the center of mass-center of pressure relationship, but not higher order processing associated with nonlinear measures. These results suggest that the MobileMat BESS may be a clinically-useful tool that provides objective linear balance measures. PMID- 26957483 TI - Clinical diffusion mismatch better discriminates infarct growth than mean transit time-diffusion weighted imaging mismatch in patients with middle cerebral artery M1 occlusion and limited infarct core. AB - BACKGROUND AND PURPOSE: Our purpose was to compare clinical diffusion mismatch (CDM) and mean transit time (MTT)-diffusion mismatch as predictors of infarct growth in patients with proximal middle cerebral artery (MCA) occlusion and small infarct core on presentation. METHODS: Retrospective analysis of consecutive stroke patients with: (1) MCA-M1 occlusion; (2) MRI performed <=10 h from symptoms onset; and (3) baseline MRI-diffusion weighted imaging (DWI) volume <=25 mL. Definitions included: CDM=baseline National Institutes of Health Stroke Scale (NIHSS) score >=8 and DWI volume <=25 mL; MTT-DWI mismatch=visually assessed unthresholded MTT lesion ((MTT-DWI))/DWI) >=20% and >=10 mL larger than the DWI lesion; and significant infarct growth (>20% (>=5 mL) increase in infarct volume on follow-up). Uni-/multivariate analyses were performed to define the predictors of infarct growth. RESULTS: 63 stroke patients with MCA-M1 occlusions and MRI within 10 h of onset were evaluated. 20 patients were excluded on the basis of DWI volume >25 mL leaving 43 patients (mean age 75.8 years; median NIHSS=13) in the study cohort. On univariate analysis, larger admission DWI volume (p<0.0001), baseline NIHSS score >=8 (p=0.001), lack of IV and/or endovascular treatment (p=0.021), glucose levels >125 mg/dL (p=0.024), poor CT angiography collaterals (p=0.046), and lower admission Alberta Stroke Program Early CT score (ASPECTS) (p=0.049) predicted infarct growth. Baseline NIHSS score >=8 was the only independent predictor of stroke growth in the multivariate analysis (p=0.001). All patients had MTT-DWI mismatch >20%. There was no significant association between the amount of MTT-DWI mismatch and infarct growth (p=0.33). CONCLUSIONS: CDM is the most powerful predictor of infarct growth in patients with MCA-M1 occlusion and small infarct core. Most of these patients will have a significant oligemic MTT lesion regardless of admission NIHSS score. PMID- 26957484 TI - 'Candidatus Tenderia electrophaga', an uncultivated electroautotroph from a biocathode enrichment. AB - Biocathode communities are of interest for a variety of applications, including electrosynthesis, bioremediation, and biosensors, yet much remains to be understood about the biological processes that occur to enable these communities to grow. One major difficulty in understanding these communities is that the critical autotrophic organisms are difficult to cultivate. An uncultivated, electroautotrophic bacterium previously identified as an uncultivated member of the family Chromatiaceae appears to be a key organism in an autotrophic biocathode microbial community. Metagenomic, metaproteomic and metatranscriptomic characterization of this community indicates that there is likely a single organism that utilizes electrons from the cathode to fix CO2, yet this organism has not been obtained in pure culture. Fluorescence in situ hybridization reveals that the organism grows as rod-shaped cells approximately 1.8 * 0.6 um, and forms large clumps on the cathode. The genomic DNA G+C content was 59.2 mol%. Here we identify the key features of this organism and propose 'Candidatus Tenderia electrophaga', within the Gammaproteobacteria on the basis of low nucleotide and predicted protein sequence identity to known members of the orders Chromatiales and Thiotrichales. PMID- 26957485 TI - [Perioperative heparin bridging is rarely indicated]. AB - Meta-analyses of cohort studies and a recent randomized, placebo-controlled study have shown that perioperative bridging of warfarin therapy with therapeutic doses of heparin results in a multi-fold increase in major bleeding but no reduction in the incidence of thromboembolism. It is time to reconsider heparin bridging: When is heparin bridging superfluous? When is prophylactic dosage indicated? And when is it safe to use therapeutic dosing? PMID- 26957481 TI - The role of airway macrophages in apoptotic cell clearance following acute and chronic lung inflammation. AB - Acute and chronic inflammatory responses in the lung are associated with the accumulation of large quantities of immune and structural cells undergoing apoptosis, which need to be engulfed by phagocytes in a process called 'efferocytosis'. Apoptotic cell recognition and removal from the lung is mediated predominantly by airway macrophages, though immature dendritic cells and non professional phagocytes, such as epithelial cells and mesenchymal cells, can also display this function. Efficient clearance of apoptotic cells from the airways is essential for successful resolution of inflammation and the return to lung homeostasis. Disruption of this process leads to secondary necrosis of accumulating apoptotic cells, release of necrotic cell debris and subsequent uncontrolled inflammatory activation of the innate immune system by the released 'damage associated molecular patterns' (DAMPS). To control the duration of the immune response and prevent autoimmune reactions, anti-inflammatory signalling cascades are initiated in the phagocyte upon apoptotic cell uptake, mediated by a range of receptors that recognise specific phospholipids or proteins externalised on, or secreted by, the apoptotic cell. However, prolonged activation of apoptotic cell recognition receptors, such as the family of receptor tyrosine kinases Tyro3, Axl and MerTK (TAM), may delay or prevent inflammatory responses to subsequent infections. In this review, we will discuss recent advances in our understanding of the mechanism controlling apoptotic cell recognition and removal from the lung in homeostasis and during inflammation, the contribution of defective efferocytosis to chronic inflammatory lung diseases, such as chronic obstructive pulmonary disease, asthma and cystic fibrosis, and implications of the signals triggered by apoptotic cells in the susceptibility to pulmonary microbial infections. PMID- 26957486 TI - [Benign liver tumours - diagnosis and management]. AB - Due to the expanding use of diagnostic imaging, an increasing number of liver tumours are discovered. Benign tumours are very common; they rarely cause symptoms and often they do not require any treatment. However, because of differences in the natural history including risk of complications and malignant transformation exact diagnosis is important. Dedicated radiological examinations serve as important diagnostic tools reducing the need for biopsy. In this review we provide an update on the diagnosis and treatment of benign liver tumours adding to existing recommendations on hepatocellular carcinomas and adenomas. PMID- 26957487 TI - [Not Available]. PMID- 26957488 TI - Evaluation of MEG vs EEG after sleep deprivation in epilepsy. AB - OBJECTIVE: MEG and EEG after sleep deprivation (EEG-SD) are applied as diagnostic tools in the evaluation of patients with possible epilepsy. There is no gold standard to check whether the diagnosis based on these two modalities is correct. The best standard available is the long-term follow-up of patients. As follow-up of an earlier study in which the additional value of MEG vs EEG-SD diagnosis was evaluated, we investigated the long-term validity of MEG-based and EEG-SD-based diagnosis. MATERIALS AND METHODS: Data collected from 46 patients were used in a comparative study of the last known diagnosis against the original one of 8 years ago. RESULTS: Long-term (3-8 years) sensitivity of sharp phenomena (combining spikes and sharp waves) in routine MEG and in EEG-SD for the diagnosis epilepsy is 71% and 62%, respectively. When compared to the original study, this hardly changed. Over time, uncertainty on diagnosis diminishes. CONCLUSION: MEG as well as EEG-SD are robust long-term predictors for epilepsy. PMID- 26957491 TI - Novel transferable erm(46) determinant responsible for emerging macrolide resistance in Rhodococcus equi. PMID- 26957489 TI - A multicenter, randomized, placebo-controlled trial of endovenous thermal ablation with or without polidocanol endovenous microfoam treatment in patients with great saphenous vein incompetence and visible varicosities. AB - Objectives * Varithena 017 Investigator Group: Michael Vasquez, MD, Venous Institute of Buffalo, Amherst, NY; Antonios Gasparis, MD, Stony Brook University Medical Center, Stony Brook, NY; Kathleen Gibson, MD, Lake Washington Vascular, Bellevue, WA; James Theodore King, MD, Vein Clinics of America, Oakbrook Terrace, IL; Nick Morrison, MD, Morrison Vein Institute, Scottsdale, AZ; Girish Munavalli, MD, Dermatology, Laser & Vein Specialists of the Carolinas, Charlotte, NC; Eulogio J. Sanchez, MD, Batey Cardiovascular Center, Bradenton, FL. Varithena(r) is a trademark of Provensis Ltd, a BTG International group company. To determine the efficacy and safety of polidocanol endovenous microfoam (PEM 0.5%, 1.0%) and placebo each administered with endovenous thermal ablation. Methods A multicenter, randomized, placebo-controlled, blinded study was conducted in patients with great saphenous vein incompetence and symptomatic and visible superficial venous disease. Co-primary endpoints were physician-assessed and patient-assessed appearance change from Baseline to Week 8. Results A total of 117 patients received treatment (38 placebo, 39 PEM 0.5%, 40 PEM 1%). Physician rated vein appearance at Week 8 was significantly better with PEM ( p = 0.001 vs. placebo); patient-assessed appearance trended similarly. Polidocanol endovenous microfoam provided improvements in clinically meaningful change in patient assessed and physician-assessed appearance ( p < 0.05), need for additional treatment ( p < 0.05), saphenofemoral junction reflux elimination, symptoms, and QOL. In PEM recipients, the most frequent adverse event was superficial thrombophlebitis (35.4%) Conclusions Endovenous thermal ablation + PEM significantly improved physician-assessed appearance at Week 8, increased the proportion of patients with a clinically meaningful change in appearance, and reduced need for additional treatment. www.clinicaltrials.gov (NCT01197833). PMID- 26957490 TI - Comparison of equal doses of continuous venovenous haemofiltration and haemodiafiltration on ciprofloxacin population pharmacokinetics in critically ill patients. AB - OBJECTIVES: Whilst commonly performed in ICUs, renal replacement therapies (RRTs) differ in their solute clearances. There is a paucity of data on ciprofloxacin clearances in different RRT techniques. The aim of this study was to compare the population pharmacokinetics of ciprofloxacin during equal doses of continuous venovenous haemofiltration (CVVHF) and continuous venovenous haemodiafiltration (CVVHDF) in septic patients. METHODS: Patients receiving 400 mg of ciprofloxacin intravenously 8 or 12 hourly and undergoing either CVVHF or CVVHDF were eligible. Up to 10 blood samples were collected over one dosing interval and analysed by a validated chromatographic method. Population pharmacokinetic analysis and Monte Carlo simulation was undertaken using Pmetrics. RESULTS: Eighteen sampling intervals were included (8 CVVHDF and 10 CVVHF) from 11 patients (6 patients having sampling during both RRT modes). A two-compartment linear model best described the data. Increasing patient weight was the only covariate associated with increasing drug clearance. The mean (SD) parameter estimates were: clearance, 10.7 (5.3) L/h; volume of distribution of the central compartment, 21.3 (11.3) L; rate constant for drug distribution from the central compartment to the peripheral compartment, 10.9 (4.3) L/h; and rate constant for drug distribution from the peripheral compartment to the central compartment, 2.3 (1.8) L/h. After accounting for patient weight, the mean ciprofloxacin clearance was not statistically different between CVVHF and CVVHDF [11.8 (9.9) and 10.3 (7.4) L/h, respectively, P = 0.43]. CONCLUSIONS: The present study indicates a high pharmacokinetic variability of ciprofloxacin during CVVHF and CVVHDF with no significant differences in clearance apparent. Based on patient weight, higher ciprofloxacin dosing regimens should be used in critically ill patients when difficult-to-treat pathogens are suspected. PMID- 26957492 TI - Association of cytokine gene polymorphisms and risk factors with otitis media proneness in children. AB - In order to assess the association between gene polymorphisms and otitis media (OM) proneness, tumor necrosis factor alpha (TNFA) -308, interleukin (IL) 10-1082 and -3575, IL6 -597, IL2 -330, and CD14 -159 genotyping was performed in 58 OM prone children and 85 controls who were exposed to similar number and frequency of environmental and host risk factors. The frequencies of genotypes (wild type vs. genotypes containing at least one polymorphic allele) were not significantly different between groups, except for IL10 -1082. Polymorphic genotypes IL10 -1082 GA and GG were more frequent in OM-prone children than in control group (RR 1.145, 95 % CI 1.011-1.298; p = 0.047). However, logistic regression did not confirm IL10 -1082 polymorphic genotypes as an independent risk factor for OM proneness. CONCLUSION: The present study indicates that high-producing IL10 -1082 GA/GG genotypes may increase the risk for OM proneness in its carriers when exposed to other environmental/host risk factors (day care attendance, passive smoking, male sex, respiratory infections, and atopic manifestations). This study revealed no significant independent genetic association, but the lack of breastfeeding in infancy was found to be the only independent risk factor for development of OM-prone phenotype, implying that breastfeeding had a protective role in development of susceptibility to OM. WHAT IS KNOWN: * The pathogenesis of OM is of multifactorial nature, dependent on infection, environmental factors, and immune response of the child. * Cytokines and CD14 play an important role in the presentation and clinical course of otitis media, but a clear link with otitis media proneness was not established. What is new: * This is the first clinical and genetic study on Montenegrin children with the otitis media-prone phenotype. * The study revealed that high-producing IL10 -1082 genotypes may influence otitis media proneness in children exposed to other environmental/host risk factors. PMID- 26957494 TI - MECHANISMS IN ENDOCRINOLOGY: Tissue-specific activation of cortisol in Cushing's syndrome. AB - Glucocorticoids are widely prescribed for their anti-inflammatory properties, but have 'Cushingoid' side effects including visceral obesity, muscle myopathy, hypertension, insulin resistance, type 2 diabetes mellitus, osteoporosis, and hepatic steatosis. These features are replicated in patients with much rarer endogenous glucocorticoid (GC) excess (Cushing's syndrome), which has devastating consequences if left untreated. Current medical therapeutic options that reverse the tissue-specific consequences of hypercortisolism are limited. In this article, we review the current evidence that local GC metabolism via the enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) plays a central role in mediating the adverse metabolic complications associated with circulatory GC excess - challenging our current view that simple delivery of active GCs from the circulation represents the most important mode of GC action. Furthermore, we explore the potential for targeting this enzyme as a novel therapeutic strategy for the treatment of both endogenous and exogenous Cushing's syndrome. PMID- 26957493 TI - Aging of perennial cells and organ parts according to the programmed aging paradigm. AB - If aging is a physiological phenomenon-as maintained by the programmed aging paradigm-it must be caused by specific genetically determined and regulated mechanisms, which must be confirmed by evidence. Within the programmed aging paradigm, a complete proposal starts from the observation that cells, tissues, and organs show continuous turnover: As telomere shortening determines both limits to cell replication and a progressive impairment of cellular functions, a progressive decline in age-related fitness decline (i.e., aging) is a clear consequence. Against this hypothesis, a critic might argue that there are cells (most types of neurons) and organ parts (crystalline core and tooth enamel) that have no turnover and are subject to wear or manifest alterations similar to those of cells with turnover. In this review, it is shown how cell types without turnover appear to be strictly dependent on cells subjected to turnover. The loss or weakening of the functions fulfilled by these cells with turnover, due to telomere shortening and turnover slowing, compromises the vitality of the served cells without turnover. This determines well-known clinical manifestations, which in their early forms are described as distinct diseases (e.g., Alzheimer's disease, Parkinson's disease, age-related macular degeneration, etc.). Moreover, for the two organ parts (crystalline core and tooth enamel) without viable cells or any cell turnover, it is discussed how this is entirely compatible with the programmed aging paradigm. PMID- 26957495 TI - Beyond TNF Inhibitors: New Pathways and Emerging Treatments for Psoriatic Arthritis. AB - Psoriatic arthritis (PsA) is a chronic inflammatory disease characterized by psoriasis, synovitis, enthesitis, spondylitis and association with other extra articular manifestations. Chronic inflammation of involved tissues possibly leads to structural damage and to a reduction in function and quality of life. The treatment of PsA dramatically changed with the introduction of anti-tumor necrosis factor (TNF)-alpha drugs, which have been shown to reduce the symptoms and signs of the disease, and slow radiographic progression. However, some patients do not respond to anti-TNFalpha or have a loss of response. Recently, the discovery of new pathogenic mechanisms have made possible the development of new drugs that target pro-inflammatory cytokines, such as interleukin (IL)-12, IL 23 and IL-17, or interfere with cellular pathways involved in skin, joint and entheseal inflammation. New molecules, namely ustekinumab, secukinumab, and apremilast have shown efficacy and safety over the various components of the disease in randomized clinical trials. These drugs have been recently approved for the treatment of PsA and included in new treatment recommendations. Other molecules are currently being tested in phase III clinical trials and are potential new treatment options for PsA. The aim of this review is to update the new pathways involved in the development of the disease and the emerging treatments for PsA beyond TNFalpha inhibition. PMID- 26957496 TI - Gastric Variceal Bleeding Caused by an Arterioportal Fistula Formation After TIPS and Related Complications. PMID- 26957497 TI - Primary Care Physician Perspectives on Hepatitis C Management in the Era of Direct-Acting Antiviral Therapy. AB - BACKGROUND: Primary care physicians (PCPs) play a critical role in the care cascade for patients with chronic hepatitis C (CHC). AIM: To assess PCP knowledge and perspectives on CHC screening, diagnosis, referral, and treatment. METHODS: An anonymous survey was distributed to PCPs who participated in routine outpatient care at our hospital. RESULTS: Eighty (36 %) eligible PCPs completed the survey. More than half were females (60 %) aged 36-50 (55 %) from family (44 %) or internal (49 %) medicine. Overall, PCPs correctly identified high-risk populations for screening, though 19 % failed to identify baby boomers and 45 % failed to identify hemodialysis patients as populations to screen. Approximately half reported they were able to screen at risk patients <50 % of the time secondary to time constraints and difficulty assessing if patients had already been screened. 71 % of PCPs reported they refer all newly diagnosed patients to specialty care. 70 % of PCPs did not feel up to date with current treatment. The majority grossly underestimated efficacy, tolerability and ease of administration, and overestimated treatment duration. Only 9 % felt comfortable treating CHC, even those without cirrhosis. Practice patterns were influenced by specialty and Veterans Affairs Hospital affiliation. CONCLUSIONS: Although the majority of PCPs are up to date with CHC screening recommendations, few are able to routinely screen in practice. Most PCPs are not up to date with treatment and do not feel comfortable treating CHC. Interventions to overcome screening barriers and expand treatment into primary care settings are needed to maximize access to and use of curative therapies. PMID- 26957499 TI - Evaluation of Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Peritoneal Carcinomatosis of Colorectal Origin in the Era of Value-Based Medicine. AB - Peritoneal spread from colorectal cancer is second only to the liver as a site for metastasis. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) is a well-established treatment option for patients with peritoneal carcinomatosis (PC) of colorectal origin. However, due to concerns regarding both its clinical benefit and high cost, its universal adoption as the standard of care for patients with limited peritoneal dissemination has been slow. The purpose of this review was to clarify the clinical utility and cost effectiveness of CRS-HIPEC in the treatment of colorectal PC using the framework of value-based medicine, which attempts to combine both benefit and cost into a single quantifiable metric. Our comprehensive review of the clinical outcomes and cost effectiveness of CRS-HIPEC demonstrate that it is a highly valuable oncologic therapy and a good use of healthcare resources. PMID- 26957500 TI - What are We Going to Do with Complete Responses After Chemoradiation of Rectal Cancer? PMID- 26957498 TI - Worse Survival in Elderly Patients with Extremity Soft-Tissue Sarcoma. AB - BACKGROUND: Nearly half of soft-tissue sarcoma (STS) patients are over the age of 65, and the behavior of cancer in these elderly patients is poorly understood. The aim of this study was to assess the impact of age, sarcoma histotype, grade, stage, and treatment modalities on survival of extremity STS (ESTS) patients. METHODS: Patients >=18 years diagnosed with ESTS between 1989 and 2008 were selected from the Netherlands Cancer Registry. Survival rates and patient and treatment characteristics were analyzed for all patients. Relative survival and relative excess risk of death were estimated for young (<65 years) and older (>65 years) patients. RESULTS: Overall, 3066 patients were included in this study. Histotype was different between young (<65 years) and elderly (>65 years) patients (p < 0.001). Patients over the age of 65 were more often diagnosed with high-stage ESTS and an increasing proportion of high-grade ESTS (p < 0.001). The proportion of patients who received no treatment increased with age, and the elderly received fewer combined-modality treatments. Age was significantly associated with relative 5-year survival [72.7 % for younger patients and 43.8 % for the oldest elderly (>85 years)]. In multivariable analysis, age still remained a significant prognostic factor. CONCLUSIONS: Different distribution of sarcoma histotypes, more high-stage and high-grade sarcomas at diagnosis, less aggressive treatment, and worse survival rates emphasize the need for optimizing sarcoma research and care of the elderly. PMID- 26957501 TI - Robotic D2 Lymph Node Dissection During Distal Subtotal Gastrectomy for Gastric Cancer: Toward Procedural Standardization. AB - BACKGROUND: This study was undertaken to outline, in detail, the procedures for robotic D2 lymph node dissection during distal gastrectomy for middle- or lower third gastric cancer, and to present data that may suggest the safety and feasibility of robotic D2 lymph node dissection.1 (-) 4 METHODS: From July 2005 to December 2009, a total of 316 robotic gastrectomies were performed at the Severance Hospital, Yonsei University Health System, Seoul, Korea. Of these, 95 distal subtotal gastrectomies with D2 lymph node dissection with partial omentectomy for gastric cancer were robotically performed. The operative procedures for robotic distal subtotal gastrectomy using the da Vinci ((r)) Si system are demonstrated in a step-by-step manner, with technical tips for each step, in the video clip. Short- and long-term follow-up results are also presented. RESULTS: The mean age of patients was 53.3 years (range 26-80) and the average body mass index was 23.2 kg/m(2) (range 16.9-33.3). All surgeries were successfully performed without open or laparoscopy conversion. The overall mean operation time was 215.7 min (range 131-296 min, and the mean estimated blood loss was 56.1 mL (range 4-396). No immediate postoperative mortality was observed, and 11 patients (11.6 %) experienced a complication after surgery. The operation-related complications consisted of six wound complications, one intra abdominal fluid collection and abscess, one anastomosis leakage, one anastomosis stenosis, one intraluminal bleeding, and one postoperative pancreatitis. The TNM stages according to the 7th American Joint Committee on Cancer (AJCC) classifications were distributed as follows: 58 stage Ia, 13 stage Ib, four stage IIa, four stage IIb, six stage IIIa, six stage IIIb, and four stage IIIc cases. No microscopic tumor involvement of the resection line was noted. A mean of 41.8 lymph nodes (range 11-89) was retrieved. Less than 15 lymph nodes were retrieved in two patients and less than 25 lymph nodes were harvested in 4 of 95 patients. The mean follow-up period was 60.5 months (range 5-97 months, median 59.5 months), with the last follow-up date being 31 December 2014. The overall survival was 92.8 % and relapse-free survival was 91.8 %. CONCLUSIONS: Our large case series demonstrates the feasibility and safety of robotic D2 lymph node dissection during distal subtotal gastrectomy. The adoption of robotic surgery could improve the quality of surgery and facilitate D2 lymph node dissection for gastric cancer. PMID- 26957502 TI - Impacts of Preoperative Serum Albumin Level on Outcomes of Cytoreductive Surgery and Perioperative Intraperitoneal Chemotherapy. AB - BACKGROUND: Only few small studies in the literature have explored the impacts of preoperative serum albumin level and clinical outcomes of patients with peritoneal surface malignancy (PSM) who underwent cytoreductive surgery (CRS) and perioperative intraperitoneal chemotherapy (PIC). This study aimed to evaluate the value of preoperative serum albumin as a prognostic factor for long-term survival outcomes after CRS and PIC in a large patient cohort and to determine whether preoperative serum albumin is correlated with perioperative complications. METHODS: This retrospective study examined prospectively collected data for patients with PSM who underwent CRS and PIC by one surgical team at St George Hospital in Sydney, Australia. The study used 35 g/L as the cuffoff for normal serum albumin level. RESULTS: The study enrolled 591 patients. Hypoalbuminemia was found to be associated with a significantly higher rate of major morbidity (p < 0.001), a longer ICU stay (p = 0.003), a longer HDU stay (p < 0.001), a longer total hospital stay (p < 0.001), and a shorter overall survival (OS) (p = 0.016). Factor analysis showed preoperative serum hypoalbuminemia to be a prognostic factor for a poor perioperative outcome (p = 0.018) and a poor OS (p = 0.026). CONCLUSION: Preoperative hypoalbuminemia is associated with poor perioperative outcomes. More importantly, it is a predictor of poorer OS for patients with PSM independent of the PCI, age, and completeness of cytoreduction. In the future, strategies should be undertaken to improve preoperative nutrition of malnourished patients as a means of improving clinical outcomes for patients with PSM. PMID- 26957503 TI - Is a Wider Margin (2 cm vs. 1 cm) for a 1.01-2.0 mm Melanoma Necessary? AB - BACKGROUND: The current NCCN recommendation for resection margins in patients with melanomas between 1.01 and 2 mm deep is a 1-2 cm radial margin. We sought to determine whether margin width had an impact on local recurrence (LR), disease specific survival (DSS), and type of wound closure. METHODS: Melanomas measuring 1.01-2.0 mm were evaluated at a single institution between 2008 and 2013. All patients had a 1 or 2 cm margin. RESULTS: We identified 965 patients who had a 1 cm (n = 302, 31.3 %) or 2 cm margin (n = 663, 68.7 %). Median age was 64 years, and 592 (61.3 %) were male; 32.5 and 48.7 % of head and neck and extremity patients had a 1 cm margin versus 18.9 % of trunk patients (p < 0.001). LR was 2.0 and 2.1 % for a 1 and 2 cm margin, respectively (p = not significant). Five year DSS was 87 % for a 1 cm margin and 85 % for a 2 cm margin (p = not significant). Breslow thickness, melanoma on the head and neck, lymphovascular invasion, and sentinel lymph node biopsy (SLNB) status significantly predicted LR on univariate analysis; however, only location and SLNB status were associated with LR on multivariate analysis. Margin width was not significant for LR or DSS. Wider margins were associated with more frequent graft or flap use only on the head and neck (p = 0.025). CONCLUSIONS: Our data show that selectively using a narrower margin of 1 cm did not increase the risk of LR or decrease DSS. Avoiding a 2 cm margin may decrease the need for graft/flap use on the head and neck. PMID- 26957505 TI - Abdominal Desmoid Tumors: Hands Off? PMID- 26957504 TI - A Prospective Study on Skin-Sparing Mastectomy for Immediate Breast Reconstruction with Latissimus Dorsi Flap After Neoadjuvant Chemotherapy and Radiotherapy in Invasive Breast Carcinoma. AB - BACKGROUND: Skin-sparing mastectomy (SSM) with immediate breast reconstruction (IBR) is increasingly used in invasive breast cancer. However, adjuvant chemotherapy (CT) and radiotherapy (RT) can increase the rate of local complications. OBJECTIVE: The aim of this study was to assess the morbidity of SSM-IBR after neoadjuvant CT and RT. METHODS: A French prospective pilot study of women aged 18-75 years with invasive breast cancer requiring mastectomy after CT and RT. Reconstruction was performed using autologous latissimus dorsi flap with or without prosthesis. The primary endpoint was the skin necrosis rate within 6 months, while secondary endpoints included pathological complete response rate (pCR) and global morbidity. RESULTS: Among 94 patients included in this study, 83 were analyzed (mean age 45.2 +/- 9.5 years, T1 23.6 %, T2 55.6 %, T3 18.1 %). All but one patient received anthracyclines and taxanes, and all patients received RT (49.3 +/- 5.2 Gy) before SSM-IBR. Prostheses were used for IBR in 32 patients (mean volume 256 +/- 73 mm(3)). Five patients had necrosis (<=2 cm(2), 2-10 cm(2) and >10 cm(2), in three, one, and one cases, respectively), and they all recovered without revision surgery. Among 50 patients who underwent upfront mastectomy, 36 % achieved pCR. CONCLUSIONS: SSM-IBR performed after CT and RT is safe, with an acceptable local morbidity rate. Long-term data are needed to evaluate recurrence rates. PMID- 26957506 TI - Late Axillary Recurrence After Negative Sentinel Lymph Node Biopsy is Uncommon. AB - BACKGROUND: This study was designed to determine the incidence of late axillary recurrence (AR) in patients with negative sentinel lymph node biopsy (SLNB) and provide a comparison with SLNB positive patients who underwent axillary lymph node dissection (ALND). METHODS: Retrospective analysis of prospectively collected data on all breast cancer patients with negative SLNB from January 1997 to December 2000 was performed on a large, institutional database. Primary outcome was cumulative incidence of AR as a first event with/without concurrent local recurrence. SLNB positive patients who went on to ALND during the same timeframe were comparatively analyzed. RESULTS: A total of 1529 eligible patients were identified (median age 58 years, median tumor size 1.0 cm): 1297 (85 %) underwent lumpectomy; 1099 (75 %) received adjuvant radiation; and 874 (80 %) were estrogen receptor-positive. At 10.8 (range 0-16) years median follow-up, overall incidence of AR as a first event was low (n = 13). Cumulative incidence was 0.6 % [95 % confidence interval (CI) 0.2-0.9] 5 years after SLNB, and 0.9 % (95 % CI 0.4-1.4, 95 % CI 0.5-1.6) at 10 and 15 years. Late AR (>5 years after surgery) occurred in five patients. Median overall survival after AR was 4.6 years; median distant disease-free survival after AR was 3.8 years. Late AR was also low in a contemporaneous group of SLNB positive patients undergoing ALND. In this group, cumulative incidence of AR was 0.7 % (95 % CI 0.1-1.3) 5 years after surgery, and 0.8 % (95 % CI 0.2-1.5) at 10 and 15 years. DISCUSSION: Late AR after negative SLNB is rare; the majority of ARs are in the first 5 years after surgery. Prognosis after these events is poor. SLNB remains a safe and effective procedure for axillary evaluation in breast cancer. PMID- 26957507 TI - Designs for Evaluating the Community-Level Impact of Comprehensive Prevention Programs: Examples from the CDC Centers of Excellence in Youth Violence Prevention. AB - This article discusses the opportunities and challenges of developing research designs to evaluate the impact of community-level prevention efforts. To illustrate examples of evaluation designs, we describe six projects funded by the Centers for Disease Control and Prevention to evaluate multifaceted approaches to reduce youth violence in high-risk communities. Each of these projects was designed to evaluate the community-level impact of multiple intervention strategies to address individual and contextual factors that place youth at risk for violent behavior. Communities differed across projects in their setting, size, and how their boundaries were defined. Each project is using multiple approaches to compare outcomes in one or more intervention communities to those in comparison communities. Five of the projects are using comparative interrupted time-series designs to compare outcomes in an intervention community to matched comparison communities. A sixth project is using a multiple baseline design in which the order and timing of intervention activities is randomized across three communities. All six projects are also using regression point displacement designs to compare outcomes within intervention communities to those within broader sets of similar communities. Projects are using a variety of approaches to assess outcomes including archival records, surveys, and direct observations. We discuss the strengths and weaknesses of the designs of these projects and illustrate the challenges of designing high-quality evaluations of comprehensive prevention approaches implemented at the community level. PMID- 26957510 TI - ACMT Position Statement: Duration of Intravenous Acetylcysteine Therapy Following Acetaminophen Overdose. PMID- 26957508 TI - Interaction of oxytocin level and past depression may predict postpartum depressive symptom severity. AB - We examined plasma oxytocin concentration and postpartum depression (PPD) symptom severity in women who were not depressed during pregnancy and whether this differed by major depressive disorder (MDD) history. We assessed psychiatric history and plasma oxytocin in 66 healthy pregnant women in the third trimester (M = 35 +/- 3 weeks) and depressive symptoms at 6 weeks postpartum (M = 5.9 +/- 0.8 weeks). Linear regression analysis was used to examine oxytocin and PPD symptom severity and moderation of oxytocin and PPD by past MDD. Women with (n = 13) and without (n = 53) past MDD differed in third trimester depressive symptom severity, but not oxytocin level, demographic factors, or birth outcomes. Controlling for third trimester depressive symptoms, oxytocin level was unrelated to PPD symptom severity [B(SE) = -.019 (.084); beta = -.025; t = -.227; p = .821]. However, oxytocin level interacted with past MDD to predict PPD symptom severity [B(SE) = 7.489 (2.429); beta = .328; t = 3.084; p = .003]. Higher oxytocin predicted greater PPD symptom severity in women with past MDD (p = .019), but not in women without (p = .216). Replication in a larger sample and methodologic challenges are discussed. PMID- 26957509 TI - Impact of maternal prenatal and parental postnatal stress on 1-year-old child development: results from the OTIS antidepressants in pregnancy study. AB - Perinatal psychological stress has been associated with unfavorable maternal and neonatal outcomes. We aimed to assess the impact of perinatal stress on infant development at 1 year of age. We recruited pregnant women calling North American Teratogen Information Services or attending outpatient clinics at CHU Sainte Justine (Montreal) between 2008 and 2010 and their spouses. To be part of our study, women had to be (1) >18 years of age, (2) <15 weeks of gestational age at recruitment, (3) living within 250-km radius of Montreal, and (4) taking antidepressants or non-teratogenic drugs. Stress was assessed using the telephone administered four-item perceived stress scale during pregnancy in mothers and at 2 months postpartum in both parents. Child development at 1 year of age was evaluated with the Bayley III scales. Socio-demographic and potential confounders were collected through telephone interviews. Multivariable linear regression models were built to assess the association between perinatal parental stress and child development. Overall, 71 couples and their infants were included. When adjusted for potential confounders, maternal prenatal stress was positively associated with motor development (adjusted beta = 1.85, CI 95 % (0.01, 3.70)). Postpartum maternal and paternal stresses were negatively associated with motor and socio-emotional development, respectively (adjusted beta = -1.54, CI 95 % ( 3.07, -0.01) and adjusted beta = -1.67, CI 95 % (-3.25, -0.10), respectively). Maternal and paternal postnatal stress seems to be harmful for the motor and socio-emotional development in 1-year-old children. No association was demonstrated between parental stress and cognitive, language, and adaptive behavioral development. However, prenatal maternal stress appears to improve motor skills. PMID- 26957511 TI - Articles You May Have Missed. PMID- 26957512 TI - Prostate Cancer Prevention: Concepts and Clinical Trials. AB - Prevention is an important treatment strategy for diminishing prostate cancer morbidity and mortality and is applicable to both early- and late-stage disease. There are three basic classifications of cancer prevention: primary (prevention of incident disease), secondary (identification and treatment of preclinical disease), and tertiary (prevention of progression or recurrence). Based on level I evidence, 5-alpha reductase inhibitors (5-ARIs) should be considered in selected men to prevent incident prostate cancer. Level I evidence also supports the consideration of dutasteride, a 5-ARI, for tertiary prevention in active surveillance and biochemical recurrence patients. Vitamins and supplements, including selenium or vitamin E, have not been proven in clinical trials to prevent prostate cancer and in the case of Vitamin E has been found to increase the risk of incident prostate cancer. Ongoing and future trials may further elucidate the role of diet and immunotherapy for prevention of prostate cancer. PMID- 26957513 TI - Health locus of control in patients undergoing coronary artery surgery - changes and associated outcomes: a seven-year cohort study. AB - INTRODUCTION: Health locus of control is a measure of an individual's beliefs in factors that are thought to determine health experiences. Scores are generated and form a graduated linear scale from external to internal control, with respect to their views on health causality. Health locus of control has been considered to be a relatively stable entity. However, it is not clear if this status changes in the advent of serious health challenges, such as coronary artery bypass graft surgery. The aim of this study is to explore the variability of health locus of control and its association with postoperative health in this context. METHODS: In a longitudinal cohort study of patients undergoing coronary artery bypass graft surgery, a purposive sample ( n=215) were recruited from the waiting list and followed up postoperatively, at approximately one year and seven years later. RESULTS: Patients undergoing coronary artery bypass graft surgery demonstrated marked fluctuations in health locus of control in their peri-operative and rehabilitative phases. Mean health locus of control became more external (often associated with poorer outcomes) peri-operatively, and more internal (generally associated with better health outcomes) in the rehabilitative period. CONCLUSIONS: Health locus of control scores were shown to be changeable during a major health care intervention, with possible consequences for patient outcomes and care needs. The significant health belief upheaval demonstrated in this cohort should be considered in assessing patients preoperatively, and managed as part of the patients' clinical journey by both acute and rehabilitation staff. It is likely to have particular importance in individualised assessment and management of future prevention advice for patients. PMID- 26957514 TI - Author's reply to Blake. PMID- 26957515 TI - Government's lack of knowledge of how medical hierarchy is structured. PMID- 26957516 TI - Slippery Slope of Triglycerides: They Are Associated With Risk, But in the Statin Era, Does Targeting Them Confer Benefit? PMID- 26957517 TI - Elevated Triglyceride Level Is Independently Associated With Increased All-Cause Mortality in Patients With Established Coronary Heart Disease: Twenty-Two-Year Follow-Up of the Bezafibrate Infarction Prevention Study and Registry. AB - BACKGROUND: The independent association between elevated triglycerides and all cause mortality among patients with established coronary heart disease is controversial. The aim of this study was to investigate this association in a large cohort of patients with proven coronary heart disease. METHODS AND RESULTS: The study cohort comprised 15 355 patients who were screened for the Bezafibrate Infarction Prevention (BIP) trial. Twenty-two-year mortality data were obtained from the national registry. Patients were divided into 5 groups according to strata of fasting serum triglycerides: (1) low-normal triglycerides (<100 mg/dL); (2) high-normal triglycerides (100-149 mg/dL); (3) borderline hypertriglyceridemia triglycerides (150-199 mg/dL); (4) moderate hypertriglyceridemia triglycerides (200-499 mg/dL); (5) severe hypertriglyceridemia triglycerides (>=500 mg/dL). Age- and sex-adjusted survival was 41% in the low-normal triglycerides group than 37%, 36%, 35%, and 25% in groups with progressively higher triglycerides (P<0.001). In an adjusted Cox regression for various covariates including high-density lipoprotein cholesterol, each 1 unit of natural logarithm (Ln) triglycerides elevation was associated with a corresponding 6% (P=0.016) increased risk of 22-year all-cause mortality. The 22-year mortality risk for patients with severe hypertriglyceridemia was increased by 68% when compared with patients with low-normal triglycerides (P<0.001). CONCLUSIONS: In patients with established coronary heart disease, higher triglycerides levels are independently associated with increased 22-year mortality. Even in patients with triglycerides of 100 to 149 mg/dL, the elevated risk for death could be detected than in patients with lower triglycerides levels, whereas severe hypertriglyceridemia denotes a population with particularly increased mortality risk. PMID- 26957518 TI - Adult Congenital Heart Disease Patients Experience Similar Symptoms of Disease Activity. AB - BACKGROUND: There is a lack of objective data on the symptoms characterizing disease activity among adults with congenital heart disease (ACHD). The purpose of this study was to elicit the most important symptoms from patients across the spectrum of ACHD and to examine whether reported symptoms were similar across the spectrum of ACHD as a foundation for creating a patient-reported outcome measure(s). METHODS AND RESULTS: We constructed a 39-item survey using input from physicians specializing in ACHD to assess the symptoms patients associate with disease activity. Patients (n=124) prospectively completed this survey, and the results were analyzed based on underlying anatomy and disease complexity. A confirmatory cohort of patients (n=40) was then recruited prospectively to confirm the validity of the initial data. When grouped based on underlying anatomy, significant differences in disease-related symptom rankings were found for only 6 of 39 symptoms. Six symptoms were identified which were of particular significance to patients, regardless of underlying anatomy. Patients with anatomy of great complexity experienced greater overall symptom severity than those with anatomy of low or moderate complexity, attributable exclusively to higher ranking of 5 symptoms. The second patient cohort had symptom experiences similar to those of the initial cohort, differing in only 5 of 39 symptoms. CONCLUSIONS: This study identified 6 symptoms relevant to patients across the spectrum of ACHD and remarkable homogeneity of patient experience, suggesting that a single disease specific patient-reported outcome can be created for quality and outcome assessments. PMID- 26957519 TI - The Cryptic dsdA Gene Encodes a Functional D-Serine Dehydratase in Pseudomonas aeruginosa PAO1. AB - D-Serine, an important neurotransmitter, also contributes to bacterial adaptation and virulence in humans. It was reported that Pseudomonas aeruginosa PAO1 can grow on D-serine as the sole nitrogen source, and growth was severely reduced in the dadA mutant devoid of the D-alanine dehydrogenase with broad substrate specificity. In this study, the dsdA gene (PA3357) encoding a putative D-serine dehydratase was subjected to further characterization. Growth on D-serine as the sole source of nitrogen was retained in the ?dsdA mutant and was abolished completely in the ?dadA and ?dadA-?dsdA mutants. However, when complemented by dsdA on a plasmid, the double mutant was able to grow on D-serine as the sole source of carbon and nitrogen, supporting the proposed biochemical function of DsdA in the conversion of D-serine into pyruvate and ammonia. Among D- and L amino acids tested, only D-serine and D-threonine could serve as the substrates of DsdA, and the Km of DsdA with D-serine was calculated to be 330 MUM. Comparative genomics revealed that this cryptic dsdA gene was highly conserved in strains of P. aeruginosa, and that most strains of Pseudomonas putida possess putative dsdCAX genes encoding a transcriptional regulator DsdC and a D-serine transporter DsdX as in enteric bacteria. In conclusion, this study supports the presence of a cryptic dsdA gene encoding a functional D-serine dehydratase in P. aeruginosa, and the absence of dsdA expression in response to exogenous D-serine might be due to the loss of regulatory elements for gene activation during evolution. PMID- 26957520 TI - Muscle Activation and Estimated Relative Joint Force During Running with Weight Support on a Lower-Body Positive-Pressure Treadmill. AB - Running on a lower-body positive-pressure (LBPP) treadmill allows effects of weight support on leg muscle activation to be assessed systematically, and has the potential to facilitate rehabilitation and prevent overloading. The aim was to study the effect of running with weight support on leg muscle activation and to estimate relative knee and ankle joint forces. Runners performed 6-min running sessions at 2.22 m/s and 3.33 m/s, at 100%, 80%, 60%, 40%, and 20% body weight (BW). Surface electromyography, ground reaction force, and running characteristics were measured. Relative knee and ankle joint forces were estimated. Leg muscles responded differently to unweighting during running, reflecting different relative contribution to propulsion and antigravity forces. At 20% BW, knee extensor EMGpeak decreased to 22% at 2.22 m/s and 28% at 3.33 m/s of 100% BW values. Plantar flexors decreased to 52% and 58% at 20% BW, while activity of biceps femoris muscle remained unchanged. Unweighting with LBPP reduced estimated joint force significantly although less than proportional to the degree of weight support (ankle). It was concluded that leg muscle activation adapted to the new biomechanical environment, and the effect of unweighting on estimated knee force was more pronounced than on ankle force. PMID- 26957521 TI - Dynamic Engagement of Cognitive Control Modulates Recovery From Misinterpretation During Real-Time Language Processing. AB - Speech unfolds swiftly, yet listeners keep pace by rapidly assigning meaning to what they hear. Sometimes, though, initial interpretations turn out to be wrong. How do listeners revise misinterpretations of language input moment by moment to avoid comprehension errors? Cognitive control may play a role by detecting when processing has gone awry and then initiating behavioral adjustments accordingly. However, no research to date has investigated a cause-and-effect interplay between cognitive-control engagement and the overriding of erroneous interpretations in real time. Using a novel cross-task paradigm, we showed that Stroop-conflict detection, which mobilizes cognitive-control procedures, subsequently facilitates listeners' incremental processing of temporarily ambiguous spoken instructions that induce brief misinterpretation. When instructions followed incongruent Stroop items, compared with congruent Stroop items, listeners' eye movements to objects in a scene reflected more transient consideration of the false interpretation and earlier recovery of the correct one. Comprehension errors also decreased. Cognitive-control engagement therefore accelerates sentence-reinterpretation processes, even as linguistic input is still unfolding. PMID- 26957523 TI - Development of a Computational Elbow Model with Experimental Validation of Kinematics and Muscle Forces. AB - A computational elbow joint model was developed with a main goal of providing complimentary data to experimental results. The computational model was developed and validated using an experimental elbow joint phantom consisting of a linked total joint replacement. An established in-vitro motion simulator was used to actively flex/extend the experimental elbow in multiple orientations. Muscle forces predicted by the computational model were similar to the experimental model in 4 out of the 5 orientations with errors less than 7.5 N. Valgus angle kinematics were in agreement with differences less than 2.3 degrees . In addition, changes in radial head length, a clinically relevant condition following elbow reconstruction, were simulated in both models and compared. Both lengthening and shortening of the radial head prosthesis altered muscle forces by less than 3.5 N in both models, and valgus angles agreed within 1 degrees . The computational model proved valuable in cross validation with the experimental model, elucidating important limitations in the in-vitro motion simulator's controller. With continued development, the computational model can be a complimentary tool to experimental studies by providing additional noninvasive outcome measurements. PMID- 26957524 TI - Diagnostic Evaluation and Home Monitor Use in Late Preterm to Term Infants With Apnea, Bradycardia, and Desaturations. AB - Apnea, bradycardia, and oxygen desaturation events are a common in neonatal intensive care units, with relevant literature to date largely focusing on very low birth weight and extremely low birth weight infants. We conducted a retrospective review of infants born at >=34 weeks gestational age at 2 tertiary neonatal intensive care units in Boston, MA, between January 2009 and December 2013. Our objectives included (1) describing the diagnostic evaluations performed in late preterm to term infants with discharge-delaying apnea, bradycardia, or oxygen desaturation events and (2) identifying variables associated with home monitor use. Of the 741 eligible infants identified, diagnostic evaluations were variable and infrequent with blood culture, blood glucose, and head ultrasound performed most commonly. The likelihood of home monitor use was greater in infants with either a prolonged inpatient stay or greater gestational age at birth. PMID- 26957522 TI - The transcriptional coactivator Bob1 promotes the development of follicular T helper cells via Bcl6. AB - Follicular T helper (Tfh) cells are key regulators of the germinal center reaction and long-term humoral immunity. Tfh cell differentiation requires the sustained expression of the transcriptional repressor Bcl6; however, its regulation in CD4(+)T cells is incompletely understood. Here, we report that the transcriptional coactivator Bob1, encoded by thePou2af1gene, promotes Bcl6 expression and Tfh cell development. We found that Bob1 together with the octamer transcription factors Oct1/Oct2 can directly bind to and transactivate theBcl6andBtlapromoters. Mixed bone marrow chimeras revealed that Bob1 is required for the expression of normal levels of Bcl6 andBTLA, thereby controlling the pool size and composition of the Tfh compartment in a T cell-intrinsic manner. Our data indicate that T cell-expressed Bob1 is directly involved in Tfh cell differentiation and required for mounting normal T cell-dependent B-cell responses. PMID- 26957526 TI - Authors' reply to House. PMID- 26957525 TI - Thromboxane Governs the Differentiation of Adipose-Derived Stromal Cells Toward Endothelial Cells In Vitro and In Vivo. AB - RATIONALE: Autologous adipose-derived stromal cells (ASCs) offer great promise as angiogenic cell therapy for ischemic diseases. Because of their limited self renewal capacity and pluripotentiality, the therapeutic efficacy of ASCs is still relatively low. Thromboxane has been shown to play an important role in the maintenance of vascular homeostasis. However, little is known about the effects of thromboxane on ASC-mediated angiogenesis. OBJECTIVE: To explore the role of the thromboxane-prostanoid receptor (TP) in mediating the angiogenic capacity of ASCs in vivo. METHODS AND RESULTS: ASCs were prepared from mouse epididymal fat pads and induced to differentiate into endothelial cells (ECs) by vascular endothelial growth factor. Cyclooxygenase-2 expression, thromboxane production, and TP expression were upregulated in ASCs on vascular endothelial growth factor treatment. Genetic deletion or pharmacological inhibition of TP in mouse or human ASCs accelerated EC differentiation and increased tube formation in vitro, enhanced angiogenesis in in vivo Matrigel plugs and ischemic mouse hindlimbs. TP deficiency resulted in a significant cellular accumulation of beta-catenin by suppression of calpain-mediated degradation in ASCs. Knockdown of beta-catenin completely abrogated the enhanced EC differentiation of TP-deficient ASCs, whereas inhibition of calpain reversed the suppressed angiogenic capacity of TP re-expressed ASCs. Moreover, TP was coupled with Galphaq to induce calpain mediated suppression of beta-catenin signaling through calcium influx in ASCs. CONCLUSION: Thromboxane restrained EC differentiation of ASCs through TP-mediated repression of the calpain-dependent beta-catenin signaling pathway. These results indicate that TP inhibition could be a promising strategy for therapy utilizing ASCs in the treatment of ischemic diseases. PMID- 26957527 TI - Laparoscopic Wide Mesocolic Excision and Central Vascular Ligation for Carcinoma of the Colon. AB - BACKGROUND AND AIMS: The principle of complete mesocolic excision for colon cancer has been introduced to improve oncologic outcome. However, this approach is scantily discussed for laparoscopic surgery and there is a lack of randomized trials. This study examined oncologic and clinical outcome after laparoscopic wide mesocolic excision and central vascular ligation for colon cancer. MATERIAL AND METHODS: This is a review of prospectively gathered data from a single institution colorectal cancer database. This study was conducted in the Central Hospital of Central Finland. From January 2003 to December 2011, 222 patients underwent laparoscopic colonic resections with wide mesocolic excision and central vascular ligation in the multimodal setting. The main measures of outcome were cancer recurrence and survival, with early recovery, 30d-mortality and morbidity, reoperation, readmission, and late complications as secondary outcomes. RESULTS: The median follow-up was 5.5 (interquartile range (IQR) = 3.7 8.0) years. The 5-year overall survival for all 222 patients was 80.2% and disease-specific survival was 87.5%, and for those 210 R0-patients with stage I III disease, 83.9% and 91.3%, respectively. The 5-year disease-free survival was 85.8%: stage I was 94.7%, stage II was 90.8%, and stage III was 75.6% ( p = 0.004). Increasing lymph node ratio significantly decreased the 5-year disease free survival. Conversion rate to open surgery was 12.2%. Thirty-day mortality was 1.3% and morbidity, 19.7%. Median postoperative hospital stay was 5 (IQR = 3 7) days. CONCLUSION: Laparoscopic wide mesocolic excision and central vascular ligation for colon cancer resulted in good long-term oncologic outcome. Randomized trials are needed to show that laparoscopic complete mesocolic excision technique would become the standard of care for the carcinoma of the colon. PMID- 26957528 TI - Smoking and Air Pollution as Pro-Inflammatory Triggers for the Development of Rheumatoid Arthritis. AB - INTRODUCTION: Smoking is now well recognized not only as a risk factor for rheumatoid arthritis (RA), but also as a determinant of disease activity, severity, response to therapy, and possibly mortality. METHODS: Studies, mostly recent, which have provided significant insights into the molecular and cellular mechanisms which underpin the pathogenesis of smoking-related RA, as well as the possible involvement of other types of outdoor and indoor pollution form the basis of this review. RESULTS: Smoking initiates chronic inflammatory events in the lungs. These, in turn, promote the release of the enzymes, peptidylarginine deiminases 2 and 4 from smoke-activated, resident and infiltrating pulmonary phagocytes. Peptidylarginine deiminases mediate conversion of various endogenous proteins to putative citrullinated autoantigens. In genetically susceptible individuals, these autoantigens trigger the production of anti-citrullinated peptide, pathogenic autoantibodies, an event which precedes the development of RA. CONCLUSIONS: An increasing body of evidence has linked chronic inflammatory events in the lungs of smokers, to the production of anti-citrullinated peptide autoantibodies and development of RA. Creation of awareness of the associated risks, assessment of smoking status and implementation of compelling antismoking strategies must be included in the routine clinical management of patients presenting with suspected RA. IMPLICATIONS: Chronic inflammatory mechanisms operative in the lungs of smokers lead to the production of anti-citrullinated protein antibodies which, in turn, drive the development of RA. These mechanistic insights not only reinforce the association between smoking and risk for RA, but also the necessity to increase the level of awareness in those at highest risk. PMID- 26957530 TI - Pulsed Electromagnetic Fields for Postoperative Pain Treatment after Breast Augmentation: A Double-Blind, Placebo-Controlled Study. PMID- 26957529 TI - Family income and young adolescents' perceived social position: associations with self-esteem and life satisfaction in the UK Millennium Cohort Study. AB - BACKGROUND: Self-esteem and life satisfaction are important aspects of positive mental health in young people, and both are socially distributed. However, the majority of evidence is based on socioeconomic characteristics of the family. As children enter adolescence and gain independence, perceptions of their own social position are likely to influence mental health. DESIGN AND OBJECTIVES: Using data on 11-year-olds from the UK Millennium Cohort Study, we investigated associations of both family income and young adolescents' perception of their social position with self-esteem and life satisfaction. We hypothesised that there would be differences in the impact of perceived social position on positive mental health when investigating the full scale scoring distribution or the bottom of the distribution. Therefore, we estimated proportional odds for having greater positive mental health (across the distribution of scores) and ORs for poor outcomes (lowest 10% scores). RESULTS: The likelihood of greater self-esteem and life satisfaction increased with income; similarly, the risk of having poor self esteem and life satisfaction increased as income decreased. Young adolescents who perceived their family as poorer than their friends (instead of about the same) were less likely to have greater self-esteem and life satisfaction and were more likely to have poor outcomes. Young adolescents who perceived their family as richer were more likely to have poor self-esteem, but were not less likely to have greater self-esteem. For life satisfaction, young adolescents who perceived their families as richer were less likely to have greater and more likely to have poor life satisfaction. CONCLUSIONS: Policies to redistribute income in families with children are likely to benefit the mental health of young people. However, it is also important to consider the impact of social comparison on young people's mental health as they enter adolescence. PMID- 26957531 TI - Angiographic and Intracoronary Manifestations of Coronary Fibromuscular Dysplasia. AB - BACKGROUND: We previously described a strong association between fibromuscular dysplasia (FMD) and spontaneous coronary artery dissection. Angiographic manifestations of coronary FMD aside from dissection were considered rare. However, we observed several coronary FMD angiographic abnormalities with corresponding optical coherence tomography abnormalities. METHODS AND RESULTS: Baseline demographics and imaging of patients with suspected coronary FMD at Vancouver General Hospital were reviewed. Presence of multifocal (string-of beads) extracoronary FMD was confirmed by 2 specialists. In these patients, coronary angiographic findings (excluding dissected segments) were reviewed and classified by 2 experienced angiographers for irregular stenosis, that is, stenosis with irregular borders in a focal or diffuse pattern with/without systolic accentuation; smooth stenosis, diffuse or focal; segmental dilatation/ectasia; and tortuosity. Optical coherence tomography was performed in a subset of patients. Of 32 patients with extracoronary FMD and suspected coronary involvement, 28 were women (88%), and their mean age was 59.4+/-9.9 years. Nineteen presented with myocardial infarction (13 caused by spontaneous coronary artery dissection), and 13 had stable symptoms. The observed coronary angiographic abnormalities included tortuosity in all cases (91% were moderate to severe), irregular stenosis in 59%, smooth stenosis in 19%, and segmental dilatation/ectasia in 56%. Fifteen patients had optical coherence tomography of the abnormal segments showing abnormalities, including multiple areas of patchy or diffuse intimal, medial or adventitial abnormalities with thickening/accumulation of varied reflectivities, macrophage infiltration, loss/duplication of elastic membranes, and cavitation. CONCLUSIONS: This is the first case series describing findings suggestive of angiographic and intracoronary manifestations of coronary FMD. Future studies should prospectively review these features in patients with extracoronary FMD. PMID- 26957532 TI - Trends in Enrollment, Clinical Characteristics, Treatment, and Outcomes According to Age in Non-ST-Segment-Elevation Acute Coronary Syndromes Clinical Trials. AB - BACKGROUND: Representation by age ensures appropriate translation of clinical trial results to practice, but, historically, older patients have been underrepresented in clinical trial populations. As the general population has aged, it is unknown whether clinical trial enrollment has changed in parallel. METHODS AND RESULTS: We studied time trends in enrollment, clinical characteristics, treatment, and outcomes by age among 76 141 patients with non-ST segment-elevation acute coronary syndrome enrolled in 11 phase III clinical trials over 17 years (1994-2010). Overall, 19.7% of patients were >=75 years; this proportion increased from 16% during 1994 to 1997 to 21% during 1998 to 2001 and 23.2% during 2002 to 2005, but declined to 20.2% in 2006 to 2010. The number of comorbidities increased with successive time periods irrespective of age. There were substantial increases in the use of evidence-based medication in hospital and at discharge regardless of age. Although predicted 6-month mortality increased slightly over time, observed 6-month mortality declined significantly in all age strata (1994-1997 versus 2006-2010: <65 years: 3.0% versus 1.9%; 65-74 years: 7.5% versus 3.4%; 75-79 years: 13.0% versus 6.5%; 80-84 years: 17.6% versus 8.2%; and >=85 years: 24.8% versus 12.6%). CONCLUSIONS: The distribution of enrollment by age in phase III non-ST-segment-elevation acute coronary syndrome trials was unchanged over time. Irrespective of age, post-myocardial infarction mortality decreased significantly over time, concurrent with increased evidence-based care and despite increasing comorbidities. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00089895. PMID- 26957533 TI - A Family-Based, Culturally Tailored Diabetes Intervention for Hispanics and Their Family Members. AB - PURPOSE: The purpose of this study was to test efficacy of a family-based, culturally tailored intervention for Hispanics with type 2 diabetes and their family members. METHODS: Hispanic patients with type 2 diabetes and their family members recruited from community clinics and ethnic churches were assigned to groups (N = 186). The intervention group received an 8-week culturally tailored diabetes educational program delivered in Spanish while the attention control group received 8 weekly sessions on general health information and 2 sessions on diabetes after completion of the study. Data were collected at baseline, after intervention, and at 1- and 6-month follow-ups for both patients and families. Comparisons of change over time were performed using growth curve analyses after propensity score adjustment. RESULTS: Intervention patients improved in diabetes knowledge and diabetes self-efficacy over time (but did not sustain at 6-month follow-up). A1C was lower at 1-month follow-up. Family members had improvements in diabetes knowledge and physical health-related quality of life. CONCLUSIONS: Including families in the interventions may improve glycemic control, diabetes knowledge, self-efficacy, and physical health-related quality of life. However, strategies for sustaining improvements are needed. PMID- 26957534 TI - Influence of Patient-Centered Decision Making on Sustained Weight Loss and Risk Reduction Following Lifestyle Intervention Efforts in Rural Pennsylvania. AB - PURPOSE: The purpose of this study was to determine whether weight loss and cardiovascular disease risk factor reduction was maintained following a lifestyle intervention. METHODS: Five hundred fifty-five individuals without diabetes from 8 rural communities were screened for BMI >=25 kg/m(2) and abdominal obesity (86.1% female, 95.1% white, 55.8% obese). Communities and eligible participants (n = 493; mean age, 51 years, 87.6% female, 94.1% Caucasian) were assigned to 4 study groups: face-to-face, DVD, Internet, and self-selection (SS) (n = 101). Self-selection participants chose the intervention modality (60% face-to-face, 40% Internet, 0% DVD). Outcomes included weight change and risk factor reduction at 18 months. RESULTS: All groups achieved maintenance of 5% weight loss in over half of participants. Self-selection participants had the largest proportion maintain (89.5%). Similarly, nearly 75% of participants sustained risk factor reduction. After multivariate adjustment, participants in SS were 2.3 times more likely to maintain 5% weight loss compared to the other groups, but not risk factor reduction. CONCLUSION: Despite the modality, lifestyle intervention was effective at maintaining weight loss and risk reduction. However, SS participants were twice as likely to sustain improvements compared to other groups. The importance of patient-centered decision making in health care is paramount. PMID- 26957535 TI - Reply. PMID- 26957536 TI - Retraction. PMID- 26957537 TI - Nanotoxicology: The Toxicology of Nanomaterials and Nanostructures. PMID- 26957539 TI - American College of Toxicology 2015 Poster Abstracts. PMID- 26957538 TI - Applied Nanotoxicology. AB - Nanomaterials, including nanoparticles and nanoobjects, are being incorporated into everyday products at an increasing rate. These products include consumer products of interest to toxicologists such as pharmaceuticals, cosmetics, food, food packaging, household products, and so on. The manufacturing of products containing or utilizing nanomaterials in their composition may also present potential toxicologic concerns in the workplace. The molecular complexity and composition of these nanomaterials are ever increasing, and the means and methods being applied to characterize and perform useful toxicologic assessments are rapidly advancing. This article includes presentations by experienced toxicologists in the nanotoxicology community who are focused on the applied aspect of the discipline toward supporting state of the art toxicologic assessments for food products and packaging, pharmaceuticals and medical devices, inhaled nanoparticle and gastrointestinal exposures, and addressing occupational safety and health issues and concerns. This symposium overview article summarizes 5 talks that were presented at the 35th Annual meeting of the American College of Toxicology on the subject of "Applied Nanotechnology." PMID- 26957540 TI - The Role of PIWIL4, an Argonaute Family Protein, in Breast Cancer. AB - P-element-induced wimpy testis (PIWI) proteins bind to PIWI-interacting RNAs and play key roles in the biogenesis and functions of PIWI-interacting RNAs. It has been reported that PIWI proteins are essential for stem cell self-renewal and germline development in diverse organisms and that they are ectopically expressed in multiple forms of cancer. However, the role of PIWI in cancer remains elusive. Here we report that one of the four PIWI proteins in humans, PIWIL4, is highly expressed in both breast cancer tissues and the cytoplasm of MDA-MB-231 cells derived from breast cancer. Reducing PIWIL4 expression drastically impairs the migration ability of MDA-MB-231 cells, significantly increases their apoptosis, and mildly affects their proliferation. Our transcriptome and proteome analysis reveal that these functions are at least partially achieved via the PIWIL4 regulation of TGF-beta and FGF signaling pathways and MHC class II proteins. These findings suggest that PIWIL4 may serve as a potential therapeutic target for breast cancer. PMID- 26957541 TI - Trehalose Alters Subcellular Trafficking and the Metabolism of the Alzheimer associated Amyloid Precursor Protein. AB - The disaccharide trehalose is commonly considered to stimulate autophagy. Cell treatment with trehalose could decrease cytosolic aggregates of potentially pathogenic proteins, including mutant huntingtin, alpha-synuclein, and phosphorylated tau that are associated with neurodegenerative diseases. Here, we demonstrate that trehalose also alters the metabolism of the Alzheimer disease related amyloid precursor protein (APP). Cell treatment with trehalose decreased the degradation of full-length APP and its C-terminal fragments. Trehalose also reduced the secretion of the amyloid-beta peptide. Biochemical and cell biological experiments revealed that trehalose alters the subcellular distribution and decreases the degradation of APP C-terminal fragments in endolysosomal compartments. Trehalose also led to strong accumulation of the autophagic marker proteins LC3-II and p62, and decreased the proteolytic activation of the lysosomal hydrolase cathepsin D. The combined data indicate that trehalose decreases the lysosomal metabolism of APP by altering its endocytic vesicular transport. PMID- 26957542 TI - Drosophila O-GlcNAcase Deletion Globally Perturbs Chromatin O-GlcNAcylation. AB - Gene expression during Drosophila development is subject to regulation by the Polycomb (Pc), Trithorax (Trx), and Compass chromatin modifier complexes. O GlcNAc transferase (OGT/SXC) is essential for Pc repression suggesting that the O GlcNAcylation of proteins plays a key role in regulating development. OGT transfers O-GlcNAc onto serine and threonine residues in intrinsically disordered domains of key transcriptional regulators; O-GlcNAcase (OGA) removes the modification. To pinpoint genomic regions that are regulated by O-GlcNAc levels, we performed ChIP-chip and microarray analysis after OGT or OGA RNAi knockdown in S2 cells. After OGA RNAi, we observed a genome-wide increase in the intensity of most O-GlcNAc-occupied regions including genes linked to cell cycle, ubiquitin, and steroid response. In contrast, O-GlcNAc levels were strikingly insensitive to OGA RNAi at sites of polycomb repression such as the Hox and NK homeobox gene clusters. Microarray analysis suggested that altered O-GlcNAc cycling perturbed the expression of genes associated with morphogenesis and cell cycle regulation. We then produced a viable null allele of oga (oga(del.1)) in Drosophila allowing visualization of altered O-GlcNAc cycling on polytene chromosomes. We found that trithorax (TRX), absent small or homeotic discs 1 (ASH1), and Compass member SET1 histone methyltransferases were O-GlcNAc-modified in oga(del.1) mutants. The oga(del.1) mutants displayed altered expression of a distinct set of cell cycle related genes. Our results show that the loss of OGA in Drosophila globally impacts the epigenetic machinery allowing O-GlcNAc accumulation on RNA polymerase II and numerous chromatin factors including TRX, ASH1, and SET1. PMID- 26957543 TI - Strain-specific Loss of Formyl Peptide Receptor 3 in the Murine Vomeronasal and Immune Systems. AB - Formyl peptide receptor 3 (Fpr3, also known as Fpr-rs1) is a G protein-coupled receptor expressed in subsets of sensory neurons of the mouse vomeronasal organ, an olfactory substructure essential for social recognition. Fpr3 has been implicated in the sensing of infection-associated olfactory cues, but its expression pattern and function are incompletely understood. To facilitate visualization of Fpr3-expressing cells, we generated and validated two new anti Fpr3 antibodies enabling us to analyze acute Fpr3 protein expression. Fpr3 is not only expressed in murine vomeronasal sensory neurons but also in bone marrow cells, the primary source for immune cell renewal, and in mature neutrophils. Consistent with the notion that Fpr3 functions as a pathogen sensor, Fpr3 expression in the immune system is up-regulated after stimulation with a bacterial endotoxin (lipopolysaccharide). These results strongly support a dual role for Fpr3 in both vomeronasal sensory neurons and immune cells. We also identify a large panel of mouse strains with severely altered expression and function of Fpr3, thus establishing the existence of natural Fpr3 knock-out strains. We attribute distinct Fpr3 expression in these strains to the presence or absence of a 12-nucleotide in-frame deletion (Fpr3Delta424-435). In vitro calcium imaging and immunofluorescence analyses demonstrate that the lack of four amino acids leads to an unstable, truncated, and non-functional receptor protein. The genome of at least 19 strains encodes a non-functional Fpr3 variant, whereas at least 13 other strains express an intact receptor. These results provide a foundation for understanding the in vivo function of Fpr3. PMID- 26957544 TI - The GTP-bound and Sumoylated Form of the rab17 Small Molecular Weight GTPase Selectively Binds Syntaxin 2 in Polarized Hepatic WIF-B Cells. AB - A major focus for our laboratory is identifying the molecules and mechanisms that regulate polarized apical protein sorting in hepatocytes, the major epithelial cells of the liver. These trafficking pathways are regulated, in part, by small molecular weight rab GTPases. We chose to investigate rab17, whose expression is restricted to polarized epithelial cells, is enriched in liver, and has been implicated in regulating basolateral to apical transcytosis. To initiate our studies, we generated three recombinant adenoviruses expressing wild type, constitutively active (GTP bound), or dominant-negative (GDP bound) rab17. Immunoblotting revealed rab17 immunoreactive species at 25 kDa (the predicted rab17 molecular mass) and 40 kDa. We determined that mono-sumoylation of the 25 kDa rab17 is responsible for the shift in molecular mass, and that rab17 prenylation is required for sumoylation. We further determined that sumoylation selectively promotes interactions with syntaxin 2 (but not syntaxins 3 or 4) and that these interactions are nucleotide dependent. Furthermore, a K68R-mutated rab17 led to the redistribution of syntaxin 2 and 5' nucleotidase from the apical membrane to subapical puncta, whereas multidrug resistance protein 2 distributions were not changed. Together these data are consistent with the proposed role of rab17 in vesicle fusion with the apical plasma membrane and further implicate sumoylation as an important mediator of protein-protein interactions. The selectivity in syntaxin binding and apical protein redistribution further suggests that rab17 and syntaxin 2 mediate fusion of transcytotic vesicles at the apical surface. PMID- 26957547 TI - Training Guidelines for Endovascular Ischemic Stroke Intervention: An International multi-society consensus document. AB - ContributorsAmerican Academy of Neurological Surgeons/ Congress of Neurological Surgeons (AANS/CNS): S.D. Lavine, K Cockroft, B Hoh, N Bambakidis, AA Khalessi, H Woo, H Riina. A. SiddiquiAmerican Society of Neuroradiology (ASNR): J. A. HirschAsian Australasian Federation of Interventional and Therapeutic Neuroradiology (AAFITN): W. ChongAustralian and New Zealand Society of Neuroradiology - Conjoint Committee for Recognition of Training in Interventional Neuroradiology (CCINR) representing the RANZCR (ANZSNR), ANZAN and NSA: H. Rice, J Wenderoth, P Mitchell, A Coulthard, TJ Signh, C Phatorous, M KhangureCanadian Interventional Neuro Group (CING): P. Klurfan, K. Terbrugge, D Iancu, T. GunnarssonEuropean Society of Neuroradiology (ESNR); O. Jansen, M. MutoEuropean Society of Minimally Invasive Neurologic Therapy (ESMINT): I. Szikora L. Pierot P. Brouwer J. Gralla, S. Renowden, T. Andersson, J. Fiehler, F. Turjman, P. White, AC Januel, L Spelle, Z Kulcsar, R Chapot, L Spelle, A Biondi, S Dima, C Taschner, M Szajner, A KrajinaJapanese Society for Neuroendovascular therapy (JSNET): N.Sakai, Y. Matsumaru, S. YoshimuraSociedad Ibero Latino Americana de Neuroradiologica (SILAN): O.Diaz, P.LylykSociety of NeuroInterventional Surgery (SNIS): M.V. Jayaraman, A. Patsalides, C. D. Gandhi, S.K.Lee, T. Abruzzo, B. Albani, S. A. Ansari, A.S. Arthur, B.W. Baxter, K.R.Bulsara, M. Chen, J.E.Delgado Almandoz, J.F.Fraser, D.V. Heck, S.W. Hetts, M.S.Hussain, R.P. Klucznik, T.M. Leslie-Mawzi, W.J.Mack, R.A.McTaggart, P.M.Meyers, J. Mocco, C.J.Prestigiacomo, G.L.Pride, P.A.Rasmussen, R.M.Starke, P.J.Sunenshine, R.W.Tarr, D.F.FreiSociety of Vascular and Interventional Neurology (SVIN): M.Ribo, R.G.Nogeuira, O.O. Zaidat, T. Jovin, I. Linfante, D. Yavagal, D. Liebeskind, R. NovakovicWorld Federation of Interventional and Therapeutic Neuroradiology (WFITN): S. Pongpech, G Rodesch, M Soderman, K ter Brugge, A. Taylor, T Krings, D Orbach, A. Biondi, L Picard, D C Suh, M. Tanaka, HQ Zhang. PMID- 26957545 TI - Inhibition of Heat Shock Protein 90 Prevents HIV Rebound. AB - HIV evades eradication because transcriptionally dormant proviral genomes persist in long-lived reservoirs of resting CD4(+) T cells and myeloid cells, which are the source of viral rebound after cessation of antiretroviral therapy. Dormant HIV genomes readily produce infectious virus upon cellular activation because host transcription factors activated specifically by cell stress and heat shock mediate full-length HIV transcription. The molecular chaperone heat shock protein 90 (Hsp90) is overexpressed during heat shock and activates inducible cellular transcription factors. Here we show that heat shock accelerates HIV transcription through induction of Hsp90 activity, which activates essential HIV-specific cellular transcription factors (NF-kappaB, NFAT, and STAT5), and that inhibition of Hsp90 greatly reduces gene expression mediated by these factors. More importantly, we show that Hsp90 controls virus transcription in vivo by specific Hsp90 inhibitors in clinical development, tanespimycin (17-(allylamino)-17 demethoxygeldanamycin) and AUY922, which durably prevented viral rebound in HIV infected humanized NOD scid IL-2Rgamma(-/-) bone marrow-liver-thymus mice up to 11 weeks after treatment cessation. Despite the absence of rebound viremia, we were able to recover infectious HIV from PBMC with heat shock. Replication competent virus was detected in spleen cells from these nonviremic Hsp90 inhibitor-treated mice, indicating the presence of a tissue reservoir of persistent infection. Our novel findings provide in vivo evidence that inhibition of Hsp90 activity prevents HIV gene expression in replication-competent cellular reservoirs that would typically cause rebound in plasma viremia after antiretroviral therapy cessation. Alternating or supplementing Hsp90 inhibitors with current antiretroviral therapy regimens could conceivably suppress rebound viremia from persistent HIV reservoirs. PMID- 26957548 TI - Analysis of novel Sir3 binding regions in Saccharomyces cerevisiae. AB - In Saccharomyces cerevisiae, the HMR, HML, telomere and rDNA regions are silenced. Silencing at the rDNA region requires Sir2, and silencing at the HMR, HML and telomere regions requires binding of a protein complex, consisting of Sir2, Sir3 and Sir4, that mediates repression of gene expression. Here, several novel Sir3 binding domains, termed CN domains (Chromosomal Novel Sir3 binding region), were identified using chromatin immunoprecipitation (ChIP) on chip analysis of S. cerevisiae chromosomes. Furthermore, analysis of G1-arrested cells demonstrated that Sir3 binding was elevated in G1-arrested cells compared with logarithmically growing asynchronous cells, and that Sir3 binding varied with the cell cycle. In addition to 14 CN regions identified from analysis of logarithmically growing asynchronous cells (CN1-14), 11 CN regions were identified from G1-arrested cells (CN15-25). Gene expression at some CN regions did not differ between WT and sir3Delta strains. Sir3 at conventional heterochromatic regions is thought to be recruited to chromosomes by Sir2 and Sir4; however, in this study, Sir3 binding occurred at some CN regions even in sir2Delta and sir4Delta backgrounds. Taken together, our results suggest that Sir3 exhibits novel binding parameters and gene regulatory functions at the CN binding domains. PMID- 26957549 TI - Do Toxic Synergies of Underlying Etiologies Predispose the Positive Association Between Traumatic Brain Injury and ADHD? AB - OBJECTIVE: In their meta-analysis, Adeyemo et al. reported a strong association between mild traumatic brain injury (mTBI) and ADHD. However, less is understood about why such an association exists. METHOD: This commentary focuses on the underlying etiologies of both conditions to reveal potential toxic synergisms that could explain this association. RESULTS: Alcohol and substance abuse are recognized comorbidities in both conditions. The author of this commentary has recently been the first to propose that chronic exposure to nitrous oxide (N2O), an increasing environmental air pollutant and greenhouse gas, may contribute to the cognitive impairment seen in conditions such as ADHD and autism. The toxic synergisms from combined GABA-mimetics, such as ethanol, and nontoxic N2O exposure have been previously elucidated and are further contextualized here. CONCLUSION: The conclusion of this commentary is that the toxicological interdependence of the underlying etiologies for mTBI and ADHD may help to explain their association as found in the meta-analysis conducted by Adeyemo et al. This commentary explores this dynamic further and, in so doing, underscores the need for additional research to validate these important conclusions. PMID- 26957546 TI - Structural Basis for Translocation of a Biofilm-supporting Exopolysaccharide across the Bacterial Outer Membrane. AB - The partially de-N-acetylated poly-beta-1,6-N-acetyl-d-glucosamine (dPNAG) polymer serves as an intercellular biofilm adhesin that plays an essential role for the development and maintenance of integrity of biofilms of diverse bacterial species. Translocation of dPNAG across the bacterial outer membrane is mediated by a tetratricopeptide repeat-containing outer membrane protein, PgaA. To understand the molecular basis of dPNAG translocation, we determined the crystal structure of the C-terminal transmembrane domain of PgaA (residues 513-807). The structure reveals that PgaA forms a 16-strand transmembrane beta-barrel, closed by four loops on the extracellular surface. Half of the interior surface of the barrel that lies parallel to the translocation pathway is electronegative, suggesting that the corresponding negatively charged residues may assist the secretion of the positively charged dPNAG polymer. In vivo complementation assays in a pgaA deletion bacterial strain showed that a cluster of negatively charged residues proximal to the periplasm is necessary for biofilm formation. Biochemical analyses further revealed that the tetratricopeptide repeat domain of PgaA binds directly to the N-deacetylase PgaB and is critical for biofilm formation. Our studies support a model in which the positively charged PgaB-bound dPNAG polymer is delivered to PgaA through the PgaA-PgaB interaction and is further targeted to the beta-barrel lumen of PgaA potentially via a charge complementarity mechanism, thus priming the translocation of dPNAG across the bacterial outer membrane. PMID- 26957550 TI - Exploring Workforce Participation Patterns and Chronic Diseases Among Middle-Aged Australian Men and Women Over the Life Course. AB - OBJECTIVE: This study identified associations between chronic diseases (diabetes, asthma, depression, and arthritis) and workforce participation patterns with a gendered perspective. METHOD: We used data from 1,261 middle-aged participants of the Australian Life Histories and Health (LHH) Survey, aged 60 to 64 years in 2011. Latent class analysis identified dominant workforce patterns and associations between chronic diseases and these patterns were explored by multinomial regression models. RESULTS: Diabetes, asthma, depression, and arthritis were less prevalent in men and women in class "mostly full-time work," compared with other workforce patterns. The odds of "mostly full-time work" were lower for men reporting depression or arthritis, whereas among women, depression was associated with "increasing part-time work" after adjusting early and adult life factors. DISCUSSION: The results strengthen the importance of gender focused policies aimed to promote and preserve health of young and middle-aged workers, and creating supportive environment for those with chronic health issues over the life course. PMID- 26957551 TI - An observational study of type, timing, and severity of childhood maltreatment and preterm birth. AB - BACKGROUND: Childhood maltreatment has been linked to preterm birth (<37 weeks gestation) in some studies, but these findings have been inconsistent, and it remains unclear whether type, timing or severity of maltreatment are associated with risk of preterm birth. The aim of this observational study was to explore type of maltreatment (child and adolescent physical and sexual abuse and harsh parenting) as risk factors for preterm birth. METHODS: We examined these associations in a cross-sectional analysis of the Nurses' Health Study II cohort of female nurses. Women completed a questionnaire about experiences of sexual abuse, physical abuse or harsh parenting, along with pregnancy outcomes. Logistic regression models adjusted for relevant covariates including age, race, alcohol and cigarette use during pregnancy, age at menarche, marital status, adult income, body mass index (kg/m(2)) at age 18, physical abuse in pregnancy, and childhood socioeconomic position. RESULTS: Among 51 434 first births, 4110 were preterm (8% of births). Forced sexual activity in childhood or adolescence was associated with a 22% increased odds of preterm birth (OR=1.22, 95% CI 1.10 to 1.35). Maltreatment involving sexual touch, physical abuse or harsh parenting was not associated with preterm birth in this sample. CONCLUSIONS: Women who experience forced sexual activity in childhood or adolescence may have an increased likelihood of delivering preterm in adulthood. PMID- 26957552 TI - Phenology of Asian Citrus Psyllid (Hemiptera: Liviidae), With Special Reference to Biological Control by Tamarixia radiata, in the Residential Landscape of Southern California. AB - Since its discovery in 2008, the pestiferous Asian citrus psyllid, Diaphorina citri Kuwayama (Hemiptera: Liviidae), has become widely established in residential citrus trees throughout southern California. In 2011, Tamarixia radiata (Waterston) (Hymenoptera: Eulophidae), a host-specific parasitoid of D. citri, sourced from Punjab Pakistan, was introduced into California as part of a classical biological program aimed at suppressing D. citri populations in urban areas. Despite these release efforts, little is known about the population dynamics of D. citri in urban citrus or the efficacy of T. radiata in controlling psyllid populations in urban-grown citrus. To address this shortcoming, the population phenology of D. citri was monitored biweekly for 2-3 yr on five different host plants (Rutaceae) at 11 residential sites across Riverside and Los Angeles Counties in southern California. Citrus flush growth patterns and parasitoid activity levels were also assessed. Urban D. citri populations were present year round at each site, with highest densities occurring over July through November. Temperature was an important indicator of overall D. citri densities with positive correlations across all life stages. Regularly flushing lime trees consistently supported the highest densities of psyllid eggs and nymphs, while equally vigorous flushing curry leaf plants supported the highest adult densities. While T. radiata activity was detected at all sites, average year-round percent parasitism was low throughout the study, averaging <5% in 2012, 2013, and 2014. PMID- 26957553 TI - Introductory paragraph. PMID- 26957554 TI - Homologous Recombination Deficiency (HRD) Score Predicts Response to Platinum Containing Neoadjuvant Chemotherapy in Patients with Triple-Negative Breast Cancer. AB - PURPOSE: BRCA1/2-mutated and some sporadic triple-negative breast cancers (TNBC) have DNA repair defects and are sensitive to DNA-damaging therapeutics. Recently, three independent DNA-based measures of genomic instability were developed on the basis of loss of heterozygosity (LOH), telomeric allelic imbalance (TAI), and large-scale state transitions (LST). EXPERIMENTAL DESIGN: We assessed a combined homologous recombination deficiency (HRD) score, an unweighted sum of LOH, TAI, and LST scores, in three neoadjuvant TNBC trials of platinum-containing therapy. We then tested the association of HR deficiency, defined as HRD score >=42 or BRCA1/2 mutation, with response to platinum-based therapy. RESULTS: In a trial of neoadjuvant platinum, gemcitabine, and iniparib, HR deficiency predicted residual cancer burden score of 0 or I (RCB 0/I) and pathologic complete response (pCR; OR = 4.96, P = 0.0036; OR = 6.52, P = 0.0058). HR deficiency remained a significant predictor of RCB 0/I when adjusted for clinical variables (OR = 5.86, P = 0.012). In two other trials of neoadjuvant cisplatin therapy, HR deficiency predicted RCB 0/I and pCR (OR = 10.18, P = 0.0011; OR = 17.00, P = 0.0066). In a multivariable model of RCB 0/I, HR deficiency retained significance when clinical variables were included (OR = 12.08, P = 0.0017). When restricted to BRCA1/2 nonmutated tumors, response was higher in patients with high HRD scores: RCB 0/I P = 0.062, pCR P = 0.063 in the neoadjuvant platinum, gemcitabine, and iniparib trial; RCB 0/I P = 0.0039, pCR P = 0.018 in the neoadjuvant cisplatin trials. CONCLUSIONS: HR deficiency identifies TNBC tumors, including BRCA1/2 nonmutated tumors more likely to respond to platinum-containing therapy. Clin Cancer Res; 22(15); 3764 73. (c)2016 AACR. PMID- 26957555 TI - Pharmacology in the Era of Targeted Therapies: The Case of PI3K Inhibitors. AB - The PI3K pathway is often aberrantly activated in estrogen receptor positive (ER(+)) breast cancer and therapies combining PI3K inhibitors and antiestrogens are under clinical development. Given that many PI3K inhibitors have substantial toxicities with continuous dosing and that alternate dosing schedules are equally active, further clinical exploration is warranted. Clin Cancer Res; 22(9); 2099 101. (c)2016 AACRSee related article by Yang et al., p. 2250. PMID- 26957556 TI - Transposon Mutagenesis Reveals Fludarabine Resistance Mechanisms in Chronic Lymphocytic Leukemia. AB - PURPOSE: To identify resistance mechanisms for the chemotherapeutic drug fludarabine in chronic lymphocytic leukemia (CLL), as innate and acquired resistance to fludarabine-based chemotherapy represents a major challenge for long-term disease control. EXPERIMENTAL DESIGN: We used piggyBac transposon mediated mutagenesis, combined with next-generation sequencing, to identify genes that confer resistance to fludarabine in a human CLL cell line. RESULTS: In total, this screen identified 782 genes with transposon integrations in fludarabine-resistant pools of cells. One of the identified genes is a known resistance mediator DCK (deoxycytidine kinase), which encodes an enzyme that is essential for the phosphorylation of the prodrug to the active metabolite. BMP2K, a gene not previously linked to CLL, was also identified as a modulator of response to fludarabine. In addition, 10 of 782 transposon-targeted genes had previously been implicated in treatment resistance based on somatic mutations seen in patients refractory to fludarabine-based therapy. Functional characterization of these genes supported a significant role for ARID5B and BRAF in fludarabine sensitivity. Finally, pathway analysis of transposon-targeted genes and RNA-seq profiling of fludarabine-resistant cells suggested deregulated MAPK signaling as involved in mediating drug resistance in CLL. CONCLUSIONS: To our knowledge, this is the first forward genetic screen for chemotherapy resistance in CLL. The screen pinpointed novel genes and pathways involved in fludarabine resistance along with previously known resistance mechanisms. Transposon screens can therefore aid interpretation of cancer genome sequencing data in the identification of genes modifying sensitivity to chemotherapy. Clin Cancer Res; 22(24); 6217-27. (c)2016 AACR. PMID- 26957557 TI - Cytotoxic Cutaneous Adverse Drug Reactions during Anti-PD-1 Therapy. AB - PURPOSE: Immunotherapy has experienced impressive progress in cancer treatment. Antibodies against PD-1 improved survival in different types of cancer including melanoma. They are generally well tolerated. However, skin toxicities including pruritus, rashes, and vitiligo are reported. Although frequent, they have not been characterized further yet. In this analysis, we aimed to systematically assess and characterize the adverse cutaneous reactions observed in patients with melanoma treated with anti-PD-1 antibodies. EXPERIMENTAL DESIGN: Patients with melanoma were treated with anti-PD-1 antibodies within clinical trials and an early-access program. Adverse cutaneous eruptions that emerged in our melanoma patient cohort were systematically investigated and classified using histology and gene expression profiling in comparison with maculopapular drug rash, cutaneous GVHD, and the severe drug eruption toxic epidermal necrolysis (TEN). RESULTS: Between February 2013 and September 2015, 68 patients with stage IV melanoma were treated at the University Hospital Zurich (Zurich, Switzerland); 15 patients (22%) developed cutaneous reactions and 10 (15%) vitiligo. The cutaneous reactions ranged from small erythematous papules with mild pruritus to disseminated erythematous maculopapular rashes (MPR) without signs of epidermal involvement to severe MPRs, including epidermal detachment and mucosal involvement. Although skin involvement varied from mild rash to bullous drug eruptions, gene expression profiling pathogenically classified all investigated cases as TEN-like reactions. CONCLUSIONS: As predicted by the PD-1 knockout mouse, anti-PD-1 antibodies frequently cause adverse cutaneous reactions. Gene expression profiling reminds in all cases of a TEN-like pattern, suggesting that PD-1/PD-L1 interaction is required to preserve epidermal integrity during inflammatory skin reactions. Clin Cancer Res; 22(16); 4023-9. (c)2016 AACR. PMID- 26957559 TI - Predictive Biomarkers for PD-1 Axis Therapies: The Hidden Treasure or a Call for Research. AB - Blockade of the PD-1 axis has emerged as an effective anticancer immunotherapy against various tumor types. Diverse studies have identified biomarkers associated with response to these therapies. However, the clinical use of such tests is limited by their variable performance and restricted understanding of their biologic significance. Clin Cancer Res; 22(9); 2102-4. (c)2016 AACRSee related article by Ock et al., p. 2261. PMID- 26957560 TI - Targeting Suppressive Myeloid Cells Potentiates Checkpoint Inhibitors to Control Spontaneous Neuroblastoma. AB - PURPOSE: Neuroblastoma is the most common extracranial solid cancer type in childhood, and high-risk patients have poor prognosis despite aggressive multimodal treatment. Neuroblastoma-driven inflammation contributes to the induction of suppressive myeloid cells that hamper efficient antitumor immune responses. Therefore, we sought to enhance antitumor immunity by removing immunosuppression mediated by myeloid cells. EXPERIMENTAL DESIGN: The prognostic values of myeloid cells are demonstrated by analyzing genomic datasets of neuroblastoma patients. The impact of tumor-derived factors on myelopoiesis and local induction of suppressive myeloid cells is dissected by in vitro culture models using freshly isolated human CD34(+) hematopoietic stem cells, primary human monocytes, and murine bone marrow cells. To test the therapeutic efficacy of BLZ945 as a monotherapy or in combination with checkpoint inhibitors, we used a transgenic murine model (TH-MYCN) that develops aggressive spontaneous neuroblastoma. RESULTS: We report that infiltrating CSF-1R(+) myeloid cells predict poor clinical outcome in patients with neuroblastoma. In vitro, neuroblastoma-derived factors interfere with early development of myeloid cells and enable suppressive functions on human monocytes through M-CSF/CSF-1R interaction. In a transgenic mouse model (TH-MYCN) resembling high-risk human neuroblastoma, antagonizing CSF-1R with a selective inhibitor (BLZ945) modulates the induction of human and murine suppressive myeloid cells and efficiently limit tumor progression. While checkpoint inhibitors are insufficient in controlling tumor growth, combining BLZ945 with PD-1/PD-L1 blocking antibodies results in superior tumor control. CONCLUSIONS: Our results demonstrate the essential role of CSF-1R signaling during the induction of suppressive myeloid cells and emphasize its clinical potential as an immunotherapy for human cancers. Clin Cancer Res; 22(15); 3849-59. (c)2016 AACR. PMID- 26957558 TI - MicroRNA MIR21 (miR-21) and PTGS2 Expression in Colorectal Cancer and Patient Survival. AB - PURPOSE: Prostaglandin-endoperoxide synthase 2 (PTGS2, cyclooxygenase-2; a target of aspirin) produces inflammatory mediator prostaglandin E2 (PGE2), and contributes to colorectal neoplasia development. PTGS2-driven inflammatory responses can induce tumor expression of microRNA MIR21 (miR-21) that can increase local PGE2 level by downregulating PGE2-metabolizing enzymes. We hypothesized that the prognostic association of tumor MIR21 expression level in colorectal carcinoma might depend on inflammatory tumor microenvironment and be stronger in tumors expressing high-level PTGS2. EXPERIMENTAL DESIGN: Utilizing 765 rectal and colon cancer specimens in the Nurses' Health Study and the Health Professionals Follow-up Study, we measured MIR21 expression by quantitative reverse transcription PCR, and PTGS2 expression by immunohistochemistry. Cox proportional hazards regression model was used to assess statistical interaction between MIR21 and PTGS2 in colorectal cancer-specific survival analysis, controlling for potential confounders including microsatellite instability, CpG island methylator phenotype, LINE-1 methylation level, and KRAS, BRAF, and PIK3CA mutations. RESULTS: Tumor MIR21 expression level was associated with higher colorectal cancer-specific mortality (Ptrend = 0.029), and there was a statistically significant interaction between MIR21 and PTGS2 (Pinteraction = 0.0004). The association between MIR21 expression and colorectal cancer-specific mortality was statistically significant in PTGS2-high cancers (multivariable hazard ratio of the highest vs. lowest quartile of MIR21, 2.28; 95% confidence interval, 1.42-3.67; Ptrend = 0.0004) but not in PTGS2-absent/low cancers (Ptrend = 0.22). CONCLUSIONS: MIR21 expression level in colorectal carcinoma is associated with worse clinical outcome, and this association is stronger in carcinomas expressing high-level PTGS2, suggesting complex roles of immunity and inflammation in tumor progression. Clin Cancer Res; 22(15); 3841-8. (c)2016 AACR. PMID- 26957561 TI - Tumor Evolution Inferred by Patterns of microRNA Expression through the Course of Disease, Therapy, and Recurrence in Breast Cancer. AB - PURPOSE: Molecular evolution of tumors during progression, therapy, and metastasis is a major clinical challenge and the main reason for resistance to therapy. We hypothesized that microRNAs (miRNAs) that exhibit similar variation of expression through the course of disease in several patients have a significant function in the tumorigenic process. EXPERIMENTAL DESIGN: Exploration of evolving disease by profiling 800 miRNA expression from serial samples of individual breast cancer patients at several time points: pretreatment, posttreatment, lymph nodes, and recurrence sites when available (58 unique samples from 19 patients). Using a dynamic approach for analysis, we identified expression modulation patterns and classified varying miRNAs into one of the eight possible temporal expression patterns. RESULTS: The various patterns were found to be associated with different tumorigenic pathways. The dominant pattern identified an miRNA set that significantly differentiated between disease stages, and its pattern in each patient was also associated with response to therapy. These miRNAs were related to tumor proliferation and to the cell-cycle pathway, and their mRNA targets showed anticorrelated expression. Interestingly, the level of these miRNAs was lowest in matched recurrent samples from distant metastasis, indicating a gradual increase in proliferative potential through the course of disease. Finally, the average expression level of these miRNAs in the pretreatment biopsy was significantly different comparing patients experiencing recurrence to recurrence-free patients. CONCLUSIONS: Serial tumor sampling combined with analysis of temporal expression patterns enabled to pinpoint significant signatures characterizing breast cancer progression, associated with response to therapy and with risk of recurrence. Clin Cancer Res; 22(14); 3651 62. (c)2016 AACR. PMID- 26957562 TI - Tumor-Produced Interleukin-8 Attracts Human Myeloid-Derived Suppressor Cells and Elicits Extrusion of Neutrophil Extracellular Traps (NETs). AB - PURPOSE: Myeloid-derived suppressor cells (MDSC) are considered an important T cell immunosuppressive component in cancer-bearing hosts. The factors that attract these cells to the tumor microenvironment are poorly understood. IL8 (CXCL8) is a potent chemotactic factor for neutrophils and monocytes. EXPERIMENTAL DESIGN: MDSC were characterized and sorted by multicolor flow cytometry on ficoll-gradient isolated blood leucokytes from healthy volunteers (n = 10) and advanced cancer patients (n = 28). In chemotaxis assays, sorted granulocytic and monocytic MDSC were tested in response to recombinant IL8, IL8 derived from cancer cell lines, and patient sera. Neutrophil extracellular traps (NETs) formation was assessed by confocal microscopy, fluorimetry, and time-lapse fluorescence confocal microscopy on short-term MDSC cultures. RESULTS: IL8 chemoattracts both granulocytic (GrMDSC) and monocytic (MoMDSC) human MDSC. Monocytic but not granulocytic MDSC exerted a suppressor activity on the proliferation of autologous T cells isolated from the circulation of cancer patients. IL8 did not modify the T-cell suppressor activity of human MDSC. However, IL8 induced the formation of NETs in the GrMDSC subset. CONCLUSIONS: IL8 derived from tumors contributes to the chemotactic recruitment of MDSC and to their functional control. Clin Cancer Res; 22(15); 3924-36. (c)2016 AACR. PMID- 26957563 TI - SLTAB2 is the paramutated SULFUREA locus in tomato. AB - The sulfurea (sulf) allele is a silent epigenetic variant of a tomato (Solanum lycopersicum) gene affecting pigment production. It is homozygous lethal but, in a heterozygote sulf/+, the wild-type (wt) allele undergoes silencing so that the plants exhibit chlorotic sectors. This transfer of the silenced state between alleles is termed paramutation and is best characterized in maize. To understand the mechanism of paramutation we mapped SULF to the orthologue SLTAB2 of an Arabidopsis gene that, consistent with the pigment deficiency, is involved in the translation of photosystem I. Paramutation of SLTAB2 is linked to an increase in DNA methylation and the production of small interfering RNAs at its promoter. Virus-induced gene silencing of SLTAB2 phenocopies sulf, consistent with the possibility that siRNAs mediate the paramutation of SULFUREA Unlike the maize systems, the paramutagenicity of sulf is not, however, associated with repeated sequences at the region of siRNA production or DNA methylation. PMID- 26957564 TI - Blue light-dependent changes in loosely bound calcium in Arabidopsis mesophyll cells: an X-ray microanalysis study. AB - Calcium is involved in the signal transduction pathway from phototropins, the blue light photoreceptor kinases which mediate chloroplast movements. The chloroplast accumulation response in low light is controlled by both phot1 and phot2, while only phot2 is involved in avoidance movement induced by strong light. Phototropins elevate cytosolic Ca(2+) after activation by blue light. In higher plants, both types of chloroplast responses depend on Ca(2+), and internal calcium stores seem to be crucial for these processes. Yet, the calcium signatures generated after the perception of blue light by phototropins are not well understood. To characterize the localization of calcium in Arabidopsis mesophyll cells, loosely bound (exchangeable) Ca(2+) was precipitated with potassium pyroantimonate and analyzed by transmission electron microscopy followed by energy-dispersive X-ray microanalysis. In dark-adapted wild-type Arabidopsis leaves, calcium precipitates were observed at the cell wall, where they formed spherical structures. After strong blue light irradiation, calcium at the apoplast prevailed, and bigger, multilayer precipitates were found. Spherical calcium precipitates were also detected at the tonoplast. After red light treatment as a control, the precipitates at the cell wall were smaller and less numerous. In the phot2 and phot1phot2 mutants, calcium patterns were different from those of wild-type plants. In both mutants, no elevation of calcium after blue light treatment was observed at the cell periphery (including the cell wall and a fragment of cytoplasm). This result confirms the involvement of phototropin2 in the regulation of Ca(2+) homeostasis in mesophyll cells. PMID- 26957565 TI - The unique structural and biochemical development of single cell C4 photosynthesis along longitudinal leaf gradients in Bienertia sinuspersici and Suaeda aralocaspica (Chenopodiaceae). AB - Temporal and spatial patterns of photosynthetic enzyme expression and structural maturation of chlorenchyma cells along longitudinal developmental gradients were characterized in young leaves of two single cell C4 species, Bienertia sinuspersici and Suaeda aralocaspica Both species partition photosynthetic functions between distinct intracellular domains. In the C4-C domain, C4 acids are formed in the C4 cycle during capture of atmospheric CO2 by phosphoenolpyruvate carboxylase. In the C4-D domain, CO2 released in the C4 cycle via mitochondrial NAD-malic enzyme is refixed by Rubisco. Despite striking differences in origin and intracellular positioning of domains, these species show strong convergence in C4 developmental patterns. Both progress through a gradual developmental transition towards full C4 photosynthesis, with an associated increase in levels of photosynthetic enzymes. Analysis of longitudinal sections showed undeveloped domains at the leaf base, with Rubisco rbcL mRNA and protein contained within all chloroplasts. The two domains were first distinguishable in chlorenchyma cells at the leaf mid-regions, but still contained structurally similar chloroplasts with equivalent amounts of rbcL mRNA and protein; while mitochondria had become confined to just one domain (proto-C4 D). The C4 state was fully formed towards the leaf tips, Rubisco transcripts and protein were compartmentalized specifically to structurally distinct chloroplasts in the C4-D domains indicating selective regulation of Rubisco expression may occur by control of transcription or stability of rbcL mRNA. Determination of CO2 compensation points showed young leaves were not functionally C4, consistent with cytological observations of the developmental progression from C3 default to intermediate to C4 photosynthesis. PMID- 26957567 TI - Calibrating Parameters for Microsimulation Disease Models: A Review and Comparison of Different Goodness-of-Fit Criteria. AB - BACKGROUND: Calibration (estimation of model parameters) compares model outcomes with observed outcomes and explores possible model parameter values to identify the set of values that provides the best fit to the data. The goodness-of-fit (GOF) criterion quantifies the difference between model and observed outcomes. There is no consensus on the most appropriate GOF criterion, because a direct performance comparison of GOF criteria in model calibration is lacking. METHODS: We systematically compared the performance of commonly used GOF criteria (sum of squared errors [SSE], Pearson chi-square, and a likelihood-based approach [Poisson and/or binomial deviance functions]) in the calibration of selected parameters of the MISCAN-Colon microsimulation model for colorectal cancer. The performance of each GOF criterion was assessed by comparing the 1) root mean squared prediction error (RMSPE) of the selected parameters, 2) computation time of the calibration procedure of various calibration scenarios, and 3) impact on estimated cost-effectiveness ratios. RESULTS: The likelihood-based deviance resulted in the lowest RMSPE in 4 of 6 calibration scenarios and was close to best in the other 2. The SSE had a 25 times higher RMSPE in a scenario with considerable differences in the values of observed outcomes, whereas the Pearson chi-square had a 60 times higher RMSPE in a scenario with multiple studies measuring the same outcome. In all scenarios, the SSE required the most computation time. The likelihood-based approach estimated the cost-effectiveness ratio most accurately (up to -0.15% relative difference versus 0.44% [SSE] and 13% [Pearson chi-square]). CONCLUSIONS: The likelihood-based deviance criteria lead to accurate estimation of parameters under various circumstances. These criteria are recommended for calibration in microsimulation disease models in contrast with other commonly used criteria. PMID- 26957566 TI - What Is a "Good" Treatment Decision? Decisional Control, Knowledge, Treatment Decision Making, and Quality of Life in Men with Clinically Localized Prostate Cancer. AB - OBJECTIVE: We explored whether active patient involvement in decision making and greater patient knowledge are associated with better treatment decision-making experiences and better quality of life (QOL) among men with clinically localized prostate cancer. Localized prostate cancer treatment decision making is an advantageous model for studying patient treatment decision-making dynamics because there are multiple treatment options and a lack of empirical evidence to recommend one over the other; consequently, it is recommended that patients be fully involved in making the decision. METHODS: Men with newly diagnosed clinically localized prostate cancer (N = 1529) completed measures of decisional control, prostate cancer knowledge, and decision-making experiences (decisional conflict and decision-making satisfaction and difficulty) shortly after they made their treatment decision. Prostate cancer-specific QOL was assessed at 6 months after treatment. RESULTS: More active involvement in decision making and greater knowledge were associated with lower decisional conflict and higher decision making satisfaction but greater decision-making difficulty. An interaction between decisional control and knowledge revealed that greater knowledge was only associated with greater difficulty for men actively involved in making the decision (67% of sample). Greater knowledge, but not decisional control, predicted better QOL 6 months after treatment. CONCLUSIONS: Although men who are actively involved in decision making and more knowledgeable may make more informed decisions, they could benefit from decisional support (e.g., decision making aids, emotional support from providers, strategies for reducing emotional distress) to make the process easier. Men who were more knowledgeable about prostate cancer and treatment side effects at the time that they made their treatment decision may have appraised their QOL as higher because they had realistic expectations about side effects. PMID- 26957568 TI - Spontaneous Age-related Lesions of the Kidney Fornices in Sprague-Dawley Rats. AB - The upper portion of the rat kidney pelvis has specialized anatomic structures referred to as fornices. Fornices have a role in urine concentration. Spontaneous lesions including mineralization, epithelial hyperplasia, and inflammatory cell infiltration may occur in the area of the fornices. However, little information regarding specific historical control data or the spontaneous development of these findings in male and female fornices is known. Understanding spontaneous age-related lesions in the area of the fornices versus other portions of the kidney pelvis may be relevant in the identification of test article-induced changes. A retrospective study was conducted of male and female Sprague-Dawley rat kidney fornices over several time points to determine the incidence and severity of mineralization, epithelial hyperplasia, and inflammatory cell infiltration. Based on this investigation, these lesions appeared to increase over time and, in general, occurred earlier and with a greater incidence in females. Regarding those chemicals that may result in lesions of the kidney pelvis, it may be important for pathologists to separately diagnose lesions of the fornices from other portions of the kidney pelvis to help differentiate between any spontaneous age-related and induced changes. PMID- 26957569 TI - Depletion of Hepatic Macrophages Aggravates Liver Lesions Induced in Rats by Thioacetamide (TAA). AB - Hepatic macrophages play crucial roles in hepatotoxicity. We investigated immunophenotypes of macrophages in liver injury induced in rats by thioacetamide (TAA; 300 mg/kg, intraperitoneal) after hepatic macrophage depletion; hepatic macrophages were depleted by liposomal clodronate (CLD; 10 ml/kg, i.v.) one day before TAA injection. Samples were obtained on post-TAA injection days 0, 1, 2, 3, 5, and 7. TAA injection induced coagulation necrosis of hepatocytes on days 1 through 3 and subsequent reparative fibrosis on days 5 and 7 in the centrilobular area, accompanied by increased numbers of M1 macrophages (expressing cluster of differentiation [CD]68 and major histocompatibility complex class II) and M2 macrophages (expressing CD163 and CD204) mainly on days 1 through 3. TAA + CLD treatment markedly decreased the numbers of M1 and M2 macrophages mainly on days 1 through 3; CD163(+) Kupffer cells were most sensitive to CLD depletion. In TAA + CLD-treated rats, interestingly, coagulation necrosis of hepatocytes was prolonged with more increased levels of hepatic enzymes (aspartate transaminase, alanine transaminase, and alkaline phosphatase) to TAA-treated rats; reparative fibrosis was incomplete and replaced by dystrophic calcification in the injured area, indicating the aggravated damage. Furthermore, in TAA + CLD-treated rats, inflammatory factors (monocyte chemoattractant protein [MCP]-1, interferon-gamma, tumor necrosis factor-alpha, and interleukin-10) and fibrosis-related factors (transforming growth factor-beta1, matrix metalloproteinase-2, tissue inhibitor of metalloproteinase-1) were decreased at messenger RNA levels, indicating abnormal macrophage functions. It was clearly demonstrated that hepatic macrophages have important roles in tissue damage and remodeling in hepatotoxicity. PMID- 26957570 TI - Reporting Sexual Victimization During Incarceration: Using Ecological Theory as a Framework to Inform and Guide Future Research. AB - The U.S. Department of Justice estimates that between 149,200 and 209,400 incidents of sexual victimization occur annually in prisons and jails. However, very few individuals experiencing sexual victimization during incarceration report these incidents to correctional authorities. Federal-level policy recommendations derived from the Prison Rape Elimination Act suggest mechanisms for improving reporting as well as standards for the prevention, investigation, and prosecution of prison-based sexual victimization. Despite these policy recommendations, sexual assault persists in prisons and jails, with only 8% of prisoners who experience sexual assault reporting their victimization. This review focuses on gaps in the existing research about what factors influence whether adult victims in incarcerated systems will report that they have been sexually assaulted. Using ecological theory to guide this review, various levels of social ecology are incorporated, illuminating a variety of factors influencing the reporting of sexual victimization during incarceration. These factors include the role of individual-level behavior, assault characteristics, the unique aspects and processes of the prison system, and the social stigma that surrounds individuals involved in the criminal/legal system. This review concludes with recommendations for future research, policy, and practice, informed by an ecological conceptualization of reporting. PMID- 26957571 TI - Genetic mutations you want. PMID- 26957573 TI - Advances in the diagnosis of acute aortic syndromes: Role of imaging techniques. AB - Aortic diseases include a wide range of pathological conditions: aortic aneurysms, pseudoaneurysms, acute aortic syndromes, atherosclerotic and inflammatory conditions, genetic diseases and congenital anomalies. Acute aortic syndromes have acute onset and may be life-threatening. They include aortic dissection, intramural haematoma, penetrating aortic ulcer and traumatic aortic injury. Pain is the common denominator to all acute aortic syndromes. Pain occurs regardless of age, gender and other associated clinical conditions. In this review, we deal with the main findings in the clinical setting and the most recent indications for diagnostic imaging, which are aimed to start an appropriate treatment and improve the short- and long-term prognosis of these patients. PMID- 26957574 TI - Invasive evaluation of plaque morphology of symptomatic superficial femoral artery stenoses using combined near-infrared spectroscopy and intravascular ultrasound. AB - The purpose of this study is to characterize the plaque morphology of severe stenoses in the superficial femoral artery (SFA) employing combined near-infrared spectroscopy and intravascular ultrasound (NIRS-IVUS). Atherosclerosis is the most common cause of symptomatic peripheral arterial disease. Plaque composition of SFA stenoses has been characterized as primarily fibrous or fibrocalcific by non-invasive and autopsy studies. NIRS has been validated to detect lipid-core plaque (LCP) in the coronary circulation. We imaged severe SFA stenoses with NIRS IVUS prior to revascularization in 31 patients (46 stenoses) with Rutherford claudication ? class 3. Angiographic parameters included lesion location and stenosis severity. IVUS parameters included plaque burden and presence of calcium. NIRS images were analyzed for LCP and maximum lipid-core burden index in a 4-mm length of artery (maxLCBI4mm). By angiography, 38 (82.6%) lesions were calcified and 9 (19.6%) were chronic total occlusions. Baseline stenosis severity and lesion length were 86.0 +/- 11.0% and 36.5 +/- 46.5 mm, respectively. NIRS IVUS identified calcium in 45 (97.8%) lesions and LCP in 17 (37.0%) lesions. MaxLCBI4mm was 433 +/- 244. All lesions with LCP also contained calcium; there were no non-calcified lesions with LCP. In conclusion, this is the first study of combined NIRS-IVUS in patients with PAD. NIRS-IVUS demonstrates that nearly all patients with symptomatic severe SFA disease have fibrocalcific plaque, and one third of such lesions contain LCP. These findings contrast with those in patients with acute coronary syndromes, and may have implications regarding the pathophysiology of atherosclerosis in different vascular beds. PMID- 26957583 TI - Characterization of an fungal l-fucokinase involved in Mortierella alpina GDP-l fucose salvage pathway. AB - GDP-l-fucose functions as a biological donor for fucosyltransferases, which are required for the catalysis of l-fucose to various acceptor molecules including oligosaccharides, glycoproteins and glycolipids. Mortierella alpina is one of the highest lipid-producing fungi and can biosynthesis GDP-l-fucose in the de novo pathway. Analysis of the M. alpina genome suggests that there is a gene encoding l-fucokinase (FUK) for the conversion of fucose to l-fucose-1-phosphate in the GDP-l-fucose salvage pathway, which has never been found in fungi before. This gene was characterized to explore its role in GDP-l-fucose synthesis. The yield of GDP-l-fucose is relatively higher in lipid accumulation phase (0.096 mg per g cell) than that in cell multiplication phase (0.074 mg per g cell) of M. alpina Additionally, the transcript level of FUK is up regulated by nitrogen exhaustion when M. alpina starts to accumulate lipid, highlights the functional significance of FUK in the GDP-l-fucose biosynthesis in M. alpina Gene encoding FUK was expressed heterologously in Escherichia coli and the resulting protein was purified to homogeneity. The product of FUK reaction was analyzed by liquid chromatography and mass spectrometry. Kinetic parameters and other properties of FUK were investigated. Comparative analyses between the FUK protein and other homologous proteins were performed. To our knowledge, this study is the first to report a comprehensive characterization of FUK in a fungus. Mortierella alpina could be used as an alternative source for the production of GDP-l-fucose. PMID- 26957584 TI - Identifying the 'Right' colon lesion. PMID- 26957585 TI - Erratum. Topically applied AaeIAP1 double-stranded RNA kills female adults of Aedes aegypti. Journal of Medical Entomology 45(3):414-420. PMID- 26957591 TI - Application of low vacuum scanning electron microscopy for Papanicolaou-stained slides for cytopathology examinations. AB - Papanicolaou (Pap)-stained slides are usually observed using a transmitted light microscope for cytopathology. However, progress in pathological examinations has created a need for new diagnostic tools, because cytopathological preparations do not allow additional examinations without a loss of specimen, unlike histopathology. Low-vacuum scanning electron microscopy (LVSEM) can reveal the surface topography at an ultrastructual resolution without metal coating. The aim of this study was to determine the conditions required for observing Pap-stained slides of oral smears using LVSEM without any loss of specimen and to reexamine the same slides again using light microscopy, while preserving the cytopathological information. PMID- 26957592 TI - Changing fisheries productivity and food security. PMID- 26957593 TI - Reply to Glezerman: Why differences between brains of females and brains of males do not "add up" to create two types of brains. PMID- 26957594 TI - Yes, there is a female and a male brain: Morphology versus functionality. PMID- 26957595 TI - Reply to Szuwalski: Recognizing ecological income inequality in the ocean. PMID- 26957596 TI - Perceptual learning of degraded speech by minimizing prediction error. AB - Human perception is shaped by past experience on multiple timescales. Sudden and dramatic changes in perception occur when prior knowledge or expectations match stimulus content. These immediate effects contrast with the longer-term, more gradual improvements that are characteristic of perceptual learning. Despite extensive investigation of these two experience-dependent phenomena, there is considerable debate about whether they result from common or dissociable neural mechanisms. Here we test single- and dual-mechanism accounts of experience dependent changes in perception using concurrent magnetoencephalographic and EEG recordings of neural responses evoked by degraded speech. When speech clarity was enhanced by prior knowledge obtained from matching text, we observed reduced neural activity in a peri-auditory region of the superior temporal gyrus (STG). Critically, longer-term improvements in the accuracy of speech recognition following perceptual learning resulted in reduced activity in a nearly identical STG region. Moreover, short-term neural changes caused by prior knowledge and longer-term neural changes arising from perceptual learning were correlated across subjects with the magnitude of learning-induced changes in recognition accuracy. These experience-dependent effects on neural processing could be dissociated from the neural effect of hearing physically clearer speech, which similarly enhanced perception but increased rather than decreased STG responses. Hence, the observed neural effects of prior knowledge and perceptual learning cannot be attributed to epiphenomenal changes in listening effort that accompany enhanced perception. Instead, our results support a predictive coding account of speech perception; computational simulations show how a single mechanism, minimization of prediction error, can drive immediate perceptual effects of prior knowledge and longer-term perceptual learning of degraded speech. PMID- 26957597 TI - Human symbionts inject and neutralize antibacterial toxins to persist in the gut. AB - The human gut microbiome is a dynamic and densely populated microbial community that can provide important benefits to its host. Cooperation and competition for nutrients among its constituents only partially explain community composition and interpersonal variation. Notably, certain human-associated Bacteroidetes--one of two major phyla in the gut--also encode machinery for contact-dependent interbacterial antagonism, but its impact within gut microbial communities remains unknown. Here we report that prominent human gut symbionts persist in the gut through continuous attack on their immediate neighbors. Our analysis of just one of the hundreds of species in these communities reveals 12 candidate antibacterial effector loci that can exist in 32 combinations. Through the use of secretome studies, in vitro bacterial interaction assays and multiple mouse models, we uncover strain-specific effector/immunity repertoires that can predict interbacterial interactions in vitro and in vivo, and find that some of these strains avoid contact-dependent killing by accumulating immunity genes to effectors that they do not encode. Effector transmission rates in live animals can exceed 1 billion events per minute per gram of colonic contents, and multiphylum communities of human gut commensals can partially protect sensitive strains from these attacks. Together, these results suggest that gut microbes can determine their interactions through direct contact. An understanding of the strategies human gut symbionts have evolved to target other members of this community may provide new approaches for microbiome manipulation. PMID- 26957598 TI - Atomic resolution probe for allostery in the regulatory thin filament. AB - Calcium binding and dissociation within the cardiac thin filament (CTF) is a fundamental regulator of normal contraction and relaxation. Although the disruption of this complex, allosterically mediated process has long been implicated in human disease, the precise atomic-level mechanisms remain opaque, greatly hampering the development of novel targeted therapies. To address this question, we used a fully atomistic CTF model to test both Ca(2+) binding strength and the energy required to remove Ca(2+) from the N-lobe binding site in WT and mutant troponin complexes that have been linked to genetic cardiomyopathies. This computational approach is combined with measurements of in vitro Ca(2+) dissociation rates in fully reconstituted WT and cardiac troponin T R92L and R92W thin filaments. These human disease mutations represent known substitutions at the same residue, reside at a significant distance from the calcium binding site in cardiac troponin C, and do not affect either the binding pocket affinity or EF-hand structure of the binding domain. Both have been shown to have significantly different effects on cardiac function in vivo. We now show that these mutations independently alter the interaction between the Ca(2+) ion and cardiac troponin I subunit. This interaction is a previously unidentified mechanism, in which mutations in one protein of a complex indirectly affect a third via structural and dynamic changes in a second to yield a pathogenic change in thin filament function that results in mutation-specific disease states. We can now provide atom-level insight that is potentially highly actionable in drug design. PMID- 26957600 TI - Quantum communication complexity advantage implies violation of a Bell inequality. AB - We obtain a general connection between a large quantum advantage in communication complexity and Bell nonlocality. We show that given any protocol offering a sufficiently large quantum advantage in communication complexity, there exists a way of obtaining measurement statistics that violate some Bell inequality. Our main tool is port-based teleportation. If the gap between quantum and classical communication complexity can grow arbitrarily large, the ratio of the quantum value to the classical value of the Bell quantity becomes unbounded with the increase in the number of inputs and outputs. PMID- 26957599 TI - Microscopic interpretation of folding phi-values using the transition path ensemble. AB - All-atom molecular dynamics simulations now allow us to create movies of proteins folding and unfolding. However, it is difficult to assess the accuracy of the folding mechanisms observed because experiments cannot yet directly resolve events occurring along the transition paths between unfolded and folded states. Protein folding phi-values provide residue-resolved information about folding mechanisms by comparing the effects of mutations on folding rates and stability, but determining phi-values by separately simulating mutant proteins would be computationally demanding and prone to large statistical errors. Here we use transition path theory to develop a method for computing phi-values directly from the transition path ensemble, without the need for additional simulations. This path-based approach uses the full transition path information available from equilibrium folding and unfolding trajectories, or from transition path sampling, and does not require identification of folding transition states. Applying our approach to a set of simulations of 10 small proteins by Shaw and coworkers [Lindorff-Larsen K, Piana S, Dror RO, Shaw DE (2011) Science 334(6055):517-520; Piana S, Lindorff-Larsen K, Shaw DE (2011) Biophys J100(9):L47-L49; and Piana S, Lindorff-Larsen K, Shaw DE (2013) Proc Natl Acad Sci USA 110(15):5915-5920], we find good agreement with experiments in most cases where data are available. We can further resolve the contributions to fractional phi-values coming from partial contact formation versus transition path heterogeneity. Although in some cases, there is substantial heterogeneity of folding mechanism, in others, such as Ubiquitin, the mechanism is strongly conserved. PMID- 26957601 TI - Energy landscape in protein folding and unfolding. AB - We use (1)H NMR to probe the energy landscape in the protein folding and unfolding process. Using the scheme ? reversible unfolded (intermediate) -> irreversible unfolded (denatured) state, we study the thermal denaturation of hydrated lysozyme that occurs when the temperature is increased. Using thermal cycles in the range 295 < T < 365 K and following different trajectories along the protein energy surface, we observe that the hydrophilic (the amide NH) and hydrophobic (methyl CH3 and methine CH) peptide groups evolve and exhibit different behaviors. We also discuss the role of water and hydrogen bonding in the protein configurational stability. PMID- 26957603 TI - Topologically associated domains enriched for lineage-specific genes reveal expression-dependent nuclear topologies during myogenesis. AB - The linear distribution of genes across chromosomes and the spatial localization of genes within the nucleus are related to their transcriptional regulation. The mechanistic consequences of linear gene order, and how it may relate to the functional output of genome organization, remain to be fully resolved, however. Here we tested the relationship between linear and 3D organization of gene regulation during myogenesis. Our analysis has identified a subset of topologically associated domains (TADs) that are significantly enriched for muscle-specific genes. These lineage-enriched TADs demonstrate an expression dependent pattern of nuclear organization that influences the positioning of adjacent nonenriched TADs. Therefore, lineage-enriched TADs inform cell-specific genome organization during myogenesis. The reduction of allelic spatial distance of one of these domains, which contains Myogenin, correlates with reduced transcriptional variability, identifying a potential role for lineage-specific nuclear topology. Using a fusion-based strategy to decouple mitosis and myotube formation, we demonstrate that the cell-specific topology of syncytial nuclei is dependent on cell division. We propose that the effects of linear and spatial organization of gene loci on gene regulation are linked through TAD architecture, and that mitosis is critical for establishing nuclear topologies during cellular differentiation. PMID- 26957602 TI - Autoantibody-boosted T-cell reactivation in the target organ triggers manifestation of autoimmune CNS disease. AB - Multiple sclerosis (MS) is caused by T cells that are reactive for brain antigens. In experimental autoimmune encephalomyelitis, the animal model for MS, myelin-reactive T cells initiate the autoimmune process when entering the nervous tissue and become reactivated upon local encounter of their cognate CNS antigen. Thereby, the strength of the T-cellular reactivation process within the CNS tissue is crucial for the manifestation and the severity of the clinical disease. Recently, B cells were found to participate in the pathogenesis of CNS autoimmunity, with several diverse underlying mechanisms being under discussion. We here report that B cells play an important role in promoting the initiation process of CNS autoimmunity. Myelin-specific antibodies produced by autoreactive B cells after activation in the periphery diffused into the CNS together with the first invading pathogenic T cells. The antibodies accumulated in resident antigen presenting phagocytes and significantly enhanced the activation of the incoming effector T cells. The ensuing strong blood-brain barrier disruption and immune cell recruitment resulted in rapid manifestation of clinical disease. Therefore, myelin oligodendrocyte glycoprotein (MOG)-specific autoantibodies can initiate disease bouts by cooperating with the autoreactive T cells in helping them to recognize their autoantigen and become efficiently reactivated within the immune deprived nervous tissue. PMID- 26957604 TI - Rapid expansion of the protein disulfide isomerase gene family facilitates the folding of venom peptides. AB - Formation of correct disulfide bonds in the endoplasmic reticulum is a crucial step for folding proteins destined for secretion. Protein disulfide isomerases (PDIs) play a central role in this process. We report a previously unidentified, hypervariable family of PDIs that represents the most diverse gene family of oxidoreductases described in a single genus to date. These enzymes are highly expressed specifically in the venom glands of predatory cone snails, animals that synthesize a remarkably diverse set of cysteine-rich peptide toxins (conotoxins). Enzymes in this PDI family, termed conotoxin-specific PDIs, significantly and differentially accelerate the kinetics of disulfide-bond formation of several conotoxins. Our results are consistent with a unique biological scenario associated with protein folding: The diversification of a family of foldases can be correlated with the rapid evolution of an unprecedented diversity of disulfide rich structural domains expressed by venomous marine snails in the superfamily Conoidea. PMID- 26957605 TI - Dual function of C/D box small nucleolar RNAs in rRNA modification and alternative pre-mRNA splicing. AB - C/D box small nucleolar RNAs (SNORDs) are small noncoding RNAs, and their best understood function is to target the methyltransferase fibrillarin to rRNA (for example, SNORD27 performs 2'-O-methylation of A27 in 18S rRNA). Unexpectedly, we found a subset of SNORDs, including SNORD27, in soluble nuclear extract made under native conditions, where fibrillarin was not detected, indicating that a fraction of the SNORD27 RNA likely forms a protein complex different from canonical snoRNAs found in the insoluble nuclear fraction. As part of this previously unidentified complex,SNORD27 regulates the alternative splicing of the transcription factor E2F7p re-mRNA through direct RNA-RNA interaction without methylating the RNA, likely by competing with U1 small nuclear ribonucleoprotein (snRNP). Furthermore, knockdown of SNORD27 activates previously "silent" exons in several other genes through base complementarity across the entire SNORD27 sequence, not just the antisense boxes. Thus, some SNORDs likely function in both rRNA and pre-mRNA processing, which increases the repertoire of splicing regulators and links both processes. PMID- 26957607 TI - Necessity of capillary modes in a minimal model of nanoscale hydrophobic solvation. AB - Modern theories of the hydrophobic effect highlight its dependence on length scale, emphasizing the importance of interfaces in the vicinity of sizable hydrophobes. We recently showed that a faithful treatment of such nanoscale interfaces requires careful attention to the statistics of capillary waves, with significant quantitative implications for the calculation of solvation thermodynamics. Here, we show that a coarse-grained lattice model like that of Chandler [Chandler D (2005)Nature437(7059):640-647], when informed by this understanding, can capture a broad range of hydrophobic behaviors with striking accuracy. Specifically, we calculate probability distributions for microscopic density fluctuations that agree very well with results of atomistic simulations, even many SDs from the mean and even for probe volumes in highly heterogeneous environments. This accuracy is achieved without adjustment of free parameters, because the model is fully specified by well-known properties of liquid water. As examples of its utility, we compute the free-energy profile for a solute crossing the air-water interface, as well as the thermodynamic cost of evacuating the space between extended nanoscale surfaces. These calculations suggest that a highly reduced model for aqueous solvation can enable efficient multiscale modeling of spatial organization driven by hydrophobic and interfacial forces. PMID- 26957606 TI - Orange carotenoid protein burrows into the phycobilisome to provide photoprotection. AB - In cyanobacteria, photoprotection from overexcitation of photochemical centers can be obtained by excitation energy dissipation at the level of the phycobilisome (PBS), the cyanobacterial antenna, induced by the orange carotenoid protein (OCP). A single photoactivated OCP bound to the core of the PBS affords almost total energy dissipation. The precise mechanism of OCP energy dissipation is yet to be fully determined, and one question is how the carotenoid can approach any core phycocyanobilin chromophore at a distance that can promote efficient energy quenching. We have performed intersubunit cross-linking using glutaraldehyde of the OCP and PBS followed by liquid chromatography coupled to tandem mass spectrometry (LC/MS-MS) to identify cross-linked residues. The only residues of the OCP that cross-link with the PBS are situated in the linker region, between the N- and C-terminal domains and a single C-terminal residue. These links have enabled us to construct a model of the site of OCP binding that differs from previous models. We suggest that the N-terminal domain of the OCP burrows tightly into the PBS while leaving the OCP C-terminal domain on the exterior of the complex. Further analysis shows that the position of the small core linker protein ApcC is shifted within the cylinder cavity, serving to stabilize the interaction between the OCP and the PBS. This is confirmed by a DeltaApcC mutant. Penetration of the N-terminal domain can bring the OCP carotenoid to within 5-10 A of core chromophores; however, alteration of the core structure may be the actual source of energy dissipation. PMID- 26957609 TI - Promising the Moon! PMID- 26957610 TI - Somatostatin Analogues in Neuroendocrine Tumors. PMID- 26957608 TI - Forkhead box A3 mediates glucocorticoid receptor function in adipose tissue. AB - Glucocorticoids (GCs) are widely prescribed anti-inflammatory agents, but their chronic use leads to undesirable side effects such as excessive expansion of adipose tissue. We have recently shown that the forkhead box protein A3 (Foxa3) is a calorie-hoarding factor that regulates the selective enlargement of epididymal fat depots and suppresses energy expenditure in a nutritional- and age dependent manner. It has been demonstrated that Foxa3 levels are elevated in adipose depots in response to high-fat diet regimens and during the aging process; however no studies to date have elucidated the mechanisms that control Foxa3's expression in fat. Given the established effects of GCs in increasing visceral adiposity and in reducing thermogenesis, we assessed the existence of a possible link between GCs and Foxa3. Computational prediction analysis combined with molecular studies revealed that Foxa3 is regulated by the glucocorticoid receptor (GR) in preadipocytes, adipocytes, and adipose tissues and is required to facilitate the binding of the GR to its target gene promoters in fat depots. Analysis of the long-term effects of dexamethasone treatment in mice revealed that Foxa3 ablation protects mice specifically against fat accretion but not against other pathological side effects elicited by this synthetic GC in tissues such as liver, muscle, and spleen. In conclusion our studies provide the first demonstration, to our knowledge, that Foxa3 is a direct target of GC action in adipose tissues and point to a role of Foxa3 as a mediator of the side effects induced in fat tissues by chronic treatment with synthetic steroids. PMID- 26957611 TI - BRAF Inhibition in BRAFV600E-Positive Anaplastic Thyroid Carcinoma. AB - The efficacy of targeted monotherapy for BRAF(V600E)-positive anaplastic thyroid carcinomas (ATC) is not established. We report 2 cases of BRAF(V600E)-positive ATC treated with a BRAF inhibitor. A 49-year-old woman with a T4bN1bM0 ATC manifested symptomatic metastatic disease 8 weeks after radical chemoradiotherapy. Within 1 month of BRAF inhibitor monotherapy, a complete symptomatic response was observed, with FDG-PET scan confirming metabolic and radiologic response. Treatment was terminated after 3 months because of disease progression. The patient died 11 months after primary diagnosis. A 67-year-old man received first-line BRAF inhibitor for a T4aN1bM0 ATC. Within 10 days of treatment his pain had stabilized and his tumor had clinically halved in size. Stable disease was achieved for 11 weeks but the patient died 11 months after diagnosis because of disease progression. BRAF inhibitor monotherapy in ATC may obtain clinical benefit of short duration. Upfront combination therapy should be investigated in this patient subgroup. PMID- 26957613 TI - NCCN Work Group Report: Emerging Issues in Tissue Allocation. AB - Expanding research interests in molecular profiling over the past several years have led researchers in academia and pharmaceutical and biotechnology companies to significantly increase their need for access to tissue specimens collected through clinical care and clinical trials. As a result, tissue allocation has become a growing issue for many clinical and translational investigators. High quality biospecimens are needed by all stakeholders in order to have scientifically accurate studies and results. At the center of the process are the patients, who have increasingly become active partners in the clinical research enterprise as individuals and through highly sophisticated patient advocacy organizations. All stakeholders must recognize that human specimens, including tissue, represent a valuable and unique resource that must have proper acquisition, handling, custodianship, and consent for use in accordance with best practices for biospecimen resources. PMID- 26957612 TI - NCCN Guidelines Insights: Non-Small Cell Lung Cancer, Version 4.2016. AB - These NCCN Guidelines Insights focus on recent updates in the 2016 NCCN Guidelines for Non-Small Cell Lung Cancer (NSCLC; Versions 1-4). These NCCN Guidelines Insights will discuss new immunotherapeutic agents, such as nivolumab and pembrolizumab, for patients with metastatic NSCLC. For the 2016 update, the NCCN panel recommends immune checkpoint inhibitors as preferred agents (in the absence of contraindications) for second-line and beyond (subsequent) therapy in patients with metastatic NSCLC (both squamous and nonsquamous histologies). Nivolumab and pembrolizumab are preferred based on improved overall survival rates, higher response rates, longer duration of response, and fewer adverse events when compared with docetaxel therapy. PMID- 26957614 TI - Outcome Assessments and Cost Avoidance of an Oral Chemotherapy Management Clinic. AB - BACKGROUND: Increasing use of oral chemotherapy drugs increases the challenges for drug and patient management. An oral chemotherapy management clinic was developed to provide patients with oral chemotherapy management, concurrent medication (CM) education, and symptom management services. This evaluation aims to measure the need and effectiveness of this practice model due to scarce published data. METHODS: This is a case series report of all patients referred to the oral chemotherapy management clinic. Data collected included patient demographics, depression scores, CMs, and types of intervention, including detection and management outcomes collected at baseline, 3-day, 7-day, and 3 month follow-ups. Persistence rate was monitored. Secondary analysis assessed potential cost avoidance. RESULTS: A total of 86 evaluated patients (32 men and 54 women, mean age of 63.4 years) did not show a high risk for medication nonadherence. The 3 most common cancer diagnoses were rectal, pancreatic, and breast, with capecitabine most prescribed. Patients had an average of 13.7 CMs. A total of 125 interventions (detection and management of adverse drug event detection, compliance, drug interactions, medication error, and symptom management) occurred in 201 visits, with more than 75% of interventions occurring within the first 14 days. A persistence rate was observed in 78% of 41 evaluable patients. The total estimated annual cost avoidance per 1.0 full time employee (FTE) was $125,761.93. CONCLUSIONS: This evaluation demonstrated the need for additional support for patients receiving oral chemotherapy within standard of care medical service. A comprehensive oral chemotherapy management referral service can optimize patient care delivery via early interventions for adverse drug events, drug interactions, and medication errors up to 3 months after initiation of treatment. PMID- 26957615 TI - Use of Palliative Chemotherapy for Advanced Bladder Cancer: Patterns of Care in Routine Clinical Practice. AB - BACKGROUND: Palliative chemotherapy for advanced bladder cancer is recommended in clinical practice guidelines. Patterns of care in routine clinical practice have not been well described. This article describes use rates of chemotherapy and referral rates to medical oncology in the last year of life among patients who have died of bladder cancer. METHODS: A population-based cohort of patients with bladder cancer was identified from the Ontario Cancer Registry; the study population included patients who died of bladder cancer between 1995 and 2009. Electronic records of treatment and physician billing records were used to identify treatment patterns and referral to medical oncology. Log-binomial and modified Poisson regression were used to examine factors associated with chemotherapy use and medical oncology consultation. RESULTS: A total of 8,005 patients died of bladder cancer, 25% (n=1,964) of whom received chemotherapy in the last year of life. Use was independently associated with patient age, comorbidities, socioeconomic status, sex, time period, and treatment region. A total of 68% (n=5,426) of patients were seen by a medical oncologist. Referral to medical oncology was associated with age, comorbidities, year of death. Geographic variation was seen with chemotherapy use-from 18% to 30%-that persisted on adjusted analysis. CONCLUSIONS: The efficacy of palliative chemotherapy demonstrated in clinical trials and recommended in guidelines has not translated into widespread use in practice. Understanding the extent to which patient preferences and health system factors influence use is needed. Access to acceptable palliative systemic treatments remains an unmet need for most patients dying of bladder cancer. PMID- 26957617 TI - A Discrete Choice Experiment to Examine the Preferences of Patients With Cancer and Their Willingness to Pay for Different Types of Health Care Appointments. AB - BACKGROUND: This study sought to understand the preferences of patients with cancer and the trade-offs between appointment attributes using discrete choice experiment (DCE). METHODS AND STUDY DESIGN: Patients with cancer at 3 hospitals completed a self-administered DCE. Each scenario described 6 attributes: expertise of health care professionals (HCPs), familiarity of doctors with patients' medical history, waiting time, accompaniment by family/friends, travel time, and out-of-pocket costs. Patient preferences were estimated using logistic regression. Willingness to pay (WTP) estimates were derived from regression coefficients. RESULTS: Of 512 patients contacted, 185 returned the questionnaire. The mean age was 61 years, and 60% of respondents were female. The mean time since cancer diagnosis was 34 months, 90% had received treatment; and 61% had early-stage disease. The most important attributes were expertise and familiarity of doctors with patients' medical history; distance traveled was least likely to influence patient preferences. The WTP analysis estimated that patients were willing to pay $680 (95% CI, 470-891) for an appointment with a specialist, $571 (95% CI, 388-754) for doctors familiar with their history, $422 (95% CI, 262-582) for shorter waiting times, $399 (95% CI, 249-549) to be accompanied by family/friends, and $301 (95% CI, 162-441) for shorter traveling times. Male patients had a stronger preference for accompaniment by family/friends. The expertise of HCP was the most important attribute for patients regardless of geographic remoteness. CONCLUSIONS: Our study can assist the development of patient-centered health care models that improve patient access to experienced HCPs, support the role of primary care providers during the cancer journey, and educate patients about the roles of non-oncology HCPs to cope with increasing demand for cancer care. PMID- 26957618 TI - Invasive Breast Cancer Version 1.2016, NCCN Clinical Practice Guidelines in Oncology. AB - Breast cancer is the most common malignancy in women in the United States and is second only to lung cancer as a cause of cancer death. The overall management of breast cancer includes the treatment of local disease with surgery, radiation therapy, or both, and the treatment of systemic disease with cytotoxic chemotherapy, endocrine therapy, biologic therapy, or combinations of these. This article outlines the NCCN Guidelines specific to breast cancer that is locoregional (restricted to one region of the body), and discusses the management of clinical stage I, II, and IIIA (T3N1M0) tumors. For NCCN Guidelines on systemic adjuvant therapy after locoregional management of clinical stage I, II and IIIA (T3N1M0) and for management for other clinical stages of breast cancer, see the complete version of these guidelines at NCCN.org. PMID- 26957616 TI - Documentation of Fertility Preservation Discussions for Young Adults With Cancer: Examining Compliance With Treatment Guidelines. AB - BACKGROUND: Professional guidelines have been developed to promote discussion between providers and newly diagnosed young adults with cancer about the possibility of cancer treatment-related infertility, but previous research suggests many young adults fail to receive this information. The aim of this study was to examine rates of and factors predictive of oncologists' compliance with national guidelines for discussing potential treatment-related infertility with newly diagnosed young adults with cancer seen at an NCI-designated comprehensive cancer center. METHODS: We reviewed data from the electronic medical record for new clinic encounters between medical oncologists and young adults with cancer (ages 18-39 years) from 2010 to 2012. Data from oncologist discussions of fertility preservation were abstracted, as were patient (age, sex, race, ethnicity, cancer type) and oncologist (gender, graduation year from fellowship) characteristics. RESULTS: A total of 1,018 cases were reviewed, with 454 patients (mean, 31.5 years; 67.8% women) meeting inclusion criteria. Overall, 83% of patients were informed about potential treatment-related infertility, with patients with breast cancer (85% informed), Hodgkin lymphoma (95% informed), non Hodgkin's lymphoma (94% informed), leukemia (88% informed), or testicular cancer (100% informed) more likely to be informed than those with other cancer types (60%-74% informed). There was a significant effect for patient sex (odds ratio, 3.57; CI, 1.33, 9.60; P=.012), with women being more likely to be informed than men. CONCLUSIONS: Reported compliance with fertility preservation guidelines was greater than published rates. Higher compliance rates in female patients and in patients with cancers more common among young adults may reflect greater awareness of fertility-related concerns among these patients and their providers. PMID- 26957619 TI - Fertility Preservation in Patients With Breast Cancer: Necessity, Methods, and Safety. AB - As treatment paradigms improve and young women live longer after a breast cancer diagnosis, there is an increasing need to define the fertility-related problems that premenopausal women with breast cancer face, and, more importantly, to find solutions. This article discusses what is known regarding fertility risks associated with standard breast cancer treatment regimens and limitations of that information. We outline established and emerging techniques for fertility preservation, including recent developments surrounding the controversial utility of gonadotropin-releasing hormone agonists through chemotherapy, and review available data on the safety of pregnancy in breast cancer survivors. We highlight opportunities for further investigation, and contextualize fertility related concerns in the modern treatment landscape. Above all, we stress the importance of this topic in a patient-centered approach to breast cancer care for young women. PMID- 26957620 TI - How Should Research Be Funded? Difficulties With the Argument for Proportionality to Causes of Death or Years of Life Lost. PMID- 26957621 TI - Re: "Clinical Sequencing Contributes to a BRCA-Associated Cancer Rediagnosis That Guides an Effective Therapeutic Course". PMID- 26957623 TI - Erratum. PMID- 26957625 TI - Impact of dietary branched chain amino acids concentration on broiler chicks during aflatoxicosis. AB - A 20-day trial was conducted to determine the effects of dietary branched-chain amino acids (BCAA) on performance, nutrient digestibility, and gene expression of the mTOR pathway in broiler chicks when exposed to aflatoxin B1 (AFB1). The 6 dietary treatments were arranged in a 2 * 3 factorial with 3 BCAA concentrations (1.16, 1.94, and 2.73%) with or without 1.5 mg/kg AFB1 (1.77 mg/kg analyzed). Each diet was fed to 8 replicate cages (6 chicks per cage) from 6 to 20 d of age. Exposure to AFB1 significantly reduced gain:feed ratio and breast muscle weight (P < 0.05), and tended to decrease cumulative BW gain (P = 0.087), while increasing dietary BCAA improved all performance measures (P <= 0.0002), except relative breast muscle weight. Apparent ileal digestibility of N and 9 amino acids were increased by AFB1 (P <= 0.05), but were reduced by higher dietary BCAA (P <= 0.023). Jejunum histology was not affected by AFB1, while higher dietary BCAA tended to increase villus height (P = 0.08). Additionally, the gene expression of mTOR pathway (mTOR, 4EBP1, and S6K1) from liver and jejunum were not affected by dietary treatments, while muscle expression of S6K1 tended to be increased by AFB1 (P = 0.07). No significant interaction between AFB1 and dietary BCAA were observed for any measures in the current study. Results from this study suggested that feed AFB1 contamination can significantly reduce growth performance and breast muscle growth in broiler chicks at 20 d. Higher BCAA supply may have beneficial impact on bird performance, but this effect is independent of AFB1 exposure. PMID- 26957624 TI - Distribution of alpha-transducin and alpha-gustducin immunoreactive cells in the chicken (Gallus domesticus) gastrointestinal tract. AB - The expression and distribution patterns of the taste signaling molecules, alpha gustducin (Galphagust) and alpha-transducin (Galphatran) G-protein subunits, were studied in the gastrointestinal tract of the chicken (Gallus domesticus) using the immunohistochemical method. Galphagust and Galphatran immunoreactive (-IR) cells were observed in the mucosal layer of all examined segments, except the esophagus, crop, and the saccus cranialis of the gizzard. The highest numbers of Galphagust and Galphatran-IR cells were found in the proventriculus glands and along the villi of the pyloric, duodenum, and rectal mucosa. Galphagust and Galphatran-IR cells located in the villi of the jejunum, ileum, and cloaca were much less numerous, while only a few Galphagust and Galphatran-IR cells were detected in the mucosa of the proventriculus and cecum. In the crypts, IR cells were observed in the small and large intestine as well as in the cloaca. Galphagust and Galphatran-IR cells displayed elongated ("bottle-" or "pear-like") or rounded shape. The demonstration of Galphagust and Galphatran expression provides evidence for taste receptor mediated mucosal chemosensitivity in the chicken gastrointestinal tract. PMID- 26957626 TI - Deletion of the BAC sequences from recombinant meq-null Marek's disease (MD) virus increases immunosuppression while maintaining protective efficacy against MD. AB - Marek's disease virus (MDV) GX0101 is a field strain of MDV with a naturally occurring insertion of the reticuloendotheliosis virus (REV) long terminal repeat (LTR) fragment. Both copies of the meq gene were knocked out in the GX0101 bacterial artificial chromosome (BAC) clone to construct the recombinant virus SC9-1, resulting in a complete lack of pathogenicity and providing better protection against MD than CVI988/Rispens. In the present study, the BAC sequences in SC9-1 were removed using a cre-loxP system, and the virus termed SC9 2. SC9-2 showed a significant increase in replication in vitro and in vivo. There was a significant decrease in chicken weight, immune organ index, and antibody levels compared with those of SC9-1-inoculated chickens. The immune protection index of SC9-2 was similar to that of SC9-1, and the difference was not significant. The results of our studies demonstrate that the SC9-2 virus provides protection in specific pathogen free (SPF) chickens when challenged with a very virulent MDV rMd5, but it induces immunosuppressive effects in SPF chickens. PMID- 26957627 TI - Effect of egg weight on composition, embryonic growth, and expression of amino acid transporter genes in yolk sac membranes and small intestines of the domestic pigeon (Columba livia). AB - The objective of this study was to investigate the effect of egg weight on the composition of the egg, the growth of the embryo, and the expression of amino acid transporter genes in the yolk sac membranes and small intestines of the domestic pigeon (Columba livia). A total of 240 fertilized eggs were collected and divided into two groups based on the weight of the eggs, light (LE) and heavy (HE). The composition of 20 eggs from each group was measured, and the remaining eggs were weighed and placed in an incubator. On embryonic days (E) 9, 11, 13, and 15 and day of hatch (DOH), 15 embryos/hatchlings from each group were measured for embryonic growth, and samples were collected. The HE had heavier yolk and albumen weights than the LE (P < 0.01). Compared with the LE, the HE had heavier yolk-free embryonic body and yolk sac weights from E13 to DOH (P < 0.05). Additionally, the HE had larger yolk sac membrane weights from E13 to E15 (P < 0.05) and had more residual yolk sac content on DOH than those of the LE (P < 0.01). The yolk absorption was greater for the HE than for the LE from E11 to E13 (P < 0.05). Furthermore, the abundance of CAT2 and PepT1 mRNA in the yolk sac membranes was greater in the HE than in the LE on E13 (P < 0.05). Compared with the LE, the gene expression of EAAT2 in the intestine on E13 was greater in the HE, whereas the expression of EAAT3 was lower in the HE (P < 0.05). Taken together, our results suggest that egg weight influenced the composition of the eggs, embryonic development, and expression of amino acid transporter genes in the yolk sac membranes and small intestines of pigeon embryos. PMID- 26957628 TI - Effect of electrical water bath stunning on physical reflexes of broilers: evaluation of stunning efficacy under field conditions. AB - The effects of different amounts and frequencies of stunning sine wave alternating current were investigated under field conditions. Seven hundred and fifty broilers were stunned in an electrical water bath with an average root mean square (RMS) current of 150, 200, and 250 mA and frequencies of 200, 400, 600, 800, and 1,200 Hz. The occurrence of corneal reflex, spontaneous eye blinking, and a positive response to a painful stimulus were monitored and recorded immediately after the stunning and at 20 s post-stun. Statistical analysis showed that the electrical stunning frequency (P=0.0004), the stunning RMS current (P<0.0001) and the interaction between stunning frequency and stunning current (P<0.0001) had a significant effect on the occurrence of animals experiencing an abolition of corneal reflex at 20 s post-stun.At a current of 150 mA, the probability of a successful stun was over 90% at 200 Hz, approximately 40% at 400 Hz, and below 5% for frequencies greater than 600 Hz. So, stunning at frequencies greater than 600 Hz cannot be recommended when a RMS current of 150 mA is applied. The maximum probability of a successful stun was obtained for a current level of 200 mA at 400 Hz and for a current level of 250 mA at 400 and 600 Hz, whereas the stunning treatments at 1,200 Hz provided the lowest probability of a successful stun. Assessment of spontaneous eye blinking and responses to comb pinching confirmed the indications coming from the analysis of corneal reflex. PMID- 26957629 TI - Effect of egg composition and oxidoreductase on adaptation of Tibetan chicken to high altitude. AB - Tibetan chickens have good adaptation to hypoxic conditions, which can be reflected by higher hatchability than lowland breeds when incubated at high altitude. The objective of this trial was to study changes in egg composition and metabolism with regards the adaptation of Tibetan chickens to high altitude. We measured the dry weight of chicken embryos, egg yolk, and egg albumen, and the activity of lactate dehydrogenase (LDH) and succinic dehydrogenase (SDH) in breast muscle, heart, and liver from embryos of Tibetan chicken and Dwarf chicken (lowland breed) incubated at high (2,900 m) and low (100 m) altitude. We found that growth of chicken embryos was restricted at high altitude, especially for Dwarf chicken embryos. In Tibetan chicken, the egg weight was lighter, but the dry weight of egg yolk was heavier than that of Dwarf chicken. The LDH activities of the three tissues from the high altitude groups were respectively higher than those of the lowland groups from d 15 to hatching, except for breast muscle of Tibetan chicken embryos on d 15. In addition, under the high altitude environment, the heart tissue from Tibetan chicken had lower LDH activity than that from Dwarf chicken at d 15 and 18. The lactic acid content of blood from Tibetan chicken embryos was lower than that of Dwarf chicken at d 12 and 15 of incubation at high altitude. There was no difference in SDH activity in the three tissues between the high altitude groups and the lowland groups except in three tissues of hatchlings and at d 15 of incubation in breast muscle, nor between the two breeds at high altitude except in the heart of hatchlings. Consequently, the adaptation of Tibetan chicken to high altitude may be associated with higher quantities of yolk in the egg and a low metabolic oxygen demand in tissue, which illuminate the reasons that the Tibetan chicken have higher hatchability with lower oxygen transport ability. PMID- 26957630 TI - Physicochemical composition and sensory quality evaluation of capon and rooster meat. AB - The aim of the present study was to evaluate the effect of caponization on the physicochemical and sensory characteristics of rooster and capon meat (2 Portuguese autochthonous chicken breeds of roosters:Amarela and Pedres), raised under the same production. The birds were castrated at 9 wk of age and bred until 140 d of age. Forty Amarela (20 roosters and 20 capons-castrated male) and 40 Pedres Portuguesa (20 roosters and 20 capons) breed chickens, 5 free-range chickens, and 5 broilers were used. From the breast, leg, and wing muscles, physicochemical parameters such as pH, water activity (aw), physical color, moisture content, ash, CP, pigments, collagen, and total fat and fatty acids profile, were analyzed according to standard procedures. Caponization did not affect pH, aw, lightness (L*), yellowness (b*), ash, protein, collagen, saturated fatty acids (SFA), polyunsaturated fatty acids (PUFA), and the ratio of unsaturated fatty acids (UFA)/SFA. Results show that caponization decreased (P<=0.05) moisture content and increased (P<=0.05) pigments and intramuscular fat content. Capons showed higher (P<=0.001) redness (a*) and chroma (C*), and lower (P<=0.001) hue (H*) compared to roosters. Caponization increased (P<=0.05) monounsaturated fatty acids content and PUFA/SFA. The main fatty acids found were oleic (C18:1), palmitic (C16:0), and linoleic (C18:2). Capons had greater (P<= 0.05) C18:1 content but lower (P<=0.01) butyric acid (C4:0), caprylic acid (C8:0), stearic acid (C18:0), and (P<=0.05) arachidonic acid (C20.4) content than roosters. The objective of sensory analysis was making the comparison of the Amarela and Pedresmeat with a free-range chicken and a broiler. Panelists classified the capon meat (Amarela and Pedres) as juicier and less tough and fibrous than rooster meat. Broilers were in general juicier, tenderer, and less fibrous than the other chickens in this study. The results of sensory evaluation complement those obtained in physicochemical analysis, suggesting that caponization promotes an overall improvement in meat quality. PMID- 26957631 TI - The gut-brain axis interactions during heat stress and avian necrotic enteritis. AB - The gut-brain axis is known to modulate behavioral and immune responses in animals; evidence supporting this modulation in chickens, however, is elusive. Here, we analyzed the effects of heat stress and/orClostridium perfringens (CP) infection on behavior, intestinal morphology, brain activity, and corticosterone serum levels in chickens. Broilers were randomly divided into 5 equal groups: a naive group (N), a thioglycolate group (T), a thioglycolate heat-stressed group (T/HS35), an infected group (I), and an infected/stressed (I/HS35) group. Broilers in the I and I/HS35 groups were experimentally infected withClostridium perfringensfrom the 15th to the 19th day of life. Heat stress (35+/-1 degrees C) was constantly applied to the broilers in the stressed groups from the 14th to the 19th day of life. Our data showed that heat stress andC. perfringensinfection produced significant differential responses in the chickens' behavior and in c fosexpression in the paraventricular nucleus of the hypothalamus (PVN), nucleus taenia of the amygdala (Tn), medial preoptic area (POM), andglobus pallidus (GP) of the chickens. Heat stress ameliorated some of the intestinal lesions and the neuroendocrine changes induced byC. perfringensin the birds. Our results suggest the existence of clear relationships between the degree of intestinal lesions, the chickens' behavioral outcomes, brain activity, and serum levels of corticosterone. Together, they reinforce the importance of neuroimmunomodulation and especially of brain-gut axis interactions. PMID- 26957632 TI - Effects of breeder age, broiler strain, and eggshell temperature on development and physiological status of embryos and hatchlings. AB - Breeder age and broiler strain can influence the availability of nutrients and oxygen, particularly through differences in yolk size and shell conductance. We hypothesized that these egg characteristics might affect embryonic responses to changes in eggshell temperature (EST). This study aimed to investigate the effect of breeder age, broiler strain, and EST on development and physiological status of embryos. A study was designed as a 2 * 2 * 2 factorial arrangement using 4 batches of 1,116 hatching eggs of 2 flock ages at 29 to 30 wk (young) and 54 to 55 wk (old) of Ross 308 and Cobb 500. EST of 37.8 (normal) or 38.9 degrees C (high) was applied from incubation d 7 (E7) until hatching. The results showed that breeder age rather than broiler strain had an influence on yolk size (P = 0.043). The shell conductance was higher in Ross 308 than in Cobb 500 (P < 0.001). A high EST resulted in a higher yolk free body mass (YFBM) compared to the normal EST at E14 and E16, but at 3 h after hatch YFBM was lower when eggs were incubated at high EST compared to normal EST (all P < 0.001). Cobb 500 eggs yielded embryos with a lower YFBM at E14, E18, and 3 h after hatch (all P < 0.05) than Ross 308 eggs. Breeder age had no effect on YFBM, but the RSY weight was higher in embryos from the old flock compared to the young flock embryos at E14 and E16 (both P < 0.05). A 3-way interaction among breeder age, strain, and EST was found, especially for incubation duration, navel quality, and relative heart and stomach weights at 3 h after hatch (all P < 0.05). Based on the results obtained, we conclude that oxygen availability rather than nutrient availability determines embryonic development, and the egg characteristics affected embryonic responses to changes of EST, especially for variables related to chick quality. PMID- 26957633 TI - Observations of turkey eggs stored up to 27 days and incubated for 8 days: embryo developmental stage and weight differences and the differentiation of fertilized from unfertilized germinal discs. AB - For logistical reasons, egg storage prior to incubation is a growing practice in the commercial turkey industry. Yet the consequence of increasing egg storage over 7 d is a progressive increase in embryo mortality. The objective of this study was to provide the information necessary to differentiate an early dead embryo from an unfertilized egg after 8 days of incubation (DOI). Five groups of eggs each from inseminated and virgin hens were stored for progressively increasing periods of time (5-d or less, 6 to 10 d, 11 to 15 d, 16 to 20 d, and 21 to 27 d) and incubated. At 8 DOI, eggs were examined and the stage of development (Hamburger and Hamilton, 1951) and embryo weights in normally developed eggs were determined. There was a significant negative correlation between the stage of development and embryo weight with increasing storage periods. All remaining eggs from the inseminated and virgin hens were broken-out and the appearance of the yolk and the fertilized and unfertilized germinal discs examined. The yolks of both hen groups with unfertilized ova maintained a homogeneous uniform yellow-orange color. In contrast, yolks of ova that had been fertilized, with or without early-dead embryos, and yolks from virgin hens that showed evidence of parthenogenetic development (3%) had a heterogeneous appearance. Using fluorescence microscopy, the heterogeneous appearance was due to sheets of aberrant cells and less frequently dispersed cells and folds of the perivitelline layer. It was concluded that clear egg breakouts need to be performed to more accurately assess the impact of egg storage on embryonic mortality. Furthermore, such breakouts should be performed with a high intensity light directed across the surface of the germinal disc to clearly differentiate the subtle differences between an early-dead embryo and an unfertilized germinal disc. PMID- 26957634 TI - Investigation of the effect of coccidial vaccine challenge on apparent and standardized ileal amino acid digestibility in grower and finisher broilers and its evaluation in 21-day-old broilers. AB - The effect of coccidial vaccine challenge (CVC, Coccivac((r))B; challenged, CHA; or unchallenged, NCH) on ileal endogenous amino acid (IEAA) losses and standardized ileal AA digestibility (SIAAD) in 21- and 42-day-old broilers fed a corn-soybean meal-dried distillers' grains with solubles-poultry by-product meal based diet (Expt. 1) and the effect of supplemental AA in ameliorating the effect of CVC (Expt. 2) were evaluated. Expt. 1 was designed as a 2 (d 21 or 42) x 2 (NCH or CHA) factorial arrangement of treatments with 8 replicates in a complete randomized design. The CVC birds were gavaged with 12 x coccidial vaccine on d 15 and 36 and were sampled on 6 d post challenge. SIAAD was determined by correcting apparent ileal AA digestibility for IEAA losses. Feed intake (FI) and BW gain were higher (P <= 0.05) in 21-day-old NCH birds compared to the 21-day-old CHA birds while 42-day-old birds had higher FI and BW gain than 21-day-old NCH and CHA birds. Ileal endogenous nitrogen loss was higher (P <= 0.05) in 42-day-old CHA birds compared to 42-day-old NCH birds. Apparent ileal AA digestibility in 21 day-old CHA birds was lower (P <= 0.05) than for 21-day-old NCH and 42-day-old NCH and CHA birds. SIAAD in 21-day-old CHA birds was lower (indispensable AA = 15.2 and dispensable AA = 17.8%-unit; P <= 0.05) than for 21-day-old NCH and 42 day-old NCH and CHA birds. Apparent ileal digestibility and total tract utilization of DM, N, and energy were not different between d 21 NCH and d 42 NCH and CHA birds but higher (P <= 0.05) than for d 21 CHA birds. Supplemental AA restored feed efficiency, but not BW gain, to that of the positive control (0.715 vs. 0.737). Results from Expt.1 showed that CVC significantly influenced ileal AA digestibility in 21- but not in 42-day-old birds. Expt. 2 showed that consideration of SIAAD in feed formulation may benefit feed efficiency. PMID- 26957635 TI - Identification and comparative proteomic study of quail and duck egg white protein using 2-dimensional gel electrophoresis and matrix-assisted laser desorption/ionization time-of-flight tandem mass spectrometry analysis. AB - A proteomic study of egg white proteins from 2 major poultry species, namely quail (Coturnix coturnix) and duck (Anas platyrhynchos), was performed with comparison to those of chicken (Gallus gallus) through 2-dimensional polyacrylamide gel electrophoresis (2-DE) analysis. By using matrix-assisted laser desorption/ionization time-of-flight tandem mass spectrometry (MALDI-TOF MS/MS), 29 protein spots representing 10 different kinds of proteins as well as 17 protein spots designating 9 proteins were successfully identified in quail and duck egg white, respectively. This report suggested a closer relationship between quail and chicken egg white proteome patterns, whereas the duck egg white protein distribution on the 2-DE map was more distinct. In duck egg white, some well known major proteins, such as ovomucoid, clusterin, extracellular fatty acid binding protein precursor (ex-FABP), and prostaglandin D2 synthase (PG D2 synthase), were not detected, while two major protein spots identified as "deleted in malignant brain tumors 1" protein (DMBT1) and vitellogenin-2 were found specific to duck in the corresponding range on the 2-DE gel map. These interspecies diversities may be associated with the egg white protein functions in cell defense or regulating/supporting the embryonic development to adapt to the inhabiting environment or reproduction demand during long-term evolution. The findings of this work will give insight into the advantages involved in the application on egg white proteins from various egg sources, which may present novel beneficial properties in the food industry or related to human health. PMID- 26957637 TI - Increased plasma leptin attenuates adaptive metabolism in early lactating dairy cows. AB - Mammals meet the increased nutritional demands of lactation through a combination of increased feed intake and a collection of adaptations known as adaptive metabolism (e.g., glucose sparing via insulin resistance, mobilization of endogenous reserves, and increased metabolic efficiency via reduced thyroid hormones). In the modern dairy cow, adaptive metabolism predominates over increased feed intake at the onset of lactation and develops concurrently with a reduction in plasma leptin. To address the role of leptin in the adaptive metabolism of early lactation, we asked which adaptations could be countered by a constant 96-h intravenous infusion of human leptin (hLeptin) starting on day 8 of lactation. Compared to saline infusion (Control), hLeptin did not alter energy intake or milk energy output but caused a modest increase in body weight loss. hLeptin reduced plasma glucose by 9% and hepatic glycogen content by 73%, and these effects were associated with a 17% increase in glucose disposal during an insulin tolerance test. hLeptin attenuated the accumulation of triglyceride in the liver by 28% in the absence of effects on plasma levels of the anti-lipolytic hormone insulin or plasma levels of free fatty acids, a marker of lipid mobilization from adipose tissue. Finally, hLeptin increased the plasma concentrations of T4 and T3 by nearly 50% without affecting other neurally regulated hormones (i.e., cortisol and luteinizing hormone (LH)). Overall these data implicate the periparturient reduction in plasma leptin as one of the signals promoting conservation of glucose and energy at the onset of lactation in the energy-deficient dairy cow. PMID- 26957638 TI - Folliculostellate cell interacts with pericyte via TGFbeta2 in rat anterior pituitary. AB - The anterior pituitary gland comprises five types of endocrine cells plus non endocrine cells including folliculostellate cells, endothelial cells, and capillary mural cells (pericytes). In addition to being controlled by the hypothalamic-pituitary-target organ axis, the functions of these cells are likely regulated by local cell and extracellular matrix (ECM) interactions. However, these complex interactions are not fully understood. We investigated folliculostellate cell-mediated cell-to-cell interaction. Using S100beta-GFP transgenic rats, which express GFP in folliculostellate cells, we designed a three-dimensional cell culture to examine the effects of folliculostellate cells. Interestingly, removal of folliculostellate cells reduced collagen synthesis (Col1a1 and Col3a1). Because pericytes are important collagen-producing cells in the gland, we stained for desmin (a pericyte marker). Removal of folliculostellate cells resulted in fewer desmin-positive pericytes and less desmin mRNA. We then attempted to identify the factor mediating folliculostellate cell-pericyte interaction. RT-PCR and in situ hybridization revealed that the important profibrotic factor transforming growth factor beta-2 (TGFbeta2) was specifically expressed in folliculostellate cells and that TGFbeta receptor II was expressed in pericytes, endothelial cells, and parenchymal cells. Immunocytochemistry showed that TGFbeta2 induced SMAD2 nuclear translocation in pericytes. TGFbeta2 increased collagen synthesis in a dose-dependent manner. This action was completely blocked by TGFbeta receptor I inhibitor (SB431542). Diminished collagen synthesis in folliculostellate cell-deficient cell aggregates was partially recovered by TGFbeta2. TGFbeta2-mediated folliculostellate cell pericyte interaction appears to be essential for collagen synthesis in rat anterior pituitary. This finding sheds new light on local cell-ECM interactions in the gland. PMID- 26957636 TI - Combinatorial protein engineering of proteolytically resistant mesotrypsin inhibitors as candidates for cancer therapy. AB - Engineered protein therapeutics offer advantages, including strong target affinity, selectivity and low toxicity, but like natural proteins can be susceptible to proteolytic degradation, thereby limiting their effectiveness. A compelling therapeutic target is mesotrypsin, a protease up-regulated with tumour progression, associated with poor prognosis, and implicated in tumour growth and progression of many cancers. However, with its unique capability for cleavage and inactivation of proteinaceous inhibitors, mesotrypsin presents a formidable challenge to the development of biological inhibitors. We used a powerful yeast display platform for directed evolution, employing a novel multi-modal library screening strategy, to engineer the human amyloid precursor protein Kunitz protease inhibitor domain (APPI) simultaneously for increased proteolytic stability, stronger binding affinity and improved selectivity for mesotrypsin inhibition. We identified a triple mutant APPIM17G/I18F/F34V, with a mesotrypsin inhibition constant (Ki) of 89 pM, as the strongest mesotrypsin inhibitor yet reported; this variant displays 1459-fold improved affinity, up to 350 000-fold greater specificity and 83-fold improved proteolytic stability compared with wild type APPI. We demonstrated that APPIM17G/I18F/F34V acts as a functional inhibitor in cell-based models of mesotrypsin-dependent prostate cancer cellular invasiveness. Additionally, by solving the crystal structure of the APPIM17G/I18F/F34V-mesotrypsin complex, we obtained new insights into the structural and mechanistic basis for improved binding and proteolytic resistance. Our study identifies a promising mesotrypsin inhibitor as a starting point for development of anticancer protein therapeutics and establishes proof-of-principle for a novel library screening approach that will be widely applicable for simultaneously evolving proteolytic stability in tandem with desired functionality for diverse protein scaffolds. PMID- 26957640 TI - Beta-Testing of Next-Generation DNA Sequencing for Patients With Advanced Cancers Treated at Community Hospitals. PMID- 26957639 TI - Chemotherapy Errors: A Call for a Standardized Approach to Measurement and Reporting. AB - The Massachusetts General Hospital (MGH) Cancer Center is a multidisciplinary cancer center that delivers chemotherapy to 150 to 200 patients daily and adheres to the Oncology Nursing Society and ASCO guidelines for safe chemotherapy administration. An error that occurred at MGH in the summer of 2012 prompted a review of all safety events, the process of classification, and the monitoring of safety events. This article reviews safety monitoring in the oncology setting, details the oncology safety-event reporting program at MGH, summarizes all chemotherapy-related safety events that have occurred over the past 5 years, and concludes with summary recommendations and potential steps to standardize safety reporting and analysis in chemotherapy administration. PMID- 26957642 TI - Use of Biomarkers to Guide Decisions on Adjuvant Systemic Therapy for Women With Early-Stage Invasive Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline Summary. PMID- 26957641 TI - Are Small Reimbursement Changes Enough to Change Cancer Care? Reimbursement Variation in Prostate Cancer Treatment. AB - PURPOSE: The Centers for Medicare and Medicaid Services recently initiated small reimbursement adjustments to improve the value of care delivered under fee-for service. To estimate the degree to which reimbursement influences physician decision making, we examined utilization of gonadotropin-releasing hormone (GnRH) agonists among urologists as Part B drug reimbursement varied in a fee-for service environment. METHODS: We analyzed treatment patterns of urologists treating 15,128 men included in SEER-linked Medicare claims who were diagnosed with localized prostate cancer between January 1, 2000, and December 31, 2003. We calculated a reimbursement generosity index to measure differences in GnRH agonist reimbursement among regional Medicare carriers and over time. We used multilevel analysis to control for patient and provider characteristics. RESULTS: Among urologists treating early-stage and lower grade prostate cancer, variation in reimbursement was not associated with overuse of GnRH agonists from 2000 to 2003, a period of guideline stability (odds ratio, 1.00; 95% CI, 0.99 to 1.00). CONCLUSION: Small differences in androgen-deprivation therapy reimbursement generosity were not associated with differential use. Fee-for-service reimbursement changes currently being implemented to improve quality in fee-for service Medicare may not affect patterns of cancer care. PMID- 26957643 TI - Women and heart disease, the underrecognized burden: sex differences, biases, and unmet clinical and research challenges. AB - For many years the significance of heart disease in women was vastly underappreciated, and women were significantly underrepresented in cardiovascular clinical research. We now know that cardiovascular disease is the leading cause of death for women. Women and men share many similarities in the pathophysiology and manifestations of heart disease. However, as research advances with the continued inclusion of more women, knowledge about gender differences between the female and male heart, both on a physiological and pathophysiological basis, grows. These differences can be found in all domains of cardiovascular health and disease, including heart rhythm, heart failure, coronary disease and valvular disease. Further understanding of gender differences in the heart is crucial for advancing our ability to maintain a healthy population and identify and treat heart disease in both women and men. Specific examples within the spectrum of heart disease will be discussed in this review paper, and areas for further research will be proposed. PMID- 26957644 TI - Copper dyshomoeostasis in Parkinson's disease: implications for pathogenesis and indications for novel therapeutics. AB - Copper is a biometal essential for normal brain development and function, thus copper deficiency or excess results in central nervous system disease. Well characterized disorders of disrupted copper homoeostasis with neuronal degeneration include Menkes disease and Wilson's disease but a large body of evidence also implicates disrupted copper pathways in other neurodegenerative disorders, including Parkinson's disease, Alzheimer's disease, Amyotrophic lateral sclerosis, Huntington's disease and prion diseases. In this short review we critically evaluate the data regarding changes in systemic and brain copper levels in Parkinson's disease, where alterations in brain copper are associated with regional neuronal cell death and disease pathology. We review copper regulating mechanisms in the human brain and the effects of dysfunction within these systems. We then examine the evidence for a role for copper in pathogenic processes in Parkinson's disease and consider reports of diverse copper modulating strategies in in vitro and in vivo models of this disorder. Copper modulating therapies are currently advancing through clinical trials for Alzheimer's and Huntington's disease and may also hold promise as disease modifying agents in Parkinson's disease. PMID- 26957646 TI - Self-care after hospital discharge: knowledge is not enough. PMID- 26957645 TI - Fully reduced granulin-B is intrinsically disordered and displays concentration dependent dynamics. AB - Granulins (Grns) are a family of small, cysteine-rich proteins that are generated upon proteolytic cleavage of their precursor, progranulin (Pgrn). All seven Grns (A-G) contain 12 conserved cysteines that form 6 intramolecular disulfide bonds, rendering this family of proteins unique. Grns are known to play multi-functional roles, including wound healing, embryonic growth, and inflammation and are implicated in neurodegenerative diseases. Despite their manifold functions, there exists a dearth of information regarding their structure-function relationship. Here, we sought to establish the role of disulfide bonds in promoting structure by investigating the fully reduced GrnB (rGrnB). We report that monomeric rGrnB is an intrinsically disordered protein (IDP) at low concentrations. rGrnB undergoes dimerization at higher concentrations to form a fuzzy complex without a net gain in the structure-a behavior increasingly identified as a hallmark of some IDPs. Interestingly, we show that rGrnB is also able to activate NF-kappaB in human neuroblastoma cells in a concentration-dependent manner. This activation correlates with the observed monomer-dimer dynamics. Collectively, the presented data establish that the intrinsic disorder of rGrnB governs conformational dynamics within the reduced form of the protein, and suggest that the overall structure of Grns could be entirely dictated by disulfide bonds. PMID- 26957647 TI - Intratracheal Administration of Antimicrobial Agents in Mechanically Ventilated Adults: An International Survey on Delivery Practices and Safety. AB - BACKGROUND: Intratracheal antibiotic administration is increasingly used for treating respiratory infections. Limited information is available on delivery devices, techniques, and safety. METHODS: An online survey on intratracheal administration of anti-infective agents in mechanically ventilated adults was answered by health-care workers from 192 ICUs to assess the most commonly used devices, current delivery practices, and safety issues. We investigated whether ICU usage experience (>=3 y) impacted its performance. RESULTS: Intratracheal antibiotic administration was a current practice in 87 ICUs (45.3%), with 40 (46%) having experience with the technique (>=3 y). Sixty-six (78.6%) of 84 health-care workers reported avoiding intratracheal antibiotic administration due to an absence of evidence-based guidelines (78.6%). Jet nebulizers were the most commonly used devices for delivery, in 24 less experienced ICUs (27.6%) and in 18 (20.7%) experienced ICUs. Direct tracheal instillation (6; 6.9%) was still considered for drug prescription in 12 ICUs (6.9%). More experience resulted in neither greater adherence to measures improving the drug's delivery efficiency (93 measures in the experienced group; 27.9%) nor a greater adoption of measures to increase safety. Indeed, the expiratory filter was changed after each nebulization in only 2 experienced ICUs (6.9%), whereas 15 (51.7%) changed it daily instead. CONCLUSIONS: Intratracheal antibiotic administration is a common therapeutic modality in ICUs, but inadequate practices were widely encountered, independent of the level of experience with the technique. This suggests a need to develop standardization to reduce variability and improve safety and efficacy. PMID- 26957648 TI - Sinopulmonary Complications in Subjects With Primary Immunodeficiency. AB - BACKGROUND: The aim of this work was to describe the frequency and spectrum of sinopulmonary complications among subjects with primary immunodeficiency disorders. METHODS: The subjects included all patients with primary immunodeficiency who were registered prospectively between January 2004 and December 2013 in the Kuwait National Primary Immunodeficiency Disorders Registry. RESULTS: A total of 202 subjects were registered during the study period. Subjects with combined immunodeficiencies were the most prevalent (65 subjects, 32.1%), followed by well-defined syndromes with immunodeficiency (45 subjects, 22.2%) and predominantly antibody deficiencies (35 subjects, 17.3%). A total of 295 sinopulmonary manifestations were observed in 127 subjects (63%); 157 manifestations (53.2%) were observed among the presenting symptoms, and 138 manifestations (46.8%) occurred after establishment of the primary immunodeficiency disorder diagnosis. Sinopulmonary manifestations were more common in subjects with predominantly antibody deficiencies (2.3 manifestations/subject), followed by subjects with combined immunodeficiencies (1.75 manifestations/subject). Pneumonia was the most common manifestation (108 episodes affecting 80 subjects), followed by otitis media (81 episodes affecting 59 subjects), bronchiectasis in 28 subjects (13.8%), and asthma in 22 subjects (11%). Microbial organisms were isolated during 46 episodes of pneumonia (42.5%) (cytomegalovirus and Pneumocystis jirovecii were the most common). There were 57 deaths (28%) during the study period. Twenty-four deaths (42%) were due to pulmonary complications as follows: pneumonia (16 subjects, 8%), pulmonary hemorrhage (6 subjects, 3%), and aspiration pneumonia (2 subjects, 1%). CONCLUSIONS: Sinopulmonary complications are common in subjects with primary immunodeficiency. They can be serious and continue to occur even after proper treatment is initiated. The pulmonologist should play an important role in the management of subjects with primary immunodeficiency disorder. PMID- 26957649 TI - Temperature dependence of dielectric, elastic, and piezoelectric constants of [001]c poled Mn-doped 0.24Pb(In1/2Nb1/2)O3-0.46Pb(Mg1/3Nb2/3)O3-0.30PbTiO3 single crystal. AB - In order to simulate the performance of electromechanical devices at elevated temperatures, full tensor properties of piezoelectric materials at high temperatures are needed. Such data are extremely difficult to get for relaxor based single crystals because their properties are determined by domain structures, which are strongly geometry dependent. We report here the temperature dependence of full tensor material constants of [001]c poled Mn-doped 0.24Pb(In1/2Nb1/2)O3-0.46Pb(Mg1/3Nb2/3)O3-0.30PbTiO3 single crystals from 25 degrees C to 55 degrees C, which were determined by the resonant ultrasound spectroscopy. Because only one sample was used, high degree of self-consistency was achieved for the tensor constants at all measured temperatures. PMID- 26957650 TI - A latent profile analysis of math achievement, numerosity, and math anxiety in twins. AB - Underperformance in math is a problem with increasing prevalence, complex etiology, and severe repercussions. This study examined the etiological heterogeneity of math performance in a sample of 264 pairs of 12-year-old twins assessed on measures of math achievement, numerosity and math anxiety. Latent profile analysis indicated five groupings of individuals representing different patterns of math achievement, numerosity and math anxiety, coupled with differing degrees of familial transmission. These results suggest that there may be distinct profiles of math achievement, numerosity and anxiety; particularly for students who struggle in math. PMID- 26957651 TI - A Message from the Editor. PMID- 26957652 TI - Oral Health in America, 2000 to Present: Progress made, but Challenges Remain. PMID- 26957653 TI - Fruit and Vegetable Consumption in Schools. PMID- 26957654 TI - Amin et al. Respond. PMID- 26957656 TI - AHRQ's Role in Improving Quality, Safety, and Health System Performance. PMID- 26957658 TI - The Congressional Public Health Caucus. PMID- 26957657 TI - Thirdhand Smoke: State of the Science and a Call for Policy Expansion. PMID- 26957659 TI - U.S. Department of Health and Human Services Oral Health Strategic Framework, 2014-2017. PMID- 26957660 TI - Sharing Overdose Data Across State Agencies to Inform Public Health Strategies: A Case Study. AB - Data sharing and analysis are important components of coordinated and cost effective public health strategies. However, legal and policy barriers have made data from different agencies difficult to share and analyze for policy development. To address a rise in overdose deaths, Maryland used an innovative and focused approach to bring together data on overdose decedents across multiple agencies. The effort was focused on developing discrete intervention points based on information yielded on decedents' lives, such as vulnerability upon release from incarceration. Key aspects of this approach included gubernatorial leadership, a unified commitment to data sharing across agencies with memoranda of understanding, and designation of a data management team. Preliminary results have yielded valuable insights and have helped inform policy. This process of navigating legal and privacy concerns in data sharing across multiple agencies may be applied to a variety of public health problems challenging health departments across the country. PMID- 26957661 TI - Online Hookup Sites for Meeting Sexual Partners Among Men Who Have Sex with Men in Rhode Island, 2013: A Call for Public Health Action. AB - Frequent use of websites and mobile telephone applications (apps) by men who have sex with men (MSM) to meet sexual partners, commonly referred to as "hookup" sites, make them ideal platforms for HIV prevention messaging. This Rhode Island case study demonstrated widespread use of hookup sites among MSM recently diagnosed with HIV. We present the advertising prices and corporate social responsibility (CSR) programs of the top five sites used by newly diagnosed HIV positive MSM to meet sexual partners: Grindr, Adam4Adam, Manhunt, Scruff, and Craigslist. Craigslist offered universal free advertising. Scruff offered free online advertising to selected nonprofit organizations. Grindr and Manhunt offered reduced, but widely varying, pricing for nonprofit advertisers. More than half (60%, 26/43) of newly diagnosed MSM reported meeting sexual partners online in the 12 months prior to their diagnosis. Opportunities for public health agencies to promote HIV-related health messaging on these sites were limited. Partnering with hookup sites to reach high-risk MSM for HIV prevention and treatment messaging is an important public health opportunity for reducing disease transmission risks in Rhode Island and across the United States. PMID- 26957662 TI - Characteristics of Local Health Departments Associated with Implementation of Electronic Health Records and Other Informatics Systems. AB - OBJECTIVE: Assessing local health departments' (LHDs') informatics capacities is important, especially within the context of broader, systems-level health reform. We assessed a nationally representative sample of LHDs' adoption of information systems and the factors associated with adoption and implementation by examining electronic health records, health information exchange, immunization registry, electronic disease reporting system, and electronic laboratory reporting. METHODS: We used data from the National Association of County and City Health Officials' 2013 National Profile of LHDs. We performed descriptive statistics and multinomial logistic regression for the five implementation-oriented outcome variables of interest, with three levels of implementation (implemented, plan to implement, and no activity). Independent variables included infrastructural and financial capacity and other characteristics associated with informatics capacity. RESULTS: Of 505 LHDs that responded to the survey, 69 (13.5%) had implemented health information exchanges, 122 (22.2%) had implemented electronic health records, 245 (47.5%) had implemented electronic laboratory reporting, 368 (73.0%) had implemented an electronic disease reporting system, and 416 (83.8%) had implemented an immunization registry. LHD characteristics associated with health informatics adoption included provision of greater number of clinical services, greater per capita public health expenditures, health information systems specialists on staff, larger population size, decentralized governance system, one or more local boards of health, metropolitan jurisdiction, and top executive with more years in the job. CONCLUSION: Many LHDs lack health informatics capacity, particularly in smaller, rural jurisdictions. Cross jurisdictional sharing, investment in public health informatics infrastructure, and additional training may help address these shortfalls. PMID- 26957663 TI - Timing of Clinical Billing Reimbursement for a Local Health Department. AB - OBJECTIVES: A major responsibility of a local health department (LHD) is to assure public health service availability throughout its jurisdiction. Many LHDs face expanded service needs and declining budgets, making billing for services an increasingly important strategy for sustaining public health service provision. Yet, little practice-based data exist to guide practitioners on what to expect financially, especially regarding timing of reimbursement receipt. This study provides results from one LHD on the lag from service delivery to reimbursement receipt. METHODS: Reimbursement records for all transactions at Maricopa County Department of Public Health immunization clinics from January 2013 through June 2014 were compiled and analyzed to determine the duration between service and reimbursement. Outcomes included daily and cumulative revenues received. Time to reimbursement for Medicaid and private payers was also compared. RESULTS: Reimbursement for immunization services was received a median of 68 days after service. Payments were sometimes taken back by payers through credit transactions that occurred a median of 333 days from service. No differences in time to reimbursement between Medicaid and private payers were found. CONCLUSIONS: Billing represents an important financial opportunity for LHDs to continue to sustainably assure population health. Yet, the lag from service provision to reimbursement may complicate budgeting, especially in initial years of new billing activities. Special consideration may be necessary to establish flexibility in the budget-setting processes for services with clinical billing revenues, because funds for services delivered in one budget period may not be received in the same period. LHDs may also benefit from exploring strategies used by other delivery organizations to streamline billing processes. PMID- 26957664 TI - The Association Between Neighborhood Poverty and HIV Diagnoses Among Males and Females in New York City, 2010-2011. AB - OBJECTIVE: We assessed the association of neighborhood poverty with HIV diagnosis rates for males and females in New York City. METHODS: We calculated annual HIV diagnosis rates by ZIP Code, sex, and neighborhood poverty level using 2010-2011 New York City (NYC) HIV surveillance data and data from the U.S. Census 2010 and American Community Survey 2007-2011. Neighborhood poverty levels were percentage of residents in a ZIP Code with incomes below the federal poverty threshold, categorized as 0%-<10% (low poverty), 10%-<20% (medium poverty), 20%-<30% (high poverty), and 30%-100% (very high poverty). We used sex-stratified negative binomial regression models to measure the association between neighborhood-level poverty and HIV diagnosis rates, controlling for neighborhood-level education, race/ethnicity, age, and percentage of men who have sex with men. RESULTS: In 2010-2011, 6,184 people were newly diagnosed with HIV. Median diagnosis rates per 100,000 population increased by neighborhood poverty level overall (13.7, 34.3, 50.6, and 75.6 for low-, medium-, high-, and very high-poverty ZIP Codes, respectively), for males, and for females. In regression models, higher neighborhood poverty remained associated with higher diagnosis rates among males (adjusted rate ratio [ARR] = 1.63, 95% confidence interval [CI] 1.34, 1.97) and females (ARR=2.14, 95% CI 1.46, 3.14) for very high- vs. low-poverty ZIP Codes. CONCLUSION: Living in very high- vs. low-poverty urban neighborhoods was associated with increased HIV diagnosis rates. After controlling for other factors, the association between poverty and diagnosis rates was stronger among females than among males. Alleviating poverty may help decrease HIV-related disparities. PMID- 26957665 TI - Mycobacterium Tuberculosis Infection, Immigration Status, and Diagnostic Discordance: A Comparison of Tuberculin Skin Test and QuantiFERON-TB Gold In-Tube Test Among Immigrants to the U.S. AB - OBJECTIVE: We used a recent source of nationally representative population data on tuberculosis (TB) infection to characterize concordance between the tuberculin skin test (TST) and the QuantiFERON-TB Gold In-Tube (QFT-GIT) blood test for immigrants in the United States. METHODS: We used TB screening data from the 2011 2012 National Health and Nutrition Examination Survey to examine concordance between the TST and QFT-GIT--an interferon-gamma release assay (IGRA) blood test- for 7,097 U.S. natives, naturalized citizens, and noncitizens. RESULTS: Consistent with prior findings, one in five immigrants in the survey was identified with latent TB infection (LTBI), a rate 14 times higher than for U.S. natives. We also found higher rates of discordant TST/IGRA results among immigrants than among U.S. natives. Unadjusted discordance between TST and IGRA was 3% among U.S. natives (weighted N=5,684,274 of 191,179,213) but ranged up to 19% for noncitizens (weighted N=3,722,960 of 19,377,147). Adjusting for age, sex, and race/ethnicity, noncitizens had more than nine times the odds of having a positive TST result but negative QFT-GIT result compared with U.S. natives. CONCLUSIONS: Our findings suggest that whether and how either of these tests should be deployed is highly context sensitive. Significant discordance in test results when used among immigrants raises the possibility of missed opportunities for harm reduction in this already at-risk population. However, we found little distinction between the tests in terms of diagnostic outcome when used in a U.S. native population, suggesting little benefit to the adoption and use of the QFT GIT test in place of TST on the basis of test performance alone for this population. PMID- 26957666 TI - HIV Testing Among Men at Risk for Acquiring HIV Infection Before and After the 2006 CDC Recommendations. AB - OBJECTIVES: Testing for human immunodeficiency virus (HIV) is the key first step in HIV treatment and prevention. In 2006, the Centers for Disease Control and Prevention (CDC) recommended annual HIV testing for people at high risk for HIV infection. We evaluated HIV testing among men with high-risk heterosexual (HRH) contact and sexually active men who have sex with men (MSM) before and after the CDC recommendations. METHODS: We used data from the National Survey of Family Growth, 2002 and 2006-2010, to assess proportions of HRH respondents and MSM reporting HIV testing in the prior 12 months, compare rates of testing before and after release of the 2006 CDC HIV testing guidelines, and examine demographic variables and receipt of health-care services as correlates of HIV testing. RESULTS: Among MSM, the proportion tested was 37.2% (95% confidence interval [CI] 28.2, 47.2) in 2002, 38.2% (95% CI 25.9, 52.2) in 2006-2008, and 41.7% (95% CI 29.2, 55.3) in 2008-2010; among HRH respondents, the proportion was 23.7% (95% CI 20.5, 27.3) in 2002, 24.5% (95% CI 20.9, 28.7) in 2006-2008, and 23.9% (95% CI 20.2, 28.1) in 2008-2010. HIV testing was more likely among MSM and HRH respondents who received testing or treatment for sexually transmitted disease in the prior 12 months, received a physical examination in the prior 12 months (MSM only), or were incarcerated in the prior 12 months. CONCLUSIONS: The rate of annual HIV testing was low for men with sexual risk for HIV infection, and little improvement took place from 2002 to 2006-2010. Interventions aimed at men at risk, especially MSM, in both nonmedical and health-care settings, likely could increase HIV testing. PMID- 26957668 TI - Distribution, Determinants, and Prevention of Falls Among the Elderly in the 2011 2012 California Health Interview Survey. AB - OBJECTIVES: Falls in the geriatric population are a major public health issue. With the anticipated aging of the population, falls are expected to increase nationally and globally. We estimated the prevalence and determinants of falls in adults aged >=65 years and calculated the proportion of elderly who fell and made lifestyle changes as a result of professional recommendations. METHODS: We included adults aged >=65 years from the 2011-2012 California Health Interview Survey (CHIS) and categorized them into two groups based on whether or not they had had at least two falls in the previous 12 months. We performed logistic regression analysis adjusted for the complex survey design to determine risk factors for falls and compare the odds of receiving professional recommendations among elderly with vs. without falls. RESULTS: Of an estimated 4.3 million eligible elderly participants in the CHIS (2011-2012), an estimated 527,340 (12.2%) fell multiple times in the previous 12 months. Of those, 204,890 (38.9%) were told how to avoid falls by a physician and 211,355 (40.1%) received medical treatment, although fewer than 41.0% had made related preventive changes to avoid future falls. Falls were associated with older age, less walking, and poorer physical or mental health. Non-Asians had higher odds of falling compared with Asians (adjusted odds ratio = 1.69, 95% confidence interval 1.16, 2.45). Most participants reported changing medications, home, or daily routines on their own initiative rather than after professional recommendations. CONCLUSION: Patients with a history of falls did not consistently receive professional recommendations on fall prevention-related lifestyle or living condition changes. Given the high likelihood of a serious fall, future interventions should focus on involving primary care physicians in active preventive efforts before a fall occurs. PMID- 26957667 TI - Physician Attitudes Toward Adult Vaccines and Other Preventive Practices, United States, 2012. AB - OBJECTIVES: We described the following among U.S. primary care physicians: (1) perceived importance of vaccines recommended by the Advisory Committee on Immunization Practices relative to U.S. Preventive Services Task Force (USPSTF) preventive services, (2) attitudes toward the U.S. adult immunization schedule, and (3) awareness and use of Medicare preventive service visits. METHODS: We conducted an Internet and mail survey from March to June 2012 among national networks of general internists and family physicians. RESULTS: We received responses from 352 of 445 (79%) general internists and 255 of 409 (62%) family physicians. For a 67-year-old hypothetical patient, 540/606 (89%, 95% confidence interval [CI] 87, 92) of physicians ranked seasonal influenza vaccine and 487/607 (80%, 95% CI 77, 83) ranked pneumococcal vaccine as very important, whereas 381/604 (63%, 95% CI 59, 67) ranked Tdap/Td vaccine and 288/607 (47%, 95% CI 43, 51) ranked herpes zoster vaccine as very important (p<0.001). All Grade A USPSTF recommendations were considered more important than Tdap/Td and herpes zoster vaccines. For the hypothetical patient aged 30 years, the number and percentage of physicians who reported that the Tdap/Td vaccine (377/604; 62%, 95% CI 59, 66) is very important was greater than the number and percentage who reported that the seasonal influenza vaccine (263/605; 43%, 95% CI 40, 47) is very important (p<0.001), and all Grade A and Grade B USPSTF recommendations were more often reported as very important than was any vaccine. A total of 172 of 587 physicians (29%) found aspects of the adult immunization schedule confusing. Among physicians aware of "Welcome to Medicare" and annual wellness visits, 492/514 (96%, 95% CI 94, 97) and 329/496 (66%, 95% CI 62, 70), respectively, reported having conducted fewer than 10 such visits in the previous month. CONCLUSIONS: Despite lack of prioritization of vaccines by ACIP, physicians are prioritizing some vaccines over others and ranking some vaccines below other preventive services. These attitudes and confusion about the immunization schedule may result in missed opportunities for vaccination. Medicare preventive visits are not being used widely despite offering a venue for delivery of preventive services, including vaccinations. PMID- 26957669 TI - Female Genital Mutilation/Cutting in the United States: Updated Estimates of Women and Girls at Risk, 2012. AB - OBJECTIVES: In 1996, the U.S. Congress passed legislation making female genital mutilation/cutting (FGM/C) illegal in the United States. CDC published the first estimates of the number of women and girls at risk for FGM/C in 1997. Since 2012, various constituencies have again raised concerns about the practice in the United States. We updated an earlier estimate of the number of women and girls in the United States who were at risk for FGM/C or its consequences. METHODS: We estimated the number of women and girls who were at risk for undergoing FGM/C or its consequences in 2012 by applying country-specific prevalence of FGM/C to the estimated number of women and girls living in the United States who were born in that country or who lived with a parent born in that country. RESULTS: Approximately 513,000 women and girls in the United States were at risk for FGM/C or its consequences in 2012, which was more than three times higher than the earlier estimate, based on 1990 data. The increase in the number of women and girls younger than 18 years of age at risk for FGM/C was more than four times that of previous estimates. CONCLUSION: The estimated increase was wholly a result of rapid growth in the number of immigrants from FGM/C-practicing countries living in the United States and not from increases in FGM/C prevalence in those countries. Scientifically valid information regarding whether women or their daughters have actually undergone FGM/C and related information that can contribute to efforts to prevent the practice in the United States and provide needed health services to women who have undergone FGM/C are needed. PMID- 26957670 TI - The Great Recession of 2007-2009 and Public Insurance Coverage for Children in Alabama: Enrollment and Claims Data from 1999-2011. AB - OBJECTIVES: This study examined the impact of the Great Recession of 2007-2009 on public health insurance enrollment and expenditures in Alabama. Our analysis was designed to provide a framework for other states to conduct similar analyses to better understand the relationship between macroeconomic conditions and public health insurance costs. METHODS: We analyzed enrollment and claims data from Medicaid and the Children's Health Insurance Program (CHIP) in Alabama from 1999 through 2011. We examined the relationship between county-level unemployment rates and enrollment in Medicaid and CHIP, as well as total county-level expenditures in the two programs. We used linear regressions with county fixed effects to estimate the impact of unemployment changes on enrollment and expenditures after controlling for population and programmatic changes in eligibility and cost sharing. RESULTS: A one-percentage-point increase in a county's unemployment rate was associated with a 4.3% increase in Medicaid enrollment, a 0.9% increase in CHIP enrollment, and an overall increase in public health insurance enrollment of 3.7%. Each percentage-point increase in unemployment was associated with a 6.2% increase in total public health insurance expenditures on children, with Medicaid spending rising by 7.5% and CHIP spending rising by 1.8%. In response to the 6.4 percentage-point increase in the state's unemployment rate during the Great Recession, combined enrollment of children in Alabama's public health insurance programs increased by 24% and total expenditures rose by 40%. CONCLUSION: Recessions have a substantial impact on the number of children enrolled in CHIP and Medicaid, and a disproportionate impact on program spending. Programs should be aware of the likely magnitudes of the effects in their budget planning. PMID- 26957671 TI - Sociodemographic Differences Among U.S. Children and Adults Exposed to Secondhand Smoke at Home: National Health Interview Surveys 2000 and 2010. AB - OBJECTIVE: We examined the levels and change in prevalence of self-reported secondhand smoke (SHS) exposure at home, and analyzed sociodemographic differences in exposure among children (aged 0-17 years) and nonsmoking adults (aged >=18 years) in the United States in 2000 and 2010. METHODS: We included 18,731 children and 44,049 adults from the 2000 and 2010 National Health Interview Survey Cancer Control Supplements. We used multivariate logistic regression to determine the factors associated with exposure. RESULTS: The prevalence of self-reported SHS exposure declined from 2,627 of 10,636 (24.7%) to 663 of 8,095 (8.2%) for children and from 2,863 of 23,665 (12.1%) to 897 of 20,384 (4.4%) for adults from 2000 to 2010. SHS exposure declined for all population subgroups between the two years, but differences were found. Compared with 2000, children aged 12-17 years in 2010 were no longer more likely than children aged 0-5 years to be exposed to SHS. Non-Hispanic black children and adults were more likely than non-Hispanic white children and adults to be exposed to SHS in 2010. In 2010, no differences were found for children whose parents had a higher level of education, and no differences were observed for children or adults with high family income vs. other levels of family income. Children living in the Midwest and South had higher levels of SHS exposure than children in other regions in 2010. CONCLUSIONS: Self-reported SHS exposure at home declined for all population subgroups from 2000 to 2010, but socioeconomic differences existed for some subgroups in both years. Current tobacco control policies need to be improved to reach all population subgroups so that SHS exposure can be further reduced, especially among vulnerable populations. PMID- 26957672 TI - Defining Sickle Cell Disease Mortality Using a Population-Based Surveillance System, 2004 through 2008. AB - OBJECTIVE: Population-based surveillance data from California and Georgia for years 2004 through 2008 were linked to state death record files to determine the all-cause death rate among 12,143 patients identified with sickle cell disease (SCD). METHODS: All-cause death rates, by age, among these SCD patients were compared with all-cause death rates among both African Americans and the total population in the two states. All-cause death rates were also compared with death rates for SCD derived from publicly available death records: the compressed mortality files and multiple cause of death files. RESULTS: Of 12,143 patients identified with SCD, 615 patients died. The all-cause mortality rate for the SCD population was lower than the all-cause mortality rate among African Americans and similar to the total population all-cause mortality rates from birth through age 4 years, but the rate was higher among those with SCD than both the African American and total population rates from ages 5 through 74 years. The count of deceased patients identified by using population-based surveillance data (n=615) was more than twice as high as the count identified in compressed mortality files using SCD as the underlying cause of death alone (n=297). CONCLUSION: Accurate assessment of all-cause mortality and age at death requires long-term surveillance via population-based registries of patients with accurately diagnosed SCD. PMID- 26957675 TI - Raising the Tobacco Sales Age to 21: Surveying the Legal Landscape. PMID- 26957676 TI - Drinking water and sanitation: progress in 73 countries in relation to socioeconomic indicators. AB - OBJECTIVE: To assess progress in the provision of drinking water and sanitation in relation to national socioeconomic indicators. METHODS: We used household survey data for 73 countries - collected between 2000 and 2012 - to calculate linear rates of change in population access to improved drinking water (n = 67) and/or sanitation (n = 61). To enable comparison of progress between countries with different initial levels of access, the calculated rates of change were normalized to fall between -1 and 1. In regression analyses, we investigated associations between the normalized rates of change in population access and national socioeconomic indicators: gross national income per capita, government effectiveness, official development assistance, freshwater resources, education, poverty, Gini coefficient, child mortality and the human development index. FINDINGS: The normalized rates of change indicated that most of the investigated countries were making progress towards achieving universal access to improved drinking water and sanitation. However, only about a third showed a level of progress that was at least half the maximum achievable level. The normalized rates of change did not appear to be correlated with any of the national indicators that we investigated. CONCLUSION: In many countries, the progress being made towards universal access to improved drinking water and sanitation is falling well short of the maximum achievable level. Progress does not appear to be correlated with a country's social and economic characteristics. The between country variations observed in such progress may be linked to variations in government policies and in the institutional commitment and capacity needed to execute such policies effectively. PMID- 26957677 TI - Thwarted Belongingness Mediates the Relationship between Fear of Negative Evaluation and Suicidal Ideation. AB - Fear of negative evaluation has been documented as a mechanism that explains variations in feelings of belongingness. According to the interpersonal theory of suicide (Joiner, 2005), feelings of thwarted belongingness, that one does not belong, can significantly increase desire and risk for suicide. We proposed that differences in thwarted belongingness may explain variations in suicidal ideation and behavior as a function of levels of fear of negative evaluation. This hypothesis was tested by examining self-reported fears of negative evaluation, thwarted belongingness, and suicidal ideation in 107 young adults, many who were explicitly targeted for recruitment due to a history of suicidal ideation and behavior (13.1% had thoughts about suicide without a previous attempt; 15.9% reported at least one previous attempt [max = 5 attempts]). Mediation analyses were conducted with suicidal ideation entered as the outcome variable. Results indicated that greater fears of negative evaluation were significantly and positively associated with levels of suicidal ideation. Differences in thwarted belongingness fully accounted for the relationship between fears of negative evaluation and suicidal ideation. We conclude with clinical implications and future directions. PMID- 26957679 TI - Development of proton computed tomography detectors for applications in hadron therapy. AB - Radiation therapy with protons and heavier ions is an attractive form of cancer treatment that could enhance local control and survival of cancers that are currently difficult to cure and lead to less side effects due to sparing of normal tissues. However, particle therapy faces a significant technical challenge because one cannot accurately predict the particle range in the patient using data provided by existing imaging technologies. Proton computed tomography (pCT) is an emerging imaging modality capable of improving the accuracy of range prediction. In this paper, we describe the successive pCT scanners designed and built by our group with the goal to support particle therapy treatment planning and image guidance by reconstructing an accurate 3D map of the stopping power relative to water in patient tissues. The pCT scanners we have built to date consist of silicon telescopes, which track the proton before and after the object to be reconstructed, and an energy or range detector, which measures the residual energy and/or range of the protons used to evaluate the water equivalent path length (WEPL) of each proton in the object. An overview of a decade-long evolution of the conceptual design of pCT scanners and their calibration is given. Results of scanner performance tests are presented, which demonstrate that the latest pCT scanner approaches readiness for clinical applications in hadron therapy. PMID- 26957680 TI - Assessing the age of deep vein thrombus: A need for future perioperative medicine and anesthesia. PMID- 26957678 TI - Shared and Distinct Cognitive/Affective Mechanisms in Intrusive Cognition: An Examination of Worry and Obsessions. AB - Generalized anxiety disorder and obsessive-compulsive disorder are defined by chronic intrusive thoughts. The aim of the present study was to evaluate the relationship between cognitive (attentional control) and motivational (negative urgency) mechanisms potentially underlying worry and obsessions. Participants (N = 526) completed an online questionnaire battery consisting of self-report measures of worry, OCD symptoms, attentional control (AC), negative urgency (NU), and trait negative affect. After controlling for trait negative affect, self reported AC was negatively related to worry, repugnant obsessions, and ordering symptoms. Greater NU was associated with increased worry and repugnant obsessions. Further, self-reported AC and NU interacted such that greater NU was associated with greater worry at high but not low levels of AC. AC and NU were independently associated with repugnant obsessions. Perceived executive functioning impairments may confer risk for intrusive thoughts, particularly worries, whereas distress-driven impulsivity may contribute to the involuntary, ego-dystonic features of intrusions. PMID- 26957681 TI - Irreversible pulpitis and achieving profound anesthesia: Complexities and managements. AB - Dental pain management is one of the most critical aspects of modern dentistry. Irreversible pulpitis and further root canal therapy might cause an untolerated pain to the patients. The improvements in anesthetic agents and techniques were one of the advantages of studying nerve biology and stimulation. This article tried to overview of the nerve activities in inflammatory environments or induced pain. Furthermore, the proper advises, and supplementary techniques were reviewed for better pain management of irreversible pulpitis. PMID- 26957682 TI - Anesthetic considerations in the patients of chronic obstructive pulmonary disease undergoing laparoscopic surgeries. AB - The aim of this study was to review the various anesthetic options which can be considered for laparoscopic surgeries in the patients with the chronic obstructive pulmonary disease. The literature search was performed in the Google, PubMed, and Medscape using key words "analgesia, anesthesia, general, laparoscopy, lung diseases, obstructive." More than thirty-five free full articles and books published from the year 1994 to 2014 were retrieved and studied. Retrospective data observed from various studies and case reports showed regional anesthesia (RA) to be valid and safer option in the patients who are not good candidates of general anesthesia like patients having obstructive pulmonary diseases. It showed better postoperative patient outcome with respect to safety, efficacy, postoperative pulmonary complications, and analgesia. So depending upon disease severity RA in various forms such as spinal anesthesia, paravertebral block, continuous epidural anesthesia, combined spinal epidural anesthesia (CSEA), and CSEA with bi-level positive airway pressure should be considered. PMID- 26957684 TI - Oral clonidine and gabapentin suppress pressor response: A prospective, randomized, double blind study. AB - BACKGROUND: Pressor response is a part of stress response caused by reflex sympathetic discharge due to direct laryngoscopy and tracheal intubation resulting in tachycardia, hypertension and arrhythmias. Both clonidine, and gabapentin administered orally can effectively blunt this detrimental hemodynamic response. AIM: To study the effect of oral clonidine to blunt the pressor response to direct laryngoscopy and to compare it with oral gabapentin. To observe for postoperative sedation and side effects if any. SETTINGS AND DESIGN: Sixty patients of American Society of Anaesthesiologist Grade I and II scheduled for surgery under general anesthesia were considered in this prospective randomized double-blind study. They were randomly allocated into two groups of 30 each using computerized randomization. MATERIALS AND METHODS: Group A was given oral clonidine 5 MUg/kg and Group B was given oral gabapentin 800 mg. Both the drugs were given 90 min prior to surgery. Heart rate (HR) and blood pressure were monitored at baseline, 0, 1, 3, 5, 10, 15, and 30(th) min of laryngoscopy. Sedation was monitored by Ramsay Sedation Scale score and side effects were noted. RESULTS: HR decreased in both groups at 0 and 1 min, increased at 3(rd) min and gradually decreased by 30(th) min. Statistically, significant difference was found between two groups at 1, 3, 5, 10, and 15(th) min (P < 0.05). Though there was no significant difference in systolic blood pressure, diastolic blood pressure and mean arterial pressure between the two groups, there was no rise in these parameters. Gabapentin produced more sedation than clonidine postoperatively, and few side effects were noted. CONCLUSION: Both oral clonidine and gabapentin are effective in obtunding pressor response to direct laryngoscopy, clonidine being better in terms of controlling HR. Gabapentin produces more postoperative sedation than clonidine. PMID- 26957683 TI - A brief review on the efficacy of different possible and nonpharmacological techniques in eliminating discomfort of local anesthesia injection during dental procedures. AB - Dental anxiety and fear of needle injection is one of the most common problems encountered by dental practitioners, especially in the pediatric patient. In consequences, it might affect the patient's quality of life. Several methods are suggested to lower the discomfort of local anesthesia injection during dental procedures. Desensitization of injection site is one of the recommended strategies. Among chemical anesthetic topical agents that are effective but might have allergic side effects, using some nonpharmacological and safe techniques might be useful. This study aimed to overview the efficacy of using cooling techniques, mostly by ice or popsicles, warming or pH buffering of drug, and using modern devices to diminish the discomfort of local anesthesia injection during dental procedures. PMID- 26957685 TI - A comparative study on postoperative pain relief in laparoscopic cholecystectomy: Intraperitoneal bupivacaine versus combination of bupivacaine and buprenorphine. AB - CONTEXT: To assess the analgesic efficacy of the combination of bupivacaine and buprenorphine in alleviating postoperative pain following laparoscopic cholecystectomy. AIMS: Laparoscopic cholecystectomy is comparatively advantageous as it offers less pain in the postoperative period and requires a shorter hospital stay. There are only a few studies performed to evaluate the analgesic efficacy of intraperitoneal instillation of buprenorphine and bupivacaine during laparoscopic cholecystectomy. SETTINGS AND DESIGN: The present research is a randomized, double-blind controlled study conducted in the Department of Anaesthesiology, Dayanand Medical College and Hospital Ludhiana, Punjab after formal ethical approval from Hospital's Ethics Committee. SUBJECTS AND METHODS: This study analyzed 90 adults admitted for elective laparoscopic cholecystectomy. After the procedure, subjects were divided into three equal groups to conduct the study. Three Groups A, B, and C had intraperitoneal instillation of the 25 ml of physiological saline (0.9% normal saline), 0.25% of bupivacaine, 0.25% bupivacaine, and 0.3 mg buprenorphine, respectively. Necessary vitals were monitored and recorded. Visual analog scale (VAS) and verbal rating scale (VRS) scores were recorded and analyzed systematically. STATISTICAL ANALYSIS USED: All observations were analyzed using analysis of variance and Student's t-test. RESULTS: The mean pain scores were highest in Group A compared to Group B and Group C. Mean VAS and VRS scores were highest in Group C comparatively and lowest in Group A. CONCLUSION: Combination of buprenorphine and bupivacaine intraperitoneally is comparatively more effective in relieving postoperative pain in comparison to intraperitoneal instillation of bupivacaine alone for postoperative pain management after laparoscopic cholecystectomy. PMID- 26957686 TI - Lipid composition and lidocaine effect on immediate and delayed injection pain following propofol administration. AB - BACKGROUND: Propofol has been used for the induction and maintenance of anesthesia. However, patients experience vascular pain during its injection. AIMS: The objective of this study was to compare the effect of the lipid type used in propofol preparations and that of lidocaine on the immediate and delayed vascular pain induced by propofol administration. MATERIALS AND METHODS: In this double-blinded clinical study, 150 patients at American Society of Anesthesiologists level I-II were randomly divided into three equally sized groups. A propofol with medium and long-chain triglycerides (propofol-MCT/LCT) was administered to the first group. The second group received propofol containing propofol-LCT, and the third group received propofol-LCT and pretreatment lidocaine 20 mg. The incidence and the intensity of immediate (during injection) and delayed injection pain (after 20 s) were evaluated on a verbal analog scale (1-10) until patients' unconsciousness. STATISTICAL ANALYSIS: Sample size was calculated with SigmaPlot version 12.5 software. Data were analyzed with Statistical Package for the Social Sciences (SPSS) version 16, one way analysis of variance, and post-hoc Tukey. P < 0.05 was considered statistically significant. RESULTS: The demographic parameters of the three groups were similar. The lidocaine group experienced the least immediate vascular pain. The intensity of pain was highest in the propofol-LCT group (P = 0.04). Additionally, the intensity of delayed pain was lowest in the propofol-MCT/LCT group (P = 0.01). The incidence of pain associated with the propofol administration was 26.5, 44, and 18%, respectively, in propofol-MCT/LCT, propofol LCT, and lidocaine and propofol-LCT groups. CONCLUSION: The results indicate an effect of the lipid type on delayed pain reduction, especially propofol-MCT/LCT. On the other hand, the lidocaine decreases immediate propofol-LCT vascular pain. PMID- 26957687 TI - Six percent hetastarch versus lactated Ringer's solution - for preloading before spinal anesthesia for cesarean section. AB - BACKGROUND: Regional anesthesia has been the choice of preference for elective cesarean sections. This study was designed to determine whether preoperative administration of 6% hetastarch decreases the incidence of hypotension. MATERIALS AND METHODS: This study was conducted on 50 nonlaboring American Society of Anesthesiologists class I and II women undergoing elective cesarean section. Patients were randomly divided into two groups and were preloaded either with 1000 ml Ringer's lactate (RL) or 500 ml of 6% hetastarch 30 min prior to the surgery. Spinal anesthesia was performed with patients in the left lateral position and 2 cc (10 mg) of 0.5% of bupivacaine injected into subarachnoid space. Hemodynamic variables (heart rate, noninvasive blood pressure, and SpO2) were recorded from prior to preloading until the recovery from the subarachnoid blockade. RESULTS: Our study showed the incidence of hypotension to be 28% in the hetastarch group and 80% in the RL group. Rescue ephedrine requirements for the treatment of hypotension were significantly less in patients who were preloaded with 6% hetastarch prior to cesarean section. The neonatal outcome, as determined by Apgar scores was good and similar in both groups. CONCLUSION: Hence, we conclude that 6% hydroxyl ethyl starch is more effective than lactated Ringers solution and that its routine use for preloading prior to spinal anesthesia should be considered. PMID- 26957688 TI - Effects of adding low-dose clonidine to intrathecal hyperbaric ropivacaine: A randomized double-blind clinical trial. AB - BACKGROUND: Clonidine added to bupivacaine prolongs the duration of anesthesia and postoperative analgesia with minimal side effects. Ropivacaine has lower lipid solubility and better safety profile as compared to bupivacaine. This study is designed to evaluate the effects of low-dose clonidine when added to hyperbaric ropivacaine. MATERIALS AND METHODS: Ninety patients belonging to American Society of Anesthesiologists-I scheduled for lower limb or lower abdominal surgeries under spinal anesthesia were randomly allocated into three groups (n = 30). Group R: 0.5% hyperbaric ropivacaine 12 mg + saline, Group 15C: 0.5% hyperbaric ropivacaine 12 mg + 15 mcg clonidine and Group 30C: 0.5% hyperbaric ropivacaine 12 mg + 30 mcg clonidine for spinal anesthesia in a total volume of 3.2 ml. Block characteristics, hemodynamic parameters, and side effects were monitored. RESULTS: Addition of low-dose clonidine to hyperbaric ropivacaine, significantly prolongs the duration of sensory and motor blockade as well as postoperative analgesia compared with placebo (mean +/- standard deviation min; 152.50 +/- 15.3, 246 +/- 23.5, and 217 +/- 37.73, respectively with 15 mcg clonidine, 193 +/- 16.59, 284 +/- 23.28, and 234.83 +/- 36.45, respectively with 30 mcg clonidine, 131 +/- 14.7, 211.5 +/- 24.39, and 192.33 +/- 37.02, respectively with saline). The addition of low-dose clonidine significantly increases the incidence of intra-operative hypotension (46.7% and 83.3%, respectively compared to 16.7%), bradycardia (6.7% and 23.3%, respectively compared to 0%). CONCLUSIONS: Addition of low-dose clonidine to intrathecal hyperbaric ropivacaine causes a significant prolongation of the duration of sensory and motor blockade as well as postoperative analgesia compared with saline placebo. However, it increases the incidence of hypotension and bradycardia which can be managed with routine clinical measures. PMID- 26957689 TI - Epidural ropivacaine with dexmedetomidine reduces propofol requirement based on bispectral index in patients undergoing lower extremity and abdominal surgeries. AB - BACKGROUND AND AIM: To assess the amount of propofol required for induction based on bispectral index (BIS) after administering epidural anesthesia with ropivacaine alone and ropivacaine with dexmedetomidine in patients undergoing lower extremities and abdominal surgeries. SUBJECTS AND METHODS: A double-blinded randomized clinical trial was carried out in 60 patients over a period of 2 years in a tertiary care hospital. American Society of Anaesthesiologists I or II in age group 18-65 years were included in the study. Group R received epidural anesthesia with ropivacaine alone, and Group D received ropivacaine and dexmedetomidine. General anesthesia was induced with propofol under BIS monitoring after 15 min. Onset of sensory and motor block, time for loss of consciousness and total amount of propofol used during induction to achieve the BIS value < 55 were recorded. Student's t-test and Chi-square test were used to find the significance of study parameters. RESULTS: Time of onset of sensory block (Group R 11.30 +/- 1.64/Group D 8.27 +/- 0.83 min), motor block (Group R 14.16 +/- 1.33/Group D 12.63 +/- 1.22 min), time for loss of consciousness (Group R 90.57 +/- 11.05/Group D 73.67 +/- 16.34 s), and total amount of propofol (Group R 129.83 +/- 22.38/Group D 92.13 +/- 12.93 s) were reduced in Group D which was statistically significant with P < 0.001. CONCLUSION: Epidural ropivacaine with dexmedetomidine significantly reduces the total propofol dose required for induction of anesthesia. Also, it decreases the onset time of sensory and motor block and provides good hemodynamic stability. PMID- 26957690 TI - A retrospective cohort study of perioperative prognostic factors associated with intra-abdominal sepsis. AB - CONTEXT: Intra-abdominal sepsis following laparotomy for acute abdomen remains still a challenging condition. The understanding of various perioperative risk factors by anesthesiologists are crucial in optimum management these patients. AIMS: The objective of this study is to assess the perioperative risk factors, which predicts the outcome of treatment. SETTINGS AND DESIGN: This retrospective observational study of 603 patients who underwent Laparotomies between March 2012 and March 2015 at our University Medical College. Of 603 patients, 52 consecutive patients with intra-abdomen sepsis who underwent surgical procedures and admitted in Intensive Care Unit (ICU) were selected and analyzed for prognostic risk factors in relation to severity of the disease. SUBJECTS AND METHODS: 52 consecutive patients who developed intra-abdominal sepsis following laparotomy was allocated one of two groups; Group Sepsis, patients with peritonitis without systemic hypotension (mean arterial pressure [MAP] >60 mm of Hg); and Group septic shock, patients with peritonitis with systemic hypotension (mean arterial pressure [MAP] <60 mm of Hg) and patients were analyzed for prognostic risk factors. STATISTICAL ANALYSIS USED: Categorical variables were analyzed by using Fisher's exact (two-tail) test and continuous variable were analyzed by using Mann-Whitney (two-tail) U-test. RESULTS: Out of 603 patients who underwent laparotomy 52 patients developed an intra-abdominal septic complication. Of these 52 cases studied 28 patients developed septic shock and required a longer duration of admission in ICU and more inotropic support. Preoperative albumin and hematocrit level were significantly low in septic shock patients as compared to the patients with sepsis without systemic hypotension. PaCO2: FiO2 was also significantly low in these patients. CONCLUSIONS: Preoperative low hematocrit, low albumin level, and delay in laparotomy more than 72 h were also associated with adverse outcome in the patients with intra-abdominal sepsis. Clinicians should maintain equipoise on this topic pending prospective randomized clinical trials. PMID- 26957691 TI - Diagnostic accuracy of bedside tests for predicting difficult intubation in Indian population: An observational study. AB - BACKGROUND: Unanticipated difficult intubation can be challenging to anesthesiologists, and various bedside tests have been tried to predict difficult intubation. AIMS: The aim of this study was to determine the incidence of difficult intubation in the Indian population and also to determine the diagnostic accuracy of bedside tests in predicting difficult intubation. SETTINGS AND DESIGN: In this study, 200 patients belonging to age group 18-60 years of American Society of Anesthesiologists I and II, scheduled for surgery under general anesthesia requiring endotracheal intubation were enrolled. Patients with upper airway pathology, neck mass, and cervical spine injury were excluded from the study. MATERIALS AND METHODS: An attending anesthesiologist conducted preoperative assessment and recorded parameters such as body mass index, modified Mallampati grading, inter-incisor distance, neck circumference, and thyromental distance (NC/TMD). After standard anesthetic induction, laryngoscopy was performed, and intubation difficulty assessed using intubation difficulty scale on the basis of seven variables. STATISTICAL ANALYSIS: The Chi-square test or student t-test was performed when appropriate. The binary multivariate logistic regression (forward-Wald) model was used to determine the independent risk factors. RESULTS: Among the 200 patients, 26 patients had difficult intubation with an incidence of 13%. Among different variables, the Mallampati score and NC/TMD were independently associated with difficult intubation. Receiver operating characteristic curve showed a cut-off point of 3 or 4 for Mallampati score and 5.62 for NC/TMD to predict difficult intubation. CONCLUSION: The diagnostic accuracy of NC/TM ratio and Mallampatti score were better compared to other bedside tests to predict difficult intubation in Indian population. PMID- 26957692 TI - Intraoperative hemodynamics with vecuronium bromide and rocuronium for maintenance under general anesthesia. AB - AIMS: The present study is undertaken to compare the hemodynamic effects using vecuronium versus rocuronium for maintenance in patients undergoing general surgical procedures. SETTINGS AND DESIGN: It is a prospective, randomized, and cohort study. SUBJECTS AND METHODS: 100 patients were randomly divided into two groups. All patients were induced with 5 mg/kg of thiopentone sodium, and intubation conditions were achieved with 1.5 mg/kg of suxamethonium, using a well lubricated cuffed endotracheal tube of appropriate size. When the patient started to breathe spontaneously, they were administered either 0.6 mg/kg of rocuronium (Group A) or 0.1 mg/kg of vecuronium (Group B). Hemodynamic parameters (heart rate and mean arterial pressure [MAP]) were monitored before administering the drug; at 1, 5, 10, 15, and 20 min after the drug and at the end of the surgery. STATISTICAL ANALYSIS USED: Data were compiled, analyzed and presented as frequency, proportions, mean, standard deviation, percentages, and t-test using SPSS (version 16). A P < 0.05 was considered as significant. RESULTS: The heart rate increased significantly at 1-min and 5-min after administration of rocuronium (83.76 +/- 10.37 and 86.8 +/- 9.98), unlike vecuronium. However, it gradually declined towards normal, and change in heart rate with either drug was not significant beyond 10 min. The MAP decreased significantly at 1-min after administration of rocuronium (96.68 +/- 7.57) which later showed a gradual increasing trend when compared to vecuronium which had no statistically significant change at any time. CONCLUSIONS: For short surgical procedures rocuronium is a good alternative to vecuronium, as the drug is reasonably cardio stable, produces excellent intubation conditions, has a shorter duration of action, and shows minimal cumulative effect. PMID- 26957693 TI - Effect of intrathecal clonidine versus fentanyl on bupivacaine spinal block in transurethral resection of prostate surgeries. AB - AIMS: Our study aimed at comparing the onset, degree and recovery time of sensory and motor block, the hemodynamic effects and postoperative pain relief using intrathecal bupivacaine alone, bupivacaine along with fentanyl and clonidine. MATERIALS AND METHODS: A total of 90 patients, undergoing transurethral resection of prostate (TURP) surgeries under spinal anesthesia were studied. Patients were randomly divided in a double-blind manner into three groups of 30 patients each. Group A (control) patients given subarachnoid block with 0.5% hyperbaric bupivacaine with 0.5 ml of normal saline. Group B patients were given subarachnoid block with 0.5% hyperbaric bupivacaine along with fentanyl 25 MUg. Group C patients were given subarachnoid block with 0.5% hyperbaric bupivacaine 10 mg along with clonidine 30 MUg and 0.3 ml of normal saline. After administering the subarachnoid block, vitals were recorded before and after surgery. Level of sensory block, the duration of motor block (DOMB), duration of sensory blockade (DOSB), the quality of postoperative analgesia using linear visual analog scale (VAS), and side effects were evaluated. RESULTS: The time required to attain a maximum height of the block was significantly more in Group B as compared to Groups A and C, which was statistically significant. However, there was no statistically significant difference between Groups A and C. The mean DOSB in Groups A, B, and C were 90.83 +/- 9.48 min, 135.33 +/- 12.59 min, and 155.17 +/- 17.49 min, respectively. The mean DOMB in Groups A, B, and C were 83.83 +/- 6.52 min, 115.50 +/- 14.70 min and 120.67 +/- 11.50, respectively. Time of the first request of analgesia in Groups A, B and C in postoperative period were 132.50 +/- 21.53 min, 296.00 +/- 50.07 min, and 311.83 +/- 65.34 min. patients had. VAS was significantly of higher value in Group A than Groups B and C. CONCLUSIONS: Intrathecal clonidine in a combination of bupivacaine for TURP provides more satisfactory anesthesia and analgesia and has less side effects. PMID- 26957694 TI - Postoperative analgesia after inguinal hernia repair - Comparison of ropivacaine with bupivacaine: A randomized controlled trial. AB - BACKGROUND: Postoperative pain management by surgical site infiltration has an edge over other methods of analgesia as it is simple and has lesser side effects. This study was designed to compare the analgesic effects provided by bupivacaine, a classical long-acting local anesthetic and ropivacaine, a new amino amide local anesthetic agent. SUBJECTS AND METHODS: Ninety patients scheduled for elective inguinal herniorrhaphy were randomly allocated to one of the three groups: Group I - R 0.5, group II - R 0.25, and group III - B 0.25. General anesthesia was given. The surgical site was infiltrated before incision with 20 ml of drugs - ropivacaine 0.5% in group I, ropivacaine 0.25% in group II, bupivacaine 0.25% in group III. Intraoperatively hemodynamics were recorded every 15 min until the end of surgery and at the time of skin incision, at the time of cord pulling, and at the time of skin closure. Postoperatively, rest pain, pain on coughing, and pain on movements were assessed using visual analog scale (VAS) score immediately at the end of the surgery and hourly up to 4 h. The time of the first request for rescue analgesia was noted. RESULTS: VAS scores at rest, during coughing and movements were higher in group R 0.25 and the time of rescue analgesia was shorter with group R 0.25 when compared with other groups. CONCLUSION: Ropivacaine is less potent than bupivacaine at equal concentrations. PMID- 26957695 TI - Comparative evaluation of dexmedetomidine and clonidine with low dose ropivacaine in cervical epidural anesthesia for modified radical mastectomy: A prospective randomized, double-blind study. AB - CONTEXT: Alpha-2 adrenergic agonists clonidine and dexmedetomidine, are well known to produce analgesia through an opioid independent mechanism. Alpha-2 agonists are used as an adjuvant to local anesthetic agents to extend the duration of spinal, epidural and brachial plexus blocks. AIMS: We compared clonidine and dexmedetomidine as an adjuvant to Ropivacaine in cervical epidural anesthesia (CEA) with respect to onset and duration of sensory block, duration of analgesia and adverse effects. SUBJECTS AND METHODS: A total 150 American Society of Anesthesiologists Class I or II adult female patients who were scheduled to undergo modified radical mastectomy were randomly allocated to the following two groups to receive CEA: Group D receive 15 mL of 0.375% ropivacaine combined with 1 MUg/kg of dexmedetomidine; Group C received 15 mL of 0.375% ropivacaine combined with 1.5 MUg/kg of clonidine. The onset of sensory block, duration of analgesia, mean arterial pressure (MAP), heart rate (HR), sedation scores, and the incidences of adverse effects, such as hypotension, bradycardia, and oxygen desaturation were recorded. RESULTS: The addition of dexmedetomidine to ropivacaine (Group D) resulted in faster onset of sensory block time compared with the addition of clonidine to ropivacaine (Group C) (95% confidence interval [CI]: 14.53 +/- 2.96 vs. 16.72 +/- 4.43 P = 0.032). The duration of analgesia block in Group D was significantly longer than that in Group C (95% CI: 234.65 +/ 23.76 vs. 286.76 +/- 34.65; P = 0.037). The Ramsay sedation score at in Group D were significantly higher between 20 and 60 min as compared to Group C (P < 0.022). MAP level and HR level in Group D and Group C were comparable. CONCLUSION: The addition of dexmedetomidine to low dose ropivacaine for CEA could shorten the onset of sensory block and extend the duration of analgesia with optimum sedation without episodes of hypoxemia as compared to addition of clonidine to ropivacaine. PMID- 26957696 TI - Postoperative pain relief with epidural buprenorphine versus epidural butorphanol in laparoscopic hysterectomies: A comparative study. AB - BACKGROUND: The purpose of this study was to compare the safety and efficacy of postoperative analgesia with epidural buprenorphine and butorphanol tartrate. METHODS: Sixty patients who were scheduled for elective laparoscopic hysterectomies were randomly enrolled in the study. At the end of the surgery, in study Group A 1 ml (0.3 mg) of buprenorphine and in Group B 1 ml (1 mg) of butorphanol tartrate both diluted to 10 ml with normal saline was injected through the epidural catheter. Visual analog pain scales (VAPSs) were assessed every hour till the 6(th) h, then 2(nd) hourly till the 12(th) h. To assess sedation, Ramsay sedation score was used. The total duration of postoperative analgesia was taken as the period from the time of giving epidural drug until the patients first complain of pain and the VAPS is more than 6. Patients were observed for any side effects such as respiratory depression, nausea, vomiting, hypotension, bradycardia, pruritus, and headache. RESULTS: Buprenorphine had a longer duration of analgesia when compared to butorphanol tartrate (586.17 +/- 73.64 vs. 342.53 +/- 47.42 [P < 0.001]). Nausea, vomiting (13% vs. 10%), and headache (20% vs. 13%) were more in buprenorphine group; however, sedation score and pruritus (3% vs. 6%) were found to be more with butorphanol. CONCLUSION: Epidural buprenorphine significantly reduced pain and increased the quality of analgesia with a longer duration of action and was a better alternative to butorphanol for postoperative pain relief. PMID- 26957697 TI - Assessment of suitability of i-gel and laryngeal mask airway-supreme for controlled ventilation in anesthetized paralyzed patients: A prospective randomized trial. AB - CONTEXT: Laryngeal mask airway supreme (LMA-S) has an inflatable cuff while i-gel has a noninflatable cuff made of thermoplastic elastomer. AIMS: To study the efficacy of ventilation and the laryngeal seal pressures (LSPs) with either device. Our secondary objectives were to compare the ease of insertion, adequacy of positioning the device, hemodynamic response to device insertion, and any postoperative oropharyngeal morbidity. SETTINGS AND DESIGN: A prospective, randomized, single-blinded study at Teaching Medical School in South India. MATERIALS AND METHODS: Forty-two patients posted for surgery under general anesthesia were randomly divided into two groups - LMA-S and i-gel. After a standardized premedication and anesthesia induction sequence, the supra-glottic devices were introduced. Ease of insertion was assessed from the number of attempts taken to insert, insertion time, and any maneuvers required to insert the device. Position of the device was assessed by the ease of gastric catheter placement and the fibreoptic grading of laryngeal visualization. Efficacy of ventilation was determined from the LSP, peak inspiratory pressure (PIP), and end tidal carbon dioxide (EtCO2)values. Any postoperative oropharyngeal morbidity was also recorded. STATISTICAL ANALYSIS: Descriptive analysis was reported as a mean and standard deviation, median, and range of continuous variables. Demographics were analyzed using a unpaired t-test for parametric data and Chi-square test for nonparametric data. Respiratory and hemodynamic data was analyzed using one-way ANOVA to find statistical difference within and between the two groups. RESULTS: LMA-S was successfully inserted in 95% of patients and i-gel in 85.5% of patients. There was a significant difference (P = 0.021) in the LSPs between the two groups (18.15 cmH2O in LMA-S and 21.28 cmH2O in the i-gel group). There was no significant difference in the PIPs, leak fraction, and the EtCO2values. CONCLUSION: Both devices are suitable for positive pressure ventilation (PPV) in anesthetized paralyzed patients. However, i-gel gives a better laryngeal seal when compared to LMA-S and may be chosen preferentially for PPV. PMID- 26957698 TI - Comparative study of hyoscine doses as antisialagogue for patients receiving ketofol sedation undergoing colonoscopy procedures. AB - OBJECTIVE: To compare the effects of different regimens of hyoscine as antisialagogue in patients undergoing ketofol sedation for colonoscopy procedures. PATIENTS AND METHODS: In this prospective double-blind randomized controlled trial 200 American Society of Anesthesiologists I-II aged 20-60-year old undergoing colonoscopy were randomly assigned into four equal groups, group A received 5 mg hyoscine intravenous, group B received 10 mg, group C received 20 mg intravenous, and control group (D) that was received saline. All patients were sedated using ketofol titrated to achieve Ramsey Sedation Score 4, hemodynamic variables and occurrence of increased secretions were evaluated and recorded. RESULTS: Hyoscine in a dose of 10 mg was the optimum dose to achieve least salivation with the least side effect while hyoscine 5 mg was not efficient to achieve dry field or good surgical conditions. However, hyoscine 20 mg achieved dry field and fair surgical conditions in expenses of tachycardia. CONCLUSION: Hyoscine 10 mg was the least effective dose that significantly reduced hypersalivation in patients receiving ketofol sedation for colonoscopy procedures, this dose was as effective as 20 mg in draying secretion but with significantly less tachycardia. PMID- 26957699 TI - Arousal from sedation in lower abdominal surgeries under spinal anesthesia: Comparison between dexmedetomidine and clonidine. AB - BACKGROUND AND AIM: Dexmedetomidine and clonidine are commonly used drugs for sedation during regional anesthesia. However, data regarding arousal time from sedation with these drugs is sparse. Hence, we designed a study to compare arousal time from sedation with dexmedetomidine and clonidine during spinal anesthesia. We also tried to find out the correlation between clinical and objective method used for assessing the depth of sedation. MATERIALS AND METHODS: In this study, 120 patients were randomly assigned in two groups to receive either dexmedetomidine (Group DE, n = 60) or Clonidine (Group CL, n = 60). Group DE received 1 MUg/kg of dexmedetomidine followed by infusion at 0.5 MUg/kg/h while Group CL received 1 MUg/kg of clonidine followed by infusion at 1 MUg/kg/h and titration until targeted Ramsay sedation scale (RSS) score of 3-5 was achieved and maintained. RSS and bispectral (BIS) were monitored until arousal of the patients. The time to achieve RSS of 2 and BIS of 90 during recovery, the correlation between BIS and RSS score in both the study groups and duration of postoperative analgesia were noted. STATISTICAL ANALYSIS USED: Chi-square tests for nonparametric data and Student's t-test for parametric data were used. Correlation between RSS and BIS was calculated with spearman correlation method. RESULTS: Arousal time from sedation and time to reach BIS score 90 was lower for Group DE as compared to Group CL (P = 0.001). Dexmedetomidine also increased the time to first postoperative analgesic request when compared with clonidine (198.23 +/- 33.15 min vs. 150.65 +/- 28.55 min, P = 0.01). CONCLUSIONS: Intravenous dexmedetomidine infusion has shorter arousal time from sedation than clonidine during spinal anesthesia. A strong correlation exists between BIS and RSS during recovery from sedation. PMID- 26957700 TI - Intraoperative wide bore nasogastric tube knotting: A rare incidence. AB - Nasogastric tubes are commonly used in anesthetic practice for gastric decompression in surgical patients intraoperatively. The indications for its use are associated with a number of potential complications. Knotting of small-bore nasogastric tubes is usually common both during insertion and removal as compared to wide bore nasogastric tubes. Knotting of wide bore nasogastric tube is a rare complication and if occurs usually seen in long standing cases. We hereby report a case of incidental knotting of wide bore nasogastric tube that occurred intraoperatively. PMID- 26957701 TI - Anesthetic management of a rare case of extra-adrenal pheochromocytoma. AB - Anesthetic management of pheochromocytoma is complicated and challenging. Extra adrenal pheochromocytoma is a rare neuroendocrine tumor that produces, stores and secretes catecholamines. The main-stay in the management of pheochromocytoma surgeries is Preoperative preparation which has improved perioperative outcome. Modern anesthetic drugs with advanced monitoring have contributed to intraoperative stability. Resection of the tumor results in acute withdrawal of catecholamines, which may lead to severe hypotension. In perioperative period, adequate hydration should be maintained. Beta-blockers, nitroglycerine, sodium nitroprusside and phenylephrine are required to avoid hemodynamic fluctuations and should be used appropriately. PMID- 26957702 TI - Obstetric hemorrhage in a case of hypertrophic obstructive cardiomyopathy with automatic implantable cardioverter defibrillator: Anaesthesia and intensive care management. AB - The physiological changes occurring during pregnancy and labor may reveal or exacerbate the symptoms of hypertrophic obstructive cardiomyopathy (HOCM). The addition of obstetric hemorrhage to this presents a unique challenge to the anesthesiologists and intensivists managing these patients in the operation theatres and the Intensive Care Units. Here we present a case of HOCM with automatic implantable cardioverter defibrillator in situ and postpartum hemorrhagic shock. PMID- 26957703 TI - Role of anesthesiologist in managing a rare case of homicidal cut-throat injury. AB - Management of homicidal cut-throat injuries requires a multi-disciplinary approach. The role of an anesthesiologist in instituting an airway using an endotracheal intubation or tracheostomy before wound exploration and repair of transected tissues, is challenging, as, such injuries are most of the time associated with distortion of the normal anatomy of the airway. We hereby report a case of 60-year-old lady diagnosed as homicidal cut-throat injury with vocal cords exposed externally and injury of thyroid cartilage and pharyngeal muscles. Patients with cut-throat injury may present with airway compromise, aspiration, and acute blood loss with hypoxemia because of injury to the airway and major vessels. Securing an airway becomes the first priority in patients with cut throat injuries. It could be done by an endotracheal intubation, cricothyroidotomy, or by an emergency tracheostomy. For the effective management of patients with a cut-throat injury, there is a need for a multidisciplinary approach by a team consisting of an otorhinolaryngologist, anesthesiologist, and a psychiatrist. PMID- 26957704 TI - Anesthetic management of staged thoracoscopic repair of bilateral eventration of diaphragm in a neonate. AB - Congenital eventration of the diaphragm is a rare disorder, the perioperative management of which is challenging. The introduction of thoracoscopic repair of these defects has considerably reduced the perioperative morbidity and mortality in these patients. In spite of the advantages of thoracoscopy which include smaller chest incisions, reduced postoperative pain, and more rapid postoperative recovery compared with thoracotomy, it is still inherent with complications unique to it. A clear understanding of the pathophysiologic changes, potential complications and institution of appropriate monitoring and good planning is essential for the safe conduct of thoracoscopic procedures in neonates. We describe the anesthetic management of staged thoracoscopic repair of bilateral congenital eventration of the diaphragm in a neonate. PMID- 26957705 TI - Case report on effective cardiopulmonary resuscitation in a pregnant woman. AB - The management of cardiac arrest in pregnancy is an important task for the emergency physicians. Some reasons for cardiac arrest are reversible and should be recognized and managed promptly. Cardiopulmonary resuscitation follows general advanced cardiac life support guidelines with several modifications for pregnant women, taking into account the lives of both mother and fetus. Here, we present the case of 23-year-old pregnant patient who came to Guru Nanak Dev Hospital, Amritsar; in shock, had a cardiac arrest, successfully resuscitated in Intensive Care Unit (ICU), delivered by emergency cesarean section and was discharged from ICU on 9(th) day in healthy state. PMID- 26957706 TI - Anesthetic management for magnetic resonance imaging in a pediatric patient addicted to palm wine: An alcoholic beverage. AB - The incidence of drug and alcohol abuse is on rise despite increasing awareness and education about health hazards related to it. Anesthesiologist may come across patients with alcohol abuse in elective as well as emergency situations. We report a rare case of excessive requirement of anesthetics in a pediatric patient of only six years for MRI, addicted to palm wine, an alcoholic beverage created from the sap of various species of palm tree. PMID- 26957707 TI - Case series on anesthesia for video-assisted thoracoscopic surgery for congenital diaphragmatic hernia in children. AB - Video-assisted thoracoscopic surgery (VATS) in the pediatric population is a challenging task for any anesthesiologist, moreover considering the high incidence of associated congenital anomalies which are individual predictors of poor prognosis. A thorough preoperative evaluation, knowledge of the physiology of one lung ventilation - pertaining to various methods of lung isolation, individualized meticulous planning, and continuous vigilance to detect any untoward event at the earliest with good communication between the anesthesiology and surgical teams contributes to a safe and successful surgery. We present a case series of anesthetic management of congenital diaphragmatic hernia with VATS. PMID- 26957708 TI - A modified submental orotracheal intubation. AB - In patients with concomitant occurrence of maxillofacial and basilar skull fractures, open reduction and internal fixation is the treatment. It requires intermittent intra operative dental occlusion which precludes oral or nasal intubation. In such cases submental intubation (SMI) is a recognized technique in practice. We describe a modified technique for smooth exteriorization of the endotracheal tube (ETT) during SMI. As the SMI technique is unusual for the performer, emphasis is laid on the applied aspects to minimize probable complications during the procedure. With the modified technique we performed SMI uneventfully on five patients. PMID- 26957709 TI - Acute normovolemic hemodilution to avoid blood transfusion during intracranial aneurysm surgery in a patient with atypical antibodies. AB - Acute normovolemic haemodilution (ANH) has been used in neurosurgical operations to reduce the incidence of homologous blood transfusions. We report a case of anterior communicating artery aneurysm in a patient with atypical antibodies in the serum, who was posted for clipping of the said aneurysm, and was managed with ANH in the perioperative period in order to avoid blood transfusions. PMID- 26957710 TI - Rosai-Dorfman's disease presenting as vallecular mass: An anesthetic overview. AB - Rosai-Dorfman's disease (RDD) is a rare multisystemic histiocytic disorder, commonly presenting as cervical lymphadenopathy in a young male. Its extranodal form is very unusual. We report a case of extranodal RDD presenting as a large vallecular mass. Management of an airway mass is always a challenge to the anesthesiologist. This problem is accentuated when the mass is due to RDD, as RDD can involve multiple system of the body such as central nervous system, upper respiratory tract, orbit and eyelid, gastrointestinal tract, and skin. Autoimmune phenomenon though rare is also an important concern. Individualized plan based upon thorough evaluation and anticipation is the key for better outcome. PMID- 26957711 TI - Leg amputation: A rare complication of intra-aortic balloon pump. AB - Intra-aortic balloon pump (IABP) is a bridge to definitive management in a patient with compromised systolic function. It is a life-saving mechanical support to the failing myocardium. It is a procedure that should be employed judiciously with utmost caution. In this correspondence, we aim to highlight a rather serious complication associated with IABP use. A patient with triple vessel disease was posted for coronary artery bypass grafting with poor left ventricular function (ejection fraction 30%) and previous myocardial infarction 4 months back. An IABP was inserted in the left femoral artery following which he developed irreversible ischemia of the left lower limb leading to amputation of the limb. This catastrophic complication is one of the most dreaded impediments in the use of IABP. The clinician needs to weigh the pros and cons carefully and employ this vital procedure only when its use is explicitly justified. PMID- 26957712 TI - Intraoperative tumor lysis syndrome in a child with Wilms' tumor. AB - Tumor lysis syndrome in an onco-metabolic emergency resulting from massive lysis of rapidly proliferating malignant cells seen commonly in patients with hematological malignancies such as acute lymphocytic leukemia and Burkitt's lymphoma and is quite rare in solid tumors. Spontaneous development of tumor lysis has been described among other trigger factors such as corticosteroid therapy, anesthesia, tumor manipulation during surgery and pyrexia. We describe such a case in a 5-year-old boy posted for excision and staging of a massive Wilms' tumor who developed a hyperkalemic cardiac arrest during the procedure and its subsequent intraoperative and postoperative management. Intraoperative cardiac arrest is a stressful situation for both the anesthesiologist and the surgeon, more so when it involves a child. The aim of this report is to make the anesthesiologist aware of the possibility and occurrence of such a phenomenon in children and be adequately prepared for such an emergency. PMID- 26957713 TI - Neonate with hypoglycemia for pancreatectomy: Anesthetic challenge. AB - Persistent hyperinsulinemic hypoglycemia of infancy (PHHI) is rare and an important cause of hypoglycemia in neonates. It can lead to brain damage or death secondary to severe hypoglycemia. We present the anesthetic management in a diagnosed case of PHHI in an 8-day-old male neonate for total pancreatectomy. PMID- 26957714 TI - An account of the anesthetist's vigilance and prevention of adversity during donor nephrectomy. AB - Here, we present the case of a 42 year old female patient, ASA1 and donor for renal transplant surgery of her husband. The pre-anesthesia visit did not reveal any co-morbidity on history and the physical examination was also within normal limits. The patient was taken to the operating room and routine monitoring in the form of non-invasive blood pressure (NIBP), SpO2 probe and five lead electrocardiogram were applied. Anesthesia was induced with midazolam 1mg intravenous (i/v), fentanyl 100 MUg i.v, propofol 100mg i/v and vecuronium bromide 5 mg. i/v. At the end of surgery, anesthesia was reversed and breathing attempts were observed. Suddenly the monitor displayed a drop in the ETCO2 to 5-6 mmHg. Immediately the ventilator circuit was checked which was found to be in place and on chest auscultation, bilateral equal air entry was heard. Sudden bradycardia with heart beat dropping to 32 beats per minute and a blood pressure reading of 90/50 mmHg was displayed on the monitor. Surgeons were informed about the possibility of an intra-abdominal bleed. On surgical exploration, the renal artery pedicle ligature was found to have slipped away resulting in torrential amount of bleeding. The bleeder having been identified was secured and a complete inspection of other possible bleeding sites was done. Post operatively, the patient was shifted to the intensive care unit with inotropic support. It was decided to keep the patient mechanically ventilated on volume control mode of ventilation. The patient remained stable on post-operative day 5, the patient was shifted to the ward. PMID- 26957715 TI - Postoperative pulmonary complication after neurosurgery: A case of unilateral lung collapse. AB - Pulmonary complications, especially postoperative pulmonary complications, are an important cause of morbidity and mortality in neurosurgical patients. Hypoxemia due to mucus plug causing lung collapse is a rare event. We report a case of a 40 year-old female with right cerebellopontine angle space occupying lesion, scheduled for elective craniotomy and tumor excision. The patient underwent surgery uneventfully and was shifted to Intensive Care Unit (ICU) for monitoring. Eight hours after extubation, she developed hypoxemia due to mucus plug resulting in left lung collapse. She was intubated, and mucus plug was aspirated through sterile endobronchial tube suction which resulted in reexpansion of the collapsed lung. The patient was managed with postural drainage, chest physiotherapy, and antibiotics and extubated after 24 h. This type of pulmonary complication may have a catastrophic course, especially in neurosurgical patients, if not diagnosed and managed in time. PMID- 26957716 TI - Intubation by using exaggerated curve: A modification of technique for underprivileged area. PMID- 26957717 TI - Airway management in neonate with Microcuff((r)) Pediatric endotracheal tube for correction of bilateral choanal atresia. PMID- 26957718 TI - Retraction: Intrathecal dextmedetomidine to reduce shoulder tip pain in laparoscopic cholecystectomies under spinal anesthesia. AB - [This retracts the article on p. 320 in vol. 9, PMID: 26712967.]. PMID- 26957719 TI - Influence of bilevel positive airway pressure on autonomic tone in hospitalized patients with decompensated heart failure. AB - [Purpose] This study evaluated the effect of Bilevel Positive Airway (BiPAP) on the autonomic control of heart rate, assessed by heart rate variability (HRV), in patients hospitalized with decompensated heart failure. [Subjects and Methods] This prospective cross-sectional study included 20 subjects (age: 69+/-8 years, 12 male, left ventricular ejection fraction: 36 +/-8%) diagnosed with heart failure who were admitted to a semi-intensive care unit with acute decompensation. Date was collected for HRV analysis during: 10 minutes spontaneous breathing in the resting supine position; 30 minutes breathing with BiPAP application (inspiratory pressure = 20 cmH2O and expiratory pressure = 10 cmH2O); and 10 minutes immediately after removal of BiPAP, during the return to spontaneous breathing. [Results] Significantly higher values for indices representative of increased parasympathetic activity were found in the time and frequency domains as well as in nonlinear Poincare analysis during and after BiPAP in comparison to baseline. Linear HRV analysis: standard deviation of the average of all R-R intervals in milliseconds = 30.99+/-4.4 pre, 40.3+/-6.2 during, and 53.3+/-12.5 post BiPAP. Non-linear HRV analysis: standard deviations parallel in milliseconds = 8.31+/-4.3 pre, 12.9+/-5.8 during, and 22.8 +/-6.3 post BiPAP. [Conclusion] The present findings demonstrate that BiPAP enhances vagal tone in patients with heart failure, which is beneficial for patients suffering from acute decompensation. PMID- 26957720 TI - Effect of combining passive muscle stretching and whole body vibration on spasticity and physical performance of children and adolescents with cerebral palsy. AB - [Purpose] This study evaluated the immediate and short-term effects of a combination of prolonged passive muscle stretching (PMS) and whole body vibration (WBV) on the spasticity, strength and balance of children and adolescents with cerebral palsy. [Subjects and Methods] A randomized two-period crossover trial was designed. Twelve subjects with cerebral palsy aged 10.6 +/- 2.4 years received both PMS alone as a control group (CG) and a combination of PMS and WBV as an experimental group (EG). After random allocation to the trial schedules of either EG-CG or CG-EG, CG received prolonged PMS while standing on a tilt-table for 40 minutes/day, and EG received prolonged PMS for 30 minutes, followed by 10 minutes WBV. Both CG and EG received the treatment 5 days/week for 6 weeks. [Results] Immediately after one treatment, EG resulted in better improvement in scores on the Modified Ashworth Scale than CG. After the 6-week intervention, EG also showed significantly decreased scores on the Modified Ashworth Scale compared to CG. Both CG and EG showed significantly reduced the performance times in the five times sit to stand test, and EG also showed significantly increased scores on the pediatric balance scale. [Conclusion] This study showed that 6 weeks of combined prolonged PMS and WBV had beneficial effects on the spasticity, muscle strength and balance of children and adolescents with CP. PMID- 26957721 TI - Relationships of ultrasound measures of intrinsic foot muscle cross-sectional area and muscle volume with maximum toe flexor muscle strength and physical performance in young adults. AB - [Purpose] To investigate the relationships between toe flexor muscle strength with (TFS-5-toes) and without (TFS-4-toes) the contribution of the great toe, anatomical and physiological muscle cross-sectional areas (CSA) of intrinsic toe flexor muscle and physical performance were measured. [Subjects] Seventeen men (82% sports-active) and 17 women (47% sports-active), aged 20 to 35 years, volunteered. [Methods] Anatomical CSA was measured in two intrinsic toe flexor muscles (flexor digitorum brevis [FDB] and abductor hallucis) by ultrasound. Muscle volume and muscle length of the FDB were also estimated, and physiological CSA was calculated. [Results] Both TFS-5-toes and TFS-4-toes correlated positively with walking speed in men (r=0.584 and r=0.553, respectively) and women (r=0.748 and r=0.533, respectively). Physiological CSA of the FDB was significantly correlated with TFS-5-toes (r=0.748) and TFS-4-toes (r=0.573) in women. In men, physiological CSA of the FDB correlated positively with TFS-4-toes (r=0.536), but not with TFS-5-toes (r=0.333). [Conclusion] Our results indicate that physiological CSA of the FDB is moderately associated with TFS-4-toes while toe flexor strength correlates with walking performance. PMID- 26957722 TI - Efficacy of virtual reality-based balance training versus the Biodex balance system training on the body balance of adults. AB - [Purpose] This study investigated efficacy of virtual reality (VR)-based balance training on enhancing balance and postural reactions of adults as a low-cost new modality compared to the established Biodex Balance System (BBS). [Subjects] Thirty normal adults of both genders were divided randomly into two equal-sized experimental groups of 15: BBS balance training and VR balance training. [Methods] The training programmes were conducted in 12 sessions, three 15-min sessions per week. The Nintendo((r)) Wii Fit Plus (NWFP) and its balance board were used to train of the VR group. Each participant answered a questionnaire concerning usability, enjoyment, balance improvement, and fatigue at the end of the training programs. [Results] The study found a significant increase the measure of mean overall balance (OLB) in both groups. No significant difference was found between the groups, but a significant decrease in the mean balance-test time was found for both groups, with no significant difference between the two training methods. The VR programme was rated highly enjoyable by 81.8% of the group. [Conclusion] The Wii Fit Plus system with the balance board as a new VR balance-training technique, can be considered an effective and enjoyable tool for the training of adults' body balance. PMID- 26957723 TI - Application of the Blobo bluetooth ball in wrist rehabilitation training. AB - [Purpose] The introduction of emerging technologies such as the wireless Blobo bluetooth ball with multimedia features can enhance wrist physical therapy training, making it more fun and enhancing its effects. [Methods] Wrist injuries caused by fatigue at work, improper exercise, and other conditions are very common. Therefore, the reconstruction of wrist joint function is an important issue. The efficacy of a newly developed integrated wrist joint rehabilitation game using a Blobo bluetooth ball with C# software installed was tested in wrist rehabilitation (Flexion, Extension, Ulnar Deviation, Radial Deviation). [Results] Eight subjects with normal wrist function participated in a test of the system's stability and repeatability. After performing the Blobo bluetooth ball wrist physical therapy training, eight patients with wrist dysfunction experienced approximately 10 degrees improvements in range of motion (ROM) of flexion extension, and ulnar deviation and about 6 degrees ROM improvement in radial deviation. The subjects showed progress in important indicators of wrist function. [Conclusion] This study used the Blobo bluetooth ball in wrist physical therapy training and the preliminary results were encouraging. In the future, more diverse wrist or limb rehabilitation games should be developed to meet the needs of physical therapy training. PMID- 26957724 TI - The development and evaluation of a program for leg-strengthening exercises and balance assessment using Kinect. AB - [Purpose] In this study, a program was developed for leg-strengthening exercises and balance assessment using Microsoft Kinect. [Subjects and Methods] The program consists of three leg-strengthening exercises (knee flexion, hip flexion, and hip extension) and the one-leg standing test (OLST). The program recognizes the correct exercise posture by comparison with the range of motion of the hip and knee joints and provides a number of correct action examples to improve training. The program measures the duration of the OLST and presents this as the balance age. The accuracy of the program was analyzed using the data of five male adults. [Results] In terms of the motion recognition accuracy, the sensitivity and specificity were 95.3% and 100%, respectively. For the balance assessment, the time measured using the existing method with a stopwatch had an absolute error of 0.37 sec. [Conclusion] The developed program can be used to enable users to conduct leg-strengthening exercises and balance assessments at home. PMID- 26957725 TI - Factors affecting metabolic syndrome by lifestyle. AB - [Purpose] The aim of this study was to explore lifestyle factors in relation to metabolic syndrome so as to be able to utilize the results as baseline data for the furtherance of health-care and medical treatment. [Subjects and Methods] This study was conducted with patients who visited a health care center located in Seoul and had abdominal ultrasonography between 2 March 2013 and 28 February, 2014. Heights, weights, and blood pressures were measured by automatic devices. Three radiologists examined the patients using abdominal ultrasonography for gallstone diagnosis. The statuses of patients with regard to smoking, alcohol, coffee, and physical activities were explored for the lifestyle investigation. For investigating baseline demographics, we first used descriptive statistics. We then used the chi(2) test to analyze lifestyles and gallstone prevalence with regard to the presence of metabolic syndrome. Lastly, logistic regression analysis was conducted to discover the risk factors of metabolic syndrome. [Results] For men, body mass index, maximum gallstone size, and waist circumference were revealed as risk factors for metabolic syndrome, in descending order of the degree of risk. For females, gallstone presence was the most significant risk factor, followed by waist circumference. [Conclusion] Metabolic disease mainly presents itself along with obesity, and we should become more focused on preventing and treating this disease. A large-scale prospective study is needed in the future, as the cause of nonalcoholic steatohepatitis remained unclear in this study. PMID- 26957726 TI - The effects of self-mobilization techniques for the sciatic nerves on physical functions and health of low back pain patients with lower limb radiating pain. AB - [Purpose] This study aimed to examine the effects of self-mobilization techniques for the sciatic nerves on the quality of life in patients with chronic low back pain in the lower limbs accompanied by radiating pain. [Subjects and Methods] The subjects were divided into two groups: a group receiving of lumbar segmental stabilization exercise training including sciatic nerve mobilization techniques, which included 8 males and 7 females, and a group receiving lumbar segmental stabilization exercise training, which included 8 males and 7 females. [Results] There were statistically significant differences in comparison of measurement results between the groups before and after the intervention. [Conclusion] Application of mobilization techniques for the sciatic nerves may promote healing of the soft tissues by stimulating the functions of the nervous system to improve nervous system adaptability and decrease sensitivity, helping to alleviate the symptoms. PMID- 26957728 TI - Risk factors associated with musculoskeletal symptoms in Korean dental practitioners. AB - [Purpose] The purpose of this study was to investigate the association between psychosocial stress, occupational stress, and musculoskeletal symptoms in Korean dental practitioners. [Subjects and Methods] Self-reported questionnaires were distributed to 401 dental practitioners in Korea. To assess the risk factors related to musculoskeletal disorders, the Nordic Musculoskeletal Questionnaire, the Korean Occupational Stress Scale, and Psychosocial Well-Being Index Short Form were used. General and work-related characteristics of the subjects consisted of seven items, including age, career, height, weight, working days/week, working hours/day, and physical strain levels. [Results] In this study, 86.8% of the practitioners experienced musculoskeletal symptoms (shoulders, 72.8%; neck, 69.3%; waist, 68.3%; wrist, 58.4%; back, 44.1%; ankle, 38.7%; knee, 36.9%; hip, 20.4%; and elbows, 9.2%). Moreover, psychosocial and occupational stress can affect the occurrence of musculoskeletal disorders. In particular, we found that psychosocial stress has significant influence on the occurrence of musculoskeletal disorders. [Conclusion] To increase the quality of life and provide high-quality medical service for dental practitioners, risk factors for musculoskeletal disorders must be managed. Accordingly, dental practitioners must maintain good posture, get an appropriate amount of rest, and perform regular stretching exercise to reduce psychological stress and improve the work environment. PMID- 26957727 TI - Intrarater reliabilities of shoulder joint horizontal adductor muscle strength measurements using a handheld dynamometer for geriatric and stroke patients. AB - [Purpose] This study aimed to verify the appropriate number of measurements and the intrarater reliabilities of shoulder joint horizontal adductor muscle strength measurements using a handheld dynamometer (HHD) for geriatric and stroke patients. [Subjects and Methods] The subjects were 40 inpatients, who were divided into two groups: 20 stroke patients in the stroke group (SG), and 20 geriatric patients in the no-stroke group (N-SG). Measurements were performed three times using an HHD with a belt. The reliability was verified using Bland Altman analysis and the intraclass correlation coefficient (ICC). [Results] ICC (1, 1) was >0.9. A systematic bias was not observed between the first and second measurement values except for the right side in N-SG. A systematic bias between the maximum value obtained during the first and second measurements and third measurement value was observed on the left side in N-SG, and on the non-paralyzed side in SG: the third measurement values were small in both cases. [Conclusion] Intrarater reliabilities were high for shoulder horizontal adductor strength measurements using an HHD with a belt for geriatric and stroke patients. Taking the systematic bias into consideration, these findings suggest that the required number of measurements is two. PMID- 26957729 TI - The effects of kinesiology taping therapy on degenerative knee arthritis patients' pain, function, and joint range of motion. AB - [Purpose] The purpose of the present study was to examine the effects of kinesiology taping therapy on degenerative knee arthritis patients' pain, function, and joint range of motion. [Subjects] To conduct the experiment in the present study, 30 patients with degenerative knee arthritis were divided into a control group (the conservative treatment group) of 15 patients, who received conservative physical therapy, and an experimental group (the kinesiology taping group) of 15 patients, who received kinesiology taping therapy. [Methods] All patients received treatment three times per week for four weeks. The kinesiology taping group had elastic tapes applied to the hamstring muscles, anterior tibialis, quadriceps femoris, and gastrocnemius. The range of motion was measured using joint goniometers, pain was measured using visual analog scales, and functional evaluation was conducted using the Korean Western Ontario and McMaster Universities Osteoarthritis Index. [Results] In intragroup comparisons of the kinesiology taping group and the conservative treatment group, the visual analog scale and Korean Western Ontario and McMaster Universities Osteoarthritis Index scores significantly decreased, and the range of motion increased more than significantly. In intergroup comparisons, the kinesiology taping group showed significantly lower visual analog scale and Korean Western Ontario and McMaster Universities Osteoarthritis Index scores and significantly larger ranges of motion than the conservative treatment group. [Conclusion] Kinesiology taping therapy is considered to be an effective nonsurgical intervention method for pain relief, daily living activities, and range of motion of degenerative knee arthritis patients. PMID- 26957730 TI - Impact of the difference in surgical site on the physique in gastrointestinal tract cancer patients. AB - [Purpose] The purpose of the present study was to observe physical function, physique (only BMI), and nutrition status (evaluated by serum albumin levels) from before surgery to after discharge among perioperative patients with gastrointestinal tract cancer and to examine the effect of difference in surgical site (i.e., stomach, colon, and rectum) in these patients. [Subjects and Methods] The study subjects were 70 patients who underwent surgical treatment for gastrointestinal tract cancer [36 males and 34 females, aged 59.3 +/- 11.4 years (mean +/- SD)]. The subjects were classified into three levels according to surgical site (stomach, colon, and rectum). We evaluated patients' physical function, physique, and nutrition status in the three points: before surgery, after surgery, and after discharge. The 6-minute walk distance was measured for physical function. Body mass index was measured for physique. The serum albumin level was measured for nutrition status. [Results] Significant declines in 6 minute walk distance, body mass index, and serum albumin were observed after surgery among the study subjects. In addition, a significant decline in body mass index was observed after discharge compared with before surgery. Regarding body mass index, a significant interaction between surgical site and evaluation times was observed for ANOVA. [Conclusion] These results suggest that BMI after discharge is significantly less than that before surgery and that body mass index changes from before surgery to after surgery are efficacy the difference of surgical site in patients who undergo surgical treatment for gastrointestinal tract cancer. PMID- 26957731 TI - The influence of the stomatognathic system on explosive strength: a pilot study. AB - [Purpose] Recent findings suggest there is an interesting interaction between the stomatognathic system and the musculoskeletal system. The aim of this study was therefore to examine the influence of the temporomandibular joint on the explosive strength of the lower limbs. [Subjects and Methods] An observational study was carried out. The subjects were 60 male football players who voluntarily participated in the investigation. After a warm-up phase of 10 minutes, each participant performed three Squat Jumps (SJ) with different mandible positions: mouth closed and mouth open. SJ heights were recorded using a Sensor Medica force platform and the FreeMed system. [Results] Sixty participants were enrolled in this study (age: 24 +/- 7 yrs; height: 174 +/- 4.6 cm; weight 63.7 +/- 7.6 kg). The SJ heights with the mouth closed, 38.50 +/- 4.0 cm, were shorter than those with the mouth open, 40.4 +/- 4.1 cm. Statistical analysis showed there was a statistically significant difference between the performances. [Conclusion] This pilot study highlighted that occlusal factors can influence physical performance and this could have practical applications in sports and exercise science. However, our results have to be confirmed in studies with larger numbers of participants and supported by other investigations. PMID- 26957732 TI - Effect of low frequency transcutaneous electrical nerve stimulation of TE5 (waiguan) and PC6 (neiguan) acupoints on cold-induced pain. AB - [Purpose] This study assesse the effect of low frequency transcutaneous electrical nerve stimulation (TENS) of theTE5 (waiguan) and PC6 (neiguan) acupoints on cold-induced pain. [Subjects and Methods] Forty-eight subjects were divided by convenience into three groups: TENS with electrodes of 1 cm(2) area, TENS with electrodes of area 15 cm(2) and a placebo group. The study consisted of three phases: cold-induced pain without electroanalgesia, cold-induced pain with electroanalgesia or placebo, and cold-induced pain post-electroanalgesia or placebo. [Results] Acupuncture like TENS increased the pain threshold latency during treatment (45.7 +/- 11.7s) compared to pre-treatment (30.9 +/- 8.9s) in the TENS group with 1 cm(2) electrodes. In the TENS group with 15 cm(2) electrodes, the pain threshold latency increased at post-treatment (36.2 +/- 12.9s) compared to pre-treatment (25.5 +/- 7.4s). The placebo group showed no significant changes. The group with 1 cm(2) electrodes showed a significantly higher pain threshold latency (45.7 +/- 11.7s) than the other two groups. At post treatment, the pain threshold latencies of both the 1 cm(2) (39.4 +/- 11.5s) and 15 cm(2) (36.2 +/- 12.9s) TENS group were higher than that of the placebo group (22.4 +/- 7.4s). [Conclusion] Acupuncture like TENS applied to PC6 and TE5 acupoints increased the pain threshold latency. The pain intensity was reduced by TENS with an electrode area of 1 cm(2). PMID- 26957733 TI - The effects of multidirectional stepping training on balance, gait ability, and falls efficacy following stroke. AB - [Purpose] The purpose of this study was to determine whether a multidirectional stepping training improves balance, gait ability, and falls efficacy in stroke patients. [Subjects] Firty patients who met the selection criteria and agreed to participate in research at hospital N were randomly allocated and enrolled in this study. Twenty of the subjects were assigned to an experimental group that participated in combined stepping exercise, and the other twenty subjects were assigned to a control group that received general physical therapy. [Methods] In the two groups, balance was measured using the Berg Balance Scale, gait ability was measured using the 10-m Walk Test, and falls efficacy was measured using the Falls Efficacy Scale before training and after 6 weeks of training. [Results] Comparative analysis of the experimental group's pretest and post-test results showed statistically significant differences in the Berg Balance Scale, 10-m Walk Test, and Falls Efficacy Scale scores. There were significant between-group differences in the Berg Balance Scale, 10-m Walk Test, and Falls Efficacy Scale scores. [Conclusion] The results suggest that a combined stepping exercise can be an effective intervention to improve the balance, gait ability, and falls efficacy in stroke patients. PMID- 26957734 TI - Effects of increased standing balance on pain in patients with knee osteoarthritis. AB - [Purpose] The purpose of this study was to examine the relationship between standing balance increased through muscle-strengthening exercises and pain in knee osteoarthritis patients. [Subjects and Methods] Thirty knee osteoarthritis patients were equally divided into a strengthening exercise group and an unstable exercise group. Before and after the six-week experiment, the visual analogue scale was measured, and bilateral one-leg standing tests were performed. [Results] In both the strengthening exercise group and unstable exercise group, the bilateral one-leg standing time significantly increased after the six-week experiment. Regarding the visual analogue scale, a pain measurement scale, the strengthening exercise group had significantly decreased pain. The unstable exercise group also had decreased pain, but the decrease was not statistically significant. [Conclusion] In knee osteoarthritis patients, exercises using an unstable base of support and knee-extensor strengthening exercises with gradually increased loads had a positive effect on improving balance ability and decreasing pain. PMID- 26957735 TI - Effect of neck flexion restriction on sternocleidomastoid and abdominal muscle activity during curl-up exercises. AB - [Purpose] The purpose of this study was to investigate the effect of neck flexion restriction on sternocleidomastoid (SCM), rectus abdominis (RA), and external oblique (EO) muscle activity during a traditional curl-up exercise and a curl-up with neck flexion restriction. [Subjects] In total, 13 healthy male subjects volunteered for this study. [Methods] All subjects performed a traditional curl up exercise and a curl-up exercise in which neck flexion was restricted by the subject's hand. Surface electromyography (EMG) signals were recorded from the SCM, RA, and EO during the curl-up. [Results] There was significantly lower EMG activity of the SCM during the curl-up exercise with neck flexion restriction compared to the traditional curl-up exercise. Conversely, the activity of the RA and EO muscles was significantly higher in the curl-up exercise with neck flexion restriction than in the traditional curl-up exercise. [Conclusion] Neck flexion restriction is recommended to prevent excessive activation of superficial cervical flexors during the curl-up exercise. PMID- 26957736 TI - Effect of wearing tight pants on the trunk flexion and pelvic tilting angles in the stand-to-sit movement and a seated posture. AB - [Purpose] The purpose of this study was to evaluate the effect of wearing the tight pants on the trunk flexion and pelvic tilting angles in the stand-to-sit movement and a seated posture. [Subjects] Nine male subjects were recruited. [Methods] The trunk flexion angle and pelvic posterior tilting angle were measured using a motion-capture system during the stand-to-sit movement and in a seated posture. [Results] The trunk flexion and the posterior pelvic tilting angles during the stand-to-sit movement and in the seated posture when wearing tight pants significantly increased compared with those when wearing of general pants. [Conclusion] Therefore, wearing tight pants could produce musculoskeletal disorders via abnormal movement and posture in the lumbar spine and pelvis. So the effects of wearing tight pants need to be investigated in further studies to reveal their direct relationship to musculoskeletal problems. PMID- 26957737 TI - The effects of central post-stroke pain on quality of life and depression in patients with stroke. AB - [Purpose] The aim of this study was to assess the effects of central poststroke pain on quality of life, functionality, and depression in stroke. [Subjects and Methods] Twenty-four patients with stroke having central poststroke pain (a mean age of 60.6+/-8.5 years; 14 males, 10 females; Group I) and 24 similar age-and gender-matched patients with stroke without central poststroke pain (Group II) were enrolled. Characteristics of pain were recorded in patients with stroke having central poststroke pain. The Visual Analogue Scale and Leeds Assessment of Neuropathic Symptoms and Signs pain scale were used to evaluate pain. The Functional Independence Measure was used to assess functionality, the 36-Item Short-Form Health Survey was used to assess quality of life (QoL), and the Beck Depression Inventory was used to assess depression. [Results] There were no significant differences in Functional Independence Measure and Beck Depression Inventory. Some of the 36-Item Short-Form Health Survey domains (physical role limitations, pain, and physical scores) in Group II were significantly higher than those in Group I. Additionally, we found that a unit increase in Leeds Assessment of Neuropathic Symptoms and Signs score led to 0.679 decrease in physical score and 0.387 decrease in mental score. [Conclusion] The physical component of the 36-Item Short-Form Health Survey is negatively affected in patient with central poststroke pain, but the mood and mental components of the scale unaffected. PMID- 26957739 TI - Effects of inspiratory muscle training on balance ability and abdominal muscle thickness in chronic stroke patients. AB - [Purpose] This study evaluated the effects of inspiratory muscle training on pulmonary function, deep abdominal muscle thickness, and balance ability in stroke patients. [Subjects] Twenty-three stroke patients were randomly allocated to an experimental (n = 11) or control group (n = 12). [Methods] The experimental group received inspiratory muscle training-based abdominal muscle strengthening with conventional physical therapy; the control group received standard abdominal muscle strengthening with conventional physical therapy. Treatment was conducted 20 minutes per day, 3 times per week for 6 weeks. Pulmonary function testing was performed using an electronic spirometer. Deep abdominal muscle thickness was measured by ultrasonography. Balance was measured using the Berg balance scale. [Results] Forced vital capacity, forced expiratory volume in 1 second, deep abdominal muscle thickness, and Berg balance scale scores were significantly improved in the experimental group than in the control group. [Conclusion] Abdominal muscle strengthening accompanied by inspiratory muscle training is recommended to improve pulmonary function in stroke patients, and may also be used as a practical adjunct to conventional physical therapy. PMID- 26957738 TI - Postural control systems in two different functional movements: a comparison of subjects with and without chronic ankle instability. AB - [Purpose] The aim of this study was to evaluate postural control during two different movements of the Functional Movement Screen in patients with chronic ankle instability compared with healthy subjects. [Subjects] This study was a cross-sectional survey of 50 participants comprised of 25 chronic ankle instability patients and 25 healthy subjects. [Methods] All subjects were subjected to measurement of the Foot and Ankle Disability Index and center of pressure and Functional Movement Screen testing. The deep squat and hurdle step were performed for the lower extremities in Functional Movement Screen testing. Then, the center of pressure was measured with balance assessment software using a Nintendo Wii Balance Board. The center of pressure path length, velocity, and area of the 95% confidence ellipse and Functional Movement Screen scores were evaluated for all subjects. [Results] The results showed significant differences in center of pressure path length, velocity, and area of the 95% confidence ellipse between the groups for the hurdle step with the non-affected limb. However, there were no significant differences between groups for the deep squat and hurdle step with the affected limb. [Conclusion] The results of this study showed that there was a difference in the hurdle step with the non-affected limb in chronic ankle instability patients compared with normal subjects. PMID- 26957740 TI - The perception of physical therapy leaders in Saudi Arabia regarding physical therapy scope of practice in primary health care. AB - [Purpose] To explore the views of the physical therapy service leaders in Saudi Arabia regarding the integration of physical therapy service in primary health care settings. [Subjects and Methods] A self-administered questionnaire consisting of both open and closed ended questions was distributed during May July 2013 via email to physical therapy leaders representing different regions and health care providers in Saudi Arabia. [Results] Twenty-six participants answered the questionnaire. Eighty five percent of the sample had >= 10 years of experience with 57.6% of them holding a post-graduate degree. Participants were from different health care providers and represented different geographical regions of Saudi Arabia. Eighty one percent of the sample reported that the adoption of physical therapy services in primary health care would be advantageous, as it would offer earlier access to health care and would be more cost-effective. The respondents also stated that such a service would contribute towards the prevention of common non-communicable health diseases. [Conclusion] The results of this survey provide generally positive recommendations for the provision of physical therapy service in Saudi Arabia primary health care centers. However, challenges and barriers identified by this study require consideration during the development of the service. PMID- 26957741 TI - Effects of topical oxygen therapy on ischemic wound healing. AB - [Purpose] This study evaluated the effects of topical oxygen therapy on the hind limb wounds of rats under ischemic conditions. [Subjects and Methods] Twelve injured rats were treated with topical oxygen on skin wounds located on the hind limb and compared with twelve injured control rats. Indexes including gross morphology of the wound, wound healing time, wound healing rate, and histological and immunohistochemical staining of sections of wound tissue were examined at different time points after intervention. [Results] The wound healing time was shorter in the topical oxygen therapy group than the control group. The wound healing rate and granulation tissue formation in the topical oxygen therapy group showed significant improvement on days 3, 7, and 14. Through van Gieson staining, the accumulation of collagen fiber in the topical oxygen therapy group was found to have improved when compared with the control group on day 7. Through semiquantitative immunohistochemical staining, many more new vessels were found in the topical oxygen therapy group compared with the model control group on day 7. [Conclusion] The results of the experiment showed that topical oxygen therapy improved ischemic wound healing. PMID- 26957742 TI - The influence of antagonist muscle electrical stimulation on maximal hip adduction force. AB - [Purpose] The aim of this study was to determine whether electrical stimulation of the tensor fascia lata muscle decreases voluntary maximum resistance to passive abduction motion in participants without disease of the central nervous system. [Subjects] The participants were 16 healthy men. [Methods] The hip joint was moved from 10 degrees adduction to 0 degrees adduction with an angular velocity of 7 degrees /s. During the passive leg motion, the subject was asked to resist the motion with maximum force. Two experimental conditions were prepared: (1) electrical stimulation provided to the tensor fascia lata muscle during the passive motion; and (2) no electrical stimulation provided. [Results] The force was 10.2 +/- 3.5 kgf with electrical stimulation and 12.2 +/- 3.8 kgf without electrical stimulation. [Conclusion] The results suggested that the maximum hip adduction force decreased in participants because of electrical stimulation of the tensor fascia lata muscle. PMID- 26957743 TI - Effects of forward head posture on forced vital capacity and respiratory muscles activity. AB - [Purpose] This study investigated the effects of forward head posture on forced vital capacity and deep breathing. [Subjects] Twenty-six subjects, divided into the two groups (normal and forward head posture groups), participated in this study. [Methods] Forced vital capacity and forced expiratory volume in 1 second were measured using respiratory function instrumentation that met the American Thoracic Society's recommendation for diagnostic spirometry. Accessory respiratory muscle activity during deep breathing was measured by electromyography. A Mann-Whitney test was used to compare the measure variables between the normal and forward head posture group. [Results] Forced vital capacity and forced expiratory volume in 1 second were significantly lower in the forward head posture group than in the normal group. Accessory respiratory muscle activity was also lower in the forward head posture group than in the normal group. In particular, the sternocleidomastoid and pectoralis major activity of the forward head posture group was significantly lower than that of normal group. Activities of the other muscles were generally decreased with forward head posture, but were not significantly different between the two groups. [Conclusion] These results indicate that forward head posture could reduce vital capacity, possibly because of weakness or disharmony of the accessory respiratory muscles. PMID- 26957744 TI - Comparison of the thoracic flexion relaxation ratio and pressure pain threshold after overhead assembly work and below knee assembly work. AB - [Purpose] The purpose of this study was to compare the thoracic flexion relaxation ratio following overhead work and below-knee work. [Subjects and Methods] Ten men (20-30 years) were recruited to this study. The thoracic flexion relaxation ratio and pressure pain threshold was measured after both overhead work and below-knee work. [Results] The pressure-pain thresholds of the thoracic erector spinae muscle decreased significantly from initial, to overhead, to below knee work. Similarly, the thoracic flexion relaxation ratio decreased significantly from initial, to overhead, to below-knee work. [Conclusion] Below knee work results in greater thoracic pain than overhead work. Future studies should investigate below-knee work in detail. This study confirmed the thoracic relaxation phenomenon in the mid-position of the thoracic erector spinae. PMID- 26957745 TI - Contents of supervision needed by physical and occupational therapists for ability development: focusing on their clinical experience. AB - [Purpose] This study examined the contents of supervision needed by novice therapists to develop clinical abilities, focusing on their clinical experience and using an original evaluation table. [Subjects and Methods] An evaluation of clinical abilities basic attitudes, therapeutic skills, and clinical practice related thoughts was conducted in 29, 21, and 9 therapists with clinical experience of 0-1 (1 year group), 1-2 (2 years group), and 2-3 (3 years group) years, respectively. [Results] There were no significant differences among the 3 groups in basic attitudes. Therapeutic skills markedly varied between the 1 and 3 years groups. In clinical practice-related thoughts, significant differences were observed between the 1 and 3 years groups and between the 2 and 3 years groups. [Conclusion] It may be appropriate for educators to provide technical education regarding skills that are achievable for students in the early stages in consideration of applied movements. Also, education for novices should be provided with importance attached to abilities influenced by clinical experience. PMID- 26957746 TI - Association between the physical activity level and the quality of life of patients with type 2 diabetes mellitus. AB - [Purpose] Physical activity and regular exercise play an important role in glycemic control, which is considered an important part of the treatment of type 2 diabetes mellitus. This study evaluated physical activity level and its relationship with quality of life in patients with type 2 diabetes mellitus. [Subjects and Methods] We evaluated 129 subjects with type 2 diabetes mellitus through a face-to-face interview using the short version of the International Physical Activity Questionnaire and Diabetes-39. Demographic data, diabetes symptoms, time of initial diagnosis, and treatment procedure/approaches were recorded. [Results] Of the study subjects, 51 (39.5%) had low, 67 had moderate (51.9%), and 11 (8.5%) had high activity levels. The mean weekly sitting duration was 302 minutes. The mean weekly walking time was 231.7 minutes. Except for the "diabetes control" domain, scores for all the subgroups and the total score in the quality-of-life assessment had a statistically significant negative correlation with physical activity level. [Discussion] Physical inactivity negatively affects the quality of life of diabetic patients. A planned exercise education program and incorporation of exercise into the lifestyle can improve the quality of life of patients with type 2 diabetes mellitus. PMID- 26957747 TI - Driving Trail Making Test part B: a variant of the TMT-B. AB - [Purpose] The Trail Making Test part B (TMT-B) is used in evaluating driving abilities and includes testing for the executive function. A driving simulator version of this test (DTMT-B) was developed to measure drivers' executive abilities in three-dimensional space. The purpose of the present study was to assess the validity of the DTMT-B for driving assessment. [Subjects] Thirty stroke patients and 65 healthy subjects were recruited. [Methods] Participants performed the TMT-B and DTMT-B. The DTMT-B was run on a driving simulator in which the individual performed a task on virtual roads connecting the lettered and numbered TMT-B points by simulated driving instead of connecting them with lines as in the paper or computerized TMT-B. Intra-class correlation coefficients (ICCs) were used to assess validities. Significant correlations were found between the TMT-B and DTMT-B. [Results] Participants performed the TMT-B and DTMT B. Intra-class correlation coefficients (ICCs) were used to assess validities. Significant correlations were found between the TMT-B and DTMT-B. [Conclusion] The results suggest that the DTMT-B may be useful as part of driver screening assessment using a driving simulator for stroke patients and that it may also be used to assess the executive functions for healthy people. PMID- 26957748 TI - Electromyographic analysis of the infraspinatus and scapular stabilizing muscles during isometric shoulder external rotation at various shoulder elevation angles. AB - [Purpose] This study aimed to clarify activation of the infraspinatus and scapular stabilizing muscles during shoulder external rotation at various shoulder elevation angles. [Subjects] Twenty subjects participated in this study and all measurements were performed on the right shoulder. [Methods] Isometric shoulder external rotation strength and surface electromyographic data were measured with the shoulder at 0 degrees , 45 degrees , 90 degrees , and 135 degrees elevation in the scapular plane. The electromyographic data were collected from the infraspinatus, upper trapezius, middle trapezius, lower trapezius, and serratus anterior muscles. These measurements were compared across the various shoulder elevation angles. [Results] The strength measurements did not differ significantly by angulation. The infraspinatus activity was 92%, 75%, 68%, and 57% of the maximum voluntary contraction, which significantly decreased as shoulder elevation increased. The serratus anterior activity was 24%, 48%, 53%, and 62% of the maximum voluntary contraction, which significantly increased as shoulder elevation increased. [Conclusion] Shoulder external rotation torque was maintained regardless of shoulder elevation angle. The shoulder approximated to the zero position as the shoulder elevation increased so that infraspinatus activity decreased and the scapular posterior tilting by the serratus anterior might generate shoulder external rotation torque. PMID- 26957749 TI - The effects of whole-body vibration exercise on isokinetic muscular function of the knee and jump performance depending on squatting position. AB - [Purpose] The purpose of this study was to investigate the effects of whole-body vibration exercise (WBVE) on isokinetic muscular function of the knee and jump performance depending on different squatting positions. [Subjects] The subjects were 12 healthy adult men who did not exercise regularly between the ages of 27 and 34. [Methods] WBVE was performed with high squat position (SP), middle SP, and low SP. Before and after the intervention, isokinetic muscular function of the knees and jump performance were measured. [Results] Knee flexion peak torque at 60 degrees /s and total work at 180 degrees /s were significantly increased after implementing WBVE. Jump height also significantly increased after completing the exercise at all positions in comparison with the pre-exercise programs. [Conclusion] The results of this study suggest that SP during WBVE is an important factor stimulating positive effects on muscular function. PMID- 26957750 TI - Dehydration, skeletal muscle damage and inflammation before the competitions among the elite wrestlers. AB - [Purpose] The present study aimed to identify weight-loss and hydration levels before competitions among elite wrestlers and determine the skeletal muscle damage and inflammation levels after dehydration. [Subjects] Seventy-two elite wrestlers who participated in the Turkish Wrestling Championship. [Methods] With the help of specialists, 5 cc of blood were drawn from the forearm veins of the wrestlers. Laboratory analyses of Na(+), BUN, Glucose, CK, LDH, AST, ALT, C-RP levels were performed. Using a mathematical formula for hydration the POsm levels of the athletes were calculated. [Results] The wrestlers were divided into two groups based on hydration status. There were significant correlations between hydration indicators of Na(+), BUN and PBWL values. There were significant differences between AST, LDH, CK values and skeletal muscle damage indicators of the two groups, but there were no significant differences between the inflammation levels and C-RP values of the groups. [Conclusion] No differences existed in inflammation levels among the wrestlers, although dehydrated wrestlers suffered from higher level of skeletal muscle damage than wrestlers who were not dehydrated. PMID- 26957751 TI - Clinical application of circuit training for subacute stroke patients: a preliminary study. AB - [Purpose] To investigate how task-oriented circuit training for the recovery motor control of the lower-extremity, balance and walking endurance could be clinically applied to subacute stroke inpatient group therapy. [Subjects and Methods] Twenty subacute stroke patients were randomly assigned to the intervention group (n=10) or the control group (n=10). The intervention consisted of a structured, progressive, inpatient circuit training program focused on mobility and gait training as well as physical fitness training that was performed for 90 minutes, 5 days a week for 4 weeks. The control group received individual physiotherapy of neurodevelopmental treatment for 60 minutes, 5 days a week for 4 weeks. Outcome measures were lower-extremity motor control, balance, gait endurance and activities of daily living before and after 4 weeks. [Results] There were no significant differences at baseline between the two groups. After 4 weeks, both groups showed significant improvements in all outcome measures, but there were no significant differences between the two groups during the invention period. [Conclusion] In spite of the small sample size, these findings suggest that task-oriented circuit training might be used as a cost-effective and alternative method of individual physiotherapy for the motor recovery of lower extremity, balance and walking endurance of subacute stroke patients. PMID- 26957752 TI - Effect of thoracic manipulation and deep craniocervical flexor training on pain, mobility, strength, and disability of the neck of patients with chronic nonspecific neck pain: a randomized clinical trial. AB - [Purpose] To investigate the effects of thoracic manipulation and deep craniocervical flexor training on the muscle strength and endurance, range of motion, and the disability index of the neck of patients with chronic nonspecific neck pain. [Subjects and Methods] Forty-six patients with chronic neck pain participated. They received an intervention for 35 minutes a day, three times a week for 10 weeks. Subjects were randomly assigned to one control and two experimental groups: group A (thoracic manipulation combined with deep craniocervical flexor training, n=16), group B (deep craniocervical flexor training, n=15), and group C (active self-exercise as a control group, n=15). Muscle strength and endurance, pain, neck disability index, and range of motion of the cervical and thoracic spine were measured before and after the intervention. [Results] Group A showed significant increases in muscle strength, endurance, and cervical and thoracic range of motion, and significant decreases in the pain and neck disability index, compared with groups B and C. [Conclusion] Although deep craniocervical flexor training is effective at improving neck function, thoracic manipulation combined with deep craniocervical flexor training was a more effective intervention for pain relief and improving the range of motion, muscle function, and neck disability of patients with nonspecific chronic neck pain. PMID- 26957753 TI - Effects of visual feedback with a mirror on balance ability in patients with stroke. AB - [Purpose] This study aimed to examine the effects of a visual feedback obtained from a mirror on balance ability during quiet standing in patients with stroke. [Subjects] Fifteen patients with stroke (9 males, 6 females) enrolled in the study. [Methods] Experimental trials (duration, 20s) included three visual conditions (eyes closed, eyes open, and mirror feedback) and two support surface conditions (stable, and unstable). Center of pressure (COP) displacements in the mediolateral and anteroposterior directions were recorded using a force platform. [Results] No effect of condition was observed along all directions on the stable surface. An effect of condition was observed on the unstable surface, with a smaller mediolateral COP distance in the mirror feedback as compared to the other two conditions. Similar results were observed for the COP speed. [Conclusion] Visual feedback from a mirror is beneficial for improving balance ability during quiet standing on an unstable surface in patients with stroke. PMID- 26957754 TI - The effect of smartphone usage time on posture and respiratory function. AB - [Purpose] The aim of this study was to evaluate the changes in posture and respiratory functions depending on the duration of smartphone usage. [Subjects and Methods] Participants were randomly allocated to 2 groups: group 1 (subjects who used smartphones for <4 hours/day, n=25) and group 2 (subjects who used smartphones for >4 hours/day, n=25). The craniovertebral angles of all participants were measured and scapular indices were calculated to assess the change in posture and forced vital capacity, forced expiratory volume in 1 second, the ratio of forced expiratory volume in 1 second to forced vital capacity, and peak expiratory flow were measured to assess changes in respiratory function. [Results] There were significant differences in the craniovertebral angle, scapular index, and peak expiratory flow depending on the duration of smartphone usage. [Conclusion] The result of this study showed that prolonged use of smartphones could negatively affect both, posture and respiratory function. PMID- 26957755 TI - Effects of the Otago exercise program on fall efficacy, activities of daily living and quality of life in elderly stroke patients. AB - [Purpose] The purpose of this study was to determine the effects of the Otago exercise program on fall efficacy, activities of daily living, and quality of life in elderly stroke patients. [Subjects and Methods] Eight subjects performed the Otago exercise program three times per week, for 8 weeks. The outcome measures were the Fall Efficacy Scale score for fall efficacy, modified Barthel index for activities of daily living, and EQ-5D for quality of life. [Results] In our comparison of the results before and after the intervention, we found that the Otago exercise program improved fall efficacy significantly as well as the score for activities of daily living and quality of life, though not significantly. [Conclusion] We consider that the Otago exercise program is an effective method for improving fall efficacy in elderly stroke patients. PMID- 26957756 TI - The effect of enhanced trunk control on balance and falls through bilateral upper extremity exercises among chronic stroke patients in a standing position. AB - [Purpose] This study examined the effects of bilateral upper extremity exercises on trunk control, balance, and risk of falls in stroke patients. [Subjects and Methods] A total of 30 study subjects were selected and randomly divided into experimental and control groups containing 15 subjects each, who received bilateral upper extremity activities and conventional rehabilitation treatment, respectively. [Results] There were statistically significant differences between groups in all sub-items and total trunk impairment and Berg Balance scale scores. Significant differences between groups were also observed in all sub-items of the trunk impairment scale, except for static sitting balance. [Conclusion] Bilateral upper extremity exercises are effective for trunk control and balance as well as for fall prevention. PMID- 26957757 TI - Effect of body awareness training on balance and walking ability in chronic stroke patients: a randomized controlled trial. AB - [Purpose] To investigate the effects of body awareness training on balance and walking ability in chronic stroke patients. [Subjects] The subjects were randomly assigned to a body awareness training group (n=6) and a control group (n=6). [Methods] Patients in the body awareness training group received body awareness training for 20 minutes, followed by walking training for 30 minutes a day, 5 days a week for 4 weeks. The control group received walking training for 30 minutes a day, 5 days a week for 4 weeks. [Results] After the intervention, both groups showed significant improvements in the Berg Balance Scale, Timed Up and Go Test, and 10 m walk test compared with baseline results. The body awareness training group showed more significant improvements in the Berg Balance Scale and Timed Up and Go Test than the control group. There was no significant difference in the 10 m walk test between the groups. [Conclusion] The results of this study suggest that body awareness training has a positive effect on balance in patients with chronic stroke. PMID- 26957758 TI - Views of physiatrists and physical therapists on the use of gait-training robots for stroke patients. AB - [Purpose] Gait-training robots have been developed for stroke patients with gait disturbance. It is important to survey the views of physiatrists and physical therapists on the characteristics of these devices during their development. [Subjects and Methods] A total of 100 physiatrists and 100 physical therapists from 38 hospitals participated in our questionnaire survey. [Results] The most common answers about the merits of gait-training robots concern improving the treatment effects (28.5%), followed by standardizing treatment (19%), motivating patients about treatment (17%), and improving patients' self-esteem (14%). The subacute period (1-3 months post-stroke onset) was most often chosen as the ideal period (47.3%) for the use of these devices, and a functional ambulation classification of 0-2 was the most selected response for the optimal patient status (27%). The preferred model was the treadmill type (47.5%) over the overground walking type (40%). The most favored commercial price was $50,000 $100,000 (38.3%). The most selected optimal duration for robot-assisted gait therapy was 30-45 min (47%), followed by 15-30 min (29%), 45-60 min (18%), >= 60 min (5%), and < 15 min (1%). [Conclusion] Our study findings could guide the future designs of more effective gait-training robots for stroke patients. PMID- 26957759 TI - Evaluating the effectiveness of frozen shoulder treatment on the right and left sides. AB - [Purpose] To evaluate treatments with interferential current, hot pack, ultrasound therapy, stretching, strengthening and range-of-motion exercises, comparing between the right and left shoulders in terms of pain and functional capacity in patients with frozen shoulder. This was a retrospective study. [Subjects and Methods] Sixty-four patients (34 right side, 30 left side) were treated with interferential current and hot pack application for 20 min each, ultrasound therapy for 3 min, regular range-of-motion exercises, stretching exercises, strengthening with a Theraband in all directions and post-exercise proprioceptive neuromuscular facilitation techniques. All cases were evaluated with visual analogue scales for pain, passive and active range of motion, Constant score, and the shoulder disability questionnaire, at baseline and 7 and 12 weeks after baseline. [Results] Marked improvement was noted in all patients in both right and left sides after treatment, and at 7 and 12 weeks of follow-up compared with baseline. There was no significant difference between the right and left shoulder groups, in all outcome measures. [Conclusion] The combination of physical therapy, exercise, and manual techniques is effective in treating frozen shoulder. The location of the lesion in the right or left shoulder does not, in itself, affect the prognosis or treatment outcome. PMID- 26957760 TI - Effects of resistance exercise on cardiopulmonary factors in sedentary individuals. AB - [Purpose] This study investigated the effects of resistance exercise on cardiopulmonary functions in young sedentary subjects. [Subjects] Forty-two young and healthy subjects with a sedentary lifestyle were included in this study. [Methods] The subjects were randomly divided into 2 groups: control and experimental. The control group (n=21) received health education and continued with normal activities of daily living. The experimental group (n=21) underwent resistance training, health education, and continued with normal activities of daily living. The resistance exercise program consisted of 3 postural exercises: chest press, dumbbell pullover, and flat-bench dumbbell fly. The subjects received this intervention 3 times/week for 8 weeks. [Results] The baseline characteristics were comparable between the 2 groups. The 6-minute-walk test score, peak expiratory flow, forced vital capacity, forced expiratory volume in 1 second, maximal voluntary ventilation, and chest expansions were significantly improved post-intervention in the experimental group and between the 2 groups. [Conclusion] Cardiopulmonary functions in young sedentary subjects were significantly improved with the 8-week resistance exercise program. PMID- 26957761 TI - Effect of kinesio taping on the isokinetic muscle function in football athletes with a knee injury. AB - [Purpose] The purpose of this study was to determine the difference in isokinetic muscle function in football athletes with a knee injury with and without kinesio taping. [Subjects] The subjects for this study were 10 football athletes (males) with a knee injury. [Methods] Measurements were performed by using Cybex dynamometer under uniform motion before and after the application of kinesio tape to the quadriceps and hamstring muscle. Maximal concentric knee extension and flexion at three angular velocities (60 degrees /s, 120 degrees /s, and 180 degrees /s) were measured. [Results] A significant difference was found in peak torque and total work of the flexion at 120 degrees /s and 180 degrees /s, as well as in the average power of extension at 180 degrees /s. [Conclusion] Though it is not the main therapy for muscle function in football athletes with injury, kinesio taping was an effective adjunct therapy. PMID- 26957762 TI - Comparison of lower limb muscle activation with ballet movements (releve and demi plie) and general movements (heel rise and squat) in healthy adults. AB - [Purpose] The aim of this study was to demonstrate therapeutic grounds for rehabilitation exercise approach by comparing and analyzing muscular activities of Ballet movements: the releve movement (RM) and the demi-plie movement (DM). [Methods] Four types of movements such as RM vs. heel rise (HM) and DM vs. squat movement (SM) were randomized and applied in 30 healthy male and female individuals while measuring 10-s lower limb muscular activities (gluteus maximus [GMa], gluteus medius [GMe], rectus femoris [RF], adductor longus [AL], medial gastrocnemius [MG], and lateral gastrocnemius [LG]) by using surface electromyography (EMG). [Results] Significant differences were found in GMa, GMe, AL and MG activities for DM and in all of the six muscles for RM, in particular when the two groups were compared (RM vs HM and DM vs SM). [Conclusion] The RM and DM have a greater effect on lower limb muscular force activities compared to HM and SM and could be recommended as clinical therapeutic exercises for lower limb muscle enhancement. PMID- 26957763 TI - Effects of different seat cushions on interface pressure distribution: a pilot study. AB - [Purpose] The purpose of this study was to evaluate pressure redistribution on the supporting area of healthy volunteers when using different cushions. [Subjects and Methods] Twenty healthy individuals ranging in age from 19-23 years old and 20 older adults age 60 or above participated in the study. All participants lived in urban communities in South Korea. Group differences according to gender, age, and cushion types were analyzed with one-way analysis of variance and post-hoc analysis. [Results] Statistically significant differences in peak pressure and mean pressure were identified between age, gender, and cushion types. Peak pressure and mean pressure were higher on firm surfaces and on the air cushion than other cushion types. The pressure ratio was lower when an air cushion was used in the buttock area and was higher when it was used under the thighs compared to that in other conditions. [Conclusion] This study showed that interface pressure can be distributed differently depending on what cushions are used. Therefore, when using seat cushions, individuals should seek advice to help them choose the appropriate cushion for their needs. PMID- 26957764 TI - Analysis of injuries in taekwondo athletes. AB - [Purpose] The present study aims to provide fundamental information on injuries in taekwondo by investigating the categories of injuries that occur in taekwondo and determining the locations of these injuries. [Subjects and Methods] The data of 512 taekwondo athletes were collected. The sampling method was convenience sampling along with non-probability sampling extraction methods. Questionnaire forms were used to obtain the data. [Results] The foot, knee, ankle, thigh, and head were most frequently injured while practicing taekwondo, and contusions, strains, and sprains were the main injuries diagnosed. [Conclusion] It is desirable to decrease the possibility of injuries to the lower extremities for extending participation in taekwondo. Other than the lower extremities, injuries of other specific body parts including the head or neck could be important factors limiting the duration of participation. Therefore, it is necessary to cope with these problems before practicing taekwondo. PMID- 26957765 TI - Usefulness of ceruloplasmin testing as a screening methodology for geriatric patients with osteoporosis. AB - [Purpose] To evaluate serum ceruloplasmin levels in geriatric patients with osteoporosis. [Subjects and Methods] Seventy geriatric patients over 65 years of age were recruited. Patients were divided into two groups: group 1 ('OP', n=35) consisted of patients with osteoporosis, and group 2 (n=35) consisted of patients without osteoporosis. Dual-energy X-ray absorptiometry scanning was used in the measurement of bone mineral density in all cases. Inflammatory parameters, including C-reactive protein, sedimentation rate, and serum ceruloplasmin levels were analyzed in blood samples. [Results] No statistical differences in inflammatory parameters were observed between the two groups, however, serum ceruloplasmin levels were significantly higher in group 1 than in group 2. In Pearson analysis, serum ceruloplasmin levels were not found to be correlated with any biochemical parameters. Receiver operator characteristic curve analysis revealed that serum ceruloplasmin levels were predictive of osteoporosis with 85.7% sensitivity and 85.7% specificity over the level of 830.15. [Conclusion] Our study demonstrated that measurement of serum ceruloplasmin levels may have potential as a screening methodology for geriatric patients with osteoporosis. PMID- 26957766 TI - Health related quality of life in patients with epilepsy in Turkey. AB - [Purpose] This study measured the quality of life in epilepsy and determined associated demographic and clinical factors by means of the Short Form-36 health survey. [Subjects and Methods] 124 consecutive epilepsy patients were enrolled and their demographic variables and clinical characteristics recorded. The Short Form-36 questionnaire was completed independently by each participant. Short Form 36 dimensional and composite scores were computed and scaled with data from an extensive survey of the healthy population. [Results] Short Form-36 scores for physical dimensions were similar to healthy values, but those for mental dimensions except for energy/vitality were remarkably and significantly lower than normal. All Short Form-36 average scores for women were lower than those for men and significantly so for mental health composite scores. Patients responding well to treatment were aware of their improving health as measured by the Change in Health score and had better dimensional scores than those with a poor response. [Conclusion] Patients with epilepsy do not perceive impaired physical health status. However, their mental health appears vulnerable, especially in women. Therefore, the major burden in epilepsy is in the mental health category. A positive treatment response is also an important determinant of the related quality of life measure. PMID- 26957767 TI - Changes in joint space width during Kaltenborn traction according to traction grade in healthy adults. AB - [Purpose] The aim of this study was to analyze the joint space width of the humeral head and glenoid fossa during traction under 2 grade conditions (grade 2/grade 3). [Subjects and Methods] The subjects were 20 healthy male adults who had not experienced any shoulder injury. Three radiographs were obtained with the subjects in the supine position (resting, grades 2 and 3). The glenohumeral joint space was examined on radiography. Joint space width was measured by a radiologist at the points described by Petersson and Redlund-Johnell. A radiologist blinded to the variable "resting" or "traction" performed all radiographic measurements. The joint space widths were compared by using one-way repeated-measures analysis of variance. [Results] The results of this study indicated significant differences in the changes in joint space width according to traction grade. Compared to resting, grades 2 and 3 traction significantly increased joint space width. However, no significant difference in joint space width was found between grades 2 and 3 traction. [Conclusion] Although no significant differences were found between grades 2 and 3 traction during glenohumeral joint traction, the increase in joint space width between the glenoid fossa and humeral head was highest during grade 3 traction. PMID- 26957768 TI - Comparative study on isokinetic capacity of knee and ankle joints by functional injury. AB - [Purpose] To collect basic data for exercise programs designed to enhance functional knee and ankle joint stability based on isokinetic measurement and muscle strength evaluations in normal and impaired functional states. [Subjects and Methods] Twenty-four subjects were randomly assigned to the athlete group and the control group (n = 12 each). Data were collected of isokinetic knee extensor and flexor strength at 60 degrees /sec, 180 degrees /sec, and 240 degrees /sec and ankle plantar and dorsiflexor strength at 30 degrees /sec and 120 degrees /sec. [Results] Significant intergroup differences were observed in peak torque of the right extensors at 60 degrees /sec, 180 degrees /sec, and 240 degrees /sec and the right flexors at 240 degrees /sec. Significant differences were observed in peak torque/body weight in the right extensors at 60 degrees /sec, 180 degrees /sec, and 240 degrees /sec and in the right flexors at 180 degrees /sec and 240 degrees /sec. Significant peak torque differences were noted in the left ankle joint dorsiflexor at 30 degrees /sec and 120 degrees /sec, right plantar flexor at 120 degrees /sec, left plantar flexor at 30 degrees /sec, left dorsiflexor at 30 degrees /sec and 120 degrees /sec, and right dorsiflexor at 120 degrees /sec. [Conclusion] Isokinetic evaluation stimulates muscle contraction at motion dependent speeds and may contribute to the development of intervention programs to improve knee and ankle joint function and correct lower-extremity instability. PMID- 26957769 TI - Effect of thoracic and cervical joint mobilization on pulmonary function in stroke patients. AB - [Purpose] This study aimed to conduct thoracic and cervical mobilization in stroke patients and determine its effects on respiratory function. [Subjects and Methods] Twenty-one stroke patients were studied. Subjects were divided into a control group (control group, n=11) who did not undergo thoracic and cervical joint mobilization, and an experimental group (thoracic and cervical mobilization group, n=10) who underwent thoracic and cervical joint mobilization. Forced vital capacity and forced expiratory volume in the first second, well-known indicators of respiratory capabilities, were measured. Peak cough flow was measured as an indicator of cough capability. [Results] After the exercise, respiratory function in the thoracic and cervical mobilization group showed statistically significant improvements demonstrated by increases in forced vital capacity, forced expiratory volume in the first second, and peak cough flow. [Conclusion] The findings indicate that thoracic and cervical mobilization can improve the thoracic movements of stroke patients resulting in improved pulmonary function. PMID- 26957770 TI - The effects of standing balance in anteroposterior and mediolateral directions on knee strengthening in post-total knee replacement. AB - [Purpose] The purpose of this study was to examine the association between muscle strengthening exercises applied to the knee extensor muscles and the maintenance of standing balance in both, the anteroposterior and mediolateral directions in patients who had undergone total knee replacement. [Subjects and Methods] Thirty patients who underwent total knee replacement with bilateral artificial joints participated in this study. During the eight-week study period, the load on the knee extensors was gradually increased, and the standing balance ability was measured by differentiating the anteroposterior and mediolateral directions both, before and after the experimental period. [Results] In both, the anteroposterior and the mediolateral directions, there were statistically significant increases after the eight-week experiment, with a 29% increase in standing balance maintenance in the anteroposterior direction and a 22% increase in the mediolateral direction. [Conclusion] In patients who underwent bilateral total knee replacement, strengthening exercises applied to the knee extensor muscles with gradually increasing load positively affected standing balance in both anteroposterior and mediolateral directions. PMID- 26957772 TI - Clinical effects of deep cervical flexor muscle activation in patients with chronic neck pain. AB - [Purpose] The purpose of this study was to investigate clinical effects of deep cervical flexor (DCF) muscles exercise on pain, Neck Disability Index (NDI), and neck and shoulder postures in patients with chronic neck pain. [Subjects and Methods] Twenty-eight patients with chronic neck pain were randomly assigned into either the general strengthening exercise (GSE) group or the DCF activation group as control and experimental groups, respectively. All exercises were performed three times per week over 4 weeks. NDI and numeric rating scale (NRS) score for pain were determined and radiological assessment of neck-shoulder postures (head tilt angle [HTA], neck flexion angle [NFA], and forward shoulder angle [FSA]) was performed before (baseline), 4 weeks after, and 8 weeks after exercise in order to directly compare the exercise effects between the groups. [Results] In the DCF group, the NDI, NRS score, and neck-shoulder postures (analyzed by uisng HTA, NFA, and FSA) were significantly improved. [Conclusion] DCF activation exercise was effective to alleviate pain, recover functions, and correct forward head posture in the patients with neck pain. Hence, it might be recommended in the rehabilitation of patients with chronic neck pain. PMID- 26957771 TI - Change in trunk muscle activities with prone bridge exercise in patients with chronic low back pain. AB - [Purpose] The aim of this study was to determine the effect of three different bridge exercises on internal oblique, external oblique, transverse abdominis, and erector spinae activities. [Subjects and Methods] Forty-five subjects with chronic low back pain participated in this study. The training outcome was evaluated with three different testing methods: supine bridge exercise, supine bridge on Swiss ball exercise, and prone bridge exercise. The activities of the transverse abdominis, internal oblique, external oblique, and erector spinae were measured using surface electromyography. [Results] There were significant differences in the internal oblique, external oblique, and erector spinae according to the three kinds of bridging exercises. The internal oblique, external oblique and transverse abdominis activities were highest in the prone bridge exercise, followed by those in the supine bridge on Swiss ball exercise, and supine bridge exercises. The activity of erector spine was highest in the supine bridge on Swiss ball exercise followed by the supine bridge exercise and prone bridge exercise. [Conclusion] These results suggest that prone bridge exercise is more effective than conventional supine bridge exercise and supine bridge on Swiss ball in increasing trunk muscle activity of chronic low back pain patients. PMID- 26957773 TI - Effects of forward head posture on static and dynamic balance control. AB - [Purpose] To determine the effects of forward head posture on static and dynamic balance control. [Subjects and Methods] This study included 30 participants who were included into a forward head posture group (n = 14) and a control group (n = 16) according to their craniovertebral angles. Static balance control was assessed according to center of gravity sway velocity and total sway distance using an automatic balance calibration system. Dynamic balance control was assessed using the diagnosis mode of a body-tilt training and measurement system. [Results] Sway velocities on a hard surface with eyes open and closed and those on an unstable sponge surface with eyes closed were significantly higher in the forward head posture group than in the control group. Furthermore, on both the hard and sponge surfaces in the eyes open and closed conditions, total sway distances were significantly higher in the forward head posture group than in the control group. Results of dynamic balance control were not significantly different between groups. [Conclusion] Forward head posture has a greater effect on static balance control than on dynamic balance control. PMID- 26957774 TI - Effect of shoulder flexion angle and exercise resistance on the serratus anterior muscle activity during dynamic hug exercise. AB - [Purpose] The primary aim of this study was to determine the effect of shoulder flexion angle and exercise resistance on the serratus anterior muscle during dynamic hug exercise. [Subjects] Ten men aged 22-32 years were recruited. [Methods] The subjects performed dynamic hug exercise at different shoulder flexion angles and under resistance weight conditions. Serratus anterior muscle activities were measured by using the surface electromyographic system during the dynamic hug exercises. After performing the exercise, each subject described the exercise intensity by using the Borg rating of perceived exertion (RPE) scale. [Results] The normalized serratus anterior muscle activity increased significantly in the order of Conditions 1 and 4 < Condition 3 < Condition 2. The Borg RPE scale increased significantly in the order of Condition 1 < Condition 2 < Condition 3 < Condition 4. [Conclusion] The results suggest that dynamic hug exercise with the use of a multi-air-cushion biofeedback device is an effective scapular stability exercise. PMID- 26957775 TI - Biomechanical effects of lateral and medial wedge insoles on unilateral weight bearing. AB - [Purpose] Lateral wedge insoles reduce the peak external knee adduction moment and are advocated for patients with knee osteoarthritis. However, some patients demonstrate adverse biomechanical effects with treatment. In this study, we examined the immediate effects of lateral and medial wedge insoles under unilateral weight bearing. [Subjects and Methods] Thirty healthy young adults participated in this study. The subjects were assessed by using the foot posture index, and were divided into three groups: normal foot, pronated foot, and supinated foot groups. The knee adduction moment and knee-ground reaction force lever arm under the studied conditions were measured by using a three-dimensional motion capture system and force plates. [Results] In the normal and pronated groups, the change in knee adduction moment significantly decreased under the lateral wedge insole condition compared with the medial wedge insole condition. In the normal group, the change in the knee-ground reaction force lever arm also significantly decreased under the lateral wedge insole condition than under the medial wedge insole condition. [Conclusion] Lateral wedge insoles significantly reduced the knee adduction moment and knee-ground reaction force lever arm during unilateral weight bearing in subjects with normal feet, and the biomechanical effects varied according to individual foot alignment. PMID- 26957776 TI - Comparative gait analysis between children with autism and age-matched controls: analysis with temporal-spatial and foot pressure variables. AB - [Purpose] The purpose of this study was to investigate the gait pattern of children with autism by using a gait analysis system. [Subjects] Thirty children were selected for this study: 15 with autism (age, 11.2 +/- 2.8 years; weight, 48.1 +/- 14.1 kg; height, 1.51 +/- 0.11 m) and 15 healthy age-matched controls (age, 11.0 +/- 2.9 years; weight, 43.6 +/- 10 kg; height, 1.51 +/- 0.011 m). [Methods] All participants walked three times on the GAITRite((r)) system while their plantar pressure was being recorded. [Results] The results showed a reduction in cadence, gait velocity, and step length, and an increase in step width in children with autism. Plantar pressure variables highlight the differences between the active pressure areas, especially in the hindfoot of children with autism. [Conclusion] The results suggest that children with autism have an abnormal gait compared with that of age-matched controls, and thus they need extra attention to correct these abnormal gait patterns. PMID- 26957777 TI - Impact of brisk walking and aerobics in overweight women. AB - [Purpose] Lack of physical activity and an uncontrolled diet cause excessive weight gain, which leads to obesity and other metabolic disorders. Studies have indicated that brisk walking and aerobics are the best methods for controlling and reducing weight and body mass composition. [Subjects and Methods] In this study, 45 overweight women were enrolled and divided into 3 groups. Women not involved in brisk walking or aerobics were included in group A (n = 15) as control subjects; women involved in brisk walking were in group B (n = 15); and those involved in aerobics were in group C (n = 15). [Results] This program was carried out 5 days/week for 10 weeks. Pre- and post-measurements of body mass index, waist and hip circumference, and skinfold thickness of the abdomen, subscapular area, biceps, and triceps were recorded for the women in all 3 groups. All values decreased in women who participated in brisk walking and aerobics for 10 weeks. [Conclusion] These results indicate that aerobics with diet therapy is a more effective intervention program for controlling and reducing body mass index and skinfold thickness than brisk walking with diet therapy in North Indian women. PMID- 26957778 TI - Cross-cultural adaptation and validation of the Turkish version of the pain catastrophizing scale among patients with ankylosing spondylitis. AB - [Purpose] This study describes the cultural adaptation, validation, and reliability of the Turkish version of the Pain Catastrophizing Scale in patients with ankylosing spondylitis. [Methods] The validity of the Turkish version of the Pain Catastrophizing Scale was assessed by evaluating data quality (missing data and floor and ceiling effects), principal components analysis, internal consistency (Cronbach's alpha), and construct validity (Spearman's rho). Reproducibility analyses included standard measurement error, minimum detectable change, limits of agreement, and intraclass correlation coefficients. [Results] Sixty-four adult patients with ankylosing spondylitis with a mean age of 42.2 years completed the study. Factor analysis revealed that all questionnaire items could be grouped into two factors. Excellent internal consistency was found, with a Chronbach's alpha value of 0.95. Reliability analyses showed an intraclass correlation coefficient (95% confidence interval) of 0.96 for the total score. There was a low correlation coefficient between the Turkish version of the Pain Catastrophizing Scale and body mass index, pain levels at rest and during activity, health-related quality of life, and fear and avoidance behaviors. [Conclusion] The results of this study indicate that the Turkish version of the Pain Catastrophizing Scale is a valid and reliable clinical and research tool for patients with ankylosing spondylitis. PMID- 26957779 TI - Effects of rehabilitation for pain relief in patients with rheumatoid arthritis: a systematic review. AB - [Purpose] The purpose of this study was to find evidence for the effectiveness of rehabilitation for pain relief in patients with rheumatoid arthritis. [Subjects and Methods] A systematic review was conducted of MEDLINE, The Cochrane Central Register of Controlled Trials (CENTRAL), and OVID, for studies published from July 2005 to July 2015. We extracted data regarding patients, intervention, comparison, and outcomes, and assessed the methodological quality of the data. [Results] Nine randomized controlled trials comparing the effects of pain relief in patients with rheumatoid arthritis were found. [Conclusion] Physical therapy and occupational therapy can reduce pain in rheumatoid arthritis. PMID- 26957780 TI - Effects of ankle plantar flexors stretching with closed kinetic chain on pelvic movements and gait speed in hemiplegia patients: a case study. AB - [Purpose] The purpose of this study was to identify the effects of ankle plantar flexors stretching with closed kinetic chain (CKC) in hemiplegia patients. [Methods] This study used a reversal design (A-B-A') for a stroke with hemiplagia. The intervention program consisted of 30 min sessions, once a day, for 15 days. The subjects were trained for 15 sessions in total. Pelvic movements (anterior .posterior tilting, elevation, depression, forward.backward rotation) during walking and gait speed were measured in hemiplegia patients. [Results] Overall, the angle of pelvic movements was increased in Treatment and, Baseline II compared with Baseline I. The gait speed was maximally increased in Baseline II, followed by Treatment and Baseline I. [Conclusion] These results suggest that ankle plantar flexors stretching with closed kinetic chain had a positive effect on pelvic movements and gait speed in hemiplegia patients. Also, after treatment, its effect on gait of hemiplegia patients was maintained. PMID- 26957781 TI - Effects of heel support banding using an elastic band on chronic pain at the achilles tendon in a mountaineer. AB - [Purpose] This study developed heel support banding (HSB) using an elastic band for flexible heel support and investigated its effect on chronic Achilles tendon pain of a mountaineer. [Subject] A 40-year-old male mountaineer with chronic Achilles tendon pain [Methods] Ankle dorsiflexion and plantar flexion angles, VISA-A questionnaire, load-induced pain, total pain threshold and tenderness at 3 kg of pressure were measured before and after applying HSB. [Results] After one month of applying HSB, the dorsiflexion and plantar flexion angles increased; the VISA-A questionnaire score increased; the load-induced pain assessment score decreased; the pain threshold increased; and tenderness at 3 kg decreased. [Conclusion] These results indicate that HSB use improves ankle range of motion, decreases pressure and pain, and could provide a new approach for effective intervention and management of chronic Achilles tendon pain. PMID- 26957782 TI - Effects of task-oriented training on upper extremity function and performance of daily activities in chronic stroke patients with impaired cognition. AB - [Purpose] This study aimed to determine the effects of task-oriented training on upper extremity function and performance of daily activities in chronic stroke patients with impaired cognition. [Subjects and Methods] In this study, 2 chronic hemiplegic stroke patients underwent task-oriented training. The training was conducted once a day for 30 minutes, 5 times/week, for 2 weeks. The patients were evaluated 3 times before and after the task-oriented training. Changes in upper extremity function were assessed using the manual function test, and changes in the ability to carry out daily activities were assessed using the functional independence measure. [Results] The patients showed improvement in both the upper extremity function and ability to perform daily activities after task-oriented training. [Conclusion] Task-oriented training was proven effective in improving upper extremity function and ability to perform daily activities in chronic hemiplegic stroke patients with impaired cognition. PMID- 26957783 TI - Contributions of Morphological Skill to Children's Essay Writing. AB - Morphological skills have previously been found to reliably predict reading skill, including word reading, vocabulary, and comprehension. However, less is known about how morphological skills might contribute to writing skill, aside from its well-documented role in the development of spelling. This correlational study examines whether morphological skill, as measured by a sentence generation task tapping both derivational morphology and meta-syntactic skills, predicts performance on a standardized essay writing task for fifth- and eighth-grade U.S. students (N = 233), after controlling for grade level, comprehension, and writing fluency. Multilevel analyses indicated that morphological skill and writing fluency were each uniquely predictive of essay quality, and this finding was consistent regardless of whether accurate spelling was required in the morphological task. Our results suggest that morphological skills play an important role in writing, as has been previously documented in reading and spelling. PMID- 26957784 TI - The revised guidelines of the Medical Council of India for the academic promotions: Need for a rethink. PMID- 26957785 TI - Effect of pretreatment diclofenac sodium on postendodontic pain: A randomised controlled trial. AB - INTRODUCTION: Effective management of endodontic pain represents a continuing challenge. Many of the dental professionals are facing significant problems associated with postendodontic pain. Hence, the postendodontic pain has to be prevented at its primary stage without waiting for its occurrence. This trial was carried out to evaluate the use of a preoperative, single oral dose of diclofenac sodium for the prevention and control of postendodontic pain. MATERIALS AND METHODS: Fifty patients were randomly assigned to two groups, placebo and diclofenac sodium (100 mg). The medications were administered 30 min before the start of standard endodontic treatment. Postoperative pain was assessed after 6, 12, and 24 h by using a visual analog scale. RESULTS: Postendodontic pain showed a statistically significant difference between both groups at 6 and 12 h (P < 0.05) and there was no significant difference at 24 h. CONCLUSION: Postendodontic pain was substantially reduced by preoperative administration of single oral dose of diclofenac sodium. It is thus possible to conclude that these favorable results might help to prevent postendodontic pain, especially in patients with a low pain threshold. PMID- 26957787 TI - Effectiveness of N-acetyl cysteine, 2% chlorhexidine, and their combination as intracanal medicaments on Enterococcus faecalis biofilm. AB - AIM: The purpose of this study was to evaluate the antibacterial efficacies of 2% chlorhexidine (CHX), N-acetyl cysteine (NAC) and assess their synergistic or antagonist action as intracanal medicament. MATERIALS AND METHODS: Agar diffusion test was performed with 2% CHX, NAC, and their combination against E. faecalis planktonic cells. The diameters of the zones of bacterial inhibition were measured and recorded for each solution. The assay was further extended to 2 weeks old E. faecalis dentinal biofilm. Sixteen freshly extracted teeth were vertically sectioned into two halves resulting in a total of 32 samples. The samples were inoculated with bacterial suspension and incubated at 37 degrees C for 2 weeks for biofilm formation. The samples were then divided into four experimental groups with 8 samples in each group. The samples were gently washed in saline and placed in culture wells containing the test solutions, i.e., 2% CHX, NAC, a combination of 2% CHX and NAC in 1:1 ratio, and a control group containing saline. The biofilm formed on the root canal surface were removed with a sterile scalpel and inoculated on blood agar plates to check for the formation of E. faecalis colonies. STATISTICAL ANALYSIS: For agar diffusion test, data were analyzed statistically using one-way analysis of variance and then by post-hoc Scheffe's test to compare the antimicrobial efficacy between the groups. Statistical analysis was not done for the cultures obtained from the biofilm as there was no growth in all the three test groups except the control group, i.e., saline. RESULTS: In agar diffusion test, among the three groups tested, 2% CHX and NAC showed almost equal zones of inhibition whereas maximum inhibition was shown by a combination of NAC and 2% CHX suggesting a synergistic action. The results obtained were highly significant (P < 0.001) for the combination of medicament when compared to individual test group. In culture analysis, which was done for the biofilm, no growth was observed in all the three test groups. The results obtained were biologically significant but statistically insignificant. CONCLUSION: NAC has almost equal antimicrobial property as 2% CHX whereas their combination showed a synergistic action. PMID- 26957786 TI - Effect of digluconate chlorhexidine on bond strength between dental adhesive systems and dentin: A systematic review. AB - AIM: This study aimed to systematically review the literature for the effect of digluconate chlorhexidine (CHX) on bond strength between dental adhesive systems and dentin of composite restorations. MATERIALS AND METHODS: The electronic databases that were searched to identify manuscripts for inclusion were Medline via PubMed and Google search engine. The search strategies were computer search of the database and review of reference lists of the related articles. Search words/terms were as follows: (digluconate chlorhexidine*) AND (dentin* OR adhesive system* OR bond strength*). RESULTS: Bond strength reduction after CHX treatments varied among the studies, ranging 0-84.9%. In most of the studies, pretreatment CHX exhibited lower bond strength reduction than the control experimental groups. Researchers who previously investigated the effect of CHX on the bond strength of dental adhesive systems on dentin have reported contrary results, which may be attributed to different experimental methods, different designs of the experiments, and different materials investigated. CONCLUSIONS: Further investigations, in particular clinical studies, would be necessary to clarify the effect of CHX on the longevity of dentin bonds. PMID- 26957788 TI - The bond strength of highly filled flowable composites placed in two different configuration factors. AB - OBJECTIVE: The aim of this study was to evaluate the microtensile bond strength (MUTBS) of different flowable composite resins placed in different configuration factors (C-factors) into Class I cavities. MATERIALS AND METHODS: Fifty freshly extracted human molars were divided into 10 groups. Five different composite resins; a universal flowable composite (AeliteFlo, BISCO), two highly filled flowable composites (GrandioSO Flow, VOCO; GrandioSO Heavy Flow, VOCO), a bulk fill flowable composite (smart dentin replacement [SDR], Dentsply), and a conventional paste-like composite (Filtek Supreme XT, 3M ESPE) were placed into Class I cavities (4 mm deep) with 1 mm or 2 mm layers. Restored teeth were sectioned vertically with a slow-speed diamond saw (Isomet 1000, Buehler) and four micro-specimens (1 mm * 1 mm) were obtained from each tooth (n = 20). Specimens were subjected to MUTBS test. Data were recorded and statistically analyzed with two-way analysis of variance and Tukey's post-hoc test. Fractured surfaces were examined using a scanning electron microscope. RESULTS: The MUTBS in SDR-1 mm were higher than other groups, where Filtek Supreme XT-2 mm and GrandioSO Flow-2 mm were lower. No significant differences were found between C factors for any composite resin (P > 0.05). CONCLUSION: Bulk-fill flowable composite provided more satisfactory MUTBS than others. Different C-factors did not affect mean MUTBS of the materials tested. PMID- 26957789 TI - Effect of cleaning methods on bond strength of self-etching adhesive to dentin. AB - AIM: The aim of this study was to investigate the influence of cleaning methods to remove zinc oxide-eugenol-based root canal sealer (Endomethasone) on the bond strength of the self-etching adhesive to dentin. MATERIALS AND METHODS: Twenty crowns of bovine incisors were cut to expose the pulp chamber. A zinc oxide- and eugenol-based sealer was placed for 10 min in contact with the pulp chamber dentin. Specimens were divided into four groups according to the cleaning method of dentin used: G1, no root canal sealer (control); G2, 0.9% sodium chlorite (NaCl); G3, ethanol; and G4, followed by diamond drill. After cleaning, the teeth were restored with composite resin and Clearfil SE Bond. All specimens were sectioned to produce rectangular sticks and dentin/resin interface was submitted to microtensile bond testing. The mean bond strengths were analyzed using ANOVA/Tukey (alpha = 0.05). RESULTS: G3 and G4 showed bond strengths similar to the G1 (P > 0.05). A significant decrease in the bond strength in the G2 was observed (P < 0.05). G1, G3, and G4, the predominant failure mode was the mixed type. The prevalence of adhesive failure mode was verified in the G2. CONCLUSION: The cleaning methods affected the bond strength of the self-etching adhesive to dentin differently. PMID- 26957790 TI - Ability of three desensitizing agents in dentinal tubule obliteration and durability: An in vitro study. AB - AIM: The purpose of this study was to evaluate the effectiveness of three desensitizing agents on dentinal tubule obliteration and their durability in use on the dentinal tubules. MATERIALS AND METHODS: Sixty specimens were obtained from 30 extracted sound human maxillary first premolars. Each tooth was mesiodistally sectioned to obtain 30 buccal and 30 lingual surfaces, and enamel was removed in order to simulate hypersensitive dentin. Specimens were divided into four groups with 15 specimens each. Group 1 samples were immersed in artificial saliva, Group 2 samples were coated with Vivasens, Group 3 samples were coated with VOCO Admira Protect, and Group 4 samples were coated with Neo Active Apatite suspension. These specimens were examined under scanning electron microscope (SEM) to find out the occluding ability of the respective products. The specimens were brushed to find out their durability for 1 week and 1 month and were examined under SEM. STATISTICAL ANALYSIS: The results were statistically analyzed by analysis of variance (ANOVA) and Tukey's test. RESULTS: Group 1 differed significantly from the Vivasens, Admira, and Neo Active Apatite groups at 5% level of significance (P < 0.05). The Vivasens group differed significantly from the Admira and Neo Active Apatite groups at 5% level of significance (P < 0.05). CONCLUSION: The Ormocer-based Admira Protect showed the best results. PMID- 26957792 TI - Comparative study of fluoride released and recharged from conventional pit and fissure sealants versus surface prereacted glass ionomer technology. AB - CONTEXT: The fluoride release of sealants in vitro shows a marked decrease. Giomers are distinguishable from manufactured resin-based sealants and contain prereacted glass-ionomer particles (PRG). AIMS: To compare the amounts of fluoride released from the main pit and fissure of a resin-based sealant with that from a Giomer and to assess the abilities of the sealant and the Giomer to recharge when exposed to regular use of fluoride rinse. MATERIALS AND METHODS: The readings for the fluoride concentration were carried out for 60 days using a fluoride ion-specific electrode. After this period, the samples were recharged using a fluoride mouth rinse. The amount of fluoride released after this recharge was determined for 5 days. The data were analyzed using Student's t- and analysis of variance tests. RESULTS: In general, all materials presented higher fluoride release in the first 24 h; G1 and G4 showed a higher fluoride release in this period. On the other hand, G3 and G1 presented the most constant fluoride release until the 8(th) day, wherein all the sealants considerably decreased in the amount of fluoride released. CONCLUSION: G1 and G3 released higher concentrations of fluoride, although no significant differences were found. Giomers recharged in the first 24 h after polymerization presented an improved and sustained fluoride release. PMID- 26957791 TI - Effect of different polishing systems on the surface roughness of nano-hybrid composites. AB - OBJECTIVE: The study aimed to investigate the influence of different polishing systems on the surface roughness of nano-hybrid composite resins. BACKGROUND: Different shapes of polishing systems are available according to the site of work. To minimize variability, a new system with single shape is developed that can be utilized in both anterior as well as posterior teeth. MATERIALS AND METHODS: Seventy composite discs were fabricated using Teflon well (10 mm * 3 mm). Two main group of nano-hybrid composite Group I - Filtek Z350 and Group II - Tetric N-Ceram were used (n = 35 for each group). Both groups were further divided into four subgroups. Subgroup a - OneGloss (n = 10), Subgroup b - PoGo (n = 10), Subgroup c - Sof-Lex spiral (n = 10), Subgroup d - Mylar strip (control, n = 5). Samples were polished according to the manufacturer's recommendations. Surface roughness test was performed using contact profilometer. The obtained data were analyzed using the one-way analysis of variance test. RESULT: Tetric N Ceram produced smoother surfaces than Filtek Z350 (P < 0.05). Mylar strip and "PoGo" created equally smooth surfaces, while significantly rougher surfaces were obtained after applications of "Sof-Lex spiral" and "OneGloss" (P < 0.05). CONCLUSION: Polishing ability of Tetric N-Ceram is better than Filtek Z350 XT. "PoGo" seems to be a better polishing system than "OneGloss" and "Sof-Lex Spiral." PMID- 26957793 TI - Color changes in resin cement polymerized with different curing lights under indirect restorations. AB - AIM: The aim of the study was to investigate the effects of different interface materials and curing units on color changes in a resin cement material. MATERIALS AND METHODS: Three interface materials and different curing systems, quartz tungsten-halogen and polywave and monowave light-emitting diode (LED) light curing units, were studied at two-time intervals. Polystyrene strip was used as a control group. All measurements were made on a white background for standard color measurement. According to the CIE L*a*b* color space, the baseline color values of each specimen were measured. Differences between the measurements were calculated as DeltaE, DeltaL, Deltaa, and Deltab. Data were analyzed using analysis of variance (ANOVA) and Duncan's tests (alpha = 0.05) with SPSS 20.0 software (SPSS Inc., Chicago, IL, USA). ANOVA revealed significance for interface materials and curing units and time for DeltaE (P < 0.05). RESULTS: Interaction between polymerizing units, material and time was not significant (P > 0.05). Monowave LED exhibited significantly higher color changes than the other units ([P < 0.05] [DeltaE 2.94 +/- 0.44]). QTH promoted composite specimens significantly less color change ([P < 0.05] [DeltaE 0.87 +/- 0.41]). CONCLUSION: This study concluded that color of resin cement used in the adhesion of indirect restorations was affected by curing device light and indirect restoration material type. PMID- 26957794 TI - Surface roughness and erosion of nanohybrid and nanofilled resin composites after immersion in red and white wine. AB - AIMS: This study aimed to investigate the effects of red and white wine on the surface roughness and erosion of nanohybrid and nanofilled resin composites. MATERIALS AND METHODS: Sixty specimens of each resin-based composite (RBC) were prepared. Before immersion, baseline data roughness values were recorded using a profilometer. Three groups of discs (n = 20) were then alternately immersed in red wine, white wine, and deionized water (as a control) for 25 min and artificial saliva for 5 min over four cycles. The specimens were then stored in artificial saliva for 22 h. This process was repeated for 5 days following immersion in artificial saliva for 2 days. Subsequently, the process was repeated. After immersion, the specimens were evaluated and data were analyzed by two-way repeated analysis of variance (ANOVA) and Tukey's honestly significant difference (HSD) (alpha = 0.05). RESULTS: Red wine caused significantly greater roughness and erosion than did white wine and deionized water (P < 0.05). Nanohybrid resin composites were significantly rougher than nanofilled resin composites (P < 0.05). CONCLUSION: The effects of red and white wine on the surface roughness and erosion of resin composite restorative materials depended upon the physical and chemical composition of the restorative materials and the types of wine. PMID- 26957795 TI - Evaluation of surface roughness of different restorative composites after polishing using atomic force microscopy. AB - INTRODUCTION: Resin based composites are widely used aesthetic restorative materials in clinical restorative dentistry. The filler size and the percentage of fillers affects smooth surface, clinical durability, aesthetics, better optical properties, compatibility with natural enamel tissue, surface gloss, and preventing the discoloration of the restoration. The finishing and polishing of tooth-coloured restorations are necessary clinical steps for better aesthetics and longevity of restored teeth. AIM: In this study nano composites were chosen, because these contain nano particles which provide better overall composites features, including the quality of polished surface. The aim of this study was to evaluate the surface roughness of different newer posterior composites. MATERIAL AND METHOD: Five commercially available posterior restorative composite were tested in this study. All the specimens were polished with shofu multi step polishing system. After polishing the samples were all analyzed by atomic force microscopy which is used to study surface topography and surface morphology of materials. RESULTS: The values of surface roughness of each specimen were statistically analyzed using Kruskal Wallis ANOVA, and Pair wise comparisons by Mann-Whitney U test setting the statistical significance at p <= 0.05. CONCLUSION: Tetric Evo Ceram, Z350 exhibited less surface roughness compared to Ever X, Clearfil Majesty and Sure fil SDR. There was no statistical difference between groups regarding surface rough ness between groups. PMID- 26957796 TI - Influence of remaining dentin wall thickness on the fracture strength of endodontically treated tooth. AB - BACKGROUND: Remaining dentin wall thickness may influence the fracture resistance of tooth. AIMS: To investigate the effect of various coronal dentin wall widths on the fracture strength of root canal treated teeth. MATERIALS AND METHODS: Fifty recently extracted single canal mandibular premolars were used for the study. Ten unrestored teeth were used as control (Group 1); remaining teeth were root canal treated and divided into four groups (n = 10). The Groups 2a, 2b and 3a, 3b were having 2.5 mm, 1.5 mm remaining dentin with and without post, respectively. The samples fracture resistance was tested under the universal testing machine. The data were analyzed with one-way ANOVA and post-hoc Tukey test for comparative evaluation. RESULTS: The mean fracture strength observed in Group 1 was (29.75 Mpa) followed by Group 2a (28.97 Mpa), Group 2b (27.70 Mpa), Group 3a (23.39 Mpa), and Group 3b (16.38 Mpa). There was no statistically significant difference between control and Groups 2a and 2b with P > 0.05. The post contributed significantly for fracture resistance in Group 3a. CONCLUSION: The endodontic post is not required in root canal treated teeth >2.5 mm coronal dentin wall width while the post is essential for a tooth with <1.5 mm dentin wall width to improve fracture resistance. PMID- 26957797 TI - Comparison of apically extruded debris associated with several nickel-titanium systems after determining working length by apex locator. AB - BACKGROUND/AIM: To compare apically extruded debris using ProTaper Universal (PTU), ProTaper Next (PTN), WaveOne (WO), Twisted File (TF), M-Two (MT), and Revo S (RS) after determining the working length (WL) with root ZX. MATERIALS AND METHODS: Seventy-two teeth were selected. The WL determination was performed with root ZX. The teeth were divided into six experimental groups, randomly. In groups, root canals were prepared with PTU to size F4/0.06, with PTN to size X4/0.06, with WO to size 40/0.08, with TF to size 40/0.04, with MT to size 40/0.06, and with RS to size AS40/0.06. After preparations were completed, final irrigation was performed with 2 mL distilled water, and a total of 10 mL of distilled water was used in each tooth. Tubes were stored in an incubator at 68 degrees C for 5 days to evaporate the distilled water before weighing the dry debris. Data were analyzed by the Mann-Whitney U-test. RESULTS: The RS group led to the highest amount of extruded debris, however, WO led to the least amount of extruded debris. There was no statistically difference among the groups (P > 0.05). CONCLUSIONS: The authors conclude that the results obtained might depend on the apex locator used to determine the WL. PMID- 26957798 TI - The efficacy of the Self-Adjusting File versus WaveOne in removal of root filling residue that remains in oval canals after the use of ProTaper retreatment files: A cone-beam computed tomography study. AB - AIM: The current ex vivo study compared the efficacy of removing root fillings using ProTaper retreatment files followed by either WaveOne reciprocating file or the Self-Adjusting File (SAF). MATERIALS AND METHODS: Forty maxillary canines with single oval root canal were selected and sectioned to obtain 18-mm root segments. The root canals were instrumented with WaveOne primary files, followed by obturation using warm lateral compaction, and the sealer was allowed to fully set. The teeth were then divided into two equal groups (N = 20). Initial removal of the bulk of root filling material was performed with ProTaper retreatment files, followed by either WaveOne files (Group 1) or SAF (Group 2). Endosolv R was used as a gutta-percha softener. Preoperative and postoperative high resolution cone-beam computed tomography (CBCT) was used to measure the volume of the root filling residue that was left after the procedure. Statistical analysis was performed using t-test. RESULTS: The mean volume of root filling residue in Group 1 was 9.4 (+/-0.5) mm(3), whereas in Group 2 the residue volume was 2.6 (+/ 0.4) mm(3), (P < 0.001; t-test). CONCLUSIONS: When SAF was used after ProTaper retreatment files, significantly less root filling residue was left in the canals compared to when WaveOne was used. PMID- 26957799 TI - Influence of composite insertion technique on gap formation. AB - AIM: To compare newer bulk-fill composites with an incrementally filled composite for adaptability and subsequent gap formation at the pulpal floor. MATERIALS AND METHODS: Class I cavities were prepared in 60 intact molars, with a shallow depression in the center of the pulpal floor. The samples were divided into four groups (n = 15), according to the material used; smart dentine replacement (SDR), SonicFill, Ever X Flow and Z350 XT, restored to a depth of 4 mm. Following thermocycling, samples were sectioned buccolingually and examined under a stereomicroscope. Seven samples from each group were coated with nail varnish except for approximately 1 mm around the tooth restoration junction. These samples were examined under stereomicroscope after staining with 2% buffered methylene blue dye. The remaining samples were examined under a scanning electron microscope for gap formation. The data were statistically analyzed using one-way ANOVA and post-hoc Bonferroni test. RESULTS: SDR showed the significantly best adaptability as compared to both SonicFill and Ever X Flow (comparable). However, significantly least adaptive capacity was seen in the incrementally filled group (Z350 XT). CONCLUSION: Bulk-fill composites performed better than incremental composites, demonstrating better adaptability and less gap formation at the pulpal floor. PMID- 26957800 TI - Effect of irrigating solutions used for postspace treatment on the push-out bond strength of glass fiber posts. AB - AIM: To evaluate the effect of different irrigating solutions on postspace treatments on the push-out bond strength of glass fiber posts. MATERIALS AND METHODS: Thirty mandibular premolar roots were decoronated and endodontically treated. Postspaces were prepared and roots were divided into three groups: In group 1: 2.5% sodium hypochlorite irrigation (control), group 2: 17% ethylenediaminetetraacetic acid (EDTA) with hand activation, group 3: 17% EDTA irrigation with photon-induced photoacoustic streaming (PIPS) has been done to the postspaces. Scanning electron microscope (SEM) analysis has been made for two samples of each group. Fiber posts were then luted with resin cement. Each root was prepared for push-out test. Data have been statistically analyzed. RESULTS: SEM results showed clean postwalls with both group 2 and group 3, whereas group 1 showed adhesion of resin cement to intraradicular dentine. When all groups were compared, the bond strength values are higher with group 2 followed by group 3. CONCLUSION: Within the limitations of the study, clean postwalls and the highest bond strength values were obtained from 17% EDTA with hand activation and 17% EDTA with PIPS. PMID- 26957801 TI - Effect of different final irrigating solutions on smear layer removal in apical third of root canal: A scanning electron microscope study. AB - AIM: The aim of this in vitro study is to compare the smear layer removal efficacy of different irrigating solutions at the apical third of the root canal. MATERIALS AND METHODS: Forty human single-rooted mandibular premolar teeth were taken and decoronated to standardize the canal length to 14 mm. They were prepared by ProTaper rotary system to an apical preparation of file size F3. Prepared teeth were randomly divided into four groups (n = 10); saline (Group 1; negative control), ethylenediaminetetraacetic acid (Group 2), BioPure MTAD (Group 3), and QMix 2 in 1 (Group 4). After final irrigation with tested irrigants, the teeth were split into two halves longitudinally and observed under a scanning electron microscope (SEM) for the removal of smear layer. The SEM images were then analyzed for the amount of smear layer present using a three score system. STATISTICAL ANALYSIS: Data are analyzed using the Kruskal-Wallis test and Mann Whitney U-test. RESULTS: Intergroup comparison of groups showed statistically significant difference in the smear layer removal efficacy of irrigants tested. QMix 2 in 1 is most effective in removal of smear layer when compared to other tested irrigants. CONCLUSION: QMix 2 in 1 is the most effective final irrigating solution for smear layer removal. PMID- 26957802 TI - Three-dimensional evaluation of surface roughness of resin composites after finishing and polishing. AB - AIM: This study aims to investigate the effects of finishing and polishing procedures on four novel resin composites using three-dimensional optical profilometer. MATERIALS AND METHODS: Four composites classified according to their filler size, were selected: FiltekTM Z350 XT/Nanofill (3MTM ESPETM), Esthet X HD/Hybrid (Dentsply Caulk), Te Econom/Microfill (Ivoclar Vivadent((r))), Tetric EvoCeram((r)) /Nanohybrid (Ivoclar Vivadent((r))). Composite specimens were made in Plexiglass mold and polished with Soflex (3M ESPE), Enhance + Pogo (Dentsply Caulk). Both the systems were used according to the manufacturers' instructions, and the polished surfaces were assessed with an optical profilometer. STATISTICAL ANALYSIS USED: Kruskal-Wallis test and further pairwise comparison were performed by Mann-Whitney test. RESULTS: The smoothest surfaces for all the resin composites tested were obtained from the Mylar strip; statistically significant differences were observed among them (P = 0.001). The order of composites was ranked from the lowest to highest surface roughness; Filtek Z350 XT < Te Econom < Tetric EvoCeram < Esthet XHD. Pairwise multiple comparison with Mann-Whitney test showed Filtek Z350 to have the smoothest surface and the least with Teric EvoCeram. Among the polishing systems, Soflex showed the smoothest surface and was significantly different from Pogo (P = 0.046). CONCLUSIONS: The effectiveness of the polishing systems seems to be dependent on the material used, treatment modality and also on the filler particle size. PMID- 26957803 TI - The effects of chlorhexidine and ethanol on push-out bond strength of fiber posts. AB - CONTEXT: Irrigation of root canals with chlorhexidine (CHX) and ethanol is common practice to prevent root canal infection during postplacement. However, pretreatment with these solvents may interfere with the bond strength of posts. AIMS: This study aimed to evaluate if root dentin pretreatment using CHX and/or ethanol influences the push-out bond strength of fiber-reinforced composite resin (FRCR) posts. MATERIALS AND METHODS: Fifty space posts prepared in endodontically treated extracted human canine roots were randomly divided into five groups (n = 10) according to the dentin pretreatment: Distilled water (W); 1% CHX diacetate solution (1C); CHX diacetate + 99% ethanol (1CE); 99% ethanol (E); and 2% CHX digluconate solution (2C). After pretreatment, the adhesive system (Peak Universal Bond; Ultradent, South Jordan, UT, USA) was applied in the root dentin and the FRCR was cemented with resin cement. Then, horizontal slices of 2 mm were obtained from each root third and the push-out bond strength was assessed. Statistical analysis was done using analysis of variance (ANOVA) and Tukey's tests (P = 0.05). RESULTS: At all thirds, 1CE and E groups presented similar push out bond strength values (P > 0.05), which were higher than the other groups (P < 0.05). W, 1C, and 2C groups were similar (P > 0.05). CONCLUSION: The root dentin pretreatment with ethanol, alone or mixed with CHX diacetate increased the bond strength of FRCR luted with resin cement. PMID- 26957805 TI - Accidental injection of 2% chlorhexidine gluconate instead of an anesthetic agent: A case report. AB - We report a case where 2% chlorhexidine (CHX) gluconate was mistaken for an anesthetic solution and infiltrated into the buccal vestibule during routine root canal treatment. Accidentally, 2% CHX gluconate solution was injected in the right upper buccal vestibule (16) of a 23-year-old male during routine root canal treatment. The patient experienced pain and a burning sensation over the injected area shortly after injection. Swelling with mild extraoral redness over the right cheek area was observed clinically. The patient was immediately administered dexamethasone intramuscularly, and was prescribed antibiotics, analgesics, and antihistamines. The patient complained of a loss of sensation over the right cheek by the 15(th) day. The swelling reduced gradually over a period of 15 days. Reversal of sensation was attained after 35 days. PMID- 26957806 TI - Thrombus formation on a defibrillator lead with conductor externalization. PMID- 26957804 TI - In vitro comparison of antimicrobial effect of sodium hypochlorite solution and Zataria multiflora essential oil as irrigants in root canals contaminated with Candida albicans. AB - INTRODUCTION: This study compared the antifungal effect of Zataria multiflora essential oil (EO) with that of sodium hypochlorite (NaOCl) as an irrigant for root canals infected with Candida albicans. MATERIALS AND METHODS: Sixty mandibular premolars were infected with C. albicans suspension. After 72 h of incubation, the samples were divided into four groups. Teeth in Group 1 were irrigated with minimum fungicidal concentration (MFC) of Z. multiflora EO, in Group 2 with twice the MFC of Z. multiflora, in Group 3 with MFC of NaOCl, and in Group 4 with distilled water (DW). Pre- and post-operative samples were cultured, and fungal colony count of each specimen was obtained. Data were analyzed using Kruskal-Wallis and Mann-Whitney tests (P < 0.05). RESULTS: NaOCl at MFC and Z. multiflora EO at twice the MFC showed the highest antifungal efficacy, with no significant difference (P > 0.05). However, antifungal efficacies of these irrigants were significantly different from those of Z. multiflora EO at MFC and DW (P < 0.05). CONCLUSION: Our results showed that Z. multiflora EO at twice the MFC had the same antifungal efficacy as NaOCl at MFC. PMID- 26957807 TI - Changing scenario in the art of clinical medicine. PMID- 26957808 TI - Dermatological and respiratory problems in migrant construction workers of Udupi, Karnataka. AB - BACKGROUND: India being a developing country has tremendous demand of physical infrastructure and construction work as a result there is a raising demand of construction workers. Workers in construction industry are mainly migratory and employed on contract or subcontract basis. These workers face temporary relationship between employer and employee, uncertainty in working hours, contracting and subcontracting system, lack of basic continuous employment, lack basic amenities, and inadequacy in welfare schemes. OBJECTIVE: To estimate the prevalence of respiratory and dermatological symptoms among migratory construction workers. MATERIALS AND METHODS: This cross-sectional study was conducted in Manipal, Karnataka, among 340 male migratory construction workers. A standard modified questionnaire was used as a tool by the interviewer and the physical examination of the workers was done by a physician. The statistical analysis was done using Statistical Package for the Social Sciences (SPSS) version 15.0. RESULT: Eighty percent of the workers belong to the age group of 18 30 years. The mean age of the workers was 26 +/- 8.2 years. Most (43.8%) of the workers are from West Bengal followed by those from Bihar and Jharkhand. The rates of prevalence of respiratory and dermatological symptoms were 33.2% and 36.2%, respectively. CONCLUSION: The migrant construction workers suffer from a high proportion of respiratory and dermatological problems. PMID- 26957809 TI - Study of skin and mucous membrane disorders among workers engaged in the sodium dichromate manufacturing industry and chrome plating industry. AB - BACKGROUND: Inhalation of dusts and fumes arising during the manufacture of sodium dichromate from chrome ore, chromic acid mist emitted during electroplating, and skin contact with chromate produce hazards to workers. OBJECTIVES: (1) To elucidate the prevalence of skin and mucous membrane disorders among the workers engaged in the sodium dichromate manufacturing industry and chrome plating industry. (2) To know the relationship of prevalence with the duration of exposure to chrome mist, dust, and fumes. SETTINGS AND DESIGN: A cross-sectional study was conducted among all the workers engaged in sodium dichromate manufacturing and chrome plating from several industries situated near the Delhi-Haryana border in the districts of Faridabad and Sonepat of Haryana, India from January 01, 2014 to December 31, 2014. MATERIALS AND METHODS: All the workers available from the concerned industries for the study were interviewed and medically examined after obtaining their informed consent. A total of 130 workers comprising 66 workers from the sodium dichromate manufacturing industry and 64 workers from the chrome plating industry were examined on a pretested schedule. STATISTICAL ANALYSIS: Descriptive statistical methods (proportions, relative risk, and Chi-square test of significance with P value analyzed using Epi Info version 7). RESULTS: All the workers were found to be males and of the adult age group. Out of the total examined, 69.69% and 56.22% of the workers had disorders of the nasal mucous membrane in the sodium dichromate manufacturing industry and the chrome plating industry, respectively. 42.42% and 28.22% of the workers had perforation of the nasal septum in the sodium dichromate manufacturing industry and chrome plating industry, respectively. 6.06% and 3.12% workers had skin ulcers in the sodium dichromate manufacturing industry and chrome plating industry, respectively. Nasal irritation and rhinorrhea were the most commonly found symptoms in both the processes. 48.48% and 90.52% of the workers were using hand gloves in the sodium dichromate manufacturing and chrome plating industry, respectively. Only 27.27% and 37.50% of the workers were using masks in the sodium dichromate manufacturing industry and chrome plating industry, respectively. No worker was using protective clothing or barrier cream in the sodium dichromate manufacturing industry. 40.65% and 12.50% workers were using protective clothing and barrier cream in the chrome plating industry. CONCLUSION: Workers engaged in sodium dichromate manufacturing and chrome plating are at a great risk of skin and mucous membrane disorders including chrome holes and nasal septum perforation. Protective measures and awareness of the management and workers about the exposure hazards and safeguarding against them will be useful public measures to prevent these occupational hazards among workers engaged in these processes. PMID- 26957810 TI - Occupational stress and health-related quality of life among public sector bank employees: A cross-sectional study in Mysore, Karnataka, India. AB - BACKGROUND: Occupational morbidities have been estimated to cause an economic loss up to 10-20% of the gross national product of a country. It is an important cause of occupational morbidity and decreased quality of life (QOL) for the workers. AIM: The aim of the present study is to assess the level of occupational stress and its association with the QOL among the public sector bank employees. MATERIALS AND METHODS: The present study was conducted among employees of public sector banks in Mysore district, Karnataka, India. A cross-sectional study design was used for the study. Job stress was measured by using occupational stress index (OSI) scale questionnaire and health-related QOL was measured using the short form 12 (SF-12) questionnaire. The sample size estimated for the study was 526 and cluster random sampling technique was used. Chi-square test was used to find the association between the study variables and level of stress. Multiple linear regression model was used to find the determinants of health-related QOL among the study subjects. RESULTS: The total number of the study subjects was 546 out of which 57% were males and 43% were females. The proportion of study subjects reporting to be current smokers was 4.2% and almost all study subjects reported occasional alcohol consumption. The mean physical component summary (PCS) score and mental component summary (MCS) using the original United States standardization were 47.90 and 48.30, respectively. The individuals with mild stress scored higher in both PCS and MCS than the individuals who had moderate to severe stress levels. There was significant association of health related quality of life with the age of the respondent,presence of at least one morbidity and level of stress with health-related QOL. CONCLUSION: This study has shown an association of occupational stress with the QOL. There is a need for interventions aimed at mitigating the occupational stress among employees of the banking sector. PMID- 26957811 TI - Disability evaluation in acoustic blast trauma. AB - INTRODUCTION: Acoustic blast trauma is different from Noise induced hearing loss. Blast trauma can damage the tympanic membrane, ossicles and cochlea singly or in combination. It produces immediate severe hearing loss and may be associated with tinnitus and vestibular symptoms. Hearing loss recovers spontaneously in many cases but may be permanent in 30-55% cases. Thirteen patients working in an explosive manufacturing unit in Andhra Pradesh were exposed to blast trauma at work place. All these workers complained of immediate hearing loss and were subjected to audiological investigations. METHODS: Initial evaluation showed a severe sensorineural type of hearing loss 10 of the 13 cases (77%). They were referred to our Medical board for disability evaluation after 2-3 years of initial injury. Pure tone audiometry indicated severe hearing loss in 12 of 13 cases (92%) that was not correlating clinically. Re-evaluation with Acoustic reflex and ABR (BERA) tests were done and permanent disability was evaluated with the results of these investigations. OBSERVATIONS: No significant hearing loss was found in most patients and these patients had minimal disability. CONCLUSION: Objective hearing tests should be carried out after one year or more before evaluation of permanent disability. PMID- 26957812 TI - Peculiarities of hearing impairment depending on interaction with acoustic stimuli. AB - AIMS: The functional state of the auditory analyzer of several operators groups was study. The objective of this study was to determine some characteristics of hearing impairment in relation with features of acoustic stimuli and informative significance of noise. MATERIALS AND METHODS: 236 employees (middle age 35.4 +/- 0.74 years) were divided into four groups according to features of noise perception at the workplaces. The levels of permanent shifts of acoustic thresholds were estimated using audiometric method. STATISTICAL ANALYSIS USED: Common statistical methods were used in research. Mean quantity and mean absolute errors were calculated. Statistical significance between operators' groups was calculated with 0.05 confidential intervals. RESULTS: The peculiarities of hearing impairment in observed groups were different. Operators differentiating acoustic signals had peak of hearing impairment in the field of language frequencies, while the employees who work with noise background at the workplaces had maximal hearing threshold on the 4000 Hz frequency (P <= 0.05). CONCLUSIONS: Hearing impairment depends both on energy and human interaction with acoustic irritant. The distinctions in hearing impairment may be related with the necessity of recognizing of acoustic signals and their frequency characteristics. PMID- 26957813 TI - An epidemiological study on the predictors of health status of food handlers in food establishments of teaching hospitals of North India. AB - INTRODUCTION: The US Centers for Disease Control and Prevention (USDHHS-CDC 1996) revealed that the outbreaks of food borne diseases include inadequate cooking, heating, or re-heating of foods consumption of food from unsafe sources, cooling food inappropriately and allowing too much of a time lapse. As we all know that the food handlers have been working in various types of community kitchen and their health status can affect the status of food hygiene which can lead to contamination of foods attributing to acute gastroenteritis and food poisoning in various subgroups of the population e.g., medical/dental/nursing students. The background characteristics of these food handlers may have important role to affect health status of these handlers. METHODS: The indexed study was carried out among the food handlers working in the food establishments the 5 teaching hospitals of Bareilly city in U.P. India during one year i.e., from August 2013 to July 2014. The survey method using schedule was conducted to get information about the background characteristics and food handlers and each food handler was examined clinically for assessing health status. Chi-Square test was used as test of significance and regression analysis was also done to nullifying the effect of confounders. RESULTS: The health status of the mess workers was found to be significantly associated with use of gloves, hand washing after toilet and hand washing before cooking and serving food. CONCLUSION: The rationale of this study was that though many studies have been carried out to show the health status of the food handlers and their background characteristics, no study has highlighted the association of these background characteristics and personal hygiene practices with the health status of food handlers. PMID- 26957814 TI - Perceived heat stress and health effects on construction workers. AB - INTRODUCTION: Increasing heat waves-particularly in urban areas where construction is most prevalent, highlight a need for heat exposure assessment of construction workers. This study aims to characterize the effects of heat on construction workers from a site in Gandhinagar. MATERIALS AND METHODS: This study involved a mixed methods approach consisting of a cross sectional survey with anthropometric measurements (n = 219) and four focus groups with construction workers, as well as environmental measurements of heat stress exposure at a construction site. Survey data was collected in two seasons i.e., summer and winter months, and heat illness and symptoms were compared between the two time periods. Thematic coding of focus group data was used to identify vulnerability factors and coping mechanisms of the workers. Heat stress, recorded using a wet bulb globe temperature monitor, was compared to international safety standards. RESULTS: The survey findings suggest that heat-related symptoms increased in summer; 59% of all reports in summer were positive for symptoms (from Mild to Severe) as compared to 41% in winter. Focus groups revealed four dominant themes: (1) Non-occupational stressors compound work stressors; (2) workers were particularly attuned to the impact of heat on their health; (3) workers were aware of heat-related preventive measures; and (4) few resources were currently available to protect workers from heat stress. Working conditions often exceed international heat stress safety thresholds. Female workers and new employees might be at increased risk of illness or injury. CONCLUSION: This study suggests significant health impacts on construction workers from heat stress exposure in the workplace, showed that heat stress levels were higher than those prescribed by international standards and highlights the need for revision of work practices, increased protective measures, and possible development of indigenous work safety standards for heat exposure. PMID- 26957816 TI - Prevalence, pattern, and factors associated with work-related musculoskeletal disorders among pluckers in a tea plantation in Tamil Nadu, India. AB - CONTEXT: Musculoskeletal pain is common among tea leaf pluckers and is attributed to the load they carry, long working hours, the terrain, and insufficient job rotations. As a result of this, their health and work capacity are affected. AIMS: To assess the prevalence, patterns, and factors associated with work related musculoskeletal disorders (WRMDs) among pluckers in a tea plantation in Annamalai, Tamil Nadu, India. SETTINGS AND DESIGN: This cross-sectional study surveyed 195 pluckers selected by simple random sampling aged between 18 years and 60 years. MATERIALS AND METHODS: The interview schedule had four parts- sociodemographic detail, Standard Nordic Scale, numeric and facial pain rating tool, and a tool to assess factors associated with WRMDs. STATISTICAL ANALYSIS USED: Statistical Package for the Social Sciences (SPSS) version 16. RESULTS: Prevalence of musculoskeletal pain in the last 12 months and the last 7 days was 83.6% and 78.5%, respectively. The most common site for last 1 year was shoulder (59%) and for last 7 days was the lower back (52.8%). Independent t-test revealed that the mean age of those with pain was 6.59 year more and mean years of employment was 1.38 years more among the workers with pain compared to workers without pain. Increasing morbidities among workers was also significantly associated with an increase in WRMDs on Chi-square test. CONCLUSIONS: The prevalence of musculoskeletal pain was high among tea pluckers and the most common site during the last 12 months and the last 7 days was the shoulder and lower back respectively was mild in character. Increase in age and duration of employment was associated with WRMDs. PMID- 26957815 TI - Nonoccupational anthracofibrosis/anthracosilicosis from Ladakh in Jammu and Kashmir, India: A case series. AB - BACKGROUND: Nonoccupational anthracosis and silicosis has been reported from various parts of the world including Ladakh in Jammu and Kashmir, India; however, anthracosilicosis has only been reported in industrial workers till date. MATERIALS AND METHODS: Six cases from the Ladakh region in Jammu and Kashmir, India with similar clinico-radiological-pathological features, i.e., anthracosilicosis/anthracofibrosis have been analyzed. Of these, four were analyzed retrospectively and two prospectively. RESULT: All the patients were homemakers and resided in Ladakh in Jammu and Kashmir, India since birth with an age range of 42-62 years and an average age of 56 years. Their average duration of symptoms was 4 years. Spirometry showed small and/or large airway disease in 5/6 cases. On computed tomography (CT), 4/6 cases showed progressive massive fibrosis (PMF) with calcified mediastinal lymph nodes. There were random or centrilobular nodules in all the six cases. Bronchoscopy in 5/6 cases showed multiple anthracotic pigments with narrowing and distortion of the bronchus (anthracofibrosis). Malignancy was suspected clinico-radiologically in four cases and pathologically in two cases. On histopathology, anthracosis was demonstrated in all and silicosis in three cases. CONCLUSION: Anthracosilicosis can occur due to environmental exposure. Ladakh in Jammu and Kashmir, India is the only place across the globe with unique environmental features having the presence of both free silica and biomass fuel. The disease was observed predominantly in older women. Awareness would prevent unnecessary investigation for malignancy. Treatment with the bronchodilator is useful as it has evidence of airway disease. Finally, environmental measures and a proper study need to be undertaken for knowing the relative role of silica versus soot in causing the lung disease and preventing this irreversible condition. PMID- 26957817 TI - Performing CPR on a commercial diver inside the diving bell. AB - CPR in a diving bell is difficult. It is taught by diving companies and training institutes but has not been subjected to the tenets of evidence based medicine. The diving bell lacks space as well as a flat hard surface to lay the patient on and therefore conventional methods of administering CPR are not possible. The diver is hung from a pulley tied to the diver's harness, and the bell flooded with water to reduce pooling of blood. Airway is established using a cervical collar to hyperextend the neck and inserting an appropriate oropharyngeal airway. Cardiac compressions are administered by the bellman using his head or the knee while holding the patient with his arms from behind. The bell can be recovered to surface only when spontaneous breathing and circulation have started. Diving bell offers a unique environment for management of unconscious casualties. Even though the method is at variance with the conventional method of administering CPR, it is the only method possible inside the bell. It is important that the method be scrutinized and refined so as to be more effective and efficacious inside the bell.